PMID- 28707694 TI - Trapping-desorption and direct-scattering of formaldehyde at Au(111). AB - Nonreactive surface scattering of atoms, molecules and clusters can be almost universally described by two mechanisms: trapping-desorption and direct scattering. A hard cube model with an attractive square well provides a zeroth order description of the branching ratio between these two mechanisms as a function of the incidence energy. However, the trapping process is likely to be enhanced by excitation of internal degrees of freedom during the collision. In this molecular beam surface scattering study, we characterize formaldehyde/Au(111) scattering using angle resolved time-of-flight techniques. The two mechanisms are found to compete in the range of the investigated normal incidence energies between 0.1 and 1.3 eV. Whereas at low incidence energies trapping-desorption dominates, direct-scattering becomes more likely at incidence energies above 0.37 eV. This incidence energy is slightly higher than the desorption energy which is found to be 0.32 +/- 0.03 eV by temperature programmed desorption techniques. A simple hard cube model underestimates the observed trapping probabilities indicating the importance of trapping induced by excitation of internal molecular degrees of freedom. PMID- 28707695 TI - Lewis acid catalyzed diastereoselective [3+4]-annulation of donor-acceptor cyclopropanes with anthranils: synthesis of tetrahydro-1-benzazepine derivatives. AB - A Lewis acid catalyzed [3+4]-annulation reaction between cyclopropane 1,1 diesters and anthranils has been developed. This annulation consists of a reaction sequence involving ring-opening/aromatization/nucleophilic addition. Thereinto, aromatization is the driving force for this annulation. Using this reaction, a series of 8-oxa-1-azabicyclo[3.2.1]octanes can be prepared conveniently with excellent diastereoselectivity. PMID- 28707696 TI - Zinc-promoted cyclization of tosylhydrazones and 2-(dimethylamino)malononitrile: an efficient strategy for the synthesis of substituted 1-tosyl-1H-pyrazoles. AB - A Zn(OTf)2-promoted cyclization reaction of tosylhydrazones with 2 (dimethylamino)malononitrile has been successfully developed providing an efficient strategy for the synthesis of substituted 1-tosyl-1H-pyrazoles. PMID- 28707697 TI - Shift work, long working hours, and later risk of dementia: A long-term follow-up of the Copenhagen Male Study. AB - Objectives The aim of this study was to investigate the effect of shift work and long working hours in midlife on the risk of dementia in old age. Methods The present study comprised 4766 participants from the Copenhagen Male Study. We used information on shift work (collected in 1970-1971 and 1985-1986), long working hours defined as >45 hours per week (collected in 1970-1971), socioeconomic status, sleep, stress, and cardiovascular risk factors. Information about dementia diagnoses was obtained from registers. Participants were followed until 2014 (mean length of follow-up was 17.8 years). We employed Poisson regression for the survival analyses and estimated incidence rate ratios (IRR) and their 95% confidence intervals (CI). Results We found no statistically significant association between shift work (IRR 0.86, 95% CI 0.70-1.05) or long working hours (IRR 0.97, 95% CI 0.79-1.19) and dementia. Adjustment for potential confounders and mediators did not change the estimates. Working shifts at both time points of exposure assessment was not associated with a higher incidence of dementia compared with non-shift workers at both time points (IRR 0.99, 95% CI 0.69-1.42). The lowest incidence of dementia was observed among participants who reported shift work at one time point (only in 1985-1986: IRR 0.44, 95% CI 0.16-1.23 and only in 1970-1971: IRR 0.58, 95% CI 0.31-1.11). Conclusion We did not find positive evidence of an association between shift work or long working hours and the incidence of dementia, but the negative findings may reflect the crude assessment of shift work and long working hours, which is a major limitation of the present study. PMID- 28707698 TI - Cost-effectiveness of intraoperative nerve monitoring in avoidance of bilateral recurrent laryngeal nerve injury in patients undergoing total thyroidectomy. AB - BACKGROUND: Intraoperative nerve monitoring (IONM) provides dynamic neural information and is recommended for high-risk thyroid surgery. In this analysis, the cost-effectiveness of IONM in preventing bilateral recurrent laryngeal nerve (RLN) injury was investigated. METHODS: A Markov chain model was constructed based on IONM use. The base-case patient was defined as a 40-year-old woman presenting with a 4.1-cm left-sided papillary thyroid cancer who developed RLN injury with loss of monitoring signal during planned bilateral thyroidectomy. It was hypothesized that, if the surgeon had used IONM, the RLN injury would have been detected and the operation would have been concluded as a thyroid lobectomy to avoid the risk of contralateral RLN injury. Cost in US dollars was converted to euros; probabilities and utility scores were identified from the literature and government resources. Length of follow-up was set as 20 years, and willingness-to-pay (WTP) as ?38 000 (US $50 000) per quality-adjusted life-year (QALY). RESULTS: At the end of year 20, the not using IONM strategy accrued ?163 995.40 (US $215 783.43) and an effectiveness of 14.15 QALYs, whereas use of the IONM strategy accrued ?170 283.68 (US $224 057.48) and an effectiveness of 14.33 QALYs. The incremental cost-effectiveness ratio, comparing use versus no use of IONM, was ?35 285.26 (US $46 427.97) per QALY, which is below the proposed WTP, indicating that IONM is the preferred and cost-effective management plan. A Monte Carlo simulation test that considered variability of the main study factors in a hypothetical sample of 10 000 patients showed IONM to be the preferred strategy in 85.8 per cent of the population. CONCLUSION: Use of IONM is cost-effective in patients undergoing bilateral thyroid surgery. PMID- 28707700 TI - Deleting the Arntl clock gene in the granular layer of the mouse cerebellum: impact on the molecular circadian clockwork. AB - The suprachiasmatic nucleus houses the central circadian clock and is characterized by the timely regulated expression of clock genes. However, neurons of the cerebellar cortex also contain a circadian oscillator with circadian expression of clock genes being controlled by the suprachiasmatic nucleus. It has been suggested that the cerebellar circadian oscillator is involved in food anticipation, but direct molecular evidence of the role of the circadian oscillator of the cerebellar cortex is currently unavailable. To investigate the hypothesis that the circadian oscillator of the cerebellum is involved in circadian physiology and food anticipation, we therefore by use of Cre-LoxP technology generated a conditional knockout mouse with the core clock gene Arntl deleted specifically in granule cells of the cerebellum, since expression of clock genes in the cerebellar cortex is mainly located in this cell type. We here report that deletion of Arntl heavily influences the molecular clock of the cerebellar cortex with significantly altered and arrhythmic expression of other central clock and clock-controlled genes. On the other hand, daily expression of clock genes in the suprachiasmatic nucleus was unaffected. Telemetric registrations in different light regimes did not detect significant differences in circadian rhythms of running activity and body temperature between Arntl conditional knockout mice and controls. Furthermore, food anticipatory behavior did not differ between genotypes. These data suggest that Arntl is an essential part of the cerebellar oscillator; however, the oscillator of the granular layer of the cerebellar cortex does not control traditional circadian parameters or food anticipation. PMID- 28707699 TI - Predict disease progression from T-cell phenotypes in northern pig-tailed macaques (Macaca leonina) during SIVmac239 infection. AB - Macaca leonina (northern pig-tailed macaques, NPMs) have variable disease progression during SIVmac239 infection. In the present study, we analysed, for the first time, the correlations between T-cell phenotypes and disease progression in NPMs during SIVmac239 infection. In comparison to normal progressors (NPs), slow progressors (SPs) had lower chronic T-cell activation and exhaustion levels. In addition, SPs showed higher peripheral CD4+ T-cell count and CD4 : CD8 ratio, and lower plasma viral load than NPs. CD4+ T-cell count and CD4 : CD8 ratio decreased more sharply in NPs than in SPs. Furthermore, T cells in NPs were more highly differentiated, at least in acute infection, than in SPs. These results indicated that T-cell phenotypes were correlated with disease progression in SIVmac239-infected NPMs and these correlations may provide valuable guidance for the improvement of therapeutic strategies tested in NPMs. PMID- 28707701 TI - Variable selection for joint models of multivariate longitudinal measurements and event time data. AB - Joint modeling of longitudinal and survival data has attracted a great deal of attention. Some research has been undertaken to extend the joint model to incorporate multivariate longitudinal measurements recently. However, there is a lack of variable selection methods in the joint modeling of multivariate longitudinal measurements and survival time. In this article, we develop penalized likelihood methods for the selection of longitudinal features in the survival submodel. A multivariate linear mixed effect model is used to model multiple longitudinal processes where random intercepts and slopes serve as essential features of the trajectories. We introduce L1 penalty functions to select both random effects in the survival submodel and off-diagonal elements in the covariance matrix of random effects. An estimation procedure is developed based on Laplace approximation. Our simulations demonstrate excellent selection properties of the proposed procedure. We apply our methods to explore the relationship between mortality and multiple longitudinal processes for end stage renal disease patients on hemodialysis. We find that lower levels of albumin, higher levels of neutrophil-to-lymphocyte ratio, and higher levels of interdialytic weight gain at the beginning of the follow-up time, as well as decrease in predialysis systolic blood pressure and increase of neutrophil-to lymphocyte ratio over time are associated with higher mortality hazard rates. PMID- 28707702 TI - Secondary immune response of rainbow trout following repeated immersion vaccination. AB - Teleosts are able to raise a protective immune response, comprising both innate and adaptive elements, against various pathogens. This is the basis for a widespread use of vaccines, administered as injection or immersion, in the aquaculture industry. It has been described that repeated injection vaccination of fish raises a secondary immune response, consisting of rapid, accelerated and increased antibody reaction. This study reports how rainbow trout responds to repeated immersion vaccination against yersiniosis (ERM) caused by the bacterial pathogen Yersinia ruckeri. It was found that rainbow trout does not raise a classical secondary response following repeated immersion vaccination. Serum antibody titres were merely slightly increased even after three immunizations, using 30-s immersion into a bacterin consisting of formalin-inactivated Y. ruckeri (serotype O1, biotypes 1 and 2), performed over a 3-month period. The densities of IgM-positive lymphocytes in spleen of fish immunized three times were increased compared to control fish, but no general trend for an increase with the number of immunizations was noted. The lack of a classical secondary response following repeated immersion vaccination may partly be explained by limited uptake of antigen by immersion compared to injection. PMID- 28707703 TI - Poorly differentiated soft tissue sarcoma in an Arabian carpet shark Chiloscyllium arabicum (Gubanov): A case report. PMID- 28707704 TI - First record of Glugea plecoglossi (Takahashi & Egusa, 1977), a microsporidian parasite of ayu (Plecoglossus altivelis altivelis Temminck & Schlegel, 1846) in Mainland China. PMID- 28707705 TI - A Minchinia mercenariae-like parasite infects cockles Cerastoderma edule in Galicia (NW Spain). AB - The cockle Cerastoderma edule fishery has traditionally been the most important shellfish species in terms of biomass in Galicia (NW Spain). In the course of a survey of the histopathological conditions affecting this species in the Ria of Arousa, a haplosporidan parasite that had not been observed in Galicia was detected in one of the most productive cockle beds of Galicia. Uni- and binucleate cells and multinucleate plasmodia were observed in the connective tissue mainly in the digestive area, gills and gonad. The parasite showed low prevalence, and it was not associated with abnormal cockle mortality. Molecular identification showed that this parasite was closely related to the haplosporidan Minchinia mercenariae that had been reported infecting hard clams Mercenaria mercenaria from the Atlantic coast of the United States. The molecular characterization of its SSU rDNA region allowed obtaining a fragment of 1,796 bp showing 98% homology with M. mercenariae parasite. Phylogenetic analysis supported this identification as this parasite was clustered in the same clade as M. mercenariae from the United States and other M. mercenariae-like sequences from the UK, with bootstrap value of 99%. The occurrence of M. mercenariae-like parasites infecting molluscs outside the United States is confirmed. PMID- 28707706 TI - The bone degenerative processes in senile fishes from Holocene Brazilian shell mounds. AB - Zooarchaeological collections from shell mounds in Rio de Janeiro (2,470-4,632 cal BP) contain a high prevalence of swollen fish bones belonging to the Atlantic spadefish (Chaetodipterus faber), crevalle jack (Caranx hippos) and fat snook (Centropomus parallelus). Given the lack of knowledge of the bone degenerative process in senile fishes, this study analysed hyperostotic bone in zooarchaeological and modern specimens to obtain high-resolution morphology and microstructure reconstruction. We used microCT as well as X-ray diffraction to characterize the crystallographic changes associated with fish senility. Our results showed that trabecular microstructures in hyperostotic bones were consistent with estimated values of the per cent bone volume-to-total volume ratio (BV/TV) and were greater than 60% in cortical bone. Hyperostotic bones indicated a high radiograph density, and X-ray diffractograms showed a decrease in hydroxyapatite [Ca10 (PO4 )6 (OH)2 ] and calcite (CaCO3 ) neocrystallization. These crystalline and density changes revealed an advanced stage of fish senile and indicate the vulnerability of ageing fish populations. PMID- 28707707 TI - Evidence for capitation reform in a New Rural Cooperative Medical Scheme in Pudong New Area, Shanghai: A longitudinal study. AB - Currently, China has been experiencing rapid growth of medical costs, serious waste of medical resources, increasing disease burden for residents, and a medical insurance fund deficit. Therefore, an urgent problem that needs to be solved is to choose a rational payment for the insurance system. To empirically evaluate the long-term effects of capitation reform in a New Rural Cooperative Medical Scheme in Pudong New Area, we collected and analysed data regarding financing, fund operation, medical service cost, and medical care-seeking behaviour from 2011 to 2015, a duration that includes data before and after reform. The data for financing and behaviours were compared year by year, and the monthly data for inpatient and outpatient costs were evaluated in a retrospective time series study. The capitation reform in Pudong New Area showed strong evidence of the power of medical cost control in the long run, while it was weak in reversing the number of patients flowing into secondary and tertiary hospitals. To make the payment of capitation play a bigger role in cost control in China, a tighter alignment of capitation with the general practitioner system and achieving dual referral is critical for future studies. PMID- 28707708 TI - Identification and quantification of phenolic compounds in edible wild leafy vegetables by UHPLC/Orbitrap-MS. AB - BACKGROUND: A recent interest in edible wild leafy vegetables has been documented. Consumers often associate these species with health promotion. In this study, several wild species of the Asteraceae family and Knautia integrifolia (Dipsacaceae) were locally documented for their use in traditional cuisine and sampled from the wild. RESULTS: Phenolic compounds were identified and quantified by ultra-high-performance liquid chromatography coupled to Orbitrap high-resolution mass spectrometry. Hydroxycinnamic acids ranging from 1388 to 53 076 mg kg-1 dry weight (DW) were the most abundant compounds in all species (69-98% of the total phenolic content) except Tragopogon pratensis. Thirty compounds were identified as flavonoids, mostly as glycosidic forms of luteolin, apigenin, kaempferol and quercetin. The sum of flavonoids ranged between 212 and 12 598 mg kg-1 DW; they represented 65% of the total phenolic content for T. pratensis. Three anthocyanins were detected, representing in most cases less than 1% of the total phenolic content (3-627 mg kg-1 DW). Higher anthocyanin contents were observed for Cichorium types. CONCLUSION: Different phenolic profiles were observed between species, especially considering the class of flavonoids. Individual species may be of some interest for their content of specific minor flavonoids. (c) 2017 Society of Chemical Industry. PMID- 28707709 TI - A period prevalence study of being a parent in a secure psychiatric hospital and a description of the parents, the children and the impact of admission on parent child contact. AB - BACKGROUND: Most secure psychiatric hospital patients are of childbearing age, but their parental status is minimally researched. AIM: The aim of the study is to describe the parent patients in one regional secure hospital and explore post admission child-parent contact. METHODS: A 9-year records survey of a complete secure hospital admissions cohort was conducted. RESULTS: Nearly half of the cohort of 165 patients (46%) were parents. Parent patients were less likely than childless patients to have diagnostic co-morbidity or to have received childhood mental health care but were more likely to have committed a homicide/life threatening index offence with family or friend victims. Men, whether fathers or not, and childless women were unlikely ever to have harmed a child, but it was more likely than not that mother patients had. Records indicated minimal discussion about childlessness. Ninety-four (60%) of the 157 children involved were under 18 years on parental admission. Adult children who had been living with the parent patient before the parent's admission invariably maintained contact with them afterwards, but nearly half (48%) of such under 18-year-olds lost all contact. The only characteristic related to such loss was the index offence victim having been a nuclear family member. CONCLUSIONS: As the discrepancy in whether or not parent patients and their children continued contact with each other after the parent's admission seemed to depend mainly on the child's age and his or her resultant freedom to choose, acquisition of accurate data about affected children's perspective on visiting seems essential. Given that parent patients had experienced relative stability in interpersonal relationships and had rarely had childhood disorders, parenting support in conjunction with treatment seems appropriate. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28707710 TI - Perception and image of dermatology in the German general population 2002-2014. AB - BACKGROUND: In contrast to other European countries, dermatologists in Germany provide health care for a broad spectrum of diseases of the skin and mucous membranes. Current population-based data on the perception of dermatology were lacking to date. OBJECTIVE: Analysis of the perception of dermatology from the general population's perspective with regard to utilization, satisfaction and responsibility. METHODS: Nation-wide survey on awareness, utilization, rating and image of dermatology in October 2014 through computer-assisted telephone interviews on a representative sample of the adult general population (n = 1015), performed by the FORSA institute. RESULTS: Dermatologists as a medical specialist group are familiar to 88% of the population (2002: 65%), and approx. 82% of respondents underwent dermatological treatment in the past. Satisfaction with this treatment is high to very high in 80-90% of respondents. The majority (60 80%) name dermatologists as the desired primary provider of care for the largest share of common skin diseases. For allergic diseases, mucous membrane diseases, venous disorders and paediatric skin diseases, this rate is significantly below 50%. CONCLUSIONS: In Germany, dermatologists are perceived and valued as providers of care. In the case of skin cancer and chronic inflammatory skin diseases, they are experienced as primary care givers, whereas they are associated less frequently than their competence would justify with providing treatment for allergic and mucous membrane diseases and venous disorders. Further education of the general public and medical profession is required. PMID- 28707711 TI - Rosettes in actinic keratosis and squamous cell carcinoma: distribution, association to other dermoscopic signs and description of the rosette pattern. AB - BACKGROUND: Rosettes, a dermoscopic structure characterized by four white points arranged as a 4-leaf clover, supports the dermoscopic diagnosis of actinic keratosis (AK) or squamous cell carcinoma (SCC). OBJECTIVE: The association of rosettes with other dermoscopic structures in AK or SCC and their distribution has not been analysed yet. METHODS: We conducted a prospective study of patients with histologically proven AK or SCC who presented dermoscopic rosettes at initial evaluation. RESULTS: A total of 56 tumours were collected (94.6% AK and 5.4% SCC). Thirty-seven (66.1%) lesions were non-pigmented and 19 (33.9%) pigmented. The most common dermoscopic findings were erythema (53; 94.6%) and scale (42; 75%). White circles were present in 21 lesions (37.5%); pigmented pseudonetwork in 18 (32.1%) and multiple grey to brown dots and globules in 14 (25%). Rosettes were distributed focally in 9 (16.1%) and generalized in 47 (83.9%). The rosette pattern (rosettes as the main structure) was observed only in AK (19; 35.8%). LIMITATIONS: The analysis was not blinded. The distinction between focal distribution (up to 3 rosettes) or generalized could be considered arbitrary. CONCLUSION: The rosette pattern identified in AK may be a specific pattern for AK. PMID- 28707712 TI - Acne prevalence and associations with lifestyle: a cross-sectional online survey of adolescents/young adults in 7 European countries. AB - BACKGROUND: Although acne vulgaris is a common skin disorder, limited epidemiological data exist specifically for European populations. OBJECTIVE: To determine the prevalence of self-reported acne among young people in Europe and evaluate the effect of lifestyle on acne. METHODS: We conducted a cross-sectional population-based online survey in representative samples of individuals aged 15 24 years in Belgium, Czech and Slovak Republics, France, Italy, Poland and Spain (n = 10 521), identified by a quota sampling method based on age, geographic location and socio-professional category. RESULTS: The overall adjusted prevalence of self-reported acne was 57.8% (95% confidence interval 56.9% to 58.7%). The rates per country ranged from 42.2% in Poland to 73.5% in the Czech and Slovak Republics. The prevalence of acne was highest at age 15-17 years and decreased with age. On multivariate analysis, a history of maternal or paternal acne was associated with an increased probability of having acne (odds ratio 3.077, 95% CI 2.743 to 3.451, and 2.700, 95% CI 2.391 to 3.049, respectively; both P < 0.0001), as was the consumption of chocolate (OR 1.276, 95% CI 1.094 to 1.488, for quartile 4 vs. quartile 1). Increasing age (OR 0.728, 95% CI 0.639 to 0.830 for age 21-24 years vs. 15-17 years) and smoking tobacco (OR 0.705, 95% CI 0.616 to 0.807) were associated with a reduced probability of acne. CONCLUSION: The overall prevalence of self-reported acne was high in adolescents/young adults in the European countries investigated. Heredity was the main risk factor for developing acne. PMID- 28707713 TI - Controllable Organic Resistive Switching Achieved by One-Step Integration of Cone Shaped Contact. AB - Conductive filaments (CFs)-based resistive random access memory possesses the ability of scaling down to sub-nanoscale with high-density integration architecture, making it the most promising nanoelectronic technology for reclaiming Moore's law. Compared with the extensive study in inorganic switching medium, the scientific challenge now is to understand the growth kinetics of nanoscale CFs in organic polymers, aiming to achieve controllable switching characteristics toward flexible and reliable nonvolatile organic memory. Here, this paper systematically investigates the resistive switching (RS) behaviors based on a widely adopted vertical architecture of Al/organic/indium-tin-oxide (ITO), with poly(9-vinylcarbazole) as the case study. A nanoscale Al filament with a dynamic-gap zone (DGZ) is directly observed using in situ scanning transmission electron microscopy (STEM) , which demonstrates that the RS behaviors are related to the random formation of spliced filaments consisting of Al and oxygen vacancy dual conductive channels growing through carbazole groups. The randomicity of the filament formation can be depressed by introducing a cone shaped contact via a one-step integration method. The conical electrode can effectively shorten the DGZ and enhance the localized electric field, thus reducing the switching voltage and improving the RS uniformity. This study provides a deeper insight of the multiple filamentary mechanisms for organic RS effect. PMID- 28707714 TI - Ultrathin Single-Crystalline CdTe Nanosheets Realized via Van der Waals Epitaxy. AB - Due to the novel physical properties, high flexibility, and strong compatibility with Si-based electronic techniques, 2D nonlayered structures have become one of the hottest topics. However, the realization of 2D structures from nonlayered crystals is still a critical challenge, which requires breaking the bulk crystal symmetry and guaranteeing the highly anisotropic crystal growth. CdTe owns a typical wurtzite crystal structure, which hinders the 2D anisotropic growth of hexagonal-symmetry CdTe. Here, for the first time, the 2D anisotropic growth of ultrathin nonlayered CdTe as thin as 4.8 nm via an effective van der Waals epitaxy method is demonstrated. The anisotropic ratio exceeds 103 . Highly crystalline nanosheets with uniform thickness and large lateral dimensions are obtained. The in situ fabricated ultrathin 2D CdTe photodetector shows ultralow dark current (~100 fA), as well as high detectivity, stable photoswitching, and fast photoresponse speed (taurising = 18.4 ms, taudecay = 14.7 ms). Besides, benefitting from its 2D planar geometry, CdTe nanosheet exhibits high compatibility with flexible substrates and traditional microfabrication techniques, indicating its significant potential in the applications of flexible electronic and optoelectronic devices. PMID- 28707715 TI - Myelinating cocultures of rodent stem cell line-derived neurons and immortalized Schwann cells. AB - Myelination is one of the most remarkable biological events in the neuron-glia interactions for the development of the mammalian nervous system. To elucidate molecular mechanisms of cell-to-cell interactions in myelin synthesis in vitro, establishment of the myelinating system in cocultures of continuous neuronal and glial cell lines are desirable. In the present study, we performed co-culture experiments using rat neural stem cell-derived neurons or mouse embryonic stem (ES) cell-derived motoneurons with immortalized rat IFRS1 Schwann cells to establish myelinating cultures between these cell lines. Differentiated neurons derived from an adult rat neural stem cell line 1464R or motoneurons derived from a mouse ES cell line NCH4.3, were mixed with IFRS1 Schwann cells, plated, and maintained in serum-free F12 medium with B27 supplement, ascorbic acid, and glial cell line-derived neurotrophic factor. Myelin formation was demonstrated by electron microscopy at 4 weeks in cocultures of 1464R-derived neurons or NCH4.3 derived motoneurons with IFRS1 Schwann cells. These in vitro coculture systems utilizing the rodent stable stem and Schwann cell lines can be useful in studies of peripheral nerve development and regeneration. PMID- 28707716 TI - Paraneoplastic systemic lupus erythematosus in association with oat cell tumour of the lung. PMID- 28707717 TI - An autopsied case of corticobasal degeneration presenting with frontotemporal dementia followed by myoclonus. AB - A Japanese woman developed frontotemporal dementia (FTD)-like symptoms of abnormal behavior, such as stereotyped behavior and disinhibition. The patient developed these symptoms at the age of 59 years, although aphasia symptoms were not apparent at early disease stages. Progressive parkinsonism was dominant on the left side, and conspicuous myoclonus was recognized in the late disease stage. MRI indicated severe, right side-dominant frontotemporal lobe atrophy with white matter degeneration. Brainstem and cerebellar atrophy were also observed. The patient underwent gastrostomy 7 years after the onset of her symptoms and died at the age of 70 years. Neuropathological examination showed diffuse neuron loss with gliosis and tissue rarefaction in the frontotemporal lobe, particularly in the right anterior portion of the frontal lobe. Spongiform changes and ballooned neurons were also observed in the frontotemporal cortex, particularly in the superficial layer and deeper layers, respectively. Gallyas-Braak silver staining and anti-phosphorylated tau immunostaining indicated numerous argyrophilic and tau-positive structures, including pretangles, astrocytic plaques, coiled bodies and neuropil threads. We speculate that the myoclonus observed in the present case was at least partly caused by or related to the spongiform change and ballooned neurons in the cerebral cortex. The clinical phenotypes of corticobasal degeneration (CBD) vary considerably, and the clinical presentation of the present patient was compatible with frontal behavioral spatial syndrome in the early disease stage. However, in the later disease stages, her symptoms were reflective of corticobasal syndrome. Because it is not rare for the clinical phenotype to change along with disease progression in cases of CBD, we should consider CBD in cases presenting with FTD at symptom onset. PMID- 28707718 TI - Bracketed radioactive seed localization vs bracketed wire-localization in breast surgery. AB - Multiple localizers placed in a bracketed fashion facilitates excision of radiographically extensive breast lesions. In this study, bracketed radioactive seed localization (bRSL) was compared to bracketed wire localization (bWL). We hypothesized that bRSL would achieve adequate margins and decrease re-operation rates with similar or less specimen volumes (SV) than bWL. Retrospective review identified patients who underwent bracketed breast procedures at an academic medical center. Data collected included patient demographics, tumor features, treatment variables, and surgical outcomes. Wilcoxon rank-sum test and chi-square test were used to compare continuous and categorical data, respectively. A multivariable logistic regression model was used to evaluate the association between re-excision and localization technique after adjusting for clinically relevant variables. Patients who underwent bWL were 3.9 times more likely to undergo re-excision compared to patients in bRSL group (OR=3.9, 95% CI: 2.0-7.4). Initial and total SV did not significantly differ between the two groups (P=.4). Patients were significantly more likely to undergo a mastectomy in the bWL group than in the bRSL group (24% vs 7%; P<.01). For patients undergoing excision of radiologically extensive breast lesions, bRSL serves as an alternative to bWL. In this retrospective study, bRSL was associated with a decreased re-excision rate with similar SV and a lower rate of mastectomy when compared to bWL. PMID- 28707719 TI - Extracorporeal membrane oxygenation application in post-partum hemorrhage patients: Is post-partum hemorrhage contraindicated? AB - Extracorporeal membrane oxygenation (ECMO) is commonly used in patients who experience circulatory arrest or significant cardiac dysfunction and is associated with improved clinical outcomes. We conducted a retrospective observational study on ECMO application at a single tertiary center over a five year period. Five patients who suffered post-partum hemorrhage resulting from uterine atony were treated with ECMO. The mean age was 36.8 +/- 3.9 years; the mean gestational age was 37.8 +/- 2.2 weeks; the initial mean maternal hemoglobin level was 5.0 +/- 2.4 mg/dL; and the mean estimated blood loss was 3260 +/- 1545 mL before treatment. All patients were treated with venoarterial ECMO and one was treated with both venoarterial and venovenous ECMO. The mean ECMO usage duration was 32.6 +/- 18.8 h (range 10-54). Four (80%) patients survived until discharge without experiencing neurological sequela. ECMO should not be a contraindication for treatment of post-partum hemorrhage and such patients should be weaned as soon as possible to ensure the early recovery of cardiac function. PMID- 28707720 TI - Efficacy and safety of anagrelide in childhood essential thrombocythemia. PMID- 28707721 TI - Contractile actin belt and mesh structures provide the opposite dependence of epithelial stiffness on the spontaneous curvature of constituent cells. AB - Actomyosin generates contractile forces within cells, which have a crucial role in determining the macroscopic mechanical properties of epithelial tissues. Importantly, actin cytoskeleton, which propagates actomyosin contractile forces, forms several characteristic structures in a 3D intracellular space, such as a circumferential actin belt lining adherence junctions and an actin mesh beneath the apical membrane. However, little is known about how epithelial mechanical property depends on the intracellular contractile structures. We performed computational simulations using a 3D vertex model, and demonstrated the longitudinal tensile test of an epithelial tube, whose inside and outside are defined as the apical and basal surfaces, respectively. As a result, these subcellular structures provide the contrary dependence of epithelial stiffness and fracture force on the spontaneous curvature of constituent cells; the epithelial stiffness increases with increasing the spontaneous curvature in the case of belt, meanwhile it decreases in the case of mesh. This qualitative difference emerges from the different anisotropic deformability of apical cell surfaces; while belt preserves isotropic apical cell shapes, mesh does not. Moreover, the difference in the anisotropic deformability determines the frequency of cell rearrangements, which in turn effectively decrease the tube stiffness. These results illustrate the importance of the intracellular contractile structures, which may be regulated to optimize mechanical functions of individual epithelial tissues. PMID- 28707722 TI - Response to 'Safety of elastography applied to the placenta: Be careful with ultrasound radiation force'. PMID- 28707723 TI - Novel SGCE mutation (p.Glu65*) in a Japanese family with myoclonus-dystonia. PMID- 28707724 TI - Phenytoin-induced dysglycemia in a child. PMID- 28707725 TI - Preventive effect of human papillomavirus vaccination on the development of uterine cervical lesions in young Japanese women. AB - AIM: To examine the effect that human papillomavirus (HPV) vaccination has had in Akita Prefecture, by comparing cervical cytology results from women aged 20-24 years with or without HPV vaccination. METHODS: We examined cervical cytology results from 2425 subjects who underwent cervical cancer screening under the jurisdiction of the Akita Foundation for Healthcare between January 2014 and October 2016. We compared the prevalence of cytologic abnormalities among women aged 20-24 years with or without HPV vaccination. RESULTS: The rate of atypical squamous cells of undetermined significance (ASC-US) or worse was 0.242% (1/413) with HPV vaccination, and 2.04% (41/2012) without HPV vaccination. Overall, the prevalence of abnormal cytology results was significantly lower in women aged 20 24 years who had received an HPV vaccination than in those who had not (P = 0.011). The reduction in the rate of abnormal cervical cytology results by HPV vaccination was 88.1%. CONCLUSION: Within a 4-year-5-year period following vaccination, women aged 20-24 years who received an HPV vaccination had significantly lower rates of abnormal cervical cytology results than those who did not receive the vaccine. PMID- 28707726 TI - IVIG-triggered tubulointerstitial nephritis in X-linked agammaglobulinemia. PMID- 28707727 TI - In vitro renin-angiotensin system inhibition and in vivo antihypertensive activity of peptide fractions from lima bean (Phaseolus lunatus L.). AB - BACKGROUND: The renin-angiotensin system is key in the physiopathology of arterial hypertension because it converts angiotensin I, via angiotensin I converting enzyme (ACE), into angiotensin II. In vitro analyses were done of the ACE-inhibitory and renin-inhibitory activities of peptide fractions isolated by enzymatic hydrolysis of lima bean (Phaseolus lunatus) protein. Antihypertensive activity was confirmed in vivo using a rat model. RESULTS: Lima bean protein was hydrolyzed with one of two sequential enzymatic systems (pepsin-pancreatin or Alcalase(r)-Flavourzyme(r)). Ultrafiltration of the hydrolysates produced fractions of different molecular weights. The >3 kDa fraction of the pepsin pancreatin hydrolysate had the highest ACE-inhibitory activity (60.15%, IC50: 172.62 ug mL-1 ), while the >3 KDa fraction of the Alcalase(r)-Flavourzyme(r) hydrolysate had the highest in vitro renin-inhibitory activity. A weak correlation (r = 0.44) was found between ACE-inhibitory and renin-inhibitory activities. When tested in vivo, the latter fraction lowered systolic blood pressure by 64% and diastolic blood pressure by 51%. CONCLUSION: Peptide fractions from lima bean Phaseolus lunatus protein hydrolysates exhibit both in vitro and in vivo antihypertensive activity. Bioactive peptides from lima bean have potential applications as ingredients in functional foods. (c) 2017 Society of Chemical Industry. PMID- 28707728 TI - Association of adenylate cyclase-associated protein 1 with coronary artery disease. AB - BACKGROUND: Adenylate cyclase-associated protein 1 (CAP1) is a recently identified receptor for human resistin. As resistin has been related to CAD development and progression and CAP1 has never been evaluated in CAD, the aim of this study was to determine its peripheral blood mononuclear cells (PBMCs) mRNA in patients with CAD, and resistin plasma concentration, PBMCs resistin and CD36 mRNA, considering resistins ability to stimulate CD36 expression in vitro. MATERIALS AND METHODS: This case-controlled study included 27 healthy subjects (CG) and 66 patients requiring coronary angiography. Of the latter, 42 had nonsignificant CAD whereas 24 had significant CAD. Circulating resistin was measured by ELISA; PBMCs CAP1, resistin and CD36 mRNA were determined by real time PCR. RESULTS: Patients with significant as well as patients with nonsignificant CAD had significantly higher resistin concentrations compared to the CG (P < 0.001; P = 0.003). Resistin mRNA did not show significant difference between the investigated groups. CAP1 and CD36 mRNA were significantly higher in significant CAD (P < 0.001; P < 0.001, respectively) and nonsignificant CAD (P < 0.001; P < 0.001, respectively) compared to the CG; significant CAD showed significantly higher CD36 mRNA (P = 0.040) compared to the nonsignificant CAD group. Multiple linear regression analysis identified Tg and CD36 mRNA as independent predictors of CAP1 (R2 = 0.402; adjR2 = 0.376). CONCLUSION: Significant up-regulation of PBMCs CAP1, CD36 mRNA and plasma resistin found in significant CAD, as well as in nonsignificant CAD compared to CG, indicates that resistin could be able to exert its effects stronger on cells with up-regulated CAP1 mRNA thus contributing atherosclerosis development. PMID- 28707729 TI - SOX11 promotes invasive growth and ductal carcinoma in situ progression. AB - Here, we show that SOX11, an embryonic mammary marker that is normally silent in postnatal breast cells, is expressed in many oestrogen receptor-negative preinvasive ductal carcinoma in situ (DCIS) lesions. Mature mammary epithelial cells engineered to express SOX11 showed alterations in progenitor cell populations, including an expanded basal-like population with increased aldehyde dehydrogenase (ALDH) activity, and increased mammosphere-forming capacity. DCIS.com cells engineered to express SOX11 showed increased ALDH activity, which is a feature of cancer stem cells. The CD44+/CD24-/ALDH+ cell population was increased in DCIS.com cells that expressed SOX11. Upregulating SOX11 expression in DCIS.com cells led to increased invasive growth both in vitro and when they were injected intraductally in a mouse model of DCIS that recapitulates human disease. Invasive lesions formed sooner and tumour growth was augmented in vivo, suggesting that SOX11 contributes to the progression of DCIS to invasive breast cancer. We identified potential downstream effectors of SOX11 during both microinvasive and invasive tumour growth stages, including several with established links to regulation of progenitor cell function and prenatal developmental growth. Our findings suggest that SOX11 is a potential biomarker for DCIS lesions containing cells harbouring distinct biological features that are likely to progress to invasive breast cancer. (c) 2017 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. PMID- 28707730 TI - Complement and contact system activation in acute congestive heart failure patients. AB - Recent experimental data indicate a pathogenic role of complement activation in congestive heart failure (CHF). The aim of this study was to evaluate contact and complement systems activation in patients hospitalized for an acute episode of CHF. Forty-two of 80 consecutive patients admitted at our hospital with confirmed diagnosis of acute CHF were enrolled. They underwent blood sampling within 24 h from admission (T0) and at clinical stability (T1). Patients were stratified for ejection fraction (EF) based on echocardiographic test. We measured plasma levels of C3, C4, sC5b-9 and cleaved high molecular weight kininogen (contact activation marker). At T1, C3 levels increased significantly compared to T0 (97 +/- 2 versus 104 +/- 3% of total pooled plasma, P < 0.01). Classifying patients according to EF, only patients with preserved EF presented a significant increase of C3 from T0 to T1 (99 +/- 3 versus 108 +/- 4%, P = 0.03). When the sample was stratified according to clinical outcome, C3 (98 +/- 3 versus 104 +/- 4%, P = 0.03) and sC5b 9 levels (204 +/- 10 versus 230 +/- 11 ng/ml, P = 0.03) were increased in patients who had positive outcome after hospitalization. CHF patients with preserved EF and positive outcome after hospitalization showed higher levels of sC5b-9 in the T1 period compared with T0 (211 +/- 14 versus 243 +/- 14 ng/ml, P = 0.04). Our results suggest that the complement system reacts differently if CHF occurs with preserved or reduced EF. This finding is interesting if we consider the difference in epidemiology, pathogenesis and possible therapeutic approaches of these two clinical entities. PMID- 28707731 TI - Contribution of benthic microalgae to the temporal variation in phytoplankton assemblages in a macrotidal system. AB - Suspended marine benthic microalgae in the water column reflect the close relationship between the benthic and pelagic components of coastal ecosystems. In this study, a 12-year phytoplankton time-series was used to investigate the contribution of benthic microalgae to the pelagic system at a site along the French-Atlantic coast. Furthermore, all taxa identified were allocated into different growth forms in order to study their seasonal patterns. The highest contribution of benthic microalgae was observed during the winter period, reaching up to 60% of the carbon biomass in the water column. The haptobenthic growth form showed the highest contribution in terms of biomass, dominant in the fall-winter period when the turbidity and the river flow were high. The epipelic growth form did not follow any seasonal pattern. The epiphytic diatom Licmophora was most commonly found during summer. As benthic microalgae were found in the water column throughout the year, the temporal variation detected in the structure of pelagic assemblages in a macrotidal ecosystem was partly derived from the differentiated contribution of several benthic growth forms. PMID- 28707732 TI - Authors' reply re: Dilute versus concentrated vasopressin administration during laparoscopic myomectomy: a randomised controlled trial. PMID- 28707733 TI - A new equation to predict peak VO2 in obese patients during cardiopulmonary exercise testing. AB - We aimed to develop an equation to predict peak VO2 in obese subjects undergoing CPET. In addition, we evaluated and compared three published equations. We randomized 346 obese subjects undergoing CPET into a group for developing the equation (n = 272) and a group for cross-validation (n = 74), compared through the Bland and Altman method. Height, sex and age were responsible for 85.5% of total variability of the peak VO2. Additional 1% and 0.7% of the variability were, respectively, explained by physical inactivity and diabetes. The equation devised was as follows: peakVO2mlmin-1= 677.8+(2135.9*heightm)+(706.8*sexmales=1;females=0)-(15.5*ageyears) (161.1*physicalinactivityyes=1;no=0)-(176.3*diabetesyes=1;no=0). The mean difference between the estimated and measured peak VO2 was 7 ml min-1 , with a 23.9% bias. Published equations overestimated the peak VO2 by 35.3%, 49.1% and 46.2% bias. The equation developed in this study performed better in predicting peak VO2 in obese adults improving ramp protocol design and CRF evaluations in obese subjects. PMID- 28707734 TI - Re: The fetal safety of clomiphene citrate: a population based retrospective cohort study. PMID- 28707735 TI - Re: Dilute versus concentrated vasopressin administration during laparoscopic myomectomy: a randomised controlled trial. PMID- 28707736 TI - Genetically encoded iron-associated proteins as MRI reporters for molecular and cellular imaging. AB - All cell imaging applications rely on some form of specific cell labeling to achieve visualization of cells contributing to disease or cell therapy. The purpose of this review article is to summarize the published data on genetically encoded iron-based imaging reporters. The article overviews regulation of iron homeostasis as well as genetically encoded iron-associated molecular probes and their applications for noninvasive magnetic resonance imaging (MRI) of transplanted cells. Longitudinal repetitive MRI of therapeutic cells is extremely important for providing key functional endpoints and insight into mechanisms of action. Future directions in molecular imaging and techniques for improving sensitivity, specificity and safety of in vivo reporter gene imaging are discussed. WIREs Nanomed Nanobiotechnol 2018, 10:e1482. doi: 10.1002/wnan.1482 This article is categorized under: Diagnostic Tools > In Vivo Nanodiagnostics and Imaging. PMID- 28707737 TI - 18 F-sodium fluoride positron emission tomography of the equine distal limb: Exploratory study in three horses. AB - BACKGROUND: Positron emission tomography (PET) is a cross-sectional, functional imaging modality that has recently become available to the horse. The use of 18 F sodium fluoride (18 F-NaF), a PET bone tracer, has not previously been reported in this species. OBJECTIVES: To assess the feasibility of 18 F-NaF PET in the equine distal limb and explore possible applications in the horse in comparison with other imaging modalities. STUDY DESIGN: Exploratory descriptive study involving three research horses. METHODS: Horses were placed under general anaesthesia prior to intravenous (i.v.) administration of 1.5 MBq/kg of 18 F-NaF. Positron emission tomography imaging of both front feet and fetlocks was performed using a portable scanner. Computed tomography (CT) of the distal limb was performed under a separate anaesthetic episode. Bone scintigraphy and magnetic resonance imaging (MRI) were subsequently performed under standing sedation. Images obtained from PET and other imaging modalities were independently assessed and the results correlated. RESULTS: Positron emission tomography images were obtained without complication. The radiation exposure rate was similar to equine bone scintigraphy. Positron emission tomography detected focal 18 F-NaF uptake in areas where other imaging modalities did not identify any abnormalities. This included sites of ligamentous attachment, subchondral compact bone plate and the flexor cortex of the navicular bone. 18 F-NaF uptake was identified in some, but not all, osseous fragments and areas of osseous formation, suggesting a distinction between active and inactive lesions. MAIN LIMITATIONS: A small number of horses were included and histopathology was not available. CONCLUSIONS: 18 F-NaF PET imaging of the equine distal limb provides useful additional information when compared with CT, MRI and scintigraphy and has the potential for both research and clinical applications in the horse. The Summary is available in Chinese - see Supporting information. PMID- 28707738 TI - Prenatal exposure to dexamethasone in the mouse induces sex-specific differences in placental gene expression. AB - Prenatal stress during pregnancy leads to sex-specific effects on fetal development and disease susceptibility over the life span; however, the origin of sex differences has not been identified. The placenta not only plays a key role in fetal growth and development throughout pregnancy, but also affects the fetal programming underlying subsequent adult health and accounts. Therefore, sex specific adaptation of the placenta may be central to the sex differences in fetal growth and survival. Here, we analyzed the effects of prenatal dexamethasone (Dex) on sex-specific changes in placental gene expression using RNA-Seq. Placental tissues from males and females were separated into two developmentally distinct fetal and maternal parts at E11.5 stage. The majority of genes in female placentas were downregulated by prenatal Dex, whereas those were mostly maintained or rather upregulated in male placentas. RNA-Seq results were validated using independent biological replicates from the same stage and placental tissue samples from E18.5 by realtime PCR assays. Activation of various inflammatory response-related genes, chemokines and their receptors, particularly in male placentas, strongly implies that prenatal Dex exposure causes sex specific physiological responses that can lead to inflammatory diseases involving vascular pathology. PMID- 28707739 TI - Angiotensin II-preconditioning is associated with increased PKCepsilon/PKCdelta ratio and prosurvival kinases in mitochondria. AB - Angiotensin II-preconditioning (APC) has been shown to reproduce the cardioprotective effects of ischaemic preconditioning (IPC), however, the molecular mechanisms mediating the effects of APC remain unknown. In this study, Langendorff-perfused rat hearts were subjected to IPC, APC or both (IPC/APC) followed by ischaemia-reperfusion (IR), to determine translocation of PKCepsilon, PKCdelta, Akt, Erk1/2, JNK, p38 MAPK and GSK-3beta to mitochondria as an indicator of activation of the protein kinases. In agreement with previous observations, IPC, APC and IPC/APC increased the recovery of left ventricular developed pressure (LVDP), reduced infarct size (IS) and lactate dehydrogenase (LDH) release, compared to controls. These effects were associated with increased mitochondrial PKCepsilon/PKCdelta ratio, Akt, Erk1/2, JNK, and inhibition of permeability transition pore (mPTP) opening. Chelerythrine, a pan-PKC inhibitor, abolished the enhancements of PKCepsilon but increased PKCdelta expression, and inhibited Akt, Erk1/2, and JNK protein levels. The drug had no effect on the APC- and IPC/APC-induced cardioprotection as previously reported, but enhanced the post-ischaemic LVDP in controls. Losartan, an angiotensin II type 1 receptor (AT1 R) blocker, abolished the APC-stimulated increase of LVDP and reduced PKCepsilon, Akt, Erk1/2, JNK, and p38. Both drugs reduced ischaemic contracture and LDH release, and abolished the inhibition of mPTP by the preconditioning. Chelerythrine also prevented the reduction of IS by APC and IPC/APC. These results suggest that the cardioprotection induced by APC and IPC/APC involves an AT1-R-dependent translocation of PKCepsilon and survival kinases to the mitochondria leading to mPTP inhibition. In chelerythrine-treated hearts, however, alternate mechanisms appear to maintain cardiac function. PMID- 28707740 TI - Design of a ruthenium(III) immobilized affinity material based on a beta cyclodextrin-functionalized poly(glycidyl methacrylate-ethylene dimethacrylate) monolith for the enrichment of hippuric acid. AB - Immobilized metal affinity chromatography has drawn great attention as a widespread separation and purification approach. In this work, ruthenium was firstly introduced into the preparation of immobilized metal affinity chromatography considering its affinity to N,O-donor ligands. A beta-cyclodextrin functionalized poly(glycidyl methacrylate-ethylene dimethacrylate) monolith was designed and employed as the supporting material in immobilized metal affinity chromatography. Thiosemicarbazide was introduced into the synthesis process, which not only acted as a bridge between beta-cyclodextrin and glycidyl methacrylate, but also chelated with ruthenium because of its mixed hard-soft donor characteristics. The developed monolithic ruthenium(III)-immobilized metal affinity chromatography column was utilized for the adsorption and separation of hippuric acid, a biological indicator of toluene exposure. To achieve high extraction capacity, the parameters affecting the extraction efficiency were investigated with an orthogonal experiment design, L9 (34 ). Under the optimized conditions, the enrichment factor of hippuric acid was 16.7-fold. The method reproducibility was investigated in terms of intra- and interday precisions with relative standard deviations lower than 8.7 and 9.5%, respectively. In addition, ruthenium(III)-immobilized metal affinity chromatography material could be used for up to 80 extractions without an apparent change in extraction recovery. PMID- 28707741 TI - Randomized clinical trial of psychological support and sleep adjuvant measures for postoperative sleep disturbance in patients undergoing oesophagectomy. AB - BACKGROUND: Major surgery such as oesophagectomy requires a postoperative stay in intensive care. Painful stimuli lead to sleep disturbance and impairment in quality of life. The aim of this study was to evaluate the effect of psychological counselling and sleep adjuvant measures on postoperative quality of sleep and quality of life. METHODS: This RCT was performed between January 2013 and October 2015. Patients undergoing oesophagectomy for cancer were randomized into one of four groups receiving: psychological counselling plus sleep adjuvant measures during the ICU stay; psychological counselling alone; sleep adjuvant measures alone during the ICU stay; or standard care. The primary endpoint was impairment in quality of life measured using the European Organisation for Research and Treatment of Cancer C30-QL2 questionnaire between admission for surgery and discharge from hospital. The secondary endpoint was impairment in quality of sleep assessed by means of the Pittsburgh Sleep Quality Index between admission for surgery and hospital discharge. RESULTS: The local ethics committee approved the early termination of the study because of relevant changes in the ICU setting. Some 87 patients were randomized and 74 patients were evaluated in the analysis. Psychological counselling reduced the impairment in quality of life (odds ratio 0.23, 95 per cent c.i. 0.09 to 0.61) and in quality of sleep (odds ratio 0.27, 0.10 to 0.73). CONCLUSION: Perioperative psychological support reduces impairment in quality of life and quality of sleep after oesophagectomy. Registration number: NCT01738620 (http://www.clinicaltrials.gov). PMID- 28707742 TI - Intramolecular Locked Dithioalkylbithiophene-Based Semiconductors for High Performance Organic Field-Effect Transistors. AB - New 3,3'-dithioalkyl-2,2'-bithiophene (SBT)-based small molecular and polymeric semiconductors are synthesized by end-capping or copolymerization with dithienothiophen-2-yl units. Single-crystal, molecular orbital computations, and optical/electrochemical data indicate that the SBT core is completely planar, likely via S(alkyl)?S(thiophene) intramolecular locks. Therefore, compared to semiconductors based on the conventional 3,3'-dialkyl-2,2'-bithiophene, the resulting SBT systems are planar (torsional angle <1 degrees ) and highly pi conjugated. Charge transport is investigated for solution-sheared films in field effect transistors demonstrating that SBT can enable good semiconducting materials with hole mobilities ranging from ~0.03 to 1.7 cm2 V-1 s-1 . Transport difference within this family is rationalized by film morphology, as accessed by grazing incidence X-ray diffraction experiments. PMID- 28707743 TI - Workplace continuing education for nurses caring for hospitalised older people. AB - AIMS AND OBJECTIVES: To develop, implement and evaluate a workplace continuing education programme about nursing care of hospitalised older people. BACKGROUND: The healthcare system cannot rely solely upon nurses' prelicensure education to prepare them to meet the evolving needs of hospitalised older patients. Over the past decade, there has been a dramatic rise in the proportion of older people in hospitals, yet many nurses do not have specialised knowledge about the unique care needs of this population. DESIGN: A multimethod pre-to post-design was employed. METHODS: Between September 2013 and April 2014, data were collected via surveys, focus groups and interviews. Thirty-two Registered Nurses initially enrolled in the programme of which 22 completed all data points. Three managers also participated in interviews. One-way repeated-measures ANOVAs were conducted to evaluate the effect of the programme and change over time. Qualitative data were analysed using thematic analysis. RESULTS: Survey results indicated improvements in perceptions about nursing care of older people but no changes in knowledge. Themes generated from the qualitative data focused on participants' experiences of taking part in the programme and included: (i) relevance of content and delivery mode, (ii) value of participating in the programme and (iii) continuing education in the context of acute care. CONCLUSIONS: This study illustrated the potential role of workplace continuing education in improving care for hospitalised older people, particularly the potential to change nurses' perceptions about this population. Nurses prefer learning opportunities that are varied in delivery of educational elder-focused content and accessible at work. Organisational leaders need to consider strategies that minimise potential barriers to workplace continuing education. IMPLICATIONS FOR PRACTICE: Workplace continuing education can play a key role in improving quality of care for hospitalized older adults and ought to be a priority for employers planning education for nurses. PMID- 28707744 TI - The impact of molecular subtype on breast cancer recurrence in young women treated with contemporary adjuvant therapy. AB - Breast cancer is the leading cause of cancer death in women younger than 40 years. Triple-negative breast cancer (TNBC) and human epidermal growth factor receptor-2 (HER2) positive subtypes have a particularly poor prognosis in this age group. The purpose of this study was to compare rates of recurrence among breast cancer subtypes in young patients treated with modern adjuvant systemic therapy. A retrospective review of breast cancer patients managed at a major academic breast center between May 2000 and November 2014 was performed. We included 239 women with breast cancer who were diagnosed and treated at age <=40 years. Clinical, pathological, therapeutic, and outcome data were recorded. Patients were classified into the following molecular subtypes: luminal A/B (estrogen receptor [ER] positive and/or progesterone receptor [PR] positive, and HER2 negative), luminal/HER2 (ER positive and/or PR positive, and HER2 positive), HER2- enriched (ER negative, PR negative, and HER2 positive) and TNBC (ER negative, PR negative, and HER2 negative). Descriptive statistics were used to characterize the study cohort. Kaplan-Meier survival analysis was performed to estimate recurrence-free survival (RFS). Median follow-up time was 29 months. Mean age was 34.5 years. Among all patients, 193 (80.8%) were diagnosed with Invasive breast cancer and 46 (19.2%) with ductal carcinoma in situ with or without microinvasion. Subclassification into molecular subtypes was complete for 199 patients among which, 50.7% were classified as luminal A/B, 21.1% luminal/HER2, 12.1% HER2-enriched and 16.1% TNBC. Of the 199 patients, 25.1% received neo-adjuvant chemotherapy and 59.2% received adjuvant chemotherapy. Among HER2-positive patients, 81.3% received HER2 directed therapy. Twenty-eight patients (11.7%) had recurrences (13 loco-regional, seven distant, and eight both). At 3 years, the HER2 subtype had the highest RFS 100%, compared to 91.1% in luminal A/B, 85.6% in luminal/HER2 and 81.9% in TNBC. In comparing outcomes among subtypes, the HER2 positive subtype was associated with improved RFS, likely reflecting the impact of HER2 directed therapy. Those young patients with triple-negative subtype continued to have the poorest outcomes. PMID- 28707745 TI - Survival of the fetus during maternal thoracotomy under cardiopulmonary bypass for infective endocarditis. AB - Infective endocarditis (IE) during pregnancy is a rare but serious condition. Cardiopulmonary bypass during pregnancy has a high rate of fetal morbidity and mortality. We here report the case of a 22-year-old pregnant woman with confirmed IE. Multiple large cardiac valve vegetations, severe aortic valve regurgitation, and hemodynamic compromise were observed. With full implementation of fetal monitoring and protection strategies, open heart surgery was performed at 31.4 weeks' gestation to aid survival, followed by an elective cesarean delivery at 34.4 weeks. As of the 3-month follow-up, both the mother and infant were in good health. This shows that a fetus can survive maternal thoracotomy under cardiopulmonary bypass with proper perioperative management, which means that this technique does not need to be excluded from consideration in the treatment of IE complicating pregnancy. PMID- 28707746 TI - Gas Evolution in Activated-Carbon-Based Supercapacitors with Protic Deep Eutectic Solvent as Electrolyte. AB - One of the primary causes of aging in supercapacitors are the irreversible faradaic reactions occurring near the operating-voltage limit that lead to the production of gases resulting in device swelling, increased resistance, and lowering of the capacitance. In this study, a protic deep eutectic solvent (DES) consisting of mixture of lithium bis(fluorosulfonyl)imide (LiFSI) with formamide (FMD) as H-bond donor (xLiFSI =0.25; C=2.5 m LiFSI) is investigated as electrolyte for activated carbon (AC)-based electrical double layer capacitors (EDLCs). Characterization of the viscosity, conductivity, and the ionicity of the electrolyte in a wide range of temperatures indicates >88 % salt dissociation. In situ pressure measurements are performed to understand the effect of cycling conditions on the rate of gas generation, quantified by the in operando pressure variation dP/dt. These measurements demonstrate that about 25 % of the faradaic reactions leading to gas generation are electrochemically reversible. Cell aging studies demonstrate promising potential of the LiFSI/FMD as a protic electrolyte for AC-based EDLCs and high energy density close to 30 Wh kg-1 at 2.4 V. PMID- 28707747 TI - Delayed hemorrhage as a result of ruptured uterine artery pseudoaneurysm after transmyometrial oocyte retrieval: Management by transcatheter arterial embolization using N-butyl-2-cyanoacrylate. AB - Uterine artery pseudoaneurysm is a rare but potentially life-threatening complication that can occur after various uterine manipulations. A 34-year-old nulliparous patient with a previous history of four consecutive miscarriages with unknown etiologies underwent transmyometrial oocyte retrieval as a result of malpositioning of the right ovary. Six days later, she experienced massive vaginal bleeding after a day of intermittent bleeding and was transferred to our hospital. At triage, continuous bleeding from the cervical canal was observed. Color Doppler ultrasonography and three-dimensional computerized tomographic angiography revealed a ruptured pseudoaneurysm originating from the peripheral branch of the right uterine artery in the lower uterine segment. It was successfully treated by transcatheter arterial embolization with N-butyl-2 cyanoacrylate. Transcatheter arterial embolization with N-butyl-2-cyanoacrylate is a feasible option for uterus-preserving management of late massive hemorrhage resulting from a ruptured uterine artery pseudoaneurysm after transmyometrial oocyte retrieval. PMID- 28707748 TI - Catalytic Nitrene Transfer To Alkynes: A Novel and Versatile Route for the Synthesis of Sulfinamides and Isothiazoles. AB - A novel transformation is reported for the reaction of terminal or internal alkynes with the nitrene precursor PhI=NTs (Ts=p-toluenesulfonyl) in the presence of catalytic amounts of TpBr3 Cu(NCMe) (TpBr3 =hydrotris(3,4,5-tribromo pyrazolylborate). Two products containing an imine functionality have been isolated from the reaction mixtures, identified as sulfinamides and isothiazoles. The former correspond to the formal reduction of the sulfone group into sulfoxide, whereas the latter involves the insertion of an alkyne carbon atom into the aromatic ring of the N-tosyl moiety. PMID- 28707749 TI - New insights into sinusoidal obstruction syndrome. AB - BACKGROUND: Entry criteria included patients who developed sinusoidal obstruction syndrome (SOS) at a single centre from January 2000 to December 2011. Patients who underwent haemopoietic stem cell transplantation or actinomicyn-based chemotherapy for nephroblastoma were selected. The study group comprised five patients with SOS who were compared with a control group of seven patients without SOS. AIM: To study the relationships between endothelial extracellular vesicles (EV) and plasminogen-activator inhibitor type 1(PAI-1) to assess their modification in the early phase of SOS. METHODS: Consecutive blood samples were tested for cell-derived EV, PAI-1 and coagulation parameters. Any statistically significant correlation between all datasets was searched. RESULTS: Antithrombin level and platelet count were statistically significantly reduced in SOS patients, suggesting a consumption status. PAI-1:Ag and PAI-1:act showed an inverse relationship with platelet counts (coef. -0.034, SE = 0.016; P = 0.041 and -0.052, SE = 0.019; P = 0.011 respectively). During follow up, PAI-1:Ag was inversely related to EV CD144+ (coef. -0.261, SE = 0.094; P = 0.007) and antithrombin (coef -0.509, SE = 0.175; P = 0.005). PAI-1:act showed an inverse association with EV CD144+ (coef.-0.251, SE = 0.121; P = 0.043), EV CD31+/CD41+ (coef. -0.004, SE = 0.002; P = 0.026) and antithrombin (coef. -0.470, SE = 0.220; P = 0.038). EV generated by rupture of gap junctions (EV CD144+) were increased in SOS patients and also showed a change over time. CONCLUSION: This study demonstrates the existence of an ongoing procoagulant and hypofibrinolytic status in SOS, indicating a possible role for anticoagulant therapy. Moreover, these findings suggest a role for EV CD 144+, either alone or in combination with PAI 1, as a new biomarker for SOS. PMID- 28707750 TI - Arterial immune protein expression demonstrates the complexity of immune responses in Kawasaki disease arteritis. AB - A more complete understanding of immune-mediated damage to the coronary arteries in children with Kawasaki disease (KD) is required for improvements in patient treatment and outcomes. We recently reported the transcriptional profile of KD coronary arteritis, and in this study sought to determine protein expression of transcriptionally up-regulated immune genes in KD coronary arteries from the first 2 months after disease onset. We examined the coronary arteries of 12 fatal KD cases and 13 childhood controls for expression of a set of proteins whose genes were highly up-regulated in the KD coronary artery transcriptome: allograft inflammatory factor 1 (AIF1), interleukin 18 (IL-18), CD74, CD1c, CD20 (MS4A1), Toll-like receptor 7 (TLR-7) and Z-DNA binding protein 1 (ZBP1). Immunohistochemistry and immunofluorescence studies were performed to evaluate protein expression and co-localization, respectively. AIF1 was expressed transmurally in KD arteritis and localized to macrophages and myeloid dendritic cells. CD74, which interacts with major histocompatibility complex (MHC) class II on antigen-presenting cells, localized to the intima-media. CD1c, a marker of myeloid dendritic cells, was expressed in a transmural pattern, as were IL-18 and CD20. ZBP1 and TLR-7 were up-regulated compared to controls, but less highly compared to the other proteins. These findings provide evidence of antigen presentation and interferon response in KD arteritis. In combination with prior studies demonstrating T lymphocyte activation, these results demonstrate the complexity of the KD arterial immune response. PMID- 28707751 TI - Oral antifungal medication for toenail onychomycosis. AB - BACKGROUND: Fungal infection of the toenails, also called onychomycosis, is a common problem that causes damage to the nail's structure and physical appearance. For those severely affected, it can interfere with normal daily activities. Treatment is taken orally or applied topically; however, traditionally topical treatments have low success rates due to the nail's physical properties. Oral treatments also appear to have shorter treatment times and better cure rates. Our review will assist those needing to make an evidence based choice for treatment. OBJECTIVES: To assess the effects of oral antifungal treatments for toenail onychomycosis. SEARCH METHODS: We searched the following databases up to October 2016: the Cochrane Skin Group Specialised Register, CENTRAL, MEDLINE, Embase, and LILACS. We also searched five trials registers and checked the reference lists of included and excluded studies for further references to relevant randomised controlled trials (RCTs). We sought to identify unpublished and ongoing trials by correspondence with authors and by contacting relevant pharmaceutical companies. SELECTION CRITERIA: RCTs comparing oral antifungal treatment to placebo or another oral antifungal treatment in participants with toenail onychomycosis, confirmed by one or more positive cultures, direct microscopy of fungal elements, or histological examination of the nail. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We included 48 studies involving 10,200 participants. Half the studies took place in more than one centre and were conducted in outpatient dermatology settings. The participants mainly had subungual fungal infection of the toenails. Study duration ranged from 4 months to 2 years.We assessed one study as being at low risk of bias in all domains and 18 studies as being at high risk of bias in at least one domain. The most common high-risk domain was 'blinding of personnel and participants'.We found high quality evidence that terbinafine is more effective than placebo for achieving clinical cure (risk ratio (RR) 6.00, 95% confidence interval (CI) 3.96 to 9.08, 8 studies, 1006 participants) and mycological cure (RR 4.53, 95% CI 2.47 to 8.33, 8 studies, 1006 participants). Adverse events amongst terbinafine-treated participants included gastrointestinal symptoms, infections, and headache, but there was probably no significant difference in their risk between the groups (RR 1.13, 95% CI 0.87 to 1.47, 4 studies, 399 participants, moderate-quality evidence).There was high-quality evidence that azoles were more effective than placebo for achieving clinical cure (RR 22.18, 95% CI 12.63 to 38.95, 9 studies, 3440 participants) and mycological cure (RR 5.86, 95% CI 3.23 to 10.62, 9 studies, 3440 participants). There were slightly more adverse events in the azole group (the most common being headache, flu-like symptoms, and nausea), but the difference was probably not significant (RR 1.04, 95% CI 0.97 to 1.12; 9 studies, 3441 participants, moderate-quality evidence).Terbinafine and azoles may lower the recurrence rate when compared, individually, to placebo (RR 0.05, 95% CI 0.01 to 0.38, 1 study, 35 participants; RR 0.55, 95% CI 0.29 to 1.07, 1 study, 26 participants, respectively; both low-quality evidence).There is moderate-quality evidence that terbinafine was probably more effective than azoles for achieving clinical cure (RR 0.82, 95% CI 0.72 to 0.95, 15 studies, 2168 participants) and mycological cure (RR 0.77, 95% CI 0.68 to 0.88, 17 studies, 2544 participants). There was probably no difference in the risk of adverse events (RR 1.00, 95% CI 0.86 to 1.17; 9 studies, 1762 participants, moderate-quality evidence) between the two groups, and there may be no difference in recurrence rate (RR 1.11, 95% CI 0.68 to 1.79, 5 studies, 282 participants, low-quality evidence). Common adverse events in both groups included headache, viral infection, and nausea.Moderate-quality evidence shows that azoles and griseofulvin probably had similar efficacy for achieving clinical cure (RR 0.94, 95% CI 0.45 to 1.96, 5 studies, 222 participants) and mycological cure (RR 0.87, 95% CI 0.50 to 1.51, 5 studies, 222 participants). However, the risk of adverse events was probably higher in the griseofulvin group (RR 2.41, 95% CI 1.56 to 3.73, 2 studies, 143 participants, moderate-quality evidence), with the most common being gastrointestinal disturbance and allergic reaction (in griseofulvin-treated participants) along with nausea and vomiting (in azole-treated participants). Very low-quality evidence means we are uncertain about this comparison's impact on recurrence rate (RR 4.00, 0.26 to 61.76, 1 study, 7 participants).There is low quality evidence that terbinafine may be more effective than griseofulvin in terms of clinical cure (RR 0.32, 95% CI 0.14 to 0.72, 4 studies, 270 participants) and mycological cure (RR 0.64, 95% CI 0.46 to 0.90, 5 studies, 465 participants), and griseofulvin was associated with a higher risk of adverse events, although this was based on low-quality evidence (RR 2.09, 95% CI 1.15 to 3.82, 2 studies, 100 participants). Common adverse events included headache and stomach problems (in griseofulvin-treated participants) as well as taste loss and nausea (in terbinafine-treated participants). No studies addressed recurrence rate for this comparison.No study addressed quality of life. AUTHORS' CONCLUSIONS: We found high-quality evidence that compared to placebo, terbinafine and azoles are effective treatments for the mycological and clinical cure of onychomycosis, with moderate-quality evidence of excess harm. However, terbinafine probably leads to better cure rates than azoles with the same risk of adverse events (moderate-quality evidence).Azole and griseofulvin were shown to probably have a similar effect on cure, but more adverse events appeared to occur with the latter (moderate-quality evidence). Terbinafine may improve cure and be associated with fewer adverse effects when compared to griseofulvin (low-quality evidence).Only four comparisons assessed recurrence rate: low-quality evidence found that terbinafine or azoles may lower the recurrence rate when compared to placebo, but there may be no difference between them.Only a limited number of studies reported adverse events, and the severity of the events was not taken into account.Overall, the quality of the evidence varied widely from high to very low depending on the outcome and comparison. The main reasons to downgrade evidence were limitations in study design, such as unclear allocation concealment and randomisation as well as lack of blinding. PMID- 28707753 TI - Psoriasis and migraine. AB - BACKGROUND: Psoriasis and migraine share several pathogenetic mechanisms due to systemic inflammation, which increase the risk of developing cardiovascular disease. OBJECTIVE: Our aim was to investigate the prevalence of migraine with (MA) and without aura (MO) in the psoriatic population, investigating a possible new comorbidity of the psoriatic disease. METHODS: We referred 68 psoriatic patients to a nine questions survey formulated on the basis of the International Headache Society (IHS) diagnostic criteria for migraine. Then, in the case of MA, the mean monthly number of migraine crises was assessed. Data of psoriatic patients were then compared with those of a psoriasis-free control group composed of 235 migraine patients (with and without aura). RESULTS: A clinical diagnosis of migraine was performed in 32 psoriasis patients with a great prevalence in women (F: 87.50% - M: 12.5%). Moreover, we found a much higher prevalence (62.5%) of MA, with the remaining 37.5% diagnosed with MO. Comparing the prevalence of MA between psoriasis + migraine patients and the control group we observed a statistical significative difference (P < 0.0001); furthermore, the number of MA crises was significantly higher (P < 0.0001) in patients with psoriasis with respect to the MA control group. CONCLUSIONS: We showed a significant association between psoriasis and migraine, especially MA, probably due to common pathogenetic mechanisms, but further studies are needed to assess their interplay in developing cardiovascular diseases. PMID- 28707752 TI - Analysis of the correlation between knee extension torque and patellar tendon elastic property. AB - PURPOSE: Quadriceps strength and patellar tendon (PT) are directly linked and intimately related to daily activities and lower limb function. However, the correlation between knee extension torque (KT) and PT Young's modulus (E) measured directly is still unknown. METHOD: We used supersonic shearwave imaging (SSI) to evaluate the elastic property of PT in healthy young men and analysed its correlation with KT. Twenty-two healthy young males were included and both knees were examined. The E of the PT in the dominant and non-dominant legs was assessed by SSI elastography. KT in maximal voluntary isometric contraction was measured with an isokinetic dynamometer. RESULT: No correlations between KT and PT E were observed in dominant or non-dominant side (P = 0.458 and 0.126, respectively). No significant differences in KT or PT E were observed between both legs (P = 0.096 and 0.722, respectively). Intra-day ICC was rated good (D1 - 0.886, P<0.001 and 0.88, P<0.001) and excellent (D2 - 0.928, P<0.001 and 0.900, P<0.001) for both legs. Inter-day ICC was rated moderate for both legs (0.651, P = 0.016 and 0.630, P = 0.018, respectively). CONCLUSION: No significant correlations were found between KT and PT E, suggesting that quadriceps strength is not an accurate predictor for PT mechanical properties in subjects with no specific training engagement. Habitual loading pattern can play a determinant role in PT mechanical properties, regardless of quadriceps strength. Further investigation on SSI acquisition protocols should be conducted to guarantee higher inter-day ICC values. PMID- 28707754 TI - Non-sibling hematopoietic stem cell transplantation using myeloablative conditioning regimen in children with Maroteaux-Lamy syndrome: A brief report. AB - Maroteaux-Lamy syndrome is a rare inherited lysosomal storage disorder with a progressive course. HSCT is a curable option for treatment in these patients. The following report describes our experience in HSCT for three patients with Maroteaux-Lamy syndrome using non-sibling donors. All of the patients received the same myeloablative regimen consisting of intravenous busulfan, cyclophosphamide, and rabbit antithymocyte globulin. Patients underwent HSCT from haploidentical other-related (n=1), full-matched other-related (n=1), and one locus-mismatched unrelated donor. Stem cell sources included bone marrow (n=1), peripheral blood (n=1), and cord blood (n=1). Currently, two patients who received transplant from other-related donors showed full engraftment and regression of the symptoms of the disease, while for the patient with unrelated cord blood donor, graft failure resulted in progression of the disease and death. The result of our study showed beneficial effects of HSCT even from heterozygote donor. Due to rarity of the disease, future multicenter studies are recommended to find the best treatment approaches based on the patients' status. PMID- 28707755 TI - Non-invasive detection of myocardial fibrosis in pediatric heart transplant recipients: The role of cardiovascular magnetic resonance. PMID- 28707756 TI - Does standardization improve care or stifle innovation? PMID- 28707757 TI - Supramolecular Nanotubules as a Catalytic Regulator for Palladium Cations: Applications in Selective Catalysis. AB - Despite the recent development of highly efficient and stable metal catalysts, conferral of regulatory characteristics to the catalytic reaction in heterogeneous systems remains a challenge. Novel supramolecular nanotubules were prepared by alternative stacking from trimeric macrocycles, which was found to be able to coordinate with Pd cations. The Pd complexes exhibited a high catalytic performance for C-C coupling reaction. Notably, the tubular catalyst was observed to be controlled by supramolecular reversible assembly and showed superior heterogeneous catalytic activity, which was maintained for a number of cycles or reuse under an aerobic environment. Furthermore, the supramolecular catalyst showed unprecedented selectivity for the multifunctional coupling reaction and was able to serve as a new constructor of asymmetrical compounds. PMID- 28707759 TI - Columnar dyskeratosis-A clue to Wong-type dermatomyositis? PMID- 28707760 TI - Should deep sedation be used during all catheter ablation procedures as a routine? PMID- 28707761 TI - Letter to 'Novel approach to uterine artery pseudoaneurysm embolization for delayed post-partum hemorrhage': Thrombin really necessary? PMID- 28707762 TI - Pharmacokinetics and tissue distribution study of clevidipine and its primary metabolite H152/81 in rats. AB - This present study was designed to investigate the pharmacokinetic profiles and tissue distribution characteristics of clevidipine and its primary metabolite H152/81 in rats following a single intravenous administration of clevidipine butyrate injectable emulsion. For this study, a sensitive and selective liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was established and validated for the simultaneous quantitation of clevidipine and H152/81 in rat whole blood and various tissues. A Hedera ODS-2 column with two gradient elution programs was employed for the troubleshooting of matrix effect on the detection of analytes among different biological samples. The experimental data showed that clevidipine represented quick elimination from blood with a half-life of about 4.3 min and rapid distribution in all of the investigated tissues after administration; the highest concentration of clevidipine was found in the heart whereas the lowest concentration was detected in the liver. In addition, clevidipine was almost undetectable in most tissues except for heart and brain at 90 min post-dosing, suggesting that there was no apparent long-term accumulation in rat tissues. For H152/81, the peak concentration of 3714 +/- 319 ng/mL occurred at 0.129 +/- 0.048 h, the half-life was 10.08 +/- 1.45 h and area under the concentration-time curve was 42091 +/- 3812 ng h/mL after drug administration. In addition, H152/81 was found at significant concentration levels in all tissues, in descending order of lung, kidney, heart, liver, spleen and brain at each time point. The results of current study offer useful clues for better understanding the distribution and metabolism of clevidipine butyrate injectable emulsion in vivo. PMID- 28707763 TI - In vivo knockdown of antisense non-coding mitochondrial RNAs by a lentiviral encoded shRNA inhibits melanoma tumor growth and lung colonization. AB - The family of non-coding mitochondrial RNAs (ncmtRNA) is differentially expressed according to proliferative status. Normal proliferating cells express sense (SncmtRNA) and antisense ncmtRNAs (ASncmtRNAs), whereas tumor cells express SncmtRNA and downregulate ASncmtRNAs. Knockdown of ASncmtRNAs with oligonucleotides induces apoptotic cell death of tumor cells, leaving normal cells unaffected, suggesting a potential application for developing a novel cancer therapy. In this study, we knocked down the ASncmtRNAs in melanoma cell lines with a lentiviral-encoded shRNA approach. Transduction with lentiviral constructs targeted to the ASncmtRNAs induced apoptosis in murine B16F10 and human A375 melanoma cells in vitro and significantly retarded B16F10 primary tumor growth in vivo. Moreover, the treatment drastically reduced the number of lung metastatic foci in a tail vein injection assay, compared to controls. These results provide additional proof of concept to the knockdown of ncmtRNAs for cancer therapy and validate lentiviral-shRNA vectors for gene therapy. PMID- 28707764 TI - Development of systemic lupus erythematosus 5 years after onset of thrombotic thrombocytopenic purpura. PMID- 28707765 TI - Tissue microarray methodology identifies complement pathway activation and dysregulation in progressive multiple sclerosis. AB - The complement pathway has potential contributions to both white (WM) and grey matter (GM) pathology in Multiple Sclerosis (MS). A quantitative assessment of complement involvement is lacking. Here we describe the use of Tissue MicroArray (TMA) methodology in conjunction with immunohistochemistry to investigate the localization of complement pathway proteins in progressive MS cortical GM and subcortical WM. Antibodies targeting complement proteins C1q, C3b, regulatory proteins C1 inhibitor (C1INH, complement receptor 1 (CR1), clusterin, factor H (FH) and the C5a anaphylatoxin receptor (C5aR) were utilised alongside standard markers of tissue pathology. All stained slides were digitised for quantitative analysis. We found that numbers of cells immunolabelled for HLA-DR, GFAP, C5aR, C1q and C3b were increased in WM lesions (WML) and GM lesions (GML) compared to normal appearing WM (NAWM) and GM (NAGM), respectively. The complement regulators C1INH, CR1, FH and clusterin were more abundant in WM lesions, while the number of C1q+ neurons were increased and the number of C1INH+, clusterin+, FH+ and CR1+ neurons decreased in GM lesions. The number of complement component positive cells (C1q, C3b) correlated with complement regulator expression in WM, but there was no statistical association between complement activation and regulator expression in the GM. We conclude that TMA methodology and quantitative analysis provides evidence of complement dysregulation in MS GML, including an association of the numerical density of C1q+ cells with tissue lesions. Our work confirms that complement activation and dysregulation occur in all cases of progressive MS and suggest that complement may provide potential biomarkers of the disease. PMID- 28707766 TI - Fe-Containing Zeolites for NH3 -SCR of NOx : Effect of Structure, Synthesis Procedure, and Chemical Composition on Catalytic Performance and Stability. AB - The direct preparation of different iron-containing Beta and CHA zeolites has been attempted under diverse synthesis conditions, including in alkaline and fluoride media, to evaluate the influence of their physicochemical properties on the selective catalytic reduction (SCR) of NOx using NH3 as reductant. Of the different Fe-Beta zeolites, the sample prepared in the absence of alkali cations with a Si/Al ratio of around 13 showed high NO conversion values (>90 %). However, this catalyst suffered from severe deactivation when aged at high temperatures in the presence of steam. The preparation of more hydrophobic Fe Beta zeolites did not improve the resistance of the catalyst against steam. In contrast, Fe-CHA zeolites prepared by a one-pot method under alkaline conditions with a Si/Al ratio of around 13 by using N,N,N-trimethyladamantylammonium as template not only showed excellent catalytic activity but also high hydrothermal stability, especially when sodium cations were selectively removed. Moreover, the Fe-CHA material synthesized by using the less expensive tetraethylammonium template also resulted in an active and hydrothermally stable catalyst. PMID- 28707767 TI - If, Why, and When Subjective Well-Being Influences Health, and Future Needed Research. AB - We review evidence on whether subjective well-being (SWB) can influence health, why it might do so, and what we know about the conditions where this is more or less likely to occur. This review also explores how various methodological approaches inform the study of the connections between subjective well-being and health and longevity outcomes. Our review of this growing literature indicates areas where data are substantial and where much more research is needed. We conclude that SWB can sometimes influence health, and review a number of reasons why it does so. A key open question is when it does and does not do so-in terms of populations likely to be affected, types of SWB that are most influential (including which might be harmful), and types of health and illnesses that are most likely to be affected. We also describe additional types of research that are now much needed in this burgeoning area of interest, for example, cross cultural studies, animal research, and experimental interventions designed to raise long-term SWB and assess the effects on physical health. This research area is characterised both by potentially extremely important findings, and also by pivotal research issues and questions. PMID- 28707768 TI - Schwannoma of the breast: A common tumor in an uncommon location. PMID- 28707769 TI - Embryonic development of Eucorydia yasumatsui Asahina, with special reference to external morphology (Insecta: Blattodea, Corydiidae). AB - As the first step in the comparative embryological study of Blattodea, with the aim of reconstructing the groundplan and phylogeny of Dictyoptera and Polyneoptera, the embryonic development of a corydiid was examined and described in detail using Eucorydia yasumatsui. Ten to fifteen micropyles are localized on the ventral side of the egg, and aggregated symbiont bacterial "mycetomes" are found in the egg. The embryo is formed by the fusion of paired blastodermal regions, with higher cellular density on the ventral side of the egg. This type of embryo formation, regarded as one of the embryological autapomorphies of Polyneoptera, was first demonstrated for "Blattaria" in the present study. The embryo undergoes embryogenesis of the short germ band type, and elongates to its full length on the ventral side of the egg. The embryo undergoes katatrepsis and dorsal closure, and then finally, it acquires its definitive form, keeping its original position on the ventral side of the egg, with its anteroposterior axis never reversed throughout development. The information obtained was compared with that of previous studies on other insects. "Micropyles grouped on the ventral side of the egg" is thought to be a part of the groundplan of Dictyoptera, and "possession of bacteria in the form of mycetomes" to be an apomorphic groundplan of Blattodea. Corydiid embryos were revealed to perform blastokinesis of the "non reversion type (N)", as reported in blaberoid cockroaches other than Corydiidae ("Ectobiidae," Blaberidae, etc.) and in Mantodea; the embryos of blattoid cockroaches (Blattidae and Cryptocercidae) and Isoptera undergo blastokinesis of the "reversion type (R)," in which the anteroposterior axis of the embryo is reversed during blastokinesis. Dictyopteran blastokinesis types can be summarized as "Mantodea (N) + Blattodea [= Blaberoidea (N) + Blattoidea (R) + Isoptera (R)]". PMID- 28707770 TI - Comparison of the paracrine activity of mesenchymal stem cells derived from human umbilical cord, amniotic membrane and adipose tissue. AB - AIM: The study was conducted to investigate secretory activity and define the paracrine potential of mesenchymal stem cells from human umbilical cord and amniotic membrane (UC-MSCs and AM-MSCs, respectively). METHODS: UC-MSCs (n = 6) were obtained from tissue explants using an adherent method after two weeks of incubation. AM-MSCs (n = 6) were obtained by digestion with tripsin and collagenase. MSC phenotype was confirmed in vitro by performing flow cytometry, differentiation assays and vimentin staining. Supernatants were collected after 48 h culturing in serum-free conditions and the following concentrations were determined: epidermal growth factor (EGF), interleukin (IL)-6, IL-10, tumor necrosis factor-alpha, transforming growth factor-beta (TGF-beta), vascular endothelial growth factor-alpha (VEGF-alpha) and metalloproteinase (MMP) 1, 8 and 13, using multiplex supernatant cytokine assay. Data were compared with adipose tissue derived MSCs (AD-MSCs, n = 6). RESULTS: Both UC-MSC and AM-MSC populations were positively identified as MSCs by flow cytometry and differentiation potential into bone, cartilage and adipose tissue. Using a multiple cytokine detection assay, we proved that both UC-MSCs and AM-MSCs show high secretive capacity. However, the secretion profile differed between cells from various sources. UC-MSCs showed significantly higher production of TGF-beta and lower production of VEGF-alpha, compared to AD-MSCs (P = 0.004) and AM-MSCs (P = 0.039) and lower levels of EGF (P = 0005). AM-MSCs showed significantly lower levels of MMP-8 than UC-MSCs (P = 0.024); however, there was no difference in levels of released cytokines compared to AD-MSCs. CONCLUSION: AM-MSCs show similar IL production as AD-MSCs, while UC-MSCs have a significantly different profile, which suggests diverse biological potential of both cell types for immunomodulative and regenerative therapy. PMID- 28707771 TI - Effect of vaginal progesterone in tocolytic therapy during preterm labor in twin pregnancies: Secondary analysis of a placebo-controlled randomized trial. AB - AIM: Our aim was to investigate the effect of the prophylactic use of vaginal progesterone on the latency period from the initiation of tocolytic therapy to delivery in twin pregnancies with preterm labor. METHODS: This study was a secondary analysis of a randomized, double-blind, placebo-controlled trial of twin pregnancies in mothers who were exposed to a 200 mg vaginal progesterone ovule or a placebo ovule daily from 18 to 34 weeks gestation. Patients who were administered tocolysis with Atosiban because of preterm labor were included. The latency from tocolysis to delivery, mean gestational age at delivery and the rates of delivery within 48 h and within seven days were compared between progesterone and placebo groups. RESULTS: The analysis included 27 women in the progesterone group and 30 in the placebo group. The baseline characteristics were similar between the groups. Overall, there were no differences in the latency period to delivery (17.54 +/- 13.54 days and 21.58 +/- 13.52 days; P = 0.289), rates of delivery within 48 h (14.8% and 6.7%; P = 0.40) or within seven days (29.64% and 23.3%; P = 0.76) or mean gestational age at delivery (32.53 +/- 3.33 and 34.13 +/- 2.87; P = 0.08) between the progesterone and placebo groups, respectively. CONCLUSIONS: Prophylactic use of 200 mg of vaginal progesterone does not influence the latency to delivery in women with twin pregnancies treated with tocolysis because of preterm labor. PMID- 28707772 TI - Clinicopathological characteristics of desmoplastic ameloblastoma: A systematic review. AB - The aim of the present review was to systematically present the clinicopathological data of desmoplastic ameloblastoma (DA) from articles published in the literature. A comprehensive search of the databases (PubMed, Medline, SCOPUS, Web of Science, and Google Scholar) for published articles on DA was conducted. A total of 238 cases were identified and analyzed from 76 published papers. DA showed a slight male predilection (male: female=1.07:1) with a predominance in the fourth and fifth decades of life. Mandibular involvement (52.55%) was most commonly seen with a marked tendency for the anterior region (mandible: 40.9%, maxilla: 48.07%). The size of the lesion ranged from .5 cm to 20.4 cm, with the majority of cases measuring more than 3 cm in size (53.84%). Radiologically, most of the lesions presented mixed radiolucency and radiopacity (62%), and root resorption was observed in only seven cases. The majority of the lesions showed ill-defined margins upon radiographic examination (65.78%). Most of the cases were treated with resection (78.57%), and five of the 10 recurrent cases were treated by enucleation/curettage. DA is characterized by the unique presentation of clinicopathological parameters. It is not possible to comment on its aggressive/recurrent nature and best treatment modality due to inadequate follow-up data. PMID- 28707773 TI - Sudden onset of pheochromocytoma multisystem crisis at 38 weeks of gestation resulted in intrauterine fetal death: A case report. AB - A 24-year-old woman at 38 weeks of gestation with no past medical history was transferred to our hospital because of acute onset of severe dyspnea. Her conscious level was E4V2M5 on the Glasgow Coma Scale and she displayed stress cardiomyopathy (Takotsubo cardiomyopathy) with multiple organ failure. Intrauterine fetal death was confirmed. After immediate application of intubated ventilation, percutaneous cardiopulmonary support and hemodialysis, she was diagnosed with pheochromocytoma multisystem crisis. After multidisciplinary team discussion, surgical resection of the left pheochromocytoma was performed on the same day. However, the bleeding from retroperitoneal drainage did not decrease, therefore, on the fourth day of hospitalization, embolization of the left renal artery under angiography was performed. A 2774 g female infant was stillborn spontaneously on the seventh day of hospitalization. Percutaneous cardiopulmonary support was discontinued on the fifth day of hospitalization and the tracheal tube was extubated on the 11th day. The patient was discharged after 30 days. PMID- 28707774 TI - Hsa_circ_0020397 regulates colorectal cancer cell viability, apoptosis and invasion by promoting the expression of the miR-138 targets TERT and PD-L1. AB - Colorectal cancer (CRC) is a common human gastrointestinal cancer, and recent studies indicate that circular RNA (circRNA) may regulate cancer development. In this study, we assess the role of circRNA specifically in colorectal cancer. Our quantitative PCR assays demonstrate an upregulation of the circRNA has_circ_0020397 and a downregulation of miR-138 in CRC cells, as well as a negative correlation between these two. Using a dual-luciferase reporter assay, we show evidence of miR-138-binding sites on hsa_circ_0020397, and that overexpression of hsa_circ_0020397 could inhibit the downregulation of luciferase activity by miR-138. Although hsa_circ_0020397 did not influence miR-138 expression per se, has_circ_0020397 did inhibit miR-138 activity, as examined via the expression of miR-138 targets telomerase reverse transcriptase (TERT) and programmed death-ligand 1 (PD-L1). Control treatments with plasmids overexpressing linear hsa_circ_0020397 did not have these effects. Hsa_circ_0020397 promoted cell viability and invasion of CRC cells and inhibited their apoptosis, whereas miR-138 had the opposite effect. Nevertheless, hsa_circ_0020397 antagonized miR-138 suppression of cell growth. When TERT or PD L1 expression was suppressed with siRNAs, the above functions of hsa_circ_0020397 were attenuated, suggesting that hsa_circ_0020397 can regulate CRC cell viability, apoptosis and invasion by promoting the expression of miR-138 target genes. These findings support the role of circRNA in CRC pathogenesis. PMID- 28707775 TI - Giant fetal hydrometrocolpos associated with cloacal anomaly causing postnatal respiratory distress. AB - Persistent cloaca is a rare presentation wherein the urethra, vagina, and rectum converge into a common channel with a single perineal opening. Fetal hydrometrocolpos can result if fluid accumulates behind an obstruction of this common channel. A 29-year-old woman (G4P1021) was referred at 36 2/7 weeks of gestation for evaluation of a fetal abdominal cystic mass. Detailed ultrasonography and magnetic resonance imaging showed two symmetric cystic masses, bilateral hydronephrosis, and oligohydramnios. Elective cesarean delivery was performed at 37 0/7 weeks; the baby weighed 4043 g with Apgar scores of 5 and 6 at 1 and 5 min. Intubation was performed for respiratory distress, and the infant was noted to have an imperforate anus; persistent cloaca was diagnosed. Drainage of the hydrometrocolpos improved the infant's breathing remarkably, and extubation was achieved. This child's imaging findings are among the largest ever reported, and resulted in neonatal respiratory distress. PMID- 28707776 TI - Re: Effect of beam profile measurement on arc therapy plan quality assurance: A case study. PMID- 28707777 TI - Pain Assessment Discrepancies: A Cross-Sectional Study Highlights the Amount of Underrated Pain. AB - BACKGROUND: Inadequately treated postoperative pain can lead to longer healing processes, longer hospital stays, and the development of chronic pain. In a 900 bed university hospital in Switzerland, pain scores were assessed systematically. The study's primary aim was to define whether the routine pain assessment on the ward is accurate and reproducible. Subsequently the obtained data were used for a benchmark analysis to determine the hospital's performance in pain assessment quality compared with similar centers. METHODS: During a 3-month period, PAIN OUT questionnaires were used for patients' interviews. Patients were included randomly according to the daily surgical schedule. Pain scores were assessed routinely by nursing staff on the wards and compared to PAIN OUT data. The ascertained data were analyzed by descriptive statistics as well as the Wilcoxon test for nonparametric values using IBM SPSS. RESULTS: 658 patients were included in the study. Comparing routine pain measurements with PAIN OUT results revealed that within the first 24 hours on the ward, pain scores were significantly lower than measured with PAIN OUT questionnaires. This difference increased with increasing pain scores. The quality of pain management of the hospital in which this study was performed ranged around the 50th percentile when compared to similar centers. CONCLUSION: The cross-sectional data comparison of pain assessment by the ward staff and by interviews with the PAIN OUT questionnaire showed a large gap of underrated pain. The benchmark analysis with the method of PAIN OUT suggests a decent pain management among reference groups. PMID- 28707778 TI - Role of quantitative hepatitis B core antibody levels in predicting significant liver inflammation in chronic hepatitis B patients with normal or near-normal alanine aminotransferase levels. AB - AIM: Chronic hepatitis B (CHB) patients with normal alanine aminotransferase (ALT) levels are not free from significant hepatic lesions. Recently, there has been an improved understanding of the clinical significance of quantitative hepatitis B core antibody levels (qAnti-HBc) during CHB management. In this cross sectional study, we evaluated the utility of qAnti-HBc in identifying significant liver inflammation in CHB patients. METHODS: A total of 469 patients (training set, n = 363; validation set, n = 106) who underwent liver biopsy (LB) were included. The qAnti-HBc levels were quantified and the relationship between histology and serum markers was systematically analyzed. RESULTS: In the training set, qAnti-HBc levels were found to have significant diagnostic value for moderate to severe liver inflammation (>=G2) in all patients (area under the receiver operating characteristic curve [AUROC] = 0.768; 95% confidence interval [CI], 0.721-0.810; P < 0.001) and in patients with normal or near-normal ALT levels (AUROC = 0.767; 95% CI, 0.697-0.828; P < 0.001). Our novel index (AC index) for the identification of >=G2 inflammation, which combined the qAnti-HBc and ALT levels, significantly improved diagnostic performance (AUROC = 0.813; 95% CI, 0.768-0.852) compared to the use of ALT alone (AUROC = 0.779; 95% CI, 0.732 0.821) in all patients. In the validation set, the AC index showed an improved AUROC of 0.890 (95% CI, 0.814-0.942) and 0.867 (95% CI, 0.749-0.943) in all patients and patients with normal ALT levels, respectively. CONCLUSIONS: The qAnti-HBc level predicts significant liver inflammation well, even in patients with normal or near-normal ALT levels. Compared with the conventional ALT level, the AC index is a more reliable non-invasive biomarker for significant liver inflammation in CHB patients. PMID- 28707779 TI - Belatacept Rescue Therapy in Kidney Transplant Recipients With Vascular Lesions: A Case Control Study. AB - Immunosuppression in kidney transplant recipients with decreased graft function and severe histological vascular changes can be particularly challenging. Belatacept could be a valuable option, as a rescue therapy in this context. We report a retrospective case control study comparing a CNI to belatacept switch in 17 patients with vascular damage and low eGFR to a control group of 18 matched patients with CNI continuation. Belatacept switch was performed on average 51.5 months after kidney transplantation (6.2-198 months). There was no difference between the two groups regarding eGFR at inclusion, and 3 months before inclusion. In the "CNI to belatacept switch group," mean eGFR increased significantly from 23.5 +/- 6.7 mL/min/1.73m2 on day 0, to 30.4 +/- 9.1 mL/min/1.73 m2 on month 6 (p < 0.001) compared to the control group, in which no improvement was observed. These results were still significant on month 12. Two patients experienced biopsy-proven acute rejection. One was effectively treated without belatacept discontinuation. Two patients needed belatacept discontinuation for infection. In conclusion, the remplacement of CNI with belatacept in patients with decreased allograft function and vascular lesions is associated with an improvement in eGFR. PMID- 28707780 TI - Long non-coding RNA LINC00261 inhibits cell growth and migration in endometriosis. AB - AIM: A previous study reported that LINC00261 is significantly downregulated in human ectopic endometrial tissues. The present study aimed to explore whether LINC00261 is functional in endometriosis cell proliferation, apoptosis and migration. METHODS: By transfecting human endometriosis cell line CRL-7566 with plasmids containing LINC00261, we successfully established the cell CRL 7566/LINC00261 with a high LINC00261 expression level. Cell-counting kit-8 and colony formation assays were conducted to evaluate the effect of LINC00261 on cell proliferation, and flow cytometry analysis and transwell migration assay were conducted to evaluate its effect on cell apoptosis and cell migration, respectively. RESULTS: Cell-counting kit-8 and colony formation assays both indicated that LINC00261 could inhibit cell proliferation in CRL-7566. Flow cytometry analysis confirmed that LINC00261 mediated inhibition of cell proliferation, which might be a consequence of inducting apoptosis. Furthermore, transwell migration assay indicated that LINC00261 could inhibit cell migration in endometriosis. CONCLUSION: LncRNA LINC00261 is capable of inhibiting cell growth and migration in endometriosis. PMID- 28707781 TI - John Cunningham virus conversion in relation to natalizumab concentration in multiple sclerosis patients. AB - BACKGROUND AND PURPOSE: Infection with the John Cunningham virus (JCV) is required for the development of progressive multifocal leukoencephalopathy, the feared complication of natalizumab treatment in multiple sclerosis patients. The JCV seroconversion rate seems higher in natalizumab treated patients than in the normal population, with an unknown cause. METHODS: Natalizumab concentration was correlated to JCV antibody status and seroconversion in a large cohort of multiple sclerosis patients. RESULTS: One hundred and thirty-five patients were included. No correlation was found between natalizumab concentration and JCV status, JCV seroconversion or JCV index. CONCLUSIONS: Higher natalizumab concentrations do not explain the increased JCV seroconversion rate in natalizumab treated patients. PMID- 28707782 TI - Exchanging implements: the micro-materialities of multidisciplinary work in the operating theatre. AB - Surgical procedures rely upon an array of commonplace tools, implements and materials that mediate practice and disciplinary collaboration within the operating theatre. Substantial time is dedicated to the issue and provision of these artefacts and their timely exchange is critical to the successful accomplishment of surgical procedures. In this article, we consider the practice, knowledge and agency that informs how particular implements and materials are passed by the scrub nurse to the surgeon that in turn enables their deployment with regard to the particular procedure and the contingencies 'at hand'. We address the technicalities of these 'non-technical skills' and examine how they rely upon a disciplinary vision and interactional organisation that informs both the scrutiny of action and the ways in which implements and materials are handled and exchanged. We explore the implications of our analysis for our understanding of agency in action and the growing interest in developing robots or autonomous agents to support work and collaboration in health care. PMID- 28707783 TI - Aggressive necrotizing pseudomonal sinonasal infections. AB - BACKGROUND: Pseudomonas aeruginosa is a gram-negative bacterium frequently implicated in recalcitrant sinonasal infections, especially in immunocompromised hosts. We report 6 cases of rapidly progressive pseudomonal acute rhinosinusitis producing tissue necrosis and, in certain cases, cranial nerve palsies. METHODS: Retrospective review of 6 patients with aggressive necrotizing sinonasal infections treated at 4 tertiary academic medical centers with sinonasal cultures growing P. aeruginosa in the absence of other pathology. RESULTS: A total of 6 patients were identified. In all cases, there was tissue necrosis that appeared to mimic an invasive process such as mucormycosis, prompting urgent surgical intervention. Pathologic analysis revealed fibropurulent exudates in backgrounds of positive P. aeruginosa cultures without evidence of invasive fungal organisms or malignancy. Four of the 6 patients presented with cranial nerve palsies, with 3 patients having vision changes and 3 complaining of trigeminal neuropathy. Four of 6 patients improved clinically over time after surgery and antibiotic therapy; 1 remains in follow-up without complete improvement and 1 has succumbed to other causes. CONCLUSION: P. aeruginosa is a tenacious organism that is frequently associated with severe, recalcitrant sinonasal infections. We report the first case series of necrotizing sinonasal infections caused by this organism, and illustrate that, in rare cases, P. aeruginosa may mimic and behave like life threatening conditions such as fulminant invasive fungal sinusitis or malignancy. PMID- 28707784 TI - Separator Decoration with Cobalt/Nitrogen Codoped Carbon for Highly Efficient Polysulfide Confinement in Lithium-Sulfur Batteries. AB - A macro-/mesoporous Co-N-C-decorated separator is proposed to confine and reutilize migrating polysulfides. Endowed with a desirable structure and synchronous lithio- and sulfiphilic chemistry, the macro-/mesoporous Co-N-C interface manipulates large polysulfide adsorption uptake, enabling good polysulfide adsorption kinetics, reversible electrocatalysis toward redox of anchored polysulfides, and facile charge transport. It significantly boosts the performance of a simple 70 wt % S/MWCNTs (MWCNTs=multi-walled carbon nanotubes) cathode, achieving high initial capacities (e.g., 1406 mAh g-1 at 0.2C, 1203 mAh g-1 at 1C), nearly 100 % Coulombic efficiencies, and high reversible capacities after cycle tests (e.g., 828.4 mAh g-1 at 1C after 100 cycles) at both low and high current rates. These results demonstrate that decorating separator with macro-/mesoporous Co-N-C paves a feasible way for developing advanced Li-S batteries. PMID- 28707785 TI - Equine hepacivirus persistent infection in a horse with chronic wasting. AB - Equine hepacivirus is the closest homologue of hepatitis C virus. Limited data on the clinical features of this infection are available. We report the identification of a horse with high-titre viremia by equine hepacivirus. Over a 15-month follow-up, the clinical signs and the viremic status persisted, suggesting a chronic evolution. PMID- 28707786 TI - Letter: Mendelian randomisation to investigate moderate alcohol consumption in nonalcoholic fatty liver disease; modest effects need large numbers-authors' reply. PMID- 28707787 TI - Editorial: mesalazine to prevent recurrent acute diverticulitis-the final nail in the coffin. Authors' reply. PMID- 28707788 TI - Editorial: different tests for different drugs in Crohn's disease, or different tests for different people? Authors' reply. PMID- 28707789 TI - Editorial: migration studies to determine risk and cause of inflammatory bowel disease. PMID- 28707790 TI - Letter: Mendelian randomisation to investigate moderate alcohol consumption in nonalcoholic fatty liver disease; modest effects need large numbers. PMID- 28707791 TI - Editorial: liver transplantation in patients with non-alcoholic fatty liver disease and obesity. PMID- 28707792 TI - Editorial: migration studies to determine risk and cause of inflammatory bowel disease-authors' reply. PMID- 28707793 TI - Editorial: changing nature of paediatric IBD-new insights from Irish data. Author's reply. PMID- 28707794 TI - Letter: there is something about the Neutrophil-to-Lymphocyte ratio (NLR)... authors' reply. PMID- 28707795 TI - Editorial: different tests for different drugs in Crohn's disease, or different tests for different people? PMID- 28707796 TI - Editorial: mesalazine to prevent recurrent acute diverticulitis-the final nail in the coffin. PMID- 28707797 TI - Letter: sprue-like enteropathy associated with angiotensin II receptor blockers other than olmesartan-authors'reply. PMID- 28707798 TI - Letter: direct-acting agent therapy and HCV-related Child C cirrhosis. PMID- 28707799 TI - Editorial: liver transplantation in patients with non-alcoholic fatty liver disease and obesity-authors' reply. PMID- 28707800 TI - Letter: liver transplantation for acute HEV infection in cirrhotic patients in France. PMID- 28707801 TI - Letter: there's something about the Neutrophil-to-Lymphocyte ratio (NLR).... PMID- 28707802 TI - Letter: sprue-like enteropathy associated with angiotensin II receptor blockers other than olmesartan. PMID- 28707803 TI - Editorial: changing nature of paediatric IBD-new insights from Irish data. PMID- 28707804 TI - Letter: clinical response to pioglitazone in nonalcoholic steatohepatitis [NASH] treatment-use of pharmacokinetic surrogate. PMID- 28707805 TI - Decreased parvalbumin mRNA levels in cerebellar Purkinje cells in autism. AB - : Recent neuropathology studies in human brains indicate that several areas of the prefrontal cortex have decreased numbers of parvalbumin interneurons or decreased parvalbumin expression in Autism Spectrum disorders (ASD) [Hashemi, Ariza, Rogers, Noctor, & Martinez-Cerdeno, 2017; Zikopoulos & Barbas, ]. These data suggest that a deficit in parvalbumin may be a key neuropathology of ASD and contribute to altered GABAergic inhibition. However, it is unclear if a deficit in parvalbumin is a phenomenon that occurs in regions other than the cerebral cortex. The cerebellum is a major region where neuropathology was first detected in ASD over three decades ago [Bauman & Kemper, ]. In view of the documented association between parvalbumin-expressing neurons and autism, the objective of the present study was to determine if parvalbumin gene expression is also altered in Purkinje neurons of the cerebellum. Radioisotopic in situ hybridization histochemistry was used on human tissue sections from control and ASD brains in order to detect and measure parvalbumin mRNA levels at the single cell level in Purkinje cells of Crus II of the lateral cerebellar hemispheres. Results indicate that parvalbumin mRNA levels are significantly lower in Purkinje cells in ASD compared to control brains. This decrease was not influenced by post-mortem interval or age at death. This result indicates that decreased parvalbumin expression is a more widespread feature of ASD. We discuss how this decrease may be implicated in altered cerebellar output to the cerebral cortex and in key ASD symptoms. Autism Res 2017, 10: 1787-1796. (c) 2017 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: The cerebellum of the brain controls movement and cognition, including memory and language. This study investigated mechanisms of cerebellar function in Autism. Our hypothesis is that parvalbumin, a molecule that controls and coordinate many cellular brain functions, contributes to the excitatory/inhibitory imbalance in Autism. We report that parvalbumin expression is depressed in Purkinje cells of the cerebellum in autism. This finding contributes to elucidate the cellular and molecular underpinings of autism and should provide a direction for future therapies. PMID- 28707806 TI - Selective Adsorption and Separation of Organic Dyes with Spherical Polyelectrolyte Brushes and Compressed Carbon Dioxide. AB - Dye-containing wastewater has caused serious environmental pollution. Herein, rationally designed spherical polyelectrolyte brushes (SPBs) with cationic charges, polystyrene-poly(2-aminoethylmethacrylate hydrochloride) (PS-PAEMH) as the absorbent, and compressed carbon dioxide as the antisolvent are proposed for the separation of the anionic dye eosin Y (EY) from a solution of mixed dyes. The adsorption behavior of EY onto PS-PAEMH was highly dependent on CO2 pressure, contact time, and initial concentration. The maximum adsorption capacity of PS PAEMH was 335.20 mg g-1 . FTIR and UV/Vis measurements proved that the electrostatic interactions between EY and PS-PAEMH played an important role in the absorbance process. The adsorption process fitted the pseudo-second-order kinetic model and Freundlich isotherm model very well. The combined dye and polymer brush could be easily separated through ion exchange by adding an aqueous solution of NaCl. Recovered PS-PAEMH retained a high adsorption capacity even after ten cycles of regeneration. This method provides a simple and effective way to separate ionic materials for environmental engineering. PMID- 28707807 TI - Accuracy of computer-assisted navigation: significant augmentation by facial recognition software. AB - BACKGROUND: Over the past 20 years, image guidance navigation has been used with increasing frequency as an adjunct during sinus and skull base surgery. These devices commonly utilize surface registration, where varying pressure of the registration probe and loss of contact with the face during the skin tracing process can lead to registration inaccuracies, and the number of registration points incorporated is necessarily limited. The aim of this study was to evaluate the use of novel facial recognition software for image guidance registration. METHODS: Consecutive adults undergoing endoscopic sinus surgery (ESS) were prospectively studied. Patients underwent image guidance registration via both conventional surface registration and facial recognition software. The accuracy of both registration processes were measured at the head of the middle turbinate (MTH), middle turbinate axilla (MTA), anterior wall of sphenoid sinus (SS), and nasal tip (NT). RESULTS: Forty-five patients were included in this investigation. Facial recognition was accurate to within a mean of 0.47 mm at the MTH, 0.33 mm at the MTA, 0.39 mm at the SS, and 0.36 mm at the NT. Facial recognition was more accurate than surface registration at the MTH by an average of 0.43 mm (p = 0.002), at the MTA by an average of 0.44 mm (p < 0.001), and at the SS by an average of 0.40 mm (p < 0.001). The integration of facial recognition software did not adversely affect registration time. CONCLUSION: In this prospective study, automated facial recognition software significantly improved the accuracy of image guidance registration when compared to conventional surface registration. PMID- 28707808 TI - Cytotoxic necrotizing factor 1 promotes prostate cancer progression through activating the Cdc42-PAK1 axis. AB - Uropathogenic Escherichia coli (UPEC) is the leading cause of urinary tract infections and plays a role in prostatic carcinogenesis and prostate cancer (PCa) progression. However, the mechanisms through which UPEC promotes PCa development and progression are unclear. Cytotoxic necrotizing factor 1 (CNF1) is one of the most important UPEC toxins and its role in PCa progression has never been studied. We found that UPEC-secreted CNF1 promoted the migration and invasion of PCa cells and PCa metastasis. In vitro studies showed that CNF1 promotes pro migratory and pro-invasive activity through entering PCa cells and activating Cdc42, which subsequently induced PAK1 phosphorylation and up-regulation of MMP-9 expression. CNF1 also promoted pulmonary metastasis in a xenograft mouse model through these mechanisms. PAK1 phosphorylation correlated with advanced grades of PCa in human clinical PCa tissues. These results suggest that CNF1 derived from UPEC plays an important role in PCa progression through activating a Cdc42-PAK1 signal axis and up-regulating the expression of MMP-9. Therefore, surveillance for and treatment of cnf1-carrying UPEC strains may diminish PCa progression and thus have an important clinical therapeutic impact. Copyright (c) 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 28707809 TI - Structural Features of Europium(II)-Containing Cryptates That Influence Relaxivity. AB - EuII -containing complexes were studied with respect to properties relevant to their use as contrast agents for magnetic resonance imaging. The influences of molecular parameters and field strength on relaxivity were studied for a series of EuII -containing cryptates and their adducts with beta-cyclodextrins, poly beta-cyclodextrins, and human serum albumin. Solid- and solution-phase characterization of EuII -containing complexes is presented that demonstrates the presence of inner-sphere molecules of water. Additionally, relaxivity, water exchange rate, rotational correlation time, and electronic relaxation times were determined using variable-temperature 17 O NMR, nuclear magnetic relaxation dispersion, and electron paramagnetic resonance spectroscopic techniques. These results are expected to be instrumental in the design of future EuII -based contrast agents. PMID- 28707811 TI - Systemic Inflammation and Endothelial Dysfunction-a Possible Link Between Osteoarthritis and Hypertension: Comment on the Article by Niu et al. PMID- 28707810 TI - Curative effect of 1.88-mg and 3.75-mg gonadotrophin-releasing hormone agonist on stage III-IV endometriosis: Randomized controlled study. AB - AIM: To compare the therapeutic effect of 1.88-mg and 3.75-mg gonadotrophin releasing hormone agonist (GnRHa) in the treatment of stage III-IV endometriosis after laparoscopic surgery. METHODS: Fifty patients with stage III-IV endometriosis diagnosed on laparoscopy were randomized into two groups according to GnRHa dose. Sex hormone level, symptoms of estrogen deficiency and lumbar vertebrae bone density were compared and analyzed between the two groups. RESULTS: Bone density was decreased in both groups at 20 weeks after treatment, and the degree of bone density loss in the full-dose group (5.6%) was higher than in the half-dose group (1.2%; P < 0.05). Surgery combined with the 3.75-mg GnRHa or with the 1.88-mg GnRHa relieved the degree of dysmenorrhea, although one case of light dysmenorrhea occurred in each group, but there was no significant difference (P > 0.05) after resumption of menstruation. Both groups had symptoms of perimenopause at 8 weeks after treatment (P > 0.05), but change in Kupperman score with time differed between the groups. At 16, 20 weeks after treatment, the symptoms of perimenopause in the half-dose group were improved, and Kupperman score was lower than at 8 weeks after treatment. In the full-dose group, however, Kupperman score was higher than at 8 weeks after treatment and higher than in the half-dose group (P < 0.05). After treatment, follicle-stimulating hormone and luteinizing hormone both decreased in both groups (P < 0.05), but there was no difference between the two groups (P > 0.05). Estradiol (E2) in the full-dose group was significantly lower than in the half-dose group (P < 0.05). CONCLUSION: The 1.88-mg GnRHa treatment can be used in III-IV endometriosis patients after laparoscopic surgery, to reduce perimenopausal symptoms, significantly improve bone loss, and achieve a good clinical effect. PMID- 28707812 TI - Anti-N-methyl-D-aspartate receptor encephalitis and Epstein-Barr virus: another tale on autoimmunity? PMID- 28707813 TI - Response to comments on: 'Respiratory impairment in multiple sclerosis: a study of respiratory function in wheelchair-bound patients'. PMID- 28707814 TI - Prognosis of status epilepticus in adults: recent advances and future directions. PMID- 28707816 TI - Management of ureteral endometriosis with hydronephrosis: Experience from a tertiary medical center. AB - AIM: We report the clinical characteristics and experience of the surgical management of ureteral endometriosis in our institution. METHODS: We retrospectively reviewed the data of patients with hydronephrosis resulting from ureteral endometriosis. RESULTS: Forty-six patients with different degrees of hydronephrosis were included in the study; 35% had urinary tract symptoms. Concomitant involvement of the ipsilateral ovary occurred in more than two-thirds of the patients. Four patients had nephrectomy, one of which involved ureterolysis because of hydronephrosis recurrence six months later. CONCLUSIONS: Hydronephrosis may be caused by uncommon reasons, such as ureteral endometriosis, which can even cause silent loss of renal function. Routine ultrasound scanning of the upper urinary tract for severe stages of endometriosis is very important in order to detect any potential ureteral lesions. Ureterolysis should be considered as the first surgical step, not only to avoid iatrogenic ureteral injuries but also to better evaluate ureter involvement for further procedures. To warrant tension-free and lesion-free anastomosis, it is wise to perform ureteroneocystostomy for long-term sound results. PMID- 28707817 TI - Evaluation of free or anchored antimicrobial peptides as candidates for the prevention of orthopaedic device-related infections. AB - The prevention of implant-associated infection, one the most feared complications in orthopaedic surgery, remains a major clinical challenge and urges development of effective methods to prevent bacterial colonization of implanted devices. Alpha-helical antimicrobial peptides (AMPs) may be promising candidates in this respect due to their potent and broad-spectrum antimicrobial activity, their low tendency to elicit resistance and possible retention of efficacy in the immobilized state. The aim of this study was to evaluate the potential of five different helical AMPs, the cathelicidins BMAP-27 and BMAP-28, their (1-18) fragments and the rationally designed, artificial P19(9/G7) peptide, for the prevention of orthopaedic implant infections. Peptides were effective at micromolar concentrations against 22 Staphylococcus and Streptococcus isolates from orthopaedic infections, while only BMAP-28 and to a lesser extent BMAP-27 were active against Enterococcus faecalis. Peptides in solution showed activities comparable to those of cefazolin and linezolid, on a molar basis, and also a variable capacity to neutralize bacterial lipopolysaccharide, while devoid of adverse effects on MG-63 osteoblast cells at concentrations corresponding to the MIC. The (1-18) BMAP fragments and P19(9/G7) were selected for further examination, based on better selectivity indices, and showed effectiveness in the presence of hyaluronic acid and in synovial fluid, while human serum affected their activity to variable extents, with BMAP-27(1-18) best retaining activity. This peptide was immobilized on streptavidin-resin beads and retained activity against reference Staphylococcus epidermidis and Staphylococcus aureus strains, with negligible toxicity towards osteoblasts, underlining its potential for the development of infection-resistant biomaterials for orthopaedic application. Copyright (c) 2017 European Peptide Society and John Wiley & Sons, Ltd. PMID- 28707818 TI - Inhibition of fibroblast growth factor receptor with AZD4547 mitigates juvenile nasopharyngeal angiofibroma. AB - BACKGROUND: Juvenile nasopharyngeal angiofibroma (JNA) is a benign tumor that presents in adolescent males. Although surgical excision is the mainstay of treatment, recurrences complicate treatment. There is a need to develop less invasive approaches for management. JNA tumors are composed of fibroblasts and vascular endothelial cells. We identified fibroblast growth factor receptor (FGFR) and vascular endothelial growth factor (VEGF) expression in JNA-derived fibroblasts. FGFR influences fibroblast proliferation and VEGF is necessary for angiogenesis. We hypothesized that targeting FGFR would mitigate JNA fibroblast proliferation, invasion, and migration, and that targeting the VEGF receptor would attenuate endothelial tubule formation. METHODS: After informed consent, fibroblasts from JNA explants of 3 patients were isolated. Fibroblasts were treated with FGFR inhibitor AZD4547, 0 to 25 MUg/mL for 72 hours and proliferation was quantified using CyQuant assay. Migration and invasion of JNA were assessed using 24-hour transwell assays with subsequent fixation and quantification. Mitigation of FGFR and downstream signaling was evaluated by immunoblotting. Tubule formation was assessed in human umbilical vein endothelial cells (HUVECs) treated with vehicle control (dimethylsulfoxide [DMSO]) or semaxanib (SU5416) as well as in serum-free media (SFM) or JNA conditioned media (CM). Tubule length was compared between treatment groups. RESULTS: Compared to control, AZD4547 inhibited JNA fibroblast proliferation, migration, and invasion through inhibition of FGFR and downstream signaling, specifically phosphorylation of - p44/42 mitogen activated protein kinase (p44/42 MAPK). JNA fibroblast CM significantly increased HUVEC tubule formation (p = 0.0039). CONCLUSION: AZD4547 effectively mitigates FGFR signaling and decreases JNA fibroblast proliferation, migration, and invasion. SU5416 attenuated JNA fibroblast-induced tubule formation. AZD4547 may have therapeutic potential in the treatment of JNA. PMID- 28707819 TI - Catalytic Regio- and Enantioselective [4+2] Annulation Reactions of Non-activated Allenes by a Chiral Cationic Indium Complex. AB - Regio- and enantioselective [4+2] annulation between beta,gamma-unsaturated alpha keto esters and non-activated allenes was achieved by using a chiral cationic indium(III)/phosphate catalyst. The reaction affords the corresponding C3 selective dihydropyrans in good yields and with high enantioselectivity (up to 99 % ee). PMID- 28707820 TI - Isolation, identification and retrospective study of foot-and-mouth disease virus from affected Mithun (Bos frontalis) in north-eastern India. AB - Foot-and-mouth disease (FMD) is a contagious disease of cloven-hoofed animals that causes substantial and perpetual economic loss. Apart from the contagious nature of the disease, the FMD virus can establish in a "carrier state" among all cloven-hoofed animals. The Mithun (Bos frontalis), popularly called the "Cattle of Mountain," is found in the geographically isolated, hilly region of north-east India: Arunachal Pradesh, Nagaland, Manipur and Mizoram. Despite the geographical inaccessibility, infection by FMD virus has emerged as the single most devastating disease among Mithun after the eradication of rinderpest from this region. Samples from outbreaks of FMD in Mithun were analysed by sandwich ELISA, multiplex RT-PCR (MRT-PCR) and liquid-phase blocking enzyme-linked immunosorbent assay and isolated in the BHK-21 cell line. The results indicate the presence of FMDV serotype "O." The sequencing and molecular phylogenies have revealed close relationships in the lineage of type "O" isolates from Bangladesh. The findings will provide useful information for further research and development of a sustainable programme for the progressive control of FMD in the Mithun population. PMID- 28707821 TI - Splenic Vein Thrombosis Following Pancreas Transplantation: Identification of Factors That Support Conservative Management. AB - Prophylaxis for graft portal/splenic venous thrombosis following pancreas transplant varies between institutions. Similarly, treatment of venous thrombosis ranges from early re-exploration to conservative management with anticoagulation. We wished to determine the prevalence of graft splenic vein (SV) thrombosis, as well as the clinical significance of non-occlusive thrombus observed on routine imaging. Records of 112 pancreas transplant recipients over a 5-year period at a single center were reviewed. Venous thrombosis was defined as absence of flow or presence of thrombus identified in any part of the graft SV on ultrasound. Thirty patients (27%) had some degree of thrombus or absence of flow in the SV on postoperative ultrasound. There were 5 graft losses in this group. Four were due to venous thrombosis, and occurred within 20 days of transplant. All patients with non-occlusive partial SV thrombus but normal arterial signal on Doppler ultrasound were successfully treated with IV heparin followed by warfarin for 3-6 months, and remained insulin independent. Findings of arterial signal abnormalities, such as absence or reversal of diastolic flow within the graft, require urgent operative intervention since this finding can be associated with more extensive thrombus that may lead to graft loss. PMID- 28707827 TI - Cat scratch disease: U.S. clinicians' experience and knowledge. AB - Cat scratch disease (CSD) is a zoonotic infection caused primarily by the bacterium Bartonella henselae. An estimated 12,000 outpatients and 500 inpatients are diagnosed with CSD annually, yet little is known regarding clinician experience with and treatment of CSD in the United States. Questions assessing clinical burden, treatment and prevention of CSD were posed to 3,011 primary care providers (family practitioners, internists, paediatricians and nurse practitioners) during 2014-2015 as part of the annual nationwide DocStyles survey. Among the clinicians surveyed, 37.2% indicated that they had diagnosed at least one patient with CSD in the prior year. Clinicians in the Pacific and Southern regions were more likely to have diagnosed CSD, as were clinicians who saw paediatric patients, regardless of specialty. When presented with a question regarding treatment of uncomplicated CSD, only 12.5% of clinicians chose the recommended treatment option of analgesics and monitoring, while 71.4% selected antibiotics and 13.4% selected lymph node aspiration. In a scenario concerning CSD prevention in immunosuppressed patients, 80.6% of clinicians chose some form of precaution, but less than one-third chose the recommended option of counseling patients to treat their cats for fleas and avoid rough play with their cats. Results from this study indicate that a substantial proportion of U.S. clinicians have diagnosed CSD within the past year. Although published guidelines exist for treatment and prevention of CSD, these findings suggest that knowledge gaps remain. Therefore, targeted educational efforts about CSD may benefit primary care providers. PMID- 28707828 TI - ? PMID- 28707829 TI - [Total Hip arthroplasty in patients younger than 50 years]. AB - Total hip replacement can provide pain relief and restore function in patients suffering from hip arthritis, including in those under the age of 50. However, shortened implant longevity in this age group has been a concern because the clinical results after revision surgery are inferior to those after primary hip arthroplasty. Technical choices (approach, implants, type of fixation and bearing couple) must be made to maximise longevity based on published data and thoroughly discussed with the patient. Finally, long term results (clinical outcome and implant longevity) associated with this surgery are such that it appears unnecessary to postpone the surgery once the indication is established. PMID- 28707830 TI - [Patients with metal-on-metal hip arthroplasty: evaluation and management of complications]. AB - The potentially severe complications related to metal-on-metal (MoM) hip replacements have led to a dramatic decrease of their use. Large diameter heads are more likely to fail than smaller diameters, but complications have been described even with " small " diameters. Therefore, monitoring of MoM arthroplasties is mandatory. This includes physical examination, X-Rays, metal ion levels, and potentially cross-sectional imaging. Despite pathophysiology of adverse reactions to metal debris (ARMD) is better understood, their evolution and the potential systemic complications remain unclear. Symptomatic hip arthroplasties, elevated ions levels, and ARMD may lead to revision of the components. In such a situation, an adaquate stategy must be achieved given the high potential for complications. PMID- 28707831 TI - [Prevention of perioperative infections in orthopaedic surgery - Role of general practitioner]. AB - Total joint replacement comes with a high success rate and has been shown to have a very positive impact on our patients suffering from arthritis. Against all efforts about 2 % of our patients will suffer an implant related infection. As the treatment of infected arthroplasties is difficult and expensive the knowledge of risk factors is becoming more and more important for the treatment team in order to improve our preventive measures. Prevention must be performed pre-, intra- and postoperatively. Preoperative optimization of blood sugar levels, nutritional status and correction of general anaemia for example are paramount and the general practitioner as well as the surgeon should be aware of these and other modifiable risk factors in order to operate on the patient in the best possible conditions. PMID- 28707832 TI - [Surgical management of the spinal metastases]. AB - Seventy per cent of patients with cancer have evidence of metastases and spinal involvement may occur in up to 50 %. Pain is the most frequent symptom and it occurs in 90 % of the patients. It exist three different type of spinal pain : inflammatory, radicular and mechanical pain. Pain could be related to a neurological compromise and treatment becomes urgent. Steroids are introduced even if surgery is indicated. The Spinal Instability Neoplastic Score is a useful tool in order to determine instability in spinal metastases. Early recognition of instability could allow to minimal invasive surgery and even vertebroplasty. Tokuhashi score facilitates patient's selection during the decision-making process to the multidisciplinary team. PMID- 28707833 TI - [Sarcoma centres : a necessary tool in the management of patients and for research.] AB - Sarcomas are rare diseases, the treatment of which requires an appropriate technical plateform and a broad spectrum of multidisciplinary specialists. Many are initially treated by unplanned excision, and then referred to specialized centres. Secondary treatments may lead to higher complication rates and local recurrence, with lower functional outcome, life quality and possibly overall survival. In order to improve the accessibility for referral to a specialist centre, the coordination of clinical and research activities, and the quality of the management of sarcomas in general, Lausanne University Hospital (CHUV) has opened a Sarcoma centre on October 1st 2016. The objective of the present paper is to illustrate the concept and provide useful clinical recommendations. PMID- 28707834 TI - [Update on the treatment of articular cartilage lesions in the knee]. AB - Despite articular cartilage lesions being common, there is no evidence-based treatment protocol for them. The preoperative assessment must diagnose all of the concurrent pathologies that need to be treated at the same time. Several types of treatments exist, and each has its advantages and disadvantages. First-line therapy consists of well-conducted conservative treatment. Surgical treatment is the second choice. It is chosen according to the size of the lesion, its depth, damage to the subchondral bone, and the condition of the neighboring cartilage. The few studies that have compared the different methods used to treat these lesions have reported contradictory results. PMID- 28707835 TI - ? PMID- 28707836 TI - ? PMID- 28707837 TI - ? PMID- 28707838 TI - ? PMID- 28707840 TI - ? AB - L'article " L'urogeriatrie du medecin generaliste " [ Frequent uro-geriatric symptoms : helpful tools for general practitioners], Rev Med Suisse 2016;12:2077 82 [PMID: 28700153] paru dans le numero 541 du 30 novembre 2016 de la Revue medicale suisse, a egalement ete coecrit par le Dr Caroline Carera Sager, Service d'urologie, HUG, Geneve. Les auteurs sont donc : Drs Guillaume Altwegg, Jacques Klein, Gregory Wirth, Caroline Carera Sager et Pr Christophe E. Iselin. PMID- 28707839 TI - ? PMID- 28707841 TI - ? PMID- 28707842 TI - Leisure time physical activity and risk of prostate cancer: a dose-response meta analysis. AB - INTRODUCTION: Physical activity (PA) may be a protect factor against prostate cancer (PCa). We aim to investigate and establish the potential relationship between leisure time PA and PCa. EVIDENCE ACQUISITION: PubMed, Embase databases were searched for eligible studies (cohort) before Aug-11, 2016. We conducted a meta-analysis to pool the dose-specific effects between leisure time PA and PCa. Subgroup analysis was employed to investigate the potential variation among each group. Sensitivity analysis was used to examine whether our results were stable. EVIDENCE SYNTHESIS: Twenty-one cohort studies were identified, with a total of 803,872 subjects and 28,707 PCa cases. In our meta-analysis, no obvious evidence of non-linear relationship was observed. The RRs of each 500 MET-s/week increment of leisure time PA was 1.00 (95% CI: 0.99-1.01) for total PCa, 1.00 (95% CI: 0.98 1.01) for local PCa, and 1.00 (95% CI: 0.98-1.02) for advanced PCa. In subgroup analysis, for Americans, the RR of each 500 MET-s/week increment of leisure time PA was 1.00 (95% CI: 0.99-1.01); and for Europeans the RR was 1.00 (95% CI: 0.99 1.01). Sensitivity analysis suggested our results were stable. CONCLUSIONS: Current evidence based on observational studies suggests no obvious association between leisure time activity and risk of prostate cancer, regardless of total PCa, local PCa, or advanced PCa. PMID- 28707843 TI - Health information quality on the internet for bladder cancer and urinary diversion: a multi-lingual analysis. AB - INTRODUCTION: Bladder cancer patients undergoing radical cystectomy and urinary diversion are faced with difficult decisions regarding mode of urinary diversion. Although these patients may use the Internet as a guide to diagnosis and treatment options, online resources remain largely unregulated leading to a great variation in quality of medical information. Further variation in quality is seen between languages. Fortunately, tools such as an automated toolbar developed by the World Health Organization Health on the Net (HON) Foundation exist to assist physicians in recommending quality online health information to patients. We set out to compare and assess the quality of bladder cancer, ileal conduit and orthotopic neobladder web sites in 2016 on the basis of the HON principles for English language. EVIDENCE ACQUISITION: The Google search engine imbedded with the HON toolbar was used to assess 1350 Web sites using the keywords "bladder cancer", "ileal conduit" and "orthotopic neobladder" in English, Italian and Spanish. The first 150 results of each search were identified and screened. A further analysis was completed comparing results between 2009 and 2016. EVIDENCE SYNTHESIS: Less than 20% of English, Italian and Spanish "bladder cancer" and urinary diversion ("ileal conduit" and "orthotopic neobladder") web sites are HON accredited. HON-accredited web sites featured preferentially in the first 50 search results for bladder cancer (P=0.0001) and ileal conduit (P=0.03) web sites. Comparing 2016 results to 2009, percentage of HON-accreditation has not shown statistically significant change (-13%, P=0.23), while overall number of search results has increased (+44%). CONCLUSIONS: A lack of validation of bladder cancer sites is present, which is consistent across modes of urinary diversion (orthotopic neobladder and ileal conduit) and languages. It is important that physicians involved in the care of bladder cancer patients undergoing radical cystectomy and urinary diversion participate in the development of informative, ethical, and reliable health Web sites and direct patients to them. PMID- 28707845 TI - Clinical ethics: what the anesthesiologist and the intensivist need to know. AB - Clinical ethics if often perceived as an intuitive understanding of what is right versus wrong. This is insufficient for healthcare workers in general, but particularly for anesthesiologists and intensivists, who often must weigh up complex and emergent life or death decisions and subsequently justify these decisions to their team and patients, as well as patient's families. Articulating the rationale for such decisions is an arduous task. Thus, a brief introduction to the basic conceptual framework and vocabulary of clinical ethics may be useful to this population of physicians. The most important concept is that interventions offered should be both clinically appropriate and ethically proportionate, desirable by both the patient and the medical team, and offering a meaningful benefit to the patient within the context of his or her own life narrative. This puts an emphasis on understanding, from the patient or his/her proxies, not just who the patient is biologically but also biographically: that is what gives meaning to his/her life subjectively, and what quality of life would be compatible with this level of functioning, as well as when he/she would wish life sustaining therapy to be withheld or withdrawn. PMID- 28707844 TI - Castration-resistance prostate cancer: what is in the pipeline? AB - INTRODUCTION: To evaluate the available evidence on the standard diagnosis and management of men with metastatic castration resistant prostate cancer (mCRPC), and providing the timely update on new pharmacological treatments. EVIDENCE ACQUISITION: A systematic literature search from from January 2000 until March 2017 was performed by combining the following MESH terms: castrate resistant prostate cancer, abiraterone, enzalutamide, 223radium, sipuleucel-T, docetaxel, cabazitaxel, resistance mechanisms, resistance to androgen deprivation, androgen receptor (AR) mutations, amplifications, splice variants, and AR alterations. We followed the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA). EVIDENCE SYNTHESIS: In the few last years the introduction of new treatment modalities as abiraterone or enzalutamide have significantly change our prospective in mCRPC management increasing patients survival and quality of life. The standard imaging modalities to define the presence of regional or distant metastasis or the different resistant mechanisms to the available treatments are still an issue of debate, however several studies are ongoing to define the standard of care and to reduce treatments' resistance. Data from ongoing phase III trials are awaited to introduce in clinical new effective treatments that can be used in patients resistant to abiraterone/enzalutamide or more probably in a different phase of the disease. CONCLUSIONS: Castration resistant prostate cancer is now the key issue in prostate cancer management and research. Our challenge in the near future will be to identify the right treatment or better the right combination and sequencing of treatments that should be used in patients with mCRPC or even with advanced prostate cancer. PMID- 28707846 TI - Palliative sedation: ethical aspects. AB - Palliative sedation (PS), the medical act of decreasing a patient's awareness to relieve otherwise intractable suffering, is considered by some commentators to be controversial because of its consequences on residual survival and/or quality of life, and to be inappropriate for treating pure existential suffering. We will argue that PS must be always proportional, i.e. controlling refractory symptoms while keeping the loss of personal values (communication, affective relationships, care relationship) as low as possible, and that imminence of death is necessary too, from an ethical point of view, if a deep and continuous sedation (DCS) is proposed. Moreover, in case of pure existential suffering DCS should only be considered after repeated trials of respite sedation. The use of progressive consent and advance care planning to share the decision with the patient and to involve the family in the decision process as much as the patient desires is another ethical aspect to be pursued. Producing, implementing and sustaining guidelines at the higher scientific and professional level promise to help in improving both clinical and ethical aspects of the practice of PS. PMID- 28707847 TI - Is sedation for endoscopy as safe as you think? PMID- 28707848 TI - Frontiers in non-invasive cardiac mapping: future implications for arrhythmia treatment. AB - Electrocardiographic mapping (ECM) is a noninvasive technique using body surface potentials and CT geometry to reconstruct epicardial maps. ECM is emerging as an important tool not only for diagnostic mapping, but also as a guide for trans catheter ablation of complex arrhythmias such as atrial fibrillation. It provides the clinician with an immediate global view of the substrate, allowing easier pre procedural planning, potentially improving clinical outcomes. Panoramic mapping of ventricular fibrillation (VF) is helping to develop a better understanding of its physiology, with future implications for the identification of therapeutic targets in patients with structural heart disease, as well as in idiopathic VF. PMID- 28707849 TI - Malnutrition after bariatric surgery. AB - BACKGROUND: Malnutrition is a rare but severe complication following obesity surgery. Our objective was to analyze these cases of malnutrition and their management at the Grenoble University Hospital. METHODS: Retrospective data between 2006 to 2016 was analyzed from Department of Medical Information, Severe Obesity Outcome Network, and register of the Department of Artificial Nutrition. Data collected concerned age, sex, anthropometric data, surgical procedures and history of obesity surgery, initial surgical follow-up, delay from surgery, nutritional characteristics, nutritional and surgical management, follow-up and outcomes. RESULTS: Six patients had protein malnutrition after obesity surgery. Five patients (N.=5/6 83%) were initially operated on in other establishments. Only 1 patient in the cohort of 484 patients operated at on our institution was suffering from malnutrition (N.=1/484, 0.2%). All patients showed an excess weight loss of over 100%. Albumin level averaged 24.8 g/L at time of diagnosis. Patients were mainly operated on for an omega bypass (N.=4/6, 66%). Delay of malnutrition was 17.25 months in this category of patients whereas it was 84 months in patients having been operated on by another intervention. 3 patients (i.e. 50%) had chronic kidney disease when their initial surgery was performed. Two patients presented acute idiopathic pancreatitis following obesity surgery. CONCLUSIONS: Patients are at risk of malnutrition, especially after omega bypass and in patients with chronic kidney disease. Occurrence of acute pancreatitis is an alert to the risk of malnutrition. PMID- 28707850 TI - The Virtues of Scientific Practice: MacIntyre,Virtue Ethics, and the Historiography of Science. AB - "Practice" has become a ubiquitous term in the history of science,and yet historians have not always reflected on its philosophical import andin particular on its potential connections with ethics. This essay draws on thework of the virtue ethicist Alasdair MacIntyre to develop a theory of "communalpractices" and explore how such an approach can inform the historyof science, including allegations about the corruption of science by wealth orpower, consideration of scientific ethics or "moral economies," the role of valuesin science, the ethical distinctiveness (or not) of scientific vocations, andthe relationship between history of science and the practice of science itself. PMID- 28707851 TI - Fertility preservation options in prepubertal females: feasibility, safety and outcomes. AB - Fertility preservation is a developing area of reproductive biology and successes in adult populations has led to an emerging interest in prepubertal populations. Advances in treatment strategies for many disease processes including childhood cancer means that many patients now survive their initial diagnosis. Ovarian insufficiency is a recognized side-effect of chemotherapy and as such advances in reproductive technologies are now possible to attempt to overcome the so called late effects. Questions regarding the outcomes and safety of these treatments still exist. A review of the available literature with regard to fertility preservation options in prepubertal females was undertaken with consideration given to the need for options, availability of options, safety of available techniques and current outcomes. The new discipline of onco-fertility is rapidly advancing. Work to facilitate accurate and robust identification of those in need of fertility preservation and the optimization of strategies for fertility restoration are ongoing. With time it is hoped that the techniques used to freeze store ovarian tissue and to conduct auto-transplantation will undergo refinement and so advance from the research arena into mainstream clinical practice. Further research is likely to be fruitful and will offer significant hope to those at risk of premature ovarian insufficiency whether from underlying genetic causes or as a result of ablative therapies. It is important that research advancements are disseminated widely as this will help to inform clinical practitioners, nurses and counsellors of strategies and to ensure that appropriate treatments are offered to patients who are at risk of fertility loss. PMID- 28707852 TI - Medicine and the Making of a City:Spaces of Pharmacy and Scholarly Medicinein Seventeenth-Century Stockholm. AB - This essay takes seventeenth-century Stockholm as its point of departurein discussing the many spaces to which early modern medicine belonged,in particular the court, the cityscape, the site of the pharmacy, and thecity's Collegium Medicum. It shows how scholarly medicine and pharmacyarose along with the city itself. They were a part of the city and of its many interlacedlocal, European, and global flows and relationships. Thus the essay offersnew perspectives on medicine as part of, and a driving force behind, Stockholm'stransition from a medieval town to the capital of an early modern state,as well as the city's integration into the early modern system of global trade. Italso shows how a switch of perspective may relocate pharmacy to the centerof the seventeenth century medical world. By focusing on the city, rather thanon specific professional groups, the essay seeks to problematize the alleged specialimportance of physicians for early modern medicine and the view that physiciansheld a superior status in relation to other medical practitioners, as wellas to artisans/craftsmen. PMID- 28707853 TI - The East India Company, the Company'sMuseum, and the Political Economy of NaturalHistory in the Early Nineteenth Century. AB - At the turn of the nineteenth century, at its headquarters in the Cityof London, the Honourable East India Company established a new museumand library. By midcentury this museum would contain one of Europe's mostextensive collections of the natural history, arts, and sciences of Asia. This essayuses the early history of the company's museum, focusing in particular onits natural history collections, to explore the material relationship betweenscientific practice and the imperial political economy. Much of the collectionshad been gathered in the wake of military campaigns, trade missions, or administrativesurveys. Once specimens and reports arrived in Leadenhall Streetand passed through the museum storage areas, this plunder would become thestuff of science, going on to feed the growth of disciplines, societies, and projectsin Britain and beyond. In this way, the East India Company was integralto the information and communication infrastructures within which manysciences then operated. Collections-based disciplines and societies flourishedin this period; their growth, it is argued, was coextensive with administrativeand political economic change at institutions like the East India Company.The essay first explores the company's practices and patterns of collecting andthen considers the consequences of this accumulation for aspects of scientificpractice-particularly the growth of scientific societies in both London and Calcutta. PMID- 28707854 TI - A Eurasian Mineralogy: Aleksandr Fersman'sConception of the Natural World. AB - Thoroughly a product of imperial Russia's aristocratic culture, themineralogist and geochemist Aleksandr Fersman rose to the top of the country'sscientific establishment after the Bolsheviks took control. He then remained astaunch supporter of various industrial projects through much of the Stalinistperiod. This essay puts Fersman's thinking about the natural world in conversationwith a quite distinctive mode of intellectual inquiry that developed contemporaneously.Eurasianism was a philosophical doctrine of a group of Russianemigres who emphasized Russia's unique status straddling Europe and Asia.While Fersman did not belong to this group of thinkers, a number of his ideasdrew on specific experiences in the environments of the Eurasian landmass.Indeed, the article argues that Fersman's dualistic understanding of nature, hisadvocacy for the field of geochemistry, his definition of deserts, and a schemehe proposed for industrial operations owed much to the Eurasian settings ofthe science he practiced. Furthermore, this case of a Eurasian mineralogist illuminatesnovel aspects of the interplay between national and global sciences. PMID- 28707855 TI - Science and Orthodox Christianity:An Overview and Six Comments. PMID- 28707856 TI - Science and Orthodox Christianity:An Overview. AB - This essay offers an overview of the history of the relations between scienceand Eastern Christianity based on Greek-language sources. The civilizations concernedare the Byzantine Empire, the Christian Orthodox communities of the OttomanEmpire, and modern Greece, as a case study of a national state. Beginning withthe Greek Church Fathers, the essay investigates the ideas of theologians and scholarson nature. Neoplatonism, the theological debates of Iconoclasm and Hesychasm, theproposed union of the Eastern and Western Churches, and the complex relations withthe Hellenic past all had notable impacts on the conception of science held by theByzantine Orthodox. From the sixteenth through the eighteenth centuries, the ChristianOrthodox world did not actively participate in the making of the new science thatwas developing in modern Europe. It had to deal with the assimilation of scientificideas produced by Western Christianity, and its main concern was the "legitimacy" ofknowledge that did not originate directly from its own spiritual tradition. Finally, withregard to the Greek state, beyond the specific points of contact between the sciencesand Orthodox Christianity pertaining, for example, to materialism, evolution, andthe calendar-the essay presents the constant background engagement with religionvisible in most public pronouncements of scientists and intellectuals. PMID- 28707857 TI - Debunking the myth of low incidence of intracranial aneurysms in the Middle East and North Africa. PMID- 28707858 TI - Should anterior cervical discectomy and fusion be performed on a Parkinson's patient? PMID- 28707859 TI - Independent predictors for functional outcome after drainage of chronic subdural hematoma identified using a logistic regression model. AB - BACKGROUND: Chronic subdural hematoma (CSDH) is a common indication for undergoing neurosurgery, but the outcome may remain limited despite timely surgical treatment. The factors potentially associated with the functional outcome have not been sufficiently investigated. We set out to identify independent predictors associated with the functional outcome after surgical treatment of CSDH, avoiding arbitrary classifications and thresholds or subjective imaging assessment. METHODS: We retrospectively reviewed 197 consecutive surgical cases of CSDH. Univariate and multivariate analyses were performed to identify the relationship between clinical plus radiographic factors and outcome. Imaging analysis was performed using computer-assisted 3D-volumetric analysis. RESULTS: One-hundred and sixty four (83.2%) patients had a favorable (GOS grade 5 and 4) and 33 (16.8%) an unfavorable clinical outcome (GOS grade 1 3). The multivariate logistic regression analysis determined 4 independent prognostic factors: age over or under 77 years, preoperative clinical condition (Markwalder Score), recurrence and surgical technique applied. Patients treated with mini-craniotomy procedures had worse outcomes than those treated with single or two burr-hole craniostomies. The percentage of the hematoma drained correlated strongly with recurrence and was by itself not an independent predictor for outcome. CONCLUSIONS: In our study age, pre-operative neurological status, surgical technique and recurrence were found to be independent prognostic factors for the functional outcome in patients with CSDH. PMID- 28707860 TI - Theology and Science in the Orthodox World:Some Doubts from a Latin Perspective. AB - Efthymios Nicolaidis et alii open their essay with what amounts to a paradox:they maintain that Orthodox Christianity "scarcely participated in the making of thenew European science" but also quote John William Draper's positive assessment ofthe openness of the Orthodox Church to the sciences. Whether they manage to resolvethis paradox is unclear. This response to their overview suggests that they neglect twokey elements: the categorical difference between medieval scientia and modern science;and the role of institutions such as universities and scientific societies. Furthermore,to gauge the relation of Orthodox Christianity to modern science, one wouldalso have had to take the Russian Orthodox Church into account, as after the fall ofConstantinople the Greek Orthodox Church was deprived of much of its political andinstitutional power. PMID- 28707862 TI - Gastric emptying and related symptoms in patients treated with buspirone, amitriptyline or clebopride: a "real world" study by 13C-octanoic Acid Breath Test. AB - BACKGROUND: Gastric motility is a key-factor in the pathogenesis of functional dyspepsia (FD). 13C-octanoic Acid Breath Test (OBT) is a tool used for measuring gastric emptying time in clinical setting. We aimed to investigate the variation in FD symptoms and OBT parameters after treatment with buspirone, amitriptyline or clebopride. METHODS: Between Jan-2007 and Dec-2014, we enrolled 59 patients with FD unresponsive to first-line therapy with proton pump inhibitors and/or domperidone that underwent OBT before and after 3 months of buspirone (N.=32), amitriptyline (N.=16) or clebopride (N.=11) treatment. RESULTS: Early satiation severity was positively correlated with gastric half emptying time (t1/2) (r=0.3789, P=0.003) and gastric lag phase (r=0.3371, P=0.011), and negatively correlated with gastric emptying coefficient (r=-0.3231, P=0.015). A reduction in t1/2 measurement in association to postprandial fullness, and early satiation severity improvement was observed (P=0.009, P=0.005 and P<0.001, respectively). Patients treated with buspirone obtained both a decrease in t1/2 (P=0.005) and an amelioration in early satiation (P=0.001). Patients under amitriptyline treatment experienced an improvement in postprandial fullness (P=0.046), whereas no variation was reported in patients treated with clebopride. CONCLUSIONS: Patients with FD, non-responders to first-line therapy and reporting meal-related discomfort, may benefit from buspirone or amitriptyline-based therapies. PMID- 28707863 TI - Science and Russian Orthodox Scholarship. AB - In Russia the theme of science and religion found its strongest resonance atthe levels of humanistic scholarship and Christianity in general, where visions of harmonydominated and doctrinal and confessional particularity was largely absent. Thefraught relations of both the Holy Synod and the Imperial Academy of Sciences withthe Russian state since the early eighteenth century had the collateral consequenceof minimal institutional contacts between theology and natural philosophy. Though"scientific apologetics" eventually found a place in the seminaries, scientists did notcontribute to this scholarship in the nineteenth century. The rare prominent scientistwho entertained religious beliefs posited either harmony or conflict in public writingseven more rarely, and it is the varieties of religious indifference-not solely Soviet inorigin-that invite historical inquiry. PMID- 28707864 TI - Oxidative stress, antioxidants, and lipid profile in the serum and saliva of individuals with coronary heart disease: is there a link with periodontal health? AB - BACKGROUND: Oxidative stresses and dyslipidemia are an important risk factor in the development of coronary atherosclerotic complications like angina pectoris and myocardial infarction. The aim of this study was to find the relationship between the salivary lipid profile, lipid peroxidation and antioxidants and the periodontal health status of patients with acute coronary heart disease (CHD). METHODS: Forty patients who had experienced a recent attack of angina pectoris or myocardial infarction and another 40 noncardiac patients matched for age, sex and residence (control) were recruited. The lipid profile level, lipid peroxidation and antioxidant status were measured in the serum and saliva of all participants together with lactate dehydrogenase (LDH) and C-reactive protein. The studied parameters were then correlated with the periodontal status of the participant using the Clinical Periodontal Sum Score (CPSS). A multiple linear regression was used to assess the net effect of each set of independent variables on the outcome variable using SPSS-21. A P value <=0.05 was considered statistically significant. RESULTS: Salivary total cholesterol, triglycerides, low density lipoprotein-cholesterol, very low density lipoprotein-cholesterol, malondialdehyde, uric acid, superoxide dismutase and LDH levels increased with the upper tertile of the CPSS, while salivary high-density lipoprotein cholesterol decreased with the upper tertile of the CPSS. CONCLUSIONS: Periodontal health status could be considered as an independent risk factor for acute CHD. PMID- 28707865 TI - Religion and Science in the EasternMediterranean. AB - "Science and Orthodox Christianity: An Overview" is an ambitious surveythat reminds scholars of science in Islamic societies that the conversation between Islamand science is really a conversation between Islam and science in different contextsand that conversations between Islam and science can be found with less renownedscientific developments such as prophetic medicine. This response points out parallelsin how Greek Orthodox and Ottoman Muslim scholars mediated new developmentsin Western European science and in how both Greek Orthodox and some OttomanMuslim scholars propounded a mathematical humanism. Finally, it argues that theaccount of post-1453 scientific exchange is more complex than "Science and OrthodoxChristianity" intimates. At the least, if there was no scholarly exchange betweenGreek Orthodox Christians, on the one hand, and, on the other hand, Muslims andJews-who, in turn, enjoyed scholarly exchange with the West well after 1453-thereare clearly two different Easts. PMID- 28707866 TI - Two Orthodoxies and Science:Comparative Reflections. AB - This essay offers a comparative discussion of attitudes to science within Jewishand Christian Orthodoxies. When it touches on the contemporary period, it dealswith different varieties of Jewish Orthodoxy rather than the more liberal Jewish denominations.Debates about science and religion, rarely involving active let aloneprominent-scientists, take place within both religious traditions. The issues can beroughly divided in two categories-cognitive and social-even though the two mayoccasionally intersect. The first category, apparently more important for the Greek Orthodox,addresses issues of the content of research and of its influence on ethics. Socialissues constitute the other important aspect of the interaction between religion andmodernity: Is it desirable to spend time on anything but religious studies and to engagein modern society at all, lest its more permissive norms and ideas corrupt proper behavior?This aspect seems to preoccupy Jewish Orthodoxy more than Greek Orthodoxy. PMID- 28707867 TI - Science, Eastern Orthodoxy, andProtestantism. AB - This essay considers some of the major theological differences between Easternand Western traditions of Christianity and puts forward proposals about how thesemight be related to the divergent trajectories of the formal study of nature in these twocultural contexts. A key difference lies in the "other-worldly" orientation of Eastern Orthodoxyand its emphasis on deification, which contrast sharply with ideas of originalsin and fall-redemption theology in the West. These latter ideas came to play a significantrole in the rise of Western science, with the sciences being understood as part ofa practical redemptive exercise that could help alleviate the material consequences oforiginal sin. PMID- 28707869 TI - Science, Eastern Orthodoxy, andWorld Religions. AB - The history of Orthodoxy and science invites contrasts with other religioustraditions. In contradistinction to the Latin West, for example, Eastern Orthodoxythroughout its history embraced the "pagan" scientific achievements of ancientGreece. Also unlike in the West, where ecclesiastical institutions often supportedscientific activities, scholars in the East-in both the Byzantine and Ottoman periods-relied primarily on temporal sources to sustain their investigations of nature.Islam, with its strenuous resistance to any assimilation of the human to the divine, providesanother contrasting example, as does the later Protestant justification for sciencegrounded in the need to restore a fallen world through the application of experimentalresearch. Not surprisingly, Eastern Orthodox believers seem to have paid little attentionto non-Christian faiths, with the exception of Islam and Judaism, until well intothe twentieth century. PMID- 28707870 TI - News of the Profession: Eloge. PMID- 28707871 TI - A Copernican Renaissance? PMID- 28707872 TI - Povidone-Iodine-Based Polymeric Nanoparticles for Antibacterial Applications. AB - As microbial contamination is becoming more and more serious, antibacterial agents play an important role in preventing and removing bacterial pathogens from microbial pollution in our daily life. To solve the issues with water solubility and antibacterial stability of PVP-I2 (povidone-iodine) as a strong antibacterial agent, we successfully obtain hydrophobic povidone-iodine nanoparticles (povidone iodine NPs) by a two-step method related to the advantage of nanotechnology. First, the synthesis of poly(N-vinyl-2-pyrrolidone-co-methyl methacrylate) nanoparticles, i.e., P(NVP-MMA) NPs, was controlled by tuning a feed ratio of NVP to MMA. Then, the products P(NVP-MMA) NPs were allowed to undergo a complexation reaction with iodine, resulting in the formation of a water-insoluble antibacterial material, povidone-iodine NPs. It is found that the feed ratio of NVP to MMA has an active effect on morphology, chemical composition, molecular weight, and hydrophilic-hydrophobic properties of the P(NVP-MMA) copolymer after some technologies, such as SEM, DLS, elemental analysis, 1H NMR, GPC, and the contact angle test, were used in the characterizations. The antibacterial property of povidone-iodine NPs was investigated by using Escherichia coli (E. coli), Staphylococcus aureus (S. aureus), and Pseudomonas aeruginosa (P. aeruginosa) as model bacteria with the colony count method. Interestingly, three products, such as glue, ink, and dye, after the incorporation of povidone-iodine NPs, show significant antibacterial properties. It is believed that, with the advantage of nanoscale morphology, the final povidone-iodine NPs should have great potential for utilization in various fields where antifouling and antibacterial properties are highly required. PMID- 28707873 TI - Light Activation of Calcein Inhibits Vesicle Release of Catecholamines. AB - Calcein, a fluorescent fluid phase marker, has been used to track and visualize cellular processes such as synaptic vesicle fusion. It is also the fluorophore for live cells in the commonly used Live/Dead viability assay. In pilot studies designed to determine fusion pore open size and vesicle movement in secretory cells, imaging analysis revealed that calcein reduced the number of vesicles released from the cells when stimulated with nicotine. Using amperometry to detect individual vesicle release events, we show that when calcein is present in the media, the number of vesicles that fuse with the cellular membrane is reduced when cells are stimulated with either nicotine or high K+. Experimentally, amperometric electrodes are not undergoing fouling in the presence of calcein. We hypothesized that calcein, when activated by light, releases reactive oxygen species that cause a reduction in secreted vesicles. We show that when calcein is protected from light during experimentation, little to no reduction of vesicle secretion occurred. Therefore, photoactivated calcein can cause deleterious results for measurements of cellular processes, likely to be the result of release of reactive oxygen species. PMID- 28707874 TI - Designing Probes for Immunodiagnostics: Structural Insights into an Epitope Targeting Burkholderia Infections. AB - Structure-based epitope prediction drives the design of diagnostic peptidic probes to reveal specific antibodies elicited in response to infections. We previously identified a highly immunoreactive epitope from the peptidoglycan associated lipoprotein (Pal) antigen from Burkholderia pseudomallei, which could also diagnose Burkholderia cepacia infections. Here, considering the high phylogenetic conservation within Burkholderia species, we ask whether cross reactivity can be reciprocally displayed by the synthetic epitope from B. cenocepacia. We perform comparative analyses of the conformational preferences and diagnostic performances of the corresponding epitopes from the two Burkholderia species when presented in the context of the full-length proteins or as isolated peptides. The effects of conformation on the diagnostic potential and cross-reactivity of Pal peptide epitopes are rationalized on the basis of the 1.8 A crystal structure of B. cenocepacia Pal and through computational analyses. Our results are discussed in the context of designing new diagnostic molecules for the early detection of infectious diseases. PMID- 28707875 TI - NIR Ratiometric Luminescence Detection of pH Fluctuation in Living Cells with Hemicyanine Derivative-Assembled Upconversion Nanophosphors. AB - It is crucial for cell physiology to keep the homeostasis of pH, and it is highly demanded yet challenging to develop luminescence resonance energy transfer (LRET) based near-infrared (NIR) ratiometric luminescent sensor for the detection of pH fluctuation with NIR excitation. As promising energy donors for LRET, upconversion nanoparticles (UCNPs) have been widely used to fabricate nanosensors, but the relatively low LRET efficiency limits their application in bioassay. To improve the LRET efficiency, core/shell/shell structured beta NaGdF4@NaYF4:Yb,Tm@NaYF4 UCNPs were prepared and decorated with hemicyanine dyes as an LRET-based NIR ratiometric luminescent pH fluctuation-nanosensor for the first time. The as-developed nanosensor not only exhibits good antidisturbance ability, but it also can reversibly sense pH and linearly sense pH in a range of 6.0-9.0 and 6.8-9.0 from absorption and upconversion emission spectra, respectively. In addition, the nanosensor displays low dark toxicity under physiological temperature, indicating good biocompatibility. Furthermore, live cell imaging results revealed that the sensor can selectively monitor pH fluctuation via ratiometric upconversion luminescence behavior. PMID- 28707876 TI - Fluorescence Light-Up Biosensor for MicroRNA Based on the Distance-Dependent Photoinduced Electron Transfer. AB - It is demonstrated that miRNAs exhibit significant regulatory roles in a series of biological processes and associated with diverse human diseases. Herein, we report a convenient fluorescent biosensor for the quantitative determination of miR-21, a key miRNA related to cardio-cerebrovascular diseases. Our proposal involves not only the rational design of single stranded DNA as the probe, successively including a C-rich sequence as the synthetic template of DNA/Ag nanoclusters (DNA/AgNCs), a complementary (Com) sequence to hybridize with the miR-21, and a G-rich sequence to form a complex of G-quadruplex/hemin but also the distance-dependent property of photoinduced electron transfer (PET) between the preformed DNA/AgNCs (electron donor) and G-quadruplex/hemin complex (electron acceptor). In the presence of the target miR-21, the initial flexible single strand Com in the probe turns to the rigid Com/RNA heteroduplexes, and then the PET could be interrupted owing to the extended distance between the electron donor and acceptor, accompanying with the fluorescence quenching and recovery of DNA/AgNCs. Therefore, a fluorescence light-up biosensor for miR-21 could be developed through the monitoring of the degree of fluorescence recovery of DNA/AgNCs. Preferential to other previous PET-based detection methods, we construct the biosensor by utilizing the distance dependent property for the first time and only need to adjust the sequences of Com in different miRNAs assays. PMID- 28707877 TI - Free-Energy-Driven Lock/Open Assembly-Based Optical DNA Sensor for Cancer-Related microRNA Detection with a Shortened Time-to-Result. AB - Quantification of cancer biomarker microRNAs (miRs) by exquisitely designed biosensors with a short time-to-result is of great clinical significance. With immobilized capture probes (CPs) and fluorescent-labeled signal probes (SPs), surface-involved sandwich-type (SST) biosensors serve as powerful tools for rapid, highly sensitive, and selective detection of miR in complex matrices as opposed to the conventional techniques. One key challenge for such SST biosensors is the existence of false-negative signals when the amount of miRs exceeds SPs in solution phase for a surface with a limited number of CP. To meet this challenge, a dynamic lock/open DNA assembly was designed to rationally program the pathway for miR/SP hybrids. Based on secondary structure analysis and free-energy assessment, a "locker" strand that partially hybridizes with target miR by two separated short arms was designed to stabilize target miR, preventing possible false-negative signals. The strategy was demonstrated on a fiber-based fluorescent DNA-sensing platform. CP/miR/SP sandwiches formed on the fiber surface would generate fluorescent signals for quantitative analysis. The developed SST biosensor was able to detect miR Hsa let-7a with a detection limit of 24 pM. The applicability of this free-energy-driven lock/open assembly-based optical DNA sensor was further confirmed with spiked human urine and serum samples. PMID- 28707878 TI - Abundant Acceptor Emission from Nitrogen-Doped ZnO Films Prepared by Atomic Layer Deposition under Oxygen-Rich Conditions. AB - Nitrogen-doped and undoped ZnO films were grown by thermal atomic layer deposition (ALD) under oxygen-rich conditions. Low-temperature photoluminescence spectra reveal a dominant donor-related emission at 3.36 eV and characteristic acceptor-related emissions at 3.302 and 3.318 eV. Annealing at 800 degrees C in oxygen atmosphere leads to conversion of conductivity from n- to p-type, which is reflected in photoluminescence spectra. Annealing does not increase any acceptor related emission in the undoped sample, while in the ZnO:N it leads to a considerable enhancement of the photoluminescence at 3.302 eV. The high resolution cathodoluminescence cross-section images show different spatial distribution of the donor-related and the acceptor-related emissions, which complementarily contribute to the overall luminescence of the annealed ZnO:N material. Similar area of both emissions indicates that the acceptor luminescence comes neither from the grain boundaries nor from stacking faults. Moreover, in ZnO:N the acceptor-emission regions are located along the columns of growth, which shows a perspective to achieve a ZnO:N material with homogeneous acceptor conductivity at least at the micrometer scale. PMID- 28707879 TI - Interparticle Interactions in Colloidal Systems: Toward a Comprehensive Mesoscale Model. AB - Intermolecular interactions control the collective behavior of colloidal clusters. The overwhelming majority of literature focuses on cohesive attributes of intermolecular forces as they govern the jamming process. However, the overlooked sliding component plays a critical role in the slow relaxation dynamics of colloidal aggregates and the emergence of discontinuous shear thickening in dense suspensions. Here, we use crystalline calcium-silicate hydrate (C-S-H) as a model system to explore synergistic cohesive and sliding interactions. We use the free energy perturbation approach to reconstruct potential of mean force profile between two finite-sized nanolayers in an aqueous environment. We show that sliding free energy barriers decay exponentially as the separation distance increases. The characteristic length scale of the decay is related to the interface corrugation. We introduce a simple yet effective mechanism to capture the sliding behavior of colloids with surface roughness. Moreover, we develop a global free energy landscape model by juxtaposing cohesive and sliding interactions. This model enables us to measure the height of energy barriers, which is essential to elucidate deformation mechanism and dynamics of colloidal aggregates. For cohesive colloids, our approach predicts a sublinear relation between applied normal and shear stress at the onset of sliding that is in contrast to Amontons' laws of friction. We demonstrate that the sublinear trend is due to the adhesion and nature of soft contact at the nanoscale. The proposed framework provides a new route to draw a more realistic picture of intermolecular interactions in nanoparticulate systems such as geomaterials, cementitious systems, complex colloidal assemblies, and dense suspensions. PMID- 28707880 TI - Pinpoint Chemical Modification of the Quinone-Access Channel of Mitochondrial Complex I via a Two-Step Conjugation Reaction. AB - We previously showed that a bulky ring-strained cycloalkyne possessing a rhodamine fluorophore directly reacts (via strain-promoted click chemistry) with the azido group incorporated (via ligand-directed tosyl chemistry) into Asp160 in the 49 kDa subunit of complex I in bovine heart submitochondrial particles [Masuya, T., et al. (2014) Biochemistry 53, 7816-7823]. This two-step conjugation may be a promising technique for specific chemical modifications of the quinone access channel in complex I by various molecular probes, which would lead to new methodologies for studying the enzyme. However, because the reactivities of ring strained cycloalkynes are generally high, they also react with other nucleophilic amino acids in mitochondrial proteins, resulting in significant undesired side reactions. To minimize side reactions and achieve precise pinpoint chemical modification of 49 kDa Asp160, we investigated an optimal pair of chemical tags for the two-step conjugation reaction. We found that instead of strain-promoted click chemistry, Diels-Alder cycloaddition of a pair of cyclopropene incorporated into 49 kDa Asp160 (via ligand-directed tosyl chemistry) and externally added tetrazine is more efficient for the pinpoint modification. An excess of quinone site inhibitors did not interfere with Diels-Alder cycloaddition between the cyclopropene and tetrazine. These results along with the previous findings (cited above) strongly suggest that in contrast to the predicted quinone-access channel modeled by X-ray crystallographic and single-particle cryo-electron microscopic studies, the channel is open or undergoes large structural rearrangements to allow bulky ligands into the proximity of 49 kDa Asp160. PMID- 28707881 TI - Methane Activations by Titanium Neopentylidene Complexes: Electronic Resilience and Steric Control. AB - The titanium neopentylidene complex (PNP)Ti?CHtBu(CH2tBu) (PNP = N[2-PiPr2-4 methylphenyl]2-) is capable of activating both sp2 and sp3 C-H bonds under mild conditions. In addition to methane C-H activation, competition between the initial hydrogen abstraction reaction to form the methane activation product and the tautomerization reaction of this product to form a terminal methylidene was also explored. Several modifications of the PNP and CHtBu ligands were explored to determine the effect of these changes on C-H bond activation. In general, on the one hand, the modifications involving electronic effects have small and inconsistent influence on the stability of the intermediates and products and on the reaction barriers. On the other hand, the use of bulky groups in the ligands favors the methane activation process. By replacing the iPr groups in the PNP ligand with tBu groups, both methane activation and tautomerization reactions become more energetically favorable than in the unmodified complex. On the one hand, the largest acceleration of the methane C-H activation occurs when tBu groups in the phosphine are combined with an extra CH2 linker between the aromatic ring and the phosphine. On the other hand, replacing the nitrogen in the PNP ligand by phosphorus results in lower barriers for the tautomerization reaction and the stabilization of the product of the tautomerization although it remains slightly less stable than product of methane C-H activation. While several ligand modifications related to the electronic effects were examined, it is interesting that most of them did not make a significant change on the barriers for either reaction, indicating a significant resilience of this titanium complex, which could be used to enhance the practical aspects of the complex without a significant loss of its activity. PMID- 28707882 TI - Improvement of the Cathode Electrolyte Interphase on P2-Na2/3Ni1/3Mn2/3O2 by Atomic Layer Deposition. AB - Atomic layer deposition (ALD) is a commonly used coating technique for lithium ion battery electrodes. Recently, it has been applied to sodium ion battery anode materials. ALD is known to improve the cycling performance, Coulombic efficiency of batteries, and maintain electrode integrity. Here, the electrochemical performance of uncoated P2-Na2/3Ni1/3Mn2/3O2 electrodes is compared to that of ALD-coated Al2O3 P2-Na2/3Ni1/3Mn2/3O2 electrodes. Given that ALD coatings are in the early stage of development for NIB cathode materials, little is known about how ALD coatings, in particular aluminum oxide (Al2O3), affect the electrode electrolyte interface. Therefore, full characterizations of its effects are presented in this work. For the first time, X-ray photoelectron spectroscopy (XPS) is used to elucidate the cathode electrolyte interphase (CEI) on ALD-coated electrodes. It contains less carbonate species and more inorganic species, which allows for fast Na kinetics, resulting in significant increase in Coulombic efficiency and decrease in cathode impedance. The effectiveness of Al2O3 ALD coating is also surprisingly reflected in the enhanced mechanical stability of the particle which prevents particle exfoliation. PMID- 28707883 TI - Noninvasive and Highly Selective Monitoring of Intracellular Glucose via a Two Step Recognition-Based Nanokit. AB - Accurate determination of intracellular glucose is very important for exploring its chemical and biological functions in metabolism events of living cells. In this paper, we developed a new noninvasive and highly selective nanokit for intracellular glucose monitoring via two-step recognition. The liposome-based nanokit coencapsulated the aptamer-functionalized gold nanoparticles (AuNPs) and the Shinkai's receptor together. When the proposed nanokit was transfected into living cells, the Shinkai's receptor could recognize glucose first and then changed its conformation to endow aptamers with binding and sensing properties which were not readily accessible otherwise. Then, the binary complexes formed by the intracellular glucose and the Shinkai's receptor can in situ displace the complementary oligonucleotide of the aptamer on the surface of AuNPs. The fluorophore-labeled aptamer was away from the AuNPs, and the fluorescent state switched from "off" to "on". Through the secondary identification of aptamer, the selectivity of the Shinkai's receptor could be greatly improved while the intracellular glucose level was assessed by fluorescence signal recovery of aptamer. In the follow-up application, the approach exhibits excellent selectivity and is noninvasive for intracellular glucose monitoring under normoxia and hypoxia. To the best of our knowledge, this is the first time that the advantages of organic receptors and nucleic acids have been combined and highly selective monitoring of intracellular glucose has been realized via two step recognition. We expect it to open up new possibilities to integrate devices for diagnosis of various metabolic diseases and insulin delivery. PMID- 28707884 TI - Rapid and Programmable Protein Mutagenesis Using Plasmid Recombineering. AB - Comprehensive and programmable protein mutagenesis is critical for understanding structure-function relationships and improving protein function. There is thus a need for robust and unbiased molecular biological approaches for the construction of the requisite comprehensive protein libraries. Here we demonstrate that plasmid recombineering is a simple and robust in vivo method for the generation of protein mutants for both comprehensive library generation as well as programmable targeting of sequence space. Using the fluorescent protein iLOV as a model target, we build a complete mutagenesis library and find it to be specific and comprehensive, detecting 99.8% of our intended mutations. We then develop a thermostability screen and utilize our comprehensive mutation data to rapidly construct a targeted and multiplexed library that identifies significantly improved variants, thus demonstrating rapid protein engineering in a simple protocol. PMID- 28707885 TI - Continuous and Inexpensive Monitoring of Nonpurgeable Organic Carbon by Coupling High-Efficiency Photo-oxidation Vapor Generation with Miniaturized Point Discharge Optical Emission Spectrometry. AB - Currently, no applicable analyzers are available to accomplish online continuous monitoring of organic pollution, which is one of the most important factors contributing to water shortages around the world, particularly in developing countries. In this work, a sensitive, miniaturized, inexpensive, and online nonpurgeable organic carbon (NPOC) analysis system was developed for continuous monitoring of such organic pollution. This system consists of a specially designed high-efficiency UV photo-oxidation vapor generation (HE-POVG) reactor and a miniaturized, low-power (7 W) point-discharge microplasma optical emission spectrometer (PD-OES). Organics present in sample or standard solutions are pumped to the HE-POVG and efficiently converted into CO2, which is separated and further transported to the PD-OES for NPOC analysis via highly sensitive detection of carbon atomic emission at 193.0 nm. Under optimal conditions, a limit of detection of 0.05 mg.L-1 (as C) is obtained, with precision better than 5.0% (relative standard deviation) at 5 mg.L-1. This system overcomes many shortcomings associated with conventional chemical oxygen demand or total organic carbon analyzers such as long analysis time, use of expensive and toxic chemicals, production of secondary toxic waste, requirement of large, power consuming and expensive instrumentation and difficulties implementing continuous online monitoring. The system was successfully applied to sensitive and accurate determination of NPOC in various water samples and for continuous monitoring of such organic pollution in tap water. PMID- 28707886 TI - Diarylheptanoids from Rhizomes of Alpinia officinarum Inhibit Aggregation of alpha-Synuclein. AB - Two new diarylheptanoids, alpinin A (1) and alpinin B (2), together with 18 known diarylheptanoids (3-20), were isolated from the rhizomes of Alpinia officinarum. Their structures were elucidated by comprehensive spectroscopic analysis, including high-resolution mass spectrometry, infrared spectroscopy, and one- and two-dimensional nuclear magnetic resonance spectroscopy. Structurally, alpinin A is a new member of the small family of oxa-bridged diarylheptanoids and contains the characteristic 2,6-cis-configured tetrahydropyran motif (C1-C5 oxa bridge). The absolute configuration of alpinin A was confirmed by asymmetric total synthesis of the enantiomer (ent-1), corroborating the assignment of the molecular structure. The absolute configuration of alpinin B was determined on the basis of the analysis of the circular dichroism exciton chirality spectrum. We evaluated the inhibitory activity of all isolated diarylheptanoids against alpha-synuclein aggregation at 10 MUM. Alpinins A and B significantly inhibited alpha-synuclein aggregation by 66 and 67%, respectively. PMID- 28707887 TI - Full Characterization of Localization Diversity in the Human Protein Interactome. AB - Spatial-temporal regulation among proteins forms dynamic networks in cells. Coexistence in common cell compartments can improve biological reliability of the protein-protein interactions. However, this is usually overlooked by most proteomic studies and leads to unrealistic discoveries. In this paper, we systematically characterize the interaction localization diversity in the human protein interactome using the localization coefficient, a novel metric proposed for assessing how diversely the interactions localize among cell compartments. Our analysis reveals the following: (1) the subcellular networks of the nucleus, cytosol, and mitochondrion are dense but the interactions tend to localize in specific cell compartments, whereas the subnetworks of the secretory-pathway, membrane, and extracellular region are sparse but the interactions are diversely localized; (2) the housekeeping proteins tend to appear in multiple compartments, while the tissue-specific proteins present a relatively flat profile of localization breadth; (3) the autophagy proteins tend to diversely localize in multiple compartments, especially those with high connectivity, compared with the apoptosis proteins; (4) the proteins targeted by small-molecule drugs show no preference for compartments, whereas the proteins directed by antibody-based drugs tend to belong to transmembrane regions with a strong diversity. In summary, our analysis provides a comprehensive view of the subcellular localization for interacting proteins, demonstrates that localization diversity is an important feature of protein interactions, and shows its ability to highlight meaningful biological functions. PMID- 28707889 TI - Gold Nanorod Mediated Chlorhexidine Microparticle Formation and Near-Infrared Light Induced Release. AB - Gold nanorods (GNR) are good light harvesting species for elaboration of near infrared (NIR) responsive drug delivery systems. Herein, chlorhexidine microparticles are grown directly on the surface of gold nanorods and then stabilized with polyelectrolyte multilayer encapsulation, producing novel composite drug-GNR particles with high drug loading and NIR light sensitivity. Crystallization of chlorhexidine is caused by the ionic strength of the chloride solution that has been demonstrated via formation of a homogeneous porous spherical structure at 0.33 M CaCl2. By introducing GNRs into the CaCl2 solution, the nucleation of chlorhexidine molecules and size of produced spheres are affected, since GNRs act as sites for chlorhexidine nucleation. Similarly, when GNRs are replaced by chlorhexidine seeds (5.2 +/- 1.7 MUm), a core-shell crystal structure is observed. The encapsulated GNR/chlorhexidine composites are responsive to NIR light (840 nm) that increases the temperature at the chlorhexidine crystals, followed by microparticle dissolution and rupture of capsules which is illustrated with confocal microscopy and SEM. Furthermore, a stepwise burst release of chlorhexidine can be induced by multiple cycles of NIR light exposure. The GNR/chlorhexidine composites show good biocompatibility and antimicrobial activity. The proposed method of antibacterial drug release may therefore indicate that this NIR responsive chlorhexidine composite may be useful for future clinical applications. PMID- 28707888 TI - Mechanism of Initiation, Association, and Formation of Amyloid Fibrils Modeled with the N-Terminal Peptide Fragment, IKYLEFIS, of Myoglobin G-Helix. AB - Some peptides and proteins undergo self-aggregation under certain conditions, leading to amyloid fibrils formation, which is related to many disease conditions. It is important to understand such amyloid fibrils formation to provide mechanistic detail that governs the process. A predominantly alpha helical myoglobin has been reported recently to readily form amyloid fibrils at a higher temperature, similar to its G-helix segment. Here, we have investigated the mechanism of amyloid fibrils formation by performing multiple long molecular dynamics simulations (27 MUs) on the N-terminal segment of the G-helix of myoglobin. These simulations resulted in the formation of a single-layered tetrameric beta-sheet with mixed parallel and antiparallel beta-strands and this is the most common event irrespective of many different starting structures. Formation of the single-layered tetrameric beta-sheet takes place following three distinctive pathways. The process of fibril initiation is dependent on temperature. Further, this study provides mechanistic insights into the formation of multilayered fibrilar structure, which could be applicable to a wider variety of peptides or proteins to understand the amyloidogenesis. PMID- 28707891 TI - Correction to "Ultrafast Dynamics of Photongenerated Holes at a CH3OH/TiO2 Rutile Interface". PMID- 28707890 TI - Immersion Depths of Lipid Carbons in Bicelles Measured by Paramagnetic Relaxation Enhancement. AB - Myriads of biological processes occur in or at cellular lipid membranes. Knowledge about the localization of proteins, lipids, and other molecules within biological membranes is thus crucial for the understanding of such processes. Here, we present a method to determine the immersion depths of lipid carbon atoms in membranes by paramagnetic relaxation enhancement (PRE) caused by the presence of doxylated lipids. As membrane mimetics, we employ small isotropic bicelles made of synthetic lipids and of natural Escherichia coli phospholipid extract. Bicelles are particularly suitable for solution state NMR since they maintain a lipid bilayer while they are at the same time amenable to solution state NMR experiments. PREs were measured in the presence of different doxylated lipids with the nitroxide radical located in the headgroup and at various positions in the acyl chain. Theoretical PREs were calculated assuming a simple bicelle model using the Solomon-Bloembergen equations. Immersion depths of the lipid carbon atoms were obtained by a least-squares fit of the theoretical to the experimental PREs. The carbon immersion depths correspond well to results obtained by other methods and differences do not exceed 3-5 A. This means that the method presented here provides sufficient resolution to distinguish the localization of carbons in different regions of the lipid bilayer, despite considerable simplifications of the underlying theory. These simplifications include a simple form of the spectral density function, which we find is sufficient to reliably determine immersion depths. A more complicated spectral density function that includes bicelle, lipid, and local motions may only improve the results if its parametrization is good enough. The approach presented here may be extended to the determination of protein localization in membranes employing realistic membrane mimetics like the bicelles made of E. coli phospholipid extract used here. PMID- 28707892 TI - Redox Electrocatalysis of Floating Nanoparticles: Determining Electrocatalytic Properties without the Influence of Solid Supports. AB - Redox electrocatalysis (catalysis of electron-transfer reactions by floating conductive particles) is discussed from the point-of-view of Fermi level equilibration, and an overall theoretical framework is given. Examples of redox electrocatalysis in solution, in bipolar configuration, and at liquid-liquid interfaces are provided, highlighting that bipolar and liquid-liquid interfacial systems allow the study of the electrocatalytic properties of particles without effects from the support, but only liquid-liquid interfaces allow measurement of the electrocatalytic current directly. Additionally, photoinduced redox electrocatalysis will be of interest, for example, to achieve water splitting. PMID- 28707893 TI - Dislocations in AlGaN: Core Structure, Atom Segregation, and Optical Properties. AB - We conducted a comprehensive investigation of dislocations in Al0.46Ga0.54N. Using aberration-corrected scanning transmission electron microscopy and energy dispersive X-ray spectroscopy, the atomic structure and atom distribution at the dislocation core have been examined. We report that the core configuration of dislocations in AlGaN is consistent with that of other materials in the III Nitride system. However, we observed that the dissociation of mixed-type dislocations is impeded by alloying GaN with AlN, which is confirmed by our experimental observation of Ga and Al atom segregation in the tensile and compressive parts of the dislocations, respectively. Investigation of the optical properties of the dislocations shows that the atom segregation at dislocations has no significant effect on the intensity recorded by cathodoluminescence in the vicinity of the dislocations. These results are in contrast with the case of dislocations in In0.09Ga0.91N where segregation of In and Ga atoms also occurs but results in carrier localization limiting non-radiative recombination at the dislocation. This study therefore sheds light on why InGaN-based devices are generally more resilient to dislocations than their AlGaN-based counterparts. PMID- 28707894 TI - Vitamin D Receptor Regulates Amyloid Beta 1-42 Production with Protein Disulfide Isomerase A3. AB - The challenge of understanding the biology of neuronal amyloid processing could provide a basis for understanding the amyloid pathology in Alzheimer's disease (AD). Based on our previous studies, we have suggested that AD might be the consequence of a hormonal imbalance in which the critical hormone is vitamin D. The present study primarily focused on the creation of a condition that prevents the genomic or nongenomic action of vitamin D by disrupting vitamin D receptors (VDR or PDIA3/1,25MARRS); the effects of these disruptions on the series of proteins involved in secretases that play a crucial role in amyloid pathology and on amyloid beta (Abeta) production in primary cortical neurons were observed. VDR and PDIA3/1,25MARRS genes were silenced separately or simultaneously in E16 primary rat cortical neurons. The expression of target genes involved in APP processing, including Presenilin1, Presenilin2, Nicastrin, BACE1, ADAM10, and APP, was investigated with qRT-PCR and Western blot in this model. 1,25 Dihydroxyvitamin D3 treatments were used to verify any transcriptional regulation data gathered from siRNA treatments by determining the mRNA expression of the target genes. Immunofluorescence labeling was used for the verification of silencing experiments and intracellular Abeta1-42 production. Extracellular Abeta1-42 level was assessed with ELISA. mRNA and protein expression results showed that 1,25-dihydroxyvitamin D3 might affect the transcriptional regulation of the genes involved in APP processing. The intracellular and extracellular Abeta1-42 measurements in our study support this suggestion. Consequently, we suggest that 1,25-dihydroxyvitamin D3 and its receptors are important parts of the amyloid processing pathway in neurons. PMID- 28707895 TI - Lightweight and Ultrastrong Polymer Foams with Unusually Superior Flame Retardancy. AB - High-performance flame-retardant materials are urgently needed to address outstanding issues that pertain to safety. Traditional flame retardants are toxic to the environment and/or lack the physical properties required for use in many contemporary applications. Here, we show that isocyanate-based polyimide (PI) foam, a flammable material, can exhibit unusually superior flame retardancy as well as other excellent properties, such as being lightweight and displaying high mechanical strength, by incorporating red phosphorus (RP)-hybridized graphene. The covalent bonds formed between the graphene platelets and the PI matrix provide the resultant PI foam with a specific Young's modulus (83 kNm kg-1) that is comparable to or even higher than those displayed by state-of-the-art foams, including silica aerogels, polystyrene foams, and polyurethane foams. In addition, even a low content of the RP-hybridized graphene (2.2 wt %) results in an exceptionally higher limiting oxygen index (39.4) than those of traditional flame-retardant polymer-based materials (typically 20-30). The resultant PI foam also exhibits thermal insulation properties that are similar to that of air. Moreover, the RP-hybridized graphene is prepared using a one-step ball milling process in 100% yield, and does not require solvent or produce waste. The preparation of the flame-retardant PI foams can be scaled as the starting materials are commercially available and the techniques employed are industrially compatible. PMID- 28707896 TI - Smart Floor with Integrated Triboelectric Nanogenerator As Energy Harvester and Motion Sensor. AB - A smart floor is demonstrated by integrating a square-frame triboelectric nanogenerator (SF-TENG) into a standard wood floor. The smart floor has two working modes based on two pairs of triboelectric materials: one is purposely chosen polytetrafluoroethylene films and aluminum (Al) balls, and the other is the floor itself and the objects that can be triboelectrically charged, such as basketball, shoe soles, and Scotch tape, etc. Utilizing the Al balls enclosed inside shallow boxes, the smart floor is capable of harvesting vibrational energy and, hence, provides a nonintrusive way to detect sudden falls in elderly people. In addition, when the basketball is bounced repeatedly on the floor, the average output voltage and current are 364 +/- 43 V and 9 +/- 1 MUA, respectively, and 87 serially connected light-emitting diodes can be lit up simultaneously. Furthermore, the friction between the triboelectrically chargeable objects and the floor can also induce an alternating current output in the external circuit without the vibration of the Al balls. Normal human footsteps on the floor produce a voltage of 238 +/- 17 V and a current of 2.4 +/- 0.3 MUA. Therefore, this work presents a smart floor with built-in SF-TENG without compromising the flexibility and stability of the standard wood floor and also demonstrates a way to harvest ambient energy solely by using conventional triboelectric materials in our daily life. PMID- 28707897 TI - Redox Interconversion of Non-Oxido Vanadium Complexes Accompanied by Acid-Base Chemistry of Thiol and Thiolate. AB - The redox nature of the non-oxido vanadium sulfur center is associated with several biological systems such as vanadium nitrogenase, the reduction of vanadium ion in ascidians, and the function of amavadin, which is a vanadium(IV) natural product contained in Amanita mushrooms. But the related chemistry is less explored and understood compared to oxido vanadium species due to the oxophilic character of high valent vanadium ions. Herein, we present a class of non-oxido vanadium thiolate complexes, [VIII(PS2"SH)2]- (1) (PS2"SH = [P(C6H3-3-Me3Si-2 S)2(C6H3-3-Me3Si-2-SH)]2-), [VIV(PS3")(PS2"SH)]- (2) (PS3" = [P(C6H3-3-Me3Si-2 S)3]3-), [V(PS3")2]- (3), [V(PS3")(PS2"SH)] (4), and [VIV(PS3*)2]2- (5a) (PS3* = [P(C6H3-3-Ph-2-S)3]3-), and study their interconversion through the redox and acid-base reactions. Complex 1 consists of a six-coordinate octahedral vanadium center; complexes 2 and 4 are seven-coordinate with distorted capped trigonal prismatic geometry. Vanadium centers of 3 and 5a are both eight-coordinate; the former adopts ideal dodecahedral geometry, but the latter is better viewed as a distorted square antiprism. Complex 1 is oxidized to complex 2 and then to complex 3 with dioxygen. Each one-electron oxidation process is accompanied by the deprotonation of unbound thiol to bound thiolate. Complex 3 is also produced from complex 2 through stepwise addition of Fe(Cp)2+/n-BuLi, or in the reverse order. The formation of 2 from 3 is achieved in the order of adding Co(Cp)2 and acid or, as with the previous complex, inversely. Notably, the reduction of complex 2 to complex 1 accompanying the protonation of bound thiolate to unbound thiol only occurs with the presence of both Co(Cp)2 and acid, indicating a cooperative effect between the metal-centered reduction and bound thiolate protonation. The conversions among these complexes are observed with ESI-MS and UV-vis-NIR spectroscopies. The work demonstrates two-electron redox interconversion in these complexes mediated by transformations between unbound thiol and bound thiolate. PMID- 28707898 TI - Synthesis, Thermodynamic Properties, and Crystal Structure of RNA Oligonucleotides Containing 5-Hydroxymethylcytosine. AB - 5-Hydroxymethylcytosine (hm5C) is an RNA modification that has attracted significant interest because of the finding that RNA hydroxymethylation can favor mRNA translation. For insight into the mechanistic details of hm5C function to be obtained, the availability of RNAs containing this modification at defined positions that can be used for in vitro studies is highly desirable. In this work, we present an eight-step route to 5-hydroxymethylcytidine (hm5rC) phosphoramidite for solid-phase synthesis of modified RNA oligonucleotides. Furthermore, we examined the effects of hm5rC on RNA duplex stability and its impact on structure formation using the sarcin-ricin loop (SRL) motif. Thermal denaturation experiments revealed that hm5rC increases RNA duplex stability. By contrast, when cytosine within an UNCG tetraloop motif was replaced by hm5rC, the thermodynamic stability of the corresponding hairpin fold was attenuated. Importantly, incorporation of hm5rC into the SRL motif resulted in an RNA crystal structure at 0.85 A resolution. Besides changes in the hydration pattern at the site of modification, a slight opening of the hm5rC-G pair compared to the unmodified C-G in the native structure was revealed. PMID- 28707899 TI - Experimental and DFT Computational Insight into Nitrosamine Photochemistry-Oxygen Matters. AB - A nitrosamine photooxidation reaction is shown to generate a peroxy intermediate by experimental physical-organic methods. The irradiation of phenyl and methyl substituted nitrosamines in the presence of isotopically labeled 18-oxygen revealed that an O atom was trapped from a peroxy intermediate to trimethylphosphite or triphenylphosphine, or by nitrosamine itself, forming two moles of nitramine. The unstable peroxy intermediate can be trapped at low temperature in postphotolyzed solution in the dark. Chemiluminescence was also observed upon thermal decomposition of the peroxy intermediate, that is, when a postphotolysis low-temperature solution is brought up to room temperature. A DFT study provides tentative information for cyclic nitrogen peroxide species on the reaction surface. PMID- 28707900 TI - Aerosol Fragmentation Driven by Coupling of Acid-Base and Free-Radical Chemistry in the Heterogeneous Oxidation of Aqueous Citric Acid by OH Radicals. AB - A key uncertainty in the heterogeneous oxidation of carboxylic acids by hydroxyl radicals (OH) in aqueous-phase aerosol is how the free-radical reaction pathways might be altered by acid-base chemistry. In particular, if acid-base reactions occur concurrently with acyloxy radical formation and unimolecular decomposition of alkoxy radicals, there is a possibility that differences in reaction pathways impact the partitioning of organic carbon between the gas and aqueous phases. To examine these questions, a kinetic model is developed for the OH-initiated oxidation of citric acid aerosol at high relative humidity. The reaction scheme, containing both free-radical and acid-base elementary reaction steps with physically validated rate coefficients, accurately predicts the experimentally observed molecular composition, particle size, and average elemental composition of the aerosol upon oxidation. The difference between the two reaction channels centers on the reactivity of carboxylic acid groups. Free-radical reactions mainly add functional groups to the carbon skeleton of neutral citric acid, because carboxylic acid moieties deactivate the unimolecular fragmentation of alkoxy radicals. In contrast, the conjugate carboxylate groups originating from acid-base equilibria activate both acyloxy radical formation and carbon-carbon bond scission of alkoxy radicals, leading to the formation of low molecular weight, highly oxidized products such as oxalic and mesoxalic acid. Subsequent hydration of carbonyl groups in the oxidized products increases the aerosol hygroscopicity and accelerates the substantial water uptake and volume growth that accompany oxidation. These results frame the oxidative lifecycle of atmospheric aerosol: it is governed by feedbacks between reactions that first increase the particle oxidation state, then eventually promote water uptake and acid-base chemistry. When coupled to free-radical reactions, acid-base channels lead to formation of low molecular weight gas-phase reaction products and decreasing particle size. PMID- 28707901 TI - Toward Chemically Resolved Computer Simulations of Dynamics and Remodeling of Biological Membranes. AB - Cellular membranes are fundamental constituents of living organisms. Apart from defining the boundaries of the cells, they are involved in a wide range of biological functions, associated with both their structural and the dynamical properties. Biomembranes can undergo large-scale transformations when subject to specific environmental changes, including gel-liquid phase transitions, change of aggregation structure, formation of microtubules, or rupture into vesicles. All of these processes are dependent on a delicate interplay between intermolecular forces, molecular crowding, and entropy, and their understanding requires approaches that are able to capture and rationalize the details of all of the involved interactions. Molecular dynamics-based computational models at atom level resolution are, in principle, the best way to perform such investigations. Unfortunately, the relevant spatial and time dimensionalities involved in membrane remodeling phenomena would require computational costs that are today unaffordable on a routinely basis. Such hurdles can be removed by coarse-graining the representations of the individual molecular components of the systems. This procedure anyway reduces the possibility of describing the chemical variations in the lipid mixtures composing biological membranes. New hybrid particle field multiscale approaches offer today a promising alternative to the more traditional particle-based simulations methods. By combining chemically distinguishable molecular representations with mesoscale-based computationally affordable potentials, they appear as one of the most promising ways to keep an accurate description of the chemical complexity of biological membranes and, at the same time, cover the required scales to describe remodeling events. PMID- 28707902 TI - Observation of Phase-Filling Singularities in the Optical Dielectric Function of Highly Doped n-Type Ge. AB - Phase-filling singularities in the optical response function of highly doped (>10^{19} cm^{-3}) germanium are theoretically predicted and experimentally confirmed using spectroscopic ellipsometry. Contrary to direct-gap semiconductors, which display the well-known Burstein-Moss phenomenology upon doping, the critical point in the joint density of electronic states associated with the partially filled conduction band in n-Ge corresponds to the so-called E_{1} and E_{1}+Delta_{1} transitions, which are two-dimensional in character. As a result of this reduced dimensionality, there is no edge shift induced by Pauli blocking. Instead, one observes the "original" critical point (shifted only by band gap renormalization) and an additional feature associated with the level occupation discontinuity at the Fermi level. The experimental observation of this feature is made possible by the recent development of low-temperature, in situ doping techniques that allow the fabrication of highly doped films with exceptionally flat doping profiles. PMID- 28707903 TI - Erratum: Discrete Time Crystals: Rigidity, Criticality, and Realizations [Phys. Rev. Lett. 118, 030401 (2017)]. AB - This corrects the article DOI: 10.1103/PhysRevLett.118.030401. PMID- 28707904 TI - Floquet Dynamics of Boundary-Driven Systems at Criticality. AB - A quantum critical system described at low energy by a conformal field theory (CFT) and subjected to a time-periodic boundary drive displays multiple dynamical regimes, depending on the drive frequency. We compute the behavior of quantities including the entanglement entropy and Loschmidt echo, confirming analytic predictions from field theory by exact numerics on the transverse field Ising model and demonstrate universality by adding nonintegrable perturbations. The dynamics naturally separate into three regimes: a slow-driving limit, which has an interpretation as multiple quantum quenches with amplitude corrections from CFT; a fast-driving limit, in which the system behaves as though subject to a single quantum quench; and a crossover regime displaying heating. The universal Floquet dynamics in all regimes can be understood using a combination of boundary CFT and Kibble-Zurek scaling arguments. PMID- 28707905 TI - Unifying Microscopic and Continuum Treatments of van der Waals and Casimir Interactions. AB - We present an approach for computing long-range van der Waals (vdW) interactions between complex molecular systems and arbitrarily shaped macroscopic bodies, melding atomistic treatments of electronic fluctuations based on density functional theory in the former with continuum descriptions of strongly shape dependent electromagnetic fields in the latter, thus capturing many-body and multiple scattering effects to all orders. Such a theory is especially important when considering vdW interactions at mesoscopic scales, i.e., between molecules and structured surfaces with features on the scale of molecular sizes, in which case the finite sizes, complex shapes, and resulting nonlocal electronic excitations of molecules are strongly influenced by electromagnetic retardation and wave effects that depend crucially on the shapes of surrounding macroscopic bodies. We show that these effects together can modify vdW interaction energies and forces, as well as molecular shapes deformed by vdW interactions, by orders of magnitude compared to previous treatments based on Casimir-Polder, nonretarded, or pairwise approximations, which are valid only at macroscopically large or atomic-scale separations or in dilute insulating media, respectively. PMID- 28707906 TI - Nuclear Force Imprints Revealed on the Elastic Scattering of Protons with ^{10}C. AB - How does nature hold together protons and neutrons to form the wide variety of complex nuclei in the Universe? Describing many-nucleon systems from the fundamental theory of quantum chromodynamics has been the greatest challenge in answering this question. The chiral effective field theory description of the nuclear force now makes this possible but requires certain parameters that are not uniquely determined. Defining the nuclear force needs identification of observables sensitive to the different parametrizations. From a measurement of proton elastic scattering on ^{10}C at TRIUMF and ab initio nuclear reaction calculations, we show that the shape and magnitude of the measured differential cross section is strongly sensitive to the nuclear force prescription. PMID- 28707907 TI - Phase-Imposing Initiation of Cherenkov Superradiance Emission by an Ultrashort Seed Microwave Pulse. AB - For the first time, we demonstrate experimentally the possibility of Cherenkov superradiant generation with a phase imposed by an ultrashort seed microwave pulse. The phases of seed and initiated Ka-band microwave pulses were correlated with the accuracy of 0.5-0.7 rad for the power ratio down to -35 dB. Characteristics of such a process were determined in the frame of a basic theoretical model that describes both spontaneous and stimulated emission of an electron beam moving in corrugated waveguides. The obtained results open up opportunities of reaching extremely high radiation power density in phased arrays of short-pulse coherently operating microwave generators. PMID- 28707908 TI - Mechanical Properties of Transcription. AB - The mechanical properties of transcription have recently been shown to play a central role in gene expression. However, a full physical characterization of this central biological process is lacking. In this Letter, we introduce a simple description of the basic physical elements of transcription where RNA elongation, RNA polymerase rotation, and DNA supercoiling are coupled. The resulting framework describes the relative amount of RNA polymerase rotation and DNA supercoiling that occurs during RNA elongation. Asymptotic behavior is derived and can be used to experimentally extract unknown mechanical parameters of transcription. Mechanical limits to transcription are incorporated through the addition of a DNA supercoiling-dependent RNA polymerase velocity. This addition can lead to transcriptional stalling and resulting implications for gene expression, chromatin structure and genome organization are discussed. PMID- 28707909 TI - Can Topology and Geometry be Measured by an Operator Measurement in Quantum Gravity? AB - In the context of Lin-Lunin-Maldacena geometries, we show that superpositions of classical coherent states of trivial topology can give rise to new classical limits where the topology of spacetime has changed. We argue that this phenomenon implies that neither the topology nor the geometry of spacetime can be the result of an operator measurement. We address how to reconcile these statements with the usual semiclassical analysis of low energy effective field theory for gravity. PMID- 28707910 TI - Amplitude Sensing below the Zero-Point Fluctuations with a Two-Dimensional Trapped-Ion Mechanical Oscillator. AB - We present a technique to measure the amplitude of a center-of-mass (c.m.) motion of a two-dimensional ion crystal of ~100 ions. By sensing motion at frequencies far from the c.m. resonance frequency, we experimentally determine the technique's measurement imprecision. We resolve amplitudes as small as 50 pm, 40 times smaller than the c.m. mode zero-point fluctuations. The technique employs a spin-dependent, optical-dipole force to couple the mechanical oscillation to the electron spins of the trapped ions, enabling a measurement of one quadrature of the c.m. motion through a readout of the spin state. We demonstrate sensitivity limits set by spin projection noise and spin decoherence due to off-resonant light scattering. When performed on resonance with the c.m. mode frequency, the technique demonstrated here can enable the detection of extremely weak forces (<1 yN) and electric fields (<1 nV/m), providing an opportunity to probe quantum sensing limits and search for physics beyond the standard model. PMID- 28707911 TI - Markov Property of the Conformal Field Theory Vacuum and the a Theorem. AB - We use strong subadditivity of entanglement entropy, Lorentz invariance, and the Markov property of the vacuum state of a conformal field theory to give new proof of the irreversibility of the renormalization group in d=4 space-time dimensions the a theorem. This extends the proofs of the c and F theorems in dimensions d=2 and d=3 based on vacuum entanglement entropy, and gives a unified picture of all known irreversibility theorems in relativistic quantum field theory. PMID- 28707912 TI - Chiral Spin Liquid on a Kagome Antiferromagnet Induced by the Dzyaloshinskii Moriya Interaction. AB - The quantum spin liquid material herbertsmithite is described by an antiferromagnetic Heisenberg model on the kagome lattice with a non-negligible Dzyaloshinskii-Moriya interaction (DMI). A well-established phase transition to the q=0 long-range order occurs in this model when the DMI strength increases, but the precise nature of a small-DMI phase remains controversial. Here, we describe a new phase obtained from Schwinger-boson mean-field theory that is stable at small DMI, and which can explain the dispersionless spectrum seen in the inelastic neutron scattering experiment by Han et al. [Nature (London) 492, 406 (2012)NATUAS0028-083610.1038/nature11659]. It is a time-reversal symmetry breaking Z_{2} spin liquid, with the unique property of a small and constant spin gap in an extended region of the Brillouin zone. The phase diagram as a function of DMI and spin size is given, and dynamical spin structure factors are presented. PMID- 28707913 TI - Efficiently Controllable Graphs. AB - We investigate graphs that can be disconnected into small components by removing a vanishingly small fraction of their vertices. We show that, when a controllable quantum network is described by such a graph and the gaps in eigenfrequencies and in transition frequencies are bounded exponentially in the number of vertices, the network is efficiently controllable, in the sense that universal quantum computation can be performed using a control sequence polynomial in the size of the network while controlling a vanishingly small fraction of subsystems. We show that networks corresponding to finite-dimensional lattices are efficiently controllable and explore generalizations to percolation clusters and random graphs. We show that the classical computational complexity of estimating the ground state of Hamiltonians described by controllable graphs is polynomial in the number of subsystems or qubits. PMID- 28707914 TI - First Elastic Electron Scattering from ^{132}Xe at the SCRIT Facility. AB - The first elastic electron scattering has been successfully performed at the self confining radioactive-isotope ion target (SCRIT) facility, the world's first electron scattering facility for SCRIT technique achieved high luminosity (over 10^{27} cm^{-2} s^{-1}, sufficient for determining the nuclear shape) with only 10^{8} target ions. While ^{132}Xe used in this time as a target is a stable isotope, the charge density distribution was first extracted from the momentum transfer distributions of the scattered electrons by comparing the results with those calculated by a phase shift calculation. PMID- 28707915 TI - Interacting Electrons in Graphene: Fermi Velocity Renormalization and Optical Response. AB - We have developed a Hartree-Fock theory for electrons on a honeycomb lattice aiming to solve a long-standing problem of the Fermi velocity renormalization in graphene. Our model employs no fitting parameters (like an unknown band cutoff) but relies on a topological invariant (crystal structure function) that makes the Hartree-Fock sublattice spinor independent of the electron-electron interaction. Agreement with the experimental data is obtained assuming static self-screening including local field effects. As an application of the model, we derive an explicit expression for the optical conductivity and discuss the renormalization of the Drude weight. The optical conductivity is also obtained via precise quantum Monte Carlo calculations which compares well to our mean-field approach. PMID- 28707916 TI - Hidden Area and Mechanical Nonlinearities in Freestanding Graphene. AB - We investigated the effect of out-of-plane crumpling on the mechanical response of graphene membranes. In our experiments, stress was applied to graphene membranes using pressurized gas while the strain state was monitored through two complementary techniques: interferometric profilometry and Raman spectroscopy. By comparing the data obtained through these two techniques, we determined the geometric hidden area which quantifies the crumpling strength. While the devices with hidden area ~0% obeyed linear mechanics with biaxial stiffness 428+/-10 N/m, specimens with hidden area in the range 0.5%-1.0% were found to obey an anomalous nonlinear Hooke's law with an exponent ~0.1. PMID- 28707917 TI - Topological Bound States in the Continuum in Arrays of Dielectric Spheres. AB - We consider Bloch bound states in the radiation continuum in periodic arrays of dielectric spheres. It is demonstrated that the bound states are associated with phase singularities of the quasimode coupling strength. That makes the bound states topologically protected and, therefore, robust against any variation of parameters preserving the periodicity and rotational symmetry about the array axis. It is shown that under variation of parameters the bound states can only be destroyed by either annihilation of the topological charge or by migration to the sector of the parametric space where the second radiation channel is open. PMID- 28707918 TI - Large Electroweak Corrections to Vector-Boson Scattering at the Large Hadron Collider. AB - For the first time full next-to-leading-order electroweak corrections to off shell vector-boson scattering are presented. The computation features the complete matrix elements, including all nonresonant and off-shell contributions, to the electroweak process pp->MU^{+}nu_{MU}e^{+}nu_{e}jj and is fully differential. We find surprisingly large corrections, reaching -16% for the fiducial cross section, as an intrinsic feature of the vector-boson-scattering processes. We elucidate the origin of these large electroweak corrections upon using the double-pole approximation and the effective vector-boson approximation along with leading-logarithmic corrections. PMID- 28707919 TI - Exact Solution for the Interacting Kitaev Chain at the Symmetric Point. AB - The Kitaev chain model with a nearest neighbor interaction U is solved exactly at the symmetry point Delta=t and chemical potential MU=0 in an open boundary condition. By applying two Jordan-Wigner transformations and a spin rotation, such a symmetric interacting model is mapped onto a noninteracting fermion model, which can be diagonalized exactly. The solutions include a topologically nontrivial phase at |U|t. The two phases are related by dualities. Quantum phase transitions in the model are studied with the help of the exact solution. PMID- 28707920 TI - Large Fluctuations for Spatial Diffusion of Cold Atoms. AB - We use a new approach to study the large fluctuations of a heavy-tailed system, where the standard large-deviations principle does not apply. Large-deviations theory deals with tails of probability distributions and the rare events of random processes, for example, spreading packets of particles. Mathematically, it concerns the exponential falloff of the density of thin-tailed systems. Here we investigate the spatial density P_{t}(x) of laser-cooled atoms, where at intermediate length scales the shape is fat tailed. We focus on the rare events beyond this range, which dominate important statistical properties of the system. Through a novel friction mechanism induced by the laser fields, the density is explored with the recently proposed non-normalized infinite-covariant density approach. The small and large fluctuations give rise to a bifractal nature of the spreading packet. We derive general relations which extend our theory to a class of systems with multifractal moments. PMID- 28707921 TI - Collective Modes of a Soliton Train in a Fermi Superfluid. AB - We characterize the collective modes of a soliton train in a quasi-one dimensional Fermi superfluid, using a mean-field formalism. In addition to the expected Goldstone and Higgs modes, we find novel long-lived gapped modes associated with oscillations of the soliton cores. The soliton train has an instability that depends strongly on the interaction strength and the spacing of solitons. It can be stabilized by filling each soliton with an unpaired fermion, thus forming a commensurate Fulde-Ferrell-Larkin-Ovchinnikov (FFLO) phase. We find that such a state is always dynamically stable, which paves the way for realizing long-lived FFLO states in experiments via phase imprinting. PMID- 28707922 TI - Skyrmion-Anti-Skyrmion Pair Creation by in-Plane Currents. AB - Magnetic Skyrmions can be considered as localized vortexlike spin textures which are topologically protected in continuous systems. Because of their stability, their small size, and the possibility to move them by low electric currents, they are promising candidates for spintronic devices. Without changing the topological charge, it is possible to create Skyrmion-anti-Skyrmion pairs. We derive a Skyrmion equation of motion which reveals how spin-polarized charge currents create Skyrmion-anti-Skyrmion pairs. It allows us to identify general prerequisites for the pair creation process. We corroborate these general principles by numerical simulations. On a lattice, where the concept of topological protection has to be replaced by that of a finite energy barrier, the anti-Skyrmion partner of the pairs is annihilated and only the Skyrmion survives. This eventually changes the total Skyrmion number and yields a new way of creating and controlling Skyrmions. PMID- 28707923 TI - Quantum Griffiths Phase Inside the Ferromagnetic Phase of Ni_{1-x}V_{x}. AB - We study by means of bulk and local probes the d-metal alloy Ni_{1-x}V_{x} close to the quantum critical concentration, x_{c}~11.6%, where the ferromagnetic transition temperature vanishes. The magnetization-field curve in the ferromagnetic phase takes an anomalous power-law form with a nonuniversal exponent that is strongly x dependent and mirrors the behavior in the paramagnetic phase. Muon spin rotation experiments demonstrate inhomogeneous magnetic order and indicate the presence of dynamic fluctuating magnetic clusters. These results provide strong evidence for a quantum Griffiths phase on the ferromagnetic side of the quantum phase transition. PMID- 28707924 TI - Suppression of Alfven Modes on the National Spherical Torus Experiment Upgrade with Outboard Beam Injection. AB - In this Letter we present data from experiments on the National Spherical Torus Experiment Upgrade, where it is shown for the first time that small amounts of high pitch-angle beam ions can strongly suppress the counterpropagating global Alfven eigenmodes (GAE). GAE have been implicated in the redistribution of fast ions and modification of the electron power balance in previous experiments on NSTX. The ability to predict the stability of Alfven modes, and developing methods to control them, is important for fusion reactors like the International Tokamak Experimental Reactor, which are heated by a large population of nonthermal, super-Alfvenic ions consisting of fusion generated alpha's and beam ions injected for current profile control. We present a qualitative interpretation of these observations using an analytic model of the Doppler shifted ion-cyclotron resonance drive responsible for GAE instability which has an important dependence on k_{?}rho_{L}. A quantitative analysis of this data with the hym stability code predicts both the frequencies and instability of the GAE prior to, and suppression of the GAE after the injection of high pitch-angle beam ions. PMID- 28707925 TI - Phoretic Interactions Generically Induce Dynamic Clusters and Wave Patterns in Active Colloids. AB - We introduce a representative minimal model for phoretically interacting active colloids. Combining kinetic theory, linear stability analyses, and a general relation between self-propulsion and phoretic interactions in autodiffusiophoretic and autothermophoretic Janus colloids collapses the parameter space from six to two dimensionless parameters: area fraction and Peclet number. This collapse arises when the lifetime of the self-generated phoretic fields is not too short, and leads to a universal phase diagram showing that phoretic interactions generically induce pattern formation in typical Janus colloids, even at very low density. The resulting patterns include waves and dynamic aggregates closely resembling the living clusters found in experiments on dilute suspension of Janus colloids. PMID- 28707926 TI - Charge-Induced Saffman-Taylor Instabilities in Toroidal Droplets. AB - We show that charged toroidal droplets can develop fingerlike structures as they expand due to Saffman-Taylor instabilities. While these are commonly observed in quasi-two-dimensional geometries when a fluid displaces another fluid of higher viscosity, we show that the toroidal confinement breaks the symmetry of the problem, effectively making it quasi-two-dimensional and enabling the instability to develop in this three-dimensional situation. We control the expansion speed of the torus with the imposed electric stress and show that fingers are observed provided the characteristic time scale associated with this instability is smaller than the characteristic time scale associated with Rayleigh-Plateau break up. We confirm our interpretation of the results by showing that the number of fingers is consistent with expectations from linear stability analysis in radial Hele-Shaw cells. PMID- 28707927 TI - Light-by-Light Scattering Constraint on Born-Infeld Theory. AB - The recent measurement by ATLAS of light-by-light scattering in LHC Pb-Pb collisions is the first direct evidence for this basic process. We find that it excludes a range of the mass scale of a nonlinear Born-Infeld extension of QED that is ?100 GeV, a much stronger constraint than those derived previously. In the case of a Born-Infeld extension of the standard model in which the U(1)_{Y} hypercharge gauge symmetry is realized nonlinearly, the limit on the corresponding mass reach is ~90 GeV, which, in turn, imposes a lower limit of ?11 TeV on the magnetic monopole mass in such a U(1)_{Y} Born-Infeld theory. PMID- 28707928 TI - PHz-Wide Spectral Interference Through Coherent Plasma-Induced Fission of Higher Order Solitons. AB - We identify a novel regime of soliton-plasma interactions in which high-intensity ultrashort pulses of intermediate soliton order undergo coherent plasma-induced fission. Experimental results obtained in gas-filled hollow-core photonic crystal fiber are supported by rigorous numerical simulations. In the anomalous dispersion regime, the cumulative blueshift of higher-order input solitons with ionizing intensities results in pulse splitting before the ultimate self compression point, leading to the generation of robust pulse pairs with PHz bandwidths. The novel dynamics closes the gap between plasma-induced adiabatic soliton compression and modulational instability. PMID- 28707929 TI - Optimal Wall-to-Wall Transport by Incompressible Flows. AB - We consider wall-to-wall transport of a passive tracer by divergence-free velocity vector fields u. Given an enstrophy budget ?|?u|^{2}?<=Pe^{2} we construct steady two-dimensional flows that transport at rates Nu(u)?Pe^{2/3}/(logPe)^{4/3} in the large enstrophy limit. Combined with the known upper bound Nu(u)?Pe^{2/3} for any such enstrophy-constrained flow, we conclude that maximally transporting flows satisfy Nu~Pe^{2/3} up to possible logarithmic corrections. Combined with known transport bounds in the context of Rayleigh-Benard convection, this establishes that while suitable flows approaching the "ultimate" heat transport scaling Nu~Ra^{1/2} exist, they are not always realizable as buoyancy-driven flows. The result is obtained by exploiting a connection between the wall-to-wall optimal transport problem and a closely related class of singularly perturbed variational problems arising in the study of energy-driven pattern formation in materials science. PMID- 28707930 TI - Trapped Ions in Rydberg-Dressed Atomic Gases. AB - We theoretically study trapped ions that are immersed in an ultracold gas of Rydberg-dressed atoms. By off-resonant coupling on a dipole-forbidden transition, the adiabatic atom-ion potential can be made repulsive. We study the energy exchange between the atoms and a single trapped ion and find that Langevin collisions are inhibited in the ultracold regime for these repulsive interactions. Therefore, the proposed system avoids recently observed ion heating in hybrid atom-ion systems caused by coupling to the ion's radio frequency trapping field and retains ultracold temperatures even in the presence of excess micromotion. PMID- 28707931 TI - Disorder-Free Localization. AB - The venerable phenomena of Anderson localization, along with the much more recent many-body localization, both depend crucially on the presence of disorder. The latter enters either in the form of quenched disorder in the parameters of the Hamiltonian, or through a special choice of a disordered initial state. Here, we present a model with localization arising in a very simple, completely translationally invariant quantum model, with only local interactions between spins and fermions. By identifying an extensive set of conserved quantities, we show that the system generates purely dynamically its own disorder, which gives rise to localization of fermionic degrees of freedom. Our work gives an answer to a decades old question whether quenched disorder is a necessary condition for localization. It also offers new insights into the physics of many-body localization, lattice gauge theories, and quantum disentangled liquids. PMID- 28707932 TI - 1.5 MUm Lasers with Sub-10 mHz Linewidth. AB - We report on two ultrastable lasers each stabilized to independent silicon Fabry Perot cavities operated at 124 K. The fractional frequency instability of each laser is completely determined by the fundamental thermal Brownian noise of the mirror coatings with a flicker noise floor of 4*10^{-17} for integration times between 0.8 s and a few tens of seconds. We rigorously treat the notorious divergences encountered with the associated flicker frequency noise and derive methods to relate this noise to observable and practically relevant linewidths and coherence times. The individual laser linewidth obtained from the phase noise spectrum or the direct beat note between the two lasers can be as small as 5 mHz at 194 THz. From the measured phase evolution between the two laser fields we derive usable phase coherence times for different applications of 11 to 55 s. PMID- 28707933 TI - Optimal Detection of a Localized Perturbation in Random Networks of Integrate-and Fire Neurons. AB - Experimental and theoretical studies suggest that cortical networks are chaotic and coding relies on averages over large populations. However, there is evidence that rats can respond to the short stimulation of a single cortical cell, a theoretically unexplained fact. We study effects of single-cell stimulation on a large recurrent network of integrate-and-fire neurons and propose a simple way to detect the perturbation. Detection rates obtained from simulations and analytical estimates are similar to experimental response rates if the readout is slightly biased towards specific neurons. Near-optimal detection is attained for a broad range of intermediate values of the mean coupling between neurons. PMID- 28707934 TI - Topological Quantum Liquids with Long-Range Couplings. AB - Very few topological systems with long-range couplings have been considered so far due to our lack of analytic approaches. Here we extend the Kitaev chain, a 1D quantum liquid, to infinite-range couplings and study its topological properties. We demonstrate that, even though topological phases are intimately linked to the notion of locality, the infinite-range couplings give rise to topological zero and nonzero energy Majorana end modes depending on the boundary conditions of the system. We show that the analytically derived properties are to a large degree stable against modifications to decaying long-range couplings. Our work opens new frontiers for topological states of matter that are relevant to current experiments, where systems with interactions of variable range can be designed. PMID- 28707935 TI - Multipoint Measurements of the Electron Jet of Symmetric Magnetic Reconnection with a Moderate Guide Field. AB - We report observations from the Magnetospheric Multiscale (MMS) satellites of the electron jet in a symmetric magnetic reconnection event with moderate guide field. All four spacecraft sampled the ion diffusion region and observed the electron exhaust. The observations suggest that the presence of the guide field leads to an asymmetric Hall field, which results in an electron jet skewed towards the separatrix with a nonzero component along the magnetic field. The jet appears in conjunction with a spatially and temporally persistent parallel electric field ranging from -3 to -5 mV/m, which led to dissipation on the order of 8 nW/m^{3}. The parallel electric field heats electrons that drift through it, and is associated with a streaming instability and electron phase space holes. PMID- 28707936 TI - Standard Model Background of the Cosmological Collider. AB - The inflationary universe can be viewed as a "cosmological collider" with an energy of the Hubble scale, producing very massive particles and recording their characteristic signals in primordial non-Gaussianities. To utilize this collider to explore any new physics at very high scales, it is a prerequisite to understand the background signals from the particle physics standard model. In this Letter we describe the standard model background of the cosmological collider. PMID- 28707938 TI - Micropillar Resonators for Optomechanics in the Extremely High 19-95-GHz Frequency Range. AB - Strong confinement, in all dimensions, and high mechanical frequencies are highly desirable for quantum optomechanical applications. We show that GaAs/AlAs micropillar cavities fully confine not only photons but also extremely high frequency (19-95 GHz) acoustic phonons. A strong increase of the optomechanical coupling upon reducing the pillar size is observed, together with record room temperature Q-frequency products of 10^{14}. These mechanical resonators can integrate quantum emitters or polariton condensates, opening exciting perspectives at the interface with nonlinear and quantum optics. PMID- 28707939 TI - Implications of the Occurrence of Glitches in Pulsar Free Precession Candidates. AB - The timing properties of radio pulsars provide a unique probe of neutron star interiors. Recent observations have uncovered quasiperiodicities in the timing and pulse properties of some pulsars, a phenomenon that has often been attributed to free precession of the neutron star, with profound implications for the distribution of superfluidity and superconductivity in the star. We advance this program by developing consistency relations between free precession and pulsars glitches, and we show that there are difficulties in reconciling the two phenomena in some precession candidates. This indicates that the precession model used here needs to be modified or some other phenomenon is at work in producing the quasiperiodicities, or even that there is something missing in terms of our understanding of glitches. PMID- 28707940 TI - Ultralight Dark Matter Resonates with Binary Pulsars. AB - We consider the scenario where dark matter (DM) is represented by an ultralight classical scalar field performing coherent periodic oscillations. We point out that such DM perturbs the dynamics of binary systems either through its gravitational field or via direct coupling to ordinary matter. This perturbation gets resonantly amplified if the frequency of DM oscillations is close to a (half )integer multiple of the orbital frequency of the system and leads to a secular variation of the orbital period. We suggest using binary pulsars as probes of this scenario and estimate their sensitivity. While the current accuracy of observations is not yet sufficient to probe the purely gravitational effect of DM, it already yields constraints on direct coupling that are competitive with other bounds. The sensitivity will increase with the upcoming radio observatories such as the Square Kilometer Array. PMID- 28707941 TI - Individual Tracer Atoms in an Ultracold Dilute Gas. AB - We report on the experimental investigation of individual Cs atoms impinging on a dilute cloud of ultracold Rb atoms with variable density. We study the relaxation of the initial nonthermal state and detect the effect of single collisions which has so far eluded observation. We show that, after few collisions, the measured spatial distribution of the tracer atoms is correctly described by a Langevin equation with a velocity-dependent friction coefficient, over a large range of Knudsen numbers. Our results extend the simple and effective Langevin treatment to the realm of light particles in dilute gases. The experimental technique developed opens up the microscopic exploration of a novel regime of diffusion at the level of individual collisions. PMID- 28707942 TI - Device-Independent Bounds on Detection Efficiency. AB - In many quantum information applications, a minimum detection efficiency must be exceeded to ensure success. Protocols depending on the violation of a Bell inequality, for instance, may be subject to the so-called detection loophole: Imperfect detectors may yield spurious violations, which consequently cannot be used to ensure, say, quantum cryptographic security. Hence, we investigate the possibility of giving lower bounds on detector efficiency even if an adversary has full control over both the source and the detectors. To this end, we present a technique to systematically derive Bell inequalities free from the detection loophole using only the observed measurements statistics. The violation of these inequalities certifies that the detectors used exceed a certain minimal efficiency. PMID- 28707937 TI - First Searches for Axions and Axionlike Particles with the LUX Experiment. AB - The first searches for axions and axionlike particles with the Large Underground Xenon experiment are presented. Under the assumption of an axioelectric interaction in xenon, the coupling constant between axions and electrons g_{Ae} is tested using data collected in 2013 with an exposure totaling 95 live days *118 kg. A double-sided, profile likelihood ratio statistic test excludes g_{Ae} larger than 3.5*10^{-12} (90% C.L.) for solar axions. Assuming the Dine-Fischler Srednicki-Zhitnitsky theoretical description, the upper limit in coupling corresponds to an upper limit on axion mass of 0.12 eV/c^{2}, while for the Kim Shifman-Vainshtein-Zhakharov description masses above 36.6 eV/c^{2} are excluded. For galactic axionlike particles, values of g_{Ae} larger than 4.2*10^{ 13} are excluded for particle masses in the range 1-16 keV/c^{2}. These are the most stringent constraints to date for these interactions. PMID- 28707943 TI - Calorimetric Measurements of Magnetic-Field-Induced Inhomogeneous Superconductivity Above the Paramagnetic Limit. AB - We report the first magnetocaloric and calorimetric observations of a magnetic field-induced phase transition within a superconducting state to the long-sought exotic Fulde-Ferrell-Larkin-Ovchinnikov (FFLO) superconducting state, first predicted over 50 years ago. Through the combination of bulk thermodynamic calorimetric and magnetocaloric measurements in the organic superconductor kappa (BEDT-TTF)_{2}Cu(NCS)_{2} as a function of temperature, magnetic field strength, and magnetic field orientation, we establish for the first time that this field induced first-order phase transition at the paramagnetic limit H_{p} is a transition to a higher-entropy superconducting phase, uniquely characteristic of the FFLO state. We also establish that this high-field superconducting state displays the bulk paramagnetic ordering of spin domains required of the FFLO state. These results rule out the alternate possibility of spin-density wave ordering in the high-field superconducting phase. The phase diagram determined from our measurements-including the observation of a phase transition into the FFLO phase at H_{p}-is in good agreement with recent NMR results and our own earlier tunnel-diode magnetic penetration depth experiments but is in disagreement with the only previous calorimetric report. PMID- 28707944 TI - Scaling Universality between Band Gap and Exciton Binding Energy of Two Dimensional Semiconductors. AB - Using first-principles GW Bethe-Salpeter equation calculations and the k.p theory, we unambiguously show that for two-dimensional (2D) semiconductors, there exists a robust linear scaling law between the quasiparticle band gap (E_{g}) and the exciton binding energy (E_{b}), namely, E_{b}~E_{g}/4, regardless of their lattice configuration, bonding characteristic, as well as the topological property. Such a parameter-free universality is never observed in their three dimensional counterparts. By deriving a simple expression for the 2D polarizability merely with respect to E_{g}, and adopting the screened hydrogen model for E_{b}, the linear scaling law can be deduced analytically. This work provides an opportunity to better understand the fantastic consequence of the 2D nature for materials, and thus offers valuable guidance for their property modulation and performance control. PMID- 28707945 TI - Publisher's Note: Particle-Hole Duality in the Lowest Landau Level [Phys. Rev. Lett. 118, 206602 (2017)]. AB - This corrects the article DOI: 10.1103/PhysRevLett.118.206602. PMID- 28707947 TI - Extracting Work from Quantum Measurement in Maxwell's Demon Engines. AB - The essence of both classical and quantum engines is to extract useful energy (work) from stochastic energy sources, e.g., thermal baths. In Maxwell's demon engines, work extraction is assisted by a feedback control based on measurements performed by a demon, whose memory is erased at some nonzero energy cost. Here we propose a new type of quantum Maxwell's demon engine where work is directly extracted from the measurement channel, such that no heat bath is required. We show that in the Zeno regime of frequent measurements, memory erasure costs eventually vanish. Our findings provide a new paradigm to analyze quantum heat engines and work extraction in the quantum world. PMID- 28707948 TI - Interpretation and Utility of the Moments of Small-Angle X-Ray Scattering Distributions. AB - Small angle x-ray scattering has been proven to be a valuable method for accessing structural information below the spatial resolution limit implied by direct imaging. Here, we theoretically derive the relation that links the subpixel differential phase signal provided by the sample to the moments of scattering distributions accessible by refraction sensitive x-ray imaging techniques. As an important special case we explain the scatter or dark-field contrast in terms of the sample's phase signal. Further, we establish that, for binary phase objects, the nth moment scales with the difference of the refractive index decrement to the power of n. Finally, we experimentally demonstrate the utility of the moments by quantitatively determining the particle sizes of a range of powders with a laboratory-based setup. PMID- 28707949 TI - Magnetically Induced Optical Transparency on a Forbidden Transition in Strontium for Cavity-Enhanced Spectroscopy. AB - In this Letter we realize a narrow spectroscopic feature using a technique that we refer to as magnetically induced optical transparency. A cold ensemble of ^{88}Sr atoms interacts with a single mode of a high-finesse optical cavity via the 7.5 kHz linewidth, spin forbidden ^{1}S_{0} to ^{3}P_{1} transition. By applying a magnetic field that shifts two excited state Zeeman levels, we open a transmission window through the cavity where the collective vacuum Rabi splitting due to a single level would create destructive interference for probe transmission. The spectroscopic feature approaches the atomic transition linewidth, which is much narrower than the cavity linewidth, and is highly immune to the reference cavity length fluctuations that limit current state-of-the-art laser frequency stability. PMID- 28707950 TI - Disentangling Gratitude: A Theoretical and Psychometric Examination of the Gratitude Resentment and Appreciation Test-Revised Short (GRAT-RS). AB - This study extended our theoretical and applied understanding of gratitude through a psychometric examination of the most popular multidimensional measure of gratitude, the Gratitude, Resentment, and Appreciation Test-Revised Short form (GRAT-RS). Namely, the dimensionality of the GRAT-RS, the model-based reliability of the GRAT-RS total score and 3 subscale scores, and the incremental evidence of validity for its latent factors were assessed. Dimensionality measures (e.g., explained common variance) and confirmatory factor analysis results with 426 community adults indicated that the GRAT-RS conformed to a multidimensional (bifactor) structure. Model-based reliability measures (e.g., omega hierarchical) provided support for the future use of the Lack of a Sense of Deprivation raw subscale score, but not for the raw GRAT-RS total score, Simple Appreciation subscale score, or Appreciation of Others subscale score. Structural equation modeling results indicated that only the general gratitude factor and the lack of a sense of deprivation specific factor accounted for significant variance in life satisfaction, positive affect, and distress. These findings support the 3 pillars of gratitude conceptualization of gratitude over competing conceptualizations, the position that the specific forms of gratitude are theoretically distinct, and the argument that appreciation is distinct from the superordinate construct of gratitude. PMID- 28707951 TI - Three-dimensional alteration of constricted alveolar ridge affected by root thrusting with and without open-flap decortication. AB - OBJECTIVE: To investigate the morphometric and histological alterations of the constricted alveolar ridge when affected by root thrusting with and without open flap decortication. MATERIALS AND METHODS: Eight beagles were divided into three groups: C, control without root thrusting; R, root thrusting only; RD, root thrusting with alveolar decortication. The ridge constriction model was prepared in 16 mandibular quadrants after extraction of the third premolars. Reciprocal root thrusting of the second and fourth premolars was performed toward the constricted ridge for 10 weeks, having a moment of 900 g-mm. Open-flap decortication was conducted on the constricted bone surface in group RD. Micro-CT based histomorphometric analysis and trichrome-staining-based tissue fractional analysis were performed to evaluate morphometric and microstructural changes on the ridge. RESULTS: Group R revealed a higher percentage of bone volume (P < .001), lower bone mineral density (P < .01), and higher trabecular number (P < .001) than did group C, which was supported by a higher bone fraction woven to lamellar bone (P < .05) resulting from histologic fractional analysis. However, group RD showed no significant difference from group C. CONCLUSIONS: Root thrusting toward the constricted ridge induced hypertrophic bone modeling with a high trabecular fraction on the ridge. However, combined open-flap decortication with root thrusting did not improve the volume or quality of the constricted ridge. PMID- 28707952 TI - Systemic Delivery of Dysferlin Overlap Vectors Provides Long-Term Gene Expression and Functional Improvement for Dysferlinopathy. AB - Dysferlinopathies comprise a family of disorders caused by mutations in the dysferlin (DYSF) gene, leading to a progressive dystrophy characterized by chronic muscle fiber loss, fat replacement, and fibrosis. To correct the underlying histopathology and function, expression of full-length DYSF is required. Dual adeno-associated virus vectors have been developed, defined by a region of homology, to serve as a substrate for reconstitution of the full 6.5 kb dysferlin cDNA. Previous work studied the efficacy of this treatment through intramuscular and regional delivery routes. To maximize clinical efficacy, dysferlin-deficient mice were treated systemically to target all muscles through the vasculature for efficacy and safety studies. Mice were evaluated at multiple time points between 4 and 13 months post treatment for dysferlin expression and functional improvement using magnetic resonance imaging and magnetic resonance spectroscopy and membrane repair. A systemic dose of 6 * 1012 vector genomes resulted in widespread gene expression in the muscles. Treated muscles showed a significant decrease in central nucleation, collagen deposition, and improvement of membrane repair to wild-type levels. Treated gluteus muscles were significantly improved compared to placebo-treated muscles and were equivalent to wild type in volume, intra- and extramyocellular lipid accumulation, and fat percentage using magnetic resonance imaging and magnetic resonance spectroscopy. Dual-vector treatment allows for production of full-length functional dysferlin with no toxicity. This confirms previous safety data and validates translation of systemic gene delivery for dysferlinopathy patients. PMID- 28707953 TI - Neural correlates of visual memory in patients with diffuse axonal injury. AB - PRIMARY OBJECTIVE: To investigate the neural substrates of visual memory in a sample of patients with traumatic brain injury (TBI). We hypothesized that patients with decreased grey and white matter volume in frontal and parietal cortices as well as medial temporal and occipital lobes would perform poorly on the tests of visual memory analysed. METHODS AND PROCEDURES: 39 patients and 53 controls were assessed on tests of visual memory and learning from the Cambridge Neuropsychological Test Automated Battery (CANTAB). Patients with TBI were scanned with magnetic resonance imaging (MRI). Partial correlations and multiple regression analyses were used to examine relationships between cognitive variables and MRI volumetric findings. This study complements and extends previous studies by performing volumetric comparisons on a variety of resolution levels, from whole brain to voxel-based level analysis. MAIN OUTCOMES AND RESULTS: Patients with TBI performed significantly worse than controls in all the tasks assessed. Performance was associated with wide-spread reductions in grey and white matter volume of several cortical and subcortical structures as well as with cerebrospinal fluid space enlargement in accordance with previous studies of memory in patients with TBI and cognitive models suggesting that memory problems involve the alteration of multiple systems. CONCLUSIONS: Our results propose that compromised visual memory in patients with TBI is related to a distributed pattern of volume loss in regions mediating memory and attentional processing. PMID- 28707954 TI - Lymphoepithelial carcinoma of salivary glands: CT and MR imaging findings. AB - OBJECTIVES: To depict the CT and MRI characteristics of salivary gland lymphoepithelial carcinoma (LEC) and provide more diagnostic information for this malignancy. METHODS: 103 salivary gland LEC subjects were retrospectively reviewed. The subjects include 35 males with a mean age of 40.8 years and 68 females with a mean age of 49.4 years. Of the 103 subjects, 86 had carcinomas in the parotid gland, 5 in the submandibular gland, 1 in the sublingual gland, 3 in the cheek and 8 in the palate. All subjects underwent routine CT and MRI (plain and contrast-enhanced scans) prior to surgical treatment and histopathological examination. RESULTS: Based on the pathological outcomes, all the salivary gland LECs were classified into two types from CT and MRI scans: solitary LEC (56 cases, 54.4%) and multiple LEC (47 cases, 45.6%). The latter included solitary salivary gland LEC with extraglandular lymph-node metastases (12 cases), parotid gland LEC with ipsilateral intraglandular lymph-node metastases (11 cases), parotid gland LEC with ipsilateral intra- and extraglandular lymph-node metastases (23 cases) and bilateral parotid gland LEC (1 case). The salivary gland LEC was depicted on CT and MRI scans as a lobular mass in 64 of 104 (61.5%), homogeneous mass in 65 of 104 (62.5%) or enhanced neoplasm in 94 of 104 (90.4%). CONCLUSIONS: Salivary gland LEC has a predilection for females in the fourth to fifth decade of life and the parotid gland. CT and MRI findings between solitary and multiple salivary LECs vary. A majority of multiple parotid gland LECs are characterized by metastasis of ipsilateral intraglandular lymph nodes, which may accompany with or without extraglandular lymph-node metastases. PMID- 28707955 TI - Use of Fluoroscopy and Potential Long-Term Radiation Effects on Cataract Formation. AB - INTRODUCTION: The lens of the eye is extremely susceptible to radiation and long term exposure can induce cataract formation. Our objective was to explore the risk of cataract formation for urologists at our institution. METHODS: A retrospective review of a multisurgeon database of fluoroscopic cases between October 2013 to December 2014 was queried. Procedures were performed by different subspecialties and ranged from stent insertion/ureteroscopy to percutaneous nephrolithotomy. Fluoroscopic parameters were recorded from all cases and the radiation dosimetry was calculated through methods described by the National Council on Radiation Protection. The data were extrapolated to determine the risk of cataract formation. The technical specifications of the GE OEC 990 mobile C arm unit were used for calculations. RESULTS: A total of 780 cases were analyzed, of which 182 were endourology cases. Average fluoroscopic time was 34.86 seconds per case. Average tube potential and current were 86.84 kV and 1.95 mA, respectively. Pediatric urologists utilized fluoroscopy the least, 11.84 seconds per case (p = 0.0022). Endourology trained faculty had fluoroscopy exposure of 68.35 seconds per case (p < 0.0001), whereas others were exposed 26.24 seconds per case (p < 0.0001). For the highest exposed urologist, the estimated dose to the eyes was 5.64 MUGy per case. Total estimated cumulative dose over the study timeframe was 997.58 MUGy, or 748.19 MUGy per year. CONCLUSIONS: The defined threshold in the absorbed dose for cataract formation is 0.5 Gy. Resident exposure was the highest, at 11% of the annual limit, and the most exposed urologists had an estimated dose of 5% of the annual limit. At current exposure levels, it would not be feasible to reach the stated safety limit during 50 to 60 years of practice. However, changing exposure guidelines could result in stricter safety limits. PMID- 28707956 TI - Use of the 21-Item Test with children and adolescents 5 to 16 years of age. AB - The goals of the present study were to: (a) collect preliminary normative data on the 21-Item Test in children and adolescents and to determine if cutoffs for biased responding in adults can be generalized to a younger population; (b) determine if Caucasian and Hispanic children perform differently on the test; and (c) ascertain the relationships of age and verbal intelligence with effort test performance. The 21-Item Test was administered to 153 children attending either a public (n = 96) or private (n = 57) school. The Wechsler Intelligence Scale for Children-Fourth Edition (WISC-IV) was also administered to the private school sample. The results indicated that the 21-Item Test has potential as a tool for identifying children who do not put forth maximal effort during formal assessment and that the adult cutoffs appear applicable to children 8 years and older. Caucasian and Hispanic participants performed similarly on the test. Forced choice scores <=12 were associated with age and lower levels of performance on the Verbal Comprehension Index of the WISC-IV. PMID- 28707957 TI - Impact of psychiatric symptomatology on neuropsychological assessment performance in persons with TBI: A comparison of OEF/OIF veteran and civilian samples. AB - OBJECTIVE: To assess whether increased incidence of post-traumatic stress disorder and depressive symptomatology in veterans with combat-related traumatic brain injury might help account for neurocognitive impairment relative to civilians with traumatic brain injury. PARTICIPANTS: Neuropsychological assessment data of 53 Operation Enduring Freedom/Operation Iraqi Freedom veterans and 48 civilians with positive history of traumatic brain injury were analyzed to assess differences with respect to cognitive performance. DESIGN: Retrospective analysis of data including neurocognitive test performance and self-reported symptoms of post-traumatic stress disorder and depression. RESULTS: Results showed worse neurocognitive performance (i.e. RBANS Total Index score) in the veteran sample relative to the civilian sample [F(1,99) = 3.92, p = .05, n2 = .04], particularly on tasks measuring attentional capabilities [F(1,99) = 9.18, p = .003, n2 = .09]. Additional analyses found that after controlling for post traumatic stress disorder symptomatology, differences were no longer significant. Broad correlations between measures also showcased attenuated relationships after controlling for both post-traumatic stress disorder and depressive symptomatology using partial correlations Conclusion: Findings suggest that the presence of post traumatic stress disorder and depressive symptomatology negatively impacts cognitive performance across neuropsychological assessment above and beyond deficits related to traumatic brain injury. PMID- 28707958 TI - Gadofosveset-enhanced thoracic MR venography: a comparative study evaluating steady state imaging versus conventional first-pass time-resolved dynamic imaging. AB - Background Dedicated blood-pool contrast agents combined with optimal angiographic protocols could improve the diagnostic accuracy of thoracic magnetic resonance angiography (MRA). Purpose To assess the clinical utility of Gadofesveset-enhanced imaging and compare an optimized steady-state (SS) sequence against conventional first-pass dynamic multi-phase (DMP) imaging. Material and Methods Twenty-nine patients (17 men, 12 women; mean age = 42.7, age range = 18 72 years) referred for MR thoracic venography were recruited. Imaging was performed on a 1.5T MRI system. A blood-pool contrast agent (Gadofesveset) was administered intravenously. Thirty temporal phases were acquired using DMP. This was immediately followed by a high-resolution SS sequence. Three radiologists in consensus reviewed seven thoracic vascular segments after randomizing the acquisition order. Image quality, stenoses, thromboses, and artifacts were graded using a categorical scoring system. The image quality for both approaches was compared using Wilcoxon's signed-rank test. McNemar's test was used to compare the proportions of stenosis grades, thrombus and artifacts. Results SS had significantly better image quality than DMP (3.14 +/- 0.73 and 2.92 +/- 0.60, respectively; P < 0.001). SS identified fewer stenoses (>50%) than DMP; the differences in stenosis categorizations was statistically significant ( P = 0.013). There was no significant difference in the proportions of vessels with thromboses ( P = 0.617). DMP produced more artifacts than SS (101 versus 85); however, the difference was not statistically significant ( P = 0.073). Conclusion Gadofesveset-enhanced thoracic angiography is clinically feasible. SS imaging produces better image quality and fewer artifacts than conventional DMP imaging. PMID- 28707959 TI - Interactions of the Salience Network and Its Subsystems with the Default-Mode and the Central-Executive Networks in Normal Aging and Mild Cognitive Impairment. AB - Previous functional magnetic resonance imaging (fMRI) investigations suggest that the intrinsically organized large-scale networks and the interaction between them might be crucial for cognitive activities. A triple network model, which consists of the default-mode network, salience network, and central-executive network, has been recently used to understand the connectivity patterns of the cognitively normal brains versus the brains with disorders. This model suggests that the salience network dynamically controls the default-mode and central-executive networks in healthy young individuals. However, the patterns of interactions have remained largely unknown in healthy aging or those with cognitive decline. In this study, we assess the patterns of interactions between the three networks using dynamical causal modeling in resting state fMRI data and compare them between subjects with normal cognition and mild cognitive impairment (MCI). In healthy elderly subjects, our analysis showed that the salience network, especially its dorsal subnetwork, modulates the interaction between the default mode network and the central-executive network (Mann-Whitney U test; p < 0.05), which was consistent with the pattern of interaction reported in young adults. In contrast, this pattern of modulation by salience network was disrupted in MCI (p < 0.05). Furthermore, the degree of disruption in salience network control correlated significantly with lower overall cognitive performance measured by Montreal Cognitive Assessment (r = 0.295; p < 0.05). This study suggests that a disruption of the salience network control, especially the dorsal salience network, over other networks provides a neuronal basis for cognitive decline and may be a candidate neuroimaging biomarker of cognitive impairment. PMID- 28707961 TI - Encephalocraniocutaneous lipomatosis: A case report with review of literature. AB - Encephalocraniocutaneous lipomatosis (ECCL) or Haberland syndrome is an uncommon sporadic neurocutaneous syndrome of unknown origin. The rarity and common ignorance of the condition often makes diagnosis difficult. The hallmark of this syndrome is the triad of skin, ocular and central nervous system (CNS) involvement and includes a long list of combination of conditions. Herein we report a case of a 5-month-old male child who presented to our centre with complaint of seizure. The patient had various cutaneous and ocular stigmatas of the disease in the form of patchy alopecia of the scalp, right-sided limbal dermoid and a nodular skin tag near the lateral canthus of the right eye. MRI of the brain was conducted which revealed intracranial lipoma and arachnoid cyst. The constellation of signs and symptoms along with the skin, ocular and CNS findings led to the diagnosis of ECCL. PMID- 28707960 TI - Biofunctionalized Hybrid Magnetic Gold Nanoparticles as Catalysts for Photothermal Ablation of Colorectal Liver Metastases. AB - Purpose To demonstrate that anti-MG1 conjugated hybrid magnetic gold nanoparticles (HNPs) act as a catalyst during photothermal ablation (PTA) of colorectal liver metastases, and thus increase ablation zones. Materials and Methods All experiments were performed with approval of the institutional animal care and use committee. Therapeutic and diagnostic multifunctional HNPs conjugated with anti-MG1 monoclonal antibodies were synthesized, and the coupling efficiency was determined. Livers of 19 Wistar rats were implanted with 5 * 106 rat colorectal liver metastasis cell line cells. The rats were divided into three groups according to injection: anti-MG1-coupled HNPs (n = 6), HNPs only (n = 6), and cells only (control group, n = 7). Voxel-wise R2 and R2* magnetic resonance (MR) imaging measurements were obtained before, immediately after, and 24 hours after injection. PTA was then performed with a fiber-coupled near-infrared (808 nm) diode laser with laser power of 0.56 W/cm2 for 3 minutes, while temperature changes were measured. Tumors were assessed for necrosis with hematoxylin-eosin staining. Organs were analyzed with inductively coupled plasma mass spectrometry to assess biodistribution. Therapeutic efficacy and tumor necrosis area were compared by using a one-way analysis of variance with post hoc analysis for statistically significant differences. Results The coupling efficiency was 22 MUg/mg (55%). Significant differences were found between preinfusion and 24-hour postinfusion measurements of both T2 (repeated measures analysis of variance, P = .025) and T2* (P < .001). Significant differences also existed for T2* measurements between the anti-MG1 HNP and HNP-only groups (P = .034). Mean temperature +/- standard deviation with PTA in the anti-MG1-coated HNP, HNP, and control groups was 50.2 degrees C +/- 7.8, 51 degrees C +/- 4.4, and 39.5 degrees C +/- 2.0, respectively. Inductively coupled plasma mass spectrometry revealed significant tumor targeting and splenic sequestration. Mean percentages of tumor necrosis in the anti-MG1-coated HNP, HNP, and control groups were 38% +/- 29, 14% +/- 17, and 7% +/- 8, respectively (P = .043). Conclusion Targeted monoclonal antibody-conjugated HNPs can serve as a catalyst for photothermal ablation of colorectal liver metastases by increasing ablation zones. (c) RSNA, 2017. PMID- 28707962 TI - Towards an individualized management strategy for patients with chronic venous disease: Results of a Delphi consensus. AB - Objective To obtain consensus on management criteria for symptomatic patients with chronic venous disease (CVD; C2-C6) and superficial venous reflux. Method We used a Delphi method by means of 36 statements sent by email to experts in the field of phlebology across the world over the course of three rounds. The statements addressed criteria for different venous treatments in patients with different characteristics (e.g. extensive comorbidities, morbid obesity and peripheral arterial disease). If at least 70% of the ratings for a specific statement were between 6 and 9 (agreement) or between 1 and 3 (disagreement), experts' consensus was reached. Results Twenty-five experts were invited to participate, of whom 24 accepted and completed all three rounds. Consensus was reached in 25/32 statements (78%). However, several statements addressing UGFS, single phlebectomies, patients with extensive comorbidities and morbid obesity remained equivocal. Conclusion Considerable consensus was reached within a group of experts but also some gaps in available research were highlighted. PMID- 28707963 TI - In Vivo Assessment of Ovarian Tumor Response to Tyrosine Kinase Inhibitor Pazopanib by Using Hyperpolarized 13C-Pyruvate MR Spectroscopy and 18F-FDG PET/CT Imaging in a Mouse Model. AB - Purpose To assess in a mouse model whether early or late components of glucose metabolism, exemplified by fluorine 18 (18F) fluorodeoxyglucose (FDG) positron emission tomography (PET) and hyperpolarized carbon 13 (13C)-pyruvate magnetic resonance (MR) spectroscopy, can serve as indicators of response in ovarian cancer to multityrosine kinase inhibitor pazopanib. Materials and Methods In this Animal Care and Use Committee approved study, 17 days after the injection of 2 * 106 human ovarian SKOV3 tumors cells into 14 female nude mice, treatment with vehicle or pazopanib (2.5 mg per mouse peroral every other day) was initiated. Longitudinal T2-weighted MR imaging, dynamic MR spectroscopy of hyperpolarized pyruvate, and 18F-FDG PET/computed tomographic (CT) imaging were performed before treatment, 2 days after treatment, and 2 weeks after treatment. Results Pazopanib inhibited ovarian tumor growth compared with control (0.054 g +/- 0.041 vs 0.223 g +/- 0.112, respectively; six mice were treated with pazopanib and seven were control mice; P < .05). Significantly higher pyruvate-to-lactate conversion (lactate/pyruvate + lactate ratio) was found 2 days after treatment with pazopanib than before treatment (0.46 +/- 0.07 vs 0.31 +/- 0.14, respectively; P < .05; six tumors after treatment, seven tumors before treatment). This was not observed with the control group or with 18F-FDG PET/CT imaging. Conclusion The findings suggest that hyperpolarized 13C-pyruvate MR spectroscopy may serve as an early indicator of response to tyrosine kinase (angiogenesis) inhibitors such as pazopanib in ovarian cancer even when 18F-FDG PET/CT does not indicate a response. (c) RSNA, 2017 Online supplemental material is available for this article. PMID- 28707965 TI - Effects of a Brief Mindfulness Induction on Death-Related Anxiety. AB - This study examined effects of a mindfulness induction on proximal and distal defense responses to mortality salience and negative affect. Three experimental conditions were included: mindfulness, mind-wandering, and worrying. Participants in the mindfulness condition underwent a mindfulness induction at the experiment's outset, while participants in the other two conditions underwent a mind-wandering or worry induction. Inductions involved following guided audio instructions presented via headphones. All conditions ( N = 77) underwent a mortality salience induction after experimental manipulation, involving a written exercise pertaining to one's death. Results indicated fewer proximal responses in the mindfulness and mind-wandering groups, compared with the worrying group, but no differences in distal responses. Negative affect was lower in the mindfulness group than in the worrying group following mortality salience. Results suggest that mindfulness exercises effectively buffer against negative affect and some responses to mortality salience, although these effects are not different from those of mind-wandering. PMID- 28707964 TI - Roles of Diffusion Dynamics in Stem Cell Signaling and Three-Dimensional Tissue Development. AB - Recent advancements in the ability to construct three-dimensional (3D) tissues and organoids from stem cells and biomaterials have not only opened abundant new research avenues in disease modeling and regenerative medicine but also have ignited investigation into important aspects of molecular diffusion in 3D cellular architectures. This article describes fundamental mechanics of diffusion with equations for modeling these dynamic processes under a variety of scenarios in 3D cellular tissue constructs. The effects of these diffusion processes and resultant concentration gradients are described in the context of the major molecular signaling pathways in stem cells that both mediate and are influenced by gas and nutrient concentrations, including how diffusion phenomena can affect stem cell state, cell differentiation, and metabolic states of the cell. The application of these diffusion models and pathways is of vital importance for future studies of developmental processes, disease modeling, and tissue regeneration. PMID- 28707966 TI - Targeted molecular ablation of cancer stem cells for curing gastrointestinal cancers. AB - INTRODUCTION: Abundance of the ATPase-binding cassette (ABC) transporters and deranged self-renewal pathways characterize the presence of cancer stem cells (CSCs) in gastrointestinal cancers (GI cancers), which play crucial roles in tumorigenesis, chemotherapy resistance, tumor recurrence, and cancer metastasis. Therefore, in order to ensure high cure rates, chemoquiescence, CSCs should be ablated. Recent advances in either understanding CSCs or biomarker identification enable scientists to develop techniques for ablating CSCs and clinicians to provide cancer cure, especially in GI cancers characterized by inflammation driven carcinogenesis. Areas covered: A novel approach to ablate CSCs in GI cancers, including esophageal, gastric, and colon cancers, is introduced along with explored underlying molecular mechanisms. Expert commentary: Though CSC ablation is still in the empirical stages and not in clinical practice, several strategies for ablating CSCs in GI cancers had been published, proton-pump inhibitors (PPIs) that regulate the membrane-bound ABC transporters, which underlie drug resistance; chloroquine (CQ) that inhibits autophagy, which is responsible for tumor survival; Hedgehog/Wnt/Notch inhibitors that influence the underlying stem-cell growth, and some natural products including Korean red ginseng, cancer-preventive kimchi, Artemisia extract, EGCG from green tea, and walnut extracts. PMID- 28707967 TI - Mechanical Ventilation. PMID- 28707968 TI - Accelerometry: Improving Objective Assessments of Therapeutic Impact in Pediatric Pulmonary Arterial Hypertension. PMID- 28707969 TI - IPF: Moving from Idiopathic to Infectious Pulmonary Fibrosis? PMID- 28707970 TI - Mite Avoidance as a Logical Treatment for Severe Asthma in Childhood. Why Not? PMID- 28707971 TI - Magnetic Resonance Imaging in Pulmonary Arterial Hypertension. Panacea or Pixelation? PMID- 28707946 TI - Measurement of the CP Violation Parameter A_{Gamma} in D^{0}->K^{+}K^{-} and D^{0}->pi^{+}pi^{-} Decays. AB - Asymmetries in the time-dependent rates of D^{0}->K^{+}K^{-} and D^{0} >pi^{+}pi^{-} decays are measured in a pp collision data sample collected with the LHCb detector during LHC Run 1, corresponding to an integrated luminosity of 3 fb^{-1}. The asymmetries in effective decay widths between D^{0} and D[over ]^{0} decays, sensitive to indirect CP violation, are measured to be A_{Gamma}(K^{+}K^{-})=(-0.30+/-0.32+/-0.10)*10^{-3} and A_{Gamma}(pi^{+}pi^{ })=(0.46+/-0.58+/-0.12)*10^{-3}, where the first uncertainty is statistical and the second systematic. These measurements show no evidence for CP violation and improve on the precision of the previous best measurements by nearly a factor of two. PMID- 28707972 TI - Neutralizing Extracellular Histones in Acute Respiratory Distress Syndrome. A New Role for an Endogenous Pathway. PMID- 28707973 TI - Whole-Genome Sequencing in Common Respiratory Diseases. Ready, Set, Go! PMID- 28707974 TI - The Effect of Benign and Malignant Pleural Disease on Chest Wall Mechanics. PMID- 28707975 TI - The Road Not Taken: Missed Opportunities in Managing Acute Exacerbations of Hypercapnic Respiratory Failure. PMID- 28707976 TI - Comment on Expression of Concern: TLR4 Is Necessary for Hyaluronan-mediated Airway Hyperresponsiveness after Ozone Inhalation. PMID- 28707977 TI - Physicians Rarely Elicit Critically Ill Patients' Previously Expressed Treatment Preferences in Intensive Care Units. PMID- 28707978 TI - Immunomodulatory Cell Therapy to Target Cystic Fibrosis Inflammation. AB - Cystic fibrosis (CF) is associated with exaggerated and prolonged inflammation in the lungs, which contributes to lung injury, airway mucus obstruction, bronchiectasis, and loss of lung function. This hyperinflammatory phenotype appears to be caused by an imbalance between the pro- and antiinflammatory regulatory pathways, with heightened proinflammatory stimuli, a decreased counter regulatory response, and reduced effectiveness of immune cell function and inflammatory resolution. Thus, therapies that can target this inflammatory environment would have a major impact on preventing the progression of lung disease. Because of the complex phenotype of CF inflammation, current antiinflammatory regimens have proven to be inadequate for the targeting of these multiple dysregulated pathways and effects. Several approaches using cell therapies have shown potential therapeutic benefit for the treatment of CF inflammation. This review provides an overview of the immune dysfunctions in CF and current therapeutic regimens; explores the field of cell therapy as a treatment for CF inflammation; and focuses on the various cell types used, their immunomodulatory functions, and the current approaches to mitigate the inflammatory response and reduce the long-term damage for patients with CF. PMID- 28707980 TI - Extranuclear Sirtuins and Metabolic Stress. AB - SIGNIFICANCE: Extranuclear sirtuins in cytosol (SIRT2) and mitochondria (SIRT3, SIRT4, and SIRT5) are key regulators of metabolic enzymes and the antioxidative defense mechanisms. They play an important role in the adjustment of metabolic pathways in alterations of the nutritional status. Recent Advances: Recent studies have shown that in addition to lysine deacetylation, sirtuins catalyze several different lysine deacylation reactions, removal of lipid modifications, and adenosine diphosphate-ribosylation. Large-scale studies have revealed hundreds of target proteins regulated by different sirtuin modifications. CRITICAL ISSUES: Sensing of the metabolic state and regulation of the sirtuin function and expression are critical components of the machinery, optimizing cellular functions in the switch from fed to fasting condition. Overfeeding, obesity, and metabolic diseases cause metabolic stress that dysregulates the sirtuins, which may play a role in the pathogenesis and complications of metabolic diseases such as type 2 diabetes, fatty liver disease, and cardiac diseases. In the current review, we will discuss the significance of the extranuclear sirtuins as metabolic regulators and in protection against the reactive oxygen species, and also how these sirtuins are regulated by metabolic status and their putative role in metabolic diseases. FUTURE DIRECTIONS: To efficiently utilize sirtuins as drug targets for treatment of the metabolic diseases, better understanding of the sirtuin functions, targets, regulation, and cross talk is needed. Furthermore, more studies in humans are needed to confirm the many observations mainly made in animal and cell models so far. Antioxid. Redox Signal. 28, 662-676. PMID- 28707981 TI - Thermo-Optical Properties of Perfluorinated Sulfonic Acid Membranes: An Investigation of Hydration Based on Absorption Spectra. AB - The Nafion membranes are widely used in electrochemical applications such as fuel cells, chlor-alkali cells, and actuators-sensors. In this work, the thermal optical characterization of Nafion in acid form was performed by photoacoustic spectroscopy, thermogravimetry, and differential scanning calorimetry. In the experimental procedure three distinct hydration levels were considered: (1) pristine membrane (lambda ? H2O/-SO3H ? 5.6); (2) swelling process (lambda ? 17.4); and (3) drying at controlled room temperature after swelling process (lambda ? 6.5). The discovered behaviors showed significant irreversible structural changes induced by water retention in the membrane. These structural changes depend on the water population present in the clusters and also affect the directional thermal diffusivity of the membrane irreversibly. PMID- 28707979 TI - Emerging Roles for SIRT5 in Metabolism and Cancer. AB - SIGNIFICANCE: Developing evidence in the literature suggests that sirtuin 5 (SIRT5) may be involved in metabolic reprogramming, an emerging hallmark of cancer by which neoplastic cells reconfigure their metabolism to support the anabolic demands of rapid cell division. SIRT5 is one of the seven members of the nicotinamide adenine dinucleotide-dependent sirtuin family of lysine deacetylases. It removes succinyl, malonyl, and glutaryl groups from protein targets within the mitochondrial matrix and other subcellular compartments. SIRT5 substrates include a number of proteins integral to metabolism. Recent Advances: New work has begun to elucidate the roles of SIRT5 in glycolysis, tricarboxylic acid cycle, fatty acid oxidation, nitrogen metabolism, pentose phosphate pathway, antioxidant defense, and apoptosis. CRITICAL ISSUES: In this study, we summarize biological functions of SIRT5 reported in normal tissues and in cancer and discuss potential mechanisms whereby SIRT5 may impact tumorigenesis, particularly focusing on its reported roles in metabolic reprogramming. Finally, we review current efforts to target SIRT5 pharmacologically. FUTURE DIRECTIONS: The biological significance of SIRT5 has been elucidated in the context of only an extremely small fraction of its targets and interactors. There is no doubt that further studies in this area will provide a wealth of insights into functions of SIRT5 and its targets in normal and neoplastic cells. Antioxid. Redox Signal. 28, 677-690. PMID- 28707982 TI - Dual-Domain Calibration Transfer Using Orthogonal Projection. AB - We report the use of dual-domain regression models, which were built utilizing a wavelet prism decomposition and paired with transfer by orthogonal projection, for the calibration transfer of near-infrared (NIR) spectra. The new method is based on obtaining specific frequency components for a spectrum via wavelet analysis, projecting the frequency components of the primary instrument onto the subspace orthogonal to the mean instrumental difference between spectra from the primary and the secondary instrument, and weighting each frequency component model according to the cross-validation error of the frequency components of the projected primary instrument's spectra to generate a stacked ensemble model robust to contributions to the spectra from instrumental variations. The method, which does not require property values from the secondary data set, is tested on three NIR data sets, and is compared with orthogonal projection in the wavelength domain, orthogonal signal correction, and with model updating approaches. For the data sets we examined, we show that the prediction performance of the new method is competitive with orthogonal projections in the wavelength domain, as well as orthogonal signal correction and model updating approaches, both of which require property values for spectra from the secondary instrument. Examination of the spectral data reconstructed from the projected frequency components indicates that aspects of the data that may be attributable to instrumental or physical phenomena (i.e., instrumental baseline shifts or discretized intensity changes which may be attributed to scatter) are suppressed, but those associated with the chemical phenomena are retained. The benefits of orthogonal projection on each individual frequency component are further corroborated by the fact that the models based on frequency component projection generalize better to unseen instruments compared with the other methods. PMID- 28707983 TI - Signs of Gas Trapping in Normal Lung Density Regions in Smokers. AB - RATIONALE: A substantial proportion of subjects without overt airflow obstruction have significant respiratory morbidity and structural abnormalities as visualized by computed tomography. Whether regions of the lung that appear normal using traditional computed tomography criteria have mild disease is not known. OBJECTIVES: To identify subthreshold structural disease in normal-appearing lung regions in smokers. METHODS: We analyzed 8,034 subjects with complete inspiratory and expiratory computed tomographic data participating in the COPDGene Study, including 103 lifetime nonsmokers. The ratio of the mean lung density at end expiration (E) to end inspiration (I) was calculated in lung regions with normal density (ND) by traditional thresholds for mild emphysema (-910 Hounsfield units) and gas trapping (-856 Hounsfield units) to derive the ND-E/I ratio. Multivariable regression analysis was used to measure the associations between ND E/I, lung function, and respiratory morbidity. MEASUREMENTS AND MAIN RESULTS: The ND-E/I ratio was greater in smokers than in nonsmokers, and it progressively increased from mild to severe chronic obstructive pulmonary disease severity. A proportion of 26.3% of smokers without airflow obstruction had ND-E/I greater than the 90th percentile of normal. ND-E/I was independently associated with FEV1 (adjusted beta = -0.020; 95% confidence interval [CI], -0.032 to -0.007; P = 0.001), St. George's Respiratory Questionnaire scores (adjusted beta = 0.952; 95% CI, 0.529 to 1.374; P < 0.001), 6-minute-walk distance (adjusted beta = -10.412; 95% CI, -12.267 to -8.556; P < 0.001), and body mass index, airflow obstruction, dyspnea, and exercise capacity index (adjusted beta = 0.169; 95% CI, 0.148 to 0.190; P < 0.001), and also with FEV1 change at follow-up (adjusted beta = 3.013; 95% CI, -4.478 to -1.548; P = 0.001). CONCLUSIONS: Subthreshold gas trapping representing mild small airway disease is prevalent in normal-appearing lung regions in smokers without airflow obstruction, and it is associated with respiratory morbidity. Clinical trial registered with www.clinicaltrials.gov (NCT00608764). PMID- 28707984 TI - Social influences on sorority and fraternity member smoking. AB - OBJECTIVE: To understand how the Greek system uniquely influences smoking attitudes, beliefs, and behaviors among college students who belong to a social sorority or fraternity. PARTICIPANTS: Active members of sororities (n = 16) and fraternities (n = 17) were interviewed between February 2013 and October 2015. METHODS: In-depth interviews were conducted examining the social influences of the Greek system on member smoking. Transcribed interviews were coded and analyzed for themes. RESULTS: Sorority and fraternity members experienced different social influences on smoking. Sorority stigmatization of smoking outside bars or parties caused sorority members to hide their smoking. Fraternity members had no social penalties for smoking and allowed smoking at the fraternity house. Fraternity members influenced both fraternity members and sorority members to smoke by sharing cigarettes and smoking at parties. CONCLUSIONS: Sororities and fraternities have created social environments that both promote smoking and stigmatize it, presenting unique challenges in college student smoking prevention and cessation efforts. PMID- 28707985 TI - Nondispersive Infrared Gas Analyzer for Vapor Density Measurements of a Carbonyl Containing Organometallic Cobalt Precursor. AB - A nondispersive infrared (NDIR) gas analyzer was demonstrated for measuring the vapor-phase density of the carbonyl-containing organometallic cobalt precurso MU2 eta2-(tBu-acetylene) dicobalthexacarbonyl (CCTBA). This sensor was based on direct absorption by CCTBA vapor in the C=O stretching spectral region and utilized a stable, broadband IR filament source, an optical chopper to modulate the source, a bandpass filter for wavelength isolation, and an InSb detector. The optical system was calibrated by selecting a calibration factor to convert CCTBA absorbance to a partial pressure that, when used to calculate CCTBA flow rate and CCTBA mass removed from the ampoule, resulted in an optically determined mass that was nominally equal to a gravimetrically-determined mass. In situ Fourier transform infrared (FT-IR) spectroscopy was performed simultaneously with the NDIR gas analyzer measurements under selected conditions in order to characterize potential spectroscopic interferences. Interference due to CO evolution from CCTBA was found to be small under the flow conditions employed here. A CCTBA minimum detectable molecular density as low as ~3 * 1013 cm-3 was calculated (with no signal averaging and for a sampling rate of 200 Hz). While this NDIR gas analyzer was specifically tested for CCTBA, it is suitable for characterizing the vapor delivery of a range of carbonyl-containing precursors. PMID- 28707986 TI - Developing ADHD in preschool: Testing the dual pathway model of temperament. AB - The dual pathway model of Attention Deficit Hyperactivity Disorder (ADHD) suggests that effortful control and positive approach, or surgency, are independent pathways leading to ADHD. This model has been proven on the basis of temperament in school children, however not in preschool children. In this study we tested whether the dual pathway model of ADHD can be replicated in preschool children using temperamental measures. One hundred and nineteen children (59 girls, M-age = 4.97 years, SD = 0.96) participated in a study. Parents rated temperament on the Child Behavior Questionnaire (CBQ) and parents and teachers rated ADHD symptoms (SDQ). We found that effortful control and surgency independently predicted preschool ADHD symptoms but there were no moderations or mediations. Our findings support the dual pathway model of temperament but not compensatory models of ADHD. Ratings of temperament might be an important predictor of which child is at risk to develop clinical ADHD later on and therefore an important part of prevention. PMID- 28707987 TI - Neonatal Caffeine Treatment and Respiratory Function at 11 Years in Children under 1,251 g at Birth. AB - RATIONALE: Caffeine in the newborn period shortens the duration of assisted ventilation and reduces the incidence of bronchopulmonary dysplasia, but its effects on respiratory function in later childhood are unknown. OBJECTIVES: To determine if children born with birth weight less than 1,251 g who were treated with neonatal caffeine had improved respiratory function at 11 years of age compared with children treated with placebo. METHODS: Children enrolled in the CAP (Caffeine for Apnea of Prematurity) randomized controlled trial and assessed at the Royal Women's Hospital in Melbourne at 11 years of age had expiratory flow rates measured according to the standards of the American Thoracic Society. Values were converted to z-scores predicted for age, height, ethnicity, and sex. Parents completed questionnaires related to their child's respiratory health. MEASUREMENTS AND MAIN RESULTS: A total of 142 children had expiratory flows measured. Expiratory flows were better in the caffeine group, by approximately 0.5 SD for most variables (e.g., FEV1; mean z-score, -1.00 vs. -1.53; mean difference, 0.54; 95% confidence interval, 0.14-0.94; P = 0.008). Fewer children in the caffeine group had values for FVC below the fifth centile (11% vs. 28%; odds ratio, 0.31; 95% confidence interval, 0.12-0.77; P = 0.012). When adjusted for bronchopulmonary dysplasia, the difference in flow rates between groups diminished. CONCLUSIONS: Caffeine treatment in the newborn period improves expiratory flow rates in midchildhood, which seems to be achieved by improving respiratory health in the newborn period. Follow-up lung function testing in adulthood is vital for these individuals. Future placebo-controlled randomized trials of neonatal caffeine are unlikely. Clinical trial registered with www.clinicaltrials.gov (NCT00182312). PMID- 28707988 TI - First clinical report of helical tomotherapy with simultaneous integrated boost for synchronous bilateral breast cancer. AB - OBJECTIVE: Radiotherapy (RT) for synchronous bilateral breast cancer (SBBC) is technically very challenging. This study reports the clinical feasibility, dosimetry and safety of helical tomotherapy (HT) with simultaneous integrated boost (SIB) in patients treated with adjuvant radiotherapy for SBBC. METHODS: 21 women with SBBC treated with HT from January 2013 to June 2016 were retrospectively evaluated. Radiation lung toxicity was assessed using pulmonary function test (PFT) and high-resolution computerized tomography scan (HRCT) scan at baseline and 1 yearpost-RT in 18 patients. Survival was calculated using Kaplan-Meier curves. Significance of the difference between pre- and post-RT PFT values was assessed using paired t-test. RESULTS: The dose prescription was 50Gy to the breast, chest wall or regional nodes and 61Gy to the tumour bed as SIB, delivered in 25 fractions. Dosimetric outcome was excellent both for target volumes and normal tissues. Acute skin and oesophageal toxicities were minimal. Symptomatic radiation-induced pnuemonitis was not observed. Subclinical radiological Grade I-II changes were apparent in 14 patients. Only one patient developed Grade III radiological change whereas no change was documented for three patients. PFTs did not show any significant change in any of the measured parameters. At a median follow-up of 25 months, 3-year disease-free survival, overall survival and loco-regional control were 65.6%, 83.3% and 85.7% respectively. CONCLUSION: Women with SBBC can be safely treated with HT and this is not associated with adverse short- to intermediate term radiation toxicity. Advances in knowledge: This is the first report that establishes the safety of HT for adjuvant RT using SIB technique in SBBC. PMID- 28707989 TI - Breast density scales: the metric matters. AB - OBJECTIVE: Measures of percent mammographic density (PMD) are often categorized using various density scales. The purpose of this study was to examine information loss associated with the use of categorical density scales. METHODS: Baseline PMD was assessed at 1% precision for 2,374 females. The data were used to create 21-category, 4-category and 2-category density scales. R-squared and root mean square error were used to evaluate the effect of categorizing PMD. The area under the receiver operator characteristic curves were compared between cancer risk models employing solely categorical PMD scales and solely baseline PMD for a subset of females (424 cases, 848 controls). RESULTS: R-squared value decreased from 1.00 (1% PMD) to 0.56 (2-category scale), while root mean square error increased from 0.00 (1% PMD) to 10.83 (2-category scale). The area under the receiver operator characteristic curve decreased from 0.64 for a cancer risk model using 1% PMD to 0.58 for a risk model using a 21-category density scale (p < 0.0001), 0.55 for a 4-category Breast Imaging, Reporting and Data System-like scale (p < 0.0001) and 0.50 for a 2-category Breast Imaging, Reporting and Data System-like scale (high vs low) (p < 0.0001). CONCLUSION: Categorizing PMD measures into categorical density scales leads to a significant loss of information. Indeed, a simple high versus low split of PMD using a 50% cut point yields a cancer risk model with no discriminatory power. Advances in knowledge: Use of categorical mammographic density scales rather than continuous percent mammographic density measures leads to significant loss of information. Breast cancer risk models using categorical mammographic density scales perform more poorly than models using continuous PMD measures. PMID- 28707990 TI - Clinical usefulness of the mDIXON Quant the method for estimation of the salivary gland fat fraction: comparison with MR spectroscopy. AB - OBJECTIVE: To estimate the fat fraction (FF) in the salivary glands (SGs) by the mDIXON method and the 1H-MR spectroscopy (MRS) method, and to compare the results. METHODS: 16 healthy volunteers were enrolled. mDIXON Quant and MRS (point-resolved spectroscopy: PRESS) with a single TE were employed to measure the FF in the parotid gland (PG) and submandibular gland (SMG). Multiple TEs were applied in 10 volunteers to correct for T2 decay. In addition, we assumed that the 1.3 ppm peak accounted for 60% of the total fat peak and estimated the FF (MRS all) as a gold standard. On mDIXON Quant images, volumes of interest were set on the bilateral SGs and we obtained the FF (mDIXON) of each volume of interest. RESULTS: There was a strong correlation between the results of the mDIXON Quant method and the MRS (single TE) method (R2 = 0.960, slope = 0.900). Using PRESS with multiple TEs, there was also a strong correlation between FF (mDIXON) and FF (MRS all) (R2 = 0.963, slope = 1.18). FF (MRS all) was 24.9+/ 12.7% in the PG and 4.5+/-3.0% in the SMG, while FF (mDIXON) was 29.4+/-16.2% in the PG and 6.4+/-4.7% in the SMG. There were no significant differences between the two methods, but the Bland-Altman plot showed that FF (mDIXON) was slightly larger than FF (MRS all) for small FF areas. CONCLUSION: The mDIXON Quant method could be clinically useful for evaluating the FF of SGs, but the absolute values need careful interpretation. Advance in knowledge: This study suggested the potential clinical usefulness of the mDIXON Quant method for the SGs. PMID- 28707991 TI - A Case Study of Intractable Diarrhea Due to Neonatal Microvillous Inclusion Disease. AB - BACKGROUND: Microvillous inclusion disease (MVID) is one of the most severe congenital diarrhea disorders, caused by a genetic defect in enterocyte differentiation and polarization. CASE REPORT: We describe a neonate who presented with severe weight loss, hypernatremic dehydration and metabolic acidosis due to intractable diarrhea due to MVID, confirmed by electron microscopy. CONCLUSION: MVID can present with severe weight loss, hypernatremic dehydration and metabolic acidosis that is life threatening. The diagnosis is made by typical findings on light microscopy and electron microscope of small bowel biopsies. The only therapeutic options at this time are total parenteral nutrition and bowel rest and intestinal transplantation. PMID- 28707992 TI - Transitional care services: a quality and safety process improvement program in neurosurgery. AB - OBJECTIVE Readmissions increasingly serve as a metric of hospital performance, inviting quality improvement initiatives in both medicine and surgery. However, few readmission reduction programs have targeted surgical patient populations. The objective of this study was to establish a transitional care program (TCP) with the goal of decreasing length of stay (LOS), improving discharge efficiency, and reducing readmissions of neurosurgical patients by optimizing patient education and postdischarge surveillance. METHODS Patients undergoing elective cranial or spinal neurosurgery performed by one of 5 participating surgeons at a quaternary care hospital were enrolled into a multifaceted intervention. A preadmission overview and establishment of an anticipated discharge date were both intended to set patient expectations for a shorter hospitalization. At discharge, in-hospital prescription filling was provided to facilitate medication compliance. Extended discharge appointments with a neurosurgery TCP-trained nurse emphasized postoperative activity, medications, incisional care, nutrition, signs that merit return to medical attention, and follow-up appointments. Finally, patients received a surveillance phone call 48 hours after discharge. Eligible patients omitted due to staff limitations were selected as controls. Patients were matched by sex, age, and operation type-key confounding variables-with control patients, who were eligible patients treated at the same time period but not enrolled in the TCP due to staff limitation. Multivariable logistic regression evaluated the association of TCP enrollment with discharge time and readmission, and linear regression with LOS. Covariates included matching criteria and Charlson Comorbidity Index scores. RESULTS Between 2013 and 2015, 416 patients were enrolled in the program and matched to a control. The median patient age was 55 years (interquartile range 44.5-65 years); 58.4% were male. The majority of enrolled patients underwent spine surgery (59.4%, compared with 40.6% undergoing cranial surgery). Hospitalizations averaged 62.1 hours for TCP patients versus 79.6 hours for controls (a 16.40% reduction, 95% CI 9.30%-23.49%; p < 0.001). The intervention was associated with a higher proportion of morning discharges, which was intended to free beds for afternoon admissions and improve patient flow (OR 3.13, 95% CI 2.27-4.30; p < 0.001), and decreased 30-day readmissions (2.5% vs 5.8%; OR 2.43, 95% CI 1.14-5.27; p = 0.02). CONCLUSIONS This neurosurgical TCP was associated with a significantly shorter LOS, earlier discharge, and reduced 30-day readmission after elective neurosurgery. These results underscore the importance of patient education and surveillance after hospital discharge. PMID- 28707993 TI - Erratum. Attenuation of neurological injury with early baicalein treatment following subarachnoid hemorrhage in rats. PMID- 28707994 TI - Do craniopharyngioma molecular signatures correlate with clinical characteristics? AB - OBJECTIVE Exome sequencing studies have recently demonstrated that papillary craniopharyngiomas (PCPs) and adamantinomatous craniopharyngiomas (ACPs) have distinct genetic origins, each primarily driven by mutually exclusive alterations: either BRAF ( V600E), observed in 95% of PCPs, or CTNNB1, observed in 75%-96% of ACPs. How the presence of these molecular signatures, or their absence, correlates with clinical, radiographic, and outcome variables is unknown. METHODS The pathology records for patients who underwent surgery for craniopharyngiomas between May 2000 and March 2015 at Weill Cornell Medical College were reviewed. Craniopharyngiomas were identified and classified as PCP or ACP. Patients were placed into 1 of 3 groups based on their genomic mutations: BRAF mutation only, CTNNB1 mutation only, and tumors with neither of these mutations detected (not detected [ND]). Demographic, radiological, and clinical variables were collected, and their correlation with each genomic group was tested. RESULTS Histology correlated strongly with mutation group. All BRAF tumors with mutations were PCPs, and all CTNNB1 with mutations and ND tumors were ACPs. Preoperative and postoperative clinical symptoms and radiographic features did not correlate with any mutation group. There was a statistically significant relationship (p = 0.0323) between the age group (pediatric vs adult) and the mutation groups. The ND group tumors were more likely to involve the sella (p = 0.0065). CONCLUSIONS The mutation signature in craniopharyngioma is highly predictive of histology. The subgroup of tumors in which these 2 mutations are not detected is more likely to occur in children, be located in the sella, and be of ACP histology. PMID- 28707995 TI - Hypertrichosis lanuginosa acquisita associated with intracranial melanoma: case illustration. PMID- 28707996 TI - Effect of the degree of head elevation on the incidence and severity of venous air embolism in cranial neurosurgical procedures with patients in the semisitting position. AB - OBJECTIVE The semisitting position of a patient confers numerous advantages in various neurosurgical procedures, but venous air embolism is one of the associated complications of this position. To date, no prospective studies of the relationship between the degree of head elevation and the rate and severity of venous air embolism for patients undergoing a procedure in this position have been performed. In this study, the authors compared changes in the severity of venous air embolism according to the degree of head elevation (30 degrees or 45 degrees ) in patients undergoing an elective cranial neurosurgical procedure in the semisitting position. METHODS One hundred patients undergoing an elective infratentorial craniotomy in the semisitting position were included, and each patient was assigned to 1 of 2 groups. In Group 1, each patient's head was elevated 30 degrees during surgery, and in Group 2, each patient's head elevation was 45 degrees . Patients were assigned to their group according to the location of their lesion. During surgery, the standard anesthetic protocol was used with total intravenous anesthesia, and transesophageal echocardiography was used to detect air in the blood circulation. Any air embolism seen on the echocardiography screen was classified as Grade 0 to 4. If multiple events occurred, the worst graded attack was used for statistical analysis. During hemodynamic changes caused by emboli, fluid and vasopressor requirements were recorded. Surgical and anesthetic complications were recorded also. All results were compared statistically, and a p value of < 0.05 was considered statistically significant. RESULTS There was a statistically significant difference between groups for the total rates of venous air emboli detected on transesophageal echocardiography (22.0% [n = 11] in Group 1 and 62.5% [n = 30] in Group 2; p < 0.0001). The rate and severity of air embolism were significantly lower in Group 1 than in Group 2 (p < 0.001). The rates of clinically important venous air embolism (Grade 2, 3, or 4, venous air embolism with decreased end-tidal carbon dioxide levels and/or hemodynamic changes) were 8.0% (n = 4) in Group 1 and 50.0% (n = 24) in Group 2 (p < 0.0001). There was no association between the rate and severity of venous air embolism with patient demographics (p > 0.05). An association was found, however, between the rate of venous air embolism and the type of surgical pathology (p < 0.001); venous embolism occurred more frequently in patients with a meningioma. There were no major surgical or anesthetic complications related to patient position during the postoperative period. CONCLUSIONS For patients in the semisitting position, an increase in the degree of head elevation is related directly to a higher rate of venous air embolism. With a 30 degrees head elevation and our standardized technique of positioning, the semisitting position can be used safely in neurosurgical practice. PMID- 28707997 TI - Gamma Knife radiosurgery for large vestibular schwannomas greater than 3 cm in diameter. AB - OBJECTIVE Stereotactic radiosurgery (SRS) is an important alternative management option for patients with small- and medium-sized vestibular schwannomas (VSs). Its use in the treatment of large tumors, however, is still being debated. The authors reviewed their recent experience to assess the potential role of SRS in larger-sized VSs. METHODS Between 2000 and 2014, 35 patients with large VSs, defined as having both a single dimension > 3 cm and a volume > 10 cm3, underwent Gamma Knife radiosurgery (GKRS). Nine patients (25.7%) had previously undergone resection. The median total volume covered in this group of patients was 14.8 cm3 (range 10.3-24.5 cm3). The median tumor margin dose was 11 Gy (range 10-12 Gy). RESULTS The median follow-up duration was 48 months (range 6-156 months). All 35 patients had regular MRI follow-up examinations. Twenty tumors (57.1%) had a volume reduction of greater than 50%, 5 (14.3%) had a volume reduction of 15% 50%, 5 (14.3%) were stable in size (volume change < 15%), and 5 (14.3%) had larger volumes (all of these lesions were eventually resected). Four patients (11.4%) underwent resection within 9 months to 6 years because of progressive symptoms. One patient (2.9%) had open surgery for new-onset intractable trigeminal neuralgia at 48 months after GKRS. Two patients (5.7%) who developed a symptomatic cyst underwent placement of a cystoperitoneal shunt. Eight (66%) of 12 patients with pre-GKRS trigeminal sensory dysfunction had hypoesthesia relief. One hemifacial spasm completely resolved 3 years after treatment. Seven patients with facial weakness experienced no deterioration after GKRS. Two of 3 patients with serviceable hearing before GKRS deteriorated while 1 patient retained the same level of hearing. Two patients improved from severe hearing loss to pure tone audiometry less than 50 dB. The authors found borderline statistical significance for post-GKRS tumor enlargement for later resection (p = 0.05, HR 9.97, CI 0.99-100.00). A tumor volume >= 15 cm3 was a significant factor predictive of GKRS failure (p = 0.005). No difference in outcome was observed based on indication for GKRS (p = 0.0761). CONCLUSIONS Although microsurgical resection remains the primary management choice in patients with VSs, most VSs that are defined as having both a single dimension > 3 cm and a volume > 10 cm3 and tolerable mass effect can be managed satisfactorily with GKRS. Tumor volume >= 15 cm3 is a significant factor predicting poor tumor control following GKRS. PMID- 28707998 TI - Behavioural changes in dementia and their impact on professional caregivers: A grounded theory approach. AB - Aim The present study aimed to explore the impact that changes in behavioural symptoms of people living with dementia have on professional caregiver and resident relationships. Method A total of 21 interviews were carried out with professional caregivers of people living with dementia. A grounded theory approach was used to investigate everyday experiences of provision of professional care in dementia settings, focussing specifically on the effect of behavioural change on such relationships. Results A core category emerged from this analysis: 'Developing behaviour in dementia impacts relationships on a personal and professional level'. Discussion Professionals have recognized as part of their everyday practice an eventual deterioration in relationships between themselves as professional caregivers and the residents, but also between the residents and their family members and among residents themselves. Importantly, understanding patients' behaviour and behavioural change was identified as a crucial factor to achieve and sustain good relationships between professionals and residents suffering with dementia. PMID- 28707999 TI - Development of a membrane of poly (L-co-D,L lactic acid-co-trimethylene carbonate) with aloe vera: An alternative biomaterial designed to improve skin healing. AB - The search for new therapies and drugs that act as topical agents to relieve pain and control the infectious processes in burns always attracted interest in clinical trials. As an alternative to synthetic drugs, the use of natural extracts is useful in the development of new strategies and formulations for improving the life quality. The aim of this study was to develop a wound dressing using Poly(L-co-D,L lactic acid-co-TMC) (PLDLA-co-TMC) containing aloe vera (AV). This natural plant extract is known for its modulatory effects under healing process. The membrane of PLDLA-co-TMC+aloe vera was prepared at different concentrations of AV (5, 10, 15 and 50%). The FTIR showed no change in the PLDLA co-TMC spectrum after AV addition, while the swelling test showed changes only in PLDLA-co-TMC+AV at 50%. The wettability measurements showed decrease in the contact angle in all samples after the AV addition in the polymer, while the AV release test showed that PLDLA-co-TMC+50%AV sample has higher AV release rate than the sample with other AV concentrations. The SEM analysis showed that AV was homogeneously distributed at 5% only. Tensile tests demonstrated an increase in the Young's modulus and a reduction in the elongation till rupture of the PLDLA co-TMC after the addition of AV. Biocompatibility in vitro evaluation with fibroblast cells seeded in the membranes of PLDLA-co-TMC+AV showed that the cells were able to adhere, proliferate and maintain mitochondrial activity in all AV concentrations tested. Due to the known skin medicinal properties attributed to AV and the results here obtained, we suggest that after in vivo trials, the PLDLA co-TMC+AV should be a promising biomaterial for application as a device for skin curative and healing agent. PMID- 28708000 TI - Reactive Oxygen Species and Mitochondrial Homeostasis as Regulators of Stem Cell Fate and Function. AB - SIGNIFICANCE: The precise role and impact of reactive oxygen species (ROS) in stem cells, which are essential for lifelong tissue homeostasis and regeneration, remain of significant interest to the field. The long-term regenerative potential of a stem cell compartment is determined by the delicate balance between quiescence, self-renewal, and differentiation, all of which can be influenced by ROS levels. Recent Advances: The past decade has seen a growing appreciation for the importance of ROS and redox homeostasis in various stem cell compartments, particularly those of hematopoietic, neural, and muscle tissues. In recent years, the importance of proteostasis and mitochondria in relation to stem cell biology and redox homeostasis has garnered considerable interest. CRITICAL ISSUES: Here, we explore the reciprocal relationship between ROS and stem cells, with significant emphasis on mitochondria as a core component of redox homeostasis. We discuss how redox signaling, involving cell-fate determining protein kinases and transcription factors, can control stem cell function and fate. We also address the impact of oxidative stress on stem cells, especially oxidative damage of lipids, proteins, and nucleic acids. We further discuss ROS management in stem cells, and present recent evidence supporting the importance of mitochondrial activity and its modulation (via mitochondrial clearance, biogenesis, dynamics, and distribution [i.e., segregation and transfer]) in stem cell redox homeostasis. FUTURE DIRECTIONS: Therefore, elucidating the intricate links between mitochondria, cellular metabolism, and redox homeostasis is envisioned to be critical for our understanding of ROS in stem cell biology and its therapeutic relevance in regenerative medicine. Antioxid. Redox Signal. 00, 000-000. PMID- 28708004 TI - Psychological Trait Resilience Within Ecological Systems Theory: The Resilient Systems Scales. AB - This project describes the development of the Resilient Systems Scales, created to address conceptual and methodological ambiguities in assessing the ecological systems model of resilience. Across a number of samples (total N = 986), our findings suggest that the Resilient Systems Scales show equivalence to a previously reported assessment (Maltby, Day, & Hall, 2015 ) in demonstrating the same factor structure, adequate intercorrelation between the 2 measures of resilience, and equivalent associations with personality and well-being. The findings also suggest that the Resilient Systems Scales demonstrate adequate test retest reliability, compare well with other extant measures of resilience in predicting well-being, and map, to varying degrees, onto positive expression of several cognitive, social, and emotional traits. The findings suggest that the new measure can be used alongside existing measures of resilience, or singly, to assess positive life outcomes within psychology research. PMID- 28708003 TI - ARNTL, CLOCK and PER3 polymorphisms - links with chronotype and affective dimensions. AB - Recently, seven single nucleotide polymorphisms (SNPs) of ARNTL, TIM and PER3 genes were found associated with affective temperaments in bipolar disorder patients. This study aimed to test whether a) the same associations appear in a non-clinical sample; b) the SNPs are related to other affective dimensions; c) the SNPs underpin the associations between chronotype and affective temperaments/dimensions. Three hundred thirty-eight university students completed the Temperament Scale of Memphis, Pisa, Paris and San Diego Auto-questionnaire, the Centre for Epidemiological Studies Depression Scale, the Perceived Stress Scale, the General Health Questionnaire, the Seasonal Pattern Assessment Questionnaire and the Composite Scale of Morningness. Seven SNPs of the ARNTL, TIM and PER3 genes were genotyped. According to nominal significance, ARNTL rs7107287 was associated with a cyclothymic temperament, depressive and stress symptoms, general mental health and perceived negative impact of seasonality, while TIM rs10876890 was associated with a hyperthymic temperament, and the TIM rs2291738 was associated with chronotype. Different SNPs were related to chronotype and affective temperaments/dimensions, and therefore, they seem to not underpin relationships between chronotype and affective dysfunction, that is, in the present study, eveningness was related to dysthymic, cyclothymic and irritable temperaments, more symptoms of depression, stress, worse mental health and a negative impact of seasonality, while morningness was related to hyperthymic temperament. The SNPs associations need further replication given that they did not achieve Bonferroni criteria of significance accounting for the number of polymorphisms considered and tests conducted. PMID- 28708001 TI - Applying Full Spectrum Analysis to a Raman Spectroscopic Assessment of Fracture Toughness of Human Cortical Bone. AB - A decline in the inherent quality of bone tissue is a ? Equal contributors contributor to the age-related increase in fracture risk. Although this is well known, the important biochemical factors of bone quality have yet to be identified using Raman spectroscopy (RS), a nondestructive, inelastic light scattering technique. To identify potential RS predictors of fracture risk, we applied principal component analysis (PCA) to 558 Raman spectra (370-1720 cm-1) of human cortical bone acquired from 62 female and male donors (nine spectra each) spanning adulthood (age range = 21-101 years). Spectra were analyzed prior to R-curve, nonlinear fracture mechanics that delineate crack initiation (Kinit) from crack growth toughness (Kgrow). The traditional nu1phosphate peak per amide I peak (mineral-to-matrix ratio) weakly correlated with Kinit (r = 0.341, p = 0.0067) and overall crack growth toughness (J-int: r = 0.331, p = 0.0086). Sub peak ratios of the amide I band that are related to the secondary structure of type 1 collagen did not correlate with the fracture toughness properties. In the full spectrum analysis, one principal component (PC5) correlated with all of the mechanical properties (Kinit: r = - 0.467, Kgrow: r = - 0.375, and J-int: r = - 0.428; p < 0.0067). More importantly, when known predictors of fracture toughness, namely age and/or volumetric bone mineral density (vBMD), were included in general linear models as covariates, several PCs helped explain 45.0% (PC5) to 48.5% (PC7), 31.4% (PC6), and 25.8% (PC7) of the variance in Kinit, Kgrow, and J-int, respectively. Deriving spectral features from full spectrum analysis may improve the ability of RS, a clinically viable technology, to assess fracture risk. PMID- 28708005 TI - Taurine Protects Lens Epithelial Cells Against Ultraviolet B-Induced Apoptosis. AB - BACKGROUND: The massive uptake of compatible osmolytes is a self-protective response shared by lens exposed to hypertonic stress and ultraviolet stress. OBJECTIVE: This study aimed to investigate the protective effects of taurine against ultraviolet B-induced cytotoxicity in the lens epithelial cells. METHODS: Real-time PCR was used to measure osmolytes transport. Radioimmunoassay was used to measure osmolytes uptake. Cell counting kit-8 assays were used to measure cellular viability. Flow cytometry analysis was used to measure apoptosis level. RESULTS: Compared with normotonic stress, hypertonic stress-induced osmolytes uptake into the lens epithelial cells such as betaine, myoinositol and taurine. UVB exposure increased osmolytes transporter mRNA expression together with osmolytes uptake. Moreover, taurine suppressed UVB-induced cell apoptosis in the lens epithelial cells significantly. CONCLUSIONS: The effect of compatible osmolyte taurine on cell survival rate may play an important role in cell resistance and adaption to UVB exposure. PMID- 28708006 TI - A Near Visual Acuity Test for Dentists. AB - Unimpaired near vision is crucial in dentistry, but appropriate visual tests at dental working distance are not publicly available. The aim of this study was to validate a novel visual triage test for dentists that is easy to use and freely available. The near visual acuity at 300 mm of 106 dental professionals (aged 21 65 years) was assessed with 1) a validated near visual test for scientific purposes miniaturized on a microfilm; 2) an experimental test using a US $5 bill, in which the first five words of each line in the Lincoln Memorial frieze had to be read under a dental operating light. The Spearman rank correlation coefficient of 0.784 revealed a strong correlation between the two tests (p<0.0001). The ability to read six or more words in the memorial frieze meant there was a 94% chance of having a validated near visual acuity greater than or equal to the median score of the dentists tested. If none of the words could be read, the chance of having a near visual acuity below the median of the peer group was 89%. The influence of the dentists' age and experience on their visual performance reported in former studies was corroborated with this new test. The US $5 bill offers a simple and easily available near visual test to rank individuals' near vision relative to that of other dentists and to recognize the progression of presbyopia with increasing age. PMID- 28708007 TI - Effect of Hydrofluoric Acid Concentration and Etching Time on Bond Strength to Lithium Disilicate Glass Ceramic. AB - The aim of this study was to evaluate the influence of different concentrations of hydrofluoric acid (HF) associated with varied etching times on the microshear bond strength (MUSBS) of a resin cement to a lithium disilicate glass ceramic. Two hundred seventy-five ceramic blocks (IPS e.max Press [EMX], Ivoclar Vivadent), measuring 8 mm * 3 mm thickness, were randomly distributed into five groups according to the HF concentrations (n=50): 1%, 2.5%, 5%, 7.5%, and 10%. Further random distribution into subgroups was performed according to the following etching times (n=10): 20, 40, 60, 120, and 20 + 20 seconds. After etching, all blocks were treated with a silane coupling agent followed by a thin layer of an unfilled resin. Three resin cement cylinders (?=1 mm) were made on each EMX surface, which was then stored in deionized water at 37 degrees C for 24 hours before testing. The MUSBS was in a universal testing machine at a crosshead speed of 1 mm/min until failure. Data were submitted to two-way analysis of variance, and multiple comparisons were performed using the Tukey post hoc test (alpha=0.05). One representative EMX sample was etched according to the description of each subgroup and evaluated using scanning electron microscopy for surface characterization. The HF concentrations of 5%, 7.5%, and 10% provided significantly higher MUSBS values than 1% and 2.5% (p<0.05), regardless of the etching times. For 1% and 2.5% HF, the etching times from 40 to 120 seconds increased the MUSBS values compared with 20 seconds (p<0.05), but etching periods did not differ within the 5%, 7.5%, and 10% HF groups (p>0.05). The effect of re etching was more evident for 1% and 2.5% HF (p<0.05). Different HF concentrations/etching times directly influenced the bond strength and surface morphology of EMX. PMID- 28708008 TI - Long-term follow up of intractable chronic short lasting unilateral neuralgiform headache disorders treated with occipital nerve stimulation. AB - Background Occipital nerve stimulation is a potential treatment option for medically intractable short-lasting unilateral neuralgiform headache attacks. We present long-term outcomes in 31 patients with short-lasting unilateral neuralgiform headache attacks treated with occipital nerve stimulation in an uncontrolled open-label prospective study. Methods Thirty-one patients with intractable short-lasting unilateral neuralgiform headache attacks were treated with bilateral occipital nerve stimulation from 2007 to 2015. Data on attack characteristics, quality of life, disability and adverse events were collected. Primary endpoint was change in mean daily attack frequency at final follow-up. Results At a mean follow-up of 44.9 months (range 13-89) there was a 69% improvement in attack frequency with a response rate (defined as at least a 50% improvement in daily attack frequency) of 77%. Attack severity reduced by 4.7 points on the verbal rating scale and attack duration by a mean of 64%. Improvements were seen in headache-related disability and depression. Adverse event rates were favorable, with no electrode migration or erosion reported. Conclusion Occipital nerve stimulation appears to offer a safe and efficacious treatment for refractory short-lasting unilateral neuralgiform headache attacks with significant improvements sustained in the long term. The procedure has a low adverse event rate when conducted in highly specialised units. PMID- 28708009 TI - Triggering trigeminal neuralgia. AB - Introduction Although it is widely accepted that facial pain paroxysms triggered by innocuous stimuli constitute a hallmark sign of trigeminal neuralgia, very few studies to date have systematically investigated the role of the triggers involved. In the recently published diagnostic classification, triggered pain is an essential criterion for the diagnosis of trigeminal neuralgia but no study to date has been designed to address this issue directly. In this study, we set out to determine, in patients with trigeminal neuralgia, how frequently triggers are present, which manoeuvres activate them and where cutaneous and mucosal trigger zones are located. Methods Clinical characteristics focusing on trigger factors were collected from 140 patients with trigeminal neuralgia, in a cross-sectional study design. Results Provocation of paroxysmal pain by various trigger manoeuvres was reported by 136 of the 140 patients. The most frequent manoeuvres were gentle touching of the face (79%) and talking (54%). Trigger zones were predominantly reported in the perioral and nasal region. Conclusion This study confirms that in trigeminal neuralgia, paroxysmal pain is associated with triggers in virtually all patients and supports the use of triggers as an essential diagnostic feature of trigeminal neuralgia. PMID- 28708010 TI - The cost of minority stress: Risky alcohol use and coping-motivated drinking behavior in African American college students. AB - A motivational drinking framework is utilized to understand the relationship between minority stressors (e.g., race-related stress and acculturative stress) and alcohol use behaviors (risky alcohol use and coping-motivated drinking) among a large sample of Black American college students. Six hundred forty-nine Black college students from 8 colleges and universities in the United States were recruited as part of a large, multiwave, cross-sectional study investigating the stress and coping experiences of Black emerging adults. Results from the current investigation provide support for the independent contributions of acculturative stress and race-related stress to the risky alcohol use behavior of Black college students, while acculturative stress significantly predicted coping-motivated drinking behaviors in the sample. Findings underscore the need to better understand the unique relationships between minority stress and risky alcohol use behaviors of Black college students, namely, relationships not shared by their nonminority peers that increase their risk of problem drinking. PMID- 28708011 TI - Effect of local zoledronate delivery on osseointegration: a systematic review of preclinical studies. AB - PURPOSE: The aim of the present systematic review was to assess the effect of local zoledronate (ZOL) delivery (topical or as implant surface coatings) on osseointegration. MATERIALS AND METHODS: In this systematic review, the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. To address the focused question, 'Does local zoledronate delivery enhance osseointegration?' indexed databases were searched without time or language restrictions up to and including April 2017 using various combination of the following keywords: 'zoledronate', 'bisphosphonates', 'osseointegration' and 'topical administration'. Letters to the Editor, historic reviews, commentaries, case-series and case-reports were excluded. RESULTS: Initially, 383 articles were identified out of which, 23 experimental studies fulfilled the inclusion criteria. In 18 studies, ZOL was incorporated into implants surfaces as a coating and in five studies ZOL was applied topically (bone graft or irrigation) into the bone cavities. Results from 87% studies reported that local delivery of ZOL (coating or topical) is effective in enhancing osseointegration or new bone formation around implants. CONCLUSIONS: Local ZOL delivery (coating or topical) seems to enhance osseointegration in animals; however, from a clinical perspective, further randomized control trials with long-term follow-up are needed in this regard. PMID- 28708012 TI - How do patients perceive the British orthodontic society online information resource about orthognathic treatment? A qualitative study. AB - OBJECTIVES: To explore the accessibility, usability and relevance of the British Orthodontic Society (BOS) online information resource (OIR), Your Jaw Surgery. DESIGN: Qualitative, cross-sectional study. SETTING: 5 UK sites. PARTICIPANTS: Patients before, during and after treatment for non-cleft skeletal discrepancy. METHODS: Patients were identified at joint clinics and recruited after having time to view the OIR. Semi-structured interviews were conducted with 17 patients (aged 16-46 years). The interviews were transcribed and thematic analysis was undertaken using a framework approach. RESULTS: The main themes identified were the overall usefulness, personal relevance and positive perceptions of the OIR. The OIR was seen to be useful for patients considering treatment, and potentially useful for patients undergoing treatment. Participants were looking for a personally relevant resource that would give them the best possible idea of how they would look and feel after surgery. The OIR was perceived as trusted, positive and reassuring. CONCLUSIONS: Patients at different stages of treatment found the OIR helpful and reassuring. Clinicians may find it useful to direct patients to the OIR to complement a professional consultation, but should be aware that patients may perceive it as presenting a positive image of the long term benefits of orthognathic surgery. PMID- 28708013 TI - Psychometric evaluation of an abbreviated version of the intragroup marginalization inventory. AB - Tobacco and marijuana use among U.S. young adults is a top public health concern, and racial/ethnic minorities may be at particular risk. Past research examining cultural variables has focused on the individual in relation to the mainstream U.S. culture; however, an individual can also experience within-group stress, or intragroup marginalization. We used the 2014 San Francisco Bay Area Young Adult Health Survey to validate an abbreviated measure of intragroup marginalization and identify associations between intragroup marginalization and tobacco and marijuana use among ethnic minority young adults (N = 1,058). Exploratory factor analysis was conducted to identify factors within the abbreviated scale, and logistic regressions were conducted to examine relationships between intragroup marginalization and tobacco and marijuana use. Two factors emerged from the abbreviated scale. The first factor encompassed items related to belonging and membership, capturing whether individuals experienced marginalization due to not fitting in because of physical appearance or behavior. The second factor encompassed whether individuals shared similar hopes and dreams to their friends and family members. Factor 1 (membership) was associated with increased odds of marijuana use (OR = 1.34, p < .05) and lower odds of using cigars (OR = 0.79, p < .05), controlling for sociodemographic factors. Results suggest that young adults may use marijuana as a means to build connection and belonging to cope with feeling marginalized. Health education programs focused on ethnic minority young adults are needed to help them effectively cope with intragroup marginalization without resorting to marijuana use. PMID- 28708014 TI - State Definitions of Social Work Practice: Implications for our Professional Identity. AB - PURPOSE: For over a century, the social work profession has been concerned with describing the unique and specific characteristics that define its core functions in society; however, the profession has yet to agree to a single definition of social work. In the absence of a unifying definition, 51 different statutory definitions of social work have been created by each state and the District of Columbia. METHODS: Using qualitative methods, each statutory definition of social work was analyzed to gain an understanding of how social work is defined and understood across the United States. RESULTS: Findings indicate that 57% of the statutory language blend the full range of micro to macro social work practice skills into their definition. However, even within these and those remaining, there are vast differences in definitions. DISCUSSION: Implications for state licensing laws, are considered, along with how this impacts education, the work force, and professional identity. PMID- 28708015 TI - Relationship between PPARalpha mRNA expression and mitochondrial respiratory function and ultrastructure of the skeletal muscle of patients with COPD. AB - Peripheral muscle dysfunction is an important complication in patients with chronic obstructive pulmonary disease (COPD). The objective of this study was to explore the relationship between the levels of peroxisome proliferator-activated receptor alpha (PPARalpha) mRNA expression and the respiratory function and ultrastructure of mitochondria in the vastus lateralis of patients with COPD. Vastus lateralis biopsies were performed on 14 patients with COPD and 6 control subjects with normal lung function. PPARalpha mRNA levels in the muscle tissue were detected by real-time PCR. A Clark oxygen electrode was used to assess mitochondrial respiratory function. Mitochondrial number, fractional area in skeletal muscle cross-sections, and Z-line width were observed via transmission electron microscopy. The PPARalpha mRNA expression was significantly lower in COPD patients with low body mass index (BMIL) than in both COPD patients with normal body mass index (BMIN) and controls. Mitochondrial respiratory function (assessed by respiratory control ratio) was impaired in COPD patients, particularly in BMIL. Compared with that in the control group, mitochondrial number and fractional area were lower in the BMIL group, but were maintained in the BMIN group. Further, the Z-line became narrow in the BMIL group. PPARalpha mRNA expression was positively related to mitochondrial respiratory function and volume density. In COPD patients with BMIN, mitochondria volume density was maintained, while respiratory function decreased, whereas both volume density and respiratory function decreased in COPD patients with BMIL. PPARalpha mRNA expression levels are associated with decreased mitochondrial respiratory function and volume density, which may contribute to muscle dysfunction in COPD patients. PMID- 28708016 TI - Emergency separation of craniopagus twins: case report. AB - Craniopagus is a very rare congenital anomaly that tends to affect females more often than males. It is classified as partial or total. Most affected twins are either stillborn or die during the perinatal period. Those who survive birth should undergo detailed radiological evaluations soon after their condition becomes stable so that the precise anatomy of the conjoined part can be defined and surgery can be planned in detail by a multidisciplinary team. Recommendations for decreasing the risk of unsuccessful surgery include performing surgery on an elective basis after extensive preoperative radiological evaluations as well as when the twins are at an acceptable age and weight for a complex surgical separation, generally as staged procedures. In addition, the operation should be performed by a well-equipped expert multidisciplinary team. When one of the conjoined twins dies, however, surgical separation cannot be postponed because the shared circulatory system predisposes the alive child to life-threatening complications, including coagulopathy. The authors report on the successful separation of craniopagus twins performed on an emergency basis at 32 weeks of gestational age because of the sudden death of one of them. At the time of separation surgery, the twins each weighed 1250 g. To the best of the authors' knowledge, this is the youngest age and lowest weight yet reported for successful surgical separation. The surviving twin developed a pseudomeningocele, which required a second operation and placement of a cystoperitoneal shunt 4 months after the operation. Additional surgery is planned to repair a cranial defect that resulted from the pseudomeningocele, but his general physical and mental condition was otherwise good at latest follow-up (12 months after separation surgery). PMID- 28708017 TI - Editorial. Separation of craniopagus twins. PMID- 28708018 TI - Endoscopic third ventriculostomy and repeat endoscopic third ventriculostomy in pediatric patients: the Dutch experience. AB - OBJECTIVE After endoscopic third ventriculostomy (ETV), some patients develop recurrent symptoms of hydrocephalus. The optimal treatment for these patients is not clear: repeat ETV (re-ETV) or CSF shunting. The goals of the study were to assess the effectiveness of re-ETV relative to initial ETV in pediatric patients and validate the ETV success score (ETVSS) for re-ETV. METHODS Retrospective data of 624 ETV and 93 re-ETV procedures were collected from 6 neurosurgical centers in the Netherlands (1998-2015). Multivariable Cox proportional hazards modeling was used to provide an adjusted estimate of the hazard ratio for re-ETV failure relative to ETV failure. The correlation coefficient between ETVSS and the chance of re-ETV success was calculated using Kendall's tau coefficient. Model discrimination was quantified using the c-statistic. The effects of intraoperative findings and management on re-ETV success were also analyzed. RESULTS The hazard ratio for re-ETV failure relative to ETV failure was 1.23 (95% CI 0.90-1.69; p = 0.20). At 6 months, the success rates for both ETV and re-ETV were 68%. ETVSS was significantly related to the chances of re-ETV success (tau = 0.37; 95% bias corrected and accelerated CI 0.21-0.52; p < 0.001). The c statistic was 0.74 (95% CI 0.64-0.85). The presence of prepontine arachnoid membranes and use of an external ventricular drain (EVD) were negatively associated with treatment success, with ORs of 4.0 (95% CI 1.5-10.5) and 9.7 (95% CI 3.4-27.8), respectively. CONCLUSIONS Re-ETV seems to be as safe and effective as initial ETV. ETVSS adequately predicts the chance of successful re-ETV. The presence of prepontine arachnoid membranes and the use of EVD negatively influence the chance of success. PMID- 28708019 TI - Peripheral and Alveolar Cell Transcriptional Programs Are Distinct in Acute Respiratory Distress Syndrome. PMID- 28708020 TI - From Last to First - Could the U.S. Health Care System Become the Best in the World? PMID- 28708021 TI - An examination of the impact of maladaptive coping on the association between stressor type and alcohol use in college. AB - OBJECTIVE: Examine the impact of maladaptive coping style on the association between source of stress (academic, interpersonal, intrapersonal, environmental) and alcohol use (consumption, heavy episodic drinking, driving under the influence) among college students. PARTICIPANTS: 1,027 college students completed an online survey in April 2014. METHODS: To test the mediating effects of maladaptive coping on the association between academic stress and alcohol use variables, indirect effects were examined using the PROCESS analytical framework for SPSS. RESULTS: Maladaptive coping and academic stress were associated with alcohol use outcomes. Moreover, maladaptive coping mediated the relationship between academic stress and two of three alcohol use outcomes (consumption, heavy episodic drinking). CONCLUSIONS: Among college students, the association between academic stress and alcohol use may be driven by maladaptive coping. College students may benefit from interventions that seek to improve coping skills, potentially alleviating the burden of academic stress and decreasing problematic alcohol use. PMID- 28708022 TI - Is Intravenous Administration of Iodixanol Associated with Increased Risk of Acute Kidney Injury, Dialysis, or Mortality? A Propensity Score-adjusted Study. AB - Purpose To compare the rates of acute kidney injury (AKI), emergent dialysis, and short-term mortality between patients who underwent intravenous administration of the iso-osmolar contrast material (IOCM) iodixanol 320 and patients who underwent a noncontrast computed tomography (CT) examination. Materials and Methods Study design and implementation were overseen by an institutional review board and conformed to HIPAA guidelines on patient data integrity. All patients who underwent an iodixanol-enhanced (IOCM group) or a noncontrast (noncontrast group) CT examination from January 2003 to December 2014 were identified. Patients were subdivided into subgroups of those with stage 1-2 chronic kidney disease (CKD) (estimated glomerular filtration rate [eGFR], >= 60 mL/min/1.73 m2), those with stage 3 CKD (eGFR, 30-59 mL/min/1.73 m2), and those with stage 4-5 CKD (eGFR < 30 mL/min/1.73 m2) and separately underwent propensity score stratification and matching. Rates of AKI, emergent dialysis, and mortality were compared between IOCM and noncontrast groups. Additional analyses incorporating intravenous fluid administration, including additional CT studies at other sites within a single institution, and a paired analysis of patients who underwent both IOCM and noncontrast CT studies during the study time frame, were also performed. Results A total of 5758 patients (1538 with stage 1-2 CKD, 2899 with stage 3 CKD, and 1321 with stage 4-5 CKD) were included in the study. After propensity score adjustment, rates of AKI, dialysis, and mortality were not significantly higher in the IOCM group compared with the noncontrast group for all CKD subgroups (AKI odds ratios [ORs], 0.74-0.91, P = .16-0.69; dialysis ORs, 0.74-2.00, P = .42-.76; mortality ORs, 0.98-1.24, P = .39-.88). Sensitivity analyses yielded similar results. Conclusion Among patients at the highest perceived risk of postcontrast AKI, intravenous administration of iodixanol for contrast material enhanced CT was not an independent risk factor for AKI, dialysis, or mortality. (c) RSNA, 2017 Online supplemental material is available for this article. PMID- 28708023 TI - Comparison of drug-eluting balloon angioplasty with self-expanding interwoven nitinol stent deployment in patients with complex femoropopliteal lesions. AB - Objective The aim of this study was to compare the drug-eluting balloon with self expanding interwoven nitinol stent deployment in patients with complex femoropopliteal lesions. Methods We retrospectively identified patients at our clinic with complex femoropopliteal artery lesions treated either with self expanding interwoven nitinol stent or drug-eluting balloon. All patients had ankle-brachial index measured before and after the intervention, and regular clinical follow-up with Doppler ultrasonography was performed at six months and one year. Patients underwent peripheral angiography if needed. Results From April 2012 to July 2015, 107 patients with complex femoropopliteal lesions treated with using self-expanding interwoven nitinol stent ( N = 49, mean length 143.5 mm, mean follow-up of 14.1 +/- 3.7 months) or drug-eluting balloon ( N = 58, mean length 140.6 mm, mean follow-up of 13.8 +/- 4.1 months). The technical success rate was 100% in Supera(r) and 96.6% in drug-eluting balloon group. There were seven restenosis in self-expanding interwoven nitinol stent (SUS) group (84.8% patency) and 11 restenosis in drug-eluting balloon group (79.2% patency). A significant increase in the ankle-brachial index in both groups after intervention demonstrated a hemodynamic success (SUS group 0.45 +/- 0.06, drug eluting balloon group 0.43 +/- 0.07). The mean Rutherford Becker Class significantly decreased in both groups after a follow-up of 12 months (SUS group 0.70 +/- 0.73, drug-eluting balloon group 0.74 +/- 0.75). Conclusion Deploying drug-eluting balloon or self-expanding interwoven nitinol stent in patients with complex femoropopliteal lesions are both safe and effective with high patency rates with no statistical difference for one-year primary patency rates between them. PMID- 28708024 TI - Quality improvement initiative: Preventative Surgical Site Infection Protocol in Vascular Surgery. AB - : Objective A quality improvement initiative was employed to decrease single institution surgical site infection rate in open lower extremity revascularization procedures. SUMMARY BACKGROUND DATA: In an attempt to lower patient morbidity, we developed and implemented the Preventative Surgical Site Infection Protocol in Vascular Surgery. Surgical site infections lead to prolonged hospital stays, adjunctive procedure, and additive costs. We employed targeted interventions to address the common risk factors that predispose patients to post-operative complications. Methods Retrospective review was performed between 2012 and 2016 for all surgical site infections after revascularization procedures of the lower extremity. A quality improvement protocol was initiated in January 2015. Primary outcome was the assessment of surgical site infection rate reduction in the pre-protocol vs. post-protocol era. Secondary outcomes evaluated patient demographics, closure method, perioperative antibiotic coverage, and management outcomes. Results Implementation of the protocol decreased the surgical site infection rate from 6.4% to 1.6% p = 0.0137). Patient demographics and comorbidities were assessed and failed to demonstrate a statistically significant difference among the infection and no infection groups. Wound closure with monocryl suture vs. staple proved to be associated with decreased surgical site infection rate ( p < 0.005). Conclusions Preventative measures, in the form of a standardized protocol, to decrease surgical site infections in the vascular surgery population are effective and necessary. Our data suggest that there may be benefit in the incorporation of MRSA and Gram-negative coverage as part of the Surgical Care Improvement Project perioperative guidelines. PMID- 28708025 TI - Chlamydia and gonorrhea screening and expedited partner therapy (EPT) practices of college student health centers. AB - OBJECTIVE: To examine college student health centers' (SHCs) practices related to sexually transmitted disease (STD) screening and treatment over a 5-year period. PARTICIPANTS: College SHCs that completed the ACHA Pap and STI Survey between 2010 and 2014. METHODS: Chi-square tests were conducted with Cramer's V providing a measure of association. RESULTS: Chlamydia screening of women under 25 years of age was a well-established practice. Almost one-third of SHCs did not report screening practices of men who have sex with men (MSM) consistent with current chlamydia and gonorrhea guidelines; however, there was improvement over time. Few college SHCs utilized expedited partner therapy (EPT), though fewer had blanket restrictions prohibiting its use in 2014 compared to 2010. CONCLUSIONS: Over the 5-year period, more SHCs followed current best practices. Improvement in compliance with guidelines related to MSM STD screening as well as increased usage of EPT is needed to best address the needs of the diverse college student population. PMID- 28708026 TI - Visual Search: You Are Who You Are (+ A Learning Curve). AB - Not everyone is equally well suited for every endeavor-individuals differ in their strengths and weaknesses, which makes some people better at performing some tasks than others. As such, it might be possible to predict individuals' peak competence (i.e., ultimate level of success) on a given task based on their early performance in that task. The current study leveraged "big data" from the mobile game, Airport Scanner (Kedlin Company), to assess the possibility of predicting individuals' ultimate visual search competency using the minimum possible unit of data: response time on a single visual search trial. Those who started out poorly were likely to stay relatively poor and those who started out strong were likely to remain top performers. This effect was apparent at the level of a single trial (in fact, the first trial), making it possible to use raw response time to predict later levels of success. PMID- 28708027 TI - Do Valenced Odors and Trait Body Odor Disgust Affect Evaluation of Emotion in Dynamic Faces? AB - Disgust is a core emotion evolved to detect and avoid the ingestion of poisonous food as well as the contact with pathogens and other harmful agents. Previous research has shown that multisensory presentation of olfactory and visual information may strengthen the processing of disgust-relevant information. However, it is not known whether these findings extend to dynamic facial stimuli that changes from neutral to emotionally expressive, or if individual differences in trait body odor disgust may influence the processing of disgust-related information. In this preregistered study, we tested whether a classification of dynamic facial expressions as happy or disgusted, and an emotional evaluation of these facial expressions, would be affected by individual differences in body odor disgust sensitivity, and by exposure to a sweat-like, negatively valenced odor (valeric acid), as compared with a soap-like, positively valenced odor (lilac essence) or a no-odor control. Using Bayesian hypothesis testing, we found evidence that odors do not affect recognition of emotion in dynamic faces even when body odor disgust sensitivity was used as moderator. However, an exploratory analysis suggested that an unpleasant odor context may cause faster RTs for faces, independent of their emotional expression. Our results further our understanding of the scope and limits of odor effects on facial perception affect and suggest further studies should focus on reproducibility, specifying experimental circumstances where odor effects on facial expressions may be present versus absent. PMID- 28708028 TI - The association between changes in blood pressure components and incident cardiovascular diseases. AB - PURPOSE: To determine the association of changes in blood pressure (BP) components between baseline examination (1999-2001) and a second visit (2002 2005) with incident cardiovascular diseases (CVD). METHODS: In 3569 (2048 female) Iranian subjects >=30 y, systolic BP, diastolic BP, mean arterial pressure (MAP) and pulse pressure (PP) were evaluated in two consecutive visits. Subjects were then followed for cardiovascular events. Multivariate sex-adjusted Cox Proportional-Hazards models were built for each BP component's change, and further adjusted for baseline BP values, traditional cardiovascular risk factors, and their changes. RESULTS: During a median follow-up of 6.09 years after the second examination, 303 CVD cases occurred. A 1 SD increase in systolic BP, diastolic BP and MAP were significantly associated with 21%, 22%, and 95% increased CVD risk after adjustments for baseline values of BP components and other common risk factors (all p-values <0.05). Importantly, diastolic BP change resisted after further adjustment with systolic BP change (hazard ratio 1.21, CI 95% 1.05-1.39). PP change showed no significant association with CVD. CONCLUSIONS: In a middle-aged population, three-year rises in systolic BP, diastolic BP, MAP, but not PP were associated with increased incident CVD. The significant association between diastolic BP change and CVD was shown independent of systolic BP change. PMID- 28708029 TI - Effect of Surface Roughness in Model and Fresh Fruit Systems on Microbial Inactivation Efficacy of Cold Atmospheric Pressure Plasma. AB - This study investigates the efficacy of cold atmospheric pressure plasma (CAPP) on microbial inactivation as influenced by surface roughness of two types of surfaces: sandpaper and fresh fruit peel. Different grits of closed-coat sandpaper were selected, with their roughness (Pq) values ranging from 6 to 16 MUm. Apple, orange, and cantaloupe peels were selected for roughness values that were similar to the sandpapers. The sandpapers and the fruit peel surfaces were spot inoculated with Enterobacter aerogenes (109 CFU/63.64 cm2) and exposed to CAPP for 492 s. Similar microbial enumeration techniques were used for both systems to quantify the microbial inactivation. The smoothest sandpaper showed a 0.52-log higher inactivation of E. aerogenes (2.08 log CFU/63.64 cm2 sandpaper surface inactivation) than did the roughest sandpaper (1.56 log CFU/63.64 cm2 sandpaper surface inactivation), and the difference was statistically significant (P < 0.05). The smoothest fresh fruit peel surface (apple) showed a 1.25-log higher inactivation of the microorganism (1.86 log CFU/63.64 cm2 fruit peel surface inactivation) than did the roughest fresh fruit peel surface (cantaloupe; 0.61 log CFU/63.64 cm2 fruit peel surface inactivation), and the difference was statistically significant (P < 0.05). As the surface roughness increased, microbial inactivation efficacy of CAPP decreased for both systems. The results from sandpaper show that, in a scenario in which the surface roughness was the only parameter of difference, the microbial inactivation efficacy of CAPP decreased with increasing surface roughness. The results from fruit surfaces show high variability and were not directly predictable from the sandpaper data. This suggests that the microbial inactivation efficacy of CAPP in real-world food systems, such as on fresh fruit peels, is affected by factors in addition to surface roughness. PMID- 28708030 TI - Growth Kinetics of Listeria monocytogenes in Cut Produce. AB - Cut produce continues to constitute a significant portion of the fresh fruit and vegetables sold directly to consumers. As such, the safety of these items during storage, handling, and display remains a concern. Cut tomatoes, cut leafy greens, and cut melons, which have been studied in relation to their ability to support pathogen growth, have been specifically identified as needing temperature control for safety. Data are needed on the growth behavior of foodborne pathogens in other types of cut produce items that are commonly offered for retail purchase and are potentially held without temperature control. This study assessed the survival and growth of Listeria monocytogenes in cut produce items that are commonly offered for retail purchase, specifically broccoli, green and red bell peppers, yellow onions, canned green and black olives, fresh green olives, cantaloupe flesh and rind, avocado pulp, cucumbers, and button mushrooms. The survival of L. monocytogenes strains representing serotypes 1/2a, 1/2b, and 4b was determined on the cut produce items for each strain individually at 5, 10, and 25 degrees C for up to 720 h. The modified Baranyi model was used to determine the growth kinetics (the maximum growth rates and maximum population increases) in the L. monocytogenes populations. The products that supported the most rapid growth of L. monocytogenes, considering the fastest growth and resulting population levels, were cantaloupe flesh and avocado pulp. When stored at 25 degrees C, the maximum growth rates for these products were 0.093 to 0.138 log CFU/g/h and 0.130 to 0.193 log CFU/g/h, respectively, depending on the strain. Green olives and broccoli did not support growth at any temperature. These results can be used to inform discussions surrounding whether specific time and temperature storage conditions should be recommended for additional cut produce items. PMID- 28708031 TI - Persistence of Escherichia coli O157:H7 and Total Escherichia coli in Feces and Feedlot Surface Manure from Cattle Fed Diets with and without Corn or Sorghum Wet Distillers Grains with Solubles. AB - Feeding corn wet distillers grains with solubles (WDGS) to cattle can increase the load of Escherichia coli O157:H7 in feces and on hides, but the mechanisms are not fully understood. The objective of these experiments was to examine a role for the persistence of E. coli O157:H7 in the feces and feedlot pen surfaces of cattle fed WDGS. In the first study, feces from steers fed 0, 20, 40, or 60% corn WDGS were inoculated with E. coli O157:H7. The E. coli O157:H7 numbers in feces from cattle fed 0% corn WDGS rapidly decreased (P < 0.05), from 6.28 to 2.48 log CFU/g of feces by day 14. In contrast, the E. coli O157:H7 numbers in feces from cattle fed 20, 40, and 60% corn WDGS were 4.21, 5.59, and 6.13 log CFU/g of feces, respectively, on day 14. A second study evaluated the survival of E. coli O157:H7 in feces from cattle fed 0 and 40% corn WDGS. Feces were collected before and 28 days after the dietary corn was switched from high moisture corn to dry-rolled corn. Within dietary corn source, the pathogen persisted at higher concentrations (P < 0.05) in 40% corn WDGS feces at day 7 than in 0% WDGS. For 40% corn WDGS feces, E. coli O157:H7 persisted at higher concentrations (P < 0.05) at day 7 in feces from cattle fed high-moisture corn (5.36 log CFU/g) than from those fed dry-rolled corn (4.27 log CFU/g). The percentage of WDGS had no effect on the E. coli O157:H7 counts in feces from cattle fed steam-flaked corn-based diets containing 0, 15, and 30% sorghum WDGS. Greater persistence of E. coli O157:H7 on the pen surfaces of animals fed corn WDGS was not demonstrated, although these pens had a higher prevalence of the pathogen in the feedlot surface manure after the cattle were removed. Both or either the greater persistence and higher numbers of E. coli O157:H7 in the environment of cattle fed WDGS may play a part in the increased prevalence of E. coli O157:H7 in cattle by increasing the transmission risk. PMID- 28708032 TI - Comparison of a Newly Developed Liquid Chromatography with Tandem Mass Spectrometry Method and Enzyme-Linked Immunosorbent Assay for Detection of Multiple Mycotoxins in Red Pepper Powder. AB - In this study, we aimed to establish a method for determination of multiple mycotoxins such as aflatoxins, ochratoxin A, and zearalenone in red pepper powder samples based on the quick, easy, cheap, effective, rugged, and safe (QuEChERS) approach for extraction and cleanup, with detection and quantification by high performance liquid chromatography coupled with tandem mass spectrometry (LC MS/MS) in both positive- and negative-ion modes. The developed LC-MS/MS analytical method was compared with an enzyme-linked immunosorbent assay (ELISA) to improve the reliability of our developed method. The linearity, precision, and accuracy were validated for the LC-MS/MS methods. The results obtained with the LC-MS/MS were linear, with a correlation coefficient (R2) of >0.998. The limits of detection and quantification for mycotoxins were 0.07 to 0.71 MUg/kg and 0.20 to 1.81 MUg/kg, respectively. Intra- and interday precision tests (expressed as the relative standard deviation) for each analyte were 1.58 to 5.97% and 0.97 to 9.01%, respectively. Average recoveries were 85.70 to 94.99%. The validation results for the ELISA were linear (R2 > 0.995), and recoveries were 77.13 to 93.93%. Both analytical methods were applied to determine the presence of mycotoxins in commercial red pepper powder samples from South Korea. Four of the total 56 samples were contaminated with aflatoxins, and 6 samples were contaminated with ochratoxin A; these results were consistent for the two methods (P > 0.05). Therefore, our developed LC-MS/MS with QuEChERS approach for determination of multiple mycotoxins may be useful for controlling the quality and safety of red pepper powder. PMID- 28708033 TI - Neuropsychological profile and social cognition in congenital central hypoventilation syndrome (CCHS): Correlation with neuroimaging in a clinical case. AB - INTRODUCTION: Congenital central hypoventilation syndrome (CCHS) is a rare genetic disorder due to paired-like homeobox gene (PHOX2B) mutations. CCHS patients suffer from dysregulation of the autonomic nervous system characterized by the absence of or extremely reduced response to hypercapnia and hypoxia, with neuropsychological deficits. The aim of this exploratory study is to describe the longitudinal neuropsychological profile and its correlations with magnetic resonance imaging (MRI) of a child with CCHS with a PHOX2B mutation. METHOD: A comprehensive neuropsychological evaluation was conducted serially at age 7 years 4 months and 10 years 3 months, including assessment of intellectual functioning (IQ), motor functioning, perception, attention, executive functions, language, memory, social cognition, academic skills, and psychopathology. Reliable change index (RCI) scores were used to assess changes between assessments. We collected spin lattice relaxation time (T1)-weighted, fluid-attenuated inversion recovery (FLAIR), and spin spin lattice relaxation time (T2)-weighted images from the child at age 10 years 3 months using a 1.5-tesla MRI scanner. RESULTS: IQ, processing speed index (PSI), social cognition (theory of mind and facial emotion recognition), selective attention, naming, academic skills (reading/comprehension), and manual speed with right hand declined in the second evaluation relative to the initial evaluation, while visuoconstructional praxis, receptive vocabulary, working memory, and arithmetic skill improved. The patient showed a remarkable global deterioration in executive functions (planning, task flexibility, behavioral regulation, and metacognition) as revealed by parental report and clinical evaluation. MRI revealed gliosis from the head to tail of the hippocampus and thinning of parahippocampal gyri. CONCLUSIONS: In a clinical case of CCHS, serial evaluation revealed deterioration of executive functions and social cognition over a 3-year interval. These changes corresponded to hippocampal damage as revealed in MRI, which may have affected social cognition through its role in the default mode network. Serial neuropsychological assessment is clinically useful in managing the needs of these patients. PMID- 28708035 TI - Evidence That an Ebola Outbreak Influenced Voting Preferences, Even After Controlling (Mindfully) for Autocorrelation: Reply to Tiokhin and Hruschka (2017). PMID- 28708034 TI - Ultrasound guided percutaneous common carotid artery access in piglets for intracoronary stem cell infusion. AB - In pigs, the deep location of the common carotid artery and overlying sternomastoideus muscle in the neck has led to the recommendation for a surgical cutdown for common carotid access, as opposed to minimally invasive techniques for vascular access. We sought to determine if direct percutaneous common carotid artery access in piglets is attainable. Seventeen piglets were anesthetized and intubated. Under two-dimensional and color flow Doppler ultrasound guidance, a 21 gauge needle was utilized to access the right common carotid artery. Following arterial puncture, the Seldinger technique was applied to place a 4 or 5 French introducer. Upon completion of cardiac catheterization with intracoronary stem cell infusion the introducer was removed and manual pressure was applied to prevent hematoma development. Successful access with an introducer was achieved in all 17 piglets. The average weight was 8.5 +/- 1.7 kg. One piglet developed a hematoma with hemorrhaging from the catheterization site and was euthanized. This piglet was given bivalirudin for the procedure. After this incident, subsequent piglets were not given anticoagulation and no other complications occurred. Ultrasound guided percutaneous common carotid artery access in piglets is attainable in a safe, reliable, and reproducible manner when performed by microvascular experts. PMID- 28708036 TI - Amniotic Fluid Cells Show Higher Pluripotency-Related Gene Expression Than Allantoic Fluid Cells. AB - Amniotic fluid represents an abundant source of multipotent stem cells, referred as broadly multipotent given their differentiation potential and expression of pluripotency-related genes. However, the origin of this broadly multipotent cellular fraction is not fully understood. Several sources have been proposed so far, including embryonic and extraembryonic tissues. In this regard, the ovine developmental model uniquely allows for direct comparison of fetal fluid-derived cells from two separate fetal fluid cavities, the allantois and the amnion, over the entire duration of gestation. As allantoic fluid mainly collects fetal urine, cells originating from the efferent urinary tract can directly be compared with cells deriving from the extraembryonic amniotic tissues and the fetus. This study shows isolation of cells from the amniotic [ovine amniotic fluid cells (oAFCs)] and allantoic fluid [ovine allantoic fluid cells (oALCs)] in a strictly paired fashion with oAFCs and oALCs derived from the same fetus. Both cell types showed cellular phenotypes comparable to standard mesenchymal stem cells (MSCs), with trilineage differentiation potential, and expression of common ovine MSC markers. However, the expression of MSC markers per single cell was higher in oAFCs as measured by flow cytometry. oAFCs exhibited higher proliferative capacities and showed significantly higher expression of pluripotency-related genes OCT4, STAT3, NANOG, and REX1 by quantitative real-time polymerase chain reaction compared with paired oALCs. No significant decrease of pluripotency-related gene expression was noted over gestation, implying that cells with high differentiation potential may be isolated at the end of pregnancy. In conclusion, this study suggests that cells with highest stem cell characteristics may originate from the fetus itself or the amniotic fetal adnexa rather than from the efferent urinary tract or the allantoic fetal adnexa. PMID- 28708037 TI - Greater Sensitivity of Oral Fibroblasts to Smoked Versus Smokeless Tobacco. AB - BACKGROUND: Smokers have an increased incidence and severity of periodontal disease. Although cigarette smoke contains >4,000 chemical components that could affect periodontal tissues, less is understood about the effect of smokeless tobacco. Therefore, this study compares the effects of cigarette smoke extract (CSE) and smokeless tobacco extract (STE) on cell survival and motility of periodontal ligament (PDL) and gingival fibroblasts in vitro. METHODS: PDL and gingival fibroblasts were exposed to various concentrations of CSE, STE, or nicotine alone. Viable cells were labeled with calcein acetoxymethyl, visualized using fluorescent microscopy, and quantified using a fluorescence multi-well plate reader. In vitro wounding and collagen gel contraction assays were used to assess cell motility. RESULTS: Both gingival and PDL fibroblasts displayed reduced cell viability with increasing concentrations of CSE and STE. Based on relative nicotine content, CSE was significantly more cytotoxic than STE. PDL fibroblasts were also more sensitive to both CSE and STE compared with gingival fibroblasts. Finally, sublethal doses of CSE reduced cell motility and gel contraction, whereas STE had less effect. Nicotine alone <=0.5 mM had little to no effect in any of these assays. CONCLUSIONS: Many of the underlying effects of tobacco products on periodontal tissues may be due to direct inhibition of normal fibroblast function. CSE is found to be more deleterious to the function of both PDL and gingival fibroblasts than STE. PDL fibroblasts appear to be more sensitive to CSE and STE than gingival fibroblasts. Therefore, cigarette smoke may have more profound effects than smokeless tobacco. PMID- 28708038 TI - Influence of Implant Neck Surface and Placement Depth on Crestal Bone Changes Around Platform-Switched Implants: A Clinical and Radiographic Study in Dogs. AB - BACKGROUND: The aim of this animal study is to analyze bone remodeling around platform-switching (PS) implants with and without a machined (MACH) collar placed at different levels in relation to the crestal bone in a canine model. METHODS: All mandibular premolars and first molars were extracted in five dogs. After 6 months, grit-blasted acid-etched (GBAE) PS implants with and without a MACH neck were randomly inserted in each hemimandible, positioning the implant-abutment interface in either a supracrestal (+1.5 mm), equicrestal, or subcrestal (-1.5 mm) position, and healing abutments were connected. Implant abutments were dis/reconnected at 12, 14, 16, and 18 weeks after implant placement. After 6 months of healing, animals were sacrificed. Clinical parameters and periapical radiographs were registered on the day of implant placement, at 2 months, at every abutment dis/reconnection, and at sacrifice. Crestal bone changes were calculated and defined as the primary outcome variable. RESULTS: When crestal bone changes from implant placement to 6 months were compared between MACH and GBAE groups, no significant differences were encountered except for implants placed in an equicrestal position (P = 0.04). However, multivariable regression analysis revealed no significant differences between MACH and GBAE implants placed in a supracrestal (beta = -0.08; P = 0.45), equicrestal (beta = -0.05; P = 0.50), or subcrestal (beta = -0.13; P = 0.19) position. CONCLUSION: Surface treatment of the implant neck had no significant influence on crestal bone changes around PS implants with and without a MACH collar. PMID- 28708039 TI - Comparison of Endothelial Function in Healthy Patients and Patients With Chronic Periodontitis and Myocardial Infarction. AB - BACKGROUND: The inflammatory burden as a result of severe periodontal disease acts as an insult to the endothelium. This disruption in the function of the endothelium predisposes it toward formation of atherosclerotic plaque, which may be a subsequent risk for coronary artery disease. The aim of this study is to estimate and compare endothelial function via flow-mediated dilation (FMD) assessment in periodontal health and disease. METHODS: A total of 120 patients were selected and categorized equally into three groups: 1) healthy (control); 2) chronic periodontitis (CP); and 3) myocardial infarction (MI). Periodontal inflamed surface area (PISA) and FMD were assessed in all patients. Fasting blood samples were collected to estimate lipid profile. Analysis of variance was used for comparison of lipid profile, whereas Kruskal-Wallis test was used for comparison of FMD and PISA scores among the study groups with P <0.05. RESULTS: Comparison of FMD levels among the three groups showed statistically significant difference, with P <0.001. The value was statistically significant when the healthy group was compared with the CP and MI groups but not when the CP group was compared with the MI group. Lipid profile levels were statistically significant on comparison between the healthy and CP groups and between the CP and MI groups. CONCLUSION: Endothelial function was impaired in patients with CP compared with healthy patients, and the dysfunction observed was similar to that observed in the MI group based on FMD values. PMID- 28708040 TI - Anterior lumbar discectomy and fusion for acute cauda equina syndrome caused by recurrent disc prolapse: report of 3 cases. AB - There is a lack of information and consensus regarding the optimal treatment for recurrent disc herniation previously treated by posterior discectomy, and no reports have described an anterior approach for recurrent disc herniation causing cauda equina syndrome (CES). Revision posterior decompression, irrespective of the presence of CES, has been reported to be associated with significantly higher rates of dural tears, hematomas, and iatrogenic nerve root damage. The authors describe treatment and outcomes in 3 consecutive cases of patients who underwent anterior lumbar discectomy and fusion (ALDF) for CES caused by recurrent disc herniations that had been previously treated with posterior discectomy. All 3 patients were operated on within 12 hours of presentation and were treated with an anterior retroperitoneal lumbar approach. Follow-up ranged from 12 to 24 months. Complete retrieval of herniated disc material was achieved without encountering significant epidural scar tissue in all 3 cases. No perioperative infection or neurological injury occurred, and all 3 patients had neurological recovery with restoration of bladder and bowel function and improvement in back and leg pain. ALDF is one option to treat CES caused by recurrent lumbar disc prolapse previously treated with posterior discectomy. The main advantage is that it avoids dissection around epidural scar tissue, but the procedure is associated with other risks and further evaluation of its safety in larger series is required. PMID- 28708041 TI - Microendoscopic laminotomy versus conventional laminoplasty for cervical spondylotic myelopathy: 5-year follow-up study. AB - OBJECTIVE The goal of this study was to characterize the long-term clinical and radiological results of articular segmental decompression surgery using endoscopy (cervical microendoscopic laminotomy [CMEL]) for cervical spondylotic myelopathy (CSM) and to compare outcomes to conventional expansive laminoplasty (ELAP). METHODS Consecutive patients with CSM who required surgical treatment were enrolled. All enrolled patients (n = 78) underwent CMEL or ELAP. All patients were followed postoperatively for more than 5 years. The preoperative and 5-year follow-up evaluations included neurological assessment (Japanese Orthopaedic Association [JOA] score), JOA recovery rates, axial neck pain (using a visual analog scale), the SF-36, and cervical sagittal alignment (C2-7 subaxial cervical angle). RESULTS Sixty-one patients were included for analysis, 31 in the CMEL group and 30 in the ELAP group. The mean preoperative JOA score was 10.1 points in the CMEL group and 10.9 points in the ELAP group (p > 0.05). The JOA recovery rates were similar, 57.6% in the CMEL group and 55.4% in the ELAP group (p > 0.05). The axial neck pain in the CMEL group was significantly lower than that in the ELAP group (p < 0.01). At the 5-year follow-up, cervical alignment was more favorable in the CMEL group, with an average 2.6 degrees gain in lordosis (versus 1.2 degrees loss of lordosis in the ELAP group [p < 0.05]) and lower incidence of postoperative kyphosis. CONCLUSIONS CMEL is a novel, less invasive technique that allows for multilevel posterior cervical decompression for the treatment of CSM. This 5-year follow-up data demonstrates that after undergoing CMEL, patients have similar neurological outcomes to conventional laminoplasty, with significantly less postoperative axial pain and improved subaxial cervical lordosis when compared with their traditional ELAP counterparts. PMID- 28708042 TI - Editorial. Use of anterior lumbar discectomy and interbody fusion in the management of recurrent lumbar disc herniation and cauda equina syndrome. PMID- 28708043 TI - Reirradiation spine stereotactic body radiation therapy for spinal metastases: systematic review. AB - OBJECTIVE Spinal metastases that recur after conventional palliative radiotherapy have historically been difficult to manage due to concerns of spinal cord toxicity in the retreatment setting. Spine stereotactic body radiation therapy (SBRT), also known as stereotactic radiosurgery, is emerging as an effective and safe means of delivering ablative doses to these recurrent tumors. The authors performed a systematic review of the literature to determine the clinical efficacy and safety of spine SBRT specific to previously irradiated spinal metastases. METHODS A systematic literature review was conducted, which was specific to SBRT to the spine, using MEDLINE, Embase, Cochrane Evidence-Based Medicine Database, National Guideline Clearinghouse, and CMA Infobase, with further bibliographic review of appropriate articles. Research questions included: 1) Is retreatment spine SBRT efficacious with respect to local control and symptom control? 2) Is retreatment spine SBRT safe? RESULTS The initial literature search retrieved 2263 articles. Of these articles, 160 were potentially relevant, 105 were selected for in-depth review, and 9 studies met all inclusion criteria for analysis. All studies were single-institution series, including 4 retrospective, 3 retrospective series of prospective databases, 1 prospective, and 1 Phase I/II prospective study (low- or very low-quality data). The results indicated that spine SBRT is effective, with a median 1-year local control rate of 76% (range 66%-90%). Improvement in patients' pain scores post SBRT ranged from 65% to 81%. Treatment delivery was safe, with crude rates of vertebral body fracture of 12% (range 0%-22%) and radiation-induced myelopathy of 1.2%. CONCLUSIONS This systematic literature review suggests that SBRT to previously irradiated spinal metastases is safe and effective with respect to both local control and pain relief. Although the evidence is limited to low quality data, SBRT can be a recommended treatment option for reirradiation. PMID- 28708044 TI - Relationship between attachment and executive dysfunction in the homeless. AB - The executive functions of the homeless may be contributing to the success or failure of social integration processes. The goal of this study was to analyze the relationship between attachment and executive dysfunction in the homeless, specifically, to analyze the prevalence of adult attachment and executive dysfunction patterns, as well as the predictive power of different types of attachment for executive functioning. Participants were 107 homeless. Descriptive analysis revealed the prevalence of insecure attachment, and a high prevalence of clinically significant executive dysfunction. Regression analysis showed that attachment predicts all the executive functions, although the predictive power of attachment decreased when entering the variable drug addiction. People in a situation of chronic social exclusion are characterized by an insecure attachment style and moderate levels of executive dysfunction. PMID- 28708045 TI - Spontaneous pneumomediastinum: Case presentation to a college student health clinic. AB - The author describes a case of spontaneous pneumomediastinum (SPM) in a 19-year old man presenting to a college student health clinic. The author also provides a review on SPM, including clinical manifestations, diagnostic evaluation, and management. PMID- 28708046 TI - Analysis of MTNR1B gene polymorphisms in relationship with IRS2 gene variants, epicardial fat thickness, glucose homeostasis and cognitive performance in the elderly. AB - ABSTARCT Genome-wide association studies pinpointed common variants in or near the MTNR1B gene encoding MT2 melatonin receptor to be strongly associated with fasting glucose levels. IRS2 gene polymorphisms impact insulin resistance and epicardial fat (EF) thickness, which in turn is correlated with visceral adiposity, cognitive ability and risk for metabolic plus cardiovascular disease. We aimed to discover the interactions between MTNR1B and IRS2 gene polymorphisms, insulin sensitivity, EF thickness and cognitive performance in the elderly. In 60 subjects aged 60 years and older, we evaluated five single nucleotide polymorphisms (SNPs) within the MTNR1B locus (rs10830962, rs4753426, rs12804291, rs10830963, rs3781638), the Gly1057Asp variant of IRS2 gene (rs1805097), biochemical parameters, cognitive performance by the Mini Mental State Examination (MMSE) and EF thickness by transthoracic echocardiography. We found that MTNR1B and IRS2 gene variants impacted EF thickness, lipid profile and glucose homeostasis. IRS2 but not MTNR1B variants impacted MMSE scores. In conclusion, MTNR1B SNPs interact with IRS2 gene variant, correlate with the amount of epicardial adipose tissue and impact glucose homeostasis and lipid profile influencing cardiometabolic risk. PMID- 28708047 TI - Temporal patterns of chronic wasting disease prion excretion in three cervid species. AB - Chronic wasting disease (CWD) is the only naturally occurring transmissible spongiform encephalopathy affecting free-ranging wildlife populations. Transmission of CWD occurs by direct contact or through contaminated environments; however, little is known about the temporal patterns of CWD prion excretion and shedding in wild cervids. We tested the urine and faeces of three species of captive cervids (elk, mule and white-tailed deer) at 6, 12, 18 and 24 months after oral inoculation to evaluate the temporal, species- and genotype specific factors affecting the excretion of CWD prions. Although none of the animals exhibited clinical signs of CWD during the study, we determined that all three cervid species were excreting CWD prions by 6 months post-inoculation. Faecal samples were consistently positive for CWD prions for all three cervid species (88 %), and were more likely to be positive than urine samples (28 %). Cervids with genotypes encoding for the prion protein (PRNP) that were considered to be more susceptible to CWD were more likely to excrete CWD prions (94 %) than cervids with genotypes considered to be less susceptible (64 %). All cervids with CWD prions in their urine also had positive faeces (n=5), but the converse was not true. Our study is the first to demonstrate CWD prion excretion in urine by asymptomatic elk and mule deer. Our results indicate that the excretion of CWD prions in faeces and, to a lesser extent, urine may provide an important avenue for depositing prions in the environment. PMID- 28708048 TI - Quantitative and structural analyses of the in vitro and ex vivo biofilm-forming ability of dermatophytes. AB - PURPOSE: The aim of this study was to evaluate the in vitro and ex vivo biofilm forming ability of dermatophytes on a nail fragment. METHODOLOGY: Initially, four isolates of Trichophyton rubrum, six of Trichophyton tonsurans, three of Trichophyton mentagrophytes, ten of Microsporum canis and three of Microsporum gypseum were tested for production biomass by crystal violet assay. Then, one strain per species presenting the best biofilm production was chosen for further studies by optical microscopy (Congo red staining), confocal laser scanning (LIVE/DEAD staining) and scanning electron (secondary electron) microscopy. RESULTS: Biomass quantification by crystal violet assay, optical microscope images of Congo red staining, confocal microscope and scanning electron microscope images revealed that all species studied are able to form biofilms both in vitro and ex vivo, with variable density and architecture. M. gypseum, T. rubrum and T. tonsurans produced robust biofilms, with abundant matrix and biomass, while M. canis produced the weakest biofilms compared to other species. CONCLUSION: This study sheds light on biofilms of different dermatophyte species, which will contribute to a better understanding of the pathophysiology of dermatophytosis. Further studies of this type are necessary to investigate the processes involved in the formation and composition of dermatophyte biofilms. PMID- 28708050 TI - Hyperinvasiveness and increased intercellular spread of Listeria monocytogenes sequence type 1 are independent of listeriolysin S, internalin F and internalin J1. AB - PURPOSE: Listeria monocytogenes is a genetically heterogeneous species, which is divided into evolutionary lineages and clonal complexes (CCs). Not all L. monocytogenes isolates are equally likely to cause disease, with CC1, and in particular sequence type (ST) 1, being the most prevalent complex in human and ruminant infections and more specifically in neurolisteriosis. While the major factors that determine neurotropism are unknown, the L. monocytogenes CC1 strains harbour listeriolysin S (lls) and particular alleles of internalin (inl) F and inlJ, which are not present in CCs commonly isolated from food and the environment. The aim of this study was to analyse the role of these factors in cellular infection. METHODOLOGY: A ST1 field strain (JF5203) from CC1 isolated from a bovine rhombencephalitis case was used to create deletion mutants. These were tested alongside the parental strain and EGD-e (CC9), in different culture models representing L. monocytogenes targets (neurons, microglia, placenta, intestine and macrophages). The phenotype was assessed by quantification of c.f.u. from cell lysates and immunofluorescence analysis. RESULTS: Compared to EGD-e, the ST1 strain JF5203 was hyperinvasive and exhibited increased intercellular spread. However, deletion of llsB, inlF or inlJ1, had no significant effect on infection or growth in the culture models tested. CONCLUSION: Our results underline the importance of using relevant clinical strains when investigating L. monocytogenes virulence. We show that despite the association with CC1, llsB, inlF and inlJ1 are not involved in the hyperinvasiveness and efficient intercellular spread of ST1 in various cell types. PMID- 28708049 TI - Identification of two novel functional tRNA-derived fragments induced in response to respiratory syncytial virus infection. AB - Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infection (LRTI) in children from infancy up to early childhood. Recently, we demonstrated that RSV infection alters cellular small non-coding RNA (sncRNA) expression, most notably the tRNA-derived RNA fragments (tRFs). However, the functions of the tRFs in virus-host interaction are largely unknown. Herein, we examined the role of three RSV-induced tRFs derived from the 5-end of mature tRNAs decoding GlyCCC, LysCTT and CysGCA (named tRF5-GlyCCC, tRF5-LysCTT and tRF5 CysGCA, respectively) in controlling RSV replication. We found that tRF5-GlyCCC and tRF5-LysCTT, but not tRF5-CysGCA, promote RSV replication, demonstrating the functional specificity of tRFs. The associated molecular mechanisms underlying the functions of tRF5-GlyCCC and tRF5-LysCTT were also investigated. Regulating the expression and/or activity of these tRFs may provide new insights into preventive and therapeutic strategies for RSV infection. The study also accumulated data for future development of a tRF targeting algorithm. PMID- 28708051 TI - Ralstonia solanacearum novel E3 ubiquitin ligase (NEL) effectors RipAW and RipAR suppress pattern-triggered immunity in plants. AB - Ralstonia solanacearum is the causal agent of bacterial wilt in solanaceous crops. This pathogen injects more than 70 effector proteins into host plant cells via the Hrp type III secretion system to cause a successful infection. However, the function of these effectors in plant cells, especially in the suppression of plant immunity, remains largely unknown. In this study, we characterized two Ralstonia solanacearum effectors, RipAW and RipAR, which share homology with the IpaH family of effectors from animal and plant pathogenic bacteria, that have a novel E3 ubiquitin ligase (NEL) domain. Recombinant RipAW and RipAR show E3 ubiquitin ligase activity in vitro. RipAW and RipAR localized to the cytoplasm of plant cells and significantly suppressed pattern-triggered immunity (PTI) responses such as the production of reactive oxygen species and the expression of defence-related genes when expressed in leaves of Nicotiana benthamiana. Mutation in the conserved cysteine residue in the NEL domain of RipAW completely abolished the E3 ubiquitin ligase activity in vitro and the ability to suppress PTI responses in plant leaves. These results indicate that RipAW suppresses plant PTI responses through the E3 ubiquitin ligase activity. Unlike other members of the IpaH family of effectors, RipAW and RipAR had no leucine-rich repeat motifs in their amino acid sequences. A conserved C-terminal region of RipAW is indispensable for PTI suppression. Transgenic Arabidopsis plants expressing RipAW and RipAR showed increased disease susceptibility, suggesting that RipAW and RipAR contribute to bacterial virulence in plants. PMID- 28708052 TI - High prevalence of antibodies to core+1/ARF protein in HCV-infected patients with advanced cirrhosis. AB - Hepatitis C virus (HCV) possesses a second open reading frame (ORF) within the core gene encoding an additional protein, known as the alternative reading frame protein (ARFP), F or core+1. The biological significance of the core+1/ARF protein remains elusive. However, several independent studies have shown the presence of core+1/ARFP antibodies in chronically HCV-infected patients. Furthermore, a higher prevalence of core+1/ARFP antibodies was detected in patients with HCV-associated hepatocellular carcinoma (HCC). Here, we investigated the incidence of core+1/ARFPantibodies in chronically HCV-infected patients at different stages of cirrhosis in comparison to chronically HCV infected patients at earlier stages of disease. Using ELISA, we assessed the prevalence of anti-core+1 antibodies in 30 patients with advanced cirrhosis [model for end-stage liver disease (MELD) >=15] in comparison with 50 patients with mild cirrhosis (MELD <15) and 164 chronic HCV patients without cirrhosis. 28.7 % of HCV patients with cirrhosis were positive for anti-core+1 antibodies, in contrast with 16.5 % of non-cirrhotic HCV patients. Moreover, there was significantly higher positivity for anti-core+1 antibodies in HCV patients with advanced cirrhosis (36.7 %) compared to those with early cirrhosis (24 %) (P<0.05). These findings, together with the high prevalence of anti-core+1 antibodies in HCV patients with HCC, suggest that core+1 protein may have a role in virus-associated pathogenesis, and provide evidence to suggest that the levels of anti-core+1 antibodies may serve as a marker for disease progression. PMID- 28708053 TI - Rapid diagnosis of extrapulmonary tuberculosis with Xpert Mycobacterium tuberculosis/rifampicin assay. AB - PURPOSE: XpertMycobacterium tuberculosis/rifampicin (Xpert MTB/RIF) assay has been endorsed by the World Health Organization (WHO) for diagnosis of extrapulmonary tuberculosis (EPTB), while the sensitivity and specificity have not been fully evaluated. We aimed to evaluate the performance of Xpert MTB/RIF assay in the detection of different extrapulmonary specimens. METHODS: A total of 420 nonrespiratory specimens were detected with acid-fast bacilli (AFB) smear microscopy, solid culture, conventional drug susceptibility testing (DST) and Xpert MTB/RIF assay. Using solid culture and conventional DST as the gold standard, we assessed the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) of the Xpert MTB/RIF assay for detecting MTB and rifampin resistance, respectively. RESULTS: When setting the solid culture results as the gold standard, the sensitivity, specificity, PPV, NPV and Kappa value of Xpert MTB/RIF assay and AFB smear results were 70.6 % (48/68), 91.96 % (318/346), 63.2 % (48/76), 94.1 % (318/338), 0.60, respectively. In addition, when compared with conventional DST results, the sensitivity, specificity, PPV, NPV and Kappa of the Xpert MTB/RIF assay for detecting rifampin resistance were 91.7 % (11/12), 100.0 % (47/47), 100.0 % (11/11), 97.9 % (47/48) and 0.95, respectively. CONCLUSION: Compared with AFB smear and solid culture, Xpert MTB/RIF assay has high sensitivities and short detection time, so could be used as an alternative for the rapid diagnosis of EPTB and rifampin resistance in clinical practice. PMID- 28708054 TI - The P gene of rodent brain-adapted measles virus plays a critical role in neurovirulence. AB - In rare cases, measles virus (MV) in children leads to fatal neurological complications such as primary measles encephalitis, post-acute measles encephalitis, subacute sclerosing panencephalitis and measles inclusion-body encephalitis. To investigate the pathogenesis of MV-induced encephalitis, rodent brain-adapted MV strains CAM/RB and CAMR40 were generated. These strains acquired mutations to adapt to the rodent brain during 40 passages in rat brain. However, it is still unknown which genes confer the neurovirulence of MV. We previously established a rescue system for recombinant MVs possessing the backbone of wild type strain HL, an avirulent strain in mice. In the present study, to identify the genes in CAMR40 that elicit neurovirulence, we generated chimeric recombinant MVs based on strain HL. As a result, recombinant wild-type MV in which the haemagglutinin (H) gene was substituted with that of CAMR40 caused a non-lethal mild disease in mice, while additional substitution of the HL phosphoprotein (P) gene with that of strain CAMR40 caused lethal severe neurological signs comparable to those of CAMR40. These results clearly indicated that, in addition to the H gene, the P gene is required for the neurovirulence of MV CAMR40. PMID- 28708056 TI - Metarhizium robertsii produces indole-3-acetic acid, which promotes root growth in Arabidopsis and enhances virulence to insects. AB - The plant root colonizing insect-pathogenic fungus Metarhizium robertsii has been shown to boost plant growth, but little is known about the responsible mechanisms. Here we show that M. robertsii promotes lateral root growth and root hair development of Arabidopsis seedlings in part through an auxin [indole-3 acetic acid (IAA)]-dependent mechanism. M. robertsii, or its auxin-containing culture filtrate promoted root proliferation, activated IAA-regulated gene expression and rescued the root hair defect of the IAA-deficient rhd6 Arabidopsis mutant. Substrate feeding assays suggest that M. robertsii possesses tryptamine (TAM) and indole-3-acetamide tryptophan (Trp)-dependent auxin biosynthetic pathways. Deletion of Mrtdc impaired M. robertsii IAA production by blocking conversion of Trp to TAM but the reduction was not sufficient to affect plant growth enhancement. We also show that M. robertsii secretes IAA on insect cuticle. ?Mrtdc produced fewer infection structures and was less virulent to insects than the wild-type, whereas M. robertsii spores harvested from culture media containing IAA were more virulent. Furthermore, exogenous application of IAA increased appressorial formation and virulence. Together, these results suggest that auxins play an important role in the ability of M. robertsii to promote plant growth, and the endogenous pathways for IAA production may also be involved in regulating entomopathogenicity. Auxins were also produced by other Metarhizium species and the endophytic insect pathogen Beauveria bassiana suggesting that interplay between plant- and fungal-derived auxins has important implications for plant-microbe-insect interactions. PMID- 28708055 TI - Prion disease pathogenesis in the absence of the commensal microbiota. AB - Prion diseases are a unique group of transmissible, typically sub-acute, neurodegenerative disorders. During central nervous system (CNS) prion disease, the microglia become activated and are thought to provide a protective response by scavenging and clearing prions. The mammalian intestine is host to a large burden of commensal micro-organisms, especially bacteria, termed the microbiota. The commensal microbiota has beneficial effects on host health, including through the metabolism of essential nutrients, regulation of host development and protection against pathogens. The commensal gut microbiota also constitutively regulates the functional maturation of microglia in the CNS, and microglial function is impaired when it is absent in germ-free mice. In the current study, we determined whether the absence of the commensal gut microbiota might also affect prion disease pathogenesis. Our data clearly show that the absence of the commensal microbiota in germ-free mice did not affect prion disease duration or susceptibility after exposure to prions by intraperitoneal or intracerebral injection. Furthermore, the magnitude and distribution of the characteristic neuropathological hallmarks of terminal prion disease in the CNS, including the development of spongiform pathology, accumulation of prion disease-specific protein (PrP), astrogliosis and microglial activation, were similar in conventionally housed and germ-free mice. Thus, although the commensal gut microbiota constitutively promotes the maintenance of the microglia in the CNS under steady-state conditions in naive mice, our data suggest that dramatic changes to the abundance or complexity of the commensal gut microbiota are unlikely to influence CNS prion disease pathogenesis. PMID- 28708057 TI - Erythrobacter xanthus sp. nov., isolated from surface seawater of the South China Sea. AB - A Gram-reaction-negative, aerobic, oxidase- and catalase-positive, yellow pigmented, non-flagellated, rod-shaped bacterium, designed strain SM1501T, was isolated from surface seawater of the South China Sea. SM1501T grew at 7-42 degrees C and with 0-11 % (w/v) NaCl. Phylogenetic analyses based on 16S rRNA gene sequences revealed that SM1501T represented a member of the genus Erythrobacter, sharing the highest 16S rRNA gene sequence similarity (97.4 %) with Erythrobacter luteus and 94.2-96.5 % 16S rRNA gene sequence similarities to other species of the genus Erythrobacterwith validly published names. The average nucleotide identity (ANI) value and in silico DNA-DNA hybridization value between SM1501T and E. luteus were only 74.6 and 20.0 %, respectively. The predominant cellular fatty acids of SM1501T were C17 : 1omega6c, C18 : 1omega7c and summed feature 3 (C16 : 1omega7c and/or iso-C15 : 0 2-OH). The major polar lipids of the strain were phosphatidylethanolamine, phosphatidylglycerol, sphingoglycolipid, diphosphatidylglycerol and phosphatidylcholine and the main respiratory quinone of was Q-10. Polyphasic data presented in this paper support the notion that SM1501T represents a novel species in the genus Erythrobacter, for which the name Erythrobacter xanthus sp. nov. is proposed. The type strain of Erythrobacterxanthus is SM1501T (=KCTC 42669T=CCTCC AB 2015396T). PMID- 28708058 TI - Kiloniella antarctica sp. nov., isolated from a polynya of Amundsen Sea in Western Antarctic Sea. AB - A taxonomic study was conducted on strain soj2014T, which was isolated from the surface water of a polynya in the Antarctic Sea. Comparative 16S rRNA gene sequence analysis showed that strain soj2014T belongs to the family Kiloniellaceae and is closely related to Kiloniella spongiae MEBiC09566T, 'Kiloniella litopenaei' P1-1T and Kiloniella laminariae LD81T (98.0 %, 97.8 % and 96.2 % 16S rRNA gene sequence similarity, respectively). The DNA-DNA hybridization values between strain soj2014T and closely related strains were below 28.6 %. The G+C content of the genomic DNA of strain soj2014T was 45.5 mol%. The predominant cellular fatty acids were summed feature 8 (composed of C18 : 1omega6c/C18 : 1omega7c, 57.0 %) and summed feature 3 (composed of C16 : 1omega6c/C16 : 1omega7c, 23.5 %). Strain soj2014T was Gram-stain-negative, slightly curved, spiral-shaped, and motile with a single polar flagellum. The strain grew at 0-30 degrees C (optimum, 25 degrees C), in 1.5-5.1 % (w/v) NaCl (optimum, 2.1-2.4 %) and at pH 5.5-9.5 (optimum, 7.5-8.0). It also had differential carbohydrate utilization traits and enzyme activities compared with closely related strains. Based on these phylogenetic, phenotypic and chemotaxonomic analyses, strain soj2014T represents a distinct species, separable from the reference strains, and is, therefore, proposed as a novel species, Kiloniella antarctica sp. nov. The type strain is soj2014T (=KCTC 42186T=JCM 30386T). PMID- 28708059 TI - A tunable refractive index matching medium for live imaging cells, tissues and model organisms. AB - In light microscopy, refractive index mismatches between media and sample cause spherical aberrations that often limit penetration depth and resolution. Optical clearing techniques can alleviate these mismatches, but they are so far limited to fixed samples. We present Iodixanol as a non-toxic medium supplement that allows refractive index matching in live specimens and thus substantially improves image quality in live-imaged primary cell cultures, planarians, zebrafish and human cerebral organoids. PMID- 28708060 TI - SynEM, automated synapse detection for connectomics. AB - Nerve tissue contains a high density of chemical synapses, about 1 per um3 in the mammalian cerebral cortex. Thus, even for small blocks of nerve tissue, dense connectomic mapping requires the identification of millions to billions of synapses. While the focus of connectomic data analysis has been on neurite reconstruction, synapse detection becomes limiting when datasets grow in size and dense mapping is required. Here, we report SynEM, a method for automated detection of synapses from conventionally en-bloc stained 3D electron microscopy image stacks. The approach is based on a segmentation of the image data and focuses on classifying borders between neuronal processes as synaptic or non synaptic. SynEM yields 97% precision and recall in binary cortical connectomes with no user interaction. It scales to large volumes of cortical neuropil, plausibly even whole-brain datasets. SynEM removes the burden of manual synapse annotation for large densely mapped connectomes. PMID- 28708062 TI - The absence of race in Norway? PMID- 28708063 TI - Observations on race and racism in Greece. PMID- 28708061 TI - Locus coeruleus to basolateral amygdala noradrenergic projections promote anxiety like behavior. AB - Increased tonic activity of locus coeruleus noradrenergic (LC-NE) neurons induces anxiety-like and aversive behavior. While some information is known about the afferent circuitry that endogenously drives this neural activity and behavior, the downstream receptors and anatomical projections that mediate these acute risk aversive behavioral states via the LC-NE system remain unresolved. Here we use a combination of retrograde tracing, fast-scan cyclic voltammetry, electrophysiology, and in vivo optogenetics with localized pharmacology to identify neural substrates downstream of increased tonic LC-NE activity in mice. We demonstrate that photostimulation of LC-NE fibers in the BLA evokes norepinephrine release in the basolateral amygdala (BLA), alters BLA neuronal activity, conditions aversion, and increases anxiety-like behavior. Additionally, we report that beta-adrenergic receptors mediate the anxiety-like phenotype of increased NE release in the BLA. These studies begin to illustrate how the complex efferent system of the LC-NE system selectively mediates behavior through distinct receptor and projection-selective mechanisms. PMID- 28708064 TI - Race and society in Portugal: two notes and a remark. PMID- 28708065 TI - Homogeneous crystal nucleation in polymers. AB - The pathway of crystal nucleation significantly influences the structure and properties of semi-crystalline polymers. Crystal nucleation is normally heterogeneous at low supercooling, and homogeneous at high supercooling, of the polymer melt. Homogeneous nucleation in bulk polymers has been, so far, hardly accessible experimentally, and was even doubted to occur at all. This topical review summarizes experimental findings on homogeneous crystal nucleation in polymers. Recently developed fast scanning calorimetry, with cooling and heating rates up to 106 K s-1, allows for detailed investigations of nucleation near and even below the glass transition temperature, including analysis of nuclei stability. As for other materials, the maximum homogeneous nucleation rate for polymers is located close to the glass transition temperature. In the experiments discussed here, it is shown that polymer nucleation is homogeneous at such temperatures. Homogeneous nucleation in polymers is discussed in the framework of the classical nucleation theory. The majority of our observations are consistent with the theory. The discrepancies may guide further research, particularly experiments to progress theoretical development. Progress in the understanding of homogeneous nucleation is much needed, since most of the modelling approaches dealing with polymer crystallization exclusively consider homogeneous nucleation. This is also the basis for advancing theoretical approaches to the much more complex phenomena governing heterogeneous nucleation. PMID- 28708066 TI - Novel Selective Detection Method of Tumor Angiogenesis Factors Using Living Nano Robots. AB - This paper reports a novel self-detection method for tumor cells using living nano-robots. These living robots are a nonpathogenic strain of E. coli bacteria equipped with naturally synthesized bio-nano-sensory systems that have an affinity to VEGF, an angiogenic factor overly-expressed by cancer cells. The VEGF affinity/chemotaxis was assessed using several assays including the capillary chemotaxis assay, chemotaxis assay on soft agar, and chemotaxis assay on solid agar. In addition, a microfluidic device was developed to possibly discover tumor cells through the overexpressed vascular endothelial growth factor (VEGF). Various experiments to study the sensing characteristic of the nano-robots presented a strong response toward the VEGF. Thus, a new paradigm of selective targeting therapies for cancer can be advanced using swimming E. coli as self navigator miniaturized robots as well as drug-delivery vehicles. PMID- 28708067 TI - Enhanced Handover Decision Algorithm in Heterogeneous Wireless Network. AB - Transferring a huge amount of data between different network locations over the network links depends on the network's traffic capacity and data rate. Traditionally, a mobile device may be moved to achieve the operations of vertical handover, considering only one criterion, that is the Received Signal Strength (RSS). The use of a single criterion may cause service interruption, an unbalanced network load and an inefficient vertical handover. In this paper, we propose an enhanced vertical handover decision algorithm based on multiple criteria in the heterogeneous wireless network. The algorithm consists of three technology interfaces: Long-Term Evolution (LTE), Worldwide interoperability for Microwave Access (WiMAX) and Wireless Local Area Network (WLAN). It also employs three types of vertical handover decision algorithms: equal priority, mobile priority and network priority. The simulation results illustrate that the three types of decision algorithms outperform the traditional network decision algorithm in terms of handover number probability and the handover failure probability. In addition, it is noticed that the network priority handover decision algorithm produces better results compared to the equal priority and the mobile priority handover decision algorithm. Finally, the simulation results are validated by the analytical model. PMID- 28708068 TI - Mechanomyography and Torque during FES-Evoked Muscle Contractions to Fatigue in Individuals with Spinal Cord Injury. AB - A mechanomyography muscle contraction (MC) sensor, affixed to the skin surface, was used to quantify muscle tension during repetitive functional electrical stimulation (FES)-evoked isometric rectus femoris contractions to fatigue in individuals with spinal cord injury (SCI). Nine persons with motor complete SCI were seated on a commercial muscle dynamometer that quantified peak torque and average torque outputs, while measurements from the MC sensor were simultaneously recorded. MC-sensor-predicted measures of dynamometer torques, including the signal peak (SP) and signal average (SA), were highly associated with isometric knee extension peak torque (SP: r = 0.91, p < 0.0001), and average torque (SA: r = 0.89, p < 0.0001), respectively. Bland-Altman (BA) analyses with Lin's concordance (rhoC) revealed good association between MC-sensor-predicted peak muscle torques (SP; rhoC = 0.91) and average muscle torques (SA; rhoC = 0.89) with the equivalent dynamometer measures, over a range of FES current amplitudes. The relationship of dynamometer torques and predicted MC torques during repetitive FES-evoked muscle contraction to fatigue were moderately associated (SP: r = 0.80, p < 0.0001; SA: r = 0.77; p < 0.0001), with BA associations between the two devices fair-moderate (SP; rhoC = 0.70: SA; rhoC = 0.30). These findings demonstrated that a skin-surface muscle mechanomyography sensor was an accurate proxy for electrically-evoked muscle contraction torques when directly measured during isometric dynamometry in individuals with SCI. The novel application of the MC sensor during FES-evoked muscle contractions suggested its possible application for real-world tasks (e.g., prolonged sit-to-stand, stepping,) where muscle forces during fatiguing activities cannot be directly measured. PMID- 28708069 TI - Distinct Mechanisms Underlying Resveratrol-Mediated Protection from Types of Cellular Stress in C6 Glioma Cells. AB - The polyphenolic phytostilbene, trans-resveratrol, is found in high amounts in several types and tissues of plants, including grapes, and has been proposed to have beneficial effects in the central nervous system due to its activity as an antioxidant. The objective of the present study was to identify the mechanisms underlying the protective effects of resveratrol under conditions of oxidative stress or DNA damage, induced by the extracellularly applied oxidant, tert-butyl hydrogen peroxide, or UV-irradiation, respectively. In C6 glioma cells, a model system for glial cell biology and pharmacology, resveratrol was protective against both types of insult. Prevention of tau protein cleavage and of the formation of neurofibrillary tangles were identified as mechanisms of action of resveratrol-mediated protection in both paradigms of cellular damage. However, depending on the type of insult, resveratrol exerted its protective activity differentially: under conditions of chemically induced oxidative stress, inhibition of caspase activity, while with DNA damage, resveratrol regulated tau phosphorylation at Ser422. Results advance our understanding of resveratrol's complex impact on cellular signaling pathway and contribute to the notion of resveratrol's role as a pleiotropic therapeutic agent. PMID- 28708070 TI - miR-206-3p Inhibits 3T3-L1 Cell Adipogenesis via the c-Met/PI3K/Akt Pathway. AB - MicroRNAs (miRNAs) are important post-transcriptional regulators during adipocyte adipogenesis. MiR-206-3p, a tissue-specific miRNA, is absent in white adipocytes. In this study, we examined the roles of mmu-miR-206-3p in the adipogenic differentiation of 3T3-L1 preadipocytes. The miR-206-3p expression has shown an apparent decreasing trend after induction, and sustained low expression throughout the differentiation of 3T3-L1 cells. miR-206-3p blocked the adipogenic differentiation of 3T3-L1 cells by attenuating c-Met expression; the inhibition effect of miR-206 to the adipogenic differentiation can be counteracted by restoring c-Met expression. In addition, miR-206-3p decreased the phosphorylation of Akt, which is the downstream effector of c-Met in the PI3K/Akt signaling pathway. These data indicate that miR-206-3p inhibits adipocyte adipogenesis through silencing c-Met and subsequently inactivating the PI3K/Akt signaling pathway. PMID- 28708071 TI - Evolutionary Origins of Cancer Driver Genes and Implications for Cancer Prognosis. AB - The cancer atavistic theory suggests that carcinogenesis is a reverse evolution process. It is thus of great interest to explore the evolutionary origins of cancer driver genes and the relevant mechanisms underlying the carcinogenesis. Moreover, the evolutionary features of cancer driver genes could be helpful in selecting cancer biomarkers from high-throughput data. In this study, through analyzing the cancer endogenous molecular networks, we revealed that the subnetwork originating from eukaryota could control the unlimited proliferation of cancer cells, and the subnetwork originating from eumetazoa could recapitulate the other hallmarks of cancer. In addition, investigations based on multiple datasets revealed that cancer driver genes were enriched in genes originating from eukaryota, opisthokonta, and eumetazoa. These results have important implications for enhancing the robustness of cancer prognosis models through selecting the gene signatures by the gene age information. PMID- 28708072 TI - Iron Fortified Complementary Foods Containing a Mixture of Sodium Iron EDTA with Either Ferrous Fumarate or Ferric Pyrophosphate Reduce Iron Deficiency Anemia in 12- to 36-Month-Old Children in a Malaria Endemic Setting: A Secondary Analysis of a Cluster-Randomized Controlled Trial. AB - Iron deficiency anemia (IDA) is a major public health problem in sub-Saharan Africa. The efficacy of iron fortification against IDA is uncertain in malaria endemic settings. The objective of this study was to evaluate the efficacy of a complementary food (CF) fortified with sodium iron EDTA (NaFeEDTA) plus either ferrous fumarate (FeFum) or ferric pyrophosphate (FePP) to combat IDA in preschool-age children in a highly malaria endemic region. This is a secondary analysis of a nine-month cluster-randomized controlled trial conducted in south central Cote d'Ivoire. 378 children aged 12-36 months were randomly assigned to no food intervention (n = 125; control group), CF fortified with 2 mg NaFeEDTA plus 3.8 mg FeFum for six days/week (n = 126; FeFum group), and CF fortified with 2 mg NaFeEDTA and 3.8 mg FePP for six days/week (n = 127; FePP group). The outcome measures were hemoglobin (Hb), plasma ferritin (PF), iron deficiency (PF < 30 MUg/L), and anemia (Hb < 11.0 g/dL). Data were analyzed with random-effect models and PF was adjusted for inflammation. The prevalence of Plasmodium falciparum infection and inflammation during the study were 44-66%, and 57-76%, respectively. There was a significant time by treatment interaction on IDA (p = 0.028) and a borderline significant time by treatment interaction on iron deficiency with or without anemia (p = 0.068). IDA prevalence sharply decreased in the FeFum (32.8% to 1.2%, p < 0.001) and FePP group (23.6% to 3.4%, p < 0.001). However, there was no significant time by treatment interaction on Hb or total anemia. These data indicate that, despite the high endemicity of malaria and elevated inflammation biomarkers (C-reactive protein or alpha-1-acid glycoprotein), IDA was markedly reduced by provision of iron fortified CF to preschool-age children for 9 months, with no significant differences between a combination of NaFeEDTA with FeFum or NaFeEDTA with FePP. However, there was no overall effect on anemia, suggesting most of the anemia in this setting is not due to ID. This trial is registered at clinicaltrials.gov (NCT01634945). PMID- 28708073 TI - Solvent Supercritical Fluid Technologies to Extract Bioactive Compounds from Natural Sources: A Review. AB - Supercritical fluid technologies offer a propitious method for drug discovery from natural sources. Such methods require relatively short processing times, produce extracts with little or no organic co-solvent, and are able to extract bioactive molecules whilst minimising degradation. Supercritical fluid extraction (SFE) provides a range of benefits, as well as offering routes to overcome some of the limitations that exist with the conventional methods of extraction. Unfortunately, SFE-based methods are not without their own shortcomings; two major ones being: (1) the high establishment cost; and (2) the selective solvent nature of CO2, i.e., that CO2 only dissolves small non-polar molecules, although this can be viewed as a positive outcome provided bioactive molecules are extracted during solvent-based SFE. This review provides an update of SFE methods for natural products and outlines the main operating parameters for extract recovery. Selected processing considerations are presented regarding supercritical fluids and the development and application of ultrasonic-assisted SFE methods, as well as providing some of the key aspects of SFE scalability. PMID- 28708074 TI - Into the Woods or a Stroll in the Park: How Virtual Contact with Nature Impacts Positive and Negative Affect. AB - This study examined the effects of virtual contact with nature on positive and negative affect, and investigated the psychological process of perceived restorativeness as a mediator of this relationship. A sample of 220 Australians aged between 18 and 75 years (M = 49.07, SD = 14.34, female = 72%) participated in the study. Participants were randomly allocated to one of the three experimental conditions experienced through video presentations: (1) 'wild' nature, (2) 'urban' nature, and (3) non-nature control. They then completed measures of perceived restorativeness as well as positive and negative affect. Compared to the non-nature control condition, the experience of wild nature resulted in significantly higher levels of positive affect and lower levels of negative affect. The experience of urban nature resulted in significantly lower levels of negative affect only compared to the non-nature control video. Experience of wild and urban nature resulted in greater perceptions of restorativeness as compared to the non-nature control video. Restorativeness was a significant underlying psychological mediating path through which nature experience exerted its influence on affect. These results have the potential to inform nature-based green care interventions for mental health as well as for urban planning to maximize beneficial effects of natural environments. PMID- 28708075 TI - The Impact of a Horse Riding Intervention on the Social Functioning of Children with Autism Spectrum Disorder. AB - This paper reports a case-control study of a horse riding intervention for children with autism spectrum disorder (ASD). A sample of 26 children, aged 6 to 9 years, were assigned to either the intervention (n = 12) or control group conditions (n = 14). Pre- and post-tests were carried out using the Childhood Autism Rating Scale, Second Edition (CARS2) and the Aberrant Behaviour Checklist Community Edition (ABC-C). An observational measure of compliance and behaviour during the horse riding sessions was completed for the intervention group. There was a significant reduction in the severity of ASD symptoms and hyperactivity from pre- to post-test for the intervention group only. These results indicate that the intervention improves some aspects of social functioning for children with ASD. PMID- 28708077 TI - Environmental Drivers and Predicted Risk of Bacillary Dysentery in Southwest China. AB - Bacillary dysentery has long been a considerable health problem in southwest China, however, the quantitative relationship between anthropogenic and physical environmental factors and the disease is not fully understand. It is also not clear where exactly the bacillary dysentery risk is potentially high. Based on the result of hotspot analysis, we generated training samples to build a spatial distribution model. Univariate analyses, autocorrelation and multi-collinearity examinations and stepwise selection were then applied to screen the potential causative factors. Multiple logistic regressions were finally applied to quantify the effects of key factors. A bootstrapping strategy was adopted while fitting models. The model was evaluated by area under the receiver operating characteristic curve (AUC), Kappa and independent validation samples. Hotspot counties were mainly mountainous lands in southwest China. Higher risk of bacillary dysentery was found associated with underdeveloped socio-economy, proximity to farmland or water bodies, higher environmental temperature, medium relative humidity and the distribution of the Tibeto-Burman ethnicity. A predictive risk map with high accuracy (88.19%) was generated. The high-risk areas are mainly located in the mountainous lands where the Tibeto-Burman people live, especially in the basins, river valleys or other flat places in the mountains with relatively lower elevation and a warmer climate. In the high-risk areas predicted by this study, improving the economic development, investment in health care and the construction of infrastructures for safe water supply, waste treatment and sewage disposal, and improving health related education could reduce the disease risk. PMID- 28708076 TI - Dendritic Architecture of Principal Basolateral Amygdala Neurons Changes Congruently with Endocrine Response to Stress. AB - Animals cope with changing environments through changes in behavior. Such plasticity is, however, marked by substantial inter-individual variability. Neuroendocrine reactivity to challenging environments can be an important predictor of resilience. Both basolateral amygdala (BLA) neurons and adrenal glucocorticoid signaling are integral parts of the stress neuroendocrine response. In this report, we test if individual variation in hormonal response to stress is associated with individual variation in the dendritic complexity of BLA neurons. We report a positive correlation between inter-individual variability in glucocorticoid response and neuronal plasticity in the BLA subsequent to a stressor. This suggests that stressful experiences in the past act as significant sculptors of BLA neuronal plasticity and congruent neuroendocrine response. PMID- 28708078 TI - Spatial Variation of Soil Organic Carbon and Total Nitrogen in the Coastal Area of Mid-Eastern China. AB - Soils play an important role in sequestrating atmospheric CO2. Coastal tidal flats have been intensively reclaimed for food security and living spaces worldwide. We aimed to identify the changes of soil organic carbon (SOC) and total nitrogen (TN) following coastal reclamation and their spatial variation in the coastal area of mid-Eastern China to provide information for coastal cropland management. We measured SOC and TN of 463 soil samples in the coastal plain of mid-Eastern China. The results showed that SOC and TN increased highly from the uncultivated coastal tidal flat (2.49 g.kg-1 and 0.21 g.kg-1, respectively) to the cropland (10.73 g.kg-1 and 1.3 g.kg-1, respectively). After long-term cultivation, SOC and TN in the old farmland (12.98 g.kg-1 and 1.49 g.kg-1, respectively) were greater than those in the young farmland (5.76 g.kg-1 and 0.86 g.kg-1, respectively). The density of SOC in the uncultivated coastal tidal flat, young farmland, and old farmland were 0.68 kg.C.m-2, 1.52 kg.C.m-2, and 3.31 kg.C.m-2, respectively. The density of TN in the uncultivated coastal tidal flat, young farmland and old farmland were 0.05 kg.N.m-2, 0.23 kg.N.m-2, and 0.38 kg.N.m-2, respectively. The C/N (11.17) in the uncultivated coastal tidal flat was highest comparing to that in the young and old farmland due to lower nitrogen. The C/N increased from 6.78 to 8.71 following cultivation. Reclaimed coastal tidal flats had high carbon and nitrogen sequestration potential that not only mitigated the threat of global warming, but also improved soil fertility for crop production. Coastal management of cropland should consider the spatial distribution of SOC and TN to improve ecosystem services of coastal soils. PMID- 28708079 TI - Comparison of Erosion Behavior and Particle Contamination in Mass-Production CF4/O2 Plasma Chambers Using Y2O3 and YF3 Protective Coatings. AB - Yttrium fluoride (YF3) and yttrium oxide (Y2O3) protective coatings prepared using an atmospheric plasma spraying technique were used to investigate the relationship between surface erosion behaviors and their nanoparticle generation under high-density plasma (1012-1013 cm-3) etching. As examined by transmission electron microscopy, the Y2O3 and YF3 coatings become oxyfluorinated after exposure to the plasma, wherein the yttrium oxyfluoride film formation was observed on the surface with a thickness of 5.2 and 6.8 nm, respectively. The difference in the oxyfluorination of Y2O3 and YF3 coatings could be attributed to Y-F and Y-O bonding energies. X-ray photoelectron spectroscopy analyses revealed that a strongly fluorinated bonding (Y-F bond) was obtained on the etched surface of the YF3 coating. Scanning electron microscopy and energy dispersive X-ray diffraction analysis revealed that the nanoparticles on the 12-inch wafer are composed of etchant gases and Y2O3. These results indicate that the YF3 coating is a more erosion-resistant material, resulting in fewer contamination particles compared with the Y2O3 coating. PMID- 28708080 TI - Phenoliner: A New Field Phenotyping Platform for Grapevine Research. AB - In grapevine research the acquisition of phenotypic data is largely restricted to the field due to its perennial nature and size. The methodologies used to assess morphological traits and phenology are mainly limited to visual scoring. Some measurements for biotic and abiotic stress, as well as for quality assessments, are done by invasive measures. The new evolving sensor technologies provide the opportunity to perform non-destructive evaluations of phenotypic traits using different field phenotyping platforms. One of the biggest technical challenges for field phenotyping of grapevines are the varying light conditions and the background. In the present study the Phenoliner is presented, which represents a novel type of a robust field phenotyping platform. The vehicle is based on a grape harvester following the concept of a moveable tunnel. The tunnel it is equipped with different sensor systems (RGB and NIR camera system, hyperspectral camera, RTK-GPS, orientation sensor) and an artificial broadband light source. It is independent from external light conditions and in combination with artificial background, the Phenoliner enables standardised acquisition of high-quality, geo referenced sensor data. PMID- 28708081 TI - Modeling the Effects of Urban Design on Emergency Medical Response Calls during Extreme Heat Events in Toronto, Canada. AB - Urban residents are at risk of health-related illness during extreme heat events but the dangers are not equal in all parts of a city. Previous studies have found a relationship between physical characteristics of neighborhoods and the number of emergency medical response (EMR) calls. We used a human energy budget model to test the effects of landscape modifications that are designed to cool the environment on the expected number of EMR calls in two neighborhoods in Toronto, Canada during extreme heat events. The cooling design strategies reduced the energy overload on people by approximately 20-30 W m-2, resulting in an estimated 40-50% reduction in heat-related ambulance calls. These findings advance current understanding of the relationship between the urban landscape and human health and suggest straightforward design strategies to positively influence urban heat health. PMID- 28708082 TI - Pathogenic Role of IL-17-Producing Immune Cells in Obesity, and Related Inflammatory Diseases. AB - Obesity is associated with low-grade chronic inflammation. Indeed, adipose tissues (AT) in obese individuals are the former site of progressive infiltration by pro-inflammatory immune cells, which together with increased inflammatory adipokine secretion induce adipocyte insulin resistance. IL-17-producing T (Th17) cells are part of obese AT infiltrating cells, and are likely to be promoted by adipose tissue-derived mesenchymal stem cells, as previously reported by our team. Whereas Th17 cell are physiologically implicated in the neutralization of fungal and bacterial pathogens through activation of neutrophils, they may also play a pivotal role in the onset and/or progression of chronic inflammatory diseases, or cancer, in which obesity is recognized as a risk factor. In this review, we will highlight the pathogenic role of IL-17A producing cells in the mechanisms leading to inflammation in obesity and to progression of obesity related inflammatory diseases. PMID- 28708083 TI - Ten-Year Trends (1999-2010) of Adherence to the Mediterranean Diet among the Balearic Islands' Adult Population. AB - The aim of this work was to assess ten-year trends (1999-2010) of adherence to the Mediterranean dietary pattern (MDP) among the Balearic Islands' adult population. Two independent cross-sectional dietary surveys (1999-2000, n = 1200 and 2009-2010 n = 1388, including participants aged 16-65 years) were carried out in the Balearic Islands, Spain. Dietary habits were assessed by means of two 24 h diet recalls and a validated semi-quantitative food-frequency questionnaire that covers 145 food items. Adherence to the MDP was defined according to a score constructed considering the consumption of nine MDP characteristic components: high monounsaturated fatty acids:saturated fatty acids (MUFA:SFA) ratio, moderate ethanol consumption, high legumes, cereals and roots, fruits, vegetables, and fish consumption, and low consumption of meat and milk. Socio-economic status, education level, lifestyle factors and health status were also assessed. Adherence to the MDP was 43.1% (SD 5.8) in 1999-2000 and 44.6% (SD 8.3) in 2009 2010. Higher age was directly associated with higher adherence to the MDP, and this association was stronger in males than in females. Young generations and smokers showed the lowest adherence to MDP, whereas people with higher educational and socio-economic level, and who were physically active showed the highest adherence. According to the place of birth, the increase in the percentage of the adherence to the MDP was observed to be smaller among the Balearic Island's natives than among people born abroad. In 2009-2010, individuals in the MDP's fourth quartile were more likely to be older (aged 46-65 years), and were less likely to have a low occupational level, to have a light physical activity level and to be smoker than in 1999-2000. The adherence to the MDP has been stabilized and slightly recovered among the Balearic Islands' adult population in the last decade. PMID- 28708084 TI - Molecular Mechanisms of Human Papillomavirus Induced Skin Carcinogenesis. AB - Infection of the cutaneous skin with human papillomaviruses (HPV) of genus betapapillomavirus (betaHPV) is associated with the development of premalignant actinic keratoses and squamous cell carcinoma. Due to the higher viral loads of betaHPVs in actinic keratoses than in cancerous lesions, it is currently discussed that these viruses play a carcinogenic role in cancer initiation. In vitro assays performed to characterize the cell transforming activities of high risk HPV types of genus alphapapillomavirus have markedly contributed to the present knowledge on their oncogenic functions. However, these assays failed to detect oncogenic functions of betaHPV early proteins. They were not suitable for investigations aiming to study the interactive role of betaHPV positive epidermis with mesenchymal cells and the extracellular matrix. This review focuses on betaHPV gene functions with special focus on oncogenic mechanisms that may be relevant for skin cancer development. PMID- 28708085 TI - Is Sweet Taste Perception Associated with Sweet Food Liking and Intake? AB - A range of psychophysical taste measurements are used to characterize an individual's sweet taste perception and to assess links between taste perception and dietary intake. The aims of this study were to investigate the relationship between four different psychophysical measurements of sweet taste perception, and to explore which measures of sweet taste perception relate to sweet food intake. Forty-four women aged 20-40 years were recruited for the study. Four measures of sweet taste perception (detection and recognition thresholds, and sweet taste intensity and hedonic liking of suprathreshold concentrations) were assessed using glucose as the tastant. Dietary measurements included a four-day weighed food record, a sweet food-food frequency questionnaire and a sweet beverage liking questionnaire. Glucose detection and recognition thresholds showed no correlation with suprathreshold taste measurements or any dietary intake measurement. Importantly, sweet taste intensity correlated negatively with total energy and carbohydrate (starch, total sugar, fructose, glucose) intakes, frequency of sweet food intake and sweet beverage liking. Furthermore, sweet hedonic liking correlated positively with total energy and carbohydrate (total sugar, fructose, glucose) intakes. The present study shows a clear link between sweet taste intensity and hedonic liking with sweet food liking, and total energy, carbohydrate and sugar intake. PMID- 28708086 TI - Celiac Disease Presenting with Peripheral Neuropathy in Children: A Case Report. AB - Background: Clinically relevant neurological manifestations in children with celiac disease (CD) are unusual, especially when they are considered as signs of the onset of the disease. In this paper, a case of Guillain-Barre syndrome (GBS) as the first manifestation of CD in a 23-month-old child is reported. Case presentation: We describe a case of CD onset with peripheral neuropathy in a 23 month-old Bulgarian boy presenting with a sudden refusal to walk and absence of deep tendon reflexes in both lower limbs. Neurological symptoms were preceded by two months of gastrointestinal symptoms such as vomiting, abdominal distention, and clear signs of malnutrition and weight loss. When we evaluated the child six months after the onset of the symptoms, clinical and laboratory findings showed clear signs of peripheral neuropathy associated with malnutrition. Serum deamidated gliadin and tissue transglutaminase antibodies were therefore measured. The anti-gliadin levels were more than sixteen times higher than normal and the IgA anti-transglutaminase levels were four times higher than normal. Anti endomysium antibodies were positive, and human leukocyte antigens (HLA) II typing confirmed a genetic predisposition to CD (DQ2 positive and DQ8 negative). Given the association between the clinical evidence of the disease and the results of the celiac screening tests, a diagnosis of CD was made without biopsy confirmation of the enteropathy. The child began a restricted gluten-free diet that led to complete recovery of the peripheral neuropathy, walking, reflexes, and overall improvement after three months on the diet. Conclusion: Our case underlines the rare but possible associations between CD and peripheral neuropathy in children as an onset symptom, even in the absence of gastrointestinal manifestations, thus suggesting that CD should always be considered in the differential diagnosis of peripheral neuropathy in children. A good knowledge of the extra-intestinal manifestations of CD is essential for the rapid introduction of a gluten-free diet that could be useful for the resolution of the neurological symptoms. PMID- 28708087 TI - Resveratrol-Induced AMP-Activated Protein Kinase Activation Is Cell-Type Dependent: Lessons from Basic Research for Clinical Application. AB - Despite the promising effects of resveratrol, its efficacy in the clinic remains controversial. We were the first group to report that the SIRT1 activator resveratrol activates AMP-activated protein kinase (AMPK) (Diabetes 2005; 54: A383), and we think that the variability of this cascade may be responsible for the inconsistency of resveratrol's effects. Our current studies suggest that the effect of SIRT1 activators such as resveratrol may not be solely through activation of SIRT1, but also through an integrated effect of SIRT1-liver kinase B1 (LKB1)-AMPK. In this context, resveratrol activates SIRT1 (1) by directly binding to SIRT1; and (2) by increasing NAD+ levels by upregulating the salvage pathway through Nampt activation, an effect mediated by AMPK. The first mechanism promotes deacetylation of a limited number of SIRT1 substrate proteins (e.g., PGC 1). The second mechanism (which may be more important than the first) activates other sirtuins in addition to SIRT1, which affects a broad spectrum of substrates. Despite these findings, detailed mechanisms of how resveratrol activates AMPK have not been reported. Here, we show that (1) resveratrol-induced activation of AMPK requires the presence of functional LKB1; (2) Resveratrol increases LKB1 activity, which involves translocation and phosphorylation at T336 and S428; (3) Activation of LKB1 causes proteasomal degradation of LKB1; (4) At high concentrations (50-100 uM), resveratrol also activates AMPK through increasing AMP levels; and (5) The above-mentioned activation mechanisms vary among cell types, and in some cell types, resveratrol fails to activate AMPK. These results suggest that resveratrol-induced activation of AMPK is not a ubiquitous phenomenon. In addition, AMPK-mediated increases in NAD+ in the second mechanism require several ATPs, which may not be available in many pathological conditions. These phenomena may explain why resveratrol is not always consistently beneficial in a clinical setting. PMID- 28708088 TI - Metal-Free Regiodivergent Addition of Carbon Nucleophiles to alpha,beta Unsaturated Electrophiles. AB - A mild and metal-free regiodivergent addition of carbon nucleophiles to alpha,beta-unsaturated electrophiles was developed. Total 1,2-regioselectivity was observed in the addition of nitrobenzyl chloride derivative 1 to alpha,beta unsaturated aldehydes 2 in the presence of TDAE. Moreover, the reaction between p nitrobenzyl chloride 1a and alpha,beta-unsaturated iminium salts 4 led to the formation of the 1,4-adduct with total regioselectivity. PMID- 28708089 TI - Effects of Consuming Xylitol on Gut Microbiota and Lipid Metabolism in Mice. AB - The sugar alcohol xylitol inhibits the growth of some bacterial species including Streptococcus mutans. It is used as a food additive to prevent caries. We previously showed that 1.5-4.0 g/kg body weight/day xylitol as part of a high-fat diet (HFD) improved lipid metabolism in rats. However, the effects of lower daily doses of dietary xylitol on gut microbiota and lipid metabolism are unclear. We examined the effect of 40 and 200 mg/kg body weight/day xylitol intake on gut microbiota and lipid metabolism in mice. Bacterial compositions were characterized by denaturing gradient gel electrophoresis and targeted real-time PCR. Luminal metabolites were determined by capillary electrophoresis electrospray ionization time-of-flight mass spectrometry. Plasma lipid parameters and glucose tolerance were examined. Dietary supplementation with low- or medium dose xylitol (40 or 194 mg/kg body weight/day, respectively) significantly altered the fecal microbiota composition in mice. Relative to mice not fed xylitol, the addition of medium-dose xylitol to a regular and HFD in experimental mice reduced the abundance of fecal Bacteroidetes phylum and the genus Barnesiella, whereas the abundance of Firmicutes phylum and the genus Prevotella was increased in mice fed an HFD with medium-dose dietary xylitol. Body composition, hepatic and serum lipid parameters, oral glucose tolerance, and luminal metabolites were unaffected by xylitol consumption. In mice, 40 and 194 mg/kg body weight/day xylitol in the diet induced gradual changes in gut microbiota but not in lipid metabolism. PMID- 28708090 TI - Successful Community-Based Conservation: The Story of Millbank and Pterourus (Papilio) homerus. AB - The literature on community-based environmental management is very extensive and the discussion of the pros and cons is continuing. Presented here is an example of a successful interaction between university-based entomologists and a local rural community, detailing the change in the attitude of the town of Millbank, Jamaica, from a Giant Swallowtail Butterfly collecting site to a model for community protection of a species and its environment. A review of some of the research work on community-based conservation efforts is included. These linkages take a considerable time to establish and the efforts spent by scientific personnel, governmental representatives and eco-tourists are itemized to emphasize how specific conservation activities have inspired confidence in the local community, thus engendering trust and mutual respect between the two groups. Reviews of the developed legislative support from both international and state entities also must be in place, and these are included in chronological detail as much as possible. Finally, a review of the long-term funding of educational and other local programs providing a level of stability to the conservation effort, until the local community can take over the protection of the species and/or habitat, is provided. Of utmost importance is a comprehensive educational campaign to not only sensitize the community, but the larger society, so that there can be buy-in from all stakeholders. PMID- 28708092 TI - The Exact Nuclear Overhauser Enhancement: Recent Advances. AB - Although often depicted as rigid structures, proteins are highly dynamic systems, whose motions are essential to their functions. Despite this, it is difficult to investigate protein dynamics due to the rapid timescale at which they sample their conformational space, leading most NMR-determined structures to represent only an averaged snapshot of the dynamic picture. While NMR relaxation measurements can help to determine local dynamics, it is difficult to detect translational or concerted motion, and only recently have significant advances been made to make it possible to acquire a more holistic representation of the dynamics and structural landscapes of proteins. Here, we briefly revisit our most recent progress in the theory and use of exact nuclear Overhauser enhancements (eNOEs) for the calculation of structural ensembles that describe their conformational space. New developments are primarily targeted at increasing the number and improving the quality of extracted eNOE distance restraints, such that the multi-state structure calculation can be applied to proteins of higher molecular weights. We then review the implications of the exact NOE to the protein dynamics and function of cyclophilin A and the WW domain of Pin1, and finally discuss our current research and future directions. PMID- 28708091 TI - TRAIL, Wnt, Sonic Hedgehog, TGFbeta, and miRNA Signalings Are Potential Targets for Oral Cancer Therapy. AB - Clinical studies and cancer cell models emphasize the importance of targeting therapies for oral cancer. The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is highly expressed in cancer, and is a selective killing ligand for oral cancer. Signaling proteins in the wingless-type mouse mammary tumor virus (MMTV) integration site family (Wnt), Sonic hedgehog (SHH), and transforming growth factor beta (TGFbeta) pathways may regulate cell proliferation, migration, and apoptosis. Accordingly, the genes encoding these signaling proteins are potential targets for oral cancer therapy. In this review, we focus on recent advances in targeting therapies for oral cancer and discuss the gene targets within TRAIL, Wnt, SHH, and TGFbeta signaling for oral cancer therapies. Oncogenic microRNAs (miRNAs) and tumor suppressor miRNAs targeting the genes encoding these signaling proteins are summarized, and the interactions between Wnt, SHH, TGFbeta, and miRNAs are interpreted. With suitable combination treatments, synergistic effects are expected to improve targeting therapies for oral cancer. PMID- 28708093 TI - Real-Time Communication Support for Underwater Acoustic Sensor Networks ?. AB - Underwater sensor networks represent an important and promising field of research due to the large diversity of underwater ubiquitous applications that can be supported by these networks, e.g., systems that deliver tsunami and oil spill warnings, or monitor submarine ecosystems. Most of these monitoring and warning systems require real-time communication in wide area networks that have a low density of nodes. The underwater communication medium involved in these networks is very harsh and imposes strong restrictions to the communication process. In this scenario, the real-time transmission of information is done mainly using acoustic signals, since the network nodes are not physically close. The features of the communication scenario and the requirements of the communication process represent major challenges for designers of both, communication protocols and monitoring and warning systems. The lack of models to represent these networks is the main stumbling block for the proliferation of underwater ubiquitous systems. This paper presents a real-time communication model for underwater acoustic sensor networks (UW-ASN) that are designed to cover wide areas with a low density of nodes, using any-to-any communication. This model is analytic, considers two solution approaches for scheduling the real-time messages, and provides a time constraint analysis for the network performance. Using this model, the designers of protocols and underwater ubiquitous systems can quickly prototype and evaluate their solutions in an evolving way, in order to determine the best solution to the problem being addressed. The suitability of the proposal is illustrated with a case study that shows the performance of a UW-ASN under several initial conditions. This is the first analytic model for representing real-time communication in this type of network, and therefore, it opens the door for the development of underwater ubiquitous systems for several application scenarios. PMID- 28708094 TI - Cholinesterase and Prolyl Oligopeptidase Inhibitory Activities of Alkaloids from Argemone platyceras (Papaveraceae). AB - Alzheimer's disease is an age-related, neurodegenerative disorder, characterized by cognitive impairment and restrictions in activities of daily living. This disease is the most common form of dementia with complex multifactorial pathological mechanisms. Many therapeutic approaches have been proposed. Among them, inhibition of acetylcholinesterase, butyrylcholinesterase, and prolyl oligopeptidase can be beneficial targets in the treatment of Alzheimer's disease. Roots, along with aerial parts of Argemone platyceras, were extracted with ethanol and fractionated on an alumina column using light petrol, chloroform and ethanol. Subsequently, repeated preparative thin-layer chromatography led to the isolation of (+)-laudanosine, protopine, (-)-argemonine, allocryptopine, (-) platycerine, (-)-munitagine, and (-)-norargemonine belonging to pavine, protopine and benzyltetrahydroisoquinoline structural types. Chemical structures of the isolated alkaloids were elucidated by optical rotation, spectroscopic and spectrometric analysis (NMR, MS), and comparison with literature data. (+) Laudanosine was isolated from A. platyceras for the first time. Isolated compounds were tested for human blood acetylcholinesterase, human plasma butyrylcholinesterase and recombinant prolyl oligopeptidase inhibitory activity. The alkaloids inhibited the enzymes in a dose-dependent manner. The most active compound (-)-munitagine, a pavine alkaloid, inhibited both acetylcholinesterase and prolyl oligopeptidase with IC50 values of 62.3 +/- 5.8 uM and 277.0 +/- 31.3 uM, respectively. PMID- 28708095 TI - Predictors of Daily Mobility of Adults in Peri-Urban South India. AB - Daily mobility, an important aspect of environmental exposures and health behavior, has mainly been investigated in high-income countries. We aimed to identify the main dimensions of mobility and investigate their individual, contextual, and external predictors among men and women living in a peri-urban area of South India. We used 192 global positioning system (GPS)-recorded mobility tracks from 47 participants (24 women, 23 men) from the Cardiovascular Health effects of Air pollution in Telangana, India (CHAI) project (mean: 4.1 days/person). The mean age was 44 (standard deviation: 14) years. Half of the population was illiterate and 55% was in unskilled manual employment, mostly agriculture-related. Sex was the largest determinant of mobility. During daytime, time spent at home averaged 13.4 (3.7) h for women and 9.4 (4.2) h for men. Women's activity spaces were smaller and more circular than men's. A principal component analysis identified three main mobility dimensions related to the size of the activity space, the mobility in/around the residence, and mobility inside the village, explaining 86% (women) and 61% (men) of the total variability in mobility. Age, socioeconomic status, and urbanicity were associated with all three dimensions. Our results have multiple potential applications for improved assessment of environmental exposures and their effects on health. PMID- 28708097 TI - Nano-Silica Sol-Gel and Carbon Nanotube Coupling Effect on the Performance of Cement-Based Materials. AB - Carbon nanotubes (CNTs) have shown promise for improving the mechanical performance of cement composites through crack-bridging and frictional pull-out. The interactive behaviors between CNTs and cement matrix act are crucial in optimizing the reinforcement of CNTs in cement composites. This study investigates the effects of nano-silica (NS) sol-gel on the interactive behaviors of CNTs and the cement matrix through a series of experiments and analyses. UV visible spectrometer results show that CNTs are well-dispersed in suspension and the addition of NS has a negligible effect on the stability of CNT dispersion. Calorimetry tests and dynamic mechanical analysis demonstrate the nucleation and frictional performance of CNTs in cement matrix, respectively. The paper shows that the physical adsorption of NS on the CNT surface could result in the acceleration of cement hydration. Morphology observation confirms that a denser interface between CNTs and cement hydrates is formed. Finally, the improved interaction between CNTs and cement hydrates leads to a substantial increase in friction between CNTs and the cement matrix under periodic loading. NS may act as an ideal admixture for improving both the interactive behaviors between CNTs and cement matrix and the damping properties of cement composite. PMID- 28708096 TI - Characterization of Non-Nutritive Sweetener Intake in Rural Southwest Virginian Adults Living in a Health-Disparate Region. AB - Few data assessing non-nutritive sweetener (NNS) intake are available, especially within rural, health-disparate populations, where obesity and related co morbidities are prevalent. The objective of this study is to characterize NNS intake for this population and examine the variance in demographics, cardio metabolic outcomes, and dietary intake between NNS consumers and non-consumers. A cross-sectional sample (n = 301) of Virginian adults from a randomized controlled trial (data collected from 2012 to 2014) targeting sugar-sweetened beverage (SSB) intake completed three 24-h dietary recalls, and demographics and cardio metabolic measures were assessed. The frequency, types, and sources of NNS consumption were identified. Thirty-three percent of participants reported consuming NNS (n = 100). Sucralose was the largest contributor of mean daily NNS intake by weight (mg), followed by aspartame, acesulfame potassium, and saccharin. NNS in tabletop sweeteners, diet tea, and diet soda were the top contributors to absolute NNS intake. The most frequently consumed NNS sources were diet sodas, juice drinks, and tabletop sweeteners. Although mean body mass index (BMI) was greater for NNS consumers, they demonstrated significantly lower food, beverage, and SSB caloric intake and energy density, and higher overall dietary quality. It remains unclear whether NNS use plays a role in exacerbating weight gain. NNS consumers in this sample may have switched from drinking predominantly SSB to drinking some NNS beverages in an effort to cope with weight gain. Future studies should explore motivations for NNS use across a variety of weight and health categories. PMID- 28708098 TI - Combining Primed Photoconversion and UV-Photoactivation for Aberration-Free, Live Cell Compliant Multi-Color Single-Molecule Localization Microscopy Imaging. AB - Super-resolution fluorescence microscopy plays a major role in revealing the organization and dynamics of living cells. Nevertheless, single-molecule localization microscopy imaging of multiple targets is still limited by the availability of suitable fluorophore combinations. Here, we introduce a novel imaging strategy which combines primed photoconversion (PC) and UV photoactivation for imaging different molecular species tagged by suitable fluorescent protein combinations. In this approach, the fluorescent proteins can be specifically photoactivated/-converted by different light wavelengths using PC and UV-activation modes but emit fluorescence in the same spectral emission channel. We demonstrate that this aberration-free, live-cell compatible imaging method can be applied to various targets in bacteria, yeast and mammalian cells and can be advantageously combined with correlative imaging schemes. PMID- 28708099 TI - Role Played by Signalling Pathways in Overcoming BRAF Inhibitor Resistance in Melanoma. AB - The discovery of the BRAFV600E mutation led to the development of vemurafenib (PLX4032), a selective BRAF inhibitor specific to the kinase, for the treatment of metastatic melanomas. However, initial success of the drug was dampened by the development of acquired resistance. Melanoma was shown to relapse in patients following treatment with vemurafenib which eventually led to patients' deaths. It has been proposed that mechanisms of resistance can be due to (1) reactivation of the mitogen-activated protein kinase (MAPK) signalling pathway via secondary mutations, amplification or activation of target kinase(s), (2) the bypass of oncogenic pathway via activation of alternative signalling pathways, (3) other uncharacterized mechanisms. Studies showed that receptor tyrosine kinases (RTK) such as PDGFRbeta, IGF1R, EGFR and c-Met were overexpressed in melanoma cells. Along with increased secretion of growth factors such as HGF and TGF-alpha, this will trigger intracellular signalling cascades. This review discusses the role MAPK and Phosphatidylinositol-3-kinase-protein kinase B-mammalian target of rapamycin (PI3K-AKT-mTOR) pathways play in the mechanism of resistance of melanomas. PMID- 28708100 TI - Airborne PM2.5-Induced Hepatic Insulin Resistance by Nrf2/JNK-Mediated Signaling Pathway. AB - Animal and epidemiological studies have suggested that exposure to airborne particulate matter (PM) with an aerodynamic diameter less than 2.5 MUm (PM2.5) is associated with the risk of developing type 2 diabetes. However, the mechanism underlying this risk is poorly understood. In the present study, we investigated the effects of PM2.5 exposure on glucose homeostasis and related signaling pathways in mice. Wild-type and nuclear factor erythroid 2-related factor 2 (Nrf2) knockout (Nrf2-/-) C57BL/6 male mice were exposed to either ambient concentrated PM2.5 or filtered air (FA) for 12 weeks through a whole-body PM exposure system. At the end of the exposure, we assessed liver damage, and performed metabolic studies, gene expressions, as well as molecular signal transductions to determine the signaling pathways involving oxidative responses, insulin signaling, and glucose metabolism. Our results indicated that PM2.5 exposure for 12 weeks caused significant liver damage as evidenced by elevated levels of aminotransferase (AST) and alanine aminotransferase (ALT). Furthermore, PM2.5 exposure induced impaired glucose tolerance and inhibited glycogen synthesis, leading to hepatic insulin resistance indicated by higher glucose levels, higher area under the curve (AUC), and homeostasis model assessment of insulin resistance (HOMA-IR) values. We further found that PM2.5 exposure significantly increased the expressions of Nrf2 and Nrf2-regulated antioxidant genes. Moreover, PM2.5 exposure activated the c-Jun N-terminal kinase (JNK) signaling pathway and increased insulin receptor substrate-1 (IRS-1) phosphorylation at Ser307, but reduced protein kinase B phosphorylation at Ser473. Taken together, our study demonstrated PM2.5 exposure triggered Nrf2 mediated oxidative responses and activated the JNK-mediated inhibitory signaling pathway, resulting in hepatic insulin resistance. PMID- 28708101 TI - The Association of Domestic Incense Burning with Hypertension and Blood Pressure in Guangdong, China. AB - Abstract: Domestic incense burning is a common activity in China. Although it generates serious air pollution and has been linked to various health outcomes, it remains unknown whether it is associated with blood pressure and hypertension. A community-based survey including 1153 hypertensive subjects and 4432 normotensive participants in Guangdong (China) was used to examine this question. Two-level logistic regression was used to estimate the odds ratio (OR) and 95% confidence interval (CI). The analyses showed that, compared with non-users, OR of hypertension was 1.24 (95% CI: 1.03-1.50) for users, and 1.37 (95% CI: 1.04 1.80) for daily users with a clear dose-response relationship. The estimated increases in systolic and diastolic blood pressures were 1.02 mmHg (95% CI: 0.06 1.99) and 1.26 mmHg (95% CI: 0.69-1.83) for users, 0.67 mmHg (95% CI: -0.35-1.68) and 1.25 mmHg (95% CI: 0.66-1.85) for occasional users, and 2.09 mmHg (95% CI: 0.79-3.39) and 1.28 mmHg (95% CI: 0.52-2.05) for daily users, respectively. The results remained after adjusting for potential confounders and more pronounced associations were found among females. This study suggests that domestic incense burning may increase the risk of hypertension and blood pressure in the study population, and women are more vulnerable to these effects than men. PMID- 28708102 TI - Ability of Soil Isolated Actinobacterial Strains to Prevent, Bind and Biodegrade Ochratoxin A. AB - Ochratoxin A (OTA) is one of the most important mycotoxins, and contaminates several agricultural products, particularly cereals, grapes, maize, barley, spices and coffee. The aim of this project was to reduce the levels of OTA by supplementing the artificially contaminated solutions with seven strains of actinobacteria (AT10, AT8, SN7, MS1, ML5, G10 and PT1) in order to evaluate their capacity for binding and metabolizing the OTA, as well as their ability to reduce the expression of the genes responsible for its production in A. carbonarius. In the first part of this study, we evaluated the capacity of Streptomyces strains for binding OTA on their surfaces after 0, 30 and 60 min of incubation with PBS solution supplemented with OTA. In the second part, we tested the ability of these strains, as well as their supernatants, to detoxify the ISP2 medium. Finally, we studied the effect of the Streptomyces cocultured with Aspergillus carbonarius on the expression of OTA biosynthesis genes. Results showed that, among the strains co-cultured with A. carbonarius, the strain G10 was able to reduce the expression of acpks, acOTApks, acOTAnrps and vea genes, thus reducing OTA from solid PDA medium to 13.50% of reduction. This strain was remarkably able to detoxify and bind OTA up to 47.07%. Strain AT8 was stronger in detoxifying OTA (52.61%), but had no significant effect on the studied gene expression. PMID- 28708103 TI - Pharmacogenomics of Targeted Agents for Personalization of Colorectal Cancer Treatment. AB - The use of targeted agents in the treatment of metastatic colorectal cancer (CRC) has improved patient outcomes. Anti-epidermal growth factor receptor (anti-EGFR) agents (cetuximab and panitumumab) and antiangiogenic molecules (bevacizumab, regorafeninb, ramucirumab, and aflibercept) have been successfully integrated into clinical practice. Other drugs have been designed to target additional deregulated pathways in CRC, such as MAPK (mitogen-activated protein kinase)/PI3K AKT (phosphatidylinositol-3-kinase-AKT serine/threonine kinase)/mTOR (mammalian target of rapamycin), HER-2 and 3 ( human epidermal growth factor receptor-2 and 3), and BRAF. A major issue with targeted treatment is early identification of patients with primary or secondary drug resistance. Pharmacogenomic research has demonstrated its value in this field, highlighting some tumor mutations that could discriminate responders from non-responders. The tumor genetic profile of the RAS/RAF pathway is needed before treatment with anti-EGFR agents; mutations in EGFR pathway genes have also been explored in relation to antiangiogenic molecules although further data are required prior to their integration into clinical practice. The introduction of immunotherapy has paved the way for a new generation of predictive markers, including genome-wide assessment of the tumor landscape. Furthermore, the development of next generation sequencing technology and non-invasive approaches to analyze circulating tumor DNA will make real-time monitoring of the tumor pharmacogenomic markers possible in the clinical routine, rendering precision medicine available to every patient. PMID- 28708104 TI - Fruit and Juice Epigenetic Signatures Are Associated with Independent Immunoregulatory Pathways. AB - Epidemiological evidence strongly suggests that fruit consumption promotes many health benefits. Despite the general consensus that fruit and juice are nutritionally similar, epidemiological results for juice consumption are conflicting. Our objective was to use DNA methylation marks to characterize fruit and juice epigenetic signatures within PBMCs and identify shared and independent signatures associated with these groups. Genome-wide DNA methylation marks (Illumina Human Methylation 450k chip) for 2,148 individuals that participated in the Framingham Offspring exam 8 were analyzed for correlations between fruit or juice consumption using standard linear regression. CpG sites with low P-values (P < 0.01) were characterized using Gene Set Enrichment Analysis (GSEA), Ingenuity Pathway Analysis (IPA), and epigenetic Functional element Overlap analysis of the Results of Genome Wide Association Study Experiments (eFORGE). Fruit and juice-specific low P-value epigenetic signatures were largely independent. Genes near the fruit-specific epigenetic signature were enriched among pathways associated with antigen presentation and chromosome or telomere maintenance, while the juice-specific epigenetic signature was enriched for proinflammatory pathways. IPA and eFORGE analyses implicate fruit and juice specific epigenetic signatures in the modulation of macrophage (fruit) and B or T cell (juice) activities. These data suggest a role for epigenetic regulation in fruit and juice-specific health benefits and demonstrate independent associations with distinct immune functions and cell types, suggesting that these groups may not confer the same health benefits. Identification of such differences between foods is the first step toward personalized nutrition and ultimately the improvement of human health and longevity. PMID- 28708105 TI - Resveratrol Improves Glycemic Control in Type 2 Diabetic Obese Mice by Regulating Glucose Transporter Expression in Skeletal Muscle and Liver. AB - Insulin resistance participates in the glycaemic control disruption in type 2 diabetes mellitus (T2DM), by reducing muscle glucose influx and increasing liver glucose efflux. GLUT4 (Slc2a4 gene) and GLUT2 (Slc2a2 gene) proteins play a fundamental role in the muscle and liver glucose fluxes, respectively. Resveratrol is a polyphenol suggested to have an insulin sensitizer effect; however, this effect, and related mechanisms, have not been clearly demonstrated in T2DM. We hypothesized that resveratrol can improve glycaemic control by restoring GLUT4 and GLUT2 expression in muscle and liver. Mice were rendered obese T2DM in adult life by neonatal injection of monosodium glutamate. Then, T2DM mice were treated with resveratrol for 60 days or not. Glycaemic homeostasis, GLUT4, GLUT2, and SIRT1 (sirtuin 1) proteins (Western blotting); Slc2a4, Slc2a2, and Pck1 (key gluconeogenic enzyme codifier) mRNAs (RT-qPCR); and hepatic glucose efflux were analysed. T2DM mice revealed: high plasma concentration of glucose, fructosamine, and insulin; insulin resistance (insulin tolerance test); decreased Slc2a4/GLUT4 content in gastrocnemius and increased Slc2a2/GLUT2 content in liver; and increased Pck1 mRNA and gluconeogenic activity (pyruvate tolerance test) in liver. All alterations were restored by resveratrol treatment. Additionally, in both muscle and liver, resveratrol increased SIRT1 nuclear content, which must participate in gene expression regulations. In sum, the results indisputably reveals that resveratrol improves glycaemic control in T2DM, and that involves an increase in muscle Slc2a4/GLUT4 and a decrease in liver Slc2a2/GLUT2 expression. This study contributes to our understanding how resveratrol might be prescribed for T2DM according to the principles of evidence based medicine. PMID- 28708106 TI - Evodiamine Exerts an Anti-Hepatocellular Carcinoma Activity through a WWOX Dependent Pathway. AB - Evodiamine is one of the main components isolated from Evodia rutaecarpa, and it has been reported to exert inhibitory effects on cancers by anti-proliferative and apoptosis-inducing activities. Although the anti-cancer activity of evodiamine has been identified, the precise mechanisms of this action remain obscure. While previous studies indicated that evodiamine exerts anti-tumor effects through inhibiting beta-catenin activity, and WW domain-containing oxidoreductase (WWOX) regulates beta-catenin accumulation in cytoplasm, the effects of evodiamine on the expression of WWOX are still unknown. In this study, we provide evidence that evodiamine dose- and time-dependently inhibits both Mus musculus and Homo sapiens hepatocellular carcinoma (HCC) cells, as well as Hepa1 6 and HepG2 cell proliferation. We further tested the therapeutic effects of evodiamine in Hepa1-6 hepatoma-bearing mice, and we found that treatment of evodiamine by oral gavage significantly decreased the tumor size of the mice. Moreover, the expressions of WWOX were dose-dependently increased in HCC cell lines as well as in Hepa1-6 hepatoma-bearing mice after the treatment with evodiamine. Knockdown of WWOX in HepG2 and Hepa1-6 cells diminished the effects of evodiamine on the inhibitory effect of cancer cell growth, indicating that evodiamine induced anti-cancer activity through a WWOX-dependent pathway. As such, evodiamine activated WWOX to exert an anti-HCC activity, and might be a potential therapeutic or preventive candidate for HCC treatment. PMID- 28708107 TI - Family Communication at the End of Life. AB - People often feel awkward and ill at ease when faced with the opportunity for communication at the end of life, thus the overall theme for the articles in this special issue is the creation of more awareness and knowledge regarding the depth, breadth, and importance of current research exploring family communication at the end of life. This introductory essay attempts to accomplish the following: (1) discuss the importance of talk regarding death; (2) highlight the formative role of family interactions on the death and dying process; and (3) outline the articles in this special issue. Scholars contributing to this special issue on "Family Communication at the End of Life" have provided evidence that communication is important between and for terminally ill individuals, family members, and healthcare/palliative care specialists. Overall, research exploring communication at the end of life is especially relevant because every person experiences the death and loss of loved ones, and ultimately faces the reality of their own death. PMID- 28708109 TI - Synthesis of Poly(norbornene-methylamine), a Biomimetic of Chitosan, by Ring Opening Metathesis Polymerization (ROMP). AB - ROMP is an effective method for preparing functional polymers due to its having characteristics of "living" polymerization and rapid development of catalysts. In the present work, poly(norbornene-methylamine), a mimic of chitosan, was synthesized via ROMP reaction. The amino-protected product, 5-norbornene-2-(N methyl)-phthalimide, was prepared by a reaction of 5-norbornene-2-methylamine with phthalic anhydride, which was then subjected to the ROMP reaction in the presence of Hoveyda-Grubbs 2nd catalyst to afford poly(norbornene-(N-methyl) phthalimide). The target product, poly(norbornene-methylamine), was obtained by deprotection reaction of poly(norbornene-(N-methyl)-phthalimide). The products in each step were characterized by FTIR and 1H-NMR, and their thermal stabilities were determined by TG analysis. The effects of molar ratio between monomer ([M]/[I]) and catalyst on the average relative molecular weight ( M n - ) and molecular weight distribution of the produced polymer products were determined by gel permeation chromatography (GPC). It was found that the M n - of poly(norbornene-(N-methyl)-phthalimide) was controllable and exhibited a narrow polydispersity index (PDI) (~1.10). The synthesis condition of 5-norbornene-2-(N methyl)-phthalimide was optimized by determining the yields at different reaction temperatures and reaction times. The highest yield was obtained at a reaction temperature of 130 degrees C and a reaction time of 20 min. Our work provides a new strategy to synthesize polymers with controllable structures and free -NH2 groups via ROMP. PMID- 28708108 TI - Gut-CNS-Axis as Possibility to Modulate Inflammatory Disease Activity Implications for Multiple Sclerosis. AB - In the last decade the role of environmental factors as modulators of disease activity and progression has received increasing attention. In contrast to classical environmental modulators such as exposure to sun-light or fine dust pollution, nutrition is an ideal tool for a personalized human intervention. Various studies demonstrate a key role of dietary factors in autoimmune diseases including Inflammatory Bowel Disease (IBD), rheumatoid arthritis or inflammatory central nervous system (CNS) diseases such as Multiple Sclerosis (MS). In this review we discuss the connection between diet and inflammatory processes via the gut-CNS-axis. This axis describes a bi-directional communication system and comprises neuronal signaling, neuroendocrine pathways and modulation of immune responses. Therefore, the gut-CNS-axis represents an emerging target to modify CNS inflammatory activity ultimately opening new avenues for complementary and adjunctive treatment of autoimmune diseases such as MS. PMID- 28708110 TI - Cognitive Changes in the Spinocerebellar Ataxias Due to Expanded Polyglutamine Tracts: A Survey of the Literature. AB - The dominantly-inherited ataxias characterised by expanded polyglutamine tracts spinocere bellar ataxias (SCAs) 1, 2, 3, 6, 7, 17, dentatorubral pallidoluysian atrophy (DRPLA) and, in part, SCA 8-have all been shown to result in various degrees of cognitive impairment. We survey the literature on the cognitive consequences of each disorder, attempting correlation with their published neuropathological, magnetic resonance imaging (MRI) and clinical features. We suggest several psychometric instruments for assessment of executive function, whose results are unlikely to be confounded by visual, articulatory or upper limb motor difficulties. Finally, and with acknowledgement of the inadequacies of the literature to date, we advance a tentative classification of these disorders into three groups, based on the reported severity of their cognitive impairments, and correlated with their neuropathological topography and MRI findings: group 1-SCAs 6 and 8-mild dysexecutive syndrome based on disruption of cerebello-cortical circuitry; group 2-SCAs 1, 2, 3, and 7-more extensive deficits based largely on disruption of striatocortical in addition to cerebello-cerebral circuitry; and group 3-SCA 17 and DRPLA-in which cognitive impairment severe enough to cause a dementia syndrome is a frequent feature. PMID- 28708112 TI - A Pulse Rate Detection Method for Mouse Application Based on Multi-PPG Sensors. AB - Heart rate is an important physiological parameter for healthcare. Among measurement methods, photoplethysmography (PPG) is an easy and convenient method for pulse rate detection. However, as the PPG signal faces the challenge of motion artifacts and is constrained by the position chosen, the purpose of this paper is to implement a comfortable and easy-to-use multi-PPG sensor module combined with a stable and accurate real-time pulse rate detection method on a computer mouse. A weighted average method for multi-PPG sensors is used to adjust the weight of each signal channel in order to raise the accuracy and stability of the detected signal, therefore reducing the disturbance of noise under the environment of moving effectively and efficiently. According to the experiment results, the proposed method can increase the usability and probability of PPG signal detection on palms. PMID- 28708111 TI - An Evaluation of Ischaemic Preconditioning as a Method of Reducing Ischaemia Reperfusion Injury in Liver Surgery and Transplantation. AB - Liver Ischaemia Reperfusion (IR) injury is a major cause of post-operative liver dysfunction, morbidity and mortality following liver resection surgery and transplantation. There are no proven therapies for IR injury in clinical practice and new approaches are required. Ischaemic Preconditioning (IPC) can be applied in both a direct and remote fashion and has been shown to ameliorate IR injury in small animal models. Its translation into clinical practice has been difficult, primarily by a lack of knowledge regarding the dominant protective mechanisms that it employs. A review of all current studies would suggest that IPC/RIPC relies on creating a small tissue injury resulting in the release of adenosine and l-arginine which act through the Adenosine receptors and the haem-oxygenase and endothelial nitric oxide synthase systems to reduce hepatocyte necrosis and improve the hepatic microcirculation post reperfusion. The next key step is to determine how long the stimulus requires to precondition humans to allow sufficient injury to occur to release the potential mediators. This would open the door to a new therapeutic chapter in this field. PMID- 28708114 TI - One Size Does Not Fit All: Contextualising Family Physical Activity Using a Write, Draw, Show and Tell Approach. AB - Understanding family physical activity (PA) behaviour is essential for designing effective family-based PA interventions. However, effective approaches to capture the perceptions and "lived experiences" of families are not yet well established. The aims of the study were to: (1) demonstrate how a "write, draw, show and tell" (WDST) methodological approach can be appropriate to family-based PA research, and (2) present two distinct family case studies to provide insights into the habitual PA behaviour and experiences of a nuclear and single-parent family. Six participants (including two "target" children aged 9-11 years, two mothers and two siblings aged 6-8 years) from two families were purposefully selected to take part in the study, based on their family structure. Participants completed a paper-based PA diary and wore an ActiGraph GT9X accelerometer on their left wrist for up to 10 weekdays and 16 weekend days. A range of WDST tasks were then undertaken by each family to offer contextual insight into their family-based PA. The selected families participated in different levels and modes of PA, and reported contrasting leisure opportunities and experiences. These novel findings encourage researchers to tailor family-based PA intervention programmes to the characteristics of the family. PMID- 28708113 TI - Dietary Phytochemicals Promote Health by Enhancing Antioxidant Defence in a Pig Model. AB - Phytochemical-rich diets are protective against chronic diseases and mediate their protective effect by regulation of oxidative stress (OS). However, it is proposed that under some circumstances, phytochemicals can promote production of reactive oxygen species (ROS) in vitro, which might drive OS-mediated signalling. Here, we investigated the effects of administering single doses of extracts of red cabbage and grape skin to pigs. Blood samples taken at baseline and 30 min intervals for 4 hours following intake were analyzed by measures of antioxidant status in plasma, including Trolox equivalent antioxidant capacity (TEAC) and glutathione peroxidase (GPx) activity. In addition, dose-dependent production of hydrogen peroxide (H2O2) by the same extracts was measured in untreated commercial pig plasma in vitro. Plasma from treated pigs showed extract dose dependent increases in non-enzymatic (plasma TEAC) and enzymatic (GPx) antioxidant capacities. Similarly, extract dose-dependent increases in H2O2 were observed in commercial pig plasma in vitro. The antioxidant responses to extracts by treated pigs were highly correlated with their respective yields of H2O2 production in vitro. These results support that dietary phytochemicals regulate OS via direct and indirect antioxidant mechanisms. The latter may be attributed to the ability to produce H2O2 and to thereby stimulate cellular antioxidant defence systems. PMID- 28708115 TI - Crystal Structure Analysis of the First Discovered Stability-Enhanced Solid State of Tenofovir Disoproxil Free Base Using Single Crystal X-ray Diffraction. AB - Tenofovir disoproxil (TD), an anti-virus drug, is currently marketed under its most stable form, Form-I of Tenofovir disoproxil fumarate (TDF). However, studies regarding the properties of TD free base crystal as a promising drug as well as its crystal structure have not yet been reported. This assumption was made because TD free base is not directly produced in a solid form during the manufacturing process. TD free base is first obtained in an oil form, and is then synthesized into TDF crystal. In this regard, the present study was conducted to investigate both the potentiality of TD free base to be an active pharmaceutical ingredient (API) and its crystal structure. Here, TD free base solid was produced by means of drowning-out crystallization. Next, single crystal X-ray diffraction (SXD) was employed to determine the crystal structure. Powder X-ray diffraction (PXRD) and a differential scanning calorimetry (DSC) analysis were performed to evaluate the crystal's properties. Furthermore, experiments were carried out at 15%, 35%, 55%, 75%, and 95% relative humidity (RH) for 12 h using a hygroscopic tester to determine and to compare the hygroscopicity and stability of TD free base with TDF crystal. Additionally, experiments were conducted under accelerated (40 degrees C, RH 75%) and stress storage (60 degrees C, RH 75%) conditions for 30 days to investigate the changes in purity and the formation of dimer. In this work, we report that TD free base possesses lower hygroscopicity, and thus does not generate dimer impurity from hydrolysis. Primarily, this is attributed to the fact that TD free base is not an easily ionized salt but comprises neutral hydrophobic molecules. According to the structural properties, the improved hygroscopic property of the TD free base crystal was due to the decrease of crystal polarity owing to the intermolecular H-bonds present in TD free base rings. In addition, the solubility investigation study carried out in aqueous solution and at gastrointestinal pH revealed a similarity in TDF and TD free base solubility under the mentioned conditions. Accordingly, we could confirm the potentiality of TD free base as an active pharmaceutical ingredient. PMID- 28708116 TI - Functionalization of Endohedral Metallofullerenes with Reactive Silicon and Germanium Compounds. AB - Exohedral derivatization of endohedral metallofullerenes (EMFs) has been exploited as a useful method for characterizing the structural and chemical properties of EMFs, and for functionalizing them for potential applications. The introduction of heteroatoms, such as electropositive silicon atoms, to fullerene cages is a novel functionalization method that remarkably affects the electronic characteristics of fullerenes. This review comprehensively describes the results of the reactions of monometallofullerene, dimetallofullerene, and trimetallic nitride template EMFs with disilirane, silirane, silylene, and digermirane, which afforded the corresponding silylated and germylated fullerenes. Several examples emphasize that exohedral functionalization regulates the dynamic behaviors of the encapsulated metal atoms and clusters in the fullerene cages. The electronic effects of silyl and germyl groups are represented by comparing the redox properties of silylated and germylated EMFs with those of other EMFs derivatized with carbon-atom-based functional groups. PMID- 28708117 TI - Solar or UVA-Visible Photocatalytic Ozonation of Water Contaminants. AB - An incipient advanced oxidation process, solar photocatalytic ozonation (SPO), is reviewed in this paper with the aim of clarifying the importance of this process as a more sustainable water technology to remove priority or emerging contaminants from water. The synergism between ozonation and photocatalytic oxidation is well known to increase the oxidation rate of water contaminants, but this has mainly been studied in photocatalytic ozonation systems with lamps of different radiation wavelength, especially of ultraviolet nature (UVC, UVB, UVA). Nowadays, process sustainability is critical in environmental technologies including water treatment and reuse; the application of SPO systems falls into this category, and contributes to saving energy and water. In this review, we summarized works published on photocatalytic ozonation where the radiation source is the Sun or simulated solar light, specifically, lamps emitting radiation to cover the UVA and visible light spectra. The main aspects of the review include photoreactors used and radiation sources applied, synthesis and characterization of catalysts applied, influence of main process variables (ozone, catalyst, and pollutant concentrations, light intensity), type of water, biodegradability and ecotoxicity, mechanism and kinetics, and finally catalyst activity and stability. PMID- 28708118 TI - Low Energy Turnover of Physically Inactive Participants as a Determinant of Insufficient Mineral and Vitamin Intake in NHANES. AB - Micronutrient requirements do not scale linearly with physical activity-related energy expenditure (AEE). Inactive persons may have insufficient micronutrient intake because of low energy intake (EI). We extracted data from NHANES 2003-2006 on 4015 adults (53 +/- 18 years (mean +/- SD), 29 +/- 6 kg/m2, 48% women) with valid physical activity (accelerometry) and food intake (2 * 24 h-dietary recall) measures. Total energy expenditure (TEE) was estimated by summing the basal metabolic rate (BMR, Harris-Benedict), AEE, and 10% of TEE for the thermic effect of food, to calculate the physical activity levels (PAL = TEE/BMR). Energy intake (EI) was scaled to match TEE assuming energy balance. Adjusted food intake was then analyzed for energy and micronutrient content and compared to estimated average requirements. The NHANES population was physically insufficiently active. There were 2440 inactive (PAL < 1.4), 1469 lightly to moderately active (PAL1.4 < 1.7), 94 sufficiently active (PAL1.7 < 2.0), and 12 very active participants (PAL >= 2.0). The inactive vs. active had significantly lower intake for all micronutrients apart from vitamin A, B12, C, K, and copper (p < 0.05). The inactive participants had insufficient intake for 6/19 micronutrients, while the active participants had insufficient intake for 5/19 (p < 0.05) micronutrients. Multiple linear regression indicated a lower risk for insufficient micronutrient intake for participants with higher PAL and BMI (p < 0.001). Symmetrical up scaling of PAL and EI to recommended physical activity levels reduced the frequency of micronutrient insufficiencies. It follows that prevalence of insufficient micronutrient intake from food in NHANES might be partly determined by low energy turnover from insufficient PAL. PMID- 28708120 TI - On Operating a Nanofiltration Membrane for Olive Mill Wastewater Purification at Sub- and Super-Boundary Conditions. AB - In the last decades, membrane processes have gained a significant share of the market for wastewater purification. Although the product (i.e., purified water) is not of high added value, these processes are feasible both technically and from an economic point of view, provided the flux is relatively high and that membrane fouling is strongly inhibited. By controlling membrane fouling, the membrane may work for years without service, thus dramatically reducing operating costs and the need for membrane substitution. There is tension between operating at high permeate fluxes, which enhances fouling but reduces capital costs, and operating at lower fluxes which increases capital costs. Operating batch membrane processes leads to increased difficulties, since the feed fed to the membrane changes as a function of the recovery value. This paper is concerned with the operation of such a process. Membrane process designers should therefore avoid membrane fouling by operating membranes away from the permeate flux point where severe fouling is triggered. The design and operation of membrane purification plants is a difficult task, and the precision to properly describe the evolution of the fouling phenomenon as a function of the operating conditions is a key to success. Many reported works have reported on the control of fouling by operating below the boundary flux. On the other hand, only a few works have successfully sought to exploit super-boundary operating conditions; most super-boundary operations are reported to have led to process failures. In this work, both sub- and super-boundary operating conditions for a batch nanofiltration membrane process used for olive mill wastewater treatment were investigated. A model to identify a priori the point of transition from a sub-boundary to a super-boundary operation during a batch operation was developed, and this will provide membrane designers with a helpful tool to carefully avoid process failures. PMID- 28708119 TI - Correlations of Biomarkers and Self-Reported Seafood Consumption among Pregnant and Non-Pregnant Women in Southeastern Louisiana after the Gulf Oil Spill: The GROWH Study. AB - Seafood contains health-promoting fatty acids, but is often contaminated with mercury (Hg), complicating recommendations and choices around fish consumption during pregnancy. Self-reported diet may be subject to inaccuracy and this inaccuracy could differ according to pregnancy status. We investigated correlations between self-reported seafood consumption and blood levels of Hg and n-3 polyunsaturated fatty acids (PUFAs) in women affected by the Deepwater Horizon oil spill. Spearman correlation coefficients were calculated comparing log blood Hg and n-3 PUFAs to seafood consumption, then stratified by pregnancy status. Crude and adjusted linear regression models were constructed using biomarkers of Hg and n-3 PUFA and seafood consumption, adjusting for age and pregnancy status. Weak but significant correlations were found between log Hg levels and intake of Hg-containing seafood ( r = 0.15) and were slightly stronger among pregnant women ( r = 0.22, vs. r = 0.10). Biomarkers for n-3 PUFAs were significantly correlated with seafood consumption ( r = 0.12). Hg-containing seafood consumption was associated with increased blood level Hg in the highest quartile in both unadjusted (beta = 0.34, 95% CI: 0.15-0.53) and adjusted models (beta = 0.28, 95% CI: 0.08-0.48). Self-reported seafood consumption was correlated with biomarkers of both n-3 PUFA and Hg, but this association was different when stratified by pregnancy status. Pregnant women may have better recall of Hg-containing seafood compared to nonpregnant women. PMID- 28708121 TI - Sex Differences in the Relationship between Sleep Behavior, Fish Consumption, and Depressive Symptoms in the General Population of South Korea. AB - Sleep, fish consumption, and depression have a close relationship; however, the role of sex differences in sleep, fish consumption, and depression research is not yet well-established. This study aimed to examine whether the impact of bedtime, sleep-onset latency, sleep duration, sleep quality, and fish consumption on depressive symptoms differed in women and men. An online survey was conducted in South Korea with a stratified random sample of 600 participants between the ages of 20 and 69, whose gender and age were proportional to estimates of Korea's general population. The 20-item Center for Epidemiologic Studies Depression Scale was used to measure depressive symptoms with a cut-off score of 16. The Pittsburgh Sleep Quality Index (PSQI) was applied to evaluate sleep timing, sleep onset latency, sleep duration, and sleep quality. Our results indicated that late bedtime and short sleep duration were independently associated with depressive symptoms in women. Sleep-onset latency and poor sleep quality were independently associated with increased prevalence of depressive symptoms in both men and women. Higher fish consumption was significantly associated with decreased prevalence of depressive symptoms in men only. Our findings suggested the importance of a different approach for men and women in terms of promoting healthy sleep habits. In addition, higher fish consumption may be beneficial in the primary prevention of depression in Korean men. Further research is needed to confirm the findings from this cross-sectional study. PMID- 28708123 TI - The Feasibility and Functional Performance of Ternary Borate-Filled Hydrophilic Bone Cements: Targeting Therapeutic Release Thresholds for Strontium. AB - We examine the feasibility and functionality of hydrophilic modifications to a borate glass reinforced resin composite; with the objective of meeting and maintaining therapeutic thresholds for Sr release over time, as a potential method of incorporating antiosteoporotic therapy into a vertebroplasty material. Fifteen composites were formulated with the hydrophilic agent hydroxyl ethyl methacrylate (HEMA, 15, 22.5, 30, 37.5 or 45 wt% of resin phase) and filled with a borate glass (55, 60 or 65 wt% of total cement) with known Sr release characteristics. Cements were examined with respect to degree of cure, water sorption, Sr release, and biaxial flexural strength over 60 days of incubation in phosphate buffered saline. While water sorption and glass degradation increased with increasing HEMA content, Sr release peaked with the 30% HEMA compositions, scanning electron microscope (SEM) imaging confirmed the surface precipitation of a Sr phosphate compound. Biaxial flexural strengths ranged between 16 and 44 MPa, decreasing with increased HEMA content. Degree of cure increased with HEMA content (42 to 81%), while no significant effect was seen on setting times (209 to 263 s). High HEMA content may provide a method of increasing monomer conversion without effect on setting reaction, providing sustained mechanical strength over 60 days. PMID- 28708122 TI - Role of Zucchini and Its Distinctive Components in the Modulation of Degenerative Processes: Genotoxicity, Anti-Genotoxicity, Cytotoxicity and Apoptotic Effects. AB - Zucchini (Cucurbita pepo subsp. pepo) is a seasonal vegetable with high nutritional and medical values. Many useful properties of this fruit are attributed to bioactive compounds. Zucchini fruits ("Yellow" and "Light Green" varieties) and four distinctive components (lutein, beta-carotene, zeaxanthin and dehydroascorbic acid) were selected. Firstly, the lutein, beta-carotene, zeaxanthin and dehydroascorbic acid contents were determined in these fruits. Then, in order to evaluate the safety and suitability of their use, different assays were carried out: (i) genotoxicity and anti-genotoxicity tests to determine the safety and DNA-protection against hydrogen peroxide; (ii) cytotoxicity; and (iii) DNA fragmentation and Annexin V/PI (Propidium Iodide) assays to evaluate the pro-apoptotic effect. Results showed that: (i) all the substances were non-genotoxic; (ii) all the substances were anti-genotoxic except the highest concentration of lutein; (iii) "Yellow" zucchini epicarp and mesocarp exhibited the highest cytotoxic activity (IC50 > 0.1 mg/mL and 0.2 mg/mL, respectively); and (iv) "Light Green" zucchini skin induced internucleosomal DNA fragmentation, beta-carotene being the possible molecule responsible for its pro apoptotic activity. To sum up, zucchini fruit could play a positive role in human health and nutrition due to this fruit and its components were safe, able to inhibit significantly the H2O2-induced damage and exhibit anti-proliferative and pro-apoptotic activities toward HL60 (human promyelocytic leukemia cells) tumor cells. The information generated from this research should be considered when selecting potential accessions for breeding program purposes. PMID- 28708124 TI - Considerations and Future Research Directions for E-Cigarette Warnings-Findings from Expert Interviews. AB - Tobacco warning labels are important sources of risk information but research historically has been cigarette-centric. This qualitative study aimed to inform future direction and research on warnings for e-cigarettes. Between June and August 2016, we conducted interviews with 10 researchers with expertise in tobacco warning label research. Interviewees were registrants of a 2016 National Cancer Institute grantee meeting on tobacco warnings. Several participants agreed that the Food and Drug Administration's new nicotine addiction warning for e cigarettes could be informative but that it might not resonate with young people. Many agreed that more than one warning would be important as e-cigarette science evolves and that research on additional warning themes (e.g., nicotine exposure, harmful constituents) and execution styles (including use of pictorials) was important. Participants were somewhat mixed about the use of reduced-risk messages within e-cigarette warnings, but agreed that research on how to communicate about cigarette/e-cigarette relative risks was needed. Overall, more research is needed on tobacco warnings for non-cigarette products, including on the message content, placement, execution and potential impact on audiences' product knowledge, risk perceptions and use intentions. This is particularly needed for products such as e-cigarettes which may have harm-reduction potential relative to cigarettes and require unique considerations. PMID- 28708125 TI - Structure Elucidation and Botanical Characterization of Diterpenes from a Specific Type of Bee Glue. AB - Investigation of the single plant source bee glue type originating from Southern Australia resulted in the isolation and structure elucidation of major serrulatane diterpenes, novel 7,8,18-trihydroxyserrulat-14-ene (1), along with its oxidized product, 5,18-epoxyserrulat-14-en-7,8-dione (3) and known (18RS) 5,18-epoxyserrulat-14-en-8,18-diol (2). Exploration into the botanical origin revealed Myoporum insulare R. Br, as the plant source of the bee glue materials. This discovery was made through comparative analysis of the myoporum bee glue samples collected from the beehives, analyses of plant resinous exudate, and resin carried on the hind legs of bees foraging for bee glue. PMID- 28708126 TI - The Effect of a 12-Week Beta-hydroxy-beta-methylbutyrate (HMB) Supplementation on Highly-Trained Combat Sports Athletes: A Randomised, Double-Blind, Placebo Controlled Crossover Study. AB - The aim of this study was to verify the effect of beta-hydroxy-beta methylbutyrate (HMB) supplementation on physical capacity, body composition and the value of biochemical parameters in highly-trained combat sports athletes. Forty-two males highly-trained in combat sports were subjected to 12 weeks of supplementation with HMB and a placebo in a randomized, placebo controlled, double-blind crossover manner. Over the course of the experiment, aerobic and anaerobic capacity was determined, while analyses were conducted on body composition and levels of creatine kinase, lactate dehydrogenase, testosterone, cortisol and lactate. Following HMB supplementation, fat-free mass increased (p = 0.049) with a simultaneous reduction of fat mass (p = 0.016) in comparison to placebo. In turn, after HMB supplementation, the following indicators increased significantly in comparison to the placebo: the time to reach ventilatory threshold (p < 0.0001), threshold load (p = 0.017) and the threshold HR (p < 0.0001), as well as anaerobic peak power (p = 0.005), average power (p = 0.029), maximum speed (p < 0.001) and post-exercise lactate concentrations (p < 0.0001). However, when compared to the placebo, no differences were observed in blood marker levels. The results indicate that supplying HMB promotes advantageous changes in body composition and stimulates an increase in aerobic and anaerobic capacity in combat sports athletes. PMID- 28708127 TI - An active bacterial community linked to high chl-a concentrations in Antarctic winter-pack ice and evidence for the development of an anaerobic sea-ice bacterial community. AB - Antarctic sea-ice bacterial community composition and dynamics in various developmental stages were investigated during the austral winter in 2013. Thick snow cover likely insulated the ice, leading to high (<4 MUg l-1) chlorophyll-a (chl-a) concentrations and consequent bacterial production. Typical sea-ice bacterial genera, for example, Octadecabacter, Polaribacter and Glaciecola, often abundant in spring and summer during the sea-ice algal bloom, predominated in the communities. The variability in bacterial community composition in the different ice types was mainly explained by the chl-a concentrations, suggesting that as in spring and summer sea ice, the sea-ice bacteria and algae may also be coupled during the Antarctic winter. Coupling between the bacterial community and sea-ice algae was further supported by significant correlations between bacterial abundance and production with chl-a. In addition, sulphate-reducing bacteria (for example, Desulforhopalus) together with odour of H2S were observed in thick, apparently anoxic ice, suggesting that the development of the anaerobic bacterial community may occur in sea ice under suitable conditions. In all, the results show that bacterial community in Antarctic sea ice can stay active throughout the winter period and thus possible future warming of sea ice and consequent increase in bacterial production may lead to changes in bacteria-mediated processes in the Antarctic sea-ice zone. PMID- 28708128 TI - Applying allometric theory to fungi. PMID- 28708129 TI - Validation of a novel imaging approach using multi-slice CT and cone-beam CT to follow-up on condylar remodeling after bimaxillary surgery. AB - The main goal of this study was to introduce a novel three-dimensional procedure to objectively quantify both inner and outer condylar remodelling on preoperative multi-slice computed tomography (MSCT) and postoperative cone-beam computed tomography (CBCT) images. Second, the reliability and accuracy of this condylar volume quantification method was assessed. The mandibles of 20 patients (11 female and 9 male) who underwent bimaxillary surgery were semi-automatically extracted from MSCT/CBCT scans and rendered in 3D. The resulting condyles were spatially matched by using an anatomical landmark-based registration procedure. A standardized sphere was created around each condyle, and the condylar bone volume within this selected region of interest was automatically calculated. To investigate the reproducibility of the method, inter- and intra-observer reliability was calculated for assessments made by two experienced radiologists twice five months apart in a set of ten randomly selected patients. To test the accuracy of the bone segmentation, the inner and outer bone structures of one dry mandible, scanned according to the clinical set-up, were compared with the gold standard, micro-CT. Thirty-eight condyles showed a significant (P<0.05) mean bone volume decrease of 26.4%+/-11.4% (502.9 mm3+/-268.1 mm3). No significant effects of side, sex or age were found. Good to excellent (ICC>0.6) intra- and inter observer reliability was observed for both MSCT and CBCT. Moreover, the bone segmentation accuracy was less than one voxel (0.4 mm) for MSCT (0.3 mm+/-0.2 mm) and CBCT (0.4 mm+/-0.3 mm), thus indicating the clinical potential of this method for objective follow-up in pathological condylar resorption. PMID- 28708130 TI - Clinical and prognostic significance of e1a2 BCR-ABL1 transcript subtype in chronic myeloid leukemia. PMID- 28708132 TI - In the news: EAN highlights European success in neurology. PMID- 28708134 TI - Neurodegenerative disease: Loss of TDP-43 in microglia - friend or foe? PMID- 28708131 TI - A clinicopathological approach to the diagnosis of dementia. AB - The most definitive classification systems for dementia are based on the underlying pathology which, in turn, is categorized largely according to the observed accumulation of abnormal protein aggregates in neurons and glia. These aggregates perturb molecular processes, cellular functions and, ultimately, cell survival, with ensuing disruption of large-scale neural networks subserving cognitive, behavioural and sensorimotor functions. The functional domains affected and the evolution of deficits in these domains over time serve as footprints that the clinician can trace back with various levels of certainty to the underlying neuropathology. The process of phenotyping and syndromic classification has substantially improved over decades of careful clinicopathological correlation, and through the discovery of in vivo biomarkers of disease. Here, we present an overview of the salient features of the most common dementia subtypes - Alzheimer disease, vascular dementia, frontotemporal dementia and related syndromes, Lewy body dementias, and prion diseases - with an emphasis on neuropathology, relevant epidemiology, risk factors, and signature signs and symptoms. PMID- 28708133 TI - Autoantibodies in chronic inflammatory neuropathies: diagnostic and therapeutic implications. AB - The chronic inflammatory neuropathies (CINs) are rare, very disabling autoimmune disorders that generally respond well to immune therapies such as intravenous immunoglobulin (IVIg). The most common forms of CIN are chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), multifocal motor neuropathy, and polyneuropathy associated with monoclonal gammopathy of unknown significance. The field of CIN has undergone a major advance with the identification of IgG4 autoantibodies directed against paranodal proteins in patients with CIDP. Although these autoantibodies are only found in a small subset of patients with CIDP, they can be used to guide therapeutic decision-making, as these patients have a poor response to IVIg. These observations provide proof of concept that identifying the target antigens in tissue-specific antibody-mediated autoimmune diseases is important, not only to understand their underlying pathogenic mechanisms, but also to correctly diagnose and treat affected patients. This state-of-the-art Review focuses on the role of autoantibodies against nodes of Ranvier in CIDP, a clinically relevant emerging field of research. The role of autoantibodies in other immune-mediated neuropathies, including other forms of CIN, primary autoimmune neuropathies, neoplasms, and systemic diseases that resemble CIN, are also discussed. PMID- 28708135 TI - Regulation of PLK1 through competition between hnRNPK, miR-149-3p and miR-193b 5p. AB - Polo-like kinase 1 (PLK1) is a critical regulator of cell cycle progression and apoptosis. However, its regulation remains poorly understood. In the present study, we investigated the molecular mechanism underlying the post transcriptional regulation of PLK1. We observed that heterogeneous nuclear ribonucleoprotein K (hnRNPK) and PLK1 were positively associated in several different cancers and high expression levels of them correlated with poor prognosis in patients with cancer. Knockdown of hnRNPK resulted in reduced expression of PLK1, whereas conversely, PLK1 expression was increased in hnRNPK overexpressing cells. We found that hnRNPK regulated PLK1 expression through KH1- and KH2-dependent interactions with the 3'UTR of PLK1 mRNA. In addition, microRNA 149-3p (miR-149-3p) and miR-193b-5p suppressed PLK1 expression by targeting the 3'UTR of PLK1 mRNA. MicroRNA-elicited enrichment of PLK1 mRNA in Ago2 immunoprecipitation was altered by the presence or absence of hnRNPK. Furthermore, the deletion of the cytosine (C)-rich sequences of the 3'UTR of PLK1 mRNA abolished the decreased PLK1 expression observed via hnRNPK silencing and administration of miRNAs, a finding that suggests that hnRNPK shares this C-rich motif with miR-149-3p and miR-193b-5p. We also found that downregulation of PLK1 by either silencing hnRNPK or overexpression of miR-149-3p and miR-193b-5p decreased clonogenicity and induced apoptosis. Our findings from this study demonstrate that hnRNPK regulates PLK1 expression by competing with the PLK1 targeting miRNAs, miR-149-3p and miR-193b-5p. PMID- 28708136 TI - Differential requirements for Tousled-like kinases 1 and 2 in mammalian development. AB - The regulation of chromatin structure is critical for a wide range of essential cellular processes. The Tousled-like kinases, TLK1 and TLK2, regulate ASF1, a histone H3/H4 chaperone, and likely other substrates, and their activity has been implicated in transcription, DNA replication, DNA repair, RNA interference, cell cycle progression, viral latency, chromosome segregation and mitosis. However, little is known about the functions of TLK activity in vivo or the relative functions of the highly similar TLK1 and TLK2 in any cell type. To begin to address this, we have generated Tlk1- and Tlk2-deficient mice. We found that while TLK1 was dispensable for murine viability, TLK2 loss led to late embryonic lethality because of placental failure. TLK2 was required for normal trophoblast differentiation and the phosphorylation of ASF1 was reduced in placentas lacking TLK2. Conditional bypass of the placental phenotype allowed the generation of apparently healthy Tlk2-deficient mice, while only the depletion of both TLK1 and TLK2 led to extensive genomic instability, indicating that both activities contribute to genome maintenance. Our data identifies a specific role for TLK2 in placental function during mammalian development and suggests that TLK1 and TLK2 have largely redundant roles in genome maintenance. PMID- 28708139 TI - Geometric phase morphology of Jones matrices. AB - We demonstrate an innovative technique based on the Pancharatnam-Berry phase that can be used to determine whether an optical system characterized by a Jones matrix is homogeneous or inhomogeneous, containing orthogonal or nonorthogonal eigenpolarizations, respectively. Homogeneous systems have a symmetric geometric phase morphology showing line dislocations and sets of polarization states with an equal geometric phase. In contrast, the morphology of inhomogeneous systems exhibits phase singularities, where the Pancharatnam-Berry phase is undetermined. The results show an alternative to extract polarization properties such as diattenuation and retardance, and can be used to study the transformation of space-variant polarized beams. PMID- 28708140 TI - Wideband tunable opto-electronic oscillator based on frequency translation. AB - We demonstrate a new method to obtain a widely tunable low phase-noise opto electronic oscillator (OEO), based on translating the OEO signal into a lower intermediate frequency (IF) signal. The OEO signal is downconverted to IF by using a local oscillator (LO) signal, filtered by a high-Q filter; its frequency is then upconverted back into the high OEO frequency. The combination of a narrowband filter at a fixed central frequency with a tunable LO forms a tunable high-Q bandpass filter (BPF) that can be used to change the OEO frequency over a broad frequency region. The effect of the LO phase noise on the OEO is suppressed by the dual frequency conversions. Hence, a tunable LO with a high phase noise can be used to control the frequency of a very low phase-noise OEO. The use of a BPF with a lower center frequency than that of the OEO signal also enables increasing the effective Q-factor of the OEO filter. PMID- 28708137 TI - FAS apoptotic inhibitory molecule 2 is a stress-induced intrinsic neuroprotective factor in the retina. AB - We report the neuroprotective role of FAS apoptotic inhibitory molecule 2 (FAIM2), an inhibitor of the FAS signaling pathway, during stress-induced photoreceptor apoptosis. Retinal detachment resulted in increased FAIM2 levels in photoreceptors with higher amounts detected at the tips of outer segments. Activation of FAS death receptor via FAS-ligand led to JNK-mediated FAIM2 phosphorylation, decreased proteasome-mediated degradation and increased association with the FAS receptor. Photoreceptor apoptosis was accelerated in Faim2 knockout mice following experimental retinal detachment. We show that FAIM2 is primarily involved in reducing stress-induced photoreceptor cell death but this effect was transient. FAIM2 was found to interact with both p53 and HSP90 following the activation of the FAS death pathway and FAIM2/HSP90 interaction was dependent on the phosphorylation of FAIM2. Lack of FAIM2 led to increased expression of proadeath genes Fas and Ripk1 in the retina under physiologic conditions. These results demonstrate that FAIM2 is an intrinsic neuroprotective factor activated by stress in photoreceptors and delays FAS-mediated photoreceptor apoptosis. Modulation of this pathway to increase FAIM2 expression may be a potential therapeutic option to prevent photoreceptor death. PMID- 28708138 TI - Blocking endothelin-1-receptor/beta-catenin circuit sensitizes to chemotherapy in colorectal cancer. AB - The limited clinical response to conventional chemotherapeutics observed in colorectal cancer (CRC) may be related to the connections between the hyperactivated beta-catenin signaling and other pathways in CRC stem-like cells (CRC-SC). Here, we show the mechanistic link between the endothelin-1 (ET-1)/ET-1 receptor (ET-1R) signaling and beta-catenin pathway through the specific interaction with the signal transducer beta-arrestin1 (beta-arr1), which initiates signaling cascades as part of the signaling complex. Using a panel of patient-derived CRC-SC, we show that these cells secrete ET-1 and express ETAR and beta-arr1, and that the activation of ETAR/beta-arr1 axis promotes the cross talk with beta-catenin signaling to sustain stemness, epithelial-to-mesenchymal transition (EMT) phenotype and response to chemotherapy. Upon ETAR activation, beta-arr1 acts as a transcription co-activator that binds beta-catenin, thereby promoting nuclear complex with beta-catenin/TFC4 and p300 and histone acetylation, inducing chromatin reorganization on target genes, such as ET-1. The enhanced transcription of ET-1 increases the self-sustained ET-1/beta-catenin network. All these findings provide a strong rationale for targeting ET-1R to hamper downstream beta-catenin/ET-1 autocrine circuit. Interestingly, treatment with macitentan, a dual ETAR and ETBR antagonist, able to interfere with tumor and microenvironment, disrupts the ET-1R/beta-arr1-beta-catenin interaction impairing pathways involved in cell survival, EMT, invasion, and enhancing sensitivity to oxaliplatin (OX) and 5-fluorouracil (5-FU). In CRC-SC xenografts, the combination of macitentan and OX or 5-FU enhances the therapeutic effects of cytotoxic drugs. Together, these results provide mechanistic insight into how ET 1R coopts beta-catenin signaling and offer a novel therapeutic strategy to manage CRC based on the combination of macitentan and chemotherapy that might benefit patients whose tumors show high ETAR and beta-catenin expression. PMID- 28708141 TI - Static FT imaging spectrometer based on a modified waveguide MZI array. AB - We proposed a large aperture push-broom static Fourier transform (FT) imaging spectrometer for hyper-spectral imaging. The spectroscopic system was based on the silicon-on-insulator (SOI) platform, consisting of spot size converters, a Mach-Zehnder interferometer (MZI) array, and a detector array. The arm length differences of the 201 MZI arrays are linearly varied. It is one on-chip FT spectrometer operating in a large spectral range from 1100 to 1700 nm with a resolution of 24 cm-1 and small foot print (chip size: 11 mm*15 mm). The waveguide-MZI-based large aperture push-broom FT spectrometer can provide a compact solution for high spectral resolution remote sensing in both the fore-optic lens and the spectroscopic system. PMID- 28708142 TI - Experimental validation of phase-only pre-compensation over 494 m free-space propagation. AB - It is anticipated that ground-to-geostationary orbit (GEO) laser communication will benefit from pre-compensation of atmospheric turbulence for laser beam propagation through the atmosphere. Theoretical simulations and laboratory experiments have determined its feasibility; extensive free-space experimental validation has, however, yet to be fulfilled. Therefore, we designed and implemented an adaptive optical (AO)-box which pre-compensates an outgoing laser beam (uplink) using the measurements of an incoming beam (downlink). The setup was designed to approximate the baseline scenario over a horizontal test range of 0.5 km and consisted of a ground terminal with the AO-box and a simplified approximation of a satellite terminal. Our results confirmed that we could focus the uplink beam on the satellite terminal using AO under a point-ahead angle of 28 MUrad. Furthermore, we demonstrated a considerable increase in the intensity received at the satellite. These results are further testimony to AO pre compensation being a viable technique to enhance Earth-to-GEO optical communication. PMID- 28708143 TI - Tunable higher-order orbital angular momentum using polarization-maintaining fiber. AB - For the first time, to the best of our knowledge, light with orbital angular momentum (OAM) of +/-2h per photon is produced using commercially available polarization-maintaining fiber with modal purity of 96%. Twist measurements demonstrate that the average orbital angular momentum can be continuously tuned between +/-2h. The authors consider beams of non-integer OAM, created using the presented method, as superpositions of integer OAM states. PMID- 28708144 TI - Coherent field transients below 15 THz from phase-matched difference frequency generation in 4H-SiC. AB - We experimentally demonstrate tunable, phase-matched difference frequency generation covering the spectral region below 15 THz using 4H-SiC as a nonlinear crystal. This material combines a non-centrosymmetric lattice and strong birefringence with broadband transparency at low optical frequencies. Thorough refractive index measurements in the terahertz spectral range allow us to calculate phase-matching conditions for any near-infrared pump laser source. 4H SiC is also exploited as a detector crystal for electro-optic sampling. The results allow us to estimate the effective second-order nonlinear coefficient. PMID- 28708145 TI - Tunable THz polariton laser based on 1342 nm wavelength for enhanced terahertz wave extraction. AB - We detail the operation of a THz laser source based on non-linear stimulated polariton scattering (SPS) in Mg:LiNbO3. This system utilizes a fundamental wavelength of 1342 nm to completely avoid the negative effect of free carrier generation within high-resistivity silicon (Si) prisms used to extract THz radiation from the Mg:LiNbO3 crystal. THz power of up to 23.6 MUW (62.3 MUW when chopped at 50% duty cycle) was detected at 1.33 THz, and frequency tunability across the range 1.05-2.2 THz was achieved. PMID- 28708146 TI - Impact of curvature on the optimal configuration of flexible luminescent solar concentrators. AB - Flexible luminescent solar concentrators (LSCs) could deliver integrated photovoltaics in all aspects of our lives, from architecture to wearable electronics. We present and experimentally verify a model for the optimization of the external optical efficiency of LSCs under varying degrees of curvature. We demonstrate differences between the optimization of flat and bent LSCs, showing that optimal fluorophore concentrations can differ by a factor of two. PMID- 28708147 TI - Real-time online photonic random number generation. AB - We present a real-time scheme for ultrafast random number (RN) extraction from a broadband photonic entropy source. Ultralow jitter mode-locked pulses are used to sample the stochastic intensity fluctuations of the entropy source in the optical domain. A discrete self-delay comparison technology is exploited to quantize the sampled pulses into continuous RN streams directly. This scheme is bias free, eliminates the electronic jitter bottleneck confronted by currently available physical RN generators, and has no need for threshold tuning and post-processing. To demonstrate its feasibility, we perform a proof-of-principle experiment using an optically injected chaotic laser diode. RN streams at up to 7 Gb/s with verified randomness were thereby successfully extracted in real time. With the provision of a photonic entropy source with sufficient bandwidth, the present approach is expected to provide RN generation rates of several tens of gigabits per second. PMID- 28708148 TI - Real-time fiber-optic anemometer based on a laser-heated few-layer graphene in an aligned graded-index fiber. AB - A real-time all-fiber anemometer based on laser-heated few-layer graphene in aligned graded-index fibers has been proposed and experimentally demonstrated. The proposed fiber-optic anemometer was composed of a pair of all-fiber collimators by using aligned graded-index fibers that was coated with the few layer graphene. The few-layer graphene was heated through a heating light from a 532-nm laser, which changed the optical transmittance of signal light with the wavelength of 1550 nm. The wind speed can be measured through the transmission power of the signal light based on the wind cooling effects on the heated few layer graphene, acting as a "hot-wire" anemometer. The experimental results show that the maximum sensitivity of the anemometer reaches -22.03 MUW/(m/s), and a fast response time of as 0.064 s can be achieved. The proposed fiber sensor can be used for the real-time measurement of wind speed in the fields of environmental monitoring, oil exploration, oceanography research, etc. PMID- 28708149 TI - Photonic jet: key role of injection for etchings with a shaped optical fiber tip. AB - We demonstrate the key role of the laser injection into a multimode fiber to obtain a photonic jet (PJ). PJ, a high concentrated propagating beam with a full width at half-maximum smaller than the diffraction limit, is here generated with a shaped optical fiber tip using a pulsed laser source (1064 nm, 100 ns, 35 kHz). Three optical injection systems of light are compared. For similar etched marks on silicon with diameters around 1 MUm, we show that the required ablation energy is minimum when the injected light beam is close to the fundamental mode diameter of the fiber. Thus, we confirm experimentally that to obtain a PJ out of an optical fiber, light injection plays a role as important as that of the tip shape and, therefore, the role of the fundamental mode in the process. PMID- 28708150 TI - Effects of ambient air pressure on surface structures produced by ultrashort laser pulse irradiation. AB - We report an experimental analysis addressing striking effects of residual air ambient pressure, from atmospheric conditions (103 mbar) to high vacuum (10-4 mbar), on the surface structures induced on a silicon target by direct femtosecond laser irradiation. We observe an interesting direct impact of the ambient pressure on the period and depth of the generated ripples as well as on the formation of microgrooves. Moreover, a significant correlation is observed between the ripples' period and depth. The change of pressure is accompanied by a variation of the degree of nanoparticle coverage, which is eventually recognized as an important factor for the development of the final surface structures. These results shed light on the intriguing mechanisms underlying the formation of the various surface textures, also evidencing that the ambient pressure can act as an effective parameter to tailor some characteristic features of the processed surface. PMID- 28708151 TI - Dependence of atmospheric refractive index structure parameter (Cn2) on the residence time and vertical distribution of aerosols. AB - Effects of absorbing atmospheric aerosols in modulating the tropospheric refractive index structure parameter (Cn2) are estimated using high resolution radiosonde and multi-satellite data along with a radiative transfer model. We report the influence of variations in residence time and vertical distribution of aerosols in modulating Cn2 and why the aerosol induced atmospheric heating needs to be considered while estimating a free space optical communication link budget. The results show that performance of the link is seriously affected if large concentrations of absorbing aerosols reside for a long time in the atmospheric path. PMID- 28708152 TI - Optical frequency comb generation with ultra-narrow spectral lines. AB - We demonstrate an optical comb source that generates 550 ultra-narrow spectral lines with a spectral linewidth of 1.5-3 kHz, spanning over the C-band. The source originates from a single-mode Brillouin laser processed with phase modulation, pulse compression, and four-wave mixing. As a result, the narrow linewidth of the Brillouin laser improves the phase noise of every spectral line of the frequency comb. PMID- 28708153 TI - Stabilization of femtosecond optical parametric oscillators for infrared frequency comb generation. AB - A synchronously pumped optical parametric oscillator (SP-OPO) is one of the most common techniques to generate femtosecond frequency combs in the mid-infrared region. Stable long-term operation of an SP-OPO requires active locking of the OPO resonator round-trip time to the pump pulse interval. A simple modulation free locking method based on stabilization of narrow-band frequency-doubled power of the SP-OPO output comb is demonstrated in this Letter. The method relies on the strong dependency of frequency-doubled power on spectral shape of the comb, leading to better stability of the comb envelope spectrum than the commonly used dither-and-lock method. PMID- 28708154 TI - Frequency-domain light intensity spectrum analyzer based on temporal convolution. AB - We propose and experimentally demonstrate a new type of all-optical radio frequency (RF) spectrum analyzer based on temporal convolution and cross-phase modulation (XPM) that can be regarded as the frequency-domain counterpart of a conventional light intensity spectrum analyzer (LISA). The XPM effect converts the intensity envelope of an optical signal to the phase of the probe signal, while the temporal convolution helps to enable the RF spectrum to be temporally resolved with a high frame rate. This frequency-domain LISA (f-LISA) has experimentally demonstrated an 800-GHz observation bandwidth with 1.25-GHz resolution (1 GHz for a single frequency) and a 94-MHz frame rate. To showcase its potential applications, this analyzer has successfully characterized the dynamic RF spectrum of an ultrafast wavelength-switching signal with a 10-ns switching interval. We believe that it is promising for some ultrafast dynamic RF spectrum acquisition applications, e.g., fast tuning lasers and real-time channel monitoring. PMID- 28708155 TI - Adaptive aberration correction of a 5 J/6.6 ns/200 Hz solid-state Nd:YAG laser. AB - In this Letter, we present an adaptive aberration correction system to simultaneously compensate for aberrations and reshaping the beams. A low-order aberration corrector is adapted. In this corrector, four lenses are mounted on a motorized rail, whose positions can be obtained using a ray tracing method based on the beam parameters detected by a wavefront sensor. After automatic correction, the PV value of the wavefront is reduced from 26.47 to 1.91 MUm, and the beam quality beta is improved from 18.42 to 2.86 times that of the diffraction limit. After further correction with a deformable mirror, the PV value of the wavefront is less than 0.45 MUm, and the beam quality is 1.64 times that of the diffraction limit. To the best of our knowledge, this is the highest performance from such a high-power, high-pulse repetition rate Nd:YAG solid-state laser ever built. PMID- 28708156 TI - 2 W single-longitudinal-mode Yb:YAG distributed-feedback waveguide laser. AB - Single longitudinal mode (SLM) lasers are important tools for many scientific and commercial applications. SLM operation can be achieved in distributed-feedback (DFB) lasers based on Bragg structures. Semiconductor waveguide DFB lasers are well-established devices, but their output power is limited to a few hundred milliwatts. DFB lasers have also been demonstrated in dielectric waveguides. However, in this case the output power was even lower. Here we present the first monolithic Yb:YAG DFB laser. The waveguide and the DFB structure were fabricated in the volume of an Yb:YAG crystal by ultrafast laser inscription. The DFB laser delivered 2 W of output power at a slope efficiency of 61% in SLM operation under pumping with an optically pumped semiconductor laser. This power level outperforms previously demonstrated dielectric DFB waveguide lasers by nearly an order of magnitude. Our approach paves the way for compact, robust, and highly efficient high-power SLM laser sources. PMID- 28708157 TI - Complex decorrelation averaging in optical coherence tomography: a way to reduce the effect of multiple scattering and improve image contrast in a dynamic scattering medium. AB - We demonstrate that complex decorrelation averaging can reduce the effect of multiple scattering and improve optical coherence tomography (OCT) imaging contrast. Complex decorrelation averaging calculates the product of an A-scan and the complex conjugate of a subsequent A-scan. The resultant signal is the product of the amplitudes and the phase difference. All these resulting complex signals at a particular location are then averaged. We take advantage of the fact that complex averaging, in contrast to conventional magnitude averaging, is sensitive to phase decorrelation. Sample motion that increases signal phase variance results in lower signal magnitude after complex averaging. Such motion preferentially results in a faster decorrelation of the multiple scattering signal when compared to the single scattering signal with each scattering event spreading the phase. This indicates that we may reduce multiple scattering by implementing complex decorrelation averaging to preferentially reduce the magnitude of the multiply scattered light signal in OCT images. By adjusting the time between phase-differenced A-scans, one can regulate the amount of measured decorrelation. We have performed experiments on liquid phantoms that give experimental evidence for this hypothesis. A substantial improvement in OCT image contrast using complex decorrelation averaging is demonstrated. PMID- 28708158 TI - Silicon microring modulator-based RF mixer for millimeter-wave phase-coded signal generation. AB - Phase-coded radio frequency (RF) pulses are widely adopted for radar systems as an effective signal format to enable high-range resolution. However, generating such signals conventionally requires high-speed electronics and complex RF circuitry that impose burdens on the system cost and power consumption. In particular, modern radar systems desire features such as high frequencies, e.g., in the millimeter-wave region, high compactness, and high system flexibility, which pose great challenges for the conventional all-electronics solutions. In contrast, integrated microwave photonics opens a way to solutions that are able to provide those features simultaneously, together with potential for full integration and low cost fabrication. Here, we present an integrated microwave photonic method of a binary-phase-coded millimeter-wave signal generation. The core device is a silicon microring modulator with a device size of 0.13 mm*0.32 mm and a modulation bandwidth of 23 GHz. Using RF seed frequencies of 17.5 GHz and 20 GHz, respectively, we experimentally demonstrated the generation of binary phase-coded signals at 35 GHz and 40 GHz using our proposed approach, the performance of which was verified by a pulse compression ratio of 94 and 106, respectively. The result of this work points to the realization of a chip-scale flexible millimeter-wave signal generator. PMID- 28708159 TI - Orbital angular momentum beams generated by passive dielectric phase masks and their performance in a communication link. AB - We demonstrate the generation of orbital angular momentum (OAM) beams using high efficient polarization-insensitive phase masks. The OAM beams generated by the phase masks are characterized in terms of their tolerance to misalignment (lateral displacement or tilt) between the incident beam and phase mask. For certain scenarios, our results show that (a) when the tilt angle is within the range of -20 to +20 deg, the crosstalk among modes is less than -15 dB; and (b) lateral displacement of 0.3 mm could cause a large amount of power leaked to adjacent modes. Finally, OAM beams generated by the phase masks are demonstrated over a two-channel OAM-multiplexing link, each channel carrying a 40 Gbit/s data stream. An optical signal-to-noise-ratio (OSNR) penalty of ~1 dB is measured without crosstalk at the bit error rate (BER) of 3.8*10-3. With crosstalk, an OSNR penalty of <1.5 dB is observed at the same BER. PMID- 28708160 TI - Coexistence of cavity solitons with different polarization states and different power peaks in all-fiber resonators. AB - We theoretically investigate a weakly birefringent all-fiber cavity subject to linearly polarized optical injection. We describe the propagation of light inside the cavity using, for each linear polarization component of the electric field, the Lugiato-Lefever model. These two components are coupled by cross-phase modulation. We show that, for a wide range of parameters, there is a coexistence between a homogeneous steady state and two different types of temporal vector cavity solitons, which can be hosted in the same system. They differ by their polarization state and peak intensity. We construct their bifurcation diagram and show that they are connected through a saddle-node bifurcation. Finally, we show that vector cavity solitons exhibit multistability involving different polarization states with different energies. PMID- 28708161 TI - Entanglement in a four-wave mixing process. AB - We investigate different kinds of entanglement in a four-wave mixing process with a degenerate pump. After analyses on means and quantum fluctuations of the three output beams (Stokes, anti-Stokes, and pump), we verify the existence of genuine tripartite entanglement, and quantify bipartite, two-mode, as well as tripartite entanglement with the covariance matrix. We find out that the input pump power and the nonlinear coupling strength are the physical origins to enhance entanglement at a given photon loss. PMID- 28708162 TI - High-energy Nd:YAG laser system with arbitrary sub-nanosecond pulse shaping capability. AB - We report on a laser system capable of generating high-energy (>270 mJ) temporally shaped pulses at 1064 nm with 0.43-ns shaping resolution. The pulses are generated by modulation of a continuous-wave seed laser and subsequent amplification by a dual-stage grazing-incidence Nd:YVO4 "bounce" amplifier and a Nd:YAG power amplifier (all quasi-continuous diode-pumped). The system produces pulses with a high-quality top-hat spatial beam profile with up to 0.6 GW of peak power and 44 W of average power, a power stability of 0.22% rms, and fully programmable complex temporal shapes. PMID- 28708163 TI - Compact tunable photonic comb filter on a silicon platform. AB - We propose and demonstrate a compact wavelength- and bandwidth-tunable photonic comb filter on a silicon platform. It is a Fabry-Perot (FP) cavity fabricated on silicon-on-insulator, which is composed of two cascaded Sagnac loop mirrors (SLMs) with multimode-interferometer-assisted Mach-Zehnder interferometer (MZI) couplers. The effective length of the FP cavity and the reflectivity of the SLMs can be dynamically changed based on thermal-optical effects by tuning three phase shifters along the cavity length and MZI arms, leading to center wavelength tuning and bandwidth tuning of the comb filter. Three tuning cases are investigated. By independently or simultaneously tuning three microheaters, center wavelength tuning with a tuning efficiency of ~0.017 nm/mW and bandwidth tuning from 4.37 to 27.6 GHz are achieved in the experiment. PMID- 28708164 TI - High-efficiency broadband excitation and propagation of second-mode spoof surface plasmon polaritons by a complementary structure. AB - A complementary structure based on coplanar waveguides (CPWs) with periodical etching slots is proposed to support spoof surface plasmon polaritons (SSPPs). In contrast to the traditional slotline-based complementary SSPP structure, a dispersion curve of the second mode by the proposed structure has a much lower starting point from the origin which exhibits greatly improved operating bandwidth. Moreover, tighter confinements of SSPPs in the region of small wave vectors corresponding to lower frequencies can be predicted from the dispersion analysis, which means enhancement of transmission efficiency. Then a simple and efficient transition structure with tapered CPWs and gradient slots is proposed to realize high-efficiency and broadband excitation of the second mode of SSPPs for the first time, to the best of our knowledge. Based on the proposed structure, a seamless connection between CPWs and the SSPP structure can be achieved. The measured insertion loss and return loss below 6.6 GHz is better than -0.86 and -13.62 dB, respectively. Furthermore, it can be seen from the measurement results that a 3 dB bandwidth ranges from 0 to 10.57 GHz, and the return loss is better than -10 dB from 0 to 8.96 GHz. The proposed structure can promote the development of plasmonic integrate circuits and functional devices at microwave frequencies. PMID- 28708165 TI - Optical heterodyne-enhanced chirped laser dispersion spectroscopy. AB - A proof-of-concept heterodyne-enhanced chirped laser dispersion spectroscopy system is presented. In remote sensing systems where low return powers are expected, the addition of an optical local oscillator and subsequent nonlinear processing can provide improved performance in chirped laser dispersion spectroscopy. Details about the system configuration, phase noise cancellation, and experimental verification are discussed. PMID- 28708167 TI - Broadband etching-free metal grating couplers embedded in titanium dioxide waveguides. AB - Metal grating couplers embedded into a titanium dioxide layer are proposed. A coupling efficiency better than 20% is experimentally demonstrated with a 3 dB bandwidth of 86 nm which is in agreement with simulation results. This allowed us to perform error-free transmissions of 10 Gbit/s wavelength multiplexed signals in the C-band. PMID- 28708166 TI - Low photon count based digital holography for quadratic phase cryptography. AB - Recently, the vulnerability of the linear canonical transform-based double random phase encryption system to attack has been demonstrated. To alleviate this, we present for the first time, to the best of our knowledge, a method for securing a two-dimensional scene using a quadratic phase encoding system operating in the photon-counted imaging (PCI) regime. Position-phase-shifting digital holography is applied to record the photon-limited encrypted complex samples. The reconstruction of the complex wavefront involves four sparse (undersampled) dataset intensity measurements (interferograms) at two different positions. Computer simulations validate that the photon-limited sparse-encrypted data has adequate information to authenticate the original data set. Finally, security analysis, employing iterative phase retrieval attacks, has been performed. PMID- 28708168 TI - Portable laser spectrometer for airborne and ground-based remote sensing of geological CO2 emissions. AB - A 24 kg, suitcase sized, CW laser remote sensing spectrometer (LARSS) with a ~2 km range has been developed. It has demonstrated its flexibility in measuring both atmospheric CO2 from an airborne platform and terrestrial emission of CO2 from a remote mud volcano, Bledug Kuwu, Indonesia, from a ground-based sight. This system scans the CO2 absorption line with 20 discrete wavelengths, as opposed to the typical two-wavelength online offline instrument. This multi-wavelength approach offers an effective quality control, bias control, and confidence estimate of measured CO2 concentrations via spectral fitting. The simplicity, ruggedness, and flexibility in the design allow for easy transportation and use on different platforms with a quick setup in some of the most challenging climatic conditions. While more refinement is needed, the results represent a stepping stone towards widespread use of active one-sided gas remote sensing in the earth sciences. PMID- 28708169 TI - Competition between Raman and Kerr effects in microresonator comb generation. AB - We investigate the effects of Raman and Kerr gain in crystalline microresonators and determine the conditions required to generate mode-locked frequency combs. We show theoretically that a strong, narrowband Raman gain determines a maximum microresonator size allowable to achieve comb formation. We verify this condition experimentally in diamond and silicon microresonators and show that there exists a competition between Raman and Kerr effects that leads to the existence of two different comb states. PMID- 28708170 TI - Widely wavelength tunable fast intensity-modulated light source for biophotonic applications. AB - High modulation depth, fast (megahertz to gigahertz), intensity-modulated light sources of various wavelengths within the 0.7-1.35 MUm bio-penetration window are highly desirable for many biophotonic diagnosis systems. In this Letter, we present a novel scheme of a wavelength tunable, ultra-broadband light source which simply consists of a pump laser, a nonlinear fiber, and demodulation circuits. The working wavelength range of the light source is from 0.7 to 1.35 MUm which covers a vast part of the bio-penetration window, and its modulation frequencies extends from tens of megahertz to gigahertz. The performances of the proposed light source in either working wavelength range or modulation frequency bandwidth are much superior to any typical laser diodes or solid state lasers currently employed in the frequency-domain or other biophotonic utilization. The wide applicability of this novel light source in diverse biophotonic applications can be observed from our carefully designed diffused optical spectroscopy phantom measurement. PMID- 28708171 TI - Bragg grating inscription in PMMA optical fibers using 400-nm femtosecond pulses. AB - In this Letter, we report the fast growth of high quality uniform Bragg gratings in trans-4-stilbenemethanol (TS)-doped poly(methyl methacrylate) (PMMA) step index optical fibers. Grating manufacturing was obtained using a 400 nm femtosecond pulsed laser and a 1060-nm-period uniform phase mask. For 20 mW mean laser beam power, the grating reflectivity reaches 98% in ~60 s. PMID- 28708172 TI - Design rules for combined label-free and fluorescence Bloch surface wave biosensors. AB - We report on the fabrication and physical characterization of optical biosensors implementing simultaneous label-free and fluorescence detection and taking advantage of the excitation of Bloch surface waves at a photonic crystal's truncation interface. Two types of purposely designed one-dimensional photonic crystals on molded organic substrates with micro-optics were fabricated. These crystals feature either high or low finesse of the Bloch surface wave resonances and were tested on the same optical readout system. The experimental results show that designing biochips with a large resonance quality factor does not necessarily lead in the real case to an improvement of the biosensor performance. The conditions for optimal biochip design and operation of the complete bio sensing platform are established. PMID- 28708173 TI - On-chip reconfigurable optical add-drop multiplexer for hybrid wavelength/mode division-multiplexing systems. AB - A silicon-based on-chip reconfigurable optical add-drop multiplexer (ROADM) is presented for hybrid wavelength-division-multiplexing-mode-division-multiplexing systems. The present ROADM consists of a four-channel mode demultiplexer, four wavelength-selective thermo-optic switches based on microring resonators, and a four-channel mode multiplexer. With the present ROADM, one can add/drop one of wavelength channels of any mode to/from the multimode bus waveguide successfully with an excess loss of 2-5 dB and an extinction ratio of ~20 dB over a wavelength range of 1525-1555 nm. PMID- 28708174 TI - Versatile backconversion-inhibited broadband optical parametric amplification based on an idler-separated QPM configuration. AB - Conversion efficiency and phase-matching (PM) bandwidth are both critical issues for broadband parametric processes. In some sense, they determine the highest peak power achieved via the optical parametric amplification. In this Letter, a versatile idler-separated quasi-phase matching scheme capable of both backconversion circumvention and ultra-broadband PM is presented. Full dimensional spatial-temporal simulations for the typical optical parametric chirped pulse amplification processes at 800 nm and 3.4 MUm were presented in detail. By virtue of the broad PM bandwidth on account of the non-collinear PM configuration, the backconversion circumvention on account of the idler-separated design, and the walk-off self-compensation on account of the symmetrical tilting grating patterns, significantly improved gain bandwidth, extremely high conversion efficiency, and a well-preserved beam profile are simultaneously achieved. Compared with the collinear configuration, the peak power can be potentially enhanced by 5-10 times under the same operation circumstances. PMID- 28708175 TI - Plasmonic nanohole electrodes for active color tunable liquid crystal transmissive pixels. AB - Plasmonic pixels have been shown to offer numerous advantages over pigment-based color filters used in modern commercial liquid crystal (LC) displays. However, wideband dynamic tunability across the visible spectrum remains challenging. We experimentally demonstrate transmissive electrically tunable LC-nanohole pixels operating across the visible spectrum with unpolarized input light. An ultrathin Al nanohole electrode is designed to exhibit a polarized spectral response based on surface plasmon resonances. An output analyzer in combination with a nematic LC layer enables pixel color to be electronically controlled through an applied voltage across the device, where LC reorientation leads to tunable mixing of the relative contributions from the plasmonic color input. The nanostructured Al layer, acting as a combined electrode, polarizer, and functional color filter, is highly promising for electro-optic display applications. PMID- 28708176 TI - Lens-free all-fiber probe with an optimized output beam for optical coherence tomography. AB - A high-efficiency lensless all-fiber probe for optical coherence tomography (OCT) is presented. The probe is composed of a segment of large-core multimode fiber (MMF), a segment of tapered MMF, and a length of single-mode fiber (SMF). A controllable output beam can be designed by a simple adjustment of its probe structure parameters (PSPs), instead of the selection of fibers with different optical parameters. A side-view probe with a diameter of 340 MUm and a rigid length of 6.37 mm was fabricated, which provides an effective imaging range of ~0.6 mm with a full width at half-maximum beam diameter of less than 30 MUm. The insertion loss of the probe was measured to be 0.81 dB, ensuring a high sensitivity of 102.25 dB. Satisfactory images were obtained by the probe-based OCT system, demonstrating the feasibility of the probe for endoscopic OCT applications. PMID- 28708177 TI - Topology optimization of multi-track ring resonators and 2D microcavities for nonlinear frequency conversion. AB - We exploit recently developed topology-optimization techniques to design complex, wavelength-scale resonators for enhancing various nonlinear chi(2) and chi(3) frequency conversion processes. In particular, we demonstrate aperiodic, multi-track ring resonators and two-dimensional slab microcavities exhibiting long lifetimes Q?104, small modal volumes V?(lambda/2n)3, and among the largest nonlinear overlaps (a generalization of phase matching in large-etalon waveguides) possible, paving the way for efficient, compact, and wide-bandwdith integrated nonlinear devices. PMID- 28708178 TI - Multiple-view diffuse optical tomography system based on time-domain compressive measurements. AB - Compressive sensing is a powerful tool to efficiently acquire and reconstruct an image even in diffuse optical tomography (DOT) applications. In this work, a time resolved DOT system based on structured light illumination, compressive detection, and multiple view acquisition has been proposed and experimentally validated on a biological tissue-mimicking phantom. The experimental scheme is based on two digital micromirror devices for illumination and detection modulation, in combination with a time-resolved single element detector. We fully validated the method and demonstrated both the imaging and tomographic capabilities of the system, providing state-of-the-art reconstruction quality. PMID- 28708179 TI - High-average-power femtosecond laser at 258 nm. AB - We present an ultrafast fiber laser system delivering 4.6 W average power at 258 nm based on two-stage fourth-harmonic generation in beta barium borate (BBO). The beam quality is close to being diffraction limited with an M2 value of 1.3*1.6. The pulse duration is 150 fs, which, potentially, is compressible down to 40 fs. A plain BBO and a sapphire-BBO compound are compared with respect to the achievable beam quality in the conversion process. This laser is applicable in scientific and industrial fields. Further scaling to higher average power is discussed. PMID- 28708180 TI - 4D spatiotemporal evolution of combustion intermediates in turbulent flames using burst-mode volumetric laser-induced fluorescence. AB - High-speed (20 kHz rate), volumetric laser-induced-fluorescence imaging of combustion intermediates such as a formaldehyde (CH2O) and polycyclic aromatic hydrocarbon (PAH) species is demonstrated for tracking the four dimensional (4D) evolution of turbulent flames. The third-harmonic, 355 nm output of a burst-mode Nd:YAG laser with a 130 mJ/pulse is expanded to 30 mm diameter for volume illumination of the base region of a methane-hydrogen jet diffusion flame. Eight simultaneous images from different viewing angles are used to collect the resulting fluorescence signal for reconstruction of 200 time sequential three-dimensional volumes over 10 ms duration. The signal-to-noise ratio (SNR) of 300:1 is achieved after reconstruction with a temporal resolution of 100 ns and spatial resolution of 0.85-1.5 mm. PMID- 28708181 TI - Polarization-dependent strong coupling between surface plasmon polaritons and excitons in an organic-dye-doped nanostructure. AB - In this work, we demonstrate polarization-dependent strong coupling between surface plasmon polaritons (SPPs) and excitons in the J-aggregates-attached aperture array. It is shown that the excitons strongly couple with the polarization-dependent SPPs, and Rabi splittings are consequently observed. As a result, the polarization-dependent polariton bands are generated in the system. Increasing the incident angle, the polaritons disperse to higher energies under transverse-electric illumination, while the polaritons disperse to lower energies under transverse-magnetic illumination. Therefore, at different polarization incidence, we experimentally achieve distinct polaritons with opposite dispersion directions. In this way, tuning the polarization of the incident light, we can excite different polaritons whose energy propagates to different directions. Furthermore, by retrieving the mixing fractions of the components in these polariton bands, we find that the dispersion properties of the polaritons are inherited from both the SPPs and the excitons. Our investigation may inspire related studies on tunable photon-exciton interactions and achieve some potential applications on active polariton devices. PMID- 28708182 TI - Multi-beam pulsed-laser patterning of plasmonic films using broadband diffractive optical elements. AB - Multi-sector broadband diffractive optical elements (DOEs) were designed and fabricated from fused silica for high-efficiency multiplexing of femtosecond and nanosecond Gaussian laser beams into multiple (up to one 100) optically tunable microbeams with increased high-numerical aperture (NA) focal depths. Various DOE related issues, such as high-NA laser focusing, laser pulsewidth, and DOE symmetry-dependent heat conduction effects, as well as the corresponding spatial resolution, were discussed in the context of high-throughput laser patterning. The increased focal depths provided by such DOEs, their high multiplexing efficiency and damage threshold, as well as easy-to-implement optical shaping of output microbeams provide advanced opportunities for direct, mask-free, and vacuum-free high-throughput subtractive (ablative) and displacive pulsed-laser patterning of various nanoplasmonic films for surface-enhanced spectroscopy, sensing, and light control. PMID- 28708183 TI - Circular dichroism of a tilted U-shaped nanostructure. AB - The circular dichroism (CD) effect plays an important role in biological detection, analytical chemistry, and plasmonic sensing. Tilted 3D structures can generate CD signals under normal illumination. However, fabricating tilted 3D structures is complex and expensive. In this study, we fabricate a tilted U shaped nanostructure (TUSN) on a polystyrene (PS) nanosphere through the glancing angle deposition method. One branch of the U-shaped nanostructure is tilted by raising a sheet of SiO2 on the PS nanosphere. And the CD signal of the TUSN is enhanced because the phase difference increases with increasing thickness of the SiO2 sheet. This work proposes a method for fabricating tilted nanostructures and elucidates the mechanism of the CD effect for future research. PMID- 28708184 TI - Tailorable dispersion in a four-wave mixing laser. AB - We present experimental results demonstrating controllable dispersion in a ring laser by monitoring the lasing-frequency response to cavity-length variations. Pumping on an N-type level configuration in Rb87, we tailor the intra-cavity dispersion slope by varying experimental parameters, such as pump-laser frequency, atomic density, and pump power. As a result, we can tune the pulling factor, i.e., the ratio of the laser frequency shift to the empty cavity frequency shift, of our laser by more than an order of magnitude. PMID- 28708185 TI - Visibility of dielectrically passivated graphene films. AB - The visibility of monolayer graphene is dependent on its surrounding dielectric environment and the presence of any contamination associated with 2D layer transfer. Here, the optical contrast of residually contaminated monolayer graphene encased within a range of dielectric stacks characteristic of realistic devices is examined, highlighting the utility of optical microscopy for a graphene assessment, both during and after lithographic processing. Practically, chemical vapor deposited graphene is encapsulated in dielectric stacks of varying thicknesses of SiO2. Optical contrast is then measured and compared to predictions of a multilayer model. Experimentally measured contrast is in close agreement with simulation only when contamination is included. PMID- 28708186 TI - Tunable coupling-induced resonance splitting in a self-coupled silicon ring cavity with robust spectral characteristics. AB - We propose and demonstrate a self-coupled micro-ring resonator for resonance splitting by mutual mode coupling of a cavity mode and a counter-propagating mode in a silicon-on-insulator platform. The resonator is constructed with a self coupling region that can excite a counter-propagating mode. We experimentally study the effect of self-coupling on the resonance splitting, resonance extinction, and quality-factor evolution and stability. Based on the coupling, we achieve 72% of the free spectral range (FSR) splitting for a cavity with an FSR of 2.1 nm with <5% variation in the cavity quality factor. The self-coupled resonance splitting shows a highly robust spectral characteristic that can be exploited for sensing and optical signal processing. PMID- 28708187 TI - Strain induced insulator-to-conductor transition in conducting polymer composites from the auxetic behaviour of hierarchical microstructures. AB - Above their 'percolation threshold', intrinsically conducting polymer (ICP) based composites exhibit an increase or decrease in conductivity with strain. However, in this study we report an increase in conductivity and an associated insulator to-conductor transition observed in certain conducting polymer composites below their percolation threshold under uniaxial tensile strain, thereby shifting the percolation to lower volume fractions. The 'auxetic behaviour' possible in certain types of 'hierarchical' microstructures is shown to be responsible for such changes in the polyaniline (PANI) composites studied. Using percolation models, the size and shape of the 'conducting units' that contribute to the percolation and its changes with strain were predicted. These conducting units are secondary and tertiary 'hierarchical structures' formed by the agglomeration of primary units of nano-rods (10 nm). An increase in the aspect ratio of these 'conducting units' is necessary for lowering the percolation threshold, which is possible in tertiary rod-like assemblies of PANI and not in secondary rod-like or platelet-like hierarchical structures. 'Auxetic behaviour' or a negative Poisson's ratio results in the expansion of the agglomerates and increase in the aspect ratio. This demonstrates the possibility of 'auxetic behaviour' contributing to changes in conductivity, which has not been reported before and could be used for novel applications. PMID- 28708188 TI - Validation of a membrane touch biosensor for the qualitative detection of IgG class antibodies to herpes simplex virus type 2. AB - A novel type of biosensor was assessed for application to the qualitative determination of circulating antibodies to herpes simplex virus type 2 (HSV-2). The device utilises a high activity HSV-2 type specific gG2 antigen for antibody capture and commercially available ELISA reagents. The study compares the diagnostic performance of a prototype HSV-2 biochip to well-established in vitro tests routinely applied in clinical procedures. A panel of human serum samples (n = 60) previously characterised for HSV-2 serological status using the DiaSorin LIAISON(r) HSV-2 chemiluminescent immunoassay were assayed on the HSV-2 biochip and the Focus Diagnostics HerpeSelect(r) 2 ELISA IgG kit to determine concordance with the predicate test method. Sensitivity and specificity of the HSV-2 biochip were found comparable to both the DiaSorin and Focus test methods. Sample index values calculated from the immunoassay response of the biochip's coulometric sensors indicated a high degree of linear correlation of the dataset with the corresponding index values from the DiaSorin LIAISON(r) test (r2 0.8799) and Focus HerpeSelect(r) test (r2 0.8794). The HSV-2 biochip demonstrated excellent diagnostic performance in qualitative and semi-quantitative measurements, matching closely the performance of two diagnostic industry standard predicate methods. PMID- 28708189 TI - Structural and reactivity insights into covalently linked Cu(i) complex-Anderson polyoxometalates. AB - The synthesis, crystallographic analysis and full characterization of the Cu(i) complex-functionalized Anderson polyoxomolybdate anions (nBu4N)[MMo6O18((OCH2)3CNCH(C47H37N2P2OCu)2)] (M = Mn3+, Fe3+, Co3+) is reported. For the first time, direct crystallographic evidence for the covalent attachment of a photoactive metal complex to an organo-functionalized polyoxometalate is obtained. Initial electrochemical and photochemical studies report fundamental properties and solution stability of the compounds. PMID- 28708190 TI - Ligand sensitized strong luminescence from Eu3+-doped LiYF4 nanocrystals: a photon down-shifting strategy to increase solar-to-current conversion efficiency. AB - Lanthanide (Ln)-doped nanocrystals generally display low luminescence quantum efficiency due to forbidden nature of the 4f-4f transition besides possessing low absorption cross sections (~10 M-1 cm-1). Considering the demand for these materials, particularly for light emission and bioimaging applications, it is very important to improve their quantum efficiency. This work demonstrates a strategy to enhance Si solar cell efficiency via sensitization of Eu3+ ions luminescence from colloidal nanocrystals. We have for the first time developed a simple ligand exchange approach to attach 4,4,4-trifluoro-1-phenyl-1,3 butanedione (TPB) to the surface of Eu3+-doped LiYF4 nanocrystals (NCs). Owing to the good overlap between the emission of the TPB ligands and the energy levels of Eu3+ ions, an efficient energy transfer takes place from the ligand to Eu3+ ions upon ultraviolet (UV) excitation of the ligand, leading to intense red emission. The sensitization of Eu3+ ions greatly enhanced the quantum yield of Eu3+ ions (~31%) compared to the ~5% obtained via direct excitation of Eu3+ ions (lambdaexi = 394 nm) in Eu3+-doped LiYF4 NCs. A device was fabricated by embedding the nanocrystals on a Si solar cell to capture the UV photons and convert them into visible ones, which subsequently creates charge carriers inside the cell. Upon exposure to UV light, the nanocrystal embedded Si solar cell shows overall enhancement in the photocurrent upon excitation under UV radiation. PMID- 28708191 TI - Brownmillerite thin films as fast ion conductors for ultimate-performance resistance switching memory. AB - An oxide-based resistance memory is a leading candidate to replace Si-based flash memory as it meets the emerging specifications for future memory devices. The non uniformity in the key switching parameters and low endurance in conventional resistance memory devices are preventing its practical application. Here, a novel strategy to overcome the aforementioned challenges has been unveiled by tuning the growth direction of epitaxial brownmillerite SrFeO2.5 thin films along the SrTiO3 [111] direction so that the oxygen vacancy channels can connect both the top and bottom electrodes rather directly. The controlled oxygen vacancy channels help reduce the randomness of the conducting filament (CF). The resulting device displayed high endurance over 106 cycles, and a short switching time of ~10 ns. In addition, the device showed very high uniformity in the key switching parameters for device-to-device and within a device. This work demonstrates a feasible example for improving the nanoscale device performance by controlling the atomic structure of a functional oxide layer. PMID- 28708192 TI - Can Texas' Physicians Be as Diverse as Texas? AB - The United States and Texas have a chronic shortage of doctors, but the shortage of minority physicians is even more acute. To address this, and the health disparities that come with it, Texas medical schools are working to increase minority enrollment, but challenges remain. PMID- 28708193 TI - Drawing the Line. AB - Politicians have long touted giving consumers the ability to buy health insurance across state lines as part of health care reform. Several states have passed laws of their own allowing interstate sales, but health plan action on those has been minimal. What is the potential impact in Texas if interstate health plan sales were to become more of a reality? PMID- 28708194 TI - Getting Into Urgent Care. AB - Many primary care physicians opt to open "urgent care" facilities or add urgent care services to their practices. Although there are advantages - such as billing and appointment scheduling flexibility - there are headaches as well. PMID- 28708195 TI - Build Your Own Payment Model. AB - Physicians participating in MACRA have a unique opportunity to create and submit their own alternative payment models to the government and take command of their own future payments. At least one Texas physician is taking a crack at developing his own model. PMID- 28708196 TI - Assessment of mitral apparatus in patients with acute inferoposterior myocardial infarction and ischaemic mitral regurgitation with two-dimensional echocardiography from anatomically correct imaging planes. AB - BACKGROUND: Ischaemic mitral regurgitation (IMR) is associated with adverse prognosis after myocardial infarction (MI) as a result of left ventricular remodelling and geometric deformation of the mitral apparatus (MA). AIM: The aim of this study was to assess MA from anatomically correct imaging planes in acute inferoposterior MI and IMR. METHODS: Ninety-three patients with no structural cardiac valve abnormalities and the first acute inferoposterior MI were prospectively enrolled into the study. Two-dimensional transthoracic echocardiography for MA assessment was performed within 48 h of presentation after reperfusion therapy. Based on the degree of mitral regurgitation (MR), patients were divided into either a no significant MR (NMR) group (n = 52 with no or mild, grade 0-I MR) or an IMR group (n = 41 with grade >= 2 MR). The control group consisted of 45 healthy individuals. RESULTS: Ischaemic MR was related with dilatation of the left ventricle chambers, decrease in ejection fraction, increase in mitral annulus diameter and area, and changes in subvalvular apparatus when compared with the NMR group or healthy individuals. CONCLUSIONS: Ischaemic MR in acute inferoposterior MI is related with worse lesions in MA geometry that cause insufficiency of mitral valve function. PMID- 28708197 TI - Risk stratification personalised model for prediction of life-threatening ventricular tachyarrhythmias in patients with chronic heart failure. AB - BACKGROUND: The development of prognostic factors of life-threatening ventricular tachyarrhythmias (VTA) and sudden cardiac death (SCD) continues to maintain its priority and relevance in cardiology. The development of a method of personalised prognosis based on multifactorial analysis of the risk factors associated with life-threatening heart rhythm disturbances is considered a key research and clinical task. AIM: To design a prognostic and mathematical model to define personalised risk for life-threatening VTA in patients with chronic heart failure (CHF). METHODS: The study included 240 patients with CHF (mean-age of 50.5 +/- 12.1 years; left ventricular ejection fraction 32.8 +/- 10.9%; follow-up period 36.8 +/- 5.7 months). The participants received basic therapy for heart failure. The elec-trocardiogram (ECG) markers of myocardial electrical instability were assessed including microvolt T-wave alternans, heart rate turbulence, heart rate deceleration, and QT dispersion. Additionally, echocardiography and Holter monitoring (HM) were performed. The cardiovascular events were considered as primary endpoints, including SCD, paroxysmal ventricular tachycardia/ventricular fibrillation (VT/VF) based on HM-ECG data, and data obtained from implantable device interrogation (CRT-D, ICD) as well as appropriated shocks. RESULTS: During the follow-up period, 66 (27.5%) subjects with CHF showed adverse arrhythmic events, including nine SCD events and 57 VTAs. Data from a stepwise discriminant analysis of cumulative ECG-markers of myocardial electrical instability were used to make a mathematical model of preliminary VTA risk stratification. Uni- and multivariate Cox logistic regression analysis were performed to define an individualised risk stratification model of SCD/VTA. A binary logistic regression model demonstrated a high prognostic significance of discriminant function with a classification sensitivity of 80.8% and specificity of 99.1% (F = 31.2; c2 = 143.2; p < 0.0001). CONCLUSIONS: The method of personalised risk stratification using Cox logistic regression allows correct classification of more than 93.9% of CHF cases. A robust body of evidence concerning logistic regression prognostic significance to define VTA risk allows inclusion of this method into the algorithm of subsequent control and selection of the optimal treatment modality to treat patients with CHF. PMID- 28708198 TI - The effect of radiofrequency catheter ablation of frequent premature ventricular complexes and arrhythmia burden on left ventricular function. AB - BACKGROUND: Frequent premature ventricular complexes (PVC) are related to reversible tachycardia-induced cardiomyopathy. However, the role of arrhythmia burden on the outcome of the catheter ablation has not been fully recognised. AIM: The aim of this study was to assess the effect of catheter ablation and PVC burden in patients with and without structural heart disease (SHD) on left ventricular ejection fraction (LVEF). METHODS: Transthoracic echocardiography was done before and six months after radiofrequency catheter ablation in 109 consecutive patients (61 men, age 55 +/- 17 years) with frequent PVCs. Sixty-five (59.6%) patients had underlying SHD. RESULTS: The catheter ablation procedure was successful in 93 (85.3%) patients. Baseline PVC burden was higher in patients with SHD (22,267 +/- 12,934) compared to those without concomitant SHD (15,546 +/ 7888), p = 0.005. Nevertheless, patients with LVEF <= 50% at baseline presented greater LVEF recovery (from 44% to 56%) than those with LVEF > 50% at baseline after catheter ablation. In both groups, the LVEF improved (p < 0.001); however, no difference was observed be-tween patients with SHD (5.7% +/- 1.37%) and without (4.6% +/- 0.96%) SHD; p = 0.89. PVC burden was higher in patients with (24,350 +/- 2776 PVC/day) compared to those without (17,588 +/- 1970 PVC/day) improvement of LVEF. In multivariate regression analysis PVC burden > 20,000/day (but not age, p = 0.95; gender, p = 0.89; presence of SHD, p = 0.53; QRS complex width of the treated PVC, p = 0.21, LVEF before ablation, p = 0.19; and site of origin, p = 47) predicted improvement in LVEF after successful catheter ablation (odds ratio: 3.53; 95% confidence interval: 1.15-10.75; p = 0.023). CONCLUSIONS: Catheter ablation of frequent PVCs improves left ventricular function in multivariate analysis predicted improvement of LVEF within six months after the successful catheter ablation procedure in patients with PVC burden exceeding 20,000/24 h. PMID- 28708199 TI - Management of transposed arteriovenous fistula swing point stenosis at the basilic vein angle of transposition by stent grafts. AB - INTRODUCTION: Transposed basilic vein arteriovenous fistulas suffer from stenosis at their basilic angle of transposition (BAT). This lesion exhibits frequent recurrence after angioplasty. The primary goal of this study was to determine the effect of stent-graft placement on BAT lesion- and access-patency. The secondary goals were to determine the frequency of intervention pre- and post-stent placement and stent-associated stenosis. METHODS: Thirty-seven cases had stent grafts placed at their BAT to manage stenosis. Cases served as their own controls by analyzing their lesion- and access-patency pre- and post-stent placement. Student's t-test was used for analysis of continuous variables. Categorical variables were evaluated by Fisher's exact test. Tests were considered significant when p was <=0.05. RESULTS: At 6 and 12 months, pre-stent lesion primary patency rates were 29% and 3%, and post-stent were 57% and 40%, respectively. Lesion primary assisted patency rates were 39% and 13%, and post stent were 91% and 80%, respectively. At 6 and 12 months, pre-stent access primary patency rates were 29% and 3%, and post-stent were 26% and 19%, respectively. Pre-stent primary access assisted patency rates were 36% and 10%, and post-stent were 82% and 75%, respectively. Lesion intervention rates averaged 0.47/month pre-stent and 0.13/month post-stent. Access intervention rate averaged 0.50/month pre-stent, and 0.15/month post-stent. Stent-associated stenosis was seen in 23 cases. CONCLUSIONS: Treatment of BAT stenosis with stent-grafts had positive impact on the target lesion and the dialysis access circuit. PMID- 28708200 TI - Periacetabular bone densitometry after total hip arthroplasty with highly porous titanium cups: a 2-year follow-up prospective study. AB - INTRODUCTION: Trabecular Titanium is an advanced cellular solid structure, composed of regular multiplanar hexagonal interconnected cells that mimic the morphology of the trabecular bone. This biomaterial demonstrated improved mechanical properties and enhanced osteoinduction and osteoconduction in several in vitro and in vivo studies. The aim of this study was to assess Trabecular Titanium osseointegration by measuring periacetabular changes in bone mineral density (BMD) with dual-emission X-ray absorptiometry (DEXA). METHODS: 89 patients (91 hips) underwent primary total hip arthroplasty (THA) with acetabular Trabecular Titanium cups. Clinical (Harris Hip Score (HHS), SF-36) and radiographic assessment were performed preoperatively, and postoperatively at 7 days and at 3, 6, 12 and 24 months. DEXA analysis was performed only postoperatively, using the BMD values measured at 7 days as baselines. RESULTS: After an initial decrease from baseline to 6 months, BMD increased and progressively stabilised in all 3 regions of interest (ROIs). Median (IQR) HHS and SF-36 increased from 48 (39-62) and 49 (37-62) preoperatively to 99 (96-100) and 86 (79-92) at 24 months, indicating a considerable improvement in terms of pain relief, functional recovery and quality of life. BMD patterns and radiographic evaluation showed evident signs of periacetabular bone remodelling and osseointegration; all cups were stable at the final follow-up without radiolucent lines, loosening or osteolysis. No revisions were performed. CONCLUSIONS: After an initial reduction in periacetabular BMD, all 3 ROIs exhibited stabilisation or slight recovery. Although clinical outcomes and functional recovery proved satisfactory, longer follow-ups are necessary to assess this cup long-term survivorship. PMID- 28708201 TI - The impact of trabecular metal on hip centre of rotation in revision and complex primary hip arthroplasty, a radiological review. AB - INTRODUCTION: Total hip arthroplasty (THA) is a very successful procedure. Revision THA is becoming increasingly common. Recent developments to improve outcomes include the development of large trabecular metal (TM) acetabular cups and augments. There is a paucity of data on the benefit of these new techniques. METHODS: A single-centre retrospective review consisting of a radiological review of post-op revision THA anteroposterior pelvis. Data collection was performed using the Irish National Orthopaedic Register (INOR) and from a previous project. We used a technique developed by Fessy et al in 1999 to measure the centre of rotation (COR) of the hip. We then compared our study to that of a study measuring the COR of healthy native hips. RESULTS: 127 revision THA analysed. Native COR calculated by Fessy et al showed a mean horizontal (x) axis 33.6 mm (standard deviation [SD] 5.74) and a vertical (y) axis 16.4 mm (SD 4.67). Non-TM revisions showed a mean x axis of 29 mm (SD 3.9) and y axis 17.9 (SD 5.9). TM Augments had a mean x axis 29.2 mm (SD 7.9) and y axis of 21.5 (SD 8.4). TM Cups alone had a mean x axis 27 mm (SD 6.9) and y axis 22 mm (SD 10.18). CONCLUSIONS: COR of TM implants showed considerable deviation from the norm. Non-TM implants showed a COR within acceptable physiological range. TM components consistently failed to restore a natural COR in our cohort. The implications of this remain uncertain but must be considered in any decision to use TM. PMID- 28708202 TI - Experience after 12 cases with the adjustable transobturator male sling for postprostatectomy stress urinary incontinence. AB - OBJECTIVES: The aim of the study was the prospective evaluation of the efficacy of the adjustable transobturator male system (ArgusT(r)) for the treatment of postprostatectomy stress urinary incontinence (PPI). METHODS: Twelve consecutive patients were treated with ArgusT system for PPI. All patients were comprehensively evaluated preoperatively and after 3 and 6 months regarding daily pad use, residual urine, Incontinence Quality of Life Scale (I-QoL) score and International Consultation on Incontinence Questionnaire Short Form (ICIQ-SF) score. Cure rate was defined as no pad use or one pad (used for security reasons). RESULTS: At 3 and 6 months, we achieved a cure rate of 91%. The mean number of pads per day decreased from 4 +/- 1.3 to 0.7 +/- 0.9 and 0.5 +/- 0.9 after 3 and 6 months, respectively (p<0.001). Only one patient showed no significant improvement. Compared with baseline, the mean ICIQ-SF score dropped from 17.3 +/- 2.8 to 2.7 +/- 3.8 and 2.4 +/- 3.8, at 3 and 6 months, respectively (p<0.001). The mean I-QoL score also improved significantly from 53.1 +/- 20.3 to 99.5 +/- 11 and 96.8 +/- 12.5 after 3 and 6 months, respectively (p<0.001). Postoperative acute urinary retention was seen in one patient. CONCLUSIONS: In our early experience, the ArgusT system offers effective, safe and minimally invasive treatment option for PPI. PMID- 28708204 TI - Abstracts from XIV AIMAT National Congress, XI National Conference on Materials Science and Technology, July 2017, Ischia, Italy. PMID- 28708203 TI - Medical treatment of erectile dysfunction: too many medical prescriptions? AB - Erectile dysfunction (ED) is a worldwide commonly reported condition; epidemiological data showed a prevalence ranging from 2.3 to 53.4% within different population subsets. In this context, the advent of phosphodiesterase type 5 inhibitors (PDE5is) in the second mid of 1990s has deeply changed the treatment scenario of this bothersome condition. Being user-friendly compounds with an excellent overall safety profile, PDE5is emerged as the first-line treatment for ED, thus overcoming topical alprostadil and intracavernous injections (ICIs). However, available data on treatment-utilization patterns and medical prescriptions of PDE5is showed a range of as wide as 22-78% of patients reporting to purchase PDE5is even without a proper medical prescription. Moreover, an increase in the recreational use of PDE5is among young men has been observed in the last decades, with a worrisome diffusion of potential health risky behaviours associated with this habit. Indeed, treatment of ED should carefully follow internationally based clinical guidelines to avoid inappropriate drug prescriptions, which may eventually expose treated patients to drug-related side effects. Thereof, a careful assessment of the so-called modifiable and reversible ED risk factors along with a patient-tailored screening for potential contraindications to the treatment itself should be performed in every case. Lastly, although conclusive data still lack, the potential association between life-risky PDE5is side effects (i.e. cardiovascular adverse events, melanoma skin cancer and worsening of prostate cancer outcomes) should be carefully taken into account when counselling patients for ED treatment. PMID- 28708205 TI - MiR-411 functions as a tumor suppressor in renal cell cancer. AB - BACKGROUND: Recent studies have revealed that microRNAs (miRNAs) play important roles as oncogenes or tumor suppressors in tumorigenesis and tumor development, by negatively regulating protein expression. A previous study of microarrays identified that miR-411 was down-regulated in renal cell carcinoma (RCC), while few studies investigating the role of miR-411 in the pathogenesis of RCC have been performed. METHODS: We assessed the miR-411 expression in RCC and paired adjacent normal tissues, as well as in RCC cell lines and a normal renal cell line, by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). Furthermore, the effects of miR-411 on RCC and normal renal cell proliferation, apoptosis and migration were determined using MTT assay, CCK-8 assay, flow cytometry and scratch wound assay following restoration of miR-411 with synthetic mimics. RESULTS: Results of qRT-PCR indicated that the expression of miR-411 was down-regulated in RCC tissues and cell lines when compared with adjacent normal tissues and a normal renal cell line. Further, results of CCK-8, MTT, cell scratch and transwell assay showed that over-expression of miR-411 suppressed RCC cell (786-O and ACHN) proliferation and migration. Flow cytometry assay revealed that miR-411 could induce RCC cell apoptosis. However, overexpression of miR-411 had no obvious effect on normal renal cell line 293T. CONCLUSIONS: To sum up, miR 411 is significantly down-regulated and plays a role as a tumor suppressor in RCC. Further studies are warranted to determine the mechanisms of miR-411 in RCC pathogenesis and define the target genes of miR-411 in RCC. PMID- 28708206 TI - IQGAP1 silencing suppresses the malignant characteristics of laryngeal squamous cell carcinoma cells. AB - BACKGROUND: Laryngeal squamous cell carcinoma (LSCC) has a poor prognosis due to recurrence and metastasis. IQ-domain GTPase-activating protein 1 (IQGAP1), a scaffold protein, plays an important role in tumorigenesis and malignant development. In this study, we aimed to explore the role of IQGAP1 in LSCC. METHODS: Expression of IQGAP1 in human LSCC specimens was assessed by immunohistochemistry. We also evaluated the roles of IQGAP1 in cell proliferation, migration and invasion and epithelial-to-mesenchymal transition (EMT) in Hep-2 cells. RESULTS: The expression of IQGAP1 protein was significantly up-regulated in LSCC tissues compared with normal laryngeal tissues (p = 0.002). Furthermore, the knockdown of IQGAP1 in Hep-2 cells inhibited cell growth, migration and invasion. Moreover, we found that IQGAP1 silencing reversed EMT. CONCLUSIONS: These results show for the first time that IQGAP1 is up-regulated in LSCC tissues and plays an important role in LSCC cell proliferation and invasiveness, which indicates that IQGAP1 could work as an oncogene and may serve as a promising molecular target for treatment of LSCC. PMID- 28708207 TI - Variations in transrenal DNA and comparison with plasma DNA as a diagnostic marker for colorectal cancer. AB - BACKGROUND: Transrenal DNA can potentially be useful in the disease management of colorectal cancer (CRC) and has potential diagnostic utility. Our study aimed to conduct preoperative and postoperative analysis of KRAS-positive patients, using transrenal DNA compared with plasma DNA. This is critically needed for disease diagnostics and treatment response monitoring. METHODS: CRC patients at different stages of the disease and with different molecular profiles were recruited for serial time-point analysis. Preoperative and postoperative urine specimens were extracted and compared with tumor tissues and plasma DNA. RESULTS: Our analysis demonstrated that transrenal DNA offered comparable sensitivity and specificity to plasma DNA analysis. Collection of transrenal DNA, being noninvasive, is an attractive assay and easily allows serial monitoring of the disease. Results from preoperative detection showed a close correlation to tumor tissue profiling and demonstrated close associations to the disease. We also observed significant decreases in mutant KRAS DNA concentration after surgery, which confirmed transrenal DNA's sensitivity to treatment response. CONCLUSIONS: The use of transrenal DNA offers a possible alternative method of disease profiling, detection and tracking. Our study is one of the first to systematically analyze a relatively large number of different CRC patients using transrenal DNA. The positive correlation with disease demonstrates the assay's viability in the clinical setting, and our method further opens up the possibility to use transrenal DNA for clinical intervention investigations. PMID- 28708208 TI - Relationship between clinical toxicities and ERCC1 rs3212986 and XRCC3 rs861539 polymorphisms in cervical cancer patients. AB - BACKGROUND: Several studies have suggested that there are single nucleotide polymorphisms (SNPs) that can be considered potential biomarkers in the prognosis and therapeutic response of cancer patients. The present study investigated the association between ERCC1 rs3212986 and XRCC3 rs861539 polymorphisms and clinical toxicities induced by chemoradiotherapy (CRT) in cervical cancer. METHODS: This hospital-based retrospective cohort study included 260 patients with cervical cancer, FIGO stages Ib2-IVa, who underwent CRT (cisplatin). Genetic polymorphisms analysis was performed by allelic discrimination with real-time polymerase chain reaction (RT-PCR). RESULTS: Our results indicated a link between ERCC1 rs3212986 and the onset of late gastrointestinal toxicity (p = 0.038). Furthermore, using a recessive model (AA vs. CC/CA), we found that patients carrying AA homozygous genotype presented a fourfold increased risk of developing late gastrointestinal toxicity when compared with patients with the C allele (odds ratio = 3.727, 95% confidence interval, 1.199-11.588; p = 0.017). No association was found regarding the XRCC3 rs861539 polymorphism and any clinical toxicity event. CONCLUSIONS: This is the first study evaluating the relationship between these polymorphisms and clinical toxicities in cervical cancer patients submitted to CRT with cisplatin. These results may contribute toward a better understanding of the influence of genetic polymorphisms in genes associated with DNA repair in the clinical response to CRT of patients with cervical cancer. PMID- 28708209 TI - Changes of peritoneal transport parameters with time on dialysis: assessment with sequential peritoneal equilibration test. AB - BACKGROUND: Sequential peritoneal equilibration test (sPET) is based on the consecutive performance of the peritoneal equilibration test (PET, 4-hour, glucose 2.27%) and the mini-PET (1-hour, glucose 3.86%), and the estimation of peritoneal transport parameters with the 2-pore model. It enables the assessment of the functional transport barrier for fluid and small solutes. The objective of this study was to check whether the estimated model parameters can serve as better and earlier indicators of the changes in the peritoneal transport characteristics than directly measured transport indices that depend on several transport processes. METHODS: 17 patients were examined using sPET twice with the interval of about 8 months (230 +/- 60 days). RESULTS: There was no difference between the observational parameters measured in the 2 examinations. The indices for solute transport, but not net UF, were well correlated between the examinations. Among the estimated parameters, a significant decrease between the 2 examinations was found only for hydraulic permeability LpS, and osmotic conductance for glucose, whereas the other parameters remained unchanged. These fluid transport parameters did not correlate with D/P for creatinine, although the decrease in LpS values between the examinations was observed mostly for patients with low D/P for creatinine. CONCLUSIONS: We conclude that changes in fluid transport parameters, hydraulic permeability and osmotic conductance for glucose, as assessed by the pore model, may precede the changes in small solute transport. The systematic assessment of fluid transport status needs specific clinical and mathematical tools beside the standard PET tests. PMID- 28708210 TI - Particle image velocimetry tests on pediatric 45-cc and 30-cc ventricle assist devices: effects of heart rate on VAD operation. AB - BACKGROUND: This study investigated flow analysis inside pediatric ventricle assist devices (VADs) designed and manufactured at the Foundation for Cardiac Surgery Development (FRK), Zabrze, Poland. The main goal of the experiment was to define the minimal heart rate admissible in clinical practice. METHODS: The flow was directed by mechanical, single-disc valves developed at the Lodz University of Technology, Institute of Turbomachinery in Lodz, Poland. VAD operation conditions under different heart rates were analyzed. Measurements were performed on Religa PED pediatric VADs (45 cm3 and 30 cm3) with a particle image velocimetry (PIV) system. RESULTS: Due to the PIV method used, the measurements were made without interference of the measuring system onto the flow structure in the investigated channel, as the measurement procedure is noninvasive. During the investigations conducted in different measurement planes, the majority of the flow volume in the chamber was observable. CONCLUSIONS: The measurements at different heart rates demonstrated a significant influence of this parameter on the flow nature in the heart ventricle. Additionally, it was found that the heart rate affected the operation of heart valves in the VAD. PMID- 28708211 TI - Direct-acting antivirals for hepatitis C virus in patients on maintenance dialysis. AB - The frequency of hepatitis C virus (HCV) infection remains high in patients with chronic kidney disease (CKD) and plays a detrimental role in mortality in this population. According to the latest survey, the adjusted hazard ratio for HCV positive versus HCV-negative patients on long-term dialysis was 1.12 (95% CI, 1.05 to 1.20) and 1.10 (95% CI, 0.98 to 1.22) for all-cause and cardiovascular mortality, respectively. An impairment on quality of life has also been documented in HCV-infected patients undergoing regular dialysis. Most clinicians have been so far reluctant to treat hepatitis C in patients with advanced CKD, due to concerns regarding low efficacy and safety of interferon-based regimens. The advent of all-oral, direct-acting antivirals (DAAs) has revolutionized treatment paradigms for HCV, including patients with other comorbidities such as CKD. Two combinations of DAAs have been recently approved for the treatment of HCV in advanced CKD: elbasvir/grazoprevir (evaluated in 1 randomized controlled trial) and ombitasvir/paritaprevir/ritonavir/dasabuvir with or without ribavirin (examined in some observational, single-arm studies). These antiviral combinations have provided high safety and efficacy (SVR12 rates >90%) in HCV infected patients with stage 4-5 CKD. Sofosbuvir, a nucleotide analogue inhibitor of the HCV NS5B polymerase, is the cornerstone of most anti-HCV current regimens but is not currently recommended for patients with severe renal insufficiency (eGFR <30 mL/min per 1.73 m2). However, several small-sized studies have been published on the safety and efficacy of sofosbuvir-based regimens for patients with hepatitis C on maintenance dialysis; overall, the viral response was satisfactory (SVR12 rates ranging between 58% and 100%) with a few drug-related drop-outs. Studies are in progress to assess whether ribavirin-free antiviral combinations with novel DAAs are a viable option for patients with severe renal impairment and chronic HCV infection. PMID- 28708212 TI - Albumin-corrected total/ionized calcium ratio is not superior to total/ionized calcium ratio as an indicator of citrate accumulation. AB - BACKGROUND: Total/ionized calcium ratio has been used as an indirect index of increased plasma citrate concentration during citrate anticoagulation. However, they were obtained without any adjustment of total calcium for albumin. Herein, we investigated whether the albumin-corrected total/ionized calcium ratio performed better than total/ionized calcium ratio. METHODS: 20 critically ill patients were treated with continuous venovenous hemofiltration (CVVH) using citrate anticoagulation. The systemic total, ionized calcium and albumin levels were dynamically measured, and correlations between different calcium parameters and plasma citrate levels were analyzed. RESULTS: The highest correlation was found between plasma citrate level and total/ionized calcium ratio at the third hour (R = 0.88, p<0.001). The albumin-corrected total/ionized calcium ratio was not superior to total/ionized calcium ratio. CONCLUSIONS: The total/ionized calcium ratio at the third hour after the start of citrate-CVVH is an early and simple indicator to reflect increased plasma citrate level. Adjustment of systemic total calcium for serum albumin is not necessary. PMID- 28708213 TI - Novel use of low-dose thalidomide in refractory gastrointestinal bleeding in left ventricular assist device patients. AB - BACKGROUND: Gastrointestinal bleeding (GIB) is a complication reported in patients post left ventricular assist device (LVAD) implantation that is associated with high mortality rates. Thalidomide is an anti-angiogenic compound that may offer a potential option for management of refractory LVAD-related GIB. METHODS: A single-center, retrospective review was conducted from January 2009 to October 2016 at a tertiary cardiology center. It included LVAD patients initiated on thalidomide for refractory GIB. RESULTS: All patients (n = 11) were started on thalidomide 50 mg nocte and there was resolution of GIB in all patients except one (90.9%) during initial thalidomide treatment.The median duration of thalidomide therapy was 98 days (interquartile range: 34-215). The dose of thalidomide was reduced for 2 patients due to adverse effects. Thalidomide therapy was discontinued in 6 patients due to cessation of GIB (n = 4) and adverse effects (n = 2). Reported adverse effects included LVAD thrombosis (n = 2), somnolence (n = 1), neuropathy (n = 1), constipation (n = 1), and transaminitis (n = 1).Recurrent GIB occurred in 4 patients (45.4%) post discontinuation of thalidomide therapy, which led to the re-initiation of therapy. CONCLUSIONS: Thalidomide appears to be a safe and effective option for management of refractory LVAD-related GIB. Monitoring for recurrent GIB should be performed closely following cessation of thalidomide therapy. PMID- 28708214 TI - Hypomagnesemia and cause-specific mortality in hemodialysis patients: 5-year follow-up analysis. AB - INTRODUCTION: The aim of this prospective study was to evaluate the association between serum magnesium (Mg) and mortality, in particular the cause-specific mortality of Mg and other risk factors in hemodialysis (HD) patients. METHODS: We studied a cohort of 185 HD patients receiving thrice-weekly HD treatment, on a dialysate Mg concentration of 0.5 mmol/L. We stratified 3 patient groups according to the level of Mg: lower (<1.1 mmol/L), intermediate-reference (1.1 to <1.3 mmol/L), and higher (Mg >1.3 mm/L). RESULTS: During the 5-year follow-up, 60 patients died, with cardiovascular (CV) disease as the predominant cause (73.3%). Hazard ratio (HR) for all-cause and CV mortality were 2.55 and 2.67 in the lower versus intermediate Mg group, but there was no significant association between the higher and intermediate Mg group. Univariate Cox regression analysis showed that Mg <1.1 versus 1.1-1.30 mml/L with HR 2.34, was a significant univariate predictor for increased mortality in addition to the Hb <110 g/L, Alb <40 g/L, C reactive protein (CRP) >=10 mg/L and brain natriuretic peptide >1,200 pg/mL. However, in the multivariate analysis only CRP >=10 mg/L with HR 3.89 was a significant predictor of mortality. Subgroup analyses showed that among patients with CRP >10 mg/L, HR for all-cause and CV mortality of the lower versus intermediate Mg group were 1.96 and 2.39, respectively, not reaching significance for the higher versus intermediate Mg group. Conversely, there was no association between Mg level and all-cause and CV mortality within these 3 groups among patients with CRP <10 mg/L. CONCLUSIONS: Lower serum Mg level was significantly associated with an increased all-cause and cardiovascular mortality in HD patients, especially in inflamed patients. PMID- 28708215 TI - Changes in the levels of beta-thromboglobulin and inflammatory mediators during extracorporeal membrane oxygenation support. AB - BACKGROUND: Extracorporeal membrane oxygenation (ECMO) has been associated with platelet dysfunction, but no markers of platelet dysfunction during ECMO have been identified. METHODS: We investigated the potential uses of beta thromboglobulin (beta-TG) and platelet factor 4 (PF4) as markers of platelet activation induced by ECMO in vivo. RESULTS: 13 patients who received ECMO for acute respiratory failure were included. Generalized estimating equations were used to examine the associations between days on ECMO and the plasma levels of beta-TG and PF4 and of proinflammatory markers. Analyses were performed before ECMO (baseline) and 24, 48, 72 and 168 hours after the commencement of ECMO. The plasma levels of biomolecules were measured by ELISA and Luminex assay.Percentages of platelets varied widely without statistical significance (p = 0.17). Beta-TG levels significantly decreased over the first 72 hours (p<0.001), but PF4 levels decreased nonsignificantly (p = 0.17). Inflammatory markers, that is, plasma IL-6 (p = 0.03), IL-18 (p<0.001), and MMP-8 (p<0.01) levels stabilized during an early period of ECMO support. CONCLUSIONS: Our data suggest that ECMO use may not affect platelet activation during the first 3 days of ECMO. Plasma beta-TG levels may allow assessment of the time-dependent extent of ECMO-induced platelet dysfunction in patients with acute respiratory failure. PMID- 28708216 TI - Colonoscopy in automated peritoneal dialysis patients: value of prophylactic antibiotics: a prospective study on a single antibiotic. AB - OBJECTIVE: To evaluate the need for prophylactic antibiotics in automated peritoneal dialysis (APD) patients undergoing flexible colonoscopy. PATIENTS AND METHODS: A total of 93 patients on automated peritoneal dialysis (APD) undergoing diagnostic colonoscopy were enrolled in a prospective, randomized study. Patients were randomized into 2 age- and sex-matched groups; group A (46 patients) with intraperitoneal (IP) ceftazidime prior to colonoscopy and group B (47 patients) without prophylactic antibiotics. The relations between peritonitis and different parameters were analyzed. RESULTS: Of all colonoscopies, 60.2% showed normal findings, 17.2% with colonic polyps at different sites, 12.9% with angiodysplastic-like lesions, 5.4% with colonic ulcer(s), 3.2% with diverticulae without diverticulitis and 1.1% had transverse colon stricture. Post-colonoscopy peritonitis was documented in 3 (6.5%) and 4 (8.5%) patients in groups A and B, respectively (p = 0.2742); the causative organisms were mainly gram negative bacteria. Polypectomy was not associated with increased peritonitis episodes. By multiple logistic regression analysis, diabetes mellitus was the only independent variable that entered into the best predictive equation over the development of post-colonoscopy peritonitis but not antibiotic use. CONCLUSIONS: The relation between prophylactic antibiotic use prior to colonoscopy in APD patients and the risk of peritonitis was lacking. Only diabetes mellitus appears to be of significance. Polypectomy did not increase peritonitis episodes. PMID- 28708217 TI - Evaluation of calcium (Ca2+) and hydroxide (OH-) ion diffusion rates of indirect pulp capping materials. AB - INTRODUCTION: The aim of this study was to evaluate and compare the calcium (Ca2+) and hydroxide (OH-) ion release of 4 artificially produced pulp capping materials (MTA, Biodentin, TheraCal LC, Calsimol) used for indirect pulp capping treatment. METHODS: In total, 70 freshly extracted human third molar teeth were used for the study. Cavities of extracted teeth were prepared by round burs. The remaining dentin thickness (1 +/- 0.3 mm) tissue was measured by a micrometer and cone beam computerized tomography. Indirect pulp capping was performed in the cavities using Calcimol, MTA, TheraCal LC and Biodentin. The leached Ca2+ were measured using optical emission spectrometry and the release of OH- ions using a pH meter. The measurements were performed after 24 hours, 7 days and 28 days in saline solution. Statistical analysis was performed using 1-way and 2-way analysis of variance (ANOVA) tests (p<0.05). RESULTS: Ca2+ ions were detected in treated saline solution during the experimental period for all materials. All the measurements of Biodentin and Theracal LC levels for Ca2+ ions were higher than those of the other materials (p<0.05). For all materials, Ca2+-ion release increased during the first 7 days followed by a linear decrease during the subsequent study periods. The Biodentine group showed the highest OH- ion rates compared to the other materials in the 24-hour examination period, while the scores gradually decreased during the subsequent measurement periods (p<0.05). CONCLUSIONS: Tricalcium silicate materials such as Biodentine and TheraCal LC used in this study may be preferable for indirect pulp capping because of their stimulation of hard tissue formation and ion-releasing ability. PMID- 28708218 TI - Microbial characteristics of post-traumatic infective keratitis. AB - PURPOSE: To determine the demographics, risk factors, clinical and microbiological characteristics, and treatment outcome of post-traumatic infective keratitis. METHODS: Consecutive patients with post-traumatic infective keratitis presenting to the Ophthalmology Department of a tertiary referral hospital in Singapore between March 2012 and March 2016 were prospectively identified. A standardized data collection form was used to document patient demographics, microbiological diagnosis, antibiotic sensitivity, and pretreatment and posttreatment ocular characteristics. Any contact lens-induced keratitis was excluded from the study. RESULTS: In total, 26 patients were included for analysis. The mean age was 40.0 years (SD +/- 19.4) and 84.6% of the patients were male. The majority of the patients (69.2%, n = 18) had sustained work related injury in their eyes. Gram-negative organisms were predominant isolates (75.0%, n = 12) in culture-positive corneal scrapings (n = 16). Pan-sensitive Pseudomonas aeruginosa was the commonest organism isolated among the culture positive cases (56.2%, n = 9). Three patients (18.7%) had developed fungal keratitis and Acanthamoeba was isolated in 1 patient (6.2%) with polymicrobial keratitis. Infections resolved with medical treatment in 22 eyes (84.6%) and 4 eyes (15.3%) required therapeutic corneal transplantation. CONCLUSIONS: A shift of practice in post-traumatic infective keratitis should be considered in tropical countries to include Gram-negative cover. Work safety practices with vigilance in initiating treatment and education by front-line physicians such as ophthalmology and general practitioners should be reinforced. PMID- 28708219 TI - One-Year Efficacy and Safety of 0.1% Cyclosporine a Cationic Emulsion in the Treatment of Severe Dry Eye Disease. AB - PURPOSE: The SANSIKA study evaluated the efficacy/safety of 0.1% (1 mg/mL) cyclosporine A cationic emulsion (CsA CE) for treating dry eye disease (DED) with severe keratitis. The double-masked phase demonstrated that CsA CE was effective in reducing corneal damage and ocular surface inflammation, and was well tolerated over 6 months. Here we report efficacy and safety findings of SANSIKA's open-label extension (OLE). METHODS: In this multicenter, double-masked, phase III study, patients with severe DED (corneal fluorescein staining [CFS] grade 4, modified Oxford scale) were randomized to once-daily CsA CE (Ikervis(r)) or its vehicle for 6 months, followed by 6-month open-label, once-daily CsA CE (CsA CE/CsA CE and vehicle/CsA CE groups). RESULTS: A total of 177 patients completed the OLE. Efficacy results reiterated the double-masked phase: CsA CE reduced CFS score and human leukocyte antigen-antigen D related expression, improved corneal clearing, and produced continuous improvements in global symptom scores (ocular surface disease index [OSDI], visual analogue scale). The CFS-OSDI response rates (>=2 CFS points, >=30% OSDI improvement vs baseline) at 12 vs 6 months were 39.1% vs 28.6%, respectively, for CsA CE/CsA CE and 38.0% vs 23.1% for vehicle/CsA CE. Cyclosporine A CE's safety profile was similar to the initial 6 months. The most common treatment-related treatment-emergent adverse event was instillation site pain (7.8%, CsA CE/CsA CE group; 19.0%, vehicle/CsA CE group). No unexpected safety signals were observed; systemic CsA levels were undetectable/negligible in all patients except 2 previously treated with systemic CsA. CONCLUSIONS: In this 12-month study, once-daily CsA CE was well-tolerated and showed reductions in ocular surface inflammation and improvements in signs/symptoms in DED patients with severe keratitis. PMID- 28708220 TI - Comments to: Povidone-Iodine 3-Minute Exposure Time is Viable in Preparation for Cataract Surgery. PMID- 28708221 TI - Rapid response to dexamethasone intravitreal implant in diabetic macular edema. AB - PURPOSE: To evaluate the early effects of dexamethasone (DEX) intravitreal implants in patients with diabetic macular edema (DME). METHODS: This was a prospective, single-arm, interventional clinical series. Eighteen patients (18 eyes) with chronic/recalcitrant or naive DME were included. Patients underwent single DEX intravitreal implant. Clinical assessments, including ophthalmologic examination, central retinal thickness (CRT) measurement by spectral-domain optical coherence tomography (SD-OCT) scan, best-corrected visual acuity (BCVA), and intraocular pressure (IOP) were carried out at baseline, 1-3 hours, and then 3, 7, and 30 days after treatment. The main outcome was change in CRT on SD-OCT, while secondary outcome measures included visual acuity (VA) and changes in IOP following implant. RESULTS: Mean CRT significantly decreased from 565 +/- 171 um at baseline to 310 +/- 89 um at end of follow-up (p<0.001), with reduction becoming evident 1-3 hours after injection. Mean BCVA also significantly improved 7 days and 30 days after treatment up to 0.14 logMAR (p<0.05). All patients had a controlled IOP after the injection with only 1/18 eyes having a transient increase in IOP during follow-up. CONCLUSIONS: This is the first study showing very early effects of DEX implants on CRT reduction and VA improvement in DME. PMID- 28708222 TI - Multimodal Imaging in a Patient with Traumatic Choroidal Ruptures. AB - PURPOSE: To describe the case and the follow-up of a traumatic choroidal rupture characterized by means of multimodal imaging including color fundus photographs, infrared reflectance, blue autofluorescence, swept-source optical coherence tomography, fluorescein angiography (FA), indocyanine green angiography (ICGA), and optical coherence tomography angiography (OCT-A). METHODS: Case report. RESULTS: A 17-year-old boy was referred to our clinic complaining of reduction in visual acuity in the right eye (RE) after a blunt ocular trauma during a soccer match. Dilated fundus examination of RE showed 2 peripapillary choroidal ruptures located temporally and inferiorly to the optic disc. Among different imaging tools useful in the diagnosis and study of choroidal ruptures, particular attention must be paid to OCT-A, which showed the lesions as breaks in the choriocapillaris plexus with a hypointense appearance due to the lack of substance. Moreover, along the break it was possible to see the projection of the underlying choroidal vasculature, which appeared hyperintense. The retinal vascular plexa were spared. CONCLUSIONS: All patients presenting with blunt ocular trauma should undergo fundus examination to exclude damage to the optic nerve, retina, and choroid, and need close follow-up to avoid the development of secondary complications such as choroidal neovascularization. Optical coherence tomography angiography might add relevant information in the global evaluation and follow-up of choroidal ruptures in a noninvasive fashion, and could replace other invasive modalities such as FA or ICGA. PMID- 28708223 TI - Author's Reply to Comments to: Povidone-Iodine 3-Minute Exposure Time is Viable in Preparation for Cataract Surgery. PMID- 28708225 TI - Clinical outcomes of salvage chemoradiotherapy for locally recurrent biliary tract cancer. AB - PURPOSE: The purpose of this study was to investigate the clinical outcomes and prognostic factors of concurrent chemoradiotherapy (CCRT) for locally recurrent biliary tract cancer (BTC) after curative surgical resection. METHODS: We performed a retrospective cohort study of patients with locally recurrent BTC treated with CCRT between October 2004 and December 2013. The study included and analyzed 42 patients with a history of curative-intent surgical resection of confirmed adenocarcinoma originating from the biliary tract. RESULTS: The median time to recurrence after surgery was 16.1 months (range, 4.5-77.8 months). Median follow-up after CCRT was 26.9 months (range, 5.2-81.9) with no grade 3 or higher gastrointestinal toxicities. Analysis of the first site of failure showed local progression (LP) developed in 20 patients (47.6%); among these, 16 (38.1%) had isolated LP. The median values were 15.8 months (range, 1.7-81.7) for LP-free survival (LPFS), 10.6 months (range, 1.7 - 81.7) for progression-free survival (PFS) and 41.2 months (range, 5.2-81.9) for overall survival (OS). Multivariate analysis showed that the level of pre-CCRT carbohydrate antigen (CA) 19-9 and the chemotherapy regimen were significant prognostic factors for LPFS and PFS; pT stage was the only significant prognostic factor for OS. CONCLUSIONS: CCRT for locally recurrent BTC showed promising outcomes as a salvage modality, but LP was still frequent. The pre-CCRT CA 19-9 level and the chemotherapy regimen were prognostic factors for LPFS and PFS. PMID- 28708224 TI - Carbonic Anhydrase Inhibitor with Topical NSAID Therapy to Manage Cystoid Macular Edema in a Case of Gyrate Atrophy. AB - PURPOSE: Gyrate atrophy of the choroid and retina (GACR) is a rare chorioretinal dystrophy characterized by a deficiency of the enzyme ornithine aminotransferase, inherited in an autosomal recessive pattern. CASE REPORT: We report a case of a 17-year-old girl with GACR, for whom the level of serum ornithine had been reduced by an arginine-restricted diet. The patient was responsive to an association of topical nonsteroidal anti-inflammatory drugs (NSAIDs) and a carbonic anhydrase inhibitor (CAI) to reduce cystoid macular edema (CME). CONCLUSIONS: The efficacy of topical NSAIDs and systemic CAI association indicates that the imbalance in the distribution of retinal pigment epithelium membrane-bound carbonic anhydrase could play a major role in CME pathogenesis in GACR. To our knowledge, this is the first case of therapy with CAI treatment for GACR-related CME. PMID- 28708226 TI - A giant intradiaphragmatic bronchogenic cyst: case report and literature review. AB - Bronchogenic cysts are congenital lesions developing during early embryogenesis. The intradiaphragmatic location is extremely rare. We present a giant bronchogenic cyst arising from the left crus of diaphragm. Based on our literature review results, intradiaphragmatic bronchogenic cysts have the following characteristics: 1) they are more common in female patients; 2) the patients are usually asymptomatic, or present with symptoms of chest pain, abdominal pain, and hiccups; 3) the cysts located in the left diaphragm are more than those in the right diaphragm, most of which are located in the area of the left diaphragm crus. PMID- 28708227 TI - A correlation study of fluorouracil pharmacodynamics with clinical efficacy and toxicity. AB - PURPOSE: Plasma 5-fluorouracil (5-FU) concentrations vary greatly between individuals who have received standard dosage. Pharmacokinetic adjusted doses have been hypothesized to overcome the possibility of potential toxicity and ineffectiveness related to inappropriate plasma levels of 5-FU. In this study, we prospectively investigated the clinical benefit and toxicity of 5-FU in relation to its pharmacokinetic properties. METHODS: Pharmacokinetics, effectiveness, and toxicity of 5-FU were investigated in 101 patients. The 5-FU pharmacokinetics were measured on day 2 of chemotherapy infusions. Clinicodemographic characteristics are outlined. RESULTS: All 101 patients who received adjuvant chemotherapy were alive at the end of a median 45 months of the follow-up period. At least one grade 1 adverse event (AE) was observed in 69.3% of the patients and grade two AEs were observed in 10.1% of the patients. The 5-FU levels ranged between 103 and 4311 ug/L and area under the curve (AUC) measurements ranged between 4.5 and 189.7 mg min/L. Pharmacokinetic measurements were not significantly correlated with clinical efficacy (log-rank p = 0.21). However, higher AUC levels were positively correlated with toxicity (p = 0.02) and with the severity of adverse events. The risks of mucositis (odds ratio [OR] 1.45; p = 0.042) and neurotoxicity (OR 2.01; p = 0.009) were significantly increased in a logistic regression model. CONCLUSIONS: There is no clear evidence that increased plasma levels or pharmacokinetic adjusted doses of 5-FU were related to better efficacy. However, toxicity might be closely associated with increased plasma levels of 5-FU. Toxicities can be deferred via dose adjustments without any expense in efficacy. PMID- 28708228 TI - Clinical and subclinical cardiac late effects in pediatric Hodgkin's lymphoma survivors. AB - PURPOSE: Cardiac late effects are responsible for a significant burden of mortality and morbidity among pediatric Hodgkin's lymphoma (HL) survivors (HLS). The aim of our study was to assess clinical and subclinical cardiac sequelae in a cohort of childhood HLS treated in the 1980s with doxorubicin, bleomycin, vinblastine, and dacarbazine (the ABVD regimen) and limited-field radiotherapy (RT). METHODS: We retrospectively examined a series of HLS treated from 1979 to 1989. We searched for subtle cardiac abnormalities in a subgroup of asymptomatic individuals, who underwent rest and exercise echocardiography at least 20 years after completing their therapies. Their cardiac assessment included physical examination, electrocardiogram (ECG), and resting and postexercise echocardiograms. RESULTS: On thorough cardiac assessment a mean of 21 years after their diagnosis, none of the 53 unselected asymptomatic HLS showed physical signs or significant ECG abnormalities during or after the stress echo test. Twenty-two (41%) of the 53 patients revealed valvular abnormalities, with mitral regurgitation in 28%, aortic regurgitation in 9%, and both in 4%. No significant myocardial dysfunction as a result of previous combined doxorubicin treatment and chest RT was identified. Only 2 individuals had mild pericardial alterations. CONCLUSIONS: The present study shows that long-term cardiac effects are common in HLS treated with the ABVD regimen and RT. The most frequent complications observed in this sample were essentially coronary artery disease and valvular abnormalities. None of the survivors in this sample showed overt congestive heart failure, a finding in contrast with larger studies. PMID- 28708229 TI - Adjuvant chemoradiotherapy (gemcitabine-based) in pancreatic adenocarcinoma: the Pisa University experience. AB - INTRODUCTION: The role of adjuvant chemoradiotherapy in patients with pancreatic adenocarcinoma (PA) is controversial. In this study we aimed to assess the feasibility, disease-free survival (DFS) and overall survival (OS) of adjuvant chemoradiotherapy (gemcitabine based) in patients with resected PA and their correlation with prognostic factors. METHODS: 122 resected patients (stage >=IIa) treated between February 1999 and December 2013 were analyzed. Two cycles of gemcitabine (1,000 mg/m2 on days 1, 8 and 15 every 28 days) were administered before concomitant radiotherapy (45 Gy/25 fractions) and chemotherapy (gemcitabine 300 mg/m2 weekly). RESULTS: Median follow-up was 22.7 months (range 4-109). Gastrointestinal toxicity (G3), neutropenia (G3-G4) and cardiac toxicity (G2-G3) were observed in 2.4%, 10.6% and 1.6% of patients, respectively. OS at 12, 24 and 60 months was 79%, 55% and 31%, respectively (median 25 months). Two year OS in patients with postoperative Karnofsky performance status (KPS) <=70 and >=80 was 37.1% and 62.3%, respectively (p<0.0001). OS was better in the group of patients with a postoperative CA 19-9 level <=100 U/mL (p = 0.014). Median DFS was 17 months. CONCLUSIONS: The combination of concomitant gemcitabine and radiotherapy in patients with radically resected PA was well tolerated and associated with a low incidence of local recurrences. Five-year OS was significantly influenced by postoperative KPS and CA 19-9 values. PMID- 28708230 TI - Short course radiotherapy concomitant with temozolomide in GBM patients: a phase II study. AB - PURPOSE: Despite recent advances, the prognosis of glioblastoma (GBM) remains poor. The aim of this study was to assess the efficacy and tolerability of multiple daily fraction radiotherapy performed with multiple temozolomide (TMZ) administrations in newly diagnosed patients with GBM. METHODS: This trial was a prospective, open-label, monocentric, nonrandomized, single arm, phase II study. The primary endpoint was the proportion of progression-free patients at 12 months, and the secondary endpoints were overall survival (OS) and toxicity. Thirty-five patients underwent two radiotherapy courses concomitant with TMZ after surgery. At each course, radiation was delivered 3 times daily, 2 Gy/fraction, for 5 consecutive days, and the total dose was 60 Gy; concurrent TMZ was administered in a total dose of 150-200 mg/m2/day. RESULTS: The primary endpoint failed to be applied; Macdonald criteria could be used in 16 (46%) patients with local or intracerebral recurrence (group A). In 12 patients, due to suspicion of radiation necrosis vs recurrence, Macdonald criteria were not applied (group B). The OS was 22 months, and OS probabilities at 12, 18, and 24 months were 82%, 59%, and 44%, respectively. Hematologic toxicities generally did not exceed grade 2. The quality of life and cognitive functioning did not significantly change between baseline and the first follow-up. In the multivariate analysis, necrosis and pseudoprogression were significant prognostic factors of OS. CONCLUSIONS: To improve local control and OS, a more aggressive treatment schedule should be explored. The related higher necrosis risk and its implications regarding local control deserve further investigation. PMID- 28708231 TI - Ibrutinib treatment of a patient with relapsing chronic lymphocytic leukemia and sustained remission of Richter syndrome. AB - PURPOSE: Richter syndrome (RS) is a rare event in chronic lymphocytic leukemia (CLL) that is influenced by biological factors and prior CLL treatments. Ibrutinib is a Bruton tyrosine kinase inhibitor that has shown remarkable efficacy in CLL; however, little is known about its relationship to RS. We report a case of ibrutinib efficacy against CLL in a patient with prolonged remission of RS. METHODS: The patient was diagnosed with CLL in 2003. Biological findings at onset included absent ZAP70 expression, mutated IGVH, and NOTCH1 mutation. He was treated with FCR with partial response. In 2013, he progressed to RS, not clonally related to the underlying CLL. The patient was treated with anthracycline- and platinum-based regimens, obtaining a complete remission. After 3 years, he presented a CLL progression with worsening lymphocytosis, anemia, thrombocytopenia, increased splenomegaly, and lymphadenopathies. Positron emission tomography-computed tomography scan excluded pathologic uptake. Thus, he was started on ibrutinib. RESULTS: At 12 months' follow-up, we observed white blood cell normalization, increased hemoglobin and platelet levels, disappearance of lymphadenopathy, and spleen size reduction. Therapy was well-tolerated with no evidence of RS. CONCLUSION: This case demonstrates sustained RS remission in a patient with CLL under ibrutinib therapy, thus improving our knowledge on the use of this new drug in CLL and beyond. PMID- 28708232 TI - Primary signet ring cell carcinoma of the pancreas with a good response to chemotherapy: case report and literature review. AB - PURPOSE: Although pancreatic cancer is a common malignancy, signet ring cell carcinoma of the pancreas is a very rare histologic type with only 6 cases reported so far. We present a patient with primary signet ring cell carcinoma of the pancreas and a good response to neoadjuvant chemotherapy. CASE REPORT: A 67 year-old woman presented at a regional hospital with a 2-week history of painless progressive jaundice. Abdominal computed tomography showed a tumor in the head of the pancreas, 4.5 cm in largest diameter. Since endoscopic biopsy and biliary stenting were not available, the patient had undergone palliative choledochoduodenostomy and tru-cut needle biopsy of the lesion. Histopathology revealed primary signet ring cell carcinoma of the pancreas. The tumor was considered borderline resectable and 3-month neoadjuvant chemotherapy with gemcitabine alone was administered due to the low creatinine clearance rates. Follow-up abdominal scan demonstrated very good response to chemotherapy and significant tumor regression to 1.5 cm in largest diameter. Radical cephalic duodenopancreatectomy was performed. CONCLUSION: Significant tumor downsizing in our patient clearly demonstrates good response to neoadjuvant gemcitabine monotherapy. The optimal preoperative chemotherapy leading to tumor reduction and disease control in patients with borderline resectable and locally advanced pancreatic carcinoma is controversial, necessitating further randomized studies including combined chemoradiotherapy and multidrug combination regimens. PMID- 28708233 TI - Treatment in EGFR-mutated non-small cell lung cancer: how to block the receptor and overcome resistance mechanisms. AB - In non-small cell lung cancer (NSCLC), the identification of epidermal growth factor receptor (EGFR) mutations and the parallel development of EGFR tyrosine kinase inhibitors (TKIs) have radically changed the therapeutic management strategies. Currently, erlotinib, gefitinib, and afatinib are all approved as standard first-line treatment in EGFR-mutated NSCLC. However, despite the proven efficacy, some EGFR-mutated NSCLCs do not respond to EGFR TKIs, while some patients, after a favorable and prolonged response to EGFR TKIs, inevitably progress within about 10-14 months. Epidermal growth factor receptor-dependent mechanisms, activation of alternative pathways, or phenotypic transformation can cause the resistance to EGFR TKIs. The exon 20 p.Thr790Met point mutation (T790M) is responsible for about 60% of cases of resistance when progression occurs. A third-generation TKI, osimertinib, improved outcome in patients harboring T790M after first- and second-generation TKI treatment. However, resistance develops even after treatment with third-generation drugs. To date, the Cys797Ser (C797S) mutation in exon 20 of EGFR is the most well-known resistance mutation after osimertinib. Fourth-generation TKIs are already under development. Nevertheless, additional information is needed to better understand and effectively overcome resistance. The aim of this review is to report recent advances and future perspectives in the treatment of EGFR-mutated NSCLC, highlighting the resistance mechanisms that underlie disease progression. PMID- 28708235 TI - The Birder. PMID- 28708234 TI - Physicists' views on hadrontherapy: a survey of members of the Italian Association of Medical Physics (AIFM). AB - BACKGROUND: This study was based on a survey to investigate perceptions of hadrontherapy of the members of the Italian Association of Medical Physics (AIFM). The survey was digitally submitted to the 991 members between the end of January and the beginning of April 2016. METHODS: A 19-item questionnaire was designed focusing on advantages and disadvantages of hadrontherapy, current status and possible future improvements, and need and opportunities for future investments in Italy and abroad. Information about professional qualifications, main fields of clinical involvement and specific competencies of the respondents was also collected. RESULTS: The survey was completed by 121 AIFM members (response rate 12.2%). In the answers collected, it was shown that medical physicists expressed interest in hadrontherapy mainly for reasons of personal interest rather than for professional needs (90% +/- 2.5% vs. 52% +/- 4.3% of the respondents, respectively), with a good knowledge of the related basic aspects as well as of the pros and cons of its application. However, poor knowledge of the current status of hadrontherapy was observed among the medical physicists not directly involved at a professional level, who were less than 3% of the physicists working in radiotherapy. CONCLUSIONS: In light of these results, the implementation of new training and education initiatives should be devised to promote a deeper and global knowledge of hadrontherapy-related issues, not only from a theoretical point of view but also in practical terms. Moreover, a close collaboration between highly specialized medical physicists employed in hadrontherapy centers and others in oncology hospitals should be -encouraged. PMID- 28708236 TI - Psychosocial interventions for fatigue during cancer treatment with palliative intent. AB - BACKGROUND: Fatigue is a prevalent and burdensome symptom for patients with incurable cancer receiving cancer treatment with palliative intent and is associated with reduced quality of life. Psychosocial interventions seem promising for management of fatigue among cancer patients. OBJECTIVES: To assess the effects of psychosocial interventions for fatigue in adult patients with incurable cancer receiving cancer treatment with palliative intent. SEARCH METHODS: We searched the following databases: CENTRAL, MEDLINE, Embase, CINAHL, PsycINFO, and seven clinical trial registries; we also searched the reference lists of articles. The date of our most recent search was 29 November 2016. SELECTION CRITERIA: We included randomised controlled trials that compared psychosocial interventions in adults aged 18 years or over undergoing cancer treatment with palliative intent for incurable cancer versus usual care or other controls. Psychosocial interventions were defined as various kinds of interventions provided to influence or change cognitions, emotions, behaviours, social interactions, or a combination of these. Psychosocial interventions of interest to this review had to involve at least two interactions between the patient and the care provider in which the care provider gave the patient personal feedback concerning changes sought by these interventions. We included trials that reported fatigue as an outcome of interest. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Two review authors independently considered trials for inclusion in the review, assessed risk of bias, and extracted data, including information on adverse events. We assessed the quality of evidence using GRADE (Grading of Recommendations Assessment, Development, and Evaluation) and created a 'Summary of findings' table. MAIN RESULTS: We identified 14 studies (16 reports) that met inclusion criteria for this review and involved 3077 randomised participants in total. Most of these studies included a mixed sample of participants; we obtained data for the subset of interest for this review (diagnosis of incurable cancer and receiving cancer treatment) from the study investigators of 12 studies, for which we included 535 participants in the subset meta-analysis for fatigue post intervention. Researchers investigated a broad range of psychosocial interventions with different intervention aims and durations. We identified sources of potential bias, including lack of description of methods of blinding and allocation concealment and inclusion of small study populations.Findings from our meta-analysis do not support the effectiveness of psychosocial interventions for reducing fatigue post intervention (standardised mean difference (SMD) -0.25, 95% confidence interval (CI) -0.50 to 0.00; not significant; 535 participants, 12 studies; very low-quality evidence). First follow-up findings on fatigue suggested benefit for participants assigned to the psychosocial intervention compared with control (SMD -0.66, 95% CI -1.00 to -0.32; 147 participants, four studies; very low-quality evidence), which was not sustained at second follow-up (SMD -0.41, 95% CI -1.12 to 0.30; not significant; very low-quality evidence).Results for our secondary outcomes revealed very low-quality evidence for the efficacy of psychosocial interventions in improving physical functioning post intervention (SMD 0.32, 95% CI 0.01 to 0.63; 307 participants, seven studies). These findings were not sustained at first follow-up (SMD 0.37, 95% CI 0.20 to 0.94; not significant; 122 participants, two studies; very low-quality evidence). Findings do not support the effectiveness of psychosocial interventions for improving social functioning (mean difference (MD) 4.16, 95% CI -11.20 to 19.53; not significant; 141 participants, four studies), role functioning (MD 3.49, 95% CI -12.78 to 19.76; not significant; 143 participants, four studies), emotional functioning (SMD -0.11, 95% CI -0.56 to 0.35; not significant; 115 participants, three studies), or cognitive functioning (MD 2.23, 95% CI -12.52 to 8.06; not significant; 86 participants, two studies) post intervention. Only three studies evaluated adverse events. These studies found no difference between the number of adverse events among participants in the intervention versus control group.Using GRADE, we considered the overall quality of evidence for our primary and secondary outcomes to be very low. Therefore, we have very little confidence in the effect estimate, and the true effect is likely to be substantially different from the estimate of effect. Limitations in study quality and imprecision due to sparse data resulted in downgrading of the quality of data. Additionally, most studies were at high risk of bias owing to their small sample size for the subset of patients with incurable cancer (fewer than 50 participants per arm), leading to uncertainty about effect estimates. AUTHORS' CONCLUSIONS: We found little evidence around the benefits of psychosocial interventions provided to reduce fatigue in adult patients with incurable cancer receiving cancer treatment with palliative intent. Additional studies with larger samples are required to assess whether psychosocial interventions are beneficial for addressing fatigue in patients with incurable cancer. PMID- 28708237 TI - Playing With Ideas: Evaluating the Impact of the Ultimate Block Party, a Collective Experiential Intervention to Enrich Perceptions of Play. AB - Parental attitudes shape play opportunities afforded to children in home, community, and school settings. This study presents evaluation of an intervention designed to enrich parent's conception of play and its relationship with socially valued skills and capacities. On the basis of data from 291 racially and ethnically diverse parents/caregivers of young children (median age between 3 and 6) attending an event in NYC, we find the intervention helped parents conceptualize play in complex ways and altered perceptions of its impact on children's current-but not future-lives. Multivariate analyses reveal the causal pathway for these changes as exposure to multiple play sites, rather than time at the event-a finding with direct implications for exposing parents to developmental science in community settings. PMID- 28708238 TI - Family Context Moderates the Association of Maternal Postpartum Depression and Stability of Infant Temperament. AB - Maternal postpartum depression, maternal sensitivity, and family functioning were examined as predictors of the stability of observed infant temperament over the first 30 months of life (N = 147 families). Eight observations at 8, 15, and 30 months postpartum were used to assess infant temperament. Structured clinical interviews were used to assess maternal depression, and observational assessments were used to assess family functioning and maternal sensitivity. Family context moderated the effect of maternal depression on change in infant temperament. Maternal depression was associated with change in infant temperament when maternal sensitivity was low but not when maternal sensitivity was high. Family functioning similarly moderated these links. Results underscore the centrality of the family context in shaping child behavior over time. PMID- 28708239 TI - Novel non-neutral mitochondrial DNA mutations found in childhood acute lymphoblastic leukemia. AB - Mitochondria produce adenosine triphosphate (ATP) for energy requirements via the mitochondrial oxidative phosphorylation (OXPHOS) system. One of the hallmarks of cancer is the energy shift toward glycolysis. Low OXPHOS activity and increased glycolysis are associated with aggressive types of cancer. Mitochondria have their own genome (mitochondrial DNA [mtDNA]) encoding for 13 essential subunits of the OXPHOS enzyme complexes. We studied mtDNA in childhood acute lymphoblastic leukemia (ALL) to detect potential pathogenic mutations in OXPHOS complexes. The whole mtDNA from blood and bone marrow samples at diagnosis and follow-up from 36 ALL patients were analyzed. Novel or previously described pathogenic mtDNA mutations were identified in 8 out of 36 patients. Six out of these 8 patients had died from ALL. Five out of 36 patients had an identified poor prognosis genetic marker, and 4 of these patients had mtDNA mutations. Missense or nonsense mtDNA mutations were detected in the genes encoding subunits of OXPHOS complexes, as follows: MT-ND1, MT-ND2, MT-ND4L and MT-ND6 of complex I; MT-CO3 of complex IV; and MT-ATP6 and MT-ATP8 of complex V. We discovered mtDNA mutations in childhood ALL supporting the hypothesis that non-neutral variants in mtDNA affecting the OXPHOS function may be related to leukemic clones. PMID- 28708240 TI - Comparative analysis of general dental practitioners' fees and scheduled fees for root canal treatment and coronal restorations in the adult population of Sweden: a 5-year follow-up of data from the Swedish Dental Register. AB - AIM: To investigate the fees charged by Swedish dentists for root fillings, coronal restorations and further dental interventions during a follow-up period of 5-6 years. METHODOLOGY: A total of 248 299 root fillings were linked with the tooth, the patient and the provider and entered into the Swedish Social Insurance Agency register in 2009. The data register also recorded the subsidy-based (scheduled) fee and the fee actually charged for the root fillings. Fees charged for direct or indirect coronal restorations and additional interventions during the follow-up period were also recorded. One-way anova and t-test were used for statistical analysis. RESULTS: The mean overall fee charged for a root filling was approximately 332 Euro and differed only marginally (13 Euro) from the scheduled fee. The total mean fee for preservation of a root filled tooth was 717 Euro, which included the root canal treatment, the coronal restoration and any additional interventions during the follow-up period. The fees for indirectly restored root filled teeth were significantly higher (1105 Euro) than for directly restored teeth (610 Euro), despite further additional treatment (P < 0.001). The mean fee for teeth which were subsequently extracted was higher (769 Euro) than for the retained teeth (711 Euro) (P < 0.001). CONCLUSIONS: Fees charged by Swedish dentists for root canal treatment were in accordance with the scheduled fees. The overall mean fee was significantly higher for root filled teeth with indirect restorations than for teeth with direct coronal restorations. However, prospective clinical cost-effectiveness studies are needed to analyse the total costs. PMID- 28708241 TI - Religious Development in African American Adolescents: Growth Patterns That Offer Protection. AB - Although religiosity promotes resilient outcomes in African American (AA) adolescents, there is a lack of research that examines the protective role of religious development in the context of stressful life events (SLEs). In 1,595 AA adolescents, a cohort-sequential design was used from ages 12 to 18 to examine subtypes of religiosity, as well as distinct developmental patterns within subtypes. The protective role of religious development was also examined in the context of SLEs. The study findings indicated two subtypes of religiosity extrinsic and intrinsic religiosity-as well as low and high developmental patterns in the identified subtypes. Furthermore, the protective influence of extrinsic and intrinsic religiosity gradually diminished from age 12 to 18 in the context of SLEs. PMID- 28708243 TI - The depletion of MARVELD1 leads to murine placenta accreta via integrin beta4 dependent trophoblast cell invasion. AB - The placenta is a remarkable organ, it serves as the interface between the mother and the fetus. Proper invasion of trophoblast cells is required for a successful pregnancy. Previous studies have found that the adhesion molecule integrin beta4 plays important roles during trophoblast cell invasion. Here, we found that the overall birth rate of the MARVELD1 knockout mouse is much lower than that of the wild-type mouse (p < 0.001). In E18.5 MARVELD1 knockout mice, we observed an over invasion of trophoblast cells, and indeed, the pregnant mice had a partial placenta accreta phenotype. The HTR8/SVneo cell line was used as an in vitro model to elucidate the underlying mechanisms of MARVELD1-mediated trophoblast invasion. We detected a diminished expression of integrin beta4 upon the downregulation of MARVELD1 and enhanced migrate and invasive abilities of trophoblast cells both in vivo and in vitro. The integrin beta4 rescue assay also supported the results. In conclusion, this study found that MARVELD1 mediated the invasion of trophoblast cells via regulating the expression of integrin beta4 during placenta development. PMID- 28708244 TI - miR-199a-3p is involved in estrogen-mediated autophagy through the IGF-1/mTOR pathway in osteocyte-like MLO-Y4 cells. AB - To date, evidence indicates that estrogen partially modulates cellular processes through microRNAs. Autophagy is a catabolic process that is regulated by multiple factors and is associated with skeletal diseases. However, whether estrogen regulates osteocyte autophagy via microRNAs is largely unknown. In this study, we observed the up-regulation of microRNA-199a-3p, a post-transcriptional regulatory factor, in osteocytic areas in ovariectomized (OVX) mice. The mature forms of miR 199a-3p and pri-miR-199a were produced in response to estrogen signaling in osteocyte-like MLO-Y4 cells. Western blotting, autophagic flux detection, mRFP GFP-LC3 fluorescence, and electron microscopy confirmed that miR-199a-3p induced autophagy in MLO-Y4 cells, although cellular apoptosis was not affected. Additionally, we documented the ability of estrogen to mediate osteocyte autophagy. Based on our in vivo data, estrogen deficiency induced autophagy in osteocytes. Treatment of starved MLO-Y4 cells with 17beta-estradiol suppressed the excess autophagy induced by starvation via activation of mammalian target of rapamycin (mTOR)-related signaling cascades, while administration of rapamycin reversed the effects of 17beta-estradiol. Meanwhile, miR-199a-3p overexpression reversed 17beta-estradiol-mediated regulation of autophagy in MLO-Y4 cells. According to mechanistic studies, miR-199a-3p inhibited the mTOR pathway by directly binding to the 3'-untranslated regions of insulin growth factor-1 (IGF 1) and mTOR. However, overexpression of miR-199a-3p inhibited IGF-1 phosphorylation and mTOR-related pathways. Knockdown of mTOR and IGF-1 abolished estrogen signaling and restored LC3-II expression through mTOR re-activation, respectively. Thus, miR-199a-3p appears to be involved in the estrogen regulatory networks that mediate bone cell autophagy, potentially by targeting IGF-1 and mTOR. PMID- 28708245 TI - Health-equity issues related to childhood obesity: a scoping review. AB - PURPOSE: The purpose of this scoping review was to determine the health-equity issues that relate to childhood obesity. METHODS: Health-equity issues related to childhood obesity were identified by analyzing food environment, natural and built environment, and social environment. The authors searched Medline, PubMed, and Web of Science, using the keywords "children" and "obesity." Specific terms for each environment were added: "food desert," "advertising," "insecurity," "price," "processing," "trade," and "school" for food environment; "urban design," "land use," "transportation mode," "public facilities," and "market access" for natural and built environment; and "financial capacity/poverty," "living conditions," "transport access," "remoteness," "social support," "social cohesion," "working practices," "eating habits," "time," and "social norms" for social environment. Inclusion criteria were studies or reports with populations under age 12, conducted in the United States, and published in English in 2005 or later. RESULTS: The final search yielded 39 references (16 for food environment, 11 for built environment, and 12 for social environment). Most food-environment elements were associated with obesity, except food insecurity and food deserts. A natural and built environment that hinders access to physical activity resources and access to healthy foods increased the risk of childhood obesity. Similarly, a negative social environment was associated with childhood obesity. More research is needed on the effects of food production, living conditions, time for shopping, and exercise, as related to childhood obesity. CONCLUSIONS: Most elements of food, natural and built, and social-environments were associated with weight in children under age 12, except food insecurity and food deserts. PMID- 28708246 TI - Three-Dimensional Power Doppler Evaluation of Cerebral Vascular Blood Flow: A Novel Tool in the Assessment of Fetal Growth Restriction. AB - OBJECTIVES: To determine whether fetuses with fetal growth restriction (FGR) are more likely to have abnormal cerebral vascular flow patterns compared to fetuses who are appropriate for gestational age (AGA) when quantified by using 3 dimensional (3D) power Doppler ultrasound. METHODS: We conducted a prospective cohort study of singleton gestations presenting for growth ultrasound examination between 24 and 36 weeks' gestation. Patients with FGR (estimated fetal weight < 10th percentile) were enrolled and matched 1:1 for gestational age (+/-7 days) with AGA fetuses. A standardized 3D power Doppler image of the middle cerebral artery territory was obtained from each patient. The vascularization index (VI), flow index (FI), and vascularization-flow index (VFI) were calculated by the Virtual Organ computer-aided analysis technique (GE Healthcare, Milwaukee, WI). These indices were compared between FGR and AGA fetuses and correlated with 2 dimensional Doppler parameters. Neonatal outcomes were also compared with respect to the 3D parameters. RESULTS: Of 306 patients, there were 151 cases of FGR. There was no difference in the VI (6.0 versus 5.7; P = .65) or VFI (2.0 versus 1.8; P = .31) between the groups; however, the FI was significantly higher in FGR fetuses compared to AGA controls (33.9 versus 32.3; P = .009). There was a weak, but significant, negative correlation between the FI and both the middle cerebral artery pulsatility index (r = -0.34; P < .001) and cerebroplacental ratio (r = 0.29; P < .001). Within the FGR group, there was no difference in any of the 3D vascular indices with regard to neonatal outcomes. CONCLUSIONS: Three-dimensional power Doppler measurement of cerebral blood flow, but not the vascularization pattern, is significantly altered in FGR. This measurement may play a future role in distinguishing pathologic FGR from constitutionally small growth. PMID- 28708247 TI - Adolescents with type 1 diabetes mellitus and attention-deficit/hyperactivity disorder require specific support from healthcare professionals. AB - AIM: Managing type 1 diabetes mellitus requires efficient cognitive and executive skills, and adolescents who have attention-deficit/hyperactivity disorder (ADHD) may face specific challenges. This study explored young people's experiences of diabetes treatment and care. METHOD: In a population-based study, comprising 175 patients aged 5-16 years with type 1 diabetes mellitus in two Swedish counties, we found that eight also met criteria for ADHD. Six of these, aged 14.5-16 years, participated 2013-2014 in interviews that targeted aspects of their diabetes treatment. Conducted by two psychologists, these used the inductive qualitative, semi-structured interview format. RESULTS: The two boys and four girls all reported difficulties in creating routines for their diabetes treatment and that problems were aggravated during stress. They had been criticised by their parents and the diabetes team when their blood levels indicated inadequate diabetes control. They requested ongoing information, involvement of their friends, group meetings and easy access to the healthcare system during difficult times. CONCLUSION: Patients with type 1 diabetes mellitus and concomitant ADHD faced problems with their diabetes management, especially during stressful situations. Diabetes care provision should pay particular attention to patients with co existing neuropsychiatric and neurodevelopmental disorders such as ADHD. PMID- 28708248 TI - Oral and upper gastrointestinal Crohn's disease. AB - Crohn's disease is a heterogeneous, inflammatory condition that can affect any location of the gastrointestinal tract. Proximal gastrointestinal involvement occurs in 0.5-16% of patients, and it is usually diagnosed after recognition of intestinal disease. Symptoms are often mild and nonspecific; however, upper gastrointestinal disease predicts a more severe Crohn's phenotype with a greater frequency of complications such as obstruction and perforation. Gastroscopy and biopsy is the most sensitive diagnostic investigation. There is a paucity of data examining the treatment of this condition. Management principles are similar to those for intestinal disease, commencing with topical therapy where appropriate, progressing to systemic therapy such as glucocorticoids, 5-aminosalicylic acid, immunomodulators, and biologics. Acid suppression therapy has symptomatic but no anti-inflammatory benefit for gastroduodenal and esophageal involvement. Surgical intervention with bypass, strictureplasty, or less frequently, endoscopic balloon dilation may be required for complications or failed medical therapy. PMID- 28708249 TI - The impact of anthropogenic pressure on the virological quality of water from the Tiber River, Italy. AB - : The objective of the present study was to assess the occurrence of major waterborne enteric viruses (enterovirus, norovirus, adenovirus, rotavirus, hepatitis A and E virus) along the Tiber River in Italy, in areas affected by different kinds of anthropogenic pressure (agricultural, urban, industrial and pristine). Moreover, in light of the recent abundant detection of human bocavirus in urban wastewater samples in Italy, the occurrence of this virus was also assessed. Virus detection was based on nested PCR followed by sequencing, and on real-time PCR. A correlation with anthropogenic pressure was observed. The urban and industrial areas were the most contaminated (100 and 75% of samples were positive for at least one virus respectively). The agricultural area was less contaminated, with 50% of samples positive. None of the samples collected in a pristine area were positive for viruses. The most frequently detected virus was human bocavirus, identified in 37.5% of samples, followed by norovirus and enterovirus (28% each) and adenovirus (21.6%). Rotavirus, and hepatitis A and E viruses were less common (<9%). Although Human Bocavirus is not considered a waterborne pathogen, the widespread contamination of river waters suggests that virus transmission via the water route should not be neglected. SIGNIFICANCE AND IMPACT OF THE STUDY: To the best of our knowledge, this study constitutes the first attempt to assess the occurrence of enteric viruses in river waters, in areas differentially influenced by anthropogenic pressure. Enteric viruses (enterovirus, norovirus, adenovirus, rotavirus, hepatitis A and E viruses, and bocavirus) were widespread in the industrial and urban areas, and were less frequently detected in the agricultural area. Interestingly, human bocavirus was the most frequently detected virus, outnumbering even adenoviruses, known to be widespread in water environments. The widespread presence of bocavirus in surface waters suggests that a potential role of water in its transmission should not be excluded. PMID- 28708250 TI - Cutaneous syncytial myoepithelioma: A recently described neoplasm which may mimic nevoid melanoma and epithelioid sarcoma. AB - Cutaneous syncytial myoepithelioma is a recently described rare tumor of the dermis. It is derived and composed purely of myoepithelial cells and shows a characteristic syncytial growth pattern of neoplastic cells with little intervening stroma and no recognizable ductal structures. It represents a diagnostic challenge to dermatopathologists given its rarity and unusual immunophenotype. Molecular testing for rearrangement of the EWSR1 gene plays a significant role in confirming the diagnosis in most cases. Herein, we present 2 cases with mundane clinical presentations and challenging histopathological findings. In both cases, the lesion was composed of relatively well-circumscribed proliferation of epithelioid and spindle cells in the superficial dermis growing in a syncytial fashion and showing focal adipocytic metaplasia. The 2 cases had slightly different immunohistochemical profiles, but shared focal positivity for S100, EMA and pan-keratin or p63. Break-apart FISH demonstrated the presence of an EWSR1 gene rearrangement confirming the diagnosis in both cases. We discuss the most important differential diagnoses, particularly melanocytic lesions and epithelioid sarcoma and the original diagnostic considerations that the cases were referred to us with. We also review the molecular features and spectrum of immunohistochemical findings in these lesions and their role in excluding entities in the differential diagnosis. PMID- 28708251 TI - Efficacy of photon-initiated photoacoustic streaming on apically extruded debris with different preparation systems in curved canals. AB - AIM: To determine the effect of photon-initiated photoacoustic streaming (PIPS) on the extrusion of debris using multiple-file (ProTaper Next-PTN) and single file (One Shape-OS) continuous rotary systems in curved canals in human molar teeth. METHODOLOGY: Sixty extracted maxillary first molar teeth with curved mesial roots, mature apices and of similar lengths were selected. Teeth having canals with apical diameters larger than size 15 were discarded. The teeth were randomly divided into four experimental groups (n = 15 teeth per group) according to the file used and irrigation systems: (i) OS with PIPS with a 2940 nm Er:YAG laser (0.3 W, 15 Hz, and 20 mJ), (ii) OS with conventional needle irrigation (CNI) with a 27-G needle, (iii) PTN with PIPS and (iv) PTN with CNI. The PIPS and CNI was applied during each file change for 20 s. Total irrigation and activation time was 1 min, and a total volume of 7.5 mL of bidistilled water was used as the irrigant. The apically extruded debris was collected into pre-weighed Eppendorf tubes. The tubes were then stored in an incubator at 70 degrees C for 5 days. The weight of dry extruded debris was assessed by subtracting the initial weight of the tube from the final weight. The results were analysed statistically using one-way analysis of variance and Tukey's post hoc tests. Bonferroni correction was used to compare the groups. RESULTS: The PIPS irrigation technique was associated with significantly more debris extrusion than the CNI system (P < 0.05). The single-file (One Shape-OS) rotary system was associated with more debris than the multiple-file (ProTaper Next-PTN) rotary systems when the same irrigation system was used (P > 0.05). The total amount of debris extruded apically by PIPS activation was significantly greater than that by CNI (P < 0.05). CONCLUSIONS: All file and irrigation systems extruded debris apically. PIPS activation was associated with significantly more extrusion debris in curved canals compared with no activation. PMID- 28708253 TI - Cytomegalovirus appendicitis after hematopoietic stem cell transplantation. AB - We present the case of a young man with acute lymphoblastic leukemia who developed cytomegalovirus (CMV) appendicitis after receiving alemtuzumab for acute refractory graft-versus-host disease after allogeneic hematopoietic stem cell transplantation (HSCT). CMV appendicitis is a rare complication; and we are reporting the first case to our knowledge of CMV appendicitis following HSCT. Our case highlights the importance of recognition of CMV viral reactivation following the use of alemtuzumab. Using a preemptive strategy of checking CMV PCR, with initiation of early effective treatment on detection of CMV replication, may be appropriate following use of alemtuzumab in hematologic malignancies in patients after HSCT. PMID- 28708254 TI - Preconceptional folic acid supplementation in Japan. PMID- 28708255 TI - Palladium-Catalyzed Spirocyclization through C-H Activation and Regioselective Alkyne Insertion. AB - A Pd-catalyzed spirocyclization involving a sequential carbopalladation, intramolecular C-H activation, and a highly regioselective alkyne insertion to afford spirooxindoles and spirodihydrobenzofurans has been achieved. The spirocyclic products were generated in good to excellent yields with complete regiocontrol in a readily scalable procedure. PMID- 28708252 TI - Redundant and regulatory roles for Toll-like receptors in Leishmania infection. AB - Toll-like receptors (TLRs) are germline-encoded, non-clonal innate immune receptors, which are often the first receptors to recognize the molecular patterns on pathogens. Therefore, the immune response initiated by TLRs has far reaching consequences on the outcome of an infection. As soon as the cell surface TLRs and other receptors recognize a pathogen, the pathogen is phagocytosed. Inclusion of TLRs in the phagosome results in quicker phagosomal maturation and stronger adaptive immune response, as TLRs influence co-stimulatory molecule expression and determinant selection by major histocompatibility complex (MHC) class II and MHC class I for cross-presentation. The signals delivered by the TCR peptide-MHC complex and co-stimulatory molecules are indispensable for optimal T cell activation. In addition, the cytokines induced by TLRs can skew the differentiation of activated T cells to different effector T cell subsets. However, the potential of TLRs to influence adaptive immune response into different patterns is severely restricted by multiple factors: gross specificity for the molecular patterns, lack of receptor rearrangements, sharing of limited number of adaptors that assemble signalling complexes and redundancy in ligand recognition. These features of apparent redundancy and regulation in the functioning of TLRs characterize them as important and probable contributory factors in the resistance or susceptibility to an infection. PMID- 28708256 TI - Longitudinal study shows that depression in childhood is associated with a worse evolution of headaches in adolescence. AB - AIM: The aim of this study was to examine the course of headache diagnosis, headache frequency, anxiety, comorbid depressive symptoms and school absenteeism in adolescents with migraine and tension-type headaches five years after baseline. METHODS: We followed a group of 122 children with a mean age of 10.1 (+/-1.3) years, with headache from a paediatric migraine centre in Paris who had taken part in a previous study from September 2007 to June 2008. This five-year longitudinal study took place in January to June 2012. The measures that were used included demographic variables, headache diagnosis, headache data and a psychological assessment. RESULTS: At the five-year point, about 22% of the children had become headache free, 34% had little to no disability, and 36% had a changed diagnosis. Moreover, a longer history of headache at baseline was associated with a worse evolution of headache at follow-up. Lastly, high depression scores, but not anxiety, were a predictor of more headache disability at follow-up. CONCLUSION: High depression scores in childhood were a risk factor that was associated with persistence and worsening of headaches in adolescence. This suggests that mental health assessments should be carried out in paediatric headache pain clinics. PMID- 28708257 TI - Aquaporin1 and 3 modification as a result of chondrogenic differentiation of human mesenchymal stem cell. AB - Chondrocytes are cells of articular cartilage particularly sensitive to water transport and ionic and osmotic changes from extracellular environment and responsible for the production of the synovial fluid. Aquaporins (AQPs) are a family of water and small solute transport channel proteins identified in several tissues, involved in physiological pathways and in manifold human diseases. In a recent period, AQP1 and 3 seem to have a role in metabolic water regulation in articular cartilage of load bearing joints. The aim of this study was to examine the levels of AQP1 and 3 during the chondrogenic differentiation of human mesenchymal stem cells (MSCs) derived from adipose tissue (AT). For the determination of chondrogenic markers and AQPs levels, glycosaminoglycans (GAGs) quantification, immunocytochemistry, RT-PCR, and Western blot were used after 0, 7, 14, 21, and 28 days from the start of differentiation. At 21 days, chondrocytes derived from AT-MSCs were able to produce augmented content of GAGs and significant quantity of SOX-9, lubricin, aggrecan, and collagen type II, suggesting hyaline cartilage formation, in combination with an increase of AQP3 and AQP1. However, while AQP1 level decreased after 21 days; AQP3 reached higher values at 28 days. The expression of AQP1 and 3 is a manifestation of physiological adaptation of functionally mature chondrocytes able to respond to the change of their internal environment influenced by extracellular matrix. The alteration or loss of expression of AQP1 and 3 could contribute to destruction of chondrocytes and to development of cartilage damage. PMID- 28708258 TI - Creating chimeras: Embryonic stem cells incorporated. PMID- 28708259 TI - Rapid modulation of the silent information regulator 1 by melatonin after hypoxia ischemia in the neonatal rat brain. AB - Increasing evidence indicates that melatonin possesses protective effects toward different kinds of damage in various organs, including the brain. In a neonatal model of hypoxia-ischemia (HI), melatonin was neuroprotective and preserved the expression of the silent information regulator 1 (SIRT1) 24 hours after the insult. This study aimed to gain more insight into the role of SIRT1 in the protective effect of melatonin after HI by studying the early (1 hour) modulation of SIRT1 and its downstream targets, and the consequences on necrosis, apoptosis, autophagy, and glial cell activation. We found that melatonin administered 5 minutes after the ischemic insult significantly reduced necrotic cell death assessed 1 hour after its administration. In parallel, we found a reduced activation of the early phases of intrinsic apoptosis, detected by reduced BAX translocation to the mitochondria and preservation of the mitochondrial expression of cytochrome C, indicating a reduced outer mitochondrial membrane permeabilization in the melatonin-treated ischemic animals. These effects were concomitant to increased expression and activity of SIRT1, reduced expression and acetylation of p53, and increased autophagy activation. Melatonin also reduced HI induced glial cells activation. SIRT1 was expressed in neurons after HI and melatonin but not in reactive glial cells expressing GFAP. Colocalization between SIRT1 and GFAP was found in some cells in control conditions. In summary, our results provide more insight into the connection between SIRT1 and melatonin in neuroprotection. The possibility that melatonin-induced SIRT1 activity might contribute to differentiate neuronal progenitor cells during the neurodegenerative process needs to be further investigated. PMID- 28708260 TI - Effect of optogenetic manipulation of accumbal medium spiny neurons expressing dopamine D2 receptors in cocaine-induced behavioral sensitization. AB - Repetitive exposure to addictive drugs causes synaptic modification in the mesocorticolimbic dopamine (DA) system. Dopamine D1 receptors (D1R) or D2 receptors (D2R) expressed in the medium spiny neurons (MSNs) of the nucleus accumbens (NAc) play critical roles in the control of addictive behaviors. Optogenetic activation of D2R-expressing MSNs (D2R-MSNs) in the NAc previously demonstrated that these neurons play a key role in withdrawal-induced plasticity. Here, we examined the effect of optogenetic inhibition of D2R-MSNs in the NAc on cocaine-induced behavioral sensitization. Adeno-associated viral vectors encoding archaerhodopsin (ArchT) were delivered into the NAc of D2-Cre transgenic mice. Activation of ArchT produced photoinhibition of D2R-MSNs and caused disinhibition of neighboring MSNs in the NAc. However, such optogenetic silencing of D2R-MSNs in the NAc in vivo affected neither the initiation nor the expression of cocaine induced behavioral sensitization. Similarly, photoinhibition of NAc D2R-MSNs in the NAc during the drug withdrawal period did not affect the expression of cocaine-induced behavioral sensitization. More detailed analysis of the effects of optogenetic activation of D2R-MSNs suggests that D2R-MSNs in the NAc exert important modulatory effects on neighboring MSN neurons, which may control the balanced output of NAc MSNs to control addictive behaviors. PMID- 28708261 TI - Ultrasound for the Diagnosis of Carotidynia. AB - The purpose of this work is to draw attention to the characteristic sonographic features of carotidynia, which, in the context of a typical clinical picture support its diagnosis. Six patients presented with primary symptoms of neck pain and focal tenderness. In all patients, focal wall thickening of the distal end of the common carotid artery was found exactly in the region of tenderness, leading to mild lumen narrowing. Treatment with nonsteroidal anti-inflammatory drugs or glucocorticoids led to full symptom resolution. Carotidynia will often be encountered first on sonography performed for evaluation of neck pain and has a characteristic sonographic appearance. PMID- 28708262 TI - Characterization of spaC-type Erysipelothrix sp. isolates causing systemic disease in ornamental fish. AB - Since 2012, low-to-moderate mortality associated with an Erysipelothrix sp. bacterium has been reported in ornamental fish. Histological findings have included facial cellulitis, necrotizing dermatitis and myositis, and disseminated coelomitis with abundant intralesional Gram-positive bacterial colonies. Sixteen Erysipelothrix sp. isolates identified phenotypically as E. rhusiopathiae were recovered from diseased cyprinid and characid fish. Similar clinical and histological changes were also observed in zebrafish, Danio rerio, challenged by intracoelomic injection. The Erysipelothrix sp. isolates from ornamental fish were compared phenotypically and genetically to E. rhusiopathiae and E. tonsillarum isolates recovered from aquatic and terrestrial animals from multiple facilities. Results demonstrated that isolates from diseased fish were largely clonal and divergent from E. rhusiopathiae and E. tonsillarum isolates from normal fish skin, marine mammals and terrestrial animals. All ornamental fish isolates were PCR positive for spaC, with marked genetic divergence (<92% similarity at gyrB, <60% similarity by rep-PCR) between the ornamental fish isolates and other Erysipelothrix spp. isolates. This study supports previous work citing the genetic variability of Erysipelothrix spp. spa types and suggests isolates from diseased ornamental fish may represent a genetically distinct species. PMID- 28708263 TI - Genome-wide analysis of carbohydrate-active enzymes in Pyramimonas parkeae (Prasinophyceae). AB - The wall-less green flagellate Pyramimonas parkeae is classified in clade I of the prasinophytes, a paraphyletic assemblage representing the last common ancestor of Viridiplantae, a monophyletic group composed of the green algae and land plants. Consequently, P. parkeae and other prasinophytes illuminate early evolved Viridiplantae traits likely fundamental in the systems biology of green algae and land plants. Cellular structure and organellar genomes of P. parkeae are now well understood, and transcriptomic sequence data are also publically available for one strain of this species, but corresponding nuclear genomic sequence data are lacking. For this reason, we obtained shotgun genomic sequence and assembled a draft nuclear genome for P. parkeaeNIES254 to use along with existing transcriptomic sequence to focus on carbohydrate-active enzymes. We found that the P. parkeae nuclear genome encodes carbohydrate-active protein families similar to those previously observed for other prasinophytes, green algae, and early-diverging embryophytes for which full nuclear genomic sequence is publically available. Sequences homologous to genes related to biosynthesis of starch and cell wall carbohydrates were identified in the P. parkeae genome, indicating molecular traits common to Viridiplantae. For example, the P. parkeae genome includes sequences clustering with bacterial genes that encode cellulose synthases (Bcs), including regions coding for domains common to bacterial and plant cellulose synthases; these new sequences were incorporated into phylogenies aimed at illuminating the evolutionary history of cellulose production by Viridiplantae. Genomic sequences related to biosynthesis of xyloglucans, pectin, and starch likewise shed light on the origin of key Viridiplantae traits. PMID- 28708264 TI - Redox regulation at the site of primary growth: auxin, cytokinin and ROS crosstalk. AB - To maintain the activity of meristems is an absolute requirement for plant growth and development, and the role of the plant hormones auxin and cytokinin in apical meristem function is well established. Only little attention has been given, however, to the function of the reactive oxygen species (ROS) gradient along meristematic tissues and its interplay with hormonal regulatory networks. The interdependency between auxin-related, cytokinin-related and ROS-related circuits controls primary growth and development while modulating plant morphology in response to detrimental environmental factors. Because ROS interaction with redox active compounds significantly affects the cellular redox gradient, the latter constitutes an interface for crosstalk between hormone and ROS signalling pathways. This review focuses on the mechanisms underlying ROS-dependent interactions with redox and hormonal components in shoot and root apical meristems which are crucial for meristems maintenance when plants are exposed to environmental hardships. We also emphasize the importance of cell type and the subcellular compartmentalization of ROS and redox networks to obtain a holistic understanding of how apical meristems adapt to stress. PMID- 28708265 TI - Feasibility of using self-reported ethnicity in pregnancy according to the gestation-related optimal weight classification: a cross-sectional study. AB - OBJECTIVE: To evaluate the feasibility of self-reported ethnicity using the gestation-related optimal growth (GROW) classification in a contemporary multicultural antenatal population. DESIGN: Cross-sectional study. SETTING: Tertiary obstetric hospital in Melbourne, Australia. POPULATION: Pregnant women attending the antenatal clinic. METHODS: We surveyed pregnant women during April June 2016 regarding their understanding of the term 'ethnicity', and how they would classify the ethnicity of themselves, their partner, and family members according to the Australian GROW classification. RESULTS: Two hundred and thirty five women completed the survey. When describing 'ethnicity', most women (103, 44%) chose multiple descriptors, most frequently country of birth (54%) and region of ancestry (47%). Interpretation of 'ethnicity' varied significantly between ethnic groups: those choosing 'country of birth' were more likely to identify as Indian (odds ratio, OR 3.5, P = 0.03), whereas those choosing 'physical appearance' were more likely to identify as Chinese (OR 3.0, P = 0.047). Thirty participants (13%) were unable to describe their ethnicity from the available GROW options. Sixty-one (26%) respondents' ethnicity was inconsistent with that of their parents' heritage. A further 35% had a partner of different ethnicity. The agreement between country of birth and self-reported ethnicity was only fair (kappa 0.73, 95% confidence interval, 95% CI 0.64-0.82). CONCLUSION: This study confirms the complexity of defining ethnicity in contemporary multicultural settings. Self-reported ethnicity is often inaccurate, concepts of ethnicity vary by ethnic group, and country of birth is a poor descriptive surrogate. Adjustment for maternal ethnicity should be undertaken with caution in the customised assessment of fetal growth. TWEETABLE ABSTRACT: Is self-reported maternal ethnicity reliable? We think not. PMID- 28708266 TI - Belatacept conversion in an HIV-positive kidney transplant recipient following anti-thymocyte globulin induction. AB - Herein, we describe a case of early belatacept conversion in a human immunodeficiency virus (HIV)-positive kidney transplant recipient in an effort to improve suboptimal graft function and avoid drug interactions following anti thymocyte globulin (ATG) administration. We observed improvement in renal function without HIV disease progression or opportunistic infections. Donor specific antibodies appeared shortly after conversion but cleared without intervention. This case highlights belatacept as a means to improve renal function and avoid significant drug interactions even following ATG induction. PMID- 28708267 TI - Moderating effect of age on the association between future time perspective and preventive coping. AB - The present study aimed to investigate the moderating effect of age on the relationship between future time perspective (FTP) and future-oriented coping. A total of 1,915 participants aged 9-84 years completed measures of FTP and future oriented coping. Moderation analyses were conducted to examine whether age played a role in the association between FTP and future-oriented coping (proactive and preventive). Results showed that proactive and preventive coping were negatively correlated with age, and age moderated the association between FTP and preventive coping but not proactive coping. Furthermore, the strength of the positive association between FTP and preventive coping was strongest among the older participants, moderate among the middle-aged participants, and weakest among the younger participants. These results suggest that the association between FTP and preventive coping varies across the lifespan. PMID- 28708269 TI - Heme Oxygenase Database (HemeOxDB) and QSAR Analysis of Isoform 1 Inhibitors. AB - Due to increasing interest in the field of heme oxygenases (HOs), we built a ligand database called HemeOxDB that includes the entire set of known HO-1 and HO 2 inhibitors, resulting in more than 400 compounds. The HemeOxDB is available online at http://www.researchdsf.unict.it/hemeoxdb/, and having a robust search engine allows end users to build complex queries, sort tabulated results, and generate color-coded two- and three-dimensional graphs. This database will grow to be a tool for the design of potent and selective HO-1 or HO-2 inhibitors. We were also interested in virtually searching for alternative inhibitors, and, for the first time in the field of HOs, a quantitative structure-activity relationship (QSAR) model was built using half-maximal inhibitory concentration (IC50 ) values of the whole set of known HO-1 inhibitors, taken from the HemeOxDB and employing the Monte Carlo technique. The statistical quality suggested that the model is robust and possesses desirable predictive potential. The screening of US Food and Drug Administration (FDA)-approved drugs, external to our dataset, suggested new predicted inhibitors, opening the way for replacing imidazole groups. The HemeOxDB and the QSAR model reported herein may help in prospectively identifying or repurposing new drugs with optimal structural attributes for HO enzyme inhibition. PMID- 28708268 TI - Screening protocols to monitor respiratory status in primary immunodeficiency disease: findings from a European survey and subclinical infection working group. AB - Many patients with primary immunodeficiency (PID) who have antibody deficiency develop progressive lung disease due to underlying subclinical infection and inflammation. To understand how these patients are monitored we conducted a retrospective survey based on patient records of 13 PID centres across Europe, regarding the care of 1061 adult and 178 paediatric patients with PID on immunoglobulin (Ig) G replacement. The most common diagnosis was common variable immunodeficiency in adults (75%) and hypogammaglobulinaemia in children (39%). The frequency of clinic visits varied both within and between centres: every 1-12 months for adult patients and every 3-6 months for paediatric patients. Patients diagnosed with lung diseases were more likely to receive pharmaceutical therapies and received a wider range of therapies than patients without lung disease. Variation existed between centres in the frequency with which some clinical and laboratory monitoring tests are performed, including exercise tests, laboratory testing for IgG subclass levels and specific antibodies, and lung function tests such as spirometry. Some tests were carried out more frequently in adults than in children, probably due to difficulties conducting these tests in younger children. The percentage of patients seen regularly by a chest physician, or who had microbiology tests performed following chest and sinus exacerbations, also varied widely between centres. Our survey revealed a great deal of variation across Europe in how frequently patients with PID visit the clinic and how frequently some monitoring tests are carried out. These results highlight the urgent need for consensus guidelines on how to monitor lung complications in PID patients. PMID- 28708270 TI - Transcriptional and cellular effects of benzotriazole UV stabilizers UV-234 and UV-328 in the freshwater invertebrates Chlamydomonas reinhardtii and Daphnia magna. AB - Benzotriazole ultra violet stabilizers (BZT-UVs) are compounds used in many applications and products to prevent photochemical degradation. Despite their widespread presence in aquatic ecosystems and persistence in the environment, there are very limited data on their effects and toxicity, and their modes of action remain largely unknown. The objectives of the present study were to evaluate the chronic effects of 2 BZT-UVs, 2-(2H-benzotriazol-2-yl)-4,6-bis(1 methyl-1-phenylethyl)phenol (UV-234) and 2-(2H-benzotriazol-2-yl)-4,6-di-tert pentylphenol (UV-328), on the freshwater green algae Chlamydomonas reinhardtii and the freshwater crustacean Daphnia magna. Organisms were exposed to 0.01 and 10 MUg/L of UV-234, UV-328, as well as a mixture of the 2 compounds. Life-history endpoints (viability, reproduction, and growth) and oxidative stress-related biomarkers (gene transcription, reactive oxygen species [ROS] production, and lipid peroxidation) were measured. Daphnia magna growth, reproduction, and gene transcription were not impacted by 21-d individual or mixed exposure. After 96-h of exposure, no differences were observed on the cellular viability of C. reinhardtii for either of the 2 BZT-UVs. In the algae, results showed increased ROS production in response to UV-328 and lipid peroxidation following exposure to UV-234. Synergistic effects of the 2 BZT-UVs were evident at the transcriptional level with 2 to 6 times up-regulation of glutathione peroxidase (gpx ) in response to the mixture for all treatment conditions. The transcription of superoxide dismutase (sod), catalase (cat), and ascorbic peroxidase (apx) was also regulated by UV-234 and UV-328 in the green algae, most likely as a result of ROS production and lipid peroxidation. Results from the present study suggest potential impacts of UV-234 and UV-328 exposure on the antioxidant defense system in C. reinhardtii. Environ Toxicol Chem 2017;36:3333-3342. (c) 2017 Crown in the Right of Canada. Published by Wiley Periodicals Inc., on behalf of SETAC. PMID- 28708271 TI - Melatonin protects against the pathological cardiac hypertrophy induced by transverse aortic constriction through activating PGC-1beta: In vivo and in vitro studies. AB - Melatonin, a circadian molecule secreted by the pineal gland, confers a protective role against cardiac hypertrophy induced by hyperthyroidism, chronic hypoxia, and isoproterenol. However, its role against pressure overload-induced cardiac hypertrophy and the underlying mechanisms remains elusive. In this study, we investigated the pharmacological effects of melatonin on pathological cardiac hypertrophy induced by transverse aortic constriction (TAC). Male C57BL/6 mice underwent TAC or sham surgery at day 0 and were then treated with melatonin (20 mg/kg/day, via drinking water) for 4 or 8 weeks. The 8-week survival rate following TAC surgery was significantly increased by melatonin. Melatonin treatment for 8 weeks markedly ameliorated cardiac hypertrophy. Compared with the TAC group, melatonin treatment for both 4 and 8 weeks reduced pulmonary congestion, upregulated the expression level of alpha-myosin heavy chain, downregulated the expression level of beta-myosin heavy chain and atrial natriuretic peptide, and attenuated the degree of cardiac fibrosis. In addition, melatonin treatment slowed the deterioration of cardiac contractile function caused by pressure overload. These effects of melatonin were accompanied by a significant upregulation in the expression of peroxisome proliferator-activated receptor-gamma co-activator-1 beta (PGC-1beta) and the inhibition of oxidative stress. In vitro studies showed that melatonin also protects against angiotensin II-induced cardiomyocyte hypertrophy and oxidative stress, which were largely abolished by knocking down the expression of PGC-1beta using small interfering RNA. In summary, our results demonstrate that melatonin protects against pathological cardiac hypertrophy induced by pressure overload through activating PGC-1beta. PMID- 28708273 TI - Pediatric obesity-related curricular content and training in dental schools and dental hygiene programs: systematic review and recommendations. AB - OBJECTIVES: The authors conducted a systematic review to determine: a) What dental schools and dental hygiene programs are doing to promote knowledge and skills related to addressing childhood obesity and to reduce consumption of sugar sweetened beverages (SSBs) and b) What else these schools and programs could do to better equip future oral health professionals to address childhood obesity and reduce consumption of SSBs. METHODS: The authors searched PubMed, Scopus, Education Full Text (EBSCOHost), and ERIC (EBSCOHost) to identify peer-reviewed publications reporting on obesity or dietetic-related curricula in dental and dental hygiene education within the last 20 years. Three studies met inclusion and exclusion criteria. Outcomes of the identified studies were abstracted and summarized independently by two investigators. RESULTS: The first study describes a 2009 survey of pediatric dentistry residents. Approximately, half had received formal training yet they lacked essential knowledge or skills for managing children who were obese. The second study describes nutrition-related coursework offered in the second year of a predoctoral dental school curriculum in Saudi Arabia, and the third study reports on the development of an "oral health rotation" dietetic internship in a pediatric dentistry clinic, in the context of interprofessional education (IPE). CONCLUSIONS: Evidence of dental schools' and dental hygiene programs' efforts to address obesity and SSB consumption in children in their curricula is scant, while Commission on Dental Accreditation standards make sporadic mentions of diet and nutrition. Opportunities exist to leverage existing resources and innovative, experiential approaches, including IPE, to formally, and effectively address this important issue in predoctoral oral health education. PMID- 28708272 TI - Prognostic accuracy of cerebroplacental ratio and middle cerebral artery Doppler for adverse perinatal outcome: systematic review and meta-analysis. AB - OBJECTIVE: Doppler ultrasonographic assessment of the cerebroplacental ratio (CPR) and middle cerebral artery (MCA) is widely used as an adjunct to umbilical artery (UA) Doppler to identify fetuses at risk of adverse perinatal outcome. However, reported estimates of its accuracy vary considerably. The aim of this study was to review systematically the prognostic accuracies of CPR and MCA Doppler in predicting adverse perinatal outcome, and to compare these with UA Doppler, in order to identify whether CPR and MCA Doppler evaluation are of added value to UA Doppler. METHODS: PubMed, EMBASE, the Cochrane Library and ClinicalTrials.gov were searched, from inception to June 2016, for studies on the prognostic accuracy of UA Doppler compared with CPR and/or MCA Doppler in the prediction of adverse perinatal outcome in women with a singleton pregnancy of any risk profile. Risk of bias and concerns about applicability were assessed using the QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies-2) tool. Meta-analysis was performed for multiple adverse perinatal outcomes. Using hierarchal summary receiver-operating characteristics meta-regression models, the prognostic accuracy of CPR vs MCA Doppler was compared indirectly, and CPR and MCA Doppler vs UA Doppler compared directly. RESULTS: The search identified 4693 articles, of which 128 studies (involving 47 748 women) were included. Risk of bias or suboptimal reporting was detected in 120/128 studies (94%) and substantial heterogeneity was found, which limited subgroup analyses for fetal growth and gestational age. A large variation was observed in reported sensitivities and specificities, and in thresholds used. CPR outperformed UA Doppler in the prediction of composite adverse outcome (as defined in the included studies) (P < 0.001) and emergency delivery for fetal distress (P = 0.003), but was comparable to UA Doppler for the other outcomes. MCA Doppler performed significantly worse than did UA Doppler in the prediction of low Apgar score (P = 0.017) and emergency delivery for fetal distress (P = 0.034). CPR outperformed MCA Doppler in the prediction of composite adverse outcome (P < 0.001) and emergency delivery for fetal distress (P = 0.013). CONCLUSION: Calculating the CPR with MCA Doppler can add value to UA Doppler assessment in the prediction of adverse perinatal outcome in women with a singleton pregnancy. However, it is unclear to which subgroup of pregnant women this applies. The effectiveness of the CPR in guiding clinical management needs to be evaluated in clinical trials. (c) 2017 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology. PMID- 28708274 TI - Utility of 360 degrees Real-time Endoanal Sonography for Evaluation of Perianal Fistulas. AB - OBJECTIVES: To assess the diagnostic accuracy and performance of 360 degrees endoanal sonography for preoperative evaluation of perianal fistulas using surgical results as a reference standard. METHODS: Between January 2012 and May 2016, 122 patients with suspicious anal fistulas and perianal abnormalities had real-time endoanal sonographic examinations using a 360 degrees cross-sectional endoanal transducer (5-13 MHz) for preoperative evaluation of the disease. All patients underwent surgical interventions. The sonographic findings, including the fistulas and other inflammatory lesions, were correlated with surgical results. The types of fistulas on endoanal sonography were compared with the surgical classification of Parks et al (Br J Surg 1976; 63:1-2), and the internal opening of the fistula on endoanal sonography was confirmed by surgical results as a reference standard. RESULTS: The 122 patients studied included 111 male and 11 female patients. Endoanal sonography was able to show and track hypoechoic lesions, their locations, and internal openings of the fistulas. Compared with surgical results, endoanal sonography had sensitivity of 92.2%, specificity of 100%, and accuracy of 93.4% for the diagnosis of perianal fistulas. Also, endoanal sonography had accuracy of 87.4% for determining fistula types based on the Parks classification and 94.6% for identifying internal openings of the fistulas. CONCLUSIONS: Endoanal sonography is an accurate and noninvasive imaging modality for evaluation of fistulas. It is a very useful tool for preoperative management and surgical planning by providing precise and detailed information on fistulas. PMID- 28708275 TI - Frequency of endometrial cancer and atypical hyperplasia in infertile women undergoing hysteroscopic polypectomy. AB - AIM: We aimed to determine the frequency of endometrial cancer in infertile women undergoing hysteroscopic endometrial polypectomy for endometrial polyps. METHODS: A total of 1035 infertile patients who underwent office-based hysteroscopic polypectomy at Sugiyama Clinic Marunouchi between July 2011 and October 2015 were eligible for this retrospective study. All patients had been diagnosed with endometrial polyps via hysterofiberscopy prior to operation, and they underwent hysteroscopic endometrial polypectomy using a resectoscope with monopolar resection. Surgical specimens were examined histopathologically. Characteristics of patients diagnosed with endometrial cancer on histopathological examination were evaluated retrospectively. RESULTS: The median age of patients was 32 years (range, 19-44 years). On histopathological examination, endometrial cancer was found in 10 patients (0.97%). Each histological type of endometrial cancer was represented as follows: three cases of endometrioid adenocarcinoma G1; one of endometrioid adenocarcinoma G2; two of endometrioid adenocarcinoma G3; and four of atypical endometrial hyperplasia. The median age of endometrial cancer patients was 34 years (range, 28-41 years), and the median body mass index was 21.2 kg/m2 (range, 16.7-29.9 kg/m2 ). Nine endometrial cancer patients were nulliparous, and all had undergone infertility treatment, with only one woman having delivered a healthy baby. An ovulation disorder was noted in four patients, with obesity (body mass index > 25 kg/m2 ) in just two. Polycystic ovary syndrome was concomitantly observed in one patient. However, abnormal vaginal bleeding was not noted in any of these patients. CONCLUSION: Hysteroscopic polypectomy should be performed when endometrial polyps are detected on investigational screening, and surgical specimens should be checked for the presence of malignancy. PMID- 28708276 TI - Comparison of sigma-Hole and pi-Hole Tetrel Bonds Formed by Pyrazine and 1,4 Dicyanobenzene: The Interplay between Anion-pi and Tetrel Bonds. AB - The sigma-hole tetrel bond in pyrazine/1,4-dicyanobenzene???TH3 F (T=C and Si) and the pi-hole tetrel bond in pyrazine/1,4-dicyanobenzene???F2 TO have been compared. The pi-hole tetrel bond is stronger than the corresponding sigma-hole tetrel bond, with a larger interaction energy, shorter binding contact, greater electron density, and bigger charge transfer. Pyrazine forms a more stable tetrel bonded complex than 1,4-dicyanobenzene even though the nitrogen atom in the former has a smaller negative electrostatic potential than the latter. An interesting cooperative effect was found when anion-pi and tetrel-bond interactions coexisted in the same multicomponent complex of X- ???pyrazine/1,4 dicyanobenzene???TH3 F/F2 TO (X=F, Cl, and Br). Both interactions displayed a positive cooperative effect, as shown by the larger interaction energies, shorter binding separations, and greater electron densities. The enhancement in the tetrel bond is dependent on the strength of the anion-pi interaction and it becomes larger in the order Br- 5194 mg Zn kg-1 dry soil. The data demonstrate the necessity for alternate approaches in the assessment of organo-metal complexes, with the organic moieties or parent substances warranting consideration rather than the metal ion alone. In this instance, the organometals and organic metal salts were significantly more toxic than other test substances despite their low total Zn content. Environ Toxicol Chem 2017;36:3324-3332. (c) 2017 Crown in the Right of Canada. Published by Wiley Periodicals Inc. on behalf of SETAC. PMID- 28708299 TI - Shear Wave Elastography for Surgically Verified Breast Papillary Lesions: Is It Effective for Differentiation Between Benign and Malignant Lesions? AB - OBJECTIVES: To evaluate the effectiveness of shear wave elastography (SWE) for differentiating benign from malignant breast papillary lesions METHODS: B-mode ultrasound (US) and SWE were available in 56 surgically confirmed papillary lesions (48 [85.7%] benign and 8 [14.3%] malignant). The diagnostic performances of US, SWE parameters, and combined US with SWE parameters were calculated by receiver operating characteristic curve analysis and compared. RESULTS: The highest area under the receiver operating characteristic curve (Az ) value for US was 0.500 (95% confidence interval [CI], 0.363, 0.637). The sensitivity was 100% (8 of 8), and the specificity was 0% (0 of 48). False-positive biopsy results were obtained in 48 (85.7%) of 56 lesions. The Az value for mean elasticity (0.721; 95% CI, 0.585, 0.833) was higher than that for B-mode US (P < .01) and the highest with the optimal cutoff value of 44.3 kPa (sensitivity, 75%; specificity, 75%). By adding the mean elasticity cutoff value of 44.3 kPa to B mode US, the performance was increased (Az , 0.781; 95% CI, 0.585, 0.833) with sensitivity of 87.5% and specificity of 68.8%, and false-positive biopsy results were reduced to 26.8%. CONCLUSIONS: The additional use of SWE to B-mode US may be effective for differentiating benign and malignant breast papillary lesions, with a significant decrease in the false-positive biopsy rate. PMID- 28708300 TI - Radioprotective effect of thymoquinone on salivary gland of rats exposed to total cranial irradiation. AB - BACKGROUND: The purpose of this study was to investigate the radioprotective effects of thymoquinone against radiation-induced damage in the salivary glands of rats exposed to total cranial gamma irradiation. METHODS: Thirty-two Sprague Dawley rats were divided into 4 groups to test the radioprotective effectiveness of thymoquinone by intraperitoneal injection. An appropriate control group was also studied. Biochemical parameters in liver tissue of rats were determined by spectrophotometer. RESULTS: Glutathione peroxidase (GSH-Px), glutathione-S transferase (GST), total (enzymatic plus nonenzymatic) superoxide scavenger activity (TSSA), nonenzymatic superoxide scavenger activity (NSSA), and superoxide dismutase (SOD) activities were significantly decreased, whereas xanthine oxidase, nitric oxide synthase activities, malondialdehyde, nitric oxide, and peroxynitrite levels were significantly increased in the irradiation group when compared to the control and sham control groups. CONCLUSION: Results showed that thymoquinone reduces oxidative and nitrosative stress parameters and has antioxidant effects and a free radical scavenging activity. PMID- 28708301 TI - Quantification of interfacial motions following primary and revision total knee arthroplasty: A verification study versus experimental data. AB - Motion at the bone-implant interface, following primary or revision knee arthroplasty, can be detrimental to the long-term survival of the implant. This study employs experimentally verified computational models of the distal femur to characterize the relative motion at the bone-implant interface for three different implant types; a posterior stabilizing implant (PS), a total stabilizing implant (TS) with short stem (12 mm * 50 mm), and a total stabilizing implant (TS) with long offset stem (19 mm * 150 mm with a 4 mm lateral offset). Relative motion was investigated for both cemented and uncemented interface conditions. Monitoring relative motion about a single reference point, though useful for discerning global differences between implant types, was found to not be representative of the true pattern and distribution of motions which occur at the interface. The contribution of elastic deformation to apparent reference point motion varied based on implant type, with the PS and TSSS implanted femurs experiencing larger deformations (43 and 39 MUm, respectively) than the TSLS implanted femur (22 MUm). Furthermore, the pattern of applied loading was observed to greatly influence location and magnitude of peak motions, as well as the surface area under increased motion. Interestingly, the influence was not uniform across all implant types, with motions at the interface of long stemmed prosthesis found to be less susceptible to changes in pattern of loading. These findings have important implications for the optimization and testing of orthopedic implants in vitro and in silico. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:387-396, 2018. PMID- 28708302 TI - Advancing oral health policy and advocacy to prevent childhood obesity and reduce children's consumption of sugar-sweetened beverages. AB - PURPOSE: While a large body of work documents the interconnections between oral health and obesity, less is known about the role that oral health professionals and organizations play to prevent childhood obesity, especially by influencing children's consumption of sugar-sweetened beverages (SSBs). This review identifies efforts by oral health professionals and organizations to influence such policy and advocacy, while informing future opportunities to leverage and expand on existing efforts. METHODS: A scoping review of peer-reviewed literature and a web-based review of oral health policy and advocacy initiatives addressing prevention of obesity and reducing children's consumption of SSBs were conducted. Of 30 unique references identified, four peer-reviewed and seven non-peer reviewed references met selection criteria. Qualitative and quantitative data were extracted using a priori determined headings. RESULTS: Findings suggest a strong role for oral health professionals in preventing childhood obesity and reducing children's consumption of SSBs; however, only a few national, state, and local oral-health-advocacy and -policy efforts were identified, such as policy statements by national associations, state and local education campaigns, and clinical guidelines. Evidence was limited on the role of oral health professionals in influencing broader communitywide advocacy and policy efforts such as soda taxation and limiting SSB consumption in schools. CONCLUSION: This review provides an emerging evidence base to support growing recognition among oral health professionals of their dual role in preventing childhood obesity and dental caries by targeting SSB consumption. It also identifies opportunities for oral health professionals to build on initial efforts to more proactively influence future policy and advocacy. PMID- 28708303 TI - Using medical exome sequencing to identify the causes of neurodevelopmental disorders: Experience of 2 clinical units and 216 patients. AB - Although whole-exome sequencing (WES) is the gold standard for the diagnosis of neurodevelopmental disorders (NDDs), it remains expensive for some genetic centers. Commercialized panels comprising all OMIM-referenced genes called "medical exome" (ME) constitute an alternative strategy to WES, but its efficiency is poorly known. In this study, we report the experience of 2 clinical genetic centers using ME for diagnosis of NDDs. We recruited 216 consecutive index patients with NDDs in 2 French genetic centers, corresponded to the daily practice of the units and included non-syndromic intellectual disability (NSID, n = 33), syndromic ID (NSID = 122), pediatric neurodegenerative disorders (n = 7) and autism spectrum disorder (ASD, n = 54). We sequenced samples from probands and their parents (when available) with the Illumina TruSight One sequencing kit. We found pathogenic or likely pathogenic variants in 56 index patients, for a global diagnostic yield of 25.9%. The diagnosis yield was higher in patients with ID as the main diagnosis (32%) than in patients with ASD (3.7%). Our results suggest that the use of ME is a valuable strategy for patients with ID when WES cannot be used as a routine diagnosis tool. PMID- 28708305 TI - A novel variant of DHH in a familial case of 46,XY disorder of sex development: Insights from molecular dynamics simulations. AB - OBJECTIVE: Disorders of sex development (DSD) are a heterogeneous group of conditions affecting the differentiation and development of the internal and external genitalia. Here, we aimed at identifying the genetic cause of DSD in two 46,XY sisters from a consanguineous family. DESIGN: We performed a whole-exome sequencing of two 46,XY female individuals. Sanger sequencing was used to validate the most likely candidate variant, affecting the desert hedgehog (DHH) gene. Molecular dynamics simulations were performed to get insights into the impact of the variant on protein structure and on its interaction with the protein partner BOC (brother of CDO/cell adhesion molecule, downregulated by oncogenes). PATIENTS: The index patient presented with a female phenotype, primary amenorrhoea (low oestradiol and testosterone and high FSH and LH). She also had an apparent absence of intra-abdominal gonads and uterus, facial dysmorphy, psychomotor retardation and neuropathy. Her sister displayed a similar gonadal and endocrinological picture, without dysmorphy or psychomotor retardation. RESULTS: Whole-exome sequencing revealed a homozygous variant in DHH leading to the p.Trp173Cys substitution. The relevant Trp residue is conserved, and its alteration was predicted to be deleterious. Molecular dynamics simulations showed that the mutation increases the conformational flexibility of the protein and potentially alters its interaction with BOC, a positive regulator of Hedgehog signalling. We do not exclude an interference of the mutation with DHH-intein-mediated auto-processing. CONCLUSIONS: This report increases the number of described homozygous DHH variants and highlights the importance of advanced bioinformatic tools to better understand the pathogenicity of human variants. PMID- 28708304 TI - Hyperpolarized 13 C magnetic resonance evaluation of renal ischemia reperfusion injury in a murine model. AB - Acute kidney injury (AKI) is a major risk factor for the development of chronic kidney disease (CKD). Persistent oxidative stress and mitochondrial dysfunction are implicated across diverse forms of AKI and in the transition to CKD. In this study, we applied hyperpolarized (HP) 13 C dehydroascorbate (DHA) and 13 C pyruvate magnetic resonance spectroscopy (MRS) to investigate the renal redox capacity and mitochondrial pyruvate dehydrogenase (PDH) activity, respectively, in a murine model of AKI at baseline and 7 days after unilateral ischemia reperfusion injury (IRI). Compared with the contralateral sham-operated kidneys, the kidneys subjected to IRI showed a significant decrease in the HP 13 C vitamin C/(vitamin C + DHA) ratio, consistent with a decrease in redox capacity. The kidneys subjected to IRI also showed a significant decrease in the HP 13 C bicarbonate/pyruvate ratio, consistent with impaired PDH activity. The IRI kidneys showed a significantly higher HP 13 C lactate/pyruvate ratio at day 7 compared with baseline, although the 13 C lactate/pyruvate ratio was not significantly different between the IRI and contralateral sham-operated kidneys at day 7. Arterial spin labeling magnetic resonance imaging (MRI) demonstrated significantly reduced perfusion in the IRI kidneys. Renal tissue analysis showed corresponding increased reactive oxygen species (ROS) and reduced PDH activity in the IRI kidneys. Our results show the feasibility of HP 13 C MRS for the non invasive assessment of oxidative stress and mitochondrial PDH activity following renal IRI. PMID- 28708306 TI - A Toolbox of Chromones and Quinolones for Measuring a Wide Range of ATP Concentrations. AB - A series of 26 3-hydroxychromones, three bis-flavonols and four 3 hydroxyquinolones were studied to evaluate their fluorescence response to interaction with ATP in buffer. The dyes differ by the total charge, the size and number of their aromatic units, as well as the position or electron-donating ability of their substituents. All of them were suggested to form complexes with ATP of 1:1 and 1:2 stoichiometry, which can be evidenced by their bright fluorescence and their 3000-6000 cm-1 red-shifted excitation band. These fluorescent complexes allow detection of ATP concentrations over 3 orders of magnitude, whereas most other known probes cover no more than two orders. In total, the dyes allow ATP detection from 0.001 to 57 mm. In addition, most of the dye-ATP complexes can be excited in the visible and monitored in the red region of the spectrum. The response amplitude of the described dyes to ATP is as high as for the best known probes. Considering that complexation takes place at neutral pH, the studied dyes form a toolbox of fluorescent probes for intensiometric and ratiometric measurements of ATP concentration in a broad concentration range. Finally, the obtained results stimulate the idea that most of natural 3-hydroxyflavones in living cells may form complexes with ATP. PMID- 28708307 TI - Evaluation of short-term effectiveness of eight targeted agents combined with chemotherapy for treating esophageal-gastric junction adenocarcinoma: A network meta-analysis. AB - This study aimed to evaluate the short-term effectiveness of eight targeted agents (ramucirumab, bevacizumab, rilotumumab, panitumumab, cetuximab, trebananib, trastuzumab, matuzumab) plus chemotherapy in esophageal-gastric junction adenocarcinoma (EGJA) by a network meta-analysis (NMA). PubMed, Embase, and Cochrane Library databases were systematically retrieved for randomized clinical trials (RCTs) concerning targeted agents plus chemotherapy in the treatment of EGJA. This NMA combined both direct and indirect evidence to evaluate odds ratio (OR) and to draw the surface under the cumulative ranking curve (SUCRA). In total 11 RCTs with 3649 EGJA patients (1907 patients treated with targeted agents plus chemotherapy were regarded as the case group, and 1742 patients with placebo plus chemotherapy were assigned into the control group) were enrolled in this study. Targeted agents in terms of stable disease (SD), partial response (PR), disease control rate (DCR), and overall response ratio (ORR) with the SUCRA values of 0.838, 0.807, 0.934, and 0.793, respectively. Cetuximab and trastuzumab, with the SUCRA values of 0.884 and 0.758, came on top as the best outcomes for treating EGJA in terms of progressive disease (PD) and complete response (CR). Cluster analysis results indicated that ramucirumab plus chemotherapy might be the optimal treatment for EGJA. Our findings indicated that ramucirumab plus chemotherapy might be the optimal treatment for EGJA amongst the nine treatment regimens, which provided clinical guidance for clinicians in the treatment of EGJA. PMID- 28708308 TI - Arsenic-resistant and plant growth-promoting Firmicutes and gamma-Proteobacteria species from industrially polluted irrigation water and corresponding cropland. AB - AIMS: The aim of the study was to explore irrigation water polluted with industrial waste and corresponding cropland to screen bacteria for As detoxification and plant growth promotion. METHODS AND RESULTS: Plant growth promoting (PGP) As-resistant cropland bacteria were isolated from contaminated irrigation water and corresponding agricultural soil. Phylogenetic analysis revealed that the isolates belonged to two distinct bacterial lineages; Firmicutes and gamma-Proteobacteria. Maximum As(V) resistance was exhibited by Klebsiella pneumoniae T22 and Klebsiella oxytoca N53 (550 mmol l-1 ), whereas maximum resistance against As(III) was exhibited by K. oxytoca N53 (200 mmol l-1 ). Maximum As(V) reduction was shown by K. pneumoniae T22 (6.7 mmol l-1 ), whereas maximum As(III) oxidation was exhibited by Bacillus subtilis T23 (4.8 mmol l-1 ). As resistance genes arsB and ACR3 were detected in many of the isolates through polymerase chain reaction. Many of these isolates exhibited PGP traits such as hydrogen cyanide and auxin production as well as phosphate solubilization. The bacterial strains were able to enhance Triticum aestivum growth both in the absence and presence of As, and statistically significant increase in shoot and root lengths was observed especially in case of Acinetobacter lwoffii T24 and Citrobacter freundii N52-treated plants. CONCLUSIONS: Cropland bacteria have the ability to support plant growth. Bacteria of croplands irrigated with industrially polluted water develop resistance against toxicants. These bacteria are helpful for the plant growth in such contaminated lands. SIGNIFICANCE AND IMPACT OF THE STUDY: The bacteria capable of both As detoxification and plant growth promotion, such as A. lwoffii T24 and C. freundii N52, are ideal for remediation and reclamation of polluted lands for agriculture purposes. PMID- 28708309 TI - Bone healing in an aged murine fracture model is characterized by sustained callus inflammation and decreased cell proliferation. AB - : Geriatric fractures take longer to heal and heal with more complications than those of younger patients; however, the mechanistic basis for this difference in healing is not well understood. To improve this understanding, we investigated cell and molecular differences in fracture healing between 5-month-old (young adult) and 25-month-old (geriatric) mice healing utilizing high-throughput analysis of gene expression. Mice underwent bilateral tibial fractures and fracture calluses were harvested at 5, 10, and 20 days post-fracture (DPF) for analysis. Global gene expression analysis was performed using Affymetrix MoGene 1.0 ST microarrays. After normalization, data were compared using ANOVA and evaluated using Principal Component Analysis (PCA), CTen, heatmap, and Incromaps analysis. PCA and cross-sectional heatmap analysis demonstrated that DPF followed by age had pronounced effects on changes in gene expression. Both un-fractured and 20 DPF aged mice showed increased expression of immune-associated genes (CXCL8, CCL8, and CCL5) and at 10 DPF, aged mice showed increased expression of matrix-associated genes, (Matn1, Ucma, Scube1, Col9a1, and Col9a3). Cten analysis suggested an enrichment of CD8+ cells and macrophages in old mice relative to young adult mice and, conversely, a greater prevalence of mast cells in young adult mice relative to old. Finally, consistent with the PCA data, the classic bone healing pathways of BMP, Indian Hedgehog, Notch and Wnt clustered according to the time post-fracture first and age second. CLINICAL SIGNIFICANCE: Greater understanding of age-dependent molecular changes with healing will help form a mechanistic basis for therapies to improve patient outcomes. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:149-158, 2018. PMID- 28708310 TI - Omics-prediction of bioactive peptides from the edible cyanobacterium Arthrospira platensis proteome. AB - BACKGROUND: Bioinformatics approaches are widely used to evaluate the prospects of novel protein sources in bioactive peptide research. Edible cyanobacteria are considered as potential protein precursors. However, the abundance of unicellular cyanobacterial proteins is largely unknown and highly dynamic according to the cultivation conditions, which need to be considered in this research field. The objective of this work was to evaluate the protein abundance of Arthrospira platensis, as well as to map the bioactive peptide sequences from the high abundance proteins of the A. platensis proteome. RESULTS: The high-abundance proteins of the A. platensis proteome were identified with a high-performance liquid chromatography-tandem mass spectrometry-based method. A total of 593 proteins were detected and quantified. The occurrence frequency of the bioactive peptides in A. platensis proteome was calculated according to the amino acid sequences via the bioinformatics approaches. Further in silico digested by trypsin, pepsin and chymotrypsin, these proteins liberated 78, 99, and 96 bioactive peptides, respectively. In each case, angiotensin-converting enzyme inhibitors and dipeptidyl peptidase IV inhibitors were enriched. CONCLUSION: This work will help rationally design the protocols for cyanobacterial cultivation, protein pre-treatment and peptide separation, and further produce more peptides with specific functions. (c) 2017 Society of Chemical Industry. PMID- 28708311 TI - Prenatal Assessment of the Position of Fetal Conus Medullaris as a Predictor of Fetal Spinal Lesions. AB - OBJECTIVES: The aim of this study is to compare two different methods in assessment of the position of fetal conus medullaris (CM) and to explore the significance for assessment of CM. METHODS: This study included both normal fetuses and those with the diagnosis of fetal spinal lesions. The position of fetal CM was performed sonographically using two methods: location of CM in relation to the vertebral body (CM level) and measurement of the conus sacrum (CS) distance. RESULTS: The results showed that intra-observer and interobserver concordance was high for the two methods, both in the normal and abnormal groups. There was significant association between femur length and CS distance (R2 = 0.917) and between gestational age and CS distance (R2 = 0.892). CONCLUSIONS: We propose the combined use of CM level location and CS distance measurement for the prenatal diagnosis of fetal spinal lesions for complementary needs. PMID- 28708312 TI - Arabidopsis CPR5 regulates ethylene signaling via molecular association with the ETR1 receptor. AB - The plant hormone ethylene plays various functions in plant growth, development and response to environmental stress. Ethylene is perceived by membrane-bound ethylene receptors, and among the homologous receptors in Arabidopsis, the ETR1 ethylene receptor plays a major role. The present study provides evidence demonstrating that Arabidopsis CPR5 functions as a novel ETR1 receptor interacting protein in regulating ethylene response and signaling. Yeast split ubiquitin assays and bi-fluorescence complementation studies in plant cells indicated that CPR5 directly interacts with the ETR1 receptor. Genetic analyses indicated that mutant alleles of cpr5 can suppress ethylene insensitivity in both etr1-1 and etr1-2, but not in other dominant ethylene receptor mutants. Overexpression of Arabidopsis CPR5 either in transgenic Arabidopsis plants, or ectopically in tobacco, significantly enhanced ethylene sensitivity. These findings indicate that CPR5 plays a critical role in regulating ethylene signaling. CPR5 is localized to endomembrane structures and the nucleus, and is involved in various regulatory pathways, including pathogenesis, leaf senescence, and spontaneous cell death. This study provides evidence for a novel regulatory function played by CPR5 in the ethylene receptor signaling pathway in Arabidopsis. PMID- 28708313 TI - Human biliverdin reductase regulates the molecular mechanism underlying cancer development. AB - Human biliverdin reductase (hBVR), is an enzyme, that converts biliverdin to bilirubin, and has been implicated in epithelial-mesenchymal transition (EMT) in breast cancer. However, few studies have investigated the role of hBVR in cell apoptosis in other cancers. Therefore, the aim of this study was to investigate the effects of hBVR in several lines of cancer cells. The results of this study showed that hBVR expression was up-regulated in breast, lung, and liver cancers, but not ovarian cancer. Moreover, hBVR inhibition by small interfering RNA (si hBVR) attenuated cell survival and increased caspase-3 protein expression, which was mediated by the ERK1/2 signaling pathway in relative cancer cells. In addition, the mitochondrial membrane potential and mitochondrial membrane proteins Bcl-2 and BAX were found to be necessary for activation of the mitochondria dependent apoptosis pathway. Collectively, these findings indicated, for the first time, that the anti-apoptotic effect of hBVR in cancers which portend new strategies for developing novel biomarkers and effective treatment ways for cancer patients. PMID- 28708314 TI - Proceedings from the United States Department of Agriculture and National Dairy Council Collaborative Research Planning Meeting Held August 24, 2016. PMID- 28708315 TI - Keys to Successful Grant Writing. PMID- 28708316 TI - Dietary Plant Sterols Supplementation Increases In Vivo Nitrite and Nitrate Production in Healthy Adults: A Randomized, Controlled Study. AB - A randomized, double-blinded, placebo-controlled and crossover study was conducted to simultaneously measure the effects, 3 h after consumption and after 4-wk daily exposure to plant sterols-enriched food product, on in vivo nitrite and nitrate production in healthy adults. Eighteen healthy participants (67% female, 35.3 [mean] +/- 9.5 [SD] years, mean body mass index 22.8 kg/m2 ) received 2 soy milk (20 g) treatments daily: placebo and one containing 2.0 g free plant sterols equivalent of their palmityl esters (beta-sitosterol, 55%; campesterol, 29%; and stigmasterol, 23%). Nitrite and nitrate concentrations were measured in the blood plasma and urine, using stable isotope-labeled gas chromatography-mass spectrometry. L-arginine and asymmetric dimethylarginine concentrations in blood serum were measured using commercially available enzyme immunoassays. Nitrite and nitrate concentrations in blood plasma (nitrite 5.83 +/ 0.50 vs. 4.52 +/- 0.27; nitrate 15.78 +/- 0.96 vs. 13.43 +/- 0.81 MUmol/L) and urine (nitrite 1.12 +/- 0.22 vs. 0.92 +/- 0.36, nitrate 12.23 +/- 1.15 vs. 9.71 +/- 2.04 MUmol/L) were significantly elevated after 4-wk plant sterols supplementation Placebo and 3-h treatments did not affect the blood plasma and urinary concentrations of nitrite and nitrate. Circulating levels of L-arginine and asymmetric dimethylarginine were unchanged in the placebo and treatment arms. Total plant sterols, beta-Sitosterol, campesterol, and stigmasterol concentrations were significantly elevated after 4-wk treatments compared to the placebo and 3-h treatments. Blood plasma nitrite and nitrate concentrations correlated significantly with the plasma total and specific plant sterol concentrations. Our results suggest that dietary plant sterols, in the combination used, can upregulate nitrite, and nitrate production in vivo. PMID- 28708319 TI - Experimental study on ablation of leiomyoma by combination high-intensity focused ultrasound and iodized oil in vitro. AB - AIM: The aim of the current study was to investigate whether iodized oil (IO) enhances high-intensity focused ultrasound (HIFU) ablation of uterine leiomyoma and to determine the features of hyperechoic changes in the target region. METHODS: Forty samples of uterine leiomyoma were randomly divided into an experimental group and a control group. In the experimental group, the leiomyoma was ablated by HIFU 30 min after 1 mL of iodized oil had been injected into the center of the myoma. The hyperechoic values and areas in the target region were observed by B-modal ultrasound after HIFU ablation. The samples were cut successively into slices and stained by triphenyltetrazolium chloride (TTC) solution within 1 h after HIFU ablation. The diameters of TTC-non-stained areas were measured and tissues in the borderline of the TTC-stained and -non-stained areas were observed pathologically. All procedures in the control group were the same as those in the experimental group except IO was replaced by physiological saline. RESULTS: The hyperechoic value in the target region in the experimental group was higher than that in the control group 4 min after HIFU ablation (P < 0.05). Hyperechoic areas in the target region as well as TTC-non-stained volumes in the experimental group were greater than those in the control group (P < 0.05). Routine pathologic observation showed that coagulation necrosis of leiomyoma occurred in the target region in both groups. CONCLUSION: IO causes coagulation necrosis, enlarges tissue damage, and postpones the attenuation of hyperechoic changes in the target region when HIFU ablation is carried out for leiomyoma in vitro. PMID- 28708318 TI - Current insights into the role of human beta-defensins in atopic dermatitis. AB - Anti-microbial peptides or host defence peptides are small molecules that display both anti-microbial activities and complex immunomodulatory functions to protect against various diseases. Among these peptides, the human beta-defensins (hBDs) are localized primarily in epithelial surfaces, including those of the skin, where they contribute to protective barriers. In atopic dermatitis skin lesions, altered skin barrier and immune dysregulation are believed to be responsible for reduced hBD synthesis. Impaired hBD expression in the skin is reportedly the leading cause of increased susceptibility to bacterial and viral infection in patients with atopic dermatitis. Although hBDs have considerable beneficial effects as anti-microbial agents and immunomodulators and may ameliorate atopic dermatitis clinically, recent evidence has also suggested the negative effects of hBDs in atopic dermatitis development. In the current review, we provide an overview of the regulation of hBDs and their role in the pathogenesis of atopic dermatitis. The efforts to utilize these molecules in clinical applications are also described. PMID- 28708320 TI - Monosomy 7/del (7q) in inherited bone marrow failure syndromes: A systematic review. AB - Inherited bone marrow failure syndromes (IBMFS) are rare cancer predisposition syndromes with an especially high risk of transformation to myelodysplastic syndrome (MDS) and/or acute myeloid leukemia (AML). We performed a retrospective systematic review of reported MDS/AML arising in the eight most common IBMFS to determine the frequency and outcome of chromosome 7 abnormalities. We identified 738 MDS/AML cases of 4,293 individuals. Monosomy 7 or del (7q) occurred in ~17%. Greater understanding of the roles played by sequential acquisition of genetic and cytogenetic changes will provide insights into myeloid leukemogenesis and improve the surveillance and hopefully outcomes for individuals with IBMFS. PMID- 28708321 TI - Dynamics of culturable mesophilic bacterial communities of three fresh herbs and their production environment. AB - AIM: Investigate dynamics of culturable mesophilic bacteria and selected food contaminating bacteria from three herbs and their production environment. METHODS AND RESULTS: Marjoram, basil and thyme were investigated during one growing season by sampling plants, organic fertilizers, soil, irrigation water and marketed products. Mesophilic bacteria and selected food-contaminating bacteria (Escherichia coli, Enterococcus spp., Bacillus cereus group) were cultured and identified by MALDI biotyping. Culturable mesophilic bacteria on marjoram and basil plants decreased over time by two orders of magnitude starting at above 106 colony forming units per gram (CFU per g), while they remained constant on thyme (~104 CFU per g). Compared to the last field sample, mesophilic bacteria were increased on all market-ready products by one order of magnitude. Marjoram and basil were dominated by B. cereus group, Enterobacter spp. and Pseudomonas spp., thyme by Bacillus spp. and Pseudomonas spp. All selected food-contaminating bacteria were detected in soil and reservoir-sourced irrigation water, whereas in municipal water, only B. cereus group and rarely Enterococcus spp. were found. Escherichia coli was detected only on young marjoram and basil plants (5 * 102 and 5 * 101 CFU per g, respectively), whereas Enterococcus spp. and B. cereus group were consistently detected on these two herbs. Thyme plants only contained B. cereus group consistently (above 103 CFU per g). Marketed marjoram and thyme contained Enterococcus spp. (5 * 102 and 104 CFU per g) and B. cereus group (~5 * 102 CFU per g), while no selected food-contaminating bacteria were found on marketed basil. CONCLUSIONS: Overall, culturable mesophilic bacteria were dominated by Pseudomonas spp. and Bacillus spp., with increased numbers on market ready products. Selected food-contaminating bacteria were readily detectable, however, only the B. cereus group was found throughout in all systems. SIGNIFICANCE AND IMPACT OF THE STUDY: Insight into composition and development of mesophilic bacterial communities and selected food-contaminating bacteria of fresh herbs contributes to estimating consumer exposure. PMID- 28708322 TI - Ganglioside GM3 suppresses lipopolysaccharide-induced inflammatory responses in rAW 264.7 macrophage cells through NF-kappaB, AP-1, and MAPKs signaling. AB - Gangliosides are known to specifically inhibit vascular leukocyte recruitment and consequent interaction with the injured endothelium, the basic inflammatory process. In this study, we have found that the production of nitric oxide (NO), a main regulator of inflammation, is suppressed by GM3 on murine macrophage RAW 264.7 cells, when induced by LPS. In addition, GM3 attenuated the increase in cyclooxyenase-2 (COX-2) protein and mRNA levels in lipopolysaccharide (LPS) activated RAW 264.7 cells in a dose-dependent manner. Moreover, GM3 inhibited the expression and release of pro-inflammatory cytokines of tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), and interleukin-1beta (IL-1beta) in RAW 264.7 macrophages. At the intracellular level, GM3 inhibited LPS-induced nuclear translocation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) and activator protein (AP)-1 in RAW 264.7 macrophages. We, therefore, investigated whether GM3 affects mitogen-activated protein kinase (MAPK) phosphorylation, a process known as the upstream signaling regulator. GM3 dramatically reduced the expression levels of the phosphorylated forms of ERK, JNK, and p38 in LPS-activated RAW 264.7 cells. These results indicate that GM3 is a promising suppressor of the vascular inflammatory responses and ganglioside GM3 suppresses the LPS-induced inflammatory response in RAW 264.7 macrophages by suppression of NF-kappaB, AP-1, and MAPKs signaling. Accordingly, GM3 is suggested as a beneficial agent for the treatment of diseases that are associated with inflammation. PMID- 28708323 TI - The application of serum iodine in assessing individual iodine status. AB - CONTEXT: The prevalence of thyroid disease in China is on the rise, and this could be partly associated with excessive iodine intake in some individuals; therefore, increased attention is being paid to individual iodine status. However, current indices are not appropriate for evaluating individual iodine status. OBJECTIVE: To evaluate the association between serum iodine and urinary iodine (UI), as well as thyroid diseases, and provide an excellent base for future individual iodine status assessment. DESIGN, SUBJECTS AND MEASUREMENTS: A total of 902 adults were enrolled in this study including 325, 286 and 291 subjects from regions in China where iodine is adequate, sufficient and in excess, respectively. Serum iodine, UI and thyroid function were assessed, and ultrasonography performed in all subjects. RESULTS: The median serum iodine values of adults with subclinical hypothyroidism, high serum autoantibody and thyroid nodules were significantly higher than those of euthyroid adults (P<0.05). A serum iodine level higher than 100 MUg/L was considered as a risk factor for thyroid diseases. Serum iodine had strong nonlinear correlations with UI and thyroid function. When thyroid function was taken as a gold standard, the area under the receiver operating characteristic (ROC) curve for serum iodine was 0.752 and UI was 0.507 for subjects with lower serum iodine and UI levels. The area for serum iodine was 0.773 and UI was 0.638 for subjects with higher serum iodine and UI levels. The areas under these curves were significantly different (P<0.001). CONCLUSION: In adults, serum iodine had a strong nonlinear correlation with UI and a high level of serum iodine was a risk factor for thyroid diseases. PMID- 28708324 TI - Ferrichrome Has Found Its Match: Biomimetic Analogues with Diversified Activity Map Discrete Microbial Targets. AB - Siderophores provide an established platform for studying molecular recognition principles in biological systems. Herein, the preparation of ferrichrome (FC) biomimetic analogues varying in length and polarity of the amino acid chain separating between the tripodal scaffold and the pendent FeIII chelating hydroxamic acid groups was reported. Spectroscopic and potentiometric titrations determined their iron affinity to be within the range of efficient chelators. Microbial growth promotion and iron uptake studies were conducted on E. coli, P. putida and U. maydis. A wide range of siderophore activity was observed in the current series: from a rare case of a species-specific growth promotor in P. putida to an analogue matching FC in cross-phylum activity and uptake pathway. A fluorescent conjugate of the broad-range analogue visualized siderophore destination in bacteria (periplasmic space) vs. fungi (cytosol) mapping new therapeutic targets. Quantum dots (QDs) decorated with the most potent FC analogue provided a tool for immobilization of FC-recognizing bacteria. Bacterial clusters formed around QDs may provide a platform for their selection and concentration. PMID- 28708325 TI - Editorial. PMID- 28708326 TI - Loss of benzaldehyde in the fragmentation of protonated benzoylamines: Benzoyl cation as a hydride acceptor in the gas phase. AB - In electrospray ionization tandem mass spectrometry of protonated 1-benzoylamines (1-benzoylpiperadine, 1-benzoylmorpholine, and 1-benzoyl-4-methylpiperazine), the dominant fragmentation pathway was amide bond cleavage to form benzoyl cation and neutral amine. Meanwhile, in their fragmentations, an interesting loss of benzaldehyde (106 Da) was observed and identified to derive from hydride transfer reaction between the benzoyl cation and amine. A stepwise mechanism for loss of 106 Da (benzene and CO) could be excluded with the aid of deuterium labeling experiment. Theoretical calculations indicated that hydride transfers from amines (piperadine, morpholine, and 1-methylpiperazine) to benzoyl cation were thermodynamically permitted, and 1-methylpiperazine was the best hydride donor among the 3 amines. The mass spectrometric experimental results were consistent with the computational results. The relative abundance of the iminium cation (relative to the benzoyl cation) in the fragmentation of protonated 1-benzoyl-4 methylpiperazine was higher than that in the fragmentation of the other 2 protonated 1-benzoylamines. By comparing the fragmentations of protonated 1 benzyl-4-methylpiperazine and protonated 1-benzoyl-4-methylpiperazine and the energetics of their hydride transfer reactions, this study revealed that benzoyl cation was a hydride acceptor in the gas phase, but which was weaker than benzyl cation. PMID- 28708327 TI - Sonography of Non-neoplastic Disorders of the Hand and Wrist Tendons. AB - Tendon disorders commonly cause hand and wrist disability and curtail the performance of work-related duties or routine tasks. Imaging is often needed for diagnosis, but it requires knowledge of the complex anatomic structures of the tendons of the hand and wrist as well as familiarity with related disorders. This review article aims to provide medical professionals with guidelines for the sonographic assessment of the tendons of hand and wrist and related disorders. Sonographic features of tendon disorders affecting the hand and wrist are described here, specifically: infectious tenosynovitis; tendon rupture or tearing; stenosing forms of tenosynovitis such as De Quervain disease and trigger finger; intersection syndrome; insertional tendinopathy; several forms of tendinous instability such as extensor carpi ulnaris instability, climber finger, and boxer knuckle; and tendinopathy in inflammatory rheumatic diseases. Postsurgical evaluation of the hand and wrist tendons is also discussed, including the healthy and pathologic appearances of operated tendons as well as impingement from orthopedic hardware. In conclusion, sonography is effective in assessing the tendons of the hand and wrist and related disorders and represents a valuable tool for diagnosis. PMID- 28708328 TI - Safety of elastography applied to the placenta: Be careful with ultrasound radiation force. PMID- 28708329 TI - Resting-state functional connectivity measured by diffuse correlation spectroscopy. AB - Near-infrared diffuse correlation spectroscopy (DCS) is used to record spontaneous cerebral blood flow fluctuations in the frontal cortex. Nine adult subjects participated in the experiments, in which 8-minute spontaneous fluctuations were simultaneously recorded from the left and right dorsolateral and inferior frontal regions. Resting-state functional connectivity (RSFC) was measured by the temporal correlation of the low frequency fluctuations. Our data shows the RSFC within the dorsolateral region is significantly stronger than that between the inferior and dorsolateral regions, in line with previous observations with functional near-infrared spectroscopy. This indicates that DCS is capable of investigating brain functional connectivity in terms of cerebral blood flow. PMID- 28708330 TI - Mortality in children with low-grade glioma or glioneuronal tumors: A single institution study. AB - BACKGROUND: While pediatric low-grade glioma/glioneuronal tumors (LGG/LGGNTs) are considered slow-growing, indolent tumors with excellent long-term prognosis, mortality due to the disease is not unknown. Few studies have addressed the cause of death in this population. METHODS: Retrospective review of clinicopathologic and radiologic data for children 21 years or younger with LGG/LGGNT who died at St. Jude Children's Research Hospital between April 1985 and June 2015. Our primary objective was to determine the causes and timing of mortality in affected children. RESULTS: For the 87 eligible patients, median age at diagnosis was 7.7 years (range, 0.21-21 years), median age at death was 14.26 years (range, 0.58-32 years), and median time to death from diagnosis was 4.02 years (range, 0.21-24 years). Midbrain/thalamus was the most common tumor location (n = 34), followed by suprasellar/hypothalamic (n = 18) and cerebrocortical (n = 13). Astrocytoma not otherwise specified (n = 24), pilocytic astrocytoma (n = 23), and fibrillary astrocytoma (n = 11) were the predominant histologic diagnoses. Causes of death included progressive primary disease (PD) (n = 43), progression of PD with histological features of a high-grade glioma at progression or at autopsy (PD HGG) (n = 15), second cancer (n = 3), suicide (n = 4), and vehicular accident (n = 3). Among the 15 patients with PD-HGG, 12 received radiation therapy before histologic confirmation of progression. CONCLUSIONS: PD and PD-HGG contributed to 66% of the mortality in our patient cohort. Early psychological intervention should be included as part of the multidisciplinary management approach of children with LGG/LGGNT to reduce the risk of suicide in vulnerable subjects. PMID- 28708331 TI - Gas chromatography/negative chemical ionization mass spectrometry of transfluthrin in rat plasma and brain. AB - RATIONALE: Transfluthrin is a relatively non-toxic rapid-acting synthetic pyrethroid insecticide. It is widely used in household and hygiene products. A sensitive and accurate bioanalytical method is required for quantification of its concentration in plasma and its potential target organ, the brain for studies to assess its health effects and toxicokinetics in mammals. METHODS: The samples were prepared by liquid-liquid extraction. Gas chromatography mass spectrometry (GC/MS) analysis was performed for the determination of transfluthrin in biological samples with an overall method run time of 15 min. Transfluthrin was quantified using selected-ion monitoring (SIM) in the negative chemical ionization (NCI) mode. Chromatographic separation was achieved using a Zebron(r) ZB5-MS GC column operating with 1 mL/min constant flow helium. Cis-Permethrin was used as the internal standard. RESULTS: The method was validated to be precise and accurate within the linear range of 1.0-400.0 ng/mL in plasma and 4.0-400.0 ng/mL in brain homogenate, based on a 100 MUL sample volume for both matrices. This method was applied to samples following administration of a 10 mg/kg oral dose to male adult rats. The plasma concentrations were observed to be 11.70 +/- 5.69 ng/mL and brain concentrations 12.09 +/- 3.15 ng/g when measured 2 h post dose. CONCLUSIONS: A rapid GC/NCI-MS method was demonstrated to be sensitive, specific, precise and accurate for the quantification of transfluthrin in rat plasma and brain. The optimized method was successfully used to quantify the rat plasma and brain concentrations of transfluthrin 2 h after the oral dosing of Sprague-Dawley rats. PMID- 28708332 TI - Oxidative stress and cellular and tissue damage in organogenic outbred mouse embryos after moderate perigestational alcohol intake. AB - Perigestational alcohol consumption by CF-1 mouse, from before mating up to the period of embryo organogenesis, leads to retarded early embryo development and neural tube defects. Here, we addressed if perigestational alcohol ingestion up to Day 10 of pregnancy induces oxidative stress and changes in macromolecules and organ tissues of early organogenic embryos. Adult CF-1 female mice were administered 10% ethanol in their drinking water for 17 days prior to mating and until Day 10 of gestation, whereas control females were administered ethanol-free water. Our results demonstrated significantly reduced Catalase abundance and activity and increased glutathione content in the embryos of ethanol-treated females. The nitrite level was significantly reduced, but TBARS (thiobarbituric acid reactive substances) content, an index of lipid peroxidation, did not change. Embryos derived from ethanol-treated females also showed higher abundance of 3-nitrotyrosine (3-NT)-containing proteins in all tissues, compared to the control group. Apoptosis was significantly increased in the ectoderm and mesoderm, but not in the heart-although this organ did contain more cleaved Caspase-3-positive cardiomyocytes per area of ventricular myocardium than controls. In sum, moderate perigestational alcohol ingestion up to Day 10 of gestation in mice induces oxidative stress by altering radical nitrogen species and antioxidant enzymatic and non-enzymatic mechanisms in embryos. Further, generalized protein nitration, due to unbalanced nitric oxide levels associated with tissue-specific apoptosis, was detected in embryos, suggesting that oxidative mechanisms may play an important role in the perigestational alcohol induced malformation of organogenic embryos exposed to ethanol. PMID- 28708333 TI - Conversion from calcineurin inhibitors to mTOR inhibitors as primary immunosuppressive drugs in pediatric heart transplantation. AB - There are only a few reports of successful use of mammalian target of rapamycin (mTORI) as primary immunosuppression in pediatric heart transplantation. Compared to calcineurin inhibitors, mTORI have less side effects, especially nephrotoxicity, infections, and malignancies. A retrospective study was conducted at our institution of all 170 heart transplants from 1995 to 2015. Nineteen patients were switched from tacrolimus (n=15) or cyclosporin (n=4) to everolimus (n=4) or sirolimus (n=15) due to nephrotoxicity (n=5), malignancy (n=8), EBV viremia/reactive plasmacytic changes (n=5), and immune hemolytic anemia (n=1). We monitored for rejection, infection, BUN, creatinine, hyperlipidemia, EBV and CMV copies, CBC, cardiac allograft vasculopathy (CAV), and death. Target trough levels of sirolimus and everolimus were 4-10. Four treatment failures included debilitating rash, bone marrow suppression, recurrent rejection, and renal transplantation. There were no deaths. One patient had recurrent rejection episodes, and tacrolimus was reinitiated. One patient with preexisting CAV underwent heart retransplantation. One patient, who was treated for PTLD, transformed to CD30+ Hodgkins disease, and was treated with brentuximab. There were three acute rejection episodes. Median creatinine preswitch was higher 0.82 than postswitch 0.78 (P=.016). Median eGFR was lower preswitch, 75.6, than postswitch, 91.2 (P=.0004). These results indicate that conversion to mTORI as primary immunosuppression may be safely accomplished in some pediatric heart transplant patients. PMID- 28708334 TI - Palladium-Catalyzed Suzuki-Miyaura Cross-Coupling of Secondary alpha (Trifluoromethyl)benzyl Tosylates. AB - A palladium-catalyzed C(sp3 )-C(sp2 ) Suzuki-Miyaura cross-coupling of aryl boronic acids and alpha-(trifluoromethyl)benzyl tosylates is reported. A readily available, air-stable palladium catalyst was employed to access a wide range of functionalized 1,1-diaryl-2,2,2-trifluoroethanes. Enantioenriched alpha (trifluoromethyl)benzyl tosylates were found to undergo cross-coupling to give the corresponding enantioenriched cross-coupled products with an overall inversion in configuration. The crucial role of the CF3 group in promoting this transformation is demonstrated by comparison with non-fluorinated derivatives. PMID- 28708335 TI - Heterogeneity in non-epitope loop sequence and outer membrane protein complexes alters antibody binding to the major porin protein PorB in serogroup B Neisseria meningitidis. AB - PorB is a well-characterized outer membrane protein that is common among Neisseria species and is required for survival. A vaccine candidate, PorB induces antibody responses that are directed against six variable surface-exposed loops that differ in sequence depending on serotype. Although Neisseria meningitidis is naturally competent and porB genetic mosaicism provides evidence for strong positive selection, the sequences of PorB serotypes commonly associated with invasive disease are often conserved, calling into question the interaction of specific PorB loop sequences in immune engagement. In this report, we provide evidence that antibody binding to a PorB epitope can be altered by sequence mutations in non-epitope loops. Through the construction of hybrid PorB types and PorB molecular dynamics simulations, we demonstrate that loops both adjacent and non-adjacent to the epitope loop can enhance or diminish antibody binding, a phenotype that correlates with serum bactericidal activity. We further examine the interaction of PorB with outer membrane-associated proteins, including PorA and RmpM. Deletion of these proteins alters the composition of PorB-containing native complexes and reduces antibody binding and serum killing relative to the parental strain, suggesting that both intramolecular and intermolecular PorB interactions contribute to host adaptive immune evasion. PMID- 28708336 TI - ? PMID- 28708337 TI - [Prognostication : prophecy or medical practice ?] AB - The issue of prognostication is seldom approached in medical education, even though it represents an important question for the patients. Clinical assessment alone is inaccurate and systematically over-optimistic, especially if the question is formulated in temporal terms (how long will the patient live ?). The inaccuracy augments if the doctor has known the patient for a long time. However, other ways of addressing the question exist, and several validated clinical tools are available to improve the accuracy of the prognosis. The patients' self-rating and the evaluation by the nursing staff should also be considered as valuable information. PMID- 28708338 TI - [Identification of palliative care patients :issues and screening tools]. AB - From a health care perspective, and in order to improve the quality of care, early identification of palliative patients is a necessary step for the development of palliative care. Unfortunately, this early identification is still sub-optimal, resulting in a delayed introduction of palliative care in the patients' health care pathway. Although several tools exist to support health care professionals in this endeavour, their level of validity is incomplete, and they do not distinguish between patients in need of general versus specialised palliative care. A new tool which strives to better answer these criteria is presently being developed and validated at the CHUV. PMID- 28708339 TI - [Advance directives and advance care planning]. AB - Advance directives (AD) and Advance Care Planning (ACP) are two measures a person may undertake to assure that their treatment preferences will be respected until the end of his / her life. Anticipation is based on an open and honest communication between the patient, the durable medical power of attorney and the health care professionals. ADs and ACPs are based on a person's values and beliefs that are important to his quality of life. ACP is a continuing process, initiated by health care professionals and integrated into the health care plan of a person. It should be adjusted all along the disease trajectory and favors communication and anticipation in the health care network. ADs are often a personal initiative to ensure one's wishes in relation to health issues. In Switzerland, they are based on a legal framework and their application is therefore mandatory for health care professionals. PMID- 28708340 TI - [" Doctor, I would like to stay at home " About the partnership between a specialized palliative home care team and general practitioners]. AB - During home care, general practitioners are faced with complex end-of-life situations. This leads to difficulties in taking care of the patient alone, and may require support from a multi-professional specialized palliative home care team. The palliative care teams follow these situations upon request from the GPs or home nurses, in order to provide help in encountered difficulties. The palliative care teams' activity is based on mentoring, anticipating possible future difficulties and managing crises. In order to have a real working partnership between the home palliative care teams and the GPs it is essential to have a mutual understanding of how each entity works and what kind of help they can provide. PMID- 28708341 TI - [Resuscitation of elderly people : how to approach their preferences in advance]. AB - Cardiopulmonary resuscitation (CPR) is a medical intervention whose practice is highly regulated. In Switzerland, when dealing with elderly patients, physicians decide whether resuscitation would be medically indicated in the case of a cardiorespiratory arrest and discuss it with the patient. The quality of the information provided by the physician during the first encounter with the patient may influence the latter's preferences. However, many studies emphasize the difficulties that hospital physicians face when engaging in this conversation. In order to promote a care provision that is both adequate and respectful of elderly patients, more attention should be devoted to the obstacles that hinder communication on this subject and to the resources available to physicians. PMID- 28708342 TI - [Admission to intensive care of palliative care patients : the stakes and factors influencing the decision]. AB - Palliative care patients have limited prospects of survival and the benefit of intensive care is uncertain. To make a decision there are considerations other than survival probabilities. Patients should receive appropriate care and be spared suffering. End of life in the intensive care unit has an impact on families, who may develop psychological problems or complicated grief. End of life care can be a source of conflicts and cause burnout in health providers. Finally, intensive care is an expensive resource, which must be fairly allocated. In these complex situations, patient preferences help make a decision. However, they have often not been discussed with the physicians. General practitioners have a role to play by promoting advance care planning with their patients. PMID- 28708343 TI - [Knowing where the patients would like to die]. AB - The majority of the population wishes to die at home. However, most patients die in hospitals or nursing homes. What do health care professionals know about the choices of their patients in this matter? This study concerns persons who died from natural causes during the 1st semester of 2013 in 2 districts of the canton of Vaud. 241 of their health care professionals answered a questionnaire. Only 35.6 % knew their patient's wishes pertaining to where their death should take place. Despite the opportunity to speak about it with one's GP, the issue is not usually raised. If the patients give oral or written advance directives, their wishes are respected in 66.8 % of cases. Given the high value placed nowadays on patient autonomy, providing training on end of life care to physicians could help them approach this subject with greater ease. PMID- 28708344 TI - [It's never too late to be infected with mumps]. AB - Mumps, although rare since the introduction of a systematic vaccination of children in 1981 in Switzerland, occurs principally in children and is uncommon in adults. Nevertheless, it should be considered in adult patients with a typical clinical presentation or with an atypical presentation suggesting the disease. The diagnosis is established based on the clinical presentation and the treatment is symptomatic. PMID- 28708346 TI - ? PMID- 28708345 TI - ? PMID- 28708347 TI - ? PMID- 28708349 TI - ? PMID- 28708348 TI - ? PMID- 28708350 TI - ? PMID- 28708351 TI - ? PMID- 28708352 TI - ? PMID- 28708353 TI - ? PMID- 28708354 TI - [Training in communication : medicine and its discontents]. AB - In addition to providing psychiatric care to patients with somatic diseases, liaison psychiatry plays an important role in the teaching of the relational aspects of the clinical encounter between patients and clinicians. This series of three articles proposes a critical reflection on this topic, and presents examples of undergraduate and postgraduate teaching programs developed by the psychiatric liaison service at Lausanne University Hospital. In this first article, we discuss the increasing unease we experience with regard to the way clinical communication is trained on the postgraduate level and we make specific suggestions of how to rethink the so-called communication skills training. PMID- 28708355 TI - [Undergraduate training in physician-patient communication]. AB - In addition to providing psychiatric care to patients with somatic diseases, liaison psychiatry plays an important role in the teaching of the relational aspects of the clinical encounter between patients and clinicians. This series of three articles proposes a critical reflection on this topic, and presents examples of undergraduate and postgraduate teaching programs developed by the psychiatric liaison service at Lausanne University Hospital. This article describes the general context of undergraduate teaching, and focuses on our training with simulated patient of a breaking bad news situation, taking place during the fourth year of medical studies. Individual supervision, provided for each student, is discussed as a relatively unique opportunity within the curriculum of medical school. PMID- 28708356 TI - [What remains of our Balints ?] AB - In addition to providing psychiatric care to patients with somatic diseases, liaison psychiatry plays a role in the teaching of the relational aspects of medical practice. This series of three articles offers a critical reflection on this topic and examples of educational programs developed at Lausanne University Hospital. In the Department of Ambulatory Care and Community Medicine, an intervention inspired by Balint groups offers to residents in general internal medicine the possibility of working through their clinical experiences and their evolving professional identity. PMID- 28708357 TI - [Mentalizing in liaison psychiatry ?] AB - In the past few years, there has been an increased and widespread interest for Mentalization-Based Therapies (MBTs). Although originally developed by Anthony Bateman and Peter Fonagy for the treatment of Borderline Personality Disorder (BPD), the scope of MBTs has now been broadened and is relevant in liaison psychiatry, not only to cope with personality disorders or phenomena such as emotional dysregulation and suicidal behaviours, but also because being ill and expericencieng a dependency-laden relationship with health workers tend to reduce mentalization capacities, thereby increasing the probability of misunderstandings, conflicts, treatment drop-outs or medical errors. We provide clinicians with clues to identify failures and reboot the mentalization process among their patients and colleagues. PMID- 28708358 TI - [Bariatric surgery : psychiatric issues before and after surgery]. AB - Bariatric surgery is currently the most effective therapy for the treatment of severe obesity (BMI >= 35 kg/m2). This article addresses psychiatric issues preceding and following this surgery, considering that weight loss is not the only criterion to be considered in assessing the quality of the postoperative course. Quality of life, the evolution of psychiatric and somatic comorbidities, compliance and long-term postoperative complications and possible interventions to optimize the psychological and psychiatric care for these patients are discussed. PMID- 28708359 TI - [Psychological distress and infertile couple : a global approach]. AB - Infertility treatment doesn't stop in the technical and specific processing. The psychological distress may be very important and a frequent cause of drop-out during the medical procedure. Therefore the couple should be taken into account globally. Different level of counselling sessions should be offered to give the couple complete information about the procedure. The psychological counselling should be tailored to their need in term of coping strategies in the management of the stress or more specific psychotherapeutical approach. Indeed consultation liaison psychiatric interventions should be offered when the couple is known for psychiatric comorbidities or is presenting anxio-depressive symptoms in reaction to medical procedure. PMID- 28708360 TI - [Assessment of the impact of a palliative care support team in a tertiary hospital]. AB - This study aimed to measure the effectiveness of the interventions of a palliative care support team in a tertiary hospital. It used a pre-post design and included 41 patients. The results show a significant improvement of the quality of palliative care as well as a significant reduction in the intensity and in the number of moderate to severe symptoms. The importance of a palliative care support team in a tertiary hospital is confirmed by our results. Its interventions appear to respond to the growing need for specialized palliative care, particularly in patients with complex clinical problems. PMID- 28708361 TI - [From thiamine deficiency to Wernicke encephalopathy, unknown pathology]. AB - The thiamine deficiency and its clinical consequences, especially the Wernicke encephalopathy, are still often not diagnosed. The etiologies are numerous, but the most frequent is the alcohol dependence. The diagnostic is mainly clinical and the treatment must be started as soon as possible by substituting the thiamine with intravenous injection. PMID- 28708362 TI - ? PMID- 28708363 TI - ? PMID- 28708364 TI - ? PMID- 28708365 TI - ? PMID- 28708366 TI - ? PMID- 28708367 TI - ? PMID- 28708368 TI - ? PMID- 28708369 TI - ? PMID- 28708370 TI - In Situ Formation of Microfibrillar Crystalline Superstructure: Achieving High Performance Polylactide. AB - As a biobased and biodegradable polyester, polylactide (PLA) is widely applied in disposable products, biomedical devices, and textiles. Nevertheless, due to its inherent brittleness and inferior strength, simultaneously reinforcing and toughening of PLA without sacrificing its biodegradability is highly desirable. In this work, a robust assembly consisting of compact and well-ordered microfibrillar crystalline superstructure (FCS) surrounded by slightly oriented amorphism, is achieved by a combined external force field. Unlike the classic crystalline superstructures such as shish-kebabs, cylindrites, and lamellae, the newfound FCS with diameter of about 100 nm and length of several tens of micrometers is aggregated with well-aligned crystalline nanofibers. FCS can serve as discontinuous fiber to self-reinforce the amorphous PLA; more importantly, FCS can also act as rivets to pin the propagating fibrillar crazes leading to the formation of dense fibrillar crazes during stretching, which dissipates much energy and translates the failure of PLA from brittle to ductile. Consequently, PLA with FCS exhibits exceptionally simultaneous enhancement in ductility, strength, and stiffness, outperforming normal PLA with increments of 728, 55, and 70% in elongation at break, strength, and modulus, respectively. Therefore, FSC exhibits competitive advantages in achieving high-performance PLA even for other semicrystalline polymers. More significantly, this newfound crystalline superstructure (FCS) provides a new structural model to establish the correlation between structure and performance. PMID- 28708371 TI - Exploring New Mechanisms for Effective Antimicrobial Materials: Electric Contact Killing Based on Multiple Schottky Barriers. AB - The increasing threat of multidrug-resistance organisms is a cause for worldwide concern. Progressively microorganisms become resistant to commonly used antibiotics, which are a healthcare challenge. Thus, the discovery of new antimicrobial agents or new mechanisms different from those used is necessary. Here, we report an effective and selective antimicrobial activity of microstructured ZnO (Ms-ZnO) agent through the design of a novel star-shaped morphology, resulting in modulation of surface charge orientation. Specifically, we find that Ms-ZnO particles are composed of platelet stacked structure, which generates multiple Schottky barriers due to the misalignment of crystallographic orientations. We also demonstrated that this effect allows negative charge accumulation in localized regions of the structure to act as "charged domain walls", thereby improving the antimicrobial effectiveness by electric discharging effect. We use a combination of field emission scanning electron microscopy (FE SEM), SEM-cathodoluminescence imaging, and Kelvin probe force microscopy (KPFM) to determine that the antimicrobial activity is a result of microbial membrane physical damage caused by direct contact with the Ms-ZnO agent. It is important to point out that Ms-ZnO does not use the photocatalysis or the Zn2+ released as the main antimicrobial mechanism, so consequently this material would show low toxicity and robust stability. This approach opens new possibilities to understand both the physical interactions role as main antimicrobial mechanisms and insight into the coupled role of hierarchical morphologies and surface functionality on the antimicrobial activity. PMID- 28708372 TI - Nanomechanical Encoding Method Using Enhanced Thermal Concentration on a Metallic Nanobridge. AB - We present a fast, energy-efficient nano-thermomechanical encoding scheme for digital information storage and retrieval. Digital encoding processes are conducted by the bistable electrothermal actuation of a scalable nanobridge device. The electrothermal energy is highly concentrated by enhanced electron/phonon scattering and heat insulation in a sub-100 nm metallic layer. The efficient conversion of electrothermal energy into mechanical strain allows digital switching and programming processes within 60 ns at 0.75 V with a programming energy of only 54 pJ. Furthermore, this encoding scheme together with the thermally robust design enables data retention at temperatures up to 400 degrees C. These results suggest that the proposed nano-thermomechanical encoding method could contribute to low-power electronics and robust information storage/retrieval systems. PMID- 28708373 TI - Structure-Property Study on Two New D-A Type Materials Comprising Pyridazine Moiety and the OLED Application as Host. AB - In this paper, two new pyridazine based donor-acceptor type materials, i.e., 3CzPyaPy: 9,9'-(3-(6-(9H-carbazol-9-yl)pyridazin-3-yl)pyridine-2,6-diyl)bis(9H carbazole) and 4CzPyPyaPy: 3,6-bis(2,6-di(9H-carbazol-9-yl)pyridin-3 yl)pyridazine, were synthesized with high yields. These two materials exhibited strong absorption/emission with high molar extinction coefficients and moderate photoluminescence quantum yield. The glass transition temperature of 3CzPyaPy was detected to be as high as 131 degrees C, showing its high thermal stability. Although the absorption energies and oxidation/reduction behaviors of the two materials were similar, the emission from 4CzPyPyaPy with longer effective conjugation length presented hypsochromic shift both in films and in dilute solutions, contradicting to the common sense. The single crystal structure study disclosed their different space stretching and packing: 3CzPyaPy was twisted in larger angles and adopted dimerlike packing, while 4CzPyPyaPy showed smaller torsion angles and exhibited slipped herringbone packing. The dimerlike packing in 3CzPyaPy is responsible for its bathochromic shift of emission in solid state, while its unsymmetrical molecular structure accounts for that in solution. We believe that the unsymmetrical molecular structure of 3CzPyaPy is partially responsible for its high thermal-stability and also responsible for its HOMO dispersion which renders it slightly more difficult to oxidize. 3CzPyaPy was proved to be a bipolar-transport material and when served as a phosphor host, a green phosphorescent device achieved maximum efficiencies of 54.0 cd A-1, 42.4 lm W-1, and 17.7%, which are among the best with nonoptimized device structure, demonstrating its great potential for optoelectronic application. Furthermore, the new synthesized pyridazine derivatives and the corresponding structural and molecular-packing influences on material properties give a new insight into molecule tailoring. PMID- 28708374 TI - Chemical Modification and Detoxification of the Pseudomonas aeruginosa Toxin 2 Heptyl-4-hydroxyquinoline N-Oxide by Environmental and Pathogenic Bacteria. AB - 2-Heptyl-4-hydroxyquinoline N-oxide (HQNO), a major secondary metabolite and virulence factor produced by the opportunistic pathogen Pseudomonas aeruginosa, acts as a potent inhibitor of respiratory electron transfer and thereby affects host cells as well as microorganisms. In this study, we demonstrate the previously unknown capability of environmental and pathogenic bacteria to transform and detoxify this compound. Strains of Arthrobacter and Rhodococcus spp. as well as Staphylococcus aureus introduced a hydroxyl group at C-3 of HQNO, whereas Mycobacterium abscessus, M. fortuitum, and M. smegmatis performed an O methylation, forming 2-heptyl-1-methoxy-4-oxoquinoline as the initial metabolite. Bacillus spp. produced the glycosylated derivative 2-heptyl-1-(beta-d glucopyranosydyl)-4-oxoquinoline. Assaying the effects of these metabolites on cellular respiration and on quinol oxidase activity of membrane fractions revealed that their EC50 values were up to 2 orders of magnitude higher than that of HQNO. Furthermore, cellular levels of reactive oxygen species were significantly lower in the presence of the metabolites than under the influence of HQNO. Therefore, the capacity to transform HQNO should lead to a competitive advantage against P. aeruginosa. Our findings contribute new insight into the metabolic diversity of bacteria and add another layer of complexity to the metabolic interactions which likely contribute to shaping polymicrobial communities comprising P. aeruginosa. PMID- 28708376 TI - Self-Healing Nanotextured Vascular-like Materials: Mode I Crack Propagation. AB - Here, we investigate crack propagation initiated from an initial notch in a self healing material. The crack propagation in the core-shell nanofiber mats formed by coelectrospinning and the composites reinforced by them is in focus. All samples are observed from the crack initiation until complete failure. Due to the short-time experiments done on purpose, the resin and cure released from the cores of the core-shell nanofibers could not achieve a complete curing and stop crack growth, especially given the fact that no heating was used. The aim is to elucidate their effect on the rate of crack propagation. The crack propagation speed in polyacrylonitrile (PAN)-resin-cure nanofiber mats (with PAN being the polymer in the shell) was remarkably lower than that in the corresponding monolithic PAN nanofiber mat, down to 10%. The nanofiber mats were also encased in polydimethylsiloxane (PDMS) matrix to form composites. The crack shape and propagation in the composite samples were studied experimentally and analyzed theoretically, and the theoretical results revealed agreement with the experimental data. PMID- 28708375 TI - Enzyme That Makes You Cry-Crystal Structure of Lachrymatory Factor Synthase from Allium cepa. AB - The biochemical pathway that gives onions their savor is part of the chemical warfare against microbes and animals. This defense mechanism involves formation of a volatile lachrymatory factor (LF) ((Z)-propanethial S-oxide) that causes familiar eye irritation associated with onion chopping. LF is produced in a reaction catalyzed by lachrymatory factor synthase (LFS). The principles by which LFS facilitates conversion of a sulfenic acid substrate into LF have been difficult to experimentally examine owing to the inherent substrate reactivity and lability of LF. To shed light on the mechanism of LF production in the onion, we solved crystal structures of LFS in an apo-form and in complex with a substrate analogue, crotyl alcohol. The enzyme closely resembles the helix-grip fold characteristic for plant representatives of the START (star-related lipid transfer) domain-containing protein superfamily. By comparing the structures of LFS to that of the abscisic acid receptor, PYL10, a representative of the START protein superfamily, we elucidated structural adaptations underlying the catalytic activity of LFS. We also delineated the architecture of the active site, and based on the orientation of the ligand, we propose a mechanism of catalysis that involves sequential proton transfer accompanied by formation of a carbanion intermediate. These findings reconcile chemical and biochemical information regarding thioaldehyde S-oxide formation and close a long-lasting gap in understanding of the mechanism responsible for LF production in the onion. PMID- 28708378 TI - Synthesis of Highly Conductive, Uniformly Silver-Coated Carbon Nanofibers by Electroless Deposition. AB - Noble-metal-coated carbon-based nanoparticles, when used as electrically conductive fillers, have the potential to provide excellent conductivity without the high weight and cost normally associated with metals such as silver and gold. To this effect, many attempts were made to deposit uniform metallic layers on core nanoparticles with an emphasis on silver for its high conductivity. The results so far were disheartening with the metal morphology being better described as a decoration than a coating with small effects on the electrical conductivity of the bulk particles. We tackled in this work the specific problem of electroless deposition of silver on carbon nanofibers (CNFs) with the investigation of every step of the process. We performed X-ray photoelectron spectroscopy (XPS), transmission and scanning electron microscopy (TEM, SEM), zeta potential, and electrical conductivity measurements to identify a repeatable, reliable set of parameters allowing for a uniform and fully connected silver deposition on the surface of the CNFs. The bulk particles' specific electrical conductivity (conductivity per unit mass) undergoes a more than 10 fold increase during the deposition, reaching 2500 S.cm2/g, which indicates that the added metal mass participates efficiently to the conduction network. The particles keep their high aspect ratio through the process, which enables a percolated conduction network at very low volume loadings in a composite. No byproducts are produced during the reaction so the particles do not have to be sorted or purified and can be used as produced after the short ~15 min reaction time. The particles might be an interesting replacement to conventional fillers in isotropic conductive adhesives, as a conductive network is obtained at a much lower loading. They might also serve as electrically conductive fillers in composites where a high conductivity is needed, such as lightning strike protection systems, or as high surface area silver electrodes. PMID- 28708377 TI - Membrane Association Dictates Ligand Specificity for the Innate Immune Receptor NOD2. AB - The human gut must regulate its immune response to resident and pathogenic bacteria, numbering in the trillions. The peptidoglycan component of the bacterial cell wall is a dense and rigid structure that consists of polymeric carbohydrates and highly cross-linked peptides which offers protection from the host and surrounding environment. Nucleotide-binding oligomerization domain containing protein 2 (NOD2), a human membrane-associated innate immune receptor found in the gut epithelium and mutated in an estimated 30% of Crohn's disease patients, binds to peptidoglycan fragments and initiates an immune response. Using a combination of chemical synthesis, advanced analytical assays, and protein biochemistry, we tested the binding of a variety of synthetic peptidoglycan fragments to wild-type (WT)-NOD2. Only when the protein was presented in the native membrane did binding measurements correlate with a NOD2 dependent nuclear factor kappa-light-chain-enhancer of activated B cells (NF kappaB) response, supporting the hypothesis that the native-membrane environment confers ligand specificity to the NOD2 receptor for NF-kappaB signaling. While N acetyl-muramyl dipeptide (MDP) has been thought to be the minimal peptidoglycan fragment necessary to activate a NOD2-dependent immune response, we found that fragments with and without the dipeptide moiety are capable of binding and activating a NOD2-dependent NF-kappaB response, suggesting that the carbohydrate moiety of the peptidoglycan fragments is the minimal functional epitope. This work highlights the necessity of studying NOD2-ligand binding in systems that resemble the receptor's natural environment, as the cellular membrane and/or NOD2 interacting partners appear to play a crucial role in ligand binding and in triggering an innate immune response. PMID- 28708380 TI - Strategy for Quantitative Analysis of Isomeric Bis(monoacylglycero)phosphate and Phosphatidylglycerol Species by Shotgun Lipidomics after One-Step Methylation. AB - Understanding the cellular function and metabolism of bis(monoacylglycero)phosphate (BMP), an important but low-abundance class of phospholipids, has been hindered due to its difficulties to be resolved from its structural isomer (i.e., phosphatidylglycerol, PG, another low-abundance class of phospholipids). A novel strategy for quantitative analysis of BMP and PG species was developed after one-step methylation of lipid extracts in combination with high mass accuracy/resolution mass spectrometry after direct infusion (i.e., shotgun lipidomics). The novel strategy was applied for quantitative analysis of mouse hepatic BMP and PG species and their changes induced by long-term high-fat diet (HFD) feeding. Interestingly, we revealed that HFD-fed mice display a dramatic accumulation of hepatic BMP compared to chow-fed littermates. We believe the development of this novel strategy could greatly facilitate our understanding of the role of BMP in biological systems. PMID- 28708381 TI - Microfabrication of Monolithic Microfluidic Platforms Using Low Temperature Co Fired Ceramics Suitable for Fluorescence Imaging. AB - In this work, the influence of laser ablation and lamination parameters in the fabrication of embedded microstructures using Low Temperature Co-Fired Ceramics, have been studied. First, the influence of laser ablation parameters in the dimensions of fabricated microchannels in Low Temperature Co-Fired Ceramics substrates was characterized and strategies for tailoring the microchannels aspect ratios are described. The influence of lamination conditions on the fabrication of monolithically embedded microstructures is presented. Thereafter, a ceramic microfluidic platform, was constructed using a multilayer approach. The ceramic microfluidic platforms incorporate three independent inlet channels and a microfluidic chamber with an monolithically integrated transparent optical windows. The construction procedure used ensures monolithic ceramic devices with homogeneous surface chemistry as well as homogeneous physical properties. Fluorescence dyes were used in order to characterize the hydrodynamic focusing as a function of flow rate ratio of the microfluidic chamber inlets. The results obtained open the possibility of studying chemical process, in static or flow conditions using fluorescence imaging, within the traditional fields of LTCC technology, such as high-temperature or organic solvents applications, while using a simple fabrication procedure suitable for low cost mass production. PMID- 28708379 TI - Chemical Genomics, Structure Elucidation, and in Vivo Studies of the Marine Derived Anticlostridial Ecteinamycin. AB - A polyether antibiotic, ecteinamycin (1), was isolated from a marine Actinomadura sp., cultivated from the ascidian Ecteinascidia turbinata. 13C enrichment, high resolution NMR spectroscopy, and molecular modeling enabled elucidation of the structure of 1, which was validated on the basis of comparisons with its recently reported crystal structure. Importantly, ecteinamycin demonstrated potent activity against the toxigenic strain of Clostridium difficile NAP1/B1/027 (MIC = 59 ng/MUL), as well as other toxigenic and nontoxigenic C. difficile isolates both in vitro and in vivo. Additionally, chemical genomics studies using Escherichia coli barcoded deletion mutants led to the identification of sensitive mutants such as trkA and kdpD involved in potassium cation transport and homeostasis supporting a mechanistic proposal that ecteinamycin acts as an ionophore antibiotic. This is the first antibacterial agent whose mechanism of action has been studied using E. coli chemical genomics. On the basis of these data, we propose ecteinamycin as an ionophore antibiotic that causes C. difficile detoxification and cell death via potassium transport dysregulation. PMID- 28708382 TI - The Effects of Temperature and Hydrostatic Pressure on Metal Toxicity: Insights into Toxicity in the Deep Sea. AB - Mineral prospecting in the deep sea is increasing, promoting concern regarding potential ecotoxicological impacts on deep-sea fauna. Technological difficulties in assessing toxicity in deep-sea species has promoted interest in developing shallow-water ecotoxicological proxy species. However, it is unclear how the low temperature and high hydrostatic pressure prevalent in the deep sea affect toxicity, and whether adaptation to deep-sea environmental conditions moderates any effects of these factors. To address these uncertainties we assessed the effects of temperature and hydrostatic pressure on lethal and sublethal (respiration rate, antioxidant enzyme activity) toxicity in acute (96 h) copper and cadmium exposures, using the shallow-water ecophysiological model organism Palaemon varians. Low temperature reduced toxicity in both metals, but reduced cadmium toxicity significantly more. In contrast, elevated hydrostatic pressure increased copper toxicity, but did not affect cadmium toxicity. The synergistic interaction between copper and cadmium was not affected by low temperature, but high hydrostatic pressure significantly enhanced the synergism. Differential environmental effects on toxicity suggest different mechanisms of action for copper and cadmium, and highlight that mechanistic understanding of toxicity is fundamental to predicting environmental effects on toxicity. Although results infer that sensitivity to toxicants differs across biogeographic ranges, shallow water species may be suitable ecotoxicological proxies for deep-sea species, dependent on adaptation to habitats with similar environmental variability. PMID- 28708383 TI - Unlocking Reactivity of TrpB: A General Biocatalytic Platform for Synthesis of Tryptophan Analogues. AB - Derivatives of the amino acid tryptophan (Trp) serve as precursors for the chemical and biological synthesis of complex molecules with a wide range of biological properties. Trp analogues are also valuable as building blocks for medicinal chemistry and as tools for chemical biology. While the enantioselective synthesis of Trp analogues is often lengthy and requires the use of protecting groups, enzymes have the potential to synthesize such products in fewer steps and with the pristine chemo- and stereoselectivity that is a hallmark of biocatalysis. The enzyme TrpB is especially attractive because it can form Trp analogues directly from serine (Ser) and the corresponding indole analogue. However, many potentially useful substrates, including bulky or electron deficient indoles, are poorly accepted. We have applied directed evolution to TrpB from Pyrococcus furiosus and Thermotoga maritima to generate a suite of catalysts for the synthesis of previously intractable Trp analogues. For the most challenging substrates, such as nitroindoles, the key to improving activity lay in the mutation of a universally conserved and mechanistically important residue, E104. The new catalysts express at high levels (>200 mg/L of Escherichia coli culture) and can be purified by heat treatment; they can operate up to 75 degrees C (where solubility is enhanced) and can synthesize enantiopure Trp analogues substituted at the 4-, 5-, 6-, and 7-positions, using Ser and readily available indole analogues as starting materials. Spectroscopic analysis shows that many of the activating mutations suppress the decomposition of the active electrophilic intermediate, an amino-acrylate, which aids in unlocking the synthetic potential of TrpB. PMID- 28708384 TI - Modulation of the Emission Mode of a Pt(II) Complex via Intermolecular Interactions. AB - Compounds with controllable color emissions are potentially useful as photoluminescent materials in imaging and sensing applications. Multimolecular emission can be used realizing variable-color emitters and has been demonstrated in the solid state. However, achieving multimolecular emission in solution is difficult to control. In this study, we used a combination of intermolecular interactions, namely hydrogen bonding and solvophobic effect, to modulate multimolecular emissions. A designed Pt complex demonstrated three emission colors: blue (monomer emission), yellow (emission form hydrogen-bonded dimer), and orange (aggregate emission). All of the emission modes exhibited high luminescence quantum yields, as a result of their uniform assemblies. PMID- 28708385 TI - Chloroquine-Modified Hydroxyethyl Starch as a Polymeric Drug for Cancer Therapy. AB - Hydroxyethyl starch (HES) is a clinically used polysaccharide colloidal plasma volume expander. The goal of this study was to synthesize HES modified with hydroxychloroquine (HCQ) as a novel polymeric drug with the ability to inhibit the invasive character of pancreatic cancer (PC) cells. HES was conjugated with HCQ using a simple carbonyldiimidazole coupling to prepare Chloroquine-modified HES (CQ-HES). CQ-HES with various degrees of HCQ substitution were synthesized and characterized. Atomic force microscopy was used to demonstrate a pH-dependent assembly of CQ-HES into well-defined nanoparticles. In vitro studies in multiple PC cell lines showed CQ-HES to have a similar toxicity profile as HCQ. Confocal microscopy revealed the propensity of CQ-HES to localize to lysosomes and mechanistic studies confirmed the ability of CQ-HES to inhibit autophagy in PC cells. Further studies demonstrated a greatly enhanced ability of CQ-HES to inhibit the migration and invasion of PC cells when compared with HCQ. The enhanced inhibitory actions of CQ-HES compared to HCQ appeared to arise in part from the increased inhibition of ERK and Akt phosphorylation. We found no significant HCQ release from CQ-HES, which confirmed that the observed activity was due to the action of CQ-HES as a polymeric drug. Due to its promising ability to block cancer cell invasion and the ability to form nanoparticles, CQ-HES has the potential as a drug delivery platform suitable for future development with chemotherapeutics to establish novel antimetastatic treatments. PMID- 28708387 TI - Role of Triplet-State Shelving in Organic Photovoltaics: Single-Chain Aggregates of Poly(3-hexylthiophene) versus Mesoscopic Multichain Aggregates. AB - Triplet excitons have been the focus of considerable attention with regards to the functioning of polymer solar cells because these species are long-lived and quench subsequently generated singlet excitons in their vicinity. The role of triplets in poly(3-hexylthiophene) (P3HT) has been investigated extensively with contrary conclusions regarding their importance. We probe the various roles triplets can play in P3HT by analyzing the photoluminescence (PL) from isolated single-chain aggregates and multichain mesoscopic aggregates. Solvent vapor annealing allows deterministic growth of P3HT aggregates consisting of ~20 chains, which exhibit red-shifted and broadened PL compared to single-chain aggregates. The multichain aggregates exhibit a decrease of photon antibunching contrast compared to single-chain aggregates, implying rather weak interchain excitonic coupling and energy transfer. Nevertheless, the influence of triplet quenching oxygen on PL and a photon correlation analysis of aggregate PL reveal that triplets are quenched by intermolecular interactions in the bulk state. PMID- 28708386 TI - Targeted Annotation of S-Sulfonylated Peptides by Selective Infrared Multiphoton Dissociation Mass Spectrometry. AB - Protein S-sulfinylation (R-SO2-) and S-sulfonylation (R-SO3-) are irreversible oxidative post-translational modifications of cysteine residues. Greater than 5% of cysteines are reported to occupy these higher oxidation states, which effectively inactivate the corresponding thiols and alter the electronic and physical properties of modified proteins. Such higher oxidation states are reached after excessive exposure to cellular oxidants, and accumulate across different disease states. Despite widespread and functionally relevant cysteine oxidation across the proteome, there are currently no robust methods to profile higher order cysteine oxidation. Traditional data-dependent liquid chromatography/tandem mass spectrometry (LC/MS/MS) methods generally miss low occupancy modifications in complex analyses. Here, we present a data-independent acquisition (DIA) LC/MS-based approach, leveraging the high IR absorbance of sulfoxides at 10.6 MUm, for selective dissociation and discovery of S-sulfonated peptides. Across peptide standards and protein digests, we demonstrate selective infrared multiphoton dissociation (IRMPD) of S-sulfonated peptides in the background of unmodified peptides. This selective DIA IRMPD LC/MS-based approach allows identification and annotation of S-sulfonated peptides across complex mixtures while providing sufficient sequence information to localize the modification site. PMID- 28708388 TI - Ni-Catalyzed Alkene Carboacylation via Amide C-N Bond Activation. AB - We report Ni-catalyzed formal carboacylation of o-allylbenzamides with arylboronic acid pinacol esters. The reaction is triggered by oxidative addition of an activated amide C-N bond to a Ni(0) catalyst and proceeds via alkene insertion into a Ni(II)-acyl bond. The exo-selective carboacylation reaction generates 2-benzyl-2,3-dihydro-1H-inden-1-ones in moderate to high yields (46 99%) from a variety of arylboronic acid pinacol esters and substituted o allylbenzamides. These results show that amides are practical substrates for alkene carboacylation via amide C-N bond activation, and this approach bypasses challenges associated with alkene carboacylation triggered by C-C bond activation. PMID- 28708389 TI - Nanostructured Phthalocyanine Assemblies with Protein-Driven Switchable Photoactivities for Biophotonic Imaging and Therapy. AB - Switchable phototheranostic nanomaterials are of particular interest for specific biosensing, high-quality imaging, and targeted therapy in the field of precision nanomedicine. Here, we develop a "one-for-all" nanomaterial that self-assembles from flexible and versatile phthalocyanine building blocks. The nanostructured phthalocyanine assemblies (NanoPcTBs) display intrinsically unique photothermal and photoacoustic properties. Fluorescence and reactive oxygen species generation can be triggered depending on a targeted, protein-induced, partial disassembly mechanism, which creates opportunities for low-background fluorescence imaging and activatable photodynamic therapy. In vitro evaluations indicate that NanoPcTB has a high selectivity for biotin receptor-positive cancer cells (e.g., A549) compared to biotin receptor-negative cells (e.g., WI38-VA13) and permits a combined photodynamic and photothermal therapeutic effect. Following systemic administration, the NanoPcTBs accumulate in A549 tumors of xenograft-bearing mice, and laser irradiation clearly induces the inhibition of tumor growth. PMID- 28708390 TI - Softwood Lignin Self-Assembly for Nanomaterial Design. AB - Lignin is a natural, renewable biopolymer synthesized by plants. It is a macromolecule consisting of aromatic structures with high density of functional groups making it an ideal precursor for the design of sustainable biomaterials for applications such as drug delivery. The rational design of these materials requires an in-depth understanding of the underlying lignin self-assembly in solution. Colloidal transformations from nanosized lignin assemblies to submicron sized spherical particles upon solvent exchange were studied using small-angle X ray scattering, dynamic light scattering, and electron microscopy. The surface fractal structure and stability of these particles was found to be strongly solvent and pH dependent, with aggregation to a gel-like material at low pH. The results may have important implications for the design of nanostructured lignin based functional materials for consideration in various fields such as food science and biomedicine. PMID- 28708391 TI - Enantioselective Synthesis of anti-1,2-Oxaborinan-3-enes from Aldehydes and 1,1 Di(boryl)alk-3-enes Using Ruthenium and Chiral Phosphoric Acid Catalysts. AB - A cationic ruthenium(II) complex catalyzes double-bond transposition of 1,1 di(boryl)alk-3-enes to generate in situ 1,1-di(boryl)alk-2-enes, which then undergo chiral phosphoric acid catalyzed allylation of aldehydes producing homoallylic alcohols with a (Z)-vinylboronate moiety. 1,2-Anti stereochemistry is installed in an enantioselective manner. The (Z)-geometry forged in the products allows their isolation in a form of 1,2-oxaborinan-3-enes, upon which further synthetic transformations are operated. PMID- 28708392 TI - Thiol-Triggered Release of Intraliposomal Content from Liposomes Made of Extremophile-Inspired Tetraether Lipids. AB - Liposomal drug-delivery systems have been used for delivery of drugs to targeted tissues while reducing unwanted side effects. DOXIL, for instance, is a liposomal formulation of the anticancer agent doxorubicin (DOX) that has been used to address problems associated with nonspecific toxicity of free DOX. However, while this liposomal formulation allows for a more-stable circulation of doxorubicin in the body compared to free drug, the efficacy for cancer therapy is reduced in comparison with systemic injections of free drug. A robust liposomal system that can be triggered to release DOX in cancer cells could mitigate problems associated with reduced drug efficacy. In this work, we present a serum-stable, cholesterol-integrated tetraether lipid comprising of a cleavable disulfide bond, {GcGT(S-S)PC-CH}, that is designed to respond to the reducing environment of the cell to trigger the release intraliposomal content upon cellular uptake by cancer cells. A cell viability assay revealed that DOX- loaded liposomes composed of pure GcGT(S-S)PC-CH lipids were ~20 times more toxic than DOXIL, with an IC50 value comparable to that of free DOX. The low inherent membrane-leakage properties of GcGT(S-S)PC-CH liposomes in the presence of serum, combined with an intracellular triggered release of encapsulated cargo, represents a promising approach for developing improved drug-delivery formulations for the treatment of cancer and possibly other diseases. PMID- 28708393 TI - Selective Deamination of Mutagens by a Mycobacterial Enzyme. AB - Structure-based methods are powerful tools that are being exploited to unravel new functions with therapeutic advantage. Here, we report the discovery of a new class of deaminases, predominantly found in mycobacterial species that act on the commercially important s-triazine class of compounds. The enzyme Msd from Mycobacterium smegmatis was taken as a representative candidate from an evolutionarily conserved subgroup that possesses high density of Mycobacterium deaminases. Biochemical investigation reveals that Msd specifically acts on mutagenic nucleobases such as 5-azacytosine and isoguanine and does not accept natural bases as substrates. Determination of the X-ray structure of Msd to a resolution of 1.9 A shows that Msd has fine-tuned its active site such that it is a hybrid of a cytosine as well as a guanine deaminase, thereby conferring Msd the ability to expand its repertoire to both purine and pyrimidine-like mutagens. Mapping of active site residues along with X-ray structures with a series of triazine analogues aids in deciphering the mechanism by which Msd proofreads the base milieu for mutagens. The genome location of the enzyme reveals that Msd is part of a conserved cluster that confers the organism with innate resistance toward select xenobiotics by triggering their efflux. PMID- 28708394 TI - Human Viperin Causes Radical SAM-Dependent Elongation of Escherichia coli, Hinting at Its Physiological Role. AB - Viperin (virus inhibitory protein, endoplasmic reticulum-associated, interferon inducible) is a widely distributed protein that is expressed in response to infection and causes antiviral effects against a broad spectrum of viruses. Viperin is a member of the radical S-adenosyl-l-methionine (SAM) superfamily of enzymes, which typically employ a 4Fe-4S cluster to reductively cleave SAM to initiate chemistry. Though the specific reaction catalyzed by viperin remains unknown, it has been shown that expression of viperin causes an increase in the fluidity of lipid membranes, which impedes the budding of nascent viral particles from the membrane inhibiting propagation of the infection. Herein, we show that expression of the human viperin homologue induces a dramatically elongated morphology of the host Escherichia coli cells. Mutation of an essential cysteine that coordinates the radical SAM cluster abrogates this effect. Thus, the native radical SAM activity of viperin is likely occurring in the host bacteria, indicating the elusive substrate is shared between both bacteria and humans, significantly narrowing the range of potential candidate substrates and providing a convenient bacterial platform from which future studies can occur. PMID- 28708395 TI - Dynamic Nuclear Polarization of Long-Lived Nuclear Spin States in Methyl Groups. AB - We have induced hyperpolarized long-lived states in compounds containing 13C bearing methyl groups by dynamic nuclear polarization (DNP) at cryogenic temperatures, followed by dissolution with a warm solvent. The hyperpolarized methyl long-lived states give rise to enhanced antiphase 13C NMR signals in solution, which often persist for times much longer than the 13C and 1H spin lattice relaxation times under the same conditions. The DNP-induced effects are similar to quantum-rotor-induced polarization (QRIP) but are observed in a wider range of compounds because they do not depend critically on the height of the rotational barrier. We interpret our observations with a model in which nuclear Zeeman and methyl tunnelling reservoirs adopt an approximately uniform temperature, under DNP conditions. The generation of hyperpolarized NMR signals that persist for relatively long times in a range of methyl-bearing substances may be important for applications such as investigations of metabolism, enzymatic reactions, protein-ligand binding, drug screening, and molecular imaging. PMID- 28708396 TI - Indolylmethanols as Reactants in Catalytic Asymmetric Reactions. AB - Indolylmethanols have emerged as versatile reactants in catalytic asymmetric reactions because of the facile generation of reactive intermediates from these compounds. The most common indolylmethanols are 3-indolylmethanols and 2 indolylmethanols, and the reaction types applicable to these heterocycles mainly include catalytic enantioselective substitutions and cyclizations. Using indolylmethanols as reactants in catalytic asymmetric reactions enables the enantioselective construction of a variety of indole-containing frameworks. PMID- 28708397 TI - Shape Morphologies of Icosahedral Two-Component Vesicles. AB - What are the features of partitioning of crystalline materials on the surface of a two-component icosahedral vesicle? We model the response of the rigid hardly stretchable crystalline icosahedra upon addition of a softer component on its surface. We demonstrate how the soft phase "invades" the shell regions with the highest elastic energy density around 12 5-fold topological defects. We explore the phase diagram of these inhomogeneous shells as a function of the soft material fraction, shell radius, and elastic moduli of the two phases. The findings are compared with the recent computer simulation findings, and their biological relevance, for example, for the structure of icosahedral viruses, is also discussed. PMID- 28708398 TI - Chrysogine Biosynthesis Is Mediated by a Two-Module Nonribosomal Peptide Synthetase. AB - Production of chrysogine has been reported from several fungal genera including Penicillium, Aspergillus, and Fusarium. Anthranilic acid and pyruvic acid, which are expected precursors of chrysogine, enhance production of this compound. A possible route for the biosynthesis using these substrates is via a nonribosomal peptide synthetase (NRPS). Through comparative analysis of the NRPSs from genome sequenced producers of chrysogine we identified a candidate NRPS cluster comprising five additional genes named chry2-6. Deletion of the two-module NRPS (NRPS14 = chry1) abolished chrysogine production in Fusarium graminearum, indicating that the gene cluster is responsible for chrysogine biosynthesis. Overexpression of NRPS14 enhanced chrysogine production, suggesting that the NRPS is the bottleneck in the biosynthetic pathway. PMID- 28708399 TI - Development and Validation of a Computational Model Ensemble for the Early Detection of BCRP/ABCG2 Substrates during the Drug Design Stage. AB - Breast Cancer Resistance Protein (BCRP) is an ATP-dependent efflux transporter linked to the multidrug resistance phenomenon in many diseases such as epilepsy and cancer and a potential source of drug interactions. For these reasons, the early identification of substrates and nonsubstrates of this transporter during the drug discovery stage is of great interest. We have developed a computational nonlinear model ensemble based on conformational independent molecular descriptors using a combined strategy of genetic algorithms, J48 decision tree classifiers, and data fusion. The best model ensemble consists in averaging the ranking of the 12 decision trees that showed the best performance on the training set, which also demonstrated a good performance for the test set. It was experimentally validated using the ex vivo everted rat intestinal sac model. Five anticonvulsant drugs classified as nonsubstrates for BRCP by the model ensemble were experimentally evaluated, and none of them proved to be a BCRP substrate under the experimental conditions used, thus confirming the predictive ability of the model ensemble. The model ensemble reported here is a potentially valuable tool to be used as an in silico ADME filter in computer-aided drug discovery campaigns intended to overcome BCRP-mediated multidrug resistance issues and to prevent drug-drug interactions. PMID- 28708400 TI - Contribution of MATE1 to Renal Secretion of the NMDA Receptor Antagonist Memantine. AB - The weak base memantine is actively secreted into urine, however the underlying mechanisms are insufficiently understood. Potential candidates involved in memantine renal secretion are organic cation transporter 2 (OCT2) and multidrug and toxin extrusion proteins (MATE1, MATE2-K). The aim of this in vitro study was the examination of the interaction of memantine with OCT2 and MATEs. Memantine transporter inhibition and transport were examined in HEK cells expressing human OCT2, MATE1, or MATE2-K. Monolayers of single- (MDCK-OCT2, MDCK-MATE1) and double transfected MDCK cells (MDCK-OCT2-MATE1) were used for studies on vectorial, basal to apical memantine transport. Memantine inhibited OCT2-, MATE1-, and MATE2 K-mediated metformin transport with IC50 values of 3.2, 40.9, and 315.3 MUM, respectively. In HEK cells, no relevant memantine uptake by OCT2, MATE1, or MATE2 K was detected. Vectorial transport experiments, however, indicated a role of MATE1 for memantine export: After memantine administration to the basal side of the monolayers, memantine cellular accumulation was considerably lower (MDCK MATE1 vs MDCK control cells, P < 0.01) and memantine transcellular, basal to apical transport was higher in MATE1 expressing cells (MDCK-MATE1 vs MDCK control cells, P < 0.001 at 60 and 180 min). Both effects were abolished upon addition of the MATE inhibitor cimetidine. These experiments suggest a relevant role of MATE1 for renal secretion of memantine. In the clinical setting, renal elimination of memantine could be impaired by coadministration of MATE inhibitors. PMID- 28708401 TI - Cryopreservation of Proteins Using Ionic Liquids: A Case Study of Cytochrome c. AB - Aqueous ionic liquid (IL) solutions form a glassy state at 77 K over a wide concentration of ILs. They have potential as novel cryopreservation/refolding solvents for proteins. However, even if proteins in glass-forming concentrations of ILs are preserved at 77 K, the recovery of activity and the structure of the proteins after cryopreservation are still unclear. To achieve high recovery of protein activity and structure by removal of ILs after cryopreservation at 77 K, we studied the recovery of activity and structural stability after cryopreservation of bovine heart cytochrome c in aqueous solutions with ILs, including ethylammonium nitrate (EAN) and 1-butyl-3-methylimidazolium thiocyanate ([bmim][SCN]) over wide IL concentrations using UV-vis, Fourier transform infrared (FTIR), and circular dichroism (CD) spectroscopy. On the whole, although the addition of both ILs induced a decrease of activity and unfolding of the secondary structure of cytochrome c before and after cooling to 77 K, EAN, a weak denaturant, showed a reduction in protein damage (decrease of activity and unfolding of secondary structure) during the reheating process from 77 K (protection ability). In contrast, [bmim][SCN], a strong denaturant, did not have this protective ability. A remarkable result is that although the addition of both ILs caused cytochrome c denaturation, > 90% of activity and structure after cryopreservation (X > 10 mol %IL) was recovered after the removal of both ILs by dialysis. These recoveries after the removal of ILs are slightly higher than the results for dimethyl disulfide (DMSO), another cryoprotectant. The present results indicate that concentrated aqueous IL solutions have potential as one-pot (i.e., solubilization/preservation/refolding) solvents for proteins, which easily aggregate after purification, with comparable results to DMSO. PMID- 28708402 TI - Two-Step Micellization Model: The Case of Long-Chain Carboxylates in Water. AB - The micellization behavior of the long-chain carboxylates-sodium and potassium octanoate (NaC8 and KC8), sodium decanoate (NaC10), potassium decanoate (KC10), cesium decanoate (CsC10), choline decanoate (ChC10), and sodium dodecanoate (NaC12)-in aqueous solutions were studied using isothermal titration calorimetry (ITC) in the temperature range between 288.15 and 328.15 K. Experimental data were analyzed by help of an improved model treating the micellization process as a two-step process. Furthermore, consideration of the state of the stock and titrated solutions during the experiment allowed for the elimination of all usually used empirical parameters. The proposed approach represents thus an essential improvement of the thermodynamic analysis of the micellization process and turned out to be (only) effective for the description of the micellization at carboxylates with moderate alkyl chain length (C8 and C10). By fitting the model equation to the experimental data, all the thermodynamic parameters of micellization for both steps were estimated. It was found that the first step is endothermic and thus a solely entropy driven processes in the studied temperature range for all investigated systems. The same goes also for the second step, except for KC10, Cs10, and NaC12 where at temperatures above ~320 K the micellization was detected as an exothermic process. The delicate balance between entropy and enthalpy results in weak temperature dependence of (negative) Gibbs free energy which turned out as almost counterion independent quantity. The carboxylic groups are namely able to form H-bonds with water molecules, and it is quite likely that they remain strongly hydrated even upon micellization. Thus, the interactions with counterions are less expressed in comparison to those observed by other ionic surfactants (alkyl sulfates and cationic surfactants), where the micellization process was found to be an exothermic process even below ~300 K. PMID- 28708403 TI - Pseudallicins A-D: Four Complex Ovalicin Derivatives from Pseudallescheria boydii SNB-CN85. AB - The isolation and complete structural elucidation of four complex ovalicin analogues, named pseudallicins A-D, from the fungus Pseudallescheria boydii strain SNB-CN85 are described. On the basis of structural similarities and information from the literature, a joint biosynthetic pathway for the pseudallicins is proposed. PMID- 28708404 TI - Graphene-Enhanced Brillouin Optomechanical Microresonator for Ultrasensitive Gas Detection. AB - Chemical sensing is one of the most important applications of nanoscience, whose ultimate aim is to seek higher sensitivity. In recent years, graphene with intriguing quantum properties has spurred dramatic advances ranging from materials science to optoelectronics and mechanics, showing its potential to realize individual molecule solid-state sensors. However, for optical sensing the single atom thickness of graphene greatly limits the light-graphene interactions, bottlenecking their performances. Here we demonstrate a novel approach based on the forward phase-matched Brillouin optomechanics in a graphene inner-deposited high Q (>2 * 106) microfluidic resonator, expanding the "electron-photon" interaction in conventional graphene optical devices to the "electron-phonon photon" process. The molecular adsorption induced surface elastic modulation in graphene enables the Brillouin optomechanical modes (mechanical Q ~ 43,670) extremely sensitive (200 kHz/ppm) in ammonia gas detection, achieving a noise equivalent detection limit down to 1 ppb and an unprecedented dynamic range over five orders-of-magnitude with fast response. This work provides a new platform for the researches of graphene-based optomechanics, nanophotonics, and optical sensing. PMID- 28708405 TI - Catalyst-Enabled Scaffold Diversity: Highly Chemo- and Stereoselective Synthesis of Tricyclic Ketals and Triarylmethanes. AB - The first catalytic cascade reaction of activated isocyanides with para-quinone methide-aryl esters is presented. Catalyst-enabled divergent pathways have also been achieved to deliver skeletally diverse products. While Ag catalysis leads to an unprecedented highly diastereoselective synthesis of tricyclic ketals, a simple procedure employing Cu catalysis produces oxazole-containing triarylmethanes in high efficiency through an unexpected C-C bond cleavage. PMID- 28708406 TI - Copper-Catalyzed Synthesis of Substituted 2,4-Diamino-1,3,5-triazines from 1,1 Dibromoalkenes and Biguanides. AB - An efficient copper-catalyzed synthesis of substituted 2,4-diamino-1,3,5 triazines from 1,1-dibromoalkenes and biguanides under mild conditions has been developed. The reaction occurred in moderate to good yields and tolerated alkyl-, heterocyclic-, or aryl-substituted 1,1-dibromoalkenes containing functionalities such as nitriles, ethers, and halogens. Monosubstituted to tetrasubstituted biguanidines also afforded the desired products. PMID- 28708407 TI - Enhancing p-Type Thermoelectric Performances of Polycrystalline SnSe via Tuning Phase Transition Temperature. AB - SnSe emerges as a new class of thermoelectric materials since the recent discovery of an ultrahigh thermoelectric figure of merit in its single crystals. Achieving such performance in the polycrystalline counterpart is still challenging and requires fundamental understandings of its electrical and thermal transport properties as well as structural chemistry. Here we demonstrate a new strategy of improving conversion efficiency of bulk polycrystalline SnSe thermoelectrics. We show that PbSe alloying decreases the transition temperature between Pnma and Cmcm phases and thereby can serve as a means of controlling its onset temperature. Along with 1% Na doping, delicate control of the alloying fraction markedly enhances electrical conductivity by earlier initiation of bipolar conduction while reducing lattice thermal conductivity by alloy and point defect scattering simultaneously. As a result, a remarkably high peak ZT of ~1.2 at 773 K as well as average ZT of ~0.5 from RT to 773 K is achieved for Na0.01(Sn1-xPbx)0.99Se. Surprisingly, spherical-aberration corrected scanning transmission electron microscopic studies reveal that NaySn1-xPbxSe (0 < x <= 0.2; y = 0, 0.01) alloys spontaneously form nanoscale particles with a typical size of ~5-10 nm embedded inside the bulk matrix, rather than solid solutions as previously believed. This unexpected feature results in further reduction in their lattice thermal conductivity. PMID- 28708408 TI - Comprehension of the Effect of a Hydroxyl Group in Ancillary Ligand on Phosphorescent Property for Heteroleptic Ir(III) Complexes: A Computational Study Using Quantitative Prediction. AB - A new Ir(III) complex (dfpypya)2Ir(pic-OH) (2) is theoretically designed by introduction of a simple hydroxyl group into the ancillary ligand on the basis of (dfpypya)2Ir(pic) (1) with the aim to get the high-efficiency and stable blue emitting phosphors, where dfpypya is 3-methyl-6-(2',4'-difluoro pyridinato)pyridazine, pic is picolinate, and pic-OH is 3-hydroxypicolinic acid. The other configuration (dfpypya)2Ir(pic-OH)' (3) is also investigated to compare with 2. The difference between 2 and 3 is whether the intramolecular hydrogen bond is formed in the (dfpypya)2Ir(pic-OH). The quantum yield is determined by three different methods including the semiquantitative and quantitative methods. To quantitatively determine the quantum yield is still not an easy task to be completed. This work would provide some useful advices to select the suitable method to reliably evaluate the quantum yield. Complex 2 has larger quantum yield and more stability as compared with 1 and 3. The formation of intramolecular hydrogen bond would become a new method to design new phosphor with the desired properties. PMID- 28708409 TI - Formation of "Steady Size" State for Accurate Size Control of CdSe and CdS Quantum Dots. AB - We report on the formation of a "steady size" state for the growth of CdSe and CdS quantum dots (QDs), in which the size of the QDs remains constant and independent of reaction time. Kinetic study reveals that this state exists only when certain coordinating ligands are within a range between NS and NV + NS. NS and NV represent the number of atoms on the surface of the QDs and the total amount of atoms in the QDs, respectively. Under this condition, the size R of the QDs can be controlled solely by the reaction temperature T with a relationship of 1/R2 ~ T. More importantly, a highly reproducible and accurate linear control of the emission wavelength of QDs on a subnanometer scale by the reaction temperature is achieved. The discovery enables large-scale synthesis of QDs with minimum size variation that meets critical demands on wavelength accuracy for QD based optoelectronic applications. PMID- 28708410 TI - Ab Initio Ligand-Field Theory Analysis and Covalency Trends in Actinide and Lanthanide Free Ions and Octahedral Complexes. AB - Actinide chemistry is gaining increased focus in modern research, particularly in the fields of energy research and molecular magnetism. However, the structure function and structure-property relationships of actinides have still not been studied as intensely as those for transition metals. In this work, we report a detailed ab initio study of the spectroscopic, magnetic, and bonding properties of the trivalent actinide free ions and their associated hexachloride complexes in octahedral symmetry. The electronic structures of these systems are examined using complete active-space self-consistent-field calculations followed by second order N-electron valence perturbation theory, including both scalar relativistic and spin-orbit-coupling effects. The computed energies and wave functions are further analyzed by means of ab initio ligand-field theory (AILFT) and finally chemically interpreted by means of the angular overlap model (AOM). The derived Slater-Condon and spin-orbit parameters have allowed us to systematically rationalize the spectroscopic and magnetic properties of the investigated free ions and complexes along the entire actinide series. Overall, the AILFT- and AOM derived parameters accurately reproduce the multireference electronic structure calculations. The small observed discrepancies with respect to experimentally derived ligand-field parameters are essentially due to an underestimation of the electronic correlation, which arises from both the constrained size of the active space (restricted to the f orbitals) and the limit of the perturbation approach to account for dynamical correlation. Our analysis also provides insight into the metal-ligand covalency trends along the series. Consistent with natural population analysis, the nephelauxetic (Slater-Condon parameters) and relativistic nephelauxetic (spin-orbit-coupling) reductions determined for these complexes indicate a decrease in the covalency along the series. These trends also hold, to varying extents, for the corresponding tetravalent derivatives, as well as the lanthanide analogues. PMID- 28708411 TI - Quantum Tunneling Contribution for the Activation Energy in Microwave-Induced Reactions. AB - In this study, a quantum approach is presented to explain microwave-enhanced reaction rates by considering the tunneling effects in chemical reactions. In the Arrhenius equation, the part of the Hamiltonian relative to the interaction energy during tunneling, between the particle that tunnels and the electrical field defined in the medium, whose spatial component is specified by its rms value, is taken into account. An approximate evaluation of the interaction energy leads to a linear dependence of the effective activation energy on the applied field. The evaluation of the rms value of the field for pure liquids and reaction mixtures, through their known dielectric properties, leads to an appreciable reduction in the activation energies for the proton transfer process in these liquids. The results indicate the need to move toward the use of more refined methods of modern quantum chemistry to calculate more accurately field-induced reaction rates and effective activation energies. PMID- 28708412 TI - Digital Holographic Microscopy, a Method for Detection of Microorganisms in Plume Samples from Enceladus and Other Icy Worlds. AB - Detection of extant microbial life on Earth and elsewhere in the Solar System requires the ability to identify and enumerate micrometer-scale, essentially featureless cells. On Earth, bacteria are usually enumerated by culture plating or epifluorescence microscopy. Culture plates require long incubation times and can only count culturable strains, and epifluorescence microscopy requires extensive staining and concentration of the sample and instrumentation that is not readily miniaturized for space. Digital holographic microscopy (DHM) represents an alternative technique with no moving parts and higher throughput than traditional microscopy, making it potentially useful in space for detection of extant microorganisms provided that sufficient numbers of cells can be collected. Because sample collection is expected to be the limiting factor for space missions, especially to outer planets, it is important to quantify the limits of detection of any proposed technique for extant life detection. Here we use both laboratory and field samples to measure the limits of detection of an off-axis digital holographic microscope (DHM). A statistical model is used to estimate any instrument's probability of detection at various bacterial concentrations based on the optical performance characteristics of the instrument, as well as estimate the confidence interval of detection. This statistical model agrees well with the limit of detection of 103 cells/mL that was found experimentally with laboratory samples. In environmental samples, active cells were immediately evident at concentrations of 104 cells/mL. Published estimates of cell densities for Enceladus plumes yield up to 104 cells/mL, which are well within the off-axis DHM's limits of detection to confidence intervals greater than or equal to 95%, assuming sufficient sample volumes can be collected. The quantitative phase imaging provided by DHM allowed minerals to be distinguished from cells. Off-axis DHM's ability for rapid low level bacterial detection and counting shows its viability as a technique for detection of extant microbial life provided that the cells can be captured intact and delivered to the sample chamber in a sufficient volume of liquid for imaging. Key Words: In situ life detection-Extant microorganisms-Holographic microscopy Ocean Worlds-Enceladus-Imaging. Astrobiology 17, 913-925. PMID- 28708413 TI - Systematic Error in Respiratory Impedance Using Commercial Equipment Calibrated according to the Manufacturer's Instructions. PMID- 28708414 TI - Feasibility and Acceptability of Qigong Exercise in Community-Dwelling Older Adults in the United States. AB - OBJECTIVES: Qigong exercise has been shown to improve physical and psychological well-being in adults with chronic conditions, but little is known about the feasibility and acceptability of engaging in a qigong exercise program in community-dwelling older adults in the United States. The purpose of this study was to explore the feasibility, acceptance, and adherence to an 8-week qigong exercise intervention in community-dwelling American older adults. DESIGN: An exploratory study design. SETTING: Two senior centers in southern Connecticut. SUBJECTS: Forty-five community-dwelling older adults aged 65 to 85 years enrolled. INTERVENTION: A supervised 1-h health qigong exercise session twice weekly for 8 weeks. OUTCOME MEASURES: An investigator-designed questionnaire with seven items that were rated on a 1 to 6 scale, with higher scores indicating better results, and nine open-ended questions were used to obtain data on feasibility and acceptability. Adherence was calculated as the proportion of the 16 planned sessions attended. RESULTS: Of the 45 older adults enrolled, 6 never started and 6 withdrew, with 33 evaluable at the end of the intervention. The mean age of the sample was 74.8 years; the majority were female (84.4%) and white (91.1%). Mean scores on aspects of difficulty, acceptability, suitability, or effectiveness of qigong exercise were all >=5. Participants identified benefits of qigong exercise, such as calming and relaxing feelings, inner peace, better balance, and flexibility. Attendance rate was 78.8%, with 94% performing qigong exercise at least once weekly outside the class. All participants indicated that they would recommend qigong exercise to others. No adverse events occurred. CONCLUSION: An 8-week qigong exercise program was feasible, acceptable, and safe for American older adults. Future robust randomized controlled trials are needed to confirm these findings. PMID- 28708415 TI - Assessing the Effectiveness of Yoga as a Complementary and Alternative Treatment for Post-Traumatic Stress Disorder: A Review and Synthesis. AB - OBJECTIVES: Posttraumatic stress disorder (PTSD) is a debilitating condition that affects many who have experienced trauma. In addition to skills-focused treatments, exposure-based treatments, cognitive therapy, combination treatments, and EMDR, a number of alternative treatments for PTSD have emerged in recent years. The search for alternative treatments is justified based on the empirical observation that a large percentage of individuals fail to benefit optimally from existing treatments (e.g., between 30 and 60). Moreover, current studies often utilize stringent inclusion criteria (e.g., absence of comorbid disorders), raising the likelihood that results will not generalize to many individuals currently experiencing PTSD. The primary objective of the current paper was to explore the effects of one type of alternative treatment: yoga. DESIGN: A comprehensive review of the literature was conducted targeting research examining yoga postures and PTSD. Seven randomized controlled trials (RCTs) were identified and reviewed, and effect sizes were computed for the post-test assessments. RESULTS: Cohen's d for each study ranged (in absolute value) from a low of -0.06 to a high of 1.42 (average weighted d across studies was 0.48; 95% CI: 0.26, 0.69). CONCLUSIONS: Putative mechanisms of action for the possible beneficial effects of yoga for PTSD-related symptomatology and clinical implications are discussed. PMID- 28708416 TI - Subchronic exposure to kalach 360 SL-induced endocrine disruption and ovary damage in female rats. AB - Kalach 360 SL (KL), glyphosate (G) surfactant-based herbicides, is a systemic herbicide effective against weeds. It was applied in agriculture in Tunisia and throughout the world, which can represent a risk to non-target organisms. The aim of this study was to investigate the morphological and biochemical aspects of ovary injury after exposure to KL. Female Wistar rats were divided into three groups: group 1 was used as a control; group 2 orally received 0.07 ml of KL, (126 mg of G/kg) and group 3 orally received 0.175 ml of KL (315 mg of G/kg) each day for 60 days. The subchronic exposure of KL induces impaired folliculogenesis, ovary development, decreased oestrogen secretion, promoted oxidative stress and impairments of ovary histological aspects. Histological finding shows necrosis cell, vacuolisation of follicles, dissociated oocytes and granulosa cell, associated with several atretic follicles. We conclude that KL induces endocrine disruption and ovary damage in female rats. PMID- 28708418 TI - Vaccines, Pesticides, and Narratives of Exposure and Evidence. AB - This essay considers the cultural work performed by two public health narratives the DDT narrative and the vaccine narrative - as they appeared in popular and professional discourse concerning two recent media events: controversy over an antivaccination film, and the emergence of a Zika global public health emergency. Like all narratives in the history of medicine, the stories historians and others tell about DDT and about vaccines organize a shared past to explain the present. They also point to a hoped-for future. The DDT and vaccine narratives share several themes: public health, expertise, evidence, exposure, and power. Their inclusions and exclusions, however, convey distinct messages about these themes, particularly regarding the right conduct of health citizens in the pursuit of public health. These narratives are analyzed to compare their agendas, and to propose a case study of how historical work can shed light on contemporary public health norms, practice, and challenges. PMID- 28708417 TI - Association of Antibiotics, Airway Microbiome, and Inflammation in Infants with Cystic Fibrosis. AB - RATIONALE: The underlying defect in the cystic fibrosis (CF) airway leads to defective mucociliary clearance and impaired bacterial killing, resulting in endobronchial infection and inflammation that contributes to progressive lung disease. Little is known about the respiratory microbiota in the early CF airway and its relationship to inflammation. OBJECTIVES: To examine the bacterial microbiota and inflammatory profiles in bronchoalveolar lavage fluid and oropharyngeal secretions in infants with CF. METHODS: Infants with CF from U.S. and Australian centers were enrolled in a prospective, observational study examining the bacterial microbiota and inflammatory profiles of the respiratory tract. Bacterial diversity and density (load) were measured. Lavage samples were analyzed for inflammatory markers (interleukin 8, unbound neutrophil elastase, and absolute neutrophil count) in the epithelial lining fluid. RESULTS: Thirty two infants (mean age, 4.7 months) underwent bronchoalveolar lavage and oropharyngeal sampling. Shannon diversity strongly correlated between upper and lower airway samples from a given subject, although community compositions differed. Microbial diversity was lower in younger subjects and in those receiving daily antistaphylococcal antibiotic prophylaxis. In lavage samples, reduced diversity correlated with lower interleukin 8 concentration and absolute neutrophil count. CONCLUSIONS: In infants with CF, reduced bacterial diversity in the upper and lower airways was strongly associated with the use of prophylactic antibiotics and younger age at the time of sampling; less diversity in the lower airway correlated with lower inflammation on bronchoalveolar lavage. Our findings suggest modification of the respiratory microbiome in infants with CF may influence airway inflammation. PMID- 28708419 TI - Mechanisms of the Formation of Adenine, Guanine, and Their Analogues in UV Irradiated Mixed NH3:H2O Molecular Ices Containing Purine. AB - We investigated the formation mechanisms of the nucleobases adenine and guanine and the nucleobase analogues hypoxanthine, xanthine, isoguanine, and 2,6 diaminopurine in a UV-irradiated mixed 10:1 H2O:NH3 ice seeded with precursor purine by using ab initio and density functional theory computations. Our quantum chemical investigations suggest that a multistep reaction mechanism involving purine cation, hydroxyl and amino radicals, together with water and ammonia, explains the experimentally obtained products in an independent study. The relative abundances of these products appear to largely follow from relative thermodynamic stabilities. The key role of the purine cation is likely to be the reason why purine is not functionalized in pure ammonia ice, where cations are promptly neutralized by free electrons from NH3 ionization. Amine group addition to purine is slightly favored over hydroxyl group attachment based on energetics, but hydroxyl is much more abundant due to higher abundance of H2O. The amino group is preferentially attached to the 6 position, giving 6-aminopurine, that is, adenine, while the hydroxyl group is preferentially attached to the 2 position, leading to 2-hydroxypurine. A second substitution by hydroxyl or amino group occurs at either the 6 or the 2 position depending on the first substitution. Given that H2O is far more abundant than NH3 in the experimentally studied ices (as well as based on interstellar abundances), xanthine and isoguanine are expected to be the most abundant bi-substituted photoproducts. Key Words: Astrophysical ice-Abiotic organic synthesis-Nucleic acids-Origin of life RNA world. Astrobiology 17, 771-785. PMID- 28708420 TI - Dose-Response Effect of Tualang Honey on Postprandial Antioxidant Activity and Oxidative Stress in Female Athletes: A Pilot Study. AB - OBJECTIVES: Tualang honey (TH) contains antioxidants such as ascorbic acid, phenolic acids, and flavonoids that may be protective against oxidative stress of exercise. The aim of this study was to examine the postprandial antioxidant activity and oxidative stress after ingestion of high and low dosages of TH in female athletes. MATERIALS AND METHODS: Twenty female athletes (aged 21.3 [2.1] years; body weight [BW] 54.1 [5.7] kg) were randomly assigned into two groups and consumed either 1.5 g/kg BW TH (high honey; HH; n = 10) or 0.75 g/kg BW TH (low honey; LH; n = 10). Blood sample was collected at fasting and at 0.5, 1, 2, and 3 h after TH consumption. Plasma was analyzed for total phenolic content (TPC), antioxidant activity (ferric reducing antioxidant power [FRAP]), and oxidative stress biomarkers (malondialdehyde [MDA] and reactive oxygen species [ROS]). RESULTS: The 3-h area under the curve (AUC) for MDA was significantly lower in the LH group compared with HH group, suggesting less oxidative stress in the LH group. However, the AUCs for TPC, FRAP, and ROS were not affected by the dosages. The concentrations of TPC and FRAP increased from baseline to 2 and 1 h after TH consumption, respectively, and concentrations returned toward baseline at 3 h in both LH and HH groups. MDA concentration significantly decreased (p < 0.05) from baseline to 2 h and significantly increased from 2 to 3 h in the HH group. Meanwhile, ROS levels increased significantly from 0.5 to 3 h in the HH group. The LH group showed similar trends as the HH group for MDA and ROS; however, this was not significant. CONCLUSIONS: The consumption of high and low doses of TH demonstrated a comparable response in increasing antioxidant activity and suppressing oxidative stress in female athletes. The time-course effect of TH that provides optimal antioxidant activity and oxidative stress protection was between 1 and 2 h after its consumption. PMID- 28708421 TI - Relationship between Race and the Effect of Fluids on Long-term Mortality after Acute Respiratory Distress Syndrome. Secondary Analysis of the National Heart, Lung, and Blood Institute Fluid and Catheter Treatment Trial. AB - RATIONALE: Short-term follow-up in the Fluid and Catheter Treatment Trial (FACTT) suggested differential mortality by race with conservative fluid management, but no significant interaction. OBJECTIVE: In a post hoc analysis of FACTT including 1-year follow-up, we sought to estimate long-term mortality by race and test for an interaction between fluids and race. METHODS: We performed a post hoc analysis of FACTT and the Economic Analysis of Pulmonary Artery Catheters (EAPAC) study (which included 655 of the 1,000 FACTT patients with near-complete 1-year follow up). We fit a multistate Markov model to estimate 1-year mortality for all non Hispanic black and white randomized FACTT subjects. The model estimated the distribution of time from randomization to hospital discharge or hospital death (available on all patients) and estimated the distribution of time from hospital discharge to death using data on patients after hospital discharge for patients in EAPAC. The 1-year mortality was found by combining these estimates. RESULTS: Non-Hispanic black (n = 217, 25%) or white identified subjects (n = 641, 75%) were included. There was a significant interaction between race and fluid treatment (P = 0.012). One-year mortality was lower for black subjects assigned to conservative fluids (38 vs. 54%; mean mortality difference, 16%; 95% confidence interval, 2-30%; P = 0.027 between conservative and liberal). Conversely, 1-year mortality for white subjects was 35% versus 30% for conservative versus liberal arms (mean mortality difference, -4.8%; 95% confidence interval, -13% to 3%; P = 0.23). CONCLUSIONS: In our cohort, conservative fluid management may have improved 1-year mortality for non-Hispanic black patients with ARDS. However, we found no long-term benefit of conservative fluid management in white subjects. PMID- 28708423 TI - Procalcitonin Test Availability: A Survey of Acute Care Hospitals in Massachusetts. PMID- 28708424 TI - Preparation and evaluation of novel chitosan: gelrite ocular system containing besifloxacin for topical treatment of bacterial conjunctivitis: scintigraphy, ocular irritation and retention assessment. AB - This study was aimed to prepare, characterize and evaluate in situ gel formulations based on a blend of chitosan (CS), polyvinyl alcohol (PVA) and gellan gum (GelriteTM) for a sustained ocular delivery of besifloxacin (BSF). The developed formulations were evaluated for physicochemical properties, gelation time (Tsol-gel), rheological behaviour, antimicrobial efficacy, pharmacokinetic assessment, gamma scintigraphy study and ocular irritation. The results showed BSF sol-gel system were found to be sensitive enough which underwent instantaneous phase transition upon getting physiological stimulation. The ex vivo permeation experiments indicated that the developed formulation was able to enhance the retention of BSF at corneal surface. The HET-CAM confirmed the non irritancy of developed formulation and also demonstrated the ability of ocular protection against strongly irritant substances. The results of gamma scintigraphy study revealed the higher concentration of drug retains at the corneal surface. In addition, optimized BSF sol-gel system showed enhanced anti bacterial activity compared to BSF suspension. PMID- 28708422 TI - The Epithelial Sodium Channel Is a Modifier of the Long-Term Nonprogressive Phenotype Associated with F508del CFTR Mutations. AB - Cystic fibrosis (CF) remains the most lethal genetic disease in the Caucasian population. However, there is great variability in clinical phenotypes and survival times, even among patients harboring the same genotype. We identified five patients with CF and a homozygous F508del mutation in the CFTR gene who were in their fifth or sixth decade of life and had shown minimal changes in lung function over a longitudinal period of more than 20 years. Because of the rarity of this long-term nonprogressive phenotype, we hypothesized these individuals may carry rare genetic variants in modifier genes that ameliorate disease severity. Individuals at the extremes of survival time and lung-function trajectory underwent whole-exome sequencing, and the sequencing data were filtered to include rare missense, stopgain, indel, and splicing variants present with a mean allele frequency of <0.2% in general population databases. Epithelial sodium channel (ENaC) mutants were generated via site-directed mutagenesis and expressed for Xenopus oocyte assays. Four of the five individuals carried extremely rare or never reported variants in the SCNN1D and SCNN1B genes of the ENaC. Separately, an independently enriched rare variant in SCNN1D was identified in the Exome Variant Server database associated with a milder pulmonary disease phenotype. Functional analysis using Xenopus oocytes revealed that two of the three variants in delta-ENaC encoded by SCNN1D exhibited hypomorphic channel activity. Our data suggest a potential role for delta-ENaC in controlling sodium reabsorption in the airways, and advance the plausibility of ENaC as a therapeutic target in CF. PMID- 28708425 TI - Reference Values for the Pediatric Quality of Life Inventory and the Multidimensional Fatigue Scale in Adolescent Athletes by Sport and Sex. AB - BACKGROUND: Effective use of patient-rated outcome measures to facilitate optimal patient care requires an understanding of the reference values of these measures within the population of interest. Little is known about reference values for commonly used patient-rated outcome measures in adolescent athletes. PURPOSE: To determine reference values for the Pediatric Quality of Life Inventory (PedsQL) and the Multidimensional Fatigue Scale (MFS) in adolescent athletes by sport and sex. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: A convenience sample of interscholastic adolescent athletes from 9 sports was used. Participants completed the PedsQL and MFS during one testing session at the start of their sport season. Data were stratified by sport and sex. Dependent variables included the total PedsQL score and the 5 PedsQL subscale scores: physical functioning, psychosocial functioning, emotional functioning, social functioning, and school functioning. Dependent variables for the MFS included 3 subscale scores: general functioning, sleep functioning, and cognitive functioning. Summary statistics were reported for total and subscale scores by sport and sex. RESULTS: Among 3574 males and 1329 female adolescent athletes, the PedsQL scores (100 possible points) generally indicated high levels of health regardless of sport played. Mean PedsQL total and subscales scores ranged from 82.6 to 95.7 for males and 83.9 to 95.2 for females. Mean MFS subscale scores (100 possible points) ranged from 74.2 to 90.9 for males and 72.8 to 87.4 for females. CONCLUSION: Healthy male and female adolescent athletes reported relatively high levels of health on the PedsQL subscales and total scores regardless of sport; no mean scores were lower than 82.6 points for males or 83.9 points for females. On the MFS, males and females tended to report low effect of general and cognitive fatigue regardless of sport; mean scores were higher than 83.5 points for males and 83.8 points for females. Clinically, athletes who score below the reference values for their sport have poorer health status than average adolescent athletes participating in that sport. Scores below reference values may warrant consideration of early intervention or treatment. PMID- 28708426 TI - Phenotypic Characteristics and Genetic Diversity of Salmonella enterica Serotype Derby Isolated from Human Patients and Foods of Animal Origin. AB - Salmonella enterica serotype Derby is among the three most common serotypes of nontyphoidal Salmonella isolated from patients with diarrhea in China. In this study, 133 Salmonella Derby isolates from human patients (n = 74) and foods of animal origin (n = 59) in Shanghai, China, between September 2013 and December 2014, were selected to study its phenotypic characteristics and genetic diversity. The isolates were subjected to antimicrobial susceptibility testing, plasmid replicon typing, virulence profile determination, and molecular subtyping by pulsed-field gel electrophoresis (PFGE). Isolates were frequently resistant to tetracycline (87.22%), sulfisoxazole (74.44%), and streptomycin (62.41%), and a low frequency of resistance was found toward ofloxacin (3.01%), ceftazidime (2.26%), and cefepime (1.50%); in addition, 93 (69.92%) isolates were multidrug resistant. The most common plasmid incompatibility replicon types were the IncF family (FIA, 51.31%; FIC, 27.82%; and FIB, 21.80%) and IncP types (35.34%): these plasmid types may be associated with the spread of antibiotic resistance and virulence genes. All isolates were positive for the Salmonella pathogenicity island (SPI) gene avrA and the fimbrial gene bcfC from among the 10 virulence genes detected, and most of them carried ssaQ (99.25%), mgtC (97.74%), siiD (98.50%), sopB (97.74%), and sopE (96.99%). PFGE showed 68 patterns in nine main clusters at an 85% similarity threshold. Most of the isolates from different sources possessed the same fingerprints or molecular profiles in each cluster, which strongly suggests the possibility that foods of animal origin, especially pork, serve as an important source for human infection. Moreover, this diversity may suggest strains originating from multiple clones. Therefore, surveillance on this serotype should be strengthened to prevent transmission of Salmonella Derby from foods of animal origin, especially pork, to humans. PMID- 28708427 TI - Monitoring and detection of disease recurrence after resection for Crohn's disease: the role of non-invasive fecal biomarkers. AB - INTRODUCTION: Ileocolonoscopy is the gold standard for the diagnosis and assessment of postoperative recurrence in Crohn's disease (CD). Nevertheless, endoscopy is time-consuming and invasive. A minimally invasive and simple screening test would improve patient adherence to examination and provide greater clinical benefit. A number of fecal biomarkers have been evaluated for their utility for the diagnosis and monitoring of inflammatory bowel disease as alternative tests to endoscopy. Area covered: In this review, we focused on the utility of fecal biomarkers in the management of postoperative CD. Our major endeavor was to present an evidence-based assessment of the results of clinical trials on the available data. A literature search was conducted using the Medline. Expert commentary: Calprotectin and lactoferrin, both neutrophil-derived proteins, are the two most frequently used fecal biomarkers in clinical trials and practice. Several studies evaluated the role of these fecal biomarkers in patients with postoperative CD. These studies suggest that fecal calprotectin, and to a lesser degree lactoferrin, are useful in assessing endoscopic severity and in predicting future clinical recurrence after resection for CD. However, large scale, well-designed studies are necessary to rigorously evaluate the role of fecal biomarkers in postoperative CD. PMID- 28708428 TI - Reliability and Correlation of Static and Dynamic Foot Arch Measurement in a Healthy Pediatric Population. AB - BACKGROUND: Measurement of the medial longitudinal foot arch in children is a controversial topic, as there are many different methods without a definite standard procedure. The purpose of this study was to 1) investigate intraday and interrater reliability regarding dynamic arch index and static arch height, 2) explore the correlation between both arch indices, and 3) examine the variation of the medial longitudinal arch at two different times of the day. METHODS: Eighty-six children (mean +/- SD age, 8.9 +/- 1.9 years) participated in the study. Dynamic footprint data were captured with a pedobarographic platform. For static arch measurements, a specially constructed caliper was used to assess heel to-toe length and dorsum height. A mixed model was established to determine reliability and variation. RESULTS: Reliability was found to be excellent for the static arch height index in sitting (intraday, 0.90; interrater, 0.80) and standing positions (0.88 and 0.85) and for the dynamic arch index (both 1.00). There was poor correlation between static and dynamic assessment of the medial longitudinal arch (standing dynamic arch index, r = -0.138; sitting dynamic arch index, r = -0.070). Static measurements were found to be significantly influenced by the time of day (P < .001), whereas the dynamic arch index was unchanged (P = .845). This study revealed some further important findings. The static arch height index is influenced by gender (P = .004), whereas dynamic arch index is influenced by side (P = .011) and body mass index (P < .001). CONCLUSIONS: Dynamic and static foot measurements are reliable for medial longitudinal foot arch assessment in children. The variation of static arch measurements during the day has to be kept in mind. For clinical purposes, static and dynamic arch data should be interpreted separately. PMID- 28708429 TI - Effects of altered photoperiod on circadian clock and lipid metabolism in rats. AB - Disruption of circadian clock timekeeping due to changes in the photoperiod enhances the risk of lipid metabolism disorders and metabolic syndrome. However, the effects of altered photoperiods on the circadian clock and lipid metabolism are not well understood. To explore the effects of altered photoperiods, we developed a rat model where rats were exposed to either short-day or long-day conditions. Our findings demonstrated that altered photoperiods mediated circadian clocks by partly disrupting rhythmicity and shifting phase values of clock genes. We also showed that compared to long-day conditions, rats under short-day conditions exhibited more photoperiodic changes in a variety of physiological outputs related to lipid metabolism, such as significant increases in serum triglyceride (TG), high-density lipoprotein, and leptin levels, as well as increased body weight, fat:weight ratio, and hepatic TG levels. These increments were gained possibly through upregulated expression of forkhead box O1 (FoxO1), which partly mediates the expression of peroxisome proliferator activated receptoralpha (PPARalpha) to increase the expression of phosphoenolpyruvate carboxykinase (PEPCK), peroxisome proliferator-activated receptor-g coactivator-1beta (PGC1beta), and fatty acid synthase (Fasn). In addition, the oscillation rhythms of FoxO1, PEPCK, PGC1beta, and Fasn expression levels in the livers of rats exposed to a short-day photoperiod were more robust than those exposed to a long-day photoperiod. These findings suggest that a change in photoperiod can partly disrupt the circadian rhythmcity of clock genes, impair lipid metabolism, and promote obesity. PMID- 28708431 TI - Comparative efficacy of vasoconstrictor therapies for type 1 hepatorenal syndrome: a network meta-analysis. AB - INTRODUCTION: The outcome of a comparative efficacy and safety of vasoconstrictor therapies for treatment of patients with type 1 hepatorenal syndrome (HRS-1) remain inconclusive. Areas covered: We searched literature databases for randomized controlled trials (RCTs) until 31 January 2016, and included ten eligible RCTs. In conclusion, terlipressin was the most efficacious vasoconstrictor drug for HRS-1, but had a higher probability of causing AEs. Norepinephrine was an attractive alternative to terlipressin and associated with less AEs. Expert commentary: To date, most previous traditional meta-analyses included trials with a limited population and compared terlipressin alone or with albumin against no intervention or albumin. Since different HRS types have different diagnoses and show different responses to vasoconstrictors, it may be questionable to combine data from patients with type 1 and type 2 HRS, which has been reported for most previous meta-analyses. Thus, performing a high-quality network meta-analysis of the existing literature is a valuable way to interrogate published data and to draw conclusions which may inform on the best interventional strategy. PMID- 28708430 TI - Natural extracellular nanovesicles and photodynamic molecules: is there a future for drug delivery? AB - Photodynamic molecules represent an alternative approach for cancer therapy for their property (i) to be photo-reactive; (ii) to be not-toxic for target cells in absence of light; (iii) to accumulate specifically into tumour tissues; (iv) to be activable by a light beam only at the tumour site and (v) to exert cytotoxic activity against tumour cells. However, to date their clinical use is limited by the side effects elicited by systemic administration. Extracellular vesicles are endogenous nanosized-carriers that have been recently introduced as a natural delivery system for therapeutic molecules. We have recently shown the ability of human exosomes to deliver photodynamic molecules. Therefore, this review focussed on extracellular vesicles as a novel strategy for the delivery of photodynamic molecules at cancer sites. This completely new approach may enhance the delivery and decrease the toxicity of photodynamic molecules, therefore, represent the future for photodynamic therapy for cancer treatment. PMID- 28708432 TI - Epigenetic Changes of the ESR1 Gene in Breast Tissue of Healthy Women: A Missing Link with Breast Cancer Risk Factors? AB - BACKGROUND: Reproductive history and obesity are among the well-recognized risk factors in the development of breast cancer, which are partially mediated by the increased exposure of breast tissues to estrogens. However, only a few studies have investigated the link between these risk factors and the pattern of methylation signatures in the breast tissue of healthy women. The role of the estrogen receptor 1 (ESR1) gene hypermethylation is reportedly important in the development of breast cancer. Thus, it is speculated that such ESR1 epigenetic changes may be influenced or shaped by obesity and reproductive history-related factors before and during breast carcinogenesis. MATERIALS AND METHODS: Breast samples were collected from 120 cancer-free women who had undergone cosmetic mammoplasty. DNA was extracted from the breast tissues and, then, the methylation levels at the promoter and exon 1 regions of the ESR1 gene CpG island were determined by using the methylated DNA immunoprecipitation-quantitative PCR assay. RESULTS: The methylation level of the ESR1 promoter observed in women with a body mass index (BMI) >=30 kg/m2 (p <= 0.001) was higher than in the subgroups of women of BMI <25 kg/m2 (p < 0.001) and BMI 25-29 kg/m2 (p < 0.001) and was also higher in postmenopausal women compared with that in premenopausal women (p = 0.046). Pearson correlation coefficient analyses also showed that the high methylation of the ESR1 promoter was correlated with increasing age (r = -0.246, p = 0.007) and BMI (r = -0.331, p <= 0.001). Finally, linear multivariate regression revealed a significant association between high methylation rates in the ESR1 gene promoter and increased BMI (beta = -0.285, 95% CI = -0.457 to 0.113, p = 0.001). Furthermore, a higher methylation level at the ESR1 gene exon 1 was found in the BMI >= 30 kg/m2 subgroup compared to the BMI 25-29 kg/m2 subgroup (p = 0.023). CONCLUSION: These findings provide new hints about the relationship between epigenetic changes within the ESR1 gene CpG island and postmenopausal obesity and aging in cancer-free women. In terms of lifestyle intervention opportunities, this study also highlights the significance and feasibility of such interventions for BMI as a modifiable risk factor. PMID- 28708433 TI - Physical Health Outcomes in Preschoolers with Prior Authorization for Antipsychotics. AB - OBJECTIVE: To examine incidence of adverse health outcomes and associated factors among preschoolers (under age 6) who received antipsychotic treatment through the Florida Medicaid Prior Authorization (PA) program. METHODS: Using Florida's PA registry linked to the state's Medicaid claims data, we ascertained incident outcomes during PA-approved antipsychotic use between April 2008 and September 2015 (7.5 years). Six outcomes associated with use of antipsychotics included: diabetes, obesity, hyperlipidemia, hyperprolactinemia, cardiovascular disease (CVD) (including hypertension, ventricular arrhythmia, and other CVDs), and extrapyramidal symptoms (EPS) (including dystonia, akathisia, parkinsonism, and tardive dyskinesia). Outcome-specific incidences were stratified by short-term (<=1 year) and long-term (>1-7 years) antipsychotic use. We used multivariate modified Poisson regressions to determine factors associated with these outcomes among preschoolers. RESULTS: The overall crude incidence during PA-approved antipsychotic use was highest for EPS and obesity (57 and 19 cases/1000 children years, respectively). The rate of these two outcomes differed by duration of antipsychotic use. We observed a higher obesity (23.8 vs. 9.6, p < 0.001) and dystonia incidence (7.2 vs. 2.5, p < 0.05), but lower akathisia incidence (44.4 vs. 60.6, p < 0.05) among long-term antipsychotic users compared with short-term users. Five outcomes-ventricular arrhythmia, other cardiovascular side effects, hyperprolactinemia, parkinsonism, and tardive dyskinesia-occurred rarely (<2.0/1000 children-years). Preschoolers who were younger at baseline (<=2 years old vs. 4-5 years old) and Black (vs. White) were at a higher risk of EPS. CONCLUSION: Risk for EPS and obesity deserves clinical attention during antipsychotic treatment among preschoolers. Controlled studies that allow interpretation of these incidence rates in the context of background risk and that formally quantify the incremental risk associated with antipsychotic initiation during early childhood are needed. PMID- 28708435 TI - High-throughput assay development for combined in vitro toxicity screening of hit compounds and their metabolites in early drug-discovery stage. PMID- 28708434 TI - Epithelial Cells Induce a Cyclo-Oxygenase-1-Dependent Endogenous Reduction in Airway Smooth Muscle Contractile Phenotype. AB - Airway smooth muscle cells (ASMCs) are phenotypically regulated to exist in either a proliferative or a contractile state. However, the influence of other airway structural cell types on ASMC phenotype is largely unknown. Although epithelial cells are known to drive ASM proliferation, their effects on the contractile phenotype are uncertain. In the current study, we tested the hypothesis that epithelial cells reduce the contractile phenotype of ASMCs. To do so, we measured force production by traction microscopy, gene and protein expression, as well as calcium release by Fura-2 ratiometric imaging. ASMCs incubated with epithelial-derived medium produced less force after histamine stimulation. We observed reduced expression of myocardin, alpha-smooth muscle actin, and calponin within ASMCs after coculture with epithelial cells. Peak calcium release in response to histamine was diminished, and depended on the synthesis of cyclo-oxygenase-1 products by ASM and on prostaglandin E receptors 2 and 4. Together, these in vitro results demonstrate that epithelial cells have the capacity to coordinately reduce ASM contraction by functional antagonism and by reduction of the expression of certain contractile proteins. PMID- 28708436 TI - Giving consideration to scientific validation in Japanese drug application by Japan Bioanalysis Forum discussion group. PMID- 28708437 TI - Are hearing aid owners able to identify and self-report handling difficulties? A pilot study. AB - OBJECTIVE: Although clinician administered surveys evaluating hearing aid handling skills exist, the development of a self-administered version may reduce clinical load, save consultation time, and facilitate more frequent use than face to-face consultations allow. However, there is currently no evidence to support whether hearing aid owners can accurately self-report hearing aid handling skills via self-report survey that systematically evaluates the ability to accurately perform the individual aspects of hearing aid handling required for effective hearing aid management. DESIGN: An explorative pilot study using a prospective research design. STUDY SAMPLE: Nineteen adult hearing aid owners, aged between 65 and 93 years. RESULTS: The self-administered survey demonstrated high sensitivity when compared with clinician evaluation of skills, with 93% of participants accurately self-identifying and reporting whether hearing aid handling skill training was required. CONCLUSIONS: Hearing aid owners are able to accurately self-report hearing aid handling difficulties when provided with an itemised list of skills. PMID- 28708438 TI - Can Occam's razor help physicians cut out the unnecessary data? PMID- 28708439 TI - Perspectives: Spiritual Metrics Inform and Transform Recovery-oriented Trauma informed Direct Care. PMID- 28708440 TI - Model Calculations of Regional Deposition and Disposition for Single Doses of Inhaled Liposomal and Dry Powder Ciprofloxacin. AB - BACKGROUND: Model predictions of regional deposition in the respiratory tract are useful in assessing factors that influence the effectiveness of aerosol delivery. Regional deposition models have previously been coupled with models of mucous production and clearance to estimate initial concentrations of drug deposited in the airway surface liquid (ASL) lining tracheobronchial airways. METHODS: Established models of regional deposition and ASL volumes were used to provide input to a new model evaluating the disposition of drug resulting from dissolution or release, absorption, and mucociliary clearance. Additional modeling of oral absorption, distribution, and elimination allowed prediction of systemic exposure. Herein, predicted ASL and plasma concentrations of free (dissolved or unencapsulated) ciprofloxacin over time are reported for a healthy, adult lung model following inhalation of single doses of nebulized liposomal (6 mL of liposomal ciprofloxacin for inhalation, 50 mg/mL, or 6 mL of Pulmaquin, 210 mg; Aradigm) and dry powder (32.5 and 65 mg doses; Bayer) formulations. RESULTS: Over a range of mucous production rates and tracheal clearance velocities, peak ASL concentrations of free ciprofloxacin were consistently greater for Pulmaquin than for other formulations investigated, owing to the presence of free drug in the nebulized Pulmaquin formulation. The time that ASL concentrations of free drug remained above the minimum inhibitory concentration for Pseudomonas aeruginosa was similar for all four formulations. Predicted plasma ciprofloxacin concentration profiles were in good agreement with available data from Phase I trials in healthy volunteers. CONCLUSIONS: Predictions of ASL drug concentrations over time are valuable in elucidating the roles of deposition, drug release or dissolution, and disposition on the effectiveness of inhaled aerosol therapies. For inhaled ciprofloxacin, the present results predict similar ASL concentrations of free drug over time following single doses of inhaled liposomal and dry powder formulations. The impact of multiple doses and airway disease warrants further consideration. PMID- 28708441 TI - Safe monsplasty technique. AB - INTRODUCTION: To improve their health and quality of life, obese patients undergo consultation after weight loss. In these patients, the sub-umbilical abdominal and pubic regions are often characterized by redundant skin, creating aesthetic and functional discomfort. Monsplasty is an important step in abdominoplasty or bodylift procedures. We report on an original technique used to correct deformity in the pubic region following weight loss. METHODS: All interventions were performed by the same surgeon between April and December 2015. On stretched skin, we drew two lines 5 cm lateral to the median line on both sides and connected them with the arc of a circle placed 7 cm from the vulvar fork. Then, monsplasty marks extend to abdominal fold. During lower abdominal contouring, we performed monsplasty with three separate stitches between the camper fascia and aponeurosis of the abdominal muscle. The aim was to bring tension to the pubic region without additional surgical procedure. RESULTS: We report on 21 consecutive cases of monsplasty following lower trunk contouring. No reoperation was performed due to complication or aesthetic demand (no under- or over-correction occurred). No complication (e.g. edema, seroma, disturbance of sensibility) was observed in the pubic area. The results were stable 1 year after surgery. CONCLUSIONS: We report on a simple, rapid, and reproducible monsplasty technique for all stages of Pittsburgh classifications, which achieved favorable results with no complication. We recommend performance of this effective technique simultaneously with abdominoplasty or bodylift procedures. LEVEL OF EVIDENCE: IV. PMID- 28708442 TI - Relationship between laryngoscopic and pathological characteristics of vocal cords leukoplakia. AB - BACKGROUND: To explore the relationship between the morphological characteristics and pathological diagnosis of vocal cords leukoplakia. METHODS: A total of 1635 vocal cords were collected. The morphology were classified into three types (Type I, II, III): flat and smooth; bulge and smooth; bulge and rough. The pathological reports were classified into five groups: no dysplasia, mild dysplasia, moderate dysplasia, severe dysplasia and cancerization. The number of the patients or vocal cords in each type and group was counted and their ratio was compared. RESULTS: In Type I, the number of vocal cord in Group A group was 2.2 and 2.6 times of the one in Type II and Type III respectively. In Type II, the mild, moderate dysplasia ratio was higher than those in Type I. In Type III group the ratio of severe dysplasia was 2.6 and 5.5 times of the one in Type II and Type I respectively. The ratio of Group E in Type III was 2.7 and 7.9 times of the one of Type II and Type I. The result was significant (pearson Chi-square value was 517.6, p = .00). CONCLUSIONS: The pathological results of vocal cord leukoplakia can be evaluated by morphology in most cases. PMID- 28708443 TI - Regulatory Approaches and Considerations in Establishing Bioequivalence of Inhaled Compounds. AB - To be considered bioequivalent to their branded counterparts, generic drugs must meet the standards for bioequivalence (BE) described by the regulatory agencies. While BE of generic inhalational drugs can be evaluated using a similar approach as that for oral dosage from products or drugs that are delivered systemically, the approach is insufficient to address the complexities of inhalational products (e.g., localized site of action, device-patient interface). Therefore, more considerations are needed and caution should be applied when evaluating BE of inhaled compounds. The purpose of this review is to highlight the considerations and challenges in establishing BE of inhaled compounds by (1) outlining the current regulatory approaches (from Health Canada, the U.S. Food and Drug Administration, and the European Medicines Agency) to assess BE for subsequent entry inhaled products (SEIPs) and (2) reviewing the literature pertaining to testing considerations of SEIPs to establish BE. PMID- 28708444 TI - Counselling users of hearing technology: a comprehensive literature review. AB - OBJECTIVE: The purpose of this review is to determine the scope of peer-reviewed empirical research related to counselling in audiology with patients using hearing technology and to identify limitations and gaps to guide recommendations for future research. DESIGN: A rapid evidence assessment was used to identify relevant articles for the review. STUDY SAMPLE: Eighteen articles met the inclusion criteria. RESULTS: Three themes were identified: (1) audiologist counselling perspectives, (2) counselling communication trends in practice and (3) audiologist experiences with professional training and reported patient outcomes. Findings revealed audiologists are more confident providing information than counselling that addresses adjustment aspects, and other communication gaps have been observed. CONCLUSIONS: There is limited research related to counselling in audiology. Audiologists continue to report a need for more training in counselling in their graduate programmes. Additional research is needed to determine effective ways to implement counselling in practice and to improve graduate student supervision for the development of counselling competencies and confidence in using skills in practice. PMID- 28708445 TI - Evaluation of YAP signaling in a rat tympanic membrane under a continuous negative pressure load and in human middle ear cholesteatoma. AB - OBJECTIVES: Mechanotransduction plays an important role in cell-proliferative activities. Negative pressure in the middle ear is thought to be an important factor related to the etiology of acquired middle ear cholesteatoma. However, the correlation between negative pressure in the middle ear and the mechanism of middle ear cholesteatoma formation remains unclear. In this study, we investigated the expression of key molecules for mechanotransduction immunohistochemically. METHODS: An immunohistochemical analysis was performed using anti-Wnt5a (a marker of alternative Wnt signaling), -Yes-associated protein (YAP) (a marker of mechanosensing) and -pYAP (phosphorylated YAP at Ser 127: inactivated YAP) antibody in the tympanic membrane (TM) under a negative pressure load and in human middle ear cholesteatoma tissues. RESULTS: The number of Wnt5a positive cells had increased and YAP nuclear translocation was observed in epithelial and mesenchymal cells in the pars flaccida (PF) of the TM under a negative-pressure load and in human middle ear cholesteatoma tissues. CONCLUSIONS: We demonstrated that negative pressure in the middle ear might possibly induce cell proliferation PF of TM in response to mechanical force (mechanotransduction) through YAP nuclear translocation mediated by alternative Wnt signaling, thus affecting human middle ear cholesteatoma formation. PMID- 28708446 TI - ELISA reagent coverage evaluation by affinity purification tandem mass spectrometry. AB - Host cell proteins (HCPs) must be adequately removed from recombinant therapeutics by downstream processing to ensure patient safety, product quality, and regulatory compliance. HCP process clearance is typically monitored by enzyme linked immunosorbent assay (ELISA) using a polyclonal reagent. Recently, mass spectrometry (MS) has been used to identify specific HCP process impurities and monitor their clearance. Despite this capability, ELISA remains the preferred analytical approach due to its simplicity and throughput. There are, however, inherent difficulties reconciling the protein-centric results of MS characterization with ELISA, or providing assurance that ELISA has acceptable coverage against all process-specific HCP impurities that could pose safety or efficacy risks. Here, we describe efficient determination of ELISA reagent coverage by proteomic analysis following affinity purification with a polyclonal anti-HCP reagent (AP-MS). The resulting HCP identifications can be compared with the actual downstream process impurities for a given process to enable a highly focused assessment of ELISA reagent suitability. We illustrate the utility of this approach by performing coverage evaluation of an anti-HCP polyclonal against both an HCP immunogen and the downstream HCP impurities identified in a therapeutic monoclonal antibody after Protein A purification. The overall goal is to strategically implement affinity-based mass spectrometry as part of a holistic framework for evaluating HCP process clearance, ELISA reagent coverage, and process clearance risks. We envision coverage analysis by AP-MS will further enable a framework for HCP impurity analysis driven by characterization of actual product-specific process impurities, complimenting analytical methods centered on consideration of the total host cell proteome. PMID- 28708447 TI - Coverage for Gender-Affirming Care: Making Health Insurance Work for Transgender Americans. AB - Many transgender Americans continue to remain uninsured or are underinsured because of payers' refusal to cover medically necessary, gender-affirming healthcare services-such as hormone therapy, mental health counseling, and reconstructive surgeries. Coverage refusal results in higher costs and poor health outcomes among transgender people who cannot access gender-affirming care. Research into the value of health insurance coverage for gender-affirming care for transgender individuals shows that the health benefits far outweigh the costs of insuring transition procedures. Although the Affordable Care Act explicitly protects health insurance for transgender individuals, these laws are being threatened; therefore, this article reviews their importance to transgender inclusive healthcare coverage. PMID- 28708449 TI - Promoting a Policy and Research Agenda to Protect Lesbian, Gay, Bisexual, and Transgender Health in the New Political Era. PMID- 28708450 TI - A Comparison of Kenyan Biomphalaria pfeifferi and B. Sudanica as Vectors for Schistosoma mansoni, Including a Discussion of the Need to Better Understand the Effects of Snail Breeding Systems on Transmission. AB - In Kenya, schistosomes infect an estimated 6 million people with >30 million people at risk of infection. We compared compatibility with, and ability to support and perpetuate, Schistosoma mansoni of Biomphalaria pfeifferi and Biomphalaria sudanica, 2 prominent freshwater snail species involved in schistosomiasis transmission in Kenya. Field-derived B. pfeifferi (from a stream in Mwea, central Kenya) and B. sudanica (from Nawa, Lake Victoria, in western Kenya) were exposed to S. mansoni miracidia isolated from fecal samples of naturally infected humans from Mwea or Nawa. Juvenile (<6 mm shell diameter), young adult (6-9 mm), and adult snails (>9 mm) were each exposed to a single miracidium. Schistosoma mansoni developed faster and consistently had higher infection rates (39.6-80.7%) in B. pfeifferi than in B. sudanica (2.4-21.5%), regardless of the source of S. mansoni or the size of the snails used. Schistosoma mansoni from Nawa produced higher infection rates in both B. pfeifferi and B. sudanica than did S. mansoni from Mwea. Mean daily cercariae production was greater for B. pfeifferi exposed to sympatric than allopatric S. mansoni (583-1,686 vs. 392-1,232), and mean daily cercariae production among B. sudanica were consistently low (50-590) with no significant differences between sympatric or allopatric combinations. Both non-miracidia-exposed and miracidia exposed B. pfeifferi had higher mortality rates than for B. sudanica, but mean survival time of shedding snails (9.3-13.7 wk) did not differ significantly between the 2 species. A small proportion (1.5%) of the cercariae shedding B. pfeifferi survived up to 40 wk post-exposure. Biomphalaria pfeifferi was more likely to become infected and to shed more cercariae than B. sudanica, suggesting that the risk per individual snail of perpetuating transmission in Kenyan streams or lacustrine habitats may differ considerably. High infection rates exhibited by the preferential self-fertilizing B. pfeifferi relative to the out-crossing B. sudanica point to the need to investigate further the role of host breeding systems in influencing transmission of schistosomiasis by snail hosts. PMID- 28708448 TI - Quick or quality? How mRNA escapes nuclear quality control during stress. AB - Understanding the mechanisms for mRNA production under normal conditions and in response to cytotoxic stresses has been subject of numerous studies for several decades. The shutdown of canonical mRNA transcription, export and translation is required to have enough free resources for the immediate production of heat shock proteins that act as chaperones to sustain cellular processes. In recent work we uncovered a simple mechanism, in which the export block of regular mRNAs and a fast export of heat shock mRNAs is achieved by deactivation of the nuclear mRNA quality control mediated by the guard proteins. In this point of view we combine long known data with recently gathered information that support this novel model, in which cells omit quality control of stress responsive transcripts to ensure survival. PMID- 28708451 TI - Enhanced Implant Case Planning Using Dual Scan CBCT of an Existing Prosthesis: Report of a Case. PMID- 28708452 TI - From rakhi to romance: negotiating 'acceptable' relationships in co-educational secondary schools in New Delhi, India. AB - Based on a multi-method study conducted with middle-class young people (aged 15 17) in three secondary schools in New Delhi, India, this paper focuses on heterosocial dynamics within school peer cultures as an important site of learning about gender and sexuality. Findings indicate that young people negotiate and adapt rakhi (brother-sister) relationships to form less strictly platonic heterosocial friendships, which leave open the possibility of romance. Students' preferences for certain heterosocial relationships are considered within the context of wider cultural narratives. For example, students often rejected rakhi relationships, tied to traditional, conservative values, in favour of heterosocial friendships associated with more modern and desirable social patterns. Moreover, students' own definitions of acceptable heterosocial interactions within peer cultures suggest that they are adept at negotiating norms of gender segregation that are enforced in co-educational schools. In contrast to other formal and informal sources of sexual learning available to them, experiences and stories of romances circulating in schools seemed to offer students alternative, more positive ways of understanding teenage intimacy and sexuality. PMID- 28708453 TI - Virulence and Antibiotic Resistance of Enterococci Isolated from Healthy Breastfed Infants. AB - Pathogenic ability has been extensively studied in clinical enterococci, but to a lesser extent in community-derived ones. Most studies to date in enterococci from healthy infants have been focused on Enterococcus faecalis, despite the growing concern about nosocomial infections caused by E. faecium. In this work, we studied the antibiotic resistance and virulence determinants of 26 E. faecalis and 15 E. faecium intestinal isolates from Spanish healthy breastfed infants. Overall, commensal enterococci studied contained antibiotic resistance and virulence genes, although their patterns were not according to those described for antibiotic-resistant hospital-associated enterococci. None of the isolates was resistant to vancomycin, although the majority showed resistance to some antibiotics. E. faecalis isolates harbored considerably more virulence determinants than E. faecium isolates, but some genes linked to colonization were abundant in both species. Hemolysin activity was not detected in any of the isolates; and the gelatinase gene, when present, was silent in E. faecium, whereas gelatinase activity occurred in half of the E. faecalis isolates studied. These results suggest an ambivalent role of some virulence determinants as elements of pathogenesis. PMID- 28708454 TI - Improving the production of S-adenosyl-L-methionine in Escherichia coli by overexpressing metk. AB - S-adenosyl-L-methionine (SAM) has important applications in many fields including chemical therapy and pharmaceutical industry. In this study, the recombinant Escherichia coli strain was constructed for effective production of SAM by introducing the SAM synthase gene (metK). This strain produced 34.5 mg/L of SAM in basic medium in shake flask. Yeast extract, pH, and loaded volume had a significant positive effect on the yield of SAM. Their optimal values were 35 g/L, 7.5, and 30 mL, respectively. The final conditions optimized were as follows: glucose 20, g/L; peptone, 40 g/L; yeast extract, 35 g/L; NaCl, 10 g/L; MgSO4, 1.2 g/L; L-methionine, 1 g/L; rotate speed, 220 rpm; loaded volume, 30 mL; inoculation, 1%; temperature, 37 degrees C; and initial medium, pH 7.5. The recombinant strain produced 128.2 mg/L of SAM under the above conditions in shake flask. The production of SAM in a 5 L fermentor was also investigated. The maximal biomass of the recombinant strain was 60.4 g/L after the cells were cultured for 20 hr, and the highest yield of SAM was 300.9 mg/L after induction for 8 hr in a 5 L fermentor. This study provides a good foundation for the future production and use of SAM. PMID- 28708455 TI - Functionality of tRNAs encoded in a mobile genetic element from an acidophilic bacterium. AB - The genome of the acidophilic, bioleaching bacterium Acidithiobacillus ferrooxidans, strain ATCC 23270, contains 95 predicted tRNA genes. Thirty-six of these genes (all 20 species) are clustered within an actively excising integrative-conjugative element (ICEAfe1). We speculated that these tRNA genes might have a role in adapting the bacterial tRNA pool to the codon usage of ICEAfe1 genes. To answer this question, we performed theoretical calculations of the global tRNA adaptation index to the entire A. ferrooxidans genome with and without the ICEAfe1 encoded tRNA genes. Based on these calculations, we observed that tRNAs encoded in ICEAfe1 negatively contribute to adapt the tRNA pool to the codon use in A. ferrooxidans. Although some of the tRNAs encoded in ICEAfe1 are functional in aminoacylation or protein synthesis, we found that they are expressed at low levels. These findings, along with the identification of a tRNA like RNA encoded in the same cluster, led us to speculate that tRNA genes encoded in the mobile genetic element ICEAfe1 might have acquired mutations that would result in either inactivation or the acquisition of new functions. PMID- 28708457 TI - Assessment of Self-Perceived Knowledge in e-Health Among Undergraduate Students. AB - OBJECTIVE: Growing research evidence shows the value of e-health in healthcare delivery. While efforts are made to implement e-health in mainstream healthcare, relatively modest attention has been paid to develop e-health knowledge and skills in health practitioners. Using a pre-post design, in this study, we aimed to examine self-reported knowledge and perception changes associated with an e health course offered to university undergraduate students in Australia. METHODS: Pre- and postsurveys were used to examine self-reported knowledge and perception changes relating to e-health among undergraduate students. All students enrolled in an e-health course (n = 165) were asked to complete an identical survey in the first and last week of the semester. RESULTS: The response rates were 53% (n = 87) for the presurvey and 52% (n = 85) for the postsurvey. For all items, changes in self-reported knowledge and perception were statistically significant in pre/post median scores and dichotomized negative/positive proportions. CONCLUSIONS: Students believed the course helped them to improve their knowledge regarding key aspects of e-health. It is important to design an e-health curriculum targeting competencies to provide necessary knowledge and skills to help students practice e-health in their professional careers. PMID- 28708456 TI - Mosquito-Borne Diseases and Omics: Tissue-Restricted Expression and Alternative Splicing Revealed by Transcriptome Profiling of Anopheles stephensi. AB - Malaria is one of the most debilitating mosquito-borne diseases with high global health burdens. While much of the research on malaria and mosquito-borne diseases is focused on Africa, Southeast Asia accounts for a sizable portion of the global burden of malaria. Moreover, about 50% of the Asian malaria incidence and deaths have been from India. A promising development in this context is that the completion of genome sequence of Anopheles stephensi, a major malaria vector in Asia, offers new opportunities for global health innovation, including the progress in deciphering the vectorial ability of this mosquito species at a molecular level. Moving forward, tissue-based expression profiling would be the next obvious step in understanding gene functions of An. stephensi. We report in this article, to the best of our knowledge, the first in-depth study on tissue based transcriptomic profile of four important organs (midgut, Malpighian tubules, fat body, and ovary) of adult female An. stephensi mosquitoes. In all, we identified over 20,000 transcripts corresponding to more than 12,000 gene loci from these four tissues. We present and discuss the tissue-based expression profiles of majority of annotated transcripts in An. stephensi genome, and the dynamics of their alternative splicing in these tissues, in this study. The domain-based Gene Ontology analysis of the differentially expressed transcripts in each of the mosquito tissue indicated enrichment of transcripts with proteolytic activity in midgut; transporter activity in Malpighian tubules; cell cycle, DNA replication, and repair activities in ovaries; and oxidoreductase activities in fat body. Tissue-based study of transcript expression and gene functions markedly enhances our understanding of this important malaria vector, and in turn, offers rationales for further studies on vectorial ability and identification of novel molecular targets to intercept malaria transmission. PMID- 28708458 TI - Effectiveness of a Double-Carbapenem Regimen in a KPC-Producing Klebsiella pneumoniae Infection in an Immunocompromised Patient. AB - The progressive increase of infections produced by extensively drug-resistant carbapenemase-producing Klebsiella pneumoniae (XDR-CPKP) represents an important threat to public health. Unfortunately, optimal therapeutic options are scarce. Retrospective studies have recommended combined therapy with more than one antibiotic and, more recently, a double-carbapenem regimen has been reported to be an effective alternative therapy. Here, we describe an episode of sepsis in an immunocompromised patient after allogeneic hematopoietic stem cell transplantation, caused by an XDR-CPKP. Several in vitro synergy tests revealed a synergistic effect combining ertapenem and meropenem, which were used as combination therapy achieving clinical and microbiological success. PMID- 28708459 TI - The combined effect of Macondo oil and corexit on sheepshead minnow (Cyprinodon variegatus) during early development. AB - During the 2010 Deepwater Horizon (DWH), oil spill an estimated 800 million L oil and 7.9 million L dispersant entered the environment. The potential adverse effects of the oil-dispersant mixture are poorly understood. The aim of this study was to investigate the impacts of this mixture on early development of sheepshead minnow (Cyprinodon variegatus), a small-bodied estuarine fish commonly found in the area affected by the DWH spill. Embryos were exposed to a chemically enhanced water accommodated fraction (CEWAF; 10:1 mixture of Macondo oil; Corexit 9500) for 48 hr, after which organisms were maintained in uncontaminated water for an additional 8 days. Impacts were assessed on embryonic (heart rate, development of eye pigmentation, embryonic movement measured) and larval (time to hatch, larval survival, standard length, and cyp1a gene expression) development. No significant alterations were found in survival, time to hatch or cyp1a at the end of the experiment. However, CEWAF induced significant decreases in heart rate of embryos, delayed development of eye pigmentation, reduced embryonic movement, and diminished standard length. These results indicate potential sublethal adverse consequences attributed to CEWAF exposure during early development, even in the absence of maintained cyp1a induction or survival rate, potentially affecting the fitness of organisms later in life. PMID- 28708460 TI - Tolerance to Hypercarbia Is Repeatable and Related to a Component of the Metabolic Phenotype in a Freshwater Fish. AB - Freshwater fish may be exposed to high levels of carbon dioxide (CO2) because of several actions, including anesthesia and high levels of aquatic respiration and potentially as the result of using high-CO2 plumes as a barrier to the movements of invasive fishes. Metabolic phenotype can potentially drive how freshwater fish respond to high CO2. We therefore quantified how tolerance (measured using time to equilibrium loss [ELT]) was driven by metabolic phenotype in a cosmopolitan freshwater fish species, Micropterus salmoides. ELT was repeatable, with 60% of the variance across trials attributable to individual differences. For each fish, standard metabolic rate and maximum metabolic rate were measured using respirometers and time to exhaustion after a chase test was recorded. Fish with high anaerobic performance were less tolerant to elevated CO2, potentially as a result of preexisting metabolic acidosis. Standard metabolic rate and aerobic scope did not predict ELT. Our findings define which fish may be more vulnerable to high CO2, a potential mechanism for this tolerance, and show that tolerance to high CO2 may be acted on by natural selection. Should freshwater ecosystems become elevated in CO2, by either natural means or anthropogenic means, it is possible that there is potential for heritable selection of CO2 tolerance, evidenced by the fact that ELT was found to be repeatable. PMID- 28708461 TI - Effects of Four Different Crown Materials on the Peri-Implant Clinical Parameters and Composition of Peri-Implant Crevicular Fluid. AB - This study aimed to identify the preferred crown material by measuring the peri implant clinical parameters and the concentrations of receptor activator of nuclear factor-kappaB ligand (RANKL), osteoprotegerin (OPG), and calcium in peri implant crevicular fluid (PICF) with 4 different crown materials. A total of 196 patients with a single missing posterior tooth received crown restoration with cobalt-chromium (Co-Cr) porcelain-fused-to-metal (PFM; n = 50), aurum platinum (Au-Pt) PFM (n = 48), titanium (Ti) PFM (n = 52), or zirconia (Zi) all-ceramic crown (n = 46). Fifty-one natural counterpart teeth served as controls. Before and 12 months after restoration, the PICF was collected, and the concentrations of RANKL, OPG, and calcium were quantified. The peri-implant clinical parameters (plaque index, bleeding on probing, and probing depth [PD]) and gingival crevicular fluid (GCF) volumes were assessed. Twelve months after restoration, the PD and GCF volumes for the 4 experimental groups were significantly greater than those for the control group and before restoration. The Co-Cr group showed the greatest PD, GCF volume, RANKL/OPG, RANKL, and calcium ion concentration, followed by the Au-Pt group. The Ti group had the highest OPG concentration, followed by the Zi group. The RANKL and calcium ion concentrations of the Ti and Zi groups were the smallest. The Ti group had the smallest RANKL/OPG ratio, followed by the Zi group. Different crown materials differentially affected the PD, volume, RANKL/OPG ratio, OPG, RANKL, and calcium concentration. Among the 4 tested crown materials, Zi and Ti are preferred. However, some limitations of the present study should be considered. PMID- 28708464 TI - Effect of Whole Body Hypothermia on Surfactant Function When Amniotic Fluid is Meconium Stained. AB - We provide the first complete biophysical study of surfactant by captive bubble surfactometry from a neonate with meconium-stained amniotic fluid under controlled whole body hypothermia. Surfactant function improves after 48 hours of hypothermia, as surfactant cholesterol decreases. These findings partially explain positive effect of hypothermia on respiratory outcomes during meconium aspiration syndrome. A larger study including several neonates with or without lung disease is being conducted to better define the effect of hypothermia on surfactant function. PMID- 28708462 TI - Heterogeneous Enhancement Patterns of Tumor-adjacent Parenchyma at MR Imaging Are Associated with Dysregulated Signaling Pathways and Poor Survival in Breast Cancer. AB - Purpose To identify the molecular basis of quantitative imaging characteristics of tumor-adjacent parenchyma at dynamic contrast material-enhanced magnetic resonance (MR) imaging and to evaluate their prognostic value in breast cancer. Materials and Methods In this institutional review board-approved, HIPAA compliant study, 10 quantitative imaging features depicting tumor-adjacent parenchymal enhancement patterns were extracted and screened for prognostic features in a discovery cohort of 60 patients. By using data from The Cancer Genome Atlas (TCGA), a radiogenomic map for the tumor-adjacent parenchymal tissue was created and molecular pathways associated with prognostic parenchymal imaging features were identified. Furthermore, a multigene signature of the parenchymal imaging feature was built in a training cohort (n = 126), and its prognostic relevance was evaluated in two independent cohorts (n = 879 and 159). Results One image feature measuring heterogeneity (ie, information measure of correlation) was significantly associated with prognosis (false-discovery rate < 0.1), and at a cutoff of 0.57 stratified patients into two groups with different recurrence free survival rates (log-rank P = .024). The tumor necrosis factor signaling pathway was identified as the top enriched pathway (hypergeometric P < .0001) among genes associated with the image feature. A 73-gene signature based on the tumor profiles in TCGA achieved good association with the tumor-adjacent parenchymal image feature (R2 = 0.873), which stratified patients into groups regarding recurrence-free survival (log-rank P = .029) and overall survival (log rank P = .042) in an independent TCGA cohort. The prognostic value was confirmed in another independent cohort (Gene Expression Omnibus GSE 1456), with log-rank P = .00058 for recurrence-free survival and log-rank P = .0026 for overall survival. Conclusion Heterogeneous enhancement patterns of tumor-adjacent parenchyma at MR imaging are associated with the tumor necrosis signaling pathway and poor survival in breast cancer. (c) RSNA, 2017 Online supplemental material is available for this article. PMID- 28708463 TI - Epidemiological Trends Observed from Molecular Characterization of Methicillin Resistant Staphylococcus aureus Isolates from Blood Cultures at a Japanese University Hospital, 2012-2015. AB - Despite increasing reports of skin and soft tissue infections caused by community associated methicillin-resistant Staphylococcus aureus (CA-MRSA) in Japan, the extent to which these strains cause nosocomial infections remains unknown, and this is especially true for bloodstream infections. In this study, we molecularly characterized MRSA isolates from Japanese blood samples. Among the 151 MRSA isolates collected from 53 medical facilities in 2011, 115 (76%) and 30 (20%) were classified as staphylococcal cassette chromosome mec (SCCmec) types II and IV, respectively, while the Panton-Valentine leukocidin (PVL) gene was detected in only two isolates. Among 66 MRSA isolates collected from Tokyo Medical University Hospital between 2012 and 2015, 43 (65%) and 20 (30%) were classifiable as SCCmec types II and IV, respectively. In 2015, highly virulent strains, such as the SCCmec type IV/PVL and SCCmec type IV/ toxic shock syndrome toxin-1 clonal types, increased in number. Therefore, the SCCmec type IV clone may cause invasive infections not only in community settings but also in healthcare settings in Japan. PMID- 28708465 TI - Synthesis, characterization, redox behavior, DNA and protein binding and antibacterial activity studies of ruthenium(II) complexes of bidentate schiff bases. AB - Two new ruthenium(II) complexes of Schiff base ligands (L) derived from cinnamaldehyde and ethylenediamine formulated as [Ru(L)(bpy)2](ClO4)2, where L1 = N,N'-bis(4-nitrocinnamald-ehyde)ethylenediamine and L2 = N,N'-bis(2 nitrocinnamaldehyde)-ethylenediamine for complex 1 and 2, respectively, were isolated in pure form. The complexes were characterized by physicochemical and spectroscopic methods. The electrochemical behavior of the complexes showed the Ru(III)/Ru(II) couple at different potentials with quasi-reversible voltammograms. The interaction of the complexes with calf thymus DNA (CT-DNA) using absorption, emission spectral studies and electrochemical techniques have been used to determine the binding constant, Kb and the linear Stern-Volmer quenching constant, KSV. The results indicate that the ruthenium(II) complexes interact with CT-DNA strongly in a groove binding mode. The interactions of bovine serum albumin (BSA) with the complexes were also investigated with the help of absorption and fluorescence spectroscopy tools. Absorption spectroscopy proved the formation of a ground state BSA-[Ru(L)(bpy)2](ClO4)2 complex. The antibacterial study showed that the Ru(II) complexes (1 and 2) have better activity than the standard antibiotics but weak activity than the ligands. PMID- 28708467 TI - Gender differences in surgical treatment of patients with cleft lip and palate. AB - Numerous gender-based differences in medical treatment have been recognized due to conscious or unconscious perceptions, i.e. gender bias. The aim of the present study was to investigate whether gender differences exist in the surgical treatment of patients with cleft lip and palate (CLP) anomalies. This study is a retrospective review of 235 consecutive patients with non-syndromic unilateral CLP or bilateral CLP born between 1966 and 1986. Each chart was reviewed, and 2178 surgical procedures were registered and categorized as primary surgery (primary lip, palatal and alveolar repair) or secondary surgery (aesthetic and functional revision). Different surgical procedures could be performed during the same surgical session. The number of surgeries performed was analysed and compared between genders. The results demonstrate that women with CLP received statistically significantly more secondary surgeries than men. No differences in the number of primary surgeries were identified. This study provides a gender perspective of the treatment of CLP. We identified no gender differences in primary surgery of the CLP. The standardized method of repairing the cleft is effective in preventing unjust treatment due to gender. However, we identified an indication of gender bias in cleft care regarding secondary surgeries of the nose and lip, namely, women are over-treated and/or men are under-treated. There are several possible explanations for this phenomenon, and further studies are needed. PMID- 28708466 TI - A bidirectional association between the gut microbiota and CNS disease in a biphasic murine model of multiple sclerosis. AB - The gut microbiome plays an important role in the development of inflammatory disease as shown using experimental models of central nervous system (CNS) demyelination. Gut microbes influence the response of regulatory immune cell populations in the gut-associated lymphoid tissue (GALT), which drive protection in acute and chronic experimental autoimmune encephalomyelitis (EAE). Recent observations suggest that communication between the host and the gut microbiome is bidirectional. We hypothesized that the gut microbiota differs between the acute inflammatory and chronic progressive stages of a murine model of secondary progressive multiple sclerosis (SP-MS). This non-obese diabetic (NOD) model of EAE develops a biphasic pattern of disease that more closely resembles the human condition when transitioning from relapsing-remitting (RR)-MS to SP-MS. We compared the gut microbiome of NOD mice with either mild or severe disease to that of non-immunized control mice. We found that the mice which developed a severe secondary form of EAE harbored a dysbiotic gut microbiome when compared with the healthy control mice. Furthermore, we evaluated whether treatment with a cocktail of broad-spectrum antibiotics would modify the outcome of the progressive stage of EAE in the NOD model. Our results indicated reduced mortality and clinical disease severity in mice treated with antibiotics compared with untreated mice. Our findings support the hypothesis that there are reciprocal effects between experimental CNS inflammatory demyelination and modification of the microbiome providing a foundation for the establishment of early therapeutic interventions targeting the gut microbiome that could potentially limit disease progression. PMID- 28708468 TI - A Botanical Composition from Morus alba, Ilex paraguariensis, and Rosmarinus officinalis for Body Weight Management. AB - Obesity is the largest and fastest growing public health catastrophe in the world affecting both adults and children with a prevalence impacting more than one third of United States (US) adult population. Although the long-term solution lies in lifestyle changes in the form of dieting and exercise, intervention is required for those who are already obese. Unfortunately, treatment options remain quite limited due to associated side effects of conventional therapeutics. As a natural alternative, in this study we describe the beneficial effect of a standardized composition (UP603) comprised of extracts from Morus alba, Ilex paraguariensis, and Rosmarinus officinalis in improving metabolic disorders in high fat diet (HFD) and high fat & high fructose diet (HFFD) induced obese C57BL/6J mice. Mice treated with UP603 showed dose-correlated decrease in body weight gains compared to vehicle treated HFFD group. Following 7 weeks of treatment, the changes in body weight gains from baseline were found as 6.4%, 27.3%, 2.0%, 3.1%, 0.4%, and -2.9% for normal control diet, HFFD, Orlistat, 450, 650, and 850 mg/kg UP603 treated animals, respectively. Reductions of 7.9-21.1% in total cholesterol, 25.4-44.6% in triglyceride, and 22.5-38.2% in low-density lipoprotein were observed for mice treated with 450-850 mg/kg of UP603. In a dual energy X-ray absorptiometry scan, percentage body fat of 18.9%, 47.8%, 46.1%, and 40.4% were found for mice treated with normal control, HFD, Orlistat, and UP603, respectively. Reductions of 65.5% and 16.4% in insulin and leptin, respectively, and 2.1-fold increase in ghrelin level were also observed for the UP603 group. Statistically significant improvements in nonalcoholic steatohepatitis scores were also observed from liver histology for mice treated with UP603. Hence, UP603, a standardized botanical composition from M. alba, I. paraguariensis, and R. officinalis could potentially be considered as a natural alternative to maintain healthy body weight and to manage metabolic syndrome. PMID- 28708469 TI - Aqueous two-phase assisted by ultrasound for the extraction of anthocyanins from Lycium ruthenicum Murr. AB - In this study, an efficient ultrasound-assisted aqueous two-phase extraction method was used for the extraction of anthocyanins from Lycium ruthenicum Murr. An ethanol/ammonium sulfate system was chosen for the aqueous two-phase system due to its fine partitioning and recycling behaviors. Single-factor experiments were conducted to determine the optimized composition of the system, and the response surface methodology was used for the further optimization of the ultrasound-assisted aqueous two-phase extraction. The optimal conditions were as follows: a salt concentration of 20%, an ethanol concentration of 25%, an extraction time of 33.7 min, an extraction temperature of 25 degrees C, a liquid/solid ratio of 50:1 w/w, pH value of 3.98, and an ultrasound power of 600 W. Under the above conditions, the yields of anthocyanins reached 4.71 mg/g dry sample. For the further purification, D-101 resin was used, and the purity of anthocyanins reached 25.3%. In conclusion, ultrasound-assisted aqueous two-phase extraction was an efficient, ecofriendly, and economical method, and it may be a promising technique for extracting bioactive components from plants. PMID- 28708470 TI - Safety and Efficacy of an Absorbable Filter in the Inferior Vena Cava to Prevent Pulmonary Embolism in Swine. AB - Purpose To evaluate the immediate and long-term safety as well as thrombus capturing efficacy for 5 weeks after implantation of an absorbable inferior vena cava (IVC) filter in a swine model. Materials and Methods This study was approved by the institutional animal care and use committee. Eleven absorbable IVC filters made from polydioxanone suture were deployed via a catheter in the IVC of 11 swine. Filters remained in situ for 2 weeks (n = 2), 5 weeks (n = 2), 12 weeks (n = 2), 24 weeks (n = 2), and 32 weeks (n = 3). Autologous thrombus was administered from below the filter in seven swine from 0 to 35 days after filter placement. Fluoroscopy and computed tomography follow-up was performed after filter deployment from weeks 1-6 (weekly), weeks 7-20 (biweekly), and weeks 21-32 (monthly). The infrarenal IVC, lungs, heart, liver, kidneys, and spleen were harvested at necropsy. Continuous variables were evaluated with a Student t test. Results There was no evidence of IVC thrombosis, device migration, caval penetration, or pulmonary embolism. Gross pathologic analysis showed gradual device resorption until 32 weeks after deployment. Histologic assessment demonstrated neointimal hyperplasia around the IVC filter within 2 weeks after IVC filter deployment with residual microscopic fragments of polydioxanone suture within the caval wall at 32 weeks. Each iatrogenic-administered thrombus was successfully captured by the filter until resorbed (range, 1-4 weeks). Conclusion An absorbable IVC filter can be safely deployed in swine and resorbs gradually over the 32-week testing period. The device is effective for the prevention of pulmonary embolism for at least 5 weeks after placement in swine. (c) RSNA, 2017. PMID- 28708471 TI - Use of Bisphosphonates and Risk of Breast Cancer in a French Cohort of Postmenopausal Women. AB - Purpose To assess whether bisphosphonate (BP) use is associated with decreased breast cancer incidence in a cohort of postmenopausal women. Methods The study population included 64,438 postmenopausal women participating in the French E3N (Etude Epidemiologique aupres de femmes de la Mutuelle Generale de l'Education Nationale) prospective cohort, with data self-reported in biennial questionnaires matched with data from a drug reimbursement database. Exposure to BPs and the use of other osteoporosis treatments during follow-up were determined using reimbursement data. Other covariates (breast cancer risk factors, clinical risk factors for osteoporotic fractures, and bone mineral density surveillance) originated from the questionnaires. Hazard ratios (HRs) of breast cancer were estimated using Cox proportional hazards models, considering exposure as a time varying variable. Results Over an average of 7.2 years of follow-up (2004 to 2011), 2,407 first primary breast cancer cases were identified. The HR of breast cancer associated with exposure to BPs was 0.98 (95% CI, 0.85 to 1.12). We found no effect modification by age, body mass index, time since menopause, use of hormone replacement therapy, use of calcium supplements, or use of vitamin D supplements. There was no heterogeneity across BP molecules and no trend according to cumulative dose, duration of use, or time since last use. We observed a decrease in breast cancer risk restricted to the year after treatment initiation (HR, 0.56; 95% CI, 0.36 to 0.87), which was likely explained by healthy screenee bias. Finally, we did not find any variation in HRs across breast carcinomas defined by their estrogen receptor or invasive or in situ status. Conclusion In our observational cohort of postmenopausal women observed from 2004 to 2011, BP use, likely prescribed for the management of osteoporosis, was not associated with decreased breast cancer incidence. PMID- 28708472 TI - Rectal Instillation of Cold Fluids for Targeted Temperature Management After Cardiac Arrest: A Case Report. AB - The optimal method of temperature management after cardiac arrest remains unknown. Methods that are most effective are usually invasive and expensive. Noninvasive methods are not as effective and obstruct access to the patient. Temperature management via rectal cooling offers some potential advantages in survivors of cardiac arrest, namely, relatively large volumes of temperature controlled fluids can be instilled, access to the patient is not obstructed, and fluid overload can be ameliorated by removal of a fraction of instilled fluid. We used rectal cooling in a 72-year-old male comatose survivor of cardiac arrest with an initial body temperature of 36.8 degrees C. We instilled 3000 mL of normal saline at 4 degrees C in 75 minutes, and ~2000 mL of effluent fluid was removed via gravity at 105 minutes after instillation. At 135 minutes, temperature decreased to a minimum of 35.2 degrees C. No leakage was observed. Standard procedures (insertion of central venous and arterial catheters, electrocardiography, echocardiography, chest radiography) were performed with a rectal catheter in situ. At 210 minutes after instillation, the catheter was removed and there were no clinical signs of rectal injury after removal. To conclude, rectal instillation of cold fluids resulted in a significant decrease of body temperature and we observed no major side effects. Fluid overloading was avoided by removing effluent fluid. Additional studies are needed if this technique is to gain more widespread use. PMID- 28708473 TI - MR Imaging Measurements of Altered Placental Oxygenation in Pregnancies Complicated by Fetal Growth Restriction. AB - Purpose To evaluate oxygen-enhanced and blood oxygen level-dependent (BOLD) magnetic resonance (MR) imaging parameters in normal pregnancies and those complicated by fetal growth restriction (FGR). Materials and Methods This case control study was approved by the local research ethics committee. Informed consent was obtained from all subjects. From October 2010 to October 2015, 28 women with uncomplicated pregnancies (individualized birthweight ratio [IBR] >20th percentile and delivery >37 weeks) and 23 with pregnancies complicated by FGR (IBR <5th percentile and abnormal Doppler ultrasonography [US] studies) underwent MR imaging. Differences in placental longitudinal R1 (1/T1) and transverse R2* (1/T2*) were quantified, with subjects breathing either air or oxygen. The difference in R1 (DeltaR1) after hyperoxia was converted to change in partial pressure of oxygen (DeltaPo2). Data were acquired prospectively, with retrospective interpretation of group differences (unpaired t tests). Diagnostic models were developed by using logistic regression analysis with gestational age as a covariate. Results The mean baseline R1 and R2* for normal pregnancies (R1: 0.59 sec-1, 95% confidence interval [CI]: 0.58 sec-1, 0.60 sec-1; R2*: 17 sec-1, 95% CI: 14 sec-1, 20 sec-1) were significantly different from those of pregnancies complicated by FGR (R1: 0.63 sec-1, 95% CI: 0.62 sec-1, 0.65 sec-1; R2*: 26 sec-1, 95% CI: 22 sec-1, 32 sec-1) (P < .0001). The DeltaR1 showed a significant negative association with gestational age (P < .0001) in the combined cohort, with the FGR group having a DeltaR1 that was generally 61.5% lower than that in the normal pregnancy group (P = .003). The area under the receiver operating characteristic curve for the differentiation between pregnancy complicated by FGR and normal pregnancy by using DeltaPo2, baseline R1, and baseline R2* was 0.91 (95% CI: 0.82, 0.99). Conclusion R1, R2*, and DeltaPo2 were significantly different between normal pregnancies and those complicated by severe FGR. MR imaging parameters have the potential to help identify placental dysfunction associated with FGR and may have clinical utility in correctly identifying FGR among fetuses that are small for gestational age. A larger prospective study is needed to assess the incremental benefit beyond that offered by US. (c) RSNA, 2017. PMID- 28708474 TI - Rapid Ascent: Unbridled Growth in Technology. PMID- 28708475 TI - Prevalence and Length of the Anterior Loop of the Inferior Alveolar Nerve in Iranians. AB - The anterior loop of the inferior alveolar nerve is a sensitive anatomical feature that should be taken into account during installation of dental implants anterior to the mental foramen. This study was conducted to explore the controversy regarding prevalence and length. A total of 452 mandible quadrants of 234 patients (age: 50.1 +/- 13.3 years, 113 males, 121 females) were studied using cone-beam computerized tomography. After reconstructing axial, frontal, and sagittal slices, the region between the most anterior point on the mental foramen and the most anterior part of the mandibular nerve was inspected for signs of anterior loop presence. If positive, the length of the anterior loop was measured in mm as the distance between the anterior border of mental foramen and the anterior border of the loop. Prevalence and length of the anterior loop were compared statistically between sexes and age groups. The anterior loop was observed in 106 quadrants (23.5% of 451 quadrants) of 95 patients (40.6% of 234 patients), of whom 11 had bilateral anterior loops. Prevalences were similar in males (41%) and females (39%, chi-square P =.791). The mean anterior loop length was 2.77 +/- 1.56 mm (95% CI: 2.5-3.1 mm), without significant sex (regression beta = -0.159, P = .134) or age (beta = -0.059, P = .578) differences. The anterior loop might exist in about 40% of patients, regardless of their gender. The mean safe anterior distance from the anterior loop is about 3 mm + (2.5-3.1 mm) = 5.5-6.1 mm, regardless of age. PMID- 28708476 TI - A Long-Term Study of the Diversity of OXA-48-Like Carbapenemase-Producing Bacterial Strains in Infected Patients and Carriers. AB - PURPOSE: Since their emergence at the beginning of the century, OXA-48 carbapenemases have spread in the community and in hospitals. To assess the diversity of OXA-48-producing bacterial strains and plasmids in the hospital setting, we studied the strains isolated from patients in three hospitals in the Paris area. MATERIALS AND METHODS: All possible OXA-48-like strains were included in the study. OXA-48-like and extended-spectrum beta-lactamase-encoding genes were identified, and fingerprinting analysis was performed for all Escherichia coli and Klebsiella pneumoniae strains. The backbones and close genetic environments of blaOXA-48 were assessed by amplifying genes that were specific to the pOXA-48a plasmid and PCR, encompassing the junctions between blaOXA-48 and its direct genetic environment. RESULTS: Overall, 68 strains from 30 patients were studied. These strains belonged to seven different enterobacterial species. OXA-48, OXA-204, and OXA-401 were identified in 62, 3, and 3 isolates, respectively. Additional broad-spectrum beta-lactamases were identified in 34% (23/68) of the strains. The strain diversity was high between and within patients. Identical patterns were observed only within individual patients or among epidemiologically related patients. Plasmid mapping was performed in the 62 OXA-48-producing strains and the 3 OXA-405-producing strains, resulting in the identification of 5 different patterns. CONCLUSION: Because of their ability to transfer between strains, OXA-48 carbapenemases have a high risk of dissemination and may become endemic in France. PMID- 28708477 TI - Diabetes and obesity: Managing dual epidemics. PMID- 28708478 TI - Diabetes with obesity--Is there an ideal diet? AB - For individuals who are overweight or obese, weight loss is effective in preventing and improving the management of type 2 diabetes. Together with other lifestyle factors like exercise and behavior modification, diet plays a central role in achieving weight loss. Diets vary based on the type and amount of carbohydrate, fat, and protein consumed to meet daily caloric intake goals. A number of popular diets are reviewed as well as studies evaluating the effect of various diets on weight loss, diabetes, and cardiovascular risk factors. Current trends favor the low-carbohydrate, low-glycemic index, Mediterranean, and very low-calorie diets. However, no optimal dietary strategy exists for patients with obesity and diabetes, and more research is needed. Given the wide range of dietary choices, the best diet is one that achieves the best adherence based on the patient's dietary preferences, energy needs, and health status. PMID- 28708479 TI - The essential role of exercise in the management of type 2 diabetes. AB - Exercise is typically one of the first management strategies advised for patients newly diagnosed with type 2 diabetes. Together with diet and behavior modification, exercise is an essential component of all diabetes and obesity prevention and lifestyle intervention programs. Exercise training, whether aerobic or resistance training or a combination, facilitates improved glucose regulation. High-intensity interval training is also effective and has the added benefit of being very time-efficient. While the efficacy, scalability, and affordability of exercise for the prevention and management of type 2 diabetes are well established, sustainability of exercise recommendations for patients remains elusive. PMID- 28708480 TI - Optimizing diabetes treatment in the presence of obesity. AB - Evidence of a neurophysiologic mechanism that involves hormones from adipocytes, pancreatic islet cells, and the gastrointestinal tract implicated in both obesity and diabetes has led to a search for drugs that not only either target obesity and diabetes or reduce hemoglobin A1c, but also have weight loss as a potential side effect. The authors review medications approved for the treatment of type 2 diabetes mellitus (including pramlintide, also approved for type 1 diabetes) that also have weight loss as a side effect. Drugs discussed include glucagon-like peptide-1 (GLP-1) receptor agonists, sodium-glucose cotransporter-2 (SGLT-2) inhibitors, neuroendocrine peptide hormones, alpha-glucosidase inhibitors, and metformin. Where appropriate, the authors comment on the cardiovascular effects of these drugs. PMID- 28708481 TI - Antiobesity drugs in the management of type 2 diabetes: A shift in thinking? AB - Antiobesity medications can improve metabolic control for patients with type 2 diabetes mellitus (DM) and obesity, but are underutilized. In this review, we describe the role of antiobesity drugs in the context of medically supervised and comprehensive weight-loss interventions and propose a pragmatic therapeutic algorithm for patients with type 2 DM and obesity that incorporates the use of antiobesity drugs early in the course of management. PMID- 28708482 TI - Metabolic surgery for treating type 2 diabetes mellitus: Now supported by the world's leading diabetes organizations. AB - The term metabolic surgery describes bariatric surgical procedures used primarily to treat type 2 diabetes and related metabolic conditions. Originally, bariatric surgery was used as an alternative weight-loss therapy for patients with severe obesity, but clinical data revealed its metabolic benefits in patients with type 2 diabetes. Metabolic surgery is more effective than lifestyle or medical management in achieving glycemic control, sustained weight loss, and reducing diabetes comorbidities. Perioperative adverse events are similar to other gastrointestinal surgeries. New guidelines for type 2 diabetes expand use of metabolic surgery to patients with a lower body mass index. PMID- 28708483 TI - Medical Treatment of Diabetes Mellitus. PMID- 28708485 TI - A new twist in measuring mutation rates. AB - The influenza virus mutates faster than we previously thought. PMID- 28708484 TI - Promiscuous binding by Hsp70 results in conformational heterogeneity and fuzzy chaperone-substrate ensembles. AB - The Hsp70 chaperone system is integrated into a myriad of biochemical processes that are critical for cellular proteostasis. Although detailed pictures of Hsp70 bound with peptides have emerged, correspondingly detailed structural information on complexes with folding-competent substrates remains lacking. Here we report a methyl-TROSY based solution NMR study showing that the Escherichia coli version of Hsp70, DnaK, binds to as many as four distinct sites on a small 53-residue client protein, hTRF1. A fraction of hTRF1 chains are also bound to two DnaK molecules simultaneously, resulting in a mixture of DnaK-substrate sub-ensembles that are structurally heterogeneous. The interactions of Hsp70 with a client protein at different sites results in a fuzzy chaperone-substrate ensemble and suggests a mechanism for Hsp70 function whereby the structural heterogeneity of released substrate molecules enables them to circumvent kinetic traps in their conformational free energy landscape and fold efficiently to the native state. PMID- 28708486 TI - Improved quality of porcine embryos cultured with hyaluronan due to the modification of the mitochondrial membrane potential and reactive oxygen species level. AB - Although considerable progress has been made in pig embryo culture systems, the developmental competence and quality of the produced embryos are still lower than their in vivo-derived counterparts. Because hyaluronan (HA) regulates various cellular processes and possesses antioxidant properties, this glycosaminoglycan seems to be a promising supplement in culture media. However, until now, its beneficial influence on in vitro pig embryo development has been debatable. Hence, we aimed to investigate the effect of 0.25 mg/mL, 0.5 mg/mL and 1 mg/mL concentrations of HA on the developmental potential and quality of cultured porcine embryos. We found that 1 mg/mL HA supplementation significantly increased the obtained percentages of cleaved embryos to ~95%, morulae to ~87% and blastocysts to ~77%. At 0.5 mg/mL and 1 mg/mL HA concentrations, we observed a significantly improved blastocyst quality, expressed as the total number of cells per blastocyst, number of cells in the inner cell mass, number of TUNEL-positive nuclei per blastocyst, the TUNEL index and the blastocyst diameter. Because the inner mitochondrial membrane potential (DeltaPsim) and reactive oxygen species (ROS) level are important for proper embryo development, for the first time, we measured these two parameters in cultured embryos at various HA concentrations and during their development up to the expanded blastocyst stage. For blastocysts cultured with 1 mg/mL HA, the DeltaPsim and ROS level were ~1.6 and 2.7 times lower, respectively, than those of the control blastocysts. Both DeltaPsim and the ROS level were increased in parallel during in vitro embryo development with and without HA, but this increase was less pronounced in the presence of HA. Hence, our quantitative data unequivocally show that supplementation of NCSU-23 culture medium with 1 mg/mL HA improves the developmental potential and quality of pig embryos. This effect results from a significant decrease in the ROS level induced by the HA-dependent DeltaPsim reduction. PMID- 28708487 TI - [Spontaneous uterine rupture at 34weeks gestation in a context of unscarred uterus]. PMID- 28708488 TI - Sperm structure and sperm motility of the African and Rockhopper penguins with special reference to multiple axonemes of the flagellum. AB - This study evaluated the semen of two penguin species from separate genera with reference to unique features in sperm structure using light microscopy and transmission electron microscopy. Ejaculates from African penguin (n = 51) and Rockhopper penguin (n = 9) contained on average more than 60% motile spermatozoa and a sperm concentration of 3274 * 106/ml and 1423 * 106/ml, respectively. The percentage progressive motility was similar for the two species as well as all the kinematics parameters. The sperm morphology of these two penguin species is almost identical and largely resembles that of non-passerine birds in terms of the filiform head, small acrosome and mid-piece containing 13 spherical mitochondria, arranged around the proximal and distal centrioles in a single helix. Apart from a shorter mid-piece, penguin sperm morphometrics were similar to other non-passerine birds. The ultrastructure of the sperm principal piece revealed the typical 9 + 2 microtubular arrangement without any outer dense fibres. An unusual feature in both African and Rockhopper penguin spermatozoa was the occurrence of multiple axonemes contained in one plasmalemma in 4% of spermatozoa. These double, triple and quadruple axonemal arrangements have not been described previously albeit multiple tails were reported in other bird species. It is unclear whether such a unique structural feature will be of any advantage for sperm motility and might rather be a result of the absence of sperm competition. Multiple axonemes found in penguin flagella could be an apomorphism that distinguish them from other bird spermatozoa. PMID- 28708489 TI - 2-Methoxystypandrone improves in vitro-produced bovine embryo quality through inhibition of IKBKB. AB - 2-Methoxystypandrone (2-MS), a naphthoquinone from Polygonum cuspidatum, has been reported to exhibit antioxidant activities. However, its pharmacological properties have not been fully studied in vitro culture system of oocytes and embryos development. In this study, we examined the effects of 2-MS on bovine blastocyst developmental competency during preimplantation using TUNEL assay, qRT PCR and immunocytochemistry. Oocytes were treated with 1 MUM 2-MS during maturation, followed by in vitro fertilized and the zygotes were cultured. We observed that blastocyst development was significantly higher in the 2-MS treated oocytes (45.29%) compared to control groups (32.21%). We also found that 2-MS treatment significantly increased total cell number and decreased the apoptotic cells in Day-8 blastocyst. Finally, we examined the signal pathway affecting the embryo development after the 2-MS treatment. We detected a significant decrease in the mRNA levels of NFKB1, IKBKB, COX2, NOS2, BAX, CASP3, and JAK2 after 2-MS treatment, however, the mRNA level of the anti-apoptotic gene BCL2 was significantly higher than that in the control. Moreover, protein expression levels of NFKB1, IKBKB, and COX2, and 8-oxoG DNA lesion decreased significantly in the 2-MS treatment group, compared to the control. In summary, our findings suggested that treatment of oocytes with a potential anti-oxidant, 2-MS during IVM improved in vitro developmental competence of bovine embryos. PMID- 28708490 TI - Effect of season and age on Indian red jungle fowl (Gallus gallus murghi) semen characteristics: A 4-year retrospective study. AB - The reproductive potential of the adult males is expected to vary with age/season and largely differ not only in closely related avian species but even in subspecies, breeds and/or strains of the same species. Thus, it is pre-requisite to have knowledge of seminal parameters to achieve maximum production potential of at-risk species for ex situ in vitro conservation programs. A 4-year study was designed to evaluate the effect of age and season (spring, summer, autumn and winter) on semen characteristics of Indian red jungle fowl (Gallus gallus murghi) in a retrospective manner. Semen ejaculates (n = 1148) were regularly collected from eight adult cocks 6 to 54 months of age. Quantitative and qualitative semen parameters viz; volume (MUL), concentration (1 * 109 mL-1), total sperm number per ejaculate (1 * 109 mL-1), motility (%), viability (%), plasma membrane integrity (%), acrosome integrity (%) and semen quality factor were recorded. A chronological increasing trend with age of most sperm quantitative and qualitative traits (semen volume, sperm concentration, total sperm number per ejaculate, plasma membrane integrity, viability, acrosomal integrity and semen quality factor) was observed. The highest values were observed at four years of age (P < 0.05) with the exception of sperm motility that was not affected by the age. Spring was the best season for sperm parameters viz; volume, motility, plasma membrane integrity, viability and acrosomal integrity (P < 0.05), however a remarkable sperm production was noticed all over the year. It is concluded that Indian red jungle fowl exhibits an evolution of sperm production that greatly differs in many points from other fowl sub-species. It is suggested that semen ejaculates of highest quality achieved for semen banking at the age of four year in the spring season. PMID- 28708491 TI - Different enzymatic antioxidative pathways operate within the sheep caruncular and intercaruncular endometrium throughout the estrous cycle and early pregnancy. AB - There has been a growing interest in the role played by antioxidant enzymes in the regulation of endometrial function in mammals. However, little is known about enzymatic antioxidative pathways involved in conditioning the cyclic and early pregnant endometrium for conceptus attachment and implantation in domestic ruminants. We aimed to investigate changes in activities of superoxide dismutase 1 and 2 (SOD1, SOD2), glutathione peroxidase (GPX), glutathione reductase (GR) and catalase (CAT) in sheep caruncles (CAR) and intercaruncles (ICAR) endometrial tissues of cyclic and early pregnant ewes. Irrespective of day of cycle or pregnancy, CAR demonstrated higher activities of SOD1 and SOD2 than in ICAR. On day 12 of the estrous cycle, ICAR demonstrated higher activity of GPX and GR than in CAR tissues. On days 12 and 16 the estrous cycle, ICAR demonstrated higher activity of CAT than in CAR. CAR demonstrated higher activity of GPX on day 18 than on days 4, 8, 12 and 16 of the estrous cycle. CAR demonstrated higher activity of CAT on day 18 than on days 4, 8, 12 and 16 of the estrous cycle. ICAR demonstrated higher activity of CAT on day 18 than on days 4, 8, and 16 of the estrous cycle. The activity of CAT in ICAR increased from days 4 and 8 to day 12 of the estrous cycle. The activity of SOD2 in CAR increased from day 16 to day 18 of pregnancy. On day 12 of pregnancy, CAR demonstrated higher activity of GPX than in ICAR. On day 16 of pregnancy, ICAR demonstrated higher activity of GPX than in CAR. The activity of GPX in ICAR increased from day 12 to day 16 of pregnancy. The activity of GPX in CAR increased from day 16 to day 18 of pregnancy. The activity of GR in CAR and ICAR increased from days 12 and 16 to day 18 of pregnancy. On days 16 and 18 of pregnancy, ICAR demonstrated higher activity of CAT than in CAR. The activity of CAT in CAR decreased from day 12 to days 16 and 18 of pregnancy. The activity of CAT in ICAR decreased from day 12 to day 16 of pregnancy and then increased from day 16 to day 18 of pregnancy. In conclusion, different antioxidant mechanisms operate within CAR and ICAR endometrium throughout the estrous cycle and during early pregnancy. This might be related to the different but important roles of CAR and ICAR endometrial tissues for the establishment of pregnancy. PMID- 28708492 TI - Development and proliferation of feline endometrial glands from fetal life to ovarian cyclicity. AB - In this study it was determined the progression of uterine gland development from late gestation to puberty in domestic felids. Cell proliferation patterns for luminal (LE), glandular epithelium (GE) as well as stroma (S) were also described. Twenty-four uteri from female kittens: 45 and 65 days of gestation and 1 to 5, 8, 12, 16, 20 and 24 weeks postnatally were obtained. Uterine cross sections were submitted for routine histological and immunohistochemical quantification of proliferating cell nuclear antigen (PCNA) techniques. Although prenatal uteri presented no indication of adenogenesis, 1 week old uteri revealed an incipient budding of the LE. During the second week budding increased and a mild degree of tubulogenesis of the GE into the stroma was detected. From the third to fifth weeks coiling, branching and cross-sections of glands appeared. These latter findings were more evident in week 8 when GE began to penetrate through much of the S to week 24. PCNA immunostaining revealed that DNA synthesis decreased throughout the study in the 3 cell compartments; (P < 0.01). Luminal proliferation began prenatally, it maintained up to postnatal week 8 to markedly decrease to puberty (P < 0.01). From postnatal week 3 up to week 8, GE mitotic activity was elevated becoming low thereafter (P < 0.01). Stroma actively proliferated prenatally (P < 0.01), diminishing up to week 8 (P < 0.01) and again during the last weeks (P < 0.01) of the study. It was concluded that, in domestic felids, proliferation of LE begins prenatally, histological uterine adenogenesis commenced during the first postnatal week and both events concluded by postnatal weeks 5-8. PMID- 28708493 TI - Effects of FSH addition to an enriched medium containing insulin and EGF after long-term culture on functionality of equine ovarian biopsy tissue. AB - The effect of FSH supplementation on an enriched cultured medium containing insulin (10 ng/mL) and EGF (50 ng/mL) was investigated on in vitro culture of equine ovarian biopsy tissue. Ovarian tissue fragments were collected from mares (n = 10) and distributed in the following treatments: noncultured control, cultured control, and cultured + FSH. Both treated groups were cultured for 7 or 15 days. The end points evaluated were: follicular morphology, estradiol levels in the culture medium, fluorescence intensity for TUNEL, EGFR and Ki-67 detection, and gene expression of GDF-9, BMP-15, and Cyclin-D2 in the ovarian tissue. After seven days of culture, medium supplemented with FSH had a similar (P > 0.05) percentage of morphologically normal follicles compared to the noncultured control group. Estradiol levels increased (P < 0.05) from Day 7 to Day 15 of culture for both treated groups. No difference (P > 0.05) was observed for TUNEL and EGFR intensity between the noncultured control group and the treated groups after 15 days of culture. Ki-67 intensity did not differ (P > 0.05) between treated groups after 15 days of culture, but decreased (P < 0.05) when compared with the noncultured control group. Similar (P > 0.05) mRNA expression for GDF-9, BMP-15, and Cyclin-D2 was observed among all treatments after 15 days of culture. In conclusion, an enriched medium supplemented or not with FSH was able to maintain the functionality of equine ovarian biopsy tissue after a long-term in vitro culture. PMID- 28708494 TI - Relationship between echotextural and histomorphometric characteristics of stallion testes. AB - The goal of this study was to investigate correlations between objective measures of testicular echotexture and histomorphometric attributes related to the histological composition of stallion testes. Fifty-four scrotal testes were obtained from three groups of stallions during routine castrations: colts <1 yr old (n = 18), young stallions 1-5 yrs old (n = 27), mature stallions > 5 yrs old (n = 9). In addition, two scrotal testes with degeneration, 16 retained inguinal and 10 retained abdominal testes were surgically obtained. Cross-sectional and longitudinal ultrasonograms were obtained for each testis. Mean numerical pixel values (NPVs) as well as pixel standard deviations (PSDs) were determined for each image (ImageJ-1.5 software). Histomorphometric attributes of the seminiferous tubules (STs) were derived (three tissue samples per each testis) using image analysis software [relative STs area: RSTA = ST area/total cross sectional area (TA) x 100%; relative STs lumen: RSTL = ST lumen area/TA x 100%; individual ST area; ISTA; individual ST lumen: ISTL; seminiferous epithelium height: SHE]. Degree of fibrosis was graded semi-quantitatively (0-3) in samples from 17 testes. All measures of testicular echotexture as well as all histomorphometric attributes of STs had highest values when obtained from the scrotal testes of young and mature stallions (P < 0.05). The NPVs and PSDs from the ultrasonographic images of the scrotal testes were significantly correlated with all histomorphometric attributes of STs (P < 0.001). However, there was no correlation between the majority of these measures and attributes if each group of the scrotal testes was analyzed separately. The NPVs from the ultrasonographic images of the retained inguinal testes were correlated with RSTA, RSTL, ISTA, and ISTL, while the NPVs from the retained abdominal testes were not correlated with any of the histomorphometric attributes of the STs. Testes with high degree of fibrosis had variable values of pixel intensity and pixel heterogeneity. Based on the results of this study, we concluded that the pixel intensity and pixel heterogeneity of stallion testes increase during the first year of life and remain stable in young and mature stallions. These changes occur in parallel to the development of the seminiferous tubules. Testicular echogenicity in stallions does not seem to reflect degree of testicular fibrosis. Retained abdominal testes have lower and less heterogeneous echogenicity than scrotal testes from stallions that are more than one year old. While pixel analysis cannot replace biopsy in assessing testicular histomorphology in young and mature stallions, testicular echogenicity is a good indicator of peri-pubertal growth and expansion of the seminiferous tubules. PMID- 28708495 TI - Genome-wide association studies for reproductive seasonality traits in Rasa Aragonesa sheep breed. AB - Sheep breeds from Mediterranean area show reproductive seasonal patterns of oestrous behaviour and ovulatory activity, mainly regulated by variation in the photoperiod. Maximal reproductive activity is associated with short days from August to March. The aim of this study therefore was, to identify new SNPs and genes associated to reproductive seasonality in sheep by using the Illumina OvineSNP50 Beadchip. A total of 239 adult Rasa Aragonesa breed ewes from one flock were controlled from January to August. Three reproductive seasonality traits were considered: the total days of anoestrus (TDA), based on weekly individual plasma progesterone levels and defined as the sum of days in anoestrus, considering anoestrus those periods with three or more consecutive P4 concentrations lower than 0.5 ng/ml; the progesterone cycling months (P4CM), defined for each ewe as the rate of cycling months between January and August based on progesterone determinations and the oestrus cycling months (OCM), defined for each ewe as the rate of months cycling between January and August based on oestrus records. Genotyping of 123 ewes was performed with the OvineSNP50 Infinium Beadchip. After the quality control (QC) performed on the raw genotypes, a total of 47,206 SNPs distributed over the 27 ovine chromosomes and 110 ewes were included in subsequent analyses. Principal component analysis revealed a substructure within the total dataset and identified 4 principal clusters in the experimental flock. None of the SNPs overcame the genome-wide significance level (P = 1.06 * 10-6). However, the SNPs OAR4_66002395 (9.41E-6), and OAR8_25877010 (1.86E-5) reached the genome-wide suggestive significance level (set to 2.32 * 10-5) for TDA and P4CM traits, respectively, while OAR23_14608581 was significant for both TDA (2.02E-5) and P4CM (1.05E-5) traits. Five SNPs evidenced association at chromosome-wise level: SNPs OAR4_66002395, OAR23_14608581 and s20800 (DTA), and OAR8_25877010, OAR23_14608581 and s48474 (P4CM). Several genes related to circadian and circannual rhythms were found close to these SNPs: NPSR1 (SNP OAR4_66002395), HS3ST5 (SNP OAR8_25877010), RPTOR (SNP s48474), and NPTX1 (SNP s48474) and could be considered as candidate gene related to TDA and P4CM traits. PMID- 28708496 TI - Comparative evaluation of haematological parameters and erythrocyte membrane stability in pregnant and lactating goats in different seasons of tropical Savannah. AB - Haematological parameters and erythrocyte osmotic fragility (EOF) are commonly used as indicators of health status and erythrocyte membrane integrity. Variations in haematological parameters and EOF in late gestation and early lactation during the cold-dry (CDS), hot-dry (HDS) and rainy (RAS) seasons were studied in sixty (n = 60) Red Sokoto goats (20 goats for each season). The ambient temperatures and temperature-humidity index recorded were higher in the afternoon hours of the HDS and RAS, but lower in the morning hours of the CDS as compared with the thermoneutral zone of goats. Results revealed that the pregnant goats had significantly (P < 0.05) lower PCV and RBC, but higher haemoglobin parameters (Hb, MCH and MCHC) in RAS. Unlike in the pregnant goats, higher (P < 0.05) values of PCV and RBC were observed during the HDS as compared with the CDS and RAS in lactating goats. The EOF was significantly higher during lactation than pregnancy in the CDS and HDS. Similarly, the magnitude of the left shift in fragiligram during the CDS was more marked in pregnant compared with lactating goats. During gestation, the CDS had lower (P < 0.05) EOF than HDS and RAS, with a marked left shift in the fragiligram of both pregnant and lactating goats during the CDS. In conclusion, seasonal variations exist in physiology of erythrocytes of goats during the peri-partum period, with an increase in PCV and RBC, but a decrease in haemoglobin parameters in pregnant compared with lactating goats during the RAS. Erythrocyte stability and membrane integrity were higher in pregnant than lactating goats, and also higher during the CDS than the HDS and RAS, irrespective of reproductive status. This information may be useful in the design of animal breeding and is of value in animal welfare, research, diagnosis and management of haematological conditions during the peri-partum period. PMID- 28708497 TI - Freezing dog semen using -80 degrees C ultra-freezer: Sperm function and in vivo fertility. AB - Long term storage of canine frozen semen is conventionally performed in liquid nitrogen (LN2). However, previous works in freezing canine semen using a -80 degrees C ultra-freezer (-80 degrees C-UF) showed no differences on sperm quality after thawing. The main objective of this study was to compare the effects of the freezing techniques using LN2 or -80 degrees C-UF on sperm function and in vivo fertility of frozen-thawed dog semen. The sperm-rich fraction of the ejaculate was collected separately from five Chihuahua breed, and each one divided into two aliquots, and frozen and stored in LN2 or -80 degrees C-UF. Sperm function was analyzed for motility and viability, acrosome integrity, mitochondrial function and phosphatidylserine translocation by flow cytometry before and after cryopreservation. A total of 10 bitches were intravaginal inseminated (IVAI; LN2 frozen-thawed semen = 5 and -80 degrees C-UF frozen-thawed semen = 5). Pregnancy status was confirmed 30 d after IVAI by transabdominal ultrasonography and live born puppies at term were recorded. Sperm function parameters were affected for both freezing protocols. Differences (P < 0.05) were found between freezing and storage methods in most of the parameters of sperm function analyzed, except in the phosphatidylserine translocation. The percentages of pregnancies were not different between the two freezing and storage protocols used. Semen freezing and storage using -80 degrees C UF is an effective technique for long-term preservation of canine spermatozoa. PMID- 28708498 TI - Presence of bacteria in the endometrium and placentomes of pregnant cows. AB - Bacterial invasion of the bovine uterus during the postpartum period occurs in most cows, but the general consensus is that these bacteria are eliminated before the next pregnancy. The pregnant uterus has therefore hitherto been considered a sterile environment, but this assumption has now been challenged by recent studies in humans, which indicate that bacteria can be present in the placenta of term pregnancies without causing abortion. The aim of the present study was therefore to investigate whether bacteria are present in the uterus of pregnant cows. Specimens were taken from the inter-caruncular endometrium and from placentomes of slaughtered pregnant cows (n = 43) and subjected to histology, fluorescence in situ hybridization and massive parallel sequencing. Bacteria were observed in the tissue from 90.7% (39/43) of the cows by fluorescence in situ hybridization. Fusobacterium necrophorum, Porphyromonas levii and Trueperella pyogenes were located within the endometrium, on the endometrial surface and in the caruncular stroma, but their presence was not associated with inflammation. Data from massive parallel sequencing of the 16S rRNA gene from a subset of 15 cows indicated that the most abundant bacteria were the families Porphyromonadaceae, followed by Ruminococcaceae and Lachnospiraceae. Our results indicate that the bovine uterus is not a sterile environment during pregnancy as previously assumed and that a cow can carry a pregnancy despite the presence of a few potentially pathogenic bacteria in the uterus. PMID- 28708499 TI - Split-time artificial insemination in beef cattle: III. Comparing fixed-time artificial insemination to split-time artificial insemination with delayed administration of GnRH in postpartum cows. AB - This experiment was designed to compare pregnancy rates in postpartum beef cows following split-time (STAI) or fixed-time (FTAI) artificial insemination. Estrus was synchronized for 671 cows at seven locations following administration of the 7-d CO-Synch + CIDR protocol (100 MUg GnRH + CIDR insert [1.38 g progesterone] on d 0; 25 mg prostaglandin F2alpha [PG] at CIDR removal on d 7). Cows were assigned to treatments that were balanced across locations based on age, body condition score, and days postpartum at the time treatments were initiated. All cows in treatment 1 (n = 333; FTAI) were inseminated at 66 h after PG and GnRH was administered concurrent with insemination regardless of estrus expression. For cows in treatment 2 (n = 338; STAI), inseminations were performed at 66 or 90 h after PG, and estrous status was recorded at these times. Cows in the STAI treatment that exhibited estrus by 66 h were inseminated at that time and did not receive GnRH, whereas AI was delayed 24 h until 90 h after PG for cows that failed to exhibit estrus by 66 h. Gonadotropin-releasing hormone (100 MUg) was administered concurrent with AI at 90 h only to cows failing to exhibit estrus. Estrus expression that occurred during the 24 h delay period among cows assigned to the STAI treatment increased the total proportion of cows that expressed estrus prior to insemination (1 = 60%; 2 = 86%; P < 0.001). Pregnancy rates for cows inseminated at 66 h that exhibited estrus did not differ between treatments (1 = 58%; 2 = 58%; P = 0.93); however, pregnancy rates among non-estrous cows at 66 h were improved (1 = 35%; 2 = 51%; P = 0.01) among cows assigned to the STAI treatment when insemination was postponed by 24 h. Consequently, total AI pregnancy rate tended to be higher for cows that received STAI (1 = 49%; 2 = 56%; P = 0.06). In summary, following administration of the 7-d CO-Synch + CIDR protocol, total estrous response increased and pregnancy rates resulting from AI tended to be higher among cows assigned to STAI versus FTAI treatments. PMID- 28708500 TI - Reversible meiotic arrest of bovine oocytes by EGFR inhibition and follicular hemisections. AB - The objective of this study was to investigate the effects of inhibiting the epidermal growth factor receptor (EGFR) pathway on meiosis blockage and resumption, mRNA expression of genes involved in oocyte maturation and cumulus expansion, and embryo development. Bovine cumulus-oocyte complexes (COCs) were cultured for 15 h in the presence of the EGFR inhibitor (AG1478) and follicular hemisections (FHS). Most of the oocytes (89.3%) remained at the germinal vesicle (GV) stage when cultured in the presence of FHS and 5 MUM AG1478. The inhibitory effect was reversible as most oocytes (83.8%) completed meiosis after additional 20 h maturation. Embryo development to the blastocyst stage was similar (P > 0.05) between FHS and 5 MUM AG1478 treated (39.3%) and control (41.1%) groups. In cumulus cells, mRNA abundance of early growth response protein 1 (EGR1), tumor necrosis factor alpha-induced protein 6 (TNFAIP6) and hyaluronan synthase 2 (HAS2) genes, and phosphorylated extracellular regulated kinase (p-ERK1/2) protein were lower in COCs treated with AG1478 plus FHS compared with FHS alone (P < 0.05). In granulosa cells of FHS, AG1478 treatment reduced transcript levels of PGR and ADAMTS1 (P < 0.05). The inhibitory effect of AG1478 on meiotic progression was not reverted by treatment with angiotensin II (ANG II) or prostaglandins (PGF2alpha or PGE2). This study demonstrates that inhibition of EGFR in the presence of FHS is a reliable approach to promote reversible arrest of bovine oocytes at the GV stage. PMID- 28708501 TI - Bmal1 interference impairs hormone synthesis and promotes apoptosis in porcine granulosa cells. AB - In mammals, granulosa cell proliferation, differentiation, luteinization, apoptosis, and hormone synthesis are tightly related to oocyte maturation, follicular development and ovarian function. In current study, we investigated the role of the key circadian clock gene, brain and muscle arnt-like protein-1 (Bmal1), on porcine granulosa cell hormone secretion and apoptosis. The transcription levels of circadian clock genes, including Bmal1 and period circadian clock 2 (Per2), were detected by RT-qPCR. We found that the circadian clock genes exhibited rhythmic change and were further enhanced by dexamethasone synchronization in granulosa cells. Bmal1 knockdown reduced transcriptional levels of hormone receptor genes, including follicle stimulating hormone receptor (Fshr), luteinizing hormone/choriogonadotropin receptor (Lhcgr) and estrogen receptor 2 (Esr2), and decreased the mRNA and protein levels of cytochrome P450 family 11 subfamily A member 1 (Cyp11a1), cytochrome P450 family 19 subfamily A member 1 (Cyp19a1) and steroidogenic acute regulatory protein (Star), which are the key enzymes involved in hormone synthesis. Synthesis of progesterone and estradiol were also inhibited by Bmal1 siRNA treatment in granulosa cells. Moreover, flow cytometry analysis demonstrated suppressing Bmal1 promoted granulosa cells apoptosis. Western blot analysis showed that Bmal1 interference inactivated the PI3K/Akt/mTOR signaling pathway. In conclusion, Bmal1 plays a critical role in secretion of hormone and apoptosis of porcine granulosa cells via the PI3K/Akt/mTOR signaling pathway. PMID- 28708502 TI - Temporal effect of maternal heat stress during gestation on the fertility and anti-Mullerian hormone concentration of offspring in bovine. AB - Ovarian reserve has been suggested as an important contributing factor of reproductive success in bovine. Size of ovarian reserve is determined during fetal period and it could be altered by environmental factors, with which the dam is exposed. Maternal heat stress could impair placental function and fetal development; however, there is limited information on the impact of prenatal heat stress on fertility and ovarian reserve in the offspring. Therefore, a retrospective study was conducted, in which fertility parameters and AMH concentration, as a reliable marker of ovarian reserve in bovine, were studied in the offspring of dams that had been exposed to heat stress during the first (FTE), second (STE) or third (TTE) trimester of gestation and the offspring of dams unexposed to heat stress (US). Additionally, postpartum exposure of offspring with heat stress was considered in the model to adjust the statistical analysis in this regard. Days to first service (DFS) and calving to conception interval (CCI) were prolonged in exposed than unexposed cows (P < 0.05). Days to first service and CCI were also longer in STE compared with FTE cows (P < 0.05). First service conception rate was lower in TTE than UN cows (P < 0.05). The proportion of repeat breeders was higher in exposed compared with unexposed cows (P < 0.05). Service per conception was higher in STE and TTE than UN cows (P < 0.05). Culling rate between different periods of lactation was also higher in exposed than unexposed cows (P < 0.05). Finally, AMH concentration was lower in STE and TTE than UN cows (P < 0.05); moreover, it was lower in STE compared with FTE cows (P < 0.05). In conclusion, the present study revealed detrimental effects of maternal heat stress on fertility, productive longevity and ovarian reserve in the offspring. In this context, the second and third trimesters appeared to be more critical periods. PMID- 28708503 TI - Effect of dietary supplementation of omega-3 polyunsaturated fatty acid (PUFA) rich fish oil on reproductive performance of the goat (Capra hircus). AB - Dietary supplementation of n-3 PUFA decreases the luteolytic PGF2alpha and improves the pregnancy rate in the dairy cow. However, its effect in the goat is not known. Accordingly, we studied the effect of supplementation of n-3 PUFA rich Fish oil (FO) on different reproductive events in the goat. Cycling goats (n = 30) were divided into two equal groups and fed an isocaloric and isonitrogenous diet supplemented with either FO (TRT; n = 15) or palm oil (PO) (CON; n = 15) @ 0.6 mL/kg body weight for 72 days during the breeding season. Estrus synchronization was done on day 25 and 36 of supplementation using two PG regimen and the goats in estrus were bred. Mean interval from PGF2alpha administration to the onset of estrus was 12 h longer (P < 0.05) in the TRT group than that of CON. The number of preovulatory follicles (POF) and ovulation rate was significantly higher in FO supplemented goats (P < 0.05) by 39.64 and 41.35%, respectively. Though the corpus luteum diameter was significantly higher (P < 0.05) on day 5, 8 and 11 post-breeding in the TRT group, mean serum progesterone (P4) did not differ significantly (P > 0.05). Mean concentration of serum estradiol (E2) was significantly (P < 0.01) lower in the FO supplemented group during day 0-60 post breeding which could be due to significantly low serum cholesterol (P < 0.01). Though the serum concentration of PGF2alpha metabolite (PGFM) and PGE2 metabolite (PGEM) in the pregnant goats was significantly (P < 0.05) lower in the TRT group on day 16 and 17 post-breeding, the ratio of PGEM to PGFM remained unaffected suggesting a favourable effect of FO supplementation on the early pregnancy. The number of embryos, twinning rate and kidding rate were high in FO supplemented group though it was non-significant. However, gestation length, birth weight of kids and neonatal behaviour were comparable between the groups (P > 0.05). In conclusion, supplementation of n-3 PUFA rich FO significantly increased the number of POF and ovulation rate with numerical increase in the kidding rate. Further, it decreased the serum E2 and PGFM during the critical window of pregnancy recognition in the doe. PMID- 28708504 TI - Study of lysophosphatidic acid receptors (LPARs) in buffalo uterus demonstrated upregulation of LPAR1 and LPAR6 in early pregnancy. AB - Lysophosphatidic acid (LPA) is an important factor involved in embryo implantation and pregnancy establishment in humans and domestic livestock. LPA exerts its action through six G-protein-coupled receptors (LPA1-LPA6). We investigated the types of LPA receptors expressed in buffalo uterus and also their differential expression in the nonpregnant, and early-pregnant endometrium. The nonpregnant, and early-pregnant (<42 days) uteri were collected from the local slaughterhouse. RT-PCR experiments detected mRNAs of all the six LPA receptors (LPAR1-LPAR6) in both nonpregnant, and early-pregnant endometrial tissues. Their comparative profiling by real-time PCR revealed that the early pregnant endometrium expressed more mRNAs of LPAR1 and LPAR6. All the mRNA fragments were sequenced and submitted to Genbank, NCBI. Western blot studies also showed a similar expression pattern of these two receptor proteins, including higher expression of both LPA1 and LPA6 proteins during early pregnancy. And between these two receptors, LPA6 upregulation was more pronounced than LPA1. In immunohistochemistry, these receptors were found to be localized in the endometrial glandular epithelial cells of both types of uterus. Level of LPA was also higher in early pregnant endometrial tissues. In summary, our study demonstrated expression of all the six LPAR mRNAs in buffalo uterus, wherein the early-pregnant uterus did express comparatively higher mRNA as well as protein of LPA1 and LPA6, indicating their role in pregnancy. The more pronounced expression of LPA6 possibly indicates its greater contribution to mediating LPA signaling in early pregnancy (29-42 days) of buffalo. PMID- 28708505 TI - Seasonal changes of DNA fragmentation and quality of raw and cold-stored stallion spermatozoa. AB - In this study annual fluctuations of DNA fragmentation and quality of cold-stored equine sperm were evaluated. Ejaculates were collected weekly during one year from 15 stallions. Ejaculate volume, sperm concentration and total sperm count were determined and semen was then extended and cold-stored for 48 h. Sperm motility was evaluated by CASA before and after 24 as well as 48 h of cold storage. In addition, the percentages of sperm with intact plasma membrane and acrosome (PMAI %) and with low intracellular Ca2+ level were determined in cold stored semen (24 h, 48 h). SCSATM was performed to assess mean DFI, SD of DFI and % DFI in raw frozen-thawed as well as in extended sperm after 24 and 48 h of storage. The month of semen collection affected (P < 0.05) all parameters evaluated in raw semen and all criteria except progressive motility as well as rapid cells in semen stored for 24 and 48 h, respectively. Ejaculate volume was higher and sperm concentration lower in summer compared to winter and motility lower in July than in any other month of the year (P < 0.05). In semen processed in April and stored for 24 h the percentage of rapid cells was improved compared to January and after 48 h of storage progressive motility (%) was higher in January and October than in July (P < 0.05). After 24 h of cold storage PMAI % was higher in October than in January and after 48 h values were higher in September compared to January and February as well as from April to July (P < 0.05). Regarding sperm with low intracellular Ca+2 level (%) after storage for 24 and 48 h, higher values were measured in winter and in October compared to April, June and July (P < 0.01). Seasonal changes in DNA fragmentation were most evident with respect to mean DFI. In raw frozen-thawed semen mean DFI was lower from August to November than in June and July (P < 0.001). Values were lower during winter compared to spring and early summer (P < 0.05) and lower in December than from April to September (P < 0.001). After 24 h of cold storage mean DFI was lower in September and October when compared to January, February, May, July and November (P < 0.05) and after 48 h storage mean DFI was reduced in spring and autumn compared to February, June and July (P < 0.05). In conclusion, a seasonal effect was evident on semen characteristics of raw and cold-stored sperm. Semen quality was impaired in midsummer when low sperm motility and viability were combined with an elevated DNA fragmentation and Ca2+ level of sperm. PMID- 28708506 TI - Expression and localization of cyclooxygenases in the oviduct of laying hens during the ovulatory cycle. AB - Prostaglandins (PGs) play important roles in regulation of the functions of the hen oviduct. However, little is known about the expression and localization of the rate-limiting cyclooxygenases (COX-1 and COX-2) in the oviduct. The aim of this study was to determine the COXs expression and localization in the different segments of the oviduct and to investigate changes in their expression levels during the ovulatory cycle of laying hens. White Leghorn laying hens were killed at 0, 4, 7, 16 and 24 h after oviposition, and samples from the infundibulum, magnum, isthmus, uterus, and vagina were collected. Gene and protein expressions were examined by real-time PCR and western blot, respectively, for both COX-1 and COX-2. Localization of COX-1 and COX-2 in the hen oviduct was determined by immunohistochemistry and PCR analysis of samples collected by laser capture microdissection (LCM). The expression level of COX-1 was highest in the infundibulum, while that of COX-2 was significantly higher in the uterus than in the other segments. The expression levels of COX-1 in the infundibulum and COX-2 in the uterus were higher at 0 and 24 h after oviposition, just prior to subsequent ovulation and oviposition. Western blot analysis confirmed the presence of COX-1 and COX-2 in all oviductal segments. The density of COX-2 was the highest in the uterus, and did not change during the ovulatory cycle. COX-1 and COX-2 were localized in the surface epithelium of all oviductal segments besides the uterine tubular glands. We conclude that both COXs are differentially expressed in the different oviductal segments with a temporal association to ovulation and oviposition. COX-1 and COX-2 may play an important role in the infundibulum and uterus, respectively, and COX-2 may be one of the factors regulating the induction of oviposition. PMID- 28708507 TI - Effects of diluents and plasma on honey bee (Apis mellifera L.) drone frozen thawed semen fertility. AB - Cryopreservation is an advanced method used to protect germplasm in liquid nitrogen. Honey bees are of special interest to protect because of their pollination activity and critical role in agriculture. There has been important progress in the cryopreservation of honey bee germplasm in recent years, leading to practical recovery of genetic material for breeding purposes following freezing. However, there remains room for improvement and the goal of the present study was to evaluate the effect of different "extenders" added post-thaw on the fertilization rate of cryopreserved honey bee semen. The purpose of adding extender post-thaw was to dilute the cryoprotectant to remove chemicals after centrifugation because of potential adverse effects. The control consisted of frozen-thawed semen without the addition of an extender; treatment groups included the addition of one of the following extenders: glucose solution, fresh ram semen plasma, fresh honey bee semen plasma, extender solution. All of the above treatments and frozen-thawed control were compared to fresh semen. For each group, 15 virgin queens were instrumentally inseminated with the semen-diluent solution and introduced into nucleus colonies to determine the brood patterns of the queens. Percentages of worker brood produced in the fresh semen, frozen thawed semen control, glucose, fresh ram semen plasma, fresh honey bee semen plasma, and extender solution supplemented groups were 98.+/-1.1%, 47.0 +/- 0.9%, 3.0 +/- 0.8%, 0.3 +/- 0.1%, 48.1 +/- 4.1% and 40.3 +/- 2.4%, respectively. Similiarly, spermatozoa numbers in the spermathecae of the same treatment groups were 3.6 * 106, 1.6 * 106, 7.3 * 105, 4.7 * 105, 8.1 * 105, and 4.6 * 105 spermatozoa for the same treatment, respectively. The differences in both worker brood percentage and sperm count in the spermatheca were statistically significant (P < 0.01) among all treatment groups, except the frozen-thawed control group and fresh drone semen plasma group. We found a positive correlation between sperm count in the spermatheca and the percentage of worker brood (r = 0.91). With the exception of fresh honey bee semen plasma, the fertility rate was reduced following the addition of various plasmas and diluents post-freezing. PMID- 28708508 TI - Developmental changes in the histological structure of the testes, and testosterone profiles in male guinea fowls (Numida meleagris). AB - Owing to the paucity of information on the reproductive biology of guinea fowls, a study involving a total of 66 males was conducted, and documented the developmental changes in histological structure of the testes of guinea cocks from hatching until adulthood. Changes in testosterone synthesis during sexual development were also determined. Age-related changes were analysed using univariate analysis for completely randomised design and means separated using Tukey's test/Kruskal-Wallis test and medians separated by Mann-Whitney U test. Total germ cell population per testis and testicular histological morphometric parameters increased significantly (p < 0.0001) from 12 weeks of age (WOA), and stabilized between 20 and 24 WOA. Peripheral testosterone concentrations increased gradually from 4 WOA, and peaked at 20 WOA. Correlations among all the testicular morphometric parameters were positive and highly significant (p < 0.01). Similarly, significant (p < 0.05) positive correlations existed between testicular weight and testicular sperm production, tubular diameter, Sertoli cell population, tubular length and peripheral testosterone concentration. Testicular sperm production was positively correlated with meiotic index (p < 0.01) and round spermatids population (p < 0.05). The correlations between peripheral testosterone concentrations, tubular diameter and Sertoli efficiency were also significant (p < 0.05) and positive. Testicular morphometric parameters stabilized between 20 and 24 WOA, while peripheral testosterone concentrations showed two patterns of secretion, initial and final phases of increasing and decreasing testosterone secretions, respectively, and may be implicated in the development of histological structures of the testes and spermatogenesis. PMID- 28708509 TI - GDF8 activates p38 MAPK signaling during porcine oocyte maturation in vitro. AB - Growth Differentiation Factor 8 (GDF8) is a member of the transforming growth factor-beta (TGF-beta) family and has been identified as a strong physiological regulator. This factor is expressed as a paracrine factor in mural granulosa cells. To investigate the effects of GDF8 on the in vitro maturation (IVM) of porcine oocytes, we assessed the quality of matured oocytes as well as the specific gene transcription and protein activation levels in oocytes and cumulus cells (CCs) after IVM and subsequent embryonic development after in vitro fertilization (IVF) and parthenogenetic activation (PA). Supplemental concentrations (0, 1, 10, and 100 ng/ml) of GDF8 were provided in IVM medium. Supplementation with GDF8 during IVM induced transcription of specific TGF-beta receptor genes, such as ActRIIb and Alk4/5, and the recognition of the GDF8 by these receptors induced phosphorylation of p38 MAPK. Activated p38 MAPK signaling changed oocyte maturation and cumulus expansion-related gene transcription: Nrf2 and Bcl-2 in oocytes and PCNA, Nrf2, Has2, Ptx3, and TNFAIP6 in CCs. The altered gene expression pattern during IVM resulted in a 10% lower level of intracellular ROS in mature oocytes. The improved cytoplasmic maturation led to an increase in the fertilization efficiency and subsequent embryonic developmental competence. The embryonic development showed increases in the blastocyst formation rate and higher transcription levels of POU5F1 and BCL-2 in the blastocysts. The present study suggests that supplementation of GDF8 during IVM synergistically improved the developmental potential of IVF- and PA-derived porcine embryos by reducing the intracellular ROS level in oocytes by altering the transcription of specific genes and increasing the phosphorylation of p38 MAPK during IVM. In conclusion, for the first time, our results demonstrate that GDF8 can act as a paracrine factor to modulate oocyte maturation by regulating p38 MAPK phosphorylation and intracellular ROS level during porcine IVM. PMID- 28708510 TI - Changes in localization and density of CD63-positive exosome-like substances in the hen oviduct with artificial insemination and their effect on sperm viability. AB - Avian sperm are stored in the sperm storage tubules (SSTs) of the hen oviduct for a prolonged period. However, the precise mechanisms by which sperm are kept alive in the SSTs are still not fully understood. The aim of this study was to determine whether exosomes are secreted by SST cells and play a role in the survival of sperm. Utero-vaginal junction (UVJ) tissue from approximately 50 wk old White Leghorn hens was collected before (control group) and after intravaginal insemination with seminal plasma (SP group) or semen (AI group). The samples were used to prepare frozen sections and total protein extraction. The localization of the CD63, an exosome marker, was determined by immunohistochemistry and its protein level in the UVJ mucosal tissues was examined by Western blot. Exosomes were isolated from the culture media of UVJ and vaginal mucosa cells by ultracentrifugation and characterized by SDS-PAGE and Western blot. The viability and motility of sperm incubated with exosomes were also examined. CD63 was localized in the apical region of UVJ mucosal epithelium cells and SST cells of control, SP, and AI groups. The CD63 protein decreased in SST cells surrounding resident sperm and tended to appear in the SST lumen in the AI group. The protein level of CD63 in UVJ mucosal tissues was significantly higher in the AI group than control. The CD63 protein (approximately 75 kDa) was detected in ultracentrifugation pellets from the culture medium of UVJ and vagina cells. The viability of sperm incubated with 1 MUg/MUl vaginal exosomes was significantly decreased but was not affected by UVJ exosomes. These results suggest that exosomes were synthesized by SST cells and may be secreted into SST lumen when sperm were stored in SSTs. The role of SST exosomes in sperm storage needs to be examined further. PMID- 28708511 TI - FSH receptor binding inhibitor influences estrogen production, receptor expression and signal pathway during in vitro maturation of sheep COCs. AB - Follicle-stimulating hormone (FSH) promotes secretion of follicle fluid and follicle development. FSH acts via cognate FSH receptor (FSHR). It remains unknown whether the supplement of FSH-receptor binding inhibitor (FRBI) into the in vitro maturation (IVM)medium influence the estrogen receptor expression and signal pathway of oocytes in sheep. The present study aimed to investigate FRBI effects on inositol trisphosphate (IP3) of oocytes and protein kinase A (PKA) of sheep granulosa cells, further to elucidate the signal pathway of FRBI effects. Cumulus-oocyte complexes (COCs) were recovered from antral follicles. COCs were cultured for 24 h in the IVM medium supplemented with varying concentrations of FRBI (0, 10, 20, 30 and 40 MUg/mL) and FSH (10IU/mL). ELISA was used to measure the concentrations of estradiol (E2) and IP3 in the IVM medium. Western blotting was utilized to detect protein expression of ERbeta of COCs and protein kinase A (PKA) of granulosa cells. The results showed IP3 concentrations of FRBI-3 and FRBI-4 groups were less than that of CG and FSH groups at 22 h and 24 h (P < 0.05). PKA levels of FRBI-3 and FRBI-4 groups were significantly less than that of CG and FSH group (P < 0.05 or P < 0.01). Expression levels of ERbeta mRNA and protein of FRBI-treated groups were gradually decreased in comparison to CG and FSH group. The minimum value was detected in the FRBI-4 group. ERbeta protein level of the FRBI-4 group was significantly less than that of FSH group (P < 0.05). E2 concentrations of FRBI-treated groups were elevated as compared to CG, with the highest increment of FRBI-2 group (P < 0.05). Our results revealed a higher dose of FRBI reduced IP3 production. FRBI could suppress slightly expression levels of ERbeta mRNA and protein of COCs and PKA of granulosa cells, additionally increased E2 production of sheep COCs. PMID- 28708512 TI - Insulin during in vitro oocyte maturation has an impact on development, mitochondria, and cytoskeleton in bovine day 8 blastocysts. AB - Insulin is a key metabolic hormone that controls energy homeostasis in the body, including playing a specific role in regulating reproductive functions. Conditions associated with hyperinsulinemia can lower developmental rates in bovine in vitro embryo production and are linked to decreased fertility in humans, as in cases of obesity or type 2 diabetes. Embryo quality is important for fertility outcome and it can be assessed by choosing scoring standards for various characteristics, such as developmental stage, quality grade, cell number, mitochondrial pattern or actin cytoskeleton structure. Changes in the embryo's gene expression can reflect environmental impacts during maturation and may explain morphological differences. Together with morphological evaluation, this could enable better assessment and possibly prediction of the developmental potential of the embryo. The aim of this study was to use a bovine model to identify potential gene signatures of insulin-induced changes in the embryo by combining gene expression data and confocal microscopy evaluation. Bovine embryos were derived from oocytes matured in two different insulin concentrations (10 ug mL-1 and 0.1 ug mL-1), then stained to distinguish f-Actin, DNA and active mitochondria. The total cell number of the embryo, quality of the actin cytoskeleton and mitochondrial distribution were assessed and compared to an insulin-free control group. A microarray-based transcriptome analysis was used to investigate key genes involved in cell structure, mitochondrial function and cell division. Our results indicate that insulin supplementation during oocyte maturation leads to lower blastocyst rates and a different phenotype, characterised by an increased cell number and different actin and mitochondrial distribution patterns. These changes were reflected by an up-regulation of genes involved in cell division (MAP2K2; DHCR7), cell structure (LMNA; VIM; TUBB2B; TUBB3; TUBB4B) and mitochondrial activation (ATP5D; CYP11A1; NDUFB7; NDUFB10; NDUFS8). Taken together, we hypothesise that the increased proliferation in the insulin-treated groups might impair the developmental potential of the embryos by inducing metabolic stress on the molecular level, which could be detrimental for the survival of the embryo. PMID- 28708513 TI - Interaction of extender composition and freezing method for effective semen cryopreservation in the North American river otter (Lontra canadensis). AB - Semen cryopreservation and storage in genome resource banks (GRBs), in combination with artificial insemination (AI), could be invaluable for genetic management and conservation of endangered otter species. For any applied conservation benefit, effective methods for otter sperm processing and cryopreservation first must be established. In this study, our objective was to develop an effective semen cryopreservation method for the North American river otter, evaluating the effect of extender composition (i.e., glycerol concentration, Equex STM paste supplementation) and freezing protocol (timing of glycerol addition, pre-freeze cooling rate, freezing/packaging method) on post thaw sperm motility, longevity and acrosome status. Semen was collected from 14 otters housed at 9 zoos, and following cryopreservation in an egg-yolk based extender, thawed to assess sperm motility and acrosome status immediately post thaw and during 6 h of in vitro culture. Results indicated that extender containing 4% glycerol was preferable (p < 0.05) to 8% glycerol but the temperature/timing of extender addition containing 4% glycerol did not affect (p > 0.05) post-thaw sperm parameters. Treatments with extender containing Equex and frozen by pelleting on dry ice showed greater (p < 0.05) motility and percentage of intact acrosomes compared to treatments frozen in extender without Equex, regardless of pre-freeze cooling rate. In the absence of Equex, pelleting provided superior post-thaw sperm motility (p < 0.01) and higher (p < 0.001) percentage of sperm with intact acrosomes compared to samples frozen in straws over liquid nitrogen vapor. Results of this study indicate that cryopreservation of otter sperm using an egg-yolk -TEST based extender containing 4% glycerol and 1% Equex, with the pellet freezing method, provided superior post-thaw sperm motility, longevity and acrosomal integrity compared to other combinations. Neither alterations in timing of glycerolated extender addition nor pre-freeze cooling rate had a discernable effect on post-thaw otter sperm parameters. These findings represent the first assessment of semen cryopreservation in any otter species and may be of value as a model for development of semen cryopreservation strategies in other endangered otter species. PMID- 28708514 TI - Feeding rosemary leaves powder ameliorates rooster age-related subfertility. AB - Having a high proportion of polyunsaturated fatty acids avian spermatozoa predispose to lipoperoxidation which results in fertility reduction. In the current study, rosemary leaves powder (RLP) was fed to senescent breeder roosters to improve their reproductive performance. Twenty four 70-week-old roosters were randomly divided into four groups and received following treatments including 0 (RLP-0), 2.5 (RLP-2.5), 5 (RLP-5) or 7.5 (RLP-7.5) g of RLP/kg of diet for eight consecutive weeks. Semen characteristics were evaluated weekly. Sperm penetration rate was assessed once, however, fertility, hatchability, embryonic mortality and hatchling quality evaluated twice (using eggs collected during 1st and 2nd weeks following AI) at the end of experiment. Excluding body weight and sperm abnormality percentage, other traits including semen concentration (RLP-2.5 = 3.57, RLP-5 = 4.21 and RLP-7.5 = 3.79; SEM = 0.12; p < 0.01), total sperm production (RLP-2.5 = 1.33, RLP-5 = 1.8 and RLP-7.5 = 1.47; SEM = 0.07; p < 0.01), forward motility (RLP-2.5 = 72.96, RLP-5 = 83.65 and RLP-7.5 = 78.84; SEM = 0.47; p < 0.01) and viability (RLP-2.5 = 82.93, RLP-5 = 88.69 and RLP-7.5 = 86.85; SEM = 0.45; p < 0.01) were improved in RLP treated groups compared to control group (3.08 +/- 0.12, 1.05 +/- 0.07, 68.39 +/- 0.47 and 76 +/- 0.45 for semen concentration, total sperm production, sperm forward motility and viability, respectively). In addition, semen volume and sperm plasma membrane functionality were higher in both RLP-5 (0.43 +/- 0.01 and 66.66 +/- 0.55) and RLP-7.5 (0.39 +/- 0.01 and 65.52 +/- 0.55) than control group (0.34 +/- 0.01; p < 0.05 and 62.89 +/- 0.55; p < 0.05). Supplementation of RLP significantly decreased semen Malondialdehyde (MDA) concentration. Moderate level of RLP (RLP 5) had significantly higher numbers of sperm penetration holes compared to other groups. Fertility rate of collected eggs from both RLP-5 (first week: 91.09 +/- 1.27 (P < 0.01); second week: 88.73 +/- 1.27 (p < 0.05)) and RLP-7.5 (first week: 93.11 +/- 1.27 (P < 0.01); second week: 90.87 +/- 1.27 (p < 0.05)) groups was higher than other groups at 1st and 2nd weeks of egg collection. Hatchability of eggs set at 2nd week (83.64 +/- 3.54; p < 0.05) was higher and embryonic mortality at 1st week (1-6 day mortality: 5.03 +/- 1.25 (p < 0.05); 18-21 day and pipped mortality: 8.55 +/- 1.31 (p < 0.05)) was in RLP-0.5 group than other groups, respectively. To conclude, RLP supplementation could successfully attenuate age-related sub-fertility in senescent roosters. Further studies are needed to divulge the causal mechanisms involved. PMID- 28708515 TI - Stage-specific expression of Sal-like protein 4 in boar testicular germ cells. AB - Spermatogenesis, the complex process of sperm cell development including mitotic cell division and meiosis, relies on spermatogonial stem cells (SSCs). While markers for developing germ cells have been well investigated in mice, developmental stage-specific markers of germ cells in domestic animals have not been identified. Sal-like protein 4 (SALL4) is known as a putative marker for undifferentiated spermatogonia in rodents; however, its expression in domestic animals has not been investigated. The objective of this study was to characterize the expression of SALL4 in the developmental stages of boar testes and SSCs. Interestingly, all SALL4-expressing cells responded positively to PGP9.5, which is known as a spermatogonia marker in boar testes, while some PGP9.5-positive cells did not express SALL4 in pre-pubertal boar testes. At this stage, the expression of SALL4 was observed in GFRalpha1-positive cells, and its expression was maintained in cultured pSSCs in vitro, suggesting that SALL4 is a marker of early-stage boar spermatogonia that express GFRalpha1 in pre-pubertal testes. Additionally, SALL4 expression was observed in c-Kit-positive but not in PGP9.5- or SCP3-positive cells in post-pubertal testes. In conclusion, SALL4 is expressed in early undifferentiated spermatogonia in pre-pubertal boar testes and in primary spermatocytes in post-pubertal boar testes. Therefore, SALL4 can be used as a stage-specific marker of developing germ cells in boar testes. PMID- 28708516 TI - Peroxisome proliferator-activated receptor (PPAR) isoforms are differentially expressed in peri-implantation porcine conceptuses. AB - Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor family of ligand-dependent transcription factors. PPARs are critical regulators of glucose homeostasis and lipid metabolism, and affect cell proliferation and differentiation. In the current study, we examined (1) the profiles of PPARA, PPARD, and PPARG mRNA expression and DNA binding activity in porcine conceptuses collected on Days 10-11 (spherical and tubular conceptuses), 11-12 (filamentous conceptuses), 13-14, and 15-16 (elongated conceptuses) of pregnancy, (2) the presence of PPARA, PPARD, and PPARG proteins in Days 10, 12, and 15 conceptuses. Moreover, we analyzed the abundance of retinoid X receptor (RXR; PPARs heterodimer partner) transcripts as well as the correlation between PPARs mRNA expression and the expression of genes important for and/or associated with elongation of porcine conceptuses: aromatase (CYP19A1), prostaglandin endoperoxide synthase 2 (PTGS2), glucose transporter 1 (SLC2A1), and interleukin 1B (IL1B). PPARA mRNA expression in conceptuses did not change during Days 10-14 of gestation, but was greater on Days 15-16 compared to Days 10-11 (P < 0.05). A considerable increase in PPARD and PPARG mRNA expression was observed in filamentous conceptuses from Days 11-12 compared to spherical and tubular conceptuses from Days 10-11 (P < 0.01), followed by a decrease on Days 13-14 and 15-16 (P < 0.05). PPARA, PPARD, and PPARG proteins were present in conceptus tissue demonstrating nuclear localization clearly visible on Days 12 and 15 of pregnancy. DNA binding activity of the PPARD isoform was greater in filamentous conceptuses from Days 11-12 than in spherical and tubular conceptuses from Days 10-11 (P < 0.01). Moreover, concentrations of active PPARD and PPARG proteins in nuclear fractions of conceptus tissue were greater on Days 11-12 compared to Days 13-14 and 15-16 of pregnancy (P < 0.05). RXRA, RXRD, and RXRG mRNA expression in conceptuses increased on Days 11-12 compared to Days 10-11 (P < 0.05). PPARD and PPARG mRNA expression showed strong positive correlations with PTGS2 mRNA expression (P < 0.0001). Additionally, PPARD gene expression correlated with SLC2A1 and IL1B mRNA expression (P < 0.01). Collectively, these results indicate that among all three PPARs expressed in peri-implantation porcine conceptuses, PPARD and PPARG may be involved in conceptus elongation before implantation. PMID- 28708517 TI - Factors affecting the reproductive performance of bitches: A prospective cohort study involving 1203 inseminations with fresh and frozen semen. AB - The aim of this prospective cohort study was to utilize multivariable statistical methods to identify factors that significantly affected whelping rate, litter size and gestation length in a large population of bitches of many different breeds, presented for routine breeding management. In addition, we aimed to determine the incidence of dystocia and the proportion of bitches undergoing a caesarean section procedure. A total of 1146 individual bitches representing 84 different breeds contributed 1203 inseminations over the 9 year (2007-2015) study period. Bitches were inseminated with either frozen-thawed (n = 645), fresh (n = 543) or chilled (n = 15) semen from 1371 different males. The mean (SD) whelping rate was 74+/- 4% and the mean litter size was 5.8 +/- 3.1 pups per litter for all bitches in the study. The whelping rate was significantly lower in bitches inseminated with frozen-thawed semen compared with bitches inseminated with fresh semen (71% vs 80% respectively; P < 0.001). Semen that was classified as having poor motility (<30% progressive) resulted in a significantly lower whelping rate (37%) than semen classified as good (30-65% progressive; whelping rate = 67%) or excellent (>65% progressive; whelping rate = 79%). There was a linear decline in whelping rate with advancing age. Greyhounds and Labradors demonstrated a significantly higher whelping rate (88% and 94% respectively) compared with all other breeds (71.3%, P < 0.001). Bitches inseminated with frozen-thawed semen had significantly smaller litter sizes than bitches inseminated with fresh semen (5.4 +/- 3.1 vs 6.2 +/- 3.0 pups per litter respectively; P = 0.02). Smaller breeds had significantly smaller litters (4.4 +/- 2.1 pups) than medium (5.2 +/- 2.9 pups), large (5.9 +/- 2.9 pups) or giant (6.7 +/- 3.8 pups) breeds. For each advancing year of age, litter size decreased by 0.13 pups per litter. The mean (SD) gestation length from LH0 was 65 +/- 1.9 d. Greyhounds had a significantly longer pregnancy duration (68.0 +/- 1.5 d) than other breeds. For each additional year of bitch age, gestation length increased by 0.11 days (P < 0.01), and for each additional pup per litter, gestation length was reduced by 0.08 days (P < 0.05). Of the 890 bitches for which whelping outcomes were recorded; 409 (46%) whelped normally without assistance, 249 (28%) had an elective C-section, 205 (23%) underwent an emergency C-section and 27 (3%) were medically managed or required veterinary assistance for dystocia. Brachycephalic breeds were 11.3 (95CI = 9.3-17.9; P < 0.001) times more likely to have a C-section compared to all other breeds. Bitches with litter sizes of one or two pups had a C-section rate of 83%, whereas bitches with litter sizes of three or more pups had a C section rate of 43% (P < 0.001). This study provides important clinical information to optimise whelping rates, litter size and the prediction of whelping in certain breeds for clinicians working in canine reproduction. PMID- 28708518 TI - Ultrasonography to assist with timing of spawning in European eel. AB - Ovulation in the European eel can be induced by injection of DHP (17alpha,20beta dihydroxy-4-pregnen-3-one). The timing of injection is based on the developmental stage of the oocytes. The oocyte stage is determined by invasive biopsy or through external indicators of the oocyte hydration response: body weight index (BWI) and body girth index (BGI). However, in European eel, BWI and BGI are inaccurate indicators because the individual hydration response is highly variable. The aim of this study was to identify indicators of oocyte maturation non-invasively by applying ultrasonography. Ultrasound parameters that were determined were the body wall thickness; diameter of the cloaca opening; grey scale median (GSM) of the ovary, and diameters (vertical and horizontal) and surface area of ovary, liver and swim bladder. Data of farmed and wild eels were combined for correlation analyses and principal component analyses (PCA). Ovary and liver parameters were not correlated with the average oocyte stage. Body wall thickness was negatively correlated to the average oocyte stage but variability was high. The swim bladder vertical diameter (Sbv) was negatively correlated with the average oocyte stage and with the oocyte diameter. Swim bladder area (Sba) was also negatively correlated to the average oocyte stage but less accurate. Results showed that during the final stages of oocyte maturation, the swim bladder becomes smaller. This is most probably due to the pressure that is caused by the increasing ovaries as a result of the oocyte hydration response. Females with an average oocyte stage between 4.5 and 7.0 and an average oocyte diameter higher than 800 MUm, had Sbv values decreasing from 4.3 to 2.4 mm and Sba values from 52 down to 11 mm2. The correlation between Sbv and oocyte stage is more strict than for BWI or BGI which makes Sbv not only a parameter that can be determined non-invasively but also one that is more accurate in indicating the oocyte developmental stage. Therefore, ultrasonography, and in particular the ultrasound imaging of the swim bladder, represents a useful tool to assist with the timing of spawning as induced by injection of DHP. PMID- 28708519 TI - Relationships between uterine health and metabolism in dairy cows with different dry period lengths. AB - The first objective of this study was to evaluate effects of dry period (DP) length and dietary energy source on ovarian activity, uterine health status, pregnancy rate, and days open in dairy cows in the second subsequent lactation after implementation of DP length and dietary treatments. The second objective was to determine relationships of uterine health status with ovarian activity, milk yield, energy balance (EB), and metabolic status in dairy cows. Holstein Friesian dairy cows (n = 167) were assigned randomly to 1 of 3 DP lengths (0-, 30 , or 60-d) and 1 of 2 early lactation diets (glucogenic or lipogenic diet) for 2 subsequent lactations. Milk samples were collected three times a week. At least two succeeding milk samples with concentration of progesterone >=2 ng/mL were used to indicate the occurrence of luteal activity. Vaginal discharge was scored in wk 2 and 3 after calving to evaluate uterine health status and cows were classified as having a healthy uterine environment [HU, vaginal discharge score (VDS) = 0 or 1 in both wk 2 and 3], a recovering uterine environment (RU, VDS = 2 or 3 in wk 2 and VDS = 0 or 1 in wk 3), or a non-recovering uterine environment (NRU, VDS = 2 or 3 in wk 3). Cows were monitored for milk yield, dry matter intake (DMI), and blood was sampled weekly to determine metabolic status from calving to wk 3 postcalving. Dry period length was not related with uterine health status in early lactation, pregnancy rate, or days open in dairy cows. Independent of DP length, feeding a glucogenic diet shortened the interval from calving to onset of luteal activity (25.3 vs. 31.0 d, P = 0.04), but decreased pregnancy rate compared with a more lipogenic diet (68.2 vs. 78.1 d, P = 0.03). In the first 3 wk after calving, cows with a NRU had lower milk yield (36.8 vs. 36.8 vs. 32.4 kg for cows with a HU, RU, or NRU, respectively; P < 0.01) and lower DMI than cows with a HU or RU. Cows with a RU had lower plasma glucose and insulin concentrations than cows with a NRU or HU. In conclusion, DP length did not influence fertility measures and uterine health status in the second subsequent lactation after implementation of DP length treatments. Independent of DP length, feeding a glucogenic diet leaded to earlier ovulation postcalving, but decreased pregnancy rate compared with a more lipogenic diet. In addition, a healthy uterine environment was related to greater milk yield and better metabolic status, independent of DP length. PMID- 28708520 TI - Ovulation rate, antral follicle count, and circulating anti-Mullerian hormone in Trio allele carriers, a novel high fecundity bovine genotype. AB - High fecundity genotypes in sheep are a valuable model to study the physiological mechanisms underlying follicle selection and the control of ovulation rate. Similar genotypes in cattle had not been described until the recent identification of a major bovine allele, termed Trio, which had a large effect on ovulation rate. The present study was designed to evaluate ovulation rate, antral follicle count (AFC), circulating ant-mullerian hormone (AMH), and the association among these measures in unstimulated and superstimulated Trio carrier cattle. We hypothesized that AFC and AMH would be variable among individual cows but would be similar between Trio carriers and non-carrier control cows and that there would be no association between these measures of follicle numbers and ovulation rate. In experiment 1, ovulation rate was determined during 4 consecutive estrous cycles in Trio carriers (n = 34) and non-carrier controls (n = 27). Ovulation rate, on average, was greater (P < 0.01) in Trio carriers (3.5 +/- 0.2) compared to non-carrier controls (1.1 +/- 0.1) with ~70% of carrier cycles (n = 136) having 3-4 ovulations while only ~5% had single ovulations. In contrast, non-carrier cycles (n = 108) were mostly single ovulation (89%) with none having more than two ovulations. In experiment 2, AFC, determined at wave emergence, was not different (P = 0.54) between Trio carriers (24.5 +/- 1.3; n = 45) and non-carrier controls (23.1 +/- 0.9; n = 37), and no correlation was found between AFC and mean ovulation rate in either genotype (r = -0.009 and r = -0.07; P > 0.70, respectively). In Experiment 3, circulating AMH was also not different between genotypes (P = 0.65) while correlations were found between AFC and AMH in Trio carriers (r = 0.43; P = 0.05; n = 27) and non-carrier controls (r = 0.78; P < 0.01; n = 19). In experiment 4, AFC and AMH were determined in Trio-carriers (n = 9) in relation to a synchronized follicular wave which was unstimulated or stimulated with exogenous FSH. Stimulation with FSH increased ovulation rate, compared to unstimulated Trio carriers, however no association was found between AFC or AMH and ovulation rate regardless of whether superstimulation with exogenous FSH was used. In conclusion, the novel high fecundity bovine genotype Trio, results in consistent multiple ovulations despite having similar AFC and AMH. Therefore, our results suggest that differences in antral follicle numbers during the final stages of follicle development are not a key component of the mechanism underlying multiple ovulations in Trio carriers. PMID- 28708521 TI - Flow-cytometric enrichment of Pacific bluefin tuna type A spermatogonia based on light-scattering properties. AB - We previously established surrogate broodstock in which the donor germ cells transplanted into the peritoneal cavities of xenogeneic recipients were capable of developing into functional eggs and sperm in teleost fish. In this transplantation system, only the undifferentiated germ cells such as type A spermatogonia (ASG) or a portion of the ASG population were capable of being incorporated into the genital ridges of the recipients and undergo gametogenesis. Therefore, the use of enriched ASGs can be expected to achieve efficient donor cell incorporation. Here, we established a method of isolation and enrichment of the ASG of Pacific bluefin tuna using flow cytometry. Whole testicular cell suspensions were fractionated by forward and side scatter properties, following which ASGs were enriched in a fraction in which the forward scatter signal was relatively high and side scatter signal was relatively low. The diameter of sorted cells using the fraction was identical to the size of ASGs observed in histological analysis, and these cells also expressed the vasa gene. In addition, we succeeded in applying this method to several maturation stages of Pacific bluefin tuna. Since this method was based on light-scattering characteristics of ASGs, it can potentially be applied to various teleosts. We expect that this method can contribute to the production of seeds of Pacific bluefin tuna using surrogate broodstock. PMID- 28708522 TI - iTRAQ-based proteomic profiling of granulosa cells from lamb and ewe after superstimulation. AB - The number of oocytes obtained from lambs after FSH treatment is far greater than those acquired from adult ewes. However, these oocytes typically have reduced viability in comparison with adult ewe oocytes. However, the molecular mechanisms of differences in viability between lamb and ewe oocytes remain unknown. In the present research, we applied iTRAQ coupled with LC-MS/MS proteomic analysis in order to investigate the proteomic expression profile of granulosa cells from lambs and ewes following stimulation with FSH. We detected 5649 proteins; 574 were differentially expressed between adults and juveniles. Based on Gene Ontology enrichment and KEGG pathway analysis, the majority of DEPs are participated in metabolic processes, ribosome and MAPK signaling pathways. Expression levels in ewes turned out to be lower than lambs. Protein interaction network analysis generated by STRING identified MAPK1, SMAD2, SMAD4, CDK1, FOS and ATM as the major findings among 54 significant differentially expressed of proteins. Quantitative real-time PCR analysis was applied to verify the proteomic analysis. These proteins which were identified in lambs may contribute to the reduction of oocyte quality compared to adults. The present research provides understanding of the molecular mechanism for follicle development in lambs. PMID- 28708523 TI - Timing of transcriptomic and proteomic changes in the bovine placentome after parturition. AB - Proper post-partum reproductive performance is important for reproductive efficiency in beef cows, and dystocia decreases post-partum fertility. Crossbred beef cows (n = 1676) were evaluated for lifetime performance based on degree of dystocia at presentation of the first calf. Cows that experienced moderate or severe dystocia produced fewer calves during their productive life (P < 0.01). The exact mechanism is unclear, but may be due to the contributions of dystocia to abnormal placental separation. Proteolytic activity is hypothesized to contribute to placental separation in ruminants; however, when ovine placentomes were collected following caesarian section, no proteolytic activity was detected. We hypothesized that stage 2 of parturition was necessary to stimulate proteolysis and initiate placental separation. Serial placentome collections were performed on mature cows (n = 21 initiated; 7 with complete sampling) at hourly intervals for the first 2 h after expulsion of the calf. An intact piece of each placentome was fixed for histological evaluation, and a separate piece of caruncular and cotyledonary tissue from each placentome was frozen for transcriptomic and proteolytic analysis. A full set of placentomes was collected from only 7 of 21 cows at 0, 1, and 2 h, and all cows had expelled fetal membranes by 6 h. Histological, transcriptomic and proteolytic analysis was performed on placentomes from cows from which three placentomes were collected (n = 7). The microscopic distance between maternal and fetal tissues increased at 1 h (P = 0.01). Relative transcript abundance of matrix metalloprotease 14 (MMP14) tended to increase with time (P = 0.06). The relative transcript abundance of plasminogen activator urokinase-type (PLAU) was greater in caruncles than cotyledons (P = 0.01), and tended (P = 0.10) to increase in the caruncle between 0 and 2 h while remaining unchanged in the cotyledon over the same span of time. Greater PLAU and plasminogen activator tissue-type (PLAT) proteolytic activity was detected by zymography in the caruncle than the cotyledon immediately post partum (P < 0.01). From these findings we conclude that 1) dystocia during the first parity decreases lifetime productivity in beef cattle, 2) the PA system is present at both the transcript and protein level in the bovine plactentome during parturition and 3) proteolytic activity is localized to the caruncular aspect of the placentome. PMID- 28708524 TI - Follicular waves and hormonal profiles during the estrous cycle of carriers and non-carriers of the Trio allele, a major bovine gene for high ovulation and fecundity. AB - A high fecundity bovine genotype has recently been discovered and genetic mapping indicates evidence for segregation of a major gene with influence on ovulation rate located on bovine chromosome 10. Cattle carrying the high fecundity allele, referred to as the Trio allele, have multiple ovulations while half-sibling, non carriers generally have single ovulations. The present study was designed to evaluate follicle wave patterns and associated circulating hormones during the estrous cycle of Trio allele carriers (n = 7) and non-carrier half-sib controls (n = 5). We hypothesized that Trio allele carriers would exhibit multiple smaller dominant follicles and greater circulating FSH than non-carrier controls. The proportion of Trio carrier and non-carrier cows with 2 or 3-wave patterns was not different between genotypes with the majority (>70%) exhibiting 3-wave patterns. Trio carriers had greater (P < 0.01) number of ovulations (~4 vs ~1 ovulations) and smaller preovulatory follicles (8.9 vs. 14.9 mm; P < 0.01) than non-carrier controls. However, total luteal tissue volume and circulating progesterone, normalized to the initial ovulation or to the onset of luteolysis, were not different between genotypes (P > 0.10). Follicular waves were found to be associated with an FSH surge in both genotypes. Peak FSH concentration at each follicular wave (3-wave patterns) was not different (P > 0.05) between genotypes, but circulating FSH during the decline and nadir, encompassing the day of deviation, was greater (P < 0.05) in Trio carriers. Despite a difference (P = 0.032) in the length of the estrous cycle (23.0 vs. 25.2 d; Trio carrier and non carriers respectively), the pattern of follicle growth, such as day of wave emergence, day of follicle deviation, and day of maximum diameter of the dominant follicle, when normalized to the FSH surge of each follicular wave were similar in Trio carriers compared to non-carriers although Trio carriers consistently had much smaller-sized follicles (P < 0.05). Thus, decreased follicle size and greater circulating FSH are key components of the mechanism that produces multiple ovulations in cattle that are carriers of the Trio high fecundity allele. PMID- 28708525 TI - Assessment of the age for a preventive ultrasonographic examination of the prostate in the dog. AB - The prostate commonly develops benign prostatic hyperplasia (BPH) in dogs over 5 years, while in aged dogs other pathological findings might be revealed by ultrasonographic exam. The aim of the present study was to estimate the most suitable age for a preventive ultrasonographic examination of the prostate in the dog. The prostate of 1003 intact male dogs of 64 different breeds, of different ages (1-18 years) and bodyweights (2-55 kg) was evaluated with ultrasound, irrespective of the reason for clinical examination. The age of each dog was expressed as the ratio between the actual age and the maximum longevity expected for the breed. Dogs were divided in two groups based on breeds' life expectancy as short life (SL) and long life (LL). The size of the prostate (normal, enlarged or small) and the presence of abnormal sonographic findings were recorded for each dog. The results of the present study indicate that the most suitable age for a preventive ultrasonographic exam of the prostate in the dog is approximately at 40% of its expected longevity, both in short and long life breeds, because at this age there is a strong possibility to be able to detect abnormal prostatic findings. In 47.5% of the dogs at least one abnormal finding of the prostate was revealed by ultrasonographic exam, while dogs with long life expectancy showed a significantly higher prevalence of abnormalities, than dogs with short life expectancy. The most frequent findings were the increase of prostatic size (33.5%) and the presence of at least one cyst (33.6%), with no difference between SL and LL dogs. In conclusion, a preventive examination of the prostate starting at 40% of expected longevity in dogs of short and long life breeds is strongly recommended for early detection of abnormalities, for scheduling specific follow up and for suggesting effective therapeutic protocols. PMID- 28708526 TI - Progesterone concentration and lambing rate of Karakul ewes treated with prostaglandin and GnRH combined with the ram effect during breeding and non breeding seasons. AB - The combination of ram effect with two injections of PGF2alpha 10-days apart and the same protocol plus an additional injection of GnRH prior to the first injection of PGF2alpha were examined in Karakul ewes during breeding and non breeding seasons, respectively. Plasma progesterone (P4) concentrations (to detect the presence of active corpus luteum), twin lambing, litter size and synchronization of lambing were evaluated. In each study 70 ewes (2-4 years old) were divided to a treatment (n = 40) and a control (n = 30) group. During the breeding season, on days -10 and 0 before ram release, the treatment group was injected intramuscularly with PGF2alpha (D-Cloprostenol; 0.15 mg). During the non breeding season, on day -15 before ram release the treatment group was injected with GnRH (buserelin; 4.2 MUg) intramuscularly followed by two injections of PGF2alpha on days -10 and 0. In both studies, the rams were released into the ewe flock after the second prostaglandin injection (day 0). Blood samples of ewes were collected on days -10, 0, 20 and 70 of the study in breeding season and on days -15, -10, 0, 20 and 70 during non-breeding season. The treatment group had higher P4 concentrations compared to the control ewes on day 0 in the breeding season (5.80 +/- 0.61 vs. 5.0 +/- 0.93 ng/mL) and day -10 in the non-breeding season (3.50 +/- 0.33 vs. 2.70 +/- 0.35 ng/mL) though the differences were not significant (P > 0.05). Based on plasma P4 concentrations (>1 ng/mL) on day 70, in the breeding season all control ewes (100%) and 91.9% of the treatment ewes were detected to have active corpus luteum (P = 0.09). An almost inverse result (90% vs. 97.5%; P = 0.2) was detected in the non-breeding season. The lambing rate was higher (P = 0.03) in the treatment group compared to the control ewes during the non-breeding season (90% vs. 70%), but tended to be lower (P = 0.07) in the breeding season (73% vs. 90%). Twin lambing rate was higher in the treatment group compared to the control ewes in the breeding (40.7% vs. 0.0%; P < 0.05) and non-breeding (22.2% vs. 0.0%; P < 0.05) seasons. The litter size of the control and treated ewes were 1.0 +/- 0.0 vs. 1.40 +/- 0.10 in the breeding and 1.0 +/- 0.0 vs. 1.22 +/- 0.10 in the non-breeding season (P < 0.05). No effect was observed regard to synchronization of the treated ewes. In the breeding season two injections of PGF2alpha ten days apart combined with ram effect, may lower the lambing rate, but may enhance twin pregnancies and litter size in Karakul ewes. In the non-breeding season, however, the GnRH-PGF2alpha treatment plus ram effect may enhance the lambing rate, twin pregnancies and litter size. PMID- 28708527 TI - Artificially extended photoperiod administered to pre-partum mares via blue light to a single eye: Observations on gestation length, foal birth weight and foal hair coat at birth. AB - In seasonally breeding animals, photoperiod perception is crucial for timing of important physiological events. In the horse, long day photoperiod influences the onset of ovulation and cyclicity, shedding of the heavier winter coat and the timing of parturition. In this compilation of studies, conducted across three breeding seasons and two countries, the impact of artificially extended day length was investigated on gestation length, foal birth weight and foal hair coat at birth. The light therapy was administered to pre-partum mares via mobile head worn masks which provided short wavelength blue light to a single eye. In Study 1, reductions in gestation lengths were observed following administration of artificially extended day length (124.8 +/- 15.11 days) in the final months of pregnancy to a group of Thoroughbred mares compared to controls (P < 0.05; 339.7 +/- 9.56 days vs 350.6 +/- 9.13). Study 2 revealed that pre-partum exposure to artificially extended day length (104.6 +/- 9.89 days) increased foal birth weight compared to controls (47.13 +/- 2.93 kg vs 43.51 +/- 6.14 kg; P < 0.05) in mares bred early in the year. In Study 3, artificially extended day length (87.53 +/- 19.6 days) administered to pre-partum mares affected the coat condition of foals at birth with respect to hair weight (P < 0.0001) and hair length (P < 0.0001) compared to controls (0.34 +/- 0.20 MUg vs 0.59 +/- 0.12 MUg and 1.93 +/- 0.56 cm vs 2.56 +/- 0.32 cm, respectively). Collectively, these studies serve to highlight the influential role of the circa-annual changes in photoperiod length on the pre-partum mare for normal foetal development during the natural breeding season. It also emphasizes the potential that exists to improve breeding efficiency parameters by artificially simulating this important environmental cue in the latter stages of gestation against the backdrop of an economically driven early breeding season. PMID- 28708528 TI - Competition for oestrous ewes between rams reared by their mothers or artificially reared: Effects on sexual behaviour and testosterone and cortisol serum concentrations. AB - The objective of this study was to determine how the social competition for an oestrous ewe affects the sexual behaviour and the endocrine response in two groups of rams, one reared by their mothers and another artificially reared. Thus, we compared the sexual behaviour and testosterone and cortisol changes in each group of rams in competitive and non-competitive tests, both during the first and second breeding seasons. Two groups of rams were: 1) artificially reared lambs, separated from their dams 24-36 h after birth (Week 0) and artificially fed with sheep milk until 10 weeks of age (group AR, n = 14); and 2) lambs reared by their dams until 10 weeks of age (group DR, n = 13). Rams were subjected to non-competitive and competitive tests for an oestrous ewe during their first and second breeding seasons, when they were 8 and 20 months old, respectively. Sexual behaviours toward an oestrous ewe were recorded during 20 min and the testosterone and cortisol concentrations were determined in serum samples collected immediately before the test, and 20, 40 and 60 min after it. During the first breeding season, the number of flehmen decreased in DR rams, and the number of flehmen and ano-genital sniffings also decreased in DR rams, but the frequency of some copulatory behaviours increased (matings and ejaculation/total mounts in DR rams, and total mounts in AR rams) in competitive tests. During the second breeding season, competition caused a decrease in the number of all the recorded behaviours (courtship and copulation) with the exception of flehmen in AR rams; however, in DR rams only the number of the copulatory behaviours decreased under competition. Competition did not affect the endocrine response during the first breeding season. During the second breeding season, while testosterone concentrations were greater in non-competitive than in competitive tests at 60 min (P = 0.0008) in AR rams, in DR rams it tended to be greater (P = 0.09). Competition did not affect cortisol concentrations in any group or season, but in all tests the concentrations increased at the end of the test (P < 0.05). In conclusion, the lack of the mother during rearing negatively affected the sexual motivation and the testosterone response of rams to oestrous ewes in competitive tests, effects that were more evident when adults. Neither the absence of the mother during rearing nor competition for oestrous ewes affected the stress response (evidenced by increase in cortisol concentration) in rams during both seasons. PMID- 28708529 TI - Maternal and non-maternal factors associated with late embryonic and early fetal losses in dairy cows. AB - Defining factors associated with embryonic and/or fetal losses will be helpful in overcoming such problem, either by adjusting conditions or applying therapeutic approaches to high-risk cows. The objective of this study was to investigate the association between a number of maternal and non-maternal factors and the risk of late embryonic (LED) and early fetal death (EFD) in dairy herds. Additionally, we investigated the effect of treating pregnant cows either with GnRH on day 26 post insemination, or GnRH on day 26 plus CIDR insertion between days 26 and 33 post insemination, on the risk of LED/EFD. From 3826 pregnancies, diagnosed at day 30 post-insemination, 851 cows lost the pregnancy by day 70 post-insemination. A mixed-effects logistic model was constructed to assess the effect of cow breed, calving difficulty, postpartum problems, lactation number, days in milk, insemination number, actual 305-day milk production, temperature humidity index (THI) at insemination, estrus synchronization protocols, and other factors, on the risk of LED/EFD. Our findings indicated that Holstein X Brown Swiss crossbreed cows had a lower risk for LED/EFD than Holstein cows (P < 0.05). Cows that had postpartum problems, were inseminated for the first time, produced more milk, or were inseminated at THI >=75, recorded higher risks of LED/EFD (P < 0.05). Calving difficulty, lactation number, and synchronization protocols were not found to be associated with LED/EFD. Moreover, treatment of the pregnant cows with GnRH on day 26 post-insemination plus CIDR insertion between days 26 and 33 post-insemination decreased the risk of LED/EFD. In conclusion, cows that had postpartum problems, were inseminated early postpartum, produced higher milk, and/or were inseminated at high THI, were under higher risk of LED/EFD. Treating such cows with GnRH on day 26 plus CIDR insertion between days 26 and 33 may decrease the possibility of the LED/EFD. PMID- 28708530 TI - BAMBI promotes porcine granulosa cell steroidogenesis involving TGF-beta signaling. AB - Transforming growth factor beta (TGF-beta), acting as the auto/para endocrine factors, has multi-function in mammalian follicle development. Bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI) is considered as a pseudoreceptor in the TGF-beta signal pathway which has the similar extracellular structure of TGF-beta receptor but lack of intracellular serine/threonine kinase domains. However, the biological function of BAMBI involved in porcine granulosa cell steroidogenesis remains unknown. This study was thus carried out to explore the effect of BAMBI on the steroidogenesis process in porcine primary granulosa cells. Our results showed overexpression of BAMBI promoted aromatase and StAR, but not P450scc and 3beta-HSD mRNA and protein expression levels in porcine primary granulosa cells, and increased the accumulation of estradiol and progesterone in the culture medium. Meanwhile, knockdown endogenous BAMBI decreased the mRNA expression levels of Cyp19a1 and Star and the accumulation levels of estradiol and progesterone. TGF-beta1 could decrease Cyp19a1 and Star mRNA expression and estradiol and progesterone production in a dose-dependent manner. Pre-treatment with BAMBI adenovirus reversed TGFbeta1-induced downregulation of Cyp19a1 and Star mRNA expression. Moreover, TGF-beta1 could induce the phosphorylation of SMAD3 in porcine granulosa cells. Pre-transfected with BAMBI adenovirus also inhibited TGF-beta1-induced downregulation of estradiol and progesterone production as well as TGF-beta1-induced phosphorylation of SMAD3 in porcine granulosa cells. These findings provided a potential mechanism by which BAMBI could regulate porcine granulosa cell steroidogenesis. PMID- 28708531 TI - Relationships among early postpartum luteal activity, parity, and insemination outcomes based on in-line milk progesterone profiles in Canadian Holstein cows. AB - The objectives of this retrospective study were to use in-line milk progesterone (mP4) data to investigate relationships of (1) commencement of luteal activity (CLA), and (2) luteal phase (LP) length and frequency preceding first postpartum AI, with parity and AI outcomes in Canadian Holstein cows. Starting 21 +/- 1 days postpartum (DPP), levels of mP4 were assessed every 2.2 +/- 2.0 d through an automated in-line milk analysis system (Herd NavigatorTM, DeLaval International, Tumba, Sweden) until ~55 d after first or second AI in 748 Holstein cows from two herds. The CLA was defined as the DPP of the first of at least two consecutive samples with mP4 >=5 ng/mL, and the period with elevated mP4 (>=5 ng/mL) was defined as the LP. Cows were categorized by CLA [earlier (<=) or later (>) than 28, 35, 42, 49, 56, and 63 DPP], and by the pattern of LP frequency preceding first AI as having or not: (1) one or more normal LP (LP length >=7 and <=19 d); (2) one or more abnormal LP (LP length <7 or >19 d, or interluteal period >=12 d); and (3) two or more LP (either normal or abnormal). Outcomes of first or second AI were determined by the interval between AI and cessation of the ensuing LP as: non-pregnant (mP4-decline <=30 d), presumed-pregnant (no mP4-decline until 55 d), or presumed-pregnancy loss (mP4-decline between 31 and <=55 d). The odds of pregnancy per AI (P/AI) at 55 d and pregnancy loss were evaluated using generalized linear mixed models. Primiparous cows had lower odds of having CLA <=28 DPP [Odds ratio (OR) = 0.58, P = 0.002] and one or more abnormal LP (OR = 0.73, P = 0.04) than multiparous cows. In multiparous cows, CLA <=28 DPP decreased pregnancy loss (OR = 0.48, P = 0.05) and CLA <=56 DPP increased P/AI (OR = 4.69, P < 0.01) compared to a later CLA. Primiparous and multiparous cows that had one or more normal LP before first AI had increased P/AI (OR = 3.85 and 3.45, respectively, P < 0.01) and reduced pregnancy loss (OR = 0.26 and 0.27, respectively, P < 0.01) than cows without a normal LP. Primiparous cows that had one or more abnormal LP had decreased P/AI (OR = 0.62, P = 0.04) and increased pregnancy loss (OR = 1.64, P = 0.04) compared to those without an abnormal LP. In summary, AI outcomes were improved in multiparous cows that had early CLA and in cows of both parity groups that had at least one normal LP before first AI. However, primiparous cows that had at least one abnormal LP had reduced AI outcomes. Relationships between early postpartum luteal activity and AI outcomes were inconsistent between primiparous and multiparous cows. PMID- 28708532 TI - Blood flow and echotextural differences between the future dominant and subordinate follicles before the beginning of diameter deviation in heifers. AB - Diameter deviation is the beginning of a decrease in growth rate of the largest subordinate follicle (SF) and a continuing growth rate of the dominant follicle (DF). In wave 1 in cattle, deviation begins 2 or 3 days after ovulation when the future DF is about 8.5 mm. Gray scale and power-flow Doppler ultrasound examinations were done in experiment 1 (daily examinations, n = 13) and experiment 2 (examinations every 8 h, n = 15). Blood flow and an anechoic layer in the follicle wall were normalized to the beginning of diameter deviation (day 0 or hour 0). Only waves with conventional diameter deviation (68% of waves) were used as identified by: (1) future SF greater than 7.0 mm when DF was 8.5 mm and (2) future DF and SF did not switch in diameter rank. In experiment 1, deviations in the extent of blood-flow signals and in the extent of anechoic layer began on the same day as deviation in diameter. In experiment 2, deviations in diameter, surface area (pid2), and anechoic layer began in synchrony, and deviation in blood-flow signals began 16 h earlier. Blood-flow deviation before diameter deviation was shown by (1) a first difference (P < 0.02) between follicles at hour -16 and (2) development during the hours -24 to 0 of a greater (P < 0.05) percentage difference between follicles in blood-flow signals (11.1 +/- 2.3%) than in surface area (7.4 +/- 0.7%) or diameter (4.5 +/- 0.4%). Results supported the hypothesis that the extent of blood flow in the future dominant and subordinate follicles deviates before diameter deviates. A similar hypothesis for anechoic layer was not supported; diameter and anechoic layer deviated in synchrony. PMID- 28708533 TI - Expression and molecular cloning of interferon stimulated genes in buffalo (Bubalus bubalis). AB - Buffalo, the most important livestock species in tropical India, remains to be a poor breeder mainly due to embryonic mortality (65%) occurring mostly between 16 and 18 days of pregnancy. Early and accurate diagnosis of pregnancy can thus become a boon for successful herd management in buffalo. However, most of the currently available methods allow diagnosis only after 30 days post AI. Interferon tau (IFNT), the first pregnancy recognition signal in ruminants is one such molecule, which stimulates expression of various Interferon stimulated genes (ISGs) in the peripheral blood mononuclear cells (PBMC's) concomitant with IFNT signaling which occurs around maternal recognition of pregnancy (MRP). Hence, the study was planned to demonstrate the expression dynamics of ISGs (OAS1, MX1, MX2 and ISG15) in PBMCs during peri-implantation period in buffalo and also molecular cloning and expression of suitable ISG coded protein (s) in suitable host. Blood was collected from two groups of multiparous buffaloes: Group1: (n = 10) inseminated/pregnant (Experimental) and Group2: (n = 10) anestrous/non pregnant (Control). The expression profile of ISGs was then analyzed using real time qPCR. Expression profile of most ISGs was observed to increase through day 14 to day 20 post AI and declined thereafter. On the basis of differential gene expression at day 18 post AI, OAS1 and MX2 were identified as suitable ISG candidate biomarkers for accurate pregnancy diagnosis within 18 days post AI. Molecular cloning and expression of selected ISGs in a suitable prokaryotic expression vector was done thereafter. Bulk expression of the recombinant proteins was done and purified by affinity chromatography and confirmed by Western blot using Mouse Monoclonal His probe antibodies. To conclude, as OAS1 and MX2, showed distinct differential expression at day 18 post AI, they may serve as ideal biomarkers for detection of early pregnancy in buffalo. PMID- 28708534 TI - The expressions in oxytocin and sex steroid receptors in the reproductive tissues of normal and unilateral cryptorchid dogs. AB - In males, oxytocin is involved with various physiological functions, such as reproductive tract contractility and testicular steroidogenesis. Due to the relationship between sex steroid hormones, oxytocin receptor (OTR) expression and cryptorchidism pathogenesis, this study aimed to investigate the mRNA expression and the localization of OTR in relation to sex steroid receptors in the male reproductive tract of both normal and unilateral abdominal cryptorchid dogs using quantitative PCR and immunohistochemistry. Male dogs were divided into two groups of normal and cryptorchid dogs. Samples from each cryptorchid dog were separated into two subgroups: scrotal and abdominal subgroups. The results showed that a lower percentage of positive OTR immunostaining in the testis and epididymis was observed in the cryptorchid group compared to the normal group. Within the cryptorchid group, the mRNA expression and the localization of OTR in the testis and epididymis of the abdominal subgroup was less than that of the scrotal subgroup. Moreover, the localization of OTR and estrogen receptor beta (ERbeta) in reproductive tissues was positively correlated only in the normal group and not in the cryptorchid group. In conclusion, this study proposed that OTR expression, as well as the correlation between the OTR and ERbeta in reproductive tissues of male dogs, can be disturbed by cryptorchidism. Furthermore, the OTR, ERbeta and their correlation may be involved with the pathogenesis of cryptorchidism. Therefore, the study of gene knockout models to confirm the effect of OTR and sex steroid receptors on canine cryptorchidism should be of interest for further investigation. PMID- 28708535 TI - Comparison of estrus synchronization by controlled internal drug release device (CIDR) and adhesive transdermal progestin patch in postpartum beef cows. AB - Estrous synchronization with progesterone based protocols has been essentially used in cattle industry. Although intravaginal devices have been commonly used, this technique may induce vaginitis. This study aimed at examining the efficiency of novel transdermal progestin patch on follicle development and comparing the progestin patch versus CIDR device on estrous synchronization, complication at treated site and pregnancy in beef cattle. In experiment 1, seven beef cows were treated with an adhesive transdermal progestin patch on the ventral surface of the proximal part of the tail for 7 days. The cows were daily examined the follicular development using ultrasonography starting on Day 0 till 3 days after hormone removal. Experiment 2, forty beef cows were divided into two equal groups (20 cows per group). The cows randomly allocated to received either vaginal insertion of CIDR (n = 20) or treated with an adhesive transdermal progestin patch (n = 20). The levels of plasma progesterone during the experiment and the numbers of standing estrous cows were recorded. Timed artificial inseminated (TAI) was performed at 60 h after CIDR or patch termination. Pregnancy rates were determined at 60 days after TAI. Experiment 1 revealed that the novel transdermal progestin patch could efficiently control follicular growth. All the seven treated cows had dominant follicle upon dermal patch removal indicating the effectiveness of the progestin patch. In experiment 2, the percentages of cows exhibited standing estrus were similar between transdermal patch (72.22%) and CIDR (70.00%). The levels of plasma progesterone during CIDR treatment were significantly higher (4.06 +/- 1.65 ng/mL on Day 1 and 3.62 +/- 1.60 ng/mL on Day 7) compared with transdermal patch (2.60 +/- 1.43 ng/mL on Day 1 and 1.81 +/- 1.57 ng/mL on Day 7). Three cows treated with CIDR (15%) developed vaginitis while none of cows had physically dermal reaction at adhesive site. Cows synchronized with these two protocols had similar pregnancy rates (50.00%) following fixed time artificial insemination. It is concluded that transdermal progestin patch was equally effective in estrus synchronization as compared with traditional CIDR. However, the transdermal patch demonstrated less complication. This device should therefore be considered as an alternative method for estrus synchronization in postpartum beef cattle. PMID- 28708536 TI - Relationship among circulating anti-Mullerian hormone, insulin like growth factor 1, cadmium and superovulatory response in dairy cows. AB - The objectives of this study were 1. to determine the associations among circulating anti-Mullerian hormone (AMH), insulin like growth factor 1 (IGF1) and cadmium (Cd) concentrations of lactating Holstein cows at the time of superovulation and 2. to determine the effect of circulating AMH, IGF1 and Cd concentrations on the superovulatory response in Holstein dairy cows. Holstein cows (n = 30) were milked thrice daily and housed and fed in free stall barn as a separate group. All animals were synchronized for superovulation and flushed. Three blood samples for AMH, IGF1 and Cd analysis were collected prior to superovulation, at estrus and at the time of embryo collection. The concentrations of blood makers prior to superovulation were highly correlated to superovulatory response. Circulating concentrations of AMH, IGF1 prior to superovulation were negatively correlated to Cd concentrations (P < 0.05). There was no correlation between circulating concentrations of AMH and IGF1. The number of corpus luteum (r = 0.71), total embryo (r = 0.67), total transferable embryo (r = 0.51) and total grade 1 embryo (r = 0.5) were positively correlated to AMH concentrations (P < 0.05). There was a trend for negative correlation found between circulating cadmium concentrations and total grade 1 embryo yield (P < 0.1). When cows were classified into quartiles (Q) of circulating AMH concentration, number of corpus luteum, and total embryos, total transferable embryos and total grade 1 embryos yield was significantly different for AMH quartiles. The superovulatory response parameters evaluated were increased with increased AMH concentrations; particularly we observed a >2-fold difference between first and fourth AMH quartiles in total transferable embryo yield and total grade 1 embryo yield. In conclusion, circulating AMH concentration was strongly associated with superovulatory response. Measuring AMH before enrolling cows in superovulation programs will likely allow practitioners to improve numbers of embryos produced and, thereby, reduce costs per embryo produced. PMID- 28708537 TI - A proteomic study of mesenchymal stem cells from equine umbilical cord. AB - To the best of our knowledge, this is the first study describing the proteome of equine umbilical cord intervascular matrix mesenchymal stem cells (UCIM-MSCs) in a global and functional manner. The aim of this work was to analyze the proteome of previously characterized UCIM-MSCs to determine protein abundance and classify the identified proteins according to Gene Ontology (GO) terms. Protein classification analysis according to biological process, molecular function and cellular component was performed using the PANTHER (Protein ANalysis THrough Evolutionary Relationships) Classification System, which revealed enrichment for 42 biological processes, 23 molecular functions and 18 cellular components. Protein abundance was estimated according to the emPAI method (Exponential Modified Protein Abundance Index). The two most abundant proteins in the proteome of UCIM-MSCs were the cytoskeletal proteins actin and vimentin, which have important roles in cell stability and motility. Additionally, we identified 14 cell surface antigens. Three of them, CD44, CD90 and CD105, had been previously validated by flow cytometry. In the present study, we also identified important information about the biological properties of UCIM-MSCs such as differentiation potential, low immunogenicity (low MHC-II expression) and chromosomal stability, which reinforces their use for cell therapy. Together with the proteomic findings, this information allowed us to infer the functional relevance of several activities related to primary metabolic processes, protein synthesis, production of vesicle coats, vesicle-mediated transport and antioxidant activity. In addition, the identification of different cell surface markers may help establish an immunophenotypic panel suitable for the characterization of MSCs from equine fetal membranes. PMID- 28708538 TI - Glycosidases in porcine follicular fluid and their effect on zona pellucida-AWN 1 spermadhesin interaction. AB - Oligosaccharide moieties on the surface of the oocyte belong to the key molecules that direct the course of fertilization and are subjected to changes during oocyte maturation in the follicle. In our study, we focused on the activities of five glycosidases in the fluids from porcine secondary and preovulatory follicles (alpha-l-fucosidase, alpha-d-galactosidase, beta-d-galactosidase, beta-D-N acetylhexosaminidase, and alpha-d-mannosidase). All of them were detected active at neutral and acidic pH. However, changes in their activities associated with follicle development were observed only in the case of alpha-d-mannosidase, which was increased (P < 0.001), and beta-d-galactosidase, which was decreased (P < 0.001) at neutral pH, and of alpha-d-galactosidase and beta-N acetylhexosaminidase, which were decreased (P < 0.0001) at the acidic pH. The comparison of glycosidases from follicular fluid and from blood plasma using red native electrophoresis revealed that most of the glycosidases are present in more than one isoenzyme form; some of them were detected mainly in the follicular fluid. Finally, we tested the effect of glycosidases on the interaction between zona pellucida and AWN 1 spermadhesin (putative sperm receptor of zona pellucida) and demonstrated that the effect of both beta-d-galactosidase and to a lesser degree alpha-d-mannosidase led to a decrease in this interaction. We can hypothesize that these two glycosidases modulate the amount of zona pellucida oligosaccharide moieties and/or their structures for an optimal sperm binding in pigs. PMID- 28708539 TI - PPAR expression throughout the oestrous cycle in the bovine endometrium. AB - Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear receptors that is composed of three isoforms: PPARalpha, PPARbeta/delta and PPARgamma. The ratio of two isoforms of PPARgamma (1 and 2) varies among both species and tissues. The activity of PPARs can be modified by a number of endogenous compounds, including arachidonic acid (AA), its eicosanoid metabolites and synthetic ligands. Many studies have revealed that PPARs are important in reproduction. We hypothesized that the profiles of PPARs expression vary in the bovine endometrium during certain days of the oestrous cycle. The aim of this study was to determine the immunolocalization, mRNA expression and protein expression of PPARalpha, PPARbeta/delta and PPARgamma in the bovine endometrium throughout the oestrous cycle. Endometrial tissues were obtained post mortem from heifers on days 0 (oestrus phase, n = 6), 2-5 (early luteal phase, n = 6), 8-12 (mid-luteal phase, n = 6), 15-17 (late luteal phase, n = 6) and 19-21 (follicular phase, n = 6) of the oestrous cycle. PPARs immunolocalization was determined in the endometrium using immunohistochemistry. The mRNA and protein expression were evaluated by real-time PCR and Western blotting, respectively. The results were statistically analysed by one-way ANOVA followed by a Bonferroni test. Immunolocalization revealed the protein expression of PPARalpha, PPARbeta/delta and PPARgamma in bovine endometrial structures throughout the oestrous cycle. PPARgamma1 mRNA and protein expression fluctuated in the tissue depending on the studied days of the oestrous cycle, whereas the transcript and protein levels of PPARalpha and PPARbeta/delta did not display significant differences during the oestrous cycle. We observed the highest PPARgamma1 mRNA expression at the oestrus phase and the lowest expression at the mid-luteal phase. During the late luteal and follicular phases, the mRNA and protein expression of PPARgamma1 were detectable at similar levels compared to the early luteal and mid-luteal phases of the oestrous cycle. The overall results indicate the presence of PPARalpha, PPARbeta/delta and PPARgamma in endometrial tissues, but the mRNA and protein expression of only PPARgamma1 changed throughout the oestrous cycle, especially during the oestrus and mid-luteal phases. Our findings suggest an association between the expression of PPARs in the bovine endometrium and stage of the oestrous cycle that may be a consequence of changes in ovarian steroids. PMID- 28708540 TI - Influence of two ovulation-inducing agents on the pituitary response and follicle blood flow in mares. AB - The objective of the current study was to evaluate the effects of deslorelin and hCG, two ovulation-inducing therapies, on LH surge and follicle vascularity in mares. Thirty mares were either treated with 1.5 mg IM of deslorelin, 2,500 IU IV of hCG or 2 mL IM of NaCl 0.9% (GnRH, hCG and Saline groups, respectively). Power flow Doppler examination and blood collection were performed every hour during the first 12 hours after treatment (H0) and every six hours between hours 12 (H12) and 30 (H30) after treatment. Moreover, endpoints were evaluated every hour through the last six hours before ovulation (OV-6 to OV-1). In GnRH group, plasma LH concentration progressively increased (P < 0.001) during the first 6 hours after treatment and remained high (P > 0.1) until OV-1. A significant increase in LH concentrations was first detected (P < 0.05) at 24 hours after treatment in hCG group, while no changes (P > 0.1) on LH levels were found during H0-H30 and between OV-6 and OV-1 in the Saline group. Independent of the treatment, significant variations on the percentage of the follicle wall with Doppler signals were not observed (P > 0.1) throughout the entire experiment. A weak correlation between the preovulatory follicle vascularity and the plasma LH concentration was found in GnRH, hCG and Saline groups (r = +0.29, +0.29 and 0.23, respectively; P ? 0.0001). These results described for the first time the immediate and continuous pituitary response to ovulation-inducing therapy with injectable deslorelin. Moreover, spontaneous and induced ovulations were not preceded by an increased follicle vascularity, which differs from previous reports in large animals. PMID- 28708541 TI - Total Ionizing Dose Effects on Piezoelectric Thin-Film Cantilevers With Oxide Electrodes. AB - This paper reports on the ionizing radiation effects in lead-zirconate-titanate (PZT) with varied top electrode material and bias condition during radiation. A technique to characterize the piezoelectric performance of films unclamped from the substrate is described, and used to demonstrate the effects of radiation on the material's electromechanical behavior. Both platinum and iridium oxide top electrodes were examined, and iridium oxide appears to significantly mitigate radiation-induced damage that is observed in platinum top electrode samples. This mitigation of radiation damage is attributed to the reduced number of oxygen vacancies within the PZT films when an iridium oxide top electrode is used. Devices with applied bias during radiation were compared with devices under applied bias only. Applied bias appears to slightly enhance the electromechanical response in the negative bias polarity for irradiated platinum electrode samples suggesting that the bias can cause defects to orient and therefore improve electromechanical response. Ultimately, iridium oxide top electrodes appear to mitigate radiation damage. PMID- 28708542 TI - An Ambulatory Gait Monitoring System with Activity Classification and Gait Parameter Calculation Based on a Single Foot Inertial Sensor. AB - GOAL: For healthcare and clinical use, ambulatory gait monitoring systems using inertial sensors have been developed to estimate the user gait parameters, such as walking speed, stride time, and stride length. However, to adapt the systems effectively to daily-life activities, they need to be able to classify the gait activities of daily-life to obtain the parameters for each activity. In this study, we propose a simple classification algorithm based on a single inertial sensor for ease of use, which classifies three major gait activities: leveled walk, ramp walk, and stair walk. METHOD: The classification can be performed with gait parameter estimation simultaneously. The developed system that includes classification and parameter estimation algorithms was evaluated with eight healthy subjects within a gait lab and on an outdoor daily-life walking course. RESULTS: The results showed that the estimated gait parameters were comparable to existing studies (range of walking speed root mean square error: 0.059-0.129 m/s), and the classification accuracy was sufficiently high for all three gait activities: 98.5% for the indoor gait lab experiment and 95.5% for the outdoor complex daily-life walking course experiment. CONCLUSION: The proposed system is simple and effective for daily-life gait analysis, including gait activity classification and gait parameter estimation for each activity. PMID- 28708543 TI - Proposal Flow: Semantic Correspondences from Object Proposals. AB - Finding image correspondences remains a challenging problem in the presence of intra-class variations and large changes in scene layout. Semantic flow methods are designed to handle images depicting different instances of the same object or scene category. We introduce a novel approach to semantic flow, dubbed proposal flow, that establishes reliable correspondences using object proposals. Unlike prevailing semantic flow approaches that operate on pixels or regularly sampled local regions, proposal flow benefits from the characteristics of modern object proposals, that exhibit high repeatability at multiple scales, and can take advantage of both local and geometric consistency constraints among proposals. We also show that the corresponding sparse proposal flow can effectively be transformed into a conventional dense flow field. We introduce two new challenging datasets that can be used to evaluate both general semantic flow techniques and region-based approaches such as proposal flow. We use these benchmarks to compare different matching algorithms, object proposals, and region features within proposal flow, to the state of the art in semantic flow. This comparison, along with experiments on standard datasets, demonstrates that proposal flow significantly outperforms existing semantic flow methods in various settings. PMID- 28708544 TI - Dense 3D Face Correspondence. AB - We present an algorithm that automatically establishes dense correspondences between a large number of 3D faces. Starting from automatically detected sparse correspondences on the outer boundary of 3D faces, the algorithm triangulates existing correspondences and expands them iteratively by matching points of distinctive surface curvature along the triangle edges. After exhausting keypoint matches, further correspondences are established by generating evenly distributed points within triangles by evolving level set geodesic curves from the centroids of large triangles. A deformable model (K3DM) is constructed from the dense corresponded faces and an algorithm is proposed for morphing the K3DM to fit unseen faces. This algorithm iterates between rigid alignment of an unseen face followed by regularized morphing of the deformable model. We have extensively evaluated the proposed algorithms on synthetic data and real 3D faces from the FRGCv2, Bosphorus, BU3DFE and UND Ear databases using quantitative and qualitative benchmarks. Our algorithm achieved dense correspondences with a mean localisation error of 1.28 mm on synthetic faces and detected 14 anthropometric landmarks on unseen real faces from the FRGCv2 database with 3 mm precision. Furthermore, our deformable model fitting algorithm achieved 98.5 percent face recognition accuracy on the FRGCv2 and 98.6 percent on Bosphorus database. Our dense model is also able to generalize to unseen datasets. PMID- 28708545 TI - Multi-Gait Recognition Based on Attribute Discovery. AB - Gait recognition is an important topic in biometrics. Current works primarily focus on recognizing a single person's walking gait. However, a person's gait will change when they walk with other people. How to recognize the gait of multiple people walking is still a challenging problem. This paper proposes an attribute discovery model in a max-margin framework to recognize a person based on gait while walking with multiple people. First, human graphlets are integrated into a tracking-by-detection method to obtain a person's complete silhouette. Then, stable and discriminative attributes are developed using a latent conditional random field (L-CRF) model. The model is trained in the latent structural support vector machine (SVM) framework, in which a new constraint is added to improve the multi-gait recognition performance. In the recognition process, the attribute set of each person is detected by inferring on the trained L-CRF model. Finally, attributes based on dense trajectories are extracted as the final gait features to complete the recognition. The experimental results demonstrate that the proposed method achieves better recognition performance than traditional gait recognition methods under the condition of multiple people walking together. PMID- 28708546 TI - SonoNet: Real-Time Detection and Localisation of Fetal Standard Scan Planes in Freehand Ultrasound. AB - Identifying and interpreting fetal standard scan planes during 2-D ultrasound mid pregnancy examinations are highly complex tasks, which require years of training. Apart from guiding the probe to the correct location, it can be equally difficult for a non-expert to identify relevant structures within the image. Automatic image processing can provide tools to help experienced as well as inexperienced operators with these tasks. In this paper, we propose a novel method based on convolutional neural networks, which can automatically detect 13 fetal standard views in freehand 2-D ultrasound data as well as provide a localization of the fetal structures via a bounding box. An important contribution is that the network learns to localize the target anatomy using weak supervision based on image-level labels only. The network architecture is designed to operate in real time while providing optimal output for the localization task. We present results for real-time annotation, retrospective frame retrieval from saved videos, and localization on a very large and challenging dataset consisting of images and video recordings of full clinical anomaly screenings. We found that the proposed method achieved an average F1-score of 0.798 in a realistic classification experiment modeling real-time detection, and obtained a 90.09% accuracy for retrospective frame retrieval. Moreover, an accuracy of 77.8% was achieved on the localization task. PMID- 28708547 TI - Multimodal Fusion With Reference: Searching for Joint Neuromarkers of Working Memory Deficits in Schizophrenia. AB - By exploiting cross-information among multiple imaging data, multimodal fusion has often been used to better understand brain diseases. However, most current fusion approaches are blind, without adopting any prior information. There is increasing interest to uncover the neurocognitive mapping of specific clinical measurements on enriched brain imaging data; hence, a supervised, goal-directed model that employs prior information as a reference to guide multimodal data fusion is much needed and becomes a natural option. Here, we proposed a fusion with reference model called "multi-site canonical correlation analysis with reference + joint-independent component analysis" (MCCAR+jICA), which can precisely identify co-varying multimodal imaging patterns closely related to the reference, such as cognitive scores. In a three-way fusion simulation, the proposed method was compared with its alternatives on multiple facets; MCCAR+jICA outperforms others with higher estimation precision and high accuracy on identifying a target component with the right correspondence. In human imaging data, working memory performance was utilized as a reference to investigate the co-varying working memory-associated brain patterns among three modalities and how they are impaired in schizophrenia. Two independent cohorts (294 and 83 subjects respectively) were used. Similar brain maps were identified between the two cohorts along with substantial overlaps in the central executive network in fMRI, salience network in sMRI, and major white matter tracts in dMRI. These regions have been linked with working memory deficits in schizophrenia in multiple reports and MCCAR+jICA further verified them in a repeatable, joint manner, demonstrating the ability of the proposed method to identify potential neuromarkers for mental disorders. PMID- 28708548 TI - Predicting Locations of High-Risk Plaques in Coronary Arteries in Patients Receiving Statin Therapy. AB - Features of high-risk coronary artery plaques prone to major adverse cardiac events (MACE) were identified by intravascular ultrasound (IVUS) virtual histology (VH). These plaque features are: thin-cap fibroatheroma (TCFA), plaque burden PB >= 70%, or minimal luminal area MLA <= 4 mm2. Identification of arterial locations likely to later develop such high-risk plaques may help prevent MACE. We report a machine learning method for prediction of future high risk coronary plaque locations and types in patients under statin therapy. Sixty one patients with stable angina on statin therapy underwent baseline and one-year follow-up VH-IVUS non-culprit vessel examinations followed by quantitative image analysis. For each segmented and registered VH-IVUS frame pair ( ), location specific ( mm) vascular features and demographic information at baseline were identified. Seven independent support vector machine classifiers with seven different feature subsets were trained to predict high-risk plaque types one year later. A leave-one-patient-out cross-validation was used to evaluate the prediction power of different feature subsets. The experimental results showed that our machine learning method predicted future TCFA with correctness of 85.9%, 81.7%, and 77.0% (G-mean) for baseline plaque phenotypes of TCFA, thick-cap fibroatheroma, and non-fibroatheroma, respectively. For predicting PB >= 70%, correctness was 80.8% for baseline PB >= 70% and 85.6% for 50% <= PB < 70%. Accuracy of predicted MLA <= 4 mm2 was 81.6% for baseline MLA <= 4 mm2 and 80.2% for 4 mm2 < MLA <= 6 mm2. Location-specific prediction of future high-risk coronary artery plaques is feasible through machine learning using focal vascular features and demographic variables. Our approach outperforms previously reported results and shows the importance of local factors on high-risk coronary artery plaque development. PMID- 28708549 TI - Effects of Image Quality on the Fundamental Limits of Image Registration Accuracy. AB - For image-guided procedures, the imaging task is often tied to the registration of intraoperative and preoperative images to a common coordinate system. While the accuracy of this registration is a vital factor in system performance, there is a relatively little work that relates registration accuracy to image quality factors, such as dose, noise, and spatial resolution. To create a theoretical model for such a relationship, we present a Fisher information approach to analyze registration performance in explicit dependence on the underlying image quality factors of image noise, spatial resolution, and signal power spectrum. The model yields analysis of the Cramer-Rao lower bound (CRLB), in registration accuracy as a function of factors governing image quality. Experiments were performed in simulation of computed tomography low-contrast soft tissue images and high-contrast bone (head and neck) images to compare the measured accuracy [root mean squared error (RMSE) of the estimated transformations] with the theoretical lower bound. Analysis of the CRLB reveals that registration performance is closely related to the signal-to-noise ratio of the cross correlation space. While the lower bound is optimistic, it exhibits consistent trends with experimental findings and yields a method for comparing the performance of various registration methods and similarity metrics. Further analysis validated a method for determining optimal post-processing (image filtering) for registration. Two figures of merit (CRLB and RMSE) are presented that unify models of image quality with registration performance, providing an important guide to optimizing intraoperative imaging with respect to the task of registration. PMID- 28708550 TI - Unsupervised Myocardial Segmentation for Cardiac BOLD. AB - A fully automated 2-D+time myocardial segmentation framework is proposed for cardiac magnetic resonance (CMR) blood-oxygen-level-dependent (BOLD) data sets. Ischemia detection with CINE BOLD CMR relies on spatio-temporal patterns in myocardial intensity, but these patterns also trouble supervised segmentation methods, the de facto standard for myocardial segmentation in cine MRI. Segmentation errors severely undermine the accurate extraction of these patterns. In this paper, we build a joint motion and appearance method that relies on dictionary learning to find a suitable subspace. Our method is based on variational pre-processing and spatial regularization using Markov random fields, to further improve performance. The superiority of the proposed segmentation technique is demonstrated on a data set containing cardiac phase-resolved BOLD MR and standard CINE MR image sequences acquired in baseline and ischemic condition across ten canine subjects. Our unsupervised approach outperforms even supervised state-of-the-art segmentation techniques by at least 10% when using Dice to measure accuracy on BOLD data and performs at par for standard CINE MR. Furthermore, a novel segmental analysis method attuned for BOLD time series is utilized to demonstrate the effectiveness of the proposed method in preserving key BOLD patterns. PMID- 28708551 TI - Indoor Airborne Ultrasonic Wireless Communication Using OFDM Methods. AB - Concerns still exist over the safety of prolonged exposure to radio frequency (RF) wireless transmissions and there are also potential data security issues due to remote signal interception techniques such as Bluesniping. Airborne ultrasound may be used as an alternative to RF for indoor wireless communication systems for securely transmitting data over short ranges, as signals are difficult to intercept from outside the room. Two types of air-coupled capacitive ultrasonic transducer were used in the implementation of an indoor airborne wireless communication system. One was a commercially available SensComp series 600 ultrasonic transducer with a nominal frequency of 50 kHz, and the other was a prototype transducer with a high- k dielectric layer operating at higher frequencies from 200 to 400 kHz. Binary phase-shift keying (BPSK), quadrature phase-shift keying (QPSK), and quadrature amplitude modulation (QAM)-based orthogonal frequency division multiplexing modulation methods were successfully implemented using multiple orthogonal subchannels. The modulated ultrasonic signal packets were synchronized using a wireless link, and a least-squares channel estimation algorithm was used to compensate the phase and amplitude distortion introduced by the air channel. By sending and receiving the ultrasonic signals using the SensComp transducers, the achieved maximum system data rate was up to 180 kb/s using 16-QAM with ultrasonic channels from 55 to 99 kHz, over a line-of-sight transmission distance of 6 m with no detectable errors. The transmission range could be extended to 9 and 11 m using QPSK and BPSK modulation schemes, respectively. The achieved data rates for the QPSK and BPSK schemes were 90 and 45 kb/s using the same bandwidth. For the high- k ultrasonic transducers, a maximum data rate up to 800 kb/s with no measurable errors was achieved up to a range of 0.7 m. The attainable transmission ranges were increased to 1.1 and 1.2 m with data rates of 400 and 200 kb/s using QPSK and BPSK, respectively. PMID- 28708552 TI - Dual-Phase Transmit Focusing for Multiangle Compound Shear-Wave Elasticity Imaging. AB - Shear-wave elasticity imaging (SWEI) enables the quantitative assessment of the mechanical properties of tissue. In SWEI, the effective generation of acoustic radiation force is of paramount importance. Consequently, several research groups have investigated various transmit beamforming and pulse-sequencing methods. To further improve the efficiency of the shear-wave generation, and therefore, to increase the quality of SWEI, we introduce a technique referred to as "multiangle compound SWEI" (MAC-SWEI), which uses simultaneous multiangular push beams created by dual-phase transmit focusing. By applying a constant phase offset on every other element of an array transducer, dual-phase transmit focusing creates both main and grating lobes (i.e., multiangular push beams for pushing) to simultaneously generate shear waves with several wavefront angles. The shear waves propagating at different angles are separated by multidirectional filtering in the frequency domain, leading to the reconstruction of multiple spatially co registered shear-wave velocity maps. To form a single-elasticity image, these maps are combined, while regions associated with known artifacts created by the push beams are omitted. Overall, we developed and tested the MAC-SWEI method using Field II quantitative simulations and the experiments performed using a programmable ultrasound imaging system. Our results suggest that MAC-SWEI with dual-phase transmit focusing may improve the quality of elasticity maps. PMID- 28708553 TI - Dispersion Differences and Consistency of Artificial Periodic Structures. AB - Dispersion differences and consistency of artificial periodic structures, including phononic crystals, elastic metamaterials, as well as periodic structures composited of phononic crystals and elastic metamaterials, are investigated in this paper. By developing a K(omega) method, complex dispersion relations and group/phase velocity curves of both the single-mechanism periodic structures and the mixing-mechanism periodic structures are calculated at first, from which dispersion differences of artificial periodic structures are discussed. Then, based on a unified formulation, dispersion consistency of artificial periodic structures is investigated. Through a comprehensive comparison study, the correctness for the unified formulation is verified. Mathematical derivations of the unified formulation for different artificial periodic structures are presented. Furthermore, physical meanings of the unified formulation are discussed in the energy-state space. PMID- 28708554 TI - Distance Metric Learning via Iterated Support Vector Machines. AB - Distance metric learning aims to learn from the given training data a valid distance metric, with which the similarity between data samples can be more effectively evaluated for classification. Metric learning is often formulated as a convex or nonconvex optimization problem, while most existing methods are based on customized optimizers and become inefficient for large scale problems. In this paper, we formulate metric learning as a kernel classification problem with the positive semi-definite constraint, and solve it by iterated training of support vector machines (SVMs). The new formulation is easy to implement and efficient in training with the off-the-shelf SVM solvers. Two novel metric learning models, namely positive-semidefinite constrained metric learning (PCML) and nonnegative coefficient constrained metric learning (NCML), are developed. Both PCML and NCML can guarantee the global optimality of their solutions. Experiments are conducted on general classification, face verification, and person re-identification to evaluate our methods. Compared with the state-of-the-art approaches, our methods can achieve comparable classification accuracy and are efficient in training. PMID- 28708555 TI - Going Deeper With Contextual CNN for Hyperspectral Image Classification. AB - In this paper, we describe a novel deep convolutional neural network (CNN) that is deeper and wider than other existing deep networks for hyperspectral image classification. Unlike current state-of-the-art approaches in CNN-based hyperspectral image classification, the proposed network, called contextual deep CNN, can optimally explore local contextual interactions by jointly exploiting local spatio-spectral relationships of neighboring individual pixel vectors. The joint exploitation of the spatio-spectral information is achieved by a multi scale convolutional filter bank used as an initial component of the proposed CNN pipeline. The initial spatial and spectral feature maps obtained from the multi scale filter bank are then combined together to form a joint spatio-spectral feature map. The joint feature map representing rich spectral and spatial properties of the hyperspectral image is then fed through a fully convolutional network that eventually predicts the corresponding label of each pixel vector. The proposed approach is tested on three benchmark data sets: the Indian Pines data set, the Salinas data set, and the University of Pavia data set. Performance comparison shows enhanced classification performance of the proposed approach over the current state-of-the-art on the three data sets. PMID- 28708556 TI - Deep Learning on Sparse Manifolds for Faster Object Segmentation. AB - We propose a new combination of deep belief networks and sparse manifold learning strategies for the 2D segmentation of non-rigid visual objects. With this novel combination, we aim to reduce the training and inference complexities while maintaining the accuracy of machine learning-based non-rigid segmentation methodologies. Typical non-rigid object segmentation methodologies divide the problem into a rigid detection followed by a non-rigid segmentation, where the low dimensionality of the rigid detection allows for a robust training (i.e., a training that does not require a vast amount of annotated images to estimate robust appearance and shape models) and a fast search process during inference. Therefore, it is desirable that the dimensionality of this rigid transformation space is as small as possible in order to enhance the advantages brought by the aforementioned division of the problem. In this paper, we propose the use of sparse manifolds to reduce the dimensionality of the rigid detection space. Furthermore, we propose the use of deep belief networks to allow for a training process that can produce robust appearance models without the need of large annotated training sets. We test our approach in the segmentation of the left ventricle of the heart from ultrasound images and lips from frontal face images. Our experiments show that the use of sparse manifolds and deep belief networks for the rigid detection stage leads to segmentation results that are as accurate as the current state of the art, but with lower search complexity and training processes that require a small amount of annotated training data. PMID- 28708557 TI - Blind Deep S3D Image Quality Evaluation via Local to Global Feature Aggregation. AB - Previously, no-reference (NR) stereoscopic 3D (S3D) image quality assessment (IQA) algorithms have been limited to the extraction of reliable hand-crafted features based on an understanding of the insufficiently revealed human visual system or natural scene statistics. Furthermore, compared with full-reference (FR) S3D IQA metrics, it is difficult to achieve competitive quality score predictions using the extracted features, which are not optimized with respect to human opinion. To cope with this limitation of the conventional approach, we introduce a novel deep learning scheme for NR S3D IQA in terms of local to global feature aggregation. A deep convolutional neural network (CNN) model is trained in a supervised manner through two-step regression. First, to overcome the lack of training data, local patch-based CNNs are modeled, and the FR S3D IQA metric is used to approximate a reference ground-truth for training the CNNs. The automatically extracted local abstractions are aggregated into global features by inserting an aggregation layer in the deep structure. The locally trained model parameters are then updated iteratively using supervised global labeling, i.e., subjective mean opinion score (MOS). In particular, the proposed deep NR S3D image quality evaluator does not estimate the depth from a pair of S3D images. The S3D image quality scores predicted by the proposed method represent a significant improvement over those of previous NR S3D IQA algorithms. Indeed, the accuracy of the proposed method is competitive with FR S3D IQA metrics, having ~ 91% correlation in terms of MOS. PMID- 28708558 TI - Local Directional Ternary Pattern for Facial Expression Recognition. AB - This paper presents a new face descriptor, local directional ternary pattern (LDTP), for facial expression recognition. LDTP efficiently encodes information of emotion-related features (i.e., eyes, eyebrows, upper nose, and mouth) by using the directional information and ternary pattern in order to take advantage of the robustness of edge patterns in the edge region while overcoming weaknesses of edge-based methods in smooth regions. Our proposal, unlike existing histogram based face description methods that divide the face into several regions and sample the codes uniformly, uses a two-level grid to construct the face descriptor while sampling expression-related information at different scales. We use a coarse grid for stable codes (highly related to non-expression), and a finer one for active codes (highly related to expression). This multi-level approach enables us to do a finer grain description of facial motions while still characterizing the coarse features of the expression. Moreover, we learn the active LDTP codes from the emotion-related facial regions. We tested our method by using person-dependent and independent cross-validation schemes to evaluate the performance. We show that our approaches improve the overall accuracy of facial expression recognition on six data sets. PMID- 28708559 TI - Texture Characterization Using Shape Co-Occurrence Patterns. AB - Texture characterization is a key problem in image understanding and pattern recognition. In this paper, we present a flexible shape-based texture representation using shape co-occurrence patterns. More precisely, texture images are first represented by a tree of shapes, each of which is associated with several geometrical and radiometric attributes. Then, four typical kinds of shape co-occurrence patterns based on the hierarchical relationships among the shapes in the tree are learned as codewords. Three different coding methods are investigated for learning the codewords, which can be used to encode any given texture image into a descriptive vector. In contrast with existing works, the proposed approach not only inherits the shape-based method's strong ability to capture geometrical aspects of textures and high robustness to variations in imaging conditions but also provides a flexible way to consider shape relationships and to compute high-order statistics on the tree. To the best of our knowledge, this is the first time that co-occurrence patterns of explicit shapes have been used as a tool for texture analysis. Experiments on various texture and scene data sets demonstrate the efficiency of the proposed approach. PMID- 28708560 TI - Fast and Orthogonal Locality Preserving Projections for Dimensionality Reduction. AB - The locality preserving projections (LPP) algorithm is a recently developed linear dimensionality reduction algorithm that has been frequently used in face recognition and other applications. However, the projection matrix in LPP is not orthogonal, thus creating difficulties for both reconstruction and other applications. As the orthogonality property is desirable, orthogonal LPP (OLPP) has been proposed so that an orthogonal projection matrix can be obtained based on a step by step procedure; however, this makes the algorithm computationally more expensive. Therefore, in this paper, we propose a fast and orthogonal version of LPP, called FOLPP, which simultaneously minimizes the locality and maximizes the globality under the orthogonal constraint. As a result, the computation burden of the proposed algorithm can be effectively alleviated compared with the OLPP algorithm. Experimental results on two face recognition data sets and two hyperspectral data sets are presented to demonstrate the effectiveness of the proposed algorithm. PMID- 28708561 TI - GPF: GMM-Inspired Feature-Preserving Point Set Filtering. AB - Point set filtering, which aims at reconstructing noise-free point sets from their corresponding noisy inputs, is a fundamental problem in 3D geometry processing. The main challenge of point set filtering is to preserve geometric features of the underlying geometry while at the same time removing the noise. State-of-the-art point set filtering methods still struggle with this issue: some are not designed to recover sharp features, and others cannot well preserve geometric features, especially fine-scale features. In this paper, we propose a novel approach for robust feature-preserving point set filtering, inspired by the Gaussian Mixture Model (GMM). Taking a noisy point set and its filtered normals as input, our method can robustly reconstruct a high-quality point set which is both noise-free and feature-preserving. Various experiments show that our approach can soundly outperform the selected state-of-the-art methods, in terms of both filtering quality and reconstruction accuracy. PMID- 28708562 TI - Non-Model-Based Control of a Wheeled Vehicle Pulling Two Trailers to Provide Early Powered Mobility and Driving Experiences. AB - Non-model-based control of a wheeled vehicle pulling two trailers is proposed. It is a fun train for disabled children consisting of a locomotive and two carriages. The fun train has afforded opportunities for both disabled and able bodied young people to share an activity and has provided early driving experiences for disabled children; it has introduced them to assistive and powered mobility. The train is a nonlinear system and subject to nonholonomic kinematic constraints, so that position and state depend on the path taken to get there. The train is described, and then, a robust control algorithm using proportional-derivative filtered errors is proposed to control the locomotive. The controller was not dependent on an accurate model of the train, because the mass of the vehicle and two carriages changed depending on the number, size, and shape of children and wheelchair seats on the train. The controller was robust and stable in uncertainty. Results are presented to show the effectiveness of the approach, and the suggested control algorithm is shown to be acceptable without knowing the exact plant dynamics. PMID- 28708563 TI - Evolving Spatial Clusters of Genomic Regions From High-Throughput Chromatin Conformation Capture Data. AB - High-throughput chromosome-conformation-capture (Hi-C) methods have revealed a multitude of structural insights into interphase chromosomes. In this paper, we elucidate the spatial clusters of genomic regions from Hi-C contact maps by formulating the underlying problem as a global optimization problem. Given its nonconvex objective and nonnegativity constraints, we implement several evolutionary algorithms and compare their performance with non-negative matrix factorization, revealing novel insights into the problem. In order to obtain robust and accurate spatial clusters, we propose and describe a novel hybrid differential evolution algorithm called HiCDE, which adopts non-negative matrix factorization as local search according to each candidate individual provided by differential evolution algorithm. Based on the fitness value of each individual, the population is partitioned into three subpopulations with different sizes; each subpopulation is equipped with a specific mutation strategy for either exploitation or exploration. Finally, all control parameters in the pool have equal probability to be selected for generating trial vectors. The effectiveness and robustness of HiCDE are supported by real-world performance benchmarking on chromosome-wide Hi-C contact maps of yeast and human, time complexity analysis, convergence analysis, parameter analysis, and case studies. PMID- 28708564 TI - Improved Statistical Fault Detection Technique and Application to Biological Phenomena Modeled by S-Systems. AB - In our previous work, we have demonstrated the effectiveness of the linear multiscale principal component analysis (PCA)-based moving window (MW) generalized likelihood ratio test (GLRT) technique over the classical PCA and multiscale principal component analysis (MSPCA)-based GLRT methods. The developed fault detection algorithm provided optimal properties by maximizing the detection probability for a particular false alarm rate (FAR) with different values of windows, and however, most real systems are nonlinear, which make the linear PCA method not able to tackle the issue of non-linearity to a great extent. Thus, in this paper, first, we apply a nonlinear PCA to obtain an accurate principal component of a set of data and handle a wide range of nonlinearities using the kernel principal component analysis (KPCA) model. The KPCA is among the most popular nonlinear statistical methods. Second, we extend the MW-GLRT technique to one that utilizes exponential weights to residuals in the moving window (instead of equal weightage) as it might be able to further improve fault detection performance by reducing the FAR using exponentially weighed moving average (EWMA). The developed detection method, which is called EWMA-GLRT, provides improved properties, such as smaller missed detection and FARs and smaller average run length. The idea behind the developed EWMA-GLRT is to compute a new GLRT statistic that integrates current and previous data information in a decreasing exponential fashion giving more weight to the more recent data. This provides a more accurate estimation of the GLRT statistic and provides a stronger memory that will enable better decision making with respect to fault detection. Therefore, in this paper, a KPCA-based EWMA-GLRT method is developed and utilized in practice to improve fault detection in biological phenomena modeled by S systems and to enhance monitoring process mean. The idea behind a KPCA-based EWMA GLRT fault detection algorithm is to combine the advantages brought forward by the proposed EWMA-GLRT fault detection chart with the KPCA model. Thus, it is used to enhance fault detection of the Cad System in E. coli model through monitoring some of the key variables involved in this model such as enzymes, transport proteins, regulatory proteins, lysine, and cadaverine. The results demonstrate the effectiveness of the proposed KPCA-based EWMA-GLRT method over Q , GLRT, EWMA, Shewhart, and moving window-GLRT methods. The detection performance is assessed and evaluated in terms of FAR, missed detection rates, and average run length (ARL1) values. PMID- 28708565 TI - Real-Time Adaptation to Time-Varying Constraints for Medical Video Communications. AB - The wider adoption of mobile Health video communication systems in standard clinical practice requires real-time control to provide for adequate levels of clinical video quality to support reliable diagnosis. The latter can only be achieved with real-time adaptation to time-varying wireless networks' state to guarantee clinically acceptable performance throughout the streaming session, while conforming to device capabilities for supporting real-time encoding. We propose an adaptive video encoding framework based on multi-objective optimization that jointly maximizes the encoded video's quality and encoding rate (in frames per second) while minimizing bitrate demands. For this purpose, we construct a dense encoding space and use linear regression to estimate forward prediction models for quality, bitrate, and computational complexity. The prediction models are then used in an adaptive control framework that can fine tune video encoding based on real-time constraints. We validate the system using a leave-one-out algorithm applied to ten ultrasound videos of the common carotid artery. The prediction models can estimate structural similarity quality with a median accuracy error of less than 1%, bitrate demands with deviation error of 10% or less, and encoding frame rate within a 6% margin. Real-time adaptation at a group of pictures level is demonstrated using the high efficiency video coding standard. The effectiveness of the proposed framework compared to static, nonadaptive approaches is demonstrated for different modes of operation, achieving significant quality gains, bitrate demands reductions, and performance improvements, in real-life scenarios imposing time-varying constraints. Our approach is generic and should be applicable to other medical video modalities with different applications. PMID- 28708566 TI - On-Board Object Detection: Multicue, Multimodal, and Multiview Random Forest of Local Experts. AB - Despite recent significant advances, object detection continues to be an extremely challenging problem in real scenarios. In order to develop a detector that successfully operates under these conditions, it becomes critical to leverage upon multiple cues, multiple imaging modalities, and a strong multiview (MV) classifier that accounts for different object views and poses. In this paper, we provide an extensive evaluation that gives insight into how each of these aspects (multicue, multimodality, and strong MV classifier) affect accuracy both individually and when integrated together. In the multimodality component, we explore the fusion of RGB and depth maps obtained by high-definition light detection and ranging, a type of modality that is starting to receive increasing attention. As our analysis reveals, although all the aforementioned aspects significantly help in improving the accuracy, the fusion of visible spectrum and depth information allows to boost the accuracy by a much larger margin. The resulting detector not only ranks among the top best performers in the challenging KITTI benchmark, but it is built upon very simple blocks that are easy to implement and computationally efficient. PMID- 28708567 TI - alpha-Defensin point-of-care test for diagnosis of prosthetic joint infections: neglected role of laboratory and clinical pathologists. AB - Periprosthetic joint infection (PJI) is a serious complication that may occur after native joint replacement leading to a severe health and economic burden. Currently, due to several confounding factors, PJI is difficult to diagnose. Today, a multidisciplinary approach is indispensable to correctly define a periprosthetic joint infection; indeed, tissue histology, microbiology cultures and clinical findings are used together to achieve this goal. Analysis of alpha defensin is commonly used for PJI diagnosis, as it allows the rapid detection of alpha-defensin present in the synovial fluid following a microbial infection. Currently, a point-of-care testing (POCT) assay able to detect the presence of human alpha-defensins 1-3 in synovial fluid of patients is aimed directly at orthopedic surgeons. However, many orthopedic surgeons lack experience and training in quality laboratory practices, often failing to appreciate the significance of quality control and proper documentation when using POCT assays. To guarantee the highest quality diagnostic services, the alpha-defensin test should be used together with other biochemical and microbiological criteria commonly used for PJI diagnosis. Additionally, the close cooperation and communication between laboratory, pathologists and physicians is of fundamental importance in the correct diagnosis of PJI. PMID- 28708568 TI - Reference values of fecal calgranulin C (S100A12) in school aged children and adolescents. AB - BACKGROUND: Calgranulin C (S100A12) is an emerging marker of inflammation. It is exclusively released by activated neutrophils which makes this marker potentially more specific for inflammatory bowel disease (IBD) compared to established stool markers including calprotectin and lactoferrin. We aimed to establish a reference value for S100A12 in healthy children and investigated whether S100A12 levels can discriminate children with IBD from healthy controls. METHODS: In a prospective community-based reference interval study we collected 122 stool samples from healthy children aged 5-19 years. Additionally, feces samples of 41 children with suspected IBD (who were later confirmed by endoscopy to have IBD) were collected. Levels of S100A12 were measured with a sandwich enzyme-linked immunosorbent assay (ELISA) (Inflamark(r)). The limit of detection was 0.22 MUg/g. RESULTS: The upper reference limit in healthy children was 0.75 MUg/g (90% confidence interval: 0.30 1.40). Median S100A12 levels were significantly higher in patients with IBD (8.00 MUg/g [interquartile range (IQR) 2.5-11.6] compared to healthy controls [0.22 MUg/g (IQR<0.22); p<0.001]). The best cutoff point based on receiver operating characteristic curve was 0.33 MUg/g (sensitivity 93%; specificity 97%). CONCLUSIONS: Children and teenagers with newly diagnosed IBD have significantly higher S100A12 results compared to healthy individuals. We demonstrate that fecal S100A12 shows diagnostic promise under ideal testing conditions. Future studies need to address whether S100A12 can discriminate children with IBD from non organic disease in a prospective cohort with chronic gastrointestinal complaints, and how S100A12 performs in comparison with established stool markers. PMID- 28708569 TI - Impact of heat-inactivation on anti-Toxoplasma IgM antibody levels. PMID- 28708570 TI - Serum omentin-1 is a novel biomarker for predicting the functional outcome of acute ischemic stroke patients. AB - BACKGROUND: Recent studies have suggested that omentin-1 plays a critical role in the development of cardiovascular disease. However, reported findings are inconsistent, and no study has evaluated the association between omentin-1 levels and a poor functional outcome after ischemic stroke onset. METHODS: A total of 266 acute ischemic stroke patients were included in this study. All patients were prospectively followed up for 3 months after acute ischemic stroke onset and a poor functional outcome was defined as a major disability or death occurring during the follow-up period. A multivariable logistic model was used to evaluate the association between serum omentin-1 levels and the functional outcome of ischemic stroke patients at 3 months. RESULTS: Ischemic stroke patients with poor functional outcome had significantly lower levels of serum omentin-1 than patients without poor functional outcome at the 3-month follow-up (50.2 [40.2 59.8] vs. 58.3 [44.9-69.6] ng/mL, p<0.01). Subjects in the highest tertile of serum omentin-1 levels had a 0.38-fold risk of having poor functional outcome, compared with those in the lowest tertile (p<0.05). A negative association between omentin-1 levels and poor functional outcome was found (p for trend=0.02). The net reclassification index was significantly improved in predicting poor functional outcome when omentin-1 data was added to the multivariable logistic regression model. CONCLUSIONS: Higher omentin-1 levels at baseline were negatively associated with poor functional outcome among ischemic stroke patients. Omentin-1 may represent a biomarker for predicting poor functional outcome of acute ischemic stroke patients. PMID- 28708571 TI - Monitoring screen use: a qualitative exploration of family strategies in Swiss homes. AB - Background Digital technologies make family managing more complicated, as parents are worried about their children's well-being and want to protect them from excessive Internet use. Objective The objective of this study was to investigate both youths' and parents' views on strategies and rules set at home to regulate and monitor Internet use. Subjects Thirty-five adolescents (19 females), aged between 11 and 18 years, and 27 parents (17 mothers) from the French-speaking part of Switzerland participated in different focus groups. Methods Using a qualitative approach, results were analyzed using the grounded theory. Results Eight different mediation strategies emerged. One relevant finding is that rules regarding problematic content were never mentioned, while rules about screen time and location of use were numerous. This might indicate that parents are more worried about the time spent in front of the screen than about the actual activities their children engage in. Conclusions It could be recommended to parents to keep striving for an environment contributing to open discussion and exchange on Internet use, even if their digital literacy is lower than their youngsters' are. PMID- 28708572 TI - Diet quality, overweight and daily monetary allowance of Greek adolescents. AB - Objective To investigate cross-correlates of pocket-money on diet quality and weight status of Greek adolescents. Methods A total of 172 adolescents (55.2% boys), aged between 10 and 15 years old were recruited. Body weight and height were measured, body mass index (BMI) was computed. Weight status was assessed according to the International Obesity Task Force criteria and diet quality was evaluated via the Healthy Eating Index (HEI) - 2010. Results Adolescents were allowed a mean allowance of ?4.63 +/- 3.66 daily. Among boys participants, BMI correlated with pocket money (r = 0.311, p <= 0.002) and normoweight boys received statistically less money than their overweight peers (p <= 0.019). In both sexes, normoweight was more prevalent in the lowest monetary quartiles. Pocket money was not associated with HEI. Among boys, moderate HEI was more prevalent in the third quartile of pocket money, significantly higher compared to all others (p <= 0.01 for all). For girls, the prevalence of moderate HEI declined by each ascending pocket money quartile (p <= 0.05 for all). Conclusion In our sample, adolescents exhibited high rates of pooled overweight including obesity. The majority of the participants followed a diet of moderate quality. Pocket money was associated with BMI only among boys. As pocket money was not associated with diet quality, it is highly possible that adolescents might choose to spend their money on items other than foods. Our study shows that pocket money should be controlled during adolescence and teenagers should be educated on spending their money on healthier food choices. PMID- 28708573 TI - Natural product for the treatment of Alzheimer's disease. AB - Alzheimer's disease (AD) is related to increasing age. It is mainly characterized by progressive neurodegenerative disease, which damages memory and cognitive function. Natural products offer many options to reduce the progress and symptoms of many kinds of diseases, including AD. Meanwhile, natural compound structures, including lignans, flavonoids, tannins, polyphenols, triterpenes, sterols, and alkaloids, have anti-inflammatory, antioxidant, anti-amyloidogenic, and anticholinesterase activities. In this review, we summarize the pathogenesis and targets for treatment of AD. We also present several medicinal plants and isolated compounds that are used for preventing and reducing symptoms of AD. PMID- 28708574 TI - 4D ultrasound study of fetal movement early in the second trimester of pregnancy. AB - AIM: To assess the frequency of fetal movement and reproducibility of fetal movement counting in normal singleton pregnancies early in the second trimester using four-dimensional (4D) ultrasound. METHODS: Twenty-nine singleton pregnancies were studied for 15 min employing 4D ultrasound at 14-16 (19 cases) and 17-19 (10 cases) weeks of gestation. The frequencies of eight fetal movements (head anteflexion, head retroflexion, body rotation, hand to face movement, general movement, isolated arm movement, isolated leg movement and mouthing movement) were evaluated. RESULTS: The most frequent fetal movements were isolated arm movements at 14-16 and 17-19 weeks' gestation. There was a significant difference only in the frequency of mouthing movement between 14-16 and 17-19 weeks' gestation (P<0.05). All fetal movements showed intra- and inter class correlation coefficients greater than 0.87, with good intra- and inter observer agreements. CONCLUSION: The difference in the frequency of mouthing movement at 14-16 and 17-19 weeks' gestation may be due to increasing fetal swallowing because of the increasing amniotic fluid early in the second trimester of pregnancy. To the best of our knowledge, this is the first study on the reproducibility assessment of fetal movement counting using 4D ultrasound. However, the data and their interpretation in the present study should be taken with some degree of caution because of the small number of subjects studied. Further studies involving a larger sample size are needed to assess the reproducibility of fetal movement counting using 4D ultrasound. PMID- 28708575 TI - Is forty the new thirty? Population based study of advanced maternal age. AB - OBJECTIVE: To compare perinatal outcomes in different advanced maternal age groups. PATIENTS AND METHODS: We used a population-based data set to compare perinatal outcomes in three maternal age groups: 30-34.9, 35-39.9, and in women over 40 years. RESULTS: Over a 10-year period there were 23,422 (25.2%) births in the 35-39.9 years group, 3987 (4.3%) in the over 40 years group, and 65,492 births (70.5%) in our reference group (30-34.9 years). A direct significant relationship was found between maternal age and BMI and between pregnancy complications such as diabetes and hypertensive disorders, whereas an inverse relationship was found between older age and nuliparity and spontaneous conceptions. Also, older mothers had a higher incidence of both types of cesareans, and more early as well as late preterm births. Perinatal mortality was similar in all groups. CONCLUSIONS: Advanced maternal age is associated with higher, gradually increasing, incidence, of adverse perinatal outcomes. PMID- 28708576 TI - Adiponectin concentration in mid-trimester amniotic fluid varies with the alpha amylase level and maternal and neonatal outcomes. AB - OBJECTIVE: Factors influencing intraamniotic adiponectin levels and their functional significance remain incompletely elucidated. We prospectively measured adiponectin in amniotic fluid and identified its associations with maternal parameters, mediators in amniotic fluid and pregnancy outcomes. STUDY DESIGN: Mid trimester amniotic fluid from 571 women was tested for adiponectin, interleukin (IL)-6, IL-8 and alpha-amylase by enzyme-linked immunosorbant assay (ELISA), after which clinical data were obtained. Correlations between adiponectin and clinical or laboratory variables were analyzed by the Kruskal-Wallis, Mann Whitney and Spearman rank correlation tests. RESULTS: As compared to median levels in 462 women with a term delivery (7.8 ng/mL), adiponectin was elevated in 14 women who subsequently developed preterm premature rupture of membranes (pPROM) (17.3 ng/mL) and 24 women with an iatrogenic preterm birth (IPTB) (13.9 ng/mL) (P=0.0003), but not in 30 women who subsequently had a spontaneous preterm birth with intact membranes (8.1 ng/mL) (P>0.05). Median adiponectin was also elevated in 13 women whose babies developed fetal growth restriction (FGR) (20.6 ng/mL) (P=0.0055) and in 22 women whose babies had respiratory distress syndrome (RDS) (23.0 ng/mL) (P<0.0001). The adiponectin concentration was positively correlated with amylase (P=0.0089) and inversely correlated with maternal body mass index (P=0.0045). CONCLUSION: Adiponectin is a component of mid-trimester amniotic fluid and its concentration varies with maternal body mass index and subsequent development of pPROM, IPTB, FGR and RDS. PMID- 28708577 TI - A one year review of eclampsia in an Ethiopian Tertiary Care Center (Saint Paul's Hospital Millennium Medical College, SPHMMC). AB - Eclampsia remains one of the five major causes of maternal mortality in developing countries. Advances in diagnosis and management have led to a significant reduction in maternal mortality and morbidity from this disease in developed countries. In developing countries the incidence of maternal death attributed to eclampsia remains high and, in Ethiopia, maternal mortality from this complication has instead risen over the last decade. The purpose of this study was to review the incidence of eclampsia at the largest feto-maternal center in the country over 1 year in an attempt to determine what quality improvement measures are needed and could realistically be implemented within the system to decrease this complication. There were a total of 104 eclamptic patients during the study period. The hospital incidence of eclampsia was 82/10,000 deliveries excluding those arriving to the hospital in the postpartum period (28 cases). There were eight maternal deaths making the case fatality rate one in 13 cases. The median convulsion to arrival time, referral to arrival time and magnesium sulphate administration time were found to be 3, 2 and 3 h, respectively. The probability of multiple seizures (>=3 episodes) was increased significantly with the prolongation of these time variables. Occurrence of multiple seizures was in turn significantly associated with adverse maternal outcomes (ICU admission, morbidities and mortalities). As expected, there was a high incidence of eclampsia and eclampsia related maternal death in the hospital. We recommend a thorough assessment of the referral system, upgrading and capacity building of more health facilities, organizing trainings and drills in health facilities; and availing magnesium sulphate in all health centers among others. PMID- 28708603 TI - Monte Carlo skin dose simulation in intraoperative radiotherapy of breast cancer using spherical applicators. AB - : The relatively new treatment modality electronic intraoperative radiotherapy (IORT) is gaining popularity, irradiation being obtained within a surgically produced cavity being delivered via a low-energy x-ray source and spherical applicators, primarily for early stage breast cancer. Due to the spatially dramatic dose-rate fall off with radial distance from the source and effects related to changes in the beam quality of the low keV photon spectra, dosimetric account of the Intrabeam system is rather complex. Skin dose monitoring in IORT is important due to the high dose prescription per treatment fraction. In this study, modeling of the x-ray source and related applicators were performed using the Monte Carlo N-Particle transport code. The dosimetric characteristics of the model were validated against measured data obtained using an ionization chamber and EBT3 film as dosimeters. By using a simulated breast phantom, absorbed doses to the skin for different combinations of applicator size (1.5-5 cm) and treatment depth (0.5-3 cm) were calculated. Simulation results showed overdosing of the skin (>30% of prescribed dose) at a treatment depth of 0.5 cm using applicator sizes larger than 1.5 cm. Skin doses were significantly increased with applicator size, insofar as delivering 12 Gy (60% of the prescribed dose) to skin for the largest sized applicator (5 cm diameter) and treatment depth of 0.5 cm. It is concluded that the recommended 0.5-1 cm distance between the skin and applicator surface does not guarantee skin safety and skin dose is generally more significant in cases with the larger applicators. HIGHLIGHTS: * Intrabeam x-ray source and spherical applicators were simulated and skin dose was calculated. * Skin dose for constant skin to applicator distance strongly depends on applicator size. * Use of larger applicators generally results in higher skin dose. * The recommended 0.5-1 cm skin to applicator distance does not guarantee skin safety. PMID- 28708604 TI - Oscillatory deviations from Matthiessen's rule due to interacting dislocations. AB - We theoretically examine the validity of Matthiessen's rule caused by strong dislocation-dislocation interaction using a fully quantized dislocation field, where its degree of deviation is quantified at arbitrary electron energy, dislocation-electron and dislocation-dislocation distances and interaction strengths. Contrary to intuition, we show that the electron relaxation rate deviates from the Matthiessen's rule in an oscillatory way as a function of inter dislocation distance, instead of monotonically. In addition, we show quantitatively that the deviation is larger in a material with lower mass density, higher Poisson ratio and higher elastic moduli. This study could serve as a computational tool to investigate the electronic behavior of a highly dislocated system at a full quantum field theoretical level. PMID- 28708605 TI - Modal analysis of annual runoff volume and sediment load in the Yangtze river lake system for the period 1956-2013. AB - This study focuses on detecting trends in annual runoff volume and sediment load in the Yangtze river-lake system. Times series of annual runoff volume and sediment load at 19 hydrological gauging stations for the period 1956-2013 were collected. Based on the Mann-Kendall test at the 1% significance level, annual sediment loads in the Yangtze River, the Dongting Lake and the Poyang Lake were detected with significantly descending trends. The power spectrum estimation indicated predominant oscillations with periods of 8 and 20 years are embedded in the runoff volume series, probably related to the El Nino Southern Oscillation (2 7 years) and Pacific Decadal Oscillation (20-30 years). Based on dominant components (capturing more than roughly 90% total energy) extracted by the proper orthogonal decomposition method, total change ratios of runoff volume and sediment load during the last 58 years were evaluated. For sediment load, the mean CRT value in the Yangtze River is about -65%, and those in the Dongting Lake and the Poyang Lake are -92.2% and -87.9% respectively. Particularly, the CRT value of the sediment load in the channel inflow of the Dongting Lake is even 99.7%. The Three Gorges Dam has intercepted a large amount of sediment load and decreased the sediment load downstream. PMID- 28708606 TI - Effect of hydroxypropyl cellulose (HPC), polyvinylpyrrolidone (PVP) and polyethylene glycol (PEG) on Nd-TiO2/graphene oxide nanocomposite for removal of lead(II) and copper(II) from aquatic media. AB - In order to investigate the effect of hydroxypropyl cellulose (HPC), polyvinylpyrrolidone (PVP) and polyethylene glycol (PEG) on adsorbing capacity of nanosorbent Nd-TiO2/GO, Nd-TiO2/HPC/GO, Nd-TiO2/PVP/GO and Nd-TiO2/PEG/GO nanocomposites were synthesized. Studies by Fourier transform infrared spectroscopy confirmed the expected structure and X-ray diffraction results confirmed the formation of crystalline phase of anatase titania and also graphene oxide (GO). Scanning electron microscopy pictures and energy dispersive X-ray spectroscopy analysis showed the formation of Nd-TiO2 nanoparticles. These nanocomposites were used for removal of lead(II) and copper(II) from water and the effective factors on removal were optimized. The results showed that the maximum removal for all three nanocomposites was at pH = 7. The amount of adsorbent and contact time for Nd-TiO2/HPC/GO and Nd-TiO2/PVP/GO nanocomposites was equal to 0.02 g and 20 minutes respectively, but they were equal to 0.01 g and 15 minutes for Nd-TiO2/PEG/GO nanocomposite. Investigating the effect of interfering ions showed they had no considerable effect on removal efficiency. In order to investigate the effect of photocatalytic activity in optimal conditions and in the presence of visible-ultraviolet light, the removal process was performed. The results showed an increase in removal efficiency. Furthermore, the ability of synthesized nanosorbents to decompose organic compounds available in water was confirmed and their energy band gaps were calculated. PMID- 28708607 TI - Energy capture and nutrients removal enhancement through a stacked constructed wetland incorporated with microbial fuel cell. AB - To improve the sustainability of constructed wetlands (CWs), a novel tiered wetland system integrated with a microbial fuel cell (MFC) was developed in this study. Compared to the single stage CW, chemical oxygen demand (COD) removal efficiency was improved from 83.2% to 88.7%. More significantly, this tiered system significantly enhanced total nitrogen removal efficiency (an increase from 53.1% to 75.4%). In terms of MFC integration, a gradually decreased performance in electricity production was observed during its 3 months of operation (the voltage dropped from nearly 600 mV to less than 300 mV), which resulted in a reduction of power density from around 2 W/m3 to less than 0.5 W/m3. The deterioration in performance of the air-cathode is the main reason behind this, since the electrode potential of the cathode under open circuit reduced from 348.5 mV to 49.5 mV while the anode potential kept constant at around -400 mV. However, in spite of its electrical performance reduction, it was proved that MFC integration enhanced COD removal and the nitrification process. Further work is needed to improve the stability and feasibility of this new system. PMID- 28708608 TI - Magnetic Schiff's base sorbent based on shrimp peels wastes for consummate sorption of chromate. AB - Magnetic Schiff's base chitosan composite has been prepared starting from shrimp peels as a raw material. Chitosan extraction involved three main stages as preconditioning, demineralization deproteinization and deacetylation. Chitosan modification process took place through the reaction between chitosan and polymeric Schiff's base of thiourea/glutaraldehyde in the presence of magnetite. The synthetic hybrid composite was characterized by Fourier transform infrared spectroscopy and scanning electron microscopy-energy dispersive X-ray analyses and tested as sorbent for Cr(VI) recovery from aqueous solution. The performance of the sorbent was systematically evaluated by batch sorption experiments, followed by equilibrium and kinetic studies with different mathematical models. The isotherm study demonstrate that the sorbent achieved 99.1% (sorption capacity; 252.45 mg g-1) removal efficiency in Cr(VI) solution with concentrations up to 400 mg/L. Experimental data gave better mathematical fitting towards pseudo-second-order kinetic model and Langmuir isotherm model. The distribution coefficient was obtained at different temperatures and the thermodynamic parameters have been calculated: the sorption is endothermic, spontaneous and contributes to increase the randomness of the system. The sorbent could be recycled for three cycles of sorption/desorption. PMID- 28708609 TI - Evaluation of nutrients removal (NO3-N, NH3-N and PO4-P) with Chlorella vulgaris, Pseudomonas putida, Bacillus cereus and a consortium of these microorganisms in the treatment of wastewater effluents. AB - In this research removal of NH3-N, NO3-N and PO4-P nutrients from municipal wastewater was studied, using Chlorella vulgaris, Pseudomonas putida, Bacillus cereus and an artificial consortium of them. The objective is to analyze the performance of these microorganisms and their consortium, which has not been previously studied for nutrient removal in municipal wastewater. A model wastewater was prepared simulating the physicochemical characteristics found at the wastewater plant in Chapala, Mexico. Experiments were carried out without adding an external carbon source. Results indicate that nutrient removal with Chlorella vulgaris was the most efficient with a removal of 24.03% of NO3-N, 80.62% of NH3-N and 4.30% of PO4-P. With Bacillus cereus the results were 8.40% of NO3-N, 28.80% of NH3-N and 3.80% of PO4-P. The removals with Pseudomonas putida were 2.50% of NO3-N, 41.80 of NH3-N and 4.30% of PO4-P. The consortium of Chlorella vulgaris-Bacillus cereus-Pseudomonas putida removed 29.40% of NO3-N, 4.2% of NH3-N and 8.4% of PO4-P. The highest biomass production was with Bacillus cereus (450 mg/l) followed by Pseudomonas putida (444 mg/l), the consortium (205 mg/l) and Chlorella vulgaris (88.9 mg/l). This study highlights the utility of these microorganisms for nutrient removal in wastewater treatments. PMID- 28708610 TI - Combination of novel coalescing oil water separator and electrocoagulation technique for treatment of petroleum compound contaminated groundwater. AB - In the present study a combination of a novel coalescing oil water separator (COWS) and electrocoagulation (EC) technique was used for treatment of petroleum product contaminated groundwater. In the first phase, COWS was used as the primary treatment. Two different types of coalescing media and two levels of flow rates were examined in order to find the optimum conditions. The effluent of COWS was collected in optimum conditions and was treated using an EC process in the second phase of the research. In this phase, preliminary experiments were conducted in order to investigate the effect of EC reaction time and sedimentation time on chemical oxygen demand (COD) removal efficiency. Best conditions for EC reaction time and sedimentation time were obtained to be 5 min and 30 min, respectively. Response surface methodology was applied to evaluate the effect of initial pH, current density and aeration rate on settling velocity (Vs) and effluent COD. The optimum conditions, for achieving maximum values of Vs as well as the values of effluent COD, in the range of results were obtained at conditions of 7, 34 mA.cm-2 and 1.5 L.min-1 for initial pH, current density and aeration rate, respectively. PMID- 28708611 TI - Upflow anaerobic sludge blanket and aerated constructed wetlands for swine wastewater treatment: a pilot study. AB - Swine wastewater management is often affected by two main issues: a too high volume for optimal reuse as a fertilizer and a too high strength for an economically sustainable treatment by classical solutions. Hence, an innovative scheme has been tested to treat swine wastewater, combining a low cost anaerobic reactor, upflow anaerobic sludge blanket (UASB), with intensified constructed wetlands (aerated CWs) in a pilot scale experimental study. The swine wastewater described in this paper is produced by a swine production facility situated in North Italy. The scheme of the pilot plant consisted of: (i) canvas-based thickener; (ii) UASB; (iii) two intensified aerated vertical subsurface flow CWs in series; (iv) a horizontal flow subsurface CW. The influent wastewater quality has been defined for total suspended solids (TSS 25,025 +/- 9,323 mg/l), organic carbon (chemical oxygen demand (COD) 29,350 +/- 16,983 mg/l), total reduced nitrogen and ammonium (total Kjeldahl nitrogen (TKN) 1,783 +/- 498 mg/l and N NH4+ 735 +/- 251 mg/l) and total phosphorus (1,285 +/- 270 mg/l), with nitrates almost absent. The overall system has shown excellent performances in terms of TSS, COD, N-NH4+ and TKN removal efficiencies (99.9%, 99.6%, 99.5%, and 99.0%, respectively). Denitrification (N-NO3- effluent concentration equal to 614 +/- 268 mg/l) did not meet the Italian quality standards for discharging in water bodies, mainly because the organic carbon was almost completely removed in the intensified CW beds. PMID- 28708612 TI - Short- and long-term orange dye effects on ammonium oxidizing and anammox bacteria activities. AB - The effects of orange azo dye over ammonia oxidizing bacteria (AOB) and anammox bacteria activities were tested. Performed batch tests indicated that concentrations lower than 650 mgorange/L stimulated AOB activity, while anammox bacteria activity was inhibited at concentrations higher than 25 mgorange/L. Long term performance of a continuous stirred tank reactor (CSTR) for the partial nitritation and a sequencing batch reactor (SBR) for the anammox process was tested in the presence of 50 mgorange/L. In the case of the partial nitritation process, both the biomass concentration and the specific AOB activity increased after 50 days of orange azo dye addition. Regarding the anammox process, specific activity decreased down to 58% after 12 days of operation with continuous feeding of 50 mgorange/L. However, the anammox activity was completely recovered only 54 days after stopping the dye addition in the feeding. Once the biomass was saturated the azo dye adsorption onto the biomass was insignificant in the CSTR for the partial nitritation process fed with 50 mgorange/L. However, in the SBR the absorption was determined as 6.4 mgorange/g volatile suspended solids. No biological decolorization was observed in both processes. PMID- 28708613 TI - Chlorate adsorption from chlor-alkali plant brine stream. AB - Chlorates are present in the brine stream purged from chlor-alkali plants. Tests were conducted using activated carbon from coconut shell, coal or palm kernel shell to adsorb chlorate. The results show varying levels of adsorption with reduction ranging between 1.3 g/L and 1.8 g/L. This was higher than the chlorate generation rate of that plant, recorded at 1.22 g/L, indicating that chlorate can be adequately removed by adsorption using activated carbon. Coconut based activated carbon exhibited the best adsorption of chlorate of the three types of activated carbon tested. Introducing an adsorption step prior to purging of the brine will be able to reduce chlorate content in the brine stream. The best location for introducing the adsorption step was identified to be after dechlorination of the brine and before resaturation. Introduction of such an adsorption step will enable complete recovery of the brine and prevent brine purging, which in turn will result in less release of chlorides and chlorates to the environment. PMID- 28708614 TI - Design and optimization of hydrogen production from hydrothermally pretreated sugarcane bagasse using response surface methodology. AB - Hydrogen production from hydrothermally pretreated (200 degrees C for 10 min at 16 bar) sugarcane bagasse was analyzed using response surface methodology. The yeast extract concentration and the temperature had a significant influence for hydrogen production (p-value 0.027 and 0.009, respectively). Maximum hydrogen production (17.7 mmol/L) was observed with 3 g/L yeast extract at 60 degrees C (C10). In this conditions were produced acetic acid (50.44 mg/L), butyric acid (209.71 mg/L), ethanol (38.4 mg/L), and methane (6.27 mmol/L). Lower hydrogen productions (3.5 mmol/L and 3.9 mmol/L) were observed under the conditions C7 (2 g/L of yeast extract, 35.8 degrees C) and C9 (1 g/L of yeast extract, 40 degrees C), respectively. The low yeast extract concentration and low temperature caused a negative effect on the hydrogen production. By means of denaturing gradient gel electrophoresis 20% of similarity was observed between the archaeal population of mesophilic (35 and 40 degrees C) and thermophilic (50, 60 and 64 degrees C) reactors. Likewise, similarity of 22% was noted between the bacterial population for the reactors with the lowest hydrogen production (3.5 mmol/L), at 35.8 degrees C and with the highest hydrogen production (17.7 mmol/L) at 60 degrees C demonstrating that microbial population modification was a function of incubation temperature variation. PMID- 28708615 TI - Treatment of poultry slaughterhouse wastewater using a static granular bed reactor (SGBR) coupled with ultrafiltration (UF) membrane system. AB - The South African poultry industry has grown exponentially in recent years due to an increased demand for their products. As a result, poultry plants consume large volumes of high quality water to ensure that hygienically safe poultry products are produced. Furthermore, poultry industries generate high strength wastewater, which can be treated successfully at low cost using anaerobic digesters. In this study, the performance of a bench-scale mesophilic static granular bed reactor (SGBR) containing fully anaerobic granules coupled with an ultrafiltration (UF) membrane system, as a post-treatment system, was investigated. The poultry slaughterhouse wastewater was characterized by a chemical oxygen demand (COD) range between 1,223 and 9,695mg/L, average biological oxygen demand of 2,375mg/L and average fats, oil and grease (FOG) of 554mg/L. The SGBR anaerobic reactor was operated for 9 weeks at different hydraulic retention times (HRTs), i.e. 55 and 40 h, with an average organic loading rate (OLR) of 1.01 and 3.14g COD/L.day. The SGBR results showed an average COD, total suspended solids (TSS) and FOG removal of 93%, 95% and 90% respectively, for both OLR. The UF post-treatment results showed an average of COD, TSS and FOG removal of 64%, 88% and 48%, respectively. The overall COD, TSS and FOG removal of the system (SGBR and UF membrane) was 98%, 99.8%, and 92.4%, respectively. The results of the combined SGBR reactor coupled with the UF membrane showed a potential to ensure environmentally friendly treatment of poultry slaughterhouse wastewater. PMID- 28708616 TI - Monitoring accumulation sediment characteristics in full scale sewer physical model with urban wastewater. AB - A series of experiments were carried out with real wastewater in a pilot flume located at A Coruna wastewater treatment plant (WWTP) (Spain). A full scale model was developed to test a circular (300 mm inner diameter) and an equivalent area egg-shaped plastic pipe under controlled experimental conditions (pipe slope 2 50/00, averaged discharge Q = 4 L/s). Velocity profiles and sediment accumulation in the pipe invert was daily measured. Within the 7-11 days, the average sediment accumulation rate found in the circular pipe was between 1.4 and 3.8 mm/d. The sediment height depended on the input wastewater sediment distribution and organic content. The egg-shaped pipe presented no sediment deposit for the same downstream boundary conditions, although biofilms were attached to the walls of both pipes. Besides, wastewater quality was monitored continuously and sediment composition was studied at the end of experiments. Two types of sediment were recorded: a granular bed deposit (rho = 1,460 kg/m3, d50 = 202 MUm) and wall biofilms (rho = 1,190 kg/m3, d50 = 76 MUm). PMID- 28708617 TI - Using one filter stage of unsaturated/saturated vertical flow filters for nitrogen removal and footprint reduction of constructed wetlands. AB - French vertical flow constructed wetlands (VFCW) treating raw wastewater have been developed successfully over the last 30 years. Nevertheless, the two-stage VFCWs require a total filtration area of 2-2.5 m2/P.E. Therefore, implementing a one-stage system in which treatment performances reach standard requirements is of interest. Biho-Filter(r) is one of the solutions developed in France by Epur Nature. Biho-Filter(r) is a vertical flow system with an unsaturated layer at the top and a saturated layer at the bottom. The aim of this study was to assess this new configuration and to optimize its design and operating conditions. The hydraulic functioning and pollutant removal efficiency of three different Biho Filter(r) plants commissioned between 2011 and 2012 were studied. Outlet concentrations of the most efficient Biho-Filter(r) configuration are 70 mg/L, 15 mg/L, 15 mg/L and 25 mg/L for chemical oxygen demand (COD), 5-day biological oxygen demand (BOD5), total suspended solids (TSS) and total Kjeldahl nitrogen (TKN), respectively. Up to 60% of total nitrogen is removed. Nitrification efficiency is mainly influenced by the height of the unsaturated zone and the recirculation rate. The optimum recirculation rate was found to be 100%. Denitrification in the saturated zone works at best with an influent COD/NO3-N ratio at the inflet of this zone larger than 2 and a hydraulic retention time longer than 0.75 days. PMID- 28708618 TI - Large scale application of French reed beds: municipal wastewater treatment for a 20,000 inhabitant's town in Moldova. AB - A two-stage vertical flow treatment wetlands system (French reed beds) was realized in 2012-2013 for the Orhei's town in Moldova. The treatment system occupies a total area of about 5 ha and operates in cold climate conditions during winter, with air temperatures below -20 degrees C. The first 2 years (2013-2015) of treatment performances for this system are presented here, with a particular highlight on the analysis of the commissioning phase and the operative choices taken along this period basing on the observed results. The specific classification of this application of constructed wetlands (CWs) for the primary and secondary treatment of municipal wastewater as a medium-large size system makes this technical report a relevant reference for demonstrating the possible extension to the highest numbers of inhabitants for the common application range of this family of technologies (CWs) for municipal wastewater. The observed performances for organic carbon (both as chemical oxygen demand (COD) and biochemical oxygen demand (BOD5)), suspended solids and ammonia removals in the whole first operational period consistently satisfied the national limits for discharge in rivers, respectively, with average values of 86%, 96% and 66%. The treated daily flow was measured in the range of 1,000-2,000 m3/d. PMID- 28708619 TI - Production of spore laccase from Bacillus pumilus W3 and its application in dye decolorization after immobilization. AB - Given that spore laccase from the Bacillus genus is heat- and alkali-resistant, it is more suitable for industrial applications than fungal laccase. To determine the optimal culture conditions for spore laccase production, the effects of Cu2+ concentration, oxygen content, and culture time on spore laccase production from Bacillus pumilus W3 were investigated. The optimal production parameters were 0.2 mM of Cu2+, 200 rpm shaking speed, 100 mL liquid loading, and 5 days of cultivation. Spore laccase was efficiently immobilized on amino-functionalized celite. When used in dye decolorization, the immobilized spore laccase removed 84.15% of methyl green and 69.70% of acid red 1 after 48 h of treatment. Moreover, the immobilized spore laccase retained 87.04% of its initial decolorization activity after six cycles in the decolorization of acid red 1. These insights into the culture conditions and immobilization of spore laccases should be useful in the development of spore laccase as a biocatalyst in the treatment of textile wastewater. PMID- 28708620 TI - The characteristics of dissolved organic matter (DOM) in storm sewer sediments and the binding interaction with Cu(II) in four typical regions in Beijing, China. AB - In this work, dissolved organic matter (DOM) was extracted from storm sewer sediments collected in four typical regions (residential, campus, traffic and business regions) in Beijing, China. The basic characteristics of DOM were analyzed by UV-visible spectroscopy (UV-Vis), excitation-emission matrix Fluorescence Spectroscopy and Fourier Transform Infrared Spectroscopy. Furthermore, the complexation between DOM and Cu(II) were investigated. The results showed that there were large amount of aromatic structure in the DOM extracted from storm sewer sediments. The microbial activities had also made a contribution to the DOM in storm sewer sediments. The composition of DOM influenced the complexing capacity of Cu(II) greatly, which may be attributed to the protein-like and humic-like substances in storm sewer sediments. This study demonstrated valuable information on the structure present in the DOM of storm sewer sediments and provided new insight for exploring the relationship between DOM and co-existing heavy metals in storm sewer sediments. PMID- 28708621 TI - Treatment of a mixed wood preservative leachate by a hybrid constructed wetland and a willow planted filter. AB - The performance and removal mechanisms of a hybrid constructed wetland (HCW) followed by a willow planted filter (WPF) were evaluated for the treatment of a leachate contaminated by wood pole preservatives (pentachlorophenol (PCP) and chromated copper arsenate) to reach the storm sewer discharge limits. The HCW aimed to dechlorinate the PCP and polychlorodibenzo-p dioxins/polychlorodibenzofuran (PCDD/F) and to remove metals by adsorption and precipitation. The HCW was efficient in removing PCP (>98.6%), oil, arsenic (99.4%), chromium (>99.2%), copper (>99.6%%) and iron (29%) to under their discharge limits, but it was unable to reach those of Mn and PCDD/F, with residual concentrations of 0.11 mg Mn/L and 0.32 pg TEQ/L. Iron and manganese could be removed but were subsequently released by the HCW due to low redox conditions. No dechlorination of PCDD/F was observed since its chlorination profile remained the same in the different sections of the HCW. Adsorption was the most probable removal mechanism of PCDD/F. The WPF was able to remove some residual contamination, but it released Mn at a gradually decreasing rate. Total evapotranspiration of the leachate by a larger fertilized WPF and the construction of an underground retention basin are proposed to prevent any discharge of PCDD/F traces in the environment. PMID- 28708622 TI - Synthesis of ZnO-CuO/MCM-48 photocatalyst for the degradation of organic pollutions. AB - The photocatalytic properties of ZnO-CuO catalysts supported on siliceous MCM-48 (Mobil Composition of Matter No. 48) for the degradation of organic pollutions such as methylene blue and salicylic acid under UV light irradiation were investigated. These catalysts were prepared by impregnation of MCM-48 with a mixed aqueous solution of copper acetate and zinc acetate. X-ray diffraction, N2 physisorption, high resolution transmission electron microscopy, scanning electron microscopy, Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy and photoluminescence were used to characterize these samples. Results from characterizations showed that the addition of ZnO to CuO/MCM-48 could markedly improve the photocatalytic degradation properties. The enhanced photocatalytic behaviors of ZnO-CuO/MCM-48 may be due to the formation of p-n heterojunctions between ZnO and CuO, resulting in the effective separation of photogenerated electron-hole pairs. Moreover, the photocatalysts were easily recovered and reused for five cycles without considerable loss of activity. PMID- 28708623 TI - Solar radiation (PAR, UV-A, UV-B) penetration in a shallow maturation pond operating in a tropical climate. AB - Solar radiation is considered the primary route for disinfection of pathogenic bacteria in maturation ponds. There is scarce information on depth profiling and attenuation of photosynthetically active radiation (PAR), UV-A and UV-B in shallow maturation ponds operating in tropical climates. Measurements of solar irradiance of the three wavelength ranges, together with turbidity, have been acquired from different depths for over 1 year in a shallow maturation pond (44 cm of depth) operating in Brazil. UV-A and UV-B were still detected at 10 cm from the surface, but from 15 cm both were undetectable. PAR was still detected at 30 cm of depth. Irradiation attenuation showed to be related to turbidity. Attenuation coefficients were calculated and simple models without turbidity (traditional structure) or including log10 of turbidity are proposed for predicting PAR irradiance attenuation as a function of depth. PMID- 28708624 TI - Fe-FeS2 adsorbent prepared with iron powder and pyrite by facile ball milling and its application for arsenic removal. AB - Arsenic is one of the major pollutants and a worldwide concern because of its toxicity and chronic effects on human health. An adsorbent of Fe-FeS2 mixture for effective arsenic removal was successfully prepared by mechanical ball milling. The products before and after arsenic adsorption were characterized with scanning electron microscopy, X-ray diffraction, Fourier transform infrared spectroscopy, and X-ray photoelectron spectroscopy. The adsorbent shows high arsenic removal efficiency when molar ratio of iron to pyrite is 5:5. The experimental data of As(III) adsorption are fitted well with the Langmuir isotherm model with a maximal adsorption capacity of 101.123 mg/g. And As(V) data were described perfectly by the Freundlich model with a maximal adsorption capacity of 58.341 L/mg. As(III) is partial oxidized to As(V) during the adsorption process. High arsenic uptake capability and cost-effectiveness of waste make it potentially attractive for arsenic removal. PMID- 28708625 TI - Calculation method for steady-state pollutant concentration in mixing zones considering variable lateral diffusion coefficient. AB - Prediction of the pollutant mixing zone (PMZ) near the discharge outfall in Huangshaxi shows large error when using the methods based on the constant lateral diffusion assumption. The discrepancy is due to the lack of consideration of the diffusion coefficient variation. The variable lateral diffusion coefficient is proposed to be a function of the longitudinal distance from the outfall. Analytical solution of the two-dimensional advection-diffusion equation of a pollutant is derived and discussed. Formulas to characterize the geometry of the PMZ are derived based on this solution, and a standard curve describing the boundary of the PMZ is obtained by proper choices of the normalization scales. The change of PMZ topology due to the variable diffusion coefficient is then discussed using these formulas. The criterion of assuming the lateral diffusion coefficient to be constant without large error in PMZ geometry is found. It is also demonstrated how to use these analytical formulas in the inverse problems including estimating the lateral diffusion coefficient in rivers by convenient measurements, and determining the maximum allowable discharge load based on the limitations of the geometrical scales of the PMZ. Finally, applications of the obtained formulas to onsite PMZ measurements in Huangshaxi present excellent agreement. PMID- 28708626 TI - Effects of hydraulic loading rate and aeration mode on nitrogen removal and nitrogen functional gene abundances in subsurface wastewater infiltration systems. AB - Matrix dissolved oxygen, nitrogen removal and nitrogen functional gene abundances in two artificial aeration modes, continuous aeration (CA) and intermittent aeration (IA), in subsurface wastewater infiltration systems (SWISs) under different hydraulic loading rates (HLRs) were investigated. Aeration not only successfully created aerobic conditions at 50 cm depth, but also did not change anoxic or anaerobic conditions at 80 and 110 cm depths. Meanwhile, aeration significantly enhanced chemical oxygen demand, NH4+-N, and total nitrogen (TN) removal and the enrichment of nitrogen removal functional genes (amoA, nxrA, napA, narG, nirK and qnorB) compared to the non-aerated SWIS, especially for high HLRs. IA SWIS (79.7%-85.8%) had a better performance on TN removal compared with CA SWIS (73.8%-82.2%) when the HLRs ranged from 0.06 to 0.3 m3/(m2 d). Intermittent aeration is a sensible strategy to achieve high HLR, good nitrogen removal performance and comparatively low operation cost for SWISs. PMID- 28708627 TI - Nickel adsorption onto polyurethane ethylene and vinyl acetate sorbents. AB - The present study was conducted to appraise the efficiencies of polyurethane ethylene sorbent (PES) and vinyl acetate sorbent (VAS) for nickel (Ni) adsorption. Process variables, i.e. Ni(II) ions initial concentration, pH, contact time and adsorbent dosage were optimized by response surface methodology (RSM) approach. The Ni(II) adsorption was fitted to the kinetic models (pseudo first-order and pseudo-second-order) and adsorption isotherms (Freundlich and Langmuir). At optimum conditions of process variables, 171.99 mg/g (64.7%) and 388.08 mg/g (92.7%) Ni(II) was adsorbed onto PES and VAS, respectively. The RSM analysis revealed that maximum Ni(II) adsorption can be achieved at 299 mg/L Ni(II) ions initial concentration, 4.5 pH, 934 min contact time and 1.3 g adsorbent dosage levels for PES, whereas the optimum values for VAS were found to be 402 mg/L Ni(II) ions initial concentration, 4.6 pH, 881 min contact time and 1.2 g adsorbent dosage, respectively. The -OH and -C = O- were involved in the Ni(II) adsorption onto PES and VAS adsorbents. At optimum levels, up to 53.67% and 80.0% Ni(II) was removed from chemical industry wastewater using PES and VAS, respectively, which suggest that PES and VAS could possibly be used for Ni(II) adsorption from industrial wastewater. PMID- 28708628 TI - Enhanced treatment of secondary municipal wastewater effluent: comparing (biological) filtration and ozonation in view of micropollutant removal, unselective effluent toxicity, and the potential for real-time control. AB - Ozonation and three (biological) filtration techniques (trickling filtration (TF), slow sand filtration (SSF) and biological activated carbon (BAC) filtration) have been evaluated in different combinations as tertiary treatment for municipal wastewater effluent. The removal of 18 multi-class pharmaceuticals, as model trace organic contaminants (TrOCs), has been studied. (Biological) activated carbon filtration could reduce the amount of TrOCs significantly (>99%) but is cost-intensive for full-scale applications. Filtration techniques mainly depending on biodegradation mechanisms (TF and SSF) are found to be inefficient for TrOCs removal as a stand alone technique. Ozonation resulted in 90% removal of the total amount of quantified TrOCs, but a post-ozonation step is needed to cope with an increased unselective toxicity. SSF following ozonation showed to be the only technique able to reduce the unselective toxicity to the same level as before ozonation. In view of process control, innovative correlation models developed for the monitoring and control of TrOC removal during ozonation, are verified for their applicability during ozonation in combination with TF, SSF or BAC. Particularly for the poorly ozone reactive TrOCs, statistically significant models were obtained that correlate TrOC removal and reduction in UVA254 as an online measured surrogate parameter. PMID- 28708629 TI - Successful Assessment of Vocal Cord Palsy Before Tracheal Extubation by Laryngeal Ultrasonography in a Patient After Esophageal Surgery: A Case Report. AB - Laryngeal ultrasonography has mainly been performed after tracheal extubation. However, improvements in ultrasound technology now allow assessment of vocal cord function even under conditions of endotracheal intubation. We report herein the use of laryngeal ultrasonography in an endotracheally intubated patient after esophagectomy, which allowed us to make the presumptive diagnosis of bilateral recurrent nerve palsy before tracheal extubation. Our experience suggests that laryngeal ultrasonography may be useful in assessing vocal cord function even in endotracheally intubated patients, although the indications and efficacy remain to be determined. PMID- 28708630 TI - Health benefits of physical activity: a systematic review of current systematic reviews. AB - PURPOSE OF REVIEW: The health benefits of physical activity and exercise are clear; virtually everyone can benefit from becoming more physically active. Most international guidelines recommend a goal of 150 min/week of moderate-to-vigorous intensity physical activity. Many agencies have translated these recommendations to indicate that this volume of activity is the minimum required for health benefits. However, recent evidence has challenged this threshold-centered messaging as it may not be evidence-based and may create an unnecessary barrier to those who might benefit greatly from simply becoming more active. This systematic review evaluates recent systematic reviews that have examined the relationship between physical activity and health status. RECENT FINDINGS: Systematic reviews and/or meta-analyses (based largely on epidemiological studies consisting of large cohorts) have demonstrated a dose-response relationship between physical activity and premature mortality and the primary and secondary prevention of several chronic medical conditions. The relationships between physical activity and health outcomes are generally curvilinear such that marked health benefits are observed with relatively minor volumes of physical activity. SUMMARY: These findings challenge current threshold-based messaging related to physical activity and health. They emphasize that clinically relevant health benefits can be accrued by simply becoming more physically active. VIDEO ABSTRACT: http://links.lww.com/HCO/A42. PMID- 28708631 TI - Development of Systemic Inflammatory Polyarthritis After Zygapophyseal Joint Injection With Hylan G-F 20 (Synvisc-One). AB - Hylan G-F 20 (Synvisc-One) is a hyaluronic acid derivative used for viscosupplementation of synovial fluid in osteoarthritic joints. Injection of hylan G-F 20 is Federal Drug Administration approved for use in knee osteoarthritis and is generally well tolerated with few reported adverse effects, the most common being local pain or swelling. We present the case of a 72-year old man with bilateral, diffuse, joint pain and swelling with elevated inflammatory markers suggestive of a systemic inflammatory polyarthropathy that developed acutely 2 days after lumbar zygapophyseal joint injection with hylan G F 20. Systemic effects after hylan G-F 20 injection have not been well documented, and this is the first reported case of systemic inflammatory polyarthritis after injection, to our knowledge. Further research is needed to better establish the safety and efficacy of lumbar zygapophyseal joint injections with hylan G-F 20. PMID- 28708633 TI - Response: "Prophylactic Negative Pressure Dressing Use in Closed Laparotomy Wounds Following Abdominal Operations: What We Really Know?" PMID- 28708632 TI - Innovating With Rehabilitation Technology in the Real World: Promises, Potentials, and Perspectives. AB - In this article, we discuss robotic-assisted therapy as an emerging and significant field of clinical rehabilitation and its value proposition for innovating rehabilitation clinical practice. Attempts to achieve integration among clinicians' practices and bioengineers' machines often generate new challenges and controversies. To date, the literature is indicative of a sizeable number and variety of robotic devices in the field of clinical rehabilitation, some are commercially available; however, large-scale clinical outcomes are less positive than expected. The following main themes related to integrating rehabilitation technology in real-world clinical practice will be discussed: the application of current evidence-based practice and knowledge in relation to treatment in the rehabilitation clinic, perspectives from rehabilitation professionals using robotic-aided therapy with regard to challenges, and strategies for problem solving. Lastly, we present innovation philosophies with regard to sustainability of clinical rehabilitation technologies. PMID- 28708634 TI - Design Principles for Building a Leadership Development Program in a Department of Surgery. PMID- 28708635 TI - The management of pediatric hearing loss caused by auditory neuropathy spectrum disorder. AB - PURPOSE OF REVIEW: Auditory neuropathy spectrum disorder (ANSD) is a condition in which auditory testing reveals normal otoacoustic emissions, but auditory brainstem testing is abnormal or absent and speech discrimination is poor. This constellation of findings ostensibly suggests that the cochlea is healthy and an abnormality of conduction or processing of sound occurs along the nerve fibers. As more is learned about this condition, it is becoming clear that ANSD describes heterogeneous, distinct clinical entities that must be taken into account when devising treatment modalities. RECENT FINDINGS: Modern auditory testing, genetic testing, and neuroimaging can allow for an accurate understanding of the location of the lesion causing ANSD in the auditory pathway. Contributing causes can include genetic mutations, absent or deficient cochlear nerve, hypoxia and jaundice among others. Hearing aids can be successful in the management of ANSD. Several studies suggest that cochlear implantation can lead to successful hearing outcomes in a subset of this patient population. SUMMARY: Auditory neuropathy spectrum disorder represents a relatively rare but important diagnosis for clinicians. Treatment for this condition includes hearing aids and FM systems in more mild cases, and cochlear implants in severe cases. Cochlear implantation for many patients can lead to a good hearing outcomes but the outcome can vary greatly depending on the underlying etiology of ANSD. PMID- 28708637 TI - Discussion on: Oral Propranolol for Parotid Infantile Hemangiomas. PMID- 28708636 TI - The impact of hearing loss on society in general: an underappreciated problem. PMID- 28708638 TI - Chordoid Glioma: A Neoplasm Found in the Anterior Part of the Third Ventricle. AB - Chordoid glioma is a rare low-grade tumor that originates almost exclusively in the anterior part of the third ventricle. The diagnosis and treatment of the tumor remain controversial. In this article, the authors present a novel case of chordoid glioma of the third ventricle. The patient was treated with less invasive microsurgery followed by low-dose gamma knife radiosurgery. Magnetic resonance imaging revealed a decrease in tumor size and necrosis in the central region of the tumor, without significant complications at follow-up 14 months later. Based on these findings, the authors suggest that less invasive microsurgical resection followed by low-dose gamma knife radiosurgery is safe and effective for the treatment of chordoid glioma of the third ventricle. PMID- 28708639 TI - Pulp Vitality of Maxillary Canines After Alveolar Cleft Bone Grafting: Pulse Oximetry Versus Electric Pulp Test Versus Cold Test. AB - OBJECTIVES: Assessment of pulp vitality is necessary prior to any dental treatment. The purpose of this study was to assess pulp vitality of bilateral canines in unilateral cleft patients following alveolar bone graft surgery using pulse oximetry, electrical pulp test, and cold test. METHODS: This analytical, cross-sectional study was conducted on canines of 20 unilateral cleft patients who had alveolar bone graft surgery. Pulp vitality of canines was evaluated postoperatively by pulse oximetry, electrical pulp test, and cold test. Data were analyzed using t test, Mann-Whitney test, and chi test. P <=0.05 was considered statistically significant. RESULTS: The mean pulp SpO2 was significantly lower in canines at the cleft side compared with the normal side (85.04 +/- 4.65 versus 87.78 +/- 4.01, P = 0.05). The response to cold test was not significantly different (P = 0.056). The mean response to electrical pulp was not significantly different between the 2 sides either (P = 0.62). CONCLUSION: The mean SpO2 of canines was lower at the cleft side than normal side but both sides had adequate blood supply and were vital. PMID- 28708640 TI - Is Cleft Severity Correlated With Intrinsic Growth Pattern? Observation From Unoperated Adult Patients With Submucous Cleft Palate. AB - OBJECTIVE: This study aimed to evaluate the craniofacial morphology of unoperated adult submucous cleft palate (SMCP) patients and to explore the possible correlation between the intrinsic growth insufficiency of the maxillofacial complex and the severity of the cleft. MATERIALS AND METHODS: A total of 20 unoperated SMCP patients, 20 unoperated overt cleft palate (OCP) patients, and 32 normal controls, ages between 18 and 30, were included for cephalometric analysis. One-way ANOVA and rank-sum tests were used for comparison, and the threshold of significance was at 95% (P < 0.05). RESULTS: Sagittal maxillary length (ANS-PMP, A-PMP, Ba-ANS) and mandibular ramus length (Ar-Go) were significantly smaller in the SMCP and the OCP groups than in the control (normal > SMCP = OCP). Maxillary protrusion (? S-N-ANS, ? S-N-ANS) was similar between the SMCP group and the control, but significantly reduced in the OCP group (normal = SMCP > OCP). Significant differences in ? A-N-B were found between each of the 3 groups (normal > SMCP > OCP). CONCLUSION: Compared with normal, unoperated adult SMCP patients were of smaller mandible and shorter maxillae, but almost normal maxillary protrusion. Overt clefts demonstrated significantly more evident maxillary retrusion and crossbite than SMCP, indicating a correlation between the cleft severity and the intrinsic growth pattern of the maxillofacial complex. PMID- 28708641 TI - Secondary Palatal Elongation: Improvement in Speech Quality. AB - Cleft palate is one of the challenging problems in the field of craniofacial surgery. In particular, the conventional methods of bilateral and severe cleft palate repairs have failed to achieve normal speech. In most instances, secondary procedures such as pharyngoplasty and pharyngeal flap surgery are performed to improve speech.This study introduces secondary palatal elongation (SPE) as a new approach to cleft palate repair. The patients included usually had a short palate and unrepaired palatal muscles. The authors' procedure involved dissecting the previously repaired palatal mucosa and pushing back and cutting the nasal mucosa of the palate horizontally and further pushing it back. Then, 1 or 2 buccal mucosal flaps were used to repair the nasal mucosal defect of the palate. In case of unrepaired veloplasty from the primary surgery, the levator muscles were dissected and sutured together to perform veloplasty. The range of palatal elongation was 15 to 25 mm.Secondary palatal elongation has been performed on 17 patients since 2007 with a high rate of speech improvement. Based on this 9-year experience with performing SPE, SPE is a radical anatomic technique of palatal elongation as compared with pharyngoplasty and pharyngeal flap surgery. All 17 patients who underwent SPE showed improvement in speech, from very poor to poor speech and from normal to good speech. PMID- 28708642 TI - A Novel Rhinoplasty Sculpture Technique Using Ancient Chinese Architectural Technology. AB - Rhinoplasty is one of the most delicate procedures in plastic and reconstructive surgery. Precision in every millimeter is vital in ensuring a better quality of surgical outcome. Many methods have been developed to fulfill this requirement. One such method is an implant, whether autogenous or artificial. Artificial implants involve several surgical complications, such as recipient rejection of implant material, infections, and rigid feel of the nasal tip. Hence, autogenous implants were eventually more widely applied, with material being obtained from the septum, concha, or rib cartilages. Therefore, the authors developed a new technique of rhinoplasty, using the osteochondral rib as an autogenous implant based on the ancient Chinese architectural technology called the DouGong method. The authors hereby present the results of 288 patients treated in our faculty wherein the data from the patients and the preoperative and postoperative 3 dimensional computed tomography scans were processed using Mimics software. The uniqueness of these implants is that the joint between the nasal dorsum and the columella strut is fixated without any screw, stitches, or K-wire. This procedure proved to be very useful as this technique not only minimized the application of fixation techniques, but also helped achieve a better nasofrontal angle, nasolabial angle, and columella length. After monitoring follow-ups of our patients, the authors hereby propose the use of this DouGong-based novel technique to improve the overall quality and outcome of corrective rhinoplasty. PMID- 28708643 TI - Rare Complication in Third Maxillary Molar Extraction: Dislocation in Infratemporal Fossa. AB - AIM: Removal of impacted third maxillary molar is frequently carried out without difficulties and low rate of intraoperative complications. The rare and particularly challenger to manage it is the third molar dislocation into the infratemporal fossa (IF). In this clinical report, the authors present their solution to manage and resolve this particular complication. METHODS: A 28-year old woman was referred to the emergency rescue unit of the authors' hospital by her dentistry, after the attempt to extract the left impacted maxillary third molar. During the procedure the tooth accidentally dislodged and was lost sight of it. The patient had significant mouth-opening limitation, omolateral mid face swelling and pain. Computer tomography was immediately performed to determine the exact position of the tooth, showing the dental element dislocated into the IF. RESULTS: Considering all of possible complications the best surgical option must guarantee a direct approach and a constant eye contact of the tooth, even in case of further displacement during the procedure, and allow early surgery. The authors used an endoscopic transoral approach through the preexisted access and solved all the issues reducing morbidity. CONCLUSION: Removing tooth from the IF could be burdened by serious risk of bleeding and/or nerve injury. The endoscopic approach provides direct view of the IF reducing morbidity. PMID- 28708644 TI - Comparison of the Effects of Local and Systemic Zoledronic Acid Application on Mandibular Distraction Osteogenesis. AB - Bisphosphonates are antibone resorptive drugs that are used to prevent bone tissue resorption in several skeletal diseases. The aim of this study was to examine the effects of systemic and local applications of zoledronic acid (ZA) on newly regenerated bone in a model of experimental distraction osteogenesis (DO). To do this mandibular DO was applied to 30 adult female Sprague Dawley rats, which were randomly divided into 3 groups: control, DO only, systemic zoledronic acid (SZA), and local zoledronic acid (LZA). In the LZA group, the gap between the bone fragments was filled with a gelatin sponge soaked in 2 mg of ZA and 0.1 mL of sterile saline. In the SZA group, a single dose of 0.1 mg/kg ZA was administered systemically. After the surgery, there was a 5-day latent waiting period and 10-day distraction phase. Following a 28-day consolidation period, the rats were euthanized and their mandibles were collected. The distracted bone area was seen to be filled with newly regenerated bone tissue in all 3 groups, both histologically and histomorphometrically. In addition, amounts of new bone formation, osteoblast cella, osteoclast (OC) cells, osteopontin, and vascular endothelial growth factor in the SZA and LZA groups were found to be higher when compared with the controls. Furthermore, in the SZA group, new bone formation, osteoblast, OC, osteopontin, and vascular endothelial growth factor were detected in significant amounts compared with the LZA group. Osteoclast numbers did not differ in a statistically significant manner in the SZA group with respect to the LZA group. Based on the results of this study, systemic and local applications of ZA could increase the formation of new bone in patients of DO, and systemic application is a more effective method compared with local application. PMID- 28708645 TI - A Digital Assessment of the Maxillary Deformity Correction in Infants With Bilateral Cleft Lip and Palate Using Computer-Aided Nasoalveolar Molding. AB - OBJECTIVES: To evaluate the maxillary alveolar repositioning of the infants with bilateral cleft lip and palate (BCLP) undergoing computer-aided nasoalveolar molding (CAD-NAM). METHODS: A total of 19 BCLP infants undergoing CAD-NAM were recruited as the treatment group, and 21 nonpresurgically treated BCLP patients served as controls. The upper alveolar morphology was measured and evaluated. Changes in all variables between pre- and post-CAD-NAM were compared. RESULTS: By the end of CAD-NAM, significant difference was found in the P-A, P'-A', and L ideal midline (P < 0.01); in the sagittal dimensions, significant difference was found in the P-TT', P'-TT', I-TT', A-X, and A'-X' (P < 0.01), while in the vertical dimensions, significant difference was found in the alveolus height in the bilateral canine regions (P < 0.01). CONCLUSION: Computer-aided nasoalveolar molding can effectively reduce the cleft gap, correct the alveolar midline deviation, and retract the projection and outward rotation of the premaxilla segment, and normalize the contour of the alveolus. PMID- 28708646 TI - Modified Technique of Cultured Epithelial Cells Transplantation on Facial Segmental Vitiligo. AB - BACKGROUND: Cultured epithelial cells transplantation is a known surgical technique for vitiligo. OBJECTIVE: To evaluate the factors influencing efficacy and safety of cultured epithelial cells transplantation in 9-month follow-up. METHODS: Demographic, clinical, and repigmentation outcomes were reviewed for patients with facial segmental vitiligo who had undergone cultured epithelial cells transplantation from November 2013 to July 2015 at the clinic of the Department of Dermatology, Huashan Hospital, China. RESULTS: Twenty-eight patients who had undergone cultured epithelial cells transplantation were included. A satisfactory result (>50% repigmentation) was achieved in 79% patients with facial segmental vitiligo in 9 months. The treatment effect was significantly different in 6th month (P = 0.032), 9th month (P = 0.006) compared with 3rd month. Disease stability did significantly affect repigmentation outcome in 9th month (Z = 2.113, P = 0.035). No significant difference was observed between single segmental type versus mixed type (Z = 1.081, P = 0.280). Adverse effects were nearly absent. CONCLUSION: Cultured epithelial cells transplantation is a relatively safe and effective therapy for facial segmental stable vitiligo patients. PMID- 28708647 TI - Pneumocephalus-Induced Oculomotor Nerve Palsy After Atlanto-Occipital Decompression With Dural Plasty. AB - BACKGROUND: Pneumocephalus after posterior fossa craniotomy is very common. However, cranial nerve dysfunction secondary to pneumocephalus is a very rare phenomenon. PATIENT PRESENTATION: This case reports a patient who suffers from Chiari I malformation with syringomyelia in cervical spinal cord and develops unilateral oculomotor nerve palsy after atlanto-occipital decompression with dural plasty. CONCLUSIONS: Cranial nerve dysfunction caused by pneumocephalus after craniotomy is rare and easily misdiagnosed. Timely head computed tomography or magnetic resonance imaging examination can exclude other causes and reveal the anatomic sites of pneumocephalus. Conservative treatment is available in most patients while sometimes it is necessary to drain the air. PMID- 28708648 TI - Oral Localization of Kaposi Sarcoma: Clinical Presentation and Conservative Management. AB - Kaposi sarcoma (KS) caused by human herpes virus type-8 is the most frequent immunosuppression-associated malignancy worldwide and its treatment is still controversial. We report on the clinical management of a patient who developed oral KS after liver transplantation. The disease appeared 1 month after the transplant and recurred after 4 months. The patient represents, to our knowledge, a rare case that was treated successfully only by shifting a conventional immunosuppressive therapy to everolimus alone. PMID- 28708649 TI - Global Craniofacial Care. PMID- 28708650 TI - Analysis of Stress Trajectories in Human Adult Cleft Skull. AB - The craniofacial skeleton is designed to withstand the functional forces during mastication. Distribution of these forces is along the stress trajectories that can vary in a cleft skull compared with a normal skull. In this study, the authors constructed finite element models of cleft and normal skull and subjected them for occlusal loading in the posterior teeth. The results showed variation in the trajectories between the models and between the cleft and noncleft sides within the cleft model. PMID- 28708651 TI - Locking Plate System Versus Standard Plate Fixation in the Management of Mandibular Fractures: Meta-Analysis of Randomized Controlled Trials. AB - PURPOSE: The aim of this meta-analysis was to evaluate the efficacy of the 2.0-mm locking miniplate system in comparison with the standard miniplate system in treatment of mandible fractures. METHODS: A systematic review was conducted according to PRISMA guidelines, examining Medline-Ovid, Embase, and PubMed databases, eligible studies were restricted to comparative controlled trials. Inclusion criteria were based on humans randomized controlled trials, controlled clinical trials, with the aim of comparing 2 fixation techniques, namely locking miniplate and standard miniplate (nonlocking miniplate) techniques. In addition, the incidence of complications was evaluated. RESULTS: Nine studies with 380 patients and 551 fracture sites were enrolled into the analysis. The results showed that there were no significant differences in overall complications (odds ratio [OR], 0.64; 95% confidence interval [CI], 0.34-1.22; P = 0.2), postoperative infection (OR, 0.53; 95% CI, 0.23-1.23, P = 0.15), and occlusion discrepancy (P > 0.05) when comparing 2.0-mm locking miniplates with 2.0-mm nonlocking miniplates in treating mandible fractures. However, the use of 2.0-mm locking miniplates had a lower postoperative maxillomandibular fixation rate than the use of 2.0-mm nonlocking miniplates (OR, 0.43; 95% CI, 0.22-0.83; P < 0.0001). CONCLUSIONS: Mandible fractures treated with 2.0-mm locking miniplates and standard 2.0-mm miniplates present similar short-term complication rates, and the low postoperative maxillomandibular fixation rate of using 2.0-mm locking miniplates also indicates that the 2.0-mm locking miniplate has a promising application in treatment of mandibular fractures. PMID- 28708652 TI - Clinical Application of Multimodal Neuronavigation System in Neuroendoscope Assisted Skull Base Chordoma Resection. AB - Skull base chordoma is a rare tumor arising from embryonic remnants of the notochord with invasive potential. Due to the destruction of osseous landmarks and invasion of surrounding structures, surgical resection is challenging. The authors explored the clinical value of a multimodal neuronavigation system in skull base chordoma resection using a neuroendoscope. Between January 2012 and January 2016, the authors utilized neuroendoscopy to excise skull base chordoma in 93 patients. The authors performed 45 operations assisted by multimodal neuronavigation (neuronavigation group) and 48 without intraoperative imaging guidance (control group). In the control group, 35 patients (73%) underwent gross total resection. In the neuronavigation group, all patients underwent gross total resection without radiographically identified bleeding. Only 1 patient (2%) in the neuronavigation group showed a temporary reduction in vision, which improved after symptomatic treatment. In contrast, there were 4 patients (8%) with postoperative complication, including 2 patients with intracranial hematoma and 2 with neurological deficits. Complication rates were higher than the neuronavigation group. In the follow-up period, 2 patients in the control group with subtotal resection had recurrence within 24 months, but without extracranial metastases. The multimodal neuronavigation system could contribute intraoperative real-time guidance for spatial relationships between lesions and adjacent neurovascular structures, as well as eroded and distorted anatomical landmarks through multiple image fusion and 3-dimensional reconstruction. It significantly improves surgical outcome and provides a new insight into the management of skull base chordomas. PMID- 28708653 TI - The Current Challenge for Plastic and Reconstructive Surgery in China, the Biggest Developing Country. PMID- 28708654 TI - The Status of Affected Infraorbital Nerve and Inferior Alveolar Nerve in Patients With Jaw Fibrous Dysplasia: A Clinical and Radiographic Evaluation. AB - The affected infraorbital nerve (IFBN) and inferior alveolar nerve (IFAN) status in patients with jaw fibrous dysplasia has not been definitely depicted. In this study, the authors try to explore the status of affected IFBN and IFAN in patients with jaw fibrous dysplasia. Ten patients with jaw fibrous dysplasia were included in this study. The complaints of numbness in the IFBA and IFAN innervated area were asked and recorded, and careful clinical examination was performed to evaluate the touch sense, pain sense, pressure sense, and temperature sense in the IFBA and IFAN innervated areas. Computed tomography scans also were performed to evaluate the imaging characteristics of affected IFBA and IFAN. The results showed that 1 patient with maxillary lesion showed complaints of slight numbness, and clinical examination showed that the patient exhibited slight insensitive in pain sense. In addition, 1 patient with mandibular lesion showed relative obvious complaints of numbness, and clinical examination showed that the patient exhibited slight insensitive in pain sense and temperature sense, but not serious. All other patients exhibited no numbness in the IFBA and IFAN innervated area. Although the position and morphology changed in some patients, all neural canal of affected IFBA or IFAN existed and showed no invasion of lesion. Taking these findings together, it further confirmed that evaluation of the function of IFBAN and IFAN is necessary for patients with jaw fibrous dysplasia, and the affected IFBAN and IFAN may should be reserved in most patients with jaw fibrous dysplasia when resecting or recontouring the lesion. PMID- 28708655 TI - Utility of Brainstem Trigeminal Evoked Potentials in Patients With Primary Trigeminal Neuralgia Treated by Microvascular Decompression. AB - OBJECTIVE: To investigate the characteristics of brainstem trigeminal evoked potentials (BTEP) waveform in patients with and without trigeminal neuralgia (TN), and to discuss the utility of BTEP in patients with primary TN treated by microvascular decompression (MVD). METHODS: A retrospective review of 43 patients who underwent BTEP between January 2016 and June 2016, including 33 patients with TN who underwent MVD and 10 patients without TN. Brainstem trigeminal evoked potentials characteristics of TN and non-TN were summarized, in particular to compare the BTEP changes between pre- and post-MVD, and to discover the relationship between BTEP changes and surgical outcome. RESULTS: Brainstem trigeminal evoked potentials can be recorded in patients without trigeminal neuralgia. Abnormal BTEP could be recorded when different branches were stimulated. After decompression, the original W2, W3 disappeared and then replaced by a large wave in most patients, or original wave poorly differentiated improved in some patients, showed as shorter latency and (or) amplitude increased. Brainstem trigeminal evoked potentials waveform of healthy side in patients with trigeminal neuralgia was similar to the waveform of patients without TN. In 3 patients, after decompression the W2, W3 peaks increased, and the latency, duration, IPLD did not change significantly. Until discharge, 87.9% (29/33) of the patients presented complete absence of pain without medication (BNI I) and 93.9% (31/33) had good pain control without medication (BNI I-II). CONCLUSION: Brainstem trigeminal evoked potentials can reflect the conduction function of the trigeminal nerve to evaluate the functional level of the trigeminal nerve conduction pathway. The improvement and restoration of BTEP waveforms are closely related to the postoperative curative effect. PMID- 28708656 TI - Osteoradionecrosis of the Zygoma. AB - Osteoradionecrosis occurs in 4.74% to 37.5% of patients following radiation therapy for head and neck cancer. Osteoradionecrosis mostly happens in the mandible but seldom occurs in other maxillofacial bones. Here, the authors reported a rare case of zygomatic osteoradionecrosis which occurred after maxillectomy and then radiotherapy because of maxillary myoepithelial carcinoma. After resection of zygoma sequestrum, the defect was repaired with forehead flap and healed uneventfully. PMID- 28708657 TI - Reconstruction of Facial-Cervical Scars With Pedicled Expanded Deltopectoral Flap. AB - The facial-cervical scars bring the suffering to the patients both physically and mentally. Choosing a proper donor soft tissue is always one of the critical issues, especially to Asian patients. Among the common used donor sites, the deltopectoral site was conceived as the most suitable donor tissue for the reconstruction in face and neck for its adjacent site and match in color and texture. There were 220 patients with facial-cervical scars reconstructed by the pedicled expanded deltopectoral flap between 2007 through 2015 in the authors' hospital. There are 4 stages, including tissue expansion, flap pedicled transfer, pedicle delaying, and pedicle division, for the reconstruction of the facial cervical scars using the pedicled expanded deltopectoral flap. Good skin compliance, normal contours, and emotional expression were noted in all the patients after the reconstruction. However, there were complications including expander exposure, stretch marks, flap tip necrosis, and mild postoperative hypertrophic scars. The unpleasant skin wound or color caused by the complications was repaired by further treatments such as skin grafting and laser. In conclusion, the pedicled expanded deltopectoral flap is a reliable and excellent option for the reconstruction of the facial-cervical scars. PMID- 28708658 TI - Condyle Head Reimplantation Combined With Vascularized Free Flap for Mandibular Reconstruction. AB - Due to the anatomic and functional complexity, reconstruction of the condylar process after mandibular tumor extirpation remains a surgical challenge. The aim of this study was to present the results and experience of condyle head reimplantation combined with vascularized free flap for mandibular reconstruction in our institution. In the current study, the authors evaluated the clinical features of condyle head reimplantation combined with vascularized free flap for mandibular reconstruction in 5 patients with benign mandibular intraosseous lesions from December 2013 to March 2015 in our institution. All patients showed nearly normal mouth opening, with minimal mandibular deviation and joint symptoms. The radiograph data showed that 4 patients had no obvious bone resorption of condyles while only 1 patient had prominent condyle resorption. All the condyles were cut above the condylar neck, with the biggest remaining condyle height being 2.8 cm and the smallest one being 1.1 cm. Moreover, the original vertical height of mandibular ramus was decreased by 2 to 3 mm during the surgery. In conclusion, this study revealed that combining the condyle reimplantation with vascularized free flap constitutes a reliable method in condylar reconstruction and a slight reduction of the vertical height of condyles may help to diminish unfavorable outcomes. PMID- 28708659 TI - Refractory coronary artery spasm associated with tacrolimus. PMID- 28708660 TI - A novel predictor of adverse outcomes after ST-elevation myocardial infarction: deterioration of atrioventricular conduction. PMID- 28708662 TI - Imaging Modalities for Correct Positioning of Percutaneous Right Ventricular Assist Device After Left Ventricular Assist Device Implantation. PMID- 28708663 TI - In Response. PMID- 28708664 TI - Esmolol Administration to Control Tachycardia in an Ovine Model of Peritonitis. AB - BACKGROUND: Excessive adrenergic signaling may be harmful in sepsis. Using beta blockers to reduce sympathetic overactivity may modulate sepsis-induced cardiovascular, metabolic, immunologic, and coagulation alterations. Using a randomized ovine fecal peritonitis model, we investigated whether administration of a short-acting beta-blocker, esmolol, could control tachycardia without deleterious effects on hemodynamics, renal perfusion, cerebral perfusion, cerebral metabolism, or outcome. METHODS: After induction of fecal peritonitis, 14 anesthetized, mechanically ventilated, and hemodynamically monitored adult female sheep were randomly assigned to receive a continuous intravenous infusion of esmolol to control heart rate between 80 and 100 bpm (n = 7) or a saline infusion (control group, n = 7). Esmolol was discontinued when the mean arterial pressure decreased below 60 mm Hg. Fluid resuscitation was titrated to maintain pulmonary artery occlusion pressure at baseline values. Left renal blood flow and cerebral cortex perfusion and metabolism were monitored in addition to standard hemodynamic variables. RESULTS: Esmolol was infused for 11 (9-14) hours; the target heart rate (80-100 bpm) was achieved between 3 and 8 hours after feces injection. In the first 5 hours after the start of the infusion, the decrease in heart rate was compensated by an increase in stroke volume index; later, stroke volume index was not statistically significantly different in the 2 groups, so that the cardiac work index was lower in the esmolol than in the control group. Hypotension (mean arterial pressure <60 mm Hg) occurred earlier (10 [8-12] vs 14 [11-20] hours; P= .01) in the esmolol group than in the control animals. Renal blood flow decreased earlier in the esmolol group, but there were no differences in urine output, cerebral cortex perfusion, metabolism, or survival between the groups. CONCLUSIONS: In this ovine model of abdominal sepsis, early control of tachycardia by esmolol was associated with a transient increase in stroke volume, followed by earlier hypotension. There were no significant effects of esmolol on cerebral perfusion, metabolism, urine output, or survival. PMID- 28708665 TI - Hyperbaric Versus Isobaric Bupivacaine for Spinal Anesthesia: Systematic Review and Meta-analysis for Adult Patients Undergoing Noncesarean Delivery Surgery. AB - BACKGROUND: It is widely believed that the choice between isobaric bupivacaine and hyperbaric bupivacaine formulations alters the block characteristics for the conduct of surgery under spinal anesthesia. The aim of this study was to systematically review the comparative evidence regarding the effectiveness and safety of the 2 formulations when used for spinal anesthesia for adult noncesarean delivery surgery. METHODS: Key electronic databases were searched for randomized controlled trials, excluding cesarean delivery surgeries under spinal anesthesia, without any language or date restrictions. The primary outcome measure for this review was the failure of spinal anesthesia. Two independent reviewers selected the studies and extracted the data. Results were expressed as relative risk (RR) or mean differences (MDs) with 95% confidence intervals (CIs). RESULTS: Seven hundred fifty-one studies were identified between 1946 and 2016. After screening, there were 16 randomized controlled clinical trials, including 724 participants, that provided data for the meta-analysis. The methodological reporting of most studies was poor, and appropriate judgment of their individual risk of bias elements was not possible. There was no difference between the 2 drugs regarding the need for conversion to general anesthesia (RR, 0.60; 95% CI, 0.08-4.41; P = .62; I = 0%), incidence of hypotension (RR, 1.15; 95% CI, 0.69 1.92; P = .58; I = 0%), nausea/vomiting (RR, 0.29; 95% CI, 0.06-1.32; P = .11; I = 7%), or onset of sensory block (MD = 1.7 minutes; 95% CI, -3.5 to 0.1; P = .07; I = 0%). The onset of motor block (MD = 4.6 minutes; 95% CI, 7.5-1.7; P = .002; I = 78%) was significantly faster with hyperbaric bupivacaine. Conversely, the duration of motor (MD = 45.2 minutes; 95% CI, 66.3-24.2; P < .001; I = 87%) and sensory (MD = 29.4 minutes; 95% CI, 15.5-43.3; P < .001; I = 73%) block was longer with isobaric bupivacaine. CONCLUSIONS: Both hyperbaric bupivacaine and isobaric bupivacaine provided effective anesthesia with no difference in the failure rate or adverse effects. The hyperbaric formulation allows for a relatively rapid motor block onset, with shorter duration of motor and sensory block. The isobaric formulation has a slower onset and provides a longer duration of both sensory and motor block. Nevertheless, the small sample size and high heterogeneity involving these outcomes suggest that all the results should be treated with caution. PMID- 28708666 TI - Socioeconomic Deprivation and Utilization of Anesthetic Care During Pregnancy and Delivery: A Secondary Analysis of a French Prospective, Multicenter, Cohort Study. AB - BACKGROUND: Socioeconomic deprivation is associated with reduced use of antenatal resources and poor maternal outcomes with pregnancy. Research examining the association between socioeconomic deprivation and use of obstetric anesthesia care in a country providing universal health coverage is scarce. We hypothesized that in a country providing universal health coverage, France, socioeconomic deprivation is not associated with reduced use of anesthetic care during pregnancy and delivery. This study aimed to examine the association between socioeconomic deprivation and (1) completion of a mandatory preanesthetic evaluation during pregnancy and (2) use of neuraxial analgesia during labor. METHODS: Data were from a cohort of 10,419 women who delivered between 2010 and 2011 in 4 public teaching hospitals in Paris. We used a deprivation index that included 4 criteria: social isolation, poor housing condition, no work-related household income, and state-funded health care insurance. Socioeconomic deprivation was defined as a deprivation index greater than 1. Preanesthetic evaluation was considered completed if performed more than 48 hours before delivery. The association between socioeconomic deprivation and completion of the preanesthetic evaluation and use of neuraxial labor analgesia was assessed by multivariable logistic regression adjusting for education level, country of birth, and maternal and pregnancy characteristics. RESULTS: Preanesthetic evaluation was completed for 8142 of the 8624 women (94.4%) analyzed and neuraxial labor analgesia was used by 6258 of the 6834 women analyzed (91.6%). After adjustment, socioeconomic deprivation was associated with reduced probability of completed preanesthetic evaluation (adjusted odds ratio 0.88 [95% confidence interval, 0.79-0.98]; P = .027) but not use of neuraxial labor analgesia (adjusted odds ratio 0.97 [95% confidence interval, 0.87-1.07]; P = .540). CONCLUSIONS: In a country providing universal health care coverage, women who were socioeconomically deprived showed reduced completion of preanesthetic evaluation during pregnancy but not reduced use of neuraxial labor analgesia. Interventions should be targeted to socioeconomically deprived women to increase the completion of the preanesthetic evaluation. PMID- 28708667 TI - Replication of Data Makes Statistical Analysis Difficult. PMID- 28708668 TI - Improving the Success Rate of Chest Compression-Only CPR by Untrained Bystanders in Adult Out-of-Hospital Cardiac Arrest: Maintaining Airway Patency May Be the Way Forward. PMID- 28708669 TI - The role of hypothalamic inflammation, the hypothalamic-pituitary-adrenal axis and serotonin in the cancer anorexia-cachexia syndrome. AB - PURPOSE OF REVIEW: In cancer patients, the development of cachexia (muscle wasting) is frequently aggravated by anorexia (loss of appetite). Their concurrence is often referred to as anorexia-cachexia syndrome. This review focusses on the recent evidence underlining hypothalamic inflammation as key driver of these processes. Special attention is given to the involvement of hypothalamic serotonin. RECENT FINDINGS: The anorexia-cachexia syndrome is directly associated with higher mortality in cancer patients. Recent reports confirm its severe impact on the quality of life of patients and their families.Hypothalamic inflammation has been shown to contribute to muscle and adipose tissue loss in cancer via central hypothalamic interleukine (IL)1beta induced activation of the hypothalamic-pituitary-adrenal axis. The resulting release of glucocorticoids directly stimulates catabolic processes in these tissues via activation of the ubiquitin-proteosome pathway. Next to this, hypothalamic inflammation has been shown to reduce food intake in cancer by triggering changes in orexigenic and anorexigenic responses via upregulation of serotonin availability and stimulation of its signalling pathways in hypothalamic tissues. This combination of reduced food intake and stimulation of tissue catabolism represents a dual mechanism by which hypothalamic inflammation contributes to the development and maintenance of anorexia and cachexia in cancer. SUMMARY: Hypothalamic inflammation is a driving force in the development of the anorexia-cachexia syndrome via hypothalamic-pituitary-adrenal axis and serotonin pathway activation. PMID- 28708670 TI - Color Pupillography in Dorsal Midbrain Syndrome. AB - OBJECTIVE: The purpose of this study was to evaluate the pupil response to chromatic stimuli in patients with lesions in the dorsal midbrain and possibly gain new insights into the afferent pupillary pathways. METHODS: Color pupillography was performed in 5 patients with dorsal midbrain syndrome (DMS), and their results were compared with those of 20 healthy control subjects. We used full-field red stimuli (605 nm) that primarily address the rod/cone system and blue stimuli (420 nm) that preferentially activate intrinsically photosensitive retinal ganglion cells (ipRGCs) directly, with a duration of 4 seconds and a stimulus intensity of 28 lx corneal illumination under mesopic conditions. One eye was stimulated, and the consensual pupil response was recorded and analyzed. RESULTS: The pupillary light reflex in patients with DMS was reduced, differed in shape, and showed a prolonged latency time compared to normal subjects. The blue response was less affected than the red response: the mean maximal relative amplitude (M) was 15.8% (SD = 7.8) in patients with DMS compared with 43.0% (SD = 5.5) in normal subjects for red stimulation, and M = 40.8%, SD = 8.4 (DMS) with M = 58.3%, SD = 4.8 (normals) for blue stimulation. The reduction was 63% for red stimulation but only 30% for blue stimulation in patients with DMS. Moreover, there was a preserved postillumination pupil response to blue stimulation in DMS patients. CONCLUSIONS: In DMS, the melanopsin mediated ipRGC pathway appeared relatively preserved. PMID- 28708671 TI - A Systematic Review of Primary Care Safety Climate Survey Instruments: Their Origins, Psychometric Properties, Quality, and Usage. AB - IMPORTANCE: Safety climate (SC) measurement is a common and feasible method of proactive safety assessment in primary care. However, there is no consensus on which instrument is "best" to use. OBJECTIVE: The aim of the study was to identify the origins, psychometric properties, quality, and SC domains measured by survey instruments used to assess SC in primary care settings. DATA SOURCES: Systematic searches were conducted using Medline, Embase, CINAHL, and PsycInfo in February 2016. STUDY SELECTION: English-language, peer-reviewed studies that reported the development and/or use of a SC survey in a primary care setting were included. DATA EXTRACTION AND SYNTHESIS: Two reviewers independently extracted data (survey characteristics, origins, and psychometric properties) from studies and applied the Quality Assessment Tool for Studies with Diverse Designs to assess methodological rigour. Safety climate domains within surveys were deductively analyzed and categorized into common healthcare SC themes. RESULTS: Seventeen SC surveys were identified, of which 16 had been adapted from 2 main U.S. hospital-based surveys. Only 1 survey was developed de novo for a primary care setting. The quantity and quality of psychometric testing varied considerably across the surveys. Management commitment to safety was the most frequently measured SC theme (87.5%). Workload was infrequently measured (25%). CONCLUSIONS AND RELEVANCE: Valid and reliable instruments, which are context specific to the healthcare environment for intentional use, are essential to accurately assess SC. Key recommendations include further establishing the construct and criterion-related validity of existing instruments as opposed to developing additional surveys. PMID- 28708673 TI - The Association of Employee Engagement at Work With Health Risks and Presenteeism. AB - INTRODUCTION: Employee engagement is a key factor in work performance and employee retention. The current study seeks to examine the relationship between employee engagement and health risks and productivity. METHODS: In 2012, employees of a global financial services corporation participated in a health risk appraisal (HRA) which measured employee engagement, health risks, and on-the job productivity loss (presenteeism). Three engagement categories were created. RESULTS: The highest engaged employees had significantly fewer health risk factors (69.7% overall low-risk status; 1.91 average health risks) and significantly less presenteeism (7.7%) than the mid engagement (67.9% low-risk, 1.98 risks, 9.2% presenteeism) and worst engagement (55.0% low-risk, 2.53 risks, 14.0% presenteeism) groups. CONCLUSIONS: Work engagement appears to be good for both the organization and the individual. Organizations may wish to make use of strategies which increase employee engagement. PMID- 28708672 TI - Artemisinin disrupts androgen responsiveness of human prostate cancer cells by stimulating the 26S proteasome-mediated degradation of the androgen receptor protein. AB - Androgen receptor (AR) expression and activity is highly linked to the development and progression of prostate cancer and is a target of therapeutic strategies for this disease. We investigated whether the antimalarial drug artemisinin, which is a sesquiterpene lactone isolated from the sweet wormwood plant Artemisia annua, could alter AR expression and responsiveness in cultured human prostate cancer cell lines. Artemisinin treatment induced the 26S proteasome-mediated degradation of the receptor protein, without altering AR transcript levels, in androgen-responsive LNCaP prostate cancer cells or PC-3 prostate cancer cells expressing exogenous wild-type AR. Furthermore, artemisinin stimulated AR ubiquitination and AR receptor interactions with the E3 ubiquitin ligase MDM2 in LNCaP cells. The artemisinin-induced loss of AR protein prevented androgen-responsive cell proliferation and ablated total AR transcriptional activity. The serine/threonine protein kinase AKT-1 was shown to be highly associated with artemisinin-induced proteasome-mediated degradation of AR protein. Artemisinin treatment activated AKT-1 enzymatic activity, enhanced receptor association with AKT-1, and induced AR serine phosphorylation. Treatment of LNCaP cells with the PI3-kinase inhibitor LY294002, which inhibits the PI3 kinase-dependent activation of AKT-1, prevented the artemisinin-induced AR degradation. Furthermore, in transfected receptor-negative PC-3 cells, artemisinin failed to stimulate the degradation of an altered receptor protein (S215A/S792A) with mutations in its two consensus AKT-1 serine phosphorylation sites. Taken together, our results indicate that artemisinin induces the degradation of AR protein and disrupts androgen responsiveness of human prostate cancer cells, suggesting that this natural compound represents a new potential therapeutic molecule that selectively targets AR levels. PMID- 28708674 TI - Chemotherapy-induced peripheral neuropathy: a review of recent findings. AB - PURPOSE OF REVIEW: Chemotherapy-induced peripheral neuropathy (CIPN) is a common, frequently chronic condition characterized by pain and decreased function. Given the growing number of cancer survivors and an increasing recognition of opioid therapy limitations, there is a need for critical analysis of the literature in directing an informed and thoughtful approach for the management of painful CIPN. RECENT FINDINGS: A PubMed search for 'chemotherapy-induced peripheral neuropathy AND pain' identifies 259 publications between 1 January 2016 and 31 March 2017. Based on review of this literature, we aim to present a clinically relevant update of painful CIPN. Notably, the use of duloxetine as a first-line agent in treatment of CIPN is confirmed. Moreover, clinical trials focus on nonpharmacologic strategies for managing painful CIPN. SUMMARY: Despite the volume of recent publications, there are limited preventive or therapeutic strategies for CIPN supported by high-level evidence. Duloxetine remains the only pharmacologic agent with demonstrated benefit; its clinical use should be routinely considered. Moving forward, nonopioid analgesic therapies will likely play an increasing role in CIPN treatment, but further research is necessary to confirm their utility. Promising therapies include vitamin B12 supplementation, physical therapy, and various forms of neuromodulation. PMID- 28708675 TI - The courage to fail. PMID- 28708676 TI - Is Early Goal-Directed Therapy Harmful to Patients With Sepsis and High Disease Severity? PMID- 28708677 TI - Repeated Critical Illness and Unplanned Readmissions Within 1 Year to PICUs. AB - OBJECTIVES: To determine the occurrence rate of unplanned readmissions to PICUs within 1 year and examine risk factors associated with repeated readmission. DESIGN: Retrospective cohort analysis. SETTING: Seventy-six North American PICUs that participated in the Virtual Pediatric Systems, LLC (VPS, LLC, Los Angeles, CA). PATIENTS: Ninety-three thousand three hundred seventy-nine PICU patients discharged between 2009 and 2010. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Index admissions and unplanned readmissions were characterized and their outcomes compared. Time-to-event analyses were performed to examine factors associated with readmission within 1 year. Eleven percent (10,233) of patients had 15,625 unplanned readmissions within 1 year to the same PICU; 3.4% had two or more readmissions. Readmissions had significantly higher PICU mortality and longer PICU length of stay, compared with index admissions (4.0% vs 2.5% and 2.5 vs 1.6 d; all p < 0.001). Median time to readmission was 30 days for all readmissions, 3.5 days for readmissions during the same hospitalization, and 66 days for different hospitalizations. Having more complex chronic conditions was associated with earlier readmission (adjusted hazard ratio, 2.9 for one complex chronic condition; hazard ratio, 4.8 for two complex chronic conditions; hazard ratio, 9.6 for three or more complex chronic conditions; all p < 0.001 compared no complex chronic condition). Most specific complex chronic condition conferred a greater risk of readmission, and some had considerably higher risk than others. CONCLUSIONS: Unplanned readmissions occurred in a sizable minority of PICU patients. Patients with complex chronic conditions and particular conditions were at much higher risk for readmission. PMID- 28708678 TI - Dysglycemia, Glycemic Variability, and Outcome After Cardiac Arrest and Temperature Management at 33 degrees C and 36 degrees C. AB - OBJECTIVES: Dysglycemia and glycemic variability are associated with poor outcomes in critically ill patients. Targeted temperature management alters blood glucose homeostasis. We investigated the association between blood glucose concentrations and glycemic variability and the neurologic outcomes of patients randomized to targeted temperature management at 33 degrees C or 36 degrees C after cardiac arrest. DESIGN: Post hoc analysis of the multicenter TTM-trial. Primary outcome of this analysis was neurologic outcome after 6 months, referred to as "Cerebral Performance Category." SETTING: Thirty-six sites in Europe and Australia. PATIENTS: All 939 patients with out-of-hospital cardiac arrest of presumed cardiac cause that had been included in the TTM-trial. INTERVENTIONS: Targeted temperature management at 33 degrees C or 36 degrees C. MEASUREMENTS AND MAIN RESULTS: Nonparametric tests as well as multiple logistic regression and mixed effects logistic regression models were used. Median glucose concentrations on hospital admission differed significantly between Cerebral Performance Category outcomes (p < 0.0001). Hyper- and hypoglycemia were associated with poor neurologic outcome (p = 0.001 and p = 0.054). In the multiple logistic regression models, the median glycemic level was an independent predictor of poor Cerebral Performance Category (Cerebral Performance Category, 3-5) with an odds ratio (OR) of 1.13 in the adjusted model (p = 0.008; 95% CI, 1.03-1.24). It was also a predictor in the mixed model, which served as a sensitivity analysis to adjust for the multiple time points. The proportion of hyperglycemia was higher in the 33 degrees C group compared with the 36 degrees C group. CONCLUSION: Higher blood glucose levels at admission and during the first 36 hours, and higher glycemic variability, were associated with poor neurologic outcome and death. More patients in the 33 degrees C treatment arm had hyperglycemia. PMID- 28708680 TI - Distinguishing Pneumonia From Pneumonitis to Safely Discontinue Antibiotics. PMID- 28708679 TI - Transpulmonary Pressure Describes Lung Morphology During Decremental Positive End Expiratory Pressure Trials in Obesity. AB - OBJECTIVES: Atelectasis develops in critically ill obese patients when undergoing mechanical ventilation due to increased pleural pressure. The current study aimed to determine the relationship between transpulmonary pressure, lung mechanics, and lung morphology and to quantify the benefits of a decremental positive end expiratory pressure trial preceded by a recruitment maneuver. DESIGN: Prospective, crossover, nonrandomized interventional study. SETTING: Medical and Surgical Intensive Care Units at Massachusetts General Hospital (Boston, MA) and University Animal Research Laboratory (Sao Paulo, Brazil). PATIENTS/SUBJECTS: Critically ill obese patients with acute respiratory failure and anesthetized swine. INTERVENTIONS: Clinical data from 16 mechanically ventilated critically ill obese patients were analyzed. An animal model of obesity with reversible atelectasis was developed by placing fluid filled bags on the abdomen to describe changes of lung mechanics, lung morphology, and pulmonary hemodynamics in 10 swine. MEASUREMENTS AND MAIN RESULTS: In obese patients (body mass index, 48 +/- 11 kg/m), 21.7 +/- 3.7 cm H2O of positive end-expiratory pressure resulted in the lowest elastance of the respiratory system (18.6 +/- 6.1 cm H2O/L) after a recruitment maneuver and decremental positive end-expiratory pressure and corresponded to a positive (2.1 +/- 2.2 cm H2O) end-expiratory transpulmonary pressure. Ventilation at lowest elastance positive end-expiratory pressure preceded by a recruitment maneuver restored end-expiratory lung volume (30.4 +/- 9.1 mL/kg ideal body weight) and oxygenation (273.4 +/- 72.1 mm Hg). In the swine model, lung collapse and intratidal recruitment/derecruitment occurred when the positive end-expiratory transpulmonary pressure decreased below 2-4 cm H2O. After the development of atelectasis, a decremental positive end-expiratory pressure trial preceded by lung recruitment identified the positive end-expiratory pressure level (17.4 +/- 2.1 cm H2O) needed to restore poorly and nonaerated lung tissue, reestablishing lung elastance and oxygenation while avoiding increased pulmonary vascular resistance. CONCLUSIONS: In obesity, low-to-negative values of transpulmonary pressure predict lung collapse and intratidal recruitment/derecruitment. A decremental positive end-expiratory pressure trial preceded by a recruitment maneuver reverses atelectasis, improves lung mechanics, distribution of ventilation and oxygenation, and does not increase pulmonary vascular resistance. PMID- 28708681 TI - Unplanned PICU Readmissions: A Representation of Care Gaps Within the Community. PMID- 28708682 TI - Mental Decline and Cardiac Surgery-Should We Go There? PMID- 28708683 TI - Methicillin-Resistant Staphylococcus aureus Infection in ICU: What Is the Best Prevention Strategy? PMID- 28708684 TI - The Impact of Dysglycemia and Glycemic Variability on Targeted Temperature Management. PMID- 28708685 TI - Tele-ICU Increases Interhospital Transfers: Does Big Brother Know Better? PMID- 28708686 TI - Clinical Deployment of the Esophageal Balloon Catheter-Making the Case. PMID- 28708687 TI - Toward Precision Hemodynamic Management. PMID- 28708688 TI - Respiratory Muscle Weakness and Extubation Failure in Critically Ill Children. PMID- 28708689 TI - Improving Medical ICU Outcomes: Promoting Respect and Ongoing Safety Through Patient Engagement Communication and Technology Study. PMID- 28708690 TI - Obesity Survival Paradox in the Critically Ill. PMID- 28708691 TI - The authors reply. PMID- 28708692 TI - Pulmonary Arterial Compliance and Pulmonary Vascular Resistance as a Predictor of Survival in Acute Respiratory Distress Syndrome: More Questions Than Answers. PMID- 28708694 TI - Structural Neuroimaging and Early Neuroprognostication of Hypoxic-Ischemic Brain Injury in Cardiac Arrest Survivors. PMID- 28708693 TI - The authors reply. PMID- 28708695 TI - The author replies. PMID- 28708697 TI - Simultaneous Physical and Mental Effort Alters Visual Function. AB - PURPOSE: Perceptual processing is sensitive to physiological changes. Thus, the homeostatic disturbances during and after exercise may alter the visual function. Here, we investigated the effect of simultaneous physical effort and two levels of cognitive demand on skills related to the visuoperceptual and motor processing. METHODS: Eighteen male regular exercisers performed 60 minutes of simultaneous physical exercise (cycling at 60 +/- 5% of reserve heart rate) and cognitive effort (mental workload). The same protocol was performed with a mental workload and an oddball condition of this task on different days in a counterbalanced manner. We assessed the near point of convergence, near stereoacuity, accommodative facility (Hart Charts), and eye-hand coordination before and after the two dual-tasking sessions. Also, we calculated cognitive performance scores and subjective measures of mental load. RESULTS: We found that the near point of convergence (break and recovery) is significantly (P <= .05) reduced after physical and mental effort independently of the mental level administered. Only the condition of mental workload with simultaneous constant intensity cycling promoted a significant impairment in the near stereoacuity and the eye-hand coordination (P = .006 and P = .018, respectively); however, these two parameters did not significantly change under the oddball condition. The accommodative facility showed an improvement in the oddball and mental workload conditions (P < .001 and P = .006, respectively). Confirming a successful experimental manipulation, participants experienced higher mental demand and arousal and achieved lower scores on cognitive performance during the mental workload task (both P < .001). CONCLUSIONS: The visual function is affected by simultaneous physical and mental effort, the manipulation of mental-task complexity being an important modulator of this effect. Both dual tasks, physical with or without mental workload demands, may enhance or impair visual and motor processing depending on the visual parameter tested, and those changes could be related to the activation state of the nervous system. PMID- 28708696 TI - Prevalence of Human Immunodeficiency Virus and Sexually Transmitted Infections Among Cisgender and Transgender Women Sex Workers in Greater Kuala Lumpur, Malaysia: Results From a Respondent-Driven Sampling Study. AB - BACKGROUND: Sex workers face a disproportionate burden of human immunodeficiency virus (HIV) and sexually transmitted infections (STI) worldwide. For cisgender women sex workers (CWSW), global HIV prevalence is over 10%, whereas transgender women sex workers (TWSW) face an HIV burden of 19% to 27%. METHODS: We used respondent-driven sampling to recruit 492 sex workers, including CWSW (n = 299) and TWSW (n = 193) in Greater Kuala Lumpur, Malaysia. Participants completed an in-depth survey and were screened for HIV, syphilis, Chlamydia trachomatis, and Neisseria gonorrhoeae. Sample characteristics stratified by gender identity and interview site are presented. Bivariate analyses comparing CWSW and TWSW were conducted using independent samples t tests for continuous variables and chi tests for categorical variables. RESULTS: Pooled HIV prevalence was high (11.7%; 95% confidence interval [CI], 8.8-14.5), and was similar for CWSW (11.1%) and TWSW (12.4%). Rates of syphilis 25.5% (95% CI, 21.6-29.5), C. trachomatis (14.8%; 95% CI, 11.6-18.0) and N. gonorrhoeae (5.8%; 95% CI, 3.7-7.9) were also concerning. Both groups reported lifetime HIV testing (62.4%), but CWSW were less likely to have ever been HIV tested (54.5%) than TWSW (74.6%). Median time since last HIV test was 24 months. Previous screening for STI was low. Inconsistent condom use and drug use during sex work were not uncommon. CONCLUSIONS: High HIV and STI prevalence, coupled with infrequent HIV and STI screening, inconsistent condom use, and occupational drug use, underscore the need for expanded HIV and STI prevention, screening, and treatment efforts among CWSW and TWSW in Malaysia. PMID- 28708698 TI - Cardiac Tamponade Induced by Tacrolimus Toxicity. PMID- 28708699 TI - Flumazenil for Mixed Drug Overdose. PMID- 28708700 TI - N-Acetylcysteine for Acute Hepatitis Induced by Kratom Herbal Tea. PMID- 28708701 TI - Self-reported Concussion History and Sensorimotor Tests Predict Head/Neck Injuries. AB - PURPOSE: Sport-related concussion (SRC) is a risk for players involved in high impact, collision sports. A history of SRC is a risk factor for future concussions, but the mechanisms underlying this are unknown. Despite evidence that most visible signs and symptoms associated with sports concussion resolve within 7-10 d, it has been proposed that subclinical loss of neuromuscular control and impaired motor functioning may persist and be associated with further injury. Alternatively, indicators of poor sensorimotor performance could be independent risk factors. This study investigated if a history of SRC and/or preseason sensorimotor performance predicted season head/neck injuries. METHODS: A total of 190 male rugby league, rugby union, and Australian Football League players participated. Preseason assessments included self-report of SRC within the previous 12 months and a suite of measures of sensorimotor function (balance, vestibular function, cervical proprioception, and trunk muscle function). Head/neck injury data were collected in the playing season. RESULTS: Forty-seven players (25%) reported a history of SRC. A history of concussion was related to changes in size and contraction of trunk muscles. Twenty-two (11.6%) players sustained a head/neck injury during the playing season, of which, 14 (63.6%) players had a history of SRC. Predictors of in-season head/neck injuries included history of SRC, trunk muscle function, and cervical proprioceptive errors. Five risk factors were identified, and players with three or more of these had 14 times greater risk of sustaining a season neck/head injury (sensitivity of 75% and specificity of 82.5%) than did players with two or fewer risk factors. CONCLUSIONS: The modifiable risk factors identified could be used to screen football players in the preseason and guide the development of exercise programs aimed at injury reduction. PMID- 28708702 TI - Exercise-induced Fatigue in Severe Hypoxia after an Intermittent Hypoxic Protocol. AB - PURPOSE: Exercise-induced central fatigue is alleviated after acclimatization to high altitude. The adaptations underpinning this effect may also be induced with brief, repeated exposures to severe hypoxia. The purpose of this study was to determine whether (i) exercise tolerance in severe hypoxia would be improved after an intermittent hypoxic (IH) protocol and (ii) exercise-induced central fatigue would be alleviated after an IH protocol. METHODS: Nineteen recreationally active men were randomized into two groups who completed ten 2-h exposures in severe hypoxia (IH: partial pressure of inspired O2 82 mm Hg; n = 11) or normoxia (control; n = 8). Seven sessions involved cycling for 30 min at 25% peak power (Wpeak) in IH and at a matched heart rate in normoxia. Participants performed baseline constant-power cycling to task failure in severe hypoxia (TTF-Pre). After the intervention, the cycling trial was repeated (TTF Post). Before and after exercise, responses to transcranial magnetic stimulation and supramaximal femoral nerve stimulation were obtained to assess central and peripheral contributions to neuromuscular fatigue. RESULTS: From pre- to postexercise in TTF-Pre, maximal voluntary contraction (MVC), cortical voluntary activation (VATMS), and potentiated twitch force (Qtw,pot) decreased in both groups (all P < 0.05). After IH, TTF-Post was improved (535 +/- 213 s vs 713 +/- 271 s, P < 0.05) and an additional isotime trial was performed. After the IH intervention only, the reduction in MVC and VATMS was attenuated at isotime (P < 0.05). No differences were observed in the control group. CONCLUSIONS: Whole-body exercise tolerance in severe hypoxia was prolonged after a protocol of IH. This may be related to an alleviation of the central contribution to neuromuscular fatigue. PMID- 28708703 TI - Preparticipation Sports Physicals: A Comparison of Single Provider and Station Based Models. AB - BACKGROUND: Preparticipation physical examinations (PPEs) are required for children and adolescents before sports participation to identify at-risk athletes. These evaluations can be completed in a traditional office-based setting or in a station-based format. It is unclear if one format is superior to the other in identifying at-risk athletes. METHODS: We performed a retrospective chart review of children and adolescents between the ages 10 and 18 years who received their PPE in our office or in a station-based setting in a local high school between the years 2009 and 2015. RESULTS: We reviewed 2934 PPEs total, 1136 in the office-based format and 1798 in the station-based setting. A similar proportion of athletes were excluded or required further evaluation before participation in the office compared with the station-based setting (4.84% vs 5.67%). No statistically significant associations were seen between site of PPE or athlete sex and rate of clearance. There was, however, a statistically significant association between PPE site and reason for exclusion (P = 0.0456) with higher rates of exclusion for vision-related issues in the station-based setting and higher rates of exclusion for musculoskeletal or cardiopulmonary reasons in the office-based setting. CONCLUSION: When conducted by the same examiners, the office-based and team-based PPE excluded or referred equal number of athletes, although the reason for further evaluation does differ based on setting. PMID- 28708704 TI - Shoulder Injuries in Canoeing and Kayaking. AB - OBJECTIVE: We report the largest case series of shoulder injuries among paddlers so far to establish common mechanisms and patterns of injury. We also discuss how these injuries were managed and report the proportion of paddlers that return to paddlesport. DESIGN: Case series. SETTING: Upper Limb Unit, Wrightington Hospital, United Kingdom. Manchester Arm Clinic, United Kingdom. PATIENTS: Fifty seven shoulder injuries to professional and recreational paddlers were reviewed at a mean follow-up time of 55 months from the first consultation. The patient cohort had a mean age of 36 years and consisted of 56% males. ASSESSMENT OF RISK FACTORS: Sex, mechanism of injury, acute/nonacute injury, and level of sport participation. MAIN OUTCOME MEASURES: Patient data were analyzed with regards to Constant score, QuickDASH score, and VAS satisfaction score before and after treatment. RESULTS: The most common mechanism of injury was a capsize which accounted for 15 (26%) injuries. Ten injuries caused by a capsize were labral tears all of which needed surgery. A significant improvement in patient outcome scores was noted. Patients were able to return to a high level of paddling such as 3 slalom paddlers who returned to international competition; one of whom had bilateral surgery. CONCLUSIONS: Paddlers most commonly injure their shoulder when preventing a capsize, during a capsize or while rolling. The paddles strokes performed at these times often require paddlers to place their shoulder in a dangerous abducted and externally rotated position. We believe this is one of the commonest causes of serious shoulder injuries to paddlers. PMID- 28708705 TI - Ultrasound Guidance Does Not Improve the Results of Shock Wave for Plantar Fasciitis or Calcific Achilles Tendinopathy: A Randomized Control Trial. AB - OBJECTIVE: To establish whether the use of ultrasound to direct shock waves to the area of greater calcification in calcaneal enthesopathies was more effective than the common procedure of directing shock waves to the point where the patient has the most tenderness. DESIGN: Two-armed nonblinded randomized control trial with allocation concealment. SETTING: The Sports Clinic at Sydney University. PATIENTS: Participants 18 years or older with symptomatic plantar fasciitis (PF) (with heel spur) or calcific Achilles tendinopathy (CAT). Seventy-four of 82 cases completed treatment protocol and 6-month follow-up. INTERVENTIONS: Patients were randomized to receive either ultrasound-guided (UG) or patient-guided (PG) shock wave at weekly intervals over 3 to 5 weeks. MAIN OUTCOME MEASURES: Reduced pain on visual analog scale (VAS) and improved functional score on Maryland Foot Score (MFS) (for PF) or Victorian Institute of Sport Assessment-Achilles (VISA-A) (for CAT). Follow-up was at 6 weeks and 3 and 6 months. RESULTS: Comparative 6 month improvements in MFS for the 47 PF cases were PG +20/100 and UG +14/100 (P = 0.20). Comparative 6-month improvement in VISA-A score for the 27 CAT cases were PG +35/100 and UG +27/100 (P = 0.37). Comparative (combined PF and CAT) 6-month improvement in VAS pain scores for all 38 PG cases were +38/100 with +37/100 for all 36 UG shock wave cases. CONCLUSIONS: Although both treatment groups had good clinical outcomes in this study, results for the 2 study groups were almost identical. CLINICAL RELEVANCE: This study shows that there is no major advantage in the addition of ultrasound for guiding shock waves when treating calcaneal enthesopathies (PF and CAT). PMID- 28708706 TI - Return to Driving After Hip Arthroscopy. AB - OBJECTIVE: The objective of this study was to evaluate patients' braking performance using a modern driving simulator after undergoing a right hip arthroscopy. DESIGN: This prospective study included 5 total driving sessions at which measurements were taken. SETTING: The study was conducted at an academic medical center. PATIENTS: A total of 14 patients scheduled to undergo a right hip arthroscopy were enrolled and compared with a control group of 17 participants to account for a potential learning phenomenon. INTERVENTIONS: Patients drove in the simulator preoperatively to establish a baseline, and then drove again at 2, 4, 6, and 8 weeks postoperatively. The control group did not undergo any type of surgical procedure. The main independent variable was time from surgery. MAIN OUTCOME MEASURES: A modern driving simulator was used to measure initial reaction time (IRT), throttle release time (TRT), foot movement time (FMT), and brake travel time (BTT). The braking reaction time (BRT) was calculated as the sum of IRT + TRT + FMT, and the total braking time (TBT) was calculated as the sum of BRT + BTT. RESULTS: The experimental group showed no significant changes in BTT (P = 0.11, (Equation is included in full-text article.)= 0.04) nor TBT (P = 0.20, (Equation is included in full-text article.)= 0.03) over the duration of 8 weeks. Although the experimental group did exhibit significant improvements in IRT (P = 0.002), TRT (P < 0.0001), FMT (P < 0.0001), and BRT (P = 0.0002) between preoperative and 2 weeks postoperative driving sessions, there were no significant changes thereafter. The mean preoperative TBT and 2 weeks postoperative TBT for the experimental group were 3.07 seconds (SD = 0.50) and 2.97 seconds (SD = 0.57), respectively. No learning phenomenon was observed in the control group. CONCLUSIONS: This study's findings suggest that patients may return to driving 2 weeks postoperatively from a right-sided hip arthroscopy procedure. PMID- 28708707 TI - Lightheadedness After Concussion: Not All Dizziness is Vertigo. AB - OBJECTIVE: To characterize the presence and degree of postconcussion lightheadedness in relation to postconcussion vertigo and dizziness, and to determine whether lightheadedness influences overall symptom duration. DESIGN: Prospective, cohort design. SETTING: Nationwide Children's Hospital, Sports Concussion Clinic. PARTICIPANTS: Five hundred ten patients (9-19 years of age) within 30 days of concussion injury. MAIN OUTCOME MEASURES: Patient ratings (scale 0-6) of multiple postconcussion symptoms including lightheadedness, vertigo, and dizziness, reported from the day of clinic evaluation and recalled from the day of concussion. RESULTS: Postconcussion lightheadedness occurred commonly relative to vertigo. Lightheadedness was recalled more than vertigo (70.8% vs 48.6%, P < 0.001) on concussion day and reported more than vertigo (47.1% vs 24.1%, P < 0.001) on the day of clinic evaluation. Principal component analysis demonstrated strong correlations among lightheadedness, vertigo, balance difficulties, difficulty concentrating, mental fogginess, and difficulty remembering, relative to other postconcussion symptoms. When present on the day of clinic evaluation, these highly correlated symptoms predicted prolonged concussion recovery [P = 0.028; Hazard Ratio (HR) = 1.2]. Female sex (P = 0.04; HR = 1.23), emotional symptoms recalled from the day of concussion (P = 0.007; HR = 1.23), and cephalalgic symptoms (P < 0.001; HR = 1.34) reported on the day of clinic evaluation also predicted prolonged concussion recovery. CONCLUSIONS: Not all postconcussion dizziness is vertigo. Postconcussion lightheadedness is common and, when present at the time of clinic evaluation, can influence concussion recovery. CLINICAL RELEVANCE: Distinguishing postconcussion lightheadedness from vertigo may help to inform clinical treatment and concussion research design. This study adds to the growing body of evidence that supports an association between concussion and autonomic dysfunction. PMID- 28708708 TI - Atopy in Elite Endurance Athletes. AB - OBJECTIVE: To assess the frequency of atopy (specific IgE levels), to evaluate the allergic symptoms using the Allergy Questionnaire for Athletes (AQUA), and to determine whether atopy is associated with allergic symptoms in elite endurance athletes. DESIGN: Cross-sectional study. SETTING: Assessments were performed at Hospital das Clinicas-Sao Paulo University Medical School. PARTICIPANTS: Fifty nine elite endurance athletes (triathletes and runners). MAIN OUTCOME MEASURES: Allergic symptoms were assessed by a validated self-report AQUA questionnaire and atopy by specific IgE level. RESULTS: The frequency of atopy (specific IgE to at least one inhalant allergen) and allergic symptoms was 57.6% and 54.2%, respectively. In addition, no association was observed between atopy and allergic symptoms. CONCLUSIONS: A possible implication from our results is that atopy screening in elite athletes should be performed using AQUA questionnaire and measuring specific IgE simultaneously. PMID- 28708709 TI - Genetics Influence Neurocognitive Performance at Baseline but Not Concussion History in Collegiate Student-Athletes. AB - OBJECTIVE: This study investigates 4 single-nucleotide polymorphisms [Apolipoprotein E (APOE), APOE promoter, catechol-O-methyl transferase (COMT), and dopamine D2 receptor] that have been implicated in concussion susceptibility and/or cognitive ability in collegiate student-athletes. DESIGN: Cross-sectional study. SETTING: Neuroscience laboratory at Elon University. PARTICIPANTS: Two hundred fifty division I collegiate student-athletes (66 women, 184 men) from various sports. INTERVENTION: All participants completed Immediate Postconcussion Assessment and Cognitive Testing (ImPACT) testing at baseline concussion testing and had a buccal swab taken for DNA for genotyping. MAIN OUTCOME MEASURES: Self reported history of concussions and neurocognitive performance were taken from ImPACT. RESULTS: Individuals carrying an epsilon4 allele in their APOE gene had a significantly slower reaction time (P = 0.001). Individuals homozygous for the Val allele of the COMT gene showed significantly worse impulse control scores (P = 0.014). None of the genotypes were able to predict self-reported concussion history in collegiate student-athletes. CONCLUSIONS: These results indicate that certain genotypes may influence performance on cognitive testing at baseline and that the APOE genotypes may not influence concussion susceptibility as suggested by past studies. PMID- 28708710 TI - Bone Accrual in Children and Adolescent Nonelite Swimmers: A 2-Year Longitudinal Study. AB - OBJECTIVE: To examine differences in bone mass between children and adolescents swimming competitively at nonelite levels (locally and regionally) and nonathletes and to assess changes in bone mass in these 2 groups over 24 months after taking into consideration several known confounders of bone mass. DESIGN: Observational prospective study. PARTICIPANTS: White nonelite swimmers (n = 128) and nonathletes (n = 106) 8 to 18 years of age from Memphis, Tennessee, USA. MAIN OUTCOME MEASURES: Participants underwent dual-energy x-ray absorptiometry to assess total body and hip bone mineral content (BMC) at baseline and 12 and 24 months later. RESULTS: At baseline, swimmers had 4.2% and 6.1% higher adjusted BMC for the total body and hip, respectively, compared with nonathletes (P values < 0.027). Averaging across assessment points, swimmers had 73.5 and 2.2 g higher BMC for the total body and hip, respectively, than nonathletes. Although there was a significant annual increase in total body and hip BMC in both groups (33.5 and 0.7 g, respectively), there was no difference in annualized bone accrual between swimmers and nonathletes for either total body BMC (swim by time effect; P = 0.213) or hip BMC (P = 0.265). CONCLUSIONS: Competitive swimming at nonelite levels during childhood and adolescence does not seem to compromise bone accrual. PMID- 28708711 TI - Contrast-Enhanced Ultrasound as a New Investigative Tool in Diagnostic Imaging of Muscle Injuries-A Pilot Study Evaluating Conventional Ultrasound, CEUS, and Findings in MRI. AB - OBJECTIVE: To emphasize the diagnostic value of contrast-enhanced ultrasound (CEUS) in the imaging of muscle injuries with different degrees of severity by comparing findings to established imaging modalities such as conventional ultrasound and magnetic resonance imaging (MRI). DESIGN: Case series. SETTING: Institutional study. Conventional ultrasound and CEUS were performed in the Department of Internal Medicine. Magnetic resonance imaging was carried out in the Department of Radiology within the Magnetom Avanto 1.5T and Magnetom Skyra fit 3T (Siemens Healthineers, Erlangen, Germany) and in the Institution of Imaging Diagnostics and Therapy (Magnetom Avanto 1.5T; Siemens, Erlangen, Germany). PATIENTS: Fifteen patients who underwent an acute muscle injury were recruited. MAIN OUTCOME MEASURES: The appearance and detectable size of muscle injuries were compared between each imaging modality. The injuries were assessed by 3 independent observers and blinded between imaging modalities. RESULTS: All 15 injuries were identified on MRI and CEUS, whereas 10 injuries showed abnormalities in conventional ultrasound. The determination and measurement revealed significant differences between conventional ultrasound and CEUS depending on injury severity. Contrast-enhanced ultrasound revealed an impairment of microcirculation in grade I lesions (corresponding to intramuscular edema observed in MRI), which was not detectable using conventional ultrasound. CONCLUSIONS: Our results indicate that performing CEUS seems to be a sensitive additional diagnostic modality in the early assessment of muscle injuries. Our results highlight the advantages of CEUS in the imaging of low-grade lesions when compared with conventional ultrasound, as this was the more accurate modality for identifying intramuscular edema. PMID- 28708712 TI - Extended Second Window of Protection of Sevoflurane-induced Preconditioning. AB - Late preconditioning (LPC) can be induced by volatile anesthetics and initiates cardioprotection against ischemia/reperfusion injury for 3-4 days. We investigated the possibility to extend the time window of sevoflurane-induced LPC by repeated sevoflurane administration. An in vivo rat model of regional myocardial ischemia/reperfusion injury was used. Myocardial infarct size was determined by triphenyltetrazolium chloride staining at the end of the experiment. In the first series of experiments, male Wistar rats were randomized to 5 groups (each n = 8). Control animals were not treated further. Animals in the preconditioning groups inhaled sevoflurane for 60 minutes (1 MAC) 24, 48, 72, and 96 hours, respectively, before myocardial ischemia. Based on the findings of the first experimental series, another 6 groups of animals were investigated. Again, control animals were left untreated; all other animals received a second sevoflurane stimulus 72 hours after the first sevoflurane treatment, and myocardial ischemia was induced 24, 48, 72, and 96 hours, respectively, after the second sevoflurane treatment to investigate, whether the cardioprotective effect could be extended. Sevoflurane reduced infarct size after 24, 48, and 72 hours (each P < 0.05 vs. control) but not after 96 hours. The repeated administration of sevoflurane 72 hours after the first stimulus extended the time window of protection for additional 72 hours (each P < 0.05 vs. control). There was no myocardial protection 4 days after the second preconditioning stimulus. The time window of sevoflurane-induced LPC can be extended by an additional sevoflurane stimulus up to 72 hours after the initial sevoflurane exposure. PMID- 28708713 TI - Platelet Aggregation in Direct Oral Factor Xa Inhibitors-treated Patients With Atrial Fibrillation: A Pilot Study. AB - BACKGROUND: Activated factor X (factor Xa) plays an important role in regulation of platelets. The aim of this study was to test the effect of direct oral factor Xa inhibitors-rivaroxaban and apixaban-on platelet aggregation in patients with nonvalvular atrial fibrillation. PATIENTS AND METHODS: This single-center pilot study enrolled 21 factor Xa inhibitors-treated (9 rivaroxaban-treated and 12 apixaban-treated) patients with nonvalvular atrial fibrillation. The trough and peak samples of these patients were tested for adenosine diphosphate (ADP) induced, epinephrine-induced, and collagen-induced platelet aggregation with light transmission aggregometry, and with factor Xa-calibrated anti-Xa chromogenic analysis. RESULTS: The detected trough anti-Xa activity was 57.5 +/- 43.4 MUg/L. There was a significant increase in peak anti-Xa activity to 175.9 +/ 119.6 MUg/L (P < 0.001) observed. The platelet aggregation was reduced with reduced inductor concentration. However, no significant changes in ADP-induced, or in epinephrine-induced, or in collagen-induced platelet aggregation were seen comparing trough and peak sample. There were no significant differences in anti Xa activity or in platelet aggregation comparing rivaroxaban-treated and apixaban treated patients. CONCLUSIONS: This study showed that factor Xa inhibition does not affect ADP-induced, epinephrine-induced, and collagen-induced platelet aggregation. PMID- 28708714 TI - Sleep Medications Containing Melatonin can Potentially Induce Ventricular Arrhythmias in Structurally Normal Hearts: A 2-Patient Report. AB - Idiopathic ventricular arrhythmias (IVAs) are relatively common in the general population and usually have a good prognosis. However, frequent premature ventricular contractions (PVCs) can lower the quality of life (in symptomatic cases) and can cause cardiomyopathy and sudden cardiac death. In this report, we demonstrate a novel trigger for IVAs. Melatonin use for treating sleep disorders has increased significantly in recent years. We provide here the first human evidence of its proarrhythmic effect by presenting 2 patients (with normal myocardium) with symptomatic PVCs, while on melatonin. Discontinuation of melatonin stopped PVCs in both patients. Our findings highlight the importance of identifying precipitating factors for IVAs. PMID- 28708715 TI - Relationship of Nonseptal Late Gadolinium Enhancement to Ventricular Tachyarrhythmia in Hypertrophic Cardiomyopathy. AB - OBJECTIVE: This study aimed to determine the relationship between the extent and the location of late gadolinium enhancement (LGE) and ventricular tachyarrhythmia or implantable cardioverter defibrillator (ICD) in hypertrophic cardiomyopathy (HCM). METHODS: We enrolled 115 patients with HCM and LGE. The location of LGE was divided into septal and nonseptal segments. Clinical backgrounds and LGE were compared in patients between with and without the arrhythmia or consequent ICD installation. RESULTS: There were significant differences in the number of risk markers, left ventricular ejection fraction, extent of global LGE, and extent of nonseptal LGE between the groups (P < 0.01). Multivariate analysis revealed that the number of risk markers and extent of nonseptal LGE contributed to ventricular tachyarrhythmia or ICD installation (P < 0.01). CONCLUSIONS: The nonseptal LGE is related to ventricular tachyarrhythmia or ICD installation. We should be vigilant for nonseptal LGE when applying LGE to risk stratification for HCM. PMID- 28708716 TI - The Influence of Contrast Agent's Osmolarity on Iodine Delivery Protocol in Coronary Computed Tomography Angiography: Comparison Between Iso-Osmolar Iodixanol-320 and Low-Osmolar Iomeprol-370. AB - OBJECTIVES: This study aims to assess whether iodine-contained contrast agents with different osmolarity affect iodine delivery protocol during coronary computed tomography angiography (CCTA). METHODS: Patients who underwent CCTA were randomized to receive contrast media either iodixanol-320 (iso-osmolar group) or iopromide-370 (low-osmolar group). Contrast protocols were recorded. Tube voltage of 100 kV was chosen for patients with body mass index of less than or equal to 25 (n = 224) and tube voltage of 120 kV for patients with body mass index of greater than 25 (n = 165). Both groups applied automatic current modulation technique. Mean contrast enhancement of the ascending aorta, left main coronary artery, and descending aorta was calculated. Simulated contrast flow rate and iodine delivery rate (IDR) to reach a mean contrast enhancement level of 350 HU were calculated. RESULTS: A total of the 389 patients were enrolled in the study. To achieve the same contrast enhancement of 350 HU, iso-osmolar group required higher simulated contrast flow rate (3.90 vs 3.62 mL/s, P = 0.017) but lower simulated IDR (1.34 vs 1.25 g/s, P = 0.024) compared with low-osmolar group. CONCLUSIONS: To maintain a similar level of contrast enhancement during CCTA, iodixanol-320 needs larger contrast flow rate with lower IDR compared with low osmolar iopromide-370. PMID- 28708717 TI - Automatic Measurement of the Total Visceral Adipose Tissue From Computed Tomography Images by Using a Multi-Atlas Segmentation Method. AB - BACKGROUND: The visceral adipose tissue (VAT) volume is a predictive and/or prognostic factor for many cancers. The objective of our study was to develop an automatic measurement of the whole VAT volume using a multi-atlas segmentation (MAS) method from a computed tomography. METHODS: A total of 31 sets of whole body computed tomography volume data were used. The reference VAT volume was defined on the basis of manual segmentation (VATMANUAL). We developed an algorithm, which measured automatically the VAT volumes using a MAS based on a nonrigid volume registration algorithm coupled with a selective and iterative method for performance level estimation (SIMPLE), called VATMAS_SIMPLE. The results were evaluated using intraclass correlation coefficient and dice similarity coefficients. RESULTS: The intraclass correlation coefficient of VATMAS_SIMPLE was excellent, at 0.976 (confidence interval, 0.943-0.989) (P < 0.001). The dice similarity coefficient of VATMAS_SIMPLE was also good, at 0.905 (SD, 0.076). CONCLUSIONS: This newly developed algorithm based on a MAS can measure accurately the whole abdominopelvic VAT. PMID- 28708718 TI - Pulmonary Apical Opacities on Thin-Section Computed Tomography: Relationship to Primary Spontaneous Pneumothorax in Young Male Patients and Corresponding Histopathologic Findings. AB - OBJECTIVE: The purpose of this study was to test the hypothesis that apical opacities on computed tomography (CT) are related to occurrence of primary spontaneous pneumothorax (PSP) in young male patients. METHODS: We compared the frequency of apical opacities on thin-section CT between 70 male patients with PSP (PSP group) and 74 male patients without a history of PSP (non-PSP group). We also evaluated histopathologic findings of 39 specimens from 37 surgical cases in the PSP group. RESULTS: Apical opacities were significantly more frequent in the PSP group than in the non-PSP group (right side, P = 0.01; left side, P = 0.005). Histopathologically, subpleural band-like alveolar collapse was seen in 35 specimens (89.7%), which was always accompanied by fibroelastosis and fibroblastic foci. CONCLUSIONS: Apical opacities on CT were significantly associated with PSP in young male patients. These apical opacities histopathologically correspond to fibrotic pleural thickening with subpleural alveolar collapse. PMID- 28708719 TI - Magnetic Resonance Imaging of Intracranial Hypotension: Diagnostic Value of Combined Qualitative Signs and Quantitative Metrics. AB - OBJECTIVE: The aim of this study was to investigate whether the use of combination quantitative metrics (mamillopontine distance [MPD], pontomesencephalic angle, and mesencephalon anterior-posterior/medial-lateral diameter ratios) with qualitative signs (dural enhancement, subdural collections/hematoma, venous engorgement, pituitary gland enlargements, and tonsillar herniations) provides a more accurate diagnosis of intracranial hypotension (IH). METHODS: The quantitative metrics and qualitative signs of 34 patients and 34 control subjects were assessed by 2 independent observers. Receiver operating characteristic (ROC) curve was used to evaluate the diagnostic performance of quantitative metrics and qualitative signs, and for the diagnosis of IH, optimum cutoff values of quantitative metrics were found with ROC analysis. Combined ROC curve was measured for the quantitative metrics, and qualitative signs combinations in determining diagnostic accuracy and sensitivity, specificity, and positive and negative predictive values were found, and the best model combination was formed. RESULTS: Whereas MPD and pontomesencephalic angle were significantly lower in patients with IH when compared with the control group (P < 0.001), mesencephalon anterior posterior/medial-lateral diameter ratio was significantly higher (P < 0.001). For qualitative signs, the highest individual distinctive power was dural enhancement with area under the ROC curve (AUC) of 0.838. For quantitative metrics, the highest individual distinctive power was MPD with AUC of 0.947. The best accuracy in the diagnosis of IH was obtained by combination of dural enhancement, venous engorgement, and MPD with an AUC of 1.00. CONCLUSIONS: This study showed that the combined use of dural enhancement, venous engorgement, and MPD had diagnostic accuracy of 100 % for the diagnosis of IH. Therefore, a more accurate IH diagnosis can be provided with combination of quantitative metrics with qualitative signs. PMID- 28708720 TI - Predicting Neoadjuvant Chemotherapy in Nonconcentric Shrinkage Pattern of Breast Cancer Using 1H-Magnetic Resonance Spectroscopic Imaging. AB - OBJECTIVE: The aim of this study was to explore the response to neoadjuvant chemotherapy (NAC) in nonconcentric shrinkage pattern of breast cancer (BC) patients using H-magnetic resonance spectroscopy. METHODS: Twenty-five BC patients were the study cohort. All patients received AT-based regimen as first line treatment. Tumor response to chemotherapy was evaluated after the second and fourth cycles using magnetic resonance imaging and magnetic resonance spectroscopy. Final histopathology following surgery after 4 to 8 cycles of NAC served as a reference. Changes in total choline integral* (tCho) and tumor size in response versus nonresponse groups were compared using the 2-way Mann-Whitney nonparametric test. Receiver operating characteristic (ROC) analyses were undertaken, and the area under the ROC curve compared among them. RESULTS: H magnetic resonance spectroscopy revealed a negative tCho integral* in 6 cases at the first follow-up and 14 cases at the second follow-up. Based on pathology (Miller-Payne system), there were 16 cases of response, and 9 cases of nonresponse. The tCho integral* was significantly different between the response and nonresponse groups at the second follow-up (P = 0.027). The tumor size changes were not significantly different in the response and nonresponse groups at the second follow-up study (P > 0.05). The comparison of ROC curves among the change in tCho integral* and tumor size at baseline and both follow-ups revealed the maximum area under the ROC curve of the change in tCho integral* to be 0.747 at the second follow-up, sensitivity to be 93.75%, and positive predictive value to be 78.9%. CONCLUSIONS: In nonconcentric shrinkage pattern after NAC of BC, when tumor size is difficult to reflect the response, tCho integral* reduction may be a predictive marker. PMID- 28708721 TI - Development of Correction for Signal-to-Noise Ratio Using a T2* With Improved Phase Method. AB - OBJECTIVE: This study aims to improve the signal-to-noise ratio (SNR) of the phase image focusing T2 and to develop an improved phase (iPhase) image acquired high SNR. METHODS: The iPhase images of phantom and brain were acquired with multi-echo spoiled gradient-echo. The phantom component was a gadopentetate dimeglumine (Gd-DTPA) solution made of different concentrations (0.1, 0.5, and 1 wt%) and Gd-DTPA (0.1, 0.5, and 1 wt%) with agar (1.0 wt%). We applied the iPhase image to susceptibility weighed image (SWI) and evaluated SNR of SWI. RESULTS: In phantom study, SNRs of conventional SWI at each sample were 19.8, 15.7, 7.4, 20.0, 17.4, and 27.3, respectively. Signal-to-noise ratios of SWI derived from iPhase method were 29.5, 33.7, 21.7, 28.5, 24.3, and 14.7, respectively. Then, the SNR showed an improvement of 196% at maximum (for the Gd-DTPA 1 wt% sample). In healthy volunteer study, SWI derived from iPhase method had the good contrast between white matter and gray matter. CONCLUSIONS: The iPhase image was able to improve the phase SNR. Moreover, iPhase method makes it possible to obtain a high SNR image when applying to SWI. PMID- 28708722 TI - Asymptomatic Bartholin Cyst: Evaluation With Multidetector Row Computed Tomography. AB - OBJECTIVE: The aim of this study was to determine the frequency, morphology, and attenuation characteristics of Bartholin cysts on multidetector computed tomography (MDCT) in asymptomatic women. METHODS: A total of 3280 consecutive MDCT examinations were assessed for Bartholin cysts. The diagnosis was based on shape, contrast enhancement, and anatomical location. Age, laterality, size, and attenuation patterns were recorded. Scans from patients with paravaginal-related symptoms were excluded, and any available follow-up MDCT scans or magnetic resonance images were evaluated. RESULTS: Asymptomatic Bartholin cysts were seen in 17 patients (0.52%) (mean age, 56 years). The mean maximum cyst diameter was 21.8 mm. High-attenuation cysts comprised 47% of cases, all in older (>=50 years) patients. Follow-up MDCT scans showed minimal changes over time. CONCLUSIONS: High-attenuation Bartholin cysts are more common than previously thought and are usually seen in older women. The size and attenuation of Bartholin cysts show only minimal changes over time. PMID- 28708723 TI - Preliminary Results: Can Dual-Energy Computed Tomography Help Distinguish Cardiogenic Pulmonary Edema and Acute Interstitial Lung Disease? AB - OBJECTIVE: We compared iodine concentration in pulmonary ground-glass opacity on iodine density images of contrast-enhanced chest dual-energy computed tomography (DECT) between patients with cardiogenic pulmonary edema (CPE) and acute interstitial lung disease (AILD). METHODS: Five of 12 patients who underwent contrast-enhanced chest DECT to exclude pulmonary embolism were clinically diagnosed with CPE and 7, with AILD. We compared the mean CT value on monochromatic images at 65 keV and iodine concentration on iodine density images between the affected and normal areas. RESULTS: The mean iodine concentrations were comparable between the affected and normal areas (P = 0.3048) in patients with CPE and were significantly higher in the affected than in the normal areas in those with AILD (P < 0.0001). CONCLUSIONS: Measurement of iodine concentration in pulmonary ground-glass opacity of contrast-enhanced chest DECT has the potential to help distinguish CPE and AILD. PMID- 28708724 TI - Impact of SSF on Diagnostic Performance of Coronary Computed Tomography Angiography Within 1 Heart Beat in Patients With High Heart Rate Using a 256-Row Detector Computed Tomography. AB - OBJECTIVE: The aim of this study was to investigate the impact of a motion correction algorithm on diagnostic accuracy of coronary computed tomography angiography (CCTA) within 1 heart beat in patients with high heart rate (HR) using a 256-row detector CT. METHOD: Sixty-four consecutive patients with known or suspected coronary artery disease (symptomatic) and with HR of 75 beats per minute or greater (mean [SD] HR, 82.6 [7.3] beats per minute) undergoing CCTA and invasive coronary angiography within 4 weeks were prospectively enrolled. Coronary computed tomography angiography was performed with a 256-row detector CT (Revolution CT, GE Healthcare) using prospectively electrocardiography-triggered volume scan in 1 heart beat. All images were reconstructed using standard (STD) algorithm and a motion-correction algorithm reconstruction (Snapshot Freeze SSF; GE Healthcare) technique. The image quality of coronary artery segments was evaluated by 2 experienced radiologists using a 4-point scale based on the 18 segment model. Diagnostic accuracy was compared between STD and SSF for significant lumen stenosis (>=50%) of each segment with invasive coronary angiography as the reference standard for determining significant stenosis. RESULTS: The diagnostic sensitivity, specificity, positive predictive value, and negative predictive value with STD and SSF were 93.7%, 85.1%, 50.2%, and 98.8% versus 91.9%, 95.8%, 77.9%, and 98.7% on per-segment assessment; 98.7%, 74.0%, 62.9%, and 99.2% versus 96.2%, 94.4%, 77.9%, and 98.7% on per-artery assessment; and 100%, 14.3%, 70.5%, and 100% versus 100%, 85.7%, 93.5%, and 100% on per patient assessment, respectively. There was a significant difference in accuracy between STD and SFF on per-patient level 71.9% versus 95.3%, on per-artery level 81.6% versus 94.9%, and per-segment level 86.3% versus 95.3%, respectively. The area under receiver operating characteristics curve analysis also showed a significant improvement on diagnostic performance with the SSF technique versus with the STD algorithm on per-patient level (P < 0.001), with corresponding area under the curve being 0.91 (95% confidence interval, 0.79-1.00) and 0.60 (95% confidence interval, 0.44-0.75). The mean effective dose was 2.0 mSv. CONCLUSIONS: Coronary computed tomography angiography can be performed in patients with high HR within 1 heart beat yielding low radiation dose. The use of SSF technique reconstruction for 1 heart beat CCTA achieves significant improvements in image quality and diagnostic value. PMID- 28708725 TI - Dual-Energy Computed Tomography in Stroke Imaging: Technical and Clinical Considerations of Virtual Noncontrast Images for Detection of the Hyperdense Artery Sign. AB - OBJECTIVE: The technical feasibility of virtual noncontrast (VNC) images from dual-energy computed tomography (DECT) for the detection of the hyperdense artery sign (HAS) in ischemic stroke patients was investigated. METHODS: True noncontrast (TNC) scans of 60 patients either with or without HAS (n = 30 each) were investigated. Clot presence and characteristics were assessed on VNC images from DECT angiography and compared with TNC images. Clot characterization included the level of confidence for diagnosing HAS, a qualitative clot burden score, and quantitative attenuation (Hounsfield unit [HU]) measurements. RESULTS: Sensitivity, specificity, and accuracy of VNC for diagnosing HAS were 97%, 90%, and 93%, respectively. No significant differences were found regarding the diagnostic confidence (P = 0.18) and clot burden score (P = 0.071). No significant HU differences were found among vessels with HAS in VNC (56 +/- 7HU) and TNC (57 +/- 8HU) (P = 0.691) images. CONCLUSIONS: Virtual noncontrast images derived from DECT enable an accurate detection and characterization of HAS. PMID- 28708726 TI - Measuring Cerebral Hypoperfusion Induced by Hyperventilation Challenge With Intravoxel Incoherent Motion Magnetic Resonance Imaging in Healthy Volunteers. AB - OBJECTIVES: The aim of this study was to demonstrate the feasibility to assess cerebral hypoperfusion with a hyperventilation (HV) challenge protocol using intravoxel incoherent motion (IVIM) magnetic resonance imaging. MATERIALS AND METHODS: Magnetic resonance imaging experiments were performed on 10 healthy volunteers at 1.5 T, with a diffusion IVIM magnetic resonance imaging protocol using a set of b-values optimized by Cramer-Rao Lower Bound analysis. Hypoperfusion was induced by an HV maneuver. Measurements were performed in normoventilation and HV conditions. Biexponential curve fitting was used to obtain the perfusion fraction (f), pseudodiffusion coefficient (D*), and the product fD* in gray matter (GM) regions of interest (ROIs). Regional cerebral blood flow in the same ROIs was also assessed with arterial spin labeling. RESULTS: The HV challenge led to a diminution of IVIM perfusion-related parameters, with a decrease of f and fD* in the cerebellum (P = 0.03 for f; P = 0.01 for fD*), thalamus GM (P = 0.09 for f; P = 0.01 for fD*), and lenticular nuclei (P = 0.03 for f; P = 0.02 for fD*). Mean GM cerebral blood flow (in mL/100 g tissue/min) measured with arterial spin labeling averaged over all ROIs also decreased (normoventilation: 42.7 +/- 4.1 vs HV: 33.2 +/- 2.2, P = 0.004) during the HV challenge. CONCLUSIONS: The optimized IVIM protocol proposed in the current study allows for measurements of cerebral hypoperfusion that might be of great interest for pathologies diagnosis such as ischemic stroke. PMID- 28708727 TI - Splenic Involvement in Disseminated Mycobacterium avium-intracellulare Infection: Magnetic Resonance Imaging Findings. AB - We report the imaging findings of a patient with disseminated Mycobacterium avium intracellulare complex presenting with multiple splenic lesions incompletely characterized on computed tomography in whom magnetic resonance imaging helped narrow the differential diagnosis. We discuss the magnetic resonance imaging findings suggesting the diagnosis, including the presence of focal susceptibility artifact within the lesions (ie, signal drop on T1 in-phase imaging), marked hypointensity on diffusion-weighted imaging, and faint progressive peripheral enhancement after contrast administration. We provide pathologic correlation to explain these imaging characteristics and a review of the literature of imaging characteristics in splenic involvement of M. avium-intracellulare complex infection. PMID- 28708728 TI - Differentiating Primary Central Nervous System Lymphomas From Glioblastomas and Inflammatory Demyelinating Pseudotumor Using Relative Minimum Apparent Diffusion Coefficients. AB - OBJECTIVE: Our purpose was to evaluate the diagnostic performance of diffusion weighted imaging, the relative minimum apparent diffusion coefficient (rADCmin) in differentiating primary central nervous system lymphomas (PCNSLs) from glioblastomas (GBMs) and inflammatory demyelinating pseudotumors (IDPs). MATERIALS AND METHODS: Magnetic resonance images were reviewed retrospectively in 82 patients including 39 PCNSLs, 35 GBMs, and 8 IDPs. Regions of interest were drawn around the tumor on contrast-enhanced axial images; these images were transferred onto coregistered ADC maps to obtain the ADCmin, and the normalized ADCmin ratios (rADCmin) were calculated using the formula rADCmin = ADCmin of the lesion / ADCmin of the normal white matter. The rADCmin values were compared between PCNSLs, GBMs, and IDPs using the analysis of variance test. Receiver operating characteristic curves were constructed to evaluate the diagnostic performance of rADCmin values and to determine the optimum thresholds. Simple logistic regression was analyzed to evaluate the relationship between ADCs and tumor cellularity. RESULTS: The rADCmin value was significantly lower in PCNSLs (0.675 +/- 0.113) than GBMs (0.765 +/- 0.059) and IDPs (0.834 +/- 0.067) (PCNSL vs GBM, P < 0.001; PCNSL vs IDP, P < 0.001). Relative ADCmin was a significant assessor for differentiating PCNSLs from non-PCNCLs (P < 0.001). The optimal cutoff value was 0.722 (sensitivity, 74.5%; specificity, 74.1%; area under the curve, 0.803) on receiver operating characteristic analysis. A stronger negative correlation (r = -0.755, P = 0.000) was obtained between the cytoplasm and rADCmin. CONCLUSIONS: Relative ADCmin value is helpful in differentiating PCNSL from GBM and IDP. Thus, ADC values may provide a useful supplement to the information obtained from conventional contrast-enhanced magnetic resonance imaging and assist in future treatment planning. PMID- 28708729 TI - T2*-Weighted and Diffusion Magnetic Resonance Imaging Differentiation of Cerebral Fat Embolism From Diffuse Axonal Injury. AB - OBJECTIVE: This study differentiates cerebral fat embolism (CFE) and diffuse axonal injury (DAI) on diffusion-weighted magnetic resonance imaging (DWI) and T2*-weighted magnetic resonance imaging. METHODS: Consecutive CFE and DAI cases were retrospectively selected. Hemorrhages were characterized by number, size/shape, and distribution, whereas DWI lesions by pattern. The number of hemorrhages was compared using the Mann-Whitney test with adjustment for multiple comparisons, whereas DWI abnormality was compared using Fisher exact test. RESULTS: Seven CFE and 20 DAI patients were included. Cerebral fat embolism had significantly more hemorrhages than DAI (mean, 670 +/- 407 vs 136 +/- 87; P = 0.01), particularly in the frontal (P = 0.025), parietal (P = 0.002), and occipital lobes (P = 0.01), the corpus callosum (P = 0.01), and cerebellum (P = 0.01). Cerebral fat embolism microhemorrhages were punctate/round, whereas DAI hemorrhages were small/medium sized (P < 0.001) and linear (P = 0.001). On DWI, DAI typically had few scattered abnormalities, whereas CFE had confluent abnormalities (P < 0.05). CONCLUSIONS: Magnetic resonance imaging can differentiate CFE from DAI. Cerebral fat embolism demonstrates more hemorrhages. Larger or linear hemorrhages favor DAI. Diffuse confluent diffusion restriction favors CFE, whereas few scattered foci favor DAI. PMID- 28708730 TI - Physiological Laterality of Superficial Cerebral Veins on Susceptibility-Weighted Imaging. AB - OBJECTIVE: The purpose of this study is to evaluate whether laterality of the superficial cerebral veins can be seen on susceptibility-weighted imaging (SWI) in patients with no intracranial lesions that affect venous visualization. METHODS: We retrospectively evaluated 386 patients who underwent brain magnetic resonance imaging including SWI in our institute. Patients with a lesion with the potential to affect venous visualization on SWI were excluded. Two neuroradiologists visually evaluated the findings and scored the visualization of the superficial cerebral veins. RESULTS: Of the 386 patients, 315 (81.6%) showed no obvious laterality on venous visualization, 64 (16.6%) showed left-side dominant laterality, and 7 (1.8%) showed right-side dominant laterality. CONCLUSIONS: Left-side dominant physiological laterality exists in the visualization of the superficial cerebral veins on SWI. Therefore, when recognizing left-side dominant laterality of the superficial cerebral veins on SWI, the radiologist must also consider the possibility of physiological laterality. PMID- 28708731 TI - Noncontrast Hybrid Arterial Spin-Labeled Imaging of the Intracranial Arteries. AB - OBJECTIVE: The purpose of this study is to evaluate feasibility, image quality (IQ), and accuracy of noncontrast hybrid arterial spin labeling (NoHASL) magnetic resonance angiography (MRA) compared with time of flight (TOF) MRA and contrast enhanced (CE) MRA in patients with known/suspected cerebrovascular ischemia. METHODS: Thirty inpatients were imaged at 1.5 T. Two neuroradiologists assessed 630 intracranial arterial segments for IQ (1, nondiagnostic; 3, satisfactory for diagnosis; and 5, excellent). Hemodynamically significant stenosis (>50%) was assessed against all combined techniques as reference. RESULTS: The NoHASL MRA IQ was diagnostic (3.32 +/- 0.86) but affected by signal to noise ratio and spatial resolution limitations and significantly inferior to TOF (3.48 +/- 0.68) and CE MRA (3.44 +/- 0.78) (P < 0.0001 in both comparisons). Fourteen (2.2%) of 630 segments had hemodynamically significant stenoses at the reference standard. Sensitivity/specificity was not significantly different between techniques: NoHASL MRA, 67.9%/90.0%; TOF MRA, 67.9%/97.7%; and CE MRA, 50.0%/98.7%. CONCLUSIONS: The NoHASL MRA is feasible, with diagnostic quality imaging of proximal intracranial vessels. Low disease prevalence limited the assessment of technique accuracy. PMID- 28708732 TI - Investigating the Robustness Neighborhood Gray Tone Difference Matrix and Gray Level Co-occurrence Matrix Radiomic Features on Clinical Computed Tomography Systems Using Anthropomorphic Phantoms: Evidence From a Multivendor Study. AB - OBJECTIVE: The aim of this study was to determine if optimized imaging protocols across multiple computed tomography (CT) vendors could result in reproducible radiomic features calculated from an anthropomorphic phantom. METHODS: Materials with varying degrees of heterogeneity were placed throughout the lungs of the phantom. Twenty scans of the phantom were acquired on 3 CT manufacturers with chest CT protocols that had optimized protocol parameters. Scans were reconstructed using vendor-specific standards and lung kernels. The concordance correlation coefficient (CCC) was used to calculate reproducibility between features. For features with high CCC values, Bland-Altman analysis was also used to quantify agreement. RESULTS: The mean Hounsfield unit (HU) was 32.93 HU (141.7 to -26.5 HU) for the rubber insert and 347.2 HU (-320.9 to -347.7 HU) for the wood insert. Low CCC values of less than 0.9 were calculated for all features across all scans. CONCLUSIONS: Radiomic features that are derived from the spatial distribution of voxel intensities should be particularly scrutinized for reproducibility in a multivendor environment. PMID- 28708733 TI - An Assembled Prototype Multimaterial Three-Dimensional-Printed Model of the Neck for Computed Tomography- and Ultrasound-Guided Interventional Procedures. AB - A low-cost, semirealistic, multimaterial prototype phantom of the neck was developed for computed tomography- and ultrasound-guided interventions, using three-dimensional (3D) printing with a variety of materials as well as through molding techniques. This dual-modality phantom can be used by trainees for practicing procedures and can also serve as a prototype for developing more complex and realistic 3D-printed models, particularly with the continued development and advancement in multimaterial 3D printing technologies. PMID- 28708734 TI - T2*-Correction in Dynamic Contrast-Enhanced Magnetic Resonance Imaging of Glioblastoma From a Half Dose of High-Relaxivity Contrast Agent. AB - OBJECTIVE: The aim of this study was to evaluate the arterial input function (AIF) and tissue enhancement time curve (tissue function [TF]) obtained after the administration of a half-dose gadobenate dimeglumine (0.05-mmol/kg body weight [bw]) compared with a full dose (0.1-mmol/kg bw) of a standard-relaxivity contrast agent. METHODS: We enrolled 40 adult patients with glioblastoma in an interindividual comparative study. Patients were randomized to 1 of the 2 study arms: 20 patients received 0.1-mmol/kg bw of gadoterate; the other 20 patients received 0.05-mmol/kg bw of gadobenate. The patients underwent dynamic contrast enhanced magnetic resonance imaging examinations. Arterial input function, tissue enhancement time curve (TF), tumor transfer rate (K), and tumor extracellular extravascular volume fraction (Ve) were calculated for each patients. Averaged AIF, TF, K, and Ve of both groups were compared. RESULTS: A significant difference (P = 0.001) between the peak AIF values obtained with the 2 different gadolinium-based contrast agents was observed. No difference was found between TFs (P = 0.35). Comparison on kinetic parameters revealed a significant difference for K (P = 0.047) but no difference for Ve (P = 0.74). CONCLUSIONS: The administration of half dose of the high-relaxivity contrast agent gadobenate is effective in improving AIF by reducing T2*-shortening effects on dynamic contrast-enhanced magnetic resonance imaging and ensuring at the same time an adequate signal enhancement in tumor tissue. The use of 0.05-mmol/kg bw of gadobenate not only is feasible but also can lead to a better estimation of K based on a more accurate AIF assessment. PMID- 28708735 TI - Evaluation and Minimization of the Pseudohepatic Anisotropy Artifact in Liver Intravoxel Incoherent Motion. AB - PURPOSE: The aim of this study was to evaluate the effect of the pseudohepatic anisotropy artifact on liver intravoxel incoherent motion (IVIM) metrics and whether the use of multiple gradient directions in the IVIM acquisition minimizes the artifact. MATERIALS AND METHODS: Multiple breath-holding and forced shallow free-breathing IVIM scans were performed on 8 healthy volunteers using 1 and 6 gradient directions. Cluster analysis was carried out to separate motion contaminated parenchyma from liver parenchyma and vessels. Nonlinear motion analysis was also performed to look for a possible link between IVIM metrics and nonlinear liver motion. RESULTS: On the basis of the resulted clusters, motion contaminated parenchyma is often noted in the left liver lobe, where the prominent pseudohepatic artifact has previously been identified. A significant reduction in outliers was obtained with the acquisition of 6 noncoplanar gradient directions and when using forced shallow free-breathing. CONCLUSION: The pseudohepatic anisotropy artifact can be minimized when using multiple diffusion encoding gradient directions and forced free-breathing during IVIM acquisition. PMID- 28708737 TI - Factors associated with sexual health and well being in older adulthood. AB - PURPOSE OF REVIEW: To provide an update of recent studies on factors associated with sexual well being in older people with a special focus on sexual activity, satisfaction and function. RECENT FINDINGS: Most recent studies confirmed the relationship between mental health status, especially negative affect and depressive symptoms, and sexual health in older adulthood. However, when this relationship is investigated more deeply, it seems that in fact positive psychological well being (positive affect and quality of life) accounts for sexual activity rather than the lack of depressive symptoms. Moreover, recent studies provided more insight into the relationship between marital characteristics, religion, cognitive functioning and sleeping difficulties and different dimensions of sexual health in older adulthood. SUMMARY: In summary, there is substantial previous research revealing associations between various psychosocial, health-related and demographic variables and sexual health in older adulthood. Most considered variables are, for example, age, sex, general physical and mental health. For future research, it is important to consider that relationships between specific variables and sexual health in higher age are usually more complex than they are expected to be and factors differ between different dimensions of sexual health. Communication about sexuality between health-care providers and older patients still implies a lot of barriers and lack of knowledge. Therefore, the provision of communication training for health-care providers to older people in which knowledge is gained about correlates of sexual health in older adulthood should be implemented. PMID- 28708736 TI - Mifepristone Plasma Level and Glucocorticoid Receptor Antagonism Associated With Response in Patients With Psychotic Depression. AB - BACKGROUND: Psychotic depression has no Food and Drug Administration-approved treatment. Patients demonstrate significant dysregulation of the hypothalamic pituitary-adrenal axis providing a biologically targeted treatment opportunity. The purpose of this study was to explore the clinical and biological effects of short-duration (7-day) glucocorticoid receptor antagonism with mifepristone and the role of mifepristone plasma levels in patients with psychotic depression. METHODS: This double-blind, randomized study took place at 34 US clinical research centers and included patients with a diagnosis of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, major depressive disorder, severe, with psychotic features. Patients underwent daily, observed, in clinic administration of oral study drug (mifepristone 1200 mg or placebo) for days 1 to 7 of the 56-day trial, followed by treatment with a single Food and Drug Administration-approved antidepressant on days 8 to 56. The following scales were administered on days 0, 7, 14, 28, 42, and 56: Brief Psychiatric Rating Scale (BPRS), BPRS Positive Symptom Subscale, Hamilton Rating Scale for Depression, and Columbia-Suicide Severity Rating Scale. The primary end point was a categorical analysis evaluating the proportion of patients with 50% or greater reduction from baseline in BPRS Positive Symptom Subscale score on both days 7 and 56, demonstrating early and durable response. Cortisol and adrenocorticotropic hormone were measured on days 0, 7, 28, and 56. Mifepristone plasma levels were assessed on days 0 and 7. RESULTS: An interim analysis indicated that the primary efficacy end point was unlikely to be met, and the study was stopped early with 292 of the planned 450 patients enrolled. Although the primary end point was not met, in a secondary prespecified analysis, patients who attained a mifepristone plasma level of 1637 ng/mL or greater (defined a priori and termed the high plasma level; 66.7% of patients) demonstrated statistically significant reductions in psychotic symptoms compared with patients who received placebo starting on day 28. This group also showed nonsignificant, numeric superiority on Hamilton Rating Scale for Depression improvement. No significant improvements were observed in the low-mifepristone group (<1637 ng/mL) versus the placebo group. There were no significant differences in Columbia-Suicide Severity Rating Scale suicidality ratings between groups. CONCLUSIONS: Mifepristone 1200 mg daily for 7 days was safe and well tolerated, allowing most treated patients to achieve the a priori defined therapeutic plasma level of 1637 ng/mL, the mifepristone level associated with biological effect and clinical benefit. PMID- 28708738 TI - In bed with evidence: a hospital's experience. PMID- 28708739 TI - Effectiveness of neurofeedback therapy for anxiety and stress in adults living with a chronic illness: a systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE: The objective of this review is to systematically examine the effectiveness of neurofeedback therapy for managing anxiety and stress in adults living with a chronic illness.The specific objectives are to identify which neurofeedback systems and/or protocols demonstrate effectiveness and determine the level of supporting evidence.The review question is as follows: What is the effectiveness of neurofeedback therapy for managing anxiety and stress in an adult population aged 18 years of age or older living with a chronic illness? PMID- 28708740 TI - Experiences of substitute decision makers in making decisions for older persons diagnosed with major neurocognitive disorder at end of life: a qualitative systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE: The objective of this systematic review is to identify and synthesize the best available qualitative evidence on how substitute decision makers (SDMs) are affected by and experience making decisions at end of life (EOL) for older persons diagnosed with major neurocognitive disorder (major NCD) (dementia). Addressing the objective will provide an understanding of SDMs' experiences of making decisions for older persons diagnosed with major NCD at EOL, in order to tailor supportive education and interventions and potentially decrease inopportune outcomes.Specifically, the review questions are as follows. PMID- 28708741 TI - Effect of mHealth in improving antenatal care utilization and skilled birth attendance in low- and middle-income countries: a systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE: The objective of this review is to identify and synthesize the best available evidence on the effect of mobile health (mHealth) interventions in antenatal care utilization and skilled birth attendance in low- and middle-income countries.More specifically, the review questions are as follows. PMID- 28708742 TI - Physical therapy and exercise interventions in Huntington's disease: a mixed methods systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE:: The review seeks to evaluate the effectiveness of physical therapy and exercise interventions in Huntington's disease (HD). The review question is: What is the effectiveness of physiotherapy and therapeutic exercise interventions in people with HD, and what are patients', families' and caregivers' perceptions of these interventions?The specific objectives are:This mixed methods review seeks to develop an aggregated synthesis of quantitative, qualitative and narrative systematic reviews on physiotherapy and exercise interventions in HD, in an attempt to derive conclusions and recommendations useful for clinical practice and policy decision-making. PMID- 28708743 TI - Strategies that reduce compassion fatigue and increase compassion satisfaction in nurses: a systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE: The objective of this quantitative systematic review is to determine effective strategies to reduce compassion fatigue and improve compassion satisfaction among nurses. PMID- 28708744 TI - Experiences of compassion fatigue in direct care nurses: a qualitative systematic review protocol. AB - REVIEW QUESTION/OBJECTIVES:: The objective of this qualitative systematic review is to examine available evidence on the experiences of direct care nurses of compassion fatigue (CF) within any nursing specialty or care setting. Specifically, this review will identify evidence on the following. PMID- 28708745 TI - Experiences of Scandinavian nurses in discussing sexuality with patients, clients and residents: a qualitative systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE:: The objective of this review is to critically appraise, synthesize, and present the best available evidence to address the question: How do Scandinavian nurses experience discussing sexual issues with patients, residents and clients? PMID- 28708746 TI - Incidence and prevalence of falls in adults with intellectual disability living in the community: a systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE:: The objective of this review is to synthesize the best available evidence to determine the incidence and prevalence of falls in adults with intellectual disability living in the community. PMID- 28708747 TI - Footwear and insole design features to prevent foot ulceration in people with diabetes: a systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE: The aim of this systematic review is to identify the key design features of footwear and insoles that are used to offload the plantar surface of the foot to prevent foot ulceration in adults with diabetes.More specifically, the objectives are to identify the key design features of footwear and insoles to offload the plantar surface of the foot with regard to. PMID- 28708748 TI - eHealth interventions for parents in neonatal intensive care units: a systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE: The objective of this review is to examine the effect of electronic health (eHealth) interventions used in the neonatal intensive care unit (NICU) on parent-related and infant outcomes. PMID- 28708749 TI - Effectiveness of pay-for-performance for chronic kidney disease patients on hemodialysis: a systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE:: The objective of this review is to assess the evidence on the effectiveness of implementation of a pay-for-performance program on clinical outcomes in the adult chronic kidney disease (CKD) patient receiving hemodialysis.The review question is: What is the effectiveness of implementation of a pay-for-performance program on clinical outcomes in the adult CKD patient receiving hemodialysis, as compared to the period immediately before implementation of the program?More specifically, the objectives are to identify. PMID- 28708750 TI - Effect of breastfeeding on different features of malocclusions in the primary dentition: a systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE:: The objective of this review of association (etiology) is to identify the association of breastfeeding with the development of different features of malocclusions in the primary dentition. The specific review questions are: What is the risk of developing different features of malocclusions in the primary dentition. PMID- 28708751 TI - Use of non-pharmacological interventions for comforting patients in palliative care: a scoping review. AB - BACKGROUND: Palliative care aims to provide the maximum possible comfort to people with advanced and incurable diseases. The use of non-pharmacological interventions to promote comfort in palliative care settings has been increasing.However, information on implemented and evaluated interventions, their characteristics, contexts of application, and population is scattered in the literature, hampering the formulation of accurate questions on the effectiveness of those interventions and, consequently, the development of a systematic review. OBJECTIVE: The objective of this scoping review is to examine and map the non pharmacological interventions implemented and evaluated to provide comfort in palliative care. INCLUSION CRITERIA TYPES OF PARTICIPANTS: This scoping review considered all studies that focused on patients with advanced and incurable diseases, aged 18 years or older, assisted by palliative care teams. CONCEPT: This scoping review considered all studies that addressed non-pharmacological interventions implemented and evaluated to provide comfort for patients with advanced and incurable diseases.It considered non-pharmacological interventions implemented to provide not only comfort but also well-being, and relief of pain, suffering, anxiety, depression, stress and fatigue which are comfort-related concepts. CONTEXT: This scoping review considered all non-pharmacological interventions implemented and evaluated in the context of palliative care. This included home care, hospices or palliative care units (PCUs). TYPES OF SOURCES: This scoping review considered quantitative and qualitative studies, and systematic reviews. SEARCH STRATEGY: A three-step search strategy was undertaken: 1) an initial limited search of CINAHL and MEDLINE; 2) an extensive search using all identified keywords and index terms across all included databases; and 3) a hand search of the reference lists of included articles.This review was limited to studies published in English, Spanish and Portuguese in any year. EXTRACTION OF RESULTS: A data extraction instrument was developed. Two reviewers extracted data independently. Any disagreements that arose between the reviewers were resolved through discussion, or with a third reviewer. When necessary, primary authors were contacted for further information/clarification of data. PRESENTATION OF RESULTS: Eighteen studies were included covering 10 non pharmacological interventions implemented and evaluated to provide comfort. The interventions included one to 14 sessions. The interventions lasted between five and 60 minutes. Most of the interventions were implemented in PCUs and hospice settings. Ten of the 18 interventions were implemented and evaluated exclusively in cancer patients. CONCLUSIONS: Ten non-pharmacological interventions were identified, of which the most common were music therapy and massage therapy. Their characteristics differed significantly across interventions and even in the same intervention. They were mostly implemented in palliative care units and hospices, and in patients with a cancer diagnosis. These data raise questions for future primary studies and systematic reviews. IMPLICATIONS FOR RESEARCH: Future research should focus on the implementation of interventions not only with cancer patients but also with non-cancer patients and patients receiving palliative care at home. Systematic reviews on the effect of massage therapy and music therapy should be conducted. PMID- 28708752 TI - Prevalence of burnout in health professionals working in palliative care: a systematic review. AB - BACKGROUND: More than ever, the current increasing need for palliative care leads to health professionals providing this type of care which further leads to multiple challenges, and stressful and demanding situations. The multiple challenges of working in palliative care put health professionals working in this context at the risk of burnout. OBJECTIVES: To examine the evidence on the prevalence of burnout among health professionals working in palliative care. INCLUSION CRITERIA TYPES OF PARTICIPANTS: The current review included studies that encompass qualified health professionals working in palliative care, caring for patients 18 years of age or older. CONDITION: The current review considered studies reporting on the point prevalence of burnout, measured by a burnout scale, such as, but not limited to, the Maslach Burnout Inventory, Burnout Measure and Copenhagen Burnout Inventory. CONTEXT: The current review considered studies conducted in the context of specialist palliative care, more specifically, palliative care units, specialized palliative home care or hospices. TYPES OF STUDIES: The current review considered observational study designs, including prospective and retrospective cohort, case-control and cross sectional studies. SEARCH STRATEGY: An initial search of MEDLINE (via PubMed) and CINAHL was undertaken, followed by a second search for published and unpublished studies since 1975 in major healthcare-related electronic databases. Studies written in English, Spanish and Portuguese were included. METHODOLOGICAL QUALITY: Two independent reviewers assessed the methodological quality of studies using the standardized critical appraisal instrument from the Joanna Briggs Institute. No studies were excluded from the review based on the methodological appraisal. DATA EXTRACTION: Data were extracted using a data extraction table, taking into account the review questions. DATA SYNTHESIS: Significant differences were found between condition measures, thus we were unable to perform a meta-analysis. RESULTS: Eight cross-sectional studies met the inclusion criteria, with a total of 1406 health professionals. The sample was limited to nurses, physicians and social workers. None of the included articles presented data about other health professionals. Seven of the included studies assessed the prevalence of burnout using the same instrument - the Maslach Burnout Inventory. Data revealed a prevalence of burnout of 17.3% among health professionals. Personal Accomplishment was the sub-scale from the Maslach Burnout Inventory that had the highest prevalence (19.5%). Nurses had higher levels of Emotional Exhaustion (19.5%) and Depersonalization (8.2%), and physicians had lower levels of Personal Accomplishment (41.2%). The prevalence of burnout was, however, higher in social workers (27%). The palliative care context with the highest prevalence of burnout was home care (19.6%). CONCLUSION: The current systematic review contributes to a body of empirical knowledge that can facilitate the professional development of palliative care teams by highlighting the prevalence of burnout in health professionals, which staff category is the most affected (social workers), and which palliative care context has the highest prevalence (home care). PMID- 28708753 TI - Effectiveness of preoperative intranasal dexmedetomidine, compared with oral midazolam, for the prevention of emergence delirium in the pediatric patient undergoing general anesthesia: a systematic review. AB - BACKGROUND: Emergence delirium is defined as a cognitive disturbance during emergence from general anesthesia resulting in hallucinations, delusions and confusion manifested by agitation, restlessness, involuntary physical movement and extreme flailing in bed. Postoperative emergence delirium develops in 12% to 18% of all children undergoing general anesthesia for surgery. This post anesthetic phenomenon changes cognitive and psychomotor behavior, and puts pediatric patients and health care personnel at risk of injury. A newer drug, dexmedetomidine, is a selective alpha-2 agonist, which works in the brain and spinal cord that has sedative, analgesic and anxiolytic properties. Dexmedetomidine also has the ability to lower the overall anesthetic requirements by reducing sympathetic outflow in response to painful surgical stimulation. In current literature, there is not a systematic review that compares the effectiveness of preoperative intranasal dexmedetomidine administration against oral midazolam for the prevention of emergence delirium. OBJECTIVES: The objective of this review was to identify the effectiveness of preoperative intranasal dexmedetomidine compared to oral midazolam for the prevention of emergence delirium in the pediatric patient undergoing general anesthesia. INCLUSION CRITERIA TYPES OF PARTICIPANTS: This review considered studies that included pediatric patients aged three to seven years, with an American Society of Anesthesiologists (ASA) classification of I or II, and undergoing general anesthesia for elective/ambulatory surgery. This review excluded studies that included patients who had special needs including: developmental delay, chronic pain issues, and/or any preexisting mental or physical health disorders which categorized them above an ASA II. TYPES OF INTERVENTION(S)/PHENOMENA OF INTEREST: This review considered studies that compared preoperative intranasal administration of dexmedetomidine with preoperative oral administration of midazolam for the prevention of emergence delirium. TYPES OF STUDIES: This review considered both experimental and non-experimental study designs including randomized-controlled trials (RCTs), non-randomized control trials, quasi experimental, before and after studies, prospective and retrospective cohort studies, case control studies, and analytical cross-sectional studies for inclusion. OUTCOMES: This review considered studies that included the presence of postoperative emergence delirium. Only studies that used the Pediatric Anesthesia Emergence Delirium Scale to quantify the degree of emergence delirium were included in the review. Adverse events other than emergence delirium were not considered as part of the outcomes inclusion criteria but were to be included in the discussion if any articles were identified. SEARCH STRATEGY: The search strategy aimed to discover both published as well as unpublished studies. A three step search strategy was utilized in eight databases. Studies published in English or with an English translation after 1999 were considered for inclusion in this review. METHODOLOGICAL QUALITY: Assessment of methodological quality was not conducted as no studies were identified which met the inclusion criteria. DATA EXTRACTION AND SYNTHESIS: Data extraction and synthesis was not performed since no studies were included in this systematic review. RESULTS: Following the three-step search strategy as previously described, 117 articles were identified: six in Clinical Trials, one in ProQuest, 14 in Ovid MEDLINE, 10 in CINAHL, 16 in the Cochrane Library, 13 in Scopus, 36 in Embase, and 21 in Web of Science. There were 43 duplicates which were identified and removed in Refworks by the primary reviewer. The primary and secondary reviewers independently retrieved 10 potentially relevant studies (from the initial 74) through title and abstract screening as described in the inclusion criteria. All of the retrieved studies were excluded, after assessment of full text, with reasons based on the inclusion criteria. CONCLUSIONS: There is no scientific evidence identifying the effectiveness of preoperative intranasal dexmedetomidine, compared with oral midazolam, for the prevention of emergence delirium in the pediatric patient population. PMID- 28708754 TI - The effect of vasodilatory medications on radial artery spasm in patients undergoing transradial coronary artery procedures: a systematic review. AB - BACKGROUND: The uptake of percutaneous coronary procedures via the radial artery has increased internationally due to the decreased risk of complications and increased patient satisfaction. The increased susceptibility of the radial artery to spasm however presents a potential risk for procedural failure. Although most experts agree on the need for prophylactic medications to reduce radial artery spasm, currently there is inconsistency in literature regarding the most effective vasodilatory medication or combination of medications. REVIEW OBJECTIVE: The objective of this study is to identify the effectiveness of vasodilatory medications on radial artery spasm in patients undergoing transradial coronary artery procedures. INCLUSION CRITERIA TYPES OF PARTICIPANTS: This review considered studies that included participants aged 18 years and over undergoing non-emergent transradial percutaneous coronary artery procedures. TYPES OF INTERVENTION(S): This review considered studies that used vasodilating intravenous and intra-arterial medications or combinations of medications prior to commencing and during transradial coronary approaches to reduce radial artery spasm. OUTCOMES: The outcomes of interest were the incidence of radial artery spasm during percutaneous coronary procedure using objective and/or subjective measures and its effect on the successful completion of the procedure. TYPES OF STUDIES: Randomized controlled trials published in the English language between 1989 to date were considered for inclusion. SEARCH STRATEGY: The search strategy aimed to find both published and unpublished studies. A three-step search strategy was utilized in this review. An initial search of MEDLINE, CINAHL and Scopus was undertaken, followed by a search for unpublished studies. ASSESSMENT OF METHODOLOGICAL QUALITY: Papers selected for retrieval were assessed by two independent reviewers for methodological validity prior to inclusion in the review using standardized critical appraisal instruments. Any disagreements that arose between the reviewers were resolved through discussion. DATA EXTRACTION: Quantitative data was extracted from papers included in the review using the standardized data extraction tool from RevMan5 (Copenhagen: The Nordic Cochrane Centre, Cochrane). DATA SYNTHESIS: Quantitative data, where possible, was pooled in statistical meta-analysis using RevMan5. All results were subject to double data entry. Effect sizes expressed as risk ratio (for categorical data) and weighted mean differences (for continuous data) and their 95% confidence intervals were calculated for analysis. RESULTS: Nine trials involving 3614 patients were included in the final review. Pooled data involving 992 patients on the effect of calcium channel blockers demonstrated a statistically significant reduction in the incidence of vasospasm in patients who received verapamil 5 mg compared to those who received a placebo (OR 0.33; 95%CI 0.19, 0.58). Similarly patients who received verapamil 2.5 mg or 1.25 mg had significantly fewer incidences of vasospasm when compared to those who received a placebo. Nitroglycerine 100mcg was demonstrated to be associated with a statistically significant reduction in the incidence of vasospasm. CONCLUSION: The evidence demonstrates a benefit in the use of vasodilatory medications for the reduction of vasospasm in patients having radial coronary procedures. Further large-scale multi-center trials are needed to determine the preferred medication. PMID- 28708755 TI - Computed tomography coronary angiography with heart rate control premedication: a best practice implementation project. AB - BACKGROUND: Computed tomography coronary angiography patient preparation with heart rate control premedication is employed in departments across Australia. However, the methods of administration vary widely between institutions and do not always follow best practice. OBJECTIVES: This aim of the study was to identify and promote best practice in the administration of heart rate premedication in computed tomography coronary angiography at a regional hospital in Australia. METHODS: The Joanna Briggs Institute have validated audit and feedback tools to assist with best practice implementation projects. This project used these tools, which involve three phases of activity - a pre-implementation audit, reflecting on results and implementing strategies to address non compliance, and a post-implementation audit to assess the outcomes. RESULTS: A baseline audit identified non-compliance in the majority of measured audit criteria. Following implementation of an institution-specific guideline and associated worksheet, improved compliance was shown across all audit criteria. CONCLUSIONS: Following the development and implementation of institution-specific evidence-based resources relating to heart rate control in computed tomography coronary angiography, a high level of compliance consistent with best practice was achieved. PMID- 28708756 TI - Anatomic Reconstruction of Distal Radioulnar Ligaments With Tendon Graft for Treating Distal Radioulnar Joint Instability: Surgical Technique and Outcome. AB - Among the various reasons for chronic posttraumatic ulnar-sided wrist pain, instability of the distal radioulnar joint (DRUJ) has recently received major attention and finally achieved fundamental progress in understanding thanks to anatomic and biomechanical studies. This has resulted in more physiological and successful treatment methods compared with the historic options. One and the most dramatic surgical technique consists in the replacement of the main ligamentous stabilizer of the DRUJ, the so-called triangular fibrocartilage, with a tendon graft. On the basis of our experience, the refined surgical technique is presented as well as the results obtained in a retrospective consecutive case series of 48 patients with 48 wrists followed-up for 16 months in average (6 to 43) clinically and radiographically. Out of 48 unstable DRUJ's stability was restored in 44 patients associated with a significant pain relief by 1.44 points (on a scale 0 to 4). There was however a loss of forearm rotation of 20 degrees in average (pronation-8 degrees; supination-12 degrees), whereas the range of motion of the wrist and grip strength remained unchanged. We did not find any influence on the result by performing simultaneous ulnar shortening osteotomy, the duration of cast immobilization or the positioning in the cast. There were no postoperative complications, 4 failed cases needed secondary procedures (2* rereconstruction, 2* Sauve-Kapandji-operation). PMID- 28708757 TI - Increased Incidence Rate of Trauma- and Stressor-related Disorders in Denmark After the Breivik Attacks in Norway. AB - BACKGROUND: On 22 July 2011, Anders Breivik killed 77 adults and children in Norway. Having recently documented increases in the incidence of trauma- and stressor-related disorders in Denmark after the 9/11 attacks, we hypothesized that the Breivik attacks-due to their geographic proximity-would be followed by even larger increases in Denmark. METHODS: Using population-based data from the Danish Psychiatric Central Research Register (1995-2012), we conducted an intervention analysis of the change in the incidence of trauma- and stressor related disorders after the Breivik attacks. RESULTS: The incidence rate increased by 16% over the following 11/2 years after the Breivik attacks, corresponding to 2736 additional cases. In comparison, 9/11 was followed by a 4% increase. We also present evidence of a subsequent surge in incidence stimulated by media attention. CONCLUSION: This study bolsters previous findings on extra national consequences of terrorism and indicates that geographic proximity and media coverage may exacerbate effects. PMID- 28708758 TI - Relationship Between Pelvic Organ Prolapse and Non-Human Papillomavirus Pap Smear Abnormalities. AB - OBJECTIVE: The aim of this study was to determine the association between pelvic organ prolapse (POP) and non-human papillomavirus (HPV) Papanicolaou (Pap) smear abnormalities. METHODS: This was a retrospective cohort study of women aged 40 to 70 years who presented for consultation at our institution between 2010 and 2015 and had results of a Pap smear and HPV test available within 5 years of their visit. We extracted demographic information, medical and social history, Pap smear, and HPV results from the electronic medical record. Associations between the presence of POP and non-HPV Pap smear abnormalities were estimated using univariable and multivariable analyses. RESULTS: We reviewed 1590 charts and excluded 980 women, leaving 610 women in the study: 183 with POP and 427 without POP. Women with POP were significantly older (58.2 +/- 7.2 vs 55.6 +/- 6.6, P < 0.01) and more likely to have a remote (>10 year) history of abnormal Pap smear (24.0% vs 14.8%, P < 0.01). The rate of non-HPV-associated abnormal Pap smears was higher in the POP group than in the non-POP group (12/183 [6.6%] vs 12/427 [2.8%], P = 0.029). In the POP group, the rate of non-HPV Pap smear abnormality was significantly associated with increasing prolapse stage (stage 1: 0/16 [0%], stage 2: 5/77 [6.5%], stage 3: 3/73 [4.1%], stage 4: 4/17 [23.5%]; P = 0.02). After controlling for age and remote history of abnormal Pap smear, the odds ratio for non-HPV Pap smear abnormalities in the POP group remained significant (2.49; 95% confidence interval, 1.08-5.79). CONCLUSIONS: Human papillomavirus negative Pap smear abnormalities may be related to POP. Our findings have important implications for surgeons seeking to leave the cervix in situ in women with POP. PMID- 28708759 TI - Long noncoding RNA MRAK009713 is a novel regulator of neuropathic pain in rats. AB - Long noncoding RNAs have been implicated in neuropathy. Here, we identify and validate a long noncoding RNA, MRAK009713, as the primary regulator of neuropathic pain in chronic constriction injury (CCI) rats. MRAK009713 expression was markedly increased in CCI rats associated with enhanced pain behaviors, and small interfering RNA against MRAK009713 significantly reduced both mechanical and thermal hyperalgesia in the CCI rats. MRAK009713 is predicted to interact with the nociceptive P2X3 receptor by CatRAPID, a bioinformatics technology. Overexpression of MRAK009713 markedly increased expression of P2X3 in the dorsal root ganglia of the control rats, and MRAK009713 small interfering RNA significantly inhibited the P2X3 expression in the dorsal root ganglia of the CCI rats. MRAK009713 directly interacted with the P2X3 protein heterologously expressed in the human embryonic kidney (HEK) 293 cells and potentiated P2X3 receptor function. Thus, MRAK009713 is a novel positive regulator of neuropathic pain in rats through regulating the expression and function of the P2X3 receptor. PMID- 28708761 TI - Most red flags for malignancy in low back pain guidelines lack empirical support: a systematic review. AB - Clinicians do not want to miss underlying serious pathology, but it is still unclear which red flags are relevant. We aimed to evaluate the origin and evidence on diagnostic accuracy of red flags for malignancy for management of low back pain (LBP) in primary care. We performed a comprehensive overview and searched the literature using snowballing techniques and reference checking for evidence on red flags endorsed in clinical guidelines for identifying patients with higher likelihood of malignancy. We selected studies including people with LBP without any restriction on study design. We extracted data on prevalence and diagnostic accuracy. Furthermore, we assessed the methodological quality of studies evaluating diagnostic accuracy. We identified 13 red flags endorsed in a total of 16 guidelines and 2 extra red flags not endorsed in any guideline. We included 33 publications varying from systematic reviews to case reports. The origin of many red flags was unclear or was sourced from case reports. The incidence of malignancy in patients presenting with LBP in primary care varied between 0% and 0.7%. Seven studies provided diagnostic accuracy data on red flags. We found 5 red flags with accuracy data from 2 or more studies, with 2 ("history of malignancy" and "strong clinical suspicion") considered informative. In conclusion, the origin and diagnostic accuracy of many red flags endorsed in guidelines are unclear. A "history of malignancy" and "strong clinical suspicion" are the only red flags with empirical evidence of acceptably high diagnostic accuracy. PMID- 28708760 TI - Reactive oxygen species affect spinal cell type-specific synaptic plasticity in a model of neuropathic pain. AB - Spinal synaptic plasticity is believed to drive central sensitization that underlies the persistent nature of neuropathic pain. Our recent data showed that synaptic plasticity in the dorsal horn is cell type specific: intense afferent stimulation produced long-term potentiation (LTP) in excitatory spinothalamic tract neurons (STTn), whereas it produced long-term depression (LTD) in inhibitory GABAergic interneurons (GABAn). In addition, reactive oxygen species (ROS) were shown to be involved in LTP in STTn (STTn-LTP) and in LTD in GABAn (GABAn-LTD). This study examined the roles of 2 biologically important ROS- superoxide [.O2] and hydroxyl radicals [.OH]--in neuropathic mechanical hyperalgesia and cell type-specific spinal synaptic plasticity. The [.O2] donor induced stronger mechanical hyperalgesia than the [.OH] donor in naive mice. The [.O2] scavenger showed greater antihyperalgesic effect than [.OH] scavengers in the spinal nerve ligation (SNL) mouse model of neuropathic pain. In addition, the [.O2] donor induced both STTn-LTP and GABAn-LTD, but the [.OH] donor induced only GABAn-LTD. On the other hand, the [.O2] scavenger inhibited STTn-LTP and GABAn LTD induction in naive mice and alleviated SNL-induced potentiation in STTn and depression in GABAn. The [.OH] scavenger, however, inhibited depression in GABAn but did not interfere with potentiation in STTn. These results indicate that mechanical hyperalgesia in SNL mice is the result of the combination of STTn-LTP and GABAn-LTD. Behavioral outcomes compliment electrophysiological results which suggest that [.O2] mediates both STTn-LTP and GABAn-LTD, whereas [.OH] is involved primarily in GABAn-LTD. PMID- 28708762 TI - Cognitive load selectively influences the interruptive effect of pain on attention. AB - Pain is known to interrupt attentional performance. Such interference effects seem to occur preferentially for tasks that are complex and/or difficult. However, few studies have directly manipulated memory load in the context of pain interference to test this view. Therefore, this study examines the effect of experimental manipulations of both memory load and pain on 3 tasks previously found to be sensitive to pain interference. Three experiments were conducted. A different task was examined in each experiment, each comprising of a high- and low-cognitive load versions of the task. Experiment 1 comprised an attention span (n-back) task, experiment 2 an attention switching task, and experiment 3 a divided attention task. Each task was conducted under painful and nonpainful conditions. Within the pain condition, an experimental thermal pain induction protocol was administered at the same time participants completed the task. The load manipulations were successful in all experiments. Pain-related interference occurred under the high-load condition but only for the attention span task. No effect of pain was found on either the attentional switching or divided attention task. These results suggest that while cognitive load may influence the interruptive effect of pain on attention, this effect may be selective. Because pain affected the high-load version of the n-back task but did not interrupt performance on attentional switching or dual-task paradigms, this means that our findings did not completely support our hypotheses. Future research should explore further the parameters and conditions under which pain-related interference occurs. PMID- 28708764 TI - In memoriam: Professor Stephen J Morley (1950-2017). PMID- 28708763 TI - Day-to-day experience in resolution of pain after surgery. AB - We know little about the individual pain experience of patients recovering from surgery in the first weeks after hospital discharge. Here, we examine individual differences in the day-to-day experience after 2 major surgeries: lower limb total major joint arthroplasty (TJA) and cesarean delivery (CD). Fifty-five TJA patients and 157 CD patients were recruited to complete questionnaires and record their daily pain experiences after surgery. After hospital discharge, patients recorded their pain intensity once daily for 60 days (CD) or twice daily for 2 weeks, once daily for 2 weeks, weekly for 8 weeks, and monthly for 3 months (TJA). Pain scores were modeled using growth curve and Bayesian change-point models. Individual differences in the model fits were examined for evidence of day-to-day differences in pain. A log time model was the simplest model that fit the data, but examination of the residuals revealed high autocorrelation representing misspecification. A change-point model fit the data better and revealed that the form of recovery fundamentally changed between days 10 and 21 after surgery. These data add meaningfully to our understanding of recovery from pain after surgery by extending the period of frequent observations a few days after surgery to a 2-month period. These high time resolution data suggest that there is a typical experience of pain resolution after surgery, but that meaningful subpopulations of experience may exist. They also indicate that a transition occurs within 1 month after surgery from 1 pattern of change in pain over time to another. PMID- 28708765 TI - Distinct behavioral responses evoked by selective optogenetic stimulation of the major TRPV1+ and MrgD+ subsets of C-fibers. AB - Primary C-fiber nociceptors are broadly divided into peptidergic and nonpeptidergic afferents. TRPV1 is a thermosensitive cation channel mainly localized in peptidergic nociceptors, whereas MrgD is a sensory G protein-coupled receptor expressed in most nonpeptidergic nociceptive afferents. TRPV1 and MrgD fibers have been reported to be primarily involved in thermal and mechanical nociception, respectively. Yet, their functional assessment in somatosensory transmission relied on ablation strategies that do not account for compensatory mechanisms. To achieve selective activation of these 2 major subsets of C-fibers in vivo in adult mice, we used optogenetics to specifically deliver the excitatory opsin channelrhodopsin-2 (ChR2) to TRPV1 or MrgD primary sensory neurons, as confirmed by histology and electrophysiology. This approach allowed, for the first time, the characterization of behavioral responses triggered by direct noninvasive activation of peptidergic TRPV1 or nonpeptidergic MrgD fibers in freely moving mice. Transdermal blue light stimulation of the hind paws of transgenic mice expressing ChR2 in TRPV1 neurons generated nocifensive behaviors consisting mainly of paw withdrawal and paw licking, whereas paw lifting occurrence was limited. Conversely, optical activation of cutaneous MrgD afferents produced mostly withdrawal and lifting. Of interest, in a conditioned place avoidance assay, blue light induced aversion in TRPV1-ChR2 mice, but not in MrgD-ChR2 mice. In short, we present novel somatosensory transgenic models in which control of specific subsets of peripheral unmyelinated nociceptors with distinct functions can be achieved with high spatiotemporal precision. These new tools will be instrumental in further clarifying the contribution of genetically identified C-fiber subtypes to chronic pain. PMID- 28708766 TI - Is the rationale more important than deception? A randomized controlled trial of open-label placebo analgesia. AB - Research on open-label placebos questions whether deception is a necessary characteristic of placebo effects. Yet, comparisons between open-label and deceptive placebos (DPs) are lacking. We therefore assessed effects of open-label placebos and DPs in comparison with no treatment (NT) with a standardized experimental heat pain paradigm in a randomized controlled trial in healthy participants. Participants (N = 160) were randomly assigned to NT, open-label placebo without rationale (OPR-), open-label placebo with rationale (OPR), and DP. We conducted baseline and posttreatment measurements of heat pain threshold and tolerance. Apart from the NT, all groups received an application of a placebo cream. Primary outcomes were planned comparisons of heat pain tolerance and the corresponding intensity and unpleasantness ratings. Objective posttreatment pain tolerance did not differ among groups. However, for subjective heat pain ratings at the posttreatment tolerance level, groups with a rationale (OPR and DP) reported diminished heat pain intensity (t(146) = -2.15, P = 0.033, d = 0.43) and unpleasantness ratings (t(146) = -2.43, P = 0.016, d = 0.49) compared with the OPR-group. Interestingly, the OPR and the DP groups did not significantly differ in heat pain intensity (t(146) = -1.10, P = 0.272) or unpleasantness ratings (t(146) = -0.05, P = 0.961) at the posttreatment tolerance level. Our findings reveal that placebos with a plausible rationale are more effective than without a rationale. Even more, open-label placebos did not significantly differ in their effects from DPs. Therefore, we question the ubiquitously assumed necessity of concealment in placebo administration. PMID- 28708767 TI - Long-term Patient-reported Outcomes After Laparoscopic Fenestration of Symptomatic Liver Cysts. AB - BACKGROUND: Laparoscopic fenestration is the treatment of choice for symptomatic liver cysts. Despite the benefits of minimally invasive surgery, there is limited data on long-term outcomes after laparoscopic fenestration, in terms of symptom recurrence and quality of life. The purpose of this study was to evaluate long term patient-reported outcomes and satisfaction following this procedure. METHODS: All patients who underwent laparoscopic liver cyst fenestration in a single center between 2001 and 2012 were identified from a prospectively maintained database. Long-term patient-reported outcomes including symptom relief and quality of life were prospectively evaluated by a structured telephone interview. RESULTS: A total of 98 patients underwent laparoscopic liver cyst fenestration. The median follow-up was 62 months (range, 22 to 173 mo). Follow-up data was available in 48 patients. Four patients developed radiologically confirmed evidence of recurrence with 3 undergoing further surgery. No mortality was reported in the series. Four complications occurred and the median postoperative length of hospital stay was 2 days (range, 1 to 7 d). Thirty-nine patients received immediate symptomatic relief with 98% reporting long-term satisfaction. RESULTS: Laparoscopic liver cyst fenestration is associated with low morbidity and long-term alleviation of symptoms. This should be considered the treatment modality of choice in managing patients with nonparasitic cysts. PMID- 28708768 TI - Transcranial Cerebral Oxymetric Monitoring Reduces Brain Hypoxia in Obese and Elderly Patients Undergoing General Anesthesia for Laparoscopic Cholecystectomy. AB - The aims of this prospective, observational study were to evaluate the changes of the regional cerebral saturation (rSO2) measured by near-infrared spectroscopy during elective laparoscopic cholecystectomy under total intravenous anesthesia and the association between patient's characteristics and critical decline of rSO2. Hemodynamics, rSO2, and oxygen saturation were recorded in different time points: before the anesthesia (Tbas), 2 minutes after the induction (supine position) (Tind), 2 minutes after CO2 insufflation (supine) (TCO2), 10 minutes after CO2 insufflation (reverse Trendelenburg) (TrevT), and 2 minutes after deflation (supine) (Tpost). Average age was 53+/-13 (range: 22 to 79 y). In 12 of a total of 62 patients (19.4%) the rSO2 decreased >20% (20.5% to 28.4%) in TCO2 or TrevT times. Significantly higher decrease of the rSO2 was found in patients older than 65 years and those with body mass index >30 kg/m (P<0.05). Noninvasive monitoring of cerebral oxygenation could be an important part of perioperative care in obese and older patients. PMID- 28708769 TI - A National Survey on Peri-interventional Management of Percutaneous Transhepatic Biliary Drainage. AB - PURPOSE: The purpose of this study is to evaluate knowledge about management of percutaneous transhepatic biliary drainage (PTBD) catheters among nurses taking care of hepato-pancreato-biliary (HPB) patients. METHODS: Six HPB nurses from the Dutch national HPB association created a questionnaire that was complemented by 2 HPB surgeons, 3 HPB interventional radiologists, and a methodologist. Registered nurses working at the department of gastroenterology or gastrointestinal surgery and familiar with the care for HPB patients were invited to complete the questionnaire. RESULTS: In total 120 completed questionnaires from Dutch nurses were returned. The responders were working in 38 of 64 different hospitals. About half of the respondents considered their own knowledge insufficient, which was reflected in the response to the specific questions concerning the PTBD procedure, and 70% rated the knowledge of their immediate nursing colleagues as insufficient. Less than 50% of the respondents knew whether antibiotic prophylaxis or "pain medication" was required before PTBD procedure. Only a few respondents were aware of the existence of a hospital protocol for PTBD management and its content. CONCLUSIONS: Nursing care for biliary catheters is not standardized nationwide, and consensus on management is lacking. An evidence based guideline for PTBD management is advised for nursing care of patients with HPB diseases. PMID- 28708770 TI - Laparoscopic Appendectomy for Complicated Acute Appendicitis in the Elderly: A Single-center Experience. AB - BACKGROUND: The use of laparoscopic appendectomy for complicated acute appendicitis remains controversial in the elderly. This study aimed to compare the postoperative outcomes of elderly patients who received either laparoscopic appendectomy or open appendectomy. PATIENTS AND METHODS: A single-centre retrospective analysis of the clinical records of elderly patients (age, above 65 y) who underwent operations from January 2012 to November 2015 was performed. Demographic data, intraoperative variables, length of stay, and surgical complications were retrieved. RESULTS: A total of 145 elderly patients were preoperatively diagnosed with acute appendicitis. There were 43 (29.66%) complicated and 102 (70.34%) uncomplicated appendicitis cases. A total of 65 (44.83%) procedures were performed using the open technique (OA group) and 80 (55.17%) using the laparoscopic technique (LA group). In the laparoscopic group, 19 (23.75%) patients had complicated acute appendicitis (CLA group), and 61 (76.25%) had uncomplicated acute appendicitis (UCLA group). In the complicated group, 19 (44.19%) patients underwent operation using the laparoscopic technique (CLA group) and 24 (55.81%) using the open technique (COA group). There were no significant differences between the LA and OA groups in terms of age, sex distribution, duration of symptoms, American Society of Anesthesiologists score, white blood cells, complicated appendicitis, operation time, drain apposition, days to resumption of liquids, and postoperative complications (P>0.05). Significant differences were found in days to start walking and days to resumption of solids in the LA group (P<0.05). The OA group had a longer length of hospital stay than the LA group (P<0.05). Postoperative complications were not significantly different between the groups (P>0.05). The CLA group had a significantly longer duration of symptoms, operation times, days to resumption of liquids, and days to resumption of solids than the UCLA group (P<0.05). The COA group had significantly longer days to walking and hospital stays than the CLA group (P<0.05). CONCLUSIONS: Our study demonstrated that using LA to treat complicated acute appendicitis in the elderly was not associated with additional surgical complications. Therefore, it seems feasible to use LA as a safe technique for complicated acute appendicitis in the elderly. PMID- 28708772 TI - Successful Laparoscopic Harvesting of Omental Pedicle Flap for Salvage Cerebral Revascularization in 2 Adults With Moyamoya Disease: Technique and Lessons Learned. AB - Moyamoya is an idiopathic and progressive disease that leads to occlusion of intracranial arteries. When other methods of revascularization fail, omentum can be used as an indirect bypass to improve cerebral perfusion. Laparoscopic mobilization of a pedicled omental flap with subcutaneous tunneling to the brain has been described in small case series in children. We report our techniques and outcomes in 2 adults with Moyamoya to undergo such a procedure. An omental flap based on the right gastroepiploic artery was created and intraoperative fluorescence imaging using indocyanine green was used to assess the viability of the flap and to guide lengthening of the pedicle. The flap was tunneled subcutaneously using skip incisions. There were no intraoperative complications and no postoperative complications related to the omental flap. Follow-up evaluation demonstrates viable omental flaps and improved cerebral vascularization. This technique is feasible in adults who require salvage cerebral revascularization for Moyamoya disease. PMID- 28708771 TI - Effect of Clonidine on Hemodynamic Responses During Laparoscopic Cholecystectomy: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Clonidine might be beneficial to the patients undergoing laparoscopic cholecystectomy. This meta-analysis focused on the influence of clonidine on hemodynamic responses in patients undergoing laparoscopic cholecystectomy. METHODS: We searched several databases including PubMed, EMbase, Web of science, EBSCO, and Cochrane library databases. This meta-analysis included randomized controlled trials regarding the influence of clonidine versus placebo on laparoscopic cholecystectomy. The primary outcomes were mean arterial pressure (MAP) and heart rate (HR) at pneumoperitoneum. The random-effect model was applied for this study. RESULTS: Compared with control intervention, clonidine intervention was found to significantly reduce the MAP at pneumoperitoneum [standard mean difference=-2.58; 95% confidence interval (CI),-4.63 to -0.53; P=0.01), HR at pneumoperitoneum (standard mean difference=-3.67; 95% CI, -6.57 to -0.76; P=0.01), MAP at intubation (standard mean difference=-2.40; 95% CI, -4.75 to -0.06; P=0.04), HR at intubation (standard mean difference=-3.39; 95% CI, 5.75 to -1.02; P=0.005), propofol requirement (standard mean difference=-2.25; 95% CI, -4.01 to -0.48; P=0.01), as well as postoperative nausea and vomiting (risk ratio, 0.35; 95% CI, 0.19-0.63; P=0.0005). CONCLUSIONS: Compared with control intervention, clonidine intervention was found to significantly reduce MAP and HR at pneumoperitoneum and intubation, propofol requirement, as well as postoperative nausea and vomiting in patients undergoing laparoscopic cholecystectomy. PMID- 28708773 TI - Angiotensin II responsiveness after preeclampsia: translational data from an experimental rat model and early-onset human preeclampsia. AB - OBJECTIVE: Formerly preeclamptic women have an increased risk for cardiovascular and renal disease later in life. It is unknown which mechanisms contribute to this increased risk and whether this is induced by preeclampsia or by prepregnancy factors. We hypothesized that the increased risk for cardiovascular disease is partly due to an increased angiotensin II (ang II) responsiveness postpartum and that preeclampsia itself is involved in inducing this increased ang II responsiveness. METHODS: In never-pregnant, formerly healthy pregnant rats and rats with former experimental preeclampsia [experimental preeclampsia model induced by low-dose endotoxin infusion on day 14 of pregnancy; endotoxin-infused pregnant rats (EP-rats)], ang II responsiveness was studied by measuring changes in blood pressure (BP) and proteinuria after chronic ang II infusion with osmotic minipumps (200 ng/kg per min). In addition, we measured BP and responses to ang II (0.3, 1.0 and 3.0 ng/kg per min) in 18 formerly early-onset preeclamptic, without comorbidities, and 18 formerly healthy pregnant women (controls). RESULTS: In rats, a significantly higher systolic BP at termination was observed in formerly EP-rats vs. never-pregnant rats after ang II infusion (159.5 +/- 29.5 vs. 136.7 +/- 16.8; P = 0.049). In response to ang II, there was a significant increase in proteinuria in formerly EP-rats vs. healthy pregnant and never pregnant rats (P < 0.01 for both). In humans, 1.0 ng/kg per min ang II showed a trend towards an increased mean arterial BP response in formerly preeclamptic women vs. controls (P = 0.057). CONCLUSION: Our data show an increased ang II responsiveness following (experimental) preeclampsia and support a role for preeclampsia itself in altered ang II responsiveness postpartum. PMID- 28708774 TI - Identifying unilateral disease in Chinese patients with primary aldosteronism by using a modified prediction score. AB - OBJECTIVE: The current study aimed to evaluate the role of Kupers' score in predicting unilateral aldosteronism, and develop a modified score in Chinese patients with primary aldosteronism. METHODS: The current retrospective study included 406 patients with primary aldosteronism who underwent successful adrenal venous sampling (AVS) and were divided into the unilateral (n = 211) and bilateral (n = 195) groups according to the AVS results. Normokalemia was noted in both the unilateral (n = 64) and bilateral groups (n = 84) when plasma and urinary aldosterone were measured. RESULTS: We evaluated Kupers' prediction score, which had the best cutoff value at four points [area under the curve, 0.601 (95% confidence interval 0.551-0.650); specificity, 53%; sensitivity, 62%]. Then, we modified this score by using urinary aldosterone level quartiles, history of hypokalemia, and typical adenoma more than 10 mm on computed tomography (CT) [area under the curve, 0.745 (95% confidence interval 0.667 0.813)]; sensitivity, 45.3%; specificity, 90.5%). The best cutoff value to discriminate unilateral from bilateral disease was a score of 5. This modified prediction score only applied to patients who were normokalemic when urinary aldosterone was measured. A specificity of 100% was achieved at a score of 6 for patients aged 40 years or less, and 5 when the adrenal lesion was on the right side on CT imaging. CONCLUSION: Kupers' prediction score is not suitable for our patients. Urinary aldosterone levels combined with a history of hypokalemia are useful to discriminate unilateral from bilateral aldosteronism in patients with typical adenoma on the right adrenal gland on CT or in patients 40 years old or less. PMID- 28708775 TI - Continuous Cardiac Autonomic and Hemodynamic Responses to Isometric Exercise. AB - PURPOSE: Elevated arterial blood pressure (BP) is associated with autonomic dysfunction and impaired hemodynamic control mechanisms. Isometric exercise (IE) training has been demonstrated effective at reducing BP; however, the continuous cardiovascular responses during IE are underinvestigated. We hypothesized that reflex autonomic cardiovascular control is an important mediator in reducing BP. To test our hypothesis, we investigated continuous cardiac autonomic modulation and baroreceptor reflex sensitivity (BRS) in response to IE. METHODS: Twenty-five prehypertensive participants performed a single IE wall squat training session. Total power spectral density (PSD) of HR variability (HRV) and associated low frequency (LF) and high-frequency (HF) power spectral components were recorded in absolute (ms) and normalized units (nu) before, during, and after an IE session. HR was recorded via electrocardiography and BRS via the sequence method. Continuous BP was recorded via the vascular unloading technique and stroke volume via impedance cardiography. Total peripheral resistance was calculated according to Ohm's law. RESULTS: During IE, there were significant reductions in HRV (P < 0.05) and BRS (P < 0.05) and significant increases in HR (P < 0.001), systolic, diastolic, and mean BP (all P < 0.001). In recovery from IE, HRV (P < 0.001), HFnu (P < 0.001), and BRS (P < 0.001) significantly increased with a significant decrease in LFnu (P < 0.001) and LF:HF ratio (P < 0.001), indicative of predominant parasympathetic over sympathetic activity. This autonomic response was associated with a significant reduction in systolic (23.2 +/- 18.1 mm Hg, P < 0.001), diastolic (18.7 +/- 16.9 mm Hg, P < 0.001), and mean (15.8 +/- 15.5 mm Hg, P < 0.001) BP, below baseline and a significant reduction in total peripheral resistance (P < 0.001). CONCLUSIONS: A single IE session is associated with improved cardiac autonomic modulation and hemodynamic cardiovascular control in prehypertensive males. These acute responses may be mechanistically linked to the chronic reductions in resting BP reported after IE training interventions. PMID- 28708776 TI - Sex-Specific Maximum Predicted Heart Rate and Its Prognosis for Mortality and Myocardial Infarction. AB - PURPOSE: Maximum predicted heart rate (MPHR) is traditionally calculated by (220 age). However, this formula's validity has been questioned in women. The purpose of this study was to derive sex-specific formulas for MPHR in a clinical population and compare their prognostic significance with the traditional formula. METHODS: This was a retrospective cohort of adults referred for exercise treadmill testing between 1991 and 2009. Peak heart rate versus age was plotted by sex, and linear regression analysis was used to derive sex-specific MPHR formulas. Cox models were used to calculate risk of death and myocardial infarction (MI) based on attainment of 85% MPHR using both formulas. RESULTS: Of 31,090 patients (mean +/- SD, age = 55 +/- 10 yr), there were 2824 deaths over 11 +/- 5 yr. MPHR was best estimated by 197 - 0.8 * age for women and 204 - 0.9 * age for men (P interaction < 0.001). Compared with the sex-specific formulas, the traditional formula overestimated peak heart rate by 12 +/- 2 bpm in women and 11 +/- 1 bpm in men. There were 1868 patients (6%) who achieved the target heart rate using the sex-specific formulas but not with the traditional formula. Achievement of >=85% MPHR was similarly associated with lower risk of death (adjusted hazard ratio = 0.76 [95% confidence interval = 0.60-0.97] vs 0.75 [0.62 0.90]) and MI (0.71 [0.47-1.06] vs 0.79 [0.57-1.10]) for the sex-specific versus traditional formula. CONCLUSIONS: In patients referred for exercise treadmill testing, sex-specific formulas more accurately estimated peak heart rate than the traditional MPHR formula, reclassified 6% of stress tests from inadequate to adequate, and were similarly associated with risk of MI and death. PMID- 28708777 TI - Intraoperative Topical Antibiotics for Infection Prophylaxis in Pelvic and Acetabular Surgery. AB - OBJECTIVES: To determine if topical vancomycin and tobramycin powder reduces the incidence of surgical site infection after pelvic ring and acetabulum fracture surgery. DESIGN: Retrospective cohort study. SETTING: University of Alabama at Birmingham, Academic Level I Trauma Center. PATIENTS/PARTICIPANTS: Two hundred nineteen patients (140 meeting inclusion criteria) with pelvic and acetabular fractures who underwent open reduction and internal fixation from March 2012 to November 2013. INTERVENTION: One gram vancomycin and 1.2 g tobramycin powder applied deep in the surgical wound of the treatment group. MAIN OUTCOME MEASUREMENTS: Postoperative infection rate. RESULTS: One hundred forty patients were included. Control group (n = 69) and treatment group (n = 71) were similar for sex, age, ethnicity, and body mass index. There was no difference between groups with regards to renal function postoperative day 2 (P = 0.24). The risk of infection was 14.5% and 4.2% (P = 0.04) for the control and treatment groups, respectively. No significant effect of antibiotic treatment was observed overall after adjusting for EBL (odds ratio 0.20, 95% confidence interval, 0.02-1.06). Of note, a nonsignificant 71% increase was observed among those with >=1 L EBL (odds ratio 1.71, 95% confidence interval, 0.02-147.02). CONCLUSIONS: Topical antibiotics possibly reduce the incidence of surgical site infection after open pelvic and acetabulum fixation without increasing risk of renal impairment. The protective effect of topical antibiotics may be limited to patients with minimal intraoperative blood loss. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 28708778 TI - Radiographic Investigation of the Distal Extension of Fractures Into the Articular Surface of the Tibia (The RIDEFAST Study). AB - OBJECTIVE: To determine whether radiographic measurements are predictive of involvement of the distal tibia articular surface in tibial shaft fractures. DESIGN: Retrospective review. SETTING: Academic Level-I trauma hospital. PATIENTS: Two-hundred seventeen patients with tibial shaft fractures distal to the isthmus (OTA/AO: 42-A1-3; 42-B1-3; 42-C1-3; and 43-A1-3). INTERVENTION: Analysis of anteroposterior (AP) and lateral radiographs. The following parameters were measured: (1) angle between the predominant fracture line and the plane of the tibial plafond (alpha-angle), (2) length of the shaft fracture, (3) distance from the most inferior extent of the shaft fracture to the tibial plafond (DTP), (4) width of the tibial plafond, (5) width of the tibial isthmus, (6) ratio of fracture length to DTP (FTP), and (7) fibular fracture distance. MAIN OUTCOME MEASURE: Distal intra-articular involvement (DIA). RESULTS: A total of 217 patients were identified, 56 (26%) with DIA. The FTP ratio as measured on both the AP (odds ratio: 8.20, confidence interval, 4.26-17.22, P < 0.0001) and lateral radiographs (10.00, 4.78-23.23, <0.0001) was the most effective screening measurement for DIA. AP and lateral FTP ratios of 0.224 and 0.255, respectively, achieved a negative predictive value of 100%, eliminating the need for computed tomography in 16%-23% of injuries. CONCLUSION: Involvement of the distal articular surface in patients with distal tibial shaft fractures is significantly associated with fracture geometry and pattern. The FTP ratio may be used as an effective screening tool to rule out of intra-articular involvement. LEVEL OF EVIDENCE: Diagnostic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 28708779 TI - Midshaft Fractures of the Clavicle: A Meta-analysis Comparing Surgical Fixation Using Anteroinferior Plating Versus Superior Plating. AB - OBJECTIVE: To compare the outcomes of clavicle fracture fixation using anteroinferior versus superior plate placement. METHODS: We performed a meta analysis of studies that have reported on outcomes after superior or anteroinferior plate fixation for acute midshaft clavicle fractures (Orthopaedic Trauma Association 15-B). A computerized literature search in the Pubmed, Scopus, and Cochrane Library databases was used to identify relevant articles. Only full text articles without language restrictions were evaluated. The inclusion criteria consisted of: (1) fracture of the midshaft clavicle; (2) surgery for acute fractures (within 1 month of the fracture); (3) adult patients (16 years of age and older); and (4) open reduction and internal fixation with plate application in either the anteroinferior or superior position. Studies were excluded if they did not specify plate location, evaluated multitrauma patients, investigated minimally invasive procedures, or studied operations for revision, nonunion, malunion, or infection. The primary measured outcomes were symptomatic hardware (implant prominence or irritation) and surgery for implant removal. The secondary outcomes were time to union, fracture union, nonunion, malunion, Disabilies of the Arm, Shoulder and Hand score, Constant score, and implant failure. Frequencies and proportions of cases were recorded for binary outcomes, whereas mean and standard deviations were recorded for continuous outcomes. Other summary statistics provided were used to impute mean and standard deviations under the assumption of normality when these were not reported. Continuous outcomes were compared between groups using linear mixed effects models, whereas binary outcomes were compared using mixed effects logistic regression models, including fixed group effects and random study effects. P-values less than 0.05 were considered statistically significant. All analyses were performed using SAS v. 9.4 (SAS Institute Inc, Cary, NC). RESULTS: A total of 1428 articles were identified among the 3 databases, of which 897 remained after removing duplicates. From that pool, 57 relevant studies were evaluated. Articles were excluded because of an inability to specify plate location (6), a subject pool not exclusively consisting of acute fractures (4) or midshaft fractures (2), a minimally invasive surgical approach (6), use of nonstandard plates (1), poor reporting of functional outcomes (2), and a duplicate group of patients (2). This left 34 articles to be used in the meta-analysis. Of these, 8 studies reported on patients with anteroinferior plating (N = 390) and 27 studies reported on patients with superior plating (N = 1104). No significant differences were found with respect to the functional shoulder scores (Disabilies of the Arm, Shoulder and Hand and Constant) between the 2 groups. There was no significant difference between each group for the probability of having a union (P = 0.41), malunion (P = 0.28), nonunion (0.29), or implant failure (P = 0.39). Patients in the superior plating group had a significantly higher probability of suffering from symptomatic hardware (0.17) as compared to patients in the anteroinferior plating group (0.08), (P = 0.005). In addition, the superior plating group had a significantly higher rate of surgery for implant removal (0.11 vs. 0.05), (P = 0.008). CONCLUSIONS: The findings of this investigation demonstrate that plating along the superior and anteroinferior aspects of the clavicle lead to similar operative outcomes with respect to union, nonunion, malunion, and implant failure, as well as similar functional outcomes scores. Plates applied to the superior aspect of the clavicle are associated with higher rates of symptomatic hardware and more frequent implant removal. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 28708780 TI - Syndesmotic Ankle Fractures. AB - OBJECTIVES: The diagnosis and treatment of syndesmotic ankle fractures is controversial. This systematic review was performed to clarify the current understanding addressing several clinical questions that arise in the treatment of such injuries. DATA SOURCES: The English language literature was searched using PubMed, EMBASE, and Web of Science. The search terms were "syndesmosis" or "syndesmotic" in combination with the terms "ankle fracture" or "fracture." The included dates were between 1967 and July 2015. STUDY SELECTION: Inclusion criteria were number of patients >20, patient age >=18 years, follow-up >=1 year, ankle fracture classification was reported, criteria for surgery was reported, technique of surgery was reported, and a validated outcome measure was used. Studies limited to biomechanical or imaging investigations were excluded. DATA EXTRACTION: Information was abstracted using a standardized template, which encompassed the inclusion criteria together with the study type, postoperative regimen, and complications. Study quality was evaluated using the modified CONSORT statement and Coleman criteria. Study bias was assessed, and methodological quality was rated. Any difference in ratings was resolved by consensus. DATA SYNTHESIS: None. CONCLUSIONS: The overall quality of the studies was poor. The number or placement of syndesmotic screws or the breakage of trans syndesmotic screws postoperatively had no adverse effect on outcomes (both with moderate strength of evidence). The use of alternative fixation devices (bioabsorbable and endobutton) had poor strength of evidence, as did the opinion that nondisplaced, unstable by stress test, syndesmotic injuries required fixation. There are insufficient data that link subtle rotational syndesmotic malreduction to clinical outcomes. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 28708781 TI - Fracture Site Mobility at 6 Weeks After Humeral Shaft Fracture Predicts Nonunion Without Surgery. AB - OBJECTIVES: To assess the presence of fracture site gross motion on physical examination to predict humeral shaft fracture progression to nonunion in patients managed nonoperatively. DESIGN: Retrospective cohort study. SETTING: Single trauma level 1 institutional center. PATIENTS: Eighty-four consecutive patients undergoing nonoperative treatment of a diaphyseal humeral shaft fracture were identified. The average age of the population was 48.3 years, and 50% of the cohort was men. INTERVENTION: Clinical examination for fracture stability was routinely performed on patients by the treating physicians and documented it in the medical record. Patients were followed until union or surgery for persistent fracture mobility. MAIN OUTCOME MEASUREMENTS: Stability was graded if there was motion at the site (1: motion of any kind and 0: moved as a unit). RESULTS: Seventy-three patients (87%) healed their fracture within our study cohort by 6 months postfracture. Of the remaining 11 patients, after discussion with their treating physicians about the option of surgical intervention, 8 chose to undergo open reduction internal fixation at an average of 8 months, 1 proceeded nonsurgical interventions, and 2 were lost of follow-up. If the humeral shaft fracture site was mobile at 6 weeks follow-up visit, it identified future fracture nonunion with 82% sensitivity and 99% specificity (only 1 patient with motion at 6 weeks proceeded to fracture union). CONCLUSION: With a high negative predictive value, clinical examination of fracture motion at 6 weeks should be assessed in every patient to determine which patients should obtain closer follow up for the risk of nonunion progression. Knowledge of gross fracture motion can be used in the shared decision-making model in counseling about early surgical options. LEVEL OF EVIDENCE: Diagnostic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 28708782 TI - Outcomes of Distal Femur Nonunions Treated With a Combined Nail/Plate Construct and Autogenous Bone Grafting. AB - In this study, we sought to retrospectively evaluate union and infection rates after treatment of distal femur nonunions using a combined nail/plate construct with autogenous bone grafting obtained from the ipsilateral femur using a reamer irrigator aspirator system. Ten (10) patients treated at a Level I trauma center for nonunion of a femoral fracture using a combined nail/plate construct from 2004 to 2014 were included in the study. Union rate and postoperative infection rates were recorded. Mean interval from index surgery to nonunion repair was 12 months (range 4-36 months). Follow-up at 24 months indicated that the entire cohort of 10 patients achieved clinical union and radiographic union based on radiograph union score in tibias (RUST) criteria. Treatment of distal femur nonunions with a combined nail/plate construct and autogenous bone grafting results in a high rate of union with a low complication rate. PMID- 28708783 TI - What'S New in SHOCK, AUGUST 2017? PMID- 28708784 TI - Apoptotic Diminution of Immature Single and Double Positive Thymocyte Subpopulations Contributes to Thymus Involution During Murine Polymicrobial Sepsis. AB - To generate and maintain functional T-cell receptor diversity, thymocyte development is tightly organized. Errors in this process may have dramatic consequences, provoking, for example, autoimmune diseases. Probably for this reason, the thymus reacts to septic stress with involution, decreasing the numbers of thymocytes. Because it is still unclear which thymocyte subpopulation contributes to thymus involution and whether thymocyte emigration is altered, we were interested to clarify this question in detail. Here, we show, using the cecal ligation and puncture (CLP) mouse model of polymicrobial sepsis, that predominantly immature thymocytes are reduced. The number of immature single positive thymocytes was most marked diminished (CLP: 6.54 * 10 +/- 3.79 * 10 vs. sham: 4.54 * 10 +/- 7.66 * 10 cells/thymus [24 h], CLP: 2.60 * 10 +/- 2.14 * 10 vs. sham: 2.17 * 10 +/- 1.90 * 10 cells/thymus [48 h]), and was consequently associated with the highest rate of apoptosis (8.4 [CLP] vs. 2.2% [sham]), the reduction in double positive thymocytes being associated with a smaller apoptotic response (number, CLP: 2.33 * 10 +/- 1.38 * 10 vs. sham: 1.07 * 10 +/- 2.72 * 10 cells/thymus [24 h], CLP: 2.34 * 10 +/- 9.08 * 10 vs. sham: 3.5 * 10 +/- 9.62 * 10 cells/thymus [48 h]; apoptosis: 2.5% [CLP] vs. 0.7% [sham]). Analysis of T cell receptor excision circles revealed that the emigration of mature thymocytes was not inhibited. Real-time qPCR analysis revealed upregulation of pro-apoptotic Bim expression and suggested interference between Notch receptor expression on thymocytes and the respective ligands on thymic stromal cells during CLP dependent sepsis, which might be responsible for the altered thymocyte viability in CLP-dependent sepsis. PMID- 28708785 TI - Y Box-Binding Protein 1 Promotes Epithelial-Mesenchymal Transition, Invasion, and Metastasis of Cervical Cancer via Enhancing the Expressions of Snail. AB - OBJECTIVE: Y box-binding protein 1 (YB-1) is a potent oncogenic protein. How it regulates Snail in most tumors including cervical cancer is unknown. This article is to study if YB-1 plays a role in cervical cancer via regulating the expression of Snail. METHODS: Immunohistochemical staining of YB-1, Snail, and E-cadherin (E cad) was performed on tissue specimens including 35 cases of chronic cervicitis (as a control), 35 cases of cervical intraepithelial neoplasm (CIN) I, 35 cases of CIN II/III, 28 cases of unmetastatic cervical squamous cell carcinoma, and 19 cases of metastatic cervical squamous cell carcinoma. RNA interference technique was used to knock down YB-1, E6, and Snail genes. Quantitative polymerase chain reaction, western blot, and transwell experiment were used to detect RNA, protein, and cell invasion of cervical cancer cell lines Hela and C33A, respectively. RESULTS: First, YB-1 knockdown significantly reduced messenger RNA (mRNA) and protein levels of Snail, followed by the increased mRNA and protein levels of E-cad and the decreased invasive ability in both Hela (human papillomavirus [HPV] 18+) and C33A (HPV-) cell lines. Second, YB-1 and Snail protein were correlatively expressed in the group order of metastatic cervical squamous cell carcinoma > unmetastatic cervical squamous cell carcinoma > CINs > cervicitis, with the inverse expression mode of E-cad in the group order, P value less than 0.01, between any 2 groups. Finally, HPV18 E6 knockdown reduced the mRNA and protein levels of YB-1 and Snail in Hela cells. CONCLUSIONS: The results firstly reported that YB-1 whose mRNA expression is regulated by HPV18 E6 promotes epithelial-mesenchymal transition and progression of cervical cancer via enhancing the expressions of Snail, which indicated that YB-1/Snail/epithelial mesenchymal transition axis could have a potential use in the diagnosis and therapy of cervical cancer metastasis as a cancer marker and molecular target. PMID- 28708786 TI - Venous Thromboembolism in Patients Receiving Extended Pharmacologic Prophylaxis After Robotic Surgery for Endometrial Cancer. AB - OBJECTIVE: This study aims to determine the rate of postoperative venous thromboembolism (VTE) in endometrial cancer patients undergoing robotic hysterectomy with or without extended pharmacologic VTE prophylaxis. METHODS/MATERIALS: A retrospective chart review of women undergoing robotic hysterectomy with or without other procedures for endometrial cancer from January 2010 to February 2015 was conducted at 2 institutions. Charts were manually abstracted, and rates of VTE within 30 and 60 days after surgery were determined. Patients were then stratified by those who did and did not receive extended VTE prophylaxis. RESULTS: A total of 403 patients were included, of which 367 patients (91%) received extended pharmacologic prophylaxis and 36 patients (9%) did not. Low molecular weight heparin prescriptions ranged from 7 to 30 days. Patients receiving extended prophylaxis (EP) were older (63 +/- 11 vs 57 +/- 12; P = 0.004), more frequently underwent lymphadenectomy (67% vs 34%; P < 0.001), and had higher-grade tumors compared with patients not receiving EP. Overall 30 day and 60-day VTE rates were 0.7% and 1.2%, respectively. There were no significant differences in 30-day and 60-day VTE rates among patients that did and did not receive EP, although a trend toward lower VTE rates in the EP group was observed (30-day rates 0.5% vs 2.8% respectively, P = 0.25; 60-day rates 0.8% vs 5.6%, P = 0.07). CONCLUSIONS: In this study, 30-day and 60-day VTE rates after minimally invasive surgery for endometrial cancer were low. Rates were also similar to those of previous reports in this setting in which the majority of patients did not receive extended VTE prophylaxis. Given the consistent finding that postoperative VTE in this population is rare regardless of prophylaxis use and the variability in practice patterns for VTE prophylaxis, the development of best practice guidelines for EP use specific to this setting is warranted. PMID- 28708787 TI - Factors Contributing to the Low Survival Among Women With a Diagnosis of Invasive Cervical Cancer in Ghana. AB - : : Cervical cancer is one of the most common cancers among women worldwide, and more than 85% of the disease occurs in low- and middle-income countries. Although it ranks as the most common cancer in Ghanaian women, there are no data available on cervical cancer survival. METHODS: Information on women with a diagnosis of cervical cancer from 2010 to 2013 was collected from the Komfo Anokye and Korle Bu Teaching Hospitals through review of paper-based and electronic medical records (including pathology records) at the oncology units and the departments of obstetrics and gynecology. Telephone interviews were conducted with patients and relatives to gather further information. Data were recorded using a standardized questionnaire and analyzed using summary statistics. RESULTS: Information for 821 women was available for the survival analysis. Of these, 497 (60.5%) died during follow-up. At 3 years after diagnosis, survival was 39%. Survival was lowest in women with stage IV disease. Women with squamous cell carcinoma had a survival advantage over those with adenocarcinoma. Furthermore, women who received surgery, radiotherapy, and chemotherapy had better survival than did women with other forms of treatment. CONCLUSIONS: In conclusion, cervical cancer survival is low in Ghana and is likely to be improved if a greater proportion of the disease is detected early. Improving knowledge of the disease for early diagnosis, reducing financial barriers, and greater organization of health care delivery are likely to improve survival from cervical cancer in Ghana. PMID- 28708788 TI - Therapy Modalities, Prognostic Factors, and Outcome of the Primary Cervical Carcinosarcoma: Meta-analysis of Extremely Rare Tumor of Cervix. AB - OBJECTIVE: The aim of this study was to evaluate the prognostic factors, treatment options, and survival outcomes of primary carcinosarcomas of the uterine cervix. METHODS: An electronic search of the literature was conducted from 1951 to February 2017 to identify articles on primary cervical carcinosarcoma. After comprehensive evaluation of case series and case reports, 81 cases were included in the study. RESULTS: The most common clinical FIGO (International Federation of Gynecology and Obstetrics) stage was IB at 53% of cases. Median follow-up time was 15 months (range, 1.75-156 months). Two-year disease-free survival (DFS) and overall survival (OS) of the entire cohort were 49% and 60%, respectively. Both 2-year DFS and OS were significantly higher in patients with stage I than in those with stage II disease or greater (73% vs 22%, P = 0.000 and 82% vs 33%, P = 0.000, respectively). Two-year OS was 17% for patients who received primary radiotherapy, whereas it was 68% for those who underwent only surgery (P = 0.003). Surgery followed by adjuvant radiotherapy with or without chemotherapy was significantly associated with improved DFS and OS compared with primary radiotherapy. Two-year DFS was 63% in patients who underwent primary surgery, whereas it was 100% in patients treated with primary surgery followed by adjuvant radiotherapy with chemotherapy (P = 0.030). Stage alone was an independent prognostic factor for risk of both recurrence and death (hazard ratios, 9.8 [P = 0.004] and 14 [P = 0.018], respectively). CONCLUSIONS: In due course of presentation, the tumor stage has a great importance because it is the only independent factor for prognosis. Surgery followed by adjuvant radiotherapy with or without chemotherapy seems to be related with better OS and DFS. PMID- 28708789 TI - Letter to the Editor on "Management of Para-aortic Lymph Node Disease in Patients With Cervical Cancer": What is the Best Approach? Int J Gynecol Cancer. 2017 Mar; 27(3): 543549. PMID- 28708790 TI - Trends of Gynecological Cancers in Turkey: Toward Europe or Asia? AB - OBJECTIVE: The aim of this study was to evaluate nationwide gynecological cancer trends in Turkey. METHODS: National cancer registry data (2009-2013) of Turkish Ministry of Health were evaluated. Ovarian, cervical, endometrial, vulvar, vaginal, and tubal cancers are evaluated with respect to age of diagnosis, incidence rates within years, stage, histological distributions, and mortality rates. Data were collected from active cancer registry centers, which increased from 23% in 2009 to 47.5% coverage of the whole population by 2012, and mortality data (2010-2015) were obtained from the Turkish Statistical Institute. RESULTS: A total of 16,023 gynecological cancers were evaluated among 116,940 female patients with cancer (13.7%). Average incidence for gynecological cancers was 22.7 of 100,000, representing 8437 total new cases annually. Incidence changes within time were not statistically significant, when evaluated for each tumor type. Estimated risk of gynecological cancer development before the age of 80 years was 3.08% (95% confidence interval, 3.07-3.09). The most common gynecological cancers were uterine corpus cancers, which were followed by ovarian and cervical carcinomas. Ovarian and uterine cancer incidences were closer to European levels rather than Asian countries, whereas cervical cancer incidence was extremely low. Gynecological cancers constituted an important fraction of cancer-related mortality in women by comprising approximately 10.35% of cancer related deaths. Mortality rates due to gynecological cancers did not show a statistically significant increase within years. CONCLUSIONS: This is the first national cancer registry report to be published for gynecological cancers by the Turkish Governmental Department. As a result, Turkish gynecological cancer epidemiological data were consistent with the data obtained from European and developed countries rather than Asian countries, except for cervical cancer incidence, which is extremely low. PMID- 28708791 TI - Self-Reported Long-Term Autonomic Function After Laparoscopic Total Mesometrial Resection for Early-Stage Cervical Cancer: A Multicentric Study. AB - OBJECTIVES: This multicentric retrospective study investigates the early and long term self-reported urinary, bowel, and sexual dysfunctions in early-stage cervical cancer patients who submitted to laparoscopic total mesometrial resection (L-TMMR), total laparoscopic radical hysterectomy, vaginal-assisted laparoscopic radical hysterectomy, and laparoscopic-assisted radical vaginal hysterectomy. METHODS: Cervical cancer patients, FIGO (International Federation of Gynecology and Obstetrics) stage IA2-IB1/IIA1 who submitted to nerve-sparing radical hysterectomy were recruited. Pelvic functions were assessed within 30 days (early outcome) and 12 months after surgery (long-term outcome). RESULTS: Two hundred thirteen subjects receiving nerve-sparing radical hysterectomy were enrolled. Laparoscopic total mesometrial resection was performed in 46 patients (21.6%), total laparoscopic radical hysterectomy in 65 patients (30.5%), vaginal assisted laparoscopic radical hysterectomy in 54 patients (25.4%), and laparoscopic-assisted radical vaginal hysterectomy in 48 women (22.5%). Operative time was significantly lower in the L-TMMR group (240 minutes; range, 120-670 minutes; P = 0.001). The overall perioperative complication rate was 11.3%, with no statistically significant differences among the 4 groups. Stress incontinence and sensation of bladder incomplete emptying were detected, respectively, in 54 patients (25.6%) and 65 patients (30.7%) with a significantly lower prevalence among those in the L-TMMR group, which resulted, respectively, in 11.1% (P = 0.022) and 13.3% (P = 0.036). The prevalence rates of constipation, sensation of incomplete bowel emptying, and effort during evacuation were significantly higher among those in the L-TMMR group, resulting in, respectively, 37% (P = 0.001), 42.3% (P = 0.012), and 50% (P = 0.039). One hundred forty-nine patients (70%) were sexually active. Fifty-eight women (38.9%) reported low enjoyment, 83 women (55.7%) medium enjoyment, and 8 women (5.4%) reported high enjoyment, without statistically significant differences among the 4 groups. CONCLUSIONS: Laparoscopic total mesometrial resection is associated with improved long-term urinary autonomic functions and worse gastrointestinal autonomic outcome. Further larger prospective trials are needed to evaluate both the oncological and functional outcomes in order to establish the most appropriate surgical approach for early-stage cervical cancer patients. PMID- 28708793 TI - Patulous Eustachian Tube and Otitis Media With Effusion as Complications After Trigeminal Nerve Injury. AB - OBJECTIVES: To describe three patients of patulous Eustachian tube (pET) after trigeminal nerve injury and to demonstrate for the first time their magnetic resonance imaging (MRI) findings to hypothesize the mechanism of the pET after trigeminal nerve injury. PATIENTS: Three patients presented with autophony after trigeminal nerve injury caused by the removal of intracranial tumors. MAIN OUTCOME MEASURES: Clinical patient records, audiological data, and MRI. RESULTS: Each patient initially developed transient otitis media with effusion (OME) within a few months after surgery and subsequently developed pET. The MRI of the three patients when they developed pET demonstrated atrophy and fat infiltration of the muscles innervated by the mandibular branch of the trigeminal nerve. CONCLUSION: All three patients transiently manifested OME before pET was diagnosed. Based on the MRI findings and anatomical considerations, this chronological transition from OME to pET was speculated as an initial motor paralysis of the tensor veli palatini muscle, followed by volume decrease of the muscles in the vicinity of the ET due to denervation atrophy and fat infiltration, which resulted in ET closing failure. PMID- 28708792 TI - Can Preoperative CT Scans Be Used to Predict Facial Nerve Stimulation Following CI? AB - OBJECTIVES: 1) To determine the ability of preoperative computed tomography (CT) to predict facial nerve stimulation (FNS) after cochlear implantation (CI). 2) To recognize the limitations of CT in predicting FNS. STUDY DESIGN: Patient control study. SETTING: Tertiary care academic medical center. SUBJECTS: Adult patients with CI from 2003 to 2015. METHODS: Patients with severe FNS (n = 4) were compared with randomly selected CI patients (n = 28). Three blinded reviewers evaluated preoperative temporal bone CT scans to measure the distance from the labyrinthine segment of the facial nerve to the basal turn of the cochlea and attempted to predict whether or not the subject had FNS after CI. RESULTS: In total, 32 CT scans were evaluated representing 49 ears that underwent CI.The distances (mm) measured from the labyrinthine segment of the facial nerve to the basal turn of the cochlea in both the axial (0.3 +/- 0.3 versus 0.6 +/- 0.3) and coronal (0.4 +/- 0.2 versus 0.6 +/- 0.2) orientation were significantly different between the two groups (p = 0.0001 and p = 0.0034) respectively. The intraclass correlation coefficient demonstrated good (K > 0.7) reviewer correlation in both the reviewers' measurements and predictions. The sensitivity, specificity, positive predictive value, and negative predictive value for preoperative CT scans to predict FNS were 38.5, 85.1, 19.2, and 93.8% respectively. The reviewers were 23% accurate in predicting FNS. CONCLUSION: Based on a blinded retrospective patient-control study, CT scan measurements show a significantly reduced distance between the labyrinthine facial nerve and the basal turn of the cochlea in patients with FNS. However, it is difficult to predict who will have FNS based on these measurements. PMID- 28708794 TI - Position of the Internal Aperture of Vestibular Aqueduct in Patients With Enlarged Vestibular Aqueduct. AB - OBJECTIVE: To investigate the position of the internal aperture of vestibular aqueduct and its relationship to hearing level in patients with enlarged vestibular aqueduct (EVA). METHODS: The size of the common crus and the position of the internal aperture of vestibular aqueduct were compared among control subjects, EVA patients with and without other inner ear malformations. Auditory steady-state response thresholds were compared between EVA patients with different positions of internal apertures. RESULTS: The common crus in EVA patients was shorter than in control subjects (p < 0.05). The internal aperture of the vestibular aqueduct opened solely into the common crus in control subjects, simultaneously into the common crus and vestibule in almost 45% of EVA patients, solely into the common crus, and the vestibule in almost 30 and 25% of EVA patients, respectively. Auditory steady-state response thresholds at 2000 and 4000 Hz were higher in EVA patients whose internal apertures of vestibular aqueducts opened simultaneously into the common crus and vestibule than in those whose internal apertures opened solely into the common crus. CONCLUSION: The common crus is shorter in EVA patients than in control subjects. The internal aperture of the vestibular aqueduct opens solely into the common crus in control subjects. It opens simultaneously into the common crus and vestibule in almost half of the EVA patients. The EVA patients whose internal apertures of vestibular aqueducts open solely into the common crus may have better hearing than those whose internal apertures open simultaneously into the common crus and vestibule. PMID- 28708795 TI - Proposal of a Video-recording System for the Assessment of Bell's Palsy: Methodology and Preliminary Results. AB - HYPOTHESIS: To propose a new objective video-recording procedure to assess and monitor over time the severity of facial nerve palsy. BACKGROUND: No objective methods for facial palsy (FP) assessment are universally accepted. METHODS: The face of subjects presenting with different degrees of facial nerve deficit, as measured by the House-Brackmann (HB) grading system, was videotaped after positioning, at specific points, 10 gray circular markers made of a retroreflective material. Video-recording included the resting position and six ordered facial movements. Editing and data elaboration was performed using a software instructed to assess marker distances. From the differences of the marker distances between the two sides was then extracted a score. RESULTS: The higher the FP degree, the higher the score registered during each movement. The statistical significance differed during the various movements between the different FP degrees, being uniform when closing the eyes gently; whereas when wrinkling the nose, there was no difference between the HB grade III and IV groups and, when smiling, no difference was evidenced between the HB grade IV and V groups.The global range index, which represents the overall degree of FP, was between 6.2 and 7.9 in the normal subjects (HB grade I); between 10.6 and 18.91 in HB grade II; between 22.19 and 33.06 in HB grade III; between 38.61 and 49.75 in HB grade IV; and between 50.97 and 66.88 in HB grade V. CONCLUSION: The proposed objective methodology could provide numerical data that correspond to the different degrees of FP, as assessed by the subjective HB grading system. These data can in addition be used singularly to score selected areas of the paralyzed face when recovery occurs with a different timing in the different face regions. PMID- 28708796 TI - Significance of Endolymphatic Hydrops in Ears With Unilateral Sensorineural Hearing Loss. AB - OBJECTIVE: The purpose of this study was to investigate the existence of endolymphatic hydrops (EH) in affected and unaffected ears in patients with unilateral sensorineural hearing loss (SNHL) using contrast-enhanced magnetic resonance imaging (MRI), and to evaluate the significance of EH in various otological diseases. STUDY DESIGN: Retrospective study. SETTING: University hospital. METHODS: One hundred eighty-two ears from 91 patients with unilateral SNHL were studied. The endolymphatic space was evaluated using 3-Tesla MRI with gadodiamide hydrate. Imaging data about the degree of EH in the cochlea and vestibule were analyzed and compared between ears with various otological diseases. RESULTS: All affected ears with delayed endolymphatic hydrops had EH. In affected ears with definite Meniere's disease, cochlear EH was observed in all ears and vestibular EH in 93% of ears, and these rates were significantly higher in the affected than in the unaffected ears. EH was also observed in the cochlea and vestibule in 66% and 41%, respectively, of the affected ears with idiopathic sudden SNHL; however, these percentages did not differ significantly from those in the unaffected ears (52% and 38%, respectively). CONCLUSION: MRI showed that a high percentage of ears affected by Meniere's disease or delayed endolymphatic hydrops had EH. Further studies should evaluate the implications of EH in ears, especially in those with sudden SNHL, in terms of secondary or pre-existing EH. PMID- 28708797 TI - Role of Multislice CT Imaging in Predicting the Visibility of the Round Window in Pediatric Cochlear Implantation. AB - BACKGROUND: High-resolution computed tomography (HRCT) magnifies the role of preoperative imaging for detailed inner and middle ear anatomical information and enhances more efforts for better dependent correlation and measurements of round window (RW). OBJECTIVE: To find an applicable way by HRCT imaging for the prediction of the visibility of the RW during cochlear implantation (CI) surgery. METHODS: Five radiologic measurements were performed on the axial HRCT and these measurements were correlated with the degree of RW visibility after performing posterior tympanotomy during CI surgery. RESULTS: Sixty ears of 60 children were included in the current study. A significant correlation was found between the degree of RW visibility and the following: 1) the angle between RW, facial nerve (FN), and the coronal axis (p < 0.00001); 2) the vertical distance between RW and FN (p = 0.006552); and 3) FN location to the axis of cochlea (p = 0.000419). On the other hand, nonsignificant correlation was found between the degree of RW visibility and both of the facial recess width and the angle between axis of cochlea and external auditory canal (p = 0.941363 and p = 0.59036 respectively). CONCLUSION: The angle between RW, FN, and the coronal axis and the vertical distance between RW and FN are proportionate with the degree of surgical RW visibility in children during CI. In children, surgeons can depend on those two parameters in addition to the distance between FN location to the axis of cochlea in predicting the RW visibility rather than depending on the measurements related to the external auditory canal. PMID- 28708798 TI - The Nursing Performance Instrument: Exploratory and Confirmatory Factor Analyses in Registered Nurses. AB - BACKGROUND: The optimal performance of nurses in healthcare settings plays a critical role in care quality and patient safety. Despite this importance, few measures are provided in the literature that evaluate nursing performance as an independent construct from competencies. The nine-item Nursing Performance Instrument (NPI) was developed to fill this gap. PURPOSE: The aim of this study was to examine and confirm the underlying factor structure of the NPI in registered nurses. METHOD: The design was cross-sectional, using secondary data collected between February 2008 and April 2009 for the "Fatigue in Nursing Survey" (N = 797). The sample was predominantly dayshift female nurses working in acute care settings. Using Mplus software, exploratory and confirmatory factor analyses were applied to the NPI data, which were divided into two equal subsamples. Multiple fit indices were used to evaluate the fit of the alternative models. RESULTS: The three-factor model was determined to fit the data adequately. The factors that were labeled as "physical/mental decrements," "consistent practice," and "behavioral change" were moderately to strongly intercorrelated, indicating good convergent validity. The reliability coefficients for the subscales were acceptable. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: The NPI consists of three latent constructs. This instrument has the potentialto be used as a self-monitoring instrument that addressesnurses' perceptions of performance while providing patient care. PMID- 28708801 TI - Bone and Joint Infections. PMID- 28708802 TI - Characterization and Expansion of Autologous GMP-ready Regulatory T Cells for TREG-based Cell Therapy in Patients with Ulcerative Colitis. AB - BACKGROUND: A local imbalance between regulatory (Treg) and effector T cells is believed to play a major role in gut-specific inflammation, including ulcerative colitis (UC). Restoration of this balance through an adoptive Treg transfer is an attractive new treatment approach in patients who are refractory to current standard therapies. It was our goal to develop a Good Manufacturing Practices (GMP)-conform protocol for expansion of UC Treg cells as a rational backbone for future studies on Treg therapy in UC. METHODS: CD25 blood T cells derived from patients with UC were ex vivo expanded in the presence of IL-2, rapamycin, and anti-CD3/anti-CD28 expander beads using a GMP-conform protocol. Cells were subsequently assessed for stability and function. RESULTS: Patient-derived ex vivo rapamycin-expanded GMP-ready CD25 cells were polyclonal, hypomethylated at intron 1 of the FoxP3 locus, and suppressive in carboxyfluorescein succinimidyl ester-dilution assays against autologous peripheral blood-derived and allogeneic colon-derived responder cells. Function was mediated by soluble factors, including toxic granules. In addition to CD4 T cells, suppressive hypermethylated CD8 T-cell subsets were also induced during the expansion process. CONCLUSIONS: Patient-derived rapamycin-expanded CD25 cells are stable and functional, and as such, ready to serve in a phase I dose-escalation safety study in UC. PMID- 28708803 TI - Hydrodynamic IL10 Gene Transfer in Human Colon: Results from an "EX VIVO" Study with Potential Clinical Application in Crohn's Disease. AB - BACKGROUND: The aim of this work is to evaluate the efficacy of hydrodynamic venous IL10 gene delivery to "ex vivo" human colon segments and to determine its potential interest in Crohn's disease treatment. METHODS: Twenty human colon segments were obtained from surgical resections. Hydrodynamic transfection through the main vein of the pedicle with 50 mL of hIL10 plasmid (20 MUg/mL) solution was performed on 13 of them. Tissue sections were cultured and DNA, RNA, and protein copies were determined after 1, 2, and 4 days. Data obtained were compared with 6 nontransfected specimens. Finally, 1 specimen was injected with gold nanoparticles, and their distribution was examined under electron microscope. RESULTS: IL10 DNA levels were higher in treated tissues than in controls (P < 0.001), decreasing along time. The amount of hIL10 RNA was significantly increased in treated tissues when compared with controls (P = 0.001). The indexes of protein IL10 translation in treated groups were much higher (P < 0.001) than the basal production. The protein expression was higher in transfected tissue (10-50-fold, with respect to control tissue); this difference being established during the first hours and maintained during, at least, 4 days. With electron microscopy, we hardly observed large (15 nm) gold nanoparticles within the tissue, always in the submucosa. However, multiple small (4 nm) nanoparticles were observed within the cytoplasm of enterocytes in mucosa. CONCLUSIONS: Hydrodynamic procedure efficiently delivers the IL10 gene to the human colon, achieving levels of tissue protein expression high enough to mediate pharmacological effects with interest in controlling immune response in patients with Crohn's disease. PMID- 28708804 TI - Receptive Anal Intercourse in Patients with Inflammatory Bowel Disease: A Clinical Review. AB - Receptive anal intercourse and its association with sexually transmitted infections and human papillomavirus-related anal dysplasia has been well studied in various at-risk groups including men who have sex with men. However, the relationship between receptive anal intercourse and its potential complications in patients with inflammatory bowel disease is not fully understood. This narrative review discusses sexually transmitted infections and anal dysplasia in patients with inflammatory bowel disease who engage in receptive anal intercourse and the lack of evidence-based data to guide clinical practice. It addresses the psychosocial effects of stigmatization in these patients and its consequences in the clinical encounter. We review the need for sufficient data on infection, cancer prevention, and precoital and postcoital hygienic practices with hopes that future studies establish standardized guidelines and recommendations. PMID- 28708805 TI - Serum Adalimumab Levels Predict Successful Remission and Safe Deintensification in Inflammatory Bowel Disease Patients in Clinical Practice. AB - BACKGROUND: Little is known about the association between the pharmacokinetic features of adalimumab (ADL) and disease outcome in patients with inflammatory bowel disease (IBD). AIMS: To assess the association between random serum ADL levels and clinical or biochemical remission with clinical decision making in daily practice according to these levels; and to determine the cutoff value for successful dose reduction in patients with IBD treated with ADL. METHODS: We conducted a prospective observational study of patients with IBD who received long-term maintenance therapy with ADL. RESULTS: Data were available for 157 serum samples from 87 patients. Serum ADL levels were associated with clinical remission: median 9.2 versus 6.0 MUg/mL for patients with Crohn's disease with active disease (P = 0.009) and 14.4 versus 5.2 MUg/mL in patients with ulcerative colitis with active disease (P = 0.002). Serum ADL levels were 9.2 MUg/mL for patients with a normal C-reactive protein value (<5 mg/L) and 5.2 MUg/mL for patients with a high C-reactive protein value (P = 0.002). ADL levels were significantly associated with normal fecal calprotectin value (<80 ng/g) (10.8 versus 7.6 MUg/mL, respectively, P = 0.038). Serum ADL levels were significantly associated with successful deintensification, over a 6-month period of clinical follow-up, compared with the group in which doses remained unchanged (area under the curve 0.88; 95% confidence interval, 0.81-0.95; P < 0.001), with a cutoff value for successful deintensification of 12.2 MUg/mL. CONCLUSIONS: Higher ADA levels were significantly associated with clinical and biochemical remission. Our results, which were obtained under conditions of daily clinical practice, suggest that an ADL cutoff of 12.2 MUg/mL could be appropriate for successful dose reduction in patients with IBD treated with ADL. PMID- 28708807 TI - A Systematic Review of Internet Decision-Making Resources for Patients Considering Surgery for Ulcerative Colitis. AB - BACKGROUND: Guidance from the Royal College of Surgeons advocates patient use of on-line resources to assist in decision making. Our aim was to assess the quality of on-line resources to facilitate decision making for patients considering surgery for ulcerative colitis (UC). METHODS: We undertook a systematic review based on PRISMA guidelines. This was registered on the PROSPERO database (CRD42016047177). We searched Google and repositories using several lay search terms for patient information discussing surgery for UC, published in English. Quality of content on websites was assessed using the validated DISCERN instrument and by minimum standards for decision aids (IPDASi v4.0 checklist). Decision aids were also assessed by the IPDAS checklist. Readability of written content was ascertained using the Flesch-Kincaid score. RESULTS: Our searches identified 175 websites and one decision aid-119 results were excluded at initial screen and 32 were excluded at full text assessment, leaving 25 sources for review. The mean Flesch-Kincaid score for websites was 44.9 (+/-9.73, range 28.1 61.4), suggesting material was difficult to read. No websites compared surgery to medical management or traded off patient preferences. The median IPDAS score was 5/12 (range 1-7). The median global score based on the DISCERN rating was 1/5 (range 1-5), identifying most websites as poor quality. The decision aid scored 9/12 on the IPDAS checklist, not meeting minimum standards. CONCLUSIONS: Available information for patients considering surgery for UC is generally low quality. The development of a new decision aid to support patients considering surgery for UC is recommended. PMID- 28708809 TI - Gender Differences in Outcomes of Antiretroviral Treatment Among HIV-Infected Patients in China: A Retrospective Cohort Study, 2010-2015. AB - BACKGROUD: Women now account for about half of all people living with HIV worldwide, but researchers lack clear information and large population-based study about gender differences in treatment outcomes. METHODS: A nationwide retrospective observational cohort study with data from the China National Free Antiretroviral Treatment Program was performed. Antiretroviral-naive patients older than 18 years initiating standard antiretroviral therapy between January 1, 2010, and December 31, 2011, were included and followed up to December 31, 2015. We used modified Poisson regression models to estimate the impact of gender on virological suppression and retention in treatment, and Kaplan-Meier analysis and Cox proportional hazard models to evaluate gender difference in mortality. RESULTS: Sixty-eight thousand six hundred forty-six patients [46,083 (67.1%) men and 22,563 (32.9%) women] with HIV met eligibility criteria. Women were significantly more likely to achieve virological suppression than men both at 12 months [adjusted relative risk (aRR) 1.02, 95% confidence interval (CI): 1.01 to 1.03, P < 0.001] and 48 months (aRR 1.01, 95% CI: 1.00 to 1.02, P = 0.005) after initiating antiretroviral treatment. Women were also more likely to remain in treatment at 12 months (aRR 1.02, 95% CI: 1.01 to 1.02, P < 0.001) and 48 months (aRR 1.04, 95% CI: 1.03 to 1.05, P < 0.001), although the difference became insignificant in alive patients. All-cause mortality was lower in women than in men (2.34 vs. 4.03 deaths/100PY, adjusted hazard ratio 0.72, 95% CI: 0.67 to 0.77, P < 0.001). CONCLUSIONS: In China, women are more likely to achieve virological suppression, remain in treatment, and have a significantly lower risk of death than men. Future studies could take both biological and sociobehavioral factors into analysis to clarify the influence factors. PMID- 28708808 TI - HIV Viral Load Suppression in Adults and Children Receiving Antiretroviral Therapy-Results From the IeDEA Collaboration. AB - BACKGROUND: Having 90% of patients on antiretroviral therapy (ART) and achieving an undetectable viral load (VL) is 1 of the 90:90:90 by 2020 targets. In this global analysis, we investigated the proportions of adult and paediatric patients with VL suppression in the first 3 years after ART initiation. METHODS: Patients from the IeDEA cohorts who initiated ART between 2010 and 2014 were included. Proportions with VL suppression (<1000 copies/mL) were estimated using (1) strict intention to treat (ITT)-loss to follow-up (LTFU) and dead patients counted as having detectable VL; and (2) modified ITT-LTFU and dead patients were excluded. Logistic regression was used to identify predictors of viral suppression at 1 year after ART initiation using modified ITT. RESULTS: A total of 35,561 adults from 38 sites/16 countries and 2601 children from 18 sites/6 countries were included. When comparing strict with modified ITT methods, the proportion achieving VL suppression at 3 years from ART initiation changed from 45.1% to 90.2% in adults, and 60.6% to 80.4% in children. In adults, older age, higher CD4 count pre-ART, and homosexual/bisexual HIV exposure were associated with VL suppression. In children, older age and higher CD4 percentage pre-ART showed significant associations with VL suppression. CONCLUSIONS: Large increases in the proportion of VL suppression in adults were observed when we excluded those who were LTFU or had died. The increases were less pronounced in children. Greater emphasis should be made to minimize LTFU and maximize patient retention in HIV infected patients of all age groups. PMID- 28708806 TI - Understanding the Cautions and Contraindications of Immunomodulator and Biologic Therapies for Use in Inflammatory Bowel Disease. AB - Ulcerative colitis and Crohn's disease are chronic inflammatory bowel diseases for which there are no cures. These diseases are immunopathogenic, and medical treatment is centered on the temperance of a dysregulated immune response to allow mucosal healing and prevent the sequelae of fistulation and stenosis. Accordingly, the armamentarium of medications, which has expanded immensely in recent history, is not without significant infectious and neoplastic risks. Many of these untoward effects can be mitigated by screening and avoidance of contraindicated medications. This review seeks to highlight the cautions for use of immunomodulators, anticytokine, and alpha4-integrin antagonists. The potential adverse events are further complicated by substantial heterogeneity in disease phenotype in the inflammatory bowel disease population. Large patient registries and databases provide considerable experience and knowledge to calculate the incidence of safety outcomes. To identify rarer outcomes after prolonged therapy, more prospective studies and continued adverse event reporting will aid safe application and minimize potential harms. PMID- 28708810 TI - Role of Normalized T-Cell Subsets in Predicting Comorbidities in a Large Cohort of Geriatric HIV-Infected Patients. AB - BACKGROUND: Adults aging with HIV are at greater risk for several comorbidities. The CD4 cell count and CD4/CD8 ratio often fail to normalize in elderly patients despite prolonged antiretroviral therapy; this has been associated with concomitant diseases and poor prognosis. METHODS: A cross-sectional analysis in antiretroviral-treated HIV-positive patients aged 65 years and older. The aim of the study was to describe the predictors of normalized T-cell subsets ("nT", CD4/CD8 ratio >=1 and CD4 >=500 cells/MUL) in a cohort of geriatric HIV-positive patients and its association with HIV-associated non-AIDS conditions (HANA). RESULTS: One thousand ninety-two patients were included: nT was observed in 340 patients (31.1%). Multivariate binary logistic analysis showed that plasma HIV RNA <50 copies/mL (P = 0.004), female sex (P = 0.002), and nadir CD4 cell count (P < 0.001) were independent predictors of nT. Age and sex-adjusted prevalence of hypertension (P = 0.037), lipid abnormalities (P = 0.040), and multimorbidity (P = 0.034) were higher in subjects with nT, whereas chronic obstructive pulmonary disease (COPD) and cancer were lower (respectively, P = 0.028 and P = 0.005). Multivariate analysis showed that HIV duration was an independent predictor of several comorbidities, whereas nT was protective for cancer and COPD. HIV duration and nT were simultaneously predictors of multimorbidity. CONCLUSIONS: Normalized T-cell subsets were observed in approximately one-third of geriatric HIV-positive subjects, and they were predicted by female sex and immunovirological features. HIV-associated non-AIDS conditions were more prevalent in patients with longer HIV duration, whereas nT represented a protective factor for cancer and COPD. PMID- 28708811 TI - Challenges in Translating PrEP Interest Into Uptake in an Observational Study of Young Black MSM. AB - BACKGROUND: HIV incidence among US young, black men who have sex with men (YBMSM) is high, and structural barriers (eg lack of health insurance) may limit access to Pre-exposure prophylaxis (PrEP). Research studies conducted with YBMSM must ensure access to the best available HIV prevention methods, including PrEP. METHODS: We implemented an optional, nonincentivized PrEP program in addition to the standard HIV prevention services in a prospective, observational cohort of HIV-negative YBMSM in Atlanta, GA. Provider visits and laboratory costs were covered; participant insurance plans and/or the manufacturer assistance program were used to obtain drugs. Factors associated with PrEP initiation were assessed with prevalence ratios and time to PrEP initiation with Kaplan-Meier methods. RESULTS: Of 192 enrolled YBMSM, 4% were taking PrEP at study entry. Of 184 eligible men, 63% indicated interest in initiating PrEP, 10% reported no PrEP interest, and 27% wanted to discuss PrEP again at a future study visit. Of 116 interested men, 46% have not attended a PrEP initiation appointment. Sixty-three men (63/184; 34%) initiated PrEP; 11/63 (17%) subsequently discontinued PrEP. The only factor associated with PrEP initiation was reported sexually transmitted infection in the previous year (prevalence ratio 1.50, 95% confidence interval: 1.002 to 2.25). Among interested men, median time to PrEP initiation was 16 weeks (95% confidence interval: 7 to 36). CONCLUSIONS: Despite high levels of interest, PrEP uptake may be suboptimal among YBMSM in our cohort even with amelioration of structural barriers that can limit use. PrEP implementation as the standard of HIV prevention care in observational studies is feasible; however, further research is needed to optimize uptake for YBMSM. PMID- 28708812 TI - Association Between Self-Reported Adherence and HIV Viral Load Suppression Among Older Children and Adolescents. PMID- 28708813 TI - Application and interpretation of histocompatibility data in liver transplantation. AB - PURPOSE OF REVIEW: There has been a resurgence of interest in histocompatibility as it applies to liver transplantation. The association of persistent and de-novo donor specific antibody (DSA) and outcomes after liver transplantation continues to be investigated. RECENT FINDINGS: Consensus continues to evolve regarding the existence of acute and chronic antibody-mediated rejection (AMR) and pathogenicity of DSA and associated pathologic findings after liver transplantation. The presence of persistent high level, complement fixing DSA or emergence of de novo, Class II DSA has been associated with rejection and worse long-term graft and patient survival. Significant adverse associations of DSA extend to patients after simultaneous liver kidney (SLK) transplant as well as in pediatric recipients of liver transplantation. A higher degree of HLA incompatibility has been recently associated with worse outcomes in living donor liver transplant. SUMMARY: In summary, recent consensus guidelines describe and recognize the existence of acute and chronic AMR and provide a basis upon which to build further investigation. Important adverse outcomes including decreased survival, allograft failure and liver fibrosis have been linked to the presence of DSA. Routine donor and recipient HLA typing and DSA assessment will facilitate diagnosis and provide for baseline data, which may help guide future management. Future investigations may help to clarify the role of therapeutic interventions. PMID- 28708815 TI - Incidence of Posterior Vitreous Detachment After Femtosecond LASIK Compared With Microkeratome LASIK. AB - PURPOSE: To compare the incidence of posterior vitreous detachment (PVD) after femtosecond and microkeratome laser in situ keratomileusis (LASIK). SETTING: Rowad Correction Centre, Cairo, Egypt (a private center affiliated to Cairo University). DESIGN: Prospective, nonrandomized comparative unmasked study. METHODS: The study was conducted at a single laser center. Eligible patients chose between femtosecond and microkeratome LASIK after appropriate counseling. B scan ultrasonography was performed before surgery by a single operator. Patients with preexisting PVD (partial or complete) were excluded. The axial length was also recorded. All surgery was performed by a single surgeon. During surgery, the suction time was measured. Ultrasonography was repeated 1 month after surgery by the same operator to detect PVD. RESULTS: Ten patients (20 eyes, group M) underwent LASIK using the Moria M2 microkeratome, and 10 patients (20 eyes, group F) underwent femtosecond LASIK with the IntraLase FS-150. In groups M and F, respectively, the proportion of women was 80% and 70%, and the mean age was 24.7 +/- 4 years and 25.7 +/- 3.3 years, the mean axial length was 24.2 +/- 1.2 and 23.8 +/- 1.2 mm, and the mean suction time was 18 +/- 2 seconds and 63 +/- 4 seconds (P < 0.001). After surgery, PVD was detected in 4 eyes (20%) in group M and 17 eyes (85%) in group F (P = 0.000044). CONCLUSIONS: The incidence of PVD 1 month after femtosecond LASIK was higher than after microkeratome LASIK. This may be due to longer suction time during femtosecond LASIK despite lower suction pressure. PMID- 28708814 TI - Chirp-Evoked Otoacoustic Emissions and Middle Ear Absorbance for Monitoring Ototoxicity in Cystic Fibrosis Patients. AB - OBJECTIVES: The goal of this study was to investigate the use of transient-evoked otoacoustic emissions (TEOAEs) and middle ear absorbance measurements to monitor auditory function in patients with cystic fibrosis (CF) receiving ototoxic medications. TEOAEs were elicited with a chirp stimulus using an extended bandwidth (0.71 to 8 kHz) to measure cochlear function at higher frequencies than traditional TEOAEs. Absorbance over a wide bandwidth (0.25 to 8 kHz) provides information on middle ear function. The combination of these time-efficient measurements has the potential to identify early signs of ototoxic hearing loss. DESIGN: A longitudinal study design was used to monitor the hearing of 91 patients with CF (median age = 25 years; age range = 15 to 63 years) who received known ototoxic medications (e.g., tobramycin) to prevent or treat bacterial lung infections. Results were compared to 37 normally hearing young adults (median age = 32.5 years; age range = 18 to 65 years) without a history of CF or similar treatments. Clinical testing included 226-Hz tympanometry, pure-tone air conduction threshold testing from 0.25 to 16 kHz and bone conduction from 0.25 to 4 kHz. Experimental testing included wideband absorbance at ambient and tympanometric peak pressure and TEOAEs in three stimulus conditions: at ambient pressure and at tympanometric peak pressure using a chirp stimulus with constant incident pressure level across frequency and at ambient pressure using a chirp stimulus with constant absorbed sound power across frequency. RESULTS: At the initial visit, behavioral audiometric results indicated that 76 of the 157 ears (48%) from patients with CF had normal hearing, whereas 81 of these ears (52%) had sensorineural hearing loss for at least one frequency. Seven ears from four patients had a confirmed behavioral change in hearing threshold for >=3 visits during study participation. Receiver operating characteristic curve analyses demonstrated that all three TEOAE conditions were useful for distinguishing CF ears with normal hearing from ears with sensorineural hearing loss, with an area under the receiver operating characteristic curve values ranging from 0.78 to 0.92 across methods for frequency bands from 2.8 to 8 kHz. Case studies are presented to illustrate the relationship between changes in audiometric thresholds, TEOAEs, and absorbance across study visits. Absorbance measures permitted identification of potential middle ear dysfunction at 5.7 kHz in an ear that exhibited a temporary hearing loss. CONCLUSIONS: The joint use of TEOAEs and absorbance has the potential to explain fluctuations in audiometric thresholds due to changes in cochlear function, middle ear function, or both. These findings are encouraging for the joint use of TEOAE and wideband absorbance objective tests for monitoring ototoxicity, particularly, in patients who may be too ill for behavioral hearing tests. Additional longitudinal studies are needed in a larger number of CF patients receiving ototoxic drugs to further evaluate the clinical utility of these measures in an ototoxic monitoring program. PMID- 28708816 TI - Determination of the Minimal Clinically Important Difference of the University of North Carolina Dry Eye Management Scale. AB - PURPOSE: To establish an initial estimation of the MCID of the University of North Carolina Dry Eye Management Scale (UNC DEMS) and assess its association with patient perceptions of symptom change. METHODS: Thirty-three patients (33.3% men, 67.7% women, mean age 60.5 yrs) with previous DEMS scores were recruited from a UNC ophthalmology clinic in spring 2014. We used anchor-based methods, categorizing important symptom change, to compare the change in the DEMS scores across visits to patient assessments of change; linear regression coefficients estimated the MCID. We correlated clinical assessments, patient perceptions, and DEMS scores. RESULTS: DEMS score changes correlated with global anchors [-0.4229 (P = 0.014)]. Unadjusted linear regression yielded a beta coefficient of -0.54 (confidence interval, -0.97 to -0.12, R = 0.18, P = 0.014), which estimated the DEMS MCID. Adjusting the regression model for days since the last visit and DEMS score improved the association (beta = -0.56; confidence interval, -0.99 to 0.13; R = 0.43; P = 0.013). Descriptive statistics produced an MCID of 1 point. Patients said that 2 points would represent a significant change. The DEMS modestly correlated with the Schirmer test (-0.4045, P = 0.0266), Oxford Grading Scheme (+0.3713, P = 0.0364), and tear breakup time (-0.3559, P = 0.0456). CONCLUSIONS: The UNC DEMS is a valid, responsive patient-reported outcome measure instrument, which is easy to use in the clinic and capable of showing an MCID of 1 point. PMID- 28708817 TI - Innovating cystic fibrosis clinical trial designs in an era of successful standard of care therapies. AB - PURPOSE OF REVIEW: Evolving cystic fibrosis 'standards of care' have influenced recent cystic fibrosis clinical trial designs for new therapies; care additions/improvements will require innovative trial designs to maximize feasibility and efficacy detection. RECENT FINDINGS: Three cystic fibrosis therapeutic areas (pulmonary exacerbations, Pseudomonas aeruginosa airway infections, and reduced cystic fibrosis transmembrane conductance regulator [CFTR] protein function) differ with respect to the duration for which recognized 'standards of care' have been available. However, developers of new therapies in all the three areas are affected by similar challenges: standards of care have become so strongly entrenched that traditional placebo-controlled studies in cystic fibrosis populations likely to benefit from newer therapies have become less and less feasible. Today, patients/clinicians are more likely to entertain participation in active-comparator trial designs, that have substantial challenges of their own. Foremost among these are the selection of 'valid' active comparator(s), estimation of a comparator's current clinical efficacy (required for testing noninferiority hypotheses), and effective blinding of commercially available comparators. SUMMARY: Recent and future cystic fibrosis clinical trial designs will have to creatively address this collateral result of successful past development of effective cystic fibrosis therapies: patients and clinicians are much less likely to accept simple, placebo-controlled studies to evaluate future therapies. PMID- 28708818 TI - Regional Contrast-Enhanced Ultrasonography (CEUS) Characteristics of Breast Cancer and Correlation with Microvessel Density (MVD). AB - BACKGROUND The aim of this study was to investigate the perfusion characteristics of different breast lesion regions in contrast-enhanced ultrasonography (CEUS). MATERIAL AND METHODS A total of 161 malignant and benign breast lesion cases were subjected to CEUS. Perfusion parameters were analyzed and compared between the central and peripheral lesion regions, and surrounding tissue. Mass section was marked with methylene blue. Samples were subjected to immunohistochemistry, and microvessel density (MVD) was calculated. RESULTS There were significant differences in perfusion performance between the central and peripheral lesion regions, and surrounding tissue. In the malignant tumors, the fast-in and fast out pattern was the most common type in the peripheral region (57.98%), while the slow-in and slow-out patterns were the major types in the central region and surrounding tissue (49.58% and 57.98%, respectively). Compared with the surrounding tissue, the peripheral region in the cancers exhibited hyperechoic enhancement and fast-in and slow-out pattern, with large area under the curve (AUC), while the central region showed isoechoic enhancement and equally-in and slow-out pattern, with large AUC. In the benign lesions, the peripheral region exhibited hyperechoic enhancement and fast-in and fast-out pattern, with small AUC, while the central region showed isoechoic enhancement and equally-in and out pattern, with the same AUC value. Moreover, the perfusion parameters in the central and peripheral regions were significantly associated with MVD. CONCLUSIONS It is more objective to evaluate the perfusion performance of breast lesions with the reference of surrounding tissue. Compared with the central region, the peripheral region could better reflect the perfusion characteristics of malignant lesions. PMID- 28708819 TI - Correction to: Misinformation online and its impact on the physician-patient relation. PMID- 28708820 TI - Coping with a patient?s suicide: the impact on physicians. PMID- 28708821 TI - Early career investigator highlight-October. PMID- 28708822 TI - An ancient neurotrophin receptor code; a single Runx/Cbfbeta complex determines somatosensory neuron fate specification in zebrafish. AB - In terrestrial vertebrates such as birds and mammals, neurotrophin receptor expression is considered fundamental for the specification of distinct somatosensory neuron types where TrkA, TrkB and TrkC specify nociceptors, mechanoceptors and proprioceptors/mechanoceptors, respectively. In turn, Runx transcription factors promote neuronal fate specification by regulating neurotrophin receptor and sensory receptor expression where Runx1 mediates TrkA+ nociceptor diversification while Runx3 promotes a TrkC+ proprioceptive/mechanoceptive fate. Here, we report in zebrafish larvae that orthologs of the neurotrophin receptors in contrast to terrestrial vertebrates mark overlapping and distinct subsets of nociceptors suggesting that TrkA, TrkB and TrkC do not intrinsically promote nociceptor, mechanoceptor and proprioceptor/mechanoceptor neuronal fates, respectively. While we find that zebrafish Runx3 regulates nociceptors in contrast to terrestrial vertebrates, it shares a conserved regulatory mechanism found in terrestrial vertebrate proprioceptors/mechanoceptors in which it promotes TrkC expression and suppresses TrkB expression. We find that Cbfbeta, which enhances Runx protein stability and affinity for DNA, serves as an obligate cofactor for Runx in neuronal fate determination. High levels of Runx can compensate for the loss of Cbfbeta, indicating that in this context Cbfbeta serves solely as a signal amplifier of Runx activity. Our data suggests an alteration/expansion of the neurotrophin receptor code of sensory neurons between larval teleost fish and terrestrial vertebrates, while the essential roles of Runx/Cbfbeta in sensory neuron cell fate determination while also expanded are conserved. PMID- 28708823 TI - Notch-dependent epithelial fold determines boundary formation between developmental fields in the Drosophila antenna. AB - Compartment boundary formation plays an important role in development by separating adjacent developmental fields. Drosophila imaginal discs have proven valuable for studying the mechanisms of boundary formation. We studied the boundary separating the proximal A1 segment and the distal segments, defined respectively by Lim1 and Dll expression in the eye-antenna disc. Sharp segregation of the Lim1 and Dll expression domains precedes activation of Notch at the Dll/Lim1 interface. By repressing bantam miRNA and elevating the actin regulator Enable, Notch signaling then induces actomyosin-dependent apical constriction and epithelial fold. Disruption of Notch signaling or the actomyosin network reduces apical constriction and epithelial fold, so that Dll and Lim1 cells become intermingled. Our results demonstrate a new mechanism of boundary formation by actomyosin-dependent tissue folding, which provides a physical barrier to prevent mixing of cells from adjacent developmental fields. PMID- 28708824 TI - Tex19.1 promotes Spo11-dependent meiotic recombination in mouse spermatocytes. AB - Meiosis relies on the SPO11 endonuclease to generate the recombinogenic DNA double strand breaks (DSBs) required for homologous chromosome synapsis and segregation. The number of meiotic DSBs needs to be sufficient to allow chromosomes to search for and find their homologs, but not excessive to the point of causing genome instability. Here we report that the mammal-specific gene Tex19.1 promotes Spo11-dependent recombination in mouse spermatocytes. We show that the chromosome asynapsis previously reported in Tex19.1-/- spermatocytes is preceded by reduced numbers of recombination foci in leptotene and zygotene. Tex19.1 is required for normal levels of early Spo11-dependent recombination foci during leptotene, but not for upstream events such as MEI4 foci formation or accumulation of H3K4me3 at recombination hotspots. Furthermore, we show that mice carrying mutations in Ubr2, which encodes an E3 ubiquitin ligase that interacts with TEX19.1, phenocopy the Tex19.1-/- recombination defects. These data suggest that Tex19.1 and Ubr2 are required for mouse spermatocytes to accumulate sufficient Spo11-dependent recombination to ensure that the homology search is consistently successful, and reveal a hitherto unknown genetic pathway promoting meiotic recombination in mammals. PMID- 28708825 TI - Lymphatic filariasis patient identification in a large urban area of Tanzania: An application of a community-led mHealth system. AB - BACKGROUND: Lymphatic filariasis (LF) is best known for the disabling and disfiguring clinical conditions that infected patients can develop; providing care for these individuals is a major goal of the Global Programme to Eliminate LF. Methods of locating these patients, knowing their true number and thus providing care for them, remains a challenge for national medical systems, particularly when the endemic zone is a large urban area. METHODOLOGY/PRINCIPLE FINDINGS: A health community-led door-to-door survey approach using the SMS reporting tool MeasureSMS-Morbidity was used to rapidly collate and monitor data on LF patients in real-time (location, sex, age, clinical condition) in Dar es Salaam, Tanzania. Each stage of the phased study carried out in the three urban districts of city consisted of a training period, a patient identification and reporting period, and a data verification period, with refinements to the system being made after each phase. A total of 6889 patients were reported (133.6 per 100,000 population), of which 4169 were reported to have hydrocoele (80.9 per 100,000), 2251 lymphoedema-elephantiasis (LE) (43.7 per 100,000) and 469 with both conditions (9.1 per 100,000). Kinondoni had the highest number of reported patients in absolute terms (2846, 138.9 per 100,000), followed by Temeke (2550, 157.3 per 100,000) and Ilala (1493, 100.5 per 100,000). The number of hydrocoele patients was almost twice that of LE in all three districts. Severe LE patients accounted for approximately a quarter (26.9%) of those reported, with the number of acute attacks increasing with reported LE severity (1.34 in mild cases, 1.78 in moderate cases, 2.52 in severe). Verification checks supported these findings. CONCLUSIONS/SIGNIFICANCE: This system of identifying, recording and mapping patients affected by LF greatly assists in planning, locating and prioritising, as well as initiating, appropriate morbidity management and disability prevention (MMDP) activities. The approach is a feasible framework that could be used in other large urban environments in the LF endemic areas. PMID- 28708827 TI - Deciphering the regulation of P2X4 receptor channel gating by ivermectin using Markov models. AB - The P2X4 receptor (P2X4R) is a member of a family of purinergic channels activated by extracellular ATP through three orthosteric binding sites and allosterically regulated by ivermectin (IVM), a broad-spectrum antiparasitic agent. Treatment with IVM increases the efficacy of ATP to activate P2X4R, slows both receptor desensitization during sustained ATP application and receptor deactivation after ATP washout, and makes the receptor pore permeable to NMDG+, a large organic cation. Previously, we developed a Markov model based on the presence of one IVM binding site, which described some effects of IVM on rat P2X4R. Here we present two novel models, both with three IVM binding sites. The simpler one-layer model can reproduce many of the observed time series of evoked currents, but does not capture well the short time scales of activation, desensitization, and deactivation. A more complex two-layer model can reproduce the transient changes in desensitization observed upon IVM application, the significant increase in ATP-induced current amplitudes at low IVM concentrations, and the modest increase in the unitary conductance. In addition, the two-layer model suggests that this receptor can exist in a deeply inactivated state, not responsive to ATP, and that its desensitization rate can be altered by each of the three IVM binding sites. In summary, this study provides a detailed analysis of P2X4R kinetics and elucidates the orthosteric and allosteric mechanisms regulating its channel gating. PMID- 28708826 TI - Intestinal stem cell overproliferation resulting from inactivation of the APC tumor suppressor requires the transcription cofactors Earthbound and Erect wing. AB - Wnt/beta-catenin signal transduction directs intestinal stem cell (ISC) proliferation during homeostasis. Hyperactivation of Wnt signaling initiates colorectal cancer, which most frequently results from truncation of the tumor suppressor Adenomatous polyposis coli (APC). The beta-catenin-TCF transcription complex activates both the physiological expression of Wnt target genes in the normal intestinal epithelium and their aberrantly increased expression in colorectal tumors. Whether mechanistic differences in the Wnt transcription machinery drive these distinct levels of target gene activation in physiological versus pathological states remains uncertain, but is relevant for the design of new therapeutic strategies. Here, using a Drosophila model, we demonstrate that two evolutionarily conserved transcription cofactors, Earthbound (Ebd) and Erect wing (Ewg), are essential for all major consequences of Apc1 inactivation in the intestine: the hyperactivation of Wnt target gene expression, excess number of ISCs, and hyperplasia of the epithelium. In contrast, only Ebd, but not Ewg, mediates the Wnt-dependent regulation of ISC proliferation during homeostasis. Therefore, in the adult intestine, Ebd acts independently of Ewg in physiological Wnt signaling, but cooperates with Ewg to induce the hyperactivation of Wnt target gene expression following Apc1 loss. These findings have relevance for human tumorigenesis, as Jerky (JRK/JH8), the human Ebd homolog, promotes Wnt pathway hyperactivation and is overexpressed in colorectal, breast, and ovarian cancers. Together, our findings reveal distinct requirements for Ebd and Ewg in physiological Wnt pathway activation versus oncogenic Wnt pathway hyperactivation following Apc1 loss. Such differentially utilized transcription cofactors may offer new opportunities for the selective targeting of Wnt-driven cancers. PMID- 28708829 TI - Correction: A latitudinal phylogeographic diversity gradient in birds. AB - [This corrects the article DOI: 10.1371/journal.pbio.2001073.]. PMID- 28708828 TI - High prevalence of epilepsy in onchocerciasis endemic regions in the Democratic Republic of the Congo. AB - BACKGROUND: An increased prevalence of epilepsy has been reported in many onchocerciasis endemic areas. The objective of this study was to determine the prevalence of epilepsy in onchocerciasis endemic areas in the Democratic Republic of the Congo (DRC) and investigate whether a higher annual intake of Ivermectin was associated with a lower prevalence of epilepsy. METHODOLOGY/PRINCIPLE FINDINGS: Between July 2014 and February 2016, house-to-house epilepsy prevalence surveys were carried out in areas with a high level of onchocerciasis endemicity: 3 localities in the Bas-Uele, 24 in the Tshopo and 21 in the Ituri province. Ivermectin uptake was recorded for every household member. This database allowed a matched case-control pair subset to be created that enabled putative risk factors for epilepsy to be tested using univariate logistic regression models. Risk factors relating to onchocerciasis were tested using a multivariate random effects model. To identify presence of clusters of epilepsy cases, the Kulldorff's scan statistic was used. Of 12, 408 people examined in the different health areas 407 (3.3%) were found to have a history of epilepsy. A high prevalence of epilepsy was observed in health areas in the 3 provinces: 6.8-8.5% in Bas-Uele, 0.8-7.4% in Tshopo and 3.6-6.2% in Ituri. Median age of epilepsy onset was 9 years, and the modal age 12 years. The case control analysis demonstrated that before the appearance of epilepsy, compared to the same life period in controls, persons with epilepsy were around two times less likely (OR: 0.52; 95%CI: (0.28, 0.98)) to have taken Ivermectin than controls. After the appearance of epilepsy, there was no difference of Ivermectin intake between cases and controls. Only in Ituri, a significant cluster (p-value = 0.0001) was identified located around the Draju sample site area. CONCLUSIONS: The prevalence of epilepsy in health areas in onchocerciasis endemic regions in the DRC was 2-10 times higher than in non-onchocerciasis endemic regions in Africa. Our data suggests that Ivermectin protects against epilepsy in an onchocerciasis endemic region. However, a prospective population based intervention study is needed to confirm this. PMID- 28708830 TI - Speech-in-speech perception and executive function involvement. AB - This present study investigated the link between speech-in-speech perception capacities and four executive function components: response suppression, inhibitory control, switching and working memory. We constructed a cross-modal semantic priming paradigm using a written target word and a spoken prime word, implemented in one of two concurrent auditory sentences (cocktail party situation). The prime and target were semantically related or unrelated. Participants had to perform a lexical decision task on visual target words and simultaneously listen to only one of two pronounced sentences. The attention of the participant was manipulated: The prime was in the pronounced sentence listened to by the participant or in the ignored one. In addition, we evaluate the executive function abilities of participants (switching cost, inhibitory control cost and response-suppression cost) and their working memory span. Correlation analyses were performed between the executive and priming measurements. Our results showed a significant interaction effect between attention and semantic priming. We observed a significant priming effect in the attended but not in the ignored condition. Only priming effects obtained in the ignored condition were significantly correlated with some of the executive measurements. However, no correlation between priming effects and working memory capacity was found. Overall, these results confirm, first, the role of attention for semantic priming effect and, second, the implication of executive functions in speech-in-noise understanding capacities. PMID- 28708831 TI - biochem4j: Integrated and extensible biochemical knowledge through graph databases. AB - Biologists and biochemists have at their disposal a number of excellent, publicly available data resources such as UniProt, KEGG, and NCBI Taxonomy, which catalogue biological entities. Despite the usefulness of these resources, they remain fundamentally unconnected. While links may appear between entries across these databases, users are typically only able to follow such links by manual browsing or through specialised workflows. Although many of the resources provide web-service interfaces for computational access, performing federated queries across databases remains a non-trivial but essential activity in interdisciplinary systems and synthetic biology programmes. What is needed are integrated repositories to catalogue both biological entities and-crucially-the relationships between them. Such a resource should be extensible, such that newly discovered relationships-for example, those between novel, synthetic enzymes and non-natural products-can be added over time. With the introduction of graph databases, the barrier to the rapid generation, extension and querying of such a resource has been lowered considerably. With a particular focus on metabolic engineering as an illustrative application domain, biochem4j, freely available at http://biochem4j.org, is introduced to provide an integrated, queryable database that warehouses chemical, reaction, enzyme and taxonomic data from a range of reliable resources. The biochem4j framework establishes a starting point for the flexible integration and exploitation of an ever-wider range of biological data sources, from public databases to laboratory-specific experimental datasets, for the benefit of systems biologists, biosystems engineers and the wider community of molecular biologists and biological chemists. PMID- 28708832 TI - Assessing respiratory pathogen communities in bighorn sheep populations: Sampling realities, challenges, and improvements. AB - Respiratory disease has been a persistent problem for the recovery of bighorn sheep (Ovis canadensis), but has uncertain etiology. The disease has been attributed to several bacterial pathogens including Mycoplasma ovipneumoniae and Pasteurellaceae pathogens belonging to the Mannheimia, Bibersteinia, and Pasteurella genera. We estimated detection probability for these pathogens using protocols with diagnostic tests offered by a fee-for-service laboratory and not offered by a fee-for-service laboratory. We conducted 2861 diagnostic tests on swab samples collected from 476 bighorn sheep captured across Montana and Wyoming to gain inferences regarding detection probability, pathogen prevalence, and the power of different sampling methodologies to detect pathogens in bighorn sheep populations. Estimated detection probability using fee-for-service protocols was less than 0.50 for all Pasteurellaceae and 0.73 for Mycoplasma ovipneumoniae. Non fee-for-service Pasteurellaceae protocols had higher detection probabilities, but no single protocol increased detection probability of all Pasteurellaceae pathogens to greater than 0.50. At least one protocol resulted in an estimated detection probability of 0.80 for each pathogen except Mannheimia haemolytica, for which the highest detection probability was 0.45. In general, the power to detect Pasteurellaceae pathogens at low prevalence in populations was low unless many animals were sampled or replicate samples were collected per animal. Imperfect detection also resulted in low precision when estimating prevalence for any pathogen. Low and variable detection probabilities for respiratory pathogens using live-sampling protocols may lead to inaccurate conclusions regarding pathogen community dynamics and causes of bighorn sheep respiratory disease epizootics. We recommend that agencies collect multiples samples per animal for Pasteurellaceae detection, and one sample for Mycoplasma ovipneumoniae detection from at least 30 individuals to reliably detect both Pasteurellaceae and Mycoplasma ovipneumoniae at the population-level. Availability of PCR diagnostic tests to wildlife management agencies would improve the ability to reliably detect Pasteurellaceae in bighorn sheep populations. PMID- 28708833 TI - Proliferating effect of radiolytically depolymerized carrageenan on physiological attributes, plant water relation parameters, essential oil production and active constituents of Cymbopogon flexuosus Steud. under drought stress. AB - Carrageenan has been proved as potent growth promoting substance in its depolymerized form. However, relatively little is known about its role in counteracting the adverse effects of drought stress on plants. In a pot experiment, lemongrass (Cymbopogon flexuosus Steud.), grown under different water stress regimes [(100% field capacity (FC), 80% FC and 60% FC)], was sprayed with 40, 80 and 120 mg L-1 of gamma irradiated carrageenan (ICA). Foliar application of ICA mitigated the harmful effects of drought stress to various extents and improved the biochemical characteristics, quality attributes and active constituents (citral and geraniol) of lemongrass significantly. Among the applied treatments, ICA-80 mg L-1 proved the best in alleviating detrimental effects of drought. However, drought stress (80 and 60% FC), irrespective of the growth stages, had an adverse impact on most of the studied attributes. Generally, 60% FC proved more deleterious than 80% FC. At 80% FC, application of ICA-80 mg L-1 elevated the essential oil (EO) content by 18.9 and 25%, citral content by 7.33 and 8.19% and geraniol content by 9.2 and 8.9% at 90 and 120 days after planting (DAP), respectively, as compared to the deionized-water (DW) spray treatment (80% FC+ DW). Whereas, at 60% FC, foliar application of 80 mg L-1 ICA significantly augmented the EO content by 15.4 and 17.8% and active constituents viz. citral and geraniol, by 5.01 and 5.62% and by 6.06 and 5.61% at 90 and 120 DAP, respectively, as compared to the control (water-spray treatment). PMID- 28708834 TI - OsMPH1 regulates plant height and improves grain yield in rice. AB - Plant height is a major trait affecting yield potential in rice. Using a large scale hybrid transcription factor approach, we identified the novel MYB-like transcription factor OsMPH1 (MYB-like gene of Plant Height 1), which is involved in the regulation of plant height in rice. Overexpression of OsMPH1 leads to increases of plant height and grain yield in rice, while knockdown of OsMPH1 leads to the opposite phenotypes. Microscopy of longitudinal stem sections indicated that a change in internode cell length resulted in the change in plant height. RNA sequencing (RNA-seq) analysis of transgenic rice lines showed that multiple genes related to cell elongation and cell wall synthesis, which are associated with plant height and yield phenotypes, exhibited an altered expression profile. These results imply that OsMPH1 might be involved in specific recognition and signal transduction processes related to plant height and yield formation, providing further insights into the mechanisms underlying the regulation of plant height and providing a candidate gene for the efficient improvement of rice yield. PMID- 28708835 TI - Green and facile approach for enhancing the inherent magnetic properties of carbon nanotubes for water treatment applications. AB - Current methods for preparing magnetic composites with carbon nanotubes (MCNT) commonly include extensive use of treatment with strong acids and result in massive losses of carbon nanotubes (CNTs). In this study we explore the potential of taking advantage of the inherent magnetic properties associated with the metal (alloy or oxide) incorporated in CNTs during their production. The as-received CNTs are refined by applying a permanent magnet to a suspension of CNTs to separate the high-magnetic fraction; the low-magnetic fraction is discarded with the solvent. The collected MCNTs were characterized by a suite of 10 diffraction and spectroscopic techniques. A key discovery is that metallic nano-clusters of Fe and/or Ni located in the interior cavities of the nanotubes give MCNTs their ferromagnetic character. After refinement using our method, the MCNTs show saturation magnetizations up to 10 times that of the as-received materials. In addition, we demonstrate the ability of these MCNTs to repeatedly remove atrazine from water in a cycle of dispersion into a water sample, adsorption of the atrazine onto the MCNTs, collection by magnetic attraction and regeneration by ethanol. The resulting MCNTs show high adsorption capacities (> 40 mg atrazine/g), high magnetic response, and straightforward regeneration. The method presented here is simpler, faster, and substantially reduces chemical waste relative to current techniques and the resulting MCNTs are promising adsorbents for organic/chemical contaminants in environmental waters. PMID- 28708836 TI - Urban air quality forecasting based on multi-dimensional collaborative Support Vector Regression (SVR): A case study of Beijing-Tianjin-Shijiazhuang. AB - Today, China is facing a very serious issue of Air Pollution due to its dreadful impact on the human health as well as the environment. The urban cities in China are the most affected due to their rapid industrial and economic growth. Therefore, it is of extreme importance to come up with new, better and more reliable forecasting models to accurately predict the air quality. This paper selected Beijing, Tianjin and Shijiazhuang as three cities from the Jingjinji Region for the study to come up with a new model of collaborative forecasting using Support Vector Regression (SVR) for Urban Air Quality Index (AQI) prediction in China. The present study is aimed to improve the forecasting results by minimizing the prediction error of present machine learning algorithms by taking into account multiple city multi-dimensional air quality information and weather conditions as input. The results show that there is a decrease in MAPE in case of multiple city multi-dimensional regression when there is a strong interaction and correlation of the air quality characteristic attributes with AQI. Also, the geographical location is found to play a significant role in Beijing, Tianjin and Shijiazhuang AQI prediction. PMID- 28708837 TI - Extracellular inhibitors can attenuate tumorigenic Wnt pathway activity in adenomatous polyposis coli mutants: Predictions of a validated mathematical model. AB - BACKGROUND: Despite considerable investigational efforts, no method to overcome the pathogenesis caused by loss of function (LoF) mutations in tumor suppressor genes has been successfully translated to the clinic. The most frequent LoF mutation in human cancers is Adenomatous polyposis coli (APC), causing aberrant activation of the Wnt pathway. In nearly all colon cancer tumors, the APC protein is truncated, but still retains partial binding abilities. OBJECTIVE & METHODS: Here, we tested the hypothesis that extracellular inhibitors of the Wnt pathway, although acting upstream of the APC mutation, can restore normal levels of pathway activity in colon cancer cells. To this end, we developed and simulated a mathematical model for the Wnt pathway in different APC mutants, with or without the effects of the extracellular inhibitors, Secreted Frizzled-Related Protein1 (sFRP1) and Dickhopf1 (Dkk1). We compared our model predictions to experimental data in the literature. RESULTS: Our model accurately predicts T-cell factor (TCF) activity in mutant cells that vary in APC mutation. Model simulations suggest that both sFRP1 and DKK1 can reduce TCF activity in APC1638N/1572T and Apcmin/min mutants, but restoration of normal activity levels is possible only in the former. When applied in combination, synergism between the two inhibitors can reduce their effective doses to one-fourth of the doses required under single inhibitor application. Overall, re-establishment of normal Wnt pathway activity is predicted for every APC mutant in whom TCF activity is increased by up to 11 fold. CONCLUSIONS: Our work suggests that extracellular inhibitors can effectively restore normal Wnt pathway activity in APC-truncated cancer cells, even though these LoF mutations occur downstream of the inhibitory action. The insufficient activity of the truncated APC can be quantitatively balanced by the upstream intervention. This new concept of upstream intervention to control the effects of downstream mutations may be considered also for other partial LoF mutations in other signaling pathways. PMID- 28708838 TI - Decreasing rates of disorganised attachment in infants and young children, who are at risk of developing, or who already have disorganised attachment. A systematic review and meta-analysis of early parenting interventions. AB - BACKGROUND: Disorganised attachment patterns in infants have been linked to later psychopathology. Services have variable practices for identifying and providing interventions for families of children with disorganised attachment patterns, which is the attachment pattern leading to most future psychopathology. Several recent government reports have highlighted the need for better parenting interventions in at risk groups. OBJECTIVES: The objective of this review and meta-analysis was to evaluate the clinical effectiveness of available parenting interventions for families of children at high risk of developing, or already showing, a disorganised pattern of attachment. METHODS: Population: Studies were included if they involved parents or caregivers of young children with a mean age under 13 years who had a disorganised classification of attachment or were identified as at high risk of developing such problems. Included interventions were aimed at parents or caregivers (e.g. foster carers) seeking to improve attachment. Comparators included an alternative intervention, an attention control, treatment as usual or no intervention. The primary outcome was a disorganised pattern in childhood measured using a validated attachment instrument. Studies that did not use a true Randomised Controlled Trial (RCT) design were excluded from the review. Both published and unpublished papers were included, there were no restrictions on years since publication and foreign language papers were included where translation services could be accessed within necessary timescales. RESULTS: A comprehensive search of relevant databases yielded 15,298 papers. This paper reports a systematic review as part of an NIHR HTA study identifying studies pre-2012, updated to include all papers to October 2016. Two independent reviewers undertook two stage screening and data extraction of the included studies at all stages. A Cochrane quality assessment was carried out to assess the risk of bias. In total, fourteen studies were included in the review. In a meta-analysis of these fourteen studies the interventions saw less disorganised attachment at outcome compared to the control (OR = 0.50, (0.32, 0.77), p = 0.008). The majority of the interventions targeted maternal sensitivity. We carried out exploratory analyses to examine factors that may influence treatment outcome but these should be treated with caution given that we were limited by small numbers of studies. CONCLUSIONS: Parenting interventions that target parental sensitivity show promise in reducing disorganised attachment. This is limited by few high quality studies and the fact that most studies are with mothers. More high quality randomised controlled trials are required to elucidate this further. PMID- 28708840 TI - Index extraction for electromagnetic field evaluation of high power wireless charging system. AB - This paper presents the precise dosimetry for highly resonant wireless power transfer (HR-WPT) system using an anatomically realistic human voxel model. The dosimetry for the HR-WPT system designed to operate at 13.56 MHz frequency, which one of the ISM band frequency band, is conducted in the various distances between the human model and the system, and in the condition of alignment and misalignment between transmitting and receiving circuits. The specific absorption rates in the human body are computed by the two-step approach; in the first step, the field generated by the HR-WPT system is calculated and in the second step the specific absorption rates are computed with the scattered field finite-difference time-domain method regarding the fields obtained in the first step as the incident fields. The safety compliance for non-uniform field exposure from the HR WPT system is discussed with the international safety guidelines. Furthermore, the coupling factor concept is employed to relax the maximum allowable transmitting power. Coupling factors derived from the dosimetry results are presented. In this calculation, the external magnetic field from the HR-WPT system can be relaxed by approximately four times using coupling factor in the worst exposure scenario. PMID- 28708839 TI - Tumor Necrosis Factor dynamically regulates the mRNA stabilome in rheumatoid arthritis fibroblast-like synoviocytes. AB - During rheumatoid arthritis (RA), Tumor Necrosis Factor (TNF) activates fibroblast-like synoviocytes (FLS) inducing in a temporal order a constellation of genes, which perpetuate synovial inflammation. Although the molecular mechanisms regulating TNF-induced transcription are well characterized, little is known about the impact of mRNA stability on gene expression and the impact of TNF on decay rates of mRNA transcripts in FLS. To address these issues we performed RNA sequencing and genome-wide analysis of the mRNA stabilome in RA FLS. We found that TNF induces a biphasic gene expression program: initially, the inducible transcriptome consists primarily of unstable transcripts but progressively switches and becomes dominated by very stable transcripts. This temporal switch is due to: a) TNF-induced prolonged stabilization of previously unstable transcripts that enables progressive transcript accumulation over days and b) sustained expression and late induction of very stable transcripts. TNF-induced mRNA stabilization in RA FLS occurs during the late phase of TNF response, is MAPK-dependent, and involves several genes with pathogenic potential such as IL6, CXCL1, CXCL3, CXCL8/IL8, CCL2, and PTGS2. These results provide the first insights into genome-wide regulation of mRNA stability in RA FLS and highlight the potential contribution of dynamic regulation of the mRNA stabilome by TNF to chronic synovitis. PMID- 28708841 TI - NlpD links cell wall remodeling and outer membrane invagination during cytokinesis in Escherichia coli. AB - Cytokinesis in gram-negative bacteria requires the constriction of all three cell envelope layers: the inner membrane (IM), the peptidoglycan (PG) cell wall and the outer membrane (OM). In order to avoid potentially lethal breaches in cell integrity, this dramatic reshaping of the cell surface requires tight coordination of the different envelope remodeling activities of the cytokinetic ring. However, the mechanisms responsible for this coordination remain poorly defined. One of the few characterized regulatory points in the envelope remodeling process is the activation of cell wall hydrolytic enzymes called amidases. These enzymes split cell wall material shared by developing daughter cells to facilitate their eventual separation. In Escherichia coli, amidase activity requires stimulation by one of two partially redundant activators: EnvC, which is associated with the IM, and NlpD, a lipoprotein anchored in the OM. Here, we investigate the regulation of amidase activation by NlpD. Structure function analysis revealed that the OM localization of NlpD is critical for regulating its amidase activation activity. To identify additional factors involved in the NlpD cell separation pathway, we also developed a genetic screen using a flow cytometry-based enrichment procedure. This strategy allowed us to isolate mutants that form long chains of unseparated cells specifically when the redundant EnvC pathway is inactivated. The screen implicated the Tol-Pal system and YraP in NlpD activation. The Tol-Pal system is thought to promote OM invagination at the division site. YraP is a conserved protein of unknown function that we have identified as a new OM-localized component of the cytokinetic ring. Overall, our results support a model in which OM and PG remodeling events at the division site are coordinated in part through the coupling of NlpD activation with OM invagination. PMID- 28708842 TI - Evaluating whole genome sequence data from the Genetic Absence Epilepsy Rat from Strasbourg and its related non-epileptic strain. AB - OBJECTIVE: The Genetic Absence Epilepsy Rats from Strasbourg (GAERS) are an inbreed Wistar rat strain widely used as a model of genetic generalised epilepsy with absence seizures. As in humans, the genetic architecture that results in genetic generalized epilepsy in GAERS is poorly understood. Here we present the strain-specific variants found among the epileptic GAERS and their related Non Epileptic Control (NEC) strain. The GAERS and NEC represent a powerful opportunity to identify neurobiological factors that are associated with the genetic generalised epilepsy phenotype. METHODS: We performed whole genome sequencing on adult epileptic GAERS and adult NEC rats, a strain derived from the same original Wistar colony. We also generated whole genome sequencing on four double-crossed (GAERS with NEC) F2 selected for high-seizing (n = 2) and non seizing (n = 2) phenotypes. RESULTS: Specific to the GAERS genome, we identified 1.12 million single nucleotide variants, 296.5K short insertion-deletions, and 354 putative copy number variants that result in complete or partial loss/duplication of 41 genes. Of the GAERS-specific variants that met high quality criteria, 25 are annotated as stop codon gain/loss, 56 as putative essential splice sites, and 56 indels are predicted to result in a frameshift. Subsequent screening against the two F2 progeny sequenced for having the highest and two F2 progeny for having the lowest seizure burden identified only the selected Cacna1h GAERS-private protein-coding variant as exclusively co segregating with the two high-seizing F2 rats. SIGNIFICANCE: This study highlights an approach for using whole genome sequencing to narrow down to a manageable candidate list of genetic variants in a complex genetic epilepsy animal model, and suggests utility of this sequencing design to investigate other spontaneously occurring animal models of human disease. PMID- 28708843 TI - Prevalence of respiratory viruses among adults, by season, age, respiratory tract region and type of medical unit in Paris, France, from 2011 to 2016. AB - BACKGROUND: Multiplex PCR tests have improved our understanding of respiratory viruses' epidemiology by allowing their wide range detection. We describe here the burden of these viruses in hospital settings over a five-year period. METHODS: All respiratory samples from adult patients (>20 years old) tested by multiplex-PCR at the request of physicians, from May 1 2011 to April 30 2016, were included retrospectively. Viral findings are reported by season, patient age group, respiratory tract region (upper or lower) and type of clinical unit (intensive care unit, pneumology unit, lung transplantation unit and other medical units). RESULTS: In total, 7196 samples (4958 patients) were included; 29.2% tested positive, with viral co-infections detected in 1.6% of samples. Overall, two viral groups accounted for 60.2% of all viruses identified: picornaviruses (rhinovirus or enterovirus, 34.3%) and influenza (26.6%). Influenza viruses constituted the group most frequently identified in winter (34.4%), in the upper respiratory tract (32%) and in patients over the age of 70 years (36.4%). Picornavirus was the second most frequently identified viral group in these populations and in all other groups, including lower respiratory tract infections (41.3%) or patients in intensive care units (37.6%). CONCLUSION: This study, the largest to date in Europe, provides a broad picture of the distribution of viruses over seasons, age groups, types of clinical unit and respiratory tract regions in the hospital setting. It highlights the burden associated with the neglected picornavirus group. These data have important implications for the future development of vaccines and antiviral drugs. PMID- 28708844 TI - Diagnostic accuracy of Xpert MTB/RIF for tuberculosis detection in different regions with different endemic burden: A systematic review and meta-analysis. AB - PURPOSE: To estimate the diagnostic accuracy of Xpert MTB/RIF, a systematic review and meta-analysis were carried out. METHODS: Up to June 20, 2015, multiple databases were screened for relevant studies. RESULTS: Accordingly, 106 studies included 52,410 samples were selected. Diagnostic accuracy of Xpert MTB/RIF for TB detection was validated against either culture or a composite reference standard (CRS). Additionally, selected studies were further subgrouped in four groups based on sample's type, subject's age, status of HIV co-infection and smear-positivity. The overall pooled sensitivity and specificity of Xpert MTB/RIF was 0.85 (95% confidence interval [CI] 0.82-0.88) and 0.98 (95% CI 0.96-0.98), respectively, compared to culture; while it was 0.59 (95% CI 0.44-0.72) and 0.99 (95% CI 0.97-1.00) compared to CRS. The overall sensitivity was lower in countries with high TB prevalence than countries with middle/low prevalence (0.84, 95% CI: 0.80-0.88 versus 0.89, 95% CI: 0.84-0.93). Furthermore, Xpert MTB/RIF has higher sensitivity in patients with positive smears (0.99, 95% CI 0.97-0.99), in patients with pulmonary TB samples (0.87, 95% CI 0.83-0.90), in adults (0.82, 95% CI 0.76-0.86) and in HIV-positive patients (0.81, 95% CI 0.73 0.87). CONCLUSIONS: Taken together, Xpert MTB/RIF is a quick and accurate diagnostic assay for TB which will significantly help the physicians to make their clinical decisions. PMID- 28708845 TI - Leveraging peer-based support to facilitate HIV care in Kenya. AB - Rakhi Karwa and colleagues discuss a program in which peer navigators support care for people with HIV at a Kenyan hospital. PMID- 28708846 TI - Sex, pregnancy and aortic disease in Marfan syndrome. AB - BACKGROUND: Sex-related differences as well as the adverse effect of pregnancy on aortic disease outcome are well-established phenomena in humans with Marfan syndrome (MFS). The underlying mechanisms of these observations are largely unknown. OBJECTIVES: In an initial (pilot) step we aimed to confirm the differences between male and female MFS patients as well as between females with and without previous pregnancy. We then sought to evaluate whether these findings are recapitulated in a pre-clinical model and performed in-depth cardiovascular phenotyping of mutant male and both nulliparous and multiparous female Marfan mice. The effect of 17beta-estradiol on fibrillin-1 protein synthesis was compared in vitro using human aortic smooth muscle cells and fibroblasts. RESULTS: Our small retrospective study of aortic dimensions in a cohort of 10 men and 20 women with MFS (10 pregnant and 10 non-pregnant) confirmed that aortic root growth was significantly increased in the pregnant group compared to the non pregnant group (0.64mm/year vs. 0.12mm/year, p = 0.018). Male MFS patients had significantly larger aortic root diameters compared to the non-pregnant and pregnant females at baseline and follow-up (p = 0.002 and p = 0.007, respectively), but no significant increase in aortic root growth was observed compared to the females after follow-up (p = 0.559 and p = 0.352). In the GT-8/+ MFS mouse model, multiparous female Marfan mice showed increased aortic diameters when compared to nulliparous females. Aortic dilatation in multiparous females was comparable to Marfan male mice. Moreover, increased aortic diameters were associated with more severe fragmentation of the elastic lamellae. In addition, 17beta-estradiol was found to promote fibrillin-1 production by human aortic smooth muscle cells. CONCLUSIONS: Pregnancy-related changes influence aortic disease severity in otherwise protected female MFS mice and patients. There may be a role for estrogen in the female sex protective effect. PMID- 28708847 TI - Attitudes and perceptions towards novel objective measures of ARV-based vaginal ring use: Results from a global stakeholder survey. AB - Results of recent microbicide and pre-exposure prophylaxis clinical trials have shown adherence to be a significant challenge with new HIV prevention technologies. As the vaginal ring containing dapivirine moves into two open label follow-on studies (HOPE/MTN-025 and DREAM) and other antiretroviral-based and multi-purpose prevention technology ring products advance through the development pipeline, there is a need for more accurate and reliable measures of adherence to microbicide ring products. We previously conducted a comprehensive landscape analysis to identify new technologies that could be applied to adherence measurement of vaginal rings containing antiretrovirals. To explore attitudes and perceptions towards the approaches that we identified, we conducted a survey of stakeholders with experience and expertise in microbicide and HIV prevention clinical trials. From May to July 2015 an electronic survey was distributed via email to 894 stakeholders; a total of 206 eligible individuals responded to at least one question and were included in the data analysis. Survey respondents were presented with various objective measures and asked about their perceived acceptability to trial participants, feasibility of implementation by study staff, usefulness for measuring adherence and ethical concerns. Methods that require no additional input from the participant and require no modifications to the existing ring product (i.e., measurement of residual drug or excipient, or a vaginal analyte that enters the ring) were viewed as being more acceptable to trial participants and more feasible to implement in the field. Respondents saw value in using objective measures to provide real-time feedback on adherence. However, approaches that involve unannounced home visits for sample collection or spot checks of ring use, which could provide significant value to adherence feedback efforts, were met with skepticism. Additional research on the acceptability of these methods to potential trial participants and trial staff is recommended. PMID- 28708848 TI - Predicting all-cause risk of 30-day hospital readmission using artificial neural networks. AB - Avoidable hospital readmissions not only contribute to the high costs of healthcare in the US, but also have an impact on the quality of care for patients. Large scale adoption of Electronic Health Records (EHR) has created the opportunity to proactively identify patients with high risk of hospital readmission, and apply effective interventions to mitigate that risk. To that end, in the past, numerous machine-learning models have been employed to predict the risk of 30-day hospital readmission. However, the need for an accurate and real-time predictive model, suitable for hospital setting applications still exists. Here, using data from more than 300,000 hospital stays in California from Sutter Health's EHR system, we built and tested an artificial neural network (NN) model based on Google's TensorFlow library. Through comparison with other traditional and non-traditional models, we demonstrated that neural networks are great candidates to capture the complexity and interdependency of various data fields in EHRs. LACE, the current industry standard, showed a precision (PPV) of 0.20 in identifying high-risk patients in our database. In contrast, our NN model yielded a PPV of 0.24, which is a 20% improvement over LACE. Additionally, we discussed the predictive power of Social Determinants of Health (SDoH) data, and presented a simple cost analysis to assist hospitalists in implementing helpful and cost-effective post-discharge interventions. PMID- 28708849 TI - Identification and characterization of BATF3 as a context-specific coactivator of the glucocorticoid receptor. AB - The ability of the glucocorticoid receptor (GR) to regulate the transcriptional output of genes relies on its interactions with transcriptional coregulators. However, which coregulators are required for GR-dependent activation is context dependent and can be influenced by the sequence of the DNA bound by GR and by the nature of the GR isoform responsible for the regulation of a gene. Here, we screened for GR-interacting proteins for which the interaction signal differed between two GR isoforms GRalpha and GRgamma. These isoforms diverge by a single amino acid insertion in a domain, the lever arm, which adopts DNA sequence specific conformations. We identify Basic Leucine Zipper ATF-Like Transcription Factor 3 (BATF3), an AP-1 family transcription factor, as a GR coregulator whose interaction with GR is modulated by the lever arm. Further, a combination of experiments uncovered that BATF3 acts as a gene-specific coactivator of GR whose coactivator potency is influenced by the sequence of the GR binding site. Together, our findings suggest that GR isoform and the sequence of GR binding site influence the interaction of GR with BATF3, which might direct the assembly of gene-specific regulatory complexes to fine-tune the expression of individual GR target genes. PMID- 28708850 TI - Tumor spatial heterogeneity in myxoid-containing soft tissue using texture analysis of diffusion-weighted MRI. AB - The objective of this study was to examine the tumor spatial heterogeneity in myxoid-containing soft-tissue tumors (STTs) using texture analysis of diffusion weighted imaging (DWI). A total of 40 patients with myxoid-containing STTs (23 benign and 17 malignant) were included in this study. The region of interest (ROI) was manually drawn on the apparent diffusion coefficient (ADC) map. For texture analysis, the global (mean, standard deviation, skewness, and kurtosis), regional (intensity variability and size-zone variability), and local features (energy, entropy, correlation, contrast, homogeneity, variance, and maximum probability) were extracted from the ADC map. Student's t-test was used to test the difference between group means. Analysis of covariance (ANCOVA) was performed with adjustments for age, sex, and tumor volume. The receiver operating characteristic (ROC) analysis was performed to compare diagnostic performances. Malignant myxoid-containing STTs had significantly higher kurtosis (P = 0.040), energy (P = 0.034), correlation (P<0.001), and homogeneity (P = 0.003), but significantly lower contrast (P<0.001) and variance (P = 0.001) compared with benign myxoid-containing STTs. Contrast showed the highest area under the curve (AUC = 0.923, P<0.001), sensitivity (94.12%), and specificity (86.96%). Our results reveal the potential utility of texture analysis of ADC maps for differentiating benign and malignant myxoid-containing STTs. PMID- 28708851 TI - Interpreting surveys to estimate the size of the monarch butterfly population: Pitfalls and prospects. AB - To assess the change in the size of the eastern North American monarch butterfly summer population, studies have used long-term data sets of counts of adult butterflies or eggs per milkweed stem. Despite the observed decline in the monarch population as measured at overwintering sites in Mexico, these studies found no decline in summer counts in the Midwest, the core of the summer breeding range, leading to a suggestion that the cause of the monarch population decline is not the loss of Midwest agricultural milkweeds but increased mortality during the fall migration. Using these counts to estimate population size, however, does not account for the shift of monarch activity from agricultural fields to non agricultural sites over the past 20 years, as a result of the loss of agricultural milkweeds due to the near-ubiquitous use of glyphosate herbicides. We present the counter-hypotheses that the proportion of the monarch population present in non-agricultural habitats, where counts are made, has increased and that counts reflect both population size and the proportion of the population observed. We use data on the historical change in the proportion of milkweeds, and thus monarch activity, in agricultural fields and non-agricultural habitats to show why using counts can produce misleading conclusions about population size. We then separate out the shifting proportion effect from the counts to estimate the population size and show that these corrected summer monarch counts show a decline over time and are correlated with the size of the overwintering population. In addition, we present evidence against the hypothesis of increased mortality during migration. The milkweed limitation hypothesis for monarch decline remains supported and conservation efforts focusing on adding milkweeds to the landscape in the summer breeding region have a sound scientific basis. PMID- 28708852 TI - Simultaneous silencing of isoamylases ISA1, ISA2 and ISA3 by multi-target RNAi in potato tubers leads to decreased starch content and an early sprouting phenotype. AB - Isoamylases hydrolyse (1-6)-alpha-D-glucosidic linkages in starch and are involved in both starch granule formation and starch degradation. In plants, three isoamylase isoforms with distinct functions in starch synthesis (ISA1 and ISA2) and degradation (ISA3) have been described. Here, we created transgenic potato plants with simultaneously decreased expression of all three isoamylases using a chimeric RNAi construct targeting all three isoforms. Constitutive expression of the hairpin RNA using the 35S CaMV promoter resulted in efficient silencing of all three isoforms in leaves, growing tubers, and sprouting tubers. Neither plant growth nor tuber yield was effected in isoamylase-deficient potato lines. Interestingly, starch metabolism was found to be impaired in a tissue specific manner. While leaf starch content was unaffected, tuber starch was significantly reduced. The reduction in tuber starch content in the transgenic plants was accompanied by a decrease in starch granules size, an increased sucrose content and decreased hexose levels. Despite the effects on granule size, only little changes in chain length composition of soluble and insoluble glucose polymers were detected. The transgenic tubers displayed an early sprouting phenotype that was accompanied by an increased level of sucrose in parenchyma cells below the outgrowing bud. Since high sucrose levels promote sprouting, we propose that the increased number of small starch granules may cause an accelerated turnover of glucan chains and hence a more rapid synthesis of sucrose. This observation links alterations in starch structure/degradation with developmental processes like meristem activation and sprout outgrowth in potato tubers. PMID- 28708853 TI - Selective serotonin reuptake inhibitors and venlafaxine in pregnancy: Changes in drug disposition. AB - BACKGROUND: Pregnancy may cause changes in drug disposition. The clinical consequences may be profound and even counterintuitive; in some cases pregnant women may need more than twice their usual drug dose in order to maintain therapeutic drug levels. For antidepressants, evidence on drug disposition in pregnancy is scarce. The aim of this study was to determine the effects of pregnancy on serum levels of selective serotonin reuptake inhibitors (SSRIs) and venlafaxine in a large and naturalistic patient material, in order to provide tentative dose recommendations for pregnant women. METHODS: Using patient data from two routine therapeutic drug monitoring (TDM) services in Norway with linkage to the national birth registry, dose-adjusted serum drug concentrations of SSRIs and venlafaxine during pregnancy were compared to the women's own baseline (non-pregnant) values, using a linear mixed model. FINDINGS: Overall, the TDM databases contained 196,726 serum concentration measurements from 54,393 women. After data linkage and drug selection (SSRIs or venlafaxine only), we identified 367 analyses obtained from a total of 290 pregnancies in 281 women, and 420 baseline observations from the same women. Serum concentrations in the third trimester were significantly lower than baseline for paroxetine (-51%; 95% confidence interval [CI], -66%, -30%; p<0.001), fluvoxamine (-56%; CI, -75%, 23%; p = 0.004) and citalopram (-24%; CI, -38%, -7%; p = 0,007), and higher than baseline for sertraline (+68%; CI, +37%, +106%; p<0.001). For escitalopram, fluoxetine and venlafaxine concentrations did not change significantly. CONCLUSIONS: For paroxetine and fluvoxamine the pronounced decline in maternal drug serum concentrations in pregnancy may necessitate a dose increase of about 100% during the third trimester in order to maintain stable concentrations. For fluoxetine, venlafaxine, citalopram, escitalopram and sertraline, the present study indicates that dose adjustments are generally not necessary during pregnancy. PMID- 28708854 TI - Missing in action: Species competition is a neglected predictor variable in species distribution modelling. AB - The central role of species competition in shaping community structure in ecosystems is well appreciated amongst ecologists. However species competition is a consistently missing variable in Species Distribution Modelling (SDM). This study presents results of our attempt to incorporate species competition in SDMs. We used a suit of predictor variables including Soil Adjusted Vegetation Index (SAVI), as well as distance from roads, settlements and water, fire frequency and distance from the nearest herbivore sighting (of selected herbivores) to model individual habitat preferences of five grazer species (buffalo, warthog, waterbuck, wildebeest and zebra) with the Ensemble SDM algorithm for Gonarezhou National Park, Zimbabwe. Our results showed that distance from the nearest animal sighting (a proxy for competition among grazers) was the best predictor of the potential distribution of buffalo, wildebeest and zebra but the second best predictor for warthog and waterbuck. Our findings provide evidence to that competition is an important predictor of grazer species' potential distribution. These findings suggest that species distribution modelling that neglects species competition may be inadequate in explaining the potential distribution of species. Therefore our findings encourage the inclusion of competition in SDM as well as potentially igniting discussions that may lead to improving the predictive power of future SDM efforts. PMID- 28708855 TI - A multi-domain trust management model for supporting RFID applications of IoT. AB - The use of RFID technology in complex and distributed environments often leads to a multi-domain RFID system, in which trust establishment among entities from heterogeneous domains without past interaction or prior agreed policy, is a challenge. The current trust management mechanisms in the literature do not meet the specific requirements in multi-domain RFID systems. Therefore, this paper analyzes the special challenges on trust management in multi-domain RFID systems, and identifies the implications and the requirements of the challenges on the solutions to the trust management of multi-domain RFID systems. A multi-domain trust management model is proposed, which provides a hierarchical trust management framework include a diversity of trust evaluation and establishment approaches. The simulation results and analysis show that the proposed method has excellent ability to deal with the trust relationships, better security, and higher accuracy rate. PMID- 28708856 TI - Diabetes, use of metformin, and the risk of meningioma. AB - BACKGROUND: Metformin is a commonly used oral antidiabetic agent that has been associated with decreased cancer risk. However, data regarding the association between metformin use and the risk of meningioma are unavailable. METHODS: We conducted a matched case-control analysis using data from the U.K.-based Clinical Practice Research Datalink (CPRD) to analyse diabetes status, duration of diabetes, glycemic control, and use of metformin, sulfonylureas, and insulin in relation to the risk of meningioma. We conducted conditional logistic regression analyses to determine relative risks, estimated as odds ratios (ORs) with 95% confidence intervals (CIs) and adjusted for body mass index, smoking, history of arterial hypertension, myocardial infarction, and use of estrogens (among women). RESULTS: We identified 2,027 meningioma cases and 20,269 controls. For diabetes there was the suggestion of an inverse association with meningioma (OR = 0.89; 95%CI = 0.74-1.07), which was driven by an inverse relation among women (OR = 0.78; 95%CI = 0.62-0.98), in whom we also noted a suggestive inverse association with duration of diabetes (p-value for trend = 0.071). For metformin there was a suggestive positive relation, particularly after matching on duration of diabetes and HbA1c level (OR = 1.64; 95%CI = 0.89-3.04). Sulfonylureas showed no clear association (OR = 0.91; 95%CI = 0.46-1.80). For insulin there was the suggestion of an inverse relation, in particular when comparing a high vs. low number of prescriptions (OR = 0.58; 95%CI = 0.18-1.83). CONCLUSION: Further studies are needed to solidify a possible inverse association between diabetes and meningioma risk and to clarify the role of antidiabetics in this context. PMID- 28708857 TI - Comparative transcriptome analysis of flower heterosis in two soybean F1 hybrids by RNA-seq. AB - Heterosis has been widely exploited as an approach to enhance crop traits during breeding. However, its underlying molecular genetic mechanisms remain unclear. Recent advances in RNA sequencing technology (RNA-seq) have provided an opportunity to conduct transcriptome profiling for heterosis studies. We used RNA seq to analyze the flower transcriptomes of two F1 hybrid soybeans (HYBSOY-1 and HYBSOY-5) and their parents. More than 385 million high-quality reads were generated and aligned against the soybean reference genome. A total of 681 and 899 genes were identified as being differentially expressed between HYBSOY-1 and HYBSOY-5 and their parents, respectively. These differentially expressed genes (DEGs) were categorized into four major expression categories with 12 expression patterns. Furthermore, gene ontology (GO) term analysis showed that the DEGs were enriched in the categories metabolic process and catalytic activity, while Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis found that metabolic pathway and biosynthesis of secondary metabolites were enriched in the two F1 hybrids. Comparing the DEGs of the two F1 hybrids by GO term and KEGG pathway analyses identified 26 common DEGs that showed transgressive up regulation, and which could be considered potential candidate genes for heterosis in soybean F1 hybrids. This identification of an extensive transcriptome dataset gives a comprehensive overview of the flower transcriptomes in two F1 hybrids, and provides useful information for soybean hybrid breeding. These findings lay the foundation for future studies on molecular mechanisms underlying soybean heterosis. PMID- 28708858 TI - OsCNGC13 promotes seed-setting rate by facilitating pollen tube growth in stylar tissues. AB - Seed-setting rate is a critical determinant of grain yield in rice (Oryza sativa L.). Rapid and healthy pollen tube growth in the style is required for high seed setting rate. The molecular mechanisms governing this process remain largely unknown. In this study, we isolate a dominant low seed-setting rate rice mutant, sss1-D. Cellular examination results show that pollen tube growth is blocked in about half of the mutant styles. Molecular cloning and functional assays reveals that SSS1-D encodes OsCNGC13, a member of the cyclic nucleotide-gated channel family. OsCNGC13 is preferentially expressed in the pistils and its expression is dramatically reduced in the heterozygous plant, suggesting a haploinsufficiency nature for the dominant mutant phenotype. We show that OsCNGC13 is permeable to Ca2+. Consistent with this, accumulation of cytoplasmic calcium concentration ([Ca2+]cyt) is defective in the sss1-D mutant style after pollination. Further, the sss1-D mutant has altered extracellular matrix (ECM) components and delayed cell death in the style transmission tract (STT). Based on these results, we propose that OsCNGC13 acts as a novel maternal sporophytic factor required for stylar [Ca2+]cyt accumulation, ECM components modification and STT cell death, thus facilitating the penetration of pollen tube in the style for successful double fertilization and seed-setting in rice. PMID- 28708860 TI - Charged amino acid variability related to N-glyco -sylation and epitopes in A/H3N2 influenza: Hem -agglutinin and neuraminidase. AB - BACKGROUND: The A/H3N2 influenza viruses circulated in humans have been shown to undergo antigenic drift, a process in which amino acid mutations result from nucleotide substitutions. There are few reports regarding the charged amino acid mutations. The purpose of this paper is to explore the relations between charged amino acids, N-glycosylation and epitopes in hemagglutinin (HA) and neuraminidase (NA). METHODS: A total of 700 HA genes (691 NA genes) of A/H3N2 viruses were chronologically analyzed for the mutational variants in amino acid features, N glycosylation sites and epitopes since its emergence in 1968. RESULTS: It was found that both the number of HA N-glycosylation sites and the electric charge of HA increased gradually up to 2016. The charges of HA and HA1 increased respectively 1.54-fold (+7.0 /+17.8) and 1.08-fold (+8.0/+16.6) and the number of NGS in nearly doubled (7/12). As great diversities occurred in 1990s, involving Epitope A, B and D mutations, the charged amino acids in Epitopes A, B, C and D in HA1 mutated at a high frequency in global circulating strains last decade. The charged amino acid mutations in Epitopes A (T135K) has shown high mutability in strains near years, resulting in a decrease of NGT135-135. Both K158N and K160T not only involved mutations charged in epitope B, but also caused a gain of NYT158-160. Epitope B and its adjacent N-glycosylation site NYT158-160 mutated more frequently, which might be under greater immune pressure than the rest. CONCLUSIONS: The charged amino acid mutations in A/H3N2 Influenza play a significant role in virus evolution, which might cause an important public health issue. Variability related to both the epitopes (A and B) and N-glycosylation is beneficial for understanding the evolutionary mechanisms, disease pathogenesis and vaccine research. PMID- 28708859 TI - Interleukin-17A-induced production of acute serum amyloid A by keratinocytes contributes to psoriasis pathogenesis. AB - BACKGROUND: Acute-serum Amyloid A (A-SAA), one of the major acute-phase proteins, is mainly produced in the liver but extra-hepatic synthesis involving the skin has been reported. Its expression is regulated by the transcription factors NF kappaB, C/EBPbeta, STAT3 activated by proinflammatory cytokines. OBJECTIVES: We investigated A-SAA synthesis by resting and cytokine-activated Normal Human Epidermal Keratinocytes (NHEK), and their inflammatory response to A-SAA stimulation. A-SAA expression was also studied in mouse skin and liver in a model mimicking psoriasis and in the skin and sera of psoriatic and atopic dermatitis (AD) patients. METHODS: NHEK were stimulated by A-SAA or the cytokines IL-1alpha, IL-17A, IL-22, OSM, TNF-alpha alone or in combination, previously reported to reproduce features of psoriasis. Murine skins were treated by imiquimod cream. Human skins and sera were obtained from patients with psoriasis and AD. A-SAA mRNA was quantified by RT qPCR. A-SAA proteins were dosed by ELISA or immunonephelemetry assay. RESULTS: IL-1alpha, TNF-alpha and mainly IL-17A induced A-SAA expression by NHEK. A-SAA induced its own production and the synthesis of hBD2 and CCL20, both ligands for CCR6, a chemokine receptor involved in the trafficking of Th17 lymphocytes. A-SAA expression was increased in skins and livers from imiquimod-treated mice and in patient skins with psoriasis, but not significantly in those with AD. Correlations between A-SAA and psoriasis severity and duration were observed. CONCLUSION: Keratinocytes could contribute to psoriasis pathogenesis via A-SAA production, maintaining a cutaneous inflammatory environment, activating innate immunity and Th17 lymphocyte recruitment. PMID- 28708861 TI - Incidental mood state before dissonance induction affects attitude change. AB - The way that incidental affect impacts attitude change brought about by controlled processes has so far been examined when the incidental affective state is generated after dissonance state induction. We therefore investigated attitude change when the incidental mood occurs prior to dissonance state induction. We expected a negative mood to induce systematic processing, and a positive mood to induce heuristic processing. Given that both systematic processing and attitude change are cognitively costly, we expected participants who experienced the dissonance state in a negative mood to have insufficient resources to allocate to attitude change. In our experiment, after mood induction (negative, neutral or positive), participants were divided into low-dissonance and high-dissonance groups. They then wrote a counterattitudinal essay. Analysis of their attitudes towards the essay topic indicated that attitude change did not occur in the negative incidental mood condition. Moreover, written productivity-one indicator of cognitive resource allocation-varied according to the type of incidental mood, and only predicted attitude change in the high-dissonance group. Our results suggest that incidental mood before dissonance induction influences the style of information processing and, by so doing, affects the extent of attitude change. PMID- 28708862 TI - Anti-citrullinated protein antibody positive rheumatoid arthritis is primarily determined by rheumatoid factor titre and the shared epitope rather than smoking per se. AB - OBJECTIVE: To analyse the relationship between rheumatoid factor (RF) titre, smoking and HLA-DRB1 alleles coding a "shared epitope" (SE) in relation to anti citrullinated protein antibody (ACPA) positivity in rheumatoid arthritis (RA). METHODS: RA patients (n = 658) attending rheumatology clinics in Cornwall, UK (cohort 1) were stratified according to RF and ACPA titre, and smoking pack years at diagnosis. A further 409 RA patients from North Staffordshire, UK (cohort 2) were studied to confirm the relationship between RF levels, smoking and ACPA positivity in relation to SE status. RESULTS: In cohort 1 there was a trend (p<0.01) of increasing ACPA positivity rates with increasing levels of RF without statistically significant differences between patients who had never smoked and smokers (never smoked: 15/71 (21%) RF -ve, vs. 43/64 (67%) RF weak +ve, vs 88/100 (88%) RF strong +ve, ever smoked: 18/70 (26%) RF -ve vs. 66/83 (80%) RF weak +ve vs. 196/210 (93%) RF strong +ve). No significant gender difference was observed. No significant difference between smoking and ACPA positivity was seen in RF negative patients. Smoking >20 pack years conferred an increased risk of anti-CCP positive RA (158/200 (79%)), compared to having never smoked (146/235 (62%), p = <0.01), but this increased risk correlated with smokers' RF positivity as the principal determinant on subsequent regression analysis of cohort 2. In cohort 2, ACPA positivity rates significantly increased with RF positivity and carriage of 1 or 2 SE alleles (p<0.01). Little or no relationship was observed in patients lacking SE. CONCLUSIONS: ACPA positivity in RA strongly associates with increasing RF titre independent of smoking. This relationship is dependent on carriage of SE alleles. There is no relationship between ACPA and smoking in RF negative patients. PMID- 28708863 TI - Negative modulation of suppressive HIV-specific regulatory T cells by IL-2 adjuvanted therapeutic vaccine. AB - The potential benefit in using IL-2 in immunotherapy for cancer and autoimmunity has been linked to the modulation of immune responses, which partly relies on a direct effect on Tregs populations. Here, we revisited the role of IL-2 in HIV infection and investigated whether its use as an adjuvant with therapeutic vaccination, impacts on HIV-specific responses. Antiretroviral therapy treated patients were randomized to receive 4 boosts of vaccination (ALVACHIV/Lipo-6T, weeks 0/4/8/12) followed by 3 cycles of IL-2 (weeks 16/24/32) before treatment interruption (TI) at week40. IL-2 administration increased significantly HIV specific CD4+CD25+CD134+ T-cell responses, which inversely correlated with viral load after TI (r = -0.7, p <0.007) in the vaccine/IL-2 group. IL-2 increased global CD25+CD127lowFoxP3+Tregs (p <0.05) while it decreased HIV- but not CMV- specific CD39+FoxP3+CD25+CD134+Tregs (p <0.05). HIV-specific Tregs were inversely correlated with IFN-gamma producing specific-effectors (p = 0.03) and positively correlated with viral load (r = 0.7, p = 0.01), revealing their undesired presence during chronic infection. Global Tregs, but not HIV-specific Tregs, inversely correlated with a decrease in exhausted PD1+CD95+ T-cells (p = 0.001). Altogether, our results underline the negative impact of HIV-specific Tregs on HIV-specific effectors and reveal the beneficial use of IL-2 as an adjuvant as its administration increases global Tregs that impact on T-cell exhaustion and decreases HIV-specific CD39+Tregs by shifting the balance towards effectors. PMID- 28708864 TI - Abnormal lateralization of fine motor actions in Tourette syndrome persists into adulthood. AB - Youth with Tourette syndrome (TS) exhibit, compared to healthy, abnormal ability to lateralize digital sequential tasks. It is unknown whether this trait is related to inter-hemispheric connections, and whether it is preserved or lost in patients with TS persisting through adult life. We studied 13 adult TS patients and 15 age-matched healthy volunteers. All participants undertook: 1) a finger opposition task, performed with the right hand (RH) only or with both hands, using a sensor-engineered glove in synchrony with a metronome at 2 Hz; we calculated a lateralization index [(single RH-bimanual RH)/single RH X 100) for percentage of correct movements (%CORR); 2) MRI-based diffusion tensor imaging and probabilistic tractography of inter-hemispheric corpus callosum (CC) connections between supplementary motor areas (SMA) and primary motor cortices (M1). We confirmed a significant increase in the %CORR in RH in the bimanual vs. single task in TS patients (p<0.001), coupled to an abnormal ability to lateralize finger movements (significantly lower lateralization index for %CORR in TS patients, p = 0.04). The %CORR lateralization index correlated positively with tic severity measured with the Yale Global Tic Severity Scale (R = 0.55;p = 0.04). We detected a significantly higher fractional anisotropy (FA) in both the M1-M1 (p = 0.036) and the SMA-SMA (p = 0.018) callosal fibre tracts in TS patients. In healthy subjects, the %CORR lateralization index correlated positively with fractional anisotropy of SMA-SMA fibre tracts (R = 0.63, p = 0.02); this correlation was not significant in TS patients. TS patients exhibited an abnormal ability to lateralize finger movements in sequential tasks, which increased in accuracy when the task was performed bimanually. This abnormality persists throughout different age periods and appears dissociated from the transcallosal connectivity of motor cortical regions. The altered interhemispheric transfer of motor abilities in TS may be the result of compensatory processes linked to self-regulation of motor control. PMID- 28708865 TI - A deep learning framework for financial time series using stacked autoencoders and long-short term memory. AB - The application of deep learning approaches to finance has received a great deal of attention from both investors and researchers. This study presents a novel deep learning framework where wavelet transforms (WT), stacked autoencoders (SAEs) and long-short term memory (LSTM) are combined for stock price forecasting. The SAEs for hierarchically extracted deep features is introduced into stock price forecasting for the first time. The deep learning framework comprises three stages. First, the stock price time series is decomposed by WT to eliminate noise. Second, SAEs is applied to generate deep high-level features for predicting the stock price. Third, high-level denoising features are fed into LSTM to forecast the next day's closing price. Six market indices and their corresponding index futures are chosen to examine the performance of the proposed model. Results show that the proposed model outperforms other similar models in both predictive accuracy and profitability performance. PMID- 28708866 TI - A new index for characterizing micro-bead motion in a flow induced by ciliary beating: Part II, modeling. AB - Mucociliary clearance is one of the major lines of defense of the human respiratory system. The mucus layer coating the airways is constantly moved along and out of the lung by the activity of motile cilia, expelling at the same time particles trapped in it. The efficiency of the cilia motion can experimentally be assessed by measuring the velocity of micro-beads traveling through the fluid surrounding the cilia. Here we present a mathematical model of the fluid flow and of the micro-beads motion. The coordinated movement of the ciliated edge is represented as a continuous envelope imposing a periodic moving velocity boundary condition on the surrounding fluid. Vanishing velocity and vanishing shear stress boundary conditions are applied to the fluid at a finite distance above the ciliated edge. The flow field is expanded in powers of the amplitude of the individual cilium movement. It is found that the continuous component of the horizontal velocity at the ciliated edge generates a 2D fluid velocity field with a parabolic profile in the vertical direction, in agreement with the experimental measurements. Conversely, we show than this model can be used to extract microscopic properties of the cilia motion by extrapolating the micro-bead velocity measurement at the ciliated edge. Finally, we derive from these measurements a scalar index providing a direct assessment of the cilia beating efficiency. This index can easily be measured in patients without any modification of the current clinical procedures. PMID- 28708867 TI - Transcriptome differences between enrofloxacin-resistant and enrofloxacin susceptible strains of Aeromonas hydrophila. AB - Enrofloxacin is the most commonly used antibiotic to control diseases in aquatic animals caused by A. hydrophila. This study conducted de novo transcriptome sequencing and compared the global transcriptomes of enrofloxacin-resistant and enrofloxacin-susceptible strains. We got a total of 4,714 unigenes were assembled. Of these, 4,122 were annotated. A total of 3,280 unigenes were assigned to GO, 3,388 unigenes were classified into Cluster of Orthologous Groups of proteins (COG) using BLAST and BLAST2GO software, and 2,568 were mapped onto pathways using the Kyoto Encyclopedia of Gene and Genomes Pathway database. Furthermore, 218 unigenes were deemed to be DEGs. After enrofloxacin treatment, 135 genes were upregulated and 83 genes were downregulated. The GO terms biological process (126 genes) and metabolic process (136 genes) were the most enriched, and the terms for protein folding, response to stress, and SOS response were also significantly enriched. This study identified enrofloxacin treatment affects multiple biological functions of A. hydrophila. Enrofloxacin resistance in A. hydrophila is closely related to the reduction of intracellular drug accumulation caused by ABC transporters and increased expression of topoisomerase IV. PMID- 28708868 TI - Dynamics of tactical behaviour in association football when manipulating players' space of interaction. AB - The analysis of positional data in association football allows the spatial distribution of players during matches to be described in order to improve the understanding of tactical-related constraints on the behavioural dynamics of players. The aim of this study was to identify how players' spatial restrictions affected the exploratory tactical behaviour and constrained the perceptual-motor workspace of players in possession of the ball, as well as inter-player passing interactions. Nineteen professional outfield male players were divided into two teams of 10 and 9 players, respectively. The game was played under three spatial constraints: a) players were not allowed to move out of their allocated zones, except for the player in possession of the ball; b) players were allowed to move to an adjacent zone, and; c) non-specific spatial constraints. Positional data was captured using a 5 Hz interpolated GPS tracking system and used to define the configuration states of players for each second in time. The configuration state comprised 37 categories derived from tactical actions, distance from the nearest opponent, distance from the target and movement speed. Notational analysis of players in possession of the ball allowed the mean time of ball possession and the probabilities of passing the ball between players to be calculated. The results revealed that the players' long-term exploratory behaviour decreased and their short-term exploration increased when restricting their space of interaction. Relaxing players' positional constraints seemed to increase the speed of ball flow dynamics. Allowing players to move to an adjacent sub-area increased the probabilities of interaction with the full-back during play build up. The instability of the coordinative state defined by being free from opponents when players had the ball possession was an invariant feature under all three task constraints. By allowing players to move to adjacent sub-areas, the coordinative state became highly unstable when the distance from the target decreased. Ball location relative to the scoring zone and interpersonal distance constitute key environmental information that constrains the players' coordinative behaviour. Based on our results, dynamic overlap is presented as a good option to capture tactical performance. Moreover, the selected collective (i.e. relational) variables would allow coaches to identify the effects of training drills on teams and players' behaviour. More research is needed considering these type variables to understand how the manipulation of constraints induce a more stable or flexible dynamical structure of tactical behaviour. PMID- 28708869 TI - Long-term efficacy and safety of carotid artery stenting versus endarterectomy: A meta-analysis of randomized controlled trials. AB - BACKGROUND: Many recent trials have investigated the long-term efficacy and safety of endarterectomy versus stenting in treating patients with carotid artery stenosis. We aimed to determine the long-term comparative efficacy and safety of both procedures by pooling this evidence in a meta-analysis. METHODS: We searched PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials for studies published until May 6, 2016. Randomized controlled trials, which reported outcomes of interest with a median follow-up of at least 4-year, were included. RESULTS: Eight trials involving 7005 patients and 41824 patient-years of follow up were included. In terms of the periprocedural outcomes, stenting was associated with a lower risk of myocardial infarction (OR: 0.51; 95% CI: 0.33 to 0.80; P = 0.003) but a higher risk of death or stroke (the composite endpoint, OR: 1.76; 95% CI: 1.38 to 2.25; P < 0.0001), a result that was primarily driven by minor stroke (OR: 2.19; 95% CI: 1.59 to 3.01; P < 0.0001), less so by periprocedural death (OR: 1.68; 95% CI: 0.82 to 3.44; P = 0.16) and major stroke (OR: 1.41; 95% CI: 0.95 to 2.09; P = 0.09). In terms of the long-term outcomes, stenting was associated with a higher risk of stroke (OR 1.45; 95% CI: 1.22 to 1.73; P < 0.0001) and the composite outcome of death or stroke (OR 1.25; 95% CI: 1.05 to 1.48; P = 0.01). No difference was found in long-term all-cause mortality between stenting and endarterectomy (OR: 1.09; 95% CI: 0.95 to 1.26; P = 0.21) and restenosis (OR: 1.48 (95% CI: 0.93 to 2.35; P = 0.10). No evidence of significant heterogeneity was found in any of the analyses. CONCLUSIONS: Carotid endarterectomy was found to be superior to stenting for short- and long-term outcomes, although endarterectomy was associated with a higher risk of periprocedural myocardial infarction. Carotid endarterectomy should be offered as the first choice for carotid stenosis at present, however, more evidence is needed because rapid progress in concurrent devices and medical treatments is being made. PMID- 28708870 TI - Assessment of resampling methods for causality testing: A note on the US inflation behavior. AB - Different resampling methods for the null hypothesis of no Granger causality are assessed in the setting of multivariate time series, taking into account that the driving-response coupling is conditioned on the other observed variables. As appropriate test statistic for this setting, the partial transfer entropy (PTE), an information and model-free measure, is used. Two resampling techniques, time shifted surrogates and the stationary bootstrap, are combined with three independence settings (giving a total of six resampling methods), all approximating the null hypothesis of no Granger causality. In these three settings, the level of dependence is changed, while the conditioning variables remain intact. The empirical null distribution of the PTE, as the surrogate and bootstrapped time series become more independent, is examined along with the size and power of the respective tests. Additionally, we consider a seventh resampling method by contemporaneously resampling the driving and the response time series using the stationary bootstrap. Although this case does not comply with the no causality hypothesis, one can obtain an accurate sampling distribution for the mean of the test statistic since its value is zero under H0. Results indicate that as the resampling setting gets more independent, the test becomes more conservative. Finally, we conclude with a real application. More specifically, we investigate the causal links among the growth rates for the US CPI, money supply and crude oil. Based on the PTE and the seven resampling methods, we consistently find that changes in crude oil cause inflation conditioning on money supply in the post-1986 period. However this relationship cannot be explained on the basis of traditional cost-push mechanisms. PMID- 28708871 TI - Ursodeoxycholic acid inhibits the proliferation of colon cancer cells by regulating oxidative stress and cancer stem-like cell growth. AB - INTRODUCTION: The regulation of reactive oxygen species (ROS) exists as a therapeutic target for cancer treatments. Previous studies have shown that ursodeoxycholic acid (UDCA) suppresses the proliferation of colon cancer cells. The aim of this study was to evaluate the effect of UDCA upon the proliferation of colon cancer cells as a direct result of the regulation of ROS. METHOD: Colon cancer cell lines (HT29 and HCT116) were treated with UDCA. The total number of cells and the number of dead cells were determined using cell counters. A fluorescein isothiocyanate-bromodeoxyuridine flow kit was used to analyze cell cycle variations. Upon exposure to UDCA, the protein levels of p27, p21, CDK2, CDK4 and CDK6 were determined using western blotting, and qRT-PCR was used to determine levels of mRNA. We preformed dichlorofluorescindiacetate (DCF-DA) staining to detect alteration of intracellular ROS using fluorescence activated cell sorting (FACS). Colon cancer stem-like cell lines were generated by tumorsphere culture and treated with UDCA for seven days. The total number of tumorspheres was determined using microscopy. RESULTS: We found that UDCA reduced the total number of colon cancer cells, but did not increase the number of dead cells. UDCA inhibited the G1/S and G2/M transition phases in colon cancer cells. UDCA induced expression of cell cycle inhibitors such as p27 and p21. However, it was determined that UDCA suppressed levels of CDK2, CDK4, and CDK6. UDCA regulated intracellular ROS generation in colon cancer cells, and induced activation of Erk1/2. Finally, UDCA inhibited formation of colon cancer stem-like cells. CONCLUSION: Our results indicate that UDCA suppresses proliferation through regulation of oxidative stress in colon cancer cells, as well as colon cancer stem-like cells. PMID- 28708872 TI - Nasopharyngeal microbiota in infants and changes during viral upper respiratory tract infection and acute otitis media. AB - BACKGROUND: Interferences between pathogenic bacteria and specific commensals are known. We determined the interactions between nasopharyngeal microbial pathogens and commensals during viral upper respiratory tract infection (URI) and acute otitis media (AOM) in infants. METHODS: We analyzed 971 specimens collected monthly and during URI and AOM episodes from 139 infants. The 16S rRNA V4 gene regions were sequenced on the Illumina MiSeq platform. RESULTS: Among the high abundant genus-level nasopharyngeal microbiota were Moraxella, Haemophilus, and Streptococcus (3 otopathogen genera), Corynebacterium, Dolosigranulum, Staphylococcus, Acinetobacter, Pseudomonas, and Bifidobacterium. Bacterial diversity was lower in culture-positive samples for Streptococcus pneumoniae, and Haemophilus influenzae, compared to cultured-negative samples. URI frequencies were positively associated with increasing trend in otopathogen colonization. AOM frequencies were associated with decreasing trend in Micrococcus colonization. During URI and AOM, there were increases in abundance of otopathogen genera and decreases in Pseudomonas, Myroides, Yersinia, and Sphingomonas. Otopathogen abundance was increased during symptomatic viral infection, but not during asymptomatic infection. The risk for AOM complicating URI was reduced by increased abundance of Staphylococcus and Sphingobium. CONCLUSION: Otopathogen genera played the key roles in URI and AOM occurrences. Staphylococcus counteracts otopathogens thus Staphylococcal colonization may be beneficial, rather than harmful. While Sphingobium may play a role in preventing AOM complicating URI, the commonly used probiotic Bifidobacterium did not play a significant role during URI or AOM. The role of less common commensals in counteracting the deleterious effects of otopathogens requires further studies. PMID- 28708873 TI - Impact of early cART on HIV blood and semen compartments at the time of primary infection. AB - BACKGROUND: HIV-infected cells in semen facilitate viral transmission. We studied the establishment of HIV reservoirs in semen and blood during PHI, along with systemic immune activation and the impact of early cART. METHODS: Patients in the ANRS-147-OPTIPRIM trial received two years of early cART. Nineteen patients of the trial were analyzed, out of which 8 had acute PHI (WB <=1 Ab). We quantified total cell-associated (ca) HIV-DNA in blood and semen and HIV-RNA in blood and semen plasma samples, collected during PHI and at 24 months of treatment. RESULTS: At enrollment, HIV-RNA load was higher in blood than in semen (median 5.66 vs 4.22 log10 cp/mL, p<0.0001). Semen HIV-RNA load correlated strongly with blood HIV-RNA load (r = 0.81, p = 0.02, the CD4 cell count (r = -0.98, p<0.0001), and the CD4/CD8 ratio (r = -0.85, p<0.01) in acute infection but not in later stages of PHI. Median blood and seminal cellular HIV-DNA levels were 3.59 and 0.31 log10cp/106 cells, respectively. HIV-DNA load peaked in semen later than in blood and then correlated with blood IP10 level (r = 0.62, p = 0.04). HIV-RNA was undetectable in blood and semen after two years of effective cART. Semen HIV-DNA load declined similarly, except in one patient who had persistently high IP-10 and IL-6 levels and used recreational drugs. CONCLUSIONS: HIV reservoir cells are found in semen during PHI, with gradual compartmentalization. Its size was linked to the plasma IP-10 level. Early treatment purges both the virus and infected cells, reducing the high risk of transmission during PHI. CLINICAL TRIALS REGISTRATION: NCT01033760. PMID- 28708874 TI - The enigma of the near-symmetry of proteins: Domain swapping. AB - The majority of proteins form oligomers which have rotational symmetry. Literature has suggested many functional advantages that the symmetric packing offers. Yet, despite these advantages, the vast majority of protein oligomers are only nearly symmetric. A key question in the field of proteins structure is therefore, if symmetry is so advantageous, why do oligomers settle for aggregates that do not maximize that structural property? The answer to that question is apparently multi-parametric, and involves distortions at the interaction zones of the monomer units of the oligomer in order to minimize the free energy, the dynamics of the protein, the effects of surroundings parameters, and the mechanism of oligomerization. The study of this problem is in its infancy: Only the first parameter has been explored so far. Here we focus on the last parameter the mechanism of formation. To test this effect we have selected to focus on the domain swapping mechanism of oligomerization, by which oligomers form in a mechanism that swaps identical portions of monomeric units, resulting in an interwoven oligomer. We are using continuous symmetry measures to analyze in detail the oligomer formed by this mechanism, and found, that without exception, in all analyzed cases, perfect symmetry is given away, and we are able to identify that the main burden of distortion lies in the hinge regions that connect the swapped portions. We show that the continuous symmetry analysis method clearly identifies the hinge region of swapped domain proteins-considered to be a non-trivial task. We corroborate our conclusion about the central role of the hinge region in affecting the symmetry of the oligomers, by a special probability analysis developed particularly for that purpose. PMID- 28708875 TI - Predictive value of serum progesterone level on beta-hCG check day in women with previous repeated miscarriages after in vitro fertilization. AB - OBJECTIVE: To evaluate the predictive value of the progesterone level at the beta human chorionic gonadotropin (beta-hCG) check day for ongoing pregnancy maintenance in in vitro fertilization (IVF) cycles in women with previous unexplained repeated miscarriages. MATERIALS AND METHODS: One hundred and forty eight women, with visible gestational sac after IVF, were recruited in this observational study. All subjects had unexplained recurrent miscarriages in more than two previous IVF cycles. The progesterone level at the beta-hCG check day (i.e. 14 days after oocyte retrieval) was assessed. The area under the curve (AUC) of the progesterone level was evaluated to predict the ongoing pregnancy or miscarriage outcomes. RESULTS: The overall ongoing pregnancy rate was 60.8% (90/148). The cut-off value with beta-hCG levels higher than 126.5 mIU/mL and with progesterone levels higher than 25.2 ng/mL could be the predictive factors for ongoing pregnancy maintenance (AUC = 0.788 and 0.826; sensitivity = 0.788 and 0.723; specificity = 0.689 and 0.833; P < 0.0001 and P < 0.0001, respectively). The miscarriage rates were 19.5% (15/77) in the women with beta-hCG > 126.5 mIU/mL and 13.0% (10/77) in those with > 25.2 ng/mL. In the comparison of the ROC curves between both values, a similar significance was found. The subjects with beta-hCG > 126.5 mIU/mL and progesterone > 25.2 ng/mL showed higher ongoing pregnancy rates [98.0% (49/50) vs. 41.8% (41/98)] than those with beta-hCG <= 126.5 mIU/mL or progesterone <= 25.2 ng/mL. CONCLUSIONS: The progesterone level at 14 days after oocyte retrieval can be a good predictive marker for ongoing pregnancy maintenance in women with repeated IVF failure with miscarriage, together with the beta-hCG level. The combined cut-off value of progesterone > 25.2 ng/mL and beta-hCG > 126.5 mIU/mL may suggest a good prognosis. PMID- 28708876 TI - Presentation at computed tomography (CT) scan of the thorax and first year diagnostic and treatment utilization among patients diagnosed with lung cancer. AB - BACKGROUND: As Medicare expands the use of computed tomography (CT) for diagnosing lung cancer, there is increased opportunity to diagnose lung cancer in asymptomatic patients. This descriptive study characterizes the disease-specific diagnostic and treatment services that patients with a positive diagnosis following CT received, stratified by presentation at CT. METHODS: Patients who were diagnosed with lung cancer following CT in 2013, had no history of lung cancer, survived at least 1 year, were aged 55-80 years, and had Medicare Advantage insurance were included. Patients were grouped based upon presentation at CT: morbidities unrelated to lung cancer, classic lung cancer symptoms, and cancer syndromes. Patients with none of these factors were categorized into a no diagnoses/symptoms group. The type and intensity of services used in the year following the CT was reported for each group. RESULTS: 1,261 patients were included. Early treatment services were most common in the group with morbidities unrelated to lung cancer (13.7%) and least common in the cancer syndromes group (6.6%). Advanced treatment services were used by 47.3% of the cancer syndromes group versus 23.5% of the no diagnoses/symptoms group. CONCLUSIONS: The intensity of disease-specific diagnostic and treatment services varied by presentation at CT. Patients with no symptoms or morbidities at the time of CT less frequently received advanced interventions. Learning about the utilization patterns of others with a similar presentation at CT may help patients with positive lung cancer diagnoses engage in shared decision making and in norming their experiences against those of other similarly-situated patients. PMID- 28708878 TI - Reforestation-induced changes of landscape composition and configuration modulate freshwater supply and flooding risk of tropical watersheds. AB - Impact of changes in land cover and land use on hydrological service of tropical watersheds is one of the focal research tropics in both hydrology and Land Cover Land Use Changes (LCLUC). Land fragmentation is an important feature of LCLUC, however, its impact on hydrological service of tropical watershed is unclear despite a few theoretical frameworks. In this paper, we described a simulation study of eight tropical watersheds in Puerto Rico using the Soil Water Assessment Tool. Annual average stream discharge was derived according to the simulations with the land cover maps in 1977, 1991, and 2000. Annual big stream discharge with risks of flooding and severe soil erosion was computed as the sum of daily discharge greater than 95th percentile. The impacts of changes in land cover and fragmentation represented by perimeter-to-area ratio of land patches on annual average and big discharges were further analyzed by means of the linear mixed effects model. Most mountainous watersheds were characterized by reforestation in 1977-1991 but slight deforestation in 1991-2000. Forest perimeter-to-area ratio was significantly correlated with covers of forest (correlation coefficient of 0.97), pasture (0.94), and urban (0.95). Thus forest fragmentation was reduced by reforestation but increased by deforestation. The annual average and big discharges were significantly reduced by forest cover and forest perimeter-to area ratio. The enhanced edge effect by forest fragmentation may have incurred more effective interception of the subsurface flow by forest root system, and promoted forest transpiration, thus reduced stream flows. Land cover change plays more important roles in regulating the big discharges than altering the annual average discharges. Due to the negative correlation between forest cover and fragmentation, the decreased forest fragmentation accompanied with reforestation offsets the impact of reforestation on lessening freshwater supply and flooding risk. PMID- 28708877 TI - Median raphe region stimulation alone generates remote, but not recent fear memory traces. AB - The median raphe region (MRR) is believed to control the fear circuitry indirectly, by influencing the encoding and retrieval of fear memories by amygdala, hippocampus and prefrontal cortex. Here we show that in addition to this established role, MRR stimulation may alone elicit the emergence of remote but not recent fear memories. We substituted electric shocks with optic stimulation of MRR in C57BL/6N male mice in an optogenetic conditioning paradigm and found that stimulations produced agitation, but not fear, during the conditioning trial. Contextual fear, reflected by freezing was not present the next day, but appeared after a 7 days incubation. The optogenetic silencing of MRR during electric shocks ameliorated conditioned fear also seven, but not one day after conditioning. The optogenetic stimulation patterns (50Hz theta burst and 20Hz) used in our tests elicited serotonin release in vitro and lead to activation primarily in the periaqueductal gray examined by c-Fos immunohistochemistry. Earlier studies demonstrated that fear can be induced acutely by stimulation of several subcortical centers, which, however, do not generate persistent fear memories. Here we show that the MRR also elicits fear, but this develops slowly over time, likely by plastic changes induced by the area and its connections. These findings assign a specific role to the MRR in fear learning. Particularly, we suggest that this area is responsible for the durable sensitization of fear circuits towards aversive contexts, and by this, it contributes to the persistence of fear memories. This suggests the existence a bottom-up control of fear circuits by the MRR, which complements the top-down control exerted by the medial prefrontal cortex. PMID- 28708879 TI - Real and virtual worlds alike: Adolescents' psychopathology is reflected in their videogame virtual behaviors. AB - Current research refers to videogames as a constant variable. However, games today are designed to be highly interactive and versatile: two players may be using the same videogame, but as a result of different using patterns, the game will not necessarily encompass the same content and gameplay. The current study examined the possible relationship between psychopathology and in-game playing patterns. We hypothesized that adolescents would play videogames differently, in a manner that would reflect their particular psychopathologies. We examined 47 male adolescents from three diagnostic groups: those suffering from externalizing psychopathologies, internalizing psychopathologies and controls. We performed a high-resolution examination of their gameplay, using in-game quantitative statistics mechanisms of two fundamentally different games, a structured racing game and an unstructured adventure game. While there was no difference in the groups' using patterns of the structured game, there was a high variability between the groups' using patterns when they were using a non-structured game. These findings suggest that virtual behavior in unstructured games is reflective of adolescent-players psychopathology, and might shed light on an unexplored facet of videogames research. Possible implications are discussed. PMID- 28708880 TI - Pediatric sleep apnea and depressive disorders risk: A population-based 15-year retrospective cohort study. AB - BACKGROUND: Studies have shown a higher risk of depressive disorders in children with sleep apnea than in those without sleep apnea. However, the association between sleep apnea and subsequent depressive disorders in the pediatric population remains undetermined. Thus, this study investigated the risk of depressive disorders among pediatric patients with sleep apnea. METHODS: In this study, the population-based National Health Insurance Research Database of Taiwan was used to identify patients who had first been diagnosed with sleep apnea between 1999 and 2013. Patients with sleep apnea who were younger than 18 years were included in the sleep apnea group. Controls (those without sleep apnea) were matched to patients with sleep apnea at a 1:10 ratio by age, sex, and index year. Patients who had baseline or inherited depressive disorders before the enrollment date were excluded. The two groups were followed up until December 31, 2013. The primary endpoint was the occurrence of one or more depressive disorders. RESULTS: At the end of this study, 6,237 children had been enrolled, comprising 567 children with sleep apnea and 5,670 children without sleep apnea. During the mean follow-up period of 5.87 years, a total of 77 children (1.23%) developed one or more depressive disorders; 14 (2.46%) from the sleep apnea group and 63 (1.11%) from the control group. Kaplan-Meier analysis showed that children with sleep apnea had a significantly higher risk of depressive disorders (log-rank test, p = 0.002). After adjusting for covariates, the risk of subsequent depressive disorders among children with sleep apnea was still significantly higher (hazard ratio [HR] = 2.25; 95% confidence interval [CI] = 1.25-4.05; p = 0.006). Moreover, boys with sleep apnea had a significantly higher risk than those without sleep apnea (adjusted HR = 3.77; 95% CI, 1.82-7.54; p < 0.001). Furthermore, in sleep apnea group, children older than 12 years of age had more risk to depression (hazard ratio (HR) = 7.1833, 95% confidence interval (CI), 2.3734 to 21.7411; p = 0.0004). CONCLUSIONS: This study found a significantly higher subsequent risk of depressive disorders in children with sleep apnea, particularly boys and those older than 12 years of age. The study findings strongly suggest that clinicians should provide psychological evaluation and supportive care for children with sleep apnea, in addition to medical treatment. PMID- 28708881 TI - Large anthropogenic impacts on a charismatic small carnivore: Insights from distribution surveys of red panda Ailurus fulgens in Nepal. AB - Protected areas are key to preserving biodiversity and maintaining ecosystem services. However, their ability to ensure long-term survival of threatened andendangered species varies across countries, regions and landscapes. Distribution surveys can beparticularly important for assessing the value of protected areas, and gauging their efficacy incatering to species-specific requirements. We assessed the conservation value of one such reserve for a charismatic yet globally endangered species, the red panda Ailurus fulgens,in the light of on-going land-use transformation in Nepal. We conducted field surveys forindirect signs of red pandas along forest trails in 25-km2 sampling grid cells (n = 54) of Dhorpatan Hunting Reserve, and confronted a set of ecological hypotheses to the data using hierarchical occupancy models. We estimated overall occupancy at Psi(SE) = 0.41 (0.007), with relatively high site-level detectability [p = 0.93 (SE = 0.001)]. Our results show that despitebeing a subsistence form of small-scale resource use, extraction of bamboo and livestock grazing negatively affected panda occurrence, albeit at different intensities. The amount of bamboo cover,rather than the overall proportion of forest cover, had greater influence on the panda occurrence. Despite availability of bamboo cover, areas with bamboo extraction and anthropogenic disturbances were less likely to be occupied by pandas. Together, these results suggest that long-term persistence of red pandas in this reserve and elsewhere across the species' range will require preventing commercial extractionof bamboo, coupled with case specific regulation of anthropogenic exploitation of red panda habitats. PMID- 28708882 TI - Evolution of the scattering properties of phytoplankton cells from flow cytometry measurements. AB - After the exponential growth phase, variability in the scattering efficiency of phytoplankton cells over their complete life cycle is not well characterised. Bulk measurements are impacted by senescent cells and detritrus. Thus the analysis of the evolution of the optical properties thanks to their morphological and/or intra-cellular variations remains poorly studied. Using the Cytosense flow cytometer (CytoBuoy b.v., NL), the temporal course of the forward and sideward efficiencies of two phytoplankton species (Thalassiosira pseudonana and Chlamydomonas concordia) were analyzed during a complete life-cycle. These two species differ considerably from a morphological point of view. Over the whole experiment, the forward and sideward efficiencies of Thalassiosira pseudonana were, on average, respectively 2.2 and 1.6 times higher than the efficiencies of Chlamydomonas concordia. Large intra-species variability of the efficiencies were observed over the life cycle of the considered species. It highlights the importance of considering the optical properties of phytoplankton cells as a function of the population growth stage of the considered species. Furthermore, flow cytometry measurements were combined with radiative transfer simulations and biogeochemical and optical measurements. Results showed that the real refractive index of the chloroplast is a key parameter driving the sideward signal and that a simplistic two-layered model (cytoplasm-chloroplast) seems particularly appropriate to represent the phytoplankton cells. PMID- 28708883 TI - Impact of stage, management and recurrence on survival rates in laryngeal cancer. AB - A retrospective, longitudinal study of 1,616 patients with primary laryngeal squamous cell carcinoma (LSCC) at a single center in Norway during 1983-2010 was undertaken to investigate overall survival, disease specific survival, disease free survival, prognostic factors for overall survival, and impact of recurrence among all-stage laryngeal cancer patients over 15 years' follow-up. The prognostic impact of gender, age, smoking/alcohol, subsite, tumour, node and metastasis staging, period and modality of treatment were evaluated using Kaplan Meier and Cox proportional hazard analyses. The importance of recurrence on survival was assessed based on case fatality rates. Five-year overall survival was 56.8%, 64.0% and 38.8%, and disease-specific survival was 80.2%, 87% and 61.6%, respectively, for the entire cohort and for glottic and supraglottic LSCC. Old age, advanced-stage LSCC and supraglottic cancer were associated with lower overall survival. The risk of disease-specific death plateaued after five years and varied significantly by subsite. Multivariate analysis of glottic LSCC revealed that surgical treatment improved overall survival, whereas old age, alcohol, T3-T4 status, positive N-status and no treatment were associated with worse survival. In supraglottic LSCC, age, alcohol, and positive N-status had a significant impact on overall survival by multivariate analysis. Five-year overall survival and disease-specific survival among patients with recurrent disease were 34% and 52%, respectively. In conclusion, marked difference in overall survival between glottic and supraglottic LSCC underline the importance of subsite-specific survival analysis. T-status and primary surgical management is essential only for glottic LSCC, emphasizing the importance of correct disease classification. Inferior outcomes in supraglottic LSCC are associated with old age, positive N-status, and improved follow-up routines are necessary. Primary tumor control is essential since recurrence impairs survival considerably in all subsites. The potential benefit of a primary surgical approach towards T3 LSCC awaits further investigation. PMID- 28708884 TI - A Jak1/2 inhibitor, baricitinib, inhibits osteoclastogenesis by suppressing RANKL expression in osteoblasts in vitro. AB - The Janus kinases (Jaks) are hubs in the signaling process of more than 50 cytokine or hormone receptors. However, the function of Jak in bone metabolism remains to be elucidated. Here, we showed that the inhibition of Jak1 and/or Jak2 in osteoblast-lineage cells led to impaired osteoclastogenesis due to the reduced expression of receptor activator of nuclear factor-kappaB ligand (RANKL). Murine calvaria-derived osteoblasts induced differentiation of bone marrow cells into osteoclasts in the presence of 1,25-dihydroxyvitamin D3 (1,25D3) and prostaglandin E2 (PGE2) in vitro. However, treatment with the Jak1/2 inhibitor, baricitinib, markedly inhibited osteoclastogenesis in the co-culture. On the other hand, baricitinib did not inhibit RANKL-induced osteoclast differentiation of bone marrow macrophages. These results indicated that baricitinib acted on osteoblasts, but not on bone marrow macrophages. Baricitinib suppressed 1,25D3 and PGE2-induced up-regulation of RANKL in osteoblasts, but not macrophage colony stimulating factor expression. Moreover, the addition of recombinant RANKL to co cultures completely rescued baricitinib-induced impairment of osteoclastogenesis. shRNA-mediated knockdown of Jak1 or Jak2 also suppressed RANKL expression in osteoblasts and inhibited osteoclastogenesis. Finally, cytokine array revealed that 1,25D3 and PGE2 stimulated secretion of interleukin-6 (IL-6), IL-11, and leukemia inhibitory factor in the co-culture. Hence, Jak1 and Jak2 represent novel therapeutic targets for osteoporosis as well as inflammatory bone diseases including rheumatoid arthritis. PMID- 28708885 TI - Pioglitazone ameliorates glomerular NLRP3 inflammasome activation in apolipoprotein E knockout mice with diabetes mellitus. AB - OBJECTIVE: The NLRP3 inflammasome plays an important role in the pathogenesis of inflammation in diabetic nephropathy (DN). Pioglitazone (PIO) has been found to exert an anti-inflammatory effect in patients with diabetes mellitus, but it is still unclear whether PIO exhibits a similar effect in DN. We aimed to explore the effect and underlying mechanism of PIO on DN, as well as investigate if NLRP3 is a pharmacologic target of PIO. METHODS: We divided 48 apolipoprotein E (apoE) (-/-) mice into 4 groups: apoE (-/-), apoE (-/-) with PIO, diabetic apoE (-/-), and diabetic apoE (-/-) with PIO. Wild type male C57BL/6 mice were used as controls (n = 8 per group). After 8 weeks of PIO treatment, we examined the baseline characteristics and metabolic parameters of each group, and we used enzyme-linked immunosorbent assay (ELISA), western blot, and immunohistochemical staining to evaluate the expression levels of advanced glycation end products (AGEs), receptor for advanced glycation end products (RAGE), NLRP3, nuclear factor-kappa B (NF-kappaB), caspase-1, interleukin (IL)-18, and IL-1beta in each group. RESULTS: Compared to the diabetic apoE (-/-) group, PIO treatment decreased blood glucose, cholesterol, serum blood urea nitrogen (BUN), and creatinine levels. It also depressed the glomerular mesangial expansion. PIO down regulated expression of AGEs, RAGE, and NF-kappaB, all of which further depressed NLRP3, caspase-1, IL-18, and IL-1beta levels. CONCLUSION: Pioglitazone can ameliorate diabetic renal damage, and this effect is related to the inhibition of renal AGE/RAGE axis activation and the down-regulation of NF-kappaB expression. These effects lead to a decline in NLRP3 levels and downstream secretion of inflammatory cytokines. PMID- 28708886 TI - KIR3DL01 upregulation on gut natural killer cells in response to SIV infection of KIR- and MHC class I-defined rhesus macaques. AB - Natural killer cells provide an important early defense against viral pathogens and are regulated in part by interactions between highly polymorphic killer-cell immunoglobulin-like receptors (KIRs) on NK cells and their MHC class I ligands on target cells. We previously identified MHC class I ligands for two rhesus macaque KIRs: KIR3DL01 recognizes Mamu-Bw4 molecules and KIR3DL05 recognizes Mamu-A1*002. To determine how these interactions influence NK cell responses, we infected KIR3DL01+ and KIR3DL05+ macaques with and without defined ligands for these receptors with SIVmac239, and monitored NK cell responses in peripheral blood and lymphoid tissues. NK cell responses in blood were broadly stimulated, as indicated by rapid increases in the CD16+ population during acute infection and sustained increases in the CD16+ and CD16-CD56- populations during chronic infection. Markers of proliferation (Ki-67), activation (CD69 & HLA-DR) and antiviral activity (CD107a & TNFalpha) were also widely expressed, but began to diverge during chronic infection, as reflected by sustained CD107a and TNFalpha upregulation by KIR3DL01+, but not by KIR3DL05+ NK cells. Significant increases in the frequency of KIR3DL01+ (but not KIR3DL05+) NK cells were also observed in tissues, particularly in the gut-associated lymphoid tissues, where this receptor was preferentially upregulated on CD56+ and CD16-CD56- subsets. These results reveal broad NK cell activation and dynamic changes in the phenotypic properties of NK cells in response to SIV infection, including the enrichment of KIR3DL01+ NK cells in tissues that support high levels of virus replication. PMID- 28708887 TI - Carried over: Heat stress in the egg stage reduces subsequent performance in a butterfly. AB - Increasing heat stress caused by anthropogenic climate change may pose a substantial challenge to biodiversity due to associated detrimental effects on survival and reproduction. Therefore, heat tolerance has recently received substantial attention, but its variation throughout ontogeny and effects carried over from one developmental stage to another remained largely neglected. To explore to what extent stress experienced early in life affects later life stages, we here investigate effects of heat stress experienced in the egg stage throughout ontogeny in the tropical butterfly Bicyclus anynana. We found that detrimental effects of heat stress in the egg stage were detectable in hatchlings, larvae and even resulting adults, as evidenced by decreased survival, growth, and body mass. This study shows that even in holometabalous insects with discrete life stages effects of stress experienced early in life are carried over to later stages, substantially reducing subsequent fitness. We argue that such effects need to be considered when trying to forecast species responses to climate change. PMID- 28708888 TI - Correction: Mycobacterium tuberculosis arrests host cycle at the G1/S transition to establish long term infection. AB - [This corrects the article DOI: 10.1371/journal.ppat.1006389.]. PMID- 28708889 TI - A new index for characterizing micro-bead motion in a flow induced by ciliary beating: Part I, experimental analysis. AB - Mucociliary clearance is one of the major lines of defense of the respiratory system. The mucus layer coating the pulmonary airways is moved along and out of the lung by the activity of motile cilia, thus expelling the particles trapped in it. Here we compare ex vivo measurements of a Newtonian flow induced by cilia beating (using micro-beads as tracers) and a mathematical model of this fluid flow, presented in greater detail in a second companion article. Samples of nasal epithelial cells placed in water are recorded by high-speed video-microscopy and ciliary beat pattern is inferred. Automatic tracking of micro-beads, used as markers of the flow generated by cilia motion, enables us also to assess the velocity profile as a function of the distance above the cilia. This profile is shown to be essentially parabolic. The obtained experimental data are used to feed a 2D mathematical and numerical model of the coupling between cilia, fluid, and micro-bead motion. From the model and the experimental measurements, the shear stress exerted by the cilia is deduced. Finally, this shear stress, which can easily be measured in the clinical setting, is proposed as a new index for characterizing the efficiency of ciliary beating. PMID- 28708890 TI - Electroencephalographic characterization of subgroups of children with learning disorders. AB - Electroencephalographic alterations have been reported in subjects with learning disorders, but there is no consensus on what characterizes their electroencephalogram findings. Our objective was to determine if there were subgroups within a group of scholars with not otherwise specified learning disorders and if they had specific electroencephalographic patterns. Eighty-five subjects (31 female, 8-11 years) who scored low in at least two subscales reading, writing and arithmetic- of the Infant Neuropsychological Evaluation were included. Electroencephalograms were recorded in 19 leads during rest with eyes closed; absolute power was obtained every 0.39 Hz. Three subgroups were formed according to children's performance: Group 1 (G1, higher scores than Group 2 in reading speed and reading and writing accuracy), Group 2 (G2, better performance than G1 in composition) and Group 3 (G3, lower scores than Groups 1 and 2 in the three subscales). G3 had higher absolute power in frequencies in the delta and theta range at left frontotemporal sites than G1 and G2. G2 had higher absolute power within alpha frequencies than G3 and G1 at the left occipital site. G3 had higher absolute power in frequencies in the beta range than G1 in parietotemporal areas and than G2 in left frontopolar and temporal sites. G1 had higher absolute power within beta frequencies than G2 in the left frontopolar site. G3 had lower gamma absolute power values than the other groups in the left hemisphere, and gamma activity was higher in G1 than in G2 in frontopolar and temporal areas. This group of children with learning disorders is very heterogeneous. Three subgroups were found with different cognitive profiles, as well as a different electroencephalographic pattern. It is important to consider these differences when planning interventions for children with learning disorders. PMID- 28708891 TI - Loss of Neuroligin3 specifically downregulates retinal GABAAalpha2 receptors without abolishing direction selectivity. AB - The postsynaptic adhesion proteins Neuroligins (NLs) are essential for proper synapse function, and their alterations are associated with a variety of neurodevelopmental disorders. It is increasingly clear that each NL isoform occupies specific subsets of synapses and is able to regulate the function of discrete networks. Studies of NL2 and NL4 in the retina in particular have contributed towards uncovering their role in inhibitory synapse function. In this study we show that NL3 is also predominantly expressed at inhibitory postsynapses in the retinal inner plexiform layer (IPL), where it colocalizes with both GABAA- and glycinergic receptor clusters in a 3:2 ratio. In the NL3 deletion-mutant (knockout or KO) mouse, we uncovered a dramatic reduction of the number of GABAAalpha2-subunit containing GABAA receptor clusters at the IPL. Retinal activity was thereafter assessed in KO and wild-type (WT) littermates by multi electrode-array recordings of the output cells of retina, the retinal ganglion cells (RGCs). RGCs in the NL3 KO showed reduced spontaneous activity and an altered response to white noise stimulation. Moreover, upon application of light flashes, the proportion of cells firing at light offset (OFF RGCs) was significantly lower in the NL3 KO compared to WT littermates, whereas the relative number of cells firing at light onset (ON RGCs) increased. Interestingly, although GABAAalpha2-bearing receptors have been related to direction-selective circuits of the retina, features of direction selective retinal ganglion cells recorded remained unperturbed in the NL3 KO. Together our data underscore the importance of NL3 for the integrity of specific GABAAergic retinal circuits and identifies NL3 as an important regulator of retinal activity. PMID- 28708892 TI - Cross-recognition of a pit viper (Crotalinae) polyspecific antivenom explored through high-density peptide microarray epitope mapping. AB - Snakebite antivenom is a 120 years old invention based on polyclonal mixtures of antibodies purified from the blood of hyper-immunized animals. Knowledge on antibody recognition sites (epitopes) on snake venom proteins is limited, but may be used to provide molecular level explanations for antivenom cross-reactivity. In turn, this may help guide antivenom development by elucidating immunological biases in existing antivenoms. In this study, we have identified and characterized linear elements of B-cell epitopes from 870 pit viper venom protein sequences by employing a high-throughput methodology based on custom designed high-density peptide microarrays. By combining data on antibody-peptide interactions with multiple sequence alignments of homologous toxin sequences and protein modelling, we have determined linear elements of antibody binding sites for snake venom metalloproteases (SVMPs), phospholipases A2s (PLA2s), and snake venom serine proteases (SVSPs). The studied antivenom antibodies were found to recognize linear elements in each of the three enzymatic toxin families. In contrast to a similar study of elapid (non-enzymatic) neurotoxins, these enzymatic toxins were generally not recognized at the catalytic active site responsible for toxicity, but instead at other sites, of which some are known for allosteric inhibition or for interaction with the tissue target. Antibody recognition was found to be preserved for several minor variations in the protein sequences, although the antibody-toxin interactions could often be eliminated completely by substitution of a single residue. This finding is likely to have large implications for the cross-reactivity of the antivenom and indicate that multiple different antibodies are likely to be needed for targeting an entire group of toxins in these recognized sites. PMID- 28708893 TI - Arginase activity in pathogenic and non-pathogenic species of Leishmania parasites. AB - Proliferation of Leishmania (L.) parasites depends on polyamine availability, which can be generated by the L-arginine catabolism and the enzymatic activity of arginase (ARG) of the parasites and of the mammalian hosts. In the present study, we characterized and compared the arginase (arg) genes from pathogenic L. major and L. tropica and from non-pathogenic L. tarentolae. We quantified the level of the ARG activity in promastigotes and macrophages infected with pathogenic L. major and L. tropica and non-pathogenic L. tarentolae amastigotes. The ARG's amino acid sequences of the pathogenic and non-pathogenic Leishmania demonstrated virtually 98.6% and 88% identities with the reference L. major Friedlin ARG. Higher ARG activity was observed in all pathogenic promastigotes as compared to non-pathogenic L. tarentolae. In vitro infection of human macrophage cell line (THP1) with pathogenic and non-pathogenic Leishmania spp. resulted in increased ARG activities in the infected macrophages. The ARG activities present in vivo were assessed in susceptible BALB/c and resistant C57BL/6 mice infected with L. major, L. tropica and L. tarentolae. We demonstrated that during the development of the infection, ARG is induced in both strains of mice infected with pathogenic Leishmania. However, in L. major infected BALB/c mice, the induction of ARG and parasite load increased simultaneously according to the time course of infection, whereas in C57BL/6 mice, the enzyme is upregulated solely during the period of footpad swelling. In L. tropica infected mice, the footpads' swellings were slow to develop and demonstrated minimal cutaneous pathology and ARG activity. In contrast, ARG activity was undetectable in mice inoculated with the non pathogenic L. tarentolae. Our data suggest that infection by Leishmania parasites can increase ARG activity of the host and provides essential polyamines for parasite salvage and its replication. Moreover, the ARG of Leishmania is vital for parasite proliferation and required for infection in mice. ARG activity can be used as one of the main marker of the disease severity. PMID- 28708894 TI - Magnetic resonance imaging and spectroscopy for differential assessment of liver abnormalities induced by Opisthorchis felineus in an animal model. AB - BACKGROUND: European liver fluke Opisthorchis felineus, causing opisthorchiasis disease, is widespread in Russia, Ukraine, Kazakhstan and sporadically detected in the EU countries. O. felineus infection leads to hepatobiliary pathological changes, cholangitis, fibrosis and, in severe cases, malignant transformation of bile ducts. Due to absence of specific symptoms, the infection is frequently neglected for a long period. The association of opisthorchiasis with almost incurable bile duct cancer and rising international migration of people that increases the risk of the parasitic etiology of liver fibrosis in non-endemic regions determine high demand for development of approaches to opisthorchiasis detection. METHODOLOGY/PRINCIPAL FINDINGS: In vivo magnetic resonance imaging and spectroscopy (MRI and MRS) were applied for differential assessment of hepatic abnormalities induced by O. felineus in an experimental animal model. Correlations of the MR-findings with the histological data as well as the data of the biochemical analysis of liver tissue were found. MRI provides valuable information about the severity of liver impairments induced by opisthorchiasis. An MR image of O. felineus infected liver has a characteristic pattern that differs from that of closely related liver fluke infections. 1H and 31P MRS in combination with biochemical analysis data showed that O. felineus infection disturbed hepatic metabolism of the host, which was accompanied by cholesterol accumulation in the liver. CONCLUSIONS: A non-invasive approach based on the magnetic resonance technique is very advantageous and may be successfully used not only for diagnosing and evaluating liver damage induced by O. felineus, but also for investigating metabolic changes arising in the infected organ. Since damages induced by the liver fluke take place in different liver lobes, MRI has the potential to overcome liver biopsy sampling variability that limits predictive validity of biopsy analysis for staging liver fluke-induced fibrosis. PMID- 28708896 TI - Characteristics and outcomes of a cohort hospitalized for pandemic and seasonal influenza in Germany based on nationwide inpatient data. AB - RATIONALE: From June of 2009 to August of 2010 the influenza subtype H1N1pdm09 caused a worldwide pandemic. The impact on populations and health care systems around the globe evolved differently. Substantial data come from the German national surveillance network in an outpatient and private practice setting, while information on hospitalized patients in Germany is rather limited. METHODS: Data from the Federal Statistics Office comprising health insurance claims of the entire nationwide inpatient sample from 2005 to 2012 were used to identify patients who were hospitalized for laboratory-confirmed influenza and to analyse demographical aspects, comorbidities, hospitalization duration, outcomes and ventilator use during the pandemic and seasonal waves of influenza. MEASUREMENTS AND MAIN RESULTS: A number of 34,493 admissions for laboratory-confirmed influenza occurred during waves between 2005 and 2012. During the pandemic seasonal waves, the number of hospitalizations vastly surpassed the level that was seen in any of the seasonal waves. A major demographic shift was seen with respect to patient age, as younger patients (< 60 years old) were more frequently hospitalized. Mean length of stay was shorter (149 vs. 193 hours), mean time on ventilation tended to be shorter (261 vs. 305 hours) in young children (< 4 years old) and longer (393 vs. 339 hours) in the elderly (> 60 years old). Time to ventilation was shorter in non-fatal cases (328 vs. 349 hours) and longer in fatal cases (419 vs. 358 hours). Logistic regression was used to show the impact of comorbidities and co-diagnoses on mortality and the need for ventilation, as well as differences between pandemic and seasonal influenza. CONCLUSIONS: Inpatient data suggest differences in patient populations during pandemic and seasonal influenza. Younger patients were more frequently hospitalized. Differences with respect to the presence of certain comorbidities and co diagnoses, length of stay, time to ventilation and ventilation time could be identified. PMID- 28708895 TI - Yeast-expressed recombinant As16 protects mice against Ascaris suum infection through induction of a Th2-skewed immune response. AB - BACKGROUND: Ascariasis remains the most common helminth infection in humans. As an alternative or complementary approach to global deworming, a pan-anthelminthic vaccine is under development targeting Ascaris, hookworm, and Trichuris infections. As16 and As14 have previously been described as two genetically related proteins from Ascaris suum that induced protective immunity in mice when formulated with cholera toxin B subunit (CTB) as an adjuvant, but the exact protective mechanism was not well understood. METHODOLOGY/PRINCIPAL FINDINGS: As16 and As14 were highly expressed as soluble recombinant proteins (rAs16 and rAs14) in Pichia pastoris. The yeast-expressed rAs16 was highly recognized by immune sera from mice infected with A. suum eggs and elicited 99.6% protection against A. suum re-infection. Mice immunized with rAs16 formulated with ISA720 displayed significant larva reduction (36.7%) and stunted larval development against A. suum eggs challenge. The protective immunity was associated with a predominant Th2-type response characterized by high titers of serological IgG1 (IgG1/IgG2a > 2000) and high levels of IL-4 and IL-5 produced by restimulated splenocytes. A similar level of protection was observed in mice immunized with rAs16 formulated with alum (Alhydrogel), known to induce mainly a Th2-type immune response, whereas mice immunized with rAs16 formulated with MPLA or AddaVax, both known to induce a Th1-type biased response, were not significantly protected against A. suum infection. The rAs14 protein was not recognized by A. suum infected mouse sera and mice immunized with rAs14 formulated with ISA720 did not show significant protection against challenge infection, possibly due to the protein's inaccessibility to the host immune system or a Th1-type response was induced which would counter a protective Th2-type response. CONCLUSIONS/SIGNIFICANCE: Yeast-expressed rAs16 formulated with ISA720 or alum induced significant protection in mice against A. suum egg challenge that associates with a Th2-skewed immune response, suggesting that rAS16 could be a feasible vaccine candidate against ascariasis. PMID- 28708897 TI - Climate drivers of the Amazon forest greening. AB - Our limited understanding of the climate controls on tropical forest seasonality is one of the biggest sources of uncertainty in modeling climate change impacts on terrestrial ecosystems. Combining leaf production, litterfall and climate observations from satellite and ground data in the Amazon forest, we show that seasonal variation in leaf production is largely triggered by climate signals, specifically, insolation increase (70.4% of the total area) and precipitation increase (29.6%). Increase of insolation drives leaf growth in the absence of water limitation. For these non-water-limited forests, the simultaneous leaf flush occurs in a sufficient proportion of the trees to be observed from space. While tropical cycles are generally defined in terms of dry or wet season, we show that for a large part of Amazonia the increase in insolation triggers the visible progress of leaf growth, just like during spring in temperate forests. The dependence of leaf growth initiation on climate seasonality may result in a higher sensitivity of these ecosystems to changes in climate than previously thought. PMID- 28708898 TI - Retreatment strategies following Small Incision Lenticule Extraction (SMILE): In vivo tissue responses. AB - With any refractive correction, including Small Incision Lenticule Extraction (SMILE), there may be a residual refractive error that requires a retreatment. Here, we investigated the tissue responses following various retreatment procedures in a rabbit model of SMILE. All rabbits underwent a -6.00D correction with SMILE. Two weeks later, they underwent -1.00D enhancement by: (i) VisuMax Circle, followed by excimer ablation (S+C); (ii) secondary SMILE anterior to the primary procedure (S+SE); or (iii) surface ablation (S+P), and were examined for 28 days. S+P induced corneal edema and haze, and more CD11b- (23+/-6 cells) and TUNEL-positive (36+/-4 cells) cells in the central stromal superficial layers early post-operatively (p<0.001 compared to other procedures). The corneas appeared normal on day 28 after S+P, but had a lower number of keratocytes near the laser ablated plane compared to other procedures. S+SE and S+C did not induce corneal haze and resulted similar level of fibronectin. However, S+C resulted in more inflammatory (10+/-2 cells; p = 0.001) and apoptotic cells (25+/-2 cells; p<0.001) compared to S+SE (7+/-1 inflammatory cells and 21+/-3 apoptotic cells) early post-operatively. In conclusion, each SMILE retreatment method resulted in unique tissue responses. S+SE offers advantages, such as minimal inflammation and cell death, as well as maintaining a 'flap-less' surgery, over other procedures. However, depending on the degree of enhancement, the lenticule may become too thin to be extracted and the procedure becomes more difficult to perform than S+C and S+P. S+P can maintain corneal integrity by avoiding flap creation and is technically more simple to perform than the others, but the surgery needs to be supplemented with mitomycin-C in order to reduce inflammation and modulate better wound healing. PMID- 28708899 TI - The cost effectiveness of a quality improvement program to reduce maternal and fetal mortality in a regional referral hospital in Accra, Ghana. AB - OBJECTIVE: To evaluate the cost-effectiveness of a quality improvement intervention aimed at reducing maternal and fetal mortality in Accra, Ghana. DESIGN: Quasi-experimental, time-sequence intervention, retrospective cost effectiveness analysis. METHODS: Data were collected on the cost and outcomes of a 5-year Kybele-Ghana Health Service Quality Improvement (QI) intervention conducted at Ridge Regional Hospital, a tertiary referral center in Accra, Ghana, focused on systems, personnel, and communication. Maternal deaths prevented were estimated comparing observed rates with counterfactual projections of maternal mortality and case-fatality rates for hypertensive disorders of pregnancy and obstetric hemorrhage. Stillbirths prevented were estimated based on counterfactual estimates of stillbirth rates. Cost-effectiveness was then calculated using estimated disability-adjusted life years averted and subjected to Monte Carlo and one-way sensitivity analyses to test the importance of assumptions inherent in the calculations. MAIN OUTCOME MEASURE: Incremental Cost effectiveness ratio (ICER), which represents the cost per disability-adjusted life-year (DALY) averted by the intervention compared to a model counterfactual. RESULTS: From 2007-2011, 39,234 deliveries were affected by the QI intervention implemented at Ridge Regional Hospital. The total budget for the program was $2,363,100. Based on program estimates, 236 (+/-5) maternal deaths and 129 (+/ 13) intrapartum stillbirths were averted (14,876 DALYs), implying an ICER of $158 ($129-$195) USD. This value is well below the highly cost-effective threshold of $1268 USD. Sensitivity analysis considered DALY calculation methods, and yearly prevalence of risk factors and case fatality rates. In each of these analyses, the program remained highly cost-effective with an ICER ranging from $97-$218. CONCLUSION: QI interventions to reduce maternal and fetal mortality in low resource settings can be highly cost effective. Cost-effectiveness analysis is feasible and should regularly be conducted to encourage fiscal responsibility in the pursuit of improved maternal and child health. PMID- 28708900 TI - Serum levels of interleukin-6 are linked to the severity of the disease caused by Andes Virus. AB - Andes virus (ANDV) is the etiological agent of hantavirus cardiopulmonary syndrome in Chile. In this study, we evaluated the profile of the pro inflammatory cytokines IL-1beta, IL-12p70, IL-21, TNF-alpha, IFN-gamma, IL-10 and IL-6 in serum samples of ANDV-infected patients at the time of hospitalization. The mean levels of circulating cytokines were determined by a Bead-Based Multiplex assay coupled with Luminex detection technology, in order to compare 43 serum samples of healthy controls and 43 samples of ANDV-infected patients that had been categorized according to the severity of disease. When compared to the controls, no significant differences in IL-1beta concentration were observed in ANDV-infected patients (p = 0.9672), whereas levels of IL-12p70 and IL-21 were significantly lower in infected cases (p = <0.0001). Significantly elevated levels of TNF-alpha, IFN-gamma, IL-10, and IL-6 were detected in ANDV-infected individuals (p = <0.0001, 0.0036, <0.0001, <0.0001, respectively). Notably, IL-6 levels were significantly higher (40-fold) in the 22 patients with severe symptoms compared to the 21 individuals with mild symptoms (p = <0.0001). Using multivariate regression models, we show that IL-6 levels has a crude OR of 14.4 (CI: 3.3-63.1). In conclusion, the serum level of IL-6 is a significant predictor of the severity of the clinical outcome of ANDV-induced disease. PMID- 28708901 TI - Sex-specific enhancement of palatability-driven feeding in adolescent rats. AB - It has been hypothesized that brain development during adolescence perturbs reward processing in a way that may ultimately contribute to the risky decision making associated with this stage of life, particularly in young males. To investigate potential reward dysfunction during adolescence, Experiment 1 examined palatable fluid intake in rats as a function of age and sex. During a series of twice-weekly test sessions, non-food-deprived rats were given the opportunity to voluntarily consume a highly palatable sweetened condensed milk (SCM) solution. We found that adolescent male, but not female, rats exhibited a pronounced, transient increase in SCM intake (normalized by body weight) that was centered around puberty. Additionally, adult females consumed more SCM than adult males and adolescent females. Using a well-established analytical framework to parse the influences of reward palatability and satiety on the temporal structure of feeding behavior, we found that palatability-driven intake at the outset of the meal was significantly elevated in adolescent males, relative to the other groups. Furthermore, although we found that there were some group differences in the onset of satiety, they were unlikely to contribute to differences in intake. Experiment 2 confirmed that adolescent male rats exhibit elevated palatable fluid consumption, relative to adult males, even when a non-caloric saccharin solution was used as the taste stimulus, demonstrating that these results were unlikely to be related to age-related differences in metabolic need. These findings suggest that elevated palatable food intake during adolescence is sex specific and driven by a fundamental change in reward processing. As adolescent risk taking has been hypothesized as a potential result of hypersensitivity to and overvaluation of appetitive stimuli, individual differences in reward palatability may factor into individual differences in adolescent risky decision making. PMID- 28708903 TI - Glossary of Oral and Maxillofacial Implants. AB - No abstract available. PMID- 28708902 TI - Factors associated with contralateral liver hypertrophy after unilateral radioembolization for hepatocellular carcinoma. AB - INTRODUCTION: Radioembolization for the treatment of hepatocellular carcinoma (HCC) induces liver volume changes referred to as "atrophy-hypertrophy complex". The aim of this study was to investigate lobar liver volume changes after unilateral radioembolization and to search for factors associated with hypertrophy of the untreated lobe. MATERIALS AND METHODS: Seventy-five patients were retrospectively evaluated. Inclusion criteria were: (1) right-lobar radioembolization for unresectable unilateral HCC, (2) available liver computed tomography scans before, 1, 3, and at least 6 months after radioembolization. Baseline patient characteristics included clinical features, laboratory results, spleen volume, and liver computed tomography. Absolute and relative (referred to the whole liver volume) liver lobe volumes (LLV) as well as relative LLV (rLLV) change per month were evaluated and compared. RESULTS: Absolute and relative contralateral LLV continuously increased after radioembolization (p<0.001). Mean relative contralateral LLV increased from 36+/-11.6% before radioembolization to 50+/-15.3% 6 months after radioembolization. Median contralateral rLLV increase/month (within first 6 months) was 2.5%. Contralateral rLLV increase/month was significantly lower in patients with ascites (p = 0.017) or platelet count <100/nl (p = 0.009). An inverse correlation of contralateral rLVV increase/month with spleen volume (p = 0.017), patient age (p = 0.024), Child Pugh score (p = 0.001), and tumor burden (p = 0.001) was found. CONCLUSIONS: Significant contralateral hypertrophy and ipsilateral atrophy were common after unilateral radioembolization. Small spleen volume, low patient age, low Child Pugh score, absence of ascites, platelet count >=100/nl, and low tumor burden were associated with increased contralateral hypertrophy, indicating that younger patients with compensated cirrhosis might benefit most from radioembolization in a "bridge-to-resection" setting. PMID- 28708904 TI - THEMATIC ABSTRACT REVIEW: Implantoplasty: A Valuable Method for the Management of Peri-implantitis? AB - No abstract available. PMID- 28708905 TI - Clinical Performance of Dental Implants with a Moderately Rough (TiUnite) Surface: A Meta-Analysis of Prospective Clinical Studies. AB - PURPOSE: A moderately rough anodized titanium implant surface (TiUnite) was introduced in 2000. This review and meta-analysis aimed to assess implant survival and marginal bone level (MBL) changes documented in the literature. MATERIALS AND METHODS: Repeated literature searches on dental implants were conducted, with the final search on October 7, 2016. The inclusion criteria were: prospective study, minimum of 20 patients, at least 12 months follow-up postloading, and TiUnite implant survival reported. Regression analysis was performed on implant survival and MBL change from implant surgery. Peri implantitis as defined by the primary authors was reported at the patient level. RESULTS: One hundred six out of 32,519 publications on dental implants met the inclusion criteria. Implant survival rates at 1 year were 99.50% at the implant level and 99.12% at the patient level, and survival rates at 10 years were 95.14% at the implant level and 91.50% at the patient level. Mean MBL change at 1 year was -0.409 mm at the implant level and -0.413 mm at the patient level, and at 5 years, it was -0.886 mm at the implant level and -1.029 mm at the patient level. Nineteen studies (18%) specifically reported peri-implantitis in 64 out of 1,229 patients with a mean follow-up of 47.89 months, indicating a prevalence of 5.20% at the patient level. CONCLUSION: Based on a meta-analysis of prospective studies, implants with the TiUnite surface provide a predictable treatment modality in a variety of indications. PMID- 28708906 TI - Effectiveness of Periapical Radiography Versus Cone Beam Computed Tomography with Different Kilovoltage Settings in the Detection of Chemically Created Peri implant Bone Defects: An In Vitro Study. AB - PURPOSE: To determine the effectiveness of cone beam computed tomography (CBCT) images obtained with different kilovoltage settings compared with intraoral periapical photostimulable storage phosphor (PSP) plate images in the detection of chemically created peri-implant defects utilizing a bovine rib bone model in vitro. MATERIALS AND METHODS: After placing 80 implants in bovine ribs, peri implant circumferential bone defects of different sizes were created with 70% perchloric acid. CBCT images (3D Accuitomo 170) were acquired at 90 and 75 kVp, and intraoral periapical images were acquired using a PSP system (Carestream KODAK, CS 7600). Using a 5-point Likert scale, two oral and maxillofacial radiologists (OMR) and two oral and maxillofacial surgeons (OMS) evaluated the likelihood of a bone defect being absent or present. The kappa statistic was used to compare observer agreement, and area under the curve values were compared using analysis of variance and the post hoc Tukey test. Significance was set at P <= .05. RESULTS: PSP reliability ranged from discordance to slight for small defects and fair to moderate for larger defects. For CBCT, OMRs had good agreement for defects using 90 kVp, and slight to fair using 75 kVp. Agreement for OMS observations was fair for 75 kVp, and varied from slight to good for 90 kVp. Small lesions were detected more effectively by CBCT than by PSP, and larger lesions were detected more effectively by CBCT at 90 kVp than by CBCT at 75 kVp or by PSP. CONCLUSION: CBCT imaging at 90 kVp was associated with a significantly higher rate of detection of both small and large chemically simulated bone defects than PSP or CBCT at 75 kVp. CBCT imaging at 75 kVp proved better than PSP for the detection of small defects. PMID- 28708907 TI - Local Application of Growth Hormone to Enhance Osseointegration in Osteoporotic Bones: A Morphometric and Densitometric Study. AB - PURPOSE: The aim of this study was to assess the effect of local application of growth hormone on osseointegration of dental implants inserted in osteoporotic bones. MATERIALS AND METHODS: Twenty female New Zealand rabbits were used in this study. Ten were ovariectomized and fed a low-calcium diet for 6 weeks, and the others remained intact. A titanium implant was inserted into each tibia, in both groups. In half of the rabbits, 2 IU of growth hormone was placed into the ostectomy prior to the implant insertion. Two weeks after implant surgery, all animals were sacrificed. Tibiae were dissected from soft tissues, and included in methacrylate to be studied under light microscopy. Bone-to-implant contact (BIC) and bone mineral density (BMD) were measured by morphometric and densitometric analysis, respectively. Multifactorial analysis of variance (ANOVA) was used for statistical evaluation. P < .05 was considered to be significant. RESULTS: Ovariectomy induced less BIC and BMD in regions closer to the implant compared with the control group. Local application of growth hormone was able to increase the BIC in the ovariectomized group, with statistically significant differences with respect to the control group (P < .01). Regarding the BMD, no statistically significant differences were found. CONCLUSION: Within the limitations of this experimental study, local application of 2 IU of recombinant human growth hormone at the moment of titanium implant insertion in rabbit tibiae significantly enhanced the BIC around titanium implants 15 days after the implantation in this experimental osteoporotic animal model, without affecting the BMD. PMID- 28708908 TI - Activation of Osteoblastic Function on Titanium Surface with Titanium-Doped Hydroxyapatite Nanoparticle Coating: An In Vitro Study. AB - PURPOSE: Titanium-doped hydroxyapatite (TiHA) nanoparticles contain titanium atoms in the hydroxyapatite lattice, which can physicochemically functionalize the titanium surface without modification of the surface topography. This study aimed to evaluate the physicochemical properties of machined or microroughened titanium surfaces coated with TiHA nanoparticles and the functions of osteoblasts cultured on them. MATERIALS AND METHODS: Titanium disks with commercially available surface topography, such as machined or sandblasted, large-grit, and acid-etched (SLA) surfaces, were coated with TiHA. The disks with original or TiHA-coated surfaces were evaluated in topography, wettability, and chemical composition. Osteoblastic cells from rat femurs were cultured on the disks and evaluated in proliferation and differentiation. RESULTS: TiHA coating changed from hydrophobicity to hydrophilicity on both machined and SLA surfaces. Calcium and phosphate atoms were detected all over the surface with TiHA coating regardless of the surface topography. However, the considerable change in the inherent surface topographies was not observed on both types of surfaces after TiHA coating. Osteoblastic proliferative activity at day 4 was increased by TiHA coating on both types of surfaces. TiHA coating did not enhance expressions of bone matrix-related genes such as osteocalcin, osteopontin, bone sialoprotein, alkaline phosphatase, and collagen I. However, depositions of collagen, osteocalcin, and calcium in the culture at days 7 and 20 were increased on both types of surface topographies with TiHA coating. CONCLUSION: TiHA coating enhanced extracellular matrix formation on smooth and microroughened titanium surfaces by increasing osteoblastic proliferative activity without the deterioration of differentiation through hydrophilic and chemical functionalization. PMID- 28708909 TI - Biomechanical Three-Dimensional Finite Element Analysis of Single Implant Supported Prostheses in the Anterior Maxilla, with Different Surgical Techniques and Implant Types. AB - PURPOSE: The aim of this study was to use three-dimensional finite element analysis to analyze the stress distribution transferred by single implant supported prostheses placed in the anterior maxilla using different connections (external hexagon, internal hexagon, or Morse taper), inclinations of the load (0, 30, or 60 degrees), and surgical techniques for placement (monocortical/conventional, bicortical, or bicortical with nasal floor elevation). MATERIALS AND METHODS: Nine models representing a bone block of this region were simulated by computer-aided design software (InVesalius, Rhinoceros, SolidWorks). Each model received one implant, which supported a cemented metalloceramic crown. Using FEMAP software, finite elements were discretized while simulating a 178-N load at 0, 30, and 60 degrees relative to the long axis of the implant. The problem was solved in NEi Nastran software, and postprocessing was performed in FEMAP. Von Mises stress and maximum principal stress maps were made. RESULTS: The von Mises stress analysis revealed that stress increased with increasing inclination of the load, from 0 to 30 to 60 degrees. Morse taper implants showed less stress concentration around the cervical and apical areas of the implant. The bicortical technique, associated or not with nasal floor elevation, contributed to decreasing the stress concentration in the apical area of the implant. Maximum principal stress analysis showed that the increase in inclination was proportional to the increase in stress on the bone tissue in the cervical area. Lower stress concentrations in the cortical bone were obtained with Morse taper implants and the bicortical technique compared with other connections and surgical techniques, respectively. CONCLUSION: Increasing the inclination of the applied force relative to the long axis of the implant tended to overload the peri-implant bone tissue and the internal structure of the implants. The Morse taper connection and bicortical techniques seemed to be more favorable than other connections or techniques, respectively, for restoring the anterior maxilla. PMID- 28708910 TI - Influence of the Posterior Mandible Ridge Morphology on Virtual Implant Planning. AB - PURPOSE: The purpose of this study was to examine the anatomy of the mandibular posterior region to develop an anatomical categorization for implant prosthodontic planning. MATERIALS AND METHODS: Using cone beam computed tomography scans, 313 cross-sectional views of edentulous posterior mandibular sites were evaluated with respect to the anatomical ridge morphology. Virtual implant planning was performed, and the need for bone grafting was assessed. The level of complexity for planning implants in those positions was assessed. Sites were classified as straightforward, advanced, or complex sites based on the need for bone grafting. RESULTS: Five well-defined cross-sectional configurations were observed: straight (53.6%), oblique (26.2%), s-shape (7.4%), hourglass shape (1.9%), and basal bone (10.8%). There was a statistically significant association between the ridge shape and the feasibility of placing an implant with or without bone grafting; the straight and oblique ridge shapes were more likely to be associated with a favorable anatomy for implant placement. CONCLUSION: The ridge shape significantly influenced the ease or difficulty of placing an implant. The s-shape, hourglass, and basal bone posterior mandibular cross-sectional shapes were associated with a higher degree of difficulty. PMID- 28708911 TI - Peri-implant and Paracrestal Inflammatory Biomarkers at Failing Versus Surviving Implant Sites in a Beagle Dog Study. AB - PURPOSE: This study sought to quantify three biochemical mediators of inflammation (tumor necrosis factor alpha [TNF-alpha], superoxide anion [SOA], and myeloperoxidase [MPO]) by analyzing crestal (peri-implants) and paracrestal gingival biopsy samples obtained from an experimental study on beagle dogs treated with implants inserted immediately into fresh sockets with circumferential defects. MATERIALS AND METHODS: In 10 beagle dogs, 4 roughened titanium implants (3.8 mm wide * 8 mm high) were placed in the distal sockets of the third and fourth premolars, where a circumferential defect (5 mm wide and 5 mm deep) had been previously created by trephination. After varying follow-up periods, ranging from 80 to 190 days, the dogs were explored clinically to assess implant survival, peri-implant pocket depth, and implant stability. The levels of three biochemical mediators of inflammation (MPO, TNF-alpha, and SOA) were investigated using the crestal and paracrestal gingival biopsy samples with ELISA tests. RESULTS: It was found that 37.5% of the implants were either absent or mobile. Higher levels of the inflammatory mediators were found in the crestal samples than in the paracrestal samples. The final implant stability values were significantly correlated with the final probing depth (r = -0.83, P < .01), but neither of the clinical measures were significantly correlated with any biochemical marker. The risk of implant failure was significantly proportional to the level of MPO (odds ratio: 1.1) and TNF-alpha (odds ratio: 1.1) in both the crestal and paracrestal regions. CONCLUSION: All the inflammatory mediators studied were higher in the crestal areas than in the paracrestal regions, but only the values of MPO and TNF-alpha were significant predictors of implant failure. PMID- 28708912 TI - Finite Element Analysis of Bone Stress in the Posterior Mandible Using Regular and Short Implants, in the Same Context, with Splinted and Nonsplinted Prostheses. AB - PURPOSE: The aim of this study was to compare the bone stress generated by rehabilitation using regular and short-length Morse taper implants (11 and 5 mm, respectively) in the same context and allied with splinted (SP) and nonsplinted (NSP) prostheses in the posterior area of the mandible using finite element analysis. MATERIALS AND METHODS: Three-dimensional geometric models using regular implants (O4 * 11 mm) and short implants (O4 * 5 mm) were simulated with a left posterior mandible that had the first premolar tooth and all teeth posterior to that premolar removed. The four experimental groups were as follows: Group 1 NSP (two regular implants and one short implant rehabilitated with nonsplinted prostheses), Group 1 SP (two regular implants and one short implant rehabilitated with splinted prostheses), Group 2 NSP (one regular implant and two short implants rehabilitated with nonsplinted prostheses), and Group 2 SP (one regular implant and two short implants rehabilitated with splinted prostheses). Oblique forces were simulated in molars (365 N) and premolars (200 N). Qualitative and quantitative analyses of the minimum principal stress in bone were performed using the ANSYS Workbench software, version 10.0. RESULTS: The splinted prostheses decreased the stress to the surrounding bone of short implants. Moreover, they also decreased the stress on the surrounding bone adjacent to the tooth. However, the splinted prostheses generated higher stress in the coverage of the surrounding bone for regular intermediate implants and prominently in the bone at the implant cervical region, at the edge crest, compared with the individualized groups. CONCLUSION: The benefits in the use of splinted prostheses are notable for the preservation of the bone surrounding the short implants and tooth; however, it is necessary to evaluate each clinical situation because, in this context, the regular implants are at higher stress than the individualized implants. PMID- 28708913 TI - Effect of Attachment Type on Denture Strain in Maxillary Implant Overdentures: Part 1. Overdenture with Palate. AB - PURPOSE: This study examined the effects of attachments on strain in maxillary implant overdentures supported by two or four implants. MATERIALS AND METHODS: A maxillary edentulous model with implants inserted into anterior, premolar, and molar areas was fabricated, and three types of unsplinted attachments-ball, locator, and magnet-were set on the implants distributed under various conditions. Maxillary experimental dentures were fabricated, and two strain gauges were attached at the anterior midline on the labial and palatal sides. A vertical occlusal load of 98 N was applied and shear strain of the dentures was measured. RESULTS: On both sides, magnet attachments resulted in the lowest shear strain, while ball attachments resulted in the highest shear strain under most conditions. However, differences in shear strain among the three attachment types were not significant when supported by four implants, especially molar implants. CONCLUSION: Shear strain of the maxillary implant overdenture was lowest when using magnet attachments. Magnet attachments mounted on four implants are recommended to prevent denture complications when using maxillary implant overdentures. PMID- 28708914 TI - Misfit of Three Different Implant-Abutment Connections Before and After Cyclic Load Application: An In Vitro Study. AB - PURPOSE: This study aimed to evaluate the misfit of three different implant abutment connections before and after cycling load. MATERIALS AND METHODS: One hundred twenty dental implants and correspondent prefabricated titanium abutments were used. Three different implant-abutment connections were evaluated: Morse taper (MT group), external hexagon (EH group), and internal hexagon (IH group). Forty implants and 40 abutments were used per group. The parameters for the mechanical evaluation were set as: 360,000 cycles, load of 150 N, and frequency of 4 Hz. Samples were sectioned in their longitudinal and transversal axes, and the misfit of the implant-abutment connection was evaluated by scanning electron microscopy analysis. One-way analyses of variance, Tukey post hoc analyses (alpha = .05), and t test (P < .05) were used to determine differences between groups. RESULTS: At the longitudinal direction, all the groups showed the presence of microgaps before cycling load; after cycling load, microgaps were reduced in all groups (P > .05). Transversally, only the MT group showed full fitting after cycling load compared with the other groups (EH and IH) (P < .0001). CONCLUSION: The application of cycling load produces an accommodation of the implant-abutment connection in internal, external, and Morse taper connections. In the longitudinal direction, the accommodation decreases and/or eliminates the gap observed initially (before load). In the horizontal direction, Morse cone implant abutment connections experience a complete accommodation with the elimination of the gap. PMID- 28708915 TI - Accuracy and Reproducibility of Radiographic Images for Assessing Crestal Bone Height of Implants Using the Precision Implant X-ray Locator (PIXRL) Device. AB - PURPOSE: Assessment of crestal bone levels around implants is essential to monitor success and health. This is best accomplished with intraoral radiographs exposed at 90 degrees to the long axis of the implant, but this can be challenging to achieve clinically. Radiographic paralleling devices produce orthogonal radiographs but traditionally have required access to the implant body for each exposure. This study was conducted to determine if use of the Precision Implant X-ray Locator (PIXRL), a radiographic paralleling device that indexes the implant at the time of surgical placement, can produce orthogonal radiographs of dental implants more accurately than traditional radiologic techniques for assessing crestal bone levels. MATERIALS AND METHODS: Three dental implants were inserted in dry human skulls in supracrestal positions to simulate crestal bone loss (maxillary right first premolar [site 14], maxillary right central incisor [site 11], and mandibular left second premolar [site 35]). The implants were masked with a soft tissue moulage and restored with provisional restorations. Four dental assistants exposed six radiographs using their usual and customary technique and six using the PIXRL device for each implant. A single examiner measured crestal bone levels on the radiographs relative to the implant platform shoulder on the mesial and distal of each implant. Recorded measurements were compared to the known values. Statistical analysis was completed using a generalized linear regression model to analyze the differences, and post-hoc comparisons with pairwise adjustment were applied. RESULTS: The images produced using the PIXRL device were more accurate overall compared to traditional techniques and were also more consistent. The greater degree of accuracy was statistically significant for all sites with the exception of the mesial measurements of the implant at site 11. CONCLUSION: This study demonstrates that the use of the PIXRL device can assist clinicians in obtaining more accurate orthogonal radiographs for assessing crestal bone height and would be a useful tool for researchers utilizing radiographic imaging of implants as a longitudinal measure of implant success and stability. PMID- 28708916 TI - Assessment of Parathyroid Hormone Serum Level as a Predictor for Bone Condition Around Dental Implants. AB - PURPOSE: The aim of this prospective study was to evaluate parathyroid hormone serum level as a potential single factor of bone metabolism around dental implants. MATERIALS AND METHODS: Parathyroid hormone levels were measured before implantation. Intraoral digital radiographs were taken in standardized conditions in all cases: immediately after implantation, immediately after functional loading, and 3, 6, 9, 12, 18, and 24 months after functional loading. The next phase was to align all radiographs geometrically. Two regions of interest were marked in the bone image: one in the implant neck region and another in the periapical region. Next, the entropy of the microarchitecture of the bone image was calculated, and an analysis of simple regression was performed. RESULTS: The prospective study included 107 patients of both sexes in the age range of 17 to 67 years (mean +/- SD: 45.53 +/- 12.1 years). A significant relationship was observed between higher levels of parathyroid hormone (but still in the normal range) and the decrease of textural entropy in the alveolar ridge bone at 3, 6, 12, and 18 months after functional loading. However, in the periods immediately after implantation, immediately after functional loading, and 9 and 24 months after functional loading, the relationship was not statistically significant. CONCLUSION: Assessment of the parathyroid hormone serum level can be considered a useful method to predict bone condition around a dental implant, but not as a single factor. PMID- 28708917 TI - Vertical Osseodistraction with a New Intraosseous Alveolar Distractor Prototype for Dental Implant Rehabilitation: A Pilot Study in Dogs. AB - PURPOSE: To evaluate in dogs a newly developed intraosseous alveolar distractor (Mozo-Grau Alveolar Distractor) for vertical bone augmentation to allow placement of dental implants. MATERIALS AND METHODS: Four dogs had their posterior teeth removed, and sockets were left to heal for 20 weeks. The right and left sides of the posterior mandibles were randomly allocated, according to a split-mouth design, to receive either two distractors, distracting a 32-mm-long bone segment, or two distractors supporting one bony segment 20 mm long and one 8 mm long. Each side of the jaw was treated by a different operator. Eight days after placement, distractors were activated with one complete turn (corresponding to 0.75 mm of vertical distraction) per day for 8 days, followed by a latency period of 10 weeks. Distractors were removed, and seven dental implants of two randomly allocated designs were placed in each dog. Implants were submerged for 2 months, and the dogs were sacrificed. Outcome measures were: success of the augmentation procedure (defined as a vertical gain of at least 5 mm of bone), any complications, implant failure, bone-to-implant contact (BIC), and peri-implant marginal bone level changes. RESULTS: One dog was withdrawn because of a mandible fracture. Eight complications occurred, and six osseodistractors were lost, but no implant failed. Only two segments in one dog achieved a vertical bone gain of at least 5 mm. The mean radiographic vertical bone gain was 2.28 mm, whereas the mean histologic vertical bone gain was 3.16 mm. Histologically, all the implants were osseointegrated. The mean BIC for implants placed in new distracted bone was 34.78% +/- 11.60% and 35.66% +/- 8.84% for those placed in native bone. The mean peri-implant marginal bone level loss was 0.56 +/- 0.54 mm. CONCLUSION: It is possible to achieve vertical augmentation using intraosseous alveolar distractors to allow successful implantation of dental implants; however, the technique still requires surgical refinements and a dedicated training of the surgeons before being applied to humans. PMID- 28708918 TI - The Influence of Low Insertion Torque on Primary Stability, Implant Survival, and Maintenance of Marginal Bone Levels: A Closed-Cohort Prospective Study. AB - PURPOSE: The purpose of this study was to evaluate the impact of low insertion torque on primary stability and the short-term clinical outcome of single-tooth implants placed into healed ridges and fresh extraction sockets. MATERIALS AND METHODS: A cohort of n = 30 implants was self-selected on the basis that their insertion torque measured <= 20 Ncm. The cohort was closed with the follow-up set at 1 year. Resonance frequency analysis was evaluated in both mesiodistal (MD) and buccolingual (BL) directions at the time of implant insertion and at the time of restoration. Immediate temporization was determined by the esthetic need and a minimum implant stability quotient (ISQ) reading of 55. Implants were definitively restored after approximately 3 months. Implant survival was recorded along with changes in the level of the marginal bone relative to a fixed reference point, at the 1-year follow-up. RESULTS: Twenty-two patients with a total of 30 implants were grouped by insertion torques of < 5 Ncm (spinners), > 5 < 10 Ncm, 10 Ncm, 15 Ncm, and 20 Ncm. One implant was excluded because follow-up data were unavailable. Of the remaining 29 implants, the mean ISQ measured 67 (MD) and 65 (BL) at surgery. The values increased to 80 (MD) and 79 (BL) after a period of 3 months. The survival rate at the end of the 1-year period was 96.7%, including the excluded implant, but 100% for the remaining 29 implants. The frequency of implants demonstrating no marginal bone loss was 71.4%, 0.1 to 0.5 mm bone loss was 21.4%, and bone loss > 0.5 mm (max = 2.82 mm) was only 7.2%. No implants were lost during the functional loading period. Data on immediate temporization revealed no significant difference in ISQ or marginal bone loss values for implants in this group. CONCLUSION: Lower insertion torques yield favorable survival rates with optimal marginal bone levels compared with the accepted norm. PMID- 28708919 TI - Retrospective Evaluation of the Influence of the Collar Surface Topography on Peri-implant Bone Preservation. AB - PURPOSE: To evaluate the influence of the collar surface topography on peri implant marginal bone preservation. MATERIALS AND METHODS: A total of 156 patients who received at least one cylindrical implant of regular diameter with an external-hexagon platform in the posterior region of the maxilla or mandible were recalled to the office for a retrospective evaluation. Implantation sites and implant length information were recorded, and implants were divided according to the collar surface topography: machined (M) or rough (R) surface. Each implant was assessed by digital periapical radiography, using a sensor holder for the paralleling technique. The marginal bone remodeling was determined as the distance from the implant platform to the first bone-to-implant contact, and the known implant length was used to calibrate the images in the computer software. The follow-up measurements were compared with those obtained from the radiograph taken at the time of prosthetic loading to determine the late bone remodeling. An independent t test was used to compare data. RESULTS: From 138 patients who attended the recall, 242 implants (M = 126; R = 116) were evaluated with a mean follow-up period of 4.6 +/- 0.9 years. Similar success rates were found in both groups (M = 95.0%; R = 95.9%). Late bone remodeling in the maxilla was not influenced by the implant collar (P = .504); however, lower marginal bone loss was observed in the R group (1.20 +/- 0.52 mm) compared with the M group (1.58 +/ 0.73 mm) in the mandible (P = .007). CONCLUSION: Although the implant collar design did not influence the success rate of dental implants, the rough collar design reduced the late marginal bone remodeling around external-hexagon implants in the mandible. The maxilla was not benefited by the rough collar design. PMID- 28708920 TI - Complications and Clinical Considerations of the Implant-Retained Zirconia Complete-Arch Prosthesis with Various Opposing Dentitions. AB - PURPOSE: To evaluate the performance of the implant-retained zirconia complete arch prosthesis with various opposing dentitions. MATERIALS AND METHODS: The 40 patients included in this retrospective case series study were treated with one or two implant-retained zirconia complete-arch prostheses (ZIRCAP) using the Zirkonzahn protocol. Prettau zirconia frames were created with strategic cutbacks in the structure to extend zirconia incisal coverage of the esthetic anterior sextants and complete monolithic zirconia in the molar areas; subsequent layers of porcelain were applied to nonfunctional and esthetic areas. Patients had three possible occlusal scenarios: (1) maxillary ZIRCAP and mandibular ZIRCAP, (2) maxillary ZIRCAP and mandibular natural dentition, and (3) maxillary ZIRCAP and mandibular conventional hybrid prosthesis. Complications were recorded during follow-up appointments 3, 6, and 12 months after definitive prosthesis delivery. The mean treatment observation period was 33 months. RESULTS: Eight prosthetic complications were noted for the 40 implant-retained zirconia complete-arch prostheses (18.18%), including six cases of minor porcelain chipping and two cases of debonding of the metal insert from the zirconia framework. Maxillary ZIRCAP opposing mandibular ZIRCAP and maxillary ZIRCAP opposing mandibular natural dentition occlusal scenarios presented the same complication ratio of 4. No complications were seen in the maxillary ZIRCAP opposing mandibular conventional hybrid prosthesis group, yet 16 complications were found as denture tooth fractures in 12 mandibular conventional hybrid prostheses (ratio of 0.75). CONCLUSION: The results indicate that the implant-retained zirconia complete-arch prosthesis offers acceptable performance for use as an alternative to the conventional titanium framework acrylic veneer prosthesis for complete edentulism with a lower incidence of prosthetic complications and fewer maintenance appointments. Chipping of veneering porcelain was the most common complication, but a low incidence was observed in this study. Acrylic denture teeth may represent the weakest link when restoring complete edentulism with a maxillary ZIRCAP and mandibular conventional hybrid prosthesis. PMID- 28708921 TI - Outcomes Assessment of Treating Completely Edentulous Patients with a Fixed Implant-Supported Profile Prosthesis Utilizing a Graftless Approach. Part 1: Clinically Related Outcomes. AB - PURPOSE: To assess outcomes of treating completely edentulous patients with a fixed implant-supported profile prosthesis utilizing a graftless approach for the maxilla and for the mandible, with emphasis on clinically related outcomes, specifically implant and prosthesis survival. MATERIALS AND METHODS: This was a retrospective study with the following inclusion criteria: completely edentulous patients rehabilitated with a fixed implant-supported profile denture utilizing a graftless approach. Patients fulfilling the inclusion criteria were asked to participate in the study during their follow-up visits, and hence a consecutive sampling strategy was used. Data regarding implant and prosthesis cumulative survival rates (CSRs) were gathered and calculated. RESULTS: Thirty-four patients were identified with a total of 220 implants placed. An overall CSR of 98.2% was recorded with an observation of up to 10 years. For tilted, axial, and zygomatic implants, CSRs of 96.9%, 98.0%, and 100%, respectively, were observed for up to 10 years. For provisional prostheses, CSRs of 92.3% at 1 year, and 84.6% at 2 years were observed. For final prostheses, a CSR of 93.8% was observed at 10 years. CONCLUSION: The results suggest that treating completely edentulous patients with a fixed profile prosthesis utilizing a graftless approach in the maxilla and the mandible can be a reliable treatment option. PMID- 28708922 TI - Assessment of Long-Term Survival of Immediately Loaded Tilted Implants Supporting a Maxillary Full-Arch Fixed Prosthesis. AB - PURPOSE: To analyze the long-term outcome of fixed prostheses supported by six implants, two of which were tilted, placed in the maxilla and immediately loaded more than 10 years earlier. MATERIALS AND METHODS: A retrospective review of implants placed between May 29, 2003 and February 12, 2005 and used to support immediately loaded fixed dental prostheses in the maxilla was conducted. The features of failed implants were analyzed. In the most recent follow-up visits, survival of individual implants and prostheses was verified, and modified Plaque Index as well as modified Sulcular Bleeding Index were assessed. Patients also filled out a questionnaire requiring graded responses from 0 (poor) to 10 (excellent) that was designed to assess their quality of life. RESULTS: A total of 162 implants were placed between May 29, 2003 and February 12, 2005 to support immediately loaded maxillary fixed prostheses of 27 totally edentulous patients (19 female, 8 male). Three patients (1 male, 2 female) dropped out, so 144 implants were followed up. Seven of the 144 original implants failed, corresponding to a survival rate of 95.1% over 10 years. All the failures occurred within 2 years after surgery. Patients' responses to the questionnaire produced an average score of 8.4 to 8.8, showing a relevant degree of satisfaction. CONCLUSION: Based upon this study of 27 patients who received immediately loaded maxillary full-arch fixed implant-supported prostheses supported by two tilted and four axial implants, it appears that this is a reliable procedure with a high long-term survival rate and a high level of patient satisfaction. PMID- 28708923 TI - Preoperative Anxiety and Its Influence on Patient and Surgeon Satisfaction in Patients Receiving Dental Implant Surgeries Performed Under Intravenous Conscious Sedation. AB - PURPOSE: The aims of this study were to evaluate the relationship of age, sex, and type and duration of the surgery with preoperative anxiety in patients undergoing dental implant surgeries under intravenous conscious sedation, and to assess preoperative anxiety association with the postoperative satisfaction of both the patient and surgeon. MATERIALS AND METHODS: This prospective study included 180 patients receiving dental implant surgeries under intravenous conscious sedation by means of midazolam, fentanyl, and propofol. Preoperative anxiety (Corah Dental Anxiety Scale), number of implants, duration of surgery, surgeon satisfaction (evaluated as three categories: patient too awake and nervous, adequate sedation, or patient too asleep), and patient satisfaction (classified as five levels: agreeable, neither agreeable nor disagreeable, slightly uncomfortable, unpleasant, traumatic) were recorded. RESULTS: All 180 patients completed the study, and 72.2% of them experienced moderate or high levels of anxiety. The mean Corah scale score was 9.2 +/- 3.5. Anxiety was significantly higher among men but showed no relation to age. A significant relationship was found between patient anxiety and the number of implants: those patients who received eight or more implants, with a duration of surgery longer than 60 minutes, had lower anxiety. Surgeon satisfaction was adequate in 90% of the cases. Patients evaluated the procedure as agreeable in 34.4% of cases, neither agreeable nor disagreeable in 26.7%, slightly uncomfortable in 29.4%, unpleasant in 7.8%, and traumatic in 1.7%. High anxiety levels were related with poor patient satisfaction but not with surgeon satisfaction. CONCLUSION: Preoperative anxiety was moderate or high in two-thirds of patients undergoing dental implant surgeries, having a negative influence on patient satisfaction, but not affecting surgeon satisfaction. Additionally, the intravenous conscious sedation technique was considered a satisfactory technique by the surgeon to control anxiety. PMID- 28708924 TI - Bone and Soft Tissue Response in Bone-Level Implants Restored with Platform Switching: A 5-Year Clinical Prospective Study. AB - PURPOSE: The aim of this prospective study was to evaluate radiographic levels of peri-implant bone crest as well as soft tissue response, papilla height, and buccal mucosa recession, in bone-level implants restored with platform switching after 1-year and 5-year follow-ups. MATERIALS AND METHODS: This prospective study called for the placement of 59 implants to obtain a target of 90% power. To compensate for possible dropouts, the sample size was adjusted to 67 implants. To assess marginal bone level changes, periapical radiographs were taken at baseline, 1 year, and 5 years after the definitive restorations. Peri-implant soft tissue modifications were evaluated by performing a photographic sequence at 15 days, 1 year, and 5 years after implant restoration. Parameters measured were: (1) distance from the tip of the papilla to the contact point and (2) apicocoronal crown length. RESULTS: A one-way analysis of variance (ANOVA rank test) was used to compare quantitative data among the three time points studied. Mean marginal bone level changes were as follows: -0.06 +/- 0.32 mm from baseline to 1 year, -0.23 +/- 0.38 mm from 1 to 5 years, and -0.28 +/- 0.45 mm from baseline to 5 years. In bone-level outcomes, no statistically significant differences were found between baseline and 1 year, while the mean differences between 1 and 5 years and baseline and 5 years showed statistically significant differences. In the soft tissue analysis, the distance from the tip of the papilla to the contact point showed the following values: baseline, 2.08 mm; 1 year, 1.54 mm; 5 years, 1.31 mm. No statistically significant differences were found between baseline and 1 year, whereas statistically significant differences between 1 and 5 years and baseline and 5 years were found. Apicocoronal crown length measurements showed the following values: baseline, 9.44 mm; 1 year, 9.28 mm; 5 years, 9.81 mm. No significant differences were found between times studied. CONCLUSION: This prospective clinical study of 67 bone-level implants restored according to the platform-switching concept reported that radiographic levels of peri-implant bone crest were statistically significant between 1 and 5 years and baseline and 5 years. For the soft tissue response, the greatest reduction in the distance from the papilla to the contact point from 1 to 5 years and baseline to 5 years was observed. No significant differences were shown in the buccal margin. PMID- 28708925 TI - Survival Rate of Dental Implants in Patients with History of Periodontal Disease: A Retrospective Cohort Study. AB - PURPOSE: To evaluate the differences between the survival rates of implants placed in patients with no history of periodontal disease (NP) and in patients with a history of chronic periodontal disease (CP). MATERIALS AND METHODS: A retrospective cohort study was conducted in which all consenting patients treated with dental implants in a private clinic in Oporto, Portugal, from November 2, 2002 through February 11, 2011 were included. All patients were treated consecutively by the same experimental operator. This study aimed to analyze how the primary outcomes (presence of disease, time of placement, and time of loading) and the secondary outcomes (severity-generalized periodontitis, brand, implant length, prosthesis type, prosthesis metal-ceramic extension) influence the survival rate of dental implants. The survival analysis was performed through the Kaplan-Meier method, and the equality of survival distributions for all groups was tested with the log-rank test with a significance level of .05 for all comparisons. RESULTS: The sample consisted of 202 patients (47% NP and 53% CP) and 689 implants (31% NP and 69% CP). The survival rate in the NP and CP groups showed no statistically significant differences (95.8% versus 93.1%; P >= .05). Implants were lost before loading in 54.9% of the cases. The majority of the implants were lost in the first year and stabilized after the second year. Survival rates in the NP and CP patients showed no statistically significant differences when comparing the following factors: subclassification of the disease, implant brands, implant length (short/standard), type of prosthesis, extension of the prosthesis metal-ceramic, and time of placement and loading (P >= .05). CONCLUSION: This work disclosed no statistically significant differences in terms of survival rates when compared with the control group. Placing implants in patients with a history of periodontal disease appears to be viable and safe. PMID- 28708926 TI - Comparison of Two Porcine Collagen Membranes Combined with rhBMP-2 and rhBMP-9 on Osteoblast Behavior In Vitro. AB - PURPOSE: To investigate the bone-inducing properties of two types of collagen membranes in combination with recombinant human bone morphogenetic protein (rhBMP)-2 and rhBMP-9 on osteoblast behavior. MATERIALS AND METHODS: Porcine pericardium collagen membranes (PPCM) and porcine dermis-derived collagen membranes (PDCM) were coated with either rhBMP-2 or rhBMP-9. The adsorption and release abilities were first investigated via enzyme-linked immunosorbent assay up to 10 days. Moreover, murine bone stromal ST2 cell adhesion, proliferation, and osteoblast differentiation were assessed by MTS assay; real-time polymerase chain reaction for genes encoding runt-related transcription factor 2 (Runx2); alkaline phosphatase (ALP); and osteocalcin, ALP assay, and alizarin red staining. RESULTS: Both rhBMP-2 and rhBMP-9 adsorbed to collagen membranes and were gradually released over time up to 10 days. PPCM showed significantly less cell attachment, whereas PDCM demonstrated comparable cell attachment with the control tissue culture plastic at 8 hours. While both rhBMPs were shown not to affect cell proliferation, collagen membranes combined with rhBMP-9 significantly increased ALP activity at 7 days and ALP mRNA levels at either 3 or 14 days compared with the control tissue culture plastic. Furthermore, rhBMP-9 increased osteocalcin mRNA levels and alizarin red staining at 14 days compared with the control tissue culture plastic. CONCLUSION: The results from this study suggest that both porcine-derived collagen membranes combined with rhBMP-9 accelerated the osteopromotive potential of ST2 cells. Interestingly, rhBMP-9 demonstrated additional osteogenic differentiation compared with rhBMP-2 and may serve as a suitable growth factor for future clinical use. PMID- 28708927 TI - Orotidine-Containing RNA: Implications for the Hierarchical Selection (Systems Chemistry Emergence) of RNA. AB - The prebiotic synthesis of canonical nucleobases from HCN is a cornerstone for the RNA world hypothesis. However, their role in the primordial pathways to RNA is still debated. The very same process starting from HCN also gives rise to orotic acid, which (via orotidine) plays a crucial role in extant biology in the de novo synthesis of uridine and cytidine, the informational base-pairs in RNA. However, orotidine itself is absent in RNA. Given the prebiotic and biological relevance of orotic acid vis-a-vis uracil, we investigated orotidine-containing RNA oligonucleotides and show that they have severely compromised base-pairing properties. While not unexpected, these results suggest that the emergence of extant RNA cannot just be a consequence of the plausible prebiotic formation of its chemical constituents/building blocks. In combination with other investigations on alternative prebiotic nucleobases, sugars, and linkers, these findings imply that the selection of the components of extant RNA occurred at a higher hierarchical level of an oligomer/polymer based on its functional properties-pointing to a systems chemistry emergence of RNA from a library of precursors. PMID- 28708928 TI - The Milan System for Reporting Salivary Gland Cytopathology: Analysis and suggestions of initial survey. AB - BACKGROUND: An international panel of experts in the field of salivary gland cytology (SGC), supported by the American Society of Cytopathology (ASC) and the International Academy of Cytology, conducted a survey to seek evidence and practice patterns regarding SGC. Results were used to provide focus for the proposed Milan System for Reporting Salivary Gland Cytopathology. METHODS: The study group, formed during the 2015 European Congress of Cytology held in Milan, Italy, generated a survey that included 49 specific questions related to the taxonomies, practices, and diagnostic entities of salivary cytology. Qualtrics software was used as the study platform. Software and server support were provided by the division of information technology at the University of Wisconsin. The survey was available online from November 2015 until February 2016. Participants were invited through the Web sites of the ASC, the International Academy of Cytology, and the Papanicolaou Society of Cytopathology as well as by the ASC e-mail "ListServe"; responses were evaluated by the Milan System editors. RESULTS: Responses from a total of 515 participants were collected and reviewed. A total of 347 participants provided demographic data information. Responses revealed variations in diagnostic practice and subsequent management. Participants believed that the acceptable rate for nondiagnostic samples should not be higher than 10%. There were varied opinions regarding the approach to neoplastic lesions of uncertain malignant potential, those that may or may have not local invasion and distant spread. CONCLUSIONS: Results of the survey demonstrated strong support for the development of a unified system for reporting SGC. Cancer Cytopathol 2017;125:757-66. (c) 2017 American Cancer Society. PMID- 28708929 TI - Stereotactic body radiotherapy for unresected pancreatic cancer: A nationwide review. AB - BACKGROUND: The role of conventional radiotherapy in the management of pancreatic cancer has yet to be elucidated. Over the past decade, stereotactic body radiotherapy (SBRT) has emerged as a novel therapeutic option in pancreatic cancer care. This study evaluated the survival impact of SBRT on patients with unresected pancreatic cancer. METHODS: The National Cancer Data Base was queried for unresected patients who received chemotherapy for nonmetastatic pancreatic adenocarcinoma between 2004 and 2012. Four treatment groups were identified: chemotherapy alone, chemotherapy combined with external-beam radiotherapy (EBRT), chemotherapy combined with intensity-modulated radiotherapy (IMRT), and chemotherapy combined with SBRT. Propensity score models predicting the odds of receiving SBRT were created to control for potential selection bias, and patients were matched by propensity scores. The survival analysis was performed with the Kaplan-Meier method. RESULTS: A total of 14,331 patients met the inclusion criteria. Chemotherapy alone was delivered to 5464 patients (38.1%); 6418 (44.8%), 322 (2.3%), and 2127 (14.8%) received chemotherapy along with EBRT, IMRT, and SBRT, respectively. The unadjusted median survival before matching was 9.9, 10.9, 12.0, and 13.9 months for patients treated with chemotherapy, EBRT, IMRT, and SBRT, respectively. In separate matched analyses, SBRT remained superior to chemotherapy alone (log-rank P < .0001) and EBRT (log-rank P = .0180). After matching, survival did not differ between patients receiving IMRT and patients receiving SBRT (log-rank P = .0492). CONCLUSIONS: SBRT is associated with a significantly better outcome than chemotherapy alone or in conjunction with traditional EBRT. These results support the idea that SBRT is a promising treatment approach for patients with unresected pancreatic cancer. Cancer 2017;123:4158-4167. (c) 2017 American Cancer Society. PMID- 28708930 TI - Effects of high-intensity aerobic interval training on cardiovascular disease risk in testicular cancer survivors: A phase 2 randomized controlled trial. AB - BACKGROUND: Testicular cancer survivors (TCS) have an increased risk of treatment related cardiovascular disease (CVD), which may limit their overall survival. We evaluated the effects of high-intensity aerobic interval training (HIIT) on traditional and novel CVD risk factors and surrogate markers of mortality in a population-based sample of TCS. METHODS: This phase 2 trial (ClinicalTrials.gov identifier NCT02459132) randomly assigned 63 TCS to usual care (UC) or 12 weeks of supervised HIIT (ie, alternating periods of vigorous-intensity and light intensity aerobic exercise). The primary outcome was peak aerobic fitness (VO2peak ) assessed via a treadmill-based maximal cardiorespiratory exercise test. Secondary endpoints included CVD risk (eg, Framingham Risk Score), arterial health, parasympathetic nervous system function, and blood-based biomarkers. RESULTS: Postintervention VO2peak data were obtained for 61 participants (97%). HIIT participants attended 99% of the exercise sessions and achieved 98% of the target exercise intensity. Analysis of covariance demonstrated that HIIT was superior to UC for improving VO2peak (adjusted between-group mean difference, 3.7 mL O2 /kg/min; 95% confidence interval, 2.4-5.1 [P<.001]) and multiple secondary outcomes including CVD risk (P = .011), arterial thickness (P<.001), arterial stiffness (P<.001), postexercise parasympathetic reactivation (P = .001), inflammation (P = .045), and low-density lipoprotein (P = .014). Overall, HIIT reduced the prevalence of modifiable CVD risk factors by 20% compared with UC. CONCLUSIONS: This randomized trial provides the first evidence that HIIT improves cardiorespiratory fitness, multiple pathways of CVD risk, and surrogate markers of mortality in TCS. These findings have important implications for the management of TCS. Further research concerning the long-term effects of HIIT on CVD morbidity and mortality in TCS is warranted. Cancer 2017;123:4057-65. (c) 2017 American Cancer Society. PMID- 28708931 TI - A randomized phase 2 study of idarubicin and cytarabine with clofarabine or fludarabine in patients with newly diagnosed acute myeloid leukemia. AB - BACKGROUND: Fludarabine and clofarabine are purine nucleoside analogues with established clinical activity in patients with acute myeloid leukemia (AML). METHODS: Herein, the authors evaluated the efficacy and safety of idarubicin and cytarabine with either clofarabine (CIA) or fludarabine (FIA) in adults with newly diagnosed AML. Adults with newly diagnosed AML who were deemed suitable for intensive chemotherapy were randomized using a Bayesian adaptive design to receive CIA (106 patients) or FIA (76 patients). Patients received induction with idarubicin and cytarabine, plus either clofarabine or fludarabine. Responding patients could receive up to 6 cycles of consolidation therapy. Outcomes were compared with a historical cohort of patients who received idarubicin and cytarabine. RESULTS: The complete remission/complete remission without platelet recovery rate was similar among patients in the CIA and FIA arms (80% and 82%, respectively). The median event-free survival was 13 months and 12 months, respectively (P = .91), and the median overall survival was 24 months and not reached, respectively (P = .23), in the 2 treatment arms. CIA was associated with more adverse events, particularly transaminase elevation, hyperbilirubinemia, and rash. Early mortality was similar in the 2 arms (60-day mortality rate of 4% for CIA vs 1% for FIA; P = .32). In an exploratory analysis of patients aged <50 years, FIA was found to be associated with improved survival compared with idarubicin and cytarabine (2-year event-free survival rate: 58% vs 30% [P = .05] and 2-year overall survival rate: 72% vs 36% [P = .009]). CONCLUSIONS: CIA and FIA have similar efficacy in younger patients with newly diagnosed AML, although FIA is associated with a better toxicity profile. Cancer 2017;123:4430-9. (c) 2017 American Cancer Society. PMID- 28708933 TI - Colorectal cancer screening at US community health centers: Examination of sociodemographic disparities and association with patient-provider communication. AB - BACKGROUND: Colorectal cancer (CRC) screening rates are low among underserved populations. High-quality patient-physician communication potentially influences patients' willingness to undergo CRC screening. Community health centers (HCs) provide comprehensive primary health care to underserved populations. This study's objectives were to ascertain national CRC screening rates and to explore the relations between sociodemographic characteristics and patient-provider communication on the receipt of CRC screening among HC patients. METHODS: Using 2014 Health Center Patient Survey data, bivariate and multivariate analyses examined the association of sociodemographic variables (sex, race/ethnicity, age, geography, preferred language, household income, insurance, and employment status) and patient-provider communication with the receipt of CRC screening. RESULTS: Patients between the ages of 65 and 75 years (adjusted odds ratio [aOR], 2.49; 95% confidence interval [CI], 1.33-4.64) and patients not in the labor force (aOR, 2.32; 95% CI, 1.37-3.94) had higher odds of receiving CRC screening, whereas patients who were uninsured (aOR, 0.33; 95% CI, 0.18-0.61) and patients who were non-English-speaking (aOR, 0.42; 95% CI, 0.18-0.99) had lower odds. Patient-provider communication was not associated with the receipt of CRC screening. CONCLUSIONS: The CRC screening rate for HC patients was 57.9%, whereas the rate was 65.1% according to the 2012 Behavioral Risk Factor Surveillance System and 58.2% according to the 2013 National Health Interview Survey. The high ratings of patient-provider communication, regardless of the screening status, suggest strides toward a patient-centered medical home practice transformation that will assist in a positive patient experience. Addressing the lack of insurance, making culturally and linguistically appropriate patient education materials available, and training clinicians and care teams in cultural competency are critical for increasing future CRC screening rates. Cancer 2017;123:4185-4192. (c) 2017 American Cancer Society. PMID- 28708932 TI - Tandem repeat variation near the HIC1 (hypermethylated in cancer 1) promoter predicts outcome of oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer. AB - BACKGROUND: The hypermethylated in cancer 1/sirtuin 1 (HIC1/SIRT1) axis plays an important role in regulating the nucleotide excision repair pathway, which is the main oxaliplatin-induced damage-repair system. On the basis of prior evidence that the variable number of tandem repeat (VNTR) sequence located near the promoter lesion of HIC1 is associated with HIC1 gene expression, the authors tested the hypothesis that this VNTR is associated with clinical outcome in patients with metastatic colorectal cancer who receive oxaliplatin-based chemotherapy. METHODS: Four independent cohorts were tested. Patients who received oxaliplatin-based chemotherapy served as the training cohort (n = 218), and those who received treatment without oxaliplatin served as the control cohort (n = 215). Two cohorts of patients who received oxaliplatin-based chemotherapy were used for validation studies (n = 176 and n = 73). The VNTR sequence near HIC1 was analyzed by polymerase chain reaction analysis and gel electrophoresis and was tested for associations with the response rate, progression-free survival, and overall survival. RESULTS: In the training cohort, patients who harbored at least 5 tandem repeats (TRs) in both alleles had a significantly shorter PFS compared with those who had fewer than 4 TRs in at least 1 allele (9.5 vs 11.6 months; hazard ratio, 1.93; P = .012), and these findings remained statistically significant after multivariate analysis (hazard ratio, 2.00; 95% confidence interval, 1.13-3.54; P = .018). This preliminary association was confirmed in the validation cohort, and patients who had at least 5 TRs in both alleles had a worse PFS compared with the other cohort (7.9 vs 9.8 months; hazard ratio, 1.85; P = .044). CONCLUSIONS: The current findings suggest that the VNTR sequence near HIC1 could be a predictive marker for oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer. Cancer 2017;123:4506 14. (c) 2017 American Cancer Society. PMID- 28708934 TI - Botrytis cinerea B05.10 promotes disease development in Arabidopsis by suppressing WRKY33-mediated host immunity. AB - The large WRKY transcription factor family is mainly involved in regulating plant immune responses. Arabidopsis WRKY33 is a key transcriptional regulator of hormonal and metabolic processes towards Botrytis cinerea strain 2100 infection and is essential for resistance. In contrast to B. cinerea strain 2100, the strain B05.10 is virulent on wild-type (WT) Col-0 Arabidopsis plants highlighting the genetic diversity within this pathogen species. We analysed how early WRKY33 dependent responses are affected upon infection with strain B05.10 and found that most of these responses were strongly dampened during this interaction. Ectopic expression of WRKY33 resulted in complete resistance towards this strain indicating that virulence of B05.10, at least partly, depends on suppressing WRKY33 expression/protein accumulation. As a consequence, the expression levels of direct WRKY33 target genes, including those involved in the biosynthesis of camalexin, were also reduced upon infection. Concomitantly, elevated levels of the phytohormone abscisic acid (ABA) were observed. Molecular and genetic studies revealed that ABA negatively influences defence to B05.10 and effects jasmonic acid/ethylene (JA/ET) and salicylic acid (SA) levels. Susceptibility/resistance was determined by the antagonistic effect of ABA on JA, and this crosstalk required suppressing WRKY33 functions at early infection stages. This indicates that B. cinerea B05.10 promotes disease by suppressing WRKY33-mediated host defences. PMID- 28708936 TI - Hybrid model for the personal exposure meter response in an outdoor environment. AB - When a personal exposure meter (PEM) is worn by a human subject, the electric field strength measured at the PEM is affected by a body shadowing effect. In our study, a hybrid model is proposed for modeling the body shadowing effect for when the PEM is used in an outdoor environment. The hybrid model contains responses to direct and diffused waves, the factors related to the transmission path and cross polarization discrimination, respectively. To derive the hybrid model, responses for the direct and diffused waves are measured using a human phantom in an anechoic chamber and a reverberation chamber, respectively. Responses are measured at multiple locations in an outdoor environment and compared to the responses of the hybrid model. The hybrid model response has quartiles that deviate by an average of only 2.2 dB (1.29) from the same quartiles of the outdoor responses. Such quartile deviations are significantly smaller than those of the previous model with a body shadowing effect. Bioelectromagnetics. 38:626 647, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28708935 TI - Testing the nicotine dependence measure mFTQ for adolescent smokers: A multinational investigation. AB - BACKGROUND AND OBJECTIVES: As a measure of nicotine dependence among adolescent smokers, the modified Fagerstrom Tolerance Questionnaire (mFTQ; seven items), has been successfully used in the United States (USA). Nonetheless, the validity and reliability of mFTQ at the international level is still needed. The current study is the first to test the validity and reliability of mFTQ in four countries: Thailand, Spain, the USA, and Russia. METHODS: In a cross-sectional survey, mFTQ, risk factors of nicotine dependence, and sociodemographic characteristics were assessed. Risk factors included age of first cigarette, frequency of alcohol use, frequency of marijuana use, and number of cigarettes smoked yesterday. Salivary cotinine was also obtained in Thailand and Spain. RESULTS: For all four countries, mFTQ exhibited a single factor structure, as supported by previous work in the USA. For all studied countries except Thailand, mFTQ presented acceptable internal reliability. Overall, risk factors of nicotine dependence have predicted mFTQ scores across countries. Frequency of alcohol use in the USA and frequency of marijuana use in Thailand and Spain were not associated with mFTQ scores. DISCUSSION AND CONCLUSIONS: mFTQ is a single-factor measure of nicotine dependence that shows acceptable internal consistency and validity across countries. Further work can advance the scale and tailor it to different cultures. SCIENTIFIC SIGNIFICANCE: mFTQ can be a clinically practical international measure of nicotine dependence. This study provides initial support for the utility of the mFTQ among Thai, Spanish, American, and Russian adolescents. Further research is needed to test and advance mFTQ across cultures. (Am J Addict 2017;26:689-696). PMID- 28708937 TI - Malignant central nervous system tumors among adolescents and young adults (15-39 years old) in 14 Southern-Eastern European registries and the US Surveillance, Epidemiology, and End Results program: Mortality and survival patterns. AB - BACKGROUND: Unique features and worse outcomes have been reported for cancers among adolescents and young adults (AYAs; 15-39 years old). The aim of this study was to explore the mortality and survival patterns of malignant central nervous system (CNS) tumors among AYAs in Southern-Eastern Europe (SEE) in comparison with the US Surveillance, Epidemiology, and End Results (SEER) program. METHODS: Malignant CNS tumors diagnosed in AYAs during the period spanning 1990-2014 were retrieved from 14 population-based cancer registries in the SEE region (n = 11,438). Age-adjusted mortality rates were calculated and survival patterns were evaluated via Kaplan-Meier curves and Cox regression analyses, and they were compared with respective 1990-2012 figures from SEER (n = 13,573). RESULTS: Mortality rates in SEE (range, 11.9-18.5 deaths per million) were higher overall than the SEER rate (9.4 deaths per million), with decreasing trends in both regions. Survival rates increased during a comparable period (2001-2009) in SEE and SEER. The 5-year survival rate was considerably lower in the SEE registries (46%) versus SEER (67%), mainly because of the extremely low rates in Ukraine; this finding was consistent across age groups and diagnostic subtypes. The highest 5-year survival rates were recorded for ependymomas (76% in SEE and 92% in SEER), and the worst were recorded for glioblastomas and anaplastic astrocytomas (28% in SEE and 37% in SEER). Advancing age, male sex, and rural residency at diagnosis adversely affected outcomes in both regions. CONCLUSIONS: Despite definite survival gains over the last years, the considerable outcome disparities between the less affluent SEE region and the United States for AYAs with malignant CNS tumors point to health care delivery inequalities. No considerable prognostic deficits for CNS tumors are evident for AYAs versus children. Cancer 2017;123:4458-71. (c) 2017 American Cancer Society. PMID- 28708939 TI - Ligand-Mediated Receptor Assembly as an End Point for High-Throughput Chemical Toxicity Screening. AB - The high throughput screening of chemicals for interaction with intracellular targets is gaining prominence in the toxicity evaluation of environmental chemicals. We describe ligand-mediated receptor assembly as an early event in receptor signaling and its application to the screening of chemicals for interaction with targeted receptors. We utilized bioluminescence resonance energy transfer (BRET) to detect and quantify assembly of the methyl farnesoate receptor (MfR) in response to various high-production volume and other chemicals. The hormone methyl farnesoate binds to the MfR to regulate various aspects of reproduction and development in crustaceans. The MfR protein subunits Met and SRC, cloned from Daphnia pulex, were fused to the fluorophore, mAmetrine and the photon generator, Rluc2, respectively. Ligand-mediated receptor assembly was measured by photon transfer from the photon donor to the fluorophore resulting in fluorescence emission. Overall, the BRET assay had comparable or greater sensitivity as compared to a traditional reporter gene assay. Further, chemicals that screened positive in the BRET assay also stimulated phenotypic outcomes in daphnids that result from MfR signaling. We concluded the BRET assay is an accurate, sensitive, and cost/time efficient alternative to traditional screening assays. PMID- 28708938 TI - Interactions between Quinolones and Bacillus anthracis Gyrase and the Basis of Drug Resistance. AB - Gyrase appears to be the primary cellular target for quinolone antibacterials in multiple pathogenic bacteria, including Bacillus anthracis, the causative agent of anthrax. Given the significance of this type II topoisomerase as a drug target, it is critical to understand how quinolones interact with gyrase and how specific mutations lead to resistance. However, these important issues have yet to be addressed for a canonical gyrase. Therefore, we utilized a mechanistic approach to characterize interactions of quinolones with wild-type B. anthracis gyrase and enzymes containing the most common quinolone resistance mutations. Results indicate that clinically relevant quinolones interact with the enzyme through a water-metal ion bridge in which a noncatalytic divalent metal ion is chelated by the C3/C4 keto acid of the drug. In contrast to other bacterial type II topoisomerases that have been examined, the bridge is anchored to gyrase primarily through a single residue (Ser85). Substitution of groups at the quinolone C7 and C8 positions generated drugs that were less dependent on the water-metal ion bridge and overcame resistance. Thus, by analyzing the interactions of drugs with type II topoisomerases from individual bacteria, it may be possible to identify specific quinolone derivatives that can overcome target-mediated resistance in important pathogenic species. PMID- 28708940 TI - Street-Like Synthesis of Krokodil Results in the Formation of an Enlarged Cluster of Known and New Morphinans. AB - "Krokodil" is the street name for a homemade injectable drug that has been used as a cheap substitute for heroin. Codeine is the opioid starting material for krokodil synthesis, and desomorphine is claimed to be the main opioid of krokodil and the main component responsible for its addictive and psychoactive characteristics. However, due to its peculiar manufacture, using cheap raw materials, krokodil is composed of a large and complex mixture of different substances. In order to shed some light upon the chemical complexity of krokodil, its profiling was conducted by reverse phase high performance liquid chromatography coupled to a photodiode array detector (RP-HPLC-DAD) and by liquid chromatography coupled to high resolution tandem mass spectrometry (LC-ESI-IT Orbitrap-MS). Besides desomorphine, codeine, and morphine, profiting from the high resolution mass spectrometry (HRMS) data, an endeavor to study the morphinans content in krokodil was set for the first time. Considering codeine as the only morphinan precursor and the possible chemical transformations that can occur during krokodil synthesis, the morphinan chemical space was designed, and 95 compounds were defined. By making use of the morphinan chemical space in krokodil, the exact masses featured by HRMS, and the morphinan mass fragmentations patterns, a targeted identification approach was designed and implemented.The proposed 95 morphinans were searched using the full scan chromatogram of krokodil, and findings were validated by mass fragmentation of the correspondent precursor ions (MS2 spectra). Following this effort, a total of 54 morphinans were detected, highlighting the fact that these additional morphinans may contribute to the psychotropic effects of krokodil. PMID- 28708941 TI - Regulation of the insulin-Akt signaling pathway and glycolysis during dehydration stress in the African clawed frog Xenopus laevis. AB - Estivation is an adaptive stress response utilized by some amphibians during periods of drought in the summer season. In this study, we examine the regulation of the insulin signaling cascade and glycolysis pathway in the African clawed frog Xenopus laevis during the dehydration stress induced state of estivation. We show that in the brain and heart of X. laevis, dehydration reduces the phosphorylation of the insulin growth factor-1 receptor (IGF-1R), and this is followed by similar reductions in the phosphorylation of the Akt and mechanistic target of rapamycin (mTOR) kinase. Interestingly, phosphorylation levels of IGF 1R and mTOR were not affected in the kidney, and phosphorylation levels of P70S6K and the ribosomal S6 protein were elevated during dehydration stress. Animals under estivation are also susceptible to periods of hypoxia, suggesting that glycolysis may also be affected. We observed that protein levels of many glycolytic enzymes remained unchanged during dehydration; however, the hypoxia response factor-1 alpha (HIF-1alpha) protein was elevated by greater than twofold in the heart during dehydration. Overall, we provide evidence that shows that the insulin signaling pathway in X. laevis is regulated in a tissue-specific manner during dehydration stress and suggests an important role for this signaling cascade in mediating the estivation response. PMID- 28708942 TI - Commentary on "Better Prognosis of Senile Patients with Intertrochanteric Femoral Fracture by Treatment with Open Reduction Internal Fixation than by Hip Arthroplasty". PMID- 28708944 TI - Indirect comparison of bronchial thermoplasty versus omalizumab for uncontrolled severe asthma. AB - OBJECTIVE: Bronchial thermoplasty (BT) as an add-on therapy for uncontrolled severe asthma is an alternative to biologic therapies like omalizumab (OM). We conducted an indirect treatment comparison (ITC) to appraise comparative effectiveness of BT and OM. METHODS: A systematic literature review identified relevant randomized controlled trials. The ITC followed accepted methodology. RESULTS: The ITC comprised a sham-controlled trial of BT (AIR2) and two placebo controlled trials of OM (INNOVATE; EXTRA). Comparing the BT post-treatment period to ongoing treatment with OM, showed no significant differences in the rate ratios (RRs) for severe exacerbations (RR of BT versus OM = 0.91 [95% CI: 0.64, 1.30]; p = 0.62) or hospitalizations (RR = 0.57 [95% CI: 0.17, 1.86]; p = 0.53); emergency department visits were significantly reduced by 75% with BT (RR = 0.25 [95% CI: 0.07, 0.91]; p = 0.04); the proportions of patients with clinically meaningful response on the asthma quality-of-life questionnaire were comparable (RR = 1.06 [95% CI: 0.86, 1.34]; p = 0.59). The RR for exacerbations statistically favours OM over the total study period in AIR2 (RR = 1.50 [95% CI: 1.11, 2.02]; p = 0.009) likely reflecting a transient increase in events during the BT peri-treatment period. CONCLUSIONS: The ITC should be interpreted cautiously considering the differences between patient populations in the included trials. However, based on the analysis, BT compares well with a potentially more costly pharmacotherapy for asthma. Clinicians evaluating the relative merits of using these treatments should consider the totality of evidence and patient preferences to make an informed decision. PMID- 28708945 TI - Methods used for immunization coverage assessment in Canada, a Canadian Immunization Research Network (CIRN) study. AB - Accurate and complete immunization data are necessary to assess vaccine coverage, safety and effectiveness. Across Canada, different methods and data sources are used to assess vaccine coverage, but these have not been systematically described. Our primary objective was to examine and describe the methods used to determine immunization coverage in Canada. The secondary objective was to compare routine infant and childhood coverage estimates derived from the Canadian 2013 Childhood National Immunization Coverage Survey (cNICS) with estimates collected from provinces and territories (P/Ts). We collected information from key informants regarding their provincial, territorial or federal methods for assessing immunization coverage. We also collected P/T coverage estimates for select antigens and birth cohorts to determine absolute differences between these and estimates from cNICS. Twenty-six individuals across 16 public health organizations participated between April and August 2015. Coverage surveys are conducted regularly for toddlers in Quebec and in one health authority in British Columbia. Across P/Ts, different methodologies for measuring coverage are used (e.g., valid doses, grace periods). Most P/Ts, except Ontario, measure up-to-date (UTD) coverage and 4 P/Ts also assess on-time coverage. The degree of concordance between P/T and cNICS coverage estimates varied by jurisdiction, antigen and age group. In addition to differences in the data sources and processes used for coverage assessment, there are also differences between Canadian P/Ts in the methods used for calculating immunization coverage. Comparisons between P/T and cNICS estimates leave remaining questions about the proportion of children fully vaccinated in Canada. PMID- 28708946 TI - Sports Participation, Functional Outcome, and Complications After Ankle Arthrodesis: Midterm Follow-up. AB - BACKGROUND: Ankle arthrodesis provides satisfactory functional outcome based on basic daily activities, but information regarding more demanding tasks is limited. Also, studies reporting longer term survival and complication rates are sparse and concern small study populations. This study reports functional outcome with more focus on demanding tasks and sports and reports the mid- to long-term union and complication rates in a large study population. METHODS: Between 2005 and 2010, an ankle arthrodesis was performed on 185 ankles. Clinical results were retrospectively assessed with the Foot Function Index (FFI), visual analog scale (VAS) for pain, and the Foot and Ankle Ability Measure (FAAM). Information regarding sports pre- and postoperatively was obtained through a questionnaire. In addition, postoperative complications, reoperations, and failures (defined as nonunion of the ankle arthrodesis) were determined. Mean follow-up time was 8 years. RESULTS: FFI scores significantly improved, the FAAM ADL score was 70%, and the mean VAS for pain at the ankle/hindfoot at follow-up was 20. Sports participation slightly diminished from 79.5% prior to the onset of disabling complaints to 68.9% postoperatively. Of the patients, 73.1% were able to hike with a median hiking time of 40 minutes (range, 2-600 minutes). Kneeling could be performed on average 10 minutes (range, 2-60 minutes) in 39.8% and jumping down from steps by 23.5% of the patients. A small selection of patients was able to sprint (14%), and 16.8% of the patients were able to run a median distance of 60 meters (range, 3-1000 meters). Failure occurred in 9.2% and other postoperative complications were present in 21.6%, requiring reoperation in 8.6% of the cases. CONCLUSION: Ankle arthrodesis led to satisfactory functional outcome and pain reduction. Most patients remained active in sports, but a transition to less demanding sporting activities was seen. The complication and failure rates were similar with previous literature, and the incidence of nonrevision secondary surgery was relatively low. LEVEL OF EVIDENCE: Level III, retrospective comparative study. PMID- 28708947 TI - Kv10.1 potassium channel: from the brain to the tumors. AB - The KCNH1 gene encodes the Kv10.1 (Eag1) ion channel, a member of the EAG (ether a-go-go) family of voltage-gated potassium channels. Recent studies have demonstrated that KCHN1 mutations are implicated in Temple-Baraitser and Zimmermann-Laband syndromes and other forms of developmental deficits that all present with mental retardation and epilepsy, suggesting that Kv10.1 might be important for cognitive development in humans. Although the Kv10.1 channel is mainly expressed in the mammalian brain, its ectopic expression occurs in 70% of human cancers. Cancer cells and tumors expressing Kv10.1 acquire selective advantages that favor cancer progression through molecular mechanisms that involve several cellular pathways, indicating that protein-protein interactions may be important for Kv10.1 influence in cell proliferation and tumorigenesis. Several studies on transcriptional and post-transcriptional regulation of Kv10.1 expression have shown interesting mechanistic insights about Kv10.1 role in oncogenesis, increasing the importance of identifying the cellular factors that regulate Kv10.1 expression in tumors. PMID- 28708949 TI - Comparing executive functions between patients with chronic asthma and healthy subjects. AB - OBJECTIVE: Allergic diseases have different levels of prevalence all over the world. Among them, asthma is the most common chronic disease. Up to now, little attention has been paid to the impact of this chronic disease on people's executive functions. The present study aimed at comparing the executive functions in patients with chronic asthma and healthy subjects. METHODS: The study population was patients with chronic asthma who were referred to Al-Zahra hospital in Isfahan Province and their visitors who were assigned as the control group. Thirty patients with chronic asthma and 30 patient visitors were enrolled in this study, and three software programs (Wisconsin, Stroop, and Continuous Performance Tests) were used. RESULTS: The results of multivariate variance analysis showed that there is a significant difference between patients with chronic asthma and healthy subjects in terms of set shifting, inhibition, and attention performance. CONCLUSIONS: This study revealed that the executive functions of patients with chronic asthma have significant defects. PMID- 28708948 TI - Hospitalizations associated with malignant neoplasia and in situ carcinoma in the anus and penis in men and women during a 5-year period (2009-2013) in Spain: An epidemiological study. AB - BACKGROUND: Approximately 40,000 new cases of anal cancer and 26,000 new cases of penile cancer occurred in 2012 worldwide. Human Papillomavirus (HPV) infection is responsible for 88.3% and 33.0% of these cancers, respectively. The aim of this study was to describe the hospital burden associated with malignant neoplasm (MN) and in situ carcinoma (ISC) in the anus and penis in Spain from 2009 to 2013. METHODS: This observational, retrospective study used discharge information obtained from the national surveillance system for hospital data, Conjunto Minimo Basico de Datos, provided by the Ministry of Health. RESULTS: We found 3,668 hospitalizations due to MN and ISC in the anus for both genders, and more than 55% of these hospitalizations occurred in men and were associated with a lower median age of hospitalization (p < 0.001), higher average length of hospital stay (ALOS) (p = 0.0032), higher hospitalization costs (p < 0.001) and higher hospitalization rate (2.141 per 100,000 males aged > 14 y old and 1.604 per 100,000 women aged > 14 y old, p < 0.001) than in women. During the same period, 4,156 hospitalizations due to MN and ISC of the penis were registered. The hospitalization rate was 4.320 per 100,000 males aged > 14 y old. The hospitalization rate due to MN and ISC in the anus in males increased significantly during this period (p = 0.048). CONCLUSION: Our study provides relevant information about the hospital burden of anal and penile MN and ISC in Spain. This information could be useful for cost effectiveness analysis of universal HPV vaccination and for future HPV vaccination impact monitoring in Spain, and for other countries of similar socioeconomic status. PMID- 28708950 TI - A "real-life" study on height in prepubertal asthmatic children receiving inhaled steroids. AB - INTRODUCTION: Asthma is the most common chronic respiratory disease in children and inhaled corticosteroids (ICS) constitute the first line of treatment for these patients. However, the potential growth-inhibiting effect of ICS has often been a cause of concern for both caregivers as well as physicians, and there still remains conflict regarding their safety profile. OBJECTIVE: To assess whether the administration of ICS in low or medium doses is associated with height reduction in prepubertal children. METHODS: We performed a retrospective study to examine the association between ICS treatment and growth deceleration in children with mild persistent asthma. The comparison of height measurements every 6 months from 3 to 8 years of age was conducted among three groups of patients: patients not receiving ICS, patients being treated with low dose of ICS and patients being treated with medium dose of ICS (GINA Guidelines 2015). RESULTS: This study included 284 patients (198 male, 86 female) aged 3-8 years; 75 patients were not receiving ICS, 63 patients were on low-dose ICS and 146 patients were on medium-dose ICS. The measured height every 6 months did not differ significantly (p > 0.05) among the three groups while the difference remained stable (p > 0.05), even when we evaluated males and females separately. CONCLUSIONS: In this "real-life" study we found that long-term treatment with ICS in low or medium doses is not associated with height reduction in prepubertal children with asthma. PMID- 28708951 TI - Control of a community outbreak of hepatitis A in an area of low endemicity, Wales, 2016. AB - Incidence of hepatitis A in Wales is low (average of 0.48/100,000 inhabitants from 2004-2015). We describe a community outbreak of hepatitis A involving 3 schools (primary and secondary) in South Wales between March and June 2016 and reflect on the adequacy of the control measures used. Anyone in South Wales epidemiologically linked to a serological and/or RNA positive confirmed case of hepatitis A during the 15-50 d before onset of symptoms (diarrhea, vomiting, fever, nausea, AND jaundice, or jaundice-associated symptom) was defined as a case. Case identification was based on laboratory or GP suspicion notification, changing to active surveillance toward the end. As per national guidance, household contacts were identified and offered immunisation while in schools vaccination followed evidence of transmission. We went beyond guidance by vaccinating street play mates and in secondary schools. Mass vaccination uptake was calculated. There were 17 cases, mostly in children under 16 y of age. All cases had an epidemiological link to either a school or a household case (except primary) and no travel history. Street playing was the only epidemiological link between 2 cases in different schools. A total of 139 household contacts were identified. All schools, including secondary one, had a transmission event preceding mass vaccination (overall uptake 85%, reaching 1,574 individuals) and no tertiary cases emerged after the campaigns. We recommend extending guidance to include actions taken that helped curb this outbreak: 1) vaccinating in secondary school and 2) broadening the household contact definition. Based on our learning we further suggest 3) vaccinating upon identification of a single case who attended school while infectious regardless of source and 4) active case finding by serologically testing contacts. PMID- 28708952 TI - Influenza vaccination during pregnancy for prevention of influenza confirmed illness in the infants: A systematic review and meta-analysis. AB - Infants younger than 6 months of age are at particular risk for serious illness from influenza infection. Currently available influenza vaccines are, however, not licensed for use in infants <6 months old. Influenza vaccination during pregnancy elicits robust antibody responses in the women that will protect the infants against influenza infection during the first few months of life. We aimed to determine the impact of influenza vaccination during pregnancy to prevent laboratory-confirmed influenza infection and influenza-associated hospitalisations in infants <6 months old. An electronic search identified all studies assessing the proposed outcomes in infants after administration of influenza vaccine during pregnancy. Two meta-analyses were performed accordingly to studies restricting the evaluation to influenza-associated hospitalisations or not. Four randomized control trials and 3 observational studies reported on the prevention of laboratory-confirmed influenza infection in infants <6 months old. Maternal influenza vaccination was associated with a 48% [95% confidence interval (CI): 33 to 59] reduced risk of infants having laboratory-confirmed influenza infection. Four observational studies reported on the prevention of hospitalizations associated with laboratory-confirmed influenza infection and the pool estimate was 72% (95%CI: 39% to 87%). Receipt of influenza vaccine during pregnancy was associated with decreased risk of laboratory-confirmed influenza infection in the infants. PMID- 28708953 TI - Trends of influenza B during the 2010-2016 seasons in 2 regions of north and south Italy: The impact of the vaccine mismatch on influenza immunisation strategy. AB - Influenza A and B viruses are responsible for respiratory infections, representing globally seasonal threats to human health. The 2 viral types often co-circulate and influenza B plays an important role in the spread of infection. A 6-year retrospective surveillance study was conducted between 2010 and 2016 in 2 large administrative regions of Italy, located in the north (Liguria) and in the south (Sicily) of the country, to describe the burden and epidemiology of both B/Victoria and B/Yamagata lineages in different healthcare settings. Influenza B viruses were detected in 5 of 6 seasonal outbreaks, exceeding influenza A during the season 2012-2013. Most of influenza B infections were found in children aged <= 14 y and significant differences were observed in the age-groups infected by the different lineages. B/Victoria strains prevailed in younger population than B/Yamagata, but also were more frequently found in the community setting. Conversely, B/Yamagata viruses were prevalent among hospitalized cases suggesting their potential role in the development of more severe disease. The relative proportions of viral lineages varied from year to year, resulting in different lineage-level mismatch for the B component of trivalent influenza vaccine. Our findings confirmed the need for continuous virological surveillance of seasonal epidemics and bring attention to the adoption of universal influenza immunization program in the childhood. The use of tetravalent vaccine formulations may be useful to improve the prevention and control of the influenza burden in general population. PMID- 28708954 TI - Pneumococcal and influenza vaccination status of hospitalized adults with community acquired pneumonia and the effects of vaccination on clinical presentation. AB - BACKGROUND: Previous reports have shown that vaccination rates of adult at-risk populations are low in Turkey. There are differing reports with regards to the effectiveness of the influenza and the pneumococcal polysaccharide vaccine (PPSV23) on the clinical outcomes of community acquired pneumonia (CAP). The purpose of this study was to analyze the influenza (FV) and pneumococcal vaccination (PV) status, the factors that influence the receipt of influenza/pneumococcal vaccine and the effects of prior vaccination on the clinical outcomes in adults hospitalized with CAP. PATIENTS AND METHODS: Patients hospitalized with CAP between March 2009 and October 2013 and registered at the web-based Turkish Thoracic Society Pneumonia Database (TURCAP) were included in this multicentric, observational study. Of a total of 787 cases, data were analyzed for 466 patients for whom self-reported information on PV and FV was available. RESULTS: In this adult population with CAP, the vaccination rate with both the pneumococcal and influenza vaccines was found to be 6%. Prior FV was found to be the sole variable that was associated with the receipt of PV [OR 17.8, 95% CI (25-75:8.56-37.01), p < 0.001]. Conversely, being vaccinated with PPSV23 was the only predictor of receipt of FV [OR 18.1, 95% CI (25 - 75:8.75 - 37.83), p < 0.001]. Compared to the unvaccinated cases, the chest radiograms of the vaccinated patients revealed less consolidation. The latter also reported fatigue, muscle pain and gastrointestinal symptoms less frequently. Although there was a trend for lower 30-day mortality and for lower rates of intensive care unit (ICU) admission, these did not reach statistical significance. A pneumonia severity index (PSI) score >= 90, CURB-65 score >=3 and multilobar involvement, but not the vaccination status, were identified as independent determinants of ICU admission. CONCLUSIONS: This study showed that, among patients hospitalized with CAP, the FV and/or PV rates are low. Prior vaccination does not appear to significantly affect the clinical outcomes. PMID- 28708955 TI - Nonweightbearing Radiographs in Patients With a Subtle Lisfranc Injury. AB - BACKGROUND: A midfoot sprain can be easily missed because of minimal findings on initial radiographs, which are almost universally nonweightbearing. We investigated preoperative nonweightbearing plain radiographic images in patients who were found to have unstable subtle Lisfranc injuries. METHODS: We retrospectively reviewed 51 patients who were operated on between February 2004 and March 2015. Abnormal preoperative radiographic findings and intraoperative instability were compared. The relationship was calculated with Fisher's exact test. RESULTS: Based on intraoperative findings, medial cuneiform (C1)-second metatarsal (M2) instability was observed in 50 cases (98%), which was the most common. Thirty-nine cases (76.4 %) had multiple joint (at least 2) instability. In the preoperative radiologic findings, C1-M2 diastasis was the most common abnormal finding, in 46 cases (90.1%). Specificity and positive predictive value were 1.0 in C1-M2 avulsion, diastasis, and C1-intermediate cuneiform (C2) diastasis. Abnormal findings of C1-C2, C1-M1, and C2-M2 showed a significant relationship with intraoperative instability ( P < .05). CONCLUSION: C1-M2 avulsion and diastasis and C1-C2 diastasis were definite preoperative predictors of instability. In unstable subtle Lisfranc injuries, 90% had at least a minor radiographic abnormality at the C1-M2 joint on nonweightbearing radiographs. However, caution should be exercised to identify instability without radiographic abnormality in the C1-M2 joint. LEVEL OF EVIDENCE: Level IV, retrospective case series. PMID- 28708956 TI - The power of combining adoptive cell therapy (ACT) and pathogen-boosted vaccination to treat solid tumors. AB - Recent advancements in adoptive cell therapy (ACT) are opening up new frontiers for cancer immunotherapy. CAR T cells targeting CD19 have emerged as a remarkable T cell-based therapy for the successful treatment of certain types of leukemia and lymphomas. Despite these clinical successes, as well as significant breakthroughs in T cell engineering, the treatment of solid tumors with ACT remains a relentless challenge. Thus, the current consensus of the field is that an urgent need exists for the design of innovative approaches that can improve the efficacy of ACT in treating solid cancers while maintaining a high degree of reliability and safety. PMID- 28708958 TI - Racial disparities in family-provider interactions for pediatric asthma care. AB - OBJECTIVE: Black and Latino children experience significantly worse asthma morbidity than their white peers for multifactorial reasons. This study investigated differences in family-provider interactions for pediatric asthma, based on race/ethnicity. METHODS: This was a cross-sectional study of parent surveys of asthmatic children within the Population-Based Effectiveness in Asthma and Lung Diseases Network. Our study population comprised 647 parents with survey response data. Data on self-reported race/ethnicity of the child were collected from parents of the children with asthma. Outcomes studied were responses to the questions about family-provider interactions in the previous 12 months: (1) number of visits with asthma provider; (2) number of times provider reviewed asthma medications with patient/family; (3) review of a written asthma treatment plan with provider; and (4) preferences about making asthma decisions. RESULTS: In multivariate adjusted analyses controlling for asthma control and other co morbidities, black children had fewer visits in the previous 12 months for asthma than white children: OR 0.63 (95% CI 0.40, 0.99). Additionally, black children were less likely to have a written asthma treatment plan given/reviewed by a provider than their white peers, OR 0.44 (95% CI 0.26, 0.75). There were no significant differences by race in preferences about asthma decision-making nor in the frequency of asthma medication review. CONCLUSION: Black children with asthma have fewer visits with their providers and are less likely to have a written asthma treatment plan than white children. Asthma providers could focus on improving these specific family-provider interactions in minority children. PMID- 28708957 TI - Influenza vaccination in the elderly. AB - Seasonal influenza is a prevalent and serious annual illness resulting in widespread morbidity and economic disruption throughout the population; the elderly and immunocompromised are particularly vulnerable to serious sequelae and mortality. The changing demographics worldwide to an aging society have important implications for public health policy and pharmaceutical innovations. For instance, primary prevention via immunization is effective in reducing the burden of influenza illness among the elderly. However, the elderly may be insufficiently protected by vaccination due to the immunosenescence which accompanies aging. In addition, vaccine hesitancy among the younger populations increases the likelihood of circulating infectious diseases, and thus concomitant exposure. While it is clear that the development of more immunogenic vaccines is an imperative and worthy endeavor, clinical trials continue to demonstrate that the current influenza vaccine formulation remains highly effective in reducing morbidity and mortality when well matched to circulating strains. PMID- 28708959 TI - Assessment of the potential public health impact of Herpes Zoster vaccination in Germany. AB - The aim of this study was to compare the public health impact of introducing 2 Herpes Zoster (HZ) vaccines, Zoster Vaccine Live (ZVL) versus a non-live adjuvanted subunit candidate vaccine (HZ/su), in the German population aged 50+ years split into 3 age cohorts, i.e. 50-59, 60-69 and 70+ years, respectively. A multi-cohort static Markov model was developed following age cohorts over their lifetime. Demographic data were obtained from the German federal statistical office. HZ incidence and the proportion of HZ individuals developing post herpetic neuralgia (PHN) were derived from German specific sources. Age-specific vaccine efficacy and waning rates were based on published clinical trial data. Vaccine coverage for both vaccines was assumed to be 40%, with compliance of the second dose of the HZ/su vaccine of 70%. Sensitivity analyses were performed to assess the robustness of the results. It was estimated that, over the remaining lifetime since vaccination, the HZ/su vaccine would reduce the number of HZ cases by 725,233, 533,162 and 486,794 in the 3 age cohorts, respectively, compared with 198,477, 196,000 and 104,640, using ZVL. The number needed to vaccinate (NNV) to prevent one HZ case ranged from 8 to 11 using the HZ/su vaccine compared with 20 to 50 using ZVL. Corresponding NNV to prevent one PHN case ranged from 39 to 53 using the HZ/su vaccine compared with 94 to 198 using ZVL. Due to the higher, sustained vaccine efficacy, the candidate HZ/su vaccine demonstrated superior public health impact compared with ZVL. PMID- 28708960 TI - Jorg Langowski 1955-2017. PMID- 28708961 TI - Hamilton and Hardy: Mentoring and Friendship in the Service of Occupational Health. AB - This article explores the mentoring relationship between Alice Hamilton and Harriet Hardy, two female physician-researchers who had a tremendous impact on the development of the field of occupational health in the United States during the 20th century. The article relies on letters the women wrote to each other. Hamilton, the elder, supported and furthered Hardy's career by asking her to coauthor the second edition of a seminal occupational health text. After beginning this intellectual collaboration, Hamilton remained a mentor to Hardy, and a decades-long friendship ensued. The article explores their relationship within the historical, political, and social context in which the women worked and made remarkable contributions to public health. PMID- 28708963 TI - A qualitative study adopting a user-centered approach to design and validate a brain computer interface for cognitive rehabilitation for people with brain injury. AB - Cognitive rehabilitation is established as a core intervention within rehabilitation programs following a traumatic brain injury (TBI). Digitally enabled assistive technologies offer opportunities for clinicians to increase remote access to rehabilitation supporting transition into home. Brain Computer Interface (BCI) systems can harness the residual abilities of individuals with limited function to gain control over computers through their brain waves. This paper presents an online cognitive rehabilitation application developed with therapists, to work remotely with people who have TBI, who will use BCI at home to engage in the therapy. A qualitative research study was completed with people who are community dwellers post brain injury (end users), and a cohort of therapists involved in cognitive rehabilitation. A user-centered approach over three phases in the development, design and feasibility testing of this cognitive rehabilitation application included two tasks (Find-a-Category and a Memory Card task). The therapist could remotely prescribe activity with different levels of difficulty. The service user had a home interface which would present the therapy activities. This novel work was achieved by an international consortium of academics, business partners and service users. PMID- 28708962 TI - Open-label phase I clinical trial of Ad5-EBOV in Africans in China. AB - BACKGROUND: To determine the safety and immunogenicity of a novel recombinant adenovirus type 5 vector based Ebola virus disease vaccine (Ad5-EBOV) in Africans in China. METHODS: A phase 1, dose-escalation, open-label trial was conducted. 61 healthy Africans were sequentially enrolled, with 31 participants receiving one shot intramuscular injection and 30 participants receiving a double-shot regimen. Primary and secondary end points related to safety and immunogenicity were assessed within 28 d after vaccination. This study was registered with ClinicalTrials.gov (NCT02401373). RESULTS: Ad5-EBOV is well tolerated and no adverse reaction of grade 3 or above was observed. 53 (86.89%) participants reported at least one adverse reaction within 28 d of vaccination. The most common reaction was fever and the mild pain at injection site, and there were no significant difference between these 2 groups. Ebola glycoprotein-specific antibodies appeared in all 61 participants and antibodies titers peaked after 28 d of vaccination. The geometric mean titres (GMTs) were similar between these 2 groups (1919.01 vs 1684.70 P = 0.5562). The glycoprotein-specific T-cell responses rapidly peaked after 14 d of vaccination and then decreased, however, the percentage of subjects with responses were much higher in the high-dose group (60.00% vs 9.68%, P = 0.0014). Pre-existing Ad5 neutralizing antibodies could significantly dampen the specific humoral immune response and cellular response to the vaccine. CONCLUSION: The application of Ad5-EBOV demonstrated safe in Africans in China and a specific GP antibody and T-cell response could occur 14 d after the first immunization. This acceptable safety profile provides a reliable basis to proceed with trials in Africa. PMID- 28708964 TI - Compounds from Ilex paraguariensis extracts have antioxidant effects in the brains of rats subjected to chronic immobilization stress. AB - Immobilization induces oxidative damage to the brain. Ilex paraguariensis extracts (Mate) and their major natural compound, chlorogenic acid (CGA), exert protective effects against reactive oxygen species formation. Here, the effects of Mate and CGA on oxidative damage induced by chronic immobilization stress (CIS) in the cortex, hippocampus, and striatum were investigated. For CIS, animals were immobilized for 6 h every day for 21 consecutive days. Rats received Mate or CGA by intragastric gavage 30 min before every restraint session. Endpoints of oxidative stress (levels of lipid peroxidation, protein carbonylation, and reduced (GSH) and oxidized (GSSG) forms of glutathione) were evaluated following CIS. While CIS increased oxidized lipid and carbonyl levels in all brain regions, CGA (and Mate to a lesser extent) attenuated lipid and protein oxidation as compared with control groups. GSH/GSSG balance showed a tendency to increase in all regions in response to stress and antioxidants. Taken together, our results support a protective role of dietary antioxidants against the neuronal consequences of stress. PMID- 28708965 TI - Letter from the editor. PMID- 28708966 TI - Human Vaccines & Immunotherapeutics: News. PMID- 28708967 TI - Investigation of the Effect of Milrinone on Renal Damage in an Experimental Non Heart Beating Donor Model. AB - PURPOSE: In our study, it was aimed to investigate the preventive effect of milrinone on renal damage in experimental controlled non-heart-beating donors (NHBDs) model. MATERIALS AND METHODS: Sixteen rats randomly divided into 2 groups, 8 rats in each were used. Group 1 was control, group 2 was milrinone group. Group 1 rats received 1.25 ml 0.09% NaCl intraperitoneally equivalent to the milrinone diluted volume. Group 2 rats were administered intraperitoneally with 0.5 mg/kg of milrinone 2 hours before cardiac arrest. After the cardiac arrest, left nephrectomy was applied to the rats. Malondialdehyde, superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx) activities, Caspase-3 (apoptotic index) and histopathological evaluation were performed in the tissues. RESULTS: In the milrinone group, the total injury score was significantly lower relative to the control group (p = 0.001). Caspase-3 staining was moderately strong in the control group but weaker in the milrinone group. Apoptotic index was significantly lower in the milrinone group compared to the control group (p = 0.001). In comparison between groups, SOD and GPx in the milrinone group was significantly higher than the control group (p = 0.008, p = 0.006). CONCLUSIONS: Milrinone has been shown to be effective in the prevention of tissue damage due to oxidative stress and inflammatory process in the renal of warm ischemia in the experimental NHBDs model and in protecting the renal. Milrinone increases antioxidant activity while reducing apoptosis. Systemic administration of milrinone prior to cardiac arrest may be beneficial. Administration of milrinone to the recipient in the perioperative period may contribute to donor function. PMID- 28708970 TI - Editorial Comment. PMID- 28708969 TI - A Case of Early Pneumoparotid Presenting With Oral Noises. AB - A 53-year-old man presented with the chief complaint of oral noises. No lesion could be observed in the oral cavity. Ultrasound detected several high echogenicity areas inside the bilateral parotid ducts, and the initial stage of pneumoparotid was diagnosed. It was considered that air had entered each duct in retrograde fashion through the parotid papilla because of repeated compression of the bilateral parotid glands by the patient who had the habit of compressing the buccal region. This case suggests that ultrasound is effective for diagnosing the initial stage of pneumoparotid. PMID- 28708968 TI - Rv3723/LucA coordinates fatty acid and cholesterol uptake in Mycobacterium tuberculosis. AB - Pathogenic bacteria have evolved highly specialized systems to extract essential nutrients from their hosts. Mycobacterium tuberculosis (Mtb) scavenges lipids (cholesterol and fatty acids) to maintain infections in mammals but mechanisms and proteins responsible for the import of fatty acids in Mtb were previously unknown. Here, we identify and determine that the previously uncharacterized protein Rv3723/LucA, functions to integrate cholesterol and fatty acid uptake in Mtb. Rv3723/LucA interacts with subunits of the Mce1 and Mce4 complexes to coordinate the activities of these nutrient transporters by maintaining their stability. We also demonstrate that Mce1 functions as a fatty acid transporter in Mtb and determine that facilitating cholesterol and fatty acid import via Rv3723/LucA is required for full bacterial virulence in vivo. These data establish that fatty acid and cholesterol assimilation are inexorably linked in Mtb and reveals a key function for Rv3723/LucA in in coordinating thetransport of both these substrates. PMID- 28708971 TI - Short-Term Alcohol Abstinence Improves Antibacterial Defenses of Chronic Alcohol Consuming Mice against Gut Bacteria-Associated Sepsis Caused by Enterococcus faecalis Oral Infection. AB - The effects of short-term alcohol abstinence on host antibacterial resistance against Enterococcus faecalis oral infection was investigated in chronic alcohol consuming mice [mice with 0.1 g/day of 20% ethanol consumption for 12 or 16 weeks (CAC-mice)]. These mice were highly susceptible to the infection; however, after 7 days of alcohol abstinence (aaCAC-mice), their antibacterial resistances were completely restored to the normal mouse level. Normal mice inoculated with CAC mouse hepatic macrophages were shown to be susceptible to the infection, whereas the same macrophage preparation from aaCAC-mice did not impair the antibacterial resistance of normal mice. aaCAC-mouse liver macrophages protected nonobese diabetic-severe combined immunodeficiency IL-2Rgammanull mice exposed to E. faecalis, whereas those from CAC-mice did not. Monocyte-derived (MD) M2b macrophages were predominantly isolated from CAC-mouse livers, but these cells were not significantly isolated from aaCAC-mouse livers. Hepatic MD macrophages from aaCAC-mice switched to M1 macrophages in response to bacterial antigen, whereas the same macrophage preparation from CAC-mice did not. M1 Kupffer cells, M2a Kupffer cells, and MD M2b macrophages were shown to be not bactericidal, whereas E. faecalis was killed effectively by M1 macrophages derived from aaCAC mouse hepatic MD macrophages. These results indicate that MD M2b macrophages predominantly distributed in the liver are responsible for the impaired resistance of CAC-mice to E. faecalis oral infection, and aaCAC-mice without MD M2b macrophages in the livers are resistant to the infection. PMID- 28708972 TI - UV Irradiation of Skin Enhances Glycolytic Flux and Reduces Migration Capabilities in Bone Marrow-Differentiated Dendritic Cells. AB - A systemic immunosuppression follows UV irradiation of the skin of humans and mice. In this study, dendritic cells (DCs) differentiating from the bone marrow (BM) of UV-irradiated mice had a reduced ability to migrate toward the chemokine (C-C motif) ligand 21. Fewer DCs also accumulated in the peritoneal cavity of UV chimeric mice (ie, mice transplanted with BM from UV-irradiated mice) after injection of an inflammatory stimulus into that site. We hypothesized that different metabolic states underpin altered DC motility. Compared with DCs from the BM of nonirradiated mice, those from UV-irradiated mice produced more lactate, consumed more glucose, and had greater glycolytic flux in a bioenergetics stress test. Greater expression of 3-hydroxyanthranilate 3,4 dioxygenase was identified as a potential contributor to increased glycolysis. Inhibition of 3-hydroxyanthranilate 3,4-dioxygenase by 6-chloro-dl-tryptophan prevented both increased lactate production and reduced migration toward chemokine (C-C motif) ligand 21 by DCs differentiated from BM of UV-irradiated mice. UV-induced prostaglandin E2 has been implicated as an intermediary in the effects of UV radiation on BM cells. DCs differentiating from BM cells pulsed in vitro for 2 hours with dimethyl prostaglandin E2 were functionally similar to those from the BM of UV-irradiated mice. Reduced migration of DCs to lymph nodes associated with increased glycolytic flux may contribute to their reduced ability to initiate new immune responses in UV-irradiated mice. PMID- 28708973 TI - Concordance of Beta-papillomavirus across anogenital and oral anatomic sites of men: The HIM Study. AB - We evaluated the concordance between beta-HPVs detected in external genital skin, anal canal, and oral cavity specimens collected simultaneously from 717 men that were participating in the multinational HIM Study. Viral genotyping was performed using the Luminex technology. Species- and type-specific concordance was measured using kappa statistics for agreement. Overall, concordance of beta-HPVs across sites was low and mainly observed among paired genital/anal canal samples. When grouped by species, solely beta-4 HPVs showed moderate concordance in genital/anal pairs (kappa = 0.457), which could be attributed to the substantial concordance of HPV-92 in men from Brazil and Mexico (kappa > 0.610). beta-HPV type concordance was higher in Mexico, where HPV-19 was consistently concordant in all anatomic site combinations. Our analysis indicates that type-specific concordance across sites is limited to few viral types; however, these infections seem to occur more often than would be expected by chance, suggesting that although rare, there is agreement among sites. PMID- 28708974 TI - Overestimation of threat from neutral faces and voices in social anxiety. AB - BACKGROUND AND OBJECTIVES: Social anxiety (SA) is associated with a tendency to interpret social information in a more threatening manner. Most of the research in SA has focused on unimodal exploration (mostly based on facial expressions), thus neglecting the ubiquity of cross-modality. To fill this gap, the present study sought to explore whether SA influences the interpretation of facial and vocal expressions presented separately or jointly. METHODS: Twenty-five high socially anxious (HSA) and 29 low socially anxious (LSA) participants completed a forced two-choice emotion identification task consisting of angry and neutral expressions conveyed by faces, voices or combined faces and voices. Participants had to identify the emotion (angry or neutral) of the presented cues as quickly and precisely as possible. RESULTS: Our results showed that, compared to LSA, HSA individuals show a higher propensity to misattribute anger to neutral expressions independent of cue modality and despite preserved decoding accuracy. We also found a cross-modal facilitation effect at the level of accuracy (i.e., higher accuracy in the bimodal condition compared to unimodal ones). However, such effect was not moderated by SA. LIMITATIONS: Although the HSA group showed clinical cut-off scores at the Liebowitz Social Anxiety Scale, one limitation is that we did not administer diagnostic interviews. Upcoming studies may want to test whether these results can be generalized to a clinical population. CONCLUSIONS: These findings highlight the usefulness of a cross-modal perspective to probe the specificity of biases in SA. PMID- 28708976 TI - Health and economic burden of preeclampsia: no time for complacency. PMID- 28708975 TI - Short-term costs of preeclampsia to the United States health care system. AB - BACKGROUND: Preeclampsia is a leading cause of maternal morbidity and mortality and adverse neonatal outcomes. Little is known about the extent of the health and cost burden of preeclampsia in the United States. OBJECTIVE: This study sought to quantify the annual epidemiological and health care cost burden of preeclampsia to both mothers and infants in the United States in 2012. STUDY DESIGN: We used epidemiological and econometric methods to assess the annual cost of preeclampsia in the United States using a combination of population-based and administrative data sets: the National Center for Health Statistics Vital Statistics on Births, the California Perinatal Quality Care Collaborative Databases, the US Health Care Cost and Utilization Project database, and a commercial claims data set. RESULTS: Preeclampsia increased the probability of an adverse event from 4.6% to 10.1% for mothers and from 7.8% to 15.4% for infants while lowering gestational age by 1.7 weeks (P < .001). Overall, the total cost burden of preeclampsia during the first 12 months after birth was $1.03 billion for mothers and $1.15 billion for infants. The cost burden per infant is dependent on gestational age, ranging from $150,000 at 26 weeks gestational age to $1311 at 36 weeks gestational age. CONCLUSION: In 2012, the cost of preeclampsia within the first 12 months of delivery was $2.18 billion in the United States ($1.03 billion for mothers and $1.15 billion for infants), and was disproportionately borne by births of low gestational age. PMID- 28708977 TI - Relative cortico-subcortical shift in brain activity but preserved training induced neural modulation in older adults during bimanual motor learning. AB - To study age-related differences in neural activation during motor learning, functional magnetic resonance imaging scans were acquired from 25 young (mean 21.5-year old) and 18 older adults (mean 68.6-year old) while performing a bimanual coordination task before (pretest) and after (posttest) a 2-week training intervention on the task. We studied whether task-related brain activity and training-induced brain activation changes differed between age groups, particularly with respect to the hyperactivation typically observed in older adults. Findings revealed that older adults showed lower performance levels than younger adults but similar learning capability. At the cerebral level, the task related hyperactivation in parietofrontal areas and underactivation in subcortical areas observed in older adults were not differentially modulated by the training intervention. However, brain activity related to task planning and execution decreased from pretest to posttest in temporo-parieto-frontal areas and subcortical areas in both age groups, suggesting similar processes of enhanced activation efficiency with advanced skill level. Furthermore, older adults who displayed higher activity in prefrontal regions at pretest demonstrated larger training-induced performance gains. In conclusion, in spite of prominent age related brain activation differences during movement planning and execution, the mechanisms of learning-related reduction of brain activation appear to be similar in both groups. Importantly, cerebral activity during early learning can differentially predict the amplitude of the training-induced performance benefit between young and older adults. PMID- 28708978 TI - Methotrexate, combined with cyclophosphamide attenuates murine collagen induced arthritis by modulating the expression level of Breg and DCs. AB - To explore the mechanism of methotrexate (MTX) and its combination with cyclophosphamide (CTX) in collagen-induced arthritis (CIA), we investigated the levels of several immune cells and cytokines in mice with different treatments. CIA was induced in DBA/1 mice at the age of 7 weeks by primary immunization with 100MUl emulsion containing 2mg/ml bovine type II collagen which was mixed with complete Freund's adjuvant (CFA). The booster immunization was performed with 50 100MUl emulsion containing 2mg/ml bovine type II collagen (CII) mixed with incomplete Freund's adjuvant (IFA). MTX, CTX or both were administrated after the booster immunization. Therapeutic effect was evaluated by arthritic scores, X rays and assessment of histopathological joint destruction. The expression of TNF alpha, IL-6, IL-23, IL-10 were also measured. The frequencies of different immune cell subsets in the lymph node, spleen and bone marrow were determined by flow cytometry analysis. Our results showed that CTX and MTX treatment attenuated the severity of arthritis of CIA mice and reduced the levels of several cytokines. CTX and MTX treated mice showed a lower frequency of B cells in bone marrow. Also, when treated the CIA mice with MTX, alone or together with CTX, the lymph nodes and spleen exhibited a decrease in regulatory B cells (Breg) and dendritic cells (DCs). Notably, the combination of MTX and CTX had a more pronounced effect. By measuring the levels of different immune cells those participated in the development of rheumatoid arthritis (RA), our experiment may help to evaluate the therapeutic effects and prognosis of arthritic diseases. PMID- 28708979 TI - Why human anti-Galalpha1-4Galbeta1-4Glc natural antibodies do not recognize the trisaccharide on erythrocyte membrane? Molecular dynamics and immunochemical investigation. AB - BACKGROUND: Human blood contains a big variety of natural antibodies, circulating throughout life at constant concentration. Previously, we have found natural antibodies capable of binding to trisaccharide Galalpha1-4Galbeta1-4Glc (Pk) practically in all humans. Intriguingly, the same trisaccharide is a key fragment of glycosphingolipid globotriaosylceramide (Gb3Cer) - normal component of erythrocyte and endothelial cell membrane, i.e. the antibodies and their cognate antigen coexist without any immunological reaction. AIM: To explain the inertness of human anti-Pk antibodies towards own cells. MATERIALS AND METHODS: We used a combination of immunochemical and molecular dynamics (MD) experiments. Antibodies were isolated using affinity media with Pk trisaccharide, their epitope specificity was characterized using ELISA (enzyme-linked immunosorbent assay) with a set of synthetic glycans related to Pk synthetic glycans and FACS (Fluorescence-Activated Cell Sorting) analysis of cells with inserted natural Gb3Cer and its synthetic analogue. Conformations and clustering of glycolipids immersed into a lipid bilayer were studied using MD simulations. RESULTS: Isolated specific antibodies were completely unable to bind natural Gb3Cer both inserted into cells and in artificial membrane, whereas strong interaction took place with synthetic analogue differing by the presence of a spacer between trisaccharide and lipid part. MD simulations revealed: i) although membrane-bound glycans do not form stable long-living aggregates, their transient packing is more compact in natural Gb3 as compared with the synthetic analog, ii) similar conformation of Pk glycan in composition of the glycolipids, iii) no effect on the mentioned above results when cholesterol was inserted into membrane, and iv) better accessibility of the synthetic version for interaction with proteins. CONCLUSIONS: Both immunochemical and molecular dynamics data argue that the reason of the "tolerance" of natural anti-Pk antibodies towards cell-bound Gb3Cer is the spatial inaccessibility of Pk glycotope for interaction. We can conclude that the antibodies are not related to the blood group P system. PMID- 28708980 TI - CD3/CD28 dynabeads induce expression of tn antigen in human t cells accompanied by hypermethylation of the cosmc promoter. AB - Glycosylation is an important protein post-translational modification. In this process, the intermediate product, Tn antigen, arises from somatic mutations in core1beta3-galactosyltransferase-specific molecular chaperone (Cosmc), which is required for the formation of active core1beta3-galactosyltransferase (T synthase). As a type of tumor-associated carbohydrate antigen, Tn antigen is mainly expressed in many human tumor cells and is absent in normal cells. Surprisingly, it is also expressed in normal activated T cells after in vitro stimulation, but the mechanism underlying its expression remains unclear. This study demonstrated that Tn antigen was expressed in activated T cells and that the percentage of positive (Tn+) cells increased and subsequently decreased within 72h after stimulation with CD3/CD28 Dynabeads, with peak expression occurring at 48h. During activation, interleukin-4 (IL-4) expression in the T cell supernatant consistently increased with Tn+ cells, and was inversely correlated with serum interferon gamma (IFN-gamma) levels. Compared with unactivated (without CD3/CD28 Dynabead stimulation) T cells, the level of T synthase transcription in activated T cells did not significantly change, whereas T-synthase activity and Cosmc transcription significantly decreased, accompanied by a further increase in methylation of the Cosmc promoter. The results also showed that Cosmc transcription and translation decreased and then increased, and that Cosmc promoter methylation was a dynamic process during T cell activation. These data suggest that hypermethylation of the Cosmc promoter may induce the expression of Tn antigen in activated T cells. PMID- 28708981 TI - A comparison of the validity of the Demirjian, Willems, Nolla and Haavikko methods in determination of chronological age of 5-15 year-old Indian children. AB - BACKGROUND: Demirjian's method has been the most popular and extensively tested radiographic method of age estimation. More recently, Willems' method has been reported to be a better predictor of age. Nolla's and Haavikko's methods have been used to a lesser extent. Very few studies have compared all four methods in non-Indian and Indian populations. Most Indian research is limited by inadequate sample sizes, age structures and grouping and different approaches to statistical analysis. AIM: The present study aimed to evaluate and compare the validity of the Demirjian, Willems, Nolla and Haavikko methods in determination of chronological age of 5 to 15 year-old Indian children. DESIGN: In this cross sectional observational study, four methods were compared for validity in estimating the age of 1200 Indian children aged 5-15 years. RESULTS: Demirjian's method overestimated age by +0.24 +/- 0.80, +0.11 +/- 0.81 and +0.19 +/- 0.80 years in boys, girls and the total sample, respectively. With Willems' method, overestimations of +0.09 +/- 0.80, +0.08 +/- 0.80 and +0.09 +/- 0.80 years were obtained in boys, girls and the total sample, respectively. Nolla's method underestimated age by -0.13 +/- 0.80, -0.30 +/- 0.82 and -0.20 +/- 0.81 years in boys, girls and the total sample, respectively. Haavikko's method underestimated age by -0.17 +/- 0.80, -0.29 +/- 0.83 and -0.22 +/- 0.82 years in boys, girls and the total sample, respectively. Statistically significant differences were observed between dental and chronological ages with all methods (p < 0.001). Significant gender-based differences were observed with all methods except Willems' (p < 0.05). Gender-specific regression formulae were derived for all methods. CONCLUSION: Willems' method most accurately estimated age, followed by Demirjian's, Nolla's and Haavikko's methods. All four methods could be applicable for estimating age in the present population, mean prediction errors being lower than 0.30 years (3.6 months). PMID- 28708982 TI - Green synthesis of graphene from recycled PET bottle wastes for use in the adsorption of dyes in aqueous solution. AB - Polyethyleneterephthalate (PET) is an important component of post-consumer plastic waste. This study focuses on the potential of utilizing "waste-treats waste" by synthesis of graphene using PET bottle waste as a source material. The synthesized graphene is characterized by SEM, TEM, BET, Raman, TGA, and FT-IR. The adsorption of methylene blue (MB) and acid blue 25 (AB25) by graphene is studied and parameters such as contact time, adsorbent dosage were optimized. The Response Surface Methodology (RSM) is applied to investigate the effect of three variables (dye concentration, time and temperature) and their interaction on the removal efficiency. Adsorption kinetics and isotherm are followed a pseudo-second order model and Langmuir and Freundlich isotherm models, respectively. Thermodynamic parameters demonstrated that adsorption of dye is spontaneous and endothermic in nature. The plastic waste can be used after transformation into valuable carbon-based nanomaterials for use in the adsorption of organic contaminants from aqueous solution. PMID- 28708983 TI - Preparation of nanoscale iron (oxide, oxyhydroxides and zero-valent) particles derived from blueberries: Reactivity, characterization and removal mechanism of arsenate. AB - The application of iron nanoparticles (FeNPs) to the removal of various pollutants has received wide attention over the last few decades. A synthesis alternative to obtain these nanoparticles without using harmful chemical reagents, such as NaBH4, is the use of extracts from different natural sources that allow a lesser degree of agglomeration, in a process known as green synthesis. In this study, FeNPs were synthesized by 'green' (hereafter, BB-Fe NPs) and 'chemical' (hereafter, nZVI) methods. Extracts of leaves and blueberry shoots (Vaccinium corymbosum) were used as reducing agents for FeCl3.6H2O solution in the green synthesis method. FeNPs were characterized using transmission electron microscopy (TEM), scanning electron microscopy (SEM), electrophoretic migration, Brunauer-Emmett-Teller (BET) surface area analysis and X-ray diffraction (XRD) and evaluated for the removal of As(V) from aqueous systems. In both synthesis methods, XRD analysis confirmed the presence of the different kinds of iron nanoparticles. SEM analysis showed that the average size of BB-Fe NPs was 52.4nm and that a variety of nanoparticles of different forms and associated structures, such as lepidocrocite, magnetite, and nZVI, were present, while the dimensions of nZVI were 80.2nm. Comparatively significant differences regarding the electrophoretic mobility were found between both materials pre- and post-sorption of As(V). The velocity of As(V) removal by BB-Fe NPs was slower than that by nZVI, reaching equilibrium at 120min compared to 60min for nZVI. The removal kinetics of As(V) were adequately described by the pseudo-second-order kinetic model, and the maximum adsorbed amounts of this analyte are in close accordance with the experimental results. The Langmuir Freundlich model is in good agreement with our experimental data, where the sorption capacity of nZVI and BB-Fe NPs was found to be 52.23 +/- 6.06 and 50.40 +/- 5.90 (mg.g-1), respectively. The use of leaves of Vaccinium corymbosum affords an easy-to-synthesize, low-cost, and eco-friendly material with capabilities similar to nZVI. BB-Fe NPs are promising for arsenic remediation, which has emerged as a new alternative for water purification and sanitation. PMID- 28708984 TI - Comparison of social behavior responses of Japanese medaka (Oryzias latipes) to lethal and sublethal chlorpyrifos concentrations at different exposure times. AB - Chlorpyrifos (CPF) is one of the most widely used insecticides and has been found in both urban and rural water bodies. In this study, we studied variations in the social behavioral patterns, swimming behavior, and brain acetylcholinesterase (AChE) activity of Japanese medaka exposed to lethal (0.12mg/L) and sublethal (0.012mg/L) concentrations of CPF after different exposure times. Group behavior performance (schooling, shoaling, and solitary) was determined on day 4 of lethal exposure and on days 4, 8, and 12 of sublethal exposure. Swimming speed and brain AChE activity were measured on days 4, 8, 12, 16, and 20 of sublethal CPF exposure. We observed significant decreases in social behavior and swimming speed (i.e., hypoactivity) in fish exposed to lethal CPF concentrations for 4 days. At the sublethal concentration, there was increased schooling duration and hyperactivity of fish on day 8 but not on day 4. In contrast, 12 days of sublethal CPF exposure resulted in social behavior responses similar to those after 4 days' lethal exposure, i.e., significant decreases in schooling frequency and duration with a notable increase in duration of solitary behavior. Brain AChE activity was inhibited in a time-dependent manner. Altered fish behavior in response to organophosphorus pesticides such as CPF may be mediated by more than AChE inhibition alone. PMID- 28708985 TI - Ultrastructural, protein and photosynthetic alterations induced by Pb and Cd in Cynara cardunculus L., and its potential for phytoremediation. AB - The effects of cadmium and lead were investigated in Cynara cardunculus L. Plant uptake by root and shoot, changes in cell ultrastructure and photosynthetic efficiency, photosynthetic key protein levels, as well as regulation of stress induced Hsp70 were examined. Cynara cardunculus accumulated Cd and Pb in their tissue, with a different trend for the two metals. The prompt translocation of Cd to the shoot may justify the ultrastructural injuries, especially observed in chloroplasts. However, Cd- treated plants did not show any decline in photochemistry; it is likely that Cd in shoot tissue triggers defense mechanisms, increasing the level of proteins involved in photosynthesis (i.e., Rubisco and D1 increased 7 and 4.5 fold respectively) as a compensatory response to neutralize chloroplast damage. The accumulation of Pb mainly in root, can explain the increase in Hsp70 level (23 folds) in this tissue. Pb reached the shoots, even at low amounts, causing an overall significant change in some photochemical parameters (QY and NPQ decreases and increases of 25%, respectively). The results suggest a higher sensitivity of C. cardunculus to Pb than Cd, although maximal photochemical efficiency suggests that this species seems to tolerate Pb and Cd and hence, it is a suitable candidate for phytoremediation. PMID- 28708986 TI - Listener estimates of talker age in a single-talker, 50-year longitudinal sample. AB - PURPOSE: While many studies have shown that listeners make relatively accurate age judgments from hearing talkers' voices, most have used just one age per talker. The present study evaluated listeners' age estimation abilities for a longitudinal sample: a single talker recorded over nearly five decades. METHOD: We extracted 60 samples from addresses given by a male talker over 48 years. For each sample, listeners gave a direct estimate of his age. We also asked listeners if they could identify the talker, who was known locally, from the recordings. RESULTS: While correlations between the talker's chronological age and direct estimates of age were generally strong, the relationship was particularly strong when the talker was older than 68 years, although listeners underestimated chronological age by approximately 5 years. When the talker was between 49 and 68 years, direct age estimates were less accurate and less strongly correlated with chronological age. Additionally, direct age estimates were more accurate when listeners recognized the talker. CONCLUSIONS: Corroborating cross-sectional studies, our listeners overestimated the talker's age when he was younger and underestimated it when he was older. However, the crossover between overestimation and underestimation, the point where estimated and chronological ages were equal, occurred at a later talker age for this longitudinal study than in previous cross-sectional studies. Additionally, listeners who recognized the talker made more accurate age estimates when the talker's chronological age was near the age where they would have known him. We propose future studies explore the relationship between familiarity and estimated age. PMID- 28708987 TI - A Delphi study to validate competency-based criteria to assess undergraduate midwifery students' competencies in the maternity ward. AB - BACKGROUND: workplace learning plays a crucial role in midwifery education. Twelve midwifery schools in Flanders (Belgium) aimed to implement a standardised and evidence-based method to learn and assess competencies in practice. This study focuses on the validation of competency-based criteria to guide and assess undergraduate midwifery students' postnatal care competencies in the maternity ward. METHOD: an online Delphi study was carried out. During three consecutive sessions, experts from workplaces and schools were invited to score the assessment criteria as to their relevance and feasibility, and to comment on the content and their formulation. A descriptive quantitative analysis, and a qualitative thematic content analysis of the comments were carried out. A Mann Whitney U-test was used to investigate differences between expert groups. FINDINGS: eleven competencies and fifty-six assessment criteria were found appropriate to assess midwifery students' competencies in the maternity ward. Overall median scores were high and consensus was obtained for all criteria, except for one during the first round. Although all initial assessment criteria (N=89) were scored as relevant, some of them appeared not feasible in practice. Little difference was found between the expert groups. Comments mainly included remarks about concreteness and measurability. CONCLUSION: this study resulted in validated criteria to assess postnatal care competencies in the maternity ward. PMID- 28708988 TI - Early colonisation of urban indoor carcasses by blow flies (Diptera: Calliphoridae): An experimental study from central Spain. AB - Due to their ubiquity and synanthropy, blow flies (Diptera: Calliphoridae) are generally the first colonisers of cadavers and, therefore, frequently used to estimate a minimum post-mortem interval (minPMI). Whereas in outdoor situations blow flies are expected to locate and colonise exposed cadavers within hours or even minutes after death, it is usually assumed that the colonisation of a cadaver indoors might be delayed for an uncertain period of time. This uncertainty severely limits the informativity of minPMI estimates based on entomological evidence. Moreover, these limitations are emphasised by the lack of experimental data on insect colonisation of indoor carrion and by the fact that most of the forensic cases involving entomological evidence have been reported to occur indoors. In this study we investigate the early colonisation of pig carcasses placed indoors in a building located in the centre of an urban environment in central Spain. Three carcasses were placed in three equal rooms with a window half opened during five experimental trials: summer 2013, autumn 2013, winter 2014, spring 2014 and summer 2014. The species composition and their contribution to the carrion colonisation differed among seasons. Calliphora vicina Robineau-Desvoidy was the sole coloniser of carcasses in winter and colonised the carcasses within the first 24-48h in every season, although Lucilia sericata (Meigen) was the first coloniser of most summer carcasses. On the other hand, Calliphora vomitoria (L.) and Chrysomya albiceps (Wiedemann) colonised the carcasses significantly later in spring and in spring and summer, respectively, with a delay of several days. In autumn, however, there were no significant differences in the colonisation times by C. vicina, L. sericata and Ch. albiceps. C. vicina and L. sericata showed a clear preference for ovipositing in the natural orifices of the carcasses, whereas Ch. albiceps oviposited more frequently on the trunk and legs. PMID- 28708989 TI - Sex-specific hip osteoarthritis-associated gait abnormalities: Alterations in dynamic hip abductor function differ in men and women. AB - BACKGROUND: Hip osteoarthritis results in abnormal gait mechanics, but it is not known whether abnormalities are the same in men and women. The hypothesis tested was that gait abnormalities are different in men and women with hip osteoarthritis vs. sex-specific asymptomatic groups. METHODS: 150 subjects with mild through severe radiographic hip osteoarthritis and 159 asymptomatic subjects were identified from an Institutional Review Board-approved motion analysis data repository. Sagittal plane hip range of motion and peak external moments about the hip, in all three planes, averaged from normal speed walking trials, were compared for men and women, with and without hip osteoarthritis using analysis of variance. FINDINGS: There were significant sex by group interactions for the external peak hip adduction and external rotation moments (P=0.009-0.045). Although asymptomatic women had peak adduction and external rotation moments that were respectively 12% higher and 23% lower than asymptomatic men (P=0.026-0.037), these variables did not differ between men and women with hip osteoarthritis (P>=0.684). The osteoarthritis vs. asymptomatic group difference in the peak hip adduction moment was 45% larger in women than in men. The osteoarthritis vs. asymptomatic group difference in the peak hip external rotation moment was 55% larger for men than for women (P<0.001). Sex did not influence the association between radiographic severity and gait variables. INTERPRETATION: Normal sex differences in gait were not seen in hip osteoarthritis. Sex-specific adaptations may reflect different aspects of hip abductor function. Men and women with hip osteoarthritis may require different interventions to improve function. PMID- 28708990 TI - Electroporation by concentric-type needle electrodes and arrays. AB - The efficacy of genomic medicine depends on gene transfer efficiency. In this area, electroporation has been found to be a highly promising method for physical gene transfer. However, electroporation raises issues related to electrical safety, tissue damage, and the number of required wounds. Concentric-type needle electrodes seek to address these issues by using a lower bias (10V), a single wound, fewer processing steps, and a smaller working area (~10mm3), thus offering greater accuracy and precision. Moreover, the needle can be arrayed to simultaneously treat several target regions. This paper proposes a novel method using concentric-type needle electrodes to improve the efficacy of genomic medicine in terms of electrical safety, human factor and usability engineering. PMID- 28708991 TI - Tiny Answers to Big Questions. PMID- 28708992 TI - Biology Gone Wild. AB - To study how genes, cells, or organisms operate in natural environments, researchers often need to leave the bench and venture into the field. Here are a few approaches that field biologists use in designing and conducting semi-wild experiments and the many challenges they face. PMID- 28708993 TI - IL-4Ralpha Inhibitor for Atopic Disease. AB - Dupilumab is a fully human IgG4 monoclonal antibody directed against the IL 4Ralpha subunit of IL-4 and IL-13 receptors. It blocks the signaling pathways of IL-4 and IL-13, key cytokines that drive type 2 inflammatory response. In March 2017, dupilumab was approved for use in the treatment of atopic dermatitis (eczema). To view this Bench to Bedside, open or download the PDF. PMID- 28708994 TI - Unshielding Exosomal RNA Unleashes Tumor Growth And Metastasis. AB - Reciprocal interactions between tumor cells and their microenvironment drive cancer progression and therapy resistance. In this issue, Nabet et al. demonstrate that dynamic feedback between tumor and stroma subverts normal inflammatory responses by triggering the release of exosomes containing unshielded RNAs that activate pattern recognition receptors, thereby promoting tumor growth and metastasis. PMID- 28708996 TI - Functional Profiling of a Plasmodium Genome Reveals an Abundance of Essential Genes. AB - The genomes of malaria parasites contain many genes of unknown function. To assist drug development through the identification of essential genes and pathways, we have measured competitive growth rates in mice of 2,578 barcoded Plasmodium berghei knockout mutants, representing >50% of the genome, and created a phenotype database. At a single stage of its complex life cycle, P. berghei requires two-thirds of genes for optimal growth, the highest proportion reported from any organism and a probable consequence of functional optimization necessitated by genomic reductions during the evolution of parasitism. In contrast, extreme functional redundancy has evolved among expanded gene families operating at the parasite-host interface. The level of genetic redundancy in a single-celled organism may thus reflect the degree of environmental variation it experiences. In the case of Plasmodium parasites, this helps rationalize both the relative successes of drugs and the greater difficulty of making an effective vaccine. PMID- 28708998 TI - Profiling Ssb-Nascent Chain Interactions Reveals Principles of Hsp70-Assisted Folding. AB - The yeast Hsp70 chaperone Ssb interacts with ribosomes and nascent polypeptides to assist protein folding. To reveal its working principle, we determined the nascent chain-binding pattern of Ssb at near-residue resolution by in vivo selective ribosome profiling. Ssb associates broadly with cytosolic, nuclear, and hitherto unknown substrate classes of mitochondrial and endoplasmic reticulum (ER) nascent proteins, supporting its general chaperone function. Ssb engages most substrates by multiple binding-release cycles to a degenerate sequence enriched in positively charged and aromatic amino acids. Timely association with this motif upon emergence at the ribosomal tunnel exit requires ribosome associated complex (RAC) but not nascent polypeptide-associated complex (NAC). Ribosome footprint densities along orfs reveal faster translation at times of Ssb binding, mainly imposed by biases in mRNA secondary structure, codon usage, and Ssb action. Ssb thus employs substrate-tailored dynamic nascent chain associations to coordinate co-translational protein folding, facilitate accelerated translation, and support membrane targeting of organellar proteins. PMID- 28708997 TI - Vaccine Mediated Protection Against Zika Virus-Induced Congenital Disease. AB - The emergence of Zika virus (ZIKV) and its association with congenital malformations has prompted the rapid development of vaccines. Although efficacy with multiple viral vaccine platforms has been established in animals, no study has addressed protection during pregnancy. We tested in mice two vaccine platforms, a lipid nanoparticle-encapsulated modified mRNA vaccine encoding ZIKV prM and E genes and a live-attenuated ZIKV strain encoding an NS1 protein without glycosylation, for their ability to protect against transmission to the fetus. Vaccinated dams challenged with a heterologous ZIKV strain at embryo day 6 (E6) and evaluated at E13 showed markedly diminished levels of viral RNA in maternal, placental, and fetal tissues, which resulted in protection against placental damage and fetal demise. As modified mRNA and live-attenuated vaccine platforms can restrict in utero transmission of ZIKV in mice, their further development in humans to prevent congenital ZIKV syndrome is warranted. PMID- 28708995 TI - Evolution of the Human Nervous System Function, Structure, and Development. AB - The nervous system-in particular, the brain and its cognitive abilities-is among humans' most distinctive and impressive attributes. How the nervous system has changed in the human lineage and how it differs from that of closely related primates is not well understood. Here, we consider recent comparative analyses of extant species that are uncovering new evidence for evolutionary changes in the size and the number of neurons in the human nervous system, as well as the cellular and molecular reorganization of its neural circuits. We also discuss the developmental mechanisms and underlying genetic and molecular changes that generate these structural and functional differences. As relevant new information and tools materialize at an unprecedented pace, the field is now ripe for systematic and functionally relevant studies of the development and evolution of human nervous system specializations. PMID- 28708999 TI - Splicing Activation by Rbfox Requires Self-Aggregation through Its Tyrosine-Rich Domain. AB - Proteins of the Rbfox family act with a complex of proteins called the Large Assembly of Splicing Regulators (LASR). We find that Rbfox interacts with LASR via its C-terminal domain (CTD), and this domain is essential for its splicing activity. In addition to LASR recruitment, a low-complexity (LC) sequence within the CTD contains repeated tyrosines that mediate higher-order assembly of Rbfox/LASR and are required for splicing activation by Rbfox. This sequence spontaneously aggregates in solution to form fibrous structures and hydrogels, suggesting an assembly similar to the insoluble cellular inclusions formed by FUS and other proteins in neurologic disease. Unlike the pathological aggregates, we find that assembly of the Rbfox CTD plays an essential role in its normal splicing function. Rather than simple recruitment of individual regulators to a target exon, alternative splicing choices also depend on the higher-order assembly of these regulators within the nucleus. PMID- 28709000 TI - Regulatory Expansion in Mammals of Multivalent hnRNP Assemblies that Globally Control Alternative Splicing. AB - Alternative splicing (AS) patterns have diverged rapidly during vertebrate evolution, yet the functions of most species- and lineage-specific splicing events are not known. We observe that mammalian-specific AS events are enriched in transcript sequences encoding intrinsically disordered regions (IDRs) of proteins, in particular those containing glycine/tyrosine repeats that mediate formation of higher-order protein assemblies implicated in gene regulation and human disease. These evolutionary changes impact nearly all members of the hnRNP A and D families of RNA binding proteins. Regulation of these events requires formation of unusual, long-range mammalian-specific RNA duplexes. Differential inclusion of the alternative exons controls the formation of tyrosine-dependent multivalent hnRNP assemblies that, in turn, function to globally regulate splicing. Together, our results demonstrate that AS control of IDR-mediated interactions between hnRNPs represents an important and recurring mechanism underlying splicing regulation. Furthermore, this mechanism has expanded the regulatory capacity of mammalian cells. PMID- 28709001 TI - Ciliary Hedgehog Signaling Restricts Injury-Induced Adipogenesis. AB - Injured skeletal muscle regenerates, but with age or in muscular dystrophies, muscle is replaced by fat. Upon injury, muscle-resident fibro/adipogenic progenitors (FAPs) proliferated and gave rise to adipocytes. These FAPs dynamically produced primary cilia, structures that transduce intercellular cues such as Hedgehog (Hh) signals. Genetically removing cilia from FAPs inhibited intramuscular adipogenesis, both after injury and in a mouse model of Duchenne muscular dystrophy. Blocking FAP ciliation also enhanced myofiber regeneration after injury and reduced myofiber size decline in the muscular dystrophy model. Hh signaling through FAP cilia regulated the expression of TIMP3, a secreted metalloproteinase inhibitor, that inhibited MMP14 to block adipogenesis. A pharmacological mimetic of TIMP3 blocked the conversion of FAPs into adipocytes, pointing to a strategy to combat fatty degeneration of skeletal muscle. We conclude that ciliary Hh signaling by FAPs orchestrates the regenerative response to skeletal muscle injury. PMID- 28709002 TI - Exosome RNA Unshielding Couples Stromal Activation to Pattern Recognition Receptor Signaling in Cancer. AB - Interactions between stromal fibroblasts and cancer cells generate signals for cancer progression, therapy resistance, and inflammatory responses. Although endogenous RNAs acting as damage-associated molecular patterns (DAMPs) for pattern recognition receptors (PRRs) may represent one such signal, these RNAs must remain unrecognized under non-pathological conditions. We show that triggering of stromal NOTCH-MYC by breast cancer cells results in a POL3-driven increase in RN7SL1, an endogenous RNA normally shielded by RNA binding proteins SRP9/14. This increase in RN7SL1 alters its stoichiometry with SRP9/14 and generates unshielded RN7SL1 in stromal exosomes. After exosome transfer to immune cells, unshielded RN7SL1 drives an inflammatory response. Upon transfer to breast cancer cells, unshielded RN7SL1 activates the PRR RIG-I to enhance tumor growth, metastasis, and therapy resistance. Corroborated by evidence from patient tumors and blood, these results demonstrate that regulation of RNA unshielding couples stromal activation with deployment of RNA DAMPs that promote aggressive features of cancer. VIDEO ABSTRACT. PMID- 28709003 TI - 3D Chromatin Structures of Mature Gametes and Structural Reprogramming during Mammalian Embryogenesis. AB - High-order chromatin structure plays important roles in gene expression regulation. Knowledge of the dynamics of 3D chromatin structures during mammalian embryo development remains limited. We report the 3D chromatin architecture of mouse gametes and early embryos using an optimized Hi-C method with low-cell samples. We find that mature oocytes at the metaphase II stage do not have topologically associated domains (TADs). In sperm, extra-long-range interactions (>4 Mb) and interchromosomal interactions occur frequently. The high-order structures of both the paternal and maternal genomes in zygotes and two-cell embryos are obscure but are gradually re-established through development. The establishment of the TAD structure requires DNA replication but not zygotic genome activation. Furthermore, unmethylated CpGs are enriched in A compartment, and methylation levels are decreased to a greater extent in A compartment than in B compartment in embryos. In summary, the global reprogramming of chromatin architecture occurs during early mammalian development. PMID- 28709004 TI - Mapping the Neural Substrates of Behavior. AB - Assigning behavioral functions to neural structures has long been a central goal in neuroscience and is a necessary first step toward a circuit-level understanding of how the brain generates behavior. Here, we map the neural substrates of locomotion and social behaviors for Drosophila melanogaster using automated machine-vision and machine-learning techniques. From videos of 400,000 flies, we quantified the behavioral effects of activating 2,204 genetically targeted populations of neurons. We combined a novel quantification of anatomy with our behavioral analysis to create brain-behavior correlation maps, which are shared as browsable web pages and interactive software. Based on these maps, we generated hypotheses of regions of the brain causally related to sensory processing, locomotor control, courtship, aggression, and sleep. Our maps directly specify genetic tools to target these regions, which we used to identify a small population of neurons with a role in the control of walking. PMID- 28709005 TI - Retraction Notice to: Vulnerability of Glioblastoma Cells to Catastrophic Vacuolization and Death Induced by a Small Molecule. PMID- 28709006 TI - Compartmental HBV evolution and replication in liver and extrahepatic sites after nucleos/tide analogue therapy in chronic hepatitis B carriers. AB - BACKGROUND: Hepatitis B virus (HBV) variants are associated with nucleos/tide analogue (NA) response and liver disease but it is unknown whether NA influences extrahepatic HBV persistence. OBJECTIVES: To investigate HBV replication and genetic evolution in hepatic and extrahepatic sites of chronic hepatitis B (CHB) before and after NA therapy. STUDY DESIGN: A total of 13 paired plasma, peripheral blood mononuclear cells (PBMC), were collected from chronic HBV carriers at baseline and after a median 53 weeks NA therapy as well as liver biopsy (N=7 baseline, N=5 follow-up). HBV covalently closed circular DNA (cccDNA) and messenger (m) RNA in liver and PBMC were analyzed. HBV polymerase (P)/surface (S), basal core promoter (BCP)/pre-core (PC)/C gene clonal sequencing was done in plasma, peripheral blood mononuclear cells (PBMC), and liver. RESULTS: Compare to baseline, at ~53 weeks follow-up, there was no significant change in HBV cccDNA levels in liver (0.2-0.08 copies/hepatocyte, p>0.05) or in PBMC 0.003-0.02 copies/PBMC, p>0.05), and HBV mRNA remained detectable in both sites. At baseline, BCP variants were higher in PBMC vs. liver and plasma. After therapy, drug resistant (DR) and immune escape (IE) variants increased in liver but IE and PC variants were more frequent in PBMC. HBV P/S diversity was significantly higher in PBMC compared to plasma. CONCLUSION: Continuous HBV replication occurs in liver and PBMC and shows compartmentalized evolution under selective pressure of potent NA therapy. PMID- 28709007 TI - A patient with childhood-onset aggressive parasomnia diagnosed 50 years later with idiopathic REM sleep behavior disorder and a history of sleepwalking. PMID- 28709008 TI - Iatrogenic B12-deficient peripheral neuropathy following nitrous oxide administration for functional tonic leg spasm: A case report. PMID- 28709009 TI - An evaluation of hospital attractiveness and primary care availability leading to increasing emergency department visits. PMID- 28709010 TI - Eco-Aging: stem cells and microbes are controlled by aging antagonist FoxO. AB - The review highlights the dual role that the conserved master regulator FoxO has in aging by coordinating both stem cell proliferation and antimicrobial peptides, effector molecules of the innate immune system. As observed in non-senescent Hydra, continuously high activity of the transcription factor FoxO contributes to continuous stem cell proliferation and could support robust colonization of epithelia with a stable microbiome. The integration of research from stem cell biology, microbiology and ecology into aging concepts (Eco-Aging) acknowledges the multi-organismic nature of all living beings and presents a new conceptual framework for explaining the process of aging. PMID- 28709011 TI - The acoustic sensor for rapid analysis of bacterial cells in the conductive suspensions. AB - The possibility of using the acoustic sensor on the basis of a two-channel delay line for rapid analysis of bacterial cells in the conductive suspensions was investigated. The dependencies of change in phase and insertion loss of output signal of the sensor on conductivity of buffer solution with various concentrations of cells due to a specific interaction "bacterial cells - mini antibodies" for electrically open and electrically shorted channels of delay line were measured. It has been found that these changes have the most values for the electrically open channel. It has been also shown that the sensor rapidly responds to the specific interaction and the time stabilization of the phase and insertion loss of output signal is less than 10min. PMID- 28709012 TI - De-escalation of aggressive behaviour in healthcare settings: Concept analysis. AB - BACKGROUND: De-escalation is the recommended first-line response to potential violence and aggression in healthcare settings. Related scholarly activity has increased exponentially since the 1980s, but there is scant research about its efficacy and no guidance on what constitutes the gold standard for practice. OBJECTIVES: To clarify the concept of de-escalation of violence and aggression as described within the healthcare literature. DESIGN: Concept analysis guided by Rodgers' evolutionary approach. DATA SOURCES: Multiple nursing and healthcare databases were searched using relevant terms. REVIEW METHODS: High quality and/or highly cited, or otherwise relevant published empirical or theoretical English language literature was included. Information about surrogate terms, antecedents, attributes, consequences, and the temporal, environmental, disciplinary, and theoretical contexts of use were extracted and synthesised. Information about the specific attributes of de-escalation were subject to thematic analysis. Proposed theories or models of de-escalation were assessed against quality criteria. RESULTS: N=79 studies were included. Mental health settings were the most commonly reported environment in which de-escalation occurs, and nursing the disciplinary group most commonly discussed. Five theories of de-escalation were proposed; while each was adequate in some respects, all lacked empirical support. Based on our analysis the resulting theoretical definition of de-escalation in healthcare is "a collective term for a range of interwoven staff-delivered components comprising communication, self-regulation, assessment, actions, and safety maintenance which aims to extinguish or reduce patient aggression/agitation irrespective of its cause, and improve staff-patient relationships while eliminating or minimising coercion or restriction". CONCLUSIONS: While a number of theoretical models have been proposed, the lack of advances made in developing a robust evidence-base for the efficacy of de escalation is striking and must, at least in part, be credited to the lack of a clear conceptualisation of the term. This concept analysis provides a framework for researchers to identify the theoretical model that they purport to use, the antecedents that their de-escalation intervention is targeting, its key attributes, and the key negative and positive consequences that are to be avoided or encouraged. PMID- 28709014 TI - A rapid liquid chromatography-tandem mass spectrometry for the quantification of Fosfomycin in plasma, urine, and aqueous fluids. AB - A simple and fast ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method for the analysis of Fosfomycin in different matrices (human plasma/urine, and aqueous fluid) has been established and validated. Sample cleanup consists, depending on the matrix used, on protein precipitation or dilution with methanol containing isotopically labeled Fosfomycin as internal standard. Compounds, separated on a Luna Omega PS C18 column, were detected in multiple reactions monitoring in negative ion mode using API4000 system. With a total run time of 2min and using low volume of samples (plasma: 10MUl, urine: 2MUl, and aqueous fluid: 5MUl), the covered ranges were: plasma (12.5-800MUg/mL), urine (62.5-4000MUg/mL), and aqueous fluid (1 160MUg/mL). The method proved to be precise and accurate. The inaccuracy and imprecision in each matrix at the four tested quality controls including the lower limit of quantification were:: plasma (<= 6.5%, <= 8%), urine (<= 5.8%, <= 6.3%), and aqueous fluid (<= 10.6%, <=12%). The method is fast and robust which makes it relevant for pharmacokinetic studies and therapeutic drug monitoring. The appropriateness of the developed method in clinical application is also confirmed. PMID- 28709013 TI - Association of nurse work environment and safety climate on patient mortality: A cross-sectional study. AB - BACKGROUND: There are two largely distinct research literatures on the association of the nurse work environment and the safety climate on patient outcomes. OBJECTIVE: To determine whether hospital safety climate and work environment make comparable or distinct contributions to patient mortality. DESIGN: Cross-sectional secondary analysis of linked datasets of Registered Nurse survey responses, adult acute care discharge records, and hospital characteristics. SETTING: Acute care hospitals in California, Florida, New Jersey, and Pennsylvania. PARTICIPANTS: The sample included 600 hospitals linked to 27,009 nurse survey respondents and 852,974 surgical patients. METHODS: Nurse survey data included assessments of the nurse work environment and hospital safety climate. The outcome of interest was in-hospital mortality. Data analyses included descriptive statistics and multivariate random intercept logistic regression. RESULTS: In a fully adjusted model, a one standard deviation increase in work environment score was associated with an 8.1% decrease in the odds of mortality (OR 0.919, p<0.001). A one-standard deviation increase in safety climate score was similarly associated with a 7.7% decrease in the odds of mortality (OR 0.923, p<0.001). However, when work environment and safety climate were modeled together, the effect of the work environment remained significant, while safety climate became a non-significant predictor of mortality odds (OR 0.940, p=0.035 vs. OR 0.971, p=0.316). CONCLUSIONS: We found that safety climate perception is not predictive of patient mortality beyond the effect of the nurse work environment. To advance hospital safety and quality and improve patient outcomes, organizational interventions should be directed toward improving nurse work environments. PMID- 28709016 TI - Spray-drying-assisted reassembly of uniform and large micro-sized MIL-101 microparticles with controllable morphologies for benzene adsorption. AB - Significant research has been focused on the synthesis of metal-organic frameworks (MOFs) with controllable compositions and structures, while much fewer works have been devoted to the construction of large micro-sized MOFs with uniform sizes and morphologies, which could be beneficial for practical applications. In this paper, a unique microfluidic jet spray drying technology has been adopted to reassemble nano-sized MIL-101 building blocks into hierarchical microparticles with uniform and large particle sizes. Specifically, suspension precursors of nano-sized MIL-101 building blocks are atomized into uniform droplets and then converted to microparticles on a one-to-one basis through a fast and scalable spray drying process. The particle size and morphology can be controlled by adjusting the solid concentration of the suspension and the drying temperature. The particle formation process with evolution of different morphologies are discussed. The resultant uniform MIL-101 microparticles possess hierarchical porosities and maintain the intrinsic crystal structure, microporosity and thermal stability of the nano-sized building blocks. They demonstrate a high efficiency toward benzene adsorption from n-octane solutions with high adsorption rates and very high adsorption capacities under batch conditions. Moreover, the large particle size and hierarchical structure make them applicable as filler of a fixed bed for dynamic flow separation of benzene from n-octane solutions with promising performance. The microfluidic jet spray drying technology can also be extended for the reassembly of other uniform MOF microparticles. PMID- 28709017 TI - The role of clotting factor IX in the development of atherosclerosis. PMID- 28709015 TI - Human cells contain a factor that facilitates the DNA glycosylase-mediated excision of oxidized bases from occluded sites in nucleosomes. AB - Reactive oxygen species generate some 20,000 base lesions per human cell per day. The vast majority of these potentially mutagenic or cytotoxic lesions are subject to base excision repair (BER). Although chromatin remodelers have been shown to enhance the excision of oxidized bases from nucleosomes in vitro, it is not clear that they are recruited to and act at sites of BER in vivo. To test the hypothesis that cells possess factors that enhance BER in chromatin, we assessed the capacity of nuclear extracts from human cells to excise thymine glycol (Tg) lesions from exogenously added, model nucleosomes. The DNA glycosylase NTHL1 in these extracts was able to excise Tg from both naked DNA and sites in nucleosomes that earlier studies had shown to be sterically accessible. However, the same extracts were able to excise lesions from sterically-occluded sites in nucleosomes only after the addition of Mg2+/ATP. Gel mobility shift assays indicated that nucleosomes remain largely intact following the Mg2+/ATP dependent excision reaction. Size exclusion chromatography indicated that the NTHL1-stimulating activity has a relatively low molecular weight, close to that of NTHL1 and other BER glycosylases; column fractions that contained the very large chromatin remodeling complexes did not exhibit this same stimulatory activity. These results indicate that cells possess a factor(s) that promotes the initiation of BER in chromatin, but differs from most known chromatin remodeling complexes. PMID- 28709018 TI - ADHD research in India: A narrative review. AB - INTRODUCTION: Attention Deficit Hyperactivity Disorder (ADHD) is a neurodevelopmental disorder with no clear etiopathogenesis. Owing to unique socio cultural milieu of India, it is worthwhile reviewing research on ADHD from India and comparing findings with global research. Thereby, we attempted to provide a comprehensive overview of research on ADHD from India. METHODS: A boolean search of articles published in English from September 1966 to January 2017 on electronic search engines Google Scholar, PubMed, IndMED, MedIND, using the search terms "ADHD", "Attention Deficit and Hyperactivity Disorder", "Hyperactivity" ,"Child psychiatry", "Hyperkinetic disorder", "Attention Deficit Disorder", "India"was carried out and peer - reviewed studies conducted among human subjects in India were included for review. Case reports, animal studies, previous reviews were excluded from the current review. RESULTS: Results of 73 studies found eligible for the review were organized into broad themes such as epidemiology, etiology, course and follow up, clinical profile and comorbidity, assessment /biomarkers, intervention/treatment parameters, pathways to care and knowledge and attitude towards ADHD. DISCUSSION: There was a gap noted in research from India in the domains of biomarkers, course and follow up and non pharmacological intervention. The prevalence of ADHD as well as comorbidity of Bipolar Disorder was comparatively lower compared to western studies. The studies found unique to India include comparing the effect of allopathic intervention with Ayurvedic intervention, yoga as a non pharmacological intervention. There is a need for studies from India on biomarkers, studies with prospective research design, larger sample size and with matched controls. PMID- 28709019 TI - Biocompatible PEGylated bismuth nanocrystals: "All-in-one" theranostic agent with triple-modal imaging and efficient in vivo photothermal ablation of tumors. AB - Biocompatible single-component theranostic agents integrating multimodal imaging and therapeutic functions (namely, "all-in one" agents) are highly desired for clinical cancer treatments. Herein, PEGylated pure metallic bismuth nanocrystals (Bi-PEG NCs) have been developed to be a competent theranostic agent for in vivo high-performance multimodal bio-imaging and photothermal ablation of tumors. The resultant Bi-PEG NCs show excellent physiological stability, biocompatibility, prolonged blood circulation half-life and preferential tumor accumulation. Thanking to the strong near-infrared (NIR) absorbance as well as the high photothermal conversion efficiency and conversion stability, highly effective in vivo photothermal ablation on tumors has been realized upon NIR irradiation, without noticeable toxicity. Impressively, the Bi-PEG NCs show ultrahigh X-ray computed topography (CT) enhancement efficiency (~60.3 HU mL mg-1), overwhelming all CT contrast agents reported so far. Combining the strong CT contrast ability and photoacoustic/photothermal effect, high-contrast CT, photoacoustic (PA) and infrared thermal (IRT) triple-modal imaging have been demonstrated both in vitro and in vivo. This work highlights the potentials of such NCs as a powerful "all in-one" theranostic nanoplatform for bioimaging and antitumor therapy, and may have provided a rather promising candidate for clinically-applied antitumor treatments based on single-component agents. PMID- 28709020 TI - Ruthenium complexes/polypeptide self-assembled nanoparticles for identification of bacterial infection and targeted antibacterial research. AB - Bacterial infection has been a threat to human health, and so early diagnosis and treatment of bacterial infection is an urgent problem that needs to be solved. In this work, a multifunctional theranostic selenium nanoplatform (Se@PEP-Ru NPs) with early imaging diagnosis and efficient treatment of bacterial infections was designed and constructed. First, the antibacterial peptide UBI29-41 (PEP) was linked to functionalized Selenium nanoparticles (NPs), which enhanced the stability of the antimicrobial peptide and also caused the nanocomposites to specifically target bacterial infection. Ruthenium complexes with good antibacterial activity and fluorescence properties were then coated on to their outer layers. It was worth mentioning that, when the resulting nanoprobe was injected into mice by intravenous injection it was found to be sensitive to sites of bacterial infection for selective fluorescence imaging and targeted therapy. Thus, it can be used to distinguish between bacterial infection, inflammation, and tumor-induced tissue infection with high specificity. In the further antibacterial activity experiments, Ruthenium complexes showed synergistic antimicrobial activity with Se NPs, which indicated that the antibacterial activity of Se@PEP-Ru NPs was the strongest that could promote wound healing. Thus, Se@PEP-Ru NPs appears to be a promising antimicrobial with good biocompatibility, excellent selectivity, and potent antimicrobial activity. PMID- 28709021 TI - Architecting the myelin landscape. AB - Myelin increases the speed and efficiency of action potential propagation. Yet, not all axons are myelinated and some axons are discontinuously myelinated, prompting the question of how myelinating glia select axons for myelination. Whereas myelination by Schwann cells depends on axonal induction, oligodendrocytes can form myelin membrane in the absence of axons. However, oligodendrocytes alone cannot architect the complex myelination patterns of the central nervous system and recent advances have implicated axonal signaling in this process. This review considers how oligodendrocytes and their precursors could be influenced by inductive, attractive, permissive, repulsive, and preventative cues, and discusses recent evidence identifying synaptic activity and membrane-bound adhesion molecules as such cues directing axon selection. PMID- 28709022 TI - Comparing brief interventions for suicidal individuals not engaged in treatment: A randomized clinical trial. AB - BACKGROUND: Non-treatment-engaged individuals experiencing suicidal thoughts have been largely overlooked in the intervention literature, despite reviews suggesting most individuals who die by suicide were not in treatment immediately prior to their death. Most intervention studies recruit individuals from treatment providers, potentially neglecting those individuals who are not already engaged in services. These individuals clearly represent a group in need of additional empirical attention. METHODS: A randomized clinical trial was conducted to compare a single-session dialectical behavior therapy skills-based intervention to a relaxation training control condition. Ninety-three non treatment-engaged subjects participated in a single in-person assessment, received one of the intervention protocols, and completed follow-up phone interviews for three months including measures of suicidal ideation, emotion dysregulation, and coping skills, as well as other relevant assessments. RESULTS: Both conditions reported significantly reduced levels of suicidal ideation, depression, and anxiety; however, analyses revealed no significant differences between conditions on the main outcome measures of suicidal ideation, emotion dysregulation, skills use, depression, or anxiety. LIMITATIONS: The two interventions may have been too similar to permit detection of differential effects with this sample size. Specifically, the control condition may have been too active and there may have been stylistic overlap by providers who delivered both interventions. CONCLUSIONS: Encouragingly, half of subjects contacted other mental health services during the follow-up period. Although the two interventions under investigation did not yield differential results, the significant changes in important domains across interventions suggest that brief interventions may hold promise for this difficult-to-reach population. PMID- 28709023 TI - Prevalence and correlates of depressive symptoms among adults living in the Amazon, Brazil: A population-based study. AB - BACKGROUND: Depression is an affective disorder and one of the main contributors to the burden of disease worldwide. Our purpose is to estimate the prevalence of depressive symptoms and associated factors in the population of the Manaus Metropolitan Region. METHODS: We conducted a population-based, cross-sectional study with a probabilistic three-phase sampling in 2015, based on a previously calculated sample size. Adults living in Manaus and seven inner cities of the metropolitan region were surveyed for depressive symptoms using the Patient Health Questionnaire (PHQ-9) and a cutoff score of >= 9. We performed a Poisson regression with robust variance using a hierarchical approach to calculate the prevalence ratio (PR) of depression and 95% confidence intervals (CIs). RESULTS: Among 4001 participants (response rate 76%), the prevalence of current depressive symptoms was 7% (95% CI: 6-8%). Depressive symptoms were more frequent in inhabitants of Manaus than in those from the countryside (PR = 6.13, 95% CI: 2.91 12.91); in women than in men (PR = 2.55, 95% CI: 1.96-3.33); in indigenous than in white people (PR = 2.56, 95% CI: 1.24-5.30); and in those with hypertension (PR = 1.47, 95% CI: 1.13-1.92), cardiac disease (PR = 1.62, 95% CI: 1.12-2.33), and poor health status (fair: PR = 5.10, 95% CI: 2.50-10.37; bad: PR = 10.27, 95% CI: 4.92-21.44 very bad: PR = 21.14, CI 95%: 10.16-43.99). High school education (PR = 0.55, 95% CI: 0.32-0.95) and middle class economic status (PR = 0.33, 95% CI: 0.12-0.89) were protective factors. LIMITATIONS: Limitations include the lack of measurement of physical activity, religious beliefs, leisure time, and use of alcohol and other drugs since these factors can affect depression and health status. CONCLUSION: Seven out of every 100 adults from the Manaus Metropolitan Region have depressive symptoms. This rate is higher in women, individuals living in Manaus, indigenous people, people with hypertension or chronic cardiac disease, and those with a poor health status. PMID- 28709024 TI - Neurocognition in patients with psychotic and non-psychotic bipolar I disorder. A comparative study with individuals with schizophrenia. AB - BACKGROUND: It has been suggested that patients with bipolar disorder with psychotic symptoms (BD-P) have larger neurocognitive impairment than patients with bipolar disorder without a history of psychotic symptoms (BD-NP). The objective of this study was to compare neurocognitive performance of BD-P and BD NP relative to a group of patients with schizophrenia (SZ), and healthy controls (HC). METHODS: Neurocognitive function was examined in 100 subjects with bipolar I disorder (50 BD-P, 50 BD-NP), 50 SZ, and 51 HC. All patients with BD fulfilled criteria for euthymia, while all SZ patients were stabilised for at least the previous 3 months. RESULTS: Patients with BD-P and BD-NP performed worse than HC in all neurocognitive measures, except for sustained attention. Differences between BD-P and BD-NP were subtle and circumscribed to the working memory domain (effect size: 0.29). SZ performed worse than BD-NP in the neurocognitive composite index (NCI) and in the working memory domain. There were no differences between SZ and BD-P in any neurocognitive measure. LIMITATIONS: The relatively small sample size, the cross-sectional design and, that patients were receiving pharmacological treatment are the main limitations of this study. CONCLUSIONS: Our findings show that the three groups of patients have a large neurocognitive impairment. Differences are quantitative and only present in some neurocognitive domains, such as working memory. These results suggest that patients with BD and SZ can benefit from the same strategies of cognitive remediation. PMID- 28709025 TI - Adult attachment's unique contribution in the prediction of postpartum depressive symptoms, beyond personality traits. AB - BACKGROUND: Personality traits such as neuroticism can help identify pregnant women at risk of postpartum depressive symptoms (PPDS). However, it is unclear whether attachment style could have an additional contribution to this risk elevation. This study aimed to examine the overlap of adult attachment insecurity and neuroticism/trait anxiety as PPDS predictors, taking into account baseline depressive symptoms. METHODS: A Swedish population-based sample of pregnant women reported on adult attachment and either neuroticism (n = 1063) or trait anxiety (n = 555). Depressive symptoms were assessed at baseline, and at six weeks and six months postpartum. Correlations between attachment and neuroticism/trait anxiety were calculated. Generalized linear models of PPDS tested the effect of attachment anxiety and avoidance, adjusting for neuroticism/trait anxiety and baseline depression. Logistic regression models with combined high attachment anxiety and neuroticism/trait anxiety visualized their value as risk factors beyond antenatal depression. RESULTS: Attachment and neuroticism/trait anxiety were highly correlated (r = .55-.77). Attachment anxiety exerted a partially independent effect on PPDS at six weeks (p < .05) and at six months (p < .05) adjusting for neuroticism. Among antenatally non-depressed, combined high attachment anxiety and high neuroticism or trait anxiety was predictive of PPDS at both assessment points. LIMITATIONS: Low acceptance rate, exclusive use of self-reports. CONCLUSIONS: Beyond personality, attachment anxiety had a small independent effect on the risk of PPDS. Combining items of adult attachment and neuroticism/trait anxiety could prove useful in antenatal screening for high risk of PPDS. PMID- 28709026 TI - Regulation of calcium and magnesium homeostasis in plants: from transporters to signaling network. AB - Calcium (Ca2+) and magnesium (Mg2+) are the most abundant divalent cations in plants. As a nutrient and a signaling ion, Ca2+ levels in the cell are tightly controlled by an array of channels and carriers that provide mechanistic basis for Ca2+ homeostasis and the generation of Ca2+ signals. Although a family of CorA-type Mg2+ transporters plays a key role in controlling Mg2+ homeostasis in plants, more components are yet to be identified. Ca2+ and Mg2+ appear to have antagonistic interactions in plant cells, and therefore plants depend on a homeostatic balance between Ca2+ and Mg2+ for optimal growth and development. Maintenance of such a balance in response to changing nutrient status in the soil emerges as a critical feature of plant mineral nutrition. Studies have uncovered signaling mechanisms that perceive nutrient status as a signal and regulate transport activities as adaptive responses. This 'nutrient sensing' network is exemplified by the Ca2+-dependent CBL (calcineurin B-like)-CIPK (CBL-interacting protein kinase) pathway that serves as a major link between environmental nutrient status and transport activities. In this review, we analyze the recent literature on Ca2+ and Mg2+ transport systems and their regulation and provide our perspectives on future research. PMID- 28709027 TI - Singlet oxygen triggers chloroplast rupture and cell death in the zeaxanthin epoxidase defective mutant aba1 of Arabidopsis thaliana under high light stress. AB - The two Arabidopsis thaliana mutants, aba1 and max4, were previously identified as sharing a number of co-regulated genes with both the flu mutant and Arabidopsis cell suspension cultures exposed to high light (HL). On this basis, we investigated whether aba1 and max4 were generating high amounts of singlet oxygen (1O2) and activating 1O2-mediated cell death. Thylakoids of aba1 produced twice as much 1O2 as thylakoids of max4 and wild type (WT) plants when illuminated with strong red light. 1O2 was measured using the spin probe 2,2,6,6 tetramethyl-4-piperidone hydrochloride. 77-K chlorophyll fluorescence emission spectra of thylakoids revealed lower aggregation of the light harvesting complex II in aba1. This was rationalized as a loss of connectivity between photosystem II (PSII) units and as the main cause for the high yield of 1O2 generation in aba1. Up-regulation of the 1O2 responsive gene AAA-ATPase was only observed with statistical significant in aba1 under HL. Two early jasmonate (JA)-responsive genes, JAZ1 and JAZ5, encoding for two repressor proteins involved in the negative feedback regulation of JA signalling, were not up-regulated to the WT plant levels. Chloroplast aggregation followed by chloroplast rupture and eventual cell death was observed by confocal imaging of the fluorescence emission of leaf cells of transgenic aba1 plants expressing the chimeric fusion protein SSU-GFP. Cell death was not associated with direct 1O2 cytotoxicity in aba1, but rather with a delayed stress response. In contrast, max4 did not show evidence of 1O2-mediated cell death. In conclusion, aba1 may serve as an alternative model to other 1O2-overproducing mutants of Arabidopsis for investigating 1O2-mediated cell death. PMID- 28709028 TI - In vitro investigation of the dose-rate effect on the biological effectiveness of megavoltage X-ray radiation doses. AB - Radiation therapy is rapidly evolving toward the delivery of higher dose rates to improve cancer treatment. In vitro experiments were performed to investigate the response of 9L and MCF-7 cancer cell lines, exposed to 10MV X-ray radiations. Up to 8Gy was delivered at a dose-rate of 50cGy/min compared to 5Gy/min. The data obtained emphasizes the importance of taking into account not only the physical, but also the radiobiological parameters, when planning a particular cancer treatment. PMID- 28709029 TI - Study of sampling rate influence on neutron-gamma discrimination with stilbene coupled to a silicon photomultiplier. AB - Choosing a digitizer with an appropriate sampling rate is often a trade-off between performance and economy. The influence of sampling rates on the neutron gamma Pulse Shape Discrimination (PSD) with a solid stilbene scintillator coupled to a Silicon Photomultiplier was investigated in this work. Sampling rates from 125MSPS to 2GSPS from a 10-bit digitizer were used to collect detector pulses produced by the interactions of a Cf-252 source. Due to the decreased signal-to noise ratio (SNR), the PSD performance degraded with reduced sampling rates. The reason of PSD performance degradation was discussed. Then, an efficient combination of filtering and digital signal processing (DSP) was then applied to suppress the timing noise and electronic background noise. The results demonstrate an improved PSD performance especially at low sampling rates, down to 125MSPS. Using filtering and DSP, the ascribed Figure of Merit (FOM) at 125keVee (+/- 10keVee) increased from 0.95 to 1.02 at 125MSPS. At 300keVee and above, all the FOMs are better than 2.00. Our study suggests that 250MSPS is a good enough sampling rate for neutron-gamma discrimination in this system in order to be sensitive to neutrons at and above ~ 125keVee. PMID- 28709030 TI - Measurement of large angle Rayleigh scattering cross sections for 39.5, 40.1 and 45.4keV photons in elements with 26 <= Z <= 83. AB - The present work reports Rayleigh scattering cross section measurements for the 39.5keV (Sm- Kalpha2), 40.1keV (Sm-Kalpha1) and 45.4keV (Sm-Kbeta1,3) X-ray photons in 35 elements with 26 <= Z <= 83 at backward angle of 139 degrees . The scattering measurements were performed in reflection mode geometrical set up involving a secondary photon source consisting of Samarium (62Sm) target excited by the 59.54keV gamma-rays from the 241Am radioactive source. The scattered photons were detected using a low energy germanium (LEGe) detector. The product of detector efficiency, intensity of incident photons and other geometrical factors were determined by measuring the K X-ray yields from targets with 47 <= Z <= 59 and knowledge of the respective K X-ray fluorescence cross sections. The measured cross sections are compared with the theoretical cross sections based on the modified form factor (MF) formalisms and the second-order S-matrix approach. The experimental results demonstrate large deviations from the MF values for the elements with K shell binding energy (BK) in vicinity of the incident photon energy (Ein), which smooth out with inclusion of the anomalous scattering factors (ASFs). The S-matrix values, in general, agree with the measured cross sections for all the elements under investigation. PMID- 28709031 TI - Bisphenol A induces COX-2 through the mitogen-activated protein kinase pathway and is associated with levels of inflammation-related markers in elderly populations. AB - Bisphenol A (BPA) is a well-known endocrine-disrupting chemical, and it is one of the highest volume chemicals produced worldwide. Even though several in vivo and in vitro studies showed positive associations of BPA exposure with pro inflammatory cytokines such as tumor necrosis factor-alpha and interleukin (IL) 6, the mechanism by which BPA induces inflammation is unclear. We investigated the mechanism by which BPA induces inflammation (expression of inflammation related genes, changes in oxidative stress, and cell proliferation and migration) and evaluated the effect of BPA exposure on inflammation-related markers in epidemiologic studies using repeat urine and serum samples from elderly subjects. BPA induced COX-2 expression via nuclear translocation of NF-kappaB and activation of mitogen-activated protein kinase (MAPK) by phosphorylation of ERK1/2 and enhanced the migration of lung cancer A549 and breast cancer MDAMB-231 cells. In two epidemiologic studies, we detected associations of BPA with six inflammation-related markers (WBC, CRP, IL-10, ALT, AST, and gamma-GTP levels). Our findings probably suggest that BPA exposure induces inflammation and exacerbates tumorigenesis. PMID- 28709032 TI - Children and youth's biopsychosocial wellbeing in the context of energy resource activities. AB - BACKGROUND: Children and youth emerge as key populations that are impacted by energy resource activities, in part because of their developmental vulnerabilities, as well as the compounding effects of energy systems on their families, communities, and physical environments. While there is a larger literature focused on fossil fuel emissions and children, the impacts of many aspects of energy systems on children and youth remain under examined and scattered throughout the health, social science, and environmental science literatures. OBJECTIVES: This systematic interdisciplinary review examines the biological, psychosocial, and economic impacts of energy systems identified through social science research - specifically focused on household and industrial extraction and emissions - on children and youth functioning. METHODS: A critical interpretive search of interdisciplinary and international social sciences literature was conducted using an adaptive protocol focusing on the biopsychosocial and economic impacts of energy systems on children and youth. The initial results were complemented with a purposeful search to extend the breadth and depth of the final collection of articles. DISCUSSION: Although relatively few studies have specifically focused on children and youth in this context, the majority of this research uncovers a range of negative health impacts that are directly and indirectly related to the development and ongoing operations of natural resource production, particularly oil and gas, coal, and nuclear energy. Psychosocial and cultural effects, however, remain largely unexamined and provide a rich avenue for further research. CONCLUSIONS: This synthesis identifies an array of adverse biopsychosocial health outcomes on children and youth of energy resource extraction and emissions, and identifies gaps that will drive future research in this area. PMID- 28709034 TI - A bioactive coating with submicron-sized titania crystallites fabricated by induction heating of titanium after tensile deformations. AB - Thermal oxidation technology was widely investigated as one of effective surface modification method for improving the bioactivity and biocompatibility of titanium and its alloys. In this work, the induction heat oxidization method, a fast, efficient, economical and environmental protective technology, was applied to prepare the submicron-morphological oxide coating with variable rutile TiO2 equiaxed crystallites on the surface of pure Ti substrates after cold-drawing with 10-20% deformations. The results showed the plastic-deformed Ti cylinders recrystallized during induction heating treatment (IHT) for 10-20s which resulted in evolution of microstructures as well as slight improvement of microhardness. The surface characteristics of TiO2 crystallites in oxidation layers were determined by the microstructural evolutions of Ti substrate in terms of the nucleation and growth of TiO2 crystallites. Specially, the oxidized surface with 50-75nm roughness and more uniform and finer equiaxed oxide grains remarkablely improved the apatite deposition after bioactive evaluation in 1.5 * SBF for 7 days. This work provided a potential method to create controlled bioactive oxide coatings with submicro-/nano-scaled TiO2 crystallites on titanium substrate in terms of the role of metallographic microstructure in the formation process of titanium oxides. PMID- 28709035 TI - Case study: Reinforcement of 45S5 bioglass robocast scaffolds by HA/PCL nanocomposite coatings. AB - The purpose of this study is to analyze the mechanical enhancement provided by nanocomposite coatings deposited on robocast 45S5 bioglass (BG) scaffolds for bone tissue regeneration. In particular, a nanocomposite layer consisting of hydroxyapatite (HA) nanoparticles, as reinforcing phase, in a polycaprolactone (PCL) matrix was deposited onto the surface of the BG struts conforming the scaffold. Three different HA nanopowders were used in this study. The effect of particle size and morphology of these HA nanopowders on the mechanical performance of 45S5 BG scaffolds is evaluated. PMID- 28709033 TI - Vegetated land cover near residence is associated with reduced allostatic load and improved biomarkers of neuroendocrine, metabolic and immune functions. AB - BACKGROUND: Greater exposure to urban green spaces has been linked to reduced risks of depression, cardiovascular disease, diabetes and premature death. Alleviation of chronic stress is a hypothesized pathway to improved health. Previous studies linked chronic stress with a biomarker-based composite measure of physiological dysregulation known as allostatic load. OBJECTIVE: This study's objective was to assess the relationship between vegetated land cover near residences and allostatic load. METHODS: This cross-sectional population-based study involved 206 adult residents of the Durham-Chapel Hill, North Carolina metropolitan area. Exposure was quantified using high-resolution metrics of trees and herbaceous vegetation within 500m of each residence derived from the U.S. Environmental Protection Agency's EnviroAtlas land cover dataset. Eighteen biomarkers of immune, neuroendocrine, and metabolic functions were measured in serum or saliva samples. Allostatic load was defined as a sum of potentially unhealthy biomarker values dichotomized at 10th or 90th percentile of sample distribution. Regression analysis was conducted using generalized additive models with two-dimensional spline smoothing function of geographic coordinates, weighted measures of vegetated land cover allowing decay of effects with distance, and geographic and demographic covariates. RESULTS: An inter-quartile range increase in distance-weighted vegetated land cover was associated with 37% (95% Confidence Limits 46%; 27%) reduced allostatic load; significantly reduced adjusted odds of having low level of norepinephrine, dopamine, and dehydroepiandrosterone, and high level of epinephrine, fibrinogen, vascular cell adhesion molecule-1, and interleukin-8 in serum, and alpha-amylase in saliva; and reduced odds of previously diagnosed depression. CONCLUSIONS: The observed effects of vegetated land cover on allostatic load and individual biomarkers are consistent with prevention of depression, cardiovascular disease and premature mortality. PMID- 28709036 TI - Hydroxyapatite and bioactive glass surfaces for fiber reinforced composite implants via surface ablation by Excimer laser. AB - In skeletal reconstructions, composites, such as bisphenol-A glycidyldimethacrylate resin reinforced with glass fibers, are potentially useful alternatives to metallic implants. Recently, we reported a novel method to prepare bioactive surfaces for these composites. Surface etching by Excimer laser was used to expose bioactive glass granules embedded in the resin. The purpose of this study was to analyze two types of bioactive surfaces created by this technique. The surfaces contained bioactive glass and hydroxyapatite granules. The selected processing parameters were adequate for the creation of the surfaces. However, the use of porous hydroxyapatite prevented the complete exposure the granules. In cell culture, for bioactive glass coatings, the pattern of proliferation of MG63 cells was comparable to that in the positive control group (Ti6Al4V) while inferior cell proliferation was observed on the surfaces containing hydroxyapatite granules. Scanning electron microscopy revealed osteointegration of implants with both types of surfaces. The technique is suitable for the exposure of solid bioactive glass granules. However, the long term performance of the surfaces needs further assessment. PMID- 28709037 TI - Finite element analysis and clinical complications in mandibular implant overdentures opposing maxillary dentures. AB - Denture fracture is a common clinical complication caused by improper material selection, design, or fabrication technique. This study aimed to investigate the effect of two attachment systems on fracture risk of the implant-overdentures (IOD) via finite element analysis (FEA), using the force distributions obtained from patients' occlusal analyses and to compare the obtained results with the clinical complications associated with these attachments. A three-dimensional jaw model comprised of the edentulous bones was constructed. Three types of mandibular prostheses including complete denture (CD) (model LCD), IOD with Locator attachment (model LID-L), and IOD with telescopic attachment (model LID T), as well as a maxillary CD (model UCD) were assembled. The vertical occlusal forces at anterior and posterior quadrants were obtained from the patients wearing mandibular CDs or IODs. The FEA results were further compared with the mechanical failures of different prostheses observed at patient recalls. In overall, the fracture risk of mandibular prostheses was lower than the maxillary compartments. The UCD opposing LCD underwent higher strains than that opposing LID-L and LID-T, which was mostly concentrated at the anterior mid-palatal polished surface. On the other hand, LID-L showed the lowest strain, followed by LID-T, and LCD. The obtained results were consistent with the clinical complications observed in the patient recalls. PMID- 28709038 TI - Rare earths, zirconium and hafnium distribution in coastal areas: The example of Sabella spallanzanii (Gmelin, 1791). AB - The Zr, Hf, Y and lanthanide (REE) distribution in biological tissues of Sabella spallanzanii and Styela plicata species collected from two harbours from the northern Sicily is studied for providing information regarding the Zr, Hf and REE uptake from the environment. Previous studies determined the fractionation of dissolved REE scavenged on binding sites onto biological surfaces. By comparing the recognised shale-normalised REE patterns of studied samples with evidence from reference data, the observed behaviour of these elements in biological tissues of Sabella spallanzanii and Styela plicata is interpreted to result from the preferential uptake of intermediate REE onto carboxylic sites. Moreover, the relationship observed between the Fe content and Zr/Hf ratio suggests that preferential Hf accumulation occurs via siderophore-like binding sites. Features of the REE bioaccumulation factors (BAF), in addition to the absolute La, Ce and Sm contents and Zr-Hf fractionation, allow definition of the different origins of studied elements in the investigated localities. Higher BAF values for La and Ce associated with larger REE contents and lower Zr/Hf values strongly suggest that the environmental REE distribution in the Termini Imerese harbour is influenced by the delivery of particles from industrial sources and power plants. On the contrary, the REE contents of biological tissues collected in the Cala tourist harbour are affected by the dust dissolution from automotive traffic. These results suggest that the geochemical behaviour of REE and Zr/Hf signature can be used in environmental studies of biological tissues for reconstructing the nature of anthropogenic contaminations. PMID- 28709039 TI - Agricultural management of an Oxisol affects accumulation of heavy metals. AB - Soil contamination may result from the inadequate disposal of substances with polluting potential or prolonged agricultural use. Therefore, cadmium (Cd), chromium (Cr) and nickel (Ni) concentrations were assessed in a Eutroferric Red Oxisol under a no-tillage farming system with mineral fertilizer applications, a conventional tillage system with mineral fertilizer application and a conventional tillage system with sewage sludge application in an area used for agriculture for more than 80 years. We evaluated the spatial distributions of these elements in the experimental area and the effect of the different management practices on the soil retention of these metals. The concentrations of metals extracted from 422 soil samples by open-system digestion with HNO3, H2O2 and HCl were assessed by flame atomic absorption spectroscopy. The pH and soil organic matter were also assessed, and spatial distribution maps were designed. The mean concentrations of Cd, Cr and Ni (1.0, 50 and 14 mg kg-1, respectively) in the native forest were higher than the reference values (100, 25 and 8% greater, respectively) in Brazilian legislation, indicating that the source material was the determining factor of the high metal concentrations in the study soils. Soil management with sewage sludge was the major contributor to the accumulation of Cd and Ni, whereas Cr concentration did not vary with management type. Approximately 0.3, 12 and 16% of the experimental area is contaminated with Ni, Cd and Cr, respectively, because their concentrations exceeded the values for alertness or prevention in Brazilian legislation. PMID- 28709040 TI - Low concentrations of bisphenol A promote human ovarian cancer cell proliferation and glycolysis-based metabolism through the estrogen receptor-alpha pathway. AB - Bisphenol A (BPA) is one of the most prevalent chemicals in many products used on a daily basis, making human exposure to it incredibly pervasive and raising concerns about its health consequences. One area of research focus has been the role of BPA exposure in promoting the development of ovarian cancer; however, the doses used in most of previous studies are relatively high and most likely exceed physiologically relevant levels. At the same time, few studies have described potential mechanisms underlying the link between BPA and increased cancer risk. To address these concerns we investigated the mechanism(s) by which low concentrations of BPA promote proliferation and energy metabolism in the human ovarian cancer cell line OVCAR-3. We found that even sub-toxic BPA concentrations not only drove increased OVCAR-3 cell proliferation but also promoted glycolysis based metabolism, as evidenced by elevated cell viability, accelerated cell proliferation, increased levels of intracellular ATP, lactate, and pyruvic acid. Importantly, all of these effects were estrogen receptor alpha (ERalpha) dependent, as siRNA-mediated ERalpha silencing decreased BPA-induced proliferation, pinpointing the crucial role of ERalpha-conducted signaling in BPA induced biological effects. Together, our findings revealed a new mechanism through which BPA promoted cell proliferation by reinforcing glycolysis-based energy production dependent on ER signaling. This study would thus open a new path to understand BPA-induced biological effects on tumor cells. PMID- 28709041 TI - Long-term monitoring of atmospheric PCDD/Fs at Mount Lulin during spring season: PCDD/F source apportionment through a simultaneous measurement in Southeast Asia. AB - A long term assessment of atmospheric polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) at Mt. Lulin, located in center of Taiwan was carried out from 2008 to 2013 (n = 81) assuming Mt. Lulin to be background area. During monitoring processes, PCDD/F samples collected in the field occasionally reached high concentration. To investigate this situation, simultaneous sample collection was carried out in Southeast Asia countries (i.e., Vietnam and Thailand) and Taiwan in 2013. The average concentration of atmospheric PCDD/Fs in biomass burning source regions, namely Son La and Doi Ang Khang were 19.8 +/- 12.1 fg I TEQ m-3 (n = 19) and 17.8 +/- 12.4 fg I-TEQ m-3 (n = 20), respectively. In the downwind area of Mt. Lulin, the average concentration of PCDD/Fs was found to be 4.64 +/- 3.77 fg I-TEQ m-3 (n = 18). PCDD/F concentration in the source region was much higher than that in the downwind region. On March 19, 2013, the atmospheric PCDD/F concentrations increased dramatically from 7.71 to 484 fg I TEQ m-3 at Mt. Lulin, which many times exceeded that of assumed source region in Southeast Asia. Moreover, mainland Southeast Asia and the southeast coast of China was suspected to be the main contributors of atmospheric PCDD/Fs and biomass markers, such as nonsea-salt K+ and NH4+, during the spring. WRF-Chem and Potential Source Contribution Function (PSCF) simulations have confirmed this correlation. It can be concluded that atmospheric PCDD/Fs observed at Mt. Lulin during spring mostly derived from the air mass transport not only from Southeast Asia but also the southeast coast of China. PMID- 28709042 TI - Perinatal exposure of pregnant rats to cypermethrin delays testicular descent, impairs fertility in F1 male progeny leading to developmental defects in F2 generation. AB - Cypermethrin (CYP) is a widely used synthetic pyrethroid insecticide and regarded as a potential endocrine disruptor. CYP exposure may pose a great risk to human health including adverse effect on their reproductive functions. This study aimed to delineate the effects of perinatal exposure of rats to CYP on the sexual maturation and fertility of F1 male progeny. Pregnant rats (F0) were gavaged daily with CYP (0, 1, 10, 25 mg/kg BW/day) and Diethylestilbestrol (DES, 10 MUg/kg BW/day), as positive control from gestation day 6 to postnatal day 21. The effects of CYP on body weight gain and reproductive functions were evaluated at the Juvenile (PND 22), peri-pubertal (PND 45) and adult (PND 75) stages of development. A significant delay in the age of testicular descent and prepuce separation was observed at 1 and 25 mg/kg doses of CYP. At the same dose level, reproductive organ development and their functions were also affected. A significant alteration in testicular histology, expression of steroid hormone receptors, and circulatory steroid hormones was observed throughout development. Reduced sperm count and motility were observed at PND 75 leading to subfertility and reduced litter size. These adult male rats when cohabitated with unexposed normal cycling females, the F2 fetuses exhibited developmental defects. Taken together, CYP perinatal exposure caused significant long lasting effects of the reproductive functions of F1 generation male rats, which were vertically transmitted to F2 generation leading to developmental defects. The mechanism of transgenerational effects needs to be explored in details. PMID- 28709043 TI - Improvement effects of cytokinin on EDTA assisted phytoremediation and the associated environmental risks. AB - Soil samples containing excess Cd (0.82 mg kg-1), Pb (92.7 mg kg-1) and Cu (72.7 mg kg-1) relative to their corresponding safe thresholds (0.3, 80 and 50 mg kg-1, respectively) from a notorious e-waste disposing and recycling place in southern China were phytoremediated with EDTA addition to evaluate the promotion effects of cytokinin on the remediation efficiency of Eucalyptus globulus. Biomass production of the plant, evapotranspiration amount of the soil, metals accumulation in plant organs and the volume of leachate under various treatments were compared. Relative to the planting control, EDTA application shortened the time required for Cd, Pb and Cu decontamination by 1.7-5.5 times but led to significantly more leachate (996 vs 1256 mL), indicating the negative influence of the chelate treatment on the species and the surrounding environment. The foliar application of cytokinin can expand the advantage and alleviate the adverse impact of individual EDTA application simultaneously as manifested by the increased biomass yield, less time consumption for purification and decreased leachate volume. Cytokinin accelerated the transpiration rate of the plant proved by the least volume of leachate in individual cytokinin treatment. The major factors for effective phytoremediation were the resistance of species to high concentrations of contaminants and less environmental risks generation during the remediation processes. Therefore, synergistic use of such components provides more efficient decontamination of metals and more security for the environment. PMID- 28709044 TI - Comparison of inoculum sources for long-term process performance and fate of ANAMMOX bacteria niche in poly(vinyl alcohol)/sodium alginate gel beads. AB - The process performance and microbial niche of anaerobic ammonia oxidation (ANAMMOX) bacteria were compared in two identical bioreactors inoculated with different inoculum sources (i.e., pre-cultured ANAMMOX bacteria: PAB and activated sludge: AS) entrapped in poly(vinyl alcohol)/sodium alginate (PVA/SA) gel beads for a long-term period (i.e., 1.5 years). The start-up period with AS was longer than that with PAB; however, both bioreactors were successfully operated over the long-term with stable ANAMMOX activity. After long-term operation, the 16S rRNA gene concentration of ANAMMOX bacteria in both bioreactors was significantly increased, and thereby became comparable. In addition, Candidatus Jettenia sp. became the dominant ANAMMOX species in both bioreactors. Our results suggested that the ANAMMOX performance and microbial niche of ANAMMOX bacteria became nearly identical during long-term operation despite the use of different inoculum sources. Therefore, the use of PVA/SA gel beads entrapping AS appears to be a relevant option for constructing an ANAMMOX process in places where a full-scale ANAMMOX process has never been done previously. PMID- 28709045 TI - Enhancing performance expectancies through visual illusions facilitates motor learning in children. AB - In a recent study by Chauvel, Wulf, and Maquestiaux (2015), golf putting performance was found to be affected by the Ebbinghaus illusion. Specifically, adult participants demonstrated more effective learning when they practiced with a hole that was surrounded by small circles, making it look larger, than when the hole was surrounded by large circles, making it look smaller. The present study examined whether this learning advantage would generalize to children who are assumed to be less sensitive to the visual illusion. Two groups of 10-year olds practiced putting golf balls from a distance of 2m, with perceived larger or smaller holes resulting from the visual illusion. Self-efficacy was increased in the group with the perceived larger hole. The latter group also demonstrated more accurate putting performance during practice. Importantly, learning (i.e., delayed retention performance without the illusion) was enhanced in the group that practiced with the perceived larger hole. The findings replicate previous results with adult learners and are in line with the notion that enhanced performance expectancies are key to optimal motor learning (Wulf & Lewthwaite, 2016). PMID- 28709046 TI - Ankle brachial index, MRI markers and cognition: The Epidemiology of Dementia in Singapore study. AB - BACKGROUND AND AIMS: Previous studies showed an independent association of low ankle-brachial index (ABI) with cognitive impairment. However, the association between low ABI and cognition in the presence of both cerebrovascular disease (CeVD) and neurodegeneration is lacking. We aimed at investigating a) the association of low ABI with markers of CeVD and cortical thickness, and b) whether the association of low ABI with cognition is influenced by these markers. METHODS: Data was drawn from the Epidemiology of Dementia In Singapore (EDIS) study where all participants (n = 832) underwent neuropsychological tests and 3T brain magnetic resonance imaging (MRI) to assess CeVD markers as well as cortical thicknesses. Cognitive function was expressed as a global composite z-score and domain-specific z-scores of a comprehensive neuropsychological battery. RESULTS: Multivariate analyses showed low ABI to be independently associated with intracranial stenosis [odds ratios (OR): 1.51; 95% confidence interval (CI):1.23 1.87] and lacunar infarcts [OR: 1.29; 95% CI: 1.06-1.57]. A low ABI was also independently associated with smaller cortical thickness globally [beta: 0.09; 95% CI: 0.27-0.16] as well as with the limbic [beta: 0.10; 95% CI: 0.03-0.17], temporal [beta: 0.09; 95% CI: 0.02-0.15], parietal [beta: 0.08; 95% CI: 0.02 0.15], and occipital [beta: 0.09; 95% CI: 0.03-0.16] lobes. Low ABI was associated with worse performance in verbal memory [beta: 0.06; 95% CI: 0.01 0.12], which became attenuated in the presence of MRI markers. CONCLUSIONS: A low ABI is associated with MRI markers, and affects cognition in the presence of CeVD and neurodegeneration. Atherosclerosis should be targeted as a potentially modifiable risk factor to prevent cognitive disorders. PMID- 28709047 TI - Persistence of immersed blood and hair DNA: A preliminary study based on casework. AB - In some cases, evidence is collected from rivers, canals, lakes or sink pipes. To determine the utility of analyzing these samples and for cases in which DNA was recovered from submerged bulletproof vest parts, we evaluated the time necessary to degrade the blood and, subsequently, DNA on bulletproof vests. In a second experiment, also based on cases, blood was diluted in water from a kitchen sink pipe and incubated at room temperature for different times. Subsequently, DNA quality was assessed. In a parallel experiment, hair roots were incubated in spring water for different time periods. This study demonstrates that after one week of immersion of the bulletproof vest parts in a canal only one sample from more than 100 samples gave a partial genetic profile. No genetic profile were obtained for the 99 other samples. After one month immersion and despite the finding that blood remained detectable on bulletproof vest parts, no genetic profile was obtained for all samples using the classical STR approach. For longer immersion times, no genetic profiles were obtained. In sink pipe water, an incubation time of 72 h (h) was necessary before significant blood degradation occurred. Nevertheless, high inter-sample variability was observed. This high variability may be explained by the variability of water composition coming from nine different sink pipes. For hair root cells incubated in water, we observed that more than 90% of the DNA was degraded after 72 h. PMID- 28709048 TI - Intentional burn injury: Assessment of allegations of self-infliction. AB - This study investigates the question of whether there is evidence that suggests the possibility of self-infliction, or self-infliction by proxy, of burn injury among a group of asylum claimants in the UK who have attributed such injuries to torture, and how such evidence might be assessed. The question arose from the observations of doctors at the UK-based charity Freedom from Torture that increasing numbers of individuals from Sri Lanka who described a history of torture had suffered severe and disfiguring burn injuries from heated metal objects, and the suggestion from asylum decision-makers that in some cases such injuries could have been acquired deliberately by self-infliction or self infliction by proxy rather than by torture as claimed. This suggestion has not been confined to Sri Lankan cases, but due to the large numbers of Sri Lankan asylum claimants referred to Freedom from Torture in recent years, including many with this type of injury, the case set for this study was drawn from this population. As many of these injuries are found to be on the back, where self infliction would be extremely difficult, the possibility of self-infliction by proxy was specifically investigated. An observational data set was examined in detail, comprising medico-legal reports for Sri Lankans with heated metal object burn injuries documented in 2011-14 by the Medico-Legal Reports Service at Freedom from Torture. All had described detention in Sri Lanka since the end of the civil war in 2009. The study reviewed the documented evidence of these injuries alongside other physical and psychological evidence attributed to torture and relevant contextual factors documented in each case. Findings were compared with previous research on torture in Sri Lanka and patterns of injury identified in forensic medicine for both self-infliction and self-infliction by proxy. Thorough examination of the evidence found no indication in this data set to suggest the possibility of self-infliction or self-infliction by proxy and supported the view that, as indicated in the Istanbul Protocol, the overall conclusion on likelihood of torture should be made on evaluation of all the physical and psychological evidence over and above the scrutiny of an individual lesion. PMID- 28709049 TI - Idiopathic spontaneous pulmonary torsion of the lingula: A case report. AB - INTRODUCTION: Spontaneous pulmonary torsion is an extremely rare event and is known to occur as a complication of thoracic surgery and traumatic injuries. PRESENTATION OF CASE: An 18-year-old man presented to our hospital with pain in the left back region. Clinical examination, computed tomography and bronchoscopy are crucial for diagnosis of pulmonary torsion. During thoracotomy, the lingula segment was observed to be bent on the head side and turned 180 degrees counterclockwise; subsequently, lingulectomy was performed. DISCUSSION: Spontaneous pulmonary torsion may occur in pulmonary conditions such as pneumothorax, atelectasis, infection, pleural effusion, congenital defect, or tumor. Furthermore, it can be speculated that torsion of the segment is possible only in the patients with an accessory fissure or those who have undergone a segmentectomy. CONCLUSION: We have reported an extremely rare case with respect to the fact that the pulmonary torsion occurred spontaneously in an unseparated segment, and that the etiological factor could not be identified. PMID- 28709050 TI - Anomalous V2 of the left pulmonary vein detected using three-dimensional computed tomography in a patient with lung cancer: A case report. AB - We report one of the rare anatomical variations of the pulmonary vein wherein the left V2 drained into the inferior pulmonary vein. A 63-year-old man was referred to our hospital because of an abnormal shadow in the left lower lung field that was noted on chest X-ray. Computed tomography (CT) revealed a tumor in the left lower lobe. A biopsied tumor specimen was diagnosed as an adenocarcinoma, and thus, left lower lobectomy was performed. Preoperative three-dimensional CT revealed that an anomalous V2 of the left lung drained from the superior segment into the inferior pulmonary vein. This variation type was confirmed during thoracoscopic left lower lobectomy. We were able to perform left lower lobectomy with the preservation of the anomalous V2. The postoperative course was uneventful, and the patient was discharged on postoperative day 12. It is important to identify anatomical variations of the pulmonary vein and reliably preserve and process the affected area to prevent postoperative complications. PMID- 28709051 TI - Collision tumor of choriocarcinoma and small cell carcinoma of the stomach: A case report. AB - INTRODUCTION: Both gastric choriocarcinoma and small cell carcinoma are extremely rare, both accounting for approximately 0.1% of all gastric cancers. Therefore, simultaneous occurrence of gastric choriocarcinoma and small cell carcinoma is even rarer. PRESENTATION OF CASE: An 84-year-old Japanese man was referred to our hospital with the chief complaint of dysphagia. Laboratory data showed iron deficiency anemia. Contrast-enhanced computed tomography of the abdomen revealed thickened wall of the stomach at the fundus and several enlarged abdominal lymph nodes. Upper gastrointestinal endoscopy showed a friable gastric tumor with necrosis in the gastric cardia extending to the abdominal esophagus. Small cell carcinoma was diagnosed based on pathological examination of biopsy specimens. The anemia, which was probably because of tumor bleeding, progressed despite repeated transfusion; therefore, a semi-urgent laparotomy was performed to control hemorrhage. Finally, total gastrectomy and lymph node resection were performed. Based on pathological findings, a diagnosis of collision tumor of choriocarcinoma and small cell carcinoma of the stomach was confirmed. DISCUSSION: When encountering large tumors with necrosis or hemorrhage in the stomach, the possibility of choriocarcinoma component should be considered. Moreover, when small cell carcinoma is morphologically suspected, even if slightly, additional immunohistochemical staining must be performed. CONCLUSION: This report detailed an extremely rare case of collision tumor of choriocarcinoma and small cell carcinoma of the stomach. PMID- 28709052 TI - Colon cancer metastasis to the thyroid gland: A case report. AB - INTRODUCTION: Thyroid metastases from colorectal cancer are uncommon and few cases are described in literature. CASE PRESENTATION: A 64-year-old female patient presented with an asymptomatic right cervical nodule with a rapid growth six years after sigmoidectomy for cancer and two years after resection of colorectal lung metastases. Increased CA 19.9 was identified and a thoracoabdominal CT scan revealed the onset of new metastatic bilateral pulmonary lesions. Neck ultrasonography showed a suspicious nodule in the right thyroid lobe, and Fine-needle Aspiration Cytology (FNAC) of the nodule lead to the diagnosis of colorectal cancer metastasis. A right thyroid lobectomy with right central lymph node dissection was performed. The patient underwent chemotherapy with response, but this was posteriorly suspended due to haematological side effects, and the disease spread. DISCUSSION: Thyroid metastases from colorectal cancer are rare, but, with the improvement of radiologic exams and the higher survival rate of these patients, more cases are being described. The majority of the cases present pulmonary and hepatic metastases and the prognosis is poor. The decision to operate and the type of operation depend on the extent of the metastatic disease and the patient's overall condition. CONCLUSION: A low threshold of suspicion is crucial to make a timely diagnosis of thyroid metastases from colorectal cancer. Treatment is controversial, but, without surgery, the need may arise for tracheostomy. PMID- 28709053 TI - Transport and retention of biochar nanoparticles in a paddy soil under environmentally-relevant solution chemistry conditions. AB - Land application of biochar has been increasingly recommended as a powerful strategy for carbon sequestration and soil remediation. However, the biochar particles, especially those in the nanoscale range, may migrate or carry the inherent contaminants along the soil profile, posing a potential risk to the groundwater. This study investigated the transport and retention of wood chip derived biochar nanoparticles (NPs) in water-saturated columns packed with a paddy soil. The environmentally-relevant soil solution chemistry including ionic strength (0.10-50 mM), electrolyte type (NaCl and CaCl2), and natural organic matter (0-10 mg L-1 humic acid) were tested to elucidate their effects on the biochar NPs transport. Higher mobility of biochar NPs was observed in the soil at lower ionic strengths, with CaCl2 electrolyte being more effective than NaCl in decreasing biochar NPs transport. The retained biochar NPs in NaCl was re entrained (~57.7%) upon lowering transient pore-water ionic strength, indicating that biochar NPs were reversibly retained in the secondary minimum. In contrast, negligible re-entrainment of biochar NPs occurred in CaCl2 due to the primary minimum and/or particle aggregation. Humic acid increased the mobility of biochar NPs, likely due to enhanced electrosteric repulsive interactions. The transport behaviors of biochar NPs can be well interpreted by a two-site kinetic retention model that assumes reversible retention for one site, and irreversible retention for the other site. Our findings indicated that the transport of wood chip biochar NPs is significant in the paddy soil, highlighting the importance of understanding the mobility of biochar NPs in natural soils for accurately assessing their environmental impacts. PMID- 28709054 TI - Probing the relationship between external and internal human exposure of organophosphate flame retardants using pharmacokinetic modelling. AB - Human external exposure (i.e. intake) of organophosphate flame retardants (PFRs) has recently been quantified, but no link has yet been established between external and internal exposure. In this study, we used a pharmacokinetic (PK) model to probe the relationship between external and internal exposure data for three PFRs (EHDPHP, TNBP and TPHP) available for a Norwegian cohort of 61 individuals from 61 different households. Using current literature on metabolism of PFRs, we predicted the metabolite serum/urine concentrations and compared it to measured data from the study population. Unavailable parameters were estimated using a model fitting approach (least squares method) after assigning reasonable constraints on the ranges of fitted parameters. Results showed an acceptable comparison between PK model estimates and measurements (<10-fold deviation) for EHDPHP. However, a deviation of 10-1000 was observed between PK model estimates and measurements for TNBP and TPHP. Sensitivity and uncertainty analysis on the PK model revealed that EHDPHP results showed higher uncertainty than TNBP or TPHP. However, there are indications that (1) current biomarkers of exposure (i.e. assumed metabolites) for TNBP and TPHP chemicals might not be specific and ultimately affecting the outcome of the modelling and (2) some exposure pathways might be missing. Further research, such as in vivo laboratory metabolism experiments of PFRs including identification of better biomarkers will reduce uncertainties in human exposure assessment. PMID- 28709055 TI - Declining atmospheric deposition of heavy metals over the last three decades is reflected in soil and foliage of 97 beech (Fagus sylvatica) stands in the Vienna Woods. AB - Rigorous studies on long-term changes of heavy metal distribution in forest soils since the implementation of emission controls are rare. Hence, we resampled 97 old-growth beech stands in the Vienna Woods. This study exploits an extensive data set of soil (infiltration zone of stemflow and between trees area) and foliar chemistry from three decades ago. It was hypothesized that declining deposition of heavy metals is reflected in soil and foliar total contents of Pb, Cu, Zn, Ni, Mn and Fe. Mean soil contents of Pb in the stemflow area declined at the highest rate from 223 to 50 mg kg-1 within the last three decades. Soil contents of Pb and Ni decreased significantly both in the stemflow area and the between trees area down to 80-90 cm soil depth from 1984 to 2012. Top soil (0-5 cm) accumulation and simultaneous loss in the lower soil over time for the plant micro nutrients Cu and Zn are suggested to be caused by plant uptake from deep horizons. Reduced soil leaching, due to a mean soil pH (H2O) increase from 4.3 to 4.9, and increased plant cycling are put forward to explain the significant increase of total Mn contents in the infiltration zone of beech stemflow. Top soil Pb contents in the stemflow area presently exceed the critical value at which toxicity symptoms may occur at numerous sites. Mean foliar contents of all six studied heavy metals decreased within the last three decades, but plant supply with the micro nutrients Cu, Zn, Mn and Fe is still in the optimum range for beech trees. It is concluded that heavy metal pollution is not critical for the studied beech stands any longer. PMID- 28709056 TI - The power of Random Forest for the identification and quantification of technogenic substrates in urban soils on the basis of DRIFT spectra. PMID- 28709057 TI - Predictive validity of the Short-Term Assessment of Risk and Treatability (START) for multiple adverse outcomes: The effect of diagnosis. AB - The Short-Term Assessment of Risk and Treatability (START) assists risk assessment for seven risk outcomes based on scoring of risk and protective factors and assignment of clinically-informed risk levels. Its predictive validity for violence and self-harm has been established in males with schizophrenia, but accuracy across pathologically diverse samples is unknown. Routine START assessments and 3-month risk outcome data of N = 527 adult, inpatients in a UK secure mental health facility were collected. The sample was divided into diagnostic groups; predictive validity was established using receiver operating characteristics regression (rocreg) analysis in which potential covariates were controlled. In most single-diagnosis groups START risk factors ('vulnerabilities'), protective factors ('strengths'), and clinically informed estimates predicted multiple risk outcomes with effect sizes similar to previous research. Self-harm was not predicted among patients with an organic diagnosis. The START risk estimates predicted physical aggression in all diagnostic groups, and verbal aggression, self-harm and self-neglect in most diagnostic groups. The START can assist assessment of aggressive, self-harm, and self-neglect across a range of diagnostic groups. Further research with larger sample sizes of those with multiple diagnoses is required. PMID- 28709058 TI - Blood cadmium and depressive symptoms: Confounded by cigarette smoking. AB - Our aim was to explore the association between blood cadmium (BCd) and depressive symptoms, adjusting for pack years and blood cotinine, and also stratifying by smoking status. Using data from the US National Health and Nutrition Examination Survey (NHANES) 2005-2012, we categorized depressive symptoms using the PHQ-9 (Patient Health Questionnaire-9) survey and modeled depressive symptoms in relation to BCd adjusted for blood cotinine, pack years of smoking, and other covariates. We also stratified by self-reported smoking status (current, former, never). There were 11,209 subjects from 2005 to 2012, age >= 18 with PHQ-9, smoking, and blood cadmium data available. 876 (7.8%) met criteria for depressive symptoms. Depressive symptoms were associated with BCd levels in a crude model and with adjustment for pack years and cotinine. The association disappeared when analyzed among current, former, or never smokers. Consistent with the literature, we found an association between BCd and depressive symptoms; however, that association disappears in analyses stratified by smoking status. This suggests residual confounding may be present. It is important to stratify by smoking status when investigating health outcomes associated with BCd. PMID- 28709059 TI - Negative trust and depression among female sex workers in Western China: The mediating role of thwarted belongingness. AB - Female sex workers are at high risk for depression in China but they are understudied and underserved. Based on cognitive models of depression, dysfunctional beliefs about oneself and others may act as vulnerability factors for depression. However, the association between negative trust and depression is still under debate. The present study aimed to test the hypothesis that negative trust positively relates to depression through thwarted belongingness among female sex workers. Four hundred and fifty-seven participants completed measures of negative trust, thwarted belongingness, and depression. Stepwise multiple linear regression analyses showed that both negative trust and thwarted belongingness significantly positively predicted depression, and thwarted belongingness was positively predicted by negative trust. The results from the mediation analysis suggest that thwarted belongingness might be an underlying mechanism linking negative trust and depression. Psychological interventions could focus on helping female sex workers form and strengthen meaningful social connectedness (the behavioral/observable indicators of the constructs of thwarted belongingness). PMID- 28709060 TI - The association between suicidal ideation and sleep quality in elderly individuals: A cross-sectional study in Shandong, China. AB - Previous studies have identified global associations between sleep quality and suicidal ideation. However, little is known regarding the relationship between sleep quality and suicidal ideation among Chinese older adults. We examined the relationship between sleep quality and suicidal ideation in older adults in China. A cross-sectional study was conducted in 3313 seniors in Shandong, China. Suicidal ideation was assessed using the interviewees' answers to the question "Have you ever seriously considered wanting to die?". Sleep quality was assessed using the Pittsburgh Sleep Quality Index. Logistic regression was performed to estimate odds ratios and 95% confidence intervals adjusted for confounders. When controlling for sex, age, living condition, economic status, marital status, education, past occupation, relationship with children, non-communicable diseases, and mental health, the odds of suicidal ideation increased in association with an increase in the total score for sleep quality and its components (subjective sleep quality, sleep duration, habitual sleep efficiency, and daytime dysfunction). Poor sleep quality was associated with increased odds of suicidal ideation in Chinese older adults. Sleep-based interventions should be developed to prevent suicide in older adults in China. PMID- 28709061 TI - Exploring DSM-5 criterion A in Acute Stress Disorder symptoms following natural disaster. AB - The present study examines the DSM-5 Acute Stress Disorder (ASD) diagnostic criteria of exposure, in the context of a natural disaster. The study is based on the reports of 1001 Filipinos following the aftermath of super typhoon Haiyan in 2013. Participants reported exposure to injury, psychological distress and ASD symptoms. Findings indicated the association of criterion A with the prevalence of meeting all other ASD diagnostic criteria and high psychological distress. The diagnostic properties of Criterion A are discussed. PMID- 28709063 TI - Regulation of Rho GTPase proteins during spine structural plasticity for the control of local dendritic plasticity. AB - While it is generally appreciated that learning involves the structural rearrangement of neuronal circuits, the underlying orchestration of molecular events that drives these changes is not as well understood. Recent studies on the spatiotemporal organization of synaptic signaling events have provided new insights into the biochemical underpinnings of various expressions of structural neuronal plasticity, as well as the functional consequences that emerge because of the particular behavior of the molecules involved. In particular, activity patterns of and interplay among a class of morphogenic signaling proteins, the Rho GTPases, and their downstream signals, are found to be critical for linking neuronal activity with various forms of neuronal plasticity. We review recent findings on this topic and discuss their physiological implications. PMID- 28709062 TI - Cancer incidence in the AGRICAN cohort study (2005-2011). AB - BACKGROUND: Numerous studies have been conducted among farmers, but very few of them have involved large prospective cohorts, and few have included a significant proportion of women and farm workers. Our aim was to compare cancer incidence in the cohort (overall, by sex, and by work on farm, occupational status and pesticide use) within the general population. METHODS: More than 180,000 participants in the AGRICAN cohort were matched to cancer registries to identify cancer cases diagnosed from enrolment (2005-2007) to 31st December 2011. We calculated standardized incidence ratios (SIRs) and 95% confidence intervals (95%CIs). RESULTS: Over the period, 11,067 incident cancer cases were identified (7304 men and 3763 women). Overall cancer incidence did not differ between the cohort and the general population. Moreover, SIRs were significantly higher for prostate cancer (SIR=1.07, 95%CI 1.03-1.11) and non-Hodgkin lymphoma (SIR=1.09, 95%CI 1.01-1.18) among men, skin melanoma among women (SIR=1.23, 95%CI 1.05-1.43) and multiple myeloma (men: SIR=1.38, 95%CI 1.18-1.62; women: SIR=1.26, 95%CI 1.02 1.54). In contrast, SIRs were lower for upper aerodigestive tract and respiratory cancers. Increase in risk was greater in male farm workers for prostate and lip cancer, in female farm workers for skin melanoma, and in male farm owners for multiple myeloma. Moreover, incidence of multiple myeloma and skin melanoma was higher among male and female pesticide users respectively. CONCLUSION: We found a decreased incidence for tobacco-related cancers and an increased incidence of prostate cancers, skin melanoma and multiple myeloma. Specific subgroups had a higher cancer incidence related to occupational status and pesticide use. PMID- 28709064 TI - Environmental economics of lignin derived transport fuels. AB - This paper explores the environmental and economic aspects of fast pyrolytic conversion of lignin, obtained from 2G ethanol plants, to transport fuels for both the marine and automotive markets. Various scenarios are explored, pertaining to aggregation of lignin from several sites, alternative energy carries to replace lignin, transport modalities, and allocation methodology. The results highlight two critical factors that ultimately determine the economic and/or environmental fuel viability. The first factor, the logistics scheme, exhibited the disadvantage of the centralized approach, owing to prohibitively expensive transportation costs of the low energy-dense lignin. Life cycle analysis (LCA) displayed the second critical factor related to alternative energy carrier selection. Natural gas (NG) chosen over additional biomass boosts well-to wheel greenhouse gas emissions (WTW GHG) to a level incompatible with the reduction targets set by the U.S. renewable fuel standard (RFS). Adversely, the process' economics revealed higher profits vs. fossil energy carrier. PMID- 28709065 TI - Waste-to-methanol: Process and economics assessment. AB - The waste-to-methanol (WtM) process and related economics are assessed to evidence that WtM is a valuable solution both from economic, strategic and environmental perspectives. Bio-methanol from Refuse-derived-fuels (RdF) has an estimated cost of production of about 110?/t for a new WtM 300t/d plant. With respect to waste-to-energy (WtE) approach, this solution allows various advantages. In considering the average market cost of methanol and the premium as biofuel, the WtM approach results in a ROI (Return of Investment) of about 29%, e.g. a payback time of about 4years. In a hybrid scheme of integration with an existing methanol plant from natural gas, the cost of production becomes a profit even without considering the cap for bio-methanol production. The WtM process allows to produce methanol with about 40% and 30-35% reduction in greenhouse gas emissions with respect to methanol production from fossil fuels and bio resources, respectively. PMID- 28709066 TI - Evaluation of an up-flow anaerobic sludge bed (UASB) reactor containing diatomite and maifanite for the improved treatment of petroleum wastewater. AB - Novel diatomite (R1) and maifanite (R2) were utilized as support materials in an up-flow anaerobic sludge bed (UASB) reactor for the treatment of recalcitrant petroleum wastewater. At high organic loadings (11kg-COD/m3.d), these materials were efficient at reducing COD (92.7% and 93.0%) in comparison with controls (R0) (88.4%). Higher percentages of large granular sludge (0.6mm or larger) were observed for R1 (30.3%) and R2 (24.6%) compared with controls (22.6%). The larger portion of granular sludge provided a favorable habitat that resulted in greater microorganism diversity. Increased filamentous bacterial communities are believed to have promoted granular sludge formation promoting a conductive environment for stimulation methanogenic Archaea. These communities had enhanced pH tolerance and produced more methane. This study illustrates a new potential use of diatomite and maifanite as support materials in UASB reactors for increased efficiency when treating refractory wastewaters. PMID- 28709067 TI - Coupling process study of lipid production and mercury bioremediation by biomimetic mineralized microalgae. AB - Considering the high concentration of mercury in industrial wastewater, such as coal-fired power plants and gold mining wastewater, this research study investigated the coupling process of lipid production and mercury bioremediation using microalgae cells. Chlorella vulgaris modified by biomimetic mineralization. The cultivation was divided in two stages: a natural cultivation for 7days and 5days of Hg2+ addition (10-100MUg/L) for cultivation at different pH values (4-7) after inoculation. Next, the harvested cells were eluted, and lipid was extracted. The fluorescein diacetate (FDA) dye tests demonstrated that the mineralized layer enhanced the biological activity of microalgae cells in Hg2+ contaminated media. Hg distribution tests showed that the Hg removal capacity of modified cells was increased from 62.85% to 94.74%, and 88.72% of eluted Hg2+ concentration was observed in modified cells compared to 48.42% of raw cells, implying that more mercury was transferred from lipid and residuals into elutable forms. PMID- 28709068 TI - Simultaneous phosphorus and nitrogen recovery from anaerobically digested sludge using a hybrid system coupling hydrothermal pretreatment with MAP precipitation. AB - In order to dispose excess sewage sludge and recycle its nitrogen and phosphorus resources, hydrothermal pretreatment coupling with MgNH4PO3.6H2O (MAP) crystallization was investigated. Hydrothermal pretreatment at different temperature and residence time were performed on anaerobically digested sludge to maximize phosphate and ammonium release and their recovery from the resultant hydrolysate. Results showed that hydrothermal pretreatment at 200 degrees C for 30min favored phosphate and ammonium release achieving phosphate and ammonium concentrations at 579.98mg-P/L and 456.85mg-N/L, respectively. During the subsequent MAP precipitation, the optimum condition for N and P recovery was determined at pH 9 and Mg/P molar ratio of 1, realizing P and N recovery of 91.60% and 54.88% respectively from the hydrolysate in addition to MAP purity of 84.24%. The produced MAP was confirmed by FTIR and XRD analysis, which fulfills the related standards and can be used as fertilizer with high promise. PMID- 28709069 TI - Characterization of changes in floc morphology, extracellular polymeric substances and heavy metals speciation of anaerobically digested biosolid under treatment with a novel chelated-Fe2+ catalyzed Fenton process. AB - A novel chelated-Fe2+ catalyzed Fenton process (CCFP) was developed to enhance dewatering performance of anaerobically digested biosolid, and changes in floc morphology, extracellular polymeric substances (EPS) and heavy metals speciation were also investigated. The results showed that addition of chelating agents caused EPS solubilization by binding multivalent cations. Like traditional Fenton, CCFP performed well in improving anaerobically digested sludge dewatering property. The highly active radicals (OH, O2-) produced in classical Fenton and CCFP were responsible for sludge flocs destruction and consequently degradation of biopolymers into small molecules. Furthermore, more plentiful pores and channels were presented in cake after Fenton treatment, which was conducive to water drainage under mechanical compression. Additionally, a portion of active heavy metals in the form of oxidizable and reducible states were dissolved under CCFP. Therefore, CCFP could greatly simplify the operating procedure of Fenton conditioning and improve its process adaptability for harmless treatment of biological sludge. PMID- 28709070 TI - Ethanol production in a simultaneous saccharification and fermentation process with interconnected reactors employing hydrodynamic cavitation-pretreated sugarcane bagasse as raw material. AB - In this study, sugarcane bagasse (SCB) pretreated with alkali assisted hydrodynamic cavitation (HC) was investigated for simultaneous saccharification and fermentation (SSF) process for bioethanol production in interconnected column reactors using immobilized Scheffersomyces stipitis NRRL-Y7124. Initially, HC was employed for the evaluation of the reagent used in alkaline pretreatment. Alkalis (NaOH, KOH, Na2CO3, Ca(OH)2) and NaOH recycled black liquor (successive batches) were used and their pretreatment effectiveness was assessed considering the solid composition and its enzymatic digestibility. In SSF process using NaOH-HC pretreatment SCB, 62.33% of total carbohydrate fractions were hydrolyzed and 17.26g/L of ethanol production (0.48g of ethanol/g of glucose and xylose consumed) was achieved. This proposed scheme of HC-assisted NaOH pretreatment together with our interconnected column reactors showed to be an interesting new approach for biorefineries. PMID- 28709071 TI - Rapid start-up of partial nitritation and simultaneously phosphorus removal (PNSPR) granular sludge reactor treating low-strength domestic sewage. AB - Obtaining desirable partial nitritation (PN) is crucial for successful application of the combined PN and anammox process. In this study, the partial nitritation and simultaneously phosphorus removal (PNSPR)1 granular sludge reactor treating low-strength domestic sewage was rapidly started up in 67days through seeding denitrifying phosphorus removal (DPR)2 sludge. The nitrite/ammonium ratio in effluent was approximately 1 and the nitrite accumulation rate (NAR) was more than 95%, about 93% of orthophosphate was removed. The DPR sludge rich in phosphate accumulating organisms (PAOs) with few nitrifying bacteria could promote the achievement of PNSPR. Quantitative microbial analysis showed that the ammonium oxidizing bacteria (AOB) gene ratio in sludge increased from 0.21% to 3.43%, while nitrite oxidizing bacteria (NOB) gradually decreased to 0.07%. The average particle size of sludge increased from 114 to 421MUm, indicating the formation of PNSPR granules. The high phosphorus content in sludge and phosphorus removal facilitated rapid granulation. PMID- 28709072 TI - Stimulation effect of electric current density (ECD) on microbial community of a three dimensional particle electrode coupled with biological aerated filter reactor (TDE-BAF). AB - Improving the stimulation effect of electric current density (ECD) on microbial community is critical in designing and operating TDE-BAF. This study investigated the effect of ECD at 0.00, 4.08, 6.12, 12.20, 14.25, 16.30 and 20.20A.m-2 on the removal performance, diversity and structure of microbial community in TDE-BAF. Results indicated that the ECD of 14.25A.m-2 exhibited the highest COD, TOC and NH4+-N average removal rates with 93.33%, 91.26% and 93.87%, respectively; Under high ECD, especially exceeding 14.25A.m-2, the inhibition of growth and activity because of plasmatorrhexis was in agreement with the sharp biomass decline; there was no significant relation between community richness and diversity and removal efficiency below optimum ECD, while above optimal ECD, it was just the opposite; Microbial communities mainly including Hydrogenophaga, Saprospiraceae_uncultured, Delftia, Enterobacter, Pseudomonas, Pseudoxanthomonas, and Nitrosospira and physicochemical properties well explained the excellent removal performance at the optimum ECD. PMID- 28709073 TI - Predictive modeling to de-risk bio-based manufacturing by adapting to variability in lignocellulosic biomass supply. AB - Commercial-scale bio-refineries are designed to process 2000tons/day of single lignocellulosic biomass. Several geographical areas in the United States generate diverse feedstocks that, when combined, can be substantial for bio-based manufacturing. Blending multiple feedstocks is a strategy being investigated to expand bio-based manufacturing outside Corn Belt. In this study, we developed a model to predict continuous envelopes of biomass blends that are optimal for a given pretreatment condition to achieve a predetermined sugar yield or vice versa. For example, our model predicted more than 60% glucose yield can be achieved by treating an equal part blend of energy cane, corn stover, and switchgrass with alkali pretreatment at 120 degrees C for 14.8h. By using ionic liquid to pretreat an equal part blend of the biomass feedstocks at 160 degrees C for 2.2h, we achieved 87.6% glucose yield. Such a predictive model can potentially overcome dependence on a single feedstock. PMID- 28709074 TI - Increased methane production in cyanobacteria and methanogenic microbe co cultures. AB - A novel light-to-bioenergy system produced 3.5 times the baseline methane output using a co-culture of cyanobacteria (Oscillatoria sp.) and a methanogenic microbial community. Analysis of micronutrients in the system during the growth phase indicated that cobalt, iron, nickel and zinc were not appreciably consumed. The stable consumption and return of macronutrients calcium and magnesium were also observed. Essential macronutrients nitrogen, in the form of nitrate, and phosphorus showed no cycling during the growth phase and were depleted at rates of 0.35mg/L/day and 0.40ug/L/day, respectively. Biofilm formation increased the resilience of biomass to bacterial degradation in an anaerobic digester, as shown by viability assays of cyanobacterial biofilms in the co-culture. PMID- 28709075 TI - Effects of chromium(III) on enzyme activities and bacterial communities during swine manure composting. AB - The present study investigated the effects of different concentrations of chromium (i.e., 200 and 700mgkg-1 Cr corresponding to Cr200 and Cr700, respectively) on the microorganisms in swine manure compost. The results demonstrated that a high concentration of Cr(III) could inhibit the activity of key microbial enzymes (i.e., dehydrogenase, cellulase, and urease) in the early composting stages, with maximal inhibition rates of 54.9%, 32.8%, and 46.7% for cellulase, urease, and dehydrogenase, respectively. Furthermore, the bacterial abundances were determined by quantitative PCR and their compositions were evaluated by denaturing gradient gel electrophoresis. Cr200 and Cr700 had significant inhibitory effects on the abundances of bacteria. The DGGE results showed that Cr200 and Cr700 changed the bacterial community structure and diversity, where Cr(III) might enhance the abundance of pathogenic bacteria (e.g., Saccharomonospora) and decrease the abundances of bacteria that degrade cellulose and lignin (e.g., Paenibacillus) during composting. PMID- 28709076 TI - Coupling autotrophic denitrification with partial nitritation-anammox (PNA) for efficient total inorganic nitrogen removal. AB - The performance of and the microbial ecology in an integrated lab scale set up comprising of a PN/A bioreactor and an elemental sulfur-supported packed bed autotrophic denitrification (ESSAD) are reported. The PN/A reactor exhibited an average removal rate of 0.56+/-0.103kgNm-3d-1, whereas the ESSAD reactor removed an average of 0.0018kg NO3--Nm-3d-1. The combined average removal rate was 0.6kgNm-3d-1, yielding an overall total inorganic nitrogen efficiency of 97%. Based on 16S rRNA gene clone libraries from the ESSAD reactor, the extracted Operational Taxonomic Units (OTUs) formed a clade with Thiobacillus denitrificans sp. indicating a common ancestral relationship. High throughput amplicon sequencing targeting V3 region of 16S rRNA gene for the biofilm in the ESSAD also revealed an abundance of the Thiobacillus genus. Additionally, 16s rRNA amplicon sequencing of the genomic DNA from the PN/A reactor reflected a dominance of the Planctomycetes phylum. PMID- 28709077 TI - Phytonanotherapy for management of diabetes using green synthesis nanoparticles. AB - The world has a rich diversity of indigenous medicinal plants. The World Health Organization (WHO) gives high priority to eco-friendly, non-hazardous and cost effective healthcare such as the use of medicinal plants to treat various illnesses, including Human immunodeficiency virus (HIV) infection and Acquired immune deficiency syndrome (AIDS), tuberculosis (TB), diabetes mellitus (DM), malaria, and cancer. In developing countries, a high proportion of the population tends to use complementary and alternative medicines (CAM) together with conventional prescription drugs. Globally, CAM has been used in both developed and developing countries. In China, 30-50% of medicinal use is based on traditional alternative medicine. In Africa, it is estimated that 80% of primary health care is CAM, whilst in the USA, about 158 million people us CAM. This increase is due to three main influences: improve their eminence of life, relieve symptoms and preclude long-term complications. Despite the advances and advantages of conventional pharmaceutical medication, these are associated with long-term side effects and pose risks of inefficacy for treatment of chronic diseases such as cancer and DM. The biosynthesis of metal nanoparticles (NPs) using medicinal plants has received considerable attention as a proper alternative to using hazardous chemical and physical synthetic techniques. Plants are being exploited for their unique metal tolerance and effective production of gold metal NPs. A single medicinal plant contains an orchestra of chemical elements (e.g. proteins, vitamins, enzymes, amino acids, polysaccharides and organic compounds) that are "environmentally benign, yet chemically complex" and therefore serve as ideal tools for enhanced medicinal applications. It is reported that phytocompounds such as terpenoids, polysaccharides, polyols and flavones take part in the bio-reduction, stabilization and bio-capping mechanisms to form stable gold and silver NPs. Also the inhibitory potential of plant compounds against diabetic targets followed by a study of enzyme inhibitor kinetics, ligand binding dynamics supported by in silico docking studies that reveal the mode of bioactive compounds and their inhibitory activities. The present review focuses on the potential anticancer, antidiabetic and antimicrobial activity of phyto-synthesized gold and silver NPs. In phytonanotherapy, synergistic features of plant and metal NPs are unique as they offer healing properties that may be the clinical bioequivalent to many synthetic drugs, with minimal side effects. This could provide alternative treatment for chronic diseases that is efficient to overcome the disadvantages of synthetic monotherapy and allows medicinal plant therapy to co-exist with current synthetic treatments. This creates a much needed paradigm shift for further clinical studies in non-communicable and communicable diseases. PMID- 28709078 TI - Insomnia in people with epilepsy: A review of insomnia prevalence, risk factors and associations with epilepsy-related factors. AB - BACKGROUND: Insomnia is a common sleep complaint in the general population, and sleep loss may be a trigger for epileptic seizures. OBJECTIVES: To conduct a comprehensive review of the literature of insomnia symptoms and insomnia disorder, their prevalence and epilepsy-related risk factors in people with epilepsy (PWE). METHODS: A PUBMED search was performed for articles indexed to June 2016 involving human subjects, excluding papers in languages other than English, Spanish and Portuguese and case reports. Eligible studies were those using a clear definition of insomnia and reporting quantitative data on prevalence rates and risk factors. The search included the following terms: insomnia, sleep disorder(s), sleep disturbance(s) and sleep-wake in the title and abstract; and epilep* in the title. 425 papers were reviewed and 31 were selected for the final analysis (21 adult and 10 paediatric). Twenty-one studies used a control group. Two reviewer authors independently extracted all data and a third author resolved disagreements. RESULTS: Most studies were hospital-based, cross sectional and evaluated convenience samples representing highly select populations. Various insomnia inventories were used. Fourteen assessed insomnia (10 in adults, four, children), but only five as primary outcome (none in children). Four evaluated insomnia disorder based on international classification criteria (International Classification of Sleep Disorders - ICSD-2-in 3, and DSM IV-TR, in 1). In adults, insomnia prevalence was 28.9-51% based on the Insomnia Severity Index >=15 and 36-74.4% based on DSM-IV-TR or ICSD-2. The prevalence of insomnia in children was 13.1-31.5% using the Sleep Disturbance Scale for Children and 11% based on ICSD-2 diagnostic criteria. Compared to control groups, PWE usually had higher frequencies of insomnia symptoms and disorder. Insomnia was associated with greater impairment in quality of life and higher degree of depressive symptoms in several studies, and was inconsistently related to female gender, poor seizure control and antiepileptic drug polytherapy. In children, insomnia was associated with developmental delay, focal epilepsies and poor seizure control. CONCLUSION: Insomnia symptoms and insomnia disorder are highly prevalent among PWE based on a limited number of studies with variable inclusion criteria and methodology. Excessive daytime sleepiness (EDS) was not found to be related to insomnia disorder or symptoms, and the exclusion of individuals with EDS may explain the higher frequencies of insomnia found in some studies. Additional investigations are needed given the potential impact of insomnia on seizure control, mood and QOL in PWE. PMID- 28709079 TI - Breastfeeding initiation, duration and exclusivity in mothers with epilepsy from South West China. AB - PURPOSES: 1) To study the breastfeeding initiation, duration and exclusivity rates, and common reasons for early weaning in Chinese mothers with epilepsy (MWE); 2) To identify potential perinatal breastfeeding correlations with selected sociodemographic and clinical factors. METHODS: A semi-structured questionnaire was administered to 281 MWE attending hospitals in South-west China from February 2014 to July 2015. Data about breastfeeding behaviors, sociodemographic, obstetric, and epileptic variables were collected. Descriptive analyses, followed by univariate and multivariate logistic regression analyses, were utilized to examine associations with breastfeeding, its duration and exclusivity. RESULTS: Breastfeeding initiation rate in MWE was 59.4%. At 3 months post partum total breastfeeding rate was 49.5% and exclusive breastfeeding rate was 36.3%. At 6 months, about one third (33.1%) of MWE had continued breastfeeding their babies and 12.8% of enrolled infants were exclusively breastfed. During lactation, fear of exposure of the babies to antiepileptic drugs (AEDs) via breast milk, frequent seizures, and insufficient breast milk supply were the commonest reasons for early cessation of breastfeeding. Mothers with epilepsy who had babies delivered at full term were more inclined to breastfeed their babies. Mothers who had gestational non-active epilepsy were more likely to engage in long-term breastfeeding. AED polytherapy was associated with poor breastfeeding behaviors in all aspects. CONCLUSION: MWE in our study had a lower prevalence of breastfeeding than what would be expected in the general population, where approximately 95% breastfeed. Good seizure control and optimal antiepileptic therapy during gestation and lactation were associated with a higher rate of breastfeeding. Targeted intervention programs enhancing antenatal care services and breastfeeding consultation are needed. PMID- 28709080 TI - The relationship between the UPPS-P impulsive personality traits and substance use psychotherapy outcomes: A meta-analysis. AB - BACKGROUND: Although impulsive personality traits have been well implicated in substance use disorder (SUD) risk, little work has established how specific impulsive personality traits influence and are influenced by SUD psychotherapy outcomes. The purpose of this meta-analysis was to quantitatively review existing work to examine 1) how impulsive personality traits affect SUD psychotherapy outcomes and 2) reductions in impulsive personality traits during SUD psychotherapy. METHODS: Studies were identified by conducting a comprehensive review of the literature. RESULTS: For aim one (k=6), significant effects were found for lack of premeditation (g=0.60, SE=0.30, 95% CI 0.01-1.20; z=1.99, p=0.05) and negative urgency (g=0.55, SE=0.17, 95% CI 0.22-0.88, z=3.30, p=0.001), with trait scores related to poorer SUD psychotherapy outcomes. For aim two (k=10), decreases in sensation seeking (g=-0.10, SE=0.05, 95% CI -0.20 to 0.004; z=-1.88, p=0.02) and negative urgency (g=-0.25, SE=0.14, 95% CI -0.53 to 0.03; z=-1.75, p=0.03) during SUD psychotherapy were significant. CONCLUSIONS: Overall, our quantitative synthesis suggests that lack of premeditation and negative urgency are related to poorer SUD psychotherapy outcomes. Although negative urgency and sensation seeking are decreasing during SUD psychotherapy, the magnitude of the change is quite small. Overall, we suggest that the measurement and targeting of impulsive personality traits in psychotherapy has strong potential to improve clinical outcomes across SUDs and a wide range of clinical problems and disorders. PMID- 28709082 TI - The measurement of intensities in the Rotation Electron Diffraction Technique. AB - The Rotation Electron Diffraction Technique, recently developed at the University of Stockholm, has been used to acquire three-dimensional electron diffraction data. A mathematical expression to calculate the excitation errors, sg, is suggested by considering the diffraction geometry and the rotation axis. In order to plot the rocking curves, diffraction patterns taken from CoP3 cubic structure (a=7.708A, space group Im3-) are used as examples. Intensities of some reflections are derived by Multigauge software during the beam tilt series. Rocking curves for two Friedel pair reflections with different angles from the rotation axis are plotted. PMID- 28709081 TI - Experiences with SCRAMx alcohol monitoring technology in 100 alcohol treatment outpatients. AB - BACKGROUND: Transdermal alcohol monitoring technology allows for new research on alcohol use disorders. This study assessed feasibility, acceptability, and adherence with this technology in the context of two clinical research trials. METHODS: Participants were the first 100 community-based alcohol treatment outpatients enrolled in randomized studies that monitored drinking with the secure continuous remote alcohol monitor (SCRAMx(r)) for 12 weeks. Study 1 participants were randomized to usual care (n=36) or usual care with contingency management incentives for treatment attendance (CM-Att; n=30). Study 2 participants were randomized to usual care (n=17) or usual care with CM for each day of no drinking per SCRAMx (CM-Abst; n=17). After 12 weeks, participants completed a survey about the bracelet. RESULTS: Nine percent of individuals screened (54 of 595) declined participation because of the bracelet. Of participants, 84% provided 12weeks of data, and 96% of bracelets were returned fully intact. Ninety-four equipment tampers occurred, affecting 2% of monitoring days; 56% (67) of tampers coincided with detected drinking. Common concerns reported by participants were skin marks (58%), irritation (54%), and interfered with clothing choices (51%), but severity ratings were generally mild (60%-94%). Eighty-one percent of participants reported that the bracelet helped them reduce drinking, and 75% indicated that they would wear it for longer. A common suggestion for improvement was to reduce the size of the bracelet. CONCLUSIONS: Results support the viability of transdermal monitoring in voluntary substance abuse treatment participants for an extended duration. Issues to consider for future applications of this technology are discussed. PMID- 28709083 TI - The peculiar extra-acrosomal structure of the Collembola (Hexapoda) spermatozoa. AB - The springtail Collembola are characterized by having rolled spermatozoa, with a long cylindrical extracellular structure adhering to the acrosome. This structure is produced by the secretory activity of the testes epithelial cells at almost the end of spermiogenesis. At the beginning of its formation, it is a thin extension with a helical wall and a dense axial region. Later the cylindrical structure shows an inner organization which is different in the several species examined: species of Entomobryidae contain material with a paracrystalline structure, whilst some of Symphypleona contain ovoid structures. The outer envelope of the extracellular structure consists of two overlapped layers orthogonally arranged, clearly identified by cryo-preparations. Immunoblot analysis and lectin stainings have indicated that the cylindrical structure has a glycoproteic composition. As the structure is no longer visible after the sperm transfer into the female spermatheca, it is suggested that it could contain enzymes able to activate the sperm unwinding process and possibly allowing the reacquisition of sperm motility. PMID- 28709084 TI - Aberration measurement of the probe-forming system of an electron microscope using two-dimensional materials. AB - The geometric and chromatic aberration coefficients of the probe-forming system in an aberration corrected transmission electron microscope have been measured using a Ronchigram recorded from monolayer graphene. The geometric deformations within individual local angular sub-regions of the Ronchigram were analysed using an auto-correlation function and the aberration coefficients for the probe forming lens were calculated. This approach only requires the acquisition of a single Ronchigram allowing rapid measurement of the aberration coefficients. Moreover, the measurement precision for defocus and two-fold astigmatism is improved over that which can be achieved from analysis of Ronchigrams recorded from amorphous films. This technique can also be applied to aberration corrected STEM imaging of any hexagonal two-dimensional material. PMID- 28709085 TI - Amplification of electrochemical signal by a whole-cell redox reactivation module for ultrasensitive detection of pyocyanin. AB - A bioelectrochemical sensing system based on a novel whole-cell redox reactivation/cycling module for ultrasensitive detection of pyocyanin (the biomarker of Pseudomonas aeruginosa infections) was developed. The electroactive bacteria mediated redox reactivation module was constructed using Shewanella oneidensis MR-1 cells as the bioelectro-catalyst and lactate as the electron donor. It could regenerate reductive pyocyanin from its oxidative state, which enabled pyocyanin molecule repeatedly registered by the electrode. Uniquely, with this redox reactivation module, the electrochemical response of pyocyanin was amplified about 405 times (1.3 MUA/nM vs. 3.2nA/nM). Thus, an ultrasensitive bioelectrochemical sensing system for pyocyanin quantification was developed by integrating the pyocyanin reactivation module with conventional electrochemical detection system. Remarkably, with this developed biosensing system, an extremely low LOD of 47+/-1pM was reached. Additionally, this biosensing system showed excellent resistance to interferences from human fluids or bacterial contamination. This work provided a simple, ultrasensitive and robust tool for pyocyanin detection, and more importantly, demonstrated a new dimension for electrochemical signal amplification in biosensing. PMID- 28709086 TI - Sensitive detection of brucine an anti-metastatic drug for hepatocellular carcinoma at carbon nanotubes - nafion composite based biosensor. AB - A neoteric approach for the electrochemical analysis of brucine in biological environment has been developed. The glassy carbon electrode modified with single walled carbon nanotubes and nafion composite film is delineated for the first time to determine brucine employing square wave voltammetry. The quantification of brucine at physiological pH 7.2 manifests remarkable performance at the developed biosensor. The effect of several operational parameters has been studied in the present investigation. Under optimized conditions, a dynamic linear range from 1nM to 8uM with a high sensitivity of 340.8uAuM-1 and limit of detection corresponding to 0.11nM was achieved. The interfering effect of some coexisting metabolites on the current response of brucine has been reported. The method was successfully applied for the detection of brucine in traditional pharmaceutical formulations. The biological relevance of the present method has been demonstrated by the analysis of the alkaloid in human serum and urine samples. The analytical utility was further assessed by the selective determination of brucine in Strychnos nux-vomica seeds exhibiting considerable potential as a diagnostic tool. PMID- 28709087 TI - Novel electrochemiluminescence of silver nanoclusters fabricated on triplex DNA scaffolds for label-free detection of biothiols. AB - Electrochemiluminescence (ECL) of metal nanoclusters and their application have been widely reported due to the good biocompatibility, fascinating electrocatalytic activity and so on. Using DNA as synthesis template opens new opportunities to modulate the physical properties of AgNCs. Triplex DNA has been reported for the site-specific, homogeneous and highly stable silver nanoclusters (AgNCs) fabrication from our recent research. Here we further explore their extraordinary ECL properties and applications in biosensor utilization. By reasonable design of DNA sequence, AgNCs were obtained in the predefined position of CG.C+ sites of triplex DNA, and the ECL emission at a low potential was observed with this novel DNA template. Finally, a simple and label-free method was developed for biothiols detection based on the enhanced catalytic reaction and a robust interaction between the triplex-AgNCs and cysteine, by influencing the microenvironment provided by DNA template. PMID- 28709088 TI - Integrated amplified aptasensor with in-situ precise preparation of copper nanoclusters for ultrasensitive electrochemical detection of microRNA 21. AB - MicroRNA 21 (MIR21) has garnered much attention in recent years as an important disease biomarker. The detection of it in human system shows great significance for the healthy evaluation and major diseases early detection. Herein, a novel approach tactfully manipulates the in-situ precise preparation of copper nanoclusters on overlapping Y-shaped ds-DNA for MIR21 analysis were developed in the proposed integrated aptasensor. In the presence of target MIR21, overlapping Y-shaped ds-DNA was constructed on electrode. Copper nanoclusters were in-situ prepared on this effective template for target detection. Taking advantage of exonuclease T7 triggered targets recycling, hybridization chain reaction (HCR) and copper nanoclusters triple amplification strategy, linear detection of MIR21 was achieved from 10pM to 0.1fM with a detection limit down to 10aM (S/N > 3). This approach provides a good model for integrating both synthesis and detection into one electrochemistry component. It showed promising potential for applications in aptamer related target detection in human serum analysis. PMID- 28709089 TI - An electrochemical sensor for indole in plasma based on MWCNTs-chitosan modified screen-printed carbon electrode. AB - Indole is an essential metabolite in intestinal tract. The dysregulation of plasma indole concentration occurred in various diseases. In this study, the indole in plasma was determined directly using electrochemical sensor with multiwall carbon nanotubes-chitosan (MWCNTs-CS) modified screen-printed carbon electrode (SPCE). The electrochemical behavior of indole was elucidated by cyclic voltammetry (CV) and differential pulse voltammetry (DPV) on the MWCNTs-CS composites modified SPCE (MWCNTs-CS/SPCE). The results showed that the current responses of indole improved greatly due to the high catalytic activity and electron transfer reaction of nano-composites. Under the optimized conditions, the linear range of indole was from 5 to 100MUgL-1 with the detection limit of 0.5MUgL-1 (S/N = 3). This novel electrochemical sensor exhibited acceptable accuracies and precisions with the variations less than 7.3% and 9.0%, respectively. Furthermore, high performance liquid chromatography (HPLC) method was utilized to compare with the established electrochemical method for the determination of indole in plasma. The results showed a high correlation between the two methods. At last, the electrochemical sensor was successfully applied to detect the level of indole in plasma samples with satisfactory selectivity and sensitivity. The concentrations of plasma indole in healthy pregnant women and gestational diabetes mellitus (GDM) patients were 5.3 (4.1-7.0)MUgL-1 and 7.2 (4.5-9.4)MUgL-1, respectively. PMID- 28709090 TI - The presence of non-native species is not associated with native fish sensitivity to water pollution in greatly hydrologically altered rivers. AB - There is a risk of 'ecological surprises' if multiple potentially interacting stressors are managed individually, which is a question attracting significant current interest. Habitat degradation and species introductions are major threats to global biodiversity, and riverine fish are among the most threatened taxa in the world. Our interest was whether the presence of non-native species can affect native fish sensitivity to water quality deterioration in a large region in northeastern Spain (99,700km2, 15 catchments, 530 sites). We used a 'base model' with geographical and hydro-morphological variables, which are the major shaping factors in rivers. We tested whether water pollution, non-native species, or their interaction provided an improved understanding of patterns of distributions and health measurements of the twelve most common native species. There was little evidence that variation in native species abundance, where they occurred, the presence of diseases and changes in mean fish length or body condition was affected by water deterioration, the presence of non-native species, or their interaction. The disease rate and occurrence of native species might be affected, to a minor degree, by water quality changes and the presence of non-native species. Environmental conditions between sites with and without non-native fish differed in the condition of riparian areas and in water quality. Based on presence-absence data and changes in abundances through weighted average equations we also derived potential safe levels of salinization, nutrient pollution, and pH for the native fish. Overall, additive effects of stressors prevail over interactions, and the restoration of natural hydro-morphology in rivers is likely to be the most effective management approach to improving the prospects for the native fish fauna. PMID- 28709091 TI - Evaluating the photocatalytic treatment of stevioside by TiO2 in different aqueous matrices and identification of transformation products. AB - The present study reports the photocatalytic transformation of stevioside, under simulated solar irradiation using TiO2 as a photocatalyst. As a tool of investigating the effect of various aqueous matrices, as well as, the initial stevioside concentration on the variation of the photocatalytic efficiency, a fully nested experimental design was employed. A significant impact on the degradation rate of the sweetener was observed: degradation rate decreases in the order distilled water>river water>lake water, attributed to the increased natural organic matter content of the respective natural water samples. Moreover, the investigation has involved the identification of intermediate compounds, as well as the assessment of mineralization and toxicity evaluation. More than one hundred unknown transformation products, most of them in the form of several isobaric species, were identified. By employing accurate mass determination, we were able to attribute an empirical formula to each species and through MSn analyses we were capable to distinguish several isobaric species. The overall transformation mechanism was assessed and involved the hydroxylation/oxidation of the molecule and the subsequent loss of the glucose units bound to the parent compound. PMID- 28709092 TI - Exposure to benzophenones, parabens and triclosan among pregnant women in different trimesters. AB - Humans are potentially exposed to many environmental pollutants, many of which may cause adverse health effects, especially to pregnant women and their fetuses. In this study, 11 environmental pollutants from three different chemical classes, including benzophenones, parabens and triclosan were measured in 627 urine samples collected from 209 pregnant women to evaluate exposure and trends as a function of pregnancy stage. Methylparaben (MeP), ethylparaben, propylparaben (PrP), butylparaben, 2,4-dihydroxybenzophenone (BP-1), 2-hydroxy-4 methoxybenzophenone (BP-3) and 4-hydroxybenzophenone were detected in >50% samples. The concentrations of BP-1 and BP-3 (Spearman's r=0.57, p<0.01) and those of MeP and PrP (Spearman's r=0.68, p<0.01) were found to be correlated. The urinary concentrations of BP-1 and BP-3 in the first trimester were significantly higher than those in the second or third trimester (Mann-Whitney U test, p<0.05). These findings provide valuable information for improving the prediction of maternal exposure to these emerging pollutants and for assessing their potential health risks to the mother as well as the offspring. PMID- 28709093 TI - Evolutionary process of saline-water intrusion in Holocene and Late Pleistocene groundwater in southern Laizhou Bay. AB - Saline water intrusion is one of the most serious groundwater problems in southern Laizhou Bay. In this study, formation of groundwater with different qualities and saline water intrusion were analyzed using hydrochemical and stable isotopic methods, and the Hydrochemical Facies Evolution Diagram (HFE-Diagram). The results demonstrate that the structure of the sedimentary layer in this area is the dominant controlling factor of groundwater distribution. From the south (land) to the north (sea), the hydrochemical distribution presents a regular changing pattern following the order: HCO3-Na.Mg and HCO3.Cl-Mg.Ca (fresh water), HCO3.Cl-Na.Mg (brackish water), Cl-Na.Mg (saline water), Cl-Na (saline water) and Cl.HCO3-Na (brackish water). Hydrochemical data show that saline water and brine are not the result of evaporation or the concentration of seawater. Brackish water and saline water with low mineralization in Holocene groundwater are formed by the mixing of fresh water and highly mineralized saline water, dissolution of evaporates by meteoric water, and water/salt interaction. And the saline water formed through dissolution of evaporates in Holocene and Late Pleistocene groundwater. Isotopic results reveal that the main recharge of saline water in Holocene groundwater and Late Pleistocene groundwater is a combination of the meteoric water and lateral recharge from rivers. Saline water intrusion was found to follow a wedge-shaped intrusion pattern. Significant variations in Cl- and Na+indicate saline intrusion in the southern area. The degree of saline water intrusion in Holocene groundwater was found to be more serious than that in Late Pleistocene groundwater. Hydrochemical data and HFE-Diagram show that there is an intrusion process in Holocene groundwater. In this process, it is accepted the fresh water recharge, such as meteoric water and lateral recharge from rivers. In Late Pleistocene groundwater, it presents a simple intrusion process from saline water to fresh water. PMID- 28709094 TI - Fit-for-purpose wastewater treatment: Conceptualization to development of decision support tool (I). AB - This article is the first in a series of two papers. Paper I focuses on model conceptualization and development, and Paper II in the series focuses on model validation and implementation. The amount of water reuse has been increasing across the globe. Wastewater can be treated based on the intended end use of reclaimed water. Fit-for-purpose wastewater treatment (WWT) simultaneously considers intended end use, economic viability, and environmental sustainability. WWT technologies differ mainly in terms of treatment efficiency, cost, energy use, and associated carbon emissions. The planning and evaluation of water reuse projects requires a decision support tool (DST) to evaluate alternative WWT trains and water reuse applications. However, such a DST is not available in the publically accessible literature. A DST, FitWater, has been developed for the evaluation of WWT for various urban reuses. The evaluation is based on the following criteria: amount of reclaimed water production, health risk of water reuse, cost, energy use, and carbon emissions. The cost is estimated as annualized life cycle cost and health risk is estimated using quantitative microbial risk assessment. The uncertainty analysis has been performed using probabilistic and fuzzy-based methods. A multi-criteria decision analysis, using fuzzy weighted average, is employed to aggregate different criteria and generate a final score. FitWater ranks alternative WWT trains based on the resulting final score. The proposed FitWater DST is user-friendly, and its application is demonstrated using an example. The DST can be enhanced to include additional treatment technologies and carbon emissions of different treatment processes. PMID- 28709095 TI - Assessment of the effects of multiple extreme floods on flow and transport processes under competing flood protection and environmental management strategies. AB - Extreme floods are regarded as one of the most catastrophic natural hazards and can result in significant morphological changes induced by pronounced sediment erosion and deposition processes over the landscape. However, the effects of extreme floods of different return intervals on the floodplain and river channel morphological evolution with the associated sediment transport processes are not well explored. Furthermore, different basin management action plans, such as engineering structure modifications, may also greatly affect the flood inundation, sediment transport, solute transport and morphological processes within extreme flood events. In this study, a coupled two-dimensional hydrodynamic, sediment transport and morphological model is applied to evaluate the impact of different river and basin management strategies on the flood inundation, sediment transport dynamics and morphological changes within extreme flood events of different magnitudes. The 10-year, 50-year, 100-year and 200-year floods are evaluated for the Lower Cache Creek system in California under existing condition and a potential future modification scenario. Modeling results showed that select locations of flood inundation within the study area tend to experience larger inundation depth and more sediment is likely to be trapped in the study area under potential modification scenario. The proposed two dimensional flow and sediment transport modeling approach implemented with a variety of inflow conditions can provide guidance to decision-makers when considering implementation of potential modification plans, especially as they relate to competing management strategies of large water bodies, such as the modeling area in this study. PMID- 28709096 TI - Extensive green roof CO2 exchange and its seasonal variation quantified by eddy covariance measurements. AB - The CO2 surface-atmosphere exchange of an unirrigated, extensive green roof in Berlin, Germany was measured by means of the eddy covariance method over a full annual cycle. The present analysis focusses on the cumulative green roof net ecosystem exchange of CO2 (NEE), on its seasonal variation and on green roof physiological characteristics by applying a canopy (A-gs) model. The green roof was a carbon sink with an annual cumulative NEE of -313gCO2m-2year-1, equivalent to -85gCm-2year-1. Three established CO2 flux gap-filling methods were applied to estimate NEE and to study the performance during different meteorological situations. A best estimate NEE time series was established, which chooses the gap filling method with the highest performance. During dry periods daytime carbon uptake was shown to decline linearly with substrate moisture below a threshold of 0.05m3m-3, whereas night-time respiration was unaffected by substrate moisture variation. The roof turned into a temporary C source during dry conditions in summer 2015. We conclude that the carbon uptake of the present green roof can be optimized when substrate moisture is kept above 0.05m3m-3. PMID- 28709097 TI - Effects of land use and climate change on ecosystem services in Central Asia's arid regions: A case study in Altay Prefecture, China. AB - The sustainable use of ecosystem services (ES) can contribute to enhancing human well-being. Understanding the effects of land use and climate change on ES can provide scientific and targeted guidance for the sustainable use of ES. The objective of this study was to reveal the way in which land use and climate change influence the spatial and temporal variations of ES in the mountain-oasis desert system (MODS). In this study, we assessed water yield, soil conservation, crop production, and sand fixation in 1990, 2000, and 2010 in Altay Prefecture, which is representative of the MODS, based on widely used biophysical models. Moreover, we analyzed the effects of different land use and climate change conditions on ES. The results show that the area of forest and bare land decreased in Altay Prefecture. In contrast, the area of grassland with low coverage and cropland increased. The climate of this area presented an overall warming-wetting trend, with warming-drying and cooling-wetting phenomena in some areas. Soil conservation in the mountain zone, water yield in the oasis zone, and sand fixation in the desert zone all decreased under the influence of land use change alone. The warming-drying trend led to decreased water yield in the oasis zone and increased wind erosion in the desert zone. Based on the results, we recommend that local governments achieve sustainable use of ES by planting grasslands with high coverage in the oasis zone, increasing investment in agricultural science and technology, and establishing protected areas in the mountain and desert zones. The methodology in our study can also be applied to other regions with a MODS structure. PMID- 28709098 TI - Virtual Special Issue Preface: Forest Response to Environmental Stress: Impacts and Adaptation. PMID- 28709099 TI - Halide removal from waters by silver nanoparticles and hydrogen peroxide. AB - The objective of this study was to remove halides from waters by silver nanoparticles (AgNPs) and hydrogen peroxide (H2O2). The experimental parameters were optimized and the mechanism involved was also determined. The AgNP/H2O2 process proved efficacious for bromide and chloride removal from water through the selective precipitation of AgCl and AgBr on the AgNP surface. The optimal AgNP and H2O2 concentrations to be added to the solution were determined for the halide concentrations under study. The removal of Cl- and Br- anions was more effective at basic pH, reaching values of up to 100% for both ions. The formation of OH, O2-, radicals was detected during the oxidation of Ag(0) into Ag(I), determining the reaction mechanism as a function of solution pH. Moreover, the results obtained show that: i) the efficacy of the oxidation of Ag(0) into Ag(I) is higher at pH11, ii) AgNPs can be generated by the O2- radical formation, and iii) the presence of NaCl and dissolved organic matter (tannic acid [TAN]) on the solution matrix reduces the efficacy of bromide removal from the medium due to: i) precipitation of AgCl on the AgNP surface, and ii) the radical scavenger capacity of TAN. AgNPs exhausted can be regenerated by using UV or solar light, and toxicity test results show that AgNPs inhibit luminescence of Vibrio fischeri bacteria. PMID- 28709100 TI - Domestic well locations and populations served in the contiguous U.S.: 1990. AB - We estimate the location and population served by domestic wells in the contiguous United States in two ways: (1) the "Block Group Method" or BGM, uses data from the 1990 census, and (2) the "Road-Enhanced Method" or REM, refines the locations by using a buffer expansion and shrinkage technique along roadways to define areas where domestic wells exist. The fundamental assumption is that houses (and therefore domestic wells) are located near a named road. The results are presented as two nationally-consistent domestic-well population datasets. While both methods can be considered valid, the REM map is more precise in locating domestic wells; the REM map has a smaller amount of spatial bias (Type 1 and Type 2 errors nearly equal vs biased in Type 1), total error (10.9% vs 23.7%), and distance error (2.0km vs 2.7km), when comparing the REM and BGM maps to a calibration map in California. However, the BGM map is more inclusive of all potential locations for domestic wells. Independent domestic well datasets from the USGS, and the States of MN, NV, and TX show that the BGM captures about 5 to 10% more wells than the REM. One key difference between the BGM and the REM is the mapping of low density areas. The REM reduces areas mapped as low density by 57%, concentrating populations into denser regions. Therefore, if one is trying to capture all of the potential areas of domestic-well usage, then the BGM map may be more applicable. If location is more imperative, then the REM map is better at identifying areas of the landscape with the highest probability of finding a domestic well. Depending on the purpose of a study, a combination of both maps can be used. PMID- 28709101 TI - The impact of prenatal perfluoroalkyl substances exposure on neonatal and child growth. AB - BACKGROUND: Perfluoroalkyl substances (PFASs) are wildly distributed environmental pollutants. Laboratory mice exposed prenatally to PFASs develop smaller birth weight but are more likely to become obese in adulthood. The evidences in human studies are still inconclusive. METHODS: The participants were 429 mother-infant pairs from Taiwan Birth Panel Study. These children were followed serially and growth data were collected through face to face interviews and records in Child Healthcare Handbooks until 108months of age. The age specific z-scores for weight (WAZ), length/height (LAZ/HAZ) and BMI (BMIAZ) were calculated. PFASs in umbilical cord blood were analyzed by ultra-high-performance liquid chromatography/tandem mass spectrometry. RESULTS: At birth, perfluorooctyl sulfonate (PFOS) levels were negatively associated with weight and height [per ln unit: adjusted beta (95% confidence interval, CI)=-0.14 (-0.26, -0.01) for WAZ and -0.16 (-0.31, -0.02) for LAZ]. However, these adverse impacts diminished as children grow up. When stratified the analysis by gender, the effects of prenatal PFOS exposure were more obvious for girls especially during the time span of 6 to 12 and 12 to 24months of age [per ln unit: adjusted beta (95% CI)=-0.25 (-0.47, 0.04) and -0.24 (-0.41, -0.04) for WAZ, respectively; per ln unit: adjusted beta (95% CI)=-0.33 (-0.59, -0.08) and -0.25 (-0.45, -0.05) for BMIAZ, respectively]. Later in the period of 60 to 108months of age, positive association between prenatal PFOS exposure and girls' BMI was observed [per ln unit: adjusted beta (95% CI)=0.34 (0.007, 0.68) for BMIAZ]. There was little evidence in these data for a consistent association of perfluorooctanoic acid (PFOA) with any of the indicators. CONCLUSIONS: Our study had shown that higher prenatal PFOS exposure was associated with decreased fetal growth, but the effects were diminished as children grow up. Modest effect of gender specific manner was observed. PMID- 28709102 TI - Adsorption and degradation of 14C-bisphenol A in a soil trench. AB - Bisphenol A (BPA) has caused widespread concern among scholars as a result of its estrogenic toxicity. It exists mainly in natural waters, sediments, and soil, as well as sewage and wastewater sludge. Considering that BPA is a common environmental pollutant that is removed along with chemical oxygen demand (COD), nitrogen, and phosphorus in drainage treatment systems, it is important to research the fate of BPA in sewage treatment systems. In this research, laboratory batch experiments on soil degradation and adsorption were conducted with 14C-BPA, aiming to discuss the transport and degradation characteristics of BPA in both simulated facilities and a soil trench. Based on the experimental results, the Freundlich model could be applied to fit the isothermal adsorption curve of the BPA in soil. A low mobility characteristic of BPA was discovered. The mineralization rate of BPA was fast and that of the reaction showed small fluctuations. After degradation, 21.3 and 17.7% of the BPA groups (the experimental group treated with ammonia oxidase (AMO) inhibitor and the control group) were converted into 14CO2, respectively. This indicates that the nitrification and degradation of BPA had a certain competitive relationship. Besides, nitrification did not significantly affect the soil residue of BPA. Through the soil trench test, the average removal rate of BPA in the soil trench was 85.5%. 14CO2 was discharged via the mineralization of BPA, accounting for 2.5% of the initial input. BPA easily accumulated in the bottom soil of the soil trench. BPA and its metabolites in the effluent accounted for 14.5% of the initial dosage. The residual extractable BPA and its metabolites in the soil accounted for 51.3%, and the remaining part of the unextractable residue represented 19.8% of the initial radioactive dosage. PMID- 28709103 TI - End-user perspective of low-cost sensors for outdoor air pollution monitoring. AB - Low-cost sensor technology can potentially revolutionise the area of air pollution monitoring by providing high-density spatiotemporal pollution data. Such data can be utilised for supplementing traditional pollution monitoring, improving exposure estimates, and raising community awareness about air pollution. However, data quality remains a major concern that hinders the widespread adoption of low-cost sensor technology. Unreliable data may mislead unsuspecting users and potentially lead to alarming consequences such as reporting acceptable air pollutant levels when they are above the limits deemed safe for human health. This article provides scientific guidance to the end-users for effectively deploying low-cost sensors for monitoring air pollution and people's exposure, while ensuring reasonable data quality. We review the performance characteristics of several low-cost particle and gas monitoring sensors and provide recommendations to end-users for making proper sensor selection by summarizing the capabilities and limitations of such sensors. The challenges, best practices, and future outlook for effectively deploying low-cost sensors, and maintaining data quality are also discussed. For data quality assurance, a two-stage sensor calibration process is recommended, which includes laboratory calibration under controlled conditions by the manufacturer supplemented with routine calibration checks performed by the end-user under final deployment conditions. For large sensor networks where routine calibration checks are impractical, statistical techniques for data quality assurance should be utilised. Further advancements and adoption of sophisticated mathematical and statistical techniques for sensor calibration, fault detection, and data quality assurance can indeed help to realise the promised benefits of a low-cost air pollution sensor network. PMID- 28709104 TI - Biological attenuation of arsenic and iron in a continuous flow bioreactor treating acid mine drainage (AMD). AB - Passive water treatments based on biological attenuation can be effective for arsenic-rich acid mine drainage (AMD). However, the key factors driving the biological processes involved in this attenuation are not well-known. Here, the efficiency of arsenic (As) removal was investigated in a bench-scale continuous flow channel bioreactor treating As-rich AMD (~30-40 mg L-1). In this bioreactor, As removal proceeds via the formation of biogenic precipitates consisting of iron and arsenic-rich mineral phases encrusting a microbial biofilm. Ferrous iron (Fe(II)) oxidation and iron (Fe) and arsenic removal rates were monitored at two different water heights (4 and 25 mm) and with/without forced aeration. A maximum of 80% As removal was achieved within 500 min at the lowest water height. This operating condition promoted intense Fe(II) microbial oxidation and subsequent precipitation of As-bearing schwertmannite and amorphous ferric arsenate. Higher water height slowed down Fe(II) oxidation, Fe precipitation and As removal, in relation with limited oxygen transfer through the water column. The lower oxygen transfer at higher water height could be partly counteracted by aeration. The presence of an iridescent floating film that developed at the water surface was found to limit oxygen transfer to the water column and delayed Fe(II) oxidation, but did not affect As removal. The bacterial community structure in the biogenic precipitates in the bottom of the bioreactor differed from that of the inlet water and was influenced to some extent by water height and aeration. Although potential for microbial mediated As oxidation was revealed by the detection of aioA genes, removal of Fe and As was mainly attributable to microbial Fe oxidation activity. Increasing the proportion of dissolved As(V) in the inlet water improved As removal and favoured the formation of amorphous ferric arsenate over As-sorbed schwertmannite. This study proved the ability of this bioreactor system to treat extreme As concentrations and may serve in the design of future in-situ bioremediation system able to treat As-rich AMD. PMID- 28709105 TI - Fundamental mechanisms and reactions in non-catalytic subcritical hydrothermal processes: A review. AB - The management and disposal of solid waste is of increasing concern across the globe. Hydrothermal processing of sludge has been suggested as a promising solution to deal with the considerable amounts of sludge produced worldwide. Such a process not only degrades organic compounds and reduces waste volume, but also provides an opportunity to recover valuable substances. Hydrothermal processing comprises two main sub-processes: wet oxidation (WO) and thermal hydrolysis (TH), in which the formation of various free radicals results in the production of different intermediates. Volatile fatty acids (VFAs), especially acetic acid, are usually the main intermediates which remain as a by-product of the process. This paper aims to review the fundamental mechanism for hydrothermal processing of sludge, and the formation of different free radicals and intermediates therein. In addition, the proposed kinetic models for the two processes (WO and TH) from the literature are reviewed and the advantages and disadvantages of each model are outlined. The effect of mass transfer as a critical component of the design and development of the processes, which has been neglected in most of these proposed models, is also reviewed, and the effect of influencing parameters on the processes' controlling step (reaction or mass transfer) is discussed. PMID- 28709106 TI - Microcosms for evaluating microbial indicator persistence and mobilization in fluvial sediments during rainfall events. AB - Mediterranean rivers, which are subject to long, dry periods and heavy rainfall events, could be particularly useful for understanding future climate scenarios. This study generated microcosms that mimicked riverbank sediment resuspension into the water of a typical Mediterranean river as a consequence of heavy rainfall. The mobilization and inactivation of six fecal pollution indicators and microbial source tracking markers were evaluated. The T90 values in the sediments were: 4 days for sorbitol-fermenting Bifidobacterium, 11 days for culturable E. coli, 36 days for bacteriophages infecting Bacteroides thetaiotaomicron strain GA17 and more than 42 days for qPCR-detected E. coli, somatic coliphages and sulfite-reducing clostridia spores. Bacteriophages and bacteria showed different resuspension and sedimentation patterns. The data obtained could be used in predictive models to assess the effects of climate change on surface water quality. Pathogen mobilization into the water column poses a risk for humans, animals and the natural environment, and breaches the One Health approach. PMID- 28709107 TI - Efficient bacterial inactivation with Z-scheme AgI/Bi2MoO6 under visible light irradiation. AB - A novel Z-scheme AgI/Bi2MoO6 hybrid photocatalyst was fabricated via a solvothermal-precipitation approach to disinfect bacteria in water. Powder X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), scanning electron microscopic (SEM) equipped with energy-dispersive X-ray spectroscopy (EDX), high resolution transmission electron microscope (HRTEM), UV-vis diffuse reflectance spectra (DRS), as well as photoluminescence spectra (PL) were employed to characterize the fabricated photocatalyst. Due to the stronger redox potential and better separation of charge carriers induced by the Z-scheme structure, the optimal synthesized AgI/Bi2MoO6 exhibited excellent disinfection activity towards both Gram-negative strain Escherichia coli (E. coli) and Gram-positive strain Staphylococcus aureus (S. aureus) under visible light irradiation. 5.0 * 107 CFU mL-1 of E. coli and S. aureus cells were completely disinfected within 30 min and 90 min, respectively. Ag+ ions did not contribute to the disinfection activity, while active species including h+, O2-, e-, and H2O2 contributed to the cell inactivation. By changing the interaction force and being involved in the photocatalytic reactions, the common anions (Cl-, NO3-, SO42-, and H2PO4-) would affect the disinfection activity. Moreover, AgI/Bi2MoO6 exhibited effective disinfection activity in four consecutive reused cycles. Thus, AgI/Bi2MoO6 could be used as a promising photocatalyst for water disinfection. PMID- 28709108 TI - Vibrio parahaemolyticus- and V. alginolyticus-associated meningo-encephalitis in a bottlenose dolphin (Tursiops truncatus) from the Adriatic coast of Italy. AB - A case of Vibrio parahaemolyticus- and V. alginolyticus-associated meningo encephalitis in a bottlenose dolphin (Tursiops truncatus) found stranded along the Adriatic coast of Italy in 2016 is herein reported, along with a minireview on V. parahaemolyticus and V. alginolyticus infections in aquatic mammals. Macroscopically, two abscesses were found in the dolphin's forebrain, along with an extensive, bilateral, parasitic broncho-pneumonia. Histologically, a suppurative-to-pyogranulomatous meningo-encephalitis involved the brain but not the cerebellum. Microbiological investigations yielded isolation of V. parahaemolyticus and V. alginolyticus from the aforementioned abscesses and from the brain parenchyma, respectively, with simultaneous recovery of Shewanella algae from the heart and of Photobacterium damselae from a blowhole swab. Although V. parahaemolyticus and V. alginolyticus, which are widely distributed across marine ecosystems worldwide, likely played a role in the development of the suppurative meningo-encephalitis in this dolphin, we are not aware of previous isolations of any of these two bacteria neither from cetacean brain lesions, nor from abscesses in aquatic mammals. PMID- 28709109 TI - No arousal-biased competition in focused visuospatial attention. AB - Arousal sometimes enhances and sometimes impairs perception and memory. A recent theory attempts to reconcile these findings by proposing that arousal amplifies the competition between stimulus representations, strengthening already strong representations and weakening already weak representations. Here, we report a stringent test of this arousal-biased competition theory in the context of focused visuospatial attention. Participants were required to identify a briefly presented target in the context of multiple distractors, which varied in the degree to which they competed for representation with the target, as revealed by psychophysics. We manipulated arousal using emotionally arousing pictures (Experiment 1), alerting tones (Experiment 2) and white-noise stimulation (Experiment 3), and validated these manipulations with electroencephalography and pupillometry. In none of the experiments did we find evidence that arousal modulated the effect of distractor competition on the accuracy of target identification. Bayesian statistics revealed moderate to strong evidence against arousal-biased competition. Modeling of the psychophysical data based on Bundesen's (1990) theory of visual attention corroborated the conclusion that arousal does not bias competition in focused visuospatial attention. PMID- 28709110 TI - A full Bayesian approach to appraise the safety effects of pedestrian countdown signals to drivers. AB - Although they are meant for pedestrians, pedestrian countdown signals (PCSs) give cues to drivers about the length of the remaining green phase, hence affecting drivers' behavior at intersections. This study focuses on the evaluation of the safety effectiveness of PCSs to drivers, in the cities of Jacksonville and Gainesville, Florida, using crash modification factors (CMFs) and crash modification functions (CMFunctions). A full Bayes (FB) before-and-after with comparison group method was used to quantify the safety impacts of PCSs to drivers. The CMFs were established for distinctive categories of crashes based on crash type (rear-end and angle collisions) and severity level (total, fatal and injury (FI), and property damage only (PDO) collisions). The CMFs findings indicated that installing PCSs result in a significant improvement of drivers' safety, at a 95% Bayesian credible interval (BCI), for total, PDO, and rear-end collisions. The results of FI and angle crashes were not significant. The CMFunctions indicate that the treatment effectiveness varies considerably with post-treatment time and traffic volume. Nevertheless, the CMFs on rear-end crashes are observed to decline with post-treatment time. In summary, the results suggest the usefulness of PCSs for drivers. The findings of this study may prompt a need for a broader research to investigate the need to design PCSs that will serve the purpose not only of pedestrians, but drivers as well. PMID- 28709111 TI - Genome-wide identification of 52 cytochrome P450 (CYP) genes in the copepod Tigriopus japonicus and their B[alpha]P-induced expression patterns. AB - Cytochrome P450s (CYPs) are enzymes with a heme-binding domain that are found in all living organisms. CYP enzymes have important roles associated with detoxification of xenobiotics and endogenous compounds (e.g. steroids, fatty acids, and hormones). Although CYP enzymes have been reported in several invertebrates, including insects, little is known about copepod CYPs. Here, we identified the entire repertoire of CYP genes (n=52) from whole genome and transcriptome sequences of the benthic copepod Tigriopus japonicus, including a tandem duplication (CYP3026A3, CYP3026A4, CYP3026A5), and examined patterns of gene expression over various developmental stages and in response to benzo[alpha]pyrene (B[alpha]P) exposure. Through phylogenetic analysis, the 52 T. japonicus CYP genes were assigned to five distinct clans: CYP2 (22 genes), CYP3 (19 genes), CYP4 (two genes), CYP20 (one gene), and mitochondrial (eight genes). Developmental stage and gender-specific expression patterns of the 52 T. japonicus CYPs were analyzed. CYP3022A1 was constitutively expressed during all developmental stages. CYP genes in clans 2 and 3 were induced in response to B[alpha]P, suggesting that these differentially modulated CYP transcripts are likely involved in defense against exposure to B[alpha]P and other pollutants. This study enhances our understanding of the repertoire of CYP genes in copepods and of their potential role in development and detoxification in copepods. PMID- 28709112 TI - Mens inversus in corpore inverso? Language lateralization in a boy with situs inversus totalis. AB - Situs inversus totalis is a rare condition where the visceral organs are organized as a mirror image of default organ position. In this study we picture the co-development between brain and visceral organs in a case of situs inversus totalis from a fetal stage to adolescence and compare our findings to an age-, gender-, and education-matched control with normal position of thoracic and abdominal organs. We show that in this case of situs inversus, functional and structural brain lateralization do not coincide with visceral organ situs. Furthermore, cognitive development in situs inversus is normal. To our knowledge, this is the first report of antenatal cerebral origins of structural and functional brain asymmetry in a case of situs inversus totalis. PMID- 28709114 TI - Isolated pachymeningeal metastasis from breast cancer: Clinical features and prognostic factors. AB - PURPOSE: To evaluate the clinical features and prognoses of patients with isolated pachymeningeal metastasis (IPM) from breast cancer. METHODS: We reviewed the medical records of all patients with metastatic breast cancer (MBC) treated from January 2009 to August 2016. Eligibility criteria included diagnosis of pachymeningeal metastasis based on brain magnetic resonance imaging and histologic diagnosis of primary breast cancer. We excluded patients with concomitant parenchymal or leptomeningeal metastases. RESULTS: Thirty-eight patients who matched our inclusion criteria were included in this study. The incidence of IPM in breast cancer was 1.5% of all patients with MBC. The molecular subtype distribution was: triple negative, 29.0%; ER+/HER2-, 44.7%; ER+/HER2+, 18.4%; and ER-/HER2+, 7.9%. All isolated pachymeningeal involvement resulted from the direct extension of skull metastases. The median time to IPM from systemic metastasis was 28.6 (95% CI: 23.6-33.6) months. The median time to IPM from skull metastasis was 5.2 (95% CI: 0-10.9) months. The median overall survival (OS) from IPM was 4.0 (95% CI: 2.5-5.5) months. In patients who received chemotherapy the OS was longer than for those who received radiotherapy or supportive care only [median OS 8.9 (95% CI: 0.0-18.4), 2.8 (95% CI: 0.5-5.0), and 0.8 (95% CI: 0.6-1.1) months, respectively (p = 0.006)]. Multivariate analysis revealed that good performance status and chemotherapy were associated with better survival outcomes. CONCLUSION: Stratified evaluation is required for patients with skull metastasis from breast cancer, as pachymeningeal involvement can develop and be associated with unsuspected outcomes. PMID- 28709115 TI - Development and validation of the Korea Dementia Comorbidity Index (KDCI): A nationwide population-based cohort study from 2002 to 2013. AB - This study develop and validate a simple and accessible measure of comorbidity, named the Korean Dementia Comorbidity index (KDCI), to assist in predicting the onset of dementia. This study used the National Health Insurance Service-Cohort Sample Database from 2002 to 2013 (n=23,856). Cox proportional hazard model was used to estimate incident dementia (International Classification of Disease, 10th edition (ICD-10) codes: F00-F03, G30, G311), with a hazard ratio higher than 1.05 for each comorbid condition being assigned a score. Scores ranging from 1 to 4 were assigned based on the magnitude of the hazard ratio (HR): 1 (1.050<=HR<=1.099), 2 (1.100<=HR<=1.149), 3 (1.150<=HR<=1.199), and 4 (HR>=1.200) Summated scores of comorbidities for each individual constituted the Korean Dementia Comorbidity Index (KDCI). Five patterns were extracted: (1) disease of the eye and adnexa; (2) endocrine and metabolic disease, and disease of circulatory system; (3) disease of the musculoskeletal system and connective tissue; (4) disease of the respiratory system; and (5) disease of the nervous system, and mental and behavioral disorders through factor analysis. Fitting performance by Akaike information criterion (AIC) of CCI by Charlson, CCI by Quan and KDCI adjusting for age and sex was 29,486, 29,488 and 29,444, respectively. Our analysis results on discriminatory abilities provided evidence that KDCI is superior to other comorbidity indices on incident dementia in terms of comorbidity adjustment. Therefore, KDCI can be a useful tool to identify incident dementia. This has implications for clinical management of patients with multimorbidity as well as risk adjustment for database studies. PMID- 28709113 TI - Reprogramming cellular functions with engineered membrane proteins. AB - Taking inspiration from Nature, synthetic biology utilizes and modifies biological components to expand the range of biological functions for engineering new practical devices and therapeutics. While early breakthroughs mainly concerned the design of gene circuits, recent efforts have focused on engineering signaling pathways to reprogram cellular functions. Since signal transduction across cell membranes initiates and controls intracellular signaling, membrane receptors have been targeted by diverse protein engineering approaches despite limited mechanistic understanding of their function. The modular architecture of several receptor families has enabled the empirical construction of chimeric receptors combining domains from distinct native receptors which have found successful immunotherapeutic applications. Meanwhile, progress in membrane protein structure determination, computational modeling and rational design promise to foster the engineering of a broader range of membrane receptor functions. Marrying empirical and rational membrane protein engineering approaches should enable the reprogramming of cells with widely diverse fine tuned functions. PMID- 28709116 TI - Morbidity persistence and comorbidity of mood, anxiety, and eating disorders among preoperative bariatric patients. AB - The current study investigates the patterns of disease persistence and comorbidity of psychiatric disorders among patients with class III obesity in pre operative period. For 393 treatment-seeking patients with severe obesity recruited from a bariatric center, we ascertained their psychiatric diagnosis through Structured Clinical Interview for DSM-IV (SCID-I). Following, the frequency, persistence and comorbidity pattern of psychiatric disorders in this sample were determined. Current psychiatric disorders were observed in over half of patients during preoperative period, being anxiety disorders the most frequent diagnosis. For lifetime disorders, mood disorders were the most frequent diagnosis. Most of the sample presented 2 or more concurrent lifetime psychiatric disorders. While mood and eating disorders were frequent conditions, anxiety disorders were the most persistent conditions (the highest one month-to-lifetime prevalence ratio) and were significantly correlated with bipolar, depressive and eating disorders. Psychiatric disorders are frequent and enduring conditions among patients looking for bariatric surgery. Comorbid anxiety, mood, and eating disorders are remarkable features in treatment-seeking patients with obesity. Prognostic implications of preoperative psychiatric disorders on surgery outcome should be demonstrated prospectively in intervention studies. PMID- 28709117 TI - Increased risk of bipolar disorder in patients with scabies: A nationwide population-based matched-cohort study. AB - Both scabies and bipolar disorder (BD) are common and troublesome disorders. There are several similarities in both diseases: pruritus, a higher prevalence in crowded environments, and cytokine-mediated inflammatory processes in the pathophysiology. We conducted this nationwide population-based study to investigate the possible relationship between scabies and BD. Based on the National Health Insurance Research Database (NHIRD) of Taiwan, a total of 7096 patients with scabies were identified as a study group and 28,375 matched patients as a control. We tracked the patients in both groups for a 7-year period to identify those newly diagnosed with BD. The demographic characteristics and comorbidities of the patients were analyzed, and Cox proportional hazard regressions were performed to calculate the hazard ratio (HR) of BD. Of the 35,471 patients in this study, 183 (0.5%) patients with newly diagnosed BD were identified, with 58 (0.8%) from the scabies group and 125 (0.4%) from the control group. The patients with scabies had a higher risk of subsequent BD, with a crude hazard ratio of 1.86 and an adjusted hazard ratio of 1.55 (95% confidence interval: 1.12-2.09, P < 0.05). This study shows there is an increased risk for BD among patients with scabies. Immunopathology may contribute to this association. PMID- 28709118 TI - Combat exposure and pain in male and female Afghanistan and Iraq veterans: The role of mediators and moderators. AB - Veterans experience physical health problems associated with disability and poor quality of life following combat exposure (CE). Understanding the CE-physical health relationship, specifically pain intensity and somatic pain, may inform etiological models and interventions. This study examined the CE-pain relationship, associated mediators, and gender as a moderator. 2381 veterans at the VA San Diego Healthcare System completed paper or electronic self-report measures of pain intensity and somatic pain. Analyses examined associations of pain with CE and posttraumatic stress disorder (PTSD), depression, and resilience as mediators of the CE-pain association. Moderated mediation models explored gender as a moderator of significant mediated pathways. Controlling for age, veterans with CE had significantly higher pain intensity and somatic pain, and PTSD and depression scores significantly mediated the CE-pain relationships. Gender significantly moderated the CE-pain intensity association through depression scores such that the indirect effect was stronger for female veterans relative to male veterans. CE is associated with pain intensity and somatic pain, with greater levels of PTSD and depression mediating the CE-pain link and gender moderating the depression mediated CE-pain association. Future studies should examine gender differences and mediators in the CE-pain relationships using longitudinal designs to inform etiological models and targeted pain interventions. PMID- 28709119 TI - A compensating income variation approach to valuing 34 health conditions in Iceland. AB - Using data from an Icelandic health-and-lifestyle survey carried out in 2007, 2009, and 2012, we employ a compensating income variation (CIV) approach to estimate the monetary value sufficient to compensate individuals for the presence of various sub-optimal health conditions. This method is inexpensive and easy on subjects and has been applied to several desiderata that do not have revealed market prices. The CIV literature is, however, still limited in its application to health and thus information about its suitability is limited. With the aim of shedding light on the methods appropriateness we thus provide a broad-view analysis including a spectrum of diseases and conditions that can be held up against more traditionally used methods. CIV for physical conditions vary greatly, but paralysis, fibromyalgia, chronic back pain, rheumatoid arthritis, urinary incontinence, severe headache and thyroid disease were among those consistently associated with substantial well-being reductions. Mental-health results using this method should be read with caution. The societal value of health interventions is multidimensional, including for example increased productivity in the population. However, one of the main positive aspects of increased health is undoubtedly the increased well-being of the treated subjects. Such quality-of-life effects should thus preferably be taken into account. For this reason, information on the value individuals place on recovery from various sub-optimal health conditions is useful when it comes to prioritizing scarce capital in the health sector. It is therefore vital to estimate the importance individuals place on various health states and hold them up against each other. Furthermore, this paper has scientific value as it sheds light on attributes of a potentially useful method in health evaluations. PMID- 28709120 TI - Advances in design of protein folds and assemblies. AB - Conceptual and computational advances triggered an explosion of designed protein structures in the recent years. Various protein fold geometries have been robustly designed with atomic accuracy, including protein folds unseen in nature. The same principles and tools have been extended to design multi-chain assemblies. By exploiting symmetry, mega-Dalton structures have been created with exciting potential applications for synthetic biology. In this review we focus on design of single chain and multi polypeptide chain assemblies of defined size and composition. Several innovative strategies have been developed to create de novo protein assemblies, with the two main approaches to the design of multi-chain assemblies being genetic fusion of interacting modules and engineering of novel protein-protein interfaces. PMID- 28709121 TI - Spatiotemporal propagation patterns of generalized ictal spikes in childhood absence epilepsy. AB - OBJECTIVE: This work investigates the spatial distribution in time of generalized ictal spikes in the typical absences of childhood absence epilepsy (CAE). METHODS: We studied twelve children with CAE, who had more than two typical absences during their routine video-EEG. Seizures were identified, and ictal spikes were marked over the maximum electronegative peak, clustered, waveform averaged and spatiotemporaly analyzed in 2D electrode space. RESULTS: Consistency of spatiotemporal patterns of ictal spikes was high between the absences of the same child, but low between children. Three main discharge patterns were identified: of anterio-posterior propagation, of posterio-anterior propagation and confined to the frontal/prefrontal regions. In 4 patients, the propagation patterns transformed during the seizure into either a lateralized diminished or a non-lateralized reverse direction form. Most spikes originated fronto-temporaly, all maximized over the frontal/prefrontal electrodes and mostly decayed prefrontaly. In 4 patients, lateralized propagation patterns were identified. CONCLUSIONS: Ictal spike propagation patterns suggest that epileptogenic CAE networks are personalized, interconnect distal areas in the brain - not the entire cortex - with a tendency to generate bilateral symmetrical discharges, sometimes unsuccessfully. The transformation of propagation patterns during the seizure indicates the existence of dynamic interplay within epileptogenic networks. SIGNIFICANCE: Our results support the revised concept of ictogenesis of ILAE definition in genetic (also known as idiopathic) generalized epilepsies. Understanding the focal features in CAE avoids misdiagnosis as focal epilepsy and inappropriate treatment. PMID- 28709122 TI - TMS-evoked long-lasting artefacts: A new adaptive algorithm for EEG signal correction. AB - OBJECTIVE: During EEG the discharge of TMS generates a long-lasting decay artefact (DA) that makes the analysis of TMS-evoked potentials (TEPs) difficult. Our aim was twofold: (1) to describe how the DA affects the recorded EEG and (2) to develop a new adaptive detrend algorithm (ADA) able to correct the DA. METHODS: We performed two experiments testing 50 healthy volunteers. In experiment 1, we tested the efficacy of ADA by comparing it with two commonly used independent component analysis (ICA) algorithms. In experiment 2, we further investigated the efficiency of ADA and the impact of the DA evoked from TMS over frontal, motor and parietal areas. RESULTS: Our results demonstrated that (1) the DA affected the EEG signal in the spatiotemporal domain; (2) ADA was able to completely remove the DA without affecting the TEP waveforms; (3). ICA corrections produced significant changes in peak-to-peak TEP amplitude. CONCLUSIONS: ADA is a reliable solution for the DA correction, especially considering that (1) it does not affect physiological responses; (2) it is completely data-driven and (3) its effectiveness does not depend on the characteristics of the artefact and on the number of recording electrodes. SIGNIFICANCE: We proposed a new reliable algorithm of correction for long-lasting TMS-EEG artifacts. PMID- 28709123 TI - Subclinical white matter lesions and medial temporal lobe atrophy are associated with EEG slowing in a memory clinic cohort. AB - OBJECTIVE: The aim of the study was to describe the relationship between electroencephalographic (EEG) findings obtained by standardized visual analysis, subclinical white matter lesions (WML) and brain atrophy in a large memory clinic population. METHODS: Patients with Alzheimer's disease (AD, n=58), mild cognitive impairment (MCI, n=141), subjective cognitive impairment (SCI, n=194) had clinical, MRI based WML severity and regional atrophy assessments, and routine resting EEG recording. Background activity (BA) and episodic and continuous abnormalities were assessed visually in EEG. RESULTS: WML (p=0.006) and atrophy in medial temporal regions (MTA) (p=<0.001) were associated with slower BA in all diagnoses. WML were associated in SCI with total episodic EEG abnormalities (p=0.03). CONCLUSIONS: EEG is associated with subclinical WML burden and cortical brain atrophy in a memory clinic population. SIGNIFICANCE: Even the standard visually assessed EEG can complement a memory clinic diagnostic workup. PMID- 28709124 TI - We could predict good responders to vagus nerve stimulation: A surrogate marker by slow cortical potential shift. AB - OBJECTIVE: We investigated whether vagus nerve stimulation (VNS) induces a positive shift of slow cortical potentials (SCPs) in patients with >50% seizure reduction (responders) but not in non-responders. METHODS: We analyzed routine clinical electroencephalograms (EEGs) from 24 patients who were undergoing seizure treatment by VNS. The patients were divided into 2 groups by hardware time constant (TC) of EEG: the TC 10-s group (10 patients) and TC 2-s group (14 patients). We compared SCPs at 5 electrodes (Cz and adjacent ones) between the 2 states of VNS: during stimulation and between stimulations. Seizure reduction was independently judged. Correlation between SCP (positivity or not) and seizure reduction (>50% or not) was estimated. RESULTS: In the TC 10-s group, the correlation between SCP and seizure reduction was significant (p<0.05) (i.e., both good results in 4 and both negative results in 5). In TC 2-s group, the correlation between SCP and seizure reduction was not significant (p=0.209). CONCLUSIONS: A positive shift of SCP recorded by using a TC of 10s could be a surrogate marker for VNS response. SIGNIFICANCE: SCP could be a biomarker of good responders to VNS. PMID- 28709125 TI - Ciprofloxacin-nitroxide hybrids with potential for biofilm control. AB - As bacterial biofilms display extreme tolerance to conventional antibiotic treatments, it has become imperative to develop new antibacterial strategies with alternative mechanisms of action. Herein, we report the synthesis of a series of ciprofloxacin-nitroxide conjugates and their corresponding methoxyamine derivatives in high yield. This was achieved by linking various nitroxides or methoxyamines to the secondary amine of the piperazine ring of ciprofloxacin using amide bond coupling. Biological evaluation of the prepared compounds on preformed P. aeruginosa biofilms in flow cells revealed substantial dispersal with ciprofloxacin-nitroxide hybrid 25, and virtually complete killing and removal (94%) of established biofilms in the presence of ciprofloxacin-nitroxide hybrid 27. Compounds 25-28 were shown to be non-toxic in both human embryonic kidney 293 (HEK 293) cells and human muscle rhabdomyosarcoma (RD) cells at concentrations up to 40 MUM. Significantly, these hybrids demonstrate the potential of antimicrobial-nitroxide agents to overcome the resistance of biofilms to antimicrobials via stimulation of biofilm dispersal or through direct cell killing. PMID- 28709126 TI - Effects of increasing temperature alone and combined with copper exposure on biochemical and physiological parameters in the zooxanthellate scleractinian coral Mussismilia harttii. AB - Effects of increasing temperature alone and in combination with exposure to dissolved copper (Cu) were evaluated in the zooxanthellate scleractinian coral Mussismilia harttii using a marine mesocosm system. Endpoints analyzed included parameters involved in metabolism [maximum photosynthetic capacity of zooxanthellae (Fv/Fm), chlorophyll a and ATP concentrations], calcification [carbonic anhydrase (CA) and Ca2+-Mg2+-ATPase activity], and oxidative status [antioxidant capacity against peroxyl radicals (ACAP) and lipid peroxidation (LPO)]. Coral polyps were collected, acclimated and exposed to three increasing temperature conditions [25.0+/-0.1 degrees C (control; average temperature of local seawater), 26.6+/-0.1 degrees C and 27.3+/-0.1 degrees C] using a marine mesocosm system. They were tested alone and in combination with four environmentally relevant concentrations of dissolved Cu in seawater [2.9+/-0.7 (control; average concentration in local seawater), 3.8+/-0.8, 5.4+/-0.9 and 8.6+/-0.3MUg/L] for 4, 8 and 12days. Fv/Fm reduced over the experimental period with increasing temperature. Combination of increasing temperature with Cu exposure enhanced this effect. CA and Ca2+-Mg2+-ATPase activities increased up to 8days of exposure, but recovered back after 12days of experiment. Short-term exposure to increasing temperature or long-term exposure to the combination of stressors reduced LPO, suggesting the occurrence of a remodeling process in the lipid composition of biological membranes. ACAP, ATP and chlorophyll a were not significantly affected by the stressors. These findings indicate that increasing temperature combined with exposure to dissolved Cu increase susceptibility to bleaching and reduce growth in the zooxanthellate scleractinian coral M. harttii. PMID- 28709127 TI - Chemometrically assisted development and validation of LC-MS/MS method for the analysis of potential genotoxic impurities in meropenem active pharmaceutical ingredient. AB - A sensitive Liquid Chromatography tandem mass spectrometry (LC-MS/MS) method was developed and validated for the quantitative analysis of three potential genotoxic impurities (318BP, M9, S5) in meropenem Active Pharmaceutical Ingredient (API). Due to the requirement for LOD values in ppb range, a high concentration of meropenem API (30mg/mL) had to be injected. Therefore, efficient determination of meropenem from its impurities became a critical aim of this study, in order to divert meropenem to waste, via a switching valve. After the selection of the important factors affecting analytes' elution, a Box-Behnken design was utilized to set the plan of experiments conducted with UV detector. As responses, the separation factor s between the last eluting impurity and meropenem, as well as meropenem retention factor k were used. Grid point search methodology was implemented aiming to obtain the optimal conditions that simultaneously comply to the conflicted criteria. Optimal mobile phase consisted of ACN, methanol and 0.09% HCOOH at a ratio 71/3.5/15.5v/v. All impurities and internal standard omeprazole were eluted before 7.5min and at 8.0min the eluents were directed to waste. The protocol was transferred to LC-MS/MS and validated according to ICH guidelines. PMID- 28709128 TI - Identification and interconversion of isomeric 4,5-functionalized 1,2,3 thiadiazoles and 1,2,3-triazoles in conditions of electrospray ionization. AB - 1,2,3-Triazoles and 1,2,3-thiadiazoles have been receiving permanent interest due to their exciting chemical reactivity and interesting biological properties including antibacterial, anticancer and antiviral activities. There are four compounds bearing 1H-1,2,3-triazole core in clinical studies which may appear in the market of drugs in nearest future. Definitely reliable methods of their identification and quantification should be developed by that time. Mass spectrometry showed itself as the most reliable method of analysis when dealing with trace levels of organic compounds in the mixtures and in the most complex matrices, including biological ones. In the present study tandem mass spectrometry was used to study fragmentation pathways of protonated and deprotonated molecules of isomeric 4,5-functionalized 1,2,3-thiadiazoles and 1,2,3-triazoles in conditions of electrospray ionization (ESI). A group of marker ions allowing differentiation between the targeted isomeric compounds was established. Besides, interconversion of these isomers into one another was studied in the gas phase in conditions mimicking these processes in solution. PMID- 28709129 TI - Dissolution assessment of allopurinol immediate release tablets by near infrared spectroscopy. AB - The purpose of this study was to develop a NIR spectroscopic method for assessment of drug dissolution from allopurinol immediate release tablets. Thirty three different batches of allopurinol immediate release tablets containing constant amount of the active ingredient, but varying in excipients content and physical properties were introduced in a PLS calibration model. Correlating allopurinol dissolution reference values measured by the routinely used UV/Vis method, with the data extracted from the NIR spectra, values of correlation coefficient, bias, slope, residual prediction determination and root mean square error of prediction (0.9632, 0.328%, 1.001, 3.58, 3.75%) were evaluated. The obtained values implied that the NIR diffuse reflectance spectroscopy could serve as a faster and simpler alternative to the conventional dissolution procedure, even for the tablets with a very fast dissolution rate (>85% in 15minutes). Apart from the possibility of prediction of the allopurinol dissolution rate, the other multivariate technique, PCA, provided additional data on the non-chemical characteristics of the product, which could not be obtained from the reference dissolution values. Analysis on an independent set of samples confirmed that a difference between the UV/Vis reference method and the proposed NIR method was not significant. According to the presented results, the proposed NIR method may be suitable for practical application in routine analysis and for continuously monitoring the product's chemical and physical properties responsible for expected quality. PMID- 28709130 TI - Bacterial adhesins, the pathogenic weapons to trick host defense arsenal. AB - Adhesins are bacterial proteins with host cell adhesive properties. These proteins occur in diverse architectures, ranging from capsules, vesicles, pili, fimbri, to enzymes. These proteins interact with host cell surface receptor proteins, for cross-membrane- trafficking and the invasion of host cells. Thus, they lead to inflammation and pathogenesis, of chronic as well as acute type. Inhibition of adhesin-mediated immune activation can be possible by mannose supplementation, assembly disruption, and host receptor blockage, among other approaches. Almost all bacterial pathogenesis is mediated by adhesins, yet when elaborated by normal flora, they might also be important for the exclusion of pathogens. For their ubiquity in bacterial pathogenesis, these lectin-like virulence proteins have been drug targets and vaccine components. Adhesins hold the clue for bacterial persistence and drug resistance as well, which can be detected through the annotation of hypothetical genes, the coding genes with sparsely-characterized functionality. This work takes a unique perspective on adhesins for better management of infectious diseases. PMID- 28709131 TI - Tiron ameliorates oxidative stress and inflammation in titanium dioxide nanoparticles induced nephrotoxicity of male rats. AB - Although the widespread use of titanium dioxide nanoparticles (TiO2 NPs), few studies were conducted on its hazard influence on human health. Tiron a synthetic vitamin E analog was proven to be a mitochondrial targeting antioxidant. The current investigation was performed to assess the efficacy of tiron against TiO2 NPs induced nephrotoxicity. Eighty adult male rats divided into four different groups were used: group I was the control, group II received TiO2 NPs (100mg?Kg BW), group III received TiO2 NPs plus tiron (470mg?kg BW), and group IV received tiron alone. Urea, creatinine and total protein concentrations were measured in serum to assess the renal function. Antioxidant status was estimated by determining the activities of glutathione peroxidase, superoxide dismutase, malondialdehyde (MDA) level and glutathione concentration in renal tissue. As well as Renal fibrosis was evaluated though measuring of transforming growth factor-beta1 (TGFbeta1) and matrix metalloproteinase 9 (MMP9) expression levels and histopathological examination. TiO2 NPs treated rats showed marked elevation of renal indices, depletion of renal antioxidant enzymes with marked increase in MDA concentration as well as significant up-regulation in fibrotic biomarkers TGFbeta1 and MMP9. Oral administration of tiron to TiO2 NPs treated rats significantly attenuate the renal dysfunction through decreasing of renal indices, increasing of antioxidant enzymes activities, down-regulate the expression of fibrotic genes and improving the histopathological picture for renal tissue. In conclusion, tiron was proved to attenuate the nephrotoxicity induced by TiO2 NPs through its radical scavenging and metal chelating potency. PMID- 28709133 TI - Exhaustive rotamer search of the 4C1 conformation of alpha- and beta-d galactopyranose. AB - An exhaustive search approach was used to establish all possible rotamers of alpha- and beta-d-galactopyranose using DFT at the B3LYP/6-311+G** and M06-2X/6 311+G** levels, both in vacuum calculations, and including two variants of continuum solvent models as PCM and SMD to simulate water solutions. Free energies were also calculated. MM3 was used as the starting point for calculations, using a dielectric constant of 1.5 for vacuum modeling, and 80 for water solution modeling. For the vacuum calculations, out of the theoretically possible 729 rotamers, only about a hundred rendered stable minima, highly stabilized by hydrogen bonding and scattered in a ca. 14 kcal/mol span. The rotamer with a clockwise arrangement of hydrogen bonds was the most stable for the alpha-anomer, whereas that with a counterclockwise arrangement was the most stable for the beta-anomer. Free energy calculations, and especially solvent modeling, tend to flatten the potential energy surface. With PCM, the total range of energies was reduced to 9-10 kcal/mol (alpha-anomer) or 7-8 kcal/mol (beta anomer). These figures fall to 4.5-6 kcal/mol using SMD. At the same time, the total number of possible rotamers increases dramatically to about 300 with PCM, and to 400 with SMD. Both models show a divergent behavior: PCM tends to underestimate the effect of solvent, thus rendering as the most stable many common rotamers with vacuum calculations, and giving underestimations of populations of beta-anomers and gt rotamers in the equilibrium. On the other hand, SMD gives a better estimation of the solvent effect, yielding correct populations of gt rotamers, but more beta-anomers than expected by the experimental values. The best agreement is observed when the functional M06-2X is combined with SMD. Both DFT models show minimal geometrical differences between the optimized conformers. PMID- 28709132 TI - Protective effects of 6-Gingerol on vascular endothelial cell injury induced by high glucose via activation of PI3K-AKT-eNOS pathway in human umbilical vein endothelial cells. AB - 6-Gingerol (6-Gin), an active constituent of Zingiber officinale, has been reported to have anti-inflammatory, anti-oxidative, anti-cancerous etc. bioactivities. However, little is known about its endothelial protective effects and the underlying mechanisms. In this study, our purpose was to investigate the protective effects of 6-Gin and its underlying mechanisms. HUVECs were exposed to high glucose (HG, 33mM glucose) for 48h, followed by 50MUM 6-Gin with or without LY294002 (10MUM), AKT inhibitor IV (0.5MUM) or L-NAME (5mM) for another 24h. Cell viability, levels of NO, LDH and ROS were detected. In addition, the expression levels of IKK, IRS-1, PI3K, AKT, eNOS and their phosphorylated proteins were measured by western blots. Compared with the control, HUVECs were significantly impaired by HG, characterized by decreased levels of the cell viability, NO, pY458-PI3K, pS473-AKT and pS1177-eNOS while increased levels of LDH, pS176-IKK, and p-S312-IRS-1. Conversely, 6-Gin remarkably protected HUVECs against HG induced injury in a concentration- and time-dependent manner. However, the protective effects of 6-Gin were abolished by co-treatment with LY294002, AKT inhibitor IV or L-NAME at the HG state. Collectively, 6-Gin attenuated the injury of HUVECs induced by HG through the activation of PI3K-AKT-eNOS signal pathway. The findings provide a novel potential for 6-Gin to prevent and treat the angiopathy resulting from diabetes mellitus. PMID- 28709134 TI - BCR-ABL1-like acute lymphoblastic leukaemia: From bench to bedside. AB - Acute lymphoblastic leukaemia (ALL) occurs in approximately 1:1500 children and is less frequently found in adults. The most common immunophenotype of ALL is the B cell lineage and within B cell precursor ALL, specific genetic aberrations define subtypes with distinct biological and clinical characteristics. With more advanced genetic analysis methods such as whole genome and transcriptome sequencing, novel genetic subtypes have recently been discovered. One novel class of genetic aberrations comprises tyrosine kinase-activating lesions, including translocations and rearrangements of tyrosine kinase and cytokine receptor genes. These newly discovered genetic aberrations are harder to detect by standard diagnostic methods such as karyotyping, fluorescent in situ hybridisation (FISH) or polymerase chain reaction (PCR) because they are diverse and often cryptic. These lesions involve one of several tyrosine kinase genes (among others, v-abl Abelson murine leukaemia viral oncogene homologue 1 (ABL1), v-abl Abelson murine leukaemia viral oncogene homologue 2 (ABL2), platelet-derived growth factor receptor beta polypeptide (PDGFRB)), each of which can be fused to up to 15 partner genes. Together, they compose 2-3% of B cell precursor ALL (BCP-ALL), which is similar in size to the well-known fusion gene BCR-ABL1 subtype. These so called BCR-ABL1-like fusions are mutually exclusive with the sentinel translocations in BCP-ALL (BCR-ABL1, ETV6-RUNX1, TCF3-PBX1, and KMT2A (MLL) rearrangements) and have the promising prospect to be sensitive to tyrosine kinase inhibitors similar to BCR-ABL1. In this review, we discuss the types of tyrosine kinase-activating lesions discovered, and the preclinical and clinical evidence for the use of tyrosine kinase inhibitors in the treatment of this novel subtype of ALL. PMID- 28709135 TI - Inhibition of lymphangiogenesis impairs antitumour effects of photodynamic therapy and checkpoint inhibitors in mice. AB - Photodynamic therapy (PDT) has been shown to destroy tumour-associated lymphatic vessels. Therefore, we sought to investigate the functional outcomes of PDT mediated damage to the lymphatic vessels. We observed that PDT with verteporfin, completely but transiently, blocks the functional lymphatic drainage in the orthotopic mammary tumour models. Sustained inhibition of lymphatic vessels regeneration induced by lenalidomide or the soluble form of vascular endothelial growth factor receptor 3 (sVEGFR3) that neutralises lymphangiogenic vascular endothelial growth factor C (VEGF-C), significantly impaired antitumour efficacy of PDT. Antilymphangiogenic compounds also significantly inhibited the ability of intratumourally inoculated dendritic cells (DCs) to translocate to local lymph nodes and diminished the number of tumour-infiltrating interferon-gamma-secreting or tumour antigen-specific CD8+ T cells. Lenalidomide also abrogated antitumour effects of the combination immunotherapy with PDT and anti-programmed death ligand 1 (PD-L1) antibodies. Altogether, these findings indicate that PDT mediated damage to the lymphatic vessels negatively affects development of antitumour immunity, and that drugs that impair lymphatic vessel regeneration might not be suitable for the use in combination with PDT. PMID- 28709136 TI - Tetracyclines as a potential antiviral therapy against Crimean Congo hemorrhagic fever virus: Docking and molecular dynamic studies. AB - Crimean-Congo Hemorrhagic Fever Virus (CCHFV) is one of the deadliest human diseases with mortality rate near 50%. Special attention should be paid to this virus since there is no approved treatment for it. On the other hand, the recent outbreak of Ebola virus which is a member of hemorrhagic fever viruses shows this group of viruses can be extremely dangerous. Previous studies have indicated that nucleoprotein of CCHFV, a pivotal protein in virus replication, is an appropriate target for antiviral drug development. The aim of this study is finding inhibitor(s) of this protein. Herein, a virtual screening procedure employing docking followed by molecular dynamic was used to identify small molecule inhibitors of the nucleoprotein from FDA-approved drugs. Regarding CCHFV, using in-silico method is a safe way to achieve its inhibitor(s) since this virus is categorized as a World Health Organization (WHO) biosafety level 4 pathogen and therefore investigation in general laboratories is restricted. In conclusion, considering docking and molecular dynamic results alongside with bioavailability of FDA-approved drugs, doxycycline and minocycline are proposed as potential inhibitors of CCHFV nucleoprotein. There is hope, this study encourage other research groups for in-vitro and in-vivo studies about the efficacy of those two medicines in CCHFV treatment. PMID- 28709137 TI - Some observations on the greenhouse effect at the Earth's surface. AB - It is shown that the greenhouse gases carbon dioxide and water vapour reflect back to the surface, all IR radiation originating at the surface within their respective spectral bands. This reflection occurs in a very thin layer at the surface, not much over 12cm in thickness. Heat is lost from the surface by heat exchange with the atmosphere and by loss of radiation. About 52% of radiation leaves the surface in two principal window regions but this is not enough to account for the earth's equilibrium temperature. This window radiation seems to disappear quite quickly and is replaced by black body radiation. It is this which eventually contributes to the earth's radiation balance, and has to originate approximately between 40 and 50km altitude where the temperature is about correct, near 255K. Doubling the CO2 concentration increases the surface temperature by about 0.9 degrees C and this need not have any influence higher up in the atmosphere. The surface temperature seems indeed to have no direct influence on the earth's external radiation balance. PMID- 28709138 TI - Multimodal nonlinear microscope based on a compact fiber-format laser source. AB - We present a multimodal non-linear optical (NLO) laser-scanning microscope, based on a compact fiber-format excitation laser and integrating coherent anti-Stokes Raman scattering (CARS), stimulated Raman scattering (SRS) and two-photon excitation fluorescence (TPEF) on a single platform. We demonstrate its capabilities in simultaneously acquiring CARS and SRS images of a blend of 6-MUm poly(methyl methacrylate) beads and 3-MUm polystyrene beads. We then apply it to visualize cell walls and chloroplast of an unprocessed fresh leaf of Elodea aquatic plant via SRS and TPEF modalities, respectively. The presented NLO microscope, developed in house using off-the-shelf components, offers full accessibility to the optical path and ensures its easy re-configurability and flexibility. PMID- 28709139 TI - The Raman and SERS spectra of indigo and indigo-Ag2 complex: DFT calculation and comparison with experiment. AB - Using time-dependent density functional theory in conjunction with B3LYP functional and LANL2DZ/6-31+g(d,p) basis sets, static and pre-resonance Raman spectra of the indigo-Ag2 complex have been calculated. Structure optimization, excitation energies and pre-resonance Raman spectra of the indigo molecule have been obtained at the same level of theory. The available experimental Raman spectra at 1064, 785 and 514nm and the SERS spectra at 785 and 514nm have been well reproduced by the calculation. Experimental SERS spectra are confronted with the calculated pre-resonance Raman spectra obtained for the indigo-Ag2 complex. The Raman activities calculated under the infinite lifetime approximation show a strong dependence upon the proximity to the energy and the oscillator strength of the excitation electronic transition. The comparison of the integrated EFs for indigo and indigo-Ag2 calculated Raman spectra, gave some hints as to the enhancement mechanisms acting for the different excitation wavelengths. Whereas for excitation at a wavelength corresponding to 785nm, the enhancement mechanism for the Raman spectrum of the metal complex seems the chemical one, the strong increment (ten times) of the integrated EF of the Raman spectra of the complex in the case of 514nm excitation, suggests the onset of other enhancement mechanisms. Assuming that intra-cluster transitions with high oscillator strength can be thought of as to mimic surface plasmons excitations, we suggest the onset of the electromagnetic mechanisms (EM) as the origin of the Raman spectrum enhancement. Nevertheless, other enhancement effects cannot be ruled out, as a new molecular transition gains strength in the proximity of the excitation wavelength, as a consequence of the symmetry lowering of the molecule in the complex. A large variation across vibrational modes, by a factor of at least 104, was found for the EFs. This large variation in the EFs can indicate that B-term Herzberg-Teller scattering, due to metal and/or charge transfer states, can feed intensity to the inactive (in the molecule) and/or non totally symmetric modes. PMID- 28709140 TI - Spectroelectrochemical insights into structural and redox properties of immobilized endonuclease III and its catalytically inactive mutant. AB - Endonuclease III is a Fe-S containing bifunctional DNA glycosylase which is involved in the repair of oxidation damaged DNA. Here we employ surface enhanced IR spectroelectrochemistry and electrochemistry to study the enzyme from the highly radiation- and desiccation-resistant bacterium Deinococcus radiodurans (DrEndoIII2). The experiments are designed to shed more light onto specific parameters that are currently proposed to govern damage search and recognition by endonucleases III. We demonstrate that electrostatic interactions required for the redox activation of DrEndoIII2 may result in high electric fields that alter its structural and thermodynamic properties. Analysis of inactive DrEndoIII2 (K132A/D150A double mutant) interacting with undamaged DNA, and the active enzyme interacting with damaged DNA also indicate that the electron transfer is modulated by subtle differences in the protein-DNA complex. PMID- 28709141 TI - Pt@Ag and Pd@Ag core/shell nanoparticles for catalytic degradation of Congo red in aqueous solution. AB - Platinum/silver (Pt@Ag) and palladium/silver (Pd@Ag) core/shell NPs have been synthesized in two steps reaction using the citrate method. The progress of nanoparticle formation was followed by the UV/Vis spectroscopy. Transmission electron microscopy revealed spherical shaped core/shell nanoparticles with average particle diameter 32.17nm for Pt@Ag and 8.8nm for Pd@Ag. The core/shell NPs were further characterized by FT-IR and XRD. Reductive degradation of the Congo red dye was chosen to demonstrate the excellent catalytic activity of these core/shell nanostructures. The nanocatalysts act as electron mediators for the transfer of electrons from the reducing agent (NaBH4) to the dye molecules. Effect of reaction parameters such as nanocatalyst dose, dye and NaBH4 concentrations on the dye degradation was investigated. A comparison between the catalytic activities of both nanocatalysts was made to realize which of them the best in catalytic performance. Pd@Ag was the higher in catalytic activity over Pt@Ag. Such greater activity is originated from the smaller particle size and larger surface area. Pd@Ag nanocatalyst was catalytically stable through four subsequent reaction runs under the utilized reaction conditions. These findings can thus be considered as possible economical alternative for environmental safety against water pollution by dyes. PMID- 28709142 TI - Application of Taguchi L16 design method for comparative study of ability of 3A zeolite in removal of Rhodamine B and Malachite green from environmental water samples. AB - This study aimed to investigate the efficiency of 3A zeolite as a novel adsorbent for removal of Rhodamine B and Malachite green dyes from water samples. To increase the removal efficiency, effecting parameters on adsorption process were investigated and optimized by adopting Taguchi design of experiments approach. The percentage contribution of each parameter on the removal of Rhodamine B and Malachite green dyes determined using ANOVA and showed that the most effective parameters in removal of RhB and MG by 3A zeolite are initial concentration of dye and pH, respectively. Under optimized condition, the amount predicted by Taguchi design method and the value obtained experimentally, showed good closeness (more than 94.86%). Good adsorption efficiency obtained for proposed methods indicates that, the 3A zeolite is capable to remove the significant amounts of Rhodamine B and Malachite green from environmental water samples. PMID- 28709143 TI - Using silicon-coated gold nanoparticles to enhance the fluorescence of CdTe quantum dot and improve the sensing ability of mercury (II). AB - The effect of silicon-coated gold nanoparticles with different gold core diameter and silica shell thickness on the fluorescence emission of CdTe quantum dots (QDs) was investigated. For gold nanoparticles with a diameter of 15nm, silica coating can only results in fluorescence recover of the bare gold nanoparticle induced quenching of QDs. However, when the size of gold nanoparticle is increased to 60nm, fluorescence enhancement of the QDs could be obtained by silica coating. Because of the isolation of the silica shell-reduced quenching effect and local electric field effect, the fluorescence of QDs gets intense firstly and then decreases. The maximum fluorescence enhancement takes place as the silica shell has a thickness of 30nm. This enhanced fluorescence from silicon coated gold nanoparticles is demonstrated for sensing of Hg2+. Under optimal conditions, the enhanced fluorescence intensity decreases linearly with the concentration of Hg2+ ranging from 0 to 200ng/mL. The limit of detection for Hg2+ is 1.25ng/mL. Interference test and real samples detection indicate that the influence from other metal ions could be neglected, and the Hg2+ could be specifically detected. PMID- 28709144 TI - The spectrum of peri-ictal MRI changes; four illustrative cases. AB - PURPOSE: Seizure induced neuronal hyperexcitability and increased unmet metabolic neuronal demand results in failure of the sodium/potassium ATP pump. Sodium and water accumulates intracellularly with cellular swelling and reduced extracellular volume demonstrating hyperintensity on DWI and reduced ADC. The aim of this study was to describe 4 clinical cases where we identified abnormalities in diffusion restriction in the acute peri-ictal period and followed them longitudinally. METHODS: Patients were recruited from the emergency department, clinical consultation service and epilepsy monitoring unit of two tertiary referral centres. Patients underwent either 1.5T or 3.0T MRI with DWI, ADC, T2 weighted and post contrast studies during their acute admission and again after a period of follow up. RESULTS: Four patients were identified as having visible diffusion restriction and reduced ADC in one or both hippocampi and the splenium of the corpus callosum. These lesions either completely resolved, showed interval improvement or demonstrated atrophy on follow up imaging. The two patients with persisting abnormalities had presented with status epilepticus. CONCLUSIONS: These acute ictal imaging changes give clinicians an important in-vivo look at the dynamic neuronal metabolic environment in the peri-ictal period. Areas that appear most susceptible include the mesial temporal structures and corpus callosum. Close imaging follow up to document resolution or evolution of long lasting sequelae is vital. There is no clear consensus as to why some patients develop ictal related imaging changes and others do not. Seizure length and time interval from ictus to scan appear to play a role but larger prospective studies are needed to confirm this. PMID- 28709152 TI - Squatting Biomechanics in Individuals with Symptomatic Femoroacetabular Impingement. AB - PURPOSE: Identification of the biomechanical alterations in individuals with symptomatic femoroacetabular impingement (FAI) is critical to understand the pathology and inform treatments. Yet hip function in this condition is poorly defined. Squatting requires large hip flexion range and involves motion toward the position of hip impingement; thus, it is likely to expose modified biomechanics in these individuals. This study aimed to determine whether hip and pelvis biomechanics differ between individuals with and without symptomatic FAI during an unconstrained deep squat and a constrained squat designed to limit compensation by the pelvis and trunk. METHODS: Fifteen participants with symptomatic cam-type or combined (cam plus pincer) FAI who were scheduled for arthroscopic surgery and 14 age- and sex-matched controls without FAI underwent three-dimensional motion analysis during the two squatting tasks. Trunk, pelvis, and hip kinematics and hip kinetics were compared between groups. RESULTS: There were no between-group differences in normalized squat depth for either task. Descent speed was slower for the FAI group during the unconstrained squat (P < 0.05). During the constrained squat, individuals with FAI demonstrated greater pelvic rise (P = 0.01) and hip adduction (P = 0.04) on the symptomatic side than controls. The hip external rotation moment was less in FAI patients during descent (P = 0.04), as was transverse plane hip angle variability (P = 0.04). CONCLUSIONS: Individuals with symptomatic FAI can squat to a depth comparable with controls, regardless of task design. When the task is constrained, FAI patients demonstrate greater ipsilateral pelvic rise and maintain a more adducted hip position, which may coincide with a compensatory strategy to avoid end range flexion as the hip approaches impingement. These biomechanical alterations may put additional stress on adjacent regions and have relevance for rehabilitation. PMID- 28709145 TI - Diagnosis of attention deficit hyperactivity disorder using imaging and signal processing techniques. AB - Attention Deficit Hyperactivity Disorder (ADHD) is the most common childhood psychiatric disorder that may continue through adolescence and adulthood. Hyperactivity, inattention and impulsivity are the key behavioral features observed in children with ADHD. ADHD is normally diagnosed only when a child continues to have symptoms of hyperactivity, impulsivity and inattention at a greater degree than the normal for six months or more. In recent years there has been significant research to diagnose ADHD in a quantitative way using medical imaging and signal processing techniques. This paper presents a review of recent research on diagnosis of ADHD using medical imaging and signal processing techniques. This research is especially valuable for early diagnosis of ADHD. PMID- 28709154 TI - Contributions to Leg Stiffness in High- Compared with Low-Arched Athletes. AB - PURPOSE: High-arched (HA) athletes exhibit greater lower extremity stiffness during functional tasks than low-arched (LA) athletes. The contributions of skeletal and muscular structures to stiffness may underlie the distinct injury patterns observed in these athletes. The purpose of this study was to compare skeletal and muscular contributions to leg stiffness in HA and LA athletes during running and landing tasks. METHODS: Ten HA and 10 LA female athletes performed five overground running trials at a self-selected pace and five step off bilateral landing trials from a height of 30 cm. Three-dimensional kinematics and kinetics were collected using a motion capture system and a force platform. Leg stiffness and its skeletal and muscular contributions were calculated. Independent t-tests were used to compare variable means between arch type groups and Cohen's d were computed to assess effect sizes of mean differences. RESULTS: In running, HA athletes had greater leg stiffness (P = 0.010, d = 1.03) and skeletal stiffness (P = 0.016, d = 0.81), although there are no differences in muscular stiffness (P = 0.134). During landing, HA had greater leg stiffness (P = 0.015, d = 1.06) and skeletal stiffness (P < 0.001, d = 1.84), whereas LA athletes had greater muscular stiffness (P = 0.025, d = 0.96). CONCLUSIONS: These findings demonstrate that HA athletes place a greater reliance on skeletal structures for load attenuation during running and landing, whereas LA athletes rely more greatly on muscle contributions during landing only. These findings may provide insight into the distinct injury patterns observed in HA and LA athletes. PMID- 28709153 TI - Age Reduces Microvascular Function in the Leg Independent of Physical Activity. AB - : The microvasculature is critical in the control of blood flow. Aging and reduced physical activity (PA) may both decrease microvascular function. PURPOSE: The primary aim was to evaluate the influence of age on microvascular function in adults with similar PA levels. Secondary aims were to assess the reliability of muscle functional magnetic resonance imaging in older adults (OA) and the relationship between PA and microvascular function in OA. METHODS: Microvascular blood-oxygen-level dependent (BOLD) responses were measured in young adults (YA, n = 12, mean +/- SD age = 21 +/- 1 yr old, PA = 239 +/- 73 * 10 counts per day) and OA (n = 13, 64 +/- 4 yr old, PA = 203 +/- 48 * 10 counts per day). Functional magnetic resonance images (3T, echo planar BOLD) of the leg were acquired after brief (1 s) maximal voluntary isometric contractions. The test-retest reliability of BOLD responses and the Pearson correlation between peak BOLD and PA were assessed in a group of OA (OA-r) with a broad range of PA (66 +/- 5 yr old, n = 9, PA range = 54 * 10 to 674 * 10 counts per day). RESULTS: Peak BOLD microvascular responses were reduced for OA compared with YA. OA peak BOLD was 27% lower in the soleus (3.3% +/- 0.8% OA vs 4.5% +/- 1.4% YA; P = 0.017) and 40% lower in the anterior compartment (1.6% +/- 0.6% OA vs 2.7% +/- 1.1% YA; P = 0.006). Coefficients of variation were 8.6% and 11.8% for peak BOLD in the soleus and anterior compartment, respectively, with an intraclass correlation of 0.950 for both muscle regions. The correlation between peak BOLD and PA was r >= 0.715, P <= 0.030. CONCLUSIONS: Aging was associated with reduced microvascular function in leg muscles, independent of PA. The findings also revealed good reliability for BOLD magnetic resonance imaging in OA for the soleus and anterior compartment muscles. PMID- 28709155 TI - Variable Accuracy of Wearable Heart Rate Monitors during Aerobic Exercise. AB - PURPOSE: Athletes and members of the public increasingly rely on wearable HR monitors to guide physical activity and training. The accuracy of newer, optically based monitors is unconfirmed. We sought to assess the accuracy of five optically based HR monitors during various types of aerobic exercise. METHODS: Fifty healthy adult volunteers (mean +/- SD age = 38 +/- 12 yr, 54% female) completed exercise protocols on a treadmill, a stationary bicycle, and an elliptical trainer (+/-arm movement). Each participant underwent HR monitoring with an electrocardiogaphic chest strap monitor (Polar H7), forearm monitor (Scosche Rhythm+), and two randomly assigned wrist-worn HR monitors (Apple Watch, Fitbit Blaze, Garmin Forerunner 235, and TomTom Spark Cardio), one on each wrist. For each exercise type, HR was recorded at rest, light, moderate, and vigorous intensity. Agreement between HR measurements was assessed using Lin's concordance correlation coefficient (rc). RESULTS: Across all exercise conditions, the chest strap monitor (Polar H7) had the best agreement with ECG (rc = 0.996) followed by the Apple Watch (rc = 0.92), the TomTom Spark (rc = 0.83), and the Garmin Forerunner (rc = 0.81). Scosche Rhythm+ and Fitbit Blaze were less accurate (rc = 0.75 and rc = 0.67, respectively). On treadmill, all devices performed well (rc = 0.88-0.93) except the Fitbit Blaze (rc = 0.76). While bicycling, only the Garmin, Apple Watch, and Scosche Rhythm+ had acceptable agreement (rc > 0.80). On the elliptical trainer without arm levers, only the Apple Watch was accurate (rc = 0.94). None of the devices was accurate during elliptical trainer use with arm levers (all rc < 0.80). CONCLUSION: The accuracy of wearable, optically based HR monitors varies with exercise type and is greatest on the treadmill and lowest on elliptical trainer. Electrode-containing chest monitors should be used when accurate HR measurement is imperative. PMID- 28709156 TI - Gastrointestinal Impedance Spectroscopy to Detect Hypoperfusion During Hemorrhage. AB - BACKGROUND: Changes in tissue impedance (Omega) have been proposed as early signs of impaired tissue perfusion. We hypothesized that hemorrhage may induce early changes in alimentary tract tissue impedance and that these can be detected by impedance spectroscopy. We evaluated impedance spectroscopy in an acute hemorrhage model in pigs. METHODS: Twenty anesthetized pigs were randomized to stepwise hemorrhage to mean arterial blood pressure (MAP) targets of 60 mm Hg, 50 mm Hg, 45 mm Hg, and 40 mm Hg, followed by retransfusion in two steps, or control (n = 10 each). In the end, 500 mL of enteral nutrition was administered in both groups. Omega in four sites (sublingually, esophagus, stomach, proximal jejunum) and cardiac output (Qtot thermodilution), superior mesenteric artery blood flow (QSMA; Doppler ultrasound), and jejunal mucosal blood flow (LDF; laser Doppler) were measured. FINDINGS: The bleeding (total volume 838 +/- 185 mL; mean +/- SD) resulted in progressive hypotension (actual MAP 65 +/- 3 mm Hg, 59 +/- 4 mm Hg, 55 +/- 5 mm Hg, and 46 +/- 6 mm Hg) and decrease in Qtot, QSMA, and mucosal LDF. Bleeding did not change Omega in any of the monitoring sites. Retransfusion restored the blood flows to at least baseline levels, again without change in Omega. Enteral nutrition did not alter Omega or any of the blood flows.Five animals (three in the hemorrhage group, two in the control group) had histologically proven acute gastric focal necrosis at the site of It transducer. CONCLUSIONS: Gastrointestinal impedance spectroscopy does not detect early changes in tissue perfusion during progressive hemorrhage or retransfusion. Omega spectroscopy is unlikely to provide any additional information of hypovolemia induced early changes in gastrointestinal perfusion. PMID- 28709157 TI - Hypotensive Resuscitation with Hypertonic Saline Dextran Improves Survival in a Rat Model of Hemorrhagic Shock at High Altitude. AB - OBJECTIVE: To compare the efficacy of hypotensive resuscitation with hypertonic saline dextran 70 (HSD) and lactated Ringer (LR) solutions in a rat model of hemorrhagic shock at a simulated altitude of 4,000 m. METHODS: Anesthetized rats were bled to maintain their mean arterial pressure (MAP) at 45 mm Hg for 1 h. The distal quarter of the tail was then amputated to allow free blood loss; rats were simultaneously resuscitated with 4 mL kg HSD (HSD group, n = 10) or 4 mL kg LR (LR group, n = 10), followed by hypotensive resuscitation with LR to maintain MAP at 55 to 60 mm Hg for 1 h. A control group received no resuscitation (n = 10). Afterward, the cut end of the tail was ligated. The MAP, acid-base balance, blood loss, volume of fluid infused, and survival were recorded. RESULTS: Compared with controls, HSD resuscitation improved MAP (without increasing uncontrolled blood loss), increased arterial pH and oxygen saturation (SaO2), decreased arterial lactate concentration at the end of resuscitation, and resulted in higher survival rate (P < 0.05). Hypotensive resuscitation with LR also maintained higher MAP, pH, and SaO2 than the control group, but was associated with increased blood loss and inferior survival (P > 0.05). CONCLUSIONS: For hemorrhagic shock at simulated high altitude, resuscitation of rats with a bolus of HSD was associated with reduced blood loss and serum lactate concentration, and superior SaO2, hemoglobin concentration and survival rate, compared with LR solution. PMID- 28709158 TI - Dexmedetomidine Protects Against Multi-Organ Dysfunction Induced by Heatstroke via Sustaining The Intestinal Integrity. AB - Previous studies have indicated that gut-derived endotoxin played a pivotal role for aggravating systemic inflammatory response to multi-organ dysfunction under heatstroke. Dexmedetomidine (DEX) could protect against inflammation and multi organ injury in various scenarios. The aim of this study was to explore the protective effect of DEX on heatstroke and the mechanism involved. Male C57BL/6 mice were placed in a controlled climate chamber (40 +/- 1 degrees C) until the maximum core temperature (Tc, Max) of 42.7 degrees C, the received criterion of heatstroke, was attained, DEX (25 MUg/kg) or 0.9% saline was injected intraperitoneally immediately. The results showed that DEX could significantly attenuate multi-organ injury induced by heatstroke, simultaneously decrease levels of serum inflammatory cytokines through inhibiting the intestinal nuclear factor-kappaB activation. Furthermore, to assess the effects of DEX on intestine mucosal barrier under heatstroke, the levels of plasma endotoxin, FD4, and D lactate were detected and the expression of tight junction proteins occludin and ZO-1 was analyzed by western blot and immunohistochemistry. Meanwhile, transmission electron microscopy was employed to confirm the ultrastructure of intestine. Interestingly, we found that DEX decreased the intestinal permeability and sustained the integrity of intestinal barrier. Finally, to evaluate the anti apoptosis effect of DEX, the pro-apoptotic protein Bax and anti-apoptotic protein Bcl-2 were analyzed by western blot, and terminal deoxynucleotidyl-transferase mediated dUTP nick end labeling (TUNEL) staining was conducted. The results showed that DEX decreased TUNEL-positive cells induced by heatstroke in a Bax/Bcl 2-related manner. Taken together, our results indicate that DEX could protect against inflammation and multi-organ injury induced by heatstroke via sustaining the intestinal integrity. PMID- 28709159 TI - Packed Red Blood Cells Accumulate Oxidative Stress With Increased Storage Duration. PMID- 28709160 TI - Effectiveness of Palivizumab in High-risk Infants and Children: A Propensity Score Weighted Regression Analysis. AB - BACKGROUND: Infants with premature birth <=35 weeks gestational age, chronic lung disease of prematurity and congenital heart disease are at an increased risk for lower respiratory tract infections and hospitalization from respiratory syncytial virus (RSV), which has been shown in randomized trials to be prevented by palivizumab. However, palivizumab effectiveness (PE) has not been studied in a large clinical setting. METHODS: A multicenter study among high-risk US and Canadian children younger than 24 months hospitalized with lower respiratory tract infection and whose nasopharyngeal aspirates were tested for human metapneumovirus (HMPV) and RSV were the subjects of the trial. We conducted a test-negative case-control study in these subjects to determine PE. We used an inverse propensity score weighted (IPSW) multiple logistic regression model to adjust PE. RESULTS: Palivizumab was used in 434 (51%) of 849 eligible children. RSV was identified in 403 (47%) children. The unadjusted PE was 43% [95% confidence interval (CI), 34%-51%)]. After IPSW adjustment, the adjusted PE was 58% (95% CI, 43%-69%). Palivizumab prevented intensive care unit admissions (PE, 62%; 95% CI, 35%-78%). PE for 29-35 weeks gestational age and <=6 months of chronologic age without chronic lung disease of prematurity or congenital heart disease was 74% (95% CI, 56%-85%). CONCLUSIONS: Using a test-negative case control design with RSV molecular detection, palivizumab is shown to prevent RSV hospitalizations and intensive care unit admissions in high-risk infants. PMID- 28709161 TI - Roles of Medication Responsibility, Executive and Adaptive Functioning in Adherence for Children and Adolescents With Perinatally Acquired HIV. AB - BACKGROUND: Medication adherence is a critical but challenging developmental task for children and adolescents with perinatally acquired HIV (PHIV). Understanding how medication responsibility, executive functions (EFs) and adaptive functioning (AF) influence adherence may help prepare adolescents for transition to adulthood. METHODS: Participants included PHIV children and adolescents 7-16 years of age enrolled in the Pediatric HIV/AIDS Cohort Study Adolescent Master Protocol, who were prescribed antiretroviral medications. Measures included caregiver report and child self-report measures of adherence, medication responsibility and EF, caregiver report of child AF, examiner-administered tests of EF and processing speed and demographic and health characteristics. RESULTS: Two hundred fifty-six participants with PHIV (mean age: 12 years old) were 51% female, 80% black and 79% non-Hispanic. Per 7-day recall, 72% were adherent (no missed doses). Children/adolescents self-reported that 22% had sole and 55% had shared medication responsibility. Adjusted logistic models revealed significantly higher odds of adherence with sole caregiver responsibility for medication [odds ratio (OR): 4.10, confidence interval (CI): 1.43-11.8, P = 0.009], child nadir CD4% <15% (OR: 2.26, CI: 1.15-4.43, P = 0.018), better self-reported behavioral regulation (OR: 0.65, CI: 0.44-0.96, P = 0.029) and slower processing speed (OR: 0.54, CI: 0.38-0.77, P < 0.001), adjusting for demographic variables (age, race and caregiver education). CONCLUSIONS: Among children and adolescents with PHIV, continued caregiver medication management, especially during adolescence, is essential. Although global EF and AF were not significantly associated with adherence, behavioral regulation was. Given that EF and AF develop throughout adolescence, their relationships to adherence should be evaluated longitudinally, especially as youth transition to adulthood and caregiver responsibility diminishes. PMID- 28709162 TI - Late-onset Sepsis in Extremely Premature Infants: 2000-2011. AB - BACKGROUND: Late-onset sepsis (LOS) is an important cause of death and neurodevelopmental impairment in premature infants. The purpose of this study was to assess overall incidence of LOS, distribution of LOS-causative organisms and center variation in incidence of LOS for extremely premature infants over time. METHODS: In a retrospective analysis of infants 401-1000 g birth weight and 22-28 6/7 weeks of gestational age born at 12 National Institute of Child Health and Human Development Neonatal Research Network centers in the years 2000-2005 (era 1) or 2006-2011 (era 2) who survived >72 hours, we compared the incidence of LOS and pathogen distribution in the 2 eras using the chi test. We also examined the effect of birth year on the incidence of LOS using multivariable regression to adjust for nonmodifiable risk factors and for center. To assess whether the incidence of LOS was different among centers in era 2, we used a multivariable regression model to adjust for nonmodifiable risk factors. RESULTS: Ten-thousand one-hundred thirty-one infants were studied. LOS occurred in 2083 of 5031 (41%) infants in era 1 and 1728 of 5100 (34%) infants in era 2 (P < 0.001). Birth year was a significant predictor of LOS on adjusted analysis, with birth years 2000 2009 having a significantly higher odds of LOS than the reference year 2011. Pathogens did not differ, with the exception of decreased fungal infection (P < 0.001). In era 2, 9 centers had significantly higher odds of LOS compared with the center with the lowest incidence. CONCLUSIONS: The incidence of LOS decreased over time. Further investigation is warranted to determine which interventions have the greatest impact on infection rates. PMID- 28709164 TI - Neonatal Acute Kidney Injury: A Survey of Neonatologists' and Nephrologists' Perceptions and Practice Management. AB - BACKGROUND: Neonatal acute kidney injury (AKI) occurs in 40 to 70% of critically ill neonatal intensive care admissions. This study explored the differences in perceptions and practice variations among neonatologists and pediatric nephrologists in diagnostic criteria, management, and follow-up of neonatal AKI. METHODS: A survey weblink was emailed to nephrologists and neonatologists in Australia, Canada, New Zealand, India, and the United States. Questions consisted of demographic and unit practices, three clinical scenarios assessing awareness of definitions of neonatal AKI, knowledge, management, and follow-up practices. RESULTS: Many knowledge gaps among neonatologists, and to a lesser extent, pediatric nephrologists were identified. Neonatologists were less likely to use categorical definitions of neonatal AKI (p < 0.00001) or diagnose stage 1 AKI (p < 0.00001) than pediatric nephrologists. Guidelines for creatinine monitoring for nephrotoxic medications were reported by 34% (aminoglycosides) and 62% (indomethacin) of respondents. Nephrologists were more likely to consider follow up after AKI than neonatologists (p < 0.00001). Also, 92 and 86% of neonatologists and nephrologists, respectively, reported no standardization or infrastructure for long-term renal follow-up. CONCLUSION: Neonatal AKI is underappreciated, particularly among neonatologists. A lack of evidence on neonatal AKI contributes to this variation in response. Therefore, dissemination of current knowledge and areas for research should be the priority. PMID- 28709163 TI - Current Management of Congenital Pulmonary Airway Malformations: A "European Pediatric Surgeons' Association" Survey. AB - AIM: To define current management of congenital pulmonary airway malformation (CPAM). METHODS: A total of 181 European Pediatric Surgeons' Association members (91% senior) from 48 countries completed an online questionnaire. MAIN RESULTS: Prenatal: 93% respondents work in centers with prenatal diagnosis facilities, and 27% in centers offering in utero surgery. Prenatal counseling is performed by 86% respondents, 22% of whom see >10 cases per year. Risk of single pre-/postnatal complications is deemed low (<5%) by more than 60% of respondents. Eighty-six percent respondents do not offer pregnancy termination for prenatally diagnosed CPAM. Fetal hydrops is the most frequent indication for termination (87%), followed by parental willingness (52%). Prenatal surgery is an option for 44% respondents, preferring thoracoamniotic shunt (82%).Postnatal: 75% respondents operate on asymptomatic patients, 18% before 6 months of age, 62% between 6 and 12 months of age, and 20% after 12 months of age. Risk of infection (86%), cancer (63%), and symptoms development (62%) are indications for surgery in asymptomatic CPAM. Sixty-three percent prefer a thoracotomy. Lobectomy is the preferred procedure (58% respondents). Motivations against surgery include lesion <1 cm (64%), risk of postoperative complications (37%), and lack of evidence favoring surgery (27%). Seventeen percent respondents have seen at least one patient with CPAM with lung cancer, in 89% of the cases within the CPAM. Of all the respondents, 83% and 22% offered dedicated follow-up and genetic screening, respectively. CONCLUSION: Current pre- and postnatal management of CPAM lacks uniformity, particularly for surgical indication, timing, and approach. Efforts should be made toward standardization. Risk of CPAM-associated cancer is not clear. PMID- 28709165 TI - Insulin Delivery Method and Admission for Glycemic Control in Pregnant Women with Type 1 Diabetes Mellitus. AB - OBJECTIVE: To determine if there was a difference in glycemic control admissions or perinatal outcomes in women with type 1 diabetes mellitus (DM) treated with multiple daily injections (MDIs) versus continuous subcutaneous insulin infusion (CSII). MATERIALS AND METHODS: This was a retrospective cohort study of women with type 1 DM with a singleton gestation who delivered between 2006 and 2014 at a tertiary hospital and received care at a dedicated DM clinic. Women who used MDI were compared with those who used CSII. The primary outcome was glycemic control admission during pregnancy. Secondary outcomes included adverse perinatal outcomes. RESULTS: There were a total of 156 women; 107 treated with MDI and 49 with CSII. Women treated with MDI had higher rates of glycemic control admissions versus those treated with CSII (68.2 vs. 30.6%, p < 0.001). Adjusting for age, ethnicity, public insurer, duration of DM, first recorded hemoglobin A1c (HbA1c), and DM comorbidities, the likelihood of admission remained higher in women on MDI versus CSII (AOR 5.9 [1.7-20.6]). Women treated with MDI had higher rates of postprandial hypoglycemia. Other perinatal outcomes were similar between the groups. CONCLUSION: Women with type 1 DM treated with MDI were more likely to have glycemic control admissions and postprandial hypoglycemia than those treated with CSII. PMID- 28709168 TI - [Editorial: Ultrasound in Zeitschrift fur Gastroenterologie]. PMID- 28709166 TI - Erratum to: Long-Term Follow-Up after Phrenic Nerve Reconstruction for Diaphragmatic Paralysis: A Review of 180 Patients. PMID- 28709169 TI - The challenge of liver resection in benign solid liver tumors in modern times - in which cases should surgery be done? AB - Background Due to improved diagnostical and therapeutical approaches, benign liver tumors represent a challenge in clinical management. We here report our experience with patients undergoing liver resection for benign liver tumors. Methods 188 One hundred eighty-eight consecutive patients, who underwent surgery for solid benign liver tumors from 1992 - 2014, were analyzed retrospectively. The focus was on diagnostic pathways, indications for surgery, and perioperative and postoperative quality of life (QoL). Results Of 188 patients, 100 had focal nodular hyperplasia (FNH) (53.2 %), 33 had hepatocellular adenoma (17.5 %), and 55 had hemangioma (29.3 %). In most patients, there was more than one 1 indication for liver resection, including tumor-associated symptoms (n = 82, 43.6 %), suspicion of malignancy (n = 104, 55.3 %), tumor disease in the medical history (n = 48, 25.5 %), or tumor enlargement (n = 27, 14.4 %). Serious complications (>grade III;, Clavien-Dindo) occurred in 9.5 % of patients. Perioperative mortality was 0.5 %. Patient pain scores decreased over time (p < 0.001). QoL after liver resection significantly improved (p = 0.007). Conclusion Uncertainty of the tumor entity remains an issue in preoperative diagnostics. If indicated, liver resection for benign liver tumors represents a safe approach and leads to significant improvements of QoL. PMID- 28709170 TI - [Leptomeningeal carcinomatosis as a rare metastatic spreading of BRAF-mutated microsatellite stable colon cancer]. AB - Leptomeningeal carcinomatosis is a rare but serious complication of solid tumors such as melanoma, breast and lung cancer, as well as gastrointestinal carcinomas. Its clinical manifestation is highly variable, presenting as radicular pain with or without neurological deficits, as well as with headaches and hallucinatory irritation symptoms. Leptomeningeal carcinomatosis is often misdiagnosed, which delays treatment. Here we report a rare case of a patient with BRAF-mutated microsatellite stable colon carcinoma with lymphatic and skeletal metastases, who developed neurological symptoms one month after the initial diagnosis of malignancy. Based on the cytological detection of tumor cells in the cerebrospinal fluid, a leptomeningeal carcinomatosis was diagnosed, despite normal findings on MRI. Intrathecal chemotherapy with methotrexate, combined with intensive systemic immunochemotherapy, resulted in a good partial remission of the underlying malignant disease. However, approximately 8 months after the start of therapy, the patient developed progressive leptomeningeal carcinomatosis and died a few weeks later. PMID- 28709171 TI - Omental actinomycosis imitating a foreign body infection. AB - Actinomycosis is a rare chronic disease caused by a group of anaerobic Gram positive bacteria that colonize the mouth, colon, and urogenital tract. Infection involving the cervicofacial area is the most common clinical presentation, followed by that of the pelvic and thoracic areas. The preoperative diagnosis of abdominal actinomycosis is difficult because the condition can be easily confused with malignancy, tuberculosis, or other inflammatory diseases. We report a case of omental actinomycosis mimicking a foreign body. Actinomycosis is diagnosed based on the histopathologic demonstration of sulfur granules in a tissue or organ that was surgically removed. Following confirmative diagnosis by surgical intervention, the patient was treated with oral doxycycline 100 mg twice daily for 6 months. A follow-up abdominopelvic computed tomography after 16 months showed no evidence of inflammation. Moreover, the patient no longer had disease associated symptoms and exhibited normal laboratory findings. PMID- 28709173 TI - ? PMID- 28709172 TI - Irritable bowel syndrome - dissection of a disease. A 13-steps polemic AB - The last 35 years (since about 1985) have produced a vast amount of scientific publications with respect to the irritable bowel syndrome (IBS), but no real progress: The etiology and pathogenesis of IBS is still incompletely understood, and diagnosis and therapy is left to the individual understanding of the treating physicians in general medicine, gastroenterology and psychosomatic/psychiatry. In this gloss, three prominent representatives of neurogastroenterology in Germany assess their own contributions and those of their colleagues and lament the huge gap between ambitions and reality in clinical and basic science in IBS. PMID- 28709174 TI - ? PMID- 28709175 TI - ['Healthy sick' or: How Genetic Risks Lever the Disease Concept of the Healthcare System]. AB - Currently it is not clear, whether and which specific prophylactic measures the healthcare system should provide as a standard offer for persons with genetic risks. Furthermore, there is no theoretical model for transparent regulation in this context. In the concrete case of BRCA1/2 carriers, the consequences of these defects become obvious: requests for medical measures are subjected to decision making procedures of health insurance companies that are not wholly transparent. Against the background of medical advance in relation to complex diseases and in order to address this problem of the healthcare system, this article develops a healthy-sick model. This model gives a frame for identifying the medical demand of persons at risk of genetic diseases and for classifying the status of the persons concerned in the healthcare system. PMID- 28709176 TI - New Method of Injured Nerve Repair. AB - BACKGROUND: Innovative surgical techniques form the basis of therapeutic approaches to address the negative consequences of nerve damage. This study evaluated the effectiveness of nerve trunk regeneration after the use of an electrosurgical instrument by looking at the patterns of morphological changes in the injured nerve and the structural elements of the segment motor center. METHODOLOGY: The study was performed on male Wistar rats divided into four groups: group 1, control; group 2, rats with simulated sciatic nerve injury with epineural sutures; 3, rats subjected to an experimental surgical procedure using high-frequency electric welding technology; and 4, rats with simulated sciatic nerve injury without posttransection repair. To study changes in the peripheral stump of the transected nerves and L5 segments of the spinal cord, we used histologic, immunohistochemical, and morphometric methods. RESULTS: At week 12 after the surgery, there were more S-100+ Schwann cells, increased expression of neurofilaments (NFs), and glial fibrillary acidic protein in the peripheral stump in group 3 than in groups 2 and 4, which indicates enhanced neurotization and myelination. Group 3 animals demonstrated reduced expression of S-100 and NFs in the motor center of the spinal cord compared with group 2 that suggests less pronounced reactive changes caused by electric welding technology. CONCLUSIONS: The study showed a novel surgical method using an electrosurgical instrument in a welding mode to stimulate regeneration of the injured nerve and to cause less prominent reactive changes in its segment motor center. PMID- 28709177 TI - Effects of testosterone therapy on BMI, blood pressure, and laboratory profile of transgender men: a systematic review. AB - Testosterone is the main hormonal agent used for cross-sex hormone therapy in female-to-male transgender persons. Our aim was to systematically review the literature concerning the effects of testosterone on body mass index (BMI), blood pressure, hematocrit, hemoglobin, lipid profile, and liver enzymes in transgender men. PUBMED and EMBASE were searched for studies published until March 2017. Studies were included if they reported interventions with any dose of testosterone and comparison of variables before and during treatment. Of 455 potentially eligible articles, 13 were reviewed. Study duration ranged from 6 to 60 months, sample size ranged from 12 to 97 patients, and the most common treatment was parenteral testosterone undecanoate 1000 mg/12 weeks. Slight but significant increases in BMI were reported (from 1.3 to 11.4%). Three out of seven studies assessing the impact of different testosterone formulations on blood pressure detected modest increases or clinically irrelevant changes in this variable. In another study, however, two patients developed hypertension, which was resolved after cessation of testosterone therapy. Decreases in HDL cholesterol and increases in LDL-cholesterol were consistently observed. Eight studies observed a relationship between testosterone and increased hemoglobin (range: 4.9-12.5%) and hematocrit (range: 4.4-17.6%), but discontinuation of androgen therapy was not necessary. In one study, two patients developed erythrocytosis (hematocrit >52%) after 9 and 12 months of treatment. One study analyzing testosterone formulations observed smaller increases in hemoglobin and hematocrit with testosterone gel. Six studies assessing liver function showed slight or no changes. Overall, the quality of evidence was low, given the lack of randomized clinical/controlled trials and the small sample sizes. In conclusion, exogenous testosterone administration to transgender men was associated with modest increases in BMI, hemoglobin/hematocrit, and LDL-cholesterol, and with decreases in HDL-cholesterol. Long-term studies are needed to assess the long term risks of testosterone therapy, particularly as they relate to cardiometabolic risks such as diabetes, dyslipidemia and the metabolic syndrome. PMID- 28709178 TI - Inflammatory reaction found in prostate-specific material - method standardization and proposed optimal cut-off points. AB - : Prostatitis classification as well as treatment decisions are primarily based on differentiation of the inflammatory status in prostate-specific material. At the same time, methods used for detection of inflammation are semi-quantitative and not finally standardized. The main aim of this study was to suggest more precise methods for detection of prostate inflammatory status. Additional aims were to define optimal cut-off points of various tests in order to discriminate between inflammatory and non-inflammatory condition and to analyze the prevalence of inflammatory prostatitis in the groups of symptomatic prostatitis, lower urinary tract symptoms and control subjects. This prospective study included 541 patients (with prostatitis symptoms, with lower urinary tract symptoms and controls) at Tartu University Hospital, Estonia. Leukocyte counts in first-void urine, expressed prostatic secretion and post-massage urine as well as interleukin-6 in prostate secretion specimens were determined. Based on ROC curve analysis, we detected potential normal values for leukocytes in expressed prostatic secretion (<0.5 m/mL), leukocytes in post-massage urine (<4 WBCs per HPF) and IL-6 in prostatic secretion (<50 nmol/mL). Using these newly defined normal values, we detected inflammatory reaction in prostate-specific materials in 24.3%, 53.4% and 69% in control, lower urinary tract symptoms and prostatitis group, respectively. LIMITATION: only subjects with prostatic fluid volume >0.04 mL were included. We propose standardized method for analysis of inflammatory reaction in prostate-specific materials. Based on these newly defined normal values, we verified high prevalence of inflammatory forms of disease in both study groups, but also high prevalence of asymptomatic inflammatory prostatitis among control group of Estonian men. Combining results of analysis of the different inflammatory markers from available prostate-specific materials allows us to differentiate better between inflammatory and non-inflammatory forms of prostate diseases and hence to choose more precise treatment strategies. PMID- 28709179 TI - Modeling of nanoscale liquid mixture transport by density functional hydrodynamics. AB - Modeling of multiphase compositional hydrodynamics at nanoscale is performed by means of density functional hydrodynamics (DFH). DFH is the method based on density functional theory and continuum mechanics. This method has been developed by the authors over 20 years and used for modeling in various multiphase hydrodynamic applications. In this paper, DFH was further extended to encompass phenomena inherent in liquids at nanoscale. The new DFH extension is based on the introduction of external potentials for chemical components. These potentials are localized in the vicinity of solid surfaces and take account of the van der Waals forces. A set of numerical examples, including disjoining pressure, film precursors, anomalous rheology, liquid in contact with heterogeneous surface, capillary condensation, and forward and reverse osmosis, is presented to demonstrate modeling capabilities. PMID- 28709180 TI - Linear and nonlinear perturbation analysis of the symmetry breaking in time periodic propulsive wakes. AB - The two-dimensional and time-periodic wake flows produced by a pitching foil are investigated numerically for a fixed flapping amplitude. As the flapping frequency is increased, three regimes are identified in the time-marching nonlinear simulations. The first regime is characterized by nondeviated wake flows with zero time-averaged lift. In the second regime, the wake flow is slightly deviated from the streamwise direction and the time-averaged lift is slightly positive or negative. The third regime is characterized by larger deviations of the wake, associated with larger values of both the time-averaged lift and the thrust. The transition from the first to the second regime is examined by performing a Floquet stability analysis of the nondeviated wake. A specific method is introduced to compute the time-periodic, nondeviated wake when it is unstable. It is found that one synchronous antisymmetric mode becomes unstable at the critical frequency where deviation occurs. Investigation of its instantaneous and time-averaged characteristics show that it acts as a displacement mode translating the nondeviated wake away from the streamwise direction. Finally, it is demonstrated that the transition from the second to the third regime is linked to nonlinear effects that amplify both antisymmetric and symmetric perturbations around the foil. PMID- 28709181 TI - Q-voter model with nonconformity in freely forming groups: Does the size distribution matter? AB - We study a q-voter model with stochastic driving on a complete graph with q being a random variable described by probability density function P(q), instead of a constant value. We investigate two types of P(q): (1) artificial with the fixed expected value , but a changing variance and (2) empirical of freely forming groups in informal places. We investigate also two types of stochasticity that can be interpreted as different kinds of nonconformity (anticonformity or independence) to answer the question about differences observed at the macroscopic level between these two types of nonconformity in real social systems. Moreover, we ask the question if the behavior of a system depends on the average value of the group size q or rather on probability distribution function P(q). PMID- 28709182 TI - Performance optimization in two-dimensional Brownian rotary ratchet models. AB - With a model for two-dimensional (2D) Brownian rotary ratchets being capable of producing a net torque under athermal random forces, its optimization for mean angular momentum (L), mean angular velocity (omega), and efficiency (eta) is considered. In the model, supposing that such a small ratchet system is placed in a thermal bath, the motion of the rotor in the stator is described by the Langevin dynamics of a particle in a 2D ratchet potential, which consists of a static and a time-dependent interaction between rotor and stator; for the latter, we examine a force [randomly directed dc field (RDDF)] for which only the direction is instantaneously updated in a sequence of events in a Poisson process. Because of the chirality of the static part of the potential, it is found that the RDDF causes net rotation while coupling with the thermal fluctuations. Then, to maximize the efficiency of the power consumption of the net rotation, we consider optimizing the static part of the ratchet potential. A crucial point is that the proposed form of ratchet potential enables us to capture the essential feature of 2D ratchet potentials with two closed curves and allows us to systematically construct an optimization strategy. In this paper, we show a method for maximizing L, omega, and eta, its outcome in 2D two-tooth ratchet systems, and a direction of optimization for a three-tooth ratchet system. PMID- 28709183 TI - GOE-GUE-Poisson transitions in the nearest-neighbor spacing distribution of magnetoexcitons. AB - Recent investigations on the Hamiltonian of excitons by Schweiner et al.. [Phys. Rev. Lett. 118, 046401 (2017)]PRLTAO0031-900710.1103/PhysRevLett.118.046401 revealed that the combined presence of a cubic band structure and external fields breaks all antiunitary symmetries. The nearest-neighbor spacing distribution of magnetoexcitons can exhibit Poissonian statistics, the statistics of a Gaussian orthogonal ensemble (GOE), or a Gaussian unitary ensemble (GUE) depending on the system parameters. Hence, magnetoexcitons are an ideal system to investigate the transitions between these statistics. Here we investigate the transitions between GOE and GUE statistics and between Poissonian and GUE statistics by changing the angle of the magnetic field with respect to the crystal lattice and by changing the scaled energy known from the hydrogen atom in external fields. Comparing our results with analytical formulas for these transitions derived with random matrix theory, we obtain a very good agreement and thus confirm the Wigner surmise for the exciton system. PMID- 28709184 TI - From dynamical systems with time-varying delay to circle maps and Koopman operators. AB - In this paper, we investigate the influence of the retarded access by a time varying delay on the dynamics of delay systems. We show that there are two universality classes of delays, which lead to fundamental differences in dynamical quantities such as the Lyapunov spectrum. Therefore, we introduce an operator theoretic framework, where the solution operator of the delay system is decomposed into the Koopman operator describing the delay access and an operator similar to the solution operator known from systems with constant delay. The Koopman operator corresponds to an iterated map, called access map, which is defined by the iteration of the delayed argument of the delay equation. The dynamics of this one-dimensional iterated map determines the universality classes of the infinite-dimensional state dynamics governed by the delay differential equation. In this way, we connect the theory of time-delay systems with the theory of circle maps and the framework of the Koopman operator. In this paper, we extend our previous work [A. Otto, D. Muller, and G. Radons, Phys. Rev. Lett. 118, 044104 (2017)PRLTAO0031-900710.1103/PhysRevLett.118.044104] by elaborating the mathematical details and presenting further results also on the Lyapunov vectors. PMID- 28709185 TI - Fluctuation relations between hierarchical kinetically equivalent networks with Arrhenius-type transitions and their roles in systems and structural biology. AB - The legality of using simple kinetic schemes to determine the stochastic properties of a complex system depends on whether the fluctuations generated from hierarchical equivalent schemes are consistent with one another. To analyze this consistency, we perform lumping processes on the stochastic differential equations and the generalized fluctuation-dissipation theorem and apply them to networks with the frequently encountered Arrhenius-type transition rates. The explicit Langevin force derived from those networks enables us to calculate the state fluctuations caused by the intrinsic and extrinsic noises on the free energy surface and deduce their relations between kinetically equivalent networks. In addition to its applicability to wide classes of network related systems, such as those in structural and systems biology, the result sheds light on the fluctuation relations for general physical variables in Keizer's canonical theory. PMID- 28709186 TI - Weighted growing simplicial complexes. AB - Simplicial complexes describe collaboration networks, protein interaction networks, and brain networks and in general network structures in which the interactions can include more than two nodes. In real applications, often simplicial complexes are weighted. Here we propose a nonequilibrium model for weighted growing simplicial complexes. The proposed dynamics is able to generate weighted simplicial complexes with a rich interplay between weights and topology emerging not just at the level of nodes and links, but also at the level of faces of higher dimension. PMID- 28709187 TI - Modeling energy storage and structural evolution during finite viscoplastic deformation of glassy polymers. AB - The enthalpic response of amorphous polymers depends strongly on their thermal and deformation history. Annealing just below the glass transition temperature (T_{g}) causes a large endothermic overshoot of the isobaric heat capacity at T_{g} as measured by differential scanning calorimetry, while plastic deformation (cold work) can erase this overshoot and create an exothermic undershoot. This indicates that a strong coupling exists between the polymer structure, thermal response, and mechanical deformation. In this work, we apply a recently developed thermomechanical model for glassy polymers that couples structural evolution and viscoplastic deformation to investigate the effect of annealing and plastic deformation on the accumulation of stored energy during cold work and calorimetry measurements of heat flow. The thermomechanical model introduces the effective temperature as an additional state variable in a nonequilibrium thermodynamics setting to describe the structural evolution of the material. The results show that the model accurately describes the stress and enthalpy response of quenched and annealed polymers with different plastic predeformations. The model also shows that at 30% strain in uniaxial compression, 45% of the applied work is converted into stored energy, which is consistent with experimental data from literature. PMID- 28709188 TI - Solitons in the nonlinear Schrodinger equation with two power-law nonlinear terms modulated in time and space. AB - A nonlinear Schrodinger equation that includes two terms with power-law nonlinearity and external potential modulated both on time and on the spatial coordinates is considered. The model appears in various branches of contemporary physics, especially in the case of lower values of the nonlinearity power. A significant generalization of the similarity transformations approach to construct explicit localized solutions for the model with arbitrary power-law nonlinearities is introduced. We obtain the exact analytical bright and kink soliton solutions of the governing equation for different nonlinearities and potentials that are of particular interest in applications to Bose-Einstein condensates and nonlinear optics. Necessary conditions on the physical parameters for propagating envelope formation are presented. The obtained results can be straightforwardly applied to a large variety of nonlinear Schrodinger models and hence would be of value to understand nonlinear phenomena in a diversity of nonlinear media. PMID- 28709189 TI - Discovering phases, phase transitions, and crossovers through unsupervised machine learning: A critical examination. AB - We apply unsupervised machine learning techniques, mainly principal component analysis (PCA), to compare and contrast the phase behavior and phase transitions in several classical spin models-the square- and triangular-lattice Ising models, the Blume-Capel model, a highly degenerate biquadratic-exchange spin-1 Ising (BSI) model, and the two-dimensional XY model-and we examine critically what machine learning is teaching us. We find that quantified principal components from PCA not only allow the exploration of different phases and symmetry breaking, but they can distinguish phase-transition types and locate critical points. We show that the corresponding weight vectors have a clear physical interpretation, which is particularly interesting in the frustrated models such as the triangular antiferromagnet, where they can point to incipient orders. Unlike the other well-studied models, the properties of the BSI model are less well known. Using both PCA and conventional Monte Carlo analysis, we demonstrate that the BSI model shows an absence of phase transition and macroscopic ground state degeneracy. The failure to capture the "charge" correlations (vorticity) in the BSI model (XY model) from raw spin configurations points to some of the limitations of PCA. Finally, we employ a nonlinear unsupervised machine learning procedure, the "autoencoder method," and we demonstrate that it too can be trained to capture phase transitions and critical points. PMID- 28709190 TI - Anisotropy of electrostatic interaction in free-standing smectic-C^{*} films. AB - The correlation function of the director fluctuations in a free-standing smectic ferroelectric film is calculated theoretically. In the functional of free energy, the anisotropy of the Coulomb interaction of polarization charges is taken into account. The results of calculations were used to obtain the angular dependences of scattered light intensity. It has been shown that for relatively thick films, the anisotropy of the Coulomb interaction of polarization charges can change significantly the scattered light intensity. PMID- 28709191 TI - Discontinuous change of shear modulus for frictional jammed granular materials. AB - The shear modulus of jammed frictional granular materials with harmonic repulsive interaction under an oscillatory shear is numerically investigated. It is confirmed that the storage modulus, the real part of the shear modulus, for frictional grains with sufficiently small strain amplitude gamma_{0} discontinuously emerges at the jamming transition point. The storage modulus for small gamma_{0} differs from that of frictionless grains even in the zero friction limit, whereas they are almost identical with each other for sufficiently large gamma_{0}, where the transition becomes continuous. The stress strain curve exhibits a hysteresis loop even for a small strain, which connects a linear region for sufficiently small strain to another linear region for larger strain. We propose a scaling law to interpolate between the states of small and large gamma_{0}. PMID- 28709193 TI - Escape routes, weak links, and desynchronization in fluctuation-driven networks. AB - Shifting our electricity generation from fossil fuel to renewable energy sources introduces large fluctuations to the power system. Here, we demonstrate how increased fluctuations, reduced damping, and reduced intertia may undermine the dynamical robustness of power grid networks. Focusing on fundamental noise models, we derive analytic insights into which factors limit the dynamic robustness and how fluctuations may induce a system escape from an operating state. Moreover, we identify weak links in the grid that make it particularly vulnerable to fluctuations. These results thereby not only contribute to a theoretical understanding of how fluctuations act on distributed network dynamics, they may also help designing future renewable energy systems to be more robust. PMID- 28709192 TI - Entropy measures, entropy estimators, and their performance in quantifying complex dynamics: Effects of artifacts, nonstationarity, and long-range correlations. AB - Entropy measures are widely applied to quantify the complexity of dynamical systems in diverse fields. However, the practical application of entropy methods is challenging, due to the variety of entropy measures and estimators and the complexity of real-world time series, including nonstationarities and long-range correlations (LRC). We conduct a systematic study on the performance, bias, and limitations of three basic measures (entropy, conditional entropy, information storage) and three traditionally used estimators (linear, kernel, nearest neighbor). We investigate the dependence of entropy measures on estimator- and process-specific parameters, and we show the effects of three types of nonstationarities due to artifacts (trends, spikes, local variance change) in simulations of stochastic autoregressive processes. We also analyze the impact of LRC on the theoretical and estimated values of entropy measures. Finally, we apply entropy methods on heart rate variability data from subjects in different physiological states and clinical conditions. We find that entropy measures can only differentiate changes of specific types in cardiac dynamics and that appropriate preprocessing is vital for correct estimation and interpretation. Demonstrating the limitations of entropy methods and shedding light on how to mitigate bias and provide correct interpretations of results, this work can serve as a comprehensive reference for the application of entropy methods and the evaluation of existing studies. PMID- 28709194 TI - Effects of communication burstiness on consensus formation and tipping points in social dynamics. AB - Current models for opinion dynamics typically utilize a Poisson process for speaker selection, making the waiting time between events exponentially distributed. Human interaction tends to be bursty though, having higher probabilities of either extremely short waiting times or long periods of silence. To quantify the burstiness effects on the dynamics of social models, we place in competition two groups exhibiting different speakers' waiting-time distributions. These competitions are implemented in the binary naming game and show that the relevant aspect of the waiting-time distribution is the density of the head rather than that of the tail. We show that even with identical mean waiting times, a group with a higher density of short waiting times is favored in competition over the other group. This effect remains in the presence of nodes holding a single opinion that never changes, as the fraction of such committed individuals necessary for achieving consensus decreases dramatically when they have a higher head density than the holders of the competing opinion. Finally, to quantify differences in burstiness, we introduce the expected number of small time activations and use it to characterize the early-time regime of the system. PMID- 28709195 TI - Finite-size analysis of the detectability limit of the stochastic block model. AB - It has been shown in recent years that the stochastic block model is sometimes undetectable in the sparse limit, i.e., that no algorithm can identify a partition correlated with the partition used to generate an instance, if the instance is sparse enough and infinitely large. In this contribution, we treat the finite case explicitly, using arguments drawn from information theory and statistics. We give a necessary condition for finite-size detectability in the general SBM. We then distinguish the concept of average detectability from the concept of instance-by-instance detectability and give explicit formulas for both definitions. Using these formulas, we prove that there exist large equivalence classes of parameters, where widely different network ensembles are equally detectable with respect to our definitions of detectability. In an extensive case study, we investigate the finite-size detectability of a simplified variant of the SBM, which encompasses a number of important models as special cases. These models include the symmetric SBM, the planted coloring model, and more exotic SBMs not previously studied. We conclude with three appendices, where we study the interplay of noise and detectability, establish a connection between our information-theoretic approach and random matrix theory, and provide proofs of some of the more technical results. PMID- 28709196 TI - Characterizing time series via complexity-entropy curves. AB - The search for patterns in time series is a very common task when dealing with complex systems. This is usually accomplished by employing a complexity measure such as entropies and fractal dimensions. However, such measures usually only capture a single aspect of the system dynamics. Here, we propose a family of complexity measures for time series based on a generalization of the complexity entropy causality plane. By replacing the Shannon entropy by a monoparametric entropy (Tsallis q entropy) and after considering the proper generalization of the statistical complexity (q complexity), we build up a parametric curve (the q complexity-entropy curve) that is used for characterizing and classifying time series. Based on simple exact results and numerical simulations of stochastic processes, we show that these curves can distinguish among different long-range, short-range, and oscillating correlated behaviors. Also, we verify that simulated chaotic and stochastic time series can be distinguished based on whether these curves are open or closed. We further test this technique in experimental scenarios related to chaotic laser intensity, stock price, sunspot, and geomagnetic dynamics, confirming its usefulness. Finally, we prove that these curves enhance the automatic classification of time series with long-range correlations and interbeat intervals of healthy subjects and patients with heart disease. PMID- 28709197 TI - Picosecond time-resolved measurements of dense plasma line shifts. AB - Picosecond time-resolved x-ray spectroscopy is used to measure the spectral line shift of the 1s2p-1s^{2} transition in He-like Al ions as a function of the instantaneous plasma conditions. The plasma temperature and density are inferred from the Al He_{alpha} complex using a nonlocal-thermodynamic-equilibrium atomic physics model. The experimental spectra show a linearly increasing redshift for electron densities of 1-5*10^{23}cm^{-3}. The measured line shifts are broadly consistent with a generalized analytic line-shift model based on calculations of a self-consistent field ion-sphere model. PMID- 28709198 TI - Revoking amplitude and oscillation deaths by low-pass filter in coupled oscillators. AB - When in an ensemble of oscillatory units the interaction occurs through a diffusion-like manner, the intrinsic oscillations can be quenched through two structurally different scenarios: amplitude death (AD) and oscillation death (OD). Unveiling the underlying principles of stable rhythmic activity against AD and OD is a challenging issue of substantial practical significance. Here, by developing a low-pass filter (LPF) to track the output signals of the local system in the coupling, we show that it can revoke both AD and OD, and even the AD to OD transition, thereby giving rise to oscillations in coupled nonlinear oscillators under diverse death scenarios. The effectiveness of the local LPF is proven to be valid in an arbitrary network of coupled oscillators with distributed propagation delays. The constructive role of the local LPF in revoking deaths provides a potential dynamic mechanism of sustaining a reliable rhythmicity in real-world systems. PMID- 28709199 TI - Gain and loss in open quantum systems. AB - Photosynthesis is the basic process used by plants to convert light energy in reaction centers into chemical energy. The high efficiency of this process is not yet understood today. Using the formalism for the description of open quantum systems by means of a non-Hermitian Hamilton operator, we consider initially the interplay of gain (acceptor) and loss (donor). Near singular points it causes fluctuations of the cross section which appear without any excitation of internal degrees of freedom of the system. This process occurs therefore very quickly and with high efficiency. We then consider the excitation of resonance states of the system by means of these fluctuations. This second step of the whole process takes place much slower than the first one, because it involves the excitation of internal degrees of freedom of the system. The two-step process as a whole is highly efficient, and the decay is biexponential. We provide, if possible, the results of analytical studies, otherwise characteristic numerical results. The similarities of the obtained results to light harvesting in photosynthetic organisms are discussed. PMID- 28709200 TI - Frustrated crystallization of a monolayer of magnetized beads under geometrical confinement. AB - We present a systematic experimental study of the confinement effect on the crystallization of a monolayer of magnetized beads. The particles are millimeter scale grains interacting through the short range magnetic dipole-dipole potential induced by an external magnetic field. The grains are confined by repulsing walls and are homogeneously distributed inside the cell. A two-dimensional (2d) Brownian motion is induced by horizontal mechanical vibrations. Therefore, the balance between magnetic interaction and agitation allows investigating 2d phases through direct visualization. The effect of both confinement size and shape on the grains' organization in the low-energy state has been investigated. Concerning the confinement shape, triangular, square, pentagonal, hexagonal, heptagonal, and circular geometries have been considered. The grain organization was analyzed after a slow cooling process. Through the measurement of the averaged bond order parameter for the different confinement geometries, it has been shown that cell geometry strongly affects the ordering of the system. Moreover, many kinds of defects, whose observation rate is linked to the geometry, have been observed: disclinations, dislocations, defects chain, and also more exotic defects such as a rosette. Finally, the influence of confinement size has been investigated and we point out that no finite-size effect occurs for a hexagonal cell, but the finite-size effect changes from one geometry to another. PMID- 28709201 TI - Electrohydrodynamic instability of ion-concentration shock wave in electrophoresis. AB - Capillary electrophoresis techniques often involve ion-concentration shock waves in an electrolyte solution, propagating under the effect of an external electric field. These shock waves are characterized by self-sharpening gradients in ion concentrations and electrical conductivity that are collinear with the electric field. The coupling of electric field and fluid motion at the shock interface sometimes leads to an undesirable electrohydrodynamic (EHD) instability. Using linear stability analysis, we describe the motion of small-amplitude disturbances of an electrophoretic shock wave. Our analysis shows that the EHD instability results due to the competition between destabilizing electroviscous flow and stabilizing electromigration of the shock wave. The ratio of timescales corresponding to electroviscous flow and electromigration yields a threshold criterion for the onset of instability. We present a validation of this threshold criterion with published experimental data and also describe the physical mechanism underlying the EHD instability of the electrophoretic shock wave. PMID- 28709202 TI - Fluctuation-induced forces in confined ideal and imperfect Bose gases. AB - Fluctuation-induced ("Casimir") forces caused by thermal and quantum fluctuations are investigated for ideal and imperfect Bose gases confined to d-dimensional films of size infinity^{d-1}*D under periodic (P), antiperiodic (A), Dirichlet Dirichlet (DD), Neumann-Neumann (NN), and Robin (R) boundary conditions (BCs). The full scaling functions Upsilon_{d}^{BC}(x_{lambda}=D/lambda_{th},x_{xi}=D/xi) of the residual reduced grand potential per area phi_{res,d}^{BC}(T,MU,D)=D^{-(d 1)}Upsilon_{d}^{BC}(x_{lambda},x_{xi}) are determined for the ideal gas case with these BCs, where lambda_{th} and xi are the thermal de Broglie wavelength and the bulk correlation length, respectively. The associated limiting scaling functions Theta_{d}^{BC}(x_{xi})=Upsilon_{d}^{BC}(infinity,x_{xi}) describing the critical behavior at the bulk condensation transition are shown to agree with those previously determined from a massive free O(2) theory for BC=P,A,DD,DN,NN. For d=3, they are expressed in closed analytical form in terms of polylogarithms. The analogous scaling functions Upsilon_{d}^{BC}(x_{lambda},x_{xi},c_{1}D,c_{2}D) and Theta_{d}^{R}(x_{xi},c_{1}D,c_{2}D) under the RBCs (?_{z} c_{1})phi|_{z=0}=(?_{z}+c_{2})phi|_{z=D}=0 with c_{1}>=0 and c_{2}>=0 are also determined. The corresponding scaling functions Upsilon_{infinity,d}^{P}(x_{lambda},x_{xi}) and Theta_{infinity,d}^{P}(x_{xi}) for the imperfect Bose gas are shown to agree with those of the interacting Bose gas with n internal degrees of freedom in the limit n->infinity. Hence, for d=3, Theta_{infinity,d}^{P}(x_{xi}) is known exactly in closed analytic form. To account for the breakdown of translation invariance in the direction perpendicular to the boundary planes implied by free BCs such as DDBCs, a modified imperfect Bose gas model is introduced that corresponds to the limit n >infinity of this interacting Bose gas. Numerically and analytically exact results for the scaling function Theta_{infinity,3}^{DD}(x_{xi}) therefore follow from those of the O(2n)phi^{4} model for n->infinity. PMID- 28709203 TI - Pragmatical access to the viscous flow of undercooled liquids. AB - The paper derives a relation for the viscosity of undercooled liquids on the basis of the pragmatical model concept of Eshelby relaxations with a finite lifetime. From accurate shear relaxation data in the literature, one finds that slightly less than half of the internal stresses relax directly via single Eshelby relaxations; the larger part dissolves at the terminal lifetime, which is a combined effect of many Eshelby relaxations. PMID- 28709204 TI - Lattice Boltzmann solution of the transient Boltzmann transport equation in radiative and neutron transport. AB - Applications of the transient Boltzmann transport equation (BTE) have undergone much investigation, such as radiative heat transfer and neutron transport. This paper provides a lattice Boltzmann model to efficiently resolve the multidimensional transient BTE. For a higher angular resolution, enough transport directions are considered while the transient BTE in each direction is treated as a conservation law equation and solved independently. Both macroscopic equations recovered from a Chapman-Enskog expansion and simulated results of typical benchmark problems show not only the second-order accuracy but also the flexibility and applicability of the proposed lattice Boltzmann model. This approach may contribute a powerful technique for the parallel simulation of large scale engineering and some alternative perspectives for solving the nonlinear transport problem further. PMID- 28709205 TI - Fourth-order analysis of a diffusive lattice Boltzmann method for barrier coatings. AB - We examine the applicability of diffusive lattice Boltzmann methods to simulate the fluid transport through barrier coatings, finding excellent agreement between simulations and analytical predictions for standard parameter choices. To examine more interesting non-Fickian behavior and multiple layers of different coatings, it becomes necessary to explore a wider range of parameters. However, such a range of parameters exposes deficiencies in such an implementation. To investigate these discrepancies, we examine the form of higher-order terms in the hydrodynamic limit of our lattice Boltzmann method. We identify these corrections to fourth order and validate these predictions with high accuracy. However, it is observed that the validated correction terms do not fully explain the bulk of observed error. This error was instead caused by the standard finite boundary conditions for the contact of the coating with the imposed environment. We identify a self-consistent form of these boundary conditions for which these errors are dramatically reduced. The instantaneous switching used as a boundary condition for the barrier problem proves demanding enough that any higher-order corrections meaningfully contribute for a small range of parameters. There is a large parameter space where the agreement between simulations and analytical predictions even in the second-order form are below 0.1%, making further improvements to the algorithm unnecessary for such an application. PMID- 28709206 TI - Spectral partitioning in equitable graphs. AB - Graph partitioning problems emerge in a wide variety of complex systems, ranging from biology to finance, but can be rigorously analyzed and solved only for a few graph ensembles. Here, an ensemble of equitable graphs, i.e., random graphs with a block-regular structure, is studied, for which analytical results can be obtained. In particular, the spectral density of this ensemble is computed exactly for a modular and bipartite structure. Kesten-McKay's law for random regular graphs is found analytically to apply also for modular and bipartite structures when blocks are homogeneous. An exact solution to graph partitioning for two equal-sized communities is proposed and verified numerically, and a conjecture on the absence of an efficient recovery detectability transition in equitable graphs is suggested. A final discussion summarizes results and outlines their relevance for the solution of graph partitioning problems in other graph ensembles, in particular for the study of detectability thresholds and resolution limits in stochastic block models. PMID- 28709207 TI - Population annealing simulations of a binary hard-sphere mixture. AB - Population annealing is a sequential Monte Carlo scheme well suited to simulating equilibrium states of systems with rough free energy landscapes. Here we use population annealing to study a binary mixture of hard spheres. Population annealing is a parallel version of simulated annealing with an extra resampling step that ensures that a population of replicas of the system represents the equilibrium ensemble at every packing fraction in an annealing schedule. The algorithm and its equilibration properties are described, and results are presented for a glass-forming fluid composed of a 50/50 mixture of hard spheres with diameter ratio of 1.4:1. For this system, we obtain precise results for the equation of state in the glassy regime up to packing fractions phi~0.60 and study deviations from the Boublik-Mansoori-Carnahan-Starling-Leland equation of state. For higher packing fractions, the algorithm falls out of equilibrium and a free volume fit predicts jamming at packing fraction phi~0.667. We conclude that population annealing is an effective tool for studying equilibrium glassy fluids and the jamming transition. PMID- 28709208 TI - Amplitude death in a pair of one-dimensional complex Ginzburg-Landau systems coupled by diffusive connections. AB - This paper shows that, in a pair of one-dimensional complex Ginzburg-Landau (CGL) systems, diffusive connections can induce amplitude death. Stability analysis of a spatially uniform steady state in coupled CGL systems reveals that amplitude death never occurs in a pair of identical CGL systems coupled by no-delay connection, but can occur in the case of delay connection. Moreover, amplitude death never occurs in coupled identical CGL systems with zero nominal frequency. Based on these analytical results, we propose a procedure for designing the connection delay time and the coupling strength to induce spatial-robust stabilization, that is, a stabilization of the steady state for any system size and any boundary condition. Numerical simulations are performed to confirm the analytical results. PMID- 28709209 TI - Universality in quasi-two-dimensional granular shock fronts above an intruder. AB - We experimentally study quasi-two-dimensional dilute granular flow around intruders whose shape, size, and relative impact speed are systematically varied. Direct measurement of the flow field reveals that three in-principle independent measurements of the nonuniformity of the flow field are in fact all linearly related: (1) granular temperature, (2) flow-field divergence, and (3) shear strain rate. The shock front is defined as the local maxima in each of these measurements. The shape of the shock front is well described by an inverted catenary and is driven by the formation of a dynamic arch during steady flow. We find universality in the functional form of the shock front within the range of experimental values probed. Changing the intruder size, concavity, and impact speed only results in a scaling and shifting of the shock front. We independently measure the horizontal lift force on the intruder and find that it can be understood as a result of the interplay between the shock profile and the intruder shape. PMID- 28709210 TI - Columnar domains and anisotropic growth laws in dipolar systems. AB - Magnetic and dielectric solids are well-represented by the Ising model with dipolar interactions (IM+DI). The latter are long-ranged, fluctuating in sign, and anisotropic. Equilibrium studies have revealed novel consequences of these complicated interactions, but their effect on nonequilibrium behavior is not explored. We perform a deep temperature quench to study the kinetics of domain growth in the d=3 IM+DI. Our main observations are (i) the emergence of columnar domains along the z axis (Ising axis) with a transient periodicity in the xy plane; (ii) anisotropic growth laws: l_{rho}(t)~t^{phi}; l_{z}(t)~t^{psi}, where rho[over ?]=(x,y) and l is the characteristic length scale; (iii) generalized dynamical scaling for the correlation function: C(rho,z;t)=g(rho/l_{rho},z/l_{z}); and (iv) an asymptotic Porod tail in the corresponding structure factor: S(k_{rho},0;t)~k_{rho}^{-3}; S(0,k_{z};t)~k_{z}^{ 2}. Our results explain the experimentally observed columnar morphologies in a wide range of dipolar systems, and they have important technological implications. PMID- 28709211 TI - Combustion instability mitigation by magnetic fields. AB - The present interdisciplinary study combines electromagnetics and combustion to unveil an original and basic experiment displaying a spontaneous flame instability that is mitigated as the non-premixed sooting flame experiences a magnetic perturbation. This magnetic instability mitigation is reproduced by direct numerical simulations to be further elucidated by a flow stability analysis. A key role in the stabilization process is attributed to the momentum and thermochemistry coupling that the magnetic force, acting mainly on paramagnetic oxygen, contributes to sustain. The spatial local stability analysis based on the numerical simulations shows that the magnetic field tends to reduce the growth rates of small flame perturbations. PMID- 28709212 TI - Contribution of electron-atom collisions to the plasma conductivity of noble gases. AB - We present an approach which allows the consistent treatment of bound states in the context of dc conductivity in dense partially ionized noble gas plasmas. Besides electron-ion and electron-electron collisions, further collision mechanisms owing to neutral constituents are taken into account. Especially at low temperatures of 10^{4}to10^{5} K, electron-atom collisions give a substantial contribution to the relevant correlation functions. We suggest an optical potential for the description of the electron-atom scattering which is applicable for all noble gases. The electron-atom momentum-transfer cross section is in agreement with experimental scattering data. In addition, the influence of the medium is analyzed, the optical potential is advanced including screening effects. The position of the Ramsauer minimum is influenced by the plasma. Alternative approaches for the electron-atom potential are discussed. Good agreement of calculated conductivity with experimental data for noble gas plasmas is obtained. PMID- 28709213 TI - When memory pays: Discord in hidden Markov models. AB - When is keeping a memory of observations worthwhile? We use hidden Markov models to look at phase transitions that emerge when comparing state estimates in systems with discrete states and noisy observations. We infer the underlying state of the hidden Markov models from the observations in two ways: through naive observations, which take into account only the current observation, and through Bayesian filtering, which takes the history of observations into account. Defining a discord order parameter to distinguish between the different state estimates, we explore hidden Markov models with various numbers of states and symbols and varying transition-matrix symmetry. All behave similarly. We calculate analytically the critical point where keeping a memory of observations starts to pay off. A mapping between hidden Markov models and Ising models gives added insight into the associated phase transitions. PMID- 28709214 TI - Stochastic thermodynamics in the strong coupling regime: An unambiguous approach based on coarse graining. AB - We consider a classical and possibly driven composite system X?Y weakly coupled to a Markovian thermal reservoir R so that an unambiguous stochastic thermodynamics ensues for X?Y. This setup can be equivalently seen as a system X strongly coupled to a non-Markovian reservoir Y?R. We demonstrate that only in the limit where the dynamics of Y is much faster than X, our unambiguous expressions for thermodynamic quantities, such as heat, entropy, or internal energy, are equivalent to the strong coupling expressions recently obtained in the literature using the Hamiltonian of mean force. By doing so, we also significantly extend these results by formulating them at the level of instantaneous rates and by allowing for time-dependent couplings between X and its environment. Away from the limit where Y evolves much faster than X, previous approaches fail to reproduce the correct results from the original unambiguous formulation, as we illustrate numerically for an underdamped Brownian particle coupled strongly to a non-Markovian reservoir. PMID- 28709215 TI - Auxiliary variables for numerically solving nonlinear equations with softly broken symmetries. AB - General methods for solving simultaneous nonlinear equations work by generating a sequence of approximate solutions that successively improve a measure of the total error. However, if the total error function has a narrow curved valley, the available techniques tend to find the solution after a very large number of steps, if ever. The solver first converges rapidly to the valley, but once there it converges extremely slowly to the solution. In this paper we show that in the specific physically important case where these valleys are the result of a softly broken symmetry, the solution can often be found much more quickly by adding the generators of the softly broken symmetry as auxiliary variables. This makes the number of variables more than the equations and hence there will be a family of solutions, any one of which would be acceptable. We present a procedure for finding solutions in this case and apply it to several simple examples and an important problem in the physics of false vacuum decay. We also provide a Mathematica package that implements Powell's hybrid method with the generalization to allow more variables than equations. PMID- 28709216 TI - Einstein relation and hydrodynamics of nonequilibrium mass transport processes. AB - We derive hydrodynamics of paradigmatic conserved-mass transport processes on a ring. The systems, governed by chipping, diffusion, and coalescence of masses, eventually reach a nonequilibrium steady state, having nontrivial correlations, with steady-state measures in most cases not known. In these processes, we analytically calculate two transport coefficients, bulk-diffusion coefficient and conductivity. Remarkably, the two transport coefficients obey an equilibrium-like Einstein relation even when the microscopic dynamics violates detailed balance and systems are far from equilibrium. Moreover, we show, using a macroscopic fluctuation theory, that the probability of large deviation in density, obtained from the above hydrodynamics, is in complete agreement with the same derived earlier by Das et al. [Phys. Rev. E 93, 062135 (2016)2470 004510.1103/PhysRevE.93.062135] using an additivity property. PMID- 28709217 TI - Predicting mixing via resonances: Application to spherical piecewise isometries. AB - We present an analytic method to find the areas of nonmixing regions in orientation-preserving spherical piecewise isometries (PWIs), and apply it to determine the mixing efficacy of a class of spherical PWIs derived from granular flow in a biaxial tumbler. We show that mixing efficacy has a complex distribution across the protocol space, with local minima in mixing efficacy, termed resonances, that can be determined analytically. These resonances are caused by the interaction of two mode-locking-like phenomena. PMID- 28709218 TI - Transient hydrodynamic finite-size effects in simulations under periodic boundary conditions. AB - We use lattice-Boltzmann and analytical calculations to investigate transient hydrodynamic finite-size effects induced by the use of periodic boundary conditions. These effects are inevitable in simulations at the molecular, mesoscopic, or continuum levels of description. We analyze the transient response to a local perturbation in the fluid and obtain the local velocity correlation function via linear response theory. This approach is validated by comparing the finite-size effects on the steady-state velocity with the known results for the diffusion coefficient. We next investigate the full time dependence of the local velocity autocorrelation function. We find at long times a crossover between the expected t^{-3/2} hydrodynamic tail and an oscillatory exponential decay, and study the scaling with the system size of the crossover time, exponential rate and amplitude, and oscillation frequency. We interpret these results from the analytic solution of the compressible Navier-Stokes equation for the slowest modes, which are set by the system size. The present work not only provides a comprehensive analysis of hydrodynamic finite-size effects in bulk fluids, which arise regardless of the level of description and simulation algorithm, but also establishes the lattice-Boltzmann method as a suitable tool to investigate such effects in general. PMID- 28709219 TI - Erratum: Relationship between bond-breakage correlations and four-point correlations in heterogeneous glassy dynamics: Configuration changes and vibration modes [Phys. Rev. E 86, 041504 (2012)]. AB - This corrects the article DOI: 10.1103/PhysRevE.86.041504. PMID- 28709220 TI - Three-dimensional mechanisms of macro-to-micro-scale transport and absorption enhancement by gut villi motions. AB - We evaluate the potential for physiological control of intestinal absorption by the generation of "micromixing layers" (MMLs) induced by coordinated motions of mucosal villi coupled with lumen-scale "macro" eddying motions generated by gut motility. To this end, we apply a three-dimensional (3D) multigrid lattice Boltzmann model of a lid-driven macroscale cavity flow with microscale fingerlike protuberances at the lower surface. Integrated with a previous 2D study of leaflike villi, we generalize to 3D the 2D mechanisms found there to enhance nutrient absorption by controlled villi motility. In three dimensions, increased lateral spacing within villi within groups that move axially with the macroeddy reduces MML strength and absorptive enhancement relative to two dimensions. However, lateral villi motions create helical 3D particle trajectories that enhance absorption rate to the level of axially moving 2D leaflike villi. The 3D enhancements are associated with interesting fundamental adjustments to 2D micro macro-motility coordination mechanisms and imply a refined potential for physiological or pharmaceutical control of intestinal absorption. PMID- 28709221 TI - Artificial living crystals in confined environment. AB - Similar to the spontaneous formation of colonies of bacteria, flocks of birds, or schools of fish, "living crystals" can be formed by artificial self-propelled particles such as Janus colloids. Unlike usual solids, these "crystals" are far from thermodynamic equilibrium. They fluctuate in time forming a crystalline structure, breaking apart and re-forming again. We propose a method to stabilize living crystals by applying a weak confinement potential that does not suppress the ability of the particles to perform self-propelled motion, but it stabilizes the structure and shape of the dynamical clusters. This gives rise to such configurations of living crystals as "living shells" formed by Janus colloids. Moreover, the shape of the stable living clusters can be controlled by tuning the potential strength. Our proposal can be verified experimentally with either artificial microswimmers such as Janus colloids, or with living active matter. PMID- 28709222 TI - Population density equations for stochastic processes with memory kernels. AB - We present a method for solving population density equations (PDEs)--a mean-field technique describing homogeneous populations of uncoupled neurons-where the populations can be subject to non-Markov noise for arbitrary distributions of jump sizes. The method combines recent developments in two different disciplines that traditionally have had limited interaction: computational neuroscience and the theory of random networks. The method uses a geometric binning scheme, based on the method of characteristics, to capture the deterministic neurodynamics of the population, separating the deterministic and stochastic process cleanly. We can independently vary the choice of the deterministic model and the model for the stochastic process, leading to a highly modular numerical solution strategy. We demonstrate this by replacing the master equation implicit in many formulations of the PDE formalism by a generalization called the generalized Montroll-Weiss equation-a recent result from random network theory-describing a random walker subject to transitions realized by a non-Markovian process. We demonstrate the method for leaky- and quadratic-integrate and fire neurons subject to spike trains with Poisson and gamma-distributed interspike intervals. We are able to model jump responses for both models accurately to both excitatory and inhibitory input under the assumption that all inputs are generated by one renewal process. PMID- 28709223 TI - Instability evolution of the viscous elliptic liquid jet in the Rayleigh regime. AB - For jet flow emanating from noncircular orifices, an unbalanced surface tension force leads to capillary instability, which is independent of influence from the ambient air in the Rayleigh regime. In the present article, the dynamic behavior of incompressible elliptical jets in the Rayleigh regime is investigated. Theoretically, with the consideration of the fluid viscosity, the solution of the Cosserat equation consists of a particular solution and a complementary solution. For the complementary solution the wave number of disturbance modes has two complex conjugate roots, which are responsible for the jet breakup. To match the nonzero particular solution, a spatial wave needs to be introduced, which is independent of external perturbations. Physically, such a spatial wave is interpreted as the axis-switching phenomenon. The predicted features of the axis switching wavelength and the damping effect from the fluid viscosity have been successfully verified by experimental results. Moreover, the dispersion relations from the present theory suggest that the growth rate of spatial instability is influenced by orifice eccentricity, the Weber number, and the Ohnesorge number. PMID- 28709224 TI - Entropy production and time asymmetry in the presence of strong interactions. AB - It is known that the equilibrium properties of open classical systems that are strongly coupled to a heat bath are described by a set of thermodynamic potentials related to the system's Hamiltonian of mean force. By adapting this framework to a more general class of nonequilibrium states, we show that the equilibrium properties of the bath can be well defined, even when the system is arbitrarily far from equilibrium and correlated with the bath. These states, which retain a notion of temperature, take the form of conditional equilibrium distributions. For out-of-equilibrium processes we show that the average entropy production quantifies the extent to which the system and bath state is driven away from the conditional equilibrium distribution. In addition, we show that the stochastic entropy production satisfies a generalized Crooks relation and can be used to quantify time asymmetry of correlated nonequilibrium processes. These results naturally extend the familiar properties of entropy production in weakly coupled systems to the strong coupling regime. Experimental measurements of the entropy production at strong coupling could be pursued using optomechanics or trapped-ion systems, which allow strong coupling to be engineered. PMID- 28709225 TI - Ultra-long-range dynamic correlations in a microscopic model for aging gels. AB - We use large-scale computer simulations to explore the nonequilibrium aging dynamics in a microscopic model for colloidal gels. We find that gelation resulting from a kinetically arrested phase separation is accompanied by "anomalous" particle dynamics revealed by superdiffusive particle motion and compressed exponential relaxation of time correlation functions. Spatiotemporal analysis of the dynamics reveals intermittent heterogeneities producing spatial correlations over extremely large length scales. Our study is a microscopically resolved model reproducing all features of the spontaneous aging dynamics observed experimentally in soft materials. PMID- 28709226 TI - Kinetic modeling of x-ray laser-driven solid Al plasmas via particle-in-cell simulation. AB - Solid-density plasmas driven by intense x-ray free-electron laser (XFEL) radiation are seeded by sources of nonthermal photoelectrons and Auger electrons that ionize and heat the target via collisions. Simulation codes that are commonly used to model such plasmas, such as collisional-radiative (CR) codes, typically assume a Maxwellian distribution and thus instantaneous thermalization of the source electrons. In this study, we present a detailed description and initial applications of a collisional particle-in-cell code, picls, that has been extended with a self-consistent radiation transport model and Monte Carlo models for photoionization and KLL Auger ionization, enabling the fully kinetic simulation of XFEL-driven plasmas. The code is used to simulate two experiments previously performed at the Linac Coherent Light Source investigating XFEL-driven solid-density Al plasmas. It is shown that picls-simulated pulse transmissions using the Ecker-Kroll continuum-lowering model agree much better with measurements than do simulations using the Stewart-Pyatt model. Good quantitative agreement is also found between the time-dependent picls results and those of analogous simulations by the CR code scfly, which was used in the analysis of the experiments to accurately reproduce the observed Kalpha emissions and pulse transmissions. Finally, it is shown that the effects of the nonthermal electrons are negligible for the conditions of the particular experiments under investigation. PMID- 28709227 TI - Broadband cloaking of flexural waves. AB - The governing equation for elastic waves in flexural plates is not form invariant, and hence designing a cloak for such waves faces a major challenge. Here, we present the design of a perfect broadband cloak for flexural waves through the use of a nonlinear transformation in the region of the cloak and by matching term by term the original and transformed equations and also assuming a prestressed material with body forces. For a readily achievable flexural cloak in a physical setting, we further present an approximate adoption of our perfect cloak under more restrictive physical constraints. Through direct simulation of the governing equations, we show that this cloak, as well, maintains a consistently high cloaking efficiency over a broad range of frequencies. The methodology developed here may be used for steering waves and designing cloaks in other physical systems with non-form-invariant governing equations. PMID- 28709228 TI - Direct numerical simulation of an arbitrarily shaped particle at a fluidic interface. AB - A consistent formulation is presented for the direct numerical simulation of an arbitrarily shaped colloidal particle at a deformable fluidic interface. The rigid colloidal particle is decomposed into a collection of solid spherical beads and the three-phase boundaries are replaced with smoothly spreading interfaces. The major merit of the present formulation lies in the ease with which the geometrical decomposition of the colloidal particle is implemented, yet allows the dynamic simulation of intricate three-dimensional colloidal shapes in a binary fluid. The dynamics of a rodlike, a platelike, and a ringlike particle are presently tested. It is found that platelike particles attach more rapidly to a fluidic interface and are subsequently harder to dislodge when subject to an external force. Using the Bond number, i.e., the ratio of the gravitational force to the reference capillary force, a spherical particle with equal affinity for the two fluids breaks away from a fluidic interface at the critical value Bo=0.75. This value is in line with our numerical experiments. It is here shown that a plate and a ring of equivalent masses detach at greater critical Bond numbers approximately equal to Bo=1.3. Results of this study will find applications in the stabilization of emulsions by colloids and in the recovery of colloidal particles by rising bubbles. PMID- 28709229 TI - Phenomenology of stochastic exponential growth. AB - Stochastic exponential growth is observed in a variety of contexts, including molecular autocatalysis, nuclear fission, population growth, inflation of the universe, viral social media posts, and financial markets. Yet literature on modeling the phenomenology of these stochastic dynamics has predominantly focused on one model, geometric Brownian motion (GBM), which can be described as the solution of a Langevin equation with linear drift and linear multiplicative noise. Using recent experimental results on stochastic exponential growth of individual bacterial cell sizes, we motivate the need for a more general class of phenomenological models of stochastic exponential growth, which are consistent with the observation that the mean-rescaled distributions are approximately stationary at long times. We show that this behavior is not consistent with GBM, instead it is consistent with power-law multiplicative noise with positive fractional powers. Therefore, we consider this general class of phenomenological models for stochastic exponential growth, provide analytical solutions, and identify the important dimensionless combination of model parameters, which determines the shape of the mean-rescaled distribution. We also provide a prescription for robustly inferring model parameters from experimentally observed stochastic growth trajectories. PMID- 28709230 TI - Thermodynamics of quantum information scrambling. AB - Scrambling of quantum information can conveniently be quantified by so-called out of-time-order correlators (OTOCs), i.e., correlators of the type <[W_{tau},V]^{?}[W_{tau},V]>, whose measurements present a formidable experimental challenge. Here we report on a method for the measurement of OTOCs based on the so-called two-point measurement scheme developed in the field of nonequilibrium quantum thermodynamics. The scheme is of broader applicability than methods employed in current experiments and provides a clear-cut interpretation of quantum information scrambling in terms of nonequilibrium fluctuations of thermodynamic quantities, such as work and heat. Furthermore, we provide a numerical example on a spin chain which highlights the utility of our thermodynamic approach when understanding the differences between integrable and ergodic behaviors. We also discuss how the method can be used to extend the reach of current experiments. PMID- 28709231 TI - Output-only parameter identification of a colored-noise-driven Van-der-Pol oscillator: Thermoacoustic instabilities as an example. AB - The problem of output-only parameter identification for nonlinear oscillators forced by colored noise is considered. In this context, it is often assumed that the forcing noise is white, since its actual spectral content is unknown. The impact of this white-noise forcing assumption upon parameter identification is quantitatively analyzed. First, a Van-der-Pol oscillator forced by an Ornstein Uhlenbeck process is considered. Second, the practical case of thermoacoustic limit cycles in combustion chambers with turbulence-induced forcing is investigated. It is shown that in both cases, the system parameters are accurately identified if time signals are appropriately band-pass-filtered around the oscillator eigenfrequency. PMID- 28709232 TI - Coupling conditions for globally stable and robust synchrony of chaotic systems. AB - We propose a set of general coupling conditions to select a coupling profile (a set of coupling matrices) from the linear flow matrix of dynamical systems for realizing global stability of complete synchronization (CS) in identical systems and robustness to parameter perturbation. The coupling matrices define the coupling links between any two oscillators in a network that consists of a conventional diffusive coupling link (self-coupling link) as well as a cross coupling link. The addition of a selective cross-coupling link in particular plays constructive roles that ensure the global stability of synchrony and furthermore enables robustness of synchrony against small to nonsmall parameter perturbation. We elaborate the general conditions for the selection of coupling profiles for two coupled systems, three- and four-node network motifs analytically as well as numerically using benchmark models, the Lorenz system, the Hindmarsh-Rose neuron model, the Shimizu-Morioka laser model, the Rossler system, and a Sprott system. The role of the cross-coupling link is, particularly, exemplified with an example of a larger network, where it saves the network from a breakdown of synchrony against large parameter perturbation in any node. The perturbed node in the network transits from CS to generalized synchronization (GS) when all the other nodes remain in CS. The GS is manifested by an amplified response of the perturbed node in a coherent state. PMID- 28709233 TI - Chiral smectic-A and smectic-C phases with de Vries characteristics. AB - Infrared and dielectric spectroscopic techniques are used to investigate the characteristics of two chiral smectics, namely, 1,1,3,3,5,5,5 heptamethyltrisiloxane 1-[4^{'}-(undecyl-1-oxy)-4-biphenyl(S,S)-2-chloro-3 methylpentanoate] (MSi_{3}MR_{11}) and tricarbosilane-hexyloxy-benzoic acid (S) 4'-(1-methyl-hexyloxy)-3'-nitro-biphenyl-4-yl ester (W599). The orientational features and the field dependencies of the apparent tilt angle and the dichroic ratio for homogeneous planar-aligned samples were calculated from the absorbance profiles obtained at different temperatures especially in the smectic-A* phase of these liquid crystals. The dichroic ratios of the C-C phenyl ring stretching vibrations were considered for the determination of the tilt angle at different temperatures and different voltages. The low values of the order parameter obtained with and without an electric field applied across the cell in the Sm A^{*} phase for both smectics are consistent with the de Vries concept. The generalized Langevin-Debye model introduced in the literature for explaining the electro-optical response has been applied to the results from infrared spectroscopy. The results show that the dipole moment of the tilt-correlated domain diverges as the transition temperature from Sm-A^{*} to Sm-C^{*} is approached. The Debye-Langevin model is found to be extremely effective in confirming some of the conclusions of the de Vries chiral smectics and gives additional results on the order parameter and the dichroic ratio as a function of the field across the cell. Dielectric spectroscopy finds large dipolar fluctuations in the Sm-A^{*} phase for both compounds and again these confirm their de Vries behavior. PMID- 28709234 TI - Does greed help a forager survive? AB - We investigate the role of greed on the lifetime of a random-walking forager on an initially resource-rich lattice. Whenever the forager lands on a food containing site, all the food there is eaten and the forager can hop S more steps without food before starving. Upon reaching an empty site, the forager comes one time unit closer to starvation. The forager is also greedy-given a choice to move to an empty or to a food-containing site in its local neighborhood, the forager moves preferentially toward food. Surprisingly, the forager lifetime varies nonmonotonically with greed, with different senses of the nonmonotonicity in one and two dimensions. Also unexpectedly, the forager lifetime in one dimension has a huge peak for very negative greed where the forager is food averse. PMID- 28709235 TI - Mechanical excitation of rodlike particles by a vibrating plate. AB - The experimental realization and investigation of granular gases usually require an initial or permanent excitation of ensembles of particles, either mechanically or electromagnetically. One typical method is the energy supply by a vibrating plate or container wall. We study the efficiency of such an excitation of cylindrical particles by a sinusoidally oscillating wall and characterize the distribution of kinetic energies of excited particles over their degrees of freedom. The influences of excitation frequency and amplitude are analyzed. PMID- 28709236 TI - Publisher's Note: X-ray shadow imprint of hydrodynamic instabilities on the surface of inertial confinement fusion capsules by the fuel fill tube [Phys. Rev. E 95, 031204(R) (2017)]. AB - This corrects the article DOI: 10.1103/PhysRevE.95.031204. PMID- 28709237 TI - Log-log growth of channel capacity for nondispersive nonlinear optical fiber channel in intermediate power range. AB - We consider a model nondispersive nonlinear optical fiber channel with an additive Gaussian noise. Using Feynman path-integral technique, we find the optimal input signal distribution maximizing the channel's per-sample mutual information at large signal-to-noise ratio in the intermediate power range. The optimal input signal distribution allows us to improve previously known estimates for the channel capacity. We calculate the output signal entropy, conditional entropy, and per-sample mutual information for Gaussian, half-Gaussian, and modified Gaussian input signal distributions. We demonstrate that in the intermediate power range the capacity (the per-sample mutual information for the optimal input signal distribution) is greater than the per-sample mutual information for half-Gaussian input signal distribution considered previously as the optimal one. We also show that the capacity grows as loglogP in the intermediate power range, where P is the signal power. PMID- 28709238 TI - Numerical investigations of potential systematic uncertainties in iron opacity measurements at solar interior temperatures. AB - Iron opacity calculations presently disagree with measurements at an electron temperature of ~180-195 eV and an electron density of (2-4)*10^{22}cm^{-3}, conditions similar to those at the base of the solar convection zone. The measurements use x rays to volumetrically heat a thin iron sample that is tamped with low-Z materials. The opacity is inferred from spectrally resolved x-ray transmission measurements. Plasma self-emission, tamper attenuation, and temporal and spatial gradients can all potentially cause systematic errors in the measured opacity spectra. In this article we quantitatively evaluate these potential errors with numerical investigations. The analysis exploits computer simulations that were previously found to reproduce the experimentally measured plasma conditions. The simulations, combined with a spectral synthesis model, enable evaluations of individual and combined potential errors in order to estimate their potential effects on the opacity measurement. The results show that the errors considered here do not account for the previously observed model-data discrepancies. PMID- 28709239 TI - Transient flows in active porous media. AB - Stimuli-responsive materials that modify their shape in response to changes in environmental conditions-such as solute concentration, temperature, pH, and stress-are widespread in nature and technology. Applications include micro- and nanoporous materials used in filtration and flow control. The physiochemical mechanisms that induce internal volume modifications have been widely studied. The coupling between induced volume changes and solute transport through porous materials, however, is not well understood. Here, we consider advective and diffusive transport through a small channel linking two large reservoirs. A section of stimulus-responsive material regulates the channel permeability, which is a function of the local solute concentration. We derive an exact solution to the coupled transport problem and demonstrate the existence of a flow regime in which the steady state is reached via a damped oscillation around the equilibrium concentration value. Finally, the feasibility of an experimental observation of the phenomena is discussed. PMID- 28709240 TI - Extreme events in FitzHugh-Nagumo oscillators coupled with two time delays. AB - We study two identical FitzHugh-Nagumo oscillators which are coupled with one or two different time delays. If only a single-delay coupling is used, the length of the delay determines whether the synchronization manifold is transversally stable or unstable, exhibiting mixed-mode or chaotic oscillations in which the small amplitude oscillations are always in phase but the large amplitude oscillations are in phase or out of phase, respectively. For two delays we find an intricate dynamics which comprises an irregular alteration of small amplitude oscillations, in-phase and out-of-phase large amplitude oscillations, also called extreme events. This transient chaotic dynamics is sandwiched between a bubbling transition and a blowout bifurcation. PMID- 28709242 TI - Thermodynamics of random number generation. AB - We analyze the thermodynamic costs of the three main approaches to generating random numbers via the recently introduced Information Processing Second Law. Given access to a specified source of randomness, a random number generator (RNG) produces samples from a desired target probability distribution. This differs from pseudorandom number generators (PRNGs) that use wholly deterministic algorithms and from true random number generators (TRNGs) in which the randomness source is a physical system. For each class, we analyze the thermodynamics of generators based on algorithms implemented as finite-state machines, as these allow for direct bounds on the required physical resources. This establishes bounds on heat dissipation and work consumption during the operation of three main classes of RNG algorithms-including those of von Neumann, Knuth, and Yao and Roche and Hoshi-and for PRNG methods. We introduce a general TRNG and determine its thermodynamic costs exactly for arbitrary target distributions. The results highlight the significant differences between the three main approaches to random number generation: One is work producing, one is work consuming, and the other is potentially dissipation neutral. Notably, TRNGs can both generate random numbers and convert thermal energy to stored work. These thermodynamic costs on information creation complement Landauer's limit on the irreducible costs of information destruction. PMID- 28709241 TI - Careful accounting of extrinsic noise in protein expression reveals correlations among its sources. AB - In order to grow and replicate, living cells must express a diverse array of proteins, but the process by which proteins are made includes a great deal of inherent randomness. Understanding this randomness-whether it arises from the discrete stochastic nature of chemical reactivity ("intrinsic" noise), or from cell-to-cell variability in the concentrations of molecules involved in gene expression, or from the timings of important cell-cycle events like DNA replication and cell division ("extrinsic" noise)-remains a challenge. In this article we analyze a model of gene expression that accounts for several extrinsic sources of noise, including those associated with chromosomal replication, cell division, and variability in the numbers of RNA polymerase, ribonuclease E, and ribosomes. We then attempt to fit our model to a large proteomics and transcriptomics data set and find that only through the introduction of a few key correlations among the extrinsic noise sources can we accurately recapitulate the experimental data. These include significant correlations between the rate of mRNA degradation (mediated by ribonuclease E) and the rates of both transcription (RNA polymerase) and translation (ribosomes) and, strikingly, an anticorrelation between the transcription and the translation rates themselves. PMID- 28709243 TI - Ensemble dynamics and the emergence of correlations in one- and two-dimensional wave turbulence. AB - We investigate statistical properties of wave turbulence by monitoring the dynamics of ensembles of trajectories. The system under investigation is a simplified model for surface gravity waves in one and two dimensions with a square-root dispersion and a four-wave interaction term. The simulations of decaying turbulence confirm the Kolmogorov-Zakharov spectral power distribution of wave turbulence theory. Fourth-order correlations are computed numerically as ensemble averages of trajectories. The shape, scaling, and time evolution of the correlations agree with the predictions of wave turbulence theory. PMID- 28709244 TI - Chiral edge fluctuations of colloidal membranes. AB - We study edge fluctuations of a flat colloidal membrane comprised of a monolayer of aligned filamentous viruses. Experiments reveal that a peak in the spectrum of the in-plane edge fluctuations arises for sufficiently strong virus chirality. Accounting for internal liquid crystalline degrees of freedom by the length, curvature, and geodesic torsion of the edge, we calculate the spectrum of the edge fluctuations. The theory quantitatively describes the experimental data, demonstrating that chirality couples in-plane and out-of-plane edge fluctuations to produce the peak. PMID- 28709245 TI - Shear-rate-dependent transport coefficients in granular suspensions. AB - A recent model for monodisperse granular suspensions is used to analyze transport properties in spatially inhomogeneous states close to the simple (or uniform) shear flow. The kinetic equation is based on the inelastic Boltzmann (for low density gases) with the presence of a viscous drag force that models the influence of the interstitial gas phase on the dynamics of grains. A normal solution is obtained via a Chapman-Enskog-like expansion around a (local) shear flow distribution which retains all the hydrodynamic orders in the shear rate. To first order in the expansion, the transport coefficients characterizing momentum and heat transport around shear flow are given in terms of the solutions of a set of coupled linear integral equations which are approximately solved by using a kinetic model of the Boltzmann equation. To simplify the analysis, the steady state conditions when viscous heating is compensated by the cooling terms arising from viscous friction and collisional dissipation are considered to get the explicit forms of the set of generalized transport coefficients. The shear-rate dependence of some of the transport coefficients of the set is illustrated for several values of the coefficient of restitution. PMID- 28709246 TI - Strong correlations between the exponent alpha and the particle number for a Renyi monoatomic gas in Gibbs' statistical mechanics. AB - Appealing to the 1902 Gibbs formalism for classical statistical mechanics (SM) the first SM axiomatic theory ever that successfully explained equilibrium thermodynamics-we show that already at the classical level there is a strong correlation between Renyi's exponent alpha and the number of particles for very simple systems. No reference to heat baths is needed for such a purpose. PMID- 28709247 TI - Intermittent many-body dynamics at equilibrium. AB - The equilibrium value of an observable defines a manifold in the phase space of an ergodic and equipartitioned many-body system. A typical trajectory pierces that manifold infinitely often as time goes to infinity. We use these piercings to measure both the relaxation time of the lowest frequency eigenmode of the Fermi-Pasta-Ulam chain, as well as the fluctuations of the subsequent dynamics in equilibrium. The dynamics in equilibrium is characterized by a power-law distribution of excursion times far off equilibrium, with diverging variance. Long excursions arise from sticky dynamics close to q-breathers localized in normal mode space. Measuring the exponent allows one to predict the transition into nonergodic dynamics. We generalize our method to Klein-Gordon lattices where the sticky dynamics is due to discrete breathers localized in real space. PMID- 28709248 TI - From bulk self-assembly to electrical diffuse layer in a continuum approach for ionic liquids: The impact of anion and cation size asymmetry. AB - Ionic liquids are solvent-free electrolytes, some of which possess an intriguing self-assembly at finite length scale due to Coulombic interactions. Using a continuum framework (based on Onsager's relations), it is shown that bulk nanostructures arise via linear (supercritical) and nonlinear (subcritical) bifurcations (morphological phase transitions), which also directly affect the electrical double layer structure. A Ginzburg-Landau amplitude equation is derived and the bifurcation type is related to model parameters, such as temperature, potential, and interactions. Specifically, the nonlinear bifurcation occurs for geometrically dissimilar ions and, surprisingly, is induced by perturbations on the order of thermal fluctuations. Finally, qualitative insights and comparisons to the experimentally decaying charge layers within the electrical double layer are discussed. PMID- 28709249 TI - Stochastic uncertainty of advected curves in finite-time unsteady flows. AB - Identifying coherent structures in unsteady flows acting over a finite-time is a well-established research area, in part due to the applicability to realistic velocities obtained from experimental, observational, or numerically generated data. More recently, there is an emerging need to understand the impact of small scale uncertainties on larger scale structures; for example, the "stochastic parametrization" problem in climate models. This article establishes a rigorous tool in this direction, specifically quantifying the uncertainty of advected curves in the presence of small stochasticity. Explicit expressions are derived for the expectation and the variance of the curves' location. The velocity field may be unsteady and compressible, and the Wiener process driving the stochasticity can have general spatiotemporal dependence. Monte Carlo simulations are used to verify the uncertainty expressions. PMID- 28709250 TI - Nonlinear dynamics and band transport in a superlattice driven by a plane wave. AB - A quantum particle transport induced in a spatially periodic potential by a propagating plane wave has a number of important implications in a range of topical physical systems. Examples include acoustically driven semiconductor superlattices and cold atoms in an optical crystal. Here we apply a kinetic description of the directed transport in a superlattice beyond standard linear approximation, and utilize exact path-integral solutions of the semiclassical transport equation. We show that the particle drift and average velocities have nonmonotonic dependence on the wave amplitude with several prominent extrema. Such nontrivial kinetic behavior is related to global bifurcations developing with an increase of the wave amplitude. They cause dramatic transformations of the system phase space and lead to changes of the transport regime. We describe different types of phase trajectories contributing to the directed transport and analyze their spectral content. PMID- 28709251 TI - Degeneracy and relativistic microreversibility relations for collisional radiative equilibrium models. AB - We present the relativistic expressions of standard nonrelativistic microreversibility relations that can be used in collisional-radiative equilibrium models to calculate the transition rates including the free electron degeneracy for collisional excitation and deexcitation, collisional ionization and three-body recombination, dielectronic capture and autoionization, photoexcitation and photodeexcitation, and radiative recombination and photoionization. Semiempirical expressions or more refined calculations can be used for the cross sections of interest as long as they are calculated by taking into account either nonrelativistic, relativistic, or ultrarelativistic effects for both the bound and free electrons. The bound and the free electrons should be treated on the same footing. This is crucial for the internal consistency of the approach valid at arbitrary degeneracy and relativistic degrees. PMID- 28709252 TI - Magnetorheological response of highly filled magnetoactive elastomers from perspective of mechanical energy density: Fractal aggregates above the nanometer scale? AB - The dynamic shear modulus of magnetoactive elastomers containing 70 and 80 mass % of carbonyl iron microparticles is measured as a function of strain amplitude via dynamic torsion oscillations in various magnetic fields. The results are presented in terms of the mechanical energy density and considered in the framework of the conventional Kraus model. The form exponent of the Kraus model is further related to a physical model of Huber et al. [Huber et al., J. Phys.: Condens. Matter 8, 409 (1996)10.1088/0953-8984/8/29/003] that uses a realistic representation for the cluster network possessing fractal structure. Two mechanical loading regimes are identified. At small strain amplitudes the exponent beta of the Kraus model changes in an externally applied magnetic field due to rearrangement of ferromagnetic-filler particles, while at large strain amplitudes, the exponent beta seems to be independent of the magnetic field. The critical mechanical energy characterizing the transition between these two regimes grows with the increasing magnetic field. Similarities between agglomeration and deagglomeration of magnetic filler under simultaneously applied magnetic field and mechanical shear and the concept of jamming transition are discussed. It is proposed that the magnetic field should be considered as an additional parameter to the jamming phase diagram of rubbers filled with magnetic particles. PMID- 28709253 TI - Publisher's Note: General scaling relations for locomotion in granular media [Phys. Rev. E 95, 052901 (2017)]. AB - This corrects the article DOI: 10.1103/PhysRevE.95.052901. PMID- 28709254 TI - Bose-Einstein condensation in chains with power-law hoppings: Exact mapping on the critical behavior in d-dimensional regular lattices. AB - Recent experimental progress on the realization of quantum systems with highly controllable long-range interactions has impelled the study of quantum phase transitions in low-dimensional systems with power-law couplings. Long-range couplings mimic higher-dimensional effects in several physical contexts. Here, we provide the exact relation between the spectral dimension d at the band bottom and the exponent alpha that tunes the range of power-law hoppings of a one dimensional ideal lattice Bose gas. We also develop a finite-size scaling analysis to obtain some relevant critical exponents and the critical temperature of the BEC transition. In particular, an irrelevant dangerous scaling field has to be taken into account when the hopping range is sufficiently large to make the effective dimensionality d>4. PMID- 28709255 TI - Achilles' heel of a traveling pulse subject to a local external stimulus. AB - The response of a traveling pulse to a local external stimulus is considered numerically for a modified three-component Oregonator, which is a model system for the photosensitive Belousov-Zhabotinsky (BZ) reaction. The traveling pulse is traced and constantly stimulated, with the distance between the pulse and the stimulus being kept constant. We are interested in the minimal strength of the spatially localized stimulus in order to eliminate the pulse. The use of a stimulus of small width allows us to detect the point in the pulse most sensitive to the external stimulus, referred to as the "Achilles' heel" of the traveling pulse, at which minimal strength of stimulus causes a collapse of the pulse. Our findings are demonstrated experimentally as well with the photosensitive BZ reaction. PMID- 28709257 TI - Monte Carlo study of the ordering in a strongly frustrated liquid crystal. AB - We have performed Monte Carlo simulations to investigate the temperature dependence of the ordering of the side chains of the X-shaped liquid crystal molecules which are arranged in a hexagonal array. Each hexagon contains six side chains, one from each side of the hexagon. Each liquid crystal molecule has two, dissimilar, side chains, one that contains silicon and one that contains fluorine. Like chains attract each other more strongly than unlike chains and this drives an order-disorder transition. The system is frustrated because it is not possible to find a configuration in which all the hexagons are occupied by either all silicon or all fluorine chains. There are two phase transitions. If only pairwise interactions are included it is found that there is an interesting fluctuating phase between the disordered phase and the fully ordered ground state. This did not agree with the experiments where an intermediate phase was seen that had long range order on one of the three sublattices. Agreement was found when the calculations were modified to include attractive three-body interactions between the silicon chains. PMID- 28709256 TI - Modeling polymorphic transformation of rotating bacterial flagella in a viscous fluid. AB - The helical flagella that are attached to the cell body of bacteria such as Escherichia coli and Salmonella typhimurium allow the cell to swim in a fluid environment. These flagella are capable of polymorphic transformation in that they take on various helical shapes that differ in helical pitch, radius, and chirality. We present a mathematical model of a single flagellum described by Kirchhoff rod theory that is immersed in a fluid governed by Stokes equations. We perform numerical simulations to demonstrate two mechanisms by which polymorphic transformation can occur, as observed in experiments. First, we consider a flagellar filament attached to a rotary motor in which transformations are triggered by a reversal of the direction of motor rotation [L. Turner et al., J. Bacteriol. 182, 2793 (2000)10.1128/JB.182.10.2793-2801.2000]. We then consider a filament that is fixed on one end and immersed in an external fluid flow [H. Hotani, J. Mol. Biol. 156, 791 (1982)10.1016/0022-2836(82)90142-5]. The detailed dynamics of the helical flagellum interacting with a viscous fluid is discussed and comparisons with experimental and theoretical results are provided. PMID- 28709258 TI - Universal lower bound on the free-energy cost of molecular measurements. AB - The living cell uses a variety of molecular receptors to read and process chemical signals that vary in space and time. We model the dynamics of such molecular level measurements as Markov processes in steady state, with a coupling between the receptor and the signal. We prove exactly that, when the signal dynamics is not perturbed by the receptors, the free energy consumed by the measurement process is lower bounded by a quantity proportional to the mutual information. Our result is completely independent of the receptor architecture and dependent on signal properties alone, and therefore holds as a general principle for molecular information processing. PMID- 28709259 TI - Memory erasure using time-multiplexed potentials. AB - We study the thermodynamics of a Brownian particle under the influence of a time multiplexed harmonic potential of finite width. The memory storage mechanism and the erasure protocol based on time-multiplexed potentials are utilized to experimentally realize erasure with work performed close to Landauer's bound. We quantify the work performed on the system with respect to the duty ratio of time multiplexing, which also provides a handle for approaching reversible erasures. A Langevin dynamics based simulation model is developed for the proposed memory bit and the erasure protocol, which guides the experimental realization. The study also provides insight into transport on the microscale. PMID- 28709260 TI - Pneumatic fractures in confined granular media. AB - We perform experiments where air is injected at a constant overpressure P_{in}, ranging from 5 to 250 kPa, into a dry granular medium confined within a horizontal linear Hele-Shaw cell. The setup allows us to explore compacted configurations by preventing decompaction at the outer boundary, i.e., the cell outlet has a semipermeable filter such that beads are stopped while air can pass. We study the emerging patterns and dynamic growth of channels in the granular media due to fluid flow, by analyzing images captured with a high speed camera (1000 images/s). We identify four qualitatively different flow regimes, depending on the imposed overpressure, ranging from no channel formation for P_{in} below 10 kPa, to large thick channels formed by erosion and fingers merging for high P_{in} around 200 kPa. The flow regimes where channels form are characterized by typical finger thickness, final depth into the medium, and growth dynamics. The shape of the finger tips during growth is studied by looking at the finger width w as function of distance d from the tip. The tip profile is found to follow w(d)?d^{beta}, where beta=0.68 is a typical value for all experiments, also over time. This indicates a singularity in the curvature d^{2}d/dw^{2}~kappa~d^{1 2beta}, but not of the slope dw/dd~d^{beta-1}, i.e., more rounded tips rather than pointy cusps, as they would be for the case beta>1. For increasing P_{in}, the channels generally grow faster and deeper into the medium. We show that the channel length along the flow direction has a linear growth with time initially, followed by a power-law decay of growth velocity with time as the channel approaches its final length. A closer look reveals that the initial growth velocity v_{0} is found to scale with injection pressure as v_{0}?P_{in}^{3/2}, while at a critical time t_{c} there is a cross-over to the behavior v(t)?t^{ alpha}, where alpha is close to 2.5 for all experiments. Finally, we explore the fractal dimension of the fully developed patterns. For example, for patterns resulting from intermediate P_{in} around 100-150 kPa, we find that the box counting dimensions lie within the range D_{B}?[1.53,1.62], similar to viscous fingering fractals in porous media. PMID- 28709261 TI - Growth-dependent behavioral difference in bacterial chemotaxis. AB - Cells can adjust to their growth environments and regulate their behavior accordingly. To study how cells accomplish this growth-dependent adjustment from the molecular to the behavioral level, we used bacterial chemotaxis as a model system to explore the behavioral difference for bacteria grown in nutrient-rich and nutrient-poor media. We found that bacteria grown in a nutrient-poor medium exhibit faster chemotaxis adaptation, and this enables them to respond more rapidly to a changing environment and increases their ability to localize to a nutrient concentration peak. We identified the molecular mechanisms behind this behavioral difference through coarse-grained modeling, and demonstrated its physiological consequences by simulating bacterial chemotactic motion in spatiotemporally varying environments and in a static environment with a nutrient concentration peak. PMID- 28709262 TI - Coexisting origins of subdiffusion in internal dynamics of proteins. AB - Subdiffusion in conformational dynamics of proteins is observed both experimentally and in simulations. Although its origin has been attributed to multiple mechanisms, including trapping on a rugged energy landscape, fractional Brownian noise, or a fractal topology of the energy landscape, it is unclear which of these, if any, is most relevant. To obtain insights into the actual mechanism, we introduce an analytically tractable hierarchical trapping model and apply it to molecular dynamics simulation trajectories of three proteins in solution. The analysis of the simulations introduces a subdiffusive exponent that varies with time and associates plateaus in the mean-squared displacement with traps on the energy landscape. This analysis permits us to separate the component of subdiffusion due to a trapping mechanism from that due to an underlying fluctuating process, such as fractional Brownian motion. The present results thus provide insights concerning the physical origin of subdiffusion in the dynamics of proteins. PMID- 28709263 TI - Impact of diffusion on transverse dispersion in two-dimensional ordered and random porous media. AB - Solute dispersion in fluid flow results from the interaction between advection and diffusion. The relative contributions of these two mechanisms to mass transport are characterized by the reduced velocity nu, also referred to as the Peclet number. In the absence of diffusion (i.e., when the solute diffusion coefficient D_{m}=0 and nu->infinity), divergence-free laminar flow of an incompressible fluid results in a zero-transverse dispersion coefficient (D_{T}=0), both in ordered and random two-dimensional porous media. We demonstrate by numerical simulations that a more realistic realization of the condition nu->infinity using D_{m}?0 and letting the fluid flow velocity approach infinity leads to completely different results for ordered and random two dimensional porous media. With increasing reduced velocity, D_{T} approaches an asymptotic value in ordered two-dimensional porous media but grows linearly in disordered (random) structures depending on the geometrical disorder of a structure: a higher degree of heterogeneity results in a stronger growth of D_{T} with nu. The obtained results reveal that disorder in the geometrical structure of a two-dimensional porous medium leads to a growth of D_{T} with nu even in a uniform pore-scale advection field; however, lateral diffusion is a prerequisite for this growth. By contrast, in ordered two-dimensional porous media the presence of lateral diffusion leads to a plateau for the transverse dispersion coefficient with increasing nu. PMID- 28709264 TI - Experimental investigations on characteristics of stable water electrospray in air without discharge. AB - An experimental study was conducted to resolve previous conflicting results on water electrospray in air at atmospheric pressure. Using a small flow rate relative to that used in previous studies and a small nonmetallic nozzle, we observed stable electrospray of water in air without discharge and distinguished three distinct operating regimes for applied voltage and flow rate. The well known cone-jet mode was observed and the general scaling law of the generated droplet size in the cone-jet mode was confirmed by direct visualization of the meniscus, jet, and generated droplets. We also observed and analyzed whipping motion in the electrified water jet. PMID- 28709265 TI - From synchronous to one-time delayed dynamics in coupled maps. AB - We study the completely synchronized states (CSSs) of a system of coupled logistic maps as a function of three parameters: interaction strength (E), range of the interaction (alpha), that can vary from first neighbors to global coupling, and a parameter (beta) that allows one to scan continuously from nondelayed to one-time delayed dynamics. In the alpha-E plane we identify periodic orbits, limit cycles, and chaotic trajectories, and describe how these structures change with delay. These features can be explained by studying the bifurcation diagrams of a two-dimensional nondelayed map. This allows us to understand the effects of one-time delays on CSSs, e.g., regularization of chaotic orbits and synchronization of short-range coupled maps, observed when the dynamics is moderately delayed. Finally, we substitute the logistic map with cubic and logarithmic maps, in order to test the robustness of our findings. PMID- 28709266 TI - Lattice Boltzmann simulations of heat transfer in fully developed periodic incompressible flows. AB - Flow and heat transfer in periodic structures are of great interest for many applications. In this paper, we carefully examine the periodic features of fully developed periodic incompressible thermal flows, and incorporate them in the lattice Boltzmann method (LBM) for flow and heat transfer simulations. Two numerical approaches, the distribution modification (DM) approach and the source term (ST) approach, are proposed; and they can both be used for periodic thermal flows with constant wall temperature (CWT) and surface heat flux boundary conditions. However, the DM approach might be more efficient, especially for CWT systems since the ST approach requires calculations of the streamwise temperature gradient at all lattice nodes. Several example simulations are conducted, including flows through flat and wavy channels and flows through a square array with circular cylinders. Results are compared to analytical solutions, previous studies, and our own LBM calculations using different simulation techniques (i.e., the one-module simulation vs. the two-module simulation, and the DM approach vs. the ST approach) with good agreement. These simple, however, representative simulations demonstrate the accuracy and usefulness of our proposed LBM methods for future thermal periodic flow simulations. PMID- 28709267 TI - Aggregation and fragmentation dynamics in random flows: From tracers to inertial aggregates. AB - We investigate the aggregation and fragmentation dynamics of tracers and inertial aggregates in random flows leading to steady-state size distributions. Our objective is to elucidate the impact of changes in aggregation rates due to differences in advection dynamics, especially with respect to the influence of inertial effects. This aggregation process is, at the same time, balanced by fragmentation triggered by local hydrodynamic stress. Our study employs an individual-particle-based model, tracking the position, velocity, and size of each aggregate. We compare the steady-state size distribution formed by tracers and inertial aggregates, characterized by different sizes and densities. On the one hand, we show that the size distributions change their shape with changes in the dilution rate of the suspension. On the other hand, we obtain that the size distributions formed with different binding strengths between monomers can be rescaled to a single form with the use of a characteristic size for both dense inertial particles and tracer monomers. Nevertheless, this last scaling relation also fails if the size distribution contains aggregates that behave as tracer like and inertial-like, which results in a crossover between different scalings. PMID- 28709268 TI - Lateral trapping of DNA inside a voltage gated nanopore. AB - The translocation of a short DNA fragment through a nanopore is addressed when the perforated membrane contains an embedded electrode. Accurate numerical solutions of the coupled Poisson, Nernst-Planck, and Stokes equations for a realistic, fully three-dimensional setup as well as analytical approximations for a simplified model are worked out. By applying a suitable voltage to the membrane electrode, the DNA can be forced to preferably traverse the pore either along the pore axis or at a small but finite distance from the pore wall. PMID- 28709269 TI - Sparse modeling approach to analytical continuation of imaginary-time quantum Monte Carlo data. AB - A data-science approach to solving the ill-conditioned inverse problem for analytical continuation is proposed. The root of the problem lies in the fact that even tiny noise of imaginary-time input data has a serious impact on the inferred real-frequency spectra. By means of a modern regularization technique, we eliminate redundant degrees of freedom that essentially carry the noise, leaving only relevant information unaffected by the noise. The resultant spectrum is represented with minimal bases and thus a stable analytical continuation is achieved. This framework further provides a tool for analyzing to what extent the Monte Carlo data need to be accurate to resolve details of an expected spectral function. PMID- 28709270 TI - Orientational phase transitions and the assembly of viral capsids. AB - We present a Landau theory for large-l orientational phase transitions and apply it to the assembly of icosahedral viral capsids. The theory predicts two distinct types of ordering transitions. Transitions dominated by the l=6,10,12, and 18 icosahedral spherical harmonics resemble robust first-order phase transitions that are not significantly affected by chirality. The remaining transitions depend essentially on including mixed l states denoted as l=15+16 corresponding to a mixture of l=15 and l=16 spherical harmonics. The l=15+16 transition is either continuous or weakly first-order and it is strongly influenced by chirality, which suppresses spontaneous chiral symmetry breaking. The icosahedral state is in close competition with states that have tetrahedral, D_{5}, and octahedral symmetries. We present a group-theoretic method to analyze the competition between the different symmetries. The theory is applied to a variety of viral shells. PMID- 28709271 TI - Multicritical points and topology-induced inverse transition in the random-field Blume-Capel model in a random network. AB - The interplay between quenched disorder provided by a random field (RF) and network connectivity in the Blume-Capel (BC) model is the subject of this paper. The replica method is used to average over the network randomness. It offers an alternative analytic route to both numerical simulations and standard mean field approaches. The results reveal a rich thermodynamic scenario with multicritical points that are strongly dependent on network connectivity. In addition, we also demonstrate that the RF has a deep effect on the inverse melting transition. This highly nontrivial type of phase transition has been proposed to exist in the BC model as a function of network topology. Our results confirm that the topological mechanism can lead to an inverse melting transition. Nevertheless, our results also show that as the RF becomes stronger, the paramagnetic phase is affected in such way that the topological mechanism for inverse melting is disabled. PMID- 28709272 TI - Multiscaling behavior of atomic-scale friction. AB - The scaling behavior of friction between rough surfaces is a well-known phenomenon. It might be asked whether such a scaling feature also exists for friction at an atomic scale despite the absence of roughness on atomically flat surfaces. Indeed, other types of fluctuations, e.g., thermal and instrumental fluctuations, become appreciable at this length scale and can lead to scaling behavior of the measured atomic-scale friction. We investigate this using the lateral force exerted on the tip of an atomic force microscope (AFM) when the tip is dragged over the clean NaCl (001) surface in ultra-high vacuum at room temperature. Here the focus is on the fluctuations of the lateral force profile rather than its saw-tooth trend; we first eliminate the trend using the singular value decomposition technique and then explore the scaling behavior of the detrended data, which contains only fluctuations, using the multifractal detrended fluctuation analysis. The results demonstrate a scaling behavior for the friction data ranging from 0.2 to 2 nm with the Hurst exponent H=0.61+/-0.02 at a 1sigma confidence interval. Moreover, the dependence of the generalized Hurst exponent, h(q), on the index variable q confirms the multifractal or multiscaling behavior of the nanofriction data. These results prove that fluctuation of nanofriction empirical data has a multifractal behavior which deviates from white noise. PMID- 28709273 TI - Laser-driven shock waves studied by x-ray radiography. AB - Multimegabar laser-driven shock waves are unique tools for studying matter under extreme conditions. Accurate characterization of shocked matter is for instance necessary for measurements of equation of state data or opacities. This paper reports experiments performed at the LULI facility on the diagnosis of shock waves, using x-ray-absorption radiography. Radiographs are analyzed using standard Abel inversion. In addition, synthetic radiographs, which also take into account the finite size of the x-ray source, are generated using density maps produced by hydrodynamic simulations. Reported data refer to both plane cylindrical targets and hemispherical targets. Evolution and deformation of the shock front could be followed using hydrodynamic simulations. PMID- 28709274 TI - Coherence of biochemical oscillations is bounded by driving force and network topology. AB - Biochemical oscillations are prevalent in living organisms. Systems with a small number of constituents cannot sustain coherent oscillations for an indefinite time because of fluctuations in the period of oscillation. We show that the number of coherent oscillations that quantifies the precision of the oscillator is universally bounded by the thermodynamic force that drives the system out of equilibrium and by the topology of the underlying biochemical network of states. Our results are valid for arbitrary Markov processes, which are commonly used to model biochemical reactions. We apply our results to a model for a single KaiC protein and to an activator-inhibitor model that consists of several molecules. From a mathematical perspective, based on strong numerical evidence, we conjecture a universal constraint relating the imaginary and real parts of the first nontrivial eigenvalue of a stochastic matrix. PMID- 28709275 TI - Nonequilibrium dynamics of a pure dry friction model subjected to colored noise. AB - We investigate the impact of noise on a two-dimensional simple paradigmatic piecewise-smooth dynamical system. For that purpose, we consider the motion of a particle subjected to dry friction and colored noise. The finite correlation time of the noise provides an additional dimension in phase space, causes a nontrivial probability current, and establishes a proper nonequilibrium regime. Furthermore, the setup allows for the study of stick-slip phenomena, which show up as a singular component in the stationary probability density. Analytic insight can be provided by application of the unified colored noise approximation, developed by Jung and Hanggi [Phys. Rev. A 35, 4464(R) (1987)0556 279110.1103/PhysRevA.35.4464]. The analysis of probability currents and of power spectral densities underpins the observed stick-slip transition, which is related with a critical value of the noise correlation time. PMID- 28709276 TI - Kaiser-Bessel basis for particle-mesh interpolation. AB - In this work, we introduce the Kaiser-Bessel interpolation basis for the particle mesh interpolation in the fast Ewald method. A reliable a priori error estimate is developed to measure the accuracy of the force computation in correlated charge systems, and is shown to be effective in optimizing the shape parameter of the Kaiser-Bessel basis in terms of accuracy. By comparing the optimized Kaiser Bessel basis with the traditional B-spline basis, we demonstrate that the former is more accurate than the latter in part of the working parameter space, say, a relatively small real-space cutoff, a relatively small reciprocal space mesh, and a relatively large truncation of basis. In some cases, the Kaiser-Bessel basis is found to be more than one order of magnitude more accurate. PMID- 28709277 TI - Rattleback dynamics and its reversal time of rotation. AB - A rattleback is a rigid, semielliptic toy which exhibits unintuitive behavior; when it is spun in one direction, it soon begins pitching and stops spinning, then it starts to spin in the opposite direction, but in the other direction, it seems to spin just steadily. This puzzling behavior results from the slight misalignment between the principal axes for the inertia and those for the curvature; the misalignment couples the spinning with the pitching and the rolling oscillations. It has been shown that under the no-slip condition and without dissipation the spin can reverse in both directions, and Garcia and Hubbard obtained the formula for the time required for the spin reversal t_{r} [Proc. R. Soc. Lond. A 418, 165 (1988)1364-502110.1098/rspa.1988.0078]. In this work, we reformulate the rattleback dynamics in a physically transparent way and reduce it to a three-variable dynamics for spinning, pitching, and rolling. We obtain an expression of the Garcia-Hubbard formula for t_{r} by a simple product of four factors: (1) the misalignment angle, (2) the difference in the inverses of inertia moment for the two oscillations, (3) that in the radii for the two principal curvatures, and (4) the squared frequency of the oscillation. We perform extensive numerical simulations to examine validity and limitation of the formula, and find that (1) the Garcia-Hubbard formula is good for both spinning directions in the small spin and small oscillation regime, but (2) in the fast spin regime especially for the steady direction, the rattleback may not reverse and shows a rich variety of dynamics including steady spinning, spin wobbling, and chaotic behavior reminiscent of chaos in a dissipative system. PMID- 28709279 TI - Structure and reentrant percolation in an inverse patchy colloidal system. AB - Two-dimensional systems of inverse patchy colloids modeled as disks with a central charge and having their surface decorated with oppositely pointlike charged patches are investigated using molecular dynamics simulations. The self assembly of the patchy colloids leads to diverse ground state configurations ranging from crystalline arrangements of monomers to linear clusters, ramified linear clusters and to percolated configurations. Two structural phase diagrams are constructed: (1) as a function of the net charge and area fraction, and (2) as a function of the net charge and the range of the pair interaction potential. An interesting reentrant percolation transition is obtained as a function of the net charge of the colloids. We identify distinct mechanisms that lead to the percolation transition. PMID- 28709278 TI - Bubble gating in biological ion channels: A density functional theory study. AB - We study the behavior of a waterlike liquid inside the gate of a biological ion channel following the basic geometry of the well studied potassium channel KcsA. We calculate the three-dimensional density distribution rho(r) of the liquid within the framework of classical density functional theory and observe the formation of a low density region (bubble) when the gate is narrow. This observation corresponds to a finite-size form of capillary evaporation and supports the so-called bubble-gate theory. From the density profile we also compute the energy landscape of the gate and the energy required to change the gate from a closed (narrow) to an open (wide) state and vice versa. PMID- 28709280 TI - Collapse of resilience patterns in generalized Lotka-Volterra dynamics and beyond. AB - Recently, a theoretical framework aimed at separating the roles of dynamics and topology in multidimensional systems has been developed [Gao et al., Nature (London) 530, 307 (2016)10.1038/nature16948]. The validity of their method is assumed to hold depending on two main hypotheses: (i) The network determined by the the interaction between pairs of nodes has negligible degree correlations; (ii) the node activities are uniform across nodes on both the drift and the pairwise interaction functions. Moreover, the authors consider only positive (mutualistic) interactions. Here we show the conditions proposed by Gao and collaborators [Nature (London) 530, 307 (2016)10.1038/nature16948] are neither sufficient nor necessary to guarantee that their method works in general and validity of their results are not independent of the model chosen within the class of dynamics they considered. Indeed we find that a new condition poses effective limitations to their framework and we provide quantitative predictions of the quality of the one-dimensional collapse as a function of the properties of interaction networks and stable dynamics using results from random matrix theory. We also find that multidimensional reduction may work also for an interaction matrix with a mixture of positive and negative signs, opening up an application of the framework to food webs, neuronal networks, and social and economic interactions. PMID- 28709281 TI - How the fittest compete for leadership: A tale of tails. AB - We investigate how leaders emerge as a consequence of the competitive dynamics between coupled papers in a model citation network. Every paper is allocated an initial fitness depending on its intrinsic quality. Its fitness then involves dynamically as a consequence of the competition between itself and all the other papers in the field. It picks up citations as a result of this adaptive dynamics, becoming a leader if it has the highest citation count at a given time. Extensive analytical and numerical investigations of this model suggest the existence of a universal phase diagram, divided into regions of weak and strong coupling. In the former, we find an "extended" and rather structureless distribution of citation counts among many fit papers; leaders are not necessarily those with the maximal fitness at any given time. By contrast, the strong-coupling region is characterized by a strongly hierarchical distribution of citation counts, that are "localized" among only a few extremely fit papers, and exhibit strong history to-history fluctuations, as a result of the complex dynamics among papers in the tail of the fitness distribution. PMID- 28709282 TI - Hybrid smoothed dissipative particle dynamics and immersed boundary method for simulation of red blood cells in flows. AB - In biofluid flow systems, often the flow problems of fluids of complex structures, such as the flow of red blood cells (RBCs) through complex capillary vessels, need to be considered. The smoothed dissipative particle dynamics (SDPD), a particle-based method, is one of the easy and flexible methods to model such complex structure fluids. It couples the best features of the smoothed particle hydrodynamics (SPH) and dissipative particle dynamics (DPD), with parameters having specific physical meaning (coming from SPH discretization of the Navier-Stokes equations), combined with thermal fluctuations in a mesoscale simulation, in a similar manner to the DPD. On the other hand, the immersed boundary method (IBM), a preferred method for handling fluid-structure interaction problems, has also been widely used to handle the fluid-RBC interaction in RBC simulations. In this paper, we aim to couple SDPD and IBM together to carry out the simulations of RBCs in complex flow problems. First, we develop the SDPD-IBM model in details, including the SDPD model for the evolving fluid flow, the RBC model for calculating RBC deformation force, the IBM for treating fluid-RBC interaction, and the solid boundary treatment model as well. We then conduct the verification and validation of the combined SDPD-IBM method. Finally, we demonstrate the capability of the SDPD-IBM method by simulating the flows of RBCs in rectangular, cylinder, curved, bifurcated, and constricted tubes, respectively. PMID- 28709283 TI - Out-of-equilibrium protocol for Renyi entropies via the Jarzynski equality. AB - In recent years entanglement measures, such as the von Neumann and the Renyi entropies, provided a unique opportunity to access elusive features of quantum many-body systems. However, extracting entanglement properties analytically, experimentally, or in numerical simulations can be a formidable task. Here, by combining the replica trick and the Jarzynski equality we devise an alternative effective out-of-equilibrium protocol for measuring the equilibrium Renyi entropies. The key idea is to perform a quench in the geometry of the replicas. The Renyi entropies are obtained as the exponential average of the work performed during the quench. We illustrate an application of the method in classical Monte Carlo simulations, although it could be useful in different contexts, such as in quantum Monte Carlo, or experimentally in cold-atom systems. The method is most effective in the quasistatic regime, i.e., for a slow quench. As a benchmark, we compute the Renyi entropies in the Ising universality class in 1+1 dimensions. We find perfect agreement with the well-known conformal field theory predictions. PMID- 28709284 TI - Phase ordering dynamics of reconstituting particles. AB - We consider the large-time dynamics of one-dimensional processes involving adsorption and desorption of extended hard-core particles (dimers, trimers, ..., k-mers), while interacting through their constituent monomers. Desorption can occur whether or not these latter adsorbed together, which leads to reconstitution of k-mers and the appearance of sectors of motion with nonlocal conservation laws for k>=3. Dynamic exponents of the sector including the empty chain are evaluated by finite-size scaling analyses of the relaxation times embodied in the spectral gaps of evolution operators. For attractive interactions it is found that in the low-temperature limit such time scales converge to those of the Glauber dynamics, thus suggesting a diffusive universality class for k>=2. This is also tested by simulated quenches down to T=0, where a common scaling function emerges. By contrast, under repulsive interactions the low-temperature dynamics is characterized by metastable states which decay subdiffusively to a highly degenerate and partially jammed phase. PMID- 28709285 TI - Publisher's Note: Fluctuating lattice Boltzmann method for the diffusion equation [Phys. Rev. E 94, 033302 (2016)]. AB - This corrects the article DOI: 10.1103/PhysRevE.94.033302. PMID- 28709286 TI - Equilibrium structure and off-equilibrium kinetics of a magnet with tunable frustration. AB - We study numerically a two-dimensional random-bond Ising model where frustration can be tuned by varying the fraction a of antiferromagnetic coupling constants. At low temperatures the model exhibits a phase with ferromagnetic order for sufficiently small values of a, aa_{a}, an antiferromagnetic phase exists. After a deep quench from high temperatures, slow evolution is observed for any value of a. We show that different amounts of frustration, tuned by a, affect the dynamical properties in a highly nontrivial way. In particular, the kinetics is logarithmically slow in phases with ferromagnetic or antiferromagnetic order, whereas evolution is faster, i.e., algebraic, when spin-glass order is prevailing. An interpretation is given in terms of the different nature of phase space. PMID- 28709287 TI - Mode-locking behavior of Izhikevich neurons under periodic external forcing. AB - Many neurons in the auditory system of the brain must encode periodic signals. These neurons under periodic stimulation display rich dynamical states including mode locking and chaotic responses. Periodic stimuli such as sinusoidal waves and amplitude modulated sounds can lead to various forms of n:m mode-locked states, in which a neuron fires n action potentials per m cycles of the stimulus. Here, we study mode-locking in the Izhikevich neurons, a reduced model of the Hodgkin Huxley neurons. The Izhikevich model is much simpler in terms of the dimension of the coupled nonlinear differential equations compared with other existing models, but excellent for generating the complex spiking patterns observed in real neurons. We obtained the regions of existence of the various mode-locked states on the frequency-amplitude plane, called Arnold tongues, for the Izhikevich neurons. Arnold tongue analysis provides useful insight into the organization of mode-locking behavior of neurons under periodic forcing. We find these tongues for both class-1 and class-2 excitable neurons in both deterministic and noisy regimes. PMID- 28709288 TI - Energy transfer channels and turbulence cascade in Vlasov-Maxwell turbulence. AB - Analysis of the Vlasov-Maxwell equations from the perspective of turbulence cascade clarifies the role of electromagnetic work, and reveals the importance of the pressure-strain relation in generating internal energy. Particle-in-cell simulation demonstrates the relative importance of the several energy exchange terms, indicating that the traceless pressure-strain interaction "Pi-D" is of particular importance for both electrons and protons. The Pi-D interaction and the second tensor invariants of the strain are highly localized in similar spatial regions, indicating that energy transfer occurs preferentially in coherent structures. The collisionless turbulence cascade may be fruitfully explored by study of these energy transfer channels, in addition to examining transfer across spatial scales. PMID- 28709289 TI - Plasma anisotropy around a dust particle placed in an external electric field. AB - A self-consistent model of plasma polarization around an isolated micron-sized dust particle under the action of an external electric field is presented. It is shown that the quasineutral condition is fulfilled and the formed volume charge totally screens the dust particle. The ion focusing and wake formation behind the dust particle are demonstrated for different ion mean free paths and the external electric fields. It is obtained that at low values of the external electric field the trapped ions play the main role in the screening of the dust particle charge. For high external electric fields, the density of trapped ions decreases and the dust particle is screened mainly by the free ions. PMID- 28709290 TI - Stochastic dynamics for reinfection by transmitted diseases. AB - The use of stochastic models to study the dynamics of infectious diseases is an important tool to understand the epidemiological process. For several directly transmitted diseases, reinfection is a relevant process, which can be expressed by endogenous reactivation of the pathogen or by exogenous reinfection due to direct contact with an infected individual (with smaller reinfection rate sigmabeta than infection rate beta). In this paper, we examine the stochastic susceptible, infected, recovered, infected (SIRI) model simulating the endogenous reactivation by a spontaneous reaction, while exogenous reinfection by a catalytic reaction. Analyzing the mean-field approximations of a site and pairs of sites, and Monte Carlo (MC) simulations for the particular case of exogenous reinfection, we obtained continuous phase transitions involving endemic, epidemic, and no transmission phases for the simple approach; the approach of pairs is better to describe the phase transition from endemic phase (susceptible, infected, susceptible (SIS)-like model) to epidemic phase (susceptible, infected, and removed or recovered (SIR)-like model) considering the comparison with MC results; the reinfection increases the peaks of outbreaks until the system reaches endemic phase. For the particular case of endogenous reactivation, the approach of pairs leads to a continuous phase transition from endemic phase (SIS like model) to no transmission phase. Finally, there is no phase transition when both effects are taken into account. We hope the results of this study can be generalized for the susceptible, exposed, infected, and removed or recovered (SEIR_{I}^{E}) model, for which the state exposed (infected but not infectious), describing more realistically transmitted diseases such as tuberculosis. In future work, we also intend to investigate the effect of network topology on phase transitions when the SIRI model describes both transmitted diseases (sigma<1) and social contagions (sigma>1). PMID- 28709291 TI - Continuous-variable approach to the spectral properties and quantum states of the two-component Bose-Hubbard dimer. AB - A bosonic gas formed by two interacting species trapped in a double-well potential features macroscopic localization effects when the interspecies interaction becomes sufficiently strong. A repulsive interaction spatially separates the species into different wells while an attractive interaction confines both species in the same well. We perform a fully analytic study of the transitions from the weak- to the strong-interaction regime by exploiting the semiclassical method in which boson populations are represented in terms of continuous variables. We find an explicit description of low-energy eigenstates and spectrum in terms of the model parameters which includes the neighborhood of the transition point. To test the effectiveness of the continuous-variable method we compare its predictions with the exact results found numerically. Numerical calculations confirm the spectral collapse evidenced by this method when the space localization takes place. PMID- 28709292 TI - Breather-to-soliton transformation rules in the hierarchy of nonlinear Schrodinger equations. AB - We study the exact first-order soliton and breather solutions of the integrable nonlinear Schrodinger equations hierarchy up to fifth order. We reveal the underlying physical mechanism which transforms a breather into a soliton. Furthermore, we show how the dynamics of the Akhmediev breathers which exist on a constant background as a result of modulation instability, is connected with solitons on a zero background. We also demonstrate that, while a first-order rogue wave can be directly transformed into a soliton, higher-order rogue wave solutions become rational two-soliton solutions with complex collisional structure on a background. Our results will have practical implications in supercontinuum generation, turbulence, and similar other complex nonlinear scenarios. PMID- 28709293 TI - Fluorescence correlation spectroscopy experiments to quantify free diffusion coefficients in reaction-diffusion systems: The case of Ca^{2+} and its dyes. AB - Many cell signaling pathways involve the diffusion of messengers that bind and unbind to and from intracellular components. Quantifying their net transport rate under different conditions then requires having separate estimates of their free diffusion coefficient and binding or unbinding rates. In this paper, we show how performing sets of fluorescence correlation spectroscopy (FCS) experiments under different conditions, it is possible to quantify free diffusion coefficients and on and off rates of reaction-diffusion systems. We develop the theory and present a practical implementation for the case of the universal second messenger, calcium (Ca^{2+}) and single-wavelength dyes that increase their fluorescence upon Ca^{2+} binding. We validate the approach with experiments performed in aqueous solutions containing Ca^{2+} and Fluo4 dextran (both in its high and low affinity versions). Performing FCS experiments with tetramethylrhodamine-dextran in Xenopus laevis oocytes, we infer the corresponding free diffusion coefficients in the cytosol of these cells. Our approach can be extended to other physiologically relevant reaction-diffusion systems to quantify biophysical parameters that determine the dynamics of various variables of interest. PMID- 28709294 TI - Size dependence of the surface tension of a free surface of an isotropic fluid. AB - We report on the size dependence of the surface tension of a free surface of an isotropic fluid. The size dependence of the surface tension is evaluated based on the Gibbs-Tolman-Koenig-Buff equation for positive and negative values of curvatures and the Tolman lengths. For all combinations of positive and negative signs of curvature and the Tolman length, we succeed to have a continuous function, avoiding the existing discontinuity at zero curvature (flat interfaces). As an example, a water droplet in the thermodynamical equilibrium with the vapor is analyzed in detail. The size dependence of the surface tension and the Tolman length are evaluated with the use of experimental data of the International Association for the Properties of Water and Steam. The evaluated Tolman length of our approach is in good agreement with molecular dynamics and experimental data. PMID- 28709295 TI - Classical counterparts of quantum attractors in generic dissipative systems. AB - In the context of dissipative systems, we show that for any quantum chaotic attractor a corresponding classical chaotic attractor can always be found. We provide a general way to locate them, rooted in the structure of the parameter space (which is typically bidimensional, accounting for the forcing strength and dissipation parameters). In cases where an approximate pointlike quantum distribution is found, it can be associated with exceptionally large regular structures. Moreover, supposedly anomalous quantum chaotic behavior can be very well reproduced by the classical dynamics plus Gaussian noise of the size of an effective Planck constant h_{eff}. We give support to our conjectures by means of two paradigmatic examples of quantum chaos and transport theory. In particular, a dissipative driven system becomes fundamental in order to extend their validity to generic cases. PMID- 28709296 TI - Critical behavior of a two-step contagion model with multiple seeds. AB - A two-step contagion model with a single seed serves as a cornerstone for understanding the critical behaviors and underlying mechanism of discontinuous percolation transitions induced by cascade dynamics. When the contagion spreads from a single seed, a cluster of infected and recovered nodes grows without any cluster merging process. However, when the contagion starts from multiple seeds of O(N) where N is the system size, a node weakened by a seed can be infected more easily when it is in contact with another node infected by a different pathogen seed. This contagion process can be viewed as a cluster merging process in a percolation model. Here we show analytically and numerically that when the density of infectious seeds is relatively small but O(1), the epidemic transition is hybrid, exhibiting both continuous and discontinuous behavior, whereas when it is sufficiently large and reaches a critical point, the transition becomes continuous. We determine the full set of critical exponents describing the hybrid and the continuous transitions. Their critical behaviors differ from those in the single-seed case. PMID- 28709297 TI - Interference of two codirectional exclusion processes in the presence of a static bottleneck: A biologically motivated model. AB - We develop a two-species exclusion process with a distinct pair of entry and exit sites for each species of rigid rods. The relatively slower forward stepping of the rods in an extended bottleneck region, located in between the two entry sites, controls the extent of interference of the codirectional flow of the two species of rods. The relative positions of the sites of entry of the two species of rods with respect to the location of the bottleneck are motivated by a biological phenomenon. However, the primary focus of the study here is to explore the effects of the interference of the flow of the two species of rods on their spatiotemporal organization and the regulations of this interference by the extended bottleneck. By a combination of mean-field theory and computer simulation, we calculate the flux of both species of rods and their density profiles as well as the composite phase diagrams of the system. If the bottleneck is sufficiently stringent, then some of the phases become practically unrealizable, although not ruled out on the basis of any fundamental physical principle. Moreover, the extent of suppression of flow of the downstream entrants by the flow of the upstream entrants can also be regulated by the strength of the bottleneck. We speculate on the possible implications of the results in the context of the biological phenomenon that motivated the formulation of the theoretical model. PMID- 28709298 TI - Direct numerical simulation study of statistically stationary propagation of a reaction wave in homogeneous turbulence. AB - A three-dimensional (3D) direct numerical simulation (DNS) study of the propagation of a reaction wave in forced, constant-density, statistically stationary, homogeneous, isotropic turbulence is performed by solving Navier Stokes and reaction-diffusion equations at various (from 0.5 to 10) ratios of the rms turbulent velocity U^{'} to the laminar wave speed, various (from 2.1 to 12.5) ratios of an integral length scale of the turbulence to the laminar wave thickness, and two Zeldovich numbers Ze=6.0 and 17.1. Accordingly, the Damkohler and Karlovitz numbers are varied from 0.2 to 25.1 and from 0.4 to 36.2, respectively. Contrary to an earlier DNS study of self-propagation of an infinitely thin front in statistically the same turbulence, the bending of dependencies of the mean wave speed on U^{'} is simulated in the case of a nonzero thickness of the local reaction wave. The bending effect is argued to be controlled by inefficiency of the smallest scale turbulent eddies in wrinkling the reaction-zone surface, because such small-scale wrinkles are rapidly smoothed out by molecular transport within the local reaction wave. PMID- 28709299 TI - Anisotropic hydrodynamic function of dense confined colloids. AB - Dense colloidal dispersions exhibit complex wave-vector-dependent diffusion, which is controlled by both direct particle interactions and indirect nonadditive hydrodynamic interactions mediated by the solvent. In bulk the hydrodynamic interactions are probed routinely, but in confined geometries their studies have been hitherto hindered by additional complications due to confining walls. Here we solve this issue by combining high-energy x-ray photon correlation spectroscopy and small-angle x-ray-scattering experiments on colloid-filled microfluidic channels to yield the confined fluid's hydrodynamic function in the short-time limit. Most importantly, we find the confined fluid to exhibit a strongly anisotropic hydrodynamic function, similar to its anisotropic structure factor. This observation is important in order to guide future theoretical research. PMID- 28709300 TI - Apex predator and the cyclic competition in a rock-paper-scissors game of three species. AB - This work deals with the effects of an apex predator on the cyclic competition among three distinct species that follow the rules of the rock-paper-scissors game. The investigation develops standard stochastic simulations but is motivated by a procedure which is explained in the work. We add the apex predator as the fourth species in a system that contains three species that evolve following the standard rules of migration, reproduction, and predation, and study how the system evolves in this new environment, in comparison with the case in the absence of the apex predator. The results show that the apex predator engenders the tendency to spread uniformly in the lattice, contributing to destroy the spiral patterns, keeping biodiversity but diminishing the average size of the clusters of the species that compete cyclically. PMID- 28709301 TI - Criteria for drop generation in multiphase microfluidic devices. AB - A theory is presented for the transition between the coflowing and the drop generation regimes observed in microfluidic channels with a rectangular cross section. This transition is characterized by a critical ratio of the dispersed- to continuous-phase volume flow rates. At flow-rate ratios higher than this critical value, drop generation is suppressed. The critical ratio corresponds to the fluid cross section where the dispersed-phase fluid is just tangent to the channel walls. The transition criterion is a function of the ratio of the fluid viscosities, the three-phase contact angle formed between the fluid phases and the channel walls, and the aspect ratio of the channel cross section; the transition is independent of interfacial tension. Hysteretic behavior of drop generation with respect to the flow-rate ratio is predicted for partially wetting dispersed-phase fluids. Experimental data are consistent with this theory. PMID- 28709302 TI - Bifurcation trees of Stark-Wannier ladders for accelerated Bose-Einstein condensates in an optical lattice. AB - In this paper we show that in the semiclassical regime of periodic potential large enough, the Stark-Wannier ladders become a dense energy spectrum because of a cascade of bifurcations while increasing the ratio between the effective nonlinearity strength and the tilt of the external field; this fact is associated to a transition from regular to quantum chaotic dynamics. The sequence of bifurcation points is explicitly given. PMID- 28709303 TI - Acoustic multipole sources for the regularized lattice Boltzmann method: Comparison with multiple-relaxation-time models in the inviscid limit. AB - In this paper, a variant of the acoustic multipole source (AMS) method is proposed within the framework of the lattice Boltzmann method. A quadrupole term is directly included in the stress system (equilibrium momentum flux), and the dependency of the quadrupole source in the inviscid limit upon the fortuitous discretization error reported in the works of E. M. Viggen [Phys. Rev. E 87, 023306 (2013)PLEEE81539-375510.1103/PhysRevE.87.023306] is removed. The regularized lattice Boltzmann (RLB) method with this variant AMS method is presented for the 2D and 3D acoustic problems in the inviscid limit, and without loss of generality, the D3Q19 model is considered in this work. To assess the accuracy and the advantage of the RLB scheme with this AMS for acoustic point sources, the numerical investigations and comparisons with the multiple relaxation-time (MRT) models and the analytical solutions are performed on the 2D and 3D acoustic multipole point sources in the inviscid limit, including monopoles, x dipoles, and xx quadrupoles. From the present results, the good precision of this AMS method is validated, and the RLB scheme exhibits some superconvergence properties for the monopole sources compared with the MRT models, and both the RLB and MRT models have the same accuracy for the simulations of acoustic dipole and quadrupole sources. To further validate the capability of the RLB scheme with AMS, another basic acoustic problem, the acoustic scattering from a solid cylinder presented at the Second Computational Aeroacoustics Workshop on Benchmark Problems, is numerically considered. The directivity pattern of the acoustic field is computed at r=7.5; the present results agree well with the exact solutions. Also, the effects of slip and no slip wall treatments within the regularized boundary condition on this pure acoustic scattering problem are tested, and compared with the exact solution, the slip wall treatment can present a better result. All simulations demonstrate that the RLB scheme with the AMS method is capable of accurately simulating 2D and 3D acoustic generation, propagation, and scattering at zero viscosity. PMID- 28709304 TI - Shear-induced laning transition in a confined colloidal film. AB - Using Brownian dynamics simulations, we investigate a dense system of charged colloids exposed to shear flow in a confined (slit-pore) geometry. The equilibrium system at zero flow consists of three well-pronounced layers with a squarelike crystalline in-plane structure. We demonstrate that, for sufficiently large shear rates, the middle layer separates into two sublayers where the particles organize into moving lanes with opposite velocities. The formation of this "microlaned" state results in a destruction of the applied shear profile; it also has a strong impact on the structure of the system, and on its rheology as measured by the elements of the stress tensor. At higher shear rates, we observe a disordered state and finally a recrystallization reminiscent of the behavior of bilayer films. We also discuss the system size dependence and the robustness of the microlaned state against variations of the slit-pore width. In fact, for a pore width allowing for four layers, we observe a similar shear-induced state in which the system splits into two domains with opposite velocities. PMID- 28709305 TI - Information trimming: Sufficient statistics, mutual information, and predictability from effective channel states. AB - One of the most basic characterizations of the relationship between two random variables, X and Y, is the value of their mutual information. Unfortunately, calculating it analytically and estimating it empirically are often stymied by the extremely large dimension of the variables. One might hope to replace such a high-dimensional variable by a smaller one that preserves its relationship with the other. It is well known that either X (or Y) can be replaced by its minimal sufficient statistic about Y (or X) while preserving the mutual information. While intuitively reasonable, it is not obvious or straightforward that both variables can be replaced simultaneously. We demonstrate that this is in fact possible: the information X's minimal sufficient statistic preserves about Y is exactly the information that Y's minimal sufficient statistic preserves about X. We call this procedure information trimming. As an important corollary, we consider the case where one variable is a stochastic process' past and the other its future. In this case, the mutual information is the channel transmission rate between the channel's effective states. That is, the past-future mutual information (the excess entropy) is the amount of information about the future that can be predicted using the past. Translating our result about minimal sufficient statistics, this is equivalent to the mutual information between the forward- and reverse-time causal states of computational mechanics. We close by discussing multivariate extensions to this use of minimal sufficient statistics. PMID- 28709306 TI - Diffusion in the presence of a local attracting factor: Theory and interdisciplinary applications. AB - In many complex diffusion processes the drift of random walkers is not caused by an external force, as in the case of Brownian motion, but by local variations of fitness perceived by the random walkers. In this paper, a simple but general framework is presented that describes such a type of random motion and may be of relevance in different problems, such as opinion dynamics, cultural spreading, and animal movement. To this aim, we study the problem of a random walker in d dimensions moving in the presence of a local heterogeneous attracting factor expressed in terms of an assigned position-dependent "attractiveness function." At variance with standard Brownian motion, the attractiveness function introduced here regulates both the advection and diffusion of the random walker, thus providing testable predictions for a specific form of fluctuation-relations. We discuss the relation between the drift-diffusion equation based on the attractiveness function and that describing standard Brownian motion, and we provide some explicit examples illustrating its relevance in different fields, such as animal movement, chemotactic diffusion, and social dynamics. PMID- 28709307 TI - Determination of the conformal-field-theory central charge by the Wang-Landau algorithm. AB - We present a simple method to estimate the central charge of the conformal field theory corresponding to a critical point of a two-dimensional lattice model from Monte Carlo simulations. The main idea is to use the Wang-Landau flat-histogram algorithm, which allows us to obtain the free energy of a lattice model on a torus as a function of torus radii. The central charge is calculated with good precision from a free-energy scaling at the critical point. We apply the method to the Ising, tricritical Ising (Blume-Capel), Potts, and site-diluted Ising models, and we also discuss an estimation of the conformal weights. PMID- 28709308 TI - Temporal disorder as a mechanism for spatially heterogeneous diffusion. AB - A fundamental issue in analyzing diffusion in heterogeneous media is interpreting the space dependence of the associated diffusion coefficient. This reflects the well-known Ito-Stratonovich dilemma for continuous stochastic processes with multiplicative noise. In order to resolve this dilemma it is necessary to introduce additional constraints regarding the underlying physical system. Here we introduce a mechanism for generating nonlinear Brownian motion based on a form of temporal disorder. Motivated by switching processes in molecular biology, we consider a Brownian particle that randomly switches between two distinct conformational states with different diffusivities. In each state the particle undergoes normal diffusion (additive noise) so there is no ambiguity in the interpretation of the noise. However, if the switching rates depend on position, then in the fast-switching limit one obtains Brownian motion with a space dependent diffusivity. We show that the resulting multiplicative noise process is of the Ito form. In particular, we solve a first-passage time problem for finite switching rates and show that the mean first-passage time reduces to the Ito version in the fast-switching limit. PMID- 28709309 TI - Symmetries and nonequilibrium thermodynamics. AB - Thermodynamic systems can be defined as composed by many identical interacting subsystems. Here it is shown how the dynamics of relaxation toward equilibrium of a thermodynamic system is closely related to the symmetry group of the Hamiltonian of the subsystems of which it is composed. The transitions between states driven by the interactions between identical subsystems correspond to elements of the root system associated to the symmetry group of their Hamiltonian. This imposes constraints on the relaxation dynamics of the complete thermodynamic system, which allow formulating its evolution toward equilibrium as a system of linear differential equations in which the variables are the thermodynamic forces of the system. The trajectory of a thermodynamic system in the space of thermodynamic forces corresponds to the negative gradient of a potential function, which depends on the symmetry group of the Hamiltonian of the individual interacting subsystems. PMID- 28709310 TI - Phase-field-crystal investigation of the morphology of a steady-state dendrite tip on the atomic scale. AB - Through phase-field-crystal (PFC) simulations, we investigated, on the atomic scale, the crucial role played by interface energy anisotropy and growth driving force during the morphological evolution of a dendrite tip at low growth driving force. In the layer-by-layer growth manner, the interface energy anisotropy drives the forefront of the dendrite tip to evolve to be highly similar to the corner of the corresponding equilibrium crystal from the aspects of atom configuration and morphology, and thus affects greatly the formation and growth of a steady-state dendrite tip. Meanwhile, the driving force substantially influences the part behind the forefront of the dendrite tip, rather than the forefront itself. However, as the driving force increases enough to change the layer-by-layer growth to the multilayer growth, the morphology of the dendrite tip's forefront is completely altered. Parabolic fitting of the dendrite tip reveals that an increase in the influence of interface energy anisotropy makes dendrite tips deviate increasingly from a parabolic shape. By quantifying the deviations under various interface energy anisotropies and growth driving forces, it is suggested that a perfect parabola is an asymptotic limit for the shape of the dendrite tips. Furthermore, the atomic scale description of the dendrite tip obtained in the PFC simulation is compatible with the mesoscopic results obtained in the phase-field simulation in terms of the dendrite tip's morphology and the stability criterion constant. PMID- 28709311 TI - Diffusion-controlled formation and collapse of a d-dimensional A-particle island in the B-particle sea. AB - We consider diffusion-controlled evolution of a d-dimensional A-particle island in the B-particle sea at propagation of the sharp reaction front A+B->0 at equal species diffusivities. The A-particle island is formed by a localized (point) A source with a strength lambda that acts for a finite time T. We reveal the conditions under which the island collapse time t_{c} becomes much longer than the injection period T (long-living island) and demonstrate that regardless of d the evolution of the long-living island radius r_{f}(t) is described by the universal law zeta_{f}=r_{f}/r_{f}^{M}=sqrt[etau|lntau|], where tau=t/t_{c} and r_{f}^{M} is the maximal island expansion radius at the front turning point t_{M}=t_{c}/e. We find that in the long-living island regime the ratio t_{c}/T changes with the increase of the injection period T by the law ?(lambda^{2}T^{2 d})^{1/d}, i.e., increases with the increase of T in the one-dimensional (1D) case, does not change with the increase of T in the 2D case and decreases with the increase of T in the 3D case. We derive the scaling laws for particles death in the long-living island and determine the limits of their applicability. We demonstrate also that these laws describe asymptotically the evolution of the d dimensional spherical island with a uniform initial particle distribution generalizing the results obtained earlier for the quasi-one-dimensional geometry. As striking results, we present a systematic analysis of the front relative width evolution for fluctuation, logarithmically modified, and mean-field regimes, and we demonstrate that in a wide range of parameters the front remains sharp up to a narrow vicinity of the collapse point. PMID- 28709312 TI - Minimal motor for powering particle motion from spin imbalance. AB - We introduce a minimalistic quantum motor for coupled energy and particle transport. The system is composed of two spins, each coupled to a different bath and to a particle which can move on a ring consisting of three sites. We show that the energy flowing from the baths to the system can be partially converted to perform work against an external driving, even in the presence of moderate dissipation. We also analytically demonstrate the necessity of coupling between the spins. We suggest an experimental realization of our model using trapped ions or quantum dots. PMID- 28709313 TI - Emergence of robustness in networks of networks. AB - A model of interdependent networks of networks (NONs) was introduced recently [Proc. Natl. Acad. Sci. (USA) 114, 3849 (2017)PNASA60027 842410.1073/pnas.1620808114] in the context of brain activation to identify the neural collective influencers in the brain NON. Here we investigate the emergence of robustness in such a model, and we develop an approach to derive an exact expression for the random percolation transition in Erdos-Renyi NONs of this kind. Analytical calculations are in agreement with numerical simulations, and highlight the robustness of the NON against random node failures, which thus presents a new robust universality class of NONs. The key aspect of this robust NON model is that a node can be activated even if it does not belong to the giant mutually connected component, thus allowing the NON to be built from below the percolation threshold, which is not possible in previous models of interdependent networks. Interestingly, the phase diagram of the model unveils particular patterns of interconnectivity for which the NON is most vulnerable, thereby marking the boundary above which the robustness of the system improves with increasing dependency connections. PMID- 28709314 TI - Dynamical transition in a jammed state of a quasi-two-dimensional foam. AB - The states of foam are empirically classified into dry foam and wet foam by the volume fraction of the liquid. Recently, a transition between the dry foam state and the wet foam state has been found by characterizing the bubble shapes [Furuta et al., Sci. Rep. 6, 37506 (2016)2045-232210.1038/srep37506]. In the literature, it is indirectly ascertained that the transition from the dry to the wet form is related to the onset of the rearrangement of the bubbles, namely, the liquid fraction at which the bubbles become able to move to replace their positions. The bubble shape is a static property, and the rearrangement of the bubbles is a dynamic property. Thus, we investigate the relation between the bubble shape transition and the rearrangement event occurring in a collapsing process of the bubbles in a quasi-two-dimensional foam system. The current setup brings a good advantage to observe the above transitions, since the liquid fraction of the foam continuously changes in the system. It is revealed that the rearrangement of the bubbles takes place at the dry-wet transition point where the characteristics of the bubble shape change. PMID- 28709315 TI - Heat perturbation spreading in the Fermi-Pasta-Ulam-beta system with next-nearest neighbor coupling: Competition between phonon dispersion and nonlinearity. AB - We employ the heat perturbation correlation function to study thermal transport in the one-dimensional Fermi-Pasta-Ulam-beta lattice with both nearest-neighbor and next-nearest-neighbor couplings. We find that such a system bears a peculiar phonon dispersion relation, and thus there exists a competition between phonon dispersion and nonlinearity that can strongly affect the heat correlation function's shape and scaling property. Specifically, for small and large anharmoncities, the scaling laws are ballistic and superdiffusive types, respectively, which are in good agreement with the recent theoretical predictions; whereas in the intermediate range of the nonlinearity, we observe an unusual multiscaling property characterized by a nonmonotonic delocalization process of the central peak of the heat correlation function. To understand these multiscaling laws, we also examine the momentum perturbation correlation function and find a transition process with the same turning point of the anharmonicity as that shown in the heat correlation function. This suggests coupling between the momentum transport and the heat transport, in agreement with the theoretical arguments of mode cascade theory. PMID- 28709316 TI - Effect of impurities on chirality conversion by grinding. AB - We study the effect of chiral impurities on Viedma ripening using a simple reaction model. The exponential amplification of the enantiomeric excess (EE) is greatly accelerated by a smaller growth rate of solids with monomers caused by the chiral impurities. From the analysis of the model, it is found that the time evolution of the EE is essentially described by a second-order differential equation. The effect of chiral impurities is that the unstable fixed point is shifted from the racemic point, which leads to the linear amplification behavior observed experimentally. The analysis also shows a possibility of an oscillatory decay of the EE. PMID- 28709317 TI - Stability of gas channels in a dense suspension in the presence of obstacles. AB - We investigate experimentally the influence of a fixed obstacle on gas rising in a dense suspension. Air is injected at a constant flow rate by a single nozzle at the bottom center of a Hele-Shaw cell. Without obstacles, previous works have shown that a fluidized zone is formed with a parabolic shape, with a central air channel and two granular convection rolls on its sides. Here, we quantify the influence of the obstacle's shape, size, and height on the location and dynamics of the central air channel. Different regimes are reported: the air channel can simply deviate (stable), or it can switch sides over time (unstable), leading to two signatures not only above the obstacle, but sometimes also below it. This feedback also influences the channel deviation when bypassing the obstacle. A wake of less or no motion is reported above the largest obstacles as well as the maximum probability of gas location, which can be interesting for practical applications. The existence of a critical height h_{c}?7 cm is discussed and compared with the existence of an air finger that develops from the injection nozzle and is stable in time. A dimensionless number describing the transition between air fingering and fracturing makes it possible to predict the channel's stability. PMID- 28709318 TI - Curvature-controlled defect dynamics in active systems. AB - We have studied the collective motion of polar active particles confined to ellipsoidal surfaces. The geometric constraints lead to the formation of vortices that encircle surface points of constant curvature (umbilics). We have found that collective motion patterns are particularly rich on ellipsoids with four umbilics where vortices tend to be located near pairs of umbilical points to minimize their interaction energy. Our results provide a perspective on the migration of living cells, which most likely use the information provided from the curved substrate geometry to guide their collective motion. PMID- 28709319 TI - Golf-course and funnel energy landscapes: Protein folding concepts in martensites. AB - We use protein folding energy landscape concepts such as golf course and funnel to study re-equilibration in athermal martensites under systematic temperature quench Monte Carlo simulations. On quenching below a transition temperature, the seeded high-symmetry parent-phase austenite that converts to the low-symmetry product-phase martensite, through autocatalytic twinning or elastic photocopying, has both rapid conversions and incubation delays in the temperature-time transformation phase diagram. We find the rapid (incubation delays) conversions at low (high) temperatures arises from the presence of large (small) size of golf course edge that has the funnel inside for negative energy states. In the incubating state, the strain structure factor enters into the Brillouin-zone golf course through searches for finite transitional pathways which close off at the transition temperature with Vogel-Fulcher divergences that are insensitive to Hamiltonian energy scales and log-normal distributions, as signatures of dominant entropy barriers. The crossing of the entropy barrier is identified through energy occupancy distributions, Monte Carlo acceptance fractions, heat emission, and internal work. PMID- 28709320 TI - Weak nanoscale chaos and anomalous relaxation in DNA. AB - Anomalous nonexponential relaxation in hydrated biomolecules is commonly attributed to the complexity of the free-energy landscapes, similarly to polymers and glasses. It was found recently that the hydrogen-bond breathing of terminal DNA base pairs exhibits a slow power-law relaxation attributable to weak Hamiltonian chaos, with parameters similar to experimental data. Here, the relationship is studied between this motion and spectroscopic signals measured in DNA with a small molecular photoprobe inserted into the base-pair stack. To this end, the earlier computational approach in combination with an analytical theory is applied to the experimental DNA fragment. It is found that the intensity of breathing dynamics is strongly increased in the internal base pairs that flank the photoprobe, with anomalous relaxation quantitatively close to that in terminal base pairs. A physical mechanism is proposed to explain the coupling between the relaxation of base-pair breathing and the experimental response signal. It is concluded that the algebraic relaxation observed experimentally is very likely a manifestation of weakly chaotic dynamics of hydrogen-bond breathing in the base pairs stacked to the photoprobe and that the weak nanoscale chaos can represent an ubiquitous hidden source of nonexponential relaxation in ultrafast spectroscopy. PMID- 28709321 TI - Finite-time and finite-size scalings in the evaluation of large-deviation functions: Numerical approach in continuous time. AB - Rare trajectories of stochastic systems are important to understand because of their potential impact. However, their properties are by definition difficult to sample directly. Population dynamics provides a numerical tool allowing their study, by means of simulating a large number of copies of the system, which are subjected to selection rules that favor the rare trajectories of interest. Such algorithms are plagued by finite simulation time and finite population size, effects that can render their use delicate. In this paper, we present a numerical approach which uses the finite-time and finite-size scalings of estimators of the large deviation functions associated to the distribution of rare trajectories. The method we propose allows one to extract the infinite-time and infinite-size limit of these estimators, which-as shown on the contact process-provides a significant improvement of the large deviation function estimators compared to the standard one. PMID- 28709322 TI - Linearization-based method for solving a multicomponent diffusion phase-field model with arbitrary solution thermodynamics. AB - This article describes a phase-field model for an isothermal multicomponent, multiphase system which avoids implicit interfacial energy contributions by starting from a grand potential formulation. A method is developed for incorporating arbitrary forms of the equilibrium thermodynamic potentials in all phases to determine an explicit relationship between chemical potentials and species concentrations. The model incorporates variable densities between adjacent phases, defect migration, and dependence of internal pressure on object dimensions ranging from the macro- to nanoscale. A demonstrative simulation of an overpressurized nanoscopic intragranular bubble in nuclear fuel migrating to a grain boundary under kinetically limited vacancy diffusion is shown. PMID- 28709323 TI - Noise-induced stabilization of collective dynamics. AB - We illustrate a counterintuitive effect of an additive stochastic force, which acts independently on each element of an ensemble of globally coupled oscillators. We show that a very small white noise not only broadens the clusters, wherever they are induced by the deterministic forces, but can also stabilize a linearly unstable collective periodic regime: self-consistent partial synchrony. With the help of microscopic simulations we are able to identify two noise-induced bifurcations. A macroscopic analysis, based on a perturbative solution of the associated nonlinear Fokker-Planck equation, confirms the numerical studies and allows determining the eigenvalues of the stability problem. We finally argue about the generality of the phenomenon. PMID- 28709324 TI - Geometric structure and information change in phase transitions. AB - We propose a toy model for a cyclic order-disorder transition and introduce a geometric methodology to understand stochastic processes involved in transitions. Specifically, our model consists of a pair of forward and backward processes (FPs and BPs) for the emergence and disappearance of a structure in a stochastic environment. We calculate time-dependent probability density functions (PDFs) and the information length L, which is the total number of different states that a system undergoes during the transition. Time-dependent PDFs during transient relaxation exhibit strikingly different behavior in FPs and BPs. In particular, FPs driven by instability undergo the broadening of the PDF with a large increase in fluctuations before the transition to the ordered state accompanied by narrowing the PDF width. During this stage, we identify an interesting geodesic solution accompanied by the self-regulation between the growth and nonlinear damping where the time scale tau of information change is constant in time, independent of the strength of the stochastic noise. In comparison, BPs are mainly driven by the macroscopic motion due to the movement of the PDF peak. The total information length L between initial and final states is much larger in BPs than in FPs, increasing linearly with the deviation gamma of a control parameter from the critical state in BPs while increasing logarithmically with gamma in FPs. L scales as |lnD| and D^{-1/2} in FPs and BPs, respectively, where D measures the strength of the stochastic forcing. These differing scalings with gamma and D suggest a great utility of L in capturing different underlying processes, specifically, diffusion vs advection in phase transition by geometry. We discuss physical origins of these scalings and comment on implications of our results for bistable systems undergoing repeated order-disorder transitions (e.g., fitness). PMID- 28709325 TI - Transitions between multiple dynamical states in a confined dense active-particle system. AB - We study the collective motion of a dense suspension of active swimmers in a viscous fluid medium. The swimmers are modeled as soft spheres moving in a highly viscous fluid medium. The magnitude of the propelling thrust exerted by each particle is taken to be a constant and the direction is aligned to its velocity. Depending on the magnitude of the exerted thrust, several nonequilibrium steady states are observed. The transitions between the steady states are characterized using the total dissipation as a function of the magnitude of the thrust. The transitions between the nonequilibrium states are characterized by changes in exponent at low thrust values. At high thrust values, hysteretic transitions between ordered and disordered states are observed. PMID- 28709326 TI - Curvature-driven stability of defects in nematic textures over spherical disks. AB - Stabilizing defects in liquid-crystal systems is crucial for many physical processes and applications ranging from functionalizing liquid-crystal textures to recently reported command of chaotic behaviors of active matters. In this work, we perform analytical calculations to study the curvature-driven stability mechanism of defects based on the isotropic nematic disk model that is free of any topological constraint. We show that in a growing spherical disk covering a sphere the accumulation of curvature effect can prevent typical +1 and +1/2 defects from forming boojum textures where the defects are repelled to the boundary of the disk. Our calculations reveal that the movement of the equilibrium position of the +1 defect from the boundary to the center of the spherical disk occurs in a very narrow window of the disk area, exhibiting the first-order phase-transition-like behavior. For the pair of +1/2 defects by splitting a +1 defect, we find the curvature-driven alternating repulsive and attractive interactions between the two defects. With the growth of the spherical disk these two defects tend to approach and finally recombine towards a +1 defect texture. The sensitive response of defects to curvature and the curvature-driven stability mechanism demonstrated in this work in nematic disk systems may have implications towards versatile control and engineering of liquid-crystal textures in various applications. PMID- 28709327 TI - Spatially periodic deformations in planar and twisted flexoelectric nematic layers. AB - Electric field induced deformations in twisted and untwisted planar layers of nematic liquid crystals possessing flexoelectric properties were investigated numerically. The spatially periodic deformations, taking the form of parallel stripes, were found to have smaller free energy than the homogeneous deformations. The structures of distorted layers as well as the evolution of deformations during changes of bias voltage were recognized. The role of flexoelectric properties was analyzed. Calculations taking into account the peculiar elastic properties of the bent-core nematics were also performed. In the untwisted planar layers the stripes were parallel to the initial director orientation. In the twisted layers, two different kinds of periodic deformation were distinguished. They had different structures and different directions with respect to the initial director distribution. The results were consistent with existing experimental data. PMID- 28709328 TI - Autonomous rotor heat engine. AB - The triumph of heat engines is their ability to convert the disordered energy of thermal sources into useful mechanical motion. In recent years, much effort has been devoted to generalizing thermodynamic notions to the quantum regime, partly motivated by the promise of surpassing classical heat engines. Here, we instead adopt a bottom-up approach: we propose a realistic autonomous heat engine that can serve as a test bed for quantum effects in the context of thermodynamics. Our model draws inspiration from actual piston engines and is built from closed system Hamiltonians and weak bath coupling terms. We analytically derive the performance of the engine in the classical regime via a set of nonlinear Langevin equations. In the quantum case, we perform numerical simulations of the master equation. Finally, we perform a dynamic and thermodynamic analysis of the engine's behavior for several parameter regimes in both the classical and quantum case and find that the latter exhibits a consistently lower efficiency due to additional noise. PMID- 28709329 TI - Empirical resistive-force theory for slender biological filaments in shear thinning fluids. AB - Many cells exploit the bending or rotation of flagellar filaments in order to self-propel in viscous fluids. While appropriate theoretical modeling is available to capture flagella locomotion in simple, Newtonian fluids, formidable computations are required to address theoretically their locomotion in complex, nonlinear fluids, e.g., mucus. Based on experimental measurements for the motion of rigid rods in non-Newtonian fluids and on the classical Carreau fluid model, we propose empirical extensions of the classical Newtonian resistive-force theory to model the waving of slender filaments in non-Newtonian fluids. By assuming the flow near the flagellum to be locally Newtonian, we propose a self-consistent way to estimate the typical shear rate in the fluid, which we then use to construct correction factors to the Newtonian local drag coefficients. The resulting non Newtonian resistive-force theory, while empirical, is consistent with the Newtonian limit, and with the experiments. We then use our models to address waving locomotion in non-Newtonian fluids and show that the resulting swimming speeds are systematically lowered, a result which we are able to capture asymptotically and to interpret physically. An application of the models to recent experimental results on the locomotion of Caenorhabditis elegans in polymeric solutions shows reasonable agreement and thus captures the main physics of swimming in shear-thinning fluids. PMID- 28709330 TI - Backward renormalization-group inference of cortical dipole sources and neural connectivity efficacy. AB - Proper neural connectivity inference has become essential for understanding cognitive processes associated with human brain function. Its efficacy is often hampered by the curse of dimensionality. In the electroencephalogram case, which is a noninvasive electrophysiological monitoring technique to record electrical activity of the brain, a possible way around this is to replace multichannel electrode information with dipole reconstructed data. We use a method based on maximum entropy and the renormalization group to infer the position of the sources, whose success hinges on transmitting information from low- to high resolution representations of the cortex. The performance of this method compares favorably to other available source inference algorithms, which are ranked here in terms of their performance with respect to directed connectivity inference by using artificially generated dynamic data. We examine some representative scenarios comprising different numbers of dynamically connected dipoles over distinct cortical surface positions and under different sensor noise impairment levels. The overall conclusion is that inverse problem solutions do not affect the correct inference of the direction of the flow of information as long as the equivalent dipole sources are correctly found. PMID- 28709331 TI - Scales and multimodal flux distributions in stationary metabolic network models via thermodynamics. AB - In this work it is shown that scale-free tails in metabolic flux distributions inferred in stationary models are an artifact due to reactions involved in thermodynamically unfeasible cycles, unbounded by physical constraints and in principle able to perform work without expenditure of free energy. After implementing thermodynamic constraints by removing such loops, metabolic flux distributions scale meaningfully with the physical limiting factors, acquiring in turn a richer multimodal structure potentially leading to symmetry breaking while optimizing for objective functions. PMID- 28709332 TI - Separation of two attractive ferromagnetic ellipsoidal particles by hydrodynamic interactions under alternating magnetic field. AB - In applications where magnetic particles are used to detect and dose targeted molecules, it is of major importance to prevent particle clustering and aggregation during the capture stage in order to maximize the capture rate. Elongated ferromagnetic particles can be more interesting than spherical ones due to their large magnetic moment, which facilitates their separation by magnets or the detection by optical measurement of their orientation relaxation time. Under alternating magnetic field, the rotational dynamics of elongated ferromagnetic particles results from the balance between magnetic torque that tends to align the particle axis with the field direction and viscous torque. As for their translational motion, it results from a competition between direct magnetic particle-particle interactions and solvent-flow-mediated hydrodynamic interactions. Due to particle anisotropy, this may lead to intricate translation rotation couplings. Using numerical simulations and theoretical modeling of the system, we show that two ellipsoidal magnetic particles, initially in a head-to tail attractive configuration resulting from their remnant magnetization, can repel each other due to hydrodynamic interactions when alternating field is operated. The separation takes place in a range of low frequencies f_{c1}infinity, and the region determined by the inequalities beta<2 and 2betaH_{0}<1+beta-sqrt[1+2beta-beta^{2}], for which consensus, with respect to B, is never reached. PMID- 28709342 TI - Extended states with Poisson spectral statistics. AB - Contrary to the prevailing notion, we find that the spectrum associated with the extended states in a complex system may belong to the Poisson universality class if the system is subjected to a specific set of constraints. Our results are based on an exact theoretical as well as numerical analysis of column constrained chiral ensembles with circulant off-diagonal blocks and are relevant for a complete understanding of the eigenfunction localization and related physical properties. PMID- 28709343 TI - Internal rupture and rapid bouncing of impacting drops induced by submillimeter scale textures. AB - We demonstrate an internal breakup mechanism for high Weber number drop impact on superhydrophobic surfaces uniformly patterned with submillimeter-scale textures, in which the liquid film ruptures from both interior and rim. The employment of submillimeter-scale posts could help decrease the critical Weber number of internal rupture, due to the small solid fraction and the large dimension ratio between primary structures and droplets. The internal rupture is found to promote more rapid drop bouncing than conventional rebound and rim breakup on superhydrophobic surfaces with small roughness, with a 10%-50% reduction of contact time. The internal rupture results from the film instability inside and the jet instability outside. PMID- 28709344 TI - Effect of head group orientation on phospholipid assembly. AB - The relationship between bilayer stability and lipid head group orientation is reported. In this work, molecular-dynamics simulations are performed to analyze the structure-property relationship of lipid biomembranes, taking into account coarse-grained model lipid interactions. The work explains the molecular scale mechanism of the phase behavior of lipid systems due to ion-lipid or anesthetic lipid interactions, where reorientations of dipoles play a key role in modifying lipid phases and thereby alter biomembrane function. Our study demonstrates that simple dipolar reorientation is indeed sufficient in tuning a bilayer to a randomly flipped nonbilayer lamellar phase. This study may be used to assess the impact of changes in lipid phase characteristics on biomembrane structure due to the presence of anesthetics and ions. PMID- 28709345 TI - Electro-osmotic flow through nanopores in thin and ultrathin membranes. AB - We theoretically study how the electro-osmotic fluid velocity in a charged cylindrical nanopore in a thin solid state membrane depends on the pore's geometry, membrane charge, and electrolyte concentration. We find that when the pore's length is comparable to its diameter, the velocity profile develops a concave shape with a minimum along the pore axis unlike the situation in very long nanopores with a maximum velocity along the central pore axis. This effect is attributed to the induced pressure along the nanopore axis due to the fluid flow expansion and contraction near the exit or entrance to the pore and to the reduction of electric field inside the nanopore. The induced pressure is maximal when the pore's length is about equal to its diameter while decreasing for both longer and shorter nanopores. A model for the fluid velocity incorporating these effects is developed and shown to be in a good agreement with numerically computed results. PMID- 28709346 TI - Asymptotic modeling of transport phenomena at the interface between a fluid and a porous layer: Jump conditions. AB - We develop asymptotic modeling for two- or three-dimensional viscous fluid flow and convective transfer at the interface between a fluid and a porous layer. The asymptotic model is based on the fact that the thickness d of the interfacial transition region Omega_{fp} of the one-domain representation is very small compared to the macroscopic length scale L. The analysis leads to an equivalent two-domain representation where transport phenomena in the transition layer of the one-domain approach are represented by algebraic jump boundary conditions at a fictive dividing interface Sigma between the homogeneous fluid and porous regions. These jump conditions are thus stated up to first-order in O(d/L) with d/L?1. The originality and relevance of this asymptotic model lies in its general and multidimensional character. Indeed, it is shown that all the jump interface conditions derived for the commonly used 1D-shear flow are recovered by taking the tangential component of the asymptotic model. In that case, the comparison between the present model and the different models available in the literature gives explicit expressions of the effective jump coefficients and their associated scaling. In addition for multi-dimensional flows, the general asymptotic model yields the different components of the jump conditions including a new specific equation for the cross-flow pressure jump on Sigma. PMID- 28709347 TI - Emergence of dispersive shocks and rarefaction waves in power-law contact models. AB - In the present work, motivated by generalized forms of the Hertzian dynamics associated with granular crystals, we consider the possibility of such models to give rise to both dispersive shock and rarefaction waves. Depending on the value p of the nonlinearity exponent, we find that both of these possibilities are realizable. We use a quasicontinuum approximation of a generalized inviscid Burgers model in order to predict the solution profile up to times near the formation of the dispersive shock, as well as to estimate when it will occur. Beyond that time threshold, oscillations associated with the highly dispersive nature of the underlying model emerge, which cannot be captured by the quasicontinuum approximation. Our analytical characterization of the above features is complemented by systematic numerical computations. PMID- 28709348 TI - Dielectric relaxation process of a partially unwound helical structure in ferroelectric liquid crystals. AB - The fluctuations of unwound helical structure have been observed in deformed helix ferroelectric liquid crystal (DHFLC) and conventional FLC sample cells. The helix is partially unwound by strong anchoring on the substrates. In such sample cells, the helical decarlization lines are not observed in the texture under crossed polarized microscope. The dielectric spectroscopy is employed to observe the behavior of dielectric relaxation processes in these sample cells. A dielectric relaxation process is observed at a lower frequency than the Goldstone mode processes in DHFLC and FLC, which we call partially unwound helical mode (p UHM). However, the p-UHM process is not observed in the sample cell in which the helical lines appear. The application of various amplitudes of probing ac voltages on this mode has shown the higher frequency shift, i.e., the larger the amplitude of ac voltage, the higher is the relaxation frequency of p-UHM. At sufficient amplitude of applied probing ac voltage, the p-UHM merges with the Goldstone mode process and is difficult to detect. However, the Goldstone mode relaxation frequency is almost independent of the cell geometry and sample configuration. The electro-optical behavior of the p-UHM has also been confirmed by electro-optical technique. The dielectric relaxation of UHM at a frequency lower than the Goldstone mode is interpreted as the fluctuation of partially unwound helix. PMID- 28709349 TI - Influence of measurement error on Maxwell's demon. AB - In any general cycle of measurement, feedback, and erasure, the measurement will reduce the entropy of the system when information about the state is obtained, while erasure, according to Landauer's principle, is accompanied by a corresponding increase in entropy due to the compression of logical and physical phase space. The total process can in principle be fully reversible. A measurement error reduces the information obtained and the entropy decrease in the system. The erasure still gives the same increase in entropy, and the total process is irreversible. Another consequence of measurement error is that a bad feedback is applied, which further increases the entropy production if the proper protocol adapted to the expected error rate is not applied. We consider the effect of measurement error on a realistic single-electron box Szilard engine, and we find the optimal protocol for the cycle as a function of the desired power P and error E. PMID- 28709350 TI - Representation of the direct correlation function of the hard-sphere fluid. AB - An accurate representation of the structural pair correlation functions of the hard sphere (HS) fluid up to the freezing density is proposed which combines the pole expression for the total correlation function h(r), the Ornstein-Zernike equation, and molecular dynamics (MD) computer simulation data. In the scheme, h(r) is expressed in terms of a set of pole parameters, which reveals how the tail of the Fourier transform of h(r) contains information on the discontinuities in the derivatives of the direct correlation function (DCF). This formulation leads to a DCF expressed as the sum of a numerically obtainable part and an analytic part which consists of elementary integral terms, some of which are found to give rise to the discontinuities. An exact formula for the magnitude of these discontinuities is derived, which indicates that there is a particular density (rho?0.133) below which the magnitude of the discontinuities decreases with increasing order of the derivative. With the accurate MD simulation data the set of parameters that specifies h(r) was determined. These can be used to obtain the different structural functions of the HS fluid, and following the calculation stages of the pole structure scheme the DCF is obtained. From this route to the DCF the second pole of the HS fluid can be determined and the non-negligible role of the "out of core" part of the DCF at high densities is revealed. The density dependent separation range where the two pole approximation represents well the h(r) has been determined. PMID- 28709351 TI - Fluctuations of absorption of interacting diffusing particles by multiple absorbers. AB - We study fluctuations of particle absorption by a three-dimensional domain with multiple absorbing patches. The domain is in contact with a gas of interacting diffusing particles. This problem is motivated by living cell sensing via multiple receptors distributed over the cell surface. Employing the macroscopic fluctuation theory, we calculate the covariance matrix of the particle absorption by different patches, extending previous works which addressed fluctuations of a single current. We find a condition when the sign of correlations between different patches is fully determined by the transport coefficients of the gas and is independent of the problem's geometry. We show that the fluctuating particle flux field typically develops vorticity. We establish a simple connection between the statistics of particle absorption by all the patches combined and the statistics of current in a nonequilibrium steady state in one dimension. We also discuss connections between the absorption statistics and (i) statistics of electric currents in multiterminal diffusive conductors and (ii) statistics of wave transmission through disordered media with multiple absorbers. PMID- 28709353 TI - Escape dynamics through a continuously growing leak. AB - We formulate a model that describes the escape dynamics in a leaky chaotic system in which the size of the leak depends on the number of the in-falling particles. The basic motivation of this work is the astrophysical process, which describes the planetary accretion. In order to study the dynamics generally, the standard map is investigated in two cases when the dynamics is fully hyperbolic and in the presence of Kolmogorov-Arnold-Moser islands. In addition to the numerical calculations, an analytic solution to the temporal behavior of the model is also derived. We show that in the early phase of the leak expansion, as long as there are enough particles in the system, the number of survivors deviates from the well-known exponential decay. Furthermore, the analytic solution returns the classical result in the limiting case when the number of particles does not affect the leak size. PMID- 28709352 TI - Asymmetry-induced synchronization in oscillator networks. AB - A scenario has recently been reported in which in order to stabilize complete synchronization of an oscillator network-a symmetric state-the symmetry of the system itself has to be broken by making the oscillators nonidentical. But how often does such behavior-which we term asymmetry-induced synchronization (AISync) occur in oscillator networks? Here we present the first general scheme for constructing AISync systems and demonstrate that this behavior is the norm rather than the exception in a wide class of physical systems that can be seen as multilayer networks. Since a symmetric network in complete synchrony is the basic building block of cluster synchronization in more general networks, AISync should be common also in facilitating cluster synchronization by breaking the symmetry of the cluster subnetworks. PMID- 28709354 TI - Crossing fitness canyons by a finite population. AB - We consider the Wright-Fisher model of the finite population evolution on a fitness landscape defined in the sequence space by a path of nearly neutral mutations. We study a specific structure of the fitness landscape: One of the intermediate mutations on the mutation path results in either a large fitness value (climbing up a fitness hill) or a low fitness value (crossing a fitness canyon), the rest of the mutations besides the last one are neutral, and the last sequence has much higher fitness than any intermediate sequence. We derive analytical formulas for the first arrival time of the mutant with two point mutations. For the first arrival problem for the further mutants in the case of canyon crossing, we analytically deduce how the mean first arrival time scales with the population size and fitness difference. The location of the canyon on the path of sequences has a crucial role. If the canyon is at the beginning of the path, then it significantly prolongs the first arrival time; otherwise it just slightly changes it. Furthermore, the fitness hill at the beginning of the path strongly prolongs the arrival time period; however, the hill located near the end of the path shortens it. We optimize the first arrival time by applying a nonzero selection to the intermediate sequences. We extend our results and provide a scaling for the valley crossing time via the depth of the canyon and population size in the case of a fitness canyon at the first position. Our approach is useful for understanding some complex evolution systems, e.g., the evolution of cancer. PMID- 28709355 TI - Genuine localization transition in a long-range hopping model. AB - We introduce and study a banded random matrix model describing sparse, long-range quantum hopping in one dimension. Using a series of analytic arguments, numerical simulations, and a mapping to a long-range epidemics model, we establish the phase diagram of the model. A genuine localization transition, with well defined mobility edges, appears as the hopping rate decreases slower than l^{-2}, where l is the distance. Correspondingly, the decay of the localized states evolves from a standard exponential shape to a stretched exponential and finally to a exp( Cln^{kappa}l) behavior, with kappa>1. PMID- 28709356 TI - Erratum: Modeling rigid magnetically rotated microswimmers: Rotation axes, bistability, and controllability [Phys. Rev. E 90, 063006 (2014)]. AB - This corrects the article DOI: 10.1103/PhysRevE.90.063006. PMID- 28709357 TI - Coulomb collision model for use in nonthermal plasma simulation. AB - In kinetic simulations of non-Maxwellian plasmas, the calculation of particle scattering due to Coulomb collisions has no simple approximation. In such simulations, the number of collision interactions a particle experiences in a single time step is typically too large for direct calculation. In this work, the cumulative effect of a series of binary collisions is calculated numerically in a stochastic manner, and heuristic trends are produced as functions of the local plasma parameters. The result is a collision model suitable for implementation into a kinetic plasma simulation. The presence of low-probability, high-angle scattering due to close collision encounters is defined and described, and this effect is demonstrated in a test problem simulation of weakly collisional counterstreaming ion beams. PMID- 28709358 TI - Analytic solutions throughout a period doubling route to chaos. AB - We show examples of dynamical systems that can be solved analytically at any point along a period doubling route to chaos. Each system consists of a linear part oscillating about a set point and a nonlinear rule for regularly updating that set point. Previously it has been shown that such systems can be solved analytically even when the oscillations are chaotic. However, these solvable systems show few bifurcations, transitioning directly from a steady state to chaos. Here we show that a simple change to the rule for updating the set point allows for a greater variety of nonlinear dynamical phenomena, such as period doubling, while maintaining solvability. Two specific examples are given. The first is an oscillator whose set points are determined by a logistic map. We present analytic solutions describing an entire period doubling route to chaos. The second example is an electronic circuit. We show experimental data confirming both solvability and a period doubling route to chaos. These results suggest that analytic solutions may be a more useful tool in studying nonlinear dynamics than was previously recognized. PMID- 28709359 TI - Self-propulsion and crossing statistics under random initial conditions. AB - We investigate the crossing of an energy barrier by a self-propelled particle described by a Rayleigh friction term. We reveal the existence of a sharp transition in the external force field whereby the amplitude dramatically increases. This corresponds to a saddle point transition in the velocity flow phase space, as would be expected for any type of repulsive force field. We use this approach to rationalize the results obtained by Eddi et al. [Phys. Rev. Lett. 102, 240401 (2009)PRLTAO0031-900710.1103/PhysRevLett.102.240401] who studied the interaction between a drop propelled by its accompanying wave field and a submarine obstacle. This wave particle entity can overcome potential barrier, suggesting the existence of a "macroscopic tunneling effect." We show that the effect of self-propulsion is sufficiently strong to generate crossing of the high-energy barrier. By assuming a random distribution of initial angles, we define a probability distribution to cross the potential barrier that matches with the data of Eddi et al. This probability is similar to the one encountered in statistical physics for Hamiltonian systems, i.e., a Boltzmann exponential law. PMID- 28709360 TI - Computational aspects of the smectization process in liquid crystals: An example study of a perfectly aligned two-dimensional hard-boomerang system. AB - A replica method for calculation of smectic liquid crystal properties within the Onsager theory has been presented and applied to an exemplary case of two dimensional perfectly aligned needlelike boomerangs. The method allows one to consider the complete influence of the interaction terms in contrast to the Fourier expansion method which uses mostly first or second order terms of expansion. The program based on the replica algorithm is able to calculate a single representative layer as an equivalent set of layers, depending on the size of the considered width of the sample integration interval. It predicts successfully smectic density distributions, energies, and layer thicknesses for different types of layer arrangement-of the antiferroelectric or of the smectic A order type. Specific features of the algorithm performance and influence of the numerical accuracy on the physical properties are presented. Future applications of the replica method to freely rotating molecules are discussed. PMID- 28709361 TI - Entanglement and its relationship to classical dynamics. AB - We present an analysis of the entangling quantum kicked top focusing on the few qubit case and the initial condition dependence of the time-averaged entanglement S_{Q} for spin-coherent states. We show a very strong connection between the classical phase space and the initial condition dependence of S_{Q} even for the extreme case of two spin-1/2 qubits. This correlation is not related directly to chaos in the classical dynamics. We introduce a measure of the behavior of a classical trajectory which correlates far better with the entanglement and show that the maps of classical and quantum initial-condition dependence are both organized around the symmetry points of the Hamiltonian. We also show clear (quasi-)periodicity in entanglement as a function of number of kicks and of kick strength. PMID- 28709362 TI - Tuning bacterial hydrodynamics with magnetic fields. AB - Magnetotactic bacteria are a group of motile prokaryotes that synthesize chains of lipid-bound, magnetic nanoparticles called magnetosomes. This study exploits their innate magnetism to investigate previously unexplored facets of bacterial hydrodynamics at surfaces. Through use of weak, uniform, external magnetic fields and local, micromagnetic surface patterns, the relative strength of hydrodynamic, magnetic, and flagellar force components is tuned through magnetic control of the bacteria's orientation. The resulting swimming behaviors provide a means to experimentally determine hydrodynamic parameters and offer a high degree of control over large numbers of living microscopic entities. The implications of this controlled motion for studies of bacterial motility near surfaces and for micro- and nanotechnology are discussed. PMID- 28709363 TI - Relating the large-scale structure of time series and visibility networks. AB - The structure of time series is usually characterized by means of correlations. A new proposal based on visibility networks has been considered recently. Visibility networks are complex networks mapped from surfaces or time series using visibility properties. The structures of time series and visibility networks are closely related, as shown by means of fractional time series in recent works. In these works, a simple relationship between the Hurst exponent H of fractional time series and the exponent of the distribution of edges gamma of the corresponding visibility network, which exhibits a power law, is shown. To check and generalize these results, in this paper we delve into this idea of connected structures by defining both structures more properly. In addition to the exponents used before, H and gamma, which take into account local properties, we consider two more exponents that, as we will show, characterize global properties. These are the exponent alpha for time series, which gives the scaling of the variance with the size as var~T^{2alpha}, and the exponent kappa of their corresponding network, which gives the scaling of the averaged maximum of the number of edges, ~N^{kappa}. With this representation, a more precise connection between the structures of general time series and their associated visibility network is achieved. Similarities and differences are more clearly established, and new scaling forms of complex networks appear in agreement with their respective classes of time series. PMID- 28709364 TI - Structural interactions in ionic liquids linked to higher-order Poisson-Boltzmann equations. AB - We present a derivation of generalized Poisson-Boltzmann equations starting from classical theories of binary fluid mixtures, employing an approach based on the Legendre transform as recently applied to the case of local descriptions of the fluid free energy. Under specific symmetry assumptions, and in the linearized regime, the Poisson-Boltzmann equation reduces to a phenomenological equation introduced by Bazant et al. [Phys. Rev. Lett. 106, 046102 (2011)]PRLTAO0031 900710.1103/PhysRevLett.106.046102, whereby the structuring near the surface is determined by bulk coefficients. PMID- 28709365 TI - Work extraction in an isolated quantum lattice system: Grand canonical and generalized Gibbs ensemble predictions. AB - We study work extraction (defined as the difference between the initial and the final energy) in noninteracting and (effectively) weakly interacting isolated fermionic quantum lattice systems in one dimension, which undergo a sequence of quenches and equilibration. The systems are divided in two parts, which we identify as the subsystem of interest and the bath. We extract work by quenching the on-site potentials in the subsystem, letting the entire system equilibrate, and returning to the initial parameters in the subsystem using a quasistatic process (the bath is never acted upon). We select initial states that are direct products of thermal states of the subsystem and the bath, and consider equilibration to the generalized Gibbs ensemble (GGE, noninteracting case) and to the Gibbs ensemble (GE, weakly interacting case). We identify the class of quenches that, in the thermodynamic limit, results in GE and GGE entropies after the quench that are identical to the one in the initial state (quenches that do not produce entropy). Those quenches guarantee maximal work extraction when thermalization occurs. We show that the same remains true in the presence of integrable dynamics that results in equilibration to the GGE. PMID- 28709366 TI - Correspondence between spanning trees and the Ising model on a square lattice. AB - An important problem in statistical physics concerns the fascinating connections between partition functions of lattice models studied in equilibrium statistical mechanics on the one hand and graph theoretical enumeration problems on the other hand. We investigate the nature of the relationship between the number of spanning trees and the partition function of the Ising model on the square lattice. The spanning tree generating function T(z) gives the spanning tree constant when evaluated at z=1, while giving the lattice green function when differentiated. It is known that for the infinite square lattice the partition function Z(K) of the Ising model evaluated at the critical temperature K=K_{c} is related to T(1). Here we show that this idea in fact generalizes to all real temperatures. We prove that [Z(K)sech2K]^{2}=kexp[T(k)] , where k=2tanh(2K)sech(2K). The identical Mahler measure connects the two seemingly disparate quantities T(z) and Z(K). In turn, the Mahler measure is determined by the random walk structure function. Finally, we show that the the above correspondence does not generalize in a straightforward manner to nonplanar lattices. PMID- 28709367 TI - Geometric determination of classical actions of heteroclinic and unstable periodic orbits. AB - Semiclassical sum rules, such as the Gutzwiller trace formula, depend on the properties of periodic, closed, or homoclinic (heteroclinic) orbits. The interferences embedded in such orbit sums are governed by classical action functions and Maslov indices. For chaotic systems, the relative actions of such orbits can be expressed in terms of phase-space areas bounded by segments of stable and unstable manifolds and Moser invariant curves. This also generates direct relations between periodic orbits and homoclinic (heteroclinic) orbit actions. Simpler, explicit approximate expressions following from the exact relations are given with error estimates. They arise from asymptotic scaling of certain bounded phase-space areas. The actions of infinite subsets of periodic orbits are determined by their periods and the locations of the limiting homoclinic points on which they accumulate. PMID- 28709368 TI - Three-dimensional to two-dimensional transition in mode-I fracture microbranching in a perturbed hexagonal close-packed lattice. AB - Mode-I fracture exhibits microbranching in the high velocity regime where the simple straight crack is unstable. For velocities below the instability, classic modeling using linear elasticity is valid. However, showing the existence of the instability and calculating the dynamics postinstability within the linear elastic framework is difficult and controversial. The experimental results give several indications that the microbranching phenomenon is basically a three dimensional (3D) phenomenon. Nevertheless, the theoretical effort has been focused mostly on two-dimensional (2D) modeling. In this paper we study the microbranching instability using three-dimensional atomistic simulations, exploring the difference between the 2D and the 3D models. We find that the basic 3D fracture pattern shares similar behavior with the 2D case. Nevertheless, we exhibit a clear 3D-2D transition as the crack velocity increases, whereas as long as the microbranches are sufficiently small, the behavior is pure 3D behavior, whereas at large driving, as the size of the microbranches increases, more 2D like behavior is exhibited. In addition, in 3D simulations, the quantitative features of the microbranches, separating the regimes of steady-state cracks (mirror) and postinstability (mist-hackle) are reproduced clearly, consistent with the experimental findings. PMID- 28709369 TI - Deposition and light absorption characteristics of precipitation dissolved organic carbon (DOC) at three remote stations in the Himalayas and Tibetan Plateau, China. AB - The concentrations, depositions and optical properties of precipitation DOC at three remote stations (Nam Co, Lulang and Everest) were investigated in the Himalayas and Tibetan Plateau (HTP). The results showed that their volume weighted mean DOC concentrations were 1.05+/-1.01mgCL-1, 0.83+/-0.85mgCL-1 and 0.86+/-0.91mgCL-1, respectively, close to those of other remote areas in the world and lower than those of typical polluted urban cities. Combined with precipitation amounts, the DOC depositions at these three stations were calculated to be 0.34+/-0.32gCm-2yr-1, 0.84+/-0.86gCm-2yr-1 and 0.16+/-0.17gCm 2yr-1, respectively. The annual DOC deposition in the HTP was approximately 0.94+/-0.87TgC, the highest and lowest values appeared in the southeastern and northwestern plateau, respectively. The sources of DOC in the precipitation at these three stations were remarkably different, indicating large spatial heterogeneity in the sources of precipitation DOC over the HTP. Nam Co presented combustion sources from South Asia and local residents, Lulang showed biomass combustion source from South Asia, and Everest was mainly influenced by local mineral dust. The values of the MACDOC at 365nm were 0.48+/-0.47m2g-1, 0.25+/ 0.15m2g-1, and 0.64+/-0.49m2g-1, respectively, for the precipitation at the three stations. All of these values were significantly lower than those of corresponding near-surface aerosol samples because precipitation DOC contains more secondary organic aerosol with low light absorption abilities. Additionally, this phenomenon was also observed in seriously polluted urban areas, implying it is universal in the atmosphere. Because precipitation DOC contains information for both particle-bound and gaseous components from the near surface up to the altitude of clouds where precipitation occurs, the MACDOC of precipitation is more representative than that of near-surface aerosols for a given region. PMID- 28709370 TI - Sewers as potential reservoirs of antibiotic resistance. AB - Wastewater transport along sewers favors the colonization of inner pipe surfaces by wastewater-derived microorganisms that grow forming biofilms. These biofilms are composed of rich and diverse microbial communities that are continuously exposed to antibiotic residues and antibiotic resistant bacteria (ARB) from urban wastewater. Sewer biofilms thus appear as an optimal habitat for the dispersal and accumulation of antibiotic resistance genes (ARGs). In this study, the concentration of antibiotics, integron (intI1) and antibiotic resistance genes (qnrS, sul1, sul2, blaTEM, blaKPC, ermB, tetM and tetW), and potential bacterial pathogens were analyzed in wastewater and biofilm samples collected at the inlet and outlet sections of a pressurized sewer pipe. The most abundant ARGs detected in both wastewater and biofilm samples were sul1 and sul2 with roughly 1 resistance gene for each 10 copies of 16s RNA gene. Significant differences in the relative abundance of gene intI1 and genes conferring resistance to fluoroquinolones (qnrS), sulfonamides (sul1 and sul2) and betalactams (blaTEM) were only measured between inlet and outlet biofilm samples. Composition of bacterial communities also showed spatial differences in biofilms and a higher prevalence of Operational Taxonomic Units (OTUs) with high sequence identity (>98%) to well-known human pathogens was observed in biofilms collected at the inlet pipe section. Our study highlights the role of sewer biofilms as source and sink of ARB and ARGs and supports the idea that community composition rather than antibiotic concentration is the main factor driving the diversity of the sewage resistome. PMID- 28709371 TI - Relationship of fish indices with sampling effort and land use change in a large Mediterranean river. AB - Fish are invaluable ecological indicators in freshwater ecosystems but have been less used for ecological assessments in large Mediterranean rivers. We evaluated the effects of sampling effort (transect length) on fish metrics, such as species richness and two fish indices (the new European Fish Index EFI+ and a regional index, IBICAT2b), in the mainstem of a large Mediterranean river. For this purpose, we sampled by boat electrofishing five sites each with 10 consecutive transects corresponding to a total length of 20 times the river width (European standard required by the Water Framework Directive) and we also analysed the effect of sampling area on previous surveys. Species accumulation curves and richness extrapolation estimates in general suggested that species richness was reasonably estimated with transect lengths of 10 times the river width or less. The EFI+ index was significantly affected by sampling area, both for our samplings and previous data. Surprisingly, EFI+ values in general decreased with increasing sampling area, despite the higher observed richness, likely because the expected values of metrics were higher. By contrast, the regional fish index was not dependent on sampling area, likely because it does not use a predictive model. Both fish indices, but particularly the EFI+, decreased with less forest cover percentage, even within the smaller disturbance gradient in the river type studied (mainstem of a large Mediterranean river, where environmental pressures are more general). Although the two fish-based indices are very different in terms of their development, methodology, and metrics used, they were significantly correlated and provided a similar assessment of ecological status. Our results reinforce the importance of standardization of sampling methods for bioassessment and suggest that predictive models that use sampling area as a predictor might be more affected by differences in sampling effort than simpler biotic indices. PMID- 28709372 TI - Occurrence of and human exposure to parabens, benzophenones, benzotriazoles, triclosan and triclocarban in outdoor swimming pool water in Changsha, China. AB - The entry of personal care products (PCPs) into the environment has, in turn, caused negative influences to human health. Public swimming pools are places that have attracted increasing concerns. In this article, 35 outdoor swimming pools in Changsha City (China) were examined in view of the occurrence of 22 target PCPs contaminants, which fall into four categories: preservatives, UV filters, anticorrosion agents, and antimicrobials. Out of them, 16 compounds were detected in the collected samples. The preservatives was the most dominant category, with methyl paraben being the top compound (a.v. 0.85MUg/L) followed by p hydroxybenzoic acid (a.v. 0.13MUg/L) and 1H-benzotriazole (a.v. 0.14MUg/L). The correlations among 22 PCPs and their four categories were evaluated using the nonparametric Spearman correlations analysis. In the source tracing investigation, the level of PCPs in swimming pools was determined to be primarily associated with the consumption of these products while weakly related to the filling waters. The quantitative risk assessment revealed that the PCPs concentrations were at a safe level. PMID- 28709373 TI - One-pot synthesis of magnetic iron oxide nanoparticle-multiwalled carbon nanotube composites for enhanced removal of Cr(VI) from aqueous solution. AB - Magnetic nanoparticle-multiwalled carbon nanotubes composites (MNP/MWCNTs) were prepared using 1,6-hexanediamine functionalized Fe3O4 nanoparticles (MNP) linked to carboxylic MWCNTs by facile one-pot solvothermal synthesis for highly efficient removal of Cr(VI) from aqueous solution. The easily obtained magnetic nanocomposites were systematically characterized, and several major factors affecting the adsorption-based removal were investigated, including solution pH, adsorbent dosage, temperature and contact time. The removal efficiency was highly dependent on solution pH; low pH facilitated removal with the maximum efficiency at pH 2.0. The adsorption isotherm was well fitted with the Langmuir isotherm model and the adsorption capacity increased with the temperature increasing. The adsorption kinetic data could be well described by the pseudo-second-order and the intraparticle diffusion models, indicating that the intraparticle diffusion was not the only rate-limiting step. The MNP/MWCNTs displayed excellent selectivity and high anti-interference ability toward Cr(VI) when confronted with commonly coexisting ions. By using an external magnetic field, the exhausted MNP/MWCNTs could be readily separated from the solution after adsorption of Cr(VI) and well regenerated, and could keep about 80% removal efficiency in the fifth adsorption-desorption cycle. The simple, rapid and reliable MNP/MWCNT-based method proved to be a cost-effective, convenient and potentially applicable way to targeted pollutant removal and wastewater treatment. PMID- 28709374 TI - Nanoparticles as Efflux Pump and Biofilm Inhibitor to Rejuvenate Bactericidal Effect of Conventional Antibiotics. AB - The universal problem of bacterial resistance to antibiotic reflects a serious threat for physicians to control infections. Evolution in bacteria results in the development of various complex resistance mechanisms to neutralize the bactericidal effect of antibiotics, like drug amelioration, target modification, membrane permeability reduction, and drug extrusion through efflux pumps. Efflux pumps acquire a wide range of substrate specificity and also the tremendous efficacy for drug molecule extrusion outside bacterial cells. Hindrance in the functioning of efflux pumps may rejuvenate the bactericidal effect of conventional antibiotics. Efflux pumps also play an important role in the exclusion or inclusion of quorum-sensing biomolecules responsible for biofilm formation in bacterial cells. This transit movement of quorum-sensing biomolecules inside or outside the bacterial cells may get interrupted by impeding the functioning of efflux pumps. Metallic nanoparticles represent a potential candidate to block efflux pumps of bacterial cells. The application of nanoparticles as efflux pump inhibitors will not only help to revive the bactericidal effect of conventional antibiotics but will also assist to reduce biofilm-forming capacity of microbes. This review focuses on a novel and fascinating application of metallic nanoparticles in synergy with conventional antibiotics for efflux pump inhibition. PMID- 28709375 TI - Examining the Roles of Emulsion Droplet Size and Surfactant in the Interfacial Instability-Based Fabrication Process of Micellar Nanocrystals. AB - The interfacial instability process is an emerging general method to fabricate nanocrystal-encapsulated micelles (also called micellar nanocrystals) for biological detection, imaging, and therapy. The present work utilized fluorescent semiconductor nanocrystals (quantum dots or QDs) as the model nanocrystals to investigate the interfacial instability-based fabrication process of nanocrystal encapsulated micelles. Our experimental results suggest intricate and intertwined roles of the emulsion droplet size and the surfactant poly (vinyl alcohol) (PVA) used in the fabrication process of QD-encapsulated poly (styrene-b-ethylene glycol) (PS-PEG) micelles. When no PVA is used, no emulsion droplet and thus no micelle is successfully formed; Emulsion droplets with large sizes (~25 MUm) result in two types of QD-encapsulated micelles, one of which is colloidally stable QD-encapsulated PS-PEG micelles while the other of which is colloidally unstable QD-encapsulated PVA micelles; In contrast, emulsion droplets with small sizes (~3 MUm or smaller) result in only colloidally stable QD-encapsulated PS PEG micelles. The results obtained in this work not only help to optimize the quality of nanocrystal-encapsulated micelles prepared by the interfacial instability method for biological applications but also offer helpful new knowledge on the interfacial instability process in particular and self-assembly in general. PMID- 28709376 TI - The Enhanced Photo-Electrochemical Detection of Uric Acid on Au Nanoparticles Modified Glassy Carbon Electrode. AB - In this work, a sensitive and novel method for determining uric acid (UA) has been developed, in which the glassy carbon electrode (GCE) was modified with electrodeposition Au nanoparticles and used to monitor the concentration of UA with the assistant of visible light illumination. The morphology of the Au nanoparticles deposited on GCE surface were characterized by scanning electron microscope (SEM) and the nanoparticles were found to be well-dispersed spheres with the average diameter approaching 26.1 nm. A series of cyclic voltammetry (CV) and differential pulse voltammetry (DPV) measurements have revealed that the introduction of visible light can greatly enhance both the strength and stability of response current due to the surface plasmon resonance (SPR). Specifically, the DPV showed a linear relationship between peak current and UA concentration in the range of 2.8 to 57.5 MUM with the equation of I pa (MUA) = 0.0121c UA (MUM) + 0.3122 (R 2 = 0.9987). Herein, the visible light illuminated Au/GCE possesses a potential to be a sensitive electrochemical sensor in the future. PMID- 28709378 TI - Forced Spreading of Aqueous Solutions on Zwitterionic Sulfobetaine Surfaces for Rapid Evaporation and Solute Separation. AB - Solute separation of aqueous mixtures is mainly dominated by water vaporization. The evaporation rate of an aqueous drop grows with increasing the liquid-gas interfacial area. The spontaneous spreading behavior of a water droplet on a total wetting surface provides huge liquid-gas interfacial area per unit volume; however, it is halted by the self-pinning phenomenon upon addition of nonvolatile solutes. In this work, it is shown that the solute-induced self-pinning can be overcome by gravity, leading to anisotropic spreading much faster than isotropic spreading. The evaporation rate of anisotropic spreading on a zwitterionic sulfobetaine surface is 25 times larger as that on a poly(methyl methacrylate) surface. Dramatic enhancement of evaporation is demonstrated by simultaneous formation of fog atop liquid film. During anisotropic spreading, the solutes are quickly precipitated out within 30 s, showing the rapid solute-water separation. After repeated spreading process for the dye-containing solution, the mean concentration of the collection is doubled, revealing the concentration efficiency as high as 100%. Gravity-enhanced spreading on total wetting surfaces at room temperature is easy to scale-up with less energy consumption, and thus it has great potentials for the applications of solute separation and concentration. PMID- 28709377 TI - Combining Graphical and Analytical Methods with Molecular Simulations To Analyze Time-Resolved FRET Measurements of Labeled Macromolecules Accurately. AB - Forster resonance energy transfer (FRET) measurements from a donor, D, to an acceptor, A, fluorophore are frequently used in vitro and in live cells to reveal information on the structure and dynamics of DA labeled macromolecules. Accurate descriptions of FRET measurements by molecular models are complicated because the fluorophores are usually coupled to the macromolecule via flexible long linkers allowing for diffusional exchange between multiple states with different fluorescence properties caused by distinct environmental quenching, dye mobilities, and variable DA distances. It is often assumed for the analysis of fluorescence intensity decays that DA distances and D quenching are uncorrelated (homogeneous quenching by FRET) and that the exchange between distinct fluorophore states is slow (quasistatic). This allows us to introduce the FRET induced donor decay, epsilonD(t), a function solely depending on the species fraction distribution of the rate constants of energy transfer by FRET, for a convenient joint analysis of fluorescence decays of FRET and reference samples by integrated graphical and analytical procedures. Additionally, we developed a simulation toolkit to model dye diffusion, fluorescence quenching by the protein surface, and FRET. A benchmark study with simulated fluorescence decays of 500 protein structures demonstrates that the quasistatic homogeneous model works very well and recovers for single conformations the average DA distances with an accuracy of < 2%. For more complex cases, where proteins adopt multiple conformations with significantly different dye environments (heterogeneous case), we introduce a general analysis framework and evaluate its power in resolving heterogeneities in DA distances. The developed fast simulation methods, relying on Brownian dynamics of a coarse-grained dye in its sterically accessible volume, allow us to incorporate structural information in the decay analysis for heterogeneous cases by relating dye states with protein conformations to pave the way for fluorescence and FRET-based dynamic structural biology. Finally, we present theories and simulations to assess the accuracy and precision of steady state and time-resolved FRET measurements in resolving DA distances on the single molecule and ensemble level and provide a rigorous framework for estimating approximation, systematic, and statistical errors. PMID- 28709379 TI - Structure of Supported and Unsupported Catalytic Rh Nanoparticles: Effects on Nucleation of Single-Walled Carbon Nanotubes. AB - Achieving a better control of the nucleation and growth of single-walled carbon nanotubes requires understanding of the changes in the catalyst structure and the interfacial phenomena occurring at the solid surface and the gaseous phase from the early stages of the synthesis process. Carbon nanotubes produced by chemical vapor deposition typically use carbon-philic metal catalysts such as Fe, Ni, and Co, in which both surface C and dissolved C atoms contribute to the nanotube formation. We use density functional theory to investigate the interactions of Rh, a noble metal, with carbon both as individual atoms gradually deposited on the catalyst surface from the precursor gas decomposition and as a nucleating seed adhered to the catalyst. Adsorption and limited dissolution of carbon atoms in the subsurface are found to be favorable in unsupported clusters of various sizes (Rh38, Rh55, and Rh68) and in Rh32 clusters supported on MgO(100) and MgO(111) surfaces. Changes in solubility, electron density transfer, and interactions of the Rh clusters with the support and the nascent nanotube are explored for increasing contents of carbon adsorbed on or dissolved inside the particles. The adhesion energy of small Rh38 clusters on the different MgO surfaces studied can differ by as much as 1 eV compared with the same-sized Rh2C particles. Also, the adhesion of graphene differs on the Rh particles by as much as 5.7 eV with respect to Rh2C supported nanoparticles. This demonstrates the influence that the presence of dissolved carbon can have on the catalyst interactions with the support and nucleating nanotube. A discussion on how such factors affect the lattice and electronic structure of the catalyst particles is presented in the interest of obtaining insight that will allow the design of improved catalysts for controlled nanotube synthesis. PMID- 28709380 TI - The Clinical Quality Fellowship Program: Developing Clinical Quality Leadership in the Greater New York Region. AB - The Institute of Medicine has noted that a key factor underlying patient safety problems in the United States is a paucity of quality and safety training programs for clinicians. The Greater New York Hospital Association and United Hospital Fund created the Clinical Quality Fellowship Program (CQFP) to develop quality improvement leaders in the New York region. The goals of this article are to describe the CQFP's structure and curriculum, program participants' perceived value, improvement projects, and career paths. Eighty-seven participants completed the CQFP from 2010 to 2014. Among program participants completing self assessment evaluations, significant improvements were observed across all quality improvement skill areas. Capstone project categories included inpatient efficiency, transitional care, and hospital infection. Fifty-six percent of participants obtained promotions following program completion. A training program emphasizing diverse curricular elements, varied learning approaches, and applied improvement projects increased participants' self-perceived skills, generated diverse improvement initiatives, and was associated with career advancement. PMID- 28709381 TI - Dementia with Lewy bodies presenting as psychotic depression. PMID- 28709382 TI - Severe Aortic Valve Stenosis Due to Alkaptonuric Ochronosis. AB - Alkaptonuric ochronosis is a rare cause of aortic valve stenosis. We report the case of a 61-year-old female patient with alkaptonuria who presented to our institute with the clinical picture of severe aortic valve stenosis, which was confirmed by transthoracic echocardiography. On aortotomy, she was noted to have an impressive black discoloration of ascending aorta and the aortic root complex involving the aortic valve leaflets. She underwent an uneventful aortic valve replacement. She was discharged home 10 days postoperatively. PMID- 28709383 TI - What is the current level of mental health service delivery and expenditure on infants, children, adolescents, and young people in Australia? AB - OBJECTIVES: The study aim was to estimate the current level of ambulatory mental health service delivery to young people aged 0-24 years in Australia and associated government expenditure. Recognising the importance of the early years for the development of mental illness and socioeconomic outcomes, we were particularly interested in service access by infants and young children. METHODS: We extracted information from government administrative datasets on the number of people who received mental health services, number of services and expenditure through the health sector for 2014-2015. Results are primarily reported by age groups 0-4, 5-11, 12-17 and 18-24 years. RESULTS: Less than 1% of 0- to 4-year olds received a mental health service in any one service setting, whereas nearly 11% of 18- to 24-year-olds received a mental health service through the Medicare Benefits Schedule Better Access programme alone. Many more services were delivered to 12- to 24-year-olds (>4 million) than to 0- to 11-year-olds (552,000). Medicare Benefits Schedule Better Access delivers services to more children and youth than do state/territory community mental health services, although the latter provide more services per client. In 2013-2014, Australian Government expenditure on ambulatory mental health services for 0- to 24-year olds was AUD428 million, similar to the AUD491 million spent by state/territory governments. CONCLUSION: The study provides a benchmark for data-driven service planning to ensure that the mental health needs of infants, children and young people are met. Our results indicate that the youngest age group are underserviced relative to need, even noting infants and children may receive services for behavioural/mental health issues from providers not captured in our study (such as paediatricians). The developmental origins of mental illness underlies the urgency of adequate provision by governments of perinatal, infant and child mental health services to avoid loss of life potential and reduce the pressures on the justice, child protection and welfare systems. PMID- 28709384 TI - Beyond Words: Using Qualitative Video Methods for Researching Occupation With Young Children. AB - Researching with children is fundamental for furthering our understanding of children's occupational worlds. Furthermore, researching occupation from a transactional perspective is important for gaining a deeper understanding. However historically, most approaches to researching with children do not capture the transactional nature of occupation. The use of video methods in qualitative research is proposed as a potential solution. This article illustrates how videography can be used as an effective, inclusive qualitative research method, and uses a study of infant play occupation to illuminate video techniques. Drawing on a longitudinal study with five infants and their families, methodological challenges are presented. We discuss key considerations in data generation and analysis when utilizing videography and outline insights gained regarding infant occupational development and meaning-making in the physical environment. Video methods are an effective means of researching from a transactional perspective and have potential to strengthen occupation-centered research particularly with infants. PMID- 28709385 TI - Recurrent Childhood Animal Cruelty and Its Link to Recurrent Adult Interpersonal Violence. AB - In the early 1960s, researchers began to examine the potential link between childhood animal cruelty and future interpersonal violence. Findings since then have been inconsistent in establishing a relationship between the two. This may be due to researchers failing to measure the recurrency of childhood animal abuse and the recurrency of later violent acts committed in adulthood. The current study, using data from 257 inmates at a medium-security prison in a Southern state, is a replication of research conducted by Tallichet and Hensley, and Hensley, Tallichet, and Dutkiewicz, which examined this recurrency issue. The only statistically significant predictor of recurrent adult interpersonal violence in this study was recurrent childhood animal cruelty. Inmates who engaged in recurrent childhood animal cruelty were more likely to commit recurrent adult interpersonal violence. Respondents' race, education, and childhood residence were not significant predictors of the outcome variable. PMID- 28709386 TI - Health complaints in late adolescence; Frequency, factor structure and the association with socio-economic status. AB - AIMS: Little is known about social disparities in health in late adolescence. Among boys and girls aged 17-19, we aimed to (1) describe frequency of health complaints, (2) investigate the factor structure of health complaints and (3) examine the association between health complaints and socio-economic status (SES). METHODS: Data from the large population-based youth@hordaland survey ( n=10,253) were used. Health complaints were assessed by five items from the Health Behaviour in School-Aged Children Symptoms Checklist, SES by parental education and perceived family economy. Associations between health complaints and SES were investigated using analysis of variance, and the factor structure of health complaints using confirmatory factor analyses. RESULTS: At least one weekly complaint was reported by 47% of girls and 21% of boys. The items showed a good fit to a simple one-factor model when back pain and neck/shoulder pain were allowed to correlate. Health complaints were more frequent among adolescents reporting poor perceived family economy and lower parental education. CONCLUSIONS: Our results suggest that health complaints are common in adolescence and might, as in adults, be part of everyday life. Health complaints are more frequent among adolescents from families with lower SES. PMID- 28709387 TI - Response. PMID- 28709388 TI - Leveraging Medical Conferences and Webinars for Hands-On Clinical Quality Improvement: An Intervention to Improve Health Literacy-Informed Communication in Pediatrics. PMID- 28709389 TI - Characterization of (Uropathogenic) E. coli isolated from urinary tract infections: phylogenetic typing and distribution of virulence-associated traits. PMID- 28709390 TI - Elevated homocysteine in human abdominal aortic aneurysmal tissues. AB - An abnormally high level of homocysteine (Hcy) has been consistently observed in the blood of abdominal aortic aneurysm (AAA) patients. However, the expression of Hcy in human AAA tissues has not been investigated. In this study, the expression of Hcy in aneurysmal tissues from AAA patients ( n=30) was compared with non aneurysmal tissues from organ donors ( n=31) by dot blotting and immunohistochemistry. A significantly higher expression of Hcy was observed in AAA than control tissues ( p<0.001). Furthermore, the associations of methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism, detected by polymerase chain reaction-restriction fragment length polymorphism, with both AAA and tissue Hcy expression were evaluated. Our results showed MTHFR C677T polymorphism was not significantly associated with AAA or tissue Hcy expression. Lastly, the expression of Hcy in vascular smooth muscle cells (VSMCs), which were isolated from human aortic tissues by explant culture, and their release to cultured media was investigated by dot blotting. The AAA VSMCs expressed and released a significantly higher level of Hcy than the control VSMCs ( p<0.001). In summary, our novel findings showed Hcy expression was abnormally elevated in human AAA tissues, which may not be dependent on MTHFR C677T polymorphism. PMID- 28709391 TI - GP Training practices in England: a description of their unique features based on national data. AB - Postgraduate general practitioner (GP) training structures have been reorganised with the formation of Health Education England (HEE). We aimed to broaden the findings of previous studies and identify key features of GP training practices. In particular, we wanted to extend previous findings regarding QOF achievement and patient experience derived from the General Practice Patient Survey (GPPS), with recent data on the use of urgent cancer referral pathways ('Two Week Wait', or '2WW,' referrals) and secondary care utilisation by GP training Practices. We compared training and non-training practices, adjusting for differences in practice size and demographic features. Compared with non-training practices, we found reported patient satisfaction with 'access' was 2.0% higher (p < 0.001), 'communication' 0.75% higher (p < 0.001), 'overall experience' 2.8% higher (p < 0.001), 'continuity of care' 2.2% lower (p < 0.001). Mean QOF scores were 11 points higher in training practices (p < 0.001). There were few differences between the two types of practice in terms of Emergency hospital admissions, Ambulatory Care Sensitive (ACSC) admissions, Accident and Emergency attendances and Out-Patient attendances. Training practices used the 2WW referral pathway more frequently than non-training practices resulting in a 1.1% higher 'cancer detection rate' (p = 0.007). PMID- 28709392 TI - African American Fathers' Occupational Participation: "Keeping the Mothers in a Positive Vibe". AB - Infant mortality is a major public health issue in the United States that disproportionally affects African Americans. Evidence suggests reducing stress on African American women and engaging African American fathers may improve health and social outcomes for families. This study sought to understand the experiences of African American fathers through a positivistic lens and to inform future interventions that support father engagement. A descriptive, qualitative study using the Person, Environment, Occupation-Performance (PEO-P) model as a framework for analysis was conducted involving 45 fathers participating in four focus groups and one member-checking group. An initial content analysis was followed by constant comparative methods to identify categories related to the PEO-P model. Transcripts revealed a range of factors that enable or inhibit fathers' occupational performance and engagement including environmental barriers such as societal expectations and perceptions. Occupational therapy practitioners may utilize population health approaches to support African American fathers' occupational engagement. PMID- 28709393 TI - Microbiome Associated with Severe Caries in Canadian First Nations Children. AB - Young Indigenous children in North America suffer from a higher degree of severe early childhood caries (S-ECC) than the general population, leading to speculation that the etiology and characteristics of the disease may be distinct in this population. To address this knowledge gap, we conducted the first microbiome analysis of an Indigenous population using modern molecular techniques. We investigated the caries-associated microbiome among Canadian First Nations children with S-ECC. Thirty First Nations children <72 mo of age with S ECC and 20 caries-free children were recruited in Winnipeg, Canada. Parents or caregivers completed a questionnaire on general and dental health, diet, and demographics. The plaque microbiome was investigated by sequencing the 16S rRNA gene. Sequences were clustered into operational taxonomic units and taxonomy assigned via the Human Oral Microbiome Database, then analyzed at the community level with alpha and beta diversity measures. Compared with those who were caries free, children with S-ECC came from households with lower income; they were more likely to live in First Nations communities and were more likely to be bottle fed; and they were weaned from the bottle at a later age. The microbial communities of the S-ECC and caries-free groups did not differ in terms of species richness or phylogenetic diversity. Beta diversity analysis showed that the samples significantly clustered into groups based on caries status. Twenty eight species-level operational taxonomic units were significantly different between the groups, including Veillonella HOT 780 and Porphyromonas HOT 284, which were 4.6- and 9-fold higher, respectively, in the S-ECC group, and Streptococcus gordonii and Streptococcus sanguinis, which were 5- and 2-fold higher, respectively, in the caries-free group. Extremely high levels of Streptococcus mutans were detected in the S-ECC group. Overall, First Nations children with S-ECC have a significantly different plaque microbiome than their caries-free counterparts, with the S-ECC group containing higher levels of known cariogenic organisms. PMID- 28709394 TI - Intravenous Vancomycin Associated With the Development of Nephrotoxicity in Patients With Class III Obesity. AB - BACKGROUND: A consensus statement recommends initial intravenous (IV) vancomycin dosing of 15-20 mg/kg every 8- 24 hours, with an optional 25- to 30-mg/kg loading dose. Although some studies have shown an association between weight and the development of vancomycin-associated nephrotoxicity, results have been inconsistent. OBJECTIVE: To evaluate the correlation between incidence of nephrotoxicity associated with weight-based IV vancomycin dosing strategies in nonobese and obese patients. METHODS: This retrospective cohort study evaluated hospitalized adult patients admitted who received IV vancomycin. Patients were stratified into nonobese (body mass index [BMI] <25 kg/m2), obesity class I and II (BMI 30-39.9kg/m2), and obesity class III (BMI>=40 kg/m2) groups; patients who were overweight but not obese were excluded. Incidence of nephrotoxicity and serum vancomycin trough concentrations were evaluated. RESULTS: Of a total of 62 documented cases of nephrotoxicity (15.1%), 13 (8.7%), 23 (14.3%), and 26 (26.3%) cases were observed in nonobese, obesity class I and II, and obesity class III groups, respectively ( P=0.002). Longer durations of therapy ( P<0.0001), higher initial maintenance doses in both total milligrams/day ( P=0.0137) and milligrams/kilogram ( P=0.0307), and any trough level >20 mg/L ( P<0.0001) were identified as predictors of development of nephrotoxicity. Concomitant administration of piperacillin/tazobactam, diuretics, and IV contrast were associated with development of nephrotoxicity ( P<0.005, all). Patients with class III obesity were 3-times as likely to develop nephrotoxicity when compared with nonobese patients (odds ratio [OR]=2.99; CI=1.12-7.94) and obesity class I and II patients (OR=3.14; CI=1.27-7.75). CONCLUSIONS: Obesity and other factors are associated with a higher risk of vancomycin-associated nephrotoxicity. PMID- 28709395 TI - Karyotype differentiation in tellin shells (Bivalvia: Tellinidae). AB - BACKGROUND: Although Tellinidae is one of the largest and most diverse families of bivalves, its taxonomy is utterly chaotic. This is mainly due to the morphological diversity and homoplasy displayed by their shells and to the scarcity of the molecular phylogenetic studies performed on them. A molecular cytogenetic analysis of four tellin shell species, Bosemprella incarnata, Macomangulus tenuis, Moerella donacina and Serratina serrata, was performed. To molecularly characterize the analyzed specimens, the sequence of a fragment of the mitochondrial cytochrome c oxidase subunit I (COI) was also studied. RESULTS: The karyotypes of the four species were composed of different amounts of bi-armed and telocentric chromosomes. The chromosomal mapping of 45S and 5S rDNA and H3 histone gene clusters by fluorescent in situ hybridization also revealed conspicuous differences on the distribution of these DNA sequences on their karyotypes. Vertebrate type telomeric sequences were located solely on both ends of each chromosome in all four tellin shells. CONCLUSION: We present clear evidence of the valuable information provided by FISH signals in both analyzing chromosome evolution in Tellinidae and as a further tool in identifying tellin shell specimens for molecular phylogenies. PMID- 28709396 TI - Rapid diversification of homothorax expression patterns after gene duplication in spiders. AB - BACKGROUND: Gene duplications provide genetic material for the evolution of new morphological and physiological features. One copy can preserve the original gene functions while the second copy may evolve new functions (neofunctionalisation). Gene duplications may thus provide new genes involved in evolutionary novelties. RESULTS: We have studied the duplicated homeobox gene homothorax (hth) in the spider species Parasteatoda tepidariorum and Pholcus phalangioides and have compared these data with previously published data from additional spider species. We show that the expression pattern of hth1 is highly conserved among spiders, consistent with the notion that this gene copy preserves the original hth functions. By contrast, hth2 has a markedly different expression profile especially in the prosomal appendages. The pattern in the pedipalps and legs consists of several segmental rings, suggesting a possible role of hth2 in limb joint development. Intriguingly, however, the hth2 pattern is much less conserved between the species than hth1 and shows a species specific pattern in each species investigated so far. CONCLUSIONS: We hypothesise that the hth2 gene has gained a new patterning function after gene duplication, but has then undergone a second phase of diversification of its new role in the spider clade. The evolution of hth2 may thus provide an interesting example for a duplicated gene that has not only contributed to genetic diversity through neofunctionalisation, but beyond that has been able to escape evolutionary conservation after neofunctionalisation thus forming the basis for further genetic diversification. PMID- 28709397 TI - Use of haplotypes to identify regions harbouring lethal recessive variants in pigs. AB - BACKGROUND: Lethal recessive genetic variants are maintained at relatively low frequencies in a population in the heterozygous state, but by definition are fatal and therefore unobserved in the homozygous state. Since haplotypes allow the tagging of rare and untyped genetic variants, they have potential for studying lethal recessive variants. In this study, we used a large commercial population to identify putative lethal recessive haplotypes that impact either the total number born (TNB) or the number born alive (NBA) as a proportion of the total number born (NBA/TNB). We also compared the use of haplotypes with a single nucleotide polymorphism (SNP)-by-SNP approach and examined the benefits of using additional haplotypes imputed from low-density genotype data for the detection of lethal recessive variants. Candidate haplotypes were identified using population wide haplotype frequencies and within-family analyses. These candidate haplotypes were subsequently assessed for putative lethal recessive effects on TNB and NBA/TNB by comparing carrier-to-carrier matings with carrier-to-non-carrier matings. RESULTS: Using both medium-density and imputed low-density genotype data six regions were identified as containing putative lethal recessive haplotypes that had an effect on TNB. It is likely that these regions were related to at least four putative lethal recessive variants, each located on a different chromosome. Evidence for putative lethal recessive effects on TNB was found on chromosomes 1, 6, 10 and 14 using haplotypes. Using haplotypes from individuals genotyped only at medium-density or a SNP-by-SNP approach did not detect any lethal recessive effects. No lethal recessive haplotypes or SNPs were detected that had an effect on NBA/TNB. CONCLUSIONS: We show that the use of haplotypes from combining medium-density and imputed low-density genotype data is superior for the identification of lethal recessive variants compared to both a SNP-by-SNP approach and to the use of only medium-density data. We developed a formal statistical framework that provided sufficient power to detect lethal recessive variants in species, which produce large full-sib families, while reducing false positive or type I errors. Applying this framework results in improvements in reproductive performance by purging lethal recessive alleles from a population in a timely and cost-effective manner. PMID- 28709398 TI - Cannibalism and activity rate in larval damselflies increase along a latitudinal gradient as a consequence of time constraints. AB - BACKGROUND: Predation is ubiquitous in nature. One form of predation is cannibalism, which is affected by many factors such as size structure and resource density. However, cannibalism may also be influenced by abiotic factors such as seasonal time constraints. Since time constraints are greater at high latitudes, cannibalism could be stronger at such latitudes, but we know next to nothing about latitudinal variation in cannibalism. In this study, we examined cannibalism and activity in larvae of the damselfly Lestes sponsa along a latitudinal gradient across Europe. We did this by raising larvae from the egg stage at different temperatures and photoperiods corresponding to different latitudes. RESULTS: We found that the more seasonally time-constrained populations in northern latitudes and individuals subjected to greater seasonal time constraints exhibited a higher level of cannibalism. We also found that activity was higher at north latitude conditions, and thus correlated with cannibalism, suggesting that this behaviour mediates higher levels of cannibalism in time-constrained animals. CONCLUSIONS: Our results go counter to the classical latitude-predation pattern which predicts higher predation at lower latitudes, since we found that predation was stronger at higher latitudes. The differences in cannibalism might have implications for population dynamics along the latitudinal gradients, but further experiments are needed to explore this. PMID- 28709399 TI - Draft sequencing and assembly of the genome of the world's largest fish, the whale shark: Rhincodon typus Smith 1828. AB - BACKGROUND: The whale shark (Rhincodon typus) has by far the largest body size of any elasmobranch (shark or ray) species. Therefore, it is also the largest extant species of the paraphyletic assemblage commonly referred to as fishes. As both a phenotypic extreme and a member of the group Chondrichthyes - the sister group to the remaining gnathostomes, which includes all tetrapods and therefore also humans - its genome is of substantial comparative interest. Whale sharks are also listed as an endangered species on the International Union for Conservation of Nature's Red List of threatened species and are of growing popularity as both a target of ecotourism and as a charismatic conservation ambassador for the pelagic ecosystem. A genome map for this species would aid in defining effective conservation units and understanding global population structure. RESULTS: We characterised the nuclear genome of the whale shark using next generation sequencing (454, Illumina) and de novo assembly and annotation methods, based on material collected from the Georgia Aquarium. The data set consisted of 878,654,233 reads, which yielded a draft assembly of 1,213,200 contigs and 997,976 scaffolds. The estimated genome size was 3.44Gb. As expected, the proteome of the whale shark was most closely related to the only other complete genome of a cartilaginous fish, the holocephalan elephant shark. The whale shark contained a novel Toll-like-receptor (TLR) protein with sequence similarity to both the TLR4 and TLR13 proteins of mammals and TLR21 of teleosts. The data are publicly available on GenBank, FigShare, and from the NCBI Short Read Archive under accession number SRP044374. CONCLUSIONS: This represents the first shotgun elasmobranch genome and will aid studies of molecular systematics, biogeography, genetic differentiation, and conservation genetics in this and other shark species, as well as providing comparative data for studies of evolutionary biology and immunology across the jawed vertebrate lineages. PMID- 28709400 TI - Broad-range potential of Asphodelus microcarpus leaves extract for drug development. AB - BACKGROUND: Many plants have been used in traditional medicine for their antibacterial, antifungal, antiprotozoal, antiviral, antidiarrhoeal, analgesic, antimalarial, antioxidant, anti-inflammatory and anticancer activities. In order to find novel antimicrobial and antiviral agents, the aim of the present study was the evaluation of the antibacterial and antibiofilm susceptibility of Asphodelus microcarpus leaves extract. Moreover, the antiviral activity and the phytochemical composition of the active extract were also determined. METHODS: Antimicrobial and antibiofilm activities of leaves ethanol extract of A. microcarpus were evaluated on 13 different microbial strains. We selected three different sets of microorganisms: (i) Gram-positive bacteria, (ii) Gram-negative bacteria and (iii) yeasts. The potential antiviral activity of A. microcarpus leaves ethanol extract was evaluated with a luciferase reporter gene assay in which the dsRNA-dependent RIG-I-mediated IFN-beta activation was inducted or inhibited by the Ebola virus VP35 protein. HPLC-DAD-MS was used to identify phenolic profile of the active extract. RESULTS: A. microcarpus leaves extract showed a potent inhibitory activity on Gram-positive bacteria while only a reduced inhibition was observed on Gram-negative bacteria. No activity was detected against Yeasts. The extract also showed an interesting antibiofilm motif on various bacterial strains (E. coli, S. aureus, S. haemolyticus and B. clausii). Moreover, this extract significantly affected the Ebola virus VP35 inhibition of the viral RNA (vRNA) induced IFN response. CONCLUSIONS: The overall results provide supportive data on the use of A. microcarpus as antimicrobial agent and a potential source of anti-viral natural products. Data collected set the bases for further studies for the identification of single active components and the development of new pharmaceuticals. PMID- 28709401 TI - Signal transducer and activator of transcription 3 (STAT3) promoter methylation and expression in pituitary adenoma. AB - BACKGROUND: Pituitary adenoma (PA) is a benign brain tumor that can cause neurological, endocrinological and ophthalmological aberrations. Till now there is a need to identify factors that can influence the tumor invasiveness and recurrence. The aim of this study was to evaluate the associations between the signal transducer and activator of transcription 3 (STAT3) promoter methylation, mRNA expression and the invasiveness or recurrence of PAs and patient clinical characteristics. METHODS: Study participants comprised of 102 subjects with a diagnosis of PA: 54 functioning and 48 non-functioning, 58 invasive and 30 non invasive PAs and 14 relapses. The bisulfite treatment of tumor DNA and methylation-specific polymerase chain reaction (MS-PCR) method was used to determine the STAT3 gene promoter methylation. For the STAT3 mRNA expression, the first-strand cDNA was produced from total RNA by using reverse transcriptase and quantitative real-time PCR (qRT-PCR) was performed. RESULTS: In 10.78% (11/102) of PA tissues STAT3 gene promoter was methylated. A gender of male and patient group older than 60 years were significantly associated with reduced STAT3 mRNA expression (Mann-Whitney test, p = 0.025, p = 0.047, respectively). However, no more statistical differences were found between STAT3 promoter methylation, mRNA expression and patient clinical characteristics or PA invasiveness or recurrence. CONCLUSIONS: Further investigations are needed to clarify the influence of STAT3 gene promoter methylation and mRNA expression changes in PAs. PMID- 28709402 TI - Dissemination and implementation research in dementia care: a systematic scoping review and evidence map. AB - BACKGROUND: The need to better understand implementing evidence-informed dementia care has been recognised in multiple priority-setting partnerships. The aim of this scoping review was to give an overview of the state of the evidence on implementation and dissemination of dementia care, and create a systematic evidence map. METHODS: We sought studies that addressed dissemination and implementation strategies or described barriers and facilitators to implementation across dementia stages and care settings. Twelve databases were searched from inception to October 2015 followed by forward citation and grey literature searches. Quantitative studies with a comparative research design and qualitative studies with recognised methods of data collection were included. Titles, abstracts and full texts were screened independently by two reviewers with discrepancies resolved by a third where necessary. Data extraction was performed by one reviewer and checked by a second. Strategies were mapped according to the ERIC compilation. RESULTS: Eighty-eight studies were included (30 quantitative, 34 qualitative and 24 mixed-methods studies). Approximately 60% of studies reported implementation strategies to improve practice: training and education of professionals (94%), promotion of stakeholder interrelationships (69%) and evaluative strategies (46%) were common; financial strategies were rare (15%). Nearly 70% of studies reported barriers or facilitators of care practices primarily within residential care settings. Organisational factors, including time constraints and increased workload, were recurrent barriers, whereas leadership and managerial support were often reported to promote implementation. Less is known about implementation activities in primary care and hospital settings, or the views and experiences of people with dementia and their family caregivers. CONCLUSION: This scoping review and mapping of the evidence reveals a paucity of robust evidence to inform the successful dissemination and implementation of evidence-based dementia care. Further exploration of the most appropriate methods to evaluate and report initiatives to bring about change and of the effectiveness of implementation strategies is necessary if we are to make changes in practice that improve dementia care. PMID- 28709404 TI - Accounting for treatment use when validating a prognostic model: a simulation study. AB - BACKGROUND: Prognostic models often show poor performance when applied to independent validation data sets. We illustrate how treatment use in a validation set can affect measures of model performance and present the uses and limitations of available analytical methods to account for this using simulated data. METHODS: We outline how the use of risk-lowering treatments in a validation set can lead to an apparent overestimation of risk by a prognostic model that was developed in a treatment-naive cohort to make predictions of risk without treatment. Potential methods to correct for the effects of treatment use when testing or validating a prognostic model are discussed from a theoretical perspective.. Subsequently, we assess, in simulated data sets, the impact of excluding treated individuals and the use of inverse probability weighting (IPW) on the estimated model discrimination (c-index) and calibration (observed:expected ratio and calibration plots) in scenarios with different patterns and effects of treatment use. RESULTS: Ignoring the use of effective treatments in a validation data set leads to poorer model discrimination and calibration than would be observed in the untreated target population for the model. Excluding treated individuals provided correct estimates of model performance only when treatment was randomly allocated, although this reduced the precision of the estimates. IPW followed by exclusion of the treated individuals provided correct estimates of model performance in data sets where treatment use was either random or moderately associated with an individual's risk when the assumptions of IPW were met, but yielded incorrect estimates in the presence of non-positivity or an unobserved confounder. CONCLUSIONS: When validating a prognostic model developed to make predictions of risk without treatment, treatment use in the validation set can bias estimates of the performance of the model in future targeted individuals, and should not be ignored. When treatment use is random, treated individuals can be excluded from the analysis. When treatment use is non-random, IPW followed by the exclusion of treated individuals is recommended, however, this method is sensitive to violations of its assumptions. PMID- 28709403 TI - The role of vitamin D in pre-eclampsia: a systematic review. AB - BACKGROUND: The etiology of pre-eclampsia (PE) is not yet fully understood, though current literature indicates an upregulation of inflammatory mediators produced by the placenta as a potential causal mechanism. Vitamin D is known to have anti-inflammatory properties and there is evidence of an inverse relationship between dietary calcium intake and the incidence of PE. Evidence of the role of vitamin D status and supplementation in the etiology and prevention of PE is reviewed in this article along with identification of research gaps to inform future studies. METHODS: We conducted a structured literature search using MEDLINE electronic databases to identify published studies until February 2015. These sources were retrieved, collected, indexed, and assessed for availability of pregnancy-related data on PE and vitamin D. RESULTS: Several case-control studies and cross-sectional studies have shown an association between vitamin D status and PE, although evidence has been inconsistent. Clinical trials to date have been unable to show an independent effect of vitamin D supplementation in preventing PE. CONCLUSIONS: The included clinical trials do not show an independent effect of vitamin D supplementation in preventing PE; however, issues with dose, timing, and duration of supplementation have not been completely addressed. PMID- 28709405 TI - Rehabilitation access and effectiveness for persons with back pain: the protocol of a cohort study (REHAB-BP, DRKS00011554). AB - BACKGROUND: Back pain is one of the most common chronic diseases in Germany and has a major impact on work ability and social participation. The German Pension Insurance (GPI) is the main provider of medical rehabilitation to improve work ability and prevent disability pensions in Germany. However, over half of the persons granted a disability pension have never used a medical rehabilitation service. Furthermore, evidence on the effects of medical rehabilitation in Germany is inconclusive. Consequently, this study has two aims: first, to determine barriers to using rehabilitation services, and second, to examine the effectiveness of medical rehabilitation in German residents with chronic back pain. METHODS: In 2017 a postal questionnaire will be sent to 45,000 persons aged 45 to 59 years whose pension insurance contributions are managed by the GPI North or the GPI Central Germany. In 2019 respondents who report back pain in the first survey (n = 5760 expected) will be sent a second questionnaire. Individuals will be eligible for the first survey if they are employed, have neither used nor applied for a rehabilitation programme during the last 4 years and neither received nor applied for a disability pension. The sample will be drawn randomly from the registers of the GPI North (n = 22,500) and the GPI Central Germany (n = 22,500) and stratified by sex and duration of sickness absence benefits. Barriers to rehabilitation services will be related to socio-demographic and social characteristics, pain and attitudes to pain, health and health behaviour, healthcare utilisation, experiences and cognitions about rehabilitation services and job conditions. Propensity score matched analyses will be used to examine the effectiveness of rehabilitation services. Data on use of medical rehabilitation will be extracted from administrative records. The primary outcome is pain disability. Secondary outcomes are pain intensity and days of disability, pain self-efficacy, fear avoidance beliefs, self-rated health, depression, healthcare utilisation, self-rated work ability and subjective prognosis of employability, sickness absence benefits, and disability pensions. DISCUSSION: This study identifies barriers to use of rehabilitation services and determines the effectiveness of medical rehabilitation for patients with chronic back pain. TRIAL REGISTRATION: German Clinical Trials Register ( DRKS00011554 , January 26, 2017). PMID- 28709406 TI - Using structural equation modeling for network meta-analysis. AB - BACKGROUND: Network meta-analysis overcomes the limitations of traditional pair wise meta-analysis by incorporating all available evidence into a general statistical framework for simultaneous comparisons of several treatments. Currently, network meta-analyses are undertaken either within the Bayesian hierarchical linear models or frequentist generalized linear mixed models. Structural equation modeling (SEM) is a statistical method originally developed for modeling causal relations among observed and latent variables. As random effect is explicitly modeled as a latent variable in SEM, it is very flexible for analysts to specify complex random effect structure and to make linear and nonlinear constraints on parameters. The aim of this article is to show how to undertake a network meta-analysis within the statistical framework of SEM. METHODS: We used an example dataset to demonstrate the standard fixed and random effect network meta-analysis models can be easily implemented in SEM. It contains results of 26 studies that directly compared three treatment groups A, B and C for prevention of first bleeding in patients with liver cirrhosis. We also showed that a new approach to network meta-analysis based on the technique of unrestricted weighted least squares (UWLS) method can also be undertaken using SEM. RESULTS: For both the fixed and random effect network meta-analysis, SEM yielded similar coefficients and confidence intervals to those reported in the previous literature. The point estimates of two UWLS models were identical to those in the fixed effect model but the confidence intervals were greater. This is consistent with results from the traditional pairwise meta-analyses. Comparing to UWLS model with common variance adjusted factor, UWLS model with unique variance adjusted factor has greater confidence intervals when the heterogeneity was larger in the pairwise comparison. The UWLS model with unique variance adjusted factor reflects the difference in heterogeneity within each comparison. CONCLUSION: SEM provides a very flexible framework for univariate and multivariate meta-analysis, and its potential as a powerful tool for advanced meta-analysis is still to be explored. PMID- 28709408 TI - Erratum to: screening for chronic kidney disease of uncertain aetiology in Sri Lanka: usability of surrogate biomarkers over dipstick proteinuria. PMID- 28709409 TI - Misuse of emergent healthcare in contemporary Japan. AB - BACKGROUND: Medical care is obviously an important public service to ensure the health of a nation; however, medical resources are not always used appropriately. 'Convenience-store consultations' and inappropriate ambulance transportation represent instances of such improper use by contemporary Japanese citizens in recent years. This article illustrates two examples of misuse and discusses potential countermeasures by considering factors contributing to these behaviours. MAIN BODY: From both public and medical perspectives, these patient behaviours are problematic, causing potential harm to others, negative consequences to such patients themselves, exhaustion of healthcare staff, and breakdown of emergency medical services. Although citizens need to recognize the public nature and scarcity of medical care, the more immediate need may be to identify and to remove personal and social causes inducing such misuse. In addition, healthcare professionals should become more trustworthy. To combat these issues, one-sided penalties such as accusations or sanctions for patients who misuse the system cannot be justified in principle. If measures taken to prevent misuse are ineffective, imposing surcharges or restricting consultations may be considered official policy, but these are not acceptable for several reasons. CONCLUSION: For now, we conclude that we must rely on the spontaneous motivation of patients who engage in 'convenience-store consultations' and ambulance transportation instead of taking a taxi. PMID- 28709407 TI - Trop2 enhances invasion of thyroid cancer by inducing MMP2 through ERK and JNK pathways. AB - BACKGROUND: Mounting evidence has showed that Tumor-associated calcium signal transducer 2 (Trop2) is upregulated in various kinds of human cancers and plays important roles in tumorigenesis. However, the expression status and functional significance of Trop2 in thyroid cancer are largely unknown. METHODS: We first determined the expression of Trop2 by using RNAseqV2 data sets for thyroid cancer deposited on The Cancer Genome Atlas (TCGA) website. The expression of Trop2 was then confirmed by real-time reverse transcription-polymerase chain reaction (RT PCR) and immunohistochemistry assays. Cell invasion and migration were assessed by conducting Transwell and wound healing assays. Furthermore, we explored the underlying mechanisms by using real-time RT-PCR, Western blot, zymography, and luciferase reporter assays. RESULTS: In this study, we demonstrated that the expression of Trop2 was significantly elevated in thyroid cancer and that its expression level was correlated with the tumor-node-metastasis (TNM) staging and N classification. Dysregulation of Trop2 altered the invasive capability of thyroid cancer cells. Further mechanistic study revealed that MMP2 expression was upregulated by Trop2. Moreover, we found that the effects of Trop2 were dependent on ERK and JNK pathways. The results from clinical specimens showed that Trop2 expression correlated with MMP2 expression in primary thyroid cancer. CONCLUSION: The current study suggests that elevated expression of Trop2 may represent an important molecular hallmark that is biologically and clinically relevant to the progression of thyroid cancer. PMID- 28709410 TI - Identification of barriers and facilitators for optimal cesarean section care: perspective of professionals. AB - BACKGROUND: The cesarean section (CS) rate has increased over recent decades with poor guideline adherence as a possible cause. The objective of this study was to explore barriers and facilitators for delivering optimal care as described in clinical practice guidelines. METHODS: Key recommendations from evidence-based guidelines were used as a base to explore barriers and facilitators for delivering optimal CS care in The Netherlands. Both focus group and telephone interviews among 29 different obstetrical professionals were performed. Transcripts from the interviews were analysed. Barriers and facilitators were identified and categorised in six domains according to the framework developed by Grol: the guideline recommendations (I), the professional (II), the patient (III), the social context (IV), the organizational context (V) and the financial/legislation context (VI). RESULTS: Most barriers were found in the professional and organizational domain. Barriers mentioned by healthcare professionals were disagreement with specific guideline recommendations, and hesitation to allow women to be part of the decision making process. Other barriers are lack of adequately trained personal staff, lack of collaboration between professionals, and lack of technical equipment. CONCLUSIONS: Clear facilitators and barriers for guideline adherence were identified in all domains. Several barriers may be addressed by using decision aids on mode of birth or prediction models to individualise care in women in whom both planned vaginal birth and CS are equal options. In women with an intended vaginal birth, adequate staffing and the availability of both fetal blood sampling and epidural analgesia are important. PMID- 28709413 TI - Who wants to be involved in health care decisions? Comparing preferences for individual and collective involvement in England and Sweden. AB - BACKGROUND: Patient and public involvement (PPI) is framed as positive for individuals, the health system, public health, as well as for communities and society as a whole. We investigated whether preferences for PPI differed between two countries with Beveridge type health systems-Sweden and England. We measured willingness to be involved in individual treatment decisions and in decisions about the organization and provision of local health and social care services. METHODS: This was a comparative cross-sectional study of the general population's preferences. Together, the two samples included 3125 respondents; 1625 in England and 1500 in Sweden. Country differences were analysed in a multinomial regression model controlling for gender, age and educational attainment. RESULTS: Overall, 68% of respondents wanted a passive patient role and 44% wanted to be involved in local decisions about organization and provision of services. In comparison with in Sweden, they were in England less likely to want a health professional such as a GP or consultant to make decisions about their treatment and also more likely to want to make their own decisions. They were also less likely to want to be involved in local service development decisions. An increased likelihood of wanting to be involved in organizational decision-making was associated with individuals wanting to make their own treatment decisions. Women were less likely to want health professionals to make decisions and more likely to want to be involved in organizational decisions. CONCLUSIONS: An effective health system that ensures public health must integrate an effective approach to PPI both in individual treatment decisions and shaping local health and social care priorities. To be effective, involvement activities must take in to account the variation in the desire for involvement and the implications that this has for equity. More work is needed to understand the relationship between the desire to be involved and actually being involved, but both appear related to judgements of the impact of involvement on health care decisions. PMID- 28709411 TI - Rho kinase proteins display aberrant upregulation in vascular tumors and contribute to vascular tumor growth. AB - BACKGROUND: The serine/threonine protein kinases ROCK1 and 2 are key RhoA mediated regulators of cell shape and cytoskeletal dynamics. These proteins perform multiple functions in vascular endothelial cell physiology and are attractive targets for cancer therapy based on their roles as oncogenes and metastatic promoters. Given their critical functions in both of these processes, we hypothesized that molecular targeting of ROCK proteins would be exceedingly effective against vascular tumors such as hemangiomas and angiosarcomas, which are neoplasms composed of aberrant endothelial cells. METHODS: In this study, we compared ROCK1 and 2 protein expression in a large panel of benign and malignant vascular tumors to that of normal vasculature. We then utilized shRNA technology to knockdown the expression of ROCK1 and 2 in SVR tumor-forming vascular cells, and evaluated tumor size and proliferation rate in a xenograft model. Finally, we employed proteomics and metabolomics to assess how knockdown of the ROCK paralogs induced alterations in protein expression/phosphorylation and metabolite concentrations in the xenograft tumors. RESULTS: Our findings revealed that ROCK1 was overexpressed in malignant vascular tumors such as hemangioendotheliomas and angiosarcomas, and ROCK2 was overexpressed in both benign and malignant vascular tumors including hemangiomas, hemangioendotheliomas, hemangiopericytomas, and angiosarcomas. shRNA-mediated knockdown of ROCK2, but not ROCK1, in xenograft vascular tumors significantly reduced tumor size and proliferative index compared to control tumors. Proteomics and metabolomics analysis of the xenograft tumors revealed both overlapping as well as unique roles for the ROCK paralogs in regulating signal transduction and metabolite concentrations. CONCLUSIONS: Collectively, these data indicate that ROCK proteins are overexpressed in diverse vascular tumors and suggest that specific targeting of ROCK2 proteins may show efficacy against malignant vascular tumors. PMID- 28709412 TI - Study protocol: safety and efficacy of propranolol 0.2% eye drops in newborns with a precocious stage of retinopathy of prematurity (DROP-ROP-0.2%): a multicenter, open-label, single arm, phase II trial. AB - BACKGROUND: Retinopathy of prematurity (ROP) still represents one of the leading causes of visual impairment in childhood. Systemic propranolol has proven to be effective in reducing ROP progression in preterm newborns, although safety was not sufficiently guaranteed. On the contrary, topical treatment with propranolol eye micro-drops at a concentration of 0.1% had an optimal safety profile in preterm newborns with ROP, but was not sufficiently effective in reducing the disease progression if administered at an advanced stage (during stage 2). The aim of the present protocol is to evaluate the safety and efficacy of propranolol 0.2% eye micro-drops in preterm newborns at a more precocious stage of ROP (stage 1). METHODS: A multicenter, open-label, phase II, clinical trial, planned according to the Simon optimal two-stage design, will be performed to analyze the safety and efficacy of propranolol 0.2% eye micro-drops in preterm newborns with stage 1 ROP. Preterm newborns with a gestational age of 23-32 weeks, with a stage 1 ROP will receive propranolol 0.2% eye micro-drops treatment until retinal vascularization has been completed, but for no longer than 90 days. Hemodynamic and respiratory parameters will be continuously monitored. Blood samplings checking metabolic, renal and liver functions, as well as electrocardiogram and echocardiogram, will be periodically performed to investigate treatment safety. Additionally, propranolol plasma levels will be measured at the steady state, on the 10th day of treatment. To assess the efficacy of topical treatment, the ROP progression from stage 1 ROP to stage 2 or 3 with plus will be evaluated by serial ophthalmologic examinations. DISCUSSION: Propranolol eye micro-drops could represent an ideal strategy in counteracting ROP, because it is definitely safer than oral administration, inexpensive and an easily affordable treatment. Establishing the optimal dosage and treatment schedule is to date a crucial issue. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02504944, registered on July 19, 2015, updated July 12, 2016. EudraCT Number 2014-005472-29. PMID- 28709414 TI - Effects of selected socio-demographic characteristics on nutrition knowledge and eating behavior of elementary students in two provinces in China. AB - BACKGROUND: National and international child health surveys have indicated an increase in childhood obesity in China. The increase has been attributed to a rising standard of living, increasing availability of unhealthy foods, and a lack of knowledge about healthy diet. The objective of this study was to assess the effect of selected socio-demographic characteristics on the BMI, nutrition knowledge, and eating behavior of elementary school children. METHODS: Multistage stratified cluster sampling was used. Information on demographics, nutrition knowledge, and eating behavior was gathered by means of questionnaires. The schools' doctors provided the height and weight data. The study was set in one economically advantaged and one economically disadvantaged province in China. The participants were Grade 3 students, ages 8-10 years (N = 3922). RESULTS: A cluster analysis identified four socio-demographic variables distinguished by parental education and family living arrangement. A one-way ANOVA compared differences among the clusters in BMI, child nutrition knowledge, and child eating behavior. Students in the cluster with lowest parent education level had the lowest nutrition knowledge scores and eating behavior scores. There was no significant benefit from college education versus high school education of parents in the other three clusters. BMI was not affected by parent education level. CONCLUSION: The nutrition status of elementary school age children will benefit most by increasing the general level of education for those adults who are presently least educated. PMID- 28709415 TI - Assessing anesthesiology residents' out-of-the-operating-room (OOOR) emergent airway management. AB - BACKGROUND: At many academic institutions, anesthesiology residents are responsible for managing emergent intubations outside of the operating room (OOOR), with complications estimated to be as high as 39%. In order to create an OOOR training curriculum, we evaluated residents' familiarity with the content and correct adherence to the American Society of Anesthesiologists' Difficult Airway Algorithm (ASA DAA). METHODS: Residents completed a pre-simulation multiple-choice survey measuring their understanding and use of the DAA. Residents then managed an emergent, difficult OOOR intubation in the simulation center, where two trained reviewers assessed performance using checklists. Post simulation, the residents completed a survey rating their behaviors during the simulation. The primary outcome was comprehension and adherence to the DAA as assessed by survey responses and behavior in the simulation. RESULTS: Sixty-three residents completed both surveys and the simulation. Post-survey responses indicated a shift toward decreased self-perceived familiarity with the DAA content compared to pre-survey responses. During the simulation, 22 (35%) residents were unsuccessful with intubation. Of these, 46% placed an LMA and 46% prepared for cricothyroidotomy. Nineteen residents did not attempt intubation. Of these, only 31% considered LMA placement, and 26% initiated cricothyroidotomy. CONCLUSIONS: Many anesthesiology residency training programs permit resident autonomy in managing emergent intubations OOOR. Residents self-reported familiarity with the content of and adherence to the DAA was higher than that observed during the simulation. Curriculum focused on comprehension of the DAA, as well as improving communication with higher-level physicians and specialists, may improve outcomes during OOORs. PMID- 28709416 TI - Warfarin-induced toxic epidermal necrolysis in combination therapy of Henoch Schonlein purpura nephritis: a case report. AB - BACKGROUND: Toxic epidermal necrolysis (TEN) is a rare life-threatening condition almost exclusively attributed to drugs. The main etiologic factors for TEN are sulphonamides, anticonvulsants, and antibiotics; however, there are no published reports of warfarin causing TEN. CASE PRESENTATION: We present the case of a 3 year-old patient who developed TEN while receiving treatment for Henoch-Schonlein purpura nephritis (HSPN). With multiple-drug therapy comprising prednisolone, mizoribine, dipyridamole, and warfarin, it is difficult to detect which drug is the causative agent. While in most cases, diagnosis of the causative drug is based on clinical history without a lymphocyte transformation test (LTT), we performed the test three times and identified the causative drug as warfarin at the late phase. We continued HSPN treatment without warfarin, and results showed good renal function without life-threatening complications. CONCLUSION: To our knowledge, this is the first report about TEN caused by warfarin. Repeated LTTs could be useful for identifying TEN-causative drugs even in the late phase. PMID- 28709417 TI - Putting women at the center: a review of Indian policy to address person-centered care in maternal and newborn health, family planning and abortion. AB - BACKGROUND: Person-centered care is a critical component of quality care, essential to enable treatment adherence, and maximize health outcomes. Improving the quality of health services is a key strategy to achieve the new global target of zero preventable maternal deaths by 2030. Recognizing this, the Government of India has in the last decade initiated a number of strategies to address quality of care in health and family welfare services. METHODS: We conducted a policy review of quality improvement strategies in India from 2005 to 15, covering three critical areas- maternal and newborn health, family planning, and abortion (MNHFP + A). Based on Walt and Gilson's policy triangle framework, we analyzed the extent to which policies incorporated person-centered care, while identifying unaddressed issues. Data was sourced from Government of India websites, scientific and grey literature databases. RESULTS: Twenty-two national policy documents, comprising two policy statements and 20 implementation guidelines of specific schemes were included in the review. Quality improvement strategies span infrastructure, commodities, human resources, competencies, and accountability that are driving quality assurance in MNHFP + A services. However, several implementation challenges have affected compliance with person-centered care, thereby affecting utilization and outcomes. CONCLUSION: Focus on person-centered care in Indian MNHFP + A policy has increased in recent years. Nevertheless, some aspects must still be strengthened, such as positive interpersonal behavior, information sharing and promptness of care. Implementation can be improved through better provider training, patient feedback and monitoring mechanisms. Moreover, unless persisting structural challenges are addressed implementation of person-centered care in facilities will not be effective. PMID- 28709418 TI - Single leg squat performance in physically and non-physically active individuals: a cross-sectional study. AB - BACKGROUND: Single-leg squat (SLS) is a functional test visually rated by clinicians for assessing lower limb function as a preventive injury strategy. SLS clinical rating is a qualitative evaluation and it does not count objective outcomes as kinematics data and surface electromyography (sEMG) assessment. Based on the SLS rating, the aims of this study were (i) to determine the clinical rating agreement among six raters and (ii) to assess kinematic and sEMG predictors of good SLS performance in physically and non-physically active individuals. METHODS: Seventy-two healthy adults, divided in physically active and non-physically active groups, performed three SLSs on their dominant leg. Clinical ratings, kinematic data and sEMG were acquired. By using a validated clinical scale, six expert clinicians rated each SLS watching a video at three different time points. Intra and inter-rater agreement of clinical ratings were undertaken and a binary logistic regression analysis was used to determine kinematic and sEMG as predictors of SLS performance. RESULTS: The weighted kappa coefficient for intra-rater reliability within each rater ranged between moderate and almost perfect agreement (0.55-0.85) whereas the weighted kappa coefficient for inter-rater reliability among raters was fair (0.34, time point 0; 0.31, time point 1; 0.30, time point 2). SLS analyses of physically active compared to non physically active group showed a statistically significant difference in knee flexion and hip flexion (p = 0.041 and p = 0.023 respectively) and no difference in clinical ratings (p = 0.081). Greater knee flexion can predict the good SLS performance taking into account the belonging group (p = 0.019). CONCLUSIONS: Physically active individuals seemed to be at less risk to perform a non-good SLS and they had greater knee and hip flexions kinematics than non-physically active individuals. Knee flexion can predict the SLS performance quality therefore a greater knee flexion might also be considered a protective element from injuries. TRIAL REGISTRATION: ClinicalTrials.gov identifier (trial has been registred retrospectively: NCT03203083. Date registration: June 21, 2017. PMID- 28709419 TI - The clinical and virological features of the first imported case causing MERS-CoV outbreak in South Korea, 2015. AB - BACKGROUND: In 2015, the largest outbreak of Middle East respiratory syndrome coronavirus (MERS-CoV) infection outside the Middle East occurred in South Korea. We summarized the epidemiological, clinical, and laboratory findings of the first Korean case of MERS-CoV and analyzed whole-genome sequences of MERS-CoV derived from the patient. CASE PRESENTATION: A 68-year-old man developed fever and myalgia 7 days after returning to Korea, following a 10-day trip to the Middle East. Before diagnosis, he visited 4 hospitals, potentially resulting in secondary transmission to 28 patients. On admission to the National Medical Center (day 9, post-onset of clinical illness), he presented with drowsiness, hypoxia, and multiple patchy infiltrations on the chest radiograph. He was intubated (day 12) because of progressive acute respiratory distress syndrome (ARDS) and INF-alpha2a and ribavirin treatment was commenced. The treatment course was prolonged by superimposed ventilator associated pneumonia. MERS-CoV PCR results converted to negative from day 47 and the patient was discharged (day 137), following rehabilitation therapy. The complete genome sequence obtained from a sputum sample (taken on day 11) showed the highest sequence similarity (99.59%) with the virus from an outbreak in Riyadh, Saudi Arabia, in February 2015. CONCLUSIONS: The first case of MERS-CoV infection had high transmissibility and was associated with a severe clinical course. The patient made a successful recovery after early treatment with antiviral agents and adequate supportive care. This first case in South Korea became a super-spreader because of improper infection control measures, rather than variations of the virus. PMID- 28709420 TI - Area-based socioeconomic factors and Human Papillomavirus (HPV) vaccination among teen boys in the United States. AB - BACKGROUND: This study is the first to examine associations between several area based socioeconomic factors and human papillomavirus (HPV) vaccine uptake among boys in the United States (U.S.). METHODS: Data from the 2012-2013 National Immunization Survey-Teen restricted-use data were analyzed to examine associations of HPV vaccination initiation (receipt of >=1 dose) and series completion (receipt of three doses) among boys aged 13-17 years (N = 19,518) with several individual-level and ZIP Code Tabulation Area (ZCTA) census measures. Multivariable logistic regression was used to estimate the odds of HPV vaccination initiation and series completion separately. RESULTS: In 2012-2013 approximately 27.9% (95% CI 26.6%-29.2%) of boys initiated and 10.38% (95% CI 9.48%-11.29%) completed the HPV vaccine series. Area-based poverty was not statistically significantly associated with HPV vaccination initiation. It was, however, associated with series completion, with boys living in high-poverty areas (>=20% of residents living below poverty) having higher odds of completing the series (AOR 1.22, 95% CI 1.01-1.48) than boys in low-poverty areas (0-4.99%). Interactions between race/ethnicity and ZIP code-level poverty indicated that Hispanic boys living in high-poverty areas had a statistically significantly higher odds of HPV vaccine initiation (AOR 1.43, 95% CI 1.03-1.97) and series completion (AOR 1.56, 95% CI 1.05-2.32) than Hispanic boys in low-poverty areas. Non-Hispanic Black boys in high poverty areas had higher odds of initiation (AOR 2.23, 95% CI 1.33-3.75) and completion (AOR 2.61, 95% CI 1.06 6.44) than non-Hispanic Black boys in low-poverty areas. Rural/urban residence and population density were also significant factors, with boys from urban or densely populated areas having higher odds of initiation and completion compared to boys living in non-urban, less densely populated areas. CONCLUSION: Higher HPV vaccination coverage in urban areas and among racial/ethnic minorities in areas with high poverty may be attributable to factors such as vaccine acceptance, health-care practices, and their access to HPV vaccines through the Vaccines for Children Program, which provides free vaccines to uninsured and under-insured children. Given the low HPV vaccination rates among boys in the U.S., these results provide important evidence to inform public health interventions to increase HPV vaccination. PMID- 28709423 TI - Erratum to: Acute airway compromise due to parathyroid tumour apoplexy: an exceptionally rare and potentially life-threatening presentation. PMID- 28709422 TI - Evaluation on equality and efficiency of health resources allocation and health services utilization in China. AB - BACKGROUND: China is faced with a daunting challenge to equality and efficiency in health resources allocation and health services utilization in the context of rapid economic growth. This study sought to evaluate the equality and efficiency of health resources allocation and health services utilization in China. METHODS: Demographic, economic, and geographic area data was sourced from China Statistical Yearbook 2012-2016. Data related to health resources and health services was obtained from China Health Statistics Yearbook 2012-2016. Furthermore, we evaluated the equality of health resources allocation based on Gini coefficient. Concentration index was used to measure the equality in utilization of health services. Data envelopment analysis (DEA) was employed to assess the efficiency of health resources allocation. RESULTS: From 2011 to 2015, the Gini coefficients for health resources by population ranged between 0.0644 and 0.1879, while the Gini coefficients for the resources by geographic area ranged from 0.6136 to 0.6568. Meanwhile, the concentration index values for health services utilization ranged from -0.0392 to 0.2110. Moreover, in 2015, 10 provinces (32.26%) were relatively efficient in terms of health resources allocation, while 7 provinces (22.58%) and 14 provinces (45.16%) were weakly efficient and inefficient, respectively. CONCLUSIONS: There exist distinct regional disparities in the distribution of health resources in China, which are mainly reflected in the geographic distribution of health resources. Furthermore, the people living in the eastern developed areas are more likely to use outpatient care, while the people living in western underdeveloped areas are more likely to use inpatient care. Moreover, the efficiency of health resources allocation in 21 provinces (67.74%) of China was low and needs to be improved. Thus, the government should pay more attention to the equality based on geographic area, guide patients to choose medical treatment rationally, and optimize the resource investments for different provinces. PMID- 28709421 TI - Health related quality of life in patients with idiopathic pulmonary fibrosis in clinical practice: insights-IPF registry. AB - BACKGROUND: The INSIGHTS-IPF registry provides one of the largest data sets of clinical data and self-reported patient related outcomes including health related quality of life (QoL) on patients with idiopathic pulmonary fibrosis (IPF). We aimed to describe associations of various QoL instruments between each other and with patient characteristics at baseline. METHODS: Six hundred twenty-three IPF patients with available QoL data (St George's Respiratory Questionnaire SGRQ, UCSD Shortness-of-Breath Questionnaire SoB, EuroQol visual analogue scale and index EQ-5D, Well-being Index WHO-5) were analysed. Mean age was 69.6 +/- 8.7 years, 77% were males, mean disease duration 2.0 +/- 3.3 years, FVC pred was 67.5 +/- 17.8%, DLCO pred 35.6 +/- 17%. RESULTS: Mean points were SGRQ total 48.3, UCSD SoB 47.8, EQ-5D VAS 66.8, and WHO-5 13.9. These instruments had a high or very high correlation (exception WHO-5 to EQ-5D VAS with moderate correlation). On bivariate analysis, QoL by SGRQ total was statistically significantly associated with clinical symptoms (NYHA; p < 0.001), number of comorbidities (p < 0.05), hospitalisation rate (p < 0.01) and disease severity (as measured by GAP score, CPI, FVC and 6-min walk test; p < 0.05 each). Multivariate analyses showed a significant association between QoL (by SGRQ total) and IPF duration, FVC, age, NYHA class and indication for long-term oxygen treatment. CONCLUSIONS: Overall, IPF patients under real-life conditions have lower QoL compared to those in clinical studies. There is a meaningful relationship between QoL and various patient characteristics. TRIAL REGISTRATION: The INSIGHTS-IPF registry is registered at Clinicaltrials.gov ( NCT01695408 ). PMID- 28709425 TI - Erratum to: Metabolic syndrome and its predictors in an urban population in Kenya: a cross sectional study. PMID- 28709424 TI - Genotypic diversity and phenotypic traits of Streptococcus mutans isolates and their relation to severity of early childhood caries. AB - BACKGROUND: Early childhood caries (ECC) is an aggressive condition that can affect teeth of young children. This study aimed to evaluate genotypic diversity and phenotypic traits of S. mutans isolated from dental biofilms of children with different caries status in comparison with caries free (CF) children. METHODS: Streptococcus mutans strains were isolated from supragingival biofilm samples of CF, ECC and severe-ECC (S-ECC) children and genotyped by arbitrary-primer polymerase chain reaction - AP-PCR. S. mutans genotypes were tested for their ability to reduce the suspension pH through glycolysis, to tolerate extreme acid challenge and by their ability to form biofilm. Response variables were analyzed by ANOVA/Tukey or Kruskal-Wallis/Mann-Whitney tests at a 5% of significance. RESULTS: There was an increase in the prevalence of Streptococcus mutans in biofilms with the severity of dental caries. No differences in genotypic diversity and in acidogenicity of genotypes were found among CF, ECC and S-ECC children. S mutans strains with genotypes more characteristic for ECC and S-ECC children formed more biofilms than those identified in CF children. The strains isolated from S-ECC children were highly acid tolerant. CONCLUSION: Although S. mutans genotypic diversity was similar among the groups of children, phenotypic traits of S. mutans, especially the acid tolerance response, could explain the severity of early childhood caries. PMID- 28709426 TI - Xue-fu-Zhu-Yu decoction protects rats against retinal ischemia by downregulation of HIF-1alpha and VEGF via inhibition of RBP2 and PKM2. AB - BACKGROUND: Retinal ischemia-related eye diseases result in visual dysfunction. This study investigates the protective effects and mechanisms of Xue-Fu-Zhu-Yu decoction (XFZYD) with respect to retinal ischemia. METHODS: Retinal ischemia (I) was induced in Wistar rats by a high intraocular pressure (HIOP) of 120 mmHg for 1 h, which was followed by reperfusion of the ischemic eye; the fellow untreated eye acted as a control. Electroretinogram (ERG), biochemistry and histopathology investigations were performed. RESULTS: Significant ischemic changes occurred after ischemia including decreased ERG b-wave ratios, less numerous retinal ganglion cells (RGCs), reduced inner retinal thickness, fewer choline acetyltransferase (ChAT) labeled amacrine cell bodies, increased glial fibrillary acidic protein (GFAP) immunoreactivity and increased vimentin Muller immunolabeling. These were accompanied by significant increases in the mRNA/protein concentrations of vascular endothelium growth factor, hypoxia inducible factor-1alpha, pyruvate kinase M2 and retinoblastoma-binding protein 2. The ischemic changes were concentration-dependently and significantly altered when XFZYD was given for seven consecutive days before or after retina ischemia, compared to vehicle. These alterations included enhanced ERG b-wave amplitudes, more numerous RGCs, enhanced inner retinal thickness, a greater number of ChAT immunolabeled amacrine cell bodies and decreased GFAP/vimentin immunoreactivity. Furthermore, decreased mRNA levels of VEGF, HIF-1alpha, PKM2, and RBP2 were also found. Reduced protein concentrations of VEGF, HIF-1alpha, PKM2, and RBP2 were also demonstrated. Furthermore, there was an inhibition of the ischemia associated increased ratios (target protein/beta-actin) in the protein levels of VEGF, HIF-1alpha, PKM2, and RBP2, which were induced by Shikonin, JIB-04 or Avastin. CONCLUSION: XFZYD would seem to protect against well-known retinal ischemic changes via a synergistic inhibition of RBP2 and PKM2, as well as down regulation of HIF-1alpha and a reduction in VEGF secretion. PMID- 28709427 TI - Investigation of irradiated volume in linac-based brain hypo-fractionated stereotactic radiotherapy. AB - BACKGROUND: Emerging techniques such as brain hypo-fractionated radiotherapy (HF RT) involve complex cases with limited guidelines for plan quality and normal tissue tolerances. The purpose of the present study was to statistically parameterize irradiated volume independently of dose prescription, or margin to determine what spread in achievable irradiated volume one may expect for a given case. METHODS: We defined EXT as the total tissue within the external contour of the patient (including the target) and we defined BMP as the contour of the brain minus PTV. Irradiated volumes of EXT and BMP at specific doses (i.e. 50, 60%, etc., of the prescribed dose) were extracted from 135 single-target HF-RT clinical cases, each planned with a single-arc, homogeneous (SAHO) approach in which target maximum dose (Dmax) was constrained to <130% of the prescribed dose. Irradiated volumes were subsequently measured for cases involving 2 targets (N = 29), 3 targets (N = 7) and >3 targets (N = 10) to investigate the effect of target number. We also examined the effect of shape complexity. A series of best fit curves with confidence and prediction intervals were generated for irradiated volume versus total target volume and the resulting model was subsequently validated on a subsequent set of 23 consecutive prospective cases not originally used in curve-fitting. A subset of 30 HF-RT cases were re-planned with a well published four-arc, heterogeneous (FAHE) radiosurgery planning approach (Dmax could exceed 130%) to demonstrate how technique affects irradiated volume. RESULTS: For SAHO, strong correlation (R2 > 0.98) was found for predicting irradiated volumes. For a given total target volume, irradiated-volume increased by a range of 1.4-2.9* for >3 versus single-targets depending on isodose level. Shape complexity had minor impact on irradiated volume. There was no statistical difference in irradiated volumes between validation and input data (p > 0.2). The FAHE-generated irradiated volumes yielded curves and prediction and confidence bands that agreed well with published data indicating that the proposed approach is feasible for cross-institutional comparisons. CONCLUSIONS: A description of irradiated volume for linac-based HF-RT is proposed based on population data. We have demonstrated that the proposed approach is feasible for inter and intra institutional comparisons. PMID- 28709428 TI - A systematic comparison of statistical methods to detect interactions in exposome health associations. AB - BACKGROUND: There is growing interest in examining the simultaneous effects of multiple exposures and, more generally, the effects of mixtures of exposures, as part of the exposome concept (being defined as the totality of human environmental exposures from conception onwards). Uncovering such combined effects is challenging owing to the large number of exposures, several of them being highly correlated. We performed a simulation study in an exposome context to compare the performance of several statistical methods that have been proposed to detect statistical interactions. METHODS: Simulations were based on an exposome including 237 exposures with a realistic correlation structure. We considered several statistical regression-based methods, including two-step Environment-Wide Association Study (EWAS2), the Deletion/Substitution/Addition (DSA) algorithm, the Least Absolute Shrinkage and Selection Operator (LASSO), Group-Lasso INTERaction-NET (GLINTERNET), a three-step method based on regression trees and finally Boosted Regression Trees (BRT). We assessed the performance of each method in terms of model size, predictive ability, sensitivity and false discovery rate. RESULTS: GLINTERNET and DSA had better overall performance than the other methods, with GLINTERNET having better properties in terms of selecting the true predictors (sensitivity) and of predictive ability, while DSA had a lower number of false positives. In terms of ability to capture interaction terms, GLINTERNET and DSA had again the best performances, with the same trade off between sensitivity and false discovery proportion. When GLINTERNET and DSA failed to select an exposure truly associated with the outcome, they tended to select a highly correlated one. When interactions were not present in the data, using variable selection methods that allowed for interactions had only slight costs in performance compared to methods that only searched for main effects. CONCLUSIONS: GLINTERNET and DSA provided better performance in detecting two-way interactions, compared to other existing methods. PMID- 28709429 TI - Efficacy of rituximab in non-paraneoplastic autoimmune retinopathy. AB - BACKGROUND: Autoimmune retinopathy (AIR) is a rare but potentially blinding condition that is often underdiagnosed. Common features in AIR presentation include rapidly progressive vision loss with abnormal electrophysiological responses of the retina associated with positive anti-retinal antibodies. AIR is also challenging to treat, and thus, the introduction of new potential therapeutic agents is welcomed. The goal of this communication is to assess the effects of rituximab infusions on electroretinogram (ERG) responses and visual function outcomes in patients with non-paraneoplastic autoimmune retinopathy (npAIR). RESULTS: Following infusion(s), three out of five patients showed no evidence of disease progression or improved, while two patients continued to progress on ERG. One patient demonstrated improvement in visual acuity (2 lines) in both eyes. ERG responses provided objective monitoring of patients' visual function and response to immunosuppression over time. CONCLUSIONS: These findings suggest that patients with npAIR unresponsive to other immunosuppression therapies may benefit from rituximab infusion, although stabilization rather than improvement was more frequently the outcome in our case series. Furthermore, regularly scheduled ERG follow-up examinations are recommended for monitoring patients' progression during treatment. PMID- 28709430 TI - Exploring the factor structure of the Health of the Nation Outcomes Scale (HoNOS) in a sample of patients with schizophrenia, schizotypal and delusional disorders. AB - BACKGROUND: The Health of the Nation Outcomes Scale (HoNOS) is recommended for use by the English National Service Framework for Mental Health and by the working group on outcome indicators for severe mental illnesses to the Department of Health. It was developed to measure the health and social functioning of people with severe mental illness. Since the development of the HoNOS many have debated its latent structure. This paper examines the latent structure of the HoNOS using current factor analysis techniques. METHOD: HoNOS data for 12,910 patients with ICD10 diagnoses F20 to F29 at a UK National Health Service Mental Health Trust were analysed using exploratory, confirmatory and bifactor analysis for categorical data. The fit of models was assessed using relative and absolute fit indices. RESULTS: Exploratory followed by confirmatory factor analysis identified a four factor solution which fit the data better than existing models. The corresponding bifactor factor solution identified three robust factors and one weak factor after accounting for a general factor. The factor loadings on the general factor were not appreciably different when compared to a unidimensional factor solution indicating the existence of a common trait. CONCLUSION: Existing models proposed in the literature did not fit well in our data. Factor analysis identified a new four factor solution. These factors showed clinical relevance according to published literature. The bifactor model demonstrated that there is not much loss of information when the HoNOS is used as a unidimensional construct. Further studies should explore this structure in larger samples and in alternative sample populations. A bifactor approach may have implications for how the HoNOS is used in practice, since there is ongoing debate on whether HoNOS item scores should be aggregated for interpretation. PMID- 28709431 TI - Is gentrification all bad? Positive association between gentrification and individual's perceived neighborhood collective efficacy in Montreal, Canada. AB - BACKGROUND: Collective efficacy has been associated with many health benefits at the neighborhood level. Therefore, understanding why some communities have greater collective efficacy than others is important from a public health perspective. This study examined the relationship between gentrification and collective efficacy, in Montreal Canada. METHODS: A gentrification index was created using tract level median household income, proportion of the population with a bachelor's degree, average rent, proportion of the population with low income, and proportion of the population aged 30-44. Multilevel linear regression analyses were conducted to measure the association between gentrification and individual level collective efficacy. RESULTS: Gentrification was positively associated with collective efficacy. Gentrifiers (individuals moving into gentrifying neighborhoods) had higher collective efficacy than individuals that lived in a neighborhood that did not gentrify. Perceptions of collective efficacy of the original residents of gentrifying neighborhoods were not significantly different from the perceptions of neighborhood collective efficacy of gentrifiers. CONCLUSIONS: Our results indicate that gentrification was positively associated with perceived collective efficacy. This implies that gentrification could have beneficial health effects for individuals living in gentrifying neighborhoods. PMID- 28709432 TI - Specialist treatment of chronic fatigue syndrome/ME: a cohort study among adult patients in England. AB - BACKGROUND: NHS specialist chronic fatigue syndrome (CFS/ME) services in England treat approximately 8000 adult patients each year. Variation in therapy programmes and treatment outcomes across services has not been described. METHODS: We described treatments provided by 11 CFS/ME specialist services and we measured changes in patient-reported fatigue (Chalder, Checklist Individual Strength), function (SF-36 physical subscale, Work & Social Adjustment Scale), anxiety and depression (Hospital Anxiety & Depression Scale), pain (visual analogue rating), sleep (Epworth, Jenkins), and overall health (Clinical Global Impression) 1 year after the start of treatment, plus questions about impact of CFS/ME on employment, education/training and domestic tasks/unpaid work. A subset of these outcome measures was collected from former patients 2-5 years after assessment at 7 of the 11 specialist services. RESULTS: Baseline data at clinical assessment were available for 952 patients, of whom 440 (46.2%) provided 1-year follow-up data. Treatment data were available for 435/440 (98.9%) of these patients, of whom 175 (40.2%) had been discharged at time of follow-up. Therapy programmes varied substantially in mode of delivery (individual or group) and number of sessions. Overall change in health 1 year after first attending specialist services was 'very much' or 'much better' for 27.5% (115/418) of patients, 'a little better' for 36.6% (153/418), 'no change' for 15.8% (66/418), 'a little worse' for 12.2% (51/418), and 'worse' or 'very much worse' for 7.9% (33/418). Among former patients who provided 2- to 5-year follow-up (30.4% (385/1265)), these proportions were 30.4% (117/385), 27.5% (106/385), 11.4% (44/385), 13.5% (52/385), and 17.1% (66/385), respectively. 85.4% (327/383) of former patients responded "Yes" to "Do you think that you are still suffering from CFS/ME?" 8.9% (34/383) were "Uncertain", and 5.7% (22/383) responded "No". CONCLUSIONS: This multi-centre NHS study has shown that, although one third of patients reported substantial overall improvement in their health, CFS/ME is a long term condition that persists for the majority of adult patients even after receiving specialist treatment. PMID- 28709433 TI - Erratum to: toxicity and antitumor potential of Mesosphaerum sidifolium (Lamiaceae) oil and fenchone, its major component. PMID- 28709435 TI - Erratum to: Impact of metabolic syndrome and its components on heart rate variability during hemodialysis: a cross-sectional study. PMID- 28709434 TI - Integrating multi-omics analyses of Nonomuraea dietziae to reveal the role of soybean oil in [(4'-OH)MeLeu]4-CsA overproduction. AB - BACKGROUND: Nonomuraea dietziae is a promising microorganism to mediate the region-specific monooxygenation reaction of cyclosporine A (CsA). The main product [(4'-OH)MeLeu]4-CsA possesses high anti-HIV/HCV and hair growth stimulating activities while avoiding the immunosuppressive effect of CsA. However, the low conversion efficiency restricts the clinical application. In this study, the production of [(4'-OH)MeLeu]4-CsA was greatly improved by 55.6% from 182.8 to 284.4 mg/L when supplementing soybean oil into the production medium, which represented the highest production of [(4'-OH)MeLeu]4-CsA so far. RESULTS: To investigate the effect of soybean oil on CsA conversion, some other plant oils (corn oil and peanut oil) and the major hydrolysates of soybean oil were fed into the production medium, respectively. The results demonstrated that the plant oils, rather than the hydrolysates, could significantly improve the [(4'-OH)MeLeu]4-CsA production, suggesting that soybean oil might not play its role in the lipid metabolic pathway. To further unveil the mechanism of [(4' OH)MeLeu]4-CsA overproduction under the soybean oil condition, a proteomic analysis based on the two-dimensional gel electrophoresis coupled with MALDI TOF/TOF mass spectrometry was implemented. The results showed that central carbon metabolism, genetic information processing and energy metabolism were significantly up-regulated under the soybean oil condition. Moreover, the gas chromatography-mass spectrometry-based metabolomic analysis indicated that soybean oil had a great effect on amino acid metabolism and tricarboxylic acid cycle. In addition, the transcription levels of cytochrome P450 hydroxylase (CYP) genes for CsA conversion were determined by RT-qPCR and the results showed that most of the CYP genes were up-regulated under the soybean oil condition. CONCLUSIONS: These findings indicate that soybean oil could strengthen the primary metabolism and the CYP system to enhance the mycelium growth and the monooxygenation reaction, respectively, and it will be a guidance for the further metabolic engineering of this strain. PMID- 28709436 TI - Satisfaction, discomfort, obligations, and concerns in population-based breast cancer screening: cross-sectional study in a Danish population. AB - BACKGROUND: Potential barriers to breast cancer screening adherence include patient satisfaction, as well as pain, feeling obliged to participate, and other concerns that might compromise the level of satisfaction. The present study aimed to assess the overall satisfaction of Danish citizens with their breast cancer screening experiences, as well as their level of discomfort, concerns, and feelings of obligation to participate. Furthermore, we analyzed the associations between overall satisfaction and the remaining outcomes. METHODS: Questionnaires were mailed to 3000 women in the Central Denmark Region who received screening examination results in the fall of 2013. The questionnaire assessed satisfaction (overall, telephone hot-line, and web-based self-service), discomfort (pain and boundaries of modesty), concerns (at invitation, while waiting for results, and after receiving results), and feelings of obligation to participate. Background information was retrieved from Statistics Denmark. Pearson's chi-square test was used to test differences in outcomes and demographic characteristic distributions between respondents and non-respondents and highly satisfied vs. less satisfied participants. Prevalence ratios (PR) with 95% CI were assessed using Poisson regression with robust variance, to estimate associations between satisfaction and the remaining outcomes. RESULTS: Among the participants, 70.3% and 29.4%, respectively, reported really good and good impressions of the screening program. Lower satisfaction was associated with feeling pain (prevalence ratio (PR), 0.82), feeling that modesty boundaries were transgressed (PR, 0.79), experiencing screening-induced concerns (PR, 0.84), and feeling obliged to participate (PR, 0.96). Of the participants, 36.2% and 12.9%, respectively, felt very much and moderately obliged to participate. A total of 72.6% reported no screening-induced concerns, including 73.3% of those with negative screening results and 38.1% of those with positive screening results. CONCLUSIONS: Overall satisfaction with breast cancer screening was very high, but discomfort, feelings of obligation, and concerns were associated with lower satisfaction levels. A continuing focus on high service in breast cancer screening is important for achieving the highest benefit from the program. This includes initiatives to employ the least painful techniques, to respect the patients' modesty as much as possible, and to deliver fast screening results and thus minimize concerns among women awaiting results. PMID- 28709437 TI - Profile and predictors of health related quality of life among type II diabetes mellitus patients in Quetta city, Pakistan. AB - BACKGROUND: This study aims to assess the profile and predictors of Health Related Quality of Life (HRQoL) in Type II Diabetes Mellitus (T2DM) patients in Quetta, Pakistan. METHODS: The study was designed as a questionnaire based, cross sectional analysis. 300 Type II diabetic patients attending public and private hospitals were targeted for data collection. In addition to demographic and disease related information, Euroqol Quality of Life was used to measure HRQoL. Moreover, Drug Attitude Inventory and Michigan Diabetes Knowledge Test were used to assess medication adherence and diabetes related knowledge respectively. Treatment satisfaction was assessed by patient's experience towards health care professionals and available facilities. Descriptive statistics were used to elaborate patients' demographic and disease related characteristics. Binary logistic regression was used to predict factors independently associated with HRQoL. SPSS v. 20 was used for data analysis and p < 0.05 was taken as significant. RESULTS: Patients in the current study reported poor HRQoL with a mean score of 0.48 +/- 0.36. Age, duration of disease, number of prescribed drugs, medication adherence and treatment satisfaction were significantly associated (p < 0.05) with HRQoL in the cross tabulation analysis. The significant variables were entered into the model that showed significant goodness of fit with highly significant Omnibus Test of Model Coefficient (Chi square = 12.983, p = 0.030, df = 4). Medication adherence was reported as a significant predictor of HRQoL with an increase of one adherence score was associated with improvement of HRQoL by a factor of 1.75 provided other variables remain constant. CONCLUSION: The study presents a model that is associated with HRQoL with patient with T2DM, where medication adherence shaped as a predictor of HRQoL. Healthcare professionals should pay special attention on patients' medication taking behavior and should put their efforts in explaining the benefits of the medication adherence to the patients. PMID- 28709438 TI - Surgical treatment for mediastinal abscess induced by endobronchial ultrasound guided transbronchial needle aspiration: a case report and literature review. AB - BACKGROUND: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a useful and less invasive procedure for the definitive diagnosis of mediastinal and hilar lymph nodes. However, infectious complications can occur after EBUS-TBNA, although they are extremely rare. CASE PRESENTATION: A 66-year old man with necrotic and swollen lower paratracheal lymph nodes underwent EBUS TBNA. A mediastinal abscess developed 9 days post-procedure. Surgical drainage and debridement of the abscess were performed along with lymph node biopsy followed by daily washing of the thoracic cavity. Surgical treatment was effective, leading to remission of the abscess. Biopsy revealed that the tumor was squamous cell carcinoma with no radiologically detected cancer elsewhere in the body. Mediastinal lung cancer was thus confirmed. Subsequent chemoradiotherapy led to the remission of the tumor. CONCLUSIONS: Mediastinitis after EBUS-TBNA is rare but should be considered, particularly if the target lymph nodes are necrotic. Mediastinitis can lead to serious and rapid deterioration of the patient's condition, for which surgical intervention is the treatment of choice. PMID- 28709439 TI - Enhanced antimicrobial de-escalation for pneumonia in mechanically ventilated patients: a cross-over study. AB - BACKGROUND: Antibiotics are commonly administered to hospitalized patients with infiltrates for possible bacterial pneumonia, often leading to unnecessary treatment and increasing the risk for resistance emergence. Therefore, we performed a study to determine if an enhanced antibiotic de-escalation practice could improve antibiotic utilization in mechanically ventilated patients with suspected pneumonia cared for in an academic closed intensive care unit (ICU). METHODS: This was a prospective cross-over trial comparing routine antibiotic management (RAM) and enhanced antimicrobial de-escalation (EAD) performed within two medical ICUs (total 34 beds) at Barnes-Jewish Hospital, an academic referral center. Patients in the EAD group had their antibiotic orders and microbiology results reviewed daily by a dedicated team comprised of a second-year critical care fellow, an ICU attending physician and an ICU pharmacist. Antibiotic de escalation recommendations were made when appropriate based on microbiologic test results and clinical response to therapy. RESULTS: There were 283 patients evaluable, with suspected pneumonia requiring mechanical ventilation: 139 (49.1%) patients in the RAM group and 144 (50.9%) in the EAD group. Early treatment failure based on clinical deterioration occurred in 33 (23.7%) and 40 (27.8%) patients, respectively (P = 0.438). In the remaining patients, antimicrobial de escalation occurred in 70 (66.0%) and 70 (67.3%), respectively (P = 0.845). There was no difference between groups in total antibiotic days ((median (interquartile range)) 7.0 days (4.0, 9.0) versus 7.0 days (4.0, 8.8) (P = 0.616)); hospital mortality (25.2% versus 35.4% (P = 0.061)); or hospital duration (12.0 days (6.0, 20.0) versus 11.0 days (6.0, 22.0) (P = 0.918). CONCLUSIONS: The addition of an EAD program to a high-intensity daytime staffing model already practicing a high level of antibiotic stewardship in an academic ICU was not associated with greater antibiotic de-escalation or a reduction in the overall duration of antibiotic therapy. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02685930 . Registered on 26 January 2016. PMID- 28709440 TI - The effect of 'Out of hours surgery Service' in Israel on hip fracture fixation outcomes: a retrospective analysis. AB - BACKGROUND: 'Out of Hours Surgery Service' (OHSS) was implemented in Israel, amongst other reasons, in order to reduce the time interval between hospital admission and surgery and consequently improve outcomes. The OHSS is currently operated in the public hospitals in Israel. In this study we compared the data of patients before and after OHSS implementation to determine its efficacy in improving patient care. METHODS: This is a retrospective observational study of 792 adult patients who underwent hip fracture surgery between 2002 and 2007 in a single hospital. The study population included two groups: patients that were operated before the implementation of the OHSS (2002-2004) and after the implementation of the OHSS (2005-2007). Data regarding all patients was collected using the institution's computer program. The following variables were analyzed: patients' demographics, time interval from hospitalization to surgery, causes for delaying surgery, post-operative length of hospitalization and mortality. RESULTS: Patients in the post-OHSS group had more illnesses and higher ASA classification than those in the pre-OHSS group. The post-OHSS group had a significantly decreased length of stay in the hospital before and after the surgery. After adjusting for ASA score and age, the post-OHSS group was found to have decreased post-operative hospitalization and lower post-operative mortality. Surgery was delayed in pre-OHSS period mainly due to operating rooms unavailability. CONCLUSION: Implementation of OHSS facilitated operating room availability, thus early operation and reduced post-operative mortality. In accordance with other studies, patient's outcome is greatly influenced by the time from admission to hip fracture surgery. PMID- 28709441 TI - Mortality outcomes of low-dose computed tomography screening for lung cancer in urban China: a decision analysis and implications for practice. AB - BACKGROUND: Mortality outcomes in trials of low-dose computed tomography (CT) screening for lung cancer are inconsistent. This study aimed to evaluate whether CT screening in urban areas of China could reduce lung cancer mortality and to investigate the factors that associate with the screening effect. METHODS: A decision tree model with three scenarios (low-dose CT screening, chest X-ray screening, and no screening) was developed to compare screening results in a simulated Chinese urban cohort (100,000 smokers aged 45-80 years). Data of participant characteristics were obtained from national registries and epidemiological surveys for estimating lung cancer prevalence. The selection of other tree variables such as sensitivities and specificities of low-dose CT and chest X-ray screening were based on literature research. Differences in lung cancer mortality (primary outcome), false diagnoses, and deaths due to false diagnosis were calculated. Sensitivity analyses were performed to identify the factors that associate with the screening results and to ascertain worst and optimal screening effects considering possible ranges of the variables. RESULTS: Among the 100,000 subjects, there were 448, 541, and 591 lung cancer deaths in the low-dose CT, chest X-ray, and no screening scenarios, respectively (17.2% reduction in low-dose CT screening over chest X-ray screening and 24.2% over no screening). The costs of the two screening scenarios were 9387 and 2497 false diagnoses and 7 and 2 deaths due to false diagnosis among the 100,000 persons, respectively. The factors that most influenced death reduction with low-dose CT screening over no screening were lung cancer prevalence in the screened cohort, low-dose CT sensitivity, and proportion of early-stage cancers among low-dose CT detected lung cancers. Considering all possibilities, reduction in deaths (relative numbers) with low-dose CT screening in the worst and optimal cases were 16 (5.4%) and 288 (40.2%) over no screening, respectively. CONCLUSIONS: In terms of mortality outcomes, our findings favor conducting low-dose CT screening in urban China. However, approaches to reducing false diagnoses and optimizing important screening conditions such as enrollment criteria for screening are highly needed. PMID- 28709442 TI - Can recurrences be predicted in craniopharyngiomas? beta-catenin coexisting with stem cells markers and p-ATM in a clinicopathologic study of 45cases. AB - BACKGROUND: Recurrence is a common feature of craniopharyngiomas, benign tumors that origin from squamous epithelial remnants of Rathke's pouch- arising at any segment of its whole course. There are two histotypes, showing different morphology and clinical behavior: adamantinomatous(adaCP) and papillary (papCP). An univocal strategy of management has not yet been defined, being considered the combination of surgery and radiotherapy the most effective, especially in case of incomplete resection. Therefore, the identification of factors influencing the biological and clinical behaviour is of paramount importance. beta-catenin is a cell-cell adhesion protein, whose nuclear localization has been linked to the pathogenesis of adaCP: its nuclear accumulation is associated to the presence of a tumor stem cell subpopulation. The latter is made of cells capable of self renewal, hence believed to be responsible of recurrence, metastases and resistance to therapy in all tumors. ATM is a kinase activated by autophosphorylation (p-ATM) upon DNA double-strand breaks. It is involved not only in DNA repair, but also in tumor migration and invasiveness. Its expression may have prognostic implications in many neoplastic diseases. METHODS: In this study, we measured the immunohistochemical expression of beta-catenin, stem cell markers (CD133, CD166), Ki67 and pATMin 45 craniopharyngiomas and correlated it with clinicopathologic features. RESULTS: Statistical analysis revealed strong correlation of beta-catenin with recurrence (p = 0.0039), Ki67 (p = 0.0011, r = 0.4903) and CD166 (p = 0.0002, r = 0.6218). A slight tendency to a higher expression of beta-catenin was recorded for adaCP rather than papCP (p = 0.0895).Fisher's exact test showed that CD166 was significantlyrelated with recurrence (p = 0.0040). Furthermore, cytoplasmic pATM was more expressed in adaCPs (p = 0.0470), compared to papCPs that displayed a more evident nuclear signal (p = 0.0313) instead. CONCLUSIONS: Backing upon these data, we could weigh in on the need of identifying beta-catenin and CD166 as prognostic markersthat could be useful in predicting thebiologicalbehavior, as recurrence risk incraniopharyngiomas. The final goal is to drew up a prognostic algorithm to be of aid in the planning of an appropriate treatment strategy. Furthermore, our findings demonstrate that pATM could be used as additional distinction-marker between the two histotypes. PMID- 28709444 TI - Exploring the potential confounder of nitrogen fertilizers in the relationship between pesticide exposures and risk of leukemia: a Poisson regression with two way fixed-effects analysis. PMID- 28709443 TI - Severity of acute gastrointestinal injury grade is a predictor of all-cause mortality in critically ill patients: a multicenter, prospective, observational study. AB - BACKGROUND: In 2012, the European Society of Intensive Care Medicine proposed a definition for acute gastrointestinal injury (AGI) based on current medical evidence and expert opinion. The aim of the present study was to evaluate the feasibility of using the current AGI grading system and to investigate the association between AGI severity grades with clinical outcome in critically ill patients. METHODS: Adult patients at 14 general intensive care units (ICUs) with an expected ICU stay >=24 h were prospectively studied. The AGI grade was assessed daily on the basis of gastrointestinal (GI) symptoms, intra-abdominal pressures, and feeding intolerance (FI) in the first week of admission to the ICU. RESULTS: Among the 550 patients enrolled, 456 patients (82.9%) received mechanical ventilation, and 470 patients were identified for AGI. The distribution of the global AGI grade was 24.5% with grade I, 49.4% with grade II, 20.6% with grade III, and 5.5% with grade IV. AGI grading was positively correlated with 28- and 60-day mortality (P < 0.0001). Univariate Cox regression analysis showed that age, sepsis, diabetes mellitus, coronary artery disease, the use of vasoactive drugs, serum creatinine and lactate levels, mechanical ventilation, Acute Physiology and Chronic Health Evaluation II (APACHE II) score, and the global AGI grade were significantly (P <= 0.02) associated with 60-day mortality. In a multivariate analysis including these variables, diabetes mellitus (HR 1.43, 95% CI 1.03-1.87; P = 0.05), the use of vasoactive drugs (HR 1.56, 95% CI 1.12-2.11; P = 0.01), serum lactate (HR 1.15, 95% CI 1.06-1.24; P = 0.03), global AGI grade (HR 1.65, 95% CI 1.28-2.12; P = 0.008), and APACHE II score (HR 1.04, 95% CI 1.02-1.06; P < 0.001) were independently associated with 60-day mortality. In a subgroup analysis of 402 patients with 7-day survival, in addition to clinical predictors and the AGI grade on the first day of ICU stay, FI within the first week of ICU stay had an independent and incremental prognostic value for 60-day mortality (chi2 = 41.9 vs. 52.2, P = 0.007). CONCLUSIONS: The AGI grading scheme is useful for identifying the severity of GI dysfunction and could be used as a predictor of impaired outcomes. In addition, these results support the hypothesis that persistent FI within the first week of ICU stay is an independent determinant for mortality. TRIAL REGISTRATION: Chinese Clinical Trial Registry identifier: ChiCTR-OCS-13003824 . Registered on 29 September 2013. PMID- 28709445 TI - Twin-Twin Transfusion Syndrome: study protocol for developing, disseminating, and implementing a core outcome set. AB - BACKGROUND: Twin-Twin Transfusion Syndrome (TTTS) is associated with an increased risk of perinatal mortality and morbidity. Several treatment interventions have been described for TTTS, including fetoscopic laser surgery, amnioreduction, septostomy, expectant management, and pregnancy termination. Over the last decade, fetoscopic laser surgery has become the primary treatment. The literature to date reports on many different outcomes, making it difficult to compare results or combine data from individual studies, limiting the value of research to guide clinical practice. With the advent and ongoing development of new therapeutic techniques, this is more important than ever. The development and use of a core outcome set has been proposed to address these issues, prioritising outcomes important to the key stakeholders, including patients. We aim to produce, disseminate, and implement a core outcome set for TTTS. METHODS: An international steering group has been established to oversee the development of this core outcome set. This group includes healthcare professionals, researchers and patients. A systematic review is planned to identify previously reported outcomes following treatment for TTTS. Following completion, the identified outcomes will be evaluated by stakeholders using an international, multi perspective online modified Delphi method to build consensus on core outcomes. This method encourages the participants towards consensus 'core' outcomes. All key stakeholders will be invited to participate. The steering group will then hold a consensus meeting to discuss results and form a core outcome set to be introduced and measured. Once core outcomes have been agreed, the next step will be to determine how they should be measured, disseminated, and implemented within an international context. DISCUSSION: The development, dissemination, and implementation of a core outcome set in TTTS will enable its use in future clinical trials, systematic reviews and clinical practice guidelines. This is likely to advance the quality of research studies and their effective use in order to guide clinical practice and improve patient care, maternal, short-term perinatal outcomes and long-term neurodevelopmental outcomes. TRIAL REGISTRATION: Core Outcome Measures in Effectiveness Trials (COMET), 921 Registered on July 2016. International Prospective Register of Systematic Reviews (PROSPERO), CRD42016043999 . Registered on 2 August 2016. PMID- 28709446 TI - Omitting duodenal biopsy in children with suspected celiac disease and extra intestinal symptoms. AB - BACKGROUND: The aim of our study is to evaluate if in children with highly positive serology and HLA-DQ2/DQ8 (triple test, TT) and only extra-intestinal symptoms, it is possible to omit performing an intestinal biopsy for celiac disease (CD) diagnosis, as suggested by the new European Society for Pediatric Gastroenterology, Hepatology and Nutrition ESPGHAN guidelines. METHODS: In this retrospective study a total of 105 patients, suspected of having CD because of extra-intestinal symptoms and showing serum tissue transglutaminase antibody (anti-tTG) and anti-endomysial antibody (EMA) measurements and HLA genotyping, were considered for the final analysis (33 boys and 72 girls; age range 1.5-17.6 years). RESULTS: Histological findings confirmed diagnosis of CD in 97 (92.4%) patients. Forty-one patients (39%) showed anti-tTG >10 times normal values, positive EMA and positive HLA-DQ2/DQ8 (positive TT). All of them had a diagnosis of CD, therefore there were no false positive cases. Sixty-four patients were negative for the TT. In eight cases, CD was ruled out and these were considered true negative cases. In the remaining 56 negative TT patients, intestinal biopsy confirmed CD diagnosis and they were considered false negatives. Based on these results, specificity for the TT was 100% and sensitivity was 42.3%. CONCLUSIONS: On the basis of the present study, diagnosis of CD can be reliably performed without a duodenal biopsy in children with only extra-intestinal symptoms. PMID- 28709447 TI - Cryptic amyloidogenic elements in mutant NEFH causing Charcot-Marie-Tooth 2 trigger aggresome formation and neuronal death. AB - Neurofilament heavy chain (NEFH) gene was recently identified to cause autosomal dominant axonal Charcot-Marie-Tooth disease (CMT2cc). However, the clinical spectrum of this condition and the physio-pathological pathway remain to be delineated. We report 12 patients from two French families with axonal dominantly inherited form of CMT caused by two new mutations in the NEFH gene. A remarkable feature was the early involvement of proximal muscles of the lower limbs associated with pyramidal signs in some patients. Nerve conduction velocity studies indicated a predominantly motor axonal neuropathy. Unique deletions of two nucleotides causing frameshifts near the end of the NEFH coding sequence were identified: in family 1, c.3008_3009del (p.Lys1003Argfs*59), and in family 2 c.3043_3044del (p.Lys1015Glyfs*47). Both frameshifts lead to 40 additional amino acids translation encoding a cryptic amyloidogenic element. Consistently, we show that these mutations cause protein aggregation which are recognised by the autophagic pathway in motoneurons and triggered caspase 3 activation leading to apoptosis in neuroblastoma cells. Using electroporation of chick embryo spinal cord, we confirm that NEFH mutants form aggregates in vivo and trigger apoptosis of spinal cord neurons. Thus, our results provide a physiological explanation for the overlap between CMT and amyotrophic lateral sclerosis (ALS) clinical features in affected patients. PMID- 28709448 TI - No added diagnostic value of non-phosphorylated tau fraction (p-taurel) in CSF as a biomarker for differential dementia diagnosis. AB - BACKGROUND: The Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers Abeta1-42, t-tau, and p-tau181 overlap with other diseases. New tau modifications or epitopes, such as the non-phosphorylated tau fraction (p-taurel), may improve differential dementia diagnosis. The goal of this study is to investigate if p taurel can improve the diagnostic performance of the AD CSF biomarker panel for differential dementia diagnosis. METHODS: The study population consisted of 45 AD, 45 frontotemporal lobar degeneration (FTLD), 45 dementia with Lewy bodies (DLB), and 21 Creutzfeldt-Jakob disease (CJD) patients, and 20 cognitively healthy controls. A substantial subset of the patients was pathology-confirmed. CSF levels of Abeta1-42, t-tau, p-tau181, and p-taurel were determined with commercially available single-analyte enzyme-linked immunosorbent assay (ELISA) kits. Diagnostic performance was evaluated by receiver operating characteristic (ROC) curve analyses, and area under the curve (AUC) values were compared using DeLong tests. RESULTS: The diagnostic performance of single markers as well as biomarker ratios was determined for each pairwise comparison of different dementia groups and controls. The addition of p-taurel to the AD biomarker panel decreased its diagnostic performance when discriminating non-AD, FTLD, and DLB from AD. As a single marker, p-taurel increased the diagnostic performance for CJD. No significant difference was found in AUC values with the addition of p taurel when differentiating between AD or non-AD dementias and controls. CONCLUSIONS: The addition of p-taurel to the AD CSF biomarker panel failed to improve differentiation between AD and non-AD dementias. PMID- 28709449 TI - A novel Alzheimer's disease drug candidate targeting inflammation and fatty acid metabolism. AB - BACKGROUND: CAD-31 is an Alzheimer's disease (AD) drug candidate that was selected on the basis of its ability to stimulate the replication of human embryonic stem cell-derived neural precursor cells as well as in APPswe/PS1DeltaE9 AD mice. To move CAD-31 toward the clinic, experiments were undertaken to determine its neuroprotective and pharmacological properties, as well as to assay its therapeutic efficacy in a rigorous mouse model of AD. RESULTS: CAD-31 has potent neuroprotective properties in six distinct nerve cell assays that mimic toxicities observed in the old brain. Pharmacological and preliminary toxicological studies show that CAD-31 is brain-penetrant and likely safe. When fed to old, symptomatic APPswe/PS1DeltaE9 AD mice starting at 10 months of age for 3 additional months in a therapeutic model of the disease, there was a reduction in the memory deficit and brain inflammation, as well as an increase in the expression of synaptic proteins. Small-molecule metabolic data from the brain and plasma showed that the major effect of CAD-31 is centered on fatty acid metabolism and inflammation. Pathway analysis of gene expression data showed that CAD-31 had major effects on synapse formation and AD energy metabolic pathways. CONCLUSIONS: All of the multiple physiological effects of CAD-31 were favorable in the context of preventing some of the toxic events in old age associated neurodegenerative diseases. PMID- 28709450 TI - (Dis)Trust your gut: the gut microbiome in age-related inflammation, health, and disease. AB - Chronic inflammation represents one of the most consistent biologic features of aging. However, the precise etiology of persistent low-grade increases in inflammation remains unclear. Recent evidence suggests that the gut microbiome may play a key role in age-related inflammation. Indeed, several studies have indicated that older adults display an altered composition of the gut microbiota, and early evidence indicates that this dysbiosis is associated with the presence of several key circulating inflammatory analytes. The present review summarizes knowledge on age-related inflammation and discusses how potential relationships with gut dysbiosis may lead to novel treatment strategies in the future."The pattern of disease is an expression of the response of man to his total environment (physical, biological, and social); this response is, therefore, determined by anything that affects man himself or his environment." - Rene Dubos, 1961. PMID- 28709452 TI - Influence of the patient-practitioner interaction context on acupuncture outcomes in functional dyspepsia: study protocol for a multicenter randomized controlled trial. AB - BACKGROUND: In the treatment of functional dyspepsia, the placebo effect has been reported to be high, and the influence of the patient-practitioner relationship may be a major component of this effect. The specific and non-specific effects of acupuncture cannot be easily distinguished, and the patient-practitioner relationship may influence the total therapeutic effect in clinical practice. There have been no studies that investigate the influence of patient-practitioner relationship on acupuncture treatment for patients with functional dyspepsia. METHODS: Patients with postprandial distress syndrome, a functional dyspepsia subtype, will be recruited at three hospitals (two in Korea and one in USA) for an international, multi-center, randomized, patient/assessor-blinded, clinical trial. The total anticipated sample size is 88. The participants will be randomly allocated into two groups: an augmented interaction group and a limited interaction group. Acupuncture, with total 12 acupoints, will be performed twice weekly for 4 weeks in both groups. Trained practitioners will provide an "augmented" or "limited" interaction context, as determined by random allocation. The primary outcome measure is the proportion of responders, the proportion of participants who answer "yes" to more than half of the adequate relief questions during the study. Secondary outcome measures include questionnaires for quality of life and symptoms of dyspepsia, and maximum tolerable volume of nutrient drink test. Data will be collected at baseline and following 4 weeks of acupuncture. DISCUSSION: This study will evaluate the influence of the patient-practitioner interaction on clinical effects of acupuncture in patients with functional dyspepsia. TRIAL REGISTRATION: CRIS Identifier: ( KCT0002229 ). PMID- 28709453 TI - Validation of multisource electronic health record data: an application to blood transfusion data. AB - BACKGROUND: Although data from electronic health records (EHR) are often used for research purposes, systematic validation of these data prior to their use is not standard practice. Existing validation frameworks discuss validity concepts without translating these into practical implementation steps or addressing the potential influence of linking multiple sources. Therefore we developed a practical approach for validating routinely collected data from multiple sources and to apply it to a blood transfusion data warehouse to evaluate the usability in practice. METHODS: The approach consists of identifying existing validation frameworks for EHR data or linked data, selecting validity concepts from these frameworks and establishing quantifiable validity outcomes for each concept. The approach distinguishes external validation concepts (e.g. concordance with external reports, previous literature and expert feedback) and internal consistency concepts which use expected associations within the dataset itself (e.g. completeness, uniformity and plausibility). In an example case, the selected concepts were applied to a transfusion dataset and specified in more detail. RESULTS: Application of the approach to a transfusion dataset resulted in a structured overview of data validity aspects. This allowed improvement of these aspects through further processing of the data and in some cases adjustment of the data extraction. For example, the proportion of transfused products that could not be linked to the corresponding issued products initially was 2.2% but could be improved by adjusting data extraction criteria to 0.17%. CONCLUSIONS: This stepwise approach for validating linked multisource data provides a basis for evaluating data quality and enhancing interpretation. When the process of data validation is adopted more broadly, this contributes to increased transparency and greater reliability of research based on routinely collected electronic health records. PMID- 28709451 TI - Comparing very low birth weight versus very low gestation cohort methods for outcome analysis of high risk preterm infants. AB - BACKGROUND: Compared to very low gestational age (<32 weeks, VLGA) cohorts, very low birth weight (<1500 g; VLBW) cohorts are more prone to selection bias toward small-for-gestational age (SGA) infants, which may impact upon the validity of data for benchmarking purposes. METHOD: Data from all VLGA or VLBW infants admitted in the 3 Networks between 2008 and 2011 were used. Two-thirds of each network cohort was randomly selected to develop prediction models for mortality and composite adverse outcome (CAO: mortality or cerebral injuries, chronic lung disease, severe retinopathy or necrotizing enterocolitis) and the remaining for internal validation. Areas under the ROC curves (AUC) of the models were compared. RESULTS: VLBW cohort (24,335 infants) had twice more SGA infants (20.4% vs. 9.3%) than the VLGA cohort (29,180 infants) and had a higher rate of CAO (36.5% vs. 32.6%). The two models had equal prediction power for mortality and CAO (AUC 0.83), and similarly for all other cross-cohort validations (AUC 0.81 0.85). Neither model performed well for the extremes of birth weight for gestation (<1500 g and >=32 weeks, AUC 0.50-0.65; >=1500 g and <32 weeks, AUC 0.60-0.62). CONCLUSION: There was no difference in prediction power for adverse outcome between cohorting VLGA or VLBW despite substantial bias in SGA population. Either cohorting practises are suitable for international benchmarking. PMID- 28709454 TI - Comparison of skin-sparing mastectomy using LigaSureTM Small Jaw and electrocautery. AB - BACKGROUND: Skin-sparing mastectomy (SSM) is increasingly used in patients with breast cancer. We compared the differences between use of electrocautery and LigaSureTM Small Jaw in patients with breast cancer who underwent SSM. METHODS: Between January 2012 and December 2015, 81 patients with breast cancer who underwent SSM were selected and were divided into the electrocautery group and the LigaSureTM Small Jaw group based on the devices that were used. Clinicopathological characteristics, body mass index, operative time, and weight of removed breast were obtained from medical records. Total amount and days of drain use, until removal, and postoperative skin necrosis, requiring debridement, were also analyzed. RESULTS: The study population consisted of 50 patients in the electrocautery group and 31 in the LigaSureTM Small Jaw group. The latter group has significantly shorter operative time (117.5 +/- 16.9 vs. 104.0 +/- 23.6 min, P = 0.004). The mean total volume of drainage was less (805 +/- 278 vs. 694 +/- 131 mL, P = 0.017) and mean duration of drainage was also significantly shorter in the LigaSureTM Small Jaw group (11.3 +/- 2.5 vs. 10.1 +/- 2.0 days, P = 0.029). CONCLUSIONS: The use of LigaSureTM Small Jaw during skin-sparing mastectomy shortened the operative time and duration of drainage and reduced the total volume of drainage. PMID- 28709455 TI - Barriers and facilitators to reducing frequent laboratory testing for patients who are stable on warfarin: a mixed methods study of de-implementation in five anticoagulation clinics. AB - BACKGROUND: Patients on chronic warfarin therapy require regular laboratory monitoring to safely manage warfarin. Recent studies have challenged the need for routine monthly blood draws in the most stable warfarin-treated patients, suggesting the safety of less frequent laboratory testing (up to every 12 weeks). De-implementation efforts aim to reduce the use of low-value clinical practices. To explore barriers and facilitators of a de-implementation effort to reduce the use of frequent laboratory tests for patients with stable warfarin management in nurse/pharmacist-run anticoagulation clinics, we performed a mixed-methods study conducted within a state-wide collaborative quality improvement collaborative. METHODS: Using a mixed-methods approach, we conducted post-implementation semi structured interviews with a total of eight anticoagulation nurse or pharmacist staff members at five participating clinic sites to assess barriers and facilitators to de-implementing frequent international normalized ratio (INR) laboratory testing among patients with stable warfarin control. Interview guides were based on the Tailored Implementation for Chronic Disease (TICD) framework. Informed by interview themes, a survey was developed and administered to all anticoagulation clinical staff (n = 62) about their self-reported utilization of less frequent INR testing and specific barriers to de-implementing the standard (more frequent) INR testing practice. RESULTS: From the interviews, four themes emerged congruent with TICD domains: (1) staff overestimating their actual use of less frequent INR testing (individual health professional factors), (2) barriers to appropriate patient engagement (incentives and resources), (3) broad support for an electronic medical record flag to identify potentially eligible patients (incentives and resources), and (4) the importance of personalized nurse/pharmacist feedback (individual health professional factors). In the survey (65% response rate), staff report offering less frequent INR testing to 56% (46 66%) of eligible patients. Most survey responders (n = 24; 60%) agreed that an eligibility flag in the electronic medical record would be very helpful. Twenty four (60%) respondents agreed that periodic, personalized feedback on use of less frequent INR testing would also be helpful. CONCLUSIONS: Leveraging information system notifications, reducing additional work load burden for participating patients and providers, and providing personalized feedback are strategies that may improve adoption and utilization new policies in anticoagulation clinics that focus on de-implementation. PMID- 28709456 TI - Analyses of distribution and dosimetry of brain metastases in small cell lung cancer with relation to the neural stem cell regions: feasibility of sparing the hippocampus in prophylactic cranial irradiation. AB - BACKGROUND: This work aims to assess the feasibility of selectively sparing the hippocampus during prophylactic cranial irradiation (PCI) for small cell lung cancer (SCLC). METHODS: SCLC patients with brain metastases (BMs) diagnosed with MRI were enrolled. Lesions localized to the neural stem cell (NSC) compartments [subventricular zone (SVZ) or hippocampus] were analyzed. Patients were categorized by the total number of intracranial metastases, the therapy processes and the symptoms. Hippocampi and enhanced lesions within 15 mm from the hippocampus were contoured. IMRT treatment plans were generated for hippocampal avoidance (HA)-PCI (25Gy in 10 fractions). RESULTS: From Jan 2011 to Oct 2014, 1511 metastases were identified in 238 patients. The overall ratio of metastatic lesions located in NSC regions was 2.0% in the 1511 total metastases and 9.7% in the 238 overall patients. Among the NSC region metastases, 15 (1.0%) lesions involved the HA region of 14 (5.9%) patients and another 15 (1.0%) involved the SVZ of 15 (6.3%) patients. The involvement of HA region or SVZ was significantly different between patients with oligometastatic and non-oligometastatic BMs (P < 0.05). Based on the dosimetric analysis, 26 (10.9%) patients with 41 (2.7%) metastases within 15 mm from the hippocampus had inadequate dosage in case that HA-PCI was applied. CONCLUSIONS: Our retrospective review of 1511 metastases in 238 patients (among whom 89.5% were male) suggests that the metastatic involvement of the NSC regions (especially hippocampus) is unusual and limited primarily to patients with non-oligometastatic disease in SCLC. Also, dosimetric analysis shows that about 10% of patients may have adequate dosage due to HA-PCI treatment. But we believe that this is still an acceptable clinical treatment strategy for SCLC. PMID- 28709457 TI - Tubulointerstitial nephritis and uveitis (TINU) syndrome: a systematic review of its epidemiology, demographics and risk factors. AB - Tubulointerstitial nephritis and uveitis (TINU) syndrome is a rare oculorenal inflammatory condition that was first described in 1975. In 2001 a major review identified 133 cases in the world literature and proposed key diagnostic criteria for the condition. Although acknowledged as rare, the limited data available prevented reliable estimates of the prevalence of the condition, and hampered elucidation of the relationship between genetic and environmental factors that contribute to its pathogenesis.In this review we have performed a systematic search on the epidemiology, demographics and proposed risk factors for TINU. Estimates of prevalence based on studies that explicitly report TINU cases suggest that it is diagnosed in 0.2-2% of patients attending specialist uveitis services, with variation reflecting a number of factors including level of diagnostic certainty required. The prevalence of uveitis in patients with tubulointerstitial nephritis (TIN) may be higher than currently recognised, particularly in the paediatric population.The prevalence of TINU is higher in younger age groups and there is a female preponderance although this gender effect appears weaker than suggested by early studies. Although important genetic contributions have been proposed, the small size of studies and variation between reports currently preclude identification of a 'pro-TINU' haplotype. Drugs and infections have been proposed as the leading acquired risk factors for the development of TINU; whilst the small size of TINU cohorts and issues of study design limit interpretation of many studies. Larger datasets from the renal literature suggest that the majority of these cases are precipitated by a drug induced hypersensitivity reaction; however in many ophthalmic cases no clear precipitant is identified. PMID- 28709458 TI - Markers of nitric oxide are associated with sepsis severity: an observational study. AB - BACKGROUND: Nitric oxide (NO) regulates processes involved in sepsis progression, including vascular function and pathogen defense. Direct NO measurement in patients is unfeasible because of its short half-life. Surrogate markers for NO bioavailability are substrates of NO generating synthase (NOS): L-arginine (lArg) and homoarginine (hArg) together with the inhibitory competitive substrate asymmetric dimethylarginine (ADMA). In immune cells ADMA is cleaved by dimethylarginine-dimethylaminohydrolase-2 (DDAH2). The aim of this study was to investigate whether concentrations of surrogate markers for NO bioavailability are associated with sepsis severity. METHOD: This single-center, prospective study involved 25 controls and 100 patients with surgical trauma (n = 20), sepsis (n = 63), or septic shock (n = 17) according to the Sepsis-3 definition. Plasma lArg, hArg, and ADMA concentrations were measured by mass spectrometry and peripheral blood mononuclear cells (PBMCs) were analyzed for DDAH2 expression. RESULTS: lArg concentrations did not differ between groups. Median (IQR) hArg concentrations were significantly lower in patient groups than controls, being 1.89 (1.30-2.29) MUmol/L (P < 0.01), with the greatest difference in the septic shock group, being 0.74 (0.36-1.44) MUmol/L. In contrast median ADMA concentrations were significantly higher in patient groups compared to controls, being 0.57 (0.46-0.65) MUmol/L (P < 0.01), with the highest levels in the septic shock group, being 0.89 (0.56-1.39) MUmol/L. The ratio of hArg:ADMA was inversely correlated with disease severity as determined by the Sequential Organ Failure Assessment (SOFA) score. Receiver-operating characteristic analysis for the presence or absence of septic shock revealed equally high sensitivity and specificity for the hArg:ADMA ratio compared to the SOFA score. DDAH2 expression was lower in patients than controls and lowest in the subgroup of patients with increasing SOFA. CONCLUSIONS: In patients with sepsis, plasma hArg concentrations are decreased and ADMA concentrations are increased. Both metabolites affect NO metabolism and our findings suggest reduced NO bioavailability in sepsis. In addition, reduced expression of DDAH2 in immune cells was observed and may not only contribute to blunted NO signaling but also to subsequent impaired pathogen defense. PMID- 28709459 TI - Association of lipocalin-2 level, glycemic status and obesity in type 2 diabetes mellitus. AB - BACKGROUND: Management of type 2 diabetes mellitus aims to maintain a normal glycemic status, which if not, it may lead to acute and/or chronic diabetic complications. Earlier studies found Lipocalin-2 elevated in complications associated with type 2 diabetes mellitus such as ischemic heart disease. These lipocalin-2 changes had been linked to obesity and uncontrolled diabetes. So, it could be useful to understand the effect of glycemic control and obesity on lipocalin-2. METHODS: This was a case control study. Fifty-seven patients with type 2 diabetes and 30 non-diabetic controls participated after getting a written consent. Weight (kg), height (m) and waist circumference (cm) were measured then the body mass index (kg/m2) was determined. Blood samples were collected after an overnight fasting. HbA1c, lipid profile and serum creatinine were measured using enzymatic methods. Lipocalin-2 was measured using sandwich ELISA. RESULTS: Lipocalin-2 was found significantly higher in patients with type 2 diabetes (P = 0.001). However, it had no significant correlation with any of the studied variables. Females had elevated BMI compared to males in the patients group (P < 0.001). HbA1c, serum creatinine, LDL and total cholesterol were elevated in patients with diabetes (P < 0.02). HDL was lower in the patients (P = 0.002). Significant elevation in HbA1c was found in male patients (P = 0.028) compared to female patients. Patients were further classified into controlled, uncontrolled diabetics, obese and non-obese. There was a significant elevation in waist circumference in uncontrolled diabetics compared to controlled ones. Lipocalin-2 had no significant changes between controlled and uncontrolled diabetics nor non obese and obese patients. CONCLUSION: Patients with type 2 diabetes mellitus have elevated level of serum lipocalin-2. There was no significant association found between lipocalin-2 and glycemic control nor obesity. PMID- 28709460 TI - Semi-quantitative Influenza A population averages from a multiplex respiratory viral panel (RVP): potential for reflecting target sequence changes affecting the assay. AB - BACKGROUND: Yearly influenza virus mutations potentially affect the performance of molecular assays, if nucleic acid changes involve the sequences in the assay. Because individual patient viral loads depend on variables such as duration of illness, specimen type, age, and immunosuppression, we examined seasonal population averages of positive tests to smooth inherent variability. METHODS: We studied the population seasonal averages of the semi-quantitative nAMPs for the influenza matrix and hemagglutinin genes in the GenMark (Carlsbad, CA) Respiratory Viral Panel assay between 3 institutions over 3 Influenza seasons. RESULTS: Population average nAMPs were strikingly consistent between separate institutions, but differed substantially between H3N2 and H1N1 seasons. In the 2012-2013 and 2014-2015 influenza seasons, matrix gene H3N2 nAMP averages were 50 70% less than those of the same assay in the 2013-2014 H1N1 season. Influenza strains representative of these seasons were grown in tissue culture and when the supernatant virus was adjusted to the same copy number using a TaqMan assay, the same relative differences were reproduced in the RVP assay. Because the sequences for the PCR and PCR product detection in the GenMark assay are proprietary, the manufacturer provided single stranded DNA matching the capture probe for the representative H3N2 (3 mismatches) and H1N1 strains (2 different mismatches). Equimolar concentrations of these synthetic DNA sequences gave average nAMP values that closely correlated with the average nAMPS of the representative strains and their respective seasonal averages. CONCLUSIONS: Seasonal averages of semi-quantitative data may provide a means to follow assay performance as a reflection of the effects of molecular drift. PMID- 28709461 TI - Do public nursing home care providers deliver higher quality than private providers? Evidence from Sweden. AB - BACKGROUND: Swedish nursing home care has undergone a transformation, where the previous virtual public monopoly on providing such services has been replaced by a system of mixed provision. This has led to a rapidly growing share of private actors, the majority of which are large, for-profit firms. In the wake of this development, concerns have been voiced regarding the implications for care quality. In this article, we investigate the relationship between ownership and care quality in nursing homes for the elderly by comparing quality levels between public, for-profit, and non-profit nursing home care providers. We also look at a special category of for-profit providers; private equity companies. METHODS: The source of data is a national survey conducted by the Swedish National Board of Health and Welfare in 2011 at 2710 nursing homes. Data from 14 quality indicators are analyzed, including structure and process measures such as staff levels, staff competence, resident participation, and screening for pressure ulcers, nutrition status, and risk of falling. The main statistical method employed is multiple OLS regression analysis. We differentiate in the analysis between structural and processual quality measures. RESULTS: The results indicate that public nursing homes have higher quality than privately operated homes with regard to two structural quality measures: staffing levels and individual accommodation. Privately operated nursing homes, on the other hand, tend to score higher on process-based quality indicators such as medication review and screening for falls and malnutrition. No significant differences were found between different ownership categories of privately operated nursing homes. CONCLUSIONS: Ownership does appear to be related to quality outcomes in Swedish nursing home care, but the results are mixed and inconclusive. That staffing levels, which has been regarded as a key quality indicator in previous research, are higher in publicly operated homes than private is consistent with earlier findings. The fact that privately operated homes, including those operated by for profit companies, had higher processual quality is more unexpected, given previous research. Finally, no significant quality differences were found between private ownership types, i.e. for-profit, non-profit, and private equity companies, which indicates that profit motives are less important for determining quality in Swedish nursing home care than in other countries where similar studies have been carried out. PMID- 28709462 TI - Enhancing medical students' reflectivity in mentoring groups for professional development - a qualitative analysis. AB - BACKGROUND: Professional competence is important in delivering high quality patient care, and it can be enhanced by reflection and reflective discourse e.g. in mentoring groups. However, students are often reluctant though to engage in this discourse. A group mentoring program involving all preclinical students as well as faculty members and co-mentoring clinical students was initiated at Witten-Herdecke University. This study explores both the attitudes of those students towards such a program and factors that might hinder or enhance how students engage in reflective discourse. METHODS: A qualitative design was applied using semi-structured focus group interviews with preclinical students and semi-structured individual interviews with mentors and co-mentors. The interview data were analyzed using thematic content analysis. RESULTS: Students' attitudes towards reflective discourse on professional challenges were diverse. Some students valued the new program and named positive outcomes regarding several features of professional development. Enriching experiences were described. Others expressed aversive attitudes. Three reasons for these were given: unclear goals and benefits, interpersonal problems within the groups hindering development and intrapersonal issues such as insecurity and traditional views of medical education. Participants mentioned several program setup factors that could enhance how students engage in such groups: explaining the program thoroughly, setting expectations and integrating the reflective discourse in a meaningful way into the curriculum, obliging participation without coercion, developing a sense of security, trust and interest in each other within the groups, randomizing group composition and facilitating group moderators as positive peer and faculty role models and as learning group members. CONCLUSIONS: A well-designed and empathetic setup of group mentoring programs can help raise openness towards engaging in meaningful reflective discourse. Reflection on and communication of professional challenges can, in turn, improve professional development, which is essential for high quality patient care. PMID- 28709463 TI - Clonal competition in BcrAbl-driven leukemia: how transplantations can accelerate clonal conversion. AB - BACKGROUND: Clonal competition in cancer describes the process in which the progeny of a cell clone supersedes or succumbs to other competing clones due to differences in their functional characteristics, mostly based on subsequently acquired mutations. Even though the patterns of those mutations are well explored in many tumors, the dynamical process of clonal selection is underexposed. METHODS: We studied the dynamics of clonal competition in a BcrAbl-induced leukemia using a gamma-retroviral vector library encoding the oncogene in conjunction with genetic barcodes. To this end, we studied the growth dynamics of transduced cells on the clonal level both in vitro and in vivo in transplanted mice. RESULTS: While we detected moderate changes in clonal abundancies in vitro, we observed monoclonal leukemias in 6/30 mice after transplantation, which intriguingly were caused by only two different BcrAbl clones. To analyze the success of these clones, we applied a mathematical model of hematopoietic tissue maintenance, which indicated that a differential engraftment capacity of these two dominant clones provides a possible explanation of our observations. These findings were further supported by additional transplantation experiments and increased BcrAbl transcript levels in both clones. CONCLUSION: Our findings show that clonal competition is not an absolute process based on mutations, but highly dependent on selection mechanisms in a given environmental context. PMID- 28709464 TI - Developing mentorship in a resource-limited context: a qualitative research study of the experiences and perceptions of the makerere university student and faculty mentorship programme. AB - BACKGROUND: The aim of mentorship is to build the mentees capacity, enhance their skills and improve their ability to produce desired outcomes. However, the mentoring relationship is vulnerable to a number of challenges that may undermine its effectiveness and sustainability. We aimed to explore the experiences and perceptions of student and junior faculty mentees and senior faculty mentors at the Makerere University College of Health Sciences and identify the key factors defined by mentees and mentors as necessary for a successful mentorship program. METHODS: A qualitative design involving focus group discussions (FGDs) and key informant interviews (KII) was used. A total of eight KII and four FGDs were conducted, audio recorded and transcribed verbatim. Open coding of the transcripts was performed, and major themes were identified through multiple readings based on thematic analysis. RESULTS: Six key themes were shared by the mentees and mentors including: 1) defining the role of the mentor; 2) desired characteristics of a mentor and a mentoring relationship, with an emphasis on mutual trust and respect; 3) overlapping roles of mentors and supervisors; 4) issues with the process for identifying mentors, including the benefits and drawbacks of the mentee selecting mentor vs. being assigned a mentor; 5) current barriers to mentoring, including lack of knowledge about current program, lack of formal structure, uncertainly about who should initiate relationship, and unclear roles and expectations and 6) recommendations for the future development of mentoring programme, including the need for a formalized programme, and training adapted to the local context. CONCLUSIONS: The mentees and mentors described the role of the mentor and desired characteristics of mentors and a mentoring relationship similarly. Most concerns about mentoring occurred when current mentoring programmes and practices were not well aligned with these desired characteristics. Recommendations for future development of mentoring included greater formalization of mentoring with mentoring programmes based on shared expectations and adapted to the local context. PMID- 28709465 TI - Subclinical focal Cholangitis mimicking liver metastasis in asymptomatic patients with history of pancreatic Ductal Adenocarcinoma and Biliary tree intervention. AB - BACKGROUND: Cholangitis is an inflammatory process of the biliary tract with a wide range of clinical manifestations and it is not always considered in the differential diagnosis in asymptomatic patients. To the best of our knowledge there is no previous report in the English literature of focal cholangitis manifesting exclusively as liver parenchymal changes mimicking liver metastasis in asymptomatic patients with pancreatic ductal adenocarcinoma (PDAC) and history of manipulation of the biliary tree. The purpose of this article is to present six cases of subclinical focal cholangitis mimicking liver metastasis in asymptomatic patients with history of PDAC and biliary tree intervention. CASE PRESENTATION: There are six cases with new hepatic lesions detected on follow-up scans in asymptomatic patients with history of PDAC and manipulation of biliary tree. Overall seven lesions were detected, all of them were on the liver periphery, five were hypovascular and two were hypervascular. None of those patients had elevation of CA 19.9 compared with the previous exams. The three patients that had magnetic resonance imaging presented restriction on diffusion weighted imaging and high signal intensity on T2-weighted image. Two patients underwent liver biopsy, which showed only inflammatory changes. All patients were treated with antibiotics and underwent imaging follow-up, which demonstrated resolution of the lesions. None of the patients showed imaging or clinical signs of disease progression during this interval. CONCLUSION: Radiologists and oncologists need to be aware of the possibility of focal cholangitis causing hepatic lesions mimicking neoplasia in patients with history of biliary tree intervention, even in the absence of clinical symptoms. PMID- 28709466 TI - Effects of inhaled hypertonic (7%) saline on lung function test in preschool children with cystic fibrosis: results of a crossover, randomized clinical trial. AB - BACKGROUND: This crossover, randomized, double-blind study (conducted over a 32 week period) was performed to determine, in clinically stable Cystic fibrosis (CF) preschool children: the effects of 7% inhaled hypertonic saline on spirometry and interrupter resistance technique (Rint), and the possible side effects. METHODS: Twelve CF children (6M, mean age +/- SD: 5.7 +/- 0.8 yrs) were enrolled and randomly assigned to receive hypertonic saline (HS-4 ml 7% sodium chloride), or normal saline (NS-0.9% sodium chloride) twice a day. After a 16 weeks period, therapy was exchanged to allow all the patients enrolled in the study to carry out both treatments. Monitoring visits, spirometry (COSMED Quark PFT4 ergo) and Rint were scheduled at 0,4,16,20,32 weeks. At T0, spirometric measurements and Rint were performed immediately before and 30 min after the inhalation therapy. Salbutamol (400 mcg) was administered before the drug at each visit. RESULTS: After a 16-weeks treatment with HS an improvement of FVC (p = 0.02) and a favorable trend of FEV1 were registered. A worsening of FEV1 (p < 0.0001) and of FEF25-75 (p = 0.019) were found in NS group. No differences were found in expiratory and inspiratory Rint in both groups. No serious adverse events occurred. CONCLUSIONS: Seven percent hypertonic saline therapy proved to be a useful and safe treatment in young CF children with clinically stable conditions. TRIAL REGISTRATION: ISRCTN12345678 . PMID- 28709467 TI - Amitriptyline-induced ventricular tachycardia: a case report. AB - BACKGROUND: In Bangladesh, each emergency physician faces amitriptyline overdose nearly a day. An acute cardiovascular complication, one of the worst complications is mainly responsible for the mortality in tricyclic overdose. Recently, we managed ventricular tachycardia in a young female presented with an impaired consciousness 10 h after intentionally ingesting 2500 mg amitriptyline. Here, we report it, discuss how the electrocardiography is vital to acknowledge and predict it and its' complications and also the recent update of the management of it. CASE PRESENTATION: A young married Bangladeshi-Bengali girl, 25 year-old, having a history of disharmony with her husband, came with an impaired consciousness after intentionally ingesting 2500 mg amitriptyline about 10 h before arrival. There was blood pressure 140/80 mmHg, heart rate 140 beats-per min, temperature 103 degrees F, Glasgow coma scale 10/15, wide complex tachycardia with QRS duration of 178 ms in electrocardiography, blood pH 7.36. Initially, treated with 100 ml 8.4% sodium bicarbonate. After that, QRS duration came to 100 ms in electrocardiography within 10 min of infusion. To maintain the pH 7.50-7.55 over the next 24 h, the infusion of 8.4% sodium bicarbonate consisting of 125 ml dissolved in 375 ml normal saline was started and titrated according to the arterial blood gas analysis. Hence, a total dose of 600 mmol sodium bicarbonate was given over next 24 h. In addition to this, gave a 500 ml intravenous lipid emulsion over 2 h after 24 h of admission as she did not regain her consciousness completely. Afterward, she became conscious, though, in electrocardiography, ST/T wave abnormality persisted. So that, we tapered sodium bicarbonate infusion slowly and stopped it later. At the time of discharge, she was by heart rate 124/min, QRS duration 90 ms in electrocardiogram along with other normal vital signs. CONCLUSION: Diagnosis of amitriptyline-induced ventricular tachycardia is difficult when there is no history of an overdose obtained. Nevertheless, it should be performed in the clinical background and classic electrocardiographic changes and wise utilization of sodium bicarbonate, intravenous lipid emulsion, and anti-arrhythmic drugs may save a life. PMID- 28709468 TI - IL-32gamma promotes the healing of murine cutaneous lesions caused by Leishmania braziliensis infection in contrast to Leishmania amazonensis. AB - BACKGROUND: Interleukin 32 (IL-32) is a pro-inflammatory cytokine induced in patients with American tegumentary leishmaniasis (ATL) caused by Leishmania braziliensis. Here, we investigated whether IL-32 is also expressed in patient lesions caused by L. amazonensis. In addition, we evaluated experimental L. amazonensis and L. braziliensis infections in C57BL/6 transgenic mice for human IL-32gamma (IL-32gammaTg) in comparison with wild-type (WT) mice that do not express the IL-32 gene. RESULTS: Human cutaneous lesions caused by L. amazonensis express higher levels of IL-32 than healthy control skin. In mice, the presence of IL-32gamma promoted the control of cutaneous lesions caused by L. braziliensis, but not lesions caused by L. amazonensis in an ear dermis infection model. In addition, IL-32gammaTg mice displayed less tissue parasitism and inflammation in IL-32gammaTg than WT mice during the healing phase of L. braziliensis infection. Production of antigen-specific pro-inflammatory cytokines was higher in IL-32gammaTg mice than in WT mice during L. braziliensis infection but not during L. amazonensis infection. CONCLUSIONS: Human cutaneous lesions caused by L. amazonensis express high levels of IL-32. In mice, the presence of IL-32gamma contributes to the lesion healing caused by L. braziliensis but not by L. amazonensis. Data suggest that despite the ability for both species to induce IL-32 in humans, the connections between this cytokine and other immune players induced by related species of parasites can lead to distinct outcomes of the murine infections. PMID- 28709469 TI - Prevalence and sociodemographic patterns of physical activity among Bangladeshi young adults. AB - BACKGROUND: Physical activity offers physical and psychosocial health benefits that are important during young adulthood and later in life. However, little is known about the physical activity of young adults in low- and middle-income countries. The purpose of this study was to estimate the participation of physical activity in Bangladeshi young adults and to assess differences by gender, age and family income. METHODS: This cross-sectional study with a self administered survey used a convenience sample of 573 young adults aged 18-24 years from six purposively selected universities in Dhaka City, Bangladesh. Data were collected during September-November 2015. Medians and their interquartile ranges of weekly time spent in total physical activity, and in different domains of physical activity, were computed. Non-parametric equality of medians test was used to examine gender differences in the median values. Chi-square test and Fisher's exact test were used to examine gender differences in the prevalence of meeting physical activity recommendations and frequency of participation in different leisure-time physical activities, and differences in meeting the activity recommendations by age and family income. RESULTS: Seventeen percent of the participants were meeting moderate-to-vigorous physical activity (MVPA) recommendations with a significantly higher proportion of males than females (27 vs. 6%, p < .0001). Median duration of MVPA was significantly higher (p < .0001) for males [120 min/week (80, 190)] than females [90 min/week (50, 120)]. Jogging/running was the most commonly reported leisure-time physical activity, with 20% of males and 12% of females doing this at least once a week. Age and family income were not significantly associated with meeting MVPA recommendations. CONCLUSIONS: Four out of five young adults in Dhaka City did not meet the physical activity recommendations. Additional population-based studies, including regional and metropolitan areas, and using objective measurement, are needed to understand the physical activity patterns of Bangladeshi young adults. PMID- 28709470 TI - The effects of Cognitive Bias Modification training and oxytocin administration on trust in maternal support: study protocol for a randomized controlled trial. AB - BACKGROUND: Lack of trust in parental support is a transdiagnostic risk factor for the development of psychological problems throughout the lifespan. Research suggests that children's cognitive attachment representations and related information processing biases could be an important target for interventions aiming to build trust in the parent-child relationship. A paradigm that can alter these biases and increase trust is that of Cognitive Bias Modification (CBM), during which a target processing bias is systematically trained. Trust-related CBM training effects could possibly be enhanced by oxytocin, a neuropeptide that has been proposed to play an important role in social information processing and social relationships. The present article describes the study protocol for a double-blind randomized controlled trial (RCT) aimed at testing the individual and combined effects of CBM training and oxytocin administration on trust in maternal support. METHODS/DESIGN: One hundred children (aged 8-12 years) are randomly assigned to one of four intervention conditions. Participants inhale a nasal spray that either contains oxytocin (OT) or a placebo. Additionally, they receive either a CBM training aimed at positively modifying trust-related information processing bias or a neutral placebo training aimed to have no trust related effects. Main and interaction effects of the interventions are assessed on three levels of trust-related outcome measures: trust-related interpretation bias; self-reported trust; and mother-child interactional behavior. Importantly, side-effects of a single administration of OT in middle childhood are monitored closely to provide further information on the safety of OT administration in this age group. DISCUSSION: The present RCT is the first study to combine CBM training with oxytocin to test for individual and combined effects on trust in mother. If effective, CBM training and oxytocin could be easily applicable and nonintrusive additions to interventions that target trust in the context of the parent-child relationship. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT02737254 . Registered on 23 March 2016. PMID- 28709471 TI - Acceptability and design preferences of supervised injection services among people who inject drugs in a mid-sized Canadian City. AB - BACKGROUND: Supervised injection services (SIS) have been shown to reduce the public- and individual-level harms associated with injection drug use. While SIS feasibility research has been conducted in large urban centres, little is known about the acceptability of these services among people who inject drugs (PWID) in mid-sized cities. We assessed the prevalence and correlates of willingness to use SIS as well as design and operational preferences among PWID in London, Canada. METHODS: Between March and April 2016, peer research associates administered a cross-sectional survey to PWID in London. Socio-demographic characteristics, drug use patterns, and behaviours associated with willingness to use SIS were estimated using bivariable and multivariable logistic regression models. Chi square tests were used to compare characteristics with expected frequency of SIS use among those willing to use SIS. Design and operational preferences are also described. RESULTS: Of 197 PWID included in this analysis (median age, 39; interquartile range (IQR), 33-50; 38% female), 170 (86%) reported willingness to use SIS. In multivariable analyses, being female (adjusted odds ratio (AOR) 0.29; 95% confidence interval (CI) 0.11-0.75) was negatively associated with willingness to use, while public injecting in the last 6 months (AOR 2.76; 95% CI 1.00-7.62) was positively associated with willingness to use. Participants living in unstable housing, those injecting in public, and those injecting opioids and crystal methamphetamine daily reported higher expected frequency of SIS use (p < 0.05). A majority preferred private cubicles for injecting spaces and daytime operational hours, while just under half preferred PWID involved in service operations. CONCLUSIONS: High levels of willingness to use SIS were found among PWID in this setting, suggesting that these services may play a role in addressing the harms associated with injection drug use. To maximize the uptake of SIS, programme planners and policy makers should consider the effects of gender and views of PWID regarding SIS design and operational preferences. PMID- 28709473 TI - Amita N. Vyas, PhD, MHS, Named Editor-in-Chief of Women's Health Issues. PMID- 28709474 TI - Foreword. PMID- 28709472 TI - Potential and active functions in the gut microbiota of a healthy human cohort. AB - BACKGROUND: The study of the gut microbiota (GM) is rapidly moving towards its functional characterization by means of shotgun meta-omics. In this context, there is still no consensus on which microbial functions are consistently and constitutively expressed in the human gut in physiological conditions. Here, we selected a cohort of 15 healthy subjects from a native and highly monitored Sardinian population and analyzed their GMs using shotgun metaproteomics, with the aim of investigating GM functions actually expressed in a healthy human population. In addition, shotgun metagenomics was employed to reveal GM functional potential and to compare metagenome and metaproteome profiles in a combined taxonomic and functional fashion. RESULTS: Metagenomic and metaproteomic data concerning the taxonomic structure of the GM under study were globally comparable. On the contrary, a considerable divergence between genetic potential and functional activity of the human healthy GM was observed, with the metaproteome displaying a higher plasticity, compared to the lower inter individual variability of metagenome profiles. The taxon-specific contribution to functional activities and metabolic tasks was also examined, giving insights into the peculiar role of several GM members in carbohydrate metabolism (including polysaccharide degradation, glycan transport, glycolysis, and short-chain fatty acid production). Noteworthy, Firmicutes-driven butyrogenesis (mainly due to Faecalibacterium spp.) was shown to be the metabolic activity with the highest expression rate and the lowest inter-individual variability in the study cohort, in line with the previously reported importance of the biosynthesis of this microbial product for the gut homeostasis. CONCLUSIONS: Our results provide detailed and taxon-specific information regarding functions and pathways actively working in a healthy GM. The reported discrepancy between expressed functions and functional potential suggests that caution should be used before drawing functional conclusions from metagenomic data, further supporting metaproteomics as a fundamental approach to characterize the human GM metabolic functions and activities. PMID- 28709475 TI - Evolution of American Academic Medicine: A View of Its Contributions to World Medicine and Reflections Influenced by Personal Role Models. AB - The changes in American academic medicine in the last 6 decades has been a success. During these years, I participated in this development through patients care, research, editorship of major Journals and as a member of governing boards of several professional organizations. This discussion will describe some of the developments of medicine and will recount my own professional career and my mentors who help me to achieve my goals. PMID- 28709476 TI - Erratum to: "Perioperative fluid therapy recommendations for major abdominal surgery. Via RICA recommendations revisited. Part I: Physiological background" [Rev Esp Anestesiol Reanim. 2017;64(6):328-338]. PMID- 28709477 TI - Erratum to: "Fluid therapy recommendations for major abdominal surgery. Via RICA recommendations revisited. Part II: Goal directed hemodynamic therapy. Rationale for optimising intravascular volume" [Rev Esp Anestesiol Reanim. 2017;64(6):339 347]. PMID- 28709478 TI - Erratum to: "Fluid therapy recommendations for major abdominal surgery. Via RICA recommendations revisited. Part III: Goal directed hemodynamic therapy. Rationale for maintaining vascular tone and contractility" [Rev Esp Anestesiol Reanim. 2017;64(6):348-359]. PMID- 28709479 TI - Uncovering the secrets of protein interactions with the DNA enforcing genomic stability. PMID- 28709480 TI - TB treatment options: Beyond DOTS. PMID- 28709481 TI - Extensively Drug-resistant Tuberculosis (XDR-TB): A daunting challenge to the current End TB Strategy and policy recommendations. AB - Extensively Drug-resistant Tuberculosis (XDR-TB) has emerged as one of the most formidable challenges to the End TB Strategy that has targeted a 95% reduction in TB deaths and 90% reduction in cases by 2035. Globally, there were an estimated 55,100 new XDR-TB cases in 2015 in 117 countries. However, only one in 30 XDR-TB cases had been reported so far. Drug susceptibility test (DST) is the mainstay for diagnosing XDR-TB, but the lack of laboratory facilities in the resource limited endemic countries limit its uses. A few new drugs including bedaquiline and delamanid, have the potential to improve the efficiency of XDR-TB treatment, but the drugs have been included in 39 countries only. The costs of XDR-TB treatment are several folds higher than that of the MDR-TB. Despite the financing from the donors, there is an urgent need to fill the current funding gap of US$ 2 billion to ensure effective treatment and robust surveillance. In the review article we have addressed current update on XDR-TB, including surveillance, diagnosis and the interventions needed to treat and limit its spread, emphasis on extensive financial support for implementing of current recommendations to meet the goals of End TB Strategy. PMID- 28709482 TI - Parotid tuberculosis. AB - Parotid gland tuberculosis is an uncommon manifestation of one of the most common infections even in the developing countries, caused by Mycobacterium tuberculosis. There are no specific symptoms or clinical signs of parotid tuberculosis, and such an infection most commonly presents as a slow growing painless parotid mass. Because of its rarity, tuberculosis of parotid gland is often mistaken for a malignant growth, and it most commonly gets diagnosed after superficial protidectomy. Complete cure is possible with standard antituberculous therapy. Most of our knowledge about this rare entity comes from case reports and short case series. The authors encountered three cases of parotid tuberculosis in the last 10 years. This article aims at presenting a comprehensive review of all the available literature and thus providing detailed information and an update on parotid tuberculosis and our experience of three cases. PMID- 28709483 TI - What remains to surgeons in the management of abdominal tuberculosis? A 10 years experience in an endemic area. AB - BACKGROUND: Tuberculosis (TB) is a common endemic disease in Tunisia. Abdominal location is rare. Early diagnosis of abdominal TB remains difficult due to its non-specific clinical presentations. The aim of our study is to highlight the characteristics of the different presentations, to characterize tools contributing to a positive preoperative diagnosis, and finally to assess the role of surgery in the management of this entity. MATERIALS AND METHODS: A retrospective review from 2005 to 2015 identified 90 cases of confirmed abdominal TB managed in the Department of General Surgery of the Habib Thameur Hospital. The diagnosis was established by histopathology examination for all cases. This study was approved by the ethical committee. RESULTS: The mean age of the patient was 44.13 years with a sex ratio (M/F) of 0.34. We collected 56 cases of peritoneal TB, 12 cases of abdominal lymph node TB, 10 cases of intestinal TB, four cases of hepatic TB, and two cases of gallbladder's TB. For six patients, an association of many localizations was noted. The diagnosis was suspected on clinical, biological, and morphological arguments, but the confirmation was always made by surgical exploration and pathological examination of removed specimens. Surgical management was urgent in complicated cases (13.3%). Laparoscopy was performed in 71 cases (78.9%). Laparoscopic features of peritoneal TB were specific and always confirmed by histological examination. CONCLUSION: Despite the wide range of examination available for the preoperative exploration of abdominal TB, diagnosis is usually late and difficult. TB is a medical condition. However, surgical exploration is frequently needed in the management. PMID- 28709484 TI - Concomitant female genital tuberculosis and endometriosis. AB - AIMS: To demonstrate an association between female genital tuberculosis (FGTB) and endometriosis. METHODS: A total of 16 women who underwent laparoscopy (12 cases) or laparotomy (4 cases) and were found to have female genital tuberculosis and endometriosis were enrolled in this retrospective study. RESULTS: The mean age and parity were 28.2 years and 0.2, respectively. Past history of tuberculosis was present in 75% of the women (pulmonary in 50%). Menstrual dysfunction (especially oligomenorrhoea and dysmenorrhoea), constitutional symptoms, infertility, abdominal pain and lump were the main complaints. Diagnosis of FGTB was made by positive acid-fast bacilli (AFB) on microscopy, culture of endometrial aspirate, positive polymerase chain reaction (PCR), histopathological finding of epitheliod granuloma or findings of TB on laparoscopy or laparotomy. Diagnosis of endometriosis was made by laparoscopy or laparotomy. Pelvic adhesions were seen in all women, whereas frozen pelvis was seen in 7 (43.7%) women. Surgery was performed, which was laparoscopic adhesiolysis in 12 (75%), drainage of endometrioma in 12 (75%), cystectomy in 8 (50%), and total abdominal hysterectomy with bilateral salpingo-oophorectomy in 4 (25%) cases. With more then one type of (surgery in many cases). DISCUSSION: Female genital tuberculosis and endometriosis may have similar manifestations and can co-exist. PMID- 28709485 TI - Biofilm colonization of Mycobacterium abscessus: New threat in hospital-acquired surgical site infection. AB - INTRODUCTION: Rapidly growing non-tuberculous mycobacteria (NTM) are hazardous cause of post-operative soft tissue infection leading to nosocomial outbreaks following various surgical procedures, especially laparoscopic surgeries using heat sensitive, non-autoclavable surgical instruments. METHODOLOGY: Surgery department of our hospital noticed increase in rate of post-laparoscopic abdominal port site infection (PSI) and informed the Microbiology Department. A prospective investigational study of defined cases with the aim of source tracing and formulation of infection control measures was initiated. Pus or wound scrapings were collected and processed for aerobic, anaerobic bacteria and Mycobacterium, both by staining and culture. Environmental samples were collected from laparoscopic instruments, and different parts of operation theatre (OT). Mycobacterial isolates were speciated by line probe assay. All the cases were treated with clarithromycin and ofloxacin+/-amikacin. RESULTS: Among 15 cases of PSI, 11 patients had undergone laparoscopic cholecystectomy, 3 had laparoscopic mesh hernioplasty and one had laparoscopic orchidopexy. Of the 13 pus/discharge specimens examined, 11 revealed growth of NTM. All the isolates were identified as Mycobacterium abscessus by line probe assay. Scraping of biofilm from the disinfectant tray also produced growth of the same organism. Plastic trays used for disinfectants were replaced with metal trays and instructed to do mechanical scrubbing before autoclaving at regular interval. No similar PSI cases were notified after those measures were taken, till date. CONCLUSIONS: This study has shown the need of culture and identification of pathogens causing persistent post surgical wound infections and illuminated importance of rapid source tracing in resource constraint situation which could control outbreak. PMID- 28709486 TI - Diagnosis of tuberculous meningitis: Current scenario from a Tertiary Neurocare Centre in India. AB - BACKGROUND: Tuberculous meningitis (TBM) is a condition that is caused by Mycobacterium tuberculosis complex and is difficult to diagnose due to the nonspecificity of the presentations. The study analyzed the different modes of diagnosis available in a developing country set up over a period of five years to understand the diagnostic values of the current conventional and automated methods of diagnosis of TBM among the patients suspected with chronic meningitis. METHODS: A total of 10,281 cerebrospinal fluid samples (CSF) were collected from suspected chronic meningitis patients, of which 790 samples were from individuals who had clinically suspected TBM. The samples were subjected to CSF cytology and staining, culturing, immunological tests, molecular techniques, and methods for detection of drug resistance. RESULTS: The TBM patients were predominantly male, with a mean age of 21-40 years. CSF pleocytosis and lymphocytic predominance were noted. Culture had 40.13% positivity among clinically suspected TBM patients. The multidrug-resistant M. tuberculosis (MDR-TB) constituted 3.14% of the total clinical isolates. With IS6110 PCR, a specificity of 92.86% and sensitivity of 100% are seen with an assay threshold of 30pg/ml. Line probe assay (LPA) using culture isolates had a sensitivity of 97.67% and a specificity of 100%. Direct CSF LPA showed a sensitivity of 96.15% and a specificity of 100%. CONCLUSIONS: A combination of techniques that involved culture, cytology, and DNA amplification methods was found to be promising in specific, accurate, and rapid detection of M. tuberculosis in the CSF samples from patients. PMID- 28709487 TI - Factors affecting applicability of "home-based interventional model" for active case finding among household contacts of index cases of pulmonary tuberculosis in Kashmir. AB - BACKGROUND: There are various biological, behavioural and social determinants associated with the epidemiology of pulmonary tuberculosis (P-TB) which have been extensively described in literature. Present study was conducted to know the influence of such factors on the "home-based interventional model" for active case finding among household contacts of index P-TB cases. METHODS: In a quasi randomized controlled interventional study, the "home-based interventional model" for active case finding was applied to index P-TB cases and their household contacts of interventional group of study subjects. Study was conducted from January 2014 to June 2015 for evaluation of the model in comparison to the existing usual practice of contact tracing. Baseline data regarding factors associated with epidemiology of P-TB likely to influence effectiveness of intervention were collected, collated and analysed. RESULTS: The overall acceptance of intervention was 70.74% which was statically significantly influenced by gender (p<0.0001), age group (p=0.0006), education (p<0.0001), occupation (p<0.0001) and relationship of household contacts with index case (p<0.0001). Total 27 (4.51%) cases were detected among contacts. Out of personal and family level characteristics "relationship with index case" (p=0.0418) and "overcrowding in house" (p=0.0017) were found to statistically significantly influencing the effectiveness of interventional model. The prevalent risk factors for TB among contacts, level of exposer of household contacts to index cases, grade sputum positivity and type of index case were not found statistically significantly influencing the yield of interventional model. CONCLUSION: Factors/determinants influencing the applicability of interventional model for active case finding among household contacts were identified and their impact on acceptance and yield of intervention was assessed. PMID- 28709488 TI - Endobronchial ultrasound experience in a high tuberculosis prevalence setting. AB - BACKGROUND: Most of the published endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) data are from the western countries, establishing the role of EBUS-TBNA in the diagnosis and staging of lung cancer. The etiology of mediastinal lymphadenopathy may be different in an ethnic group with a high prevalence of tuberculosis (TB). OBJECTIVE: To assess the etiology of mediastinal adenopathy in a high TB prevalence setting and to determine the performance of various tests in the diagnosis of tuberculous mediastinal lymphadenitis. METHODS: Retrospective analysis of bronchoscopic data of patients who underwent endobronchial ultrasound (EBUS) in a tertiary care center in India. RESULTS: Out of 138 patients who underwent EBUS, 63 (46%) had granulomatous disease. Of the 35 patients with a diagnosis of TB, in 10 (29%), microbiology of EBUS specimens was diagnostic and in 3 (9%), this was the sole diagnostic feature. In 5 (14%) mycobacterial cultures were positive, in 6 (17%) GeneXpert for Mycobacterium tuberculosis/rifampicin resistance (Xpert MTB/RIF) was positive, and in 3 (9%) acid fast smears were positive. CONCLUSION: In high TB prevalence countries, EBUS diagnoses a higher number of granulomatous than malignant diseases. EBUS specimen should, therefore, be subjected also to mycobacterial smear, culture, and Xpert MTB/RIF for optimal results. PMID- 28709489 TI - The success and safety profile of sputum induction in patients with chronic obstructive pulmonary disease: An Indian experience. AB - BACKGROUND: Neutrophilic inflammation is common in chronic obstructive pulmonary disease while Asthma COPD overlap syndrome has eosinophilic predominance. Identifying the type of inflammation will aid in better management of COPD, but published studies show that induced sputum examination is more frequently used in asthma than COPD, with safety being the limiting factor. We aimed to determine the success and safety of sputum induction (SI) in COPD patients. METHODS: 116 stable COPD patients underwent SI. Success was defined as adequate sputum sample resulting in a cytospin sufficient to assess differential count while safety by the fall in FEV1. RESULTS: The mean (SD) FEV1% predicted post bronchodilator was 58.8 (17.8) and 59 (51.8%) patients had moderate COPD. Success was 98.28%. The procedure was safe with overall fall in FEV1 of 11.1% (5.1, 15.2). >=20% fall was noted in 13 (11.4%) patients, 10-20% in 24 (21.0%) patients, and less than 10% in 29 (25.4%) patients while 48 (42.1%) had no fall. There was an inverse correlation between reversibility in FEV1 and percentage fall in FEV1; r=-0.437 and p=0.001. Stepwise multivariate linear regression showed reversibility as an independent predictor of fall in FEV1; R2=0.137. CONCLUSIONS: Sputum induction is successful and safe in COPD. Even a fall in FEV1>20% is reversible. PMID- 28709490 TI - Serum levels of soluble urokinase plasminogen activator receptor (suPAR) as a marker of tuberculosis treatment efficacy. AB - BACKGROUND: Upon diagnosis, Pulmonary Tuberculosis patients are treated for TB for a period of 6-9 months. At present, there exists very little indication of the efficacy of the particular treatment. A few previous studies have shown that soluble urokinase plasminogen activator receptor (SuPAR) may be used as treatment efficacy marker. SuPAR is a cellular receptor for serine protease urokinase plasminogen activator (uPA). Bacterial endotoxins and cytokines of the innate immune system stimulate the secretion of uPA in monocytes & neutrophils. Serum SuPAR levels are elevated when TB is active and decrease when the patient responds positively to therapy. OBJECTIVE: To investigate if SuPAR levels decline upon treatment and whether serum SuPAR levels may be used as a biomarker to monitor Tuberculosis treatment efficacy. DESIGN: The study was conducted in the department of Biochemistry at VIMS, Ballari, Karnataka. The study subjects were randomly selected from RNTCP centre of VIMS. CONTROLS: Twelve tuberculin skin test positive healthy controls from the community. CASES: A total of 60 cases were enrolled for the study and were divided into 3 groups with 20 in each, based on the duration of TB treatment. Group I (n=20): Newly diagnosed pulmonary TB patients before initiation of DOTS. Group II (n=20): TB patients, 2-3 months after initiation of DOTS. Group III (n=20): TB patients who had completed 6 months of DOTS. METHODOLOGY: Hb%, TC, DC(P)%, DC(L)% & ESR were measured by standard procedures. Serum suPAR was measured by the quantitative sandwich enzyme immunoassay technique using the R & D systems Human uPAR Quantikine ELISA Kit. RESULTS: The suPAR levels were elevated before treatment (3.27+2.08ng/ml) and dropped significantly in groups after 2 months of initiation of therapy (2.18+1.17ng/ml) and after completion of 6 months of treatment (1.50+0.93ng/ml). CONCLUSION: The decrease in suPAR levels in PTB patients with treatment is a manifestation of treatment efficacy. Hence suPAR levels can be used to guide clinical decisions in TB management. PMID- 28709491 TI - Band pattern analysis of mutations in rifampicin resistance strain of Mycobacterium tuberculosis by Line Probe assay in patients from Delhi, India. AB - BACKGROUND: The GenoType MTBDRplus, a commercial Line Probe Assay (LPA) kit from Hain Lifescience, Germany, is endorsed by India's RNTCP Program for diagnosis of DRTB cases among smear-positive sputum samples. Although the LPA has been studied in several laboratories, there is a wide variation in existing M. tuberculosis strains across the globe, and false results can occur due to the presence of unique genetic mutations in different settings. AIM AND OBJECTIVE: An attempt was made to carry out band pattern analysis using LPA and also to observe uncommon mutations in MDR strains. MATERIALS AND METHODS: Sputum samples were collected from MDR suspects and transported to intermediate reference laboratory (IRL) at New Delhi Tuberculosis Centre in Delhi. Sputum decontamination, DNA extraction, amplification, hybridization, and band pattern analysis of Line Probe assay strips was performed as per manufacturer's instructions. RESULTS: Among the 3000 samples with interpretable LPA strips, rifampicin drug resistance with or without isoniazid was observed in 600 samples. The most common mutation detected by LPA in the rpoB gene was Ser516Leu (29.0%). Novel mutations reported in this study include mutation from CAG (Gin) to CAT (His) at codon 517, AGC (Ser)-AGG (Arg) at codon 512, ACA (Thr) to GCA (Ala) at codon 526, TTG (Leu)-CTG (Leu)s at codon 524. CONCLUSION: High frequencies of uncommon mutations in rpoB gene by LPA were observed, highlighting possibility of those in-silico detected mutations that may not impart phenotypic resistance further. PMID- 28709492 TI - Diagnosis at a glance of radiological imaging. AB - A 14-year-old boy was referred to our outpatient department with complaints of dry cough, high-grade fever for 20 days and chest X-ray (CXR) opacity. The clinical examination was normal. His CXR showed a right mid-zone lobulated, homogenous opacity. Computed tomography (CT) of thorax showed a well-defined cystic lesion in right upper lobe with 5-10HU (Hounsfield unit) suggesting a fluid filled cyst. CT guided aspiration of cyst was undertaken and revealed clear fluid with no cells. Post-aspiration high-resolution CT images demonstrated classical signs of hydatid cyst. PMID- 28709493 TI - Sternoclavicular joint tuberculosis: A series of 9 cases. AB - Tuberculosis (TB) is a chronic disease that may affect any part of the human body. Though the osteoarticular TB is not uncommonly seen, TB of the sternoclavicular joint (SC joint) is an infrequently reported condition. The very fact that many physicians have never seen a single case of SC joint TB in their entire career makes them never think of this condition in cases of chronic swellings of the medial end of clavicle. We are reporting here our experience with nine cases of SC joint TB that were treated by us. Delay in diagnosis in each of the case was a common feature, and they had been treated in line of inflammation elsewhere. Diagnosis was arrived at by clinical, radiological, and microscopic examinations. Six of the reported cases responded well to antitubercular chemotherapy, and in one of the cases, chemotherapy was combined with debridement, which was actually done during biopsy and primarily for tissue diagnosis; in another two cases, immunomodulation therapy for HIV was given along with antitubercular therapy. Tuberculous etiology should be considered for patients presenting with atypical sites of skeletal inflammation, and a high index of suspicion by the treating physician is necessary to make early diagnosis and appropriate treatment. PMID- 28709494 TI - Multiple abdominal abscesses - A not so common presentation of NTM. AB - Non-tuberculous Mycobacteria/Mycobacterium other than tuberculosis (MOTT) are ubiquitous organisms. They are acid fast bacilli often giving trouble to the physician to distinguish it from Mycobacterium tuberculosis. These organisms are a menace for the treating physician as when to treat and when not to treat. They are often difficult to diagnose and may present in a variety of forms with propensity to cause number of infections of different body parts and organs. They are more common in immunocompromised individuals e.g. HIV infection. Here we are reporting a not so common manifestation of NTM which presented as multiple abdominal abscesses in a middle aged female probably secondary to surgical site infection, however she responded dramatically to the designed treatment. PMID- 28709495 TI - Unusual case of coexistent pulmonary cryptococcosis and tuberculosis in an immuno competent host. AB - Coexistence of pulmonary cryptococcosis with other infections has commonly been described in immuno-suppressed individuals. In immuno-competent hosts, such coexistence is rare and mostly described in disseminated disease or uncommonly involving different sites. The simultaneous coinfection of cryptococcosis and tuberculosis of lung in an immuno-competent host is extremely rare with only one previously reported case in the literature. This is the second such case and the first to be reported in India. We describe a case of a 36-year-old immuno competent male who presented with haemoptysis and cough. Computed tomography showed a sub-pleural lung nodule. Diagnostic thoracoscopic wedge resection of the right lung nodule revealed granulomatous inflammation with cryptococcus on histopathology. Coexistent tuberculosis was diagnosed by microbiological culture study on lung tissue. The patient responded clinically to fluconazole and anti tubercular therapy. This case shows that although rare, coexistent infections can occur in immuno-competent persons and highlights the importance of careful evaluation and tissue microbiological culture examination. PMID- 28709496 TI - Drug-resistant tuberculosis coexisting with invasive candidiasis in an immunocompetent 30-year-old woman: A case report. AB - Invasive candidiasis coexisting with drug-resistant Mycobacterium tuberculosis (DR-TB) in the immunocompetent patient is a rare entity. We report a 30-year-old woman, nondiabetic, who presented to us with complaints of acute onset cough, breathlessness, and fever since 20 days. On thorough investigations, she was diagnosed to be suffering from coexisting drug-resistant tuberculosis and invasive candidiasis. Prompt treatment initiated at right time helped us in saving her life. The unique presentation of this case and that too in an immunocompetent female makes it an interesting case. PMID- 28709497 TI - Assessing worldwide research productivity on tuberculosis over a 40-year period: A bibliometric analysis. PMID- 28709500 TI - The definition of "palliative nutrition" is misleading. PMID- 28709499 TI - Increased Occipital Gyrification and Development of Psychotic Disorders in Individuals With an At-Risk Mental State: A Multicenter Study. AB - BACKGROUND: Anomalies of brain gyrification have been reported in schizophrenia, possibly reflecting its neurodevelopmental pathology. However, it remains elusive whether individuals at risk for psychotic disorders exhibit deviated gyrification patterns, and whether such findings, if present, are predictive of transition to psychotic disorders. METHODS: This multicenter magnetic resonance imaging study investigated brain gyrification and its relationship to later transition to psychotic disorders in a large sample of at-risk mental state (ARMS) individuals. T1-weighted magnetic resonance imaging scans were obtained from 104 ARMS individuals, of whom 21 (20.2%) exhibited the transition to psychotic disorders during clinical follow-up (mean = 4.9 years, SD = 2.6 years), and 104 healthy control subjects at 4 different sites. The local gyrification index (LGI) of the entire cortex was compared across the groups using FreeSurfer software. RESULTS: Compared with the control subjects, ARMS individuals showed a significantly higher LGI in widespread cortical areas, including the bilateral frontal, temporal, parietal, and occipital regions, which was partly associated with prodromal symptomatology. ARMS individuals who exhibited the transition to psychotic disorders showed a significantly higher LGI in the left occipital region compared with individuals without transition. CONCLUSIONS: These findings suggested that increased LGI in diverse cortical regions might represent vulnerability to psychopathology, while increased LGI in the left occipital cortex might be related to subsequent manifestation of florid psychotic disorders as a possible surrogate marker. PMID- 28709501 TI - Sleep in enchanted colors. PMID- 28709502 TI - Sleep Health receives its first CiteScore. PMID- 28709498 TI - Targeting Fyn Kinase in Alzheimer's Disease. AB - The past decade has brought tremendous progress in unraveling the pathophysiology of Alzheimer's disease (AD). While increasingly sophisticated immunotherapy targeting soluble and aggregated brain amyloid-beta (Abeta) continues to dominate clinical research in AD, a deeper understanding of Abeta physiology has led to the recognition of distinct neuronal signaling pathways linking Abeta to synaptotoxicity and neurodegeneration and to new targets for therapeutic intervention. Identifying specific signaling pathways involving Abeta has allowed for the development of more precise therapeutic interventions targeting the most relevant molecular mechanisms leading to AD. In this review, I highlight the discovery of cellular prion protein as a high-affinity receptor for Abeta oligomers, and the downstream signaling pathway elucidated to date, converging on nonreceptor tyrosine kinase Fyn. I discuss preclinical studies targeting Fyn as a therapeutic intervention in AD and our recent experience with the safety, tolerability, and cerebrospinal fluid penetration of the Src family kinase inhibitor saracatinib in patients with AD. Fyn is an attractive target for AD therapeutics, not only based on its activation by Abeta via cellular prion protein but also due to its known interaction with tau, uniquely linking the two key pathologies in AD. Fyn is also a challenging target, with broad expression throughout the body and significant homology with other members of the Src family kinases, which may lead to unintended off-target effects. A phase 2a proof-of concept clinical trial in patients with AD is currently under way, providing critical first data on the potential effectiveness of targeting Fyn in AD. PMID- 28709503 TI - National Sleep Foundation sets the standard for sleep as a vital sign of health. PMID- 28709504 TI - Commentary on Keller et al, 2017: The problem with interpreting low base rate behaviors. PMID- 28709505 TI - Response to Troxel commentary: further evidence that school start times are associated with behavioral problems in elementary schools. PMID- 28709506 TI - Corrigendum to "Text message intervention improves objective sleep hours among adolescents: the moderating role of race-ethnicity" [Sleep Health 3 (2017) 62 67]. PMID- 28709507 TI - Indexing America's sleep health. PMID- 28709508 TI - The National Sleep Foundation's Sleep Health Index. AB - OBJECTIVES: A validated survey instrument to assess general sleep health would be a useful research tool, particularly when objective measures of sleep are not feasible. Thus, the National Sleep Foundation spearheaded the development of the Sleep Health Index (SHI). DESIGN: The development of the SHI began with a task force of experts who identified key sleep domains and questions. An initial draft of the survey was created and questions were refined using cognitive testing and pretesting. The resulting 28-question survey was administered via random-sample telephone interviews to nationally representative samples of adults in 2014 (n=1253) and 2015 (n=1250). These data were combined to create the index. A factor analysis linked 14 questions to 3 discrete domains: sleep quality, sleep duration, and disordered sleep. These were assembled as sub-indices, then combined to form the overall SHI, with scores ranging from 0 to 100 (higher score reflects better sleep health). RESULTS: Americans earned an overall SHI score of 76/100, with sub-index scores of 81/100 in disordered sleep, 79/100 in sleep duration, and 68/100 in sleep quality. In regression analyses, the strongest independent predictors of sleep health were self-reported stress (beta=-0.26) and overall health (beta=0.26), which were also the strongest predictors of sleep quality (beta=-0.32 and beta=0.27 respectively). CONCLUSIONS: The current 12-item SHI is a valid, reliable research tool that robustly measures 3 separate but related elements of sleep health-duration, quality, and disorders-and assesses the sleep health status of adults in the United States. PMID- 28709509 TI - Poor tap water quality experiences and poor sleep quality during the Flint, Michigan Municipal Water Crisis. AB - OBJECTIVES: After inadequate official response to community concerns over water quality following changes in Flint's municipal water supply, this study sought evidence for a relationship between water quality and community mental health. DESIGN: The Speak to Your Health Community Survey is a community-based participatory component of the health surveillance system in Genesee County, Michigan. This cross-sectional survey recruits participants from every residential Census Tract of the county and strives for demographic representativeness. RESULTS: Respondents (n=834) rated their tap water quality (taste, smell, appearance) as poor (36%), fair (18%), good (20%), very good (17%), and excellent (10%). They rated their sleep quality as poor (12%), fair (28%), good (39%), very good (18%), and excellent (4%), and had an average (SD) sleep length of 408(90) minutes. Controlling for age, sex, years of education, and whether respondents were African American and Hispanic/Latino/a, lower perceived tap water quality was associated with lower sleep quality and shorter sleep length. CONCLUSION: Results indicate that adverse health conditions related to the water crisis extend beyond lead poisoning in children and include deterioration of sleep conditions among adult residents. PMID- 28709510 TI - Sleep apnea, psychopathology, and mental health care. AB - OBJECTIVE: Sleep apnea has been shown to be associated with mental health conditions. This study examined the association between sleep apnea and psychopathology and mental health service utilization in a US nationally representative sample. DESIGN: National Survey on Drug Use and Health (NSDUH). SETTING: United States. PARTICIPANTS: We used data on 264,653 individuals who participated in the 2008-2014 waves of the NSDUH, of which 5498 (3.3%) reported having sleep apnea within the past year. INTERVENTION: Not applicable. MEASUREMENTS: Based on NSDUH responses, participants were categorized as having depression, suicidal ideation, anxiety, and serious psychological distress within the past year. Analyses consisted of using logistic regression models with sleep apnea as the main predictor and mental health conditions as the outcomes of interest, controlling for potential confounding variables. RESULTS: Compared with those without sleep apnea, those reporting past-year sleep apnea had 3.11 (95% confidence interval [CI], 2.77-3.50) times increased odds of having depression, 2.75 (95% CI, 2.34-3.23) times increased odds of suicidal ideation, 3.68 (95% CI, 3.30-4.10) times increased odds of anxiety, and 2.88 (95% CI, 2.61-3.17) times increased odds of severe psychological distress, after controlling for confounders. Among those with each psychiatric outcome, individuals with sleep apnea were substantially more likely to report unmet need for mental health care, despite reporting greater mental health service use. CONCLUSIONS: Individuals with sleep apnea have increased risk for psychopathology, including suicidal ideation. Efforts to address the mental health care needs of those with sleep apnea are needed. PMID- 28709511 TI - Erectile dysfunction is independently associated with apnea-hypopnea index and oxygen desaturation index in elderly, but not younger, community-dwelling men. AB - OBJECTIVE(S): To examine the association between obstructive sleep apnea (OSA) and other sleep indices using polysomnography (PSG) data and erectile dysfunction (ED) in a representative cohort of men. DESIGN: Cross-sectional. SETTING: Community-based. PARTICIPANTS: Aged 40+ years (n=734; mean age [SD], 60.8 [10.9]). MEASUREMENTS: Men with no prior OSA diagnosis who underwent in-home PSG (Embletta X100; 2010-11) and ED assessment (Global Impotence Rating) were selected. Un-adjusted and multi-adjusted regression models of ED were fitted against PSG measures, along with qualifying sociodemographic, lifestyle, and health-related covariates. Mediation effects were examined using the Baron-Kenny method. RESULTS: Of the men examined, 24.7% (n=181) had ED, most notably in men older than 65years (cf. men 35-49 and 50-64years; P<.001). There was no significant association between ED and any of the PSG measures for allaged men. Given an observed ageinteraction within OSA categories (P=.005), analyses were repeated in age-stratified samples (<65 years; 65+ years). In men younger than 65years, only severe OSA was found to have an association with ED (2.01; 1.13 4.69) in unadjusted models. For men aged 65+ years, an independent association with ED was found for apnea-hyponea index (AHI; 1.55;1.02-2.36), moderate (AHI:10.0-19.9; 1.79;1.18-2.43), and severe (AHI:20.0+; 4.84;2.56-9.93) OSA, and oxygen desaturation index (ODI; both continuous [1.48;1.03-1.99] and >16 seconds [2.79;1.23-6.32]). The effect of AHI on ED was shown to be primarily mediated through ODI (63.4%, Sobel P value=.29). CONCLUSIONS: In younger, community-based men, there appeared no independent relationship between objective measures of sleep and ED. However, there appears a strong, independent relationship between OSA, ODI, and ED in men 65 years and older. PMID- 28709512 TI - Correlates of sleep quality and sleep duration in a sample of urban-dwelling elderly Nigerian women. AB - OBJECTIVES: Aging, female sex, and urbanization increase the risk of sleep impairment. Sleep in urban-dwelling elderly African women has been sparsely studied. We studied the characteristics and correlates of sleep quality and habitual sleep duration in a primary care population of urban-living Nigerian women. METHODS: Sleep quality and sleep duration over the previous 1 month were estimated using the Pittsburgh Sleep Quality Index (PSQI). Excessive daytime sleepiness, risk of obstructive sleep apnea (OSA), and depressive symptoms were also assessed. RESULTS: Of the 428 subjects included, 117 (27.3%) were poor sleepers endorsing PSQI scores >5, whereas 126 (29.4%) slept <7 hours. The poor sleepers were more likely to be obese (P = .022), to have a high risk for OSA (P = .013), and to have clinically significant depressive symptoms (P = .001) compared with the good sleepers. Habitual sleep duration of <7 hours was associated with past oral contraceptive use (P = .025) and a trend toward a higher likelihood of high risk for OSA (P = .05) and coffee consumption (P = .05). On regression, the odds of high risk for OSA were higher with poor sleep quality and sleep duration <7 hours, respectively, whereas the odds of coffee consumption were higher with sleep duration <7 hours. CONCLUSIONS: Poor sleep quality and inadequate sleep are common in our population of elderly women. High risk for OSA independently predicts poor sleep quality and, along with report of coffee consumption, independently predicts habitual sleep duration of <7 hours. PMID- 28709513 TI - Associations between physical and sedentary activity regularity and sleep in preschoolers and kindergartners. AB - Short sleep duration in childhood has been associated with increased risk for overweight and obesity. Research suggests that physical activity might mediate this association. However, studies examining associations between physical activity and sleep in young children have reported equivocal findings. A possible explanation for these inconsistencies is that past studies have looked at total physical activity rather than examining physical activity regularity. We aimed to explore the associations between physical and sedentary activity regularity (ie, consistent vs intermittent behavior) and sleep in preschoolers and kindergartners. One hundred and thirty-one children (ages 4-6) wore waist-worn accelerometers for 3 days and 3 nights. Associations between physical and sedentary activity regularity and attaining adequate sleep duration were assessed using logistic regression. There was no association between the number of days that children engaged in >=60 minutes of total physical activity and sufficient sleep. Furthermore, there was no association between the number of days that children engaged in >=20 minutes of vigorous activity and sufficient sleep. Children who engaged in minimal sedentary activity had greater odds of obtaining sufficient sleep as compared with children who engaged in more sedentary activity. PMID- 28709514 TI - Sleep timing is associated with self-reported dietary patterns in 9- to 15-year olds. AB - OBJECTIVE: To examine sleep timing differences in self-reported dietary patterns of children and adolescents. DESIGN: Cross-sectional. PARTICIPANTS: Students aged 9-15 years (n=119, 11.7+/-1.3 years, 76% female) attending a summer program for the gifted. The upper and lower quartiles of reported midsleep time (weighted weekday-weekend average) were used to identify early (n=28) and late (n=27) sleep timing groups. METHODS: Sleep patterns were assessed via self-report. Participants also rated their likelihood to consume 9 different categories of food and drinks on a 5-point scale ranging from "no likelihood" to "high likelihood." Foods were grouped as follows: (1) sugary and caffeinated beverages; (2) high-energy-dense, nutrient-poor foods (ie, sugary, salty, fatty foods); and (3) low-energy-dense, nutrient-rich foods (ie, vegetables, proteins, carbohydrates, fruits). RESULTS: Midsleep time was 02:11+/-00:25 for the early and 06:14+/-01:00 for the late sleep timing groups. Participants reporting later sleep timing were more likely to consume sugary/caffeinated beverages and high energy-dense, nutrient-poor foods throughout the day compared with their early sleep timing peers. The late vs the early sleep timing group also had a higher likelihood of overall consumption of foods and drinks from all categories into the evening and nighttime hours. CONCLUSION: Our findings indicate that children and adolescents who exhibit late sleep timing are more likely to make poorer dietary choices, which may have important implications for understanding pathways to adiposity and obesity risk during this sensitive period of development. PMID- 28709516 TI - Social relationships and the sleep-health nexus in adolescence: evidence from a comprehensive model with bi-directional effects. AB - OBJECTIVE: The goal of this study was to assess the bi-directional effects of sleep and health (body mass index [BMI], depression, and substance use) among adolescents in the presence of comprehensive controls for social relationships and daily stressors and supports. DESIGN: Longitudinal survey. SETTING: Data were obtained from the Study of Early Child Care and Youth Development, a longitudinal survey designed and administered by the Eunice Kennedy Shriver National Institute of Child Health and Human Development. PARTICIPANTS: At total of 974 adolescents ages 12-15; 50% girls. MEASUREMENTS: Total sleep time was derived from difference between usual bedtime and arise time; youths self-reported the frequency of using alcohol, tobacco, and marijuana, and most of the predictors of sleep-health (e.g., parental monitoring, school and peer attachment); youth's body mass index and physical development (i.e., Tanner stage score) were assessed in clinics. RESULTS: Teen sleep duration declined and health deteriorated from age 12-15, but results from a 2-stage least squares analysis showed and that sleep duration was among the strongest predictors of teen health; by contrast, BMI, depression, and substance use had no effect on sleep duration. Youth sleep and health were both determined by changes in family structure, income, parental monitoring, school and peer attachment, time spent in homework and on the computer, and physical development (health only). CONCLUSIONS: The constellation of teens' social ties and daily stressors affects the sleep-health nexus, and future studies should account for this complexity and diversity of teens' lives. PMID- 28709515 TI - Adolescents' technology and face-to-face time use predict objective sleep outcomes. AB - OBJECTIVES: The present study examined both within- and between-person associations between adolescents' time use (technology-based activities and face to-face interactions with friends and family) and sleep behaviors. We also assessed whether age moderated associations between adolescents' time use with friends and family and sleep. DESIGN: Adolescents wore an actigraph monitor and completed brief evening surveys daily for 3 consecutive days. PARTICIPANTS: Adolescents (N=71; mean age=14.50 years old, SD=1.84; 43.7% female) were recruited from 3 public high schools in the Midwest. MEASURES: We assessed 8 technology-based activities (eg, texting, working on a computer), as well as time spent engaged in face-to-face interactions with friends and family, via questions on adolescents' evening surveys. Actigraph monitors assessed 3 sleep behaviors: sleep latency, sleep hours, and sleep efficiency. RESULTS: Hierarchical linear models indicated that texting and working on the computer were associated with shorter sleep, whereas time spent talking on the phone predicted longer sleep. Time spent with friends predicted shorter sleep latencies, while family time predicted longer sleep latencies. Age moderated the association between time spent with friends and sleep efficiency, as well as between family time and sleep efficiency. Specifically, longer time spent interacting with friends was associated with higher sleep efficiency but only among younger adolescents. Furthermore, longer family time was associated with higher sleep efficiency but only for older adolescents. CONCLUSION: Findings are discussed in terms of the importance of regulating adolescents' technology use and improving opportunities for face-to-face interactions with friends, particularly for younger adolescents. PMID- 28709517 TI - Continuity of sleep problems from adolescence to young adulthood: results from a longitudinal study. AB - BACKGROUND: Considering the lack of evidence on incidence and continuity of sleep problems from adolescence to young adulthood, this study explores sleep problems' incidence and their continuation rates from 14 to 21 years. METHODS: Sleep data from the 14-year (n = 4,924) and 21-year (n = 3660) follow-up of the Mater University of Queensland Study of Pregnancy cohort were used. Sociodemographic, lifestyle, and psychological conditions were explored for their role in sleep problems. Modified Poisson regression with a robust error variance was used to identify predictors. Inverse probability weights were used to account for attrition. RESULTS: Of all subjects, 26.0% of the subjects at 14 years and 28.3% of the subjects at 21 years reported "often" sleep problems, with 41.7% of adolescent sleep problems persisting at 21 years. Perinatal and early-life maternal factors, for example, drug abuse (incidence rate ratio (IRR), 1.32; 95% confidence interval [CI], 1.02-1.71), smoking, depression, and anxiety, were significant predictors of adolescent sleep problems. Female sex (IRR, 2.13; 95% CI, 1.55-2.94), advanced pubertal stages, and smoking were the important predictors of sleep problems at 21 years. Adolescent depression/anxiety supported the continuity of sleep problems (IRR, 1.21; 95% CI, 1.05-1.40), whereas exercise was seen to exert a protective effect. CONCLUSION: This study indicates high rates of sleep problems in young subjects, with around half of sleep problems originating in adolescence persisting in young adulthood. Therefore, early interventions are needed to manage sleep problems in young subjects and prevent further progression to other life stages. Future studies should explore if sleep problems in young adults also persist in later life stages and identify the factors supporting the continuity of sleep problems. PMID- 28709518 TI - Developing a state-wide infrastructure for safe sleep promotion. AB - OBJECTIVES: Sleep-related deaths are the third leading cause of infant death in Kansas. This manuscript describes implementation of an infrastructure of regional trainers to educate on the American Academy of Pediatrics safe sleep recommendations. DESIGN: Prospective evaluation of training program on knowledge transfer. SETTING: Instructors were recruited from throughout the state of Kansas and trained to provide safe sleep education in their communities. PARTICIPANTS: Instructors were a mix of healthcare workers and community members. Their trainees encompassed both professionals and caregivers. INTERVENTION: Instructors attended a 2-day training, including completing 18-item pre and post-training knowledge tests, a training evaluation survey, and performing a portion of the structured safe sleep presentation and crib demonstration for feedback. MEASUREMENT: Instructors were evaluated before and after training. After conducting trainings in their region, instructors submitted trainees' pre and post-test results. Scores were compared using t-test. RESULTS: Twenty-three instructors were trained. Scores averaged 13.5 (SD=2.4) for the pre-test and 15.3 (SD=2.4) for the post-test. Those scoring <80% post-training (n=6) received additional instruction. In the subsequent year, 13 trainers provided safe sleep education at 21 events to a total of 378 trainees. Trainee scores averaged 11.4 (SD=2.7) on the pre-test and increased to 13.9 (SD=2.5) on the post-test (P<.001). Findings were consistent when adjusting for variation between individual trainers. CONCLUSIONS: Safe sleep instructors can be trained to disseminate safe sleep guidelines; however, only half provided at least 1 training within 1 year. Future recommendations include over-recruiting potential instructors, incorporating trainings into existing positions or otherwise incentivizing trainers. PMID- 28709519 TI - Racial discrimination and perinatal sleep quality. AB - OBJECTIVE: This research examined the association between perceived everyday racial discrimination, as a psychosocial stressor, and perinatal sleep quality. DESIGN: Cross-sectional (N=640) and longitudinal associations (N=133) between everyday experiences of discrimination and sleep quality were examined using a pregnancy and postpartum data registry. PARTICIPANTS: We studied a sample of 640 unique women from the Perinatal Research Repository (PRR), a longitudinal study of mothers, fathers, and babies recruited from Nationwide Children's Hospital and The Ohio State University in Columbus, Ohio. MEASUREMENTS: Discrimination and sleep quality were assessed using the Experiences of Discrimination Scale and the Pittsburgh Sleep Quality Index, respectively. RESULTS: Overall, everyday discrimination was associated with poorer global sleep quality and all but three sleep sub-measures of the PSQI cross-sectionally, but not longitudinally. When stratified, the adverse effects of everyday discrimination varied by race and perinatal time period. Increases in everyday discrimination were independently associated with poorer sleep initiation, poorer sleep maintenance and poorer daytime dysfunction. CONCLUSIONS: Findings suggest that the immediate stressors of everyday racial discrimination were independently associated with poorer sleep quality among pregnant women cross-sectionally. Poorer sleep quality has been associated with numerous adverse perinatal outcomes and this association may be important in understanding racial discrimination as a risk factor. Our failure to identify a longitudinal association makes the direction of causation uncertain, however. Further longitudinal studies are necessary to clarify the association, given the potential importance of poor sleep quality in the pathogenesis of pregnancy complications. PMID- 28709520 TI - Strategies to reduce disparities in maternal morbidity and mortality: The role of obesity and metabolic disease. AB - Maternal obesity, excessive gestational weight gain, and preexisting diabetes are known risk factors for increased maternal and neonatal morbidity. These conditions are more prevalent in certain racial and ethnic minorities. Identification and acknowledgement of racial and ethnic inequalities related to maternal metabolic disease is crucial for clinicians to provide the most comprehensive care in pregnancy. Research and clinical efforts should focus on implementation of healthy lifestyle interventions preconceptually and risk reduction efforts in disease complications during pregnancy. In addition, obstetrical providers can provide the framework and ongoing support for sustainable lifestyle modifications, thereby, improving a woman's long-term metabolic health. PMID- 28709521 TI - Management of plastic wastes at Brazilian ports and diagnosis of their generation. AB - This study evaluated the management of plastic wastes at 20 Brazilian maritime ports, from three sources: vessels, leased and non-leased areas. The data were obtained from documents on port wastes organized in a relational database with defined protocols (closed form). Analysis of the spreadsheets prepared and field visits revealed that the main bottleneck in managing plastic wastes at ports is their segregation. In general, more material is segregated and sent for recycling from leased areas than non-leased ones (administered by the government). This relatively better performance in managing the wastes generated in leased areas is probably due to the need for private operators to comply with the international standards such as the Code of Environmental Practice to satisfy the international market. PMID- 28709522 TI - Microplastic contamination of intertidal sediments of Scapa Flow, Orkney: A first assessment. AB - The concentration of microplastic particles and fibres was determined in the intertidal sediments at selected sites in Scapa Flow, Orkney, using a super saturated NaCl flotation technique to extract the plastic and FT-IR spectroscopy to determine the polymer types. Mean concentrations were 730 and 2300kg-1 sediment (DW), respectively. Detailed spatial and quantitative analysis revealed that their distribution was a function of proximity to populated areas and associated wastewater effluent, industrial installations, degree of shore exposure and complex tidal flow patterns. Sediment samples from Orkney showed similar levels of microplastic contamination as in two highly populate industrialized mainland UK areas, The Clyde and the Firth of Forth. It was concluded that relative remoteness and a comparative small island population are not predictors of lower microplastic pollution. Furthermore, a larger concerted effort across Scotland and the UK is required to establish a baseline microplastic database for the evaluation of future policy measures. PMID- 28709523 TI - Modelling oil plumes from subsurface spills. AB - An oil plume model to simulate the behavior of oil from spills located at any given depth below the sea surface is presented, following major modifications to a plume model developed earlier by Malacic (2001) and drawing on ideas in a paper by Yapa and Zheng (1997). The paper presents improvements in those models and numerical testing of the various parameters in the plume model. The plume model described in this paper is one of the numerous modules of the well-established MEDSLIK oil spill model. The deep blowout scenario of the MEDEXPOL 2013 oil spill modelling exercise, organized by REMPEC, has been applied using the improved oil plume module of the MEDSLIK model and inter-comparison with results having the oil spill source at the sea surface are discussed. PMID- 28709524 TI - The estimation for ballast water discharged to China from 2007 to 2014. AB - Ballast water has been identified as one of the main causes for worldwide transfer of non-indigenous marine species. The volume and source of ballast water are the fundamental elements for an evaluation of the risk posed. However, it is difficult to obtain the volume of ballast water discharged to China, because of the absence of information platform, and until now there is no public report. In this paper, the total volume of ballast water discharged to China and Chinese five major port-groups were estimated. Results showed: the total volume of ballast water exhibited a trend of slow increase from 2007 to 2014, and reached 311 million tons in 2014. Yangtze River Delta received the highest volume of ballast water among all port-groups. The information provided in this research may play an important role in helping policy decision-makers manage such coastal discharges. PMID- 28709525 TI - The toxic exposure of flamingos to per- and Polyfluoroalkyl substances (PFAS) from firefighting foam applications in Bonaire. AB - In 2010 an oil terminal next to nature reservation Salina Goto (Bonaire) caught fire. Firefighting resulted in elevated per- and polyfluoroalkyl substances (PFAS) concentrations in the salt lake. Within months flamingo abundance in Goto dropped to near complete absence. After statistical analysis, rainfall was deemed an unlikely cause for this decline. Toxicological effects on abundance of prey are likely the main cause for the flamingo absence. This reduced PFAS exposure via food and thus risk towards flamingos during the first years after the fires. Although the sediment is still polluted with persistent PFAS, flamingos returned, and started to feed on organisms with PFAS levels that exceed safety thresholds, placing the birds and other wildlife at risk. Monitoring bird populations is advised to assess potential toxic effects on birds and their offspring. This case suggests that applying persistent chemicals to reduce incident impacts may be more harmful than the incident itself. PMID- 28709526 TI - Mangrove sediments reveal records of development during the previous century (Coffs Creek estuary, Australia). AB - A mangrove sediment core was studied to evaluate possible pollution of an urban estuary in Coffs Harbour, Australia. The heavy metal and nutrient profiles revealed a ~2.5-fold enrichment in more recent sediments. Lead-210 dating showed increasing phosphorous (P) and copper (Cu) accumulation following agricultural activity and population growth in the catchment after 1950. In contrast, nitrogen (N) did not show enrichment suggesting no external sources. Mercury (Hg) depositional fluxes and recent enrichment may be associated to an increase in fossil fuel emissions in the region. Down-core lead (Pb) profiles reflect an increase in leaded gasoline in the 1950s, then a decrease as a result of phasing out leaded gasoline in 1986. The heavy metal and nutrient depositional fluxes are well preserved in mangrove sediments and were related to historical events in the catchment. PMID- 28709527 TI - Predicting the capability of carboxymethyl cellulose-stabilized iron nanoparticles for the remediation of arsenite from water using the response surface methodology (RSM) model: Modeling and optimization. AB - This study aimed to investigate the feasibility of carboxymethyl cellulose stabilized iron nanoparticles (C-nZVI) for the removal of arsenite ions from aqueous solutions. Iron nanoparticles and carboxymethyl cellulose-stabilized iron nanoparticles were freshly synthesized. The synthesized nanomaterials had a size of 10nm approximately. The transmission electron microscope (TEM) images depicted bulkier dendrite flocs of non-stabilized iron nanoparticles. It described nanoscale particles as not discrete resulting from the aggregation of particles. The scanning electron microscopy (SEM) image showed that C-nZVI is approximately discrete, well-dispersed and an almost spherical shape. The energy dispersive x ray spectroscopy (EDAX) and X-ray diffraction (XRD) spectrum confirmed the presence of Fe0 in the C-nZVI composite. The central composite design under the Response Surface Methodology (RSM) was employed in order to investigate the effect of independent variables on arsenite removal and to determine the optimum condition. The reduced full second-order model indicated a well-fitted model since the experimental values were in good agreement with it. Therefore, this model is used for the prediction and optimization of arsenite removal from water. The maximum removal efficiency was estimated to be 100% when all parameters are considered simultaneously. The predicted optimal conditions for the maximum removal efficiency were achieved with initial arsenite concentration, 0.68mgL-1; C-nZVI, 0.3 (gL-1); time, 31.25 (min) and pH, 5.2. PMID- 28709528 TI - Rules of thumb - An educational tool in teaching clinical communication to medical students. PMID- 28709529 TI - Margin Analysis: Squamous Cell Carcinoma of the Oral Cavity. AB - This article primarily focuses on defining terms including negative margin, close margin, and positive margin. Furthermore, this review delineates the current role of frozen section analysis and adjuvant therapy in treating oral squamous cell carcinoma with respect to surgical margin status. PMID- 28709530 TI - Margin Analysis: Squamous Cell Carcinoma of the Oropharynx. AB - Because of the common shared risk factors of smoking and heavy alcohol consumption, literature involving oropharyngeal squamous cell carcinoma (OPSCC) is often combined with oral squamous cell carcinoma. Human papilloma virus is now confirmed to be a major risk factor of OPSCC with its distinct epidemiology and favorable treatment outcome. The impact of adjuvant chemoradiation in the setting of positive surgical margins remains unclear but is likely influenced by tumor biology. This article reviews the tumor biology of OPSCC and summarizes recent findings on outcomes following surgical treatment of OPSCC. PMID- 28709531 TI - Bone Margin Analysis for Osteonecrosis and Osteomyelitis of the Jaws. AB - Bone margin analysis in cases of osteomyelitis, osteoradionecrosis, and medication-related osteonecrosis of the jaw is a controversial topic. There is little evidence to guide treatment and the interpretation of bone margin results. This article examines the significance of margin status and any possible effect on progression of the disease process. A review of various treatment adjuncts used for intraoperative margin analysis during removal of affected tissue is provided. Literature on the role of imaging is also discussed with regards to treatment planning for surgical resection. The histology of the three separate entities including the approach to surgical and pathologic evaluation of margins is also discussed. PMID- 28709532 TI - Margins for Benign Salivary Gland Neoplasms of the Head and Neck. AB - The proper ablation of any neoplasm of the head and neck requires the inclusion of linear and anatomic barrier margins surrounding the neoplasm. Extirpative surgery of the major and minor salivary glands is certainly no exception to this surgical principle. To this end, the selection and execution of the most appropriate ablative surgical procedure for a major or minor benign salivary gland neoplasm is an essential exercise in oral and maxillofacial surgery. Of equal importance is the intraoperative identification and preservation of the pseudocapsule surrounding the benign neoplasm. This article reviews these important elements specifically related to ablative surgery of benign neoplasms of the parotid, submandibular and minor salivary glands with strict attention to observed nomenclature. PMID- 28709533 TI - Margin Analysis: Cutaneous Malignancy of the Head and Neck. AB - This article focuses only on margin analysis of the cutaneous malignancy of the skin. It discusses basal cell carcinoma, squamous cell carcinoma, and cutaneous melanoma. The management of the neck and distant disease are beyond the scope of this article, but it answers what is the appropriate surgical margin when excising these skin tumors, whether frozen sections are accurate for the analysis of these tumors, and treatment algorithm and rationale for a positive resection margin. PMID- 28709535 TI - Surgical Margins: The Perspective of Pathology. AB - Neoplasms of the head and neck constitute a broad spectrum of benign and malignant entities. When treatment involves resection, assessment of the surgical margins represents an important component of the pathologic examination. Margin status is an important indicator of a complete surgical resection. The ability to generalize conclusions such as 'safe distance' measurements from work performed mSCCa or cutaneous malignancy to other types of neoplasms in the head and neck region seems limited. This article reviews conditions and considerations for reliable margin assessment and interpretation. PMID- 28709534 TI - Margin Analysis: Sarcoma of the Head and Neck. AB - Head and neck sarcomas are rare but are associated with significant morbidity/mortality and management difficulties. These tumors are best managed in a multidisciplinary setting. Open or core biopsy is essential for histologic diagnosis and grading. Complete surgical tumor resection with negative margins at the first attempt is the best chance for potential cure. In most patients, except those with small resectable low-grade lesions, adjuvant radiotherapy and chemotherapy are added to maximize local control with variable results. Resection margins effect on recurrence rate and treatment modalities in selective types of head and neck sarcomas are discussed in this article. PMID- 28709536 TI - Margin Analysis-Has Free Tissue Transfer Improved Oncologic Outcomes for Oral Squamous Cell Carcinoma? AB - Microvascular reconstruction of ablative defects has become a mainstay of contemporary management of head and neck cancer patients. These techniques offer myriad tissue options that vary in character, volume, and components and have vastly improved the esthetic and functional outcomes achieved in this patient population. Although consensus exists regarding the reliability and functional and esthetic benefits of free tissue transfer, the same cannot be said for oncologic outcomes. The increase in resources required for the routine use of free tissue transfer has led to asking this question-Do vascularized free flaps allow for increased surgical margins and improvements in oncologic outcomes? PMID- 28709537 TI - Introduction. PMID- 28709538 TI - Evaluation of the Surgical Margin: An Interdisciplinary Approach. PMID- 28709539 TI - REMOVED: Skin as Material and Medium for Artistic Creation. PMID- 28709540 TI - Psoriatic Arthritis: What the Dermatologist needs to Know, Part 1. AB - Psoriatic arthritis is defined as inflammatory arthritis occurring in patients with psoriasis and is classified as a seronegative spondyloarthropathy associated with human leukocyte antigen B27. Between 25 and 35% of patients with psoriasis go on to develop psoriatic arthritis during the course of their disease. Given that the skin is affected before the joints in most cases, the dermatologist must be able to recognize the signs and symptoms in order to make a diagnosis and start the most appropriate treatment. This review aims to cover key aspects of the initial diagnostic workup and clinical evaluation. It examines the epidemiology, pathogenesis, and manifestations of psoriatic arthritis, as well as the complementary tests and diagnostic tools the dermatologist should be aware of in order to make the correct diagnosis. PMID- 28709541 TI - Lipid Nutrition and the Epidermal Barrier: The Connection Between Immune-Mediated Inflammatory Diseases and Peroxisome Proliferator-Activated Receptors, a New Therapeutic Target in Psoriasis and Atopic Dermatitis. AB - The authors describe peroxisome proliferator-activated receptor (PPAR) transcription factors as connectors between the enzymatic mechanisms of the epidermal barrier and the abnormal immune and inflammatory responses that characterize atopic dermatitis and psoriasis. Also described is a new connection between lipid metabolism and the epidermal barrier. A suggestion that emerges is that atopic dermatitis and psoriasis share at least 2 pathogenic mechanisms namely, deficient expression of PPAR-#a and impaired production of interleukin-10 and interferon-gamma-in spite of differences in causes and manifestations. A standardized olive oil formulation with powerful bactericidal and fungicidal effects also has the ability to increase serum levels of these 2 cytokines and regulate serum levels of high-density lipoprotein cholesterol in patients at high risk for inflammatory and cardiovascular disease, suggesting that these may be among the mechanisms responsible for the benefits observed following oral and/or topical administration in patients with atopic dermatitis or psoriasis. PMID- 28709542 TI - Guidelines on the Use of Methotrexate in Psoriasis. AB - Psoriasis, a chronic multifactorial inflammatory disease that develops in genetically predisposed individuals, affects approximately 1.5% of the Spanish population. This disease has a negative impact on patients' quality of life, and long-term therapy is often required to control the symptoms. In addition to the classical systemic treatments (methotrexate, acitretin, cyclosporine, and ultraviolet light), the group of drugs known as biologics (etanercept, infliximab, adalimumab, and ustekinumab) provides the dermatologist with an expanded therapeutic armamentarium, thereby improving the likelihood of controlling psoriasis in patients with severe and/or extensive disease. Methotrexate, a classic antipsoriatic drug, is still very useful either as single drug therapy or in combination with other systemic drugs, particularly as a rescue therapy or combined with biologics. This article aims to establish the role of methotrexate in the treatment of psoriasis. We considered it of interest to develop guidelines for using methotrexate in the management of psoriasis with a view to ensuring the safe and proper use of this drug in the management of psoriasis. This document was developed by consensus among members of the Psoriasis Group of the Spanish Academy of Dermatology and Venereology. PMID- 28709543 TI - Botulinum Toxin Type A for the Treatment of Primary Hyperhidrosis: A Prospective Study of 52 Patients. AB - BACKGROUND AND OBJECTIVES: Primary hyperhidrosis is characterized by excessive sweating in a defined region of the body. It should not be considered a purely cosmetic problem as it has a significant impact on the social and professional relationships of affected individuals. The aim of this study was to determine the clinical profile of patients with primary hyperhidrosis and assess the results obtained with the use of botulinum toxin type A (BTX-A) in clinical practice. MATERIAL AND METHODS: The study included 52 patients (39 women and 13 men) with a diagnosis of primary hyperhidrosis treated for the first time with BTX-A. All patients completed a questionnaire that included the following information: age; sex; profession; age at onset, family history, and site of hyperhidrosis; accompanying signs and symptoms, and previous treatment; time to effect of BTX-A; local or systemic side effects; and severity of hyperhidrosis before and after BTX-A treatment. RESULTS AND CONCLUSIONS: Primary hyperhidrosis began during puberty in 61.5% of the patients included in the study, 75% were women, and the mean age was 29.9 years. In 36.5% of patients, first-degree relatives also had primary hyperhidrosis. Hyperhidrosis was classified as palmar in 61.5% of cases, plantar in 53.8%, and axillary in 59.6%. Other sites were affected less frequently. The most common accompanying symptoms were facial erythema (32.7%), palpitations (30.7%), muscle tension (28.8%), shivering (23%), and headache (17.3%). Treatment with BTX-A was well tolerated and there was a highly significant reduction in the severity of hyperhidrosis 2 months after performing the treatment (P<0.001). PMID- 28709544 TI - Cost Analysis of Mohs Micrographic Surgery in High-Risk Facial Basal Cell Carcinoma. AB - INTRODUCTION: Mohs micrographic surgery (MMS) is the treatment of choice for high risk facial basal cell carcinoma (BCC) as it offers the greatest chance of cure with maximum preservation of healthy tissue. Its use in Spanish public health care hospitals is still limited, however, due to the controversy surrounding its cost. OBJECTIVES: To determine the cost of MMS with fresh tissue to treat high risk facial BCC and compare this to the estimated cost of conventional surgery in a Spanish public hospital. A secondary objective was to identify cost optimization strategies for MMS. MATERIAL AND METHODS: Cross-sectional study of a consecutive series of patients with high-risk facial BCC who underwent MMS at the Department of Dermatology at Hospital Costa del Sol in Malaga, Spain between July 2006 and December 2007. We performed a descriptive analysis of the clinical characteristics of the patients and surgical factors. We calculated the total and mean cost of MMS and compared the results to the estimated costs of conventional surgery using patients as their own controls. Differences were analyzed according to tumor site and size, histologic subtype, and recurrence. RESULTS: Seventy-nine patients (mean age, 62 years) with 81 high-risk facial BCCs, 97.5% of which were primary tumors, underwent MMS. The most common tumor site was the nose (57%) followed by the orbital region (25%). Histology showed that 64% of the tumors were infiltrative or micronodular carcinomas. Tumor-free margins were achieved in all patients, with no more than 2 stages required in 88% of the cases. The most common surgical reconstruction techniques were direct closure (21%) and closure with a local skin flap or graft (71%); the corresponding estimates for conventional surgery were 2% and 89%, respectively. The total and mean cost of MMS was e106,129.07 and e1325.80, respectively (compared to e97 700 and e1208.70 for conventional surgery). The difference in mean costs between MMS and conventional surgery was not significant (P=0.534). CONCLUSIONS: MMS is a viable, effective technique that does not generate significantly higher costs than conventional surgery in selected patients with high-risk facial BCC. Certain technical and organizational strategies could contribute to optimizing the cost of MMS. PMID- 28709545 TI - Clinical Management of Psoriatic Arthritis in Spain: The CALIPSO Study. AB - OBJECTIVE: To describe the clinical management of psoriatic arthritis for patients being treated by dermatologists and rheumatologists in Spain. METHODS: Multicenter, retrospective, naturalistic observational study in which demographic and clinical variables were recorded for patients diagnosed with psoriatic arthritis. Data referred to the previous 12 months and were collected during a single visit with the physician. RESULTS: A total of 266 patients were enrolled; 78.1% were being treated by rheumatologists and 21.9% by dermatologists. The data covered 1138 visits. The main reason for consulting a physician was to monitor psoriatic arthritis (82.7% of the visits). The most widely used examination was to determine the tender- and swollen-joint count (73.1%). The tests most frequently ordered were acute-phase reactants: erythrocyte sedimentation rate (79.8%) and C reactive protein level (74.5%). Affected body surface area and the Psoriasis Area and Severity Index were the main assessments used by dermatologists. Rheumatologists tended to examine the joints and record biochemical markers. A disease-modifying antirheumatic drug was prescribed for 71.1% of the patients; 51.8% were prescribed a biologic agent (61.5% in combination with another treatment). Treatment approach differed by specialty and was modified if response was nil or partial (the rationale for 45.1% of all changes). CONCLUSION: Differences in the management of psoriatic arthritis in dermatology and rheumatology were evident in both diagnostic and treatment approaches. These 2 specialties should cooperate to establish common practice guidelines for use in Spain. PMID- 28709546 TI - New Mutation in the Birt Hogg Dube Gene. AB - Patients with Birt-Hogg-Dube syndrome have an increased risk of developing hamartomas of the pilosebaceous unit, renal tumors of various types, lung cysts, and spontaneous pneumothorax. We present the case of a 54-year-old woman with a long history of whitish papules in the central region of the face and a family history of similar lesions. Biopsy and genetic study revealed a new mutation of the gene involved in Birt-Hogg-Dube syndrome. PMID- 28709547 TI - Cold, erythematous-violaceous macules on both breasts of a 66-year-old woman. PMID- 28709548 TI - Episodes of flushing and blistering. PMID- 28709549 TI - Relieving the Pain Associated with Plantar Warts. PMID- 28709550 TI - Facial Granulomatous Dermatoses. PMID- 28709551 TI - Perifollicular Palpable Purpura as the Initial Manifestation of HIV Infection. PMID- 28709552 TI - Pachydermodactyly: A rare form of acquired digital fibromatosis. PMID- 28709553 TI - Subungual Squamous Cell Carcinoma. Presentation of two Cases. PMID- 28709554 TI - Lessons Learned from Two Decades of Anticancer Drugs. AB - Tremendous efforts have been made to elucidate the basis of cancer biology with the aim of promoting anticancer drug development. Especially over the past 20 years, anticancer drug development has developed from conventional cytotoxic agents to target-based and immune-related therapies. Consequently, more than 200 anticancer drugs are available on the market. However, anticancer drug development still suffers high attrition during the later phases of clinical development and is considered to be a difficult and risky therapeutic category within the drug development arena. The disappointing performance of investigational anticancer candidates implies that there are some shortcomings in the translation of preclinical in vitro and in vivo models to humans, and that heterogeneity in the patient population presents a significant challenge. Here, we summarize both successful and failed experiences in anticancer development during the past 20 years and help identify why the current paradigm may be suboptimal. We also offer potential strategies for improvement. PMID- 28709555 TI - Repeated seasonal influenza vaccination among elderly in Europe: Effects on laboratory confirmed hospitalised influenza. AB - In Europe, annual influenza vaccination is recommended to elderly. From 2011 to 2014 and in 2015-16, we conducted a multicentre test negative case control study in hospitals of 11 European countries to measure influenza vaccine effectiveness (IVE) against laboratory confirmed hospitalised influenza among people aged >=65years. We pooled four seasons data to measure IVE by past exposures to influenza vaccination. We swabbed patients admitted for clinical conditions related to influenza with onset of severe acute respiratory infection <=7days before admission. Cases were patients RT-PCR positive for influenza virus and controls those negative for any influenza virus. We documented seasonal vaccination status for the current season and the two previous seasons. We recruited 5295 patients over the four seasons, including 465A(H1N1)pdm09, 642A(H3N2), 278 B case-patients and 3910 controls. Among patients unvaccinated in both previous two seasons, current seasonal IVE (pooled across seasons) was 30% (95%CI: -35 to 64), 8% (95%CI: -94 to 56) and 33% (95%CI: -43 to 68) against influenza A(H1N1)pdm09, A(H3N2) and B respectively. Among patients vaccinated in both previous seasons, current seasonal IVE (pooled across seasons) was -1% (95%CI: -80 to 43), 37% (95%CI: 7-57) and 43% (95%CI: 1-68) against influenza A(H1N1)pdm09, A(H3N2) and B respectively. Our results suggest that, regardless of patients' recent vaccination history, current seasonal vaccine conferred some protection to vaccinated patients against hospitalisation with influenza A(H3N2) and B. Vaccination of patients already vaccinated in both the past two seasons did not seem to be effective against A(H1N1)pdm09. To better understand the effect of repeated vaccination, engaging in large cohort studies documenting exposures to vaccine and natural infection is needed. PMID- 28709556 TI - Intussusception among children less than 2years of age: Findings from pre-vaccine introduction surveillance in Pakistan. AB - BACKGROUND: Rotavirus vaccination introduction in routine immunization is under consideration in Pakistan. Data on the baseline epidemiology of intussusception will inform surveillance strategies for intussusception after rotavirus vaccine introduction in Pakistan. We describe the epidemiology of intussusception associated hospitalizations among children <2years of age in Karachi, Pakistan. METHODS: We conducted a retrospective chart review for July 01, 2012 through June 30, 2015 at the National Institute of Child Health (NICH) and Aga Khan University Hospital (AKUH) Karachi. At AKUH, the International Classification of Disease, ninth revision, code 560.0 for intussusception was used to retrieve intussusception case records. At NICH, daily Operation Theater, Emergency Room, and surgical daycare log sheets and surgical ward census sheets were used to identify cases. Records of children who fulfilled eligibility criteria and the Brighton Collaboration level one case definition of intussusception were selected for data analysis. We used structured case report forms to extract data for the descriptive analysis. RESULTS: We identified 158 cases of confirmed intussusception; 30 cases (19%) were from AKUH. More than half (53%) of the cases occurred in children aged 6-12months, followed by 35% among those aged <6months. Two-thirds (106/158) of the cases were male. The most common presenting complaints were vomiting and bloody stool. At NICH, almost all (93%) were managed surgically, while at AKUH, ~57% of the cases were managed with enemas. Three deaths occurred, all from NICH. Cases occurred without any seasonality. At NICH, 4% (128/3618) of surgical admissions among children aged <2years were attributed to intussusception, while that for AKUH was 2% (30/1702). CONCLUSION: In this chart review, intussusception predominantly affected children 0-6months of age and occurred more commonly in males. This information on the baseline epidemiology of intussusception will inform post-vaccine introduction adverse event monitoring related to intussusception in Pakistan. PMID- 28709557 TI - A bivalent live-attenuated influenza vaccine for the control and prevention of H3N8 and H3N2 canine influenza viruses. AB - Canine influenza viruses (CIVs) cause a contagious respiratory disease in dogs. CIV subtypes include H3N8, which originated from the transfer of H3N8 equine influenza virus (EIV) to dogs; and the H3N2, which is an avian-origin virus adapted to infect dogs. Only inactivated influenza vaccines (IIVs) are currently available against the different CIV subtypes. However, the efficacy of these CIV IIVs is not optimal and improved vaccines are necessary for the efficient prevention of disease caused by CIVs in dogs. Since live-attenuated influenza vaccines (LAIVs) induce better immunogenicity and protection efficacy than IIVs, we have combined our previously described H3N8 and H3N2 CIV LAIVs to create a bivalent vaccine against both CIV subtypes. Our findings show that, in a mouse model of infection, the bivalent CIV LAIV is safe and able to induce, upon a single intranasal immunization, better protection than that induced by a bivalent CIV IIV against subsequent challenge with H3N8 or H3N2 CIVs. These protection results also correlated with the ability of the bivalent CIV LAIV to induce better humoral immune responses. This is the first description of a bivalent LAIV for the control and prevention of H3N8 and H3N2 CIV infections in dogs. PMID- 28709558 TI - Not a so peaceful end: Could adult death during sleep be due to hyper-adrenergic mechanism? PMID- 28709559 TI - Blood pressure components and the risk for proteinuria in Japanese men: The Kansai Healthcare Study. AB - BACKGROUND: We examined prospectively which of the four blood pressure (BP) components (systolic BP [SBP], diastolic BP [DBP], pulse pressure [PP], and mean arterial pressure [MAP]) was best in predicting the risk of proteinuria. METHODS: This prospective study included 9341 non-diabetic Japanese middle-aged men who had no proteinuria and an estimated glomerular filtration rate >=60 mL/min/1.73 m2 and were not taking antihypertensive medications at entry. Persistent proteinuria was defined if proteinuria was detected two or more times consecutively and persistently at the annual examination until the end of follow up. We calculated the difference in values of Akaike's information criterion (DeltaAIC) in comparison of the BP components-added model to the model without them in a Cox proportional hazards model. RESULTS: During the 84,587 person-years follow-up period, we confirmed 151 cases of persistent proteinuria. In multiple adjusted models that included a single BP component, the hazard ratios for persistent proteinuria for the highest quartile of SBP, PP, and MAP were 3.11 (95% confidence interval [CI], 1.79-5.39), 1.87 (95% CI, 1.18-2.94), and 2.21 (95% CI, 1.33-3.69) compared with the lowest quartile of SBP, PP, and MAP, respectively. The hazard ratio for the highest quartile of DBP was 2.69 (95% CI, 1.65-4.38) compared with the second quartile of DBP. Of all models that included a single BP component, those that included SBP alone or DBP alone had the highest values of DeltaAIC (14.0 and 13.1, respectively) in predicting the risk of persistent proteinuria. CONCLUSIONS: Of all BP components, SBP and DBP were best in predicting the risk of persistent proteinuria in middle-aged Japanese men. PMID- 28709560 TI - An alternative view on the necessity of EGD before sleeve gastrectomy. AB - BACKGROUND: Esophagogastroduodenoscopy (EGD) is particularly recommended for choosing a surgical method to be used with asymptomatic patients and for the assessment of symptomatic patients prior to sleeve gastrectomy. The presence of hiatal hernia, for instance, is a relative contraindication. EGD is used for malignancy scanning as well as surgical planning, but seems inefficient in determining postoperative complications. OBJECTIVE: Our aim was to investigate the effectiveness of the pathological evaluation of endoscopic biopsies obtained with esophagogastroduodenoscopy (EGD) according to Sydney classification prior to sleeve gastrectomy in identifying the risk of staple line leak, independently of clinical diagnosis. SETTING: Bakirkoy Dr. Sadi Konuk Training and Research Hospital, Department of General Surgery. METHODS: Patients who underwent laparoscopic sleeve gastrectomy between January 2014-December 2016 received preoperative EGD as per the clinic's protocol and upon obtaining ethics board approval and patient consent. Biopsies were taken from the patients according to the Sydney protocol. The pathology results were examined retrospectively by considering the exclusion criteria. The results were given in line with the Sydney classification, and patients with and without Staple Line Leak were statistically compared. RESULTS: A total of 630 patients were enrolled in the study. Of these, 71.1% (n = 448) were female and 28.9% (n = 182) were male. Mean age was 38.9 years (17-68), mean body weight was 130.8kg (94-240) and body mass index (BMI) values were 47.4kg/m2 (36-106). In evaluation of median values, no statistically significant relationship was found between staple line leak and H. pylori occurrence grade (P = 0.438; P>0.05), activation grade (P = 0.568; P>0.05) or intestinal metaplasia grade (P = 0.319; P>0.05). Atrophy (P = 0.001; P<0.01) and chronic inflammation grade (P = 0.026; P<0.05) were significantly higher in Staple Line Leak patients. CONCLUSIONS: EGD prior to sleeve gastrectomy and biopsies obtained in line with the Sydney protocol predict Staple Line Leak risk. PMID- 28709561 TI - Factors Associated With Need for Revascularisation in Non-coronary Arterial Occlusive Lesions Secondary to Takayasu's Arteritis. AB - OBJECTIVE/BACKGROUND: Takayasu's arteritis (TA) is rare inflammatory large vessel form of vasculitis. The objective of this study was to evaluate experience in the management of TA patients and to identify the influence of inflammatory markers and clinical variables associated with disease progression, worsening ischaemic symptoms, and the need for interventions. METHODS: Demographics, and laboratory and clinical variables in patients that required revascularisation procedures were compared with those who had adequate symptomatic control with medical management. Categorical data were analysed with Fisher's exact test, continuous variables with two-sample t test, and a life table analysis was used to study the recurrence of symptoms in intervened patients. RESULTS: From January 1995 to May 2016, 47 patients (mean age 30 years; range 14-59 years) were managed; 44 (94%) were female. During the mean follow-up period of 120 months, 21 (45%) underwent 23 procedures (17 of these [74%] open, six [26%] endovascular). From the intervened group, eight (38%) patients presented with transient ischaemic attacks, five (24%) with renovascular hypertension, and four (19%) with upper extremity and four (19%) lower extremity claudication. Comparative analysis demonstrated that elevation of erythrocyte sedimentation rate (ESR) at the time of the diagnosis (revascularisation group: median value 28 mm/hour; medical management group: median value 15 mm/hour) was associated with progression of the disease, worsening symptoms, and subsequent need for intervention (p = .04). Active smoking was a factor connected with the need for revascularisation (p = .05). Immediate symptomatic improvement occurred in 19 (90%) patients that underwent surgical or endovascular revascularisation. CONCLUSION: Patients with TA who underwent interventions had higher ESR at the time of diagnosis; this factor and active smoking were associated with progression of the disease and worsening ischaemic symptoms despite medical therapy. Revascularisation procedures are effective at relieving symptoms; lifelong surveillance is necessary. PMID- 28709562 TI - Atopic dermatitis: Part I. PMID- 28709563 TI - The history of atopic dermatitis. AB - Fred Wise (1881-1950) and Marion Sulzberger (1895-1983) are often credited with introducing the term atopic dermatitis to dermatology in 1933. This definition was based on atopy, a term first created by Arthur Coca (1875-1959) and Robert Cooke (1880-1960) in 1923, when they recognized an association between allergic rhinitis and asthma. Despite its recent introduction into our medical lexicon, historical precursors of atopic dermatitis date back to at least as early as 69 140 ce. In this contribution, we highlight both the prominent individuals credited with shaping the disorder into our current interpretation and the suspected historical precursors of this disease and reported treatments. PMID- 28709564 TI - Current and emerging concepts in atopic dermatitis pathogenesis. AB - Atopic dermatitis is a common skin disorder with a complex, evolving pathogenesis. Research on the pathogenesis has shifted from focusing primarily on generalized immune system abnormalities in T helper 1/T helper 2 (Th1/Th2) activity to more targeted immune and skin barrier abnormalities contributing to the overall phenotype. Specific signaling pathways recently implicated in atopic dermatitis include production of interleukin (IL) 4 and IL-13, which promote immunoglobulin E production, Th17 and Th22 cells, and production of cytokines. Barrier defect abnormalities, such as a shared filaggrin mutation noted in ichthyosis vulgaris and atopic dermatitis, as well as reduced structural proteins and lipids (eg, ceramides), have been discovered as well. These alterations contribute to increased transepidermal water loss in addition to increased allergen exposure, resulting in debate over the "inside out" versus "outside in" theories-that is, the concept that immunity triggers barrier breakdown versus barrier abnormalities triggering immunologic alteration toward atopy. In fact, it is likely that all of these contribute to pathogenesis, with some individuals initially experiencing immunologic abnormalities more strongly than barrier defects and vice versa. Genetic analyses have continued to advance, leading to the discovery of potential candidate genes relating both to the impaired skin barrier and the altered immune system pathways. This review outlines the evolution of the field of current pathogenesis of atopic dermatitis, highlighting the most pertinent recent findings. PMID- 28709565 TI - Typical and atypical clinical appearance of atopic dermatitis. AB - Atopic dermatitis is a complex, systemic inflammatory disorder associated with a variety of clinical features. The original criteria of Hanifin and Rajka include major criteria and a list of about two dozen minor criteria however, even the minor criteria do not include some features of atopic dermatitis noted less commonly but still seen with some frequency. This contribution first reviews the common clinical appearance of atopic dermatitis in infancy, childhood, and adulthood, as well as the less typical appearances, including lichenoid atopic dermatitis; juvenile plantar dermatosis; nummular-type atopic dermatitis; follicular atopic dermatitis; alopecia of atopic dermatitis; eczema coxsackium; and psoriasiform, perineal, and lip licker's dermatitis. The clinician will be able to recognize and treat rarer forms of atopic dermatitis and incorporate this into their daily practice. PMID- 28709566 TI - Selected comorbidities of atopic dermatitis: Atopy, neuropsychiatric, and musculoskeletal disorders. AB - Atopic dermatitis (AD) is a chronic pruritic inflammatory skin disease with substantial morbidity and quality of life impairment. There are a number of comorbid health problems that occur in patients with AD, aside from the cutaneous signs and symptoms. Chronic pruritus and inflammation can lead to sleep disturbances and mental health symptoms, which are not mutually exclusive. AD is associated with and may predispose to higher risk of other atopic disorders, including asthma and hay fever. Persons with AD appear to be at higher risk for multiple neuropsychiatric disorders, including depression, attention deficit/hyperactivity disorder, speech disorders in childhood, headaches, and seizures. There is also a multifactorial association of AD with osteoporosis, injuries, and fractures. Elucidating the comorbidities of AD is important for disease management and improving overall clinical outcomes. This review summarizes recent developments in the atopic and neuropsychiatric comorbidities of AD. PMID- 28709568 TI - Current and emerging topical therapies for atopic dermatitis. AB - The pathogenesis of atopic dermatitis (AD) involves epidermal barrier dysfunction and T helper cell type 2 (Th2) lymphocyte-driven inflammation. Cytokines, such as interleukin 4 (IL-4) and IL-13, are important in this reaction. They stimulate B cells to produce immunoglobulin E, causing atopic disease. This process has been well characterized, and new therapies for AD, such as phosphodiesterase 4 (PDE-4) inhibitors, Th2-expressed chemoattractant receptor-homologous molecule antagonists, and Janus kinase inhibitors, work by antagonizing this cellular pathway. Recently, there have been many advances in treatment strategies and novel therapies for AD. This review summarizes the clinical evidence supporting the use of current and emerging topical treatments for AD, as well as their safety and efficacy profiles. Crisaborole, a novel PDE-4 inhibitor, is of particular note because phase III clinical trials were recently completed, as summarized here. It is prudent for dermatologists to be current with updates in the field because therapies are constantly changing. In addition to the academic interest, this results in improvement of patient care and advancement of the field. PMID- 28709567 TI - Contact dermatitis considerations in atopic dermatitis. AB - Complex immunologic pathways, influenced by both genetic and environment triggers, contribute to the development of atopic dermatitis and allergic contact dermatitis. Suppressing mechanisms between the Th1-driven allergic contact dermatitis and the Th2-driven atopic dermatitis conditions were thought to reduce the simultaneous expression of both; however, recent evidence indicates that pediatric patients with atopic dermatitis are likely to develop clinically relevant positive patch tests and more likely to react to specific allergens, such as lanolin. We review the potential role of skin barrier defects, such as filaggrin mutations and impaired barrier function, including aberrancies in epidermal pH buffering capabilities, which may promote bacterial biofilms and create an environment favoring sensitization. PMID- 28709569 TI - Selected active naturals for atopic dermatitis: Atopic Dermatitis Part 1. AB - The desire for naturally derived agents is a growing trend for patients, physicians, and pharmaceutical companies. Studies indicate that complementary and alternative medicine is often used by patients and parents of children with atopic dermatitis, not necessarily with beneficial results. A half-dozen natural agents (ie, topical agents: coconut oil, colloidal oatmeal, sunflower oil, mustard oil, glycerin, and oral Chinese herbal therapy) are discussed because they have become popular for their expected activity in the therapy of atopic dermatitis. A critical review of the published literature on these agents is presented with specific focus on potential such side effects as hepatotoxicity with Chinese herbals. PMID- 28709570 TI - Systemic therapies in atopic dermatitis: The pipeline. AB - Atopic dermatitis (AD), the most prevalent inflammatory skin disease, is characterized by robust T-cell activation. The disease has several subtypes, all having a common T helper type 2 (Th2)/Th22 polarization, but it also displays differential immune skewing, such as increased Th17/interleukin 23 skewing in the skin of intrinsic, Asian, and early pediatric AD patients. Current systemic treatments for moderate to severe AD are largely unsatisfactory, associated with significant adverse effects and low compliance. A large unmet need exists for better therapeutics for moderate to severe AD. The translational revolution, first transforming the psoriasis treatment paradigm, is now becoming applicable for AD, with multiple targeted drugs being investigated in trials. The new treatments often have increased tolerability and specificity and higher efficacy compared with conventional treatments. The clinical testing of these targeted drugs can also provide an opportunity to further elucidate AD pathogenesis by dissecting the contribution of specific cytokines to the disease phenotype. By reviewing developing therapeutics for AD according to their pathway-specific mechanisms, this contribution also outlines the complex molecular characteristics of AD. PMID- 28709571 TI - Timing of food introduction and atopy prevention. AB - The apparent increase in atopic disease, particularly food allergy, over the past 2 decades has resulted in reconsideration of prevention strategies aimed at the infant's diet. Early advice to have atopy-prone infants delay ingestion of potential food allergens, such as egg, cow's milk, and peanut, was rescinded, as new evidence emerged that did not support these approaches. More recently, randomized controlled trials have provided data to support an opposite strategy, promoting early ingestion of allergens as a means of food allergy prevention. Specifically, new guidelines suggest early ingestion of peanut as a means to prevent peanut allergy. Additional dietary approaches regarding breastfeeding, early introduction of other types of food allergens, formula feeding, dietary nutrients, and probiotics are also under scrutiny as potential preventative strategies. This review focuses on the timing of food introduction as a preventative strategy for food allergy and also discusses other aspects of the infant diet that may provide opportunities for prevention of atopic disease. PMID- 28709572 TI - The balancing act of societies and of clinical histories. AB - Individuals and societies are, respectively, confederations of cells and individuals. They function well only if their constituents work in a complementary and harmonious way. This is regulated by control mechanisms. Failure or malfunction of these leads to disease or social upheaval, respectively. Medicine, including dermatology, and government act by restoring homeostasis when self-regulation is unable to do so. Long-term or even permanent survival of individuals and societies can be achieved when profound understanding of control mechanisms becomes a reality. PMID- 28709574 TI - Progress of the Journal of Prosthodontic Research under the four-year action plan. PMID- 28709573 TI - "Wolf's isotopic response": the originators speak their mind and set the record straight. AB - Having been the first to have introduced the concept of "isotopic response" three decades ago, we wanted to express some of our thoughts on its current application, now that more than 100 such cases have been reported in the literature. It is, of course, gratifying to read about its appropriate application, and it is our hope that others will refrain from distorting its original meaning. PMID- 28709576 TI - There are probably no differences in the oral health-related quality of life of partially edentulous patients who received oral rehabilitation with shortened dental arch versus conventional treatment. PMID- 28709577 TI - Insufficient evidence suggesting an association between maternal tobacco exposure and cleft lip and palate. PMID- 28709578 TI - Insufficient evidence to support benefits of ibuprofen sodium dihydrate over ibuprofen acid to reduce pain in patients with acute odontogenic pain. PMID- 28709579 TI - Use of a microscope during endodontic treatment seems to have helped locating second mesiobuccal root in maxillary first molars that needed retreatment. PMID- 28709580 TI - Premolar extraction as part of orthodontic treatment may result in a small increase in retromolar space and improve third-molar angulation. PMID- 28709581 TI - Trends in end-of-life care and health care spending in women with uterine cancer. AB - BACKGROUND: High-intensity care including hospitalizations, chemotherapy, and other interventions at the end of life is costly and often of little value for cancer patients. Little is known about patterns of end-of-life care and resource utilization for women with uterine cancer. OBJECTIVE: We examined the costs and predictors of aggressive end-of-life care for women with uterine cancer. STUDY DESIGN: In this observational cohort study the Surveillance, Epidemiology, and End Results-Medicare linked database was used to identify women age >=65 years who died from uterine cancer from 2000 through 2011. Resource utilization in the last month of life including >=2 hospital admissions, >1 emergency department visit, >=1 intensive care unit admission, or use of chemotherapy in the last 14 days of life was examined. High-intensity care was defined as the occurrence of any of the above outcomes. Logistic regression models were developed to identify factors associated with high-intensity care. Total Medicare expenditures in the last month of life are reported. RESULTS: Of the 5873 patients identified, the majority had stage IV cancer (30.2%), were white (79.9%), and had endometrioid tumors (47.6%). High-intensity care was rendered to 42.5% of women. During the last month of life, 15.0% had >=2 hospital admissions, 9.0% had a hospitalization >14 days, 15.3% had >1 emergency department visits, 18.3% had an intensive care unit admission, and 6.6% received chemotherapy in the last 14 days of life. The percentage of women who received high-intensity care was stable over the study period. Characteristics of younger age, black race, higher number of comorbidities, stage IV disease, residence in the eastern United States, and more recent diagnosis were associated with high-intensity care. The median Medicare payment during the last month of life was $7645. Total per beneficiary Medicare payments remained stable from $9656 (interquartile range $3190-15,890) in 2000 to $9208 (interquartile range $3309-18,554) by 2011. The median health care expenditure was 4 times as high for those who received high-intensity care compared to those who did not (median $16,173 vs $4099). CONCLUSION: Among women with uterine cancer, high-intensity care is common in the last month of life, associated with substantial monetary expenditures, and does not appear to be decreasing. PMID- 28709582 TI - The incidence of transfusion and associated risk factors in pelvic reconstructive surgery. AB - BACKGROUND: Almost 400,000 female pelvic reconstructive operations were performed in 2010 for urinary incontinence and pelvic organ prolapse in the United States, and it is likely that this will continue to increase each year. There is a lack of population-based data evaluating the risk of blood transfusion after urogynecologic procedures. OBJECTIVE: We sought to assess the incidence of blood transfusion related to pelvic reconstructive surgery in a large national surgical quality database and to identify transfusion-associated risk factors. STUDY DESIGN: This retrospective cohort study was performed using the National Surgical Quality Improvement Program database from the years 2010 through 2014. All women undergoing surgery for pelvic floor disorders were identified by Current Procedural Terminology code. Demographic and clinical variables were abstracted. The incidence of blood transfusion was determined. A multivariate logistic regression analysis was performed to identify clinical factors independently associated with blood transfusion. RESULTS: A total of 54,387 women underwent pelvic reconstructive surgery from 2010 through 2014 in the National Surgical Quality Improvement Program database. Of these subjects, 686 (1.26%) received a blood transfusion. The median age was 57 (range 28-89) years. Of the population, 0.81% was underweight (body mass index <18.5), 27.0% was normal weight (body mass index 18.5-24.9), 35.6% was overweight (body mass index 25-29.9), and 36.7% was obese (body mass index >=30). The majority of subjects in the study cohort were Caucasian (91.4%) followed by African Americans (4.6%); the remainder included Asian, American Indian/Alaska Native, and Native Hawaiian/Pacific Islander. Hispanic ethnicity was reported in 9.3% of the population. American Society of Anesthesiologists class 1 and 2 represented a majority of the sample (76.5%). Concomitant hysterectomy was performed in 20,735 (38.1%) of the population. In the multivariate analysis, preoperative hematocrit <30% (odds ratio, 13.68; 95% confidence interval, 10.65-17.59), history of coagulopathy (odds ratio, 3.74; 95% confidence interval, 2.50-5.60), and concomitant hysterectomy (odds ratio, 1.77; 95% confidence interval, 1.49-2.12) were factors independently associated with receiving blood transfusion (all P < .05). When compared to American Society of Anesthesiologists class 1, patients who were class 3 (odds ratio, 2.82, P < .01; 95% confidence interval, 2.02-3.93) or class 4 (odds ratio, 6.56, P < .01; 95% confidence interval, 3.65-11.78) were more likely to require a transfusion. When compared to Caucasians, African Americans (odds ratio, 1.73, P < .01; 95% confidence interval, 1.27-2.36) and Hispanics (odds ratio, 1.92, P < .01; 95% confidence interval, 1.54-2.40) were more likely to require a transfusion. In this cohort, overweight (odds ratio, 0.75; 95% confidence interval, 0.62-0.93) and obese (odds ratio, 0.61; 95% confidence interval, 0.49-0.75) subjects were less likely to receive a transfusion. When compared to a vaginal approach, patients who had a minimally invasive approach (odds ratio, 0.63; 95% confidence interval, 0.49-0.83) were less likely to receive a transfusion, while those with an open approach were more likely to receive a transfusion (odds ratio, 5.43; 95% confidence interval, 4.49-6.56). Age was not a risk factor for transfusion. CONCLUSION: Transfusion after pelvic reconstructive surgery is uncommon. The variables associated with transfusion are preoperative hematocrit <30%, American Society of Anesthesiologists class, bleeding disorders, nonwhite race, Hispanic ethnicity, and concomitant hysterectomy. Recognition of these factors can help guide preoperative counseling regarding transfusion risk after pelvic reconstructive surgery and individualize preoperative preparation. PMID- 28709583 TI - Interactions among pelvic organ protrusion, levator ani descent, and hiatal enlargement in women with and without prolapse. AB - BACKGROUND: Pelvic organ prolapse has 2 components: (1) protrusion of the pelvic organs beyond the hymen; and (2) descent of the levator ani. The Pelvic Organ Prolapse Quantification system measures the first component, however, there remains no standard measurement protocol for the second mechanism. OBJECTIVE: We sought to test the hypotheses that: (1) difference in the protrusion area is greater than the area created by levator descent in prolapse patients compared with controls; and (2) prolapse is more strongly associated with levator hiatus compared to urogenital hiatus. STUDY DESIGN: Midsagittal magnetic resonance imaging scans from 30 controls, 30 anterior predominant, and 30 posterior predominant prolapse patients were assessed. Levator area was defined as the area above the levator ani and below the sacrococcygeal inferior pubic point line. Protrusion area was defined as the protruding vaginal walls below the levator area. The levator hiatus and urogenital hiatus were measured. Bivariate analysis and multiple comparisons were performed. Bivariate logistic regression was performed to assess prolapse as a function of levator hiatus, urogenital hiatus, levator area, and protrusion. Pearson correlation coefficients were calculated. RESULTS: The levator area for the anterior (34.0 +/- 6.5 cm2) and posterior (35.7 +/- 8.0 cm2) prolapse groups were larger during Valsalva compared to controls (20.9 +/- 7.8 cm2, P < .0001 for both); similarly, protrusion areas for the anterior (14.3 +/- 6.2 cm2) and posterior (14.4 +/- 5.7 cm2) prolapse groups were both larger compared to controls (5.0 +/- 1.8 cm2, P < .0001 for both). The levator hiatus length for the anterior (7.2 +/- 1 cm) and posterior (6.9 +/- 1 cm) prolapse groups were longer during Valsalva compared to controls (5.2 +/- 1.5 cm, P < .0001 for both); similarly, urogenital hiatus lengths for the anterior (5.7 +/- 1 cm) and posterior (6.3 +/- 1.1 cm) prolapse groups were both longer than controls (3.8 +/- 0.8 cm, P < .0001 for both). The difference in levator area in prolapse patients compared with controls was greater than the difference in protrusion area (14.0 +/- 7.2 cm2 vs 9.4 +/- 5.9 cm2, P < .0002). The urogenital hiatus was more strongly associated with prolapse than the levator hiatus (odds ratio, 12.9; 95% confidence interval, 4.1-39.2, and odds ratio, 4.3; 95% confidence interval, 2.3-7.5). Levator hiatus and urogenital hiatus are both correlated with levator and protrusion areas, and all were associated with maximum prolapse size (P <= .001, for all comparisons). CONCLUSION: In prolapse, the levator area increases more than the protrusion area and both the urogenital hiatus and levator hiatus are larger. The odds of prolapse for an increase in the urogenital hiatus are 3 times larger than for the levator hiatus, which leads us to reject both the original hypotheses. PMID- 28709584 TI - First sacral nerve and anterior longitudinal ligament anatomy: clinical applications during sacrocolpopexy. AB - BACKGROUND: The recommended location of graft attachment during sacrocolpopexy is at or below the sacral promontory on the anterior surface of the first sacral vertebra. Graft fixation below the sacral promontory may potentially involve the first sacral nerve. OBJECTIVE: The objectives of this study were to examine the anatomy of the right first sacral nerve relative to the midpoint of the sacral promontory and to evaluate the thickness and ultrastructural composition of the anterior longitudinal ligament at the sacral promontory level. STUDY DESIGN: Anatomic relationships were examined in 18 female cadavers (8 unembalmed and 10 embalmed). The midpoint of the sacral promontory was used as reference for all measurements. The most medial and superior point on the ventral surface of the first sacral foramen was used as a marker for the closest point at which the first sacral nerve could emerge. Distances from midpoint of sacral promontory and the midsacrum to the most medial and superior point of the first sacral foramen were recorded. The right first sacral nerve was dissected and its relationship to the presacral space was noted. The anterior longitudinal ligament thickness was examined at the sacral promontory level in the midsagittal plane. The ultrastructural composition of the ligament was evaluated using transmission electron microscopy. Height of fifth lumbar to first sacral disc was also recorded. Descriptive statistics were used for data analyses. RESULTS: Median age of specimens was 78 years and median body mass index was 20.1 kg/m2. Median vertical distance from midpoint of sacral promontory to the level of the most medial and superior point of the first sacral foramen was 26 (range 22-37) mm. Median horizontal distance from the midsacrum to the first sacral foramen was 19 (range 13-23) mm. In all specimens, the first sacral nerve was located just behind the layer of parietal fascia covering the piriformis muscle, and thus, outside the presacral space. Median anterior longitudinal ligament thickness at the sacral promontory level was 1.9 (range 1.2-2.5) mm. Median fifth lumbar to first sacral disc height was 16 (8.3-17) mm. CONCLUSION: Awareness of the first sacral nerve position, approximately 2.5 cm below the midpoint of the sacral promontory and 2 cm to the right of midline, should help anticipate and avoid somatic nerve injury during sacrocolpopexy. Knowledge of the approximate 2-mm thickness of the anterior longitudinal ligament should help reduce risk of discitis and osteomyelitis, especially when graft is affixed above the level of the sacral promontory. PMID- 28709585 TI - Patients come from populations and populations contain patients. A two-stage scientific and ethics review: The next adaptation for single institutional review boards. AB - INTRODUCTION: For nearly 50 years, institutional review boards (IRB) and independent ethics committees have featured local oversight as a core function of research ethics reviews. However growing complexity in Alzheimer's clinical research suggests current approaches to research volunteer safety is hampering development of new therapeutics. As a partial response to this challenge, the NIH has mandated that all NIH-funded multi-site studies will use a single Institutional Review Board. The perspective describes a joint program to provide a single IRB of record (sIRB) for phases of multi-site studies. METHODS: The approach follows two steps. One, an expert Scientific Review Committee (SRC) of senior researchers in the field will conduct the review principally of scientific merit, significance, feasibility, and the likelihood of meaningful results. The second step will be the IRB's regulatory and ethics review. The IRB will apply appropriate regulatory criteria for approval including minimization of risks to subjects and risks reasonable in relation to anticipated benefits, equitable subject selection, informed consent, protections for vulnerable populations, and application of local context considerations, among others. RESULTS: There is a steady demand for scientific, ethical and regulatory review of planned Alzheimer's studies. As of January 15, 2017, there are nearly 400 open studies, Phase II and III, industry and NIH sponsored trials on disease indications affecting memory, movement and mood in the US. CONCLUSIONS: The effort will initially accept protocols for studies of Alzheimer's disease, dementia, and related disorders effecting memory, movement and mood. Future aims will be to provide scientific review and, where applicable, regulatory and ethical review in an international context outside North America with sites possibly in Asia, Europe and Australia. PMID- 28709586 TI - Muscle strength can better differentiate between gradations of functional performance than muscle quality in healthy 50-70y women. AB - OBJECTIVE: It is not known which laboratory indices of muscle mass, strength or quality can distinguish functional performance in healthy middle aged women. The aim of this study was to (a) examine the association between upper leg lean tissue mass, knee extensor strength, muscle quality (strength per unit lean tissue mass) and functional performance and (b) to determine the utility of tertiles of muscle strength and muscle quality to distinguish gradations of functional capacity in healthy 50-70y women. METHODS: Using a cross-sectional study design, one hundred and twenty-eight healthy 50-70y women (mean age: 60.4, SD=5.1y) underwent body composition assessment (dual X-ray absorptiometry) and performed maximal voluntary isometric contractions of the knee extensors (Con Trex Dynamometer). Functional performance was assessed using a 5 repetition and 30s chair rise test and 900m gait speed test. RESULTS: Ordered by muscle strength or muscle quality, those in the highest tertile (T1) demonstrated greater functional performance than those in lowest tertile (T3). There was no association between upper leg lean tissue mass and functional performance (r=<=0.06). Muscle strength explained a greater proportion of the variance in all functional performance measures relative to muscle quality (R2=0.13-0.36 vs. R2=0.11-0.16). CONCLUSION: Upper leg lean tissue mass is not associated with physical performance in healthy 50-70y women. These results suggest strength relative to the body mass being accelerated distinguishes gradations in functional performance better than muscle quality healthy 50-70y women. PMID- 28709587 TI - Reference values for the bilateral heel-rise test. AB - BACKGROUND: The bilateral heel-rise test is an instrument that evaluates the performance of the triceps surae. Normative parameters need to be established for the use of the heel-rise test in clinical practice. OBJECTIVE: To determine the reference values for the bilateral heel-rise test. METHODS: This cross-sectional study assessed healthy subjects using the bilateral heel-rise test. We analyzed the number of repetitions, time (in seconds), and repetition rate (repetitions/second) during execution of the heel-rise test, until the point of voluntary fatigue. The estimates were stratified by age and gender. Multiple linear regression was performed to define the reference equation for the bilateral heel-rise test. RESULTS: A total of 147 individuals were included. The median age was 37 years (IQR 28-46). It was observed that the number of repetitions decreases with age, with a higher number of repetitions in male participants compared to female participants. Gender, body mass index, and maximum activity scores predict 14% of the number of plantar flexions performed in the bilateral heel-rise test. Age and adjusted activity scores predict 18% of the repetition rate in the bilateral heel-rise test. CONCLUSION: The bilateral heel-rise test reference values for an adult population were defined as scores above the 25th percentile for number of repetitions, time, and repetition rate. The number of heel-rise test repetitions that corresponds to the 25th percentile, according to age and gender, is as follows: age 20-29, 65 repetitions for men and 45.5 for women; age 30-39, 62.75 men and 41.5 women; age 40-49, 67.25 men and 45 women; and age 50-59, 54 men and 39.25 women. PMID- 28709590 TI - Striatal necrosis due to the m.14459G>A mutation. PMID- 28709592 TI - Vascular calcification in chronic kidney disease: here to stay? AB - Vascular calcification is common in patients with advanced kidney disease, and has been strongly linked to cardiovascular morbidity and mortality in the general population. Recent clinical and translational studies demonstrate that vascular calcification is also associated with cardiovascular morbidity in the setting of chronic kidney disease, and that once established, may persist even when kidney function is restored. PMID- 28709588 TI - Postural disorders in mouth breathing children: a systematic review. AB - BACKGROUND: Mouth breathing syndrome can cause sleep disturbances that compromise the performance of children in school. It might also cause postural abnormalities involving the head and cervical spine; however, the association between postural abnormalities and mouth breathing in children is unclear. OBJECTIVE: To assess the methodological quality of studies and determine if there is an association between mouth breathing and postural disorders in children. METHODS: Databases comprised MEDLINE, CINAHL, PEDro, LILACS, EMBASE and Cochrane Central Registrar of Controlled Trials. Searches were until March 2016 and included studies that evaluated postural disorders in children diagnosed with mouth breathing. The Downs and Black checklist was used to evaluate the quality of the evidences. RESULTS: Ten studies were included totaling 417 children from 5 to 14 years. Two studies used the New York State Postural Rating Scale, seven used photography and one used motion capture to measure posture. The methods used to analyze the data included the Postural Analysis Software (SAPO), Fisiometer, ALCimagem and routines in MATLAB program. Quality assessment resulted in low scores (<14) for all the studies. The main areas of weakness were a clear description of the participants, of the methods used to access posture, of the principal confounders and lack of power analysis. External and internal validity were also threatened by the lack of a representative sample and blinding of the participants and assessors, respectively. CONCLUSIONS: The review provides low evidence that mouth breathing pattern in children between the ages 5-14 years is associated with postural deviations. PMID- 28709589 TI - Initial experience of transcatheter closure of subarterial VSD with the Amplatzer duct occluder. AB - BACKGROUND: The traditional treatment of subarterial ventricular septal defect (VSD) is open heart surgery. This study aimed to evaluate the feasibility, safety and outcome of transcatheter closure with the Amplatzer duct occluder (ADO). METHODS: Between March 2012 and June 2015, a total of 16 patients (8 male and 8 female) with subarterial VSD who underwent transcatheter closure with the ADO were enrolled retrospectively. Their age ranged from 3.0 to 65.6 years, with the median of 35.6 years; their body weights ranged from 14 to 92 kg with the median of 60 kg. All patients had prolapse of the right coronary cusp without subaortic rim. Mild aortic regurgitation was noted in 11 (69%) patients. RESULTS: Left ventriculogram showed VSD size ranged from 1.3 to 9.3 mm with the median of 3.5 mm. The device was successfully implanted in 88% (14/16) of the patients. Although one patient had mild skin allergy to contrast medium, no other complication was noted. Complete closure rate was 64%, 86%, 86% and 86% at 1-day, 1-month, 6-month and 12-month follow-up, respectively. Two patients developed new or worsening aortic regurgitation during follow-up. CONCLUSION: Transcatheter closure of subarterial VSD with ADO is technically feasible and safe in patients older than 7 years of age. However, development or worsening of aortic regurgitation requires long-term follow-up. PMID- 28709593 TI - Mucosal corticosteroid therapy of IgA nephropathy. AB - The value of systemic immunosuppressive therapy for IgA nephropathy is uncertain. A recently completed randomized controlled phase II trial demonstrates that specially encapsulated budesonide, released preferentially in the terminal ileum, can reduce proteinuria and stabilize glomerular filtration rate in patients with IgA nephropathy. PMID- 28709594 TI - Emerging roles of nuclear phosphatase SCP4 in CKD-associated muscle wasting. AB - Cachexia with wasting of muscle protein is a serious complication of chronic kidney disease (CKD). Muscle protein phosphorylation is a potential therapeutic target. Liu et al. reported that small C-terminal domain phosphatase (SCP) 4 was increased in muscles of patients and mice with CKD. Importantly, knockdown of SCP4 significantly ameliorated muscle wasting in CKD mice. Inhibition of SCP4 may represent a novel therapeutic intervention for muscle wasting in patients with CKD. PMID- 28709595 TI - Losing their footing: Rac1 signaling causes podocyte detachment and FSGS. AB - Selective modulation of Rho GTPase activity in podocytes recapitulates characteristic features of human nephrosis. Using a mouse model, Robins et al. found that high levels of Rac1 activation in podocytes caused podocyte detachment and glomerulosclerosis. Podocyte Rac1 activity was enhanced in biopsy specimens from patients with nephrosis, and serum from this patient population activated Rac1 in cultured podocytes. These data provide a causal link between podocyte Rac1 activation and human nephrotic diseases. PMID- 28709596 TI - Be on alert for pediatric AKI. AB - Acute kidney injury in children is associated with adverse outcomes, although much of our current understanding originates from studies in intensive care units. Holmes et al. used an automated acute kidney injury detection method to obtain epidemiologic data on pediatric acute kidney injury at a national level in outpatient, inpatient, and intensive care unit settings. We discuss the impact of these important results and the considerations needed with this approach. PMID- 28709597 TI - Outcomes and renal function trajectory after acute kidney injury: the narrow road to perdition. AB - Analyses of the Grampian Laboratory Outcomes Morbidity and Mortality Study-II cohort support the notion that acute kidney injury (AKI) increases the risk of progression of glomerular filtration rate after recovery from AKI to a new baseline. However, the findings have to be considered in the bigger context of the absolute event rates for de novo progression versus nonrecovery and the competing risk of death after AKI. Examination of the data raises important implications for the design and implementation of clinical trials with interventions that target the AKI-to-chronic kidney disease transition. PMID- 28709598 TI - Simplifying the hemodialysis prescription in patients with ethylene glycol poisoning. AB - The management of ethylene glycol poisoning is multimodal and usually includes hemodialysis. The usual approach for guiding treatment duration is iterative, based on serial measurements of ethylene glycol concentration and routine biochemistry. In this issue, Iliuta et al. present a simplified approach to determining the duration of hemodialysis based on a single ethylene glycol concentration. Although this appears reasonable in many cases, there are circumstances in which further consideration is warranted and it only applies to high-efficiency intermittent hemodialysis. PMID- 28709599 TI - Recurrence of glomerulonephritis: an underestimated and unmet medical need. AB - Recurrent glomerulonephritis is increasingly recognized as an important contributor to premature renal allograft failure. The incidence of recurrent glomerulonephritis varies widely depending on original disease, renal biopsy policy, and time of observation. Biopsy-documented clinical recurrence rates underestimate the true prevalence. The impact of recurrent glomerulonephritis on graft survival parameters also widely varies and requires large collaborative efforts with more detailed and balanced evaluations, such as other major causes for chronic renal allograft dysfunction. PMID- 28709601 TI - Nonosmotic Na+ storage and the Edelman equation. PMID- 28709600 TI - Challenges in conducting clinical trials in nephrology: conclusions from a Kidney Disease-Improving Global Outcomes (KDIGO) Controversies Conference. AB - Despite the high costs of treatment of people with kidney disease and associated comorbid conditions, the amount of reliable information available to guide the care of such patients is very limited. Some treatments have been assessed in randomized trials, but most such trials have been too small to detect treatment effects of a magnitude that would be realistic to achieve with a single intervention. Therefore, KDIGO convened an international, multidisciplinary controversies conference titled "Challenges in the Conduct of Clinical Trials in Nephrology" to identify the key barriers to conducting trials in patients with kidney disease. The conference began with plenary talks focusing on the key areas of discussion that included appropriate trial design (covering identification and evaluation of kidney and nonkidney disease outcomes) and sensible trial execution (with particular emphasis on streamlining both design and conduct). Break out group discussions followed in which the key areas of agreement and remaining controversy were identified. Here we summarize the main findings from the conference and set out a range of potential solutions. If followed, these solutions could ensure future trials among people with kidney disease are sufficiently robust to provide reliable answers and are not constrained by inappropriate complexities in design or conduct. PMID- 28709602 TI - The Authors Reply. PMID- 28709603 TI - The Authors Reply. PMID- 28709604 TI - Proton pump inhibitors and chronic kidney disease. PMID- 28709605 TI - Complement-dependent, monoclonal gammapathy-associated thrombotic microangiopathy. PMID- 28709606 TI - Prospective studies using risk scores are needed for established associations for worse clinical outcomes. PMID- 28709607 TI - The Authors Reply. PMID- 28709608 TI - APOL1 G2 risk allele-clarifying nomenclature. PMID- 28709609 TI - Adenovirus pyelonephritis in the late posttransplant period. PMID- 28709610 TI - A critically ill newborn with a distended abdomen. PMID- 28709612 TI - Editorial. PMID- 28709611 TI - The Case | Epistasis and urolithiasis. PMID- 28709613 TI - A regional registry study of 216 patients investigating if patient satisfaction after total knee arthroplasty changes over a time period of five to 20years. AB - AIMS: To determine the temporal changes in patient dissatisfaction following primary knee arthroplasty surgery (TKA). PATIENTS AND METHODS: Three hundred and ninety patients that had previously indicated they were either dissatisfied or unsure with their TKA at one-year post-surgery in our region were mailed a simple questionnaire in addition to the Oxford Knee Score and EQ-5D. RESULTS: A 55% response rate was achieved. The mean follow-up time period was 9.1years. Of the 120 patients who were initially dissatisfied, 46.7% remained so. Of the 96 patients who were initially unsure, 20.8% remained so, 21.9% and 57.3% became dissatisfied and satisfied, respectively. The primary reason for continued dissatisfaction was persistent pain. Of the 19.4% of patients who had revision surgery, 47.6% remained dissatisfied. 54.2% of patients stated that they would be happy to have a primary TKA again and 55.6% indicated that they would recommend one to a friend. Patients who had concurrent hip pain were six times more likely to remain unsure or dissatisfied over time (OR 6.7, p-value 0.0000). Patients who had back pain or contralateral knee pain were two or three times as likely to remain unsure or dissatisfied. CONCLUSION: In time half of the patients who stated that they were not satisfied with their arthroplasty, at one year, go on to be satisfied with their knee. PMID- 28709614 TI - Generation of recombinant protein shells of Johnson grass chlorotic stripe mosaic virus in tobacco plants and their use as drug carrier. AB - The development and use of virus-like particles (VLPs) is a growing field with a powerful potential in generation of nanoparticles. In the present study we have attempted to generate and use empty shells of Johnson grass chlorotic stripe mosaic virus (JgCSMV, a member of the genus Aureusvirus, family Tombusviridae) as VLP nanoparticles for drug loading. In order to successfully produce recombinant JgCSMV-derived VLPs, we followed an approach based on cloning of the JgCSMV CP gene into pBI121 vector and introduction of the latter into Agrobacterium rhizogenes and transformation of tobacco cells for coat protein expression. Expression in tobacco tissue was demonstrated in transformed hairy roots as a model system. Recombinant VLPs were purified, analyzed by immune assay and visulalized by electron microscopy. Next, we explored the possibility of using JgCSMV-derived VLPs as a nanocontainer for loading the anticancer drug doxorubicin (DOX), taking advantage of the reversible swelling of VLPs in vitro. The results showed that transformed hairy roots produced high levels of the recombinant protein that readily assembled to form empty shells with overall structure similar to native virus particles. In addition, we demonstrated that JgCSMV-VLPs could function as vehicles able to load the chemotherapeutic drug doxorubicin. To our knowledge, this is the first research addressing the question of how this icosahedral virus (JgCSMV) can be used for the production of nanocontainers for biomedical applications. PMID- 28709616 TI - Intense Local Reaction at the Sites of Injection of Lipolytic Mesotherapy. PMID- 28709615 TI - Transcriptional profiling of Rickettsia prowazekii coding and non-coding transcripts during in vitro host-pathogen and vector-pathogen interactions. AB - Natural pathogen transmission of Rickettsia prowazekii, the etiologic agent of epidemic typhus, to humans is associated with arthropods, including human body lice, ticks, and ectoparasites of eastern flying squirrel. Recently, we have documented the presence of small RNAs in Rickettsia species and expression of R. prowazekii sRNAs during infection of cultured human microvascular endothelial cells (HMECs), which represent the primary target cells during human infections. Bacterial noncoding transcripts are now well established as critical post transcriptional regulators of virulence and adaptation mechanisms in varying host environments. Despite their importance, little is known about the expression profile and regulatory activities of R. prowazekii sRNAs (Rp_sRs) in different host cells encountered as part of the natural life-cycle. To investigate the sRNA expression profile of R. prowazekii during infection of arthropod host cells, we employed an approach combining in vitro infection, bioinformatics, RNA sequencing, and PCR-based quantitation. Global analysis of R. prowazekii transcriptome by strand-specific RNA sequencing enabled us to identify 67 cis acting (antisense) and 26 trans-acting (intergenic) Rp_sRs expressed during the infection of Amblyomma americanum (AAE2) cells. Comparative evaluation of expression during R. prowazekii infection of HMECs and AAE2 cells by quantitative RT-PCR demonstrated significantly higher expression of four selected Rp_sRs in tick AAE2 cells. Examination of the coding transcriptome revealed differential up regulation of >150 rickettsial genes in either HMECs or AAE2 cells and yielded evidence for host cell-dependent utilization of alternative transcription start sites by 18 rickettsial genes. Our results thus suggest noticeable differences in the expression of both Rp_sRs as well as the coding transcriptome and the exploitation of multiple transcription initiation sites for select genes during the infection of human endothelium and tick vector cells as the host and yield new insights into rickettsial virulence and transmission mechanisms. PMID- 28709617 TI - Mumps, Measles, and Rubella Vaccine for the Treatment of a Recalcitrant Subungual Wart. PMID- 28709618 TI - Lupus Erythematosus Affecting the Genitalia: An Unusual Site. PMID- 28709619 TI - Umbilicated Papules on the Elbows of a Woman With Systemic Vasculitis. PMID- 28709620 TI - Synthesis and anti-diabetic activity of new N,N-dimethylphenylenediamine derivatized nitrilotriacetic acid vanadyl complexes. AB - Vanadium compounds are promising anti-diabetic agents. However, reducing the metal toxicity while keeping/improving the hypoglycemic effect is still a big challenge towards the success of anti-diabetic vanadium drugs. To improve the therapeutic potency using the anti-oxidative strategy, we synthesized new N,N dimethylphenylenediamine (DMPD)-derivatized nitrilotriacetic acid vanadyl complexes ([VO(dmada)]). The in vitro biological evaluations revealed that the DMPD-derivatized complexes showed improved antioxidant capacity and lowered cytotoxicity on HK-2 cells than bis(maltolato)oxidovanadium (IV) (BMOV). In type II diabetic mice, [VO(p-dmada)] (0.15mmolkg-1/day) exhibited better hypoglycemic effects than BMOV especially on improving glucose tolerance and alleviating the hyperglycemia-induced liver damage. These insulin enhancement effects were associated with increased expression of peroxisome proliferator-activated receptor alpha and gamma (PPARalpha/gamma) in fat, activation of Akt (v-Akt murine thymoma viral oncogene)/PKB (protein kinase-B) in fat and liver, and inactivation of c-Jun NH2-terminal protein kinases (JNK) in liver. Moreover, [VO(p-dmada)] showed no tissue toxicity at the therapeutic dose in diabetic mice and the oral acute toxicity (LD50) was determined to be 1640mgkg-1. Overall, the experimental results indicated that [VO(p-dmada)] can be a potent insulin enhancement agent with improved efficacy-over- toxicity index for further drug development. In addition, the results on brain Tau phosphorylation suggested necessary investigation on the effects of vanadyl complexes on the pathology of the Alzheimer's disease in the future. PMID- 28709621 TI - Role of N-acetyl galactosamine-4-SO4, a ligand of CD206 in HSV-induced mouse model of Behcet's disease. AB - CD206 is a macrophage mannose receptor involved in variety of autoimmune and inflammatory diseases. This study aimed to identify the pathogenic role of CD206 in a herpes simplex virus (HSV) induced Behcet's disease (BD) mouse model. CD206 positive cells were detected in peripheral blood mononuclear cells and quantified by flow cytometry. Levels of cytokines were measured by ELISA. CD206 was found to be down-regulated both in vitro (10-6M) and in vivo (200MUg/mouse) after treatment with N-acetylgalactosamine (GalNAc), a ligand for CD206. The down regulation of CD206 was correlated with improvement in BD symptoms. Colchicine (2MUg/mouse) or pentoxifylline (400MUg/mouse) treated mice displayed improvement in BD symptoms with fewer CD206 positive cells. The prevalence of CD206-positive cells differed between ligand-responsive and non-responsive BD mice. Inhibition of CD206 was associated with down-regulated serum level of interleukin-17 in GalNAc-treated BD mice. These results suggest that the expression of CD206 is correlated with HSV-induced BD symptoms in mice, implicating that CD206 might have a pathogenic role in BD. PMID- 28709624 TI - The use of vancomycin paste to reduce sternal wound infections after cardiac surgery-why is this still a "sticky" subject. PMID- 28709623 TI - Endovascular treatment of aortic arch aneurysm with a single-branched double stage stent graft. PMID- 28709622 TI - Genipin protects d-galactosamine and lipopolysaccharide-induced hepatic injury through suppression of the necroptosis-mediated inflammasome signaling. AB - Acute liver failure (ALF) is a life-threatening syndrome resulting from massive inflammation and hepatocyte death. Necroptosis, a programmed cell death controlled by receptor-interacting protein kinase (RIP) 1 and RIP3, has been shown to play an important role in regulating inflammation via crosstalk between other intracellular signaling. The inflammasome is a major intracellular multiprotein that induces inflammatory responses by mediating immune cell infiltration, thus potentiating injury. Genipin, a major active compound of the gardenia fruit, exhibits anti-inflammatory, antioxidant, and anti-apoptotic properties. This study investigated the hepatoprotective mechanisms of genipin on d-galactosamine (GalN) and lipopolysaccharide (LPS)-induced ALF, particularly focusing on interaction between necroptosis and inflammasome. Mice were given an intraperitoneal injection of genipin (25, 50, and 100mg/kg) or necrostatin-1 (Nec 1, a necroptosis inhibitor; 1.8mg/kg) 1h prior to GalN (800mg/kg)/LPS (40MUg/kg) injection and were killed 3h after GalN/LPS injection. Genipin improved the survival rate and attenuated increases in serum aminotransferase activities and inflammatory cytokines after GalN/LPS injection. Genipin reduced GalN/LPS-induced increases in RIP3, phosphorylated RIP1 and RIP3 protein expression, and RIP1/RIP3 necrosome complex, similar to the effects of Nec-1. GalN/LPS significantly increased serum levels of high-mobility group box 1 and interleukin (IL)-33, which were attenuated by genipin and Nec-1. Moreover, similar to Nec-1, genipin attenuated GalN/LPS-induced increases in the protein expression levels of NLRP3, ASC, and caspase-1, inflammasome components, and levels of liver and serum IL 1beta. Taken together, our findings suggest that genipin ameliorates GalN/LPS induced hepatocellular damage by suppressing necroptosis-mediated inflammasome signaling. PMID- 28709625 TI - The cost of intraoperative adverse events in abdominal and pelvic surgery: A systematic review. AB - BACKGROUND: The assessment of intra-operative adverse events (iAEs) is a vastly under researched area with the potential to provide new methods on how to improve patient outcomes and hospital costs. Our objective was to determine the relationship between iAEs and total hospital costs in abdominal and pelvic surgery. DATA SOURCES: We used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) framework. Embase, MEDLINE and EBM Reviews online databases were searched to identify all studies that reported iAE rates and total hospital costs. We then analyzed the costing approach used in each article using the Drummond tool and evaluated articles quality using the GRADE method. CONCLUSIONS: In total, 1709 unique references were identified through our literature search. After review, 23 were included. All studies that reported iAE rates and cost as the primary outcome found that iAEs significantly increased total hospital costs. We identified a relationship between iAEs and increased hospital costs. Future studies need to be performed to further evaluate the relationship between iAEs and cost as current studies are of low quality. PMID- 28709626 TI - Subtotal colectomy versus left hemicolectomy for the elective treatment of splenic flexure colonic neoplasia. AB - BACKGROUND: Optimal elective surgical treatment for splenic flexure neoplasm (SFN) is unclear. Subtotal colectomy (STC) and left hemicolectomy (LHC) are the two more common strategies used. METHODS: Observational multicentric study comparing postoperative morbidity, mortality and long-term survival on patients with SFN electively operated by STC versus LHC between 2003 and 2014. RESULTS: After revision of the databases, 144 patients were included (STC group, n = 68; LHC group, n = 76). No differences were found on epidemiological and surgical data. A higher global morbidity (58%vs37%, p = 0.014), surgical morbidity (50%vs33%, p = 0.037), postoperative ileus (37%vs20%, p = 0.023) and harvested lymph nodes (26vs18, p = 0.0001) were found on the STC group. No significant differences in complications according to severity, reoperation rate, hospital stay, mortality, recurrence or long-term survival were found between groups. CONCLUSIONS: A higher surgical morbidity was found on the STC group, mainly due to mild postoperative ileus. No differences on long-term oncological results were found. PMID- 28709627 TI - Plasma concentration of osimertinib in a non-small cell lung cancer patient with chronic renal failure undergoing hemodialysis. PMID- 28709628 TI - Prostaglandin E1-Induced Periostitis and Reversibility with Discontinuation. PMID- 28709629 TI - What Happens to Blood Glucose Concentrations After Oral Treatment for Neonatal Hypoglycemia? AB - OBJECTIVE: To determine the change in blood glucose concentration after oral treatment of infants with hypoglycemia in the first 48 hours after birth. STUDY DESIGN: We analyzed data from 227 infants with hypoglycemia (blood glucose <46.8 mg/dL, 2.6 mmol/L) born at a tertiary hospital who experienced 295 episodes of hypoglycemia. Blood glucose concentrations were measured (glucose oxidase) within 90 minutes after randomization to dextrose or placebo gel plus feeding with formula, expressed breast milk, or breast feeding. RESULTS: The overall mean increase in blood glucose concentration was 11.7 mg/dL (95% CI 10.4-12.8). The increase was greater after buccal dextrose gel than after placebo gel (+3.0 mg/dL; 95% CI 0.7-5.3; P = .01) and greater after infant formula than after other feedings (+3.8 mg/dL; 95% CI 0.8-6.7; P = .01). The increase in blood glucose concentration was not affected by breast feeding (+2.0 mg/dL; 95% CI -0.3 to 44.2; P = .09) or expressed breast milk (-1.4 mg/dL; 95% CI -3.7 to 0.9; P = .25). However, breast feeding was associated with reduced requirement for repeat gel treatment (OR = 0.52; 95% CI 0.28-0.94; P = .03). CONCLUSIONS: Treatment of infants with hypoglycemia with dextrose gel or formula is associated with increased blood glucose concentration and breast feeding with reduced need for further treatment. Dextrose gel and breast feeding should be considered for first line oral treatment of infants with hypoglycemia. PMID- 28709630 TI - Validity and Reliability of the Brazilian Version of the Weight Control Behaviors Scale. AB - OBJECTIVE: To develop and validate the weight-control behaviors (WCBs) scale and to evaluate its psychometric properties. STUDY DESIGN: We made use of data from a cluster-randomized trial assessing the effectiveness of the Brazilian New Moves Program. The Brazilian New Moves Program was a multicomponent intervention aimed at preventing weight-related problems among adolescent girls in public schools in Sao Paulo, Brazil. RESULTS: Healthy and unhealthy WCBs were strongly associated. A 2-factor solution was the best model to explain the correlation across items, including following constructs: (1) healthy WCB: exercising, eating more fruits and vegetables, drinking less regular soda or sweetened drinks, eating fewer sweets, and paying attention to portion sizes; and (2) unhealthy WCB: skipping meals and the presence of any other, combined unhealthy weight-control behaviors, including fasting, eating little, going on a diet, vomiting, taking diet pills, using diuretics (water pills), using laxatives, using food substitutes (powder/special drinks), and smoking more cigarettes. The WCB scale was determined to be reliable (internally consistent) and valid, with high scores positively associated with body dissatisfaction and high body mass index values. Individual reliability values were high for factors representing healthy and unhealthy WCBs. CONCLUSIONS: Our findings support the use of the WCB scale as a screening tool for overall weight control behaviors among female adolescents. This assessment tool should be considered in future observational and experimental prospective studies. TRIAL REGISTRATION: Brazilian Registry of Clinical Trials: RBR-6ddpb3. PMID- 28709631 TI - Neurodevelopmental Profiles of Children with Congenital Heart Disease at School Age. AB - OBJECTIVES: To assess 6-year neurodevelopmental outcomes in a current cohort of children with congenital heart disease (CHD) who underwent cardiopulmonary bypass surgery (CPB), and to determine risk factors for adverse outcomes. STUDY DESIGN: Outcomes were examined in 233 prospectively enrolled children with CHD (including 64 with a recognized genetic disorder) who underwent CPB between 2004 and 2009. Follow-up assessment included standardized neurologic, motor, and cognitive tests. Variables were collected prospectively, and multiple regression analysis was performed to determine independent risk factors for adverse outcome. RESULTS: The mean patient age at assessment was 6.3 years (range, 5.1-6.8 years). IQ was lower in children with a genetic disorder (median, 55; range, 17-115) compared with children without a genetic disorder (median, 95; range, 47-135; P < .001). Cognitive and motor performance also were lower in children without a genetic disorder compared with the norm (P < .01 for both). The prevalence of children without a genetic disorder performing below -2 SD (IQ 70) was higher than the norm (5.3% vs 2.3%; P = .008), and the prevalence of poor motor performance (<10th percentile) ranged from 21.2% to 41.1% (P < .01 for all). Significant independent risk factors for poor neurodevelopmental outcome included a genetic disorder, longer length of intensive care stay, lower birth weight, postoperative seizures, and lower socioeconomic status. CONCLUSIONS: Current cohorts of children with CHD undergoing CPB show favorable outcomes but remain at risk for long-term neurodevelopmental impairments, particularly those with a genetic disorder and a complicated postoperative course. Close neurodevelopmental surveillance is necessary to provide early therapeutic support. PMID- 28709632 TI - Call for a European Paediatric Association/Union of National European Paediatric Societies and Associations Survey on National Child Health Care Services for European Children with Malignancies. PMID- 28709633 TI - Treatment and Nontreatment of the Patent Ductus Arteriosus: Identifying Their Roles in Neonatal Morbidity. PMID- 28709635 TI - Histopathological investigation of intranodular echogenic foci detected by thyroid ultrasonography. AB - OBJECTIVE: To determine the predictability of sonography for detection of calcifications in thyroid nodules by histopathologic examination and to demonstrate the association between calcification pattern and malignancy. METHODS: We prospectively evaluated 81 dominant nodules from 81 patients. Thyroid glands were assessed preoperatively with thyroid ultrasonography, and the presence of sonographic calcification was specified as intranodular macro (coarse) and micro calcification. Micro and macro calcification in surgery specimens were specified postoperatively as present or absent in the histopathological evaluation. The correlation between sonographic and histopathologic calcifications and the relationship between malignancy and calcification patterns were determined. RESULTS: Calcification was detected histopathologically in 66.7% of the sonographically calcified nodules and in 12.8% of the sonographically noncalcified nodules. The sensitivity and specificity of sonography for detecting histopathologic calcification were 84.8 and 70.8%, respectively, while positive and negative predictive values were 66.7 and 87.2%, respectively. The sonographical and histopathological outcomes for detection of macro and micro calcification showed 85 and 50% compatibility, respectively. The difference in malignancy rates between sonographic macro and micro calcified nodules was not significant (p=0.976). Histopathologic detection of calcification showed no significant difference between malignant and benign nodules (p=0.129). CONCLUSION: Histopathology confirmed a high rate of sonographic macrocalcifications. The micro and macro patterns of sonographic calcification showed no particular association with thyroid malignancy. The preoperative risk of malignancy should be determined in conjunction with other known sonographic risk factors and diagnostic tests. PMID- 28709634 TI - Examining the Role of the Pediatric Emergency Department in Reducing Unintended Adolescent Pregnancy. AB - OBJECTIVES: To determine pregnancy risk and receptiveness to emergency department (ED)-based pregnancy prevention interventions among adolescents accessing care in the ED. STUDY DESIGN: Cross-sectional electronic survey of adolescent females in a pediatric ED used to calculate the Pregnancy Risk Index, a validated measure estimating the annual risk of becoming pregnant based on recent sexual activity, contraceptive method(s), method-specific contraceptive failure rates, and interest in receipt of ED-based contraceptive services. RESULTS: Of 229 participants, 219 were not pregnant, and 129 reported sexual experience. Overall, 72.4% (n = 166) endorsed negative pregnancy intentions. The overall Pregnancy Risk Index for the 219 nonpregnant participants was 9.6 (95% CI 6.8-12.4), and was 17.5 (95% CI 12.8-22.2) for the 129 sexually experienced participants. A Pregnancy Risk Index greater than the national average of 5 was associated with older age (aOR 3.0; 95% CI 1.5-5.85), nonprivate insurance (aOR 7.1; 95% CI 1.6 32.1), prior pregnancy (aOR 2.7; 95% CI 1.2-6.0), and chief complaint potentially related to a reproductive health concern (aOR 2.6; 95% CI 1.4-5.1). In this cohort, 85.1% (n = 194) believed that the ED should provide information about pregnancy prevention, the majority of whom (64.9%; n = 148) believed that pregnancy prevention services should be offered at all ED visits. CONCLUSION: This study demonstrates a high unintended pregnancy risk among adolescents accessing care in the ED. Adolescents report interest in receiving pregnancy prevention information and services in the ED, regardless of reason for visit. Strategies to incorporate successfully the provision of reproductive health services into ED care should be explored. PMID- 28709636 TI - Effects of climate and fine particulate matter on hospitalizations and deaths for heart failure in elderly: A population-based cohort study. AB - BACKGROUND: There are limited data on the effects of climate and air pollutant exposure on heart failure (HF) within taking into account individual and contextual variables. OBJECTIVES: We measured the lag effects of temperature, relative humidity, atmospheric pressure and fine particulate matter (PM2.5) on hospitalizations and deaths for HF in elderly diagnosed with this disease on a 10 year period in the province of Quebec, Canada. METHODS: Our population-based cohort study included 112,793 elderly diagnosed with HF between 2001 and 2011. Time dependent Cox regression models approximated with pooled logistic regressions were used to evaluate the 3- and 7-day lag effects of daily temperature, relative humidity, atmospheric pressure and PM2.5 exposure on HF morbidity and mortality controlling for several individual and contextual covariates. RESULTS: Overall, 18,309 elderly were hospitalized and 4297 died for the main cause of HF. We observed an increased risk of hospitalizations and deaths for HF with a decrease in the average temperature of the 3 and 7days before the event. An increase in atmospheric pressure in the previous 7days was also associated with a higher risk of having a HF negative outcome, but no effect was observed in the 3-day lag model. No association was found with relative humidity and with PM2.5 regardless of the lag period. CONCLUSIONS: Lag effects of temperature and other meteorological parameters on HF events were limited but present. Nonetheless, preventive measures should be issued for elderly diagnosed with HF considering the burden and the expensive costs associated with the management of this disease. PMID- 28709639 TI - Ganoderma triterpenes retard renal cyst development by downregulating Ras/MAPK signaling and promoting cell differentiation. AB - Autosomal dominant polycystic kidney disease (ADPKD) is a common monogenetic disease characterized by the progressive development of renal cysts with further need for effective therapy. Here our aim was to investigate the effect of Ganoderma triterpenes (GT) on the development of kidney cysts. Importantly, GT attenuated cyst development in two mouse models of ADPKD with phenotypes of severe cystic kidney disease. Assays for tubulogenesis showed that GT promoted epithelial tubule formation in MDCK cells, suggesting a possible effect on epithelial cell differentiation. The role of GT in regulating key signaling pathways involved in the pathogenesis of PKD was further investigated by immune blotting. This showed that GT specifically downregulated the activation of the Ras/MAPK signaling pathway both in vitro and in vivo without detectable effect on the mTOR pathway. This mechanism may be involved in GT downregulating intracellular cAMP levels. Screening of 15 monomers purified from GT for their effects on cyst development indicated that CBLZ-7 (ethyl ganoderate C2) had a potent inhibitory effect on cyst development in vitro. Additionally, like GT, CBLZ-7 was able to downregulate forskolin-induced activation of the Ras/MAPK pathway. Thus, GT and its purified monomer CBLZ-7 may be potential therapeutic regents for treating ADPKD. PMID- 28709637 TI - Tubulointerstitial fibrosis can sensitize the kidney to subsequent glomerular injury. AB - Chronic glomerular injury is associated with eventual development of tubulointerstitial fibrosis. Here we aimed to assess whether, and how, mild chronic tubulointerstitial injury affects glomeruli. For this, we generated mice expressing different toxin receptors, one on their proximal tubular epithelial cells (diphtheria toxin receptor [DTR]) and the other only on podocytes (human CD25 [IL-2R] driven by the nephrin promoter [Nep25]), allowing serial induction of tubule-specific and glomerular (podocyte)-specific injury, respectively. Six weeks after diphtheria toxin injection, mild interstitial fibrosis was found in Nep25+/DTR+, but not in Nep25+/DTR- mice. However, atubular glomeruli and neuronal nitric oxide synthase, a mediator of tubuloglomerular feedback, were higher in Nep25+/DTR+ than in DTR- mice and these atubular glomeruli had less podocyte density as assessed by WT-1 biomarker expression. Peritubular capillary density, hypoxia-inducible factor-1 and -2, and cyclooxygenase 2 expression were similar at week six in the two groups. At week seven, all mice were given the immunotoxin LMB-2, which binds to CD25 to induce podocyte injury. Ten days later, proteinuria, podocyte injury, and glomerulosclerosis were more severe in Nep25+/DTR+ than Nep25+/DTR- mice with more severe sclerosis in the tubule connected glomeruli. This supports the concept that even mild preexisting tubulointerstitial injury sensitizes glomeruli to subsequent podocyte-specific injury. Thus, increased atubular glomeruli and abnormal tubuloglomerular feedback significantly contribute to the crosstalk between the tubulointerstitium and glomeruli. PMID- 28709640 TI - Genome-wide identification of genes essential for podocyte cytoskeletons based on single-cell RNA sequencing. AB - Gene expression differs substantially among individual cells of the same type. We speculate that genes that are expressed in all but a portion of cells of a given cell type would be likely essential and required for either the cell survival (housekeeping) or for the cell type's unique structure and function, enabling the organism to survive. Here, we performed RNA-seq of 20 mouse podocytes using the Fluidigm C1 system and identified 335 genes that were expressed in all of them. Among them, 239 genes were also expressed in mesangial and endothelial cells and were involved in energy metabolism, protein synthesis, etc., as housekeeping genes. In contrast, 92 genes were preferentially expressed in podocytes (over five-fold versus expression in mesangial and endothelial cells) and are, therefore, the essential candidate genes specific for podocytes. Assessments by bioinformatics, conserved expression in human podocytes, and association with injury/disease all support the essentiality of these genes for podocytes. Factually, 27 of the 92 genes are already known to be essential for podocyte structure and function. Thirty-seven novel genes were functionally analyzed by siRNA silencing, and we found that a deficiency of 30 genes led to either cytoskeletal injury (FGFR1, AOX1, AIF1L, HAUS8, RAB3B, LPIN2, GOLIM4, CERS6, ARHGEF18, ARPC1A, SRGAP1, ITGB5, ILDR2, MPP5, TSC22D1, DNAJC11, SEPT10, MOCS2, FNBP1L, and TMOD3) or significant downregulation of CD2AP and synaptopodin (IFT80, MYOM2, ANXA4, CYB5R4, GPC1, ZNF277, NSF, ITGAV, CRYAB, and MTSS1). Thus, the list of genes essential for podocyte cytoskeletons is expanded by single-cell RNA sequencing. It appears that podocyte-specific essential genes are mainly associated with podocyte cytoskeletons. PMID- 28709638 TI - DNA methylation protects against cisplatin-induced kidney injury by regulating specific genes, including interferon regulatory factor 8. AB - DNA methylation is an epigenetic mechanism that regulates gene transcription without changing primary nucleotide sequences. In mammals, DNA methylation involves the covalent addition of a methyl group to the 5-carbon position of cytosine by DNA methyltransferases (DNMTs). The change of DNA methylation and its pathological role in acute kidney injury (AKI) remain largely unknown. Here, we analyzed genome-wide DNA methylation during cisplatin-induced AKI by reduced representation bisulfite sequencing. This technique identified 215 differentially methylated regions between the kidneys of control and cisplatin-treated animals. While most of the differentially methylated regions were in the intergenic, intronic, and coding DNA sequences, some were located in the promoter or promoter regulatory regions of 15 protein-coding genes. To determine the pathological role of DNA methylation, we initially examined the effects of the DNA methylation inhibitor 5-aza-2'-deoxycytidine and showed it increased cisplatin-induced apoptosis in a rat kidney proximal tubular cell line. We further established a kidney proximal tubule-specific DNMT1 (PT-DNMT1) knockout mouse model, which showed more severe AKI during cisplatin treatment than wild-type mice. Finally, interferon regulatory factor 8 (Irf8), a pro-apoptotic factor, was identified as a hypomethylated gene in cisplatin-induced AKI, and this hypomethylation was associated with a marked induction of Irf8. In the rat kidney proximal tubular cells, the knockdown of Irf8 suppressed cisplatin-induced apoptosis, supporting a pro-death role of Irf8 in renal tubular cells. Thus, DNA methylation plays a protective role in cisplatin-induced AKI by regulating specific genes, such as Irf8. PMID- 28709641 TI - GlucoCEST magnetic resonance imaging in vivo may be diagnostic of acute renal allograft rejection. AB - Acute cellular renal allograft rejection (AR) frequently occurs after kidney transplantations. It is a sterile T-cell mediated inflammation leading to increased local glucose metabolism. Here we demonstrate in an allogeneic model of Brown Norway rat kidneys transplanted into uninephrectomized Lewis rats the successful implementation of the recently developed glucose chemical exchange saturation transfer (glucoCEST) magnetic resonance imaging. This technique is a novel method to assess and differentiate AR. Renal allografts undergoing AR showed significantly increased glucoCEST contrast ratios of cortex to medulla of 1.61 compared to healthy controls (1.02), syngeneic Lewis kidney to Lewis rat transplants without rejection (0.92), kidneys with ischemia reperfusion injury (0.99) and kidneys affected by cyclosporine A toxicity (1.10). Receiver operating characteristic curve analysis showed an area under the curve value of 0.92, and the glucoCEST contrast ratio predicted AR with a sensitivity of 100% and a specificity of 69% at a threshold level over 1.08. In defined animal models of kidney injuries, the glucoCEST contrast ratios of cortex to medulla correlated positively with mRNA expression levels of T-cell markers (CD3, CD4, CD8a/b), but did not correlate to impaired renal perfusion. Thus, the glucoCEST parameter may be valuable for the assessment and follow up treatment of AR. PMID- 28709642 TI - A multicenter cohort study of potential living kidney donors provides predictors of living kidney donation and non-donation. AB - This multicenter prospective potential living kidney donor cohort study investigated which sociodemographic and other factors predict progression to living kidney donation or donor withdrawal as little is known on this topic. Therefore, we examined data on individuals undergoing living donor assessment at seven hospitals in the United Kingdom. Multivariable logistic regression was used to explore the relationships between donor and recipient characteristics and likelihood of kidney donation. A total of 805 individuals presented for directed donation to 498 intended recipients, of which 112 received a transplant from a living donor. Potential donors were less likely to donate if their intended recipient was female rather than male with an odds ratio of 0.60, a friend rather than relative 0.18, or had renal failure due to a systemic disease rather than another cause 0.41. The most socioeconomically deprived quintile was less likely to donate than the least 0.49, but the trend with deprivation was consistent with chance. Higher body mass index was associated with a lower likelihood of donation (odds ratio per each kg/m2 increase, 0.92). Younger potential donors (odds ratio per each year increase 0.97), those of nonwhite ethnicity 2.98, and friend donors 2.43 were more likely to withdraw from work-up. This is the first study in the United Kingdom of potential living kidney donors to describe predictors of non donation. Qualitative work with individuals who withdraw might identify possible ways of supporting those who wish to donate but experience difficulties doing so. PMID- 28709644 TI - Horizontal transfer of miR-106a/b from cisplatin resistant hepatocarcinoma cells can alter the sensitivity of cervical cancer cells to cisplatin. AB - Recent studies indicate that horizontal transfer of genetic material can act as a communication tool between heterogenous populations of tumour cells, thus altering the chemosensitivity of tumour cells. The present study was designed to check whether the horizontal transfer of miRNAs released by cisplatin resistant (Cp-r) Hepatocarcinoma cells can alter the sensitivity of cervical cancer cells. For this exosomes secreted by cisplatin resistant and cisplatin sensitive HepG2 cells (EXres and EXsen) were isolated and characterised. Cytotoxicity analysis showed that EXres can make Hela cells resistant to cisplatin. Analysis of miR 106a/b levels in EXres and EXsen showed that their levels vary. Mechanistic studies showed that miR-106a/b play an important role in EXsen and EXres mediated change in chemosensitivity of Hela cells to cisplatin. Further SIRT1 was identified as a major target of miR-106a/b using in silico tools and this was proved by experimentation. Also the effect of miR-106a/b in chemosensitivity was seen to be dependent on regulation of SIRT1 by miR-106a/b. In brief, this study brings into light, the SIRT1 dependent mechanism of miR-106a/b mediated regulation of chemosensitivity upon the horizontal transfer from one cell type to another. PMID- 28709643 TI - Hypoxia-induced suppression of c-Myc by HIF-2alpha in human pulmonary endothelial cells attenuates TFAM expression. AB - The adaptive response to hypoxia is mediated in large part by stabilization of the hypoxia-inducible factors, HIF-1alpha and HIF-2alpha. A hallmark of this response is the metabolic shift to decreased oxidative phosphorylation and increased glycolysis. We hypothesized that hypoxic responses would include a suppression of mitochondrial gene expression. We determined the effects of hypoxia on TFAM, a key mitochondrial transcription factor, in normal pulmonary artery endothelial cells. Hypoxia decreased gene expression of TFAM and that of its upstream regulator, the transcriptional co-activator PGC1beta. Although HIF 1alpha and HIF-2alpha pathways both contributed to hypoxia-mediated PGC1beta suppression, TFAM suppression was regulated solely by HIF-2alpha-dependent mechanisms. We found that HIF-2alpha suppresses TFAM by decreasing c-Myc expression. In addition, we show a role for c-Jun in this pathway, linking HIF 2alpha with attenuation of c-Jun activation. Taken together, these findings establish a new link between HIF-2alpha and MAPK-signaling that mediates the adaptive regulation of mitochondrial gene expression under low oxygen tension. PMID- 28709645 TI - Usefulness of computed tomography density of a tumor in predicting the response of advanced esophageal cancer to preoperative chemotherapy. AB - BACKGROUND: In Japan, preoperative chemotherapy is considered essential for resectable stage II or III esophageal cancers. It is important to identify nonresponders for preoperative chemotherapy because continuing ineffective chemotherapy is not beneficial for them. We investigated the correlation between the computed tomography number of tumor and the effect of preoperative chemotherapy in patients with esophageal cancer. METHODS: This retrospective study included 50 patients receiving preoperative chemotherapy with docetaxel, cisplatin, and 5-fluorouracil for stage II or III esophageal cancer. The computed tomography number of tumor was measured as the mean of Hounsfield Units of the primary lesion on a plain computed tomography measured within a freehand region of interest drawn around the tumor border. For analysis, the patients were classified into responders and nonresponders to chemotherapy, with the pathologic response evaluated using the Japanese and Mandard classification. We analyzed the associations between the computed tomography number of tumor and clinical factors; histopathologic features, including the tumor size, depth of tumor invasion, capillary invasion, Ki-67, p53, and CK5/6 expression; the pathologic response to chemotherapy and prognosis. RESULTS: There was a significant association between the computed tomography number of tumor and the response to chemotherapy. The cut-off value of the computed tomography number of tumor in predicting responders to chemotherapy was 40 Hounsfield Units (area under the receiver operating characteristic curve = 0.73, P = .009); patients with computed tomography number of tumor greater than this value significantly responded to chemotherapy (P = .02 in the Japanese and P = .009 in the Mandard classification) with good postoperative prognosis (P = .04). Only Ki-67 expression among the histopathogic features were associated with the computed tomography number of tumor in histopathologic features (P = .01). CONCLUSION: The computed tomography number of tumor may be useful to predict the efficacy of preoperative chemotherapy and subsequent prognosis for patients with advanced esophageal cancer. PMID- 28709646 TI - Challenge of balancing duration of stay and readmissions in children's operation. AB - BACKGROUND: Surgeons balance competing interests of minimizing duration of stay with readmissions. Complications that occur early after discharge often result in readmissions. This study examines the relationship between duration of stay, timing of complications, and readmission risk. METHODS: Cases from the 2012-2014 National Surgical Quality Improvement Project-Pediatric were organized into 30 procedural groups. Procedures where duration of stay approximated the median day of complication were identified. A theoretical model was applied to minimize readmissions by extending duration of stay. RESULTS: From 30 procedure groups, 3 were identified where duration of stay approximated median day of compilations: complicated appendectomy, antireflux operation, and abdominal operation without bowel resection. The complicated appendectomy readmission rate drops from 12.2% to 8.2%, increasing duration of stay from 3 to 8 days at the cost of 16,428 additional hospital days among 4,740 patients (3.5 days/patient). Readmission optimization tapers after duration of stay of 8 days. Similar findings were observed for antireflux operation and abdominal operation without bowel resection with readmission optimization at duration of stay of 5 days (2.6 days/patient) and 7 days (5.3 days/patient), respectively. CONCLUSION: Our theoretical model aimed at balancing readmissions by extending duration of stay to capture early complications results in a substantial increase in hospital days illustrating the conflict between competing quality metrics and limited resources. PMID- 28709647 TI - Reply to: Threshold of number of rib fractures in elderly blunt trauma: A simple or complex matter of numbers? PMID- 28709648 TI - Deficiency in cold-inducible RNA-binding protein attenuates acute respiratory distress syndrome induced by intestinal ischemia-reperfusion. AB - BACKGROUND: Intestinal ischemia-reperfusion can occur in shock and mesenteric occlusive diseases, causing significant morbidity and mortality. Aside from local injury, intestinal ischemia-reperfusion can result in remote organ damage, particularly in the lungs. Cold-inducible RNA-binding protein (CIRP) was identified as a novel inflammatory mediator. We hypothesized that a deficiency in CIRP would protect the lungs during intestinal ischemia-reperfusion injury. METHODS: Intestinal ischemia was induced in adult male C57BL/6 wild-type and CIRP knock-out (CIRP-/-) mice via clamping of the superior mesenteric artery for 60 minutes. Reperfusion was allowed for 4 hours or 20 hours, and blood, gut, and lung tissues were harvested for various analyses. RESULTS: After intestinal ischemia-reperfusion, the elevated levels of serum lactate dehydrogenase and inflammatory cytokine interleukin-6 were reduced by 68% and 98%, respectively, at 20 hours after ischemia-reperfusion in CIRP-/- mice compared with the wild-type mice. In the gut, mRNA levels of inflammatory cytokine interleukin-6 were reduced by 67% at 4 hours after ischemia-reperfusion in CIRP-/- mice. In the lungs, inflammatory cytokine interleukin-6 protein and myeloperoxidase activity were reduced by 78% and 26% at 20 hours and 4 hours after ischemia-reperfusion, respectively, in CIRP-/- mice. Finally, the elevated lung caspase-3 was significantly decreased by 55%, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive cells decreased by 91%, and lung injury score decreased by 37% in CIRP-/- mice at 20 hours after ischemia-reperfusion. CONCLUSION: Increased levels of proinflammatory cytokines, myeloperoxidase, and apoptosis are the hallmarks of acute respiratory distress syndrome. We noticed after intestinal ischemia-reperfusion the proinflammatory milieu in lungs was elevated significantly, while the CIRP-/- mice had significantly decreased levels of proinflammatory cytokine, myeloperoxidase, and apoptotic cells leading to decreased lung injury. These findings strongly established a causal link between CIRP and acute respiratory distress syndrome during intestinal ischemia reperfusion injuries. Targeting CIRP may therefore be beneficial for treatment of intestinal ischemia-reperfusion-associated acute respiratory distress syndrome acute respiratory distress syndrome. PMID- 28709649 TI - Analysis of oxylipins in human plasma: Comparison of ultrahigh-performance liquid chromatography and ultrahigh-performance supercritical fluid chromatography coupled to mass spectrometry. AB - The potential of ultrahigh-performance liquid chromatography-mass spectrometry (UHPLC/MS) and ultrahigh-performance supercritical fluid chromatography (UHPSFC) coupled to negative-ion electrospray ionization mass spectrometry (ESI-MS) for the analysis of 46 oxylipins and 2 fatty acid standards is compared in terms of their chromatographic resolution with the emphasis on distinguishing isobaric interferences and the method sensitivity. UHPLC provides the baseline separation of 24 isobaric oxylipins within 13min, while UHPSFC enables the separation of only 20 isobaric oxylipins within 8min. Moreover, the UHPLC/ESI-MS method provides an average improvement of sensitivity by 3.5-fold. A similar trend is observed in the analysis of human plasma samples, but lower ion suppression effects caused by lysophospholipids (LPL) are observed in case of UHPSFC/ESI-MS due to better separation of LPL. Both methods are fully applicable for the analysis of oxylipins, but UHPLC/ESI-MS method is preferred due to better separation and higher sensitivity, which results in the identification of 31 oxylipins in human plasma based on available standards and additional tentative 20 identifications based on accurate m/z values and the fragmentation behavior known from the literature. PMID- 28709650 TI - Anticoagulation Control in Warfarin-Treated Patients Undergoing Cardioversion of Atrial Fibrillation (from the Edoxaban Versus Enoxaparin-Warfarin in Patients Undergoing Cardioversion of Atrial Fibrillation Trial). AB - In the Edoxaban Versus Enoxaparin-Warfarin in Patients Undergoing Cardioversion of Atrial Fibrillation (ENSURE-AF) study (NCT 02072434), edoxaban was compared with enoxaparin-warfarin in 2,199 patients undergoing electrical cardioversion of nonvalvular atrial fibrillation (AF). In this multicenter prospective randomized open blinded end-point trial, we analyzed patients randomized to enoxaparin warfarin. We determined time to achieve therapeutic range (TtTR); time in therapeutic range (TiTR); their clinical determinants; relation to sex, age, medical history, treatment, tobacco use, race risk (SAMe-TT2R2) score; and impact on primary end points (composite of stroke, systemic embolic event[SEE], myocardial infarction [MI], and cardiovascular death [CVD] and composite of major + clinically relevant nonmajor bleeding). Among 1,104 patients randomized to enoxaparin-warfarin, 27% were naive to oral anticoagulants. Mean age was 64.2 +/- 11 years and mean congestive heart failure, hypertension, age >=75 (doubled), diabetes mellitus, prior stroke or transient ischemic attack (doubled), vascular disease, age 65-74, female (CHA2DS2-VASc) score was 2.6. Mean TtTR was 7.7 days (median 7 days) and mean TiTR after reaching an international normalized ratio of 2.0 to 3.0 was 71%. In 695 patients who had an INR <2.0 before the first dose and who reached an INR >=2.0, 436 had a SAMe-TT2R2 score <=2 and 259 had a score >2. On multivariate regression, an independent predictor of extended TtTR was creatinine clearance (p = 0.02). TtTR was marginally related to stroke/SEE/MI/CVD (p = 0.06; odds ratio 0.23, 95% confidence interval 0.02 to 1.17) but not to any bleeding. Independent predictors of TiTR were previous vitamin K antagonist experience (p<0.01) and low hypertension, abnormal renal or liver function, stroke, bleeding, labile INRs, age >65, concomitant drugs or alcohol (HAS-BLED) score (p = 0.02). TiTR was related to any bleeding (p = 0.02; odds ratio 0.39, 95% confidence interval 0.16 to 0.88), but not stroke/SEE/MI/CVD. In this cohort of warfarin users with a high TiTR no difference was seen between TtTR and TiTR in relation to SAMe-TT2R2 score. In conclusion, even in this short-term study, TiTR was significantly related to bleeding events. PMID- 28709651 TI - Modeling and analysis of fractional order DC-DC converter. AB - Due to the non-idealities of commercial inductors, the demand for a better model that accurately describe their dynamic response is elevated. So, the fractional order models of Buck, Boost and Buck-Boost DC-DC converters are presented in this paper. The detailed analysis is made for the two most common modes of converter operation: Continuous Conduction Mode (CCM) and Discontinuous Conduction Mode (DCM). Closed form time domain expressions are derived for inductor currents, voltage gain, average current, conduction time and power efficiency where the effect of the fractional order inductor is found to be strongly present. For example, the peak inductor current at steady state increases with decreasing the inductor order. Advanced Design Systems (ADS) circuit simulations are used to verify the derived formulas, where the fractional order inductor is simulated using Valsa Constant Phase Element (CPE) approximation and Generalized Impedance Converter (GIC). Different simulation results are introduced with good matching to the theoretical formulas for the three DC-DC converter topologies under different fractional orders. A comprehensive comparison with the recently published literature is presented to show the advantages and disadvantages of each approach. PMID- 28709652 TI - Cooperative path following control of multiple nonholonomic mobile robots. AB - Cooperative path following control problem of multiple nonholonomic mobile robots has been considered in this paper. Based on the framework of decomposition, the cooperative path following problem has been transformed into path following problem and cooperative control problem; Then cascaded theory of non-autonomous system has been employed in the design of controllers without resorting to feedback linearization. One time-varying coordinate transformation based on dilation has been introduced to solve the uncontrollable problem of nonholonomic robots when the whole group's reference converges to stationary point. Cooperative path following controllers for nonholonomic robots have been proposed under persistent reference or reference target that converges to stationary point respectively. Simulation results using Matlab have illustrated the effectiveness of the obtained theoretical results. PMID- 28709653 TI - Set-point manipulation approach towards online performance improvement in existing process control loops. AB - The majority of current industrial process control systems are based on PID control. However, in many of these systems, once the initial setup has been carried out, it is difficult to implement subsequent continuous improvements on the control performance without shutting down the production and disarming the overall system to retrofit alternative controllers. These measures to integrate additional instruments for allowing such flexibility incur heavy costs in terms of time and resources. In this paper, we propose an approach towards achieving the control adaptations which cannot be achieved easily with an existing closed architectural system. The approach leverages on a set-point manipulation mechanism which allows a virtual modification of the closed-architectural system. In this way, process performance of existing plants can be continuously improved without the need to continuously alter the existing closed loop system. The implementation of the proposed configuration is illustrated with respect to a PID controller although the framework proposed is amenable to higher order controller as well. Simulation examples and experimental results are furnished to show the motivation for such an approach and the improved performance achievable with the proposed approach. PMID- 28709654 TI - Outdoor flocking of quadcopter drones with decentralized model predictive control. AB - In this paper, we present a multi-drone system featured with a decentralized model predictive control (DMPC) flocking algorithm. The drones gather localized information from neighbors and update their velocities using the DMPC flocking algorithm. In the multi-drone system, data packages are transmitted through XBee(r) wireless modules in broadcast mode, yielding such an anonymous and decentralized system where all the calculations and controls are completed on an onboard minicomputer of each drone. Each drone is a double-layered agent system with the coordination layer running multi-drone flocking algorithms and the flight control layer navigating the drone, and the final formation of the flock relies on both the communication range and the desired inter-drone distance. We give both numerical simulations and field tests with a flock of five drones, showing that the DMPC flocking algorithm performs well on the presented multi drone system in both the convergence rate and the ability of tracking a desired path. PMID- 28709655 TI - New stability and stabilization conditions for nonlinear systems with time varying delay based on delay-partitioning approach. AB - This paper focuses on stability analysis and stabilization of nonlinear systems with interval time-varying delay, modeled by Takagi-Sugeno (T-S) fuzzy approach. To achieve more relaxation in the feasibility region, delay-partitioning approach is used for all integral terms in the Lyapunov-Krasovskii functional (LKF). A fuzzy Lyapunov function is proposed instead of non-integral term in LKF, and moreover, some slack matrices variables are offered to enlarge the design space. By doing this, new delay-dependent stability criteria are obtained. During the derivation of stability conditions, Jensen's integral inequality is applied to deal with integral terms. Furthermore, in this paper the problem of controller design via the parallel distributed compensation (PDC) scheme is studied. Stability and stabilization conditions with less conservative are achieved in terms of linear matrix inequality (LMI). Finally, two numerical examples are presented to show the effectiveness of the proposed results. PMID- 28709656 TI - Analyses of integrated aircraft cabin contaminant monitoring network based on Kalman consensus filter. AB - The modern civil aircrafts use air ventilation pressurized cabins subject to the limited space. In order to monitor multiple contaminants and overcome the hypersensitivity of the single sensor, the paper constructs an output correction integrated sensor configuration using sensors with different measurement theories after comparing to other two different configurations. This proposed configuration works as a node in the contaminant distributed wireless sensor monitoring network. The corresponding measurement error models of integrated sensors are also proposed by using the Kalman consensus filter to estimate states and conduct data fusion in order to regulate the single sensor measurement results. The paper develops the sufficient proof of the Kalman consensus filter stability when considering the system and the observation noises and compares the mean estimation and the mean consensus errors between Kalman consensus filter and local Kalman filter. The numerical example analyses show the effectiveness of the algorithm. PMID- 28709657 TI - Detection of the hepatitis B virus (HBV) covalently-closed-circular DNA (cccDNA) in mice transduced with a recombinant AAV-HBV vector. AB - Hepatitis B Virus (HBV) persists in infected hepatocytes as an episomal covalently-closed-circular DNA mini-chromosome, called cccDNA. As the main nuclear transcription template, HBV cccDNA is a key replication intermediate in the viral life cycle. Little is known about the mechanisms involved in its formation, maintenance and fate under antiviral therapies. This is mainly due to the lack of small immune-competent animal models able to recapitulate the entire HBV replication cycle, including formation of HBV cccDNA. Here we report that HBV cccDNA can be detected by Southern blot analyses in the liver of C57BL6 mice transduced with AAV-HBV. HBV cccDNA persists in the liver of these animals together with the AAV-HBV episome. We also set up a PCR strategy to distinguish the HBV cccDNA from the AAV-HBV episome. These suggest that the AAV-HBV/mouse model might be relevant to test drugs targeting HBV cccDNA regulation and persistence. PMID- 28709658 TI - NgAgo-gDNA system efficiently suppresses hepatitis B virus replication through accelerating decay of pregenomic RNA. AB - Covalently closed circular DNA (cccDNA) in the hepatocytes nucleus is responsible for persistent infection of Hepatitis B virus (HBV). Current antiviral therapy drugs nucleos(t)ide analogs or interferon fail to eradicate HBV cccDNA. Genome editing technique provides an effective approach for HBV treatment through targeting viral cccDNA. Natronobacterium gregoryi Argonaute (NgAgo)-guide DNA (gDNA) system with powerful genome editing prompts us to explore its application in inhibiting HBV replication. Preliminary function verification indicated that NgAgo/EGFP-gDNA obviously inhibited EGFP expression. To further explore the potential role of NgAgo in restricting HBV replication, 10 of gDNAs targeting the critical region of viral genome were designed, only S-142, P-263 and P-2166 gDNAs led to significant inhibition on HBsAg, HBeAg and pregenomic RNA (pgRNA) level in Huh7 and HepG2 cells transfected with pcDNA-HBV1.1 plasmid. Similar results were also found in HBV infected HLCZ01 cells and Huh7-NTCP cells. However, we failed to detect any DNA editing in S-142, P-263 and P-2166 targeting region through T7E1 assay and Sanger sequencing. Remarkably, we found that NgAgo/P-2166 significantly accelerated the decay of viral pgRNA. Taken together, our results firstly demonstrate the potential of NgAgo/gDNA in inhibiting HBV replication through accelerating pgRNA degradation, but not DNA editing. PMID- 28709659 TI - In vivo hip joint loads and pedal forces during ergometer cycling. AB - The rising prevalence of osteoarthritis and an increase in total hip replacements calls for attention to potential therapeutic activities. Cycling is considered as a low impact exercise for the hip joint and hence recommended. However, there are limited data about hip joint loading to support this claim. The aim of this study was to measure synchronously the in vivo hip joint loads and pedal forces during cycling. The in vivo hip joint loads were measured in 5 patients with instrumented hip implants. Data were collected at several combinations of power and cadence, at two saddle heights. Joint loads and pedal forces showed strong linear correlation with power. So the relationship between the external pedal forces and internal joint forces was shown. While cycling at different cadences the minimum joint loads were acquired at 60RPM. The lower saddle height configuration results in an approximately 15% increase compared to normal saddle height. The results offered new insights into the actual effects of cycling on the hip joint and can serve as useful tools while developing an optimum cycling regimen for individuals with coxarthrosis or following total hip arthroplasty. Due to the relatively low contact forces, cycling at a moderate power level of 90W at a normal saddle height is suitable for patients. PMID- 28709660 TI - Effect of Gastrointestinal Malformations on the Outcomes of Patients With Congenital Heart Disease. AB - BACKGROUND: The goal of this study was to assess the effect of associated gastrointestinal malformations (GI) on the outcomes of patients undergoing congenital heart operations. METHODS: Neonates and infants with thoracic (esophageal atresia, tracheoesophageal fistula) and abdominal (duodenal stenosis/atresia, imperforate anus, Hirschsprung disease) GI malformations undergoing congenital heart operations between 1995 and 2015 were included. Two control groups were created, one for each group. Patients were matched by diagnosis, procedure, history of prematurity, presence of genetic syndrome, and a propensity score including weight and year of operation. RESULTS: The cohort included 383 patients: 52 (14%) with thoracic GI malformations and 98 (25%) thoracic GI controls, 80 (21%) with abdominal GI malformations and 153 (40%) abdominal GI controls. Median follow-up was 6 years (range, 16 days to 20 years). Patients with thoracic GI malformations had longer length of stay (p < 0.001), longer intubation times (p = 0.002), and higher perioperative death (p = 0.015) than controls. There was a tendency for worse overall survival than controls, mainly explained by the higher risk of early death (p = 0.06). No difference was found in outcomes between patients with abdominal GI malformations and controls. CONCLUSIONS: Patients with thoracic GI malformations have worse perioperative outcomes than controls, but their long-term survival does not seem to be significantly different. Abdominal GI malformations do not have a significant effect on outcomes. The presence of GI malformations should likely not preclude patients from undergoing congenital heart operations, but careful family counseling is necessary, especially for thoracic GI malformations. PMID- 28709661 TI - Left-Sided Reoperations After Arterial Switch Operation: A European Multicenter Study. AB - BACKGROUND: We sought to report the frequency, types, and outcomes of left-sided reoperations (LSRs) after an arterial switch operation (ASO) for patients with D transposition of the great arteries (D-TGA) and double-outlet right ventricle (DORV) TGA-type. METHODS: Seventeen centers belonging to the European Congenital Heart Surgeons Association (ECHSA) contributed to data collection. We included 111 patients who underwent LSRs after 7,951 ASOs (1.4%) between January 1975 and December 2010. Original diagnoses included D-TGA (n = 99) and DORV TGA-type (n = 12). Main indications for LSR were neoaortic valve insufficiency (n = 52 [47%]) and coronary artery problems (CAPs) (n = 21 [19%]). RESULTS: Median age at reoperation was 8.2 years (interquartile range [IQR], 2.9-14 years). Seven patients died early after LSRs (6.3%); 4 patients with D-TGA (5.9%) and 3 patients with DORV TGA-type (25%) (p = 0.02). Median age at last follow-up was 16.1 years (IQR, 9.9-21.8 years). Seventeen patients (16%) required another reoperation, which was more frequent in patients with DORV- TGA type (4 of 9 [45%]) than in patients with D-TGA (13 of 95 [14%]). Late death occurred in 4 patients (4 of 104 [3.8%]). The majority of survivors were asymptomatic at last clinical examination (84 of 100 [84%]). CONCLUSIONS: Reoperations for residual LSRs are infrequent but may become necessary late after an ASO, predominantly for neoaortic valve insufficiency and CAPs. Risk at reoperation is not negligible, and DORV TGA-type anatomy, as well as procedures on the coronary arteries, were significantly associated with a higher morbidity and a lower overall survival. Recurrent reoperations after LSRs may be required. PMID- 28709662 TI - Neonatal Aortic Arch Reconstruction With Direct Splanchnic Perfusion Avoids Deep Hypothermia. AB - BACKGROUND: Neonatal aortic arch reconstruction, typically performed with deep hypothermia and selective cerebral perfusion, leaves splanchnic organ protection dependent on hypothermia alone. A simplified method of direct in-field descending aortic perfusion during neonatal arch reconstruction permits the avoidance of deep hypothermia. We hypothesize that direct splanchnic perfusion at mild hypothermia provides improved or equivalent safety compared with deep hypothermia and may contribute to postoperative extracardiac organ recovery. METHODS: Included were 138 biventricular patients aged younger than 90 days undergoing aortic arch reconstruction with cardiopulmonary bypass. Patients were grouped according to perfusion method A (selective cerebral perfusion with deep hyperthermia at 18 degrees to 20 degrees C) or method B (selective cerebral perfusion and splanchnic perfusion at 30 degrees to 32 degrees C). Patient characteristics and perioperative clinical and serologic data were analyzed. Significance was assigned for p of less than 0.05. RESULTS: Of the 138 survivors, 63 underwent method A and 75 underwent method B. The median age at operation was 8.5 days (range, 6 to 15 days), and median weight was 3.2 kg (range, 2.8 to 3.73 kg), with no significant differences between groups. Cardiopulmonary bypass times were comparable between the two perfusion methods (p = 0.255) as were the ascending aortic cross-clamp times (p = 0.737). The postoperative glomerular filtration rate was significantly different between our groups (p = 0.028 to 0.044), with method B achieving a higher glomerular filtration rate. No significant differences were seen in ventilator time, postoperative length of stay, fractional increase of postoperative serum creatinine over preoperative serum creatinine, and postoperative lactate. CONCLUSIONS: A simplified method of direct splanchnic perfusion during neonatal aortic arch reconstruction avoids the use of deep hypothermia and provides renal protection at least as effective as deep hypothermia. PMID- 28709663 TI - Pulmonary Resection for Second Lung Cancer After Pneumonectomy: A Population Based Study. AB - BACKGROUND: Pulmonary resection for a second lung cancer after pneumonectomy is generally considered to be at prohibitive risk. Using a population-based database, we examined treatment patterns and survival in patients who underwent pulmonary resection after pneumonectomy for lung cancer. METHODS: We queried the Surveillance, Epidemiology, and End Results (SEER) database (1988-2012) to identify patients who underwent pneumonectomy and subsequently experienced contralateral non-small cell lung cancer (NSCLC). Multivariate logistic regression was performed to identify the factors associated with the receipt of surgical resection. Survival was estimated with the Kaplan-Meier method. RESULTS: Of 13,370 patients who underwent pneumonectomy, 402 (3.0%) experienced subsequent contralateral NSCLC, and 170 (42%) met the selection criteria. Surgical resection was performed in 63 (37.1%) cases (sublobar n = 56, lobectomy, n = 7). Patients with stage I/II disease and tumor size 2 cm or smaller were more likely to undergo surgical procedures. The 1-month and 3-month mortality after resection was 11.1% (sublobar resection 10.7%, lobectomy 14.3%) and 12.7% (sublobar 12.5%, lobectomy 14.3%), respectively. The overall 1-year and 3-year survival after surgical resection was 79% and 54%, respectively. The patients who underwent sublobar resection had higher median overall survival than did those who underwent lobectomy (42 vs 18 months). Similarly, median survival after resection for metachronous tumors was higher than after resection for metastatic cancers (40 vs 28 months). CONCLUSIONS: On the basis of our analysis of the SEER database, sublobar resection can be performed in selected patients with small tumors (<=2 cm) and early-stage disease (stage I/II). Although perioperative mortality is significant, the favorable 1-year and 3-year survival may justify the role of an additional procedure on the single lung. PMID- 28709664 TI - Current Results of Single Ventricle Palliation of Patients With Double Inlet Left Ventricle. AB - BACKGROUND: Double inlet left ventricle (DILV) is a heterogeneous single ventricle anomaly in which initial presentation, and consequently, timing and palliation mode vary based on morphology and degree of pulmonary or systemic outflow obstruction. Very few reports, mostly old, focused on palliation outcomes of DILV. We report current-era results and examine whether morphologic and subsequently surgical factors influence survival. METHODS: Fifty-eight infants with DILV underwent single ventricle palliation. Echocardiographic examination showed pulmonary (n = 29, 50%), systemic outflow tract (n = 11, 19%), and arch (n = 17, 29%) obstruction. Factors associated with death or transplantation were examined. RESULTS: Forty-four patients (76%) required neonatal first-stage palliation: modified Blalock-Taussig shunt (n = 15, 26%), Norwood (n = 15, 26%), or pulmonary artery band (n = 14, 24%), whereas 14 (24%) received primary Glenn. There was 1 hospital death (2%) and 2 interstage deaths before Glenn, in addition to 1 late death that was noncardiac. Overall 10-year survival was 94% and was comparable for different palliative surgeries (p = 0.49). Three patients (6%) underwent heart transplantation after first-stage palliation (n = 1) or after Glenn (n = 2) for ventricular noncompaction (n = 1), ventricular and atrioventricular valve dysfunction (n = 1), and pacemaker-induced cardiomyopathy (n = 1). Overall 10-year freedom from death or transplantation was 87% and was comparable for different palliative surgeries (p = 0.58). On regression risk analysis, none of the tested morphologic or surgical variables was associated with the risk of death or transplantation. CONCLUSIONS: Current outcomes of multistage palliation of DILV are relatively good compared with published reports of other single ventricle anomalies. Survival is not greatly affected by cardiac morphology or initial palliative surgery type. PMID- 28709665 TI - Risk-Adjusted Margin Positivity Rate as a Surgical Quality Metric for Non-Small Cell Lung Cancer. AB - BACKGROUND: Incomplete lung cancer resection connotes poor prognosis; the incidence varies with patient demographic, clinical, and institutional factors. We sought to develop a valid, survival impactful, facility-based surgical quality metric that adjusts for related patient demographic and clinical characteristics. METHODS: Facilities performing resections for patients diagnosed with stage I to IIIA non-small cell lung cancer in the National Cancer Data Base between 2004 and 2011 were identified. Multivariate logistic regression modeling was used to estimate the expected number of margin-positive cases by adjusting for patient risk mix and calculate the observed-to-expected ratio for each facility. Facilities were categorized as outperformers (observed-to-expected ratio less than 1, p < 0.05), nonoutliers (p > 0.05), and underperformers (observed-to expected ratio greater than 1, p < 0.05); and their characteristics across performance categories were compared by chi2 tests. Multivariate Cox proportional hazard analyses were conducted, adjusting for patient demographic and clinical characteristics. RESULTS: A total of 96,324 patients underwent surgery at 809 facilities. The overall observed margin-positive rate was 4.4%. Sixty-one facilities (8%) were outperformers, 644 (80%) were nonoutliers, and 104 (13%) were underperformers. One third (36%) of National Cancer Institute-designated facilities, 13% of academic comprehensive cancer programs, 5% of comprehensive community cancer programs, and 13% of "other" facilities achieved outperforming status but no community cancer programs did. Interestingly, 9% of National Cancer Institute-designated facilities and 11% of academic comprehensive cancer program facilities were underperformers. Adjusting for patient demographic and clinical characteristics, outperformers had a 5-year all-cause hazard ratio of 0.88 (95% confidence interval: 0.85 to 0.91, p < 0.0001) compared with nonoutliers, and 0.80 (95% confidence interval: 0.77 to 0.84, p < 0.0001) compared with underperformers. CONCLUSIONS: Facility performance in lung cancer surgery can be captured by the risk-adjusted margin-positivity rate, potentially providing a valid quality improvement metric. PMID- 28709666 TI - Novel Rotational Speed Modulation System Used With Venoarterial Extracorporeal Membrane Oxygenation. AB - BACKGROUND: Femoral venoarterial extracorporeal membrane oxygenation (VA-ECMO) is widely used to maintain blood flow in patients with cardiogenic shock. However, retrograde blood flow increases left ventricular (LV) afterload during femoral VA ECMO. Additional support by means of an intraaortic balloon pump (IABP) alleviates LV afterload but is associated with significant adverse events. We previously developed a system for rotational speed modulation in synchrony with the native cardiac cycle, for use with implantable continuous-flow LV assist devices. Here, we aimed to evaluate whether our novel rotation speed modulation system can improve coronary artery flow and reduce LV during femoral VA-ECMO. METHODS: VA-ECMO was installed by means of right atrial drainage and distal abdominal aortic perfusion in six adult goats. Cardiogenic shock was induced with beta-adrenergic antagonist infusion. An IABP was placed in the descending aorta. LV stroke work, LV end-systolic pressure, and coronary arterial flow were evaluated. Data were collected under five conditions (modes): baseline, circuit clamp (cardiogenic shock), continuous mode (constant rotational speed), counterpulse mode (increasing rotational speed during diastole), and continuous mode with IABP support. RESULTS: LV stroke work and LV end-systolic pressure tended to be lower in the counterpulse mode, indicating decreased LV work load and afterload in this mode. Furthermore, coronary arterial flow tended to be higher in the counterpulse mode. CONCLUSIONS: Our system enabled an increase in coronary arterial flow and a decrease in LV work load and afterload during VA ECMO. The system offers the effects of VA-ECMO and an IABP in a single device. PMID- 28709667 TI - Routine Use of Topical Bacitracin to Prevent Sternal Wound Infections After Cardiac Surgery. AB - BACKGROUND: The development of sternal wound infections remains a serious complication after cardiac surgery. A number of studies have assessed the use of topical antibiotics placed on the sternal edges. We evaluated the routine use of bacitracin ointment applied over the sternotomy skin incision as a prophylactic measure against sternal wound infections. METHODS: A retrospective review of all coronary artery bypass graft and valve surgery cases performed at a single institution between 2006 and 2015 was performed (n = 1,495). Appropriate preoperative intravenous antibiotics were administered for all patients. Bacitracin topical antibiotic ointment was routinely applied to the sternal surgical incision after skin closure for all patients during this period. The incidence of sternal wound infection was assessed. RESULTS: During this 9-year experience, no episodes of deep sternal wound infections were observed, compared with a predicted rate of 0.29% (interquartile range: 0.19% to 0.46%) based on The Society of Thoracic Surgeons National Database risk calculator. Four episodes of superficial sternal wound infections were noted; gram-positive organisms were cultured in the majority of these cases. Bacitracin ointment was well tolerated by patients, with no serious adverse effects reported. CONCLUSIONS: This study suggests that the routine application of topical bacitracin over the surgical skin incision is safe after cardiac surgery. Deep sternal wound infections were notably absent during this period. As a readily available and inexpensive therapy, this simple intervention may be a useful adjunct strategy in preventing sternal wound infections. PMID- 28709669 TI - Follow-up study of patients treated with olanzapine pamoate in France in real life treatment situation. AB - OBJECTIVE: To characterize patients treated with olanzapine pamoate in French centers and investigate the conditions of use of olanzapine pamoate in real-life treatment situation. METHODS: Data came from French sites participating in an international post-authorization safety study. In this observational study, patients diagnosed with schizophrenia were receiving commercially available olanzapine pamoate, in accordance with their physician's usual standard of care. Data were collected during routine visits within the standard course of patient care. RESULTS: One hundred and thirty eight patients (male, 73.9%; mean age, 39.4 years; mean duration of disease, 12.7years) received olanzapine pamoate and were included in the study by 32 investigative psychiatrists distributed across 20 different sites (psychiatric hospitals). During the period of analysis, a total of 2975 injections of olanzapine pamoate was administered to the patients. The mean duration of olanzapine pamoate exposure was 475 days (1.3years). During follow-up, 13.8% of all patients had at least one psychiatric hospitalization, 15.9% had at least one same-day psychiatric hospitalization (information documented for 116patients), and 44.2% received at least one concomitant drug. Three cases of post-injection delirium/sedation syndrome were reported during the analysis period. Treatment emergent adverse events (incidence, 20.3%) were in line with the known profile of olanzapine. CONCLUSION: Patients were administered olanzapine pamoate and monitored in compliance with label recommendations. The safety profile assessment of olanzapine pamoate in actual conditions was consistent with that described in clinical studies. PMID- 28709670 TI - Arterial stiffness in normotensive and hypertensive subjects: Frequency in community pharmacies. AB - BACKGROUND AND OBJECTIVE: Arterial stiffness (AS) is a well-recognized target organ lesion. This study aims to determine: 1) the frequency of AS in community pharmacies; 2) if stiffened subjects identified by brachial oscillometry have more CV risk factors than normal subjects, and 3) the dependence of stiffness on using either age-adjusted values or a fixed threshold. PATIENTS AND METHOD: Observational, cross-sectional study in 32 community pharmacies of the Valencia Community, between November/2015 and April/2016. Stiffness was as pulse wave velocity (PWV) measured with a semi-automatic, validated device (Mobil-O Graph(r), IEM), followed by a 10-item questionnaire. RESULTS: Mean age of the 1,427 consecutive recruited patients was 56.6 years. Overall proportion of patients with AS was 17.4% with age-adjusted PWV (9.4% in normotensives, 28.3% in hypertensives). Multivariate logistic regression showed independent association of stiffness in normotensives with male gender, obesity, higher pulse pressure and heart rate, in hypertensives, with higher pulse pressure and lower age. AS was globally found in 20.5% of subjects, defining stiffness by PWV>10m/s (6.2% in normotensives, 40.2% in hypertensives). It was associated with higher age and pulse pressure in both groups. Concordance in classifying stiffness was 74.6%. CONCLUSIONS: Frequency of AS varied between 17.4-20.5%. Age-adjusted stiffness is associated in normotensives with male gender, pulse pressure, obesity and heart rate, in hypertensives with pulse pressure and inversely to age. Stiffness by 10m/s is determined by higher pulse pressure and higher age. Both definitions of PWV are not interchangeable. PMID- 28709672 TI - Evaluation of color stability of preshaded and liquid-shaded monolithic zirconia. AB - STATEMENT OF PROBLEM: The effect of thermal aging on the color stability of monolithic zirconia has not been thoroughly investigated. PURPOSE: The purpose of this in vitro study was to evaluate the color stability before and after thermocycling of monolithic zirconia specimens, which were either preshaded or characterized in the laboratory through the assessment of color parameters L*, a*, and b*. MATERIAL AND METHODS: A total of 80 specimens (10*10*15 mm) were prepared from zirconia disks (BruxZir) and divided into 2 groups. The first group consisted of preshaded specimens from disks 100, 200, 300, and 400, and the second group consisted of white specimens characterized before the sintering stage with coloring liquids in shades A2, B2, C2, and D2. Ten specimens of each shade were used. A double-beam ultraviolet-visible light recording spectrophotometer was used to assess the color parameters L*, a*, and b* before and after thermocycling. The color difference DeltaE was calculated based on DeltaEpsilon=[(DeltaL*)2+(Deltaa*)2+(Deltab*)2]1/2. The reliability of the examiner was investigated by MedCalc v12.5 software, and the tests of normality, homogeneity of variances, and 1-way ANOVA statistical analysis of variance were performed by IBM Statistics SPSS v20.0 software (alpha=.05). RESULTS: No statistically significant DeltaEpsilon (P>.05) was observed among the different groups after thermocycling. All DeltaEpsilon values were below the limit of the 3.7 that an untrained observer can perceive. Only for the specimens in shades 200 and 400 was DeltaEpsilon above 1, revealing a visible color difference, which, however, was still clinically acceptable. The L*, a*, and b* values for both liquid-shaded and preshaded zirconia specimens were not significantly affected by thermocycling. A higher color stability for laboratory-characterized compared with preshaded monolithic zirconia was observed irrespective of the color shade. CONCLUSIONS: Within the limitations of this in vitro study, monolithic zirconia specimens of any shade, either preshaded or characterized in the laboratory, can be considered as color-stable materials after thermocycling. PMID- 28709673 TI - Stereophotogrammetric impression making for polyoxymethylene, milled immediate partial fixed dental prostheses. AB - Immediate post-extraction and same-day placement of interim prostheses have increased patient acceptance of implant-supported prostheses. However, for immediate prostheses supported by multiple implants, meeting passive fit and esthetic standards is often challenging. In this clinical report, implant photogrammetry was combined with conventionally obtained digitized casts to prepare an interim, milled prosthesis from a polyoxymethylene (POM) disk, using computer-aided design and computer-aided manufacturing techniques. The following 2 conclusions were drawn. First, stereophotogrammetric scanning appears to be a reliable method for making impressions of immediate, implant-supported partial prostheses, and second, POM is suitable for preparing immediate interim screw retained prosthetic implants. PMID- 28709671 TI - Mechanism and properties of positive allosteric modulation of N-methyl-d aspartate receptors by 6-alkyl 2-naphthoic acid derivatives. AB - The theory that N-methyl-d-aspartate receptor (NMDAR) hypofunction is responsible for the symptoms of schizophrenia is well supported by many pharmacological and genetic studies. Accordingly, positive allosteric modulators (PAMs) that augment NMDAR signaling may be useful for treating schizophrenia. Previously we have identified several NMDAR PAMs containing a carboxylic acid attached to naphthalene, phenanthrene, or coumarin ring systems. In this study, we describe several functional and mechanistic properties of UBP684, a 2-naphthoic acid derivative, which robustly potentiates agonist responses at each of the four GluN1a/GluN2 receptors and at neuronal NMDARs. UBP684 increases the maximal l glutamate/glycine response while having minor subunit-specific effects on agonist potency. PAM binding is independent of agonist binding, and PAM activity is independent of membrane voltage, redox state, and the GluN1 exon 5 N-terminal insert. UBP684 activity is, however, markedly pH-dependent, with greater potentiation occurring at lower pHs and inhibitory activity at pH 8.4. UBP684 increases channel open probability (Po) and slows receptor deactivation time upon removal of l-glutamate, but not glycine. The structurally related PAM, UBP753, reproduced most of these findings, but did not prolong agonist removal deactivation time. Studies using cysteine mutants to lock the GluN1 and GluN2 ligand-binding domains (LBDs) in the agonist-bound states indicate that PAM potentiation requires GluN2 LBD conformational flexibility. Together, these findings suggest that UBP684 and UBP753 stabilize the GluN2 LBD in an active conformation and thereby increase Po. Thus, UBP684 and UBP753 may serve as lead compounds for developing agents to enhance NMDAR activity in disorders associated with NMDAR hypofunction. PMID- 28709674 TI - Accuracy of CAD-CAM-fabricated removable partial dentures. AB - STATEMENT OF PROBLEM: The conventional fabrication of removable partial dentures (RPDs) is a complex, error-prone, time-consuming, and expensive process. The use of computer-aided design and computer-aided manufacturing (CAD-CAM) techniques, especially rapid prototyping, promises a more effective method for fabricating RPD frameworks. PURPOSE: The purpose of this in vitro study was to evaluate the fit of RPD clasps fabricated by means of 4 different CAD-CAM-systems and to compare those fittings with that of the conventional lost-wax casting technique (LWT). MATERIAL AND METHODS: A master model of a partially edentulous maxilla with the canines and second molars as the remaining teeth was fabricated. After the model was optically scanned, we designed a quadrangularly supported RPD with 4 clasps and a palatal strap major connector. A standard tessellation language data set was used to fabricate 12 identical RPDs by using 4 different CAD-CAM techniques: indirect rapid prototyping (wax inject printing combined with LWT), direct rapid prototyping (selective laser melting), indirect milling (wax milling with LWT), and direct milling (resin milling [polyetheretherketone]). Three conventionally cast RPDs (LWT) served as the control group. The fit accuracy of the clasps (n=12 for each group) was determined in both the horizontal and vertical dimensions by using light microscopy. RESULTS: Indirectly milled RPDs (117 +/-34 MUm horizontal and 45 +/-21 MUm vertical) and directly milled RPDs (43 +/-23 MUm horizontal, and 38 +/-21 MUm vertical) showed significantly better (P<.05) fit than did conventionally fabricated LWT RPDs (133 +/-59 MUm horizontal; 73 +/-25 MUm vertical). The worst fit was found for RPDs fabricated using indirect rapid prototyping (323 +/-188 MUm horizontal and 112 +/-60 MUm vertical) or direct rapid prototyping (365 +/-205 MUm horizontal and 363 +/-133 MUm vertical), which were unstable on the master model, making them unsuitable for clinical use. Most RPDs exhibited smaller vertical measuring distances. CONCLUSIONS: Compared with the LWT, milling techniques enabled fabrication of RPDs with comparable or better fit. However, RPDs fabricated with rapid prototyping techniques showed distinct fitting irregularities. PMID- 28709675 TI - A digital technique for fabricating implant-supported interim restorations in the esthetic zone. AB - A digital technique for fabricating an implant-supported interim restoration is presented. The labial cervical architecture of the natural tooth is captured before extraction and registered to form the emergence profile of the interim restoration. A well-contoured interim restoration is fabricated before surgery and connected to the immediately placed implant with a customized interim abutment. PMID- 28709676 TI - Fracture load of complete-arch implant-supported prostheses reinforced with nylon silica mesh: An in vitro study. AB - STATEMENT OF PROBLEM: Complete-arch implant-supported prostheses without a framework have a high risk of failure: a straightforward and inexpensive reinforcement material, such as nylon mesh, could improve their longevity. PURPOSE: The purpose of this in vitro study was to evaluate a nylon-silica mesh compound on the fracture strength of acrylic resin and the fracture load of complete-arch implant-supported prostheses. MATERIAL AND METHODS: Twenty-four complete mandibular arch implant-supported prostheses were divided into 2 groups according to cantilever length (molar and premolar) and subdivided into another 2 subgroups according to the presence or absence of reinforcing mesh. The specimens were submitted to a maximum load-to-fracture test in a universal testing machine, with a 100-N load cell, a 2 mm/min crosshead speed, and a spherical metal tip diameter of 4 mm at different points (molar and premolar). These were submitted to 1-way analysis of variance for repeated measurement and the post hoc Tukey multiple comparison test (alpha=.05). RESULTS: The mean maximum load +/-standard deviation for the molar group was 393.4 +/-95.0 N with reinforcement and 305.4 +/ 76.3 N without reinforcement (P=.02); and for the premolar group was 1083.3 +/ 283.7 N with reinforcement and 605.3 +/-90.5 N without reinforcement (P=.001). CONCLUSIONS: Reinforcement with nylon mesh increased the mean maximum load of implant-supported complete-arch prostheses at both cantilever lengths. The cantilever to the premolar (5 mm) presented the highest maximum load values to fracture. PMID- 28709677 TI - Functional and esthetic restorative treatment with preheated resins in a patient with ectodermic dysplasia: A clinical report. AB - Ectodermal dysplasia is a heterogeneous genetic condition affecting 1.6 to 22 per 100000 people. Oral manifestations associated with this condition include hyperdontia, hypodontia, microdontia, and conical teeth. Traditional treatment consists of a combination of orthodontic and rehabilitation therapies. The initial treatment stage uses removable prostheses and interim crowns for long periods, thus increasing risks for developing secondary caries. This clinical report describes the use of direct composite resin bonding with preheated compactable resins applied to vacuum-formed trays filled with clear silicone. This restorative treatment provides predictable, inexpensive, minimally invasive, functional, and esthetic recovery before orthodontic treatment. PMID- 28709678 TI - Annual review of selected scientific literature: Report of the committee on scientific investigation of the American Academy of Restorative Dentistry. AB - This review was conducted to assist the busy dentist in keeping abreast of the latest scientific information regarding the clinical practice of dentistry. Each of the authors, who are considered experts in their disciplines, was asked to peruse the scientific literature in their discipline published in 2016 and review the articles for important information that may affect treatment decisions. Comments on experimental methodology, statistical evaluation, and the overall validity of conclusions are included with many of the reviews. The reviews are not meant to stand alone but are intended to inform the interested reader about what has been discovered in the past year. The readers are then invited to go to the source, if they want more detail. PMID- 28709679 TI - The all-on-4 modified polyetheretherketone treatment approach: A clinical report. AB - A modified polyetheretherketone (PEEK) implant framework material in combination with prefabricated high-impact poly(methyl methacrylate) (PMMA) veneers was used as an alternative material for the fabrication of a complete maxillary arch implant-supported fixed restoration. The elastic performance of the PEEK framework (elastic modulus of 4 GPa) combined with PMMA veneers may reduce the occlusal forces, protecting the implant-supported restoration and the opposing dentition, especially in all-on-4 treatments, where lack of proprioception and wide interimplant distance are present. Long-term clinical evidence is required before recommending the application as an alternative restorative material for such a prosthesis. PMID- 28709680 TI - Patient satisfaction with laser-sintered removable partial dentures: A crossover pilot clinical trial. AB - STATEMENT OF PROBLEM: Clinical data regarding newly introduced laser-sintered removable partial dentures (RPDs) are needed before this technique can be recommended. Currently, only a few clinical reports have been published, with no clinical studies. PURPOSE: This clinical trial compared short-term satisfaction in patients wearing RPDs fabricated with conventional or computer-aided design and computer-aided manufacturing (CAD-CAM) laser-sintering technology. MATERIAL AND METHODS: Twelve participants with partial edentulism were enrolled in this pilot crossover double-blinded clinical trial. Participants were randomly assigned to wear cast or CAD-CAM laser-sintered RPDs for alternate periods of 30 days. The outcome of interest was patient satisfaction as measured using the McGill Denture Satisfaction Instrument. Assessments was conducted at 1, 2, and 4 weeks. The participant's preference in regard to the type of prosthesis was assessed at the final evaluation. The linear mixed effects regression models for repeated measures were used to analyze the data, using the intention-to-treat principle. To assess the robustness of potential, incomplete adherence, sensitivity analyses were conducted. RESULTS: Statistically significant differences were found in patients' satisfaction between the 2 methods of RPD fabrication. Participants were significantly more satisfied with laser-sintered prostheses than cast prostheses in regard to general satisfaction, ability to speak, ability to clean, comfort, ability to masticate, masticatory efficiency, and oral condition (P<.05). At the end of the study, 5 participants preferred the laser-sintered, 1 preferred the cast RPD, and 3 had no preference. CONCLUSIONS: The use of CAD-CAM laser-sintering technology in the fabrication of removable partial dentures may lead to better outcomes in terms of patient satisfaction in the short term. The conclusion from this pilot study requires confirmation by a larger randomized controlled trial. CLINICAL TRIAL: ClinicalTrials.gov. A study about patient satisfaction with laser-sintered removable partial dentures; NCT02769715. PMID- 28709681 TI - Customized Locator abutment fabrication on inclined implants: A clinical report. AB - Implant parallelism is rarely achieved, particularly when anatomic limitations are present. The problem of nonparallel implants has been addressed by using angled or bar abutments to compensate for the implant angulation. However, an angled abutment or bar attachment has disadvantages in terms of cost, laboratory process, and the maintenance of oral hygiene. In this clinical report, a solution for the management of an inclined implant is presented by using customized Locator abutment fabricated by computer-aided design and computer-aided manufacturing (CAD-CAM). PMID- 28709682 TI - Hemifield coding in ventral object-sensitive areas - Evidence from visual hemiagnosia. AB - Electrophysiological monkey and human neuroimaging studies have reported a lateralization of signal processing in object perception. However, it is unclear whether these results point to a unique topographically organized signal processing in either hemisphere, or if these results represent a rather negligible spatial organization of otherwise redundant object perception systems in both hemispheres. We tested a group of 10 patients with lesions to ventral object processing regions and spared primary visual functions with lateral presentations of different categories of object stimuli. Object perception in the contralesional visual field was impaired while object perception on the ipsilesional hemifield was intact. These results demonstrate that the object perception system needs two intact ventral pathways for unimpaired object perception across the whole visual field; the loss of one system cannot be fully compensated by its contralateral homolog or spared parts of the lesioned ventral stream. PMID- 28709683 TI - 10,000 steps into the digital age. PMID- 28709684 TI - Hairpin structures with conserved sequence motifs determine the 3' ends of non polyadenylated invertebrate iridovirus transcripts. AB - Previously, we observed that the transcripts of Invertebrate iridescent virus 6 (IIV6) are not polyadenylated, in line with the absence of canonical poly(A) motifs (AATAAA) downstream of the open reading frames (ORFs) in the genome. Here, we determined the 3' ends of the transcripts of fifty-four IIV6 virion protein genes in infected Drosophila Schneider 2 (S2) cells. By using ligation-based amplification of cDNA ends (LACE) it was shown that the IIV6 mRNAs often ended with a CAUUA motif. In silico analysis showed that the 3'-untranslated regions of IIV6 genes have the ability to form hairpin structures (22-56 nt in length) and that for about half of all IIV6 genes these 3' sequences contained complementary TAATG and CATTA motifs. We also show that a hairpin in the 3' flanking region with conserved sequence motifs is a conserved feature in invertebrate-infecting iridoviruses (genus Iridovirus and Chloriridovirus). PMID- 28709685 TI - Biometrical evaluation of the performance of the revised OECD Test Guideline 402 for assessing acute dermal toxicity. AB - A comprehensive biometrical assessment was conducted to compare the performance of multiple test designs for acute dermal systemic toxicity to support the animal welfare update to the original OECD Test Guideline (TG) 402 for acute dermal toxicity. The test designs evaluated included: (1) two, three, or five animals per dose group (2) evident toxicity or lethality endpoints and (3) absence or presence of a one-animal sighting study. The revision of TG 402 respected the 3R principles (replace, reduce, refine) of animal testing. The results demonstrate that the TG 402 test design can be optimised with reduced animal numbers per test group, such that a scenario of two animals per group following a sighting study at a starting dose of 200 mg/kg bw (unless further information is available to better define the starting dose) would provide a classification which in most cases is conservative, without compromising both the statistical ability of the study to assess dermal toxicity, or the relevant classification outcome. PMID- 28709686 TI - Toxicologic evaluations of recombinant liver-targeting interferon IFN-CSP: Genotoxicity and tegenicratoity. AB - Interferon alpha as the one of FDA recommended drugs for Hepatitis B virus (HBV) infection has many side effects. Targeting IFNalpha to the liver may be a strategy to increase its efficacy locally and may increase efficacy of IFNalpha based therapy of HBV infection. We have prepared a novel liver-targeting fusion interferon (IFN-CSP) combining IFN alpha2b with plasmodium region I peptide and have revealed it may be an excellent candidate as a liver-targeting anti-HBV agent. In this study, we investigated the genotoxic and teratogenic effects of IFN-CSP. The genotoxicity of IFN-CSP was evaluated by using a standard battery of tests (bacterial reverse mutation assay, mouse bone marrow micronucleus assay, and mouse sperm malformation assay). The results showed that IFN-CSP did not increase the number of revertant colonies in the plates of four strains, had no marked effect on the incidence of mouse bone marrow micronucleus and did not affect sperm deformity proportion at doses up to 8.8 * 108IU/kg, which was 1128.2 folds of the maximum' clinical equivalent dosage. Meanwhile, for teratogenicity test of IFN-CSP in female SD rats at the dosage of 6.3 * 107 IU/kg, no toxicological signs were observed. These results indicated that IFN-CSP has no genotoxicity and teratogenicity under the testing conditions. PMID- 28709687 TI - 'New Wilderness' Requires Algorithmic Transparency: A Response to Cantrell et al. PMID- 28709688 TI - Multidisciplinary Consensus on the Nonadherence to Clinical Management of Inhaled Therapy in Spanish asthma patients. AB - PURPOSE: Rates of nonadherence to asthma treatment in Spain are between 24% and 76%, which results in poor disease control and increased health care costs. The main objective of this multidisciplinary consensus was to investigate the opinions of health professionals and patients regarding adherence to inhaled therapy in Spain. The results will help to identify the causes of nonadherence and to establish strategies to detect and correct the problem. METHODS: This research was conducted by using a modified Delphi method organized into 2 rounds and involving a panel of 64 physicians, 16 nurses, and 10 community pharmacists. In addition, 70 patients with asthma completed a simplified 1-round survey, based on the Delphi questionnaire. The items proposed to reach a consensus included topics such as impact and causes of nonadherence, as well as strategies to improve adherence to treatment. FINDINGS: Expert panelists reached a consensus on ~80% of the items proposed. They agreed that the lack of control in asthma has an important economic impact. The causes of nonadherence with more agreement were the patients' beliefs about treatment and the complexity of the inhalation devices. Panelists agreed that the most important strategies to improve adherence were modification of patients' beliefs, training of professionals in the management of adherence, and personalization of interventions. Most patients only agreed with items that referred to strategies to improve adherence. IMPLICATIONS: Although the problems, impact, causes, and interventions regarding nonadherence to asthma treatment are known, adequate monitoring of adherence to treatment is not performed. A multidisciplinary and personalized approach is necessary to control and improve adherence. PMID- 28709689 TI - Psychiatric reactions to continuous traumatic stress: A Latent Profile Analysis of two Israeli samples. AB - Many individuals worldwide are exposed to continuous traumatic stress (CTS). However, the psychiatric sequela of CTS and the relevance of posttraumatic stress disorder (PTSD) diagnostic criteria in this situation have yet to be determined. Filling this gap, the present study assessed psychiatric reactions to CTS and the relationship between such reactions and functional impairment among two representative samples of adults exposed to ongoing shelling over 6 (n=387) and 9 years (n=468). Assessment included PTSD symptomatology (i.e., intrusion, avoidance, hyperarousal), anxiety, somatization, and depression. Profile categorization aimed to underscore variations in symptom clustering and severity, and determine whether or not a profile is dominated by PTSD symptoms. Latent Profile analyses (LPA) of sample I revealed four distinct symptoms profiles: (1) 'symptomatically resilient'; (2) 'symptomatically low-moderate'; (3) 'symptomatically moderate-high'; and (4) 'symptomatically overall high'. LPA of sample II revealed three distinct symptoms profiles: (1) 'symptomatically resilient'; (2) 'symptomatically low-moderate'; (3) "symptomatically moderate high". Moreover, profile variation was implicated in dysfunction. Consistent with studies focusing on single trauma exposure, the findings revealed that the most prevalent profile was the symptomatically resilient, indicating that most people exposed to CTS seem to evince a scarce number of psychiatric symptoms. Moreover, reactions to CTS proved broader than the existing PTSD symptomatology. Examining symptom dominance and severity in relation to impairment and dysfunction, and clinical considerations are discussed. PMID- 28709690 TI - Municipal solid waste system analysis through energy consumption and return approach. AB - Inappropriate waste management and poor resource efficiency are two of the biggest problems which European Union is trying to solve through Landfill Directive, Waste Framework Directive and Circular Economy Package by increasing recycling and reuse and reducing waste disposal. In order to meet set goals, new European Union member states must quickly change national legislature and implement appropriate solutions. In the circumstances of strong EU resource and energy dependence, decision makers need to analyse which of the considered waste management systems leads to higher overall benefits ie. which is more sustainable. The main problem in this kind of analysis is a wide range of possible technologies and the difference in inputs and outputs. Sustainability of these systems is analysed through single-score LCA based assessment, using primary energy used to produce materials and energy vectors as a common measure. To ensure reliable results, interoperability between different data sources and material flows of waste and its components are monitored. Tracking external and internal material, and energy flows enable modelling of mutual interactions between different facilities. Resulting PERI, primary energy return based index, is used for comparison of different waste management scenarios. Results show that time and legislation dependent changes have great influence on decision making related to waste management and interconnected systems. PMID- 28709691 TI - [Arguments for the need to regulate surrogacy]. PMID- 28709692 TI - AMPK orchestrates an elaborate cascade protecting tissue from fibrosis and aging. AB - Fibrosis is a common process characterized by excessive extracellular matrix (ECM) accumulation after inflammatory injury, which is also a crucial cause of aging. The process of fibrosis is involved in the pathogenesis of most diseases of the heart, liver, kidney, lung, and other organs/tissues. However, there are no effective therapies for this pathological alteration. Annually, fibrosis represents a huge financial burden for the USA and the world. 5'-AMP-activated protein kinase (AMPK) is a pivotal energy sensor that alleviates or delays the process of fibrogenesis. In this review, we first present basic background information on AMPK and fibrogenesis and describe the protective roles of AMPK in three fibrogenic phases. Second, we analyze the protective action of AMPK during fibrosis in myocardial, hepatic, renal, pulmonary, and other organs/tissues. Third, we present a comprehensive discussion of AMPK during fibrosis and draw a conclusion. This review highlights recent advances, vital for basic research and clinical drug design, in the regulation of AMPK during fibrosis. PMID- 28709693 TI - Squamous proliferations on the legs of women: Qualitative examination of histopathology, TP53 sequencing, and implications for diagnosis in a series of 30 cases. AB - BACKGROUND: Women with multiple squamous cell carcinomas (SCCs) of the legs have a striking clinical phenotype. Numerous tumors can develop in a short period of time. OBJECTIVE: Because histopathologic findings can vary in women with multiple SCC lesions, from keratoacanthoma-like to well-differentiated SCC, we hypothesized that TP53 variants might shed light on the appropriate classification. METHODS: We sequenced TP53 in 30 SCCs from 6 women who had multiple SCCs on their legs during a 21-month time frame. RESULTS: Histopathologic analysis showed 16 of the 30 lesions did not have prominent cytologic atypia and were distinguished by having expanded follicle-like structures composed of large, glassy, eosinophilic keratinocytes; these lesions resembled keratoacanthoma and were categorized as keratoacanthoma-like squamous proliferations (KASPs). The 14 remaining tumors had more prominent cytologic atypia and remained classified as SCC. Twenty of 30 tumors (including the KASPs) from the 6 different patients lacked detectable TP53 mutations. Ten of the 14 tumors that remained classified as SCC had detectable TP53 mutations. LIMITATIONS: This is a small series. CONCLUSION: These findings suggest that some cutaneous squamous proliferations on the legs of women with multiple lesions lack prominent cytologic atypia as well as TP53 mutations and might be more akin to keratoacanthoma than SCC or might represent a reactive phenomenon. PMID- 28709694 TI - Early clinical manifestations of Sezary syndrome: A multicenter retrospective cohort study. AB - BACKGROUND: Classic Sezary syndrome (SS) is defined by erythroderma, generalized lymphadenopathy, and leukemic blood involvement. Clinical observations suggest that SS begins as a nonerythrodermic disease. OBJECTIVE: To describe the early clinical characteristics of patients with SS. METHODS: A retrospective, multicenter chart review was performed for 263 confirmed cases of SS diagnosed during 1976-2015. RESULTS: Erythroderma was the earliest recorded skin sign of SS in only 25.5% of cases, although most patients (86.3%) eventually developed erythroderma. In patients without erythroderma during their initial visit, the first cutaneous signs of SS were nonspecific dermatitis (49%), atopic dermatitis like eruption (4.9%), or patches and plaques of mycosis fungoides (10.6%). The mean diagnostic delay was 4.2 years overall, 2.2 years for cases involving erythroderma at the initial presentation, and 5.0 years for cases not involving erythroderma at the initial presentation. LIMITATIONS: This study is retrospective. CONCLUSION: Erythroderma is uncommon as an initial sign of SS. Early SS should be considered in cases of nonerythrodermic dermatitis that is refractory to conventional treatments. In these cases, examination of the blood by PCR for monoclonal T-cell receptor rearrangement and by flow cytometry to identify an expanded or aberrant T-cell population should be considered. PMID- 28709696 TI - Corrigendum to "Externally validated HPV-based prognostic nomogram for oropharyngeal carcinoma patients yields more accurate predictions than TNM staging" [Radiother Oncol 113 (2014) 324-30]. PMID- 28709697 TI - Effects of P limitation and molecules from peanut root exudates on pqqE gene expression and pqq promoter activity in the phosphate-solubilizing strain Serratia sp. S119. AB - The mineral phosphate-solubilizing phenotype in bacteria is attributed predominantly to secretion of gluconic acid produced by oxidation of glucose by the glucose dehydrogenase enzyme and its cofactor, pyrroloquinoline quinone. This study analyzes pqqE gene expression and pqq promoter activity in the native phosphate-solubilizing bacterium Serratia sp S119 growing under P-limitation, and in the presence of root exudates obtained from peanut plants, also growing under P-limitation. Results indicated that Serratia sp. S119 contains a pqq operon composed of six genes (pqqA,B,C,D,E,F) and two promoters, one upstream of pqqA and other between pqqA and pqqB. PqqE gene expression and pqq promoter activity increased under P-limiting growth conditions and not under N-deficient conditions. In the plant-bacteria interaction assay, the activity of the bacterial pqq promoter region varied depending on the concentration and type of root exudates and on the bacterial growth phase. Root exudates from peanut plants growing under P-available and P-limiting conditions showed differences in their composition. It is concluded from this study that the response of Serratia sp. S119 to phosphorus limitation involves an increase in expression of pqq genes, and that molecules exuded by peanut roots modify expression of these phosphate solubilizing bacterial genes during plant-bacteria interactions. PMID- 28709698 TI - Revisiting the sensitivity of sodium channel blocker testing in Brugada syndrome using obligate transmittance. PMID- 28709695 TI - Peripheral biomarkers of major depression and antidepressant treatment response: Current knowledge and future outlooks. AB - BACKGROUND: In recent years, we have accomplished a deeper understanding about the pathophysiology of major depressive disorder (MDD). Nevertheless, this improved comprehension has not translated to improved treatment outcome, as identification of specific biologic markers of disease may still be crucial to facilitate a more rapid, successful treatment. Ongoing research explores the importance of screening biomarkers using neuroimaging, neurophysiology, genomics, proteomics, and metabolomics measures. RESULTS: In the present review, we highlight the biomarkers that are differentially expressed in MDD and treatment response and place a particular emphasis on the most recent progress in advancing technology which will continue the search for blood-based biomarkers. LIMITATIONS: Due to space constraints, we are unable to detail all biomarker platforms, such as neurophysiological and neuroimaging markers, although their contributions are certainly applicable to a biomarker review and valuable to the field. CONCLUSIONS: Although the search for reliable biomarkers of depression and/or treatment outcome is ongoing, the rapidly-expanding field of research along with promising new technologies may provide the foundation for identifying key factors which will ultimately help direct patients toward a quicker and more effective treatment for MDD. PMID- 28709699 TI - Strategy to identify subjects with diabetes mellitus more suitable for selective echocardiographic screening: The DAVID-Berg study. AB - BACKGROUND: Despite the burden of pre-clinical heart failure (HF) among diabetes mellitus (DM) patients, routine screening echocardiography is not currently recommended. We prospectively assessed risk prediction for HF/death of a screening strategy combining clinical data, electrocardiogram, NTproBNP, and echocardiogram, aiming to identify DM patients more suitable for selective echocardiography. METHODS: Among 4047 screened subjects aged>=55/<=80years, the DAVID-Berg Study prospectively enrolled 623 outpatients with DM, or hypertension, or known cardiovascular disease but with no HF history/symptoms. The present analysis focuses on data obtained during a longitudinal follow-up of the 219 patients with DM. RESULTS: Mean age was 68years, 61% were men, and median DM duration was 4.9years. During a median follow-up of 5.2years, 50 subjects developed HF or died. A predictive model using clinical data demonstrated moderate predictive power, which significantly improved by adding electrocardiogram (C-statistic 0.75 versus 0.70; p<0.05), but not NTproBNP (C statistic 0.72, p=0.20). Subjects with normal clinical variables or abnormal clinical variables but normal electrocardiogram had low events rate (1.3 versus 2.4events/100-person-years, p=NS). Conversely, subjects with both clinical and electrocardiogram abnormalities (47%) carried higher risk (9.0events/100-person years, p<0.001). The predictive power for mortality/HF development increased when echocardiography was added (13.6events/100-person-years, C-statistic 0.80, p<0.05). CONCLUSIONS: Our prospective study found that a selective echocardiographic screening strategy guided by abnormal clinical/electrocardiogram data can reliably identify DM subjects at higher risk for incident HF and death. This screening approach may hold promise in guiding HF prevention efforts among DM patients. PMID- 28709700 TI - Prasugrel as opposed to clopidogrel improves endothelial nitric oxide bioavailability and reduces platelet-leukocyte interaction in patients with unstable angina pectoris: A randomized controlled trial. AB - BACKGROUND: Platelet inhibition has been linked to improved endothelial function, a prognostic factor in coronary artery disease. Whether prasugrel, a potent platelet inhibitor, affects endothelial function remains unknown. METHODS: This was a double-blind, randomized, active-controlled, parallel trial. Patients with unstable angina pectoris undergoing percutaneous coronary intervention (PCI) received either a daily dose of clopidogrel 75mg (n=23) or prasugrel 10mg (n=22). Flow-mediated dilation (FMD), circulating nitrate and nitrite, inflammatory markers and platelet-leukocyte aggregates (PLAs) were assessed the day after PCI and after 3months. RESULTS: Baseline patient demographics were well matched between treatment groups. Prasugrel led to a significant improvement of FMD after 3months (9.01+/-3.64% vs. 6.65+/-3.24%, p=0.001). In contrast, no significant change was observed in the clopidogrel group (7.21+/-2.84% vs. 6.30+/-2.97%, p=0.187). Adjusted for baseline FMD, hyperlipidemia and statin use, the treatment effect on change in FMD favoured prasugrel by an absolute 1.97% (95% CI 0.29% to 3.66%, p=0.023). A significant reduction of plasma hsCRP, myeloperoxidase and neutrophil elastase and an increase of nitrate levels were noted in both treatment arms. Interestingly, only prasugrel significantly reduced sCD40 ligand and RANTES and increased nitrite levels. Prasugrel reduced the ADP-stimulated increase in PLAs by 40% (IR: 82 to 13), whereas clopidogrel revealed no such effect (1% increase (IR: 13 to 50) (p=0.01). CONCLUSION: Prasugrel exhibits beneficial mid-term effects on endothelial nitric oxide bioavailability and inflammatory markers. (EudraCT number: 2009-015406-19). PMID- 28709701 TI - Optical coherence tomography guidance for the management of angiographically intermediate left main bifurcation lesions: Early clinical experience. AB - BACKGROUND: Left main (LM) atherosclerotic lesions affect clinical outcomes. Frequency domain-optical coherence tomography (FD-OCT) allows detailed characterization of non-ostial coronary atherosclerotic lesions. The clinical impact of FD-OCT assessment of LM bifurcation disease on the revascularization decision is unknown. METHODS: Patients who underwent FD-OCT assessment to guide management of angiographically intermediate distal LM stenosis were retrospectively selected. The FD-OCT LM criteria for percutaneous or surgical revascularization were: Clinical follow-up was obtained to evaluate the occurrence of target vessel failure (TVF) defined as cardiac death and/or acute myocardial infarction (AMI) not related to other vessel and/or target vessel revascularization. RESULTS: Out of 131 patients underwent FD-OCT assessment of LM, 122 patients (93%) entered the study. Based on FD-OCT features, 58 (48%) patients were conservatively managed, while the remaining 64 (52%) were revascularized by stenting (n=48) or surgery (n=16). After a mean follow-up of 18months, TVF-free survival was not different between patients undergoing conservative management vs. revascularization (HR 0.40, CI 95% 0.10-1.61, P=0.20). Of note, two patients only in the conservative management group had TVF (elective LM stenting, no death or myocardial infarction). CONCLUSIONS: This preliminary experience suggests that a FD-OCT based management for patients with angiographically-intermediate LM bifurcation stenosis may help identify patients in whom revascularization could be deferred. Such observation calls for further evaluations by appropriately designed trials. PMID- 28709702 TI - Clinical and Morphologic Characteristics of MEK Inhibitor-Associated Retinopathy: Differences from Central Serous Chorioretinopathy. AB - PURPOSE: To investigate the clinical and morphologic characteristics of serous retinal disturbances in patients taking mitogen-activated protein kinase kinase (MEK) inhibitors. PARTICIPANTS: A total of 313 fluid foci in 50 eyes of 25 patients receiving MEK inhibitors for treatment of their metastatic cancer, who had evidence of serous retinal detachments confirmed by optical coherence tomography (OCT). DESIGN: Single-center, retrospective cohort study. METHODS: Clinical examination and OCT were used to evaluate MEK inhibitor-associated subretinal fluid. The morphology, distribution, and location of fluid foci were serially evaluated for each eye. Choroidal thickness was measured at each time point (baseline, fluid accumulation, and fluid resolution). Two independent observers performed all measurements. Statistical analysis was used to correlate interobserver findings and compare choroidal thickness and visual acuity at each time point. MAIN OUTCOME MEASURES: Comparison of OCT characteristics of retinal abnormalities at baseline to fluid accumulation. RESULTS: The majority of patients had fluid foci that were bilateral (92%) and multifocal (77%) and at least 1 focus involving the fovea (83.3%). All fluid foci occurred between the interdigitation zone and an intact retinal pigment epithelium. The 313 fluid foci were classified into 4 morphologies, as follows: 231 (73.8%) dome, 36 (11.5%) caterpillar, 31 (9.9%) wavy, and 15 (4.8%) splitting. Best-corrected visual acuity at fluid resolution was not statistically different from baseline; and no eye lost more than 2 Snellen lines from baseline at the time of fluid accumulation. There was no statistical difference in the choroidal thickness between the different time points (baseline, fluid accumulation, and fluid resolution). A strong positive interobserver correlation was obtained for choroidal thickness measurements (r = 0.97, P < 0.0001) and grading of foci morphology (r = 0.97, P < 0.0001). CONCLUSION: The subretinal fluid foci associated with MEK inhibitors have unique clinical and morphologic characteristics, which can be distinguished from the findings of central serous chorioretinopathy. In this series, MEK inhibitors did not cause irreversible loss of vision or serious eye damage. PMID- 28709703 TI - Extent of lymphovascular space invasion may predict lymph node metastasis in uterine serous carcinoma. AB - OBJECTIVES: Emerging evidence suggests that extent of lymphovascular space invasion (LVSI) predicts for risk of lymph node metastasis in endometrioid uterine cancers. However, this correlation remains unknown in the setting of uterine serous carcinoma (USC). We sought to examine the association between extent of LVSI and other histopathologic characteristics with risk of nodal metastasis for women with USC. MATERIALS/METHODS: Pathological data from all cases of uterine serous carcinoma between July 1998 to July 2015 at our institution were reviewed. Descriptive, univariate, and multivariate logistic regression analysis of selected pathologic features were performed. RESULTS: 88 patients with USC underwent total abdominal or laparoscopic hysterectomy, bilateral salpingo-oophorectomy, and selective lymphadenectomy. Surgical staging revealed the following FIGO stage distributions: I (41%), II (8%), III (32%), IV (19%). LVSI was present in 44 (50%) patients. 36 patients (41%) had LN metastases with median number of total nodes removed of 17 (range, 1-49). On univariate analysis, depth of myometrial invasion, LVSI, tumor size, and cervical stromal involvement were significantly associated with nodal involvement. In a multivariate model, LVSI (OR 6.25, 95% CI 2.2-18.0, p<0.01) and cervical stromal involvement (OR 3.33, 95% CI 1.10-10.0, p=0.03) were the only factors that remained significant. Among patients with LVSI-positive disease, extensive LVSI was associated with increased risk of nodal involvement compared to focal LVSI (90% vs 29%, p=0.04). CONCLUSIONS: Presence and extent of LVSI, and cervical stromal invasion are important predictors for lymph node metastasis in uterine serous carcinoma. PMID- 28709704 TI - Epigenetic silencing of MLH1 in endometrial cancers is associated with larger tumor volume, increased rate of lymph node positivity and reduced recurrence-free survival. AB - OBJECTIVES: To determine the relationship between mismatch repair (MMR) classification and clinicopathologic features including tumor volume, and explore outcomes by MMR class in a contemporary cohort. METHODS: Single institution cohort evaluating MMR classification for endometrial cancers (EC). MMR immunohistochemistry (IHC)+/-microsatellite instability (MSI) testing and reflex MLH1 methylation testing was performed. Tumors with MMR abnormalities by IHC or MSI and MLH1 methylation were classified as epigenetic MMR deficiency while those without MLH1 methylation were classified as probable MMR mutations. Clinicopathologic characteristics were analyzed. RESULTS: 466 endometrial cancers were classified; 75% as MMR proficient, 20% epigenetic MMR defects, and 5% as probable MMR mutations. Epigenetic MMR defects were associated with advanced stage, higher grade, presence of lymphovascular space invasion, and older age. MMR class was significantly associated with tumor volume, an association not previously reported. The epigenetic MMR defect tumors median volume was 10,220mm3 compared to 3321mm3 and 2,846mm3, for MMR proficient and probable MMR mutations respectively (P<0.0001). Higher tumor volume was associated with lymph node involvement. Endometrioid EC cases with epigenetic MMR defects had significantly reduced recurrence-free survival (RFS). Among advanced stage (III/IV) endometrioid EC the epigenetic MMR defect group was more likely to recur compared to the MMR proficient group (47.7% vs 3.4%) despite receiving similar adjuvant therapy. In contrast, there was no difference in the number of early stage recurrences for the different MMR classes. CONCLUSIONS: MMR testing that includes MLH1 methylation analysis defines a subset of tumors that have worse prognostic features and reduced RFS. PMID- 28709705 TI - Phase II trial of neoadjuvant chemotherapy followed by chemoradiation in locally advanced cervical cancer. AB - OBJECTIVE: Cervical cancer is a global public health challenge. Since 1999, platin based chemoradiation (CRT) is the standard treatment for those patients with locally advanced disease. However, this population still has a dismal prognosis and, alternatives approaches such as adjuvant chemotherapy are controversial, especially because of increased toxicity. Neoadjuvant chemotherapy (NACT) could be an option for more intensive treatment with manageable toxicity. METHODS: A phase II, prospective, non-randomized trial was conducted at a reference center in Recife, Brazil. Locally advanced cervical cancer patients (Ib2-IVa) were treated with neoadjuvant cisplatin 35mg/m2 and gemcitabine 1000mg/m2 D1 and D8, for 2cycles. Then, they received CRT (50.4Gy) with weekly cisplatin 40mg/m2 followed by brachytherapy. Response rate (RR) and toxicity were the primary endpoints. Progression-free survival (PFS) and overall survival (OS) were secondary endpoints. RESULTS: Between Sep/2013 and Oct/2015, 50 patients were initiated on NACT and CRT. RR was 81% at the end of treatment. Hematological and gastrointestinal toxicity were most common. Grade 3/4 toxicity was 20% during NACT and 44% during CRT. Late adverse events were present in 20% of patients. PFS at 1 and 3-years were 73.4% (IC 58.7-83.6) and 53.9% (IC 36.9-68.3), respectively; and, OS at 1 and 3-years were 93.9% (IC 82.4-98.0) and 71.3% (IC 53.3-83.3), respectively. CONCLUSION: In our hands NACT in locally advanced cervical cancer patients did not show a meaningful improvement in ORR. Nevertheless, we believe it should be further explored in prospective trials. PMID- 28709706 TI - Taxifolin inhibits rat and human 11beta-hydroxysteroid dehydrogenase 2. AB - Taxifolin is a flavonoid in food plants. Kidney 11beta-hydroxysteroid dehydrogenase 2 (11beta-HSD2) is an NAD+-dependent oxidase that inactivates glucocorticoid cortisol (human) or corticosterone (rodents) into biologically inert 11 keto glucocorticoids. The present study investigated the effects of taxifolin on rat and human kidney microsomal 11beta-HSD2. Taxifolin noncompetitively inhibited rat and human 11beta-HSD2 against steroid substrates, with IC50 values of 33.08 and 13.14MUM, respectively. Administration of 5 and 10mg/kg taxifolin for 30min ex vivo inhibited 11beta-HSD2 significantly and also in vivo decreased cortisol metabolism, as shown in the significant increase of area under curve (AUC). This result shows that taxifolin is a potent 11beta-HSD2 inhibitor, possibly causing side effects. PMID- 28709707 TI - Endovascular treatment of acute ischemic stroke with ERIC device. AB - BACKGROUND AND PURPOSE: After 6 positive randomized trials, mechanical thrombectomy with stent-retriever is now recommended as a first-line treatment for acute ischemic stroke (AIS). The ERIC device is a device with several interlinked cage-like spheres fixed on a pusher wire. Neurothrombectomy France (NTF) is a registry conducted in France to analyze the results of mechanical thrombectomy. In order to analyze its performances, the subgroup of patients treated with the ERIC device was analyzed. MATERIALS AND METHODS: NTF is a prospective, multicenter registry dedicated to the evaluation of endovascular treatment for AIS. Primary endpoint was modified Rankin Scale (mRS) at 3months. Secondary endpoints were revascularization at the end of the procedure evaluated with the Thrombolysis In Cerebral Infarction (TICI) scale and rate of procedural complications. Patients treated with the ERIC device were extracted from the NTF registry and analyzed. RESULTS: From April 2013 to May 2014, 230 patients were included in the NTF registry. Thirty-one patients (13.5%) were treated with ERIC (male: 64.5%; median age: 61years). Median baseline NIHSS was 16. Median ASPECTS was 6. Occlusion location was internal carotid artery (51.6%), middle cerebral artery-M1 (45.2%), and basilar artery (3.2%). Cervical occlusion was associated in 16.1%. Revascularization (TICI 2b-3) was obtained in 87.1%. Good clinical outcome (mRS 0-2) at 3months was obtained in 55.2%. Death rate was 6.9% related to the stroke. CONCLUSION: This prospective, multicenter series shows good performances of the ERIC device in the treatment of acute ischemic stroke with revascularization in 87.1% and favorable clinical outcome in 55.2%. PMID- 28709708 TI - Functional proteomics of light-harvesting complex proteins under varying light conditions in diatoms. AB - Comparative proteome analysis of subcellular compartments like thylakoid membranes and their associated supercomplexes can deliver important in-vivo information on the molecular basis of physiological functions which go far beyond to that what can be learnt from transcriptional-based gene expression studies. For instance, the finding that light intensity influences mainly the relative stoichiometry of subunits could be obtained only by high resolution proteome analysis. The high sensitivity of LC-ESI-MS/MS based proteome analysis allows the determination of proteins in very small subfractions along with their non-labeled semi quantitative analysis. This provides insights in the protein-protein interactions of supercomplexes that are the operative units in intact cells. Here, we have focused on functional proteome approaches for the identification of microalgal light-harvesting complex proteins in chloroplasts and the eyespot in general and in detail for those of diatoms that are exposed to varying light conditions. PMID- 28709709 TI - Triple therapy with dual antiplatelet treatment and direct oral anticoagulants. PMID- 28709710 TI - Something is not anymore there. PMID- 28709711 TI - Where do they need us? Determining the future of emergency medicine. PMID- 28709712 TI - Addressing the high rate of opioid prescriptions for dental pain in the emergency department. PMID- 28709713 TI - Using a brain electrical activity biomarker could aid in the objective identification of mild Traumatic Brain Injury patients. PMID- 28709714 TI - Usefulness of serial measurement of the red blood cell distribution width to predict 28-day mortality in patients with trauma. AB - BACKGROUND: This is the first study to evaluate the association between the serially measured RDW values and clinical severity in patients surviving >24 h after sustaining trauma. We evaluated the serial measurement and cut-off values of RDW to determine its significance as a prognostic marker of early mortality in patients with suspected severe trauma. METHODS: This study retrospectively analyzed prospective data of eligible adult patients who were admitted to the ED with suspected severe trauma. The RDW was determined on each day of hospitalization. The primary outcome was all-cause mortality within 28-days of ED admission. RESULTS: We included 305 patients who met our inclusion criteria. The multivariate Cox regression model demonstrated that higher RDW values on day 1 (hazard ratio [HR], 1.558; 95% confidence interval [CI], 1.09-2.227; p=0.015) and day 2 (HR, 1.549; 95% CI, 1.046-2.294; p=0.029) were strong independent predictors of short-term mortality among patients with suspected severe trauma. Considering the clinical course of severe trauma patients, the RDW is an important ancillary test for determining severity. Specifically, we found that RDW values >14.4% on day 1 (HR, 4.227; 95% CI: 1.672-10.942; p<0.001) and >14.7% on day 2 (HR, 6.041; 95% CI: 2.361-15.458; p<0.001) increased the hazard 28-day all-cause mortality. CONCLUSION: An increased RDW value is an independent predictor of 28-day mortality in patients with suspected severe trauma. The RDW, routinely obtained as part of the complete blood count without added cost or time, can be serially measured as indicator of severity after trauma. PMID- 28709715 TI - Social media for health care education - Can it make a difference? PMID- 28709716 TI - The analytical process to search for metabolomics biomarkers. AB - The scant number of available metabolomics biomarkers does not reflect the extent of the research in this field. Looking for the reasons of failure, the authors, as analytical chemists, critically discuss each of the steps in the analytical process that requires improvements. They find insufficient information about how the experimental part is developed. After revising the steps from sampling to obtainment of the analytical sample (from typical samples such as blood and urine to others less common such as sweat or saliva), the need for data and metadata for either reproduction of a given study or for taking the study as starting point after biomarker discovery is criticized. The separation and analysis steps are also revised as does data treatment. After the sources of errors from the analytical process are overcome, subsequent steps in the implementation of biomarkers to reach the final aim of clinical adoption should be supported as required. PMID- 28709717 TI - [Minocycline induced hyperpigmentation]. PMID- 28709718 TI - Gadoxetic acid-enhanced high temporal-resolution hepatic arterial-phase imaging with view-sharing technique: Impact on the LI-RADS category. AB - PURPOSE: To evaluate the value of view-sharing multi-hepatic arterial-phase (mHAP) imaging for diagnosis of hypervascular hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Forty-seven consecutive patients with HCC underwent gadoxetic acid-enhanced magnetic resonance (MR) imaging before angiographic and lipiodol CT. Hepatic arterial-phase images were obtained at 5 consecutive phases with shared central k-space of 25%, followed by portal venous, late (2 and 3min), and hepatobiliary phase imaging. One-hundred-eight HCC nodules (size: 5-88mm, mean size: 18.2mm) confirmed on angiographic CT and lipiodol CT were evaluated for LI-RADS category and compared with single arterial-phase and mHAP findings regarding wash out, capsule, corona enhancement, and image quality. RESULTS: Twenty-four HCCs (22.2%) (size: 6-19mm, mean size: 12.3mm) were categorized as LR 3 based on the single arterial-phase. Capsule appearance (25.9%) and washout (57.4%) were most frequently observed in late phase (2min). Corona enhancement was observed in 73.1% of all HCCs on mHAP. For the 24 HCCs of LR-3, corona enhancement was observed in 75% on mHAP and contributed to upgrade category. No significant difference was found in the frequency of corona enhancement between mHAP and angiographic CT (P=0.11). Image quality was valued as good or excellent in all cases. CONCLUSION: View-sharing mHAP was feasible without compromising image quality and contributed to the improvement in diagnostic confidence for hypervascular HCC in gadoxetic acid-enhance MR imaging. PMID- 28709719 TI - Metformin effects on the heart and the cardiovascular system: A review of experimental and clinical data. AB - BACKGROUND: Metformin, the eldest and most widely used glucose lowering drug, is likely to be effective also on cardiac and vascular disease prevention. Nonetheless, uncertainty still exists with regard to its effects on the cardiovascular system as a whole and specifically on the myocardium, both at the organ and cellular levels. METHODS: We reviewed the available data on the cardiac and vascular effects of metformin, encompassing both in vitro, either tissue or isolated organ, and in vivo studies in experimental animals and humans, as well as the evidence generated by major clinical trials. RESULTS: At the cellular level metformin's produces both AMP-activated kinase (AMPK) dependent and independent effects. At the systemic level, possibly also through other pathways, this drug improves endothelial function, protects from oxidative stress and inflammation, and from the negative effects of angiotensin II. On the myocardium it attenuates ischemia-reperfusion injury and prevents adverse remodeling induced by humoral and hemodynamic factors. The effects on myocardial cell metabolism and contractile function being not evident at rest or in more advanced stages of cardiac dysfunction, could be relevant during transient ischemia, during an acute increase in workload and in the early stages of diabetic/hypertensive cardiomyopathy as confirmed by few small clinical trials and some observational studies. The overall evidence emerging from both clinical trials and real world registry is in favor of a protective effect of metformin with respect to both coronary events and progression to heart failure. CONCLUSIONS: Given this potential, its efficacy and its safety (and also its low cost) metformin remains the central pillar of the therapy of diabetes. PMID- 28709720 TI - Burden of rare variants in ALS genes influences survival in familial and sporadic ALS. AB - Genetic variants are implicated in the development of amyotrophic lateral sclerosis (ALS), but it is unclear whether the burden of rare variants in ALS genes has an effect on survival. We performed whole genome sequencing on 8 familial ALS (FALS) patients with superoxide dismutase 1 (SOD1) mutation and whole exome sequencing on 46 sporadic ALS (SALS) patients living in Hong Kong and found that 67% had at least 1 rare variant in the exons of 40 ALS genes; 22% had 2 or more. Patients with 2 or more rare variants had lower probability of survival than patients with 0 or 1 variant (p = 0.001). After adjusting for other factors, each additional rare variant increased the risk of respiratory failure or death by 60% (p = 0.0098). The presence of the rare variant was associated with the risk of ALS (Odds ratio 1.91, 95% confidence interval 1.03-3.61, p = 0.03), and ALS patients had higher rare variant burden than controls (MB, p = 0.004). Our findings support an oligogenic basis with the burden of rare variants affecting the development and survival of ALS. PMID- 28709721 TI - Screening for TMEM230 mutations in young-onset Parkinson's disease. AB - TMEM230 gene mutations have been reported to be linked with Parkinson's disease (PD) recently. To investigate the prevalence of this gene in southeastern Chinese patients with PD, whole exome sequencing was performed in young-onset and familial PD patients and healthy controls in our Asian population. One heterozygous missense p.Phe121Ser mutation was detected in a healthy 76-year-old control subject and no other TMEM230 mutations were found in PD patients and controls. These data suggest that TMEM230 mutation might be a rare cause of Chinese familial and sporadic PD patients and a larger sample size will be needed to evaluate the association of TMEM230 polymorphic variants with PD. PMID- 28709722 TI - Involvement of dopamine beta-hydroxylase in the neuroendocrine-immune regulatory network of white shrimp, Litopenaeus vannamei. AB - In shrimp, the biosynthesis of catecholamines, including dopamine and norepinephrine, is required for physiological and immunological responses against stress. Dopamine beta-hydroxylase (DBH), a copper-containing monooxygenase enzyme that plays an important role in catecholamine synthesis of the neuroendocrine regulatory network, was identified in Litopenaeus vannamei. In the present study, the potential role of DBH in the immunocompetence of L. vannamei was further estimated by depleting DBH by pharmaceutical inhibition of disulfiram and a gene silencing technique of L. vannamei DBH-double-stranded (ds)RNA (LvDBH-dsRNA). Immunocompetence was evaluated following the determination of the total hemocyte count, differential hemocyte count, phenoloxidase activity, respiratory bursts, superoxide dismutase activity, phagocytic activity, and the clearance efficiency as well as the susceptibility against Vibrio alginolyticus infection. At 30-120 min after shrimp had received disulfiram, they exhibited significantly reduced total hemocyte count, phenoloxidase activity of hemocytes in hemolymph, respiratory bursts of hemocytes in hemolymph and per hemocyte, phagocytic activity, clearance efficiency, and survival ratio against V. alginolyticus infection, compared to those injected with saline. In addition, the significantly lower total hemocyte count, phagocytic activity, clearance efficiency, and resistance to V. alginolyticus infection were observed in shrimp that received LvDBH-dsRNA at 3 days post injection compared to those injected with diethyl pyrocarbonate-water or non-targeting gene-dsRNA. The DBH depleted L. vannamei revealed immunosuppression and decreased the survival ratio to V. alginolyticus infection, which indicated that DBH played a crucial role in the neuroendocrine immune regulatory network. PMID- 28709723 TI - Synbiotic dietary supplement affects growth, immune responses and intestinal microbiota of Apostichopus japonicus. AB - A feeding experiment was conducted to investigate the effects of dietary administration of synbiotic with Bacillus lincheniformis WS-2 (CGMCC No. 12813) and alginate oligosaccharides (AOS) on the growth, innate immune response, and intestinal microbiota of the sea cucumber Apostichopus japonicus and its resistance to Vibrio infection. Sea cucumbers were given a control diet (non supplemented), pro diet (basal diet plus 1 * 109 cfu (g diet)-1B. lincheniformis WS-2), syn diet (basal diet plus 1 * 109 cfu (g diet)-1B. lincheniformis WS-2 and 10 g (kg diet) -1 AOS) or pre diet (basal diet plus 10 g (kg diet) -1 AOS) over a period of 60 days, and the growth performance and various innate immune parameters of the animals were evaluated after 30 and 60 days of feeding. No significant difference in growth performance was observed between the group fed with the syn and the group fed with the pro diet, but both these groups exhibited significant (P < 0.05) enhancement in growth performance compared to the control group. At the same time, both syn and pro diets also resulted in the animals having significantly higher levels of amylase, protease and alginate lyase activities compared to the con diet. Individuals fed with the syn or pro diet showed enhanced levels of various immune enzyme activities, compared to those fed with the con diet. At the end of the growth period, the sea cucumbers were challenged with Vibrio splendidus via intraperitoneal injection. The survival rates of sea cucumbers fed with the syn, pro or pre diet were significantly improved compared to that of sea cucumbers fed with the con diet, with sea cucumbers fed with synbiotic having the highest survival. In addition, increased proportions of Bacillus and Lactococcus were found in the intestinal tract of sea cucumbers fed with the syn diet (9.5% and 7.3%) compared to those of sea cucumbers fed with the pro diet (6.1% and 4.6%), con diet (4.0% and 3.4%), or pre diet (5.2% and 6.8%) after 60 days of feeding. Furthermore, the proportion of Vibrio in the intestinal tracts of sea cucumbers fed with the pro diet (2%) or syn diet (3.1%) was lower than that of sea cucumbers fed with the con diet (5.5%) or pre diet (3.8%), although no significant difference was detected between the pro diet and syn diet groups (P > 0.05). Overall, the results suggested that dietary synbiotic consisting of Bacillus lincheniformis and alginate oligosaccharides (AOS) could have positive benefit for sea cucumber aquaculture. PMID- 28709725 TI - Reply to Erridge et al. 'Re: Gavriilidis et al., 'Survival following Redo Hepatectomy vs Radiofrequency Ablation for Recurrent Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis''. PMID- 28709724 TI - A probiotic Bacillus strain containing amorphous poly-beta-hydroxybutyrate (PHB) stimulates the innate immune response of Penaeus monodon postlarvae. AB - In this study, the PHB-accumulating Bacillus sp. JL47 strain (capable of accumulating 55% PHB on cell dry weight) was investigated for its effects on the immune response of giant tiger shrimp (Penaeus monodon) postlarvae (PL) before and after the Vibrio campbellii challenge. Briefly, shrimp PL were cultured and fed with Artemia nauplii enriched with Bacillus sp. JL47. Shrimp receiving the Artemia nauplii without JL47 enrichment were used as control. After 15 days of feeding, the shrimp were challenged with pathogenic V. campbellii LMG 21363 at 106 cells mL-1 by immersion. Relative expression of the immune related genes encoding for prophenoloxidase (proPO), transglutaminase (TGase) and heat shock protein 70 (Hsp70) in the shrimp were measured before (0 h) and after (3, 6, 9, 12, 24 h) the Vibrio challenge by quantitative real-time PCR using beta-actin as the reference gene. The expressions of TGase and proPO were significantly up regulated (p < 0.05) within 9 h and 12 h, respectively after challenge in shrimp receiving the Bacillus sp. JL47 as compared to the challenged and non-challenged controls. Hsp70 expression was significantly increased (p < 0.05) at 3 h post challenge in all challenged shrimp. Interestingly, proPO and TGase genes were significantly up-regulated (p < 0.05) in Bacillus sp. JL47 treated shrimp even before the Vibrio challenge was applied. No up-regulation in the Hsp70 gene, however, was observed under these conditions. The data suggest that the protective effect of the PHB-accumulating Bacillus sp. JL47 in shrimp was due to its capacity to stimulate the innate immune related genes of the shrimp, specifically the proPO and TGase genes. The application of probiotic Bacillus species, capable of accumulating a significant amount of PHB, is suggested as potential immunostimulatory strategy for aquaculture. PMID- 28709726 TI - Induction and maintenance of regulatory T cells by transcription factors and epigenetic modifications. AB - Regulatory T cells (Tregs) are an essential cell subset for the maintenance of immune homeostasis. Foxp3 (Forkhead box P3) is the Treg master gene which is essential for immune suppressing activity. In addition, Tregs are characterized by a distinct pattern of gene expression, including upregulation of immune suppressive genes and silencing of inflammatory genes. The molecular mechanisms of Treg development and maintenance have been intensively investigated. Tregs are characterized by expression of the transcription factor Foxp3. Several intronic enhancers and a promoter at the Foxp3 gene locus were shown to play important roles in Treg differentiation. The enhancers have been designated as conserved non-coding sequences (CNSs) 0, 1, 2, and 3. We showed that the transcription factors Nr4a and Smad2/3 are essential for the development of thymic Tregs and induced Tregs, respectively. Recently, Treg-specific DNA demethylation has been shown to play an important role in Treg stability. DNA demethylation of CNS2 has been implicated in Treg stability, and recent reports have revealed that the ten eleven translocation (Tet) family of demethylation factor plays an important role in CpG demethylation at CNS2. This article reviews the recent progress on the roles of transcription factors and epigenetic modifications in the differentiation, maintenance, and function of Tregs. PMID- 28709727 TI - Consensus Bundle on Severe Hypertension During Pregnancy and the Postpartum Period. AB - Complications arising from hypertensive disorders of pregnancy are among the leading causes of preventable severe maternal morbidity and mortality. Timely and appropriate treatment has the potential to significantly reduce hypertension related complications. To assist health care providers in achieving this goal, this patient safety bundle provides guidance to coordinate and standardize the care provided to women with severe hypertension during pregnancy and the postpartum period. This is one of several patient safety bundles developed by multidisciplinary work groups of the National Partnership for Maternal Safety under the guidance of the Council on Patient Safety in Women's Health Care. These safety bundles outline critical clinical practices that should be implemented in every maternity care setting. Similar to other bundles that have been developed and promoted by the Partnership, the hypertension safety bundle is organized into four domains: Readiness, Recognition and Prevention, Response, and Reporting and Systems Learning. Although the bundle components may be adapted to meet the resources available in individual facilities, standardization within an institution is strongly encouraged. This commentary provides information to assist with bundle implementation. PMID- 28709728 TI - Re: Philipp Mandel, Felix Preisser, Markus Graefen, et al. High Chance of Late Recovery of Urinary and Erectile Function Beyond 12 Months After Radical Prostatectomy. Eur Urol 2017;71:848-50. PMID- 28709729 TI - Reply to Jae Heon Kim, Bora Lee, and Benjamin I. Chung's Letter to the Editor re: Philipp Mandel, Felix Preisser, Markus Graefen, et al. High Chance of Late Recovery of Urinary and Erectile Function Beyond 12 Months After Radical Prostatectomy. Eur Urol 2017;71:848-50. PMID- 28709730 TI - Antibiotic susceptibility surveillance of Gram-negative anaerobes: RedMiVa 2010 2016. PMID- 28709731 TI - Evaluation of rapid phenotypic identification and antimicrobial susceptibility testing in a pediatric oncology center. AB - Identification (ID) and antimicrobial susceptibility testing (AST) remain rate limiting steps in producing actionable data for clinical care of bloodstream infections. Rapid, automated phenotypic ID and AST by fluorescent in situ hybridization and automated microscopy were used to characterize blood stream infections in a predominantly pediatric oncology patient population. Results were compared to standard of care (SOC) phenotypic methods. The Accelerate Pheno System (AXDX) had a sensitivity of 91.2% and an accuracy of 100% to the genus level for identification, and an overall categorical agreement 91.2-91.8% for susceptibility, depending on the breakpoints used. The AXDX required a mean time of 1.4hours for identification and 6.6hours for susceptibility testing compared to SOC, requiring 32.5 and 46.7hours, respectively. Identification and susceptibility by rapid phenotypic methods shows a high degree of accuracy; the marked reduction in time to results may have significant implications for patient care. PMID- 28709732 TI - Medial geniculate neurons show diverse effects in response to electrical stimulation of prefrontal cortex. AB - Phantom perceptions have been proposed to arise due to dysfunctional sensory gating at the level of the thalamus. Recently, it has been suggested that tinnitus, a phantom perception of sound, may arise from altered cortico-limbic circuitry and its connection with the auditory thalamus, the medial geniculate nucleus (MGN). Indeed, some elements of this cortico-limbic circuitry, such as the prefrontal cortex (PFC), as well as elements of the auditory pathway, have been shown to be altered in humans with tinnitus. However, the functional connectivity between PFC and MGN has not yet been explored. We therefore investigated the effects of activation of the PFC on neuronal activity in MGN in normal anaesthetized Wistar rats. Bipolar electrical stimulation was delivered to the PFC while recording single neuron activity in the MGN. The majority (81%) of MGN neurons sampled showed a change in their spontaneous firing rate in response to electrical stimulation of the PFC. The effects observed varied greatly between neurons and included combinations of inhibitory and excitatory effects with a wide range of latencies. The effects were not dependent on acoustic response type or MGN subdivision. These data demonstrate that PFC activation can modulate MGN neuronal activity and this connection could potentially play a role in sensory gating of auditory signals. PMID- 28709733 TI - Effectiveness of vedolizumab for Crohn's disease with spondyloarthritis in fail with two TNF blocking agents. PMID- 28709734 TI - Evaluation of arteriovenous fistula blood flow in patients with calcium chelation therapy. PMID- 28709735 TI - Genetic variation and correlated changes in reproductive performance of a red tilapia line selected for improved growth over three generations. AB - The present study examines genetic variation and correlated changes in reproductive performance traits in a red tilapia (Oreochromis spp.) population selected over three generations for improved growth. A total of 328 breeding females (offspring of 111 sires and 118 dams) had measurements of body weight prior to spawning (WBS), number of fry at hatching (NFH), total fry weight (TFW) and number of dead fry (NDF) or mortality of fry including unhatched eggs at hatching (MFH). Restricted maximum likelihood (REML) analysis in a multi-trait model showed that there are heritable genetic components for all traits studied. The heritability for WBS was very high (0.80). The estimates for traits related to fecundity (NFH, TFW) and survival (NDF) were low and they were associated with high standard errors. Genetic correlations of WBS with other reproductive performance traits (NFH, TFW and NDF) were generally positive. However, NFH was negatively correlated genetically with TFW. As expected, body measurements during growth stage exhibited strong positive genetic correlations with WBS. The genetic correlations between body traits and reproductive performance (NFH, TFW, NDF) were not significant. Correlated responses in reproductive traits were measured as changes in least squares means between generations or spawning years. Except for WBS that increased with the selection programs, the phenotypic changes in other reproductive traits observed were not statistically significant (P>0.05). It is concluded that the selection program for red tilapia has resulted in very little changes in reproductive performance of the animals after three generations. However, periodic monitoring of genetic changes in fecundity and fitness related traits such as NDF or MFH should be made in selective breeding programs for red tilapia. PMID- 28709736 TI - Supplementation of tris-based extender with plasma egg yolk of six avian species and camel skim milk for chilled preservation of dromedary camel semen. AB - The present study was conducted to investigate a suitable source (Expt. 1) and concentration (Expt. 2) of plasma egg yolk (PEY) and concentration of camel skim milk (CSM; Expt. 3) to supplement tris based extender for chilled storage of dromedary camel semen. In Expt. 1, PEY (20%) of six avian species (domestic chicken, domestic duck, Japanese quail, partridge, pigeon and guinea fowl) was added to semen extender. In Expt. 2, different concentrations (0, 10, 20, 30 and 40%) of selected PEY from Expt.1 were added to semen extender. In both Expt. 1 and 2, CSM remained constant (20%). In Expt. 3, semen extender was supplemented with different concentrations of CSM (0, 20, 40, 60 and 80%) while the concentration of PEY remained constant. The sperm viability parameters were assessed at 6, 12 and 24h following chilled storage. In Expt. 1, progressive forward motility (PFM) of diluted semen supplemented with pigeon PEY was similar to domestic duck and Japanese quail PEYs (P>0.05) and superior to other PEYs (P<0.05). In Expt. 2, PFM following the addition of 20% pigeon PEY was similar to 10 and 30% (P>0.05) and greater than 0 and 40% (P<0.05). In Expt. 3, total motility, PFM and live percentage of sperm were better in 20% compared to 40, 60 and 80% CSM (P<0.05). In the last experiment, PFM in 20% was better than 0% CSM (P<0.05). In conclusion, pigeon PEY at the concentration of 20% and CSM at the concentration of 20% could provide beneficial effect on some of the sperm viability parameters during chilled storage of dromedary camel semen. PMID- 28709737 TI - Ilioinguinal approach versus Stoppa approach for open reduction and internal fixation in the treatment of displaced acetabular fractures: A systematic review and meta-analysis. AB - PURPOSE: To compare the efficacy and safety of open reduction and internal fixation through ilioinguinal approach and Stoppa approach for the treatment of displaced acetabular fractures. METHODS: Case-controlled trials (CCTs) published from January 2010 to August 2015 that compared the ilioinguinal approach and Stoppa approach in the management of displaced acetabular fractures were retrieved from the databases of Cochrane Library, Pubmed, CNKI, and so on. Methodological quality of the trials was critically assessed. Statistical software RevMan 5.0 was used for data analysis. RESULTS: Eight articles were included in the meta-analysis. Through comparing the efficacy and safety of ilioinguinal approach and Stoppa approach in the treatment of displaced acetabular fracture, statistical significance was found in the average operation time [WMD = 68.29, 95% CI (10.52, 126.05), p < 0.05] and the median intraoperative blood loss [WMD = 142.26, 95% CI (9.30, 275.23), p < 0.05]. However, there existed no statistical significance in the fracture end reset satisfaction rate [RR = 0.63, 95% CI (0.17, 2.37), p > 0.05], the early complications rate [RR = 0.89, 95% CI (0.33, 2.40), p > 0.05], the late complications rate [RR = 0.91, 95% CI (0.27, 3.01), p > 0.05], and Harris hip score good function rate [RR = 0.52, 95% CI (0.25, 1.10), p > 0.05]. CONCLUSION: Though both techniques can obtain satisfactory clinical functions in the treatment of displaced acetabular fractures, Stoppa approach is superior to the ilioinguinal approach in terms of operation time and intraoperative blood loss. PMID- 28709738 TI - Results of the CCRI(II)-S12.H-3 supplementary comparison: Comparison of methods for the calculation of the activity and standard uncertainty of a tritiated-water source measured using the LSC-TDCR method. AB - A comparison of calculations of the activity of a 3H2O liquid scintillation source using the same experimental data set collected at the LNE-LNHB with a triple-to-double coincidence ratio (TDCR) counter was completed. A total of 17 laboratories calculated the activity and standard uncertainty of the LS source using the files with experimental data provided by the LNE-LNHB. The results as well as relevant information on the computation techniques are presented and analysed in this paper. All results are compatible, even if there is a significant dispersion between the reported uncertainties. An output of this comparison is the estimation of the dispersion of TDCR measurement results when measurement conditions are well defined. PMID- 28709740 TI - Effects of size and thermophilic pre-hydrolysis of banana peel during anaerobic digestion, and biomethanation potential of key tropical fruit wastes. AB - Methane production potential of tropical fruit wastes, namely lady-finger banana peel, rambutan waste and longan waste were compared using BMP assay and stoichiometric modified Buswell and Mueller equation. Methane yields based on volatile solid (VS) were in the order of ground banana peel, chopped banana peel, chopped longan waste, and chopped rambutan waste (330.6, 268.3, 234.6 and 193.2 mLCH4/gVS) that corresponded to their calculated biodegradability. In continuous operations of banana peel digestion at feed concentrations based on total solid (TS) 1-2%, mesophilic single stage digester run at 20-day hydraulic retention time (20-day HRT) failed at 2%TS, but successfully recovered at 1.5%TS. Pre hydrolysis thermophilic reactor (4-d HRT) was placed as pre-treatment to mesophilic reactor (20-d HRT). Higher biogas (with an evolution of H2) and energy yields were obtained and greater system stability was achieved over the single stage digestion, particularly at higher solid feedstock. The best performance of two stage digestion was 68.5% VS destruction and energy yield of 2510.9kJ/kgVS added at a feed concentration of 2%TS. PMID- 28709739 TI - Structured lifestyle intervention in patients with the metabolic syndrome mitigates oxidative stress but fails to improve measures of cardiovascular autonomic neuropathy. AB - AIMS: To assess the role of oxidative stress in mediating adverse outcomes in metabolic syndrome (MetS) and resultant cardiovascular autonomic neuropathy (CAN), and to evaluate the effects of lifestyle interventions on measures of oxidative stress and CAN in subjects with MetS. METHODS: Pilot study in 25 non diabetic subjects with MetS (age 49+/-10years, 76% females) participating in a 24 week lifestyle intervention (supervised aerobic exercise/Mediterranean diet), and 25 age-matched healthy controls. CAN was assessed by cardiovascular reflex tests, heart rate variability (HRV) and PET imaging with sympathetic analog [11C] meta hydroxyephedrine ([11C]HED). Specific oxidative fingerprints were measured by liquid-chromatography/mass-spectrometry (LC/MS). RESULTS: At baseline, MetS subjects had significantly higher oxidative stress markers [3-nitrotyrosine (234+/-158 vs. 54+/-47MUmol/mol tyrosine), ortho-tyrosine (59+/-38 vs. 18+/ 10MUmol/molphenylalanine, all P<0.0001], and impaired HRV at rest and during deep breathing (P=0.039 and P=0.021 respectively) compared to controls. Twenty-four week lifestyle intervention significantly reduced all oxidative stress markers (all P<0.01) but did not change any of the CAN measures. CONCLUSIONS: Subjects with MetS present with signs of CAN and increased oxidative stress in the absence of diabetes. The 24-week lifestyle intervention was effective in ameliorating oxidative stress, but did not improve measures of CAN. Larger clinical trials with longer duration are required to confirm these findings. PMID- 28709741 TI - Do hand outcome measures reflect cultural influences? AB - OBJECTIVE: The aim of this study was to compare the activities listed in DASH, MHQ, QuickDASH with the activities listed in Canadian Occupational Performance Measure (COPM) in a Turkish patient population with hand injury. METHODS: COPM questionnaire was administered to 163 participants (61 male and 102 female; mean age 40.72 +/- 13.70 years). The activities that were stated in COPM were categorized and checked whether they were present in DASH-T, MHQ, QuickDASH. RESULTS: The highest rated stated activities were "carrying a heavy object" (39.2%), "cleaning the house" (25.7%) and "writing" (15.9%). DASH reflects 30% whereas MHQ and QuickDASH reflect 16.32% and 10.2% of the problematic activities, respectively. CONCLUSION: None of three questionnaires have satisfactory results for reflecting the problematic activities among hand injured Turkish people. Open ended interviews should be irrevocable part of assessment process in order to describe a person-center treatment program. PMID- 28709742 TI - Age and Gender Differences in the Association between Serum 25-Hydroxyvitamin D and Stroke in the General US Population: The National Health and Nutrition Examination Survey, 2001-2006. AB - BACKGROUND: Previous findings on the association between serum 25(OH)D level and stroke have been controversial. We aimed to examine whether these controversial findings could be possibly due to difference in study participant characteristics, especially age and gender differences in these studies, by analyzing the data from a representative sample of the general US population. METHODS: Data of 13,642 adults 20 years or older who participated in the 2001 2006 National Health and Nutrition Examination Survey were analyzed in this study. Serum 25(OH)D was used to reflect vitamin D status. Stroke history was self-reported using questionnaires. Unadjusted and adjusted logistic regression models were fitted using SAS survey procedures to investigate the associations between 25(OH)D level and stroke for the pooled sample and age-gender subgroups (men versus women, <50 years old versus >=50 years old), respectively. RESULTS: After adjusting for demographic and lifestyle covariates, vitamin D deficiency (defined as serum 25(OH)D < 12 ng/mL) was significantly associated with increased risk of stroke (adjusted odds ratio [OR] = 1.62, 95% confidence interval [CI] = 1.11, 2.36), and higher vitamin D levels were significantly associated with reduced risk of stroke (adjusted OR = .70, 95% CI = .51, .96). The association between high levels of serum 25(OH)D and stroke was particularly evident among young females (age <=20 years to <50 years) (adjusted OR = .26, 95% CI = .14, .49). CONCLUSIONS: The findings add to the evidence suggesting maintaining ideal 25(OH)D levels may reduce the risk of stroke among US adults, particularly in adult women younger than 50 years. PMID- 28709743 TI - Ischemic Stroke with Cardiac Pacemaker Implantation: Comparison of Physiological and Ventricular Pacing Modes. AB - BACKGROUND: The clinical characteristics of ischemic stroke in patients with a pacemaker (PM) are not well understood. METHODS: Forty-six ischemic stroke patients with a PM were investigated retrospectively, and the impact of different pacing modes was compared. RESULTS: The patients were divided into a physiological pacing group (n = 22) and a ventricular pacing group (n = 24). The prevalence of atrial fibrillation (AF) was significantly higher in the ventricular pacing group (36% versus 75%; P = .008). The mean left atrial dimension was relatively large in the ventricular pacing group than in the physiological pacing group (44.5 +/- 6.7 mm versus 39.1 +/- 8.5 mm, respectively; P = .071). Twenty-four percent of the patients were receiving anticoagulants, whereas 41% of the patients were receiving antiplatelet drugs. Cardioembolism was the most common stroke subtype in both groups. Although there was no statistically significant difference, neurological severity on admission was higher in the ventricular pacing group than in the physiological pacing group (P = .061). Functional outcomes, excluding patients with transient ischemic attack or prior stroke, significantly declined in the ventricular pacing group compared with the physiological pacing group (P = .044). CONCLUSIONS: The avoidance of the ventricular pacing mode may result in improved clinical outcomes. In patients without persistent AF, it may be important to select physiological pacing instead of ventricular pacing to decrease potential stroke severity. PMID- 28709744 TI - The matching method for veins images. AB - BACKGROUND: A common problem in medical practice is the localization of subcutaneous veins and arteries. Automatization of this procedure may help to develop bloodbot rigs and improve use of image guided surgery. METHOD: It is not necessary to have a full 3D model in order to determine their location by calculating the spatial coordinates of veins axes in the adopted coordinate system. A much better solution is pre-segmentation, which provides veins axes, and further search for stereo correspondence in the segmented images. The computational complexity of this approach is much smaller, which ensures its quick operation. A disparity map necessary for the calculation of spatial coordinates is created according to the principle that the most likely correct distance between homologous elements is the minimum distance value. To increase the effectiveness of the method, the difference in the distance between the homologous points and their neighbours is further analysed. RESULTS: The method is illustrated with examples of the authors' own images of subcutaneous veins as well as standard images used for the evaluation of new methods for seeking stereo correspondence. In addition, the method has been compared with three recognized and widely used algorithms for matching images. The effectiveness of the new method reaches 100% of properly matched pixels. The largest percentage of mismatches is 27%. The lowest value of standard deviation is 0.1 and the highest 10 pixels. The proposed method is at least two times faster than other presented methods. PMID- 28709745 TI - Personal sleep pattern visualization using sequence-based kernel self-organizing map on sound data. AB - We propose a method to discover sleep patterns via clustering of sound events recorded during sleep. The proposed method extends the conventional self organizing map algorithm by kernelization and sequence-based technologies to obtain a fine-grained map that visualizes the distribution and changes of sleep related events. We introduced features widely applied in sound processing and popular kernel functions to the proposed method to evaluate and compare performance. The proposed method provides a new aspect of sleep monitoring because the results demonstrate that sound events can be directly correlated to an individual's sleep patterns. In addition, by visualizing the transition of cluster dynamics, sleep-related sound events were found to relate to the various stages of sleep. Therefore, these results empirically warrant future study into the assessment of personal sleep quality using sound data. PMID- 28709746 TI - The most promising advances in our understanding and treatment of functional (psychogenic) movement disorders. AB - The name functional rather than psychogenic is getting to be more widely used for terminology of this condition. It is better accepted by patients and keeps an open mind in searching for greater understanding of the pathophysiology. Advances in the pathophysiology show an overactive limbic system with connections to the motor system. Moreover, there is a disruption of the self-agency network, possibly due to a failure of feedforward signaling. There has recently been more success in treating patients. The strongest evidence is for intensive physical therapy coupled with at least some psychological support. Psychotherapy with cognitive behavioral therapy may well also be useful. PMID- 28709747 TI - Interaction of the innate immune system with positive-strand RNA virus replication organelles. AB - The potential health risks associated with (re-)emerging positive-strand RNA (+RNA) viruses emphasizes the need for understanding host-pathogen interactions for these viruses. The innate immune system forms the first line of defense against pathogenic organisms like these and is responsible for detecting pathogen associated molecular patterns (PAMPs). Viral RNA is a potent inducer of antiviral innate immune signaling, provoking an antiviral state by directing expression of interferons (IFNs) and pro-inflammatory cytokines. However, +RNA viruses developed various methods to avoid detection and downstream signaling, including isolation of viral RNA replication in membranous viral replication organelles (ROs). These structures therefore play a central role in infection, and consequently, loss of RO integrity might simultaneously result in impaired viral replication and enhanced antiviral signaling. This review summarizes the first indications that the innate immune system indeed has tools to disrupt viral ROs and other non- or aberrant-self membrane structures, and may do this by marking these membranes with proteins such as microtubule-associated protein 1A/1B-light chain 3 (LC3) and ubiquitin, resulting in the recruitment of IFN-inducible GTPases. Further studies should evaluate whether this process forms a general effector mechanism in +RNA virus infection, thereby creating the opportunity for development of novel antiviral therapies. PMID- 28709748 TI - A Rare Presentation of Primary Breast Carcinoma in the Vulva: A Case Report and Literature Review. PMID- 28709749 TI - The brown-fat-secreted adipokine neuregulin 4 is decreased in gestational diabetes mellitus. AB - AIMS: Neuregulin 4 has recently been recognized as a novel adipokine secreted by brown adipose tissue (BAT), with beneficial effects on murine insulin resistance and hepatic steatosis. Yet, thus far, neither regulation of neuregulin 4 in gestational diabetes mellitus (GDM) nor its longitudinal changes in the peripartum period have been elucidated. METHODS: Circulating neuregulin 4 levels were measured by ELISA in 74 women with GDM and 74 healthy, gestational-age matched controls. Also, neuregulin 4 was quantified during pregnancy and compared with postpartum levels in a follow-up study of 25 women with previous GDM and 25 healthy control women. RESULTS: Women with GDM had lower median serum levels of the novel BAT-secreted adipokine neuregulin 4 (3.0MUg/L) compared with healthy (non-GDM) pregnant controls (3.5MUg/L; P=0.020), and the area under the glucose curve (AUCGlucose) was an independent and negative predictor of circulating neuregulin 4 (P=0.033). Also, median postpartum serum concentrations of neuregulin 4 (3.2MUg/L) were not significantly different from prepartum levels (2.8MUg/L; P=0.328). In addition, neuregulin 4 was positively and independently associated with irisin (P=0.009), but not other BAT-secreted adipokines. CONCLUSION/INTERPRETATION: Women with GDM have significantly lower circulating neuregulin 4 levels compared with healthy pregnant controls, and the AUCGlucose is negatively and independently associated with neuregulin 4 during pregnancy. Neuregulin 4 is positively correlated with irisin during pregnancy, as well as in a longitudinal fashion. Future studies are now needed to better elucidate the precise pathomechanisms of the regulation of BAT-secreted adipokines during pregnancy. PMID- 28709750 TI - Health outcomes of school-aged children conceived using donor sperm. AB - The use of donor sperm is increasing, yet limited information is available about the health and development of children conceived from donor sperm. This retrospective descriptive study aimed to assess health and development in a cohort of school-aged children who were conceived using donor sperm. Participants included 224 children, aged 5-11 years, who were conceived using donor sperm. Participants' mothers completed a questionnaire comprising validated scales examining their child's current and past physical, psychosocial and mental health, healthcare needs and child development, as well as the mothers' health and wellbeing. At the conclusion of the study, the response rate was 296 out of 407 (72.7%), with a participation rate of 224 out o 407 (55.0%). Compared with the normative Australian population, sperm donor-conceived children had similar physical, psychosocial and mental health and development. A modest increase in healthcare needs was evident. The study concludes that in school-aged children conceived using donor sperm, most aspects of child health and wellbeing are similar to the general population. PMID- 28709751 TI - Does Muscle Atrophy and Fatty Infiltration Plateau or Persist in Chronic Spinal Cord Injury? AB - Atrophy and fatty infiltration of lower extremity muscle after spinal cord injury (SCI) predisposes individuals to metabolic syndrome and related diabetes and cardiovascular disease. The objective of this study was to prospectively measure changes in muscle atrophy and fat content of distal lower extremity muscles and explore related factors in a cohort of adults with chronic SCI and diverse impairments. Muscle cross-sectional area and density were calculated from peripheral quantitative computed tomography scans of the 66% site of the calf from 70 participants with chronic SCI (50 male, mean age 49 years, C2-T12, American Spinal Injury Association Impairment Scale A-D) at study enrollment and annually for 2 years. Mixed-model repeated measures analysis of variance (rANOVA) examined longitudinal changes in muscle area and density, and regression analyses explored factors related to muscle changes using 16 potential correlates selected a priori. A high degree of individual variation in muscle area and density change was observed over 2 years (range: 8.5 to -22.6 cm2; 6.4 to -8.6 mg/cm3). Repeated measures analysis of variance revealed significant reductions in muscle area (estimated mean difference [95% confidence intervals] -1.76 [-3.29 to 0.23]) cm2, p = 0.025) and density (-1.04 [-1.94 to -0.14] mg/cm3, p < 0.024); however, changes in area were not significant with outliers removed. Regression analyses explained a small proportion of the variability in muscle density change; however, none of the preselected variables were significantly related to changes in muscle density after post hoc sensitivity analyses. Lower extremity muscle size and fat content may not reach a "steady-state" after chronic SCI. Progressive atrophy and fatty infiltration of lower extremity muscle may have adverse implications for metabolic syndrome and cardiovascular disease risk and related mortality after chronic SCI. PMID- 28709752 TI - Safer Conception and Contraceptive Counseling By Providers of Men Living With HIV in San Francisco. PMID- 28709754 TI - Nondestructive mechanical characterization of developing biological tissues using inflation testing. AB - One of the hallmarks of biological soft tissues is their capacity to grow and remodel in response to changes in their environment. Although it is well-accepted that these processes occur at least partly to maintain a mechanical homeostasis, it remains unclear which mechanical constituent(s) determine(s) mechanical homeostasis. In the current study a nondestructive mechanical test and a two-step inverse analysis method were developed and validated to nondestructively estimate the mechanical properties of biological tissue during tissue culture. Nondestructive mechanical testing was achieved by performing an inflation test on tissues that were cultured inside a bioreactor, while the tissue displacement and thickness were nondestructively measured using ultrasound. The material parameters were estimated by an inverse finite element scheme, which was preceded by an analytical estimation step to rapidly obtain an initial estimate that already approximated the final solution. The efficiency and accuracy of the two step inverse method was demonstrated on virtual experiments of several material types with known parameters. PDMS samples were used to demonstrate the method's feasibility, where it was shown that the proposed method yielded similar results to tensile testing. Finally, the method was applied to estimate the material properties of tissue-engineered constructs. Via this method, the evolution of mechanical properties during tissue growth and remodeling can now be monitored in a well-controlled system. The outcomes can be used to determine various mechanical constituents and to assess their contribution to mechanical homeostasis. PMID- 28709753 TI - Leveraging Social Media to Explore Black Women's Perspectives on HIV Pre-exposure Prophylaxis. PMID- 28709755 TI - Validity and Usefulness of the Hospital Anxiety and Depression Scale in Carers of People with Dementia: Evidence from Confirmatory Factor Analysis, Concurrent Validity, and Measurement Invariance in a Large Sample. AB - OBJECTIVE: The Hospital Anxiety and Depression Scale (HADS) is a self-report measure of anxiety and depression. It is recommended for clinical assessment and has been used as the primary outcome in large clinical trials with carers of people with dementia. Its validity and utility have never been examined in this population. The current study addresses this. METHODS: In a secondary analysis of baseline data from a recent intervention trial (N = 284) with cross-validation in baseline data from a second trial (N = 230), the authors used confirmatory factor analysis to test whether a one-, two-, or three-factor structure best fit the data and used indices of model misspecification to respecify. Internal consistency, concurrent validity of obtained factors, and measurement invariance across gender, age, kinship, and cohabitation status were assessed. RESULTS: A three-factor structure best fit the data. Removal of one item improved model fit. The factors showed good internal consistency and high levels of concurrent validity. Measurement invariance was adequate across gender and kinship but not age or cohabitation status. Results were replicated in the cross-validation sample, enhancing reliability. CONCLUSION: In this group the HADS measured three factors; depression, anxiety, and negative affectivity. The depression scale can be used as originally intended, supporting results of large clinical trials. The HADS does not validly measure distress or anxiety. Consequently, clinical practice recommendations could be revisited, and future research trials should not use HADS anxiety or distress as outcomes. Researchers should pay attention to measurement invariance when using HADS to compare carer subgroups. PMID- 28709757 TI - Current Trends in Pain Management in Total Hip and Knee Arthroplasties. PMID- 28709756 TI - Postoperative Outcomes Associated With Neuraxial vs General Anesthesia Following Bilateral Total Knee Arthroplasty. AB - BACKGROUND: There is sparse evidence on the benefit of neuraxial (NA) vs general anesthesia (GA) as the primary anesthetic in postoperative outcomes following bilateral total knee arthroplasty. We sought to elucidate differences in outcomes in this surgical population using a national database. METHODS: We used data from the National Surgical Quality Improvement Program from 2007 to 2013 and compared rates of various postoperative outcomes in propensity-matched cohorts (NA vs GA). RESULTS: After exclusion, there were 1957 patients included in the final analysis, of which 26% received NA as the primary anesthetic. Propensity-matched cohorts were generated to ensure no differences in various comorbidities (including bleeding disorders or inadequate cessation of anticoagulation therapy), case duration, and patient demographics between both cohorts. Among the matched cohorts, there were no differences in preoperative platelet count, hematocrit, or international normalized ratio. NA was associated with decreased blood transfusion requirement and decreased total number of units of blood products transfused (P < .0001 for both outcomes). However, there were no differences in other outcomes, including hospital length of stay, pulmonary embolism, deep vein thrombosis, or urinary tract infections. CONCLUSION: Our study demonstrates that in matched cohorts, NA is associated with decreased blood transfusion requirements in patients undergoing bilateral total knee arthroplasty when compared to GA as the primary anesthetic. PMID- 28709758 TI - Supplement to Proceedings-2016 AAHKS Annual Meeting. PMID- 28709759 TI - Total Hip Arthroplasty Outcomes: An 18-Year Experience in a Single Center: Is Systemic Lupus Erythematosus a Potential Risk Factor for Adverse Outcomes? AB - BACKGROUND: In patients with systemic lupus erythematosus (SLE), persistent joint activity and treatment with glucocorticoids are associated with musculoskeletal complications. About 30% of these patients become candidates for surgical treatment. The aim of this study was to evaluate postoperative outcomes after total hip arthroplasty (THA) in SLE patients. METHODS: We performed a retrospective cohort study at a tertiary care center in Mexico City between 1995 and 2013. All patients with SLE who underwent THA during that period were included (n = 58). They were compared with 2 control groups, one from another inflammatory arthropathy (rheumatoid arthritis, n = 58) and other noninflammatory (osteoarthritis, n = 58), matched by gender and date of surgery. The primary outcome was the frequency of postoperative complications during follow-up. RESULTS: We included 174 patients who underwent THA during the study period. Patients with SLE were younger (P < .0001), had a longer hospitalization stay (P = .001), and required more transfusions (P = .004). Global complications in THA in patients with SLE were more prevalent than rheumatoid arthritis (36.2% vs 15.5%, P = .029) and osteoarthritis (36.2% vs 5.1%, P < .0001) patients. After multivariate analysis, risk factors for THA complications were: SLE (hazard ratio 2.8, 95% confidence interval 1.2-6.8; P = .018) and low postoperative hemoglobin (hazard ratio 0.77, 95% confidence interval 0.73-0.83; P < .0001). Long-term complications after THA were similar among groups. CONCLUSION: This is the largest single-center study regarding clinical outcomes after THA in SLE patients. Our data suggest that SLE is an independent risk factor for adverse postoperative outcomes, mainly immediate complications, but the long-term outcome is good enough to offer surgical treatment that will improve quality of life. PMID- 28709760 TI - Clinical and pathologic implications of extending the spectrum of maternal autoantibodies reactive with ribonucleoproteins associated with cutaneous and now cardiac neonatal lupus from SSA/Ro and SSB/La to U1RNP. AB - While the relationship between maternal connective tissue diseases and neonatal rashes was described in the 1960s and congenital heart block in the 1970s, the "culprit" antibody reactivity to the SSA/Ro-SSB/La ribonucleoprotein complex was not identified until the 1980s. However, studies have shown that approximately 10 15% of cases of congenital heart block are not exposed to anti-SSA/Ro-SSB/La. Whether those cases represent a different disease entity or whether another antibody is associated has yet to be determined. Moreover, the cutaneous manifestations of neonatal lupus have also been identified in infants exposed only to anti-U1RNP antibodies. In this review, we describe what we believe to be the first case of congenital heart block exposed to maternal anti-U1RNP antibodies absent anti-SSA/Ro-SSB/La. The clinical and pathologic characteristics of this fetus are compared to those typically seen associated with SSA/Ro and SSB/La. Current guidelines for fetal surveillance are reviewed and the potential impact conferred by this case is evaluated. PMID- 28709761 TI - Central nervous system involvement in eosinophilic granulomatosis with polyangiitis (Churg-Strauss): Report of 26 patients and review of the literature. AB - BACKGROUND: Although peripheral nervous system involvement is common in eosinophilic granulomatosis with polyangiitis (EGPA), central nervous system (CNS) manifestations are poorly described. This study aimed to describe CNS involvement in EGPA. PATIENTS AND METHODS: This retrospective, observational, multicenter study included patients with EGPA and CNS involvement affecting cranial nerves, brain and/or spinal cord. We also undertook a systematic literature review. RESULTS: We analyzed 26 personal cases and 62 previously reported cases. At EGPA diagnosis, asthma was noted in 97%, eosinophilia in 98%, peripheral neuropathy in 55% and cardiac involvement in 41%. 38/71 (54%) were ANCA-positive, with a perinuclear-labeling pattern and/or anti-MPO specificity. CNS was involved in 86% at EGPA diagnosis, preceded EGPA in 2%, and occurred during follow-up in 12% after a median of 24months. Main neurological manifestations were ischemic cerebrovascular lesions in 46 (52%), intracerebral hemorrhage and/or subarachnoid hemorrhage in 21 (24%), loss of visual acuity in 28 (33%) (15 with optic neuritis, 9 with central retinal artery occlusion, 4 with cortical blindness), and cranial nerves palsies in 18 (21%), with 25 patients having >=1 of these clinical CNS manifestations. Among the 81 patients with assessable neurological responses, 43% had complete responses without sequelae, 43% had partial responses with long-term sequelae and 14% refractory disease. After a mean follow-up of 36months, 11 patients died including 5 from intracerebral hemorrhages. CONCLUSION: EGPA-related CNS manifestations form 4 distinct neurological pictures: ischemic lesions, intracerebral hemorrhages, cranial nerve palsies and loss of visual acuity. Such manifestation should prompt practitioners to consider EGPA in such conditions. Long-term neurological sequelae were common, and intracerebral hemorrhages had the worst prognostic impact. PMID- 28709763 TI - The Role of Occupational Voice Demand and Patient-Rated Impairment in Predicting Voice Therapy Adherence. AB - OBJECTIVE: Examine the relationship among the severity of patient-perceived voice impairment, perceptual dysphonia severity, occupational voice demand, and voice therapy adherence. Identify clinical predictors of increased risk for therapy nonadherence. METHODS: A retrospective cohort study of patients presenting with a chief complaint of persistent dysphonia at an interdisciplinary voice center was done. The Voice Handicap Index-10 (VHI-10) and the Voice-Related Quality of Life (V-RQOL) survey scores, clinician rating of dysphonia severity using the Grade score from the Grade, Roughness Breathiness, Asthenia, and Strain scale, occupational voice demand, and patient demographics were tested for associations with therapy adherence, defined as completion of the treatment plan. Classification and Regression Tree (CART) analysis was performed to establish thresholds for nonadherence risk. RESULTS: Of 166 patients evaluated, 111 were recommended for voice therapy. The therapy nonadherence rate was 56%. Occupational voice demand category, VHI-10, and V-RQOL scores were the only factors significantly correlated with therapy adherence (P < 0.0001, P = 0.018, and P = 0.008, respectively). CART analysis found that patients with low or no occupational voice demand are significantly more likely to be nonadherent with therapy than those with high occupational voice demand (P < 0.001). Furthermore, a VHI-10 score of <=29 or a V-RQOL score of >40 is a significant cutoff point for predicting therapy nonadherence (P < 0.011 and P < 0.004, respectively). CONCLUSION: Occupational voice demand and patient perception of impairment are significantly and independently correlated with therapy adherence. A VHI-10 score of <=9 or a V-RQOL score of >40 is a significant cutoff point for predicting nonadherence risk. PMID- 28709762 TI - Prevalence of paroxysmal atrial fibrillation in a population assessed by continuous 24-hour monitoring. AB - INTRODUCTION: Atrial fibrillation (AF) is the most common sustained arrhythmia in clinical practice and a major cause of morbidity, due to the associated risk of stroke. However, since it is often paroxysmal, it is commonly underdiagnosed and undertreated. OBJECTIVES: The primary objective of this prospective study was to determine the prevalence of paroxysmal atrial fibrillation (PAF) in patients aged 40 and above in a population who underwent continuous 24-hour electrocardiographic monitoring. The secondary objectives were to determine the overall prevalence of AF/atrial flutter (AFL) regardless of the type and to compare the population with AF with the general population and patients with PAF with patients with AF. RESULTS: A total of 4843 consecutive patients were analyzed, 58% women, 26.2% aged 70-79 years (n=1269), 25.9% (n=1252) aged 60-69 years, and 19.0% (n=923) aged 50-59 years; the others were aged either >80 years (n=712, 14.7%) or <50 years (n=686, 14.2%). At least one episode of PAF was detected in 123 patients, a prevalence of 2.5% (95% CI: 2.1-3.0). The prevalence of persistent AF throughout the monitoring period was 9.4% (95% CI: 8.6-10.2) (n=454). Additionally, 39 cases of typical AFL were detected, but in 23 of them (sustained or paroxysmal) this appeared isolated, a prevalence of 0.8% (95% CI: 0.6-1.1). The overall prevalence of AF/AFL was thus 12.4%. The presence of some type of AF/AFL was significantly correlated with male gender (p<0.001), age (especially in the 70-79 and >80 age-groups) (p<0.001) and hypertension (p<0.001). This group had a significantly higher prevalence of previous stroke (56 patients [9.3%], p=0.001) and acute myocardial infarction (5.3%, p<0.001). Comparing the population with PAF and/or paroxysmal AFL (PAF/PAFL) to those with persistent AF (during 24-hour monitoring), significant differences were found: a higher prevalence of PAF/PAFL in younger individuals (40-49, 50-59 and 60-69 age groups) and lower in older individuals (70-79 and >80 age-groups) (p<0.001), higher prevalence of history of stroke (p=0.024), and lower levels of hypertension (p<0.001). Only 12.8% of patients with PAF were taking anticoagulant drugs. CONCLUSIONS: The prevalence of PAF found in a population referred for continuous 24-hour electrocardiographic monitoring for diverse reasons was 2.5% and the overall AF/AFL prevalence was 12.4%. PAF was more prevalent in younger patients. Patients with PAF showed a significantly lower prevalence of hypertension and significantly higher rates of stroke. Systematically detecting patients with PAF is a major public health concern, since early diagnosis is essential to identify candidates for oral anticoagulation and catheter ablation, which is frequently curative when applied at this stage. PMID- 28709764 TI - Using Receiver Operating Characteristic Curve to Define the Cutoff Points of Voice Handicap Index Applied to Young Adult Male Smokers. AB - Voice performance is an inextricable key factor of everyday life. Obviously, the deterioration of voice quality can cause various problems to human communication and can therefore reduce the performance of social skills (relevant to voice). The deterioration could be originated from changes inside the system of the vocal tract and larynx. Various prognostic methods exist, and among them is the Voice Handicap Index (VHI). This tool includes self-reported questionnaires, used for determining the cutoff points of total score and of its three domains relevant to young male Greek smokers. The interpretation of the calculated cutoff points can serve as a strong indicator of imminent or future evaluation by a clinician. Consistent with previous calculation, the VHI can also act as a feedback for smokers' voice condition and as monitoring procedure toward smoking cessation. Specifically, the sample consisted of 130 male nondysphonic smokers (aged 18-33 years) who all participated in the VHI test procedure. The test results (through receiver operating characteristic analysis) concluded to a total cutoff point score of 19.50 (sensitivity: 0.838, 1-specificity: 0). Also, in terms of constructs, the Functional domain was equal to 7.50 (sensitivity: 0.676, 1 specificity: 0.032), the Physical domain was equal to 7.50 (sensitivity: 0.706, 1 specificity: 0.032), and the Emotional domain was equal to 6.50 (sensitivity: 0.809, 1-specificity: 0.048). PMID- 28709766 TI - Lipschutz Ulcer: A Rare Cause of Acute Genital Ulcers. PMID- 28709765 TI - Acoustic and Perceived Measurements Certifying Tango as Voice Treatment Method. AB - Voice disorders are affecting everyday life in many levels, and their prevalence has been studied extensively in certain and general populations. Notably, several factors have a cohesive influence on voice disorders and voice characteristics. Several studies report that health and environmental and psychological etiologies can serve as risk factors for voice disorders. Many diagnostic protocols, in the literature, evaluate voice and its parameters leading to direct or indirect treatment intervention. This study was designed to examine the effect of tango on adult acoustic voice parameters. Fifty-two adults (26 male and 26 female) were recruited and divided into four subgroups (male dancers, female dancers, male nondancers, and female nondancers). The participants were asked to answer two questionnaires (Voice Handicap Index and Voice Evaluation Form), and their voices were recorded before and after the tango dance session. Moreover, water consumption was investigated. The study's results indicated that the voices' acoustic characteristics were different between tango dancers and the control group. The beneficial results are far from prominent as they prove that tango dance can serve stand-alone as voice therapy without the need for hydration. Also, more research is imperative to be conducted on a longitudinal basis to obtain a more accurate result on the required time for the proposed therapy. PMID- 28709767 TI - Obstetrical Brachial Plexus Palsy. AB - Obstetrical brachial plexus palsy is a disorder of the peripheral nervous system and occurs in as many as 0.4% of infants born. It is associated with shoulder dystocia, use of mechanical extraction, and macrosomia; it occurs more frequently in infants born by vaginal delivery. The unilateral injury to the brachial plexus complex occurs during the delivery phase as lateral traction is applied to the head to permit shoulder clearance. The infant typically presents in the delivery room with decreased active movements of the affected arm and asymmetrical primitive reflex responses. The severity of nerve involvement can range from a stretch injury to complete avulsion. While full recovery is possible, prognosis is variable and up to 35% of children may have some degree of life-long functional impairment of the affected limb. PMID- 28709768 TI - Plasma sphingosine-1-phosphate concentrations are associated with systolic heart failure in patients with ischemic heart disease. AB - OBJECTIVE: Sphingosine-1-Phosphate (S1P) is a bioactive sphingolipid with important functions in immunity, inflammation and cardiovascular biology. S1P is associated with prevalence and severity of coronary artery disease and myocardial infarction. However, its relevance in ischemic cardiomyopathy is unknown. We aimed to investigate associations of plasma S1P and other sphingolipids with the extent of heart failure in patients with ischemic heart disease. METHODS AND RESULTS: 74 patients with ischemic heart disease were investigated in this observational study. Plasma concentrations of S1P, C16 ceramide and sphingomyelin (SM) were measured using liquid chromatography/tandem mass-spectrometry and associated with objective (echocardiography) and subjective (dyspnea) signs of heart failure. Plasma S1P and SM but not C16 ceramide concentrations were negatively associated with left ventricular ejection fraction (LVEF) and dyspnea (ranked by New York Heart Association; LVEF: S1P standardized coefficient beta: 0.25; 95%CI: -273 to -13nM, p=0.03; SM beta: -0.24; 95%CI: -16,310 to -413nM, p=0.04; NYHA: S1P beta: -0.3; 95%CI: -174 to -26nM, p=0.009; SM beta: -0.46; 95%CI: -13,462 to -5013nM, p<0.001). ROC analysis revealed that S1P and SM predicted impaired LVEF with optimal cut-off levels below 843nM and 77MUM, respectively. CONCLUSION: S1P is associated with the impairment of LVEF and dyspnea. Considering the major effects of S1P on cardiac and vascular functions in experimental models, we put forward the hypothesis that S1P is causally involved in the pathophysiology of heart failure. Interfering pharmacologically with S1P receptors may have an impact on ischemic cardiomyopathy. PMID- 28709771 TI - Gesture impairments in schizophrenia are linked to increased movement and prolonged motor planning and execution. AB - Schizophrenia patients present with a variety of impaired nonverbal communication skills. Performance of hand gestures is frequently impaired and associated with ratings of motor abnormalities. However, the impact of motor abnormalities to gesture performance remains unclear. To test the association between quantitative measures of motor behavior and qualitative ratings of gesture performance, we quantified movement parameters semi-automatically in videotaped recordings of gesture assessment. Thirty-one patients with schizophrenia (77.4%), schizophreniform (19.4%) or schizoaffective disorder (3.2%) and 32 healthy controls matched for age, gender and education underwent clinical assessment. Performance of the test of upper limb apraxia (TULIA) was video-taped in all subjects. The videos were analyzed with motion energy analysis software (MEA) to determine motion and time parameters. Patients and controls differed significantly in quantitative gesture performance: patients required more movement and more time to complete the tasks. Differences increased in patients with qualitatively impaired gesture production ratings (p<0.01). Group differences were most pronounced in the pantomime domain, when gestures are performed following verbal instruction. In patients, ratings of motor abnormalities correlated with duration of movement, while behavioral disorganization correlated with the amount of movements during gesture performance. Disorder related motor symptoms, aberrant action observation, planning and monitoring as well as internal clock abnormalities may explain the poor performance of hand gestures in schizophrenia. Quantitative video analysis offers a unique possibility to analyze movement patterns as a direct functional output of the motor system. In the future, it may assist monitoring, staging and prognosis in schizophrenia. PMID- 28709772 TI - Physical health promotion in patients with functional psychoses receiving community psychiatric services: Results of the PHYSICO-DSM-VR study. AB - OBJECTIVES: Psychotic patients have poorer health behaviours, including poor diets and sedentary lifestyles increasing their risk for obesity, diabetes, hypertension, and dyslipidaemia, and tend to have a shorter life expectancy as compared to nonpsychiatric populations. Lifestyle intervention programmes that target modifiable risk factors in such patients have produced uneven results. The objective was to evaluate the efficacy of a package of health promotion strategies to improve diet and physical exercise in psychotic patients. Our hypothesis was that a pre- to post-treatment improvement in physical activity and dietary habits would occur in the group receiving intervention. METHOD: This randomised controlled trial was carried out in four psychiatric services. The intervention included psychoeducation sessions on diet and physical activity and regular participation in walking groups (experimental group). The control group received routine treatment. The primary outcome was an improvement of at least one World Health Organization recommendation on diet and exercise. RESULTS: Of a total of 326 subjects recruited, 169 were randomly assigned to the experimental group and 157 to the control group. An improvement in one or more World Health Organization criteria over baseline was observed in 25.4% of experimental group subjects and in 12.2% of control group subjects (odds ratio 2.46, 95% confidence interval 1.22-4.97; p=0.01). CONCLUSIONS: A statistically significant proportion of the sample achieved post-treatment improvement in lifestyle habits, especially as regarded increased physical activity. A post-intervention reduction in lifestyle variability was also noted. Interventions directly addressing dietary habits may be desirable in psychotic patients. PMID- 28709769 TI - Exploring the mitochondrial microRNA import pathway through Polynucleotide Phosphorylase (PNPase). AB - Cardiovascular disease is the primary cause of mortality for individuals with type 2 diabetes mellitus. During the diabetic condition, cardiovascular dysfunction can be partially attributed to molecular changes in the tissue, including alterations in microRNA (miRNA) interactions. MiRNAs have been reported in the mitochondrion and their presence may influence cellular bioenergetics, creating decrements in functional capacity. In this study, we examined the roles of Argonaute 2 (Ago2), a protein associated with cytosolic and mitochondrial miRNAs, and Polynucleotide Phosphorylase (PNPase), a protein found in the inner membrane space of the mitochondrion, to determine their role in mitochondrial miRNA import. In cardiac tissue from human and mouse models of type 2 diabetes mellitus, Ago2 protein levels were unchanged while PNPase protein expression levels were increased; also, there was an increase in the association between both proteins in the diabetic state. MiRNA-378 was found to be significantly increased in db/db mice, leading to decrements in ATP6 levels and ATP synthase activity, which was also exhibited when overexpressing PNPase in HL-1 cardiomyocytes and in HL-1 cells with stable miRNA-378 overexpression (HL-1-378). To assess potential therapeutic interventions, flow cytometry evaluated the capacity for targeting miRNA-378 species in mitochondria through antimiR treatment, revealing miRNA-378 level-dependent inhibition. Our study establishes PNPase as a contributor to mitochondrial miRNA import through the transport of miRNA-378, which may regulate bioenergetics during type 2 diabetes mellitus. Further, our data provide evidence that manipulation of PNPase levels may enhance the delivery of antimiR therapeutics to mitochondria in physiological and pathological conditions. PMID- 28709773 TI - Demographic, psychosocial, clinical, and neurocognitive baseline characteristics of Black Americans in the RAISE-ETP study. AB - This study compared baseline characteristics of Black Americans and Caucasians with first-episode psychosis in the Recovery After an Initial Schizophrenia Episode Early Treatment Program (RAISE-ETP). Black American (N=152) and Caucasian (N=218) participants were compared on demographic, psychosocial, clinical, and neurocognitive measures. Results indicated several notable racial differences in baseline characteristics: a greater proportion of Black Americans than Caucasians were female, and Black Americans reported less personal and parental education than Caucasians. Black Americans were also less likely to have private insurance, more likely to be homeless or transient, had significantly poorer quality of life, more severe disorganized symptoms, worse neurocognition, and were less likely to abuse alcohol than Caucasians. The implications of these findings are discussed, and suggestions are provided for future avenues of treatment and research on racial disparities in first-episode psychosis. PMID- 28709770 TI - Meta-analysis of mismatch negativity to simple versus complex deviants in schizophrenia. AB - Mismatch negativity (MMN) deficits in schizophrenia (SCZ) have been studied extensively since the early 1990s, with the vast majority of studies using simple auditory oddball task deviants that vary in a single acoustic dimension such as pitch or duration. There has been a growing interest in using more complex deviants that violate more abstract rules to probe higher order cognitive deficits. It is still unclear how sensory processing deficits compare to and contribute to higher order cognitive dysfunction, which can be investigated with later attention-dependent auditory event-related potential (ERP) components such as a subcomponent of P300, P3b. In this meta-analysis, we compared MMN deficits in SCZ using simple deviants to more complex deviants. We also pooled studies that measured MMN and P3b in the same study sample and examined the relationship between MMN and P3b deficits within study samples. Our analysis reveals that, to date, studies using simple deviants demonstrate larger deficits than those using complex deviants, with effect sizes in the range of moderate to large. The difference in effect sizes between deviant types was reduced significantly when accounting for magnitude of MMN measured in healthy controls. P3b deficits, while large, were only modestly greater than MMN deficits (d=0.21). Taken together, our findings suggest that MMN to simple deviants may still be optimal as a biomarker for SCZ and that sensory processing dysfunction contributes significantly to MMN deficit and disease pathophysiology. PMID- 28709775 TI - Ethnic differences in physician follow-up after a first diagnosis of psychotic disorder. PMID- 28709774 TI - The association between cardio-respiratory fitness and cognition in schizophrenia. AB - OBJECTIVE: Schizophrenia is associated with reduced cardio-respiratory fitness (CRF), and impaired cognition is a core feature of the disorder. Despite their particular significance to schizophrenia disparately, the relationship between these two variables has not yet been thoroughly assessed. In this study we aimed to investigate naturally occurring associations between CRF and all cognitive domains within this patient population. METHOD: Eighty outpatients with schizophrenia spectrum disorders participated in the study. Neurocognition was assessed with the Wechsler Adult Intelligence Scale version 4 General Ability Index (WAIS GAI) and the MATRICS Consensus Cognitive Battery (MCCB). Oxygen uptake was measured directly by analyzing O2 and CO2 content in expired air during a maximum exercise session on a treadmill using a modified Balke protocol. Clinical symptom load was assessed with the Positive and Negative Syndrome Scale (PANSS). Hierarchical multiple regression analyses were conducted, controlling for sex and age, and negative psychotic symptom levels. RESULTS: CRF explained a significant 8.2% and 9.1% of the variance in general intellectual ability and state-sensitive cognitive functioning respectively, beyond the impact of negative psychotic symptom load. CONCLUSION: The study indicates a direct relation between CRF and cognition in schizophrenia. Impaired cognition is a difficult-to-treat expression of the disorder, and identifying modifiable factors possibly mediating cognition, such as CRF, is of great clinical value. PMID- 28709776 TI - Effects of four atypical antipsychotics on autonomic nervous system activity in schizophrenia. AB - Antipsychotic drugs are associated with autonomic nervous system (ANS) dysfunction in patients with schizophrenia, but the effects of individual atypical antipsychotic drugs are not clear. This study investigated how four atypical antipsychotic drugs-risperidone, olanzapine, aripiprazole, and quetiapine-differ in their effects on ANS activity. A total of 241 Japanese patients with schizophrenia participated in this study. All of the participants received an atypical antipsychotic as monotherapy: 90 participants received risperidone, 68 olanzapine, 52 aripiprazole, and 31 quetiapine. ANS activity was assessed by means of a power spectral analysis of heart rate variability. The quetiapine group showed significantly diminished sympathetic and parasympathetic activity compared with the risperidone and aripiprazole groups and significantly lower sympathetic activity relative to olanzapine. In addition, multiple regression analysis showed that the type of antipsychotic drug significantly influenced ANS activity. We suggest that, among the antipsychotics examined risperidone, olanzapine, aripiprazole and quetiapine-quetiapine has the strongest effect on ANS activity. PMID- 28709777 TI - Fear of childbirth in primiparous Italian pregnant women: The role of anxiety, depression, and couple adjustment. AB - BACKGROUND: The prevalence of fear of childbirth in pregnant women is described to be about 20-25%, while 6-10% of expectant mothers report a severe fear that impairs their daily activities as well as their ability to cope with labour and childbirth. Research on fear of childbirth risk factors has produced heterogeneous results while being mostly done with expectant mothers from northern Europe, northern America, and Australia. AIMS: The present research investigates whether fear of childbirth can be predicted by socio-demographic variables, distressing experiences before pregnancy, medical-obstetric factors and psychological variables with a sample of 426 Italian primiparous pregnant women. METHODS: Subjects, recruited between the 34th and 36th week of pregnancy, completed a questionnaire packet that included the Wijma Delivery Expectancy Questionnaire, the Edinburgh Postnatal Depression Scale, the State-Trait Anxiety Inventory, the Dyadic Adjustment Scale, the Multidimensional Scale of Perceived Social Support, as well as demographic and anamnestic information. Fear of childbirth was treated as both a continuous and a dichotomous variable, in order to differentiate expectant mothers as with a severe fear of childbirth. FINDINGS: Results demonstrate that anxiety as well as couple adjustment predicted fear of childbirth when treated as a continuous variable, while clinical depression predicted severe fear of childbirth. CONCLUSIONS: Findings support the key role of psychological variables in predicting fear of childbirth. Results suggest the importance of differentiating low levels of fear from intense levels of fear in order to promote adequate support interventions. PMID- 28709778 TI - Midwives' personal use of complementary and alternative medicine (CAM) influences their recommendations to women experiencing a post-date pregnancy. AB - : Complementary and Alternative Medicine (CAM) have increasingly been used by pregnant women with a steady rise in interest by midwives. Literature describing CAM and self-help options midwives recommend to women experiencing a post-date pregnancy is sparse. This study aimed to investigate if Australian midwives' personal CAM use impacts on discussions and recommendations of CAM/Self-help strategies. METHODOLOGY/DESIGN: A survey of a national midwifery association midwifery members (n=3,552) was undertaken at a midwifery conference (October 2015) and via e-bulletins (November 2015-March 2016). The self-administered survey included questions on what self-help and CAM strategies midwives discuss and recommend to women with a post-date pregnancy, midwives' confidence levels on discussing or recommending CAM, midwives' own personal use of CAM. FINDINGS: A total of 571 registered midwives completed the survey (16%). Demographics (age, years as a midwife, state of residence) reflected Australian midwives and the midwifery association membership. Most respondents discuss (91.2%) and recommend (88.6%) self-help/CAM strategies to women with a post-date pregnancy. The top five CAM recommended were Acupuncture (65.7%), Acupressure (58.1%), Raspberry Leaf (52.5%), Massage (38.9%) and Hypnosis/Calmbirthing/Hypnobirthing (35.7%). Midwives were more likely to discuss strategies if they personally used CAM (p<.001), were younger (p<.001) or had worked less years as midwives (p=.004). Midwives were more likely to recommend strategies if they used CAM in their own pregnancies (p=.001). CONCLUSION: Midwives' personal use of CAM influenced their discussions and recommendations of CAM/self-help strategies to women experiencing a post-date pregnancy. This study has implications for inclusion of CAM in midwifery education curricula. PMID- 28709779 TI - Bronchial hyper-responsiveness after preterm birth. AB - Being born preterm often adversely affects later lung function. Airway obstruction and bronchial hyperresponsiveness (BHR) are common findings. Respiratory symptoms in asthma and in lung disease after preterm birth might appear similar, but clinical experience and studies indicate that symptoms secondary to preterm birth reflect a separate disease entity. BHR is a defining feature of asthma, but can also be found in other lung disorders and in subjects without respiratory symptoms. We review different methods to assess BHR, and findings reported from studies that have investigated BHR after preterm birth. The area appeared understudied with relatively few and heterogeneous articles identified, and lack of a pervasive understanding. BHR seemed related to low gestational age at delivery and a neonatal history of bronchopulmonary dysplasia. No studies reported associations between BHR after preterm birth and the markers of eosinophilic inflammatory airway responses typically found in asthma. This should be borne in mind when treating preterm born individuals with BHR and airway symptoms. PMID- 28709780 TI - Radiologists Should Not Be "Ordered" Around. PMID- 28709781 TI - Radiology Resident Supply and Demand: A Regional Perspective. AB - PURPOSE: Radiology was subject to crippling deficits in the number of jobs available to graduates of training programs from 2012 through 2015. As the specialty transitions to the assimilation of osteopathic training programs and the welcoming of direct competition from new integrated interventional radiology programs, the assessment of growth in radiology training positions over the 10 years preceding this pivotal time will serve to characterize the genesis of the crisis while inspiring stakeholders to avoid similar negative fluctuations in the future. METHODS: The number of per capita radiology trainees in each region was derived from data published by the National Resident Matching Program, as were annual match statistics over the years 2012 through 2016. Data regarding new interventional radiology and diagnostic radiology enrollees were also obtained from the National Resident Matching Program. RESULTS: The seven states with the most per capita radiology residents were in the Mid-Atlantic and Northeastern United States in both 2006 and 2016, and three of these seven also showed the greatest per capita growth over the course of the 10 years studied. New radiology programs were accredited during the peak of the job shortage. Integrated interventional radiology training created 24 de novo radiology residents in the 2017 match. Fill rates are weakly positively correlated with program size. CONCLUSIONS: Unregulated radiology program growth persisted during the decade leading up to 2016. The region with the fewest jobs available since 2012 is also home to the greatest number of per capita radiology residents. Numerous published opinions during the crisis did not result in enforced policy change. PMID- 28709782 TI - Contextualizing Oncologic Imaging Utilization Through End-of-Life Spending Patterns. AB - PURPOSE: The aim of this study was to assess the effect of spending patterns during the final year of life on high-cost imaging utilization in the final 3 months of life. METHODS: An academic comprehensive cancer center's radiology, cancer registry, and claims records were matched to identify decedents with dates of death from April 2013 through June 2014. Spending patterns in the final year of life were identified using group-based trajectory modeling. Descriptive analysis of CT, MRI, and PET utilization across trajectories was conducted. Multivariate logistic regressions modeled the likelihood of imaging utilization in the final 3 months of life, and a sensitivity analysis assessed the impact of spending trajectories on model fit. RESULTS: Six spending trajectories were identified. Membership in the late rising trajectory was the strongest predictor of high-cost imaging in the final 3 months of life (odds ratio, 11.61; P = .000), followed by diagnosis 12 to 6 months premortem (odds ratio, 7.49; P = .000). The likelihood of imaging the final 3 months of life was no different between high persistent and low persistent trajectory patients, despite the heterogeneity between the two patient groups. Sensitivity analysis indicated that spending trajectory improved the prediction of imaging in the final 3 months of life to a greater extent than temporal proximity to death at the time of diagnosis, which may serve as a proxy for severity and/or complexity. CONCLUSIONS: Clinical measures of severity and patients' utilization histories should be considered by hospital administrators in estimations of aggregate and individual oncologic imaging utilization. This analytic approach may aid in evaluating participation in advanced payment models. PMID- 28709783 TI - Role of the lateral habenula in memory through online processing of information. AB - Our memory abilities, whether they involve short-term working memory or long-term episodic or procedural memories, are essential for our well-being, our capacity to adapt to constraints of our environment and survival. Therefore, several key brain regions and neurotransmitter systems are engaged in the processing of sensory information to either maintain such information in working memory so that it will quickly be used, and/or participate in the elaboration and storage of enduring traces useful for longer periods of time. Animal research has recently attracted attention on the lateral habenula which, as shown in rodents and non human primates, seems to process information stemming in the main regions involved in memory processing, e.g., the medial prefrontal cortex, the hippocampus, the amygdala, the septal region, the basal ganglia, and participates in the control of key memory-related neurotransmitters systems, i.e., dopamine, serotonin, acetylcholine. Recently, the lateral habenula has been involved in working and spatial reference memories, in rodents, likely by participating in online processing of contextual information. In addition, several behavioral studies strongly suggest that it is also involved in the processing of the emotional valance of incoming information in order to adapt to particularly stressful situations. Therefore, the lateral habenula appears like a key region at the interface between cognition and emotion to participate in the selection of appropriate behaviors. PMID- 28709784 TI - Individual decision-making in the causal pathway to addiction: contributions and limitations of rodent models. AB - The causal pathway from vulnerability to drug use and addiction involves a complex interaction between genetic, environmental, and behavioral factors. An individual can intervene on this causal pathway by two major types of individual decision. There is the inaugural, momentous decision to use a drug for the first time. This decision is influenced by both prior knowledge on the drug and its expected effects, and also by prior self-knowledge on one's own vulnerability. After an individual has used a drug for the first time, there is the decision to repeat drug use. This decision is influenced by the same factors that were involved in the inaugural decision to initiate drug use, except for one crucial difference. The first drug use has now acted on the individual, changing its brain acutely and also potentially persistently in a way that could bias subsequent decision-making in favor of repeated drug use. The goal of this review article is to assess the contributions and limitations of rodent models (i.e., rats, mice) to understand how prior drug use can influence decision-making in a way that favors future drug use. Overall, research on rodents shows that prior drug use can increase impulsive, risky and/or potentially harmful decision making. However, this does not apparently translate into more drug use when rodents have the choice between a drug and a competing, nondrug option, except when the expected value of the latter is considerably decreased. The delayed drug reward hypothesis is developed to resolve and explain this apparent discrepancy. This novel hypothesis makes several unique predictions, some of them counterintuitive, and suggests that extrapolation of rodent research to humans should not only take into account differences in drug choice situations but also inherent species-specific differences in individual decision-making. PMID- 28709785 TI - Implementing and Evaluating a Telephone-Based Centralized Maternity Care Coordination Program for Pregnant Veterans in the Department of Veterans Affairs. AB - PURPOSE: The purpose of this study was to develop and evaluate a comprehensive, telephonic maternity care coordination (MCC) program for all pregnant veterans enrolled for care at New England Department of Veterans Affairs (VA) facilities that comprise the Veterans Integrated Service Network 1. RESEARCH DESIGN: Telephone interviews were conducted with postpartum women veterans who had participated in the MCC program during their pregnancies. The program evaluation instrument assessed satisfaction and use of MCC services, prenatal education classes, and infant and maternal outcomes (e.g., newborn birthweight, insurance status, maternal depression) using both closed-ended and open-ended questions. RESULTS: A substantial majority (95%) of women enrolled in the MCC program expressed satisfaction with the services they received in the program. Women were most satisfied with help understanding VA maternity benefits and acquiring VA services and equipment, such as breast pumps and pregnancy-related medications. More than one-third of women noted their infants had experienced health problems since delivery, including neonatal intensive care unit hospitalizations. A majority of women planned to return to VA care in the future. CONCLUSIONS: Our findings suggest that MCC services play an important role for women veterans as they navigate both VA and non-VA care systems. MCC staff members coordinated maternity, medical, and mental health care services for women veterans. Additionally, by maintaining contact with the veteran during the postpartum period, MCC staff were able to assess the health of the mother and the infant, and refer women and their infants to medical and psychosocial services in the community as needed. PMID- 28709786 TI - [PCSK-9 inhibitors, effects on LDL-C and future implications: What you should know]. AB - The discovery of proprotein convertase subtilisin/kexin type 9 (PCSK9) in 2003 in families with familial hypercholesterolemia (HF) later generated the development of pharmacological strategies in order to inhibit this protein. Twelve years after this discovery, the first two biological compounds (monoclonal antibodies) were approved, which have been shown to substantially decrease LDL-C and other lipid subfractions. The objective of the present article is to review the history of the discovery of PCSK9, its physiology and pathophysiology and subsequent pharmacological development. The objectives and goals reached to date and the pending questions regarding the efficacy and safety of its clinical use are presented. PMID- 28709787 TI - Technique of Split Flexor Carpi Ulnaris Opponensplasty. AB - The classic donor motor units for opponensplasty are the flexor digitorum superficialis, the extensor indicis proprius, the palmaris longus, and the abductor digiti minimi. Occasionally, all classic donor motor units are not available for the opponensplasty; a review of the literature revealed that the flexor carpi ulnaris opponensplasty has not been previously described. The surgical technique of the split flexor carpi ulnaris opponensplasty is described in the current paper along with a clinical example. The result in our patient was satisfactory with the ability to oppose the thumb tip to reach the tip of the ring finger with the wrist in neutral position. PMID- 28709788 TI - Making Sense of Metal Allergy and Hypersensitivity to Metallic Implants in Relation to Hand Surgery. AB - All metals implanted into a biological system undergo some degree of corrosion depending upon its composition. The electrochemical process of corrosion produces free metal ions, which may activate the host's immune system through a variety of mechanisms. Whereas dermal metal hypersensitivity is common, affecting 10% to 15% of the population, the immune reaction from implanted metals is much less common (< 0.1%), but has been associated with metal allergy and hypersensitivity producing a multitude of patient symptoms. Superficial symptoms may be mild to severe forms of dermatitis, urticaria, pruritus, and vasculitis, whereas deep sequelae include metallosis-related pseudotumor, implant loosening, and joint stiffness. Currently, there are clinical tests to evaluate patients for metal hypersensitivity, but there is little agreement regarding the ideal timing and clinical situation prompting the work-up of a patient for a metal allergy or hypersensitivity. An understanding of the epidemiology, etiology, basic science, diagnostic testing, and treatment of patients with suspected metal allergy, as it pertains to the current literature, will aid orthopedic and plastic surgeons of all subspecialties in the management of patients requiring metallic implants. PMID- 28709789 TI - Extra-Axial Chordoma of the Hand. AB - Chordomas are low-grade malignant tumors that are locally aggressive and have the potential to metastasize. They most often occur in the sacrococcygeal and spheno occipital portions of the vertebral column. Morphologically similar tumors have been found outside the axial skeleton and are referred to as extra-axial chordomas. Several case reports have described the radiologic, microscopic, and immunologic profiles of these tumors and their similarities to axial chordomas. The authors report a 24-year-old man who presented with a mass in his left hand and underwent surgical excision. Specimens stained positive for pancytokeratin, S100, and brachyury. Brachyury is a protein that is present during embryogenesis and is expressed by chordomas. This is the first report of an extra-axial chordoma within the interosseous muscle compartment of the hand in a young patient. PMID- 28709791 TI - Molecular Biology of Flexor Tendon Healing in Relation to Reduction of Tendon Adhesions. AB - Tendon injuries are encountered after major and minor hand trauma. Despite meticulous repair technique, adhesion formation can occur, limiting recovery. Although a great deal of progress has been made toward understanding the mechanism of tendon healing and adhesions, clinically applicable solutions to prevent adhesions remain elusive. The goal of this paper is to review the most recent literature relating to the tendon healing and adhesion prevention. PMID- 28709790 TI - Corrective Osteotomy for Malunited Diaphyseal Forearm Fractures Using Preoperative 3-Dimensional Planning and Patient-Specific Surgical Guides and Implants. AB - PURPOSE: Three-dimensional planning based on computed tomography images of the malunited and the mirrored contralateral forearm allows preoperative simulations of corrective osteotomies, the fabrication of patient-specific osteotomy guides, and custom-made 3-dimensional printed titanium plates. This study aims to assess the precision and clinical outcome of this technique. METHODS: This was a prospective pilot study with 5 consecutive patients. The mean age at initial injury was 11 years (range, 4-16 years), and the mean interval from the time of injury to the time of corrective surgery was 32 months (range, 7-107 months). Patient-specific osteotomy guides and custom-made plates were used for multiplanar corrective osteotomies of both forearm bones at the distal level in 1 patient and at the middle-third level in 4 patients. Patients were assessed before and after surgery after a mean follow-up of 42 months (range, 29-51 months). RESULTS: The mean planned angular corrections of the ulna and radius before surgery were 9.9 degrees and 10.0 degrees , respectively. The mean postoperative corrections obtained were 10.1 degrees and 10.8 degrees with corresponding mean errors in correction of 1.8 degrees (range, 0.3 degrees -5.2 degrees ) for the ulna and 1.4 degrees (range, 0.2 degrees -3.3 degrees ) for the radius. Forearm supination improved significantly from 47 degrees (range, 25 degrees -75 degrees ) before surgery to 89 degrees (range, 85 degrees -90 degrees ) at final review. Forearm pronation improved from 68 degrees (range, 45 degrees -84 degrees ) to 87 degrees (range, 82 degrees -90 degrees ). In addition, there was a statistically significant improvement in pain and grip strength. CONCLUSIONS: This study demonstrates that 3-dimensional planned patient specific guides and implants allow the surgeon to perform precise corrective osteotomies of complex multiplanar forearm deformities with satisfactory preliminary results. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic V. PMID- 28709792 TI - Fixation of Ultrasmall Proximal Pole Scaphoid Fractures Using Bioabsorbable Osteochondral Fixation Nails. AB - Surgical treatment of ultrasmall proximal pole scaphoid fractures poses a number of challenges. The fragment may be too small to fix with conventional headless screw fixation owing to the high risk of fragmentation upon insertion. However, excision of the fragment risks compromising the scapholunate ligament complex and also exposes the radioscaphoid joint to potential degenerative changes. Under these circumstances, we describe the use of bioabsorbable osteochondral fixation nails that allows stable low-profile fixation while minimizing the risk of fracturing the proximal pole. PMID- 28709793 TI - Dorsal Scaphoid Subluxation on Sagittal Magnetic Resonance Imaging as a Marker for Scapholunate Ligament Tear. AB - PURPOSE: To evaluate the diagnostic utility of scaphoid dorsal subluxation on magnetic resonance imaging (MRI) as a predictor of scapholunate interosseous ligament (SLIL) tears and compare this with radiographic findings. METHODS: Thirty-six MRIs were retrospectively reviewed: 18 with known operative findings of complete Geissler IV SLIL tears that were surgically repaired, and 18 MRIs performed for ulnar-sided wrist pain but no SLIL tear. Dorsal subluxation of the scaphoid was measured on the sagittal MRI cut, which demonstrated the maximum subluxation. Independent samples t tests were used to compare radiographic measurements of scapholunate (SL) gap, SL angle, and capitolunate/third metacarpal-lunate angles between the SLIL tear and the control groups and to compare radiographic measurements between wrists that had dorsal subluxation of the scaphoid and wrists that did not have dorsal subluxation. Interrater reliability of subluxation measurements on lateral radiographs and on MRI were calculated using kappa coefficients. RESULTS: Thirteen of 18 wrists with complete SLIL tears had greater than 10% dorsal subluxation of the scaphoid relative to the scaphoid facet. Average subluxation in this group was 34%. Four of 18 wrists with known SLIL tears had no subluxation. No wrists without SLIL tears (control group) had dorsal subluxation. The SL angle, capitolunate/third metacarpal-lunate angle and SL gap were greater in wrists that had dorsal subluxation of the scaphoid on MRI. Interrater reliability of measurements of dorsal subluxation of the scaphoid was superior on MRI than on lateral x-ray. CONCLUSIONS: An MRI demonstration of dorsal subluxation of the scaphoid, of as little as 10%, as a predictor of SLIL tear had a sensitivity of 72% and a specificity of 100%. The high positive predictive value indicates that the presence of dorsal subluxation accurately predicts SLIL tear. TYPE OF STUDY/LEVEL OF EVIDENCE: Diagnostic II. PMID- 28709794 TI - Performance of Patient-Reported Outcomes Measurement Information System (PROMIS) Upper Extremity (UE) Versus Physical Function (PF) Computer Adaptive Tests (CATs) in Upper Extremity Clinics. AB - PURPOSE: To examine the performance of the Patient-Reported Outcomes Measurement Information System (PROMIS) Upper Extremity (UE) Function Computer Adaptive Test (CAT) relative to the PROMIS Physical Function (PF) CAT in patients seeking specialty care for upper extremity conditions. METHODS: This observational trial analyzed prospectively collected PROMIS UE and PF CAT scores from 5,202 adult patients with 10,344 outpatient clinic visits presenting to a tertiary orthopedic clinic. Pearson correlation coefficient was utilized to evaluate the association between initial PF and UE scores as well as the association between changes in PF and UE scores between visits. Differences in scores between populations presenting with hand conditions versus shoulder and elbow conditions were evaluated via Student t test, as were differences in scores between new and return patient visits. RESULTS: The PROMIS UE CAT scores were strongly correlated with PROMIS PF CAT scores. However, patients averaged 8 points lower scoring on UE CAT testing than on PF CAT scores. The UE CAT demonstrated a ceiling effect at a score of 56 that affected 7% of patients with a secondary ceiling at 50. Changes in PF and UE scores between visits were moderately correlated with a mean difference of less than 1 point. Patients presenting for hand conditions achieved better PF and UE scores than patients presenting for shoulder and elbow conditions. CONCLUSIONS: The PROMIS UE module appears responsive to changes over time. However, the current UE CAT has a ceiling score of 56, which does not allow for improvement of scores 0.6 SD higher than the presumptive normative population mean of 50. Although a specific assessment of upper extremity function is desirable, continued refinement of the PROMIS UE CAT is required to better assess patients with higher levels of function. TYPE OF STUDY/LEVEL OF EVIDENCE: Diagnostic II. PMID- 28709795 TI - A Biomechanical Comparison of Extensor Carpi Ulnaris Subsheath Reconstruction Techniques. AB - PURPOSE: Several surgical stabilization techniques have been described to address pathological subluxation of the extensor carpi ulnaris (ECU) tendon, with no comparative data available. This study compares ECU stability after subsheath reconstruction, with and without ulnar groove deepening, to stability with an intact subsheath in a cadaveric model. METHODS: Position of the ECU tendon relative to the ulnar groove was measured in 5 human cadaveric specimens with the subsheath intact, sectioned, and after 3 reconstruction scenarios: reconstructed, reconstructed with ulnar groove deepened, and ulnar groove deepened with subsheath sectioned. Position of the tendon relative to the radial side of the ulnar groove was recorded with digital calipers in 9 combinations of wrist/forearm positions (wrist flexion, extension, and neutral; forearm pronation, supination, and neutral). Dislocation events, defined as the tendon being completely ulnar to the groove, were recorded. RESULTS: Extensor carpi ulnaris tendon displacement was not significantly different between intact subsheath, subsheath reconstruction, and reconstruction with groove deepening (1.5 mm vs 0.5 mm vs -0.3). Extensor carpi ulnaris tendon displacement after groove deepening with the subsheath sectioned was not significantly different from displacement with a fully sectioned subsheath. Sectioning of the subsheath induced dislocation events of the ECU tendon in multiple positions. Subsheath reconstruction with and without groove deepening allowed no dislocation events. CONCLUSIONS: In this cadaveric model, groove deepening did not improve stability of the ECU tendon compared with the reconstructed subsheath, and reconstruction alone was equally effective at eliminating dislocation events. CLINICAL RELEVANCE: Stabilization techniques that focus on restoration of the important ulnar attachment of the ECU subsheath are favored over routine deepening of the ulnar groove in attempts to stabilize the ECU tendon. PMID- 28709796 TI - Efficacy of PROMIS Pain Interference and Likert Pain Scores to Assess Physical Function. AB - PURPOSE: The Patient Reported Outcome Measurement Information System (PROMIS), developed by the National Institutes of Health, utilizes a health domain related to Pain Interference (PI). We evaluated this domain and its association with physical function (as determined by PROMIS Physical Function [PF]), administered as a computer adaptive test (CAT), and secondarily its association to a numerical 0 to 10 pain score. Our null hypothesis was that PI, as measured by CAT, has no correlation to PF and thus, there is no difference between comparisons of numerical pain scores and PROMIS PF. METHODS: Adult patients presenting to an upper extremity clinic from February to December 2015 completed PROMIS PF, PI, and numerical 0 to 10 pain score questionnaires. The PROMIS modules were completed electronically in their computer adaptive form. Mean population scoring on each module is defined at 50. Patients were also asked to rate their pain on a 0 to 10 scale. These data were collected as routine clinical care and were extracted from the electronic health record for cross-sectional evaluation. Bivariate Pearson correlation analysis defined the association between the PROMIS modules and the numerical pain scores. Correlations between PF and PI were compared with correlations between PF and pain scores. RESULTS: We recorded data from patients' 10,574 first, 5,210 second, 2,633 third, 1,382 fourth, and 722 fifth visits. The PROMIS PI was negatively correlated to the PROMIS PF. Numerical pain scores were also negatively correlated to PROMIS PF. Numerical pain scores were less correlated than PROMIS PI through time relative to PF. CONCLUSIONS: Both PROMIS PI and numerical pain scores had significant correlations with PF for each office visit. The PI had a larger correlation to PF than did numerical pain scores. The PI and numerical pain scale scores are also correlated. CLINICAL RELEVANCE: Patient-reported pain using a 0 to 10 pain score can be a predictor of patients' level of function, and although pain score does not replace other patient-reported outcomes, it can provide useful information, particularly when other patient-reported outcomes are not available. PMID- 28709797 TI - Smoldering Multiple Myeloma: Who and When to Treat. AB - Smoldering multiple myeloma (SMM) is an asymptomatic plasma cell disorder characterized by the presence of >= 3 g/dL serum M-protein and/or 10% to 60% bone marrow plasma cell infiltration with no myeloma-defining event. The risk of progression to active multiple myeloma (MM) is not uniform, and several markers are useful for identifying patients at high risk of progression. The definition of the disease has recently been revisited and asymptomatic MMs at 80% to 90% of progression risk at 2 years are now considered to be active MM candidates for treatment. In the future, more precise biomarkers are necessary for accurate risk stratification to plan an optimized follow-up according to the risk of progression, as well as to expand the group of patients that can obtain a benefit if they receive early treatment. A phase 3, randomized trial in high-risk patients with SMM comparing early treatment versus observation has shown a significant benefit in terms of time to progression and overall survival for early intervention and confirmatory clinical trials will definitively contribute to establish the early treatment as standard of care in high-risk SMM. PMID- 28709798 TI - Risk of Second Primary Malignancies in Patients With Follicular Lymphoma: A United States Population-based Study. AB - BACKGROUND: With the improving outcomes of patients with follicular lymphoma (FL), it is imperative to focus on survivorship issues, including the development of second primary malignancies (SPMs). We used a large US database to measure the risk of SPMs among FL survivors. MATERIALS AND METHODS: We used the Surveillance, Epidemiology, and End Results-13 registry to identify FL patients from 1992 to 2011. We calculated the risk of SPMs, developing >= 6 months after diagnosis, using the standardized incidence ratio (SIR) and absolute excess risk. We calculated the cumulative incidence of SPMs using the competing risk method and risk factors for SPMs using univariate and multivariate methods. RESULTS: Of a total of 15,517 patients with FL followed up for a median of 71 months, 1540 (9.9%) developed SPMs, with a SIR of 1.08 and absolute excess risk of 11.3 per 10,000 person-years. A significantly increased risk was noted for Hodgkin lymphoma (SIR, 5.85), acute myeloid leukemia (SIR, 4.88), and the following sites: oral cavity and pharynx (SIR, 1.43), stomach (SIR, 1.43), lung and bronchus (SIR, 1.35), melanoma of skin (SIR, 1.38), other nonepithelial cancers of the skin (SIR, 2.88), urinary bladder (SIR, 1.24), and kidney/renal pelvis (SIR, 1.43). The cumulative incidence of SPMs was 11.06% at 10 years. Multivariate regression showed that age > 65 years (SIR, 1.57; P < .001), male gender (SIR, 1.43; P < .001), and receipt of radiation (SIR, 1.24; P = .001) predicted a higher rate of SPMs. CONCLUSION: Patients with FL have increased risk of both hematologic and solid malignancies. Risk factors for SPMs include advanced age, male gender, and receipt of radiation therapy. PMID- 28709799 TI - Trough dabrafenib plasma concentrations can predict occurrence of adverse events requiring dose reduction in metastatic melanoma. AB - INTRODUCTION: Dabrafenib and trametinib bitherapy provides significant benefits in BRAFV600mut metastatic melanoma patients; however, adverse events (AE) occur, leading to dose reduction in 33% of patients. We aimed to investigate a relation between plasma dabrafenib and trametinib concentrations and occurrence of AE. METHODS: Plasma samples from metastatic BRAFV600mut melanoma patients treated with dabrafenib+/-trametinib were prospectively collected at trough concentration before any dose reduction. Dabrafenib and trametinib were measured by UPLC-MS/MS. Plasma threshold of concentration associated with dose reduction for AE was studied by ROC-curve analysis. RESULTS: Twenty-seven patients (13M/14F) were included. Dabrafenib trough plasma concentrations displayed high interindividual variability, ranging from 15.4 to 279.6ng/ml, mean+/-SD 58.7+/-61.1ng/ml. Trough trametinib plasma concentrations ranged from 4.1 to 23.8ng/ml, mean+/-SD 11.9+/ 4.1ng/ml. Mean trough dabrafenib plasma concentration was higher in patients with AE requiring dose reduction (30%) than in other patients: 118.6ng/ml and 33.5ng/ml respectively (P<0.0001). Adverse events leading to dabrafenib dose reduction were all grade>=2. No differences in mean trametinib trough plasma concentrations were observed in patients requiring or not dose reduction. A dabrafenib trough plasma threshold of 48ng/ml can predict the occurrence of adverse events requiring dose reduction. PMID- 28709800 TI - Detection of autoantibodies to 3-hydroxy-3-methylglutaryl-coenzyme a reductase by ELISA in a reference laboratory setting. AB - BACKGROUND: We investigated the performance of an ELISA for the detection of 3 hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) IgG antibodies in immune mediated necrotizing myopathies (IMNM). METHODS: Patients positive for HMGCR antibodies (n=61) or negative (n=78) by protein immunoprecipitation (IP), and healthy controls (n=100) were used to evaluate the ELISA. Unique consecutive serum samples (n=155) received at ARUP Laboratories for HMGCR IgG testing by ELISA were also investigated and analysed for serum muscle enzymes (aldolase, creatine kinase, and myoglobin). The ELISA's sensitivity, specificity, and percentage agreement were assessed relative to IP. Correlation between specific muscle enzyme concentration and the presence of HMGCR antibody was determined. RESULTS: Overall agreement between ELISA and IP was 93.4%. Using the IP as reference, the sensitivity and specificity of the ELISA was 95.1%, and 100%, respectively. Inter- and intra-assay coefficient of variation of the ELISA was <10.0%, and <=15.0%, respectively. In the consecutive cohort, 21 (13.6%) samples tested positive for HMGCR IgG. Concentrations of aldolase, creatine kinase, and myoglobin were significantly higher (all p<0.0001) in patients positive for HMGCR antibodies at the time of evaluation. CONCLUSIONS: We confirm significant reliability of HMGCR antibodies as measured by the ELISA for the evaluation of IMNM. PMID- 28709801 TI - Lymphatic Endothelial Cells Control Initiation of Lymph Node Organogenesis. AB - Lymph nodes (LNs) are strategically situated throughout the body at junctures of the blood vascular and lymphatic systems to direct immune responses against antigens draining from peripheral tissues. The current paradigm describes LN development as a programmed process that is governed through the interaction between mesenchymal lymphoid tissue organizer (LTo) cells and hematopoietic lymphoid tissue inducer (LTi) cells. Using cell-type-specific ablation of key molecules involved in lymphoid organogenesis, we found that initiation of LN development is dependent on LTi-cell-mediated activation of lymphatic endothelial cells (LECs) and that engagement of mesenchymal stromal cells is a succeeding event. LEC activation was mediated mainly by signaling through receptor activator of NF-kappaB (RANK) and the non-canonical NF-kappaB pathway and was steered by sphingosine-1-phosphate-receptor-dependent retention of LTi cells in the LN anlage. Finally, the finding that pharmacologically enforced interaction between LTi cells and LECs promotes ectopic LN formation underscores the central LTo function of LECs. PMID- 28709802 TI - Human Secretory IgM Emerges from Plasma Cells Clonally Related to Gut Memory B Cells and Targets Highly Diverse Commensals. AB - Secretory immunoglobulin A (SIgA) enhances host-microbiota symbiosis, whereas SIgM remains poorly understood. We found that gut IgM+ plasma cells (PCs) were more abundant in humans than mice and clonally related to a large repertoire of memory IgM+ B cells disseminated throughout the intestine but rare in systemic lymphoid organs. In addition to sharing a gut-specific gene signature with memory IgA+ B cells, memory IgM+ B cells were related to some IgA+ clonotypes and switched to IgA in response to T cell-independent or T cell-dependent signals. These signals induced abundant IgM which, together with SIgM from clonally affiliated PCs, recognized mucus-embedded commensals. Bacteria recognized by human SIgM were dually coated by SIgA and showed increased richness and diversity compared to IgA-only-coated or uncoated bacteria. Thus, SIgM may emerge from pre existing memory rather than newly activated naive IgM+ B cells and could help SIgA to anchor highly diverse commensal communities to mucus. PMID- 28709805 TI - Effect of diseases on symbiotic systems. AB - There are many species living in symbiotic communities. In this study, we analyzed models in which populations are in the mutualism symbiotic relations subject to a disease spreading among one of the species. The main goal is the characterization of symbiotic relations of coexisting species through their mutual influences on their respective carrying capacities, taking into account that this influence can be quite strong. The functional dependence of the carrying capacities reflects the fact that the correlations between populations cannot be realized merely through direct interactions, as in the usual predator prey Lotka-Volterra model, but also through the influence of each species on the carrying capacities of the other one. Equilibria are analyzed for feasibility and stability, substantiated via numerical simulations, and global sensitivity analysis identifies the important parameters having a significant impact on the model dynamics. The infective growth rate and the disease-related mortality rate may alter the stability behavior of the system. Our results show that introducing a symbiotic species is a plausible way to control the disease in the population. PMID- 28709804 TI - Identification of Natural Regulatory T Cell Epitopes Reveals Convergence on a Dominant Autoantigen. AB - Regulatory T (Treg) cells expressing the transcription factor Foxp3 are critical for the prevention of autoimmunity and the suppression of anti-tumor immunity. The major self-antigens recognized by Treg cells remain undefined, representing a substantial barrier to the understanding of immune regulation. Here, we have identified natural Treg cell ligands in mice. We found that two recurrent Treg cell clones, one prevalent in prostate tumors and the other associated with prostatic autoimmune lesions, recognized distinct non-overlapping MHC-class-II restricted peptides derived from the same prostate-specific protein. Notably, this protein is frequently targeted by autoantibodies in experimental models of prostatic autoimmunity. On the basis of these findings, we propose a model in which Treg cell responses at peripheral sites converge on those self-proteins that are most susceptible to autoimmune attack, and we suggest that this link could be exploited as a generalizable strategy for identifying the Treg cell antigens relevant to human autoimmunity. PMID- 28709803 TI - An Ocular Commensal Protects against Corneal Infection by Driving an Interleukin 17 Response from Mucosal gammadelta T Cells. AB - Mucosal sites such as the intestine, oral cavity, nasopharynx, and vagina all have associated commensal flora. The surface of the eye is also a mucosal site, but proof of a living, resident ocular microbiome remains elusive. Here, we used a mouse model of ocular surface disease to reveal that commensals were present in the ocular mucosa and had functional immunological consequences. We isolated one such candidate commensal, Corynebacterium mastitidis, and showed that this organism elicited a commensal-specific interleukin-17 response from gammadelta T cells in the ocular mucosa that was central to local immunity. The commensal specific response drove neutrophil recruitment and the release of antimicrobials into the tears and protected the eye from pathogenic Candida albicans or Pseudomonas aeruginosa infection. Our findings provide direct evidence that a resident commensal microbiome exists on the ocular surface and identify the cellular mechanisms underlying its effects on ocular immune homeostasis and host defense. PMID- 28709806 TI - The sugar code: Why glycans are so important. AB - The cell surface is the platform for presentation of biochemical signals that are required for intercellular communication. Their profile necessarily needs to be responsive to internal and external factors in a highly dynamic manner. The structural features of the signals must meet the criterion of high-density information coding in a minimum of space. Thus, only biomolecules that can generate many different oligomers ('words') from few building blocks ('letters') qualify to meet this challenge. Examining the respective properties of common biocompounds that form natural oligo- and polymers comparatively, starting with nucleotides and amino acids (the first and second alphabets of life), comes up with sugars as clear frontrunner. The enzymatic machinery for the biosynthesis of sugar chains can indeed link monosaccharides, the letters of the third alphabet of life, in a manner to reach an unsurpassed number of oligomers (complex carbohydrates or glycans). Fittingly, the resulting glycome of a cell can be likened to a fingerprint. Conjugates of glycans with proteins and sphingolipids (glycoproteins and glycolipids) are ubiquitous in Nature. This implies a broad (patho)physiologic significance. By looking at the signals, at the writers and the erasers of this information as well as its readers and ensuing consequences, this review intends to introduce a broad readership to the principles of the concept of the sugar code. PMID- 28709808 TI - Editorial Commentary: Important contributions of basic electrophysiology to the prevention and therapy of drug induced cardiac arrhythmias. PMID- 28709807 TI - Identification of a new B4GalNAcT1 (GM2/GD2/GA2 synthase) isoform, and regulation of enzyme stability and intracellular transport by arginine-based motif. AB - Glycosphingolipids (GSLs) are abundant in plasma membranes of mammalian cells, and their synthesis is strictly regulated in the Golgi apparatus. Disruption of GSL homeostasis is the cause of numerous diseases. Hundreds of molecular species of GSLs exist, and the detailed mechanisms underlying their homeostasis remain unclear. We investigated the physiological significance of isoform production for beta1,4-N-acetyl-galactosaminyl transferase 1/B4GALNT1 (B4GN1), an enzyme involved in synthesis of ganglio-series GSLs GM2/GD2/GA2. We discovered a new mRNA variant (termed variant 2) of B4GN1 through EST clone search. A new isoform, M1-B4GN1, which has an NH2-terminal cytoplasmic tail longer than that of previously-known isoform M2-B4GN1, is translated from variant 2. M1-B4GN1 has R based motif (a retrograde transport signal) in the cytoplasmic tail. M1-B4GN1 is partially localized in the endoplasmic reticulum (ER) depending on the R-based motif, whereas M2-B4GN1 is localized in the Golgi. Stability of M1-B4GN1 is higher than that of M2-B4GN1 because of the R-based motif. M2-B4GN1 forms a homodimer via disulfide bonding. When M1-B4GN1 and M2-B4GN1 were co-expressed in CHO-K1 cells, the two isoforms formed a heterodimer. The M1/M2-B4GN1 heterodimer was more stable than the M2-B4GN1 homodimer, but the heterodimer was not transported from the Golgi to the ER. Our findings indicate that stabilization of M1-B4GN1 homodimer and M1/M2-B4GN1 heterodimer by R-based motif is related to prolongation of Golgi retention, but not to retrograde transport from the Golgi to the ER. Coexistence of several B4GN1 isoforms having distinctive characteristics presumably helps maintain overall enzyme stability and GSL homeostasis. PMID- 28709809 TI - Editorial Commentary: Tuning in to sympathetic activity cutaneously in humans-A bench to bedside saga. PMID- 28709810 TI - Editorial Commentary: Optimization of dose selection for nonvitamin K antagonist oral anticoagulants. PMID- 28709811 TI - Arrhythmic risk stratification in non-ischemic dilated cardiomyopathy: Where do we stand after DANISH? AB - Publication of the DANISH randomized trial led to considerable debate, given that it demonstrated no survival benefit stemming from current implantable cardioverter-defibrillator (ICD) allocation criteria in patients with non ischemic dilated cardiomyopathy (NIDCM). Consequently, a thorough reconsideration of our approach to sudden cardiac death (SCD)-risk stratification appears to be in order. NIDCM encompasses a wide spectrum of disease entities, often with differing arrhythmogenicity; however, in its kernel, is still defined by the fundamentals of electrophysiology that dictate that abnormal tissue, exhibiting altered electrophysiological properties is necessary for arrhythmogenesis, but not enough, given that formation of functional circuits is required. In this review article, we will attempt a presentation of the current status in SCD-risk stratification in NIDCM and introduce the concept of multifactorial tiered approach, bringing together non-invasive indices of arrhythmic potential and programmed ventricular stimulation, as an alternative approach, in order to finally delineate a potential basis for the design and realization of trials necessary to achieve a paradigm shift and improvement in NIDCM SCD-risk stratification. PMID- 28709812 TI - Patent foramen ovale and cryptogenic stroke. AB - The presence of a patent foramen ovale (PFO) has been found to be associated with an increased risk of cryptogenic stroke in many case-control studies. This paper reviews the current understanding of the pathophysiology and diagnosis of PFO, and therapeutic options of patients with PFO and cryptogenic stroke. PMID- 28709813 TI - Editorial Commentary: Where do we stand after DANISH? It's tough to make predictions, especially about the future. PMID- 28709815 TI - Urgent need to implement transition programs. PMID- 28709814 TI - The therapeutic implication of a novel SCN2A mutation associated early-onset epileptic encephalopathy with Rett-like features. AB - Epileptic encephalopathies are highly heterogeneous and phenotypical disorders with different underlying genetic defects. Mutations in the SCN2A gene cause different epilepsy syndromes, including epilepsy of infancy with migrating focal seizures, Ohtahara syndrome, and West syndrome. We utilized a targeted next generation sequencing (NGS) approach on a girl with early-onset seizures and Rett like features, including autistic behavior, limited hand function with chorea, and profound intellectual disability, to identify novel missense mutation (c.1270G>A; p.V424M) in the SCN2A gene, which encodes the alphaII-subunit of the voltage-gated Na+ channel (Nav1.2). The identified SCN2A mutation responsible for the development of the disease is confirmed to be de novo for the proband. Our findings broaden the clinical spectrum of SCN2A mutations, which resembles clinical phenotypes of SCN1A mutations by manifesting as fever sensitive seizures, and highlights that SCN2A mutations are an important cause of early onset epileptic encephalopathies with movement disorders. In addition, the use of levetiracetam to treat SCN2A epileptic encephalopathy, when Na+ channel-blocking anticonvulsants are ineffective, is also recommended. PMID- 28709816 TI - [Current knowledge on perioperative treatments of non-small cell lung carcinomas]. AB - Surgery is still the main treatment in early-stage of non-small cell lung cancer with 5-year survival of stage IA patients exceeding 80%, but 5-year survival of stage II patients rapidly decreasing with tumor size, N status, and visceral pleura invasion. The major metastatic risk in such patients has supported clinical research assessing systemic or loco-regional perioperative treatments. Modern phase 3 trials clearly validated adjuvant or neo-adjuvant platinum-based chemotherapy in resected stage I-III patients as a standard treatment of which value has been reassessed several independent meta-analyses, showing a 5% benefit in 5y-survival, and a decrease of the relative risk for death around from 12 to 25%. Conversely perioperative treatments were not validated for stage IA and IB patients. In more advanced stage patients, neo-adjuvant radio-chemotherapy has not been validated either. Adjuvant radiotherapy for N2 patients is currently tested in the large international phase 3 trial Lung-ART/IFCT-0503. The development of video-assisted thoracic surgery (VATS) has helped adjuvant chemotherapies for elderly patients. Perioperative targeted treatments in NSCLC with EGFR or ALK molecular alterations is currently assessed in the U.S. ALCHEMIST prospective trial. Finally, the role of immune check-points inhibitors is currently evaluated in a large international phase 3 trial testing adjuvant anti-PD-L1 monoclonal antibody, the BR31/IFCT-1401 trial, while a proof-of principle neo-adjuvant trial IONESCO/IFCT-1601, has just begun by the end of the 2016 year, with survival results of both trials expected in 5 to 7 years. PMID- 28709817 TI - Evaluation of a Guidelines-Based Approach to the Treatment of Chronic Spontaneous Urticaria. AB - BACKGROUND: International scientific associations have made recommendations for the management of chronic spontaneous urticaria (CSU) that have been summarized in clinical guidelines. OBJECTIVE: To evaluate the clinical impact of guideline recommendations for CSU management. METHODS: A multicenter, triple-blinded, prospective, randomized study (the Urticaria Research of Tropical Impact and Control Assessment project; ClinicalTrials.gov identifier: NCT01940393) was performed. Patients older than 12 years and diagnosed with CSU were recruited and treated according to the European Academy of Allergy and Clinical Immunology/Global Allergy and Asthma European Network/European Dermatology Forum/World Allergy Organization guideline recommendations. The Dermatology Quality of Life Index (DLQI) was assessed every 2 weeks. As a first line of treatment, patients received a daily oral dose of antihistamine. After 4 weeks, in those patients without clinical response (DLQI <= 5), a higher dose (up to 4 times) of antihistamine was administered as a second line of therapy. After 2 months of follow-up, unresponsive patients received omalizumab or cyclosporine (as add-on therapy) for 4 months as a third line of treatment. RESULTS: One hundred fifty patients were enrolled. After the first line of treatment, 88 patients (58.7%) reached a DLQI of 5 or less. With the second line of treatment, disease control rate was 76.7%. With the third line, 12 patients from the omalizumab group (8%) and 11 patients from the cyclosporine group (7.3%) reached a good clinical control (additional 15.3%). Control rate with line 1 treatment was superior at 1 month than at 2 weeks (P < .0001). CONCLUSIONS: The application of these guideline recommendations for CSU led to a high rate of disease control, assessed by scoring severity and patients' perception of quality of life. These results support the usefulness of guideline recommendations. PMID- 28709818 TI - Are Allergen Immunotherapy Dose Adjustments Needed for Local Reactions, Peaks of Season, or Gaps in Treatment? PMID- 28709819 TI - Drivers of health care costs for adults with persistent asthma. PMID- 28709821 TI - The Mandarin version of the Kiddie-Schedule for Affective Disorders and Schizophrenia-Epidemiological version for DSM-5 - A psychometric study. AB - BACKGROUND/PURPOSE: Changes of diagnostic coverage and criteria for psychiatric disorders in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) published in 2013 cause a need for updating the Kiddie-Schedule for Affective Disorders and Schizophrenia-Epidemiological version (K-SADS-E). This study examined the preliminary psychometric properties, including inter rater reliability, and convergent and divergent validity of the modified K-SADS-E for DSM-5. METHODS: A national survey of a school-based sample of 3242 students in grade 3, 5, and 7 from 44 schools was conducted in Northern, Central, and Southern Taiwan. Psychiatric diagnoses were made by the K-SADS-E interviews. Clinical questionnaires for attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and emotional and behavioral problems were examined using the Chinese version of the Swanson, Nolan, and Pelham IV scale, Social Responsiveness Scale, and Child Behavior Checklist. RESULTS: The K-SADS-E showed satisfactory inter-rater reliability (prevalence adjusted bias adjusted kappa = 0.80-1.00) among eight interviewers. The diagnoses of K-SADS-E demonstrated good convergent and divergent validity with most corresponding clinical questionnaires. CONCLUSION: Our finding suggests that the K-SADS-E is a reliable and valid instrument for diagnosing child and adolescent psychiatric disorders based on DSM-5. Further study will examine the sensitivity, specificity, and test-retest reliability of the K-SADS-E in clinical and community samples. PMID- 28709820 TI - Sex-dependent difference in the relationship between adipose-tissue cholesterol efflux and estradiol concentrations in young healthy humans. AB - BACKGROUND: Impaired adipose tissue function and lower levels of high density lipoprotein cholesterol (HDL-C) have been implicated in the development of vascular dementia, and metabolic diseases such as hypertension, atherosclerosis, type 2 diabetes (T2D) and metabolic syndrome. Interestingly, both the substrate fluxes in adipose tissue and HDL-C concentration differ between men and women. Moreover, adipose tissue cholesterol efflux has been implicated in modulation of HDL-C levels. Thus, we aimed to determine if the association between serum estradiol levels and adipose tissue cholesterol efflux is sex-dependent. METHOD: We evaluated the serum estradiol levels and adipose tissue cholesterol efflux in young healthy men (n=5) and women (n=3). Adipose tissue cholesterol efflux was determined using subcutaneous microdialysis probes. Linear regression analyses were used to determine the relationship between the parameters, p<0.05 was considered as statistically significant. RESULTS: Our data demonstrated that serum estradiol levels directly associated with adipose tissue cholesterol efflux; however, the relationships may be sex-dependent. We discussed our results in the context of currently available data regarding sex-dependent variability in adipose tissue function and HDL-C metabolism as a potential contributor to higher rates of vascular dementia in men. Further research is required to understand the sex-dependent and -independent variabilities in adipose tissue metabolism to determine novel targets for interventions to prevent the development of vascular dementia. PMID- 28709822 TI - Occurrence of trigeminocardiac reflex during dental implant surgery: An observational prospective study. AB - BACKGROUND/PURPOSE: Trigeminocardiac reflex (TCR) is a clinical phenomenon that manifests as s sudden onset of hemodynamic perturbations. TCR has been reported in cranio-maxillofacial surgery resulting in severe medical risks. Monitoring the hemodynamic changes during cranio-maxillofacial surgery can provide important information to ensure the continuous evaluation of patient's physical conditions. This prospective observational study was conducted to determine the hemodynamic alterations related to the possibly of occurrence of TCR in patients during dental implant surgery. METHODS: One hundred and thirty-five patients (69 males and 66 females) received dental implant placement were enrolled in this study. The hemodynamic changes were evaluated by monitoring heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse oximetry (SpO2). The above data were collected before, during, and after dental implant surgery. RESULTS: The data demonstrated that the minimal values of HR, SBP, and DBP as well as MABP decreased significantly during operation comparing with the corresponding values before operation (p < 0.0001). In addition, HR and SBP decreased significantly in post-operation stage comparing with the corresponding values in pre-operation stage (p < 0.0001). Comparing to dental implant placement in the mandible, patients received dental implant placement in the maxilla had more risks to confront with MABP reduction (OR = 3.98; 95% confidence interval: 1.12-13.2). CONCLUSION: A significant HR and BP reduction possibly due to TCR can occur during dental implant surgery. Therefore, the dentists should monitor the hemodynamic changes during dental implant surgery to prevent the possible occurrence of medical risks related to TCR. PMID- 28709823 TI - Intracardiac foreign body resulting from a transmediastinal gunshot mimics an extracardiac foreign body: An image presentation. AB - A transmediastinal gunshot wound (TMGW) is one of the most severe traumatic injuries, with a high mortality rate. Prompt diagnosis and emergency surgical intervention with or without cardiopulmonary bypass are usually required to save lives. We report a particular case of TMGW in which the computed tomography imaging findings indicated an extracardiac foreign body. However, intraoperative findings revealed an intracardiac foreign body, and urgent cardiopulmonary bypass was performed to remove the foreign body. We suggest that cardiopulmonary bypass should be on standby during an exploratory sternotomy for TMGW, when the trajectory of the bullet hints at a cardiac-penetrating injury according to imaging studies and the location of the bullet remains unaffected by the patient's postural changes. PMID- 28709824 TI - Under-representation of certain disability groups by the American Community Survey (ACS). PMID- 28709825 TI - The Ambiguous Role of gammadelta T Lymphocytes in Antitumor Immunity. AB - gammadelta T cells play a role in immune surveillance because they recognize stress-induced surface molecules and metabolic intermediates that are frequently dysregulated in transformed cells. Hence, gammadelta T cells have attracted much interest as effector cells in cell-based immunotherapy. Recently, however, it has been realized that gammadelta T cells can also promote tumorigenesis through various mechanisms including regulatory activity and IL-17 production. In this review we outline both the pathways involved in cancer cell recognition and killing by gammadelta T cells as well as current evidence for their protumorigenic activity in various models. Finally, we discuss strategies to improve the tumor reactivity of gammadelta T cells and to counteract their protumorigenic activities, which should open improved perspectives for their clinical application. PMID- 28709826 TI - Synthesis, antioxidant and antiproliferative activities of 1,3,4-thiadiazoles derived from phenolic acids. AB - Two 2-amino-1,3,4-thiadiazoles containing phenolic hydroxyl groups were combined with different carboxylic acid chlorides giving sixteen amide derivatives with good antioxidant and antiproliferative potential. The compound 3'c with an adamantane ring displayed excellent DPPH radical scavenging activity and good cytotoxic activity against human acute promyelocytic leukemia HL-60 cells, while 1,3,4-thiadiazole 3'h with 4-chlorophenyl moiety was found to be the most effective in inhibition of survival of lung carcinoma A549 cells. All examined thiadiazoles except 3a and 3'a exerted higher cytotoxic activities on A549 and HL 60 cancer cells when compared with normal fibroblasts MRC-5, pointing to selectivity in their antiproliferative action. Some of the most active novel compounds 3c, 3'c, 3'g and 3'h induced significant increase in the percentage of HL-60 cells in the subG1 cell cycle phase in comparison with the control cells. The induction of cell death in HL-60 cells by these compounds was at least partially dependent on activation of caspase-3 and caspase-8. The compounds 3c and 3'c exerted strong antiangiogenic activity. Furthermore, compounds 3c, 3'c, 3'g and 3'h showed the ability to down-regulate the MMP2 and VEGFA expression levels in the treated HL-60 cells when compared with the control cell samples. PMID- 28709827 TI - 20(R)-Ginsenoside Rg3 protects SH-SY5Y cells against apoptosis induced by oxygen and glucose deprivation/reperfusion. AB - As shown in our previous studies, 20(R)-ginsenoside Rg3 [20(R)-Rg3] exerts a neuroprotective effect on a rat model of transient focal cerebral ischemia, and the mechanism through which it decreases the mRNA expression of calpain I and caspase-3 has been delineated. However, researchers do not know whether 20(R)-Rg3 exhibits a neuroprotective effect following oxygen-glucose deprivation and reperfusion (OGD/R) injury in vitro. In the present study, 20(R)-Rg3 increased cell viability, decreased the LDH leakage rate, and inhibited the apoptosis rate in a concentration-dependent manner. In addition, 20(R)-Rg3 markedly decreased cleaved caspase-3 protein expression. Furthermore, 20(R)-Rg3 significantly decreased the Bax mRNA and protein levels and increased the levels of Bcl-2 mRNA and protein, subsequently decreasing the Bax/Bcl-2 protein ratio. Based on these findings, 20(R)-Rg3 exerts a neuroprotective effect against OGD/R-induced apoptosis. PMID- 28709828 TI - Augmenting the efficacy of anti-cocaine catalytic antibodies through chimeric hapten design and combinatorial vaccination. AB - Given the need for further improvements in anti-cocaine vaccination strategies, a chimeric hapten (GNET) was developed that combines chemically-stable structural features from steady-state haptens with the hydrolytic functionality present in transition-state mimetic haptens. Additionally, as a further investigation into the generation of an improved bifunctional antibody pool, sequential vaccination with steady-state and transition-state mimetic haptens was undertaken. While GNET induced the formation of catalytically-active antibodies, it did not improve overall behavioral efficacy. In contrast, the resulting pool of antibodies from GNE/GNT co-administration demonstrated intermediate efficacy as compared to antibodies developed from either hapten alone. Overall, improved antibody catalytic efficiency appears necessary to achieve the synergistic benefits of combining cocaine hydrolysis with peripheral sequestration. PMID- 28709829 TI - Aging, rule-violation checking strategies, and strategy combination: An EEG study in arithmetic. AB - In arithmetic, rule-violation checking strategies are used while participants solve problems that violate arithmetic rules, like the five rule (i.e., products of problems including five as an operand end with either five or zero; e.g., 5*14=70) or the parity rule (i.e., when at least one of the two operands is even, the product is also even; otherwise the product is odd; e.g., 4*13=52). When problems violate both rules, participants use strategy combination and have better performance on both-rule than on one-rule violation problems (i.e., five or parity rule). Aging studies found that older adults efficiently use one-rule violation checking strategies but have difficulties to combine two strategies. To better understand these aging effects, we used EEG and found important age related changes while participants used rule-violation checking strategies. We compared participants' performance while they verified arithmetic problems that differ in number and type of violated rule. More specifically, both-rule violation problems elicited larger negativity than one-rule violation problems between 600 and 800ms. Five-rule violation problems differed from parity-rule violation problems between 1100 and 1200ms. Moreover, rule-violation checking strategies and strategy combination involved delta, theta, and lower alpha frequencies. Age-related changes in ERPs and frequency were associated with less efficient strategy combination. Moreover, efficient use of one-rule violation checking strategies in older adults was associated with changes in ERPs and frequency. These findings contribute to further our understanding of age-related changes and invariance in arithmetic strategies, and in combination of arithmetic strategies. PMID- 28709831 TI - Clinical impact of JOABPEQ mental health scores in patients with low back pain: Analysis using the neuropathic pain screening tool painDETECT. AB - BACKGROUND: In patients with low back pain (LBP) who combine psychosocial factors with clinical findings of pain, there is a possibility that the psychosocial factors modify the pain. In the current study, we investigated the relationship between the Japanese Orthopaedic Association Back Pain Evaluation Questionnaire (JOABPEQ) mental health score and the characteristics of LBP. METHODS: Of 650 patients with LBP, 319 were excluded, leaving 331 patients included in this study. All patients between the ages of 20 and 79 were asked to complete a set of questionnaires including the Japanese version of the painDETECT (PDQ-J), Numeric Rating Scale (NRS), the JOABPEQ, and the Short Form 36 (SF-36). Based on their JOABPEQ mental health scores, the patients were divided into two groups: those with JOABPEQ mental health score of <50 were classified as low score group, and those scoring >=50 were classified as the high score group. To identify any differences between the two groups, age, sex, PDQ-J score, NRS score, duration of symptoms, percentage of pain components, percentage of lower limb symptoms and self-reported general health were compared. RESULTS: 196 patients (59.2%) were classified into the low score group, and 135 (40.8%) into the high score group. The mean PDQ-J and NRS scores and percentage of LBP patients with neuropathic pain and lower limb symptoms were higher in the low score group. We also evaluated the relationship between lower limb symptoms and JOABPEQ mental health scores in 331 LBP patients. The results show that a significantly greater number of LBP patients in the low mental score group had lower limb symptoms compared to the high mental score group. CONCLUSION: We found that psychological factors may modify pain intensity and may lead to an exaggerated or histrionic presentation of the pain, or neuropathic LBP may be exacerbating psychological factors. PMID- 28709830 TI - Pathologic findings in breast, fallopian tube, and ovary specimens in non-BRCA hereditary breast and/or ovarian cancer syndromes: a study of 18 patients with deleterious germline mutations in RAD51C, BARD1, BRIP1, PALB2, MUTYH, or CHEK2. AB - Germline BRCA mutations account for a significant proportion of genetic/familial risk of breast and ovarian cancer (GBOC) susceptibility, but a broader spectrum of GBOC susceptibility genes has emerged in recent years. Genotype-to-phenotype correlations are known for some established forms of GBOC; however, whether such correlations exist for less common GBOC variants is unclear. We reviewed our institution's experience with non-BRCA GBOC, looking specifically for trends in pathologic and clinical features. Eighteen women with deleterious germline mutations in RAD51C (5 patients), BARD1 (1 patient), BRIP1 (2 patients), PALB2 (3 patients), MUTYH (2 patients), or CHEK2 (5 patients) were identified between January 2011 and December 2016. Thirteen (72%) of 18 patients developed carcinoma of the breast, fallopian tube, or ovary, with 1 patient developing 2 separate primary neoplasms. Twelve (86%) of 14 tumors occurred in the breast. One (7%) arose in the fallopian tube and another (7%) arose in the ovary. Evidence of genotype-phenotype correlation was not identified. However, some data suggest that the type of alteration in select genes may influence tumor behavior and patient outcome. In our PALB2 mutation cohort, 2 patients with frameshift mutations led to early onset and rapid progression to stage IV breast cancer in contrast to stage IA breast cancer in 1 patient with a nonsense mutation. Despite no apparent genotype-phenotype trends, our data indicate that some loss-of function variants in PALB2 may lead to differences in tumor behavior and patient outcome. PMID- 28709832 TI - Relationship between patients in hospital affects recovery from total knee arthroplasty (TKA)-A prospective study. AB - BACKGROUND: The interaction between patients is rather important source of information about surgery and recovery. Patients always prefer particularly to compare themselves with others of relatively similar ability, opinion and situation. Exploration of patients' dyads, however, is rare and needs further elaboration as to the significance of fellow patients. This study was designed to determine in whether and how preoperative assignment affects TKA's results. METHODS: We assessed early post-operative outcomes in a cohort of 520 TKA patients. Preoperative, and postoperative outcome measures at 6-months following TKA were analyzed and compared between patients who were hospitalized with a roommate whose surgical status was either similar (preoperative) or dissimilar (postoperative) and whose type of surgery was either similar (TKA) or dissimilar (THA). Mean scores, and postoperative change in scores were calculated. Outcome measures evaluated included WOMAC, SF-36, patient affiliation, preoperative anxiety, expectation and analgesic consumption, length of hospital stay. RESULTS: patients were more willing to have serious conversations with roommates whose surgical status was dissimilar (postoperative) and whose type of surgery was similar (TKA). And their SF-36 and WOMAC scores to be significantly improved better. Besides, they were released from hospital more quickly and showed significantly less preoperative anxiety. CONCLUSIONS: We recommend implementation of an assignment policy that patients prior to TKA should be assigned into a postoperative roommate undergoing TKA as well. PMID- 28709833 TI - Anterior reduction and fusion for treatment of massive tear drop fracture of axis combining with inferior endplate serious traversed lesion: A retrospective study. AB - BACKGROUND: Tear drop fracture of axis represents a very small percentage of injuries of the cervical spine, but there is controversy about the treatment method for tear drop fracture of axis, especially when a large avulsed fragment is significant displacement, which combined with the inferior endplate serious traversed lesion of axis. OBJECTIVE: To evaluate the clinical outcome of anterior reduction, graft fusion of C2-3 and plate fixation in the management of massive tear drop fracture of axis combining with inferior endplate serious traversed lesion of axis. METHODS: There were 7 patients with a massive tear drop fracture of axis combining with inferior endplate serious traversed lesion. The avulsed ratio of inferior endplate of axis was 46.8 +/- 13.4%, the average angle of rotation of the avulsed fragment was 30.4 +/- 11.7, and the average displacement was 7.7 +/- 2.8 mm. The posterior displacement of axis body was observed with three patients. All patients underwent anterior reduction, graft fusion of C2-3 and plate fixation with high anterior cervical retropharyngeal approach. The follow-up ranges from 2 years to 5 years. RESULTS: In all cases, tear drop fracture was reduced completely, avulsed fragment got bony healing, and bone graft achieved bony fusion at C2-3. There were no local angle deformity and rotated deformity in all patients, and there were normal physiological lordosis and good stabilization of upper cervical spine. The neurological function of one patient with American Spine Injury Association (ASIA) impairment scale type D was improved to type E postoperatively. Six patients without neurological lesion had no neurological syndrome after operation. CONCLUSIONS: Anterior surgical procedures would be an effective treatment of massive tear drop fracture of axis combining with inferior endplate serious traversed lesion. Complete reduction, sufficient stabilization and normal physiological lordosis of upper cervical spine could be achieved postoperatively. PMID- 28709834 TI - Radiological degenerative changes in the distal radioulnar joint after ulnar shortening osteotomy in patients with idiopathic ulnar impaction syndrome: Analysis of factors affecting degenerative lesions. AB - PURPOSE: To identify factors influencing overall radiologic changes in the distal radioulnar joint after ulnar shortening osteotomy (USO) in patients with idiopathic ulnar impaction syndrome. MATERIALS AND METHODS: A total of 310 patients who had undergone USO between May 2007 and December 2013 were included in this retrospective case-control study. The patients were classified into two groups (with or without radiologic findings of new arthritic changes), after which the following factors were analyzed: 1) demographic factors; 2) radiologic aspects, including ulnar variance (UV), morphological DRUJ type (classified according to Tolat et al.), and union period after USO; and 3) operative aspects, including the triangular fibrocartilage complex degeneration type, use of a parallel double-blade saw, type of plate used for fixation, and plate position on the volar or dorsal ulnar surface. RESULTS: Group 1 (no arthritic changes) consisted of 243 patients, whereas Group 2 (arthritic changes) consisted of 67 patients. Univariate and multivariate analyses showed that the presence of lunate cystic changes, amount of shortening, and the union period were significantly associated with newly developed arthritic changes in the distal radioulnar joint (DRUJ) after USO. The morphological DRUJ type was not a significant factor. Arthritic changes were significantly more prevalent in patients with a shortening amount >4.5 mm and a union period <3.25 months. CONCLUSIONS: Radiologic arthritic changes after USO, were associated with the presence of cystic changes in the lunate, a shortening amount (>4.5 mm), and early bony union (<3.25 months). TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic level III. PMID- 28709835 TI - The antimicrobial peptide, human beta-defensin-1, potentiates in vitro osteoclastogenesis via activation of the p44/42 mitogen-activated protein kinases. AB - Previous studies have demonstrated increased expression and raised levels of human beta-defensin (hBD)-1 in gingival tissue and crevicular fluid of patients with chronic periodontitis and peri-implantitis, oral bone-resorbing diseases caused by enhanced osteoclastogenesis. Therefore, we aimed to investigate the effect of hBD-1 on osteoclast formation and function and to elucidate the involved signaling pathway in vitro. Human peripheral blood mononuclear cells (PBMCs) were first incubated with various doses of hBD-1 and cell viability was assayed by MTT. PBMCs were treated with macrophage-colony stimulating factor and receptor activator of nuclear factor kappa-B ligand (RANKL) in the presence or absence of non-toxic doses of hBD-1. In vitro osteoclastogenesis was analyzed by tartrate-resistant acid phosphatase (TRAP) staining, osteoclast-specific gene expression, and a resorption pit assay. Involvement of mitogen-activated protein kinases (MAPKs) was studied by immunoblotting and specific MAPK inhibitors. HBD-1 potentiated induction of in vitro osteoclastogenesis by RANKL, as shown by significantly increased number of TRAP-positive multinuclear cells and resorption areas on the dentin slices, and further up-regulated expressions of osteoclast specific genes compared to those by RANKL treatment (p <0.05). However, hBD-1 treatment without RANKL failed to induce formation of osteoclast-like cells. A significant and further increase in transient phosphorylation of the p44/42 MAPKs was demonstrated by hBD-1 co-treatment (p<0.05), consistent with the inhibitory effect by pretreatment with U0126 or PD98059 on hBD-1-enhanced osteoclastogenesis. Collectively, hBD-1 potentiates the induction of in vitro osteoclastogenesis by RANKL via enhanced phosphorylation of the p44/42 MAPKs. PMID- 28709836 TI - Rupture and Release: A Role for Soluble Erythrocyte Content in the Pathology of Cerebral Malaria. AB - Cerebral malaria (CM) is the most severe form of malaria and causes high associated mortality. We propose a multistep process for CM pathology that is initiated by cytoadhesion of infected erythrocytes to the brain vasculature, followed by rupture and release of contents that complete the disruption of the blood-brain barrier. PMID- 28709837 TI - What are the possibilities of spontaneous resorption of a thoracic disc herniation occupying more than 20% of the spinal canal in the asymptomatic subject? Comparative study. AB - Thoracic disc herniation is a rare pathology for which surgical treatment is difficult. The discovery of asymptomatic or only slightly symptomatic lesions can be problematic, especially in cases of marked canal stenosis. The possibility of spontaneous resorption has been documented by a few case reports but there is no study on this subject. Our objective was to compare the clinical and radiological data for two groups of patients with significant thoracic herniation (occupying more than 20% of the spinal canal): one showing spontaneous resorption (group 1) and the other persistence of the lesion during follow up (group 2). The physiological processes of thoracic herniation are also discussed. We present a retrospective study of our database of patients with thoracic hernia. Only subjects who initially showed signs of slight or absent myelopathy (Frankel D or E) were included. Group 1 and 2 are composed of 12 and 17 patients respectively. The clinical and radiological data are compared. The two groups were not different for the following parameters: age, sex ratio, disc calcification, size, trajectory, side, hernia level. Other parameters were evaluated and were not associated with a higher rate of resorption: disc calcification, intramedullary hypersignal in T2 sequence, calcification of the posterior common vertebral ligament, calcification of another disc and Scheuerman's disease. Asymptomatic thoracic disc herniation is a condition that can disappear spontaneously, even in the case of a large lesion. To date, there are no clinical or radiological data that can predict such an evolution. PMID- 28709838 TI - Characteristics of scrub typhus, murine typhus, and Q fever among elderly patients: Prolonged prothrombin time as a predictor for severity. AB - BACKGROUND/PURPOSE: The clinical manifestations of scrub typhus, murine typhus and acute Q fever in the elderly are not clear. METHODS: We conducted a retrospective study to identify the characteristics of the elderly aged >=65 years with a comparison group aged 18-64 years among patients with scrub typhus, murine typhus, or acute Q fever who were serologically confirmed at three hospitals in Taiwan during 2002-2011. RESULTS: Among 441 cases, including 187 cases of scrub typhus, 166 acute Q fever, and 88 murine typhus, 68 (15.4%) cases were elderly patients. The elderly had a higher severe complication rate (10.3% vs. 3.5%, p = 0.022), but did not have a significantly higher mortality rate (1.47% vs. 0.54%, p = 0.396). Compared with those without severe complications, we found the elderly (p = 0.022), dyspnea (p = 0.006), less relative bradycardia (p = 0.004), less febrile illness (p = 0.004), prolonged prothrombin time (PT) (p = 0.002), higher levels of initial C-reactive protein (p = 0.039), blood leukocyte counts (p = 0.01), and lower platelet counts (p = 0.012) are significantly associated with severe complications. Only prolonged prothrombin time was associated with severe complications in multivariate analysis (p = 0.018, CI 95% 0.01-0.66). Among clinical symptoms and laboratory data, multivariate analysis revealed chills was less frequently occurred in the elderly (p = 0.012, 95% confidence interval [CI]: 1.33-9.99). CONCLUSION: The elderly cases with scrub typhus, murine typhus, or acute Q fever would be more likely to have severe complications, for which prothrombin time prolongation is an important predictor for severe complications. PMID- 28709839 TI - Fungal immunomodulatory protein-fve could modulate airway remodel through by affect IL17 cytokine. AB - BACKGROUND: Asthma is one of the most common allergic diseases. Our previous studies have reported that FIP-fve in acute allergic mouse model can reduce inflammation, improve the balance of the Th1/Th2 system. However, the effects of reducing airway remodeling on FIP-fve is still unknown. OBJECTIVE: We hypothesized that orally administrated FIP-fve should be able to reduce airway remodeling in chronic allergic models. METHODS: The chronic asthma animal model was established with 6-8 weeks female Balb/c mice. After intranasal challenges with OVA, the airway inflammation and AHR were determined by a BUXCO system. BALF was analyzed with Liu's stain and ELISA assay. Lung histopathologic changes and Collagen deposition were assayed with H&E, Masson's trichrome and IHC stain. RESULTS: FIP-fve significantly decreased the number of infiltrating inflammatory cells and Th2 cytokines and increased Th1 cytokines in BALF and serum compared with the OVA sensitized mice. FIP-fve had a better effect than corticosteroid could reduce infiltrating cells in lung especially neutrophils and eosinophils. We also found that the oral FIP-fve group suppressed IL-17 and enhanced IL-22 in the serum and BALF. In addition, oral FIP-fve decreased MMP9 expression, collagen expression and airway remodeling in lung tissues. CONCLUSION: FIP-fve had anti inflammatory effects on OVA-induced airway inflammation and an effect to inhibited Th17 cells to reduced airway remodeling and collagen expression. Moreover, FIP-fve might be a potential alternative therapy for allergic airway diseases. PMID- 28709840 TI - Rapidly progressive glomerulonephritis due to coexistent anti-glomerular basement membrane and anti-myeloperoxidase antibody. PMID- 28709841 TI - Characterization of susceptibility variants of poliovirus grown in the presence of favipiravir. AB - BACKGROUND: T-705 (favipiravir) is a potent inhibitor of RNA-dependent RNA polymerases of influenza viruses and no favipiravir-resistant virus has been isolated. Poliovirus RNA polymerase has been well characterized and isolation of resistant virus was examined in poliovirus. METHODS: Susceptibility variants of poliovirus I (Sabin strain) were isolated during passages in the presence of favipiravir and characterized for their susceptibility and the sequence of RNA polymerase. RESULTS: Five variants with 0.47-1.88 times the 50% inhibitory concentration for plaque formation of the parent poliovirus had amino acid variations in the 3D gene of the RNA polymerase. The distribution of amino acid variations was not related to ribavirin resistance, and two amino acid variation sites were found near the finger domain. CONCLUSION: Favipiravir as a chain terminator would not be incorporated and replicate to cause lethal mutagenesis as a mutagen like ribavirin, and resistant mutants were not isolated. A high replication level would generate mutations leading to favipiravir resistance as ribavirin resistance was generated, but generated mutations would be lethal to the RNA polymerase function. PMID- 28709842 TI - What compatibility in 2017 for the haematopoietic stem cell transplantation? AB - The diversification of potential donors to perform stem cell allografts now enables to propose a compatible graft cell source adapted to the different clinical situations. Transplants with a geno-identical sibling donor, otherwise with the most HLA-compatible unrelated donor, remain the first-line solutions. Alternative transplants allow to graft patients having no donors in international registries, owing to the rarity of their HLA typing. They are carried out with fairly incompatible grafts and are therefore limited by the existence in the recipient of preformed anti-HLA antibodies which predispose to their rejection. The simple prevention of acute Graft-versus-host disease in haplo-identical transplants, as well as the availability of donors, explain why they have very often replaced placental stem cell transplants. These latter remain useful for pediatric patients or in the absence of family donors. PMID- 28709843 TI - [Safety management and compliance with rules]. AB - The design of rules (laws, norms, policies, procedures, protocols) and the implementation of a management that aimed at conforming the behaviors of operators with these rules has long been the dominant approach to improve safety in socio-technical systems. This approach has proven to be effective in enhancing safety by enabling organizations to cope with predictable risks and failures. However, in our modern and constantly evolving socio-technical systems, where the management of unforeseen situation has become the rule, this approach has shown its limitations: operators' initiatives, which sometimes deviate from rules, are equally important for maintaining safety. Therefore, while the rules remain a key feature of risk management, the challenge is not the search for total compliance with rules, but the permanent monitoring of their use to detect and distinguish gaps that constitute a drift towards the accident from gaps that highlight that the rule has become inappropriate and which the compliance with may prove dangerous for safety. PMID- 28709844 TI - [Transfusion and its specific problems in pediatrics and neonatology]. AB - Principles of transfusion strategy have been used for neonates and children similar to adults. However, due to substantial discrepancies between physiology/pathology in children and in their adult counterparts, decisions, indications, and doses are different from those of adults, especially in neonates. Specific data and practice guidelines for blood product transfusion are reported owing to the experience of pediatrics and neonatology units and partners of the French Blood product bank. PMID- 28709845 TI - Fifteen years of Nucleic Acid Testing in France: Results and lessons. AB - Of the 40 million donations screened with Nucleic acid testing (NAT) between July 2001 and December 2015 in France, 20 HIV-positive, 13 HCV-positive and 17 HBV (HBV-NAT was initiated in 2005 and extended to the whole country in 2010) donations were discarded thanks to NAT. The main benefit in terms of discarded donations is related to HBV with a yield of 0.88 per million donations, which is 12.5 and 1.8 times higher than for HCV and HIV respectively. The main risk factor found in these donors during the post donation interview was having sex with men for males (n=11, all repeat blood donors), having a partner HCV positive (n=6) or at-risk partner (originated from endemic area or HBV positive) for HBV (n=8) for HIV, HCV and HBV, respectively. Although the mean viral load was high for HIV (5.6 log copies/mL) and HCV (7 log IU/mL), HBV cases show low level of DNA (1.8 log IU/mL) demonstrating the need of a highly sensitive NAT assay. Overall, the clinical benefit for recipients remains those related to the prevention of HIV contaminations since HCV avoided transmissions are extremely rare (only one case in the last 5 years thanks to NAT) and the potential infectivity of HBV-NAT only positive cases is questionable due to the low level of HBV DNA and the presence of anti-HBs in more than a half of DNA positive/HBsAg and anti-HBc negative donors. PMID- 28709846 TI - Biocatalysis for the synthesis of pharmaceuticals and pharmaceutical intermediates. AB - Biocatalysis has been increasingly used for pharmaceutical synthesis in an effort to make manufacturing processes greener and more sustainable. Biocatalysts that possess excellent activity, specificity, thermostability and solvent-tolerance are highly sought after to meet the requirements of practical applications. Generating biocatalysts with these specific properties can be achieved by either discovery of novel biocatalysts or protein engineering. Meanwhile, chemoenzymatic routes have also been designed and developed for pharmaceutical synthesis on an industrial scale. This review discusses the recent discoveries, engineering, and applications of biocatalysts for the synthesis of pharmaceuticals and pharmaceutical intermediates. Key classes of biocatalysts include reductases, oxidases, hydrolases, lyases, isomerases, and transaminases. PMID- 28709847 TI - Topographical projections from the nucleus basalis magnocellularis (Meynert) to the frontal cortex: A voltage-sensitive dye imaging study in rats. AB - BACKGROUND: The nucleus basalis magnocellularis/Meynert (NBM) has been explored as a new target for deep brain stimulation for neurological disorders. Although anatomical studies suggest the existence of cholinergic topographical projections of the NBM, it is still unknown whether NBM subregions differentially activate the frontal cortex. OBJECTIVE: To investigate the topography between the NBM and frontal cortex. METHODS: Electrical stimulation was applied to the anterior and posterior sites of the NBM in rats, and the evoked frontal activity was investigated using voltage-sensitive dye (VSD) imaging. RESULTS: VSD imaging revealed the functional topography of the NBM and frontal cortex: the anteroposterior axis of the NBM corresponded to the mediolateral axis of the dorsal frontal cortex. CONCLUSION: The present results suggest site-specific control of frontal neuronal activity by the NBM. These findings have practical implications, as the anterior and posterior parts of the NBM could be targeted to improve cognitive and motor function, respectively. PMID- 28709848 TI - Hydrogen sulfide alleviates placental injury induced by maternal cigarette smoke exposure during pregnancy in rats. AB - Maternal cigarette smoke exposure (CS) during pregnancy is a well recognized causative factor for placental injury. Hydrogen sulfide (H2S), a gaseous signal molecule, has been shown to exert a protective effect against tissue injury in many organs. This study aimed to investigate whether H2S could alleviate CS induced placental injury in rats. Pregnant SD rats were randomly divided into 4 groups: NaCl, CS, CS + NaHS (a donor of H2S) and NaHS. On gestational day 21, placental and fetal weights were measured. Placental H2S content was assessed by methylene blue method. Placental histological changes were examined by light microscopy and transmission electron microscopy. The results showed that administration of NaHS significantly attenuated CS-induced decrease in placental and fetal weights. Moreover, NaHS injection markedly alleviated CS-induced reduction in placental H2S content. Meanwhile, NaHS treatment obviously improved CS-induced morphological changes of placental junctional and labyrinthine zones. More notably, NaHS administration in CS rats was also found to ameliorate placental ultrastructural alterations, as indicated by decrease in the thickness of placental barrier, prevention of apical microvilli loss, alleviation of endoplasmic reticulum swelling and reduction in the number of vacuoles in trophoblast cells. Taken together, these findings demonstrate that administration of NaHS can alleviate CS-induced placental injuries in rats, suggesting that H2S may have therapeutic potential for treatment of placental injury caused by CS. PMID- 28709850 TI - WITHDRAWN: Removal of microcystins in water by ultrasound coupled advanced oxidation techniques. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our business/policies/article-withdrawal. PMID- 28709849 TI - Effects of Huperzin-A on the Beta-amyloid accumulation in the brain and skeletal muscle cells of a rat model for Alzheimer's disease. AB - AIMS: Alzheimer's Disease (AD) is characterized by a loss of cognitive function and also the accumulation of beta-amyloid peptide (betaAP) in the brain parenchyma, which plays an important role in this disease. However, it is often also associated with the non-cognitive symptoms such as loss of muscle function (Inclusion-Body Myositis-IBM). MAIN METHODS: Sprague-Dawley rats (13 weeks-n=68) were randomly assigned into five groups: Group C: Control; Group D: d-galactose; Group O+D: Bilateral oophorectomy+d-galactose; Group O: Bilateral oophorectomy; Group O+D+H: Bilateral oophorectomy+d-galactose+Hup-A. Tissue fixation was performed with the perfusion method. The Compound Muscle Action Potential (CMAP) and mechanical muscle activity were recorded using the standard electro biophysical techniques. Immune staining was performed with specific antibodies, and the pathological changes were examined. RNA was obtained from brain tissue samples with the Trizol Method. Then, the expression data of mature-miRNAs (rno miR-9-5p, rno-miR-29a-3p, rno-miR-106a-5p, rno-miR-107 and rno-miR-125a-3p), which may be effective in AD, were taken with Real-Time PCR. KEY FINDINGS: Impairments occurred in behavioral tests of the rats in the O+D group. betaAP accumulation and AChE activity increased significantly in the forebrain in the O+D group compared to the C group. It was seen that Huperzine-A (Hup-A) reduced AChE activity and destructed betaAP accumulation. There was a significant decrease in the maximum contractile force at different frequencies in the O+D group and in the O group compared to the C group. SIGNIFICANCE: It was found that Hup-A contributed to the healing process in rats for damage occurring both in the brain and in the neuro-muscular system. PMID- 28709851 TI - Waves of Change: National Trends in Surgical Management of Male Stress Incontinence. AB - OBJECTIVE: To determine the trend in surgical management of male stress urinary incontinence (SUI) in the context of the rate of radical prostatectomy (RP) as reported by a national database. Traditionally, the artificial urinary sphincter (AUS) has been the gold standard, but the male sling represents a newer and popular alternative. Refinements in prostate surgery may reduce the incidence and degree of subsequent SUI. MATERIALS AND METHODS: A retrospective cross-sectional analysis was performed using the National Inpatient Survey database, which captures discharge data from inpatient and overnight admissions. Cases were identified by their International Classification of Diseases, Ninth Revision procedure codes. We queried the codes 58.93 (implantation of AUS), 59.4 (suprapubic sling operation), 59.5 (retropubic urethral suspension), and 59.6 (paraurethral suspension). We also queried 60.5 (RP) for comparison. Data were collected from January 2000 to December 2012 and weighted to a national average using National Inpatient Survey guidelines. RESULTS: A total of 32,416 anti incontinence operations (20,790 AUS and 11,625 sling procedures) were performed over the study period. There was a significant downward trend in the total number of incontinence procedures (F(1,11) = 6.15, P = .03). However, when stratifying the data by procedure type, only AUS placement demonstrated a significant decline (F(1,11) = 21.70, P <.01), whereas sling procedures significantly increased (F(1,11) = 12.95, P <.01). There was no significant change in the annual incidence of RP. CONCLUSION: Inpatient surgery for male SUI is decreasing overall. Placement of the AUS declined significantly, whereas sling placement became more common. Future study will determine the etiology of these trends. PMID- 28709852 TI - Type 2 diabetes patients are more amenable to change following a contextualised diabetes education programme in Malaysia. AB - The aim of the study is to determine the impact of diabetes education on patients' glycaemic control. A prospective 18-month intervention study was conducted at four ambulatory diabetes centres. Poorly controlled type 2 diabetes patients attended an hour of structured diabetes education at their respective diabetes centres. A month post-intervention patients were contacted through telephone and followed up for 18 months. Anthropometric measurements and socio demographic details were collected during the first visit. HbA1C blood test for each patient was taken at beginning and end of study. Patients' diabetes knowledge showed 80% obtained Excellent or Very Good score. The Telephone Contact (TC) retention rate was 75.52% at 18 months. There was a significant improvement (p=0.001) in patients' glycaemic control with a reduction in HbA1C of >=1% from baseline. Diabetes education intervention contributed positively to significant glycaemic improvement and should be embedded within a structured diabetes care delivery system. PMID- 28709853 TI - Evaluation of current trends and recent development in insulin therapy for management of diabetes mellitus. AB - OBJECTIVE: Diabetes mellitus is a major health problem in developing countries. There are various insulin therapies to manage diabetes mellitus. This systematic review evaluates various insulin therapies for management of diabetes mellitus worldwide. This review also focuses on recent developments being explored for better management of diabetes mellitus. RESEARCH DESIGN AND METHOD: We reviewed a number of published articles from 2002 to 2016 to find out the appropriate management of diabetes mellitus. The paramount parameters of the selected studies include the insulin type & its dose, type of diabetes, duration and comparison of different insulin protocols. In addition, various newly developed approaches for insulin delivery with potential output have also been evaluated. RESULTS: A great variability was observed in managing diabetes mellitus through insulin therapy and the important controlling factors found for this therapy include; dose titration, duration of insulin use, type of insulin used and combination therapy of different insulin. CONCLUSION: A range of research articles on current trends and recent advances in insulin has been summarized, which led us to the conclusion that multiple daily insulin injections or continuous subcutaneous insulin infusion (insulin pump) is the best method to manage diabetes mellitus. In future perspectives, development of the oral and inhalant insulin would be a tremendous breakthrough in Insulin therapy. PMID- 28709855 TI - Subcutaneous edema in juvenile dermatomyositis. PMID- 28709854 TI - Development and psychometric evaluation of a new instrument to assess nutritional perceptions and behaviors of diabetic men. AB - BACKGROUND: It is obvious that unhealthy nutritional behaviors have caused the increasing incidence of diabetes. This study aimed to design the Measure of Nutritional Perceptions and Behaviors in diabetic men and to evaluate its psychometric properties. METHODS: A questionnaire was developed within 7 factors. Three methods of face validity, content validity, and construct validity were employed to ensure the validity of the scale. 206 men with diabetes completed the questionnaires. Internal was used to evaluate the reliability of the scale. RESULTS: The mean age of men was 58.26 (9.74) years. Results showed that each item in the final questionnaire was highly correlated with the total score of each dimension P<0.05. Moreover, factor analysis led to the extraction of 36 items with acceptable factor loadings in the range of 0.41 to 0.84, which could account for 51% of the total variance. The Cronbach's alpha coefficient equal to 0.83 was obtained for the whole scale. CONCLUSION: The reliability and validity of diabetic men's beliefs about healthy nutritional behaviors were desired and the overall structure of the questions was confirmed. This questionnaire can be used to identify individuals at risk for unhealthy nutritional behaviors and also to conduct and evaluate the impact of educational interventions. PMID- 28709856 TI - Developing smartphone apps for behavioural studies: The AlcoRisk app case study. AB - Smartphone apps have emerged as valuable research tools to sample human behaviours at their time of occurrence within natural environments. Human behaviour sampling methods, such as Ecological Momentary Assessment (EMA), aim to facilitate research that is situated in ecologically valid real world environments rather than laboratory environments. Researchers have trialled a range of EMA smartphone apps to sample human behaviours such as dieting, physical activity and smoking. Software development processes for EMA smartphones apps, however, are not widely documented with little guidance provided for the integration of complex multidisciplinary behavioural and technical fields. In this paper, the AlcoRisk app for studying alcohol consumption and risk taking tendencies is presented alongside a software development process that integrates these multidisciplinary fields. The software development process consists of three stages including requirements analysis, feature and interface design followed by app implementation. Results from a preliminary feasibility study support the efficacy of the AlcoRisk app's software development process. PMID- 28709858 TI - Malignant Pericardial Effusion as a Presentation of AIDS: The Role of Flow Cytometry in Early Diagnosis. PMID- 28709859 TI - Recurrent Cardiac Fibroelastoma. Is It Really a Benign Tumor? PMID- 28709860 TI - Chondrosarcoma: Extrinsic Compression of the Right Ventricle and Pericardial Effusion. PMID- 28709857 TI - Remodeling of the transverse tubular system after myocardial infarction in rabbit correlates with local fibrosis: A potential role of biomechanics. AB - The transverse tubular system (t-system) of ventricular cardiomyocytes is essential for efficient excitation-contraction coupling. In cardiac diseases, such as heart failure, remodeling of the t-system contributes to reduced cardiac contractility. However, mechanisms of t-system remodeling are incompletely understood. Prior studies suggested an association with altered cardiac biomechanics and gene expression in disease. Since fibrosis may alter tissue biomechanics, we investigated the local microscopic association of t-system remodeling with fibrosis in a rabbit model of myocardial infarction (MI). Biopsies were taken from the MI border zone of 6 infarcted hearts and from 6 control hearts. Using confocal microscopy and automated image analysis, we quantified t-system integrity (ITT) and the local fraction of extracellular matrix (fECM). In control, fECM was 18 +/- 0.3%. ITT was high and homogeneous (0.07 +/- 0.006), and did not correlate with fECM (R2 = 0.05 +/- 0.02). The MI border zone exhibited increased fECM within 3 mm from the infarct scar (30 +/- 3.5%, p < 0.01 vs control), indicating fibrosis. Myocytes in the MI border zone exhibited significant t-system remodeling, with dilated, sheet-like components, resulting in low ITT (0.03 +/- 0.008, p < 0.001 vs control). While both fECM and t-system remodeling decreased with infarct distance, ITT correlated better with decreasing fECM (R2 = 0.44) than with infarct distance (R2 = 0.24, p < 0.05). Our results show that t-system remodeling in the rabbit MI border zone resembles a phenotype previously described in human heart failure. T-system remodeling correlated with the amount of local fibrosis, which is known to stiffen cardiac tissue, but was not found in regions without fibrosis. Thus, locally altered tissue mechanics may contribute to t-system remodeling. PMID- 28709861 TI - Illuminating Insights Into Stent Thrombosis. PMID- 28709862 TI - 1st European Congress of Medical Physics September 1-4, 2016; Medical Physics innovation and vision within Europe and beyond. AB - Medical Physics is the scientific healthcare profession concerned with the application of the concepts and methods of physics in medicine. The European Federation of Organisations for Medical Physics (EFOMP) acts as the umbrella organization for European Medical Physics societies. Due to the rapid advancements in related scientific fields, medical physicists must have continuous education through workshops, training courses, conferences, and congresses during their professional life. The latest developments related to this increasingly significant medical speciality were presented during the 1st European Congress of Medical Physics 2016, held in Athens, September 1-4, 2016, organized by EFOMP, hosted by the Hellenic Association of Medical Physicists (HAMP), and summarized in the current volume. PMID- 28709863 TI - Dissociation and purification of the endogenous membrane-bound Vo complex from Pichia pastoris. AB - Most proteins occur and function in complexes rather than as isolated entities in membranes. In most cases macromolecules with multiple subunits are purified from endogenous sources. In this study, an endogenous membrane-protein complex was obtained from Pichia pastoris, which can be grown at high densities to significantly improve the membrane protein yield. We successfully isolated the membrane-bound Vo complex of V-ATPase from P. pastoris using a fusion FLAG tag attached to the C-terminus of subunit a to generate the vph-tag strain, which was used for dissociation and purification. After FLAG affinity and size exclusion chromatography purification, the production quantity and purity of the membrane bound Vo complex was 20 MUg l-1 and >98%, respectively. The subunits of the endogenous membrane-bound Vo complex observed in P. pastoris were similar to those obtained from S. cerevisiae, as demonstrated by liquid chromatography tandem mass spectrometry (LC-MS-MS). Therefore, successful dissociation and purification of the membrane-bound Vo complex at a high purity and sufficient quantity was achieved via a rapid and simple procedure that can be used to obtain the endogenous membrane-protein complexes from P. pastoris. PMID- 28709864 TI - The role of human natural killer-1 (HNK-1) carbohydrate in neuronal plasticity and disease. AB - BACKGROUND: The human natural killer-1 (HNK-1) carbohydrate, a unique trisaccharide possessing sulfated glucuronic acid in a non-reducing terminus (HSO3-3GlcAbeta1-3Galbeta1-4GlcNAc-), is highly expressed in the nervous system and its spatiotemporal expression is strictly regulated. Mice deficient in the gene encoding a key enzyme, GlcAT-P, of the HNK-1 biosynthetic pathway exhibit almost complete disappearance of the HNK-1 epitope in the brain, significant reduction of long-term potentiation, and aberration of spatial learning and memory formation. In addition to its physiological roles in higher brain function, the HNK-1 carbohydrate has attracted considerable attention as an autoantigen associated with peripheral demyelinative neuropathy, which relates to IgM paraproteinemia, because of high immunogenicity. It has been suggested, however, that serum autoantibodies in IgM anti-myelin-associated glycoprotein (MAG) antibody-associated neuropathy patients show heterogeneous reactivity to the HNK-1 epitope. SCOPE OF REVIEW: We have found that structurally distinct HNK 1 epitopes are expressed in specific proteins in the nervous system. Here, we overview the current knowledge of the involvement of these HNK-1 epitopes in the regulation of neural plasticity and discuss the impact of different HNK-1 antigens of anti-MAG neuropathy patients. MAJOR CONCLUSIONS: We identified the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptor subunit GluA2 and aggrecan as HNK-1 carrier proteins. The HNK-1 epitope on GluA2 and aggrecan regulates neural plasticity in different ways. Furthermore, we found the clinical relationship between reactivity of autoantibodies to the different HNK-1 epitopes and progression of anti-MAG neuropathy. GENERAL SIGNIFICANCE: The HNK-1 epitope is indispensable for the acquisition of normal neuronal function and can be a good target for the establishment of diagnostic criteria for anti MAG neuropathy. PMID- 28709865 TI - Overexpression of Pofut1 and activated Notch1 may be associated with poor prognosis in breast cancer. AB - PURPOSE: The present study was to evaluate the prognostic value of protein expression of Pofut1 and Notch1 signaling in breast cancer. MATERIAL AND METHODS: Formalin-fixed paraffin-embedded 314 breast specimens including 174 infiltrating ductal carcinoma(IDC), 50 ductal carcinoma in situ(DCIS) and 90 adjacent normal tissue(ANT) were immunohistochemically examined to evaluate the protein expression of Pofut1, activated Notch1(N1IC) and Slug on specimens. Survival analysis was performed by Kaplan-Meier method and Cox's proportional-hazards model. A online database was computationally used to further explore the prognostic role of Pofut1 and Notch1 mRNA expression by Kaplan-Meier Plotter. RESULTS: Pofut1, Slug and N1IC expression were significantly increased in IDC compared to ANT(all p < 0.05). High expression of Pofut1, Slug and N1IC were associated with tumor aggressiveness including lymph node metastasis (LNM: p = 0.005 for Pofut1, p < 0.001 for N1IC, p = 0.017 for Slug), advanced stage(p = 0.039 for Pofut1, p = 0.025 for N1IC) and higher histological grade(p = 0.001 for N1IC). Additionally, high expression of Pofut1 was found to be significantly associated with high expressions of N1IC and Slug in IDC(r = 0.244, p = 0.001; r = 0.374, p < 0.001, respectively), similar correlation was also observed between high N1IC and Slug expression(r = 0.496, p < 0.001). Moreover, Kaplan-Meier and Cox's regression analysis indicated the significant prognostic value of elevated Pofut1, N1IC, Slug expressions, positive LNM and advanced tumor stage for the prediction of a shorter disease-free survival (DFS) and overall survival(OS). The web-based analysis also suggested a significant association of high Pofut1 and Notch1 mRNA expression with worse survival outcome. CONCLUSION: Our findings suggested that overexpression of Pofut1 and activated Notch1 signaling may be associated with a poor prognosis in breast cancer. PMID- 28709866 TI - Mesenchymal stem cell transplantation carried in SVVYGLR modified self-assembling peptide promoted cardiac repair and angiogenesis after myocardial infarction. AB - The efficiency of stem cell therapy for myocardial infarction (MI) was very low due to the hostile microenvironment and poor blood perfusion. In this study, we designed a new self-assembling peptide through adding angiogenic polypeptide SVVYGLR to the carboxyl terminal of RADA16, and evaluated the therapeutic potential of mesenchymal stem cell (MSC) transplantation carried in this designer self-assembling peptide (DSP) on MI. After the model of cell ischemia and hypoxia was established in vitro, cytoprotective effect of DSP on MSC was detected by AO/EB staining. MI was induced by ligating of the left anterior descending artery in female SD rats. MSC from male rats was labled by GFP with adenovirus transfection. MSC with DSP (MSC-DSP) or without DSP (MSC) were transplanted at the border of the infarcted area. The number of survival cell was more and necrotic cell was less in DSP group than that in control group after ischemia and hypoxia treatment in vitro. At 4 weeks after cell transplantation, compared with the MSC group, improvement of cardiac function was better, infarct size was reduced, collagen content and the number of apoptotic cells was decreased, and there were more GFP or SRY positive cells in MSC-DSP group. Moreover, the number of CD31 or alpha-smooth muscle actin positive blood vessels in MSC-DSP group was significantly higher than that in MSC group. DSP not only provided a microenvironment for the survival of MSC, but also promoted the angiogenesis after transplantation. This study provided novel strategy and experimental evidence for the clinical application of biomaterials in stem cell transplantation for treatment of ischemic heart disease such as MI. PMID- 28709867 TI - Attenuation of the hypoxia-induced miR-34a protects cardiomyocytes through maintenance of glucose metabolism. AB - Ischemic injury in the heart is associated with death of cardiomyocytes and even after decades of research there is no appropriate therapeutic intervention to treat ischemic injury. The microRNA miR-34a is known to be induced in cardiomyocytes following ischemic injury. Another hallmark of ischemic injury is impaired glycolysis. The objective of the current study was to investigate the effects of short- and long-term exposure to hypoxia on miR-34a expression on apoptosis and regulation of key glycolysis metabolic enzymes. Both repeated short term (30 min) burst of hypoxia with intermittent reoxygenation (30 min) as well as long-term (4 h) exposure to hypoxia followed by 6 h of reoxygenation robustly induced miR-34a levels. Hypoxia induced changes in cardiac permeability and localization of the channel protein connexin 34 as well as induced apoptosis as evident by levels of cleaved-caspase 3/7 and impaired cell proliferation. Hypoxia was also associated with decreased expression of key glycolytic enzymes hexokinase-1, hexokinase-2, glucose-6-phosphate-isomerase, and pyruvate dehydrogenase kinase 1. Attenuation of hypoxia-induced miR-34a by anti-miR-34a antagomir, but not a control antagomir, decreased miR-34a levels to those observed under normoxia and also inhibited apoptosis, potentially by rescuing expression of the key glycolytic enzymes. Cumulatively, our results establish that therapeutic targeting of miR-34a via antagomir might be a potent therapeutic mechanism to treat ischemic injury in the heart. PMID- 28709868 TI - Protective effect of p53 on the viability of intervertebral disc nucleus pulposus cells under low glucose condition. AB - P53 is a famous cancer suppressor and plays key roles in metabolism. Intervertebral disc (IVD) is the largest avascular cartilaginous structure in humans and its degeneration is a common cause of spine diseases initiated from damaged nucleus pulposus (NP) cells. The potential cause of disc degeneration has been attributed to aging, genetic factors, mechanical factors and nutrition. In this study, we found that p53 decreased and leaked to the cytoplasm in NP cells as the glucose level decreases, in contrast to cancer cells in which p53 increases and concentrates to the nuclei. Comparing with in p53 knockdown NP cells, relative high p53 expression in normal control NP cells inhibited autophagy and the pentose phosphate pathway. Furthermore, the expression of Sox 9 and type II collagen were higher in p53 normal control than p53 knockdown NP cells. Based on these results, we believe that relative high p53 facilitates NP cell viability and integrity. PMID- 28709869 TI - Protective effect of bacillopeptidase CFR5 from Bacillus subtilis CFR5 on cerulein-induced pancreatitis. AB - Bacillopeptidase is a serine peptidase, known for its fibrinolytic activity. However, a very little information is known about its in vivo inflammatory and/or anti-inflammatory properties. Thus, to understand whether bacillopeptidase incorporation can regulate pancreatitis or not, the cerulein-induced pancreatitis model was used, and the role of bacillopeptidase on pancreatitis was studied. In this study, 46 kDa protein was purified from Bacillus subtilis and identified as bacillopeptidase CFR5 (BPC) through MS/MS analysis. The nutritional prophylactic group was orally fed with two doses of BPC (100 MUg/Kg/BW of rat) 6 h before cerulein administration and analyzed for its effect on intestine and pancreas inflammation, cytokines, and pancreatitis marker gene expression. BPC administration significantly reduced the severity of pancreatitis by decreasing serum amylase, lipase, pancreatic edema and myeloperoxidase activity. The pretreatment with BPC suppressed the pancreatic pro-inflammatory and inflammatory cytokines production including IL-6, IL-1beta, TNF-alpha, IL-2, IL-4, IL-5, IL 10, and IL-13 in both pancreas and serum samples. Moreover, BPC supplementation restored pancreatitis mediated disruption of intestinal barrier integrity by upregulating tight junction proteins (ZO-1, occludin), antimicrobial peptides (DEFB1, CRAMP), MUC-2, TFF3 expression and by enhancing SCFA's production. Pretreatment with BPC suppressed the intestinal inflammation with reduced cytokines production in the colon and ileal region of cerulein-induced pancreatitis. Thus, BPC based pretreatment protocol is a novel intervention to prevent acute pancreatitis. PMID- 28709870 TI - Astragaloside IV inhibits progression of glioma via blocking MAPK/ERK signaling pathway. AB - Glioma is one of the most common primary brain tumors in adults with a high mortality rate and relapse rate. Thus, finding better effective approaches to treat glioma has become very urgent. Astragaloside IV (AS-IV), the major active triterpenoid in Radix Astragali, has shown anti-tumorigenic properties in certain cancers. However, its role in glioma remains unclear. Here, we studied the effects of AS-IV on glioma in vitro and in vivo, and explored the underlying mechanisms. Our results revealed that AS-IV dose-dependently inhibited the proliferation of U251 cells in vitro and attenuated tumor growth in vivo. In addition, the migration and invasion ability of U251 cell has been suppressed in presence of AS-IV. The levels of proliferating cell nuclear antigen (PCNA), Ki67, matrix metallopeptidase (MMP) -2, MMP-9 and vascular endothelial growth factor (VEGF) were decreased significantly by the treatment of different concentrations AS-IV. Furthermore, AS-IV also significantly weakened the activation of Mitogen activated protein kinase/Extracellular regulated protein kinase (MAPK/ERK) signaling pathway in vitro and in vivo. Taken together our study has identified a novel function of AS-IV and provided a molecular basis for AS-IV potential applications in the treatment of glioma and other cancers. PMID- 28709871 TI - Protein-RNA complexation driven by the charge regulation mechanism. AB - Electrostatic interactions play a pivotal role in many (bio)molecular association processes. The molecular organization and function in biological systems are largely determined by these interactions from pure Coulombic contributions to more peculiar mesoscopic forces due to ion-ion correlation and proton fluctuations. The latter is a general electrostatic mechanism that gives attraction particularly at low electrolyte concentrations. This charge regulation mechanism due to titrating amino acid and nucleotides residues is discussed here in a purely electrostatic framework. By means of constant-pH Monte Carlo simulations based on a fast coarse-grained titration proton scheme, a new computer molecular model was devised to study protein-RNA interactions. The complexation between the RNA silencing suppressor p19 viral protein and the 19-bp small interfering RNA was investigated at different solution pH and salt conditions. The outcomes illustrate the importance of the charge regulation mechanism that enhances the association between these macromolecules in a similar way as observed for other protein-polyelectrolyte systems typically found in colloidal science. Due to the highly negative charge of RNA, the effect is more pronounced in this system as predicted by the Kirkwood-Shumaker theory. Our results contribute to the general physico-chemical understanding of macromolecular complexation and shed light on the extensive role of RNA in the cell's life. PMID- 28709872 TI - S-nitrosylation of the IGF-1 receptor disrupts the cell proliferative action of IGF-1. AB - The insulin-like growth factor 1 receptor (IGF-1R) is a disulfide-linked heterotetramer containing two alpha-subunits and two beta-subunits. Earlier studies demonstrate that nitric oxide (NO) can adversely affect IGF-1 action in the central nervous system. It is known that NO can induce S-nitrosylation of the cysteine residues in proteins, thereby partly contributing to the regulation of protein function. In the present study, we sought to determine whether S nitrosylation of the cysteine residues in IGF-1R is an important post translational modification that regulates its response to IGF-1. Using cultured SH-SY5Y human neuroblastoma cells as an in vitro model, we found that treatment of cells with S-nitroso-cysteine (SNOC), a NO donor that can nitrosylate the cysteine residues in proteins, induces S-nitrosylation of the beta subunit of IGF 1R but not its alpha-subunit. IGF-1Rbeta S-nitrosylation by SNOC is coupled with increased dissociation of the IGF-1R protein complex. In addition, disruption of the IGF-1R function resulting from S-nitrosylation of the IGF-1Rbeta subunit is associated with disruption of the phosphoinositide 3-kinase (PI3K) and mitogen activated protein kinase (MAPK) signaling pathways. Further, we observed that SNOC-induced IGF-1Rbeta S-nitrosylation results in a dose-dependent inhibition of cell proliferation and survival. Together, these results suggest that elevated nitrosative stress may result in dysfunction of cellular IGF-1R signaling through S-nitrosylation of the cysteine residues in the IGF-1Rbeta subunit, thereby disrupting the downstream PI3K and MAPK signaling functions and ultimately resulting in inhibition of cell proliferation and survival. PMID- 28709873 TI - Deregulation of WNT2/FZD3/beta-catenin pathway compromises the estrogen synthesis in cumulus cells from patients with polycystic ovary syndrome. AB - Mechanistic insight into estrogen deficiency by polycystic ovary syndrome (PCOS) remains a longstanding challenge in reproductive medicine. Recent advance suggest that Wingless-type MMTV integration site family members (WNTs), in concert with its Frizzled (FZD) receptors, regulate normal folliculogenesis, luteogenesis and ovarian steroidogenesis. However, no studies have so far investigated any causality between WNT-FZDs interactions and disrupted estrogen synthesis under certain pathological conditions. Here, we show that (i) FZD3 expression was significantly up-regulated in the cumulus cells (CCs) from PCOS patients. This up regulation, along with the activation of WNT2/beta-Catenin pathway, was tightly associated with insulin resistance and estrogen deficiency, two hallmarks of PCOS. (ii) Overexpression of exogenous FZD3 in human granulosa cell COV434 impaired long-term FSH incubation-induced CYP19A1 transactivation and the recruitment of beta-Catenin onto CYP19A1 promoter, and subsequently compromised FSH-stimulated estrogen production. (iii) Conversely, inhibition of FZD3 expression exhibited a therapeutic effect on estrogen synthesis in PCOS CCs. Thus, excessive FZD3 expression in CCs may act as a brake on steroidogenic activation that is normally overcome by FSH stimulation. Future endeavor in this field should help to elucidate the complicated crosstalk between energy metabolism and endocrine cells through WNT/FZD signaling molecules. PMID- 28709874 TI - Analysis of Hospital Readmissions After Prosthetic Urologic Surgery in the United States: Nationally Representative Estimates of Causes, Costs, and Predictive Factors. AB - BACKGROUND: The surgical treatment of urinary incontinence and erectile dysfunction by prosthetic devices has become part of urologic practice, although sparse data exist at a national level on readmissions and hospital costs. AIM: To assess causes and costs of early (<=30 days) and late (31-90 days) readmissions after implantation of penile prostheses (PPs), artificial urinary sphincters (AUSs), or PP + AUS. METHODS: Using the 2013 and 2014 US Nationwide Readmission Databases, sociodemographic characteristics, hospital costs, and causes of readmission were compared among PP, AUS and AUS + PP surgeries. Multivariable logistic regression models tested possible predictors of hospital readmission (early, late, and 90 days), increased hospital costs, and prolonged length of stay at initial hospitalization and readmission. OUTCOME: Outcomes were rates, causes, hospital costs, and predictive factors of early, late, and any 90-day readmissions. RESULTS: Of 3,620 patients, 2,626 (73%) had PP implantation, 920 (25%) had AUS implantation, and 74 (2%) underwent PP + AUS placement. In patients undergoing PP, AUS, or PP + AUS placement, 30-day (6.3% vs 7.9% vs <15.0%, P = .5) and 90-day (11.6% vs 12.8% vs <15.0%, P = .8) readmission rates were comparable. Early readmissions were more frequently caused by wound complications compared with late readmissions (10.9% vs <4%, P = .03). Multivariable models identified longer length of stay, Charlson Comorbidity Index score higher than 0, complicated diabetes, and discharge not to home as predictors of 90-day readmissions. Notably, hospital volume was not a predictor of early, late, or any 90-day readmissions. However, within the subset of high-volume hospitals, each additional procedure was associated with increased risk of late (odds ratio = 1.06, 95% CI = 1.03-1.09, P < .001) and 90-day (odds ratio = 1.03 95% CI = 1.02 1.05, P < .001) readmissions. AUS and PP + AUS surgeries had higher initial hospitalization costs (P < .001). A high hospital prosthetic volume decreased costs at initial hospitalization. Mechanical complications led to readmission of all patients receiving PP + AUS. CLINICAL IMPLICATIONS: High-volume hospitals showed a weaker association with increased initial hospitalization costs. Charlson Comorbidity Index, diabetes, and length of stay were predictors of 90 day readmission, showing that comorbidity status is important for surgical candidacy. STRENGTHS AND LIMITATIONS: This is the first study focusing on readmissions and costs after PP, AUS, and PP + AUS surgeries using a national database, which allows ascertainment of readmissions to hospitals that did not perform the initial surgery. Limitations are related to the limited geographic coverage of the database and lack of surgery- and surgeon-specific variables. CONCLUSIONS: Analysis of readmissions can provide better care for urologic prosthetic surgeries through better preoperative optimization, counseling, and resource allocation. Pederzoli F, Chappidi MR, Collica S, et al. Analysis of Hospital Readmissions After Prosthetic Urologic Surgery in the United States: Nationally Representative Estimates of Causes, Costs, and Predictive Factors. J Sex Med 2017;14:1059-1065. PMID- 28709875 TI - Bioelectrohydrogenesis and inhibition of methanogenic activity in microbial electrolysis cells - A review. AB - Microbial electrolysis cells (MECs) are a promising technology for biological hydrogen production. Compared to abiotic water electrolysis, a much lower electrical voltage (~0.2V) is required for hydrogen production in MECs. It is also an attractive waste treatment technology as a variety of biodegradable substances can be used as the process feedstock. Underpinning this technology is a recently discovered bioelectrochemical pathway known as "bioelectrohydrogenesis". However, little is known about the mechanism of this pathway, and numerous hurdles are yet to be addressed to maximize hydrogen yield and purity. Here, we review various aspects including reactor configurations, microorganisms, substrates, electrode materials, and inhibitors of methanogenesis in order to improve hydrogen generation in MECs. PMID- 28709876 TI - Is Cure Possible After Sequential Resection of Hepatic and Pulmonary Metastases From Colorectal Cancer? AB - BACKGROUND: Surgical resection is an established therapeutic strategy for colorectal cancer (CRC) metastasis. However, controversies exist when CRC liver and lung metastases (CLLMs) are found concomitantly or when recurrence develops after either liver or lung resection. No predictive score model is available to risk stratify these patients in preparation for surgery, and cure has not yet been reported. PATIENTS AND METHODS: All consecutive patients who had undergone surgery for CLLMs at our institution during a 20-year period were reviewed. Our policy was to propose sequential surgery of both sites with perioperative chemotherapy, if the strategy was potentially curative. Overall survival, disease free survival, and cure were evaluated. RESULTS: Sequential resection was performed in 150 patients with CLLMs. The median number of liver and lung metastases resected was 3 and 1, respectively. The median follow-up period was 59 months (range, 7-274 months). The median, 5-year, and 10-year overall survival was 76 months, 60%, and 35% respectively. CRC that was metastatic at the initial diagnosis (P = .012), a prelung resection carcinoembryonic antigen level > 100 ng/mL (P = .014), a prelung resection cancer antigen 19-9 level > 37 U/mL (P = .034), and an interval between liver and lung resection of < 24 months (P = .024) were independent poor prognostic factors for survival. The 5-year survival was significantly different for patients with <= 2 and >= 3 risk factors (77.3% vs. 26.5%). Of 75 patients with >= 5 years of follow-up data available from the first metastasis resection, 15 (20%) with disease-free survival >= 5 years were considered cured. The use of targeted therapy was the only independent predictor of cure. CONCLUSION: Curative-intent surgery provides good long-term survival and offers a chance of cure in select patients. Patients with <= 2 risk factors are good candidates for sequential resection. PMID- 28709877 TI - Impact of Duration of Neoadjuvant Radiation on Rectal Cancer Survival: A Real World Multi-center Retrospective Cohort Study. AB - BACKGROUND: The utility of neoadjuvant radiotherapy (nRT) for the treatment of stage II and III rectal cancer is well-established. However, the optimal duration of nRT in this setting remains controversial. Using a population-based cohort of patients with stage II and III rectal cancer (RC) treated with curative intent, our aims were to (1) examine the patterns of nRT use and (2) explore the relationship between different nRT schedules and survival in the real-world setting. METHODS: This is a multi-center retrospective cohort study based on population-based data from 5 regional comprehensive cancer centers in British Columbia, Canada. We analyzed patients diagnosed with clinical stage II or III RC from 2006 to 2010 and treated with either short-course (SC) or long-course (LC) nRT prior to curative intent surgery. Logistic regression models were constructed to determine the factors associated with the course of nRT delivered to patients. Kaplan-Meier methods and Cox regression that accounted for known prognostic factors were used to evaluate the relationship between nRT schedule and overall (OS), disease-free (DFS), local recurrence-free (LRFS), and distant recurrence free survival (DRFS). RESULTS: We identified 427 patients: the median age was 65 years (range, 31 to 94 years), 67% were men, 87% had T3 or T4 tumors, and 74% had N1 or N2 disease. Among them, 241 (56%) received SC and 186 (44%) received LC. Adjusting for confounders, patients with N1 or N2 disease were more likely to undergo LC (odds ratio [OR], 5.08; 95% confidence interval [CI], 2.51-11.22; P < .0001 and OR, 8.35; 95% CI, 3.35-22.39; P < .0001, respectively), whereas older age patients were less likely to receive LC (OR, 0.95; 95% CI, 0.94-0.98; P < .0001). In Kaplan-Meier analysis, there were no significant differences observed in OS, DFS, LRFS, and DRFS between SC and LC. Likewise, multivariate analyses demonstrated that OS (hazard ratio [HR], 0.91; 95% CI, 0.61-1.37; P = .66), DFS (HR, 1.06; 95% CI, 0.68-1.64; P = .80), LRFS (HR, 0.79; 95% CI, 0.39-1.57; P = .50) and DRFS (HR, 0.99; 95% CI, 0.60-1.61; P = .95) were similar regardless of nRT schedules. Additional baseline clinical and tumor characteristics did not influence outcomes (all P > .05). CONCLUSION: Appropriate preoperative selection of SC versus LC nRT for locally advanced RC based on patient and tumor characteristics was not associated with differences in survival outcomes in the real-world setting. PMID- 28709878 TI - Differential TBXA2 receptor transcript stability is dependent on the C924T polymorphism. AB - BACKGROUND: In order to better characterize the molecular mechanisms involved in processing mutated transcripts, we investigated the post-transcriptional role of the C924T polymorphism (rs4523) located in the 3' region of the TBXA2R gene. METHODS AND RESULTS: Experiments of dose response with Actinomycin D on MEG-01 human cell line showed a significant decrease on cell viability that was more evident on cells treated for 24h. In addition, we showed that treatments with 5 10MUM, 15MUM and 20MUM of actinomycin D reduced cell viability by 44%, 72% and 75%, respectively, compared to the control group. Conversely, the samples treated with 1MUM of actinomycin D did not show significant difference on cell viability as compared to the control group. Analysis of the steady state mRNA level of TBXA2R by qRT-PCR evidenced an increase in mRNA stability for the wild type (C) compared to the mutant (T) allele. Furthermore, the expression levels of TBXA2R on wild type (CC) and mutant type (TT) patients, based on C924T polymorphism, were analyzed. The wild type showed a higher expression of TBXA2 receptor also with two different degrees of glycosylation (55 and 64kDa), when compared to the mutant. These observations correlated with platelet aggregation, which was reduced in TT, independently of the platelet aggregation stimuli. CONCLUSIONS: The instability of the TBXA2R transcript and the lack of effect on platelet aggregation might suggest a protective role for the TBXA2R TT genotype against atherothrombosis and its complications in high-risk aspirin-treated patients. PMID- 28709879 TI - The neural bases of ictal tachycardia in temporal lobe seizures. AB - OBJECTIVE: Due to limited information from scalp electroencephalographic (EEG) recordings, brain areas driving changes in cardiac rhythm during Temporal lobe (TL) seizures are not clearly identified. Using stereotactic EEG (SEEG) recordings, we aimed at identifying which of the brain regions involved in autonomic control trigger ictal tachycardia. METHODS: The neural activity of several mesial temporal lobe structures including amygdala, hippocampus, insula, and lateral temporal lobe recorded with SEEG were collected during 37 TL seizures in 9 patients, using indices based on High Frequency Activity (HFA). R-R intervals (RR) monitoring and time-frequency spectral analysis were performed to assess parasympathetic (High frequency power (HF)) and sympathetic (Low frequency/High frequency (LF/HF) ratio) reactivities. RESULTS: Tachycardia was associated with a significant increase in LF/HF ratio and decrease in HF. Autonomic cardiac changes were accompanied by simultaneous SEEG signal changes with an increase in seizure-related HFA in anterior hippocampal formation and amygdala, but not in insula. CONCLUSION: In our sample, TL seizures are thus accompanied by an early decrease in parasympathetic control of cardiac rhythm and by an increase of sympathetic tone, concomitant to seizure activity in anterior hippocampus and amygdala. SIGNIFICANCE: These results support a pivotal role of hippocampus and amygdala in tachycardia occurring during TL seizures. PMID- 28709881 TI - Can Primary Care for Back and/or Neck Pain in the Netherlands Benefit From Stratification for Risk Groups According to the STarT Back Tool Classification? AB - OBJECTIVE: To evaluate whether current Dutch primary care clinicians offer tailored treatment to patients with low back pain (LBP) or neck pain (NP) according to their risk stratification, based on the Keele STarT (Subgroup Targeted Treatment) Back-Screening Tool (SBT). DESIGN: Prospective cohort study with 3-month follow-up. SETTING: Primary care. PARTICIPANTS: General practitioners (GPs) and physiotherapists included patients (N=284) with nonspecific LBP, NP, or both. INTERVENTIONS: Patients completed a baseline questionnaire, including the Dutch SBT, for either LBP or NP. A follow-up measurement was conducted after 3 months to determine recovery (using Global Perceived Effect Scale), pain (using Numeric Pain Rating Scale), and function (using Roland Disability Questionnaire or Neck Disability Index). A questionnaire was sent to the GPs and physiotherapists to evaluate the provided treatment. MAIN OUTCOME MEASURES: Prevalence of patients' risk profile and clinicians' applied care, and the percentage of patients with persisting disability at follow-up. A distinction was made between patients receiving the recommended treatment and those receiving the nonrecommended treatment. RESULTS: In total, 12 GPs and 33 physiotherapists included patients. After 3 months, we analyzed 184 patients with LBP and 100 patients with NP. In the LBP group, 52.2% of the patients were at low risk for persisting disability, 38.0% were at medium risk, and 9.8% were at high risk. Overall, 24.5% of the patients with LBP received a low-risk treatment approach, 73.5% a medium-risk, and 2.0% a high-risk treatment approach. The specific agreement between the risk profile and the received treatment for patients with LBP was poor for the low-risk and high-risk patients (21.1% and 10.0%, respectively), and fair for medium-risk patients (51.4%). In the NP group, 58.0% of the patients were at low risk for persisting disability, 37.0% were at medium risk, and 5.0% were at high risk. Only 6.1% of the patients with NP received the low-risk treatment approach. The medium-risk treatment approach was offered the most (90.8%), and the high-risk approach was applied in only 3.1% of the patients. The specific agreement between the risk profile and received treatment for patients with NP was poor for low-risk and medium-risk patients (6.3% and 48.0%, respectively); agreement for high-risk patients could not be calculated. CONCLUSIONS: Current Dutch primary care for patients with nonspecific LBP, NP, or both does not correspond to the recommended stratified-care approach based on the SBT, as most patients receive medium-risk treatment. Most low-risk patients are overtreated, and most high-risk patients are undertreated. Although the stratified-care approach has not yet been validated in Dutch primary care, these results indicate there may be substantial room for improvement. PMID- 28709882 TI - Biodegradation of food waste using microbial cultures producing thermostable alpha-amylase and cellulase under different pH and temperature. AB - The aim of this work was to study the biodegradation of food waste employing thermostable alpha-amylase and cellulase enzymes producing bacteria. Four potential isolates were identified which were capable of producing maximum amylase and cellulase and belong to the amylolytic strains, Brevibacillus borstelensis and Bacillus licheniformis; cellulolytic strains, Bacillus thuringiensis and Bacillus licheniformis, respectively. These strains were selected based on its higher cell density, enzymatic activities and stability at a wide range of pH and temperature compared to other strains. The results indicated that 1:1 ratio of pre and post consumed food wastes (FWs) were helpful to facilitate the degradation employing bacterial consortium. In addition, organic matter decomposition and chemical parameters of the end product quality also indicated that bacterial consortium was very effective for 1:1 ratio of FWs degradation as compared to the other treatments. PMID- 28709883 TI - Pyrolysis characteristics and kinetics of microalgae via thermogravimetric analysis (TGA): A state-of-the-art review. AB - Pyrolysis is a promising route for biofuels production from microalgae at moderate temperatures (400-600 degrees C) in an inert atmosphere. Depending on the operating conditions, pyrolysis can produce biochar and/or bio-oil. In practice, knowledge for thermal decomposition characteristics and kinetics of microalgae during pyrolysis is essential for pyrolyzer design and pyrolysis optimization. Recently, the pyrolysis kinetics of microalgae has become a crucial topic and received increasing interest from researchers. Thermogravimetric analysis (TGA) has been employed as a proven technique for studying microalgae pyrolysis in a kinetic control regime. In addition, a number of kinetic models have been applied to process the TGA data for kinetic evaluation and parameters estimation. This paper aims to provide a state-of-the art review on recent research activities in pyrolysis characteristics and kinetics of various microalgae. Common kinetic models predicting the thermal degradation of microalgae are examined and their pros and cons are illustrated. PMID- 28709884 TI - Applications of biochar in redox-mediated reactions. AB - Biochar is chemically more reduced and reactive than the original feedstock biomass. Graphite regions, functional groups, and redox-active metals in biochar contribute to its redox characteristics. While the functional groups such as phenolic species in biochar are the main electron donating moieties (i.e., reducers), the quinones and polycondensed aromatic functional groups are the components accepting electrons (oxidants). The redox capacity of biochar depends on feedstock properties and pyrolysis conditions. This paper aims to review and summarize the various synthesis techniques for biochars and the methods for probing their redox characteristics. We review the abiotic and microbial applications of biochars as electron donors, electron acceptors, or electron shuttles for pollutant degradation, metal(loid)s (im)mobilization, nutrient transformation, and discuss the underlying mechanisms. Furthermore, knowledge gaps that exist in the exploration and differentiation of the electron transfer mechanisms involving biochars are also identified. PMID- 28709885 TI - Modeling of acetate-type fermentation of sugar-containing wastewater under acidic pH conditions. AB - In this study, a kinetic model was developed based on Anaerobic Digestion Model No. 1 to provide insights into the directed production of acetate and methane from sugar-containing wastewater under low pH conditions. The model sufficiently described the dynamics of liquid-phase and gaseous products in an anaerobic membrane bioreactor by comprehensively considering the syntrophic bioconversion steps of sucrose hydrolysis, acidogenesis, acetogenesis and methanogenesis under acidic pH conditions. The modeling results revealed a significant pH-dependency of hydrogenotrophic methanogenesis and ethanol-producing processes that govern the sucrose fermentative pathway through changing the hydrogen yield. The reaction thermodynamics of such acetate-type fermentation were evaluated, and the implications for process optimization by adjusting the hydraulic retention time were discussed. This work sheds light on the acid-stimulated acetate-type fermentation process and may lay a foundation for optimization of resource oriented processes for treatment of food wastewater. PMID- 28709886 TI - Five-Year Followup Results of a Prospective, Multicenter Study of Patients with Overactive Bladder Treated with Sacral Neuromodulation. AB - PURPOSE: We evaluated the therapeutic success rate, changes in quality of life and safety of sacral neuromodulation 5 years after InterStimTM implantation. Included in study were subjects with bothersome symptoms of overactive bladder, including urinary urge incontinence and/or urgency-frequency, in whom at least 1 anticholinergic medication failed and 1 medication had not been tried. MATERIALS AND METHODS: Therapeutic success was defined as a urinary urge incontinence or urgency-frequency response of 50% or greater improvement in average leaks or voids per day, or return to normal voiding, defined as fewer than 8 voids per day. Quality of life was evaluated by ICIQ-OABqol (International Consultation on Incontinence Modular Questionnaire). Safety was evaluated through adverse events. RESULTS: Of the 340 subjects who completed the test stimulation 272 had an implant, of whom 91% were female. Mean age was 57 years. At baseline 202 subjects with urinary urge incontinence had a mean +/- SD of 3.1 +/- 2.7 leaks per day and 189 with urgency-frequency had a mean of 12.6 +/- 4.5 voids per day. The 5-year therapeutic success rate was 67% (95% CI 60-74) using modified completers analysis and 82% (95% CI 76-88) using completers analysis. Subjects with urinary urge incontinence had a mean reduction from baseline of 2.0 +/- 2.2 leaks per day and subjects with urgency-frequency had a mean reduction of 5.4 +/- 4.3 voids per day (each completers analysis p <0.0001). Subjects showed improvement in all ICIQ OABqol measures (p <0.0001). The most common device related adverse events were an undesirable change in stimulation in 60 of the 272 subjects (22%), implant site pain in 40 (15%) and therapeutic product ineffectiveness in 36 (13%). CONCLUSIONS: This multicenter study shows that sacral neuromodulation had sustained efficacy and quality of life improvements, and an acceptable safety profile through 5 years in subjects with overactive bladder. PMID- 28709887 TI - Frequency and Prognostic Value of PTEN Loss in Patients with Upper Tract Urothelial Carcinoma Treated with Radical Nephroureterectomy. AB - PURPOSE: To our knowledge the frequency and prognostic significance of PTEN protein expression in upper tract urothelial carcinoma have not yet been investigated in large studies. We analyzed PTEN protein status and its association with disease recurrence and survival outcomes in a large, multi institutional upper tract urothelial carcinoma cohort. MATERIALS AND METHODS: We retrospectively analyzed the records of 611 patients with upper tract urothelial carcinoma treated with radical nephroureterectomy between 1991 and 2008 at a total of 7 institutions. Median followup was 23 months. Tissue microarrays and immunohistochemical PTEN staining (monoclonal antibody) were performed. Univariable and multivariable Cox regression models were created to address the association of PTEN protein expression with disease recurrence, and cancer specific and overall mortality. RESULTS: PTEN staining was absent in 45 cases (7.4%). Patients with PTEN loss had significantly advanced pathological tumor stage and grade (p <0.001), and higher rates of lymph node metastasis (p <0.01) and lymphovascular invasion (p <0.001) compared to patients with PTEN expression. PTEN loss was associated with disease recurrence, and cancer specific and overall mortality on univariable Cox regression analyses. However, on multivariable Cox regression analyses adjusted for the effect of standard clinicopathological features PTEN loss was only associated with overall mortality (HR 1.69, 95% CI 1.09-2.61, p = 0.02). CONCLUSIONS: In patients undergoing radical nephroureterectomy for upper tract urothelial carcinoma loss of PTEN protein expression is rare but associated with features of biologically aggressive disease such as higher grade and stage as well as lymph node metastasis. Loss of PTEN expression was associated with overall mortality. PTEN loss seemed to promote worse outcomes in this relatively small group of patients. PMID- 28709888 TI - Biopsy Detected Gleason Pattern 5 is Associated with Recurrence, Metastasis and Mortality in a Cohort of Men with High Risk Prostate Cancer. AB - PURPOSE: We evaluated the relative risk of biochemical recurrence, metastasis and death from prostate cancer contributed by biopsy Gleason pattern 5 among men at high risk with Gleason 8-10 disease in the SEARCH (Shared Equal Access Regional Cancer Hospital) cohort. MATERIALS AND METHODS: Men with biopsy Gleason sum 8-10 prostate cancer treated with radical prostatectomy were evaluated. The cohort was divided into men with Gleason 4 + 4 vs those with any pattern 5 (ie Gleason 3 + 5, 5 + 3, 4 + 5, 5 + 4 or 5 + 5). Predictors of biochemical recurrence, metastases, and prostate cancer specific and overall survival were analyzed using Kaplan-Meier, log rank test and Cox proportional hazards models. RESULTS: We identified 634 men at high risk in the SEARCH database, of whom 394 (62%) had Gleason 4 + 4 and 240 (38%) had Gleason pattern 5 on biopsy. Baseline characteristics did not significantly differ between the groups. On multivariable analysis relative to Gleason 4 + 4 men at high risk with Gleason pattern 5 showed no difference in the risk of biochemical recurrence (HR 1.26, 95% CI 0.99-1.61, p = 0.065). However, they were at significantly greater risk for metastasis (HR 2.55, 95% CI 1.50-4.35, p = 0.001), prostate cancer specific mortality (HR 2.67, 95% CI 0.1.26-5.66, p = 0.010) and overall mortality (HR 1.60, 95% CI 1.09-2.34, p = 0.016). CONCLUSIONS: Preoperative subclassification of high risk prostate cancer by biopsy Gleason grade (4 + 4 vs any Gleason pattern 5) identified men at highest risk for progression. Any Gleason 5 on biopsy is associated with a greater risk of metastasis, and prostate cancer specific and overall mortality. Grouping all Gleason 8-10 tumors together as high risk lesions may fail to fully stratify men at highest risk for poor outcomes. PMID- 28709889 TI - Dynamic Contrast Enhanced Magnetic Resonance Imaging Improves Classification of Prostate Lesions: A Study of Pathological Outcomes on Targeted Prostate Biopsy. AB - PURPOSE: PI-RADSTM, version 2 stipulates that dynamic contrast enhanced imaging should be used to classify diffusion-weighted imaging score 3 peripheral zone lesions as PI-RADS score 3 (dynamic contrast enhanced imaging negative or nonenhancing) or 4 (dynamic contrast enhanced imaging positive or enhancing). However, to our knowledge it is unknown whether dynamic contrast enhanced imaging separates lesions into clinically meaningful pathological groups. We examined whether dynamic contrast enhanced imaging would improve the detection of clinically significant cancer. MATERIALS AND METHODS: We identified patients without a prior diagnosis of prostate cancer who underwent multiparametric magnetic resonance imaging-transrectal ultrasound fusion targeted biopsy of peripheral zone lesions with a diffusion-weighted imaging score of 3 or 4. Each lesion was grouped into 1 of 3 classifications, including group 1-diffusion weighted imaging score 3/nonenhancing/PI-RADS score 3, group 2-diffusion-weighted imaging score 3/enhancing/PI-RADS score 4 or group 3-diffusion-weighted imaging score 4/PI-RADS score 4. We measured the rate of grade group 2 or greater pathology detected for each lesion group with subgroup analyses in patients with vs without prior negative systematic biopsy. RESULTS: We identified a total of 389 peripheral zone diffusion-weighted imaging score 3 or 4 lesions in 290 patients. The rate of grade group 2 or greater cancer on biopsy for group 1, 2 and 3 lesions was 8.9%, 21% and 36.5%, respectively (p <0.03). The rate of grade group 2 or greater pathology was higher in group 2 than group 1 lesions in patients with prior negative systematic prostate biopsy (28% vs 5.0%, p <0.001) but not in those without such a biopsy (16% vs 12%, p = 0.5). Group 3 lesions had a higher rate of grade group 2 or greater cancer than group 2 lesions in the biopsy naive subgroup (46% vs 16%, p = 0.001). However, the rates were similar in patients with prior negative systematic prostate biopsy (27% vs 28%, p = 0.9). CONCLUSIONS: Diffusion-weighted imaging score 3 peripheral zone lesions were more likely to be clinically significant cancer (grade group 2 or greater) if they were dynamic contrast enhanced T1-weighted imaging positive. That was most apparent in patients with a prior negative systematic prostate biopsy. In such patients including a dynamic contrast enhanced sequence in multiparametric magnetic resonance imaging allowed for optimal lesion risk stratification. PMID- 28709890 TI - A Novel Collaborative Protocol for Successful Management of Penile Pain Mediated by Radiculitis of Sacral Spinal Nerve Roots From Tarlov Cysts. AB - INTRODUCTION: Since 14 years of age, the patient had experienced extreme penile pain within seconds of initial sexual arousal through masturbation. Penile pain was so severe that he rarely proceeded to orgasm or ejaculation. After 7 years of undergoing multiple unsuccessful treatments, he was concerned for his long-term mental health and for his future ability to have relationships. AIM: To describe a novel collaboration among specialists in sexual medicine, neurophysiology, and spine surgery that led to successful management. METHODS: Collaborating health care providers conferred with the referring physician, patient, and parents and included a review of all medical records. MAIN OUTCOME MEASURE: Elimination of postpubertal intense penile pain during sexual arousal. RESULTS: The patient presented to our sexual medicine facility at 21 years of age. The sexual medicine physician identifying the sexual health complaint noted a pelvic magnetic resonance imaging report of an incidental sacral Tarlov cyst. A subsequent sacral magnetic resonance image showed four sacral Tarlov cysts, with the largest measuring 18 mm. Neuro-genital testing result were abnormal. The neurophysiologist hypothesized the patient's pain at erection was produced by Tarlov cyst-induced neuropathic irritation of sensory fibers that course within the pelvic nerve. The spine surgeon directed a diagnostic injection of bupivacaine to the sacral nerve roots and subsequently morphine to the conus medullaris of the spinal cord. The bupivacaine produced general penile numbness; the morphine selectively decreased penile pain symptoms during sexual arousal without blocking penile skin sensation. The collaboration among specialties led to the conclusion that the Tarlov cysts were pathophysiologically mediating the penile pain symptoms during arousal. Long-term follow-up after surgical repair showed complete symptom elimination at 18 months after treatment. CONCLUSION: This case provides evidence that (i) Tarlov cysts can cause sacral spinal nerve root radiculitis through sensory pelvic nerve and (ii) there are management benefits from collaboration among sexual medicine, neurophysiology, and spine surgery subspecialties. Goldstein I, Komisaruk BR, Rubin RS, et al. A Novel Collaborative Protocol for Successful Management of Penile Pain Mediated by Radiculitis of Sacral Spinal Nerve Roots From Tarlov Cysts. Sex Med 2017;5:e203 e211. PMID- 28709891 TI - Neuroprotective effects of methyl 3,4 dihydroxybenzoate in a mouse model of retinitis pigmentosa. AB - Retinitis pigmentosa is a photoreceptor-degenerative disease that is currently untreatable and eventually causes blindness. Methyl 3,4 dihydroxybenzoate (MDHB) is a small molecule that exerts neuroprotective effects in vitro. The present study tests whether MDHB protects the retina of rd10 mice, a model of retinitis pigmentosa. MDHB or an equal volume of vehicle was intraperitoneally injected in rd10 mice daily from postnatal day 12 (P12) to P26. Retinal morphology was evaluated by immunostaining, and retinal function by electroretinogram (ERG) and by visual behavior. TUNEL, Iba1, GFAP staining and western blotting were applied to explore the neuroprotective mechanism of MDHB in retina. MDHB treatment significantly promoted photoreceptor survival and preserved cone morphology compared to the untreated animals. The visual behavior and ERG responses were also greatly enhanced in MDHB-treated rd10 mice. Mechanistically, following MDHB treatment, the number of TUNEL-positive cells was decreased in rd10 retina, and the expression of brain-derived neurotrophic factor (BDNF) protein and phosphorylated tropomyosin-related kinase B (TrkB) receptor were increased. Furthermore, blocking TrkB using the antagonist ANA-12 prevented the protective effect of MDHB on photoreceptor survival and structure. MDHB treatment also inhibited microglial activation and Muller cell gliosis in rd10 retina. In conclusion, MDHB treatment delays retinal degeneration in rd10 mice and preserves retinal structure and functions. These effects are likely mediated by the BDNF TrkB pathway. Due to its neurotrophic effects and ability to reduce reactive gliosis, MDHB may be useful to treat degenerative diseases in retina and brain. PMID- 28709880 TI - Low intensity transcranial electric stimulation: Safety, ethical, legal regulatory and application guidelines. AB - Low intensity transcranial electrical stimulation (TES) in humans, encompassing transcranial direct current (tDCS), transcutaneous spinal Direct Current Stimulation (tsDCS), transcranial alternating current (tACS), and transcranial random noise (tRNS) stimulation or their combinations, appears to be safe. No serious adverse events (SAEs) have been reported so far in over 18,000 sessions administered to healthy subjects, neurological and psychiatric patients, as summarized here. Moderate adverse events (AEs), as defined by the necessity to intervene, are rare, and include skin burns with tDCS due to suboptimal electrode skin contact. Very rarely mania or hypomania was induced in patients with depression (11 documented cases), yet a causal relationship is difficult to prove because of the low incidence rate and limited numbers of subjects in controlled trials. Mild AEs (MAEs) include headache and fatigue following stimulation as well as prickling and burning sensations occurring during tDCS at peak-to baseline intensities of 1-2mA and during tACS at higher peak-to-peak intensities above 2mA. The prevalence of published AEs is different in studies specifically assessing AEs vs. those not assessing them, being higher in the former. AEs are frequently reported by individuals receiving placebo stimulation. The profile of AEs in terms of frequency, magnitude and type is comparable in healthy and clinical populations, and this is also the case for more vulnerable populations, such as children, elderly persons, or pregnant women. Combined interventions (e.g., co-application of drugs, electrophysiological measurements, neuroimaging) were not associated with further safety issues. Safety is established for low intensity 'conventional' TES defined as <4mA, up to 60min duration per day. Animal studies and modeling evidence indicate that brain injury could occur at predicted current densities in the brain of 6.3-13A/m2 that are over an order of magnitude above those produced by tDCS in humans. Using AC stimulation fewer AEs were reported compared to DC. In specific paradigms with amplitudes of up to 10mA, frequencies in the kHz range appear to be safe. In this paper we provide structured interviews and recommend their use in future controlled studies, in particular when trying to extend the parameters applied. We also discuss recent regulatory issues, reporting practices and ethical issues. These recommendations achieved consensus in a meeting, which took place in Gottingen, Germany, on September 6-7, 2016 and were refined thereafter by email correspondence. PMID- 28709892 TI - Liuwei Dihuang soft capsules attenuates endothelial cell apoptosis to prevent atherosclerosis through GPR30-mediated regulation in ovariectomized ApoE deficient mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Liuwei Dihuang (LWDH), a classical traditional Chinese medicine prescription, has been widely used to prevent and to treat various diseases with symptoms of 'Kidney-Yin' deficiency syndrome for over 1000 years in China. It is commonly used to treat functional decline associated with senile disease and menopausal syndrome, especially memory decline, insomnia, diabetes and osteoporosis. Modern experimental pharmacological studies indicated that the mechanism of LWDH treatment of menopausal syndrome may be associated with enhanced estrogenic effects. However, little attention has been paid to the potential impact of LWDH on atherosclerosis (AS) associated with female menopause. The aim of this study was to evaluate the preventive effects of LWDH intake on an animal model of female menopause AS and to explore the underlying molecular mechanism. MATERIALS AND METHODS: ApoE-/- mice were randomly divided into 4 groups, with C57BN/L6 mice as the control group. All ApoE-/- mice were ovariectomized (Ovx) one week prior to oral administration and initiation of high fat diet. C57BL/6 mice were given sham operation and maintained on normal diet. The three administered groups were given simvastatin (4mg/kg via i.g.) and LWDH (4.5, 9.0g/kg via i.g.) every day for 14 weeks. Atherosclerotic lesions in the aortic root were determined by oil red O staining and hematoxylin-eosin staining. alpha-Actin and CD68 in atherosclerotic lesions were detected by immunohistological assay. Serum lipids and homocysteine (Hcy) levels were measured in the 14th week. The cleaved caspase-3, C/EBP homologous protein (CHOP) and G protein coupled estrogen receptor 30 (GPR30) expressions in the aortic arch endothelium were determined by immunohistochemistry and Western blot. The inhibitory effect of LWDH-medicated (20%, 12h) on Hcy (20%, 24h)-induced apoptosis of human umbilical vein endothelial cells (HUVECs) was examined by flow cytometry and Hoechst 33258 staining. Intracellular ROS production, nitric oxide release, and endothelial NO synthase (eNOS) activity were measured with or without LWDH-medicated serum pretreatment. In addition, CHOP, glucose-regulated protein GPR30, 78 (Grp78), Bcl-2, Bax and cleaved caspase-3 were analyzed by Western blot. Finally, the influence of G15, a specific antagonist of GPR30, on the protective effect of LWDH on endothelial cells was investigated. RESULTS: In vivo administration of LWDH prevented plaque formation and reduced plasma lipid and Hcy levels. LWDH inhibited CHOP and cleaved caspase-3 expression in vivo and in vitro while maintaining GPR30 expression. In vitro study showed that Hcy induced HUVECs apoptosis was weakened by LWDH-medicated serum pretreatment. Treatment with LWDH-medicated serum significantly upregulated NO release and eNOS activity in HUVECs. In addition, LWDH-medicated serum treatment optimized the balance between Bax and Bcl-2, and attenuated intracellular ROS production. G15 reversed the protective effect of LWDH on endothelial cells and the changes of apoptosis-related proteins. CONCLUSIONS: LWDH treatment can significantly reduce plaque formation in an animal model of menopausal AS. The mechanism may be inhibition of Hcy-induced endothelial cell apoptosis by modulating GPR30. Hence, LWDH can potentially be used to prevent AS-related vascular disease in menopausal women. PMID- 28709893 TI - Regulatory effect of baicalin on the imbalance of Th17/Treg responses in mice with allergic asthma. AB - ETHNOPHARMACOLOGY RELEVANCE: Baicalin, a flavonoid compound, was isolated from traditional Chinese medicine Scutellaria baicalensis Georgi. The study aimed to explore the regulatory effect of baicalin on immunological balance of Th17/Treg responses and the possible mechanisms in mice with allergic asthma. MATERIALS AND METHODS: Mice were sensitized and challenged with OVA+LPS by intranasal instillation, and were intragastrically treated with baicalin from days 22-36 after sensitization. The organ coefficient of lung was determined. Immunoglobulin E (IgE) level in serum and cytokine IL-17A, IL-6, IL-10 levels in bronchoalveolar lavage fluid (BALF) were measured by ELISA. Histological changes in lung and airway tissues were observed by hematoxylin and eosin (H&E) and periodic acid Schiff staining (PAS). The expressions of signal transducer and activator of transcription 3 (STAT3) and forkhead box P3 (FOXP3) in lung tissues were evaluated by immunohistochemistry and western blot methods. RESULTS: Baicalin obviously decreased OVA+LPS-induced organ coefficient of lung, inhibited serum IgE and BALF IL-7A and IL-6 secrection, promoted BALF IL-10 secrection in a dose dependent manner. Histological studies demonstrated that baicalin significantly alleviated OVA+LPS-induced inflammatory responses and mucus secretion in lung and airway tissues. Immunohistochemistry and western blot studies showed that baicalin substantially suppressed STAT3 expression and promoted FOXP3 expression in lung tissues of mice. CONCLUSIONS: These findings suggest that baicalin effectively protects against OVA+LPS-induced allergic asthma in mice by regulating the immunological imbalance of Th17/Treg responses. PMID- 28709894 TI - Adsorption and controlled release of potassium, phosphate and ammonia from modified Arabic gum-based hydrogel. AB - In this work, a modified Arabic gum-based hydrogel copolymerized with acrylamide was synthesized and characterized for application in adsorption and controlled release of potassium, phosphate and ammonia. From FT-IR results, it would be reasonable to assume that the hydrogel was effectively synthesized. The degree of swelling at pure water with pH 6.0 was 21.0g water per g dried hydrogel whereas the degrees of swelling at buffer solutions with pH 4.5 and 7.0 were 7.2 and 9.2g water per g dried hydrogel, respectively. The water diffusion mechanism was governed by Fickian transport with tendency to occur macromolecular relaxation. The adsorption capacities of potassium, phosphate and ammonia were higher by increasing the initial concentrations due to availability of active sites in the hydrogel network, nutrient size and ionic charge. Potassium, phosphate and ammonia concentrations released from the modified Arabic gum-based hydrogel increased by increasing the release time from 0 to 1440min. Release profiles indicated that this hydrogel could be applied for the enrichment and hydration of deserted soil, avoiding losses of nutrients by leaching and percolation, with an advantage of being constituted by an eco-friendly polysaccharide. PMID- 28709895 TI - Improved production and characterization of a highly stable laccase from the halophilic bacterium Chromohalobacter salexigens for the efficient delignification of almond shell bio-waste. AB - Extremozymes have gained importance for their ability to efficiently develop the processes in rigorous industrial conditions with incidence in the recycling of especially robust natural wastes. The production of an extracellular laccase from the halophilic bacterium Chromohalobacter salexigens aided for the bio delignification of almond shell was optimized using response surface methodology followed by one-factor-at-a-time, resulting in an 80-fold increase in the enzyme yield. Out of 10 different medium components, CuSO4, ZnSO4, glucose, and urea were shown to have the greatest effects on the laccase production. The crude laccase was surprisingly stable against the various solvents, salts, chemicals, pH ranges, and temperatures, and it exhibited a high catalytic efficiency to a wide range of phenolic and non-phenolic substrates. Laccase reduced the kappa number of the lignin of almond shell by approximately 27% without the aid of a mediator, and the delignification efficiency strengthened by up to 58% reduction in kappa number in the used harsh conditions. Due to the high potential of the enzyme in delignification, specifically under extreme conditions, laccase from C. salexigens can be considered as an ideal alternative for chemical treatment methods in cellulose fibres extraction of lignocellulosic bio-wastes or delignification of the lignin and lignin-derived industrial wastes. PMID- 28709896 TI - Comparative study on antifungal activities of chitosan nanoparticles and chitosan silver nano composites against Fusarium oxysporum species complex. AB - Though the metal nanoparticles (NPs) have been shown favorable results against fungal diseases, erratic environmental toxicity of NPs have raised serious concerns against their applications. Hence, it is vital to modify antifungal compounds into safe substitutes over synthetic chemicals. In this study, antifungal effects of chitosan nanoparticles (CNPs) and chitosan silver nanocomposites (CAgNCs) were compared against Fusarium oxysporum species complex. CNPs and CAgNCs were synthesized, characterized and compared based on the transmission electron microscope, X-ray diffraction, UV-vis absorbance spectra, particle size distribution, zeta potential and thermal stability analysis. Ultra structural analysis on mycelium membrane of treated F. oxysporum showed that CNPs and CAgNCs could induce a pronounced membrane damage and disruption of the mycelium surface, increase the membrane permeability, and even cell disintegration. CAgNCs showed a significantly higher radial growth inhibition than CNPs in all the tested concentrations. Both CNPs and CAgNCs were not only effective in reducing the fungal growth, but also caused morphological and ultrastructural changes in the pathogen, thereby suggesting its usage as an antifungal dispersion system to control F. oxysporum. Additionally, CNPs and CAgNCs therapy reduced the F. oxysporum infection in zebrafish. Data demonstrates biologically active CNPs and CAgNCs are promising antifungal agents against F. oxysporum. PMID- 28709897 TI - A polysaccharide (PNPA) from Pleurotus nebrodensis ameliorates hepatic ischemic/reperfusion (I/R) injury in rats. AB - The effects of a polysaccharide (PNPA) from the fruiting bodies of Pleurotus nebrodensis on hepatic ischemia/reperfusion (I/R) injury in rats were explored. Severe liver injury was shown in rats following I/R with high content of serum AST and ALT, as evidenced by histological examination, whereas less damage was noted after PNPA treatment compared to rats in the I/R group. Also, pre-treatment with PNPA (400mg/kg) could reduce the level of MDA in liver tissue and increase the activity of ROS scavengers (T-AOC, SOD, CAT, GSH-PX), Nitric oxide synthase (T-NOS and iNOS), and GSH. Moreover, PNPA could still reduce the production of I/R-induced inflammatory cytokines (IL-1beta, IL-6, TNF-alpha and NF-kappaB) in liver, along with MPO. I/R-induced high level of pro-apoptotic indicators (cytochrome c, Bax, and caspase 3) and low level of anti-apoptotic indicators Bcl 2 were reversed after PNPA pretreatment. Therefore, PNPA might be a promising candidate for preventing hepatic I/R injury. PMID- 28709898 TI - Development of a duplex Taqman real-time PCR assay for rapid identification of Vibrio splendidus-related and V. aestuarianus strains from bacterial cultures. AB - To enable the rapid and accurate identification of Vibrio splendidus-related and V. aestuarianus strains associated with Pacific cupped oyster Crassostrea gigas mortality, we developed a duplex Taqman real-time PCR assay and evaluated its efficacy. This technique proved to be rapid, sensitive, and specific and will be particularly valuable for epidemiologic studies. PMID- 28709899 TI - Prediction of protein N-formylation using the composition of k-spaced amino acid pairs. AB - As one of important protein post-translational modifications, N-formylation has been reported to be involved in various biological processes. The accurate identification of N-formylation sites is crucial for understanding the underlying mechanisms of N-formylation. Since the traditional experimental methods are generally labor-intensive and expensive, it is important to develop computational methods to predict N-formylation sites. In this paper, a predictor named NformPred is proposed to improve the prediction of N-formylation sites by using composition of k-spaced amino acid pairs encoding scheme and support vector machine algorithm. As illustrated by 10-fold cross-validation, NformPred achieves a promising performance with a Sensitivity of 86.00%, a Specificity of 96.25%, an Accuracy of 94.48% and a Matthew's correlation coefficient of 0.8099, which are much better than those of current computational method. Feature analysis shows that some k-spaced amino acid pairs such as 'IxxL', 'LV' and 'IxxxI' play the most important roles in the prediction of N-formylation sites. These predictive and analytical results suggest that NformPred might facilitate the identification of protein N-formylation. A free online service for NformPred is accessible at http://123.206.31.171/NformPred/. PMID- 28709900 TI - Development of carbon-graphene-based aptamer biosensor for EN2 protein detection. AB - In this study, we developed a screen-printed carbon-graphene-based electrochemical biosensor for EN2 protein detection. The engrailed-2 (EN2) protein, a biomarker for prostate cancer, is known to be a strong binder to a specific DNA sequence (5'-TAATTA-3') to regulate transcription. To take advantage of this intrinsic property, aptamer probes with TAATTA sequence was immobilized onto the screen-printed carbon-graphene electrode surface via EDC-NHS coupling approach. Cyclic voltammetry (CV) of the electrochemical measurement technique was employed for the quantitative detection of EN2 protein. The hindrance to the redox reaction of potassium ferricyanide on the biosensor surface due to the binding of the immobilized aptamer with its target EN2 protein quantified the protein concentration. Under optimum conditions, the aptamer biosensor can detect EN2 protein over a linear range from 35 to 185 nM with a detection limit of 38.5 nM. PMID- 28709901 TI - Multicenter collaboration study on the beta-lactam resistant Enterobacteriaceae in Japan - The 65th anniversary public interest purpose project of the Japanese Society of Chemotherapy. AB - This study was conducted using the same method of the "1-day multicenter collaborative research for Clostridium difficile infectious". This surveillance study was performed by 38 participating medical facilities across Japan. Of the 268 fecal specimens collected in this study, 5 (1.9%) carbapenem-resistant Enterobacteriaceae (CRE) were judged carbapenem resistant by the criteria of the Infectious Disease Act, Japan (2 mg/L or more and 64 mg/L or more MICs for imipenem and cefmetazole, respectively). However, no isolate was shown to have a meropenem MIC of 2 mg/L or more. No carbapenemase encoding genes were detected from the CRE. Extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae were detected from 29 specimens (11%), and the predominant ESBL-encoding gene group was blaCTX-M-9. The predominant ST-type by multilocus sequence typing of ESBL encoding gene-positive Escherichia coli was ST131. PMID- 28709902 TI - Duration of fever and other symptoms after the inhalation of laninamivir octanoate hydrate; comparison of the 2011/12 to 2015/16 Japanese influenza seasons. AB - The duration of fever and symptoms after laninamivir octanoate hydrate (laninamivir) inhalation were investigated in the Japanese 2015/16 influenza season, and the results were compared with those of the 2011/12 to 2014/15 seasons. A total of 1068 patients were evaluated for the duration of fever and symptoms in the five studied seasons. The influenza types/subtypes were 125 A(H1N1)pdm09 (62.2%), 17 A(H3N2) (8.5%), and 59 B (29.4%) in the 2015/16 season. The median durations of fever were 40.0, 41.0, and 47.0 h, and the median durations of symptoms were 87.0, 76.0, and 93.0 h for A(H1N1)pdm09, A(H3N2), and B, respectively, with no significant difference. The median durations of fever were 52.0 and 46.0 h and the median durations of symptoms 93.0 and 88.0 h for the Victoria and Yamagata B lineages, respectively, with no significant difference. Fever resolution after laninamivir inhalation by the A(H1N1)pdm09 patients was similar in the 2013/14 and 2015/16 seasons. Fever resolution after laninamivir inhalation was similar in all comparisons of the 2011/12 to 2015/16 seasons for both A(H3N2) and B, with no significant difference among the five seasons. Over the seasons tested, eight adverse drug reactions (ADRs) were reported for 1128 patients. The most frequent ADR was diarrhea, and all ADRs were resolved and not serious. These results indicate the continuing clinical effectiveness of laninamivir against influenza A(H1N1)pdm09, A(H3N2), and B, with no safety issues. PMID- 28709903 TI - Targeted delivery of Cyclosporine A by polymeric nanocarriers improves the therapy of inflammatory bowel disease in a relevant mouse model. AB - The therapy of inflammatory bowel diseases is still rather inefficient, and about 80% of patients require surgery at some stage. Improving the treatments by more efficient medication is, therefore, an urgent medical need. The objective of this project was to demonstrate targeted delivery of Cyclosporine-A (CYA) to the inflamed areas of the intestinal mucosa after oral administration, enabling improved alleviation of the symptoms and, at the same time, reduced systemic drug absorption and associated adverse effects. As had already been demonstrated in previous studies, nano- to micrometer-sized drug particles will accumulate at inflamed mucosal areas, providing a platform for such purposes. CYA as incorporated in poly-(lactic-co-glycolic-Acid) (PLGA) nano- and mirocarriers, respectively, each homogeneous in size and providing controlled drug release over 24h at intestinal pH-value. For comparative reasons, a commercial formulation (Sandimmun Neoral(r)) was included in the study. In an acute model of DSS-induced inflammation in Balb/c mice, up to three doses were administered for each formulation: 50mg/kg, 25mg/kg and 12.5mg/kg. Drug-free particles were included as control. The following parameters were evaluated: body weight, colon length, colon weight/length ratio, cytokine expression and histological analysis. Plasma levels of CYA were analysed to compare systemic bioavailability. While disease parameters, such as, e.g. colon length, always improved with an optimum dose of 25mg/kg, the commercial and the microparticulate formulations led to measurable plasma levels and adverse effects in terms of body weight loss at the highest dose. In contrast, when administering the same doses as nanoparticles, plasma concentrations remained always below the detection limit, and the body weight of the animals remained unchanged. In conclusion, this study corroborates the potential of nanocarriers enabling an improved topical delivery of CYA to the inflamed gut mucosa after oral administration yielding the same improvement of disease parameters at only half the dose in comparison to microparticles and a commercial oral formulation, respectively, and at the same time minimizing systemic exposure and associated adverse effect. PMID- 28709904 TI - The effects of gaze stabilization on gait parameters in individuals with Parkinson's disease. AB - The purpose of this study was to examine the effects of gaze fixation on head stabilization and gait during straight over ground walking in individuals with Parkinson's disease (PD). Eight individuals with PD (Age: 62.3+/-8.1 years) volunteered for the study. Full body kinematic data were collected at 120Hz using a Vicon motion capture system. Two visual conditions were used to determine the effects of gaze fixation: FREE gaze and FIXED gaze. During FIXED gaze, participants were required to fixate on a still target 13m ahead. During FREE gaze, participants were free to visually scan the environment. Five straight walking trials were performed in each experimental condition for a total of ten walking trials. Head segment stabilization strategies as well as gait parameters were compared between conditions. Step width, step length, stride time, cadence, double support time, centre of mass (CoM) velocity and CoM medial-lateral deviation were calculated for two strides of each over ground walking trial. Comparisons of mean values and variability were made using repeated measures ANOVAs. Results revealed that maintaining a FIXED gaze had no significant effect on head stabilization strategies or gait parameters with the exception of a significant increase in step width variability (p=0.003). CoM velocity was not significantly different between FREE and FIXED gaze conditions (FREE: 1.17+/ 0.20m/s; FIXED: 1.16+/-0.19m/s). CoM medial-lateral deviation was observed to be greater in FIXED (47.1+/-36.9cm) compared to FREE (26.9+/-15.1cm), though not significantly. These results suggest that gaze fixation to a target in front while walking increases step width variability and CoM M-L deviations indicative of reduced postural stability. This is an important consideration for use of visual cues to promote gait in PD. PMID- 28709905 TI - Royal jelly decreases corticosterone levels and improves the brain antioxidant system in restraint and cold stressed rats. AB - Restraint and cold stress induces the hypothalamic-pituitary-adrenal (HPA) axis to release corticosterone from the adrenal gland, which can worsen the antioxidant defense system in the central nervous system. Here, we investigated the corticosterone levels and the antioxidant defense system in the cerebellum and brain, as well as in its isolated regions, such as cerebral cortex, striatum and hippocampus of stressed rats supplemented with royal jelly (RJ). Wistar rats were supplemented with RJ for 14days and the stress induction started on the 7th day. Stressed rats increased corticosterone levels, glycemia and lipid peroxidation in the brain and cerebellum, cerebral cortex and hippocampus besides reduced glutathione defense system in the brain and striatum. Rats supplemented with RJ decreased corticosterone, maintained glycemia and decreased lipid peroxidation in the brain, cerebellum, as well as striatum and hippocampus, besides improved glutathione defense system in cerebral cortex and striatum. This study suggests an anti-stress and neuroprotective effect of RJ under stress conditions. PMID- 28709906 TI - Effects of feeding time on daily rhythms of neuropeptide and clock gene expression in the rat hypothalamus. AB - Shiftworkers are exposed to several adverse health conditions, one being eating at night. Food consumption at an unnatural time-of-day is thought to be one of the main factors responsible for the increased risk of developing metabolic diseases, such as obesity and diabetes mellitus. The underlying mechanism is considered to include disruption of the circadian organization of physiology, leading to disruption of metabolism. When food is consumed at night, the hypothalamus, a brain region central to homeostasis, receives contradicting input from the central clock and the systemic circulation. This study investigated how timing of feeding affects hypothalamic function by studying, in different hypothalamic nuclei, expression of clock genes and key neuropeptide genes involved in energy metabolism, including orexin, melanin-concentrating hormone (MCH) and neuropeptide Y. Animals with food available ad libitum showed diurnal variation in the expression of clock genes Per1 and Per2 in the perifornical area and arcuate nucleus. Clock gene rhythms were lost in both nuclei when food was restricted to the light (i.e., sleep) period. Neuropeptide genes did not display significant daily variation in either feeding groups, except for orexin-receptor 1 in ad libitum animals. Analysis of genes involved in glutamatergic and GABAergic signaling did not reveal diurnal variation in expression, nor effects of feeding time. In conclusion, feeding at the 'wrong' time-of-day not only induces desynchronization between brain and body clocks but also within the hypothalamus, which may contribute further to the underlying pathology of metabolic dysregulation. PMID- 28709907 TI - The details of structural disconnectivity in psychotic disorder: A family-based study of non-FA diffusion weighted imaging measures. AB - BACKGROUND: Diffusion tensor imaging (DTI) studies in psychotic disorder have shown reduced FA, often interpreted as disturbed white matter integrity. The observed 'dysintegrity' may be of multifactorial origin, as changes in FA are thought to reflect a combination of changes in myelination, fiber organization and number of axons. Examining the structural substrate of the diffusion tensor in individuals with (risk for) psychotic disorder may provide better understanding of the underlying structural changes. METHODS: DTI scans were acquired from 85 patients with psychotic disorder, 93 siblings of patients with psychotic disorder and 80 controls. Cross-sectional group comparisons were performed using Tract-Based Spatial Statistics (TBSS) on six DTI measures: axial diffusivity (AXD), radial diffusivity (RD), mean diffusivity (MD), and the case linear (CL), case planar (CP) and case spherical (CS) tensor shape measures. RESULTS: AXD did not differ between the groups. RD and CS values were significantly increased in patients compared to controls and siblings, with no significant differences between the latter two groups. MD was higher in patients compared to controls (but not siblings), with no difference between siblings and controls. CL was smaller in patients than in siblings and controls, and CP was smaller in both patients and siblings as compared to controls. CONCLUSION: The differences between individuals with psychotic disorder and healthy controls, derived from detailed diffusion data analyses, suggest less fiber orientation and increased free water movement in the patients. There was some evidence for association with familial risk expressed by decreased fiber orientation. PMID- 28709908 TI - Variable RNA expression from recently acquired, endogenous viral elements (EVE) of white spot syndrome virus (WSSV) in shrimp. AB - The viral accommodation hypothesis proposes that endogenous viral elements (EVE) from both RNA and DNA viruses are being continually integrated into the shrimp genome by natural host processes and that they can result in tolerance to viral infection by fortuitous production of antisense, immunospecific RNA (imRNA). Thus, we hypothesized that previously reported microarray results for the presence of white spot syndrome virus (WSSV) open reading frames (ORFs) formerly called 151, 366 and 427 in a domesticated giant tiger shrimp (Penaeus monodon) breeding stock might have represented expression from EVE, since the stock had shown uninterrupted freedom from white spot disease (WSD) for many generations. To test this hypothesis, 128 specimens from a current stock generation were confirmed for freedom from WSSV infection using two nested PCR detection methods. Subsequent nested-PCR testing revealed 33/128 specimens (26%) positive for at least one of the ORF at very high sequence identity (95-99%) to extant WSSV. Positive results for ORF 366 (now known to be a fragment of the WSSV capsid protein gene) dominated (28/33 = 84.8%), so 9 arbitrarily selected 366-positive specimens were tested by strand-specific, nested RT-PCR using DNase-treated RNA templates. This revealed variable RNA expression in individual shrimp including no RNA transcripts (n = 1), sense transcripts only (n = 1), antisense transcripts only (n = 2) or transcripts of both sense (n = 5). The latter 7 expression products indicated specimens producing putative imRNA. The variable types and numbers of the EVE and the variable RNA expression (including potential imRNA) support predictions of the viral accommodation hypothesis that EVE are randomly produced and expressed. Positive nested PCR test results for EVE of ORF 366 using DNA templates derived from shrimp sperm (germ cells), indicated that they were heritable. PMID- 28709909 TI - Pemetrexed conjugated with gold nanoparticles - Synthesis, characterization and a study of noncovalent interactions. AB - Gold nanoparticles (AuNPs) have been widely used as nanocarriers in drug delivery application. However, the binding mechanism between AuNPs and drug bases still remains a puzzle. Our study included: (i) optimization of three synthesis of the AuNPs-pemetrexed (PE) nanocomposites formation which was monitored by UV-Vis spectroscopy, (ii) identification of PE in gold nanocomposites and mechanism of PE interaction with gold nanoparticles by electrochemistry, NMR and Raman measurements, (iii) characterization of the three nanocomposites by TEM, DSL, ESL, zeta potential, XRPD and TGA analysis. The obtained nanocomposites are homogeneously shaped and have a maximum diameter of around 14nm and 88nm, as measured by the TEM and DSL techniques, respectively. The zeta potential of the nanocomposites is -43mV and suggests a high stability of the nanoparticles and lower toxicity for the normal cells. Quantum chemical calculations were also performed on model systems to estimate the strength of the AuNPs-PE interaction. Taking into account the experimental and theoretical data a mechanism of the nanocomposites' formation has been proposed in which PE interacts with the gold surface by the COOH/COO- group. PMID- 28709910 TI - Silicon-zinc-glycerol hydrogel, a potential immunotropic agent for topical application. AB - Nanoparticles synthesized using sol-gel method are promising agents for biomedical applications, in particular for the therapy and diagnosis of various diseases. Using silicon and zinc glycerolates as biocompatible precursors we synthesized by the sol-gel method a new bioactive silicon-zinc-containing glycerohydrogel combining the positive pharmacological properties of the precursors. In the present work the structural features of silicon-zinc containing glycerohydrogel and its immunotropic properties were studied. The advanced physical methods, including XRD, TEM, dynamic and electrophoretic light scattering, were used for studying the structural features of the gel. Hydrolysis of zinc monoglycerolate was investigated under gelation conditions. Evaluation of the efficiency of silicon-zinc-containing glycerohydrogel in providing immune functions was carried out using a model of the complicated wound process behind immunosuppression induced by hydrocortisone administration in the Wistar rats. It has been shown that zinc monoglycerolate exists in the state of amorphous nanoparticles in the cells of 3D-network formed due to incomplete hydrolysis of silicon glycerolates and subsequent silanol condensation. Zinc monoglycerolate is not hydrolyzed and does not enter 3D-network of the gel with the formation of Zn O-Si groups, but it forms a separate phase. Immunotropic action of silicon-zinc containing glycerohydrogel was revealed by the histology and immunohistochemistry methods. Amorphous nanoparticles of zinc monoglycerolate, water-soluble silicon glycerolates, and products of their hydrolytic transformations, which are present in a aqueous-glycerol medium, are in the first place responsible for the pharmacological activity of hydrogel. The results obtained allow us to consider silicon-zinc-containing glycerohydrogel as a promising immunotropic agent for topical application. PMID- 28709911 TI - Increased drug load and polymer compatibility of bilayered orodispersible films. AB - : The addition of enalapril maleate to a casting solution for orodispersible films (ODFs) containing hypromellose and carbomer 974P as film forming agents (standard casting solution, SCS) caused a dose dependent reduction of the viscosity. This phenomenon was a serious problem in the preparation of ODFs with an increased enalapril load (>1mg per ODF) when using the solvent casting method. The aim of the present work was twofold. Firstly, the influence of enalapril on the viscosity of SCS was studied in more detail. Secondly, two methods for increasing the enalapril load of an ODF were investigated that did not negatively influence the properties of SCS. The casting height was increased and the preparation of bilayered ODF, using the double-casting method, was explored. In the framework of the bilayered ODFs the compatibility between the film forming agents hydroxypropyl cellulose (HPC), sodium alginate (SA), hydroxyethyl cellulose (HEC) and the combination hypromellose-carbomer 974P (SCS) was investigated. RESULTS AND CONCLUSIONS: We found that enalapril concentration dependently reduced the pH, thereby negatively influencing the gel formation and the viscosity of SCS. An increased casting height did not result in a proportionally increased enalapril load. The enalapril load could be doubled when a bilayered ODF containing two layers of SCS was produced. Finally, not all combinations of film forming agents could be used for the preparation of bilayered ODFs. Besides, the sequence in which the different polymer layers were casted affected the appearance of the ODFs. In conclusion, the best formulations were produced with the polymer combinations SCS/SCS and SCS/HPC. PMID- 28709912 TI - Excipient-mediated alteration in drug bioavailability in the rat depends on the sex of the animal. AB - The pharmaceutical excipient, polyethylene glycol 400 (PEG 400), unexpectedly alters the bioavailability of the BCS class III drug ranitidine in a sex dependent manner. As ranitidine is a substrate for the efflux transporter P glycoprotein (P-gp), we hypothesized that the sex-related influence could be due to interactions between PEG 400 and P-gp. In this study, we tested this hypothesis by: i) measuring the influence of PEG 400 on the oral bioavailability of another P-gp substrate (ampicillin) and of a non-P-gp substrate (metformin); and ii) measuring the effect of PEG 400 on drug bioavailability in the presence of a P-gp inhibitor (cyclosporine A) in male and female rats. We found that PEG 400 significantly increased (p<0.05) the bioavailability of ampicillin (the P-gp substrate) in male rats, but not in female ones. In contrast, PEG 400 had no influence on the bioavailability of the non-P-gp substrate, metformin in male or female rats. Inhibition of P-gp by oral pre-treatment with cyclosporine A increased the bioavailability of the P-gp substrates (ampicillin and ranitidine) in males and females (p<0.05), and to a greater extent in males, but had no influence on the bioavailability of metformin in either male or female rats. These results prove the hypothesis that the sex-specific effect of PEG 400 on the bioavailability of certain drugs is due to the interaction of PEG 400 with the efflux transporter P-gp. PMID- 28709913 TI - Upregulation of neuronal kynurenine 3-monooxygenase mediates depression-like behavior in a mouse model of neuropathic pain. AB - Pain and depression often co-occur, but the underlying mechanisms have not been elucidated. Here, we used the spared nerve injury (SNI) model in mice to induce both neuropathic pain and depression-like behavior. We investigated whether brain interleukin (IL)-1 signaling and activity of kynurenine 3-monoxygenase (KMO), a key enzyme for metabolism of kynurenine into the neurotoxic NMDA receptor agonist quinolinic acid, are necessary for comorbid neuropathic pain and depression-like behavior. SNI mice showed increased expression levels of Il1b and Kmo mRNA in the contralateral side of the brain. The SNI-induced increase of Kmo mRNA was associated with increased KMO protein and elevated quinolinic acid and reduced kynurenic acid in the contralateral hippocampus. The increase in KMO-protein in response to SNI mostly took place in hippocampal NeuN-positive neurons rather than microglia. Inhibition of brain IL-1 signaling by intracerebroventricular administration of IL-1 receptor antagonist after SNI prevented the increase in Kmo mRNA and depression-like behavior measured by forced swim test. However, inhibition of brain IL-1 signaling has no effect on mechanical allodynia. In addition, intracerebroventricular administration of the KMO inhibitor Ro 61-8048 abrogated depression-like behavior without affecting mechanical allodynia after SNI. We show for the first time that the development of depression-like behavior in the SNI model requires brain IL-1 signaling and activation of neuronal KMO, while pain is independent of this pathway. Inhibition of KMO may represent a promising target for treating depression. PMID- 28709915 TI - Sex differences in somatic and sensory motor development after neonatal anoxia in Wistar rats. AB - Currently, one of the important causes of brain injury in new-borns is the neonatal anoxia which impacts the perinatology services worldwide. Animal models of anoxia have been used to assess its effects at cellular and behavioural levels in all ages, but few studies focus on sex differences. This study aimed to investigate some physical parameters of development, sensorimotor alterations, early neurological reflexes as well as the density of cells in motor and sensorimotor cerebral cortex of adolescent rats submitted to neonatal anoxia. The results presented significant differences in most of the evaluated parameters, such as body weight and lenght, medio-lateral head axis, eruption of superior incisor, palmar grasp, auditory startle, negative geotaxis, showing that neonatal anoxia affects physical parameters and neurological development, with sex differences. Cellular analysis revealed decreased amount of neurons in motor cortex and primary sensory hind limb and forelimb regions in anoxic group, along with gender difference, as compared to control groups. There is an important rationale for performing early assessment of sensorimotor deficits as there is similarity of the model with high risk human neonates and the sequelae in later life periods, which can be inferred from the present results with suggestion of a possible correlation between sensorimotor development delay and cellular changes in sensorimotor cortex. Furthermore, these observed sex dependent alterations certainly will address further studies and should be considered especially in treatments and strategies to avoid or minimize the neonatal anoxic effects. PMID- 28709916 TI - Lymphatic invasion and the Shields index in predicting melanoma metastases. AB - INTRODUCTION: Findings of the prognostic significance of lymphatic invasion are contradictory. To determine an as efficient cutaneous melanoma metastasis predictor as possible, Shields et al. created a new prognostic index. This study aimed to examine whether the lymphatic invasion analysis and the Shields index calculation can be used in predicting lymph node status in patients with cutaneous melanoma. METHODS: Lymphatic invasion of 100 melanoma specimens was detected by dual immunohistochemistry staining for the lymphatic endothelial marker D2-40 and melanoma cell S-100 protein. The Shields index was calculated as a logarithm by multiplying the melanoma thickness, square of peritumoural lymphatic vessel density and the number "2" for the present lymphatic invasion. RESULTS: No statistically significant difference was observed between lymph node metastatic and nonmetastatic melanomas regarding the lymphatic invasion. Metastatic melanomas showed a significantly higher Shields index value than nonmetastatic melanomas (p = 0.00). Area under the receiver operator characteristic (ROC) curve (AUC) proved that the Shields index (AUC = 0.86, 95% confidence interval (CI) 0.79-0.93, p = 0.00) was the most accurate predictor of lymph node status, followed by the melanoma thickness (AUC = 0.76, 95% CI 0.67 0.86, p = 0.00) and American Joint Committee on Cancer (AJCC) staging (AUC = 0.75, 95% CI 0.66-0.85, p = 0.00), while lymphatic invasion was not successful in predicting (AUC = 0.56, 95% CI 0.45-0.67, p = 0.31). The Shields index achieved 81.3% sensitivity and 75% specificity (cut-off mean value). CONCLUSIONS: Our findings show that D2-40/S-100 immunohistochemical analysis of lymphatic invasion cannot be used for predicting the lymph node status, while the Shields index calculation predicts disease outcome more accurately than the melanoma thickness and AJCC staging. PMID- 28709914 TI - The ratio of circulating follicular T helper cell to follicular T regulatory cell is correlated with disease activity in systemic lupus erythematosus. AB - Follicular T regulatory (Tfr) cells inhibit follicular T helper (Tfh) cells mediated B cell responses. Tfh cells are involved in the pathogenesis of systemic lupus erythematosus (SLE). However, the role of Tfr cells in SLE remains unclear. The frequency of circulating Tfr and Tfh cells were examined in SLE patients and healthy controls. The frequency of circulating Tfr cell decreased and Tfh/Tfr ratio increased in SLE patients. Serum anti-dsDNA antibody level positively correlated with frequency of Tfh cells and Tfh/Tfr ratios but negatively correlated with the frequency of Tfr cells. Moreover, the frequency of Tfr and Tfh/Tfr ratio but not that of Tfh was correlated with diseases activity. In addition, increase in Tfr cell numbers and decrease in the Tfh/Tfr ratios were observed with successful treatments. Thus, Tfr cells should be considered as a biomarker for SLE and their role in the pathogenesis of SLE warrants further investigation. PMID- 28709917 TI - What triggers in trigger finger? The flexor tendons at the flexor digitorum superficialis bifurcation. AB - To define the role of the flexor tendons in trigger finger, a high-resolution ultrasound examination was performed in 20 trigger fingers and 20 normal contralateral digits in three digital postures: full extension, mid-flexion and near-full flexion. Precise measurements of diameter and cross-sectional area of the combined tendon mass were recorded at five clearly defined locations: summit of the metacarpal head, proximal lip of the proximal phalanx (PP) and at 1/8, 1/4 and 1/2 length of the PP. In the normal tendons, there was an anatomical thickening, not previously appreciated at 1/4 length PP, in the region of the FDS bifurcation. This anatomical region moved proximally on finger flexion to the A1 pulley. In trigger fingers, the flexor tendons had greater diameter (sagittal view) and cross-sectional area than the normal side at all locations (p < 0.01, p < 0.001), with an even greater increase in diameter in the FDS bifurcation area (p < 0.001). Trigger fingers also had thicker A1 pulleys (p < 0.001). Triggering occurs on flexing the finger when the enlarged combined flexor tendon mass at the specific anatomical region of the FDS bifurcation impacts on the thickened A1 pulley, resisting its excursion. PMID- 28709918 TI - Unroofed Coronary Sinus Syndrome: An Easily Corrected Congenital Anomaly But More Diagnostic Suspicion Is Needed. AB - BACKGROUND: Unroofed coronary sinus syndrome (URCSS) is a spectrum of cardiac anomalies in which part (partial type) or the entire common wall (complete type) between the coronary sinus (CS) and left atrium is absent. It is commonly associated with a persistent left superior vena cava (PLSVC). The PLSVC can even anomalously connect to the left atrium in complete type anomaly. URCSS has been reported to be associated with delayed diagnosis and life-threatening cerebral injury. The purpose of the present study was to review our experience with surgical correction of this often-concealed malformation and discuss methods for reducing diagnostic omission. METHODS: Thirty-six patients with URCSS who underwent surgical treatment from 1998 to 2015 in our institution were enrolled in this retrospective analysis. RESULTS: The mean age of the patients was 21.8+/ 20.9 years. Type I anomalies were found in 15 (41.7%) patients, type II in 4 (11.1%), type III in 6 (16.7%), and type IV in 11 (30.6%). A patient presenting with URCSS without other defects was identified in six (16.7%). One patient (2.8%) had a history of paradoxical embolisation. Twenty-five patients (69.4%) were diagnosed before surgery. Ten patients (27.8%) were diagnosed with URCSS intraoperatively. One patient (2.8%) was diagnosed with URCSS by follow-up echocardiography after device occlusion for atrial septal defect. Coronary sinus ostium dilation was the most important clue leading to partial type lesion disclosure intraoperatively. The anomalous PLSVC of 15 patients was repaired using roof tunnel technique in four (26.7%) cases, baffle redirection in eight (53.3%) cases, posterior left atrial wall plicating in two (13.3%) cases, and extracardiac bypass in one (6.7%) case. Postoperative complete atrioventricular block occurred in one patient (2.8%). One patient died postoperatively (2.8%). All patients are doing well after discharge from hospital. CONCLUSIONS: Diagnostic suspicion can contribute to lesion disclosure. Surgical correction has good long-term outcomes and low risks. PMID- 28709919 TI - Morbidity After Cardiac Surgery in Patients With Adult Congenital Heart Disease in Comparison With Acquired Disease. AB - BACKGROUND: Due to the advancements in congenital cardiac surgery and interventional cardiology in the last 5 decades, more than 85% of congenital heart patients now survive to adulthood. METHODS: This retrospective study included 135 Adult Congenital Heart Disease (ACHD) patients, who had cardiac surgery at Southampton General Hospital over 3 consecutive years. We also included 42 patients with a structurally normal heart who had cardiac surgery for acquired cardiac conditions as a control group. Preoperative, intraoperative and postoperative data were analysed in both groups to identify risk factors for morbidity and mortality. RESULTS: In the ACHD group, in hospital mortality was 0.7%. In the control group no deaths were observed. Fifty-eight per cent of the ACHD patients had significantly higher perioperative morbidity with arrhythmias (26%), bleeding (3%), prolonged ventilation (11.3%) and renal replacement therapy 1.5%. In the non ACHD control group 32% (p=0.003) developed perioperative complications with arrhythmias (9.8%), bleeding (2.5%), prolonged ventilation (4.3%) and renal replacement therapy (2.5%). In ACHD patients total in-hospital stay was longer in patients with longer cardiopulmonary bypass (CPB) time (p=0.005), aortic cross clamp time (p=0.013) and higher preoperative alkaline phosphatase level (p=0.005). Early postoperative complications were higher in ACHD patients with longer cardiopulmonary bypass time (p=0.04) and presence of pulmonary artery hypertension (p=0.012). CONCLUSIONS: Even though the preoperative and operative characteristics are similar to both groups, the morbidity is more in ACHD group. Longer CBP time, aortic cross clamp time and presence of pulmonary hypertension are risk factors for higher morbidity in this group. PMID- 28709921 TI - Effects of pattern masks on the formation of perceptual grouping. AB - Mechanisms underlying perceptual grouping serve to bind stimulus components that are contained within grouped patterns. In order to examine the time course of grouping development, grids of spatially isolated dots were followed by pattern masks across a range of SOA. Subjects indicated the predominant perceived grouping of the dot patterns. Masks either spatially superimposed target elements (element mask), or superimposed elements as well as paths among elements (connection mask). Element masks thereby disrupted processing of target elements, while connection masks additionally disrupted representations in regions among elements. It was found that element masks disrupted grouping 12ms after target offset, after which masks had no effect. Connection masks disrupted grouping up to 47ms following target offset. Results suggest grouping mechanisms access the afferent signal for a brief period early in processing, after which binding formation proceeds for an addition 35ms. Shortening connection mask duration to 12ms enhanced performance during a brief temporal window within the interference period. For each set of conditions, target elements were visible during the time frame in which stimulus patterns could not be perceptually grouped. Full-field checkerboard masks degraded discrimination similarly as connection masks, although were more effective in disrupting discrimination with an SOA of 24 and 36ms. Degrading stimulus organization progressively extended the time scale for each masking effect. For the grouping of low-level stimulus features tested here, results support a model in which afferent signals are accessed early, followed by progressive binding among grouped elements. Effect of shortening connection masks may reflect incomplete disruption of target processing, or possibly re-entry of stimulus representations by feedback from higher processing areas. PMID- 28709920 TI - Visual discomfort and flicker. AB - Flickering lights can be uncomfortable to look at and can induce seizures in observers with photosensitive epilepsy. However, the temporal characteristics contributing to these effects are not fully known. In the spatial domain, one identified source of visual discomfort is when images have Fourier amplitude spectra that deviate from the natural (~1/frequency, 1/f) statistical characteristics of natural scenes, especially if they contain excess energy at the medium frequencies at which the visual system is most sensitive. We tested for analogous effects in the temporal domain, manipulating both the amplitude and phase spectra of the flicker. Participants judged the relative discomfort of temporal luminance variations in a pair of uniform 17 degrees fields with different temporal modulations. In general, discomfort increased with deviations from natural amplitude spectra, particularly those with excess energy at medium frequencies or biased toward sharper spectra. These ratings of discomfort were also consistent with ratings of how natural the modulations appeared. However, the temporal discomfort judgments were also strongly affected by the phase spectra of the flicker, with fixed vs. random spectra producing very different responses. This was not due to the perceived regularity or predictability of the flicker, but could arise from a number of other potential factors. Our findings suggest that, like spatial patterns, visual discomfort in time-varying patterns depends in part on how similar they are to the amplitude spectra of temporal variations in the natural visual environment, but also point to the critical role of the phase spectrum in the perceived discomfort of flicker. PMID- 28709922 TI - Pre- and post-saccadic stimulus timing in saccadic suppression of displacement - A computational model. AB - When the target of a saccadic eye movement is displaced while the eyes move this displacement is often not noticed (saccadic suppression of displacement, SSD). We present a neurobiologically motivated, computational model of SSD and compare its simulation results to experimental data. The model offers a simple explanation of the effects of pre- and post-saccadic stimulus blanking on SSD in terms of peri saccadic network dynamics. Under normal peri-saccadic conditions pre-and post saccadic stimulus traces are recurrently integrated with reference to present and future eye position, whereas blanking diminishes the pre-saccadic stimulus trace and thus leads to an uninfluenced integration of the post-saccadic stimulus trace. We show that part of the intersubject variability in SSD can be explained by differences in decision thresholds of this integration process. PMID- 28709923 TI - The spatial structure of cone-opponent receptive fields in macaque retina. AB - The receptive field structure of long (L) to middle (M) wavelength (L/M) cone opponent ganglion cells of the parafoveal macaque retina was investigated using drifting gratings. Gratings were luminance, chromatic or selective for the L- or M-cones. Based on these spatial tuning curves, receptive field profiles for the individual cones were derived. Receptive field profiles were coarse compared to single cones, and often could not be described by a simple Gaussian, having shallower flanks. There was a continuum of spatial properties, which blurred any systematic distinction between Type I and Type II receptive fields. Opponent center-surround organization within a single cone was rare. Usually, responses to all four grating types could be described based on the cone receptive field profiles. An exception was a few cells that showed irregularities of amplitude and phase at high spatial frequencies for one or other of the cone isolating conditions. The data are related to standard models of M/L opponent receptive fields and implications for central processing are considered. PMID- 28709924 TI - Training peripheral vision to read: Boosting the speed of letter processing. AB - Central-field loss necessitates the use of peripheral vision which makes reading slow and difficult. Slower temporal processing of letter recognition has been shown to be a limiting factor in peripheral letter recognition and reading. Previous studies showed that perceptual learning can increase the number of letters recognized on each fixation and is accompanied by an increase in reading speed. We hypothesized that improvement in temporal processing speed underlies the observed training effects. Here, we proposed an adaptive training procedure to focus on boosting the speed of letter recognition, and investigated whether peripheral reading would be enhanced by this training method. Seven normally sighted subjects were trained with four daily one-hour sessions of a letter recognition task at 10 degrees in the lower visual field in a pre/post design. During training, we adjusted stimulus duration on a block by block basis to maintain task difficulty near a pre-defined level of 80% performance accuracy. Stimulus duration progressively decreased with training, indicative of faster letter recognition at the 80% criterion. Following training, reading speed measured using a rapid serial visual presentation showed a substantial improvement in the trained (lower) field (41%) and the untrained (upper) field (27%), similar to the improvements observed from the training with a fixed stimulus duration. Despite being no more effective than the previous training, the adaptive temporal training method may allow individualized training, and may have advantages for clinical populations. PMID- 28709925 TI - The infinitesimal model: Definition, derivation, and implications. AB - Our focus here is on the infinitesimal model. In this model, one or several quantitative traits are described as the sum of a genetic and a non-genetic component, the first being distributed within families as a normal random variable centred at the average of the parental genetic components, and with a variance independent of the parental traits. Thus, the variance that segregates within families is not perturbed by selection, and can be predicted from the variance components. This does not necessarily imply that the trait distribution across the whole population should be Gaussian, and indeed selection or population structure may have a substantial effect on the overall trait distribution. One of our main aims is to identify some general conditions on the allelic effects for the infinitesimal model to be accurate. We first review the long history of the infinitesimal model in quantitative genetics. Then we formulate the model at the phenotypic level in terms of individual trait values and relationships between individuals, but including different evolutionary processes: genetic drift, recombination, selection, mutation, population structure, .... We give a range of examples of its application to evolutionary questions related to stabilising selection, assortative mating, effective population size and response to selection, habitat preference and speciation. We provide a mathematical justification of the model as the limit as the number M of underlying loci tends to infinity of a model with Mendelian inheritance, mutation and environmental noise, when the genetic component of the trait is purely additive. We also show how the model generalises to include epistatic effects. We prove in particular that, within each family, the genetic components of the individual trait values in the current generation are indeed normally distributed with a variance independent of ancestral traits, up to an error of order 1/M. Simulations suggest that in some cases the convergence may be as fast as 1/M. PMID- 28709926 TI - An efficient algorithm for generating the internal branches of a Kingman coalescent. AB - Coalescent simulations are a widely used approach for simulating sample genealogies, but can become computationally burdensome in large samples. Methods exist to analytically calculate a sample's expected frequency spectrum without simulating full genealogies. However, statistics that rely on the distribution of the length of internal coalescent branches, such as the probability that two mutations of equal size arose on the same genealogical branch, have previously required full coalescent simulations to estimate. Here, we present a sampling method capable of efficiently generating limited portions of sample genealogies using a series of analytic equations that give probabilities for the number, start, and end of internal branches conditional on the number of final samples they subtend. These equations are independent of the coalescent waiting times and need only be calculated a single time, lending themselves to efficient computation. We compare our method with full coalescent simulations to show the resulting distribution of branch lengths and summary statistics are equivalent, but that for many conditions our method is at least 10 times faster. PMID- 28709927 TI - Determining the distribution of fitness effects using a generalized Beta-Burr distribution. AB - In Beisel et al. (2007), a likelihood framework, based on extreme value theory (EVT), was developed for determining the distribution of fitness effects for adaptive mutations. In this paper we extend this framework beyond the extreme distributions and develop a likelihood framework for testing whether or not extreme value theory applies. By making two simple adjustments to the Generalized Pareto Distribution (GPD) we introduce a new simple five parameter probability density function that incorporates nearly every common (continuous) probability model ever used. This means that all of the common models are nested. This has important implications in model selection beyond determining the distribution of fitness effects. However, we demonstrate the use of this distribution utilizing likelihood ratio testing to evaluate alternative distributions to the Gumbel and Weibull domains of attraction of fitness effects. We use a bootstrap strategy, utilizing importance sampling, to determine where in the parameter space will the test be most powerful in detecting deviations from these domains and at what sample size, with focus on small sample sizes (n<20). Our results indicate that the likelihood ratio test is most powerful in detecting deviation from the Gumbel domain when the shape parameters of the model are small while the test is more powerful in detecting deviations from the Weibull domain when these parameters are large. As expected, an increase in sample size improves the power of the test. This improvement is observed to occur quickly with sample size n>=10 in tests related to the Gumbel domain and n>=15 in the case of the Weibull domain. This manuscript is in tribute to the contributions of Dr. Paul Joyce to the areas of Population Genetics, Probability Theory and Mathematical Statistics. A Tribute section is provided at the end that includes Paul's original writing in the first iterations of this manuscript. The Introduction and Alternatives to the GPD sections were obtained from the last iteration that Paul and I have worked on, with some adjustments. I hope that the rest gives justice to his thoughts and possible conclusions that he might have wanted to portray. PMID- 28709928 TI - A review of bioregulatory and coupled mechanobioregulatory mathematical models for secondary fracture healing. AB - Fracture healing is a complex biological process involving many cellular and molecular events. During fracture healing, biochemical signals play a regulatory role in promoting the healing process. Although many experiments have been conducted to study fracture healing, not all of the mechanisms are clearly understood. Over the past years, a lot of mathematical models and computational simulations have been established to investigate the fracture healing process. These models offer a powerful tool to study the interplay between cell behaviour, mechanical stimuli and biochemical signals and help design new treatment strategies. However, most of the mathematical models focus on the effect of mechanical stimuli and few models consider the important role of biochemical signals during fracture healing. In this review, we first emphasize the importance of biochemical signals during fracture healing. Then, existing bioregulatory and coupled mechanobioregulatory models are presented. Finally, some limitations and possible solutions are discussed. PMID- 28709929 TI - Large eddy simulations of blood dynamics in abdominal aortic aneurysms. AB - We study the effects of transition to turbulence in abdominal aortic aneurysms (AAA). The presence of transitional effects in such districts is related to the heart pulsatility and the sudden change of diameter of the vessels, and has been recorded by means of clinical measures as well as of computational studies. Here we propose, for the first time, the use of a large eddy simulation (LES) model to accurately describe transition to turbulence in realistic scenarios of AAA obtained from radiological images. To this aim, we post-process the obtained numerical solutions to assess significant quantities, such as the ensemble averaged velocity and wall shear stress, the standard deviation of the fluctuating velocity field, and vortical structures educed via the so-called Q criterion. The results demonstrate the suitability of the considered LES model and show the presence of significant transitional effects around the impingement region during the mid-deceleration phase. PMID- 28709930 TI - Particle image velocimetry study of the celiac trunk hemodynamic induced by continuous-flow left ventricular assist device. AB - Whereas left ventricular assist device (LVAD) is the gold-standard therapy for patients with heart failure, gastrointestinal bleeding is one of the most common complications. LVAD implantation may remarkably impact aortic hemodynamics so that experimental and computational flow analyses can be used to study the disease mechanisms. Here we present an experimentally-calibrated computational model of the celiac trunk hemodynamic of a LVAD-supported patient who experienced bleeding after device implantation. Specifically, both particle image velocimetry (PIV) and echocardiography were used to measure and compare flow distributions in each branch of a phantom model of the patient abdominal aorta. Then, the distribution of wall shear stress (WSS) was estimated by computational flow analysis. At a cardiac output of 5 L/min, the highest flow division was found in the mesenteric artery (13.6% for PIV and 14.6% for echocardiography), while the left renal artery exhibited the lowest amount in the celiac trunk model (2.6% for PIV and 2.4% for echocardiography). Bland-Altman analysis demonstrated a high agreement between echocardiographic and PIV-related flow measurements, while computational flow analysis revealed that WSS was high in the LVAD graft anastomosis site and just after the ostia of both the celiac trunk and mesenteric artery. This altered shear stress distribution in the celiac trunk may lead to a flow-mediated mechanism of adverse remodeling of the von Willebrand factor and ultimately to gastrointestinal bleeding as seen clinically in this patient. PMID- 28709931 TI - Non-invasive vibrometry-based diagnostic detection of acetabular cup loosening in total hip replacement (THR). AB - Total hip replacement is aimed at relieving pain and restoring function. Currently, imaging techniques are primarily used as a clinical diagnosis and follow-up method. However, these are unreliable for detecting early loosening, and this has led to the proposal of novel techniques such as vibrometry. The present study had two aims, namely, the validation of the outcomes of a previous work related to loosening detection, and the provision of a more realistic anatomical representation of the clinical scenario. The acetabular cup loosening conditions (secure, and 1 and 2 mm spherical loosening) considered were simulated using Sawbones composite bones. The excitation signal was introduced in the femoral lateral condyle region using a frequency range of 100-1500 Hz. Both the 1 and 2 mm spherical loosening conditions were successfully distinguished from the secure condition, with a favourable frequency range of 500-1500 Hz. The results of this study represent a key advance on previous research into vibrometric detection of acetabular loosening using geometrically realistic model, and demonstrate the clinical potential of this technique. PMID- 28709932 TI - Assessing glycolytic flux alterations resulting from genetic perturbations in E. coli using a biosensor. AB - We describe the development of an optimized glycolytic flux biosensor and its application in detecting altered flux in a production strain and in a mutant library. The glycolytic flux biosensor is based on the Cra-regulated ppsA promoter of E. coli controlling fluorescent protein synthesis. We validated the glycolytic flux dependency of the biosensor in a range of different carbon sources in six different E. coli strains and during mevalonate production. Furthermore, we studied the flux-altering effects of genome-wide single gene knock-outs in E. coli in a multiplex FlowSeq experiment. From a library consisting of 2126 knock-out mutants, we identified 3 mutants with high-flux and 95 mutants with low-flux phenotypes that did not have severe growth defects. This approach can improve our understanding of glycolytic flux regulation improving metabolic models and engineering efforts. PMID- 28709934 TI - Response: "Decompression and coflex interlaminar stabilization compared with conventional surgical procedures for lumbar spinal stenosis: A systematic review and meta-analysis". PMID- 28709933 TI - Identification of novel biomarker and therapeutic target candidates for diagnosis and treatment of follicular carcinoma. AB - : Distinguishing follicular carcinoma from follicular adenoma, based on cytomorphological features, has always been challenging to cytopathologists. Identification of biomarkers for improving diagnostic accuracy is important for clinical management. Meanwhile, it is critical to identify therapeutic target candidates for treatment of follicular carcinoma. Currently, no reliable diagnostic protein biomarkers and therapeutic targets are available. To explore novel protein biomarker and therapeutic target candidates, a liquid chromatography-tandem mass spectrometry approach was applied to analyze control, follicular adenoma, and follicular carcinoma using formalin-fixed, paraffin embedded tissue samples. The proteomics analysis revealed 80 protein biomarker candidates for diagnosis of thyroid follicular carcinoma. The candidates were prioritized into three categories and ranked within each category. Using the proteomics data and bioinformatics results, the top seven biomarker candidates were coiled-coil-helix-coiled-coil-helix domain-containing protein 2, mitochondrial (CHCHD2), succinyl-CoA ligase [GDP-forming] subunit beta, mitochondrial (SUCLG2), stomatin-like protein 2, mitochondrial (STOML2), ES1 protein homolog, mitochondrial (C21orf33), fumarate hydratase, mitochondrial (FH), 3-hydroxyacyl-CoA dehydrogenase type-2 (HSD17B10), and electron transfer flavoprotein subunit beta (ETFB); and the top seven therapeutic target candidates were insulin receptor (INSR), Myc proto-oncogene protein (MYC), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A), gastrin (GAST), N-myc proto-oncogene protein (MYCN), transforming growth factor beta-1 (TGFB1), and interleukin-4 (IL4). Immunohistochemical staining of SUCLG2 and ETFB is highly consistent with the discovery of proteomics, revealing that SUCLG2 has a sensitivity of 75% and a specificity of 80% to distinguish follicular carcinoma from follicular adenoma based on a specific cut-off score calculated from the IHC staining percentage and intensity. BIOLOGICAL SIGNIFICANCE: Distinguishing follicular carcinoma from follicular adenoma, based on cytomorphological features, has always been challenging to cytopathologists. Fourteen biomarker candidates were identified. Two of them were validated with Immunohistochemical staining. The Identification of biomarkers for improving diagnostic accuracy is important for clinical management. PMID- 28709935 TI - Appropriate extent of lymphadenectomy for squamous cell carcinoma of the esophagogastric junction. AB - AIM: To investigate the appropriate extent of lymphadenectomy for squamous cell carcinoma (SCC) of the esophagogastric junction (ECJ). METHODS: We retrospectively reviewed the cases of 52 patients with SCC of the ECJ who underwent extended mediastinal lymphadenectomy. We assessed potential risk factors for lymph node metastasis (LNM) in the upper/middle mediastinum by conducting univariate and multivariate analyses, and a receiver operating characteristic (ROC) curve analysis was used to evaluate the predictive value. Survival rates were calculated using the Kaplan-Meier method, and the therapeutic value index of each nodal basin dissection was calculated by multiplying the frequency of metastasis at the basin and the 5-year overall survival rate of patients with metastasis at that basin. RESULTS: Twenty patients (38%) had mediastinal LNM; 13 (25%) had metastasis in the upper/middle mediastinum, and 13 (25%) had metastasis in the lower mediastinum. Tumor length (P = 0.03) and pathological nodal status (P = 0.01) were independent risk factors for upper/middle mediastinal LNM. The optimal ROC cutoff value of tumor length was 54 mm. The 5-year overall survival rate of the patients with LNM in the upper/middle mediastinum was 46%. The therapeutic value index of upper/middle mediastinal lymphadenectomy was 11.6, which was inferior to that of perigastric lymphadenectomy at 17.3, but superior to that of lower mediastinal lymphadenectomy at 5.8. CONCLUSION: An upper/middle mediastinal lymphadenectomy may be required for patients with tumors that are >=54 mm long, and in those with suspected LNM. PMID- 28709936 TI - Effects of Klotho on fibrosis and cancer: A renal focus on mechanisms and therapeutic strategies. AB - Klotho is a membrane-bound protein predominantly expressed in the kidney, where it acts as a permissive co-receptor for Fibroblast Growth Factor 23. In its shed form, Klotho exerts anti-fibrotic effects in several tissues. Klotho-deficient mice spontaneously develop fibrosis and Klotho deficiency exacerbates the disease progression in fibrotic animal models. Furthermore, Klotho overexpression or supplementation protects against fibrosis in various models of renal and cardiac fibrotic disease. These effects are mediated at least partially by the direct inhibitory effects of soluble Klotho on TGFbeta1 signaling, Wnt signaling, and FGF2 signaling. Soluble Klotho, as present in the circulation, appears to be the primary mediator of anti-fibrotic effects. Similarly, through inhibition of the TGFbeta1, Wnt, FGF2, and IGF1 signaling pathways, Klotho also inhibits tumorigenesis. The Klotho promoter gene is generally hypermethylated in cancer, and overexpression or supplementation of Klotho has been found to inhibit tumor growth in various animal models. This review focuses on the protective effects of soluble Klotho in inhibiting renal fibrosis and fibrosis in distant organs secondary to renal Klotho deficiency. We also discuss the structure-function relationships of Klotho domains and biological effects in the context of potential targeted treatment strategies. PMID- 28709937 TI - Detection of Lung Cancer and EGFR Mutation by Electronic Nose System. AB - INTRODUCTION: Early detection of lung cancer (LC) has been well established as a significant key point in patient survival and prognosis. New highly sensitive nanoarray sensors for exhaled volatile organic compounds that have been developed and coupled with powerful statistical programs may be used when diseases such as LC are suspected. Detection of genetic aberration mutation by nanoarray sensors is the next target. METHODS: Breath samples were taken from patients who were evaluated for suspicious pulmonary lesions. Patients were classified as those with benign nodules, as patients with LC with or without the EGFR mutation, and according to their smoking status. Breath prints were recognized by nanomaterial based sensor array, and pattern recognition methods were used. RESULTS: A total of 119 patients participated in this study, 30 patients with benign nodules and 89 patients with LC (16 with early disease and 73 with advanced disease). Patients with LC who harbored the EGFR mutation (n = 19) could be discriminated from those with wild-type EGFR (n = 34) with an accuracy of 83%, sensitivity of 79%, and specificity of 85%. Discrimination of early LC from benign nodules had 87% accuracy and positive and negative predictive values of 87.7 and 87.5% respectively. Moderate discrimination (accuracy of 76%) was found between LC of heavy smokers and that of never-smokers or distant past light smokers. CONCLUSIONS: Breath analysis could discriminate patients with LC who harbor the EGFR mutation from those with wild-type EGFR and those with benign pulmonary nodules from those patients with early LC. A positive breath print for the EGFR mutation may be used in treatment decisions if tissue sampling does not provide adequate material for definitive mutation analysis. PMID- 28709938 TI - A cross-sectional comparison of brain glucose and ketone metabolism in cognitively healthy older adults, mild cognitive impairment and early Alzheimer's disease. AB - INTRODUCTION: Deteriorating brain glucose metabolism precedes the clinical onset of Alzheimer's disease (AD) and appears to contribute to its etiology. Ketone bodies, mainly beta-hydroxybutyrate and acetoacetate, are the primary alternative brain fuel to glucose. Some reports suggest that brain ketone metabolism is unchanged in AD but, to our knowledge, no such data are available for MCI. OBJECTIVE: To compare brain energy metabolism (glucose and acetoacetate) and some brain morphological characteristics in cognitively healthy older adult controls (CTL), mild cognitive impairment (MCI) and early AD. METHODS: 24 CTL, 20 MCI and 19AD of similar age and metabolic phenotype underwent a dual-tracer PET and MRI protocol. The uptake rate constants and cerebral metabolic rate of glucose (KGlu, CMRGlu) and acetoacetate (KAcAc, CMRAcAc) were evaluated with PET using [18F] fluorodeoxyglucose ([18F]-FDG), a glucose analogue, and [11C]-acetoacetate ([11C] AcAc), a ketone PET tracer. Regional brain volume and cortical thickness were evaluated by T1-weighted MRI. RESULTS: In AD compared to CTL, CMRGlu was ~11% lower in the frontal, parietal, temporal lobes and in the cingulate gyrus (p<0.05). KGlu was ~15% lower in these same regions and also in subcortical regions. In MCI compared to CTL, ~7% glucose hypometabolism was present in the cingulate gyrus. Neither regional nor whole brain CMRAcAc or KAcAc were significantly different between CTL and MCI or AD. Reduced gray matter volume and cortical thinning were widespread in AD compared to CTL, whereas, in MCI compared to CTL, volumes were reduced only in the temporal cortex and cortical thinning was most apparent in temporal and cingulate regions. DISCUSSION: This quantitative kinetic PET and MRI imaging protocol for brain glucose and acetoacetate metabolism confirms that the brain undergoes structural atrophy and lower brain energy metabolism in MCI and AD and demonstrates that the deterioration in brain energy metabolism is specific to glucose. These results suggest that a ketogenic intervention to increase energy availability for the brain is warranted in an attempt to delay further cognitive decline by compensating for the brain glucose deficit in MCI and AD. PMID- 28709939 TI - Transdermal delivery of dimethyl fumarate for Alzheimer's disease: Effect of penetration enhancers. AB - Dimethyl fumarate (DMF) is an orally administered drug with neuroprotective and immunomodulatory activities. It has potential uses in the treatment of neurodegenerative diseases such as Alzheimer's disease (AD). The objective of this study was to investigate the feasibility of transdermal delivery of DMF by studying the effect of different penetration enhancers on the skin permeation of DMF. The permeation of saturated DMF solutions was investigated in propylene glycol (PG) with varying concentrations of each of the following enhancers: Polysorbate 80 (T80), N-methyl pyrrolidone (NMP), laurocapram (Azone(r)) (Az), Transcutol P (Tc), Terpineol (Terp), and cineole (Cin) using vertical Franz diffusion cells and human cadaver skin. The results showed that all penetration enhancers improved the rate of permeation of DMF. The rank order for the highest concentration of each enhancer was as follows: Cin > Az>TC > Terp>T80>=NMP. The most effective penetration enhancer was shown to be 5% cineole with a 5.3-fold increase in the enhancement ratio (ER). The amounts of drug delivered suggest that DMF is a potential candidate for transdermal drug delivery. PMID- 28709940 TI - Investigation of L-leucine in reducing the moisture-induced deterioration of spray-dried salbutamol sulfate power for inhalation. AB - The aim of this study was to investigate the ability of L-leucine (LL) in preventing moisture-induced deterioration in the in vitro aerosolization performance of spray-dried (SD) salbutamol sulfate (SS). Increasing mass fraction of LL (5-80%) were co-spray dried with SS, and the physicochemical properties of the powders were characterized by laser diffraction, X-ray powder diffraction (XRD) and dynamic vapour sorption (DVS). Furthermore, the surface morphology and chemistry of fine particles was analyzed by scanning electron microscopy (SEM) and X-ray photoelectron spectroscopy (XPS). The in vitro aerosolization performance of powders stored at different relative humidity (RH) was evaluated by a next generation impactor (NGI). The SD SS powders were moderately hygroscopic and amorphous, of which the uptake of moisture upon storage caused a drop in the aerosolization performance. The results showed that 40% (w/w) LL was sufficient to eliminate the effect of moisture on the aerosolization performance at 60% RH. The formulation containing 40% (w/w) LL also maximized the aerosolization performance of SD SS powders (stored in desiccator) with the emitted fraction being 90.0+/-1.8%, and the fine particle fraction based on the recovered dose (FPFrecovered) and emitted dose (FPFemitted) being 78.0+/-3.7% and 86.6+/-2.9%, respectively. The underlying mechanisms were that the crystalline LL increased the degree of particle surface corrugation, and reduced particle fusion and cohesiveness to facilitate dispersion. However, there is still a great challenge to prevent the moisture-induced deterioration in the aerosolization performance at 75% RH due to the recrystallization of SD SS. In conclusion, LL is a potential excipient for reducing moisture-induced deterioration in the aerosolization performance of SD amorphous powders, but still has drawbacks in preventing the recrystallization-induced deterioration. PMID- 28709941 TI - Evolvability and robustness: A paradox restored. AB - Evolvability and robustness are crucial for the origin and maintenance of complex organisms, but may not be simultaneously achievable as robust traits are also hard to change. Andreas Wagner has proposed a solution to this paradox by arguing that the many-to-few aspect of genotype-phenotype maps creates neutral networks of genotypes coding for the same phenotype. Phenotypes with large networks are genetically robust, but they may also have more neighboring phenotypes and thus higher evolvability. In this paper, we explore the generality of this idea by sampling large numbers of random genotype-phenotype maps for Boolean genotypes and phenotypes. We show that there is indeed a preponderance of positive correlations between the evolvability and robustness of phenotypes within a genotype-phenotype map, but also that there are negative correlations between average evolvability and robustness across maps. We interpret this as predicting a positive correlation across the phenotypic states of a character, but a negative correlation across characters. We also argue that evolvability and robustness tend to be negatively correlated when phenotypes are measured on ordinal or higher scale types. We conclude that Wagner's conjecture of a positive relation between robustness and evolvability is based on strict and somewhat unrealistic biological assumptions. PMID- 28709942 TI - Generation time and fitness tradeoffs during the evolution of multicellularity. AB - The evolution of multicellular organisms from their unicellular ancestors is an example of an evolutionary transition in individuality (ETI), i.e. a change in the units of selection and adaptation. The theory of ETIs poses particular challenges because, by definition, key theoretical constructs such as fitness are shifting during an ETI. Past work emphasized the importance of life history tradeoffs during ETIs in which lower level units form groups and become individuals at a higher level. In particular, it has been hypothesized that the convexity of the lower-level tradeoff between viability and fecundity changes with group size and determines the optimality of lower-level specialization in the fitness components of the group. This is important because lower-level specialization is a key indicator of higher-level individuality. Here we show that increasing generation time can increase the convexity of the lower-level viability-fecundity tradeoff. This effect is a novel hypothesis for the positive association between cell-group size and cellular specialization in a major model system for ETIs, the volvocine algae. The pattern in this clade is thought to be an example of a more general size-complexity rule. Our hypothesis is that larger groups have longer generation times and longer generation times lead to more convex lower-level viability-fecundity tradeoffs, which could account for specialization being optimal only in larger cell groups (colonies). We discuss the robustness of this effect to various changes in the assumptions of our model. Our work is important for the study of ETIs in general because viability and fecundity are fundamental components of fitness in all systems and because generation time is expected to be changing during many ETIs. PMID- 28709943 TI - Propagation and control of gene expression noise with non-linear translation kinetics. AB - Gene expression is a stochastic process involving small numbers of molecules. As a consequence, cells in a clonal population vary randomly and sometimes substantially from one another in the concentration of mRNA and protein species, a phenomenon known as gene expression noise. Previous theoretical models of gene expression noise assumed that translation is first-order (linear) in mRNA concentration, leading to unfiltered propagation of mRNA noise to the protein level. Here I consider the biological ramifications of relaxing this assumption. Specifically, I solve for the noise statistics of gene expression assuming that translation obeys hyperbolic, Michaelis-Menten kinetics with respect to mRNA concentration. I generalize previous stochastic gene expression models by allowing the kinetic order of translation, denoted here by a, to vary continuously from zero-order (a = 0), where ribosomes are fully saturated with mRNA, to first order (a = 1), where ribosomes are unsaturated and mRNA is limiting for translation. In general, hyperbolic translation acts as a high amplitude filter of mRNA noise. This hyperbolic filtering greatly attenuates the propagation of transcriptional noise to the protein level and qualitatively changes the selective and synthetic targets of noise control. In principle, natural selection or synthetic biologists could exploit this feature to limit or amplify gene expression noise by tuning mRNA and ribosome levels to control the kinetic order of translation. PMID- 28709944 TI - Latex proteins from Calotropis procera: Toxicity and immunological tolerance revisited. AB - Many thousands of plants are disseminated worldwide in traditional and folk medicines based on the belief that their leaves, roots, seeds, bark or secretions, when adequately handled, can treat, alleviate or ameliorate numerous disease symptoms. Calotropis procera (Apocynaceae) is a popular medicinal plant and the claims of this shrub's phytomedicinal properties have been scientifically validated. In this study, further prospects towards the in vivo toxicity and oral immunological tolerance of phytomodulatory proteins isolated from the latex of C. procera are reported. Acute toxicity was determined in mice by oral and intraperitoneal administration of latex proteins (LP) and was followed behavioral, hematological and histological analyses. Oral immunological tolerance to LP was assessed by intraperitoneal immunization in mice that had received LP orally before. Animals given 5000 mg/kg orally exhibited only discrete behavioral alterations and augmentation of monocytes. Death was not notified 14 days after exposure. However, all animals receiving LP 150 mg/kg by i.p. died in 1 h. Death (20%) was documented when LP (75 mg/kg) was given in the peritoneum and signs of harmful effects were observed in the survivors (80%). Oral immunological tolerance was observed in animals previously given LP orally, when they were further immunized/challenged with peritoneal exposure to different doses of LP. This was confirmed by the lowering of IgE and IgG in the serum, IL-4 and IFN gamma in spleen homogenates and the absence of anaphylaxis signs. It is therefore concluded that LP exhibited quite discrete adverse effects when orally administrated at higher concentrations and this route of administration did not stimulate adverse immunological reactions. Instead it was observed immunological tolerance. The present study contributes very important information concerning the safe use of C. procera as a phytotherapeutic agent. PMID- 28709945 TI - Punicalagin, a polyphenol from pomegranate fruit, induces growth inhibition and apoptosis in human PC-3 and LNCaP cells. AB - Prostate cancer (PCa) is an international health problem and search for its effective treatment is in progress. Punicalagin (PN), polyphenol from pomegranate fruit, is known to exhibit potent anticancer activity in lung, breast and cervical cells. However, there is paucity of information on its effect in PCa. This study evaluated anti-proliferative effects of PN and its effects on extrinsic pathway of apoptosis in PCa cells, and angiogenesis in chicken chorioallantoic membrane (CAM). Antioxidant activities of PN were determined by 2,2-diphenyl-1-picryhydrazyl (DPPH) radical scavenging and inhibition of lipid peroxidation (LPO) methods. PCa (PC-3 and LNCaP) and normal prostate (BPH-1) cells were cultured and treated with PN (10, 50 and 100 MUM). Cytotoxicity and viability effects of PN were determined by lactate dehydrogenase (LDH) and XTT assays, respectively. Antiangiogenic effects were measured using CAM assay, while apoptosis was assessed by DNA fragmentation, enrichment factor by Cell Death Detection ELISA kit and expressions of caspases-3 and -8. Results showed that PN (10-200 MUM) significantly scavenged DPPH and inhibited LPO in a concentration dependent manner. Furthermore, PN (10-100 MUM) concentration-dependently inhibited viability in PC-3 and LNCaP, while viability in BPH-1 was insignificantly affected. PN had low toxicity on cells in vitro at concentrations tested. Also, PN (100 MUM) increased enrichment factor in PC-3 (2.34 +/- 0.05) and LNCaP (2.31 +/- 0.26) relative to control (1.00 +/- 0.00). In addition, PN (50 MUM) decreased the network of vessels in CAM, suggesting its anti-angiogenic effect. Moreso, PN increased the expressions of caspases-3 and -8 in PC-3. Overall, PN exerts anti-proliferative activity in PCa cells via induction of apoptosis and anti-angiogenic effect. PMID- 28709946 TI - Frailty and sarcopenia do not predict adverse events in an elderly population undergoing non-complex primary elective surgery for degenerative conditions of the lumbar spine. AB - BACKGROUND CONTEXT: Sarcopenia measured by normalized total psoas area (NTPA) has been shown to predict mortality and adverse events (AEs) in numerous surgical populations. The relationship between sarcopenia and postoperative outcomes after surgery for degenerative spine disease (DSD) has not been investigated. PURPOSE: This study aimed to determine the relationships between sarcopenia, frailty, and postoperative AEs in the elderly DSD population. Secondary objectives were to describe the distribution and predictors of NTPA and to determine the relationship between sarcopenia, frailty, and length of stay, discharge to a facility, and in-hospital mortality. STUDY DESIGN: This is an ambispective study from a quaternary care academic center. PATIENT SAMPLE: A total of 102 patients over 65 years old who underwent elective thoracolumbar surgery for DSD between 2009 and 2013 were included in this study. OUTCOME MEASURES: The primary outcome was a composite of perioperative AEs; the secondary outcomes were length of stay, discharge disposition, and in-hospital mortality. METHODS: Total psoas area (TPA) at mid-L3 level on preoperative computed tomography scan adjusted for height (NTPA) defined sarcopenia. The modified frailty index (mFI) of 11 clinical variables defined frailty. The distribution and predictors of sarcopenia (NTPA) were determined. The association of NTPA with AEs, length of stay, discharge disposition to care facility, and mortality was analyzed, including adjusting for known and suspected confounders using multivariate regression. RESULTS: Median Spine Surgical Invasiveness Index was 8 (interquartile range 2-10), and mean NTPA was 674 mm2/m2 (293.21-1636.25). Using the mFI, 20.6% were pre-frail and 19.6% were frail. Inter- and intraobserver reliability for determining NTPA were near perfect with kappa 0.95-0.97 and 0.94-1.00, respectively. The NTPA was independently associated with patient gender and body mass index (BMI) but not frailty (mFI). Age, BMI, mFI, and American Anesthesiologists' Society score were not associated with incidence of postoperative AEs. The NTPA did not predict the occurrence of AE (odds ratio [OR] 1.06 per 100 mm2/m2, 95% confidence interval [CI] 0.91-1.23, p=.45). Similarly, NTPA was not predictive of length of stay (rho=-0.04, p=.67), discharge home (OR 0.95 (95% CI 0.76-1.20) per 100 mm2/m2, p=.70), or death (OR 1.12 (95% CI 0.83-1.53) per 100 mm2/m2, p=.47). In contrast, increasing mFI was associated with increased risk of mortality (OR 3.12 (95% CI 1.21-8.03) per 0.1 increase in frailty score, p=.006). CONCLUSIONS: In contrast to other surgical groups, sarcopenia (NTPA) or frailty (mFI) did not predict acute care complications in a selected population of elderly patients undergoing simple lumbar spine surgery for DSD. Although NTPA can be reliably measured in this population, it may be an inappropriate surrogate for sarcopenia given its anatomical relationship to spinal function. PMID- 28709947 TI - Combination of whole-spine lateral radiograph and lateral scanogram in the assessment of global sagittal balance. AB - BACKGROUND CONTEXT: Global balance of human standing is analyzed as the geometric sum of the individual alignments extending from the spinal column to the pelvis, and to the lower limbs. The innovative EOS system has opened new perspectives for the global analysis of whole-body alignment, but its use is very limited because of its high cost. An alternative may be to combine the whole-spine lateral radiograph and the lateral scanogram in the global sagittal analysis of whole body alignment. PURPOSE: We examined to determine the validity and reliability of a lateral scanogram in the measurement of sacropelvic parameters. STUDY DESIGN/SETTING: A retrospective radiological study was carried out. PATIENT SAMPLE: We randomly selected 100 sets of digital radiographs, both whole-spine radiographs and lower-limb scanograms, from our database. OUTCOME MEASURES: Sacropelvic parameters, including pelvic incidence, sacral slope, and pelvic tilt, were measured on both whole-spine radiographs and lower-limb scanograms by three independent examiners on three separate occasions. METHODS: Agreement regarding the measurements on both image types was calculated to assess the validity of the lateral scanogram for use in whole-body alignment determinations. Intraobserver and interobserver reliabilities among the types of measurements were calculated. RESULTS: The sacropelvic area on the lateral scanogram was not visible in 19 patients (19%). In the remaining 81 patients, the sacropelvic parameters on the lateral scanogram were similar to those on the whole-spine lateral radiograph (Pearson correlation coefficient, 0.764-0.805). Intraobserver and interobserver reproducibilities for both modalities were good to excellent (intraclass correlation coefficient, 0.657-0.984). CONCLUSIONS: Sacropelvic parameter measurements on lateral scanogram were reliable and were similar to those measured on whole-spine lateral radiograph. Thus, global alignment can be evaluated using the lateral scanogram in combination with the whole-spine lateral radiograph. PMID- 28709948 TI - Mechanical ventilation strategies. AB - Although only a small proportion of full term and late preterm infants require invasive respiratory support, they are not immune from ventilator-associated lung injury. The process of lung damage from mechanical ventilation is multifactorial and cannot be linked to any single variable. Atelectrauma and volutrauma have been identified as the most important and potentially preventable elements of lung injury. Respiratory support strategies for full term and late preterm infants have not been as thoroughly studied as those for preterm infants; consequently, a strong evidence base on which to make recommendations is lacking. The choice of modalities of support and ventilation strategies should be guided by the specific underlying pathophysiologic considerations and the ventilatory approach must be individualized for each patient based on the predominant pathophysiology at the time. PMID- 28709949 TI - Pulmonary hypoplasia. AB - To survive the transition to extrauterine life, newborn infants must have lungs that provide an adequate surface area and volume to allow for gas exchange. The dynamic activities of fetal breathing movements and accumulation of lung luminal fluid are key to fetal lung development throughout the various phases of lung development and growth, first by branching morphogenesis, and later by septation. Because effective gas exchange is essential to survival, pulmonary hypoplasia is among the leading findings on autopsies of children dying in the newborn period. Management of infants born prematurely who had disrupted lung development, especially at the pre-glandular or canalicular periods, may be challenging, but limited success has been reported. Growing understanding of stem cell biology and mechanical development of the lung, and how to apply them clinically, may lead to new approaches that will lead to better outcomes for these patients. PMID- 28709951 TI - MicroRNA: Basic concepts and implications for regeneration and repair of neurodegenerative diseases. AB - MicroRNAs (miRNA) are small non-coding molecules that revolutionized our knowledge about the regulation of gene expression. Capable to target a large number of mRNA, miRNA are thought to regulate around 30% of the entire human genome. Therefore, these molecules are able to regulate several biological processes, including neuronal survival, differentiation and regeneration. Additionally, miRNA might act as valuable clinical agents in brain pathological conditions. Their specific expression patterns in the brain parenchyma and/or in circulating fluids have been highlighted as potential biomarkers, while the modulation of their activity may have therapeutic value for several neurodegenerative diseases. In this review, we describe miRNA biogenesis, signaling and regulation as well as the role of miR-9, miR-124, miR-132 and miR 137 in both adult neurogenesis and neurodegeneration, namely in Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis. The relationship between miRNA, neurodegeneration and neurogenesis will be highlighted. Moreover, the benefits, outcomes and limitations of therapies using miRNA technology for neurodegenerative disorders will also be discussed. PMID- 28709950 TI - Characterization of potent and selective iodonium-class inhibitors of NADPH oxidases. AB - The NADPH oxidases (NOXs) play a recognized role in the development and progression of inflammation-associated disorders, as well as cancer. To date, several NOX inhibitors have been developed, through either high throughput screening or targeted disruption of NOX interaction partners, although only a few have reached clinical trials. To improve the efficacy and bioavailability of the iodonium class NOX inhibitor diphenylene iodonium (DPI), we synthesized 36 analogs of DPI, focusing on improved solubility and functionalization. The inhibitory activity of the analogs was interrogated through cell viability and clonogenic studies with a colon cancer cell line (HT-29) that depends on NOX for its proliferative potential. Lack of altered cellular respiration at relevant iodonium analog concentrations was also demonstrated. Additionally, inhibition of ROS generation was evaluated with a luminescence assay for superoxide, or by Amplex Red(r) assay for H2O2 production, in cell models expressing specific NOX isoforms. DPI and four analogs (NSCs 740104, 751140, 734428, 737392) strongly inhibited HT-29 cell growth and ROS production with nanomolar potency in a concentration-dependent manner. NSC 737392 and 734428, which both feature nitro functional groups at the meta position, had >10-fold higher activity against ROS production by cells that overexpress dual oxidase 2 (DUOX2) than the other compounds examined (IC50~200-400nM). Based on these results, we synthesized and tested NSC 780521 with optimized potency against DUOX2. Iodonium analogs with anticancer activity, including the first generation of targeted agents with improved specificity against DUOX2, may provide a novel therapeutic approach to NOX-driven tumors. PMID- 28709952 TI - Potent inhibitors of human LAT1 (SLC7A5) transporter based on dithiazole and dithiazine compounds for development of anticancer drugs. AB - The LAT1 transporter is acknowledged as a pharmacological target of tumours since it is strongly overexpressed in many human cancers. The purpose of this work was to find novel compounds exhibiting potent and prolonged inhibition of the transporter. To this aim, compounds based on dithiazole and dithiazine scaffold have been screened in the proteoliposome experimental model. Inhibition was tested on the antiport catalysed by hLAT1 as transport of extraliposomal [3H]histidine in exchange with intraliposomal histidine. Out of 59 compounds tested, 8 compounds, showing an inhibition higher than 90% at 100uM concentration, were subjected to dose-response analysis. Two of them exhibited IC50 lower than 1uM. Inhibition kinetics, performed on the two best inhibitors, indicated a mixed type of inhibition with respect to the substrate. Furthermore, inhibition of the transporter was still present after removal of the compounds from the reaction mixture, but was reversed on addition of dithioerythritol, a S S reducing agent, indicating the formation of disulfide(s) between the compounds and the protein. Molecular docking of the two best inhibitors on the hLAT1 homology structural model, highlighted interaction with the substrate binding site and formation of a covalent bond with the residue C407. Indeed, the inhibition was impaired in the hLAT1 mutant C407A confirming the involvement of that Cys residue. Treatment of SiHa cells expressing hLAT1 at relatively high level, with the two most potent inhibitors led to cell death which was not observed after treatment with a compound exhibiting very poor inhibitory effect. PMID- 28709954 TI - Modulation of Itch by Conditioning Itch and Pain Stimulation in Healthy Humans. AB - : Little is known about endogenous descending control of itch. In chronic pain, descending pain inhibition is reduced as signified by lowered conditioned pain modulation. There are indications that patients with chronic itch may also exhibit reduced endogenous descending inhibition of itch and pain. This study aimed to investigate whether and the extent to which itch can be modulated by conditioning itch and pain stimuli. Twenty-six healthy volunteers participated. The study consisted of 5 conditions designed to systematically assess endogenous modulation of itch or pain: 1) itch-induced modulation of contralateral itch, 2) pain-induced modulation of contralateral itch, 3) pain-induced modulation of ipsilateral itch, 4) pain-induced modulation of contralateral pain, and 5) itch induced modulation of contralateral pain. Conditioning stimuli were cold pressor induced pain and histamine-evoked itch, whereas the test stimuli were electrical stimulation paradigms designed to evoke itch or pain. Pain was significantly reduced (conditioned pain modulation-effect) by the conditioning pain stimulus (P < .001), but not by the conditioning itch stimulus (negative control condition). Itch was significantly reduced (conditioned itch modulation-effect) by contra- as well as ipsilateral applied conditioning pain (both P < .001), whereas conditioning itch stimulation only marginally reduced itch. Endogenous descending itch inhibition through mechanisms that are independent of segmental gating can be readily evoked by heterotopic conditioning pain stimulation. However, robust descending inhibition of itch cannot be evoked with conditioning itch stimulation. PERSPECTIVE: The study showed a hierarchical prioritization favoring pain-induced central descending modulation of itch as well as pain in humans. Future studies addressing potential aberrations in pain-evoked descending modulation of itch in chronic itch patients are warranted. PMID- 28709953 TI - Association of hemodynamic variables with in-hospital mortality and favorable neurological outcomes in post-cardiac arrest care with targeted temperature management. AB - PURPOSE: Although hemodynamic instability is expected during the post-cardiac arrest period, the implications of hemodynamic parameters for outcomes remain unclear. Each phase of targeted temperature management (TTM) affects hemodynamic responses differently. This study aims to investigate the association of hemodynamic parameters with outcomes in patients receiving TTM after cardiac arrest. METHODS: The study prospectively enrolled patients who were treated with TTM (33 degrees C for 24h) after cardiac arrest. We assessed clinical and hemodynamic variables at pre-specified time points in survivors and non-survivors as well as among those with favorable vs. poor neurologic outcomes at discharge. RESULTS: The study analyzed the records of 95 patients who completed TTM; at discharge 54 (57%) were alive and 21 (22%) had favorable neurological outcomes. Heart rate(HR) at 24h>93/min, cardiac index (CI) at 12h<2.5l/min/m2 and lower average of mean arterial blood pressure(MAP) at 36h and 48h were independently associated with in-hospital mortality (P<0.05 by Cox regression analysis respectively). MAP at 48h between 84-110mm Hg and lower HR at 48h were significantly associated with better neurological outcome at discharge (P<0.05 for by logistic regression analysis respectively). CONCLUSIONS: Our results indicate that lower MAP and HR more than 93/min are associated with in-hospital mortality during the initial 48h after ROSC. CI at 12h<2.5l/min/m2 is associated with survival but not with neurological outcome. During the course of post cardiac arrest TTM, these markers of hemodynamic status may be useful predictors of outcomes. PMID- 28709955 TI - Neonatal Injury Results in Sex-Dependent Nociceptive Hypersensitivity and Social Behavioral Deficits During Adolescence, Without Altering Morphine Response. AB - : Neonatal injury is associated with persistent changes in sensory function and altered nociceptive thresholds that give rise to aberrant pain sensitivity in later life. Although these changes are well documented in adult rodents, little is known about the consequences of neonatal injury during adolescence. Because adolescence is a critical developmental period during which persistent pain conditions can arise, we examined the effect of neonatal injury on nociception, social behavior, and response to morphine in adolescent Sprague Dawley rats. Male and female rats exposed to plantar incision injury at postnatal day 3 displayed mechanical hypersensitivity that resolved by 24 hours after incision. When these animals reached adolescence (postnatal day 28-40), neonatally-injured male rats showed ipsilaterally restricted mechanical, heat, and cold hypersensitivity, as well as social behavioral deficits. In contrast, these effects were not seen in female rats. Neonatal injury did not alter acute morphine antinociception or the development of analgesic tolerance in either sex. Morphine-induced conditioned place preference, behavioral sensitization, and physical withdrawal were also not affected by neonatal incision. Thus, early-life injury results in sex-dependent pain-related hypersensitivity and social behavior deficits during adolescence, without altering the response to opioids. PERSPECTIVE: Neonatal surgery has greater effects on adolescent male than female rats, resulting in pain-related hypersensitivity and social behavioral deficits. Neonatal surgery does not alter the antinociceptive effects of morphine or abuse liability. PMID- 28709956 TI - Activation of human gonadotropin-releasing hormone receptor promotes down regulation of ARHGAP18 and regulates the cell invasion of MDA-MB-231 cells. AB - The Gonadotropin-Releasing Hormone Receptor (GnRHR) is expressed mainly in the gonadotrope membrane of the adenohypophysis and its natural ligand, the Gonadotropin-Releasing Hormone (GnRH), is produced in anterior hypothalamus. Furthermore, both molecules are also present in the membrane of cells derived from other reproductive tissues such as the breast, endometrium, ovary, and prostate, as well as in tumors derived from these tissues. The functions of GnRH receptor and its hormone in malignant cells have been related with the decrease of proliferation and the invasiveness of those tumors however, little is known about the molecules associated with the signaling pathways regulated by both molecules in malignant cells. To further analyze the potential mechanisms employed by the GnRHR/GnRH system to reduce the tumorigenesis of the highly invasive breast cancer cell line MDA-MB-231, we performed microarrays experiments to evaluated changes in genes expression and validate these modifications by functional assays. We show that activation of human GnRHR is able to diminish the expression and therefore functions of the Rho GTPase-Activating Protein 18 (ARHGAP18). Decrease of this GAP following GnRHR activation, correlates to the higher of cell adhesion and also with reduction of tumor cell invasion, supporting the notion that GnRHR triggers intracellular signaling pathways that acts through ARHGAP18. On the contrary, although a decline of cellular proliferation was observed during GnRHR activation in MDA-MB-231, this was independent of ARHGAP18 showing the complex system in which is involved the signaling pathways regulated by the GnRHR/GnRH system. PMID- 28709957 TI - Multibacillary leprosy in a migrant from Afghanistan: A disease not to be forgotten. PMID- 28709958 TI - Zika in India and the need for transparent reporting. PMID- 28709959 TI - Reciprocal relationships between emotion regulation and motives for eating palatable foods in African American adolescents. AB - This study examines possible bidirectional relationships between emotion regulation and motives related to consuming palatable foods during adolescence. Participants included 79 adolescents (96% African American) who took part in Waves 2 and 3 of the Coping with Violence Study. The youth were recruited from four public middle schools serving low income, urban communities in Birmingham, AL. Participants completed self-report measures of emotion regulation and indicated different motives for consuming tasty foods and drinks at both waves. Results demonstrate that poorer emotion regulation at Wave 2 predicted more frequent endorsement of eating motives related to coping and conforming at Wave 3. Eating motives at Wave 2 were not associated with changes in emotion regulation at Wave 3. The results suggest that emotion regulation problems in adolescence may contribute to obesity and related negative outcomes through greater consumption of unhealthy food for coping and social conformity reasons. PMID- 28709960 TI - Eating behavior style predicts craving and anxiety experienced in food-related virtual environments by patients with eating disorders and healthy controls. AB - Eating behavior style (emotional, restrictive, or external) has been proposed as an explanation for the differences in response to food-related cues between people who overeat and those who do not, and has been also considered a target for the treatment of eating disorders (EDs) characterized by lack of control over eating and weight-related (overweight/obesity) conditions. The aim of this study was to analyze the relationship between eating behavior style and psychophysiological responses (self-reported food craving and anxiety) to food related virtual reality (VR) environments in outpatients with bulimia nervosa (BN) and binge eating disorder (BED) and to compare them with healthy participants. Fifty-eight outpatients and 135 healthy participants were exposed to palatable foods in four experimental everyday real-life VR environments (kitchen, dining room, bedroom and cafe). During exposure, cue-elicited food craving and anxiety were assessed. Participants also completed standardized instruments for the study purposes. ED patients reported significantly higher levels of craving and anxiety when exposed to the virtual food than healthy controls. Eating behavior styles showed strong associations with cue-elicited food craving and anxiety. In the healthy group, external eating was the only predictor of cue-elicited craving and anxiety. In participants with BN and BED, external and emotional eating were the best predictors of cue-elicited craving and anxiety, respectively. PMID- 28709961 TI - Bile acids, FGF15/19 and liver regeneration: From mechanisms to clinical applications. AB - The liver has an extraordinary regenerative capacity rapidly triggered upon injury or resection. This response is intrinsically adjusted in its initiation and termination, a property termed the "hepatostat". Several molecules have been involved in liver regeneration, and among them bile acids may play a central role. Intrahepatic levels of bile acids rapidly increase after resection. Through the activation of farnesoid X receptor (FXR), bile acids regulate their hepatic metabolism and also promote hepatocellular proliferation. FXR is also expressed in enterocytes, where bile acids stimulate the expression of fibroblast growth factor 15/19 (FGF15/19), which is released to the portal blood. Through the activation of FGFR4 on hepatocytes FGF15/19 regulates bile acids synthesis and finely tunes liver regeneration as part of the "hepatostat". Here we review the experimental evidences supporting the relevance of the FXR-FGF15/19-FGFR4 axis in liver regeneration and discuss potential therapeutic applications of FGF15/19 in the prevention of liver failure. This article is part of a Special Issue entitled: Cholangiocytes in Health and Disease edited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen. PMID- 28709962 TI - The role of macrophages in the development of biliary injury in a lipopolysaccharide-aggravated hepatic ischaemia-reperfusion model. AB - INTRODUCTION: Endotoxins, in the form of lipopolysaccharides (LPS), are potent inducers of biliary injury. However the mechanism by which injury develops remains unclear. We hypothesized that hepatic macrophages are pivotal in the development of endotoxin-induced biliary injury and that no injury would occur in their absence. MATERIAL AND METHODS: Clodronate liposomes were used to deplete macrophages from the liver. Forty-eight rats were equally divided across six study groups: sham operation (sham), liposome treatment and sham operation (liposomes+sham), 1mg/kg LPS i.p. (LPS), liposome treatment and LPS administration (liposomes+LPS), hepatic ischaemia-reperfusion injury with LPS administration (IRI+LPS) and liposome treatment followed by IRI+LPS (liposomes+IRI+LPS). Following 6h of reperfusion, blood, bile, and liver tissue was collected for further analysis. Small bile duct injury was assessed, serum liver tests were performed and bile composition was evaluated. The permeability of the blood-biliary barrier (BBB) was assessed using intravenously administered horseradish peroxidase (HRP). RESULTS: The presence of hepatic macrophages was reduced by 90% in LPS and IRI+LPS groups pre-treated with clodronate liposomes (P<0.001). Severe small bile duct injury was not affected by macrophage depletion, and persisted in the liposomes+IRI+LPS group (50% of animals) and liposomes+LPS group (75% of animals). Likewise, BBB impairment persisted following macrophage depletion. LPS-induced elevation of the chemokine Mcp-1 in bile was not affected by macrophage depletion. CONCLUSIONS: Depletion of hepatic macrophages did not prevent development of biliary injury following LPS or LPS enhanced IRI. Cholangiocyte activation rather than macrophage activation may underlie this injury. This article is part of a Special Issue entitled: Cholangiocytes in Health and Diseaseedited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen. PMID- 28709964 TI - The eyes as a window to improved understanding of the prenatal effects of Zika virus infection. PMID- 28709965 TI - Sensorimotor outcomes in children with prenatal exposure to methadone. AB - PURPOSE: To report the presentation and characteristics of strabismus in children with prenatal methadone exposure. METHODS: The medical records of children with prenatal methadone exposure were retrospectively reviewed. Those who were evaluated by pediatric ophthalmology were included. Information on the timing and types of prenatal exposure by trimester of pregnancy was then collected from the patients' mothers' charts. The children's perinatal histories and ophthalmologic findings were collected from their pediatric clinic charts and ophthalmology clinic charts, respectively. RESULTS: A total of 210 children with prenatal methadone exposure were identified, of whom 32 (15.2%) underwent eye examinations and 21 (10%) had strabismus. Five patients had esodeviations, with a mean age of onset of 11.6 months; 16 had exodeviations, with a mean age of onset of 6.8 months. Three patients with strabismus were born prematurely, and 2 had intracranial disease. Two patients underwent strabismus surgery. CONCLUSIONS: The incidence of strabismus in patients with prenatal methadone exposure was higher than in the general population (10% vs 3%-4%). Intermittent exotropia was the most common type of strabismus and presented earlier than in the general population, with no association with other systemic disease. Prenatal exposure to methadone was likely confounded by exposure to other substances, environmental factors, and genetics. Poor compliance with follow-up reduced the power of the study. PMID- 28709963 TI - Animal models of biliary injury and altered bile acid metabolism. AB - In the last 25years, a number of animal models, mainly rodents, have been generated with the goal to mimic cholestatic liver injuries and, thus, to provide in vivo tools to investigate the mechanisms of biliary repair and, eventually, to test the efficacy of innovative treatments. Despite fundamental limitations applying to these models, such as the distinct immune system and the different metabolism regulating liver homeostasis in rodents when compared to humans, multiple approaches, such as surgery (bile duct ligation), chemical-induced (3,5 diethoxycarbonyl-1,4-dihydrocollidine, DDC, alpha-naphthylisothiocyanate, ANIT), viral infections (Rhesus rotavirustype A, RRV-A), and genetic manipulation (Mdr2, Cftr, Pkd1, Pkd2, Prkcsh, Sec63, Pkhd1) have been developed. Overall, they have led to a range of liver phenotypes recapitulating the main features of biliary injury and altered bile acid metabolisms, such as ductular reaction, peribiliary inflammation and fibrosis, obstructive cholestasis and biliary dysgenesis. Although with a limited translability to the human setting, these mouse models have provided us with the ability to probe over time the fundamental mechanisms promoting cholestatic disease progression. Moreover, recent studies from genetically engineered mice have unveiled 'core' pathways that make the cholangiocyte a pivotal player in liver repair. In this review, we will highlight the main phenotypic features, the more interesting peculiarities and the different drawbacks of these mouse models. This article is part of a Special Issue entitled: Cholangiocytes in Health and Disease edited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen. PMID- 28709966 TI - Dose of allergens in a peanut snack (Bamba) associated with prevention of peanut allergy. PMID- 28709967 TI - Advances in asthma in 2016: Designing individualized approaches to management. AB - In this year's Advances in Asthma review, we discuss viral infections in asthmatic patients and potential therapeutic agents, the microbiome, novel genetic associations with asthma, air quality and climate effects on asthma, exposures during development and long-term sequelae of childhood asthma, patient centered outcomes research, and precision medicine. In addition, we discuss application of biomarkers to precision medicine and new information on asthma medications. New evidence indicates that rhinovirus-triggered asthma exacerbations become more severe as the degree of sensitization to dust mite and mouse increase. The 2 biggest drivers of asthma severity are an allergy pathway starting with allergic sensitization and an environmental tobacco smoke pathway. In addition, allergic sensitization and blood eosinophils can be used to select medications for management of early asthma in young children. These current findings, among others covered in this review, represent significant steps toward addressing rapidly advancing areas of knowledge that have implications for asthma management. PMID- 28709968 TI - Specific allergen profiles of peanut foods and diagnostic or therapeutic allergenic products. AB - BACKGROUND: Generic immunoassays for peanut cannot discriminate between allergen levels in peanut-derived food products or therapeutics. Clinical trials of oral immunotherapy (OIT) are strengthened by using standardized peanut preparations with defined doses of major allergens. OBJECTIVE: This article describes measurement of Ara h 1, Ara h 2, and Ara h 6 in peanut foods and in peanut flour extracts used for allergy diagnosis and OIT. METHODS: Monoclonal antibody-based enzyme immunoassays for Ara h 1, Ara h 2, and Ara h 6 were used to compare allergen levels in peanut (n = 16) and tree nut (n = 16) butter, peanut flour (n = 11), oils (n = 8), extracts used for diagnosis and OIT (n = 5), and the National Institute for Standards and Technology Peanut Butter Standard Reference Material 2387. RESULTS: Roasted peanut butters contained 991 to 21,406 MUg/g Ara h 1 and exceeded Ara h 2 and Ara h 6 levels by 2- to 4-fold. Similarly, National Institute for Standards and Technology Peanut Butter Standard Reference Material 2387 contained 11,275 MUg/g Ara h 1, 2,522 MUg/g Ara h 2, and 2,036 MUg/g Ara h 6. In contrast, peanut flours contained 787 to 14,631 MUg/g Ara h 2 and exceeded Ara h 1 levels by 2- to 20-fold. Flour extracts used for OIT contained 394 to 505 MUg/mL Ara h 1, 1,187 to 5,270 MUg/mL Ara h 2, and 1,104 to 8,092 MUg/mL Ara h 6. In most cases specific peanut allergens were not detected in tree nut butters or peanut oils. CONCLUSIONS: The results show marked differences in specific peanut allergen profiles in peanut butter and flour and peanut preparations for clinical use. Roasting can increase Ara h 1 levels in peanut butter. Variability in allergen levels could affect the outcome of clinical trials of peanut OIT, especially with respect to Ara h 1. Specific allergen measurements will improve standardization and provide accurate dosing of peanut preparations that are being used for OIT. PMID- 28709969 TI - Role of epigenome in tumorigenesis and drug resistance. AB - The last few decades have witnessed a tremendous advancement in understanding the genetic basis of major human diseases such as cancer. Intriguingly, there is also an evergrowing body of evidence that suggest the critical role of epigenetic regulation in pathogenesis. In contrast to genetic mechanisms often associated with changes in DNA sequence, epigenetics generally refers to the regulation of gene expression featuring alterations in histone modification, DNA methylation, chromatin conformation and non-coding RNAs, with the first two categories being the best-characterized so far. A growing list of epigenetic factors, including writers, readers and erasers have been identified, and huge differences in genome wide epigenetic modifications, so-called epigenome, have been reported between normal tissues and cancer. Significantly, since the epigenetic regulation is largely dependent on enzymes, they are generally reversible and thus more amenable to pharmaceutical intervention. Hence, it is believed that a comprehensive understanding of how alterations in epigenome lead to tumorigenesis, progression and drug resistance is of primary importance to develop epigenetic therapies and to ensure long-term efficacy of cancer treatment. PMID- 28709970 TI - Selective effects of whey protein concentrate on glutathione levels and apoptosis in rats with mammary tumors. AB - Glutathione (GSH) plays an important role in antioxidant defense and regulation of apoptosis. GSH deficiency is related to many diseases, including cancer, and increased GSH levels in cancer cells are associated with chemotherapy resistance because of resistance to apoptosis. In this study, we investigated the effects of whey protein concentrate (WPC), a precursor of GSH, in rats with mammary tumors induced by treatment with 7,12-dimethylbenz(a)anthracene (DMBA). DMBA treatment results in cellular changes that mimic the initiation and promotion of carcinogenesis of breast tissue. We aimed to examine the possible preventive effects of diets containing whey protein on DMBA-induced mammary tumors in rats. The results indicate that WPC (0.334 g/kg) supplementation significantly increased the liver GSH levels by 92%, and were accompanied by low Bax/Bcl-2 ratio (from 5 to 3) and cleaved caspase-3/procaspase-3 ratio (from 2.4 to 1.2) in DMBA-treated rats. Furthermore, tumor GSH levels were decreased by 47% in WPC supplemented rats, which resulted in increased Bax/Bcl-2 ratio (from 0.9 to 2) and cleaved caspase-3/procaspase-3 ratio (from 1.1 to 2.7). In conclusion, supplementation with WPC could selectively deplete tumor GSH levels and, therefore, WPC supplementation might be a promising strategy to overcome treatment resistance in cancer therapy. PMID- 28709971 TI - Epigenetic mechanisms underlying the toxic effects associated with arsenic exposure and the development of diabetes. AB - BACKGROUND: Exposure to inorganic arsenic (iAs) is a major threat to the human health worldwide. The consumption of arsenic in drinking water and other food products is associated with the risk of development of type-2 diabetes mellitus (T2DM). The available experimental evidence indicates that epigenetic alterations may play an important role in the development of diseases that are linked with exposure to environmental toxicants. iAs seems to be associated with the epigenetic modifications such as alterations in DNA methylation, histone modifications, and micro RNA (miRNA) abundance. OBJECTIVE: This article reviewed epigenetic mechanisms underlying the toxic effects associated with arsenic exposure and the development of diabetes. METHOD: Electronic databases such as PubMed, Scopus and Google scholar were searched for published literature from 1980 to 2017. Searched MESH terms were "Arsenic", "Epigenetic mechanism", "DNA methylation", "Histone modifications" and "Diabetes". RESULTS: There are various factors involved in the pathogenesis of T2DM but it is assumed that arsenic consumption causes the epigenetic alterations both at the gene-specific level and generalized genome level. CONCLUSION: The research indicates that exposure from low to moderate concentrations of iAs is linked with the epigenetic effects. In addition, it is evident that, arsenic can change the components of the epigenome and hence induces diabetes through epigenetic mechanisms, such as alterations in glucose transport and/or metabolism and insulin expression/secretion. PMID- 28709973 TI - Fractional derivatives in the diffusion process in heterogeneous systems: The case of transdermal patches. AB - In this note, we present a simple mathematical model of drug delivery through transdermal patches by introducing a memory formalism in the classical Fick diffusion equation based on the fractional derivative. This approach is developed in the case of a medicated adhesive patch placed on the skin to deliver a time released dose of medication through the skin towards the bloodstream.The main resistance to drug transport across the skin resides in the diffusion through its outermost layer (the stratum corneum). Due to the complicated architecture of this region, a model based on a constant diffusivity in a steady-state condition results in too simplistic assumptions and more refined models are required.The introduction of a memory formalism in the diffusion process, where diffusion parameters depend at a certain time or position on what happens at preceeding times, meets this requirement and allows a significantly better description of the experimental results.The present model may be useful not only for analyzing the rate of skin permeation but also for predicting the drug concentration after transdermal drug delivery depending on the diffusion characteristics of the patch (its thickness and pseudo-diffusion coefficient). PMID- 28709972 TI - Generalised approach to modelling a three-tiered microbial food-web. AB - The complexity of the anaerobic digestion process has motivated the development of complex models, such as the widely used Anaerobic Digestion Model No. 1. However, this complexity makes it intractable to identify the stability profile coupled to the asymptotic behaviour of existing steady-states as a function of conventional chemostat operating parameters (substrate inflow concentration and dilution rate). In a previous study this model was simplified and reduced to its very backbone to describe a three-tiered chlorophenol mineralising food-web, with its stability analysed numerically using consensus values for the various biological parameters of the Monod growth functions. Steady-states where all organisms exist were always stable and non-oscillatory. Here we investigate a generalised form of this three-tiered food-web, whose kinetics do not rely on the specific kinetics of Monod form. The results are valid for a large class of growth kinetics as long as they keep the signs of their derivatives. We examine the existence and stability of the identified steady-states and find that, without a maintenance term, the stability of the system may be characterised analytically. These findings permit a better understanding of the operating region of the bifurcation diagram where all organisms exist, and its dependence on the biological parameters of the model. For the previously studied Monod kinetics, we identify four interesting cases that show this dependence of the operating diagram with respect to the biological parameters. When maintenance is included, it is necessary to perform numerical analysis. In both cases we verify the discovery of two important phenomena; i) the washout steady-state is always stable, and ii) a switch in dominance between two organisms competing for hydrogen results in the system becoming unstable and a loss in viability. We show that our approach results in the discovery of an unstable operating region in its positive steady-state, where all three organisms exist, a fact that has not been reported in a previous numerical study. This type of analysis can be used to determine critical behaviour in microbial communities in response to changing operating conditions. PMID- 28709974 TI - A spatially structured metapopulation model within a stochastic environment. AB - Populations often exist, either by choice or by external pressure, in a fragmented way, referred to as a metapopulation. Typically, the dynamics accounted for within metapopulation models are assumed to be static. For example, patch occupancy models often assume that the colonisation and extinction rates do not change, while spatially structured models often assume that the rates of births, deaths and migrations do not depend on time. While some progress has been made when these dynamics are changing deterministically, less is known when the changes are stochastic. It can be quite common that the environment a population inhabits determines how these dynamics change over time. Changes to this environment can have a large impact on the survival probability of a population and such changes will often be stochastic. The typical metapopulation model allows for catastrophes that could eradicate most, if not all, individuals on an entire patch. It is this type of phenomenon that this article addresses. A Markov process is developed that models the number of individuals on each patch within a metapopulation. An approximation for the original model is presented in the form of a piecewise-deterministic Markov process and the approximation is analysed to present conditions for extinction. PMID- 28709975 TI - Buckling analysis of orthotropic protein microtubules under axial and radial compression based on couple stress theory. AB - Protein microtubules (MTs) are one of the important intercellular components and have a vital role in the stability and strength of the cells. Due to applied external loads, protein microtubules may be involved buckling phenomenon. Due to impact of protein microtubules in cell reactions, it is important to determine their critical buckling load. Considering nature of protein microtubules, various parameters are effective on microtubules buckling. The small size of microtubules and also lack of uniformity of MTs properties in different directions caused the necessity of accuracy in the analysis of these bio-structure. In fact, microtubules must be considered as a size dependent cylinder, which behave as an orthotropic material. Hence, in the present work using first-order shear deformation model (FSDT), the buckling equations of anisotropic MTs are derived based on new modified couple stress theory (NMCST). After solving the stability equations, the influences of various parameters are measured on the MTs critical buckling load. PMID- 28709976 TI - Glutathione peroxidase 4-catalyzed reduction of lipid hydroperoxides in membranes: The polar head of membrane phospholipids binds the enzyme and addresses the fatty acid hydroperoxide group toward the redox center. AB - GPx4 is a monomeric glutathione peroxidase, unique in reducing the hydroperoxide group (-OOH) of fatty acids esterified in membrane phospholipids. This reaction inhibits lipid peroxidation and accounts for enzyme's vital role. Here we investigated the interaction of GPx4 with membrane phospholipids. A cationic surface near the GPx4 catalytic center interacts with phospholipid polar heads. Accordingly, SPR analysis indicates cardiolipin as the phospholipid with maximal affinity to GPx4. Consistent with the electrostatic nature of the interaction, KCl increases the KD. Molecular dynamic (MD) simulation shows that a -OOH posed in the core of the membrane as 13 - or 9 -OOH of tetra-linoleoyl cardiolipin or 15 -OOH stearoyl-arachidonoyl-phosphaphatidylcholine moves to the lipid-water interface. Thereby, the -OOH groups are addressed toward the GPx4 redox center. In this pose, however, the catalytic site facing the membrane would be inaccessible to GSH, but the consecutive redox processes facilitate access of GSH, which further primes undocking of the enzyme, because GSH competes for the binding residues implicated in docking. During the final phase of the catalytic cycle, while GSSG is produced, GPx4 is disconnected from the membrane. The observation that GSH depletion in cells induces GPx4 translocation to the membrane, is in agreement with this concept. PMID- 28709977 TI - The surgeon-anesthesiologist relationship in the era of enhanced recovery. PMID- 28709978 TI - The severity grading of acute cholecystitis following the Tokyo Guidelines is the most powerful predictive factor for conversion from laparoscopic cholecystectomy to open cholecystectomy. AB - BACKGROUND: The relationship between the severity assessment of acute cholecystitis based on the Tokyo Guidelines and the risk for conversion from laparoscopic surgery to open surgery has been assessed in few previous reports, with conflicting results. METHODS: A retrospective review of patients with acute cholecystitis within a single system from 2010 to 2013 was performed. The diagnosis and severity of acute cholecystitis were assigned by the Tokyo Guidelines 2013 (TG13). The primary outcome measure was conversion to open cholecystectomy. RESULTS: During the period of study, 493 patients were operated by laparoscopy for acute cholecystitis. Laparoscopic cholecystectomy was intraoperatively converted to open surgery in 56 cases (11.4%). The multivariate analysis showed that the risk factors for conversion to open surgery included male gender (OR: 2.15; IC95% [1.18-3.9]), diabetes (OR: 2.22; IC95% [1.13-4.33]), total bilirubin levels (OR: 1.02; IC95% [1-1.05]), and the TG13 severity classification (OR: 4.44; IC95% [2.25-8.75]). CONCLUSIONS: The independent risk factors for conversion to open surgery included male sex, diabetes mellitus, total bilirubin level, and TG13 grade. TG13 grade was found to be the most powerful predictive factor for conversion as it had the highest OR. PMID- 28709979 TI - Reconstruction after ureteral resection during HIPEC surgery: Re-implantation with uretero-neocystostomy seems safer than end-to-end anastomosis. AB - INTRODUCTION: Resection of the pelvic ureter may be necessary in cytoreductive surgery for peritoneal carcinomatosis in combination with hyperthermic intraperitoneal chemotherapy (HIPEC). As the morbidity for cytoreductive surgery with HIPEC has decreased, expert teams have begun to perform increasingly complex surgical procedures associated with HIPEC, including pelvic reconstructions. After ureteral resection, two types of reconstruction are possible: uretero ureteral end-to-end anastomosis and uretero-vesical re-implantation or uretero neocystostomy (the so-called psoas hitch technique). By compiling the experience of three surgical teams that perform HIPEC surgeries, we have tried to compare the effectiveness of these two techniques. METHODOLOGY: A retrospective comparative case-matched multicenter study was conducted for patients undergoing operation between 2005 and 2014. Patients included had undergone resection of the pelvic ureter during cytoreductive surgery with HIPEC for peritoneal carcinomatomosis; ureteral reconstruction was by either end-to-end anastomosis (EEA group) or re-implantation uretero-neocystostomy (RUC group). The primary endpoint was the occurrence of urinary fistula in postoperative follow-up. RESULTS: There were 14 patients in the EEA group and 14 in the RUC group. The groups were comparable for age, extent of carcinomatosis (PCI index) and operative duration. Four urinary fistulas occurred in the EEA group (28.5%) versus zero fistulas in the RUC group (0%) (P=0.0308). CONCLUSION: Re implantation with uretero-neocystostomy during cytoreductive surgery with HIPEC is the preferred technique for reconstruction after ureteral resection in case of renal conservation. PMID- 28709980 TI - Downregulation of USP18 inhibits growth and induces apoptosis in hepatitis B virus-related hepatocellular carcinoma cells by suppressing BCL2L1. AB - Ubiquitin-specific peptidase 18 (USP18) is closely related with hepatitis B virus (HBV), which has been involved in tumourigenesis. However, there has been little research into the role of USP18 on the progression of hepatocellular carcinoma (HCC), especially in HBV-related HCC. In present study, we found that USP18 expression was aberrantly elevated in HCC tissues than adjacent non-tumour tissues. Importantly, USP18 expression was higher in HBV-related HCC cell lines (HepG2.2.15 and Hep3B) than HBV-unrelated HCC cell lines. Furthermore, knockdown of USP18 significantly suppressed tumour cell proliferation in vitro and tumour growth in vivo, whereas overexpression of USP18 promoted HCC cells growth. Moreover, our experimental data revealed that USP18 silencing obviously blocked cell cycle at G1 phase and increased cell apoptosis. Finally, BCL2L1, a member of BCL2 family protein, was identified as a downstream gene of USP18. Mechanistically, we found that USP18 directly bind to BCL2L1 and positively regulated its expression in HCC cells. Overall, our results suggested that USP18 has a crucial role in regulating diverse aspects of the pathogenesis of HCC, indicating that it might be a potential therapeutic target. PMID- 28709981 TI - Relative toxicity for indoor semi volatile organic compounds based on neuronal death. AB - BACKGROUND: Semi Volatile Organic Compounds (SVOCs) are contaminants commonly found in dwellings as a result of their use as plasticizers, flame retardants, or pesticides in building materials and consumer products. Many SVOCs are suspected of being neurotoxic, based on mammal experimentation (impairment of locomotor activity, spatial learning/memory or behavioral changes), raising the question of cumulative risk assessment. The aim of this work is to estimate the relative toxicity of such SVOCs, based on neuronal death. METHOD: SVOCs fulfilling the following conditions were included: detection frequency >10% in dwellings, availability of data on effects or mechanism of action for neurotoxicity, and availability of dose-response relationships based on cell viability assays as a proxy of neuronal death. Benchmark concentration values (BMC) were estimated using a Hill model, and compared to assess relative toxicity. RESULTS: Of the 58 SVOCs selected, 28 were suspected of being neurotoxic in mammals, and 21 have been documented as inducing a decrease in cell viability in vitro. 13 have at least one dose-response relationship that can be used to derive a BMC based on a 10% fall in neuronal viability. Based on this in vitro endpoint, PCB-153 appeared to be the most toxic compound, having the lowest BMC10 (0.072MUM) and diazinon the least toxic compound, having the highest BMC10 (94.35MUM). We showed that experimental designs (in particular choice of cell lines) had a significant influence on BMC calculation. CONCLUSION: For the first time, the relative in vitro toxicity of 13 indoor contaminants belonging to different chemical families has been assessed on the basis of neuronal cell viability. Lack of comparable toxicity datasets limits the number of SVOCs that can be included. More standardized protocols in terms of cell lines, species and exposure duration should be developed with a view to cumulative risk assessment. PMID- 28709982 TI - Impact of zinc oxide nanoparticles on an in vitro model of the human air-blood barrier. AB - The inhalation of zinc oxide nanoparticles (nZnO) may induce systemic diseases, damages to the alveolar epithelium and inflammatory response to endothelial cells. In this work the use of an in vitro air-blood barrier (ABB) model provided a tool to elucidate the biological mechanisms underlying the potential effects of inhaled nanoparticles (NPs). The ABB model used is composed of a Transwell co culture of a lung epithelial cell line (NCI-H441) and an immortalized pulmonary microvascular endothelial cell line (HPMEC-ST1.6R). In addition, a tri-culture model was developed by adding monocytes (THP-1) on the basal compartment of the inserts. These models have been set up to analyse the importance of the interplay among the different cell types on various responses after nZnO exposure: inflammation, endothelial damage and modulation of the immune system. The barrier integrity was assessed by measuring the transepithelial electrical resistance (TEER); the pro-inflammatory and immune cells responses were analysed by ELISA. The results have evidenced that nZnO do not affect the barrier integrity, since no TEER reduction was measured after 24h of exposure, but an activation of endothelial cells, which released pro-inflammatory mediators (IL-6, IL-8), and endothelial dysfunction markers (sICAM-1 and sVCAM-1) were induced. These results confirm that apical exposure to NPs promote endothelium activation. The in vitro ABB model here used is thus a useful tool able to evidence the interaction between lung epithelium and endothelium in inducing biological response, and the role of endothelium dysfunction following NPs inhalation. PMID- 28709983 TI - Sn- and Ge- triorganometallics exert different cytotoxicity and modulation of migration in triple-negative breast cancer cell line MDA-MB-231. AB - Among a variety of metal containing organic compounds, tin derivatives are enjoying an increasing interest and appear to be very promising as potential drug candidates. We studied eight organometallic derivatives, nuclear retinoid X receptor (RXR) ligands and two germanium containing derivates that do not serve as RXR ligands. Tributylgermanium chloride (TBGe) and triphenylgermanium chloride (TPGe) did not inhibit growth of human triple negative MDA-MB-231 breast cancer cells. On the other hand, the tributyltin derivatives were highly, the triphenyltin derivatives less cytotoxic, both groups with IC50 values of nanomolar range. All trialkyltin derivatives (tributyltin chloride, tributyltin bromide, tributyltin iodide, tributyltin hydride) and three triaryltin derivatives (triphenyltin chloride, triphenyltin hydride and triphenyltin hydroxide) caused caspase-3/7 dependent apoptosis. Those derivatives that showed no or weak cytotoxicity, TBGe, TPGe, and triphenyltin acetate, we found to reduce migration of tested triple negative breast cancer cells. PMID- 28709985 TI - Molecular phylogeny of Miltogramminae (Diptera: Sarcophagidae): Implications for classification, systematics and evolution of larval feeding strategies. AB - Miltogramminae is one of the phylogenetically most poorly studied taxa of the species-rich family Sarcophagidae (Diptera). Most species are kleptoparasites in nests of solitary aculeate wasps and bees, although parasitoids and saprophagous species are also known, and the ancestral miltogrammine life habit remains unsettled. Here, we present for the first time a comprehensive phylogenetic tree consisting of 58 representatives of Miltogramminae, reconstructed using sequence data from three mitochondrial (COI, cytB, ND4) and one nuclear (Ef-1alpha) genes. Our phylogenetic hypothesis suggests that: (1) Miltogramminae are sister to Paramacronychiinae, (2) Miltogramminae can be divided into the "lower miltogrammines" containing two clades of mainly saprophages and a clade of "higher miltogrammines" with mainly kleptoparasitic species, (3) only three genera turn out to be non-monophyletic: Miltogramma, Senotainia and Pterella and (4) the genus Sarcotachina, which traditionally has been considered as belonging to the Paramacronychiinae, is placed in one of the clades of "lower miltogrammines". Ancestral state reconstruction of larval feeding strategy and five larval characters reveals that the ancestor of Miltogramminae was likely a saprophage retaining plesiomorphic oral ridges and a cephaloskeleton with sclerotized dorsal bridge. Synapomorphies like large pseudocephalic sensory organs and well-developed cuticular sculpture suggest that the ancestral first instar larva actively searched for a buried food supply. PMID- 28709984 TI - Micrometer scale guidance of mesenchymal stem cells to form structurally oriented large-scale tissue engineered cartilage. AB - : Current clinical methods to treat articular cartilage lesions provide temporary relief of the symptoms but fail to permanently restore the damaged tissue. Tissue engineering, using mesenchymal stem cells (MSCs) combined with scaffolds and bioactive factors, is viewed as a promising method for repairing cartilage injuries. However, current tissue engineered constructs display inferior mechanical properties compared to native articular cartilage, which could be attributed to the lack of structural organization of the extracellular matrix (ECM) of these engineered constructs in comparison to the highly oriented structure of articular cartilage ECM. We previously showed that we can guide MSCs undergoing chondrogenesis to align using microscale guidance channels on the surface of a two-dimensional (2-D) collagen scaffold, which resulted in the deposition of aligned ECM within the channels and enhanced mechanical properties of the constructs. In this study, we developed a technique to roll 2-D collagen scaffolds containing MSCs within guidance channels in order to produce a large scale, three-dimensional (3-D) tissue engineered cartilage constructs with enhanced mechanical properties compared to current constructs. After rolling the MSC-scaffold constructs into a 3-D cylindrical structure, the constructs were cultured for 21days under chondrogenic culture conditions. The microstructure architecture and mechanical properties of the constructs were evaluated using imaging and compressive testing. Histology and immunohistochemistry of the constructs showed extensive glycosaminoglycan (GAG) and collagen type II deposition. Second harmonic generation imaging and Picrosirius red staining indicated alignment of neo-collagen fibers within the guidance channels of the constructs. Mechanical testing indicated that constructs containing the guidance channels displayed enhanced compressive properties compared to control constructs without these channels. In conclusion, using a novel roll-up method, we have developed large scale MSC based tissue-engineered cartilage that shows microscale structural organization and enhanced compressive properties compared to current tissue engineered constructs. STATEMENT OF SIGNIFICANCE: Tissue engineered cartilage constructs made with human mesenchymal stem cells (hMSCs), scaffolds and bioactive factors are a promising solution to treat cartilage defects. A major disadvantage of these constructs is their inferior mechanical properties compared to the native tissue, which is likely due to the lack of structural organization of the extracellular matrix of the engineered constructs. In this study, we developed three-dimensional (3-D) cartilage constructs from rectangular scaffold sheets containing hMSCs in micro-guidance channels and characterized their mechanical properties and metabolic requirements. The work led to a novel roll-up method to embed 2-D microscale structures in 3-D constructs. Further, micro-guidance channels incorporated within the 3-D cartilage constructs led to the production of aligned cell-produced matrix and enhanced mechanical function. PMID- 28709986 TI - Comparison of different strategies for using fossil calibrations to generate the time prior in Bayesian molecular clock dating. AB - Fossil calibrations are the utmost source of information for resolving the distances between molecular sequences into estimates of absolute times and absolute rates in molecular clock dating analysis. The quality of calibrations is thus expected to have a major impact on divergence time estimates even if a huge amount of molecular data is available. In Bayesian molecular clock dating, fossil calibration information is incorporated in the analysis through the prior on divergence times (the time prior). Here, we evaluate three strategies for converting fossil calibrations (in the form of minimum- and maximum-age bounds) into the prior on times, which differ according to whether they borrow information from the maximum age of ancestral nodes and minimum age of descendent nodes to form constraints for any given node on the phylogeny. We study a simple example that is analytically tractable, and analyze two real datasets (one of 10 primate species and another of 48 seed plant species) using three Bayesian dating programs: MCMCTree, MrBayes and BEAST2. We examine how different calibration strategies, the birth-death process, and automatic truncation (to enforce the constraint that ancestral nodes are older than descendent nodes) interact to determine the time prior. In general, truncation has a great impact on calibrations so that the effective priors on the calibration node ages after the truncation can be very different from the user-specified calibration densities. The different strategies for generating the effective prior also had considerable impact, leading to very different marginal effective priors. Arbitrary parameters used to implement minimum-bound calibrations were found to have a strong impact upon the prior and posterior of the divergence times. Our results highlight the importance of inspecting the joint time prior used by the dating program before any Bayesian dating analysis. PMID- 28709987 TI - The neural correlates of dealing with social exclusion in childhood. AB - Observing social exclusion can be a distressing experience for children that can be followed by concerns for self-inclusion (self-concerns), as well as prosocial behavior to help others in distress (other-concerns). Indeed, behavioral studies have shown that observed social exclusion elicits prosocial compensating behavior in children, but motivations for the compensation of social exclusion are not well understood. To distinguish between self-concerns and other-concerns when observing social exclusion in childhood, participants (aged 7-10) played a four player Prosocial Cyberball Game in which they could toss a ball to three other players. When one player was excluded by the two other players, the participant could compensate for this exclusion by tossing the ball more often to the excluded player. Using a three-sample replication (N = 18, N = 27, and N = 26) and meta-analysis design, we demonstrated consistent prosocial compensating behavior in children in response to observing social exclusion. On a neural level, we found activity in reward and salience related areas (striatum and dorsal anterior cingulate cortex (dACC)) when participants experienced inclusion, and activity in social perception related areas (orbitofrontal cortex) when participants experienced exclusion. In contrast, no condition specific neural effects were observed for prosocial compensating behavior. These findings suggest that in childhood observed social exclusion is associated with stronger neural activity for self-concern. This study aims to overcome some of the issues of replicability in developmental psychology and neuroscience by using a replication and meta-analysis design, showing consistent prosocial compensating behavior to the excluded player, and replicable neural correlates of experiencing exclusion and inclusion during middle childhood. PMID- 28709988 TI - Genetic characterisation confirms sporadic occurrence of vancomycin-resistant Enterococcus faecalis in Copenhagen, Denmark. PMID- 28709989 TI - Evaluating biapenem dosage regimens in intensive care unit patients with Pseudomonas aeruginosa infections: a pharmacokinetic/pharmacodynamic analysis using Monte Carlo simulation. AB - This study was conducted to identify optimal dosage regimens and estimate pharmacokinetic/pharmacodynamic (PK/PD) characteristics of short-infusion (SI) versus extended-infusion (EI) biapenem against Pseudomonas aeruginosa infections in Chinese intensive care unit (ICU) patients. A total of 85 strains of P. aeruginosa were collected, and the minimum inhibitory concentration (MIC) of biapenem was measured by the serial two-fold agar dilution method. We designed four frequently used clinical regimens: biapenem 300 mg I.V. q12h, q8h, and q6h, and 600 mg q12h. The Monte Carlo Simulation (MCS) was performed using previously published pharmacokinetic data to calculate the probability of target attainment (PTA) and the cumulative fraction of response (CFR) of these regimens as an SI (0.5 h) and an EI (1 h, 2 h, 3 h, and 4 h). For a target of 40%fT>MIC (serum drug concentration remains above the MIC for a dosing period), none of the regimens achieved any CFRs>90% for P. aeruginosa, multidrug-resistant P. aeruginosa (MDR PA) and even non-MDR-PA. The traditional biapenem SI regimens most commonly seen in clinical practice were insufficient in treating both MDR and non-MDR P. aeruginosa in ICU patients. However, biapenem 600 mg q12h over 2-4 h EI regimens could achieve CFR>90% with 20%fT>MIC. Clinical trials should aim to validate the potentially greater PK/PD index with higher, more frequent doses and longer extended infusions. PMID- 28709990 TI - In-vitro development of an effective treatment for Acanthamoeba keratitis. AB - The aim of this study was to develop an in-vitro topical treatment for Acanthamoeba keratitis (AK) effective against cysts and trophozoites. Qualitative assays were performed with voriconazole, chlorhexidine, propamidine, cellulase, tobramycin, ciprofloxacin and paromomycin as monotherapy and various combinations. Riboflavin with ultraviolet-A (R + UV-A) as monotherapy or combined with voriconazole and moxifloxacin was also tested. Quantitative assays to assess cyst viability after treatment were performed for the chemicals that showed the highest activity in the qualitative assays. Paromomycin and propamidine did not show antiamoebic activity. Regardless of the total dose, no amoebicidal effect was observed for R + UV-A. Tobramycin, ciprofloxacin, voriconazole, chlorhexidine and cellulase were selected for quantitative assays because they appeared to cause greater damage to the structure of amoebae. Chlorhexidine and ciprofloxacin were the most active against Acanthamoeba spp. as monotherapy. Among the combinations evaluated, ciprofloxacin-voriconazole-chlorhexidine showed the greatest amoebicidal activity, with severe damage of the cellular membrane and an important decrease in cell concentration. In summary, ciprofloxacin as monotherapy and in combination with voriconazole and chlorhexidine has been classified as promising treatment. Additional in-vivo studies in animal models and clinical trials in patients with AK should be considered to confirm the efficacy of ciprofloxacin. PMID- 28709991 TI - Drugs as habitable planets in the space of dark chemical matter. AB - A recent study demonstrated antifungal activity of dark chemical matter (DCM) compounds that were otherwise inactive in more than 100 HTS assays. These compounds were proposed to possess unique activity and 'clean' safety profiles. Here, we present an outlook of the promiscuity and safety of these compounds by retrospectively comparing their chemical and biological spaces with those of drugs. Significant amounts of marketed drugs (16%), withdrawn drugs (16.5%) and natural compounds (3.5%) share structural identity with DCM. Compound promiscuity assessment indicates that dark matter compounds could potentially interact with multiple biological targets. Further, thousands of DCM compounds showed presence of frequent-hitting pan-assay interference compound (PAINS) substructures. In light of these observations, filtering these compounds from screening libraries can be an irrevocable loss. PMID- 28709992 TI - Time-dependent evolution of seizures in a model of mesial temporal lobe epilepsy. AB - Low-voltage fast (LVF) and hypersynchronous (HYP) - onset seizures occur in the EEG obtained with depth electrodes from mesial temporal lobe epilepsy (MTLE) patients and animal models. In epileptic rats analyzed up to approximately two weeks after pilocarpine-induced status epilepticus (SE), these patterns are associated with specific high-frequency oscillation (HFO) content: ripples (80 200Hz) or fast-ripples (250-500Hz) predominate in LVF or HYP seizures, respectively. To establish whether these features change over the course of the disease, we recorded the EEG from the hippocampal CA3 subfield, subiculum, entorhinal cortex and dentate gyrus in two groups of pilocarpine-treated rats: the "early stage group" (n=8) was analyzed from day 3 to 20 post-SE while the "late stage group" (n=7) was studied from day 27 to 53 post-SE. We found that: (i) HYP and LVF seizures prevail in the early and late stage group, respectively; (ii) HYP seizures mainly originate from CA3 in the early stage group only; (iii) LVF seizures in both early and late stage group originate from a diffuse network; (iv) LVF and HYP seizures in the early stage group are mainly associated with ripples and fast ripples, respectively; but (v) fast ripples predominate in the late stage group, regardless of seizure onset pattern. Finally, extensive neuronal loss occurred in the hippocampus of the late stage group. Our results reveal that significant changes in ictogenesis and HFO occurrence, which are associated with the manifestation of severe hippocampal damage, occur over time in this MTLE model. PMID- 28709993 TI - Intracellular calcium release through IP3R or RyR contributes to secondary axonal degeneration. AB - Severed CNS axons often retract or dieback away from the injury site and fail to regenerate. The precise mechanisms underlying acute axonal dieback and secondary axonal degeneration remain poorly understood. Here we investigate the role of Ca2+ store mediated intra-axonal Ca2+ release in acute axonal dieback and secondary axonal degeneration. To differentiate between primary (directly transected) and "bystander" axonal injury (axons spared by the initial injury but then succumb to secondary degeneration) in real-time we use our previously published highly focal laser-induced spinal cord injury (LiSCI) ex vivo model. Ascending spinal cord dorsal column axons that express YFP were severed using an 800 nm laser pulse while being imaged continuously using two-photon excitation microscopy. We inhibited two major intra-axonal Ca2+ store channels, ryanodine receptors (RyR) and IP3R, with ryanodine or 2-APB, respectively, to individually determine their role in axonal dieback and secondary axonal degeneration. Each antagonist was dissolved in artificial CSF and applied 1h post-injury alone or in combination, and continuously perfused for the remainder of the imaging session. Initially following LiSCI, transected axons retracted equal distances both distal and proximal to the lesion. However, by 4h after injury, the distal axonal segments that are destined for Wallerian degeneration had significantly retracted further than their proximal counterparts. We also found that targeting either RyR or IP3R using pharmacological and genetic approaches significantly reduced proximal axonal dieback and "bystander" secondary degeneration of axons compared to vehicle controls at 6h post-injury. Combined treatment effects on secondary axonal degeneration were similar to either drug in isolation. Together, these results suggest that intra-axonal Ca2+ store mediated Ca2+ release through RyR or IP3R contributes to secondary axonal degeneration following SCI. PMID- 28709994 TI - Metabolic correction by pyruvate halts acquired epilepsy in multiple rodent models. AB - Metabolic intervention strategy of epilepsy treatment has been gaining broader attention due to accumulated evidence that hypometabolism, manifested in humans as reduced brain glucose consumption, is a principal factor in acquired epilepsy. Therefore, targeting deficient energy metabolism may be an effective approach for treating epilepsy. To confront this pathology we utilized pyruvate, which besides being an anaplerotic mitochondrial fuel possesses a unique set of neuroprotective properties as it: (i) is a potent reactive oxygen species scavenger; (ii) abates overactivation of Poly [ADP-ribose] polymerase 1 (PARP-1); (iii) facilitates glutamate efflux from the brain; (iv) augments brain glycogen stores; (v) is anti inflammatory; (vi) prevents neuronal hyperexcitability; and (vii) normalizes the cytosolic redox state. In vivo, chronic oral pyruvate administration completely abolished established epileptic phenotypes in three accepted and fundamentally different rodent acquired epilepsy models. Our study reports metabolic correction by pyruvate as a potentially highly effective treatment of acquired epilepsies. PMID- 28709995 TI - The contribution of biophysical and structural studies of protein self-assembly to the design of therapeutic strategies for amyloid diseases. AB - Many neurodegenerative disorders, including Alzheimer's, Parkinson's and the prion diseases, are characterized by a conformational conversion of normally soluble proteins or peptides into pathological species, by a process of misfolding and self-assembly that leads ultimately to the formation of amyloid fibrils. Recent studies support the idea that multiple intermediate species with a wide variety of degrees of neuronal toxicity are generated during such processes. The development of a high level of knowledge of the nature and structure of the pathogenic amyloid species would significantly enhance efforts to underline the molecular origins of these disorders and also to develop both accurate diagnoses and effective therapeutic interventions for these types of conditions. In this review, we discuss recent biophysical and structural information concerning different types of amyloid aggregates and the way in which such information can guide rational therapeutic approaches designed to target specific pathogenic events that occur during the development of these highly debilitating and increasingly common diseases. PMID- 28709996 TI - Applications of solid-state NMR to membrane proteins. AB - Membrane proteins mediate flow of molecules, signals, and energy between cells and intracellular compartments. Understanding membrane protein function requires a detailed understanding of the structural and dynamic properties involved. Lipid bilayers provide a native-like environment for structure-function investigations of membrane proteins. In this review we give a general discourse on the recent progress in the field of solid-state NMR of membrane proteins. Solid-state NMR is a variation of NMR spectroscopy that is applicable to molecular systems with restricted mobility, such as high molecular weight proteins and protein complexes, supramolecular assemblies, or membrane proteins in a phospholipid environment. We highlight recent advances in applications of solid-state NMR to membrane proteins, specifically focusing on the recent developments in the field of Dynamic Nuclear Polarization, proton detection, and solid-state NMR applications in situ (in cell membranes). This article is part of a Special Issue entitled: Biophysics in Canada, edited by Lewis Kay, John Baenziger, Albert Berghuis and Peter Tieleman. PMID- 28709997 TI - Methodological challenges for the evaluation of clinical effectiveness in the context of accelerated regulatory approval: an overview. AB - BACKGROUND: Regulatory authorities are approving innovative therapies with limited evidence. Although this level of data is sufficient for the regulator to establish an acceptable risk-benefit balance, it is problematic for downstream health technology assessment, where assessment of cost-effectiveness requires reliable estimates of effectiveness relative to existing clinical practice. Some key issues associated with a limited evidence base include using data, from nonrandomized studies, from small single-arm trials, or from single-center trials; and using surrogate end points. METHODS: We examined these methodological challenges through a pragmatic review of the available literature. RESULTS: Methods to adjust nonrandomized studies for confounding are imperfect. The relative treatment effect generated from single-arm trials is uncertain and may be optimistic. Single-center trial results may not be generalizable. Surrogate end points, on average, overestimate treatment effects. Current methods for analyzing such data are limited, and effectiveness claims based on these suboptimal forms of evidence are likely to be subject to significant uncertainty. CONCLUSION: Assessments of cost-effectiveness, based on the modeling of such data, are likely to be subject to considerable uncertainty. This uncertainty must not be underestimated by decision makers: methods for its quantification are required and schemes to protect payers from the cost of uncertainty should be implemented. PMID- 28709998 TI - Aversive smell associations shape social judgment. AB - Once associating another person with an unpleasant smell, how do we perceive and judge this person from that moment on? Here, we used aversive olfactory conditioning followed by a social attribution task during functional magnetic resonance imaging to address this question. After conditioning, where one of two faces was repeatedly paired with an aversive smell, the participants reported negative affect when viewing the smell-conditioned but not the neutral face. When subsequently confronted with the smell-conditioned face (without any smell), the participants tended to judge both positive and negative behaviors as indicative of personality traits rather than related to the situation. This effect was predicted by the degree of the preceding olfactory evaluative conditioning. Whole brain analysis of stimulus by stage interaction indicated differential activation of the ventromedial prefrontal cortex and right angular gyrus to the conditioned versus the neutral person during the attribution phase only. These results suggest that negative smell associations do not simply induce a negative perception of the target person but rather bias the attribution style towards trait attributions. The fact that this bias was evident regardless of behavior valence suggests it may reflect enhanced psychological distance. Thus, the known observation of social rejection triggered by aversive smell may be driven by a shift in social attribution style. PMID- 28709999 TI - TDCS over the right inferior frontal gyrus disrupts control of interference in memory: A retrieval-induced forgetting study. AB - Retrieving information from episodic memory may result in later inaccessibility of related but task-irrelevant information. This phenomenon, known as retrieval induced forgetting, is thought to represent a specific instance of broader cognitive control mechanisms, that would come into play during memory retrieval, whenever non-target competing memories interfere with recall of target items. Recent neuroimaging studies have shown an association between these mechanisms and the activity of the right Prefrontal Cortex. However, so far, few studies have attempted at establishing a causal relationship between this brain region and behavioural measures of cognitive control over memory. To address this missing link, we delivered transcranial Direct Current Stimulation (tDCS) over the right Inferior Frontal Gyrus (rIFG) during a standard retrieval-practice paradigm with category-exemplar word pairs. Across two experiments, tDCS abolished retrieval-induced forgetting to different degrees, compared to the sham control group whereas no effects of stimulation emerged in an ancillary measure of motor stopping ability. Moreover, influence analyses on specific subsets of the experimental material revealed diverging patterns of results, which depended upon the different categories employed in the retrieval-practice paradigm. Overall, the results support the view that rIFG has a causal role in the control of interference in memory retrieval and highlight the often underestimated role of stimulus material in affecting the effects. The present findings are therefore relevant in enriching our knowledge about memory functions from both a theoretical and methodological perspective. PMID- 28710000 TI - The perisylvian language network and language analytical abilities. AB - Aiming at exploring the brain's structural organisation underlying successful second language learning, we investigate the anatomy of the perisylvian language network in a group of healthy adults, consisting of participants with high and average language analytical abilities. Utilising deterministic tractography, six tracts per participant (left and right long direct segment, left and right indirect anterior segment and left and right indirect posterior segment) were virtually dissected and measurements pertaining to their microstructural organisation were collected. Our results obtained by means of linear discriminant analysis pointed to mean diffusivity (MD) values of three tracts (right anterior, left long and left anterior segments) as best discriminating between the two groups. By far the highest coefficient was obtained for the MD values of the right anterior segment, pointing to the role of the right white matter fronto parietal connectivity for superior language learning abilities. The results imply the importance of attentional processes and reasoning abilities for successful L2 acquisition, and support previous findings concerning right-hemispheric involvement in language learning. PMID- 28710001 TI - Congenital lingual cyst: Expression of MUC protein and report of a new case. AB - Lingual congenital cysts are uncommon lesions that alter the functions of speech, swallowing and breathing when they have considerable dimension. They usually appear from birth and increase in size gradually in childhood and adolescence. While there are a considerable number of case reports, the nomenclature and origin of this lesion are controversial. Congenital lingual cysts are composed of an epithelial lining that can show heterogeneous histological features, such as globed, ciliated, squamous and parietal cells, while the wall presents mature connective tissue and eventually smooth muscle. In the present manuscript, we report a case of a congenital lingual cyst in a 13-year-old boy, as well as the immunoexpression of MUC family proteins (MUC-1 and MUC-5AC), hoping to provide data that will help to clarify the possible etiology of this lesion. PMID- 28710002 TI - Diphtheria toxoid and N-trimethyl chitosan layer-by-layer coated pH-sensitive microneedles induce potent immune responses upon dermal vaccination in mice. AB - Dermal immunization using antigen-coated microneedle arrays is a promising vaccination strategy. However, reduction of microneedle sharpness and the available surface area for antigen coating is a limiting factor. To overcome these obstacles, a layer-by-layer coating approach can be applied onto pH sensitive microneedles. Following this approach, pH-sensitive microneedle arrays (positively charged at coating pH5.8 and nearly uncharged at pH7.4) were alternatingly coated with negatively charged diphtheria toxoid (DT) and N trimethyl chitosan (TMC), a cationic adjuvant. First, the optimal DT dose for intradermal immunization was determined in a dose-response study, which revealed that low-dose intradermal immunization was more efficient than subcutaneous immunization and that the EC50 dose of DT upon intradermal immunization is 3-fold lower, as compared to subcutaneous immunization. In a subsequent immunization study, microneedle arrays coated with an increasing number (2, 5, and 10) of DT/TMC bilayers resulted in step-wise increasing DT-specific immune responses. Dermal immunization with microneedle arrays coated with 10 bilayers of DT/TMC (corresponding with +/-0.6MUg DT delivered intradermally) resulted in similar DT specific immune responses as subcutaneous immunization with 5MUg of DT adjuvanted with aluminum phosphate (8-fold dose reduction). Summarizing, the layer-by-layer coating approach onto pH-sensitive microneedles is a versatile method to precisely control the amount of coated and dermally-delivered antigen that is highly suitable for dermal immunization. PMID- 28710003 TI - Amelioration of atherosclerotic inflammation and plaques via endothelial adrenoceptor-targeted eNOS gene delivery using redox-sensitive polymer bearing l arginine. AB - Endothelial dysfunction combined with inflammation leads to atherosclerosis. Endothelium-specific delivery of therapeutic agents at the cellular level specifically in vivo-is still a difficult task for proper management of atherosclerosis. We designed a redox-sensitive poly(oligo-l-arginine) (rsPOLA) playing dual roles as an endothelium alpha-2 adrenoceptors(alpha-2ARs)-targeted gene carrier and as a substrate for endothelial nitric oxide synthase (eNOS). Overexpression of alpha-2ARs on atherosclerotic endothelial cells was confirmed and the eNOS/rsPOLA nanoplexes following systemic injection demonstrated to 1) enhance eNOS gene delivery into endothelial cells via alpha-2ARs/l-arginine specific binding, 2) increase intracellular level of nitric oxide, 3) suppress inflammatory response in endothelium and finally 4) reduce atherosclerotic plaque in a Ldlr-/- atherosclerotic mouse model. Among the tested nanoplexes [eNOS/rsPOLA, eNOS/{poly(oligo-d-arginine), rsPODA} and eNOS/(racemic mixture, rsRM)], eNOS/rsPOLA reduced atherosclerotic inflammation most effectively as we hypothesized. Current treatment strategy provides strong potential for further development of a gene therapeutic system to ameliorate inflammation and progressive atherosclerotic plaques. PMID- 28710004 TI - Development of PEGylated carboxylic acid-modified polyamidoamine dendrimers as bone-targeting carriers for the treatment of bone diseases. AB - In this study, we aimed to develop a polyethylene glycol (PEG)-conjugated third generation polyamidoamine (PAMAM) dendrimer with multiple carboxylic acids as a bone-targeting carrier for the treatment of bone diseases. We conjugated PAMAM backbones to various carboxylic acids [aspartic acid (Asp), glutamic acid (Glu), succinic acid (Suc), or aconitic acid (Aco)] to obtain four different types of carboxylic acid-modified PAMAMs. PEG was covalently bound to carboxylic acid modified PAMAMs to obtain PEGylated carboxylic acid-modified PAMAMs. In a tissue distribution study, the amount of 111In-labeled unmodified PAMAM taken up by the bone after intravenous injection in mice was 11.3%. In contrast, the dose of 111In-labeled PEG(5)-Asp-PAMAM, PEG(5)-Glu-PAMAM, PEG(5)-Suc-PAMAM, or PEG(5)-Aco PAMAM that accumulated in the bone after injection was approximately 46.0, 15.6, 22.6, and 24.5%, respectively. The bone clearance rates of 111In-labeled PEGylated carboxylic acid-modified PAMAMs were proportional to their affinities to hydroxyapatite and Ca2+. An intra-bone distribution study showed that fluorescein isothiocyanate-labeled PEG(5)-Asp-PAMAM predominantly accumulated on eroded and quiescent surfaces, a pattern associated with the pathogenesis of bone diseases, such as rheumatoid arthritis and osteoporosis. Our findings indicate that PEG(5)-Asp-PAMAM is a promising drug carrier for efficient drug targeting to the bones. PMID- 28710005 TI - Cationic microbubbles and antibiotic-free miniplasmid for sustained ultrasound mediated transgene expression in liver. AB - Despite the increasing number of clinical trials in gene therapy, no ideal methods still allow non-viral gene transfer in deep tissues such as the liver. We were interested in ultrasound (US)-mediated gene delivery to provide long term liver expression. For this purpose, new positively charged microbubbles were designed and complexed with pFAR4, a highly efficient small length miniplasmid DNA devoid of antibiotic resistance sequence. Sonoporation parameters, such as insonation time, acoustic pressure and duration of plasmid injection were controlled under ultrasound imaging guidance. The optimization of these various parameters was performed by bioluminescence optical imaging of luciferase reporter gene expression in the liver. Mice were injected with 50MUg pFAR4-LUC either alone, or complexed with positively charged microbubbles, or co-injected with neutral MicroMarkerTM microbubbles, followed by low ultrasound energy application to the liver. Injection of the pFAR4 encoding luciferase alone led to a transient transgene expression that lasted only for two days. The significant luciferase signal obtained with neutral microbubbles decreased over 2days and reached a plateau with a level around 1 log above the signal obtained with pFAR4 alone. With the newly designed positively charged microbubbles, we obtained a much stronger bioluminescence signal which increased over 2days. The 12-fold difference (p<0.05) between MicroMarkerTM and our positively charged microbubbles was maintained over a period of 6months. Noteworthy, the positively charged microbubbles led to an improvement of 180-fold (p<0.001) as regard to free pDNA using unfocused ultrasound performed at clinically tolerated ultrasound amplitude. Transient liver damage was observed when using the cationic microbubble-pFAR4 complexes and the optimized sonoporation parameters. Immunohistochemistry analyses were performed to determine the nature of cells transfected. The pFAR4 miniplasmid complexed with cationic microbubbles allowed to transfect mostly hepatocytes compared to its co-injection with MicroMarkerTM which transfected more preferentially endothelial cells. PMID- 28710006 TI - Drug-eluting embolic microspheres for local drug delivery - State of the art. AB - Embolic microspheres or beads used in transarterial chemoembolization are an established treatment method for hepatocellular carcinoma patients. The occlusion of the tumor-feeding vessels by intra-arterial injection of the beads results in tumor necrosis and shrinkage. In this short review, we describe the utility of using these beads as devices for local drug delivery. We review the latest advances in the development of non-biodegradable and biodegradable drug-eluting beads for transarterial chemoembolization. Their capability to load different drugs, such as chemotherapeutics and anti-angiogenic compounds with different physicochemical properties, like charge and hydrophilicity/hydrophobicity, are discussed. We specifically address controlled and sustained drug release from the microspheres, and the resulting in vivo pharmacokinetics in the plasma vs. drug distribution in the targeted tissue. PMID- 28710007 TI - Toxoplasmosis treatment with diphenyl diselenide in infected mice modulates the activity of purinergic enzymes and reduces inflammation in spleen. AB - Toxoplasma gondii, an intracellular protozoan, may cause chronic infection in the brain tissue of the host inducing a systemic pro-inflammatory profile. Chronic infections can induce numerous physiological changes, such as alterations in the immune and oxidative profiles. Diphenyl diselenide (PhSe)2, an organoselenium compound, has shown antioxidant and immunomodulatory activities in recent studies. So, the aim of this study was to investigate the activity of purinergic enzymes and reactive oxygen species (ROS) in serum and spleen of mice chronically infected by T. gondii, untreated and treated with (PhSe)2. For this experiment, were divided into four groups: Group A (healthy mice), Group B (healthy mice treated with (PhSe)2), Group C (infected mice) and Group D (infected mice treated with (PhSe)2). Group C and group D were infected via oral route with ME49 Toxoplasma gondii strain. Groups B and D were treated subcutaneously with 5 MUmol kg-1 of (PhSe)2. Chronic T. gondii infection induced splenomegaly and physiological changes in the spleen and raised histologic inflammatory markers, ROS levels and the activity of purinergic enzymes activity such as NTPDase, 5'nucleotidase and ADA. In serum, the infection increased 5'nucleotidase and ADA activities. (PhSe)2per se has managed to decrease ROS levels and ADA activity and increase NTPDase and 5'nucleotidase in spleen. In infected mice, treatment with (PhSe)2 reversed splenomegaly, reduced histological inflammatory markers, ROS levels and ADA activity in the spleen. Our results prove that chronic toxoplasmosis can induce splenomegaly, heightens ROS levels and purinergic enzyme activity in mice. These results suggest that (PhSe)2 is a potential therapy for the alterations found in the spleen in chronic T. gondii infection. PMID- 28710008 TI - Identifying synthetic lethal targets using CRISPR/Cas9 system. AB - Synthetic lethality occurs when co-occurrence of two genetic events is unfavorable for the survival of the cell or organism. The conventional approach of high throughput screening of synthetic lethal targets using chemical compounds has been replaced by RNAi technology. CRISPR/Cas9, an RNA guided endonuclease system is the most recent technology for this work. Here, we have discussed the major considerations involved in designing a CRISPR/Cas9 based screening experiment for identification of synthetic lethal targets. It mainly includes CRISPR library to be used, cell types for conducting the experiment, the most appropriate screening strategy and ways of selecting the desired phenotypes from the complete cell population. The complete knockdown of genes can be achieved using CRISPR/Cas9 knockout libraries. For higher quality loss-of-function screens, haploid cells with defective homology-directed DNA repair mechanism could be used. Two widely used screening formats include arrayed and pooled screens followed by negative or positive selection of the cells with desired phenotype. However, pooled screening format with negative selection of cells serves the best. The advantages of using CRISPR/Cas9 system over the other RNAi approaches have also been discussed. Finally, some studies using CRISPR/Cas9 for genome-wide knockout screening in human cells and computational approaches for identification of synthetic lethal interactions have been discussed. PMID- 28710009 TI - mRNA interactome capture in mammalian cells. AB - Throughout their entire life cycle, mRNAs are associated with RNA-binding proteins (RBPs), forming ribonucleoprotein (RNP) complexes with highly dynamic compositions. Their interplay is one key to control gene regulatory mechanisms from mRNA synthesis to decay. To assay the global scope of RNA-protein interactions, we and others have published a method combining crosslinking with highly stringent oligo(dT) affinity purification to enrich proteins associated with polyadenylated RNA (poly(A)+ RNA). Identification of the poly(A)+ RNA-bound proteome (also: mRNA interactome capture) has by now been applied to a diversity of cell lines and model organisms, uncovering comprehensive repertoires of RBPs and hundreds of novel RBP candidates. In addition to determining the RBP catalog in a given biological system, mRNA interactome capture allows the examination of changes in protein-mRNA interactions in response to internal and external stimuli, altered cellular programs and disease. PMID- 28710010 TI - Local network component analysis for quantifying transcription factor activities. AB - : Transcription factors (TFs) could regulate physiological transitions or determine stable phenotypic diversity. The accurate estimation on TF regulatory signals or functional activities is of great significance to guide biological experiments or elucidate molecular mechanisms, but still remains challenging. Traditional methods identify TF regulatory signals at the population level, which masks heterogeneous regulation mechanisms in individuals or subgroups, thus resulting in inaccurate analyses. Here, we propose a novel computational framework, namely local network component analysis (LNCA), to exploit data heterogeneity and automatically quantify accurate transcription factor activity (TFA) in practical terms, through integrating the partitioned expression sets (i.e., local information) and prior TF-gene regulatory knowledge. Specifically, LNCA adopts an adaptive optimization strategy, which evaluates the local similarities of regulation controls and corrects biases during data integration, to construct the TFA landscape. In particular, we first numerically demonstrate the effectiveness of LNCA for the simulated data sets, compared with traditional methods, such as FastNCA, ROBNCA and NINCA. Then, we apply our model to two real data sets with implicit temporal or spatial regulation variations. The results show that LNCA not only recognizes the periodic mode along the S. cerevisiae cell cycle process, but also substantially outperforms over other methods in terms of accuracy and consistency. In addition, the cross-validation study for glioblastomas multiforme (GBM) indicates that the TFAs, identified by LNCA, can better distinguish clinically distinct tumor groups than the expression values of the corresponding TFs, thus opening a new way to classify tumor subtypes and also providing a novel insight into cancer heterogeneity. AVAILABILITY: LNCA was implemented as a Matlab package, which is available at http://sysbio.sibcb.ac.cn/cb/chenlab/software.htm/LNCApackage_0.1.rar. PMID- 28710011 TI - Antibacterial activity of food-grade chitosan against Vibrio parahaemolyticus biofilms. AB - Biofilm is a community composed of microbes and the extracellular polymeric substances. This special architecture poses a significant public health risk as it increases the fitness of bacteria in harsh conditions and renders bacterial resistance to antimicrobial agents and cleaning. In this study, we investigated the inhibition and eradication effects of chitosan on the biofilm of Vibrio parahaemolyticus, an important food-borne pathogen. The crystal violet staining, [2, 3-bis (2-methoxy-4-nitro-5- sulfophenyl)-2H-tetrazolium-5-carboxanilide] (XTT) reduction method, phenol-sulfuric acid method, fluorescence microscope and confocal laser scanning microscope (CLSM) observation were conducted. The results indicated that the minimum inhibitory concentration (MIC) of chitosan was 1.25 mg/mL. Sub-MIC of chitosan could significantly inhibit biofilm formation, reduce the metabolic activities and the secretion of extracellular polysaccharide (EPS). Moreover, chitosan at 4MIC could eradicate 85.06% mature biofilm of V. parahaemolyticus, and decrease 81.43% EPS in mature biofilm. These results were also confirmed by the visual images obtained from fluorescence microscopy and CLSM. This study elucidated that chitosan was not only effective to prevent biofilm formation, but also eradicate mature biofilms of V. parahaemolyticus. PMID- 28710012 TI - Antibiofilm activity of Vetiveria zizanioides root extract against methicillin resistant Staphylococcus aureus. AB - Methicillin-resistant Staphylococcus aureus (MRSA) is a leading human pathogen responsible for causing chronic clinical manifestation worldwide. In addition to antibiotic resistance genes viz. mecA and vanA, biofilm formation plays a prominent role in the pathogenicity of S. aureus by enhancing its resistance to existing antibiotics. Considering the role of folk medicinal plants in the betterment of human health from the waves of multidrug resistant bacterial infections, the present study was intended to explore the effect of Vetiveria zizanioides root on the biofilm formation of MRSA and its clinical counterparts. V. zizanioides root extract (VREX) showed a concentration-dependent reduction in biofilm formation without hampering the cellular viability of the tested strains. Micrographs of scanning electron microscopy (SEM) and confocal laser scanning microscopy (CLSM) portrayed the devastating impact of VREX on biofilm formation. In addition to antibiofilm activity, VREX suppresses the production of biofilm related phenotypes such as exopolysaccharide, slime and alpha-hemolysin toxin. Furthermore, variation in FT-IR spectra evidenced the difference in cellular factors of untreated and VREX treated samples. Result of mature biofilm disruption assay and down regulation of genes like fnbA, fnbB, clfA suggested that VREX targets these adhesin genes responsible for initial adherence. GC-MS analysis revealed the presence of sesquiterpenes as a major constituent in VREX. Thus, the data of present study strengthen the ethnobotanical value of V. zizanioides and concludes that VREX contain bioactive molecules that have beneficial effect over the biofilm formation of MRSA and its clinical isolates. PMID- 28710013 TI - Murine bone marrow-derived DCs activated by porcine rotavirus stimulate the Th1 subtype response in vitro. AB - Rotavirus (RV) infection causes acute, watery dehydrating diarrhea and even death in infants and other young animals, resulting in a severe economic burden; however, little is known about the innate immune mechanisms associated with RV infection. Dendritic cells (DCs), which are professional antigen-presenting cells (APCs), serve as a bridge connecting the innate and adaptive immune system. In this study, the interaction between murine bone marrow-derived DCs (BMDCs) and porcine rotavirus (PRV) was investigated in vitro. Upon stimulation, the expression levels of MHC-II, CD40, CD80, CD86 and CD83 in BMDCs increased in a time-dependent manner, indicating activation and maturation by PRV. In addition, up-regulated Toll-like receptor 2 (TLR2), TLR3 and NF-kappaB increased the production of interleukin-12 and interferon-gamma. The PRV-stimulated BMDCs also showed increased stimulatory capacity in mixed lymphocyte reactions and promoted the Th1 subtype response. PMID- 28710014 TI - Culture conditions improvement of Crassostrea gigas using a potential probiotic Bacillus sp strain. AB - It is well demonstrated that some probiotics improve rearing water quality and thereby have beneficial effects on reared organisms. We conducted this study to determine the effect of Bacillus consortium on Crassostrea gigas reared in contemned seawater with indigo dye priory treated with Bacillus or no treated. This effect was studied by assessing hemocytes death using flow cytometry analysis. We found that the percentage of decolorization of indigo dye in polluted seawater in presence of C. gigas increased from 41% to 90% when using Bacillus consortium. In these conditions, the hemocytes mortality of reared C. gigas decreased from 87% to 56%. We have demonstrated also that seawater contemned with priory treated indigo with Bacillus consortium is less toxic than seawater contemned with the no treated indigo. The percentage of hemocytes death is 81% for the contemned seawater with indigo and 56% for no contemned seawater. This consortium shows a protector effect of C. gigas against Vibrio harveyi contemning reared seawater. PMID- 28710015 TI - Bactericidal impact of Ag, ZnO and mixed AgZnO colloidal nanoparticles on H37Rv Mycobacterium tuberculosis phagocytized by THP-1 cell lines. AB - The purpose of this research project was to infection of human macrophages (THP 1) cell lines by H37Rv strain of Mycobacterium tuberculosis (H37RvMTB) and find out the ratio/dilution of mixture silver (Ag NPs) and zinc oxide nanoparticles (ZnO NPs) whose ability to eliminate phagocytized bacteria compared to rifampicin. The colloidal Ag NPs and ZnO NPs were synthesized and their characteristics were evaluated. The THP-1 cell lines were infected with different concentration of H37RvMTB. Next, the infected cells were treated with different ratios/dilutions of Ag NPs, ZnO NPs and rifampicin. The THP-1 were lysed and were cultured in Lowenstein-Jensen agar medium, for eight weeks. The TEM and AFM images of NPs and H37RvMTB were supplied. It is observed that Ag NPs, 2Ag:8ZnO and 8Ag:2ZnO did not have any anti-tubercular effects on phagocytized H37RvMTB. Conversely, ZnO NPs somehow eliminated 18.7 * 104 CFU ml-1 of H37RvMTB in concentration of ~ 0.468 ppm. To compare with 40 ppm of rifampicin, ~ 0.663 ppm of 5Ag:5ZnO had the ability to kill of H37RvMTB, too. Based on previous research, ZnO NPs had strong anti-tubercular impact against H37RvMTB to in-vitro condition, but it was toxic in concentration of ~ 0.468 ppm to both of THP-1 and normal lung (MRC-5) cell lines. It also seems that 5Ag:5ZnO is justified because in concentration of ~ 0.663 ppm of 5Ag:5ZnO, phagocytized H37RvMTB into the THP-1 had died without any toxicity effects against THP-1 and also MRC-5 cell lines. It is obvious that the mixture of colloidal silver and zinc oxide NPs with ratio of 5Ag:5ZnO would be trustworthy options as anti-tubercular nano-drugs in future researches. PMID- 28710017 TI - Response to Sequence data management for scientific purposes. PMID- 28710016 TI - Comparative study of immunopathophysiological responses induced by B. melitensis and its lipopolysaccharide in mouse model infected via intranasal route of exposure. AB - In this study, we developed a mouse model and characterized the effects of intranasal inoculation of virulent Brucella melitensis strain 16M and its lipopolysaccharide (LPS). The effects of the exposure were compared with respective control groups. Both Brucella melitensis-infected and LPS-infected groups showed no significant clinical presentation with minor relevance in the mortality associated with the infection. In Brucella melitensis-infected group, significant histopathological changes in comparison to the LPS infected group with increase bacterial burden in the lungs, reproductive and reticuloendothelial organs were observed. However, both infected groups showed elevated levels of pro inflammatory cytokine expression (IL-1beta and IL6) and antibody production (IgM an IgG) as early as 3 days post-infection with predominance in LPS infected group. In contrast, low levels of sex related hormonal changes was recorded in both infected groups throughout the experimental period. This is the first detailed investigation comparing the infection progression and host responses in relation to the immunopathophysiological aspects in mouse model after intranasal inoculation with B. melitensis and its lipopolysaccharide. The study revealed a significant difference between infected and control groups with overlap in clinical, pathological, and immunological responses as well as sex related hormonal changes resulting from the infections. PMID- 28710018 TI - First detection and genetic characterization of Toxoplasma gondii in market-sold oysters in China. AB - Toxoplasma gondii oocysts in the water might be filtered through the gills of shellfish in the process of feeding, and can be concentrated in the digestive glands. Consumers might become infected through ingestion of the shellfish unless they are discharged or inactivated by the shellfish. Thus, the purpose of this study was to evaluate the presence of T. gondii in market-sold oysters in China under natural conditions using a molecular approach. A total of 998 oysters were collected from markets in four cities (Weihai, Qingdao, Yantai and Rizhao) of Shandong province, eastern China. Of these, 26 samples (2.61%) were tested positive by nested PCR amplification of T. gondii B1 gene. Only one of the 26 positive samples was typed completely, and was identified as ToxoDB Genotype #9. This is first report of T. gondii in market-sold oysters in China, suggesting that oysters have the ability to filter and retain T. gondii oocysts in their tissues, which represents a risk to public health because oysters are frequently ingested in nature. PMID- 28710019 TI - Effects of human blood levels of two PAH mixtures on the AHR signalling activation pathway and CYP1A1 and COMT target genes in granulosa non-tumor and granulosa tumor cell lines. AB - Epidemiological studies have shown a link between problems with offspring of couples living in a contaminated environment in comparison to those who live in an uncontaminated environment. We measured the concentrations of 16 priority polycyclic aromatic hydrocarbons (PAHs) in maternal and cord blood. To explore the mechanism of the effects of PAH mixtures on nonluteinized granulosa cells (HGrC1) and granulosa tumor cells (COV434), as well as cell proliferation and apoptosis, we investigated the effect of PAH mixtures on the expression of the aryl hydrocarbon receptor (AHR), aryl hydrocarbon receptor nuclear translocator (ARNT) and aryl hydrocarbon receptor repressor (AHRR) genes, as well as the expression and activity of target genes cytochrome P450 1A1 (CYP1A1) and catechol O-methyltransferase (COMT). The cells were exposed to mixture 1 (M1), composed of all 16 priority PAHs, and mixture 2 (M2), composed of five PAHs which are not classified as human carcinogens, and which are observed in the highest amounts both in maternal and cord blood. All 16 priority PAHs were bioavailable in maternal and cord plasma, suggesting that perinatal exposure should be considered. In HGrC1 cells, M1 increased AHR and ARNT, but decreased AHRR expression, in parallel with increased CYP1A1 and COMT expression and activity. M2 decreased AHR and AHRR, and increased ARNT, with no effect on CYP1A1 expression and activity; however, it did increase COMT expression and activity. In tumor cells, M1 lowered AHR and up-regulated AHRR and ARNT expression, consequently decreasing CYP1A1 expression and COMT activity. M2 up-regulated AHR and ARNT, down-regulated AHRR, and had no effect on CYP1A1 and COMT expression, but decreased COMT activity. We hypothesise that, dependent on composition, mixtures of PAHs activate the AHR differently through varying transcription responses: in HGrC1, a canonical AHR mechanism of M1, with activation of CYP1A1 important for detoxication, while in COV434, a noncanonical AHR mechanism, probably by activation the nuclear factor NFkB. PMID- 28710020 TI - Nrf2 deficiency exacerbates ochratoxin A-induced toxicity in vitro and in vivo. AB - Several mechanisms are postulated to be responsible for nephrotoxic and nephrocarcinogenic activities of mycotoxin and food contaminant, ochratoxin A (OTA). Although Nrf2 transcription factor was suggested to be involved in OTA mediated renal injury, comprehensive study evaluating the effect of OTA toxicity in Nrf2 knock-out mice with special regard to sex-dependency has not been performed yet. Our results clearly show exacerbated OTA toxicity in porcine tubular epithelial cells after shRNA-mediated Nrf2 inhibition as well as in proximal tubular cells isolated from Nrf2-/- male mice in comparison to cells derived from their wild-type counterparts. In vivo study revealed that male mice are significantly more susceptible to OTA-mediated injury than females and this effect was further enhanced in mice lacking Nrf2. OTA increased the expression of pro-fibrotic, pro-inflammatory and pro-apoptotic factors, while concomitantly decreased the level of claudin-2 and vascular endothelial growth factor (VEGF). Importantly, miR-21, miR-34a and miR-382 were potently up-regulated after OTA delivery. Noteworthy, treatment with sulforaphane (SFN), diminished expression of OTA-induced inflammatory cytokines (IL-1beta, IL-6), pro-apoptotic factors (c myc, PUMA) and microRNAs (miR-382, miR-34a) in male mice. In summary, our data implies sex-dependent effect of OTA, with males being more sensitive. The lack of Nrf2 enhances susceptibility to mycotoxin-induced pathologies, suggesting that modulation of the Nrf2 pathway may provide a therapeutic approach to treat OTA triggered renal diseases. PMID- 28710021 TI - Identification of tumor-autonomous and indirect effects of vitamin D action that inhibit breast cancer growth and tumor progression. AB - Several epidemiological studies have found that low vitamin D levels are associated with worse prognosis and poorer outcomes in patients with breast cancer (BCa), although some studies have failed to find this association. In addition, prior research has found that BCa patients with vitamin D deficiency have a more aggressive molecular phenotype and worse prognostic biomarkers. As vitamin D deficiency is common in patients diagnosed with BCa, elucidating the cause of the association between poor outcomes and vitamin D deficiency promises to have a significant impact on improving care for patients with BCa including enabling the development of novel therapeutic approaches. Here we review our recent findings in this area, including our data revealing that reduction of the expression of the vitamin D receptor (Vdr) within BCa cells accelerates primary tumor growth and enables the development of metastases, demonstrating a tumor autonomous effect of vitamin D signaling to suppress BCa metastases. We believe that these findings are likely relevant to humans as we discovered evidence that a mechanism of VDR regulation identified in our mouse models is conserved in human BCa. In particular, we identified a negative correlation between serum 25(OH)D concentration and the level of expression of the tumor progression factor ID1 in primary tumors from patients with breast cancer. PMID- 28710022 TI - Taxifolin reduces the cholesterol oxidation product-induced neuronal apoptosis by suppressing the Akt and NF-kappaB activation-mediated cell death. AB - The taxifolin effect on the cholesterol oxidation product-induced neuronal apoptosis was investigated using differentiated PC12 cells and human neuroblastoma SH-SY5Y cells. 7-ketocholesterol induced phosphorylation of Akt, and increase in the levels of cytosolic and nuclear NF-kappaB p65, cytosolic NF kappaB p50 and cytosolic phosphorylated-IkappaB-alpha in PC12 cells. The cholesterol oxidation products also induced a decrease in the levels of Bid and Bcl-2, increase in the levels of p53 and Bax, loss of the mitochondrial transmembrane potential, release of cytochrome c, activation of caspases (-8, -9 and -3), production of reactive oxygen species, depletion of GSH and cell death in both cell lines. Taxifolin, N-acetylcysteine, trolox, Akt inhibitor and Bay11 7085 attenuated the cholesterol oxidation product-induced changes in the apoptosis-related protein levels, activation of the Akt and NF-kappaB, reactive oxygen species production, GSH depletion and cell death. These results show that taxifolin may reduce the cholesterol oxidation product-induced neuronal apoptosis by suppressing the Akt and NF-kappaB activation-mediated cell death. The suppressive effect appears to be attributed to the inhibition of reactive oxygen species production and GSH depletion. PMID- 28710023 TI - Transient brain hypothermia reduces the reperfusion injury of delayed tissue plasminogen activator and extends its therapeutic time window in a focal embolic stroke model. AB - It has been reported that restriction of reperfusion after thrombolytic therapy in ischemic stroke may reduce tissue plasminogen activator (tPA) adverse effects and extend its time window. We examined whether shortIt has been reported that restriction of reperfusion after thrombolytic therapy in ischemic stroke may reduce tissue plasminogen activator (tPA) adverse effects and extend its time window. We examined whether short-term and mild local brain cooling can prevent hyperemia and/or adverse effects of delayed tPA in rat embolic stroke model. Male animals were subjected to embolic stroke and then randomly classified into control (saline), tPA (1mg/kg; i.v.), local hypothermia (LH), and tPA+LH. The drug was injected at 6 h after ischemia. LH was conducted by direct ipsilateral (injured) hemisphere cooling at 6.5h after stroke and maintained for approximately 30min. Cerebral blood flow was monitored in duration of 60 minute after tPA administration and hyperemic response was measured. Infarct volume, blood-brain barrier (BBB) disruption, edema formation, neurological deficits, and matrix metalloproteinase-9 (MMP-9) level were measured 48 h later. A combination of tPA+LH significantly diminished infarct volume in comparison with the tPA (P< 0.001) and control (P<0.05) groups. Combination therapy also decreased BBB leakage (P<0.001), MMP-9 level or edema (P<0.05) and improved neurological functions at 24 and 48h after stroke. LH caused a gradual decrease in hyperemic response after thrombolysis compared to the control (P<0.05) or tPA (P<0.001) groups. LH alone also reduced infarct volume, BBB leakage or edema (P<0.05). The short-term local brain hypothermia may mitigate reperfusion injury following delayed tPA therapy and extend its time window up to 6h. PMID- 28710024 TI - Intranasal nerve growth factor attenuating the seizure onset via p75R/Caspase pathway in the experimental epilepsy. AB - BACKGROUND: Nerve growth factor (NGF) shows neuroprotection while it is hard to cross the blood-brain barrier due to its large molecular weight. Our study used intranasal delivery of NGF to treat the experimental epilepsy. METHODS: The seizure was induced by injection of pentylenetetrazol (40mg/kg) into the rat. Based on the behavior performance, the successful models were randomized into control and NGF groups, given medium or NGF intranasally, respectively. The onset and duration of seizure were recorded. The neuron loss was assessed by immunohistochemistry and TUNEL staining. The expressions of Caspase-3, p75R and TrkA were measured by western blotting. RESULTS: Intranasal NGF significantly reduced the seizure onset and shortened the seizure duration. Intranasal NGF alleviated the neuron loss in the epileptic brain. The number of TUNEL-positive cells in the NGF group was less than that in the control group (P<0.05). Overexpression of Caspase-3 and activation of p75R induced by seizure were inhibited by intranasal NGF. CONCLUSION: Intranasal NGF protected neurons in the epileptic brain by inactivation of p75R/Caspase pathway. Intranasal NGF may be a novel therapeutic strategy for epilepsy. PMID- 28710026 TI - Systematic review of the impact of osteoarthritis on health outcomes for comorbid disease in older people. AB - OBJECTIVE: A systematic review was undertaken examining the impact of comorbid osteoarthritis on health outcomes for people aged 50 years or older with cardiovascular disease, diabetes or obesity. DESIGN: The protocol is registered in PROSPERO (CRD42015023417). Relevant electronic databases and grey literature were systematically searched for studies published in English between January 2005 and December 2016. Two reviewers independently screened studies for selection using predetermined inclusion and exclusion criteria, and independently completed methodological quality review. Data was extracted at study level by one reviewer and independently checked by a second reviewer, using a standardized form. The results across studies were qualitatively synthesized with outcomes described and summarized. RESULTS: Of 1456 articles, we identified 15 relevant studies, with nine good to high quality studies describing significant negative impact of osteoarthritis on outcomes for cardiovascular diseases. There were too few studies focussing on diabetes and obesity to make conclusions in regard to these diseases. CONCLUSIONS: This review provides evidence that osteoarthritis should not be overlooked when impacts of chronic disease on health outcomes and related health service use are considered. There is a clear need for more studies that consider the impacts of osteoarthritis on comorbid disease, especially those that consider the impact of osteoarthritis beyond the morbidity impacts. The management of comorbid osteoarthritis should be addressed for those with cardiovascular disease, and treatment choices considered given this association. PMID- 28710025 TI - Inhibitory effects of tetramethylpyrazine on pain transmission of trigeminal neuralgia in CCI-ION rats. AB - Tetramethylpyrazine (TMP) has anti-inflammatory effects and is used to treat cerebral ischemic injury, but the mechanism of TMP on neural protection is not clear. Trigeminal neuralgia (TN) is a facial pain syndrome that is characterized by paroxysmal, shock-like pain attacks located in the somatosensory distribution of the trigeminal nerve. P2X3 receptor plays a crucial role in facilitating pain transmission. The present study investigates the effects of TMP on trigeminal neuralgia transmission mediated by P2X3 receptor of the trigeminal ganglia (TG). Chronic constriction injury of the infraorbital branch of the trigeminal nerve (CCI-ION) was used as a trigeminal neuralgia model. On day 15 after surgery, there was a significant decline in the mechanical hyperalgesia threshold in the territory of the ligated infraorbital nerve in the TN group, and an increase in expression of P2X3 receptor in the TG of the TN group compared with the Sham group. After treatment with TMP or A-317491, the mechanical hyperalgesia threshold of TN rats was significantly higher, and expression of P2X3 receptor in the TG noticeably declined compared with the TN group. Phosphorylation of p38 and ERK1/2 in the TN group was stronger than in the Sham group. However, the phosphorylation of p38 and ERK1/2 in the TN+TMP group and TN+A-317491 group was much lower than in the TN group. TMP significantly inhibited the ATP activated currents in HEK293 cells transfected with a P2X3 plasmid. Thus, TMP might have inhibitory effects on trigeminal neuralgia by suppressing the expression of P2X3 receptor in the TG and the phosphorylation of p38 and ERK1/2 in the TG. PMID- 28710027 TI - Admission lactate predicts poor prognosis independently of the CRB/CURB-65 scores in community-acquired pneumonia. AB - OBJECTIVES: Community-acquired pneumonia (CAP) is associated with a high risk of respiratory failure or septic organ dysfunction. Lactate is an established early marker of prognosis and sepsis severity, but few data exist in patients with CAP. METHODS: We performed a retrospective cohort study of consecutive adult CAP patients without treatment restrictions or direct intensive care unit admission. Lactate was measured as a point-of-care test within the capillary admission blood gas analysis, and its prognostic value was compared to the CRB/CURB-65 criteria by multivariate and receiver operating characteristic (ROC) curve analysis. The primary endpoint was the combination of need for mechanical ventilation, vasopressors, intensive care unit admission or hospital mortality. RESULTS: Of 303 included patients, 75 (25%) met the primary endpoint. After ROC analysis, lactate predicted the primary endpoint (area under the curve 0.67) with an optimal cutoff of >1.8 mmol/L. Of the 76 patients with lactate above this threshold, 35 (46%) met the primary endpoint. After multivariate analysis, the predictive value of lactate was independent of the CRB/CURB-65 scores. The addition of lactate >1.8 mmol/L to the CRB/CURB-65 scores resulted in significantly improved area under the curves (0.69 to 0.74, p 0.005 and 0.71 to 0.75, p 0.008 respectively). Fourteen (42%) of 33 and 11 (39%) of 28 patients meeting the endpoint despite presenting with 0 or 1 CRB/CURB-65 criteria had lactate >1.8 mmol/L. CONCLUSIONS: Admission lactate levels significantly improved the prognostic value of the CRB/CURB-65 scores in CAP patients. Lactate may therefore be considered a rapid, cheap and broadly available additional criterion for the assessment of risk in patients with CAP. PMID- 28710028 TI - Gene expression profiles of fin regeneration in loach (Paramisgurnus dabryanu). AB - Teleost fins can regenerate accurate position-matched structure and function after amputation. However, we still lack systematic transcriptional profiling and methodologies to understand the molecular basis of fin regeneration. After histological analysis, we established a suppression subtraction hybridization library containing 418 distinct sequences expressed differentially during the process of blastema formation and differentiation in caudal fin regeneration. Genome ontology and comparative analysis of differential distribution of our data and the reference zebrafish genome showed notable subcategories, including multi organism processes, response to stimuli, extracellular matrix, antioxidant activity, and cell junction function. KEGG pathway analysis allowed the effective identification of relevant genes in those pathways involved in tissue morphogenesis and regeneration, including tight junction, cell adhesion molecules, mTOR and Jak-STAT signaling pathway. From relevant function subcategories and signaling pathways, 78 clones were examined for further Southern-blot hybridization. Then, 17 genes were chosen and characterized using semi-quantitative PCR. Then 4 candidate genes were identified, including F11r, Mmp9, Agr2 and one without a match to any database. After real-time quantitative PCR, the results showed obvious expression changes in different periods of caudal fin regeneration. We can assume that the 4 candidates, likely valuable genes associated with fin regeneration, deserve additional attention. Thus, our study demonstrated how to investigate the transcript profiles with an emphasis on bioinformatics intervention and how to identify potential genes related to fin regeneration processes. The results also provide a foundation or knowledge for further research into genes and molecular mechanisms of fin regeneration. PMID- 28710029 TI - Decreased expression level of BER genes in Alzheimer's disease patients is not derivative of their DNA methylation status. AB - BACKGROUND: Neurodegeneration in Alzheimer's disease can be caused by accumulation of oxidative DNA damage resulting from altered expression of genes involved in the base excision repair system (BER). Promoter methylation can affect the profile of BER genes expression. Decreased expression of BER genes was observed in the brains of AD patients. AIM OF THE STUDY: The aim of our study was to compare the expression and methylation profiles of six genes coding for proteins involved in BER, namely: hOGG1, APE1, MUTYH, NEIL1, PARP1 and XRCC1, in the peripheral blood cells of AD patients and healthy volunteers. METHODS: The study consisted of 100 persons diagnosed with Alzheimer's disease according to DSM-IV criteria, and 110 healthy volunteers. DNA and total RNA were isolated from venous blood cells. Promoter methylation profiles were obtained by High Resolution Melting (HRM) analysis of bisulfide converted DNA samples. Real-time PCR with TaqMan probes was employed for gene expression analysis. RESULTS: APE1, hOGG1, MUTYH, PARP1 and NEIL1 were significantly (p<0.001) down-regulated in the lymphocytes of AD patients, as compared to healthy volunteers. Expression of XRCC1 didn't differ significantly between both groups. We did not find any differences in the methylation pattern of any of the investigated BER genes. CONCLUSIONS: The methylation status of promoters is not associated with downregulation of BER genes. Our results show that downregulation of BER genes detected in peripheral blood samples could reflect the changes occurring in the brain of patients with AD, and may be a useful biomarker of this disease. PMID- 28710030 TI - Differences of sympathetic and parasympathetic modulation in major depression. AB - Inconsistent results have been reported with respect to cardiac autonomic function in major depression. The aim of our study was to investigate autonomic function in various branches of the autonomic nervous system in order to better understand parasympathetic and sympathetic modulation in the disease. We investigated 29 unmedicated patients suffering from major depression (MD) in comparison to matched control subjects (gender, age, BMI). The autonomic assessment at rest included values of heart rate variability (HRV), blood pressure variability (BPV), baroreflex sensitivity (BRS), respiration, skin conductance (SC) as well as the calculation of pupillary diameter and the unrest index (PUI). Results were compared by means of a multivariate analysis of variance. In a classification analysis, we identified suitable parameters for patient - control separation. Finally, to analyze interrelations of pupillometric parameters and autonomic indices, we estimated Pearson correlation coefficients and fitted a linear regression model. Apart from a significantly increased heart rate (75+/-12 vs. 65+/-6min-1, p<0.001) and decreased BRS (14+/-13 vs. 20+/ 15ms/mmHg, p<0.05), we observed a lack of significant differences in HRV and BPV analysis between patients and controls. However, pupillary diameter (left: 4.3+/ 0.9 vs. 3.8+/-0.6, p<0.01; right: 4.3+/-0.9 vs. 3.7+/-0.6mm, p<0.01) and PUI (left: 14.8+/-6.0 vs. 10.7+/-4.5mm/min, p<0.01; right: 14.1+/-5.5 vs. 10.7+/ 4.8mm/min, p<0.01), as well as the level (left: 7.3+/-6.2 vs. 4.3+/-4.4 MUS, p<0.05) and fluctuations of skin conductance (left: 4.2+/-4.1 vs. 2.5+/-3.6, p<0.05; right: 4.2+/-4.4 vs. 2.6+/-3.2, p<0.05) were significantly different. The classification accuracy was 88.5% with high specificity (e=92.9%) and sensitivity (s=83.3%) including heart rate, PUI and skin conductance. HRV indices correlated to PUI in controls but not in patients. Our data add evidence to the current debate on autonomic function in major depression. We suggest that diverse results are mainly caused by methodological shortcomings, in particular by the application of HRV assessment only, which misses changes of sympathetic modulation. The application of broader analyzing tools will clarify the pattern of autonomic function in depression and ultimately its role in cardiac morbidity and mortality. PMID- 28710031 TI - Zoantharian mitochondrial genomes contain unique complex group I introns and highly conserved intergenic regions. AB - Complex group I introns represent hallmarks of hexacoral mitochondrial genomes (mtDNAs). These intron elements are expected to influence the gene organization and gene expression. We sequenced the mitochondrial genome and transcriptome of Zoanthus sansibariscus and Palythoa heliodiscus, two zoantharian species (colonial anemones) representing different families within the suborder Brachycnemina. The circular and approximately 21kb mtDNAs contained two group I introns, one in ND5 and another in COI. The ND5-717 intron harbored two conventional mitochondrial genes (ND1 and ND3) within its structure and revealed several conserved features compared to ND5-717 in sea anemones. The COI intron, however, was inserted at a unique location (after position 867), which was different from that in sea anemones (position 884) and stony corals (position 720). COI-867 contained a homing endonuclease gene (HEG) with remarkable features, including species-specific length variations and only one copy of the essential LAGLIDADG motif. Whereas transcriptome analysis indicated that all conventional mtDNA genes were expressed, HEG expression appeared significantly repressed. Finally, we identified absolutely conserved non-coding repeat motifs with antisense features and potential regulatory functions. PMID- 28710032 TI - MicroRNA-136 inhibits colon cancer cell proliferation and invasion through targeting liver receptor homolog-1/Wnt signaling. AB - An increasing number of studies have reported that microRNAs (miRNAs) are involved in the malignant behavior of colon cancer cells through directly targeting multiple tumor suppressors or oncogenes. The expression and role of miR 136 has been reported in several types of human cancer. However, the role of miR 136 in colon cancer remains unclear. In this study, we aimed to investigate the expression and function of miR-136 in colon cancer and the potential underlying mechanism. Here, we found that miR-136 was decreased in colon cancer cell lines and tissues. Overexpression of miR-136 inhibited the proliferation and invasion in SW480 and HCT116 cell lines while suppression of miR-136 exhibited the opposite effect. Liver receptor homolog-1 (LRH-1) was identified as a direct target gene of miR-136. Notably, miR-136 overexpression suppressed LRH-1 expression as well as Wnt signaling in SW480 and HCT116 cell lines. The miR-136 expression level inversely correlated with LRH-1 mRNA expression in colon cancer specimens. Moreover, overexpression of LRH-1 partially reversed the miR-136 induced antitumor effect in SW480 and HCT116 cell lines. Taken together, these findings suggest that miR-136 functions as a negative regulator in colon cancer progression by targeting LRH-1 and that miR-136 downregulation contributes to high expression of LRH-1 and aberrant activation of Wnt signaling, leaving open the possibility that miR-136 may serve as a potential therapeutic target for colon cancer. PMID- 28710033 TI - Glutathione S-transferase (GSTM1, GSTT1) polymorphisms and JOAG susceptibility: A case control study and meta-analysis in glaucoma. AB - PURPOSE: Glutathione S transferase (GST) polymorphisms have been considered risk factors for the development of glaucoma. The aim of the present study was to investigate the association of glutathione S-transferase GSTT1 and GSTM1 genotypes with juvenile open-angle glaucoma (JOAG) in Indian patients. METHODS: A case-control study was performed to investigate the associations of GSTM1 and GSTT1 in juvenile open-angle glaucoma. The genotype of GSTM1 and GSTT1 were determined in 73 juvenile open-angle glaucoma patients, and 70 controls matched by age and sex by polymerase chain reaction method. We also performed a meta analysis of sixteen published studies on GSTM1 and GSTT1 and evaluated the association between the GSTM1 and GSTT1 polymorphisms and glaucoma (JOAG & POAG). Published literature from PubMed and other databases were retrieved. All studies evaluating the association between GSTM1 and GSTT1 polymorphisms and glaucoma (JOAG & POAG) risk were included. Pooled odds ratio (OR) and 95% confidence interval (CI) were calculated using random- or fixed-effects model. RESULTS: In the present study, we observed there is no association of GSTM1 (OR=0.680; 95% CI=0.323-1.433; p=0.311) or GSTT1 (OR=0.698; 95% CI=0.307-1.586; p=0.391) with JOAG. In the present meta-analysis, significantly increased glaucoma (JOAG & POAG) risk was found among subjects carrying GSTM1 null genotype (OR=1.177; 95% CI=1.028-1.348; p=0.018) but not among subjects carrying GSTT1 deletion genotype (OR=1.186; 95% CI=0.992-1.417; p=0.061). CONCLUSIONS: The present case-control study found that GSTM1 and GSTT1 polymorphism are not associated with JOAG risk in North Indian population. The present meta-analysis suggested that there might be a significant association of GSTM1 null genotype with glaucoma (JOAG & POAG) risk. To the best of our knowledge, this is the first study in the world to investigate role of GSTM1 and GSTT1 polymorphisms with JOAG susceptibility. Given the limited sample size, the associations between GST polymorphism and glaucoma risk needs further investigation. PMID- 28710034 TI - Association of thrombomodulin c.1418C>T polymorphism and venous thromboembolism. AB - OBJECTIVES: To investigate the association between thrombomodulin c.1418C>T polymorphism and venous thrombosis. METHODS: Systematic searches of Pubmed, EMBASE, Chinese Biomedical Database, Chinese National Knowledge Infrastructure, the VIP Database and WANFANG Database were performed. Pooled odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated to assess the strength of the association. Subgroup analysis was conducted to seek for potential sources of heterogeneity. RESULTS: A total of 8 studies were collected in our analysis, including 2519 cases and 3196 controls. No significant association between thrombomodulin c.1418C>T polymorphism and venous thrombosis was shown under the five genetic models (T vs C: OR=1.02, 95% CI=0.82-1.26; TT vs CC: OR=0.90, 95% CI=0.52-1.56; CT vs CC: OR=1.07, 95% CI=0.84-1.37; CT+TT vs CC: OR=1.05, 95% CI=0.82-1.34; TT vs CT+CC: OR=0.81, 95% CI=0.59-1.11). Similar results were observed in the following subgroup analysis based on ethnicity and source of control. However, an increased risk of venous thrombosis was found in Asian populations under three genetic models (T vs C: OR=1.31, 95% CI=1.01-1.70; CT vs CC: OR=1.41, 95% CI=1.00-2.98; TT+CT vs CC vs CC: OR=1.41, 95% CI=1.02-1.95). CONCLUSION: Current studies on the thrombomodulin c.1418C>T polymorphism are of great heterogeneity. It might not be a risk factor for venous thromboembolism. PMID- 28710035 TI - Association of common genetic variants in VEGFA with biliary atresia susceptibility in Northwestern Han Chinese. AB - : Biliary atresia (BA) is a major neonatal obliterative cholangiopathy, resulting in progressive cirrhosis. The gene VEGFA encodes a heparin-binding protein that is a regulator of angiogenesis and a mediator of inflammatory reactions, and accumulating evidence have indicated that VEGFA may play a possible role in the pathogenesis of BA. Our study aim was to evaluate the association of common variants within the VEGFA gene with BA susceptibility in Northwestern Han Chinese population. Forty tag SNPs within the VEGFA gene were selected in the study, and then subsequently genotyped in 1336 Northwestern Han Chinese individuals, consisting of 311 BA patients and 1025 healthy controls. The SNP rs3025039 was found to be strongly associated with BA risk (additive P=0.000264) in our sample, and the CC genotype of rs3025039 had higher prevalence than the other two genotypes, indicating the C allele is a risk allele with an odds ratio (OR) of 1.56 and 95% confidence interval (CI) of 1.23-1.99. Haplotype analyses showed that a LD block containing rs3025039 significantly correlated with BA risk (global P<0.001). Moreover, bioinformatics analysis indicated that hsa-mir-591 and VEGFA formed miRNA/SNP target duplexes if the rs3025039 allele was in the T form, suggesting that rs3025039 may alter VEGFA expression by affecting hsa-miR 591/single-nucleotide polymorphism target duplexes. Our results indicate additional evidence supporting that there is an important role of the VEGFA gene in the increased susceptibility of BA. ABBREVIATIONS: PMID- 28710036 TI - Effect of polymorphisms in transporter genes on dosing, efficacy and toxicity of maintenance therapy in children with acute lymphoblastic leukemia. AB - The aim of the present work was to assess whether polymorphisms in genes coding for drug transport proteins may influence dosing, efficacy and toxicity of maintenance therapy with methotrexate (MTX) and 6-mercaptopurine (6MP) in childhood acute lymphoblastic leukemia (ALL). A total of 41 children with ALL were screened for 10 SNPs in the SLC19A1, ABCB1, ABCC2, ABCC4 and ABCG2 transporter genes by means of direct sequencing. Carriers of the ABCC4 934CC and ABCB1 1236TT genotypes received a lower percentage of the protocol-recommended starting dose of MTX (62.1 vs. 81.3% for 934CA carriers, p=0.001) and 6MP (73.1 vs. 87.7% for 1236CC/CT carriers; p=0.026), respectively. The C1236T SNP also increased the efficiency of myelosuppression. Median (and interquartile) number of blood tests with leukocytes levels <3109/L for the CC; CT and TT genotypes were 22 (13), 30.5 (11.75) and 33 (17.25), respectively (p=0.001). In addition, this SNP also correlated with the number of hematological adverse events (p=0.004 for the difference between same genotypes). The event more profoundly affected was neutropenia (p=0.004). In the same manner, the ABCC4 934CC genotype was also associated to more frequent hematological toxicity (p=0.041 vs. CT carriers) and raised LDH levels (p=0.004 vs. CT carriers); although only the latter association remained significant after correction by multiple testing. Overall, our findings indicate that variability in the ABCB1 and ABCC4 genes may confer higher sensitivity to maintenance chemotherapy of ALL, and therefore its determination may be helpful in individualizing this treatment. PMID- 28710037 TI - RNA editing independently occurs at three mir-376a-1 sites and may compromise the stability of the microRNA hairpin. AB - RNA editing is being recognized as an important post-transcriptional mechanism that may have crucial roles in introducing genetic variation and phenotypic diversity. Despite microRNA editing recurrence, defining its biological relevance is still under extended debate. To better understand microRNA editing function and regulation we performed an exhaustive characterization of the A-to-I site specific patterns in mir-376a-1, a mammalian microRNA which RNA editing is involved in the regulation of development and in disease. Thorough an integrative approach based on high-throughput small RNA sequencing, Sanger sequencing and computer simulations we explored mir-376a-1 editing in samples from various individuals and primate species including human placenta and macaque, gorilla, chimpanzee and human brain cortex. We observed that mir-376a-1 editing is a common phenomenon in the mature and primary microRNA molecules and it is more frequently detected in brain than in placenta. Primary mir-376a-1 is edited at three positions, -1, +4 and +44. Editing frequency estimations and in silico simulations indicated that editing was not equally recurrent along the three mir 376a-1 sites, nevertheless no epistatic interactions among them were observed. Particularly, the +4 site, located in the seed region of the mature miR-376a-5p, reached the highest editing frequency in all samples. Secondary structure predictions revealed that the +4 position was the one that conferred the highest stability to the mir-376a-1 hairpin. We suggest that molecular stability might partially explain the editing recurrence observed in certain microRNAs and that editing events conferring new functional regulatory roles in particular tissues and species could have been conserved along evolution, as it might be the case of mir-376a-1 in primate brain cortex. PMID- 28710038 TI - Steroid sulfatase and filaggrin mutations in a boy with severe ichthyosis, elevated serum IgE level and moyamoya syndrome. AB - X-linked ichthyosis (XLI) is a relatively common, recessive condition caused by mutations in the steroid sulfatase (STS) gene. Common loss-of-function mutations in the filaggrin gene (FLG) cause ichthyosis vulgaris and predispose individuals to atopic eczema. We report a case of a 6-year-old boy who presented with unusually severe XLI, an increased serum immunoglobulin E level (2120IU/ml) and moyamoya angiopathy. Whole-exome sequencing identified a gross deletion encompassing the STS in Xp22.31 and the p.K4022X FLG mutation. The deletion is at least 1.6Mb in size in the proband, based on real-time quantitative polymerase chain reaction results. No other genetic mutations related to ichthyosis, moyamoya or hyper-immunoglobulin E syndrome were detected. Furthermore, his mother's brothers suffered from mild XLI and only had a deletion encompassing the STS. Additionally, his father and older sister suffered from mild ichthyosis vulgaris and had the p.K4022X FLG mutation. We report the first case of XLI with concurrent moyamoya syndrome. Moreover, an IgE-mediated immune response may have triggered the moyamoya signaling cascade in this patient with ichthyosis. Furthermore, our study strengthens the hypothesis that filaggrin defects can synergize with an STS deficiency to exacerbate the ichthyosis phenotype in an ethnically diverse population. PMID- 28710039 TI - Cloning, expression pattern, and potential role of apoptosis inhibitor 5 in the termination of embryonic diapause and early embryo development of Artemia sinica. AB - During the embryonic development of Artemia sinica, the diapause phenomenon can be induced by high salinity or low temperature conditions. The diapause embryo at the gastrula stage is maintained under the threat of apoptosis to guarantee the embryo's normal development. In this process, apoptosis inhibitor proteins play vital roles in protecting embryos against apoptosis. Apoptosis inhibitor5 (API5) plays a pivotal role in regulating the cell cycle and preventing programmed cell death after growth factor starvation. In the present study, we cloned the full length cDNA representing the api5 gene from A. sinica (As-api5), which encodes a 372-amino acid protein. In situ hybridization experiments revealed that As-api5 expression is not tissue or organ specific. Quantitative real-time PCR analyses of the developmental expression of As-api5 showed that it reached its highest level at 10h, after which its expression decreased. High salinity and low temperature treatments increased the expression of As-api5. Western blotting was used to assess the abundance of As-API5 and related proteins (As-CyclinA, As CyclinE, As-E2F1, As-CDK2, As-APAF1, and As-Caspase9). Downregulation of As-api5 expression using a short interfering RNA resulted in increased mortality and embryo malformation of A. sinica. Taken together, the results indicated that API5 plays a crucial role in embryonic diapause termination and early embryo development of A. sinica. PMID- 28710040 TI - Evaluating the replicability, specificity, and generalizability of connectome fingerprints. AB - Establishing reliable, robust, and unique brain signatures from neuroimaging data is a prerequisite for precision psychiatry, and therefore a highly sought-after goal in contemporary neuroscience. Recently, the procedure of connectome fingerprinting, using brain functional connectivity profiles as such signatures, was shown to be able to accurately identify individuals from a group of 126 subjects from the Human Connectome Project (HCP). However, the specificity and generalizability of this procedure were not tested. In this replication study, we show both for the original and an extended HCP data set (n = 900 subjects), as well as for an additional data set of more commonly acquired imaging quality (n = 84) that (i) although the high accuracy can be replicated for the larger HCP 900 data set, accuracy is (ii) lower for standard neuroimaging data, and, that (iii) connectome fingerprinting may not be specific enough to distinguish between individuals. In addition, both accuracy and specificity are projected to drop considerably as the size of a data set increases. Although the moderate-to-high accuracies do suggest there is a portion of unique variance, our results suggest that connectomes may actually be quite similar across individuals. This outcome may be relevant to how precision psychiatry could benefit from inferences based on functional connectomes. PMID- 28710041 TI - Create, run, share, publish, and reference your LC-MS, FIA-MS, GC-MS, and NMR data analysis workflows with the Workflow4Metabolomics 3.0 Galaxy online infrastructure for metabolomics. AB - Metabolomics is a key approach in modern functional genomics and systems biology. Due to the complexity of metabolomics data, the variety of experimental designs, and the multiplicity of bioinformatics tools, providing experimenters with a simple and efficient resource to conduct comprehensive and rigorous analysis of their data is of utmost importance. In 2014, we launched the Workflow4Metabolomics (W4M; http://workflow4metabolomics.org) online infrastructure for metabolomics built on the Galaxy environment, which offers user-friendly features to build and run data analysis workflows including preprocessing, statistical analysis, and annotation steps. Here we present the new W4M 3.0 release, which contains twice as many tools as the first version, and provides two features which are, to our knowledge, unique among online resources. First, data from the four major metabolomics technologies (i.e., LC-MS, FIA-MS, GC-MS, and NMR) can be analyzed on a single platform. By using three studies in human physiology, alga evolution, and animal toxicology, we demonstrate how the 40 available tools can be easily combined to address biological issues. Second, the full analysis (including the workflow, the parameter values, the input data and output results) can be referenced with a permanent digital object identifier (DOI). Publication of data analyses is of major importance for robust and reproducible science. Furthermore, the publicly shared workflows are of high value for e-learning and training. The Workflow4Metabolomics 3.0 e-infrastructure thus not only offers a unique online environment for analysis of data from the main metabolomics technologies, but it is also the first reference repository for metabolomics workflows. PMID- 28710042 TI - New Evidence for Causal Central Mechanism of Hyperglycemia in Subarachnoid Hemorrhage Secondary to Ischemic Degenerative Disruption of Circuitry Among Insular Cortex, Nodose Ganglion, and Pancreas: Experimental Study. AB - INTRODUCTION: Although hyperglycemia is a serious complication of subarachnoid hemorrhage, its pathophysiologic mechanism based on neural circuitry has not been known. MATERIALS AND METHODS: Twenty-five rabbits were divided into 4 groups, with 5 in the control group. The SHAM and study groups received 1 mL saline and 1 mL autologous arterial blood into the sylvian cisterna, respectively. Blood glucose values (BGVs) of all animals were recorded 3 times weekly. After 2 weeks, animals were decapitated. BGVs, the number of normal and degenerated neuron densities (DNDs) of insular cortex (IC), and nodose ganglia, degenerated islands of Reil's surfaces values, were estimated by stereologically and analyzed statistically. RESULTS: The mean blood glucose values were measured as 101 +/- 10 mg/dL in the control group (n = 5), 114 +/- 11 mg/dL in the SHAM group (n = 5), and 137 +/- 12 mg/dL in the subarachnoid hemorrhage (SAH) group (n = 15). The DND of the nodose ganglion was 10 +/- 3/mm3 in the control group, while it was 45 +/- 7/mm3 in the SHAM group and 1688 +/- 191/mm3 in the SAH group. The DND of the IC was 65 +/- 12/mm3 in the control group, 689 +/- 112/mm3 in the SHAM group, and 3709 +/- 643/mm3 in the SAH group. In addition, the proportion of degenerated surface areas in the islet of Langerhans was 0.3% in the control group, 6% in the SHAM group, and 28% in the SAH group. CONCLUSION: There is an important linear relationship among the blood glucose levels, DND of the IC, and nodose ganglia and degenerated surface areas of IL following experimentally induced sylvian SAH. PMID- 28710043 TI - Minimally Invasive Computer Navigation-Assisted Endoscopic Transforaminal Interbody Fusion with Bilateral Decompression via a Unilateral Approach: Initial Clinical Experience at One-Year Follow-Up. AB - OBJECTIVE: The purpose of this study was to assess the feasibility of minimally invasive transforaminal lumbar interbody fusion (TLIF) and bilateral decompression via a unilateral approach that was performed with a novel working retractor with an endoscopic system for degenerative lumbar spondylolisthesis associated with spinal stenosis, to minimize surgical trauma without compromising the quality of the treatment outcome. METHODS: In this case series, the procedure was performed in 17 patients. Patient outcomes were scored according to operating time, intraoperative blood loss, visual analog scale, Oswestry Disability Index, Japanese Orthopaedic Association scores, and postoperative imaging studies. RESULTS: The follow-up period was 1 year. All patients showed clinical improvement, based on the visual analog scale, Oswestry Disability Index, and Japanese Orthopaedic Association score (P < 0.01). At 12 months postoperatively, all patients achieved solid bone graft fusion. CONCLUSION: The use of navigation assisted endoscopic TLIF with bilateral decompression via a unilateral approach appears safe and feasible. The endoscopic surgical procedure may be an alternative surgical option for degenerative lumbar disease. PMID- 28710044 TI - Treatment Strategies of Subarachnoid Hemorrhage from Bilateral Vertebral Artery Dissection: A Case Report and Literature Review Focusing on the Availability of Stent Placement. AB - BACKGROUND: Bilateral vertebral artery dissection (VAD) may result in subarachnoid hemorrhage (SAH). However, a variety of factors contribute to the difficulties with treating SAH. We report a case of bilateral VAD with SAH, as well as a literature review. CASE DESCRIPTION: A 32-year-old woman developed headache. Computed tomography demonstrated diffuse SAH, and 3-dimensional computed tomography indicated bilateral VAD. Her left vertebral artery was severely stenosed, and the basilar artery retrogradely flowed via the posterior communicating artery. Her bilateral VAD was trapped with the use of staged craniotomy. The postoperative course was uneventful for 13 days; however, severe neurologic deterioration remained in the area of the cerebral infarction, due to vasospasm of the internal carotid artery. This is the first report of hemorrhagic bilateral VAD treated with bilateral trapping and aggressive spasm treatment in the acute phase. However, the treatment was not successful. CONCLUSIONS: Because of the increasing use of stent therapy, there has been a shift toward this treatment choice. For cases in which stents cannot be used, treatment methods based on prestenting protocols are helpful. A literature review indicated that conservative treatment for 2 weeks, in which vasospasm and rebleeding are controlled, may be considered compared with acute-stage stent treatment. Following our literature review, in situations in which stents cannot be used, only the ruptured side should be trapped with strict blood pressure control and detailed radiological images should be observed for 2 weeks. In conclusion, patient selection is essential to subject the patient to open surgery in such cases. PMID- 28710045 TI - Management of Pediatric Atlantoaxial Rotatory Subluxation with a Simple Handmade Cervical Traction Device: Doing More with Less. AB - OBJECTIVES: To introduce a novel traction device for management of pediatric atlanto-axial rotatory subluxation (AARS) in source limiting areas. BACKGROUND: Atlanto-axial (C1-C2) joint is accountable for up to two third of total axial craniocervical rotation. Its major role in pivotal rotation of cervical spine makes it more vulnerable to a certain type of injury known as AARS. Management of AARS is based on the Fielding classification which includes closed reduction and immobilization and cervical fusion in unstable cases. There are several cervical traction devices including the Gardner-Wells tongs and halter traction device. All the available devices require insertion of pins into the calvarial periosteum which is a painful, invasive and intolerable procedure especially for the pediatric patients. METHODS: We designed a simple hand-made cervical traction device which is composed of 2 soft padded straps (40 * 4 cm) and 2 connecting strings which can be applied easily under the chin and occipital areas of the patients. RESULTS: We successfully treated a 9-year-old girl with AARS with the device. The advantage of the device is its available, inexpensive and non invasive and the patient might tolerate it more easily compared to the previously designed instruments. CONCLUSION: This hand-made simple cervical traction device in source limiting centers and hospitals is a good example of doing more with less. It was effective and the tolerance of the patient was acceptable. Further studies with larger series are required for providing appropriate evidence. PMID- 28710046 TI - Image Guidance to Aid Pedicle Screw Fixation of a Lumbar Fracture-Dislocation Injury in a Toddler. AB - BACKGROUND: Pedicle screw fixation of the lumbar spine in children age <2 years is particularly challenging, as successful cannulation of the small pedicle dimensions requires a high level of precision and there are no implants specifically designed for the infant spine. Image-guided navigation is commonly used in adult spinal surgery and may be particularly helpful for the placement of spinal screws in areas where the bony anatomy is small and/or anatomically complex, as in the upper cervical area. CASE DESCRIPTION: A 19-month-old female presented with a fracture-dislocation injury of L1-2. Intraoperative imaging using the O-arm multidimensional imaging system was networked to a workstation, and neuronavigation was used to place pedicle instrumentation with 3.5-mm diameter polyaxial screws designed for posterior cervical fixation. At a 48-month follow-up, the patient was neurologically intact, demonstrated normal physical development, and was engaging in normal physical activity for her age. Radiographs obtained approximately 4 years postsurgery showed no evidence of loss for fixation. CONCLUSIONS: Image-guided placement of pedicle screws may be a useful aid in achieving accurate and safe fixation in the small dimensions of the infant spine. PMID- 28710047 TI - Intradural Intramedullary Teratoma Presenting in the Lumbar Spine: Report of a Rare Case. AB - BACKGROUND: Intradural teratomas are an exceedingly unusual phenomenon. They are tumors with the cellular constituent source of all the 3 germ cell layers. CASE DESCRIPTION: We here report a case of an 18-year-old man with special pathologic features. There was no history of spinal dysraphism, congenital spinal abnormalities, previous spinal surgery, or lumbar puncture. Lumbosacral spine magnetic resonance imaging revealed a well-delineated, intramedullary mass at the L2-3 level. Histopathology examination of the resected tumor revealed cystic spaces lined with simple columnar epithelium as well as mucus secreting epithelium, adipose tissue, salivary gland-like serous cells, and bundles of smooth muscle cells. We have seen unusual histopathologic features in the case, for example, there were no cartilage components that are mostly found in mature teratomas, abundant Pacinian corpuscle nerve endings, and nerve trunks. There were no immature elements or malignant cells. CONCLUSIONS: Teratomas should be taken into consideration in the differential diagnosis of intramedullary lesions, even after the imaging reveals tissue homogeneity. PMID- 28710048 TI - Long-Term Results of Deep Brain Stimulation of the Anterior Cingulate Cortex for Neuropathic Pain. AB - BACKGROUND: Deep brain stimulation (DBS) of the anterior cingulate cortex (ACC) is a recent technique that has shown some promising short-term results in patients with chronic refractory neuropathic pain. Three years after the first case series, we assessed its efficacy on a larger cohort, with longer follow-up. METHODS: Twenty-four patients (19 males; average age, 49.1 years) with neuropathic pain underwent bilateral ACC DBS. Patient-reported outcome measures were collected before and after surgery, using the Numerical Rating Scale (NRS), Short-Form 36 quality of life (SF-36), McGill Pain Questionnaire (MPQ), and EuroQol 5-domain quality of life (EQ-5D) questionnaire. RESULTS: Twenty-two patients after a trial week were fully internalized and 12 had a mean follow-up of 38.9 months. Six months after surgery the mean NRS score decreased from 8.0 to 4.27 (P = 0.004). There was a significant improvement in the MPQ (mean, -36%; P = 0.021) and EQ-5D score significantly decreased (mean, -21%; P = 0.036). The physical functioning domain of SF-36 was significantly improved (mean, +54.2%; P = 0.01). Furthermore, in 83% of these patients, at 6 months, NRS score was improved by 60% (P < 0.001) and MPQ decreased by 47% (P < 0.01). After 1 year, NRS score decreased by 43% (P < 0.01), EQ-5D was significantly reduced (mean, 30.8; P = 0.05) and significant improvements were also observed for different domains of the SF-36. At longer follow-ups, efficacy was sustained up to 42 months in some patients, with an NRS score as low as 3. CONCLUSIONS: Follow-up results confirm that ACC DBS alleviates chronic neuropathic pain refractory to pharmacotherapy and improves quality of life in many patients. PMID- 28710049 TI - Trans-Anterior Communicating Artery Primary Stenting in Acute Tandem Middle Cerebral Artery-Internal Carotid Artery Occlusion Due to Thoracic Aortic Stent Graft. AB - BACKGROUND: The main target of stroke intervention is the revascularization of occluded vessels, usually achieved with thrombectomy or thrombus aspiration. Despite good results in limited series, intracranial primary stenting is controversial for increased hemorrhagic risk owing to the need for dual antiplatelet therapy. CASE DESCRIPTION: We present a case of trans-anterior communicating artery primary stenting in an acute tandem middle cerebral artery internal carotid artery occlusion in a patient harboring a thoracic aortic stent graft partially covering the origin of the left common carotid artery. CONCLUSION: Our experience with this patient demonstrates that primary intracranial stenting shoud be considered in selected cases when other revascularization techniques are difficult or impossible to perform owing to anatomic reasons. Extreme care should be taken in patient selection because of the risks associated with antiplatelet therapy. In particular, it may be recommended in patients with a small core on computed tomography perfusion or diffusion-weighted magnetic resonance imaging and in whom thrombectomy and thromboaspiration are impossible for anatomic reasons. PMID- 28710050 TI - Transforaminal Endoscopic Lumbar Discectomy for Lumbar Disc Herniation Causing Bilateral Symptoms. AB - BACKGROUND: Transforaminal endoscopic lumbar discectomy (TELD), a minimally invasive spinal technique, has advantages over open discectomy. Unilateral TELD for disc herniation causing bilateral symptoms is challenging. In this study, we describe a percutaneous endoscopic herniotomy technique by using a unilateral approach for lumbar disc herniation with bilateral obvious symptoms. METHODS: From June 2014 to October 2015, 26 patients who had back as well as bilateral leg pain and/or weakness due to lumbar disc herniation were treated by TELD with a unilateral approach. Clinical outcomes were evaluated via a visual analogue scale (VAS; 0-10), and functional status was assessed with the Oswestry Disability Index (0-100%) postoperatively and 3 and 12 months postoperatively. Surgical satisfaction rate was assessed during the final follow-up. RESULTS: The mean VAS for leg pain on the operative side improved from preoperative 8.39 +/- 1.84 to 2.18 +/- 1.26 postoperatively, 1.96 +/- 0.83 at 3 months postoperatively, and 2.05 +/- 1.42 at 1 year postoperatively (P < 0.01). The mean VAS for leg pain on the contralateral was 7.12 +/- 1.74 and improved to 1.57 +/- 1.66 postoperatively, 1.22 +/- 1.58 at 3 months postoperatively, and 1.15 +/- 1.35 at 1 year postoperatively (P < 0.01). The mean preoperative Oswestry Disability was 83.63 +/- 8.49, with 23.58 +/- 7.24 at 1 week postoperatively, 19.81 +/- 11.26 at 3 months postoperatively, and 17.54 +/- 13.40 at 12 months postoperatively (P < 0.01). Good or excellent global results were obtained in 96.2% of patients. CONCLUSIONS: TELD can be effective for lumbar disc herniation causing bilateral symptoms, through one working channel. PMID- 28710051 TI - Preoperative Embolization and Complete Tumoral Resection of a Cervical Aggressive Epithelioid Osteoblastoma. AB - BACKGROUND: Epithelioid "aggressive" osteoblastoma (EOB) is a rare and more aggressive subtype of osteoblastoma (OB) with a higher recurrence rate, greater risk of malignant transformation, larger size, and greater intraoperative blood loss. The present case report illustrates that preoperative angioembolization of an EOB can be safely performed with low intraoperative blood loss. CASE DESCRIPTION: A 21-year-old male patient presented to our institution with a 4 month history of neck discomfort, radicular pain in the proximal right arm, and mild weakness of the right biceps and triceps muscles. Imaging was suggestive of EOB, and computed tomography-guided biopsy confirmed the diagnosis. The patient underwent same-day preoperative angioembolization of the major feeding vessels and subsequent complete tumor resection. During the procedure, he experienced minimal blood loss and did not require blood transfusion. CONCLUSIONS: EOB is a highly vascular primary bony lesion. To minimize intraoperative blood loss, preoperative angioembolization should be considered in the treatment of cervical spine EOB. PMID- 28710052 TI - Rationale and design of feeding America's bravest: Mediterranean diet-based intervention to change firefighters' eating habits and improve cardiovascular risk profiles. AB - : Among US firefighters, cardiovascular disease is the leading cause of on-duty death. Poor diet contributes to this burden, but effective strategies to encourage healthy eating in the fire service are not established. "Feeding America's Bravest" motivates firefighters and their families to modify their food culture and reduce cardiometabolic risk profiles by adopting Mediterranean diet principles. Feeding America's Bravest is a cluster-randomized, controlled trial within the 44 stations of the Indianapolis Fire Department, including about 1000 firefighters. It compares a Mediterranean Diet Nutritional Intervention (MDNI) (group 1) vs. usual care (group 2) for 12months; followed by 12months of self sustained continuation phase in the group 1 and cross-over to Mediterranean Diet Nutritional Intervention in group 2. Group 2 will receive the MDNI for 6months to test the efficacy of a shorter intervention followed by 6months of self-sustained phase. The intervention includes behavioral and environmental components. The primary outcome is 12-month change in Mediterranean diet score comparing group 1 vs. group 2; we will also assess 12- and 24-month change in group 1, and 6- and 12-month change in group 2, from baseline. Secondary outcomes are changes in body weight, body composition and other cardiometabolic risk markers; and correlations between self-reported dietary habits and biomarkers of dietary adherence. This innovative trial tests a novel worksite approach to introduce Mediterranean diet among US firefighters, through multi-pronged MDNI combining evidence-based behavior change strategies with economic incentives, family and peer support and environmental changes, informing recommendations for the US fire service and potentially other similar workforces. TRIAL REGISTRATION NUMBER: NCT02941757. PMID- 28710054 TI - Preliminary Evidence for the Emergence of a Health Care Online Community of Practice: Using a Netnographic Framework for Twitter Hashtag Analytics. AB - BACKGROUND: Online communities of practice (oCoPs) may emerge from interactions on social media. These communities offer an open digital space and flat role hierarchy for information sharing and provide a strong group identity, rapid flow of information, content curation, and knowledge translation. To date, there is only a small body of evidence in medicine or health care to verify the existence of an oCoP. OBJECTIVE: We aimed to examine the emergence of an oCoP through the study of social media interactions of the free open access medical education (FOAM) movement. METHODS: We examined social media activity in Twitter by analyzing the network centrality metrics of tweets with the #FOAMed hashtag and compared them with previously validated criteria of a community of practice (CoP). RESULTS: The centrality analytics of the FOAM community showed concordance with aspects of a general CoP (in terms of community, domain, and practice), as well as some specific traits of a health care community, including social control, common purpose, flat hierarchy, and network-based and concrete achievement. CONCLUSIONS: This study demonstrated preliminary evidence of an oCoP focused on education and based on social media interactions. Further examination of the topology of the network is needed to definitely prove the existence of an oCoP. Given that these communities result in significant knowledge translation and practice change, further research in this area appears warranted. PMID- 28710053 TI - Stimulation of the ovaries in women with breast cancer undergoing fertility preservation: Alternative versus standard stimulation protocols; the study protocol of the STIM-trial. AB - BACKGROUND: Chemotherapy for breast cancer may have a negative impact on reproductive function due to gonadotoxicity. Fertility preservation via banking of oocytes or embryos after ovarian stimulation with FSH can increase the likelihood of a future live birth. It has been hypothesized that elevated serum estrogen levels during ovarian stimulation may induce breast tumour growth. This has led to the use of alternative stimulation protocols with addition of tamoxifen or letrozole. The effectiveness of these stimulation protocols in terms of oocyte yield is unknown. METHODS/DESIGN: Randomized open-label trial comparing ovarian stimulation plus tamoxifen and ovarian stimulation plus letrozole with standard ovarian stimulation in the course of fertility preservation. The study population consists of women with breast cancer who opt for banking of oocytes or embryos, aged 18-43years at randomisation. Primary outcome is the number of oocytes retrieved at follicle aspiration. Secondary outcomes are number of mature oocytes retrieved, number of oocytes or embryos banked and peak E2 levels during ovarian stimulation. DISCUSSION: Concerning the lack of evidence on which stimulation protocol should be used in women with breast cancer and the growing demand for fertility preservation, there is an urgent need to undertake this study. By performing this study, we will be able to closely monitor the effects of various stimulation protocols in women with breast cancer and pave the way for long term follow up on the safety of this procedure in terms of breast cancer prognosis. TRIAL REGISTRATION: NTR4108. PMID- 28710055 TI - What Patients Value About Reading Visit Notes: A Qualitative Inquiry of Patient Experiences With Their Health Information. AB - BACKGROUND: Patients are increasingly asking for their health data. Yet, little is known about what motivates patients to engage with the electronic health record (EHR). Furthermore, quality-focused mechanisms for patients to comment about their records are lacking. OBJECTIVE: We aimed to learn more about patient experiences with reading and providing feedback on their visit notes. METHODS: We developed a patient feedback tool linked to OpenNotes as part of a pilot quality improvement initiative focused on patient engagement. Patients who had appointments with members of 2 primary care teams piloting the program between August 2014-2015 were eligible to participate. We asked patients what they liked about reading notes and about using a feedback tool and analyzed all patient reports submitted during the pilot period. Two researchers coded the qualitative responses (kappa=.74). RESULTS: Patients and care partners submitted 260 reports. Among these, 98.5% (256/260) of reports indicated that the reporting tool was valuable, and 68.8% (179/260) highlighted what patients liked about reading notes and the OpenNotes patient reporting tool process. We identified 4 themes describing what patients value about note content: confirm and remember next steps, quicker access and results, positive emotions, and sharing information with care partners; and 4 themes about both patients' use of notes and the feedback tool: accuracy and correcting mistakes, partnership and engagement, bidirectional communication and enhanced education, and importance of feedback. CONCLUSIONS: Patients and care partners who read notes and submitted feedback reported greater engagement and the desire to help clinicians improve note accuracy. Aspects of what patients like about using both notes as well as a feedback tool highlight personal, relational, and safety benefits. Future efforts to engage patients through the EHR may be guided by what patients value, offering opportunities to strengthen care partnerships between patients and clinicians. PMID- 28710056 TI - Health-Related Coping and Social Interaction in People with Multiple Sclerosis Supported by a Social Network: Pilot Study With a New Methodological Approach. AB - BACKGROUND: Social media are a vital link for people with health concerns who find in Web communities a valid and comforting source for information exchange, debate, and knowledge enrichment. This aspect is important for people affected by chronic diseases like multiple sclerosis (MS), who are very well informed about the disease but are vulnerable to hopes of being cured or saved by therapies whose efficacy is not always scientifically proven. To improve health-related coping and social interaction for people with MS, we created an MS social network (SMsocialnetwork.com) with a medical team constantly online to intervene promptly when false or inappropriate medical information are shared. OBJECTIVE: The goal of this study was to assess the impact of SMsocialnetwork.com on the health related coping and social interaction of people with MS by analyzing areas of interest through a Web-based survey. METHODS: Referring to previous marketing studies analyzing the online platform's role in targeted health care, we conducted a 39-item Web-based survey. We then performed a construct validation procedure using a factorial analysis, gathering together like items of the survey related to different areas of interest such as utility, proximity, sharing, interaction, solving uncertainty, suggestion attitude, and exploration. RESULTS: We collected 130 Web-based surveys. The areas of interest analysis demonstrated that the users positively evaluated SMsocialnetwork.com to obtain information, approach and solve problems, and to make decisions (utility: median 4.2); improve feeling of closeness (proximity: median 5); catalyze relationships and text general personal opinions (sharing: median 5.6); get in touch with other users to receive innovative, effective, and practical solutions (interaction, solving uncertainty, and suggestion attitude medians were respectively: 4.1, 3, and 3); and share information about innovative therapeutic approaches and treatment options (suggestion attitude: median: 3.3). CONCLUSIONS: SMsocialnetwork.com was perceived by users to be a useful tool to support health-related coping and social interaction, and may suggest a new kind of therapeutic alliance between physicians and people with MS. PMID- 28710057 TI - Images of Little Cigars and Cigarillos on Instagram Identified by the Hashtag #swisher: Thematic Analysis. AB - BACKGROUND: Little cigar and cigarillo use is becoming more prevalent in the United States and elsewhere, with implications for public health. As little cigar and cigarillo use grows in popularity, big social media data (eg, Instagram, Google Web Search, Twitter) can be used to capture and document the context in which individuals use, and are marketed, these tobacco products. Big social media data may allow people to organically demonstrate how and why they use little cigars and cigarillos, unprimed by a researcher, without instrument bias and at low costs. OBJECTIVE: This study characterized Swisher (the most popular brand of cigars in the United States, controlling over 75% of the market share) little cigar- and cigarillo-related posts on Instagram to inform the design of tobacco education campaigns and the development of future tobacco control efforts, and to demonstrate the utility in using big social media data in understanding health behaviors. METHODS: We collected images from Instagram, an image-based social media app allowing users to capture, customize, and post photos on the Internet with over 400 million active users. Inclusion criteria for this study consisted of an Instagram post with the hashtag "#swisher". We established rules for coding themes of images. RESULTS: Of 1967 images collected, 486 (24.71%) were marijuana related, 348 (17.69%) were of tobacco products or promotional material, 324 (16.47%) showed individuals smoking, 225 (11.44%) were memes, and 584 (29.69%) were classified as other (eg, selfies, food, sexually explicit images). Of the marijuana-related images, 157/486 (32.3%) contained a Swisher wrapper, indicating that a Swisher product was used in blunt making, which involves hollowing out a cigar and refilling it with marijuana. CONCLUSIONS: Images from Instagram may be used to complement and extend the study of health behaviors including tobacco use. Images may be as valuable as, or more valuable than, words from other social media platforms alone. Posts on Instagram showing Swisher products, including blunt making, could add to the normalization of little cigar and cigarillo use and is an area of future research. Tobacco control researchers should design social media campaigns to combat smoking imagery found on popular sites such as Instagram. PMID- 28710058 TI - Health spending: is there another way to plan? PMID- 28710060 TI - Values Affirmation Intervention Reduces Achievement Gap between Underrepresented Minority and White Students in Introductory Biology Classes. AB - Achievement gaps between underrepresented minority (URM) students and their white peers in college science, technology, engineering, and mathematics classrooms are persistent across many white-majority institutions of higher education. Attempts to reduce this phenomenon of underperformance through increasing classroom structure via active learning have been partially successful. In this study, we address the hypothesis that the achievement gap between white and URM students in an undergraduate biology course has a psychological and emotional component arising from stereotype threat. Specifically, we introduced a values affirmation exercise that counters stereotype threat by reinforcing a student's feelings of integrity and self-worth in three iterations of an intensive active-learning college biology course. On average, this exercise reduced the achievement gap between URM and white students who entered the course with the same incoming grade point average. This result suggests that achievement gaps resulting from the underperformance of URM students could be mitigated by providing students with a learning environment that removes psychological and emotional impediments of performance through short psychosocial interventions. PMID- 28710059 TI - A FOXO1-induced oncogenic network defines the AML1-ETO preleukemic program. AB - Understanding and blocking the self-renewal pathway of preleukemia stem cells could prevent acute myeloid leukemia (AML) relapse. In this study, we show that increased FOXO1 represents a critical mechanism driving aberrant self-renewal in preleukemic cells expressing the t(8;21)-associated oncogene AML1-ETO (AE). Although generally considered as a tumor suppressor, FOXO1 is consistently upregulated in t(8;21) AML. Expression of FOXO1 in human CD34+ cells promotes a preleukemic state with enhanced self-renewal and dysregulated differentiation. The DNA binding domain of FOXO1 is essential for these functions. FOXO1 activates a stem cell molecular signature that is also present in AE preleukemia cells and preserved in t(8;21) patient samples. Genome-wide binding studies show that AE and FOXO1 share the majority of their binding sites, whereby FOXO1 binds to multiple crucial self-renewal genes and is required for their activation. In agreement with this observation, genetic and pharmacological ablation of FOXO1 inhibited the long-term proliferation and clonogenicity of AE cells and t(8;21) AML cell lines. Targeting of FOXO1 therefore provides a potential therapeutic strategy for elimination of stem cells at both preleukemic and leukemic stages. PMID- 28710061 TI - NHS patient data security is to be tightened after cyberattack. PMID- 28710062 TI - How to design efficient cluster randomised trials. PMID- 28710063 TI - 5 years later: irisin detection still an issue. PMID- 28710064 TI - Time-Course Analysis of Early Meiotic Prophase Events Informs Mechanisms of Homolog Pairing and Synapsis in Caenorhabditis elegans. AB - Segregation of homologous chromosomes during meiosis depends on their ability to reorganize within the nucleus, discriminate among potential partners, and stabilize pairwise associations through assembly of the synaptonemal complex (SC). Here we report a high-resolution time-course analysis of these key early events during Caenorhabditis elegans meiosis. Labeled nucleotides are incorporated specifically into the X chromosomes during the last 2 hr of S phase, a property we exploit to identify a highly synchronous cohort of nuclei. By tracking X-labeled nuclei through early meiotic prophase, we define the sequence and duration of chromosome movement, nuclear reorganization, pairing at pairing centers (PCs), and SC assembly. Appearance of ZYG-12 foci (marking attachment of PCs to the nuclear envelope) and onset of active mobilization occur within an hour after S-phase completion. Movement occurs for nearly 2 hr before stable pairing is observed at PCs, and autosome movement continues for ~4 hr thereafter. Chromosomes are tightly clustered during a 2-3 hr postpairing window, during which the bulk of SC assembly occurs; however, initiation of SC assembly can precede evident chromosome clustering. SC assembly on autosomes begins immediately after PC pairing is detected and is completed within ~3.5 hr. For the X chromosomes, PC pairing is contemporaneous with autosomal pairing, but autosomes complete synapsis earlier (on average) than X chromosomes, implying that X chromosomes have a delay in onset and/or a slower rate of SC assembly. Additional evidence suggests that transient association among chromosomes sharing the same PC protein may contribute to partner discrimination. PMID- 28710065 TI - The limitations of using randomised controlled trials as a basis for developing treatment guidelines. AB - Randomised controlled trials (RCTs) are considered the 'gold standard' by which novel psychotropic medications and psychological interventions are evaluated and consequently adopted into widespread clinical practice. However, there are some limitations to using RCTs as the basis for developing treatment guidelines. While RCTs allow researchers to determine whether a given medication or intervention is effective in a specific patient sample, for practicing clinicians it is more important to know whether it will work for their particular patient in their particular setting. This information cannot be garnered from an RCT. These inherent limitations are exacerbated by biases in design, recruitment, sample populations and data analysis that are inevitable in real-world studies. While trial registration and CONSORT have been implemented to correct and improve these issues, it is worrying that many trials fail to achieve such standards and yet their findings are used to inform clinical decision making. This perspective piece questions the assumptions of RCTs and highlights the widespread distortion of findings that currently undermine the credibility of this powerful design. It is recommended that the clinical guidelines include advice as to what should be considered good and relevant evidence and that external bodies continue to monitor RCTs to ensure that the outcomes published indeed reflect reality. PMID- 28710066 TI - HCR-20 shows poor field validity in clinical forensic psychiatry settings. PMID- 28710067 TI - A comparison of passive hindlimb cycling and active upper-limb exercise provides new insights into systolic dysfunction after spinal cord injury. AB - Active upper-limb and passive lower-limb exercise are two interventions used in the spinal cord injury (SCI) population. Although the global cardiac responses have been previously studied, it is unclear how either exercise influences contractile cardiac function. Here, the cardiac contractile and volumetric responses to upper-limb (swim) and passive lower-limb exercise were investigated in rodents with a severe high-thoracic SCI. Animals were divided into control (CON), SCI no exercise (NO-EX), SCI passive hindlimb cycling (PHLC), or SCI swim (SWIM) groups. Severe contusion SCI was administered at the T2 level. PHLC and SWIM interventions began on day 8 postinjury and lasted 25 days. Echocardiography and dobutamine stress echocardiography were performed before and after injury. Cardiac contractile indexes were assessed in vivo at study termination via a left ventricular pressure-volume conductance catheter. Stroke volume was reduced after SCI (91 ul in the NO-EX group vs. 188 ul in the CON group, P < 0.05) and was reversed at study termination in the PHLC (167 ul) but not SWIM (90 ul) group. Rates of contraction were reduced in NO-EX versus CON groups (6,079 vs. 9,225 mmHg, respectively, P < 0.05) and were unchanged by PHLC and SWIM training. Similarly, end-systolic elastance was reduced in the NO-EX versus CON groups (0.67 vs. 1.37 mmHg/ul, respectively, P < 0.05) and was unchanged by PHLC or SWIM training. Dobutamine infusion normalized all pressure indexes in each SCI group (all P < 0.05). In conclusion, PHLC improves flow-derived cardiac indexes, whereas SWIM training displayed no cardiobeneficial effect. Pressure-derived deficits were corrected only with dobutamine, suggesting that reduced beta adrenergic stimulation is principally responsible for the impaired cardiac contractile function after SCI.NEW & NOTEWORTHY This is the first direct comparison between the cardiac changes elicited by active upper-limb or passive lower-limb exercise after spinal cord injury. Here, we demonstrate that lower limb exercise positively influences flow-derived cardiac indexes, whereas upper limb exercise does not. Furthermore, neither intervention corrects the cardiac contractile dysfunction associated with spinal cord injury. PMID- 28710069 TI - Vitamin C mitigates oxidative/nitrosative stress and inflammation in doxorubicin induced cardiomyopathy. AB - Increase in oxidative/nitrosative stress is one of the mechanisms associated with the development of cardiotoxicity due to doxorubicin (Dox), a potent chemotherapy drug. Previously, we reported mitigation of Dox-induced oxidative/nitrosative stress and apoptosis by vitamin C (Vit C) in isolated cardiomyocytes. In the present in vivo study in rats, we investigated the effect of prophylactic treatment with Vit C on Dox-induced apoptosis, inflammation, oxidative/nitrosative stress, cardiac dysfunction, and Vit C transporter proteins. Dox (cumulative dose: 15 mg/kg) in rats reduced systolic and diastolic cardiac function and caused structural damage. These changes were associated with a myocardial increase in reactive oxygen species, reduction in antioxidant enzyme activities, increased expression of apoptotic proteins, and inflammation. Dox also caused an increase in the expression of proapoptotic proteins Bax, Bnip-3, Bak, and caspase-3. An increase in oxidative/nitrosative stress attributable to Dox was indicated by an increase in superoxide, protein carbonyl formation, lipid peroxidation, nitric oxide (NO), NO synthase (NOS) activity, protein nitrosylation, and inducible NOS protein expression. Dox increased the levels of cardiac proinflammatory cytokines TNF-alpha, IL-1beta, and IL-6, whereas the expression of Vit C transporter proteins (sodium-ascorbate cotransporter 2 and glucose transporter 4) was reduced. Prophylactic and concurrent treatment with Vit C prevented all these changes and improved survival in the Vit C + Dox group. Vit C also improved Dox-mediated systolic and diastolic dysfunctions and structural damage. These results suggest a cardioprotective role of Vit C in Dox induced cardiomyopathy by reducing oxidative/nitrosative stress, inflammation, and apoptosis, as well as improving Vit C transporter proteins.NEW & NOTEWORTHY This in vivo study provides novel data that vitamin C improves cardiac structure and function in doxorubicin-induced cardiomyopathy by reducing oxidative/nitrosative stress, apoptosis, and inflammation along with upregulation of cardiac vitamin C transporter proteins. The latter may have a crucial role in improving antioxidant status in this cardiomyopathy. PMID- 28710068 TI - Gq-activated fibroblasts induce cardiomyocyte action potential prolongation and automaticity in a three-dimensional microtissue environment. AB - Cardiac fibroblasts (CFs) are known to regulate cardiomyocyte (CM) function in vivo and in two-dimensional in vitro cultures. This study examined the effect of CF activation on the regulation of CM electrical activity in a three-dimensional (3-D) microtissue environment. Using a scaffold-free 3-D platform with interspersed neonatal rat ventricular CMs and CFs, Gq-mediated signaling was selectively enhanced in CFs by Galphaq adenoviral infection before coseeding with CMs in nonadhesive hydrogels. After 3 days, the microtissues were analyzed by signaling assay, histological staining, quantitative PCR, Western blots, optical mapping with voltage- or Ca2+-sensitive dyes, and microelectrode recordings of CF resting membrane potential (RMPCF). Enhanced Gq signaling in CFs increased microtissue size and profibrotic and prohypertrophic markers. Expression of constitutively active Galphaq in CFs prolonged CM action potential duration (by 33%) and rise time (by 31%), prolonged Ca2+ transient duration (by 98%) and rise time (by 65%), and caused abnormal electrical activity based on depolarization induced automaticity. Constitutive Gq activation in CFs also depolarized RMPCF from -33 to -20 mV and increased connexin 43 and connexin 45 expression. Computational modeling confers that elevated RMPCF and increased cell-cell coupling between CMs and CFs in a 3-D environment could lead to automaticity. In conclusion, our data demonstrate that CF activation alone is capable of altering action potential and Ca2+ transient characteristics of CMs, leading to proarrhythmic electrical activity. Our results also emphasize the importance of a 3-D environment where cell-cell interactions are prevalent, underscoring that CF activation in 3-D tissue plays a significant role in modulating CM electrophysiology and arrhythmias.NEW & NOTEWORTHY In a three-dimensional microtissue model, which lowers baseline activation of cardiac fibroblasts but enables cell-cell, paracrine, and cell-extracellular matrix interactions, we demonstrate that selective cardiac fibroblast activation by enhanced Gq signaling, a pathophysiological trigger in the diseased heart, modulates cardiomyocyte electrical activity, leading to proarrhythmogenic automaticity. PMID- 28710071 TI - Uncovering novel roles for matrix metalloproteinases in preeclampsia. PMID- 28710070 TI - TNF-alpha receptor 1 knockdown in the subfornical organ ameliorates sympathetic excitation and cardiac hemodynamics in heart failure rats. AB - In systolic heart failure (HF), circulating proinflammatory cytokines upregulate inflammation and renin-angiotensin system (RAS) activity in cardiovascular regions of the brain, contributing to sympathetic excitation and cardiac dysfunction. Important among these is the subfornical organ (SFO), a forebrain circumventricular organ that lacks an effective blood-brain barrier and senses circulating humors. We hypothesized that the tumor necrosis factor-alpha (TNF alpha) receptor 1 (TNFR1) in the SFO contributes to sympathetic excitation and cardiac dysfunction in HF rats. Rats received SFO microinjections of a TNFR1 shRNA or a scrambled shRNA lentiviral vector carrying green fluorescent protein, or vehicle. One week later, some rats were euthanized to confirm the accuracy of the SFO microinjections and the transfection potential of the lentiviral vector. Other rats underwent coronary artery ligation (CL) to induce HF or a sham operation. Four weeks after CL, vehicle- and scrambled shRNA-treated HF rats had significant increases in TNFR1 mRNA and protein, NF-kappaB activity, and mRNA for inflammatory mediators, RAS components and c-Fos protein in the SFO and downstream in the hypothalamic paraventricular nucleus, along with increased plasma norepinephrine levels and impaired cardiac function, compared with vehicle treated sham-operated rats. In HF rats treated with TNFR1 shRNA, TNFR1 was reduced in the SFO but not paraventricular nucleus, and the central and peripheral manifestations of HF were ameliorated. In sham-operated rats treated with TNFR1 shRNA, TNFR1 expression was also reduced in the SFO but there were no other effects. These results suggest a key role for TNFR1 in the SFO in the pathophysiology of systolic HF.NEW & NOTEWORTHY Activation of TNF-alpha receptor 1 in the subfornical organ (SFO) contributes to sympathetic excitation in heart failure rats by increasing inflammation and renin-angiotensin system activity in the SFO and downstream in the hypothalamic paraventricular nucleus. Cytokine receptors in the SFO may be a target for central intervention in cardiovascular conditions characterized by peripheral inflammation. PMID- 28710072 TI - Circulating acylcarnitine profile in human heart failure: a surrogate of fatty acid metabolic dysregulation in mitochondria and beyond. AB - Heart failure (HF) is associated with metabolic perturbations, particularly of fatty acids (FAs), which remain to be better understood in humans. This study aimed at testing the hypothesis that HF patients with reduced ejection fraction display systemic perturbations in levels of energy-related metabolites, especially those reflecting dysregulation of FA metabolism, namely, acylcarnitines (ACs). Circulating metabolites were assessed using mass spectrometry (MS)-based methods in two cohorts. The main cohort consisted of 72 control subjects and 68 HF patients exhibiting depressed left ventricular ejection fraction (25.9 +/- 6.9%) and mostly of ischemic etiology with >=2 comorbidities. HF patients displayed marginal changes in plasma levels of tricarboxylic acid cycle-related metabolites or indexes of mitochondrial or cytosolic redox status. They had, however, 22-79% higher circulating ACs, irrespective of chain length (P < 0.0001, adjusted for sex, age, renal function, and insulin resistance, determined by shotgun MS/MS), which reflects defective mitochondrial beta-oxidation, and were significantly associated with levels of NH2-terminal pro-B-type natriuretic peptide levels, a disease severity marker. Subsequent extended liquid chromatography-tandem MS analysis of 53 plasma ACs in a subset group from the primary cohort confirmed and further substantiated with a comprehensive lipidomic analysis in a validation cohort revealed in HF patients a more complex circulating AC profile. The latter included dicarboxylic-ACs and dihydroxy-ACs as well as very long chain (VLC) ACs or sphingolipids with VLCFAs (>20 carbons), which are proxies of dysregulated FA metabolism in peroxisomes. Our study identified alterations in circulating ACs in HF patients that are independent of biological traits and associated with disease severity markers. These alterations reflect dysfunctional FA metabolism in mitochondria but also beyond, namely, in peroxisomes, suggesting a novel mechanism contributing to global lipid perturbations in human HF.NEW & NOTEWORTHY Mass spectrometry-based profiling of circulating energy metabolites, including acylcarnitines, in two cohorts of heart failure versus control subjects revealed multiple alterations in fatty acid metabolism in peroxisomes in addition to mitochondria, thereby highlighting a novel mechanism contributing to global lipid perturbations in heart failure.Listen to this article's corresponding podcast at http://ajpheart.podbean.com/e/acylcarnitines-in-human-heart-failure/. PMID- 28710074 TI - Over 200 general practices closed or merged in England last year. PMID- 28710075 TI - The Cost-Effectiveness of Visual Triage of Human Papillomavirus-Positive Women in Three Low- and Middle-Income Countries. AB - Background: World Health Organization guidelines support human papillomavirus (HPV) testing alone (followed by treatment with cryotherapy) or in conjunction with visual inspection with acetic acid (VIA) triage testing. Our objective was to determine the cost-effectiveness of VIA triage for HPV-positive women in low resource settings.Methods: We calibrated mathematical simulation models of HPV infection and cervical cancer to epidemiologic data from India, Nicaragua, and Uganda. Using cost and test performance data from the START-UP demonstration projects, we assumed screening took place either once or three times in a lifetime between ages 30 and 40 years. Strategies included (i) HPV alone, followed by cryotherapy for all eligible HPV-positive women; and (ii) HPV testing with VIA triage for HPV-positive women, followed by cryotherapy for eligible women who were also VIA-positive (HPV-VIA). Model outcomes included lifetime risk of cervical cancer and incremental cost-effectiveness ratios (ICERs; international dollars/year of life saved).Results: In all three countries, HPV alone was more effective than HPV-VIA. In Nicaragua and Uganda, HPV alone was also less costly than HPV-VIA; ICERs associated with screening three times in a lifetime (HPV alone) were below per capita GDP. In India, both HPV alone and HPV VIA had ICERs below per capita GDP.Conclusions: VIA triage of HPV-positive women is not likely to be cost-effective in settings with high cervical cancer burden. HPV alone followed by treatment may achieve greater health benefits and value for public health dollars.Impact: This study provides early evidence on the cost effectiveness of HPV testing followed by VIA triage versus an HPV screen-and treat strategy. Cancer Epidemiol Biomarkers Prev; 26(10); 1500-10. (c)2017 AACR. PMID- 28710073 TI - Zinc mediates the SREBP-SCD axis to regulate lipid metabolism in Caenorhabditis elegans. AB - Maintenance of lipid homeostasis is crucial for cells in response to lipid requirements or surplus. The SREBP transcription factors play essential roles in regulating lipid metabolism and are associated with many metabolic diseases. However, SREBP regulation of lipid metabolism is still not completely understood. Here, we showed that reduction of SBP-1, the only homolog of SREBPs in Caenorhabditis elegans, surprisingly led to a high level of zinc. On the contrary, zinc reduction by mutation of sur-7, encoding a member of the cation diffusion facilitator (CDF) family, restored the fat accumulation and fatty acid profile of the sbp-1(ep79) mutant. Zinc reduction resulted in iron overload, which thereby directly activated the conversion activity of stearoyl-CoA desaturase (SCD), a main target of SREBP, to promote lipid biosynthesis and accumulation. However, zinc reduction reversely repressed SBP-1 nuclear translocation and further downregulated the transcription expression of SCD for compensation. Collectively, we revealed zinc-mediated regulation of the SREBP-SCD axis in lipid metabolism, distinct from the negative regulation of SREBP-1 or SREBP-2 by phosphatidylcholine or cholesterol, respectively, thereby providing novel insights into the regulation of lipid homeostasis. PMID- 28710077 TI - Tobacco Product Use Patterns, and Nicotine and Tobacco-Specific Nitrosamine Exposure: NHANES 1999-2012. AB - Background: Few studies have examined differences in product consumption patterns and nicotine and tobacco-specific nitrosamines (TSNA) exposure between single versus dual- and poly-tobacco users. We applied the Tobacco Product Use Patterns (T-PUPs) model to fill this gap in the literature.Methods: Data from adults (age >=18 years) who used any tobacco products during the 5 days prior to participating in the 1999-2012 National Health and Nutrition Examination Survey (NHANES) were analyzed. Participants were classified into seven T-PUPs: (1) cigarettes only, (2) noncigarette combustibles only, (3) noncombustibles only, (4) dual noncigarette combustibles and noncombustibles, (5) dual cigarettes and noncombustibles, (6) dual cigarettes and noncigarette combustibles, and (7) poly tobacco use. Weighted regression models were used to compare product consumption, serum cotinine, and urinary total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (i.e., NNAL) levels between single-, dual-, and poly-tobacco T-PUPs.Results: Dual and poly-tobacco T-PUPs were associated with lower product consumption compared with single-product T-PUPs only in some cases (e.g., dual cigarette and noncombustible users smoked cigarettes on 0.6 fewer days in the past 5 days compared with cigarette-only users; P < 0.05). Dual- and poly-tobacco T-PUPs had either nondistinguishable or higher levels of serum cotinine and urinary total NNAL than corresponding single-product T-PUPs.Conclusions: Product consumption, and nicotine and TSNAs exposure of dual- and poly-tobacco product category users somewhat differ from those of single-product category users as defined by the T TUPs model.Impact: Higher levels of cotinine and NNAL among dual- and poly tobacco T-TUPs users compared with the single-product T-TUPs users may indicate health concerns. Cancer Epidemiol Biomarkers Prev; 26(10); 1525-30. (c)2017 AACR. PMID- 28710076 TI - Opportunities and Challenges for Environmental Exposure Assessment in Population Based Studies. AB - A growing number and increasing diversity of factors are available for epidemiological studies. These measures provide new avenues for discovery and prevention, yet they also raise many challenges for adoption in epidemiological investigations. Here, we evaluate 1) designs to investigate diseases that consider heterogeneous and multidimensional indicators of exposure and behavior, 2) the implementation of numerous methods to capture indicators of exposure, and 3) the analytical methods required for discovery and validation. We find that case-control studies have provided insights into genetic susceptibility but are insufficient for characterizing complex effects of environmental factors on disease development. Prospective and two-phase designs are required but must balance extended data collection with follow-up of study participants. We discuss innovations in assessments including the microbiome; mass spectrometry and metabolomics; behavioral assessment; dietary, physical activity, and occupational exposure assessment; air pollution monitoring; and global positioning and individual sensors. We claim the the availability of extensive correlated data raises new challenges in disentangling specific exposures that influence cancer risk from among extensive and often correlated exposures. In conclusion, new high dimensional exposure assessments offer many new opportunities for environmental assessment in cancer development. Cancer Epidemiol Biomarkers Prev; 26(9); 1370 80. (c)2017 AACR. PMID- 28710079 TI - Locum pay bill has fallen 20% from last year. PMID- 28710080 TI - Scottish perspective on regulation of cosmetic treatments. PMID- 28710078 TI - Endocrinology and the brain: corticotropin-releasing hormone signaling. AB - Corticotropin-releasing hormone (CRH) is a key player of basal and stress activated responses in the hypothalamic-pituitary-adrenal axis (HPA) and in extrahypothalamic circuits, where it functions as a neuromodulator to orchestrate humoral and behavioral adaptive responses to stress. This review describes molecular components and cellular mechanisms involved in CRH signaling downstream of its G protein-coupled receptors (GPCRs) CRHR1 and CRHR2 and summarizes recent findings that challenge the classical view of GPCR signaling and impact on our understanding of CRHRs function. Special emphasis is placed on recent studies of CRH signaling that revealed new mechanistic aspects of cAMP generation and ERK1/2 activation in physiologically relevant contexts of the neurohormone action. In addition, we present an overview of the pathophysiological role of the CRH system, which highlights the need for a precise definition of CRHRs signaling at molecular level to identify novel targets for pharmacological intervention in neuroendocrine tissues and specific brain areas involved in CRH-related disorders. PMID- 28710081 TI - Use of a next-generation multi-durometer long guide sheath for triaxial access in flow diversion: experience in 95 consecutive cases. AB - BACKGROUND: Intracranial access techniques in modern neurointerventions have shifted towards more robust access platforms. The long guide sheath is one of the building blocks of triaxial systems used in intracranial embolizations. Here we present our experience with the AXS Infinity LS long sheath in the triaxial platform for the implantation of the Pipeline embolization device (PED). METHODS: We retrospectively identified patients who underwent PED Flex treatment with the AXS Infinity LS at a single institution. Procedural data collected included parent artery tortuosity, patient demographics, vasodilator use, aneurysm characteristics, equipment utilized, and catheter-related complications. RESULTS: A total of 95 cases were completed using the AXS Infinity LS for the triaxial platform foundation in PED Flex treatment of cerebral aneurysms. Mean patient age was 56.2+/-12.2 years (range 21-86). Average aneurysm size was 6.9+/-6.2 mm (range 1-38). There were 89 anterior circulation cases (94%) and 6 posterior circulation cases (6%). Significant cervical ICA tortuosity was present in 11/89 (12%) and moderate to severe cavernous ICA tortuosity was present in 29/89 (33%). Mean fluoroscopy time was 40.0+/-19.8 min. In 14/95 cases (15%), vasospasm prophylaxis or treatment with intra-arterial verapamil infusion was performed. Catheter access-related complications included asymptomatic iatrogenic dissection in one case (1%) from the distal intracranial catheter and groin hematoma in one case (1%). No parent vessel wall abnormalities were visualized in the region of the Infinity long sheath on final control angiography in all 95 cases. CONCLUSION: The AXS Infinity LS is the newest long guide sheath available for modern neurointerventional procedures. We have shown its utility in augmenting the triaxial access platform in PED Flex cases by providing enhanced distal tip trackability with added support in the aortic arch and proximal great vessels. PMID- 28710082 TI - Accuracy and precision of venous pressure measurements of endovascular microcatheters in the setting of dural venous sinus stenosis. AB - INTRODUCTION: Dural venous sinus stenosis (DVSS) may lead to increased intracranial pressure, sometimes requiring a stent if a high pressure gradient exists. Many neuroendovascular physicians use microcatheters to measure gradients, yet there are no studies comparing the accuracies and precisions of modern day microcatheters. We examined pressure recordings from five commonly used microcatheters in an experimental DVSS model. METHODS: Using a programmable pump, dynamic flow was established in a closed circuit mimicking the venous sinus waveform. Microcatheters with 150 cm effective lengths were connected proximally to pressure transducers. Mean recording pressures were compared with a high fidelity microcatheter (HFM) in several configurations including no stenosis, proximal to a focal stenosis, and distal to a focal stenosis in opposing orientations. RESULTS: All microcatheters recorded lower pressures than the HFM. Three of the five microcatheters successfully met intracranial pressure monitoring device standards in all conditions, while one did not meet standards in any configuration. The performance of the final microcatheter was variable, with inaccuracies occurring in unrestricted flow. All microcatheters demonstrated relatively high precision, but with variable accuracies. The larger diameter microcatheters displayed the least damping and therefore the greatest accuracies. Of the three smaller microcatheters, dimensions did not predict performance, suggesting that microcatheter construction may also play a role in pressure accuracy. CONCLUSION: The use of microcatheters to record dural venous sinus pressures must be done with an understanding of the inherent limitations and inaccuracies, especially if clinical decisions are made from the results. PMID- 28710083 TI - A review and comparison of three neuronavigation systems for minimally invasive intracerebral hemorrhage evacuation. AB - Advances in stereotactic navigation technology have helped to improve the ease, reliability, and workflow of neurosurgical intraoperative navigation. These advances have also allowed novel, minimally invasive neurosurgical techniques to emerge. Minimally invasive techniques for intracerebral hemorrhage (ICH) evacuation, including endoscopic evacuation and passive catheter drainage, are notable examples, and as these gain support in the literature and their use expands, stereotactic navigation will take on an increasingly important and central role. Each neurosurgical navigation system has unique characteristics. Operators may find that certain aspects are more important than others, depending on the environment in which the evacuation is performed and operator preferences. This review will describe the characteristics of three popular stereotactic neuronavigation systems and compare their advantages and disadvantages as they relate to minimally invasive ICH evacuation. PMID- 28710084 TI - Neuroprotective strategies following intraparenchymal hemorrhage. AB - Intracerebral hemorrhage and, more specifically, intraparenchymal hemorrhage, are devastating disease processes with poor clinical outcomes. Primary injury to the brain results from initial hematoma expansion while secondary hemorrhagic injury occurs from blood-derived products such as hemoglobin, heme, iron, and coagulation factors that overwhelm the brains natural defenses. Novel neuroprotective treatments have emerged that target primary and secondary mechanisms of injury. Nonetheless, translational application of neuroprotectants from preclinical to clinical studies has yet to show beneficial clinical outcomes. This review summarizes therapeutic agents and neuroprotectants in ongoing clinical trials aimed at targeting primary and secondary mechanisms of injury after intraparenchymal hemorrhage. PMID- 28710085 TI - Risk factors for and outcomes of intraprocedural rupture during endovascular treatment of unruptured intracranial aneurysms. AB - BACKGROUND AND PURPOSE: The risk factors for intraprocedural rupture (IPR) of unruptured intracranial aneurysms (UIAs) and the outcomes of IPR itself are unclear. This study was performed to identify the independent risk factors for and outcomes of IPR. MATERIALS AND METHODS: We retrospectively evaluated the medical records and radiologic data of 1375 patients (1406 UIAs) who underwent coil embolization from January 2001 to October 2016. RESULTS: IPR occurred in 20 aneurysms of 20 patients (1.4%). Univariate analyses showed that the rate of IPR was significantly higher in the treatment of aneurysms with a small dome size, aneurysms in the anterior communicating artery (AcomA) (6.6%), and patients with a medical history of dyslipidemia. Multivariate analyses showed that a small dome size and aneurysms in the AcomA were independently associated with IPR (p=0.0096 and p=0.0001, respectively). IPR induced by a microcatheter was associated with a higher risk of severe subarachnoid hemorrhage than other causes of IPR (57% vs 0%, respectively). Thromboembolic complications occurred in seven (35%) patients with IPR. Six (30%) patients required external ventricular drainage placement after developing symptoms of acute hydrocephalus. The overall morbidity and mortality rates from IPR were 0.22% and 0.15%, respectively. CONCLUSIONS: Aneurysms in the AcomA and with a small dome size are likely to be risk factors for IPR. IPR induced by microcatheters can result in poor outcomes. The rate of IPR-associated thromboembolic complications is high, and IPR itself is associated with acute hydrocephalus. If managed appropriately, however, most patients with IPR can survive without neurological deterioration. PMID- 28710086 TI - Onyx embolization prior to stereotactic radiosurgery for brain arteriovenous malformations: a single-center treatment algorithm. AB - BACKGROUND: Embolization before stereotactic radiosurgery (SRS) for brain arteriovenous malformations (BAVMs) is controversial. OBJECTIVE: To compare clinical and radiographic outcomes in patients undergoing pre-SRS embolization with ethylene copolymer (Onyx) with outcomes in patients undergoing SRS alone. METHODS: Seventy consecutive patients with BAVMs who underwent SRS were retrospectively reviewed. Univariate and multivariate analyses were performed to assess the factors associated with radiographic obliteration and complication. RESULTS: Forty-one (59%) patients presented without BAVM rupture and 29 (41%) patients presented with rupture. Pre-SRS embolization was used in 20 patients (28.6%; 7 unruptured and 13 ruptured). Twenty-five of 70 (36%) patients sustained a complication from treatment, including 6 (9%) patients with a post-SRS latency period hemorrhage. Ten (14%) patients had persistent neurological deficits after treatment. Functional outcome (as modified Rankin Scale), complication rate, and radiographic obliteration at last follow-up were not significantly different between embolized and non-embolized groups in both unruptured and ruptured BAVMs. For unruptured BAVMs, 3- and 5-year rates of radiographic obliteration were 23% and 73% for non-embolized patients and 20% and 60% for embolized patients, respectively. For ruptured BAVMs, 3- and 5-year rates of radiographic obliteration were 45% and 72% for non-embolized patients and 53% and 82% for embolized patients, respectively. CONCLUSION: Pre-SRS embolization with Onyx was not associated with worse clinical or radiographic outcomes than SRS treatment without embolization. Pre-SRS embolization has a low complication rate and can safely be used to target high-risk BAVM features in carefully selected patients destined for SRS. PMID- 28710087 TI - Dementia is now leading cause of death in women in England. PMID- 28710088 TI - FDA panel recommends approval of first gene therapy in US. PMID- 28710089 TI - Endothelium-Neutrophil Communication via B1-Kinin Receptor-Bearing Microvesicles in Vasculitis. PMID- 28710090 TI - The Clinical and Economic Effect of Vascular Access Selection in Patients Initiating Hemodialysis with a Catheter. AB - Patients in the United States frequently initiate hemodialysis with a central venous catheter (CVC) and subsequently undergo placement of a new arteriovenous fistula (AVF) or arteriovenous graft (AVG). Little is known about the clinical and economic effects of initial vascular access choice. We identified 479 patients starting hemodialysis with a CVC at a large medical center (during 2004 2012) who subsequently had an AVF (n=295) or AVG (n=105) placed or no arteriovenous access (CVC group, n=71). Compared with patients receiving an AVG, those receiving an AVF had more frequent surgical access procedures per year (1.01 [95% confidence interval, 0.95 to 1.08] versus 0.62 [95% confidence interval, 0.55 to 0.70]; P<0.001) but a similar frequency of percutaneous access procedures per year. Patients receiving an AVF had a higher median annual cost (interquartile range) of surgical access procedures than those receiving an AVG ($4857 [$2523-$8835] versus $2819 [$1411-$4274]; P<0.001), whereas the annual cost of percutaneous access procedures was similar in both groups. The AVF group had a higher median overall annual access-related cost than the AVG group ($10,642 [$5406-$19,878] versus $6810 [$3718-$13,651]; P=0.001) after controlling for patient age, sex, race, and diabetes. The CVC group had the highest median annual overall access-related cost ($28,709 [$11,793-$66,917]; P<0.001), largely attributable to the high frequency of hospitalizations due to catheter-related bacteremia. In conclusion, among patients initiating hemodialysis with a CVC, the annual cost of access-related procedures and complications is higher in patients who initially receive an AVF versus an AVG. PMID- 28710091 TI - Intimal Hyperplasia, Stenosis, and Arteriovenous Fistula Maturation Failure in the Hemodialysis Fistula Maturation Study. AB - Intimal hyperplasia and stenosis are often cited as causes of arteriovenous fistula maturation failure, but definitive evidence is lacking. We examined the associations among preexisting venous intimal hyperplasia, fistula venous stenosis after creation, and clinical maturation failure. The Hemodialysis Fistula Maturation Study prospectively observed 602 men and women through arteriovenous fistula creation surgery and their postoperative course. A segment of the vein used to create the fistula was collected intraoperatively for histomorphometric examination. On ultrasounds performed 1 day and 2 and 6 weeks after fistula creation, we assessed fistula venous stenosis using pre-specified criteria on the basis of ratios of luminal diameters and peak blood flow velocities at certain locations along the vessel. We determined fistula clinical maturation using criteria for usability during dialysis. Preexisting venous intimal hyperplasia, expressed per 10% increase in a hyperplasia index (range of 0%-100%), modestly associated with lower fistula blood flow rate (relative change, -2.5%; 95% confidence interval [95% CI], -4.6% to -0.4%; P=0.02) at 6 weeks but did not significantly associate with stenosis (odds ratio [OR], 1.07; 95% CI, 1.00 to 1.16; P=0.07) at 6 weeks or failure to mature clinically without procedural assistance (OR, 1.07; 95% CI, 0.99 to 1.15; P=0.07). Fistula venous stenosis at 6 weeks associated with maturation failure (OR, 1.98; 95% CI, 1.25 to 3.12; P=0.004) after controlling for case mix factors, dialysis status, and fistula location. These findings suggest that postoperative fistula venous stenosis associates with fistula maturation failure. Preoperative venous hyperplasia may associate with maturation failure but if so, only modestly. PMID- 28710092 TI - A Missense Mutation in the Extracellular Domain of alphaENaC Causes Liddle Syndrome. AB - Liddle syndrome is an autosomal dominant form of hypokalemic hypertension due to mutations in the beta- or gamma-subunit of the epithelial sodium channel (ENaC). Here, we describe a family with Liddle syndrome due to a mutation in alphaENaC. The proband was referred because of resistant hypokalemic hypertension, suppressed renin and aldosterone, and no mutations in the genes encoding beta- or gammaENaC. Exome sequencing revealed a heterozygous, nonconservative T>C single nucleotide mutation in alphaENaC that substituted Cys479 with Arg (C479R). C479 is a highly conserved residue in the extracellular domain of ENaC and likely involved in a disulfide bridge with the partner cysteine C394. In oocytes, the C479R and C394S mutations resulted in similar twofold increases in amiloride sensitive ENaC current. Quantification of mature cleaved alphaENaC in membrane fractions showed that the number of channels did not increase with these mutations. Trypsin, which increases open probability of the channel by proteolytic cleavage, resulted in significantly higher currents in the wild type than in C479R or C394S mutants. In summary, a mutation in the extracellular domain of alphaENaC causes Liddle syndrome by increasing intrinsic channel activity. This mechanism differs from that of the beta- and gamma-mutations, which result in an increase in channel density at the cell surface. This mutation may explain other cases of patients with resistant hypertension and also provides novel insight into ENaC activation, which is relevant for kidney sodium reabsorption and salt-sensitive hypertension. PMID- 28710095 TI - Acute coronary syndrome in new-onset rheumatoid arthritis: a population-based nationwide cohort study of time trends in risks and excess risks. AB - BACKGROUND: Acute coronary syndrome (ACS) and other cardiovascular diseases are the main drivers of the increased morbidity and preterm mortality in rheumatoid arthritis (RA). ACS in RA has been linked to inflammation and RA severity. During recent years and with new therapeutic options and treat-to-target strategies, increasing efforts have been made to reach RA remission as soon as possible after diagnosis, and the average level of RA disease activity has declined. Whether this has resulted in declining excess risks for RA comorbidities remains unclear. METHODS: We performed a nationwide population-based cohort study of patients with new-onset RA from 1997 to 2014, and matched general population comparators. In the Swedish healthcare system, all residents have equal access to healthcare services. Healthcare is monitored using high-quality population-based registers that can be linked together. 15 744 patients with new-onset RA, identified from the Swedish Rheumatology Quality Register, and 70 899 general population comparator subjects were included. RESULTS: Seven hundred and seventy two patients with RA developed an ACS during 103 835 person-years of follow-up (crude incidence, 7.4 per 1000), corresponding to an overall HR versus the general population of 1.41 (95% CI 1.29 to 1.54). Whereas the ACS incidence declined over calendar time in both the RA and the general population cohort, the excess and the relative risks of ACS remained the same. CONCLUSIONS: Despite improved disease control in new-onset RA, the elevated risk of ACS in RA remains a concern. PMID- 28710094 TI - Perspectives from the Kidney Health Initiative on Advancing Technologies to Facilitate Remote Monitoring of Patient Self-Care in RRT. AB - Telehealth and remote monitoring of a patient's health status has become more commonplace in the last decade and has been applied to conditions such as heart failure, diabetes mellitus, hypertension, and chronic obstructive pulmonary disease. Conversely, uptake of these technologies to help engender and support home RRTs has lagged. Although studies have looked at the role of telehealth in RRT, they are small and single-centered, and both outcome and cost-effectiveness data are needed to inform future decision making. Furthermore, alignment of payer and government (federal and state) regulations with telehealth procedures is needed along with a better understanding of the viewpoints of the various stakeholders in this process (patients, caregivers, clinicians, payers, dialysis organizations, and government regulators). Despite these barriers, telehealth has great potential to increase the acceptance of home dialysis, and improve outcomes and patient satisfaction while potentially decreasing costs. The Kidney Health Initiative convened a multidisciplinary workgroup to examine the current state of telehealth use in home RRTs as well as outline potential benefits and drawbacks, impediments to implementation, and key unanswered questions. PMID- 28710096 TI - Response to: 'Mortality in ANCA-associated vasculitis: mission incomplete' by Moiseev et al. PMID- 28710093 TI - The ciliary membrane-associated proteome reveals actin-binding proteins as key components of cilia. AB - Primary cilia are sensory, antennae-like organelles present on the surface of many cell types. They have been involved in a variety of diseases collectively termed ciliopathies. As cilia are essential regulators of cell signaling, the composition of the ciliary membrane needs to be strictly regulated. To understand regulatory processes at the ciliary membrane, we report the targeting of a genetically engineered enzyme specifically to the ciliary membrane to allow biotinylation and identification of the membrane-associated proteome. Bioinformatic analysis of the comprehensive dataset reveals high-stoichiometric presence of actin-binding proteins inside the cilium. Immunofluorescence stainings and complementary interaction proteomic analyses confirm these findings. Depolymerization of branched F-actin causes further enrichment of the actin-binding and actin-related proteins in cilia, including Myosin 5a (Myo5a). Interestingly, Myo5a knockout decreases ciliation while enhanced levels of Myo5a are observed in cilia upon induction of ciliary disassembly. In summary, we present a novel approach to investigate dynamics of the ciliary membrane proteome in mammalian cells and identify actin-binding proteins as mechanosensitive components of cilia that might have important functions in cilia membrane dynamics. PMID- 28710098 TI - Important but incomplete data analysis? PMID- 28710100 TI - Biomarker for Antitumor Immunity Identified. AB - Investigators have discovered that a certain type of immune cell in tumors, known as tissue-resident memory cells, are associated with a strong immune response and improved prognosis in lung cancer. The findings may aid in selecting appropriate immunotherapies and developing more effective vaccines for a wide range of cancers. PMID- 28710097 TI - Germinal centres in diagnostic labial gland biopsies of patients with primary Sjogren's syndrome are not predictive for parotid MALT lymphoma development. AB - OBJECTIVE: Patients with primary Sjogren's syndrome (pSS) have an increased risk of developing non-Hodgkin's lymphoma (NHL), particularly parotid gland mucosa associated lymphoid tissue (MALT) lymphomas. Presence of germinal centres (GCs) in labial gland biopsies has been suggested as predictive factor for NHL. We assessed whether presence of GCs is increased in labial gland biopsies from patients with pSS who developed parotid MALT lymphoma, the dominant NHL-subtype in pSS, compared with patients with pSS who did not develop lymphoma. METHODS: Eleven labial gland biopsies from patients with pSS that were taken prior to parotid MALT lymphoma development were compared with biopsies of 22 matched pSS controls (1:2) who did not develop lymphoma. Biopsies were evaluated for GCs (H&E and Bcl6). RESULTS: Labial gland biopsies of pSS MALT lymphoma patients, revealed GCs in 2/11 (18%) H&E sections and 3/11 (27%) Bcl6 stained sections. In controls, GCs were present in 4/22 (18%) of H&E sections and 5/22 (23%) of Bcl6 stained sections. CONCLUSION: Presence of GCs in labial gland biopsies does not differ between patients with pSS that develop parotid MALT lymphoma and patients with pSS who do not develop lymphoma. The presence of GCs in labial gland biopsies is therefore not a predictive factor for pSS-associated parotid MALT lymphomas. PMID- 28710105 TI - Regional deprivation is associated with the distribution of vulnerable asylum seekers: a nationwide small area analysis in Germany. AB - BACKGROUND: Newly arriving asylum seekers in many European Union countries are assigned a place of residence based on administrative quota. This may have important consequences for the exposure to contextual health risks. We assessed the association between regional deprivation and the distribution of asylum seekers in Germany considered as vulnerable (women, children <7 years, persons >64 years) because of their increased health needs. METHODS: Using nationally representative data, we analysed the rates of observed to expected numbers of asylum seekers and vulnerable subgroups in Bayesian spatial models. Regional deprivation was measured by the German Index of Multiple Deprivation. The analyses were performed at the district level (N=402) and adjusted for district population size, effects of federal states as well as spatial effects. RESULTS: Of the 224 993 asylum seekers, 38.7% were women, 13.8% children aged <7 years and 19.8% aged >64 years. The adjusted number of asylum seekers (totals and vulnerable subgroups) was higher in more deprived districts (Q3, Q4 and Q5) relative to districts in the lowest deprivation quintile (Q1). The adjusted rate ratios for districts with highest relative to those with lowest deprivation were 1.26 (1.03-1.53) for women, 1.28 (1.04-1.58) for children aged <7 years and 1.50 (1.08-2.08) for older asylum seekers. CONCLUSION: The adjusted number of vulnerable asylum seekers was higher in districts with medium and highest deprivation compared with districts with lowest deprivation. The disproportionate distribution was highest for older asylum seekers and children <7 years. Vulnerable subgroups tend to be exposed to more deprived places of residence, which may further increase health risks and healthcare needs. PMID- 28710107 TI - Correction: MYC Mediates Large Oncosome-Induced Fibroblast Reprogramming in Prostate Cancer. PMID- 28710108 TI - Correction: Wnt5a Drives an Invasive Phenotype in Human Glioblastoma Stem-like Cells. PMID- 28710109 TI - Palliative medicine in Mediterranean countries: different approaches, same philosophy. PMID- 28710110 TI - Impact of a patient-tailored complementary/integrative medicine programme on disturbed sleep quality among patients undergoing chemotherapy. AB - OBJECTIVES: The present study examined the impact of a patient-tailored complementary/integrative medicine (CIM) programme on sleep quality in patients undergoing chemotherapy for breast and gynaecological cancer. METHODS: Study participants received standard supportive care, with or without weekly CIM treatments. Disturbed sleep quality was defined as a score of a0/00Y4 on the Edmonton Symptom Assessment Scale (ESAS) or a score of a0/00Y3 on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30). Adherence to integrative care was defined as attending a0/00Y4 CIM treatments, with a0/00 30 days between each session. RESULTS: Of 388 eligible patients, 264 (68%) reported disturbed sleep quality. Baseline-to-follow up assessment (at 6 weeks) was optimal for 104 patients in the treatment group and for 76 controls, with 75 of treated patients found to be adherent to the CIM intervention. Sleep-related ESAS scores improved more significantly in treated patients (p=0.008), as did sleep-related concerns on EORTC (treatment group, p=0.026). CONCLUSIONS: A patient-tailored CIM programme may improve sleep quality and related concerns among patients with breast and gynaecological cancer undergoing chemotherapy. Further research is needed to better understand the impact of CIM on sleep quality in this patient population. TRIAL REGISTRATION NUMBER: NCT01860365. PMID- 28710111 TI - Managing an intentional overdose in a hospice. AB - This case report describes a patient admitted unconscious to a hospice following an intentional overdose of oxycodone. She had previously declined conventional medical treatment for cancer and had made an advance decision stating that she wished to avoid hospital admission and refusing life-prolonging treatment. This case illustrates the practical and ethical challenges of managing an intentional overdose in a palliative care setting. PMID- 28710112 TI - UK has best health system in developed world, US analysis concludes. PMID- 28710113 TI - TRAP1 ameliorates renal tubulointerstitial fibrosis in mice with unilateral ureteral obstruction by protecting renal tubular epithelial cell mitochondria. AB - Mitochondrial dysfunction causes renal tubular epithelial cell injury and promotes cell apoptosis and renal tubulointerstitial fibrosis (TIF) progression. TNF receptor-associated protein 1 (TRAP1) is a molecular chaperone protein that is localized in mitochondria. It plays an important role in cell apoptosis; however, its functional mechanism in TIF remains unclear. In this study, we observed the effects of TRAP1 in renal tubular epithelial cell mitochondria in mice with unilateral ureteral obstruction and its function in cell apoptosis and TIF. Results show that TRAP1 could protect the mitochondrial structure in renal tubular epithelial cells; maintain the levels of mitochondrial membrane potential, ATP, and mitochondrial DNA copy number; inhibit reactive oxygen species production; stabilize the expression of the mitochondrial inner membrane protein mitofilin; reduce renal tubular epithelial cell apoptosis; and inhibit TIF. These results provide new theoretical foundations for additional understanding of the antifibrotic mechanism of TRAP1 in the kidney.-Chen, J.-F., Wu, Q.-S., Xie, Y.-X., Si, B.-L., Yang, P.-P., Wang, W.-Y., Hua, Q., He, Q. TRAP1 ameliorates renal tubulointerstitial fibrosis in mice with unilateral ureteral obstruction by protecting renal tubular epithelial cell mitochondria. PMID- 28710115 TI - Acromegaly is associated with increased cancer risk: a survey in Italy. AB - It is debated if acromegalic patients have an increased risk to develop malignancies. The aim of the present study was to assess the standardized incidence ratios (SIRs) of different types of cancer in acromegaly on a large series of acromegalic patients managed in the somatostatin analogs era. It was evaluated the incidence of cancer in an Italian nationwide multicenter cohort study of 1512 acromegalic patients, 624 men and 888 women, mean age at diagnosis 45 +/- 13 years, followed up for a mean of 10 years (12573 person-years) in respect to the general Italian population. Cancer was diagnosed in 124 patients, 72 women and 52 men. The SIRs for all cancers was significantly increased compared to the general Italian population (expected: 88, SIR 1.41; 95% CI, 1.18 1.68, P < 0.001). In the whole series, we found a significantly increased incidence of colorectal cancer (SIR 1.67; 95% CI, 1.07-2.58, P = 0.022), kidney cancer (SIR 2.87; 95% CI, 1.55-5.34, P < 0.001) and thyroid cancer (SIR 3.99; 95% CI, 2.32-6.87, P < 0.001). The exclusion of 11 cancers occurring before diagnosis of acromegaly (all in women) did not change remarkably the study outcome. In multivariate analysis, the factors significantly associated with an increased risk of malignancy were age and family history of cancer, with a non-significant trend for the estimated duration of acromegaly before diagnosis. In conclusion, we found evidence that acromegaly in Italy is associated with a moderate increase in cancer risk. PMID- 28710116 TI - Expression and mutational status of USP8 in tumors causing ectopic ACTH secretion syndrome. PMID- 28710114 TI - Circadian rhythm disruption impairs tissue homeostasis and exacerbates chronic inflammation in the intestine. AB - Endogenous circadian clocks regulate 24-h rhythms of physiology and behavior. Circadian rhythm disruption (CRD) is suggested as a risk factor for inflammatory bowel disease. However, the underlying molecular mechanisms remain unknown. Intestinal biopsies from Per1/2 mutant and wild-type (WT) mice were investigated by electron microscopy, immunohistochemistry, and bromodeoxyuridine pulse-chase experiments. TNF-alpha was injected intraperitoneally, with or without necrostatin-1, into Per1/2 mice or rhythmic and externally desynchronized WT mice to study intestinal epithelial cell death. Experimental chronic colitis was induced by oral administration of dextran sodium sulfate. In vitro, caspase activity was assayed in Per1/2-specific small interfering RNA-transfected cells. Wee1 was overexpressed to study antiapoptosis and the cell cycle. Genetic ablation of circadian clock function or environmental CRD in mice increased susceptibility to severe intestinal inflammation and epithelial dysregulation, accompanied by excessive necroptotic cell death and a reduced number of secretory epithelial cells. Receptor-interacting serine/threonine-protein kinase (RIP)-3 mediated intestinal necroptosis was linked to increased mitotic cell cycle arrest via Per1/2-controlled Wee1, resulting in increased antiapoptosis via cellular inhibitor of apoptosis-2. Together, our data suggest that circadian rhythm stability is pivotal for the maintenance of mucosal barrier function. CRD increases intestinal necroptosis, thus rendering the gut epithelium more susceptible to inflammatory processes.-Pagel, R., Bar, F., Schroder, T., Sunderhauf, A., Kunstner, A., Ibrahim, S. M., Autenrieth, S. E., Kalies, K., Konig, P., Tsang, A. H., Bettenworth, D., Divanovic, S., Lehnert, H., Fellermann, K., Oster, H., Derer, S., Sina, C. Circadian rhythm disruption impairs tissue homeostasis and exacerbates chronic inflammation in the intestine. PMID- 28710117 TI - Genetic and epigenetic drivers of neuroendocrine tumours (NET). AB - Neuroendocrine tumours (NET) of the gastrointestinal tract and the lung are a rare and heterogeneous group of tumours. The molecular characterization and the clinical classification of these tumours have been evolving slowly and show differences according to organs of origin. Novel technologies such as next generation sequencing revealed new molecular aspects of NET over the last years. Notably, whole-exome/genome sequencing (WES/WGS) approaches underlined the very low mutation rate of well-differentiated NET of all organs compared to other malignancies, while the engagement of epigenetic changes in driving NET evolution is emerging. Indeed, mutations in genes encoding for proteins directly involved in chromatin remodelling, such as DAXX and ATRX are a frequent event in NET. Epigenetic changes are reversible and targetable; therefore, an attractive target for treatment. The discovery of the mechanisms underlying the epigenetic changes and the implication on gene and miRNA expression in the different subgroups of NET may represent a crucial change in the diagnosis of this disease, reveal new therapy targets and identify predictive markers. Molecular profiles derived from omics data including DNA mutation, methylation, gene and miRNA expression have already shown promising results in distinguishing clinically and molecularly different subtypes of NET. In this review, we recapitulate the major genetic and epigenetic characteristics of pancreatic, lung and small intestinal NET and the affected pathways. We also discuss potential epigenetic mechanisms leading to NET development. PMID- 28710118 TI - Correction for Wang et al., "Comparative Analysis of Chromatin Binding by Sex Comb on Midleg (SCM) and Other Polycomb Group Repressors at a Drosophila Hox Gene". PMID- 28710119 TI - Correction for Saint et al., "The TAF9 C-Terminal Conserved Region Domain Is Required for SAGA and TFIID Promoter Occupancy To Promote Transcriptional Activation". PMID- 28710120 TI - Correction for Long et al., "Insulin Receptor Substrates Irs1 and Irs2 Coordinate Skeletal Muscle Growth and Metabolism via the Akt and AMPK Pathways". PMID- 28710121 TI - Correction for Ekanayake et al., "Epigenetic Regulation of Transcription and Virulence in Trypanosoma cruzi by O-Linked Thymine Glucosylation of DNA". PMID- 28710122 TI - Correction for Linares et al., "Phosphorylation of p62 by cdk1 Controls the Timely Transit of Cells through Mitosis and Tumor Cell Proliferation". PMID- 28710123 TI - Correction for Kim et al., "Vpr-Binding Protein Antagonizes p53-Mediated Transcription via Direct Interaction with H3 Tail". PMID- 28710125 TI - Visualization of extracellular DNA released during border cell separation from the root cap. AB - PREMISE OF THE STUDY: Root border cells are programmed to separate from the root cap as it penetrates the soil environment, where the cells actively secrete >100 extracellular proteins into the surrounding mucilage. The detached cells function in defense of the root tip by an extracellular trapping process that also requires DNA, as in mammalian white blood cells. Trapping in animals and plants is reversed by treatment with DNase, which results in increased infection. The goal of this study was to evaluate the role of DNA in the structural integrity of extracellular structures released as border cells disperse from the root tip upon contact with water. METHODS: DNA stains including crystal violet, toluidine blue, Hoechst 33342, DAPI, and SYTOX green were added to root tips to visualize the extracellular mucilage as it absorbed water and border cell populations dispersed. DNase I was used to assess structural changes occurring when extracellular DNA was degraded. KEY RESULTS: Complex masses associated with living border cells were immediately evident in response to each stain, including those that are specific for DNA. Treating with DNase I dramatically altered the appearance of the extracellular structures and their association with border cells. No extracellular DNA was found in association with border cells killed by freezing or high-speed centrifugation. This observation is consistent with the hypothesis that, as with border cell extracellular proteins, DNA is secreted by living cells. CONCLUSION: DNA is an integral component of border cell extracellular traps. PMID- 28710126 TI - Incomplete lineage sorting and hybridization in the evolutionary history of closely related, endemic yellow-flowered Aechmea species of subgenus Ortgiesia (Bromeliaceae). AB - PREMISE OF THE STUDY: The yellow-flowered Aechmea subgenus Ortgiesia (yfAsO) (Bromeliaceae) is a group of seven morphologically similar bromeliads found mostly in the southern Brazilian Atlantic rainforest. The recent origin of this group probably contributes to its taxonomic complexity. The aims of this study were to investigate the levels of genetic diversity and structure at the population and species levels, to gain insight into the processes behind the diversification of the group, and to contribute to the establishment of species boundaries. METHODS: We sequenced two noncoding regions of the chloroplast genome (rpl32-trnL and rps16-trnK) and the nuclear phyC gene in 204 and 153 individuals, respectively, representing the seven species of the group. Phylogeographical and population genetics approaches were used. KEY RESULTS: Three of the seven yfAsO showed some degree of genetic differentiation among species. Divergence time for the group was dated to around 4 million years ago. Areas of conservation value were identified, and a scenario of multiple refugia in the southern Brazilian Atlantic rainforest during the Pleistocene climatic oscillations is suggested. CONCLUSIONS: We hypothesized that incomplete lineage sorting and localized hybridization events are responsible for the low levels of genetic differentiation and the taxonomic complexity observed among and within the seven yfAsO species. Further studies on Aechmea comata and Aechmea kertesziae will be necessary to clarify the boundary between these two species. Most of the populations sampled showed high genetic diversity and/or unique haplotypes; they should be prioritized for conservation purposes. PMID- 28710127 TI - Floral evolution and phylogeny of the Dialioideae, a diverse subfamily of tropical legumes. AB - PREMISE OF THE STUDY: The Dialioideae is an early diverging clade of caesalpinioid legumes containing approximately 85 species in 17 genera. Dialioideae floral morphology is highly variable and may provide clues to caesalpinioid evolution, but a well-resolved phylogeny is needed. Here, we have carried out a comprehensive morphological study of 78 Dialioideae and four outgroup species. METHODS: For all available Dialioideae DNA samples, the plastid rpS16 and trnL introns were sequenced. A combined phylogenetic analysis using the parsimony criterion was completed on a reduced taxon set for which both molecular and morphological data were available. Highly supported clades from the strict consensus tree of this analysis were then used to constrain the nodes of a second analysis on an expanded taxon set with missing molecular data for some taxa. KEY RESULTS: Several new, highly supported relationships have been discovered at the species and genus levels. The loss of the antepetalous stamen whorl was found to be a synapomorphy for most of the clade. CONCLUSIONS: A high degree of organ loss is common in the Dialioideae and often results in a bilaterally symmetrical flower. The absence of consistent morphological features in the Dialioideae, coupled with the small size of each florally diagnosed genus, suggests a lack of canalization in the floral evolution in early diverging legume lineages. PMID- 28710128 TI - BcXYG1, a Secreted Xyloglucanase from Botrytis cinerea, Triggers Both Cell Death and Plant Immune Responses. AB - In search of Botrytis cinerea cell death-inducing proteins, we found a xyloglucanase (BcXYG1) that induced strong necrosis and a resistance response in dicot plants. Expression of the BcXYG1 gene was strongly induced during the first 12 h post inoculation, and analysis of disease dynamics using PathTrack showed that a B. cinerea strain overexpressing BcXYG1 produced early local necrosis, supporting a role of BcXYG1 as an early cell death-inducing factor. The xyloglucanase activity of BcXYG1 was not necessary for the induction of necrosis and plant resistance, as a mutant of BcXYG1 lacking the xyloglucanase enzymatic activity retained both functions. Residues in two exposed loops on the surface of BcXYG1 were found to be necessary for the induction of cell death but not to induce plant resistance. Further analyses showed that BcXYG1 is apoplastic and possibly interacts with the proteins of the plant cell membrane and also that the BcXYG1 cell death-promoting signal is mediated by the leucine-rich repeat receptor-like kinases BAK1 and SOBIR1. Our findings support the role of cell death-inducing proteins in establishing the infection of necrotrophic pathogens and highlight the recognition of fungal apoplastic proteins by the plant immune system as an important mechanism of resistance against this class of pathogens. PMID- 28710129 TI - Manipulation of a Senescence-Associated Gene Improves Fleshy Fruit Yield. AB - Senescence is the process that marks the end of a leaf's lifespan. As it progresses, the massive macromolecular catabolism dismantles the chloroplasts and, consequently, decreases the photosynthetic capacity of these organs. Thus, senescence manipulation is a strategy to improve plant yield by extending the leaf's photosynthetically active window of time. However, it remains to be addressed if this approach can improve fleshy fruit production and nutritional quality. One way to delay senescence initiation is by regulating key transcription factors (TFs) involved in triggering this process, such as the NAC TF ORESARA1 (ORE1). Here, three senescence-related NAC TFs from tomato (Solanum lycopersicum) were identified, namely SlORE1S02, SlORE1S03, and SlORE1S06. All three genes were shown to be responsive to senescence-inducing stimuli and posttranscriptionally regulated by the microRNA miR164 Moreover, the encoded proteins interacted physically with the chloroplast maintenance-related TF SlGLKs. This characterization led to the selection of a putative tomato ORE1 as target gene for RNA interference knockdown. Transgenic lines showed delayed senescence and enhanced carbon assimilation that, ultimately, increased the number of fruits and their total soluble solid content. Additionally, the fruit nutraceutical composition was enhanced. In conclusion, these data provide robust evidence that the manipulation of leaf senescence is an effective strategy for yield improvement in fleshy fruit-bearing species. PMID- 28710130 TI - Dead or Alive? Using Membrane Failure and Chlorophyll a Fluorescence to Predict Plant Mortality from Drought. AB - Climate models predict widespread increases in both drought intensity and duration in the next decades. Although water deficiency is a significant determinant of plant survival, limited understanding of plant responses to extreme drought impedes forecasts of both forest and crop productivity under increasing aridity. Drought induces a suite of physiological responses; however, we lack an accurate mechanistic description of plant response to lethal drought that would improve predictive understanding of mortality under altered climate conditions. Here, proxies for leaf cellular damage, chlorophyll a fluorescence, and electrolyte leakage were directly associated with failure to recover from drought upon rewatering in Brassicarapa (genotype R500) and thus define the exact timing of drought-induced death. We validated our results using a second genotype (imb211) that differs substantially in life history traits. Our study demonstrates that whereas changes in carbon dynamics and water transport are critical indicators of drought stress, they can be unrelated to visible metrics of mortality, i.e. lack of meristematic activity and regrowth. In contrast, membrane failure at the cellular scale is the most proximate cause of death. This hypothesis was corroborated in two gymnosperms (Picea engelmannii and Pinus contorta) that experienced lethal water stress in the field and in laboratory conditions. We suggest that measurement of chlorophyll a fluorescence can be used to operationally define plant death arising from drought, and improved plant characterization can enhance surface model predictions of drought mortality and its consequences to ecosystem services at a global scale. PMID- 28710132 TI - Autophagy Deficiency Compromises Alternative Pathways of Respiration following Energy Deprivation in Arabidopsis thaliana. AB - Under heterotrophic conditions, carbohydrate oxidation inside the mitochondrion is the primary energy source for cellular metabolism. However, during energy limited conditions, alternative substrates are required to support respiration. Amino acid oxidation in plant cells plays a key role in this by generating electrons that can be transferred to the mitochondrial electron transport chain via the electron transfer flavoprotein/ubiquinone oxidoreductase system. Autophagy, a catabolic mechanism for macromolecule and protein recycling, allows the maintenance of amino acid pools and nutrient remobilization. Although the association between autophagy and alternative respiratory substrates has been suggested, the extent to which autophagy and primary metabolism interact to support plant respiration remains unclear. To investigate the metabolic importance of autophagy during development and under extended darkness, Arabidopsis (Arabidopsis thaliana) mutants with disruption of autophagy (atg mutants) were used. Under normal growth conditions, atg mutants showed lower growth and seed production with no impact on photosynthesis. Following extended darkness, atg mutants were characterized by signatures of early senescence, including decreased chlorophyll content and maximum photochemical efficiency of photosystem II coupled with increases in dark respiration. Transcript levels of genes involved in alternative pathways of respiration and amino acid catabolism were up-regulated in atg mutants. The metabolite profiles of dark-treated leaves revealed an extensive metabolic reprogramming in which increases in amino acid levels were partially compromised in atg mutants. Although an enhanced respiration in atg mutants was observed during extended darkness, autophagy deficiency compromises protein degradation and the generation of amino acids used as alternative substrates to the respiration. PMID- 28710134 TI - Heartbeat: Chocolate and atrial fibrillation. PMID- 28710135 TI - Cardiovascular highlights from non-cardiology journals. PMID- 28710131 TI - Gene Regulatory Networks for the Haploid-to-Diploid Transition of Chlamydomonas reinhardtii. AB - The sexual cycle of the unicellular Chlamydomonas reinhardtii culminates in the formation of diploid zygotes that differentiate into dormant spores that eventually undergo meiosis. Mating between gametes induces rapid cell wall shedding via the enzyme g-lysin; cell fusion is followed by heterodimerization of sex-specific homeobox transcription factors, GSM1 and GSP1, and initiation of zygote-specific gene expression. To investigate the genetic underpinnings of the zygote developmental pathway, we performed comparative transcriptome analysis of both pre- and post-fertilization samples. We identified 253 transcripts specifically enriched in early zygotes, 82% of which were not up-regulated in gsp1 null zygotes. We also found that the GSM1/GSP1 heterodimer negatively regulates the vegetative wall program at the posttranscriptional level, enabling prompt transition from vegetative wall to zygotic wall assembly. Annotation of the g-lysin-induced and early zygote genes reveals distinct vegetative and zygotic wall programs, supported by concerted up-regulation of genes encoding cell wall-modifying enzymes and proteins involved in nucleotide-sugar metabolism. The haploid-to-diploid transition in Chlamydomonas is masterfully controlled by the GSM1/GSP1 heterodimer, translating fertilization and gamete coalescence into a bona fide differentiation program. The fertilization-triggered integration of genes required to make related, but structurally and functionally distinct organelles-the vegetative versus zygote cell wall-presents a likely scenario for the evolution of complex developmental gene regulatory networks. PMID- 28710136 TI - Fifty-year-old woman with lightheadedness. PMID- 28710133 TI - Novel Stress-Inducible Antisense RNAs of Protein-Coding Loci Are Synthesized by RNA-Dependent RNA Polymerase. AB - Our previous study identified approximately 6,000 abiotic stress-responsive noncoding transcripts existing on the antisense strand of protein-coding genes and implied that a type of antisense RNA was synthesized from a sense RNA template by RNA-dependent RNA polymerase (RDR). Expression analyses revealed that the expression of novel abiotic stress-induced antisense RNA on 1,136 gene loci was reduced in the rdr1/2/6 mutants. RNase protection indicated that the RD29A antisense RNA and other RDR1/2/6-dependent antisense RNAs are involved in the formation of dsRNA. The accumulation of stress-inducible antisense RNA was decreased and increased in dcp5 and xrn4, respectively, but not changed in dcl2/3/4, nrpd1a and nrpd1b RNA-seq analyses revealed that the majority of the RDR1/2/6-dependent antisense RNA loci did not overlap with RDR1/2/6-dependent 20 30 nt RNA loci. Additionally, rdr1/2/6 mutants decreased the degradation rate of the sense RNA and exhibited arrested root growth during the recovery stage following a drought stress, whereas dcl2/3/4 mutants did not. Collectively, these results indicate that RDRs have stress-inducible antisense RNA synthesis activity and a novel biological function that is different from the known endogenous small RNA pathways from protein-coding genes. These data reveal a novel mechanism of RNA regulation during abiotic stress response that involves complex RNA degradation pathways. PMID- 28710137 TI - The Evening Shift. PMID- 28710138 TI - Disruption of Lipid Uptake in Astroglia Exacerbates Diet-Induced Obesity. AB - Neuronal circuits in the brain help to control feeding behavior and systemic metabolism in response to afferent nutrient and hormonal signals. Although astrocytes have historically been assumed to have little relevance for such neuroendocrine control, we investigated whether lipid uptake via lipoprotein lipase (LPL) in astrocytes is required to centrally regulate energy homeostasis. Ex vivo studies with hypothalamus-derived astrocytes showed that LPL expression is upregulated by oleic acid, whereas it is decreased in response to palmitic acid or triglycerides. Likewise, astrocytic LPL deletion reduced the accumulation of lipid droplets in those glial cells. Consecutive in vivo studies showed that postnatal ablation of LPL in glial fibrillary acidic protein-expressing astrocytes induced exaggerated body weight gain and glucose intolerance in mice exposed to a high-fat diet. Intriguingly, astrocytic LPL deficiency also triggered increased ceramide content in the hypothalamus, which may contribute to hypothalamic insulin resistance. We conclude that hypothalamic LPL functions in astrocytes to ensure appropriately balanced nutrient sensing, ceramide distribution, body weight regulation, and glucose metabolism. PMID- 28710139 TI - Hepatic but Not Extrahepatic Insulin Clearance Is Lower in African American Than in European American Women. AB - African Americans (AAs) tend to have higher plasma insulin concentrations than European Americans (EAs); the increased insulin concentrations have been attributed to increased secretion and/or decreased insulin clearance by liver or other tissues. This work characterizes the contributions of hepatic versus extrahepatic insulin degradation related to ethnic differences between AAs and EAs. By using a recently developed mathematical model that uses insulin and C peptide measurements from the insulin-modified, frequently sampled intravenous glucose tolerance test (FSIGT), we estimated hepatic versus extrahepatic insulin clearance in 29 EA and 18 AA healthy women. During the first 20 min of the FSIGT, plasma insulin was approximately twice as high in AAs as in EAs. In contrast, insulin was similar in AAs and EAs after the 20-25 min intravenous insulin infusion. Hepatic insulin first-pass extraction was two-thirds lower in AAs versus EAs in the overnight-fasted state. In contrast, extrahepatic insulin clearance was not lower in AAs than in EAs. The difference in insulin degradation between AAs and EAs can be attributed totally to liver clearance. The mechanism underlying reduced insulin degradation in AAs remains to be clarified, as does the relative importance of reduced liver clearance to increased risk for type 2 diabetes. PMID- 28710140 TI - Perspective: A Definition for Whole-Grain Food Products-Recommendations from the Healthgrain Forum. AB - Whole grains are a key component of a healthy diet, and enabling consumers to easily choose foods with a high whole-grain content is an important step for better prevention of chronic disease. Several definitions exist for whole-grain foods, yet these do not account for the diversity of food products that contain cereals. With the goal of creating a relatively simple whole-grain food definition that aligns with whole-grain intake recommendations and can be applied across all product categories, the Healthgrain Forum, a not-for-profit consortium of academics and industry working with cereal foods, established a working group to gather input from academics and industry to develop guidance on labeling the whole-grain content of foods. The Healthgrain Forum recommends that a food may be labeled as "whole grain" if it contains >=30% whole-grain ingredients in the overall product and contains more whole grain than refined grain ingredients, both on a dry-weight basis. For the purposes of calculation, added bran and germ are not considered refined-grain ingredients. Additional recommendations are also made on labeling whole-grain content in mixed-cereal foods, such as pizza and ready meals, and a need to meet healthy nutrition criteria. This definition allows easy comparison across product categories because it is based on dry weight and strongly encourages a move from generic whole-grain labels to reporting the actual percentage of whole grain in a product. Although this definition is for guidance only, we hope that it will encourage more countries to adopt regulation around the labeling of whole grains and stimulate greater awareness and consumption of whole grains in the general population. PMID- 28710141 TI - Perspective: Improving Nutritional Guidelines for Sustainable Health Policies: Current Status and Perspectives. AB - A large body of evidence supports the notion that incorrect or insufficient nutrition contributes to disease development. A pivotal goal is thus to understand what exactly is appropriate and what is inappropriate in food ingestion and the consequent nutritional status and health. The effective application of these concepts requires the translation of scientific information into practical approaches that have a tangible and measurable impact at both individual and population levels. The agenda for the future is expected to support available methodology in nutrition research to personalize guideline recommendations, properly grading the quality of the available evidence, promoting adherence to the well-established evidence hierarchy in nutrition, and enhancing strategies for appropriate vetting and transparent reporting that will solidify the recommendations for health promotion. The final goal is to build a constructive coalition among scientists, policy makers, and communication professionals for sustainable health and nutritional policies. Currently, a strong rationale and available data support a personalized dietary approach according to personal variables, including sex and age, circulating metabolic biomarkers, food quality and intake frequency, lifestyle variables such as physical activity, and environmental variables including one's microbiome profile. There is a strong and urgent need to develop a successful commitment among all the stakeholders to define novel and sustainable approaches toward the management of the health value of nutrition at individual and population levels. Moving forward requires adherence to well-established principles of evidence evaluation as well as identification of effective tools to obtain better quality evidence. Much remains to be done in the near future. PMID- 28710143 TI - Interindividual Variability in Biomarkers of Cardiometabolic Health after Consumption of Major Plant-Food Bioactive Compounds and the Determinants Involved. AB - Cardiometabolic disease, comprising cardiovascular diseases, type 2 diabetes, and their associated risk factors including metabolic syndrome and obesity, is the leading cause of death worldwide. Plant foods are rich sources of different groups of bioactive compounds, which might not be essential throughout life but promote health and well-being by reducing the risk of age-related chronic diseases. However, heterogeneity in the responsiveness to bioactive compounds can obscure associations between their intakes and health outcomes, resulting in the hiding of health benefits for specific population groups and thereby limiting our knowledge of the exact role of the different bioactive compounds for health. The heterogeneity in response suggests that some individuals may benefit more than others from the health effects of these bioactive compounds. However, to date, this interindividual variation after habitual intake of plant bioactive compounds has been little explored. The aim of this review is to provide an overview of the existing research that has revealed interindividual variability in the responsiveness to plant-food bioactive compound consumption regarding cardiometabolic outcomes, focusing on polyphenols, caffeine and plant sterols, and the identified potential determinants involved. PMID- 28710142 TI - Perspective: Neuroregenerative Nutrition. AB - Good health while aging depends upon optimal cellular and organ functioning that contribute to the regenerative ability of the body during the lifespan, especially when injuries and diseases occur. Although diet may help in the maintenance of cellular fitness during periods of stability or modest decline in the regenerative function of an organ, this approach is inadequate in an aged system, in which the ability to maintain homeostasis is further challenged by aging and the ensuing suboptimal functioning of the regenerative unit, tissue specific stem cells. Focused nutritional approaches can be used as an intervention to reduce decline in the body's regenerative capacity. This article brings together nutrition-associated therapeutic approaches with the fields of aging, immunology, neurodegenerative disease, and cancer to propose ways in which diet and nutrition can work with standard-of-care and integrated medicine to help improve the brain's function as it ages. The field of regenerative medicine has exploded during the past 2 decades as a result of the discovery of stem cells in nearly every organ system of the body, including the brain, where neural stem cells persist in discrete areas throughout life. This fact, and the uncovering of the genetic basis of plasticity in somatic cells and cancer stem cells, open a door to a world where maintenance and regeneration of organ systems maintain health and extend life expectancy beyond its present limits. An area that has received little attention in regenerative medicine is the influence on regulatory mechanisms and therapeutic potential of nutrition. We propose that a strong relation exists between brain regenerative medicine and nutrition and that nutritional intervention at key times of life could be used to not only maintain optimal functioning of regenerative units as humans age but also play a primary role in therapeutic treatments to combat injury and diseases (in particular, those that occur in the latter one-third of the lifespan). PMID- 28710144 TI - The Impact of the Mediterranean Diet on the Cognitive Functioning of Healthy Older Adults: A Systematic Review and Meta-Analysis. AB - Evidence from epidemiologic studies suggests a relation between the Mediterranean diet (MeDi) and cognitive function, but results are inconsistent. Prior reviews have not provided pooled data from meta-analysis of longitudinal studies and randomized controlled trials (RCTs), or they included younger adult participants. This systematic review and meta-analysis examines the impact of the MeDi on the cognitive functioning of healthy older adults. Fifteen cohort studies with 41,492 participants and 2 RCTs with 309 and 162 participants in intervention and control groups, respectively, were included. The primary outcome of interest was cognitive function, divided into domains of memory and executive function. Meta analysis of cohort studies revealed a significant association between MeDi and older adults' episodic memory (n = 25,369, r = 0.01, P = 0.03) and global cognition (n = 41,492, r = 0.05, P <= 0.001), but not working memory (n = 1487, r = 0.007, P = 0.93) or semantic memory (n = 1487, r = 0.08, P = 0.28). Meta analysis of RCTs revealed that compared with controls, the MeDi improved delayed recall (n = 429, P = 0.01), working memory (n = 566, P = 0.03), and global cognition (n = 429, P = 0.047), but not episodic memory (n = 566, P = 0.15), immediate recall (n = 566, P = 0.17), paired associates (n = 429, P = 0.20), attention (n = 566, P = 0.69), processing speed (n = 566, P = 0.35), or verbal fluency (n = 566, P = 0.12). The strongest evidence suggests a beneficial effect of the MeDi on older adults' global cognition. This article discusses the influence of study design and components of the MeDi on cognitive function and considers possible mechanisms. PMID- 28710145 TI - A Systematic Review of the Effects of Polyols on Gastrointestinal Health and Irritable Bowel Syndrome. AB - Polyols are sugar alcohols found in certain fruits, vegetables, and sugar-free sweeteners. They make up a component of the diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols, which is gaining popularity in the treatment of patients with irritable bowel syndrome (IBS). We conducted a systematic review to evaluate the effects of polyols on the gastrointestinal tract in healthy men and women and in patients with IBS. Utilizing PubMed, Ovid, and Embase databases, we conducted a search on individual polyols and each of these terms: fermentation, absorption, motility, permeability, and gastrointestinal symptoms. Standard protocols for a systematic review were followed. We found a total of 1823 eligible articles, 79 of which were included in the review. Overall, available work has shown that polyol malabsorption generally occurs in a dose-dependent fashion in healthy individuals, and malabsorption increases when polyols are ingested in combination. However, studies in patients with IBS have shown conflicting results pertaining to polyol malabsorption. Polyol ingestion can lead to intestinal dysmotility in patients with IBS. Regarding the microbiome, moderate doses of polyols have been shown to shift the microbiome toward an increase in bifidobacteria in healthy individuals and may therefore be beneficial as prebiotics. However, data are limited regarding polyols and the microbiome in patients with IBS. Polyols can induce dose-dependent symptoms of flatulence, abdominal discomfort, and laxative effects when consumed by both healthy volunteers and patients with IBS. Further research is needed to better understand the effects of specific polyols on gastrointestinal function, sensation, and the microbiome in health and gastrointestinal disorders such as IBS. PMID- 28710146 TI - Current Evidence on Associations of Nutritional Factors with Ovarian Reserve and Timing of Menopause: A Systematic Review. AB - Ovarian aging is thought to be influenced by environmental factors, including nutrition. The aim of this study was to systematically review current evidence on the associations between nutritional factors, ovarian reserve, and age at menopause. PubMed and Scopus were structurally searched until May 2016. Original studies, with either observational or interventional designs, that examined the associations of nutritional factors (serum or dietary nutrients, food groups, and/or dietary patterns) with different ovarian reserve markers and/or timing of menopause were considered eligible. Twenty-six studies met the inclusion criteria: 17 studies on ovarian reserve markers and 9 studies on menopausal age. Significant diversity was observed in nutritional factors examined across studies. In the study of nutritional factors, associations of serum 25 hydroxyvitamin D [25(OH)D] concentration and intakes of soy or soy products with ovarian reserve have been the most investigated. For associations with menopausal age, intakes of total fat, fiber, and soy products have been mainly examined. Significant associations with ovarian reserve markers were found in 4 of 7 studies on serum 25(OH)D, 2 of 6 studies on soy or soy products, 1 of 2 studies on fiber intake, 1 study on serum zinc and copper concentrations, and 1 study on serum antioxidant concentrations. Studies on nutritional factors and menopausal age provided inconsistent findings, some of which suggested modest associations. Although there is some promising evidence on the influential role of nutrition in ovarian aging, a limited number of studies, heterogeneous in their design and study of nutritional factors, makes it difficult to draw definite conclusions. To better understand this issue, examination of associations of dietary intakes or dietary patterns with more precise markers of ovarian reserve, such as anti mullerian hormone and antral follicle count, with age at menopause is needed. In addition, to explore whether nutritional factors alter the process of ovarian aging, an examination of changes in ovarian reserve markers should be considered. PMID- 28710147 TI - Dietary Guidelines for Breast Cancer Patients: A Critical Review. AB - Current dietary guidelines for breast cancer patients (BCPs) fail to address adequate dietary intakes of macro- and micronutrients that may improve patients' nutritional status. This review includes information from the PubMed and Biomed Central databases over the last 15 y concerning dietary guidelines for BCPs and the potential impact of a personalized, nutrient-specific diet on patients' nutritional status during and after antineoplastic treatment. Results indicated that BCPs should receive a nutritional assessment immediately after diagnosis. In addition, they should be encouraged to pursue and maintain a healthy body weight [body mass index (BMI; in kg/m2) 20-24.9], preserving their lean mass and avoiding an increase in fat mass. Therefore, after nutritional status diagnosis, a conservative energy restriction of 500-1000 kcal/d could be considered in the dietary intervention when appropriate. Based on the reviewed information, we propose a personalized nutrition intervention for BCPs during and after antineoplastic treatment. Specifications in the nutritional therapy should be based on the patients' nutritional status, dietary habits, schedule, activities, and cultural preferences. BCPs' daily energy intake should be distributed as follows: <30% fat/d (mainly monounsaturated and polyunsaturated fatty acids), ~55% carbohydrates (primarily whole foods such as oats, brown rice, and fruits), and 1.2-1.5 g protein ? kg-1 ? d-1 to avoid sarcopenic obesity. Findings suggest that 5-9 servings/d of fruits (~150 g/serving) and vegetables (~75 g/serving) should be encouraged. Garlic and cruciferous vegetables must also be part of the nutrition therapy. Adequate dietary intakes of food-based macro- and micronutrients rich in beta-carotene and vitamins A, E, and C can both prevent deterioration in BCPs' nutritional status and improve their overall health and prognosis. PMID- 28710149 TI - On the Accuracy of Self-Report Instruments for Measuring Food Consumption in the School Setting. PMID- 28710148 TI - Energy, Protein, Carbohydrate, and Lipid Intakes and Their Effects on Morbidity and Mortality in Critically Ill Adult Patients: A Systematic Review. AB - The guidelines for nutritional support in critically ill adult patients differ in various aspects. The optimal amount of energy and nutritional substrates supplied is important for reducing morbidity and mortality, but unfortunately this is not well known, because the topic is complex and every patient is individual. The aim of this review was to gather recent pertinent information concerning the nutritional support of critically ill patients in the intensive care unit (ICU) with respect to the energy, protein, carbohydrate, and lipid intakes and the effect of their specific utilization on morbidity and mortality. Enteral nutrition (EN) is generally recommended over parenteral nutrition (PN) and is beneficial when administered within 24-48 h after ICU admission. In contrast, early PN does not provide substantial advantages in terms of morbidity and mortality, and the time when it is safe and beneficial remains unclear. The most advantageous recommendation seems to be administration of a hypocaloric (<20 kcal . kg-1 . d-1), high-protein diet (amino acids at doses of >=2 g . kg-1 . d-1), at least during the first week of critical illness. Another important factor for reducing morbidity is the maintenance of blood glucose concentrations at 120-150 mg/dL, which is accomplished with the use of insulin and lower doses of glucose of 1-2 g . kg-1 . d-1, because this prevents the risk of hypoglycemia and is associated with a better prognosis according to recent studies. A fat emulsion is used as a source of required calories because of insulin resistance in the majority of patients. In addition, lipid oxidation in these patients is ~25% higher than in healthy subjects. PMID- 28710151 TI - GP escapes erasure after failures that led to two deaths. PMID- 28710150 TI - Reply to MM Graziose. PMID- 28710152 TI - Stimulant medication to treat attention-deficit/hyperactivity disorder. PMID- 28710154 TI - Outcomes following revision surgery performed for adverse reactions to metal debris in non-metal-on-metal hip arthroplasty patients: Analysis of 185 revisions from the National Joint Registry for England and Wales. AB - OBJECTIVES: Few studies have assessed outcomes following non-metal-on-metal hip arthroplasty (non-MoMHA) revision surgery performed for adverse reactions to metal debris (ARMD). We assessed outcomes following non-MoMHA revision surgery performed for ARMD, and identified predictors of re-revision. METHODS: We performed a retrospective observational study using data from the National Joint Registry for England and Wales. All non-MoMHAs undergoing revision surgery for ARMD between 2008 and 2014 were included (185 hips in 185 patients). Outcome measures following ARMD revision were intra-operative complications, mortality and re-revision surgery. Predictors of re-revision were identified using Cox regression. RESULTS: Intra-operative complications occurred in 6.0% (n = 11) of the 185 cases. The cumulative four-year patient survival rate was 98.2% (95% CI 92.9 to 99.5). Re-revision surgery was performed in 13.5% (n = 25) of hips at a mean time of 1.2 years (0.1 to 3.1 years) following ARMD revision. Infection (32%; n = 8), dislocation/subluxation (24%; n = 6), and aseptic loosening (24%; n = 6) were the most common re-revision indications. The cumulative four-year implant survival rate was 83.8% (95% CI 76.7 to 88.9). Multivariable analysis identified three predictors of re-revision: multiple revision indications (hazard ratio (HR) = 2.78; 95% CI 1.03 to 7.49; p = 0.043); selective component revisions (HR = 5.76; 95% CI 1.28 to 25.9; p = 0.022); and ceramic-on-polyethylene revision bearings (HR = 3.08; 95% CI 1.01 to 9.36; p = 0.047). CONCLUSIONS: Non-MoMHAs revised for ARMD have a high short-term risk of re-revision, with important predictors of future re-revision including selective component revision, multiple revision indications, and ceramic-on-polyethylene revision bearings. Our findings may help counsel patients about the risks of ARMD revision, and guide reconstructive decisions. Future studies attempting to validate the predictors identified should also assess the effects of implant design (metallurgy and modularity), given that this was an important study limitation potentially influencing the reported prognostic factors.Cite this article: G. S. Matharu, A. Judge, D. W. Murray, H. G. Pandit. Outcomes following revision surgery performed for adverse reactions to metal debris in non-metal-on-metal hip arthroplasty patients: Analysis of 185 revisions from the National Joint Registry for England and Wales. Bone Joint Res 2017;6:405-413. DOI: 10.1302/2046-3758.67.BJR-2017 0017.R2. PMID- 28710153 TI - 2017 AHA/ACC Key Data Elements and Definitions for Ambulatory Electronic Health Records in Pediatric and Congenital Cardiology: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Data Standards. PMID- 28710157 TI - New halal meat labelling proposed. PMID- 28710158 TI - Vet Futures Action Plan one year on ... reviewing the progress so far. PMID- 28710164 TI - Pamplona's 'running with the bulls' met with fierce opposition. PMID- 28710167 TI - Detecting and managing new animal health threats: how vulnerable are we? PMID- 28710169 TI - Complementary and alternative medicines PMID- 28710170 TI - Prescribing antibiotics in small animals practices. PMID- 28710171 TI - Complementary and alternative medicines PMID- 28710172 TI - Complementary and alternative medicines. PMID- 28710174 TI - Classical swine fever virus in cattle. PMID- 28710173 TI - Death notices PMID- 28710175 TI - Complementary and alternative medicines PMID- 28710176 TI - Mary-Elizabeth Raw. AB - Diagnosed with multiple sclerosis in her 20s, Mary-Elizabeth became severely disabled; she was never confined by her illness and travelled widely. She won 'Mastermind' in 1989, scoring '40 and no passes'. PMID- 28710177 TI - Married to the job: working with your partner in a vet practice. AB - Kate Holton describes what it's like to work alongside her husband as vets and co joint venture partners at their Vets4Pets practice in Yate. PMID- 28710179 TI - Omega-3 Fatty Acids (Fish Oil) Supplementation and Albuminuria: Not a Slam Dunk. PMID- 28710178 TI - Eicosapentaenoic and Docosahexaenoic Acids Attenuate Progression of Albuminuria in Patients With Type 2 Diabetes Mellitus and Coronary Artery Disease. AB - BACKGROUND: Albuminuria is a marker of inflammation and an independent predictor of cardiovascular morbidity and mortality. The current study evaluated whether eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) supplementation attenuates progression of albuminuria in subjects with coronary artery disease. METHODS AND RESULTS: Two-hundred sixty-two subjects with stable coronary artery disease were randomized to either Lovaza (1.86 g of EPA and 1.5 g of DHA daily) or no Lovaza (control) for 1 year. Percent change in urine albumin-to-creatinine ratio (ACR) was compared. Mean (SD) age was 63.3 (7.6) years; 17% were women and 30% had type 2 diabetes mellitus. In nondiabetic subjects, no change in urine ACR occurred in either the Lovaza or control groups. In contrast, ACR increased 72.3% (P<0.001) in diabetic subjects not receiving Lovaza, whereas those receiving Lovaza had no change. In diabetic subjects on an angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker, those receiving Lovaza had no change in urine ACR, whereas those not receiving Lovaza had a 64.2% increase (P<0.001). Change in ACR was directly correlated with change in systolic blood pressure (r=0.394, P=0.01). CONCLUSIONS: EPA and DHA supplementation attenuated progression of albuminuria in subjects with type 2 diabetes mellitus and coronary artery disease, most of whom were on an angiotensin-converting enzyme-inhibitor or angiotensin-receptor blocker. Thus, EPA and DHA supplementation should be considered as additional therapy to an angiotensin-converting enzyme-inhibitor or angiotensin-receptor blocker in subjects with type 2 diabetes mellitus and coronary artery disease. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01624727. PMID- 28710180 TI - Dipeptidyl Peptidase-4 Regulates Hematopoietic Stem Cell Activation in Response to Chronic Stress. AB - BACKGROUND: DPP4 (Dipeptidyl peptidase-4)-GLP-1 (glucagon-like peptide-1) and its receptor (GLP-1R) axis has been involved in several intracellular signaling pathways. The Adrbeta3 (beta3-adrenergic receptor)/CXCL12 (C-X-C motif chemokine 12) signal was required for the hematopoiesis. We investigated the novel molecular requirements between DPP4-GLP-1/GLP-1 and Adrbeta3/CXCL12 signals in bone marrow (BM) hematopoietic stem cell (HSC) activation in response to chronic stress. METHODS AND RESULTS: Male 8-week-old mice were subjected to 4-week intermittent restrain stress and orally treated with vehicle or the DPP4 inhibitor anagliptin (30 mg/kg per day). Control mice were left undisturbed. The stress increased the blood and brain DPP4 levels, the plasma epinephrine and norepinephrine levels, and the BM niche cell Adrbeta3 expression, and it decreased the plasma GLP-1 levels and the brain GLP-1R and BM CXCL12 expressions. These changes were reversed by DPP4 inhibition. The stress activated BM sca 1highc-KithighCD48lowCD150high HSC proliferation, giving rise to high levels of blood leukocytes and monocytes. The stress-activated HSC proliferation was reversed by DPP4 depletion and by GLP-1R activation. Finally, the selective pharmacological blocking of Adrbeta3 mitigated HSC activation, accompanied by an improvement of CXCL12 gene expression in BM niche cells in response to chronic stress. CONCLUSIONS: These findings suggest that DPP4 can regulate chronic stress induced BM HSC activation and inflammatory cell production via an Adrbeta3/CXCL12 dependent mechanism that is mediated by the GLP-1/GLP-1R axis, suggesting that the DPP4 inhibition or the GLP-1R stimulation may have applications for treating inflammatory diseases. PMID- 28710181 TI - Severe Aortic Stenosis in Dialysis Patients. AB - BACKGROUND: Characteristics and prognosis of hemodialysis patients with severe aortic stenosis have not yet been well defined. METHODS AND RESULTS: The CURRENT AS (contemporary outcomes after surgery and medical treatment in patients with severe aortic stenosis) registry, a Japanese multicenter registry, enrolled 3815 consecutive patients with severe aortic stenosis. There were 405 hemodialysis patients (initial aortic valve replacement [AVR] group: N=135 [33.3%], and conservative group: N=270) and 3410 nonhemodialysis patients (initial AVR group: N=1062 [31.1%], and conservative group: N=2348). The median follow-up duration after the index echocardiography was 1361 days, with 90% follow-up rate at 2 years. The cumulative 5-year incidence of all-cause death was significantly higher in hemodialysis patients than in nonhemodialysis patients in both the entire cohort (71% versus 40%, P<0.001) and in the initial AVR group (63.2% versus 17.9%, P<0.001). Among hemodialysis patients, the initial AVR group as compared with the conservative group was associated with significantly lower cumulative 5-year incidences of all-cause death (60.6% versus 75.5%, P<0.001) and sudden death (10.2% versus 31.7%, P<0.001). Nevertheless, the rate of aortic valve procedure-related death, which predominantly occurred within 6 months of the AVR procedure, was markedly higher in the hemodialysis patients than in the nonhemodialysis patients (21.2% and 2.3%, P<0.001). CONCLUSIONS: Among hemodialysis patients with severe aortic stenosis, the initial AVR strategy as compared with the conservative strategy was associated with significantly lower long-term mortality risk, particularly the risk for sudden death, although the effect size for the survival benefit of the initial AVR strategy was smaller than that in the nonhemodialysis patients. PMID- 28710183 TI - Fifteen-minute consultation: the management of microscopic haematuria. AB - Haematuria can be a troublesome symptom with various different methods of presentation and aetiologies. Microscopic haematuria is a common coincidental finding often found when the patient has presented for another reason. We will discuss the subject of haematuria but will focus the majority of this article on the discussion of microscopic haematuria, including a definition, the important features to cover in the history and examination, aetiologies to suspect in children and infants, and a suggested approach to assessing these patients in secondary care. PMID- 28710182 TI - Elevation of B-Type Natriuretic Peptide at Discharge is Associated With 2-Year Mortality After Transcatheter Aortic Valve Replacement in Patients With Severe Aortic Stenosis: Insights From a Multicenter Prospective OCEAN-TAVI (Optimized Transcatheter Valvular Intervention-Transcatheter Aortic Valve Implantation) Registry. AB - BACKGROUND: In this study, we sought to investigate the 2-year prognostic impact of B-type natriuretic peptide (BNP) levels at discharge, following transcatheter aortic valve replacement. METHODS AND RESULTS: We enrolled 1094 consecutive patients who underwent transcatheter aortic valve replacement between 2013 and 2016. Study patients were stratified into 2 groups according to survival classification and regression tree analysis (high versus low BNP groups). We evaluated the impact of high BNP on 2-year mortality compared with that of low BNP using a multivariable Cox model, and assessed whether this stratification would improve predictive accuracy for determining 2-year mortality by assessing time-dependent net reclassification improvement and integrated discrimination improvement. The median age of patients was 85 years (quartile 82-88), and 29.2% of the study population were men. The median Society of Thoracic Surgeons score was 6.8 (4.7-9.5), and BNP at discharge was 186 (93-378) pg/mL. All-cause mortality following discharge was 7.9% (95% CI, 5.8-9.9%) at 1 year and 15.4% (95% CI, 11.6-19.0%) at 2 years. The survival classification and regression tree analysis revealed that the discriminating BNP level to discern 2-year mortality was 202 pg/mL, and that elevated BNP had a statistically significant impact on outcomes, with an adjusted hazard ratio of 2.28 (1.36-3.82, P=0.002). The time dependent net reclassification improvement (P=0.047) and integrated discrimination improvement (P=0.029) analysis revealed that the incorporation of BNP stratification with other clinical variables significantly improved predictive accuracy for 2-year mortality. CONCLUSIONS: Elevation of BNP at discharge is associated with 2-year mortality after transcatheter aortic valve replacement. PMID- 28710184 TI - Diagnostic value of four-dimensional CT angiography in arterial erectile dysfunction using 320-detector row dynamic volume CT. AB - The present study aims to evaluate the diagnostic value of four-dimensional CT angiography (4D-CTA) in the diagnosis of arterial erectile dysfunction (ED) using 320-detector row dynamic volume CT. Arterial ED patients attributed to arterial insufficiency were enrolled. To induce penile erection, an intracavernous injection (ICI) of corpus cavernosum with a vasoactive drug was administered. Patients were assigned into the erection hardness score (EHS) 1/2 group or EHS 3/4 group. Color duplex Doppler ultrasound (CDDU) was used to analyze blood flow spectrum. Each patient was examined using 4D-CTA. Receiver operating characteristic (ROC) curve was plotted to evaluate the diagnostic value of 4D-CTA in arterial ED. According to Irwin Goldstein, the EHS 3/4 group (n=38) had a shorter course of ED and low proportion with history of hypertension, hyperlipidemia, and diabetes than the EHS 1/2 group (n=35). The peak systolic velocity (PSV), end diastolic velocity (EDV), and resistant index (RI) in the EHS 3/4 group were lower than those of the EHS 1/2 group. 4D-CTA showed there were a total of 35 cases in the EHS 1/2 group (two cases missed) and 38 cases in the EHS 3/4 group (seven cases misdiagnosed). Using 4D-CTA to diagnose arterial ED, the area under the ROC curve yielded a value of 0.879, with a specificity of 93.9% and a sensitivity of 82.5%. These findings indicated that 4D-CTA using 320 detector row dynamic volume CT is a promising and reliable utility in diagnosing arterial ED. PMID- 28710185 TI - Extreme ischaemic heart disease risk in people with type 1 diabetes. PMID- 28710186 TI - Glycaemic control and excess risk of major coronary events in persons with type 1 diabetes. AB - OBJECTIVE: The excess risk of major coronary events (acute myocardial infarction (AMI) or death from coronary heart disease (CHD)) in individuals with type 1 diabetes (T1D) in relation to glycaemic control and renal complications is not known. METHODS: Individuals with T1D in the Swedish National Diabetes Registry after 1 January 1998, without a previous MI (n=33 170) and 1 64 698 controls matched on age, sex and county were followed with respect to non-fatal AMI or death from CHD. Data were censored at death due to any cause until 31 December 2011. RESULTS: During median follow-up of 8.3 and 8.9 years for individuals with T1D and controls, respectively, 1500 (4.5%) and 1925 (1.2%), experienced non fatal AMI or died from CHD, adjusted HR 4.07 (95% CI 3.79 to 4.36). This excess risk increased with younger age, female sex, worse glycaemic control and severity of renal complications.The adjusted HR in men with T1D with updated mean haemoglobin A1c (HbA1c) <6.9% (52 mmol/mol) and normoalbuminuria was 1.30 (95% CI 0.90 to 1.88) and in women 3.16 (95% CI 2.14 to 4.65). HRs increased to 10.7 (95% CI 8.0 to 14.3) and 31.8 (95% CI 23.6 to 42.8) in men and women, respectively, with HbA1c >9.7% and renal complications. CONCLUSIONS: The excess risk of AMI in T1D is substantially lower with good glycaemic control, absence of renal complications and men compared with women. In women, the excess risk of AMI or CHD death persists even among patients with good glycaemic control and no renal complications. PMID- 28710187 TI - Utility of microscope-integrated optical coherence tomography (MIOCT) in the treatment of myopic macular hole retinal detachment. AB - Macular hole-associated retinal detachment in high myopia is described as a final stage in progression of myopic traction maculopathy (MTM).1a?"3 Shimada et al4 described the progressive stages of MTM from macular retinoschisis to serous retinal detachment in high myopia. Stage 4 MTM is characterised as disappearance of retinoschisis with progression to retinal detachment due to macular hole formation. It is hypothesised that vitreoschisis and abnormal vitreo-retinal interface create the premacular tangential traction.5 6 Intraoperative triamcinolone acetonide is used to visualise the residual posterior vitreous cortex (PVC). We hereby describe the utility of microscope-integrated optical coherence tomography (MIOCT) in assisting complete removal of PVC and internal limiting membrane (ILM) peeling with multilayered inverted ILM flap in the treatment of myopic macular hole retinal detachment. MIOCT helped identify vitreoschisis and confirm the position of ILM flaps over the macular hole intraoperatively. PMID- 28710188 TI - Leucocytoclastic vasculitis following influenza vaccination. AB - BACKGROUND: Influenza vaccinations are commonly administered and effectively prevent influenza. Most vaccine reactions are mild and self-limiting with few reported cases of vasculitis. We present a case of vasculitis post-vaccination unique for its dramatic visual presentation and rapid response to treatment with the aim to emphasise possible causation and timely treatment. CASE PRESENTATION: This is a case of a 60-year-old man with chronic idiopathic pulmonary fibrosis, with fever, arthralgias and rash characterised by extensive erythematous plaques on his limbs and trunk 5a?0/00days after influenza vaccination. Skin biopsy revealed leucocytoclastic vasculitis. Rash and symptoms resolved 10 days after initiating treatment with oral prednisone. CONCLUSIONS: Influenza vaccines can potentially precipitate cutaneous vasculitis, and timely treatment reduces morbidity in the elderly. PMID- 28710189 TI - Use of cabergoline for the management of persistent Cushing's disease in pregnancy. AB - Cushing's disease (CD) is rare during pregnancy and is associated with significant maternal and fetal complications. It is important to control hypercortisolism during pregnancy, either surgically or medically, for a successful maternal and fetal outcome. We report a patient with recurrent CD who was treated with low-dose cabergoline (CAB) for persistent hypercortisolism throughout pregnancy. A 36-year-old woman was diagnosed with CD at the age of 23. She underwent trans-sphenoidal surgery with initial complete remission. However, 4 years after surgery, CD recurred and she underwent Gamma Knife radiosurgery (GKRS). Following GKRS, her cortisol levels remained elevated despite no evidence of visible tumour on pituitary MRI. Medical treatment was commenced with ketoconazole and cyproheptadine. This was changed to CAB as she was keen for pregnancy. She conceived spontaneously and was on CAB throughout pregnancy. She delivered a healthy male neonate, weighing 3195 g at 40 weeks of gestation. PMID- 28710190 TI - Stigma kills! The psychological effects of emotional abuse and discrimination towards a patient with HIV in Uganda. AB - Our patient is a 58-year-old Ugandan woman. After her husband's death in 1994, the patient was forced to leave her home by her late husband's family and arrangements were made for her mother to provide care until her inevitable death. The patient suffered from multiple mental health disturbances as a result of discrimination. Socially isolated after years of self-neglect, she prepared to overdose. In 2007, she became open regarding her status after receiving psychosocial support from various sources. She opened her home as an HIV clinic with the help of a local doctor, and subsequently the majority of her psychological symptoms were resolved. This case illustrates the negative impact that stigma and discrimination can have on mental and consequently physical health, both acutely and chronically. It also highlights the importance of social and psychological support in maintaining the well-being of patients with HIV globally. PMID- 28710191 TI - Unusual sensory variant of Guillain-Barre syndrome. AB - We describe a 52-year-old woman presenting with acute onset of severe burning paraesthesia in the hands and feet associated with allodynia and antalgic gait. At the time of admission to hospital no motor weakness was present. A diagnosis of Guillain-Barre syndrome (GBS) was considered when neurophysiological studies were completed showing convincing evidence of demyelination on motor conduction studies and sural sparing on sensory nerve studies.1 We describe this case as a sensory variant of GBS. Clinical improvement followed treatment with a single course of intravenous immunoglobulin (IVIG). The patient made a complete clinical recovery within 6 months of onset and repeat neurophysiological studies showed marked improvement. We encourage clinicians to consider an atypical variant of GBS in patients presenting with acute sensory complaints. PMID- 28710192 TI - Organ-sparing surgery for large cell calcifying Sertoli cell tumour in a patient with Carney complex. AB - Carney complex is a rare genetic disease characterised by a complex of myxomas, spotty pigmentation and endocrine overactivity. At diagnosis, about one-third of male patients presents with testicular tumours, namely large cell calcifying Sertoli cell tumours, which are often multicentric and/or bilateral and have a low malignant potential. Although radical orchiectomy is the gold standard for the treatment of testicular neoplasms, a conservative approach with partial orchiectomy or tumourectomy may be the best treatment option for these patients, allowing the preservation of endocrine function, fertility and body image. We present a case of a 19-year-old man with a known history of Carney complex with early identification of a small testicular tumour treated with organ-sparing surgery. PMID- 28710193 TI - Ciliated foregut cyst of the gall bladder: the largest ever described. AB - A 78-year-old man presented to the accident and emergency department with acute abdominal pain. A CT scan done to investigate the pain showed an intra-abdominal abscess medial to the caecum and an incidental exophytic lesion in the gall bladder. This was excised during surgery and sent for histological examination. Histology showed a ciliated foregut cyst of the gall bladder. A literature review revealed that this was the 13th case worldwide, as ciliated foregut cysts are usually found either above the diaphragm or in the liver. It was also the largest cyst described, with 45a?0/00mm diameter. So far none of these cysts found in the gall bladder have shown malignant transformation, though those found in the liver have been known to become malignant. Due to histological similarity, excision of ciliated foregut cysts of the gall bladder should be considered as there is still a risk of malignant transformation. PMID- 28710194 TI - Laparoscopic excision of an inflammatory myofibroblastic tumour of the bladder disguised as deep infiltrating endometriosis. AB - Inflammatory myofibroblastic tumour (IMT) of the bladder is a rare tumour of indeterminate malignant potential with myofibroblastic differentiation, with a generally benign but rarely aggressive behaviour. Vesical IMT is usually treated by transurethral resection or partial cystectomy. Herein we describe a case of a woman who underwent laparoscopic excision of an IMT of the bladder, initially diagnosed as deep infiltrating endometriosis. PMID- 28710195 TI - Marantic endocarditis and paraneoplastic pulmonary embolism. AB - Cancer is frequently associated with a hypercoagulable state. Almost 15% of patients with cancer will suffer a thromboembolic event during their clinical course. The aetiology of this hypercoagulable state is multifactorial and includes procoagulant factors associated with malignancy as well as the host's inflammatory response. Cancer-associated thrombophilia can present as venous thromboembolism, migratory superficial thrombophlebitis, arterial thrombosis, disseminated intravascular coagulation, thrombotic microangiopathy and rarely non bacterial thrombotic endocarditis (NBTE). In this paper, we will describe an uncommon presentation of lung cancer on a non-smoker middle-aged woman, with recent diagnosis of pulmonary embolism, who develops malignant recurrent pleural effusion, NBTE with cutaneous and neurological manifestations, with a rapid evolution into shock, culminating in death. Diagnosis of NBTE requires a high degree of clinical suspicion. The mainstay of treatment is systemic anticoagulation to prevent further embolisation and underlying cancer control whenever is possible. PMID- 28710196 TI - Disseminated histoplasmosis presenting as multiple oral ulcers. AB - A 61-year-old female with a history of advanced HIV disease and chronic hepatitis B was presented with an 8-week history of painful oral ulcers. She appeared systemically well but examination revealed multiple well-demarcated clean-based ulcers on the tongue and hard palate. Biopsy of one of the lesions showed numerous histiocytes containing intracellular yeast forms consistent with Histoplasma capsulatum var. capsulatum Fungal blood cultures subsequently grew H. capsulatum var. capsulatum, confirming a diagnosis of disseminated histoplasmosis. She was treated with intravenous amphotericin B for 2 weeks followed by a prolonged course of oral itraconazole, with which her ulcers resolved completely and have not recurred. This case exemplifies how oral ulcers may be a manifestation of an underlying systemic disease and demonstrates the utility of biopsy in establishing a diagnosis. PMID- 28710197 TI - Cervical shock: a complication of incomplete abortion. AB - A case of a 37-year-old female primagravida who attended the emergency department (ED) via ambulance in hypotensive shock. She was 10 weeks pregnant, but had an inevitable miscarriage confirmed in the local Early Pregnancy Unit 3 weeks previously. She was hypotension (90/60a?0/00mm Hg), bradycardic (45 bpm) and was peripherally shut down. A provisional diagnosis of haemorrhagic shock was made, but despite intravenous fluid challenges, she appeared to be deteriorating, so a major haemorrhage protocol was activated. On examination, there was some vaginal bleeding and a protruding sac noted. The gynaecology registrar was informed and performed an Evacuation of the Retained Products of Conception in the ED. This gave instant relief to the patient and her blood pressure and heart rate became normal over a few minutes. She went on to make a full recovery. This case provides useful learning points for doctors working in the ED and other urgent care settings. PMID- 28710199 TI - Chilaiditi syndrome mimicking congestive heart failure. PMID- 28710198 TI - IVC tumoural thrombosis: an unusual complication of testicular tumour. PMID- 28710200 TI - Thyrotoxicosis in patients with hypothyroidism is not just overtreatment. AB - A 62-year-old Caucasian woman presented with hypothyroid symptoms and biochemical thyrotoxic picture. Previously, she underwent right-sided subtotal thyroidectomy and left partial thyroid lobectomy for thyroid lumps, and treated with thyroxine replacement for hypothyroidism. Although there were no significant findings on clinical examination, investigations confirmed thyrotoxicosis with positive autoimmunity against thyroid glanda?"all in line with a diagnosis of Gravesa?TM hyperthyroidism. We would like to highlight atypical presentations of thyroid dysfunction and conversion of underactive to overactive thyroid status with this case. Early recognition, diagnosis and intervention are essential to prevent and/or reduce associated morbidity and mortality. When encountered with such clinical conundrums, we recommend seeking opinion from an experienced endocrinologist while interpreting such situation. PMID- 28710201 TI - Pica, constipation and cardiorespiratory arrest. PMID- 28710202 TI - A motivational interview intervention delivered at home to improve the oral health literacy and reduce the morbidity of Chilean disadvantaged families: a study protocol for a community trial. AB - INTRODUCTION: Oral health education/promotion interventions have been identified as cost-efficient tools to improve the oral health of the population. These interventions are regularly made in contexts where the target population is captive, for example, in health centres. In Chile, there are no oral health interventions delivered at home. METHODS AND ANALYSIS: This community trial covers two disadvantaged urban areas in the province of Concepcion. Both sectors have public preschool education coverage with a traditional programme (TP) to promote oral health. The intervention will comprise four to six visits by dental hygienists trained in the delivery of a standardised oral health promotion programme using motivational interviewing (MI) at home. The experimental group will receive TP and MI, while the control group will receive only TP. If a positive and significant effect of MI is found, this will be administered to the control group. For a 50% reduction in the incidence of caries, a sample size of 120 preschoolers per group is estimated. Data will be gathered on demographic and socioeconomic variables; oral health outcomes using WHO oral health indicators (the prevalence and severity of caries, periodontal disease, dentofacial anomalies and oral hygiene); the oral health literacy of caregivers, measured by the Rapid Estimation of Adult Literacy in Dentistry and the Oral Health Literacy Instrument, both validated for the Chilean population. Assessments will take place at baseline and at 12-month follow-up. ETHICS AND DISSEMINATION: The university bioethics committee approved this study (EI/21/2014). We will submit the trial's results for presentation at international scientific meetings and to peer-reviewed journals. TRIAL REGISTRATION NUMBER: ACTRN12615000450516. PMID- 28710203 TI - Liver cirrhosis in England-an observational study: are we measuring its burden occurrence correctly? AB - OBJECTIVES: Mortality due to liver disease (of which cirrhosis is the end stage) is increasing more than any other chronic condition in the UK. This study aims to demonstrate that (1) exclusive reliance on mortality rates may not reveal the true burden of liver cirrhosis, and (2) diverse use of diagnostic coding may produce misleading estimates. DESIGN: Observational study. SETTING: The Office for National Statistics death registry was interrogated to investigate liver cirrhosis mortality trends in England and Wales from 1968 to 2011. MAIN OUTCOME: Standardised mortality trends according to three different definitions of liver cirrhosis based on the specificity of diagnostic codes were calculated: 1 (chronic liver diseases), 2 (alcoholic and unspecified cirrhosis only) and 3 (cirrhosis as end-stage liver disease). The mortality trends were compared with incidence rates established in a previous population-based study (based on definition 3), from 1998 to 2009, to investigate discrepancies between these two measures. RESULTS: Over the study period, the overall standardised liver cirrhosis mortality rates were 8.8, 5,1 and 5.4 per 100 000 person-years for definitions 1, 2 and 3, respectively. The mortality rates for definition 3 in 1998 and 2009 were 6.2 and 5.9 per 100 000 person-years, respectively; while the equivalent incidence rates were at least threefold and sixfold higher: 23.4 and 35.9 per 100 000 person-years, respectively. This discrepancy between incidence and mortality rates was also at least threefold in men and women separately and across age groups. CONCLUSION: Mortality rates underestimated the incidence of liver cirrhosis by at least threefold between 1998 and 2009 and varied with differing definitions of disease. Mortality data should not be used exclusively as an indicator for the occurrence of liver cirrhosis in the population. Routinely collected healthcare data are available to measure occurrence of this disease. Careful consideration should be taken when selecting diagnostic codes for cirrhosis. PMID- 28710204 TI - Bio-Plex immunoassay measuring the quantity of lysosomal N-acetylgalactosamine-6 sulfatase protein in dried blood spots for the screening of mucopolysaccharidosis IVA in newborn: a pilot study. AB - OBJECTIVE: Mucopolysaccharidosis (MPS) IVA (Morquio syndrome A) is an autosomal recessive lysosomal storage disorder caused by the deficiency of N acetylgalactosamine-6-sulfatase (GALNS) resulting in excessive lysosomal storage of keratan sulfate. Treatments for MPS IVA have recently become available with optimal outcomes associated with early diagnosis and treatment which can be achieved by newborn screening. DESIGN: Newborn screening programme for MPS IVA pilot study. SETTING: MacKay Memorial Hospital (MMH), Taipei and another three branch hospitals in Taiwan. PARTICIPANTS: A total of 7415 newborns were born in four branch hospitals of MMH and had joined the MPS IVA newborn screening programme. Written informed consents were obtained from parents prior to the screening process (12MMHIS188 approved by MacKay Memorial Hospital Institutional Review Board). OUTCOME MEASURES: An alternative newborn screening method for MPS IVA has been performed. Screening involved measuring the quantity of GALNS in dried blood spot (DBS) from newborn infants using the Bio-Plex immunoassay. The amount of fluorescence sorting detected by yttrium aluminium garnet laser was proportional to the quantity of GALNS protein. RESULTS: Of the 7415 neonates analysed, eight infants whose GALNS levels were below the cut-off value of 8.30 ug/L had been recalled for a second DBS collection. The reference values were 8.30-27.43 ug/L. In patients with confirmed MPS IVA (n=11), the GALNS quantities were far below 5% of the normal population. CONCLUSION: The Bio-Plex immunoassay is a validated method used for measuring GALNS protein in DBS and has the potential to be adopted for MPS IVA newborn screening study design. PMID- 28710205 TI - Effect of interdisciplinary care on weight loss: a randomised controlled trial. AB - OBJECTIVE: To determine the effectiveness of a novel interdisciplinary treatment compared with usual care on weight loss in overweight and obese adult volunteers. DESIGN: Single blinded controlled trial. Participants randomly assigned to usual care (C, general guideline-based diet and exercise advice), intervention (I, interdisciplinary protocol) or intervention + a healthy food supplement (30 g walnuts/day) (IW). SETTING: Community based study, Illawarra region, south of Sydney, Australia. PARTICIPANTS: Generally well volunteer adult residents, 25-54 years, body mass index (BMI) 25-40kg/m2 were eligible. At baseline 439 were assessed, 377 were randomised, 298 completed the 3-month intensive phase and 178 completed the 12-month follow-up. INTERVENTIONS: Treatment was provided at clinic visits intensively (0 months, 1 month, 2 months, 3 months) then quarterly to 12 months. Support phone calls were quarterly. All participants underwent blinded assessments for diet, exercise and psychological status. PRIMARY AND SECONDARY MEASURES: The primary outcome was difference in weight loss between baseline and 12 months (clinically relevant target 5% loss). Secondary outcomes were changes in blood pressure, fasting blood glucose and lipids, and changes in diet, exercise and psychological parameters. RESULTS: At 12 months, differences in weight loss were identified (p<0.001). The I group lost more than controls at 3 months (91.11 (92.23,90.00), p<0.05) and the IW more than controls at 3 months (91.25 (92.35,90.15), p<0.05) and 6 months (92.20 (93.90,90.49), p<0.01). The proportion achieving 5% weight loss was significantly different at 3 months, 6 months and 9 months (p=0.04, p=0.03, p=0.03), due to fewer controls on target at 3 months, 6 months and 9 months and more IW participants at 6 months. Reductions in secondary outcomes (systolic blood pressure, blood glucose/lipid parameters and lifestyle measures) followed the pattern of weight loss. CONCLUSIONS: An interdisciplinary intervention produced greater and more clinically significant and sustained weight loss compared with usual care. The intensive phase was sufficient to reach clinically relevant targets, but long-term management plans may be required. TRIAL REGISTRATION NUMBER: ANZCTRN 12614000581662; Post-results. PMID- 28710206 TI - Exploring how ward staff engage with the implementation of a patient safety intervention: a UK-based qualitative process evaluation. AB - OBJECTIVES: A patient safety intervention was tested in a 33-ward randomised controlled trial. No statistically significant difference between intervention and control wards was found. We conducted a process evaluation of the trial and our aim in this paper is to understand staff engagement across the 17 intervention wards. DESIGN: Large qualitative process evaluation of the implementation of a patient safety intervention. SETTING AND PARTICIPANTS: National Health Service staff based on 17 acute hospital wards located at five hospital sites in the North of England. DATA: We concentrate on three sources here: (1) analysis of taped discussion between ward staff during action planning meetings; (2) facilitators' field notes and (3) follow-up telephone interviews with staff focusing on whether action plans had been achieved. The analysis involved the use of pen portraits and adaptive theory. FINDINGS: First, there were palpable differences in the ways that the 17 ward teams engaged with the key components of the intervention. Five main engagement typologies were evident across the life course of the study: consistent, partial, increasing, decreasing and disengaged. Second, the intensity of support for the intervention at the level of the organisation does not predict the strength of engagement at the level of the individual ward team. Third, the standardisation of facilitative processes provided by the research team does not ensure that implementation standardisation of the intervention occurs by ward staff. CONCLUSIONS: A dilution of the intervention occurred during the trial because wards engaged with Patient Reporting and Action for a Safe Environment (PRASE) in divergent ways, despite the standardisation of key components. Facilitative processes were not sufficiently adequate to enable intervention wards to successfully engage with PRASE components. PMID- 28710207 TI - Comorbidities, complications and mortality in people of South Asian ethnicity with type 1 diabetes compared with other ethnic groups: a systematic review. AB - OBJECTIVE: The aim of this systematic review is to explore the association of South Asian (SA) ethnicity on comorbidities, microvascular and macrovascular complications and mortality compared with other ethnic groups in people with type 1 diabetes mellitus (T1DM). DESIGN: Systematic review. METHOD: A systematic literature search strategy was designed and carried out using Medline and Embase for full-text and abstract studies published in English from 1946 to February 2016. The initial search identified 4722 papers. We assessed 305 full-text articles in detail for potential inclusion. Ten papers met the inclusion criteria for review and an additional one paper was included from our secondary search strategy using the bibliography of included studies. In total, 11 studies were included. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Studies were included if they were published in English, involved SA participants with T1DM and compared them with non-SA participants and assessed one of the outcomes of comorbidities, microvascular complications, macrovascular complications and mortality. RESULTS: SA with T1DM have higher mortality compared with white Europeans (WE), mainly contributed to by excess cardiovascular disease. SA have significantly higher glycated haemoglobin (HbA1c), lower high-density lipoprotein (HDL) and lower rates of neuropathy compared with WE. There were no differences in rates of retinopathy and nephropathy. Compared with Africans, SA had lower levels of microalbuminuria, HbA1c and systolic blood pressure and higher HDL levels. There were no significant differences in the remaining outcomes: cardiovascular disease, retinopathy, neuropathy and body mass index. Furthermore, SA have higher HbA1c levels than Malay and Chinese and higher waista?"hip ratio and lower HDL levels compared with Chinese only. CONCLUSION: Our analysis highlights ethnic disparity in macrovascular outcomes that is so evident for type 2 diabetes mellitus may also be present for SA patients with T1DM. We highlight the need for a large, prospective, cohort study exploring the effect of ethnicity in a uniform healthcare setting. PMID- 28710208 TI - Primary care workforce and continuous medical education in China: lessons to learn from a nationwide cross-sectional survey. AB - OBJECTIVES: This study aimed to examine the education and training background of Chinese community health centres (CHCs) staff, continuous medical education (CME) and factors affecting participation in CME. DESIGN: Cross-sectional survey. SETTING: Community health centres (CHCs). PARTICIPANTS: All doctors and nurses working in selected CHCs (excluding those solely practising traditional Chinese Medicine). MAIN OUTCOME MEASURES: CME recorded by CHCs and self-reported CME participation. METHODS: A stratified random sample of CHCs based on geographical distribution and 2:1 urban-suburban ratio was selected covering three major regions of China. Two questionnaires, one for lead clinicians and another for frontline health professionals, were administered between September-December 2015, covering the demographics of clinic staff, staff training and CME activities. RESULTS: 149 lead clinicians (response rate 79%) and 1734 doctors and 1846 nurses completed the survey (response rate 86%). Of the doctors, 54.5% had a bachelor degree and only 47% were registered as general practitioners (GPs). Among the doctors, 10.5% carried senior titles. Few nurses (4.6%) had training in primary care. Those who have reported participating in CME were 91.6% doctors and 89.2% nurses. CME participation in doctors was more commonly reported by older doctors, females, those who were registered as a GP and those with intermediate or senior job titles. CME participation in nurses was more common among those with a bachelor degree or intermediate/senior job titles or those with longer working experience in the CHC. CONCLUSION: Only half of doctors have bachelor degrees or are registered as GPs as their prime registration in the primary care workforce in China. The vast majority of CHC staff participated in CME but there is room for improvement in how CME is organised. PMID- 28710209 TI - Does a one-day workshop improve clinical faculty's comfort and behaviour in practising and teaching evidence-based medicine? A Canadian mixed methods study. AB - OBJECTIVE: The purpose of this study was to determine the impact of a 1-day evidence-based medicine (EBM) workshop on physician attitudes and behaviours around teaching and practicing EBM. DESIGN: A mixed methods study using a before/after cohort. SETTING: A medical school delivering continuing professional development to 1250 clinical faculty over a large geographic area in Canada. PARTICIPANTS: 105 physician clinical faculty members. INTERVENTION: A 1-day workshop presented at 11 different sites over an 18-month period focusing on EBM skills for teaching and clinical practice. OUTCOME MEASURES: (1) A quantitative survey administered immediately before and after the workshop, and 3-6 months later, to assess the hypothesis that comfort with teaching and practising EBM can be improved.(2) A qualitative survey of the expectations for, and impact of the workshop on, participant behaviours and attitudes using a combination of pre, post and 3 to 6-month follow-up questionnaires, and telephone interviews completed 10-14 months after the workshop. RESULTS: Physician comfort with their EBM clinical skills improved on average by 0.93 points on a 5-point Likert scale, and comfort with EBM teaching skills by 0.97 points (p values 0.001). Most of this improvement was sustained 3-6 months later. Three to fourteen months after the workshop, half of responding participants reported that they were using the Population Intervention Comparator Outcome (PICO) methodology of question framing for teaching, clinical practice or both. CONCLUSIONS: Comfort in teaching and practicing EBM can be improved by a 1-day workshop, with most of this improvement sustained 3-6 months later. PICO question framing can be learnt at a 1-day workshop, and is associated with a self-reported change in clinical and teaching practice 3-14 months later. This represents both level 2 (attitudes) and level 3 (behaviours) change using the Kirkpatrick model of evaluation. PMID- 28710210 TI - Being normal, not vulnerable: case study of a 2-day residential programme for young adults with cancer. AB - OBJECTIVES: To identify and describe the outcomes and facilitating processes of participation at 'Find Your Sense of Tumour' (FYSOT), a 2-day residential programme/conference for young people with cancer, from the perspective of professionals attending and patient representatives. DESIGN: Case study. SETTING: Observation of the 'Find Your Sense of Tumour' over 18s residential programme and face-to-face interviews in hospital and phone interviews. PARTICIPANTS: Twenty six participants - 19 professionals from hospitals across the UK who accompanied young people to FYSOT; 3 programme organisers; and 4 young people from the programme steering committee. METHODS: Participant observation and semistructured interviews. RESULTS: This process evaluation of an educational, social and peer to-peer support residential weekend for young people with cancer identified key outcomes for young people - positive attitudes (increased sociability, confidence), belonging (feeling accepted, understood), recreation (trying new activities, having fun) and increased knowledge (balance between educational talks and interactions with other young people); and three overarching facilitating processes - being with other young people, the professionals accompanying young people to the event for support and guidance, and the conference/intentional programming. Being in a safe, relaxed and fun environment with other young people facilitates the development of peer support networks and increases young people's confidence and knowledge. Although the focus of the residential programme is on young people, interviewees acknowledge the impact of attending on professionals' motivation, learning and changes in practice. CONCLUSIONS: This study has extended our understanding of the role of residential programmes by identifying outcomes and facilitating mechanisms. We have shown that residential programmes have an important role in providing participants with social, emotional and informational support, as well as play an important role in redefining normality. Longitudinal quantitative and qualitative research is needed to optimise outcomes and design and implement quality programmes that support young people's development. PMID- 28710211 TI - Occupational risk for Legionella infection among dental healthcare workers: meta analysis in occupational epidemiology. AB - OBJECTIVE: The occupational risk for Legionella infection among dental healthcare workers (DHCWs) is conjectured because of the risk of routine inhalation of potentially contaminated aerosols produced by the dental instruments. Nevertheless, occupational epidemiology studies are contrasting. This meta analysis assessed the level of scientific evidence regarding the relative occupational risk for Legionella infection among DHCWs. METHODS: Literature search was performed without time and language restrictions, using broad data banks (PubMed, Scopus, Web of Science, GOOGLE Scholar) and generic keywords ('legionella' AND 'dent*'). Analytical cross-sectional studies comparing prevalence of high serum Legionella antibody levels in DHCWs and occupationally unexposed individuals were considered. The relative occupational risk was assessed through prevalence ratio (PR) with 95% CI. Between-study heterogeneity was assessed (Cochran's Q test) and was used to choose the meta-analytic method. Study quality (modified Newcastle-Ottawa Scale) and publication bias (Begg and Mazumdar's test, Egger and colleagues' test, trim and fill R0 method) were assessed formally and considered for the sensitivity analysis. Sensitivity analysis to study inclusion, subgroup analyses (dental staff categories; publication year, before vs after 1998, ie, 5 years after the release by the Centers for Disease Control and Prevention of the infection control guidelines in dental healthcare setting) were performed. RESULTS: Seven studies were included (2232 DHCWs, 1172 occupationally unexposed individuals). No evidence of publication bias was detected. The pooled PR estimate was statistically non significant at 95% level (1.7; 95% CI 0.8 to 3.2), study-quality adjustment did not change the PR considerably (PR, 1.5; 95% CI 0.5 to 4.1). PR was statistically significant before 1998 and no longer significant after 1998. Subgroup analysis according to DHCW categories was inconclusive. CONCLUSIONS: There is no scientific evidence that DHCWs are at high occupational risk. The differences between former and recent studies could be due to different characteristics of municipal water systems and the infection control guideline dissemination. PMID- 28710212 TI - Does recruitment source moderate treatment effectiveness? A subgroup analysis from the EVIDENT study, a randomised controlled trial of an internet intervention for depressive symptoms. AB - OBJECTIVE: This study aims to examine whether the effects of internet interventions for depression generalise to participants recruited in clinical settings. DESIGN: This study uses subgroup analysis of the results of a randomised, controlled, single-blind trial. SETTING: The study takes place in five diagnostic centres in Germany. PARTICIPANTS: A total of 1013 people with mild to moderate depressive symptoms were recruited from clinical sources as well as internet forums, statutory insurance companies and other sources. INTERVENTIONS: This study uses either care-as-usual alone (control) or a 12-week internet intervention (Deprexis) plus usual care (intervention). MAIN OUTCOME MEASURES: The primary outcome measure was self-rated depression severity (Patient Health Questionnaire-9) at 3 months and 6 months. Further measures ranged from demographic and clinical parameters to a measure of attitudes towards internet interventions (Attitudes towards Psychological Online Interventions Questionnaire). RESULTS: The recruitment source was only associated with very few of the examined demographic and clinical characteristics. Compared with participants recruited from clinical sources, participants recruited through insurance companies were more likely to be employed. Clinically recruited participants were as severely affected as those from other recruitment sources but more sceptical of internet interventions. The effectiveness of the intervention was not differentially associated with recruitment source (treatment by recruitment source interaction=0.28, p=0.84). CONCLUSION: Our results support the hypothesis that the intervention we studied is effective across different recruitment sources including clinical settings. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT01636752. PMID- 28710213 TI - Feeding styles, parenting styles and snacking behaviour in children attending primary schools in multiethnic neighbourhoods: a cross-sectional study. AB - OBJECTIVE: The aim of the present study was to investigate whether feeding styles and parenting styles are associated with children's unhealthy snacking behaviour and whether the associations differ according to children's ethnic background. METHOD: Cross-sectional data from the population-based 'Water Campaign' study were used. Parents (n=644) of primary school children (6-13 years) completed a questionnaire covering sociodemographic characteristics, feeding style dimensions ('control over eating', 'emotional feeding', 'encouragement to eat' and 'instrumental feeding'), parenting style dimensions ('involvement' and 'strictness') and children's unhealthy snacking behaviour. Logistic regression analyses were performed to determine whether feeding styles and parenting styles were associated with children's unhealthy snacking behaviour. RESULT: Overall, children whose parents had a higher extent of 'control over eating' had a lower odds of eating unhealthy snacks more than once per day (OR, 0.57; 95% CI 0.42 to 0.76). Further stratified analysis showed that 'control over eating' was associated with less unhealthy snacking behaviour only in children with a Dutch (OR, 0.37; 95% CI 0.20 to 0.68) or a Moroccan/Turkish (OR, 0.44; 95% CI 0.25 to 0.77) ethnic background. 'Encouragement to eat' was associated with a lower odds of eating unhealthy snacks every day in children with a Dutch ethnic background only (OR, 0.48; 95% CI 0.25 to 0.90). 'Instrumental feeding' was associated with a higher odds of eating unhealthy snacks more than once a day in children with a Moroccan/Turkish ethnic background only (OR, 1.43; 95% CI 1.01 to 2.04). CONCLUSION: Our results suggest that 'control over eating' may be associated with less unhealthy snack consumption in children. The associations of feeding styles and parenting styles with children's unhealthy snacking behaviour differed between children with different ethnic backgrounds. PMID- 28710214 TI - Trends and factors in human immunodeficiency virus and/or hepatitis C virus testing and infection among injection drug users newly entering methadone maintenance treatment in Guangdong Province, China 2006-2013: a consecutive cross sectional study. AB - OBJECTIVES: To assess trends and related factors in HIV and/or hepatitis C virus (HCV) antibody testing and infection among injection drug users (IDUs) newly entering methadone maintenance treatment (MMT) in Guangdong Province, China. METHOD: Consecutive cross sectional surveys were conducted in 14 MMT clinics from July 2006 to December 2013 in Guangdong Province, China. IDUs were excluded if they were re-enrolled or referred from other MMT clinics. Trend tests were used to examine HIV and/or HCV testing and infection, sociodemographic characteristics, drug use related behaviours and the past 3 month sexual behaviours on enrolment. Multivariate logistic regression was used to identify correlates of HIV and/or HCV testing and infection. RESULTS: 7539 IDUs with an average age of 35.6+/-6.2 years were newly enrolled with a history of injection for an average of 11.8+/-4.9 years. The average frequency of injection before enrolment had been increasing. HIV, HCV and HIV/HCV dual testing increased from 2006 to 2013 (ptrend<0.001). However, all three types of infections remained stable (ptrend>0.05) until reaching a peak in 2011, excluding the first year. Associating with fellow drug users 1-4 times during the past month, injecting for 15+ years and having multiple sexual partners during the past 3 months predicted higher percentages for HIV and/or HCV testing (p<0.05), while those injecting 4+ times per day in the past month and those who had ever shared needles were less likely to take both tests (p<0.05). Having multiple sexual partners, a longer duration of injection drug use and sharing needles or sharing more frequently were major risk factors for HIV, HCV and HIV/HCV co-infection (p<0.05). CONCLUSIONS: The prevalence of HIV and HCV were high and quite stable among new IDU entrants in MMT. Publicising MMT, routine screening, and behavioural and structural interventions is needed. PMID- 28710215 TI - A study protocol for an observational cohort investigating COGnitive outcomes and WELLness in survivors of critical illness: the COGWELL study. AB - INTRODUCTION: Up to 9 out of 10 intensive care unit (ICU) survivors will suffer some degree of cognitive impairment at hospital discharge and approximately half will have decrements that persist for years. The mechanisms for this newly acquired brain injury are poorly understood. The purpose of this study is to describe the prevalence of sleep abnormalities and their association with cognitive impairment, examine a well-known genetic risk factor for dementia (Apolipoprotein E epsilon4) that may allow for genetic risk stratification of ICU survivors at greatest risk of cognitive impairment and determine if electroencephalography (EEG) is an independent predictor of long-term cognitive impairment and possibly a candidate intermediate end point for future clinical trials. METHODS AND ANALYSIS: This is a multisite, prospective, observational cohort study. The setting for this trial will be medical and surgical ICUs of five large tertiary care referral centres. The participants will be adult patients admitted to a study ICU and invasively ventilated for >=3 days . Participants will undergo follow-up within 7 days of ICU discharge, 6 months and 1 year. At each time point, patients will have an EEG, blood work (biomarkers; gene studies), sleep study (actigraphy), complete a number of questionnaires as well as undergo neuropsychological testing. The primary outcome of this study will be long-term cognitive function at 12 months follow-up as measured by the Repeatable Battery for the Assessment of Neuropsychological Status and Trails Making Test B. ETHICS AND DISSEMINATION: The study has received the following approvals: University Health Network Research Ethics Committee (13-6425-BE), Sunnybrook Health Centre Research Ethics Committee (365-2013), Mount Sinai Research Ethics Committee (14-0194-E) and St. Michael's Hospital Research Ethics Committee (14-295). Results will be made available to critical care survivors, their caregivers, the funders, the critical care societies and other researchers. TRIAL REGISTRATION NUMBER: NCT02086877; Pre-results. PMID- 28710216 TI - Lag time for retinoblastoma in the UK revisited: a retrospective analysis. AB - OBJECTIVES: To explore current delays in diagnosis of retinoblastoma (Rb) and effect on outcome with comparison to a study from the 1990s. SETTING: Primary, secondary, tertiary care: majority from South of England. PARTICIPANTS: A retrospective analysis of 93 new referrals of sporadic (non-familial) Rb to a specialist Rb unit in London, UK from January 2006 to February 2014. PRIMARY AND SECONDARY OUTCOMES: International Intraocular Retinoblastoma Classification, lag times including parental delay and healthcare professional delay, patients requiring enucleation and requirement of adjuvant chemotherapy postenucleation (high-risk Rb). RESULTS: During the study period, 29% presented via accident and emergency (A&E). The median referral time from symptom onset to visiting primary care (PC) was 28 days and PC to ophthalmologist 3 days (range 0-181 days). The median time from local ophthalmologist to the Rb Unit was 6 days (0-33). No significant correlation was found between delay and International Classification of Retinoblastoma grade (p>0.05) or between postenucleation adjuvant chemotherapy and enucleation groups (p>0.05). Less enucleations (60%) are being performed compared with the previous study (81%) (p=0.0015). CONCLUSIONS: Parents are attending A&E more compared with the 1990s and this may reflect the effect of public awareness campaigns. More eyes are being salvaged despite a similar number of children requiring adjuvant chemotherapy. High-risk Rb and Group E eyes do not correlate with increased lag time in the UK. Other determinants such as tumour biology may be more relevant. PMID- 28710217 TI - Causes of death in patients with Itai-itai disease suffering from severe chronic cadmium poisoning: a nested case-control analysis of a follow-up study in Japan. AB - OBJECTIVE: To clarify the causes of deaths among patients with Itai-itai disease and severe cadmium (Cd) poisoning. DESIGN: Nested case-control analysis of a population-based cohort study. SETTING: Database of patients with Itai-itai disease and residents of Cd-polluted areas, maintained by the Ministry of Environment, Japan. PARTICIPANTS: Subjects included 142 women with Itai-itai disease, 111 women with Cd-induced renal tubular dysfunction and 253 controls matched for sex, age and occupation. All subjects participated in a health impact survey between 1979 and 1984 and were followed until 30 November 2005. MAIN OUTCOMES AND MEASURES: Adjusted HRs with 95% CIs for cause of death in women with Itai-itai disease and screened female cases with tubular dysfunction were compared with matched pair controls, using Cox's proportional hazard model. Vital statistics data were used to determine cause of death. Direct causes of death from autopsy records were used in 29 patients who died from Cd poisoning. RESULTS: The most common cause of death among patients with Itai-itai disease was pneumonia, with a significantly increased adjusted HR of 4.54 (95% CI 2.65 to 7.76). Renal diseases were the most common cause of death in renal tubular dysfunction cases, with an increased HR of 12.0 (95% CI 3.92 to 36.8). The adjusted HR for renal diseases was also significantly increased in patients with Itai-itai disease (19.49 (95% CI 6.43 to 59.09)), with a greater impact on mortality of patients with Itai-itai disease than screened cases. The HR for gastrointestinal (GI) diseases was significantly increased (13.79 (95% CI 3.87 to 49.10)) in patients, especially in the first 10 years (37.1 (4.81 to 286.0)). CONCLUSIONS: Among patients with Itai-itai disease, pneumonia and GI diseases contributed to increased mortality risk. Renal disease is also a significant mortality risk in patients with Itai-itai disease and women with renal tubular dysfunction. PMID- 28710218 TI - Assessing the medium-term impact of a home-visiting programme on child maltreatment in England: protocol for a routine data linkage study. AB - INTRODUCTION: Child maltreatment involves acts of omission (neglect) or commission (abuse) often by caregivers that results in potential or actual harm to a child. The Building Blocks trial (ISRCTN23019866) assessed the short-term impact of an intensive programme of antenatal and postnatal visiting by specially trained nurses to support young pregnant women in England. The Building Blocks: 2 6 Study will assess the medium-term impacts of the programme for mothers and children (n=1562), through the linkage of routinely collected data to the trial data, with a particular emphasis on the programme's impact on preventing child maltreatment. METHODS AND ANALYSIS: We have developed a bespoke model of data linkage whereby outcome data for the trial cohort will be retrieved by linked anonymous data abstraction from NHS Digital, Office for National Statistics and the Department for Education's National Pupil Database. Participants will be given reasonable opportunity to opt out of this study prior to data transfer. The information centres will match participants to the information held in their databases using standard identifiers and send extracts to a third-party safe haven. The study will have 80% power to detect a 4% difference (4%vs8%) for the binary primary outcome of child in need status (from birth to key stage 1) at a two-sided 5% alpha level by following up 602 children in each trial arm. Analysis will be by intention to treat using logistic multilevel modelling. A cost-and consequences analysis will extend the time frame of the economic analysis from the original trial. ETHICS AND DISSEMINATION: The study protocol has been approved by the National Health Service Wales Research Ethics Committee and the Health Research Authority's Confidentiality Advisory Group. Methods of innovative study design and findings will be disseminated through peer-reviewed journals and conferences; results will be of interest to clinical and policy stakeholders in the UK. TRIAL REGISTRATION NUMBER: ISRCTN23019866. PMID- 28710220 TI - Let's Talk about Children Evaluation (LTCE) study in northern Finland: a multiple group ecological study of children's health promotion activities with a municipal and time-trend design. AB - INTRODUCTION: Making change towards child and family-based and coordinated services is critical to improve quality, outcomes and value. The Let's Talk about Children (LTC) approach, which consists of brief psychoeducational discussions with parents of kindergarten-aged and school-aged children, has been launched as a municipality-specific programme in the Council of Oulu Region. The aim of this paper is to present a protocol of an ecological study evaluating the group specific effects of an intervention about LTC activities in a geographically defined population. The programme is designed to promote children's socioemotional well-being. METHODS AND ANALYSIS: A quasi-experimental ecological study protocol is implemented to evaluate whether systematic LTC practices improve children's well-being. A multi-informant setting covers 30 municipalities in northern Finland and involves all the municipal teachers, social and healthcare workers. In each municipality, a Local Management Team is responsible for implementing the LTC programme and collecting the annual data of LTC discussions and network meetings. The outcome data are retrieved from child welfare statistics and hospital registers. The population data, child welfare statistics and referrals to hospitals was retrieved at baseline (2014), and will be retrieved annually. Furthermore, the annual data of LTC discussions and network meetings will be collected of the years 2015-2018. ETHICS AND DISSEMINATION: The study design has been approved by the management of the Oulu University Hospital in accordance with the guidelines given by The Regional Ethics Committee of the Northern Ostrobothnia Hospital District in Oulu, Finland. All data are treated and implemented according to national data security laws. Study findings will be disseminated to provincial and municipal partners, collaborative community groups and the research and development community. The Let's Talk about Children Evaluation study databases will guide future regional development action and policies. PMID- 28710219 TI - Comparison of propofol and dexmedetomidine infused overnight to treat hyperactive and mixed ICU delirium: a protocol for the Basel ProDex clinical trial. AB - BACKGROUND/OBJECTIVES: Delirium is a neurobehavioural disturbance that frequently develops particularly in the intensive care unit (ICU) population. It was first described more than half a century ago, where it was already discovered as a state that might come along with serious complications such as prolonged ICU and hospital stay, reduced quality of life and increased mortality. However, in most cases, there is still lack of proof for causal relationship. Its presence frequently remains unrecognised due to suggested predominance of the hypoactive form. Furthermore, in the general ICU population, it has been shown that the duration of delirium is associated with worse long-term cognitive function. Due to the multifactorial origin of delirium, we have several but no incontestable treatment options. Nonetheless, delirium bears a high burden for patient, family members and the medical care team.The Basel ProDex Study targets improvement of hyperactive and mixed delirium therapy in critically ill patients. We will focus on reducing the duration and severity of delirium by implementing dexmedetomidine into the treatment plan. Dexmedetomidine compared with other sedatives shows fewer side effects representing a better risk profile for delirium treatment in general. This could further contribute to higher patient safety.The aim of the BaProDex Trial is to assess the superiority of dexmedetomidine to propofol for treatment of hyperactive and mixed delirium in the ICU. We hypothesise that dexmedetomidine, compared with propofol administered at night, shortens both the duration and severity of delirium. METHODS/DESIGN: The Basel ProDex Study is an investigator-initiated, one-institutional, two-centre randomised controlled clinical trial for the treatment of delirium with dexmedetomidine versus propofol in 316 critically ill patients suffering from hyperactive and mixed delirium. The primary outcome measure is delirium duration in hours. Secondary outcomes include delirium-free days at day 28, death at day 28, delirium severity, amount of ventilator days, amount of rescue sedation with haloperidol, length of ICU and hospital stay, and pharmaceutical economic analysis of the treatments. Sample size was estimated to be able to show the superiority of dexmedetomidine compared with propofol regarding the duration of delirium in hours. The trial will be externally monitored according to good clinical practice (GCP) requirements. There are no interim analyses planned for this trial. ETHICS AND DISSEMINATION: This study will be conducted in compliance with the protocol, the current version of the Declaration of Helsinki, the International Conference on Harmonization- Good Clinical Practice (ICH-GCP) or Europaische Norm International Organization for Standardization (ISO EN 14155; as far as applicable) as well as all national legal and regulatory requirements. Only the study team will have access to trial specific data. Anonymisation will be achieved by a unique patient identification code. Trial data will be archived for a minimum of 10 years after study termination. We plan to publish the data in a major peer-reviewed clinical journal. TRIALS REGISTRATION: ClinicalTrials.gov Identifier: NCT02807467 PROTOCOL VERSION: Clinical Study Protocol Version 2, 16.08.2016. PMID- 28710221 TI - Trends in readmission rates for safety net hospitals and non-safety net hospitals in the era of the US Hospital Readmission Reduction Program: a retrospective time series analysis using Medicare administrative claims data from 2008 to 2015. AB - OBJECTIVE: To compare trends in readmission rates among safety net and non-safety net hospitals under the US Hospital Readmission Reduction Program (HRRP). DESIGN: A retrospective time series analysis using Medicare administrative claims data from January 2008 to June 2015. SETTING: We examined 3254 US hospitals eligible for penalties under the HRRP, categorised as safety net or non-safety net hospitals based on the hospital's proportion of patients with low socioeconomic status. PARTICIPANTS: Admissions for Medicare fee-for-service patients, age >=65 years, discharged alive, who had a valid five-digit zip code and did not have a principal discharge diagnosis of cancer or psychiatric illness were included, for a total of 52 516 213 index admissions. PRIMARY AND SECONDARY OUTCOME MEASURES: Mean hospital-level, all-condition, 30-day risk-adjusted standardised unplanned readmission rate, measured quarterly, along with quarterly rate of change, and an interrupted time series examining: April-June 2010, after HRRP was passed, and October-December 2012, after HRRP penalties were implemented. RESULTS: 58.0% (SD 15.3) of safety net hospitals and 17.1% (SD 10.4) of non-safety net hospitals' patients were in the lowest quartile of socioeconomic status. The mean safety net hospital standardised readmission rate declined from 17.0% (SD 3.7) to 13.6% (SD 3.6), whereas the mean non-safety net hospital declined from 15.4% (SD 3.0) to 12.7% (SD 2.5). The absolute difference in rates between safety net and non safety net hospitals declined from 1.6% (95% CI 1.3 to 1.9) to 0.9% (0.7 to 1.2). The quarterly decline in standardised readmission rates was 0.03 percentage points (95% CI 0.03 to 0.02, p<0.001) greater among safety net hospitals over the entire study period, and no differential change among safety net and non-safety net hospitals was found after either HRRP was passed or penalties enacted. CONCLUSIONS: Since HRRP was passed and penalties implemented, readmission rates for safety net hospitals have decreased more rapidly than those for non-safety net hospitals. PMID- 28710222 TI - A developmental evaluation to enhance stakeholder engagement in a wide-scale interactive project disseminating quality improvement data: study protocol for a mixed-methods study. AB - INTRODUCTION: Bringing together continuous quality improvement (CQI) data from multiple health services offers opportunities to identify common improvement priorities and to develop interventions at various system levels to achieve large scale improvement in care. An important principle of CQI is practitioner participation in interpreting data and planning evidence-based change. This study will contribute knowledge about engaging diverse stakeholders in collaborative and theoretically informed processes to identify and address priority evidence practice gaps in care delivery. This paper describes a developmental evaluation to support and refine a novel interactive dissemination project using aggregated CQI data from Aboriginal and Torres Strait Islander primary healthcare centres in Australia. The project aims to effect multilevel system improvement in Aboriginal and Torres Strait Islander primary healthcare. METHODS AND ANALYSIS: Data will be gathered using document analysis, online surveys, interviews with participants and iterative analytical processes with the research team. These methods will enable real-time feedback to guide refinements to the design, reports, tools and processes as the interactive dissemination project is implemented. Qualitative data from interviews and surveys will be analysed and interpreted to provide in depth understanding of factors that influence engagement and stakeholder perspectives about use of the aggregated data and generated improvement strategies. Sources of data will be triangulated to build up a comprehensive, contextualised perspective and integrated understanding of the project's development, implementation and findings. ETHICS AND DISSEMINATION: The Human Research Ethics Committee (HREC) of the Northern Territory Department of Health and Menzies School of Health Research (Project 2015-2329), the Central Australian HREC (Project 15-288) and the Charles Darwin University HREC (Project H15030) approved the study. Dissemination will include articles in peer-reviewed journals, policy and research briefs. Results will be presented at conferences and quality improvement network meetings. Researchers, clinicians, policymakers and managers developing evidence-based system and policy interventions should benefit from this research. PMID- 28710223 TI - Sociodemographic differences in women's experience of early labour care: a mixed methods study. AB - OBJECTIVES: To explore women's experiences of early labour care focusing on sociodemographic differences, and to examine the effect of antenatal education, using mixed methods. SETTING: England, 2014. PARTICIPANTS: Women who completed postal questionnaires about their experience of maternity care, including questions about antenatal education, early labour and sociodemographic factors, included space for free-text comments. OUTCOME MEASURES: Worries about labour, contact with midwives in early labour and subsequent care. METHODS: This study was based on secondary analysis of a national maternity survey carried out in England in 2014. Quantitative data were analysed using descriptive statistics and binary logistic regression; qualitative data were analysed using a thematic content analytic approach. RESULTS: Completed questionnaires were received from 4578 women (47% response rate). There were significant differences by sociodemographic factors, particularly ethnicity, in women's worries about early labour. Compared with white women, women from black or minority ethnic groups had an adjusted OR of 1.93 (95% CI 1.56 to 2.39) of feeling worried about not knowing when labour would start. Among women who contacted a midwife at the start of labour, 84% perceived their advice as appropriate, more in older and multiparous women. Overall, 64% of women were asked to come to the hospital at this time, more in multiparous women (adjusted OR 1.63, 95% CI 1.35 to 1.96). Those who did not have access to antenatal education experienced greater worry about early labour. Five themes emerged from the qualitative analysis: 'Differentiating between early and active labour', 'Staff attitudes', 'Not being allowed...', 'Previous labours' and 'Perceived consequences for women'. CONCLUSION: These findings reinforce the importance of providing reassurance to women in early labour, taking care that women do not feel neglected or dismissed. In particular, primiparous and ethnic minority women reported greater worry about early labour and require additional reassurance. PMID- 28710224 TI - Assessing the effectiveness of a 3-month day-and-night home closed-loop control combined with pump suspend feature compared with sensor-augmented pump therapy in youths and adults with suboptimally controlled type 1 diabetes: a randomised parallel study protocol. AB - INTRODUCTION: Despite therapeutic advances, many individuals with type 1 diabetes are unable to achieve tight glycaemic target without increasing the risk of hypoglycaemia. The objective of this study is to determine the effectiveness of a 3-month day-and-night home closed-loop glucose control combined with a pump suspend feature, compared with sensor-augmented insulin pump therapy in youths and adults with suboptimally controlled type 1 diabetes. METHODS AND ANALYSIS: The study adopts an open-label, multi-centre, multi-national (UK and USA), randomised, single-period, parallel design and aims for 84 randomised patients. Participants are youths (6-21 years) or adults (>21 years) with type 1 diabetes treated with insulin pump therapy and suboptimal glycaemic control (glycated haemoglobin (HbA1c) >=7.5% (58 mmol/mol) and <=10% (86 mmol/mol)). Following a 4 week run-in period, eligible participants will be randomised to a 3-month use of automated closed-loop insulin delivery combined with pump suspend feature or to sensor-augmented insulin pump therapy. Analyses will be conducted on an intention to-treat basis. The primary outcome is the time spent in the target glucose range from 3.9 to 10.0 mmol/L based on continuous glucose monitoring levels during the 3-month free-living phase. Secondary outcomes include HbA1c at 3 months, mean glucose, time spent below and above target; time with glucose levels <3.5 and <2.8 mmol/L; area under the curve when sensor glucose is <3.5 mmol/L, time with glucose levels >16.7 mmol/L, glucose variability; total, basal and bolus insulin dose and change in body weight. Participants' and their families' perception in terms of lifestyle change, daily diabetes management and fear of hypoglycaemia will be evaluated. ETHICS AND DISSEMINATION: Ethics/institutional review board approval has been obtained. Before screening, all participants/guardians will be provided with oral and written information about the trial. The study will be disseminated by peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER: NCT02523131; Pre-results. PMID- 28710225 TI - Examining the effectiveness of parental strategies to overcome bedwetting: an observational cohort study. AB - OBJECTIVE: To examine whether a range of common strategies used by parents to overcome bedwetting in 71/2-year-old children (including lifting, restricting drinks before bedtime, regular daytime toilet trips, rewards, showing displeasure and using protection pants) are effective in reducing the risk of bedwetting at 91/2 years. DESIGN: Prospective cohort study. SETTING: General community. PARTICIPANTS: The starting sample included 1258 children (66.7% boys and 33.2% girls) who were still bedwetting at 71/2 years. OUTCOME MEASURE: Risk of bedwetting at 91/2 years. RESULTS: Using propensity score-based methods, we found that two of the parental strategies used at 71/2 years were associated with an increased risk of bedwetting at 91/2 years, after adjusting the model for child and family variables and other parental strategies: lifting (risk difference=0.106 (95% CI 0.009 to 0.202), ie, there is a 10.6% (0.9% to 20.2%) increase in risk of bedwetting at 91/2 years among children whose parents used lifting compared with children whose parents did not use this strategy) and restricting drinks before bedtime (0.123 (0.021 to 0.226)). The effect of using the other parental strategies was in either direction (an increase or decrease in the risk of bedwetting at 91/2 years), for example, showing displeasure (-0.052 ( 0.214 to 0.110)). When we re-analysed the data using multivariable regression analysis, the results were mostly consistent with the propensity score-based methods. CONCLUSION: These findings provide evidence that common strategies used to overcome bedwetting in 71/2-year-olds are not effective in reducing the risk of bedwetting at 91/2 years. Parents should be encouraged to seek professional advice for their child's bedwetting rather than persisting with strategies that may be ineffective. PMID- 28710226 TI - Evaluating the predictive strength of the LACE index in identifying patients at high risk of hospital readmission following an inpatient episode: a retrospective cohort study. AB - OBJECTIVE: To assess how well the LACE index and its constituent elements predict 30-day hospital readmission, and to determine whether other combinations of clinical or sociodemographic variables may enhance prognostic capability. DESIGN: Retrospective cohort study with split sample design for model validation. SETTING: One large hospital Trust in the West Midlands. PARTICIPANTS: All alive discharge adult inpatient episodes between 1 January 2013 and 31 December 2014. DATA SOURCES: Anonymised data for each inpatient episode were obtained from the hospital information system. These included age at index admission, gender, ethnicity, admission/discharge date, length of stay, treatment specialty, admission type and source, discharge destination, comorbidities, number of accident and emergency (A&E) visits in the 6 months before the index admission and whether a patient was readmitted within 30 days of index discharge. OUTCOME MEASURES: Clinical and patient characteristics of readmission versus non readmission episodes, proportion of readmission episodes at each LACE score, regression modelling of variables associated with readmission to assess the effectiveness of LACE and other variable combinations to predict 30-day readmission. RESULTS: The training cohort included data on 91 922 patient episodes. Increasing LACE score and each of its individual components were independent predictors of readmission (area under the receiver operating characteristic curve (AUC) 0.773; 95% CI 0.768 to 0.779 for LACE; AUC 0.806; 95% CI 0.801 to 0.812 for the four LACE components). A LACE score of 11 was most effective at distinguishing between higher and lower risk patients. However, only 25% of readmission episodes occurred in the higher scoring group. A model combining A&E visits and hospital episodes per patient in the previous year was more effective at predicting readmission (AUC 0.815; 95% CI 0.810 to 0.819). CONCLUSIONS: Although LACE shows good discriminatory power in statistical terms, it may have little added value over and above clinical judgement in predicting a patient's risk of hospital readmission. PMID- 28710228 TI - Longitudinal qualitative study describing family physicians' experiences with attempting to integrate physical activity prescriptions in their practice: 'It's not easy to change habits'. AB - OBJECTIVE: Physical activity (PA) prescriptions provided by family physicians can promote PA participation among patients, but few physicians regularly write PA prescriptions. The objective of this study was to describe family physicians' experiences of trying to implement written PA prescriptions into their practice. DESIGN: Longitudinal qualitative study where participants were interviewed four times during a 12-month period. After the first interview, they were provided with PA prescription pads. Data were analysed using thematic analysis. SETTING: Family medicine clinics in New Brunswick, Canada. PARTICIPANTS: Family physicians (n=11) with no prior experience writing PA prescriptions, but who expressed interest in changing their practice to implement written PA prescriptions. RESULTS: Initially, participants exhibited confidence in their ability to write PA prescriptions in the future and intended to write prescriptions. However, data from the follow-up interviews indicated that the rate of implementation was lower than anticipated by participants and prescriptions were not part of their regular practice. Two themes emerged as factors explaining the gap between their intentions and behaviours: (1) uncertainty about the effectiveness of written PA prescription, and (2) practical concerns (eg, changing well-established habits, time constraints, systemic institutional barriers). CONCLUSION: It may be effective to increase awareness among family physicians about the effectiveness of writing PA prescriptions and address barriers related to how their practice is organised in order to promote written PA prescription rates. PMID- 28710227 TI - Advancing Concussion Assessment in Pediatrics (A-CAP): a prospective, concurrent cohort, longitudinal study of mild traumatic brain injury in children: protocol study. AB - INTRODUCTION: Paediatric mild traumatic brain injury (mTBI) is a public health burden. Clinicians urgently need evidence-based guidance to manage mTBI, but gold standards for diagnosing and predicting the outcomes of mTBI are lacking. The objective of the Advancing Concussion Assessment in Pediatrics (A-CAP) study is to assess a broad pool of neurobiological and psychosocial markers to examine associations with postinjury outcomes in a large sample of children with either mTBI or orthopaedic injury (OI), with the goal of improving the diagnosis and prognostication of outcomes of paediatric mTBI. METHODS AND ANALYSIS: A-CAP is a prospective, longitudinal cohort study of children aged 8.00-16.99 years with either mTBI or OI, recruited during acute emergency department (ED) visits at five sites from the Pediatric Emergency Research Canada network. Injury information is collected in the ED; follow-up assessments at 10 days and 3 and 6 months postinjury measure a variety of neurobiological and psychosocial markers, covariates/confounders and outcomes. Weekly postconcussive symptom ratings are obtained electronically. Recruitment began in September 2016 and will occur for approximately 24 months. Analyses will test the major hypotheses that neurobiological and psychosocial markers can: (1) differentiate mTBI from OI and (2) predict outcomes of mTBI. Models initially will focus within domains (eg, genes, imaging biomarkers, psychosocial markers), followed by multivariable modelling across domains. The planned sample size (700 mTBI, 300 OI) provides adequate statistical power and allows for internal cross-validation of some analyses. ETHICS AND DISSEMINATION: The ethics boards at all participating institutions have approved the study and all participants and their parents will provide informed consent or assent. Dissemination will follow an integrated knowledge translation plan, with study findings presented at scientific conferences and in multiple manuscripts in peer-reviewed journals. PMID- 28710229 TI - PIRATE project: point-of-care, informatics-based randomised controlled trial for decreasing overuse of antibiotic therapy in Gram-negative bacteraemia. AB - INTRODUCTION: Antibiotic overuse drives antibiotic resistance. The optimal duration of antibiotic therapy for Gram-negative bacteraemia (GNB), a common community and hospital-associated infection, remains unknown and unstudied via randomised controlled trials (RCTs). METHODS AND ANALYSIS: This investigator initiated, multicentre, non-inferiority, informatics-based point-of-care RCT will randomly assign adult hospitalised patients receiving microbiologically efficacious antibiotic(s) for GNB to (1) 14 days of antibiotic therapy, (2) 7 days of therapy or (3) an individualised duration determined by clinical response and 75% reduction in peak C reactive protein (CRP) values. The randomisation will occur in equal proportions (1:1:1) on day 5 (+/-1) of efficacious antibiotic therapy as determined by antibiogram; patients, their physicians and study investigators will be blind to treatment duration allocation until the day of antibiotic discontinuation. Immunosuppressed patients and those with GNB due to complicated infections (endocarditis, osteomyelitis, etc) and/or non-fermenting bacilli (Acinetobacter spp, Burkholderia spp, Pseudomonas spp) Brucella spp, Fusobacterium spp or polymicrobial growth with Gram-positive organisms will be ineligible. The primary outcome is incidence of clinical failure at day 30; secondary outcomes include clinical failure, all-cause mortality and incidence of Clostridiumdifficile infection in the 90-day study period. An interim safety analysis will be performed after the first 150 patients have been followed for <=30 days. Given a chosen margin of 10%, the required sample size to determine non-inferiority is roughly 500 patients. Analyses will be performed on both intention-to-treat and per-protocol populations. ETHICS AND DISSEMINATION: Ethics approval was obtained from the cantonal ethics committees of all three participating sites. Results of the main trial and each of the secondary endpoints will be submitted for publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: This trial is registered at www.clinicaltrials.gov (NCT03101072; pre-results). PMID- 28710230 TI - The Tissue-Reconstructing Ability of Colon CSCs Is Enhanced by FK506 and Suppressed by GSK3 Inhibition. AB - Cancer stem cells (CSC) are capable of reconstructing cancer tissues, are involved in both recurrence and metastasis, and contribute to therapeutic resistance. Therefore, elucidating the molecular mechanism in CSCs is important to successfully treat unresectable cancers. Previously, we observed that colon cancer stem-like cells can be induced from human colon cancer cell lines by retrovirally introducing OCT3/4, SOX2, and KLF4, and we have designated such cells as induced cancer stem cells (iCSC). In the current study, we used iCSCs to evaluate the molecular mechanism of colon CSCs and developed new methods to control them. The spheres that were derived in vitro from the iCSCs, but not those from parental cells, mimicked human colon cancer tissues in terms of their immunohistologic patterns; therefore, sphere-forming ability was assessed as a measure of the tissue-reconstructing ability of iCSCs. Interestingly, the calcineurin inhibitor FK506 enhanced the sphere-forming ability of iCSCs, whereas GSK3 inhibition by RNAi, CHIR99021, and valproic acid (VPA) impeded the sphere forming ability and expansion of iCSCs. FK506 and GSK3 inhibition showed the opposite effect regarding the NFATc3 localization of iCSCs. These data reveal the crucial role that NFAT localization, as regulated by calcineurin and GSK3, plays in the tissue-reconstructing ability of colon cancer stem cells and the potential of GSK3 inhibitors, such as VPA, in colon cancer stem cell-targeting therapy.Implications: This study identifies signaling pathways that contribute to the tissue-reconstructing capacity of colon CSCs and suggests that clinically used drugs could be repurposed to improve unresectable colon cancers. Mol Cancer Res; 15(10); 1455-66. (c)2017 AACR. PMID- 28710232 TI - Young people with diabetes show no drop in admission rates, audit finds. PMID- 28710231 TI - Tuberin Regulates Prostaglandin Receptor-Mediated Viability, via Rheb, in mTORC1 Hyperactive Cells. AB - Tuberous sclerosis complex (TSC) is a tumor-suppressor syndrome affecting multiple organs, including the brain, skin, kidneys, heart, and lungs. TSC is associated with mutations in TSC1 or TSC2, resulting in hyperactivation of mTOR complex 1 (mTORC1). Clinical trials demonstrate that mTORC1 inhibitors decrease tumor volume and stabilize lung function in TSC patients; however, mTOR inhibitors are cytostatic not cytocidal, and long-term benefits and toxicities are uncertain. Previously, we identified rapamycin-insensitive upregulation of cyclooxygenase 2 (PTGS2/COX2) and prostaglandin E2 (PGE2) production in TSC2 deficient cells and postulated that the action of excess PGE2 and its cognate receptors (EP) contributes to cell survival. In this study, we identify upregulation of EP3 (PTGER3) expression in TSC2-deficient cells, TSC renal angiomyolipomas, lymphangioleiomyomatosis lung nodules, and epileptic brain tubers. TSC2 negatively regulated EP3 expression via Rheb in a rapamycin insensitive manner. The EP3 antagonist, L-798106, selectively suppressed the viability of TSC2-deficient cells in vitro and decreased the lung colonization of TSC2-deficient cells. Collectively, these data reveal a novel function of TSC2 and Rheb in the regulation of EP3 expression and cell viability.Implications: Therapeutic targeting of an aberrant PGE2-EP3 signaling axis may have therapeutic benefit for TSC patients and for other mTOR-hyperactive neoplasms. Mol Cancer Res; 15(10); 1318-30. (c)2017 AACR. PMID- 28710233 TI - Venobiliary fistula with haemobilia: a rare complication of percutaneous liver biopsy. AB - We describe a case of a 36-year-old man with a history of chronic hepatitis C who presented with abdominal pain 3 days after undergoing a percutaneous ultrasound guided liver biopsy. Initial investigations revealed a venobiliary fistula with haemobilia and obstructive jaundice with direct bilirubin peaking at 9.2 mg/dL. He underwent an endoscopic retrograde cholangiopancreatography with sphincterotomy and stent placement, bilirubin decreased to 3.7 mg/dL, and the patient was discharged. The patient returned with recurrent abdominal pain and upper gastrointestinal bleeding with haemoglobin of 8.6 g/dL, requiring multiple transfusions. He underwent transcatheter arterial embolisation but continued bleeding. Radiofrequency ablation was pursued and was able to achieve haemostasis. The patient was discharged. The patient returned again with a fever of 39.2 degrees C and was found to have a large right hepatic lobe abscess. The patient underwent abscess drainage with drain placement and was treated with antibiotics for 6 weeks. He followed up in the clinic with resolution of symptoms and infection. PMID- 28710235 TI - Renal fistulae: different aetiologies, similar management. AB - Iatrogenic renocolic fistulae, although have been described in literature, is a rare clinical complication. Recently its incidence is on rise due to advent of minimally invasive surgery and percutaneous surgery of kidney. It has been reported after percutaneous nephrolithotomy but its incidence after percutaneous nephrostomy is quite uncommon and rarely reported. Though spontaneous renocutaneous fistula has been reported, acquired renocutaneous fistula is very uncommon and fistula after gun shot injury has not been reported to the best of our knowledge. Herein, we present two different varieties of renal fistula with completely different history and presentation. But the interesting point is that both were managed conservatively in a similar fashion and both of them responded well. PMID- 28710234 TI - Takotsubo cardiomyopathy and transient global amnesia: a shared aetiology. AB - Takotsubo cardiomyopathy (TTC) is associated with acute, reversible left ventricular (LV) dysfunction, while transient global amnesia (TGA) is a reversible disorder of the brain characterised by anterograde amnesia. We report an unusual case of TTC occurring concurrently in a patient with TGA, and propose that catecholamine surge induced cerebral venous congestion and cardiotoxicity is the shared aetiology that leads to the concurrent manifestation of these conditions. TTC and TGA are reversible disorders that can occur concurrently in a subset of patients due to a unifying aetiology, catecholamine excess, leading to pathophysiological changes within the brain and the myocardium. PMID- 28710236 TI - Complement factor B mutation-associated aHUS and myocardial infarction. AB - A 6-month-old female infant was referred with a 3-day history of low-grade fever, slight nasal congestion and rhinorrhoea. On admission, the clinical findings were unremarkable and she was discharged home. However, she became progressively more listless with a decreased urine output and was once again seen in the emergency department. Analytically she was found to have metabolic acidosis, hyperkalaemia, thrombocytopaenia, anaemia and schistocytes in the peripheral blood smear. Based on these findings, the diagnosis of haemolytica-uremic syndrome was made. A few hours postadmission, there was an abrupt clinical deterioration. She went into cardiorespiratory arrest and she was successfully resuscitated. An ST-segment elevation was noted on the ECG monitor and the troponin I levels were raised, suggesting myocardial infarction. Despite intensive supportive therapy, she went into refractory shock and died within 30 hours. PMID- 28710237 TI - Focal neurological presentation in Hashimoto's encephalopathy mimicking a vascular occlusion of the middle cerebral artery. AB - Hashimoto's encephalopathy is a rare form of autoimmune encephalopathy. It is likely an underdiagnosed entity especially in the setting of focal neurological defects. We report a case of a 49-year-old man who presented with "strange behavior"of a day's duration. Examination was significant only for lethargy, poor attention span and agitation. Routine labs revealed leucocytosis. Head CT scan was unremarkable. Lumbar puncture showed high white blood cells with lymphocytosis and elevated protein level. The patient was empirically treated for meningitis without improvement. His symptoms progressed to sudden right-sided weakness, ataxia and right facial droop. The MRI and magnetic resonance angiogram (MRA)were normal. The patienta?TMs focal neurological signs improved spontaneously. Encephalopathy work-up was negative except for positive anti Thyroid Peroxidaseand antithyroglobulin. The patient was treated as Hashimoto encephalopathy with steroids and azathioprine with marked improvement. Our case highlights how focal neurological findings can potentially mislead the provider to consider vascular aetiologies in Hashimoto's encephalopathy. PMID- 28710238 TI - Is FCH PET able to identify foci of infection superiorly to FDG PET? AB - We report a case of a brain abscess identified on fluorine-18 choline (FCH) positron emission tomography (PET) scan, which was not identified on fluorodeoxyglucose (FDG) PET scan. To our knowledge, there are no previous case reports of incidental brain abscess identified by FCH PET imaging. A 51-year-old man, with liver cirrhosis complicated by hepatocellular carcinoma (HCC) was enrolled in a research trial comparing HCC detection in FCH PET versus FDG PET. During the course of the trial, he underwent radiofrequency ablation (RFA) for HCC. A repeat FCH PET scan post-RFA incidentally revealed a 2.5a?0/00cm lesion with avid uptake in the left occipital area of the brain. The patient was asymptomatic. MRI suggested this was an abscess. A craniotomy and drainage was performed, with culture of Streptococcus intermedius (Smilleri group) from the thick-walled collection, a causative organism for previous episode of pneumonia. He successfully completed a 6 week course of antibiotics. PMID- 28710239 TI - Anaphylaxis secondary to Parietaria judaica (wall pellitory). AB - Aeroallergens are an unusual cause of anaphylaxis with sparse reports in the literature. We describe a case of suspected anaphylaxis to Parietaria judaica pollen and the difficulties encountered in confirming this diagnosis. PMID- 28710240 TI - A rare case of gastric mixed adenoneuroendocrine carcinoma (MANEC) with gastric Helicobacter pylori-negative mucosa-associated lymphoid tissue (MALT) lymphoma. PMID- 28710241 TI - Peritoneal tuberculosis as a cause of ascites in a patient with cirrhosis. AB - A 59-year-old Portuguese Caucasian man with a history of heavy alcohol intake and no significant medical history presented with ascites, weight loss and general malaise. The ascitic fluid analysis showed 921 cells/mm3 with mononuclear predominance (93.6%), elevated total proteins and a slightly elevated serum ascites albumin gradient. The abdominal ultrasound confirmed the presence of chronic liver disease with ascites, and additionally on CT there was evidence of peritoneal thickening. On repeat paracentesis, the ascitic fluid analysis showed elevated adenosine deaminase but it was negative for the presence of mycobacteria by Ziehl-Neelsen stain, Lowenstein-Jensen culture and PCR amplification. Due to the persistent suspicion of tuberculosis, a laparoscopy was performed showing multiple small white tubercles scattered over the peritoneum. Peritoneal biopsies showed the presence of necrotising granulomas and cultures were positive for Mycobacterium tuberculosis complex. After a 6-month course of tuberculostatics, the ascites resolved completely. The patient remained asymptomatic. PMID- 28710242 TI - Pseudomonas aeruginosa as an unusual cause of cavitating lung lesion. AB - A 31-year-old woman with systemic lupus erythematosus presented to the emergency department with cough for 1a?0/00week. Chest radiograph demonstrated cavitating lesion in the right upper zone with surrounding ground-glass change. Blood culture results from the day of hospital presentation grew Pseudomonas aeruginosa Sputum sample and pleural fluid grew P. aeruginosa and were negative for acid fast bacilli. P. aeruginosa is a rare cause of cavitating lung lesion and has been associated with immunocompromised hosts. Most reports of cavitating P. aeruginosa lesions have been identified in patients who are immunocompromised secondary to HIV.The current case highlights the potential for infection in patients who are immunosuppressed therapeutically and appropriate investigations are necessary to rule out common causes of cavitating lung lesions. PMID- 28710243 TI - External revascularisation for pseudochronic total occlusion of the dorsal pedis artery due to foot drop with severe diabetes mellitus. PMID- 28710244 TI - Lupus miliaris disseminatus faciei: a distinctive facial granulomatous eruption. AB - Facial granulomatous papules are important to recognise, as some of them are associated with significant systemic association, particularly sarcoidosis and certain infectious conditions. Lupus miliaris disseminatus faciei (LMDF) is a benign granulomatous disorder of unknown aetiology characterised by symmetrical, monomorphic, reddish-brown papules on the face. It is not associated with any underlying systemic involvement. We report a case of LMDF in a middle-aged man who presented to us with multiple asymptomatic and monomorphic reddish papules on the face for 3 months. Skin biopsy showed well-formed perifollicular epithelioid cell granulomas with focus of necrosis suggestive of LMDF. The lesions significantly responded to oral steroids. PMID- 28710245 TI - Abciximab-induced acute profound thrombocytopenia postpercutaneous coronary intervention. AB - Abciximab (c7E3 Fab) is one of the three potent intravenous glycoprotein IIb/IIIa receptor inhibitors (along with eptifibatide and tirofiban) that have shown significant positive outcomes when used in patients with intracoronary thrombus. However, major side effects have been reported with its use including hypotension, major bleeding and thrombocytopenia. This case is a 53-year-old man presenting with acute chest pain diagnosed with non-ST-elevation myocardial infarction, who underwent percutaneous coronary intervention with abciximab and heparin infusion and developed acute profound thrombocytopenia (platelet count <20,000/L) within 9 hours of infusion. This case demonstrates the importance of routinely monitoring the platelet count prior to and 2-4 hours following abciximab infusion and differentiating other causes of acute profound thrombocytopenia, particularly pseudothrombocytopenia and heparin-induced thrombocytopenia. PMID- 28710246 TI - Trajectories of Motor Recovery in the First Year After Pediatric Arterial Ischemic Stroke. AB - BACKGROUND: Neuromotor impairments are common after pediatric stroke, but little is known about functional motor outcomes. We evaluated motor function and how it changed over the first 12 months after diagnosis. We also examined differences in outcome according to age at diagnosis and whether fine motor (FM) or gross motor (GM) function at 12 months was associated with adaptive behavior. METHODS: This prospective, longitudinal study recruited children (N = 64) from The Royal Children's Hospital, Melbourne who were diagnosed with acute arterial ischemic stroke (AIS) between December 2007 and November 2013. Motor assessments were completed at 3 time points after the diagnosis of AIS (1, 6, and 12 months). Children were grouped as follows: neonates (n = 27), preschool-aged (n = 19), and school-aged (n = 18). RESULTS: A larger lesion size was associated with poorer GM outcomes at 12 months (P = .016). Neonatal AIS was associated with better FM and GM function initially but with a reduction in z scores over time. For the preschool- and school-aged groups, FM remained relatively stable over time. For GM outcomes, the preschool- and the school-aged age groups displayed similar profiles, with gradual recovery over time. Overall, poor FM and GM outcomes at 12 months were associated with poorer adaptive behavior scores. CONCLUSIONS: Motor outcomes and the trajectory of recovery post-AIS differed according to a child's age at stroke onset. These findings indicate that an individualized approach to surveillance and intervention may be needed that is informed in part by age at diagnosis. PMID- 28710247 TI - Congenital Diaphragmatic Hernia and Growth to 12 Years. AB - OBJECTIVES: Growth problems are reported in patients with congenital diaphragmatic hernia during the first years of life. However, it is unknown if poor growth persists during childhood. We therefore evaluated growth of patients longitudinally until 12 years of age. METHODS: This prospective study included 172 patients (43 treated with extracorporeal membrane oxygenation [ECMO]) born from 1999 to 2014. Z scores of height-for-age (HFA), weight-for-height, and distance-to-target height were calculated at 6 months of age and at 1, 2, 5, 8, and 12 years of age. Data were analyzed by using general linear models. RESULTS: At 1 year of age, the mean weight-for-height z score had declined in ECMO (-1.30, 95% confidence interval: -1.62 to -0.97) and non-ECMO patients (-0.72, 95% confidence interval: -0.91 to -0.54; P < .05). Thereafter in ECMO patients, the mean HFA z score deteriorated between 1 (-0.43, 95% confidence interval: -0.73 to -0.13) and 5 years of age (-1.08, 95% confidence interval: -1.38 to -0.78; P < .01). In non-ECMO patients, the mean HFA z score deteriorated between 2 (-0.35, 95% confidence interval: -0.53 to -0.17) and 5 years of age (-0.56, 95% confidence interval: -0.75 to -0.37; P = .002). At 12 years of age, the mean HFA z score was still less than the norm in both groups: ECMO (-0.67, 95% confidence interval: -1.01 to -0.33) versus non-ECMO (-0.49, 95% confidence interval: -0.77 to -0.20; P < .01). Adjusting for target height improved the mean height z scores but did not bring them to normal range. CONCLUSIONS: Poor linear growth persisted at 12 years of age. The pattern of early deterioration of weight gain followed by a decline in linear growth is suggestive of inadequate nutrition during infancy. Therefore, nutritional assessment and intervention should be started early and should be continued during childhood. PMID- 28710248 TI - MicroRNA-9 regulates fetal alcohol-induced changes in D2 receptor to promote prolactin production. AB - Fetal alcohol exposure (FAE) is known to increase prolactin (PRL) secretion from the pituitary lactotropes. In this study, we determined whether microRNAs (miRs) are involved in FAE-induced alteration in PRL release. We employed a rat animal model of FAE involving feeding pregnant Fisher 344 rats with a liquid diet containing 6.7% alcohol between gestational days 7-21 (AF). Both cyclic and estradiol-implanted FAE females showed increased levels of plasma PRL and pituitary Prl mRNA but reduced levels of pituitary dopamine D2 receptor (D2r) and its short spliced form (D2s). FAE increased the expression levels of miR-9 and miR-326 and did not produce any significant changes in miR-153 or miR-200a levels in the pituitary. Effects of FAE on miR-9 and miR-326 were associated with reduced levels of D2r and D2s, increased levels of Prl in the pituitary, and in plasma. These effects of FAE on D2r, D2s and Prl were enhanced following estradiol treatment. In PRL-producing MMQ cells, ethanol increased miR-9 but not miR-326, reduced levels of D2r and D2s and increased levels of Prl Treatment of MMQ cells with an anti-miR-9 oligo reduced ethanol effects on miR-9, D2r, D2s and Prl miR-9 mimic oligos reduced the luciferase activity of reporter vector containing D2r 3'UTR, but failed to reduce the mutant luciferase activity. These data suggest that FAE programs the pituitary to produce increased amounts of miR 9 expression that represses the D2r gene and its spliced variant D2s by targeting its 3'UTR leading to an increase in PRL production and secretion. PMID- 28710249 TI - Amyloid precursor protein in pancreatic islets. AB - The amyloid precursor protein (APP) has been extensively investigated for its role in the production of amyloid beta (Abeta), a plaque-forming peptide in Alzheimer's disease (AD). Epidemiological evidence suggests type 2 diabetes is a risk factor for AD. The pancreas is an essential regulator of blood glucose levels through the secretion of the hormones insulin and glucagon. Pancreatic dysfunction is a well-characterized consequence of type 1 and type 2 diabetes. In this study, we have examined the expression and processing of pancreatic APP to test the hypothesis that APP may play a role in pancreatic function and the pathophysiology of diabetes. Our data demonstrate the presence of APP within the pancreas, including pancreatic islets in both mouse and human samples. Additionally, we report that the APP/PS1 mouse model of AD overexpresses APP within pancreatic islets, although this did not result in detectable levels of Abeta. We compared whole pancreas and islet culture lysates by Western blot from C57BL/6 (WT), APP-/- and APP/PS1 mice and observed APP-dependent differences in the total protein levels of GLUT4, IDE and BACE2. Immunohistochemistry for BACE2 detected high levels in pancreatic alpha cells. Additionally, both mouse and human islets processed APP to release sAPP into cell culture media. Moreover, sAPP stimulated insulin but not glucagon secretion from islet cultures. We conclude that APP and its metabolites are capable of influencing the basic physiology of the pancreas, possibly through the release of sAPP acting in an autocrine or paracrine manner. PMID- 28710251 TI - Role for ZAP-70 Signaling in the Differential Effector Functions of Rituximab and Obinutuzumab (GA101) in Chronic Lymphocytic Leukemia B Cells. AB - Rituximab (RTX) has been the hallmark anti-CD20 mAb for the treatment of B cell neoplasms, including B cell chronic lymphocytic leukemia (B-CLL). Recently, a novel humanized anti-CD20 mAb obinutuzumab (GA101) has been implemented as first line CLL therapy. Treatment of CLL patients with RTX is associated with CD20 loss via an FcgammaR-mediated process, trogocytosis. RTX-induced trogocytosis has been characterized as both the means of resistance to therapy, via loss of cell surface target proteins (antigenic modulation), as well as a process that alters B cell phenotype and function. This study investigates the nature and clinical relevance of GA101-mediated trogocytosis. In this study, we demonstrate that GA101 is a more potent mediator of trogocytosis than RTX in vitro in both normal B cells and B-CLL cells. Qualitative differences in the effector function of these anti-CD20 Abs appear specific to B-CLL cells. GA101-mediated CD19 and CD20 trogocytosis from B-CLL cells is associated with its ability to induce homotypic adhesion (HA). The degree of HA varies between CLL patients and positively correlates with the expression of ZAP-70, a BCR-associated kinase. Deregulation of ZAP-70 using tyrosine kinase inhibitors, gefitinib or ibrutinib, diminishes HA formation and trogocytosis by GA101. Taken together, these findings elucidate the differences in trogocytosis and HA formation mediated by anti-CD20 mAbs RTX and GA101, as well as provide a novel link between ZAP-70 expression and these effector functions. PMID- 28710250 TI - Near-Infrared 1064 nm Laser Modulates Migratory Dendritic Cells To Augment the Immune Response to Intradermal Influenza Vaccine. AB - Brief exposure of skin to near-infrared (NIR) laser light has been shown to augment the immune response to intradermal vaccination and thus act as an immunologic adjuvant. Although evidence indicates that the NIR laser adjuvant has the capacity to activate innate subsets including dendritic cells (DCs) in skin as conventional adjuvants do, the precise immunological mechanism by which the NIR laser adjuvant acts is largely unknown. In this study we sought to identify the cellular target of the NIR laser adjuvant by using an established mouse model of intradermal influenza vaccination and examining the alteration of responses resulting from genetic ablation of specific DC populations. We found that a continuous wave (CW) NIR laser adjuvant broadly modulates migratory DC (migDC) populations, specifically increasing and activating the Lang+ and CD11b-Lang- subsets in skin, and that the Ab responses augmented by the CW NIR laser are dependent on DC subsets expressing CCR2 and Langerin. In comparison, a pulsed wave NIR laser adjuvant showed limited effects on the migDC subsets. Our vaccination study demonstrated that the efficacy of the CW NIR laser is significantly better than that of the pulsed wave laser, indicating that the CW NIR laser offers a desirable immunostimulatory microenvironment for migDCs. These results demonstrate the unique ability of the NIR laser adjuvant to selectively target specific migDC populations in skin depending on its parameters, and highlight the importance of optimization of laser parameters for desirable immune protection induced by an NIR laser-adjuvanted vaccine. PMID- 28710252 TI - An Unbiased Linkage Approach Reveals That the p53 Pathway Is Coupled to NK Cell Maturation. AB - Natural killer cells constitute potent innate lymphoid cells that play a major role in both tumor immunosurveillance and viral clearance via their effector functions. A four-stage model of NK cell functional maturation has been established according to the expression of CD11b and CD27, separating mature NK (mNK) cells into distinct populations that exhibit specific phenotypic and functional properties. To identify genetic factors involved in the regulation of NK cell functional maturation, we performed a linkage analysis on F2 (B6.Rag1-/- * NOD.Rag1-/- intercross) mice. We identified six loci on chromosomes 2, 4, 7, 10, 11, and 18 that were linked to one or more mNK cell subsets. Subsequently, we performed an in silico analysis exploiting mNK cell subset microarray data, highlighting various genes and microRNAs as potential regulators of the functional maturation of NK cells. Together, the combination of our unbiased genetic linkage study and the in silico analysis positions genes known to affect NK cell biology along the specific stages of NK cell functional maturation. Moreover, this approach allowed us to uncover a novel candidate gene in the regulation of NK cell maturation, namely Trp53 Using mice deficient for Trp53, we confirm that this tumor suppressor regulates NK cell functional maturation. Additional candidate genes revealed in this study may eventually serve as targets for the modulation of NK cell functional maturation to potentiate both tumor immunosurveillance and viral clearance. PMID- 28710254 TI - The Plasticity and Stability of Regulatory T Cells during Viral-Induced Inflammatory Lesions. AB - Ocular infection with HSV causes a chronic T cell-mediated inflammatory lesion in the cornea. Lesion severity is affected by the balance of different CD4 T cell subsets, with greater severity occurring when the activity of regulatory T cells (Tregs) is compromised. In this study, fate-mapping mice were used to assess the stability of Treg function in ocular lesions. We show that cells that were once Foxp3+ functional Tregs may lose Foxp3 and become Th1 cells that could contribute to lesion expression. The instability primarily occurred with IL-2Rlo Tregs and was shown, in part, to be the consequence of exposure to IL-12. Lastly, in vitro generated induced Tregs (iTregs) were shown to be highly plastic and capable of inducing stromal keratitis when adoptively transferred into Rag1-/- mice, with 95% of iTregs converting into ex-Tregs in the cornea. This plasticity of iTregs could be prevented when they were generated in the presence of vitamin C and retinoic acid. Importantly, adoptive transfer of these stabilized iTregs to HSV-1 infected mice prevented the development of stromal keratitis lesions more effectively than did control iTregs. Our results demonstrate that CD25lo Treg and iTreg instability occurs during a viral immunoinflammatory lesion and that its control may help to avoid lesion chronicity. PMID- 28710253 TI - Dual Immunization with SseB/Flagellin Provides Enhanced Protection against Salmonella Infection Mediated by Circulating Memory Cells. AB - The development of a subunit Salmonella vaccine has been hindered by the absence of detailed information about antigenic targets of protective Salmonella-specific T and B cells. Recent studies have identified SseB as a modestly protective Ag in susceptible C57BL/6 mice, but the mechanism of protective immunity remains undefined. In this article, we report that simply combining Salmonella SseB with flagellin substantially enhances protective immunity, allowing immunized C57BL/6 mice to survive for up to 30 d following challenge with virulent bacteria. Surprisingly, the enhancing effect of flagellin did not require flagellin Ag targeting during secondary responses or recognition of flagellin by TLR5. Although coimmunization with flagellin did not affect SseB-specific Ab responses, it modestly boosted CD4 responses. In addition, protective immunity was effectively transferred in circulation to parabionts of immunized mice, demonstrating that tissue-resident memory is not required for vaccine-induced protection. Finally, protective immunity required host expression of IFN-gammaR but was independent of induced NO synthase expression. Taken together, these data indicate that Salmonella flagellin has unique adjuvant properties that improve SseB-mediated protective immunity provided by circulating memory. PMID- 28710256 TI - Anatomic and Molecular Imaging in Prostate Cancer. AB - Prostate cancer is characterized by a complex set of heterogeneous disease states. This review aims to describe how imaging has been studied within each specific state. As physicians transition into an era of precision medicine, multiparametric magnetic resonance imaging (mpMRI) is proving to be a powerful tool leading the way for a paradigm shift in the diagnosis and management of localized prostate cancer. With further research and development, molecular imaging modalities will likely change the way we approach recurrent and metastatic disease. Given the range of possible oncological progression patterns, a thorough understanding of the underlying carcinogenesis, as it relates to imaging, is a requisite if we are to appropriately manage prostate cancer in future decades. PMID- 28710255 TI - Cathelicidins Inhibit Escherichia coli-Induced TLR2 and TLR4 Activation in a Viability-Dependent Manner. AB - Activation of the immune system needs to be tightly regulated to provide protection against infections and, at the same time, to prevent excessive inflammation to limit collateral damage to the host. This tight regulation includes regulating the activation of TLRs, which are key players in the recognition of invading microbes. A group of short cationic antimicrobial peptides, called cathelicidins, have previously been shown to modulate TLR activation by synthetic or purified TLR ligands and may play an important role in the regulation of inflammation during infections. However, little is known about how these cathelicidins affect TLR activation in the context of complete and viable bacteria. In this article, we show that chicken cathelicidin-2 kills Escherichia coli in an immunogenically silent fashion. Our results show that chicken cathelicidin-2 kills E. coli by permeabilizing the bacterial inner membrane and subsequently binds the outer membrane-derived lipoproteins and LPS to inhibit TLR2 and TLR4 activation, respectively. In addition, other cathelicidins, including human, mouse, pig, and dog cathelicidins, which lack antimicrobial activity under cell culture conditions, only inhibit macrophage activation by nonviable E. coli In total, this study shows that cathelicidins do not affect immune activation by viable bacteria and only inhibit inflammation when bacterial viability is lost. Therefore, cathelicidins provide a novel mechanism by which the immune system can discriminate between viable and nonviable Gram-negative bacteria to tune the immune response, thereby limiting collateral damage to the host and the risk for sepsis. PMID- 28710257 TI - Regulation of Bone Metabolism by Sex Steroids. AB - Osteoporosis is a significant public health problem, and a major cause of the disease is estrogen deficiency following menopause in women. In addition, considerable evidence now shows that estrogen is also a major regulator of bone metabolism in men. Since the original description of the effects of estrogen deficiency on bone by Fuller Albright more than 70 years ago, there has been enormous progress in understanding the mechanisms of estrogen and testosterone action on bone using human and mouse models. Although we understand more about the effects of estrogen on bone as compared with testosterone, both sex steroids do play important roles, perhaps in a somewhat compartment-specific (i.e., cancellous vs. cortical bone) manner. This review summarizes our current knowledge of sex steroid action on bone based on human and mouse studies, identifies both agreements and potential discrepancies between these studies, and suggests directions for future research in this important area. PMID- 28710258 TI - The Evolution and Ecology of Resistance in Cancer Therapy. AB - Despite continuous deployment of new treatment strategies and agents over many decades, most disseminated cancers remain fatal. Cancer cells, through their access to the vast information of human genome, have a remarkable capacity to deploy adaptive strategies for even the most effective treatments. We note there are two critical steps in the clinical manifestation of treatment resistance. The first, which is widely investigated, requires deployment of a mechanism of resistance that usually involves increased expression of molecular machinery necessary to eliminate the cytotoxic effect of treatment. However, the emergence of a resistant phenotype is not in itself clinically significant. That is, resistant cells affect patient outcomes only when they form a sufficiently large population to allow tumor progression and treatment failure. Importantly, proliferation of the resistant phenotype is by no means certain and, in fact, depends on complex Darwinian dynamics governed by the costs and benefits of the resistance mechanisms in the context of the local environment and competing populations. Attempts to target molecular machinery of resistance have had little clinical success largely because of the diversity within the human genome therapeutic interruption of one mechanism simply results in its replacement by an alternative. We explore an alternative strategy for overcoming treatment resistance that seeks to understand and exploit the critical evolutionary dynamics that govern proliferation of the resistant phenotypes. In general, this approach has shown that, although emergence of resistance mechanisms in cancer cells to every current therapy is inevitable, proliferation of the resistant phenotypes is not and can be delayed and even prevented with sufficient understanding of the underlying ecoevolutionary dynamics. PMID- 28710259 TI - Phylogenetic Quantification of Intratumor Heterogeneity. AB - As sequencing efforts continue to reveal the extent of the intratumor heterogeneity (ITH) present in human cancers, the importance of evolutionary studies attempting to trace its etiology has increased. Sequencing multiple samples or tumor regions from the same patient has become affordable and is an effective way of tracing these evolutionary pathways, understanding selection, and detecting clonal expansions in ways impractical with single samples alone. In this article, we discuss and show the benefits of such multisample studies. We describe how multiple samples can guide tree inference through accurate phasing of germline variants and copy-number profiles. We show their relevance in detecting clonal expansions and deriving summary statistics quantifying the overall degree of ITH, and discuss how the relationship of metastatic clades might give us insight into the dominant mode of cancer progression. We further outline how multisample studies might help us better understand selective processes acting on cancer genomes and help to detect neutral evolution and mutator phenotypes. PMID- 28710260 TI - Big Bang Tumor Growth and Clonal Evolution. AB - The advent and application of next-generation sequencing (NGS) technologies to tumor genomes has reinvigorated efforts to understand clonal evolution. Although tumor progression has traditionally been viewed as a gradual stepwise process, recent studies suggest that evolutionary rates in tumors can be variable with periods of punctuated mutational bursts and relative stasis. For example, Big Bang dynamics have been reported, wherein after transformation, growth occurs in the absence of stringent selection, consistent with effectively neutral evolution. Although first noted in colorectal tumors, effective neutrality may be relatively common. Additionally, punctuated evolution resulting from mutational bursts and cataclysmic genomic alterations have been described. In this review, we contrast these findings with the conventional gradualist view of clonal evolution and describe potential clinical and therapeutic implications of different evolutionary modes and tempos. PMID- 28710261 TI - The lipid-binding side of Notch ligands. PMID- 28710262 TI - Med15B Regulates Acid Stress Response and Tolerance in Candida glabrata by Altering Membrane Lipid Composition. AB - Candida glabrata is a promising producer of organic acids. To elucidate the physiological function of the Mediator tail subunit Med15B in the response to low pH stress, we constructed a deletion strain, C. glabratamed15BDelta, and an overexpression strain, C. glabrata HTUDelta/CgMED15B Deletion of MED15B caused biomass production, glucose consumption rate, and cell viability to decrease by 28.3%, 31.7%, and 26.5%, respectively, compared with those of the parent (HTUDelta) strain at pH 2.0. Expression of lipid metabolism-related genes was significantly downregulated in the med15BDelta strain, whereas key genes of ergosterol biosynthesis showed abnormal upregulation. This caused the proportion of C18:1 fatty acids, the ratio of unsaturated to saturated fatty acids (UFA/SFA), and the total phospholipid content to decrease by 11.6%, 27.4%, and 37.6%, respectively. Cells failed to synthesize fecosterol and ergosterol, leading to the accumulation and a 60.3-fold increase in the concentration of zymosterol. Additionally, cells showed reductions of 69.2%, 11.6%, and 21.8% in membrane integrity, fluidity, and H+-ATPase activity, respectively. In contrast, overexpression of Med15B increased the C18:1 levels, total phospholipids, ergosterol content, and UFA/SFA by 18.6%, 143.5%, 94.5%, and 18.7%, respectively. Membrane integrity, fluidity, and H+-ATPase activity also increased by 30.2%, 6.9%, and 51.8%, respectively. Furthermore, in the absence of pH buffering, dry weight of cells and pyruvate concentrations were 29.3% and 61.2% higher, respectively, than those of the parent strain. These results indicated that in C. glabrata, Med15B regulates tolerance toward low pH via transcriptional regulation of acid stress response genes and alteration in lipid composition.IMPORTANCE This study explored the role of the Mediator tail subunit Med15B in the metabolism of Candida glabrata under acidic conditions. Overexpression of MED15B enhanced yeast tolerance to low pH and improved biomass production, cell viability, and pyruvate yield. Membrane lipid composition data indicated that Med15B might play a critical role in membrane integrity, fluidity, and H+-ATPase activity homeostasis at low pH. Thus, controlling membrane composition may serve to increase C. glabrata productivity at low pH. PMID- 28710263 TI - Enzymatic Mechanism for Arabinan Degradation and Transport in the Thermophilic Bacterium Caldanaerobius polysaccharolyticus. AB - The plant cell wall polysaccharide arabinan provides an important supply of arabinose, and unraveling arabinan-degrading strategies by microbes is important for understanding its use as a source of energy. Here, we explored the arabinan degrading enzymes in the thermophilic bacterium Caldanaerobius polysaccharolyticus and identified a gene cluster encoding two glycoside hydrolase (GH) family 51 alpha-l-arabinofuranosidases (CpAbf51A, CpAbf51B), a GH43 endoarabinanase (CpAbn43A), a GH27 beta-l-arabinopyranosidase (CpAbp27A), and two GH127 beta-l-arabinofuranosidases (CpAbf127A, CpAbf127B). The genes were expressed as recombinant proteins, and the functions of the purified proteins were determined with para-nitrophenyl (pNP)-linked sugars and naturally occurring pectin structural elements as the substrates. The results demonstrated that CpAbn43A is an endoarabinanase while CpAbf51A and CpAbf51B are alpha-l arabinofuranosidases that exhibit diverse substrate specificities, cleaving alpha 1,2, alpha-1,3, and alpha-1,5 linkages of purified arabinan-oligosaccharides. Furthermore, both CpAbf127A and CpAbf127B cleaved beta-arabinofuranose residues in complex arabinan side chains, thus providing evidence of the function of this family of enzymes on such polysaccharides. The optimal temperatures of the enzymes ranged between 60 degrees C and 75 degrees C, and CpAbf43A and CpAbf51A worked synergistically to release arabinose from branched and debranched arabinan. Furthermore, the hydrolytic activity on branched arabinan oligosaccharides and degradation of pectic substrates by the endoarabinanase and l-arabinofuranosidases suggested a microbe equipped with diverse activities to degrade complex arabinan in the environment. Based on our functional analyses of the genes in the arabinan degradation cluster and the substrate-binding studies on a component of the cognate transporter system, we propose a model for arabinan degradation and transport by C. polysaccharolyticusIMPORTANCE Genomic DNA sequencing and bioinformatic analysis allowed the identification of a gene cluster encoding several proteins predicted to function in arabinan degradation and transport in C. polysaccharolyticus The analysis of the recombinant proteins yielded detailed insights into the putative arabinan metabolism of this thermophilic bacterium. The use of various branched arabinan oligosaccharides provided a detailed understanding of the substrate specificities of the enzymes and allowed assignment of two new GH127 polypeptides as beta-l arabinofuranosidases able to degrade pectic substrates, thus expanding our knowledge of this rare group of glycoside hydrolases. In addition, the enzymes showed synergistic effects for the degradation of arabinans at elevated temperatures. The enzymes characterized from the gene cluster are, therefore, of utility for arabinose production in both the biofuel and food industries. PMID- 28710264 TI - Dissimilar Crystal Proteins Cry5Ca1 and Cry5Da1 Synergistically Act against Meloidogyne incognita and Delay Cry5Ba-Based Nematode Resistance. AB - Cry proteins of Bacillus thuringiensis (Bt) have been successfully used as biopesticides and in transgenic crops throughout the world. However, resources against the most serious agricultural pathogens, plant root-knot nematodes, are limited. The genomes of several highly nematicidal virulent Bt strains from our laboratory have been sequenced, facilitating the identification of novel Cry proteins and other virulence factors. We identified two novel Cry proteins, Cry5Ca1 and Cry5Da1, that exhibit high toxicity against Meloidogyne incognita Using the Caenorhabditis elegans model, the two Cry5 toxins were shown to negatively affect nematode life span, fertility, and survival. The 50% lethal concentrations (LC50s) of Cry5Ca1 and Cry5Da1 were 57.22 MUg/ml and 36.69 MUg/ml, respectively. Moreover, a synergistic effect (synergism factor, 1.61 to 2.04) was observed for nematicidal toxicity of Cry5Ca1 and Cry5Da1, which is accordant with the phylogenetic results suggesting that domain II of the two novel Cry5 toxins evolved into two independent clades. Through comparison of the depressed degree of toxicity in the beta-methylgalactoside detoxification test, we found that the novel toxin Cry5D possesses a different galactose-binding epitope; meanwhile, the finding that Cry5D does not share a motif (GXXXE) in the corresponding loop of domain II with Cry5B could explain the different galactose binding performance. Additionally, low-level cross-resistance of C. elegans bre mutant strains was evident between Cry5B and Cry5D. These results suggest that Cry5D can be used as an alternative to delay the potential resistance of nematodes to Cry5B.IMPORTANCE Although proper gene resources for Bt crops against the most serious agricultural pathogens, plant root-knot nematodes, are limited, we have identified two novel nematicidal toxins, Cry5Ca1 and Cry5Da1, against M. incognita, which have supplied more gene candidates for Bt crops designed against nematodes. Moreover, the association of the dissimilarity between Cry5Da1 and Cry5Ba1 and their low cross-resistance can be attributed not only to a low sequence similarity of domain II but also to the structural difference of the key motif and receptor binding epitope in the loops. This association facilitates the selection of a proper candidate for the prospective design of pyramided Bt crops that can delay potential resistance. PMID- 28710266 TI - Specificity of subtilin-mediated activation of histidine kinase SpaK. AB - Autoinduction via two-component systems is a widespread regulatory mechanism that senses environmental and metabolic changes. Although the lantibiotics nisin and subtilin are closely related and share the same lanthionine ring structure, they autoinduce their biosynthesis in a highly specific manner. Subtilin can only activate the two-component system SpaRK of Bacillus subtilis, whereas nisin activates solely the two-component system NisRK of Lactococcus lactis To identify components that determine the specificity of subtilin autoinduction, several variants of the respective lantibiotic were analyzed for their autoinduction capacity. In here we show that amino acid position 20 is crucial for SpaK activation as an engineered nisin molecule with phenylalanine at position 20 (nisin N20F) was able to activate SpaK in a specific manner. In combination with the N-terminal tryptophan of subtilin (nisin I1W/N20F) SpaK autoinduction reached almost the level of subtilin mediated autoinduction. Furthermore, the overall structure of subtilin is also important for its association with the histidine kinase. Destruction of the second lanthionine ring (subtilin C11A, ring B) as well as mutations which interfere with the flexibility of the hinge region located between lanthionine rings C and D (subtilin L21P/Q22P) abolished SpaK autoinduction. Although the C-terminal part of subtilin is needed for efficient SpaK autoinduction, destruction of lanthionine rings D and E had no measurable impact. Based on these findings a model for the interaction of subtilin with histidine kinase SpaK was established.ImportanceAlthough two-component systems are important regulatory systems that sense environmental changes, only little information on the molecular mechanism of sensing and the interaction of the sensor with its respective kinase is available. Due to the strong specificity of linear lantibiotics such as subtilin and nisin for their respective kinase, they provide an excellent model system to unravel the structural needs of these lantibiotics to activate their histidine kinases in a specific manner. More than that, lantibiotics autoinduce their own biosynthesis via a two-component system, therefore understanding their interaction with the histidine kinase is also a must for the biosynthesis of newly engineered peptide-antibiotics. Using a B. subtilis based reporter system, we were able to identify the molecular constraints that are necessary for specific SpaK activation and we were able to provide SpaK specificity to nisin with just two point mutations. PMID- 28710265 TI - Francisella-Like Endosymbionts and Rickettsia Species in Local and Imported Hyalomma Ticks. AB - Hyalomma ticks (Acari: Ixodidae) are hosts for Francisella-like endosymbionts (FLE) and may serve as vectors of zoonotic disease agents. This study aimed to provide an initial characterization of the interaction between Hyalomma and FLE and to determine the prevalence of pathogenic Rickettsia in these ticks. Hyalomma marginatum, Hyalomma rufipes, Hyalommadromedarii, Hyalommaaegyptium, and Hyalommaexcavatum ticks, identified morphologically and molecularly, were collected from different hosts and locations representing the distribution of the genus Hyalomma in Israel, as well as from migratory birds. A high prevalence of FLE was found in all Hyalomma species (90.6%), as well as efficient maternal transmission of FLE (91.8%), and the localization of FLE in Malpighian tubules, ovaries, and salivary glands in H. marginatum Furthermore, we demonstrated strong cophylogeny between FLE and their host species. Contrary to FLE, the prevalence of Rickettsia ranged from 2.4% to 81.3% and was significantly different between Hyalomma species, with a higher prevalence in ticks collected from migratory birds. Using ompA gene sequences, most of the Rickettsia spp. were similar to Rickettsiaaeschlimannii, while a few were similar to Rickettsiaafricae of the spotted fever group (SFG). Given their zoonotic importance, 249 ticks were tested for Crimean Congo hemorrhagic fever virus infection, and all were negative. The results imply that Hyalomma and FLE have obligatory symbiotic interactions, indicating a potential SFG Rickettsia zoonosis risk. A further understanding of the possible influence of FLE on Hyalomma development, as well as on its infection with Rickettsia pathogens, may lead to novel ways to control tick-borne zoonoses.IMPORTANCE This study shows that Francisella-like endosymbionts were ubiquitous in Hyalomma, were maternally transmitted, and cospeciated with their hosts. These findings imply that the interaction between FLE and Hyalomma is of an obligatory nature. It provides an example of an integrative taxonomy approach to simply differentiate among species infesting the same host and to identify nymphal and larval stages to be used in further studies. In addition, it shows the potential of imported Hyalomma ticks to serve as a vector for spotted fever group rickettsiae. The information gathered in this study can be further implemented in the development of symbiont-based disease control strategies for the benefit of human health. PMID- 28710267 TI - Increased Processivity, Misincorporation, and Nucleotide Incorporation Efficiency in Sulfolobus solfataricus Dpo4 Thumb Domain Mutants. AB - The present study aimed to increase the processivity of Sulfolobus solfataricus DNA polymerase Dpo4. Protein engineering and bioinformatics were used to compile a library of potential Dpo4 mutation sites. Ten potential mutants were identified and constructed. A primer extension assay was used to evaluate the processivity of Dpo4 mutants. Thumb (A181D) and finger (E63K) domain mutants showed a processivity of 20 and 19 nucleotides (nt), respectively. A little finger domain mutant (I248Y) exhibited a processivity of 17 nt, only 1 nt more than wild-type Dpo4. Furthermore, the A181D mutant showed lower fidelity and higher nucleotide incorporation efficiency (4.74 * 10-4 s-1 MUM-1) than E63K and I248Y mutants. When tasked with bypassing damage, the A181D mutant exhibited a 3.81-fold and 2.62-fold higher catalytic efficiency (kcat/Km ) at incorporating dCTP and dATP, respectively, than wild-type Dpo4. It also showed a 55% and 91.5% higher catalytic efficiency when moving beyond the damaged 8-oxoG:C and 8-oxoG:A base pairs, respectively, compared to wild-type Dpo4. Protein engineering and bioinformatics methods can effectively increase the processivity and translesion synthesis ability of Dpo4.IMPORTANCE DNA polymerases with poor fidelity can be exploited to store data and record changes in response to the intracellular environment. Sulfolobus solfataricus Dpo4 is such an enzyme, although its use is hindered by its low processivity. In this work, we used a bioinformatics and protein engineering approach to generate Dpo4 mutants with improved processivity. We identified the Dpo4 thumb domain as the most relevant in controlling processivity. PMID- 28710269 TI - Molecular mechanism and genetic determinants of buprofezin degradation. AB - Buprofezin is a widely used insect growth regulator whose residue has been frequently detected in the environment, posing a threat to aquatic organisms and non-target insects. Microorganisms play an important role in the degradation of buprofezin in the natural environment. However, the relevant catabolic pathway has not been fully characterized, and the molecular mechanism of catabolism is still completely unknown. Rhodococcus qingshengii YL-1 can utilize buprofezin as a sole source of carbon and energy for growth. In this study, the upstream catabolic pathway in strain YL-1 was identified using tandem mass spectrometry. Buprofezin is composed of a benzene ring and a heterocyclic ring. The degradation is initiated by the dihydroxylation of the benzene ring and continues via dehydrogenation, aromatic ring cleavage, breaking of an amide bond and the release of the heterocyclic ring 2-tert-butylimino-3-isopropyl-1,3,5-thiadiazinan 4-one (2-BI). A buprofezin degradation-deficient mutant strain YL-0 was isolated. Comparative genomic analysis combined with gene deletion and complementation experiments revealed that the gene cluster bfzBA3A4A1A2C is responsible for the upstream catabolic pathway of buprofezin. bfzA3A4A1A2 encodes a novel Rieske non heme iron oxygenase (RHO) system that is responsible for the dihydroxylation of buprofezin at the benzene ring; bfzB is involved in dehydrogenation, and bfzC is in charge of benzene ring cleavage. Furthermore, the products of bfzBA3A4A1A2C can also catalyze dihydroxylation, dehydrogenation and aromatic ring cleavage of biphenyl, flavanone, flavone and bifenthrin. In addition, a transcriptional study revealed that bfzBA3A4A1A2C is organized in one transcriptional unit that is constitutively expressed in strain YL-1.Importance There is an increasing concern about the residue and environmental fate of buprofezin. Microbial metabolism is an important mechanism responsible for the buprofezin degradation in natural environment. However, the molecular mechanism and genetic determinants of microbial degradation of buprofezin has not been well identified. This work revealed that gene cluster bfzBA3A4A1A2C is responsible for the upstream catabolic pathway of buprofezin in R. qingshengii YL-1. The products of bfzBA3A4A1A2C could also degrade bifenthrin, a widely used pyrethroid insecticide. These findings enhance our understanding of the microbial degradation mechanism of buprofezin and benefit the application of strain YL-1 and bfzBA3A4A1A2C in the bioremediation of buprofezin contamination. PMID- 28710268 TI - Physiological Evidence for Isopotential Tunneling in the Electron Transport Chain of Methane-Producing Archaea. AB - Many, but not all, organisms use quinones to conserve energy in their electron transport chains. Fermentative bacteria and methane-producing archaea (methanogens) do not produce quinones but have devised other ways to generate ATP. Methanophenazine (MPh) is a unique membrane electron carrier found in Methanosarcina species that plays the same role as quinones in the electron transport chain. To extend the analogy between quinones and MPh, we compared the MPh pool sizes between two well-studied Methanosarcina species, Methanosarcina acetivorans C2A and Methanosarcina barkeri Fusaro, to the quinone pool size in the bacterium Escherichia coli We found the quantity of MPh per cell increases as cultures transition from exponential growth to stationary phase, and absolute quantities of MPh were 3-fold higher in M. acetivorans than in M. barkeri The concentration of MPh suggests the cell membrane of M. acetivorans, but not of M. barkeri, is electrically quantized as if it were a single conductive metal sheet and near optimal for rate of electron transport. Similarly, stationary (but not exponentially growing) E. coli cells also have electrically quantized membranes on the basis of quinone content. Consistent with our hypothesis, we demonstrated that the exogenous addition of phenazine increases the growth rate of M. barkeri three times that of M. acetivorans Our work suggests electron flux through MPh is naturally higher in M. acetivorans than in M. barkeri and that hydrogen cycling is less efficient at conserving energy than scalar proton translocation using MPh.IMPORTANCE Can we grow more from less? The ability to optimize and manipulate metabolic efficiency in cells is the difference between commercially viable and nonviable renewable technologies. Much can be learned from methane-producing archaea (methanogens) which evolved a successful metabolic lifestyle under extreme thermodynamic constraints. Methanogens use highly efficient electron transport systems and supramolecular complexes to optimize electron and carbon flow to control biomass synthesis and the production of methane. Worldwide, methanogens are used to generate renewable methane for heat, electricity, and transportation. Our observations suggest Methanosarcina acetivorans, but not Methanosarcina barkeri, has electrically quantized membranes. Escherichia coli, a model facultative anaerobe, has optimal electron transport at the stationary phase but not during exponential growth. This study also suggests the metabolic efficiency of bacteria and archaea can be improved using exogenously supplied lipophilic electron carriers. The enhancement of methanogen electron transport through methanophenazine has the potential to increase renewable methane production at an industrial scale. PMID- 28710270 TI - Stabilization of Multimeric Proteins via Intersubunit Cyclization. AB - Proteins with high catalytic efficiency and selectivity under mild conditions have long been appreciated by industrial and medicinal fields. These proteins, which are commonly multimeric, often possess low stability, impeding wider application. Currently, strategies to improve the stability of multimeric proteins concentrate on enhancing the interaction at internal interface of the subunits. In this report, we confirmed that the largely underestimated subunit terminal ends are as significant as the internal interface for protein stability. By connecting both the terminal ends and internal interface of subunits, the tetrameric Leifsonia alcohol dehydrogenase (LnADH) protein can been cyclized into a rigid form with significantly improved thermostability and resilience. The improvement in the temperature at which enzyme activity is reduced to 50% after a 15-min heat treatment (T5015) and melting temperature (Tm ) of the modified protein was 18 degrees C and 23.3 degrees C, respectively, which is superior to the results achieved by normal protein engineering. Our study provided a novel strategy to effectively improve the stability of multimeric proteins, which is suitable not only for the short-chain dehydrogenase/reductase (SDR) family but also other classes of proteins with close terminal ends.IMPORTANCE Industrially interesting proteins are generally multimeric proteins; however, their applications are often restricted due to low stability caused by the natural tendency of subunit disassociation. Current approaches targeting this problem mainly focus on enhancing the internal interfaces of the subunits to avoid their disassociation. In this study, we identified and confirmed the external interface to be significant for improving the stability of multimeric proteins. By connecting the terminal ends and internal interface with disulfide bonds, we found that the multimeric protein LnADH cyclized into a robust monomeric-like form, resulting in superior thermostability compared to traditional protein engineering. This intersubunit cyclization approach is efficient and easy to perform, providing a novel method for engineering many important classes of multimeric proteins. PMID- 28710272 TI - Burnout among doctors. PMID- 28710271 TI - Novel Alphacoronaviruses and Paramyxoviruses Cocirculate with Type 1 and Severe Acute Respiratory System (SARS)-Related Betacoronaviruses in Synanthropic Bats of Luxembourg. AB - Several infectious disease outbreaks with high mortality in humans have been attributed to viruses that are thought to have evolved from bat viruses. In this study from Luxembourg, the genetic diversity and epidemiology of paramyxoviruses and coronaviruses shed by the bat species Rhinolophus ferrumequinum and Myotis emarginatus were evaluated. Feces collection (n = 624) was performed longitudinally in a mixed-species colony in 2015 and 2016. In addition, feces (n = 254) were collected cross-sectionally from six Myotis emarginatus colonies in 2016. By use of degenerate primers in a nested format, overall prevalences of 1.1% (10/878) and 4.9% (43/878) were determined for paramyxoviruses and coronaviruses. Sequences of the partial RNA-dependent RNA polymerase and spike glycoprotein genes of coronaviruses, as well as sequences of the partial L gene of paramyxoviruses, were obtained. Novel paramyxovirus and Alphacoronavirus strains were identified in different Myotis emarginatus colonies, and severe acute respiratory syndrome (SARS)-related Betacoronavirus strains were shed by Rhinolophus ferrumequinum Logistic regression revealed that the level of Alphacoronavirus shedding was highest in July (odds ratio, 2.8; P < 0.01), probably due to periparturient stress. Phylogenetic analyses point to close virus host coevolution, and the high genetic similarity of the study strains suggests that the Myotis emarginatus colonies in Luxembourg are socially connected. Most interestingly, we show that bats also host Betacoronavirus1 strains. The high similarity of the spike gene sequences of these viruses with mammalian Betacoronavirus 1 strains may be of concern. Both the SARS-related and Betacoronavirus 1 strains detected in bats in Luxembourg may cross the species barrier after a host adaptation process.IMPORTANCE Bats are a natural reservoir of a number of zoonotic pathogens. Several severe outbreaks in humans (e.g., a Nipah virus outbreak in Malaysia in 1998, and the almost global spread of severe acute respiratory syndrome in 2003) have been caused by bat-borne viruses that were transmitted to humans mostly after virus adaptation (e.g., in intermediate animal hosts). Despite the indigenousness of bat species that host viruses with suspected zoonotic potential and despite the zoonotic transmission of European bat 1 lyssavirus in Luxembourg, knowledge about the diversity and epidemiology of bat viruses remains limited in this country. Moreover, in contrast to other European countries, bat viruses are currently not included in the national surveillance activities of this land-locked country. We suggest that this gap in disease surveillance should be addressed, since we show here that synanthropic bats host viruses that may be able to cross the species barrier. PMID- 28710273 TI - PD-L1 up-regulation restrains Th17 cell differentiation in STAT3 loss- and STAT1 gain-of-function patients. AB - Patients with hypomorphic mutations in STAT3 and patients with hypermorphic mutations in STAT1 share several clinical and cellular phenotypes suggesting overlapping pathophysiologic mechanisms. We, therefore, examined cytokine signaling and CD4+ T cell differentiation in these cohorts to characterize common pathways. As expected, differentiation of Th17 cells was impaired in both cohorts. We found that STAT1 was hyperphosphorylated in response to cytokine stimulation in both cohorts and that STAT1-dependent PD-L1 up-regulation-known to inhibit Th17 differentiation in mouse models-was markedly enhanced as well. Overexpression of SOCS3 strongly inhibited phosphorylation of STAT1 and PD-L1 up regulation, suggesting that diminished SOCS3 expression may lead to the observed effects. Defects in Th17 differentiation could be partially overcome in vitro via PD-L1 inhibition and in a mouse model of STAT3 loss-of-function by crossing them with PD-1 knockout mice. PD-L1 may be a potential therapeutic target in several genetic diseases of immune deficiency affecting cytokine signaling. PMID- 28710274 TI - Computational tools help improve protein stability but with a solubility tradeoff. AB - Accurately predicting changes in protein stability upon amino acid substitution is a much sought after goal. Destabilizing mutations are often implicated in disease, whereas stabilizing mutations are of great value for industrial and therapeutic biotechnology. Increasing protein stability is an especially challenging task, with random substitution yielding stabilizing mutations in only ~2% of cases. To overcome this bottleneck, computational tools that aim to predict the effect of mutations have been developed; however, achieving accuracy and consistency remains challenging. Here, we combined 11 freely available tools into a meta-predictor (meieringlab.uwaterloo.ca/stabilitypredict/). Validation against ~600 experimental mutations indicated that our meta-predictor has improved performance over any of the individual tools. The meta-predictor was then used to recommend 10 mutations in a previously designed protein of moderate thermodynamic stability, ThreeFoil. Experimental characterization showed that four mutations increased protein stability and could be amplified through ThreeFoil's structural symmetry to yield several multiple mutants with >2 kcal/mol stabilization. By avoiding residues within functional ties, we could maintain ThreeFoil's glycan-binding capacity. Despite successfully achieving substantial stabilization, however, almost all mutations decreased protein solubility, the most common cause of protein design failure. Examination of the 600-mutation data set revealed that stabilizing mutations on the protein surface tend to increase hydrophobicity and that the individual tools favor this approach to gain stability. Thus, whereas currently available tools can increase protein stability and combining them into a meta-predictor yields enhanced reliability, improvements to the potentials/force fields underlying these tools are needed to avoid gaining protein stability at the cost of solubility. PMID- 28710275 TI - A pH-dependent switch promotes beta-synuclein fibril formation via glutamate residues. AB - alpha-Synuclein (alphaS) is the primary protein associated with Parkinson's disease, and it undergoes aggregation from its intrinsically disordered monomeric form to a cross-beta fibrillar form. The closely related homolog beta-synuclein (betaS) is essentially fibril-resistant under cytoplasmic physiological conditions. Toxic gain-of-function by betaS has been linked to dysfunction, but the aggregation behavior of betaS under altered pH is not well-understood. In this work, we compare fibril formation of alphaS and betaS at pH 7.3 and mildly acidic pH 5.8, and we demonstrate that pH serves as an on/off switch for betaS fibrillation. Using alphaS/betaS domain-swapped chimera constructs and single residue substitutions in betaS, we localized the switch to acidic residues in the N-terminal and non-amyloid component domains of betaS. Computational models of betaS fibril structures indicate that key glutamate residues (Glu-31 and Glu-61) in these domains may be sites of pH-sensitive interactions, and variants E31A and E61A show dramatically altered pH sensitivity for fibril formation supporting the importance of these charged side chains in fibril formation of betaS. Our results demonstrate that relatively small changes in pH, which occur frequently in the cytoplasm and in secretory pathways, may induce the formation of betaS fibrils and suggest a complex role for betaS in synuclein cellular homeostasis and Parkinson's disease. PMID- 28710276 TI - ATP binding and hydrolysis disrupt the high-affinity interaction between the heme ABC transporter HmuUV and its cognate substrate-binding protein. AB - Using the energy of ATP hydrolysis, ABC transporters catalyze the trans-membrane transport of molecules. In bacteria, these transporters partner with a high affinity substrate-binding protein (SBP) to import essential micronutrients. ATP binding by Type I ABC transporters (importers of amino acids, sugars, peptides, and small ions) stabilizes the interaction between the transporter and the SBP, thus allowing transfer of the substrate from the latter to the former. In Type II ABC transporters (importers of trace elements, e.g. vitamin B12, heme, and iron siderophores) the role of ATP remains debatable. Here we studied the interaction between the Yersinia pestis ABC heme importer (HmuUV) and its partner substrate binding protein (HmuT). Using real-time surface plasmon resonance experiments and interaction studies in membrane vesicles, we find that in the absence of ATP the transporter and the SBP tightly bind. Substrate in excess inhibits this interaction, and ATP binding by the transporter completely abolishes it. To release the stable docked SBP from the transporter hydrolysis of ATP is required. Based on these results we propose a mechanism for heme acquisition by HmuUV-T where the substrate-loaded SBP docks to the nucleotide-free outward-facing conformation of the transporter. ATP binding leads to formation of an occluded state with the substrate trapped in the trans-membrane translocation cavity. Subsequent ATP hydrolysis leads to substrate delivery to the cytoplasm, release of the SBP, and resetting of the system. We propose that other Type II ABC transporters likely share the fundamentals of this mechanism. PMID- 28710277 TI - Phosphorylation of the type II transmembrane serine protease, TMPRSS13, in hepatocyte growth factor activator inhibitor-1 and -2-mediated cell-surface localization. AB - TMPRSS13 is a member of the type II transmembrane serine protease (TTSP) family. Although various TTSPs have been characterized in detail biochemically and functionally, the basic properties of TMPRSS13 remain unclear. Here, we investigate the activation, inhibition, post-translational modification, and localization of TMPRSS13. We show that TMPRSS13 is a glycosylated, active protease and that its own proteolytic activity mediates zymogen cleavage. Full length, active TMPRSS13 exhibits impaired cell-surface expression in the absence of the cognate Kunitz-type serine protease inhibitors, hepatocyte growth factor activator inhibitor (HAI)-1 or HAI-2. Concomitant presence of TMPRSS13 with either HAI-1 or -2 mediates phosphorylation of residues in the intracellular domain of the protease, and it coincides with efficient transport of the protease to the cell surface and its subsequent shedding. Cell-surface labeling experiments indicate that the dominant form of TMPRSS13 on the cell surface is phosphorylated, whereas intracellular TMPRSS13 is predominantly non phosphorylated. These data provide novel insight into the cellular properties of TMPRSS13 and highlight phosphorylation of TMPRSS13 as a novel post-translational modification of this TTSP family member and potentially other members of this family of proteases. PMID- 28710278 TI - Phosphorylation of human aquaporin 2 (AQP2) allosterically controls its interaction with the lysosomal trafficking protein LIP5. AB - The interaction between the renal water channel aquaporin-2 (AQP2) and the lysosomal trafficking regulator-interacting protein LIP5 targets AQP2 to multivesicular bodies and facilitates lysosomal degradation. This interaction is part of a process that controls AQP2 apical membrane abundance in a vasopressin dependent manner, allowing for urine volume adjustment. Vasopressin regulates phosphorylation at four sites within the AQP2 C terminus (Ser256, Ser261, Ser264, and Thr269), of which Ser256 is crucial and sufficient for AQP2 translocation from storage vesicles to the apical membrane. However, whether AQP2 phosphorylation modulates AQP2-LIP5 complex affinity is unknown. Here we used far Western blot analysis and microscale thermophoresis to show that the AQP2 binds LIP5 in a phosphorylation-dependent manner. We constructed five phospho-mimicking mutants (S256E, S261E, S264E, T269E, and S256E/T269E) and a C-terminal truncation mutant (DeltaP242) that lacked all phosphorylation sites but retained a previously suggested LIP5-binding site. CD spectroscopy indicated that wild-type AQP2 and the phospho-mimicking mutants had similar overall structure but displayed differences in melting temperatures possibly arising from C-terminal conformational changes. Non-phosphorylated AQP2 bound LIP5 with the highest affinity, whereas AQP2-DeltaP242 had 20-fold lower affinity as determined by microscale thermophoresis. AQP2-S256E, S261E, T269E, and S256E/T269E all had reduced affinity. This effect was most prominent for AQP2-S256E, which fits well with its role in apical membrane targeting. AQP2-S264E had affinity similar to non-phosphorylated AQP2, possibly indicating a role in exosome excretion. Our data suggest that AQP2 phosphorylation allosterically controls its interaction with LIP5, illustrating how altered affinities to interacting proteins form the basis for regulation of AQP2 trafficking by post-translational modifications. PMID- 28710279 TI - UbMES and UbFluor: Novel probes for ring-between-ring (RBR) E3 ubiquitin ligase PARKIN. AB - Ring-between-ring (RBR) E3 ligases have been implicated in autoimmune disorders and neurodegenerative diseases. The functions of many RBR E3s are poorly defined, and their regulation is complex, involving post-translational modifications and allosteric regulation with other protein partners. The functional complexity of RBRs, coupled with the complexity of the native ubiquitination reaction that requires ATP and E1 and E2 enzymes, makes it difficult to study these ligases for basic research and therapeutic purposes. To address this challenge, we developed novel chemical probes, ubiquitin C-terminal fluorescein thioesters UbMES and UbFluor, to qualitatively and quantitatively assess the activity of the RBR E3 ligase PARKIN in a simple experimental setup and in real time using fluorescence polarization. First, we confirmed that PARKIN does not require an E2 enzyme for substrate ubiquitination, lysine selection, and polyubiquitin chain formation. Second, we confirmed that UbFluor quantitatively detects naturally occurring activation states of PARKIN caused by Ser65 phosphorylation (pPARKIN) and phosphorylated ubiquitin (pUb). Third, we showed that both pUb and the ubiquitin accepting substrate contribute to maximal pPARKIN ubiquitin conjugation turnover. pUb enhances the transthiolation step, whereas the substrate clears the pPARKIN~Ub thioester intermediate. Finally, we established that UbFluor can quantify activation or inhibition of PARKIN by structural mutations. These results demonstrate the feasibility of using UbFluor for quantitative studies of the biochemistry of RBR E3s and for high-throughput screening of small-molecule activators or inhibitors of PARKIN and other RBR E3 ligases. PMID- 28710280 TI - The assembly of the plant urease activation complex and the essential role of the urease accessory protein G (UreG) in delivery of nickel to urease. AB - Urease is a ubiquitous nickel metalloenzyme. In plants, its activation requires three urease accessory proteins (UAPs), UreD, UreF, and UreG. In bacteria, the UAPs interact with urease and facilitate activation, which involves the channeling of two nickel ions into the active site. So far this process has not been investigated in eukaryotes. Using affinity pulldowns of Strep-tagged UAPs from Arabidopsis and rice transiently expressed in planta, we demonstrate that a urease-UreD-UreF-UreG complex exists in plants and show its stepwise assembly. UreG is crucial for nickel delivery because UreG-dependent urease activation in vitro was observed only with UreG obtained from nickel-sufficient plants. This activation competence could not be generated in vitro by incubation of UreG with nickel, bicarbonate, and GTP. Compared with their bacterial orthologs, plant UreGs possess an N-terminal extension containing a His- and Asp/Glu-rich hypervariable region followed by a highly conserved sequence comprising two potential HXH metal-binding sites. Complementing the ureG-1 mutant of Arabidopsis with N-terminal deletion variants of UreG demonstrated that the hypervariable region has a minor impact on activation efficiency, whereas the conserved region up to the first HXH motif is highly beneficial and up to the second HXH motif strictly required for activation. We also show that urease reaches its full activity several days after nickel becomes available in the leaves, indicating that urease activation is limited by nickel accessibility in vivo Our data uncover the crucial role of UreG for nickel delivery during eukaryotic urease activation, inciting further investigations of the details of this process. PMID- 28710281 TI - Identification and quantification of protein S-nitrosation by nitrite in the mouse heart during ischemia. AB - Nitrate (NO3-) and nitrite (NO2-) are known to be cardioprotective and to alter energy metabolism in vivo NO3- action results from its conversion to NO2- by salivary bacteria, but the mechanism(s) by which NO2- affects metabolism remains obscure. NO2- may act by S-nitrosating protein thiols, thereby altering protein activity. But how this occurs, and the functional importance of S-nitrosation sites across the mammalian proteome, remain largely uncharacterized. Here we analyzed protein thiols within mouse hearts in vivo using quantitative proteomics to determine S-nitrosation site occupancy. We extended the thiol-redox proteomic technique, isotope-coded affinity tag labeling, to quantify the extent of NO2- dependent S-nitrosation of proteins thiols in vivo Using this approach, called SNOxICAT (S-nitrosothiol redox isotope-coded affinity tag), we found that exposure to NO2- under normoxic conditions or exposure to ischemia alone results in minimal S-nitrosation of protein thiols. However, exposure to NO2- in conjunction with ischemia led to extensive S-nitrosation of protein thiols across all cellular compartments. Several mitochondrial protein thiols exposed to the mitochondrial matrix were selectively S-nitrosated under these conditions, potentially contributing to the beneficial effects of NO2- on mitochondrial metabolism. The permeability of the mitochondrial inner membrane to HNO2, but not to NO2-, combined with the lack of S-nitrosation during anoxia alone or by NO2- during normoxia places constraints on how S-nitrosation occurs in vivo and on its mechanisms of cardioprotection and modulation of energy metabolism. Quantifying S nitrosated protein thiols now allows determination of modified cysteines across the proteome and identification of those most likely responsible for the functional consequences of NO2- exposure. PMID- 28710282 TI - Function of inhibitor of Bruton's tyrosine kinase isoform alpha (IBTKalpha) in nonalcoholic steatohepatitis links autophagy and the unfolded protein response. AB - Nonalcoholic fatty liver disease (steatosis) is the most prevalent liver disease in the Western world. One of the advanced pathologies is nonalcoholic steatohepatitis (NASH), which is associated with induction of the unfolded protein response (UPR) and disruption of autophagic flux. However, the mechanisms by which these processes contribute to the pathogenesis of human diseases are unclear. Herein, we identify the alpha isoform of the inhibitor of Bruton's tyrosine kinase (IBTKalpha) as a member of the UPR, whose expression is preferentially translated during endoplasmic reticulum (ER) stress. We found that IBTKalpha is located in the ER and associates with proteins LC3b, SEC16A, and SEC31A and plays a previously unrecognized role in phagophore initiation from ER exit sites. Depletion of IBTKalpha helps prevent accumulation of autophagosome intermediates stemming from exposure to saturated free fatty acids and rescues hepatocytes from death. Of note, induction of IBTKalpha and the UPR, along with inhibition of autophagic flux, was associated with progression from steatosis to NASH in liver biopsies. These results indicate a function for IBTKalpha in NASH that links autophagy with activation of the UPR. PMID- 28710283 TI - Amorphous protein aggregates stimulate plasminogen activation, leading to release of cytotoxic fragments that are clients for extracellular chaperones. AB - The misfolding of proteins and their accumulation in extracellular tissue compartments as insoluble amyloid or amorphous protein aggregates are a hallmark feature of many debilitating protein deposition diseases such as Alzheimer's disease, prion diseases, and type II diabetes. The plasminogen activation system is best known as an extracellular fibrinolytic system but was previously reported to also be capable of degrading amyloid fibrils. Here we show that amorphous protein aggregates interact with tissue-type plasminogen activator and plasminogen, via an exposed lysine-dependent mechanism, to efficiently generate plasmin. The insoluble aggregate-bound plasmin is shielded from inhibition by alpha2-antiplasmin and degrades amorphous protein aggregates to release smaller, soluble but relatively hydrophobic fragments of protein (plasmin-generated protein fragments (PGPFs)) that are cytotoxic. In vitro, both endothelial and microglial cells bound and internalized PGPFs before trafficking them to lysosomes. Clusterin and alpha2-macroglobulin bound to PGPFs to significantly ameliorate their toxicity. On the basis of these findings, we hypothesize that, as part of the in vivo extracellular proteostasis system, the plasminogen activation system may work synergistically with extracellular chaperones to safely clear large and otherwise pathological protein aggregates from the body. PMID- 28710284 TI - The neuronal protein Neurexin directly interacts with the Scribble-Pix complex to stimulate F-actin assembly for synaptic vesicle clustering. AB - Synaptic vesicles (SVs) form distinct pools at synaptic terminals, and this well regulated separation is necessary for normal neurotransmission. However, how the SV cluster, in particular synaptic compartments, maintains normal neurotransmitter release remains a mystery. The presynaptic protein Neurexin (NRX) plays a significant role in synaptic architecture and function, and some evidence suggests that NRX is associated with neurological disorders, including autism spectrum disorders. However, the role of NRX in SV clustering is unclear. Here, using the neuromuscular junction at the 2-3 instar stages of Drosophila larvae as a model and biochemical imaging and electrophysiology techniques, we demonstrate that Drosophila NRX (DNRX) plays critical roles in regulating synaptic terminal clustering and release of SVs. We found that DNRX controls the terminal clustering and release of SVs by stimulating presynaptic F-actin. Furthermore, our results indicate that DNRX functions through the scaffold protein Scribble and the GEF protein DPix to activate the small GTPase Ras related C3 Botulinum toxin substrate 1 (Rac1). We observed a direct interaction between the C-terminal PDZ-binding motif of DNRX and the PDZ domains of Scribble and that Scribble bridges DNRX to DPix, forming a DNRX-Scribble-DPix complex that activates Rac1 and subsequently stimulates presynaptic F-actin assembly and SV clustering. Taken together, our work provides important insights into the function of DNRX in regulating SV clustering, which could help inform further research into pathological neurexin-mediated mechanisms in neurological disorders such as autism. PMID- 28710285 TI - P-Rex1 and P-Rex2 RacGEFs and cancer. AB - Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger (P-Rex) proteins are RacGEFs that are synergistically activated by phosphatidylinositol 3,4,5 trisphosphate and Gbetagamma subunits of G-protein-coupled receptors. P-Rex1 and P-Rex2 share similar amino acid sequence homology, domain structure, and catalytic function. Recent evidence suggests that both P-Rex proteins may play oncogenic roles in human cancers. P-Rex1 and P-Rex2 are altered predominantly via overexpression and mutation, respectively, in various cancer types, including breast cancer, prostate cancer, and melanoma. This review compares the similarities and differences between P-Rex1 and P-Rex2 functions in human cancers in terms of cellular effects and signalling mechanisms. Emerging clinical data predict that changes in expression or mutation of P-Rex1 and P-Rex2 may lead to changes in tumour outcome, particularly in breast cancer and melanoma. PMID- 28710286 TI - How tetraspanins shape endothelial and leukocyte nano-architecture during inflammation. AB - Tetraspanins are ubiquitous membrane proteins that induce local membrane curvature and hence co-ordinate cell-to-cell contacts. This review highlights their role in inflammation, which requires control of the nano-architecture of attachment sites between endothelial cells and leukocytes. The active role of endothelial cells in preparing for transmigration of leukocytes and determining the severity of an inflammation is often underscored. A clear hint to endothelial pre-activation is their ability to protrude clustered adhesion proteins upward prior to leukocyte contact. The elevation of molecular adhesive platforms toward the blood stream is crucially dependent on tetraspanins. In addition, leukocytes require tetraspanins for their activation. The example of the B-cell receptor is referenced in some detail here, since it provides deeper insights into the receptor-coreceptor interplay. To lift the role of tetraspanins from an abstract model of inflammation toward a player of clinical significance, two pathologies are analyzed for the known contributions of tetraspanins. The recent publication of the first crystal structure of a full-length tetraspanin revealed a cholesterol-binding site, which provides a strong link to the pathophysiological condition of atherosclerosis. Dysregulation of the inflammatory cascade in autoimmune diseases by endothelial cells is exemplified by the involvement of tetraspanins in multiple sclerosis. PMID- 28710288 TI - Post-transcriptional control of gene expression following stress: the role of RNA binding proteins. AB - The ability of mammalian cells to modulate global protein synthesis in response to cellular stress is essential for cell survival. While control of protein synthesis is mediated by the regulation of eukaryotic initiation and elongation factors, RNA-binding proteins (RBPs) provide a crucial additional layer to post transcriptional regulation. RBPs bind specific RNA through conserved RNA-binding domains and ensure that the information contained within the genome and transcribed in the form of RNA is exported to the cytoplasm, chemically modified, and translated prior to folding into a functional protein. Thus, this group of proteins, through mediating translational reprogramming, spatial reorganisation, and chemical modification of RNA molecules, have a major influence on the robust cellular response to external stress and toxic injury. PMID- 28710287 TI - RNA search engines empower the bacterial intranet. AB - RNA acts not only as an information bearer in the biogenesis of proteins from genes, but also as a regulator that participates in the control of gene expression. In bacteria, small RNA molecules (sRNAs) play controlling roles in numerous processes and help to orchestrate complex regulatory networks. Such processes include cell growth and development, response to stress and metabolic change, transcription termination, cell-to-cell communication, and the launching of programmes for host invasion. All these processes require recognition of target messenger RNAs by the sRNAs. This review summarizes recent results that have provided insights into how bacterial sRNAs are recruited into effector ribonucleoprotein complexes that can seek out and act upon target transcripts. The results hint at how sRNAs and their protein partners act as pattern-matching search engines that efficaciously regulate gene expression, by performing with specificity and speed while avoiding off-target effects. The requirements for efficient searches of RNA patterns appear to be common to all domains of life. PMID- 28710289 TI - Nutritional modulation of metabolic inflammation. AB - Metabolic inflammation is a very topical area of research, wherein aberrations in metabolic and inflammatory pathways probably contribute to atherosclerosis, insulin resistance (IR) and type 2 diabetes. Metabolic insults arising from obesity promote inflammation, which in turn impedes insulin signalling and reverse cholesterol transport (RCT). Key cells in the process are metabolically activated macrophages, which up-regulate both pro- and anti-inflammatory pathways in response to lipid spillover from adipocytes. Peroxisome proliferator-activated receptors and AMP-activated protein kinase (AMPK) are regulators of cellular homeostasis that influence both inflammatory and metabolic pathways. Dietary fats, such as saturated fatty acids (SFAs), can differentially modulate metabolic inflammation. Palmitic acid, in particular, is a well-characterized nutrient that promotes metabolic inflammation via the NLRP3 (the nod-like receptor containing a pyrin domain) inflammasome, which is partly attributable to AMPK inhibition. Conversely, some unsaturated fatty acids are less potent agonists of metabolic inflammation. For example, monounsaturated fatty acid does not reduce AMPK as potently as SFA and n-3 polyunsaturated fatty acids actively resolve inflammation via resolvins and protectins. Nevertheless, the full extent to which nutritional state modulates metabolic inflammation requires greater clarification. PMID- 28710290 TI - 3'-Terminated Overhangs Regulate DNA Double-Strand Break Processing in Escherichia coli. AB - Double-strand breaks (DSBs) are lethal DNA lesions, which are repaired by homologous recombination in Escherichia coli To study DSB processing in vivo, we induced DSBs into the E. coli chromosome by gamma-irradiation and measured chromosomal degradation. We show that the DNA degradation is regulated by RecA protein concentration and its rate of association with single-stranded DNA (ssDNA). RecA decreased DNA degradation in wild-type, recB, and recD strains, indicating that it is a general phenomenon in E. coli On the other hand, DNA degradation was greatly reduced and unaffected by RecA in the recB1080 mutant (which produces long overhangs) and in a strain devoid of four exonucleases that degrade a 3' tail (ssExos). 3'-5' ssExos deficiency is epistatic to RecA deficiency concerning DNA degradation, suggesting that bound RecA is shielding the 3' tail from degradation by 3'-5' ssExos. Since 3' tail preservation is common to all these situations, we infer that RecA polymerization constitutes a subset of mechanisms for preserving the integrity of 3' tails emanating from DSBs, along with 3' tail's massive length, or prevention of their degradation by inactivation of 3'-5' ssExos. Thus, we conclude that 3' overhangs are crucial in controlling the extent of DSB processing in E. coli This study suggests a regulatory mechanism for DSB processing in E. coli, wherein 3' tails impose a negative feedback loop on DSB processing reactions, specifically on helicase reloading onto dsDNA ends. PMID- 28710291 TI - Two Types of Etiological Mutation in the Limb-Specific Enhancer of Shh. AB - An enhancer named MFCS1 regulates Sonic hedgehog (Shh) expression in the posterior mesenchyme of limb buds. Several mutations in MFCS1 induce ectopic Shh expression in the anterior limb bud, and these result in preaxial polydactyly (PPD). However, the molecular basis of ectopic Shh expression remains elusive, although some mutations are known to disrupt the negative regulation of Shh expression in the anterior limb bud. Here, we analyzed the molecular mechanism of ectopic Shh expression in PPD including in a mouse mutation-hemimelic extra toes (Hx)-and in other MFCS1 mutations in different species. First, we generated transgenic mouse lines with a LacZ reporter cassette flanked with tandem repeats of 40 bp MFCS1 fragments harboring a mutation. The transgenic mouse line with the Hx-type fragment showed reporter expression exclusively in the anterior, but not in the posterior margins of limb buds. In contrast, no specific LacZ expression was observed in lines carrying the MFCS1 fragment with other mutations. Yeast one hybrid assays revealed that the msh-like homeodomain protein, MSX1, bound specifically to the Hx sequence of MFCS1. Thus, PPD caused by mutations in MFCS1 has two major types of molecular etiology: loss of a cis-motif for negative regulation of Shh, and acquisition of a new cis-motif binding to a preexisting transcription factor, as represented by the Hx mutation. PMID- 28710292 TI - The safety of intracytoplasmic sperm injection and long-term outcomes. AB - The pioneering of intracytoplasmic sperm injection (ICSI) approximately 25 years ago revolutionized the treatment of infertile couples. Today, ICSI remains an indispensable part of assisted reproductive treatments (ART) and has resulted in the birth of millions of babies. The 25th anniversary of ICSI marks a chronologic landmark in its evolving history. This landmark also serves as an opportunity to thoroughly appraise the safety of ICSI and analyze the long-term outcomes of ICSI conceived children. In this review, we collate and analyze salient data accrued over the past 25 years pertaining to the long-term safety of ICSI and ICSI conceptions. We also evaluate the effects of ICSI on the perinatal outcomes, congenital malformation rates, cognitive development and reproductive health of ICSI-conceived neonates, children, adolescents and adults, respectively. In doing so, we also highlight the existence of potential confounders and biases that frequently obscure the interpretation of clinical follow-up studies. PMID- 28710294 TI - Steroid hormone receptors and direct effects of steroid hormones on ram spermatozoa. AB - This study was based on the assumption that steroid hormones present in the female genital tract may have a rapid effect on ram spermatozoa by interaction with specific surface receptors. We demonstrate the presence of progesterone (PR) and estrogen (ER) receptors in ram spermatozoa, their localization changes during in vitro capacitation and the actions of progesterone (P4) and 17beta-estradiol (E2) on ram sperm functionality. Immunolocalization assays revealed the presence of PR mainly at the equatorial region of ram spermatozoa. Western blot analyses showed three bands in ram sperm protein extracts of 40-45 kDa, compatible with those reported for PR in the human sperm membrane, and both classical estrogen receptors (66 kDa, ERalpha and 55 kDa, ERbeta). ERalpha was located in the postacrosomal region of all the spermatozoa and ERbeta on the apical region of 63.7% of the cells. The presence of ERbeta was correlated with the percentage of non-capacitated spermatozoa evaluated by chlortetracycline staining (R = 0.848, P < 0.001). This significantly decreased after in vitro capacitation and nearly disappeared when acrosome reaction was induced. The addition of P4 and E2 before in vitro capacitation resulted in a higher (P < 0.001) acrosome-reacted sperm rate compared with the control (13.0%), noticeably greater after 3 h and when added to a high-cAMP medium (37.3% and 47.0% with E2 and P4, respectively). In conclusion, the results of this study demonstrate for the first time that ovine spermatozoa have progesterone and estrogen receptors and that both steroid hormones are related with the induction of the acrosome reaction. PMID- 28710295 TI - Relationships between gastrointestinal microbiota and blood group antigens. AB - FUT2 is a gene for a fucosyltransferase that encodes expression of ABO blood group antigens found on gastrointestinal mucosa and secretions. We hypothesized that the fecal microbiomes of healthy subjects, with blood group antigens A, B, and O, have differing compositions. We analyzed 33 fecal and blood specimens from healthy subjects for FUT2 genotype, and the fecal microbiome was determined by 454 pyrosequencing. Our data show that being a blood group secretor is associated with less diversity at higher orders of taxonomy; and the presence of blood group A antigens in the secretor subjects are associated with an expansion families of bacteria within the gut. Furthermore, our study confirms the previous findings that secretors and nonsecretors have differing bacterial taxa. This extends the previous findings by demonstrating that the impact of being a nonsecretor is higher than that of individual blood group antigens. Additionally, we demonstrate that both secretor status and blood group antigen expression especially affect the Lachnospiraceae family of bacteria within the gut microbiome, with lower abundances noted in nonsecretors and higher abundances in secretors of various blood groups. We further note specific differences in blood group A-secretors demonstrating that the genus Blautia is lower in the group A-secretors compared with the non-A-secretors and that this reduction is accompanied by higher abundances of members of the Rikenellaceae, Peptostreptococcaceae, Clostridiales, and Turicibacter This study offers a first insight into the relationship between the fecal microbiome and blood group antigens in secretors. PMID- 28710293 TI - Probing GATA factor function in mouse Leydig cells via testicular injection of adenoviral vectors. AB - Testicular Leydig cells produce androgens essential for proper male reproductive development and fertility. Here, we describe a new Leydig cell ablation model based on Cre/Lox recombination of mouse Gata4 and Gata6, two genes implicated in the transcriptional regulation of steroidogenesis. The testicular interstitium of adult Gata4flox/flox ; Gata6flox/flox mice was injected with adenoviral vectors encoding Cre + GFP (Ad-Cre-IRES-GFP) or GFP alone (Ad-GFP). The vectors efficiently and selectively transduced Leydig cells, as evidenced by GFP reporter expression. Three days after Ad-Cre-IRES-GFP injection, expression of androgen biosynthetic genes (Hsd3b1, Cyp17a1 and Hsd17b3) was reduced, whereas expression of another Leydig cell marker, Insl3, was unchanged. Six days after Ad-Cre-IRES GFP treatment, the testicular interstitium was devoid of Leydig cells, and there was a concomitant loss of all Leydig cell markers. Chromatin condensation, nuclear fragmentation, mitochondrial swelling, and other ultrastructural changes were evident in the degenerating Leydig cells. Liquid chromatography-tandem mass spectrometry demonstrated reduced levels of androstenedione and testosterone in testes from mice injected with Ad-Cre-IRES-GFP. Late effects of treatment included testicular atrophy, infertility and the accumulation of lymphoid cells in the testicular interstitium. We conclude that adenoviral-mediated gene delivery is an expeditious way to probe Leydig cell function in vivo Our findings reinforce the notion that GATA factors are key regulators of steroidogenesis and testicular somatic cell survival.Free Finnish abstract: A Finnish translation of this abstract is freely available at http://www.reproduction online.org/content/154/4/455/suppl/DC2. PMID- 28710296 TI - Priorities for Cardiovascular Outcomes Research: A Report of the National Heart, Lung, and Blood Institute's Centers for Cardiovascular Outcomes Research Working Group. AB - The Centers for Cardiovascular Outcomes Research (CCORs) held a meeting to review how cardiovascular outcomes research had evolved in the decade since the National Heart, Lung, and Blood Institute 2004 working group report and to consider future directions. The conference involved representatives from governmental agencies, outcomes research thought leaders, and public and private healthcare partners. The main purposes of this meeting were to (1) advance collaborative high-yield, high-impact outcomes research; (2) identify priorities and barriers to important cardiovascular outcomes research; and (3) define future needs for the field. This report highlights the key topics covered during the meeting, including an examination of the recent history of outcomes research, an evaluation of the current academic climate, and a vision for the future of cardiovascular outcomes research. PMID- 28710298 TI - Surgeon Experience and Outcomes: An Age Old Question. PMID- 28710297 TI - Association of Surgeon Age and Experience With Congenital Heart Surgery Outcomes. AB - BACKGROUND: Surgeon experience concerns both families of children with congenital heart disease and medical providers. Relationships between surgeon seniority and patient outcomes are often assumed, yet there are little data. METHODS AND RESULTS: This national study used linked data from the American Medical Association Physician Masterfile and the Society of Thoracic Surgeons-Congenital Heart Surgery Database to examine associations between surgeon years since medical school and major morbidity/mortality for children undergoing cardiac surgery. Sensitivity analyses explored the effects of patient characteristics, institutional/surgeon volumes, and various measures of institutional surgeon team experience. In secondary analyses, major morbidity and mortality were examined as separate end points. We identified 206 congenital heart surgeons from 91 centers performing 62 851 index operations (2010-2014). Median time from school was 25 years (range 9-55 years). A major morbidity/mortality occurred in 11.5% of cases. In multivariable analyses, the odds of major morbidity/mortality were similar for early-career (<15 years from medical school, ~<40 years old), midcareer (15-24 years, ~40-50 years old), and senior surgeons (25-35 years, ~50-60 years old). The odds of major morbidity/mortality were ~25% higher for operations performed by very senior surgeons (35-55 years from school, ~60-80 years old; n=9044 cases). Results were driven by differences in morbidity. In extensive sensitivity analyses, these effects remained constant. CONCLUSIONS: In this study of >200 congenital heart surgeons, we found patient outcomes for surgeons with the fewest years of experience to be comparable to those of their midcareer and senior colleagues, within the context of existing referral and support practices. Very senior surgeons had higher risk-adjusted odds of major morbidity/mortality. Contemporary approaches to training, referral, mentoring, surgical planning, and other support practices might contribute to the observed outcomes of junior congenital heart surgeons being comparable to those of more experienced colleagues. Understanding and disseminating these practices might benefit the medical community at large. PMID- 28710299 TI - Takotsubo cardiomyopathy-related complete heart block and torsades de pointes. AB - Takotsubo cardiomyopathy (TCM) is a relatively recently recognised clinical entity. It frequently mimics acute coronary syndrome and is accompanied by reversible left ventricular apical ballooning in the absence of angiographically significant coronary artery stenosis. TCM is a reversible condition, and the prognosis is usually well. However, in rare instances, it can be associated with life-threatening arrhythmic complications. Herein, we report the case of a patient with TCM who developed complete atrioventricular block followed by QT prolongation and torsades de pointes. Furthermore, we undertook a literature review of this rare complication of TCM and discussed the formidable therapeutic challenge encountered in such patients. PMID- 28710300 TI - Constrictive pericarditis from an endocardial pacemaker lead. AB - Constrictive pericarditis secondary to endocardial pacemaker inflammation, without associated pericardial effusion or infection, has yet to be described in the literature. We present a case of a 42-year-old man who developed recurrent ascites from regional constrictive pericarditis following pacemaker implant. Symptoms resolved after pericardiectomy. PMID- 28710301 TI - Pituitary apoplexy: a rare complication of leuprolide therapy in prostate cancer treatment. AB - Gonadotropin-releasing hormone agonists, used widely in the treatment of metastatic prostate cancer and hormone receptor-positive breast cancer, are associated with a rare but potentially fatal outcome of pituitary apoplexy (PA). An 85-year-old man presented with sudden onset of headache, left eye pain, sensitivity to light, nausea and vomiting. The symptoms started 4 hours after initiation of leuprolide therapy for treatment of recently diagnosed metastatic prostate carcinoma. Radiological imaging of the brain demonstrated a heterogeneously enlarged pituitary gland measuring 19*16*13 mm and T1 hyperintense signal compatible with pituitary haemorrhage. Hormone function tests were indicative of panhypopituitarism, confirming the diagnosis of PA. Due to age, the patient was started on hormonal replacement therapy and eventually symptoms improved. PMID- 28710302 TI - A rare case of atypical chronic lymphocytic leukaemia presenting as nephrotic syndrome. AB - Chronic lymphocytic leukaemia (CLL) is characterised by a lymphocytosis of mature appearing clonal CD5+, CD23+ B lymphocytes. CLL cells arise from the bone marrow and infiltrate lymphoid tissues such as lymph nodes and spleen. Presentation is usually through discovery of lymphocytosis or lymphadenopathy. Unusual presentations, especially paraneoplastic syndromes are rare. Here, we describe a rare case presenting with severe nephrotic syndrome associated with the presence of a monoclonal protein in serum. Workup for suspected plasma cell dyscrasia led instead to the diagnosis of bone marrow infiltration by atypical CLL without lymphocytosis. Renal biopsy showed a glomerulonephritis that turned out to be paraneoplastic as it went into remission after treatment for CLL. Our case shows an unusual presentation of CLL and prompts for increased awareness of lymphoproliferative disorders in the context of seemingly unrelated conditions that may be paraneoplastic in origin. PMID- 28710303 TI - Intrapartum spontaneous pneumomediastinum and surgical emphysema (Hamman's syndrome) in a 30-year-old woman with asthma. AB - The authors report a case of a 30-year-old nulliparous woman with a prior medical history of asthma who developed intrapartum pneumomediastinum with surgical emphysema during the second stage of labour. She was managed conservatively with supportive care and there was complete resolution of symptoms within 4 days. Clinical and radiological findings were consistent with Hamman's syndrome (spontaneous pneumomediastinum). This case reiterates the possibility of childhood asthma or a family history of asthma as being an associated risk factor for Hamman's syndrome and reminds us of the need to distinguish such clinical findings from more important and potentially life-threatening conditions such as oesophageal rupture, pulmonary embolism and aortic dissection that can present with similar findings. PMID- 28710304 TI - Hyponatraemia-associated catatonia. AB - This is a case report highlighting the impact of low sodium levels on one's mental status. For the first time in the literature, we see two discrete episodes of catatonia associated with hyponatraemia occurring in the same patient. On both occasions, his serum sodium levels were depleted; he became profoundly psychotic with catatonic symptoms. Recovery, with complete resolution of all symptoms, was associated with normalisation of these levels. This case exemplifies the profound effect that electrolyte imbalances, in particular sodium depletion can have on a patient's mental status and is for the first time, we see this effect on two temporally unrelated occasions in the same patient. PMID- 28710305 TI - Autism spectrum disorder in Say-Barber-Biesecker-Young-Simpson syndrome. AB - Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS), also known as Ohdo syndrome SBBYS type, is a rare genetic disorder characterised by dysmorphic facial features and severe intellectual disability, as well as cardiac, dental and hearing abnormalities. There has been little psychiatric or psychological description of children with SBBYSS, although previous reports noted repetitive self-injurious behaviours, sensitivity to light and noise and severe deficits in communication. In this report, a 4-year-old male with SBBYSS is described with a focus on psychiatric and psychological assessment, including formal testing for autism spectrum disorder (ASD). Results of multiple behavioural assessment scales are reported. Testing revealed characteristic ASD features, and the patient met criteria for ASD diagnosis in the context of SBBYSS. His behaviours improved with Applied Behavioural Analysis therapy and communication skills training. This is the first documented case of ASD reported alongside SBBYSS. These results suggest ASD may be a clinical feature of SBBYSS. PMID- 28710306 TI - Ruxolitinib treatment in an infant with JAK2+ polycythaemia vera-associated Budd Chiari syndrome. AB - Budd-Chiari syndrome (BCS) is caused by hepatic venous outflow obstruction commonly seen with myeloproliferative neoplasms (MPNs). Polycythaemia vera (PV) is a very rare MPN in childhood. This is the youngest reported patient diagnosed with PV and BCS secondary to JAK V617F mutation.A 26-month-old girl was admitted with a 5-month history of abdominal distension, hepatosplenomegaly and ascites. Imaging studies revealed occlusion of the right hepatic vein and marked attenuation of the middle and left hepatic veins. BCS was diagnosed after excluding other causes of chronic liver disease. Mandatory prothrombotic workup revealed underlying PV.Partial recanalisation of hepatic veins occurred following anticoagulation therapy and PV was well controlled by pegylated interferon and hydroxycarbamide until she developed nephrotic syndrome, likely secondary to pegylated interferon. Therefore, treatment was modified to ruxolitinib, a novel JAK-2 inhibitor; the therapy has been effective for almost 20 months with a good response and has no side effects. PMID- 28710307 TI - Is it safe to acutely discontinue insulin therapy in patients with chronic hyperglycaemia starting GLP-1R agonists? AB - We report two patients with chronic hyperglycaemia secondary to type 2 diabetes who developed severe vomiting on d. The first patient was diagnosed with a mixed picture of diabetic ketoacidosis (DKA) and hyperosmolar hyperglycaemic state (HHS) and the second, with DKA. They were on insulin therapy which was discontinued on commencing d because of inefficacy and weight gain. The HHS patient developed dehydration secondary to vomiting and had lactic acidosis but no other precipitant could be found in either case. It appears that the abrupt insulin discontinuation coupled with vomiting and dehydration led to the metabolic derangements. Subsequent C-peptide levels were found to be low in both patients. In view of the predisposition of patients with chronic hyperglycaemia to glucagon-like peptide 1 receptor (GLP-1R) downregulation and the lag time to optimal efficacy of GLP-1R agonists, we propose that patients should have C peptide levels measured to determine the risk of ketosis and whether insulin should be continued with dose adjustments when starting a GLP-1R agonist. PMID- 28710308 TI - A rare cause of dysphagia. PMID- 28710310 TI - Corrigendum. PMID- 28710309 TI - Transorbital globe sparing penetrating cranial injury with a metallic screw: large cranio-orbital foreign body. PMID- 28710311 TI - Corrigendum. PMID- 28710312 TI - Aspirin Inhibits Cancer Metastasis and Angiogenesis via Targeting Heparanase. AB - Purpose: Recent epidemiological and clinical studies have suggested the benefit of aspirin for patients with cancer, which inspired increasing efforts to demonstrate the anticancer ability of aspirin and reveal the molecular mechanisms behind. Nevertheless, the anticancer activity and related mechanisms of aspirin remain largely unknown. This study aimed to confirm this observation, and more importantly, to investigate the potential target contributed to the anticancer of aspirin.Experimental Design: A homogeneous time-resolved fluorescence (HTRF) assay was used to examine the impact of aspirin on heparanase. Streptavidin pull down, surface plasmon resonance (SPR) assay, and molecular docking were performed to identify heparanase as an aspirin-binding protein. Transwell, rat aortic rings, and chicken chorioallantoic membrane model were used to evaluate the antimetastasis and anti-angiogenesis effects of aspirin, and these phenotypes were tested in a B16F10 metastatic model, MDA-MB-231 metastatic model, and MDA-MB 435 xenograft model.Results: This study identified heparanase, an oncogenic extracellular matrix enzyme involved in cancer metastasis and angiogenesis, as a potential target of aspirin. We had discovered that aspirin directly binds to Glu225 region of heparanase and inhibits the enzymatic activity. Aspirin impeded tumor metastasis, angiogenesis, and growth in heparanase-dependent manner.Conclusions: In summary, this study has illustrated heparanase as a target of aspirin for the first time. It provides insights for a better understanding of the mechanisms of aspirin in anticancer effects, and offers a direction for the development of small-molecule inhibitors of heparanase. Clin Cancer Res; 23(20); 6267-78. (c)2017 AACR. PMID- 28710315 TI - Shallow Whole Genome Sequencing on Circulating Cell-Free DNA Allows Reliable Noninvasive Copy-Number Profiling in Neuroblastoma Patients. AB - Purpose: Neuroblastoma (NB) is a heterogeneous disease characterized by distinct clinical features and by the presence of typical copy-number alterations (CNAs). Given the strong association of these CNA profiles with prognosis, analysis of the CNA profile at diagnosis is mandatory. Therefore, we tested whether the analysis of circulating cell-free DNA (cfDNA) present in plasma samples of patients with NB could offer a valuable alternative to primary tumor DNA for CNA profiling.Experimental Design: In 37 patients with NB, cfDNA analysis using shallow whole genome sequencing (sWGS) was compared with arrayCGH analysis of primary tumor tissue.Results: Comparison of CNA profiles on cfDNA showed highly concordant patterns, particularly in high-stage patients. Numerical chromosome imbalances as well as large and focal structural aberrations including MYCN and LIN28B amplification and ATRX deletion could be readily detected with sWGS using a low input of cfDNA.Conclusions: In conclusion, sWGS analysis on cfDNA offers a cost-effective, noninvasive, rapid, robust and sensitive alternative for tumor DNA copy-number profiling in most patients with NB. Clin Cancer Res; 23(20); 6305 14. (c)2017 AACR. PMID- 28710317 TI - Resistance Mechanisms to AZD9291 and Rociletinib-Letter. PMID- 28710313 TI - Ex Vivo PD-L1/PD-1 Pathway Blockade Reverses Dysfunction of Circulating CEA Specific T Cells in Pancreatic Cancer Patients. AB - Purpose: Carcinoembryonic antigen (CEA) is a candidate target for cellular immunotherapy of pancreatic cancer. In this study, we have characterized the antigen-specific function of autologous cytotoxic T lymphocytes (CTL) specific for the HLA-A2-restricted peptide, pCEA691-699, isolated from the peripheral T cell repertoire of pancreatic cancer patients and sought to determine if ex vivo PD-L1 and TIM-3 blockade could enhance CTL function.Experimental Design: CD8+ T cell lines were generated from peripheral blood mononuclear cells of 18 HLA-A2+ patients with pancreatic cancer and from 15 healthy controls. In vitro peptide specific responses were evaluated by flow cytometry after staining for intracellular cytokine production and carboxy fluorescein succinimydyl ester cytotoxicity assays using pancreatic cancer cell lines as targets.Results: Cytokine-secreting functional CEA691-specific CTL lines were successfully generated from 10 of 18 pancreatic cancer patients, with two CTL lines able to recognize and kill both CEA691 peptide-loaded T2 cells and CEA+ HLA-A2+ pancreatic cancer cell lines. In the presence of ex vivo PD-L1 blockade, functional CEA691-specific CD8+ T-cell responses, including IFNgamma secretion and proliferation, were enhanced, and this effect was more pronounced on Ag specific T cells isolated from tumor draining lymph nodes.Conclusions: These data demonstrate that CEA691-specific CTL can be readily expanded from the self restricted T-cell repertoire of pancreatic cancer patients and that their function can be enhanced by PD-L1 blockade. Clin Cancer Res; 23(20); 6178-89. (c)2017 AACR. PMID- 28710318 TI - Resistance Mechanisms to AZD9291 and Rociletinib-Response. PMID- 28710314 TI - Sarcomatoid Renal Cell Carcinoma Has a Distinct Molecular Pathogenesis, Driver Mutation Profile, and Transcriptional Landscape. AB - Purpose: Sarcomatoid renal cell carcinoma (SRCC) ranks among the most aggressive clinicopathologic phenotypes of RCC. However, the paucity of high-quality, genome wide molecular examinations of SRCC has hindered our understanding of this entity.Experimental Design: We interrogated the mutational, copy number, and transcriptional characteristics of SRCC and compared these data with those of nonsarcomatoid RCC (RCC). We evaluated whole-exome sequencing, single-nucleotide polymorphism, and RNA sequencing data from patients with SRCC (n = 65) and RCC (n = 598) across different parent RCC subtypes, including clear-cell RCC, papillary RCC, and chromophobe RCC subtypes.Results: SRCC was molecularly discrete from RCC and clustered according to its parent RCC subtype, though with upregulation of TGFbeta signaling across all subtypes. The epithelioid (E-) and spindled (S-) histologic components of SRCC did not show differences in mutational load among cancer-related genes despite a higher mutational burden in S-. Notably, sarcomatoid clear-cell RCC (SccRCC) showed significantly fewer deletions at 3p21 25, a lower rate of two-hit loss for VHL and PBRM1, and more mutations in PTEN, TP53, and RELN compared with ccRCC. A two-hit loss involving VHL predicted for ccRCC and a better prognosis, whereas mutations in PTEN, TP53, or RELN predicted for SccRCC and worse prognosis.Conclusions: SRCC segregates by parent subtype, and SccRCC has a fundamentally different early molecular pathogenesis, usually lacking the classic 3p21-25 deletion and showing distinctive mutational and transcriptional profiles. These features prompt a more precise molecular classification of RCC, with diagnostic, prognostic, and therapeutic implications. Clin Cancer Res; 23(21); 6686-96. (c)2017 AACRSee related commentary by Bergerot et al., p. 6381. PMID- 28710319 TI - Correction: Polyphenon E Enhances the Antitumor Immune Response in Neuroblastoma by Inactivating Myeloid Suppressor Cells. PMID- 28710320 TI - Correction: A Phase II Trial of Abiraterone Combined with Dutasteride for Men with Metastatic Castration-Resistant Prostate Cancer. PMID- 28710321 TI - Correction: UNC2025, a MERTK Small-Molecule Inhibitor, Is Therapeutically Effective Alone and in Combination with Methotrexate in Leukemia Models. PMID- 28710322 TI - Retraction: GRM1 is An Androgen-Regulated Gene and its Expression Correlates with Prostate Cancer Progression in Pre-Clinical Models. PMID- 28710323 TI - Organisation of services and clinical practice in acute cerebral venous sinus thrombosis: a UK survey. PMID- 28710324 TI - Brain white matter fibre tracts: a review of functional neuro-oncological relevance. AB - State-of-the-art glioma treatment aims to maximise neuro-oncological benefit while minimising losses in quality of life. Optimising this balance remains hindered by our still limited understanding of information processing in the human brain. To help understand individual differences in functional outcomes following neuro-oncological treatment, we review mounting evidence demonstrating the fundamental role that white matter connections play in complex human behaviour. We focus on selected fibre tracts whose destruction is recognised to elicit predictable behavioural deficits and consider specific indications for non invasive diffusion MRI tractography, the only existing method to map these fibre tracts in vivo, in the selection and planning of neuro-oncological treatments. Despite remaining challenges, longitudinal tract imaging, in combination with intraoperative testing and neuropsychological evaluation, offers unique opportunities to refine our understanding of human brain organisation in the quest to predict and ultimately reduce the quality of life burden of both surgical and non-surgical first-line neuro-oncological therapies. PMID- 28710325 TI - Lack of T1 hyperintensity in the dentate nucleus after 15 administrations of a macrocyclic contrast agent in multiple sclerosis. PMID- 28710326 TI - Cortical influences drive amyotrophic lateral sclerosis. AB - The early motor manifestations of sporadic amyotrophic lateral sclerosis (ALS), while rarely documented, reflect failure of adaptive complex motor skills. The development of these skills correlates with progressive evolution of a direct corticomotoneuronal system that is unique to primates and markedly enhanced in humans. The failure of this system in ALS may translate into the split hand presentation, gait disturbance, split leg syndrome and bulbar symptomatology related to vocalisation and breathing, and possibly diffuse fasciculation, characteristic of ALS. Clinical neurophysiology of the brain employing transcranial magnetic stimulation has convincingly demonstrated a presymptomatic reduction or absence of short interval intracortical inhibition, accompanied by increased intracortical facilitation, indicating cortical hyperexcitability. The hallmark of the TDP-43 pathological signature of sporadic ALS is restricted to cortical areas as well as to subcortical nuclei that are under the direct control of corticofugal projections. This provides anatomical support that the origins of the TDP-43 pathology reside in the cerebral cortex itself, secondarily in corticofugal fibres and the subcortical targets with which they make monosynaptic connections. The latter feature explains the multisystem degeneration that characterises ALS. Consideration of ALS as a primary neurodegenerative disorder of the human brain may incorporate concepts of prion-like spread at synaptic terminals of corticofugal axons. Further, such a concept could explain the recognised widespread imaging abnormalities of the ALS neocortex and the accepted relationship between ALS and frontotemporal dementia. PMID- 28710327 TI - Smoke-free signage in public parks: impacts on smoking behaviour. AB - OBJECTIVE: Behavioural interventions, such as smoke-free signage, are used to support air quality in public outdoor spaces that are not protected by a smoke free policy, such as states with preemptive clause legislation. However, there is little evidence of the effectiveness of these interventions. This paper is an evaluation of whether smoke-free signage posted in public parks altered smoking behaviours of park patrons. METHODS: A time-series quasi-experimental design was used. Cigarette butts were collected at the same day and time every week in ten amenities within four parks in 2011. Each park completed a baseline period until a stable trend emerged at six weeks, then received smoke-free signage for the six week intervention period. There were 1684 cigarette butts collected during baseline and 1008 collected during the intervention phase. FINDINGS: Wilcoxon signed-rank test demonstrated that smoking at seven out of ten amenities decreased and the overall decrease was significant at p=0.028. Individual parks and amenities grouped by type did not experience a statistically significant change. A neighbourhood median income trend was visually discovered, revealing that as income increased, there was a greater decrease in cigarette butts. CONCLUSIONS: This study provides evidence on the impact of smoke-free signage not supported by local ordinance in public parks using a reproducible measure. States, especially those with a preemptive clause legislation, may benefit from incorporating smoke-free signage in public areas to protect community members from exposure to tobacco smoke, reduce littering, and denormalise smoking. PMID- 28710328 TI - De novo telomere addition at chromosome breaks: Dangerous Liaisons. AB - Telomerase counteracts the loss of terminal DNA sequences from chromosome ends; however, it may erroneously add telomeric repeats to DNA double-strand breaks. In this issue, Ouenzar et al. (2017. J. Cell Biol. https://doi.org/10.1083/jcb.201610071) uncover cell cycle-dependent sequestration of the telomerase RNA in nucleoli, a process that excludes telomerase from DNA repair sites. PMID- 28710329 TI - Open-label trial of ranolazine for the treatment of myotonia congenita. AB - OBJECTIVE: To determine open-label, pilot study whether ranolazine could improve signs and symptoms of myotonia and muscle stiffness in patients with myotonia congenita (MC). METHODS: Thirteen participants were assessed at baseline and 2, 4, and 5 weeks. Ranolazine was started after baseline assessment (500 mg twice daily), increased as tolerated after week 2 (1,000 mg twice daily), and maintained until week 4. Outcomes included change from baseline to week 4 in self reported severity of symptoms (stiffness, weakness, and pain), Timed Up and Go (TUG), hand grip and eyelid myotonia, and myotonia on EMG. RESULTS: Self-reported severity of stiffness (p < 0.0001) and weakness (p < 0.01) was significantly improved compared with baseline. TUG and grip myotonia times were reduced (p = 0.03, p = 0.01). EMG of the abductor digiti minimi and tibialis anterior showed significantly reduced myotonia duration (p < 0.001, p < 0.01) at week 4. No participant discontinued ranolazine because of side effects. CONCLUSIONS: Ranolazine appeared to be well tolerated over a period of 4 weeks in individuals with MC, and ranolazine resulted in improvement of signs and symptoms of muscle stiffness. The findings of this study suggest that ranolazine should be investigated in a larger controlled study. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that ranolazine improves myotonia in myotonia congenita. PMID- 28710331 TI - Reply to Skinnider and Magarvey: Rates of novel natural product discovery remain high. PMID- 28710332 TI - Statistical reanalysis of natural products reveals increasing chemical diversity. PMID- 28710330 TI - Assessment of the interaction of age and sex on 90-day outcome after intracerebral hemorrhage. AB - OBJECTIVE: Because age affects hormonal production differently in women compared with men, we sought to define sex and age interactions across a multiracial/ethnic population after intracerebral hemorrhage (ICH) to uncover evidence that loss of gonadal hormone production would result in loss of the known neuroprotective effects of gonadal hormones. METHODS: Clinical and radiographic data from participants in the Ethnic/Racial Variations of Intracerebral Hemorrhage study and the Genetic and Environmental Risk Factors for Hemorrhagic Stroke study prior to December 2013 were used. Relationships among sex, age, and outcome after ICH in 616 non-Hispanic black, 590 Hispanic, and 868 non-Hispanic white participants were evaluated using multivariable logistic regression analysis. Poor outcome was defined as modified Rankin Scale score >=3 at 90 days after ICH. RESULTS: Sex differences were found in multiple variables among the racial/ethnic groups, including age at onset, premorbid neurologic status, and neurologic outcome after ICH. Overall, no sex-age interaction effect was found for mortality (p = 0.183) or modified Rankin Scale score (p = 0.378) at 90 days after ICH. In racial/ethnic subgroups, only the non-Hispanic black cohort provided possible evidence of a sex-age interaction on 90-day modified Rankin Scale score (p = 0.003). CONCLUSION: Unlike in ischemic stroke, there was no evidence that patient sex modified the effect of age on 90-day outcomes after ICH in a large multiracial/ethnic population. Future studies should evaluate biological reasons for these differences between stroke subtypes. CLINICALTRIALSGOV IDENTIFIER: NCT01202864. PMID- 28710333 TI - Different phosphodiesterases (PDEs) regulate distinct phosphoproteomes during cAMP signaling. PMID- 28710335 TI - Uncoupling protein 1 controls reactive oxygen species in brown adipose tissue. PMID- 28710334 TI - Stem cell-released oncolytic herpes simplex virus has therapeutic efficacy in brain metastatic melanomas. AB - The recent Food and Drug Administration approval of immunogenic oncolytic virus (OV) has opened a new era in the treatment of advanced melanoma; however, approximately 50% of patients with melanoma develop brain metastasis, and currently there are no beneficial treatment options for such patients. To model the progression of metastases seen in patients and to overcome the hurdles of systemic delivery of OV, we developed melanoma brain metastasis models in immunocompromised and immunocompetent mice, and tested the fate and efficacy of oncolytic herpes simplex virus (oHSV)-armed mesenchymal stem cells (MSCs). Using brain-seeking patient-derived melanoma cells and real-time in vivo imaging, we show a widespread distribution of micrometastases and macrometastases in the brain, recapitulating the progression of multifoci metastases seen in patients. We armed MSCs with different oHSV variants (MSC-oHSV) and found that intracarotid administration of MSC-oHSV, but not of purified oHSV alone, effectively tracks metastatic tumor lesions and significantly prolongs the survival of brain tumor bearing mice. In a syngeneic model of melanoma brain metastasis, a combination of MSC-oHSV and PD-L1 blockade increases IFNgamma-producing CD8+ tumor-infiltrating T lymphocytes and results in a profound extension of the median survival of treated animals. This study thus demonstrates the utility of MSCs as OV carriers to disseminated brain lesions, and provides a clinically applicable therapeutic platform to target melanoma brain metastasis. PMID- 28710337 TI - Big-time insights from a tiny bird fossil. PMID- 28710336 TI - Subunit conformational variation within individual GroEL oligomers resolved by Cryo-EM. AB - Single-particle electron cryo-microscopy (cryo-EM) is an emerging tool for resolving structures of conformationally heterogeneous particles; however, each structure is derived from an average of many particles with presumed identical conformations. We used a 3.5-A cryo-EM reconstruction with imposed D7 symmetry to further analyze structural heterogeneity among chemically identical subunits in each GroEL oligomer. Focused classification of the 14 subunits in each oligomer revealed three dominant classes of subunit conformations. Each class resembled a distinct GroEL crystal structure in the Protein Data Bank. The conformational differences stem from the orientations of the apical domain. We mapped each conformation class to its subunit locations within each GroEL oligomer in our dataset. The spatial distributions of each conformation class differed among oligomers, and most oligomers contained 10-12 subunits of the three dominant conformation classes. Adjacent subunits were found to more likely assume the same conformation class, suggesting correlation among subunits in the oligomer. This study demonstrates the utility of cryo-EM in revealing structure dynamics within a single protein oligomer. PMID- 28710338 TI - Unique radiological features of two cases of primary pulmonary diffuse large B cell lymphoma. PMID- 28710340 TI - Induction of the unfolded protein response in familial amyotrophic lateral sclerosis and association of protein-disulfide isomerase with superoxide dismutase 1. PMID- 28710341 TI - Side by side: The work of Elizabeth and James Miller. PMID- 28710339 TI - Impact of low-dose CT screening on smoking cessation among high-risk participants in the UK Lung Cancer Screening Trial. AB - BACKGROUND: Smoking cessation was examined among high-risk participants in the UK Lung Cancer Screening (UKLS) Pilot Trial of low-dose CT screening. METHODS: High risk individuals aged 50-75 years who completed baseline questionnaires were randomised to CT screening (intervention) or usual care (no screening control). Smoking habit was determined at baseline using self-report. Smokers were asked whether they had quit smoking since joining UKLS at T1 (2 weeks after baseline scan results or control assignment) and T2 (up to 2 years after recruitment). Intention-to-treat (ITT) regression analyses were undertaken, adjusting for baseline lung cancer distress, trial site and sociodemographic variables. RESULTS: Of a total 4055 individuals randomised to CT screening or control, 1546 were baseline smokers (759 intervention, 787 control). Smoking cessation rates were 8% (control n=36/479) versus 14% (intervention n=75/527) at T1 and 21% (control n=79/377) versus 24% (intervention n=115/488) at T2. ITT analyses indicated that the odds of quitting among screened participants were significantly higher at T1 (adjusted OR (aOR) 2.38, 95% CI 1.56 to 3.64, p<0.001) and T2 (aOR 1.60, 95% CI 1.17 to 2.18, p=0.003) compared with control. Intervention participants who needed additional clinical investigation were more likely to quit in the longer term compared with the control group (aOR 2.29, 95% CI 1.62 to 3.22, p=0.007) and those receiving a negative result (aOR 2.43, 95% CI 1.54 to 3.84, p<0.001). CONCLUSIONS: CT lung cancer screening for high-risk participants presents a teachable moment for smoking cessation, especially among those who receive a positive scan result. Further behavioural research is needed to evaluate optimal strategies for integrating smoking cessation intervention with stratified lung cancer screening. TRIAL REGISTRATION NUMBER: Results, ISRCTN 78513845. PMID- 28710342 TI - Vincristine, Ifosfamide, and Doxorubicin for Initial Treatment of Ewing Sarcoma in Adults. AB - BACKGROUND: There are no clinical trials specifically addressing chemotherapy for adults with Ewing sarcoma (ES). Five-year event-free survival (EFS) of adults on pediatric studies of ES (44%-47%) is worse than that of children treated with the same therapy (69%). The object of this study was to review the results of therapy with vincristine, ifosfamide, and doxorubicin (VID) in the multidisciplinary treatment of adults with ES at our institution. MATERIALS AND METHODS: Charts for adults treated for ES from 1995 to 2011 were retrospectively reviewed. Clinician reported radiographic tumor response, type of local therapy, pathologic response, and survival data were collected. RESULTS: Seventy-one patients were identified who received VID as initial therapy. The median age was 25 (range: 16-64). Forty two patients (59%) presented with a localized disease and 29 patients (41%) presented with a distant metastasis. Of all patients treated with VID, 83.6% showed a radiological response. Patients who presented with a localized disease had a 5-year overall survival (OS) of 68% (median not reached), compared with 10.3% (median: 1.9 years) in those who presented with distant metastases. Five year EFS was 67%. The nine patients with a pelvic primary tumor had inferior 5 year OS (42%) to the 33 with primary tumors at other sites (75%). The 5-year OS of those who had greater than or equal to 95% necrosis after neoadjuvant VID (n = 20; 5-year OS: 84%) was superior to those who had less than 95% necrosis (n = 13; 5-year OS: 53%). CONCLUSION: In adults with primary ES, VID combined with an adjuvant strategy based on post-treatment percent necrosis has favorable outcomes compared with historical adult controls. IMPLICATIONS FOR PRACTICE: Ewing sarcoma (ES) is a rare tumor in adults, and there are no dedicated clinical trials in the adult population. Most therapy is modeled after the published pediatric studies, although the small numbers of adult patients included on those studies did significantly worse than the children. We modeled our treatment on other adult sarcomas and reviewed the charts of 71 adult patients with ES treated with vincristine, ifosfamide, and doxorubicin (VID). In adults with primary ES, VID combined with an adjuvant strategy based on post-treatment percent necrosis has favorable outcomes compared with historical adult controls. PMID- 28710344 TI - Position of Immobilization After First-Time Traumatic Anterior Glenohumeral Dislocation: A Literature Review. AB - Anterior glenohumeral dislocation affects about 2% of the general population during the lifetime. The incidence of traumatic glenohumeral dislocation ranges from 8.2 to 26.69 per 100 000 population per year. The most common complication is recurrent dislocation occurring in 17-96% of the patients. The majority of patients are treated conservatively by closed reduction and immobilization in internal rotation for 2-3 weeks. However, no clear conservative treatment protocol exists. Immobilization in external rotation can be considered an alternative. A range of external rotation braces are commercially available. The purpose of this work was to review the current literature on conservative management of glenohumeral dislocation and to compare the results of immobilization in internal and external rotation. A comprehensive literature search and review was performed using the keywords "glenohumeral dislocation", "shoulder dislocation", "immobilization", "external rotation", and "recurrent dislocation" in PubMed, MEDLINE, Cochrane Library, Scopus, and Google Scholar databases from their inceptions to May 2016. Three cadaveric studies, 6 imaging studies, 10 clinical studies, and 4 meta-analyses were identified. The total number of 734 patients were included in the clinical studies. Literature analysis revealed better coaptation of the labrum on the glenoid rim in external rotation in cadaveric and imaging studies. However, this tendency was not confirmed by lower redislocation rates or better quality of life in clinical studies. On the basis of the available literature, we cannot confirm the superiority of immobilization in external rotation after glenohumeral dislocation when compared to internal rotation. A yet-to-be-determined group of patients with specific labroligamentous injury pattern may benefit from immobilization in external rotation. Further studies are needed to identify these patients. PMID- 28710345 TI - Deletion of the B-B' and C-C' regions of inverted terminal repeats reduces rAAV productivity but increases transgene expression. AB - Inverted terminal repeats (ITRs) of the adeno-associated virus (AAV) are essential for rescue, replication, packaging, and integration of the viral genome. While ITR mutations have been identified in previous reports, we designed a new truncated ITR lacking the B-B' and C-C' regions named as ITRDeltaBC and investigated its effects on viral genome replication, packaging, and expression of recombinant AAV (rAAV). The packaging ability was compared between ITRDeltaBC rAAV and wild-type (wt) ITR rAAV. Our results showed the productivity of ITRDeltaBC rAAV was reduced 4-fold, which is consistent with the 8-fold decrease in the replication of viral genomic DNA of ITRDeltaBC rAAV compared with wt ITR rAAV. Surprisingly, transgene expression was significantly higher for ITRDeltaBC rAAV. A preliminary exploration of the underlying mechanisms was carried out by inhibiting and degrading the ataxia telangiectasia mutated (ATM) protein and the Mre11 complex (MRN), respectively, since the rAAV expression was inhibited by the ATM and/or MRN through cis interaction or binding with wt ITRs. We demonstrated that the inhibitory effects were weakened on ITRDeltaBC rAAV expression. This study suggests deletion in ITR can affect the transgene expression of AAV, which provides a new way to improve the AAV expression through ITRs modification. PMID- 28710346 TI - The right way to kiss: directionality bias in head-turning during kissing. AB - Humans have a bias for turning to the right in a number of settings. Here we document a bias in head-turning to the right in adult humans, as tested in the act of kissing. We investigated head-turning bias in both kiss initiators and kiss recipients for lip kissing, and took into consideration differences due to sex and handedness, in 48 Bangladeshi heterosexual married couples. We report a significant male bias in the initiation of kissing and a significant bias in head turning to the right in both kiss initiators and kiss recipients, with a tendency among kiss recipients to match their partners' head-turning direction. These interesting outcomes are explained by the influences of societal learning or cultural norms and the potential neurophysiological underpinnings which together offer novel insights about the mechanisms underlying behavioral laterality in humans. PMID- 28710347 TI - Effects of Lipoic Acid on High-Fat Diet-Induced Alteration of Synaptic Plasticity and Brain Glucose Metabolism: A PET/CT and 13C-NMR Study. AB - High-fat diet (HFD)-induced obesity is accompanied by insulin resistance and compromised brain synaptic plasticity through the impairment of insulin-sensitive pathways regulating neuronal survival, learning, and memory. Lipoic acid is known to modulate the redox status of the cell and has insulin mimetic effects. This study was aimed at determining the effects of dietary administration of lipoic acid on a HFD-induced obesity model in terms of (a) insulin signaling, (b) brain glucose uptake and neuronal- and astrocytic metabolism, and (c) synaptic plasticity. 3-Month old C57BL/6J mice were divided into 4 groups exposed to their respective treatments for 9 weeks: (1) normal diet, (2) normal diet plus lipoic acid, (3) HFD, and (4) HFD plus lipoic acid. HFD resulted in higher body weight, development of insulin resistance, lower brain glucose uptake and glucose transporters, alterations in glycolytic and acetate metabolism in neurons and astrocytes, and ultimately synaptic plasticity loss evident by a decreased long term potentiation (LTP). Lipoic acid treatment in mice on HFD prevented several HFD-induced metabolic changes and preserved synaptic plasticity. The metabolic and physiological changes in HFD-fed mice, including insulin resistance, brain glucose uptake and metabolism, and synaptic function, could be preserved by the insulin-like effect of lipoic acid. PMID- 28710348 TI - Spatiotemporal expression patterns of wheat amino acid transporters reveal their putative roles in nitrogen transport and responses to abiotic stress. AB - Amino acid transporters have roles in amino acid uptake from soil, long-distance transport, remobilization from vegetative tissues and accumulation in grain. Critically, the majority of wheat grain nitrogen is derived from amino acids remobilized from vegetative organs. However, no systematic analysis of wheat AAT genes has been reported to date. Here, 283 full length wheat AAT genes representing 100 distinct groups of homeologs were identified and curated by selectively consolidating IWGSC CSSv2 and TGACv1 Triticum aestivum genome assemblies and reassembling or mapping of IWGSC CSS chromosome sorted reads to fill any gaps. Gene expression profiling was performed using public RNA-seq data from root, leaf, stem, spike, grain and grain cells (transfer cell (TC), aleurone cell (AL), and starchy endosperm (SE)). AATs highly expressed in roots are good candidates for amino acid uptake from soil whilst AATs highly expressed in senescing leaves and stems may be involved in translocation to grain. AATs in TC (TaAAP2 and TaAAP19) and SE (TaAAP13) may play important roles in determining grain protein content and grain yield. The expression levels of AAT homeologs showed unequal contributions in response to abiotic stresses and development, which may aid wheat adaptation to a wide range of environments. PMID- 28710349 TI - Lipid Driven Nanodomains in Giant Lipid Vesicles are Fluid and Disordered. AB - It is a fundamental question in cell biology and biophysics whether sphingomyelin (SM)- and cholesterol (Chol)- driven nanodomains exist in living cells and in model membranes. Biophysical studies on model membranes revealed SM and Chol driven micrometer-sized liquid-ordered domains. Although the existence of such microdomains has not been proven for the plasma membrane, such lipid mixtures have been often used as a model system for 'rafts'. On the other hand, recent super resolution and single molecule results indicate that the plasma membrane might organize into nanocompartments. However, due to the limited resolution of those techniques their unambiguous characterization is still missing. In this work, a novel combination of Forster resonance energy transfer and Monte Carlo simulations (MC-FRET) identifies directly 10 nm large nanodomains in liquid disordered model membranes composed of lipid mixtures containing SM and Chol. Combining MC-FRET with solid-state wide-line and high resolution magic angle spinning NMR as well as with fluorescence correlation spectroscopy we demonstrate that these nanodomains containing hundreds of lipid molecules are fluid and disordered. In terms of their size, fluidity, order and lifetime these nanodomains may represent a relevant model system for cellular membranes and are closely related to nanocompartments suggested to exist in cellular membranes. PMID- 28710350 TI - Environmental surveillance identifies multiple introductions of MRSA CC398 in an Equine Veterinary Hospital in the UK, 2011-2016. AB - Bacterial environmental and surgical site infection (SSI) surveillance was implemented from 2011-2016 in a UK Equine Referral Veterinary Hospital and identified 81 methicillin-resistant Staphylococcus aureus (MRSA) isolates. A cluster of MRSA SSIs occurred in early 2016 with the isolates confirmed as ST398 by multilocus sequence typing (MLST), which prompted retrospective analysis of all MRSA isolates obtained from the environment (n = 62), SSIs (n = 13) and hand plates (n = 6) in the past five years. Sixty five of these isolates were typed to CC398 and a selection of these (n = 38) were further characterised for resistance and virulence genes, SCCmec and spa typing. Overall, MRSA was identified in 62/540 (11.5%) of environmental samples, 6/81 of the hand-plates (7.4%) and 13/208 of the SSIs (6.3%). spa t011 was the most frequent (24/38) and Based Upon Repeat Pattern (BURP) analysis identified spa t011 as one of the two group founders of the main spa CC identified across the five years (spa CC011/3423). However, 3 singletons (t073, t786, t064) were also identified suggesting separate introductions into the hospital environment. This long-term MRSA surveillance study revealed multiple introductions of MRSA CC398 in a UK Equine Hospital, identifying an emerging zoonotic pathogen so far only sporadically recorded in the UK. PMID- 28710351 TI - Combination therapy for tuberculosis treatment: pulmonary administration of ethionamide and booster co-loaded nanoparticles. AB - Tuberculosis (TB) is a leading infectious cause of death worldwide. The use of ethionamide (ETH), a main second line anti-TB drug, is hampered by its severe side effects. Recently discovered "booster" molecules strongly increase the ETH efficacy, opening new perspectives to improve the current clinical outcome of drug-resistant TB. To investigate the simultaneous delivery of ETH and its booster BDM41906 in the lungs, we co-encapsulated these compounds in biodegradable polymeric nanoparticles (NPs), overcoming the bottlenecks inherent to the strong tendency of ETH to crystallize and the limited water solubility of this Booster. The efficacy of the designed formulations was evaluated in TB infected macrophages using an automated confocal high-content screening platform, showing that the drugs maintained their activity after incorporation in NPs. Among tested formulations, "green" beta-cyclodextrin (pCD) based NPs displayed the best physico-chemical characteristics and were selected for in vivo studies. The NPs suspension, administered directly into mouse lungs using a Microsprayer(r), was proved to be well-tolerated and led to a 3-log decrease of the pulmonary mycobacterial load after 6 administrations as compared to untreated mice. This study paves the way for a future use of pCD NPs for the pulmonary delivery of the [ETH:Booster] pair in TB chemotherapy. PMID- 28710352 TI - Doping-induced carrier profiles in organic semiconductors determined from capacitive extraction-current transients. AB - A method to determine the doping induced charge carrier profiles in lightly and moderately doped organic semiconductor thin films is presented. The theory of the method of Charge Extraction by a Linearly Increasing Voltage technique in the doping-induced capacitive regime (doping-CELIV) is extended to the case with non uniform doping profiles and the analytical description is verified with drift diffusion simulations. The method is demonstrated experimentally on evaporated organic small-molecule thin films with a controlled doping profile, and solution processed thin films where the non-uniform doping profile is unintentional, probably induced during the deposition process, and a priori unknown. Furthermore, the method offers a possibility of directly probing charge-density distributions at interfaces between highly doped and lightly doped or undoped layers. PMID- 28710353 TI - Potential Mediating Biomarkers underlying the Association of Body Mass Index or Waist Circumference with Blood Pressure: Results from Three Population-based Studies. AB - We conducted a comprehensive and in-depth assessment of body mass index (BMI) or waist circumference (WC) related to blood pressure (BP) and determined whether the association is mediated by the possible potential mediators in the cross sectional survey of the Harbin Cohort Study on Diet, Nutrition and Chronic Non communicable Diseases of 7094 participants aged 20-74 years, and validated the significant findings in the US National Health and Nutrition Examination Survey four cross-sectional cohorts (2005-2006, 2007-2008, 2009-2010, and 2011-2012) and the cohort data of the Harbin People's Health Study (a median of 4.2 follow-up years). We observed that BMI or WC was positively associated with BP (all P values < 0.0001). Mediation analyses consistently indicated that these associations were mediated mainly by insulin resistance (IR) as measured by the homeostasis model (HOMA-IR), followed by triglyceride (TG) and total cholesterol (TC), and fasting glucose (FG) in the three studies. The proportions via the mediation of insulin/HOMA-IR were 25~40%, TG and TC were 15~20%, and FG was 2~8%, respectively. These findings suggest that the mediators, insulin/insulin resistance, TG, TC, and FG, could be targeted for preventing hypertension among populations who were overweight or obesity. PMID- 28710354 TI - Ssu72 attenuates autoimmune arthritis via targeting of STAT3 signaling and Th17 activation. AB - Signal transducer and activator of transcription 3 (STAT3) orchestrates the differentiation of several cell types, including interleukin-17 (IL-17)-releasing Th17 cells. Dysregulation of Th17 cells results in chronic inflammatory responses. Ssu72 is a C-terminal domain phosphatase required for transcriptional regulation. However, the mechanism by which Ssu72 affects STAT3 activation and Th17 cell differentiation is unclear. Here, we found that Ssu72 overexpression suppresses STAT3 activation and Th17 cell responses in vitro. A systemic infusion of Ssu72 attenuates experimental autoimmune arthritis by reducing STAT3 activity and the differentiation of Th17 cells. It also reduces joint destruction, serum immunoglobulin concentrations and osteoclastogenesis but increases the number of marginal zone B cells and B10 cells. These effects are associated with reduced p STAT3 levels and the suppression of Th17 cell formation in vivo. Based on these data, Ssu72 is related to STAT3 activation and the inflammatory response; and Ssu72 overexpression in T-cell-mediated immunity has potential utility for the treatment of autoimmune arthritis. PMID- 28710356 TI - Determination of individual contact interfaces in carbon nanotube network-based transistors. AB - Carbon nanotubes (CNTs) used as semiconducting channels induce high mobility, thermal conductivity, mechanical flexibility, and chemical stability in field effect, thin-film transistors (TFTs). However, the contact interfaces in CNT-TFTs have contact resistances that are difficult to reduce; this contact resistance can eventually limit the overall performance of CNT-TFTs. The contact interface between the source/drain electrodes and CNTs, especially for those CNT-TFTs in which the channel comprises randomly networked CNTs, plays a particularly dominant role in determining the performance and degree of variability in CNT TFTs. However, no studies have reported a determination method that individually extracts each contact resistance at the source/drain electrodes. The present work presents an efficient method for directly determining the contact interfaces in CNT-TFTs by extracting each contact resistance produced at the source (R S ) and drain (R D ) electrodes. Moreover, we comprehensively simulated the randomly networked CNTs using an in-depth Monte-Carlo method, which provides an efficient method for visualizing the uniformity of a CNT network with various controllable CNT parameters. The proposed method provides guidance and a means for optimizing the design of the CNT network channel in CNT-TFTs and additional insights into improving the performance of CNT-TFTs. PMID- 28710357 TI - Defining thresholds of sustainable impact on benthic communities in relation to fishing disturbance. AB - While the direct physical impact on seabed biota is well understood, no studies have defined thresholds to inform an ecosystem-based approach to managing fishing impacts. We addressed this knowledge gap using a large-scale experiment that created a controlled gradient of fishing intensity and assessed the immediate impacts and short-term recovery. We observed a mosaic of taxon-specific responses at various thresholds. The lowest threshold of significant lasting impact occurred between 1 and 3 times fished and elicited a decrease in abundance of 39 to 70% for some sessile epifaunal organisms (cnidarians, bryozoans). This contrasted with significant increases in abundance and/or biomass of scavenging species (epifaunal echinoderms, infaunal crustaceans) by two to four-fold in areas fished twice and more. In spite of these significant specific responses, the benthic community structure, biomass and abundance at the population level appeared resilient to fishing. Overall, natural temporal variation in community metrics exceeded the effects of fishing in this highly dynamic study site, suggesting that an acute level of disturbance (fished over six times) would match the level of natural variation. We discuss the implications of our findings for natural resources management with respect to context-specific human disturbance and provide guidance for best fishing practices. PMID- 28710355 TI - High Resolution Imaging of DNA Methylation Dynamics using a Zebrafish Reporter. AB - As one of the major epigenetic modifications, DNA methylation is constantly regulated during embryonic development, cell lineage commitment, and pathological processes. To facilitate real-time observation of DNA methylation, we generated a transgenic zebrafish reporter of DNA methylation (zebraRDM) via knockin of an mCherry-fused methyl-CpG binding domain (MBD) probe driven by the bactin2 promoter. The probe colocalized with heterochromatin, and its intensity was positively correlated with 5 mC immunostaining at a subcellular resolution in early embryos. Biochemical assays indicated that cells with stronger fluorescence maintained a higher level of DNA methylation, and time-lapse imaging at the blastula stage showed that the level of DNA methylation was transiently strengthened during mitosis. By crossing zebraRDM with other fluorescent transgenic lines, we demonstrate that the reporter can visually distinguish different cell lineages in organs like the heart. Our zebraRDM reporter therefore serves as a convenient and powerful tool for high-resolution investigation of methylation dynamics in live animals. PMID- 28710358 TI - Latitudinal cline of chronotype. AB - The rotation of the Earth around its own axis and around the sun determines the characteristics of the light/dark cycle, the most stable and ancient 24 h temporal cue for all organisms. Due to the tilt in the earth's axis in relation to the plane of the earth's orbit around the sun, sunlight reaches the Earth differentially depending on the latitude. The timing of circadian rhythms varies among individuals of a given population and biological and environmental factors underlie this variability. In the present study, we tested the hypothesis that latitude is associated to the regulation of circadian rhythm in humans. We have studied chronotype profiles across latitudinal cline from around 0 degrees to 32 degrees South in Brazil in a sample of 12,884 volunteers living in the same time zone. The analysis of the results revealed that humans are sensitive to the different sunlight signals tied to differences in latitude, resulting in a morning to evening latitudinal cline of chronotypes towards higher latitudes. PMID- 28710359 TI - Computationally Informed Design of a Multi-Axial Actuated Microfluidic Chip Device. AB - This paper describes the computationally informed design and experimental validation of a microfluidic chip device with multi-axial stretching capabilities. The device, based on PDMS soft-lithography, consisted of a thin porous membrane, mounted between two fluidic compartments, and tensioned via a set of vacuum-driven actuators. A finite element analysis solver implementing a set of different nonlinear elastic and hyperelastic material models was used to drive the design and optimization of chip geometry and to investigate the resulting deformation patterns under multi-axial loading. Computational results were cross-validated by experimental testing of prototypal devices featuring the in silico optimized geometry. The proposed methodology represents a suite of computationally handy simulation tools that might find application in the design and in silico mechanical characterization of a wide range of stretchable microfluidic devices. PMID- 28710360 TI - DOM-mediated membrane retention of fluoroquinolone as revealed by fluorescence quenching properties. AB - In this study, membrane filtration tests showed that the membrane rejection degree of difloxacin hydrochloride (DFHC) increased significantly in the presence of Suwannee River DOM or Aldrich humic acid (2-10 mg-C/L). Titration experiments showed that the excitation and emission of Peak R belonging to DFHC exhibited blue shifts by 5 nm and 10 nm, respectively, in the presence of DOM. The presence of DFHC can, in turn, lead to more significant overlapping of the fluorescence peaks of the Suwannee River DOM and Aldrich humic acid. The parallel factor analysis (PARAFAC) of the excitation-emission matrix (EEM) spectra can well decompose the components belonging to DFHC from the DOM + DFHC mixtures. The maximum fluorescence intensity (FI max) of the antibiotic-like component (C1) sharply decreased upon the initial addition of DOM. More specifically, the Aldrich humic acid showed a larger quenching effect on DFHC than the Suwannee River DOM. The stability constants (K M ) obtained by the Ryan and Weber model also corroborated that the Aldrich humic acid had a much higher binding stability (K M = 4.07 L/mg) than the Suwannee River DOM (K M = 0.86 L/mg). These results have great implications for our understanding of the membrane filtration behavior of trace contaminants in natural waters. PMID- 28710361 TI - The dental phenotype of hairless dogs with FOXI3 haploinsufficiency. AB - Hairless dog breeds show a form of ectodermal dysplasia characterised by a lack of hair and abnormal tooth morphology. This has been attributed to a semi dominant 7-base-pair duplication in the first exon of the forkhead box I3 gene (FOXI3) shared by all three breeds. Here, we identified this FOXI3 variant in a historical museum sample of pedigreed hairless dog skulls by using ancient DNA extraction and present the associated dental phenotype. Unlike in the coated wild type dogs, the hairless dogs were characterised in both the mandibular and maxillary dentition by a loss of the permanent canines, premolars and to some extent incisors. In addition, the deciduous fourth premolars and permanent first and second molars consistently lacked the distal and lingual cusps; this resulted in only a single enlarged cusp in the basin-like heel (talonid in lower molars, talon in upper molars). This molar phenotype is also found among several living and fossil carnivorans and the extinct order Creodonta in which it is associated with hypercarnivory. We therefore suggest that FOXI3 may generally be involved in dental (cusp) development within and across mammalian lineages including the hominids which are known to exhibit marked variability in the presence of lingual cusps. PMID- 28710362 TI - Self-diffusivity, M-S and Fick diffusivity of CO2 in Na-clay: The influences of concentration and temperature. AB - Storing CO2 in underground saline aquifers is an important way to reduce CO2 emission in atmosphere, where gas/fluid diffusion in clay plays a key role in CO2 leakage and migration. Various diffusivities, self-diffusivity, Maxwell-Stefan (M S) diffusivity and Fick diffusivity, in clay interlayer are investigated by molecular dynamics (MD). Self-diffusivity varies with CO2 concentration, and reaches the maximum value at 2 molecules/unit-cell. High fluid concentration leads to clay swelling, thereby increasing self-diffusivity. However, the fractional free volume of clay explains the trend of CO2 self-diffusivity, which does not decrease with CO2 concentration monotonously but reaches the maximum when CO2 concentration reaches 2. Displacement distribution of CO2 molecules is analysed to explore the microscopic diffusion mechanism, which is characterised by logarithmic normal distribution. The mean value of such distribution further explains the self-diffusivity dependence on CO2 concentration. M-S and Fick diffusivities of CO2 are calculated by MD for the first time, both of which increase with increasing CO2 and H2O concentration and temperature. Based on self diffusivity and M-S diffusivity, a quantity representing the coupling strength between CO2 molecules is presented; it increases firstly with CO2 concentration but begins to decrease when CO2 concentration is beyond 2. PMID- 28710363 TI - Neural correlates of altered feedback learning in women recovered from anorexia nervosa. AB - Anorexia nervosa (AN) is associated with exaggerated self-control and altered reward-based decision making, but the underlying neural mechanisms are poorly understood. Consistent with the notion of excessive cognitive control, we recently found increased dorsal anterior cingulate cortex (dACC) activation in acutely ill patients (acAN) on lose-shift trials in a probabilistic reversal learning (PRL) task. However, undernutrition may modulate brain function. In attempt to disentangle trait from state factors, the current fMRI study investigated cognitive control in recovered patients (recAN). Thirty-one recAN and 31 healthy controls (HC) completed a PRL task during fMRI. Based on previous findings, we focused on hemodynamic responses during lose-shift behaviour and conducted supplementary functional connectivity analysis. RecAN showed elevated lose-shift behaviour relative to HC. On the neural level, recAN showed normal dACC responses, but increased activation in fronto-parietal control regions. A trend for increased coupling between frontal and parietal regions of interest was also evident in recAN. The current findings in recAN differ from those in our previous study in acAN. While aberrant dACC response to negative feedback may be a correlate of the underweight state in acAN, impaired behavioural adaptation and elevated activation of cognitive control regions in recAN is suggestive of altered neural efficiency. PMID- 28710364 TI - Gene-wide Association Study Reveals RNF122 Ubiquitin Ligase as a Novel Susceptibility Gene for Attention Deficit Hyperactivity Disorder. AB - Attention Deficit Hyperactivity Disorder (ADHD) is a common childhood-onset neurodevelopmental condition characterized by pervasive impairment of attention, hyperactivity, and/or impulsivity that can persist into adulthood. The aetiology of ADHD is complex and multifactorial and, despite the wealth of evidence for its high heritability, genetic studies have provided modest evidence for the involvement of specific genes and have failed to identify consistent and replicable results. Due to the lack of robust findings, we performed gene-wide and pathway enrichment analyses using pre-existing GWAS data from 607 persistent ADHD subjects and 584 controls, produced by our group. Subsequently, expression profiles of genes surpassing a follow-up threshold of P-value < 1e-03 in the gene wide analyses were tested in peripheral blood mononucleated cells (PBMCs) of 45 medication-naive adults with ADHD and 39 healthy unrelated controls. We found preliminary evidence for genetic association between RNF122 and ADHD and for its overexpression in adults with ADHD. RNF122 encodes for an E3 ubiquitin ligase involved in the proteasome-mediated processing, trafficking, and degradation of proteins that acts as an essential mediator of the substrate specificity of ubiquitin ligation. Thus, our findings support previous data that place the ubiquitin-proteasome system as a promising candidate for its involvement in the aetiology of ADHD. PMID- 28710365 TI - Suppression of cell migration by phospholipase C-related catalytically inactive protein-dependent modulation of PI3K signalling. AB - The metabolic processes of phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] into PI(3,4,5)P3 and the subsequent PI(3,4,5)P3 signalling are involved in cell migration. Dysfunctions in the control of this pathway can cause human cancer cell migration and metastatic growth. Here we investigated whether phospholipase C-related catalytically inactive protein (PRIP), a PI(4,5)P2-binding protein, regulates cancer cell migration. PRIP overexpression in MCF-7 and BT-549 human breast cancer cells inhibited cell migration in vitro and metastasis development in vivo. Overexpression of the PRIP pleckstrin homology domain, a PI(4,5)P2 binding motif, in MCF-7 cells caused significant suppression of cell migration. Consistent with these results, in comparison with wild-type cells, Prip-deficient mouse embryonic fibroblasts exhibited increased cell migration, and this was significantly attenuated upon transfection with a siRNA targeting p110alpha, a catalytic subunit of class I phosphoinositide 3-kinases (PI3Ks). PI(3,4,5)P3 production was decreased in Prip-overexpressing MCF-7 and BT-549 cells. PI3K binding to PI(4,5)P2 was significantly inhibited by recombinant PRIP in vitro, and thus the activity of PI3K was downregulated. Collectively, PRIP regulates the production of PI(3,4,5)P3 from PI(4,5)P2 by PI3K, and the suppressor activity of PRIP in PI(4,5)P2 metabolism regulates the tumour migration, suggesting PRIP as a promising target for protection against metastatic progression. PMID- 28710366 TI - miRNAs in the alga Chlamydomonas reinhardtii are not phylogenetically conserved and play a limited role in responses to nutrient deprivation. AB - The unicellular alga Chlamydomonas reinhardtii contains many types of small RNAs (sRNAs) but the biological role(s) of bona fide microRNAs (miRNAs) remains unclear. To address their possible function(s) in responses to nutrient availability, we examined miRNA expression in cells cultured under different trophic conditions (mixotrophic in the presence of acetate or photoautotrophic in the presence or absence of nitrogen). We also reanalyzed miRNA expression data in Chlamydomonas subject to sulfur or phosphate deprivation. Several miRNAs were differentially expressed under the various trophic conditions. However, in transcriptome analyses, the majority of their predicted targets did not show expected changes in transcript abundance, suggesting that they are not subject to miRNA-mediated RNA degradation. Mutant strains, defective in sRNAs or in ARGONAUTE3 (a key component of sRNA-mediated gene silencing), did not display major phenotypic defects when grown under multiple nutritional regimes. Additionally, Chlamydomonas miRNAs were not conserved, even in algae of the closely related Volvocaceae family, and many showed features resembling those of recently evolved, species-specific miRNAs in the genus Arabidopsis. Our results suggest that, in C. reinhardtii, miRNAs might be subject to relatively fast evolution and have only a minor, largely modulatory role in gene regulation under diverse trophic states. PMID- 28710367 TI - Hyperuricemia and clustering of cardiovascular risk factors in the Chinese adult population. AB - Hyperuricemia is common in China and the relevance of hyperuricemia and cardiovascular disease (CVD) risk has been highlighted, but to date there has been rarely nation-wide study in China. Here, we aim to estimate the current prevalence of hyperuricemia and evaluate the associations between hyperuricemia and cardiovascular risk factors (CRFs) clustering in a large sample of China adults including a plurality of ethnic minorities. Generally, a nationally representative sample of 22983 adults aged >=18 years was recruited from 2007 to 2011. Questionnaire data and information on anthropometric characteristics, and laboratory measurements were collected. We define hyperuricemia as SUA >=416 mmol/L for men and SUA >=357 mmol/L for women. We found that the prevalence of hyperuricemia was 13.0% (18.5% in men and 8.0% in women). To our estimation, hyperuricemic subjects had higher prevalence rates of CRFs clustering than non hyperuricemic subjects. Furthermore, there was a dose-response association between the number of CVD risk factors clustering and hyperuricemia. Our study revealed a high prevalence of hyperuricemia and CVD risk factors clustering among Chinese adults, and hyperuricemia was significantly associated with coexistence of more CVD risk factors. Therefore, guidance and effective lifestyle intervention are required to prevent hyperuricemia and CVD risk factors in China. PMID- 28710369 TI - The adipokine leptin modulates adventitial pericyte functions by autocrine and paracrine signalling. AB - Transplantation of adventitial pericytes (APCs) improves recovery from tissue ischemia in preclinical animal models by still unknown mechanisms. This study investigates the role of the adipokine leptin (LEP) in the regulation of human APC biological functions. Transcriptomic analysis of APCs showed components of the LEP signalling pathway are modulated by hypoxia. Kinetic studies indicate cultured APCs release high amounts of immunoreactive LEP following exposure to hypoxia, continuing upon return to normoxia. Secreted LEP activates an autocrine/paracrine loop through binding to the LEP receptor (LEPR) and induction of STAT3 phosphorylation. Titration studies using recombinant LEP and siRNA knockdown of LEP or LEPR demonstrate the adipokine exerts important regulatory roles in APC growth, survival, migration and promotion of endothelial network formation. Heterogeneity in LEP expression and secretion may influence the reparative proficiency of APC therapy. Accordingly, the levels of LEP secretion predict the microvascular outcome of APCs transplantation in a mouse limb ischemia model. Moreover, we found that the expression of the Lepr gene is upregulated on resident vascular cells from murine ischemic muscles, thus providing a permissive milieu to transplanted LEP-expressing APCs. Results highlight a new mechanism responsible for APC adaptation to hypoxia and instrumental to vascular repair. PMID- 28710370 TI - Triazophos (TAP) removal in horizontal subsurface flow constructed wetlands (HSCWs) and its accumulation in plants and substrates. AB - Triazophos (TAP) is a widely used phosphorus pesticide in China that possesses a potential risk for water pollution. We have studied the removal efficiency of TAP using pilot-scale horizontal subsurface flow constructed wetlands (HSCWs) as well as the contribution of plants, substrates and other pathways to its removal. For TAP concentrations of 0.12 +/- 0.04 mg L-1, 0.79 +/- 0.29 mg L-1 and 3.96 +/- 1.17 mg L-1, the removal efficiencies were 94.2 +/- 3.7%, 97.8 +/- 2.9% and 84.0 +/- 13.5%, respectively, at a hydraulic loading rate (HLR) of 100 mm d-1; at an HLR of 200 mm d-1, the removal efficiencies were 96.7 +/- 1.3%, 96.2 +/- 1.7% and 61.7 +/- 11.1%, respectively. The isopleth maps of TAP along the direction of flow indicate that most of the TAP removal occurred in the front and middle regions, while the major removal region would move forward with increasing influent TAP. Plant and substrate accumulation accounted for 0.035 +/- 0.034% and 4.33 +/- 0.43% of the total removal, respectively, indicating that over 95% of the TAP removal was achieved through other mechanisms. Thus, these results suggest HSCWs can be an effective approach with which to treat TAP contaminated water. Furthermore, the longitudinal scale and hydraulic conditions, as well as the roles of plants, substrates and microbes and their interactions, should be further considered in the design and application of CWs for pesticide pollution control. PMID- 28710368 TI - Genome-Wide Linkage Analysis of Large Multiple Multigenerational Families Identifies Novel Genetic Loci for Coronary Artery Disease. AB - Coronary artery disease (CAD) is the leading cause of death, and genetic factors contribute significantly to risk of CAD. This study aims to identify new CAD genetic loci through a large-scale linkage analysis of 24 large and multigenerational families with 433 family members (GeneQuest II). All family members were genotyped with markers spaced by every 10 cM and a model-free nonparametric linkage (NPL-all) analysis was carried out. Two highly significant CAD loci were identified on chromosome 17q21.2 (NPL score of 6.20) and 7p22.2 (NPL score of 5.19). We also identified four loci with significant NPL scores between 4.09 and 4.99 on 2q33.3, 3q29, 5q13.2 and 9q22.33. Similar analyses in individual families confirmed the six significant CAD loci and identified seven new highly significant linkages on 9p24.2, 9q34.2, 12q13.13, 15q26.1, 17q22, 20p12.3, and 22q12.1, and two significant loci on 2q11.2 and 11q14.1. Two loci on 3q29 and 9q22.33 were also successfully replicated in our previous linkage analysis of 428 nuclear families. Moreover, two published risk variants, SNP rs46522 in UBE2Z and SNP rs6725887 in WDR12 by GWAS, were found within the 17q21.2 and 2q33.3 loci. These studies lay a foundation for future identification of causative variants and genes for CAD. PMID- 28710371 TI - Lattice Thermal Conductivity of MgSiO3 Perovskite from First Principles. AB - We investigate lattice thermal conductivity kappa of MgSiO3 perovskite (pv) by ab initio lattice dynamics calculations combined with exact solution of linearized phonon Boltzmann equation. At room temperature, kappa of pristine MgSiO3 pv is found to be 10.7 W/(m . K) at 0 GPa. It increases linearly with pressure and reaches 59.2 W/(m . K) at 100 GPa. These values are close to multi-anvil press measurements whereas about twice as large as those from diamond anvil cell experiments. The increase of k with pressure is attributed to the squeeze of weighted phase-spaces phonons get emitted or absorbed. Moreover, we find kappa exhibits noticeable anisotropy, with kappa zz being the largest component and [Formula: see text] being about 25%. Such extent of anisotropy is comparable to those of upper mantle minerals such as olivine and enstatite. By analyzing phonon mean free paths and lifetimes, we further show that the weak temperature dependence of kappa observed in experiments should not be caused by phonons reaching 'minimum' mean free paths. These results clarify the microscopic mechanism of thermal transport in MgSiO3 pv, and provide reference data for understanding heat conduction in the Earth's deep interior. PMID- 28710373 TI - A method for validating Rent's rule for technological and biological networks. AB - Rent's rule is empirical power law introduced in an effort to describe and optimize the wiring complexity of computer logic graphs. It is known that brain and neuronal networks also obey Rent's rule, which is consistent with the idea that wiring costs play a fundamental role in brain evolution and development. Here we propose a method to validate this power law for a certain range of network partitions. This method is based on the bifurcation phenomenon that appears when the network is subjected to random alterations preserving its degree distribution. It has been tested on a set of VLSI circuits and real networks, including biological and technological ones. We also analyzed the effect of different types of random alterations on the Rentian scaling in order to test the influence of the degree distribution. There are network architectures quite sensitive to these randomization procedures with significant increases in the values of the Rent exponents. PMID- 28710372 TI - Phthalide Derivatives from Angelica Sinensis Decrease Hemoglobin Oxygen Affinity: A New Allosteric-Modulating Mechanism and Potential Use as 2,3-BPG Functional Substitutes. AB - Angelica sinensis (AS), one of the most versatile herbal medicines remains widely used due to its multi-faceted pharmacologic activities. Besides its traditional use as the blood-nourishing tonic, its anti-hypertensive, anti-cardiovascular, neuroprotective and anti-cancer effects have been reported. Albeit the significant therapeutic effects, how AS exerts such diverse efficacies from the molecular level remains elusive. Here we investigate the influences of AS and four representative phthalide derivatives from AS on the structure and function of hemoglobin (Hb). From the spectroscopy and oxygen equilibrium experiments, we show that AS and the chosen phthalides inhibited the oxygenated Hb from transforming into the high-affinity "relaxed" (R) state, decreasing Hb's oxygen affinity. It reveals that phthalides cooperate with the endogenous Hb modulator, 2,3-bisphosphoglycerate (2,3-BPG) to synergetically regulate Hb allostery. From the docking modeling, phthalides appear to interact with Hb mainly through its alpha1/alpha2 interface, likely strengthening four (out of six) Hb "tense" (T) state stabilizing salt-bridges. A new allosteric-modulating mechanism is proposed to rationalize the capacity of phthalides to facilitate Hb oxygen transport, which may be inherently correlated with the therapeutic activities of AS. The potential of phthalides to serve as 2,3-BPG substitutes/supplements and their implications in the systemic biology and preventive medicine are discussed. PMID- 28710374 TI - Metadiffusers: Deep-subwavelength sound diffusers. AB - We present deep-subwavelength diffusing surfaces based on acoustic metamaterials, namely metadiffusers. These sound diffusers are rigidly backed slotted panels, with each slit being loaded by an array of Helmholtz resonators. Strong dispersion is produced in the slits and slow sound conditions are induced. Thus, the effective thickness of the panel is lengthened introducing its quarter wavelength resonance in the deep-subwavelength regime. By tuning the geometry of the metamaterial, the reflection coefficient of the panel can be tailored to obtain either a custom reflection phase, moderate or even perfect absorption. Using these concepts, we present ultra-thin diffusers where the geometry of the metadiffuser has been tuned to obtain surfaces with spatially dependent reflection coefficients having uniform magnitude Fourier transforms. Various designs are presented where, quadratic residue, primitive root and ternary sequence diffusers are mimicked by metadiffusers whose thickness are 1/46 to 1/20 times the design wavelength, i.e., between about a twentieth and a tenth of the thickness of traditional designs. Finally, a broadband metadiffuser panel of 3 cm thick was designed using optimization methods for frequencies ranging from 250 Hz to 2 kHz. PMID- 28710375 TI - Electric field control of magnetization direction across the antiferromagnetic to ferromagnetic transition. AB - Electric-field-induced magnetic switching can lead to a new paradigm of ultra-low power nonvolatile magnetoelectric random access memory (MeRAM). To date the realization of MeRAM relies primarily on ferromagnetic (FM) based heterostructures which exhibit low voltage-controlled magnetic anisotropy (VCMA) efficiency. On the other hand, manipulation of magnetism in antiferromagnetic (AFM) based nanojunctions by purely electric field means (rather than E-field induced strain) remains unexplored thus far. Ab initio electronic structure calculations reveal that the VCMA of ultrathin FeRh/MgO bilayers exhibits distinct linear or nonlinear behavior across the AFM to FM metamagnetic transition depending on the Fe- or Rh-interface termination. We predict that the AFM Fe-terminated phase undergoes an E-field magnetization switching with large VCMA efficiency and a spin reorientation across the metamagnetic transition. In sharp contrast, while the Rh-terminated interface exhibits large out-of-plane (in plane) MA in the FM (AFM) phase, its magnetization is more rigid to external E field. These findings demonstrate that manipulation of the AFM Neel-order magnetization direction via purely E-field means can pave the way toward ultra low energy AFM-based MeRAM devices. PMID- 28710376 TI - Identification and expression of cysteine sulfinate decarboxylase, possible regulation of taurine biosynthesis in Crassostrea gigas in response to low salinity. AB - Taurine has been reported high amounts in marine animals to maintain osmotic balance between osmoformers and sea water. Approximately 80% of the total amino acid content is taurine in Pacific oyster Crassostrea gigas, an intertidal and euryhaline species. In this study, we cloned the two copies of cysteine sulfinate decarboxylase (CSAD), the key enzyme in taurine biosynthesis pathway, screened in oyster genome data. Sequentially, we compared the expression patterns of CgCSAD1 and CgCSAD2 under low salinity treatment (80/00 and 150/00) using different families from two populations. There was no correlation between the expression of CSAD and the different population. Notably, CgCSAD1 increased significantly in treated groups for 24 h, but CgCSAD2 had no significant differentiation. Moreover, the results of CgCSAD1 interference provided the evidence of the positive correlation between CgCSAD1 expressions and taurine contents. The zinc finger domain showed in multi-alignment results may be the important character of CgCSAD1 as the key enzyme in taurine biosynthesis to regulate taurine pool in response to low salinity. This study provides a new evidence for the important role of taurine in adaptation to low salinity in oyster. In addition, it is a good model to discuss the function and evolution of the duplication in mollusks. PMID- 28710377 TI - Antiangiogenic activity of phthalides-enriched Angelica Sinensis extract by suppressing WSB-1/pVHL/HIF-1alpha/VEGF signaling in bladder cancer. AB - The hypoxia-inducible factor-1alpha (HIF-1alpha) plays a critical role in tumor angiogenesis. It has been reported that the acetone extract of Angelica sinensis (AE-AS) rich in phthalides is able to inhibit cancer cell proliferation. However, whether AE-AS reduces cancer angiogenesis remains unknown. In this study, we demonstrated that AE-AS significantly inhibited the angiogenesis in vitro and in vivo evidenced by attenuation of the tube formation in hypoxic human umbilical vascular endothelial cells (HUVECs), and the vasculature generation in Matrigel plug, the chicken chorioallantoic membrane, and tumors. Treatment with AE-AS markedly decreased the protein accumulation and transcriptional activity of HIF 1alpha, vascular endothelial growth factor (VEGF) expression/secretion, and VEGFR2 phosphorylation in hypoxic human bladder cancer (T24) cells and tumor tissues accompanied by a reduction of tumor growth. Notably, AE-AS-induced HIF 1alpha protein degradation may, at least partly, attribute to inhibition of WSB-1 dependent pVHL degradation. Moreover, VEGFR2-activated PI3K/AKT/mTOR signaling pathway in hypoxic T24 cells was greatly inhibited by AE-AS. Collectively, AE-AS may be a potential anticancer agent by attenuating cancer angiogenesis via suppression of WSB-1/pVHL/HIF-1alpha/VEGF/VEGFR2 cascade. PMID- 28710378 TI - Sub-nanometer surface chemistry and orbital hybridization in lanthanum-doped ceria nano-catalysts revealed by 3D electron microscopy. AB - Surface chemical composition, electronic structure, and bonding characteristics determine catalytic activity but are not resolved for individual catalyst particles by conventional spectroscopy. In particular, the nano-scale three dimensional distribution of aliovalent lanthanide dopants in ceria catalysts and their effect on the surface electronic structure remains unclear. Here, we reveal the surface segregation of dopant cations and oxygen vacancies and observe bonding changes in lanthanum-doped ceria catalyst particle aggregates with sub nanometer precision using a new model-based spectroscopic tomography approach. These findings refine our understanding of the spatially varying electronic structure and bonding in ceria-based nanoparticle aggregates with aliovalent cation concentrations and identify new strategies for advancing high efficiency doped ceria nano-catalysts. PMID- 28710379 TI - Effects of dietary supplementation with two alternatives to antibiotics on intestinal microbiota of preweaned calves challenged with Escherichia coli K99. AB - The aim of this study was to investigate the effects of dietary supplementation with two alternatives to antibiotics (Candida tropicalis and mulberry leaf flavonoids) on intestinal microbiota of preweaned calves challenged with Escherichia coli K99. Sixty Holstein calves were randomly assigned to 5 treatments: fed a basal diet (N-CON); fed a basal diet and challenged with E.coli K99 (P-CON); fed a basal diet supplemented with C.tropicalis (CT), mulberry leaf flavonoids (MLF), and the combination of the two additives (CM), respectively, and challenged with E.coli K99. The MLF and CM groups had significantly higher average daily grain and feed efficiency, and significantly lower fecal scores compared with the P-CON group after E. coli K99 challenge. The supplementation groups increased the relative abundance, at the phylum level, of Bacteroidetes and Proteobacteria, whereas at the genus level, they increased the relative abundance of Prevotella, Lactobacillus, and Enterococcus. Quantitative PCR revealed that the CT, MLF, and CM groups had significantly lower copy numbers of E.coli K99 compared with the P-CON group. The CT, MLF, and CM treatments reduce days of diarrhea, improve intestinal health, and beneficially manipulate the intestinal microbiota in preweaned calves. PMID- 28710380 TI - Biological analysis of cancer specific microRNAs on function modeling in osteosarcoma. AB - Osteosarcoma (OS) is the most common bone tumor characterized with a high risk of amputation and malignant morbidity among teenagers and adolescents. However, relevant pathogenic/biological mechanisms underlying OS-genesis remains to be ambiguous. The aim of this study was to elucidate functional relationship about microRNAs-mRNAs networks and to identify potential molecular markers via a computational method. Gene expression profile (GSE70415) was recruited from Gene Expression Omnibus. 3856 differentially expressed genes and 250 significantly expressed microRNAs were identified by using GCBI. The results of GO and KEGG pathways associated proteomics analysis indicated that extracellular matrix organization, small molecule metabolic process, cell adhesion (GO IDs: 0030198, 0044281, 0007155) and pathways in cancer, PI3K-Akt signaling pathway, metabolic pathways (pathway IDs: 5200, 4151, 1100) were significantly enriched. In addition, CKMT2, miR-93b-5p, miR-29b-3p were found to be positively/negatively correlated with TP53, EGFR, and MMP members mediated OS development, including angiogenesis, migration and invasion. Further visualization of collective effect of 1181 microRNAs-mRNAs pairs and protein-protein interactions was realized by applying with cytosacpe. In summary, our work provided a better understanding of non-coding regulatory mechanisms of transcriptomics and unraveled essential molecular biomarkers in osteosarcoma. PMID- 28710381 TI - Evaluation and diagnostic potential of circulating extracellular vesicle associated microRNAs in adrenocortical tumors. AB - There is no available blood marker for the preoperative diagnosis of adrenocortical malignancy. The objective of this study was to investigate the expression of extracellular vesicle-associated microRNAs and their diagnostic potential in plasma samples of patients suffering from adrenocortical tumors. Extracellular vesicles were isolated either by using Total Exosome Isolation Kit or by differential centrifugation/ultracentrifugation. Preoperative plasma extracellular vesicle samples of 6 adrenocortical adenomas (ACA) and 6 histologically verified adrenocortical cancer (ACC) were first screened by Taqman Human Microarray A-cards. Based on the results of screening, two miRNAs were selected and validated by targeted quantitative real-time PCR. The validation cohort included 18 ACAs and 16 ACCs. Beside RNA analysis, extracellular vesicle preparations were also assessed by transmission electron microscopy, flow cytometry and dynamic light scattering. Significant overexpression of hsa-miR-101 and hsa-miR-483-5p in ACC relative to ACA samples has been validated. Receiver operator characteristics of data revealed dCT hsa-miR-483-5p normalized to cel miR-39 to have the highest diagnostic accuracy (area under curve 0.965), the sensitivity and the specifity were 87.5 and 94.44, respectively. Extracellular vesicle-associated hsa-miR-483-5p thus appears to be a promising minimally invasive biomarker in the preoperative diagnosis of ACC but needs further validation in larger cohorts of patients. PMID- 28710383 TI - Wider geographic distribution and higher diversity of hexaploids than tetraploids in Carassius species complex reveal recurrent polyploidy effects on adaptive evolution. AB - Polyploidy roles on adaptive evolution and ecological novelty have been extensively studied in plants but remained unclear in vertebrates owing to the rare polyploidy incidences. Here, a huge number of 3105 specimens in Carassius species complex including 2211 hexaploids and 894 tetraploids were sampled from 34 locations through mainland China. And hexaploids had wider geographic distribution than tetraploids especially in the areas with high altitude, high latitude and low annual precipitation. Then, an approximate 1050 bp transferrin (tf) fragments were amplified from all the samples, and 526 tf alleles were identified from a total of 37260 sequences at last. Intriguingly, higher nucleotide diversity of tf alleles in hexaploids than in tetraploids was revealed. Moreover, via phylogenetic analysis of tf alleles, potential origin center of Carassius species complex was deduced to be Yangtze River basin and hexaploids should undergo multiple independent polyploidy origins from sympatric tetraploids. These findings indicate that the hexaploids might possess stronger environmental adaptation and ecological novelty than the tetraploids, which provide an association paradigm of recurrent polyploidy and ecological context in polyploid vertebrates. PMID- 28710382 TI - Netrin-1 promotes glioma growth by activating NF-kappaB via UNC5A. AB - Gliomas, a common type of brain tumor, are characterized by aggressive infiltration, making it difficultly to cure by surgery. Netrin-1, an extracellular guidance cue critical for neuronal axon path-finding, has been reported to play an important role in cell invasion and migration in several types of cancers. However, the role of netrin-1 in glioma remains largely unknown. Here, we provide evidence suggested that Netrin-1 has a critical role in glioma growth. We found that netrin-1 was significantly increased in glioma samples and positively correlated with cell proliferation, tumor grade and malignancy. Netrin-1 knockdown reduced cell proliferation and attenuated tumor growth in a xenograft mouse model. Further studies found that netrin-1 induced NF kappaB p65ser536 phosphorylation and c-Myc expression in vitro and in vivo. Interestingly, activation of NF-kappaB by netrin-1 was dependent on UNC5A receptor, because suppression of UNC5A significantly inhibited NF-kappaB p65ser536 phosphorylation, c-Myc up-regulation and reduced cell proliferation. Taken together, these results suggested netrin-1 promotes glioma cell proliferation by activating NF-kappaB signaling via UNC5A, netrin-1 may be a potential therapeutic target for the treatment of glioma. PMID- 28710384 TI - Prospective evaluation of the diagnostic value of plasma apelin 12 levels for differentiating patients with moyamoya and intracranial atherosclerotic diseases. AB - Patients with moyamoya disease (MMD) or intracranial atherosclerotic disease (ICAD) experience similar cerebral ischaemic events. However, MMD patients show greater angiogenesis and arteriogenesis, which play crucial roles in collateral circulation development to enhance clinical prognosis and outcome. Apelins have been associated with angiogenesis and arteriogenesis. Therefore, the aim of the present study was to determine whether apelin levels were higher in patients with MMD than in patients with ICAD or in healthy controls. We compared plasma apelin levels in 29 patients with MMD, 82 patients with ICAD, and 25 healthy participants. Twelve-hour fasting blood samples were collected and analysed using commercially available kits. Univariate analyses indicated that compared with the ICAD and healthy control groups, the MMD group had higher apelin-12, apelin-13, apelin-36, and nitric oxide levels. Binary logistic regression analyses further showed that the plasma apelin-12 level was substantially higher in MMD patients than in ICAD patients. Patients with MMD were also differentiated from patients with ICAD by their mean ages, with the former being younger. Therefore, the plasma apelin-12 level is a potential diagnostic marker for differentiating MMD and ICAD and may provide a treatment strategy for enhancing collateral circulation development and clinical prognosis and outcome. PMID- 28710385 TI - Electron-transfer chain in respiratory complex I. AB - Complex I is a part of the respiration energy chain converting the redox energy into the cross-membrane proton gradient. The electron-transfer chain of iron sulfur cofactors within the water-soluble peripheral part of the complex is responsible for the delivery of electrons to the proton pumping subunit. The protein is porous to water penetration and the hydration level of the cofactors changes when the electron is transferred along the chain. High reaction barriers and trapping of the electrons at the iron-sulfur cofactors are prevented by the combination of intense electrostatic noise produced by the protein-water interface with the high density of quantum states in the iron-sulfur clusters caused by spin interactions between paramagnetic iron atoms. The combination of these factors substantially lowers the activation barrier for electron transfer compared to the prediction of the Marcus theory, bringing the rate to the experimentally established range. The unique role of iron-sulfur clusters as electron-transfer cofactors is in merging protein-water fluctuations with quantum state multiplicity to allow low activation barriers and robust operation. Water plays a vital role in electron transport energetics by electrowetting the cofactors in the chain upon arrival of the electron. A general property of a protein is to violate the fluctuation-dissipation relation through nonergodic sampling of its landscape. High functional efficiency of redox enzymes is a direct consequence of nonergodicity. PMID- 28710386 TI - Seed coat thinning during horsegram (Macrotyloma uniflorum) domestication documented through synchrotron tomography of archaeological seeds. AB - Reduction of seed dormancy mechanisms, allowing for rapid germination after planting, is a recurrent trait in domesticated plants, and can often be linked to changes in seed coat structure, in particular thinning. We report evidence for seed coat thinning between 2,000 BC and 1,200 BC, in southern Indian archaeological horsegram (Macrotyloma uniflorum), which it has been possible to document with high precision and non-destructively, through high resolution x-ray computed tomography using a synchrotron. We find that this trait underwent stepped change, from thick to semi-thin to thin seed coats, and that the rate of change was gradual. This is the first time that the rate of evolution of seed coat thinning in a legume crop has been directly documented from archaeological remains, and it contradicts previous predictions that legume domestication occurred through selection of pre-adapted low dormancy phenotypes from the wild. PMID- 28710387 TI - Protein Tyrosine Phosphatase Inhibition Prevents Experimental Cerebral Malaria by Precluding CXCR3 Expression on T Cells. AB - Cerebral malaria induced by Plasmodium berghei ANKA infection is dependent on the sequestration of cytotoxic T cells within the brain and augmentation of the inflammatory response. Herein, we demonstrate that inhibition of protein tyrosine phosphatase (PTP) activity significantly attenuates T cell sequestration within the brain and prevents the development of neuropathology. Mechanistically, the initial upregulation of CXCR3 on splenic T cells upon T cell receptor stimulation was critically decreased through the reduction of T cell-intrinsic PTP activity. Furthermore, PTP inhibition markedly increased IL-10 production by splenic CD4+ T cells by enhancing the frequency of LAG3+CD49b+ type 1 regulatory cells. Overall, these findings demonstrate that modulation of PTP activity could possibly be utilized in the treatment of cerebral malaria and other CXCR3-mediated diseases. PMID- 28710388 TI - Beam propagation management in a fractional Schrodinger equation. AB - Generalization of Fractional Schrodinger equation (FSE) into optics is fundamentally important, since optics usually provides a fertile ground where FSE related phenomena can be effectively observed. Beam propagation management is a topic of considerable interest in the field of optics. Here, we put forward a simple scheme for the realization of propagation management of light beams by introducing a double-barrier potential into the FSE. Transmission, partial transmission/reflection, and total reflection of light fields can be controlled by varying the potential depth. Oblique input beams with arbitrary distributions obey the same propagation dynamics. Some unique properties, including strong self healing ability, high capacity of resisting disturbance, beam reshaping, and Goos Hanchen-like shift are revealed. Theoretical analysis results are qualitatively in agreements with the numerical findings. This work opens up new possibilities for beam management and can be generalized into other fields involving fractional effects. PMID- 28710389 TI - Continuation of the genetic divergence of ecological speciation by spatial environmental heterogeneity in island endemic plants. AB - Divergent selection plays a critical role not only as a speciation driver but also in maintaining post-speciation divergence. In the absence of direct evidence, ancestral interspecific gene flow between incipient species can reflect ancient selective pressure for ecological speciation. In the present study, two late-Pleistocene diverged species endemic to Taiwan, Scutellaria playfairii and S. tashiroi, were spatially and ecologically partitioned with partial overlap. Multilocus genome-scan analyses and in silico evaluation revealed ancestral interspecific gene flow but distinct genetic compositions, implying that adaptive divergence contributed to their speciation. Ecological niche modeling and principal component analysis suggested incomplete divergent niches between the two species; the species distribution is therefore consistent with Hutchinson's metaphor of multidimensional hypervolume niches rather than attributable to a single factor. Constraint ordination analysis supported this inference of a combination of variables explaining the genetic structure. The rare occurrence of hybrids in the sympatric population suggested hybrid breakdown, providing further evidence of divergent selection blocking gene flow. The correlation of environmental variables with integrated genetic components demonstrated that environmental heterogeneity maintains the species and population differentiation. This study highlights the importance of environmental heterogeneity and divergent selection for the rapid speciation and recent diversification of island plants. PMID- 28710390 TI - Conformational Transitions of the Pituitary Adenylate Cyclase-Activating Polypeptide Receptor, a Human Class B GPCR. AB - The G protein-coupled pituitary adenylate cyclase-activating polypeptide receptor (PAC1R) is a potential therapeutic target for endocrine, metabolic and stress related disorders. However, many questions regarding the protein structure and dynamics of PAC1R remain largely unanswered. Using microsecond-long simulations, we examined the open and closed PAC1R conformations interconnected within an ensemble of transitional states. The open-to-closed transition can be initiated by "unzipping" the extracellular domain and the transmembrane domain, mediated by a unique segment within the beta3-beta4 loop. Transitions between different conformational states range between microseconds to milliseconds, which clearly implicate allosteric effects propagating from the extracellular face of the receptor to the intracellular G protein-binding site. Such allosteric dynamics provides structural and mechanistic insights for the activation and modulation of PAC1R and related class B receptors. PMID- 28710391 TI - Screening of microalgae for integral biogas slurry nutrient removal and biogas upgrading by different microalgae cultivation technology. AB - The microalgae-based technology has been developed to reduce biogas slurry nutrients and upgrade biogas simultaneously. In this work, five microalgal strains named Chlorella vulgaris, Scenedesmus obliquus, Selenastrum capricornutum, Nitzschia palea, and Anabaena spiroides under mono- and co cultivation were used for biogas upgrading. Optimum biogas slurry nutrient reduction could be achieved by co-cultivating microalgae (Chlorella vulgaris, Scenedesmus obliquus, and Nitzschia palea) with fungi using the pelletization technology. In addition, the effects of different ratio of mixed LED light wavelengths applying mixed light-emitting diode during algae strains and fungi co cultivation on CO2 and biogas slurry nutrient removal efficiency were also investigated. The results showed that the COD (chemical oxygen demand), TN (total nitrogen), and TP (total phosphorus) removal efficiency were 85.82 +/- 5.37%, 83.31 +/- 4.72%, and 84.26 +/- 5.58%, respectively at red: blue = 5:5 under the co-cultivation of S. obliquus and fungi. In terms of biogas upgrading, CH4 contents were higher than 90% (v/v) for all strains, except the co-cultivation with S. obliquus and fungi at red: blue = 3:7. The results indicated that co cultivation of microalgae with fungi under mixed light wavelengths treatments was most successful in nutrient removal from wastewater and biogas upgrading. PMID- 28710392 TI - Comparative study of Arabidopsis PBS1 and a wheat PBS1 homolog helps understand the mechanism of PBS1 functioning in innate immunity. AB - Arabidopsis AVRPPHB SUSCEPTIBLE1 (PBS1) serves as a "decoy" in activating RESISTANCE TO PSEUDOMONAS SYRINGAE5 (RPS5) upon cleavage by Pseudomonas phaseolicola B (AvrPphB), a Pseudomonas syringae effector. The SEMPH motif in PBS1 was thought to allow it to be distinguished by RPS5 from the closely related Arabidopsis kinases. However, the underlying mechanism is not fully understood. Here, we isolated and characterized a wheat PBS1 homolog, TaPBS1. Although this plasma membrane-localized kinase could be cleaved by AvrPphB and could associate with RPS5, it failed to trigger RPS5-mediated hypersensitive response (HR) in a transient assay. TaPBS1 harbors a STRPH motif. The association of RPS5 with TaPBS1 was weaker than with PBS1. Change of the STRPH motif to the SEMPH motif allowed TaPBS1 to trigger HR. However, the SEMPH motif is not required for association of PBS1 with RPS5. The difference between "SEMPH" and "STRPH" points to the importance of "EM" in PBS1. Furthermore we found that a negatively charged amino acid at the position of "E" in the SEMPH motif was required for recognition of PBS1 by RPS5. Additionally, both PBS1 and TaPBS1 undergo the flagellin-induced phosphorylation. Therefore, our work will help understand the mechanism of PBS1 functioning in plant innate immunity. PMID- 28710393 TI - Emergence of ON1 genotype of human respiratory syncytial virus subgroup A in China between 2011 and 2015. AB - A molecular epidemiological study of human respiratory syncytial virus (HRSV) was conducted to examine the distribution of its subgroups and genotypes, as well as to identify its transmission pattern in China. A total of 705 samples collected from 9 provinces in China between January 2008 and February 2015 were identified as HRSV-positive and were subsequently sequenced. Of these, 336 samples were HRSV subgroup A (HRSVA), 368 samples were HRSV subgroup B (HRSVB), and 1 sample contained both HRSVA and HRSVB. These 705 HRSV sequences, together with 766 HRSV sequences downloaded from GenBank, were analyzed to understand the recent circulation patterns of HRSV in China. HRSVB predominated in the 2008/2009 and 2009/2010 seasons, whereas HRSVA predominated in the 2010/2011 and 2011/2012 seasons; HRSVA and HRSVB co-circulated during 2012/2013 and 2014/2015. Phylogenetic analysis showed most of the HRSVA sequences clustered into 2 genotypes, namely, NA1 and ON1. The ON1 genotype was first detected in China in 2011, and it quickly replaced the NA1 genotype to become the most prevalent HRSVA genotype circulating in China between 2013 and 2015. Continuous epidemiological surveillance and molecular characterization of HRSV should be conducted to monitor the evolution of HRSV in China. PMID- 28710394 TI - Altered Brain Network Connectivity as a Potential Endophenotype of Schizophrenia. AB - Abnormal functional brain connectivity could be considered an endophenotype of psychosis in schizophrenia. Identifying candidate endophenotypes may serve as a tool for elucidating its biological and neural mechanisms. The present study investigated the similarities and differences of features of brain network connectivity between patients and their first-degree relatives. Independent component analysis was conducted on imaging data collected from 34 healthy controls, 33 schizophrenia patients, and 30 unaffected first-degree relatives. The correlation between functional connectivity with neurocognitive performance and clinical symptoms were calculated. Abnormalities of between-network connectivity largely overlapped in patients and first-degree relatives, but the extent of such abnormalities was relatively minor in relatives. Negative connectivity between language networks and executive control networks was impaired in schizophrenia patients and their first-degree relatives, and this decreased connectivity was correlated with performance in language processing. Similar impairments were found in high-visual network and executive network coupling, and this decreased connection was correlated with the severity of positive symptoms in patients. The results indicated that abnormal functional connectivity within and between perceptual systems (i.e., high-visual and language) and executive control networks was related to the generic risk of schizophrenia, which makes it a potential endophenotype for schizophrenia. PMID- 28710395 TI - Alterations of microbiota structure in the larynx relevant to laryngeal carcinoma. AB - The microbial communities that inhabit the laryngeal mucosa build stable microenvironments and have the potential to influence the health of the human throat. However, the associations between the microbiota structure and laryngeal carcinoma remain uncertain. Here, we explored this question by comparing the laryngeal microbiota structure in laryngeal cancer patients with that in control subjects with vocal cord polyps through high-throughput pyrosequencing. Overall, the genera Streptococcus, Fusobacterium, and Prevotella were prevalent bacterial populations in the laryngeal niche. Tumor tissue samples and normal tissues adjacent to the tumor sites (NATs) were collected from 31 laryngeal cancer patients, and the bacterial communities in laryngeal cancer patients were compared with control samples from 32 subjects. A comparison of the laryngeal communities in the tumor tissues and the NATs showed higher alpha-diversity in cancer patients than in control subjects, and the relative abundances of seven bacterial genera differed among the three groups of samples. Furthermore, the relative abundances of ten bacterial genera in laryngeal cancer patients differed substantially from those in control subjects. These findings indicate that the laryngeal microbiota profiles are altered in laryngeal cancer patients, suggesting that a disturbance of the microbiota structure might be relevant to laryngeal cancer. PMID- 28710396 TI - The CINSARC signature as a prognostic marker for clinical outcome in multiple neoplasms. AB - We previously reported the CINSARC signature as a prognostic marker for metastatic events in soft tissue sarcomas, breast carcinomas and lymphomas through genomic instability, acting as a major factor for tumor aggressiveness. In this study, we used a published resource to investigate CINSARC enrichment in poor outcome-associated genes at pan-cancer level and in 39 cancer types. CINSARC outperformed more than 15,000 defined signatures (including cancer-related), being enriched in top-ranked poor outcome-associated genes of 21 cancer types, widest coverage reached among all tested signatures. Independently, this signature demonstrated significant survival differences between risk-groups in 33 published studies, representing 17 tumor types. As a consequence, we propose the CINSARC prognostication as a general marker for tumor aggressiveness to optimize the clinical managements of patients. PMID- 28710397 TI - Brain specific Lamellipodin knockout results in hyperactivity and increased anxiety of mice. AB - Lamellipodin (Lpd) functions as an important signalling integrator downstream of growth factor and axon guidance receptors. Mechanistically, Lpd promotes actin polymerization by interacting with F-actin and the actin effectors Ena/VASP proteins and the SCAR/WAVE complex. Thereby, Lpd supports lamellipodia protrusion, cell migration and endocytosis. In the mammalian central nervous system, Lpd contributes to neuronal morphogenesis, neuronal migration during development and its C. elegans orthologue MIG-10 also supports synaptogenesis. However, the consequences of loss of Lpd in the CNS on behaviour are unknown. In our current study, we crossed our Lpd conditional knockout mice with a mouse line expressing Cre under the CNS specific Nestin promoter to restrict the genetic ablation of Lpd to the central nervous system. Detailed behavioural analysis of the resulting Nestin-Cre-Lpd knockout mouse line revealed a specific behavioural phenotype characterised by hyperactivity and increased anxiety. PMID- 28710398 TI - Unique adjustable UC luminescence pattern and directional radiation of peculiar shaped NaYF4: Yb3+/Er3+ microcrystal particle. AB - A new design of peculiar-shaped beta-NaYF4: 20% Yb3+/2% Er3+ hexagonal microcrystal (PSbetaHM) is proposed and its upconversion (UC) luminescence with adjustable color pattern is studied with near infrared excitation. Flower-like green UC luminescence emission pattern from blooming to withering process and intensive directional red emission are achieved by simply adjusting the focal point position of the excitation light. The mechanism that determines the unique UC luminescence phenomena are investigated systematically. The function of the internal light reflection and waveguide effect with annular microcavity is explored based on the structure characteristic of the hexagonal microplate. The current work may have great significant and potential applications in the development of optoelectronic device, color display, directional light and laser emission of microsystem. PMID- 28710399 TI - Downregulation of blood serum microRNA 29 family in patients with Parkinson's disease. AB - There is currently no reliable and easily applicable diagnostic marker for Parkinson's disease (PD). The aims of the present study were to compare the expression profiles of the microRNA29 family (miR-29s) in blood serum from patients with PD with healthy controls and to clarify whether the expression of miR-29s is correlated with disease severity, duration or L-dopa therapy and whether expression depends on the gender and age of patients. The levels of blood serum miR-29s in 80 patients with PD and 80 unaffected controls were assessed by reverse transcription-quantitative real-time PCR. The PCR products were confirmed by cloning and sequencing. Additionally, the expression of miR-7 in the blood serum from PD patients and control subjects was assessed. Serum miR-29 levels were significantly downregulated in PD patients compared to healthy controls. The serum miR-29 levels in female PD patients were markedly higher than in male PD patients. The expression of serum miR-29a and miR-29c expression tended to decrease with disease severity. Moreover, we found that serum miR-7 levels did not differ between PD patients and control subjects. Therefore, the reduction of serum miR-29 levels, particularly miR-29a and miR-29c, warrants further investigation of its potential serving as biomarkers for PD. PMID- 28710400 TI - Molecular inter-kingdom interactions of endophytes isolated from Lychnophora ericoides. AB - The importance of microbial natural products has been widely demonstrated in the search for new antibiotics. However, the functional role of microbial metabolites in nature remains to be deciphered. Several natural products are known to mediate microbial interactions through metabolic exchange. One approach to investigate metabolic exchange in the laboratory is through microbial interactions. Here, we describe the chemical study of selected endophytes isolated from the Brazilian medicinal plant Lychnophora ericoides by pairwise inter-kingdom interactions in order to correlate the impact of co-cultivation to their metabolic profiles. Combining mass spectrometry tools and NMR analyses, a total of 29 compounds were identified. These compounds are members of polyene macrocycles, pyrroloindole alkaloids, angucyclines, and leupeptins chemical families. Two of the identified compounds correspond to a new fungal metabolite (29) and a new actinobacterial angucycline-derivative (23). Our results revealed a substantial arsenal of small molecules induced by microbial interactions, as we begin to unravel the complexity of microbial interactions associated with endophytic systems. PMID- 28710401 TI - Capture of microparticles by bolus flow of red blood cells in capillaries. AB - Previous studies have concluded that microparticles (MPs) can more effectively approach the microvessel wall than nanoparticles because of margination. In this study, however, we show that MPs are not marginated in capillaries where the vessel diameter is comparable to that of red blood cells (RBCs). We numerically investigated the behavior of MPs with a diameter of 1 MUm in various microvessel sizes, including capillaries. In capillaries, the flow mode of RBCs shifted from multi-file flow to bolus (single-file) flow, and MPs were captured by the bolus flow of the RBCs instead of being marginated. Once MPs were captured, they rarely escaped from the vortex-like flow structures between RBCs. These capture events were enhanced when the hematocrit was decreased, and reduced when the shear rate was increased. Our results suggest that microparticles may be rather inefficient drug carriers when targeting capillaries because of capture events, but nanoparticles, which are more randomly distributed in capillaries, may be more effective carriers. PMID- 28710402 TI - PageRank versatility analysis of multilayer modality-based network for exploring the evolution of oil-water slug flow. AB - Numerous irregular flow structures exist in the complicated multiphase flow and result in lots of disparate spatial dynamical flow behaviors. The vertical oil water slug flow continually attracts plenty of research interests on account of its significant importance. Based on the spatial transient flow information acquired through our designed double-layer distributed-sector conductance sensor, we construct multilayer modality-based network to encode the intricate spatial flow behavior. Particularly, we calculate the PageRank versatility and multilayer weighted clustering coefficient to quantitatively explore the inferred multilayer modality-based networks. Our analysis allows characterizing the complicated evolution of oil-water slug flow, from the opening formation of oil slugs, to the succedent inter-collision and coalescence among oil slugs, and then to the dispersed oil bubbles. These properties render our developed method particularly powerful for mining the essential flow features from the multilayer sensor measurements. PMID- 28710403 TI - Plant recording across two centuries reveals dramatic changes in species diversity of a Mediterranean archipelago. AB - Although islands are model systems for investigating assembly of biological communities, long-term changes in archipelago communities are not well understood because of the lack of reliable data. By using a vast amount of floristic data we assembled a dataset of the plant species occurring on 16 islands of the Tuscan Archipelago, Italy, across two periods, 1830-1950 and 1951-2015. We collected 10,892 occurrence records for 1,831 species. We found major changes in the island plant assemblages between the two periods, with native flora significantly decreasing (-10.7%) and alien flora doubling (+132.1%) in richness. The species area relationships demonstrated the scale-dependence of the observed changes for native and alien species. The observed floristic changes were dependent on island area, with smaller islands displaying high variability in richness and compositional changes and larger islands having more stable species assemblages. The richness of species associated with open landscapes, that had been maintained for centuries by traditional practices, markedly reduced while the number of woody species, associated with afforestation processes and invasion by alien woody plants, significantly incresed. These results demonstrate the great power of floristic studies, often available in grey literature, for understanding long term biotic changes in insular ecosystems. PMID- 28710404 TI - Assuring quality in microplastic monitoring: About the value of clean-air devices as essentials for verified data. AB - Avoiding aerial microfibre contamination of environmental samples is essential for reliable analyses when it comes to the detection of ubiquitous microplastics. Almost all laboratories have contamination problems which are largely unavoidable without investments in clean-air devices. Therefore, our study supplies an approach to assess background microfibre contamination of samples in the laboratory under particle-free air conditions. We tested aerial contamination of samples indoor, in a mobile laboratory, within a laboratory fume hood and on a clean bench with particles filtration during the examining process of a fish. The used clean bench reduced aerial microfibre contamination in our laboratory by 96.5%. This highlights the value of suitable clean-air devices for valid microplastic pollution data. Our results indicate, that pollution levels by microfibres have been overestimated and actual pollution levels may be many times lower. Accordingly, such clean-air devices are recommended for microplastic laboratory applications in future research work to significantly lower error rates. PMID- 28710405 TI - The effect of oxygen concentration and temperature on nitrogenase activity in the heterocystous cyanobacterium Fischerella sp. AB - Heterocysts are differentiated cells formed by some filamentous, diazotrophic (dinitrogen-fixing) cyanobacteria. The heterocyst is the site of dinitrogen fixation providing the oxygen-sensitive nitrogenase with a low-oxygen environment. The diffusion of air into the heterocyst is a compromise between the maximum influx of dinitrogen gas while oxygen is kept sufficiently low to allow nitrogenase activity. This investigation tested the hypothesis that the heterocyst is capable of controlling the influx of air. Here, the thermophilic heterocystous cyanobacterium Fischerella sp. was analysed for the effects of oxygen concentration and temperature on nitrogenase activity. Dark nitrogenase activity is directly related to aerobic respiration and was therefore used as a measure of the influx of oxygen into the heterocyst. Above 30% O2, the influx of oxygen was proportional to its external concentration. Below this concentration, the influx of oxygen was higher than expected from the external concentration. A higher or lower temperature also triggered the heterocyst to increase or decrease, respectively, dark nitrogenase activity while the external concentration of oxygen was kept constant. A higher dark nitrogenase activity requires a higher rate of respiration and therefore a higher flux of oxygen. Hence, the heterocyst of Fischerella sp. is capable of controlling the influx of air. PMID- 28710406 TI - Comprehensive circular RNA profiling reveals the regulatory role of the circRNA 100338/miR-141-3p pathway in hepatitis B-related hepatocellular carcinoma. AB - Circular RNAs (circRNAs) represent a class of endogenous noncoding RNAs that have recently been recognized as important regulators of gene expression and pathological networks. However, their transcriptional activities and functional mechanisms in cancer remain largely unknown. Here, we present results from a global circRNA expression and functional analysis of patients with hepatocellular carcinoma (HCC). Using a circRNA microarray, we identified 226 differentially expressed circRNAs, of which 189 were significantly upregulated and 37 were downregulated. High expression of circRNA_100338, one of the upregulated circRNAs in HCC, is closely correlated with a low cumulative survival rate and metastatic progression in HCC patients with hepatitis B. Furthermore, our in silico and experimental analyses identified miR-141-3p as a direct target of circRNA_100338. Thus, circRNA_100338 functions as an endogenous sponge for miR-141-3p in HCC. In addition, we identified the crucial antagonistic roles of circRNA_100338 and miR 141-3p in the regulation of invasive potential in liver cancer cells. Overall, the differential expression of multiple circRNAs in HCC tissues and their clinical significance in hepatitis B-related HCC patients as revealed by our study suggests that circRNA_100338 is a potentially valuable biomarker for HCC diagnosis and target for HCC therapeutics. PMID- 28710407 TI - Role of insulin receptor substrates in the progression of hepatocellular carcinoma. AB - Several cellular signaling pathways, including insulin/IGF signaling, are known to be activated in hepatocellular carcinoma (HCC). Here, we investigated the roles of insulin receptor substrate (Irs) 1 and Irs2, both of which are the major molecules to be responsible for transducing insulin/IGF signaling in the liver, in the development of HCC by inducing chemical carcinogenesis using diethylnitrosamine (DEN) in mice. The Irs1 mRNA and protein expressions were upregulated in the tumors, along with enhanced insulin signaling. Liver-specific Irs1-knockout (LIrs1KO) mice exhibited suppression of DEN-induced HCC development, accompanied by reduced cancer cell proliferative activity and reduced activation of Akt. Gene expression analyses revealed that the tumors in the DEN-treated LIrs1KO mice showed modest metabolic alterations during hepatocarcinogenesis as well as decreased inflammation and invasion potentials. On the other hand, liver-specific Irs2-knockout (LIrs2KO) mice showed a similar pattern of HCC development to the DEN-treated control wild-type mice. Based on the knowledge that Wnt/beta-catenin signaling is activated in HCC, we focused on Wnt/beta-catenin signaling and demonstrated that Irs1 expression was induced by Wnt3a stimulation in the primary hepatocytes, associated with insulin-stimulated Akt activation. These data suggest that upregulated Irs1 by Wnt/beta-catenin signaling plays a crucial role in the progression of HCC. PMID- 28710408 TI - Non-ketogenic combination of nutritional strategies provides robust protection against seizures. AB - Epilepsy is a neurological condition that affects 1% of the world population. Conventional treatments of epilepsy use drugs targeting neuronal excitability, inhibitory or excitatory transmission. Yet, one third of patients presents an intractable form of epilepsy and fails to respond to pharmacological anti epileptic strategies. The ketogenic diet is a well-established non pharmacological treatment that has been proven to be effective in reducing seizure frequency in the pharmaco-resistant patients. This dietary solution is however extremely restrictive and can be associated with complications caused by the high [fat]:[carbohydrate + protein] ratio. Recent advances suggest that the traditional 4:1 ratio of the ketogenic diet is not a requisite for its therapeutic effect. We show here that combining nutritional strategies targeting specific amino-acids, carbohydrates and fatty acids with a low [fat]:[proteins + carbohydrates] ratio also reduces excitatory drive and protects against seizures to the same extent as the ketogenic diet. Similarly, the morphological and molecular correlates of temporal lobe seizures were reduced in animals fed with the combined diet. These results provide evidence that low-fat dietary strategies more palatable than the ketogenic diet could be useful in epilepsy. PMID- 28710409 TI - Machine Learning Algorithms for Risk Prediction of Severe Hand-Foot-Mouth Disease in Children. AB - The identification of indicators for severe HFMD is critical for early prevention and control of the disease. With this goal in mind, 185 severe and 345 mild HFMD cases were assessed. Patient demographics, clinical features, MRI findings, and laboratory test results were collected. Gradient boosting tree (GBT) was then used to determine the relative importance (RI) and interaction effects of the variables. Results indicated that elevated white blood cell (WBC) count > 15 * 109/L (RI: 49.47, p < 0.001) was the top predictor of severe HFMD, followed by spinal cord involvement (RI: 26.62, p < 0.001), spinal nerve roots involvement (RI: 10.34, p < 0.001), hyperglycemia (RI: 3.40, p < 0.001), and brain or spinal meninges involvement (RI: 2.45, p = 0.003). Interactions between elevated WBC count and hyperglycemia (H statistic: 0.231, 95% CI: 0-0.262, p = 0.031), between spinal cord involvement and duration of fever >=3 days (H statistic: 0.291, 95% CI: 0.035-0.326, p = 0.035), and between brainstem involvement and body temperature (H statistic: 0.313, 95% CI: 0-0.273, p = 0.017) were observed. Therefore, GBT is capable to identify the predictors for severe HFMD and their interaction effects, outperforming conventional regression methods. PMID- 28710410 TI - Combining molecular typing and spatial pattern analysis to identify areas of high tuberculosis transmission in a moderate-incidence county in Taiwan. AB - In total, 303 randomly selected clinical Mycobacterium tuberculosis (MTB) isolates from 303 patients (collected January to December 2012) in central Taiwan were examined. The major lineages found were Beijing (N = 114, 37.62%), Haarlem (N = 76, 25.08%) and East African-Indian (EAI) (N = 42, 13.86%). Notably, younger persons (<=30 years old) were 6.58 times more likely to be infected with a Beijing genotype compared to older persons (>70 years) (p < 0.05). Combining molecular typing methods and geographical information system (GIS) analysis, we uncovered a twofold higher incidence of Beijing strains in a hotspot area (33%) compared to non-hotspot areas (17%). By 24 MIRU-VNTR typing, persons in clustered groups were 1.96 times more likely to be infected with a Beijing strain compared with non-clustered persons, suggesting recent spread and emergence of MTB. Finally, we observed a trend in which TB incidence increased as the density/concentration of analyzed environmental factors increased, suggesting that environmental factors are associated with TB transmission; however, only population density was found to be significantly associated with increased risk of TB (p < 0.05). Molecular typing methods combined with spatial analysis suggest possible TB transmission. Early intervention to interrupt transmission may be most effective if targeted to hot zones of TB. PMID- 28710411 TI - Can weather generation capture precipitation patterns across different climates, spatial scales and under data scarcity? AB - Stochastic weather generators can generate very long time series of weather patterns, which are indispensable in earth sciences, ecology and climate research. Yet, both their potential and limitations remain largely unclear because past research has typically focused on eclectic case studies at small spatial scales in temperate climates. In addition, stochastic multi-site algorithms are usually not publicly available, making the reproducibility of results difficult. To overcome these limitations, we investigated the performance of the reduced-complexity multi-site precipitation generator TripleM across three different climatic regions in the United States. By resampling observations, we investigated for the first time the performance of a multi-site precipitation generator as a function of the extent of the gauge network and the network density. The definition of the role of the network density provides new insights into the applicability in data-poor contexts. The performance was assessed using nine different statistical metrics with main focus on the inter-annual variability of precipitation and the lengths of dry and wet spells. Among our study regions, our results indicate a more accurate performance in wet temperate climates compared to drier climates. Performance deficits are more marked at larger spatial scales due to the increasing heterogeneity of climatic conditions. PMID- 28710412 TI - Exosomes derived from pancreatic cancer cells induce insulin resistance in C2C12 myotube cells through the PI3K/Akt/FoxO1 pathway. AB - Prospective epidemiological studies have consistently suggested that pancreatic cancer-associated new-onset diabetes mellitus (PC-DM) represents a potential platform for early diagnose of pancreatic cancer (PC). Despite the studies performed, the mechanism behind this phenomenon remains ambiguous. In this study, we explored the effects of two types of exosomes released by murine pancreatic cancer and ductal epithelial cells on murine skeletal muscle cells. The results show that PC-derived exosomes can readily enter C2C12 myotubes, triggering lipidosis and glucose intake inhibition. We also demonstrate that PC-derived exosomes can inhibit insulin and PI3K/Akt signalling, in which insulin-induced FoxO1 nuclear exclusion is preserved and Glut4 trafficking is impaired. Microarray and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses show that exosomal microRNAs (miRNAs) probably play key roles in this process, an assumption that is corroborated by in vitro studies. These results confirm that the insulin resistance (IR) of skeletal muscle cells is governed by PC-derived exosomes through the insulin and PI3K/Akt/FoxO1 signalling pathways, where exosomal miRNAs potentially contribute to this phenomenon. These novel findings pave the way towards a comprehensive understanding of the cancer theories: "metabolic reprogramming" and "metabolic crosstalk". PMID- 28710413 TI - Quantifying Retail Agglomeration using Diverse Spatial Data. AB - Newly available data on the spatial distribution of retail activities in cities makes it possible to build models formalized at the level of the single retailer. Current models tackle consumer location choices at an aggregate level and the opportunity new data offers for modeling at the retail unit level lacks an appropriate theoretical framework. The model we present here helps to address these issues. Based on random utility theory, we have built it around the idea of quantifying the role of floor-space and agglomeration in retail location choice. We test this model on the inner area of Greater London. The results are consistent with a super linear scaling of a retailer's attractiveness with its floorspace, and with an agglomeration effect approximated as the total retail floorspace within a 300 m radius from each shop. Our model illustrates many of the issues involved in testing and validating urban simulation models involving spatial data and its aggregation to different spatial scales. PMID- 28710414 TI - Resonant driving of a single photon emitter embedded in a mechanical oscillator. AB - Coupling a microscopic mechanical resonator to a nanoscale quantum system enables control of the mechanical resonator via the quantum system and vice-versa. The coupling is usually achieved through functionalization of the mechanical resonator, but this results in additional mass and dissipation channels. An alternative is an intrinsic coupling based on strain. Here we employ a monolithic semiconductor system: the nanoscale quantum system is a semiconductor quantum dot (QD) located inside a nanowire. We demonstrate the resonant optical driving of the QD transition in such a structure. The noise spectrum of the resonance fluorescence signal, recorded in the single-photon counting regime, reveals a coupling to mechanical modes of different types. We measure a sensitivity to displacement of 65 fm/[Formula: see text] limited by charge noise in the device. Finally, we use thermal excitation of the different modes to determine the location of the QD within the trumpet, and calculate the contribution of the Brownian motion to the dephasing of the emitter.Resonant driving of a nanoscale quantum system coupled to a microscopic mechanical resonator may have uses in precision sensing and quantum information. The authors realize this by tailoring the geometry of a semiconductor nanowire embedding a quantum dot, detecting sub picometre displacements. PMID- 28710415 TI - Morphogenesis and Optoelectronic Properties of Supramolecular Assemblies of Chiral Perylene Diimides in a Binary Solvent System. AB - Chiral supramolecular structures are attracting great attention due to their specific properties and high potential in chiral sensing and separation. Herein, supramolecular assembling behaviors of chiral perylene diimides have been systematically investigated in a mixed solution of tetrahydrofuran and water. They exhibit remarkably different morphologies and chiral aggregation behaviors depending on the mixing ratio of the solvents, i.e., the fraction of water. The morphogenesis and optoelectronic properties of chiral supramolecular structures have been thoroughly studied using a range of experimental and theoretical methods to investigate the morphological effects of chiral supramolecular assemblies on the electrical performances and photogenerated charge-carrier behaviors. In addition, chiral perylene diimides have been discriminated by combining vibrational circular dichroism with theoretical calculations, for the first time. The chiral supramolecular nanostructures developed herein strongly absorb visible spectral region and exhibit high photoresponsivity and detectivity, opening up new opportunities for practical applications in optoelectronics. PMID- 28710416 TI - CalQuo 2 : Automated Fourier-space, population-level quantification of global intracellular calcium responses. AB - Intracellular calcium acts as a secondary messenger in a wide variety of crucial biological signaling processes. Advances in fluorescence microscopy and calcium sensitive dyes has led to the routine quantification of calcium responses in non excitable cells. However, the automatization of global intracellular calcium analysis at the single-cell level within a large population simultaneously remains challenging. One software, CalQuo (Calcium Quantification), offers some automatic features in calcium analysis. Here, we present an advanced version of the software package: CalQuo 2 . CalQuo 2 analyzes the calcium response in the Fourier-domain, allowing the number of user-defined filtering parameters to be reduced to one and a greater diversity of calcium responses to be recognized, compared to CalQuo that directly interprets the calcium intensity signal. CalQuo 2 differentiates cells that release a single calcium response and those that release oscillatory calcium fluxes. We have demonstrated the use of CalQuo 2 by measuring the calcium response in genetically modified Jurkat T-cells under varying ligand conditions, in which we show that peptide:MHCs and anti-CD3 antibodies trigger a fraction of T cells to release oscillatory calcium fluxes that increase with increasing koff rates. These results show that CalQuo 2 is a robust and user-friendly tool for characterizing global, single cell calcium responses. PMID- 28710417 TI - TALEN based HPV-E7 editing triggers necrotic cell death in cervical cancer cells. AB - Human Papillomavirus E7 and E6 oncoproteins have been considered as suitable candidate anti-viral targets since they cause malignant conversion in cervical cancers. Transcription Activator-Like Effector Nucleases (TALENs) are recent editing tools to knockout genes by inducing double stranded breaks at specific sites in the genome. In here, we have designed specific TALENs to target E7 and analyzed their efficiency in inducing cell death in cervical cancer cells. We found that designed TALENs could yield about 10-12% editing activity as observed from T7E1 and nuclease resistance assays. Down-regulation of E7 and E6 was further evident at the transcript as well as proteins levels indicating that the selected TALENs were effective. TALEN-mediated E7 editing led to cell death as ascertained by cell cycle and Annexin V assays. Annexin profiling suggested that cell death could be due to necrosis as observed by upregulation of necrotic markers such as LDH A, Rip-1, and Cyclophilin A. Necrosis appears to be a better therapeutic response as it could further activate pro-inflammatory cytokines to attract immune cells to eliminate HPV-integrated cells and therefore TALEN editing strategy has the potential to be a promising tool as an adjuvant therapy in cervical cancer along with surgery. PMID- 28710418 TI - The best alternative for estimating reference crop evapotranspiration in different sub-regions of mainland China. AB - Reference crop evapotranspiration (ET o) is a critically important parameter for climatological, hydrological and agricultural management. The FAO56 Penman Monteith (PM) equation has been recommended as the standardized ET o (ET o,s) equation, but it has a high requirements of climatic data. There is a practical need for finding a best alternative method to estimate ET o in the regions where full climatic data are lacking. A comprehensive comparison for the spatiotemporal variations, relative errors, standard deviations and Nash-Sutcliffe efficacy coefficients of monthly or annual ET o,s and ET o,i (i = 1, 2, ..., 10) values estimated by 10 selected methods (i.e., Irmak et al., Makkink, Priestley-Taylor, Hargreaves-Samani, Droogers-Allen, Berti et al., Doorenbos-Pruitt, Wright and Valiantzas, respectively) using data at 552 sites over 1961-2013 in mainland China. The method proposed by Berti et al. (2014) was selected as the best alternative of FAO56-PM because it was simple in computation process, only utilized temperature data, had generally good accuracy in describing spatiotemporal characteristics of ET o,s in different sub-regions and mainland China, and correlated linearly to the FAO56-PM method very well. The parameters of the linear correlations between ET o of the two methods are calibrated for each site with the smallest determination of coefficient being 0.87. PMID- 28710419 TI - Generation of clade- and symbiont-specific antibodies to characterize marker molecules during Cnidaria-Symbiodinium endosymbiosis. AB - The endosymbiosis between cnidarians and dinoflagellates is responsible for the formation of coral reefs. Changes in molecules have been identified during the process of cnidaria-Symbiodinium endosymbiosis. However, the complexity of the molecular interaction has prevented the establishment of a mechanistic explanation of cellular regulation in this mutualistic symbiosis. To date, no marker molecules have been identified to specifically represent the symbiotic status. Because the endosymbiotic association occurs in the symbiotic gastrodermal cells (SGCs), whole cells of isolated SGCs were used as an antigen to generate monoclonal antibodies (mAb) to screen possible molecular candidates of symbiotic markers. The results showed that one of the generated monoclonal antibodies, 2-6F, specifically recognized clade C symbiotic Symbiodinium but not its free-living counterpart or other Symbiodinium clades. The expression levels of 2-6F mAb-recognized proteins are highly correlated with the symbiotic status, and these proteins were characterized as N-linked glycoproteins via treatment with peptide N-glycosidase F. Furthermore, their glycan moieties were markedly different from those of free-living Symbiodinium, potentially suggesting host regulation of post-translational modification. Consequently, the 2-6F mAb can be used to detect the symbiotic state of corals and investigate the complex molecular interactions in cnidaria-Symbiodinium endosymbiosis. PMID- 28710420 TI - The Resilience of Life to Astrophysical Events. AB - Much attention has been given in the literature to the effects of astrophysical events on human and land-based life. However, little has been discussed on the resilience of life itself. Here we instead explore the statistics of events that completely sterilise an Earth-like planet with planet radii in the range 0.5-1.5R ? and temperatures of ~300 K, eradicating all forms of life. We consider the relative likelihood of complete global sterilisation events from three astrophysical sources - supernovae, gamma-ray bursts, large asteroid impacts, and passing-by stars. To assess such probabilities we consider what cataclysmic event could lead to the annihilation of not just human life, but also extremophiles, through the boiling of all water in Earth's oceans. Surprisingly we find that although human life is somewhat fragile to nearby events, the resilience of Ecdysozoa such as Milnesium tardigradum renders global sterilisation an unlikely event. PMID- 28710421 TI - Super-resolution Surface Microscopy of Conductors using Magnetic Resonance. AB - The spatial resolution of traditional Magnetic Resonance Imaging (MRI) techniques is typically dictated by the strength of the applied magnetic field gradients, resulting in hard resolution limits of the order of 20-50 MUm in favorable circumstances. We demonstrate here a technique which is suitable for the interrogation of regions at specified distances below the surface of conducting objects with a resolution well below these limiting values. This approach does not rely on magnetic field gradients, but rather on the spatial variation of the radiofrequency field within a conductor. Samples of aluminium and lithium metal with different sizes and morphologies are examined with this technique using 27Al and 7Li NMR. In this implementation, the slice selectivity depends on the conductivity of the material, as well as on the frequency of operation, although in the most general case, the technique could also be used to provide spatial selectivity with arbitrary B 1 field distributions in non-conductors. PMID- 28710422 TI - ENMD-1068 inhibits liver fibrosis through attenuation of TGF-beta1/Smad2/3 signaling in mice. AB - Protease-activated receptor 2 (PAR-2) plays an important role in the pathogenesis of liver fibrosis. We studied the effect of N1-3-methylbutyryl-N4-6-aminohexanoyl piperazine (ENMD-1068), a PAR-2 antagonist, on the development of CCl4-induced liver fibrosis in mice and activation of hepatic stellate cells (HSCs) isolated from the mice. Before CCl4 injection, the mice were injected intraperitoneally with either 25 mg/kg or 50 mg/kg ENMD-1068 or with 200 MUL of the vehicle control twice per week for 4 weeks. The isolated HSCs were stimulated by TGF-beta1 with or without ENMD-1068 to evaluate the role of PAR-2 in TGF-beta1 induced HSCs activation and collagen production. We showed that the levels of ALT/AST, collagen content, and alpha-smooth muscle actin (alpha-SMA) were significantly reduced by treatment with ENMD-1068 in CCl4-induced fibrotic mice. Interestingly, we found TGF-beta1 signaling-related expression levels of alpha-SMA, type I and III collagen, and C-terminal phosphorylation of Smad2/3 were significantly decreased in the ENMD-1068 treated HSCs. Moreover, we showed ENMD-1068 treatment inhibited trypsin or SLIGRL-NH2 stimulated calcium release and TGF-beta1 induced Smad transcriptional activity in HSCs. We demonstrated that ENMD-1068 reduces HSCs activation and collagen expression through the inhibiton of TGF-beta1/Smad signal transduction. PMID- 28710423 TI - Primary surface rupture of the 1950 Tibet-Assam great earthquake along the eastern Himalayan front, India. AB - The pattern of strain accumulation and its release during earthquakes along the eastern Himalayan syntaxis is unclear due to its structural complexity and lack of primary surface signatures associated with large-to-great earthquakes. This led to a consensus that these earthquakes occurred on blind faults. Toward understanding this issue, palaeoseismic trenching was conducted across a ~3.1 m high fault scarp preserved along the mountain front at Pasighat (95.33 degrees E, 28.07 degrees N). Multi-proxy radiometric dating employed to the stratigraphic units and detrital charcoals obtained from the trench exposures provide chronological constraint on the discovered palaeoearthquake surface rupture clearly suggesting that the 15th August, 1950 Tibet-Assam earthquake (Mw ~ 8.6) did break the eastern Himalayan front producing a co-seismic slip of 5.5 +/- 0.7 meters. This study corroborates the first instance in using post-bomb radiogenic isotopes to help identify an earthquake rupture. PMID- 28710424 TI - Takotsubo Syndrome - Predictable from brain imaging data. AB - Takotsubo syndrome (TTS) is characterized by acute left ventricular dysfunction, with a hospital-mortality rate similar to acute coronary syndrome (ACS). However, the aetiology of TTS is still unknown. In the present study, a multivariate pattern analysis using machine learning with multimodal magnetic resonance imaging (MRI) data of the human brain of TTS patients and age- and gender-matched healthy control subjects was performed. We found consistent structural and functional alterations in TTS patients compared to the control group. In particular, anatomical and neurophysiological measures from brain regions constituting the emotional-autonomic control system contributed to a prediction accuracy of more than 82%. Thus, our findings demonstrate homogeneous neuronal alterations in TTS patients and substantiate the importance of the concept of a brain-heart interaction in TTS. PMID- 28710425 TI - Naja sputatrix Venom Preconditioning Attenuates Neuroinflammation in a Rat Model of Surgical Brain Injury via PLA2/5-LOX/LTB4 Cascade Activation. AB - Inflammatory preconditioning is a mechanism in which exposure to small doses of inflammatory stimuli prepares the body against future massive insult by activating endogenous protective responses. Phospholipase A2/5 lipoxygenase/leukotriene-B4 (PLA2/5-LOX/LTB4) axis is an important inflammatory signaling pathway. Naja sputatrix (Malayan spitting cobra) venom contains 15% secretory PLA2 of its dry weight. We investigated if Naja sputatrix venom preconditioning (VPC) reduces surgical brain injury (SBI)-induced neuroinflammation via activating PLA2/5-LOX/LTB4 cascade using a partial frontal lobe resection SBI rat model. Naja sputatrix venom sublethal dose was injected subcutaneously for 3 consecutive days prior to SBI. We observed that VPC reduced brain edema and improved neurological function 24 h and 72 h after SBI. The expression of pro-inflammatory mediators in peri-resection brain tissue was reduced with VPC. Administration of Manoalide, a PLA2 inhibitor or Zileuton, a 5 LOX inhibitor with VPC reversed the protective effects of VPC against neuroinflammation. The current VPC regime induced local skin inflammatory reaction limited to subcutaneous injection site and elicited no other toxic effects. Our findings suggest that VPC reduces neuroinflammation and improves outcomes after SBI by activating PLA2/5-LOX/LTB4 cascade. VPC may be beneficial to reduce post-operative neuroinflammatory complications after brain surgeries. PMID- 28710427 TI - The essential role of TAp73 in bortezomib-induced apoptosis in p53-deficient colorectal cancer cells. AB - Mutations in the tumor suppressor p53 are among the most highly occurring events in colorectal cancer (CRC). Such mutations have been shown to influence the sensitivity of cancer cells to chemotherapeutic agents. However their impact on the efficacy of the proteasomal inhibitor bortezomib remains controversial. We thus re-evaluated the toxicity of bortezomib in the CRC cell lines HCT116 wt (wild-type) and its p53-/- clone. Transient resistance to bortezomib treatment was observed in p53-null cells that was later accompanied by an increase in levels and nuclear translocation of TAp73, an isoform of the p53-homologue p73, as well as induction of apoptosis. Knockdown of p73 in p53-/- cells using CRISPR/Cas9 significantly prolonged the duration of resistance. Moreover, similar results were observed in HT-29 cells carrying mutated p53, but not human fibroblasts with expression of functional p53. Thus, our results clearly demonstrated that TAp73 served as a substitute for p53 in bortezomib-induced apoptosis in p53-deficient or mutated cells, implicating that TAp73 could be a potential therapeutic target for treatment of CRCs, in particular those lacking functional p53. PMID- 28710426 TI - Targeting of dopamine transporter to filopodia requires an outward-facing conformation of the transporter. AB - Dopamine transporter (DAT) has been shown to accumulate in filopodia in neurons and non-neuronal cells. To examine the mechanisms of DAT filopodial targeting, we used quantitative live-cell fluorescence microscopy, and compared the effects of the DAT inhibitor cocaine and its fluorescent analog JHC1-64 on the plasma membrane distribution of wild-type DAT and two non-functional DAT mutants, R60A and W63A, that do not accumulate in filopodia. W63A did not bind JHC1-64, whereas R60A did, although less efficiently compared to the wild-type DAT. Molecular dynamics simulations predicted that R60A preferentially assumes an outward-facing (OF) conformation through compensatory intracellular salt bridge formation, which in turn favors binding of cocaine. Imaging analysis showed that JHC1-64-bound R60A mutant predominantly localized in filopodia, whereas free R60A molecules were evenly distributed within the plasma membrane. Cocaine binding significantly increased the density of R60A, but not that of W63A, in filopodia. Further, zinc binding, known to stabilize the OF state, also increased R60A concentration in filopodia. Finally, amphetamine, that is thought to disrupt DAT OF conformation, reduced the concentration of wild-type DAT in filopodia. Altogether, these data indicate that OF conformation is required for the efficient targeting of DAT to, and accumulation in, filopodia. PMID- 28710428 TI - The use of a hybrid Sequential Biofiltration System for the improvement of nutrient removal and PCB control in municipal wastewater. AB - This article aims to evaluate the efficiency of an innovative hybrid Sequential Biofiltration System (SBS) for removing phosphorus and nitrogen and polychlorinated biphenyls (PCBs) from original municipal wastewater produced by a Wastewater Treatment Plant under authentic operating conditions. The hybrid SBS was constructed with two barriers, a geochemical (filtration beds with limestone, coal and sawdust) and a biological barrier (wetlands with Glyceria, Acorus, Typha, Phragmites), operating in parallel. Significant differences were found between inflow and outflow from the SBS with regard to wastewater contaminant concentrations, the efficiency of removal being 16% (max. 93%) for Total Phosphorus (TP), 25% (max. 93%) for Soluble Reactive Phosphorus (SRP), 15% (max. 97%) for Total Nitrogen (TN), 17% (max. 98%) for NO3-N, and 21% for PCB equivalency (PCB EQ). In the case of PCB EQ concentration, the highest efficiency of 43% was obtained using beds with macrophytes. The SBS removed a significant load of TP (0.415 kg), TN (3.136 kg), and PCB EQ (0.223 g) per square meter per year. The use of low-cost hybrid SBSs as a post-treatment step for wastewater treatment was found to be an effective ecohydrological biotechnology that may be used for reducing point source pollution and improving water quality. PMID- 28710429 TI - The A2V mutation as a new tool for hindering Abeta aggregation: A neutron and x ray diffraction study. AB - We have described a novel C-to-T mutation in the APP gene that corresponds to an alanine to valine substitution at position 673 in APP (A673V), or position 2 of the amyloid-beta (Abeta) sequence. This mutation is associated with the early onset of AD-type dementia in homozygous individuals, whereas it has a protective effect in the heterozygous state. Correspondingly, we observed differences in the aggregation properties of the wild-type and mutated Abeta peptides and their mixture. We have carried out neutron diffraction (ND) and x-ray diffraction (XRD) experiments on magnetically-oriented fibers of Abeta1-28WT and its variant Abeta1 28A2V. The orientation propensity was higher for Abeta1-28A2V suggesting that it promotes the formation of fibrillar assemblies. The diffraction patterns by Abeta1-28WT and Abeta1-28A2V assemblies differed in shape and position of the equatorial reflections, suggesting that the two peptides adopt distinct lateral packing of the diffracting units. The diffraction patterns from a mixture of the two peptides differed from those of the single components, indicating the presence of structural interference during assembly and orientation. The lowest orientation propensity was observed for a mixture of Abeta1-28WT and a short N terminal fragment, Abeta1-6A2V, which supports a role of Abeta's N-terminal domain in amyloid fibril formation. PMID- 28710430 TI - RLR-mediated antiviral innate immunity requires oxidative phosphorylation activity. AB - Mitochondria act as a platform for antiviral innate immunity, and the immune system depends on activation of the retinoic acid-inducible gene I (RIG-I)-like receptors (RLR) signaling pathway via an adaptor molecule, mitochondrial antiviral signaling. We report that RLR-mediated antiviral innate immunity requires oxidative phosphorylation (OXPHOS) activity, a prominent physiologic function of mitochondria. Cells lacking mitochondrial DNA or mutant cells with respiratory defects exhibited severely impaired virus-induced induction of interferons and proinflammatory cytokines. Recovery of the OXPHOS activity in these mutants, however, re-established RLR-mediated signal transduction. Using in vivo approaches, we found that mice with OXPHOS defects were highly susceptible to viral infection and exhibited significant lung inflammation. Studies to elucidate the molecular mechanism of OXPHOS-coupled immune activity revealed that optic atrophy 1, a mediator of mitochondrial fusion, contributes to regulate the antiviral immune response. Our findings provide evidence for functional coordination between RLR-mediated antiviral innate immunity and the mitochondrial energy-generating system in mammals. PMID- 28710432 TI - Electro-mechanical light modulator based on controlling the interaction of light with a metasurface. AB - We demonstrate a reflective light modulator, a dynamic Salisbury screen where modulation of light is achieved by moving a thin metamaterial absorber to control its interaction with the standing wave formed by the incident wave and its reflection on a mirror. Electrostatic actuation of the plasmonic metamaterial absorber's position leads to a dynamic change of the Salisbury screen's spectral response and 50% modulation of the reflected light intensity in the near infrared part of the spectrum. The proposed approach can also be used with other metasurfaces to control the changes they impose on the polarization, intensity, phase, spectrum and directional distribution of reflected light. PMID- 28710431 TI - HIV-1 enhances mTORC1 activity and repositions lysosomes to the periphery by co opting Rag GTPases. AB - HIV-1 co-opts several host machinery to generate a permissive environment for viral replication and transmission. In this work we reveal how HIV-1 impacts the host translation and intracellular vesicular trafficking machineries for protein synthesis and to impede the physiological late endosome/lysosome (LEL) trafficking in stressful conditions. First, HIV-1 enhances the activity of the master regulator of protein synthesis, the mammalian target of rapamycin (mTOR). Second, the virus commandeers mTOR-associated late endosome/lysosome (LEL) trafficking and counteracts metabolic and environmental stress-induced intracellular repositioning of LEL. We then show that the small Rag GTPases, RagA and RagB, are required for the HIV-1-mediated LEL repositioning that is likely mediated by interactions between the Rags and the viral proteins, Gag and Vif. siRNA-mediated depletion of RagA and RagB leads to a loss in mTOR association to LEL and to a blockade of viral particle assembly and release at the plasma membrane with a marked concomitant reduction in virus production. These results show that HIV-1 co-opts fundamental mechanisms that regulate LEL motility and positioning and support the notion that LEL positioning is critical for HIV-1 replication. PMID- 28710433 TI - High-Density Genetic Linkage Map Construction and Quantitative Trait Locus Mapping for Hawthorn (Crataegus pinnatifida Bunge). AB - Genetic linkage maps are an important tool in genetic and genomic research. In this study, two hawthorn cultivars, Qiujinxing and Damianqiu, and 107 progenies from a cross between them were used for constructing a high-density genetic linkage map using the 2b-restriction site-associated DNA (2b-RAD) sequencing method, as well as for mapping quantitative trait loci (QTL) for flavonoid content. In total, 206,411,693 single-end reads were obtained, with an average sequencing depth of 57* in the parents and 23* in the progeny. After quality trimming, 117,896 high-quality 2b-RAD tags were retained, of which 42,279 were polymorphic; of these, 12,951 markers were used for constructing the genetic linkage map. The map contained 17 linkage groups and 3,894 markers, with a total map length of 1,551.97 cM and an average marker interval of 0.40 cM. QTL mapping identified 21 QTLs associated with flavonoid content in 10 linkage groups, which explained 16.30-59.00% of the variance. This is the first high-density linkage map for hawthorn, which will serve as a basis for fine-scale QTL mapping and marker-assisted selection of important traits in hawthorn germplasm and will facilitate chromosome assignment for hawthorn whole-genome assemblies in the future. PMID- 28710434 TI - Modifying Dendritic Cell Activation with Plasmonic Nano Vectors. AB - Dendritic cells (DCs) can acquire, process, and present antigens to T-cells to induce an immune response. For this reason, targeting cancer antigens to DCs in order to cause an immune response against cancer is an emerging area of nanomedicine that has the potential to redefine the way certain cancers are treated. The use of plasmonically active silver-coated gold nanorods (henceforth referred to as plasmonic nano vectors (PNVs)) as potential carriers for DC tumor vaccines has not been presented before. Effective carriers must be able to be phagocytized by DCs, present low toxicity, and induce the maturation of DCs-an early indication of an immune response. When we treated DCs with the PNVs, we found that the cell viability of DCs was unaffected, up to 200 MUg/ml. Additionally, the PNVs associated with the DCs as they were phagocytized and they were found to reside within intracellular compartments such as endosomes. More importantly, the PNVs were able to induce expression of surface markers indicative of DC activation and maturation, i.e. CD40, CD86, and MHC class II. These results provide the first evidence that PNVs are promising carriers for DC based vaccines and warrant further investigating for clinical use. PMID- 28710435 TI - Evaluation of eLIFT for Non-invasive Assessment of Liver fibrosis and Cirrhosis in Patients with Chronic Hepatitis B Virus Infection. AB - Recently, the easy Liver Fibrosis Test (eLIFT), a sum of points attributed to age, gender, gamma-glutamyl transpeptidase, aspartate transaminase, platelets, and prothrombin time, was developed for diagnosing advanced fibrosis and cirrhosis in chronic liver disease. We aimed to evaluate the performance of eLIFT to predict liver fibrosis and cirrhosis in patients with chronic hepatitis B (CHB). Histologic and laboratory data of 747 CHB patients were analyzed. The performance of eLIFT for diagnosing liver fibrosis and cirrhosis was compared with that of aspartate transaminase to platelet ratio index (APRI) and fibrosis index based on the 4 factors (FIB-4). To predict advanced fibrosis, the AUROC of eLIFT was comparable with that of APRI (0.66 vs 0.71, p = 0.095) and FIB-4 (0.66 vs 0.67, p = 0.612). To predict severe fibrosis, the AUROC of eLIFT was lower than that of APRI (0.65 vs 0.83, p < 0.001) and FIB-4 (0.65 vs 0.82, p < 0.001). To predict cirrhosis, the AUROC of eLIFT was also lower than that of APRI (0.64 vs 0.85, p = 0.001) and FIB-4 (0.64 vs 0.76, p = 0.033). The eLIFT is not a good non-invasive test for the diagnosis of liver fibrosis and cirrhosis in CHB patients. PMID- 28710436 TI - Epithelial-derived IL-33 promotes intestinal tumorigenesis in Apc Min/+ mice. AB - Increased expression of Interleukin (IL)-33 has been detected in intestinal samples of patients with ulcerative colitis, a condition associated with increased risk for colon cancer, but its role in the development of colorectal cancer has yet to be fully examined. Here, we investigated the role of epithelial expressed IL-33 during development of intestinal tumors. IL-33 expression was detected in epithelial cells in colorectal cancer specimens and in the Apc Min/+ mice. To better understand the role of epithelial-derived IL-33 in the intestinal tumorigenesis, we generated transgenic mice expressing IL-33 in intestinal epithelial cells (V33 mice). V33 Apc Min/+ mice, resulting from the cross of V33 with Apc Min/+ mice, had increased intestinal tumor burden compared with littermate Apc Min/+ mice. Consistently, Apc Min/+ mice deficient for IL-33 receptor (ST2), had reduced polyp burden. Mechanistically, overexpression of IL 33 promoted expansion of ST2+ regulatory T cells, increased Th2 cytokine milieu, and induced alternatively activated macrophages in the gut. IL-33 promoted marked changes in the expression of antimicrobial peptides, and antibiotic treatment of V33 Apc Min/+ mice abrogated the tumor promoting-effects of IL-33 in the colon. In conclusion, elevated IL-33 signaling increases tumor development in the Apc Min/+ mice. PMID- 28710438 TI - Simulation of Long-term Yield and Soil Water Consumption in Apple Orchards on the Loess Plateau, China, in Response to Fertilization. AB - The Loess Plateau, China, is the world's largest apple-producing region, and over 80% of the orchards are in rainfed (dryland) areas. Desiccation of the deep soil layer under dryland apple orchards is the main stressor of apple production in this region. Fertilization is a factor that causes soil desiccation in dryland apple orchards. Given its applicability and precision validations, the Environmental Policy Integrated Climate (EPIC) model was used to simulate the dynamics of fruit yield and deep soil desiccation in apple orchards under six fertilization treatments. During the 45 years of study, the annual fruit yield under the fertilization treatments initially increased and then decreased in a fluctuating manner, and the average fruit yields were 24.42, 27.27, 28.69, 29.63, 30.49 and 29.43 t/ha in these respective fertilization treatments. As fertilization increased, yield of the apple orchards increased first and then declined,desiccation of the soil layers occurred earlier and extended deeper, and the average annual water consumption, over-consumption and water use efficiency increased as fertilization increased. In terms of apple yields, sustainable soil water use, and economic benefits, the most appropriate fertilization rate for drylands in Luochuan is 360-480 kg/ha N and 180-240 kg/ha P. PMID- 28710437 TI - Inhibition of CTGF ameliorates peritoneal fibrosis through suppression of fibroblast and myofibroblast accumulation and angiogenesis. AB - Peritoneal fibrosis (PF) is a serious complication in various clinical settings, but the mechanisms driving it remain to be fully determined. Connective tissue growth factor (CTGF) is known to regulate fibroblast activities. We therefore examined if CTGF inhibition has anti-fibrotic effects in PF. PF was induced by repetitive intraperitoneal injections of chlorhexidine gluconate (CG) in mice with type I pro-collagen promoter-driven green fluorescent protein (GFP) expression to identify fibroblasts. FG-3019, an anti-CTGF monoclonal antibody, was used to inhibit CTGF. CG-induced PF was significantly attenuated in FG-3019 treated mice. CG challenges induced marked accumulations of proliferating fibroblasts and of myofibroblasts, which were both reduced by FG-3019. Levels of peritoneal CTGF expression were increased by CG challenges, and suppressed in FG 3019-treated mice. FG-3019 treatment also reduced the number of CD31+ vessels and VEGF-A-positive cells in fibrotic peritoneum. In vitro studies using NIH 3T3 fibroblasts and peritoneal mesothelial cells (PMCs) showed that CTGF blockade suppressed TGF-beta1-induced fibroblast proliferation and myofibroblast differentiation, PMC mesothelial-to-mesenchymal transition, and VEGF-A production. These findings suggest that the inhibition of CTGF by FG-3019 might be a novel treatment for PF through the regulation of fibroblast and myofibroblast accumulation and angiogenesis. PMID- 28710439 TI - Systematic analysis of gene expression patterns associated with postmortem interval in human tissues. AB - Postmortem mRNA degradation is considered to be the major concern in gene expression research utilizing human postmortem tissues. A key factor in this process is the postmortem interval (PMI), which is defined as the interval between death and sample collection. However, global patterns of postmortem mRNA degradation at individual gene levels across diverse human tissues remain largely unknown. In this study, we performed a systematic analysis of alteration of gene expression associated with PMI in human tissues. From the Genotype-Tissue Expression (GTEx) database, we evaluated gene expression levels of 2,016 high quality postmortem samples from 316 donors of European descent, with PMI ranging from 1 to 27 hours. We found that PMI-related mRNA degradation is tissue specific, gene-specific, and even genotype-dependent, thus drawing a more comprehensive picture of PMI-associated gene expression across diverse human tissues. Additionally, we also identified 266 differentially variable (DV) genes, such as DEFB4B and IFNG, whose expression is significantly dispersed between short PMI (S-PMI) and long PMI (L-PMI) groups. In summary, our analyses provide a comprehensive profile of PMI-associated gene expression, which will help interpret gene expression patterns in the evaluation of postmortem tissues. PMID- 28710440 TI - Ecological interactions in Cloudina from the Ediacaran of Brazil: implications for the rise of animal biomineralization. AB - At the Ediacaran/Cambrian boundary, ecosystems witnessed an unparalleled biological innovation: the appearance of shelled animals. Here, we report new paleoecological and paleobiological data on Cloudina, which was one of the most abundant shelled animals at the end of the Ediacaran. We report the close association of Cloudina tubes with microbial mat textures as well as organic-rich material, syndepositional calcite and goethite cement between their flanges, thus reinforcing the awareness of metazoan/microorganism interactions at the end of the Ediacaran. The preservation of in situ tubes suggests a great plasticity of substrate utilization, with evidence of different life modes and avoidance behavior. Geochemical analysis revealed walls composed of two secondary laminae and organic sheets. Some walls presented boreholes that are here described as predation marks. Taken together, these data add further information regarding the structuring of shelled animal communities in marine ecosystems. PMID- 28710442 TI - Spontaneous Emulsification as a Function of Material Exchange. AB - Direct visualization at 1873 K of 0% to 8% molten FeAl droplets suspended in a SiO2 enriched oxide medium was carried out to image the evolution of droplet morphology during reaction between Al and SiO2. Phenomena such as perturbation growth, necking and budding of offspring droplets from a bulk body are observed. The observations are used to discuss and inform a new approach to the nature of interfacial tension and the impact this has on concepts used to define interfacial tension for a two phase system with material exchange across the interface. The mapping of global interfacial tension coupled with free energy dissipation has been used to give an energetic reasoning as to the behaviour seen with respect to aluminium content in the metal phase. PMID- 28710441 TI - IgG3-antigen complexes are deposited on follicular dendritic cells in the presence of C1q and C3. AB - IgG3, passively administered together with small proteins, induces enhanced primary humoral responses against these proteins. We previously found that, within 2 h of immunization, marginal zone (MZ) B cells capture IgG3-antigen complexes and transport them into splenic follicles and that this requires the presence of complement receptors 1 and 2. We have here investigated the localization of IgG3 anti-2, 4, 6-trinitrophenyl (TNP)/biotin-ovalbumin-TNP immune complexes in the follicles and the involvement of classical versus total complement activation in this process. The majority (50-90%) of antigen inside the follicles of mice immunized with IgG3-antigen complexes co-localized with the follicular dendritic cell (FDC) network. Capture of antigen by MZ B cells as well as antigen deposition on FDC was severely impaired in mice lacking C1q or C3, and lack of either C1q or C3 also impaired the ability of IgG3 to enhance antibody responses. Finally, IgG3 efficiently primed for a memory response against small proteins as well as against the large protein keyhole limpet hemocyanine. PMID- 28710443 TI - Defying Dissolution: Discovery of Deep-Sea Scleractinian Coral Reefs in the North Pacific. AB - Deep-sea scleractinian coral reefs are protected ecologically and biologically significant areas that support global fisheries. The absence of observations of deep-sea scleractinian reefs in the Central and Northeast Pacific, combined with the shallow aragonite saturation horizon (ASH) and high carbonate dissolution rates there, fueled the hypothesis that reef formation in the North Pacific was improbable. Despite this, we report the discovery of live scleractinian reefs on six seamounts of the Northwestern Hawaiian Islands and Emperor Seamount Chain at depths of 535-732 m and aragonite saturation state (Omegaarag) values of 0.71 1.33. Although the ASH becomes deeper moving northwest along the chains, the depth distribution of the reefs becomes shallower, suggesting the ASH is having little influence on their distribution. Higher chlorophyll moving to the northwest may partially explain the geographic distribution of the reefs. Principle Components Analysis suggests that currents are also an important factor in their distribution, but neither chlorophyll nor the available current data can explain the unexpected depth distribution. Further environmental data is needed to elucidate the reason for the distribution of these reefs. The discovery of reef-forming scleractinians in this region is of concern because a number of the sites occur on seamounts with active trawl fisheries. PMID- 28710444 TI - Ergodicity breaking on the neuronal surface emerges from random switching between diffusive states. AB - Stochastic motion on the surface of living cells is critical to promote molecular encounters that are necessary for multiple cellular processes. Often the complexity of the cell membranes leads to anomalous diffusion, which under certain conditions it is accompanied by non-ergodic dynamics. Here, we unravel two manifestations of ergodicity breaking in the dynamics of membrane proteins in the somatic surface of hippocampal neurons. Three different tagged molecules are studied on the surface of the soma: the voltage-gated potassium and sodium channels Kv1.4 and Nav1.6 and the glycoprotein CD4. In these three molecules ergodicity breaking is unveiled by the confidence interval of the mean square displacement and by the dynamical functional estimator. Ergodicity breaking is found to take place due to transient confinement effects since the molecules alternate between free diffusion and confined motion. PMID- 28710445 TI - Microplastics in eviscerated flesh and excised organs of dried fish. AB - There is a paucity of information about the occurrence of microplastics (MPs) in edible fish tissues. Here, we investigated the potential presence of MPs in the excised organs (viscera and gills) and eviscerated flesh (whole fish excluding the viscera and gills) of four commonly consumed dried fish species (n = 30 per species). The MP chemical composition was then determined using micro-Raman spectroscopy and elemental analysis with energy-dispersive X-ray spectroscopy (EDX). Out of 61 isolated particles, 59.0% were plastic polymers, 21.3% were pigment particles, 6.55% were non-plastic items (i.e. cellulose or actinolite), while 13.1% remained unidentified. The level of heavy metals on MPs or pigment particles were below the detection limit. Surprisingly, in two species, the eviscerated flesh contained higher MP loads than the excised organs, which highlights that evisceration does not necessarily eliminate the risk of MP intake by consumers. Future studies are encouraged to quantify anthropogenic particle loads in edible fish tissues. PMID- 28710446 TI - The movement of small insects in the convective boundary layer: linking patterns to processes. AB - In fine warm weather, the daytime convective atmosphere over land areas is full of small migrant insects, among them serious pests (e.g. some species of aphid), but also many beneficial species (e.g. natural enemies of pests). For many years intensive aerial trapping studies were the only way of determining the density profiles of these small insects, and for taxon-specific studies trapping is still necessary. However, if we wish to determine generic behavioural responses to air movements shown by small day-migrating insects as a whole, the combination of millimetre-wavelength 'cloud radars' and Doppler lidar now provides virtually ideal instrumentation. Here we examine the net vertical velocities of > 1 million insect targets, relative to the vertical motion of the air in which they are flying, as a succession of fair-weather convective cells pass over the recording site in Oklahoma, USA. The resulting velocity measurements are interpreted in terms of the flight behaviours of small insects. These behaviours are accounted for by a newly-developed Lagrangian stochastic model of weakly-flying insect movements in the convective boundary layer; a model which is consistent with classic characterisations of small insect aerial density profiles. We thereby link patterns to processes. PMID- 28710447 TI - Cryo-EM reconstruction of the Cafeteria roenbergensis virus capsid suggests novel assembly pathway for giant viruses. AB - Whereas the protein composition and overall shape of several giant virus capsids have been described, the mechanism by which these large capsids assemble remains enigmatic. Here, we present a reconstruction of the capsid of Cafeteria roenbergensis virus (CroV), one of the largest viruses analyzed by cryo-electron microscopy (cryo-EM) to date. The CroV capsid has a diameter of 3,000 A and a Triangulation number of 499. Unlike related mimiviruses, the CroV capsid is not decorated with glycosylated surface fibers, but features 30 A-long surface protrusions that are formed by loops of the major capsid protein. Based on the orientation of capsomers in the cryo-EM reconstruction, we propose that the capsids of CroV and related giant viruses are assembled by a newly conceived assembly pathway that initiates at a five-fold vertex and continuously proceeds outwards in a spiraling fashion. PMID- 28710448 TI - Experimental investigation on preconditioned rate induced tipping in a thermoacoustic system. AB - Many systems found in nature are susceptible to tipping, where they can shift from one stable dynamical state to another. This shift in dynamics can be unfavorable in systems found in various fields ranging from ecology to finance. Hence, it is important to identify the factors that can lead to tipping in a physical system. Tipping can mainly be brought about by a change in parameter or due to the influence of external fluctuations. Further, the rate at which the parameter is varied also determines the final state that the system attains. Here, we show preconditioned rate induced tipping in experiments and in a theoretical model of a thermoacoustic system. We provide a specific initial condition (preconditioning) and vary the parameter at a rate higher than a critical rate to observe tipping. We find that the critical rate is a function of the initial condition. Our study is highly relevant because the parameters that dictate the asymptotic behavior of many physical systems are temporally dynamic. PMID- 28710449 TI - Combined deletion and DNA methylation result in silencing of FAM107A gene in laryngeal tumors. AB - Larynx squamous cell carcinoma (LSCC) is characterized by complex genotypes, with numerous abnormalities in various genes. Despite the progress in diagnosis and treatment of this disease, 5-year survival rates remain unsatisfactory. Therefore, the extended studies are conducted, with the aim to find genes, potentially implicated in this cancer. In this study, we focus on the FAM107A (3p14.3) gene, since we found its significantly reduced expression in LSCC by microarray profiling (Affymetrix U133 Plus 2.0 array). By RT-PCR we have confirmed complete FAM107A downregulation in laryngeal cancer cell lines (15/15) and primary tumors (21/21) and this finding was further supported by FAM107A protein immunohistochemistry (15/15). We further demonstrate that a combined two hit mechanism including loss of 3p and hypermethylation of FAM107A promoter region (in 9/15 cell lines (p < 0.0001) and in 15/21 primary tumors (p < 0.0001)) prevails in the gene transcriptional loss. As a proof of principle, we show that Decitabine - a hypomethylating agent - restores FAM107A expression (5 to 6 fold increase) in the UT-SCC-29 cell line, characterized by high DNA methylation. Therefore, we report the recurrent inactivation of FAM107A in LSCC, what may suggest that the gene is a promising tumor suppressor candidate involved in LSCC development. PMID- 28710450 TI - Interface Adhesion and Structural Characterization of Rolled-up GaAs/In0.2Ga0.8As Multilayer Tubes by Coherent Phonon Spectroscopy. AB - We present a detailed experimental and theoretical study of the acoustic phonon modes in rolled-up multilayers with thickness of the layers in the nanometre and diameters in the micrometre range. We compare our results to planar, unrolled multilayers grown by molecular beam epitaxy. For the planar multilayers the experimentally obtained acoustic modes exhibit properties of a superlattice and match well to calculations obtained by the Rytov model. The rolled-up superlattice tubes show intriguing differences compared to the planar structures which can be attributed to the imperfect adhesion between individual tube windings. A transfer matrix method including a massless spring accounting for the imperfect adhesion between the layers yields good agreement between experiment and calculations for up to five windings. Areas with sufficient mechanical coupling between all windings can be distinguished by their acoustic mode spectrum from areas where individual windings are only partially in contact. This allows the spatially resolved characterization of individual tubes with micrometre spatial resolution where areas with varying interface adhesion can be identified. PMID- 28710451 TI - Selection of complementary foods based on optimal nutritional values. AB - Human milk is beneficial for growth and development of infants. Several factors result in mothers ceasing breastfeeding which leads to introduction of breast milk substitutes (BMS). In some communities traditional foods are given as BMS, in others they are given as complementary foods during weaning. Improper food selection at this stage is associated with a high prevalence of malnutrition in children under 5 years. Here we listed the traditional foods from four continents and compared them with human milk based on their dietary contents. Vitamins such as thiamine (~[2-10] folds), riboflavin (~[4-10] folds) and ascorbic acid (<2 folds) contents of Asian and African foods were markedly lower. In order to extend the search for foods that includes similar dietary constituents as human milk, we designed a strategy of screening 8654 foods. 12 foods were identified and these foods were evaluated for their ability to meet the daily nutritional requirement of breastfed and non-breastfed infants during their first year of life. Genome-scale models of infant's hepatocytes, adipocytes and myocytes were then used to simulate in vitro growth of tissues when subjected to these foods. Key findings were that pork ham cured, fish pudding, and egg lean white induced better tissue growth, and quark with fruit, cheese quarg 45% and cheese cream 60% had similar lactose content as human milk. PMID- 28710452 TI - Factors affecting distribution patterns of organic carbon in sediments at regional and national scales in China. AB - Wetlands are an important carbon reservoir pool in terrestrial ecosystems. Light fraction organic carbon (LFOC), heavy fraction organic carbon (HFOC), and dissolved organic carbon (DOC) were fractionated in sediment samples from the four wetlands (ZR: Zhaoniu River; ZRCW: Zhaoniu River Constructed Wetland; XR: Xinxue River; XRCW: Xinxue River Constructed Wetland). Organic carbon (OC) from rivers and coasts of China were retrieved and statistically analyzed. At regional scale, HFOC stably dominates the deposition of OC (95.4%), whereas DOC and LFOC in ZR is significantly higher than in ZRCW. Concentration of DOC is significantly higher in XRCW (30.37 mg/l) than that in XR (13.59 mg/l). DOC and HFOC notably distinguish between two sampling campaigns, and the deposition of carbon fractions are limited by low nitrogen input. At the national scale, OC attains the maximum of 2.29% at precipitation of 800 mm. OC has no significant difference among the three climate zones but significantly higher in river sediments than in coasts. Coastal OC increases from Bohai Sea (0.52%) to South Sea (0.70%) with a decrease in latitude. This study summarizes the factors affecting organic carbon storage in regional and national scale, and have constructive implications for carbon assessment, modelling, and management. PMID- 28710454 TI - Stability of buried carbon in deep-ploughed forest and cropland soils - implications for carbon stocks. AB - Accumulation of soil organic carbon (SOC) may play a key role in climate change mitigation and adaptation. In particular, subsoil provides a great potential for additional SOC storage due to the assumed higher stability of subsoil SOC. The fastest way in which SOC reaches the subsoil is via burial, e.g. via erosion or deep ploughing. We assessed the effect of active SOC burial through deep ploughing on long-term SOC stocks and stability in forest and cropland subsoil. After 25-48 years, deep-ploughed subsoil contained significantly more SOC than reference subsoils, in both forest soil (+48%) and cropland (+67%). However, total SOC stocks down to 100 cm in deep-ploughed soil were greater than in reference soil only in cropland, and not in forests. This was explained by slower SOC accumulation in topsoil of deep-ploughed forest soils. Buried SOC was on average 32% more stable than reference SOC, as revealed by long-term incubation. Moreover, buried subsoil SOC had higher apparent radiocarbon ages indicating that it is largely isolated from exchange with atmospheric CO2. We concluded that deep ploughing increased subsoil SOC storage and that the higher subsoil SOC stability is not only a result of selective preservation of more stable SOC fractions. PMID- 28710453 TI - Intrinsic dynamics study identifies two amino acids of TIMP-1 critical for its LRP-1-mediated endocytosis in neurons. AB - The tissue inhibitor of metalloproteinases-1 (TIMP-1) exerts inhibitory activity against matrix metalloproteinases and cytokine-like effects. We previously showed that TIMP-1 reduces neurite outgrowth in mouse cortical neurons and that this cytokine-like effect depends on TIMP-1 endocytosis mediated by the low-density lipoprotein receptor-related protein-1 (LRP-1). To gain insight into the interaction between TIMP-1 and LRP-1, we considered conformational changes that occur when a ligand binds to its receptor. TIMP-1 conformational changes have been studied using biomolecular simulations, and our results provide evidence for a hinge region that is critical for the protein movement between the N- and C terminal TIMP-1 domains. In silico mutants have been proposed on residues F12 and K47, which are located in the hinge region. Biological analyses of these mutants show that F12A or K47A mutation does not alter MMP inhibitory activity but impairs the effect of TIMP-1 on neurite outgrowth. Interestingly, these mutants bind to LRP-1 but are not endocytosed. We conclude that the intrinsic dynamics of TIMP-1 are not involved in its binding to LRP-1 but rather in the initiation of endocytosis and associated biological effects. PMID- 28710455 TI - Retrieving Precise Three-Dimensional Deformation on the 2014 M6.0 South Napa Earthquake by Joint Inversion of Multi-Sensor SAR. AB - We reconstructed the three-dimensional (3D) surface displacement field of the 24 August 2014 M6.0 South Napa earthquake using SAR data from the Italian Space Agency's COSMO-SkyMed and the European Space Agency's Sentinel-1A satellites. Along-track and cross-track displacements produced with conventional SAR interferometry (InSAR) and multiple-aperture SAR interferometry (MAI) techniques were integrated to retrieve the east, north, and up components of surface deformation. The resulting 3D displacement maps clearly delineated the right lateral shear motion of the fault rupture with a maximum surface displacement of approximately 45 cm along the fault's strike, showing the east and north components of the trace particularly clearly. These maps also suggested a better constrained model for the South Napa earthquake. We determined a strike of approximately 338 degrees and dip of 85 degrees by applying the Okada dislocation model considering a single patch with a homogeneous slip motion. Using the distributed slip model obtained by a linear solution, we estimated that a peak slip of approximately 1.7 m occurred around 4 km depth from the surface. 3D modelling using the retrieved 3D maps helps clarify the fault's nature and thus characterize its behaviour. PMID- 28710456 TI - Genomic insights into the virulence and salt tolerance of Staphylococcus equorum. AB - To shed light on the genetic background behind the virulence and salt tolerance of Staphylococcus equorum, we performed comparative genome analysis of six S. equorum strains. Data on four previously published genome sequences were obtained from the NCBI database, while those on strain KM1031 displaying resistance to multiple antibiotics and strain C2014 causing haemolysis were determined in this study. Examination of the pan-genome of five of the six S. equorum strains showed that the conserved core genome retained the genes for general physiological processes and survival of the species. In this comparative genomic analysis, the factors that distinguish the strains from each other, including acquired genomic factors in mobile elements, were identified. Additionally, the high salt tolerance of strains enabling growth at a NaCl concentration of 25% (w/v) was attributed to the genes encoding potassium voltage-gated channels. Among the six strains, KS1039 does not possess any of the functional virulence determinants expressed in the other strains. PMID- 28710457 TI - Methyl-CpG binding domain proteins inhibit interspecies courtship and promote aggression in Drosophila. AB - Reproductive isolation and speciation are driven by the convergence of environmental and genetic variation. The integration of these variation sources is thought to occur through epigenetic marks including DNA methylation. Proteins containing a methyl-CpG-binding domain (MBD) bind methylated DNA and interpret epigenetic marks, providing a dynamic yet evolutionarily adapted cellular output. Here, we report the Drosophila MBD-containing proteins, dMBD-R2 and dMBD2/3, contribute to reproductive isolation and survival behavioral strategies. Drosophila melanogaster males with a reduction in dMBD-R2 specifically in octopamine (OA) neurons exhibit courtship toward divergent interspecies D. virilis and D. yakuba females and a decrease in conspecific mating success. Conspecific male-male courtship is increased between dMBD-R2-deficient males while aggression is reduced. These changes in adaptive behavior are separable as males with a hypermethylated OA neuronal genome exhibited a decrease in aggression without altering male-male courtship. These results suggest Drosophila MBD-containing proteins are required within the OA neural circuitry to inhibit interspecies and conspecific male-male courtship and indicate that the genetically hard-wired neural mechanisms enforcing behavioral reproductive isolation include the interpretation of the epigenome. PMID- 28710458 TI - Design of Carbon Dots Photoluminescence through Organo-Functional Silane Grafting for Solid-State Emitting Devices. AB - Advanced optical applications of fluorescent carbon dots (C-dots) require highly integrated host-guest solid-state materials with a careful design of C-dots - matrix interface to control the optical response. We have developed a new synthesis based on the grafting of an organo-functional silane (3 glycidyloxypropyltrimethoxysilane, GPTMS) on amino-functionalized C-dots, which enables the fabrication of highly fluorescent organosilica-based hybrid organic inorganic films through sol-gel process. The GPTMS grafting onto C-dots has been achieved via an epoxy-amine reaction under controlled conditions. Besides providing an efficient strategy to embed C-dots into a hybrid solid-state material, the modification of C-dots surface by GPTMS allows tuning their photoluminescence properties and gives rise to an additional, intense emission around 490 nm. Photoluminescence spectra reveal an interaction between C-dots surface and the polymeric chains which are locally formed by GPTMS polymerization. The present method is a step forward to the development of a surface modification technology aimed at controlling C-dots host-guest systems at the nanoscale. PMID- 28710459 TI - Application of A Novel Three-dimensional Printing Genioplasty Template System and Its Clinical Validation: A Control Study. AB - The purpose of this control study was to assess the accuracy and clinical validation of a novel genioplasty template system. Eighty-eight patients were enrolled and divided into 2 groups: experimental group (using genioplasty templates) and control group (without genioplasty templates). For the experimental group, the templates were designed based on computerized surgical plan and manufactured using three-dimensional printing technique. The template system included a cutting guide and a pair of repositioning guides. For the control group, traditional intraoperative measurements were used without genioplasty templates. The outcome evaluation was completed by comparing planned outcomes with postoperative outcomes. Linear and angular differences for the chin was measured and reported using root mean square deviation (RMSD) and the Bland Altman method. All surgeries were successfully completed. There was no difficulty to use genioplasty templates. For the experimental group, the largest RMSDs were 1.1 mm in anteroposterior direction and 2.6 degrees in pitch orientation. For the control group without templates, the largest RMSDs were 2.63 mm in superoinferior direction and 7.21 degrees in pitch orientation. Our findings suggest that this genioplasty template system provides greater accuracy in repositioning the chin than traditional intraoperative measurements, and the computerized plan can be transferred accurately to the patient for genioplasty. PMID- 28710460 TI - Effects of sediment smothering on the sponge holobiont with implications for dredging management. AB - One of the ways dredging can affect benthic habitats is through high levels of sediment deposition, which has the potential to smother sessile organisms such as sponges. In order to provide pressure-response values to sedimentation and tease apart the different cause-effect pathways of high turbidity, 5 sponge species, including heterotrophic and phototrophic nutritional modes, were exposed for up to 30 d to multiple sediment deposition events, each of which resulted in an initial covering of 80-100% of the surface of the sponges in a layer ~0.5 mm thick. The response of the sponges was examined using a suite of different response variables including growth, respiration, lipid content, community composition of the microbial symbionts, and maximum quantum yield and chlorophyll content of the phototrophic symbionts. Different species showed different mechanisms of sediment rejection and different patterns of sediment clearance. All species survived the treatments, were able to tolerate high levels of partial covering of their surfaces, and for most species the treatment did not alter the health of the sponge holobiont. Results from this study will guide interpretation of experiments examining the combined effects of all three dredging-related pressures, and aid the development of water quality thresholds for impact prediction purposes. PMID- 28710462 TI - Plasticity in the Oxidative Folding Pathway of the High Affinity Nerita Versicolor Carboxypeptidase Inhibitor (NvCI). AB - Nerita Versicolor carboxypeptidase inhibitor (NvCI) is the strongest inhibitor reported so far for the M14A subfamily of carboxypeptidases. It comprises 53 residues and a protein fold composed of a two-stranded antiparallel beta sheet connected by three loops and stabilized by three disulfide bridges. Here we report the oxidative folding and reductive unfolding pathways of NvCI. Much debate has gone on whether protein conformational folding guides disulfide bond formation or instead they are disulfide bonds that favour the arrangement of local or global structural elements. We show here that for NvCI both possibilities apply. Under physiological conditions, this protein folds trough a funnelled pathway involving a network of kinetically connected native-like intermediates, all sharing the disulfide bond connecting the two beta-strands. In contrast, under denaturing conditions, the folding of NvCI is under thermodynamic control and follows a "trial and error" mechanism, in which an initial quasi stochastic population of intermediates rearrange their disulfide bonds to attain the stable native topology. Despite their striking mechanistic differences, the efficiency of both folding routes is similar. The present study illustrates thus a surprising plasticity in the folding of this extremely stable small disulfide rich inhibitor and provides the basis for its redesign for biomedical applications. PMID- 28710463 TI - Erratum: Genomic RNA folding mediates assembly of human parechovirus. AB - A correction has been published and is appended to both the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 28710461 TI - Bromodomain factors of BET family are new essential actors of pericentric heterochromatin transcriptional activation in response to heat shock. AB - The heat shock response is characterized by the transcriptional activation of both hsp genes and noncoding and repeated satellite III DNA sequences located at pericentric heterochromatin. Both events are under the control of Heat Shock Factor I (HSF1). Here we show that under heat shock, HSF1 recruits major cellular acetyltransferases, GCN5, TIP60 and p300 to pericentric heterochromatin leading to a targeted hyperacetylation of pericentric chromatin. Redistribution of histone acetylation toward pericentric region in turn directs the recruitment of Bromodomain and Extra-Terminal (BET) proteins BRD2, BRD3, BRD4, which are required for satellite III transcription by RNAP II. Altogether we uncover here a critical role for HSF1 in stressed cells relying on the restricted use of histone acetylation signaling over pericentric heterochromatin (HC). PMID- 28710464 TI - Analysis of mitochondrial organization and function in the Drosophila blastoderm embryo. AB - Mitochondria are inherited maternally as globular and immature organelles in metazoan embryos. We have used the Drosophila blastoderm embryo to characterize their morphology, distribution and functions in embryogenesis. We find that mitochondria are relatively small, dispersed and distinctly distributed along the apico-basal axis in proximity to microtubules by motor protein transport. Live imaging, photobleaching and photoactivation analyses of mitochondrially targeted GFP show that they are mobile in the apico-basal axis along microtubules and are immobile in the lateral plane thereby associating with one syncytial cell. Photoactivated mitochondria distribute equally to daughter cells across the division cycles. ATP depletion by pharmacological and genetic inhibition of the mitochondrial electron transport chain (ETC) activates AMPK and decreases syncytial metaphase furrow extension. In summary, we show that small and dispersed mitochondria of the Drosophila blastoderm embryo localize by microtubule transport and provide ATP locally for the fast syncytial division cycles. Our study opens the possibility of use of Drosophila embryogenesis as a model system to study the impact of maternal mutations in mitochondrial morphology and metabolism on embryo patterning and differentiation. PMID- 28710465 TI - Effects of the mode of re-socialization after juvenile social isolation on medial prefrontal cortex myelination and function. AB - Social isolation is an important factor in the development of psychiatric disorders. It is necessary to develop an effective psychological treatment, such as cognitive rehabilitation, for children who have already suffered from social isolation, such as neglect and social rejection. We used socially isolated mice to validate whether elaborate re-socialization after juvenile social isolation can restore hypomyelination in the medial prefrontal cortex (mPFC) and the attendant functions manifested in socially isolated mice. While mice who underwent re-socialization with socially isolated mice after juvenile social isolation (Re-IS mice) demonstrated less mPFC activity during exposure to a strange mouse, as well as thinner myelin in the mPFC than controls, mice who underwent re-socialization with socially housed mice after juvenile social isolation (Re-SH mice) caught up with the controls in terms of most mPFC functions, as well as myelination. Moreover, social interaction of Re-IS mice was reduced as compared to controls, but Re-SH mice showed an amount of social interaction comparable to that of controls. These results suggest that the mode of re-socialization after juvenile social isolation has significant effects on myelination in the mPFC and the attendant functions in mice, indicating the importance of appropriate psychosocial intervention after social isolation. PMID- 28710466 TI - Dramatic increases in blood glutamate concentrations are closely related to traumatic brain injury-induced acute lung injury. AB - Traumatic brain injury-induced acute lung injury (TBI-ALI) is a serious complication after brain injury for which predictive factors are lacking. In this study, we found significantly elevated blood glutamate concentrations in patients with TBI or multiple peripheral trauma (MPT), and patients with more severe injuries showed higher blood glutamate concentrations and longer durations of elevated levels. Although the increase in amplitude was similar between the two groups, the duration was longer in the patients with TBI. There were no significant differences in blood glutamate concentrations in the patients with MPT with regard to ALI status, but the blood glutamate levels were significantly higher in the patients with TBI-ALI than in those without ALI. Moreover, compared to patients without ALI, patients with TBI showed a clearly enhanced inflammatory response that was closely correlated with the blood glutamate levels. The blood glutamate concentration was also found to be a risk factor (adjusted odds ratio, 2.229; 95% CI, 1.082-2.634) and was a better predictor of TBI-ALI than the Glasgow Coma Scale (GCS) score. These results indicated that dramatically increased blood glutamate concentrations were closely related to the occurrence of TBI-ALI and could be used as a predictive marker for "at-risk" patients. PMID- 28710467 TI - Human iPSC-derived cardiomyocytes cultured in 3D engineered heart tissue show physiological upstroke velocity and sodium current density. AB - Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) are a promising tool for drug testing and modelling genetic disorders. Abnormally low upstroke velocity is a current limitation. Here we investigated the use of 3D engineered heart tissue (EHT) as a culture method with greater resemblance to human heart tissue in comparison to standard technique of 2D monolayer (ML) format. INa was measured in ML or EHT using the standard patch-clamp technique. INa density was ~1.8 fold larger in EHT (-18.5 +/- 1.9 pA/pF; n = 17) than in ML (-10.3 +/- 1.2 pA/pF; n = 23; p < 0.001), approaching densities reported for human CM. Inactivation kinetics, voltage dependency of steady-state inactivation and activation of INa did not differ between EHT and ML and were similar to previously reported values for human CM. Action potential recordings with sharp microelectrodes showed similar upstroke velocities in EHT (219 +/- 15 V/s, n = 13) and human left ventricle tissue (LV, 253 +/- 7 V/s, n = 25). EHT showed a greater resemblance to LV in CM morphology and subcellular NaV1.5 distribution. INa in hiPSC-CM showed similar biophysical properties as in human CM. The EHT format promotes INa density and action potential upstroke velocity of hiPSC-CM towards adult values, indicating its usefulness as a model for excitability of human cardiac tissue. PMID- 28710468 TI - Core-shell NaGdF4@CaCO3 nanoparticles for enhanced magnetic resonance/ultrasonic dual-modal imaging via tumor acidic micro-enviroment triggering. AB - For cancer diagnosis, a paramount challenge still exists in the exploring of methods that can precisely discriminate tumor tissues from their surrounding healthy tissues with a high target-to-background signal ratio. Here, we report a NaGdF4@CaCO3-PEG core-shell nanoparticle which has the tumor acidic microenvironment enhanced imaging signals of ultrasound and magnetic resonance. Under the acidic conditions, the CaCO3 shell will gradually dissolve which then facilitate the interaction of NaGdF4 with the external aqueous environment to enhance water proton relaxation. Meanwhile, the CO2 bubbles generated by the CaCO3 dissolvement will generate strong elastic echo for US detection. The core shell structure of NaGdF4@CaCO3-PEG can be observed by TEM, and its composition can be determined by STEM. The acid triggered generation of CO2 bubbles and the enhancement of MRI signal could be demonstrated in vitro, and the excellent dual modal magnetic resonance/ultrasonic cancer imaging abilities of NaGdF4@CaCO3-PEG could be also proved at the tumor site in vivo. The here described proof-of concept nanoparticles with pH triggered magnetic resonance/ultrasonic dual-modal imaging enhancement, may serve as a useful guide to develop various molecular imaging strategies for cancer diagnosis in the future. PMID- 28710469 TI - Differential NF2 Gene Status in Sporadic Vestibular Schwannomas and its Prognostic Impact on Tumour Growth Patterns. AB - The great majority of sporadic vestibular schwannomas (VSs) are due to the inactivation of the NF2 gene. In this study, we found age-dependent differences in the clinical parameters of sporadic VSs. Young patients were characterized by progressive tumour behaviours, including earlier onset of initial symptoms, shorter symptom duration and larger tumour size. An increased rate of "two-hits" of both NF2 alleles, usually by mutation and allelic loss, was observed in young cases compared to older, and this correlated with the loss of protein and mRNA expression. In contrast, the tumours with a single mutation (referred to as 'one hit') exhibited obvious expression levels. Moreover, a mixture of merlin expressing tumour cells and non-expressing tumour cells was observed in 'one-hit' schwannomas, suggesting that a subset of 'one-hit' tumour cells was present in these tumours. To mimic the growth promoting effects by the second hit, we performed lentivirus-mediated NF2 knockdown in the 'one-hit' schwannoma cultures. Following the loss of NF2 expression, schwannoma cultures demonstrated increased proliferation rates. Above all, we have identified a correlation between the NF2 status and the growth patterns of sporadic VSs. The treatment decision-making, microsurgery or "wait and scan" strategy, should be carried out according to the tumour's genetic background. PMID- 28710471 TI - Effect of over-consolidation and shear rate on the residual strength of soils of silty sand in the Three Gorges Reservoir. AB - Estimation of the residual strength of the soil on the landslide sliding surface is essential for analyzing reactivated landslides. This study investigated the influence of over-consolidation ratio (OCR) and shear rate on the residual strength of SM-type (silty sand) landslide soils in the Three Gorge Reservoir using ring shear tests under drained conditions. A series of ring shear tests were conducted to measure the drained residual strength under over-consolidation ratios of 1-12 and shear rates of 0.06-30.00 mm/min. Test results showed that residual strengths of SM-type landslide soils were not affected significantly by the over-consolidation process. The effect of shear rate on residual strength did not exhibit a regular pattern at shear rates of 0.06-10.00 mm/min, and behaved negatively at a high shear rate of 30 mm/min. The reduction in residual strength at higher shear rates may be attributable to increases in the water content of the shear zone and the amount of finer particles, due to particle breakage and/or larger grains being pushed from the shear zone. PMID- 28710470 TI - Deviation of the typical AAA substrate-threading pore prevents fatal protein degradation in yeast Cdc48. AB - Yeast Cdc48 is a well-conserved, essential chaperone of ATPases associated with diverse cellular activity (AAA) proteins, which recognizes substrate proteins and modulates their conformations to carry out many cellular processes. However, the fundamental mechanisms underlying the diverse pivotal roles of Cdc48 remain unknown. Almost all AAA proteins form a ring-shaped structure with a conserved aromatic amino acid residue that is essential for proper function. The threading mechanism hypothesis suggests that this residue guides the intrusion of substrate proteins into a narrow pore of the AAA ring, thereby becoming unfolded. By contrast, the aromatic residue in one of the two AAA rings of Cdc48 has been eliminated through evolution. Here, we show that artificial retrieval of this aromatic residue in Cdc48 is lethal, and essential features to support the threading mechanism are required to exhibit the lethal phenotype. In particular, genetic and biochemical analyses of the Cdc48 lethal mutant strongly suggested that when in complex with the 20S proteasome, essential proteins are abnormally forced to thread through the Cdc48 pore to become degraded, which was not detected in wild-type Cdc48. Thus, the widely applicable threading model is less effective for wild-type Cdc48; rather, Cdc48 might function predominantly through an as-yet-undetermined mechanism. PMID- 28710473 TI - Influence of biochar and nitrogen on fine root morphology, physiology, and chemistry of Acer mono. AB - Fine roots play an important role in the overall functions of individual plants. Previous studies showed that fertilization and available soil resources have a notably profound effect on fine root, but there is lack of study centered on how fine root morphology, physiology, and chemistry respond to biochar with N additions. Different levels of biochar (0, 10, 15, and 20 g) and N (0, 2, 4 and 6 g) were applied to Acer mono seedling plants in a field nursery. The root system morphology and root chemistry and physiology were evaluated in line with root length, root diameter, SRL, N and N: C and root respiration. Biochar and N significantly affected root morphology, chemistry and root respiration. Morphological, chemical and physiological parameters were found to be at their maximum with 20 g biochar and 6 g N; however, no significant effect was noted on fourth- and fifth-order roots. Furthermore, a significant increase in root respiration was recognized with the increase in root tissue N concentration and the negative relationship of root respiration with higher branch order. Thus, overall, study parameters indicate that biochar and nitrogen positively influence the Acer mono fine root, and therefore should be used to improve fine root health. PMID- 28710472 TI - Novel data analysis method for multicolour flow cytometry links variability of multiple markers on single cells to a clinical phenotype. AB - Multicolour Flow Cytometry (MFC) produces multidimensional analytical data on the quantitative expression of multiple markers on single cells. This data contains invaluable biomedical information on (1) the marker expressions per cell, (2) the variation in such expression across cells, (3) the variability of cell marker expression across samples that (4) may vary systematically between cells collected from donors and patients. Current conventional and even advanced data analysis methods for MFC data explore only a subset of these levels. The Discriminant Analysis of MultiAspect CYtometry (DAMACY) we present here provides a comprehensive view on health and disease responses by integrating all four levels. We validate DAMACY by using three distinct datasets: in vivo response of neutrophils evoked by systemic endotoxin challenge, the clonal response of leukocytes in bone marrow of acute myeloid leukaemia (AML) patients, and the complex immune response in blood of asthmatics. DAMACY provided good accuracy 91 100% in the discrimination between health and disease, on par with literature values. Additionally, the method provides figures that give insight into the marker expression and cell variability for more in-depth interpretation, that can benefit both physicians and biomedical researchers to better diagnose and monitor diseases that are reflected by changes in blood leukocytes. PMID- 28710474 TI - Persistent circulation of Coxsackievirus A6 of genotype D3 in mainland of China between 2008 and 2015. AB - A total of 807 entire VP1 sequences of Coxsackievirus A6 (CV-A6) from mainland of China from 1992 to 2015, including 520 in this study and 287 from the GenBank database, were analysed to provide a basic framework of molecular epidemiological characteristics of CV-A6 in China. Sixty-five VP1 sequences including 46 representative CV-A6 isolates from 807 Chinese strains and 19 international strains from GenBank were used for describing the genotypes and sub-genotypes. The results revealed that CV-A6 strains can be categorised into 4 genotypes designated as A, B, C, and D according to previous data and can be further subdivided into B1-B2, C1-C2, and D1-D3 sub-genotypes. D3 is the predominant sub genotype that circulated in recent years in mainland of China and represents 734 of 807 Chinese isolates. Sixty-six strains belong to D2, whereas B1 and C1 comprise a single strain each, and five AFP strains formed B2. Sub-genotype D3 first circulated in 2008 and has become the predominant sub-genotype since 2009 and then reached a peak in 2013, while D2 was mostly undetectable in the past years. These data revealed different transmission stages of CV-A6 in mainland of China and that sub-genotype D3 may have stronger transmission ability. PMID- 28710475 TI - Isotopic signature and nano-texture of cesium-rich micro-particles: Release of uranium and fission products from the Fukushima Daiichi Nuclear Power Plant. AB - Highly radioactive cesium-rich microparticles (CsMPs) released from the Fukushima Daiichi Nuclear Power Plant (FDNPP) provide nano-scale chemical fingerprints of the 2011 tragedy. U, Cs, Ba, Rb, K, and Ca isotopic ratios were determined on three CsMPs (3.79-780 Bq) collected within ~10 km from the FDNPP to determine the CsMPs' origin and mechanism of formation. Apart from crystalline Fe-pollucite, CsFeSi2O6 . nH2O, CsMPs are comprised mainly of Zn-Fe-oxide nanoparticles in a SiO2 glass matrix (up to ~30 wt% of Cs and ~1 wt% of U mainly associated with Zn Fe-oxide). The 235U/238U values in two CsMPs: 0.030 (+/-0.005) and 0.029 (+/ 0.003), are consistent with that of enriched nuclear fuel. The values are higher than the average burnup estimated by the ORIGEN code and lower than non irradiated fuel, suggesting non-uniform volatilization of U from melted fuels with different levels of burnup, followed by sorption onto Zn-Fe-oxides. The nano scale texture and isotopic analyses provide a partial record of the chemical reactions that occurred in the fuel during meltdown. Also, the CsMPs were an important medium of transport for the released radionuclides in a respirable form. PMID- 28710476 TI - Inflammatory pain control by blocking oxidized phospholipid-mediated TRP channel activation. AB - Phospholipids occurring in cell membranes and lipoproteins are converted into oxidized phospholipids (OxPL) by oxidative stress promoting atherosclerotic plaque formation. Here, OxPL were characterized as novel targets in acute and chronic inflammatory pain. Oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3 phosphocholine (OxPAPC) and its derivatives were identified in inflamed tissue by mass spectrometry and binding assays. They elicited calcium influx, hyperalgesia and induced pro-nociceptive peptide release. Genetic, pharmacological and mass spectrometric evidence in vivo as well as in vitro confirmed the role of transient receptor potential channels (TRPA1 and TRPV1) as OxPAPC targets. Treatment with the monoclonal antibody E06 or with apolipoprotein A-I mimetic peptide D-4F, capturing OxPAPC in atherosclerosis, prevented inflammatory hyperalgesia, and in vitro TRPA1 activation. Administration of D-4F or E06 to rats profoundly ameliorated mechanical hyperalgesia and inflammation in collagen induced arthritis. These data reveal a clinically relevant role for OxPAPC in inflammation offering therapy for acute and chronic inflammatory pain treatment by scavenging OxPAPC. PMID- 28710477 TI - RNA structure refinement using NMR solvent accessibility data. AB - NMR spectroscopy is a powerful technique to study ribonucleic acids (RNAs) which are key players in a plethora of cellular processes. Although the NMR toolbox for structural studies of RNAs expanded during the last decades, they often remain challenging. Here, we show that solvent paramagnetic relaxation enhancements (sPRE) induced by the soluble, paramagnetic compound Gd(DTPA-BMA) provide a quantitative measure for RNA solvent accessibility and encode distance-to-surface information that correlates well with RNA structure and improves accuracy and convergence of RNA structure determination. Moreover, we show that sPRE data can be easily obtained for RNAs with any isotope labeling scheme and is advantageous regarding sample preparation, stability and recovery. sPRE data show a large dynamic range and reflect the global fold of the RNA suggesting that they are well suited to identify interaction surfaces, to score structural models and as restraints in RNA structure determination. PMID- 28710478 TI - Recombinant Fasciola hepatica fatty acid binding protein suppresses toll-like receptor stimulation in response to multiple bacterial ligands. AB - Recently, we reported that a native Fasciola hepatica fatty acid binding protein (FABP) termed Fh12 is a powerful anti-inflammatory protein capable of suppressing the LPS-induced expression of inflammatory markers in vivo and in vitro. Because the purification of a protein in native form is, in many situations not cost beneficial and unsuitable for industrial grade scale-up, this study accomplished the task of optimizing the expression and purification of a recombinant form of FABP (Fh15). Additionally, we ascertained whether this molecule could exhibit a similar suppressive effect on TLR-stimulation and inflammatory cytokine expression from macrophages than those previously demonstrated for the native molecule. Results demonstrated that Fh15 suppresses the expression of IL-1beta and TNFalpha in murine macrophages and THP1 Blue CD14 cells. Additionally, Fh15 suppress the LPS-induced TLR4 stimulation. This effect was not impaired by a thermal denaturing process or blocked by the presence of anti-Fh12 antibodies. Fh15 also suppressed the stimulation of various TLRs in response to whole bacteria extracts, suggesting that Fh15 could have a broad spectrum of action. These results support the possibility of using Fh15 as an excellent alternative for an anti-inflammatory drug in preclinical studies in the near future. PMID- 28710479 TI - Endothelial cells by inactivation of VHL gene direct angiogenesis, not vasculogenesis via Twist1 accumulation associated with hemangioblastoma neovascularization. AB - Inactivation of the VHL tumour suppressor gene is a highly frequent genetic event in the carcinogenesis of central nervous system-(CNS) hemangioblastomas (HBs). The patterning of the similar embryonic vasculogenesis is an increasing concern in HB-neovascularization, and the classic vascular endothelial growth factor (VEGF)-mediated angiogenesis driven by VHL loss-of-function from human endothelium have been questioned. With this regard, we identify a distinct, VHL silencing-driven mechanism in which human vascular endothelial cells by means of increasing cell proliferation and decreasing cell apoptosis, is concomitant with facilitating accumulation of Twist1 protein in vascular endothelial cells in vitro. Importantly, this molecular mechanism is also pinpointed in CNS-HBs, and associated with the process of HB-neovascularization. In contrast with recent studies of HB-neovascularization, these modified cells did not endow with the typical features of vasculogenesis, indicating that this is a common angiogenesis implementing the formation of the vascular network. Taken together, these findings suggest that vasculogenesis and angiogenesis may constitute complementary mechanisms for HB-neovascularization, and could provide a rational recognition of single anti-angiogenic intervention including targeting to the Twist1 signalling for HBs. PMID- 28710480 TI - Brain regionalization genes are co-opted into shell field patterning in Mollusca. AB - The 'brain regionalization genes' Six3/6, Otx, Pax2/5/8, Gbx, and Hox1 are expressed in a similar fashion in the deuterostome, ecdysozoan, and the cephalopod brain, questioning whether this holds also true for the remaining Mollusca. We investigated developmental Gbx-expression in representatives of both molluscan sister groups, the Aculifera and Conchifera. Gbx is expressed in the posterior central nervous system of an aculiferan polyplacophoran and solenogaster but not in a conchiferan bivalve suggesting that Gbx, together with Six3/6, Otx, Pax2/5/8, and Hox1, is involved in central nervous system regionalization as reported for other bilaterians. Gbx is, however, also expressed in the anterior central nervous system, i.e. the anlagen of the cerebral ganglia, in the solenogaster, a condition not reported for any other bilaterian so far. Strikingly, all Gbx-orthologs and the other 'posterior brain regionalization genes' such as Pax2/5/8 and Hox1 are expressed in the mantle that secretes shell(s) and spicules of mollusks (except cephalopods). In bivalves, the ancestral condition has even been lost, with Gbx and Pax2/5/8 not being expressed in the developing central nervous system anymore. This suggests an additional role in the formation of the molluscan shell field(s) and spicule-bearing cells, key features of mollusks. PMID- 28710481 TI - The LRRK2 G2385R variant is a partial loss-of-function mutation that affects synaptic vesicle trafficking through altered protein interactions. AB - Mutations in the Leucine-rich repeat kinase 2 gene (LRRK2) are associated with familial Parkinson's disease (PD). LRRK2 protein contains several functional domains, including protein-protein interaction domains at its N- and C-termini. In this study, we analyzed the functional features attributed to LRRK2 by its N- and C-terminal domains. We combined TIRF microscopy and synaptopHluorin assay to visualize synaptic vesicle trafficking. We found that N- and C-terminal domains have opposite impact on synaptic vesicle dynamics. Biochemical analysis demonstrated that different proteins are bound at the two extremities, namely beta3-Cav2.1 at N-terminus part and beta-Actin and Synapsin I at C-terminus domain. A sequence variant (G2385R) harboured within the C-terminal WD40 domain increases the risk for PD. Complementary biochemical and imaging approaches revealed that the G2385R variant alters strength and quality of LRRK2 interactions and increases fusion of synaptic vesicles. Our data suggest that the G2385R variant behaves like a loss-of-function mutation that mimics activity driven events. Impaired scaffolding capabilities of mutant LRRK2 resulting in perturbed vesicular trafficking may arise as a common pathophysiological denominator through which different LRRK2 pathological mutations cause disease. PMID- 28710482 TI - Protocol for regional implementation of community-based collaborative management of complex chronic patients. PMID- 28710483 TI - Near-infrared induced phase-shifted ICG/Fe3O4 loaded PLGA nanoparticles for photothermal tumor ablation. AB - Near-infrared (NIR) laser-induced photothermal therapy (PTT) uses a photothermal agent to convert optical energy into thermal energy and has great potential as an effective local, minimally invasive treatment modality for killing cancer cells. To improve the efficacy of PTT, we developed poly(lactide-co-glycolide) (PLGA) nanoparticles (NPs) encapsulating superparamagnetic iron oxide (Fe3O4), indocyanine green (ICG), and perfluoropentane (PFP) as synergistic agents for NIR laser-induced PTT. We fabricated a novel type of phase-shifting fluorescent magnetic NPs, Fe3O4/ICG@PLGA/PFP NPs, that effectively produce heat in response to NIR laser irradiation for an enhanced thermal ablation effect and a phase shift thermoelastic expansion effect, and thus, can be used as a photothermal agent. After in vitro treatment of MCF-7 breast cancer cells with Fe3O4/ICG@PLGA/PFP NPs and NIR laser irradiation, histology and electron microscopy confirmed severe damage to the cells and the formation of many microbubbles with iron particles at the edge or outside of the microbubbles. In vivo experiments in mice with MCF-7 tumors demonstrated that Fe3O4/ICG@PLGA/PFP NPs could achieve tumor ablation upon NIR laser irradiation with minimal toxicity to non-irradiated tissues. Together, our results indicate that Fe3O4/ICG@PLGA/PFP NPs can be used as effective nanotheranostic agents for tumor ablation. PMID- 28710484 TI - Colored and fluorescent nanofibrous silk as a physically transient chemosensor and vitamin deliverer. AB - Biodegradable and physically transient optics represent an emerging paradigm in healthcare devices by harnessing optically active system and obviating issues with chronic uses. Light emitting components that can efficiently interact with their environments have advantages of high sensitivity, visibility, and wireless operation. Here, we report a novel combination of silk biopolymer and optically active organic dyes resulting in versatile fluorescent silk nanofibers (FSNs). FSNs generated by the electrospinning method exhibit attractive functions of the doped organic dyes along with programming the system that physically disappear at prescribed time. Red-green-blue (RGB) fluorescent nanofibrous mats, eco-friendly and transient fluorescent chemosensors for acid vapor detection, and disposable membranes for nutrition delivery were successfully demonstrated using FSNs. These functions introduced using four water soluble dyes: rhodamine B, sodium fluorescein, stilbene 420, and riboflavin. The FSN with sodium fluorescein especially, showed a sensing capability for hazardous and volatile hydrochloric acid vapors. Delivering riboflavin (vitamin B2, an important nutrient for skin care) in the FSN to a biological tissue could be observed by tracing the fluorescence of riboflavin. PMID- 28710485 TI - Alternative functions of Hd1 in repressing or promoting heading are determined by Ghd7 status under long-day conditions. AB - Previous studies suggested that Hd1 promoted heading under short-day conditions (SD) and delayed heading under long-day conditions (LD). However in this study, Hd1 was demonstrated to consistently promote heading date in Zhenshan 97 (ZS97) background by upregulating Ehd1, Hd3a and RFT1 expression under both SD and LD. While the high photoperiod sensitivity of Hd1 was observed in Minghui 63 (MH63) background, with heading being suppressed in LD but promoted in SD. Comparative analysis of two sets of near isogenic lines of Hd1 in MH63 and ZS97 backgrounds indicated that the alternative functions of Hd1 in promoting or suppressing heading under LD are dependent on the previously cloned flowering repressor gene Ghd7. The interaction between proteins Ghd7 and Hd1 occurred through binding of the CCT domain of Ghd7 to the transcription-activating domain of Hd1, resulting in suppression of Ehd1 and florigen gene expression. The involvement of the transcription-activating domain of Hd1 in this protein-protein interaction probably blocked or weakened its transcriptional activity. These findings suggest that Hd1 alone essentially acts as a promoter of heading date, and the protein interaction between Ghd7 and Hd1 determines photoperiod sensitivity and integrated Hd1-mediated and Ehd1-mediated flowering pathways in rice. PMID- 28710486 TI - Comprehensive transcriptomics and proteomics analyses of pollinated and parthenocarpic litchi (Litchi chinensis Sonn.) fruits during early development. AB - Litchi (Litchi chinensis Sonn.) is an important fruit that is widely cultivated in tropical and subtropical areas. In this study, we used RNA-Seq and iTRAQ technologies to compare the transcriptomes and proteomes of pollinated (polLFs) and parthenocarpic (parLFs) litchi fruits during early development (1 day, 2 days, 4 days and 6 days). We identified 4,864 DEGs in polLFs and 3,672 in parLFs, of which 2,835 were shared and 1,051 were specifically identified in parLFs. Compared to po1LFs, 768 DEGs were identified in parLFs. iTRAQ analysis identified 551 DEPs in polLFs and 1,021 in parLFs, of which 305 were shared and 526 were exclusively identified in parLFs. We found 1,127 DEPs in parLFs compared to polLFs at different stages. Further analysis revealed some DEGs/DEPs associated with abscisic acid, auxin, ethylene, gibberellin, heat shock protein (HSP), histone, ribosomal protein, transcription factor and zinc finger protein (ZFP). WGCNA identified a large set of co-expressed genes/proteins in polLFs and parLFs. In addition, a cross-comparison of transcriptomic and proteomic data identified 357 consistent DEGs/DEPs in polLFs and parLFs. This is the first time that protein/gene changes have been studied in polLFs and parLFs, and the findings improve our understanding of litchi parthenocarpy. PMID- 28710487 TI - Decreased serum apolipoprotein A1 levels are associated with poor survival and systemic inflammatory response in colorectal cancer. AB - Recent studies have reported of an association between high serum apolipoprotein A1 (APOA1) levels and favorable prognosis in several malignancies, while the significance of apolipoprotein B (APOB) in cancer is less well-known. In this study, we analyzed the correlation between serum APOA1 and APOB levels, and APOB/APOA1 ratio, and their associations with clinicopathologic parameters, the levels of twenty systemic inflammatory markers, and survival in 144 colorectal cancer (CRC) patients. We demonstrated that low serum APOA1 levels associated with advanced T-class and TNM-stage but low serum APOB levels did not significantly correlate with tumor characteristics. Serum APOA1 levels showed strong negative correlation with the markers of systemic inflammation including serum CRP and interleukin (IL)-8 levels and blood neutrophil count, whereas high serum APOB levels associated with high serum CCL2 levels. High APOA1 and APOB levels and low APOB/APOA1 ratio associated with improved cancer specific and overall survival. APOA1 had independent prognostic value in Cox regression analysis. In conclusion, low serum APOA1 levels are associated with advanced stage and systemic inflammation, while serum APOB does not significantly correlate with tumor stage. Serum APOA1 represents a promising additional prognostic parameter in CRC. PMID- 28710488 TI - Pathological effect of arterial ischaemia and venous congestion on rat testes. AB - Many studies on various organs have concluded that venous congestion (VC) causes severe organ dysfunction with elevation of oxidative stress relative to that of arterial ischaemia (AI). However, a comparison of the pathological effects of AI and VC on the testes has not been conducted. In this study, models of AI and VC and their reperfusion in rat testes, respectively, were developed and analysed. Testicular arteries or veins were interrupted for 6 h, re-perfused and kept for 4 weeks; the effects on the testes were then evaluated. Severe spermatogenic disturbances were observed at 4 weeks after reperfusion in AI but not in VC. At 6 h after blood flow interruption, oxidative stress was significantly increased and germ cells were severely damaged in AI compared with those in VC. RT-PCR analyses revealed that haem oxygenase-1, which exhibits anti-oxidative effects, and vascular endothelial growth factor-A, which exhibits vasculogenic effects, were significantly increased in VC but not in AI. Surprisingly, the results of our experiment in rat testes differed from those of experiments in previous studies performed in other organs. Oxidative stress in testes was more easily elevated by AI than it was by VC, explainable by the different experimental conditions. PMID- 28710489 TI - Kinetic insights into the temperature dependence of DNA strand cleavage and religation by topoisomerase III from the hyperthermophile Sulfolobus solfataricus. AB - All cellular organisms encode type IA topoisomerases which catalyze DNA topological changes essential for DNA transactions. However, the kinetics of the reaction catalyzed by these enzymes remains poorly characterized. Here we measured the rapid kinetics of template binding, cleavage and religation by Sso topo III, a type IA topoisomerase from the hyperthermophilic archaeon Sulfolobus solfataricus, by using a novel FRET/PIFE-based method in a stopped-flow spectrometer. We show that Sso topo III bound the template rapidly, and the rate of binding was 2-3 orders of magnitudes higher than that of template cleavage at 25 degrees C. The rate of template cleavage was favored over that of template religation by the enzyme, and was more so at lower temperatures (25-55 degrees C). Significant template cleavage [(2.23 +/- 0.11) * 10-3 s-1] was observed while little religation was detectable at 25 degrees C. This is consistent with the presence of a higher activation energy for template religation (41 +/- 5 kcal.mol 1) than that for template cleavage (32 +/- 1 kcal.mol-1). Our results provide a kinetic interpretation for the ability of Sso topo III to relax negatively supercoiled DNA only at higher temperature and offer clues to the adaptation of the reaction mechanisms of thermophilic enzymes to high temperature. PMID- 28710490 TI - Wave manipulation with magnetically tunable metasurfaces. AB - Tunable metasurfaces have emerged as an efficient approach to manipulate the wave propagation. Different from previous work concentrating on electrically tunable mechanisms, here we demonstrate a magnetically tunable metasurface composed of ferrite rods and metallic foils. By tuning the thickness of ferrite rods, metasurfaces with different rod thickness gradients are obtained. The incident wave can propagate through the metasurfaces due to the extraordinary transmission. The deflection angle of the transmission wave is not only influenced by the rod thickness gradient, but also tuned by the applied magnetic field. This approach opens a way for the design of tunable metasurfaces. PMID- 28710491 TI - Ageing and latent CMV infection impact on maturation, differentiation and exhaustion profiles of T-cell receptor gammadelta T-cells. AB - Ageing is a broad cellular process, largely affecting the immune system, especially T-lymphocytes. Additionally to immunosenescence alone, cytomegalovirus (CMV) infection is thought to have major impacts on T-cell subset composition and exhaustion. These impacts have been studied extensively in TCRalphabeta+ T-cells, with reduction in naive, increase in effector (memory) subsets and shifts in CD4/CD8-ratios, in conjunction with morbidity and mortality in elderly. Effects of both ageing and CMV on the TCRgammadelta+ T-cell compartment remain largely elusive. In the current study we investigated Vgamma- and Vdelta-usage, maturation, differentiation and exhaustion marker profiles of both CD4 and CD8 double-negative (DN) and CD8+TCRgammadelta+ T-cells in 157 individuals, age range 20-95. We observed a progressive decrease in absolute numbers of total TCRgammadelta+ T-cells in blood, affecting the predominant Vgamma9/Vdelta2 population. Aged TCRgammadelta+ T-cells appeared to shift from naive to more (late-stage) effector phenotypes, which appeared more prominent in case of persistent CMV infections. In addition, we found effects of both ageing and CMV on the absolute counts of exhausted TCRgammadelta+ T-cells. Collectively, our data show a clear impact of ageing and CMV persistence on DN and CD8+TCRgammadelta+ T-cells, similar to what has been reported in CD8+TCRalphabeta+ T-cells, indicating that they undergo similar ageing processes. PMID- 28710493 TI - 'Greater good' versus civil liberties in the United States: Tuberculosis and Seattle's Firland Sanatorium. AB - As far back as the late 1700s, peoples in the United States were developing ways to control infectious disease without infringing on Constitutional rights. Despite acknowledgement that an infected person has certain civil liberties, the history of public health law shows that, in many instances, infectious disease isolation and quarantine proved to be scientifically questionable at best. I examine an historical example of such questionable relationship between public health and civil liberties: the locked ward at Firland Sanatorium in Seattle, Washington. Mandatory quarantine at Firland began in the late 1940s and lasted until the facility closed in the early 1970s. Can examining this history enhance understanding of the relationship between "the greater good" and an individual's civil liberties? PMID- 28710492 TI - NEK1 kinase domain structure and its dynamic protein interactome after exposure to Cisplatin. AB - NEK family kinases are serine/threonine kinases that have been functionally implicated in the regulation of the disjunction of the centrosome, the assembly of the mitotic spindle, the function of the primary cilium and the DNA damage response. NEK1 shows pleiotropic functions and has been found to be mutated in cancer cells, ciliopathies such as the polycystic kidney disease, as well as in the genetic diseases short-rib thoracic dysplasia, Mohr-syndrome and amyotrophic lateral sclerosis. NEK1 is essential for the ionizing radiation DNA damage response and priming of the ATR kinase and of Rad54 through phosphorylation. Here we report on the structure of the kinase domain of human NEK1 in its apo- and ATP mimetic inhibitor bound forms. The inhibitor bound structure may allow the design of NEK specific chemo-sensitizing agents to act in conjunction with chemo- or radiation therapy of cancer cells. Furthermore, we characterized the dynamic protein interactome of NEK1 after DNA damage challenge with cisplatin. Our data suggest that NEK1 and its interaction partners trigger the DNA damage pathways responsible for correcting DNA crosslinks. PMID- 28710494 TI - Near infrared surface-enhanced Raman scattering based on star-shaped gold/silver nanoparticles and hyperbolic metamaterial. AB - It is desirable to extend the surface-enhanced Raman scattering (SERS) from the conventionally used visible range into the infrared region, because the fluorescence background is lower in the long-wavelength regime. To do this, it is important to have a SERS substrate suitable for infrared operation. In this work, we report the near infrared SERS operation based on the substrates employing star shaped gold/silver nanoparticles and hyperbolic metamaterial (HMM) structure. We first fabricate the SERS substrate in which nanoparticles are separated from a silver film by a thin dielectric layer. Performance of the SERS substrate is investigated with a 1064-nm excitation source. Compared with similar silver film based substrates employing respectively gold and silver spherical nanoparticles, it is found that, Raman intensity scattered by the substrate with star-shaped nanoparticles is 7.4 times stronger than that with gold nanoparticles, and 3.4 times stronger than that with silver nanoparticles. Following this, we fabricate the SERS substrate where the star-shaped nanoparticles are deposited over a HMM structure. The HMM structure comprises three pairs of germanium-silver multilayers. Further experimental result shows that, with the star-shaped nanoparticles, the HMM-based substrate yields 30% higher Raman intensity for near infrared SERS operation than the silver film-based substrate does. PMID- 28710495 TI - Tracing the Vedic Saraswati River in the Great Rann of Kachchh. AB - The lost Saraswati River mentioned in the ancient Indian tradition is postulated to have flown independently of the Indus River into the Arabian Sea, perhaps along courses of now defunct rivers such as Ghaggar, Hakra and Nara. The persistence of such a river during the Harappan Bronze Age and the Iron Age Vedic period is strongly debated. We drilled in the Great Rann of Kachchh (Kutch), an infilled gulf of the Arabian Sea, which must have received input from the Saraswati, if active. Nd and Sr isotopic measurements suggest that a distinct source may have been present before 10 ka. Later in Holocene, under a drying climate, sediments from the Thar Desert probably choked the signature of an independent Saraswati-like river. Alternatively, without excluding a Saraswati like secondary source, the Indus and the Thar were the dominant sources throughout the post-glacial history of the GRK. Indus-derived sediment accelerated the infilling of GRK after ~6 ka when the Indus delta started to grow. Until its complete infilling few centuries ago, freshwater input from the Indus, and perhaps from the Ghaggar-Hakra-Nara, probably sustained a productive marine environment as well as navigability toward old coastal Harappan and historic towns in the region. PMID- 28710496 TI - Dietary geranylgeraniol can limit the activity of pitavastatin as a potential treatment for drug-resistant ovarian cancer. AB - Pre-clinical and retrospective studies of patients using statins to reduce plasma cholesterol have suggested that statins may be useful to treat cancer. However, prospective clinical trials have yet to demonstrate significant efficacy. We have previously shown that this is in part because a hydrophobic statin with a long half-life is necessary. Pitavastatin, the only statin with this profile, has not undergone clinical evaluation in oncology. The target of pitavastatin, hydroxymethylglutarate coenzyme-A reductase (HMGCR), was found to be over expressed in all ovarian cancer cell lines examined and upregulated by mutated TP53, a gene commonly altered in ovarian cancer. Pitavastatin-induced apoptosis was blocked by geranylgeraniol and mevalonate, products of the HMGCR pathway, confirming that pitavastatin causes cell death through inhibition of HMGCR. Solvent extracts of human and mouse food were also able to block pitavastatin induced apoptosis, suggesting diet might influence the outcome of clinical trials. When nude mice were maintained on a diet lacking geranylgeraniol, oral pitavastatin caused regression of Ovcar-4 tumour xenografts. However, when the animal diet was supplemented with geranylgeraniol, pitavastatin failed to prevent tumour growth. This suggests that a diet containing geranylgeraniol can limit the anti-tumour activity of pitavastatin and diet should be controlled in clinical trials of statins. PMID- 28710497 TI - Deep Learning based Radiomics (DLR) and its usage in noninvasive IDH1 prediction for low grade glioma. AB - Deep learning-based radiomics (DLR) was developed to extract deep information from multiple modalities of magnetic resonance (MR) images. The performance of DLR for predicting the mutation status of isocitrate dehydrogenase 1 (IDH1) was validated in a dataset of 151 patients with low-grade glioma. A modified convolutional neural network (CNN) structure with 6 convolutional layers and a fully connected layer with 4096 neurons was used to segment tumors. Instead of calculating image features from segmented images, as typically performed for normal radiomics approaches, image features were obtained by normalizing the information of the last convolutional layers of the CNN. Fisher vector was used to encode the CNN features from image slices of different sizes. High-throughput features with dimensionality greater than 1.6*104 were obtained from the CNN. Paired t-tests and F-scores were used to select CNN features that were able to discriminate IDH1. With the same dataset, the area under the operating characteristic curve (AUC) of the normal radiomics method was 86% for IDH1 estimation, whereas for DLR the AUC was 92%. The AUC of IDH1 estimation was further improved to 95% using DLR based on multiple-modality MR images. DLR could be a powerful way to extract deep information from medical images. PMID- 28710499 TI - A facile synthetic strategy for iron, aniline-based non-precious metal catalysts for polymer electrolyte membrane fuel cells. AB - The development of a low cost and highly active alternative to the commercial Pt/C catalysts used in the oxygen reduction reaction (ORR) requires a facile and environmentally-friendly synthesis process to facilitate large-scale production and provide an effective replacement. Transition metals, in conjunction with nitrogen-doped carbon, are among the most promising substitute catalysts because of their high activity, inexpensive composition, and high carbon monoxide tolerance. We prepared a polyaniline-derived Fe-N-C catalyst for oxygen reduction using a facile one-pot process with no additional reagents. This process was carried out by ultrasonicating a mixture containing an iron precursor, an aniline monomer, and carbon black. The half-wave potential of the synthesized Fe-N-C catalyst for the ORR was only 10 mV less than that of a commercial Pt/C catalyst. The optimized Fe-N-C catalyst showed outstanding performance in a practical anion exchange membrane fuel cell (AEMFC), suggesting its potential as an alternative to commercial Pt/C catalysts for the ORR. PMID- 28710498 TI - Gene Network Dysregulation in Dorsolateral Prefrontal Cortex Neurons of Humans with Cocaine Use Disorder. AB - Metabolic and functional alterations of neurons in the dorsolateral prefrontal cortex (dlPFC) are thought to contribute to impulsivity, which is a hallmark of addictive behaviors that underlie compulsive drug seeking and taking in humans. To determine if there is a transcriptional signature in dlPFC neurons of humans with cocaine use disorder, we performed total RNA-sequencing on neuronal nuclei isolated from post-mortem dlPFC of cocaine addicts and healthy controls. Our results point toward a transcriptional mechanism whereby cocaine alters specific gene networks in dlPFC neurons. In particular, we identified an AP-1 regulated transcriptional network in dlPFC neurons associated with cocaine use disorder that contains several differentially expressed hub genes. Several of these hub genes are GWAS hits for traits that might involve dysfunction of brain reward circuitry (Body-Mass Index, Obesity) or dlPFC (Bipolar disorder, Schizophrenia). Further study is warranted to determine their potential pathophysiological role in cocaine addiction. PMID- 28710500 TI - MEN1/Menin regulates milk protein synthesis through mTOR signaling in mammary epithelial cells. AB - The MEN1 gene, which encodes the protein Menin, was investigated for its regulatory role in milk protein synthesis in mammary glands. Menin responds to nutrient and hormone levels via the PI3K/Akt/mTOR pathway. Bovine mammary epithelial cells and tissues were used as experimental models in this study. The results revealed that the milk protein synthesis capacity of mammary epithelial cells could be regulated by MEN1/Menin. The overexpression of Menin caused significant suppression of factors involved in the mTOR pathway, as well as milk protein kappa-casein (CSNK). In contrast, a significant increase in these factors and CSNK was observed upon MEN1/Menin knockdown. The repression of MEN1/Menin on the mTOR pathway was also observed in mammary gland tissues. Additionally, MEN1/Menin was found to elicit a negative response on prolactin (PRL) and/or insulin (INS), which caused a similar downstream impact on mTOR pathway factors and milk proteins. Collectively, our data indicate that MEN1/Menin could play a regulatory role in milk protein synthesis through mTOR signaling in the mammary gland by mediating the effects of hormones and nutrient status. The discovery of Menin's role in mammary glands suggests Menin could be potential new target for the improvement of milk performance and adjustment of lactation period of dairy cows. PMID- 28710502 TI - Indicators of Marine Pollution in the North Pacific Ocean. AB - The complex nature of ocean pollution underscores the utility in identifying and characterizing a limited number of "indicators" that enables scientists and managers to track trends over space and time. This paper introduces a special issue on indicators of marine pollution in the North Pacific Ocean and builds on a scientific session that was held at the North Pacific Marine Science Organization. The special issue highlights studies using a variety of indicators to provide insight into the identification of legacy and emerging contaminants, the ranking of priority pollutants from various sources, and the effects of contaminants on ecosystem health in the North Pacific Ocean. Examples include the use of mussels to illustrate spatial and temporal trends of a number of contaminants following the 2011 tsunami in Japan, the use of molecular marker (linear alkylbenzenes, hopanes, and polycyclic aromatic hydrocarbons) profiles to identify pollution sources, and the use of plastic resin pellets to illustrate spatial trends of petroleum pollution around the world. Stable isotopes were used to strengthen the utility of the Glaucous-winged gull (Larus glaucescens) as an indicator of marine pollution. Examples also demonstrate the development and application of biomarker approaches, including gene transcripts, oxidative stress, estradiol, hatchability, and respiration and swimming behavior abnormalities, as a function of exposure to polychlorinated biphenyls, sulfur diesel, Pinghu crude oil, galaxolide and antifouling biocides. We provide a brief review of indicators of marine pollution, identify research gaps, and summarize key findings from the articles published within the issue. This special issue represents the first compilation of research pertaining to marine pollution indicators in the North Pacific Ocean and provides guidance to inform mitigation and monitoring efforts of contaminants in the region. PMID- 28710501 TI - Polycyclic Aromatic Hydrocarbons (PAHs) and Hopanes in Plastic Resin Pellets as Markers of Oil Pollution via International Pellet Watch Monitoring. AB - Oil pollution in the marine environment is an unavoidable problem due to chronic input from local sources, particularly in urban areas and oil spills. Oil pollution not only causes immediate physical damages to surrounding wildlife but also some components, including higher molecular weight PAHs, can persist in the environment for many years and pose insidious threats to the ecosystem. Long-term and nontargeted monitoring of oil pollution is important. This paper examines the ability of International Pellet Watch (IPW) for initial identification and monitoring of oil pollution by analysing PAHs and hopanes in plastic pellet samples collected globally by volunteers. PAH concentrations with the sum of 28 parent and methyl PAHs vary geographically, ranging from 0.035 to 24.4 ug/g pellet, in line with the presence or absence of local oil pollution sources, such as oil refineries or oil spill sites. This suggests that PAHs can be used to monitor petroleum pollution in IPW. A colour-coded categorization for PAH concentrations within IPW monitoring also is established to facilitate data presentation and understanding. PAH concentrations are generally higher in Western Europe, especially around the North Sea shorelines, moderate in East Asia and North America, and lower in South East Asia, Oceania, South America, and Africa. Hopane concentrations, with a smaller spatial variation (1.7-101 ug/g pellet), showed no spatial pattern. This result and the poor correlation between hopanes and PAHs suggest that hopane concentrations alone are unsuited to identify petroleum pollution. However, hopane compositions can be used for fingerprinting sources of oil pollution. Thus, both PAHs and hopanes in IPW allow for low cost, remote monitoring of global oil pollution. PMID- 28710503 TI - Rac1-mediated cardiac damage causes diastolic dysfunction in a mouse model of subacute doxorubicin-induced cardiotoxicity. AB - The anticancer efficacy of anthracyclines is limited by congestive heart failure. Clinically established markers of early onset of cardiotoxicity following anthracycline treatment and preventive measures are missing. Although statins are reported to alleviate anthracycline-induced cardiotoxicity in vivo, the molecular mechanisms involved remain elusive. In vitro data point to Rac1 as major target of the cytoprotective statin effects. Here we investigated whether specific inhibition of Rac1 by NSC23766 is as effective as lovastatin in preventing subacute cardiotoxicity following doxorubicin treatment. C57BL/6 mice were treated over 3 weeks with multiple low doses of doxorubicin (6 * 3 mg/kg BW, i.p.) and the level of DNA damage, apoptosis and regenerative proliferation as well as pro-inflammatory, pro-fibrotic and oxidative stress responses were investigated. Moreover, heart function was monitored by echocardiography. Doxorubicin induced subacute cardiotoxicity which was reflected on the level of residual DNA damage, frequency of apoptotic and mitotic cells as well as elevated mRNA expression of markers of heart failure, remodeling and mitochondrial biogenesis. These molecular markers of cardiotoxicity were mitigated to a similar extent by co-treatment with either lovastatin (10 mg/kg BW, p.o.) or NSC23766 (5 mg/kg BW, i.p.) three times a week. Moreover, doxorubicin caused diastolic dysfunction as reflected by increased E-wave acceleration time (EAT), which again was prevented by pharmacological inhibition of Rac1. Inhibition of Rac1 signaling is of major relevance for the cardioprotective effects of lovastatin in the context of anthracycline-induced cardiotoxicity. Moreover, EAT is a useful marker of subacute cardiotoxicity caused by persisting harmful effects of doxorubicin. PMID- 28710504 TI - Mapping novel aphid resistance QTL from wild soybean, Glycine soja 85-32. AB - KEY MESSAGE: Two novel QTLs conferring aphid resistance were mapped and validated on soybean chromosomes 8 and 16, respectively. Closely linked markers were developed to assist breeding for aphid resistance. Soybean aphid, Aphis glycines Matsumura, is a highly destructive pest for soybean production. E08934, a soybean advanced breeding line derived from the wild soybean Glycine soja 85-32, has shown strong resistance to aphids. To dissect the genetic basis of aphid resistance in E08934, a mapping population (070020) consisting of 140 F3-derived lines was developed by crossing E08934 with an aphid-susceptible line E00003. This mapping population was evaluated for aphid resistance in a greenhouse trial in 2010 and three field trials in 2009, 2010, and 2011, respectively. The broad sense heritability across the field trials was 0.84. In the mapping population 070020, two major quantitative trait loci (QTL) were detected as significantly associated with aphid resistance, and designated as Rag6 and Rag3c, respectively. Rag6 was mapped to a 10.5 centiMorgan (cM) interval between markers MSUSNP08-2 and Satt209 on chromosome 8, explaining 19.5-46.4% of the phenotypic variance in different trials. Rag3c was located at a 7.5 cM interval between markers MSUSNP16 10 and Sat_370 on chromosome 16, explaining 12.5-22.9% of the phenotypic variance in different trials. Rag3c had less resistance effect than Rag6 across all the trials. Furthermore, Rag6 and Rag3c were confirmed in two validation populations with different genetic backgrounds. No significant interaction was detected between Rag6 and Rag3c in either the mapping population or the validation populations. Both Rag6 and Rag3c were indicated as conferring antibiosis resistance to aphids by a no-choice test. The new aphid-resistance gene(s) derived from the wild germplasm G. soja 85-32 are valuable in improving soybeans for aphid resistance. PMID- 28710505 TI - Application of Human Acellular Breast Dermal Matrix (ABDM) in Implant-Based Breast Reconstruction: An Experimental Study. AB - BACKGROUND: The use of acellular dermal matrices (ABDM) has become more common for breast reconstruction to improve postoperative outcomes. We evaluated the efficacy of breast reconstruction by the application of human ABDM in a sheep model. METHODS: The sheep in group I (GI) (N = 4) underwent the following procedures on the right side: (1) breast reconstruction using human ABDM after total mastectomy, (2) human ABDM under the skin, near the breast area and on the left side, (3) fat injection and human ABDM after partial mastectomy, and (4) replacement of ABDM in the abdominal wall far from the breast. Sheep in group II (GII) (N = 4) underwent the following procedures. On the right side: (1) breast reconstruction using ABDM after total mastectomy, (2) replacement of ABDM under the skin, near the breast area, and on the left side, (3) application of vicryl synthetic mesh after partial mastectomy and (4) replacement of mesh under the skin, near the breast area. RESULTS: Histological evaluations of decellularized skin scaffolds demonstrated a collagen-based matrix with preserved ECM and complete nuclear removal. Histological evaluations of implanted ABDM demonstrated a viable matrix with fibroblast infiltration and revascularization in all follow ups. The overall surgical complication rate was significantly lower in the ABDM implant under the skin and near the breast in both short- and long-term follow ups. CONCLUSION: The results of this study demonstrated that the application of novel prepared ABDMs has promising outcomes for breast reconstruction to provide total coverage without the need for breast expansion before implant placement. NO LEVEL ASSIGNED: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors http://www.springer.com/00266. PMID- 28710506 TI - Obese Versus Normal-Weight Late-Adolescent Females have Inferior Trabecular Bone Microarchitecture: A Pilot Case-Control Study. AB - Though still a topic of debate, the position that skeletal health is compromised with obesity has received support in the pediatric and adult literature. The limited data relating specifically to trabecular bone microarchitecture, however, have been relatively inconsistent. The aim of this pilot cross-sectional case control study was to compare trabecular bone microarchitecture between obese (OB) and normal-weight (NW) late-adolescent females. A secondary aim was to compare diaphyseal cortical bone outcomes between these two groups. Twenty-four non Hispanic white females, ages 18-19 years, were recruited into OB (n = 12) or NW (n = 12) groups based on pre-specified criteria for percent body fat (>=32 vs. <30, respectively), body mass index (>90th vs. 20th-79th, respectively), and waist circumference (>=90th vs. 25th-75th, respectively). Participants were also individually matched on age, height, and oral contraceptive use. Using magnetic resonance imaging, trabecular bone microarchitecture was assessed at the distal radius and proximal tibia metaphysis, and cortical bone architecture was assessed at the mid-radius and mid-tibia diaphysis. OB versus NW had lower apparent trabecular thickness (radius and tibia), higher apparent trabecular separation (radius), and lower apparent bone volume to total volume (radius; all P < 0.050). Some differences in radius and tibia trabecular bone microarchitecture were retained after adjusting for insulin resistance or age at menarche. Mid-radius and mid-tibia cortical bone volume and estimated strength were lower in the OB compared to NW after adjusting for fat-free soft tissue mass (all P < 0.050). These trabecular and cortical bone deficits might contribute to the increased fracture risk in obese youth. PMID- 28710507 TI - Inequalities in the utilization of health care services in a transition European country: results from the national population health survey. AB - OBJECTIVES: To examine demographic, socio-economic, and health status inequalities in the utilization of health care services (UHCS) in the Republic of Srpska (RS), Bosnia and Herzegovina. METHODS: Data were retrieved from the 2010 National Health Survey for the RS adult population (n = 4128). A complex sample design was taken into account for statistical analysis. RESULTS: As compared to men, a higher percentage of women visited a family physician (FP), urgent care department, dentist and private doctor. Higher educated women and those worse-off (OR 1.17) more frequently visited FP. Hospitalization (OR 4.56 for males; OR 9.17 for females), visit to urgent care department (OR 3.19 for males; OR 2.42 for females) and visits to FP in females (OR 1.46) were associated with poor self perceived health. No inequalities by wealth index were found for the utilization of FP, hospitalization, urgent care and dentist among persons with poor self perceived health status. CONCLUSIONS: The present study confirmed demographic, socio-economic and health status inequalities in the UHCS in RS. These findings have significant implications for health policy makers that seek to provide equal care for all people living in RS. PMID- 28710508 TI - Risk of gastrointestinal events with newly approved (after 2011) vascular endothelial growth factor receptor tyrosine kinase inhibitors in cancer patients: a meta-analysis of randomized controlled trials. AB - PURPOSE: We performed a meta-analysis to systematically review the gastrointestinal (GI) events (diarrhea, nausea, vomiting, anorexia) of five newly approved (after 2011) VEGFR-TKIs in cancer patients. METHODS: The relevant studies of the randomized controlled trials (RCTs) in cancer patients treated with cabozantinib, vandetanib, lenvatinib, regorafenib, and axitinib were retrieved and the systematic evaluation was conducted. RESULTS: Forty-one randomized controlled trials and 10,860 patients were included. Current analysis suggested that the use of these agents increased the risk of all-grade and high grade GI events, and the diarrhea was the most common GI events. The risk of all grade and high-grade GI events varies significantly within drug types, tumor types, and VEGFR-TKIs-based regimens. CONCLUSION: The available data suggested that the use of the five newly approved VEGFR-TKIs may increase risk of GI events in cancer patients. Physicians and patients should be aware of these risks and frequent monitoring and careful management should be emphasized when managing these VEGFR-TKIs. PMID- 28710509 TI - X-shaped inferior extensor retinaculum and its doubtful use in the Brostrom-Gould procedure. AB - PURPOSE: The inferior extensor retinaculum (IER) is an aponeurotic structure located in the anterior aspect of the ankle. According to the literature, it can be used to reinforce a repair of the anterior talofibular ligament in ankle instability. Despite its usual description as an Y-shaped structure, it is still unclear which part of the retinaculum is used for this purpose, or if it is instead the crural fascia that is being used. The purpose of this study is to define the anatomical characteristics of the IER to better understand its role in the Brostrom-Gould procedure. METHODS: Twenty-one ankles were dissected. The morphology of the IER and its relationship with neighbouring structures were recorded. RESULTS: Seventeen (81%) of the IER in this study had an X-shaped morphology, with the presence of an additional oblique superolateral band. This band, by far the thinnest of the retinaculum, is supposed to be used to reinforce the repair of the anterior talofibular ligament. The intermediate dorsal cutaneous nerve (lateral branch of the superficial peroneal nerve) was found to cross the retinaculum in all cases. CONCLUSIONS: The IER is most commonly seen as an X-shaped structure, but the fact that the oblique superolateral band is a thin band of tissue probably indicates that it may not add significant strength to ankle stability. Furthermore, the close relationship of the retinaculum with the superficial peroneal nerve is another factor to consider before deciding to perform a Brostrom-Gould procedure. These anatomical findings advise against the use of the Gould augmentation. PMID- 28710510 TI - Surgical reconstruction is a cost-efficient treatment option for isolated PCL injuries. AB - PURPOSE AND HYPOTHESIS: The main purpose of the study is to put focus on the costs related to treating posterior cruciate ligament (PCL) injuries and the possible implications of chosen treatment strategy to the respective institutions and society. METHODS: Costs of treating PCL injuries nonoperatively and for both single-bundle (SB) and double-bundle (DB) reconstruction were estimated. These costs were translated into equivalent quality-adjusted life years (QALY) given a threshold value of Euro (?) 70,000 per QALY. Expected gain in knee osteoarthritis outcome score (KOOS) quality of life (QoL) following surgery based on KOOS data from 112 patients was used as a basis for calculating the cost efficiency ratio. RESULTS: The average calculated cost of nonoperative treatment was ?3382. Incremental cost for SB PCLR was ?8585 (154%) and another increment of ?5220 (61%) for DB PCLR using numbers from a European hospital. This is equivalent to increments of 0.074 (SB) and another 0.075 (DB) QALYs given the ?70,000 threshold. For DB to be as cost efficient as SB reconstruction, the incremental gain in KOOS QoL has to be at the same level as for SB reconstruction compared to nonoperative treatment. CONCLUSION: Though surgical reconstruction adds a substantial cost to nonoperative treatment alone, it can be considered cost effective. Double-bundle reconstruction is less cost efficient than SB reconstruction, but should probably still be considered the treatment of choice for certain patient categories. Randomized controlled trials looking at outcome following nonoperative, SB and DB PCL reconstruction are needed. The clinical relevance of this is that surgical reconstruction of PCL injuries is a cost efficient treatment alternative in patients with an isolated PCL injury. This finding should be taken into consideration when deciding on how to treat these injuries. LEVEL OF EVIDENCE: III. PMID- 28710511 TI - Cerebellar degeneration-related proteins 2 and 2-like are present in ovarian cancer in patients with and without Yo antibodies. AB - BACKGROUND: Cerebellar degeneration-related protein 2 (CDR2) has been presumed to be the main antigen for the onconeural antibody Yo, which is strongly associated with ovarian cancer and paraneoplastic cerebellar degeneration (PCD). Recent data show that Yo antibodies also target the CDR2-like protein (CDR2L). We, therefore, examined the expression of CDR2 and CDR2L in ovarian cancer tissue from patients with and without Yo antibodies and from various other cancerous and normal human tissues. METHODS: Ovarian cancer tissue and serum samples from 16 patients were included in the study (four with anti-Yo and PCD, two with anti-Yo without PCD, five with only CDR2L antibodies, and five without onconeural antibodies). Clinical data were available for all patients. The human tissues were examined by western blot and immunohistochemistry using rabbit CDR2 and CDR2L antibodies. RESULTS: Ovarian cancers from all 16 patients expressed CDR2 and CDR2L proteins. Both proteins were also present in normal and cancer tissue from mammary tissue, kidney, ovary, prostate, and testis. CONCLUSION: CDR2L is present in ovarian cancers from patients with and without Yo antibodies as was shown previously for CDR2. In addition, both CDR2 and CDR2L proteins are more widely expressed than previously thought, both in normal and cancerous tissues. PMID- 28710512 TI - Novel Method for Quantitative Estimation of Biofilms. AB - Biofilm protects bacteria from stress and hostile environment. Crystal violet (CV) assay is the most popular method for biofilm determination adopted by different laboratories so far. However, biofilm layer formed at the liquid-air interphase known as pellicle is extremely sensitive to its washing and staining steps. Early phase biofilms are also prone to damage by the latter steps. In bacteria like mycobacteria, biofilm formation occurs largely at the liquid-air interphase which is susceptible to loss. In the proposed protocol, loss of such biofilm layer was prevented. In place of inverting and discarding the media which can lead to the loss of the aerobic biofilm layer in CV assay, media was removed from the formed biofilm with the help of a syringe and biofilm layer was allowed to dry. The staining and washing steps were avoided, and an organic solvent tetrahydrofuran (THF) was deployed to dissolve the biofilm, and the absorbance was recorded at 595 nm. The protocol was tested for biofilm estimation of E. coli, B. subtilis and M. smegmatis, and compared with the traditional CV assays. Isoniazid drug molecule, a known inhibitor of M. smegmatis biofilm, was tested and its inhibitory effects were quantified by the proposed protocol. For ease in referring, this method has been described as the Syal method for biofilm quantification. This new method was found to be useful for the estimation of early phase biofilm and aerobic biofilm layer formed at the liquid-air interphase. The biofilms formed by all three tested bacteria-B. subtilis, E. coli and M. smegmatis, were precisely quantified. PMID- 28710513 TI - Mink (Mustela vison) Gut Microbial Communities from Northeast China and Its Internal Relationship with Gender and Food Additives. AB - It is well documented that the microbial interactions and biodiversity play an important role in health and disease in mammalian species. There is a rare study about gut microbiota of Mustelidae family. In this study, 40 male and female minks from Northeast China were divided into three groups and fed until they reached maturity. The V3 region of 16S rRNA genes was amplified and sequenced using NGS. There were 526 OTUs principally concentrated among five bacterial phyla. Two points about mink's body weight gaining were observed: (1) the weight of male individuals increased more rapidly than female individuals; (2) the weight of individuals whose feed was supplemented with Chinese herb additives increased more rapidly than individuals without giving food additives. The differences of microorganism abundance were shown in two points: (1) two genera which had >=2-fold change difference were found between male and female minks. (2) Ten genera which had a >=2-fold change difference were found among minks with and without Chinese herb additive. Findings from this study provide new and fundamental knowledge on the gut microbiota composition of minks farmed in Northeast China, which can contribute to the general well-being of minks worldwide. PMID- 28710515 TI - Quantitative LC/ESI-SRM/MS of antibody biopharmaceuticals: use of a homologous antibody as an internal standard and three-step method development. AB - Monoclonal antibody-based therapeutic agents (antibody drugs) have attracted considerable attention as a new type of drug. Concomitantly, the use of quantitative approaches for characterizing antibody drugs, such as liquid chromatography (LC)-mass spectrometry (MS), has increased. Generally, selective quantification of antibody drugs is done using unique peptides from variable regions (V H and V L) as surrogate peptides. Further, numerous internal standards (ISs) such as stable isotope-labeled (SIL)-intact proteins and SIL-surrogate peptides are used. However, developing LC-MS methodology for characterizing antibody drugs is time-consuming and costly. Therefore, LC-MS is difficult to apply for this purpose, particularly during the drug discovery stage when numerous candidates must be evaluated. Here, we demonstrate an efficient approach to developing a quantitative LC/electrospray ionization (ESI)-selected reaction monitoring (SRM)/MS method for characterizing antibody drugs. The approach consists of the following features: (i) standard peptides or SIL-IS are not required; (ii) a peptide from the homologous monoclonal antibody serves as an IS; (iii) method development is monitored using a spiked plasma sample and one quantitative MS analysis; and (iv) three predicted SRM assays are performed to optimize quantitative SRM conditions such as transition, collision energy, and declustering potential values. Using this strategy, we developed quantitative SRM methods for infliximab, alemtuzumab, and bevacizumab with sufficient precision (<20%)/accuracy (<+/-20%) for use in the drug discovery stage. We have also demonstrated that choosing a higher homologous peptide pair (from analyte mAb/IS mAb) is necessary to obtain the sufficient precision and accuracy. Graphical abstract ?. PMID- 28710516 TI - Perspectives and challenges of photon-upconversion nanoparticles - Part I: routes to brighter particles and quantitative spectroscopic studies. AB - Lanthanide-doped photon-upconversion nanoparticles (UCNPs) have been the focus of many research activities in materials and life sciences in the last 15 years because of their potential to convert light between different spectral regions and their unique photophysical properties. To fully exploit the application potential of these fascinating nanomaterials, a number of challenges have to be overcome, such as the low brightness, particularly of small UCNPs, and the reliable quantification of the excitation-power-density-dependent upconversion luminescence. In this series of critical reviews, recent developments in the design, synthesis, optical-spectroscopic characterization, and application of UCNPs are presented with special focus on bioanalysis and the life sciences. Here we guide the reader from the synthesis of UCNPs to different concepts to enhance their luminescence, including the required optical-spectroscopic assessment to quantify material performance; surface modification strategies and bioanalytical applications as well as selected examples of the use of UCNPs as reporters in different assay formats are addressed in part II. Future trends and challenges in the field of upconversion are discussed with special emphasis on UCNP synthesis and material characterization, particularly quantitative luminescence studies. Graphical Abstract Both synthesis and spectroscopy as well bioanalytical applications of UCNPs are driven and supported by COST Action CM1403 "The European Upconversion Network". PMID- 28710517 TI - Urinary profiling of tryptophan and its related metabolites in patients with metabolic syndrome by liquid chromatography-electrospray ionization/mass spectrometry. AB - Tryptophan (Trp) is an essential amino acid that plays an important role in protein synthesis and is a precursor of various substances related to diverse biological functions. An imbalance in Trp metabolites is associated with inflammatory diseases. The accurate and precise measurement of these compounds in biological specimens would provide meaningful information for understanding the biochemical states of various metabolic syndrome-related diseases, such as hyperlipidemia, hypertension, diabetes, and obesity. In this study, we developed a rapid, accurate, and sensitive liquid chromatography-tandem mass spectrometry based method for the simultaneous targeted analysis of Trp and its related metabolites of the kynurenine (Kyn), serotonin, and tryptamine pathways in urine. The application of the developed method was tested using urine samples after protein precipitation. The detection limits of Trp and its metabolites were in the range of 0.01 to 0.1 MUg/mL. The method was successfully validated and applied to urine samples from controls and patients with metabolic syndrome. Our results revealed high concentrations of Kyn, kynurenic acid, xanthurenic acid, and quinolinic acid as well as a high Kyn-to-Trp ratio (KTR) in patients with metabolic syndromes. The levels of urine Kyn and KTR were significantly increased in patients under 60 years old. The profiling of urinary Trp metabolites could be a useful indicator for age-related diseases including metabolic syndrome. ?. PMID- 28710518 TI - Encouraging results of 25G+ minimally invasive vitrectomy surgery for diabetic tractional retinal detachment- reply. PMID- 28710519 TI - Validation of the human odor span task: effects of nicotine. AB - RATIONALE: Amongst non-smokers, nicotine generally enhances performance on tasks of attention, with limited effect on working memory. In contrast, nicotine has been shown to produce robust enhancements of working memory in non-humans. OBJECTIVES: To address this gap, the present study investigated the effects of nicotine on the performance of non-smokers on a cognitive battery which included a working memory task reverse-translated from use with rodents (the odor span task, OST). Nicotine has been reported to enhance OST performance in rats and the present study assessed whether this effect generalizes to human performance. METHODS: Thirty non-smokers were tested on three occasions after consuming either placebo, 2 mg, or 4 mg nicotine gum. On each occasion, participants completed a battery of clinical and experimental tasks of working memory and attention. RESULTS: Nicotine was associated with dose-dependent enhancements in sustained attention, as evidenced by increased hit accuracy on the rapid visual information processing (RVIP) task. However, nicotine failed to produce main effects on OST performance or on alternative measures of working memory (digit span, spatial span, letter-number sequencing, 2-back) or attention (digits forward, 0-back). Interestingly, enhancement of RVIP performance occurred concomitant to significant reductions in self-reported attention/concentration. Human OST performance was significantly related to N-back performance, and as in rodents, OST accuracy declined with increasing memory load. CONCLUSIONS: Given the similarity of human and rodent OST performance under baseline conditions and the strong association between OST and visual 0-back accuracy, the OST may be particular useful in the study of conditions characterized by inattention. PMID- 28710520 TI - Psychostimulants and forced swim stress interaction: how activation of the hypothalamic-pituitary-adrenal axis and stress-induced hyperglycemia are affected. AB - RATIONALE: We recently reported that simultaneous exposure to amphetamine and various stressors resulted in reduced hypothalamic-pituitary-adrenal (HPA) and glycemic responses to the stressors. Since this is a new and relevant phenomenon, we wanted to further explore this interaction. OBJECTIVES: This study aims (i) to characterize the effect of various doses of amphetamine on the physiological response to a predominantly emotional stressor (forced swim) when the drug was given immediately before stress; (ii) to study if an interaction appears when the drug was given 30 min or 7 days before swim; and (iii) to know whether cocaine causes similar effects when given just before stress. Adult male rats were used and plasma levels of ACTH, corticosterone, and glucose were the outcomes. RESULTS: Amphetamine caused a dose-dependent activation of the HPA axis, but all doses reduced HPA and glycemic responses to swim when given just before the stressor. Importantly, during the post-swim period, the stressor potently inhibited the ACTH response to amphetamine, demonstrating mutual inhibition between the two stimuli. The highest dose of amphetamine also reduced the response to swim when given 30 min before stress, whereas it caused HPA sensitization when given 7 days before. Cocaine also reduced stress-induced HPA activation when given just before swim. CONCLUSIONS: The present results demonstrate a negative synergy between psychostimulants (amphetamine and cocaine) and stress regarding HPA and glucose responses when rats were exposed simultaneously to both stimuli. The inhibitory effect of amphetamine is also observed when given shortly before stress, but not some days before. PMID- 28710522 TI - CTA analysis and assessment of morphological factors related to rupture in 413 posterior communicating artery aneurysms. AB - Posterior communicating artery (PcomA) aneurysms are frequently encountered, but there are few publications on their morphology. A growing number of aneurysms are incidental findings, which makes evaluation of rupture risk important. Our goal was to identify morphological features and anatomical variants associated with PComA aneurysms and to assess parameters related to rupture. We studied CT angiographies of 391 consecutive patients treated between 2000 and 2014 at a single institution. We determined clinically important morphological parameters and performed univariate and multivariate analysis. There were a total of 413 PComA aneurysms: 258 (62%) were ruptured and 155 (38%) unruptured. Ruptured PComA aneurysms had the potential to cause severe bleeding with IVH and/or temporal ICH (n = 170, 66% of ruptured). The main types of PComA origin were classified as follows: (1) separate (32%), (2) side by side (21%) and (3) a joint neck with the aneurysm (6%). After the multivariate logistic regression, the morphological parameters related to PComA aneurysm rupture were an irregular aneurysm dome, neck diameter, and aspect ratio >1.5. The most marked morphological features of the PComA aneurysms were: saccular nature (99%), infero-posterior dome orientation (42%), infrequency of large or giant aneurysms (4%), narrow neck compared to the aneurysm size, PComA originating directly from the aneurysm neck or the dome (28%), and fetal or dominant PComA on the side of the aneurysm (35%). There were location-related parameters that were more strongly associated with PComA aneurysm rupture than aneurysm size: an irregular aneurysm dome, larger diameter of the aneurysm neck and aspect ratio >1.5. PMID- 28710521 TI - Efflux drug transporters at the forefront of antimicrobial resistance. AB - Bacterial antibiotic resistance is rapidly becoming a major world health consideration. To combat antibiotics, microorganisms employ their pre-existing defence mechanisms that existed long before man's discovery of antibiotics. Bacteria utilise levels of protection that range from gene upregulation, mutations, adaptive resistance, and production of resistant phenotypes (persisters) to communal behaviour, as in swarming and the ultimate defence of a biofilm. A major part of all of these responses involves the use of antibiotic efflux transporters. At the single cell level, it is becoming apparent that the use of efflux pumps is the first line of defence against an antibiotic, as these pumps decrease the intracellular level of antibiotic while the cell activates the various other levels of protection. This frontline of defence involves a coordinated network of efflux transporters. In the future, inhibition of this efflux transporter network, as a target for novel antibiotic therapy, will require the isolation and then biochemical/biophysical characterisation of each pump against all known and new antibiotics. This depth of knowledge is required so that we can fully understand and tackle the mechanisms of developing antimicrobial resistance. PMID- 28710523 TI - Short communication: emerging technologies for biometeorology. AB - The first decade of the twenty-first century saw remarkable technological advancements for use in biometeorology. These emerging technologies have allowed for the collection of new data and have further emphasized the need for specific and/or changing systems for efficient data management, data processing, and advanced representations of new data through digital information management systems. This short communication provides an overview of new hardware and software technologies that support biometeorologists in representing and understanding the influence of atmospheric processes on living organisms. PMID- 28710524 TI - Altered N100-potential associates with working memory impairment in Parkinson's disease. AB - The diagnosis of cognitive impairment and dementia often occurring with Parkinson's disease (PD) is still based on the clinical picture and neuropsychological examination. Ancillary methods to detect cognitive decline in these patients are, therefore, needed. Alterations in the latencies and amplitudes of evoked response potential (ERP) components N100 and P200 have been described in PD. Due to limited number of studies their relation to cognitive deficits in PD remains obscure. The present study was designed to examine if alterations in the N100- and P200-potentials associate with neuropsychological impairment in PD. EEG-ERP was conducted to 18 PD patients and 24 healthy controls. The patients underwent a thorough neuropsychological evaluation. The controls were screened for cognitive impairment with Consortium to Establish Alzheimer's disease (CERAD)-testing and a normal result were required to be included in the study. The N100-latency was prolonged in the patients compared to the controls (p = 0.05). In the patients, the N100 latency correlated significantly with a visual working memory task (p = 0.01). Also N100 latency was prolonged and N100 amplitude habituation diminished in the patients achieving poorly in this task. We conclude that prolonged N100-latency and diminished amplitude habituation associate with visual working memory impairment in PD. PMID- 28710525 TI - Differential role of the anterior and intralaminar/lateral thalamic nuclei in systems consolidation and reconsolidation. AB - The anterior thalamic nuclei (ATN) and the intralaminar/lateral thalamic nuclei (ILN/LT) play different roles in memory processes. The ATN are believed to be part of an extended hippocampal system, and the ILN/LT have strong connections with the medial prefrontal cortex. It was shown that the ILN/LT are involved in systems consolidation. However, whether they are necessary for memory retrieval as well remains unclear. We, therefore, used c-Fos immunohistochemistry and reversible inactivations to investigate the role of the ATN and ILN/LT in recent and remote contextual fear memory retrieval in rats. The results confirm a differential role of the ATN and ILN/LT in systems consolidation, showing the involvement of the ATN in recent but not remote memory retrieval. This study also pinpoints which specific nuclei are involved in retrieval: the anterodorsal nucleus for recent memories, and the lateral mediodorsal nucleus for remote memories. Lastly, we also show that the ATN are not involved in reconsolidation. Together, the results suggest that these nuclei provide critical feedback for successful memory retrieval and systems consolidation. PMID- 28710526 TI - Exposure, Effects and Absorption of Lead in American Woodcock (Scolopax minor): A Review. AB - Due to long term declines of American Woodcock (Scolopax minor) and widespread distribution of environmentally available lead (Pb) throughout their geographic range, it is important to assess if Pb exposure is a potential contributor to these declines. Woodcock are exposed to Pb through various environmental sources and are known to exhibit relatively high bone-Pb concentrations. Absorption of Pb by birds, and woodcock specifically, is not well understood. Some studies show that interactions among calcium, phosphorus, iron, zinc, and vitamin D levels may play an important role in Pb absorption. Therefore, when future Pb studies are performed for woodcock, and other birds, interactions among these elements should be considered. For example, these interactions are relevant in the acquisition and mobilization of calcium in female birds during egg development and shell calcification. These factors should be considered to understand potential mechanisms of Pb exposure, Pb absorption, and subsequent Pb toxicity to birds in general, and woodcock specifically. This review discusses Pb exposure routes, effects of Pb toxicity, and the distribution of Pb in American woodcock and identifies areas for future research in woodcock and other avian species. PMID- 28710527 TI - Assessment of Surface Water Contamination from Coalbed Methane Fracturing-Derived Volatile Contaminants in Sullivan County, Indiana, USA. AB - There is a growing concern over the contamination of surface water and the associated environmental and public health consequences from the recent proliferation of hydraulic fracturing in the USA. Petroleum hydrocarbon-derived contaminants of concern [benzene, toluene, ethylbenzene, and xylenes (BTEX)] and various dissolved cations and anions were spatially determined in surface waters around 15 coalbed methane fracking wells in Sullivan County, IN, USA. At least one BTEX compound was detected in 69% of sampling sites (n = 13) and 23% of sampling sites were found to be contaminated with all of the BTEX compounds. Toluene was the most common BTEX compound detected across all sampling sites, both upstream and downstream from coalbed methane fracking wells. The average concentration of toluene at a reservoir and its outlet nearby the fracking wells was ~2* higher than other downstream sites. However, one of the upstream sites was found to be contaminated with BTEX at similar concentrations as in a reservoir site nearby the fracking well. Calcium (~60 ppm) and sulfates (~175 ppm) were the dominant cations and anions, respectively, in surface water around the fracking sites. This study represents the first report of BTEX contamination in surface water from coalbed methane hydraulic fracturing wells. PMID- 28710528 TI - [Anatomy and immunology of the eye]. AB - The eye has all the mechanisms necessary for detection and processing (afferent immune reaction) as well as adequate initiation of an (efferent) immune response. Apart from the typical antigen-processing cells, locally present elements (e.g. glial cells and retinal pigment epithelium) can also be involved in the afferent reaction. For the efferent mechanisms a complex regulative system exists, which includes cellular and humoral responses and is essentially determined by surface molecules. In addition, the ocular environment is rich in immunosuppressive molecules that contribute to the regulation of immune cells. The adaptation of the anatomical and biochemical mechanisms for the creation of an immune privileged microenvironment makes this sense organ unique. The purpose of this article is to highlight the specific features of the eye and to establish a reference to frequent ocular manifestations in rheumatic diseases. PMID- 28710529 TI - Myxosporean parasites of Ceratomyxa merlangi and Myxidium gadi in whiting Merlangius merlangus: a comparative epizootiological analysis based on samples from two localities off southern and northern coasts of the Black Sea. AB - Totally 690 and 423 whiting Merlangius merlangus samples were collected from two localities off Southern (Sinop) and Northern coasts (Balaklava Bay) of the Black Sea, respectively, and examined for myxosporeans in the period from May 2011 to March 2014. Ceratomyxa merlangi and Myxidium gadi were the only myxosporean parasites identified in the content of gall bladder and their infection indices of prevalence (%) and intensity were calculated for length classes and sex of fish as well as for the seasons at both sampling localities. Overall infection prevalence of C. merlangi was 22.6% in Sinop and 27.9% in Balaklava samples while those values of M. gadi were 18.4% and 28.6% in Sinop and Balaklava samples, respectively. Both parasite species were also found to be co-existed in whiting samples. This is the first comprehensive epizootiological study yielded comparable data on C. merlangi and M. gadi infections in whiting in the southern and northern coasts of the Black Sea. PMID- 28710530 TI - Proteomic characterisation reveals active Wnt-signalling by human multipotent stromal cells as a key regulator of beta cell survival and proliferation. AB - AIMS/HYPOTHESIS: Novel strategies to stimulate the expansion of beta cell mass in situ are warranted for diabetes therapy. The aim of this study was to elucidate the secretome of human bone marrow (BM)-derived multipotent stromal cells (MSCs) with documented islet regenerative paracrine function. We hypothesised that regenerative MSCs will secrete a unique combination of protein factors that augment islet regeneration. METHODS: Human BM-derived MSCs were examined for glucose-lowering capacity after transplantation into streptozotocin-treated NOD/severe combined immunodeficiency (SCID) mice and segregated into samples with regenerative (MSCR) vs nonregenerative (MSCNR) capacity. Secreted proteins associated with islet regenerative function were identified using stable isotope labelling with amino acids in cell culture (SILAC)-based quantitative proteomics. To functionally validate the importance of active Wnt signalling, we stimulated the Wnt-signalling pathway in MSCNR samples during ex vivo expansion using glycogen synthase kinase 3 (GSK3) inhibition (CHIR99201), and the conditioned culture media (CM) generated was tested for the capacity to support cultured human islet cell survival and proliferation in vitro. RESULTS: MSCR showed increased secretion of proteins associated with cell growth, matrix remodelling, immunosuppressive and proangiogenic properties. In contrast, MSCNR uniquely secreted proteins known to promote inflammation and negatively regulate angiogenesis. Most notably, MSCR maintained Wnt signalling via Wnt5A/B (~2.5-fold increase) autocrine activity during ex vivo culture, while MSCNR repressed Wnt signalling via Dickkopf-related protein (DKK)1 (~2.5-fold increase) and DKK3 secretion. Inhibition of GSK3 activity in MSCNR samples increased the accumulation of nuclear beta-catenin and generated CM that augmented beta cell survival (13% increases) and proliferation when exposed to cultured human islets. CONCLUSIONS/INTERPRETATION: Maintenance of active Wnt signalling within human MSCs promotes the secretion of matricellular and proangiogenic proteins that formulate a niche for islet regeneration. PMID- 28710531 TI - Longitudinal Associations of Parental Emotion Socialization and Children's Emotion Regulation: The Moderating Role of ADHD Symptomatology. AB - Theory and research suggest that parents' reactions to children's emotions play a critical role in teaching children effective emotion regulation (ER) skills, but no studies have directly examined the role that parent emotion socialization plays in the development of ER in children with ADHD. Gaining insight into the causes of impaired ER, particularly in youth with ADHD who are known to have poor ER, has important theoretical and translational significance. The present study is the first to longitudinally examine whether emotion socialization predicts later physiological and adult-reported measures of ER in children with and without ADHD. It also sought to determine if these relations are moderated by ADHD symptoms. Participants were 61 children (31 girls, 30 boys; M = 10.67 years, SD = 1.28) with and without clinically significant ADHD symptoms. At Time 1, parent reports of emotion socialization and parent- and teacher-report of child ADHD symptoms were collected. At Time 2, child ER measures were collected based on parent- and teacher-report and physiological reactivity during an impossible puzzle and a social rejection task. Physiological measures included respiratory sinus arrhythmia and skin conductance level (SCL). Supportive parenting practices were associated with better parent-rated emotion regulation skills for all children and greater SCL reactivity for children with high ADHD symptoms. Non supportive parenting reactions were associated with greater adult-rated emotional lability for children with high ADHD symptoms. Results highlight the importance of considering multiple aspects of ER, including physiological manifestations. Findings suggest that parents' use of adaptive emotion socialization practices may serve as a protective factor for children's ER development and may be particularly critical for youth with ADHD. Our findings support the use of interventions addressing parent emotion socialization to help foster better ER in children. PMID- 28710532 TI - The Gap Between Adaptive Behavior and Intelligence in Autism Persists into Young Adulthood and is Linked to Psychiatric Co-morbidities. AB - For individuals with autism spectrum disorder (ASD), long-term outcomes have been troubling, and intact IQ has not been shown to be protective. Nevertheless, relatively little research into adaptive functioning among adults with ASD has been completed to date. Therefore, both adaptive functioning and comorbid psychopathology were assessed among 52 adults with ASD without intellectual disability (ID). Adaptive functioning was found to substantially lag behind IQ, and socialization was a particular weakness. Comorbid psychopathology was significantly correlated with the size of IQ-adaptive functioning discrepancy. These findings emphasize key intervention targets of both adaptive skill and psychopathology for transition-age youth and young adults with ASD, as well as the need for ongoing monitoring of anxiety and depression symptoms during this developmental window. PMID- 28710534 TI - Double plating of intra-articular multifragmentary C3-type distal femoral fractures through the anterior approach. AB - INTRODUCTION: In this prospective case series, we report a mean of 12-month follow-up of the utilization of a dual plating of distal femoral fractures. Our technique included a lateral distal femoral locked plate with a low-contact locked medial plate and bone graft through an extended medial parapatellar anterior approach for the fixation of C3-type distal femoral fractures. PATIENTS AND METHODS: Sixteen patients (11 males and 5 females) presented with supracondylar femoral fracture type C3, according to Muller long-bone classification system and its revision OA/OTA classification. These were treated using dual plating through extended anterior approach and bone grafting. Our outcomes included clinical and radiological outcomes. Secondary outcomes included postoperative complications. RESULTS: The mean time of complete radiological union in the studied population was 6.0 +/- 3.5 months with a range of 3-14 months. We have not observed postoperative varus or valgus deformity in our cohort. The majority (68.75%) of the studied patients showed significant improvement in range of motion (90 degrees -120 degrees ) during follow-up. Eleven out of sixteen patients (68.75%) had well-to-excellent functional outcome. Poor outcome was reported in only two patients (12.50%). CONCLUSIONS: Dual plating fixation using anterior approach for type C3 distal femoral fractures is an efficient method of management. It has several advantages such as precise exposure, easy manipulation, anatomical reduction and stable fixation. However, operative indications and instructions should be strictly followed. The surgical technique must be rigorous, and the biomechanical qualities of these implants must be understood to prevent the development of major complications. PMID- 28710533 TI - Performance Evaluation of a Pre-computed Brain Response Atlas in Dummy Head Impacts. AB - A pre-computed brain response atlas (pcBRA) may have the potential to accelerate the investigation of the biomechanical mechanisms of traumatic brain injury on a large-scale. In this study, we further enhance the technique and evaluate its performance using six degree-of-freedom angular velocity profiles from dummy head impacts. Using the pcBRA to simplify profiles into acceleration-only shapes, sufficiently accurate strain estimates were obtained for impacts with a major dominating velocity peak. However, they were largely under-estimated when substantial deceleration occurred that reversed the direction of the angular velocity. For these impacts, estimation accuracy was substantially improved with a biphasic profile simplification (average correlation coefficient and linear regression slope of 0.92 +/- 0.03 and 0.95 +/- 0.07 for biphasic shapes, respectively, vs. 0.80 +/- 0.06 and 0.80 +/- 0.08 for acceleration-only shapes). Peak maximum principal strain (E p) and cumulative strain damage measure (CSDM) from the estimated strains consistently correlated stronger than kinematic metrics with respect to the baseline E p and CSDM from the directly simulated responses, regardless of the brain region, and by a large margin (e.g., correlation of 0.93 vs. 0.75 compared to Brain Injury Criterion (BrIC) for E p in the whole-brain, and 0.91 vs. 0.47 compared to BrIC for CSDM in the corpus callosum). These findings further support the pre-computation technique for accurate, real-time strain estimation, which could be important to accelerate model-based brain injury studies in the future. PMID- 28710535 TI - Pharmacological inhibition of heparin-binding EGF-like growth factor promotes peritoneal angiogenesis in a peritoneal dialysis rat model. AB - BACKGROUND: Molecular mechanisms of peritoneal dialysis (PD) ultrafiltration failure, peritoneal neo-angiogenesis, and fibrosis remain to be determined. We aimed to determine the role of heparin-binding EGF-like growth factor (HB-EGF) inhibition on angiogenesis of peritoneal membrane in a PD rat model. METHODS: 32 male Wistar rats were assigned into (1) control group; (2) uremic non-PD group: subtotal nephrectomy-induced uremic rats without PD; (3) uremic rats subjected to PD: uremic rats that were dialyzed with Dianeal(r) for 4 weeks; (4) CRM 197 group: dialyzed uremic rats were supplemented with CRM197, a specific HB-EGF inhibitor. Peritoneal transport function was examined by peritoneal equilibration test. Expression of HB-EGF and EGFR in peritoneal samples were examined by real time PCR, immunohistochemical staining, and western blot. RESULTS: Progressive angiogenesis and fibrosis were observed in uremic PD rats, and there were associated with decreased net ultrafiltration (nUF), increased permeability of peritoneal membrane, and reduced expression of HB-EGF and EGFR protein and mRNA in uremic PD rats compared to uremic non-PD or control groups (both p < 0.05). CRM197 significantly induced peritoneal membrane permeability, decreased nUF, increased higher vessel density, and reduced pericyte count compared to that of uremic PD rats. The levels of HB-EGF and EGFR expression negatively correlated with vessel density in peritoneal membrane (both p < 0.001). CONCLUSION: PD therapy was associated with peritoneal angiogenesis, functional deterioration, and downregulation of HB-EGF/EGFR. Pharmacological inhibition of HB-EGF promoted PD-induced peritoneal angiogenesis and fibrosis and ultrafiltration decline, suggesting that HB-EGF downregulation contributes to peritoneal functional deterioration in the uremic PD rat model. PMID- 28710537 TI - Cardiac safety of non-anthracycline trastuzumab-based therapy for HER2-positive breast cancer. AB - PURPOSE: Trastuzumab improves overall survival for women with HER2-positive breast cancer but is associated with cardiotoxicity, especially when administered after anthracyclines. Use of non-anthracycline trastuzumab-based regimens is rising, particularly for patients with low-risk disease or with multiple cardiovascular risk factors. We performed a single-center retrospective cohort study to assess the cardiac safety of trastuzumab without anthracyclines outside of a clinical trial setting. METHODS: A retrospective chart review was conducted of patients with HER2-positive early-stage breast cancer receiving non anthracycline trastuzumab-based therapy between January 2010 and June 2014. Cardiovascular risk factors, left ventricular ejection fraction (LVEF), and treatment interruption data were collected. The primary outcome was a cardiac event (CE), defined by New York Heart Association class III or IV heart failure or cardiac death. The secondary outcome was a significant asymptomatic decline of LVEF (>10% to <55% or >16% from baseline). RESULTS: A total of 165 patients were identified with a median age of 59 years (range 32-85 years). Seventy (42%) had hypertension, 52 (32%) had hyperlipidemia, 29 (18%) had diabetes, and 5 (3%) had coronary artery disease. All patients had a LVEF >50% (median 67%; range 50-80%) at baseline. Two (1.2%) patients with multiple cardiovascular risk factors developed a CE. After discontinuation of trastuzumab, both patients had recovery of LVEF to >50% and resolution of heart failure symptoms. Ten (6.1%) patients developed significant asymptomatic LVEF decline during trastuzumab therapy. CONCLUSIONS: The overall incidence of symptomatic heart failure and asymptomatic LVEF decline among patients receiving trastuzumab without anthracyclines remains low. These findings suggest that less intensive cardiac monitoring may be appropriate during trastuzumab therapy without anthracyclines. PMID- 28710536 TI - Resistance to tomato leaf curl New Delhi virus in melon is controlled by a major QTL located in chromosome 11. AB - KEY MESSAGE: Identification of three genomic regions and underlying candidate genes controlling the high level of resistance to ToLCNDV derived from a wild melon. SNP markers appropriated for MAS management of resistance. Tomato leaf curl New Delhi virus (ToLCNDV) is a bipartite begomovirus that severely affects melon crop (Cucumis melo) in the main production areas of Spain since 2012. In this work, we evaluated the degree of resistance of four accessions (two belonging to the subsp. agrestis var. momordica and two to the wild agrestis group) and their corresponding hybrids with a susceptible commercial melon belonging to the subsp. melo (Piel de Sapo, PS). The analysis using quantitative PCR (qPCR) allowed us to select one wild agrestis genotype (WM-7) with a high level of resistance and use it to construct segregating populations (F 2 and backcrosses). These populations were phenotyped for symptom severity and virus content using qPCR, and genotyped with different sets of SNP markers. Phenotyping and genotyping results in the F 2 and BC1s populations derived from the WM-7 * PS cross were used for QTL analysis. Three genomic regions controlling resistance to ToLCNDV were found, one major locus in chromosome 11 and two additional regions in chromosomes 12 and 2. The highest level of resistance (no or mild symptoms and very low viral titer) was obtained with the homozygous WM-7WM-7 genotype at the major QTL in chromosome 11, even with PSPS genotypes at the other two loci. The resistance derived from WM-7 is useful to develop new melon cultivars and the linked SNPs selected in this paper will be highly useful in marker-assisted breeding for ToLCNDV resistance in melon. PMID- 28710538 TI - [Manifestations of autoimmune disorders in otorhinolaryngology : Classical symptoms and diagnostic approach]. AB - Manifestations of autoimmune disorders represent a diagnostic challenge. Many autoimmune disorders show typical manifestations in the ear, nose and throat and should be taken into account in the differential diagnosis. Sjogren's syndrome, various vasculitides and sarcoidosis represent the most common autoimmune disorders in otorhinolaryngology, but IgG4-related diseases, relapsing polychondritis and autoimmune disorders of the mucosa are also observed. Autoimmune diseases can lead to sensorineural deficits. Both hypo- and hyperthyroidism can be caused by autoimmune disorders. The diagnosis is usually based on the corresponding classification criteria, whose correct application can facilitate the clarification of these diseases. PMID- 28710539 TI - [Treatment outcomes of recurrent respiratory papillomatosis : Retrospective analysis of juvenile and adult cases. German version]. AB - BACKGROUND: Recurrent respiratory papillomatosis (RRP) is a rare, chronic disease of viral etiology which is characterized by multiple, recurrent growth of papillomas in the aerodigestive tract. MATERIALS AND METHODS: The surgical outcomes and the recurrence rates of 106 patients with RRP of the larynx were analyzed. The patients were treated at the University of Magdeburg between 1983 and 2014. The surgical outcomes of conventional and laser surgery regarding time to relapse and complications were compared. In addition, the influence of the quadrivalent vaccine Gardasil(r) on the disease was analyzed in 10 patients. RESULTS: Children with RRP had a statistically significant greater number of surgeries throughout their lifetimes compared to adult patients. There were no differences between the adult (n = 79) and juvenile (n = 27) groups in the time to relapse and the number of surgeries/year. The time to relapse and number of procedures/year were not influenced by the various surgical methods. Complications after conventional and laser surgery were not statistically different between the two groups. Serious complications and the need for a tracheotomy were only reported after conventional surgery. In the 10 patients who were immunized with Gardasil(r), a statistically significant lower number of surgeries/year after vaccination was achieved. CONCLUSION: RRP is a rare disease. Treatment requires experience and may be very difficult. The analysis of the course of the disease has shown that the treatment of choice is surgical excision with the CO2 laser combined with the quadrivalent or polyvalent vaccine. Consequent vaccination of both boys and girls has the potential to reduce the occurrence of RRP. PMID- 28710540 TI - Home-based exercise during preoperative therapy for pancreatic cancer. AB - PURPOSE: Exercise concurrent with neoadjuvant chemotherapy and/or chemoradiation for pancreatic adenocarcinoma (PDAC) may mitigate the decline in function that may occur as a result of the disease or its treatment in the preoperative period. The primary objective of this single-arm prospective trial was to determine adherence to a home-based exercise program administered during preoperative therapy. METHODS: Twenty patients from a quaternary cancer center with potentially resectable PDAC were enrolled. Patients were prescribed a minimum of 120 min of moderate-intensity exercise weekly: at least 60 min of aerobic exercise and 60 min of resistance exercise. Self-reported exercise was recorded in daily logs. Functional and survey measures were collected upon enrollment, following preoperative therapy, and 1 month after surgery. RESULTS: Fifteen out of 20 patients participated in the program. They reported a mean (standard deviation (SD)) of 98.6 (69.8) min of aerobic exercise weekly and 57.4 (36.0) min of strengthening exercise weekly over a median of 17 weeks (range, 5-35 weeks) of preoperative therapy, for a mean (SD) of 156.0 (64.5) min of total exercise weekly. Eighty percent reported a mean of least 120 min of total exercise weekly during preoperative therapy. Patients with low baseline physical activity based on the International Physical Activity Questionnaire significantly increased their preoperative physical activity (p = .01). There were no adverse events associated with the exercise program. CONCLUSIONS: Patients with PDAC will participate in a home-based exercise program of aerobic and strengthening exercise and will increase physical activity, concurrent with preoperative chemotherapy and/or chemoradiation. PMID- 28710542 TI - A possible dual effect of cigarette smoking on the risk of postmenopausal breast cancer. AB - Smoking seems modestly associated with breast cancer, but the potential dual effect of smoking (with opposing properties: carcinogenic vs anti-estrogenic) is understudied. The relationship between smoking before and after menopause and risk of postmenopausal breast cancer was investigated in the Netherlands Cohort Study (NLCS). In the NLCS, 62,573 women aged 55-69 years provided information on smoking, dietary and other lifestyle habits in 1986. Follow-up for cancer incidence until 2007 (20.3 years) consisted of record linkages with the Netherlands Cancer Registry and the Dutch Pathology Registry PALGA. Multivariate case-cohort analyses were based on 2526 incident breast cancer cases and 1816 subcohort members with complete data on smoking. When smoking during pre- and postmenopausal periods was mutually adjusted for, breast cancer risk was significantly positively associated with premenopausal smoking pack-years, but inversely associated with postmenopausal smoking pack-years, both in a dose dependent manner. In continuous analyses, the hazard ratios (95% CI) were 1.35 (1.10-1.65), and 0.47 (0.28-0.80) per increment of 20 premenopausal, and postmenopausal pack-years, respectively. The interaction between pre- and postmenopausal pack-years in relation to breast cancer risk was significant (P < 0.001). This study highlights the importance of distinguishing and adjusting for smoking in different life periods, and suggests dual effects of smoking on postmenopausal breast cancer risk. PMID- 28710541 TI - Injury-induced purinergic signalling molecules upregulate pluripotency gene expression and mitotic activity of progenitor cells in the zebrafish retina. AB - Damage in fish activates retina repair that restores sight. The purinergic signalling system serves multiple homeostatic functions and has been implicated in cell cycle control of progenitor cells in the developing retina. We examined whether changes in the expression of purinergic molecules were instrumental in the proliferative phase after injury of adult zebrafish retinas with ouabain. P2RY1 messenger RNA (mRNA) increased early after injury and showed maximal levels at the time of peak progenitor cell proliferation. Extracellular nucleotides, mainly ADP, regulate P2RY1 transcriptional and protein expression. The injury induced upregulation of P2RY1 is mediated by an autoregulated mechanism. After injury, the transcriptional expression of ecto-nucleotidases and ecto-ATPases also increased and ecto-ATPase activity inhibitors decreased Muller glia-derived progenitor cell amplification. Inhibition of P2RY1 endogenous activation prevented progenitor cell proliferation at two intervals after injury: one in which progenitor Muller glia mitotically activates and the second one in which Muller glia-derived progenitor cells amplify. ADPbetaS induced the expression of lin28a and ascl1a genes in mature regions of uninjured retinas. The expression of these genes, which regulate multipotent Muller glia reprogramming, was significantly inhibited by blocking the endogenous activation of P2RY1 early after injury. We consistently observed that the number of glial fibrillary acidic protein-BrdU-positive Muller cells after injury was larger in the absence than in the presence of the P2RY1 antagonist. Ecto-ATPase activity inhibitors or P2RY1 specific antagonists did not modify apoptotic cell death at the time of peak progenitor cell proliferation. The results suggested that ouabain injury upregulates specific purinergic signals which stimulates multipotent progenitor cell response. PMID- 28710543 TI - Acute non-contact anterior cruciate ligament tears are associated with relatively increased vastus medialis to semimembranosus cross-sectional area ratio: a case control retrospective MR study. AB - OBJECTIVE: Hamstring muscle deficiency is increasingly recognized as a risk factor for anterior cruciate ligament (ACL) tears. The purpose of this study is to evaluate the vastus medialis to semimembranosus cross-sectional area (VM:SM CSA) ratio on magnetic resonance imaging (MRI) in patients with ACL tears compared to controls. MATERIALS AND METHODS: One hundred knee MRIs of acute ACL tear patients and 100 age-, sex-, and side-matched controls were included. Mechanism of injury, contact versus non-contact, was determined for each ACL tear subject. The VM:SM CSA was measured on individual axial slices with a novel method using image-processing software. One reader measured all 200 knees and the second reader measured 50 knees at random to assess inter-reader variability. The intraclass correlation coefficient (ICC) was calculated to evaluate for correlation between readers. T-tests were performed to evaluate for differences in VM:SM CSA ratios between the ACL tear group and control group. RESULTS: The ICC for agreement between the two readers was 0.991 (95% confidence interval 0.984-0.995). Acute ACL tear patients have an increased VM:SM CSA ratio compared to controls (1.44 vs. 1.28; p = 0.005). Non-contact acute ACL tear patients have an increased VM:SM CSA ratio compared to controls (1.48 vs. 1.20; p = 0.003), whereas contact acute ACL tear patients do not (1.23 vs. 1.26; p = 0.762). CONCLUSION: Acute non-contact ACL tears are associated with increased VM:SM CSA ratios, which may imply a relative deficiency in hamstring strength. This study also demonstrates a novel method of measuring the relative CSA of muscles on MRI. PMID- 28710544 TI - Employers' experience of employees with cancer: trajectories of complex communication. AB - PURPOSE: Remaining in paid work is of great importance for cancer survivors, and employers play a crucial role in achieving this. Return to work (RTW) is best seen as a process. This study aims to provide insight into (1) Dutch employers' experiences with RTW of employees with cancer and (2) the employers' needs for support regarding this process. METHODS: Thirty employer representatives of medium and large for-profit and non-profit organizations were interviewed to investigate their experiences and needs in relation to employees with cancer. A Grounded Theory approach was used. RESULTS: We revealed a trajectory of complex communication and decision-making during different stages, from the moment the employee disclosed that they had been diagnosed to the period after RTW, permanent disability, or the employee's passing away. Employers found this process demanding due to various dilemmas. Dealing with an unfavorable diagnosis and balancing both the employer's and the employee's interests were found to be challenging. Two types of approach to support RTW of employees with cancer were distinguished: (1) a business-oriented approach and (2) a care-oriented approach. Differences in approach were related to differences in organizational structure and employer and employee characteristics. Employers expressed a need for communication skills, information, and decision-making skills to support employees with cancer. CONCLUSIONS: The employers interviewed stated that dealing with an employee with cancer is demanding and that the extensive Dutch legislation on RTW did not offer all the support needed. We recommend providing them with easily accessible information on communication and leadership training to better support employees with cancer. IMPLICATIONS FOR CANCER SURVIVORS: * Supporting employers by training communication and decision-making skills and providing information on cancer will contribute to improving RTW support for employees with cancer. * Knowing that the employer will usually be empathic when an employee reveals that they have been diagnosed with cancer, and that the employer also experiences difficulties and dilemmas, might lower the threshold to discuss wishes regarding disclosure, communication, and work issues. * The interests of employer and employee in relation to RTW are interrelated; both have responsibility and a role to play, and are in need of support. PMID- 28710546 TI - 18th International Conference on Biological Inorganic Chemistry. PMID- 28710545 TI - Comparative muscle proteomics/phosphoproteomics analysis provides new insight for the biosafety evaluation of fat-1 transgenic cattle. AB - The biosafety of fat-1 transgenic cattle has been a focus of our studies since the first fat-1 transgenic cow was born. In this study, we used tandem mass tag labeling, TiO2 enrichment, and nanoscale liquid chromatography coupled with tandem mass spectrometry (nanol LC-MS/MS) to compare proteomic and phosphoproteomic profiling analyses of muscle between fat-1 transgenic cows and wild-type cows. A total of 1555 proteins and 900 phosphorylation sites in 159 phosphoproteins were identified in the profiling assessments, but only four differentially expressed proteins and nine differentially expressed phosphopeptides were detected in fat-1 transgenic cows relative to wild-type cows. Bioinformatics analyses showed that all of the identified proteins and phosphoproteins were mainly related to the metabolic processes of three major nutrients: carbohydrates, lipids, and proteins. All of these differentially expressed proteins might take part in DNA recombination, repair, and regulation of the immune system. In conclusion, most of the identified proteins and phosphoproteins exhibited few changes. Our results provide new insights into the biosafety of fat-1 transgenic cattle. PMID- 28710547 TI - Cross-cultural adaptation and validation of the Italian version of the Kerlan Jobe Orthopaedic Clinic Shoulder and Elbow score. AB - BACKGROUND: The Kerlan-Jobe Orthopaedic Clinic (KJOC) Shoulder and Elbow score is a reliable and sensitive tool to measure the performance of overhead athletes. The purpose of this study was to carry out a cross-cultural adaptation and validation of the KJOC questionnaire in Italian and to assess its reliability, validity, and responsiveness. MATERIALS AND METHODS: Ninety professional athletes with a painful shoulder were included in this study and were assigned to the "injury group" (n = 32) or the "overuse group" (n = 58); 65 were managed conservatively and 25 were treated by arthroscopic surgery. To assess the reliability of the KJOC score, patients were asked to fill in the questionnaire at baseline and after 2 weeks. To test the construct validity, KJOC scores were compared to those obtained with the Italian version of the Disabilities of the Arm, Shoulder, and Hand (DASH) scale, and with the DASH sports/performing arts module. To test KJOC score responsiveness, the follow-up KJOC scores of the participants treated conservatively were compared to those of the patients treated by arthroscopic surgery. RESULTS: Statistical analysis demonstrated that the KJOC questionnaire is reliable in terms of the single items and the overall score (ICC 0.95-0.99); that it has high construct validity (r s = -0.697; p < 0.01); and that it is responsive to clinical differences in shoulder function (p < 0.0001). CONCLUSIONS: The Italian version of the KJOC Shoulder and Elbow score performed in a similar way to the English version and demonstrated good validity, reliability, and responsiveness after conservative and surgical treatment. LEVEL OF EVIDENCE: II. PMID- 28710548 TI - Retrospective evaluation and SEEG trajectory analysis for interactive multi trajectory planner assistant. AB - PURPOSE: Focal epilepsy is a neurological disease that can be surgically treated by removing area of the brain generating the seizures. The stereotactic electroencephalography (SEEG) procedure allows patient brain activity to be recorded in order to localize the onset of seizures through the placement of intracranial electrodes. The planning phase can be cumbersome and very time consuming, and no quantitative information is provided to neurosurgeons regarding the safety and efficacy of their trajectories. In this work, we present a novel architecture specifically designed to ease the SEEG trajectory planning using the 3D Slicer platform as a basis. METHODS: Trajectories are automatically optimized following criteria like vessel distance and insertion angle. Multi-trajectory optimization and conflict resolution are optimized through a selective brute force approach based on a conflict graph construction. Additionally, electrode specific optimization constraints can be defined, and an advanced verification module allows neurosurgeons to evaluate the feasibility of the trajectory. RESULTS: A retrospective evaluation was performed using manually planned trajectories on 20 patients: the planning algorithm optimized and improved trajectories in 98% of cases. We were able to resolve and optimize the remaining 2% by applying electrode-specific constraints based on manual planning values. In addition, we found that the global parameters used discards 68% of the manual planned trajectories, even when they represent a safe clinical choice. CONCLUSIONS: Our approach improved manual planned trajectories in 98% of cases in terms of quantitative indexes, even when applying more conservative criteria with respect to actual clinical practice. The improved multi-trajectory strategy overcomes the previous work limitations and allows electrode optimization within a tolerable time span. PMID- 28710550 TI - Abstracts of Original Contributions ASNC2017 The 22nd Annual Scientific Session of the American Society of Nuclear Cardiology : September 14-17, 2017, Kansas City, MO. PMID- 28710549 TI - Cervical varicosities may predict placenta accreta in posterior placenta previa: a magnetic resonance imaging study. AB - PURPOSE: The aim of this study was to prenatally predict placenta accreta in posterior placenta previa using magnetic resonance imaging (MRI). METHODS: This retrospective study was approved by the Institutional Review Board of our hospital. We identified 81 patients with singleton pregnancy who had undergone cesarean section due to posterior placenta previa at our hospital between January 2012 and December 2016. We calculated the sensitivity and specificity of several well-known findings, and of cervical varicosities quantified using magnetic resonance imaging, in predicting placenta accreta in posterior placenta previa. To quantify cervical varicosities, we calculated the A/B ratio, where "A" was the minimum distance from the most dorsal cervical varicosity to the deciduous placenta, and "B" was the minimum distance from the most dorsal cervical varicosity to the amniotic placenta. The appropriate cut-off value of the A/B ratio was determined using a receiver operating characteristic (ROC) curve. RESULTS: Three patients (3.7%) were diagnosed as having placenta accreta. The sensitivity and specificity of the well-known findings were 0 and 97.4%, respectively. Furthermore, the A/B ratio ranged from 0.02 to 0.79. ROC curve analysis revealed that the area under the combined placenta accreta and A/B ratio curve was 0.96. When the cutoff value of the A/B ratio was set 0.18, the sensitivity and specificity were 100 and 91%, respectively. CONCLUSION: It was difficult to diagnose placenta accreta in the posterior placenta previa using the well-known findings. The quantification of cervical varicosities could effectively predict placenta accreta. PMID- 28710551 TI - Advanced glycation end products (AGEs) and cardiovascular dysfunction: focus on high molecular weight AGEs. AB - Advanced glycation end products (AGEs) are a group of proteins and lipids becoming glycated and oxidized after persistent contact with reducing sugars or short-chain aldehydes with amino group and/or high degree of oxidative stress. The accumulation of AGEs in the body is a natural process that occurs with senescence, when the turnover rate of proteins is reduced. However, increased circulating AGEs have been described to arise at early lifetime and are associated with adverse outcome and survival, in particular in settings of cardiovascular diseases. AGEs contribute to the development of cardiac dysfunction by two major mechanisms: cross-linking of proteins or binding to their cell surface receptor. Recently, growing evidence shows that high-molecular weight AGEs (HMW-AGEs) might be as important as the characterized low-molecular weight AGEs (LMW-AGEs). Here, we point out the targets of AGEs in the heart and the mechanisms that lead to heart failure with focus on the difference between LMW-AGEs and the less characterized HMW-AGEs. As such, this review is a compilation of relevant papers in the form of a useful resource tool for researchers who want to further investigate the role of HMW-AGEs on cardiac disorders and need a solid base to start on this specific topic. PMID- 28710552 TI - The African froghopper Ptyelus flavescens (suborder: Cicadomorpha) contains two novel and one known peptides of the adipokinetic hormone (AKH) family: structure, function and comparison with aphid AKH (suborder: Sternorrhyncha). AB - The rationale of "green pesticides" in food security is to use information about endogenous hormones of pest insects to make peptide mimetics that will act against the pest insects to alter their behaviour or physiology, while taking care not to harm beneficial insects or other organisms in the food chain. Such "green" insecticides are designed thus, on the basis of neuropeptide ligand receptor interaction and it is of paramount interest to have finally a mimetic at hand that is harmful only to pest insects. For this concept to work, one has to identify the ligands in pest and beneficial insects. In this study we investigate adipokinetic hormones (AKHs) from a hemipteran source. The most harmful hemipterans on an economic scale are aphids (Hemiptera: Sternorrhyncha: Aphidoidea) of which the AKH is known. Here we identify the AKH complement of a member of a related suborder, the raintree bug or froghopper Ptyelus flavescens (Hemiptera: Cicadomorpha: Cercopoidea). Identification and sequence elucidation of the adipokinetic peptides of this species was achieved by a heterospecific and conspecific trehalose-mobilizing bioassay, and by liquid chromatography coupled to positive electrospray mass spectrometry (LC-ESI-MS) including tandem MS2 spectra obtained by collision-induced dissociation. High resolution MS was employed to distinguish between Gln and Lys residues in the peptides. Three AKHs are discovered in the raintree bug: an octapeptide (Peram-CAH-I: pEVNFSPNW amide) previously known from cockroaches, and two novel decapeptides (Ptyfl-AKH-I: pEINFSTGWGQ amide and Ptyfl-AKH-II: pEINFSTAWGQ amide). The novel peptides were synthesized and the sequence assignments were unequivocally confirmed by co elution of synthetic peptides and the natural equivalent and by identical MS data of the two forms. A conspecific bioassay in the froghopper describe the endogenous peptide Ptyfl-AKH-I as hypertrehalosemic. In heterologous bioassays the two novel AKHs induce an increase of circulating carbohydrates in cockroaches: Ptyfl-AKH-I is much more active than Ptyfl-AKH-II. Moreover, if the Ile2 in Ptyfl-AKH-II is replaced with a Leu2 residue, biological activity is further diminished. The current data show that the raintree AKH decapeptides differ by four amino acids from the aphid AKH (Acypi-AKH: pEVNFTPTWGQ amide). Therefore, it may be permissible to use the aphid AKH ligand-receptor pair to develop a "green" insecticide to target aphid metabolism. PMID- 28710553 TI - Metabolism and distribution of pharmacological homoarginine in plasma and main organs of the anesthetized rat. AB - L-Homoarginine (hArg) and guanidinoacetate (GAA) are produced from L-arginine (Arg) by the catalytic action of arginine:glycine amidinotransferase. Guanidinoacetate methyltransferase methylates GAA on its non-guanidine N atom to produce creatine. Arg and hArg are converted by nitric oxide synthase (NOS) to nitric oxide (NO). NO is oxidized to nitrite and nitrate which circulate in the blood and are excreted in the urine. Asymmetric dimethylarginine (ADMA), an NOS inhibitor, is widely accepted to be exclusively produced after asymmetric N G methylation of Arg residues in proteins and their regular proteolysis. Low circulating and urinary hArg concentrations and high circulating concentrations of ADMA emerged as risk markers in the human renal and cardiovascular systems. While ADMA's distribution and metabolism are thoroughly investigated, such studies on hArg are sparse. The aim of the present pilot study was to investigate the distribution of exogenous hArg in plasma, liver, kidney, lung, and heart in a rat model of takotsubo cardiomyopathy (TTC). hArg hydrochloride solutions in physiological saline were injected intra-peritoneally at potentially pharmacological, non-toxic doses of 20, 220, or 440 mg/kg body weight. Vehicle (saline) served as control. As hArg has been reported to be a pro-oxidant, plasma and tissue malondialdehyde (MDA) was measured as a biomarker of lipid peroxidation. hArg administration resulted in dose-dependent maximum plasma hArg concentrations and distribution in all investigated organs. hArg disappeared from plasma with an elimination half-life ranging between 20 and 40 min. hArg administration resulted in relatively small changes in the plasma and tissue content of Arg, GAA, ADMA, creatinine, and of the NO metabolites nitrite and nitrate. Remarkable changes were observed for tissue GAA, notably in the kidney. Plasma and tissue MDA concentration did not change upon hArg administration, suggesting that even high-dosed hArg is not an oxidant. The lowest hArg dose of 20 mg/kg bodyweight increased 25-fold the mean hArg maximum plasma concentration. This hArg dose seems to be useful as the upper limit in forthcoming studies on the putative cardioprotective effects of hArg in our rat model of TTC. PMID- 28710554 TI - Morphofunctional Changes After Sleeve Gastrectomy and Very Low Calorie Diet in an Animal Model of Non-Alcoholic Fatty Liver Disease. AB - BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease and is found in 70% of obese people. The evidence available to date suggests that bariatric surgery could be an effective treatment by reducing weight and also by improving metabolic complications in the long term. This work aimed to compare, in a diet-induced NAFLD animal model, the effect of both sleeve gastrectomy (SG) and very-low calorie diet (VLCD). METHODS: Thirty five Wistar rats were divided into control rats (n = 7) and obese rats fed a high fat diet (HFD). After 10 weeks, the obese rats were subdivided into four groups: HFD (n = 7), VLCD (n = 7), and rats submitted to either a sham operation (n = 7) or SG (n = 7). Both liver tissue and blood samples were processed to evaluate steatosis and NASH changes in histology (Oil Red, Sirius Red and H&E); presence of endothelial damage (CD31, Moesin/p-Moesin, Akt/p-Akt, eNOS/p-eNOS), oxidative stress (iNOS) and fibrosis (alphaSMA, Col1, PDGF, VEGF) proteins in liver tissue; and inflammatory (IL6, IL10, MCP-1, IL17alpha, TNFalpha), liver biochemical function, and hormonal (leptin, ghrelin, visfatin and insulin) alterations in plasma. RESULTS: Both VLCD and SG improved histology, but only SG induced a significant weight loss, improved endothelial damage, and a decreased cardiovascular risk by reducing insulin resistance (IR), leptin, total cholesterol, and triglyceride levels. There were no relevant variations in the inflammatory and fibrosis markers. CONCLUSION: Our study suggests a slight superiority of SG over VLCD by improving not only the histology but also the IR and cardiovascular risk markers related to NAFLD. PMID- 28710555 TI - Efficacy of the traditional Japanese medicine goreisan for the resolution of spermatic cord hydrocele in children. AB - PURPOSE: Goreisan, a traditional Japanese medicine, has previously been used for hydrostatic modulation. This retrospective study investigated the efficacy of goreisan for spermatic cord hydrocele resolution in children. METHODS: Seventy two boys treated for spermatic cord hydrocele between 2012 and 2015 were included; Goreisan was administered to 16 [group G, median age 3 (1-8) years], and 56 were followed without medication [group C, median age 1 (0-8) years]. An age-matched comparison was conducted between 14/16 group G patients (group g) and 14/56 group C patients (group c). RESULTS: Incidences of resolution were higher in groups G and g than in groups C and c, respectively, both during the study period and within the first 6-month observation period; groups G and g also had a significantly lower incidence of surgery for hydrocele than in groups C and c, respectively. The interval from the commencement of observation until hydrocele resolution was significantly shorter in group G than in group C, but not in group g than in group c. CONCLUSION: Goreisan can effectively promote the resolution of spermatic cord hydrocele in children and may be a valid treatment choice for this condition. PMID- 28710556 TI - Visual mismatch negativity (vMMN) for low- and high-level deviances: A control study. AB - The aim of our studies was to separate the effects of violating a sequential rule (genuine visual mismatch negativity; gvMMN) from the decreased activity in response to repeated stimuli (stimulus-specific adaptation; SSA) for simple and more complex stimuli. To accomplish this goal, different control procedures were applied with the aim of finding the correct control for vMMN studies. Event related brain electric activity (ERPs) was measured in response to nonattended visual stimuli that were presented either in an oddball manner or in various control sequences. To identify the cortical sources of the different processes, the sLORETA inverse solution was applied to the average ERP time series. In Experiment 1, the stimuli were line textures, and the deviancy was different line orientations. SSA fully explained the deviant-related ERP effects (increased posterior negativity in the 105-190 ms range). In Experiments 2 and 3, windmill patterns were used. Infrequent windmill patterns with 12 vanes elicited gvMMN (posterior negativities in the 100-200 and 200-340 ms ranges), whereas in the case of the less complex (six vanes) stimuli, SSA explained the negative deflection in both latency ranges (178-216 and 270-346 ms). In Experiment 3, infrequent stimuli with six vanes elicited deviant-related posterior negativity within the sequence of less complex (four vanes) frequent patterns. We reconcile the discrepant results by proposing that the underlying processes of vMMN are not uniform but depend strongly on the eliciting stimulus and that the complexity difference between the infrequent and frequent stimuli has considerable influence on the deviant-related response. PMID- 28710557 TI - Lysionotin attenuates Staphylococcus aureus pathogenicity by inhibiting alpha toxin expression. AB - alpha-Toxin, one of the best known pore-forming proteins produced by Staphylococcus aureus (S. aureus), is a critical virulence factor in multiple infections. The necessity of alpha-toxin for S. aureus pathogenicity suggests that this toxin is an important target for the development of a potential treatment strategy. In this study, we showed that lysionotin, a natural compound, can inhibit the hemolytic activity of culture supernatants by S. aureus by reducing alpha-toxin expression. Using real-time PCR analysis, we showed that transcription of hla (the gene encoding alpha-toxin) and agr (the locus regulating hla) was significantly inhibited by lysionotin. Lactate dehydrogenase and live/dead assays indicated that lysionotin effectively protected human alveolar epithelial cells against S. aureus, and in vivo studies also demonstrated that lysionotin can protect mice from pneumonia caused by S. aureus. These findings suggest that lysionotin is an efficient inhibitor of alpha-toxin expression and shows significant protection against S. aureus in vitro and in vivo. This study supports a potential strategy for the treatment of S. aureus infection by inhibiting the expression of virulence factors and indicates that lysionotin may be a potential treatment for S. aureus pneumonia. PMID- 28710558 TI - Pathway engineering for the production of beta-amyrin and cycloartenol in Escherichia coli-a method to biosynthesize plant-derived triterpene skeletons in E. coli. AB - Cycloartenol is biosynthetically the first sterol skeleton, which is metabolized to phytosterols such as beta-sitosterol and stigmasterol. beta-Amyrin is the most commonly occurring aglycone skeleton for oleanane-type saponins such as glycyrrhizin and saikosaponins. It has been regarded that these cyclic triterpenes are unable to be produced in Escherichia coli, while no reports are available on their production with E. coli. Here, we describe a method to synthesize triterpene skeletons from higher plants, including cycloartenol and beta-amyrin. We introduced into E. coli the biosynthetic pathway genes from farnesyl diphosphate (FPP) to cycloartenol or beta-amyrin, which contained Arabidopsis (Arabidopsis thaliana)-derived squalene synthase (AtSQS) and squalene epoxidase (AtSQE) genes in addition to the Arabidopsis cycloartenol synthase (AtCAS1) gene, or the beta-amyrin synthase (EtAS) gene of the petroleum plant Euphorbia tirucalli, along with the isopentenyl diphosphate isomerase (HpIDI) gene from a green algae Haematococcus pluvialis. The order of genes, HpIDI, AtSQS, AtSQE, driven by transcriptional read-through from a tac promoter to an rrnB terminator, was crucial for their functional expression in E. coli to produce cycloartenol or beta-amyrin. The co-expression of a bacterial NADPH regenerating gene (zwf or gdh) as well as bacterial redox partner protein genes (camA and camB, or NsRED and NsFER) was found to increase the amounts of these triterpenes several fold. The present study could open up opportunities not only to carry out functional analysis of a higher-plant-derived oxidosqualene cyclase (OSC) gene in E. coli but also to produce functional triterpenes that originate from medicinal or herbal plants. PMID- 28710559 TI - Aloe-emodin inhibits Staphylococcus aureus biofilms and extracellular protein production at the initial adhesion stage of biofilm development. AB - Staphylococcus aureus (S. aureus) biofilms are clinically serious and play a critical role in the persistence of chronic infections due to their ability to resist antibiotics. The inhibition of biofilm formation is viewed as a new strategy for the prevention of S. aureus infections. Here, we demonstrated that minimum inhibitory concentrations (MICs) of aloe-emodin exhibited no bactericidal activity against S. aureus but affected S. aureus biofilm development in a dose dependent manner. Further studies indicated that aloe-emodin specifically inhibits the initial adhesion and proliferation stages of S. aureus biofilm development. Scanning electron microscopy (SEM) indicated that the S. aureus ATCC29213 biofilm extracellular matrix is mainly composed of protein. Laser scanning confocal microscope assays revealed that aloe-emodin treatment primarily inhibited extracellular protein production. Moreover, the Congo red assay showed that aloe-emodin also reduced the accumulation of polysaccharide intercellular adhesin (PIA) on the cell surface. These findings will provide new insights into the mode of action of aloe-emodin in the treatment of infections by S. aureus biofilms. PMID- 28710560 TI - Pyrazinone derivatives from the coral-derived Aspergillus ochraceus LCJ11-102 under high iodide salt. AB - Five new pyrazin-2(1H)-one derivatives, ochramides A-D (1-4) and ochralate A (5), as well as three known analogues (6-8) were isolated from the fermentation broth of the marine coral-derived halotolerant Aspergillus ochraceus LCJ11-102 in a nutrient-limited medium containing 10% NaI. Their chemical structures were determined by analyzing NMR and X-ray diffraction data. Compounds 2, 5 and 6 showed antimicrobial activities against Enterobacter aerogenes with the MIC values of 40.0, 18.9, and 20.1 MUM, respectively. PMID- 28710561 TI - Genetic architecture of wild soybean (Glycine soja) response to soybean cyst nematode (Heterodera glycines). AB - The soybean cyst nematode (SCN) is one of the most destructive pathogens of soybean plants worldwide. Host-plant resistance is an environmentally friendly method to mitigate SCN damage. To date, the resistant soybean cultivars harbor limited genetic variation, and some are losing resistance. Thus, a better understanding of the genetic mechanisms of the SCN resistance, as well as developing diverse resistant soybean cultivars, is urgently needed. In this study, a genome-wide association study (GWAS) was conducted using 1032 wild soybean (Glycine soja) accessions with over 42,000 single-nucleotide polymorphisms (SNPs) to understand the genetic architecture of G. soja resistance to SCN race 1. Ten SNPs were significantly associated with the response to race 1. Three SNPs on chromosome 18 were localized within the previously identified quantitative trait loci (QTLs), and two of which were localized within a strong linkage disequilibrium block encompassing a nucleotide-binding (NB)-ARC disease resistance gene (Glyma.18G102600). Genes encoding methyltransferases, the calcium dependent signaling protein, the leucine-rich repeat kinase family protein, and the NB-ARC disease resistance protein, were identified as promising candidate genes. The identified SNPs and candidate genes can not only shed light on the molecular mechanisms underlying SCN resistance, but also can facilitate soybean improvement employing wild genetic resources. PMID- 28710562 TI - Significant and unique changes in phosphorylation levels of four phosphoproteins in two apple rootstock genotypes under drought stress. AB - Drought stress is a major problem around the world and there is still little molecular mechanism about how fruit crops deal with moderate drought stress. Here, the physiological and phosphoproteomic responses of drought-sensitive genotype (M26) and drought-tolerant genotype (MBB) under moderate drought stress were investigated. Our results of the physiology analysis indicated that the MBB genotype could produce more osmosis-regulating substances. Furthermore, phosphoproteins from leaves of both genotypes under moderate drought stress were analyzed using the isobaric tags for relative and absolute quantification technology. A total of 595 unique phosphopeptides, 682 phosphorylated sites, and 446 phosphoproteins were quantitatively analyzed in the two genotypes. Five and thirty-five phosphoproteins with the phosphorylation levels significantly changed (PLSC) were identified in M26 and MBB, respectively. Among these, four PLSC phosphoproteins were common to both genotypes, perhaps indicating a partial overlap of the mechanisms to moderate drought stress. Gene ontology analyses revealed that the PLSC phosphoproteins represent a unique combination of metabolism, transcription, translation, and protein processing, suggesting that the response in apple to moderate drought stress encompasses a new and unique homeostasis of major cellular processes. The basic trend was an increase in protein and organic molecules abundance related to drought. These increases were higher in MBB than in M26. Our study is the first to address the phosphoproteome of apple rootstocks in response to moderate drought stress, and provide insights into the molecular regulation mechanisms of apple rootstock under moderate drought stress. PMID- 28710563 TI - An observational study examining the effects of a surgically induced inflammatory response on the distribution of morphine and its metabolites into cerebrospinal fluid. AB - PURPOSE: Morphine is administered intravenously for pain management in the perioperative period. The effect of the inflammatory response to surgery on morphine distribution across the blood-brain barrier (BBB) in humans was investigated. We hypothesized that a graded surgically induced, systemic inflammatory response alters cerebrospinal fluid (CSF) levels of morphine, morphine-3-glucuronide (M3G), and morphine-6-glucuronide (M6G) through a temporary reduction in BBB drug efflux transporter function. METHODS: We conducted a prospective pharmacokinetic study of the plasma and CSF distribution of the P-glycoprotein (PGP) substrate morphine in 33 patients undergoing open thoracic (n = 18) or endovascular (n = 15) aortic aneurysm repair. Morphine was administered with induction of anesthesia and in the intensive care unit. Plasma and CSF concentrations of interleukin (IL)-6, morphine, M3G, M6G, and albumin were measured prior to surgery (baseline), during surgery, and postoperatively every six hours until removal of the CSF drain. The area under the curve (AUC) was determined for plasma and CSF IL-6, morphine, M3G, and M6G concentrations vs time. The primary endpoint measures were the correlations between the morphine, M6G, and M3G AUC CSF/plasma ratios and systemic inflammation as quantified by the time-normalized IL-6 exposure, which was calculated for each individual by dividing the total exposure (AUC) by time (t). A Bonferroni corrected P < 0.017 indicated a significant correlation. RESULTS: Plasma and CSF IL-6 concentrations increased postoperatively. The median [interquartile range] IL-6 exposures were significantly higher in the open vs endovascular surgical group for plasma (105 [40-256] pg.mL-1 vs 29 [16-70] pg.mL-1, respectively; P = 0.013) and CSF (79 [26 133] pg.mL-1 vs 16 [9-80] pg.mL-1, respectively; P = 0.013). For the primary endpoint, the plasma IL-6 AUC/t did not correlate with the CSF accumulation of morphine (r = -0.009; P = 0.96) or M3G (r = 0.37; P = 0.04) when corrected for surgical procedure, age, and sex. There were insufficient data on CSF concentration to complete the primary analysis for M6G. CONCLUSION: Morphine distribution into the CSF was not significantly altered in patients undergoing thoracic aortic aneurysm repair. This suggests that BBB PGP function may not be affected by the perioperative inflammatory response. TRIAL REGISTRATION: www.clinicaltrials.gov , NCT 00878371. Registered 7 April 2009. PMID- 28710564 TI - Psychological generators of stress-headaches. AB - Psychological stress triggers headaches, but how this happens is unclear. To explore this, 38 migraine sufferers, 28 with tension-type headache (T-TH) and 20 controls rated nausea, negative affect, task-expectancies and headache at 5-min intervals during an aversive 20-min mental arithmetic task with a fixed failure rate. Blood pressure and pulse rate were measured every 3 min and salivary cortisol was sampled before and after the task. Multiple regression analysis indicated that irritation, anxiety and the absence of sluggishness (i.e., alertness) independently predicted increases in headache intensity during the task (p < .001), but increases in headache were unrelated to changes in cardiovascular activity or cortisol. Changes that preceded headache onset were explored in repeated measures ANOVAs, comparing those who developed headache with those who did not. In general, nausea, negative affect and self-efficacy expectancies were higher in participants who went on to develop headache than in those who remained headache-free (p < .05 to p < .001). Together, these findings suggest that headache developed when participants overextended themselves during a stressful task, adopting an information processing style which impeded emotional adjustment to changing situational demands. Learning to modify perceptions of threat, and adopting a more flexible, less outcome-dependent processing style, might help to prevent headache from spiralling upward. PMID- 28710565 TI - Somatic symptom severity among primary care patients who are obese: examining the unique contributions of anxiety sensitivity, discomfort intolerance, and health anxiety. AB - Prior research indicates the common presentation of somatic symptoms and obesity in primary care settings, as well as links between obesity and somatic symptoms. Anxiety sensitivity, discomfort intolerance, and health anxiety are three variables relevant to somatic symptoms. How those three variables relate to somatic symptom severity among individuals who are obese and the unique variance accounted for by each variable in somatic symptom severity remains unexamined. Among a large sample of primary care patients who are obese (N = 342), anxiety sensitivity, discomfort intolerance, and health anxiety collectively accounted for 35% of variance in somatic symptom severity beyond the effects of sociodemographic variables, body mass index, medical morbidity, and depression severity. Health anxiety accounted for the largest amount of unique variance in somatic symptom severity, potentially supporting the relevance of health anxiety to the presentation of increased somatic symptoms among patients who are obese. PMID- 28710566 TI - Remarkable effects of imatinib in a family with young onset gastrointestinal stromal tumors and cutaneous hyperpigmentation associated with a germline KIT Trp557Arg mutation: case report and literature overview. AB - Gastrointestinal stromal tumors (GISTs) occur mostly sporadically. GISTs associated with a familial syndrome are very rare and are mostly wild type for KIT and platelet-derived growth factor alpha (PDGFRA). To date 35 kindreds and 8 individuals have been described with GISTs associated with germline KIT mutations. This is the third family described with a germline p.Trp557Arg mutation in exon 11 of the KIT gene. The effect of imatinib in patients harboring a germline KIT mutation has been rarely described. Moreover, in some studies imatinib treatment was withheld considering the lack of evidence for efficacy of this treatment in GIST patients harboring a germline KIT mutation. This paper describes a 52-year old patient with a de novo germline p.Trp557Arg mutation with multiple GISTs throughout the gastrointestinal tract and cutaneous hyperpigmentation. Imatinib treatment showed long-term regression of the GISTs and evident pathological response was seen after resection. Remarkably, the hyperpigmentation of the skin also diminished during imatinib treatment. Genetic screening of the family revealed the same mutation in two daughters, both with similar cutaneous hyperpigmentation. One daughter, aged 23, was diagnosed with multiple small intestine GISTs, which were resected. She was treated with adjuvant imatinib which prompted rapid regression of the cutaneous hyperpigmentation. Imatinib treatment in GIST patients harboring a germline KIT mutation shows favorable and long-term responses in both the tumor and the phenotypical hyperpigmentation. PMID- 28710567 TI - Threatened fish and fishers along the Brazilian Atlantic Forest Coast. AB - Small-scale fisheries of the Brazilian Atlantic Forest Coast (BAFC) depend on fish resources for food and income. Thus, if the catch diminishes or if fish species that are a target for fishers are overexploited or impacted, this could affect fishers' livelihoods. The exclusion of threatened fish species from the catch is believed to be a threat to small-scale fisheries, which is likely to be the case along the BAFC. Many fish species are currently listed as threatened or vulnerable, whereas there is not enough biological information available to determine the status of the majority of the other species. Failure to protect the BAFC biodiversity might negatively impact fishers' income and the regional economy of local small-scale fisheries. We collected data from 1986 to 2009 through 347 interviews and 24-h food recall surveys at seven southeastern coastal sites of the Atlantic Forest. We show that important species of consumed fish are currently threatened: of the 65 species mentioned by fishers as the most consumed fishes, 33% are decreasing and 54% have an unknown status. Thus, biological and ecological data for BAFC marine species are urgently needed, along with co management, to promote fish conservation. PMID- 28710568 TI - Microbial community analysis of simultaneous ammonium removal and Fe3+ reduction at different influent ammonium concentrations. AB - This study investigates the impacts of influent ammonium concentrations on the microbial community in immobilized heterotrophic ammonium removal system. Klebsiella sp. FC61, the immobilized species, has the ability to perform simultaneous ammonium removal and Fe3+ reduction. It was found that average ammonium removal rate decreased from 0.308 to 0.157 mg/L/h, as the influent NH4+ N was reduced from 20 to 10 mg/L. Meanwhile, at a total Fe3+ concentration of 20 mg/L, the average Fe3+ reduction removal efficiency and rate decreased from 44.61% and 0.18 mg/L/h, to 27.10% and 0.11 mg/L/h, respectively. High-throughput sequencing was used to observe microbial communities in bioreactor Samples B1, B2, and B3, after exposure to different influent NH4+-N conditions. Results show that higher influent NH4+-N concentrations increased microbial richness and diversity and that Klebsiella sp. FC61 play a functional role in the simultaneous removal of NH4+-N and Fe3+ reduction in bioreactor systems. PMID- 28710569 TI - Low-shear-modeled microgravity-grown Penicillium chrysogenum-mediated biosynthesis of silver nanoparticles with enhanced antimicrobial activity and its anticancer effect in human liver cancer and fibroblast cells. AB - Gravitational force and shear forces induce various changes in gene expression and metabolite production of microorganisms. Previous reports have shown that there are differences in the expression of different sets of proteins and enzymes under microgravity conditions compared to normal gravity. The aim of this study is to utilize culture filtrates of Penicillium chrysogenum grown under microgravity and normal conditions to synthesize silver nanoparticles and to examine whether there is any difference between their physiochemical and biological function. Synthesized nanoparticles were characterized using UV-Vis spectroscopy, FTIR, XRD, and TEM. Biological functional studies such as antimicrobial activity, cytotoxic studies, and anticancer activity were carried out. Antimicrobial activity was tested using antibiotic susceptibility testing by Kirby-Bauer method and cytotoxicity tests were carried out using 3T3-L1 normal fibroblasts cells and Hep-G2 cancer cell lines. Interestingly, our results indicated that microgravity-synthesized silver nanoparticles possess enhanced antibacterial activity and cytotoxic effect against cancer cells compared to normal gravity-synthesized silver nanoparticle. This work highlighted the importance of gravitational vector on the fungal enzyme profiles and their role in silver nanoparticle synthesis with enhanced biological activity. PMID- 28710570 TI - A methoxyflavanone derivative from the Asian medicinal herb (Perilla frutescens) induces p53-mediated G2/M cell cycle arrest and apoptosis in A549 human lung adenocarcinoma. AB - Perilla frutescens is an Asian dietary herb consumed as an essential seasoning in Japanese cuisine as well as used for a Chinese medicine. Here, we report that a newly found methoxyflavanone derivative from P. frutescens (Perilla-derived methoxyflavanone, PDMF; 8-hydroxy-5,7-dimethoxyflavanone) shows carcinostatic activity on human lung adenocarcinoma, A549. We found that treatment with PDMF significantly inhibited cell proliferation and decreased viability through induction of G2/M cell cycle arrest and apoptosis. The PDMF stimulation induces phosphorylation of tumor suppressor p53 on Ser15, and increases its protein amount in conjunction with up-regulation of downstream cyclin-dependent kinase inhibitor p21Cip1/Waf1 and proapoptotic caspases, caspase-9 and caspase-3. We also found that small interfering RNA knockdown of p53 completely abolished the PDMF-induced G2/M cell cycle arrest, and substantially abrogated its proapoptotic potency. These results suggest that PDMF represents a useful tumor-preventive phytochemical that triggers p53-driven G2/M cell cycle arrest and apoptosis. PMID- 28710571 TI - Thermodynamic DFT analysis of natural gas. AB - Density functional theory was performed for thermodynamic predictions on natural gas, whose B3LYP/6-311++G(d,p), B3LYP/6-31+G(d), CBS-QB3, G3, and G4 methods were applied. Additionally, we carried out thermodynamic predictions using G3/G4 averaged. The calculations were performed for each major component of seven kinds of natural gas and to their respective air + natural gas mixtures at a thermal equilibrium between room temperature and the initial temperature of a combustion chamber during the injection stage. The following thermodynamic properties were obtained: internal energy, enthalpy, Gibbs free energy and entropy, which enabled us to investigate the thermal resistance of fuels. Also, we estimated an important parameter, namely, the specific heat ratio of each natural gas; this allowed us to compare the results with the empirical functions of these parameters, where the B3LYP/6-311++G(d,p) and G3/G4 methods showed better agreements. In addition, relevant information on the thermal and mechanic resistance of natural gases were investigated, as well as the standard thermodynamic properties for the combustion of natural gas. Thus, we show that density functional theory can be useful for predicting the thermodynamic properties of natural gas, enabling the production of more efficient compositions for the investigated fuels. Graphical abstract Investigation of the thermodynamic properties of natural gas through the canonical ensemble model and the density functional theory. PMID- 28710572 TI - Tuning the electronic and optical properties of NDT-based conjugated polymers by adopting fused heterocycles as acceptor units: a theoretical study. AB - Donor-acceptor conjugated polymers have been successfully applied in bulk heterojunction solar cell devices. Tuning their donor and acceptor units allows the design of new polymers with desired electronic and optical properties. Here, to screen new candidate polymers based on a newly synthesized donor unit, dithieo[2,3-d:2',3'-d']naphtho[1,2-b:3,4-b']dithiophene (NDT), a series of model polymers with different acceptor units were designed and denoted NDT-A0 to NDT A12, and the structures and optical properties of those polymers were investigated using DFT and TDDFT calculations. The results of the calculations revealed that the electronic and optical properties of these polymers depend on the acceptor unit present; specifically, their HOMO energies ranged from -4.89 to -5.38 eV, their HOMO-LUMO gaps ranged from 1.30 to 2.80 eV, and their wavelengths of maximum absorption ranged from 538 to 1212 nm. The absorption spectra of NDT A1 to NDT-A6, NDT-A8, NDT-A9, and NDT-A12 occur within the visible region (<900 nm), indicating that these polymers are potential candidates for use in solar cells. On the other hand, the absorption spectra of NDT-A7, NDT-A10, and NDT-A11 extend much further into the near-infrared region, implying that they absorb near infrared light. These polymers could meet the requirements of donor units for use in tandem and ternary solar cells. Graphical abstract Theoretical calculations by TD-DFT reveal that the optical properties of NDT-based conjugated polymers can be well tuned by adopting different acceptor units, and these ploymers are potential donor materials for tandem and ternary solar cells. PMID- 28710573 TI - Sutureless inguinal hernia repair with creation of a peritoneal lesion in children: a novel laparoscopic technique with a low recurrence rate. AB - BACKGROUND: Hernia repair represents about 25% of all pediatric surgeries. Repair can be done using an open or laparoscopic technique. The open approach has a reported recurrence rate of 1.2% but requires an additional incision to repair for a contralateral hernia. With the laparoscopic approach, no additional incision is needed but the recurrence rate has been reported to be as high as 4%. The objective of this study was to assess the safety and efficacy of a novel sutureless laparoscopic inguinal hernia repair that has the advantages of both approaches. METHODS: Since April 2014 up to March 2017, 26 children (12 girls and 14 boys) aged 3 months to 13 years underwent sutureless laparoscopic inguinal hernia repair. The peritoneum around the internal inguinal ring was severed and folded into the inguinal canal. Regeneration of the peritoneum around the inguinal ring creates a scar that effectively closes the internal orifice. RESULTS: No recurrences or complications were observed in any of the 26 cases after a follow-up of 1-35 months (median, 14 months). CONCLUSIONS: Sutureless laparoscopic inguinal hernia repair provides a new option for the management of patients with a pediatric inguinal hernia. The procedure does not require advanced laparoscopic skills, is easily reproducible, and is safe. THERAPEUTIC STUDY: Level of Evidence IV. PMID- 28710574 TI - Sleep, Depression, and Burnout in Medical Students: Risk Assessment. PMID- 28710575 TI - Software-based risk stratification of pulmonary adenocarcinomas manifesting as pure ground glass nodules on computed tomography. AB - OBJECTIVES: To assess the performance of the "Computer-Aided Nodule Assessment and Risk Yield" (CANARY) software in the differentiation and risk assessment of histological subtypes of lung adenocarcinomas manifesting as pure ground glass nodules on computed tomography (CT). METHODS: 64 surgically resected and histologically proven adenocarcinomas manifesting as pure ground-glass nodules on CT were assessed using CANARY software, which classifies voxel-densities into three risk components (low, intermediate, and high risk). Differences in risk components between histological adenocarcinoma subtypes were analysed. To determine the optimal threshold reflecting the presence of an invasive focus, sensitivity, specificity, negative predictive value, and positive predictive value were calculated. RESULTS: 28/64 (44%) were adenocarcinomas in situ (AIS); 26/64 (41%) were minimally invasive adenocarcinomas (MIA); and 10/64 (16%) were invasive ACs (IAC). The software showed significant differences in risk components between histological subtypes (P<0.001-0.003). A relative volume of 45% or less of low-risk components was associated with histological invasiveness (specificity 100%, positive predictive value 100%). CONCLUSIONS: CANARY-based risk assessment of ACs manifesting as pure ground glass nodules on CT allows the differentiation of their histological subtypes. A threshold of 45% of low-risk components reflects invasiveness in these groups. KEY POINTS: * CANARY-based risk assessment allows the differentiation of their histological subtypes. * 45% or less of low-risk component reflects histological invasiveness. * CANARY has potential role in suspected adenocarcinomas manifesting as pure ground-glass nodules. PMID- 28710576 TI - The effect of iodine uptake on radiation dose absorbed by patient tissues in contrast enhanced CT imaging: Implications for CT dosimetry. AB - OBJECTIVES: To investigate the effect of iodine uptake on tissue/organ absorbed doses from CT exposure and its implications in CT dosimetry. METHODS: The contrast-induced CT number increase of several radiosensitive tissues was retrospectively determined in 120 CT examinations involving both non-enhanced and contrast-enhanced CT imaging. CT images of a phantom containing aqueous solutions of varying iodine concentration were obtained. Plots of the CT number increase against iodine concentration were produced. The clinically occurring iodine tissue uptake was quantified by attributing recorded CT number increase to a certain concentration of aqueous iodine solution. Clinically occurring iodine uptake was represented in mathematical anthropomorphic phantoms. Standard 120 kV CT exposures were simulated using Monte Carlo methods and resulting organ doses were derived for non-enhanced and iodine contrast-enhanced CT imaging. RESULTS: The mean iodine uptake range during contrast-enhanced CT imaging was found to be 0.02-0.46% w/w for the investigated tissues, while the maximum value recorded was 0.82% w/w. For the same CT exposure, iodinated tissues were found to receive higher radiation dose than non-iodinated tissues, with dose increase exceeding 100% for tissues with high iodine uptake. CONCLUSIONS: Administration of iodinated contrast medium considerably increases radiation dose to tissues from CT exposure. KEY-POINTS: * Radiation absorption ability of organs/tissues is considerably affected by iodine uptake * Iodinated organ/tissues may absorb up to 100 % higher radiation dose * Compared to non-enhanced, contrast-enhanced CT may deliver higher dose to patient tissues * CT dosimetry of contrast-enhanced CT imaging should encounter tissue iodine uptake. PMID- 28710577 TI - Detection of small-bowel tumours with CT enteroclysis using carbon dioxide and virtual enteroscopy: A preliminary study. AB - PURPOSE: The aim of this prospective study was to evaluate the feasibility, tolerance and performance of virtual enteroscopy (VE) using carbon dioxide for small-bowel distension in patients with suspected small-bowel tumours (SBTs). PATIENTS AND METHODS: After IRB approval, 17 patients with suspected SBTs were prospectively included. Radiation dose was compared to 34 matched patients (2 for 1) for age, gender and body weight, who had undergone CT-enteroclysis with neutral contrast (CTE). Performance of VE was evaluated through comparison with the current standard of reference, including surgery and/or enteroscopy and/or follow-up. RESULTS: Tolerance was excellent in 16/17 patients (94%). The radiation dose was lower for VE than for CTE (533 +/- 282 vs. 974 +/- 505 mGy.cm; p = 0.002). With VE, a total of 25 polyps >5 mm in size were depicted in 12/17 patients. On a per-lesion analysis, sensitivity and positive predictive value of VE were 92.0% and 92.0%, respectively. On a per-segment analysis VE had a sensitivity and specificity of 95.0% and 87.0%, respectively. CONCLUSION: Our preliminary study suggests that VE is a feasible and well-tolerated technique with high sensitivity and specificity for the diagnosis of SBT. KEY POINTS: * Virtual enteroscopy is feasible and well tolerated. * Virtual enteroscopy appears to be accurate for detection of small-bowel tumours. * Sensitivity and PPV of virtual enteroscopy is 92.0% and 92.0%. * Radiation dose is lower with virtual enteroscopy compared to MDCT-enteroclysis. PMID- 28710578 TI - Four-dimensional flow MRI of stented versus stentless aortic valve bioprostheses. AB - OBJECTIVES: To evaluate aortic velocity, wall shear stress (WSS) and viscous energy loss (EL) of stented and stentless bioprostheses using 4D flow MRI 1 year after surgical aortic valve replacement. METHODS: For this cross-sectional study 28 patients with stented (n = 14) or stentless (n = 14) bioprosthesis underwent non-contrast-enhanced 4D-flow MRI at 1.5 T. Analyses included a comparison of velocity, WSS and EL in the ascending aorta during peak systole for both spatially averaged values and a comparison of local differences using per-voxel analysis. RESULTS: No significant differences were found in peak and mean velocity (stented vs. stentless: 2.45 m/s vs. 2.11 m/s; p = 0.09 and 0.60 m/s vs. 0.62 m/s; p = 0.89), WSS (0.60 Pa vs. 0.59 Pa; p = 0.55) and EL (10.17 mW vs. 7.82 mW; p = 0.10). Per-voxel analysis revealed significantly higher central lumen velocity, and lower outer lumen velocity, WSS and EL for stentless versus stented prostheses. CONCLUSION: One year after aortic valve implantation with stented and stentless bioprostheses, velocity, WSS and EL were comparable when assessed for averaged values in the ascending aorta. However, the flow profile described with local analysis for stentless prosthesis is potentially favourable with a significantly higher central velocity profile and lower values for outer lumen velocity, WSS and EL. KEY POINTS: * Stentless bioprostheses can be implanted instead of stented aortic valve bioprostheses. * Haemodynamic performance of valve prosthesis can be assessed using 4D flow MRI. * Averaged ascending aorta PSV, WSS and EL are comparable 1 year post-implantation. * Centreline velocity is highest, WSS and EL is lowest for stentless prosthesis. PMID- 28710579 TI - Magnetic resonance neurography: current perspectives and literature review. AB - : Magnetic resonance neurography (also called MRN or MR neurography) refers to MR imaging dedicated to the peripheral nerves. It is a technique that enhances selective multiplanar visualisation of the peripheral nerve and pathology by encompassing a combination of two-dimensional, three-dimensional and diffusion imaging pulse sequences. Referring physicians who seek imaging techniques that can depict and diagnose peripheral nerve pathologies superior to conventional MR imaging are driving the demand for MRN. This article reviews the pathophysiology of peripheral nerves in common practice scenarios, technical considerations of MRN, current indications of MRN, normal and abnormal neuromuscular appearances, and imaging pitfalls. Finally, the emerging utility of diffusion-weighted and diffusion tensor imaging is discussed and future directions are highlighted. KEY POINTS: * Lesion relationship to neural architecture is more conspicuous on MRN than MRI. * 3D multiplanar imaging technique is essential for pre-surgical planning. * Nerve injuries can be classified on MRN using Sunderland's classification. * DTI provides quantitative information and insight into intraneural integrity and pathophysiology. PMID- 28710580 TI - Assessment of acute kidney injury with T1 mapping MRI following solid organ transplantation. AB - OBJECTIVES: To evaluate T1 mapping as a non-invasive, functional MRI biomarker in patients shortly after solid organ transplantation to detect acute postsurgical kidney damage and to correlate T1 times with renal function. METHODS: 101 patients within 2 weeks after solid organ transplantation (49 kidney transplantation, 52 lung transplantation) and 14 healthy volunteers were examined by MRI between July 2012 and April 2015 using the modified Look-Locker inversion recovery (MOLLI) sequence. T1 times in renal cortex and medulla and the corticomedullary difference were compared between groups using one-way ANOVA adjusted for multiple comparison with the Tukey test, and T1 times were correlated with renal function using Pearson's correlation. RESULTS: Compared to healthy volunteers T1 times were significantly increased after solid organ transplantation in the renal cortex (healthy volunteers 987 +/- 102 ms; kidney transplantation 1299 +/- 101 ms, p < 0.001; lung transplantation 1058 +/- 96 ms, p < 0.05) and to a lesser extent in the renal medulla. Accordingly, the corticomedullary difference was diminished shortly after solid organ transplantation. T1 changes were more pronounced following kidney compared to lung transplantation, were associated with the stage of renal impairment and significantly correlated with renal function. CONCLUSIONS: T1 mapping may be helpful for early non-invasive assessment of acute kidney injury and renal pathology following major surgery such as solid organ transplantation. KEY POINTS: * Renal cortical T1 relaxation times are prolonged after solid organ transplantation. * Cortical T1 values increase with higher stages of renal function impairment. * Corticomedullary difference decreases with higher stages of renal function impairment. * Renal cortical T1 relaxation time and corticomedullary difference correlate with renal function. * T1 mapping may be helpful for non-invasive assessment of post-operative renal pathology. PMID- 28710581 TI - Validation of a model for predicting smear-positive active pulmonary tuberculosis in patients with initial acid-fast bacilli smear-negative sputum. AB - OBJECTIVES: The objective of this study was to develop a predictive model for final smear-positive (SP) active pulmonary tuberculosis (aPTB) in patients with initial negative acid fast bacilli (AFB) sputum smears (iSN-SP-aPTB) based on high-resolution computed tomography (HRCT). METHOD AND MATERIALS: Eighty (126, 21) patients of iSN-SP-aPTB and 402 (459, 876) patients of non-initial positive acid fast bacilli (non-iSP) pulmonary disease without iSN-SP-aPTB were included in a derivation (validation, prospective) cohort. HRCT characteristics were analysed, and multivariable regression and receiver operating characteristic (ROC) curve analysis was performed to develop a score predictive of iSN-SP-aPTB. RESULTS: The derivation cohort showed clusters of nodules/mass of the right upper lobe or left upper lobe were independent predictors of iSN-SP-aPTB, while bronchiectasis in the right middle lobe or left lingual lobe were negatively associated with iSN-SP-aPTB. A predictive score for iSN-SP-aPTB based on these findings was tested in the validation and prospective cohorts. With an ideal cut off score = 1, the sensitivity, specificity, positive predictive value, and negative predictive value of the prediction model were 87.5% (90%, 90.5%), 99% (97.1%, 98.4%), 94.6% (81.3%, 57.5%), and 97.6% (97%, 99.8%) in the derivation (validation, prospective) cohorts, respectively. CONCLUSIONS: The model may help identify iSN-SP-aPTB among patients with non-iSP pulmonary diseases. KEY POINTS: * Smear-positive active pulmonary tuberculosis that is initial smear-negative (iSN-SP-aPTB) is infectious. * High-resolution computed tomography can identify iSN-SP-aPTB among non-iSP pulmonary diseases. * Clusters nodules/mass in right/left upper lobe are positively associated with iSN-SP-aPTB. * Bronchiectasis in right middle/left lingual lobe is negatively associated with iSN-SP-aPTB. * The model may have high post-test probability in identifying iSN SP-aPTB. PMID- 28710582 TI - Comparison of digital mammography and digital breast tomosynthesis in the detection of architectural distortion. AB - OBJECTIVES: To compare interobserver variability (IOV), reader confidence, and sensitivity/specificity in detecting architectural distortion (AD) on digital mammography (DM) versus digital breast tomosynthesis (DBT). METHODS: This IRB approved, HIPAA-compliant reader study used a counterbalanced experimental design. We searched radiology reports for AD on screening mammograms from 5 March 2012-27 November 2013. Cases were consensus-reviewed. Controls were selected from demographically matched non-AD examinations. Two radiologists and two fellows blinded to outcomes independently reviewed images from two patient groups in two sessions. Readers recorded presence/absence of AD and confidence level. Agreement and differences in confidence and sensitivity/specificity between DBT versus DM and attendings versus fellows were examined using weighted Kappa and generalised mixed modeling, respectively. RESULTS: There were 59 AD patients and 59 controls for 1,888 observations (59 * 2 (cases and controls) * 2 breasts * 2 imaging techniques * 4 readers). For all readers, agreement improved with DBT versus DM (0.61 vs. 0.37). Confidence was higher with DBT, p = .001. DBT achieved higher sensitivity (.59 vs. .32), p < .001; specificity remained high (>.90). DBT achieved higher positive likelihood ratio values, smaller negative likelihood ratio values, and larger ROC values. CONCLUSIONS: DBT decreases IOV, increases confidence, and improves sensitivity while maintaining high specificity in detecting AD. KEY POINTS: * Digital breast tomosynthesis decreases interobserver variability in the detection of architectural distortion. * Digital breast tomosynthesis increases reader confidence in the detection of architectural distortion. * Digital breast tomosynthesis improves sensitivity in the detection of architectural distortion. PMID- 28710585 TI - Memorial address for Carlos M. G. Duran, M.D., Ph.D. PMID- 28710583 TI - Prototype metal artefact reduction algorithm in flat panel computed tomography - evaluation in patients undergoing transarterial hepatic radioembolisation. AB - OBJECTIVE: To investigate the effect of an on-site prototype metal artefact reduction (MAR) algorithm in cone-beam CT-catheter-arteriography (CBCT-CA) in patients undergoing transarterial radioembolisation (RE) of hepatic masses. METHODS AND MATERIALS: Ethical board approved retrospective study of 29 patients (mean 63.7+/-13.7 years, 11 female), including 16 patients with arterial metallic coils, undergoing CBCT-CA (8s scan, 200 degrees rotation, 397 projections). Image reconstructions with and without prototype MAR algorithm were evaluated quantitatively (streak-artefact attenuation changes) and qualitatively (visibility of hepatic parenchyma and vessels) in near- (<1cm) and far-field (>3cm) of artefact sources (metallic coils and catheters). Quantitative and qualitative measurements of uncorrected and MAR corrected images and different artefact sources were compared RESULTS: Quantitative evaluation showed significant reduction of near- and far-field streak-artefacts with MAR for both artefact sources (p<0.001), while remaining stable for unaffected organs (all p>0.05). Inhomogeneities of attenuation values were significantly higher for metallic coils compared to catheters (p<0.001) and decreased significantly for both after MAR (p<0.001). Qualitative image scores were significantly improved after MAR (all p<0.003) with by trend higher artefact degrees for metallic coils compared to catheters. CONCLUSION: In patients undergoing CBCT-CA for transarterial RE, prototype MAR algorithm improves image quality in proximity of metallic coil and catheter artefacts. KEY POINTS: * Metal objects cause artefacts in cone-beam computed tomography (CBCT) imaging. * These artefacts can be corrected by metal artefact reduction (MAR) algorithms. * Corrected images show significantly better visibility of nearby hepatic vessels and tissue. * Better visibility may facilitate image interpretation, save time and radiation exposure. PMID- 28710584 TI - Associations between sun exposure and other lifestyle variables in Swedish women. AB - PURPOSE: Sun exposure is associated with risk of several chronic diseases including cancer. The study aim is to investigate whether sun behaviors are related to other lifestyle risk factors of cancer. METHODS: We analyzed data collected in 2003-2004 by self-completed questionnaire from 34,402 Swedish women aged 40-61 years, who comprised 70% of a cohort of originally recruited from a population registry in 1991-1992 (n = 49,259). Participants were asked about annual number of sunburns and annual number of weeks of swimming and sunbathing during 1991-2002, solarium use during 1991-1998 and current sunscreen use. RESULTS: Compared to non-drinkers, the prevalence ratio (95% CI) in women who drank >10 g of alcohol per day was 1.64 (1.49, 1.81) for having >1 sunburn per year, 1.39 (1.29, 1.51) for swimming and sunbathing >2.5 weeks per year and 1.55 (1.41, 1.70) for using a solarium >1 time per 2 months, adjusting for demographic and lifestyle variables. Tobacco smokers were less likely to report sunburn and to use sunscreen, and more likely to sunbath and use solaria, compared with non smokers. Physical activity was associated positively with swimming and sunbathing, and with the separate use of solaria and sunscreens, but not with number of sunburns. The lifestyle variables that explained most of the variation in sun behavior were alcohol and smoking. CONCLUSIONS: Our results suggest that alcohol consumption and tobacco smoking are potential lifestyle confounders which should be adjusted in studies investigating the association that sun and/or solarium exposure may have with risk of several cancer sites. PMID- 28710586 TI - Bud sprouting and floral induction and expression of FT in loquat [Eriobotrya japonica (Thunb.) Lindl.]. AB - MAIN CONCLUSION: EjFT1 and EjFT2 genes were isolated and sequenced from leaves of loquat. EjFT1 is involved in bud sprouting and leaf development, and EjFT2 in floral bud induction. Loquat [Eriobotrya japonica (Thunb.) Lindl.] is an evergreen species belonging to the family Rosaceae, such as apple and pear, whose reproductive development, in contrast with these species, is a continuous process that is not interrupted by winter dormancy. Thus, the study of the mechanism of flowering in loquat has the potential to uncover the environmental and genetic networks that trigger flowering more accurately, contributing for a better understanding of the Rosaceae floral process. As a first step toward understanding the molecular mechanisms controlling flowering, extensive defoliation and defruiting assays, together with molecular studies of the key FLOWERING LOCUS T (FT) gene, were carried out. FT exhibited two peaks of expression in leaves, the first one in early to mid-May, the second one in mid June. Two FT genes, EjFT1 and EjFT2, were isolated and sequenced and studied their expression. Expression of EjFT1 and EjFT2 peaks in mid-May, at bud sprouting. EjFT2 expression peaks again in mid-June, coinciding with the floral bud inductive period. Thus, when all leaves of the tree were continuously removed from early to late May vegetative apex differentiated into panicle, but when defoliation was performed from early to late June apex did not differentiate. On the other hand, fruit removal advanced EjFT1 expression in old leaves and the sooner the fruit detached, the sooner the bud sprouted. Accordingly, results strongly suggest that EjFT1 might be related to bud sprouting and leaf development, while EjFT2 might be involved in floral bud induction. An integrative model for FT functions in loquat is discussed. PMID- 28710587 TI - Characterization of the sulfur-formation (suf) genes in Synechocystis sp. PCC 6803 under photoautotrophic and heterotrophic growth conditions. AB - MAIN CONCLUSION: The sulfur-formation ( suf ) genes play important roles in both photosynthesis and respiration of cyanobacteria, but the organism prioritizes Fe S clusters for respiration at the expense of photosynthesis. Iron-sulfur (Fe-S) clusters are important to all living organisms, but their assembly mechanism is poorly understood in photosynthetic organisms. Unlike non-photosynthetic bacteria that rely on the iron-sulfur cluster system, Synechocystis sp. PCC 6803 uses the Sulfur-Formation (SUF) system as its major Fe-S cluster assembly pathway. The co expression of suf genes and the direct interactions among SUF subunits indicate that Fe-S assembly is a complex process in which no suf genes can be knocked out completely. In this study, we developed a condition-controlled SUF Knockdown mutant by inserting the petE promoter, which is regulated by Cu2+ concentration, in front of the suf operon. Limited amount of the SUF system resulted in decreased chlorophyll contents and photosystem activities, and a lower PSI/PSII ratio. Unexpectedly, increased cyclic electron transport and a decreased dark respiration rate were only observed under photoautotrophic growth conditions. No visible effects on the phenotype of SUF Knockdown mutant were observed under heterotrophic culture conditions. The phylogenetic distribution of the SUF system indicates that it has a co-evolutionary relationship with photosynthetic energy storing pathways. PMID- 28710589 TI - Primary Care Physician Perspectives on Barriers to Statin Treatment. AB - PURPOSE: Discontinuation of statin therapy represents a major challenge for effective cardiovascular disease prevention. It is unclear how often primary care physicians (PCPs) re-initiate statins and what barriers they encounter. We aimed to identify PCP perspectives on factors influencing statin re-initiation. METHODS: We conducted six nominal group discussions with 23 PCPs from the Deep South Continuing Medical Education network. PCPs answered questions about statin side effects, reasons their patients reported for discontinuing statins, how they respond when discontinuation is reported, and barriers they encounter in getting their patients to re-initiate statin therapy. Each group generated a list of responses in round-robin fashion. Then, each PCP independently ranked their top three responses to each question. For each PCP, the most important reason was given a weight of 3 votes, and the second and third most important reasons were given weights of 2 and 1, respectively. We categorized the individual responses into themes and determined the relative importance of each theme using a "percent of available votes" metric. RESULTS: PCPs reported that side effects, especially muscle/joint-related symptoms, were the most common reason patients reported for statin discontinuation (47% of available votes). PCPs reported statin re challenge as their most common response when a patient discontinues statin use (31% of available votes). Patients' fear of side effects was ranked as the biggest challenge PCPs encounter in getting their patients to re-initiate statin therapy (70% of available votes). CONCLUSION: PCPs face challenges getting their patients to re-initiate statins, particularly after a patient reports side effects. PMID- 28710588 TI - Identification and molecular characterization of a trans-acting small interfering RNA producing locus regulating leaf rust responsive gene expression in wheat (Triticum aestivum L.). AB - MAIN CONCLUSION: A novel leaf rust responsive ta-siRNA-producing locus was identified in wheat showing similarity to 28S rRNA and generated four differentially expressing ta-siRNAs by phasing which targeted stress responsive genes. Trans-acting-small interfering RNAs (Ta-siRNAs) are plant specific molecules generally involved in development and are also stress responsive. Ta siRNAs identified in wheat till date are all responsive to abiotic stress only. Wheat cultivation is severely affected by rusts and leaf rust particularly affects grain filling. This study reports a novel ta-siRNA producing locus (TAS) in wheat which is a segment of 28S ribosomal RNA but shows differential expression during leaf rust infestation. Four small RNA libraries prepared from wheat Near Isogenic Lines were treated with leaf rust pathogen and compared with untreated controls. A TAS with the ability to generate four ta-siRNAs by phasing events was identified along with the microRNA TamiR16 as the phase initiator. The targets of the ta-siRNAs included alpha-gliadin, leucine rich repeat, trans membrane proteins, glutathione-S-transferase, and fatty acid desaturase among others, which are either stress responsive genes or are essential for normal growth and development of plants. Expression of the TAS, its generated ta-siRNAs, and their target genes were profiled at five different time points after pathogen inoculation of susceptible and resistant wheat isolines and compared with mock inoculated controls. Comparative analysis of expression unveiled differential and reciprocal relationship as well as discrete patterns between susceptible and resistant isolines. The expression profiles of the target genes of the identified ta-siRNAs advocate more towards effector triggered susceptibility favouring pathogenesis. The study helps in discerning the functions of wheat genes regulated by ta-siRNAs in response to leaf rust. PMID- 28710590 TI - The Relationship of Children's Intelligence Quotient and Blood Lead and Zinc Levels: a Meta-analysis and System Review. AB - The purpose of this study was to analyze the existing studies and to investigate the relationship between children's full-scale intelligence quotient (FIQ), verbal IQ (VIQ), and performance IQ (PIQ) and their blood lead (Pb) and zinc (Zn) levels. All documents in Chinese and English were collected from the PubMed, Web of Science, and Chinese National Knowledge Infrastructure (CNKI) databases from inception date to December 30, 2016. RevMan software (version 5.2) was used for the meta-analysis and Stata software (version 12.0) for the meta-regression and sensitivity analyses. A total of 32 eligible literatures was included in the study. Seven prevalence studies showed that the blood Pb level was negatively correlated with children's IQ. The results of the meta-analysis from 22 case control studies indicate a significant difference between FIQ and PIQ with blood Pb levels, detailed as the FIQ score with a weighted mean difference (WMD) = 6.60 (95% CI: -9.01, -4.20), P < 0.001; PIQ WMD = -8.85 (95% CI: -12.651, -5.05), P < 0.001; but VIQ WMD = -3.32 (95% CI: -6.98, 0.33), P > 0.05. Three studies on the blood Zn concentrations were with a FIQ WMD = 7.88 (95% CI: -0.07, 15.83), VIQ WMD = 7.73 (95% CI: -7.40, 22.86), and PIQ WMD = 6.69 (95% CI: -7.13, 20.51), all P > 0.05. The results indicate that Pb is harmful to children's intelligence development, especially in PIQ. Zn is beneficial to intelligence, although more studies are needed. PMID- 28710591 TI - Effect of Dietary Phytase Supplementation on Bone and Hyaline Cartilage Development of Broilers Fed with Organically Complexed Copper in a Cu-Deficient Diet. AB - Tibial mechanical, chemical, and histomorphometrical traits were investigated for growing male Ross 308 broiler chickens fed diets that had copper (Cu) from organic source at a lowered level of 25% of the daily requirement (4 mg kg-1 of a premix) with or without phytase. Dietary treatments were control non-copper, non phytase group (0 Suppl); 4 mg kg-1 Cu non-phytase group (25%Cu); and 4 mg kg-1 Cu + 500 FTU kg-1 phytase group (25%Cu + phyt). The results show that birds fed with the addition of phytase exhibited improved weight gain and final body weight and had increased serum IGF-1 and osteocalcin concentrations. The serum concentration of Cu and P did not differ between groups; however, Ca concentration decreased in the 25%Cu + phyt group when compared to the 25%Cu group. Added Cu increased bone Ca, P, Cu, and ash content in Cu-supplemented groups, but bone weight and length increased only by the addition of phytase. Bone geometry, yield, and ultimate strengths were affected by Cu and phytase addition. A decrease of the elastic stress and ultimate stress of the tibia in Cu-supplemented groups was observed. The histomorphometric analysis showed a positive effect of Cu supplementation on real bone volume and trabecular thickness in the tibia metaphyseal trabeculae; additionally, phytase increased the trabeculea number. The supplementation with Cu significantly increased the total articular cartilage and growth plate cartilage thickness; however, the changes in thickness of particular zones were dependent upon phytase addition. In summary, dietary Cu supplements given to growing broilers with Cu in their diet restricted to 25% of the daily requirement had a positive effect on bone metabolism, and phytase supplementation additionally improved cartilage development. PMID- 28710593 TI - Gastric Band Migration Causing Jejunal Obstruction: a Life-Threatening Complication. PMID- 28710592 TI - Shame on Me! Self-Conscious Emotions and Big Five Personality Traits and Their Relations to Anxiety Disorders Symptoms in Young, Non-Clinical Adolescents. AB - This study explored the relations between self-conscious emotions, personality traits, and anxiety disorders symptoms in non-clinical youths. One-hundred-and eighteen adolescents aged 12-15 years completed the brief shame and guilt questionnaire for children (BSGQ-C) and items of the youth self-report (YSR) to measure shame and guilt, the big five personality questionnaire for children, and the youth anxiety measure for DSM-5. Results for shame indicated that this self conscious emotion-either measured by the BSGQ-C or the YSR-was uniquely and positively associated with a broad range of anxiety disorders symptoms, and correlated positively with neuroticism and negatively with extraversion. Guilt did not show significant associations with anxiety disorders symptoms once controlling for the influence of shame, and links with personality traits varied dependent on the assessment instrument that was used (BSGQ-C or YSR). Finally, when controlling for neuroticism and extraversion, shame consistently remained a significant correlate of anxiety disorders symptoms. Altogether, these results add to the growing body of evidence indicating that high levels of shame are clearly associated with anxiety pathology. PMID- 28710595 TI - Using All-Payer Claims Databases to Study Insurance and Health Care Utilization Dynamics. PMID- 28710594 TI - Addressing a Common Misconception: Ammonium Acetate as Neutral pH "Buffer" for Native Electrospray Mass Spectrometry. AB - Native ESI-MS involves the transfer of intact proteins and biomolecular complexes from solution into the gas phase. One potential pitfall is the occurrence of pH induced changes that can affect the analyte while it is still surrounded by solvent. Most native ESI-MS studies employ neutral aqueous ammonium acetate solutions. It is a widely perpetuated misconception that ammonium acetate buffers the analyte solution at neutral pH. By definition, a buffer consists of a weak acid and its conjugate weak base. The buffering range covers the weak acid pKa +/ 1 pH unit. NH4+ and CH3-COO- are not a conjugate acid/base pair, which means that they do not constitute a buffer at pH 7. Dissolution of ammonium acetate salt in water results in pH 7, but this pH is highly labile. Ammonium acetate does provide buffering around pH 4.75 (the pKa of acetic acid) and around pH 9.25 (the pKa of ammonium). This implies that neutral ammonium acetate solutions electrosprayed in positive ion mode will likely undergo acidification down to pH 4.75 +/- 1 in the ESI plume. Ammonium acetate nonetheless remains a useful additive for native ESI-MS. It is a volatile electrolyte that can mimic the solvation properties experienced by proteins under physiological conditions. Also, a drop from pH 7 to around pH 4.75 is less dramatic than the acidification that would take place in pure water. It is hoped that the habit of referring to pH 7 solutions as ammonium acetate "buffer" will disappear from the literature. Ammonium acetate "solution" should be used instead. Graphical Abstract ?. PMID- 28710597 TI - Capsule Commentary on Garland et al., Randomized Controlled Trial of Brief Mindfulness Training and Hypnotic Suggestion for Acute Pain Relief in the Hospital Setting. PMID- 28710596 TI - Patterns of and reasons for electronic cigarette use in primary care patients. AB - BACKGROUND: Electronic cigarette (e-cigarette) use is rising in both the general and clinical populations. Little is known about e-cigarette use in primary care, where physicians report discussing e-cigarette use with patients. OBJECTIVE: Identify how and why smokers in primary care use e-cigarettes. DESIGN: Cross sectional secondary data analysis from a randomized controlled trial of a tablet intervention to deliver the 5As for smoking cessation in primary care. PARTICIPANTS: Current smokers aged 18 and older in three primary care clinics in San Francisco, CA (N = 788). MAIN MEASURES: Patients reported sociodemographics, cigarette smoking habits, quitting readiness, and ever and current use of e cigarettes. We also asked reasons they have used or would use e-cigarettes. ICD-9 codes from the medical record determined comorbidities. KEY RESULTS: Fifty-two percent (n = 408) of patients reported ever using an e-cigarette, and 20% (n = 154) reported past-30-day use. Ever e-cigarette use was associated with younger age and negatively associated with being seen at practices at a public safety-net hospital compared to a practice at University-affiliated hospital. The most common reason for having used e-cigarettes among ever e-cigarette users, and for interest in future use of e-cigarettes among never e-cigarette users, was to cut down cigarette use. The mean number of days of e-cigarette use in the past 30 increased with duration of e-cigarette use. Most current e-cigarette users did not know the nicotine content of their e-cigarettes. CONCLUSIONS: Over half of smokers in primary care have ever used e-cigarettes, and one-fifth are currently using them. Most reported using e-cigarettes to cut down or quit cigarettes. Primary care providers should be prepared to discuss e-cigarettes with patients. Screening for e-cigarette use may help identify and treat patients interested in changing their cigarette smoking habits. PMID- 28710598 TI - Reflections for Clinical Pastoral Education Students in Psychiatric Settings. AB - This article focuses on Donald Capps's books on mental illness. In doing so I highlight three key insights from Capps that I have applied in my own ministry with persons with mental illness in various psychiatric hospitals. These insights, together with my own experience as a chaplain, lead to three practical lessons for clinical pastoral education students in psychiatric settings. I provide some context for my interest in mental illness and my friendship with Capps, as well as some background regarding how Capps's writings on mental illness fit with certain broader themes in his own work as a pastoral theologian. This essay is personal throughout. PMID- 28710599 TI - Task-relevant perceptual features can define categories in visual memory too. AB - Although Konkle, Brady, Alvarez, and Oliva (2010, Journal of Experimental Psychology: General, 139(3), 558) claim that visual long-term memory (VLTM) is organized on underlying conceptual, not perceptual, information, visual memory results from visual search tasks are not well explained by this theory. We hypothesized that when viewing an object, any task-relevant visual information is critical to the organizational structure of VLTM. In two experiments, we examined the organization of VLTM by measuring the amount of retroactive interference created by objects possessing different combinations of task-relevant features. Based on task instructions, only the conceptual category was task relevant or both the conceptual category and a perceptual object feature were task relevant. Findings indicated that when made task relevant, perceptual object feature information, along with conceptual category information, could affect memory organization for objects in VLTM. However, when perceptual object feature information was task irrelevant, it did not contribute to memory organization; instead, memory defaulted to being organized around conceptual category information. These findings support the theory that a task-defined organizational structure is created in VLTM based on the relevance of particular object features and information. PMID- 28710600 TI - The influence of orthographic experience on the development of phonological preparation in spoken word production. AB - Three sets of experiments using the picture naming tasks with the form preparation paradigm investigated the influence of orthographic experience on the development of phonological preparation unit in spoken word production in native Mandarin-speaking children. Participants included kindergarten children who have not received formal literacy instruction, Grade 1 children who are comparatively more exposed to the alphabetic pinyin system and have very limited Chinese character knowledge, Grades 2 and 4 children who have better character knowledge and more exposure to characters, and skilled adult readers who have the most advanced character knowledge and most exposure to characters. Only Grade 1 children showed the form preparation effect in the same initial consonant condition (i.e., when a list of target words shared the initial consonant). Both Grade 4 children and adults showed the preparation effect when the initial syllable (but not tone) among target words was shared. Kindergartners and Grade 2 children only showed the preparation effect when the initial syllable including tonal information was shared. These developmental changes in phonological preparation could be interpreted as a joint function of the modification of phonological representation and attentional shift. Extensive pinyin experience encourages speakers to attend to and select onset phoneme in phonological preparation, whereas extensive character experience encourages speakers to prepare spoken words in syllables. PMID- 28710601 TI - The effects of collective and personal transitions on the organization and contents of autobiographical memory in older Chinese adults. AB - Life transitions like war, marriage, and immigration presumably organize autobiographical memory. Yet little is known about how the magnitude of a given transition affects this mnemonic impact. To examine this issue, we collected (a) word-cued events, (b) event-dating protocols, (c) personally important events, and (d) transitional impact scores of the Cultural Revolution (1966-1976) and important events from Chinese adults who had been adolescents during the revolution. There were three main findings. First, rusticated participants, who moved from cities to rural areas during the Cultural Revolution, dated autobiographical memories in relation to this collective transition more frequently than nonrusticated participants, with the former group reporting a greater material (but not psychological) change in their lives due to this collective transition than the latter group. Second, material change predicted the degree to which the self-nominated important events served as temporal landmarks in event dating. Third, we observed that the events that people typically considered important and those that typically served as temporal landmarks changed as a function of age but displayed the similar temporal distributions. We conclude by considering the theoretical implications of these findings. PMID- 28710603 TI - The most accurate autonomic function test: the medical history. PMID- 28710602 TI - Eldecalcitol (ED-71), an analog of 1alpha,25(OH)2D3, inhibits the growth of squamous cell carcinoma (SCC) cells in vitro and in vivo by down-regulating expression of heparin-binding protein 17/fibroblast growth factor-binding protein 1 (HBp17/FGFBP-1) and FGF-2. AB - Heparin-binding protein 17 (HBp17)/fibroblast growth factor-binding protein-1 (FGFBP-1) was first purified from medium conditioned by A431 cells for its capacity to bind to fibroblast growth factors 1 and 2 (FGF-1 and -2). Among FGF family members, FGF-2 is a potent mitogen for various cell types, including vascular endothelial cells, fibroblasts, and cancer cells such as oral squamous cell carcinoma (OSCC) cells. Besides being well known in bone metabolism, the active form of vitamin D3, i.e., 1alpha,25(OH)2D3 (1,25D3), was reported to have protective effects for heart disease and cancer. Previously, we reported that 1,25D3 inhibited HBp17/FGFBP-1 expression in OSCC cell lines through NF-kappaB inhibition (IkappaBalpha activation) and resulted in the inactivation of FGF-2. In this study, we examined the potential anti-tumor effect of ED-71, an analog of 1alpha,25(OH)2D3, for squamous cell carcinoma cells in vitro and in vivo. The cell lines used were OSCC cell lines (NA-HO-1-n-1 and UE-HO-1-u-1), established from oral cancer patients in our laboratory, and an epidermoid carcinoma/SCC cell line (A431). The growth assay in serum-free culture revealed that ED-71 inhibited the growth of the cancer cell lines in a dose-dependent manner. In addition, ED 71 suppressed HBp17/FGFBP-1 expression by inhibiting the NF-kappaB pathway as did 1,25D3. Furthermore, a luciferase reporter assay revealed that the promoter activity of HBp17/FGFBP-1 (region between -217 and +61) was down-regulated by ED 71. Oral administration of ED-71 significantly inhibited the growth of A431 derived tumors in athymic nude mice. Immunohistochemical analysis revealed that the expression of HBp17/FGFBP-1, FGF-2, CD31, and Ki-67 in the tumors of ED71 treated group was down-regulated in comparison to control. These results suggest that ED-71 possesses potential anti-tumor activity for SCCs both in vitro and in vivo. This compound may act directly on the tumor cells or on endothelial cells by modulating the tumor microenvironment. PMID- 28710604 TI - Pacing and vasovagal syncope: back to our physiologic roots. PMID- 28710605 TI - Current clinical applications of coronary optical coherence tomography. AB - Optical coherence tomography (OCT) is an intra-coronary diagnostic technique that provides detailed imagings of blood vessels in the current cardiac catheterization laboratory. The higher resolution of OCT often provides superior delineation of each structure compared with intravascular ultrasound (IVUS), and it can reliably visualize the microstructure of normal and diseased arteries. The capabilities of OCT are well suited for the identification of calcified plaque and neointima formation after stent implantation. It has been reported that OCT guided percutaneous coronary intervention (PCI) resulted in equivalent clinical and angiographic outcomes in comparison with IVUS-guided PCI. Recently, the three dimensional reconstruction of OCT and a real-time point-to-point correspondence between coronary angiographic and OCT/OFDI images have been developed and provide useful information to PCI operators. The unique capabilities of OCT as an investigational tool for high-risk lesions will serve the cardiology community well, as it moves us toward a better understanding of atherosclerotic plaque. In addition, because of the development of new OCT technology, OCT has become a notable catheter-based imaging technology that can provide practical guidance for PCI in clinical settings. PMID- 28710606 TI - SBRT for Hepatocellular Carcinoma: 8-Year Experience from a Regional Transplant Center. AB - PURPOSE: The study aimed to evaluate stereotactic body radiotherapy (SBRT) for hepatocellular carcinoma (HCC) in patients not eligible for liver transplant (LT). METHODS: We retrospectively identified transplant-ineligible HCC patients treated with SBRT to the liver between 2004 and 2013. Our primary endpoint was overall survival (OS). We also report treatment toxicities using CTCAE 3.0, radiographic response, and patterns of failure. RESULTS: We identified 93 patients with median age at SBRT of 65.8 years. Forty-six percent were classified as Child-Pugh B or C and 85% had an Eastern Cooperative Oncology Group performance status of 1-2. After SBRT, 86% of patients experienced no or mild treatment-related adverse events. Only 8% of patients experienced grade 3 and 2% of patients experienced grade 4 adverse events. Overall radiographic response was complete in 1.2%, partial in 35.4%, stable in 43.9%, and progressive disease in 19.5%. Median OS was 8.8 months with 1-, 2-, and 3-year OS rates of 38.0, 29.8 and 21.2%, respectively. The Cancer of the Liver Italian Program (CLIP) score was found to strongly correlate with survival. Median OS for patients with CLIP scores of 0, 1, 2, and 3 was 21.1, 8.5, 5.1, and 7.1 months, respectively (p = 0.003). CONCLUSION: Our series demonstrates that SBRT is generally safe for HCC patients, even those with advanced liver failure. Although survival is generally poor, we were able to identify a group of patients with good liver function and early tumor stage who can achieve median OS of close to 2 years with SBRT. PMID- 28710607 TI - Evaluation of a Food and Drug Administration Mandate to Limit Acetaminophen in Prescription Combination Products. AB - INTRODUCTION: In 2014, the US Food and Drug Administration limited the production of prescription acetaminophen-opioid combination products to 325 mg per dose unit. The goal of this mandate was to decrease the likelihood of unintentional acetaminophen hepatotoxicity. This study was designed to determine if this federal regulation has succeeded in reducing unintentional acetaminophen-induced hepatotoxicity from opioid combination products. METHODS: Using data from the National Poison Data System (NPDS), we analyzed all calls to US Poison Control Centers in the years 2013 and 2015 for acetaminophen-opioid combination product exposures. We then excluded cases that were classified as intentional and those aged 12 years and younger. We used a primary endpoint of N-acetylcysteine administration; secondary endpoints included evidence of hepatotoxicity as aspartate aminotransferase elevation, opioid antagonist administration and severity of overall medical outcome. RESULTS: A total of 18,259 calls between the two yearlong periods met inclusion criteria. 5.16 and 5.01% of calls resulted in N-acetylcysteine administration in 2013 and 2015, respectively. 3.63 and 4.02% received naloxone in 2013 and 2015, respectively, and 0.9% in each year developed hepatotoxicity. Rates of N-acetylcysteine administration, naloxone administration, and hepatotoxicity did not differ significantly between 2013 and 2015. Severity of medical outcome was worse in 2015 as compared to 2013 with more cases being categorized as "major effect" and fewer cases being categorized as "no effect." CONCLUSIONS: The Food and Drug Administration limitation on acetaminophen content per dose unit in opioid combination products did not reduce the occurrence of unintentional acetaminophen-induced hepatotoxicity or N acetylcysteine administration as reported to NPDS. PMID- 28710608 TI - Vaccine platform recombinant measles virus. AB - The classic development of vaccines is lengthy, tedious, and may not necessarily be successful as demonstrated by the case of HIV. This is especially a problem for emerging pathogens that are newly introduced into the human population and carry the inherent risk of pandemic spread in a naive population. For such situations, a considerable number of different platform technologies are under development. These are also under development for pathogens, where directly derived vaccines are regarded as too complicated or even dangerous due to the induction of inefficient or unwanted immune responses causing considerable side effects as for dengue virus. Among platform technologies are plasmid-based DNA vaccines, RNA replicons, single-round infectious vector particles, or replicating vaccine-based vectors encoding (a) critical antigen(s) of the target pathogens. Among the latter, recombinant measles viruses derived from vaccine strains have been tested. Measles vaccines are among the most effective and safest life attenuated vaccines known. Therefore, the development of Schwarz-, Moraten-, or AIK-C-strain derived recombinant vaccines against a wide range of mostly viral, but also bacterial pathogens was quite straightforward. These vaccines generally induce powerful humoral and cellular immune responses in appropriate animal models, i.e., transgenic mice or non-human primates. Also in the recent first clinical phase I trial, the results have been quite encouraging. The trial indicated the expected safety and efficacy also in human patients, interestingly independent from the level of prevalent anti-measles immunity before the trial. Thereby, recombinant measles vaccines expressing additional antigens are a promising platform for future vaccines. PMID- 28710609 TI - Laparoscopic colectomy in the obese, morbidly obese, and super morbidly obese: when does weight matter? AB - PURPOSE: Previous studies have demonstrated that obese patients (BMI >30) undergoing laparoscopic colectomy have longer operative times and increased complications when compared to non-obese cohorts. However, there is little data that specifically evaluates the outcomes of obese patients based on the degree of their obesity. The aim of this study was to evaluate the impact of increasing severity of obesity on patients undergoing laparoscopic colectomy. METHODS: A retrospective review was performed of all patients undergoing laparoscopic colectomy between 1996 and 2013. Patients were classified according to their BMI as obese (BMI 30.0-39.9), morbidly obese (BMI 40.0-49.9), and super obese (BMI >50). Main outcome measures included conversion rate, operative time, estimated blood loss, post-operative complications, and length of stay. RESULTS: There were 923 patients who met inclusion criteria. Overall, 604 (65.4%), 257 (27.9%), and 62 (6.7%) were classified as obese (O), morbidly obese (MO), and super obese (SO), respectively. Clinicopathologic characteristics were similar among the three groups. The SO group had significantly higher conversion rates (17.7 vs. 7 vs. 4.8%; P = 0.031), longer average hospital stays (7.1 days vs. 4.9 vs. 3.4; P = 0.001), higher morbidity (40.3 vs. 16.3 vs. 12.4%; P = 0.001), and longer operative times (206 min vs. 184 vs. 163; P = 0.04) compared to the MO and O groups, respectively. The anastomotic leak rate in the SO (4.8%; P = 0.027) and MO males (4.1%; P = 0.033) was significantly higher than MO females (2.2%) and all obese patients (1.8%). CONCLUSION: Increasing severity of obesity is associated with worse perioperative outcomes following laparoscopic colectomy. PMID- 28710610 TI - A rare case of peristomal cutaneous B cell lymphoma. PMID- 28710611 TI - Bad bacteria in acute appendicitis: rare but relevant. AB - PURPOSE: Bacterial infections are a factor for morbidity in patients with acute appendicitis (AA). The spreading of multidrug-resistant (MDR) bacteria is a significant problem in surgery, and the most relevant MDR pathogens are summarized as Enterobacteriaceae, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterococci (ESKAPE) bacteria. Data regarding the species and distribution of bacteria in AA are available, but information about the resistances and their relevance is deficient. METHODS: In this retrospective study, we analyzed microbiological swabs of patients with AA. The outcome parameters of patients after laparoscopic appendectomy were analyzed against microbiological results, including antibiotic resistance testing. Positive swabs were compared with bacteria cultivated after alternative abdominal emergency surgery (AES). RESULTS: In total, 584 patients with AA were included and had a mean age of 35.5 years. In 216 patients (36.9%), a swab was taken, and in 128 (59.3%) swabs, bacteria could be cultivated. The most frequent organisms were Escherichia coli, Bacteroides species, and Pseudomonas. In 9.4% of the positive AA swabs, MDR germs were cultivated, and all of them were ESKAPE pathogens. Patients with MDR bacteria in AA suffered more infectious complications (p = 0.006) and needed longer hospitalizations (p < 0.009). In AES, aside from appendicitis, a different spectrum containing more MDR bacteria was cultivated (5.9 vs. 20.9%; p < 0.0001). CONCLUSIONS: Although they occur less frequently in appendectomy compared to emergency surgeries for other abdominal diseases, MDR bacteria are traceable in this common disease and contribute to additional morbidity. PMID- 28710612 TI - [Diagnostic quality of triage algorithms for mass casualty incidents]. AB - BACKGROUND: Regarding survival and quality of life, recent mass casualty incidents have once more emphasized the importance of early identification of the correct degree of injury or illness, to enable prioritizing treatment of patients and transportation to an appropriate hospital. The present study investigated international triage algorithms in terms of sensitivity (SE) and specificity (SP) as well as the process duration in a relevant emergency patient cohort. METHODS: A total of 500 consecutive air rescue missions were evaluated by means of standardized patient records. Interdisciplinary classification of patients was accomplished by 19 emergency physicians. Every case was independently classified according to the triage category by at least three physicians without considering any triage algorithm. The available triage algorithms PRIOR (Primary Ranking for Initial Orientation in Emergency Medical Services), mSTaRT (modified Simple Triage and Rapid Treatment), FTS (Field Triage Score), ASAV (Amberg-Schwandorf Algorithm for Triage), STaRT (Simple Triage and Rapid Treatment), CareFlight triage and Triage Sieve were additionally carried out for each patient in a computer-based procedure, to enable calculation of test quality criteria for all procedures. RESULTS: The analyzed cohort had a mean age of 59 +/- 25 years (+/ SD), a National Advisory Committee for Aeronautics (NACA) score of 3.5 +/- 1.1 and consisted of 57% men. On arrival 8 patients were already deceased, consequently 492 patients were included in the analysis. The distributions of triage categories I/II/III were 10%/47%/43%, respectively. The highest diagnostic quality was achieved with START, mSTaRT, and ASAV with 78% SE and 80-83% SP. The subgroup of surgical patients achieved 95% SE and 85-91% SP. The newly established algorithm PRIOR exerted an SE of 90% but an SP of only 54% in the overall cohort thereby taking the longest overall time for decisions. CONCLUSION: Triage procedures with acceptable diagnostic quality exist to identify the most severely injured. Due to its high rate of false positive results (overtriage) in this study, the recently developed PRIOR algorithm could result in exhaustion of available resources for the severely injured and therefore to undertreatment of correctly assigned triage category I cases within mass casualty incidents. Non surgical patients are still poorly allocated by the available algorithms. Contribution available free of charge by "Free Access". PMID- 28710613 TI - Self-retaining support implant: an anchorless system for the treatment of pelvic organ prolapse-2-year follow-up. AB - INTRODUCTION AND HYPOTHESIS: The search for an improved vaginal mesh prompted the development of a new anchorless implant. The objective was to report on outcome after 2 years of a technique using a self-retaining support (SRS) implant. METHODS: Patients with anterior vaginal wall prolapse, with/without apical prolapse, were recruited. Participants underwent surgical repair using the SRS device. Demographic data, pre-surgical Pelvic Organ Prolapse Quantification (POP Q) scoring, quality of life (QoL) questionnaires (Pelvic Floor Distress Inventory Short Form 20 [PFDI-20], Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire 12 [PISQ-12]), and surgical data were collected. Patients were followed at 2 weeks, 2, 6, 12, and 24 months after surgery. Objective anatomical success was defined using the NIH criteria. RESULTS: Twenty women were recruited for the study with an average age of 62.1 years and an average parity of 4.0 deliveries. Average BMI was 28. Pre-operative mean POP-Q measurements were Aa =1.40 (-1 to 3) cm, Ba = 2.3 (-1 to 6) cm and C = 0.4 (-7 to 6) cm. Surgical time averaged 31.2 min. Estimated blood loss averaged 165 ml. No intra-operative complications were observed. One case (5%) of frame erosion was documented 8 months after surgery. At 2 years' follow-up, mean POP-Q measurements were: Aa = 2.95 (-3 to -2) cm, Ba = -2.85 (-3 to -2) cm, and C point -6.90 (-10 to -3) cm. Seventeen (85%) patients had stage 0 and 3 patients (15%) had stage 1. No mesh erosions or chronic pelvic pain were documented at follow-up. The total PFDI score at follow-up was decreased by 92.8 points (p < 0.0001). CONCLUSIONS: At 2 years' follow-up, the SRS implant was found to be safe, showing no intra operative or immediate post-operative complications. All women presented with POP Q measurements of the anterior and apical compartment at normal value (Ba <= -2 cm) and statistically significant subjective improvement. PMID- 28710614 TI - Thymoma-associated renal pathology: Is renal biopsy always necessary? A clinical problem-solving exercise and teaching example for physicians. PMID- 28710615 TI - Aldosterone antagonist therapy and its relationship with inflammation, fibrosis, thrombosis, mineral-bone disorder and cardiovascular complications in peritoneal dialysis (PD) patients. AB - BACKGROUND: High aldosterone level may contribute to pathogenesis of hypertension, vessels damage and cardiovascular system deterioration in chronic kidney disease patients. Besides its classical action via mineralocorticoid receptor, aldosterone is also involved in cell growth, inflammation, oxidative stress, endothelial dysfunction and exerts fibroproliferative effects. The aim of the study was to assess whether aldosterone antagonist treatment may influence serum level of inflammatory, fibrosis, thrombosis and mineral-bone metabolism markers in peritoneal dialysis (PD) patients and blood pressure, aortic stiffness, echocardiographic indices after 12 months of treatment. METHODS: Twenty-two patients on PD were assigned to spironolactone treatment in dose of 50 mg daily during 12 months. Fifteen PD patients were assigned to control group. Echocardiographic indices, PVW, SBP, DBP (mean values from ABPM) and biochemical parameters such as: aldosterone, osteopontin, IL-6, selectin-P, TGF-beta, PTH, MMP-2 were performed at the beginning and after 12 months in spironolactone and control group. RESULTS: There were no statistically significant differences in echocardiographic indices, PWV, BP (ABPM readings) and biochemical markers: MMP 2, serum aldosterone, TGF-beta, IL-6, selectin-P, PTH level after 12 months of spironolactone treatment. There was statistically significant rise in osteopontin level after 12 months of spironolactone treatment. Episodes of life-threatening hyperkalemia were not reported. CONCLUSIONS: Aldosterone antagonists use in PD patients seems to be safe. Longer duration or higher dosage of spironolactone seems to be more effective in improving cardiovascular system status in PD patients. Further studies are required to determine relationship between mineralocorticoid receptor blockade and mineral-bone disturbances in PD patients. PMID- 28710616 TI - Are we underestimating the rates of incontinence after prostate cancer treatment? Results from NHANES. AB - PURPOSE: Local therapy for prostate cancer (PCa) includes radical prostatectomy (RP) and radiotherapy (XRT), both of which share a complication of urinary incontinence. Post-treatment incontinence has been reported to occur 6-69%, yet no truly patient-centered report has been compiled. We evaluated patient-reported incontinence rates and bother scores after treatment for prostate cancer. METHODS: The NHANES database was queried for all men who reported a diagnosis and treatment of PCa from 2001 to 2010. A control arm of men without a diagnosis of PCa age 60-80 years was constructed for baseline incontinence rates. Incontinence was patient-reported and obtained through questionnaires. Three additional cohorts were created for patients treated with RP, XRT or combination RP and XRT. RESULTS: We identified 316 men treated for prostate cancer, of which 136 reported RP and 125 reported XRT, who were compared to 3534 controls. Men that underwent RP experience significant incontinence rates of 23% compared to 12% of those patients treated with XRT, whereas those patients with combined therapy had incontinence rates of 52% (p < 0.0001). Bother scores did not significantly vary, but were increased compared to baseline. Urge incontinence did not differ between treatment groups, but stress incontinence was significantly higher in surgical patients. CONCLUSION: These data from a nationwide sample of patient-reported urinary outcomes have limited interviewer bias and report significantly higher incontinence rates, which may impact prostate cancer discussions. This further underscores the importance of patient-reported outcomes in the evaluation of treatment success and counseling for patients with prostate cancer. PMID- 28710617 TI - Steroid Bioconversions. AB - Steroid modifications by selected wild-type and engineered strains of microorganisms became an effective tool for the production of high-valued steroidal drugs and their precursors for the pharmaceutical industry. Some microorganisms are effective at the performance of sterol side-chain degradation, oxyfunctionalization of steroid core, and redox reactions at different positions of the steroid molecule. A number of bioprocesses using steroid-transforming microbial strains are well established on an industrial level. Although a range of biocatalytic methods has been developed, selection of suitable microorganisms, as well as creation of new engineered strains, is of great importance for generation of improved bioprocesses and production schemes for obtaining known and new metabolites with potent biological activity. The achievements in genetic and metabolic engineering of steroid-transforming strains in combination with novel approaches in the enzymatic and whole-cell biocatalysis provide a platform for highly effective and selective biotransformations.Here, we briefly review the current state and prospects in the field of microbial bioconversions with special attention to the application of molecular microbiology methods for the generation of new whole cell biocatalysts. PMID- 28710618 TI - Chemical Pathways of Corticosteroids, Industrial Synthesis from Sapogenins. AB - Corticosteroids are products of high industrial and commercial importance. There are dozens of different synthesis published for all of them. Some are coming from academia and some from industry. Here, industrial processes for the synthesis of prednisone, prednisolone, hydrocortisone, dexamethasone, betamethasone, and methylprednisolone are described. The starting material is diosgenin and the desired molecules are reached due to a good combination of chemistry and biotechnology that was developed along the second part of the twentieth century. PMID- 28710619 TI - Genome Sequencing of Steroid-Producing Bacteria with Illumina Technology. AB - Illumina technology is widely used for bacterial whole-genome sequencing due to its simplicity, cheapness, reliability, and abundant software for manipulation with raw data. Illumina technology belongs to a second generation of whole genome sequencing that yields great amount of short reads for genome regions. Genomic DNA is fragmented to short pieces. DNA fragments are amplified for signal increasing, and are read using sequencing-by-synthesis. Millions of short reads up to 100-300 bp in length are assembled in continuous sequences. Mate-pair technology allows resolving a long repeat.Here, we describe the principles of standard and mate-pair library preparation from DNA samples, library quality control, sequencing with MiSeq instrument and following data bioinformatics treatment. Software for genome assembly and completion are listed that assemble, map, annotate, visualize, edit and allow doing other manipulations with genomic sequences. The whole genomes sequencing of the steroid-producing Actinobacteria using these protocols is exemplified. PMID- 28710620 TI - Genome Sequencing of Steroid Producing Bacteria Using Ion Torrent Technology and a Reference Genome. AB - The Next-Generation Sequencing technology has enormously eased the bacterial genome sequencing and several tens of thousands of genomes have been sequenced during the last 10 years. Most of the genome projects are published as draft version, however, for certain applications the complete genome sequence is required.In this chapter, we describe the strategy that allowed the complete genome sequencing of Mycobacterium neoaurum NRRL B-3805, an industrial strain exploited for steroid production, using Ion Torrent sequencing reads and the genome of a close strain as the reference. This protocol can be applied to analyze the genetic variations between closely related strains; for example, to elucidate the point mutations between a parental strain and a random mutagenesis derived mutant. PMID- 28710621 TI - RNA-Seq-Based Comparative Transcriptomics: RNA Preparation and Bioinformatics. AB - The major transcriptome analysis is the determination of differentially expressed genes across experimental conditions. For this, the next-generation sequencing of RNA (RNA-seq) is an increasingly cost-effective technology for the analysis of transcriptomes with several advantages over gene expression microarrays, such as its higher sensitivity and accuracy, broader dynamic range, and the ability to detect novel transcripts, including noncoding RNA molecules, at nucleotide-level resolution. Although these advantages, many microbiology laboratories have not yet applied RNA-seq analyses to their investigations. The high cost of the equipment for next-generation sequencing is no longer an issue, since this intermediate part of the analysis can be provided by commercial or central services. Here, we detail a protocol for the first part of the analysis, the RNA extraction, and an introductory protocol to the bioinformatics analysis of the sequencing data that generates the differential expression results. PMID- 28710622 TI - Intra- and Extra-cellular Proteome Analyses of Steroid-Producer Mycobacteria. AB - The importance of the pathogenic mycobacteria has mainly focused the omic analyses on different aspects of their clinical significance. In contrast, those industrially relevant mycobacteria have received less attention, even though the steroids market sales in 2011, in example, were estimated in $8 billion.The extra cellular proteome, due to its relevance in the sterols processing and uptake; as well as the intra-cellular proteome, because of its role in steroids bioconversion, are the core of the present chapter. As a proof of concept, the obtaining methods for both sub-proteomes of Mycobacterium neoaurum NRRL B-3805, a relevant industrial strain involved in steroids production, have been developed. Thus, procedures and relevant key points of these proteomes analyses are fully described. PMID- 28710623 TI - Genetic Techniques for Manipulation of the Phytosterol Biotransformation Strain Mycobacterium neoaurum NRRL B-3805. AB - Mycobacterium neoaurum is a saprophytic, soil-dwelling bacterium. The strain NRRL B-3805 converts phytosterols to androst-4-ene-3,17-dione (androstenedione; AD), a precursor of multiple C19 steroids of importance to industry. NRRL B-3805 itself is able to convert AD to other steroid products, including testosterone (Ts) and androst-1,4-diene-3,17-dione (androstadienedione; ADD). However to improve this strain for industrial use, genetic modification is a priority. In this chapter, we describe a range of genetic techniques that can be used for M. neoaurum NRRL B 3805. Methods for transformation, expression, and gene knockouts are presented as well as plasmid maintenance and stability. PMID- 28710624 TI - Identification and Characterization of the Genes and Enzymes Belonging to the Bile Acid Catabolic Pathway in Pseudomonas. AB - The study of the catabolic potential of microbial species isolated from different habitats has allowed the identification and characterization of bacteria able to assimilate bile acids and other steroids (e.g., testosterone and 4-androsten-3,17 dione). From soil samples, we have isolated several strains belonging to genus Pseudomonas that grow efficiently in chemical defined media containing some cyclopentane-perhydro-phenantrene derivatives as carbon sources. Genetic and biochemical studies performed with one of these bacteria (P. putida DOC21) allowed the identification of the genes and enzymes belonging to the 9,10-seco pathway, the route involved in the aerobic assimilation of steroids. In this manuscript, we describe the most relevant methods required for (1) isolation and characterization of these species; (2) determining the chromosomal location, nucleotide sequence, and functional analysis of the catabolic genes (or gene clusters) encoding the enzymes from this pathway; and (3) the tools employed to establish the role of some of the proteins that participate in this route. PMID- 28710625 TI - Selection of Biodegrading Phytosterol Strains. AB - The phytosterol-biotransforming strains were selected from Mycobacterium sp., using a high concentration of beta-sitosterol. The selection was made by culturing the strains in a medium enriched with 14 g beta-sitosterol/L as the unique source of carbon. During 2 months, the bacterial cultures were transferred successively. The extraction of the biotransformation products was made with methanol and ethyl acetate. The qualitative and quantitative analysis was made by means of thin-layer chromatography, gas-liquid chromatography (GLC), and GLC-mass spectrometry. Under these conditions, it was observed that after seven transfers, the strains Mycobacterium sp. MB-3683 and the Mycobacterium fortuitum B-11045 increased their biotransformation capacity from 20% to 64% and from 34% to 55%, respectively. The products in the highest proportion identified for each trial were androstenedione and androstadienedione. The results suggest that the high substrate concentration could be a selective mechanism to obtain strains more efficient in the biotransformation of beta-sitosterol into steroidal bases. PMID- 28710626 TI - Stigmasterol Removal by an Aerobic Treatment System. AB - Stigmasterol is a phytosterol contained in Kraft mill effluent that is able to increase over 100% after aerobic biological treatment. This compound can act as an endocrine disrupter as its structure is similar to that of cholesterol. Furthermore, stigmasterol contained in Kraft mill effluent shows high toxicity (25-fold that of beta-sitosterol) to aquatic organisms such as Daphnia magna (24 48 h). However, the operation of the aerobic treatment and biomass adaptation could be affecting their removal. The performances of activated sludge (AS), aerated lagoon (AL), and moving bed biofilm reactors (MBBR) are compared for removing stigmasterol contained in Kraft mill effluent. The AL operates at a hydraulic retention time of 6 h and removes up to 90% of phytosterols. So, a 96% of stigmasterol is removed by AL when the sterol retention load is 0.6 mg/L/day. However, stigmasterol concentrations increase from 29% to 37% at a low stigmasterol load rate (0.2 mg/L/day). On the other hand, the stigmasterol is removed between 65% and 87% by an AS under a hydraulic retention time of 3 h. Moreover, a 100% of stigmasterol can be removed by the MBBR when the hydraulic retention time is 2 days. PMID- 28710627 TI - Production and Biotransformation of Phytosterol Microdispersions to Produce 4 Androstene-3,17-Dione. AB - The current state of knowledge regarding phytosterols biotransformation to produce the steroid intermediate 4-androstene-3,17-dione (AD) shows different technologies. However, the initial concentration of phytosterols in batch cultures is limited due to its low solubility in aqueous media, causing serious difficulties for scaling up because of the low mass transfer. In this chapter, we describe a fermentation method of a phytosterol microdispersion with Mycobacterium sp. B3805 in the context of an integral technology for AD production. The microdispersion generation is based on a patent application that claims the production of an aqueous phytosterol microdispersion with an average size particle of 370 nm, and high stability and solubility in water at high phytosterols concentrations (Harting et al., 2012/US0046254). Our results indicate that up to 20 g/L phytosterols can be biotransformed with this technology allowing a good dispersion and stability of reactants in the fermentation broth. PMID- 28710628 TI - beta-Sitosterol Bioconversion to Androstenedione in Microtiter Plates. AB - Microtiter plates are routinely used as low-cost miniaturized bioreactors due to the large number of experiments that can be conducted simultaneously under similar conditions and replicate all functions of bench-scale reactors at dramatically smaller volumes. These plates, due to the standard footprint, can be integrated with liquid-handling systems and associated equipment expanding considerably their application and use. However, care has to be taken to operate the microtiter plates in optimized mixing and oxygen transfer conditions, preventing medium evaporation in prolonged experiment runs. Here, we describe the production of 4-androstene-3,17-dione (androstenedione; AD), a key pharmaceutical steroid intermediate, by Mycobacterium sp. NRRL B-3805 via the selective cleavage of the side-chain of beta-sitosterol using 24-well microtiter plates. PMID- 28710629 TI - Bioconversion of Phytosterols into Androstenedione by Mycobacterium. AB - The chapter describes the bioconversion of phytosterols to androstenedione (AD) with Mycobacterium spp. in shake flasks and fermenters, as well as LC-MS based methods for analysis of phytosterols and steroid products.Phytosterols are derived as a by-product of vegetable oil refining and of manufacture of wood pulp. Phytosterols contain the same four-ring nucleus as steroids, and may be converted to high-value steroids by removing the side chain at C17 and minor changes at other sites in the ring structure.Many bacteria, including Mycobacterium spp., are able to degrade phytosterols. Mutants of Mycobacterium spp. unable of ring cleavage can, when growing on phytosterols, accumulate the steroid intermediates androstenedione (AD) and/or androstadienedione (ADD).The practical challenge with microbial conversion of phytosterols to steroids is that both the substrate and the product are virtually insoluble in water. In addition, some steroids, notably ADD, may be toxic to cells.Two main strategies have been employed to overcome this challenge: the use of two-phase systems, and the addition of chemically modified cyclodextrins. The latter method is used here.Defined cultivation and bioconversion media for both shake flask and fermenter are given, as well as suggestions to minimize the practical problems caused by the water-insoluble phytosterol. Sampling, sample extraction, and quantification of substrates and products using LC-MS analysis are described. PMID- 28710630 TI - Scale-Up of Phytosterols Bioconversion into Androstenedione. AB - Phytosterols, generated as a by-product of vegetable oils or wood pulp, contain the cyclopentane-perhydro-phenanthrene nucleus, and can be converted into steroid intermediates by removing the C17 side chain. This chapter shows the scale-up, from flask to fermentor, of the phytosterols bioconversion into 4-androstene-3,17 dione (androstenedione; AD) with Mycobacterium neoaurum B-3805. Due to the fact that phytosterols and AD are nearly insoluble in water, two-phase systems and the use of chemically modified cyclodextrins have been described as methods to solve it. Here we use a water-oil two-phase system that allows for the bioconversion of up to 20 g/L of phytosterols into AD in 20 L fermentor. PMID- 28710631 TI - Bioconversion of Phytosterols into Androstadienedione by Mycobacterium smegmatis CECT 8331. AB - The C19 steroid 1,4-androstadiene-3,17-dione (androstadienedione, ADD) is an added value product used as a synthon in the pharmaceutical industry for the commercial production of corticosteroids, mineralocorticoids, oral contraceptives, and other pharmaceutical steroids. Phytosterol biotransformation catalyzed by microbial whole cells is actually a very well-established research area in white biotechnology. The protocol below provides detailed information on ADD production by the mutant CECT 8331 of Mycobacterium smegmatis mc2155 using phytosterols as raw material in a lab scale. This protocol describes the bioconversion of phytosterols into ADD in a single fermentation step. PMID- 28710632 TI - Process for Biotransformation of Androsta-4-ene-3, 17-Dione (4-AD) to Androsta 1,4-Diene-3,17-Dione (ADD). AB - Androsta-1,4-diene-3,17-dione (androstadienedione, ADD) is key intermediate for the organic synthesis of a variety of female sex hormones such as estrone, estradiol, estriol and other related derivatives. De novo synthesis of this molecule is not yet reported in any form of living system, i.e., microbial, plant, and animal. The structural complexities due to presence of several chiral carbon centers create significant hurdles in chemical synthesis of such molecules. Microbe-mediated biotransformation offer a highly reliable, cost effective, and relatively non hazardous way for commercial manufacturing of steroidal key intermediates. Currently microbial biotransformations are extensively being exploited for large-scale production of basic intermediates such as androstenedione (AD), ADD, and several types of hydroxylated derivatives of androstane compounds. In this chapter several aspects of microbial biotransformation process of AD to ADD are discussed. PMID- 28710633 TI - Laboratory-Scale Hydroxylation of Steroids by P450BM3 Variants. AB - This chapter describes the asymmetric hydroxylation of steroids on laboratory preparative scale, using engineered variants of P450BM3 (CYP102A1) as enzyme catalyst. The following protocol covers the creation of an Escherichia coli BL21 Gold (DE3) expression strain, including necessary control experiments like plasmid preparation, test expression, and creation of storage cultures, to verify successful experimental access to recombinant expressed P450BM3 variants. The recombinant expressed P450BM3 variants are obtained as cleared cell lysate and used in a biotransformation setup to hydroxylate 2.8 mg and up to 15 mg testosterone in the presented protocol. Since P450BM3 depends on NADPH as an electron source for the reaction, a glucose and glucose dehydrogenate based recycling system is added to the reaction. The protocol further includes liquid liquid extraction of hydroxytestosterone and directs the experimenter to compound purification via column chromatography. PMID- 28710634 TI - Obtaining of 11alpha-Hydroxyandrost-4-ene-3,17-dione from Natural Sterols. AB - Two-step one-pot microbial transformation enables obtaining of valuable steroids that are difficult to produce chemically. Here we describe a method for obtaining 11alpha-hydroxyandrost-4-ene-3,17-dione (11alpha-HAD) from cheap and available natural sterols (phytosterols or cholesterol).11alpha-HAD is a primary adrenal steroid in mammals and also a key precursor in the syntheses of halogenated corticoids. Conventional routes for its obtaining are based on chemical synthesis, or microbial hydroxylation of androst-4-ene-3,17-dione (AD). AD in turn is produced primarily with microbial biotransformation of natural sterols by some actinobacteria.Consequent bioconversions of sterols using two microbial strains in one bioreactor vessel without separation and purification of AD provides high yield of 11alpha-HAD. At the first fermentation step, phytosterol is converted to AD with Mycobacterium neoaurum NRRL 3805B, or relative strains, to yield about 70% (mol/mol). At the second step, AD is almost fully (98%) hydroxylated at the position 11alpha with Aspergillus ochraceus VKM F-830, or other suitable organisms, in the same bioreactor. At the average, 30% (w/w) of the high-purity crystalline 11alpha-HAD can be obtained.The method can be exploited for production of 11alpha-HAD for practical use. PMID- 28710635 TI - Steroid 11-Alpha-Hydroxylation by the Fungi Aspergillus nidulans and Aspergillus ochraceus. AB - Steroids are a group of natural compounds derived from the cyclopentane-perhydro phenantrene nucleus that have a great interest for the pharmaceutical industries as a consequence of their physiological effects. Among their functions are anti inflammatory, immunosuppressive, or contraceptive activities. Nowadays, microbial transformation of steroid precursors is winning relevance opposite to the chemical synthesis, since it allows for decreasing time, expenses, and environmental pollution. Pharmaceutical industry tends to use cholesterol and phytosterols as starting materials due to their low cost. Aspergillus ochraceus and Aspergillus nidulans, a fungus whose biochemistry and genetics are well known, have been chosen because of their capacity of 11-alpha-hydroxylation over some steroids which confers on them their anti-inflammatory properties. We have cloned the genes encoding the 11-alpha-hydroxylase enzymatic activities with the aim to introduce them in other microorganisms, such as Mycobacterium smegmatis, used in the industry to split the side chain of phytosterols, and thus creating recombinant microorganisms able to generate useful steroids from cheap precursors in just one-step fermentation. PMID- 28710636 TI - Biotransformation of DHEA into 7alpha,15alpha-diOH-DHEA. AB - 3beta,7alpha,15alpha-Trihydroxy-5-androsten-17-one (7alpha,15alpha-diOH-DHEA) is a key intermediate of the novel oral contraceptive "Yasmin" (widely used in birth control pills and postmenopausal hormone replacement therapy pills; the active ingredient is drospirenone). It can be synthesized from dehydroepiandrosterone (DHEA) by microbial dihydroxylation at the C7 and C15 positions. Here we describe the method of bioconversion from DHEA into 7alpha,15alpha-diOH-DHEA by Colletotrichum lini. Using 6 g/L DHEA as a substrate, the DHEA conversion and the 7alpha,15alpha-diOH-DHEA molar yield were 72.6% and 51.2%, respectively. PMID- 28710637 TI - Stabilization of Enzymes by Using Thermophiles. AB - Manufactured steroid compounds have many applications in the pharmaceutical industry. Due to the chemical complexity and chirality of steroids, there is an increasing demand for enzyme-based bioconversion processes to replace those based on chemical synthesis. In this context, thermostability of the involved enzymes is a highly desirable property as both the increased half-life of the enzyme and the enhanced solubility of substrates and products will improve the yield of the reactions. Metagenomic libraries from thermal environments are potential sources of thermostable enzymes of prokaryotic origin, but the number of expected hits could be quite low for enzymes handling substrates such as steroids, rarely found in prokaryotes. An alternative to metagenome screening is the selection of thermostable variants of well-known steroid-processing enzymes. Here we review and detail a protocol for such selection, where error-prone PCR (epPCR) is used to introduce random mutations into a gene to create a variants library for further selection of thermostable variants in the thermophile Thermus thermophilus. The method involves the use of folding interference vectors where the proper folding of the enzyme of interest at high temperature is linked to the folding of a reporter encoding a selectable property such as thermostable resistance to kanamycin, leading to a life-or-death selection of variants of reinforced folding independently of the activity of the enzyme. PMID- 28710638 TI - Biocatalysis of Steroids with Mycobacterium sp. in Aqueous and Organic Media. AB - Mycobacterium sp. can convert steroids such as beta-sitosterol, campesterol, and cholesterol into commercially interesting products. In aqueous systems, the biocatalysis is limited by the low solubility of the steroids in water. This may be overcome by the introduction of an organic phase acting as a substrate and/or product reservoir.In this chapter, we describe the biocatalysis of beta sitosterol to 4-androstene-3,17-dione (AD) and 1,4-androstadiene-3,17-dione (ADD) both in aqueous and organic-aqueous systems. In the latter case, both traditional organic solvents and green solvents are proposed. PMID- 28710639 TI - Downstream Process Synthesis for Microbial Steroids. AB - Systematic and holistic process development, considering upstream and downstream processing simultaneously, is crucial for designing effective and economical production processes. Based on a multiphasic fermentation process, where oil is added to improve substrate solubility, a systematic approach for the purification of microbial steroids is presented. The design methodology incorporates expert knowledge in the form of heuristics to generate different downstream processing alternatives for processing the complex, multiphasic fermentation broth, and recovering the target steroid precursor androst-4-ene-3,17-dione (androstenedione; AD). The resulting alternative tree of different purification techniques is evaluated using scouting experiments to check the performance of each technique. Purification steps such as extraction, adsorption-desorption, and precipitation seem most promising and have been investigated in detail. Each process step selected is optimized and connected to a process route for recovering AD. PMID- 28710640 TI - Analysis of Intermediates of Steroid Transformations in Resting Cells by Thin Layer Chromatography (TLC). AB - Thin-layer chromatography (TLC) is a useful and convenient method for the analysis of steroids due to: its simple sample preparation, low time-consuming process, high sensitivity, low equipment investment and capacity to work on many samples simultaneously. Here we describe a TLC easy protocol very useful to analyze steroid molecules derived from a biotransformation carried out in wild type and mutant resting cells of Rhodococcus ruber strain Chol-4. Following this protocol, we were able to detect the presence or the absence of some well-known intermediates of cholesterol catabolism in Rhodococcus, namely AD, ADD, and 9OHAD. PMID- 28710641 TI - A Ligand-Binding Assay to Measure the Affinity and Specificity of Sterol-Binding Proteins In Vitro. AB - Sterols are major constituents of the plasma membrane of eukaryotic cells and serve as a precursor for several classes of signaling molecules, including steroids and hydroxy sterols. They maintain the functionality and permeability barrier of the plasma membrane through lipid-lipid and lipid-protein interactions. The S. cerevisiae pathogen-related yeast proteins 1, 2, and 3 (Pry) belong to a large protein superfamily known as CAP/SCP/TAPS. Members of this superfamily have been implicated in a wide variety of processes, including immune defense in mammals and plants, pathogen virulence, sperm maturation and fertilization, venom toxicity, and prostate and brain cancer. Pry proteins bind and export sterols in vivo and the purified Pry1 protein binds sterols and related small hydrophobic compounds in vitro. Here we describe a method to determine lipid binding of a purified protein in vitro. PMID- 28710642 TI - [Editorial]. PMID- 28710643 TI - [Vesicoureteral reflux : Watchful waiting, surgery or antibiotic prophylaxis?] AB - Primary vesicoureteral reflux (VUR) is a dynamic disease with several factors influencing its course. Therapeutic options range from watchful waiting to open surgery. Multiple risk factors for the development of pyelonephritis are identified, which then determine the decision for the appropriate treatment option. They include age, gender, history of pyelonephritis and renal scarring, bladder and bowel dysfunction (BBD), circumcision status and parental preference. The use of continuous antibiotic prophylaxis (CAP) is becoming increasingly controversial with antibiotic resistance being a major concern. Aggressive treatment of BBD and infant circumcision can greatly reduce the risk for pyelonephritis and should always be considered and discussed. This article is soley concerned with primary VUR. PMID- 28710644 TI - Non-electrolytic microelectroporation. AB - Micro and nano technologies are of increasing importance in microfluidics devices used for electroporation (electroporation - the permeabilization of the cell membrane with brief high electric field pulses). Electrochemical reactions of electrolysis occur whenever an electric current flows between an electrode and an ionic solution. It can have substantial detrimental effects, both on the cells and solutions during the electroporation. As electrolysis is a surface phenomenon, between electrodes and solution, the extent of electrolysis is increased in micro and nano electroporation over macro-electroporation, because the surface area of the electrodes in micro and nano electroporation is much larger. A possible way to eliminate the electrolytic effect is to develop non electrolytic microelectroporation by coating the microelectroporation devices with a dielectric insulating layer. In this study, we examine the effect of a dielectric insulating layer on the performance of a singularity microelectroporation device that we have recently designed. Using numerical analysis, we study the effects of various design parameters including, input sinusoidal voltage amplitude and frequency, geometrical configuration and material electrical properties on the electroporation performance of the non electrolytic microelectroporation device. In the simulation, we used properties of four real dielectric materials and four solutions of interest for microelectroporation. We characterized the effect of various design parameters of relevance to singularity based microelectroporation, on non-electrolytic microelectroporation. Interestingly, we found that the system behaves in some aspects as a filter and in many circumstances saturation of performance is reached. After saturation is reached, changes in parameters will not affect the performance of the device. PMID- 28710645 TI - Nutritional support for cancer patients: still a neglected right? PMID- 28710646 TI - [Outpatient emergency treatment of nursing home residents : Analysis of insurance claims data]. AB - BACKGROUND: Utilization of outpatient emergency services by nursing home residents is increasing; however, out of hours medical care (OOHC) in Germany has not yet been studied. OBJECTIVE: In Bremen the used billing codes enabled a comparison between the use of outpatient emergency care in the year before and the year after admission to a nursing home stratified by emergency departments and OOHC. MATERIAL AND METHODS: In this retrospective cohort study we used insurance claims data of residents in Bremen, who were insured in a large German statutory health insurance (DAK-Gesundheit). We compared the use of emergency care in hospitals or OOHC practices in the year before and the year after admission to a nursing home. The incidence rates of visits, distribution on weekdays and coded diagnoses were investigated. RESULTS: We included 1175 nursing home residents (77% female) with a mean age of 85 years. After admission to a nursing home the incidence rate of visits in the OOHC practices increased from 30.4 up to 63.7 and in emergency departments (ED) from 27.4 up to 50.7 per 100 person years. A total of 59% of all visits in OOHC practices were on weekends. The most common diagnoses in ED were injuries and poisoning (75%) while a wide range of diagnoses were coded in the OOHC practices. CONCLUSION: There is a significant difference between diagnoses in the ED and OOHC practices. More research is needed to assess the appropriateness of care. PMID- 28710647 TI - Impacts of Sublethal Mercury Exposure on Birds: A Detailed Review. AB - Mercury is a ubiquitous environmental contaminant known to accumulate in, and negatively affect, fish-eating and oceanic bird species, and recently demonstrated to impact some terrestrial songbirds to a comparable extent. It can bioaccumulate to concentrations of >1 MUg/g in tissues of prey organisms such as fish and insects. At high enough concentrations, exposure to mercury is lethal to birds. However, environmental exposures are usually far below the lethal concentrations established by dosing studies.The objective of this review is to better understand the effects of sublethal exposure to mercury in birds. We restricted our survey of the literature to studies with at least some exposures >5 MUg/g. The majority of sublethal effects were subtle and some studies of similar endpoints reached different conclusions. Strong support exists in the literature for the conclusion that mercury exposure reduces reproductive output, compromises immune function, and causes avoidance of high-energy behaviors. For some endpoints, notably certain measures of reproductive success, endocrine and neurological function, and body condition, there is weak or contradictory evidence of adverse effects and further study is required. There was no evidence that environmentally relevant mercury exposure affects longevity, but several of the sublethal effects identified likely do result in fitness reductions that could adversely impact populations. Overall, 72% of field studies and 91% of laboratory studies found evidence of deleterious effects of mercury on some endpoint, and thus we can conclude that mercury is harmful to birds, and the many effects on reproduction indicate that bird population declines may already be resulting from environmental mercury pollution. PMID- 28710648 TI - Clinical-associated characteristics and microbiological features of bloodstream nontyphoidal salmonella infection in adult patients receiving allogeneic hematopoietic stem cell transplantation. AB - Bloodstream nontyphoidal salmonella (NTS) infection is rare, but its associated characteristics and microbiological features in immunocompromised patients are worth paying attention to, particularly for those receiving allogeneic hematopoietic stem cell transplantation (SCT). No studies so far have analyzed post-transplant bloodstream NTS infection. Therefore, we reviewed 423 adult patients undergoing allogeneic hematopoietic SCT from 2003 to 2014. Nine out of four hundred twenty-three patients (2.13%) developed post-transplant bloodstream NTS infection, including two patients who had subsequent or combined metastatic infections. The median age at SCT was 35 years (interquartile range, 29-46) among the nine patients with bloodstream NTS infection. Male patients were predominant (78%). The median onset of bloodstream NTS infection was at 315 days after SCT (range, 207-629). Multivariate analysis revealed that extensive chronic graft versus-host disease (GVHD) (OR 8.054, p = 0.003) and nonmyeloablative transplant conditioning (OR 4.604, p = 0.037) were significant associated characteristics for NTS infection. Currently, there are no published data analyzing and exploring post-transplant bloodstream NTS infections in adult allogeneic hematopoietic SCT. Our study determined the associated characteristics and microbiological features for this infection. PMID- 28710650 TI - Letter to the editors regarding the article entitled: "paradoxical undressing associated with subarachnoid hemorrhage in a non-hypothermia case?" PMID- 28710649 TI - Calcineurin inhibitor-free GVHD prophylaxis with sirolimus and mycophenolate mofetil combination. PMID- 28710651 TI - Intoxication caused by new psychostimulants: analytical methods to disclose acute and chronic use of benzofurans and ethylphenidate. AB - The acute and chronic toxicity of several new psychoactive substances (NPS) is unknown, and only little information is available on the pharmacology and toxicology, toxicokinetics, and detectability in body samples of such new compounds. We here propose analytical methods to disclose acute and chronic use of two types of new psychostimulants: benzofurans and ethylphenidate and we applied them to a real case of a subject attending Emergency Department with signs of acute intoxication due to psychotropic drug(s). After a urinary immunoassay screening which gave a positivity to amphetamines, general unknown gas chromatography-mass spectrometry (GC-MS) urine analysis identified 5-(2 methylaminopropyl)benzofuran (5-MAPB), 5-(2-aminopropyl)benzofuran (5-APB), 5-(2 ethylaminopropyl)benzofuran (5-EAPB), ethylphenidate, and ritalinic acid. All these substances were confirmed and quantified not only in urine but also in serum samples at different times after hospitalization by GC-MS and ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS). Two subsequent 2-cm hair segments were also analyzed and tested positive for the above reported substances, evidencing repeated use. The matching quantitative results in all the analyzed biological matrices demonstrated that both analytical methodologies were suitable to correctly quantify NPS involved in the current intoxication. The objective assessment of acute and chronic intoxication by the above reported compounds demonstrate that the development of analytical methods aiming at the detection of a broad spectrum of compounds in conventional and non conventional biological matrices is helpful when facing the new challenging threat of intoxications caused by NPS. PMID- 28710652 TI - Comparison between inflammation-related markers in peri-implant crevicular fluid and clinical parameters during osseointegration in edentulous jaws. AB - OBJECTIVES: The aim of this study is to improve the understanding of interleukin mechanisms during osseointegration to enhance the monitoring of implant failure and success. Clinical parameters, implant stability, and cytokine levels in peri implant crevicular fluid (PICF) during early bone healing after implant placement were investigated. MATERIAL AND METHODS: Sixty narrow implants were placed in mandible anterior region of 30 edentulous patients (67.23 +/- 7.66 years). Bone type, insertion torque, and primary stability were registered during surgery. Clinical measurements of peri-implant health and the secondary implant stability quotient (ISQ) were recorded. Samples from the PICF were collected 1, 2, 4, 8, and 12 weeks after surgery and analyzed for IL-1beta, IL-6, IL-10, and TNF-alpha levels using ELISAs. RESULTS: The gingival index increased significantly during the first week (p = 0.05), while the plaque index increased significantly between 4 to 8 and 8 to 12 weeks (p < 0.05). The probing depth and the ISQ also reduced significantly (p < 0.05) over time. The TNF-alpha release increased significantly after the 2nd week for non-atrophic patients and 4th week for atrophic patients (p < 0.05). The IL-1beta concentrations showed a short-lived peak after 1st week (p = 0.003), specially in atrophic patients and sites with bone type I (p = 0.034; p = 0.007). The IL-6 concentrations peaked during the 1st and 2nd weeks (p < 0.05; p = 0.005) in atrophic patients and in bone type II (p = 0.023; p = 0.003). The IL-10 concentrations increased gradually over time, showing the highest concentrations at the 12th week (p < 0.005). A total of 12 implants failed at different periods. CONCLUSION: While the clinical measurements presented differences between the evaluation periods, these were not indicative of early dental implant failure or peri-implant diseases. Smoking, bone atrophy, and bone type can greatly influence the cytokines concentrations during the healing time. PMID- 28710654 TI - The influence of desiccation on the recovery process of nitrogenase activity in restored biological soil crusts. PMID- 28710653 TI - Mechanical performance of cement- and screw-retained all-ceramic single crowns on dental implants. AB - OBJECTIVES: This in-vitro study was performed to compare the contact wear, fracture strength and failure mode of implant-supported all-ceramic single crowns manufactured with various fabrication and fixation concepts. MATERIALS AND METHODS: Fifty dental implants (Conelog O 4,3mm/L11mm, Camlog Biotechnologies AG) were embedded and treated with all-ceramic molar single-crowns. Three groups received hand-layered zirconia crowns (IPS e.max Ceram/ IPS e.max ZirCAD, Ivoclar Vivadent AG): CZL (cement-retained zirconia-based layered) group crowns were cemented conventionally, SZL (screw-retained zirconia-based layered) group crowns were screw-retained, MZL (modified zirconia-based layered) group crowns showed a different coping design with screw retention. The specimens of SST (screw retained sintering-technique) and SFL (screw-retained full-contour lithium disilicate) group were CAD/CAM (Computer-aided design/computer-aided manufacturing) fabricated in the sintering technique (IPS e.max ZirCAD/IPS e.max CAD, Ivoclar Vivadent AG) and full-contour of lithium disilicate (IPS e.max CAD, Ivoclar Vivadent AG) respectively and screw-retained. All specimens underwent artificial aging, load until failure and a scanning electron microscopy (SEM) analysis. The received data were statistically compared (one-way ANOVA; Student Newman-Keuls test; Mann-Whitney U-test) at a significance level of 5%. RESULTS: Mouth-motion fatigue testing caused two abutment fractures (SST group and SZL group) and two chipping events (CZL group). Specimens of MZL group showed statistically significant less contact wear compared to the other groups (p<0.001). There was no statistical difference between the groups in terms of the maximum fracture load. SEM-analysis showed a more homogenous structure and surface of CAD/CAM fabricated specimens towards manually veneered components. CONCLUSIONS: The mode of retention did not influence the fracture resistance but the failure patterns of the specimens. CAD/CAM milled lithium-disilicate crowns seemed to be a preserving factor for dental implants. CLINICAL RELEVANCE: The mode of retention and veneering influences the mechanical performance of implant supported single crowns. PMID- 28710655 TI - About the right to be ill. AB - The article raises the issue of 'the right to be ill', formulated by Tadeusz Kielanowski, a Polish physician and humanist. According to him, the right to health should be supplemented by the principle which would serve the protection of people with diseases or disabilities. One-sided interpretation of 'the right to health' may result in various forms of intolerance and discrimination. This paper presents what dangers Kielanowski recognized and explains why his approach was considered to be a novelty; what the idea of 'the right to be ill' is, how the need for it is substantiated. This idea is considered in the context of human rights and it constitutes a starting point for the reflection on social phenomena connected with medicine. Taking into account the changes in medical ethics and culture which have taken place in the recent decades the question has been asked is it worth talking about the right to be ill these days? Giving positive answers to this question, the spheres and issues that have been presented can be analyzed and assessed from the perspective of the right to be ill. PMID- 28710656 TI - Medicine and technology. Remarks on the notion of responsibility in the technology-assisted health care. AB - The introduction of the modern diagnostic and therapeutic procedures to the medical practice provided a new challenge for the medicine. The art of medicine, with its default purpose of acting for the benefit of health, is therefore required to derive from technological progress effectively and rationally. As a result, the medical ethics has been engaged with the rules of economy and management of deficit medical procedures as well as their rational and fair distribution. The above suggests, that medics, given these recourses, should approach each patient with a consideration to their therapeutic rights. However, the physicians cannot just concentrate on the good of one particular patient, but must take into account joint responsibility for the good of a potential patient. This makes medical ethical dilemmas similar to the ethical issues of business. The notion of responsibility is the key for discriminating these two kinds of ethics. PMID- 28710657 TI - Bioenhancement of morality. PMID- 28710659 TI - Comparison of the Effect of Skin Preparation Pads on Transepidermal Water Loss in Ex Vivo Human Skin. AB - INTRODUCTION: Pre-treatment of the skin to remove scales and crusts prior to photodynamic therapy (PDT) is essential to enhance the uptake of topically applied methyl aminolevulinate (MAL) and to improve treatment efficacy. This study compared the effect of two different skin preparation pads on skin integrity in ex vivo human skin. METHODS: Ex vivo human skin samples from three donors were pre-treated in triplicates with PREPSTERTM (PR) skin preparation pad (6, 8, and 10 passages) or Ambu UnilectTM (A-UN) skin preparation pad (6, 8, and 10 passages). In addition, skin samples were pre-treated with tape strippings (10 adhesive tape strips) as a reference method for comparison. Transepidermal water loss (TEWL) was measured on intact skin and following skin barrier impairment using skin preparation pads and tape stripping. Histological analysis was performed to verify the impairment of the stratum corneum (SC) barrier function in samples from intact skin (control), 10 tape strippings (reference method), 10 passages of PR, and 10 passages of A-UN. RESULTS: TEWL increased with the increasing number of passages of skin preparation pads, with 2.4- and 3.3-fold increases following 10 passages of A-UN and PR, respectively, versus a 2.2-fold increase with 10 tape strippings (reference). Histological analysis showed only partial removal of the SC, with no damage observed on the epidermis, regardless of the procedure used. CONCLUSION: Pre-treatment of skin using PR and A-UN skin preparation pads markedly increases TEWL, indicating slight impairment of the SC barrier function. Comparison of both skin preparation pads showed that PR pad consistently induced significantly higher TEWL than A-UN pad (p < 0.05), regardless of the number of passages. Both skin preparation pads are thought to increase the uptake of MAL and can therefore be used for the preparation of skin prior to PDT. FUNDING: Nestle Skin Health - Galderma R&D. PMID- 28710660 TI - Fractional Er:YAG laser assisting topical betamethasone solution in combination with NB-UVB for resistant non-segmental vitiligo. AB - Resistant non-segmental vitiligo is difficult to be treated. Ablative erbium-YAG (Er:YAG) laser has been used in the treatment of vitiligo, but the ablation of entire epidermis frustrated the compliance of patients. The purpose of this study is to investigate the effects of fractional Er:YAG laser followed by topical betamethasone and narrow band ultraviolet B (NB-UVB) therapy in the treatment of resistant non-segmental vitiligo. The vitiligo lesions of each enrolled patient were divided into four treatment parts, which were all irradiated with NB-UVB. Three parts were, respectively, treated with low, medium, or high energy of Er:YAG laser, followed by topical betamethasone solution application. A control part was spared with laser treatment and topical betamethasone. The treatment period lasted 6 months. The efficacy was assessed by two blinded dermatologists. Treatment protocol with high energy of 1800 mJ/P of fractional Er:YAG laser followed by topical betamethasone solution and in combination with NB-UVB made 60% patients achieve marked to excellent improvement in white patches. The protocol with medium energy of 1200 mJ/P of laser assisted approximate 36% patients achieve such improvement. The two protocols, respectively, showed better efficacies than NB-UVB only protocol. However, fractional Er:YAG laser at low energy of 600 mJ/P did not provide such contributions to the treatment of vitiligo. The fractional Er:YAG laser in combination with topical betamethasone solution and NB-UVB was suitable for resistant non-segmental vitiligo. The energy of laser was preferred to be set at relatively high level. PMID- 28710661 TI - The promise of stromal cell-derived factor-1 in novel heart disease treatments. PMID- 28710658 TI - Global Disparities and Their Implications in the Occurrence and Outcome of Autoimmune Hepatitis. AB - Autoimmune hepatitis has a variable occurrence, clinical phenotype, and outcome, and the factors contributing to this variability are uncertain. The goals of this review are to examine the global disparities in the occurrence and outcome of autoimmune hepatitis, suggest bases for these disparities, and encourage investigations that extend beyond single-center experiences. Disparities in the incidence and prevalence of autoimmune hepatitis in different age groups, genders, ethnicities, and geographical regions suggest that factors other than genetic predisposition are involved. Age- and gender-related antigen exposures from the external (infections, toxins, and medications) and internal (intestinal microbiome) environment may affect the incidence of the disease, and the timeliness and nature of treatment may influence its prevalence. The increasing incidence of autoimmune hepatitis in Spain, Denmark, and the Netherlands suggests that a new etiological trigger has been introduced or that the susceptible population has changed. Variations in mortality between Western and Asian-Pacific countries may result from differences in disease detection or management, and variations in gender predilection, peak age of onset, frequency of concurrent immune diseases, and serological profile may reflect gender-biased and age related antigen exposures and genetic predispositions. Global collaborations, population-based epidemiological studies that identify case clustering, and controlled interview-based surveys are mechanisms by which to understand these disparities and improve management. In conclusion, autoimmune hepatitis has a rising incidence in some countries and variable occurrence, phenotype, and outcome between countries and subgroups within countries. These disparities suggest that unrecognized population-based environmental, infectious, or socioeconomic factors are affecting its character. PMID- 28710662 TI - Lung real time three-dimensional imaging in critically ill ventilated patients: a global diagnosis concordance study. AB - Lung ultrasound (LUS) increases clinical diagnosis performance in intensive care unit (ICU). Real-time three-dimensional (3-D) imaging was compared with two dimensional (2-D) LUS by assessing the global diagnosis concordance. In this single center, prospective, observational, pilot study, one trained operator performed a 3-D LUS immediately after a 2-D LUS in eight areas of interest on the same areas in 16 ventilated critically ill patients. All cine loops were recorded on a computer without visible link between 2-D and 3-D exams. Two experts blindly reviewed cine loops. Four main diagnoses were proposed: normal lung, consolidation, pleural effusion and interstitial syndrome. Fleiss kappa and Cohen's kappa values were calculated. In 252 LUS cine loops, the concordance between 2-D and 3-D exams was 83.3% (105/126), 77.6% (99/126) and 80.2% (101/126) for the trained operator and the experts respectively. The Cohen's kappa coefficient value was 0.69 [95% Confidence Interval (CI) 0.58-0.80] for expert 1 meaning a substantial agreement. The inter-rater reliability was very good (Fleiss' kappa value = 0.94 [95% CI 0.87-1.0]) for 3-D exams. The Cohen's kappa was excellent for pleural effusion (kappa= 0.93 [95% CI 0.76-1.0]), substantial for normal lung diagnosis (kappa = 0.68 [95% CI 0.51-0.86]) and interstitial syndrome (kappa = 0.62 [95% CI 0.45-0.80]) and fair for consolidation diagnoses (kappa = 0.47 [95% CI 0.30-0.64]). In ICU ventilated patients, there was a substantial concordance between 2-D and 3-D LUS with a good inter-rater reliability. However, the diagnosis concordance for lung consolidation is poor. PMID- 28710663 TI - A multi-train electrical stimulation protocol facilitates transcranial electrical motor evoked potentials and increases induction rate and reproducibility even in patients with preoperative neurological deficits. AB - This study sought to evaluate the facilitation effect of repetitive multi-train transcranial electrical stimulation (mt-TES) at 2 repetition rates on transcranial electrical motor evoked potential (Tc-MEP) monitoring during spinal surgery, and to assess the induction rate in patients with impaired motor function from a compromised spinal cord or spinal nerve. We studied 32 consecutive patients with impaired motor function undergoing cervical or thoracic spinal surgery (470 muscles). A series of 10 TESs with 5 pulse trains were preoperatively delivered at 2 repetition rates (1 and 5 Hz). All peak-topeak amplitudes of the MEPs of the upper and lower extremity muscles elicited by the 10 TESs were measured. The induction rates of the lower extremity muscles were also assessed with muscle and preoperative lower extremity motor function scores. In each of the muscles, MEP amplitudes were augmented by about 2-3 times at 1 Hz and 5-6 times at 5 Hz. Under the 5-Hz condition, all limb muscles showed significant amplification. Also, in all preoperative motor function score groups, the amplitudes and induction rates of the lower extremity muscles were significantly increased. Moreover, the facilitation effects tended to peak in the last half of the series of 10 TESs. In all score groups of patients with preoperative neurological deficits, repetitive mt-TES delivered at a frequency of 5 Hz markedly facilitated the MEPs of all limb muscles and increased the induction rate. We recommend this method to improve the reliability of intraoperative monitoring during spinal surgery. PMID- 28710664 TI - Role of sodium ion transporters and osmotic adjustments in stress alleviation of Cynodon dactylon under NaCl treatment: a parallel investigation with rice. AB - Comparative analyses of the responses to NaCl in Cynodon dactylon and a sensitive crop species like rice could effectively unravel the salt tolerance mechanism in the former. C. dactylon, a wild perennial chloridoid grass having a wide range of ecological distribution is generally adaptable to varying degrees of salinity stress. The role of salt exclusion mechanism present exclusively in the wild grass was one of the major factors contributing to its tolerance. Salt exclusion was found to be induced at 4 days when the plants were treated with a minimum conc. of 200 mM NaCl. The structural peculiarities of the salt exuding glands were elucidated by the SEM and TEM studies, which clearly revealed the presence of a bicellular salt gland actively functioning under NaCl stress to remove the excess amount of Na+ ion from the mesophyll tissues. Moreover, the intracellular effect of NaCl on the photosynthetic apparatus was found to be lower in C. dactylon in comparison to rice; at the same time, the vacuolization process increased in the former. Accumulation of osmolytes like proline and glycine betaine also increased significantly in C. dactylon with a concurrent check on the H2O2 levels, electrolyte leakage and membrane lipid peroxidation. This accounted for the proper functioning of the Na+ ion transporters in the salt glands and also in the vacuoles for the exudation and loading of excess salts, respectively, to maintain the osmotic balance of the protoplasm. In real-time PCR analyses, CdSOS1 expression was found to increase by 2.5- and 5-fold, respectively, and CdNHX expression increased by 1.5- and 2-fold, respectively, in plants subjected to 100 and 200 mM NaCl treatment for 72 h. Thus, the comparative analyses of the expression pattern of the plasma membrane and tonoplast Na+ ion transporters, SOS1 and NHX in both the plants revealed the significant role of these two ion transporters in conferring salinity tolerance in Cynodon. PMID- 28710666 TI - Mediators of Physical Activity Adherence: Results from an Action Control Intervention in Couples. AB - Background: Behavior change interventions targeting self-regulation skills have generally shown promising effects. However, the psychological working mechanisms remain poorly understood. Purpose: We examined theory-based mediators of a randomized controlled trial in couples targeting action control (i.e., continuously monitoring and evaluating an ongoing behavior). Self-reported action control was tested as the main mediating mechanism of physical activity adherence, and in addition self-efficacy and received social support from the partner. Methods: Overweight individuals (N = 121) and their heterosexual partners were randomly allocated to an intervention (information + action control text messages) or a control group (information only). Across a period of 28 days, participants reported on action control, self-efficacy, and received support in end-of-day diaries, and wore triaxial accelerometers to assess stable between person differences in mediators and the outcome adherence to recommended daily activity levels (>=30 min of moderate activity in bouts of at least 10 min). Results: On average, participants in the intervention group showed higher physical activity adherence levels and higher action control, self-efficacy, and received support compared to participants in the control group. Action control and received support emerged as mediating mechanisms, explaining 19.7 and 24.6% of the total intervention effect, respectively, in separate analyses, and 13.9 and 22.2% when analyzed simultaneously. No evidence emerged for self-efficacy as mediator. Conclusions: Action control and received support partly explain the effects of an action control intervention on physical activity adherence levels. Continued research is needed to better understand what drives intervention effects to guide innovative and effective health promotion. Trial Registration Number: (controlled-trials.com ISRCTN15705531). PMID- 28710665 TI - Physical exercise reduces pyruvate carboxylase (PCB) and contributes to hyperglycemia reduction in obese mice. AB - The present study evaluated the effects of exercise training on pyruvate carboxylase protein (PCB) levels in hepatic tissue and glucose homeostasis control in obese mice. Swiss mice were distributed into three groups: control mice (CTL), fed a standard rodent chow; diet-induced obesity (DIO), fed an obesity-inducing diet; and a third group, which also received an obesity-inducing diet, but was subjected to an exercise training protocol (DIO + EXE). Protocol training was carried out for 1 h/d, 5 d/wk, for 8 weeks, performed at an intensity of 60% of exhaustion velocity. An insulin tolerance test (ITT) was performed in the last experimental week. Twenty-four hours after the last physical exercise session, the animals were euthanized and the liver was harvested for molecular analysis. Firstly, DIO mice showed increased epididymal fat and serum glucose and these results were accompanied by increased PCB and decreased p-Akt in hepatic tissue. On the other hand, physical exercise was able to increase the performance of the mice and attenuate PCB levels and hyperglycemia in DIO + EXE mice. The above findings show that physical exercise seems to be able to regulate hyperglycemia in obese mice, suggesting the participation of PCB, which was enhanced in the obese condition and attenuated after a treadmill running protocol. This is the first study to be aimed at the role of exercise training in hepatic PCB levels, which may be a novel mechanism that can collaborate to reduce the development of hyperglycemia and type 2 diabetes in DIO mice. PMID- 28710667 TI - Parkinson's disease with mild cognitive impairment: severe cortical thinning antedates dementia. AB - Mild cognitive impairment (MCI) in Parkinson's disease (PD) is a risk factor for dementia and thus, it is of interest to elucidate if specific patterns of atrophy in PD-MCI patients are associated with a higher risk of developing dementia. We aim to define pattern(s) of regional atrophy in PD-MCI patients who developed dementia during 31 months of follow-up using cortical thickness analysis Twenty three PD-MCI patients and 18 controls underwent brain MRI and completed a neuropsychological examination at baseline, PD-MCI patients were followed after a 31 month follow-up in order to assess their progression to dementia. At follow up, 8 PD-MCI patients had converted to dementia (PD-MCI converters) whereas 15 remained as PD-MCI (PD-MCI non-converters). All patients were at least 60 years old and suffered PD >= 10 years. There were no baseline differences between the two groups of patients in clinical and neuropsychological variables. The cortex of PD-MCI converters was thinner than that of PD-MCI non-converters, bilaterally in the frontal, insula and the left middle temporal areas, also displaying a more widespread pattern of cortical thinning relative to the controls. This study shows that aged and long-term PD patients with MCI who convert to dementia in the short-mid term suffer a thinning of the cortex in several areas (frontal cortex, and middle temporal lobe and insula), even when their cognitive impairment was similar to that of PD-MCI non-converters. Thus, MRI analysis of cortical thickness may represent a useful measure to identify PD-MCI patients at a higher risk of developing dementia. PMID- 28710668 TI - Comment on the article: Hemiarthroplasty versus internal fixation in super-aged patients with undisplaced femoral neck fractures: a 5-year follow-up of randomized controlled trial. PMID- 28710670 TI - Management of proximal humeral fractures by the Ilizarov external fixator. AB - INTRODUCTION: External fixation can be performed in poor bone and soft tissue conditions, and can be used in patients with poor general conditions or multiple injuries as a rapid, mini-invasive procedure. The purpose of the current study was to evaluate the effectiveness and safety of the Ilizarov external fixator in the management of proximal humeral fractures. MATERIALS AND METHODS: Between May 2011 and December 2013, 14 patients with displaced proximal humeral fractures were enrolled in the current study. Nine patients were males and five were females, with mean age 42.9 years (range 21-55). All fractures were acute. The mode of injury was road traffic accident in eight patients and fall in six patients. There were six patients with two-part fracture, one of them with fracture dislocation, and eight patients presented with three-part fracture, two of them with fracture dislocation. All fractures were fixed using the Ilizarov external fixation. RESULTS: The average operative time was about 67 min (range 50 90). The mean follow-up period was (18) months (range 12-28). Healing was obtained in all 14 patients in a mean of 10.4 weeks (range 8-14). At the final follow-up, the mean constant score was 73.1 points (range 60-97 points), the mean visual analog score (VAS) for pain 3.2 (range 1-5), the mean DASH score 31.8 points (range 10-55 points), and the mean satisfaction VAS 7.6 (range 4-10). CONCLUSION: The Ilizarov external fixation is an effective technique in managing proximal humeral fractures with good outcome and low complication rates. LEVEL OF EVIDENCE: Level IV, case series. PMID- 28710669 TI - Current insights into the aetiology of adolescent idiopathic scoliosis. AB - Scoliosis occurs in about 0.2-0.6% of the general population. In the majority of cases the cause of this entity remains mostly unidentified. The search for the causes covers almost all aspects of its possible origin. We collected and systematised the contemporary theories and concepts concerning the aetiology of adolescent idiopathic scoliosis. Genetic and hereditary factors are commonly accepted as possible causes; however, the identification of the single gene responsible for the development of this condition seems impossible, which suggests multifactorial mechanism of its formation. Dysfunctions of the nervous system are recognised risks related to the development of scoliosis, but they are classified as belonging to a separate aetiological category. Scoliosis develops at the quickest rate during the child's growth spurt, which prompted the research on the role of the growth hormone in scoliosis aetiology. Melatonin is another hormone that is studied as a possible factor involved in development of this entity. In cases of progressive scoliosis, increased activity of calmodulin-a protein that regulates the levels of calcium ions-has been observed. The scientists have characterised numerous qualitative and quantitative changes in the composition of the tissue of intervertebral discs, spinal ligaments and paraspinal muscles. Some of the theories, explaining the nature of this entity, presented in this review seem to have only a purely theoretical value; their proliferation only confirms the fact that the actual nature of this condition has not been unveiled yet, and suggests its multifactorial aetiology. PMID- 28710671 TI - Functional characterization of hormone sensitive-like lipase from Bacillus halodurans: synthesis and recovery of pNP-laurate with high yields. AB - The HSL-like lipase encoding gene (Blip) from the polyextremophile Bacillus halodurans C-125 has been heterologously expressed in E.coli BL21(DE3). The enzyme is a monomer of ~42 kDa. It has extremely high thermal stability with a t 1/2 of 35 min at 100 degrees C. Thermal denaturation/renaturation studies by CD and fluorescence analysis revealed complete refolding of the protein back to its native conformation even after 30 min at 90 degrees C. Blip prefers substrates with mid to long chain fatty acids. It has a higher catalytic efficiency on para nitrophenyl fatty acyl esters as opposed to triacylglycerides (k cat/K m with pNP palmitate as a substrate was 2.52 * 105 mM-1 min-1 while that with glyceryl tripalmitin was 4.06 * 102 mM-1 min-1, respectively). The enzyme also has a unique selectivity for hydrolysis of unsaturated fatty acyl esters. The enzyme catalyses the synthesis of pNP-laurate with an optimized conversion of 95.94 +/- 0.24%. A simple procedure for purification of the product has been developed that led to 89.91 +/- 0.33% product recovery. PMID- 28710672 TI - Automated 3-D Detection of Dendritic Spines from In Vivo Two-Photon Image Stacks. AB - Despite the significant advances in the development of automated image analysis algorithms for the detection and extraction of neuronal structures, current software tools still have numerous limitations when it comes to the detection and analysis of dendritic spines. The problem is especially challenging in in vivo imaging, where the difficulty of extracting morphometric properties of spines is compounded by lower image resolution and contrast levels native to two-photon laser microscopy. To address this challenge, we introduce a new computational framework for the automated detection and quantitative analysis of dendritic spines in vivo multi-photon imaging. This framework includes: (i) a novel preprocessing algorithm enhancing spines in a way that they are included in the binarized volume produced during the segmentation of foreground from background; (ii) the mathematical foundation of this algorithm, and (iii) an algorithm for the detection of spine locations in reference to centerline trace and separating them from the branches to whom spines are attached to. This framework enables the computation of a wide range of geometric features such as spine length, spatial distribution and spine volume in a high-throughput fashion. We illustrate our approach for the automated extraction of dendritic spine features in time-series multi-photon images of layer 5 cortical excitatory neurons from the mouse visual cortex. PMID- 28710673 TI - Ensuring content validity of patient-reported outcomes: a shadow-test approach to their adaptive measurement. AB - PURPOSE: Most computerized adaptive testing (CAT) applications in patient reported outcomes (PRO) measurement to date are reliability-centric, with a primary objective of maximizing measurement efficiency. A key concern and a potential threat to validity is that, when left unconstrained, individual CAT administrations could have items with systematically different attributes, e.g., sub-domain coverage. This paper aims to provide a solution to the problem from an optimal test design framework using the shadow-test approach to CAT. METHODS: Following the approach, a case study was conducted using the PROMIS(r) (Patient Reported Outcomes Measurement Information System) fatigue item bank both with empirical and simulated response data. Comparisons between CAT administrations without and with the enforcement of content and item pool usage constraints were examined. RESULTS: The unconstrained CAT exhibited a high degree of variation in items selected from different substrata of the item bank. Contrastingly, the shadow-test approach delivered CAT administrations conforming to all specifications with a minimal loss in measurement efficiency. CONCLUSIONS: The optimal test design and shadow-test approach to CAT provide a flexible framework for solving complex test-assembly problems with better control of their domain coverage than for the conventional use of CAT in PRO measurement. Applications in a wide array of PRO domains are expected to lead to more controlled and balanced use of CAT in the field. PMID- 28710675 TI - Erratum to: Phenomenology, Structure, and Dynamic of Psychedelic States. PMID- 28710674 TI - What is the best predictor of severe ovarian hyperstimulation syndrome in IVF? A cohort study. AB - PURPOSE: The purpose of the present study is to study what is the best predictor of severe ovarian hyperstimulation syndrome (OHSS) in IVF. METHODS: This is a retrospective analysis of all consecutive IVF/intracytoplasmic injection cycles performed during a 5-year period (2009-2014) in a single university fertility centre. All fresh IVF cycles where ovarian stimulation was performed with gonadotrophins and GnRH agonists or antagonists and triggering of final oocyte maturation was induced with the administration of urinary or recombinant hCG were analyzed (2982 patients undergoing 5493 cycles). Because some patients contributed more than one cycle, the analysis of the data was performed with the use of generalized estimating equation (GEE). RESULTS: Severe OHSS was diagnosed in 20 cycles (0.36%, 95% CI 0.20-0.52). The number of follicles >=10 mm on the day of triggering final oocyte maturation represents the best predictor of severe OHSS in IVF cycles. The cutoff in the number of follicles >=10 mm with the best capacity to discriminate between women that will and will not develop severe OHSS was >=15. CONCLUSION: The presence of more than 15 follicles >=10 mm on the day of triggering final oocyte maturation represents the best predictor of severe OHSS in IVF cycles. PMID- 28710676 TI - Hypertriglyceridemia, an Underestimated Cardiovascular Risk Factor: An Epidemiological Study of the Rome Area. AB - INTRODUCTION: Hypertriglyceridemia (triglycerides >=200 mg/dL) is a major cardiovascular risk factor. Despite the high incidence of this condition in the Italian population, epidemiological information remains limited. AIM: To analyze a large database of clinical charts from general practitioners in the Rome area of Italy. METHODS: In this study, the DATAMEG database of patients treated in the Rome area between 2000 and 2015 was analyzed. The database was searched for information on (1) all patients diagnosed with hypertriglyceridemia, (2) all prescriptions for the treatment of hypertriglyceridemia, and (3) all patients who had an acute myocardial infarction. RESULTS: The overall prevalence of hypertriglyceridemia was 4.4% (3647/82,595). Among patients followed from January 1, 2015 onwards, 2786/55,345 (5.0%) were diagnosed with hypertriglyceridemia. Of these, 418 (15.0%) received at least one prescription of triglyceride-lowering treatment. Over the same period, 1653 patients had at least three measurements of triglycerides >=200 mg/dL, with only 357 (21.6%) receiving at least one prescription of triglyceride-lowering drugs in the year following the last measurement. Furthermore, 513 patients had at least one measurement of >=500 mg/dL. Of these, only 246 (48.0%) received at least one prescription of triglyceride-lowering drugs in the year following the last measurement. In total, 3485 patients had an acute myocardial infarction (prevalence, 4.3%) in 2015. Of these, only 288 (8.3%) received at least one prescription of triglyceride lowering drugs in the year following this event. CONCLUSION: These findings confirmed a pattern of inadequate treatment of hypertriglyceridemia in the Rome area. PMID- 28710678 TI - Breast magnetic resonance imaging: tips for the diagnosis of silicone-induced granuloma of a breast implant capsule (SIGBIC). AB - Complications resulting from the placement of silicone breast implants are becoming more frequent in our clinical practice. This is due to the increase in breast aesthetic surgeries at the beginning of the century, where breast augmentation using silicone implants was the main intervention performed. Generally, studies that discuss the complications of breast implants are restricted to reports of intra- or extra-capsular ruptures, contractures and haematomas. Currently, much importance has been given to anaplastic large cell lymphoma (ALCL) as a more severe complication related to silicone implants. Recently, granuloma formation induced by silicone particle bleeding from intact breast implants has been described when the free silicone comes into contact with the fibrous capsule of the implant. Few studies have demonstrated the characteristics and diagnostic keys for this entity. The objective of this study is to present cases of SIGBIC diagnosed in our service and to discuss the main findings that allow its diagnosis. Teaching Points * Breast implants induce fibrous capsule formation at the periphery of the implant. * Gel bleeding is inherent in all types of silicone breast implants. * Gel bleeding induces silicone-induced granuloma of breast implants. * Main diagnostic tips: heterogeneous mass, black-drop sign and late enhancement. PMID- 28710677 TI - Cerebellar Contributions to Persistent Auditory Verbal Hallucinations in Patients with Schizophrenia. AB - There is growing evidence that the cerebellum plays a crucial role in the pathophysiology of schizophrenia symptoms. Despite increasing evidence for cerebellar involvement in affective, attentive, and cognitive functions including language processing and perception, investigations of cerebellar contributions to auditory verbal hallucinations (AVH) in schizophrenia are lacking. Using structural magnetic resonance imaging at 3T, we investigated the data of 20 patients with schizophrenia and 14 matched healthy controls. Ten patients were classified as having chronic and treatment resistant AVH (pAVH), whereas the remaining ten patients either never had AVH in the past or were in full remission with regard to AVH (nAVH). Employing cerebellum-optimized segmentation techniques, i.e., the Spatially Unbiased Infratentorial Template (SUIT) toolbox, we investigated cerebellar gray matter volume (GMV) differences among the pAVH, nAVH, and a healthy control group, the magnitude of their expression between these groups and the relationship between GMV and schizophrenia symptom load. Lower GMV in pAVH patients compared to controls was found in lobules VIIb and VIIIa. Additionally, lower GMV in pAVH compared to nAVH patients was found in lobule VIIIa. A negative relationship between VIIIa GMV and overall positive symptoms was detected. Correlations with AVH-specific psychometric scores were not significant. This study shows that there are structural changes in the cognitive regions of the cerebellum that are linked to a clinical phenotype presenting with persistent positive symptoms such as AVH. The results suggest that the cerebellum and its associated neural circuits do play a role in the emergence of positive symptoms in schizophrenia, but probably not exclusively in AVH symptom expression. PMID- 28710679 TI - New Phage Display-Isolated Heptapeptide Recognizing the Regulatory Carboxy Terminal Domain of Human Tumour Protein p53. AB - The transcription factor tumor protein p53 (P53) controls a variety of genes most involved in cell cycle and is at the origin of apoptosis when DNA is irreparably damaged. We planned to select novel tumor protein p53-interacting peptides through the screening of hepta-peptide phage-display libraries. For this aim, human tumor suppressor protein p53 was expressed in Escherichia coli as Glutathione S-transferase fusion and purified by affinity chromatography. The phage library was then screened on this immobilized protein target. After three rounds of panning, phages were sequenced and shown to contain a consensus sequence NPNSAQG. Thereafter, either free p53 liberated from the fusion protein through thrombin treatment or Histidine-tagged p53 were recognized efficiently by the selected phage. To locate the p53-binding epitope of the selected hepta peptide, three long peptides parts of the three known domains of the protein were synthesized and screened by the selected phage/peptide. Thus, the Carboxy terminal p53 region was shown to be the target of the isolated phage as well as by its derived Fluorescein isothiocyanate-peptide. Molecular docking showed Lysine 386 as an important residue potentially engaged in this interaction. The selected hepta-peptide is a novel p53-interacting peptide, not described by other studies, and could be used as therapeutic tool in the future. PMID- 28710680 TI - Development of a Novel Tool to Assess the Impact of Itching in Pediatric Cholestasis. AB - OBJECTIVES: The aim was to develop a clinical outcome assessment (COA) for itching in children with cholestatic pruritus. METHODS: This prospective study aimed to enroll patients aged 4-30 years with Alagille syndrome (ALGS) or progressive familial intrahepatic cholestasis type 1 and caregivers of patients aged 5 months to 14 years. Eligible patients experienced itching during >=3 of the 7 days before enrollment and had not undergone liver transplant or surgical interruption of the enterohepatic circulation. Open-ended qualitative interviews confirmed that itching was a primary concern for patients and caregivers. Diaries were modified and then evaluated by participants during cognitive debriefing. Interview results were reviewed by clinical, COA and statistical experts. Diary questions were revised following an interim analysis before finalizing the Itch Reported Outcome (ItchRO). RESULTS: Thirty-six interviews were analyzed, representing 25 families of patients with ALGS. Itching was reported spontaneously (without prompting by the interviewer) by ten of 12 patients with ALGS and 19 of 20 caregivers. Consequences of itching included skin damage (78%), mood changes (59%), and difficulties staying asleep (59%) or falling asleep (53%). Two versions of the ItchRO were developed: ItchRO(Patient) for self completion by patients and ItchRO(Observer) for caregivers. The ItchRO diaries comprise a single scorable item to assess itch and are to be completed twice daily (morning and evening). CONCLUSIONS: Itching was the most bothersome ALGS symptom reported by study participants. We have developed the ItchRO(Patient) and ItchRO(Observer) to assess itching in children with ALGS and other cholestatic liver diseases. These diaries are being validated for use in clinical trials. PMID- 28710681 TI - Evaluating the European Health Literacy Survey Questionnaire in Patients with Stroke: A Latent Trait Analysis Using Rasch Modeling. AB - BACKGROUND: The effective self-management and treatment of long-term disability after stroke depends greatly on the health literacy of patients. The European Health Literacy Survey Questionnaire (HLS-EU-Q) is a comprehensive and theory based measure that captures multiple self-perceived competencies of health literacy and covers a diverse range of health contexts. However, there is no psychometric evidence on the HLS-EU-Q in the stroke population. OBJECTIVE: The aim of this study was to examine the validity of the HLS-EU-Q in patients with stroke using Rasch analysis. METHODS: We compared the model deviance among the one-domain, three-domain, four-domain, and 12-domain structures using likelihood ratio tests to determine the dimensionality of the HLS-EU-Q. Thereafter, we examined the unidimensionality of each domain, local independence, item fit, response categories, and differential item functioning (DIF) for the best fitting structure. RESULTS: A total of 311 patients with stroke participated in this study. Rasch analysis revealed that the 12-domain HLS-EU-Q demonstrated the best data-model fit. The original 4-point scales showed disordering, which can be corrected by rescaling them as 3-point scales with the two middle categories collapsed. All 47 items in the rescaled HLS-EU-Q fit the 12-domain Rasch model, demonstrated local independence, assessed the 12 unidimensional domains respectively, and had invariant difficulties between different age or education groups of the patients with stroke. CONCLUSION: We recommend using the 12-domain scores of the rescaled HLS-EU-Q to comprehensively and accurately capture the competencies to access, understand, appraise, and apply health information within the three health contexts of healthcare, disease prevention, and health promotion for patients with stroke. PMID- 28710682 TI - Thelazia callipaeda infection in a 5-month-old infant. AB - BACKGROUND: Thelazia callipaeda is the main causative organism in thelaziasis, commonly infecting orbital cavities and associated tissues of carnivores. Thelazia callipaeda infection is rarely reported in humans, especially in infants. CASE PRESENTATION: A 5-month-old male infant presented with 2 weeks of redness and increased secretions in the left eye. On examination, the left eye revealed the presence of one creamy thread-like mobile worm in the conjunctival sac. During surgical exploration, a total of 11 worms were extracted from the left eye. The worms were morphologically identified as seven female and four male T. callipaeda. Ocular symptoms resolved rapidly after the removal of the worms, with no recurrence after the 6-month follow-up. CONCLUSION: We present here detailed clinical and morphological information pertaining to T. callipaeda infection, which is considered to be a probably neglected parasitic disease of the eye. This case illustrates the importance of including thelaziasis into the differential diagnosis of ocular surface diseases, especially in infant patients. PMID- 28710684 TI - Utility of Physiologically Based Pharmacokinetic Absorption Modeling to Predict the Impact of Salt-to-Base Conversion on Prasugrel HCl Product Bioequivalence in the Presence of Proton Pump Inhibitors. AB - Prasugrel HCl may convert to prasugrel base during manufacturing or storage. It was reported that formulations with different ratios of salt to base were bioequivalent in healthy subjects, but formulations with a higher extent of conversion were not bioequivalent in subjects taking proton pump inhibitor (PPI) whose stomach pH is elevated. The objective of this study was to assess the magnitude of impact of salt-to-base conversion on prasugrel HCl products BE evaluation in healthy subjects on PPI. A physiologically based pharmacokinetic (PBPK) absorption model was constructed to predict pharmacokinetic (PK) profiles of active metabolite after oral administration of prasugrel HCl products containing various fractions of base based on the prasugrel salt and base intrinsic solubility. The intrinsic solubility was obtained by deconvoluting the model against the observed active metabolite PK profiles with various fractions of base in healthy subjects with or without PPI. The developed PBPK absorption model accurately predicted the average active metabolite PK profiles in healthy subjects without PPI for the product containing 100% salt. A model based on assumptions of the fraction of a dose absorbed remaining unchanged for formulations containing different fractions of base over predicted the reduction of bioavailability upon conversion to the base. Therefore, this represented the conservative estimate with respect to the impact of free base in a product on BE evaluation. Virtual BE trial simulation predicted that less than 20% free base in prasugrel HCl product ensures in vivo BE of the generic product including in subjects that may be taking PPI. PMID- 28710683 TI - Highly selective CB2 receptor agonist A836339 has gastroprotective effect on experimentally induced gastric ulcers in mice. AB - Cannabinoid type 2 (CB2) receptors are distributed in central and peripheral tissues, including immunocytes and the gastrointestinal (GI) tract, suggesting that CB2 receptor agonists represent potential therapeutics in GI inflammatory states. In this study, we investigated the effect of highly selective CB2 agonist, A836339, on the development of gastric lesions. We used two models of gastric ulcer (GU) induced by ethanol (EtOH) and diclofenac. To confirm the involvement of CB2 receptors, a selective CB2 antagonist, AM630 was used. Clinical parameters for gastroprotection were assessed based on inhibition of the gastric lesion area. To investigate the anti-inflammatory effect of A836339, the expression of TNF-alpha and IL-1beta was assessed. To establish the mechanism of gastroprotective action, catalase (CAT), superoxide dismutase (SOD) activity and H2O2 and glutathione (GSH) levels were measured. Moreover, expression of CB2 and cyclooxygenase-2 (COX-2) was characterized using immunohistochemistry (IHC). A836339 reduced ulcer index in a dose-dependent manner in both EtOH- and diclofenac-induced GU models. This effect was reversed by the CB2 antagonist AM630. Administration of A836339 reduced TNF-alpha and IL-1beta levels in gastric tissue. Furthermore, A836339 exhibited potent anti-oxidant activity, as demonstrated by reduced H2O2 levels and increased CAT and SOD activities. IHC studies revealed a co-localization of CB2 receptors and COX-2 in the gastric tissue. Activation of CB2 receptors exhibited gastroprotective effect through enhancement of anti-oxidative pathways in the stomach. Activation of CB2 receptors may thus become a novel therapeutic approach in the treatment of GU. PMID- 28710686 TI - [Ophthalmological assessment in the Severely Handicapped Persons Act and in blindness : Statement of the Professional Association of Ophthalmologists Germany, the German Ophthalmological Society processed by the Joint Commission on Law. Status January 2017]. PMID- 28710685 TI - Pericytes Extend Survival of ALS SOD1 Mice and Induce the Expression of Antioxidant Enzymes in the Murine Model and in IPSCs Derived Neuronal Cells from an ALS Patient. AB - Amyotrophic Lateral Sclerosis (ALS) is one of the most common adult-onset motor neuron disease causing a progressive, rapid and irreversible degeneration of motor neurons in the cortex, brain stem and spinal cord. No effective treatment is available and cell therapy clinical trials are currently being tested in ALS affected patients. It is well known that in ALS patients, approximately 50% of pericytes from the spinal cord barrier are lost. In the central nervous system, pericytes act in the formation and maintenance of the blood-brain barrier, a natural defense that slows the progression of symptoms in neurodegenerative diseases. Here we evaluated, for the first time, the therapeutic effect of human pericytes in vivo in SOD1 mice and in vitro in motor neurons and other neuronal cells derived from one ALS patient. Pericytes and mesenchymal stromal cells (MSCs) were derived from the same adipose tissue sample and were administered to SOD1 mice intraperitoneally. The effect of the two treatments was compared. Treatment with pericytes extended significantly animals survival in SOD1 males, but not in females that usually have a milder phenotype with higher survival rates. No significant differences were observed in the survival of mice treated with MSCs. Gene expression analysis in brain and spinal cord of end-stage animals showed that treatment with pericytes can stimulate the host antioxidant system. Additionally, pericytes induced the expression of SOD1 and CAT in motor neurons and other neuronal cells derived from one ALS patient carrying a mutation in FUS. Overall, treatment with pericytes was more effective than treatment with MSCs. Our results encourage further investigations and suggest that pericytes may be a good option for ALS treatment in the future. Graphical Abstract ?. PMID- 28710687 TI - Disaggregation and Reaggregation of Zebrafish Retinal Cells for the Analysis of Neuronal Layering. AB - The reaggregation of dissociated cells to form organotypic structures provides an in vitro system for the analysis of the cellular interactions and molecular mechanisms involved in the formation of tissue architecture. The retina, an outgrowth of the forebrain, is a precisely layered neural tissue, yet the mechanisms underlying layer formation are largely unexplored. Here we describe the protocol to dissociate, re-aggregate, and culture zebrafish retinal cells from a transgenic, Spectrum of Fates, line where all main cell types are labelled with a combination of fluorescent proteins driven by fate-specific promoters. These cells re-aggregate and self-organize in just 48 h in minimal culture conditions. We also describe how the patterning in these aggregates can be analyzed using isocontour profiling to compare whether different conditions affect their self-organization. PMID- 28710688 TI - Death by food. AB - Although death from food is not an uncommon finding in forensic facilities worldwide, the range of underlying lethal mechanisms and associated conditions that should be sought at the time of autopsy is quite disparate. Deaths may occur from i) infectious agents including bacteria, viruses, protozoa, cestodes, nematodes and prions; ii) natural toxins including amanita toxins, tetrodotoxin, ciguatera and scombroid; iii) anaphylaxis; iv) poisoning; v) mechanical issues around airway and gut obstruction and/or perforation; and vi) miscellaneous causes. Food-related deaths are important in terms of global mortality, and thus autopsies need to be comprehensive with full ancillary testing. Medicolegal matters may involve issues concerning likely exposure to infectious agents, possible foods ingested, the declared content and possible components of food, the significance of toxicological analyses, and aspects of duty of care in cases of cafe coronary syndrome and gastroenteritis while in care. PMID- 28710690 TI - A preliminary assessment of heavy metals in sediments from the Cipero and South Oropouche Rivers in Trinidad, West Indies. AB - The increasing urbanization and industrial processes in Trinidad within recent years could pose a possible contamination threat to the aquatic environment. The southwestern part of the island houses numerous industrial activities, and the recent sightings of schools of dead fish and other marine organisms in that locality is cause for concern prompting research into this occurrence. Sediment and surface water samples from the Cipero and South Oropouche Rivers in South Trinidad were analyzed for their heavy metal content (Cd, Cr, Cu, Mn, Ni, Pb, and Zn). Another watercourse, the Moruga River, was selected as a control, based on its location away from significant anthropogenic sources, and the levels of heavy metals obtained for this location were considered as background concentrations for both surface waters and sediments. Cadmium, Ni, and Pb were not detected in surface water samples of both rivers. The corresponding order of metals in the Cipero River was Mn > Cr > Zn > Cu, while for the South Oropouche River, the order was Mn > Cr > Cu > Zn. The individual concentrations of metals in sediments found in the Cipero and South Oropouche Rivers varied according to the following orders: Mn > Zn > Cu > Pb > Ni > Cr > Cd and Mn > Zn > Pb > Cu > Ni > Cr > Cd, respectively. Assessments of the pollution status in sediments revealed that the Cipero River was considered polluted with a moderate degree of ecological pollution while the South Oropouche River was also deemed polluted; however, the degree of ecological pollution associated with that river was low. Principal component analysis (PCA) and cluster analysis (CA) confirmed that both anthropogenic and natural sources contributed to heavy metal contamination in sediments of both rivers. PMID- 28710689 TI - Assessment of major ions and trace elements in groundwater supplied to the Monterrey metropolitan area, Nuevo Leon, Mexico. AB - The Monterrey metropolitan area (MMA) is the third greatest urban area and the second largest economic city of Mexico. More than four million people living in this megacity use groundwater for drinking, industrial and household purposes. Thus, major ion and trace element content were assessed in order to investigate the main hydrochemical properties of groundwater and determine if groundwater of the area poses a threat to the MMA population. Hierarchical cluster analysis using all the groundwater chemical data showed five groups of water. The first two groups were classified as recharge waters (Ca-HCO3) coming from the foothills of mountain belts. The third group was also of Ca-HCO3 water type flowing through lutites and limestones. Transition zone waters of group four (Ca-HCO3-SO4) flow through the valley of Monterrey, whereas discharge waters of group 5 (Ca-SO4) were found toward the north and northeast of the MMA. Principal component analysis performed in groundwater data indicates four principal components (PCs). PC1 included major ions Si, Co, Se, and Zn, suggesting that these are derived by rock weathering. Other trace elements such as As, Mo, Mn, and U are coupled in PC2 because they show redox-sensitive properties. PC3 indicates that Pb and Cu could be the less mobile elements in groundwater. Although groundwater supplied to MMA showed a high-quality, high mineralized waters of group 5 have NO3- concentrations higher than the maximum value proposed by international guidelines and SO42-, NO3-, and total dissolved solid concentrations higher than the maximum levels allowed by the Mexican normative. PMID- 28710691 TI - Monitoring of inland waters for culturing shrimp Litopenaeus vannamei: application of a method based on survival and chemical composition. AB - This study evaluated the suitability of 21 inland waters (16 well waters and 5 surface waters) from Northwest Mexico via short- (48 h) and medium-term (28 days) tests using postlarvae (PL18) of Litopenaeus vannamei. In the short test, survival was assessed at 48 h after shrimp were placed in groups of 10 postlarvae into 2-L containers of inland water, to which they had been previously acclimated. The second, medium-term test consisted of four replicates with 10 postlarvae, and each group was placed in 15-L containers with the treatment water. Weights (initial and final) and survival were evaluated weekly for 28 days. In those waters for which the short test was positive and the medium-term test was negative and which also had a deficiency of potassium and/or magnesium, a third test was conducted. These last waters were supplemented with salts, and the shrimp survival and weights (initial and final) were recorded for 28 days. The water samples from San Jose, Mochicahui, Sinaloa River, Caimanero inner Lagoon, La Pipima, Campo Santa Fe, Escopama, and Fitmar had >60% survival in the short test. The Caimanero inner Lagoon water had the highest survival (87.5 +/- 9.6%) and final mean weight (201.3 +/- 86.2 mg). In the third test, it was found that shrimp in the water from La Pipima, Campo Santa Fe, and Fitmar exhibited 100% survival for 2 weeks. Finally, in this work, a decision tree to evaluate the suitability of low-salinity water for shrimp farming was proposed, which can be applied in other regions. PMID- 28710692 TI - Host Factors Involved in Ebola Virus Replication. AB - Ebola virus (EBOV) is a highly pathogenic emerging virus that represents a serious threat to global public health and a major priority for biodefense. The 2014 West African outbreak demonstrated the potential of EBOV to cause an epidemic affecting thousands of people. The severity of disease and high case fatality rate of EBOV is largely due to the host response elicited by the virus. EBOV infection hijacks a number of host pathways to carry out replication and stimulate potent inflammatory responses, while simultaneously subverting the host antiviral immune response. Together, these events trigger a complex, systemic, often lethal febrile disease characterized by high levels of inflammatory cytokines, acute hepatitis and liver dysfunction, immune antagonism, gastrointestinal distress, and, in some cases, hemorrhage caused by coagulopathy and vascular leakage. This review presents current knowledge about the particular host responses induced and disrupted by EBOV infection and how these contribute to virus replication, immune evasion, pathogenesis, and disease outcome. PMID- 28710693 TI - Driving Cancer Tumorigenesis and Metastasis Through UPR Signaling. AB - In the tumor microenvironment, cancer cells encounter both external and internal factors that can lead to the accumulation of improperly folded proteins in the Endoplasmic Reticulum (ER) lumen, thus causing ER stress. When this happens, an adaptive mechanism named the Unfolded Protein Response (UPR) is triggered to help the cell cope with this change and restore protein homeostasis in the ER. Sequentially, one would expect that the activation of the three UPR branches, driven namely by IRE1, PERK, and ATF6, are crucial for the adaptation of cancer cells to the changing environment and thus for their survival and further propagation. Indeed, in the last few years, an increasing amount of studies has shown the implication of UPR signaling in different aspects of carcinogenesis and tumor progression. Features such as sustaining proliferation and resistance to cell death, genomic instability, altered metabolism, increased inflammation and tumor-immune infiltration, invasion and metastasis, and angiogenesis, defined as "the hallmarks of cancer", can be regulated by the UPR machinery. At the same time, new potential therapeutic interventions applicable to different kinds of cancers are being revealed. In order to describe the emerging role of UPR in cancer biology, these are the points that will be discussed in this chapter. PMID- 28710694 TI - Ecology of Filoviruses. AB - Filoviruses can cause severe and often fatal disease in humans. To date, there have been 47 outbreaks resulting in more than 31,500 cases of human illness and over 13,200 reported deaths. Since their discovery, researchers from many scientific disciplines have worked to better understand the natural history of these deadly viruses. Citing original research wherever possible, this chapter reviews laboratory and field-based studies on filovirus ecology and summarizes efforts to identify where filoviruses persist in nature, how virus is transmitted to other animals and ultimately, what drivers cause spillover to human beings. Furthermore, this chapter discusses concepts on what constitutes a reservoir host and highlights challenges encountered while conducting research on filovirus ecology, particularly field-based investigations. PMID- 28710695 TI - Serum brain-derived neurotrophic factor levels in treatment-naive boys with attention-deficit/hyperactivity disorder treated with methylphenidate: an 8-week, observational pretest-posttest study. AB - Brain-derived neurotrophic factor (BDNF) is an important neurotrophin in the brain that modulates dopaminergic neurons. In this study, we aimed to investigate the changes in serum BDNF levels of children with attention-deficit/hyperactivity disorder (ADHD) in response to OROS methylphenidate treatment. We also aimed to determine whether there were any pre-post-differences between ADHD subtypes and comorbid psychiatric disorders in serum BDNF levels. Fifty male children with ADHD and 50 male healthy controls within the age range of 6-12 years were recruited to the study. The psychiatric diagnoses were determined by applying a structured interview with Kiddie schedule for affective disorders and schizophrenia for school-age children-present and lifetime version. The symptom severity of ADHD was measured using the Clinical Global Impression ADHD Severity Scale (CGI-S). Physicians completed Du Paul ADHD questionnaires. The levels of serum BDNF were assessed before and after 8 weeks of treatment with effective dosages of OROS methylphenidate. In the present study, the mean serum BDNF levels of boys with ADHD and of the healthy controls were 2626.33 +/- 1528.05 and 2989.11 +/- 1420.08 pg/mL, respectively. Although there were no statistically significant difference between the ADHD group and healthy controls at baseline (p = 0.22), the increase of serum BDNF was statistically significant from baseline to endpoint in the ADHD group (p = 0.04). The mean serum BDNF levels at baseline and endpoint of the ADHD group were 2626.33 +/- 1528.05 and 3255.80 +/- 1908.79 pg/mL, respectively. The serum BDNF levels of ADHD-inattentive subtype were significantly lower at baseline (p = 0.02), whereas BDNF levels post-treatment showed no significant difference. The increase of serum BDNF levels with methylphenidate treatment after 8 weeks was significantly higher in the inattentive group (p = 0.005). The increase of serum BDNF levels with methylphenidate treatment after 8 weeks in boys with ADHD may support the potential role of BDNF in the pathophysiology of ADHD. The role of BDNF in ADHD subtypes in particular should be evaluated with further, larger studies. PMID- 28710696 TI - Mesocotyl Elongation is Essential for Seedling Emergence Under Deep-Seeding Condition in Rice. AB - BACKGROUND: Direct-seeding cultivation by deep-seeding of seeds (drill seeding) is becoming popular due to the scarcity of land and labor. However, poor emergence and inadequate seedling establishment can lead to yield loss in direct seeding cultivation by deep-sowing. In rice, mesocotyl and coleoptile are primarily responsible for seedling emergence from deeper levels of soil. RESULTS: Quantitative trait loci (QTLs) for mesocotyl and coleoptile length at 5-cm seeding depth were detected using 98 backcross inbred lines from a cross between Kasalath and Nipponbare. Three QTLs qMel-1, qMel-3, and qMel-6 for mesocotyl length were identified on chromosomes 1, 3, and 6, respectively, in two independent replicates. At two QTLs, qMel-1 and qMel-3, the Kasalath alleles increased mesocotyl length, whereas Nipponbare allele increased at qMel-6. The Nipponbare alleles at two QTLs (qCol-3 and qCol-5) increased the coleoptile length. Further, seeds of 54 chromosome segment substitution lines (CSSLs) from the cross between Kasalath and Nipponbare sown at 5 cm soil depth showed a significant positive correlation between seedling emergence and mesocotyl elongation (r > 0.6, P < 0.0001), but not with coleoptile elongation (r = 0.05, P = 0.7). Seedling emergence of Nipponbare, Kasalath, and the 3 of the 54 CSSLs rapidly decreased with increasing sowing depth. Seedling emergence at seeding depths of 7 and 10 cm was faster in Kasalath and CSSL-5 that harbored the Kasalath alleles across the qMel-1 and qMel-3 regions than in the other two CSSLs that contained a single QTL and Nipponbare alleles. CSSL-5 showed the longest mesocotyl among the 3 CSSLs, but no difference in coleoptile length was observed among the 3 CSSLs at seeding depths of 7 and 10 cm. CONCLUSION: Variation of mesocotyl elongation was found to be associated with seedling emergence at the seeding depth of 5 cm. To our knowledge, this is the first study performed using CSSLs to detect QTLs for mesocotyl or coleoptile elongation and to determine the effect of mesocotyl elongation on seedling emergence in rice. Our findings provides a foundation for developing rice cultivars that show higher seedling emergence after direct seeding by introgressing QTLs for mesocotyl elongation in rice breeding. PMID- 28710697 TI - The Basis of the Syllable Hierarchy: Articulatory Pressures or Universal Phonological Constraints? AB - Across languages, certain syllable types are systematically preferred to others (e.g., [Formula: see text] lbif, where [Formula: see text] indicates a preference). Previous research has shown that these preferences are active in the brains of individual speakers, they are evident even when none of these syllable types exists in participants' language, and even when the stimuli are presented in print. These results suggest that the syllable hierarchy cannot be reduced to either lexical or auditory/phonetic pressures. Here, we examine whether the syllable hierarchy is due to articulatory pressures. According to the motor embodiment view, the perception of a linguistic stimulus requires simulating its production; dispreferred syllables (e.g., lbif) are universally disliked because their production is harder to simulate. To address this possibility, we assessed syllable preferences while articulation was mechanically suppressed. Our four experiments each found significant effects of suppression. Remarkably, people remained sensitive to the syllable hierarchy regardless of suppression. Specifically, results with auditory materials (Experiments 1-2) showed strong effects of syllable structure irrespective of suppression. Moreover, syllable structure uniquely accounted for listeners' behavior even when controlling for several phonetic characteristics of our auditory materials. Results with printed stimuli (Experiments 3-4) were more complex, as participants in these experiments relied on both phonological and graphemic information. Nonetheless, readers were sensitive to most of the syllable hierarchy (e.g., [Formula: see text]), and these preferences emerged when articulation was suppressed, and even when the statistical properties of our materials were controlled via a regression analysis. Together, these findings indicate that speakers possess broad grammatical preferences that are irreducible to either sensory or motor factors. PMID- 28710698 TI - Health, Social, and Economic Outcomes Experienced by Families as a Result of Receiving Assistance from a Community-Based Diaper Bank. AB - Objectives This paper aims to describe low-income recipients of a community-based diaper bank and the multiple daily challenges they face. Our paper seeks to document the health, social, and financial outcomes recipients experienced after receiving assistance. Methods We surveyed families (n = 150) about their experiences receiving diapers from a diaper bank in the southeastern United States. Additionally, we conducted short, focused interviews with families (n = 15) about outcomes after receiving diapers. Results Families experience regularly a range of challenges meeting basic needs. These difficulties include high unmet needs for transportation, food, and nonfood essentials such as personal hygiene items. Families experiencing the greatest difficulty in paying utility or medical bills were significantly more likely to have a high level of diaper need compared to families facing these challenges less often (AORs ranging from 3.40 to 9.39). As a result of receiving diapers, families reported positive health, social, and economic outcomes. Families reported positive changes in parental mood; improved child health and happiness; increased opportunities for childcare, work, and school attendance; and the ability to divert household finances toward other basic needs, including utilities and medical care. Conclusions for Practice The monetary value of the supplemental provision of diapers is a small investment in affected families' economic, social, and health outcomes. The positive effects continue far longer than the diapers provided. We demonstrate the social value of such an operation, and recommend the expansion of federal, state, and local safety net programs to help low-income families secure a steady supply of diapers. PMID- 28710699 TI - Examining Early Childhood Health Outcomes of Children Born Late Preterm in Urban Manitoba. AB - Objective The late preterm population [34-36 weeks gestational age (GA)] is known to incur increased morbidity in the infancy stage compared to the population born at term (39-41 weeks GA). This study aimed to examine the health of these children during their early childhood years, with specific attention to the role of socioeconomic status. Methods A retrospective cohort study was conducted using data from the Manitoba Centre for Health Policy, including all live-born children born at 34-36 and 39-41 weeks GA in urban Manitoba between 2000 and 2005 (n = 28,100). Multivariable logistic regression was used to examine the association of GA with early childhood morbidity after controlling for maternal, child and family level variables. Results The late preterm population was found to have significantly greater adjusted odds of lower respiratory tract infections in the preschool years (aOR = 1.59 [1.24, 2.04]) and asthma at school age (aOR = 1.33 [1.18, 1.47]) compared to the population born at term. The groups also differed in health care utilization at ages 4 (aOR = 1.19 [1.06,1.34]) and 7 years (aOR = 1.24 [1.09, 1.42]). Additional variables associated with poor outcomes suggest that social deprivation and GA simultaneously have a negative impact on early childhood development. Conclusions for Practice Adjustment for predictors of poor early childhood development, including socioeconomic status, were found to attenuate but not eliminate health differences between children born late preterm and children born at term. Poorer health outcomes that extend into childhood have implications for practice at the population level and suggest a need for further follow-up post discharge. PMID- 28710700 TI - Enhancing State Medical Home Capacity through a Care Coordination Technical Assistance Model. AB - Introduction A practice-based care coordination (CC) model was developed by Louisiana's Title V Children's Special Health Services (CSHS) program to meet the overwhelming needs of the New Orleans post-Katrina population. The pilot clinic demonstrated an improvement in medical home (MH) capacity over the course of 3 months. The purpose of the current study is to evaluate the replicability of the model and sustainability of MH improvement over at least 2 years, while identifying factors that may modify the effect of the intervention. Methods The CSHS CC model utilizing a practice based care coordinator was implemented in 15 academic primary care pediatric clinics. Increase in MH capacity was determined using the MH Index-Short Version (MHI-SV) tool. Results The analysis of the MHI SV scores for the ten clinics with >2 years of data demonstrated a significant improvement with each of the ten MHI-SV indicators. The mean clinic MHI-SV score improved from 19.70 to 34.15 on a scale of 10-50. Characteristics associated with the greatest MHI score improvement were rural geographic location, having an electronic health record, and using social workers or nurses as care coordinators. Characteristics associated with lower MHI scores were physician or care coordinator turnover and using stand-alone databases rather than tracking CC activities within the central patient record. Conclusion This study provides a flexible framework for implementing CC services in pediatric, family medicine, and medicine-pediatric practices, and demonstrates the value of CC as a driver for improvement in medical home capacity. PMID- 28710701 TI - A Fluorescence Quenching Study of Naphthalimide Dye by Graphene: Mechanism and Thermodynamic Properties. AB - Graphene oxide is an efficient fluorescence quencher for various organic dyes. Herein the fluorescence quenching of graphene oxide has been carried out on a naphthalimide dye as a fluorescent probe model. The interaction between naphthalimide dye and graphene oxide was studied by UV-Vis and fluorescence spectroscopic techniques. The results indicated that graphene is a very efficient quencher for naphthalimide molecule. The Stern-Volmer analysis revealed that the remarkable quenching of graphene was based on a combined static and dynamic quenching mechanism and went through an energy transfer process. Graphical Abstract ?. PMID- 28710702 TI - Bayesian inference for biomarker discovery in proteomics: an analytic solution. AB - This paper addresses the question of biomarker discovery in proteomics. Given clinical data regarding a list of proteins for a set of individuals, the tackled problem is to extract a short subset of proteins the concentrations of which are an indicator of the biological status (healthy or pathological). In this paper, it is formulated as a specific instance of variable selection. The originality is that the proteins are not investigated one after the other but the best partition between discriminant and non-discriminant proteins is directly sought. In this way, correlations between the proteins are intrinsically taken into account in the decision. The developed strategy is derived in a Bayesian setting, and the decision is optimal in the sense that it minimizes a global mean error. It is finally based on the posterior probabilities of the partitions. The main difficulty is to calculate these probabilities since they are based on the so called evidence that require marginalization of all the unknown model parameters. Two models are presented that relate the status to the protein concentrations, depending whether the latter are biomarkers or not. The first model accounts for biological variabilities by assuming that the concentrations are Gaussian distributed with a mean and a covariance matrix that depend on the status only for the biomarkers. The second one is an extension that also takes into account the technical variabilities that may significantly impact the observed concentrations. The main contributions of the paper are: (1) a new Bayesian formulation of the biomarker selection problem, (2) the closed-form expression of the posterior probabilities in the noiseless case, and (3) a suitable approximated solution in the noisy case. The methods are numerically assessed and compared to the state-of-the-art methods (t test, LASSO, Battacharyya distance, FOHSIC) on synthetic and real data from proteins quantified in human serum by mass spectrometry in selected reaction monitoring mode. PMID- 28710704 TI - Systemic Analysis of miRNAs in PD Stress Condition: miR-5701 Modulates Mitochondrial-Lysosomal Cross Talk to Regulate Neuronal Death. AB - Parkinson's disease (PD) is complex neurological disorder and is prevalent in the elderly population. This is primarily due to loss of dopaminergic neurons in the substantia nigra pars compacta (SNc) region of the brain. The modulators of the selective loss of dopaminergic neurons in PD are still not well understood. The small non-coding RNAs specifically miRNAs fine-tune the protein levels by post transcriptional gene regulation. The role of miRNAs in PD pathogenesis is still not well characterized. In the current study, we identified the miRNA expression pattern in 6-OHDA-induced PD stress condition in SH-SY5Y, dopaminergic neuronal cell line. The targets of top 5 miRNAs both up- and down regulated were analyzed by using StarBase. The putative pathways of identified miRNAs included neurotrophin signaling, neuronal processes, mTOR, and cell death. The level of miR-5701 was significantly downregulated in the presence of 6-OHDA. The putative targets of miR-5701 miRNA include genes involved in lysosomal biogenesis and mitochondrial quality control. The transfection of miR-5701 mimic decreased the transcript level of VCP, LAPTM4A, and ATP6V0D1. The expression of miR-5701 mimic induces mitochondrial dysfunction, defect in autophagy flux, and further sensitizes SH-SY5Y cells to 6-OHDA-induced cell death. To our knowledge, the evidence in the current study demonstrated the dysregulation of specific pattern of miRNAs in PD stress conditions. We further characterized the role of miR-5701, a novel miRNA, as a potential regulator of the mitochondrial and lysosomal function determining the fate of neurons which has important implication in the pathogenesis of PD. PMID- 28710703 TI - IgG4-related disease involving polyserous effusions with elevated serum interleukin-6 levels: a case report and literature review. AB - Immunoglobulin G4-related disease (IgG4-RD) is a recently described immune mediated fibroinflammatory disease with a characteristic histopathologic appearance that can affect various organs. We report a 43-year-old Chinese female patient with IgG4-RD involving polyserous effusions with reports of worsening exertional dyspnea for 3 months. Laboratory blood tests revealed that serum interleukin (IL)-6, carbohydrate antigens (CA-199 and CA-125), and alpha fetoprotein levels were significantly increased, but serum IgG4 levels were normal. Repeat pleural effusion and ascite analysis showed lymphocyte-predominant exudates. In addition, computed tomography scan showed massive pleural effusion in the right pleural cavity, abdominal effusion, and some pericardial effusion with a partial compression atelectasis. Further, medical thoracoscopy was performed to examine the pleural cavity and found multiple nodules on the pleura and partly thickened pleura with a reddish color. Histopathologic and immunohistochemical examination revealed marked lymphocytes and IgG4-positive plasma cell infiltration. The patient was finally diagnosed with IgG4-RD according to the comprehensive diagnostic criteria, although the patient presented similar serological and pathological manifestations of Castleman disease (CD). Our case suggests that IgG4-RD may be one of the causes of polyserous effusions and shows the difficulties in differentiating between IgG4 RD and CD. PMID- 28710705 TI - Long-Term Outcomes of Patients with Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features (NIFTP) >=4 cm Treated Without Radioactive Iodine. PMID- 28710706 TI - Synchronous and Metastatic Papillary and Follicular Thyroid Carcinomas with Unique Molecular Signatures. AB - Despite the relatively high prevalence of thyroid cancer, the occurrence of multiple synchronous, distinct subtypes of primary thyroid carcinoma is uncommon. The incidental finding of papillary thyroid microcarcinoma in a gland with a biologically relevant follicular or medullary carcinoma is more frequent than the synchronous occurrence of multiple clinically significant carcinomas. We report a case of synchronous papillary and follicular thyroid carcinomas metastatic to lymph node and bone, respectively. Next generation sequencing showed BRAF V600E mutation in the primary papillary carcinoma and NRAS Q61R mutation in the primary follicular carcinoma and bony metastasis. To our knowledge, this is the first reported case of synchronous and metastatic primary papillary and follicular carcinomas, and the first report of synchronous BRAF V600E mutated papillary and NRAS mutated follicular carcinoma. PMID- 28710708 TI - The bridge between design and analysis. AB - The overall purpose of the 'Statistical Points and Pitfalls' series is to help readers and researchers alike increase awareness of how to use statistics and why/how we fall into inappropriate choices or interpretations. We hope to help readers understand common misconceptions and give clear guidance on how to avoid common pitfalls by offering simple tips to improve your reporting of quantitative research findings. Each entry discusses a commonly encountered inappropriate practice and alternatives from a pragmatic perspective with minimal mathematics involved. We encourage readers to share comments on or suggestions for this section on Twitter, using the hashtag: #mededstats. PMID- 28710707 TI - Prescription Patterns of Non-Vitamin K Oral Anticoagulants Across Indications and Factors Associated with Their Increased Prescribing in Atrial Fibrillation Between 2012-2015: A Study from the Norwegian Prescription Database. AB - OBJECTIVE: We studied prescription patterns for non-vitamin K oral anticoagulants (NOACs) in Norway between 2012 and 2015, and compared NOAC and warfarin patient characteristics such as age, gender and cardiovascular (CV) co-medications across reimbursed indications. Factors associated with NOAC prescribing in atrial fibrillation (AF) were also analysed. METHODS: All Norwegian patients (N = 156,124) who received at least one dispensed NOAC or warfarin prescription within the indications of AF, deep vein thrombosis and pulmonary embolism (DVT_PE) or prevention of venous thromboembolic events after a hip or knee surgery (VTE_surg) between 2012 and 2015 were included in the study. Descriptive statistics was applied to compare patient characteristics between NOACs and warfarin across indications and a logistic regression model was used to identify factors associated with NOAC prescribing in AF. RESULTS: NOACs and warfarin were most commonly prescribed in AF (83,729 patients in 2015), followed by DVT_PE (16,077 patients) and lastly in VTE_surg (4060 patients). In 2015, NOACs achieved a dominant (>50%) patient share over warfarin in AF and DVT_PE, and were prescribed in >80% of new oral anticoagulation (OAC) patients. Apixaban, despite its delayed market entry, emerged as the preferred NOAC in VTE_surg (46% share), whereas rivaroxaban captured a 43% patient share in DVT_PE. Warfarin patients were on average older and received more CV co-medication than NOAC patients in AF and DVT_PE. Age, gender and certain CV co-medications emerged as significant predictors of NOAC prescribing in AF. AF patients <70 years old had higher odds of NOAC prescribing (OR 1.19-1.29, depending on age category), in contrast to patients >74 years old (OR 0.51-0.77). Women had 32% higher odds of receiving a NOAC in AF. CONCLUSION: NOACs achieved a dominant market share over warfarin within 3 years from receiving reimbursement in Norway. There were significant differences in patient characteristics between drugs and indications. PMID- 28710709 TI - Psychological Factors Associated With Painful Versus Non-Painful HIV-Associated Sensory Neuropathy. AB - HIV-associated sensory neuropathy (HIV-SN) is a common, and frequently painful complication of HIV, but factors that determine the presence of pain are unresolved. We investigated: (i) if psychological factors associated with painful (n = 125) versus non-painful HIV-SN (n = 72), and (ii) if pain and psychological factors affected quality of life (QoL). We assessed anxiety and depression using the Hopkins Symptoms Checklist-25. Pain catastrophizing and QoL were assessed using the Pain Catastrophizing Scale and Euroqol-5D, respectively. Presence of neuropathy was detected using the Brief Neuropathy Screening Tool, and pain was characterised using the Wisconsin Brief Pain Questionnaire. Overall, there was a high burden of pain, depression and anxiety in the cohort. None of the psychological variables associated with having painful HIV-SN. Greater depressive symptoms and presence of pain were independently associated with lower QoL. In those participants with painful HIV-SN, greater depressive symptom scores were associated with increased pain intensity. In conclusion, in a cohort with high background levels of psychological dysfunction, psychological factors do not predict the presence of pain, but both depression and presence of pain are associated with poor quality of life. PMID- 28710710 TI - Interventions for Increasing HIV Testing Uptake in Migrants: A Systematic Review of Evidence. AB - Migrants have been identified as being at greater risk for late HIV testing and diagnosis. Late diagnosis is of concern because timely diagnosis and initiation of treatment can both optimise health outcomes and reduce transmission. We reviewed and evaluated interventions that aimed to increase HIV testing uptake in migrant populations. Of 6511 papers retrieved, 10 met the inclusion criteria and were included in the review. Three types of interventions were identified (exposure to HIV prevention messages, HIV education programs, and direct offer of testing). All interventions were based on individual models of behaviour change targeting migrants or GPs. While important, interventions that also address broader health system and structural factors that contribute to late HIV diagnosis in at-risk members of migrant populations are needed. Integrating PITC into existing primary healthcare settings shows promise of creating an enabling environment within patient-doctor relationships that can encourage HIV testing uptake among migrant populations. PMID- 28710711 TI - HIV-Risk Behaviors and Social Support Among Men and Women Attending Alcohol Serving Venues in South Africa: Implications for HIV Prevention. AB - Alcohol use is associated with increased HIV-risk behaviors, including unprotected sex and number of sex partners. Alcohol-serving venues can be places to engage in HIV-related sexual risk behaviors, but are also important sites of social support for patrons, which may mitigate risks. We sought to examine the relationship between alcohol-serving venue attendance, social support, and HIV related sexual risk behavior, by gender, in South Africa. Adult patrons (n = 496) were recruited from six alcohol-serving venues and completed surveys assessing frequency of venue attendance, venue-based social support, and recent sexual behaviors. Generalized estimating equations tested associations between daily venue attendance, social support, and sexual behaviors, separately by gender. Interaction effects between daily attendance and social support were assessed. Models were adjusted for venue, age, education, and ethnicity. Daily attendance at venues was similar across genders and was associated with HIV-related risk behaviors, but the strength and direction of associations differed by gender. Among women, daily attendance was associated with greater number of partners and higher proportion of unprotected sex. Social support was a significant moderator, with more support decreasing the strength of the relationship between attendance and risk. Among men, daily attendance was associated with a lower proportion of unprotected sex; no interaction effects were found for attendance and social support. Frequent venue attendance is associated with additional HIV-related risks for women, but this risk is mitigated by social support in venues. These results were not seen for men. Successful HIV interventions in alcohol-serving venues should address the gendered context of social support and sexual risk behavior. PMID- 28710712 TI - Headache and visual impairment after twin birth: a challenging diagnosis. PMID- 28710713 TI - A consensus for the development of a vector model to assess clinical complexity. AB - The progressive rise in multimorbidity has made management of complex patients one of the most topical and challenging issues in medicine, both in clinical practice and for healthcare organizations. To make this easier, a score of clinical complexity (CC) would be useful. A vector model to evaluate biological and extra-biological (socio-economic, cultural, behavioural, environmental) domains of CC was proposed a few years ago. However, given that the variables that grade each domain had never been defined, this model has never been used in clinical practice. To overcome these limits, a consensus meeting was organised to grade each domain of CC, and to establish the hierarchy of the domains. A one-day consensus meeting consisting of a multi-professional panel of 25 people was held at our Hospital. In a preliminary phase, the proponents selected seven variables as qualifiers for each of the five above-mentioned domains. In the course of the meeting, the panel voted for five variables considered to be the most representative for each domain. Consensus was established with 2/3 agreement, and all variables were dichotomised. Finally, the various domains were parametrized and ranked within a feasible vector model. A Clinical Complexity Index was set up using the chosen variables. All the domains were graphically represented through a vector model: the biological domain was chosen as the most significant (highest slope), followed by the behavioural and socio-economic domains (intermediate slope), and lastly by the cultural and environmental ones (lowest slope). A feasible and comprehensive tool to evaluate CC in clinical practice is proposed herein. PMID- 28710714 TI - Disseminated tumor cells are not associated with established risk factors, L1CAM immunoreactivity and outcome in endometrial carcinoma. AB - PURPOSE: The presence of disseminated tumor cells (DTC) in the bone marrow of endometrial carcinoma patients has been demonstrated previously. In contrast to breast cancer, no prognostic significance or association with clinicopathological features was revealed for endometrial carcinoma so far. The aim of this study was to investigate DTC in a large patient cohort with in-depth pathology review data available and to study DTC occurrence in the context of L1CAM and long-term disease specific follow-up. METHODS: Patients treated for endometrial carcinoma at the Tuebingen University Women's hospital between 2003 and 2013 were identified. Cases with previous expert central pathology review including L1CAM immunohistochemistry and bone marrow aspirates available were selected. The presence of DTC and L1CAM expression was studied immunohistochemically. RESULTS: In 395 cases with a confirmed diagnosis of endometrial carcinoma, bone marrow aspirates were available. DTC were detected in 17.2%. The presence of DTC was independent from tumor histology, grade, lymphovascular space involvement (LVSI), FIGO stage, myoinvasion, L1CAM immunoreactivity, and nodal metastasis. DTC occurred less frequently in cases with a microcystic elongated and fragmented (MELF) pattern of invasion (2.2 vs. 21.8%, p = 0.0003). Disease progression was distributed equally among patients with and without DTC present. CONCLUSIONS: We were able to confirm previous findings of DTC presence in a large well characterized cohort of endometrial carcinoma patients. DTC are detectable in almost one-fifth of endometrial carcinoma and occur less frequently with a MELF pattern of invasion. Further studies investigating the role of DTC in endometrial carcinoma are warranted. PMID- 28710715 TI - Clinical utility of a blood-based protein assay to increase screening of elevated risk patients for colorectal cancer in the primary care setting. AB - PURPOSE: Colorectal cancer (CRC) screening is effective in finding early stage CRC and dramatically improves survival rates. Despite this, the number of eligible patients who do not obtain CRC screening is unacceptably high. METHODS: We conducted a longitudinal, randomized controlled trial investigating the utility of a blood-based protein assay on the quality of care delivered by practicing PCPs in the United States. We used standardized simulated patients (CPVs), presenting with symptoms suggestive of a higher likelihood of CRC, to measure how frequently these PCPs ordered diagnostic colonoscopy. 190 PCPs cared for three patients at baseline and three patients post-intervention. The PCPs were randomized into one of two study arms: control and intervention. The intervention arm consisted of educational materials about the blood-based protein assay and positive test results. Each simulated patient in the intervention arm had a positive test result that was given to the doctor. The controls were given neither intervention materials nor blood-based protein assay results. Physician responses in both groups were scored against evidence-based criteria. Data were collected at baseline and post-intervention. RESULTS: At baseline, we found that 71% of physicians ordered diagnostic colonoscopy. In round 2, 23% of physicians in the intervention arm adopted the new blood-based protein assay. Ordering physicians were 3.88 (95% CI 1.67-9.03) times more likely to order a diagnostic colonoscopy. In percentage terms, those who ordered the assay were more likely to order colonoscopy (92%) than either intervention physicians who did not order the assay (77%) or control physicians (66%) (p < 0.001). A marginal effects estimation showed that use of the assay would increase ordering colonoscopy to nearly 95%. CONCLUSION: Over one-third of adults in the United States do not follow the recommended screening guidelines for CRC. The introduction of a blood based protein assay significantly increased the likelihood that physicians would order diagnostic colonoscopies in elevated-risk patients compared to those without access to the assay results. The overall change in clinical utility observed here has the potential to significantly improve clinical care. PMID- 28710716 TI - Humor norms for 4,997 English words. AB - Humor ratings are provided for 4,997 English words collected from 821 participants using an online crowd-sourcing platform. Each participant rated 211 words on a scale from 1 (humorless) to 5 (humorous). To provide for comparisons across norms, words were chosen from a set common to a number of previously collected norms (e.g., arousal, valence, dominance, concreteness, age of acquisition, and reaction time). The complete dataset provides researchers with a list of humor ratings and includes information on gender, age, and educational differences. Results of analyses show that the ratings have reliability on a par with previous ratings and are not well predicted by existing norms. PMID- 28710717 TI - A technological framework for running and analyzing animal head turning experiments. AB - Head turning experiments are widely used to test the cognition of both human infants and non-human animal species. Monitoring head turns allows researchers to non-invasively assess attention to acoustic or visual stimuli. In the majority of head turning experiments, the head direction analyses have been accomplished manually, which is extremely labor intensive and can be affected by subjectivity or other human errors and limitations. In the current study, we introduce an open source computer program for measuring head directions of freely moving animals including common marmoset monkeys (Callithrix jacchus), American alligators (Alligator mississippiensis), and Mongolian gerbils (Meriones unguiculatus) to reduce human effort and time in video coding. We also illustrate an exemplary framework for an animal head turning experiment with common marmoset monkeys. This framework incorporates computer-aided processes of data acquisition, preprocessing, and analysis using the aforementioned software and additional open source software and hardware. PMID- 28710718 TI - Complications after gastrectomy for cancer: Italian perspective. AB - Surgery for gastric cancer is associated with significant major morbidity and an estimated mortality rate of about 5%. A reliable comparison of post-operative outcomes is hampered by the lack of a clear, universally recognized, definition of the most frequent complications. This paper reports the final results of a project launched by the Italian Research Group for Gastric Cancer in September 2015, whose goal was to propose a comprehensive list of surgical-related, gastric cancer-specific complications, with their definitions. The project was carried out through a multicentric, mainly web-based, consensus of experts. The proposed list, following assessment and validation by a group of experts of the European Chapter of the International Gastric Cancer Association, will form the basis for implementing a "Complications Recording Sheet" that can be disseminated worldwide for proper and reliable post-operative assessment. PMID- 28710719 TI - Fragility fractures at Auckland City Hospital: we can do better. AB - : This study describes in detail the burden of caring for patients aged >= 50 years seen in one year with a fragility fracture in a large urban environment and shows that these fractures result in a long length of stay and significant mortality. Intervention to prevent further fracture was poorly done. PURPOSE: To examine the epidemiology of fragility fracture in patients over age 50 years and record the number who received appropriate secondary prevention treatment. METHODS: All patients aged >= 50 years presenting with a fracture during the 12 months following July 1st 2011, to Auckland City Hospital or residing in central Auckland at the time of their fracture, were identified from hospital and Accident Compensation Corporation records. A random sample of 55% of these patient's records were reviewed to establish the type of fracture, prior fracture and falls history, and use of bisphosphonates in the 12 months before presentation. Their length of stay (LOS) by type of fracture was recorded. The use of bisphosphonate drugs in the following 12 months was obtained from centralised national records of prescriptions. RESULTS: 2729 patients aged >= 50 years presented with a fragility fracture in the central Auckland region in one year. Fifty-six percent of these patients were seen at Auckland Hospital and of these, 82% patients required admission with a mean LOS of 20 days (SD +/- 24 days).The remaining 44% of patients were looked after in the private outpatient sector. Approximately 30% of the admissions were for hip fracture. Sixty-four percent of patients with a fragility fracture did not receive a potent bisphosphonate, 12% were considered not appropriate for treatment, and 24% received a potent bisphosphonate during their admission or in the next 12 months. CONCLUSIONS: Approximately 1 in 18 people aged >= 50 years presented in one year with a fragility fracture.Secondary prevention strategies were poorly implemented. Additional resources for identifying and initiating secondary fracture prevention care such as a Fracture Liaison Service are urgently needed. PMID- 28710720 TI - Starch accumulation in hulless barley during grain filling. AB - BACKGROUND: Starch consists of two types of molecules: amylose and amylopectin. The objective of this study was increase understanding about mechanisms related to starch accumulation in hulless barley (Hordeum vulgare L.) grain by measuring temporal changes in (i) grain amylose and amylopectin content, (ii) starch synthase activity, and (iii) the relative expressions of key starch-related genes. RESULTS: The amylopectin/amylose ratio gradually declined in both Beiqing 6 and Kunlun 12. In both cultivars, the activities of adenosine diphosphate glucose pyrophosphorylase, soluble starch synthase (SSS), granule bound starch synthase (GBSS), and starch branching enzyme (SBE) increased steadily during grain filling, reaching their maximums 20-25 days after anthesis. The activities of SSS and SBE were greater in Ganken 5 than in either Beiqing 6 or Kunlun 12. The expression of GBSS I was greater in Beiqing 6 and Kunlun 12 than in Ganken 5. In contrast, the expression of SSS I, SSS II and SBE I was greater in Ganken 5 than in Beiqing 6 and Kunlun 12. The peak in GBSS I expression was later than that of SSS I, SSS II, SBE IIa and SBE IIb. The GBSS I transcript in Kunlun 12 was expressed on average 90 times more than the GBSS II transcript. CONCLUSIONS: The results suggest that SBE and SSS may control starch synthesis at the transcriptional level, whereas GBSS I may control starch synthesis at the post transcriptional level. GBSS I is mainly responsible for amylose synthesis whereas SSS I and SBE II are mainly responsible for amylopectin synthesis in amyloplasts. PMID- 28710721 TI - Comments on "Camptocormia as presenting in lower motor neuron disease with TARDBP mutation: case report". PMID- 28710722 TI - Organosulfur compound protects against memory decline induced by scopolamine through modulation of oxidative stress and Na+/K+ ATPase activity in mice. AB - The present study investigated the possible effect of BMMS in protecting against memory impairment in an Alzheimer's disease model induced by scopolamine in mice. Another objective was to evaluate the involvement of oxidative stress and Na+/K+ ATPase activity in cerebral cortex and hippocampus of mice. Male Swiss mice were divided into four groups: groups I and III received canola oil (10 ml/kg, intragastrically (i.g.)), while groups II and IV received BMMS (10 mg/kg, i.g.). Thirty minutes after treatments, groups III and IV received scopolamine (1 mg/kg, intraperitoneal (i.p.)), while groups I and II received saline (5 ml/kg, i.p.). Behavioral tests were performed thirty minutes after scopolamine or saline injection. Cerebral cortex and hippocampus were removed to determine the thiobarbituric acid reactive species (TBARS) levels, non-protein thiols (NPSH) content, catalase (CAT) and Na+/K+ ATPase activities. The results showed that BMMS pretreatment protected against the reduction in alternation and latency time induced by scopolamine in the Y-maze test and step-down inhibitory avoidance, respectively. In the Barnes maze, the latency to find the escape box and the number of holes visited were attenuated by BMMS. Locomotor and exploratory activities were similar in all groups. BMMS pretreatment protected against the increase in the TBARS levels, NPSH content and CAT activity, as well as the inhibition on the Na+/K+ ATPase activity caused by scopolamine in the cerebral cortex. In the hippocampus, no significant difference was observed. In conclusion, the present study revealed that BMMS protected against the impairment of retrieval of short-term and long-term memories caused by scopolamine in mice. Moreover, antioxidant effect and protection on the Na+/K+ ATPase activity are involved in the effect of compound against memory impairment in AD model induced by scopolamine. PMID- 28710723 TI - Observational Review and Analysis of Concussion: a Method for Conducting a Standardized Video Analysis of Concussion in Rugby League. AB - BACKGROUND: Several professional contact and collision sports have recently introduced the use of sideline video review for club medical staff to help identify and manage concussions. As such, reviewing video footage on the sideline has become increasingly relied upon to assist with improving the identification of possible injury. However, as yet, a standardized method for reviewing such video footage in rugby league has not been published. The aim of this study is to evaluate whether independent raters reliably agreed on the injury characterization when using a standardized observational instrument to record video footage of National Rugby League (NRL) concussions. METHODS: Video footage of 25 concussions were randomly selected from a pool of 80 medically diagnosed concussions from the 2013-2014 NRL seasons. Four raters (two naive and two expert) independently viewed video footage of 25 NRL concussions and completed the Observational Review and Analysis of Concussion form for the purpose of this inter-rater reliability study. The inter-rater reliability was calculated using Cohen's kappa (kappa) and intra-class correlation (ICC) statistics. The two naive raters and the two expert raters were compared with one another separately. RESULTS: A considerable number of components for the naive and expert raters had almost perfect agreement (kappa or ICC value >= 0.9), 9 of 22 (41%) components for naive raters and 21 of 22 (95%) components for expert raters. For the concussion signs, however, the majority of the rating agreement was moderate (kappa value 0.6-0.79); both the naive and expert raters had 4 of 6 (67%) concussion signs with moderate agreement. The most difficult concussion sign to achieve agreement on was blank or vacant stare, which had weak (kappa value 0.4 0.59) agreement for both naive and expert raters. CONCLUSIONS: There appears to be value in expert raters, but less value for naive raters, in using the new Observational Review and Analysis of Concussion (ORAC) Form. The ORAC Form has high inter-rater agreement for most data elements, and it can be used by expert raters evaluating video footage of possible concussion in the NRL. PMID- 28710724 TI - Best candidates for dopamine agonist withdrawal in patients with prolactinomas. AB - PURPOSE: Dopamine agonist (DA) therapy is recommended as the first-line treatment for prolactinomas. However, it requires long treatment duration, and a high recurrence rate after DA withdrawal has been reported. We aimed to elucidate the predictors for long-term remission following DA withdrawal and propose the best candidates who can achieve complete remission after DA withdrawal. METHODS: In a retrospective cohort study, we included 89 patients with prolactinoma who have withdrawn DAs with normal prolactin (PRL) levels at Seoul National University Hospital, from 2000 to 2016. Patient's data were retrieved from the electronic medical records. RESULTS: The median age and median treatment duration of the study patients were 33 (15-73) years and 69.5 (8.3-277.4) months, respectively. The recurrence rate after drug withdrawal was 57.3% during the 23.9 (3.0-176.8) month follow-up period. Age, gender, baseline PRL level, and baseline maximum tumor diameter were similar between the remission and recurrence group. In the Cox-proportional hazard model analysis, the significant predictors for remission were nadir PRL level of <1 ng/dL (hazard ratio [95% confidence interval] = 0.37 [0.18-0.74]), invisible tumors on magnetic resonance imaging (MRI) (0.42 [0.24 0.74]), and treatment duration of >72 months (0.54 [0.30-0.96]). Of the subjects who met all the three criteria, 66.7% achieved long-term remission. CONCLUSIONS: Patients who have no tumor visible on MRI, have a nadir PRL level <1 ng/dL during drug treatment, and received drug treatment for >6 years may be the best candidates for DA withdrawal. PMID- 28710725 TI - Clinicopathologic parameters associated with postoperative complications and risk factors for tumor recurrence and mortality after tumor resection of patients with colorectal cancer. AB - OBJECTIVE: To delineate the association of postoperative complications with clinicopathologic factors and to identify risk factors for tumor recurrence and mortality after tumor resection in patients with colorectal cancer (CRC). METHODS: The clinical data of 1144 patients with CRC who underwent surgical intervention between 2003 and 2013 were retrieved. Correlations of postoperative complications with clinicopathologic factors were examined using univariate analysis. Risk factors for tumor recurrence and mortality of the patients after tumor resection were identified using multivariate Cox proportional hazards models. Time to relapse and overall survival were analyzed using log-rank test of Kaplan-Meier analysis. RESULTS: Blood carcinoembryonic antigen (CEA) significantly correlated with early symptoms, preoperative manifestations, and tumor pathology. Low differentiation grade of tumor increased the risk of recurrence after surgery in all patients with CRC. In the same cohort of patients, elevated blood CEA, low differentiation grade of tumor, laparotomy, smoking history, and TNM stage IV and III increased the mortality risk after tumor resection. In patients with advanced colon cancer, risk for postoperative mortality was increased by blood CEA, advanced tumor stage, and low tumor differentiation grade; while in those with advanced rectal cancer, blood CEA, pathologic type other than mucinous/adenocarcinoma, and laparotomy were identified as significant risk factors. In both groups of patients, postoperative chemotherapy significantly reduced the risk of mortality. CONCLUSIONS: The present work has identified clinical factors increasing the risk of recurrence as well as mortality after surgery in more than 1,000 patients with CRC. Postoperative chemotherapy is associated with a significant reduction in the risk of mortality. All of these findings should provide insights into the better management of critically ill patients with CRC. PMID- 28710726 TI - Adsorption of As(III) versus As(V) from aqueous solutions by cerium-loaded volcanic rocks. AB - Contamination of drinking water with arsenic causes severe health problems in various world regions. Arsenic exists predominantly as As(III) and As(V) depending on the prevailing redox conditions of the environment. Most of the techniques developed for treating As(V) are not very effective for As(III), which is more toxic and mobile than As(V). In this study, novel cerium-loaded pumice (Ce-Pu) and red scoria (Ce-Rs) adsorbents were developed to remove both As(III) and As(V) ions from water. The Ce-Pu and Ce-Rs adsorbents were characterized using ICP-OES, EDX, and SEM. The experimental equilibrium sorption data fitted well Freundlich and Dubinin-Radushkevich (D-R) isotherms. The adsorption was very fast and reached an equilibrium within 2 h. Both Ce-Rs and Ce-Pu showed high As(III) and As(V) removal efficiency in a wide pH range between 3 and 9, which is an important asset for practical applications. The Ce-Pu and Ce-Rs adsorbents can be recycled and used up to three adsorption cycles without significant loss of their original efficiency. Accordingly, Ce-Pu and Ce-Rs seem to be suitable for removal of arsenic from aqueous systems. PMID- 28710728 TI - Water safety plans as a tool for drinking water regulatory frameworks in Arctic communities. AB - Arctic communities often face drinking water supply challenges that are unique to their location. Consequently, conventional drinking water regulatory strategies often do not meet the needs of these communities. A literature review of Arctic jurisdictions was conducted to evaluate the current water management approaches and how these techniques could be applied to the territory of Nunavut in Canada. The countries included are all members of the Arctic Council and other Canadian jurisdictions considered important to the understanding of water management for Northern Canadian communities. The communities in Nunavut face many challenges in delivering safe water to customers due to remoteness, small community size and therefore staffing constraints, lack of guidelines and monitoring procedures specific to Nunavut, and water treatment and distribution systems that are vastly different than those used in southern communities. Water safety plans were explored as an alternative to water quality regulations as recent case studies have demonstrated the utility of this risk management tool, especially in the context of small communities. Iceland and Alberta both currently have regulated water safety plans (WSPs) and were examined to understand shortcomings and benefits if WSPs were to be applied as a possible strategy in Nunavut. Finally, this study discusses specific considerations that are necessary should a WSP approach be applied in Nunavut. PMID- 28710727 TI - The occurrence of microplastic contamination in littoral sediments of the Persian Gulf, Iran. AB - Microplastics (MPs; <5 mm) in aquatic environments are an emerging contaminant of concern due to their possible ecological and biological consequences. This study addresses that MP quantification and morphology to assess the abundance, distribution, and polymer types in littoral surface sediments of the Persian Gulf were performed. A two-step method, with precautions taken to avoid possible airborne contamination, was applied to extract MPs from sediments collected at five sites during low tide. MPs were found in 80% of the samples. Across all sites, fiber particles were the most dominate shape (88%), followed by films (11.2%) and fragments (0.8%). There were significant differences in MP particle concentration between sampling sites (p value <0.05). The sediments with the highest numbers of MPs were from sites in the vicinity of highly populated centers and municipal effluent discharges. FTIR analysis showed that polyethylene (PE), nylon, and polyethylene terephthalate (PET) were the most abundant polymer types. More than half of the observed MPs (56%) were in the size category of 1 4.7 mm length, with the remaining particles (44%) being in the size range of 10 MUm to <1 mm. Compared to literature data from other regions, intertidal sediments in the Persian Gulf cannot be characterized as a hot spot for MP pollution. The present study could, however, provide useful background information for further investigations and management policies to understand the sources, transport, and potential effects on marine life in the Persian Gulf. PMID- 28710729 TI - Performance of an integrated system combining microalgae and vertical flow constructed wetlands for urban wastewater treatment. AB - The present study investigated the performance of an integrated system, combining the sequential use of microalgae (MA) and vertical flow constructed wetland (VFCW) for the treatment of wastewaters produced at a university campus. Ecotoxicity and phytotoxicity assays were performed using respectively Daphnia magna and Lactuca sativa, whereas the genotoxicity of the wastewaters was assessed by using D. magna and Allium cepa. The results revealed that the major environmental impacts of the studied wastewaters are associated with the high eutrophication potential, due to high N-NH3 (68.8 +/- 25.7 mg L-1), total P (7.71 +/- 2.5 mg L-1), and BOD5 (526.4 +/- 177 mg L-1) values, pathogenic load, and genototoxicity (p < 0.0001). The results also showed that the integrated system (MA + VFCW) was not able to satisfactory reduce the total p values (only 4%). Nevertheless, the MA + VFCW system achieved very promising results for the nitrogen removal, with emphasis on N-NH3 removal (100%) and the highest BOD5 removal (57%). Neither the raw wastewaters nor the treated wastewaters were phytotoxic. The integrated system completely eliminated the ecotoxicity (100%) and genotoxicity (n.s.) of the raw wastewater and showed decontamination potential. Thus, the integrated system emerges as an innovative environmental technology and, with minor adjustments, might be efficiently used in large scale and eventually replace conventional wastewater treatment systems. PMID- 28710730 TI - Remediation of chromium-contaminated soil by electrokinetics and electrokinetics coupled with CaAl-LDH permeable reaction barrier. AB - The remediation of Cr(VI)-contaminated soil was investigated by electrokinetic (EK) and permeable-reactive-barrier assisted electrokinetic (EK-PRB). The medium of PRB was hydrocalumite (CaAl-LDH). The results showed that removal efficiency of hexavalent chromium (Cr(VI)) in EK-PRB and EK system was 96.49 and 85.50%, respectively. Simultaneously, the removal efficiency of total chromium (TCr) was 69.34 and 40.97% after 120-h treatment. The XRD, FTIR, and XPS analyses indicated that the reactive barrier media of CaAl-LDH successfully captured the chromium. Besides, the migration rate of chromium in EK-PRB was relatively faster than EK, since the media of PRB captured chromium in-time and reduced the influence of chromium accumulation on the migration of chromium. Moreover, the trivalent chromium (Cr(III)) was generated in EK/EK-PRB, and the chromium was stabilized in soil with the chemical speciations of oxidizable and residual fractions. Therefore, the treatment of EK-PRB and EK both increased the removal of chromium and decreased its environmental risks. PMID- 28710731 TI - Effects of salinity, C/S ratio, S/N ratio on the BESI process, and treatment of nanofiltration concentrate. AB - A laboratory-scale biodegradation and electron transfer based on the sulfur metabolism in the integrated (BESI(r)) process was used to treat a saline petrochemical nanofiltration concentrate (NFC). The integrated process consisted of activated sludge sulfate reduction (SR), and sulfide oxidation (SO) reactors, and a biofilm nitrification reactor. During the process, the total removal efficiencies of chemical oxygen demand (COD), ammonia nitrogen, and total nitrogen (TN) were 76.2, 83.8, and 73.1%, respectively. In the SR reactor, most of the organic degradation occurred and approximately 70% COD were removed by the sulfate-reducing bacteria (SRB). In the SO reactor, both the autotrophic and heterotrophic denitrifications were observed to take place. In parallel, batch experiments were conducted to detect the effects of different C/S and S/N ratios on COD removal and denitrification efficiency. The batch experiments were also conducted to detect the effects of salinity on COD and sulfate reduction. The composition of pollutants in the wastewater was complex, and some existing organics were not degraded by the SRB. The non-SRB groups also played important roles in the reactor. Under salinity-induced stress, the metabolisms of the SRBs and non-SRB groups were both inhibited. However, 6 g/L NaCl did not have much effect on the final COD removal efficiency. In the batch experiments, the added sulfide served as the electron donor for autotrophic denitrification. The added organics provided substance for heterotrophic denitrification. PMID- 28710732 TI - Economic growth and environmental pollution in Myanmar: an analysis of environmental Kuznets curve. AB - This empirical study examines the short- and long-run relationship between GDP as an economic growth indicator and CO2 emissions as an environmental pollution indicator in Myanmar by using annual time series data over the period of 1970 2014. It also carefully considered other proxies, such as trade openness, financial openness and urbanization, and structural breaks in the country. The fundamental objective of this study is to test the validity of environmental Kuznets curve (EKC) in the context of Myanmar. The dynamic estimates of the long- and short-term relationship among greenhouse gases (CO2, CH4, N2O), GDP, trade intensity, financial openness, and urbanization growth are built through an autoregressive distributed lag (ARDL) model. The empirical findings indicate that there is positive short- and long-run relationship between CO2 and GDP and thus, no evidence of EKC hypothesis is found for CO2 in Myanmar. Nevertheless, the existence of the EKC is observed for CH4 and N2O. On the other hand, trade and financial openness have inverse relationship with CO2 emissions. These results demonstrate that trade liberalization and financial openness will improve the environment quality in Myanmar in the long run. PMID- 28710733 TI - Assessing the chemical behavior and spatial distribution of yttrium and rare earth elements (YREEs) in a coastal aquifer adjacent to the Urmia Hypersaline Lake, NW Iran. AB - This study aims to shed light on the seasonal behavior of yttrium and rare earth elements (YREEs) in the Urmia Aquifer (UA), in the immediate vicinity of Urmia Lake (UL) in Iran. Samples of groundwater, collected under dry and wet conditions in coastal wells of UA, suggest a large degree of variability in both YREE abundance and normalized patterns. Although weathering or water-rock interactions (between the surface/groundwater and rock samples) were predicted to be the most probable source in explaining YREEs in groundwater samples, results to the contrary indicate that the groundwater do not inherit aquifer rock-like YREE signatures in the study area; this might be due to the relative stability of YREEs during the process of water-rock interactions, which suggest that methods based on YREEs can be beneficial in discrimination of water sources. Furthermore, findings demonstrated no significant relationship between Ce/Ce* and salinity (0.08 and 0.05 in wet and dry seasons, respectively), and between Eu/Eu* and salinity (0.1 and -0.04 in wet and dry seasons, respectively). Dissimilarity of patterns of YREEs in rock and water samples reveals YREEs as no conservative tracers in determining the UL saltwater intrusion into coastal groundwater. Therefore, the groundwater YREE concentrations and fractionation patterns in UA warrant controlling by coastal aquifer need to be controlled by other chemical weathering, adsorption, desorption, and solution complexation reactions. Finally, comparison of REE concentration values in groundwater samples with corresponding indicative admissible drinking water concentrations (IAC) demonstrated their suitability for drinking purposes. PMID- 28710734 TI - Multi-class determination of pharmaceuticals in wastewaters by solid-phase extraction and liquid chromatography tandem mass spectrometry with matrix effect study. AB - In this work, a multi-class analytical method for determination of 22 frequently used pharmaceuticals was developed and validated. Analytes were from different classes for example macrolides, fluoroquinolones, tetracyclines, sulfonamides, anthelmintics, anesthetics, and others. Method was intended for analysis of aqueous samples so the sample preparation was done using solid-phase extraction (SPE). Different sorbents (C8, C18, polymeric, and ion exchange sorbents) combining different eluents (methanol, ethanol, acetonitrile, acetone, ethyl acetate) were investigated during development of sample preparation step. Samples were analyzed using HPLC-MS/MS, and therefore, chromatographic and mass spectrometer conditions were investigated. Optimal extraction efficiencies for most of the investigated analytes were obtained with Oasis HLB polymeric sorbents with acetonitrile as eluent. A study of matrix effect was carried out for wastewater treatment plant (WWTP) influent and effluent. The method was validated for linearity, detection limits and quantification limits, repeatability, and reproducibility. Method detection limits were in the range of 2.0-204.0 ng L-1 for WWTP influent except for sulfaguanidine and dexamethasone. Also, method detection limits for WWTP effluent were from 1.0 to 115.4 ng L-1. Method was successfully applied for analysis of real wastewater samples from municipal wastewater treatment plant. In the influent, pharmaceuticals from all investigated groups were present and the concentrations were from 50.0 to 4914.3 ng L-1 for influent and 26.9 to 1699.2 ng L-1 for effluent. It was also reported that some pharmaceuticals showed higher concentrations in the wastewater effluent than in the influent. PMID- 28710735 TI - Geochemical characteristics of dissolved rare earth elements in acid mine drainage from abandoned high-As coal mining area, southwestern China. AB - Acid mine drainage (AMD) represents a major source of water pollution in the small watershed of Xingren coalfield in southwestern Guizhou Province. A detailed geochemical study was performed to investigate the origin, distribution, and migration of REEs by determining the concentrations of REEs and major solutes in AMD samples, concentrations of REEs in coal, bedrocks, and sediment samples, and modeling REEs aqueous species. The results highlighted that all water samples collected in the mining area are identified as low pH, high concentrations of Fe, Al, SO42- and distinctive As and REEs. The spatial distributions of REEs showed a peak in where it is nearby the location of discharging of AMD, and then decrease significantly with distance away from the mining areas. Lots of labile REEs have an origin of coal and bedrocks, whereas the acid produced by the oxidation of pyrite is a prerequisite to cause the dissolution of coal and bedrocks, and then promoting REEs release in AMD. The North American Shale Composite (NASC) normalized REE patterns of coal and bedrocks are enriched in light REEs (LREEs) and middle REEs (MREEs) relative to heavy REEs (HREEs). Contrary to these solid samples, AMD samples showed slightly enrichment of MREEs compared with LREEs and HREEs. This behavior implied that REEs probably fractionate during acid leaching, dissolution of bedrocks, and subsequent transport, so that the MREEs is primarily enriched in AMD samples. Calculation of REEs inorganic species for AMD demonstrated that sulfate complexes (Ln(SO4)+and Ln(SO4)2-) predominate in these species, accounting for most of proportions for the total REEs species. The high concentrations of dissolved SO42- and low pH play a decisive role in controlling the presence of REEs in AMD, as these conditions are necessary for formation of stable REEs-sulfate complexes in current study. The migration and transportation of REEs in AMD are more likely constrained by adsorption and co-precipitation of Fe-Al hydroxides/hydroxysulfate. In addition, the MREEs is preferentially captured by poorly crystalline Fe-Al hydroxides/hydroxysulfate, which favors that sediments also preserve NASC-normalized patterns with MREEs enrichment in the stream. PMID- 28710736 TI - Vegetation development and nutrients supply of trees in habitats with high sulfur concentration in reclaimed former sulfur mines Jeziorko (Southern Poland). AB - The paper presents an assessment of vegetation (composition and cover-abundance), nutrient supply, and especially sulfur accumulation in the trees foliage (birch and pine) used in reforestation and wood small-reed (Calamagrostis epigejos (L.) Roth) appearing in succession on reclaimed areas of the former Jeziorko sulfur mine (southern Poland, Tarnobrzeg region). In researched area, three categories of vegetation cover were determined: category D-degraded and unsuccessfully reforested plots, and two categories with successful reforestation: P-pine and B birch stands. On each category, four study plots (4-6 areas each, depends on site category) were established. Soil and vegetation samplings (current year and 2 year-old pine needles, birch leaves, and wood small-reed foliage) were collected on the subplots established in regular grid square (10 * 10 m) in each category. Basic soil properties and nutrient content in soils and vegetation were analyzed. Trees grew well in areas where neutralization and reclamation treatments were carried out properly and showed a good supply of nutrients (exception of phosphorus and nitrogen), while on category D, only herbaceous vegetation with low cover-abundance and dominated by wood small-reed were noted. Linear correlations between the soil and trees nutrients content occurred, while the correlations between the soil and wood small-reed did not occur. Wood small-reed did not display increased sulfur uptake which may indicate a strategy of blocking pollutant uptake from the soil and may be recommended as a species resistant to sulfurous soils. PMID- 28710737 TI - Effect of rice-straw biochar on selective biodegradation of nonylphenols in isomer specificity. AB - In a previous study, we found that rice-straw biochar degraded and removed hydrophobic organic contaminants (HOCs) through coupled adsorption biodegradation. However, few studies have determined whether biochar affects HOC isomer degradation and isomer-selective biodegradation or whether biochar can alter HOC isomer features, resulting in changes to HOC isomer residues in water environments. In this study, the effects of biochar at two dosages (0.001 and 0.01 g) on the biodegradation of ten isomers of a typical xenoestrogen of nonylphenol (NP) were evaluated. The results revealed that there were no effects of biochar on the adsorption of NP isomers. However, biochar addition affected the biodegradation of a specific isomer without altering the features of the NP isomers. The treatment of NP isomers with Pseudoxanthomonas sp. yielded degradation ratios ranging from 60.7 to 100%. At 0.001 g biochar treatment, the degradation of eight NP isomers was enhanced (except for NP194 and NP193a+b) due to their bulky structures. The degradation of the ten NP isomers was inhibited when 0.01 g biochar was added. These findings characterized the effects of biochar on NP isomer contaminants and provided basic information for the application of biochar for the remediation of NP isomer contaminants. PMID- 28710738 TI - Highly efficient and energy-conserved flocculation of copper in wastewater by pulse-alternating current. AB - Copper wastewater from industry is detrimental to plants and environment. There are some problems in the aspects of high efficiency and energy saving during treatment of wastewater. In present work, the novel double iron electrodes technique of pulse-alternating current was applied to flocculate copper in wastewater. The process parameters of the copper removal in wastewater were studied in the developed electrochemical reactors. Scanning electron microscopy, X-ray diffraction, and energy-dispersive spectroscopy were used to characterize the electrocoagulations. The copper residue in the effluent was measured by UV spectrophotometry. The adsorption mechanism was described through the isothermal adsorption curves of copper during flocculation processes. The simulated wastewater containing 100 mg dm-3 Cu2+ and 100 mg dm-3 NaCl as conductive salt was adjusted to pH 7.8-8 with ammonia or sulfuric acid. At room temperature of 20 25 degrees C, controlling the flow rate of 3 dm3 min-1, and applying pulse alternating current of 40 MUA gFe-1, the copper residue in the effluent passing through four-series reactors was reduced to 0.118 mg dm-3, which was far lower than 0.3 mg dm-3 (from GB20900-2008). The removal rate of copper could reach 99.882%. The removal of copper in the wastewater treated via our electrocoagulation technique was far more efficient than the conventional DC current coagulation and chemical flocculation. The double iron electrodes were used to reduce the concentration polarization and improved the current efficiency. The significant economic and good social benefit will be promisingly produced if our developed technique is applied in the treatment of industrial wastewater. PMID- 28710739 TI - Prevention and Management of Post-operative Complications Following ACL Reconstruction. AB - PURPOSE OF REVIEW: The goal of this paper is to review the current management and prevention of post-operative complications after anterior cruciate ligament (ACL) reconstruction. Trends in rehabilitation techniques will be presented, in addition to suggestions for interventions and expected milestones in ACL reconstruction recovery. RECENT FINDINGS: ACL reconstruction protocols have evolved to more of a criterion-based progression rather than a tissue-healing time frame. Given the evolution of ACL surgical reconstruction techniques and rehabilitation protocols, the risk of post-operative complications can arise both early and late in the recovery process. This paper will discuss the role of preventative measures as it applies to the post-operative patient with ACL reconstruction. Short-term complications following ACL reconstruction include infection and deficits to knee motion and strength, whereas long-term complications include secondary ACL injury to either the involved or contralateral knee and lack of ability to return to high-level sports following this procedure. Future research should continue to address the multifactorial causes of secondary ACL injury and limited ability of patients to return to high level activities. PMID- 28710740 TI - Mapping PROMIS Global Health Items to EuroQol (EQ-5D) Utility Scores Using Linear and Equipercentile Equating. AB - BACKGROUND: Mapping Patient-Reported Outcomes Measurement Information System Global Health (PROMIS-GH) to EuroQol 5-dimension, three-level version (EQ-5D-3L) provides a utility score for use in quality-of-life and cost-effectiveness analyses. In 2009, Revicki et al. mapped the PROMIS-GH items to EQ-5D-3L utilities using linear regression (REVReg). More recently, regression was shown to be ill-suited for mapping to preference-based measures due to regression to the mean. Linear and equipercentile equating are alternative mapping methods that avoid the issue of regression to the mean. Another limitation of the prior models is that ordinal predictors were treated as continuous. METHODS: Using data collected from the PROMIS Wave 1 sample, we refit REVReg, treating the PROMIS-GH items as categorical variables (CATReg). We applied linear and equipercentile equating to the REVReg model (REVLE, REVequip) and the CATReg model (CATLE, CATequip). We validated and compared the predictive accuracy of these models in a large sample of neurological patients at a single tertiary-care hospital. RESULTS: In the neurological disease patient sample, CATLE produced the strongest correlations between estimated and observed EQ-5D-3L scores and had the lowest mean squared error. The CATequip model had the lowest mean absolute error and had estimated scores that best matched the overall distribution of observed scores. CONCLUSIONS: Using linear and equipercentile equating, we created new models mapping PROMIS-GH items to EQ-5D-3L utility scores. EQ-5D-3L utility scores can be more accurately estimated using our models for use in cost-effectiveness studies or studies examining overall health-related quality of life. PMID- 28710741 TI - Eating disorders in musicians: a survey investigating self-reported eating disorders of musicians. AB - PURPOSE: This study aimed to estimate the prevalence of eating disorders (EDs) in musicians, and to evaluate their relation to perfectionism, stress, anxiety and depression. METHODS: It examined: (1) the prevalence of EDs using the Eating Disorder Examination Questionnaire (EDE-Q), body mass index (BMI) and self reports, (2) psychological risk factors using the Depression Anxiety Stress Scale (DASS-21) and perfectionism inventory and (3) demographic details, information about musical and career development, lifestyle, eating habits and health. A survey was distributed worldwide and a total of 301 English-speaking musicians aged 18 years and older participated. RESULTS: Our screening tools for EDs showed a high prevalence of EDs in musicians: the EDE-Q Global Score (EDE-QGS) showed pathological values in 18.66% of the musicians and when questioned about lifetime prevalence, 32.3% of the musicians answered positively. The median BMI was within the normal range. Regarding general mental health, the DASS-21 showed that depression and stress were severe, anxiety was extremely severe and the perfectionism inventory composite score was 26.53. There was no significant difference on the EDE-QGS between musicians who perform different types of music, but music students, professionals, soloists and musicians travelling overseas had a higher percentage of pathological EDE-QGS. Perfectionism was higher in classical musicians and there was a low positive correlation between EDE-QGS and the risk factors: perfectionism, depression, anxiety, stress, peer pressure and social isolation. CONCLUSION: EDs are prevalent in musicians and possible risk factors are their increased perfectionism, depression, anxiety and stress due to the demands of their job. PMID- 28710742 TI - Inpatient weight curve trajectory as a prognostic factor among adolescents with anorexia nervosa: a preliminary report. AB - OBJECTIVE: To investigate the predictive value of weight restoration trajectories for relapse within the first year after discharge from inpatient treatment among adolescents with AN. METHODS: Forty four inpatient adolescents (5 boys, 39 girls) aged 11-18 (M 14.85, SD 1.87) diagnosed with anorexia were assessed at admission and discharge from a general hospital inpatient ward. Re-hospitalizations within 1 year of discharge were recorded. Factors assessed included 1/BMI at admission, 2/BMI at discharge, 3/percent from target weight (PFTW) at discharge, 4/length of hospitalization, and 5/a weight restoration trajectory measuring weight drops during inpatient weight restoration (rates of negative cubic variation in body weight (NCV). RESULTS: Logistic regression indicated that negative cubic variation rates (NCV) predicted re-hospitalization. PFTW was found only marginally significant. CONCLUSION: Variations in weight restoration during inpatient treatment may be used to identify patients at risk for relapse. NCV can alert clinicians to initiate early relapse prevention interventions before discharge. Level of Evidence Level III, cohort study. PMID- 28710743 TI - Prevalence of TEM, SHV, and CTX-M genes of extended-spectrum beta-lactamase producing Escherichia coli strains isolated from urinary tract infections in adults. AB - Urinary tract infections (UTIs) are one of the major sources of widespread infectious diseases in the community as well as in the hospitals which increase the cause of morbidity and mortality. Prevalence of extended-spectrum-beta lactamase (ESBL)-producing uropathogenic E. coli isolates has been found to be increased rapidly across the world. The present study was undertaken to find out the frequency of bla TEM, bla CTX-M, and bla SHV genes among E. coli isolates from UTI and detect their sensitivity pattern. A total of 112 non-repeated E. coli isolates obtained from urine samples of UTI diagnosed patients were included in this study. Antibiotic susceptibility test was done by disc diffusion method. Seventy seven (68.75%) isolates were MDR and tested for ESBL. ESBL-positive isolates were screened for bla TEM, bla CTX-M, and bla SHV genes by monoplex PCR (polymerase chain reaction). Among 46 ESBL-producing E. coli isolates, 8.69% harboured all the three bla genes. The bla TEM was the predominant (93.47%) gene followed by bla CTX-M (82.6%) and bla SHV (4.34%). It can be concluded that the prevalence of MDR (multidrug resistance) ESBL-producing E. coli appears to be high and the highest identified gene was bla TEM. The knowledge of resistance pattern can help physician's select suitable empirical antibiotic regimens, so that antibiotics showing high-resistance pattern can be avoided. PMID- 28710744 TI - Cloning and characterization of F3PYC gene encoding pyruvate carboxylase in Aspergillus flavus strain (F3). AB - Pyruvate carboxylase is a major enzyme for biosynthesis of organic acids like; citric acid, fumeric acid, and L-malic acid. These organic acids play very important role for biological remediation of heavy metals. In this study, gene walking method was used to clone and characterize pyruvate carboxylase gene (F3PYC) from heavy metal resistant indigenous fungal isolate Aspergillus flavus (F3). 3579 bp of an open reading frame which encodes 1193 amino acid protein (isoelectric point: 6.10) with a calculated molecular weight of 131.2008 kDa was characterized. Deduced protein showed 90-95% similarity to those deduced from PYC gene from different fungal strains including; Aspergillus parasiticus, Neosartorya fischeri, Aspergillus fumigatus, Aspergillus clavatus, and Aspergillus niger. Protein generated from the PYC gene was a homotetramer (alpha4) and having four potential N-linked glycosylation sites and had no signal peptide. Amongst most possible N-glycosylation sites were -N-S-S-I- at 36 amino acid, -N-G-T-V- at 237 amino acid, N-G-S-S- at 517 amino acid, and N-T-S-R- at 1111 amino acid, with several functions have been proposed for the carbohydrate moiety such as thermal stability, pH, and temperature optima for activity and stabilization of the three-dimensional structure. Hence, cloning of F3PYC gene from A. flavus has important biotechnological applications. PMID- 28710746 TI - Osimertinib: A Review in T790M-Positive Advanced Non-Small Cell Lung Cancer. AB - Osimertinib (TagrissoTM) is an oral, CNS-active, third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that targets EGFR TKI-sensitizing mutations and, crucially, the T790M mutation that often underlies acquired resistance to EGFR TKI therapy. Osimertinib has been approved in numerous countries for use in patients with T790M-positive advanced NSCLC. In the pivotal, international AURA3 trial in patients with T790M-positive advanced NSCLC who had disease progression after EGFR TKI therapy, osimertinib treatment significantly prolonged progression-free survival (PFS; primary endpoint) compared with platinum-pemetrexed therapy at the time of the primary analysis. PFS results were consistent across predefined subgroups of patients, including those with CNS metastases at baseline. There was no difference between treatment groups in overall survival at 26% maturity. Objective response rates (ORRs) and patient-reported outcomes for prespecified symptoms were also significantly improved with osimertinib relative to platinum-pemetrexed, with CNS ORRs in patients with CNS metastases more than twofold higher in the osimertinib than in the platinum-pemetrexed group. Osimertinib had a manageable tolerability profile, with relatively few patients permanently discontinuing treatment because of adverse events (AEs). With limited treatment options available in this setting, osimertinib is an important option in adult patients with advanced EGFR T790M positive NSCLC. PMID- 28710745 TI - The pan-Bcl2 Inhibitor AT101 Activates the Intrinsic Apoptotic Pathway and Causes DNA Damage in Acute Myeloid Leukemia Stem-Like Cells. AB - BACKGROUND: Leukemia stem cells (LSCs) are considered to be the cause of treatment failure and relapse in acute myeloid leukemia (AML). Overexpression of the Bcl-2 family of anti-apoptotic proteins such as Bcl-2, Bcl-xl, and Mcl-1 accounts for survival and self-renewal of LSCs. AT101 binds to the BH3 motif of all Bcl-2 family anti-apoptotic proteins and demonstrates anti-tumor activity in multiple types of tumor. Thus, we hypothesized that this agent might have the potential to deplete LSCs. OBJECTIVE: The present study aims to investigate if and by what mechanism AT101 is able to target AML stem-like cells. METHODS: As LSCs and hematopoietic stem cells (HSCs) are enriched in CD34+CD38- populations, CD34+CD38- cells from KG1alpha and Kasumi-1 cell lines as well as CD34+ blasts from AML patients were used as LSC models, while CD34+ cells from healthy donors were used as normal hematopoietic cells. Cell proliferation and apoptosis were assessed by a cell counting kit-8 (CCK8) assay and an Annexin V/PI assay using flow cytometry, respectively. Colony-forming units experiments were performed to monitor the stemness features of AML cells. Western blot and quantitative real time polymerase chain reaction (qPCR) analysis were performed to examine the levels of proteins and mRNAs related to either the intrinsic apoptotic pathway or DNA damage response. RESULTS: AT101 inhibited proliferation and induced apoptosis in CD34+CD38- KG1alpha and Kasumi-1 cells in a dose- and time-dependent manner. Exposure to AT101 for 24 h resulted in apoptosis in primary CD34+ AML blasts (EC50 [concentration needed for a 50% maximal effect] = 2.45-76.00 MUmol/L), while it only had a modest effect on normal CD34+ hematopoietic cells. Mechanistically, AT101 activated the intrinsic apoptotic pathway by inhibition of Bcl-2 anti-apoptotic proteins, reflected by a decrease in mitochondrial membrane potential. Moreover, AT101 caused DNA damage (e.g., increased gammaH2AX phosphorylation), which might also contribute to its anti-leukemic effects. Interestingly, the ex vivo efficacy of AT101 in primary AML samples significantly correlated to hyperleukocytosis and FLT3-ITD mutations. AT101 was also effective against CD34+ blasts isolated from elderly patients and patients who did not achieve complete remission after induction therapy. CONCLUSIONS: AT101 effectively eliminates LSCs in vitro through the induction of DNA damage and activation of the intrinsic apoptotic pathway. AT101 is effective towards leukemic cells from patients with adverse prognostic factors, suggesting that AT101 could have the potential as an alternative salvage therapy for the treatment of relapsed and refractory AML. PMID- 28710747 TI - Phase I study of chimeric antigen receptor modified T cells in treating HER2 positive advanced biliary tract cancers and pancreatic cancers. AB - This phase I clinical trial (NCT01935843) is to evaluate the safety, feasibility, and activity of chimeric antigen receptor-engineered T cell (CART) immunotherapy targeting human epidermal growth factor receptor 2 (HER2) in patients with advanced biliary tract cancers (BTCs) and pancreatic cancers (PCs). Eligible patients with HER2-positive (>50%) BTCs and PCs were enrolled in the trial. Well cultured CART-HER2 cells were infused following the conditioning treatment composed of nab-paclitaxel (100-200 mg/m2) and cyclophosphamide (15-35 mg/kg). CAR transgene copy number in the peripheral blood was serially measured to monitor the expansion and persistence of CART-HER2 cells in vivo. Eleven enrolled patients received 1 to 2-cycle CART-HER2 cell infusion (median CAR+ T cell 2.1 * 106/kg). The conditioning treatment resulted in mild-to-moderate fatigue, nausea/vomiting, myalgia/arthralgia, and lymphopenia. Except one grade-3 acute febrile syndrome and one abnormal elevation of transaminase (>9 ULN), adverse events related to the infusion of CART-HER2 cells were mild-to-moderate. Post infusion toxicities included one case of reversible severe upper gastrointestinal hemorrhage which occurred in a patient with gastric antrum invaded by metastasis 11 days after the CART-HER2 cell infusion, and 2 cases of grade 1-2 delayed fever, accompanied by the release of C-reactive protein and interleukin-6. All patients were evaluable for assessment of clinical response, among which 1 obtained a 4.5-months partial response and 5 achieved stable disease. The median progression free survival was 4.8 months (range, 1.5-8.3 months). Finally, data from this study demonstrated the safety and feasibility of CART-HER2 immunotherapy, and showed encouraging signals of clinical activity. PMID- 28710748 TI - Longitudinal Changes in White Matter Fractional Anisotropy in Adult-Onset Niemann Pick Disease Type C Patients Treated with Miglustat. AB - Niemann-Pick disease type C (NPC) is a rare neurometabolic disorder resulting in impaired intracellular lipid trafficking. The only disease-modifying treatment currently available is miglustat, an iminosugar that inhibits the accumulation of lipid metabolites in neurons and other cells. This longitudinal diffusion tensor imaging (DTI) study examined how the rate of white matter change differed between treated and non-treated adult-onset NPC patient groups. Nine adult-onset NPC patients (seven undergoing treatment with miglustat, two not treated) underwent DTI neuroimaging. Rates of change in white matter structure as indexed by Tract Based Spatial Statistics (TBSS) of fractional anisotropy were compared between treated and untreated patients. Treated patients were found to have a significantly slower rate of white matter change in the corticospinal tracts, the thalamic radiation and the inferior longitudinal fasciculus. This is further evidence that miglustat treatment may have a protective effect on white matter structure in the adult-onset form of the disease. PMID- 28710749 TI - Express FRET Labeling and Analysis of Phagocytic Clearance. AB - Lysosomal DNase II in phagocytic digestion produces DNA ends with 3'PO4/5'OH, which differ from those created in apoptotic DNA fragmentation, and can be used to label phagocytic clearance of cell death. Here, we describe the use of these specific DNA ends as selective markers of phagocytic reaction in cell suspensions. The approach does not require cell fixation. It selectively labels blunt-ended DNA breaks with terminal 5'OH. The detection is performed by ultra fast FRET probes in a single step, closed-tube procedure. It takes 3 min and is signaled by fluorescence. The full step-by-step protocol is presented as well as instructions on analysis and representation of the results.The described DNA-end based phagocytosis marker and the new rapid FRET assay can be useful in studies of phagocytosis, apoptosis and in immune system assessments. PMID- 28710750 TI - Rapid Assessment of Genotoxicity by Flow Cytometric Detection of Cell Cycle Alterations. AB - Flow cytometry is a convenient method for the determination of genotoxic effects of environmental pollution and can reveal genotoxic compounds in unknown environmental mixtures. It is especially suitable for the analyses of large numbers of samples during monitoring programs. The speed of detection is one of the advantages of this technique which permits the acquisition of 104-105 cells per sample in 5 min. This method can rapidly detect cell cycle alterations resulting from DNA damage. The outcome of such an analysis is a diagram of DNA content across the cell cycle which indicates cell proliferation, G2 arrests, G1 delays, apoptosis, and ploidy.Here, we present the flow cytometric procedure for rapid assessment of genotoxicity via detection of cell cycle alterations. The described protocol simplifies the analysis of genotoxic effects in marine environments and is suitable for monitoring purposes. It uses marine mussel cells in the analysis and can be adapted to investigations on a broad range of marine invertebrates. PMID- 28710751 TI - Ultrasound Imaging of DNA-Damage Effects in Live Cultured Cells and in Brain Tissue. AB - High-frequency ultrasound (>20 MHz) spectroscopy can be used to detect noninvasively DNA damage in cell samples in vitro, and in live tissue both ex vivo and in vivo. This chapter focuses on the former two aspects. Experimental evidence suggests that morphological changes that occur in cells undergoing apoptosis result in changes in frequency-dependent ultrasound backscatter. With advances in research, ultrasound spectroscopy is advancing the boundaries of fast, label-free, noninvasive DNA damage detection technology with potential use in personalized medicine and early therapy response monitoring. Depending on the desired resolution, parametric ultrasound images can be computed and displayed within minutes to hours after ultrasound examination for cell death. PMID- 28710752 TI - Ultrasound Imaging of Apoptosis: Spectroscopic Detection of DNA-Damage Effects In Vivo. AB - In this chapter, we describe two new methodologies: (1) application of high frequency ultrasound spectroscopy for in vivo detection of cancer cell death in small animal models, and (2) extension of ultrasound spectroscopy to the lower frequency range (i.e., 1-10 MHz range) for the detection of cell death in vivo in preclinical and clinical settings. Experiments using tumor xenografts in mice and cancer treatments based on chemotherapy are described. Finally, we describe how one can detect cancer response to treatment in patients noninvasively early (within 1 week of treatment initiation) using low-frequency ultrasound spectroscopic imaging and advanced machine learning techniques. Color-coded images of ultrasound spectroscopic parameters, or parametric images, permit the delineation of areas of dead cells versus viable cells using high ultrasound frequencies, and the delineation of areas of therapy response in patient tumors using clinically relevant ultrasound frequencies. Depending on the desired resolution, parametric ultrasound images can be computed and displayed within minutes to hours after ultrasound examination for cell death. A noninvasive and express method of cancer response detection using ultrasound spectroscopy provides a framework for personalized medicine with regards to the treatment planning of refractory patients resulting in substantial improvements in patient survival. PMID- 28710753 TI - Fluorochrome-Labeled Inhibitors of Caspases: Expedient In Vitro and In Vivo Markers of Apoptotic Cells for Rapid Cytometric Analysis. AB - Activation of caspases is a characteristic event of apoptosis. Various cytometric methods distinguishing this event have been developed to serve as specific apoptotic markers for the assessment of apoptotic frequency within different cell populations. The method described in this chapter utilizes fluorochrome labeled inhibitors of caspases (FLICA) and is applicable to fluorescence microscopy, flow and imaging-cytometry as well as to confocal imaging. Cell-permeant FLICA reagents tagged with carboxyfluorescein or sulforhodamine, when applied to live cells in vitro or in vivo, exclusively label the cells that are undergoing apoptosis. The FLICA labeling methodology is rapid, simple, robust, and can be combined with other markers of cell death for multiplexed analysis. Examples are presented on FLICA use in combination with a vital stain (propidium iodide), detection of the loss of mitochondrial electrochemical potential, and exposure of phosphatidylserine on the outer surface of plasma cell membrane using Annexin V fluorochrome conjugates. FLICA staining followed by cell fixation and stoichiometric staining of cellular DNA demonstrate that FLICA binding can be correlated with the concurrent analysis of DNA ploidy, cell cycle phase, DNA fragmentation, and other apoptotic events whose detection requires cell permeabilization. The "time window" for the detection of apoptosis with FLICA is wider compared to the Annexin V binding, making FLICA a preferable marker for the detection of early phase apoptosis and therefore more accurate for quantification of apoptotic cells. Unlike many other biomarkers of apoptotic cells, FLICAs can be used to detect apoptosis ex vivo and in vivo in different tissues. PMID- 28710754 TI - The Fast-Halo Assay for the Detection of DNA Damage. AB - The need for express screening of the DNA damaging potential of chemicals has progressively increased over the past 20 years due to the wide number of new synthetic molecules to be evaluated, as well as the adoption of more stringent chemical regulations such as the EU REACH and risk reduction politics. In this regard, DNA diffusion assays such as the microelectrophoretic comet assay paved the way for rapid genotoxicity testing. A more significant simplification and speeding up of the experimental processes was achieved with the fast halo assay (FHA) described in the present chapter. FHA operates at the single cell level and relies on radial dispersion of the fragments of damaged DNA from intact nuclear DNA. The fragmented DNA is separated by diffusion in an alkaline solvent and is stained, visualized, and finally quantified using computer-assisted image analysis programs. This permits the rapid assessment of the extent of DNA breakage caused by different types of DNA lesions. FHA has proven to be sensitive, reliable, and flexible. This is currently one of the simplest, cheapest, and quickest assays for studying DNA damage and repair in living cells. It does not need expensive reagents or electrophoretic equipment and requires only 40 min to prepare samples for computer-based quantification. This technique can be particularly useful in rapid genotoxicity assessments and in high throughput genotoxicity screenings. PMID- 28710755 TI - Rapid Detection of Bacterial Susceptibility or Resistance to Quinolones. AB - The emergence of multidrug resistant microorganisms together with the decline in discovery and development of new antibiotics is of great concern in health-care policy. In this alarming context, an early and well-tailored antibiotic therapy is a relevant strategy not only to improve clinical outcome but also to avoid appearance and spreading of perilous resistant strains. One of the most common antibiotic classes is fluoroquinolones. They trap the DNA girase and/or topoisomerase IV on the DNA, resulting in DNA fragmentation. We have developed the Micromax(r) assay to determine, in situ, the integrity of the chromosomal DNA nucleoid from microorganisms. This was validated as a simple procedure for the rapid assessment of the susceptibility or resistance to quinolones in gram negative bacteria. After incubating with the quinolone, cells are trapped in an agarose microgel on a slide and incubated with a specific lysing solution to remove the cell wall and visualize the nucleoids under fluorescence microscopy. If the strain is susceptible to the quinolone, the bacterial nucleoids show a halo of diffusing DNA spots of fragmented DNA, whereas they appear intact in the resistant strain. The technical processing is performed in 40 min with practically total sensitivity and specificity. PMID- 28710756 TI - Rapid Detection of Apoptosis in Cultured Mammalian Cells. AB - Flow cytometry is a powerful tool for the analysis of apoptosis, the process that directly determines cell fate after the action of different stresses. Here, we describe a flow cytometry method for the assessment of early and late stages of apoptosis in non-fixed cultured cells using SYTO16, DRAQ7, and PO-PRO1 dyes simultaneously. This multicolor flow cytometry procedure requires 45 min for completion and provides a quantitative assessment of cell viability. It can be useful in evaluating the cytotoxic properties of new drugs, and antitumor interventions. PMID- 28710757 TI - Quick Detection of DNase II-Type Breaks in Formalin-Fixed Tissue Sections. AB - Blunt-ended DNase II-type breaks with 5' hydroxyls are generated in phagocytic cells of any lineage during digestion of the engulfed DNA. These breaks indicate the ongoing active phagocytic reaction. They are produced by the acid deoxyribonuclease-DNase II which is the primary endonuclease responsible for DNA degradation after its engulfment.Here, we present an express approach that detects blunt-ended 5' OH DNA breaks in fixed tissue sections. The technique is simple to perform and takes only 60 min to complete. It can be useful in studies of the clearance of dying cells in oncological, inflammatory, and autoimmune disorders. PMID- 28710758 TI - Express gamma-H2AX Immunocytochemical Detection of DNA Damage. AB - DNA can be damaged by many environmental factors including chemical agents and ionizing radiation which induce the formation of DNA double-stranded breaks (DSBs). If DSBs are not repaired in a timely fashion this may cause the disruption of genome integrity, which can result in cancer development. Typically, DSBs are followed by phosphorylation of histone protein H2AX, a member of the H2A family. Immunocytochemical detection of phosphorylated H2AX (e.g., gamma-H2AX) appears to be a useful technique for assessing DNA damage. Such an assessment is easy to do by analyzing labeling for gamma-H2AX under the microscope and does not require an expensive laboratory setup. Using HeLa cells treated with camptothecin as a model, we developed an easy-to-run protocol to analyze DSBs. Our protocol can be applied to testing the potency of different chemicals to induce DSBs in different types of cells and requires around 2 h to complete. PMID- 28710760 TI - Rapid Detection of DNA Strand Breaks in Apoptotic Cells by Flow- and Image Cytometry. AB - Extensive DNA fragmentation that generates a multitude of DNA double-stand breaks (DSBs) is a hallmark of apoptosis. We developed several variants of the widely used TUNEL methodology that is based on the use of exogenous terminal deoxynucleotidyl transferase (TdT) to label 3'OH ends in DSBs with fluorochromes. Flow- or image-cytometry is then employed to detect and quantify apoptotic cells labeled this way. Here, we describe a variant of this technique using BrdUTP as a TdT substrate. The incorporated BrdU is subsequently visualized by a fluorochrome tagged antibody. This is a particularly simple, rapid, and sensitive approach to detect DSBs.We also describe modifications of the labeling protocol permitting the use of deoxyribonucleotides other than BrdUTP to label DSBs. Concurrent differential staining of cellular DNA and multiparameter analysis of cells by flow- or image-cytometry enable correlations between apoptosis induction and the cell cycle phase. Examples of the detection of apoptotic cells in cultures of human leukemic cell lines treated with TNF-alpha and DNA topoisomerase I inhibitor topotecan are presented. The protocol can be applied to cells treated with cytotoxic drugs in vitro, ex vivo, or to clinical samples. PMID- 28710761 TI - Fast Micromethod: Determination of DNA Integrity in Cell Suspensions and in Solid Tissues. AB - The Fast Micromethod is a rapid and convenient microplate procedure for the determination of DNA integrity in cell suspensions and in solid tissues. The procedure is based on the ability of fluorochromes to preferentially interact with double-stranded DNA in alkaline conditions. Rapid sample lysis is followed by denaturation at high pH during 15 min. Only 30 ng of DNA from cell suspensions or tissue homogenates per single well are required for the analyses. The whole analysis is performed within 3 h or less (for one 96-well microplate).The Fast Micromethod is broadly used in biology and medicine. Its applications range from environmental pollution tests in marine invertebrates to the analysis of biopsy samples in cancer patients to detect DNA alterations caused by irradiation or chemotherapy.The procedure presented here describes the Fast Micromethod applied for the determination of DNA integrity in cell suspensions (HeLa cells) and solid tissues (mussel gills). PMID- 28710759 TI - Rapid Detection of gamma-H2AX by Flow Cytometry in Cultured Mammalian Cells. AB - Methods commonly used for detection of DNA double-strand breaks (DSBs) and analysis of cell death are generally time-consuming, and, therefore, any improvements in these techniques are important for researchers and clinicians. At present, flow cytometry is the most rapid method for detection of DSBs and cell viability. In this chapter, we provide our experience and methodological modification of flow cytometry protocol for the detection of gamma-H2AX, a well known marker of DSBs, in fixed mammalian fibroblasts. The modifications permit a reduction in the time required for DSB detection by flow cytometry. PMID- 28710762 TI - Quantification of DNA Damage and Repair in Mitochondrial, Nuclear, and Bacterial Genomes by Real-Time PCR. AB - DNA damage caused by genotoxic insults is often used as an indicator of specific diseases, environmental challenges, and metabolic processes. To date, various different methods have been described to detect damaged DNA. Many techniques need high amounts of DNA for the analysis and/or require the exact determination of DNA template concentration. Here, we describe a rapid and quantitative method for the evaluation of the relative levels of damage in mitochondrial, nuclear, and bacterial DNA in comparison to untreated controls. The approach is based on the real-time PCR amplification of DNA fragments of two different lengths in the respective samples. DNA damage detection using this protocol is gene-specific. The technique can also be expanded to monitor DNA repair and to detect genomic hot-spots for DNA lesions. PMID- 28710764 TI - Twelve-Gel Comet Assay Format for Quick Examination of DNA Damage and Repair. AB - The comet assay (single cell gel electrophoresis) is a sensitive, versatile method for detecting DNA damage in eukaryotic cells. The traditional comet assay format has 1 or 2 gels on a microscope slide, 1 sample per slide, and there is a limit of 40 gels per experiment given the size of a typical electrophoresis tank. To increase throughput, we have designed and tested a system with 12 minigels on one slide, allowing analysis of up to 12 times more samples in one electrophoresis run. The novel comet assay format compares well with the traditional technology. The various steps are suitable for further automation, and the formats can be adapted to fully automated scoring. The new procedures save time at all stages as fewer slides are handled, and the amounts of reagents needed are reduced significantly. This format is particularly useful for testing of numerous genotoxic agents and nanomaterials at different concentrations and on different types of cells; simultaneous analysis of different lesions using a range of enzymes; and analysis of cell extracts for DNA repair activity. PMID- 28710763 TI - Zebra Tail Amplification: Accelerated Detection of Apoptotic Blunt-Ended DNA Breaks by In Situ Ligation. AB - In situ ligation (ISL) is a simple and specific technique for apoptosis labeling in tissue sections. In its most economical version ISL uses ordinary PCR-labeled DNA fragments as probes. In tissue sections these makeshift probes are ligated to apoptotic DNA breaks by T4 DNA ligase. The approach can selectively label 5'PO4 DNA breaks with blunt ends, and is the histological equivalent of electrophoretic apoptotic ladder detection. The main drawback of this technique is its low speed, as it requires 18 h-incubation for efficient labeling. Here, we describe an easy modification of ISL which reduces the incubation time to 1 h and converts ISL into a rapid detection method taking ~3 h overall. Signal enhancement is achieved by a new type of isothermal amplification reaction which generates "zebra tails"- long and labeled extensions of the probes attached to DNA breaks. PMID- 28710765 TI - Immunofluorescence Analysis of gamma-H2AX Foci in Mammalian Fibroblasts at Different Phases of the Cell Cycle. AB - H2AX phosphorylation at Ser139 (formation of gamma-H2AX) is an indicator of double-strand breaks in DNA (DSBs) after the action of different genotoxic stresses, including ionizing radiation, environmental agents, and chemotherapy drugs. The sites of DSBs can be visualized as focal sites of gamma-H2AX using antibodies and immunofluorescence microscopy. The microscopy technique is the most sensitive method of DSB detection in individual cells. It is useful for experimental research, radiation biodosimetry, and clinical practice. In this chapter, we provide an immunochemical protocol for gamma-H2AX labeling and analysis by confocal microscopy. The advantage of the assay is that it enables the quantitation of gamma-H2AX foci in individual cells in different phases of the cell cycle. PMID- 28710766 TI - RAPD-PCR as a Rapid Approach for the Evaluation of Genotoxin-Induced Damage to Bacterial DNA. AB - RAPD PCR is a sensitive and reliable approach useful for the detection of DNA lesions due to environmental contaminants. In addition, this method is cost effective, and can be performed in any laboratory having a DNA thermocycler and gel electrophoresis system. Here, we describe its application to identify genotoxin-induced DNA damage in foodborne bacteria. DNA alterations are detected through the analysis of electrophoresis profiles with the appearance or disappearance of new bands as compared to the non-mutated control. The described RAPD PCR procedure takes 6 h for completion. It uses small amounts of DNA and can reveal even low mutation rates. PMID- 28710767 TI - Rapid Detection of gamma-H2Av Foci in Ex Vivo MMS-Treated Drosophila Imaginal Discs. AB - In Drosophila melanogaster, DNA double-strand breaks (DSBs) created by exposure to gamma or X-ray radiation can be quantified by immunofluorescent detection of phosphorylated histone H2Av (gamma-H2Av) foci in imaginal disc tissues. This technique has been less useful for studying DSBs in imaginal discs exposed to DSB inducing chemicals, since standard protocols require raising larvae in food treated with liquid chemical suspensions. These protocols typically take 3-4 days to complete and result in heterogeneous responses that do not provide information about the kinetics of DSB formation and repair. Here, we describe a novel and rapid method to quantify DSBs in imaginal discs cultured ex vivo with methyl methanesulfonate (MMS) or other DSB-inducing chemicals. The described method requires less than 24 h and provides precise control over MMS concentration and exposure time, enabling reproducible detection of transient DSBs. Furthermore, this technique can be used for nearly any chemical treatment and can be modified and adapted for several different experimental setups and downstream molecular analyses. PMID- 28710768 TI - Panobinostat sensitizes KRAS-mutant non-small-cell lung cancer to gefitinib by targeting TAZ. AB - Mutation of KRAS in non-small-cell lung cancer (NSCLC) shows a poor response to epidermal growth factor receptor (EGFR) inhibitors and chemotherapy. Currently, there are no direct anti-KRAS therapies available. Thus, new strategies have emerged for targeting KRAS downstream signaling. Panobinostat is a clinically available histone deacetylase inhibitor for treating myelomas and also shows potentiality in NSCLC. However, the therapeutic efficacy of panobinostat against gefitinib-resistant NSCLC is unclear. In this study, we demonstrated that panobinostat overcame resistance to gefitinib in KRAS-mutant/EGFR-wild-type NSCLC. Combined panobinostat and gefitinib synergistically reduced tumor growth in vitro and in vivo. Mechanistically, we identified that panobinostat-but not gefitinib-inhibited TAZ transcription, and the combination of panobinostat and gefitinib synergistically downregulated TAZ and TAZ downstream targets, including EGFR and EGFR ligand. Inhibition of TAZ by panobinostat or short hairpin RNA sensitized KRAS-mutant/EGFR-wild-type NSCLC to gefitinib through abrogating AKT/mammalian target of rapamycin (mTOR) signaling. Clinically, TAZ was positively correlated with EGFR signaling, and coexpression of TAZ/EGFR conferred a poorer prognosis in lung cancer patients. Our findings identify that targeting TAZ-mediated compensatory mechanism is a novel therapeutic approach to overcome gefitinib resistance in KRAS-mutant/EGFR-wild-type NSCLC. PMID- 28710769 TI - The biophysical properties of plasmalogens originating from their unique molecular architecture. AB - Plasmalogens are a unique class of phospholipids that are present in many organisms. Their presence in cell membranes has intrigued researchers for decades due to their unique molecular structure, namely the vinyl-ether bond at the sn-1 position, and their association with brain related disorders. Apparently, based on their amount in the cell membranes, their function is to provide exclusive structural and dynamical properties to these complex molecular assemblies. Yet, many of their physiological roles manifested through their biophysical properties have been challenging to identify. In this review, the biophysical properties of plasmalogens are discussed and compared to other lipid species. The role of plasmalogens is examined in the context of cell membrane function, and some future directions are given. PMID- 28710772 TI - Outcomes of conception subsequent to methotrexate treatment for an unruptured ectopic pregnancy. AB - OBJECTIVE: To assess the risk of adverse pregnancy outcomes in subsequent pregnancies among women treated with methotrexate for ectopic pregnancy. METHODS: In a retrospective single-center study, data were assessed for women treated with methotrexate for ectopic pregnancy at Asaf Harofe Medical Center, Zerifin, Israel, between May 2004 and May 2014. RESULTS: Overall, 226 women were treated with methotrexate for ectopic pregnancy and subsequently conceived. The median time from treatment to conception was 10 months (range 1-120 months), and 127 women conceived within 12 months of treatment. Except for early missed abortion which affected 23 (10.2%) pregnancies-adverse pregnancy outcomes such as fetal malformations were rare. The frequency of early abortion was lowest for women who conceived within 6 months of treatment with methotrexate (3/93, 3.2%), increased between 6 and 23 months (15/83, 18.1%), and remained high thereafter (7/50, 14.0%; P=0.006). CONCLUSION: The frequency of fetal malformation in a subsequent pregnancy was low among women treated with methotrexate for ectopic pregnancy. The frequency of early missed abortion was lowest during the first 6 months after treatment with methotrexate. PMID- 28710770 TI - An Arabidopsis kinase cascade influences auxin-responsive cell expansion. AB - Mitogen-activated protein kinase (MPK) cascades are conserved mechanisms of signal transduction across eukaryotes. Despite the importance of MPK proteins in signaling events, specific roles for many Arabidopsis MPK proteins remain unknown. Multiple studies have suggested roles for MPK signaling in a variety of auxin-related processes. To identify MPK proteins with roles in auxin response, we screened mpk insertional alleles and identified mpk1-1 as a mutant that displays hypersensitivity in auxin-responsive cell expansion assays. Further, mutants defective in the upstream MAP kinase kinase MKK3 also display hypersensitivity in auxin-responsive cell expansion assays, suggesting that this MPK cascade affects auxin-influenced cell expansion. We found that MPK1 interacts with and phosphorylates ROP BINDING PROTEIN KINASE 1 (RBK1), a protein kinase that interacts with members of the Rho-like GTPases from Plants (ROP) small GTPase family. Similar to mpk1-1 and mkk3-1 mutants, rbk1 insertional mutants display auxin hypersensitivity, consistent with a possible role for RBK1 downstream of MPK1 in influencing auxin-responsive cell expansion. We found that RBK1 directly phosphorylates ROP4 and ROP6, supporting the possibility that RBK1 effects on auxin-responsive cell expansion are mediated through phosphorylation dependent modulation of ROP activity. Our data suggest a MKK3 * MPK1 * RBK1 phosphorylation cascade that may provide a dynamic module for altering cell expansion. PMID- 28710771 TI - Detailed longitudinal sampling of glioma stem cells in situ reveals Chr7 gain and Chr10 loss as repeated events in primary tumor formation and recurrence. AB - Intratumoral heterogeneity at the genetic, epigenetic, transcriptomic, and morphologic levels is a commonly observed phenomenon in many aggressive cancer types. Clonal evolution during tumor formation and in response to therapeutic intervention can be predicted utilizing reverse engineering approaches on detailed genomic snapshots of heterogeneous patient tumor samples. In this study, we developed an extensive dataset for a GBM case via the generation of polyclonal and monoclonal glioma stem cell lines from initial diagnosis, and from multiple sections of distant tumor locations of the deceased patient's brain following tumor recurrence. Our analyses revealed the tissue-wide expansion of a new clone in the recurrent tumor and chromosome 7 gain and chromosome 10 loss as repeated genomic events in primary and recurrent disease. Moreover, chromosome 7 gain and chromosome 10 loss produced similar alterations in mRNA expression profiles in primary and recurrent tumors despite possessing other highly heterogeneous and divergent genomic alterations between the tumors. We identified ETV1 and CDK6 as putative candidate genes, and NFKB (complex), IL1B, IL6, Akt and VEGF as potential signaling regulators, as potentially central downstream effectors of chr7 gain and chr10 loss. Finally, the differences caused by the transcriptomic shift following gain of chromosome 7 and loss of chromosome 10 were consistent with those generally seen in GBM samples compared to normal brain in large-scale patient-tumor data sets. PMID- 28710773 TI - Reciprocal modulation of helper Th1 and Th17 cells by the beta2-adrenergic receptor agonist drug terbutaline. AB - Catecholamine hormones are powerful regulators of the immune system produced by the sympathetic nervous system (SNS). They regulate the adaptive immune system by altering T-cell differentiation into T helper (Th) 1 and Th2 cell subsets, but the effect on Th17 cells is not known. Th17 cells, defined, in part, by chemokine receptor CCR6 and cytokine interleukin (IL)-17A, are crucial for mediating certain pathogen-specific responses and are linked with several autoimmune diseases. We demonstrated that a proportion of human Th17 cells express beta 2 adrenergic receptor (beta2AR), a G protein-coupled receptor that responds to catecholamines. Activation of peripheral blood mononuclear cells, which were obtained from venous blood drawn from healthy volunteers, with anti-cluster of differentiation 3 (CD3) and anti-CD28 and with a beta2-agonist drug, terbutaline (TERB), augmented IL-17A levels (P < 0.01) in the majority of samples. TERB reduced interferon gamma (IFNgamma) indicating that IL-17A and IFNgamma are reciprocally regulated. Similar reciprocal regulation was observed with dbcAMP. Proliferation of Th cells was monitored by carboxyfluorescein diacetate N succinimidyl ester labeling and flow cytometry with antibody staining for CD3 and CD4. TERB increased proliferation by a small but significant margin (P < 0.001). Next, Th17 cells (CD4+ CXCR3- CCR6+ ) were purified using an immunomagnetic positive selection kit, which removes all other mononuclear cells. TERB increased IL-17A from purified Th17 cells, which argues that TERB acts directly on Th17 cells. Thus, hormone signals from the SNS maintain a balance of Th cells subtypes through the beta2AR. PMID- 28710775 TI - Cyclooxygenase Inhibition: Pain, Inflammation, and the Cardiovascular System. AB - Inhibitors of the cyclooxygenases (COXs), the nonsteroidal antiinflammatory drugs (NSAIDs), relieve inflammatory pain, but are associated with gastrointestinal and cardiovascular complications. Given the widespread use of NSAIDs, there has been a longstanding interest in optimizing their risk-benefit ratio, for example by reducing their gastrointestinal risk. More recently, the focus has shifted toward the cardiovascular complications of NSAIDs and very large prospective studies have been performed to compare cardiovascular risk across distinct NSAIDs. Surprisingly, much less attention has been paid to the efficacy side of the risk benefit ratio. There is marked variability in the degree of pain relief by NSAIDs due to the complex interplay of molecular mechanisms contributing to the pain sensation, variability in the disposition of NSAIDs, and imprecision in the quantification of human pain. Here we discuss how NSAIDs relieve pain, how molecular mechanisms relate to clinical efficacy, and how this may inform our interpretation of clinical trials. PMID- 28710774 TI - UCSF ChimeraX: Meeting modern challenges in visualization and analysis. AB - UCSF ChimeraX is next-generation software for the visualization and analysis of molecular structures, density maps, 3D microscopy, and associated data. It addresses challenges in the size, scope, and disparate types of data attendant with cutting-edge experimental methods, while providing advanced options for high quality rendering (interactive ambient occlusion, reliable molecular surface calculations, etc.) and professional approaches to software design and distribution. This article highlights some specific advances in the areas of visualization and usability, performance, and extensibility. ChimeraX is free for noncommercial use and is available from http://www.rbvi.ucsf.edu/chimerax/ for Windows, Mac, and Linux. PMID- 28710777 TI - Update in enteroscopy: New devices and new indications. AB - The present review provides an update of the currently available (proto-) types of device-assisted enteroscopy (DAE). In recent years, newly designed double- and single-balloon enteroscopes have emerged. They aim to improve insertion depth into the small bowel, and they also allow more efficient endoscopic interventions. Nowadays, almost all conventional endoscopic procedures are feasible using DAE, opening the door to new indications. Recently, more data have become available on pediatric DAE, DAE-assisted colonoscopy, and DAE in patients with altered anatomy, including DAE-assisted endoscopic retrograde cholangiopancreatography and direct cholangioscopy. Although new enteroscopes are being developed, few comparative studies are available in order to define which DAE suits best for each indication. It is the duty of the international endoscopy community to set up clinical research projects to provide answers to these open questions. PMID- 28710776 TI - Outcomes of patients diagnosed with acute myeloid leukemia after solid organ transplantation. AB - Organ transplant recipients are at an increased risk for subsequent cancer including acute myeloid leukemia (AML). Treatment of AML following solid transplantation represents a clinical challenge as most patients have significant comorbidities at the time of AML diagnosis. In this study, we evaluated the treatment and outcomes of patients who developed AML following solid organ transplantation at our institution and reviewed the literature on outcomes for these patients. The study cohort consisted of 14 patients (median age 66 years, range 52-77 years) with newly diagnosed AML following solid organ transplantation. The median interval time between solid organ transplantation and AML diagnosis was 72 months (range 15-368 months). Seven patients received standard induction chemotherapy, four patients received intermediate type therapy, and the remaining three patients were deemed not fit for therapy and received palliative and supportive care. Six of the 11 treated patients (55%) achieved complete remission (CR). The median overall survival (OS) for all patients was 6 months. The median OS for the patients who achieved complete remission after therapy was 17 months and 2 months for the remaining patients. Despite initial CR, relapse rates are still high, suggesting that alternative strategies for post-remission therapies are warranted. PMID- 28710778 TI - A method for detecting rash and fever illness-associated viruses using multiplex reverse transcription polymerase chain reaction. AB - In this study, a new multiplex RT-PCR method for detecting various viral genes in patients with rash and fever illnesses (RFIs) was constructed. New primer sets were designed for detection of herpes simplex viruses 1 and 2 (HSV1 and 2), and Epstein-Barr virus (EBV). The newly designed and previously reported primer sets were used to detect 13 types of RFI-associated viruses by multiplex RT-PCR assay systems. Moreover, to eliminate non-specific PCR products, a double-stranded specific DNase was used to digest double-stranded DNA derived from the templates in clinical specimens. RFI-associated viruses were detected in 77.0% of the patients (97/126 cases) by the presented method, multiple viruses being identified in 27.8% of the described cases (35/126 cases). Detected viruses and clinical diagnoses were compatible in 32.5% of the patients (41/126 cases). Sensitivity limits for these viruses were estimated to be 101 -103 copies/assay. Furthermore, non-specific PCR products were eliminated by a double-stranded specific DNase with no influence on sensitivity. These results suggest that this method can detect various RFI-associated viruses in clinical specimens with high sensitivity and specificity. PMID- 28710780 TI - Sleep disorders in patients with erectile dysfunction. AB - OBJECTIVE: To assess the prevalence of obstructive sleep apnoea (OSA) in men presenting with erectile dysfunction (ED) at a single centre. PATIENTS AND METHODS: All men attending a specialised andrology outpatient department with a new diagnosis of ED were included in this prospective study. All patients completed three questionnaires: the International Index of Erectile Function (IIEF) and two sleep questionnaires [the Obstructive Sleep Apnoea Screening questionnaire and the Insomnia Severity Index (ISI)]. Their ED management was subsequently undertaken in accordance with local and European guidelines. An OSA diagnosis was made based on a score of >=3 on the Obstructive Sleep Apnoea Screening questionnaire and those patients were referred for specialist management. RESULTS: Between February and September 2016, 129 patients with ED completed the study questionnaires. In all, 71 patients (55%) had a score of >=3 on the Obstructive Sleep Apnoea Screening questionnaire, indicating a need for specialist sleep referral. Men who scored >=3 on the Obstructive Sleep Apnoea Screening questionnaire were significantly older (61.4 vs 46.5 years; P < 0.001) and had a significantly higher body mass index (29.4 vs 26.7 kg/m2 ; P < 0.001) when compared to the control group (OSA score of <3). The sleep apnoea group (OSA score of >=3) had significantly worse IIEF-ED scores (6.2 vs 9.1; P = 0.018) and ISI scores (7.9 vs 5.5; P = 0.061). CONCLUSION: Men presenting to the andrology clinic with ED are at significant risk of having undiagnosed sleep disorders. This has serious adverse health consequences, as well as being associated with potential dangers at work and travel. The patient compliance was high with 78% completing all three questionnaires. It is feasible to screen this population for sleep disturbance and this should be part of the ED assessment. PMID- 28710779 TI - Association between thyroid dysfunction and dysglycaemia: a prospective cohort study. AB - AIMS: To compare the incidence of hyperglycaemia among participants with low, elevated and normal serum thyroid-stimulating hormone concentration, as well as the incidence of abnormal thyroid function test results among participants with normal blood glucose and those with hyperglycaemia. METHODS: In a prospective study, a cohort of 72 003 participants with normal, low and elevated serum thyroid-stimulating hormone concentration were followed from the study beginning to the first report of diabetes and prediabetes. A proportional hazards regression model was used to calculate the hazard ratios and 95% CIs for each outcome, adjusting for age, sex, education level, smoking, alcohol consumption and obesity. Analyses for the association between dysglycaemia and incident abnormal thyroid function test were also conducted. RESULTS: During a median 2.6 year follow-up, the incident rates for dysglycaemia, particularly prediabetes, were substantially higher in participants with elevated thyroid-stimulating hormone concentrations at baseline, while the rates for participants with normal and low thyroid-stimulating hormone were similar. After controlling for risk factors, participants with elevated thyroid-stimulating hormone retained a 15% increase in risk of prediabetes (adjusted hazard ratio 1.15, 95% CI 1.04-1.26), but were not at greater risk of diabetes (adjusted hazard ratio 0.96, 95% CI 0.64 1.44). By contrast, participants with normal and low thyroid-stimulating hormone concentrations had similar dysglycaemia risks. Participants with diabetes and prediabetes were not at greater risks of developing abnormal thyroid function test results when compared with participants with euglycaemia. CONCLUSIONS: People with elevated serum thyroid-stimulating hormone concentration are at greater risk of developing prediabetes. Whether this includes a greater risk of developing frank diabetes may require an extended period of follow-up to clarify. PMID- 28710781 TI - Functionalities tuned enantioselectivity of phenylcarbamate cyclodextrin clicked chiral stationary phases in HPLC. AB - The mixed chloro- and methyl- functionalities can greatly modulate the enantioselectivities of phenylcarbamate cyclodextrin (CD) clicked chiral stationary phases (CSPs). A comparison study is herein reported for per(4-chloro 3-methyl)phenylcarbamate and per(2-chloro-5-methyl)phenylcarbamate beta-CD clicked CSPs (i.e., CCC4M3-CSP and CCC2M5-CSP). The enantioselectivity dependence on column temperature was studied in both normal-phase and reversed-phase mode high performance liquid chromatography (HPLC). The thermodynamic study revealed that the stronger intermolecular interactions can be formed between CCC4M3-CSP and chiral solutes to drive the chiral separation. The higher enantioselectivities of CCC4M3-CSP were further demonstrated with the enantioseparation of 17 model racemates in HPLC. PMID- 28710782 TI - Identification and functional analysis of two P450 enzymes of Gossypium hirsutum involved in DMNT and TMTT biosynthesis. AB - The homoterpenes (3E)-4,8-dimethyl-1,3,7-nonatriene (DMNT) and (E,E)-4,8,12 trimethyl-1,3,7,11-tridecatetraene (TMTT) are major herbivore-induced plant volatiles that can attract predatory or parasitic arthropods to protect injured plants from herbivore attack. In this study, DMNT and TMTT were confirmed to be emitted from cotton (Gossypium hirsutum) plants infested with chewing caterpillars or sucking bugs. Two CYP genes (GhCYP82L1 and GhCYP82L2) involved in homoterpene biosynthesis in G. hirsutum were newly identified and characterized. Yeast recombinant expression and enzyme assays indicated that the two GhCYP82Ls are both responsible for the conversion of (E)-nerolidol to DMNT and (E,E) geranyllinalool to TMTT. The two heterologously expressed proteins without cytochrome P450 reductase fail to convert the substrates to homoterpenes. Quantitative real-time PCR (qPCR) analysis suggested that the two GhCYP82L genes were significantly up-regulated in leaves and stems of G. hirsutum after herbivore attack. Subsequently, electroantennogram recordings showed that electroantennal responses of Microplitis mediator and Peristenus spretus to DMNT and TMTT were both dose dependent. Laboratory behavioural bioassays showed that females of both wasp species responded positively to DMNT and males and females of M. mediator could be attracted by TMTT. The results provide a better understanding of homoterpene biosynthesis in G. hirsutum and of the potential influence of homoterpenes on the behaviour of natural enemies, which lay a foundation to study genetically modified homoterpene biosynthesis and its possible application in agricultural pest control. PMID- 28710783 TI - Evaluation of vegetable protein in canine diets: Assessment of performance and apparent ileal amino acid digestibility using a broiler model. AB - Recent technological advances in the human food industry with respect to meat processing have decreased the availability of animal proteins to the pet food industry which typically formulates diets with an excess of animal protein. In the long term, this is not sustainable; thus, alternative protein sources need to be investigated. This study examined three canine diets, comparing a typical animal protein-based diet (control) with two experimental diets where the animal protein was substituted in part with vegetable protein (formulated based either on total protein or amino acid content) using a broiler model. Each diet was fed to six cages each containing two birds from day 15, 18 cages in total (36 birds). Excreta were collected from days 19 to 21. On day 23, birds were euthanized and weighed, and their ileal digesta were collected and pooled for each cage. In addition, one leg per cage was collected for evaluation of muscle mass. Results showed no significant difference in animal performance (feed intake or live weight gain) or muscle to leg proportion across the diets. Birds fed the control diet and the diet balanced for amino acid content exhibited the greatest coefficients of apparent metabolizability for nitrogen (p < .001). Birds fed the diets that contained partial replacement of animal with vegetable protein generally had greater ileal digestibility of amino acids compared to birds fed the control (animal protein) diet. Analysis of excreta showed no dietary difference in terms of dry matter content; however, birds fed the diet balanced for total protein and the diet balanced for amino acid content had significantly greater excreta nitrogen than the control (p = .038). Overall, the study suggests vegetable proteins when formulated based on amino acid content are a viable alternative to animal proteins in canine diets. PMID- 28710784 TI - Pregnancy after laparoscopic ventral mesh rectopexy: implications and outcomes. AB - AIM: Surgical management of rectal prolapse varies considerably. Most surgeons are reluctant to use ventral mesh rectopexy in young women until they have completed their family. The aim of the present study was to review outcomes of pregnancy following laparoscopic ventral mesh rectopexy from a tertiary referral centre over a 10-year period (2006-2016) and to review the impact on pelvic floor symptoms. METHOD: We undertook a retrospective review of a prospectively compiled database of patients who had undergone laparoscopic ventral rectopexy in a single centre over a 10-year period. Pelvic floor symptom scores (Vaizey for incontinence and Longo for obstructive defaecation) were collected at initial presentation (pre-intervention), post-intervention and after child birth. RESULTS: In all, 954 rectopexies were performed over this 10-year period. 225 (24%) patients were women and under 45 years of age (taken as an arbitrary cut off for decreased likelihood of pregnancy). Eight (4%) of these patients became pregnant following rectopexy. The interval between rectopexy and delivery was 42 months (21-50). Six patients delivered live babies by elective lower segment caesarean section and two by spontaneous vaginal delivery. Six were first babies and two were second. No mesh related adverse outcome was reported. No difference in pelvic floor symptoms was demonstrated on comparison of post-rectopexy and post-delivery scores. CONCLUSION: This study provides the first description in the English language literature of safe delivery by elective lower segment caesarean section or spontaneous vaginal delivery following laparoscopic ventral mesh rectopexy. No adverse impact on pelvic floor related quality of life was detected. PMID- 28710785 TI - Effect of thyroid hormone on cardiac function following orthotopic heart transplantation in piglets. AB - Studies in adult HT have demonstrated improved cardiac function in the recipient following administration of T3 to the donor. The purpose of this experiment was to assess the effects of T3 on the function of the immature donor heart following HT in a piglet model. A total of 32 piglets were divided into 16 donors and 16 recipients. Following creation of brain death, half of the donor piglets were randomized to receive three doses of T3 (0.2 MUg/kg) along with hydrocortisone (1 mg/kg). The donor hearts were then transplanted into the recipient piglets on CPB. Duration of survival off CPB, inotrope score, and EF of heart following CPB were evaluated. There were no differences between the two groups in age, weight, pre-brain death EF, T3 levels, and CPB times. Post-CPB survival times were inversely related to the ischemic times in both groups (Pearson r=-0.80, P<.001), and this relationship was not influenced by T3. There was no difference in inotrope score, EF, or biochemical assessment between the two groups. Administration of T3 in combination with hydrocortisone to the brain-dead donor confers no beneficial effect on myocardial function or survival following HT in a piglet model. PMID- 28710786 TI - Comparison of perioperative and functional outcomes of robotic partial nephrectomy for cT1a vs cT1b renal masses. AB - OBJECTIVE: To compare perioperative and functional outcomes of patients with cT1a or cT1b renal masses undergoing robotic partial nephrectomy (RPN) in a large multi-institutional study PATIENTS AND METHODS: The present retrospective Institutional Review Board-approved multi-institutional study utilised a prospectively maintained database to identify patients undergoing RPN by six surgeons for a solitary cT1a (n = 1 307) or cT1b (n = 377) renal mass from 2006 to 2016. Perioperative and renal function outcomes at discharge and at a median follow-up of 12.2 months were compared in univariable and multivariable regression analyses adjusting for surgeon performing the procedure and date of surgery. RESULTS: In univariable analysis, cT1b masses were associated with longer operative time (190.0 vs 159.0 min, P < 0.001), longer warm ischaemia time (18.8 vs 15.0 min, P < 0.001), higher estimated blood loss (150.0 vs 100.0 mL, P < 0.001), more intraoperative complications (5.6% vs 2.4%, P = 0.034), and more surgical postoperative complications (10.1% vs 5.7%, P =0.002). Results were similar in multivariable analysis with additional findings including more overall postoperative complications (odds ratio 1.55, P = 0.015) and longer length of stay (P < 0.001) associated with cT1b masses. There were no differences in the risk of progression of chronic kidney disease stage at 12.2 months, positive surgical margins, or major postoperative complications. CONCLUSIONS: Although our study shows a longer operative time, longer warm ischemia time, and higher complication rate for patients undergoing RPN for cT1b renal masses, the magnitude of these differences is small. RPN should be considered for cT1b lesions when anatomical and spatial location allow for a feasible procedure. PMID- 28710787 TI - Continuing competence assessment and maintenance in occupational therapy: Scoping review with stakeholder consultation. AB - BACKGROUND/AIM: Continuing competence activities hold the promise of improving health-care service quality, especially given concerns about system inefficiencies and fragmentation. The aim of this scoping review was to describe the assessment and maintenance of occupational therapists' continuing competence and identify knowledge gaps for future research. A secondary aim was comparing scoping review findings with those from other health-care fields and considering possible impact of varying international regulations. METHODS: A series of database searches retrieved peer-reviewed and grey literature on assessment and maintenance of occupational therapy continuing competence from 1995 to 2015. Themes were developed and findings shared with stakeholders, whose comments drove a second phase: searching for reviews related to continuing competence from allied health, medicine, and nursing, and reviewing websites and documents concerning regulatory requirements for occupational therapy continuing competence in seven English-speaking nations. RESULTS: Twenty-seven sources from the scoping review search met inclusion criteria. Stakeholder consultation validated the themes and preliminary knowledge gaps. Research into other health-care specialties corresponded to findings from the scoping review. The website/document review of occupational therapy regulatory requirements revealed wide variation on both the state/province and national levels. CONCLUSIONS: This scoping review highlights gaps in research on effective methods and assessment of occupational therapy continuing competence. Findings suggest a need for research on approaches to continuing competence that incorporate the translation of evidence to practice and address the influence of external factors. Regulatory agencies may address the quality of occupational therapy services by incorporating a variety of professional development options into requirements. PMID- 28710788 TI - Aromatic Micelles as a New Class of Aqueous Molecular Flasks. AB - Micelles are a versatile class of molecular assemblies typically composed of aliphatic molecules with hydrophilic groups. Polyaromatic molecules with hydrophilic groups, on the other hand, usually do not assemble into micellar structures in water but rather form columnar, pi-stacked architectures. This Minireview article focuses on the recent development of aqueous micellar nanostructures with multiple oligoarylene rods or polyaromatic panels. The new micelles with spherical polyaromatic shells, which we name "aromatic micelles", serve as functional molecular flasks with superior binding abilities for medium to very large molecules in water. PMID- 28710789 TI - ATR-101 inhibits cholesterol efflux and cortisol secretion by ATP-binding cassette transporters, causing cytotoxic cholesterol accumulation in adrenocortical carcinoma cells. AB - BACKGROUND AND PURPOSE: To further the development of new agents for the treatment of adrenocortical carcinoma (ACC), we characterized the molecular and cellular mechanisms of cytotoxicity by the adrenalytic compound ATR-101 (PD132301 02). EXPERIMENTAL APPROACH: We compared the effects of ATR-101, PD129337, and ABC transporter inhibitors on cholesterol accumulation and efflux, on cortisol secretion, on ATP levels, and on caspase activation in ACC-derived cell lines. We examined the effects of these compounds in combination with methyl-beta cyclodextrin or exogenous cholesterol to determine the roles of altered cholesterol levels in the effects of these compounds. KEY RESULTS: ATR-101 caused cholesterol accumulation, ATP depletion, and caspase activation within 30 minutes after addition to ACC-derived cells, whereas PD129337 did not. Suppression of cholesterol accumulation by methyl-beta-cyclodextrin or exogenous cholesterol, prevented ATP depletion and caspase activation by ATR-101. ATR-101 blocked cholesterol efflux and cortisol secretion, suggesting that it inhibited ABCA1, ABCG1, and MDR1 transporters. Combinations of ABCA1, ABCG1, and MDR1 inhibitors were also cytotoxic. Combinations of ATR-101 with inhibitors of ABCG1, MDR1, or mitochondrial functions had increased cytotoxicity. Inhibitors of steroidogenesis reduced ATP depletion by ATR-101, whereas U18666A enhanced cholesterol accumulation and ATP depletion together with ATR-101. ATR-101 repressed ABCA1, ABCG1, and IDOL transcription by mechanisms that were distinct from the mechanisms that caused cholesterol accumulation. CONCLUSIONS AND IMPLICATIONS: Inhibition of multiple ABC transporters and the consequent accumulation of cholesterol mediated the cytotoxicity of ATR-101. Compounds that replicate these effects in tumours are likely to be useful in the treatment of ACC. PMID- 28710790 TI - Amino-acid composition after loop deletion drives domain swapping. AB - Rational engineering of a protein to enable domain swapping requires an understanding of the sequence, structural and energetic factors that favor the domain-swapped oligomer over the monomer. While it is known that the deletion of loops between beta-strands can promote domain swapping, the spliced sequence at the position of the loop deletion is thought to have a minimal role to play in such domain swapping. Here, two loop-deletion mutants of the non-domain-swapping protein monellin, frame-shifted by a single residue, were designed. Although the spliced sequence in the two mutants differed by only one residue at the site of the deletion, only one of them (YEIKG) promoted domain swapping. The mutant containing the spliced sequence YENKG was entirely monomeric. This new understanding that the domain swapping propensity after loop deletion may depend critically on the chemical composition of the shortened loop will facilitate the rational design of domain swapping. PMID- 28710791 TI - Origin of enhanced VCD in amyloid fibril spectra: Effect of deuteriation and pH. AB - Supramolecular chirality of amyloid fibrils, protein aggregates related to many neurodegenerative diseases, is a remarkable property associated with fibril structure and polymorphism. Since its discovery almost 10 years ago there is still little understanding of this phenomenon, including the cause of the highly enhanced vibrational circular dichroism (VCD) intensity arising from fibril supramolecular chirality. In this study, VCD spectra, enhanced by filament supramolecular chirality, are presented for lysozyme and insulin fibrils above and below pH 2 and after deuterium exchange, above and below pD 2. Supramolecular chirality (observed by VCD) and fibril morphology (documented by atomic force microscopy) are not affected by protein deuteriation. In D2 O the fibril VCD sign pattern changes to fewer bands, with implications for the amide I/II origin of enhanced VCD intensity. Separation of amide I and II signals will facilitate calculations of enhanced VCD spectra of amyloid fibrils and enable a better understanding of the origin of the VCD sign pattern. PMID- 28710793 TI - Safety and performance of a novel collagenated xenogeneic bone block for lateral alveolar crest augmentation for staged implant placement. AB - OBJECTIVES: To evaluate the performance and safety of placing a collagenated xenogeneic bone block (CXBB) graft for the lateral bone augmentation of the alveolar crest prior to implant placement. MATERIAL & METHODS: In patients with single or multiple tooth gaps and a severe horizontal collapse of the alveolar ridge, a ridge augmentation procedure was performed using CXBB fixated with osteosynthesis screws to the atrophic bone crest and complemented with deproteinized bovine bone mineral particles (DBBM) and a native bilayer collagen membrane (NBCM). Patients were examined with CBCT prior to and 24 weeks after the augmentation. Twenty-six weeks postoperatively, a re-entry procedure was performed to evaluate the bone width and availability for adequate implant placement. RESULTS: Fifteen patients received 28 CXBB, and in 13 patients, a re entry procedure was performed. Eleven patients (84.6%) gained enough bone volume for implant insertion without additional contouring or secondary bone augmentation. The mean crest width at baseline was 2.83 mm (SD 0.57), and the mean crest width at re-entry was 6.90 mm (SD 1.22), with a mean ridge width increase of 4.12 mm (SD 1.32). Soft tissue dehiscence occurred during the follow up in 5 of 14 patients (35.7%) at various time points. In addition, there was a high incidence of early implant loss (30.8% [patient-based]). CONCLUSIONS: CXBB achieved significant horizontal crestal width gains allowing a secondary implant placement in the majority of the patients. However, the occurrence of soft tissue dehiscence may notably affect the outcome of the subsequent implant therapy. PMID- 28710794 TI - Ultrasound assessment of the sural nerve in patients with neuropathic pain after ankle surgery. AB - INTRODUCTION: The sural nerve may be damaged after ankle injury. The aim of our study was to determine the diagnostic utility of high-resolution sonography in patients with ankle fractures treated by open reduction and internal fixation in whom there was a clinical suspicion of sural neuropathy. METHODS: We examined the ultrasound (US) characteristics of patients with and without postsurgical sural neuropathic pain and healthy volunteers. Cross-sectional area (CSA), echogenicity, and vascularization of the sural nerves were recorded. RESULTS: Fourteen participants and all sural nerves were identified. CSA (P < 0.001) and vascularization (P = 0.002) were increased in symptomatic patients when compared with asymptomatic patients and healthy volunteers. There were no significant differences in nerve echogenicity (P = 0.983). DISCUSSION: US may be a valuable tool for evaluating clinically suspected sural nerve damage after ankle stabilization surgery. Sural nerve abnormalities are seen in patients with postsurgical neuropathic pain. Muscle Nerve 57: 407-413, 2018. PMID- 28710792 TI - Biophysical investigation of type A PutAs reveals a conserved core oligomeric structure. AB - : Many enzymes form homooligomers, yet the functional significance of self association is seldom obvious. Herein, we examine the connection between oligomerization and catalytic function for proline utilization A (PutA) enzymes. PutAs are bifunctional enzymes that catalyze both reactions of proline catabolism. Type A PutAs are the smallest members of the family, possessing a minimal domain architecture consisting of N-terminal proline dehydrogenase and C terminal l-glutamate-gamma-semialdehyde dehydrogenase modules. Type A PutAs form domain-swapped dimers, and in one case (Bradyrhizobium japonicum PutA), two of the dimers assemble into a ring-shaped tetramer. Whereas the dimer has a clear role in substrate channeling, the functional significance of the tetramer is unknown. To address this question, we performed structural studies of four-type A PutAs from two clades of the PutA tree. The crystal structure of Bdellovibrio bacteriovorus PutA covalently inactivated by N-propargylglycine revealed a fold and substrate-channeling tunnel similar to other PutAs. Small-angle X-ray scattering (SAXS) and analytical ultracentrifugation indicated that Bdellovibrio PutA is dimeric in solution, in contrast to the prediction from crystal packing of a stable tetrameric assembly. SAXS studies of two other type A PutAs from separate clades also suggested that the dimer predominates in solution. To assess whether the tetramer of B. japonicum PutA is necessary for catalytic function, a hot spot disruption mutant that cleanly produces dimeric protein was generated. The dimeric variant exhibited kinetic parameters similar to the wild-type enzyme. These results implicate the domain-swapped dimer as the core structural and functional unit of type A PutAs. ENZYMES: Proline dehydrogenase (EC 1.5.5.2); l glutamate-gamma-semialdehyde dehydrogenase (EC 1.2.1.88). DATABASES: The atomic coordinates and structure factor amplitudes have been deposited in the Protein Data Bank under accession number 5UR2. The SAXS data have been deposited in the SASBDB under the following accession codes: SASDCP3 (BbPutA), SASDCQ3 (DvPutA 1.5 mg.mL-1 ), SASDCX3 (DvPutA 3.0 mg.mL-1 ), SASDCY3 (DvPutA 4.5 mg.mL-1 ), SASDCR3 (LpPutA 3.0 mg.mL-1 ), SASDCV3 (LpPutA 5.0 mg.mL-1 ), SASDCW3 (LpPutA 8.0 mg.mL-1 ), SASDCS3 (BjPutA 2.3 mg.mL-1 ), SASDCT3 (BjPutA 4.7 mg.mL-1 ), SASDCU3 (BjPutA 7.0 mg.mL-1 ), SASDCZ3 (R51E 2.3 mg.mL-1 ), SASDC24 (R51E 4.7 mg.mL-1 ), SASDC34 (R51E 7.0 mg.mL-1 ). PMID- 28710795 TI - Phospholipase Ddelta negatively regulates plant thermotolerance by destabilizing cortical microtubules in Arabidopsis. AB - The pattern of cortical microtubule arrays plays an important role in plant growth and adaptation in response to hormonal and environmental changes. Cortical microtubules are connected with the plasma membrane (PM); however, how the membrane affects cortical microtubule organization is not well understood. Here, we showed that phospholipase Ddelta (PLDdelta) was associated with the PM and co localized with microtubules in cells. In vitro analysis revealed that PLDdelta bound to microtubules, resulting in microtubule disorganization. Site-specific mutations that decreased PLDdelta enzymatic activity impaired its effects on destabilizing microtubule organization. Heat shock transiently activated PLDdelta, without any change of its PM localization, triggering microtubule dissociation from PM and depolymerization and seedling death in Arabidopsis, but these effects were alleviated in plddelta knockout mutants. Complementation of plddelta with wild-type PLDdelta, but not mutated PLDdelta, restored the phenotypes of microtubules and seedling survival to those of wild-type Arabidopsis. Thus, we conclude that the PM-associated PLDdelta negatively regulates plant thermotolerance via destabilizing cortical microtubules, in an activity-dependent manner, rather than its subcellular translocation. PMID- 28710797 TI - Surgical treatment associated with improved survival in patients with cutaneous angiosarcoma. PMID- 28710796 TI - Plant-produced Zika virus envelope protein elicits neutralizing immune responses that correlate with protective immunity against Zika virus in mice. AB - The global Zika virus (ZIKV) outbreak and its link to foetal and newborn microcephaly and severe neurological complications in adults call for the urgent development of ZIKV vaccines. In response, we developed a subunit vaccine based on the ZIKV envelope (E) protein and investigated its immunogenicity in mice. Transient expression of ZIKV E (zE) resulted in its rapid accumulation in leaves of Nicotiana benthamiana plants. Biochemical analysis revealed that plant produced ZIKV E (PzE) exhibited specific binding to a panel of monoclonal antibodies that recognize various zE conformational epitopes. Furthermore, PzE can be purified to >90% homogeneity with a one-step Ni2+ affinity chromatography process. PzE are found to be highly immunogenic, as two doses of PzE elicited both potent zE-specific antibody and cellular immune responses in mice. The delivery of PzE with alum induced a mixed Th1/Th2 immune response, as the antigen specific IgG isotypes were a mixture of high levels of IgG1/IgG2c and splenocyte cultures from immunized mice secreted significant levels of IFN-gamma, IL-4 and IL-6. Most importantly, the titres of zE-specific and neutralizing antibodies exceeded the threshold that correlates with protective immunity against multiple strains of ZIKV. Thus, our results demonstrated the feasibility of plant-produced ZIKV protein antigen as effective, safe and affordable vaccines against ZIKV. PMID- 28710798 TI - Can quantitative hepatitis B surface antigen levels predict the severity of liver disease in genotype E Patients? AB - The utility of quantitative Hepatitis B surface antigen (qHBsAg) level as a marker of chronic hepatitis B (CHB)-related liver damage is not fully delineated, but is becoming increasingly relevant. Quantitative HBsAg levels are linked with progression of liver disease in HBeAg-negative genotype B and C patients, but it is not clear whether this is consistent across all HBV genotypes. In this single centre, cross-sectional observational study, we evaluated whether qHBsAg levels can predict the severity of liver disease in genotype E patients. Demographic characteristics, viral, biochemical markers and qHBsAg levels were assessed at time of liver biopsy [all HBV DNA>2000 IU/mL and/or abnormal alanine transaminase (ALT)]. Patients were divided into three groups according to the severity of fibrosis on biopsy: mild (F0-1), moderate (F2-4), severe (F5-6) liver disease and into two groups according to the NI grading, low (NI 0-3) and high inflammation (NI >=4). A total of 259 HBeAg-negative CHB treatment-naive genotype E patients were studied. The median age of this cohort was 38 years, and 61% were males. Advanced (severe) fibrosis patients had higher ALT, HBV DNA, and lower HBsAg level and qHBsAg/DNA ratio. Patients with NI >=4 had higher ALT, HBV DNA, but lower qHBsAg/DNA ratio. There was no correlation between HBsAg and HBV DNA levels. Quantitative HBsAg levels were lower in more advanced liver fibrosis. There was no correlation between qHBsAg and HBV DNA levels. This may reflect discordance between viral replication and transcriptional activity or differential HBsAg expression in HBeAg-negative genotype E patients with advanced liver disease. PMID- 28710799 TI - High glucose induces O-GlcNAc glycosylation of the vitamin D receptor (VDR) in THP1 cells and in human macrophages derived from monocytes. AB - Chronic hyperglycemia increases the carbon flux through the hexosamine pathway, allowing the accumulation of UDP-GlcNAc. UDP-GlcNAc is the sugar donor for the enzyme-mediated protein glycosylation event known as OGlcNAcylation. This posttranslational modification targets several transcription factors implicated in glucose toxicity, insulin resistance, and diabetes. Vitamin D plays an important role in glucose homeostasis and insulin secretion through transcriptional mechanisms mediated by its receptor (VDR). Vitamin D deficiency has been associated with higher susceptibility to bacterial diseases in diabetic patients. However, it has not been explored whether VDR is subject to OGlcNAcylation or whether high glucose affects its transcriptional or biological activities. The aim of this study was to evaluate the effect of hyperglycemia on VDR OGlcNAcylation and its effects on vitamin D-mediated transcription. We predicted potential OGlcNAcylation sites using free software. Our results showed that hyperglycemia (30 mM) induces the OGlcNAcylation of VDR in THP1 cells and in human macrophages derived from monocytes (MDM). This condition did not hamper the vitamin D-dependent activation of LL-37 gene expression, and even did not impair the macrophage bactericidal activity. Our study provides new insight into vitamin D receptor posttranslational modification that may have relevance on the physiological responses of long-term hyperglycemia. PMID- 28710800 TI - Dissociation of spatial memory systems in Williams syndrome. AB - Williams syndrome (WS), a genetic deletion syndrome, is characterized by severe visuospatial deficits affecting performance on both tabletop spatial tasks and on tasks which assess orientation and navigation. Nevertheless, previous studies of WS spatial capacities have ignored the fact that two different spatial memory systems are believed to contribute parallel spatial representations supporting navigation. The place learning system depends on the hippocampal formation and creates flexible relational representations of the environment, also known as cognitive maps. The spatial response learning system depends on the striatum and creates fixed stimulus-response representations, also known as habits. Indeed, no study assessing WS spatial competence has used tasks which selectively target these two spatial memory systems. Here, we report that individuals with WS exhibit a dissociation in their spatial abilities subserved by these two memory systems. As compared to typically developing (TD) children in the same mental age range, place learning performance was impaired in individuals with WS. In contrast, their spatial response learning performance was facilitated. Our findings in individuals with WS and TD children suggest that place learning and response learning interact competitively to control the behavioral strategies normally used to support human spatial navigation. Our findings further suggest that the neural pathways supporting place learning may be affected by the genetic deletion that characterizes WS, whereas those supporting response learning may be relatively preserved. The dissociation observed between these two spatial memory systems provides a coherent theoretical framework to characterize the spatial abilities of individuals with WS, and may lead to the development of new learning strategies based on their facilitated response learning abilities. PMID- 28710801 TI - Phylogenetic and genomic characterization of a novel atypical porcine pestivirus in China. AB - Atypical porcine pestivirus (APPV) has been considered a novel pestivirus and causative agent of congenital tremor type A-II. An APPV CH-GX2016 strain was characterized from newly born piglets with clinical symptoms of congenital tremor in Guangxi, China. The genome of APPV CH-GX 2016 strain was 11,475 bp in length and encoded a polyprotein composed of the 3,635 amino acids. This genome sequence exhibited 88.0% to 90.8% nucleotide sequence homology with other APPV reference sequences in GenBank. Phylogenetic analysis further showed that APPV CH-GX is a novel pestivirus compared with previously described classical pestivirus strains. Therefore, APPV is present in pigs in China. PMID- 28710802 TI - Rational Control of the Selectivity of a Ruthenium Catalyst for Hydrogenation of 4-Nitrostyrene by Strain Regulation. AB - Tuning the selectivity of metal catalysts is of paramount importance yet a great challenge. A new strategy to effectively control the selectivity of metal catalysts, by tuning the lattice strain, is reported. A certain amount of Co atoms is introduced into Ru catalysts to compress the Ru lattice, as confirmed by aberration-corrected high-resolution transmission electron microscopy (HRTEM) and X-ray absorption fine structure (XAFS) measurements. We discover that the lattice strain of Ru catalysts can greatly affect their selectivity, and Ru with 3 % lattice compression exhibits extremely high catalytic selectivity for hydrogenation of 4-nitrostyrene to 4-aminostyrene compared to pristine Ru (99 % vs. 66 %). Theoretical studies confirm that the optimized lateral compressive strain facilitates hydrogenation of the nitro group but impedes the hydrogenation of the vinyl group. This study provides a new guideline for designing metal catalysts with high selectivity. PMID- 28710803 TI - Expression of the Major Vault Protein (MVP) and Cellular Vault Particles in Fish. AB - Cellular vaults are ubiquitous 13 mega Da multi-subunit ribonuceloprotein particles that may have a role in nucleocytoplasmic transport. Seventy percent of the vault's mass consists of a ~100 kDa protein, the major vault protein (MVP). In humans, a drug resistance-associated protein, originally identified as lung resistance protein in metastatic lung cancer, was ultimately shown to be the previously described MVP. In this study, a partial MVP sequence was cloned from channel catfish. Recombinant MVP (rMVP) was used to generate a monoclonal antibody that recognizes full length protein in distantly related fish species, as well as mice. MVP is expressed in fish spleen, liver, anterior kidney, renal kidney, and gills, with a consistent expression in epithelial cells, macrophages, or endothelium at the interface of the tissue and environment or vasculature. We show that vaults are distributed throughout cells of fish lymphoid cells, with nuclear and plasma membrane aggregations in some cells. Protein expression studies were extended to liver neoplastic lesions in Atlantic killifish collected in situ at the Atlantic Wood USA-EPA superfund site on the southern branch of the Elizabeth River, VA. MVP is highly expressed in these lesions, with intense staining at the nuclear membrane, similar to what is known about MVP expression in human liver neoplasia. Additionally, MVP mRNA expression was quantified in channel catfish ovarian cell line following treatment with different classes of pharmacological agents. Notably, mRNA expression is induced by ethidium bromide, which damages DNA. Anat Rec, 2017. (c) 2017 Wiley Periodicals, Inc. Anat Rec, 300:1981-1992, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28710804 TI - Clinical features and mutation spectrum in Chinese patients with CADASIL: A multicenter retrospective study. AB - AIM: To characterize clinical features and mutation spectrum in Chinese patients with CADASIL. METHODS: We collected 261 clinically suspected Chinese CADASIL patients from three hospitals located in different regions of China. Sanger sequencing is performed to screen the exons 2 to 24 of NOTCH3 gene. Clinical and genetic data were retrospectively studied. Haplotype analyses were performed in patients carrying p.Arg544Cys and p.Arg607Cys, respectively. RESULTS: A total of 214 patients were finally genetically diagnosed as CADASIL, with 45 known NOTCH3 mutations and a novel c.1817G>T mutation. We found that patients carrying p.Arg607Cys or p.Arg544Cys mutation located in exon 11 occupied nearly 35% in our mutation spectrum. In retrospectively study of clinical data, we found a higher number of patients having cognitive impairment and a lower number of patients having migraine with aura. Furthermore, we identified that patients carrying mutations in exon 11 seemed to experience a later disease onset (p=6.8*10-5 ). Additionally, a common haplotype was found in patients from eastern China carrying p.Arg607Cys, and the patients from Fujian carrying p.Arg544Cys shared the same haplotype with patients from Taiwan carrying p.Arg544Cys. CONCLUSIONS: These findings broaden the mutational and clinical spectrum of CADASIL and provide additional evidences for the existence of founder effect in CADASIL patients. PMID- 28710805 TI - A method to measure the absorbed dose of the thyroid during I-131 therapy, using a collar detector system and a SPECT acquisition. AB - PURPOSE: Due to variations in biological half-life, accurate thyroid dosimetry for I-131 therapy is not trivial in clinical practice. In recent publications, systems are described to measure the uptake of I-131 in the thyroid repeatedly over time. In this work, we present a method to calculate patient specific pharmacokinetics and absorbed dose using such a collar detector system (CoTI) in combination with a SPECT acquisition and a two-compartment model fit. METHODS: For three patients receiving I-131 therapy for benign thyroid conditions, the complete uptake profile is measured over a period of 15 to 25 days after administration. A SPECT measurement is performed to assess the functional volume of the thyroid and the amount of I-131 in the thyroid. The uptake profile measured in counts-per-second is converted to absolute activity in MBq using the absolute quantification of the SPECT. A two-compartment model is used as a fit to the uptake data of the thyroid and to estimate the activity in the blood-pool. The estimated absorbed dose to the thyroid is then calculated from the integral of the activity. The assessed parameters from the method (6- and 24-h uptake, thyroid volume and I-131 uptake concentration) are compared with the values as determined in clinical practice. Furthermore, the convergence of the calculated absorbed dose as a function of measurement series duration is determined to assess the required measurement duration of the uptake profile. RESULTS: The two compartment model fit shows a good agreement with the measured data points. Resulting dynamic uptake profiles of the three patients differ from each other. The uptake percentages differ from the pretherapy I-123 uptake measurements that are used in usual clinical practice, which shows the potential added value of the proposed method. The duration of the required measurement series appears to be patient dependent and therefore needs to be determined for each patient individually. The proposed method allows for a basic investigation of the individual dynamic uptake profile of I-131 in the thyroid and the calculation of the absorbed dose. CONCLUSIONS: The proposed measurement method is feasible and easily implementable given a system that can measure the uptake of I-131 in the thyroid repeatedly over time. The observed differences in dynamic uptake profiles and the differences in the absorbed thyroid dose as calculated with our method and the parameters of the usual clinical care support the relevance of the proposed method. In future studies, this approach may possibly be used for outcome prediction and therapeutic activity optimization. PMID- 28710807 TI - Conflicts of interest in laboratory hematology. PMID- 28710806 TI - Clinical features and prognostic impact of PRDM16 expression in adult acute myeloid leukemia. AB - High PRDM16 (also known as MEL1) expression is a representative marker of acute myeloid leukemia (AML) with NUP98-NSD1 and is a significant predictive marker for poor prognosis in pediatric AML. However, the clinical features of adult AML with PRDM16 expression remain unclear. PRDM16 is highly homologous to MDS1/EVI1, which is an alternatively spliced transcript of MECOM (also known as EVI1). We investigated PRDM16 expression in 151 AML patients, with 47 (31%) exhibiting high PRDM16 expression (PRDM16/ABL1 ratio >= 0.010). High PRDM16 expression significantly correlated with DNMT3A (43% vs. 15%, P < 0.001) and NPM1 (43% vs. 21%, P = 0.010) mutations and partial tandem duplication of KMT2A (22% vs. 1%, P < 0.001). Remarkably, high-PRDM16-expression patients were frequent in the noncomplete remission group (48% vs. 21%, P = 0.002). Overall survival (OS) was significantly worse in high-PRDM16-expression patients than in low-PRDM16 expression patients (5-year OS, 18% vs. 34%; P = 0.002). This trend was observed more clearly among patients aged <65 years (5-year OS, 21% vs. 50%; P = 0.001), particularly in FLT3-ITD-negative patients in the intermediate cytogenetic risk group (5-year OS, 25% vs. 59%; P = 0.009). These results suggest that high PRDM16 expression is a significant predictive marker for poor prognosis in adult AML patients, similar to pediatric AML patients. PMID- 28710808 TI - The application of physiologically based pharmacokinetic modelling to assess the impact of antiretroviral-mediated drug-drug interactions on piperaquine antimalarial therapy during pregnancy. AB - Antimalarial therapy during pregnancy poses important safety concerns due to potential teratogenicity and maternal physiological and biochemical changes during gestation. Piperaquine (PQ) has gained interest for use in pregnancy in response to increasing resistance towards sulfadoxine-pyrimethamine in sub Saharan Africa. Coinfection with HIV is common in many developing countries, however, little is known about the impact of antiretroviral (ARV) mediated drug drug interaction (DDI) on piperaquine pharmacokinetics during pregnancy. This study applied mechanistic pharmacokinetic modelling to predict pharmacokinetics in non-pregnant and pregnant patients, which was validated in distinct customised population groups from Thailand, Sudan and Papua New Guinea. In each population group, no significant differences in day 7 concentrations were observed during different gestational weeks (GW) (weeks 10-40), supporting the notion that piperaquine is safe throughout pregnancy with consistent pharmacokinetics, although possible teratogenicity may limit this. Antiretroviral-mediated DDIs (efavirenz and ritonavir) had moderate effects on piperaquine during different gestational weeks with a predicted AUCratio in the range 0.56-0.8 and 1.64-1.79 for efavirenz and ritonavir, respectively, over GW 10-40, with a reduction in circulating human serum albumin significantly reducing the number of subjects attaining the day 7 (post-dose) therapeutic efficacy concentrations under both efavirenz and ritonavir DDIs. This present model successfully mechanistically predicted the pharmacokinetics of piperaquine in pregnancy to be unchanged with respect to non-pregnant women, in the light of factors such as malaria/HIV co infection. However, antiretroviral-mediated DDIs could significantly alter piperaquine pharmacokinetics. Further model refinement will include collation of relevant physiological and biochemical alterations common to HIV/malaria patients. PMID- 28710809 TI - The UVB photoreceptor UVR8 mediates accumulation of UV-absorbing pigments, but not changes in plant morphology, under outdoor conditions. AB - UVB radiation is biologically active; in plants, it can induce a range of molecular, biochemical, morphological and developmental responses. Although much progress has been made in elucidating UVB perception and signalling pathways under controlled laboratory conditions, understanding of the adaptive, ecological role of UVB responses is still very limited. In this study, we looked at the functional role of UVR8 under outdoor light conditions, by studying growth, photosynthetic competence and accumulation of UV absorbing pigments in a mutant lacking functional UVR8 protein. It was found that the influence of UVB on morphology is restricted to summer and is independent of UVR8. In contrast, UVB had an effect on the content of UV-absorbing pigments and the maximal efficiency of photosystem II of photosynthesis in the uvr8-1 mutant throughout the year. It is concluded that the UVR8 photoreceptor plays a role throughout the year, in the temperate climate zone, even when UVB levels are relatively low. PMID- 28710811 TI - Insights from zebrafish on human pigment cell disease and treatment. AB - Black pigment cells, melanocytes, arise early during development from multipotent neural crest cells. Melanocytes protect human skin from DNA damaging sunrays and provide color for hair, eyes, and skin. Several disorders and diseases originate from these cells, including the deadliest skin cell cancer, melanoma. Thus, melanocytes are critical for a healthy life and for protecting humans from disease. Due to the ease of visualizing pigment cells through transparent larvae skin and conserved roles for zebrafish melanophore genes to mammalian melanocyte genes, zebrafish larvae offer a biologically relevant model for understanding pigment cell development and disease in humans. This review discusses our current knowledge of melanophore biology and how zebrafish are contributing to improving how diseases of melanocytes are understood and treated in humans. Developmental Dynamics 246:889-896, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28710810 TI - Putative binding sites for mir-125 family miRNAs in the mouse Lfng 3'UTR affect transcript expression in the segmentation clock, but mir-125a-5p is dispensable for normal somitogenesis. AB - BACKGROUND: In vertebrate embryos, a "segmentation clock" times somitogenesis. Clock-linked genes, including Lunatic fringe (Lfng), exhibit cyclic expression in the presomitic mesoderm (PSM), with a period matching the rate of somite formation. The clock period varies widely across species, but the mechanisms that underlie this variability are not clear. The half-lives of clock components are proposed to influence the rate of clock oscillations, and are tightly regulated in the PSM. Interactions between Lfng and mir-125a-5p in the embryonic chicken PSM promote Lfng transcript instability, but the conservation of this mechanism in other vertebrates has not been tested. Here, we examine whether this interaction affects clock activity in a mammalian species. RESULTS: Mutation of mir-125 binding sites in the Lfng 3'UTR leads to persistent, nonoscillatory reporter transcript expression in the caudal-most mouse PSM, although dynamic transcript expression recovers in the central PSM. Despite this, expression of endogenous mir-125a-5p is dispensable for mouse somitogenesis. CONCLUSIONS: These results suggest that mir-125a sites in the Lfng 3' untranslated region influence transcript turnover in both mouse and chicken embryos, and support the existence of position-dependent regulatory mechanisms in the PSM. They further suggest the existence of compensatory mechanisms that can rescue the loss of mir-125a-5p in mice. Developmental Dynamics 246:740-748, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28710812 TI - Temperature heterogeneity over leaf surfaces: the contribution of the lamina microtopography. AB - Temperature is spatially heterogeneous over leaf surfaces, yet the underlying mechanisms are not fully resolved. We hypothesized that the 3D leaf microtopography determines locally the amount of incoming irradiation flux at leaf surface, thereby driving the temperature gradient over the leaf surface. This hypothesis was tested by developing a model of leaf temperature heterogeneity that includes the development of the leaf boundary layer, the microtopography of the leaf surface and the physiological response of the leaf. Temperature distributions under various irradiation loads (1) over apple leaves based on their 3D microtopography, (2) over simulated flat (2D) apple leaves and (3) over 3D leaves with a transpiration rate distributed as in 2D leaves were simulated. Accuracy of the predictions was quantified by comparing model outputs and thermographic measurements of leaf surface temperature under controlled conditions. Only the model with 3D leaves predicted accurately the spatial heterogeneity of surface temperature over single leaves, whereas the mean temperature was well predicted by both 2D and 3D leaves. We suggest that in these conditions, the 3D leaf microtopography is the primary driver of leaf surface heterogeneity in temperature when the leaf is exposed to a light/heat source. PMID- 28710813 TI - Case report of a paraovarian cyst in a 15-year-old adolescent girl with premature ovarian failure. PMID- 28710814 TI - Inter-epidemic Rift Valley fever virus seroconversions in an irrigation scheme in Bura, south-east Kenya. AB - Rift Valley fever (RVF) is an acute mosquito-borne viral zoonosis whose outbreaks are often associated with prolonged rainfall and flooding, during which large numbers of vectors emerge. Recent studies into the inter-epidemic maintenance of RVF virus (RVFV) suggest that both vertical transmission in vectors and direct transmission between hosts act in combination with predisposing factors for persistence of the virus. A comparative longitudinal survey was carried out in Tana River County, Kenya, in irrigated, riverine and pastoral ecosystems from September 2014-June 2015. The objectives were to investigate the possibility of low-level RVFV transmission in these ecosystems during an inter-epidemic period (IEP), examine variations in RVFV seroprevalence in sheep and goats and determine the risk factors for transmission. Three hundred and sixteen small ruminants were selected and tested for immunoglobulin G antibodies against RVFV nucleoprotein using a competitive ELISA during six visits. Data on potential risk factors were also captured. Inter-epidemic RVFV transmission was evidenced by 15 seroconversions within the irrigated and riverine villages. The number of seroconversions was not significantly different (OR = 0.66, CI = 0.19-2.17, p = .59) between irrigated and riverine areas. No seroconversions were detected in the pastoral ecosystem. This study highlights the increased risk of inter epidemic RVFV transmission posed by irrigation, through provision of necessary environmental conditions that enable vectors access to more breeding grounds, resting places and shade, which favour their breeding and survival. PMID- 28710817 TI - The anticoagulant efficacy of rivaroxaban may be attenuated in cirrhotic patients. PMID- 28710816 TI - Electrochemical and structural characterization of Azotobacter vinelandii flavodoxin II. AB - Azotobacter vinelandii flavodoxin II serves as a physiological reductant of nitrogenase, the enzyme system mediating biological nitrogen fixation. Wildtype A. vinelandii flavodoxin II was electrochemically and crystallographically characterized to better understand the molecular basis for this functional role. The redox properties were monitored on surfactant-modified basal plane graphite electrodes, with two distinct redox couples measured by cyclic voltammetry corresponding to reduction potentials of -483 +/- 1 mV and -187 +/- 9 mV (vs. NHE) in 50 mM potassium phosphate, 150 mM NaCl, pH 7.5. These redox potentials were assigned as the semiquinone/hydroquinone couple and the quinone/semiquinone couple, respectively. This study constitutes one of the first applications of surfactant-modified basal plane graphite electrodes to characterize the redox properties of a flavodoxin, thus providing a novel electrochemical method to study this class of protein. The X-ray crystal structure of the flavodoxin purified from A. vinelandii was solved at 1.17 A resolution. With this structure, the native nitrogenase electron transfer proteins have all been structurally characterized. Docking studies indicate that a common binding site surrounding the Fe-protein [4Fe:4S] cluster mediates complex formation with the redox partners Mo-Fe protein, ferredoxin I, and flavodoxin II. This model supports a mechanistic hypothesis that electron transfer reactions between the Fe-protein and its redox partners are mutually exclusive. PMID- 28710818 TI - Fatty liver allografts are associated with primary graft non-function and high mortality after transplantation. PMID- 28710815 TI - Lacrimal gland development: From signaling interactions to regenerative medicine. AB - The lacrimal gland plays a pivotal role in keeping the ocular surface lubricated, and protecting it from environmental exposure and insult. Dysfunction of the lacrimal gland results in deficiency of the aqueous component of the tear film, which can cause dryness of the ocular surface, also known as the aqueous deficient dry eye disease. Left untreated, this disease can lead to significant morbidity, including frequent eye infections, corneal ulcerations, and vision loss. Current therapies do not treat the underlying deficiency of the lacrimal gland, but merely provide symptomatic relief. To develop more sustainable and physiological therapies, such as in vivo lacrimal gland regeneration or bioengineered lacrimal gland implants, a thorough understanding of lacrimal gland development at the molecular level is of paramount importance. Based on the structural and functional similarities between rodent and human eye development, extensive studies have been undertaken to investigate the signaling and transcriptional mechanisms of lacrimal gland development using mouse as a model system. In this review, we describe the current understanding of the extrinsic signaling interactions and the intrinsic transcriptional network governing lacrimal gland morphogenesis, as well as recent advances in the field of regenerative medicine aimed at treating dry eye disease. Developmental Dynamics 246:970-980, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28710819 TI - Hepatitis C virus eradication with direct antiviral agents and liver cancer recurrence: Is the best the enemy of the good? PMID- 28710820 TI - Response to prothrombin complex concentrate to correct acquired abnormalities of the clotting screen in patients with liver impairment. PMID- 28710821 TI - A not so easy genotype-striking regional differences in SOF/RBV treatment responses in HCV GT2. PMID- 28710822 TI - Prevalence and significance of HMGA2 expression in oesophageal adenocarcinoma. AB - AIMS: Oesophageal adenocarcinoma (EAC) tumorigenesis has been linked primarily to loss-of-function mutations in tumour suppressor genes. Knowledge of specific oncogenes that drive tumour progression, and their relationship to outcomes, is limited. High mobility group AT-hook 2 (HMGA2) has been reported to be amplified in a subset of EACs, but the clinicopathological and prognostic implications of HMGA2 expression in EAC are unknown. METHODS AND RESULTS: We performed HMGA2 immunohistochemistry and fluorescence in-situ hybridization (FISH) in EAC to determine its clinicopathological and prognostic significance. Ninety-one primary EAC resections without neoadjuvant treatment were identified and immunohistochemistry for HMGA2 was performed. The presence or absence of nuclear staining was evaluated and correlated with predetermined clinicopathological parameters and patient outcomes. A selected subset of tumours was subjected to FISH to identify alterations at the HMGA2 locus. HMGA2 expression was present in 25 of 91 (27.4%) tumours. HMGA2-expressing cells were present in solid, poorly differentiated areas of the tumours at the invasive front, or as single infiltrating cells. FISH showed that three to four copies of HMGA2 are frequently present in EAC irrespective of HMGA2 protein expression and that high level HMGA2 amplification is a rare event. HMGA2 expression was associated with numerous adverse clinicopathological parameters, including higher T- and N-stage, the presence of lymphovascular invasion and with a worse recurrence-free and overall survival. CONCLUSION: Our data suggest that HMGA2 is regulated in EAC primarily through non-chromosomal-level alterations that lead to increased HMGA2 expression. HMGA2-positive EAC correlates with adverse pathological features and worse patient outcomes. PMID- 28710823 TI - The African swine fever epidemic in West Africa, 1996-2002. AB - African swine fever (ASF) is a contagious, highly fatal, haemorrhagic viral disease that only affects members of the Suidae family. Currently, no vaccine or treatment exists, so the disease has potentially devastating consequences for the pig industries, availability of affordable protein livelihoods and trade. This study aimed to consolidate historical information generated by working towards the control and eradication of ASF in previously unaffected countries in West Africa during 1996-2002. This descriptive analysis entailed the evaluation and review of archived records and reports of outbreaks, data from veterinary services, veterinary consultants and peer-reviewed publications. Specifically, the analysis focused on establishing the sequence of events in the spread of the disease throughout the region, as well as the possible sources and pathways (mostly human-driven, i.e., movement of pigs and swill feeding). The socio economic aspects of the epidemic were also assessed. Finally, the prevention and control measures applied were described and evaluated. Major challenges for control that were identified involved lack of capacity to respond to an outbreak of animal disease and the nature of the pig sector in the affected countries. Most of the pigs were produced in low biosecurity subsistence husbandry systems. Actions taken by producers to limit economic losses due to the epidemic (e.g., illegal selling of pigs and infected pork, hiding of outbreaks) increased the risk of spread and frustrated control efforts. The disease has persisted in an endemic state ever since and has negatively affected pig production and marketing in most of these countries. The analysis of this information will allow a better understanding of the disease dynamics in a region infected for the first time, and learning how the prevention and control interventions that were implemented worked or failed. This will help the development of better tailored, sustainable and locally sound interventions. The authors provide a set of recommendations for ASF prevention and control. PMID- 28710824 TI - A novel study on association between untreated hearing loss and cognitive functions of older adults: Baseline non-verbal cognitive assessment results. AB - BACKGROUND: Age-related hearing loss (ARHL) is highly prevalent in older adults, and more than two-thirds above age of 70 years suffer from ARHL. Recent studies have established a link between ARHL and cognitive impairment; however, most of the studies have used verbally loaded cognitive measures to investigate the association between ARHL and cognition. It is possible that due to hearing impairment, the elderly may experience difficulty in following verbal instructions or completing tasks that heavily rely on hearing during cognitive assessments. This may result in overestimation of cognitive impairment in such individuals. This baseline cross-sectional study investigated the associations between untreated hearing loss and a number of cognitive functions using a battery of non-verbal cognitive tests. Further, association between hearing loss and psychological status of older adults was examined. STUDY DESIGN: Prospective case-controlled study. METHODS: A total of 119 participants (54 males, M=66.33+/ 10.50 years; 65 females M=61.51+/-11.46 years) were recruited. All participants completed a hearing assessment, a computerised test battery of non-verbal cognitive functions and the depression, anxiety and stress scale. RESULTS: Hierarchical multiple regression analysis results revealed that hearing thresholds significantly associated with the working memory (P<0.05), paired associative learning scores (P<0.05), depression (P<0.001), and anxiety (P<0.001) and stress (P<0.001) scores. Analysis of covariance results revealed that participants with moderately-severe hearing loss performed significantly poorer in paired associative learning and working memory tasks and psychological function tests compared to those with normal hearing. CONCLUSION: Results of the current study suggest a significant relationship between ARHL and both cognition and psychological status. Our results also have some implications for using non verbal cognitive tests to evaluate cognitive functions in post-lingually hearing impaired ageing adults, at least for those with more than moderately-severe levels of hearing loss. PMID- 28710826 TI - Corrigendum. PMID- 28710825 TI - Associations between antibody to hepatitis B core antigen positivity and outcomes in hepatocellular carcinoma patients undergoing hepatic resection. AB - AIM: We aimed to evaluate the effect of antibody to hepatitis B core antigen (HBcAb) positivity on clinical outcomes after hepatic resection in hepatocellular carcinoma (HCC) patients with negative hepatitis B surface antigen (HBsAg) and hepatitis C virus antibody (HCVAb), termed non-B, non-C HCC (NBNC-HCC), or with HCV-related HCC. METHODS: Two hundred and sixty-three patients who underwent hepatic resection for HCC and measurements of HBsAg, HCVAb, and HBcAb were enrolled in this study. RESULTS: The percentages of HBcAb positivity were 52.3% (n = 57) and 56.9% (n = 66) in patients with NBNC- and HCV-related HCC, respectively. The proportion of multiple NBNC-HCCs was significantly greater in patients with HBcAb positivity compared to HBcAb negativity (P = 0.028). There were no significant differences in the recurrence-free and overall survival rates between NBNC-HCC patients with HBcAb positivity versus negativity (P = 0.461 and P = 0.190, respectively). Furthermore, for HCV-related HCC patients, there were no significant differences in the baseline factors between patients with positive versus negative HBcAb. The proportion of patients with HBcAb-positive HCV-related HCC who underwent anatomical resection of the liver was significantly greater than that of HBcAb-negative patients, whereas the recurrence-free and overall survival rates were not significantly different (P = 0.158 and P = 0.191, respectively). CONCLUSION: In our study, the presence of HBcAb had no impact on surgical outcomes after hepatic resection in patients with NBNB- and HCV-related HCC. Occult HBV infection might be associated with hepatocarcinogenesis in patients with NBNC-related HCC. PMID- 28710828 TI - Introduction to Volume 9, Issue 3 of topiCS. PMID- 28710827 TI - Comparison of Non-Coding RNAs in Exosomes and Functional Efficacy of Human Embryonic Stem Cell- versus Induced Pluripotent Stem Cell-Derived Cardiomyocytes. AB - Both human embryonic stem cell-derived cardiomyocytes (ESC-CMs) and human induced pluripotent stem cell-derived CMs (iPSC-CMs) can serve as unlimited cell sources for cardiac regenerative therapy. However, the functional equivalency between human ESC-CMs and iPSC-CMs for cardiac regenerative therapy has not been demonstrated. Here, we performed a head-to-head comparison of ESC-CMs and iPSC CMs in their ability to restore cardiac function in a rat myocardial infarction (MI) model as well as their exosomal secretome. Human ESCs and iPSCs were differentiated into CMs using small molecule inhibitors. Fluorescence-activated cell sorting analysis confirmed ~85% and ~83% of CMs differentiated from ESCs and iPSCs, respectively, were positive for cardiac troponin T. At a single-cell level, both cell types displayed similar calcium handling and electrophysiological properties, with gene expression comparable with the human fetal heart marked by striated sarcomeres. Sub-acute transplantation of ESC-CMs and iPSC-CMs into nude rats post-MI improved cardiac function, which was associated with increased expression of angiogenic genes in vitro following hypoxia. Profiling of exosomal microRNAs (miRs) and long non-coding RNAs (lncRNAs) revealed that both groups contain an identical repertoire of miRs and lncRNAs, including some that are known to be cardioprotective. We demonstrate that both ESC-CMs and iPSC-CMs can facilitate comparable cardiac repair. This is advantageous because, unlike allogeneic ESC-CMs used in therapy, autologous iPSC CMs could potentially avoid immune rejection when used for cardiac cell transplantation in the future. Stem Cells 2017;35:2138-2149. PMID- 28710829 TI - Spatiotemporal evolutionary epidemiology of H5N1 highly pathogenic avian influenza in West Africa and Nigeria, 2006-2015. AB - H5N1 highly pathogenic avian influenza virus (HPAIV) was first observed in Nigeria in early 2006 and has now spread to more than 17 African countries having severe economic and public health implications. Here, we explore the spatiotemporal patterns of viral dispersal both among West African countries and within Nigeria using sequence data from hemagglutinin (HA) gene region of the virus. Analyses were performed within a statistical Bayesian framework using phylodynamic models on data sets comprising of all publically available HA sequence data collected from seven West African countries and Egypt between 2006 and 2015. Our regional-level analyses indicated that H5N1 in West Africa originated in Nigeria in three geopolitical regions, specifically north central and north-east, where backyard poultry and wild birds are in frequent contact, as well as south-west, a major commercial poultry area, then dispersed to West African countries. We inferred significant virus dispersal routes between Niger and Nigeria on one side and Burkina Faso, Ivory Coast, Ghana and Egypt on the other. Furthermore, south-west Nigeria identified as a primary source for virus dispersal within Nigeria as well as to Niger in 2006 and 2008. Niger was an important epicentre for the virus spread into other West African countries in 2015. Egyptian introductions from West Africa were sporadic and resulted most likely from poultry trade with Nigeria rather than contact with infected wild birds. Our inferred viral dispersal routes reflected the large-scale unrestricted movements of infected poultry in the region. Our study illustrates the ability of phylodynamic models to trace important HPAIV dispersal routes at a regional and national level. Our results have clear implications for the control and prevention of this pathogen across scales and will help improve molecular surveillance of transboundary HPAIVs. PMID- 28710830 TI - Prognostic significance of a comprehensive histological evaluation of reticulin fibrosis, collagen deposition and osteosclerosis in primary myelofibrosis patients. AB - AIMS: To evaluate whether a comprehensive histological evaluation of reticulin fibrosis, collagen deposition and osteosclerosis in bone marrow trephine biopsies (BMBs) of primary myelofibrosis (PMF) patients may have prognostic implications. METHODS AND RESULTS: Reticulin fibrosis, collagen deposition and osteosclerosis were graded from 0 to 3 in a series of 122 baseline BMBs. Then, we assigned to each case a comprehensive score [reticulin, collagen, osteosclerosis (RCO) score, ranging from 0 to 9] that allowed us to distinguish two groups of patients, with low-grade (RCO score 0-4) and high-grade (RCO score 5-9) stromal changes. Of 122 patients, 88 displayed a low-grade and 34 a high-grade RCO score. The latter was associated more frequently with anaemia, thrombocytopenia, peripheral blood blasts and increased lactate dehydrogenase levels. The RCO score was correlated strictly with overall mortality (P = 0.013) and International Prognostic Scoring System (IPSS) risk categories, and was able to discriminate the overall survival of both low- and high-grade patients (log-rank test: P < 0.001). Moreover, it proved to be more accurate than the European Consensus on Grading of Bone Marrow Fibrosis (ECGMF grade) in identifying high-risk patients with poor prognosis. Finally, a combined analysis of RCO scores and IPSS risk categories in an integrated clinical-pathological evaluation was able to increase the positive predictive value (PPV) for mortality in high-risk patients. CONCLUSION: The comprehensive RCO score, obtained by histological evaluation of reticulin fibrosis, collagen deposition and osteosclerosis was prognostically significant and more accurate than ECGMF grade in identifying high-risk patients and improved PPV when applied in addition to IPSS. PMID- 28710832 TI - New Species of Spirotrichonympha from Reticulitermes and the Relationships Among Genera in Spirotrichonymphea (Parabasalia). AB - Spirotrichonymphea is a class of hypermastigote parabasalids defined by their spiral rows of many flagella. They are obligate hindgut symbionts of lower termites. Despite more than 100 yr of morphological and ultrastructural study, the group remains poorly characterised by molecular data and the phylogenetic positions and taxonomic validity of most genera remain in question. The genus Spirotrichonympha has been reported to inhabit several termite genera, including Reticulitermes, Coptotermes, and Hodotermopsis. The type species for this genus, Spirotrichonympha flagellata, was described from Reticulitermes lucifugus but no molecular data are yet available for this species. In this study, three new Spirotrichonympha species are described from three species of Reticulitermes. Their molecular phylogenetic position indicates that the genus is not monophyletic, as Spirotrichonympha species from Coptotermes, Paraneotermes, and Hodotermopsis branch separately. In contrast, the genus Holomastigotoides is monophyletic, as demonstrated using new sequences from Holomastigotoides species. The presence of Holomastigotoides in Prorhinotermes and the distinct phylogenetic positions of Spirotrichonympha from Reticulitermes and Coptotermes are consistent with a previously proposed symbiont fauna replacement in the ancestor of Reticulitermes. PMID- 28710833 TI - Effect of cellobiose supplementation on in vitro fermentation activity and bacterial numbers of porcine inocula. AB - In this in vitro study, the modified Hohenheim gas test (HGT) was applied to determine fermentation activity and bacterial composition of pig's faecal microbial inoculum using different concentrations of cellobiose. Incubation procedures included normal buffered and osmotic stress conditions (elevated medium salinity). After 24 hr of fermentation, production of gas, ammonia and short-chain fatty acid (SCFA) was measured, and the gene copy numbers of total bacteria, Lactobacillus spp., Bifidobacterium spp., Roseburia spp., Clostridium Cluster IV spp. and Enterobacteriaceae were analysed using real-time polymerase chain reaction. There was a significant reduction in gas production after 24 hr when comparing osmotic stress conditions with normal buffered conditions. Under osmotic stress, increasing cellobiose concentrations linearly increased gas production (p < .001), while ammonia, acetic acid and isobutyric acid concentrations decreased (p < .001, p = .012, p = .035 respectively). Under normal buffered conditions, Roseburia spp. gene copies linearly increased with increasing cellobiose concentrations (p = .048). Lactobacillus spp. and Bifidobacterium spp. numbers were higher under osmotic stress (p < .001) compared to normal conditions. Results might point towards a positive impact of cellobiose supplementation on gut health especially under osmotic stress conditions. PMID- 28710831 TI - Dietary fiber intake and head and neck cancer risk: A pooled analysis in the International Head and Neck Cancer Epidemiology consortium. AB - The possible role of dietary fiber in the etiology of head neck cancers (HNCs) is unclear. We used individual-level pooled data from ten case-control studies (5959 cases and 12,248 controls) participating in the International Head and Neck Cancer Epidemiology (INHANCE) consortium, to examine the association between fiber intake and cancer of the oral cavity/pharynx and larynx. Odds Ratios (ORs) and their 95% Confidence Intervals (CIs) were estimated using unconditional multiple logistic regression applied to quintile categories of non-alcohol energy adjusted fiber intake and adjusted for tobacco and alcohol use and other known or putative confounders. Fiber intake was inversely associated with oral and pharyngeal cancer combined (OR for 5th vs. 1st quintile category = 0.49, 95% CI: 0.40-0.59; p for trend <0.001) and with laryngeal cancer (OR = 0.66, 95% CI: 0.54 0.82, p for trend <0.001). There was, however, appreciable heterogeneity of the estimated effect across studies for oral and pharyngeal cancer combined. Nonetheless, inverse associations were consistently observed for the subsites of oral and pharyngeal cancers and within most strata of the considered covariates, for both cancer sites. Our findings from a multicenter large-scale pooled analysis suggest that, although in the presence of between-study heterogeneity, a greater intake of fiber may lower HNC risk. PMID- 28710836 TI - Reply. PMID- 28710834 TI - Ultrastructure of Skeletal Muscles in Mice Lacking Muscle-Specific VEGF Expression. AB - Vascular endothelial growth factor-A (VEGF) influences several physiological processes including endothelial cell function, angiogenesis and maintenance of organ/tissue capillarity. While the functional aspects of VEGF were vigorously investigated, only little detail is known on structural integrity of skeletal muscle fibers and capillaries in mice lacking VEGF expression in their muscles. Therefore, we assessed systematically the architecture of the glycolytic plantaris and the oxidative soleus muscles obtained from muscle-specific VEGF knockout (mVEGF-KO, n = 7) mice and their wild-type (WT, n = 7) littermates by morphometry after transmission electron microscopy. The capillary/fiber ratio was lower (plantaris: -63.5%; soleus: -54.8%; P <= 0.05) in mVEGF-KO mice than in WT mice. In plantaris, quantification of volume density (Vv) of compartments revealed higher Vv of total mitochondria (+56.5%, P <= 0.05) as well as higher Vv values for both intrafibrillar (+39%; P <= 0.05) and subsarcolemmal (+220%; P <= 0.05) mitochondrial pools in mVEGF-KO mice than WT mice. The capillary phenotype also differed (P <= 0.05) between the two mouse-strains: Vv (-17.4%), absolute area size (-19.1%) and thickness (-19.6%) of the endothelium layer were lower and Vv of capillary lumen (+15.1%) was higher in mVEGF-KO mice than in WT littermates. In soleus, mitochondrial Vv in fibers and the structural indicators specific to the capillary phenotype exhibited the same tendency in differences between the mouse strains without reaching statistical significance. Our morphometric analysis demonstrates that the lower capillary supply in plantaris of mVEGF-KO mice is accompanied by higher mitochondrial Vv in muscle fibers as well as lumen dilation and endothelium thinning of capillaries. These structural alterations were more pronounced in a glycolytic than an oxidative muscle. Anat Rec, 300:2239-2249, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28710837 TI - Quality of life, anxiety prevalence, depression symptomatology and suicidal ideation among acne patients in Lithuania. AB - BACKGROUND/OBJECTIVE: We aimed to determine the prevalence of anxiety, depression symptomatology and suicidal ideation among patients with acne and the impact of this skin condition on the quality of life in Lithuania. METHODS: The mental health of patients with acne was assessed using an adapted Hospital Anxiety and Depression Scale, the Dermatology Quality of Life Index, questions about characteristics of acne. The study was authorized by the Regional Biomedical Research Ethics Committee. RESULTS: A total of 255 responders of 324 patients with acne included (84.4%) were assessed. 56.1% of the responders had comorbid anxiety, depression symptomatology or suicidal ideation related to acne. Among them, 38.4% had anxiety symptoms, 23.1% had depression symptoms and 12.9% had suicidal thoughts due to acne. About 96.5% of the responders had a reduced quality of life due to acne. CONCLUSION: More than a half of the patients with acne who participated at the study had comorbid emotional disorders. Anxiety was the most prevalent sign, 1.7-fold more prevalent than depression and threefold more prevalent than suicidal ideation. Depression was prevalent in more than every fourth responder and suicidal ideation afflicted every eighth acne patient. More than 90% of the patients had impaired life quality. PMID- 28710838 TI - Enzyme-Free Ligation of 5'-Phosphorylated Oligodeoxynucleotides in a DNA Nanostructure. AB - Multicomponent reactions are difficult synthetic transformations. For DNA, there is a special opportunity to align multiple strands in a folded nanostructure, so that they are preorganized to give a specific sequence. Multistrand reactions in DNA origami structures have previously been performed using photochemical crosslinking, 1,3-diploar cycloadditions or phosphoramidate-forming reactions. Here we report carbodiimide-driven phosphodiester formation in a small origami sheet that produces DNA strands up to 600 nucleotides in length in a single step. The method uses otherwise unmodified oligodeoxynucleotides with a 5'-terminal phosphate as starting materials. Compared to an enzymatic multistrand ligation involving linear duplexes, the carbodiimide-driven ligation gave fewer side products, as detected by gel electrophoresis. The full-length 600mer product was successfully amplified by polymerase chain reaction. PMID- 28710839 TI - Enhanced Carbon Dioxide Electroreduction to Carbon Monoxide over Defect-Rich Plasma-Activated Silver Catalysts. AB - Efficient, stable catalysts with high selectivity for a single product are essential if electroreduction of CO2 is to become a viable route to the synthesis of industrial feedstocks and fuels. A plasma oxidation pre-treatment of silver foil enhances the number of low-coordinated catalytically active sites, which dramatically lowers the overpotential and increases the activity of CO2 electroreduction to CO. At -0.6 V versus RHE more than 90 % Faradaic efficiency towards CO was achieved on a pre-oxidized silver foil. While transmission electron microscopy (TEM) and operando X-ray absorption spectroscopy showed that oxygen species can survive in the bulk of the catalyst during the reaction, quasi in situ X-ray photoelectron spectroscopy showed that the surface is metallic under reaction conditions. DFT calculations reveal that the defect-rich surface of the plasma-oxidized silver foils in the presence of local electric fields drastically decrease the overpotential of CO2 electroreduction. PMID- 28710840 TI - Characterization of scientific studies usually cited as evidence of adverse effects of GM food/feed. AB - GM crops are the most studied crops in history. Approximately 5% of the safety studies on them show adverse effects that are a cause for concern and tend to be featured in media reports. Although these reports are based on just a handful of GM events, they are used to cast doubt on all GM crops. Furthermore, they tend to come from just a few laboratories and are published in less important journals. Importantly, a close examination of these reports invariably shows methodological flaws that invalidate any conclusions of adverse effects. Twenty years after commercial cultivation of GM crops began, a bona fide report of an adverse health effect due to a commercialized modification in a crop has yet to be reported. PMID- 28710841 TI - Accelerated kindling epileptogenesis in Tg4510 tau transgenic mice, but not in tau knockout mice. AB - The biologic processes underlying epileptogenesis following a brain insult are not fully understood, but several lines of evidence suggest that hyperphosphorylation of tau may be an important factor in these processes. To provide further insight into the causal relationship between tau and epileptogenesis, this study applied amygdala kindling to rTg4510 mice that, concurrent with other pathologies, overexpress phosphorylated tau, tau knockout mice, or their respective wild-type controls. Mice were electrically stimulated twice daily, 5 days per week for 3 weeks. Electroencephalography was recorded to measure the primary afterdischarge duration, and the behavioral progression of kindling-induced seizures was assessed. rTg4510 mice (n = 10) had increased primary afterdischarge durations (p < 0.001), and significantly more rapid progression of kindling (p < 0.001), compared with wild-type mice (n = 10). Tau knockout mice (n = 7), however, did not differ from their wild-type counterparts (n = 8) on any of the seizure outcomes. These results suggest that Tg4510 mice are more vulnerable to epileptogenesis, but that the presence of tau itself is not necessary for kindling epileptogenesis to occur. PMID- 28710842 TI - Severe sequelae of erythema multiforme: three cases. PMID- 28710843 TI - New Directions in Health Sciences Libraries in Canada: Research and Evidence based Practice Are Key. AB - This article is the second in a new series in this regular feature. The intention of the series is to look at important global developments in health science libraries. These articles will serve as a road map, describing the key changes in the field and exploring factors driving these changes. The present article by two Canadian librarians identifies important national developments which are shaping the profession such as the centralisation of health care services, the challenge of providing consumer health information in the absence of a national strategy, government recognition of the need to recognise and respond to the health needs of indigenous peoples and the growing emphasis on managing research data. Although their profession is strong, health science librarians must find ways of providing enhanced services with fewer staff and demonstrate value to organisations. JM. PMID- 28710844 TI - Reliable HPLC separation, vibrational circular dichroism spectra, and absolute configurations of isoborneol enantiomers. AB - Resolution of chiral compounds has played an important role in the pharmaceutical field, involving detailed studies of pharmacokinetics, physiological, toxicological, and metabolic activities of enantiomers. Herein, a reliable method by high-performance liquid chromatography (HPLC) coupled with an optical rotation detector was developed to separate isoborneol enantiomers. A cellulose tris(3, 5 dimethylphenylcarbamate)-coated chiral stationary phase showed the best separation performance for isoborneol enantiomers in the normal phase among four polysaccharide chiral packings. The effects of alcoholic modifiers and column temperature were studied in detail. Resolution of the isoborneol racemate displayed a downward trend along with an increase in the content of ethanol and column temperature, indicating that less ethanol in the mobile phase and lower temperature were favorable to this process. Moreover, two isoborneol enantiomers were obtained via a semipreparative chiral HPLC technique under optimum conditions, and further characterized by analytical HPLC, and experimental and calculated vibrational circular dichroism (VCD) spectroscopy, respectively. The solution VCD spectrum of the first-eluted component was consistent with the Density Functional Theory (DFT) calculated pattern based on the SSS configuration, indicating that this enantiomer should be (1S, 2S, 4S)-(+) isoborneol. Briefly, these results have provided reliable information to establish a method for analysis, preparative separation, and absolute configuration of chiral compounds without typical chromophoric groups. PMID- 28710845 TI - Chitosan membranes applied on the prostatic neurovascular bundles after nerve sparing robot-assisted radical prostatectomy: a phase II study. AB - OBJECTIVE: To evaluate the feasibility and the safety of applying chitosan membrane (ChiMe) on the neurovascular bundles (NVBs) after nerve-sparing robot assisted radical prostatectomy (NS-RARP). The secondary aim of the study was to report preliminary data and in particular potency recovery data. PATIENTS AND METHODS: This was a single-centre, single-arm prospective study, enrolling all patients with localised prostate cancer scheduled for RARP with five-item version of the International Index of Erectile Function scores of >17, from July 2015 to September 2016. All patients underwent NS-RARP with ChiMe applied on the NVBs. The demographics, perioperative, postoperative and complications data were evaluated. Potency recovery data were evaluated in particular and any sign/symptom of local allergy/intolerance to the ChiMe was recorded and evaluated. RESULTS: In all, 140 patients underwent NS-RARP with ChiMe applied on the NVBs. Applying the ChiMe was easy in almost all the cases, and did not compromise the safety of the procedure. None of the patients reported signs of intolerance/allergy attributable to the ChiMe and potency recovery data were encouraging. CONCLUSION: In our experience, ChiMe applied on the NVBs after NS RARP was feasible and safe, without compromising the duration, difficulty or complication rate of the 'standard' procedure. No patients had signs of intolerance/allergy attributable to the ChiMe and potency recovery data were encouraging. A comparative cohort would have added value to the study. The present paper was performed before Conformite Europeene (CE)-mark achievement. PMID- 28710846 TI - Robotic mesocolic excision with a 'top to down no-touch' technique for right colon cancer - a video vignette. PMID- 28710847 TI - Effect of Passage Number and Culture Time on the Expression and Activity of Insulin-Degrading Enzyme in Caco-2 Cells AB - Background: Insulin-degrading enzyme (IDE) is a conserved zinc metallopeptidase. Here, we have evaluated the effect of passage number and culture time on IDE expression and activity in colorectal adenocarcinoma cell line (Caco-2). Methods: Caco-2 cells were cultured with different passage ranges of 5-15, 25-35, 52-63 for 48, 72, and 120 hours. Subsequently, IDE expression and enzyme activity were assessed by Western blot analysis and fluorescent assay, respectively. Results: Our results confirmed that the amount of IDE was higher in cell extract compared to supernatant, and different passage numbers and culture times had small effect on IDE expression. However, when cells were cultured in the passage number range of 5-15 for 72 hours, the IDE activity was 35% higher compared to other passage numbers (p < 0.05). Conclusion: The use of Caco-2 cells at passage number range of 5-15 and culture time of 72 hours provides proper conditions for IDE-related studies. PMID- 28710848 TI - Breaking Transmission with Vaccines: The Case of Tuberculosis. AB - Members of the Mycobacterium tuberculosis complex (MTBC) have evolved causing tuberculosis (TB) in different mammalian hosts. MTBC ecotypes have adapted to diverse animal species, with M. bovis being the most common cause of TB in livestock. Cattle-to-human transmission of M. bovis through ingestion of raw milk was common before introduction of the pasteurization process. TB in humans is mainly caused by M. tuberculosis. This bacterium is considered a genetically clonal pathogen that has coevolved with humans due to its ability to manipulate and subvert the immune response. TB is a major public health problem due to airborne person-to-person transmission of M. tuberculosis. The essential yet unanswered question on the natural history of TB is when M. tuberculosis decides to establish latent infection in the host (resambling the lysogenic cycle of lambda phage) or to cause pulmonary disease (comparable to the lytic cycle of lambda phage). In this latter case, M. tuberculosis kills the host with the aim of achieving transmission to new hosts. Combating the TB epidemic requires stopping transmission. M. bovis BCG, the present vaccine against TB, is derived from M. bovis and only protects against disseminated forms of TB. Thus, a priority in TB research is development of new effective vaccines to prevent pulmonary disease. Attenuated vaccines based on M. tuberculosis as MTBVAC are potential candidates that could contribute to break the TB transmission cycle. PMID- 28710849 TI - Long-Distance Dispersal of Fungi. AB - Dispersal is a fundamental biological process, operating at multiple temporal and spatial scales. Despite an increasing understanding of fungal biodiversity, most research on fungal dispersal focuses on only a small fraction of species. Thus, any discussion of the dispersal dynamics of fungi as a whole is problematic. While abundant morphological and biogeographic data are available for hundreds of species, researchers have yet to integrate this information into a unifying paradigm of fungal dispersal, especially in the context of long-distance dispersal (LDD). Fungal LDD is mediated by multiple vectors, including meteorological phenomena (e.g., wind and precipitation), plants (e.g., seeds and senesced leaves), animals (e.g., fur, feathers, and gut microbiomes), and in many cases humans. In addition, fungal LDD is shaped by both physical constraints on travel and the ability of spores to survive harsh environments. Finally, fungal LDD is commonly measured in different ways, including by direct capture of spores, genetic comparisons of disconnected populations, and statistical modeling and simulations of dispersal data. To unify perspectives on fungal LDD, we propose a synthetic three-part definition that includes (i) an identification of the source population and a measure of the concentration of source inoculum and (ii) a measured and/or modeled dispersal kernel. With this information, LDD is defined as (iii) the distance found within the dispersal kernel beyond which only 1% of spores travel. PMID- 28710850 TI - Efficacy and safety of beclomethasone dipropionate breath-actuated or metered dose inhaler in pediatric patients with asthma. AB - BACKGROUND: Breath-actuated inhalers (BAI) eliminate the need for hand-breath coordination and, therefore, simplify the delivery of inhaled medication. OBJECTIVE: To evaluate the efficacy and safety of beclomethasone dipropionate BAI and metered-dose inhaler (MDI) versus placebo in pediatric patients ages 4-11 years with persistent asthma. METHODS: In this double-blind, double-dummy, phase III study, 628 children with persistent asthma were randomly assigned (1:1:1:1:1) to twice-daily beclomethasone dipropionate (BAI 80 MUg/day, BAI 160 MUg/day, MDI 80 MUg/day, or MDI 160 MUg/day) or to placebo. Efficacy over 12 weeks was assessed by spirometry, peak expiratory flow (PEF) measurements and other clinical end points. The primary efficacy end point was the baseline-adjusted trough morning percent predicted forced expiratory volume in 1 second (PPFEV1) area under the effect curve from 0 to 12 weeks (AUEC[0-12 weeks]). RESULTS: PPFEV1 AUEC(0-12 weeks) showed numerical improvements from baseline in the BAI 80 MUg/day and BAI 160 MUg/day groups and MDI 80 MUg/day and MDI 160 MUg/day groups; however, these improvements were not significant versus placebo for any group after hierarchical testing was applied. Consistent improvements were noted in the active treatment groups versus placebo for the weekly average trough morning and evening PEFs, and with BAI 80 MUg/day versus placebo for rescue albuterol/salbutamol use and the total daily asthma symptom score. Most patients indicated that the BAI device was easy or very easy to use. Adverse events were comparable across the groups; the incidence of oral candidiasis ranged from 0.8 to 3.2%. CONCLUSIONS: Although the primary efficacy end point was not demonstrated, consistent improvements in PEF and other clinical end points were observed with beclomethasone dipropionate BAI, particularly at the 80 MUg/day dose. These clinical benefits, combined with the need for better symptom control in children with asthma, supported the development of beclomethasone dipropionate BAI. PMID- 28710851 TI - Generation of apoptosis-resistant HEK293 cells with CRISPR/Cas mediated quadruple gene knockout for improved protein and virus production. AB - Apoptosis has important functions during pathophysiologic processes. However, from a biopharmaceutical point of view, active apoptosis of host cells is undesirable during viral packaging or protein expression, because it decreases the efficiency of viral or protein production. Here we used the CRISPR/Cas technique to knock out four pro-apoptotic genes, Caspase3, Caspase6, Caspase7 and AIF1, in HEK293 cells, and successfully produced an apoptosis-resistant cell line. Furthermore, this cell line showed higher expression levels of pro apoptotic proteins and higher packaging efficiency for the virus carrying these proteins than control HEK293 cells. This study not only produced an apoptosis resistant cell line that is useful in producing apoptosis-inducing proteins or viruses expressing these proteins, but also provides a methodology to build other apoptosis-resistant cell lines. PMID- 28710852 TI - Mixture toxicity in the marine environment: Model development and evidence for synergism at environmental concentrations. AB - Little is known about the effect of metal mixtures on marine organisms, especially after exposure to environmentally realistic concentrations. This information is, however, required to evaluate the need to include mixtures in future environmental risk assessment procedures. We assessed the effect of copper (Cu)-Nickel (Ni) binary mixtures on Mytilus edulis larval development using a full factorial design that included environmentally relevant metal concentrations and ratios. The reproducibility of the results was assessed by repeating this experiment 5 times. The observed mixture effects were compared with the effects predicted with the concentration addition model. Deviations from the concentration addition model were estimated using a Markov chain Monte-Carlo algorithm. This enabled the accurate estimation of the deviations and their uncertainty. The results demonstrated reproducibly that the type of interaction synergism or antagonism-mainly depended on the Ni concentration. Antagonism was observed at high Ni concentrations, whereas synergism occurred at Ni concentrations as low as 4.9 MUg Ni/L. This low (and realistic) Ni concentration was 1% of the median effective concentration (EC50) of Ni or 57% of the Ni predicted-no-effect concentration (PNEC) in the European Union environmental risk assessment. It is concluded that results from mixture studies should not be extrapolated to concentrations or ratios other than those investigated and that significant mixture interactions can occur at environmentally realistic concentrations. This should be accounted for in (marine) environmental risk assessment of metals. Environ Toxicol Chem 2017;36:3471-3479. (c) 2017 SETAC. PMID- 28710854 TI - Opportunities and challenges of real-time release testing in biopharmaceutical manufacturing. AB - Real-time release testing (RTRT) is defined as "the ability to evaluate and ensure the quality of in-process and/or final drug product based on process data, which typically includes a valid combination of measured material attributes and process controls" (ICH Q8[R2]). This article discusses sensors (process analytical technology, PAT) and control strategies that enable RTRT for the spectrum of critical quality attributes (CQAs) in biopharmaceutical manufacturing. Case studies from the small-molecule and biologic pharmaceutical industry are described to demonstrate how RTRT can be facilitated by integrated manufacturing and multivariable control strategies to ensure the quality of products. RTRT can enable increased assurance of product safety, efficacy, and quality-with improved productivity including faster release and potentially decreased costs-all of which improve the value to patients. To implement a complete RTRT solution, biologic drug manufacturers need to consider the special attributes of their industry, particularly sterility and the measurement of viral and microbial contamination. Continued advances in on-line and in-line sensor technologies are key for the biopharmaceutical manufacturing industry to achieve the potential of RTRT. Related article: http://onlinelibrary.wiley.com/doi/10.1002/bit.26378/full. PMID- 28710853 TI - Real-world effectiveness of sofosbuvir-based treatment regimens for chronic hepatitis C genotype 3 infection: Results from the multicenter German hepatitis C cohort (GECCO-03). AB - There are limited data regarding the real world effectiveness of direct acting antivirals (DAA) for the therapy of chronic genotype 3 hepatitis C virus (HCV) infection. All HCV genotype 3 infected patients from the German hepatitis C cohort (GECCO), which is a prospective database of nine German hepatitis C treatment centers, were included in the study. Three hundred forty-two chronically infected HCV genotype 3 patients were analyzed (253 males [74.0%], mean age 47.3 years, 127 cirrhotic patients [37.1%] mostly with Child A cirrhosis, 113 treatment experienced patients [37.1%], 38 HCV/HIV co-infected patients [11.1%]). SVR12 rates in the "intention-to-treat" analysis were as follows: sofosbuvir/ribavirin 69.4% (75/108), sofosbuvir/peginterferon/ribavirin 80.6% (58/72), sofosbuvir/daclatasvir +/- ribavirin for 12 weeks 88.3% (53/63), sofosbuvir/daclatasvir +/- ribavirin for 24 weeks 79.3% (23/29), sofosbuvir/ledipasvir +/- ribavirin for 12 weeks 71.4% (10/14), and sofosbuvir/ledipasvir +/- ribavirin for 24 weeks 86.7% (26/30). Forty patients were lost to follow-up, 23 patients had a relapse, 4 patients stopped treatment prematurely and 1 patient died. Female sex (P = 0.038) and treatment with two different DAAs (P = 0.05) were predictors for SVR12 in the multivariate analysis. In conclusion, sofosbuvir/daclatasvir +/- ribavirin for 12 weeks and sofosbuvir/ledipasvir +/- ribavirin for 24 weeks are effective for the treatment of HCV genotype 3 infected patients including cirrhotic, treatment-experienced or HIV/HCV co-infected patients. PMID- 28710855 TI - Retrospective on The United States Environmental Protection Agency's guidelines for deriving ambient water quality criteria. PMID- 28710856 TI - Quantitative intracellular flux modeling and applications in biotherapeutic development and production using CHO cell cultures. AB - Chinese hamster ovary (CHO) cells have been widely used for producing many recombinant therapeutic proteins. Constraint-based modeling, such as flux balance analysis (FBA) and metabolic flux analysis (MFA), has been developing rapidly for the quantification of intracellular metabolic flux distribution at a systematic level. Such methods would produce detailed maps of flows through metabolic networks, which contribute significantly to better understanding of metabolism in cells. Although these approaches have been extensively established in microbial systems, their application to mammalian cells is sparse. This review brings together the recent development of constraint-based models and their applications in CHO cells. The further development of constraint-based modeling approaches driven by multi-omics datasets is discussed, and a framework of potential modeling application in cell culture engineering is proposed. Improved cell culture system understanding will enable robust developments in cell line and bioprocess engineering thus accelerating consistent process quality control in biopharmaceutical manufacturing. PMID- 28710857 TI - ROS mediated selection for increased NADPH availability in Escherichia coli. AB - The economical production of chemicals and fuels by microbial processes remains an intense area of interest in biotechnology. A key limitation in such efforts concerns the availability of key co-factors, in this case NADPH, required for target pathways. Many of the strategies pursued for increasing NADPH availability in Escherichia coli involve manipulations to the central metabolism, which can create redox imbalances and overall growth defects. In this study we used a reactive oxygen species based selection to search for novel methods of increasing NADPH availability. We report a loss of function mutation in the gene hdfR appears to increase NADPH availability in E. coli. Additionally, we show this excess NADPH can be used to improve the production of 3HP in E. coli. PMID- 28710859 TI - Carbon Nitride Aerogels for the Photoredox Conversion of Water. AB - Aerogel structures have attracted increasing research interest in energy storage and conversion owing to their unique structural features, and a variety of materials have been engineered into aerogels, including carbon-based materials, metal oxides, linear polymers and even metal chalcogenides. However, manufacture of aerogels from nitride-based materials, particularly the emerging light-weight carbon nitride (CN) semiconductors is rarely reported. Here, we develop a facile method based on self-assembly to produce self-supported CN aerogels, without using any cross-linking agents. The combination of large surface area, incorporated functional groups and three-dimensional (3D) network structure, endows the resulting freestanding aerogels with high photocatalytic activity for hydrogen evolution and H2 O2 production under visible light irradiation. This work presents a simple colloid chemistry strategy to construct 3D CN aerogel networks that shows great potential for solar-to-chemical energy conversion by artificial photosynthesis. PMID- 28710858 TI - Identification of group B rotavirus as an etiological agent in the gastroenteritis outbreak in Maharashtra, India. AB - Acute gastroenteritis outbreak occurred at Pargaon, Maharashtra, India in 1789 cases with an attack rate of 32.5% between November to December 2015. The stool specimens (n = 32) were investigated for different enteric viral agents using conventional methods. Transmission electron microscopy and RNA polyacrylamide gel electrophoresis respectively identified morphologically distinct rotavirus particles in 28% and RNA migration pattern of Group B Rotavirus (GBR) in 72% of the specimens. Reverse transcription polymerase chain reaction and nucleotide sequencing confirmed presence of GBR in 97% of the samples analyzed. The predominance of GBR infections and absence or insignificant presence of other agents confirmed GBR as an etiological agent of the gastroenteritis outbreak occurred in Maharashtra, India. PMID- 28710860 TI - Coupling the pretreatment and hydrolysis of lignocellulosic biomass by the expression of beta-xylosidases. AB - Thermochemical pretreatment and enzymatic hydrolysis are the areas contributing most to the operational costs of second generation ethanol in lignocellulosic biorefineries. The improvement of lignocellulosic enzyme cocktails has been significant in the recent years. Although the needs for the reduction of the energy intensity and chemical consumption in the pretreatment step are well known, the reduction of the severity of the process strongly affects the enzymatic hydrolysis yield. To explore the formulation requirements of the well known cellulolytic cocktail from Myceliophthora thermophila on mild pretreated raw materials, this cocktail was tested on steam exploded corn stover without acid impregnation. The low hemicellulose yield and significant accumulation of xylobiose compared with the standard pretreated material obtained with dilute acid impregnation evidenced a clear limitation in the conversion of xylan to xylose. In order to complement the beta-xylosidase limitation, a selection of enzymes was expressed and tested in this fungus. A controlled expression of xylosidases from Aspergillus nidulans, Aspergillus fumigatus, and Fusarium oxysporum allowed recovering hemicellulose yields reached with standard acid treated material. The results underline the need of parallel development of the pretreatment process with the optimization of the formulation of the enzymatic cocktails. PMID- 28710861 TI - Differential protein modulation by ketoprofen and ibuprofen underlines different cellular response by gastric epithelium. AB - Ketoprofen L-lysine salt (KLS), is widely used due to its analgesic efficacy and tolerability, and L-lysine was reported to increase the solubility and the gastric tolerance of ketoprofen. In a recent report, L-lysine salification has been shown to exert a gastroprotective effect due to its specific ability to counteract the NSAIDs-induced oxidative stress and up-regulate gastroprotective proteins. In order to derive further insights into the safety and efficacy profile of KLS, in this study we additionally compared the effect of lysine and arginine, another amino acid counterion commonly used for NSAIDs salification, in control and in ethanol challenged human gastric mucosa model. KLS is widely used for the control of post-surgical pain and for the management of pain and fever in inflammatory conditions in children and adults. It is generally well tolerated in pediatric patients, and data from three studies in >900 children indicate that oral administration is well tolerated when administered for up to 3 weeks after surgery. Since only few studies have so far investigated the effect of ketoprofen on gastric mucosa maintenance and adaptive mechanisms, in the second part of the study we applied the cMap approach to compare ketoprofen-induced and ibuprofen induced gene expression profiles in order to explore compound-specific targeted biological pathways. Among the several genes exclusively modulated by ketoprofen, our attention was particularly focused on genes involved in the maintenance of gastric mucosa barrier integrity (cell junctions, morphology, and viability). The hypothesis was further validated by Real-time PCR. PMID- 28710862 TI - Identification of EloR (Spr1851) as a regulator of cell elongation in Streptococcus pneumoniae. AB - In a screen for mutations suppressing the lethal loss of PBP2b in Streptococcus pneumoniae we identified Spr1851 (named EloR), a cytoplasmic protein of unknown function whose inactivation removed the requirement for PBP2b as well as RodA. It follows from this that EloR and the two elongasome proteins must be part of the same functional network. This network also includes StkP, as this serine/threonine kinase phosphorylates EloR on threonine 89 (T89). We found that DeltaeloR cells, and cells expressing the phosphoablative form of EloR (EloRT89A ), are significantly shorter than wild-type cells. Furthermore, the phosphomimetic form of EloR (EloRT89E ) is not tolerated unless the cell in addition acquires a truncated MreC or non-functional RodZ protein. By itself, truncation of MreC as well as inactivation of RodZ gives rise to less elongated cells, demonstrating that the stress exerted by the phosphomimetic form of EloR is relieved by suppressor mutations that reduce or abolish the activity of the elongasome. Of note, it was also found that loss of elongasome activity caused by truncation of MreC elicits increased StkP-mediated phosphorylation of EloR. Together, the results support a model in which phosphorylation of EloR stimulates cell elongation, while dephosphorylation has an inhibitory effect. PMID- 28710864 TI - Localized accumulation of cytosolic calcium near the fused sperm is associated with the calcium- and voltage-dependent block of sperm entry in the sea urchin egg. AB - Interaction of the sperm and egg depolarizes the egg membrane, allowing the sperm to enter; however, if the egg membrane is not allowed to depolarize from its resting potential (e.g., by voltage-clamp), the sperm will not enter. Previous studies demonstrated that sperm entry into sea urchin eggs that are voltage clamped at negative membrane potentials is regulated both by the egg's membrane potential and a voltage-dependent influx of calcium into the egg. In these cases, electrical or cytoplasmic continuity (sperm-egg membrane fusion) occurs at negative membrane potentials, but subsequent loss of cytoplasmic continuity results in failure of sperm entry (unfusion). The work presented herein examined where, in relation to the sperm, and when, in relation to the sperm-induced electrophysiological events, the egg's calcium influx occurs, and how these events relate to successful or failed sperm entry. When sperm entered the egg, elevation of intracellular calcium concentration ([Ca2+ ]i ) began near the fused sperm on average 5.9 s after sperm-egg membrane fusion. Conversely, when sperm failed to enter the egg, [Ca2+ ]i elevated near the site of sperm-egg fusion on average 0.7 s after sperm-egg membrane fusion, which is significantly earlier than in eggs for which sperm entered. Therefore, the accumulation of calcium near the site of sperm-egg fusion is spatially and temporally consistent with the mechanism that may be responsible for loss of cytoplasmic continuity and failure of sperm entry. PMID- 28710863 TI - Assessment of the effectiveness of HPV16/18 infection referred for colposcopy in cervical cancer screening in Northwest of China. AB - To evaluate the effectiveness of Human papillomavirus16/18 infection referral to colposcopy in cervical cancer screening for women aged 25 years and older in Chinese northwest region Shaan'xi province. A total of 2224 women were diagnosed with primary high-risk HPV infection by HPV-DNA genotyping technology during August 2014 to August 2015. A total of 1916 cases referred for colposcopy with histological evidence were enrolled, including 1124 women with HPV16/18 genotype and 792 with other High-risk human papillomavirus genotypes. A total of 1916 women aged 25 years and older with HR-HPV positive were referred to colposcopy. The distribution of HPV16, HPV18, and other HR-HPVs infection were 49.22%, 9.45%, and 41.33%, respectively. 71.56% had normal cervical histology, 7.05% had Cervical Intraepithelial Neoplasia1, 8.82% had CIN2, 7.25% had CIN3, and 5.32% had cervical cancer. The percentage of positivity of HPV16 and HPV18 was highly associated with the relative risk of cervical lesion. The sensitivity and specificity of HPV16/18 for detection of CIN2+ (CIN3+) was 82.68% (92.12%) and 47.87% (46.15%), respectively. The positive predictive value and negative predictive value of HPV16/18 for detection of CIN2+ (CIN3+) was 30.16% (19.75%) and 91.03% (97.60%), respectively. HPV16 and HVP18 are the most common genotypes in high grade cervical lesions in Shaan'xi province. Meanwhile, these two types play predominant roles in the progression of high grade cervical lesion. Primary HPV16/18 detection has high sensitivity and negative predictive value in cervical cancer screening and the strategy for women with HPV16 and HPV18 infection referral to colposcopy is efficient and feasible in northwestern region of China. PMID- 28710865 TI - Neoadjuvant chemotherapy in triple-negative breast cancer: A multicentric retrospective observational study in real-life setting. AB - We aimed to assess the efficacy of neoadjuvant chemotherapy (NACT) in a cohort of 213 triple-negative breast cancer (TNBC) patients treated in real-world practice at eight Italian cancer centers. We computed descriptive statistics for all the variable of interest. Factors testing significant in univariate analysis were included in multivariate models. Survival data were compared by Kaplan-Meier curves and log-rank test. The median follow-up was 45 months. We observed 60 (28.2%) pathological complete response (pCR). The sequential anthracyclines taxanes-based regimens produced the highest rate of pCR (42.6%), followed by concomitant anthracycline-taxane (24.2%), and other regimens (15.6%) (p = 0.008). When analyzing the role of baseline Ki-67, a 50% cut-off was the optimal threshold value for pCR prediction (p = 0.0005). The 5-year disease-free survival (DFS) was 57.3% and the 5-year overall survival (OS) was 70.8%. In patients not achieving pCR, the optimal Ki-67 variation between biopsy and surgical specimen with prognostic relevance on long-term outcomes was 13% (p = 0.04). Patients with a Ki-67 reduction (rKi-67)<13% had worse outcomes compared to those who experienced pCR or a rKi-67>=13%. The number of NACT cycles also affected long term outcomes (5-year DFS 65.7% vs 51.6% in patients having received >6 cycles compared with their counterparts, p = 0.02). In multivariate analysis, node status, grading, and bio-pathological treatment response (including pCR and rKi 67) impacted DFS and OS. Our results confirmed the advantage conferred by more than 6 cycles of a sequential antracycline-taxane-based NACT. Higher baseline Ki 67 values shows greater predictive significance on pathogical response, while the rKi-67 plays a prognostic role on long-term outcomes. PMID- 28710866 TI - Response of synthetic diamond detectors in proton, carbon, and oxygen ion beams. AB - PURPOSE: In this work, the LET-dependence of the response of synthetic diamond detectors is investigated in different particle beams. METHOD: Measurements were performed in three nonmodulated particle beams (proton, carbon, and oxygen). The response of five synthetic diamond detectors was compared to the response of a Markus or an Advanced Markus ionization chamber. The synthetic diamond detectors were used with their axis parallel to the beam axis and without any bias voltage. A high bias voltage was applied to the ionization chambers, to minimize ion recombination, for which no correction is applied (+300 V and +400 V were applied to the Markus and Advanced Markus ionization chambers respectively). RESULTS: The ratio between the normalized response of the synthetic diamond detectors and the normalized response of the ionization chamber shows an under-response of the synthetic diamond detectors in carbon and oxygen ion beams. No under-response of the synthetic diamond detectors is observed in protons. For each beam, combining results obtained for the five synthetic diamond detectors and considering the uncertainties, a linear fit of the ratio between the normalized response of the synthetic diamond detectors and the normalized response of the ionization chamber is determined. The response of the synthetic diamond detectors can be described as a function of LET as (-6.22E-4 +/- 3.17E-3) * LET + (0.99 +/- 0.01) in proton beam, (-2.51E-4 +/- 1.18E-4) * LET + (1.01 +/- 0.01) in carbon ion beam and ( 2.77E-4 +/- 0.56E-4) * LET + (1.03 +/- 0.01) in oxygen ion beam. Combining results obtained in carbon and oxygen ion beams, a LET dependence of about 0.026% (+/-0.013%) per keV/MUm is estimated. CONCLUSIONS: Due to the high LET value, a LET dependence of the response of the synthetic diamond detector was observed in the case of carbon and oxygen beams. The effect was found to be negligible in proton beams, due to the low LET value. The under-response of the synthetic diamond detector may result from the recombination of electron/hole in the thin synthetic diamond layer, due to the high LET-values. More investigations are required to confirm this assumption. PMID- 28710867 TI - To BCVA, or not to BCVA, that is the question. PMID- 28710868 TI - Continuing Professional Development. PMID- 28710869 TI - Glymphatics and lymphatics in the eye and central nervous system. PMID- 28710870 TI - Self-changing behaviour in smoking cessation linked to trait and cognitive impulsivity. AB - BACKGROUND AND AIMS: To compare impulsivity, measured using self-report and cognitive tasks in people who ceased smoking without treatment (self-changers) with each of the following groups: (i) smoking non-treatment-seekers, (ii) people in smoking cessation treatment and currently abstinent and (iii) people in smoking cessation treatment but non-abstinent. DESIGN: Cross-sectional, observational study. SETTING: The smoking cessation unit of a public general hospital, Hospital de Santa Maria, in Lleida, Spain. All participants were from the hospital's catchment area. PARTICIPANTS: One hundred and twenty participants, classified in four groups: (1) self-changers (n = 30, 21 females, mean age = 41.50 years), (2) non-treatment-seekers (n = 30, 17 females, mean age = 35.27 years), (3) people in smoking cessation treatment and currently abstinent (n = 30, 17 females, mean age = 48.93 years) and (4) people in smoking cessation treatment but non-abstinent (n = 30, 21 females, mean age = 33.70 years). MEASUREMENTS: The Barratt Impulsiveness Scale, including measures of non planning, attentional and motor impulsivity, and two behavioural tasks measuring cognitive inhibition (Stroop test) and choice impulsivity (delay-discounting task). Confounders included sex, age, education, employment, smoking severity, depression and trait and state anxiety. FINDINGS: Although not on the other three measures, we found significant group differences on trait non-planning impulsivity and Stroop performance. Self-changers, compared with non-treatment seekers, had lower non-planning impulsivity (P = 0.018, Cohen's d = 0.62) and better Stroop performance (P = 0.001, Cohen's d = 0.66). Self-changers also had better Stroop performance than participants in treatment and currently abstinent (P = 0.002, Cohen's d = 0.85). CONCLUSIONS: People who have stopped smoking without treatment appear to have lower non-planning impulsivity and more effective cognitive inhibition compared with smoking non-treatment-seekers, and better cognitive inhibition than people who cease smoking with treatment aid. PMID- 28710871 TI - Detection and quantification of coronary calcium from dual energy chest x-rays: Phantom feasibility study. AB - PURPOSE: We have demonstrated the ability to identify coronary calcium, a reliable biomarker of coronary artery disease, using nongated, 2-shot, dual energy (DE) chest x-ray imaging. Here we will use digital simulations, backed up by measurements, to characterize DE calcium signals and the role of potential confounds such as beam hardening, x-ray scatter, cardiac motion, and pulmonary artery pulsation. For the DE calcium signal, we will consider quantification, as compared to CT calcium score, and visualization. METHODS: We created stylized and anatomical digital 3D phantoms including heart, lung, coronary calcium, spine, ribs, pulmonary artery, and adipose. We simulated high and low kVp x-ray acquisitions with x-ray spectra, energy dependent attenuation, scatter, ideal detector, and automatic exposure control (AEC). Phantoms allowed us to vary adipose thickness, cardiac motion, etc. We used specialized dual energy coronary calcium (DECC) processing that includes corrections for scatter and beam hardening. RESULTS: Beam hardening over a wide range of adipose thickness (0-30 cm) reduced the change in intensity of a coronary artery calcification (DeltaICAC ) by < 3% in DECC images. Scatter correction errors of +/-50% affected the calcium signal (DeltaICAC ) in DECC images +/-9%. If a simulated pulmonary artery fills with blood between exposures, it can give rise to a residual signal in DECC images, explaining pulmonary artery visibility in some clinical images. Residual misregistration can be mostly compensated by integrating signals in an enlarged region encompassing registration artifacts. DECC calcium score compared favorably to CT mass and volume scores over a number of phantom perturbations. CONCLUSION: Simulations indicate that proper DECC processing can faithfully recover coronary calcium signals. Beam hardening, errors in scatter estimation, cardiac motion, calcium residual misregistration etc., are all manageable. Simulations are valuable as we continue to optimize DE coronary calcium image processing and quantitative analysis. PMID- 28710872 TI - GacS/GacA activates pyoluteorin biosynthesis through Gac/Rsm-RsmE cascade and RsmA/RsmE-driven feedback loop in Pseudomonas protegens H78. AB - The Gac/Rsm regulatory pathway in Pseudomonas spp. activates the production of various secondary metabolites, such as antibiotics, siderophores and exoenzymes. However, the biosynthesis of antifungal compound pyoluteorin (Plt) in Pseudomonas protegens H78 is almost entirely inhibited by double deletion of two csrA/rsmA family genes, namely, rsmA and rsmE. Here, we investigated the complicated regulatory mechanism of RsmA and RsmE in Plt biosynthesis in P. protegens H78. RsmE negatively regulated Plt biosynthesis and pltLABCDEFG expression by directly interacting with the mRNA leaders of pltR and pltAB. Conversely, the transcription of pltL-G and pltR was positively influenced by RsmA through an uncharacterized mechanism. Further analyses demonstrated that pltL-G expression was diminished in the rsmA/E mutant. The deficiency of pltL-G expression in the gacA mutant was not reversed by any of the rsmA/E single or double mutations. The double deletion of rsmA/E reduced gacA expression by approximately 50% and almost completely inhibited the promoter activities of rsmXYZ sRNAs. The rsmY mutation significantly inhibited Plt biosynthesis. Taken together, GacS/GacA modulates Plt biosynthesis through two distinct pathways: Gac/Rsm-RsmE traditional positive regulatory cascade and RsmA-mediated positive transcriptional regulation. Moreover, a new positive feedback loop between RsmA/E and GacS/A-RsmXYZ is essential for activating Plt biosynthesis. PMID- 28710873 TI - Mecamylamine treatment for alcohol dependence: a randomized controlled trial. AB - BACKGROUND AND AIMS: The nicotinic acetylcholine receptor antagonist, mecamylamine, is a potential novel pharmacotherapy for alcohol use disorder. The aims were to compare alcohol consumption between mecamylamine and placebo and test if smoking status modified treatment effects. DESIGN: Out-patient, randomized, double-blind clinical trial for 12 weeks of treatment with mecamylamine (10 mg) (n = 65) versus placebo (n = 63). SETTING: Connecticut, USA. PARTICIPANTS: Individuals had current alcohol dependence (n = 128), had an average age of 48.5 [standard deviation (SD) = 9.4], 110 (85.9%) were men, and included 74 smokers (57.8%) and 54 non-smokers (42.2%). Participants were randomized to mecamylamine 10 mg per day or placebo. All subjects also received medical management therapy administered by trained research personnel. MEASUREMENTS: Primary outcome was percentage of heavy drinking days during the last month of treatment; other outcomes included drinking days, drinks per drinking days, alcohol craving, smoking, symptoms of nicotine withdrawal and side effects. FINDINGS: There were no significant differences in the percentage of heavy drinking days at 3 months between the mecamylamine (mean = 18.4, SD = 29.0) and placebo treatment groups (mean = 20.4, SD = 29.2) [F1, 100 = 1.3, P = 0.25; effect size d = 0.07; mean difference = 2.06, 95% confidence interval (CI) = 8.96 to 13.08]. There were no significant differences in percentage of drinking days or in drinks per drinking day at month 3 between the mecamylamine and placebo groups; there were no significant interactions. CONCLUSIONS: Mecamylamine 10 mg per day did not reduce alcohol consumption significantly in treatment seeking smokers and non-smokers with alcohol use disorder. PMID- 28710874 TI - Association between universal hepatitis B prison vaccination, vaccine uptake and hepatitis B infection among people who inject drugs. AB - BACKGROUND AND AIMS: In Scotland, hepatitis B virus (HBV) vaccination for all prisoners was introduced in 1999; here, we examine the impact of this programme among people who inject drugs (PWID) in the community. This study aimed to compare rates of HBV vaccine uptake before and after implementation of the prison programme and to estimate the determinants of vaccine uptake, the levels of ever/current HBV infection and the associations between vaccine uptake and ever/current HBV infection. DESIGN: Data collected via serial cross-sectional surveys were used to compare the proportion who reported being vaccinated over time. For the 2013-14 survey, rates of ever/current HBV infection were calculated and the associations between vaccine uptake and ever/current HBV infection were examined using logistic regression. SETTING: Services providing injecting equipment and drug treatment and street sites in Glasgow (1993-2002) and throughout Scotland (2008-14). PARTICIPANTS: More than 10 000 PWID in total were recruited in the surveys. MEASUREMENTS: Participants completed a questionnaire (all years) to ascertain self-reported vaccine uptake and provided a blood spot (in 2013-14), tested for HBV core antibodies (anti-HBc) and surface antigen (HBsAg). FINDINGS: Among recent-onset PWID in Glasgow, vaccine uptake increased from 16% in 1993 to 59% in 2008-14 (P < 0.001). Among all PWID in Scotland, uptake increased further from 71% in 2008-09 to 77% in 2013-14 (P < 0.001) and was associated with incarceration [adjusted odds ratio (aOR) = 2.91, 95% confidence interval (CI) = 2.23-3.79]. The prevalence of anti-HBc and HBsAg in Scotland was 2.6 and 0.3%, respectively, among PWID who had commenced injecting in the decade since the programme's introduction. Vaccination was associated with reduced odds of ever (aOR = 0.60, CI = 0.37-0.97) and current (aOR = 0.40, CI = 0.16-0.97) HBV infection. CONCLUSIONS: In Scotland, uptake of hepatitis B virus (HBV) vaccination among people who inject drugs (PWID) in the community has increased since the 1999 introduction of universal prison vaccination, and current levels of HBV infection among PWID are low compared with other European countries. PMID- 28710875 TI - A Review on Bimetallic Nickel-Based Catalysts for CO2 Reforming of Methane. AB - In recent years, CO2 reforming of methane (dry reforming of methane, DRM) has become an attractive research area because it converts two major greenhouse gasses into syngas (CO and H2 ), which can be directly used as fuel or feedstock for the chemical industry. Ni-based catalysts have been extensively used for DRM because of its low cost and good activity. A major concern with Ni-based catalysts in DRM is severe carbon deposition leading to catalyst deactivation, and a lot of effort has been put into the design and synthesis of stable Ni catalysts with high carbon resistance. One effective and practical strategy is to introduce a second metal to obtain bimetallic Ni-based catalysts. The synergistic effect between Ni and the second metal has been shown to increase the carbon resistance of the catalyst significantly. In this review, a detailed discussion on the development of bimetallic Ni-based catalysts for DRM including nickel alloyed with noble metals (Pt, Ru, Ir etc.) and transition metals (Co, Fe, Cu) is presented. Special emphasis has been provided on the underlying principles that lead to synergistic effects and enhance catalyst performance. Finally, an outlook is presented for the future development of Ni-based bimetallic catalysts. PMID- 28710876 TI - Trunk elongation and ontogenetic changes in the axial skeleton of Triturus newts. AB - Body elongation in vertebrates can be achieved by lengthening of the vertebrae or by an increase in their number. In salamanders, longer bodies are mostly associated with greater numbers of vertebrae in the trunk or tail region. However, studies on the relative contribution of the length of single vertebra to body elongation are lacking. In this study, we focus on evolutionary and ontogenetic changes in differentiation of the trunk vertebrae and the relative contribution of individual vertebrae to trunk lengthening in Triturus newts, a monophyletic group of salamanders that shows remarkable disparity in body shape. We compared juveniles and adults of the most elongated T. dobrogicus, which has 17 trunk vertebrae, with juveniles and adults of two closely related species (T. ivanbureschi and T. anatolicus belonging to the T. karelinii species complex) representing a stout and robust morphotype with thirteen trunk vertebrae. We show that trunk vertebrae are uniform in size at the juvenile stage of both analyzed morphotypes. In adults, the trunk vertebrae of the elongated T. dobrogicus are largely uniform, while in those of T. anatolicus, the first two vertebrae differ from the remaining trunk vertebrae. There was no difference in the relative contribution of individual vertebrae to body lengthening between species or stages. We conclude that body elongation in Triturus newts is achieved by increasing the number of vertebrae but not their length. PMID- 28710877 TI - Quality attributes of bread fortified with staghorn sumac extract. AB - : Staghorn sumac (Rhus typhina) is rich in polyphenols and may be used as an innovative ingredient in maintaining and enhancing food quality. In this report, aqueous extracts of sumac fruit powder were added up to 10% in wheat bread formulation. The extract concentration-dependently delayed the mold growth (up to 5 log reduction in 7-day storage) and the staling of bread. Adding sumac extracts dose-dependently increased the total phenolic and anthocyanin contents of the breads. Minimal changes were observed in loaf volume, water activity, moisture content, texture (cohesiveness, springiness, and adhesive), and aroma of breads containing extracts of less than 4%. Overall, sumac addition altered several quality attributes of bread, including hardness, color, and sensory acceptance in appearance, flavor, and texture. Sumac holds potential as a natural preservative and an antistaling agent in bread formulation. PRACTICAL APPLICATIONS: The rising healthy food market demands bakery products fortified with novel functional ingredients. Staghorn sumac is an emerging healthy food ingredient that has attracted much research attention recently. This study provides a scientific basis to develop bread fortified with sumac-derived functional ingredients. The results pointed out the feasibility of making sumac-fortified breads with enhanced phenolic content, increased shelf life, and acceptable sensory profile. PMID- 28710879 TI - The transcription factor PstSTE12 is required for virulence of Puccinia striiformis f. sp. tritici. AB - Puccinia striiformis f. sp. tritici (Pst) is an obligate biotrophic fungus that causes extensive damage in wheat. The pathogen is now known to be a heteroecious fungus with an intricate life cycle containing sexual and asexual stages. Orthologues of the STE12 transcription factor that regulate mating and filamentation in Saccharomyces cerevisiae, as well as virulence in other fungi, have been extensively described. Because reliable transformation and gene disruption methods are lacking for Pst, knowledge about the function of its STE12 orthologue is limited. In this study, we identified a putative orthologue of STE12 from Pst in haustoria-enriched transcripts and designated it as PstSTE12. The gene encodes a protein of 879 amino acids containing three helices in the homeodomain, conserved phenylalanine and tryptophan sites, and two C2 /H2 -Zn2+ finger domains. Real-time reverse transcription-polymerase chain reaction (RT PCR) analyses revealed that the expression of PstSTE12 was highly induced during the early infection stages and peaked during haustorium formation and the pycniospore stage in the aecial host barberry. Subcellular localization assays indicated that PstSTE12 is localized in the nucleus and functions as a transcriptional activator. Yeast one-hybrid assays revealed that PstSTE12 exhibits transcriptional activity, and that its C-terminus is necessary for the activation of transcription. PstSTE12 complemented the mating defect in an alpha ste12 mutant of S. cerevisiae. In addition, it partially complemented the defects of the Magnaporthe oryzae mst12 mutant in plant infection. Knocking down PstSTE12 via host-induced gene silencing (HIGS) mediated by Barley stripe mosaic virus (BSMV) resulted in a substantial reduction in the growth and spread of hyphae in Pst and weakened the virulence of Pst on wheat. Our results suggest that PstSTE12 probably acts at an intersection participating in the invasion and mating processes of Pst, and provide new insights into the comprehension of the variation of virulence in cereal rust fungi. PMID- 28710878 TI - 6-Mercaptopurine modifies cerebrospinal fluid T cell abnormalities in paediatric opsoclonus-myoclonus as steroid sparer. AB - The purpose of this study was to evaluate the capacity of 6-mercaptopurine (6 MP), a known immunosuppressant, to normalize cerebrospinal fluid (CSF) lymphocyte frequencies in opsoclonus-myoclonus syndrome (OMS) and function as a steroid sparer. CSF and blood lymphocytes were immunophenotyped in 11 children with OMS (without CSF B cell expansion) using a comprehensive panel of cell surface adhesion, activation and maturation markers by flow cytometry, and referenced to 18 paediatric controls. Drug metabolites, lymphocyte counts and liver function tests were used clinically to monitoring therapeutic range and toxicity. In CSF, adjunctive oral 6-MP was associated with a 21% increase in the low percentage of CD4+ T cells in OMS, restoring the CD4/CD8 ratio. The percentage of CD4+ T cells that were interferon (IFN)-gamma+ was reduced by 66%, shifting the cytokine balance away from T helper type 1 (Th1) (proinflammatory) predominance. The percentage of natural killer (NK) cells decreased significantly in CSF (-32%) and blood (-67 to -82%). Low blood absolute lymphocyte count was more predictive of improvement in CSF lymphocyte proportions (correlated with % CD4+ T cells) than the 6-thioguanine level (no correlation). 6-MP was difficult to titrate: 50% achieved the target absolute lymphocyte count (< 1.5 K/mm); 20%, the 'therapeutic' 6-thioguanine level; and 40% the non-toxic 6-methylmercaptopurine level. Side effects and transaminase elevation were mild and reversible. Clinical steroid-sparing properties and lowered relapse frequency were demonstrated. 6-MP displayed unique pharmacodynamic properties that may be useful in OMS and other autoimmune disorders. Its steroid sparer capacity is limited to children in whom the therapeutic window can be reached without limiting pharmacokinetic factors or side effects. PMID- 28710880 TI - An international survey on anti-neutrophil cytoplasmic antibodies (ANCA) testing in daily clinical practice. PMID- 28710882 TI - Mid-trimester preterm premature rupture of membranes (PPROM): etiology, diagnosis, classification, international recommendations of treatment options and outcome. AB - Mid-trimester preterm premature rupture of membranes (PPROM), defined as rupture of fetal membranes prior to 28 weeks of gestation, complicates approximately 0.4% 0.7% of all pregnancies. This condition is associated with a very high neonatal mortality rate as well as an increased risk of long- and short-term severe neonatal morbidity. The causes of the mid-trimester PPROM are multifactorial. Altered membrane morphology including marked swelling and disruption of the collagen network which is seen with PPROM can be triggered by bacterial products or/and pro-inflammatory cytokines. Activation of matrix metalloproteinases (MMP) have been implicated in the mechanism of PPROM. The propagation of bacteria is an important contributing factor not only in PPROM, but also in adverse neonatal and maternal outcomes after PPROM. Inflammatory mediators likely play a causative role in both disruption of fetal membrane integrity and activation of uterine contraction. The "classic PPROM" with oligo/an-hydramnion is associated with a short latency period and worse neonatal outcome compared to similar gestational aged neonates delivered without antecedent PPROM. The "high PPROM" syndrome is defined as a defect of the chorio-amniotic membranes, which is not located over the internal cervical os. It may be associated with either a normal or reduced amount of amniotic fluid. It may explain why sensitive biochemical tests such as the Amniosure (PAMG-1) or IGFBP-1/alpha fetoprotein test can have a positive result without other signs of overt ROM such as fluid leakage with Valsalva. The membrane defect following fetoscopy also fulfils the criteria for "high PPROM" syndrome. In some cases, the rupture of only one membrane - either the chorionic or amniotic membrane, resulting in "pre-PPROM" could precede "classic PPROM" or "high PPROM". The diagnosis of PPROM is classically established by identification of nitrazine positive, fern positive watery leakage from the cervical canal observed during in specula investigation. Other more recent diagnostic tests include the vaginal swab assay for placental alpha macroglobulin-1 test or AFP and IGFBP1. In some rare cases amniocentesis and infusion of indigo carmine has been used to confirm the diagnosis of PPROM. The management of the PPROM requires balancing the potential neonatal benefits from prolongation of the pregnancy with the risk of intra-amniotic infection and its consequences for the mother and infant. Close monitoring for signs of chorioamnionitis (e.g. body temperature, CTG, CRP, leucocytes, IL-6, procalcitonine, amniotic fluid examinations) is necessary to minimize the risk of neonatal and maternal complications. In addition to delayed delivery, broad spectrum antibiotics of penicillin or cephalosporin group and/or macrolide and corticosteroids have been show to improve neonatal outcome [reducing risk of chorioamnionitis (average risk ratio (RR)=0.66), neonatal infections (RR=0.67) and abnormal ultrasound scan of neonatal brain (RR=0.67)]. The positive effect of continuous amnioinfusion through the subcutaneously implanted perinatal port system with amniotic fluid like hypo-osmotic solution in "classic PPROM" less than 28/0 weeks' gestation shows promise but must be proved in future prospective randomized studies. Systemic antibiotics administration in "pre-PPROM" without infection and hospitalization are also of questionable benefit and needs to be further evaluated in well-designed randomized prospective studies to evaluate if it is associated with any neonatal benefit as well as the relationship to possible adverse effect of antibiotics on to fetal development and neurological outcome. PMID- 28710881 TI - An ethanolic extract of Desmodium adscendens exhibits antipsychotic-like activity in mice. AB - BACKGROUND: Desmodium adscendens extract (DAE) is used traditionally in Ghana for the management of psychosis. The present study aimed at providing pharmacological evidence for its ethnomedical use by testing the hypothesis that an ethanolic extract of Desmodium adscendens may possess antipsychotic properties. METHODS: The primary behavioral effects of DAE on the central nervous system of mice were investigated using Irwin's test paradigm. Novelty-induced and apomorphine-induced locomotor and rearing behaviors in mice were explored in an open-field observational test system. Apomorphine-induced cage climbing test in mice was used as the antipsychotic animal model. The ability of DAE to induce catalepsy and enhance haloperidol-induced catalepsy was also investigated in mice. RESULTS: The DAE produced sedation, cholinergic-, and serotonergic-like effects in mice when evaluated using the Irwin's test. No lethality was observed after 24 h post treatment. The LD50 in mice was estimated to be greater than 3000 mg/kg. The DAE significantly decreased the frequency of novelty- and apomorphine-induced rearing and locomotor activities in mice. It also significantly lowered the frequency and duration of apomorphine-induced climbing activities in mice. It did not induce any cataleptic event in naive mice but only significantly enhanced haloperidol induced catalepsy at a dose of 1000 mg/kg. CONCLUSIONS: The ethanolic extract of Desmodium adscendens exhibited antipsychotic-like activities in mice. Motor side effects are only likely to develop at higher doses of the extract. PMID- 28710883 TI - An atypical type I gastric neuroendocrine tumor. AB - BACKGROUND: Gastric neuroendocrine tumors (GI-NETs) are rare lesions, usually discovered incidentally during endoscopy. Based on their pathology, there are 4 types of GI-NETs. Type I are multiple small polypoid lesions with central ulceration located in the gastric body or the fundus, associated with atrophic gastritis usually noninvasive and very rarely metastatic. We report on a rare case of a gastric NET arising from the muscularis propria layer of the pyloric ring. CASE REPORT: We present the case of a 65-year old woman with a history of alcoholic cirrhosis, investigated for melena. Upper endoscopy revealed a 30 mm submucosal pedunculated polypoid lesion located on the pylorus protruding in the duodenum, with normal overlying mucosa, fundic gastric atrophy and multiple small polyps at this level, with no active bleeding. CT scan did not reveal any distant metastases. An ultrasound endoscopy was performed, and a round hypoechoic heterogeneous solitary mass, evolving from the pyloric muscle was described. Considering a 30-mm tumor evolving from the gastric muscle layer in the absence of local invasion and with no distant metastases we decided against an endoscopical resection and we referred the patient to surgery. A laparoscopic wedge resection was performed. The pathology report described a 30/25 mm welldifferentiated neuroendocrine tumor invasive in the muscularis mucosa (pT3). CONCLUSIONS: Usually, type I neuroendocrine tumors are located in the body or the fundus of the stomach without submucosal invasion. The interesting feature in our case was that the tumor originated from the pylorus, making it an atypical presentation for a neuroendocrine tumor. PMID- 28710884 TI - Lothar Jaenicke (1923-2015) zum Gedachtnis. AB - Among the post-war European biochemists, L. Jaenicke (1923-2015) stands out as a distinctive character with bright ideas and professional elegance, yet with personal modesty. His contributions to diverse fields such as C1 metabolic pathways, signal compounds (aquatic sex attractants) of brown algae and chemotaxis appear as distinctive features not covered by his peers. His rich scientific oeuvre is documented in 291 journal articles, nine books, and a huge number of almost 570 book reviews, recensions, biographies and commentaries on the politics of science and the history of biochemistry. A quantitative approach is attempted here to make his diversified life's work more transparent through graphical analysis by the novel method of ergography. At a glance, his different strands of activities stand out clearly and speak for themselves, without the need for excessive verbal interpretation. PMID- 28710885 TI - Lothar Jaenicke and C1-metabolism: his first 25 years of research. AB - The biochemist Lothar Jaenicke died on 29 December 2015, aged 92 years old. The last time I saw him was at his 90th birthday on 14 September 2013, at the occasion of which his colleagues at the Universitat zu Koln (Cologne) in Germany had organized a symposium to honor him. PMID- 28710886 TI - The Cellular and Molecular Mechanism of Radiation-Induced Lung Injury. AB - The lung is one of several moderately radiosensitive organs. Radiation-induced lung injury (RILI), including acute radiation pneumonitis and chronic radiation induced pulmonary fibrosis, occurs most often in radiotherapy of lung cancer, esophageal cancer, and other thoracic cancers. Clinical symptoms of RILI include dry cough, shortness of breath, chest pain, fever, and even severe respiratory failure and death. The occurrence of RILI is a complex process that includes a variety of cellular and molecular interactions which ultimately leads to large fibroblast accumulation, proliferation, and differentiation, resulting in excessive extracellular matrix deposits, causing pulmonary fibrosis. The progress that has been made in recent years in the understanding of cellular and molecular mechanisms of RILI is summarized in this review. PMID- 28710888 TI - Chronic spinal cord injury causes upregulation of serotonin (5-HT)2A and 5-HT2C receptors in lumbosacral cord motoneurons. AB - OBJECTIVES: To investigate whether the voiding dysfunction caused by spinal cord injury (SCI) in rats can be improved by i.v. administration of the serotonin (5 HT)2A/2C receptor agonist 2,5-dimethoxy-4-iodophenyl-2-aminopropanehydrochloride (DOI), and to discuss whether the mechanism can be ascribed to 5-HT2A and 5-HT 2C receptor upregulation in lumbosacral cord motoneurons. MATERIALS AND METHODS: Female Sprague-Dawley rats were divided into two groups (SCI group vs normal control [NC] group). Under urethane anaesthesia, cystometry was performed to examine the variation in urodynamic variables before and after successive intrathecal (i.t.) administration of various doses of DOI into the lumbosacral cord. Changes in 5-HT2A and -2C receptors in the lumbosacral cord were also investigated using immunohistochemical staining and Western blot analysis. RESULTS: Compared with NC rats, the SCI rats had higher bladder capacity and post void residual urine volume, and lower voiding efficiency. After SCI, DOI improved voiding efficiency, probably via external urethral sphincter (EUS) activity. Immunohistochemical staining and Western blot analysis showed that 5-HT2A and -2C receptors were upregulated in lumbosacral cord motoneurons. CONCLUSION: In rats with SCI, DOI can improve voiding efficiency; this may be attributable to 5-HT2A and -2C receptor upregulation in lumbosacral cord motoneurons controlling EUS activity. PMID- 28710889 TI - Minimization of Ischemic Cholangiopathy in Donation After Cardiac Death Liver Transplantation: Is It Thrombolytic Therapy or Warm Ischemic Time Stringency and Donor Bile Duct Flush? PMID- 28710887 TI - Elfamycins: inhibitors of elongation factor-Tu. AB - Elfamycins are a relatively understudied group of antibiotics that target the essential process of translation through impairment of EF-Tu function. For the most part, the utility of these compounds has been as laboratory tools for the study of EF-Tu and the ribosome, as their poor pharmacokinetic profile and solubility has prevented implementation as therapeutic agents. However, due to the slowing of the antibiotic pipeline and the rapid emergence of resistance to approved antibiotics, this group is being reconsidered. Some researchers are using screens for novel naturally produced variants, while others are making directed, systematic chemical improvements on publically disclosed compounds. As an example of the latter approach, a GE2270 A derivative, LFF571, has completed phase 2 clinical trials, thus demonstrating the potential for elfamycins to become more prominent antibiotics in the future. PMID- 28710890 TI - Food allergy phenotypes: The key to personalized therapy. AB - Food allergies (FAs) are of increasing public health concern and are characterized by a large spectrum of diseases. Their diversity is well known for immunologic pathways (IgE, non-IgE-mediated FAs) and natural history. Many other factors and patient characteristics are involved including type of food, exposure route, allergic comorbidities, gender, racial and ethnic backgrounds, cofactors and health conditions. Food allergen components and sensitization profiles are also involved in FA phenotypes. A new approach to chronic disorders based on the identification of phenotypes through extensive knowledge of all the complex components is also applicable to FAs and could lead towards integrative care management. Diagnostic biomarkers for FAs are emerging which also contribute to better care modalities. The aim of this article was to highlight current knowledge regarding the phenotypic diversity of FA. This review will focus on IgE mediated FAs and how identifying phenotypes may help to better understand the pathophysiological complexity, improve diagnosis and lead to personalized treatment strategies. PMID- 28710891 TI - Preferential Plastid Retention by the Acquired Phototroph Mesodinium chamaeleon. AB - The ciliate genus Mesodinium contains species that rely to varying degrees on photosynthetic machinery stolen from cryptophyte algal prey. Prey specificity appears to scales inversely with this reliance: The predominantly phototrophic M. major/rubrum species complex exhibits high prey specificity, while the heterotrophic lineages M. pulex and pupula are generalists. Here, we test the hypothesis that the recently described mixotroph M. chamaeleon, which is phylogenetically intermediate between M. major/rubrum and M. pulex/pupula, exhibits intermediate prey preferences. Using a series of feeding and starvation experiments, we demonstrate that M. chamaeleon grazes and retains plastids at rates which often exceed those observed in M. rubrum, and retains plastids from at least five genera of cryptophyte algae. Despite this relative generality, M. chamaeleon exhibits distinct prey preferences, with higher plastid retention, mixotrophic growth rates and efficiencies, and starvation tolerance when offered Storeatula major, a cryptophyte that M. rubrum does not appear to ingest. These results suggest that niche partitioning between the two acquired phototrophs may be mediated by prey identity. M. chamaeleon appears to represent an intermediate step in the transition to strict reliance on acquired phototrophy, indicating that prey specificity may evolve alongside degree of phototrophy. PMID- 28710892 TI - Photochemical Reaction Between 1,2-Naphthoquinone and Adenine in Binary Water Acetonitrile Solutions. AB - The photochemical reaction between 1,2-naphthoquinone (NQ) and adenine was investigated using nanosecond time-resolved laser flash photolysis. With photolysis at 355 nm, the lowest triplet state T1 of NQ was produced via intersystem crossing from its singlet excited state. The triplet-triplet absorption of the state contributes three bands of transient spectra at 374, 596 and 650 nm, respectively, in pure acetonitrile and binary water-acetonitrile solutions. In the presence of adenine, the observation of A.+ (at 363 nm) and NQ+H. radical (at 343 and 485 nm) indicates a multistep mechanism of electron transfer process followed by a proton transfer between 3 NQ* and adenine. By fitting with the Stern-Volmer relationship, the quenching rate constant kq of 3 NQ* by adenine in binary water-acetonitrile solutions (4/1, volume ratio, v/v) is determined as 1.66 * 109 m-1 s-1 . Additionally, no spectral evidence confirms the existence of electron transfer between 3 NQ* with thymine, cytosine and uracil. PMID- 28710893 TI - Fracture of the medial intercondylar eminence of the tibia in horses treated by arthroscopic fragment removal (21 horses). AB - BACKGROUND: Fractures of the medial intercondylar eminence of the tibia (MICET) are scarcely reported in horses. OBJECTIVES: To report the clinical and diagnostic findings, surgical treatment and outcome in a series of horses presented with MICET fracture and treated with arthroscopic fragment removal. STUDY DESIGN: Multicentre retrospective case series. METHODS: Case records of horses diagnosed with MICET fractures that had undergone surgical treatment were reviewed. Follow-up information was obtained from re-examination visits and/or owners. RESULTS: Twenty-one cases were identified at 9 equine hospitals between 2004 and 2016. A history of trauma and acute onset of lameness was reported in 12 horses. All cases underwent fracture removal via arthroscopy of the medial femorotibial joint. The cranial cruciate ligament was intact in 6 horses and damaged in 15 horses (damage was <=25% [n = 9], 25-50% [n = 4] or >=50% [n = 2] of the cross-sectional area). The cranial ligament of the medial meniscus was damaged in 11 horses (<=25% [n = 8], 25-50% [n = 3]). The medial meniscus was damaged in 5 horses and articular cartilage damage was identified in 14 horses (mild [n = 8], moderate [n = 6]). Follow-up information (median 14 months; 4 months-6 years) was available for 20 cases; 2 horses were sound but convalescing; 13 horses were sound and returned to their previous or expected use. Of the 4 horses with the most severe changes to the articular soft tissue structures, 2 remained lame and 2 were subjected to euthanasia because of persistent lameness. MAIN LIMITATIONS: The retrospective, multicentre nature of this study and the limited number of horses are the main limitations. CONCLUSIONS: Fractures of the MICET are commonly associated with a traumatic event. Prompt diagnosis and early arthroscopic removal of the fracture are recommended. PMID- 28710894 TI - Short frontal plane fractures involving the dorsoproximal articular surface of the proximal phalanx: Description of the injury and a technique for repair. AB - BACKGROUND: Chip fractures of the dorsoproximal articular margin of the proximal phalanx are common injuries in racehorses. Large fractures can extend distal to the joint capsule insertion and have been described as dorsal frontal fractures. OBJECTIVES: To report the location and morphology of short frontal plane fractures involving the dorsoproximal articular surface of the proximal phalanx and describe a technique for repair under arthroscopic and radiographic guidance. STUDY DESIGN: Single centre retrospective case study. METHODS: Case records of horses with frontal plane fractures restricted to the dorsoproximal epiphysis and metaphysis of the proximal phalanx referred to Newmarket Equine Hospital were retrieved, images reviewed and lesion morphology described. A technique for repair and the results obtained are reported. RESULTS: A total of 22 fractures in 21 horses commencing at the proximal articular surface exited the dorsal cortex of the proximal phalanx distal to the metacarpophalangeal/metatarsophalangeal joint capsule in 17 hind- and five forelimbs. All were in Thoroughbred racehorses. In 16 cases these were acute racing or training injuries; 20 fractures were medial, one lateral and one was midline. All were repaired with a single lag screw using arthroscopic and radiographically determined landmarks. A total of 16 horses raced after surgery with performance data similar to their preinjury levels. MAIN LIMITATIONS: The study demonstrates substantial morphological similarities between individual lesions supporting a common pathophysiology, but does not identify precise causation. There are no cases managed differently that might permit assessment of the comparative efficacy of the treatment described. CONCLUSIONS: Short frontal plane fractures involving the dorsoproximal margin of the proximal phalanx that exit the bone distal to the metacarpophalangeal/metatarsophalangeal joint capsule have substantial morphological similarities, are amenable to minimally invasive repair and carry a good prognosis for return to training and racing. PMID- 28710896 TI - Renal Allograft Histology at 10 Years After Transplantation in the Tacrolimus Era: Evidence of Pervasive Chronic Injury. AB - Improving long-term renal allograft survival remains an important unmet need. To assess the extent of histologic injury at 10 years after transplantation in functioning grafts, we studied 575 consecutive adult solitary renal transplants performed between 2002 and 2005: 77% from living donors and 81% maintained on tacrolimus-based immunosuppression. Ten-year graft survival was 59% and death censored graft survival was 74%. Surveillance allograft biopsies were assessed at implantation, 5 years, and 10 years from 145 patients who reached 10 years. At implantation, 5% of biopsies had major histologic abnormalities (chronic transplant glomerulopathy score > 0, other chronic Banff scores >= 2, global glomerulosclerosis > 20%, or mesangial sclerosis >= 2). This increased to 54% at 5 years and 82% at 10 years. Major lesions at 10 years included the following: arteriolar hyalinosis (66%), mesangial sclerosis (67%), and global glomerulosclerosis > 20% (43%), with 48% of grafts having more than one major lesion. Transplant glomerulopathy and moderate-to-severe interstitial fibrosis were uncommon (12% each). Major lesions were associated with increased proteinuria and decreased graft function. In patients with diabetes at baseline, 52% had diabetic nephropathy/mesangial sclerosis at 10 years. We conclude that almost all renal allografts sustain major histologic injury by 10 years after transplantation. Much damage appears nonimmunologic, suggesting that new approaches are needed to decrease late injury. PMID- 28710895 TI - Erectile function after stereotactic body radiotherapy for localized prostate cancer. AB - OBJECTIVE: To elucidate the functional erection rate after prostate stereotactic body radiotherapy (SBRT) and to develop a comprehensive prognostic model of outcomes after treatment. PATIENTS AND METHODS: Between 2008 and 2013, 373 consecutive men with localized prostate cancer were treated with SBRT at a single academic institution as part of a prospective clinical trial or prospective registry. Prospective longitudinal patient-reported health-related quality of life (HRQoL) data was collected using the Expanded Prostate Cancer Index Composite (EPIC)-26 instrument. Functional erections were strictly defined as 'firm enough for intercourse' according to EPIC-26. Detailed comorbidity data were also collected. Logistic regression models were used to predict 24- and 60 month functional erection rates. Observed erection rates after SBRT were compared with those after other radiation therapies (external beam radiation therapy [EBRT] and brachytherapy) using prospectively validated models. RESULTS: The median (interquartile range) follow-up was 56 (37-73) months and the response rate at 2 years was 84%. For those with functional erections at baseline, 57% and 45% retained function at 24 and 60 months, respectively. On multivariable analysis for 24-month erectile function, significant variables included higher baseline sexual HRQoL (adjusted odds ratio [aOR] 1.55 per 10 points, 95% confidence interval [CI] 1.37-1.74; P < 0.001) and older age (aOR 0.66 per 10 years, 95% CI 0.43-1.00; P = 0.05). At 60 months, baseline HRQoL and age remained associated with erectile function, along with body mass index (aOR 0.45, 95% CI 0.26-0.78; P < 0.001). The 24- and 60-month models had excellent discrimination (c-index 0.81 and 0.84, respectively). Erection rates after SBRT were not statistically different from model-predicted rates after EBRT or brachytherapy for the whole cohort and the cohort with baseline erectile function. CONCLUSIONS: Intermediate- to long-term post-SBRT erectile function results are promising and not significantly different from other radiotherapy techniques. Clinicians can use our prognostic model to counsel patients regarding expected erectile function after SBRT. PMID- 28710897 TI - Early Life UV and Risk of Basal and Squamous Cell Carcinoma in New South Wales, Australia. AB - Sun exposure is the main cause of squamous (SCC) and basal cell carcinoma (BCC) although pattern and amount differ by cancer type, and sun sensitivity is the major host risk factor. Our study investigated risk factors and residential ambient UV in a population-based sample of Australian 45 and Up Study participants: 916 BCC cases, 433 SCC cases, 1224 controls. Unconditional logistic regression models adjusting for key covariates demonstrated 60% increased BCC risk and two-fold increased SCC risk with sun sensitivity, and three- and four fold increased risk, respectively, with solar keratoses. BCC but not SCC risk increased with higher early-life residential UV in all participants (odds ratio (OR) = 1.54; 95% CI 1.22-1.96 for intermediate; OR = 1.31; 95% CI 1.03-1.68 for high UV at birthplace) and similarly in Australian-born participants (P-values < 0.05). Risk of SCC but not BCC increased with long-term cumulative sun exposure assessed by self-reported outdoor work (OR 1.74, 95% CI 1.21-2.49). In conclusion, sun sensitivity is important for both cancers, early-life UV but not cumulative UV appears to increase BCC risk, the former an apparently novel finding, and SCC risk appears only to be related to long-term cumulative sun exposure. PMID- 28710898 TI - Projected climate changes threaten ancient refugia of kelp forests in the North Atlantic. AB - Intraspecific genetic variability is critical for species adaptation and evolution and yet it is generally overlooked in projections of the biological consequences of climate change. We ask whether ongoing climate changes can cause the loss of important gene pools from North Atlantic relict kelp forests that persisted over glacial-interglacial cycles. We use ecological niche modelling to predict genetic diversity hotspots for eight species of large brown algae with different thermal tolerances (Arctic to warm temperate), estimated as regions of persistence throughout the Last Glacial Maximum (20,000 YBP), the warmer Mid Holocene (6,000 YBP), and the present. Changes in the genetic diversity within ancient refugia were projected for the future (year 2100) under two contrasting climate change scenarios (RCP2.6 and RCP8.5). Models predicted distributions that matched empirical distributions in cross-validation, and identified distinct refugia at the low latitude ranges, which largely coincide among species with similar ecological niches. Transferred models into the future projected polewards expansions and substantial range losses in lower latitudes, where richer gene pools are expected (in Nova Scotia and Iberia for cold affinity species and Gibraltar, Alboran, and Morocco for warm-temperate species). These effects were projected for both scenarios but were intensified under the extreme RCP8.5 scenario, with the complete borealization (circum-Arctic colonization) of kelp forests, the redistribution of the biogeographical transitional zones of the North Atlantic, and the erosion of global gene pools across all species. As the geographic distribution of genetic variability is unknown for most marine species, our results represent a baseline for identification of locations potentially rich in unique phylogeographic lineages that are also climatic relics in threat of disappearing. PMID- 28710899 TI - Effects of dobutamine, dopamine, phenylephrine and noradrenaline on systemic haemodynamics and intestinal perfusion in isoflurane anaesthetised horses. AB - BACKGROUND: In the horse, effects of cardiovascular-active drugs on local perfusion of the gastrointestinal tract are poorly understood. OBJECTIVES: To determine the effect of drugs commonly used to support blood pressure, on local intestinal blood flow and tissue oxygenation under isoflurane anaesthesia. STUDY DESIGN: In vivo randomised crossover experiment. METHODS: Ten horses were anaesthetised with isoflurane. After 90 min of equilibration three doses (MUg/kg bwt/min) of dobutamine (DOB 0.5/1/3), dopamine (DA 1/2/5), noradrenaline (NA 0.1/0.2/0.5) and phenylephrine (PHE 0.5/1/3) were infused for 15 min, in a randomised order, with a 45 min washout-period. Blood flow and tissue oxygenation (sO2 ) of jejunum, colon and stomach were measured using white light remission spectrophotometry and laser doppler flowmetry; heart rate (HR), mean arterial blood pressure (MAP), cardiac output (CO) were measured and systemic vascular resistance (SVR) calculated. RESULTS: Compared to baseline high dose dobutamine significantly increased CO, HR, MAP (P<0.001) and blood flow to the jejunum (+47 +/- 26%, P = 0.001) and colon (+29 +/- 15%, P<0.001) (mean +/- s.d.). Dopamine (DA5) increased CO but decreased colonic blood flow (-39 +/- 21% from baseline, P<0.001), as well as SVR and MAP compared to baseline (P<0.001). Noradrenaline had no significant influence on intestinal perfusion, but increased MAP and SVR from baseline (P<0.001). Phenylephrine (PHE3) caused a significant decrease in blood flow and sO2 , most profoundly at the colon compared to baseline (flow -44 +/- 21%; sO2 -16 +/- 3%, P<0.001), while MAP and SVR increased and CO and HR decreased (P<0.001). MAIN LIMITATIONS: The measurement technique only allows for flow measurements in arbitrary units, which can limit comparability to other techniques. CONCLUSION: At the investigated doses dobutamine improved systemic and peripheral haemodynamics, while dopamine decreased MAP and peripheral perfusion. Noradrenaline increased MAP and SVR while peripheral blood flow was maintained, phenylephrine increased MAP, but reduced both local and systemic perfusion. PMID- 28710900 TI - Pre-Kidney Transplant Lower Extremity Impairment and Post-Kidney Transplant Mortality. AB - Prediction models for post-kidney transplantation mortality have had limited success (C-statistics <=0.70). Adding objective measures of potentially modifiable factors may improve prediction and, consequently, kidney transplant (KT) survival through intervention. The Short Physical Performance Battery (SPPB) is an easily administered objective test of lower extremity function consisting of three parts (balance, walking speed, chair stands), each with scores of 0-4, for a composite score of 0-12, with higher scores indicating better function. SPPB performance and frailty (Fried frailty phenotype) were assessed at admission for KT in a prospective cohort of 719 KT recipients at Johns Hopkins Hospital (8/2009 to 6/2016) and University of Michigan (2/2013 to 12/2016). The independent associations between SPPB impairment (SPPB composite score <=10) and composite score with post-KT mortality were tested using adjusted competing risks models treating graft failure as a competing risk. The 5-year posttransplantation mortality for impaired recipients was 20.6% compared to 4.5% for unimpaired recipients (p < 0.001). Impaired recipients had a 2.30-fold (adjusted hazard ratio [aHR] 2.30, 95% confidence interval [CI] 1.12-4.74, p = 0.02) increased risk of postkidney transplantation mortality compared to unimpaired recipients. Each one-point decrease in SPPB score was independently associated with a 1.19 fold (95% CI 1.09-1.30, p < 0.001) higher risk of post-KT mortality. SPPB-derived lower extremity function is a potentially highly useful and modifiable objective measure for pre-KT risk prediction. PMID- 28710902 TI - A brief psychological intervention for mothers of children with food allergy can change risk perception and reduce anxiety: Outcomes of a randomized controlled trial. AB - BACKGROUND: Mothers of children with food allergy have increased anxiety, which may be influenced by healthcare professionals' communication of risk. OBJECTIVE: To evaluate a brief psychological intervention for reducing anxiety in mothers of children with food allergy. METHODS: Two hundred mothers of children with food allergy were recruited from allergy clinics. A computer-generated randomization list was used to allocate participants to a single-session cognitive behavioural therapy intervention including a risk communication module, or standard care. Anxiety and risk perception were assessed at 6 weeks and 1 year. Primary outcome was state anxiety at 6 weeks. Secondary outcomes included state anxiety at 1 year, risk perception at 6 weeks and 1 year, and salivary cortisol response to a simulated anaphylaxis scenario at 1 year. RESULTS: We found no significant difference in the primary outcome state anxiety at 6 weeks, with mean 31.9 (SD 10.2) intervention, 34.0 (10.2) control; mean difference 2.1 (95% CI -0.9, 5.0; P=.17). There was significantly reduced state anxiety at 6 weeks in the intervention group, in the subgroup of participants with moderate/high anxiety at enrolment (103/200, 52%), with mean 33.0 (SD 9.3) intervention, 37.8 (SD 10.0) control; mean difference 4.8 (95% CI 0.9, 8.7; P=.016; Cohen's d effect size 0.50). The psychological intervention also reduced risk perception and salivary cortisol response (P=.032; effect size 0.36). CONCLUSION: We found evidence that a brief psychological intervention which incorporates accurate risk information may impact on anxiety, risk perception and physiological stress response in mothers of children with food allergy. PMID- 28710901 TI - Baseline and longitudinal plasma caveolin-1 level as a biomarker in active surveillance for early-stage prostate cancer. AB - OBJECTIVES: To evaluate the role of caveolin-1 (Cav-1) as a predictor of disease reclassification (DR) in men with early prostate cancer undergoing active surveillance (AS). PATIENTS AND METHODS: We analysed archived plasma samples prospectively collected from patients with early prostate cancer in a single institution AS study. Of 825 patients enrolled, 542 had >=1 year of follow-up. Baseline and longitudinal plasma Cav-1 levels were measured using an enzyme linked immunosorbent assay. Tumour volume or Gleason grade increases were criteria for DR. Logistic regression analyses were used to assess associations between clinicopathological characteristics and reclassification risk. RESULTS: In 542 patients, 480 (88.6%) had stage cT1c disease, 542 (100.0%) had a median prostate-specific antigen level of 4.1 ng/mL, and 531 (98.0%) had a median Cancer of the Prostate Risk Assessment score of 1. In all, 473 (87.3%) had a Gleason score of 3+3. After a median of 3.1 years of follow-up, disease was reclassified in 163 patients (30.1%). The mean baseline Cav-1 level was 2.2 +/- 8.5 ng/mL and the median 0.2 ng/mL (range, 0-85.5 ng/mL). In univariate analysis, baseline Cav 1 was a significant predictor for risk of DR (odds ratio [OR] 1.82, 95% confidence interval [CI] 1.24-2.65; P = 0.002). In multivariate analysis, with adjustments for age, tumour length, group risk stratification and number of positive cores, reclassification risk associated with Cav-1 remained significant (OR 1.91, 95% CI 1.28-2.84; P = 0.001). CONCLUSION: Baseline plasma Cav-1 level was an independent predictor of disease classification. New methods for refining AS and intervention may result. PMID- 28710903 TI - Stellate Cells Orchestrate Concanavalin A-Induced Acute Liver Damage. AB - Concanavalin A (ConA) causes immune cell-mediated liver damage, but the contribution of resident nonparenchymal cells (NPCs) is also evident. Hepatic stellate cells (HSCs) induce hepatic inflammation and immunological reactions; we therefore investigated their role in ConA-induced liver injury. ConA was administered i.v. to control or HSC-depleted mice; hepatic histopathology and cytokines/chemokines were determined after 6 hours. In vitro, effects of ConA conditioned HSC medium on hepatocytes were determined. ConA induced inflammation, sinusoidal congestion, and extensive midzonal hepatocyte death in control mice, which were strongly minimized in HSC-depleted mice. CD4 and natural killer T cells and neutrophils were markedly reduced in ConA-treated HSC-depleted mice compared with control mice. The increase in cytokines/chemokines of hepatic injury was much higher in ConA-treated control mice than in HSC-depleted mice. ConA-treated HSCs showed increased expression of interferon-beta, tumor necrosis factor-alpha, and CXCL1, induced oxidative stress in hepatocytes, and caused hepatocyte apoptosis. ConA induced nuclear translocation of interferon-regulatory factor-1 (IRF1) in hepatocytes in vivo, and ConA/HSC induced a similar effect in cultured hepatocytes. IRF1-knockout mice were resistant to ConA-induced liver damage, and anti-interferon beta antibody mitigated ConA/HSC-induced injury. In HSC-NPC co-culture, ConA-induced expression of inflammatory cytokines/chemokines was significantly augmented compared with NPCs alone. HSCs play an essential role in ConA-induced liver injury directly via the interferon-beta/IRF1 axis, and by modulating properties of NPCs. PMID- 28710904 TI - M1 Macrophage-Induced Endothelial-to-Mesenchymal Transition Promotes Infantile Hemangioma Regression. AB - Infantile hemangiomas are benign tumors of vascular endothelial cells (ECs), characterized by three distinct stages: proliferating phase, involuting phase, and involuted phase. The mechanisms that trigger involution of hemangioma into fibro-fatty tissue remain unknown. We report a novel mechanism by which M1 polarized macrophages induce endothelial-to-mesenchymal transition (EndMT) and promote hemangioma regression. M1- but not M2-polarized macrophages induced EndMT in ECs. Tumor necrosis factor-alpha and, to a lesser extent, IL-1beta and interferon-gamma were the most potent cytokines produced by the M1 macrophages that induce in vitro EndMT. Western blot analysis and gene expression profiling showed that ECs treated with M1 macrophages, tumor necrosis factor-alpha, or IL 1beta decreased the expression of endothelial markers, whereas mesenchymal markers increased concomitantly. Immunohistochemical staining of patient samples revealed that a significant perivascular infiltration of M1, but not M2, macrophages coincides with endothelial expression of the critical EndMT transcription factors Snail/Slug in involuting hemangiomas. Most strikingly, M1 macrophage-treated ECs isolated from patient hemangiomas (HemECs) but not untreated HemECs readily differentiated into adipocytes on adipogenic induction. Thus, in vitro EndMT and adipogenesis of HemECs have, in part, recapitulated the natural history of hemangioma regression. In conclusion, our findings indicate that EndMT induced by M1 macrophages promotes infantile hemangioma regression and may lead to novel therapeutic treatments for this vascular tumor. PMID- 28710905 TI - Administration of Fortifier by Finger Feeder During Breastfeeding in Preterm Infants. AB - OBJECTIVE: To evaluate the acceptance, adherence, and feasibility of fortifier administration by finger feeder during breastfeeding and to determine weight, length, and head circumference gains after discharge for preterm infants. DESIGN: Observational pilot study. SETTING: A Level III NICU and its outpatient clinic in Vienna, Austria. PARTICIPANTS: Infants born at younger than 34 weeks gestation were included. METHODS: Mothers were screened in a tertiary NICU and trained by certified lactation consultants to administer fortifier with a finger feeder during breastfeeding. Data on finger feeder use at home were collected by self reported feeding diaries and questionnaires. RESULTS: In total, data from 24 mother-infant dyads were analyzed. The acceptance rate was 67%. In 41.7%, more than 50% of meals were fortified. Mothers did not report problems in preparation, but 33% of the infants stopped latching on or drooled milk during finger feeder use. CONCLUSION: Use of a finger feeder to administer fortifier to preterm infants enabled mothers to exclusively breastfeed their infants and meet their nutritional needs. The development of further methods to augment preterm infant nutrition that do not interfere with breastfeeding is of great interest. PMID- 28710906 TI - Upward drift in cerebrospinal fluid amyloid beta 42 assay values for more than 10 years. AB - INTRODUCTION: The best-established cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease are levels of amyloid beta 42 (Abeta42), total tau (tau), and phosphorylated tau 181 (ptau). We examined whether a widely used commercial immunoassay for CSF Abeta42, tau, and ptau provided stable measurements for more than ~10 years. METHODS: INNOTEST assay values for CSF Abeta42, tau, and ptau from Washington University in St. Louis and VU Medical Center, Amsterdam, were evaluated. RESULTS: Abeta42 values as measured by the INNOTEST assay drifted upward by approximately 3% per year over the past decade. Tau values remained relatively stable, whereas results for ptau were mixed. DISCUSSION: Assay drift may reduce statistical power or even confound analyses. The drift in INNOTEST Abeta42 values may reduce diagnostic accuracy for Alzheimer's disease in the clinic. We recommend methods to account for assay drift in existing data sets and to reduce assay drift in future studies. PMID- 28710908 TI - Mental reinstatement of encoding context improves episodic remembering. AB - This study investigates context-dependent memory retrieval. Previous work has shown that physically re-experiencing the encoding context at retrieval improves memory accessibility. The current study examined if mental reconstruction of the original encoding context would yield parallel memory benefits. Participants performed a cued-recall memory task, preceded either by a mental or by a physical context reinstatement task, and we manipulated whether the context reinstated at retrieval overlapped with the context of the target episode. Both behavioral and electrophysiological measures of brain activity showed strong encoding-retrieval (E-R) overlap effects, with facilitated episodic retrieval when the encoding and retrieval contexts overlapped. The electrophysiological E-R overlap effect was more sustained and involved more posterior regions when context was mentally compared with physically reinstated. Additionally, a time-frequency analysis revealed that context reinstatement alone engenders recollection of the target episode. However, while recollection of the target memory is readily prompted by a physical reinstatement, target recollection during mental reinstatement is delayed and depends on the gradual reconstruction of the context. Taken together, our results show facilitated episodic remembering also when mentally reinstating the encoding context; and that such benefits are supported by both shared and partially non-overlapping neural mechanisms when the encoding context is mentally reconstructed as compared with physically presented at the time of retrieval. PMID- 28710907 TI - Distinct contributions of the fornix and inferior longitudinal fasciculus to episodic and semantic autobiographical memory. AB - Autobiographical memory (AM) is multifaceted, incorporating the vivid retrieval of contextual detail (episodic AM), together with semantic knowledge that infuses meaning and coherence into past events (semantic AM). While neuropsychological evidence highlights a role for the hippocampus and anterior temporal lobe (ATL) in episodic and semantic AM, respectively, it is unclear whether these constitute dissociable large-scale AM networks. We used high angular resolution diffusion weighted imaging and constrained spherical deconvolution-based tractography to assess white matter microstructure in 27 healthy young adult participants who were asked to recall past experiences using word cues. Inter-individual variation in the microstructure of the fornix (the main hippocampal input/output pathway) related to the amount of episodic, but not semantic, detail in AMs - independent of memory age. Conversely, microstructure of the inferior longitudinal fasciculus, linking occipitotemporal regions with ATL, correlated with semantic, but not episodic, AMs. Further, these significant correlations remained when controlling for hippocampal and ATL grey matter volume, respectively. This striking correlational double dissociation supports the view that distinct, large scale distributed brain circuits underpin context and concepts in AM. PMID- 28710909 TI - Evaluation of the interaction between genetic variants of GAD1 and miRNA in bipolar disorders. AB - BACKGROUND: Glutamic acid dehydrogenase 1 (GAD1) serves as the rate-limiting enzyme for synthesizing GABA, and is reported to be associated with several psychiatric disorders. The present study examined the effects of GAD1 genetic variants on bipolar disorder (BD) and its subtypes. Moreover, we investigated functional interactions between genetic variants and miRNAs via algorithm prediction and experimental validation. METHODS: A case-control study was conducted with 280 BD patients and 200 healthy controls. Eight tag SNPs in GAD1 were genotyped. For associated markers, we performed in silico prediction for their potential functions through SNP-miRNA interactions by establishing a scoring system to combine information from several miRNA predictive algorithms. We then tested allelic expression differences using Dual-Glo luciferase reporter assays for the selected SNP-miRNA pair. Lastly, we examined the associations of the GAD1 gene and BD in two additional independent datasets with a few thousand samples for replication. RESULTS: Marker rs3749034 was associated with BD, in particular the BD-II subtype. According to our scoring system, several candidate miRNAs were predicted to interact with rs3749034, and hsa-miR-504 had the highest score. Findings from an in vitro experiment revealed a non-statistically significant trend for lower gene expression level with the A allele of rs3749034 compared with the G allele. The association between rs3749034 and BD was not replicated in either of the independent datasets. Instead, other rarer genetic variants in GAD1 showed suggestive signals (e.g. rs575441409, p-value = 3.8*10-4, D' = 1 with rs3749034) with BD in the Taiwanese dataset. LIMITATIONS: The present study considered common genetic variants only. In addition, we only used a 293T cell-line in conducting luciferase reporter assays, as no primary cell-lines from patient samples were available to differentiate the effects between BD subtypes. CONCLUSIONS: Our results demonstrate a weak effect of the GAD1 gene on the risk of bipolar illness, and the associated marker might represent a proxy for real signals of rare variants. PMID- 28710911 TI - A Novel Technique for Reduction Malarplasty by Inward Displacement of Infractured Zygomatic Arch Without Fixation. AB - PURPOSE: Reduction malarplasty is one of the most common esthetic surgical procedures performed in the Asian population. Traditional procedures have several complications, such as bone nonunion, malunion, cheek drooping, and damage to the infraorbital nerve and maxillary sinus. Therefore, a more straightforward and effective method of reducing the width of the midface is needed. In this study, we introduce an infracture technique using inward displacement of the zygomatic arch without fixation. PATIENTS AND METHODS: A total of 680 patients received zygoma reduction using our method from 2012 to 2016 in the Department of Plastic Surgery, Minhang Shanghai Hospital. Radiologic and photographic documentation was completed preoperatively. The mean follow-up period was 24 months. The preoperative and postoperative photographs were compared. RESULTS: All patients were satisfied with their results. The mean operation time was approximately 35 minutes. The patients were discharged 5 days after the surgical procedure, and the mean recovery time was 2 weeks. The continuity of the outer cortex of the zygomatic complex and excellent bone union were observed in all patients 6 months postoperatively. The malar prominence underwent relapse in 23 patients and was reset. CONCLUSIONS: The new method that we developed has been proved safe and effective. It has 3 advantages. First, cheek drooping is avoided, and the damage caused by periosteum dissection on the whole zygomaticomaxillary area is limited. Second, bony fixation is unnecessary; thus the risk of bone nonunion, malunion, and a step-off deformity caused by improper fixation or looseness is prevented. Third, the operation time and the recovery time are short. PMID- 28710912 TI - Giants in Obstetrics and Gynecology Series: A profile of Leon Speroff, MD. PMID- 28710913 TI - Expression and promoter methylation of succinate dehydrogenase and fumarase genes in maize under anoxic conditions. AB - Succinate dehydrogenase (SDH) and fumarase enzyme activity and expression of genes encoding the SDH subunits A (Sdh1-2), B (Sdh2-3), C (Sdh3), D (Sdh4) and the mitochondrial (Fum1) and cytosolic (Fum2) isoforms of fumarase were quantified in maize (Zea mays L.) seedlings exposed to atmospheres of air (control), N2, and CO2. The catalytic activity of SDH gradually declined in plants exposed to N2 atmospheres, with ~40% activity remaining after 24h. In seedlings incubated in CO2, the suppression was even more pronounced. Fumarase activity was more stable, decreasing by one third after 24h of anoxia. The level of Sdh1-2 transcripts in seedlings declined significantly under N2 and even more rapidly upon exposure to CO2, with a concomitant increase in methylation of the corresponding promoters. The level of Sdh2-3 and Sdh3 transcripts also decreased under N2 and CO2, but the changes in promoter methylation were less pronounced, whereas the changes in the level of Sdh4 expression and promoter methylation were minor. Expression of Fum1 and Fum2 was affected by N2 and CO2 atmospheres, however without changes in corresponding promoter methylation. It is concluded that, under conditions of oxygen deficiency, succinate accumulates mainly due to downregulation of SDH gene expression and reduction of enzyme activity, and to a lesser extent due to the decrease of fumarase gene expression. PMID- 28710914 TI - High photosynthetic capability observed in the wheat germplasm with rye chromosomes. AB - Improving photosynthetic capability is one of the most important factors for increasing wheat yield potential. The photosynthetic capability of wheat germplasm with different alien chromosomes was investigated and compared with bread wheat cultivars (BC) in this study, including wheat addition lines (CA), hexaploid triticale (HT), octoploid triticale (OT), and synthetic hexaploid wheat lines (SHW). Results indicated that HT, OT, and SHW produced significantly higher biomass plant-1(BMPP), with HT displaying the highest grain yield plant-1 (GYPP). Distinct superiority of net photosynthetic rate (Pn) and carboxylation activities of ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) was observed in HT and OT. Meanwhile, OT showed the highest expression of the Rubisco large subunit gene (rbcL) in the flag leaves at heading and grain-filling stages, though the coding region of rbcL was highly conserved in all investigated materials. Further analysis indicated that OT and Chinese Spring-rye disomic addition lines displayed higher expression of Rubisco small subunit gene (rbcS). Correlation analysis revealed significant and positive correlations between Pn and the expressions of rbcL (at both heading and grain-filling stages), the expression of rbcS (at heading stage), and the carboxylation activity of Rubisco (at grain filling stage). Anatomical structure analysis of the chloroplasts showed SHW with longer chloroplasts and more chloroplast grana and grana lamella. In the present study, HT, OT, and Chinese Spring-rye disomic addition lines with rye chromosomes displayed greater photosynthetic capability than BC and SHW, and could be applied in breeding programs to improve the photosynthetic efficiency of wheat. PMID- 28710915 TI - Potent Therapeutic Activity Against Peritoneal Dissemination and Malignant Ascites by the Novel Anti-Folate Receptor Alpha Antibody KHK2805. AB - Many ovarian cancer patients often show peritoneal metastasis with malignant ascites. However, unmet medical needs remain regarding controlling these symptoms after tumors become resistant to chemotherapies. We developed KHK2805, a novel anti-folate receptor alpha (FOLR1) humanized antibody with enhanced antibody dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). The primary aim of the present study was to evaluate whether the anti tumor activity of KHK2805 was sufficient for therapeutic application against peritoneal dissemination and malignant ascites of platinum-resistant ovarian cancer in preclinical models. Here, both the ADCC and CDC of KHK2805 were evaluated in ovarian cancer cell lines and patient-derived samples. The anti tumor activity of KHK2805 was evaluated in a SCID mouse model of platinum resistant peritoneal dissemination. As results, KHK2805 showed specific binding to FOLR1 with high affinity at a novel epitope. KHK2805 exerted potent ADCC and CDC against ovarian cancer cell lines. Furthermore, primary platinum-resistant malignant ascites cells were susceptible to autologous ADCC with KHK2805. Patient derived sera and malignant ascites induced CDC of KHK2805. KHK2805 significantly reduced the total tumor burden and amount of ascites in SCID mice with peritoneal dissemination and significantly prolonged their survival. In addition, the parental rat antibody strongly stained serous and clear cell-type ovarian tumors by immunohistochemistry. Overall, KHK2805 showed cytotoxicity against both ovarian cancer cell lines and patient-derived cells. These translational study findings suggest that KHK2805 may be promising as a novel therapeutic agent for platinum-resistant ovarian cancer with peritoneal dissemination and malignant ascites. PMID- 28710916 TI - Systemic Immune-Inflammation Index and Circulating T-Cell Immune Index Predict Outcomes in High-Risk Acral Melanoma Patients Treated with High-Dose Interferon. AB - High-dose interferon alfa-2b (IFN-alpha-2b) improves the survival of patients with high-risk melanoma. We aimed to identify baseline peripheral blood biomarkers to predict the outcome of acral melanoma patients treated with IFN alpha-2b. Pretreatment baseline parameters and clinical data were assessed in 226 patients with acral melanoma. Relapse-free survival (RFS) and overall survival (OS) were assessed using the Kaplan-Meier method, and multivariate Cox regression analyses were applied after adjusting for stage, lactate dehydrogenase (LDH), and ulceration. Univariate analysis showed that neutrophil-to-lymphocyte ratio >=2.35, platelet-to-lymphocyte ratio >=129, systemic immune-inflammation index (SII) >=615 * 109/l, and elevated LDH were significantly associated with poor RFS and OS. The SII is calculated as follows: platelet count * neutrophil count/lymphocyte count. On multivariate analysis, the SII was associated with RFS [hazard ratio (HR)=1.661, 95% confidence interval (CI): 1.066-2.586, P=.025] and OS (HR=2.071, 95% CI: 1.204-3.564, P=.009). Additionally, we developed a novel circulating T-cell immune index (CTII) calculated as follows: cytotoxic T lymphocytes/(CD4+ regulatory T cells * CD8+ regulatory T cells). On univariate analysis, the CTII was associated with OS (HR=1.73, 95% CI: 1.01-2.94, P=.044). The SII and CTII might serve as prognostic indicators in acral melanoma patients treated with IFN-alpha-2b. The indexes are easily obtainable via routine tests in clinical practice. PMID- 28710917 TI - For whom does interpersonal psychotherapy work? A systematic review. AB - The efficacy of interpersonal psychotherapy (IPT) to treat depression and other disorders is well established, yet it remains unknown which patients will benefit more from IPT than another treatment. This review summarizes 46years of clinical trial research on patient characteristics that moderate the relative efficacy of IPT vs. different treatments. Across 57 studies from 33 trials comparing IPT to pharmacotherapy, another psychotherapy, or control, there were few consistent indicators of when IPT would be more or less effective than another treatment. However, IPT may be superior to school counseling for adolescents with elevated interpersonal conflict, and to minimal controls for patients with severe depression. Cognitive-behavioral therapy may outpace IPT for patients with avoidant personality disorder symptoms. There was some preliminary evidence that IPT is more beneficial than alternatives for patients in some age groups, African American patients, and patients in an index episode of depression. The included studies suffered from several limitations and high risk of Type I and II error. Obstacles that may explain the difficulty in identifying consistent moderators, including low statistical power and heterogeneity in samples and treatments, are discussed. Possible remedies include within-subjects designs, manipulation of single treatment ingredients, and strategies for increasing power such as improving measurement. PMID- 28710918 TI - Intolerance of Uncertainty in eating disorders: An update on the field. AB - Pathological fear and anxiety regarding food, eating, weight and body shape are at the core of eating disorder (ED) psychopathology. To manage anxiety, patients develop complicated repertoires of ritualistic and repetitive behaviours, which can lead to total functional impairment. Yet the cognitive processes underlying anxiety, fear, and anxiety-driven behaviours in EDs remain poorly understood. Intolerance of Uncertainty (IU) is defined as a tendency to react negatively on an emotional, cognitive, and behavioural level to uncertain situations and events. There is substantial evidence that IU is a transdiagnostic process that contributes to the maintenance of anxiety disorders; however, IU may also be relevant to the understanding and treatment of EDs. The current review summarises the growing literature examining IU in relation to ED symptoms, including restriction, bingeing, purging, ritualised behaviours, reassurance-seeking and body checking. Extending from the obsessive-compulsive disorder (OCD) and anxiety disorder literature, we propose that IU provides a novel theoretical and clinical framework from which to understand the anxiety, fixation with rules and rituals, and the cognitively rigid profile that is characteristic of ED presentations. We conclude with suggestions for future research, and discuss IU as a potential treatment target for core features of EDs and comorbid symptoms. PMID- 28710919 TI - Regulation of potassium transport and signaling in plants. AB - As an essential macronutrient, potassium (K+) plays crucial roles in diverse physiological processes during plant growth and development. The K+ concentration in soils is relatively low and fluctuating. Plants are able to perceive external K+ changes and generate chemical and physical signals in plant cells. The signals can be transducted across the plasma membrane and into the cytosol, and eventually regulates the downstream targets, particularly K+ channels and transporters. As a result, K+ homeostasis in plant cells is modulated, which facilitates plant adaptation to K+ deficient conditions. This minireview focuses on the latest research progress in the diverse functions of K+ channels and transporters as well as their regulatory mechanisms in plant response to low-K+ stress. PMID- 28710921 TI - Effects of short-term fasting on the Akt-mediated pathway involved in protein metabolism in chicken skeletal muscle. AB - In the present study, we show that short-term (4 h) fasting significantly decreased the levels of protein synthesis-related factors such as the plasma insulin concentration, skeletal muscle pAkt, and pS6 levels in 2-wk-old chickens (P < 0.05). An intravenous injection of insulin significantly elevated the contents of pAkt and p-S6 in the skeletal muscle (P < 0.01). These findings suggest that decreasing the plasma insulin causes the downregulation of the Akt/S6 pathway in chicken skeletal muscle under short-term fasting conditions. However, protein synthesis was not significantly affected by short-term fasting. In addition, no significant change was observed in the levels of proteolysis related factors such as plasma Ntau-methylhistidine, phosphorylated forkhead box class O, and muscle ring finger-1 during 4-h fasting, indicating that short-term fasting does not induce skeletal muscle proteolysis in chickens. Interestingly, atrogin-1 expression significantly increased after 2-h fasting (P < 0.05), and insulin injection significantly reversed the fasting-induced atrogin-1 expression in chicken skeletal muscle (P < 0.01). Collectively, these findings suggest that short-term fasting downregulates the insulin-stimulated Akt/S6 pathway but does not significantly affect protein synthesis and proteolysis in chicken skeletal muscle, and that atrogin-1 expression is upregulated in a FOXO1-independent manners. PMID- 28710920 TI - Thermodynamics and kinetics of RNA tertiary structure formation in the junctionless hairpin ribozyme. AB - The hairpin ribozyme consists of two RNA internal loops that interact to form the catalytically active structure. This docking transition is a rare example of intermolecular formation of RNA tertiary structure without coupling to helix annealing. We have used temperature-dependent surface plasmon resonance (SPR) to characterize the thermodynamics and kinetics of RNA tertiary structure formation for the junctionless form of the ribozyme, in which loops A and B reside on separate molecules. We find docking to be strongly enthalpy-driven and to be accompanied by substantial activation barriers for association and dissociation, consistent with the structural reorganization of both internal loops upon complex formation. Comparisons with the parallel analysis of a ribozyme variant carrying a 2'-O-methyl modification at the self-cleavage site and with published data in other systems reveal a surprising diversity of thermodynamic signatures, emphasizing the delicate balance of contributions to the free energy of formation of RNA tertiary structure. PMID- 28710922 TI - Embedded interruptions and task complexity influence schema-related cognitive load progression in an abstract learning task. AB - Cognitive processes related to schema acquisition comprise an essential source of demands in learning situations. Since the related amount of cognitive load is supposed to change over time, plausible temporal models of load progression based on different theoretical backgrounds are inspected in this study. A total of 116 student participants completed a basal symbol sequence learning task, which provided insights into underlying cognitive dynamics. Two levels of task complexity were determined by the amount of elements within the symbol sequence. In addition, interruptions due to an embedded secondary task occurred at five predefined stages over the task. Within the resulting 2x5-factorial mixed between within design, the continuous monitoring of efficiency in learning performance enabled assumptions on relevant resource investment. From the obtained results, a nonlinear change of learning efficiency over time seems most plausible in terms of cognitive load progression. Moreover, different effects of the induced interruptions show up in conditions of task complexity, which indicate the activation of distinct cognitive mechanisms related to structural aspects of the task. Findings are discussed in the light of evidence from research on memory and information processing. PMID- 28710923 TI - Diagnostic utility of distal nerve conduction studies and sural near-nerve needle recording in polyneuropathy. AB - OBJECTIVE: The electrodiagnosis of polyneuropathy (PNP) may benefit from examination using near-nerve needle technique (NNT) and from inclusion of distal nerves. This study compared the diagnostic utility of distal nerve conduction studies (NCS) and NNT recording. METHODS: Bilateral NNT and surface recording of the sural nerve and surface recording of the dorsal sural and medial plantar nerves were prospectively done in 91 patients with clinically suspected PNP. Distal NCS were additionally done in 37 healthy controls. Diagnostic reference standard was the final clinical diagnosis retrieved from the patients medical records after 1-4years. RESULTS: The clinical follow-up diagnosis confirmed PNP in 68 patients. Equally high sensitivities of the dorsal sural (72%), medial plantar (75%), and sural nerve with NNT recording (77%) were seen, while the sensitivity of conventional surface recording of the sural nerve was lower (60%). Sural NCS with both NNT and surface recording and dorsal sural NCS showed high specificities (85-95%) and positive predictive values (94-98%), while a lower specificity was seen for the medial plantar nerve (68%). CONCLUSION: NCS of distal nerves, especially the dorsal sural nerve, have high diagnostic power equalling sural NNT recording. SIGNIFICANCE: The electrodiagnostic evaluation of patients with suspected PNP benefits from NCS of distal nerves. PMID- 28710924 TI - Identification of new BACE1 inhibitors using Pharmacophore and Molecular dynamics simulations approach. AB - Inhibition of beta-Secretase (BACE1) is crucial for the treatment of Alzheimer's disease (AD). Availability of BACE1 crystal structures in both apo and complexed forms enables to find structure-based BACE1 inhibitors for controlling AD. There are two catalytic aspartates (ASP32 and ASP228) presents in the active domain of BACE1. In order to understand the binding mechanism and structure-activity relationship of amidine-containing BACE1 inhibitors, molecular docking, and pharmacophore and 3D-QSAR studies have been carried out with 34 amidine derivatives to develop a pharmacophore model. Pharmacophore-based virtual screening (PBVS) has been performed against BACE1 (PDB ID: 2FDP), using three chemical databases (CoCoCo, Enamine, Zinc), which yielded 6000 hit compounds. These compounds were further analyzed using structure-based docking in hierarchical filtering approaches of Glide such as HTVS, SP, and XP precision modes. The docking results show that binding orientations of the inhibitors at Asp dyad active site amino acid residues of beta-Secretase. Results from glide XP docking and induced fit docking showed that four leads (Lead1, Lead3, Lead4 and Lead5) have good interactions with the target protein in comparison with cocrystal (amino-ethylene BACE1 inhibitor). Further, molecular dynamics (MD) simulation for these leads bound with BACE1 shows conformational stability and difference in dynamical flap behaviors of the active site with cocrystal inhibitor. Binding free energetic using MM-GB/SA approaches suggest lead 1 and lead 3 has comparably favorable binding to cocrystal inhibitor. Thus, the present study emphasizes these leads for an effective drug to treat Alzheimer disease. PMID- 28710925 TI - An exploratory assessment of weight loss videos on YouTubeTM. AB - OBJECTIVE: To describe the variation in contents between different video sources on YouTube TM regarding weight loss. STUDY DESIGN: The 100 most widely viewed weight loss videos on YouTubeTM were selected for manual coding. METHODS: Videos were manually coded based on sources and contents, we also identify themes for each of the videos. Univariate logistic regression was used to assess difference in contents between videos from different sources. RESULTS: After excluding two videos, a sample of 98 videos remained. Among them, there were 74 consumer generated videos, 12 news videos, and 12 from commercial television and companies. Collectively, the 98 videos were viewed more than 365 million times. The odds of mentioning ongoing lifestyle that includes long-term changes in daily eating was 90% less in commercial and company videos compared to consumer videos (odds ratio [OR] = 0.10, 95% confidence interval [CI] 0.01-0.85, P = 0.03). The odds of showing a female talking in the video about weight loss was 81% less in news videos compared to consumer videos (OR = 0.19, 95% CI 0.05-0.68, P = 0.01). In addition, commercial and company videos were found to be 18 times as likely to carry a theme on workout as consumer videos (OR = 18.13, 95% CI 3.60-91.22, P < 0.01). CONCLUSION: Public health professionals need to be more creative to make their videos popular if they want to reach a wide audience. PMID- 28710926 TI - Speech and language therapy service delivery: overcoming limited provision for children. AB - OBJECTIVES: To test an alternative Speech and Language Therapy (SLT) service delivery model based on partnerships between a University and local schools and charities, and to report on the impact and feasibility of intervention based on long-term outcome measures and three case studies with individual analysis of Reliable Change. STUDY DESIGN: The following six-step model was tested: 1 establishing partnerships; 2-flagging children; 3-pre-treatment SLT assessment; 4 reporting and discussion with parents and teachers; 5-treatment; 6-post-treatment assessment. Case studies are presented. METHODS: A partnership was established with one kindergarten in a pre-test and a total of 25 kindergartens during the second phase of the process. A group of 139 children were then flagged and assessed. The following long-term outcomes (18 months post-therapy) were investigated: phonetic-phonological standardised test percentiles and raw scores; receptive and expressive language percentiles and raw scores according to a standardised language test; percentage of syllables stuttered; duration of stuttering moments; academic achievement in norm-tests' core areas (mathematics, Portuguese language and social studies). Case studies and a 95% credible interval analysis to assess Reliable Change are presented. RESULTS: Seventy five (54%) children needed SLT support. Fifty (67%) of those children returned to the clinic for long-term assessments and the analysis of all outcome measures showed significant improvements in their performance, 18 months post-therapy. Case Studies Reliable Change analysis revealed a statistically significant improvement, which also clearly shows the feasibility and the positive impact of the intervention. CONCLUSIONS: This specialised and differentiated care network constitutes an alternative delivery system of SLT services that addresses the lack of support currently experienced by children and their families. The long term outcome measures and the 95% credible interval analysis are reliable methods to determine the impact of interventions. PMID- 28710927 TI - Effects of brief mindful breathing and loving-kindness meditation on shame and social problem solving abilities among individuals with high borderline personality traits. AB - Borderline personality disorder (BPD) is a severe mental condition characterized by a range of cognitive and behavioral vulnerabilities, including chronic shame and deficits in social problem solving (SPS) abilities. Little research however, has examined strategies that may alleviate shame and SPS deficits among individuals with BPD traits. Using a laboratory experimental approach, the present study compared the effects of a brief mindfulness versus loving-kindness meditation (LKM) induction on shame and SPS abilities in a sample of adults with high BPD traits. Eighty-eight participants underwent a shame induction procedure involving recall of a negative autobiographical memory. They were then randomly assigned to 10 min of mindful breathing or LKM, or a no-instruction condition. Shame and SPS abilities were assessed via visual analogue scales and the Means Ends Problem Solving task respectively. Results indicated that there were significant decreases in shame from pre-to post-regulation in the mindfulness group versus the LKM and no-instruction groups. Groups did not differ on changes in SPS abilities from pre-to post-regulation. Overall, the findings support the efficacy of mindfulness as a strategy to regulate shame among individuals with BPD traits, and raises questions with regard to the utility of LKM in modulating shame in the context of high emotional arousal. PMID- 28710928 TI - Synthesis and characterization of cobalt-supported catalysts on modified magnetic nanoparticle: Green and highly efficient heterogeneous nanocatalyst for selective oxidation of ethylbenzene, cyclohexene and oximes with molecular oxygen. AB - In this study, a new supported cobalt nanocatalyst has been described. The Fe3O4 magnetic nanoparticles (Fe3O4 MNPs) modified by SiO2/aminopropyl trimethoxy silane/cyanuric chloride (Fe3O4@SiO2-APTMS/CC) utilized for anchoring metformin cobalt complex (Fe3O4 Ms@SiO2-APTMS/CC/Met@Co(II)). The structure of novel complex well defined by elemental analysis, ICP, AAS, BET, FT-IR, EDX, SEM, TEM, DLS, XRD, TG-DTG, VSM and XPS. The catalytic efficiency of the synthesized cobalt nanocatalyst was studied in the oxidation of ethylbenzene (EB), cyclohexene (CYHE) and various oximes using molecular oxygen as ecofriendly oxidant and high catalytic activity and selectivity toward oxidation is observed. Selective aerobic oxidation of EB and CYHE and various oximes catalyzed by the cobalt nanocatalyst without any reducing agent by using N-hydroxyphthalimide (NHPI), gave acetophenone (AcPO), 2-cyclohexene-1-one and corresponding carbonyl compounds respectively, as major products. To achieve high level of efficiency of heterogeneous nanocatalyst, various parameters such as the ratio and amount of nanocatalyst/NHPI, reaction time, temperature and solvents were evaluated. The easily preparation from inexpensive and commercially available reagent, thermal stability, suitable performance in reusability, high efficiency and selectivity in oxidation reactions, short reaction time, easy recovery and separation from reaction mixture, are advantages of this novel catalyst. PMID- 28710929 TI - Tunable emission of Cu (Mn)-doped ZnInS quantum dots via dopant interaction. AB - In this work, transition metal ion- doped zinc-based quantum dots (QDs) are synthesized via a greener controllable method to avoid the toxicity of the traditional cadmium-based QDs and broaden the tunable emission. Herein, the tunable emission of Cu-doped ZnInS/ZnS core-shell QDs (Cu:ZnInS/ZnS) can cover from 500 to 620nm by varying the Cu dopant concentration from 1 to 20% and the maximum quantum yield can reach 49.8%. Based on the single-doped QDs, Cu,Mn co doped ZnInS/ZnS core-shell QDs (Cu,Mn:ZnInS/ZnS) with a photoluminance (PL) quantum yield of 30.4% are obtained. All the as-synthesized QDs have the zinc blende structure and the average size is about 3.55nm. Besides, the interaction mechanism between the Cu and Mn dopant luminescence centers is proposed in this work, which is rarely investigated in the previous report. Diffusion priority and energy transfer between these two dopants are supposed to play an important role in the co-doped QDs and Cu ions could affect the splitting of Mn d states. Color coordinates of these doped QDs show the line-tunability from (0.200, 0.397) to (0.408, 0.508) on the Commission Internationale de L'Eclairage (CIE) chromatic diagram, showing a promising potential in high-quality white light output by integration of these QDs with blue chips. PMID- 28710930 TI - Immobilization effects on the photocatalytic activity of CdS quantum Dots Horseradish peroxidase hybrid nanomaterials. AB - The potential use of hybrid nanomaterials based on inorganic optically active nanoparticles known as quantum dots (QDs) and horseradish peroxidase (HRP) has been proposed by several authors as light-controllable nanocatalyzers, moreover, the immobilization within or over silica based supports represents an advantage over bulk-dispersed systems. However, the implications of the immobilization of such hybrid photoactivatable catalyzing systems have not been clarified with detail. Here, we present a thorough study of the functional photoactive efficiency and recycling of immobilized CdS QDs and HRP systems with different configurations, immobilized over silanized silica quartz crystal microbalance (QCM) sensors, allowing an accurate measure of the immobilized mass of each component and its correlation with the initial reaction rate of conversion of Amplex Red (AR) to resorufin. As well, the conversion efficiency is compared between the different systems and also to non-immobilized QD-HRP complexed systems. PMID- 28710931 TI - Ligustrazine modulates renal cysteine biosynthesis in rats exposed to cadmium. AB - The objective of this study was to determine the effect of ligustrazine (TMP) on cadmium (Cd)-induced nephrotoxicity and its relevant mechanism. TMP (50mg/kg) was injected intraperitoneally (i.p.) into rats 1h prior to CdCl2 exposure (at a Cd dose of 0.6mg/kg). TMP reversed Cd-induced nephrotoxicity, evidenced by the relatively normal architecture of the renal cortex. Additionally, TMP alleviated renal oxidative stress of rats that were exposed to Cd, evidenced by the decreased levels of malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), elevated levels of glutathione (GSH) and GSH/GSSG (glutathione disulfide) ratios. Furthermore, TMP also raised the decreased levels of S-adenosylmethionine (SAM) and cystathionine involved in cysteine biosynthesis in rats exposed to Cd. Further analysis revealed that TMP treatment upregulated expression of several proteins involved in cysteine biosynthesis including methionine adenosyltransferases (MATs) and cystathionine-beta-synthase (CBS). Taken together, these results suggest that TMP remodeled metabolomics of cysteine biosynthesis in rat kidneys and attenuated Cd-induced nephrotoxicity. PMID- 28710932 TI - Measurement of 239Pu in keratinous materials: A potential non-invasive bioassay for monitoring human exposure. AB - The use of hair, toenail, and fingernail as non-invasive monitors of occupational and environmental exposure to 239Pu are reported. Volunteers from US national laboratories and individuals with suspected environmental exposure to Pu were recruited to participate in the study. The exposure history of cases was assessed using a short questionnaire. Levels of Pu in keratinous materials collected from the exposed individuals were above the limit of detection in 5 of 7 cases with concentrations ranging from 0.055 to 0.78ng/kg. To our knowledge, this is the first time that Pu has been measured in hair and nail samples collected from actinide workers in the United States. The 239Pu levels in the hair and nails collected from the exposure group are comparable to individuals from Minsk, Belarus and Dubna, Russia and lower than individuals living near the Semipalatinsk region of Kazakhstan and in the Gomel region of Belarus. PMID- 28710933 TI - Measurement of neutron dose in the compensator IMRT treatment. AB - A radiation treatment delivery technique, intensity modulated radiation therapy (IMRT), has found widespread use in the treatment of cancers. One of IMRT implementing methods is IMRT compensator based, which the modulation are done by high Z materials. When photons with energies higher than 8MV interact with high Z material in path, Photoneutrons are produced. In this study, the effect of compensator on photoneutron production was investigated. The Monte Carlo code MCNPX was used to calculate the neutron dose equivalent as a function of the depth in phantom with and without compensator. Measurements were made using CR-39 track-etched detectors. CR-39 detectors, were cut in dimensions of 2.5*2.5 cm2 by laser, placed in different depths of slab phantom and then irradiated by 18MV photons. Same procedure was performed with the compensator present and absent. The measured data were compared with MCNP calculations. In both experimental and simulation results, neutron dose equivalent when compensator used, was less than non-compensator field. The calculated neutron dose equivalent was maximum at surface and decreased exponentially by increasing depth, but in experimental data, the neutron dose equivalent reached a maximum at approximately 3cm depth in the phantom and beyond which decreased with depth.CR-39 calibration was carried out in air, by considering that neutron energy spectrum changes toward thermal neutrons by depth in phantom increasing, it is suggested that for measuring equivalent neutron dose at phantom depth, should have proper neutron calibration in terms of energy spectrum. PMID- 28710934 TI - Adaption of a PIN-diode detector as an online neutron monitor for the thermal column of the TRIGA research reactor. AB - A BNCT online neutron monitoring system was tested in a TRIGA reactor, using a silicon PIN-diode with a conversion foil. The setup was tested with different reactor powers at the hot and cold ends of the irradiation channel, using activation foils to compare with measured fluxes. The results demonstrate good reproducibility and show a linear correlation between signal of the PIN-diode and neutron flux at all positions, demonstrating this approach to be suitable for online monitoring of the neutron flux. PMID- 28710935 TI - Measurement of isomeric yield ratios of 99m,g;101m,g;102m,gRh in the natPd(gamma,pxn) reactions with the bremsstrahlung end-point energies of 50 70MeV. AB - The isomeric yield ratios of 99m,gRh, 101m,ggRh, and 102m,gRh isomeric pairs produced from the natPd(gamma,pxn) reactions were measured with the bremsstrahlung end-point energies of 50-, 55-, 60-, 65-, and 70-MeV at the 100MeV electron linac of the Pohang Accelerator Laboratory, Korea. The measurements were carried out with the activation method in combination with off-line gamma-ray spectrometry. In order to improve the accuracy of the activity measurements, the separation of the overlapping gamma-rays and the necessary corrections for the counting losses were made. The new experimental results are compared with the theoretical values of the TALYS-1.6 code. PMID- 28710936 TI - Leadership mentoring in nursing research, career development and scholarly productivity: A systematic review. AB - BACKGROUND: Although nursing has been an academic discipline for decades, the infrastructure for nursing research in many countries is still fragile and struggling. Postdoctoral nurses have difficulties developing sustaining careers in nursing research due to lack of career opportunities. Considerable research has been conducted on leadership and mentoring in various areas of nursing. We aimed to systematically review the literature investigating leadership programs and mentoring for postdoctoral nurse researchers, as well as the influence of leadership and mentoring on research productivity, research career development, leadership knowledge and skills, the nurses' health and well-being, staff relationships, work culture and collaboration, salaries and postdoctoral nurses' experiences. METHODS: A systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement was conducted. The electronic databases PubMed, CINAHL and EMBASE were searched without time limits for eligible studies up to January 2016. Reference lists of included articles were also searched manually and authors were contacted to inquire about other relevant papers. Two authors independently assessed eligibility of studies for inclusion. Titles and abstracts were matched with the inclusion criteria: studies investigating leadership and mentoring programs for postdoctoral nurses and leadership and mentoring influencing research productivity, and career development; and leadership knowledge and skills and other outcomes. The quality of the studies was appraised using the Centre for Evidence-Based Medicine for surveys, the Critical Appraisal Skill Program Qualitative Appraisal Checklist for qualitative studies, and a critical appraisal list for mixed methods studies. Any disagreements were resolved by consensus. Data were extracted by two reviewers. FINDINGS: We screened 1775 titles and abstracts, resulting in 15 studies, which included quantitative, descriptive, qualitative and mixed methods designs and involved 3855 postdoctoral nurses. Two studies presenting mentoring programs for postdoctoral nurses were identified. Other studies investigated the influence of mentoring on various outcomes. The findings showed a positive influence of mentoring on research productivity, including increase in publications and grant writing and research career development, improved leadership skills and knowledge. Furthermore, mentoring positively influenced nurses' health and well being, staff relationships, work culture and collaboration. Postdoctoral nurses' experience of mentoring, mentorship, leadership and peer-support is essential in supporting ongoing research activity. CONCLUSION: Although there is a lack of studies with robust designs investigating leadership and mentoring programs, our results document some evidence of mentoring's influence on research productivity, career development and other outcomes of postdoctoral nurses. PMID- 28710937 TI - Developmental surface and phonological dyslexia in both Greek and English. AB - The hallmark of developmental surface dyslexia in English and French is inaccurate reading of words with atypical spelling-sound correspondences. According to Douklias, Masterson and Hanley (2009), surface dyslexia can also be observed in Greek (a transparent orthography for reading that does not contain words of this kind). Their findings suggested that surface dyslexia in Greek can be characterized by slow reading of familiar words, and by inaccurate spelling of words with atypical sound-spelling correspondences (Greek is less transparent for spelling than for reading). In this study, we report seven adult cases whose slow reading and impaired spelling accuracy satisfied these criteria for Greek surface dyslexia. When asked to read words with atypical grapheme-phoneme correspondences in English (their second language), their accuracy was severely impaired. A co occurrence was also observed between impaired spelling of words with atypical phoneme-grapheme correspondences in English and Greek. These co-occurrences provide strong evidence that surface dyslexia genuinely exists in Greek and that slow reading of real words in Greek reflects the same underlying impairment as that which produces inaccurate reading of atypical words in English. Two further individuals were observed with impaired reading and spelling of nonwords in both languages, consistent with developmental phonological dyslexia. Neither of the phonological dyslexics read words slowly. In terms of computational models of reading aloud, these findings suggest that slow reading by dyslexics in transparent orthographies is the consequence of a developmental impairment of the lexical (Coltheart, Rastle, Perry, Langdon, & Zeigler, 2001; Perry, Ziegler, & Zorzi, 2010) or semantic reading route (Plaut, McClelland, Seidenberg, & Patterson, 1996). This outcome provides evidence that the neurophysiological substrate(s) that support the lexical/semantic and the phonological pathways that are involved in reading and spelling are the same in both Greek and English. PMID- 28710939 TI - Evaluation of bait traps as a means to predict initial blow fly (Diptera: Calliphoridae) communities associated with decomposing swine remains in New Jersey, USA. AB - Information about blow fly (Diptera: Calliphoridae) species distributions can be valuable for criminal investigations, with regards to determining movement of remains from one location to another and time of colonization estimates, making these data extremely useful. Past work has been conducted on initial species community structure across New Jersey, USA using traps baited with beef liver; however, if these same species frequent vertebrate carrion remains unclear. In order to evaluate these data, piglet carcasses were placed out once every two weeks for a year in New Brunswick, New Jersey, USA. The same methods were implemented as those used for traps baited with beef liver, with length of collections being based on ADD values. Seven calliphorid species, Calliphora vicina (Robineau-Desvoidy), Lucilia sericata (Meigen), Lucilia coeruleiviridis (Macquart), Phormia regina (Meigen), Pollenia pediculata Macquart, Pollenia rudis (F.) and Protophormia terraenovae (Robineau-Desvoidy) were collected from the carcasses. During this experiment L. sericata, L. coeruleiviridis and P. regina were the dominant adult blow flies captured, totaling 38.2%, 29.2% and 29.2% respectively of all adults caught. All three species colonized the carcasses as well, although not all were dominant colonizers. C. vicina was recorded ovipositing in December, while the piglet was submerged in approximately 5cm of snow. All species that totaled at least 1% of the total collection (adults captured and larvae reared) were the same across baited traps and carcasses. This study supports the use of beef liver baits for surveying forensically important blow flies and the application of such information to forensic investigations. PMID- 28710938 TI - Lack of effects of a "sobering" product, "Eezup!", on the blood ethanol and congener alcohol concentration. AB - INTRODUCTION: The lifestyle product 'Eezup!' appeared on the German market and promised to normalize energy metabolism. Among vitamins (B1, B2, B6, C, E and zinc), rice protein and fructose the addition of alcohol dehydrogenase and catalase enzymes is a novel approach. The product was advertised as capable of boosting the rate of alcohol elimination. METHODS: Seventeen subjects (11 men, 6 women, 19-58 years old), participated in a two-way crossover drinking study. Unfiltered wheat beer (4.4g% alcohol content) was drank within one hour to reach blood alcohol concentrations of 10/00 (1g/kg whole blood). On one day "Eezup!" was taken according to the manufacturer's instructions before and after drinking which was substituted for a placebo on the second test day. Blood samples were taken during 9h and ethanol and congener alcohols were determined. A comparison of Cmax, tmax, area under the curve (AUC) for ethanol and congener alcohols, and the hourly elimination rate of ethanol (beta60) was performed to investigate an effect of Eezup!. RESULTS: Ethanol concentrations (Cmax) were in the range of 0,63-1,000/00 (median 0,850/00) and 0.62-1.220/00 (median 0.840/00) in the placebo and "Eezup!" condition, respectively, and not statistically different. Also tmax (1-2.5h) and AUCs did not differ. The ethanol elimination rates were 0.160/00/h (0.14-0.190/00/h) and 0.170/00/h (0.14-0.22 0/00/h) in the placebo and "Eezup!" condition without significant difference. The pharmacokinetic parameters of the congener alcohols (1-propanol, isobutanol, 3-methyl-1-butanol, 2-methyl-1 butanol) as well as of methanol did also not differ. CONCLUSIONS: The results of the present study failed to show any effect of the sobering product "Eezup!" on the amount of ethanol and congener alcohols absorbed (Cmax, tmax, AUC) and on the ethanol elimination rate (beta60). PMID- 28710940 TI - Procedural learning in Tourette syndrome, ADHD, and comorbid Tourette-ADHD: Evidence from a probabilistic sequence learning task. AB - Procedural memory, which is rooted in the basal ganglia, plays an important role in the implicit learning of motor and cognitive skills. Few studies have examined procedural learning in either Tourette syndrome (TS) or Attention Deficit Hyperactivity Disorder (ADHD), despite basal ganglia abnormalities in both of these neurodevelopmental disorders. We aimed to assess procedural learning in children with TS (n=13), ADHD (n=22), and comorbid TS-ADHD (n=20), as well as in typically developing children (n=21). Procedural learning was measured with a well-studied implicit probabilistic sequence learning task, the alternating serial reaction time task. All four groups showed evidence of sequence learning, and moreover did not differ from each other in sequence learning. This result, from the first study to examine procedural memory across TS, ADHD and comorbid TS ADHD, is consistent with previous findings of intact procedural learning of sequences in both TS and ADHD. In contrast, some studies have found impaired procedural learning of non-sequential probabilistic categories in TS. This suggests that sequence learning may be spared in TS and ADHD, while at least some other forms of learning in procedural memory are impaired, at least in TS. Our findings indicate that disorders associated with basal ganglia abnormalities do not necessarily show procedural learning deficits, and provide a possible path for more effective diagnostic tools, and educational and training programs. PMID- 28710941 TI - Procedural learning in Parkinson's disease, specific language impairment, dyslexia, schizophrenia, developmental coordination disorder, and autism spectrum disorders: A second-order meta-analysis. AB - The serial reaction time task (SRTT) has been used to study procedural learning in clinical populations. In this report, second-order meta-analysis was used to investigate whether disorder type moderates performance on the SRTT. Using this approach to quantitatively summarise past research, it was tested whether autism spectrum disorder, developmental coordination disorder, dyslexia, Parkinson's disease, schizophrenia, and specific language impairment differentially affect procedural learning on the SRTT. The main analysis revealed disorder type moderated SRTT performance (p=0.010). This report demonstrates comparable levels of procedural learning impairment in developmental coordination disorder, dyslexia, Parkinson's disease, schizophrenia, and specific language impairment. However, in autism, procedural learning is spared. PMID- 28710942 TI - Parental psychopathology and offspring attention-deficit/hyperactivity disorder in a nationwide sample. AB - OBJECTIVE: To study the associations between a wide range of parental psychiatric disorders and offspring attention-deficit/hyperactivity disorder (ADHD). METHOD: This study is based on a nested case-control design. The association between parental registered psychiatric diagnoses and offspring ADHD was examined adjusting for socioeconomic and prenatal factors. Data was linked from Finnish nationwide registers. The cases (n = 10,409) were all the children born between years 1991 and 2005 in Finland and diagnosed with ADHD by the end of 2011. Four controls without ADHD (n = 39,124) were matched for every case by sex, age and place of birth. Main outcomes were adjusted odds ratio (aOR) for parental diagnosis of cases vs controls. Analyses were further stratified by sex. Disorders diagnosed before and after birth were analyzed separately. RESULTS: The odds ratio for ADHD increased when only mother (aOR 2.2, 95% CI 2.0-2.3), only father (aOR 1.7, 95% CI 1.6-1.8) and both parents (aOR 3.6, 95% CI 3.3-4.0) were diagnosed. Maternal diagnosis showed stronger association than paternal. The weight of association between several parental disorders and offspring ADHD were similar. Maternal psychopathology overall showed stronger associations with girls than boys with ADHD. The diagnoses registered after birth did not show stronger association than the diagnoses registered before. CONCLUSIONS: Maternal psychopathology showing stronger association than paternal implies that environmental factors or their interaction with genetic factors partly mediates the risk of parental psychopathology. Similar associations between several maternal psychiatric disorders and offspring ADHD points towards the need for investigating some common mother-related risk factors. PMID- 28710943 TI - Survival after recurrence of stage I-III breast, colorectal, or lung cancer. AB - BACKGROUND: The experiences of patients with recurrent cancer are assumed to reflect those of patients with de novo stage IV disease; yet, little is truly known because most registries lack recurrence status. Using two databases with excellent recurrence and death information, we examined determinants of survival duration after recurrence of breast (BC), colorectal (CRC), and lung cancers (LC). METHODS: Recurrence status was abstracted from the medical records of patients who participated in the Cancer Care Outcomes Research and Surveillance study and who received care at two Cancer Research Network sites-the Colorado and Northwest regions of Kaiser Permanente. The analysis included 1653 patients who developed recurrence after completing definitive therapy for stages I-III cancer. Multivariable modeling identified independent determinants of survival duration after recurrence, controlling for other factors. RESULTS: Through 60 months' average follow-up, survival after recurrence for BC, CRC, and LC were 28.4, 23.1 and 16.1 months, respectively. Several factors were independently associated with shorter survival for all three cancers, including higher initial stage (III vs. I: BC -9.9 months; CRC -6.9 months; LC -7.4 months; P<=0.01). Factors associated with shorter survival for selected cancers included: distant/regional recurrence for BC and CRC; current/former smoker for LC; high grade for CRC; and <4-year time-to-recurrence for BC. CONCLUSIONS: Initial stage predicts survival duration after recurrence, whereas time-to-recurrence usually does not. The impact of biologic characteristics (e.g., grade, hormone-receptor status) on survival duration after recurrence needs further study. Predictors of survival duration after recurrence may help facilitate patient decision-making. PMID- 28710945 TI - Ancient signal for nitrogen status sensing in the green lineage: Functional evidence of CDPK repertoire in Ostreococcus tauri. AB - Calcium-dependent protein kinases (CDPKs) regulate plant development and many stress signalling pathways through the complex cytosolic [Ca2+] signalling. The genome of Ostreococcus tauri (Ot), a model prasinophyte organism that is on the base of the green lineage, harbours three sequences homologous to those encoding plant CDPKs with the three characteristic conserved domains (protein kinase, autoregulatory/autoinhibitory, and regulatory domain). Phylogenetic and structural analyses revealed that putative OtCDPK proteins are closely related to CDPKs from other Chlorophytes. We functionally characterised the first marine picophytoeukaryote CDPK gene (OtCDPK1) and showed that the expression of the three OtCDPK genes is up-regulated by nitrogen depletion. We conclude that CDPK signalling pathway might have originated early in the green lineage and may play a key role in prasinophytes by sensing macronutrient changes in the marine environment. PMID- 28710944 TI - Effect of acibenzolar-S-methyl phototransformation on its elicitation activity in tobacco cells. AB - The plant activator acibenzolar-S-methyl (BTH) undergoes phototransformation when exposed to solar radiation. Here we investigated the changes in its elicitation properties on BY-2 tobacco cells at different stages of the photochemical reaction. Both pure BTH and formulated BTH were irradiated in controlled conditions to achieve different extents of conversion. Both pure BTH (900 MUM) and Bion(r) (0.4 g.L-1) induced BY-2 cell death, but BTH photoconverted to an extent of 25 +/- 3% lowered the cell death rate. A kinetic study of beta-1,3 glucanase and chitinase activities was conducted on BY-2 extracellular medium. Exposure of tobacco cells to either pure BTH or Bion(r) resulted in a significant increase in the activities of both defense enzymes, which peaked 48 h after the treatment. The pathogenesis-related (PR) protein activities were quantified 48 h after elicitation for a range of phototransformed BTH solutions. The enzyme activities were reduced when BY-2 cells were treated with solutions in which BTH conversion was 22 +/- 3%, 42 +/- 3% and 100 +/- 3%, but were not affected by the solution in which BTH was phototransformed at 60%, suggesting that some of the secondary photoproducts also exhibit eliciting properties. Solar irradiation of BTH thus impairs its elicitation properties, but this impairment depends strongly on the extent of phototransformation. PMID- 28710946 TI - Photosynthetic parameters and redox homeostasis of Artemisia santonica L. under conditions of Elton region. AB - Structural and functional parameters and redox homeostasis in leaves of Artemisia santonica L. under environment conditions of Elton lake (the southeast region of the European part of Russia) were measured. The highest photosynthetic apparatus (PA) activity in A. santonica leaves on CO2 gas exchange as well as the highest content of green pigments was observed in the morning. Maximum share of violaxanthin cycle key pigments - zeaxanthin (Zx) and antheraxanthin (Ax) was observed in the afternoon and decreased in the evening. Lipids/chlorophyll (Chl) ratio increased in the evening due to the decrease in Chl concentration, and content of linolenic acid (S18:3n3) was decreased in the middle of the day. The content of TBA-reacting products increased 1.4-fold in the middle of the day, and decreased approximately 2-fold in the evening. The decrease of the activity was observed in diurnal dynamics of superoxide dismutase (SOD) and polyphenol oxidase (PPO). Increased accumulation of phenols and flavonoids, as well as free amino acids (FAA) in A. santonica leaves was observed in the middle of the day. Thus, the ability of A. santonica plants to resist the soil salinization, high levels of solar illumination and temperature consists of a number of protectively adaptive reactions of metabolic and photosynthetic control. PMID- 28710948 TI - Brainstem Auditory Evoked Potentials for diagnosing Autism Spectrum Disorder, ADHD and Schizophrenia Spectrum Disorders in adults. A blinded study. AB - The aim of the present study was to examine the clinical utility of complex auditory brainstem response (c-ABR) and investigate if c-ABR is helpful in the diagnostic procedure. Thirty-one adult psychiatric patients, thoroughly diagnosed with autism spectrum disorder (ASD) (n=16), ADHD (n=8), or schizophrenia spectrum disorder (SSD) (n=7) and 15 healthy controls (HC), were blindly assessed with SensoDetect BERA. This c-ABR correctly identified psychiatric diagnoses in 4 patients (13%) and provided partially correct diagnoses in 11 more patients. Of the 15 HC, 6 were misclassified as psychiatric patients. The Cohen's kappa coefficient (kappa) was substantial for HC (kappa=0.67), fair for SSD (kappa=0.37), slight for ADHD (kappa=0.09) and without agreement in ASD (kappa= 0.03). In conclusion, we found the c-ABR method unhelpful and unreliable as a tool in clinical diagnostics. PMID- 28710947 TI - Variations in biofilm formation, desiccation resistance and Benzalkonium chloride susceptibility among Listeria monocytogenes strains isolated in Canada. AB - Listeria monocytogenes is a pathogenic foodborne microorganism noted for its ability to survive in the environment and food processing facilities. Survival may be related to the phenotype of individual strains including the ability to form biofilms and resist desiccation and/or sanitizer exposure. The objectives of this research were to compare 14 L. monocytogenes strains isolated from blood (3), food (6) and water (5) with respect to their benzalkonium chloride (BAC) sensitivity, desiccation resistance, and ability to form biofilm. Correlations were tested between those responses, and the presence of the SSI-1 (Stress Survival Islet) and LGI1/CC8 (Listeria Genomic Island 1 in a clonal complex 8 background) genetic markers. Genetic sequences from four strains representing different phenotypes were also probed for predicted amino acid differences in biofilm, desiccation, and membrane related genes. The water isolates were among the most desiccation susceptible strains, while strains exhibiting desiccation resistance harboured SSI-1 or both the SSI-1 and LGI1/CC8 markers. BAC resistance was greatest in planktonic LGI1/CC8 cells (relative to non-LGI1/CC8 cells), and higher BAC concentrations were also needed to inhibit the formation of biofilm by LGI1/CC8 strains during incubation for 48h and 6days compared to other strains. Formation of biofilm on stainless steel was not significantly (p>0.05) different among the strains. Analysis of genetic sequence data from desiccation and BAC sensitive (CP4 5-1, CP5 2-3, both from water), intermediate (Lm568, food) and desiccation and BAC resistant (08 5578, blood, human outbreak) strains led to the finding of amino acid differences in predicted functional protein domains in several biofilm, desiccation and peptidoglycan related genes (e.g., lmo0263, lmo0433, lmo0434, lmo0771, lmo0973, lmo1080, lmo1224, lmo1370, lmo1744, and lmo2558). Notably, the LGI1/CC8 strain 08-5578 had a frameshift mutation in lmo1370, a gene previously associated with desiccation resistance. In conclusion, the more desiccation and BAC resistant LGI1/CC8 isolates may pose a challenge for sanitation efforts. PMID- 28710949 TI - As, Cd and Hg in the organs of Todarodes pacificus, Sepia longipes and Sepia madokai in the East China Sea. AB - Arsenic and Cadmium concentrations in Todarodes pacificus (4 males and 4 females), Sepia longipes (1 male and 3 unknown), five Sepia madokai caught in 2012 (1 male and 4 females) and five S. madokai caught in 2014 (5 females) were collected from the East China Sea (ECS) during intervals from 2010 Oct. through to 2014 Oct. The internal organs were vacuum dried and the elements were measured by ICP-MS. Among the toxic elements, As, Cd, and Hg in the digestive gland, gonads and branchial hearts of squids and cuttlefishes were measured separately. The squid T. pacificus practically inhabits offshore, whereas cuttlefishes, such as S. longipes and S. madokai, inhabit bottom coastal waters in the ECS. Cd concentration in digestive gland of T. pacificus and S. madokai is higher than similar species from other regions. This high concentration seems to be derived from anthropogenic activities and geological conditions present in the ECS. The squid and cuttlefish also accumulate high amounts of As, not only in their digestive gland but also in other organs. Arsenic could be derived from high volcanic activities. In the case of Hg, the muscles were reported to contain the highest concentration in the species studied, but unlike concentration of Cd in digestive gland, it was high compared to other studies. These elements can be utilized as indicators for environmental pollution in marine systems. For monitoring of harmful elements in squids and cuttlefish, for example Cd and As in the digestive gland and Hg in mantle should be measured. PMID- 28710951 TI - Delusional denial of pregnancy: Unique presentation of Cotard's syndrome in a patient with schizophrenia. PMID- 28710950 TI - Citric acid assisted phytoextraction of chromium by sunflower; morpho physiological and biochemical alterations in plants. AB - Soil and water contamination from heavy metals and metalloids is one of the most discussed and burning global issues due to its potential to cause the scarcity of healthy food and safe water. The scientific community is proposing a range of lab and field based physical, chemical and biological solutions to remedy metals and metalloids contaminated soils and water. The present study finds out a possibility of Chromium (Cr) extraction by sunflower from spiked soil under chelating role of citric acid (CA). The sunflower plants were grown under different concentrations of Cr (0, 5, 10 & 20mgkg-1) and CA (0, 2.5 & 5mM). Growth, biomass, gas exchange, photosynthesis, electrolyte leakage (EL), reactive oxygen species (ROS; malondialdehyde (MDA), hydrogen peroxide (H2O2) and the activities of antioxidant enzymes such as, superoxide dismutase (SOD), guaiacole values peroxidase (POD), ascorbate peroxidase (APX), catalase (CAT) were measured. The results depicted a clear decline in plant height, root length, leaf area, number of leaves and flowers per plant along with fresh and dry biomass of all parts of plant with increasing concentration of Cr in soil. Similar reduction was observed in chlorophyll a and b, total chlorophyll, carotenoids, soluble protein, gas exchange attributes and SPAD. The increasing concentration of Cr also enhanced the Cr uptake and accumulation in plant roots, stem and leaves along with the production of ROS and EL. The activities of antioxidant enzymes increased with increasing Cr concentration from 0 to 10mg, but decreased at 20mgkg-1 soil. The CA application significantly alleviated Cr-induced inhibition of plant growth, biomass, photosynthesis, gas exchange, soluble proteins and SPAD value. Presence of CA also enhanced the activities of all antioxidant enzymes and reduced the production of ROS and EL. The chelating potential of CA increased the concentration and accumulation of Cr in plant roots, stem and leaves. It is concluded that the sunflower can be a potential candidate for the remediation of Cr under CA treatment, while the possibility may vary with genotype, Cr level and CA concentration. PMID- 28710952 TI - Indices of insulin resistance and glucotoxicity are not associated with bipolar disorder or major depressive disorder, but are differently associated with inflammatory, oxidative and nitrosative biomarkers. AB - BACKGROUND: Insulin resistance (IR) is a key factor in diabetes mellitus, metabolic syndrome (MetS) and obesity and may occur in mood disorders and tobacco use disorder (TUD), where disturbances of immune-inflammatory, oxidative and nitrosative stress (IO&NS) pathways are important shared pathophysiological pathways. METHODS: This study aimed to a) examine IR and beta-cell function as measured by the homeostasis model assessment of insulin resistance (HOMA-IR) and insulin sensitivity and beta cell function (HOMA-B) and glucotoxicity (conceptualized as increased glucose levels versus lowered HOMA-B values) in 74 participants with major depressive disorder (MDD) and bipolar disorder, with and or without MetS and TUD, versus 46 healthy controls, and b) whether IR is associated with IO&NS biomarkers, including nitric oxide metabolites (NOx), lipid hydroperoxides (LOOH), plasma advanced oxidation protein products (AOPP), C reactive protein (CRP), haptoglobin (Hp) and uric acid. RESULTS: Mood disorders are not associated with changes in IR or glucotoxicity, although the number of mood episodes may increase IR. 47.8% of the variance in HOMA-IR is explained by AOPP and body mass index (BMI, both positively) and NOx, Hp and TUD (all inversely). 43.2% of the variance in HOMA-B is explained by NOx, Hp and age (all inversely associated) and higher BMI and sex. The glucotoxic index is strongly associated with NOx, Hp and BMI (positively), male gender and lower education. LIMITATIONS: This is a cross-sectional study and therefore we cannot draw firm conclusions on causal associations. CONCLUSIONS: Activated IO&NS pathways (especially increased Hp and NOx) increase glucotoxicity and exert very complex effects modulating IR. Mood disorders are not associated with increased IR. PMID- 28710953 TI - Partially distinct combinations of psychological, metabolic and inflammatory risk factors are prospectively associated with the onset of the subtypes of Major Depressive Disorder in midlife. AB - BACKGROUND: Given the well known heterogeneity of Major Depressive Disorder (MDD), dividing this complex disorder into subtypes is likely to be a more promising approach to identify its determinants than to study it as a whole. METHODS: In a prospective population-based cohort study (CoLaus|PsyCoLaus) with 5.5 years of follow-up, 1524 participants without MDD at baseline, aged 35-66 years (mean age 51.4 years, 43.4% females), participated in the physical and psychiatric baseline and the psychiatric follow-up evaluations. RESULTS: The incidence of both atypical and melancholic MDD during the follow-up period were predicted by female sex, a lifetime history of minor depressive disorders and higher neuroticism scores. Higher baseline body mass index was associated with the onset of atypical MDD, whereas the absence of hypertension and younger age were associated with the development of melancholic MDD. Unspecified MDD was predicted by younger age, low concentrations of tumor necrosis factor-alpha and elevated life-event impact scores. LIMITATIONS: The age range of our cohort restricts the identification of risk factors to MDD with onset in midlife and the recruitment in an urban area limits the generalizability of the findings. CONCLUSIONS: Our data suggest that MDD subtypes are predicted by partially distinct combinations of baseline characteristics suggesting that these subtypes not only differ in their clinical manifestations but also in factors that contribute to their development. Subjects with minor depressive episodes, especially in combination with particular personality features, deserve close clinical attention to prevent the subsequent onset of atypical and melancholic major depression. PMID- 28710954 TI - Safety of treatment with nivolumab after ipilimumab-related meningoradiculitis and bilateral optic neuropathy. PMID- 28710955 TI - Epidemiologic evaluation of canine urolithiasis in Thailand from 2009 to 2015. AB - The cross-sectional study described the epidemiology of 8560 canine urolith submissions from Thailand to the Minnesota Urolith Center between January 2009 and December 2015. The frequency of urolith types, the relationships between urolith type and breed, sex, and neutered status, and change of annual submission proportion over the study period were analyzed. Struvite was the most common canine urolith (44%), and was commonly found in intact females with a mean age of 6.3+/-3.1years. Calcium oxalate was the second most common (27%), more frequently found in intact males with a mean age of 8.8+/-3.3years. Compound, purine, cystine, calcium phosphate, and silica urolith were less common. During the study period, the proportion of struvite urolith significantly decreased from 48% in 2009 to 39% in 2015 (p<0.001). The proportion of CaOx increased from 21% in 2009 to 32% in 2015 (p<0.001). The results of this study can help veterinarians predict urolith composition to select diagnostic tests and to initiate therapy prior to urolith removal. PMID- 28710956 TI - Oxytocin receptor antagonist treatments alter levels of attachment to mothers and central dopamine activity in pre-weaning mandarin vole pups. AB - Oxytocin (OT) is known to be important in mother-infant bonding. Although the relationship between OT and filial attachment behavior has been studied in a few mammalian species, the effects on infant social behavior have received little attention in monogamous species. The present study examined the effects of OT receptor antagonist (OTA) treatment on attachment behavior and central dopamine (DA) activity in male and female pre-weaning mandarin voles (Microtus mandarinus). Our data showed that OTA treatments decreased the attachment behavior of pups to mothers, measured using preference tests at postnatal day 14, 16, 18 and 20. OTA treatments reduced serum OT concentration in pre-weaning pups and decreased tyrosine hydroxylase (TH) levels in the ventral tegmental area (VTA), indicating a decrease in central DA activity. In male and female pups, OTA reduced DA levels, DA 1-type receptor (D1R) and DA 2-type receptor (D2R) protein expression in the nucleus accumbens (NAcc). Our results indicate that OTA treatment inhibits the attachment of pre-weaning pups to mothers. This inhibition is possibly associated with central DA activity and levels of two types of dopamine receptor in the NAcc. PMID- 28710957 TI - Infection and Colonization of Nicotiana benthamiana by Grapevine leafroll associated virus 3. AB - Grapevine leafroll disease is an increasing problem in all grape-growing regions of the world. The most widespread agent of the disease, Grapevine leafroll associated virus 3 (GLRaV-3), has never been shown to infect species outside of the genus Vitis. Virus transmission to several plant species used as model systems was tested using the vine mealybug, Planococcus ficus. We show that GLRaV 3 is able to infect Nicotiana benthamiana. Working with GLRaV-3 infected N. benthamiana revealed distinct advantages in comparison with its natural host Vitis vinifera, yielding both higher viral protein and virion concentrations in western blot and transmission electron microscopy observations, respectively. Immunogold labelling of thin sections through N. benthamiana petioles revealed filamentous particles in the phloem cells of GLRaV-3 positive plants. Comparison of assembled whole genomes from GLRaV-3 infected V. vinifera vs. N. benthamiana revealed substitutions in the 5' UTR. These results open new avenues and opportunities for GLRaV-3 research. PMID- 28710958 TI - Japanese encephalitis virus counteracts BST2 restriction via its envelope protein E. AB - It has been well documented that BST2 restricts the release of enveloped viruses by cross-linking newly produced virions to the cell membrane. However, it is less clear whether and how BST2 inhibits the release of enveloped viruses which bud via the secretory pathway. Here, we demonstrated that BST2 restricts the release of Japanese encephalitis virus (JEV) whose budding occurs at the ER-Golgi intermediate compartment, and in turn, JEV infection downregulates BST2 expression. We further found that the JEV envelope protein E, but not other viral components, significantly downregulates BST2 with the viral protein M playing an auxiliary role in the process. Envelope protein E-mediated BST2 downregulation appears to undergo lysosomal degradation pathway. Additional study revealed that the transmembrane domain and the coiled-coil domain (CC) of BST2 are the target domains of viral protein E and that the N- and C-terminal membrane anchors and the CC domain of BST2 are essential for blocking JEV release. Our results together indicate that the release of enveloped viruses whose budding take place in an intracellular compartment can be restricted by BST2. PMID- 28710959 TI - Tobacco mosaic virus infection disproportionately impacts phloem associated translatomes in Arabidopsis thaliana and Nicotiana benthamiana. AB - In this study we use vascular specific promoters and a translating ribosome affinity purification strategy to identify phloem associated translatome responses to infection by tobacco mosaic virus (TMV) in systemic hosts Arabidopsis thaliana ecotype Shahdara and Nicotiana benthamiana. Results demonstrate that in both hosts the number of translatome gene alterations that occurred in response to infection is at least four fold higher in phloem specific translatomes than in non-phloem translatomes. This finding indicates that phloem functions as a key responsive tissue to TMV infection. In addition, host comparisons of translatome alterations reveal both similarities and differences in phloem responses to infection, representing both conserved virus induced phloem alterations involved in promoting infection and virus spread as well as host specific alterations that reflect differences in symptom responses. Combined these results suggest phloem tissues play a disproportion role in the mediation and control of host responses to virus infection. PMID- 28710960 TI - Bioremediation potential of arsenic by non-enzymatically biofabricated silver nanoparticles adhered to the mesoporous carbonized fungal cell surface of Aspergillus foetidus MTCC8876. AB - Our study aiming for the diminution of arsenic concentration in arsenic contaminated aqua environment by using novel adsorbents based on bio-fabricated silver nanoparticles on a fungal cell surface. Bioreduction of silver ion was done in a non-enzymatic manner in presence of the biomass of fungus Aspergillus foetidus MTCC8876. Aspergillus spp. cells were harvested following the bioreduction and made into carbon by carbonization that led to pore formation (pore width of 2.35 nm) on the cell surface. The average size of silver nanoparticles in the sample of SACF (silver nanoparticles adhered to mesoporous carbonized fungal cell) was 35 nm. Whereas mesoporous carbonized control fungal (CCF) cell was devoid of any particles on its surface. For structural characterizations of this adsorbent as well as to emerge its changes as a validation of arsenic adsorption, different biophysical methods such as FTIR, XRD, SEM, FESEM, TEM, BET surface area analysis and SERS analysis were followed. Batch mode experiments were performed to investigate the influence of As (V) concentrations, reaction time, pH of the solution and also the temperature of experiments on the efficiency of As (V) removal by adsorbents SACF & CCF. This arsenic-adsorbent interaction was proved to be endothermic in nature as well as the negative DeltaG value indicated the spontaneity. SACF showed exceptional efficiency for the removal (>93%) of arsenic rather than CCF from an aqueous environment within a very short time of 3.5 h due to its porosity and the presence of the silver nanocrystals. PMID- 28710961 TI - Epigenetic modification differences between fetal fibroblast cells and mesenchymal stem cells of the Arbas Cashmere goat. AB - To explore the epigenetic mechanisms regulating mesenchymal stem cells, we analyzed epigenetic patterns in control goat fetal fibroblast cells (gFFCs), adipose-derived stem cells (gADSCs), bone marrow stromal cells (gBMSCs), and muscle-derived satellite cells (gMDSCs). We found that the 5mC content of gBMSC genomes was lower than that of gFFC genomes, while the 5mC content of gADSC and gMDSC genomes surpassed that of gFFC genomes. H3K9 acetylation did not differ significantly among those cells; gFFCs, gADSCs, and gMDSCs contained acetylated H3K9, H3K14, H3K18, H4K5, and H4K12, but gBMSCs contained almost no acetylated H4K5 and H4K12. DNMT1, DNMT3A, and DNMT3B expression levels in gBMSCs and gMDSCs were relatively high; TET1 and TET2 expression levels in gFFCs, gADSCs, gBMSCs, and gMDSCs were relatively low; the TET3 expression level was relatively high, but was not statistically significant. The expression levels of HDAC1, HDAC6, SIRT1, Tip60, and PCAF in gADSCs, gBMSCs, and gMDSCs were higher than those in gFFCs; this observation was consistent with the real-time quantitative PCR results. P300 expression was not detected. We found that epigenetic modification was active in mesenchymal stem cells, which benefited the regulation of these cells. PMID- 28710962 TI - Discovery of potent molecular chimera (CM358) to treat human metastatic melanoma. AB - The resistance of cancer cells to chemotherapeutic agents, whether through intrinsic mechanisms or developed resistance, motivates the search for new chemotherapeutic strategies. In the present report, we demonstrate a facile synthetic strategy towards the discovery of new anti-cancer substances. This strategy is based on simple covalent coupling between known anti-cancer drugs, which results in novel 'chimeric' small molecules. One of these novel compounds, CM358, is the product of an amide bond formation between the known Topoisomerase II (Topo II) inhibitor amonafide (AM) and the known DNA mustard alkylator chlorambucil (CLB). It demonstrates significant enhanced cytotoxicity over an equimolar mixture of AM and CLB in various cancer cell lines and in a xenograft model of human metastatic melanoma. Topo II inhibition as well as in silico docking studies suggest that CM358 is a stronger Topo II binder than AM. This may be attributed, at least partially, to the placement of the CLB moiety in a favorable orientation with respect to DNA cross-linking with nearby guanines. In a human metastatic melanoma (WM 266-4) xenograft model, this compound was profoundly superior to a mixture of AM and CLB in reduction of tumor growth, maintenance of body weight and extension of overall survival. PMID- 28710963 TI - 2-Substituted 3,7,8-trimethylnaphtho[1,2-b]furan-4,5-diones as specific L-shaped NQO1-mediated redox modulators for the treatment of non-small cell lung cancer. AB - Based on the scaffold of 3,7,8-trimethylnaphtho[1,2-b]furan-4,5-dione, a series of L-shaped derivatives with substituted side chains at the position of C2 were designed by analyzing the binding mode with NQO1. The drug-like compound 6q (named as DDO-7178) emerged as the most specific substrate of the two-electron oxidoreductase NQO1 and could hardly be reduced by one-electron oxidoreductases CPR (NQO1/CPR = 20.8). In addition, compound 6q showed much improved physicochemical properties such as water solubility than the control beta-lap. The follow-up studies indicated that 6q showed a NQO1-expressing cancer-cell selective killing property. Preliminary mechanism studies on the anticancer effect indicated that 6q induced ROS production in an NQO1 dependent manner and activated Akt/MAPK pathways in a ROS-dependent fashion, thereby inducing apoptosis. In addition, emphasized compound 6q showed more significant antitumor efficacy than beta-lap without producing obvious toxic effects in vivo, which gave us a new tool for further investigation of NQO1-mediated redox modulators as anticancer drugs for the treatment of NQO1-overexpressed NSCLC. PMID- 28710964 TI - Design, synthesis and biological studies of a library of NK1-Receptor Ligands Based on a 5-arylthiosubstituted 2-amino-4,6-diaryl-3-cyano-4H-pyran core: Switch from antagonist to agonist effect by chemical modification. AB - A library of 5-arylthiosubstituted 2-amino-4,6-diaryl-3-cyano-4H-pyrans has been synthesized as a new family of non-peptide NK1 receptor ligands by a one-pot cascade process. Their biological effects via interaction with the NK1 receptor were experimentally determined as percentage of inhibition (for antagonists) and percentage of activation (for agonists), compared to the substance P (SP) effect, in IPone assay. A set of these amino compounds was found to inhibit the action of SP, and therefore can be considered as a new family of SP-antagonists. Interestingly, the acylation of the 2-amino position causes a switch from antagonist to agonist activity. The 5-phenylsulfonyl-2-amino derivative 17 showed the highest antagonist activity, while the 5-p-tolylsulfenyl-2-trifluoroacetamide derivative 20R showed the highest agonist effect. As expected, in the case of the 5-sulfinylderivatives, there was an enantiomeric discrimination in favor of one of the two enantiomers, specifically those with (SS,RC) configuration. The anticancer activity studies assessed by using human A-549 lung cancer cells and MRC-5 non-malignant lung fibroblasts, revealed a statistically significant selective cytotoxic effect of some of these 2-amino-4H-pyran derivatives toward the lung cancer cells. These studies demonstrated that the newly synthesized 4H pyran derivatives can be used as a starting point for the synthesis of novel SP antagonists with higher anticancer activity in the future. PMID- 28710966 TI - Intentions to quit tobacco smoking in 14 low- and middle-income countries based on the transtheoretical model. AB - INTRODUCTION: Over 80% of the world's one billion tobacco smokers reside in low- and middle-income countries (LMICs); therefore, it is important to understand factors that promote intention to quit smoking in these countries. This study evaluated factors associated with three stages of intention to quit tobacco smoking among adults in LMICs. METHODS: Data from 43,540 participants of the Global Adult Tobacco Survey in 14 LMICs were analyzed. Intentions to quit smoking were categorized into precontemplation (referent category), contemplation, and preparation stages based on the transtheoretical model. A multinomial logit model was used to estimate odds ratios (OR) and 95% confidence intervals (CI). RESULTS: Approximately 82%, 14%, and 4% of the smokers were in precontemplation, contemplation, and preparation stages, respectively. Rural residents had increased odds of being in contemplation stage (OR=1.41, 95% CI=1.09-1.83) compared to urban residents. Compared to homes where smoking was allowed, smoke free homes were associated with increased odds of contemplation (OR=1.77, 95% CI=1.41-2.23) and preparation (OR=2.18, 95% CI=1.78-2.66). Exposure to anti smoking messages in more than one media channel was associated with increased odds of contemplation (OR=1.60, 95% CI=1.33-1.92) and preparation (OR=1.73, 95% CI=1.28-2.33) compared to no exposure to anti-smoking messages. CONCLUSION: The results suggest that anti-smoking media campaigns and smoke-free policies may promote intention to quit smoking in LMICs. While these suggest the need for implementation of comprehensive anti-smoking campaigns and smoke-free policies, longitudinal studies are required to confirm these findings and to evaluate how intention to quit translates into quit attempts in LMICs. PMID- 28710965 TI - Structural basis for selective inhibition of Cyclooxygenase-1 (COX-1) by diarylisoxazoles mofezolac and 3-(5-chlorofuran-2-yl)-5-methyl-4-phenylisoxazole (P6). AB - The diarylisoxazole molecular scaffold is found in several NSAIDs, especially those with high selectivity for COX-1. Here, we have determined the structural basis for COX-1 binding to two diarylisoxazoles: mofezolac, which is polar and ionizable, and 3-(5-chlorofuran-2-yl)-5-methyl-4-phenylisoxazole (P6) that has very low polarity. X-ray analysis of the crystal structures of COX-1 bound to mofezolac and 3-(5-chlorofuran-2-yl)-5-methyl-4-phenylisoxazole allowed the identification of specific binding determinants within the enzyme active site, relevant to generate structure/activity relationships for diarylisoxazole NSAIDs. PMID- 28710967 TI - Illicit drug use is increasing among non-medical users of prescription drugs Results from population-based surveys 2002-2014. AB - BACKGROUND: Non-medical use of prescription drugs (NMUPD) is known to be associated with illicit drug use, but less is known about how illicit drug use has changed in NMUPD. We examined (1) the changes in illicit drug use among Finnish non-medical users of prescription drugs during the 2000s and (2) whether the trends of illicit drug use differ by non-medical use of prescription drugs in the general population. METHODS: Data were derived from population-based (aged 15 69) Drug Surveys conducted in Finland in 2002, 2006, 2010 and 2014. The response rates varied between 63% and 48%. NMUPD during the last year was measured (n=252). Past-year illicit drug use among non-medical users of prescription drugs and the reference population not reporting NMUPD (n=10,967) was compared. Logistic regression was used to estimate the p-values for trends. RESULTS: Illicit drug use has increased notably among Finnish non-medical users of prescription drugs (from 21% to 70%, p for trend<0.001). This was not explained by the respondents' gender, age, employment status or alcohol use. Among the reference population, illicit drug use also increased statistically significantly, but much more moderately (from 2.5% to 5.4%). The difference between the trends was confirmed by an interaction test (p=0.022). CONCLUSIONS: NMUPD seems to be increasingly merging with illicit drug use. This indicates an increasing prevalence of polydrug use among non-medical users of prescription drugs, which may bring about more severe harms and worse health outcomes for users and more challenges in regard to treatment. PMID- 28710968 TI - Enduring changes in brain metabolites and executive functioning in abstinent cocaine users. AB - BACKGROUND: There is a paucity of data connecting the metabolic and cognitive functioning of abstinent cocaine users. This is a pressing public health concern as approximately 1% of the Canadian population and 0.4% of the global population is estimated to have used cocaine in the past year. METHODS: Our clinical study compared the in vivo neurochemical profiles in the prefrontal cortex to cognitive tests associated with the same region in 21 moderate term abstinent cocaine users (average 187days abstinent, range 15-1432days), and 30 healthy controls using 3T 1H MRS. RESULTS: The abstinent cocaine users exhibited a 10% decrease in N acetylaspartate (NAA) relative to healthy control subjects (p<0.01, Cohen's d=1.15). When subdivided by method of administration, a significant decrease in glutamate levels in former crack smokers compared to healthy controls (p<0.05) was observed, this decrease was not present in powder users. Abstinent users were significantly worse than healthy controls on the Trail Making Test B (p<0.05), and performance on this task was inversely related to NAA levels (p<0.05). Abstinent cocaine users showed deficits in the Wisconsin card sorting test with failures to maintain set (p<0.01). CONCLUSIONS: Our work suggests that there are subtle but important changes in the brain that remain even with the moderate term cessation of cocaine use. PMID- 28710969 TI - Determination of urinary trans,trans-muconic acid using molecularly imprinted polymer in microextraction by packed sorbent followed by liquid chromatography with ultraviolet detection. AB - trans,trans-Muconic acid (tt-MA) has been introduced as biological exposure index for workers exposed to benzene. In the present study, for the first time, a novel and easy-to-use analytical method based on molecularly imprinted polymer (MIP) in microextraction by packed sorbent (MEPS), followed by high-performance liquid chromatography with ultra-violet detection (MIMEPS-HPLC-UV) was developed to determine tt-MA in urine samples. Fourier transform infrared spectroscopy was used for MIP characterization. The imprinting effect on the MIP was also evaluated. Furthermore, various parameters that affect the MEPS performance were investigated, including extraction cycles, sample volume, as well as the type and volume of washing and elution solvents. The optimised procedure was selective, sensitive, rapid and both user- and environmentally-friendly. A seven-point calibration curve was obtained in the range of 0.015-2MUg/mL (R2=0.9986). The extraction recovery was >89.8%. The limit of detection and limit of quantitation for tt-MA were 0.015 and 0.05MUg/mL, respectively. The within- and between-day precisions, given as percent relative standard deviation, were in the range of 3.4-4.7% and 3.5-6.6%, respectively. Accuracy was -8.4 to -10.2% in urine samples. The developed method is suggested as an alternative to existing conventional SPE methods for biomonitoring of benzene-exposed subjects. PMID- 28710970 TI - Validation of a probe for assessing deconjugation of glucuronide and sulfate phase II metabolites assayed through LC-MS/MS in biological matrices. AB - LC-MS/MS has been proposed in various areas such as Therapeutic Drug Monitoring (TDM), Human Biomonitoring (HBM), disease diagnosis, clinical toxicology and doping control to identify and quantify chemical parents and their metabolites in biological matrices. To determine the total content of a xenobiotic (unconjugated+conjugated forms), an enzymatic hydrolysis step is required. Most studies in the literature have not controlled the effectiveness of the deconjugation process because no method has been described for that purpose. Therefore the aim of this study was to develop and validate a deconjugation probe using a LC-MS/MS method. In order to estimate deconjugation using beta glucuronidase and/or sulfatase, 4-methyl-umbelliferone (MU) and its conjugates were used as markers. Glucuronidase/sulfatase was added to plasma or urine spiked with 4-methylumbelliferyl-beta-d-glucuronide (MUG) and 4-methylumbelliferyl sulfate (MUS) and umbelliferone, which was used as the internal standard. After incubation at 37 degrees C during 90min, MU appears as a result of the deconjugation of MUG and MUS. The concentrations of the 3 markers were determined using LC-MS/MS. Trueness and precision of the LC-MS/MS method were determined by quality control analysis at three different levels of concentration covering the whole range of calibration. In both matrices, the analytical method allows quantification of the different compounds, with good linearity, trueness and precision and negligible matrix effects. The method was applied with success to deconjugation assay using active glucuronidase/sulfatase in plasma and urine. The probe developed in this study allows to ensure that enzymatic preparation is working properly in the frame of a quality system. PMID- 28710971 TI - Intrinsic volatility of synaptic connections - a challenge to the synaptic trace theory of memory. AB - According to the synaptic trace theory of memory, activity-induced changes in the pattern of synaptic connections underlie the storage of information for long periods. In this framework, the stability of memory critically depends on the stability of the underlying synaptic connections. Surprisingly however, synaptic connections in the living brain are highly volatile, which poses a fundamental challenge to the synaptic trace theory. Here we review recent experimental evidence that link the initial formation of a memory with changes in the pattern of connectivity, but also evidence that synaptic connections are considerably volatile even in the absence of learning. Then we consider different theoretical models that have been put forward to explain how memory can be maintained with such volatile building blocks. PMID- 28710972 TI - Epidemiology, diagnosis, prevention and treatment of catheter-related thrombosis in children and adults. AB - In this narrative review, the epidemiology, diagnosis, prevention strategies, and management of catheter-related thrombosis are outlined. Central venous catheters have significantly improved the quality of life of patients requiring chemotherapy, parenteral nutrition, and chronic transfusions. Catheter-related thrombosis (CRT) complicates between 1-5% of inserted catheters, with incidence varying between patient population, catheter type, and vein cannulated. Strategies to prevent CRT, including anticoagulation and locking solutions, have largely been ineffective. Using clinical decision tools and D-dimer testing can limit radiographic testing for patients with suspected CRT. Although most patients with CRT are treated with anticoagulation, the most effective type and duration of treatment have not been established for adults or children. Many unanswered questions remain concerning risk stratification, prevention, and management of CRT. National and international collaborative research networks could be harnessed to perform these much needed studies. PMID- 28710973 TI - Identification of high risk metropolitan intersection sites in Perth, Australia. AB - As convergence points for road users approaching from multiple directions, intersections have more opportunities for conflicts, thus higher crash risk than other parts of the road network. Given the limited resources available for road safety, it is important to identify high risk intersections so that they can be prioritised for infrastructure improvement. This study used a three-stage approach to identify intersections in Perth, Western Australia: using Road Trauma Risk Analysis, then Comparative Safety Performance Analysis and finally ranking the intersections by the KSI (Killed and Serious Injury) metric. These methodologies were developed by Main Roads Western Australia. Crash data from 2011 to 2015 were used in the analyses. The results identify the top high risk intersections for each intersection type (by speed environment and control type). Recommendations are made for extensions to this process to improve identification of high risk intersections, and the use of a taxonomy to identify candidate treatments. PMID- 28710974 TI - Predictors of recovery in cyclists hospitalised for orthopaedic trauma following an on-road crash. AB - BACKGROUND: As cycling-related injury rates are on the rise, there is a need to understand the long term outcomes of these patients in order to quantify the burden of injury and to inform injury prevention strategies. This study aimed to investigate predictors of return to work and functional recovery in a cohort of cyclists hospitalised for orthopaedic trauma from crashes occurring on-road. METHODS: A retrospective analysis of data from the Victorian Orthopaedic Trauma Outcomes Registry (VOTOR) was conducted for patients who were hospitalised for orthopaedic trauma following a cycling crash that occurred on-road between July 2007 and June 2015. RESULTS: There were 1787 injured cyclists admitted at the participating hospitals. Most cyclists were male (79%), resided in major cities (89%) and were in the highest socioeconomic quintile (52%). The majority of crashes were either non-collisions (41%) or collisions with a motor vehicle (35%). A smaller proportion of cyclists who collided with motor vehicles had returned to work and had returned to pre-injury functional levels at 12 months post-injury, when compared to collisions with other impact counterparts and non collisions. Mixed effects logistic regression models revealed that compensable patients demonstrated lower odds of complete functional recovery and return to work when compared with non-compensable patients. CONCLUSION: Cyclists who collided with motor vehicles had worse outcomes compared to crashes with other impact counterparts and non-collision events. These findings provide support for reducing the potential for interaction between cyclists and motor vehicles. PMID- 28710975 TI - Paternal history of mental illness associated with posttraumatic stress disorder among veterans. AB - This study examined the association between parent and family reported history of non-PTSD mental illness (MI), PTSD specifically, and substance use problems, and participant clinical diagnosis of PTSD. Participants were drawn from the US Department of Veterans Affairs Mid-Atlantic Mental Illness Research, Education and Clinical Center (MIRECC) Post-Deployment Mental Health (PDMH) study (n = 3191), an ongoing multi-site cohort study of US Afghanistan and Iraq conflict era veterans. Participants who recalled a father history of PTSD had a 26-percentage point higher likelihood of meeting criteria for PTSD; while participants reporting any family history of PTSD had a 15-percentage point higher probability of endorsing symptoms consistent with PTSD. Mother history of substance use problems was associated with Veteran current PTSD, but results were sensitive to model specification. Current PTSD was not associated with family/parent history of non-PTSD mental illness, mother history of PTSD, or family/father history of substance use problems. Family history of PTSD may increase PTSD risk among veterans exposed to trauma, particularly when a father history is reported. Knowledge of family history could improve clinical decision-making for trauma exposed individuals and allow for more effective targeting of programs and clinical services. PMID- 28710976 TI - Comparing emissions from a cattle pen as measured by two micrometeorological techniques. AB - Accurate measurement of ammonia (NH3) emissions from livestock pens is challenging. Two micrometeorological techniques, the integrated horizontal flux (IHF) and the backward Lagrangian stochastic (bLS) dispersion techniques were used to measure NH3 emissions from an isolated cattle pen (20 * 20 m) in Victoria, Australia. The bLS technique is simple and insensitive to the presence of animals, but typically gives discontinuous measurements due to the need for target wind directions and wind conditions above accepted thresholds. In contrast, the IHF technique as implemented here gives near-continuous measurements with no restriction on wind directions. However, IHF needs more complex field measurements, and there are ambiguities when applied to an animal pen due to the presence of animals. Over the 29 days of our experiment, we collected 124 coincidental bLS and IHF emission measurements from the pen (30-min each). We found no statistical difference in the bLS and IHF calculations when the IHF turbulent flux correction factor (TFcor) was set to 15%. Our results confirm that the IHF and bLS techniques, using independent sensors and having very different equipment layouts, gives nearly equivalent results. This suggests the choice of the two methods in future experiments can focus on their different strengths and weaknesses. PMID- 28710977 TI - Assessing the toxicity and risk of salt-impacted winter road runoff to the early life stages of freshwater mussels in the Canadian province of Ontario. AB - In temperate urbanized areas where road salting is used for winter road maintenance, the level of chloride in surface waters has been increasing. While a number of studies have shown that the early-life stages of freshwater mussels are particularly sensitive to salt; few studies have examined the toxicity of salt impacted winter road runoff to the early-life stages of freshwater mussels to confirm that chloride is the driver of toxicity in this mixture. This study examines the acute toxicity of field-collected winter road runoff to the glochidia of wavy-rayed lampmussels (Lampsilis fasciola) (48 h exposure) and newly released juvenile fatmucket mussels (Lampsilis siliquoidea) (<1 week old; 96 h exposure) under different water hardness. The chronic toxicity (28 d) to older juvenile L. siliquoidea (7-12 months old) was also investigated. The 48-h EC50 and 96-h LC50 for L. fasciola glochidia and L. siliquoidea juveniles exposed to different dilutions of road run-off created with moderately hard synthetic water (~80 mg CaCO3/L) were 1177 (95% confidence interval (CI): 1011-1344 mg Cl /L) and 2276 mg Cl-/L (95% CI: 1698-2854 mg Cl-/L), respectively. These effect concentrations correspond with the toxicity of chloride reported in other studies, indicating that chloride is likely the driver of toxicity in salt impacted road-runoff, with other contaminants (e.g., metals, polycyclic aromatic hydrocarbons) playing a de minimis role. Toxicity data from the current study and literature and concentrations of chloride in the surface waters of Ontario were used to conduct a probabilistic risk assessment of chloride to early-life stage freshwater mussels. The assessment indicated that chronic exposure to elevated chloride levels could pose a risk to freshwater mussels; further investigation is warranted to ensure that the most sensitive organisms are protected. PMID- 28710978 TI - Relationships between POPs, biometrics and circulating steroids in male polar bears (Ursus maritimus) from Svalbard. AB - The aim of this study was to determine the effects of persistent organic pollutants (POPs) and biometric variables on circulating levels of steroid hormones (androgens, estrogens and progestagens) in male polar bears (Ursus maritimus) from Svalbard, Norway (n = 23). Levels of pregnenolone (PRE), progesterone (PRO), androstenedione (AN), dehydroepiandrosterone (DHEA), testosterone (TS), dihydrotestosterone (DHT), estrone (E1), 17alpha-estradiol (alphaE2) and 17beta-estradiol (betaE2) were quantified in polar bear serum by gas chromatography tandem mass spectrometry (GC-MS/MS), while POPs were measured in plasma. Subsequently, associations between hormone concentrations (9 steroids), POPs (21 polychlorinated biphenyls (PCBs), 8 OH-PCBs, 8 organochlorine pesticides (OCPs) and OCP metabolites, and 2 polybrominated diphenyl ethers (PBDEs)) and biological variables (age, head length, body mass, girth, body condition index), capture date, location (latitude and longitude), lipid content and cholesterol levels were examined using principal component analysis (PCA) and orthogonal projections to latent structures (OPLS) modelling. Average concentrations of androgens, estrogens and progestagens were in the range of 0.57 83.7 (0.57-12.4 for subadults, 1.02-83.7 for adults), 0.09-2.69 and 0.57-2.44 nmol/L, respectively. The steroid profiles suggest that sex steroids were mainly synthesized through the Delta-4 pathway in male polar bears. The ratio between androgens and estrogens significantly depended on sexual maturity with androgen/estrogen ratios being approximately 60 times higher in adult males than in subadult males. PCA plots and OPLS models indicated that TS was positively related to biometrics, such as body condition index in male polar bears. A negative relationship was also observed between POPs and DHT. Consequently, POPs and body condition may potentially affect the endocrinological function of steroids, including development of reproductive tissues and sex organs and the general condition of male polar bears. PMID- 28710979 TI - Characterization of chemical fingerprints of unconventional Bakken crude oil. AB - The ability to characterize the composition of emerging unconventional Bakken tight oil is essential to better prepare for potential spills and to assess associated environmental concerns. The present work measured and compared the physical and chemical properties of Bakken crudes with conventional crude oils from various regions and different types of refined petroleum products. The physicochemical properties of Bakken crude are overall similar to those of conventional light crudes. The Bakken crude consists of high concentrations of monoaromatic hydrocarbons and alkylated PAHs with a clear dominance of the alkylated naphthalene homologues followed by the phenanthrene series. Its pyrogenic index (PI) values are considerably lower than typical conventional crude oils. The Bakken crude oils in this study exhibit a low abundance of petroleum biomarker such as terpanes, steranes and diamondoids and bicyclic sesquiterpanes. Since tight oil from the Bakken region is produced from low permeability formations, variations in abundance and diagnostic ratios of common target petroleum hydrocarbons were found among these oils. PMID- 28710980 TI - Association of individual-level concentrations and human respiratory tract deposited doses of fine particulate matter with alternation in blood pressure. AB - Fine particulate matter (PM2.5) contributes to the risk of cardiovascular events, partially owing to its deposition in the human respiratory tract. To investigate short-term effects of ambient PM2.5 exposure on alternation of blood pressure (BP), this study was conducted during the winter-summer period between 2014 and 2015. The study included 106 community residents in Wuhan city, China. We repeatedly monitored the household and outdoor PM2.5 concentrations as well as individual-level PM2.5 in each season, and then assessed personal PM2.5 exposure (including deposited doses of PM2.5 in the human respiratory tract) by using different methodology (such as using a dosimetry model). All participants took part in the physical examination, including the inflammatory indicators, BP and lung function parameters measurements. Subsequently, we assessed the health damage of exposure to PM2.5 using generalized additive models. We observed increased BP at 2-day lag for an interquartile range increase in ambient fixed site, households, individual-level PM2.5 exposure and the corresponding lung deposited doses of each exposure concentration (p < 0.05), decreased BP at 3-day lag for an interquartile range increase in ambient fixed-site, households PM2.5 and the corresponding lung deposited doses of each exposure concentration (p < 0.05). The estimated deposited doses of PM2.5 by the deposition fractions in this study and the referenced deposition fractions by previous reported method were equivalent associated with alternation in BP. In conclusion, lung deposited dose of PM2.5 as a quantitative indicator may be used to assess adverse cardiovascular effects following the systemic inflammation. However, we require careful assessment of acute adverse cardiovascular effects using ambient fixed-site PM2.5 after short-term PM2.5 exposure. PMID- 28710981 TI - Photochemical generation and decay kinetics of superoxide and hydrogen peroxide in the presence of standard humic and fulvic acids. AB - Reactive oxygen species (ROS) such as superoxide (O2-) and hydrogen peroxide (H2O2) can be photochemically generated in aerobic waters containing natural organic matters (NOM) such as humic substances (HS). To investigate the effect of NOM molecular composition on the kinetics and mechanism of ROS transformation, photochemical O2- generation and subsequent H2O2 production via catalyzed and uncatalyzed (bimolecular dismutation) O2- decay were examined in the presence of 14 types of HS (pH 8.0). By using chemiluminescence and colorimetric techniques, the photochemical O2- generation rate, quasi-steady-state O2- concentration, catalyzed and uncatalyzed O2- decay rates, and H2O2 production rate were found to vary significantly by factors of 72, 18, 14, 320, and 7.7, respectively, depending on the type of HS and degree of photolysis. For more than half of the HS samples, both uncatalyzed and catalyzed reductive decay of photogenerated O2- were significantly involved in H2O2 generation, and their rates were comparable to those for O2- oxidative decay in which H2O2 is not generated. These results suggest that the chemical quality of HS influenced the H2O2 generation pathway. Correlation analyses indicated that rate constants associated with HS-mediated photochemical O2- and H2O2 generation are significantly correlated with HS molecular composition including total and aromatic C contents. In particular, practical indices representing NOM aromaticity including specific ultraviolet absorbance (SUVA) can be useful for predicting NOM-mediated ROS generation and decay kinetics. Overall, the present work suggests that NOM concentration and its quality influence NOM-mediated ROS dynamics in aqueous systems. PMID- 28710982 TI - Occurrence, fate, and mass balance of different classes of pharmaceuticals and personal care products in an anaerobic-anoxic-oxic wastewater treatment plant in Xiamen, China. AB - In this study, the occurrence and fate of 49 pharmaceuticals and personal care products (PPCPs) were investigated in an anaerobic-anoxic-oxic (A2/O) wastewater treatment plant (WWTP) for seven consecutive days using 24-h composite sampling technique. Special emphasis was placed to understand the distribution of PPCPs in dissolved and adsorbed phase, and to evaluate PPCP fate in different treatment units. Among the 49 PPCPs, 40 PPCPs in influent, 36 in effluent, 29 in sludge and 23 in suspended solids were detected at least once during sampling. Non-steroidal anti-inflammatory drugs (NSAIDs) and a stimulant were predominant PPCPs in influent whereas antibiotics were predominant in sludge, effluent and suspended solids. Removal efficiencies from the aqueous phase based on the dissolved PPCPs showed variable contribution in removing different PPCPs under screen and grit chamber, anaerobic treatment, anoxic treatment, oxic treatment and sedimentation UV treatments, with the highest removal percentage by anaerobic process in terms of both individual and overall treatment. Mass load analysis showed that 352 g PPCPs enter the WWTP daily while 14.5 g and 58.1 g were discharged through effluent and excess sludge to the receiving sea water and soil applications, respectively. Mass balance analysis based on both aqueous and suspended PPCPs showed 280 g (79.4%) mass of influent PPCPs was lost along the wastewater treatment processes, mainly due to degradation/transformation. PMID- 28710983 TI - Seasonal variation of bacterial community in biological aerated filter for ammonia removal in drinking water treatment. AB - Biological aerated filter (BAF) is widely used in wastewater treatment plants (WWTPs) and shows potential application of micropolluted drinking water sources with a higher NH4+-N removal efficiency during short warm seasons. Here we adopted a pilot lava-based BAF setup as a pretreatment unit of drinking water treatment plant (DWTP) and achieved a great performance of ammonia removal over a two-year operation using natural river water. We respectively observed 92.62% of NH4+-N removal efficiency, 97.88% of NO2--N removal efficiency in summer, and 77.52% NH4+-N removal efficiency in winter down to 5 degrees C. Based on DGGE analysis, AOB, NOB, as well as heterotrophic bacteria including genus Flavobacterium and Sphingomonas are responsible for the performance. Nitrosomonas and Nitrospira are found to be the dominant AOB and NOB in the BAF microbiota. The compositions of AOB including Nitrosomonas communis and Nitrosomonas oligotropha are different from the strains previously reported in BAF of WWTPs but similar to the observations in DWPTs. We observed seasonal bacterial shifts between summer and winter groups involved in AOB, NOB and heterotrophic genus Flavobacterium, which may be responsible for the seasonal performance fluctuation. The psychrophilic AOB belonging to Nitrosomonas likely contribute to the recovered NH4+-N removal efficiency when temperature is below 7 degrees C. Lack of nitrification functional psychrophilic or psychrotolerant NOB may be in charge of the severe nitrite accumulation below 7 degrees C. Our analysis suggests that the colonization of psychrophilic nitrifying bacteria in BAF needs at least two-year of natural acclimatization and is necessary for all-weather BAF in DWTPs. PMID- 28710984 TI - Aggregation behavior of TiO2 nanoparticles in municipal effluent: Influence of ionic strengthen and organic compounds. AB - The influence of ionic strengthen and dissolved organic matter (DOM) on the aggregation of TiO2 nanoparticles (NPs) in municipal effluent was investigated. The results demonstrated that DOM promoted the mobility of NPs in aquatic system by synergism between static repulsion and steric effect, while electrolytes were opposite by charge-neutralization. The physical-chemical characteristics of DOM played the major role on the mobility of NPs. Bovine serum albumin (BSA) showed the strongest enhancement on the mobility of TiO2 NPs. High adsorption of BSA introduced vast negative charges on the TiO2 NPs' surface, leading to static repulsion and neutralizing positive charges of electrolytes in surrounding as well. By contrast, another protein alpha-amylase retarded the aggregation rate of TiO2 NPs through steric repulsion of the long-chain construction. Humic substances (Fulvic acid and alginate) also reflected the combination of static repulsion and steric effect. However, in the high electrolytes concentration (especially Ca2+), the long-chain aliphatic compounds were prone to form calcium bridge which increased the hydrodynamic diameter of TiO2 aggregates consequently. Sodium dodecylbenzene sulfonate (SDBS) showed low adsorption capacity, while the unabsorbed SDBS retarded the aggregates caused by the changes of pH and electrolytes. These data indicated that decreasing of DOC concentration in aqueous system was important to reduce the mobility and potential risk of NPs in aqueous system. PMID- 28710985 TI - Spinal cord compression secondary to idiopathic thoracic epidural lipomatosis in an adolescent: A case report and review of literature. AB - INTRODUCTION: Spinal epidural lipomatosis (SEL) is a rare condition that presents with progressive spinal cord or nerve root compression. It is commonly reported in patients receiving long-term exogenous steroid therapy or in patients with endogenous steroid overproduction. The occurrence of this condition as an idiopathic entity is rarely reported. CASE PRESENTATION: The authors present the clinical course and outcome of a 16-year-old male student, who presented with progressive spastic paraparesis of a one-year duration caused by idiopathic spinal epidural lipomatosis. Magnetic resonance imaging (MRI) study of the thoracic spine revealed marked compression of the spinal cord from a large dorsally located extradural mass extending from the T-4 to T-12 vertebral bodies. The patient underwent posterior thoracic laminoplasty from the T4 to T10 vertebral levels. He experienced gradual neurological, and he was able to walk without assistant by the end of 3-month follow-up period from surgery. CONCLUSION: Idiopathic SEL is very rare, since no predisposing factors can be identified, and should be included in the differential diagnosis when patients present with spinal neurological compromise. MRI is the imaging modality of choice, and decompressive laminectomy and debulking of the fatty lesion is the main treatment modality in patients with progressive course of the disease.. PMID- 28710986 TI - Pulmonary function and respiratory health of rural farmers and artisanal and small scale gold miners in Ghana. AB - The recent increase in artisanal and small scale gold mining (ASGM) worldwide has elicited a number of public health concerns for miners and mining communities, including respiratory health. The two primary inhalational exposures of concern are crystalline silica expected to be present in gold ore and smoke from biomass fuels used in cooking. Here, measurements of pulmonary function and of respiratory symptoms were performed in an ASGM community, Kejetia, and a comparison agricultural community, Gorogo, in the Upper East Region of Ghana in May-July 2011. Of 172 participants, 159 performed spirometry, yielding 119 and 95 valid measurements for FEV1 and FVC, respectively. Percent predicted FEV1, FVC and FEV1/FVC, which were lower than predicted for a healthy population, were not significantly different between Kejetia and Gorogo or by mining status in Kejetia. Abnormal lung function was elevated for predicted FEV1 (15.0%) and FEV1/FVC (22.0%) beyond an expected five percent in healthy populations. This first examination of pulmonary function in an ASGM community in Ghana (and possibly worldwide) did not show an obvious relationship between mining involvement and lung function abnormality, but did show associations between the use of biomass fuels, adverse respiratory symptoms, and reduced pulmonary function in both populations. A number of factors including age differences between the populations and the required lag time after silica exposure for the onset of respiratory disease may have affected results. Additional research is needed with larger sample sizes and with more detailed questionnaires to further assess the impact of multiple stressors on respiratory health in ASGM communities. PMID- 28710987 TI - The long-term quality of life in patients with persistent inflammation immunosuppression and catabolism syndrome after severe acute pancreatitis: A retrospective cohort study. AB - PURPOSE: To explore clinical characteristics and long-term quality of life (QOL) in severe acute pancreatitis (SAP) patients with persistent inflammation immunosuppression and catabolism syndrome (PICS). MATERIALS AND METHODS: SAP patients admitted to ICU were eligible for the retrospective cohort study if they needed prolonged intensive care (>14days). Post-ICU QOL was assessed by a questionnaire, including 36-item Short Form Health Survey (SF-36) and record of re-work in a long-term follow-up. RESULTS: 214 SAP patients were enrolled, in which 149 (69.6%) patients met the criteria of PICS. PICS patients had more complications and ICU days compared to non-PICS patients (P<0.001), and their post-ICU mortality was higher (P=0.046). When adjusted for confounders, PICS was independently associated with higher post-ICU mortality (hazard ratio 4.5; 95% CI, 1.2 to 16.3; P=0.024). The 36-item Short Form Health Survey (SF-36) score was lower for PICS group in six subscales (P<0.001). Only 28.8% patients in the PICS group returned to work compared to 60% patients in the non-PICS group (P=0.001) CONCLUSIONS: SAP patients with prolonged ICU stay had a high morbidity of PICS, which was a risk factor for the post-ICU mortality and poor long-term QOL. PMID- 28710989 TI - Bioleaching of arsenopyrite by mixed cultures of iron-oxidizing and sulfur oxidizing microorganisms. AB - Arsenic is a critical environmental pollutant associated with acid mine drainage. Arsenopyrite is one of the major arsenic sulfide minerals whose weathering lead to the contamination of arsenic. In this study, the leaching behaviors of arsenopyrite by two mixed cultures of iron-oxidizing and sulfur-oxidizing microorganisms (Ferroplasma thermophilum and Acidithiobacillus caldus, Sulfobacillus thermosulfidooxidans and Acidithiobacillus caldus) were investigated, accompanying with community structure analysis of free microorganisms. The ratio of F. thermophilum to A. caldus of 1/1 showed a more favorable effect on the arsenic leaching than other ratios, and F. thermophilum played a dominant role in the solution all the leaching time. While adding A. caldus in the S. thermosulfidooxidans bioleaching system, the dissolution of arsenopyrite was suppressed. Notably, when the ratio of S. thermosulfidooxidans to A. caldus was 2/1, the arsenic extraction was accelerated at the early stage, but later it slowed down. The reason was because A. caldus was the predominant species at the later stage which made the redox potential decrease faster. XRD demonstrated that the proper addition of A. caldus could eliminate the sulfur passivation and promote the leaching in a degree. These studies are helpful to evaluate the environmental impact of arsenic. PMID- 28710988 TI - Intestinal fatty acid-binding protein level as a predictor of 28-day mortality and bowel ischemia in patients with septic shock: A preliminary study. AB - PURPOSE: We sought to evaluate the levels of intestinal fatty acid-binding protein (I-FABP), a biomarker of enterocyte injury, as a predictor of 28-day mortality and bowel ischemia in septic shock patients. MATERIAL AND METHODS: In this preliminary prospective observational study, 57 adult septic shock patients under mechanical ventilation were enrolled. Serum I-FABP levels and prognostic biomarkers were recorded upon intensive care unit (ICU) admission. RESULTS: The overall 28-day mortality rate of participants was 23% (13/57). Non-survivors displayed significantly higher lactate (p=0.009), I-FABP (p=0.012), and N terminal pro-B-type natriuretic peptide (p=0.039) levels compared to survivors. Only I-FABP was associated with 28-day mortality (odds ratio, 1.036; 95% confidence interval, 1.003-1.069; p=0.031) in a multiple logistic regression analysis adjusted for the Acute Physiology and Chronic Health Evaluation II score. When divided into low and high I-FABP groups based on the optimum cut-off value of 19.0ng/mL for predicting 28-day mortality, high-I-FABP patients had a significantly higher incidence of non-occlusive mesenteric ischemia (NOMI) (2% [1/43] vs 29% [4/14]; p=0.011). CONCLUSIONS: I-FABP level at ICU admission can serve as a predictor of 28-day mortality in septic shock patients and is associated with the incidence of NOMI. PMID- 28710990 TI - Biomarkers of oxidative stress and health risk assessment of heavy metal contaminated aquatic and terrestrial organisms by oil extraction industry in Ogale, Nigeria. AB - Ogale community in Rivers State, Nigeria is characterized by crude-oil contamination of its land resources. The present study aimed to evaluate the health risk and metal (Cd, Pb, Zn, Cr, and Ni) contamination level of the vegetable (Telfairia occidentalis), snail (Achatina achatina) and the catfish (Clarias gariepinus) collected from Ogale community. Samples collected from Elele Alimini community, a less polluted area was used as control. Oxidative damage was evaluated in tissues of snail and in the liver of catfish. The concentration of most of the tested metals in the food samples collected from the polluted sites were higher than those from the reference sites and in most cases exceeded the acceptable permissible limits. The accumulation of the metals by the food samples followed the order: T. occidentalis > A. achatina > C. gariepinus. The tissues of the snail from the polluted sites showed higher malondialdehyde (MDA) and lower glutathione (GSH) levels, and higher MDA and GSH levels in the fish liver compared to control values. The health risks associated with these metals in terms of dietary intake and target hazard quotients (THQs) showed higher non carcinogenic effect and carcinogenic risks especially for Pb and Cd from the ingestion of Telfairia occidentalis and Achatina achatina from polluted sites. The health hazards due to metal pollution for the highly-exposed consumers of the food samples, especially in Ogale require attention. The oxidative stress response to accumulation status of metals provides a relevant tool for the assessment of metal pollution. PMID- 28710991 TI - The impact assessment of anticancer drug imatinib on the feeding behavior of rotifers with an integrated perspective: Exposure, post-exposure and re-exposure. AB - The anticancer drugs are getting increasing attention as an emerging contaminant in the aquatic environments. In the present study, feeding behavior of the rotifer Brachionus calyciflorus under the impact of anticancer drug imatinib was evaluated. Traditional toxicological studies usually focus on dose-effect relationship at a given exposure time, while ignore the possible impact after the exposure. Thus, how the impact varied in the post-exposure and re-exposure was also considered in the present study. The feeding depression of the rotifers was attributed to the increased concentration of imatinib. Although the filtration and ingestion rate of the rotifers recovered to a certain extent after the exposure, the significant feeding inhibition still persisted even if the exposure was ended. In the re-exposure period, the feeding behavior was less depressed than those of the exposure period, which implied that rotifers might develop a tolerance to the same toxics. The activities of acetylcholine esterase (AchE) and the levels of reactive oxygen species (ROS) in rotifers were also detected. Imatinib inhibited the activities of AchE in the exposure and re-exposure while ROS levels increased significantly in the re-exposure period. Our present study provided an integrated assessment the potential environmental risks of imatinib at a new perspective. PMID- 28710992 TI - Chemical and spectral behavior of nitric acid in aqueous sulfuric acid solutions: Absorption spectrum and molar absorption coefficient of nitronium ion. AB - The chemical species formed from nitric acid in aqueous solutions of sulfuric acid (up to 18.0molL-1) were studied by optical spectroscopy method. The concentration region of nitronium ion formation was identified and NO2+ ion absorption spectrum was measured (lambdamax<=190nm and epsilon190=1040+/-50mol 1Lcm-1). PMID- 28710993 TI - Synthesis, physicochemical and optical properties of bis-thiosemicarbazone functionalized graphene oxide. AB - Fluorescent materials are important for low-cost opto-electronic and biomedical sensor devices. In this study we present the synthesis and characterization of graphene modified with bis-thiosemicarbazone (BTS). This new material was characterized using Fourier transform infrared spectroscopy (FT-IR), Ultraviolet visible (UV-Vis) and Raman spectroscopy techniques. Further evaluation by X-ray diffraction (XRD), thermo-gravimetric analysis (TGA), differential scanning calorimetry (DSC), scanning electron microscopy (SEM) and atomic-force microscopy (AFM) allowed us to fully characterize the morphology of the fabricated material. The average height of the BTSGO sheet is around 10nm. Optical properties of BTSGO evaluated by photoluminescence (PL) spectroscopy showed red shift at different excitation wavelength compared to graphene oxide or bisthiosemicarbazide alone. These results strongly suggest that BTSGO material could find potential applications in graphene based optoelectronic devices. PMID- 28710994 TI - Toxic compounds from tobacco in placenta samples analyzed by UPLC-QTOF-MS. AB - Polycyclic aromatic hydrocarbons (PAHs), tobacco-specific nitrosamines (TSNAs) and aromatic amines are carcinogens present in cigarette smoke. These compounds are distributed in the human body and they could be transferred to the foetus during the pregnancy. Placenta is the main barrier to these toxic compounds and its study is the objective of this work. A method based on solid-phase extraction (SPE) with ultra-performance liquid chromatography-tandem quadrupole-time-of flight mass spectrometry (UPLC-QTOF-MS) has been examined and optimized for the analysis of 9 target analytes (4 tobacco-specific nitrosamines and some of their metabolites, 3 aromatic amines, nicotine and cotinine) in 26 placenta samples from smoking and non-smoking women. Limits of detection (LODs) were in the range of 3-27ng/g of placenta. Nicotine, cotinine, N-nitrosoanatabine (NAT) and 4 (methylnitrosamino)-1- (3-pyridyl)-1-butanone (NNK) metabolite, 4 (methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) were detected in the placenta samples of smoking woman. Nicotine was detected in 3 out of 8 placentas from smoking women, always below the limit of quantification (88ng/g). This could be expected, as the half-life of nicotine in the body is limited to about 0.5-3h. Cotinine, the main metabolite from nicotine, was detected in all placentas from smoking women at concentrations between 17.2 and 61.8ng/g, reaching the highest values for those women that smoked the highest number of cigarettes. NAT and NNAL were detected in all placentas from smoking women, always below the limit of quantification (40ng/g and 33ng/g respectively). PMID- 28710995 TI - Enhanced and green extraction polyphenols and furanocoumarins from Fig (Ficus carica L.) leaves using deep eutectic solvents. AB - Nowadays, green extraction of bioactive compounds from medicinal plants has gained increasing attention. As green solvent, deep eutectic solvent (DES) have been highly rated to replace toxic organic solvents in extraction process. In present study, to simultaneous extraction five main bioactive compounds from fig leaves, DES was tailor-made. The tailor-made DES composed of a 3:3:3 molar ratio of glycerol, xylitol and D-(-)-Fructose showed enhanced extraction yields for five target compounds simultaneously compared with traditional methanol and non tailor DESs. Then, the tailor-made DES based extraction methods have compared and microwave-assisted extraction was selected and optimized due to its high extraction yields with lower time consumption. The influencing parameters including extraction temperature, liquid-solid ratio, and extraction time were optimized using response surface methodology (RSM). Under optimal conditions the extraction yield of caffeoylmalic acid, psoralic acid-glucoside, rutin, psoralen and bergapten was 6.482mg/g, 16.34mg/g, 5.207mg/g, 15.22mg/g and 2.475mg/g, respectively. Macroporous resin D101 has been used to recovery target compounds with recovery yields of 79.2%, 83.4%, 85.5%, 81.2% and 75.3% for caffeoylmalic acid, psoralic acid-glucoside, rutin, psoralen and bergapten, respectively. The present study suggests that DESs are truly designer and efficient solvents and the method we developed was efficient and sustainable for extraction main compounds from Fig leaves.mg/g. PMID- 28710996 TI - The fourth generation AlereTM HIV Combo rapid test improves detection of acute infection in MTN-003 (VOICE) samples. AB - BACKGROUND: Early and accurate detection of HIV is crucial when using pre exposure prophylaxis (PrEP) for HIV prevention to avoid PrEP initiation in acutely infected individuals and to minimize the risk of drug resistance in individuals with breakthrough infection. OBJECTIVE: To determine if fourth generation antigen/antibody (Ag/Ab) rapid diagnostic tests (RDT) would have detected HIV infection earlier than the third-generation RDT used in MTN-003 (VOICE). STUDY DESIGN: 5029 VOICE participants were evaluated with third generation Alere DetermineTM HIV-1/2, OraQuick ADVANCE(r) Rapid HIV-1/2, Uni GoldTM Recombigen(r) HIV-1/2 and Bio-Rad GS HIV-1/2+O EIA; and fourth-generation Alere DetermineTM HIV-1/2 Ag/Ab Combo, Conformite Europeene (CE)-Marked AlereTM HIV Combo and Bio-Rad HIV Combo Ag/Ab EIA. Multispot(r), GS HIV-1 Western Blot (WB) and GeeniusTM (Bio-Rad) were also evaluated. RESULTS: Of 57 antibody negative pre-seroconversion plasma samples with HIV RNA >20 copies/mL identified, 16 (28%) were reactive by CE-Marked AlereTM HIV Combo (1 Ab; 9 Ag; 6 Ag/Ab reactive) and 4 (7%) by Alere DetermineTM HIV-1/2 Ag/Ab Combo (2 Ab; 2 Ag; 0 Ag/Ab reactive) (p=0.0005). Multispot(r) confirmed only 1 of 16 acute infections while WB and GeeniusTM confirmed none. GS HIV Combo Ag/Ab EIA identified 27 of 57 (47%) pre-seroconversion RNA-positive samples. CONCLUSION: In VOICE, 28% of infections missed by current third-generation RDT would have been identified with the use of CE-Marked AlereTM HIV Combo. GeeniusTM, Multispot(r) and WB were all insensitive (<10%) in confirming infections detected by fourth-generation assays. An improved diagnostic algorithm that includes a fourth-generation RDT with HIV RNA testing will be essential for efficiently identifying seroconverters on PrEP. PMID- 28710997 TI - Dynamics of Torque Teno virus plasma DNAemia in allogeneic stem cell transplant recipients. AB - BACKGROUND: Torque Teno virus (TTV) plasma DNA load directly correlate with the level of immunosuppresion in different clinical settings. It is uncertain whether this may be the case in allogeneic hematopoietic stem cell transplant recipients (allo-HSCT). OBJECTIVES: We characterized the dynamics of TTV DNAemia in patients undergoing T-cell replete allo-SCT. STUDY DESIGN: Retrospective single-center observational study including 72 allo-HSCT patients. Plasma TTV DNA loads were quantified before initiating the conditioning regimen and at different time points after transplant by real-time PCR. White blood cells (WBC) and absolute lymphocyte counts (ALC) were measured by flow cytometry. RESULTS: A dramatic drop in plasma TTV DNA load was observed shortly after conditioning. The TTV DNA load increased steadily after engraftment reaching its peak at day +90 after transplant. The increase in TTV DNA load paralleled that of ALC, and was of greater magnitude in patients who developed severe (grades II-IV) acute graft vs. host disease. CONCLUSION: Repopulation of lymphocytes early after allo-HSCT correlates with an increase of plasma TTV DNA load. Prospective studies are nevertheless needed to determine whether the kinetics of TTV DNAemia may allow inference of the degree of overall immunocompetence in these patients. PMID- 28710998 TI - The potential multiple mechanisms and microbial communities in simultaneous nitrification and denitrification process treating high carbon and nitrogen concentration saline wastewater. AB - A simultaneous nitrification and denitrification (SND) process in sequencing batch biofilm reactor (SBBR) was established to treat high carbon and nitrogen saline wastewater in this study. Acetate, glucose and an organic mixture were applied as organic sources in three SBBRs, achieving average total nitrogen removal efficiency of 97.15%, 63.94% and 94.99% during 120days' operation, respectively. The underlying nitrogen removal mechanisms were investigated by 16S rRNA sequencing and batch tests. Results showed different carbon sources had great impact on microbial communities, and led to different nitrogen removal mechanism. Autotrophic and heterotrophic nitrification together contributed to the well performance of nitrification process. And denitrification was carried out by a combined anoxic and aerobic denitrificans. Furthermore, the SND process was mainly via nitrite not nitrate. Compared with ammonia-oxidizing bacteria, ammonia-oxidizing archaea with a much higher abundance contributed more to autotrophic nitrification. Pseudomonas_stutzeri and Bacillus_cereus were the predominant detected heterotrophic nitrification-aerobic denitrification bacterium. PMID- 28710999 TI - Recent changes in county-level corn yield variability in the United States from observations and crop models. AB - The United States is responsible for 35% and 60% of global corn supply and exports. Enhanced supply stability through a reduction in the year-to-year variability of US corn yield would greatly benefit global food security. Important in this regard is to understand how corn yield variability has evolved geographically in the history and how it relates to climatic and non-climatic factors. Results showed that year-to-year variation of US corn yield has decreased significantly during 1980-2010, mainly in Midwest Corn Belt, Nebraska and western arid regions. Despite the country-scale decreasing variability, corn yield variability exhibited an increasing trend in South Dakota, Texas and Southeast growing regions, indicating the importance of considering spatial scales in estimating yield variability. The observed pattern is partly reproduced by process-based crop models, simulating larger areas experiencing increasing variability and underestimating the magnitude of decreasing variability. And 3 out of 11 models even produced a differing sign of change from observations. Hence, statistical model which produces closer agreement with observations is used to explore the contribution of climatic and non-climatic factors to the changes in yield variability. It is found that climate variability dominate the change trends of corn yield variability in the Midwest Corn Belt, while the ability of climate variability in controlling yield variability is low in southeastern and western arid regions. Irrigation has largely reduced the corn yield variability in regions (e.g. Nebraska) where separate estimates of irrigated and rain-fed corn yield exist, demonstrating the importance of non climatic factors in governing the changes in corn yield variability. The results highlight the distinct spatial patterns of corn yield variability change as well as its influencing factors at the county scale. I also caution the use of process based crop models, which have substantially underestimated the change trend of corn yield variability, in projecting its future changes. PMID- 28711000 TI - Ecosystem services response to urbanization in metropolitan areas: Thresholds identification. AB - Ecosystem service is the key comprehensive indicator for measuring the ecological effects of urbanization. Although various studies have found a causal relationship between urbanization and ecosystem services degradation, the linear or non-linear characteristics are still unclear, especially identifying the impact thresholds in this relationship. This study quantified four ecosystem services (i.e. soil conservation, carbon sequestration and oxygen production, water yield, and food production) and total ecosystem services (TES), and then identified multiple advantageous area of ecosystem services in the peri-urban area of Beijing City. Using piecewise linear regression, the response of TES to urbanization (i.e., population density, GDP density, and construction land proportion) and its thresholds were detected. The results showed that, the TES was high in the north and west and low in the southeast, and there were seven multiple advantageous areas (distributed in the new urban development zone and ecological conservation zone), one single advantageous area (distributed in the ecological conservation zone), and six disadvantageous areas (mainly distributed in the urban function extended zone). TES response to population and economic urbanization each had a threshold (229personkm-2 and 107.15millionyuankm-2, respectively), above which TES decreased rapidly with intensifying urbanization. However, there was a negative linear relationship between land urbanization and TES, which indicated that the impact of land urbanization on ecosystem services was more direct and effective than that of population and economic urbanization. It was also found that the negative impact of urbanization on TES was highest in the urban function extended zone, followed in descending order by that in the new urban development zone and ecological conservation zone. According to the detected relationships between urbanization and TES, the economic and population urbanization should be strengthened accompanied by slowing or even reducing land urbanization, so as to achieve urban ecological sustainability with less ecosystem services degradation. PMID- 28711001 TI - Improvements in wheat productivity and soil quality can accomplish by co application of biochars and chemical fertilizers. AB - The beneficial role of biochar is evident in most of infertile soils, however this is argued that increment in crop yield owing to biochar application does not always achieve in cultivated/fertile soils. The nutrient biochar believed to enhance crop yield and soil fertility than structural biochar that may offset the positive effect of chemical fertilizer on crop performance but improves soil structural properties. Therefore, we investigated the effect of biochars [produced from nutrient rich feedstocks like poultry manure (PMB) and farmyard manure (FMB) and structural feedstocks such as wood chips (WCB) and kitchen waste (KWB)], and chemical fertilizers (CF) when applied alone or in combination on soil chemical properties, wheat growth, yield and nitrogen uptake in a cultivated clay loam soil. Sole biochar treatments increased the total carbon and mineral nitrogen content that were 21 and 106% higher, respectively compared to control after 128days (P<0.001). Contrarily, sole biochars application did not increase wheat biological yield and N uptake compared to control (P>0.05) except PMB, the nutrient biochar (P<0.05). Compared to control, grain yield was 6 and 12% lower in WCB and FMB, respectively but not differed from KWB, PMB or WCB-CF. Conversely, co-application of biochars and CF treatments increased crop biological yield but the increment was the highest in nutrient biochars FMB or PMB (29 or 26%), than structural biochars WCB and KWB (15 and 13%), respectively (P<0.05). For N uptake, this increment varies between 16 and 27% and again nutrient biochar has significantly higher N uptake than structural biochars. Hence, nutrient biochars (i.e. PMB) benefited the soil fertility and crop productivity more than structural biochars. Therefore, for immediate crop benefits, it is recommended to use nutrient biochar alone or in combination with chemical fertilizer. Such practice will improve crop performance and the quality of cultivated soil. PMID- 28711002 TI - Effect of temperature on sulfonamide antibiotics degradation, and on antibiotic resistance determinants and hosts in animal manures. AB - Animal manure is a main reservoir of antibiotic residues and antibiotic resistance. Here, the effect of temperature on sulfonamide antibiotics (SAs), sulfonamide-resistant (SR) genes/bacteria was investigated by aerobically incubating swine and chicken manures at different temperatures. In swine manure, the SAs concentration declined with increasing temperature, with a minimum at 60 degrees C. In chicken manure, the greatest degradation of SAs was noted at 30 degrees C. The reduction of relative abundance of antibiotic resistance genes (ARGs) and sul-positive hosts in swine manure was more pronounced during thermophilic than mesospheric incubation; neither temperature conditions effectively reduced these parameters in chicken manure. The relationship between the residual levels/distribution profiles of SAs, ARGs (sul1, sul2 and intI1), cultivable SR bacteria and sul-positive hosts was further established. The antibiotic residual profile, rather than antibiotic concentration, acted as an important factor in the prevalence of ARGs and sul-positive hosts in manure. Corynebacterium and Leucobacter from the phylum Actinobacteria tend to be main carriers of sul1 and intI1; the relative abundance of sul2 was significantly correlated with the relative abundance of cultivable SR bacteria. Overall, differences in resistant bacterial communities also constitute a dominant factor affecting ARG variation. This study contributes to management options for reducing the pollution of antibiotics and antibiotic resistance within manure. PMID- 28711003 TI - Environmentally relevant concentrations of herbicides impact non-target species at multiple sublethal endpoints. AB - There is concern over herbicide exposure effects on aquatic primary production and zooplankton as herbicides are found in aquatic ecosystems at concentrations potentially toxic to phytoplankton. We first aimed to determine the effect concentrations (growth inhibition) and mixture interactions of the herbicides diuron (0.5 to 50MUg/L) and hexazinone (0.5 to 40MUg/L) on the green algae Pseudokirchneriella subcapitata. Secondly, we evaluated chronic effects on Daphnia magna that were periodically fed on P. subcapitata that had been exposed to low, medium, and high concentrations. We hypothesized that based on the mode of action of the herbicides we would observe additive growth inhibition in algae, and sublethal effects on D. magna. Growth inhibition in P. subcapitata following mixture exposure was most consistent with the concentration addition (CA) concept; while the independent action (IA) model underestimated the combined effect. The lowest observed effect concentrations (LOEC) were 1.50MUg/L hexazinone, 1.18MUg/L diuron, and 0.125 TU (0.30MUg/L diuron*0.12MUg/L hexazinone) in the single and binary mixture exposures, respectively. High hexazinone exposure decreased D. magna survival (80% vs. 55.6%). Neonate number was reduced by 13.9% in high mixture and 23.5% in high hexazinone treatments. Gravid body length was reduced by 9.5% following exposure to the high mixture. Herbicide exposure decreased neonate size, especially in later broods. Herbicides decreased the phototaxic responses of neonates in most treatments. Herbicide exposure effects were detected at environmentally relevant concentrations, levels considered to be safe according to current USEPA aquatic life benchmarks, suggesting that these benchmarks need to be updated to improve ecological risk assessment. As herbicides are some of the most applied pesticides worldwide, sublethal endpoints can serve as sensitive early warning tools to indicate their presence and can support regulatory assessments and monitoring to protect aquatic life. PMID- 28711004 TI - Investigation of the presence and endocrine activities of pesticides found in wastewater effluent using yeast-based bioassays. AB - This study investigated the presence of a variety of pesticides (herbicides, fungicides, and insecticides) in effluent of three wastewater treatment plants as well as their endocrine activities using yeast-based in vitro assays. Although the presence of these contaminants of emerging concern is frequently reported to be present throughout the environment, their presence in wastewater treatment plants has been seldom studied. Of the 18 compounds investigated in this study, imidacloprid was the only compound not detected in all three WWTPs. Concentrations measured ranged from 3ng/L to 27MUg/L for fluconazole. The yeast estrogenic and yeast androgenic screen assays were performed on target compounds in order to investigate their endocrine disruption and potential environmental risks to receiving waters. It was found that of the 14 compounds investigated 12 showed either antiestrogenic or antiandrogenic activity and seven compounds showed pleiotropic effects. In addition to confirming endocrine activities of pesticides using the yeast-based assays this study is one of the first to report activities for novel compounds including three neonicotinoids. PMID- 28711005 TI - Pesticide occurrence in the waters of Jucar River, Spain from different farming landscapes. AB - A combined methodology to identify and quantify farming chemicals in the entire Jucar River basin has been developed. The procedure consisted of the application of environmental forensic criteria associating laboratory analytical samples, cartographic analysis using Geographical Information Systems (GIS) and synthetic statistical analysis. Sampling involved the collection of 15 samples in surface waters distributed alongside the Jucar River and its two main tributaries (Cabriel and Magro Rivers). The analytical procedure involves generic sample extraction and selective determination of up to 50 target pesticides by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). Geographical analysis was performed by mixing both sampling points with analytical results and land use-cover layers for the year 2011. PCA and descriptive statistical analysis was further performed combining land use/cover information and pesticides results to determine correlation between dominant agricultural practices (irrigation and rain fed farming) and location of sampling points. Out of 50 pesticides, 20 were identified and 18 presented concentrations higher than the limits of quantification in surface waters, with a large dispersion in concentrations: from 0.05ng/L (terbuthylazine-2 hydroxy) to 222.45ng/L (imazalil). Statistical analyses reveals that there is a correlation between the percentage of land devoted to irrigation farming, whereas correlations are weaker when analysing the relationship of pesticides in rain fed dominated areas. PMID- 28711006 TI - Assessment of the municipal water cycle in China. AB - Water produced from municipal utilities accounts for nearly 10% of the sum water demand in China. The municipal water cycle that integrates processes of urban water supply, water use, sewage treatment, and water reclamation has been assessed for 655 cities across nine drainage areas in mainland China in 2012. These cities in total extracted 55km3 raw water for municipal use from surface waterbodies and ground aquifers, approximate to the countrywide freshwater extraction of Russia or Italy. After purification and transmission, 45km3 water was distributed to industrial, service, and domestic users. 36km3 of post-use sewage was collected and environmentally safely treated; merely 3.2km3 of the treated water was reclaimed. Driven by increasing urbanization, the municipal water demand in cities of China may grow 70% by 2030. The Hai River and the Huai River basins, which harbor 137 cities and occupy a majority of the densely populated North China Plain, are most exposed to physical water scarcity. The municipal water abstraction in these cities can remain constant by promoting demand-side and process conservation in the next two decades. Interbasin transfer and unconventional sources will provide municipal water double than the cities' need. Whereas the urban water security can be technically enhanced, the challenges are to better improve water use efficiency and mitigate economic and environmental costs of the municipal system. PMID- 28711007 TI - Carbon dynamics in a Late Quaternary-age coastal limestone aquifer system undergoing saltwater intrusion. AB - This study investigates the inorganic and organic aspects of the carbon cycle in groundwaters throughout the freshwater lens and transition zone of a carbonate island aquifer and identifies the transformation of carbon throughout the system. We determined 14C and 13C carbon isotope values for both DIC and DOC in groundwaters, and investigated the composition of DOC throughout the aquifer. In combination with hydrochemical and 3H measurements, the chemical evolution of groundwaters was then traced from the unsaturated zone to the deeper saline zone. The data revealed three distinct water types: Fresh (F), Transition zone 1 (T1) and Transition zone 2 (T2) groundwaters. The 3H values in F and T1 samples indicate that these groundwaters are mostly modern. 14CDOC values are higher than 14CDIC values and are well correlated with 3H values. F and T1 groundwater geochemistry is dominated by carbonate mineral recrystallisation reactions that add dead carbon to the groundwater. T2 groundwaters are deeper, saline and characterised by an absence of 3H, lower 14CDOC values and a different DOC composition, namely a higher proportion of Humic Substances relative to total DOC. The T2 groundwaters are suggested to result from either the slow circulation of water within the seawater wedge, or from old remnant seawater caused by past sea level highstands. While further investigations are required to identify the origin of the T2 groundwaters, this study has identified their occurrence and shown that they did not evolve along the same pathway as fresh groundwaters. This study has also shown that a combined approach using 14C and 13C carbon isotope values for both DIC and DOC and the composition of DOC, as well as hydrochemical and 3H measurements, can provide invaluable information regarding the transformation of carbon in a groundwater system and the evolution of fresh groundwater recharge. PMID- 28711008 TI - Sector-wise midpoint characterization factors for impact assessment of regional consumptive and degradative water use. AB - Water availability, resulting from either a lack of water or poor water quality is a key factor contributing to regional water stress. This study proposes a set of sector-wise characterization factors (CFs), namely consumptive and degradative water stresses, to assess the impact of water withdrawals with a life cycle assessment approach. These CFs consider water availability, water quality, and competition for water between domestic, agricultural and industrial sectors and ecosystem at the watershed level. CFs were applied to a case study of regional water management of industrial water withdrawals in Taiwan to show that both regional or seasonal decrease in water availability contributes to a high consumptive water stress, whereas water scarcity due to degraded water quality not meeting sector standards has little influence on increased degradative water stress. Degradative water stress was observed more in the agricultural sector than in the industrial sector, which implies that the agriculture sector may have water quality concerns. Reducing water intensity and alleviating regional scale water stresses of watersheds are suggested as approaches to decrease the impact of both consumptive and degradative water use. The results from this study may enable a more detailed sector-wise analysis of water stress and influence water resource management policies. PMID- 28711009 TI - Comprehensive gene and microRNA expression profiling on cardiovascular system in zebrafish co-exposured of SiNPs and MeHg. AB - Air pollution has been shown to increase cardiovascular diseases. However, little attention has been paid to the combined effects of PM and air pollutants on the cardiovascular system. To explore this, a high-throughput sequencing technology was used to determine combined effects of silica nanoparticles (SiNPs) and MeHg in zebrafish. Our study demonstrated that SiNPs and MeHg co-exposure could cause significant changes in mRNA and miRNA expression patterns in zebrafish. The differentially expressed (DE) genes in profiles 17 and 26 of STC analysis suggest that SiNPs and MeHg co-exposure had more proinflammatory and cardiovascular toxicity in zebrafish than single exposure. Major gene functions associated with cardiovascular system in the co-exposed zebrafish were discerned from the dynamic gene-network, including stxbp1a, celf4, ahr1b and bai2. In addition, the prominently expressed pathway of cardiac muscle contraction was targeted by 3 DE miRNAs identified by the miRNA-pathway-network (dre-miR-7147, dre-miR-26a and dre miR-375), which included 23 DE genes. This study presents a global view of the combined SiNPs and MeHg toxicity on the dynamic expression of both mRNAs and miRNAs in zebrafish, and could serve as fundamental research clues for future studies, especially on cardiovascular system toxicity. PMID- 28711010 TI - The paralytic shellfish toxin, saxitoxin, enters the cytoplasm and induces apoptosis of oyster immune cells through a caspase-dependent pathway. AB - Exposure of the toxin-producing dinoflagellate Alexandrium catenella (A. catenella) was previously demonstrated to cause apoptosis of hemocytes in the oyster species Crassostrea gigas. In this work, a coumarin-labeled saxitoxin appeared to spread throughout the cytoplasm of the hemocytes. PSTs, including saxitoxin, were also shown to be directly responsible for inducing apoptosis in hemocytes, a process dependent on caspase activation and independent of reactive oxygen species (ROS) production. A series of in vitro labelling and microscopy experiments revealed that STX and analogs there of induced nuclear condensation, phosphatidylserine exposure, membrane permeability, and DNA fragmentation of hemocytes. Unlike in vertebrates, gonyautoxin-5 (GTX5), which is present in high concentrations in A. catenella, was found to be more toxic than saxitoxin (STX) to oyster immune cells. Altogether, results show that PSTs produced by toxic dinoflagellates enter the cytoplasm and induce apoptosis of oyster immune cells through a caspase-dependent pathway. Because of the central role of hemocytes in mollusc immune defense, PST-induced death of hemocytes could negatively affect resistance of bivalve molluscs to microbial infection. PMID- 28711011 TI - An overview of the challenges facing death investigation systems in certain resource limited countries. AB - A properly operated death investigation system (DIS) serves multiple stakeholders. Law enforcement, public health departments and members of the public, benefit in various ways from the information that it provides. This information must be collected systematically and efficiently. The system must also be flexible enough to respond to pressures on its resources such as occurs during mass disasters. These obligations on a DIS require an investment of public money. However even in affluent Western countries the recent world economic crisis has led to a cut in spending on public services that affect both the healthcare system and services associated with death investigation. Although pathologists and other stake holders (judiciary, police, families) would like to see death investigations conducted to international standards, the fact is that policy makers in resource limited countries face additional population health and sociopolitical pressures which generally result in very little funding for the service. The purpose of this paper is to review some of the challenges that impede the proper functioning of a death investigation system in resource limited countries in Sub-Saharan Africa and the Caribbean. Possible solutions are discussed. PMID- 28711012 TI - Osteopontin in hepatocellular carcinoma: A possible biomarker for diagnosis and follow-up. AB - Recently osteopontin (OPN), a protein of the extracellular matrix, has generated in hepatocellular carcinoma (HCC) a significant interest as a prognostic factor. Aim of this study was to confirm, in liver tissues of subjects with HCV-positive HCC undergoing liver transplantation (RL, n=10) and of donors (DL, n=14), the increase of OPN plasma and tissue concentration, the OPN splicing isoforms expression profiling together with those of thrombin, and to evaluate a possible association between OPN measurements. Their association with Notch-1, IV-Collagen 7s domain, IL-6 and TNF-alpha were also evaluated. Real-Time PCR experiments and immunometric assay were performed. mRNA expression resulted higher in RL than in DL for all analyzed genes and several correlations were found between them. The more relevant association were between OPN-a and OPN-b (p<0.0001), between thrombin and OPN-a (p=0.007), between 7s-collagen and OPN isoforms (p<0.05) and between Notch-1 with OPN-c (p=0.004). Both OPN plasma and liver tissue extract concentrations were assessed confirming the trend observed at the mRNA level. An important association was found between OPN plasma and protein (p<0.0001, r=0.96) even splitting patients in DL (p<0.0001, r=0.93) and RL (p<0.0001, r=0.96). A reduction of OPN plasma levels was found at 6months after transplantation. Considering MELD score as liver disease severity, the mRNA expression of our markers as well as of OPN plasma and tissue concentrations resulted increased as a function of clinical severity. Our results might be considered a useful starting point to validate OPN as a prognostic and diagnostic marker of HCC. PMID- 28711014 TI - Study of the interaction of GB virus C/Hepatitis G virus fusion peptides belonging to the E2 protein with phospholipid Langmuir monolayers. AB - In order to determine the ability of 1,2-dipalmitoyl phosphatidylcholine (DPPC) and 1,2-dioleoyl phosphatidylglycerol (DOPG) to host peptide sequences belonging to the E2 protein of GBV virus C/Hepatitis G virus, the behaviour of Langmuir monolayers formed by these phospholipids and E2 (12-26), E2 (354-363) and E2 (chimeric) peptide sequences was analysed from data of surface pressure (pi) versus area per molecule (A) isotherms, compression modulus (Cs-1), excess Gibbs energy of mixing (DeltaGexc) and total Gibbs energy of mixing (DeltaGmix). Three different behaviours were observed. Mixed films of E2 (12-26) with DPPC or DOPC showed negative values for the excess thermodynamic functions, and thus attractive interactions between mixed films components are greater than in ideal films. Mixtures of E2 (354-363) with DPPC or DOPG, exhibited positive values of excess functions, evidencing weaker interactions in the mixed films in relation to those of pure components. Finally, positive and negative excess functions were observed in E2 (chimeric)/DPPC or DOPG mixed films, depending on their composition. In short, the interaction between the phospholipids used in this work as models of cell membranes and E2 peptides varies with the type of phospholipid and the nature of the peptide (size, bulky, hydrophobicity and electric charge). PMID- 28711013 TI - Seeing the unseen: Imaging rotation in cells with designer anisotropic particles. AB - Cellular functions are enabled by cascades of transient biological events. Imaging and tracking the dynamics of these events have proven to be a powerful means of understanding the principles of cellular processes. These studies have typically focused on translational dynamics. By contrast, investigations of rotational dynamics have been scarce, despite emerging evidence that rotational dynamics are an inherent feature of many cellular processes and may also provide valuable clues to understanding those cell functions. Such studies have been impeded by the limited availability of suitable rotational imaging probes. This has recently changed thanks to the advances in the development of anisotropic particles for rotational imaging. In this review, we will summarize current techniques for imaging rotation using particle probes that are anisotropic in shape or optical properties. We will highlight two studies that demonstrate how these techniques can be applied to explore important facets of cellular functions. PMID- 28711015 TI - Hydrophilic surface modification of poly(methyl methacrylate)-based ocular prostheses using poly(ethylene glycol) grafting. AB - Ocular prostheses are custom-made polymeric inserts that can be placed in anophthalmic sockets for cosmetic rehabilitation. Prosthetic eye wearers have reduced tear amount, and they often experience dry eye symptoms including dryness, irritation, discomfort, and discharge. Most modern ocular prostheses are made of poly(methyl methacrylate) (PMMA), which is highly hydrophobic. Previous research has shown that improving the wettability of contact lens materials decreases its wearers discomfort by increasing lubrication. Therefore, hydrophilic modification of PMMA-based ocular prostheses might also improve patient discomfort by improving lubrication. We modified the surfaces of PMMA based ocular prostheses using poly(ethylene glycol) (PEG), which is hydrophilic. To do this, we used two strategies. One was a "grafting from" method, whereby PEG was polymerized from the PMMA surface. The other was a "grafting to" method, which involved PEG being covalently bonded to an amine-functionalized PMMA surface. Assessments involving the water contact angle, ellipsometry, and X-ray photoelectron spectroscopy indicated that PEG was successfully introduced to the PMMA surfaces using both strategies. Scanning electron microscopy and atomic force microscopy images revealed that neither strategy caused clinically significant alterations in the PMMA surface morphology. In vitro bacterial adhesion assessments showed that the hydrophilic modifications effectively reduced bacterial adhesion without inducing cytotoxicity. These results imply that hydrophilic surface modifications of conventional ocular prostheses may decrease patient discomfort and ocular prosthesis-related infections. PMID- 28711016 TI - Therapeutic supermolecular micelles of vitamin E succinate-grafted epsilon polylysine as potential carriers for curcumin: Enhancing tumour penetration and improving therapeutic effect on glioma. AB - Severe toxicity and poor tumour penetration are two intrinsic limited factors to hinder the broad clinical application for most of first-line chemotherapeutics. In this study, a novel vitamin E succinate-grafted epsilon-polylysine (VES-g-PLL) polymer was synthesized by using epsilon-polylysine as backbone. By adjusting VES graft ratio, VES-g-PLL (50) with a theoretic VES graft ratio of 50% could self assemble into a supermolecular micelle with a hydrodynamic diameter (Dh) of ca.20nm, and Zeta potential of 19.6mV. VES-g-PLL micelles themselves displayed a strong anti-tumour effect on glioma. The poorly water-soluble curcumin was effectively encapsulated in VES-g-PLL micelles with the drug loading amount and entrapment efficiency reaching 4.32% and 82.27%, respectively. In a physiologic medium, curcumin-loaded VES-g-PLL micelles (Cur-Micelles) not only remained stable without obvious drug leakage but also sustained the release of its encapsulated curcumin for a long time. Because of the ultra-small size and positively-charged surface, Cur-Micelles penetrated the deeper tumour zone than free curcumin, resulting in a significant inhibition of tumour spheroids growth. Moreover, in vivo strong antitumor effect of Cur-Micelles was also exhibited at assistance of ultrasound-targeted microbubble destruction and the real-time MRI imaging demonstrated a nearly complete suppression of glioma after 28days of treatment. TUNEL staining showed that the therapeutic mechanism of Cur-Micelles was relevant to the apoptosis of tumour cells. Finally, in vivo nontoxicity of Cur-Micelles against normal organs including heart, liver, spleen, lung and kidney tissues was also demonstrated by the HE staining. In conclusion, VES-g-PLL micelles may serve as a potential carrier for curcumin to enhance tumour penetration and improve therapeutic effect on glioma. PMID- 28711017 TI - Alginate/Gelatin scaffolds incorporated with Silibinin-loaded Chitosan nanoparticles for bone formation in vitro. AB - Silibinin is a plant derived flavonolignan known for its multiple biological properties, but its role in the promotion of bone formation has not yet been well studied. Moreover, the delivery of Silibinin is hindered by its complex hydrophobic nature, which limits its bioavailability. Hence, in this study, we fabricated a drug delivery system using chitosan nanoparticles loaded with Silibinin at different concentrations (20MUM, 50MUM, and 100MUM). They were then incorporated into scaffolds containing Alginate and Gelatin (Alg/Gel) for the sustained and prolonged release of Silibinin. The Silibinin-loaded chitosan nanoparticles (SCN) were prepared using the ionic gelation technique, and the scaffolds (Alg/Gel-SCN) were synthesized by the conventional method of freeze drying. The scaffolds were subjected to physicochemical and material characterization studies. The addition of SCN did not affect the porosity of the scaffolds, yet increased the protein adsorption, degradation rates, and bio mineralization. These scaffolds were biocompatible with mouse mesenchymal stem cells. The scaffolds loaded with 50MUM Silibinin promoted osteoblast differentiation, which was determined at cellular and molecular levels. Recent studies indicated the role of microRNAs (miRNAs) in osteogenesis and we found that the Silibinin released from scaffolds regulated miRNAs that control the bone morphogenetic protein pathway. Hence, our results suggest the potential for sustained and prolonged release of Silibinin to promote bone formation and, thus, these Alg/Gel-SCN scaffolds may be candidates for bone tissue engineering applications. PMID- 28711018 TI - Molecular detection of Toxoplasma gondii infection in slaughtered ruminants (sheep, goats and cattle) in Northwest Tunisia. AB - The present study aimed to estimate the molecular prevalence of T. gondii infection in meat from slaughtered sheep, goats and cattle in Northwest Tunisia (Beja district). PCRs were performed on genomic DNA extracted from 420 meat samples (150 ewes, 120 goats and 150 cows). The overall molecular prevalence of T. gondii in sheep, goats and cattle were 33.3 (50/150), 32.5 (39/120) and 19.3% (29/150), respectively. Toxoplasma gondii molecular prevalences in the three meat ruminant species were significantly higher in adults compared to young animals (p<0.001). The infection prevalence differed significantly within localities in sheep (p<0.001), goats (p<0.001) and cattle (p=0.019). These results provide important information about exposure of humans to T. gondii through the consumption of raw or undercooked ruminants' meat. Extension programmes should be implemented to decrease the risk of infection related to sheep, goats and cattle meat manipulation and raw or undercooked meat consumption. PMID- 28711019 TI - Photo-catalytic, anti-bacterial, and anti-cancer properties of phyto-mediated synthesis of silver nanoparticles from Artemisia tournefortiana Rchb extract. AB - Metal nanoparticles have largely been investigated due to their potential medicinal activities. This study demonstrates the biological properties of green synthesized silver nanoparticles (AgNPs) by using Artemisia tournefortiana Rchb ethanol extract. Instrumentations such as ultraviolet-visible spectra analysis, high-resolution transmission electron microscopy, scanning electron microscopy, energy-dispersive X-ray analysis, X-ray diffraction, and Fourier transform infrared spectroscopy were used to reveal the synthesized AgNPs. Microscopic results showed that the particles were mostly spherical in shape, having an average diameter of 22.89+/-14.82nm. The antibacterial activity of the phyto fabricated AgNPs was investigated by the determination of minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC). The in vitro cytotoxicity effect was investigated against normal human embryonic kidney (HEK293) cells and human colon adenocarcinoma cancer (HT29) cells. The apoptotic cells were identified by annexin V/PI FITC staining, and morphological assessment. The expressions of Bax and Bcl2 were evaluated by quantitative real time PCR method. The phyto-synthesized AgNPs have shown increased cell apoptosis and demonstrated dose-dependent cytotoxicity in HT29 cancer cells. Moreover, the photocatalytic activity of the phyto-synthesized AgNPs was evaluated by degradation of Coomassie Brilliant Blue G-250 under UV light exposure and these fabricated Ag nanoparticles demonstrated efficacy in degrading the dye within 60min. Overall, the present results highlighted the antibacterial and anticancer properties of fabricated AgNPs, suggesting that phyto-synthesized silver nanoparticles could possess potent anti-pathogenic bacteria and anti-colon cancer activities. PMID- 28711020 TI - Synthesis, structures, nuclease activity, cytotoxicity, DFT and molecular docking studies of two nitrato bridged homodinuclear (Cu-Cu, Zn-Zn) complexes containing 2,2'-bipyridine and a chalcone derivative. AB - Nitrato briged dinuclear complexes of type [Cu2(L)2(bpy)2(NO3)](NO3).4H2O, 1 and [Zn2(L)2(bpy)2(NO3)](NO3).4H2O, 2 (L=deprotonated form of free ligand LH, [1-(2 hydroxyphenyl)-3-(9-anthracenyl) propenone; bpy=2,2'bipyridine] are synthesized and characterized using a battery of physicochemical techniques and X-ray crystallography. A distorted square pyramidal geometry is assigned to them with N2O3 coordination core around the metal ion. The co-ligand L binds the metal ions through its O,O' atoms in anti-syn mode. The metal centers in complexes 1 and 2 are separated via bridging nitrato group at a distance of 6.073A and 5.635A respectively. Their structures and absorption spectra are supported by the computational studies using density functional theory (DFT) and TD-DFT. Both complexes exhibit nuclease activity and cleave supercoiled (form I) DNA. The complex 1 preferentially binds major groove of DNA and follows an oxidative pathway whereas complex 2 binds with minor groove of DNA via hydrolytic pathway. Both complexes inhibit topoisomerase I relaxation activity with IC50 values of 7 and 35MUM. Molecular docking studies support the groove binding and topoisomerase I binding of the complexes. The complex 1 showed a significant cytotoxicity against HeLa cell lines (a cervical cancer cell lines) in vitro with IC50 value calculated as 2.9+/-0.021MUM as compared to 28.2+/-0. 044MUMU for complex 2. Complex 2 induces the cell apoptosis at a later-stage as compared to complex 1. The cell apoptosis and topoisomerase inhibition by complexes enable them to be potential candidates as future anticancer drugs. PMID- 28711021 TI - Sensitizing effects of an organovanadium compound during adjuvant therapy with cyclophosphamide in a murine tumor model. AB - Various epidemiological and preclinical studies have already established the cancer chemopreventive potential of vanadium. In addition, recent studies have also indicated the abilities of vanadium-based compounds to induce cell death selectively towards malignant cells. Therefore, the objective of the present investigation is to improve the therapeutic efficacy and toxicity profile of an alkylating agent, cyclophosphamide, by the concurrent use of an organovanadium compound, oxovanadium(IV)-l-cysteine methyl ester complex (VC-IV). In this study, VC-IV (1mg/kg b.w., p.o.) was administered alone as well as in combination with cyclophosphamide (25mg/kg b.w., i.p.) in concomitant and pretreatment schedules. The results showed that VC-IV in combination with cyclophosphamide resulted in an improved therapeutic efficacy as evidenced by reduction of tumor growth and prolongation of life span. The observed potentiation was mediated through generation of ROS in tumor cells, which ultimately led to significant DNA damage, and apoptosis in tumor cells. Further studies revealed that VC-IV sensitized tumor cells to cyclophosphamide therapy by down-regulating the anti-apoptotic protein Bcl-2 and by up-regulating molecules like p53, Bax, cytochrome c, caspases, which led to PARP cleavage and apoptosis. Significant inhibition of angiogenesis along with reduction in the levels of VEGF-A and MMP-9 in the tumor bed by VC-IV further contributed to the sensitization accomplished by VC-IV. Moreover, VC-IV ameliorated cyclophosphamide-induced hematopoietic, hepatic and genetic damages by modulating the antioxidant status in normal organs. Thus, the present study clearly demonstrated the sensitizing and protective efficacy of VC IV and indicates it may serve as a promising adjuvant in cancer chemotherapy. PMID- 28711022 TI - Pre-clinical efficacy assessment of Malva sylvestris on chronic skin inflammation. AB - In the search for improved quality of life, the treatment of skin diseases like psoriasis (hyperproliferative disease) is valid, since it causes huge social discomfort to the patient. In this context, earlier studies showed that Malva sylvestris L. has anti-inflammatory activity demonstrated by acute animal models of skin inflammation, becoming a promising target for further studies. The present investigation aimed to verify the effect of hydroalcoholic extract of M. sylvestris (HEMS) on the chronic inflammatory and hyperproliferative response caused by multiple applications of 12-O-tetradecanoylphorbol-13-acetate (TPA) on mouse ears. Topical application of HEMS reduced oedema, leukocyte migration (mono and polymorphonuclear cells) and keratinocyte hyperproliferation, confirmed by histology and proliferating cell nuclear antigen (PCNA) immunostaining. It was found that the anti-inflammatory effects of the extract did not involve the glucocorticoid system, and its incubation with HaCaT keratinocytes caused low toxicity and reduced cell proliferation by apoptosis. Thus, HEMS proved to be effective as an anti-psoriatic therapy, with the ability to prevent keratinocyte hyperproliferation and with low toxicity by topical application. PMID- 28711023 TI - Gingival crevicular fluid and plasma oxidative stress markers and TGM-2 levels in chronic periodontitis. AB - OBJECTIVE: This study was aimed to evaluate the gingival crevicular fluid (GCF) and plasma transglutaminase-2 (TGM-2), total antioxidant capacity (TAC), total oxidant status (TOS), ferric reducing antioxidant power (FRAP) and thiobarbituric acid reactive substances (TBARS) in patients with chronic periodontal disease. MATERIALS AND METHODS: Twenty patients with chronic periodontitis (CP), 20 patients with gingivitis and 20 healthy subjects were enrolled in the study. Clinical periodontal parameters including probing depth, clinical attachment level, plaque index and papillary bleeding index were recorded. GCF and plasma levels of TGM-2, TAC, TOS, TBARS and FRAP were analyzed. RESULTS: GCF TGM-2 was significantly lower in CP group than in gingivitis patients (P=0.006). GCF FRAP in CP and gingivitis groups was significantly lower than in healthy subjects (P<0.001). Plasma FRAP level was lower in gingivitis group when compared to healthy subjects (P=0.003). There was no significant difference in GCF and plasma TAC, TOS, TBARS and plasma TGM-2 levels among the study groups (P>0.05). GCF TGM 2 level was positively correlated with GCF TAC and negatively correlated with CAL. CONCLUSIONS: Decreased FRAP in GCF and plasma indicating lower antioxidant status of CP patients might suggest the role of oxidative stress in periodontitis. GCF TGM-2 data might suggest that TGM2 is associated with stabilization of the extracellular matrix and wound healing in periodontium rather than gingival inflammation. PMID- 28711024 TI - New Ti-Ta-Zr-Nb alloys with ultrahigh strength for potential orthopedic implant applications. AB - In this study, a new series of Ti-Ta-Zr-Nb alloys (Ti-38.3Ta-22Zr-8.1Nb, Ti 38.9Ta-25Zr-5Nb, Ti-39.5Ta-28Zr-2.5Nb, designated TTZN-1, TTZN-2, TTZN-3, respectively) with high elastic strain and high mechanical strength have been developed as alternatives to conventional orthopedic implant materials. The TTZN alloys have been designed using the electronic parameters of the alloying elements, combined with the approaches of the electron-to-atom ratio (e/a) and molybdenum equivalence (Moeq). X-ray diffraction analysis has revealed that all the TTZN alloys are comprised of a single beta phase, however, transmission electron microscopy observations revealed that omega and beta phases co-existed in the microstructure. The compression strains of the TTZN alloys range from 22% to 36% and the compression strength from 1787 to 1807MPa. The tensile Young's modulus, elastic strain and yield strength are 73.12 +/- 4.43, 74.98 +/- 2.19 and 76.62 +/- 2.38 (GPa); 1.57 +/- 0.27, 1.25 +/- 0.27 and 1.29 +/- 0.16 (%); and 1107.42 +/- 144.68, 932.11 +/- 195.22 and 953.58 +/- 120.76MPa for TTZN-1, TTZN-2 and TTZN-3, respectively. Further, all the TTZN alloys exhibit excellent cytocompatibility as their cell adhesion density is higher than that of CP-Ti. This study demonstrates that these TTZN alloys can be anticipated to be promising candidate for orthopedic implant materials due to their high mechanical strength and high elastic strain. PMID- 28711025 TI - Three-dimensional mechano-electrochemical model for smooth muscle contraction of the urinary bladder. AB - The urinary bladder is a central organ of vertebrates and imposes, based on its extreme deformation (volume changes up to several 100%), special requirements on the overall bladder tissue. However, studies focusing on three-dimensional modelling of bladder deformation and bladder function during micturition are rare. Based on three fields, namely, the membrane potential, calcium concentration, and placement, a mechano-electrochemical-coupled, three dimensional model describing the contractile behaviour of urinary bladder smooth muscle is presented using a strain energy function. The strain energy functions for the different layers of the bladder wall are additively decomposed into a passive part comprising elastin, the extracellular matrix (ECM), and collagen and an active electrochemical-driven part comprising the contraction of smooth muscle cells (SMC). While the two-variable FitzHugh-Nagumo-type membrane model (FitzHugh, 1961; Nagumo et al., 1962) has been used to describe the membrane potential characteristics, the four-state, cross-bridge model of Hai and Murphy (1988) is implemented into the finite element method for the quantification of the calcium phase. Appropriate model parameters were determined experimentally using 40 tissue strips isolated from porcine bladders. Characteristic orientation dependent passive and active stress-stretch relationships were identified for muscle strips, including the entire bladder wall structure and those featuring the isolated muscle layer only. Active experiments on the smooth muscle layers revealed higher stresses in the longitudinal (28.9kPa) direction than in the transversal (22.7kPa) one. Additionally, three-dimensional deformation characteristics were recorded from single muscle strips to qualitatively confirm the strip simulations. Three-dimensional simulations at the tissue strip level and the organ level were performed to analyse the interaction among the electrical action potential, calcium distribution, chemical degree of activation, and equivalent von Mises stress. PMID- 28711026 TI - Recent advancement in biosensors technology for animal and livestock health management. AB - The term biosensors encompasses devices that have the potential to quantify physiological, immunological and behavioural responses of livestock and multiple animal species. Novel biosensing methodologies offer highly specialised monitoring devices for the specific measurement of individual and multiple parameters covering an animal's physiology as well as monitoring of an animal's environment. These devices are not only highly specific and sensitive for the parameters being analysed, but they are also reliable and easy to use, and can accelerate the monitoring process. Novel biosensors in livestock management provide significant benefits and applications in disease detection and isolation, health monitoring and detection of reproductive cycles, as well as monitoring physiological wellbeing of the animal via analysis of the animal's environment. With the development of integrated systems and the Internet of Things, the continuously monitoring devices are expected to become affordable. The data generated from integrated livestock monitoring is anticipated to assist farmers and the agricultural industry to improve animal productivity in the future. The data is expected to reduce the impact of the livestock industry on the environment, while at the same time driving the new wave towards the improvements of viable farming techniques. This review focusses on the emerging technological advancements in monitoring of livestock health for detailed, precise information on productivity, as well as physiology and well-being. Biosensors will contribute to the 4th revolution in agriculture by incorporating innovative technologies into cost-effective diagnostic methods that can mitigate the potentially catastrophic effects of infectious outbreaks in farmed animals. PMID- 28711027 TI - High-throughput and label-free parasitemia quantification and stage differentiation for malaria-infected red blood cells. AB - This work reports a high throughput and label-free microfluidic cell deformability sensor for quantitative parasitemia measurement and stage determination for Plasmodium falciparum-infected red blood cells (Pf-iRBCs). The sensor relies on differentiating the RBC deformability (a mechanical biomarker) that is highly correlated with the infection status. The cell deformability is measured by evaluating the transit time when each individual RBC squeezes through a microscale constriction (cross-section ~5um*5um). More than 30,000 RBCs can be analyzed for parasitemia quantification in under 1min with a throughput ~500 cells/s. Moreover, the device can also differentiate various malaria stages (ring, trophozoite, and schizont stage) due to their varied deformability. Using Pf-iRBCs at 0.1% parasitemia as a testing sample, the microfluidic deformability sensor achieved an excellent sensitivity (94.29%), specificity (86.67%) and accuracy (92.00%) in a blind test, comparable to the gold standard of the blood smear microscopy. As a supplement technology to the microscopy and flow cytometry, the microfluidic deformability sensor would possibly allow for label free, rapid and cost-effective parasitemia quantification and stage determination for malaria in remote regions. PMID- 28711028 TI - Fluorescence-based CdTe nanosensor for sensitive detection of cytochrome C. AB - Cytochrome c (Cyt c) is commonly used as intrinsic biomarker for several characteristics of the cell such as respiration, energy level and apoptosis. In the present study a simple colorimetric sensor should be developed and tested for the real-time detection of Cyt c in living cells. We synthesized cadmium telluride quantum dots (CdTe QDs) capped with thioglycolic acid (TGA) as a fluorometric Cyt c nanosensor. The synthesized TGA/CdTe QDs nanosensor was characterized by Fourier transform infrared spectroscopy, transmission electron microscopy, and absorption as well as fluorescence spectrophotometry. We investigated the developed TGA/CdTe QDs sensor with regard to its applicability in the fluorometric detection of Cyt c. Results showed that the TGA/CdTe QDs could be used as a sensitive fluorescence probe for the quantification of different concentrations of Cyt c ranging from 0.5 - 2.5MUM. Increased binding of QDs to Cyt c results in decreasing fluorescence. The fluorescence of the QDs is inversely correlated to the Cyt c concentration. Based on these data, a standard curve up to 2.5MUM Cyt c was established. Moreover, the developed nanosensor was applied in different concentrations on primary human dermal fibroblasts. Results showed that TGA/CdTe QDs were taken up by cells and could be visualized by fluorescence microscopy. Quantification of Cyt c within living cells via QDs is, however, influenced by various factors such as cell damage, QD aggregation or the level of reactive oxygen species, which have to be taken into account. PMID- 28711029 TI - An oxygen-independent and membrane-less glucose biobattery/supercapacitor hybrid device. AB - Enzymatic biofuel cells can generate electricity directly from the chemical energy of biofuels in physiological fluids, but their power density is significantly limited by the performance of the cathode which is based on oxygen reduction for in vivo applications. An oxygen-independent and membrane-less glucose biobattery was prepared that consists of a dealloyed nanoporous gold (NPG) supported glucose dehydrogenase (GDH) bioanode, immobilised with the assistance of conductive polymer/Os redox polymer composites, and a solid-state NPG/MnO2 cathode. In a solution containing 10mM glucose, a maximum power density of 2.3uWcm-2 at 0.21V and an open circuit voltage (OCV) of 0.49V were registered as a biobattery. The potential of the discharged MnO2 could be recovered, enabling a proof-of-concept biobattery/supercapacitor hybrid device. The resulting device exhibited a stable performance for 50 cycles of self-recovery and galvanostatic discharge as a supercapacitor at 0.1mAcm-2 over a period of 25h. The device could be discharged at current densities up to 2mAcm-2 supplying a maximum instantaneous power density of 676 MUW cm-2, which is 294 times higher than that from the biobattery alone. A mechanism for the recovery of the potential of the cathode, analogous to that of RuO2 (Electrochim. Acta 42(23), 3541-3552) is described. PMID- 28711030 TI - Carvedilol can attenuate histamine-induced paw edema and formaldehyde-induced arthritis in rats without risk of gastric irritation. AB - BACKGROUND AND AIM: Rheumatoid arthritis treatment aims to control joint damage and any associated complications such as cardiovascular disease. Most anti inflammatory drugs have a high tendency to cause gastro-intestinal irritation. The present study is designed to investigate the anti-inflammatory effect of carvedilol and to study its effect on gastric mucosa. EXPERIMENTAL APPROACH: Lornoxicam (1.3mg/kg) or carvedilol (10mg/kg) was administrated orally 1h before histamine injection into animals of a histamine-induced paw edema model and orally daily for 11days into animals of a formaldehyde-induced arthritis model. Tumor necrosis factor-alpha and prostaglandin E2 were measured in animals of the formaldehyde-induced arthritis model. The effect of lornoxicam and carvedilol on gastric mucosa was assessed in normal rats and after induction of cold stress ulcer. RESULTS: Carvedilol succeeded in reducing hind paw edema in both histamine induced paw edema and formaldehyde-induced arthritis and in reducing the elevated level of tumor necrosis factor-alpha and prostaglandin E2 nearly with near equal efficacy compared with lornoxicam. Carvedilol did not show any ulcerative effect on the gastric mucosa of normal rats, and its use was associated with an improvement of both the gross and histopathological pictures of gastric ulcers in animals of the cold stress ulcer model compared with lornoxicam treated rats. CONCLUSION: The current findings support the use of carvedilol both in the management of inflammation as well as the prevention of cardiovascular complications in rheumatoid arthritis patients. The use of carvedilol was not associated with any gastro-intestinal tract irritation. PMID- 28711031 TI - The sinomenine enteric-coated microspheres suppressed the TLR/NF-kappaB signaling in DSS-induced experimental colitis. AB - Sinomenine is a pure alkaloid with immunosuppressive effects that is extracted from the Chinese medicinal plant Sinomenium acutum. We studied the therapeutic effects of sinomenine on inflammatory bowel disease. In this study, we randomly divided mice into the following ten groups: Control group; DSS-induced colitis group; Salicylazosulfapyridine (SASP)-treated group; Chitosan-treated group; low , medium-, and high-dose sinomenine-treated and sinomenine enteric-coated microspheres-treated groups. We recorded changes in colon length, disease activity index (DAI), and colon pathology, measured TLR4, MyD88, SIGIRR, NF kappaB p65 protein levels and inflammatory serum cytokine levels. Except for the Control group, the weight of mice in each group decreased, the DAI of the DSS induced colitis group was significantly higher than the other groups, and the DAIs of the sinomenine- and sinomenine enteric-coated microspheres-treated groups were significantly lower than that of the SASP-treated group. TLR4, MyD88, NF kappaB p65 and proinflammatory cytokine expressions decreased dose dependently in the sinomenine and sinomenine enteric-coated microspheres-treated groups and were generally lower in the sinomenine enteric-coated microspheres groups. However, SIGIRR and anti-inflammatory IL-10 expressions exhibited the opposite pattern. Based on the superior therapeutic effect, sinomenine enteric-coated microspheres might regulate TLR/NF-kappaB signaling and would be beneficial for an effective and safe therapy of inflammatory bowel disease. PMID- 28711032 TI - Influence of the number and interval of treatment cycles on cytokine-induced killer cells and their adjuvant therapeutic effects in advanced non-small-cell lung cancer (NSCLC). AB - OBJECTIVE: Cytokine-induced killer (CIK) cells have important therapeutic effects in adoptive cell transfer (ACT) for the treatment of various malignancies. In this study, we focused on in vitro expansion of CIK cells and their clinical efficacy in combination with chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). METHODS: A total of 64 patients with NSCLC (enrolled from 2011 to 2012), including 32 patients who received chemotherapy alone or with sequential radiotherapy (conventional treatment, control group) and 32 patients who received conventional treatment and sequential CIK infusion (study group), were retrospectively analyzed. The time to progression (TTP), overall survival (OS) and adverse effects were analyzed and the phenotype of lymphocytes in CIK population was also determined by flow cytometry. RESULTS: After in vitro expansion, the average percentage of CIK cells was 26.35%. During the 54-month follow up, the median OS and TTP were significantly longer in the study group than in the control group (P=0.0189 and P=0.0129, respectively). The median OS of the ACT>=4cycles subgroup was significantly longer than that of the ACT<4cycles subgroup (P=0.0316). The percentage of CIK cells in patients who received >=4cycles of ACT was higher than that in patients treated with <4cycles of ACT (P=0.0376). Notably, CIK cells were difficult to expand in vitro in some patients after the first ACT cycle but became much easier as the treatment cycles increased monthly. Longer treatment interval negatively impacted the expansion of CIK cells. CONCLUSIONS: Systematic immune levels can be increasingly boosted by reinfusion of ACT. Conventional treatment plus CIK cells is an effective therapeutic strategy to prevent progression and prolong survival of patients with advanced NSCLC. PMID- 28711033 TI - Non-contact method for analysis of cavitating flows. AB - This paper presents a novel non-contact method for simultaneous analysis of pressure and velocity conditions in cavitating flows. The method (implemented in our software ADMflow) is based on high-speed camera flow visualization and was evaluated in an experiment with ultrasonically induced acoustic cavitation of different intensities. Attached cavitation with clearly visible cavitation structures occurred on the tip of an ultrasonic probe immersed in distilled water. Using the high-speed imaging data, pressure fluctuations were calculated by a computer-aided algorithm based on the Brennen's theory of cavitation cloud kinematics and a modified version of the Rayleigh-Plesset equation. Reference measurements of pressure pulsations were conducted by a hydrophone installed at the bottom of the liquid container. The analysis of cavitation structure dynamics was complemented by calculation of velocity fields from the imaging data, the algorithm for which is based on the advection-diffusion equation. Calculated pressure fluctuations were analyzed in the spatial, temporal and spectral domain. Presented results indicate a strong correlation between the fields of velocity and pressure fluctuations during the growth and collapse of cavitation structures. A comparison of time series and power spectra demonstrates that our cavitation analysis method is in a reasonably good agreement with results of the reference measurement methods and can therefore be used for non-contact analysis of pressure and velocity conditions in cavitating flows. PMID- 28711034 TI - Pressure in an exactly solvable model of active fluid. AB - We consider the pressure in the steady-state regime of three stochastic models characterized by self-propulsion and persistent motion and widely employed to describe the behavior of active particles, namely, the Active Brownian particle (ABP) model, the Gaussian colored noise (GCN) model, and the unified colored noise approximation (UCNA) model. Whereas in the limit of short but finite persistence time, the pressure in the UCNA model can be obtained by different methods which have an analog in equilibrium systems, in the remaining two models only the virial route is, in general, possible. According to this method, notwithstanding each model obeys its own specific microscopic law of evolution, the pressure displays a certain universal behavior. For generic interparticle and confining potentials, we derive a formula which establishes a correspondence between the GCN and the UCNA pressures. In order to provide explicit formulas and examples, we specialize the discussion to the case of an assembly of elastic dumbbells confined to a parabolic well. By employing the UCNA we find that, for this model, the pressure determined by the thermodynamic method coincides with the pressures obtained by the virial and mechanical methods. The three methods when applied to the GCN give a pressure identical to that obtained via the UCNA. Finally, we find that the ABP virial pressure exactly agrees with the UCNA and GCN results. PMID- 28711035 TI - Coupled cluster valence bond theory for open-shell systems with application to very long range strong correlation in a polycarbene dimer. AB - The Coupled Cluster Valence Bond (CCVB) method, previously presented for closed shell (CS) systems, is extended to open-shell (OS) systems. The theoretical development is based on embedding the basic OS CCVB wavefunction in a fictitious singlet super-system. This approach reveals that the OS CCVB amplitude equations are quite similar to those of CS CCVB, and thus that OS CCVB requires the same level of computational effort as CS CCVB, which is an inexpensive method. We present qualitatively correct CCVB potential energy curves for all low-lying spin states of P2 and Mn2+. CCVB is successfully applied to the low-lying spin states of some model linear polycarbenes, systems that appear to be a hindrance to standard density functionals. We examine an octa-carbene dimer in a side-by-side orientation, which, in the monomer dissociation limit, exhibits maximal strong correlation over the length of the polycarbene. PMID- 28711036 TI - The ePig3 state of C2: A pathway to dissociation. AB - The lowest 13 vibrational levels, v = 0-12, of the ePig3 state of the C2 molecule have been measured by laser-induced fluorescence of new bands of the Fox-Herzberg system. The newly observed levels, v = 5-12, which span the ePig3 electronic state up to and beyond the first dissociation threshold of C2, were analyzed to afford highly accurate molecular constants, including band origins, and rotational and spin-orbit constants. The spin-orbit coupling constants of the previously published lowest five levels are revised in sign and magnitude, requiring an overhaul of previously published molecular constants. The analysis is supported by high level ab initio calculations. Lifetimes of all observed levels were recorded and found to be in excellent agreement with ab initio predicted values up to v = 11. v = 12 was found to exhibit a much reduced lifetime and fluorescence quantum yield, which is attributed to the onset of predissociation. This brackets the dissociation energy of ground state XSigmag+1 C2 between 6.1803 and 6.2553 eV, in agreement with the Active Thermochemical Tables. PMID- 28711037 TI - Assessing the ability of DFT methods to describe static electron correlation effects: CO core level binding energies as a representative case. AB - We use a total energy difference approach to explore the ability of various density functional theory based methods in accounting for the differential effect of static electron correlation on the C(1s) and O(1s) core level binding energies (BEs) of the CO molecule. In particular, we focus on the magnitude of the errors of the computed C(1s) and O(1s) BEs and on their relative difference as compared to experiment and to previous results from explicitly correlated wave functions. Results show that the different exchange-correlation functionals studied here behave rather erratically and a considerable number of them lead to large errors in the BEs and/or the BE shifts. Nevertheless, the TPSS functional, its TPSSm and RevTPSS derivations, and its corresponding hybrid counterpart, TPSSh, perform better than average and provide BEs and BE shifts in good agreement with experiment. PMID- 28711038 TI - Accurate spectroscopic characterization of the HOC(O)O radical: A route toward its experimental identification. AB - A set of accurate spectroscopic parameters for the detection of the atmospherically important HOC(O)O radical has been obtained by means of state-of the-art ab initio computations. These include advanced coupled cluster treatments, involving both standard and explicitly correlated approaches, to correctly account for basis set incompleteness and core-valence effects. Geometric parameters for the X2A' and A2A'' states and, for the ground state only, vibrationally corrected rotational constants including quartic and sextic centrifugal distortion terms are reported. The infrared spectrum of the X2A' state has been simulated in the 4000-400 cm-1 wavenumber interval with an approach based on second order vibrational perturbation theory that allows accounting for anharmonic effects in both energies and intensities. Finally, the vibronic spectrum for the A <- X transition has been calculated at three different temperatures in the 9000-3000 cm-1 energy range with a time-independent technique based on the Franck-Condon approximation. PMID- 28711039 TI - Determination of onset temperature from the entropy for fragile to strong liquids. AB - In this paper, we establish a connection between the onset temperature of glassy dynamics with the change in the entropy for a wide range of model systems. We identify the crossing temperature of pair and excess entropies as the onset temperature. Below the onset temperature, the residual multiparticle entropy, the difference between excess and pair entropies, becomes positive. The positive entropy can be viewed as equivalent to the larger phase space exploration of the system. The new method of onset temperature prediction from entropy is less ambiguous, as it does not depend on any fitting parameter like the existing methods. PMID- 28711040 TI - Dynamics and structural behavior of water in large confinement with planar amorphous walls. AB - We study the structure and dynamics of liquid water confined between planar amorphous walls using molecular dynamics (MD) simulations. We report MD results for systems of more than 23 000 SPC/E water molecules confined between two hydrophilic or hydrophobic walls, separated by distances of about 15 nm. We find that the walls induce ordering of the liquid and slow down the dynamics, affecting the properties of the confined water up to distances of about 8 nm at 275 K. We quantify this influence by computing dynamic and static penetration lengths and studying their temperature dependence. Our results indicate that in the temperature range considered, hydrophobic walls perturb static properties over larger lengths compared to hydrophilic walls. We also find opposite temperature trends in the dynamic penetration lengths, with hydrophobic walls increasing their range of influence on increasing the temperature. PMID- 28711041 TI - Spectroscopic determination of the ground-state dissociation energy and isotopic shift of NaD. AB - Stimulated emission pumping with fluorescence depletion spectroscopy is used to determine the NaD X 1Sigma+ ground-state dissociation energy and its isotopic shift. A total of 230 rovibrational levels in the range 9 <= v" <= 29 and 1 <= J" <= 11 are observed, where v" = 29 is about 50 cm-1 below the dissociation limit. Analysis of the highest five vibrational levels yields the dissociation energy De = 15 822 +/- 5 cm-1 with a vibrational quantum number at dissociation vD = 31.2 +/- 0.1. The energy difference in the well depth of this isotopologue with respect to that of NaH is deltaDe = De(NaH) - De(NaD) = -7 cm-1. A new set of Dunham coefficients is derived to fit all the observed energy levels to within the experimental uncertainty. PMID- 28711042 TI - Unveiling the nature of post-linear response Z-vector method for time-dependent density functional theory. AB - We report a theoretical study on the analysis of the relaxed one-particle difference density matrix characterizing the passage from the ground to the excited state of a molecular system, as obtained from time-dependent density functional theory. In particular, this work aims at using the physics contained in the so-called Z-vector, which differentiates between unrelaxed and relaxed difference density matrices to analyze excited states' nature. For this purpose, we introduce novel quantum-mechanical quantities, based on the detachment/attachment methodology, for analysing the Z-vector transformation for different molecules and density functional theory functionals. A derivation pathway of these novel descriptors is reported, involving a numerical integration to be performed in the Euclidean space on the density functions. This topological analysis is then applied to two sets of chromophores, and the correlation between the level of theory and the behavior of our descriptors is properly rationalized. In particular, the effect of range-separation on the relaxation amplitude is discussed. The relaxation term is finally shown to be system-specific (for a given level of theory) and independent of the number of electrons (i.e., the relaxation amplitude is not simply the result of a collective phenomenon). PMID- 28711043 TI - Exploring the driving forces behind the structural assembly of biphenylthiolates on Au(111). AB - In this contribution, we use dispersion-corrected density functional theory to study inter- and intramolecular interactions in a prototypical self-assembled monolayer (SAM) consisting of biphenylthiolates bonded to Au(111) via thiolate groups. The goal is to identify the nature of the interactions that drive the monolayer into a specific conformation. Particular focus is laid on sampling realistic structures rather than high symmetry model configurations. This is achieved by studying conceptually different local minimum structures of the SAM that are obtained via exploring the potential energy surface from systematically varied starting geometries. The six obtained packing motifs differ in the relative arrangement of the two molecules in the unit cell (co-planar versus herringbone) and in the intramolecular configuration (twisted versus planar rings). We find that van der Waals interactions within the organic adsorbate and between the adsorbate and substrate are the main reason that these molecular assemblies can form stable structures at all. The van der Waals interactions are, however, very similar for all observed motifs; by analyzing various types of interactions in the course of three notional SAM-formation steps, we find that the main driving force stabilizing the actual global minimum structure originates from electrostatic interactions between the molecules. PMID- 28711044 TI - Erratum: "Distribution of distances between DNA barcode labels in nanochannels close to the persistence length" [J. Chem. Phys. 142, 064902 (2015)]. PMID- 28711045 TI - An iterative method for hydrodynamic interactions in Brownian dynamics simulations of polymer dynamics. AB - Brownian Dynamics (BD) simulations are a standard tool for understanding the dynamics of polymers in and out of equilibrium. Quantitative comparison can be made to rheological measurements of dilute polymer solutions, as well as direct visual observations of fluorescently labeled DNA. The primary computational challenge with BD is the expensive calculation of hydrodynamic interactions (HI), which are necessary to capture physically realistic dynamics. The full HI calculation, performed via a Cholesky decomposition every time step, scales with the length of the polymer as O(N3). This limits the calculation to a few hundred simulated particles. A number of approximations in the literature can lower this scaling to O(N2 - N2.25), and explicit solvent methods scale as O(N); however both incur a significant constant per-time step computational cost. Despite this progress, there remains a need for new or alternative methods of calculating hydrodynamic interactions; large polymer chains or semidilute polymer solutions remain computationally expensive. In this paper, we introduce an alternative method for calculating approximate hydrodynamic interactions. Our method relies on an iterative scheme to establish self-consistency between a hydrodynamic matrix that is averaged over simulation and the hydrodynamic matrix used to run the simulation. Comparison to standard BD simulation and polymer theory results demonstrates that this method quantitatively captures both equilibrium and steady state dynamics after only a few iterations. The use of an averaged hydrodynamic matrix allows the computationally expensive Brownian noise calculation to be performed infrequently, so that it is no longer the bottleneck of the simulation calculations. We also investigate limitations of this conformational averaging approach in ring polymers. PMID- 28711046 TI - Comparison of simulation and experimental results for a model aqueous tert butanol solution. AB - Molecular dynamics simulations are used to investigate the behavior of aqueous tert-butanol (TBA) solutions for a range of temperatures, using the CHARMM generalized force field (CGenFF) to model TBA and the TIP4P/2005 or TIP4P-Ew water model. Simulation results for the density, isothermal compressibility, constant pressure heat capacity, and self-diffusion coefficients are in good accord with experimental measurements. Agreement with the experiment is particularly good at low TBA concentration, where experiments have revealed anomalies in a number of thermodynamic properties. Importantly, the CGenFF model does not exhibit liquid-liquid demixing at temperatures between 290 and 320 K (for systems of 32 000 molecules), in contrast with the situation for several other common TBA models [R. Gupta and G. N. Patey, J. Chem. Phys. 137, 034509 (2012)]. However, whereas real water and TBA are miscible at all temperatures where the liquid is stable, we observe some evidence of demixing at 340 K and above. To evaluate the structural properties at low concentrations, we compare with both neutron scattering and recent spectroscopic measurements. This reveals that while the CGenFF model is a definite improvement over other models that have been considered, the TBA molecules still exhibit a tendency to associate at low concentrations that is somewhat stronger than that indicated by experiments. Finally, we discuss the range and decay times of the long-range correlations, providing an indication of the system size and simulation times that are necessary in order to obtain reliable results for certain properties. PMID- 28711047 TI - Global-density fluctuations in methane clathrate hydrates in externally applied electromagnetic fields. AB - Non-equilibrium molecular-dynamics simulations of bulk methane clathrate hydrates have been conducted in a range of externally applied electromagnetic (e/m) fields. Studies into frequencies of system(or "global")-mass-density fluctuations showed that these clathrates have three major modes: the dominant one is attributable to water molecules' librations and occurs at 720 cm-1, regardless of any applied e/m fields. One of the more minor system-density fluctuations arises at 10-12 cm-1 and is caused by the propagation of local-density fluctuations; again, this is independent of e/m fields. The final density fluctuation is caused by e/m fields, and it only becomes apparent for field strengths of 1.2 V/nm or higher. The frequency of this mode is always twice the frequency of the applied e/m field. It was shown that the main qualitative features of the translational and librational densities of states (DOSs) were unaffected by the application of e/m fields; however, a slight coupling effect was observed, producing a peak in all DOSs at the frequency of the applied field. This study showed that e/m fields below a certain intensity threshold do not lead to any marked structural distortion or dissociation effect on pre-existing bulk clathrates, in which the hydrogen-bonding structure of the lattice remains intact. This is verified by system-density and configurational-energy values as well as radial distribution functions. PMID- 28711048 TI - Beyond mean-field approximations for accurate and computationally efficient models of on-lattice chemical kinetics. AB - Modeling the kinetics of surface catalyzed reactions is essential for the design of reactors and chemical processes. The majority of microkinetic models employ mean-field approximations, which lead to an approximate description of catalytic kinetics by assuming spatially uncorrelated adsorbates. On the other hand, kinetic Monte Carlo (KMC) methods provide a discrete-space continuous-time stochastic formulation that enables an accurate treatment of spatial correlations in the adlayer, but at a significant computation cost. In this work, we use the so-called cluster mean-field approach to develop higher order approximations that systematically increase the accuracy of kinetic models by treating spatial correlations at a progressively higher level of detail. We further demonstrate our approach on a reduced model for NO oxidation incorporating first nearest neighbor lateral interactions and construct a sequence of approximations of increasingly higher accuracy, which we compare with KMC and mean-field. The latter is found to perform rather poorly, overestimating the turnover frequency by several orders of magnitude for this system. On the other hand, our approximations, while more computationally intense than the traditional mean field treatment, still achieve tremendous computational savings compared to KMC simulations, thereby opening the way for employing them in multiscale modeling frameworks. PMID- 28711049 TI - Quantitative estimation of localization errors of 3d transition metal pseudopotentials in diffusion Monte Carlo. AB - The necessarily approximate evaluation of non-local pseudopotentials in diffusion Monte Carlo (DMC) introduces localization errors. We estimate these errors for two families of non-local pseudopotentials for the first-row transition metal atoms Sc-Zn using an extrapolation scheme and multideterminant wavefunctions. Sensitivities of the error in the DMC energies to the Jastrow factor are used to estimate the quality of two sets of pseudopotentials with respect to locality error reduction. The locality approximation and T-moves scheme are also compared for accuracy of total energies. After estimating the removal of the locality and T-moves errors, we present the range of fixed-node energies between a single determinant description and a full valence multideterminant complete active space expansion. The results for these pseudopotentials agree with previous findings that the locality approximation is less sensitive to changes in the Jastrow than T-moves yielding more accurate total energies, however not necessarily more accurate energy differences. For both the locality approximation and T-moves, we find decreasing Jastrow sensitivity moving left to right across the series Sc-Zn. The recently generated pseudopotentials of Krogel et al. [Phys. Rev. B 93, 075143 (2016)] reduce the magnitude of the locality error compared with the pseudopotentials of Burkatzki et al. [J. Chem. Phys. 129, 164115 (2008)] by an average estimated 40% using the locality approximation. The estimated locality error is equivalent for both sets of pseudopotentials when T-moves is used. For the Sc-Zn atomic series with these pseudopotentials, and using up to three-body Jastrow factors, our results suggest that the fixed-node error is dominant over the locality error when a single determinant is used. PMID- 28711050 TI - Distinguishing dynamical features of water inside protein hydration layer: Distribution reveals what is hidden behind the average. AB - Since the pioneering works of Pethig, Grant, and Wuthrich on a protein hydration layer, many studies have been devoted to find out if there are any "general and universal" characteristic features that can distinguish water molecules inside the protein hydration layer from bulk. Given that the surface itself varies from protein to protein, and that each surface facing the water is heterogeneous, search for universal features has been elusive. Here, we perform an atomistic molecular dynamics simulation in order to propose and demonstrate that such defining characteristics can emerge if we look not at average properties but the distribution of relaxation times. We present results of calculations of distributions of residence times and rotational relaxation times for four different protein-water systems and compare them with the same quantities in the bulk. The distributions in the hydration layer are unusually broad and log-normal in nature due to the simultaneous presence of peptide backbones that form weak hydrogen bonds, hydrophobic amino acid side chains that form no hydrogen bond, and charged polar groups that form a strong hydrogen bond with the surrounding water molecules. The broad distribution is responsible for the non-exponential dielectric response and also agrees with large specific heat of the hydration water. Our calculations reveal that while the average time constant is just about 2-3 times larger than that of bulk water, it provides a poor representation of the real behaviour. In particular, the average leads to the erroneous conclusion that water in the hydration layer is bulk-like. However, the observed and calculated lower value of static dielectric constant of hydration layer remained difficult to reconcile with the broad distribution observed in dynamical properties. We offer a plausible explanation of these unique properties. PMID- 28711051 TI - A molecular dynamics study of nuclear quantum effect on diffusivity of hydrogen molecule. AB - In this paper, the nuclear quantum effect of the hydrogen molecule on its diffusivity was analyzed using the molecular dynamics (MD) method. The centroid MD (CMD) method was applied to reproduce the time evolution of the molecules. The diffusion coefficient of hydrogen was calculated using the Green-Kubo method over a wide temperature region, and the temperature dependence of the quantum effect of the hydrogen molecule on its diffusivity was addressed. The calculated results were compared with classical MD results based on the principle of corresponding state (PCS). It was confirmed that the difference in the diffusion coefficient calculated in the CMD and classical MD methods was small, and the PCS appears to be satisfied on the temperature dependence of the diffusion coefficient, even though the quantum effect of the hydrogen molecules was taken into account. It was clarified that this result did not suggest that the quantum effect on the diffusivity of the hydrogen molecule was small but that the two changes in the intermolecular interaction of hydrogen due to the quantum effect offset each other. Moreover, it was found that this tendency was related to the temperature dependence of the ratio of the kinetic energy of the quantum fluctuational motion to the classical kinetic energy. PMID- 28711052 TI - Diffusion and reaction pathways of water near fully hydrated TiO2 surfaces from ab initio molecular dynamics. AB - Ab initio molecular dynamics simulations are reported for water-embedded TiO2 surfaces to determine the diffusive and reactive behavior at full hydration. A three-domain model is developed for six surfaces [rutile (110), (100), and (001), and anatase (101), (100), and (001)] which describes waters as "hard" (irreversibly bound to the surface), "soft" (with reduced mobility but orientation freedom near the surface), or "bulk." The model explains previous experimental data and provides a detailed picture of water diffusion near TiO2 surfaces. Water reactivity is analyzed with a graph-theoretic approach that reveals a number of reaction pathways on TiO2 which occur at full hydration, in addition to direct water splitting. Hydronium (H3O+) is identified to be a key intermediate state, which facilitates water dissociation by proton hopping between intact and dissociated waters near the surfaces. These discoveries significantly improve the understanding of nanoscale water dynamics and reactivity at TiO2 interfaces under ambient conditions. PMID- 28711053 TI - Representations in neural network based empirical potentials. AB - Many structural and mechanical properties of crystals, glasses, and biological macromolecules can be modeled from the local interactions between atoms. These interactions ultimately derive from the quantum nature of electrons, which can be prohibitively expensive to simulate. Machine learning has the potential to revolutionize materials modeling due to its ability to efficiently approximate complex functions. For example, neural networks can be trained to reproduce results of density functional theory calculations at a much lower cost. However, how neural networks reach their predictions is not well understood, which has led to them being used as a "black box" tool. This lack of understanding is not desirable especially for applications of neural networks in scientific inquiry. We argue that machine learning models trained on physical systems can be used as more than just approximations since they had to "learn" physical concepts in order to reproduce the labels they were trained on. We use dimensionality reduction techniques to study in detail the representation of silicon atoms at different stages in a neural network, which provides insight into how a neural network learns to model atomic interactions. PMID- 28711054 TI - Three- and four-electron integrals involving Gaussian geminals: Fundamental integrals, upper bounds, and recurrence relations. AB - We report the three main ingredients to calculate three- and four-electron integrals over Gaussian basis functions involving Gaussian geminal operators: fundamental integrals, upper bounds, and recurrence relations. In particular, we consider the three- and four-electron integrals that may arise in explicitly correlated F12 methods. A straightforward method to obtain the fundamental integrals is given. We derive vertical, transfer, and horizontal recurrence relations to build up angular momentum over the centers. Strong, simple, and scaling-consistent upper bounds are also reported. This latest ingredient allows us to compute only the O(N2) significant three- and four-electron integrals, avoiding the computation of the very large number of negligible integrals. PMID- 28711055 TI - Perspective: Outstanding theoretical questions in polymer-nanoparticle hybrids. AB - This topical review discusses the theoretical progress made in the field of polymer nanocomposites, i.e., hybrid materials created by mixing (typically inorganic) nanoparticles (NPs) with organic polymers. It primarily focuses on the outstanding issues in this field and is structured around five separate topics: (i) the synthesis of functionalized nanoparticles; (ii) their phase behavior when mixed with a homopolymer matrix and their assembly into well-defined superstructures; (iii) the role of processing on the structures realized by these hybrid materials and the role of the mobilities of the different constituents; (iv) the role of external fields (electric, magnetic) in the active assembly of the NPs; and (v) the engineering properties that result and the factors that control them. While the most is known about topic (ii), we believe that significant progress needs to be made in the other four topics before the practical promise offered by these materials can be realized. This review delineates the most pressing issues on these topics and poses specific questions that we believe need to be addressed in the immediate future. PMID- 28711056 TI - Communication: Theoretical study of HfF+ cation to search for the T,P-odd interactions. AB - The combined all-electron and two-step approach is applied to calculate the molecular parameters which are required to interpret the ongoing experiment to search for the effects of manifestation of the T,P-odd fundamental interactions in the HfF+ cation by Loh et al. [Science 342, 1220 (2013)] and Ni et al. [J. Mol. Spectrosc. 300, 12 (2014)]. The effective electric field that is required to interpret the experiment in terms of the electron electric dipole moment is found to be 22.5 GV/cm. In the work of Pospelov and Ritz [Phys. Rev. D 89, 056006 (2014)], it was shown that another source of the T,P-odd interaction, the scalar pseudoscalar nucleus-electron interaction with the dimensionless strength constant kT,P can dominate over the direct contribution from the electron electric dipole moment within the standard model and some of its extensions. Therefore, for the comprehensive and correct interpretation of the HfF+ experiment, one should also know the molecular parameter WT,P, the value of which is reported here to be 20.1 kHz. PMID- 28711057 TI - Improved spatial separation of neutral molecules. AB - We have developed and experimentally demonstrated an improved electrostatic deflector for the spatial separation of molecules according to their dipole moment-to-mass ratio. The device features a very open structure that allows for significantly stronger electric fields as well as for stronger deflection without molecules crashing into the device itself. We have demonstrated its performance using the prototypical carbonyl sulfide molecule and we discuss opportunities regarding improved quantum-state-selectivity for complex molecules and the deflection of unpolar molecules. PMID- 28711058 TI - Dielectric and structural relaxation in water and some monohydric alcohols. AB - Relaxation times of the principal (Debye-type) relaxation terms in the dielectric spectra of water and normal alcohols have been evaluated in order to eliminate the effect of multi-molecular cross-correlations and to thus yield reorientation times of the molecular electric dipole moments. The reorientation times have been compared to relaxation times from ultraviolet and X-ray Brillouin spectra as well as from broadband ultrasonic spectra, which are considered as the structure relaxation times characterizing the density fluctuations of the liquid hydrogen bond networks. With some alcohols, shear impedance spectra indicate the network fluctuations to be tightly associated with shear viscosity relaxation. Within the limits of uncertainty, the molecular dipole moment reorientation times and the structure relaxation times feature close correlations. This finding suggests a coupling between translational and orientational molecular motions, and it is discussed in the light of the wait-and-switch model of dielectric relaxation. PMID- 28711059 TI - The effect of surface adsorption on tertiary structure formation in helical polymers. AB - The formation of tertiary structures made up of helical polymer segments is influenced by the introduction of an attractive substrate onto which the polymer can adsorb. We perform replica-exchange Monte Carlo simulations to study the formation of helical structures in the vicinity of an attractive generic substrate by means of a coarse-grained hybrid model and compare the structural phase space for both adsorbed and free helical polymers. We introduce suitable structural order parameters to understand the features of distinct structural phases. Hyperphase diagrams, parameterized by the torsional energy scale and temperature, enable the investigation of structural properties of entire classes of helical polymers. PMID- 28711060 TI - Native point defects on hydrogen-passivated 4H-SiC (0001) surface and the effects on metal adsorptions. AB - With the continued expansion of silicon carbide's (SiC) applications, atomistic understanding on the native point defects of its surfaces, particularly on those of the hydrogen-passivated (HP) 4H-SiC (0001) surface, becomes imperative. Using first-principles calculations, the structures and formation energies of several typical native point defects (e.g., ISi, IC, VSi, VC, and SiC) on the (0001) HP surface of 4H-SiC were systematically explored, including the effects of the unit cell size, environmental condition, charge state, and hydrogen incorporation. Furthermore, their adsorptions of Ag (Mo) atom on these defective sites were systematically investigated. The formation energies of these defects in the HP surface, clean surface, and bulk SiC were concluded together with their thermodynamic concentrations in the HP-surface estimated. The influences of these defects to metal (Ag, Mo) adsorptions of HP-surfaces were concluded. Based on these conclusions, the wettability improvement between the metal liquid and ion (Ag or Mo) implanted SiC substrates in the previous studies can be well understood at the atomistic scale. This study provides a theoretical guideline to SiC surface modification for the production of metal-SiC composites, brazing of SiC with metals, fabrication of electronic devices, or the growth of two dimensional nanofilms. PMID- 28711061 TI - Relation between CIDNP formed upon geminate and bulk recombination of radical pairs. AB - A theoretical approach to time-resolved Chemically Induced Dynamic Nuclear Polarization (CIDNP) is proposed, which allows one to obtain the general relation between polarization formed upon recombination of geminate spin-correlated radical pairs, the so-called G-pairs, and upon recombination of radical pairs formed by encounters of free radicals in solution, the so-called F-pairs. This relation is described by a universal parameter denoted as gamma. In this work, the gamma value is computed for the arbitrary spin multiplicity, singlet or triplet, of the precursor of the G-pairs as well as for arbitrary recombination rate constants of radical pairs in singlet and triplet states, kS and kT, respectively. Furthermore, the treatment is extended to the situation where radicals undergo transformation resulting in different reactivity or magnetic parameters for F-pairs and G-pairs. The proposed theory enables modeling of time resolved CIDNP data in cases where (i) both recombination channels are active and (ii) fast protonation/deprotonation of radicals changes the effective gamma value. PMID- 28711062 TI - Nudged elastic band calculation of the binding potential for liquids at interfaces. AB - The wetting behavior of a liquid on solid substrates is governed by the nature of the effective interaction between the liquid-gas and the solid-liquid interfaces, which is described by the binding or wetting potential g(h) which is an excess free energy per unit area that depends on the liquid film height h. Given a microscopic theory for the liquid, to determine g(h), one must calculate the free energy for liquid films of any given value of h, i.e., one needs to create and analyze out-of-equilibrium states, since at equilibrium there is a unique value of h, specified by the temperature and chemical potential of the surrounding gas. Here we introduce a Nudged Elastic Band (NEB) approach to calculate g(h) and illustrate the method by applying it in conjunction with a microscopic lattice density functional theory for the liquid. We also show that the NEB results are identical to those obtained with an established method based on using a fictitious additional potential to stabilize the non-equilibrium states. The advantages of the NEB approach are discussed. PMID- 28711063 TI - Ab initio interatomic potentials and the thermodynamic properties of fluids. AB - Monte Carlo simulations with accurate ab initio interatomic potentials are used to investigate the key thermodynamic properties of argon and krypton in both vapor and liquid phases. Data are reported for the isochoric and isobaric heat capacities, the Joule-Thomson coefficient, and the speed of sound calculated using various two-body interatomic potentials and different combinations of two body plus three-body terms. The results are compared to either experimental or reference data at state points between the triple and critical points. Using accurate two-body ab initio potentials, combined with three-body interaction terms such as the Axilrod-Teller-Muto and Marcelli-Wang-Sadus potentials, yields systematic improvements to the accuracy of thermodynamic predictions. The effect of three-body interactions is to lower the isochoric and isobaric heat capacities and increase both the Joule-Thomson coefficient and speed of sound. The Marcelli Wang-Sadus potential is a computationally inexpensive way to utilize accurate two body ab initio potentials for the prediction of thermodynamic properties. In particular, it provides a very effective way of extending two-body ab initio potentials to liquid phase properties. PMID- 28711064 TI - Methane dissociation on Ni(111): A seven-dimensional to nine-dimensional quantum dynamics study. AB - As one benchmark system of CH4 dissociation on the Ni(111) surface, it is of great significance to explore the role of each degree of freedom (DOF) of reactant CH4 in its first C-H bond dissociation from quantum dynamics simulations. Here, the influence of the CH stretching DOF of methyl limited in C3v symmetry is quantitatively investigated as well as the important role of azimuth. We calculated the sticking probabilities, S0, of ground state (GS) CH4 dissociation on a rigid Ni(111) surface by performing some seven-dimensional to nine-dimensional (9D) quantum dynamics simulations based on one highly accurate and fifteen-dimensional (15D) ab initio potential energy surface which we recently developed. Our direct quantum dynamics results show that S0 of GS CH4 on four given surface impact sites are weakly enhanced by adding the CH stretching DOF of methyl but strongly weakened by the DOF of azimuth. Furthermore, using a 9D quantum dynamics model, we improve the post-treatment model for treating the influence of surface impact sites through a linear relationship between the effective potential barriers and the distances relative to that on the transition state site. These developed high-dimensional quantum dynamics models and improved post-treatments can be usefully extended for studying some complex polyatomic gas surface reactions by other theoretical groups. PMID- 28711065 TI - Low-scaling first-order properties within second-order Moller-Plesset perturbation theory using Cholesky decomposed density matrices. AB - An efficient implementation of energy gradients and of hyperfine coupling constants in second-order Moller-Plesset perturbation theory (MP2) is presented based on our fully atomic orbital (AO)-based approach. For the latter, an unrestricted AO-based MP2 formulation is introduced. A reduction in the dependency of the computational efficiency on the size of the basis set is achieved by a Cholesky decomposition and the prefactor is reduced by the resolution-of-the-identity approximation. Significant integral contributions are selected based on distance-including integral estimates (denoted as QQR screening) and its reliability as a fully controlled screening procedure is demonstrated. The rate-determining steps are shown via model computations to scale cubically in the computation of energy gradients and quadratically in the case of hyperfine coupling constants. Furthermore, a significant speed-up of the computational time with respect to the canonical formulation is demonstrated. PMID- 28711066 TI - Ion association at discretely-charged dielectric interfaces: Giant charge inversion. AB - Giant charge reversal has been identified for the first time by Monte Carlo simulation for a discretely charged surface in contact with a trivalent electrolyte solution. It takes place regardless of the surface charge density under study and the monovalent salt. In stark contrast to earlier predictions based on the 2-dimensional Wigner crystal model to describe strong correlation of counterions at the macroion surface, we find that giant charge reversal reflects an intricate interplay of ionic volume effects, electrostatic correlations, surface charge heterogeneity, and the dielectric response of the confined fluids. While the novel phenomenon is yet to be confirmed with experiment, the simulation results appear in excellent agreement with a wide range of existing observations in the subregime of charge inversion. Our findings may have far-reaching implications to understanding complex electrochemical phenomena entailing ionic fluids under dielectric confinements. PMID- 28711068 TI - Introduction: Women's Renal Health Across the Decades. PMID- 28711067 TI - PA-6 inhibits inward rectifier currents carried by V93I and D172N gain-of function KIR2.1 channels, but increases channel protein expression. AB - BACKGROUND: The inward rectifier potassium current IK1 contributes to a stable resting membrane potential and phase 3 repolarization of the cardiac action potential. KCNJ2 gain-of-function mutations V93I and D172N associate with increased IK1, short QT syndrome type 3 and congenital atrial fibrillation. Pentamidine-Analogue 6 (PA-6) is an efficient (IC50 = 14 nM with inside-out patch clamp methodology) and specific IK1 inhibitor that interacts with the cytoplasmic pore region of the KIR2.1 ion channel, encoded by KCNJ2. At 10 MUM, PA-6 increases wild-type (WT) KIR2.1 expression in HEK293T cells upon chronic treatment. We hypothesized that PA-6 will interact with and inhibit V93I and D172N KIR2.1 channels, whereas impact on channel expression at the plasma membrane requires higher concentrations. METHODS: Molecular modelling was performed with the human KIR2.1 closed state homology model using FlexX. WT and mutant KIR2.1 channels were expressed in HEK293 cells. Patch-clamp single cell electrophysiology measurements were performed in the whole cell and inside-out mode of the patch clamp method. KIR2.1 expression level and localization were determined by western blot analysis and immunofluorescence microscopy, respectively. RESULTS: PA-6 docking in the V93I/D172N double mutant homology model of KIR2.1 demonstrated that mutations and drug-binding site are >30 A apart. PA-6 inhibited WT and V93I outward currents with similar potency (IC50 = 35.5 and 43.6 nM at +50 mV for WT and V93I), whereas D172N currents were less sensitive (IC50 = 128.9 nM at +50 mV) using inside-out patch-clamp electrophysiology. In whole cell mode, 1 MUM of PA-6 inhibited outward IK1 at -50 mV by 28 +/- 36%, 18 +/- 20% and 10 +/- 6%, for WT, V93I and D172N channels respectively. Western blot analysis demonstrated that PA-6 (5 MUM, 24 h) increased KIR2.1 expression levels of WT (6.3 +/- 1.5 fold), and V93I (3.9 +/- 0.9) and D172N (4.8 +/- 2.0) mutants. Immunofluorescent microscopy demonstrated dose-dependent intracellular KIR2.1 accumulation following chronic PA-6 application (24 h, 1 and 5 MUM). CONCLUSIONS: 1) KCNJ2 gain-of-function mutations V93I and D172N in the KIR2.1 ion channel do not impair PA-6 mediated inhibition of IK1, 2) PA-6 elevates KIR2.1 protein expression and induces intracellular KIR2.1 accumulation, 3) PA-6 is a strong candidate for further preclinical evaluation in treatment of congenital SQT3 and AF. PMID- 28711069 TI - Preterm Birth and its Impact on Renal Health. AB - Preterm birth occurs in approximately 10% of all births worldwide. Preterm infants have reduced nephron numbers at birth in proportion to gestational age, and are at increased risk of neonatal acute kidney injury as well as higher blood pressure, proteinuria, and chronic kidney disease later in life. Rapid catch-up growth in preterm infants, especially if resulting in obesity, is a risk factor for end-stage kidney disease among children with proteinuric renal disease. Preterm birth, however, is a risk factor not only for the infant because mothers who deliver preterm have an increased risk of having subsequent preterm deliveries as well as hypertension, cardiovascular disease, and renal disease later in life. Preterm birth in a female infant is also a risk factor for her future risk of having a preterm delivery, gestational hypertension, and gestational diabetes, which in turn may impact the development of fetal kidneys and the offspring's risk of hypertension and renal disease. This intergenerational programming cycle, therefore, perpetuates the risks and consequences of prematurity. Interruption of this cycle may be possible through optimization of maternal nutrition and health as well as careful antenatal care, which may in turn reduce the global burden of hypertension and renal disease in subsequent generations. PMID- 28711070 TI - Female Adolescents with Chronic or End-Stage Kidney Disease and Strategies for their Care. AB - The prevalence of chronic or end-stage kidney disease in pediatric girls is lower than in boys, however, girls have unique morbidities that can have great effect on their quality of life. For female adolescents, creatinine excretion peaks at approximately 14 years of age and is significantly less than males, owing to lower muscle mass. Females have higher nitric oxide activity, and estrogens may contribute to lower blood pressure. Females excrete less growth hormone during the prepubertal and pubertal years. Females between the ages of 8 and 10 years show increased levels of parathyroid hormone and vitamin D, however, female adolescents with chronic kidney disease have less estrogen and loss of the luteinizing hormone pulsatile pattern. These biological, hormonal, and physical changes affect the psychosocial aspects of female adolescents with chronic kidney disease/end-stage kidney disease, and they must learn to manage their health to achieve good outcomes. Patients and their parents must learn disease management through a customized health care transition preparation in both the pediatric- and adult-focused settings. Clinical strategies are suggested for the care of these special patients. PMID- 28711071 TI - Fertility, Contraception, and Novel Reproductive Technologies in Chronic Kidney Disease. AB - Chronic kidney disease (CKD) affects hypothalamic-pituitary-gonadal axis function, leading to menstrual abnormalities, sexual dysfunction, functional menopause, and loss of fertility. Pregnancy in a patient with CKD is associated with a higher risk of complications to both the mother and the fetus, highlighting the importance of contraceptive counseling at all stages of CKD. There has been limited research on the safety and efficacy of different contraceptive methods in the CKD population, and it is important to tailor the choice of contraception to the patient's lifestyle and comorbidity status. Cyclophosphamide is a commonly used immunosuppressive agent that impairs fertility in a dose-dependent fashion, with greater impact in older women of child-bearing age. Strategies to reduce the impact of cyclophosphamide on ovarian reserve as well as fertility preservation technologies are options to consider when treating immune-mediated CKD. A multidisciplinary approach in counseling the woman with CKD who wishes to contemplate or avoid pregnancy is necessary to optimize outcomes. Further research in this important area is required. PMID- 28711072 TI - Chronic Kidney Disease and Pregnancy. AB - Women with chronic kidney disease (CKD) are at risk for adverse pregnancy associated outcomes, including progression of their underlying renal dysfunction, a flare of their kidney disease, and adverse pregnancy complications such as preeclampsia and preterm delivery. Earlier-stage CKD, as a rule, is a safer time to have a pregnancy, but even women with end-stage kidney disease have attempted pregnancy in recent years. As such, nephrologists need to be comfortable with pregnancy preparation and management at all stages of CKD. In this article, we review the renal physiologic response to pregnancy and the literature with respect to both expected maternal and fetal outcomes among young women at various stages of CKD, including those who attempt to conceive while on dialysis. The general management of young women with CKD and associated complications, including hypertension and proteinuria are discussed. Finally, the emotional impact these pregnancies may have on young women with a chronic disease and the potential benefits of care in a multidisciplinary environment are highlighted. PMID- 28711073 TI - Lupus Nephritis and Pregnancy: Concerns and Management. AB - Pregnancy associated with lupus, especially lupus nephritis, is often fraught with concern for both the mother and fetus. Thus, it is paramount that care begins preconception so that proper planning in terms of optimizing the medical regimen, discontinuation of fetotoxic agents, and treatment of active disease can occur. It is well known that active nephritis at the time of conception is associated with poor outcomes. Even with quiescent disease, recent data indicate that being lupus anticoagulant-positive, nonwhite or Hispanic, and using antihypertensive medications were all predictors of worse pregnancy outcomes. Further, prior lupus nephritis also predicts higher rates of preeclampsia and HELLP (hemolysis, elevated liver enzymes, low platelet count) syndrome. Differentiating lupus nephritis from preeclampsia often presents as a conundrum, but lupus nephritis can be confirmed by the presence of decreasing complement levels and increasing double-stranded DNA (dsDNA) antibody levels in addition to new onset hypertension and proteinuria. We hope that the more mechanistic approach of measuring angiogenic markers, which are diagnostic for preeclampsia, will be the standard of care in the future. Women with lupus and prior lupus nephritis can have successful pregnancies, but outcomes are dependent on "the art of planning" as well as close communication between the obstetrician, the nephrologist, and the rheumatologist. PMID- 28711074 TI - Hereditary Renal Diseases. AB - Hereditary kidney disease comprises approximately 10% of adults and nearly all children who require renal replacement therapy. Technologic advances have improved our ability to perform genetic diagnosis and enhanced our understanding of renal and syndromic diseases. In this article, we review the genetics of renal diseases, including common monogenic diseases such as polycystic kidney disease, Alport syndrome, and Fabry disease, as well as complex disorders such as congenital anomalies of the kidney and urinary tract. We provide the nephrologist with a general strategy to approach hereditary disorders, which includes a discussion of commonly used genetic tests, a guide to genetic counseling, and reproductive options such as prenatal diagnosis or pre-implantation genetic diagnosis for at-risk couples. Finally, we review pregnancy outcomes in certain renal diseases. PMID- 28711075 TI - Diabetic Nephropathy and Pregnancy. AB - Women with diabetic nephropathy have challenging pregnancies, with pregnancy outcomes far worse than expected for the stage of chronic kidney disease. The underlying mechanisms that cause the adverse events remain poorly understood, but it is a widely held belief that substantial endothelial injury in these women likely contributes. Maternal hypertension, preeclampsia, and cesarean section rates are high, and offspring are often preterm and of low birth weight, with additional neonatal complications associated with glycemic control. This review will present the current evidence for maternal and fetal outcomes of women with diabetic nephropathy and describe prepregnancy, antenatal, and peripartum optimization strategies. PMID- 28711076 TI - Pregnancy in Renal Transplant Recipients and Donors. AB - Women with renal transplants have restoration of fertility with improved kidney function; however, pregnancy rates in renal transplant recipients appear to be lower than the general population, which might be influenced by patient choice. Women with renal transplants need to evaluate potential neonatal outcomes, graft outcomes, and risks to their own health to make informed decisions about conception. Pregnancy should be carefully planned in renal transplant recipients to reduce risk for graft loss, optimize pregnancy outcomes, and ensure immunosuppression regimes are nonteratogenic. Neonatal outcomes remain significantly worse for women with renal transplants than healthy controls, particularly for those with reduced graft function, hence prepregnancy, antenatal, and postpartum care of women with renal transplants should be guided by a multidisciplinary team of nephrologists and specialist obstetricians. PMID- 28711078 TI - Preeclampsia: Pathogenesis, Prevention, and Long-Term Complications. AB - Preeclampsia continues to afflict 5% to 8% of all pregnancies throughout the world and is associated with significant morbidity and mortality to the mother and the fetus. Although the pathogenesis of the disorder has not yet been fully elucidated, current evidence suggests that imbalance in angiogenic factors is responsible for the clinical manifestations of the disorder, and may explain why certain populations are risk. In this review, we begin by demonstrating the roles that angiogenic factors play in pathogenesis of preeclampsia and its complications in the mother and the fetus. We then continue to report on the use of angiogenic markers as biomarkers to predict and risk-stratify disease. Strategies to treat preeclampsia by correcting the angiogenic balance, either by promoting proangiogenic factors or by removing antiangiogenic factors in both animal and human studies, are discussed. We end the review by summarizing status of the current preventive strategies and the long-term cardiovascular outcomes of women afflicted with preeclampsia. PMID- 28711077 TI - Acute Kidney Injury in Pregnancy. AB - Pregnancy-related acute kidney injury (AKI) has declined in incidence in the last three decades, although it remains an important cause of maternal and fetal morbidity and mortality. Pregnancy-related causes of AKI such as preeclampsia, acute fatty liver of pregnancy, HELLP (Hemolysis, Elevated Liver function tests, Low Platelets) syndrome, and the thrombotic microangiopathies (thrombotic thrombocytopenic purpura, atypical hemolytic-uremic syndrome [HUS]) exhibit overlapping features and often present as diagnostic dilemmas. Differentiating among these conditions may be difficult or impossible based on clinical criteria only. In difficult and rare cases, a renal biopsy may need to be considered for the exact diagnosis and to facilitate appropriate treatment, but the risks and benefits need to be carefully weighed. The use of eculizumab for the treatment of atypical HUS has demonstrated efficacy in early case reports. Non-pregnancy related causes such as volume depletion and pyelonephritis require early and aggressive resuscitative as well as antibiotic measures respectively. We will discuss in this review the various etiologies of AKI in pregnancy, current diagnostic approaches, and the latest treatment strategies. Given the recent trends of increasing maternal age at the time of pregnancy, and the availability of modern reproductive methods increase the risks of AKI in pregnancy in the coming years. PMID- 28711079 TI - New Evidence in the Management of Chronic Hypertension in Pregnancy. AB - Chronic hypertension complicates 1% to 5% of all pregnancies, but debate continues regarding the benefits of lowering blood pressure in pregnancy as well as the optimal blood pressure targets. Women with chronic hypertension are at significant risk for maternal and fetal morbidity and mortality, yet it remains unclear whether antihypertensive treatment during pregnancy lowers these risks. Severe hypertension (systolic >= 160 mm Hg) should be treated, but there is considerable variability in the approach to mild-to-moderate hypertension (140 159/90-109 mm Hg). The recently published CHIPS (Control of Hypertension in Pregnancy Study) trial is an important effort to attempt to determine treatment goals in mild to moderate pregnancy hypertension. The risks and benefits of tight versus less tight control of blood pressure in nonproteinuric hypertensive women, most of whom had pre-existing hypertension, were evaluated. A main finding was an increased risk of severe hypertension (adjusted odds ratio, 1.8) when blood pressure was not tightly controlled. In this review, general management of chronic hypertension in pregnancy is discussed, including changes in treatment that may be appropriate in light of new clinical trial data. PMID- 28711080 TI - Menopause and Chronic Kidney Disease. AB - Premature menopause defined as secondary amenorrhea is common in women with kidney disease. Moreover, the aging population has resulted in increasing numbers of postmenopausal women with kidney disease. Though the pathophysiology is poorly understood, kidney transplantation and more frequent hemodialysis can restore menses and fertility, highlighting the challenges of diagnosing and managing the menopausal transition in the female population with kidney disease. Postmenopausal sex hormone levels affect renovascular physiology, but the clinical impact of menopause on kidney function is unclear. There are no guidelines on the use of postmenopausal hormone therapy specific to the population with kidney disease, and studies on the effects of postmenopausal hormone therapy in patients with kidney disease are limited to surrogate measures of cardiovascular and fracture risk. Studies examining the effects of postmenopausal hormone therapy on kidney function and albuminuria report conflicting results, which is likely reflective of differences in formulation, route of administration, accompanying progestin, and timing of initiation of treatment. Large, prospective studies examining the relationship between kidney function and menopause as well as the effects of postmenopausal hormone therapy on important clinical outcomes in women with kidney disease are warranted. PMID- 28711081 TI - Illustrative Cases of Kidney Disease Unique to Women. PMID- 28711082 TI - Bedside diagnostics in dermatology: Viral, bacterial, and fungal infections. AB - Viral, bacterial, and fungal infections are frequently encountered in clinical practice, resulting in numerous cutaneous manifestations. Although diagnosis of these infections has changed over time because of technological advancements, such as polymerase chain reaction, bedside diagnostic techniques still play an important role in diagnosis and management, enabling rapid and low-cost diagnosis and implementation of appropriate therapies. This 2-part article will review both common and infrequent uses of bedside diagnostic techniques that dermatologists can incorporate into daily practice. This article examines the utility of bedside tests for the diagnosis of viral, bacterial, and fungal infections. The second article in this series reviews the use of bedside diagnostics for parasitic and noninfectious disorders. PMID- 28711083 TI - Bedside diagnostics in dermatology: Parasitic and noninfectious diseases. AB - In addition to aiding the diagnosis of viral, bacterial, and fungal diseases, mineral oil preparation, Tzanck smear, and other techniques can be used to diagnose parasitic infections, neonatal pustular dermatoses, blistering diseases, Stevens-Johnson syndrome, and a plethora of other benign and malignant conditions, including granulomatous diseases and tumors. In many cases, these techniques are specific, reliable, and easy to perform and interpret. In others, a certain amount of training and expertise are required. In the proper clinical scenario, these tests are rapid, economical, and compare favorably with other diagnostic methods. PMID- 28711084 TI - Herpes zoster in psoriasis patients treated with tofacitinib. AB - BACKGROUND: Tofacitinib is an oral Janus kinase (JAK) inhibitor. Immunomodulatory therapies can increase the risk for herpes zoster (HZ) in patients with psoriasis. OBJECTIVE: To evaluate the relationship between tofacitinib use and HZ risk. METHODS: We used phases 2 and 3 and long-term extension (LTE) data from the tofacitinib development program in psoriasis to calculate HZ incidence rates (IR; events per 100 patient-years); potential HZ risk factors were evaluated using Cox proportional hazard models. RESULTS: One hundred thirty (3.6%) patients on tofacitinib (IR 2.55), no patients on placebo, and 2 using etanercept (IR 2.68) developed HZ. Nine patients (7%) were hospitalized, and 8 (6%) had multidermatomal HZ; no encephalitis, visceral involvement, or deaths occurred. In total, 121 (93%) patients on tofacitinib continued or resumed use after HZ. HZ risk factors included Asian descent (hazard ratio [HR] 2.92), using tofacitinib 10 mg twice daily (vs 5 mg twice daily; HR 1.72), prior use of biologics (HR 1.72), and older age (HR 1.30). LIMITATIONS: Generalizability to other psoriasis populations might be limited. The effect of HZ vaccination was not studied. CONCLUSION: Tofacitinib is associated with increased HZ risk relative to placebo. Asian race, increasing age, higher dose, and prior biologic exposure are associated with heightened risk. PMID- 28711085 TI - Risk factors for positive or equivocal margins after wide local excision of 1345 cutaneous melanomas. AB - BACKGROUND: Positive or equivocal margins after wide local excision (WLE) complicate surgical management of cutaneous melanoma. OBJECTIVE: To identify the frequency of and risk factors for positive or equivocal margins after WLE of cutaneous melanoma. METHODS: Retrospective, single-center, cross-sectional study of 1345 consecutive melanomas treated with WLE. RESULTS: The overall frequency of positive or equivocal margins was 4.2% (56/1345), ranging from 2.2% to 22.6%, depending on the size of the surgical margins, patient characteristics, biopsy history, and the clinicopathology of the melanoma. In descending order, independent risk factors associated with the greatest odds for positive or equivocal margins after multivariate analysis were noncompliance with recommended surgical margins (odds ratio [OR] 5.57, P = .002); anatomic location on the head, neck, hands, feet, genitals, or pretibial leg (OR 5.07, P < .001); histologic regression (OR 2.78, P = .007); in situ melanoma (OR 2.27, P = .011); multiple biopsies at the tumor site before WLE (OR 1.92 [per biopsy], P = .004); and increasing age (OR 1.049 [per year], P < .001). LIMITATIONS: This was a single site, retrospective observational study. CONCLUSIONS: Clinicopathologic factors, especially location in cosmetically or functionally sensitive areas and noncompliance with recommended surgical margins, identified melanomas at increased risk for positive or equivocal margins after WLE. PMID- 28711086 TI - The new paradigm of systemic therapies for metastatic melanoma. AB - New treatments for metastatic melanoma work through distinct mechanisms: enhancing the immune response and blocking cellular proliferation. Agents that enhance the immune response include ipilimumab, pembrolizumb, and nivolumab; agents that block cellular proliferation include vemurafenib, dabrafenib, trametinib, cobimetinib, binimetinib, and selumetinib. The translational impact of laboratory discoveries has revolutionized management of metastatic melanoma and enhanced the prognosis of affected patients. PMID- 28711088 TI - Association between bullous pemphigoid and psoriasis: A case-control study. PMID- 28711087 TI - Parallel, minimal needle-insertion technique for achieving a painless injection of local anesthetic. PMID- 28711089 TI - Rapid onset of action in patients with moderate-to-severe psoriasis treated with brodalumab: A pooled analysis of data from two phase 3 randomized clinical trials (AMAGINE-2 and AMAGINE-3). PMID- 28711090 TI - The quinacrine experience in a population of patients with cutaneous lupus erythematosus and dermatomyositis. PMID- 28711091 TI - Update on sunscreens distributed by major US retailers that meet American Academy of Dermatology recommendations. PMID- 28711092 TI - Cumulative oral corticosteroid use increases risk of glucocorticoid-related adverse events in patients with newly diagnosed pemphigus. PMID- 28711093 TI - Balancing patient care with profitability: Ethical considerations. PMID- 28711095 TI - Recommendations for culturally competent dermatology care of Muslim patients. PMID- 28711094 TI - The tattoo removal ethical conundrum: Should a physician be part of a minor patient's punishment? PMID- 28711098 TI - Milia: A dermoscopic pitfall. PMID- 28711099 TI - Dermoscopy of acrokeratosis verruciformis of Hopf. PMID- 28711100 TI - Dermoscopy of a solitary verrucous plaque on the back. PMID- 28711101 TI - Subclinical melasma: Determining disease extent. PMID- 28711102 TI - Liquid nitrogen cryotherapy in the treatment of chronic, unresponsive nodular scabies. PMID- 28711103 TI - Subcutaneous pedicle chin flap combined with lateral transposition flap: A novel technique for reconstruction of wide lower-lip defects. PMID- 28711104 TI - A novel anesthetic technique for palmar botulinum toxin injection. PMID- 28711105 TI - Partial auricular wedge resection for both structural support and soft tissue coverage. PMID- 28711106 TI - Atypical hand, foot, and mouth disease in adults. PMID- 28711107 TI - Psoriasis: Latitude does make a difference. PMID- 28711108 TI - Psoriasis and latitude: Analytic approaches and future data needs. PMID- 28711109 TI - Moderation of the Alliance-Outcome Association by Prior Depressive Episodes: Differential Effects in Cognitive-Behavioral Therapy and Short-Term Psychodynamic Supportive Psychotherapy. AB - Prior studies have suggested that the association between the alliance and depression improvement varies as a function of prior history of depression. We sought to replicate these findings and extend them to short-term psychodynamic supportive psychotherapy (SPSP) in a sample of patients who were randomized to one of these treatments and were administered the Helping Alliance Questionnaire (N=282) at Week 5 of treatment. Overall, the alliance was a predictor of symptom change (d=0.33). In SPSP, the alliance was a modest but robust predictor of change, irrespective of prior episodes (d=0.25-0.33). By contrast, in CBT, the effects of the alliance on symptom change were large for patients with 0 prior episodes (d=0.86), moderate for those with 1 prior episode (d=0.49), and small for those with 2+ prior episodes (d=0.12). These findings suggest a complex interaction between patient features and common vs. specific therapy processes. In CBT, the alliance relates to change for patients with less recurrent depression whereas other CBT-specific processes may account for change for patients with more recurrent depression. PMID- 28711110 TI - Psychometric Properties of the French Adaptation of the Basic Documentation for Psycho-Oncology (Po-Bado): A Distress Screening Tool. AB - We translated and adapted the French version of the Basic Documentation for Psycho-Oncology (Po-Bado standard version) and we report its psychometric properties. The Po-Bado is a 12-item documentation instrument that measures psychosocial burden in cancer patients (all types and stages). The intensity of a patient's psychological suffering is evaluated by a health care professional (e.g., doctor, psychologist, nurse) in a semiguided interview. Overall, 252 cancer patients (Mage = 57 years, SD = 12.8 years) participated, completing the Po-Bado during a supportive care consultation following initial diagnosis. Our results show good reliability of the Po-Bado scores, with high internal consistency and interrater coefficients. Low temporal stability indicated that the Po-Bado measures a state-like phenomenon (vs. trait-like). Validity analysis showed significant correlations between cancer-specific psychosocial burden and negative mood (i.e., depression, anxiety) and psychological disturbance as assessed by the General Health Questionnaire (GHQ-12). Confirmatory factor analysis validated the Po-Bado's two-factor structure (i.e., somatic and psychological burdens). A receiver operating characteristic (ROC) curve determined the optimal cutoff score of 7.5. These results suggest that the Po Bado is an easily applicable tool for clinicians and researchers to screen effectively for psychosocial burden in oncology. PMID- 28711111 TI - To Do or Not to Do? Task Control Deficit in Obsessive-Compulsive Disorder. AB - Task control is an executive control mechanism that facilitates goal-directed task selection by suppressing irrelevant automatic "stimulus-driven" behaviors. In the current study, we test the hypothesis that less efficient task control in individuals diagnosed with obsessive-compulsive disorder (OCD) is associated with OCD symptoms, and specifically, with the inability to inhibit unwanted behaviors in OCD. Thirty-five healthy controls, 30 participants with OCD, and 26 participants with generalized anxiety disorder (GAD) completed the object interference (OI) task to measure task control, the stop-signal task to measure response inhibition, and the arrow-flanker task to evaluate executive abilities not contingent upon task control. OCD patients, but not GAD patients or healthy controls, exhibited impaired performance on the OI task. The deficit in task control, but not in response inhibition, correlated with OCD symptom severity. We suggest that reduced task control may be one of the neurocognitive processes that underlie the inability to inhibit unwanted behaviors in OCD. PMID- 28711112 TI - Mobile Phone-Based Mood Ratings Prospectively Predict Psychotherapy Attendance. AB - Psychotherapy nonattendance is a costly and pervasive problem. While prior research has identified stable patient-level predictors of attendance, far less is known about dynamic (i.e., time-varying) factors. Identifying dynamic predictors can clarify how clinical states relate to psychotherapy attendance and inform effective "just-in-time" interventions to promote attendance. The present study examines whether daily mood, as measured by responses to automated mobile phone-based text messages, prospectively predicts attendance in group cognitive behavioral therapy (CBT) for depression. Fifty-six Spanish-speaking Latino patients with elevated depressive symptoms (46 women, mean age=50.92years, SD=10.90years), enrolled in a manualized program of group CBT, received daily automated mood-monitoring text messages. Patients' daily mood ratings, message response rate, and delay in responding were recorded. Patients' self-reported mood the day prior to a scheduled psychotherapy session significantly predicted attendance, even after controlling for patients' prior attendance history and age (OR=1.33, 95% CI [1.04, 1.70], p=.02). Positive mood corresponded to a greater likelihood of attendance. Our results demonstrate the clinical utility of automated mood-monitoring text messages in predicting attendance. These results underscore the value of text messaging, and other mobile technologies, as adjuncts to psychotherapy. Future work should explore the use of such monitoring to guide interventions to increase attendance, and ultimately the efficacy of psychotherapy. PMID- 28711114 TI - The Effects of Training Contingency Awareness During Attention Bias Modification on Learning and Stress Reactivity. AB - Current attention bias modification (ABM) procedures are designed to implicitly train attention away from threatening stimuli with the hope of reducing stress reactivity and anxiety symptoms. However, the mechanisms underlying effective ABM delivery are not well understood, with awareness of the training contingency suggested as one possible factor contributing to ABM efficacy. Here, 45 high anxious participants were trained to divert attention away from threat in two ABM sessions. They were randomly assigned to one of three training protocols: an implicit protocol, comprising two standard implicit ABM training sessions; an explicit protocol, comprising two sessions with explicit instruction as to the attention training contingency; and an implicit-explicit protocol, in which participants were not informed of the training contingency in the first ABM session and informed of it at the start of the second session. We examined learning processes and stress reactivity following a stress-induction task. Results indicate that relative to implicit instructions, explicit instructions led to stronger learning during the first training session. Following rest, the explicit and implicit groups exhibited consolidation-related improvement in performance, whereas no such improvement was noted for the implicit-explicit group. Finally, although stress reactivity was reduced after training, contingency awareness did not yield a differential effect on stress reactivity measured using both self-reports and skin conductance, within and across sessions. These results suggest that explicit ABM administration leads to greater initial learning during the training protocol while not differing from standard implicit administration in terms of off-line learning and stress reactivity. PMID- 28711113 TI - Effects of Tailored and ACT-Influenced Internet-Based CBT for Eating Disorders and the Relation Between Knowledge Acquisition and Outcome: A Randomized Controlled Trial. AB - This is the first trial to investigate the outcome of tailored and ACT influenced, cognitive behavioral Internet treatment for eating disorder psychopathology, and the relation between knowledge acquisition and outcome. This study utilized a randomized controlled design, with computer-based allocation to treatment or waiting list control group. Participants were recruited via advertisements in social media and newspapers in Sweden. Participants fulfilling the criteria for bulimia nervosa (BN), or Eating Disorder Not Otherwise Specified (EDNOS), with a BMI above 17.5, were enrolled in the study (N = 92). The treatment group received an Internet-based, ACT-influenced CBT intervention, developed by the authors, for eating disorders. The treatment lasted 8 weeks, and was adapted to the participant's individual needs. A clinician provided support. The main outcome measures were eating disorder symptoms and body shape dissatisfaction. Intent-to-treat analysis showed that the treatment group (n = 46) improved significantly on eating disorder symptoms and body dissatisfaction, compared with the waiting list control group (n = 46), with small to moderate effect sizes (between group effects, d = 0.35-0.64). More than a third of the participants in the treatment group (36.6%), compared to 7.1% in the waiting list control condition, made clinically significant improvements. Results showed a significant increase in knowledge in the treatment group compared to the waiting list control group (between group effect, d = 1.12), but we found no significant correlations between knowledge acquisition and outcome (r= -0.27 to -r = 0.23). The results provide preliminary support for Internet-based, tailored, and ACT influenced treatment, based on CBT for participants with eating disorder psychopathology. PMID- 28711115 TI - Anticipatory Processing, Maladaptive Attentional Focus, and Postevent Processing for Interactional and Performance Situations: Treatment Response and Relationships With Symptom Change for Individuals With Social Anxiety Disorder. AB - Anticipatory processing, maladaptive attentional focus, and postevent processing are key cognitive constructs implicated in the maintenance of social anxiety disorder (SAD). The current study examined how treatment for SAD concurrently affects these three cognitive maintaining processes and how these processes are associated with each other as well as with symptom change from pre- to posttreatment. The sample consisted of 116 participants with SAD receiving group cognitive behavioral therapy. All three cognitive maintaining processes were measured relative to a speech task and again relative to a conversation task. Across both tasks, the three cognitive process variables demonstrated decreases from pre- to posttreatment. Within the same task, a slower rate of decrease in a specific cognitive process variable from pre- to posttreatment was predicted from higher pretreatment levels of either one or both of the other cognitive process variables. Additionally, higher levels of pretreatment conversation-related anticipatory processing and maladaptive attentional focus predicted a slower rate of decrease in social anxiety symptoms from pre- to posttreatment. Results are consistent with cognitive models of SAD and have important implications for enhancing existing treatments. PMID- 28711116 TI - Results of a Pilot Study to Ameliorate Psychological and Behavioral Outcomes of Minority Stress Among Young Gay and Bisexual Men. AB - Project PRIDE (Promoting Resilience In Discriminatory Environments) is an 8 session small group intervention aimed at reducing negative mental and behavioral health outcomes resulting from minority stress. This study reports the results of a one-armed pilot test of Project PRIDE, which aimed to examine the feasibility and potential for efficacy of the intervention in a sample of 33 gay and bisexual men aged 18 to 25. The intervention appeared feasible to administer in two different sites and all participants who completed posttreatment (n = 22) or follow-up (n = 19) assessments reported high satisfaction with the intervention. Small to large effect sizes were observed for increases in self-esteem; small effect sizes were found for decreases in loneliness and decreases in minority stress variables; and small and medium effect sizes were found for reductions in alcohol use and number of sex partners, respectively. Overall, Project PRIDE appears to be a feasible intervention with promise of efficacy. PMID- 28711117 TI - Mechanisms of Change During Attention Training and Mindfulness in High Trait Anxious Individuals: A Randomized Controlled Study. AB - The first aim of this study was to compare attention manipulation techniques deriving from metacognitive therapy (the Attention Training Technique; ATT) and mindfulness-based approaches (Mindfulness-Based Progressive Muscle Relaxation, MB PMR) to a thought wandering control (TWC) condition, in terms of their impact on anxiety and four mechanisms: distancing, present-focused attention, uncontrollability and dangerousness, metacognitive beliefs, and cognitive flexibility (Stroop task). The second aim was to test indirect effects of the techniques on anxiety via the mechanism measures. High trait anxious participants (N = 81, Mage = 23.60, SDage = 7.66, 80% female) were randomized to receive ATT, MB-PMR, or the TWC condition. Measures of cognitive and somatic anxiety, distancing, present-focused attention, metacognitive beliefs, and cognitive flexibility were administered before or after the attention manipulation task. Compared to the TWC group, ATT and MB-PMR were associated with greater changes on cognitive (but not somatic) anxiety, present-focused attention, metacognitive beliefs, and uncorrected errors for threat-related words on the Stroop task. The pattern of means was similar for distancing, but this did not reach statistical significance, and Stroop speed increased equally for all conditions. Indirect effects models revealed significant effects of condition on state anxiety via distancing, metacognitive beliefs, and present-focused attention, but not via Stroop errors. ATT and MB-PMR were associated with changes on anxiety and the mechanism measures, suggesting that the mechanisms of change may be more similar than different across these techniques. PMID- 28711118 TI - Mental Imagery Training Increases Wanting of Rewards and Reward Sensitivity and Reduces Depressive Symptoms. AB - High reward sensitivity and wanting of rewarding stimuli help to identify and motivate repetition of pleasant activities. This behavioral activation is thought to increase positive emotions. Therefore, both mechanisms are highly relevant for resilience against depressive symptoms. Yet, these mechanisms have not been targeted by psychotherapeutic interventions. In the present study, we tested a mental imagery training comprising eight 10-minute sessions every second day and delivered via the Internet to healthy volunteers (N = 30, 21 female, mean age of 23.8 years, Caucasian) who were preselected for low reward sensitivity. Participants were paired according to age, sex, reward sensitivity, and mental imagery ability. Then, members of each pair were randomly assigned to either the intervention or wait condition. Ratings of wanting and response bias toward probabilistic reward cues (Probabilistic Reward Task) served as primary outcomes. We further tested whether training effects extended to approach behavior (Approach Avoidance Task) and depressive symptoms (Beck Depression Inventory). The intervention led to an increase in wanting (p < .001, eta2p= .45) and reward sensitivity (p = .004, eta2p= .27). Further, the training group displayed faster approach toward positive edibles and activities (p = .025, eta2p= .18) and reductions in depressive symptoms (p = .028, eta2p= .16). Results extend existing literature by showing that mental imagery training can increase wanting of rewarding stimuli and reward sensitivity. Further, the training appears to reduce depressive symptoms and thus may foster the successful implementation of exsiting treatments for depression such as behavioral activation and could also increase resilience against depressive symptoms. PMID- 28711120 TI - From Efficacy to Global Impact: Lessons Learned About What Not to Do in Translating Our Research to Reach. AB - Although members of the Association for Behavioral and Cognitive Therapies have made significant strides toward the collective goals outlined in our mission statement, we routinely acknowledge that our ability to develop empirically supported treatments exceeds our success in improving dissemination and implementation of said interventions. Further, as noted by Kazdin and Blase (2011), even if we succeeded in having every clinician worldwide administer our best treatments with excellent competency, we still would be unsuccessful in markedly impacting the worldwide burden of mental illness because most treatments require intensive labor by expensive providers. To this end, Kazdin and Blase and others call for increased use of alternative strategies. Examples include increased attention toward prevention; use of lower-cost, simplified interventions; task shifting; train-the-trainer models; community participatory research methodology; and identification of novel funding sources. The Body Project is an empirically supported, cognitive dissonance-based prevention intervention that targets body image, a well-established risk factor for eating disorders, negative affect, unhealthy weight control behaviors, smoking behavior, and decreased physical activity. Supported by a global village of researchers, community activists, and organizational partners, the Body Project is currently being implemented in 125 countries. The aim of this paper is to share lessons our team has learned in taking a prevention intervention from early testing to widespread implementation and connect these back to broader conversations occurring in our field regarding the importance of scalability and new directions in improving global mental health. PMID- 28711119 TI - Effects of Bias Modification Training in Binge Eating Disorder. AB - Food-related attentional biases have been identified as maintaining factors in binge eating disorder (BED) as they can trigger a binge episode. Bias modification training may reduce symptoms, as it has been shown to be successful in other appetitive disorders. The aim of this study was to assess and modify food-related biases in BED. It was tested whether biases could be increased and decreased by means of a modified dot-probe paradigm, how long such bias modification persisted, and whether this affected subjective food craving. Participants were randomly assigned to a bias enhancement (attend to food stimulus) group or to a bias reduction (avoid food stimulus) group. Food-related attentional bias was found to be successfully reduced in the bias-reduction group, and effects persisted briefly. Additionally, subjective craving for food was influenced by the intervention, and possible mechanisms are discussed. Given these promising initial results, future research should investigate boundary conditions of the experimental intervention to understand how it could complement treatment of BED. PMID- 28711121 TI - History, Principles, and Policies of Observation Medicine. AB - The history of observation medicine has paralleled the rise of emergency medicine over the past 50 years to meet the needs of patients, emergency departments, hospitals, and the US health care system. Just as emergency departments are the safety net of the health system, observation units are the safety net of emergency departments. The growth of observation medicine has been driven by innovations in health care, an ongoing shift of patients from inpatient to outpatient settings, and changes in health policy. These units have been shown to provide better outcomes than traditional care for selected patients. PMID- 28711122 TI - The Establishment and Management of an Observation Unit. AB - The current health care landscape and evidence support the establishment of observation units (OUs) for safe and efficient care for observation patients. Careful attention is required in the design of OU process, location, and layout to enable optimal care and finances. Developing and maintaining protocols to guide patient selection and clinical care are critical. OU management requires a strong, collaborative leadership model, appropriate staffing, and a robust monitoring system for quality, safety, and finances. With a better understanding of these principles of OU establishment and management, hospital leaders can generate and sustain service excellence. PMID- 28711123 TI - Care of the Patient with Chest Pain in the Observation Unit. AB - Care of the patient presenting to an emergency department (ED) with chest pain remains a common yet challenging aspect of emergency medicine. Acute coronary syndrome presents in nonspecific fashion. The development and evolution of the ED based observation unit has helped to safely assess and diagnose those most at risk for an adverse cardiac event. Furthermore, there are several provocative testing modalities to help assess for coronary artery disease. This article serves to describe and discuss the modern ED-based observation unit approach to patients with chest pain and/or angina equivalents presenting to an ED. PMID- 28711124 TI - Cardiovascular Conditions in the Observation Unit: Beyond Chest Pain. AB - The first emergency department observation units (EDOUs) focused on chest pain and potential acute coronary syndromes. However, most EDOUs now cover multiple other conditions that lend themselves to protocolized, aggressive diagnostic and therapeutic regimens. In this article, the authors discuss the management of 4 cardiovascular conditions that have been successfully deployed in EDOUs around the country. PMID- 28711125 TI - Care of Acute Gastrointestinal Conditions in the Observation Unit. AB - The Emergency Department Observation Unit (EDOU) provides a viable alternative to inpatient admission for the management of many acute gastrointestinal conditions with additional opportunities of reducing resource utilization and reducing radiation exposure. Using available evidence-based criteria to determine appropriate patient selection, evaluation, and treatment provides higher-quality medical care and improved patient satisfaction. Discussions of factors involved in creating an EDOU capable of caring for acute gastrointestinal conditions and clinical protocol examples of acute appendicitis, gastrointestinal hemorrhage, and acute pancreatitis provide a framework from which a successful EDOU can be built. PMID- 28711126 TI - Care of Metabolic and Endocrine Conditions in the Observation Unit. AB - Accelerated therapeutic protocols targeting metabolic conditions are ideal for observation unit care. Because many conditions, such as hypokalemia and hyperglycemia, have little to no diagnostic uncertainty, the care in the unit is often straightforward. Additionally, some components of care for the endocrine condition may exhaust services, such as phlebotomy. Hence, this discussion focuses resource utilization and management considerations for the purposes of matching the level of care to the severity of the conditions. When carefully selected candidates are cared for in the observation unit, hospital resources can enable a safe, efficient hospital stay. PMID- 28711127 TI - Care of Neurologic Conditions in an Observation Unit. AB - As a group, neurologic conditions represent a substantial portion of emergency department (ED) visits. Cerebrovascular disease, headache, vertigo and seizures are all common reasons for patients to seek care in the ED. Patients being treated for each of these conditions are amenable to care in an ED observation unit (EDOU) if they require further diagnostic or therapeutic interventions beyond their ED stay. EDOUs are the ideal setting for patients who require advanced imaging such as MRIs, frequent neuro checks or specialist consultation in order to determine if they require admission or can be discharged home. PMID- 28711128 TI - Care of Respiratory Conditions in an Observation Unit. AB - In adults, respiratory disorders are the second most frequent diagnoses treated in emergency department observation units (EDOUs) and account for the most frequent indication for placement of pediatric patients into an EDOU. With appropriate patient selection, chronic obstructive pulmonary disease exacerbations, and community-acquired pneumonia can be managed in the EDOU. EDOU management results in equivalent or better outcomes than inpatient care with decreased length of stay, increased patient satisfaction, lower cost and in some studies decreased mortality. Evidence-based protocols are important to ensure appropriate patients are placed in the EDOU, standardize best practice interventions, and guide disposition decisions. PMID- 28711129 TI - Care of Infectious Conditions in an Observation Unit. AB - Infectious conditions such as skin and soft tissue infections (SSTIs), Urogenital infections and peritonsillar abscesses frequently require care beyond emergency stabilization and are well-suited for short term care in an observation unit. SSTIs are a growing problem, partly due to emergence of strains of methicillin resistant S. aureus (MRSA). Antibiotic choice is guided by the presence of purulence and site of infection. Purulent cellulitis is much more likely to be associated with MRSA. Radiographic imaging should be considered to aid in management in patients who are immunosuppressed, have persistent symptoms despite antibiotic therapy, recurrent infections, sepsis or diabetes. PMID- 28711130 TI - Care of Traumatic Conditions in an Observation Unit. AB - Patients presenting to the emergency department with certain traumatic conditions can be managed in observation units. The evidence base supporting the use of observation units to manage injured patients is smaller than the evidence base supporting the management of medical conditions in observation units. The conditions that are eligible for management in an observation unit are not limited to those described in this article, and investigators should continue to identify types of conditions that may benefit from this type of health care delivery. PMID- 28711131 TI - Care of Special Populations in an Observation Unit: Pediatrics and Geriatrics. AB - Infants and children and the elderly comprise a large and growing (especially the elderly) segment of the US population. The benefits of observation medicine have been documented in these two age groups: Based on the success of observation medicine, and recognizing the growth of these special populations, it is likely that observation medicine will be expanding in the future, especially within the pediatric and geriatric populations. Future studies should be able to provide further evidence regarding the value of observation medicine in these two diverse population age groups. PMID- 28711132 TI - Additional Conditions Amenable to Observation Care. AB - ED observation units (EDOUs) are designed for patients who require diagnostics or therapeutics beyond the initial ED visit to determine the need for hospital admission. Best evidence is that this care be delivered via ordersets or protocols. Occasionally, patients present with conditions that are amenable to EDOU care but fall outside the commonly used protocols. This article details a few of these conditions: abnormal uterine bleeding, allergic reaction, alcohol intoxication, acetaminophen overdose and sickle cell vaso-occlusive crisis. It is not meant to be exhaustive as patient care needs can vary hospital to hospital. PMID- 28711133 TI - Observation Medicine. PMID- 28711135 TI - Bile acids, roles in integrative physiology and pathophysiology. PMID- 28711134 TI - Observation Medicine: Providing Safe and Cost-Effective Care Beyond the Emergency Department. PMID- 28711136 TI - Population Genetics and Natural Selection in Rheumatic Disease. AB - Human genetic diversity is the result of population genetic forces. This genetic variation influences disease risk and contributes to health disparities. Natural selection is an important influence on human genetic variation. Because immune and inflammatory function genes are enriched for signals of positive selection, the prevalence of rheumatic disease-risk alleles seen in different populations is partially the result of differing selective pressures (eg, due to pathogens). This review summarizes the genetic regions associated with susceptibility to different rheumatic diseases and concomitant evidence for natural selection, including known agents of selection exerting selective pressure in these regions. PMID- 28711138 TI - Genomic Influences on Susceptibility and Severity of Rheumatoid Arthritis. AB - Genetics in rheumatoid arthritis (RA) has moved from the finding of HLA-shared epitope decades ago toward the understanding of the role of HLA in RA and the findings of ~100 additional genetic risk variants for disease susceptibility as well as several risk variants for severe disease. These findings increased our understanding of RA abnormality. Still, the mechanisms by which many of the variants exhibit their effect are not yet understood. PMID- 28711137 TI - Genomics, Biology, and Human Illness: Advances in the Monogenic Autoinflammatory Diseases. AB - The monogenic autoinflammatory diseases are a group of illnesses with prominent rheumatic manifestations that are characterized by genetically determined recurrent sterile inflammation and are thus inborn errors of innate immunity. Molecular targeted therapies against inflammatory cytokines, such as interleukin 1 and tumor necrosis factor, and intracellular cytokine signaling pathways have proved effective in many cases. Emerging next-generation sequencing technologies have accelerated the identification of previously unreported genes causing autoinflammatory diseases. This review covers several of the prominent recent advances in the field of autoinflammatory diseases, including gene discoveries, the elucidation of new pathogenic mechanisms, and the development of effective targeted therapies. PMID- 28711140 TI - Precision Medicine in Rheumatoid Arthritis. AB - Treatment of rheumatoid arthritis (RA) has substantially improved in recent years because of the development of novel drugs. However, response is not universal for any of the treatment options, and selection of an effective therapy is currently based on a trial-and-error approach. Delayed treatment response increases the risk of progressive joint damage and resultant disability and also has a significant impact on quality of life for patients. For many drugs, the patient's genetic background influences response to therapy, and understanding the genetics of response to therapy in RA may allow for targeted personalized health care. PMID- 28711141 TI - Genomic Influences on Hyperuricemia and Gout. AB - Genome-wide association studies (GWAS) have identified nearly 30 loci associated with urate concentrations that also influence the subsequent risk of gout. The ABCG2 Q141 K variant is highly likely to be causal and results in internalization of ABCG2, which can be rescued by drugs. Three other GWAS loci contain uric acid transporter genes, which are also highly likely to be causal. However identification of causal genes at other urate loci is challenging. Finally, relatively little is known about the genetic control of progression from hyperuricemia to gout. Only 4 small GWAS have been published for gout. PMID- 28711139 TI - Human Leukocyte Antigen-Disease Associations in Rheumatoid Arthritis. AB - The cause and pathogenesis of rheumatoid arthritis (RA) are influenced by environmental and genetic risk factors. Shared epitope-coding human leukocyte antigen (HLA)-DRB1 alleles increase RA risk and severity; however, the underlying mechanisms of action remain unclear. In contrast, several other DRB1 alleles protect against RA. Additionally, genome-wide association studies suggest that RA associates with other, HLA and non-HLA, genes; but the relative contributions of such risk loci to RA are incompletely understood. Future research challenges include integrating the epidemiologic and genomic data into validated arthritogenic pathways and determining the mechanisms of interaction between RA risk genes and environmental influences. PMID- 28711142 TI - Genetics and the Causes of Ankylosing Spondylitis. AB - Ankylosing spondylitis (AS) is a common inflammatory arthritis in which genetic factors are the primary determinants of disease risk and severity. Substantial progress has been made in identifying genetic pathways involved in the disease, and in translating those discoveries to drug discovery programs. Recently discovered novel disease pathways include those involved in control of DNA methylation, bacterial sensing, and mucosal immunity. Additional pathways are likely to be identified as a higher proportion of the genetic risk of AS is determined. PMID- 28711143 TI - Genomics of Systemic Lupus Erythematosus: Insights Gained by Studying Monogenic Young-Onset Systemic Lupus Erythematosus. AB - Systemic lupus erythematosus (SLE) is a systemic, autoimmune, multisystem disease with a heterogeneous clinical phenotype. Genome-wide association studies have identified multiple susceptibility loci, but these explain a fraction of the estimated heritability. This is partly because within the broad spectrum of SLE are monogenic diseases that tend to cluster in patients with young age of onset, and in families. This article highlights insights into the pathogenesis of SLE provided by these monogenic diseases. It examines genetic causes of complement deficiency, abnormal interferon production, and abnormalities of tolerance, resulting in monogenic SLE with overlapping clinical features, autoantibodies, and shared inflammatory pathways. PMID- 28711144 TI - Genetics of Juvenile Idiopathic Arthritis. AB - Juvenile idiopathic arthritis (JIA) affects approximately 1 in 1000 US children. The cause of JIA is most likely multifactorial and due to an interplay of genetics and environmental factors. This article summarizes the known genetic risk factors for JIA that have been identified, and in some cases replicated, using a variety of methods, including genomewide association and candidate gene association studies. A brief discussion regarding pharmacogenomics and studies to data linking genetics to treatment response and outcomes is included. PMID- 28711145 TI - Integrative Approaches to Understanding the Pathogenic Role of Genetic Variation in Rheumatic Diseases. AB - The use of high-throughput omics may help to understand the contribution of genetic variants to the pathogenesis of rheumatic diseases. We discuss the concept of missing heritability: that genetic variants do not explain the heritability of rheumatoid arthritis and related rheumatologic conditions. In addition to an overview of how integrative data analysis can lead to novel insights into mechanisms of rheumatic diseases, we describe statistical approaches to prioritizing genetic variants for future functional analyses. We illustrate how analyses of large datasets provide hope for improved approaches to the diagnosis, treatment, and prevention of rheumatic diseases. PMID- 28711146 TI - Drug Repositioning Strategies for the Identification of Novel Therapies for Rheumatic Autoimmune Inflammatory Diseases. AB - Rheumatic Autoimmune Inflammatory Diseases such as Sjogren's and lupus lack modern treatments. Less than 5% of drugs approved by the FDA from 2014 to mid 2016 had a RAID indication. Many RAID standard-of-care drugs were repurposed based on serendipitous observations, similarity-of-disease categorization, and/or off-target effects. Recently, drug repurposing has become more intentional, relying on an evolving awareness of molecular underpinnings, as well as a better understanding of drug-target interactions by computational modeling. Understanding mechanisms of disease pathogenesis can be synergistic in identifying new drug candidates and target pathways using unbiased Big-Data repositioning approaches as genomics, PheWAS (disease mechanism-of-action), GWAS and/or epigenetic-profiling. PMID- 28711147 TI - Future Directions of Genomics Research in Rheumatic Diseases. AB - Recent developments in human genome genotyping and sequencing technologies, such as genome-wide association studies and whole-genome sequencing analyses, have successfully identified several risk genes of rheumatic diseases. Fine-mapping studies using the HLA imputation method revealed that classical and non-classical HLA genes contribute to the risk of rheumatic diseases. Integration of human disease genomics with biological, medical, and clinical databases should contribute to the elucidation of disease pathogenicity and novel drug discovery. Disease risk genes identified by large-scale genetic studies are considered to be promising resources for novel drug discovery, including drug repositioning and biomarker microRNA screening for rheumatoid arthritis. PMID- 28711149 TI - Genomics in Rheumatic Diseases. PMID- 28711148 TI - A Review of Systemic Corticosteroid Use in Pregnancy and the Risk of Select Pregnancy and Birth Outcomes. AB - The evidence to date regarding corticosteroid exposure in pregnancy and select pregnancy and birth outcomes is limited and inconsistent. The authors provide a narrative review of published literature summarizing the findings for oral clefts, preterm birth, birth weight, preeclampsia, and gestational diabetes mellitus. Whenever possible, the results are limited to oral or systemic administration with a further focus on use in autoimmune disease. Although previous studies of corticosteroid exposure in pregnancy reported an increased risk of oral clefts in the offspring, more recent studies have not replicated these findings. PMID- 28711150 TI - Genomics in Rheumatic Diseases: Hope for the Future. PMID- 28711151 TI - Intelligent cooperation: A framework of pedagogic practice in the operating room. AB - BACKGROUND: Surgeons who work with trainees must address their learning needs without compromising patient safety. METHODS: We used a constructivist grounded theory approach to examine videos of five teaching surgeries. Attending surgeons were interviewed afterward while watching cued videos of their cases. Codes were iteratively refined into major themes, and then constructed into a larger framework. RESULTS: We present a novel framework, Intelligent Cooperation, which accounts for the highly adaptive, iterative features of surgical teaching in the operating room. Specifically, we define Intelligent Cooperation as a sequence of coordinated exchanges between attending and trainee that accomplishes small surgical steps while simultaneously uncovering the trainee's learning needs. CONCLUSIONS: Intelligent Cooperation requires the attending to accurately determine learning needs, perform real-time needs assessment, provide critical scaffolding, and work with the learner to accomplish the next step in the surgery. This is achieved through intense, coordinated verbal and physical cooperation. PMID- 28711152 TI - Functional analysis of acquired CD28 mutations identified in cutaneous T cell lymphoma. AB - CD28 is the major costimulatory receptor on T cells regulating proliferation, survival and effector function. Acquired mutations in the extracellular domain of CD28 have been identified in patients with cutaneous T cell lymphoma, angioimmunoblastic T cell lymphoma and other T cell neoplasms, suggesting it may contribute to disease pathogenesis. We used a heterologous system in which mutant human CD28 was expressed on primary murine T cells deficient in CD28 to ascertain how specific mutations identified in a genetic screen of patients with cutaneous T cell lymphoma affected normal T cell function. All three mutant CD28 proteins examined enhanced CD28-dependent T cell proliferation and effector function. These data suggest that the mutant CD28 isoforms could accelerate tumor cell growth and increase tumor burden in affected patients. Interruption of CD28:ligand interactions may be an effective, targeted therapy for a subset of patients whose tumors bear the mutant CD28 receptor. PMID- 28711153 TI - There's no difference-are you sure? PMID- 28711154 TI - Western Diet-Induced Dysbiosis in Farnesoid X Receptor Knockout Mice Causes Persistent Hepatic Inflammation after Antibiotic Treatment. AB - Patients who have liver cirrhosis and liver cancer also have reduced farnesoid X receptor (FXR). The current study analyzes the effect of diet through microbiota that affect hepatic inflammation in FXR knockout (KO) mice. Wild-type and FXR KO mice were on a control (CD) or Western diet (WD) for 10 months. In addition, both CD- and WD-fed FXR KO male mice, which had hepatic lymphocyte and neutrophil infiltration, were treated by vancomycin, polymyxin B, and Abx (ampicillin, neomycin, metronidazole, and vancomycin). Mice were subjected to morphological analysis as well as gut microbiota and bile acid profiling. Male WD-fed FXR KO mice had the most severe steatohepatitis. FXR KO also had reduced Firmicutes and increased Proteobacteria, which could be reversed by Abx. In addition, Abx eliminated hepatic neutrophils and lymphocytes in CD-fed, but not WD-fed, FXR KO mice. Proteobacteria and Bacteroidetes persisted in WD-fed FXR KO mice even after Abx treatment. Only polymyxin B could reduce hepatic lymphocytes in WD-fed FXR KO mice. The reduced hepatic inflammation by antibiotics was accompanied by decreased free and conjugated secondary bile acids as well as changes in gut microbiota. Our data revealed that Lactococcus, Lactobacillus, and Coprococcus protect the liver from inflammation. PMID- 28711156 TI - Towards a Structural View of Drug Binding to hERG K+ Channels. AB - The human ether-a-go-go-related gene (hERG) K+ channel is of great medical and pharmaceutical relevance. Inherited mutations in hERG result in congenital long QT syndrome which is associated with a markedly increased risk of cardiac arrhythmia and sudden death. hERG K+ channels are also remarkably susceptible to block by a wide range of drugs, which in turn can cause drug-induced long-QT syndrome and an increased risk of sudden death. The recent determination of the near-atomic resolution structure of the hERG K+ channel, using single-particle cryo-electron microscopy (cryo-EM), provides tremendous insights into how these channels work. It also suggests a way forward in our quest to understand why these channels are so promiscuous with respect to drug binding. PMID- 28711157 TI - MAIA Trapeziometacarpal Joint Arthroplasty: Clinical and Radiological Outcomes of 80 Patients With More than 6 Years of Follow-Up. AB - PURPOSE: Trapeziometacarpal (TMC) total joint replacement is increasingly being performed in Europe. MAIA TMC total joint arthroplasty is a modular uncemented ball-and-socket hydroxyapatite-coated implant. This study assessed the midterm clinical and radiological results of the MAIA TMC prosthesis. METHODS: This single-center retrospective study involved 80 patients who underwent 96 MAIA TMC prosthesis implantations from February 2006 to April 2009, and who had a minimum of 5 years' follow-up. Indications for the procedure were painful TMC joint osteoarthritis affecting activities of daily living and a failure of at least 6 months of nonsurgical treatment. Pre- and postoperative clinical and radiographic data were reviewed. RESULTS: The mean age at surgery was 68 years (range, 53-84 years) and the median follow-up was 76 months (range, 60-102 months). The mean Quick Disabilities of the Arm, Shoulder, and Hand score improved from 61.3 +/- 17.1 to 17.5 +/- 16. The mobility of the thumb was restored to a range of motion comparable with that of the contralateral thumb. Opposition, defined by the Kapandji score, was almost normal (9.2 of 10; range, 6-10), as was the final mean key pinch and grip strength, which improved by 26% and 43%, respectively. Among the 96 implants, 4 (4.2%) were surgically revised for trapezium loosening. One dislocation was treated with closed reduction; 3 (3.1%) posttraumatic trapezium fractures were immobilized for 8 weeks. Among the 26 preoperative reducible z deformities, only 5 (19.2%) were not totally corrected after surgery. The procedure success, by survival analysis over 6 years, was 93% (95% confidence interval, 87-98). CONCLUSIONS: MAIA TMC total joint arthroplasty may be a reliable treatment option for TMC joint osteoarthritis, with very good results for pain relief, strength, mobility, and restoration of the thumb length, providing correction of most thumb z-deformities. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 28711155 TI - Manufacturing Cell Therapies Using Engineered Biomaterials. AB - Emerging manufacturing processes to generate regenerative advanced therapies can involve extensive genomic and/or epigenomic manipulation of autologous or allogeneic cells. These cell engineering processes need to be carefully controlled and standardized to maximize safety and efficacy in clinical trials. Engineered biomaterials with smart and tunable properties offer an intriguing tool to provide or deliver cues to retain stemness, direct differentiation, promote reprogramming, manipulate the genome, or select functional phenotypes. This review discusses the use of engineered biomaterials to control human cell manufacturing. Future work exploiting engineered biomaterials has the potential to generate manufacturing processes that produce standardized cells with well defined critical quality attributes appropriate for clinical testing. PMID- 28711158 TI - [Diffuse arthromyalgia in a 59-year-old man]. PMID- 28711159 TI - [Hemolytic and uremic syndrome and related thrombotic microangiopathies: Epidemiology, pathophysiology and clinics]. AB - Thrombotic microangiopathies (TMA) represent an eclectic group of conditions, which share hemolytic anemia and thrombocytopenia as a common defining basis. Remarkable breakthroughs in the physiopathological setting have allowed for a thorough recomposition of the disparate syndromes, which form the constellation of TMA. In this view, clinicians now discriminate thrombocytopenic thrombotic purpura (TTP) defined by a severe deficiency in ADAMTS13, which is rarely associated with a severe renal involvement and the hemolytic and uremic syndrome (HUS) in which renal impairment is the most prominent clinical feature. HUS can result from toxins stemming from bacterial infections of the digestive tract, alternate complement pathway abnormalities, metabolic or coagulation disorders or, lastly, drug and various toxic compounds. The diverse forms of HUS reflect the insights gained in the understanding of the pathophysiological mechanisms underpinning TMA. In this first part, a broad overview of the epidemiological, physiopathological and clinical aspects of HUS and related TMA syndromes is presented. PMID- 28711160 TI - 7Be and 210Pb wet/dry deposition in Melbourne, Australia and the development of deployable units for radiological emergency monitoring. AB - A large stainless-steel collection tray (with a surface area of one square metre) was purpose built and mounted on the roof of the Australian Radiation Protection and Nuclear Safety Agency (ARPANSA) building at Yallambie, Victoria, Australia. Using this system two years' worth of wet/dry deposition samples have been collected and analysed. Smaller portable units were also developed for deployment in an emergency and/or for environmental monitoring. The cosmogenic radionuclide 7Be and the naturally occurring terrestrial radionuclide 210Pb have been used to validate the systems. The data from the smaller units was successfully compared to the larger permanent collection unit for validation, thus finding the portable units fit for purpose. Monitoring of wet and dry fallout deposition is an important response to radiological emergencies. It can provide useful information in verifying predictive models of radionuclide atmospheric transport and dispersion, in addition to providing local deposition data. PMID- 28711161 TI - Role of fatty acids in cold adaptation of Antarctic psychrophilic Flavobacterium spp. AB - Cold-loving microorganisms developed numerous adaptation mechanisms allowing them to survive in extremely cold habitats, such as adaptation of the cell membrane. The focus of this study was on the membrane fatty acids of Antarctic Flavobacterium spp., and their adaptation response to cold-stress. Fatty acids and cold-response of Antarctic flavobacteria was also compared to mesophilic and thermophilic members of the genus Flavobacterium. The results showed that the psychrophiles produced more types of major fatty acids than meso- and thermophilic members of this genus, namely C15:1 iso G, C15:0 iso, C15:0 anteiso, C15:1omega6c, C15:0 iso 3OH, C17:1omega6c, C16:0 iso 3OH and C17:0 iso 3OH, summed features 3 (C16:1omega7cand/or C16:1omega6c) and 9 (C16:0 10-methyl and/or C17:1 iso omega9c). It was shown that the cell membrane of psychrophiles was composed mainly of branched and unsaturated fatty acids. The results also implied that Antarctic flavobacteria mainly used two mechanisms of membrane fluidity alteration in their cold-adaptive response. The first mechanism was based on unsaturation of fatty acids, and the second mechanism on de novo synthesis of branched fatty acids. The alteration of the cell membrane was shown to be similar for all thermotypes of members of the genus Flavobacterium. PMID- 28711162 TI - Actin cytoskeleton stiffness grades metastatic potential of ovarian carcinoma Hey A8 cells via nanoindentation mapping. AB - Recent studies have indicated that the nanoindentation measured stiffness of carcinoma adherent cells is in general lower than normal cells, thus suggesting that cell stiffness may serve as a bio-marker for carcinoma. However, the proper establishment of such a conclusion would require biophysical understanding of the underlying mechanism of the cell stiffness. In this work, we compared the elastic moduli of the actin cytoskeletons of Hey A8 ovarian carcinoma cells with and without metastasis (HM and NM), as measured by 2D atomic force microscopy (AFM) with low-depth nanoindentation via a rate-jump method. The results indicate clearly that HM cells showed lower actin cytoskeleton stiffness atop of their nucleus position and higher actin cytoskeleton stiffness at their rims, compared to NM cells, suggesting that the local stiffness on the cytoskeleton can reflect actin filament distribution. Immunofluorescence staining and scanning electron microscopy (SEM) also indicated that the difference in stiffness in Hey A8 cells with different metastasis is associated with their F-actin rearrangement. Finite element modelling (FEM) shows that a migrating cell would have its actin filaments bundled together to form stress fibers, which would exhibit lower indentation stiffness than the less aligned arrangement of filaments in a non migrating cell. The results here indicate that the actin cytoskeleton stiffness can serve as a reliable marker for grading the metastasis of adherent carcinoma cells due to their cytoskeleton change and potentially predicting the migration direction of the cells. PMID- 28711163 TI - Effects of the basic multicellular unit and lamellar thickness on osteonal fatigue life. AB - A remodeling cycle sets the size of the osteon and associated lamellae in the basic multicellular unit. Treatments and aging affect these micro-structural features. We previously demonstrated decreased fatigue life with an unexplained mechanism and decreased osteon size in cortical bone treated with high-dose bisphosphonate. Here, three finite element models were examined: type-1: a single osteon, as a homogeneous unit and with heterogeneous lamellae and interlamellae, type-2: a control, interstitial-only tissue and type-3: the osteon with cement line, set within the interstitial tissue. Models were loaded in simulated, sinusoidal bending fatigue. As osteon size was decreased, lamellar number and lamellar thickness were incrementally adjusted for each model. As hypothesized, lamellae within the larger type-1 models attained greater cycles to failure and the addition of an osteon to type-2 models (generating a type-3 model set) yielded increased fatigue life. However, as the osteon size was decreased, the potential for compressive damage nucleation was increased within the lamellae of the osteons versus the interstitium. Also, osteons with fewer, thicker lamellae displayed increased fatigue life. Osteonal microstructure plays a role in damage initiation location, especially when BMU size is smaller. Previous findings by us and others could partially be explained by this further understanding of increased probability for damage nucleation in smaller osteons. PMID- 28711164 TI - On estimating intraventricular hemodynamic forces from endocardial dynamics: A comparative study with 4D flow MRI. AB - Intraventricular pressure gradients or hemodynamic forces, which are their global measure integrated over the left ventricular volume, have a fundamental importance in ventricular function. They may help revealing a sub-optimal cardiac function that is not evident in terms of tissue motion, which is naturally heterogeneous and variable, and can influence cardiac adaptation. However, hemodynamic forces are not utilized in clinical cardiology due to the unavailability of simple non-invasive measurement tools. Hemodynamic forces depend on the intraventricular flow; nevertheless, most of them are imputable to the dynamics of the endocardial flow boundary and to the exchange of momentum across the mitral and aortic orifices. In this study, we introduce a simplified model based on first principles of fluid dynamics that allows estimating hemodynamic forces without knowing the velocity field inside the LV. The model is validated with 3D phase-contrast MRI (known as 4D flow MRI) in 15 subjects, (5 healthy and 10 patients) using the endocardial surface reconstructed from the three standard long-axis projections. Results demonstrate that the model provides consistent estimates for the base-apex component (mean correlation coefficient r=0.77 for instantaneous values and r=0.88 for root mean square) and good estimates of the inferolateral-anteroseptal component (r=0.50 and 0.84, respectively). The present method represents a potential integration to the existing ones quantifying endocardial deformation in MRI and echocardiography to add a physics-based estimation of the corresponding hemodynamic forces. These could help the clinician to early detect sub-clinical diseases and differentiate between different cardiac dysfunctional states. PMID- 28711165 TI - BRAF Mutation Status Concordance Between Primary Cutaneous Melanomas and Corresponding Metastases: A Review of the Latest Evidence. AB - The identification of B-Raf proto-oncongene (BRAF) mutation and the emergence of targeted therapy marked a turning point in the treatment of melanoma. The study of mutation status concordance between primary tumors and metastases in this cancer has major treatment implications as it facilitates the selection of candidates for targeted therapy. This review analyzes the evidence on the level of mutation status concordance between primary tumors and different types of metastases in cutaneous melanoma and provides an overview of the advantages and disadvantages of the various methods used to detect BRAF mutations. PMID- 28711166 TI - Treatment of Palmar Hyperhidrosis by Peripheral Nerve Block at the Wrist With Botulinum Toxin. PMID- 28711168 TI - Surgical treatment of intestinal complications of graft versus host disease in the pediatric population: Case series and review of literature. AB - BACKGROUND/PURPOSE: Intestinal complications of acute graft-versus-host disease (aGVHD) include hemorrhage and perforation in the short-term, and stricture with bowel obstruction in the long-term. As medical management of severe aGVHD has improved, more patients are surviving even advanced stages of intestinal aGVHD. This review summarizes the available pediatric literature on surgical treatment of complications of intestinal GVHD. METHODS: A systematic review was performed using PubMed, Cochrane, Embase, and Scopus databases. Any publication that addressed surgical treatment of acute and chronic intestinal GVHD in the pediatric population was reviewed in detail. Furthermore, we included information on 5 additional patients from the institutions of this review's authors, which had not been previously published. RESULTS: We identified 8 studies, comprising 13 patients. Surgical interventions were undertaken for a variety of intestinal GVHD complications, including small bowel obstruction owing to stricture (n=8), enterocutaneous fistulae (n=2), gastrointestinal hemorrhage/perforation (n=1 each), and esophageal stricture (n=1). Among eight patients with bowel obstruction as an indication, pathology revealed ulceration with fibrosis in all but one; 3 had signs of persistent GVHD. Surgical mortality was reported in 4 patients (31%) at an average of 6weeks postoperatively. The median overall follow up time was 20months (IQR, 2-21). CONCLUSIONS: Although intestinal aGVHD management is almost exclusively medical, a small subset of patients develops complications of intestinal GVHD that require surgical intervention. With expanding indications for stem cell transplantation as well as improved survival after previously fatal bouts of intestinal aGVHD, it is likely that surgical intervention will become more common in these complicated patients. SYSTEMATIC REVIEW: Level of Evidence: Level IV. PMID- 28711167 TI - Perioperative management of hypertensive neuroblastoma: A study from the Italian Group of Pediatric Surgical Oncologists (GICOP). AB - BACKGROUND: Hypertension (HT) is rarely reported in patients affected by Neuroblastoma (NB), and management guidelines are lacking. Clinical features and perioperative medical treatment in such patients were reviewed to 1) ascertain whether a shared treatment strategy exists among centers and 2) if possible, propose some recommendations for the perioperative management of HT in NB patients. METHODS: A retrospective multicenter survey was conducted on patients affected by NB who presented HT symptoms. RESULTS: From 2006 to 2014, 1126 children were registered in the Italian Registry of Neuroblastoma (RINB). Of these, 21 with HT (1.8%) were included in our analysis. Pre- and intraoperative HT management was somewhat dissimilar among the participating centers, apart from a certain consistency in the intraoperative use of the alpha-1 blocker urapidil. Six of the 21 patients (28%) needed persistent antihypertensive treatment at a median follow-up of 36months (range 4-96months) despite tumor removal. Involvement of the renal pedicle was the only risk factor constantly associated to HT persistency following surgery. A correlation between the presence of HT and the secretion of specific catecholamines and/or compression of the renal vascular pedicle could not be demonstrated. CONCLUSION: Based on this retrospective review of NB patients with HT, no definite therapeutic protocol can be recommended owing to heterogeneity of adopted treatments in different centers. A proposal of perioperative HT management in NB patients is however presented. LEVEL OF EVIDENCE: IV. PMID- 28711169 TI - The risk of suprascapular and axillary nerve injury in reverse total shoulder arthroplasty: An anatomic study. AB - PURPOSE: Implantation of a reverse total shoulder arthroplasty (rTSA) places the axillary and suprascapular nerves at risk. The aim of this anatomic study was to digitally analyse the location of these nerves in relation to bony landmarks in order to predict their path and thereby help to reduce the risk of neurological complications during the procedure. METHODS: A total of 22 human cadaveric shoulder specimens were used in this study. The axillary and suprascapular nerves were dissected, and radiopaque threads were sutured onto the nerves without mobilizing the nerves from their native paths. Then, 3D X-ray scans of the specimens were performed, and the distance of the nerves to bony landmarks at the humerus and the glenoid were measured. RESULTS: The distance of the inferior glenoid rim to the axillary nerve averaged 13.6mm (5.8-27.0mm, +/-5.1mm). In the anteroposterior direction, the distance between the axillary nerve and the humeral metaphysis averaged 8.1mm (0.6-21.3mm, +/-6.5mm). The distance of the glenoid centre to the suprascapular nerve passing point under the transverse scapular ligament measured 28.4mm (18.9-35.1mm, +/-3.8mm) in the mediolateral direction and 10.8mm (-4.8 to 25.3mm, +/-6.1mm) in the anteroposterior direction. The distance to the spinoglenoid notch was 16.6mm (11.1-24.9mm, +/-3.4mm) in the mediolateral direction and -11.8mm posterior (-19.3 to -4.7mm, +/-4.7mm) in the anteroposterior direction. CONCLUSIONS: Implantation of rTSA components endangers the axillary nerve because of its proximity to the humeral metaphysis and the inferior glenoid rim. Posterior and superior drilling and extraosseous screw placement during glenoid baseplate implantation in rTSA place the suprascapular nerve at risk, with safe zones to the nerve passing the spinoglenoid notch of 11mm and to the suprascapular notch of 19mm. PMID- 28711170 TI - Early selenium treatment for traumatic brain injury: Does it improve survival and functional outcome? AB - BACKGROUND: Traumatic brain injury (TBI) is a major cause of death and debility following trauma. The initial brain tissue insult is worsened by secondary reactive responses including oxidative stress reactions, inflammatory changes and subsequent permanent neurologic deficits. Effective agents to improve functional outcome and survival following TBI are scarce. Selenium is an antioxidant which has shown to reduce oxidative stress. This study examines the effect of intravenous selenium (Selenase(r)) treatment in patients with severe TBI on functional outcome and survival in a prospective study design. METHODS: Patients sustaining TBI were prospectively identified during a 12-month period at an academic urban trauma center. Study inclusion criteria applied were: age >=18 years, blunt injury mechanism and admission to neurosurgical intensive care unit (NICU). Early deaths (<=48h) and patients suffering extracranial injuries requiring invasive interventions or surgery were excluded. All consecutive admissions during a six-month period were administered intravenous Selenase(r) for a maximum 10-day period and constituted cases. Patient demographics and outcomes up to six-months post-discharge were collected for analysis. RESULTS: A total of 307 patients met inclusion criteria of which 125 were administered Selenase(r). Stepwise Poisson regression analysis identified five common predictors of poor functional outcome and in-hospital mortality: GCS <=8, age >=55 years, hypotension at admission, high Rotterdam score and invasive neurosurgical intervention. Selenase(r) significantly reduced the risk of unfavourable functional outcomes, defined as GOS-E <=4, at both discharge (adjusted RR 0.69, 95% CI 0.51-0.92, p=0.012) and at six months follow-up (adjusted RR 0.61, 95% CI 0.44-0.83, p=0.002). Following adjustment for significant group differences similar results were seen for functional outcome. Selenase(r) did not improve survival (adjusted RR 1.12, 95% CI 0.62-2.02, p=0.709). CONCLUSION: Intravenous Selenase(r) treatment demonstrates a significant improvement in functional neurologic outcome. This effect is sustained at six months following discharge. PMID- 28711171 TI - The pivotal role of the coronal fracture line for a new three-dimensional CT based fracture classification of bicondylar proximal tibial fractures. AB - INTRODUCTION: Classical fracture classifications (AO/OTA, Schatzker) are commonly used to characterize bicondylar proximal tibial fractures. However, none of these classifications allows for a treatment algorithm. The aim of our study was to use 3D appearance of these fractures in CT imaging to improve the clinical value of the classification. MATERIALS AND METHODS: 3D appearance of 81 CT scans of bicondylar proximal tibial fractures were systematically analyzed and were classified in 3 subtypes, based on the fracture lines orientation. The novel classification was compared for reliability and for clinical relevance with AO and Schatzker classification. RESULTS: A total of 159 fracture lines were identified which were most frequently oriented in sagittal (89/159), and in coronal (41/159) direction. Based on the orientation of the major fracture lines three fracture types were defined. A special emphasis was drawn to the coronal fracture line of the medial plateau leading to a surgical treatment algorithm. Interobserver reliability was analyzed for all 81 patients resulting in an excellent reliability of K=0.936 for the 3D classification scheme compared to K=0.720 for the AO/OTA, K=0.785 for the Schatzker classification. Correlations with clinical parameters were only observed for the 3D classification. DISCUSSION: The presented classification scheme based on the 3D geometry of bicondylar proximal tibial fractures demonstrates a good reliability of clinical relevance. PMID- 28711172 TI - The Effect of RNA Secondary Structure on the Self-Assembly of Viral Capsids. AB - Previous work has shown that purified capsid protein (CP) of cowpea chlorotic mottle virus (CCMV) is capable of packaging both purified single-stranded RNA molecules of normal composition (comparable numbers of A, U, G, and C nucleobases) and of varying length and sequence, and anionic synthetic polymers such as polystyrene sulfonate. We find that CCMV CP is also capable of packaging polyU RNAs, which-unlike normal-composition RNAs-do not form secondary structures and which act as essentially structureless linear polymers. Following our canonical two-step assembly protocol, polyU RNAs ranging in length from 1000 to 9000 nucleotides (nt) are completely packaged. Surprisingly, negative-stain electron microscopy shows that all lengths of polyU are packaged into 22-nm diameter particles despite the fact that CCMV CP prefers to form 28-nm-diameter (T = 3) particles when packaging normal-composition RNAs. PolyU RNAs >5000 nt in length are packaged into multiplet capsids, in which a single RNA molecule is shared between two or more 22-nm-diameter capsids, in analogy with the multiplets of 28-nm-diameter particles formed with normal-composition RNAs >5000 nt long. Experiments in which viral RNA competes for viral CP with polyUs of equal length show that polyU, despite its lack of secondary structure, is packaged more efficiently than viral RNA. These findings illustrate that the secondary structure of the RNA molecule-and its absence-plays an essential role in determining capsid structure during the self-assembly of CCMV-like particles. PMID- 28711173 TI - Presymptomatic Diagnosis of Spinal Muscular Atrophy Through Newborn Screening. AB - OBJECTIVE: To demonstrate the feasibility of presymptomatic diagnosis of spinal muscular atrophy (SMA) through newborn screening (NBS). STUDY DESIGN: We performed a screening trial to assess all newborns who underwent routine newborn metabolic screening at the National Taiwan University Hospital newborn screening center between November 2014 and September 2016. A real-time polymerase chain reaction (RT-PCR) genotyping assay for the SMN1/SMN2 intron 7 c.888+100A/G polymorphism was performed to detect homozygous SMN1 deletion using dried blood spot (DBS) samples. Then the exon 7 c.840C>T mutation and SMN2 copy number were determined by both droplet digital PCR (ddPCR) using the original screening DBS and multiplex ligation-dependent probe amplification (MLPA) using a whole blood sample. RESULTS: Of the 120 267 newborns, 15 tested positive according to the RT PCR assay. The DBS ddPCR assay excluded 8 false-positives, and the other 7 patients were confirmed by the MLPA assay. Inclusion of the second-tier DBS ddPCR screening assay resulted in a positive prediction value of 100%. The incidence of SMA was 1 in 17 181 (95% CI, 1 in 8323 to 1 in 35 468). Two of the 3 patients with 2 copies of SMN2 and all 4 patients with 3 or 4 copies of SMN2 were asymptomatic at the time of diagnosis. Five of the 8 false-positives were caused by intragenic recombination between SMN1 and SMN2. CONCLUSION: Newborn screening can detect patients affected by SMA before symptom onset and enable early therapeutic intervention. A combination of a RT-PCR and a second-tier ddPCR can accurately diagnose SMA from DBS samples with no false-positives. TRIAL REGISTRATION: ClinicalTrials.gov NCT02123186. PMID- 28711174 TI - Secondhand Smoke Exposure and Preclinical Markers of Cardiovascular Risk in Toddlers. AB - OBJECTIVE: To investigate relationships between secondhand smoke exposure in young children and several preclinical markers of cardiovascular risk that have been established as relevant to adult populations. STUDY DESIGN: There were 139 children, 2-5 years of age, enrolled in a cross-sectional study. Secondhand smoke exposure was objectively determined by hair nicotine level; a comprehensive panel of clinical markers (morning blood pressure, fasting glucose and insulin, lipid profiles, inflammation) and research markers (markers of oxidation, endothelial stress, and endothelial repair) of cardiovascular risk status were assessed. Univariate and multivariate linear regression were used to evaluate relationships between secondhand smoke exposure and cardiovascular risk markers. RESULTS: Hair nicotine levels were correlated directly with blood pressure and serum C-reactive protein, and inversely correlated with serum high-density lipoprotein cholesterol and endothelial cell progenitor cell prevalence. In multivariate analyses, these relationships remained when controlled for age, sex, body mass index z-score, maternal education, and method of payment. Additionally, in multivariate analyses, hair nicotine level was significantly negatively correlated with total antioxidant capacity. CONCLUSIONS: These results support the view that secondhand smoke exposure in the very young has a detectable relationship with several markers of cardiovascular risk, long before the emergence of clinical disease. Further studies to define mechanisms and strategies to prevent and mitigate these risks early in life are warranted. PMID- 28711176 TI - Biologic Agents in the Treatment of Childhood-Onset Rheumatic Disease. PMID- 28711175 TI - The Prevalence of Rome IV Nonerosive Esophageal Phenotypes in Children. AB - OBJECTIVES: To assess the prevalence of Rome IV nonerosive esophageal phenotypes in children using multichannel intraluminal impedance testing and to describe the rates of proton pump inhibitor (PPI) responsiveness and the frequency of microscopic esophagitis in these patients. STUDY DESIGN: We conducted a retrospective review of all children >=5 years of age who underwent esophagogastroduodenoscopy and multichannel intraluminal impedance testing off PPI therapy for evaluation of typical gastroesophageal reflux symptoms. Only children with symptoms during the multichannel intraluminal impedance testing were included. Children were categorized into the following nonerosive esophageal phenotypes using Rome IV criteria: nonerosive reflux disease, reflux hypersensitivity, and functional heartburn. Rates of esophagitis and responsiveness to acid suppression therapy were assessed. RESULTS: Forty-five children were included: 27% were categorized as having nonerosive reflux disease, 29% with reflux hypersensitivity (27% acid and 2% nonacid), and 44% with functional heartburn. Older children reported significantly more heartburn (P < .001) than younger children, whereas younger children were more likely to report nonspecific pain (P = .047). There were no differences between groups in other reflux symptoms, rates of responsiveness to PPIs, or the presence of microscopic esophagitis on biopsy. CONCLUSIONS: Functional heartburn is the most common Rome IV nonerosive esophageal phenotype in children. Neither microscopic esophagitis nor PPI responsiveness can predict phenotype in pediatric patients. PMID- 28711177 TI - Size of Facial Port-Wine Birthmark May Predict Neurologic Outcome in Sturge-Weber Syndrome. AB - OBJECTIVE: To determine whether the size of the birthmark in patients with Sturge Weber syndrome (SWS) who have brain involvement can help predict neurologic disability. STUDY DESIGN: Fifty-one patients with SWS with facial birthmarks and brain involvement documented on magnetic resonance imaging were included in this retrospective chart review. A neuroradiologist, blinded to all clinical information, assigned a previously validated SWS neuroimaging score. A pediatric neurologist prospectively assigned previously validated neurologic severity scores, based on seizures, hemiparesis, visual field cut, and cognitive impairments. Three raters, blinded to clinical scores, independently graded the size of facial birthmark in each patient based on photographs. Their scores were averaged. Birthmark scores were compared with the imaging and neurologic severity results using nonparametric correlation analysis. RESULTS: Size of facial port wine birthmark correlates with magnetic resonance imaging scores on the left and right sides (rho = 0.57 and 0.66 [P < .001], respectively). Size is also positively associated with the neurologic severity rating for patients age 6 years and above (1-sided Fisher exact, P = .032). CONCLUSIONS: The size of facial port-wine birthmark in SWS brain involvement can be developed as a tool to predict neurologic severity of the disease. PMID- 28711178 TI - Epidural dye spread in the porcine model: effects of flow rates during bolus administration. PMID- 28711179 TI - Immediate birth - an analysis of women and their babies undergoing time critical birth in a tertiary referral obstetric hospital. AB - BACKGROUND: At our institution, the emergency obstetric 'code green' activates the system for immediate birth, usually by caesarean section. This study aimed to determine the incidence of immediate birth, indications, modes of anaesthesia, and short-term neonatal and maternal outcomes. METHOD: A review was performed for all women at the Royal Women's Hospital, Parkville, Australia who underwent immediate birth over a two-year period: January 1, 2013 to December 31, 2014. RESULTS: Within the study period 14,115 women gave birth, of which 387 women underwent an immediate birth, the majority (83%) by caesarean section. The commonest indication for immediate birth was prolonged fetal bradycardia (53%), however cord prolapse (4%) produced the most rapid decision-to-delivery interval, with a median [IQR] time of 14 [13-16] min versus 18 [14-23] min for all immediate births (P<0.01). Epidural top-up was the most common anaesthesia method. Conversion to general anaesthesia following inadequate neuraxial anaesthesia occurred in 6.2% of women. Among 103 general anaesthetics, there was one failed intubation (successful ventilation) and one dental injury. Nine women (2.3%) were admitted to the high dependency or intensive care units, and there were no maternal deaths. Babies born by caesarean section with a decision-to delivery interval of less than 30min were more likely to have longer times to establish respiration (22.6% vs 16.7%, P<0.001). CONCLUSION: Request for immediate delivery is a common obstetric emergency. Epidural top-up has become the most common anaesthetic technique. Rapid delivery times can be achieved with an integrated emergency response system. PMID- 28711180 TI - Anaesthetic considerations in a parturient with Behcet's disease. PMID- 28711181 TI - Electrochemical process for electrode material of spent lithium ion batteries. AB - Electrochemical method for recovering cobalt and manganese from electrode materials of spent lithium ion batteries was studied. Electrochemical leaching of cobalt and manganese from electrode material was optimized by varying different process parameters such as time, acid concentration and current density. Both cobalt and manganese could effectively be leached out at a current density of 400A/m2 in 3h using 2M sulphuric acid. In the subsequent study, the metallic cobalt and electrolytic manganese dioxides was recovered from the leach liquor at 200A/m2, pH 2-2.5 and 90 degrees C after removing aluminum. The commercial feasibility of the study was tested in pilot scale. Overall recovery of Co, Cu and Mn was above 96%, 97% and 99%, respectively. PMID- 28711182 TI - Slaughterhouse by-products treatment using anaerobic digestion. AB - The objective of the present study is to evaluate the use of animal by-products (ABP) as substrates for anaerobic digestion, aiming at methane production. Specifically, four ABP of Category 2 and 3, namely (i) stomach and rumen, (ii) stomach contents, (iii) breasts and reproductive organs and (iv) bladders and intestines with their contents, were selected. The methane potential of each ABP was initially determined, while the feasibility of anaerobic co-digestion of ABP with two agroindustrial waste, i.e. orange peels and olive leaves was also studied. To this purpose, Biochemical Methane Potential (BMP), as well as semi continuous assays were respectively conducted. In the latter, the effect of the variation in the organic loading rate (OLR) on methane production was investigated. Results obtained from BMP assays showed that the samples containing breasts and reproductive organs, bladders and intestine, and stomach and rumen, had higher methane potentials of 815, 787 and 759 mLCH4,STP/gVS, respectively. Moreover, according to the results of the semi-continuous assays, maximum methane yields between 253 and 727mLCH4/gVSfed were obtained at an OLR of 0.8gVS/L/d. The only case in which methanogenesis inhibition phenomena, due to increased ammonia concentrations, were observed, was the assay being fed with a mixture of breasts and reproductive organs and orange peels, at the highest OLR. This inhibition phenomenon was attributed to an inappropriate C/N ratio. PMID- 28711183 TI - Fast protocol for radiochromic film dosimetry using a cloud computing web application. AB - PURPOSE: To investigate the feasibility of a fast protocol for radiochromic film dosimetry to verify intensity-modulated radiotherapy (IMRT) plans. METHOD AND MATERIALS: EBT3 film dosimetry was conducted in this study using the triple channel method implemented in the cloud computing application (Radiochromic.com). We described a fast protocol for radiochromic film dosimetry to obtain measurement results within 1h. Ten IMRT plans were delivered to evaluate the feasibility of the fast protocol. The dose distribution of the verification film was derived at 15, 30, 45min using the fast protocol and also at 24h after completing the irradiation. The four dose maps obtained per plan were compared using global and local gamma index (5%/3mm) with the calculated one by the treatment planning system. Gamma passing rates obtained for 15, 30 and 45min post exposure were compared with those obtained after 24h. RESULTS: Small differences respect to the 24h protocol were found in the gamma passing rates obtained for films digitized at 15min (global: 99.6%+/-0.9% vs. 99.7%+/-0.5%; local: 96.3%+/ 3.4% vs. 96.3%+/-3.8%), at 30min (global: 99.5%+/-0.9% vs. 99.7%+/-0.5%; local: 96.5%+/-3.2% vs. 96.3+/-3.8%) and at 45min (global: 99.2%+/-1.5% vs. 99.7%+/ 0.5%; local: 96.1%+/-3.8% vs. 96.3+/-3.8%). CONCLUSIONS: The fast protocol permits dosimetric results within 1h when IMRT plans are verified, with similar results as those reported by the standard 24h protocol. PMID- 28711184 TI - Establishing national diagnostic reference levels (DRLs) for computed tomography in Egypt. AB - OBJECTIVES: To establish national diagnostic reference levels (DRLs) in Egypt for computed tomography (CT) examinations of adults and identify the potential for optimization. METHODS: Data from 3762 individual patient's undergoing CT scans of head, chest (high resolution), abdomen, abdomen-pelvis, chest-abdomen-pelvis and CT angiography (aorta and both lower limbs) examinations in 50 CT facilities were collected. This represents 20% of facilities in the country and all of the 27 Governorates. Results were compared with DRLs of UK, USA, Canada, Japan, Australia and France. RESULTS: The Egyptian DRLs for CTDIvol in mGy are for head: 30, chest (high resolution): 22, abdomen (liver metastasis): 31, abdomen-pelvis: 31, chest-abdomen-pelvis: 33 and CT angiography (aorta and lower limbs): 37. The corresponding DRLs for DLP in mGy.cm are 1360, 420, 1425, 1325, 1320 and 1320. For head CT, the Egyptian DRL for CTDIvol is 2-3 times lower than the DRLs from other countries. However, the DRL in terms of DLP is in the same range or higher as compared to others. The Egyptian DRL for chest CT (high resolution) is similar to others for DLP but higher for CTDIvol. For abdomen and abdomen-pelvis DRLs for CTDIvol are higher than others. For DLP, the DRLs for abdomen are higher than DRL in UK and lower than those in Japan, while for abdomen-pelvis they are higher than other countries. CONCLUSION: Despite lower DRLs for CTDIvol, an important consistent problem appears to be higher scan range as DRLs for DLP are higher. PMID- 28711185 TI - Dosimetric characterization of 3D printed bolus at different infill percentage for external photon beam radiotherapy. AB - BACKGROUND AND PURPOSE: 3D printing is rapidly evolving and further assessment of materials and technique is required for clinical applications. We evaluated 3D printed boluses with acrylonitrile butadiene styrene (ABS) and polylactide (PLA) at different infill percentage. MATERIAL AND METHODS: A low-cost 3D printer was used. The influence of the air inclusion within the 3D printed boluses was assessed thoroughly both with treatment planning system (TPS) and with physical measurements. For each bolus, two treatment plans were calculated with Monte Carlo algorithm, considering the computed tomography (CT) scan of the 3D printed bolus or modelling the 3D printed bolus as a virtual bolus structure with a homogeneous density. Depth dose measurements were performed with Gafchromic films. RESULTS: High infill percentage corresponds to high density and high homogeneity within bolus material. The approximation of the bolus in the TPS as a homogeneous material is satisfying for infill percentages greater than 20%. Measurements performed with PLA boluses are more comparable to the TPS calculated profiles. For boluses printed at 40% and 60% infill, the discrepancies between calculated and measured dose distribution are within 5%. CONCLUSIONS: 3D printing technology allows modulating the shift of the build-up region by tuning the infill percentage of the 3D printed bolus in order to improve superficial target coverage. PMID- 28711186 TI - Megavoltage 2D topographic imaging: An attractive alternative to megavoltage CT for the localization of breast cancer patients treated with TomoDirect. AB - PURPOSE: To show the usefulness of topographic 2D megavoltage images (MV2D) for the localization of breast cancer patients treated with TomoDirect (TD), a radiotherapy treatment technique with fixed-angle beams performed on a TomoTherapy system. METHODS: A method was developed to quickly localize breast cancer patients treated with TD by registering the MV2D images produced before a TD treatment with reference images reconstructed from a kilovoltage CT simulation scanner and by using the projection of the beam-eye-view TD treatment field. Dose and image quality measurements were performed to determine the optimal parameters for acquiring MV2D images. A TD treatment was simulated on a chest phantom equipped with a breast attachment. MVCT and MV2D images were performed for 7 different shifted positions of the phantom and registered by 10 different operators with the simulation kilovoltage CT images. RESULTS: Compared to MVCT, MV2D imaging reduces the dose by a factor of up to 45 and the acquisition time by a factor of up to 49. Comparing the registration shift values obtained for the phantom images obtained with MVCT in the coarse mode to those obtained with MV2D, the mean difference is 1.0+/-1.1mm, -1.1mm+/-1.1, and -0.1+/-2.2mm, respectively, in the lateral, longitudinal, and vertical directions. CONCLUSIONS: With dual advantages (very fast imaging and a potentially reduced dose to the heart and contralateral organs), MV2D topographic images may be an attractive alternative to MVCT for the localization of breast cancer patients treated with TomoDirect. PMID- 28711187 TI - Development of an in vitro diaphragm motion reproduction system. AB - This study developed an in vitro diaphragm motion reproduction system (IVDMRS) based on noninvasive and real-time ultrasound imaging to track the internal displacement of the human diaphragm and diaphragm phantoms with a respiration simulation system (RSS). An ultrasound image tracking algorithm (UITA) was used to retrieve the displacement data of the tracking target and reproduce the diaphragm motion in real time using a red laser to irradiate the diaphragm phantom in vitro. This study also recorded the respiration patterns in 10 volunteers. Both simulated and the respiration patterns in 10 human volunteers signals were input to the RSS for conducting experiments involving the reproduction of diaphragm motion in vitro using the IVDMRS. The reproduction accuracy of the IVDMRS was calculated and analyzed. The results indicate that the respiration frequency substantially affects the correlation between ultrasound and kV images, as well as the reproduction accuracy of the IVDMRS due to the system delay time (0.35s) of ultrasound imaging and signal transmission. The utilization of a phase lead compensator (PLC) reduced the error caused by this delay, thereby improving the reproduction accuracy of the IVDMRS by 14.09-46.98%. Applying the IVDMRS in clinical treatments will allow medical staff to monitor the target displacements in real time by observing the movement of the laser beam. If the target displacement moves outside the planning target volume (PTV), the treatment can be immediately stopped to ensure that healthy tissues do not receive high doses of radiation. PMID- 28711188 TI - Plan delivery quality assurance for CyberKnife: Statistical process control analysis of 350 film-based patient-specific QAs. AB - PURPOSE: Robotic radiosurgery requires plan delivery quality assurance (DQA) but there has never been a published comprehensive analysis of a patient-specific DQA process in a clinic. We proposed to evaluate 350 consecutive film-based patient specific DQAs using statistical process control. We evaluated the performance of the process to propose achievable tolerance criteria for DQA validation and we sought to identify suboptimal DQA using control charts. METHODS AND MATERIAL: DQAs were performed on a CyberKnife-M6 using Gafchromic-EBT3 films. The signal-to dose conversion was performed using a multichannel-correction and a scanning protocol that combined measurement and calibration in a single scan. The DQA analysis comprised a gamma-index analysis at 3%/1.5mm and a separate evaluation of spatial and dosimetric accuracy of the plan delivery. Each parameter was plotted on a control chart and control limits were calculated. A capability index (Cpm) was calculated to evaluate the ability of the process to produce results within specifications. RESULTS: The analysis of capability showed that a gamma pass rate of 85% at 3%/1.5mm was highly achievable as acceptance criteria for DQA validation using a film-based protocol (Cpm>1.33). 3.4% of DQA were outside a control limit of 88% for gamma pass-rate. The analysis of the out-of-control DQA helped identify a dosimetric error in our institute for a specific treatment type. CONCLUSION: We have defined initial tolerance criteria for DQA validations. We have shown that the implementation of a film-based patient-specific DQA protocol with the use of control charts is an effective method to improve patient treatment safety on CyberKnife. PMID- 28711189 TI - Effective atomic number estimation using kV-MV dual-energy source in LINAC. AB - Dual-energy computed tomography (DECT) imaging can measure the effective atomic number (EAN) as well as the electron density, and thus its adoption may improve dose calculations in brachytherapy and external photon/particle therapy. An expanded energy gap in dual-energy sources is expected to yield more accurate EAN estimations than conventional DECT systems, which typically span less than 100kV. The aim of this paper is to assess a larger energy gap DECT by using a linear accelerator (LINAC) radiotherapy system with a kV X-ray imaging device, which are combined to provide X-rays in both the kV- and MV-energy ranges. Traditionally, the EAN is determined by parameterising the Hounsfield Unit; however, this is difficult in a kV-MV DECT due to different uncertainties in the reconstructed attenuation coefficient at each end of the energy spectrum. To overcome this problem, we included a new calibration step to produce the most likely linear attenuation coefficients, based upon the X-ray spectrum. To determine the X-ray spectrum, Monte Carlo calculations using GEANT4 were performed. Then the images were calibrated using information from eight inserts of known materials in a CIRS phantom (CIRS Inc., Norfolk, VA). Agreement between the estimated and empirical EANs in these inserts was within 11%. Validation was subsequently performed with the CatPhan500 phantom (The Phantom Laboratory, Salem). The estimated EAN for seven inserts agreed with the empirical values to within 3%. Accordingly, it can be concluded that, given properly reconstructed images based upon a well determined X-ray spectrum, kV-MV DECT provides an excellent prediction for the EAN. PMID- 28711190 TI - Role of Demodex mite infestation in rosacea: A systematic review and meta analysis. AB - BACKGROUND: The reported prevalence and degrees of Demodex mite infestation in rosacea vary widely. OBJECTIVE: We sought to conduct an evidence-based meta analysis of the prevalence and degrees of Demodex mite infestation in patients with rosacea. METHODS: Systematic literature review and meta-analysis were conducted. Odds ratios for prevalence of infestation and standardized mean difference (SMD) for Demodex density in patients with rosacea were pooled. Subgroup analysis for type of rosacea, control group, and sampling and examination methods were also performed. RESULTS: Twenty-three case-control studies included 1513 patients with rosacea. Compared with the control patients, patients with rosacea were more likely to be infested by Demodex mites [odds ratio, 9.039; 95% confidence interval (CI), 4.827-16.925] and had significantly higher Demodex density (SMD, 1.617; 95% CI, 1.090-2.145). Both erythematotelangiectatic rosacea (SMD, 2.686; 95% CI, 1.256-4.116) and papulopustular rosacea (SMD, 2.804; 95% CI, 1.464-4.145) had significantly higher Demodex density than did healthy control patients. LIMITATIONS: Interstudy variability was high, and a causal relationship could not be established by case control studies. CONCLUSIONS: Patients with rosacea had significantly higher prevalence and degrees of Demodex mite infestation than did control patients. Demodex mites may play a role in both erythematotelangiectatic rosacea and papulopustular rosacea. PMID- 28711191 TI - The relationships between violence in childhood and educational outcomes: A global systematic review and meta-analysis. AB - This is the first study to estimate the association globally between violence in childhood on educational outcomes, addressing a significant gap in the current evidence base. Systematic reviews and meta-analyses were conducted to identify 67 and 43 studies respectively from 21 countries to estimate the relationship between different types of violence in childhood on educational outcomes including school dropout/graduation, school absence, academic achievement and other educational outcomes such as grade retention, learning outcomes and remedial classes. Findings show that all forms of violence in childhood have a significant impact on educational outcomes. Children who have experienced any form of violence in childhood have a 13% predicted probability that they will not graduate from school. Males who are bullied are nearly three times more likely to be absent from school and girls who have experienced sexual violence have a three fold increased risk of being absent, AOR 2.912, 95% CI (0.904-4.92) and AOR 3.147, 95% CI (0.033-4.57) respectively. Violence in childhood also has a significant impact on children's academic achievement on standardized tests. This study shows how different forms of violence in childhood contribute to inequalities in education-for both boys and girls and that an increased investment in prevention is needed in order to meet the global Sustainable Development Goals of ending violence, raising learning outcomes and creating safe, non-violent and inclusive learning environments. More work is also needed to further define, monitor and measure the link between violence in childhood and educational outcomes in order to achieve the Sustainable Development Goals. PMID- 28711192 TI - Predictors of anxiety in early-stage Parkinson's disease - Results from the first two years of a prospective cohort study. AB - AIM: Anxiety has a negative impact on daily functioning and quality of life in patients with Parkinson's disease (PD). This study aims at assessing which sociodemographic and clinical characteristics predict the course of anxiety in early PD. METHODS: The participants of this two-year prospective cohort study were recently diagnosed PD patients not receiving psychiatric medications or dopamine replacement therapy at baseline. Assessments were performed annually after baseline. The primary outcome measure was anxiety, as measured with the State-Trait Anxiety Inventory (STAI). Covariates were age, gender, family history, striatal dopamine transporter binding ratios, and severity of motor and non-motor features of PD at baseline. Data were analyzed using a mixed model analysis. RESULTS: Inclusion criteria were met by 306 subjects. An increase in STAI total score was predicted by older age, lower score on the Montreal Cognitive Assessment, and the presence of a probable REM-sleep behavior disorder (RBD) at baseline. A decrease in STAI total score over time was predicted by a higher baseline score on the 15-item Geriatric Depression Scale, compulsive behavior at baseline and a family history of PD. CONCLUSIONS: More severe baseline anxiety was associated with compulsive behavior and depressive symptoms. These symptoms had a parallel course, showing a decrease over time. An increase in anxiety was predicted by older age, worse cognitive functioning and the presence of RBD. Our findings, when replicated in a sample of PD patients in a more advanced disease stage, could provide starting points for prevention of anxiety in PD patients. PMID- 28711193 TI - Nociceptin Receptors in Alcohol Use Disorders: A Positron Emission Tomography Study Using [11C]NOP-1A. AB - BACKGROUND: The neuropeptide transmitter nociceptin, which binds to the nociceptin/orphanin FQ peptide (NOP) receptor, is a core component of the brain's antistress system. Nociceptin exerts its antistress effect by counteracting the functions of corticotropin-releasing factor, the primary stress-mediating neuropeptide in the brain. Basic investigations support a role for medications that target nociceptin receptors in the treatment of alcohol use disorders. Thus, it is of high interest to measure the in vivo status of NOP receptors in individuals with alcohol use disorders. METHODS: Here, we used [11C]NOP-1A and positron emission tomography to measure the in vivo binding to NOP receptors in 15 alcohol-dependent humans as identified by DSM-IV and 15 healthy control subjects matched for age, sex, and smoking status. Alcohol-dependent individuals with no comorbid psychiatric, medical, or drug abuse disorders were scanned following 2 weeks of outpatient monitored abstinence (confirmed with three times per week urine alcohol metabolite testing). [11C]NOP-1A distribution volume in regions of interest (including the amygdala, hippocampus, and midbrain, striatal, and prefrontal cortical subdivisions) was measured with kinetic analysis using the arterial input function. RESULTS: Regional [11C]NOP-1A distribution volume in alcohol dependence was not significantly different compared with healthy control subjects. No relationship between [11C]NOP-1A distribution volume and other clinical measures (including duration and severity of alcohol abuse, craving, and anxiety or depressive symptoms) were significant after correction for the multiple hypotheses tested. CONCLUSIONS: The results of this study do not support alterations in the binding to NOP receptors in alcohol dependence. However, this finding does not necessarily rule out alterations in nociceptin transmission in alcohol dependence. PMID- 28711194 TI - Factors associated with epinephrine administration for anaphylaxis in children before arrival to the emergency department. AB - BACKGROUND: Epinephrine is the first-line treatment for anaphylaxis but may be underused by patients and medical personnel. OBJECTIVE: To evaluate factors associated with anaphylaxis management before arrival at the emergency department (ED) or urgent care center (UCC). METHODS: We performed a retrospective review of electronic medical records for all patients aged 0 to 25 years presenting with anaphylaxis to the ED or UCC at a pediatric academic referral center during 2009 to 2013. RESULTS: A total of 408 patients (mean age, 7.25 years; 62% male) were included for analysis. Only 148 patients (36.3%) received epinephrine before arrival at the ED or UCC. Reactions occurring at home (n = 36/114) were less likely to be treated with epinephrine compared with reactions occurring at school (n = 30/49) (odds ratio [OR], 0.29; 95% confidence interval [CI], 0.15-0.59). The odds of receiving epinephrine before arrival at the ED or UCC were significantly lower with a 2-organ system (OR, 0.50; 95% CI, 0.30-0.85) or 3-organ system (OR, 0.41; 95% CI, 0.21-0.81) presentation compared with 1-organ system involvement. Foods (342 [83.8%]) were the most commonly reported provoking trigger. Patients who did not receive epinephrine before arrival at the ED or UCC were significantly less likely to be discharged to home (OR, 0.56; 95% CI, 0.37-0.86; P = .01). CONCLUSION: This study identifies factors associated with prehospital management of anaphylaxis for children, which highlight that epinephrine administration may be occurring with considerable delay. Increased awareness and education of caregivers, patients, and medical professionals are necessary to provide optimal management. PMID- 28711195 TI - Comparison of MDRD, CKD-EPI, and Cockcroft-Gault equation in relation to measured glomerular filtration rate among a large cohort with diabetes. AB - AIMS: To analyze the performance of Modification of Diet in Renal Disease (MDRD), Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), Cockcroft-Gault (CG), and CG calculated with ideal bodyweight (CG-IBW) equations to estimate glomerular filtration rate (eGFR) based on serum creatinine in a large diabetic population. METHODS: 24,516 adults with type-1-diabetes or type-2-diabetes from the multicenter diabetes prospective follow-up registry DPV were analyzed. We compared eGFR and measured GFR (mGFR) based on 24-h urine collection by calculating mean bias (difference), precision (SD of this difference), accuracy (proportion of eGFR within +/-10% of mGFR), Bland-Altman-plots. RESULTS: CG overestimates, whereas MDRD, CKD-EPI, and CG-IBW underestimate. Smallest mean bias and highest accuracy (75.3%) were observed for MDRD compared to the other equations (p<0.0001). MDRD and CKD-EPI estimated most accurately in stages 1 (MDRD:57.7%, CKD-EPI:57.3%) and 2 (MDRD:80.2%, CKD-EPI:80.7%). In stages 3 to 5, highest accuracy was observed for the MDRD (stage 3:82.3%, stage 4:77.8%, stage 5:71.0%). Among younger subjects, accuracy was higher using the CKD-EPI (18 <40years:63.7%, 40-<60years:72.8%). Above age 60years, MDRD estimated most accurately (60-<70years:77.3%, >=70years:78.8%). In males and females, MDRD estimated most accurately (males:75.3%, females:75.3%). CONCLUSION: In this large diabetic cohort, smallest bias and highest accuracy were observed for the MDRD. PMID- 28711196 TI - Identifying Areas of Need in Tropical Research: A Reply to Stroud and Feeley. PMID- 28711197 TI - The Multifaceted Nature of Vulnerability in Managed Bees: A Response to Klein et al. PMID- 28711198 TI - Science of diabetic complications: How poor access is a risk factor for complications. PMID- 28711199 TI - Dual-Energy Computed Tomography: Physical Principles, Approaches to Scanning, Usage, and Implementation: Part 1. AB - There are increasing applications of dual-energy computed tomography (CT), a type of spectral CT, in neuroradiology and head and neck imaging. In this 2-part review, the fundamental principles underlying spectral CT scanning and the major considerations in implementing this type of scanning in clinical practice are reviewed. In the first part of this 2-part review, the physical principles underlying spectral CT scanning are reviewed, followed by an overview of the different approaches for spectral CT scanning, including a discussion of the strengths and challenges encountered with each approach. PMID- 28711200 TI - Dual-Energy Computed Tomography: Physical Principles, Approaches to Scanning, Usage, and Implementation: Part 2. AB - There are increasing applications and use of spectral computed tomography or dual energy computed tomography (DECT) in neuroradiology and head and neck imaging in routine clinical practice. Part 1 of this 2-part review covered fundamental physical principles underlying DECT scanning and the different approaches for scanning. Part 2 focuses on important and practical considerations for implementing and using DECT in clinical practice, including a review of different images and reconstructions produced by these scanners and important and practical issues, ranging from image quality and radiation dose to workflow-related aspects of DECT scanning, that routinely come up during operationalization of DECT. PMID- 28711201 TI - Dual-Energy Computed Tomographic Applications for Differentiation of Intracranial Hemorrhage, Calcium, and Iodine. AB - This article reviews the physical principles of dual-energy material decomposition and its current implementation. Clinical applications of dual energy material decomposition including differentiation of calcification from hemorrhage and iodinated contrast from hemorrhage are highlighted, and their applications to neuroimaging are reviewed. PMID- 28711202 TI - Miscellaneous and Emerging Applications of Dual-Energy Computed Tomography for the Evaluation of Intracranial Pathology. AB - Dual-energy computed tomography (CT) has the potential to improve detection of abnormalities and increase diagnostic confidence in the evaluation of a variety of neurologic conditions by using different x-ray energy-dependent absorption behaviors of different materials. This article reviews the virtual monochromatic imaging applications of dual-energy CT, particularly material decomposition algorithms to improve lesion conspicuity, define lesion-normal tissue interface using different reconstruction techniques, and discuss miscellaneous emerging applications of dual-energy CT for neuroimaging, with an emphasis on their potential clinical utility. PMID- 28711203 TI - Dual-Energy Computed Tomography Angiography of the Head and Neck and Related Applications. AB - Dual-energy computed tomography (DECT) has become an increasingly widespread and useful component of the neuroimaging armamentarium, offering automated bone removal, metallic artifact reduction, and improved characterization of iodinated contrast enhancement. The application of these techniques to CT neuroangiography enables a number of benefits including more efficient 3D post-processing, contrast dose reduction opportunities, successful differentiation of hemorrhage from contrast staining following thromboembolic recanalization therapy, improved detection of active contrast extravasation in the setting of intracranial hemorrhage, and more precise characterization of atheromatous steno-occlusive disease. PMID- 28711204 TI - Applications of Dual-Energy Computed Tomography for the Evaluation of Head and Neck Squamous Cell Carcinoma. AB - There are multiple emerging applications of dual-energy computed tomography (DECT) for the evaluation of pathology in the head and neck, in particular head and neck squamous cell carcinoma. Studies suggest that DECT image sets reconstructed as supplements to routine diagnostic images may improve lesion visualization, determination of tumor extent, and identification of invasion of critical anatomic structures. This article reviews the evidence for the use and potential advantages of supplementary DECT reconstructions for the evaluation of head and neck squamous cell carcinoma. A summary of potentially useful reconstructions and a suggested approach for multiparametric DECT evaluation of head and neck cancer based on current evidence are presented. PMID- 28711205 TI - Dual-Energy Computed Tomography Applications for the Evaluation of Cervical Lymphadenopathy. AB - There is recent interest in the use of dual-energy computed tomography (CT) in head and neck imaging, and the results are encouraging. This article reviews dual energy CT applications as complementary tools to conventional CT scanning in the evaluation of cervical lymphadenopathy. The article cites the most relevant studies and highlights their results. Single-source and dual-source dual-energy applications including virtual noncontrast images, linear and nonlinear image blending, monochromatic images, iodine quantification, and spectral Hounsfield unit attenuation curve analysis are reviewed. Future directions and research suggestions are discussed in brief. PMID- 28711206 TI - Miscellaneous and Emerging Applications of Dual-Energy Computed Tomography for the Evaluation of Pathologies in the Head and Neck. AB - Dual-energy computed tomography (DECT) and its specific algorithms and applications have been increasingly recognized in clinical practice as a valuable advance in technology beyond what is possible with the established postprocessing capabilities of single-energy multidetector computed tomography, mainly because of its potential benefits regarding image quality and contrast. DECT may represent an alternative approach to purely attenuation-based imaging of the head and neck, because it provides a material-specific visualization based on spectral information. With this approach, owing to its physical properties, iodine can be assessed as a potential "biological tracer" to improve depiction of tumor conspicuity and grade of invasion. PMID- 28711207 TI - Dual Energy Computed Tomography Applications for the Evaluation of the Spine. AB - Capturing the energy-dependent x-ray attenuation of different tissues, dual energy computed tomography offers multiple benefits in the imaging of the spine, such as bone and iodinated contrast removal, monosodium urate imaging, and robust reduction of beam-hardening artifacts. The emerging new applications of this technique include bone marrow imaging in acute trauma and myeloinfiltrative disorders, improved bone density determination, and noninvasive assessment of spinal gout. PMID- 28711208 TI - Applications of Dual-Energy Computed Tomography for Artifact Reduction in the Head, Neck, and Spine. AB - Conventional computed tomography (CT) uses a polychromatic energy beam to offer superb anatomic detail of the head and spine. However, technical challenges remain that can degrade the diagnostic image quality of these examinations. Dual energy CT analyzes the changes in attenuation of soft tissues at different energy levels, from which different reconstructions can be made to yield the optimal contrast-to-noise ratio, reduce beam-hardening artifact, or evaluate tissue composition. In this article, selective applications of the dual energy CT technique are discussed, highlighting a powerful tool in the diagnostic CT evaluation of the head, neck, and spine. PMID- 28711209 TI - Dual-Energy Computed Tomography of the Neck: A Pictorial Review of Normal Anatomy, Variants, and Pathologic Entities Using Different Energy Reconstructions and Material Decomposition Maps. AB - There is increasing use of dual-energy computed tomography (DECT) for the evaluation of head and neck pathologic entities. Optimal DECT utilization requires familiarity with the appearance of normal tissues variants, and pathologic entities on different DECT reconstructions that may be used in clinical practice. The purpose of this article is to provide a practical, pictorial review of the appearance of normal anatomic structures and different neoplastic and nonneoplastic head and neck pathologic entities on commonly used DECT reconstructions. PMID- 28711210 TI - Routine Dual-Energy Computed Tomography Scanning of the Neck in Clinical Practice: A Single-Institution Experience. AB - There is increasing use and popularity of dual-energy computed tomography (DECT) in many subspecialties in radiology. This article reviews the practical workflow implications of routine DECT scanning based on the experience at a single institution where a large percentage of elective neck CTs are acquired in DECT mode. The article reviews factors both on the production (technologist) and on the interpretation (radiologist) side, focusing on challenges posed and potential solutions for seamless workflow implementation. PMID- 28711212 TI - Dual-Energy Computed Tomography: Applications in Neurologic, Head, and Neck Imaging. PMID- 28711211 TI - Advanced Tissue Characterization and Texture Analysis Using Dual-Energy Computed Tomography: Horizons and Emerging Applications. AB - In the last article of this issue, advanced analysis capabilities of DECT is reviewed, including spectral Hounsfield unit attenuation curves, virtual monochromatic images, material decomposition maps, tissue effective Z determination, and other advanced post-processing DECT tools, followed by different methods of analysis of the attenuation curves generated using DECT. The article concludes with exciting future horizons and potential applications, such as the use of the rich quantitative data in dual energy CT scans for texture or radiomic analysis and the use of machine learning methods for generation of prediction models using spectral data. PMID- 28711213 TI - Dual-Energy Computed Tomography in Neuroradiology and Head and Neck Imaging: State-of-the-Art. PMID- 28711214 TI - Post-colonoscopy colorectal cancer: Next enemy to beat. PMID- 28711215 TI - Changes occurring in mucosal contractility of the inferior turbinate and mucociliary clearance following total laryngectomy: A prospective clinical trial. AB - OBJECTIVE: In this study, changes occurring in the contractility capacity of the inferior turbinate and mucociliary clearance time due to the interruption of nasal air flow were examined. MATERIAL & METHODS: A total of 23 patients undergone total laryngectomy between June 2010 and June 2012 were included in the study. Acoustic rhinometry test was performed in the patients before and after 0.05% oxymetazoline nasal topical decongestant administration. In addition, saccharin test was applied in order to measure mucociliary clearance. The same measurements were repeated at the postoperative months 1, 6 and 12 and the data obtained were statistically compared. RESULTS: In evaluation of the patients' contractility capacity at MCA-1 and MCA-2, contractility capacity was found to be significantly decreased from the postoperative first month compared to the preoperative values. The contractility capacity at the postoperative 6th month was significantly lower than that of the postoperative first month. The contractility capacity at the postoperative 12th month was significantly lower than that of the postoperative 6th month. Mucociliary clearance time did not change significantly at the postoperative first month compared to the preoperative value, while this value was significantly decreased at the postoperative 6th month. No statistically significant difference was observed in mucociliary clearance between the postoperative 6th and 12th months. CONCLUSION: Contractility capacity of the inferior turbinate decrease over time in patients undergoing total laryngectomy. This indicates that the dysfunction developing in the nasal mucosal structure in the chronical absence of nasal air flow may be resulted from the decreased choncal contractility. PMID- 28711216 TI - National nursing science priorities: Creating a shared vision. AB - BACKGROUND: Nursing science is essential to advance population health through contributions at all phases of scientific inquiry. Multiple scientific initiatives important to nursing science overlap in aims and population focus. PURPOSE: This article focused on providing the American Academy of Nursing and nurse scientists in the Unites States with a blueprint of nursing science priorities to inform a shared vision for future collaborations, areas of scientific inquiry, and resource allocation. METHODS: The Science Committee convened four times and using Delphi methods identified priorities with empirical evidence and expert opinion for prioritization, state of the science, expert interest, and potential target stakeholders. DISCUSSION: Nursing science priorities for 2017 were categorized into four themes including: (a) precision science, (b) big data and data analytics, (c) determinants of health, and (d) global health. CONCLUSION: Nurse scientists can generate new knowledge in priority areas that advances the health of the world's populations. PMID- 28711217 TI - Psychosis Due to Disseminated Cryptococcal Infection and Delirium in an Immunocompetent Patient: A Case Report and Review of the Literature. PMID- 28711218 TI - Significant Axial Elongation with Minimal Change in Refraction in 3- to 6-Year Old Chinese Preschoolers: The Shenzhen Kindergarten Eye Study. AB - PURPOSE: To document the distribution of ocular biometry and to evaluate its associations with refraction in a group of Chinese preschoolers. DESIGN: Population-based cross-sectional study. PARTICIPANTS: A total of 1133 preschoolers 3 to 6 years of age from 8 representative kindergartens. METHODS: Biometric measurements including axial length (AL), anterior chamber depth (ACD), and corneal radius of curvature (CR) were obtained from partial-coherence laser interferometry (IOL Master; Carl Zeiss Meditec, Oberkochen, Germany) before cycloplegia. Lens power (LP) and AL-to-CR ratio were calculated. Cycloplegic refraction (3 drops of 1% cyclopentolate) was measured using an autorefractor (KR8800; Topcon Corp., Tokyo, Japan), and spherical equivalent refraction (SER) was calculated. Biometric and refractive parameters were assessed as a function of age and gender. Multiple regression analysis was performed to explore the associations between refraction and ocular biometry. MAIN OUTCOME MEASURES: Ocular biometric distributions and their relationships to refraction. RESULTS: Among the 1127 children (99.5%) with successful cycloplegic refraction, mean SER was 1.37+/-0.63 diopters (D). Prevalence of myopia increased from 0% at 3 years of age to 3.7% (95% confidence interval, 1.0%-6.5%) at 6 years of age. Biometric parameters followed Gaussian distributions with means of 22.39+/-0.68 mm for AL, 7.79+/-0.25 mm for CR, and 24.61+/-1.42 D for calculated LP; and non-Gaussian distributions with means of 3.34+/-0.24 mm for ACD and 2.88+/-0.06 for AL-to-CR ratio. Axial length, ACD, and AL-to-CR ratio increased from 3 to 6 years of age, CR remained stable, whereas LP declined. Overall, SER declined slightly. For the SER variance, AL explained 18.6% and AL-to-CR ratio explained 39.8%, whereas AL, CR, and LP accounted for 80.0% after adjusting for age and gender. CONCLUSIONS: Young Chinese children are predominantly mildly hyperopic, with a low prevalence of myopia by the age of 6 years. An increase of 1 mm in AL was associated with only 0.45 D of myopic change. Decreases in LP reduce the myopic shifts that normally would be associated with increases in AL, and thus play a key role in refractive development in this age group. PMID- 28711219 TI - Effect of feeding three lysine to energy diets on growth, body composition and age at puberty in replacement gilts. AB - This study evaluated the effect of diets differing in standard ileal digestible (SID) lysine on lysine intake, growth rate, body composition and age at puberty on maternal line gilts. Crossbred Large White*Landrace gilts (n=641) were fed corn-soybean diets differing in SID lysine concentration (%, g SID lysine:Mcal ME); diets were not isocaloric. Gilts received three grower, finisher diet combinations: low (0.68% lysine grower, 0.52% lysine finisher), medium (0.79% lysine grower, 0.60% lysine finisher) or high (0.90% lysine grower, 0.68% lysine finisher). Grower diets were fed from 100 until 142days of age, and finisher diets were fed until they reached 220days of age. Body weight (BW), backfat thickness (BF), and loin depth (LD) were recorded every 28days. From 160-220days of age, gilts were exposed daily to vasectomized boars and observed for behavioral estrus. Gilts fed the low lysine diet had lower average daily gain and BW (P<0.05), but not fat depth:LD ratio. The percentage of gilts that displayed natural estrus by 220days of age was low but not different among dietary treatments (low 27.7%, medium 31.0% and high 37.7%, respectively; P=0.1201). Gilts fed the high and medium diets reached puberty 10 and 6days earlier, however, than gilts fed the low lysine diet (P<0.05). The rate of puberty attainment may have been less because all gilts contracted porcine epidemic diarrhea (PEDv) just as boar exposure was to begin for the first group of gilts. Results from the present study indicate that growth rate and age at puberty can be altered by ad libitum fed diets that differ in SID lysine concentration. PMID- 28711220 TI - Analysis of small molecule drugs, excipients and counter ions in pharmaceuticals by capillary electromigration methods - recent developments. AB - Capillary electromigration techniques have become important tools for the analysis of pharmaceutical drugs. The present review updates on recent developments of the analysis of small molecule drugs, excipients and counter ions dating between January 2014 and May 2017. Capillary electrophoresis (CE) continues to be a very popular method for the analysis of the active pharmaceutical ingredients and their related substances in pharmaceutical formulations, especially for the determination of the stereoisomeric purity of chiral drugs, which is evidenced by a large number of related literature reported in the reviewed period of time. The simultaneous analysis of several drugs has been easily achieved by CE. Moreover, the flexibility of the technique has been clearly illustrated by the application of various separation modes including capillary zone electrophoresis, isotachophoresis as well as various modes of electrokinetic chromatography such as micellar electrokinetic chromatography or microemulsion electrokinetic chromatography in combination with various detection modes including direct and indirect UV, laser-induced fluorescence, mass spectrometry and contactless conductivity detection. A general trend also observed in other analytical techniques is the application of quality by design principles in CE. PMID- 28711221 TI - The evolution of lung transplantation for cystic fibrosis: A 2017 update. AB - Lung transplantation (LTx) is an established therapy for patients with end-stage cystic fibrosis (CF). Indeed, CF is the commonest indication for those aged<50years of age needing LTx. CF LTx is associated with a 45% 10year survival according to the world's largest registry. It is important all otherwise suitable CF patients with severe lung disease have a timely referral for discussion and consideration of the possibility of LTx. LTx discussions must carefully consider colonisation or infection with Burkholderia cenocepacia, Mycobacterium abscessus and Scediosporium - as good LTx outcomes cannot be guaranteed. A bridge to LTx with extra-corporeal lung support is a realistic option, but remains a relative contraindication to LTx. Improvements in LTx matching technology and post-operative management are steadily improving overall long-term outcomes, although chronic allograft rejection remains problematic. Expert multidisciplinary life-long post-LTx care remains the key to success. PMID- 28711222 TI - Retrospective observational study of French patients with cystic fibrosis and a Gly551Asp-CFTR mutation after 1 and 2years of treatment with ivacaftor in a real world setting. AB - BACKGROUND: Ivacaftor has been shown to improve lung function and body weight in patients with CF and a gating mutation. Real-world evaluation is warranted to examine its safety and effectiveness over the long term. METHODS: A retrospective observational multicentre study collected clinical data in the year before and the 2years after ivacaftor initiation in patients with CF and a Gly551Asp-CFTR mutation. RESULTS: Fifty-seven patients were included. Mean absolute change in FEV1% predicted improved from baseline to Year 1 (8.4%; p<0.001) and Year 2 (7.2%; p=0.006). Statistically significant benefits were observed with increased body mass index, fewer Pseudomonas aeruginosa and Staphylococcus aureus positive cultures, and decreased IV antibiotics and maintenance treatment prescriptions (including azithromycin, Dornase alpha and nutritional supplements). No significant adverse events were reported. CONCLUSION: The clinical benefits of ivacaftor reported in previous clinical trials were confirmed in a real-world setting two years post-initiation, also reducing treatment burden. PMID- 28711223 TI - Role of Sexuality in Body Integrity Identity Disorder (BIID): A Cross-Sectional Internet-Based Survey Study. AB - BACKGROUND: Body integrity identity disorder (BIID)-a strong desire for amputation or paralysis-is often accompanied by feelings and cognitions of sexual arousal, although this sexual component has been largely neglected in the recent literature. AIM: To examine the presence of BIID-related sexual arousal in subjects with BIID and explore clinical and demographic variables of subjects with BIID who do and do not possess this sexual arousal. METHODS: Eighty individuals with BIID responded to an internet-based survey we created. For all subjects, restoring identity was the primary motivation for preferred body modification. We collected data about respondents' demographic, clinical, and sexual characteristics. Based on responses to questions about BIID-specific sexual desires, subjects were assigned to the group with BIID-related sexual feelings (S-BIID; n = 57) or the group without such feelings (NS-BIID; n = 23). OUTCOMES: Differences in clinical, demographic, and sexual characteristics between S-BIID and NS-BIID groups. RESULTS: Of the respondents, 71.3% endorsed S BIID. Subjects with S-BIID were significantly more often men, religious, and of a homosexual identity compared with the NS-BIID group. Subjects with S-BIID also significantly more often reported a change in localization and/or intensity of their BIID feelings over time. Furthermore, 66.7% of subjects with S-BIID reported S-BIID as an additional motivation for body modification. Seven of the 57 subjects with S-BIID achieved their preferred body modification through (self) amputation, whereas none of the subjects with NS-BIID did. CLINICAL IMPLICATIONS: BIID is a heterogeneous disorder in which subjects who self-reported comorbid sexual arousal more often resorted to (self-induced) amputation. STRENGTHS AND LIMITATIONS: This study contains the largest BIID cohort presented in the literature and is the first to genuinely research sexuality in BIID. The first limitation is the lack of face-to-face interviews with the subjects, so no clinical diagnoses could be made. Moreover, there is an ascertainment bias because subjects were collected through the internet and in English, which excluded those who spoke other languages or subjects without an internet connection. CONCLUSION: The present study provides preliminary evidence for a subpopulation or distinct group of individuals with BIID based on the presence of S-BIID. Blom RM, van der Wal SJ, Vulink NC, Denys D. Role of Sexuality in Body Integrity Identity Disorder (BIID): A Cross-Sectional Internet-Based Survey Study. J Sex Med 2017;14:1028-1035. PMID- 28711224 TI - The radioprotector ortho-phospho-L-tyrosine (pTyr) attenuates the side effects of fractionated irradiation in retinoblastoma mouse models but also decreases the local tumour control. AB - BACKGROUND: Radiotherapy (RT) is used to treat retinoblastoma (Rb), the most frequent ocular tumour in children. Besides eradicating the tumour, RT can cause severe side effects including secondary malignancies. This study aimed to define whether the radioprotector ortho-phospho-L-tyrosine (pTyr) prevents RT-induced side effects and affects local tumour control in a xenograft and a genetic orthotopic Rb mouse model. METHODS: B6;129-Rb1tm3Tyj/J (Rb+/-) and Y79-Rb cell xenografted nude mice were fractionated external beam irradiated (15 fractions of 5Gy 6MV photons during 3weeks) with or without pTyr pre-treatment (100mg/kg BW, 16h prior to each irradiation). One, three, six and nine months after RT, tumour control and RT toxicity were evaluated using in vivo imaging and histology. We also analysed pTyr dependant post irradiation cell survival and p53 activity in vitro. RESULTS: In vitro pTyr pre-treatment showed no radioprotection on Y79 cells, but led to p53 stabilisation in unirradiated Y79 cells and to a facilitation of radiation-induced p21 up-regulation, confirming a modulation of p53 activity by pTyr. In both mouse models, secondary tumours were undetectable. In Rb+/- mice, pTyr significantly lowered RT-induced greying of the fur, retinal thickness reduction and photoreceptor loss. However, in the xenografted Rb model, pTyr considerably decreased RT-mediated tumour control, which was observed in 16 out of 22 control eyes but in none of the 24 pTyr treated eyes. CONCLUSIONS: In Rb+/- mice pTyr significantly prevents RT-induced greying of the fur as well as retinal degeneration. However, since non-irradiated control mice were not used in our study, a formal possibility exists that the effect shown in the retina of Rb+/- mice may be due to ageing of the animals and/or actions of pTyr alone. Unfortunately, as tested in a xenograft model, pTyr treatment reduced the control of Rb tumours. PMID- 28711225 TI - [Arsenic pesticides as an uncommon cause of basal cell carcinoma in an octogenarian patient]. PMID- 28711226 TI - [Pain, cannabis, psychosis. A logical sequence?] PMID- 28711228 TI - Atypical paraneoplastic syndrome with no onconeuronal antibodies: A case report. PMID- 28711227 TI - Oncogenic Activities of IDH1/2 Mutations: From Epigenetics to Cellular Signaling. AB - Gliomas and leukemias remain highly refractory to treatment, thus highlighting the need for new and improved therapeutic strategies. Mutations in genes encoding enzymes involved in the tricarboxylic acid (TCA) cycle, such as the isocitrate dehydrogenases 1 and 2 (IDH1/2), are frequently encountered in astrocytomas and secondary glioblastomas, as well as in acute myeloid leukemias; however, the precise molecular mechanisms by which these mutations promote tumorigenesis remain to be fully characterized. Gain-of-function mutations in IDH1/2 have been shown to stimulate production of the oncogenic metabolite R-2-hydroxyglutarate (R 2HG), which inhibits alpha-ketoglutarate (alphaKG)-dependent enzymes. We review recent advances on the elucidation of oncogenic functions of IDH1/2 mutations, and of the associated oncometabolite R-2HG, which link altered metabolism of cancer cells to epigenetics, RNA methylation, cellular signaling, hypoxic response, and DNA repair. PMID- 28711229 TI - [Public Health for migrants and refugees in Europe (as well)]. PMID- 28711230 TI - [Against so-called surrogacy. Human rights and global justice against neoliberal bioethics]. PMID- 28711231 TI - Drivers for human papillomavirus vaccination in Valencia (Spain). AB - OBJECTIVE: To describe the drivers associated with HPV vaccination in adolescent girls and their parent's opinion on the vaccine. METHODS: We conducted an observational and cross-sectional study on adolescent girls and their parents in Valencia (Spain), between September 2011 and June 2012. A consultation was made at a random sample of schools of the 14-year-old girls that should have received the vaccine in the free vaccination programme. We ran a personal survey on knowledge and attitudes regarding HPV infection and the vaccine. A binary logistic regression model was performed to determine which factors were most associated with vaccination. RESULTS: The survey was run on a binomial of 1,278 girls/mothers in 31 schools, to which 833 girls and their mothers responded (64.0%). The factors associated with vaccination were: country of origin of the families (adjusted OR [aOR]: 0.49; 95% confidence interval [95%CI]: 0.24-0.98), civil status of the parents (aOR: 0.33; 95%CI: 0.13-0.81), knowledge/beliefs about the vaccine when the source of information was the nurse (aOR: 1.83; 95%CI: 1.01-3.35), information source about the vaccine (aOR: 2.32; 95%CI: 1.37-3.92), preventive health centre visits (aOR: 2.1; 95%CI: 1.10-4.07), and nurse advice (aOR: 6.6; 95%CI: 3.19-13.56). CONCLUSIONS: The main factor associated with HPV vaccination was the advice of health professionals. Therefore, the most effective interventions to improve vaccination coverage should focus on health professionals. PMID- 28711232 TI - Sleep: An underemphasized aspect of health and development in neurorehabilitation. AB - Sleep deficiency has unique causes and implications for children with neonatal brain injury; contributing to the development or exacerbation of neurodevelopmental impairments and yet it is an underemphasized aspect of health and development. There is very little research evidence to guide the management of sleep disorders in children with cerebral palsy, a common neurodevelopmental disability of childhood. This paper is a comprehensive review and analysis of the literature regarding what is known about sleep quantity and quality in children with cerebral palsy. The specific implications for children with cerebral palsy are explored including the adverse effects of sleep deficiency on general child development, physical health and growth, and mental functioning. The consequences for the family are also discussed. Finally, the assessment and management of sleep problems are summarized to provide guidance to clinicians who work in neurodevelopmental medicine. PMID- 28711233 TI - Review of sleep-EEG in preterm and term neonates. AB - Neonatal sleep is a crucial state that involves endogenous driven brain activity, important for neuronal survival and guidance of brain networks. Sequential EEG sleep analysis in preterm infants provides insights into functional brain integrity and can document deviations of the biologically pre-programmed process of sleep ontogenesis during the neonatal period. Visual assessment of neonatal sleep-EEG, with integration of both cerebral and non-cerebral measures to better define neonatal state, is still considered the gold standard. Electrographic patterns evolve over time and are gradually time locked with behavioural characteristics which allow classification of quiet sleep and active sleep periods during the last 10weeks of gestation. Near term age, the neonate expresses a short ultradian sleep cycle, with two distinct active and quiet sleep, as well as brief periods of transitional or indeterminate sleep. Qualitative assessment of neonatal sleep is however challenged by biological and environmental variables that influence the expression of EEG-sleep patterns and sleep organization. Developing normative EEG-sleep data with the aid of automated analytic methods, can further improve our understanding of extra-uterine brain development and state organization under stressful or pathological conditions. Based on those developmental biomarkers of normal and abnormal brain function, research can be conducted to support and optimise sleep in the NICU, with the ultimate goal to improve therapeutic interventions and neurodevelopmental outcome. PMID- 28711234 TI - Sleep related breathing disorders and indications for polysomnography in preterm infants. AB - There is a range of breathing problems which occur and may persist in preterm infants, such as central apneas, obstructive apneas and periodic breathing. Preterm infants may also suffer from respiratory distress syndrome and chronic lung disease necessitating prolonged use of oxygen therapy after discharge from the hospital. Due to these persistent breathing pattern abnormalities in preterm infants, there is a higher risk of altered sleep and apparent life threatening events. Polysomnography can be a helpful tool to identify those infants who have abnormalities in their breathing pattern, to identify those infants who have an increased risk to get a sleep related breathing event at home and to decide about the discontinuation of oxygen therapy. PMID- 28711235 TI - Assessing, improving and utilizing sleep in high risk neonates. PMID- 28711236 TI - Temporal bone computed tomography findings associated with feasibility of endoscopic ear surgery. AB - PURPOSE: There are no formal radiologic criteria to stratify patients for transcanal (TEES) or transmastoid endoscopic ear surgery for resection of cholesteatoma. We aim to determine 1) whether standard preoperative computed tomography (CT) findings are associated with the need for conversion to a transmastoid approach and 2) the amount of time added for conversion from TEES to transmastoid techniques. MATERIALS AND METHODS: Retrospective chart review of consecutive pediatric and adult cases of TEES for primary cholesteatoma from 2013 through 2015 (n=52). TEES cases were defined as endoscope-only procedures that did not require a transmastoid approach (n=33). Conversion cases were defined as procedures that began as TEES however, required conversion to a transmastoid approach due to the inability to complete cholesteatoma removal (n=19). Preoperative CT findings and total operating room (OR) times of TEES and conversion cases were compared. RESULTS: Preoperative CT scan characteristics that were associated with conversion included tegmen erosion (p=0.026), malleus erosion (p<0.001), incus erosion (p=0.009), mastoid opacification (p=0.009), soft tissue opacification extending into the aditus ad antrum (p=0.009) and into antrum (p=0.006). Total OR time for TEES cases was significantly shorter than conversion cases (median 143min versus 217min, p<0.001). CONCLUSIONS: Preoperative CT findings, notably extension of soft tissue in the aditus ad antrum, antrum and mastoid, are associated with need for conversion to transmastoid technique to achieve removal of cholesteatoma. Endoscope-only cases were significantly faster than cases that required conversion to a transmastoid approach. PMID- 28711237 TI - Precise role of dermal fibroblasts on melanocyte pigmentation. AB - Dermal fibroblasts are traditionally recognized as synthesizing, remodeling and depositing collagen and extracellular matrix, the structural framework for tissues, helping to bring thickness and firmness to the skin. However, the role of fibroblasts on skin pigmentation arouses concern recently. More is known about the interactions between epidermal melanocytes and keratinocytes. This review highlights the importance of fibroblast-derived melanogenic paracrine mediators in the regulation of melanocyte activities. Fibroblasts act on melanocytes directly and indirectly through neighboring cells by secreting a large number of cytokines (SCF), proteins (DKK1, sFRP, Sema7a, CCN, FAP-alpha) and growth factors (KGF, HGF, bFGF, NT-3, NRG-1, TGF-beta) which bind to receptors and modulate intracellular signaling cascades (MAPK/ERK, cAMP/PKA, Wnt/beta-catenin, PI3K/Akt) related to melanocyte functions. These factors influence the growth, the pigmentation of melanocytes via the expression of melanin-producing enzymes and melanosome transfer, as well as their dendricity, mobility and adhesive properties. Thus, fibroblasts are implicated in both skin physiological and pathological pigmentation. In order to investigate their contribution, various in vitro models have been developed, based on cellular senescence. UV exposure, a major factor implicated in pigmentary disorders, may affect the secretory crosstalk between dermal and epithelial cells. Therefore, identification of the interactions between fibroblasts and melanocytes could provide novel insights not only for the development of melanogenic agents in the clinical and cosmetic fields, but also for a better understanding of the melanocyte biology and melanogenesis regulation. PMID- 28711238 TI - CCL3/MIP1alpha represents a biomarker but not a mandatory cytokine for disease development in experimental epidermolysis bullosa acquisita. PMID- 28711239 TI - Short communication: Correlation between within-herd antibody-prevalence and bulk tank milk antibody levels to Mycobacterium avium ssp. paratuberculosis using 2 commercial immunoassays. AB - The objective of this study was to determine the correlation between the results obtained with the ELISA technique for antibodies to Mycobacterium avium ssp. paratuberculosis in serum and bulk tank milk at the herd level. For this purpose, 203 samples of bulk tank milk were analyzed with 2 commercial ELISA from dairy herds with a prevalence of seropositive animals that was also determined. In regard to the reference test (results in blood serum), the sensitivity of the bulk tank milk test to detect high-positive herds (>=10% seroprevalence) ranged from 85.7 to 71.4%. The specificity to detect herds with no seropositive animals ranged from 70.5 to 53%. In a quantitative approach, Pearson correlation coefficients, reported as a measure of the linear association between herd seroprevalences and transformed optical density values recorded in bulk tank milk, were 0.39 and 0.54 for the studied ELISA. Although the test results were relatively fairly correlated with the within-herd prevalence, the practical utility of bulk tank milk testing for Mycobacterium avium ssp. paratuberculosis seems limited, especially regarding specificity. PMID- 28711240 TI - Characterization and bioactivities of the exopolysaccharide from a probiotic strain of Lactobacillus plantarum WLPL04. AB - Exopolysaccharide (EPS) was extracted and purified from Lactobacillus plantarum WLPL04, which has been confirmed previously as a potential probiotic for its antagonistic and immune-modulating activity. It has a molecular weight of 6.61 * 104 Da, consisting of xylose, glucose, and galactose in an approximate molar ratio of 3.4:1.8:1. Microstructural studies demonstrated that the EPS appeared as a smooth sheet structure with many homogeneous rod-shaped lumps. The preliminary in vitro assays indicated that the EPS could significantly inhibit the adhesion of Escherichia coli O157:H7 to HT-29 cells in competition, replacement, and inhibition assays at a dose of 1.0 mg/mL, with an inhibition rate of 20.24 +/- 2.23, 29.71 +/- 1.21, and 30.57 +/- 1.73%, respectively. Additionally, the EPS exhibited strong inhibition against biofilm formation by pathogenic bacteria, including Pseudomonas aeruginosa CMCC10104, E. coli O157:H7, Salmonella Typhimurium ATCC13311, and Staphylococcus aureus CMCC26003. Furthermore, the EPS showed good inhibitory activity against the proliferation of HT-29 cells. The characteristics and bioactivities of this EPS may make it a promising candidate in developing functional food. PMID- 28711241 TI - Analysis of farmers' willingness to participate in pasture grazing programs: Results from a discrete choice experiment with German dairy farmers. AB - Over the last decades, the usage of pasture for grazing of dairy cows has decreased considerably. Pasture grazing programs initiated by dairy companies try to counteract this trend. The present paper investigates farmers' willingness to participate in such grazing programs. A special aim was to quantify the price premiums farmers require for program participation and to identify determinants influencing the premium level. The empirical analysis is based on a discrete choice experiment with 293 German dairy farmers. Models are estimated in terms of willingness to accept. It was found that farmers have no substantial preference for whether the pasture grazing program is financed by the food industry, a governmental scheme, or the dairy company. However, an extension of the annual or daily grazing period results in a decreasing willingness of farmers to participate in a pasture grazing program. In addition, farmers decline the option of a feeding standard prescribing the use of only green fodder when offered an alternative program that merely reduces the amount of concentrated feed or maize silage in the diet. Farmers' with an aversion toward program participation have a significant higher price demand for fulfilling the program requirements. Furthermore, the required price premiums increase with growing milk yields and a greater number of cows kept on the farm. However, if the availability of pasture is high, farmers are more likely to participate. The estimated price premiums and factors influencing farmers' willingness to participate found by this study should be considered by dairies and policymakers to gain insights into the design of possible pasture grazing programs from the perspective of farmers. Thereby, paying price premiums to farmers may increase the attractiveness of pasture grazing, which could finally result in an extended usage of pasture grazing. PMID- 28711242 TI - A method of outdoor housing dairy calves in pairs using individual calf hutches. AB - Interest in housing dairy calves in groups is currently growing. Group housing using individual calf hutches, a resource already available in most dairy farms in North America, could provide a novel housing method that can be a simple way to implement group housing on farm. The main objective of this study was to determine whether pair housing dairy calves in hutches outdoors would result in similar weight gain and milk intake compared with individual housing in hutches. The study was designed to avoid competition for resources (including milk and solid feed, teat, bucket, outdoor space, and hutch) to test a setup that has the potential to maximize performance and calf growth. Secondary objectives were to document how calves in both treatments use their environment in terms of time spent and behaviors performed in each area, how paired calves interact, and the time they spend together. Single calves (n = 6/season) were housed in 1 hutch with an attached outdoor environment; paired calves (n = 6 pairs/season) were given twice the resources. Calves were fed up to 16 L/d of milk replacer. Daily milk intake and weekly weight gains were recorded. Behavioral observations were recorded live once per week for 5 (summer) or 4 (winter) nonconsecutive periods. Paired and single calves had similar weight gain (averaging from 1.1 to 1.3 kg/d across trials) and milk intake (averaging from 11.1 to 13.7 kg/d across trials), showing no difference in performance between treatments. Low occurrences of cross sucking (averaging from 0.1 to 0.4 bouts/h of observation per pen across trials) and displacements at the teat (0.8 to 1.4 bouts/h of observation per pen across trials) were found. All calves altered their behavior in some way to accommodate companions; paired calves were seen interacting and spending time together (i.e., lying in the same hutch), and in the summer trial single calves spent less time lying inside the hutch than paired calves, presumably to have visual access to other calves. The solution of mixed indoor and outdoor housing environments tested as part of this study showed that calves make use of all spaces provided to them in winter and in summer conditions while maintaining good performance. Housing calves in pairs using individual hutches can be a suitable alternative to housing calves individually in hutches outdoors. PMID- 28711243 TI - Genetic correlations between the cumulative pseudo-survival rate, milk yield, and somatic cell score during lactation in Holstein cattle in Japan using a random regression model. AB - Trends in genetic correlations between longevity, milk yield, and somatic cell score (SCS) during lactation in cows are difficult to trace. In this study, changes in the genetic correlations between milk yield, SCS, and cumulative pseudo-survival rate (PSR) during lactation were examined, and the effect of milk yield and SCS information on the reliability of estimated breeding value (EBV) of PSR were determined. Test day milk yield, SCS, and PSR records were obtained for Holstein cows in Japan from 2004 to 2013. A random subset of the data was used for the analysis (825 herds, 205,383 cows). This data set was randomly divided into 5 subsets (162-168 herds, 83,389-95,854 cows), and genetic parameters were estimated in each subset independently. Data were analyzed using multiple-trait random regression animal models including either the residual effect for the whole lactation period (H0), the residual effects for 5 lactation stages (H5), or both of these residual effects (HD). Milk yield heritability increased until 310 to 351 d in milk (DIM) and SCS heritability increased until 330 to 344 DIM. Heritability estimates for PSR increased with DIM from 0.00 to 0.05. The genetic correlation between milk yield and SCS increased negatively to under -0.60 at 455 DIM. The genetic correlation between milk yield and PSR increased until 342 to 355 DIM (0.53-0.57). The genetic correlation between the SCS and PSR was -0.82 to -0.83 at around 180 DIM, and decreased to -0.65 to -0.71 at 455 DIM. The reliability of EBV of PSR for sires with 30 or more recorded daughters was 0.17 to 0.45 when the effects of correlated traits were ignored. The maximum reliability of EBV was observed at 257 (H0) or 322 (HD) DIM. When the correlations of PSR with milk yield and SCS were considered, the reliabilities of PSR estimates increased to 0.31-0.76. The genetic parameter estimates of H5 were the same as those for HD. The rank correlation coefficients of the EBV of PSR between H0 and H5 or HD were greater than 0.9. Additionally, the reliabilities of EBV of PSR of H0 were similar to those for H5 and HD. Therefore, the genetic parameter estimates in H0 were not substantially different from those in H5 and HD. When milk yield and SCS, which were genetically correlated with PSR, were used, the reliability of PSR increased. Estimates of the genetic correlations between PSR and milk yield and between PSR and SCS are useful for management and breeding decisions to extend the herd life of cows. PMID- 28711244 TI - Wheat is more potent than corn or barley for dietary mitigation of enteric methane emissions from dairy cows. AB - Wheat is the most common concentrate fed to dairy cows in Australia, but few studies have examined the effects of wheat feeding on enteric methane emissions, and no studies have compared the relative potencies of wheat, corn, and barley for their effects on enteric methane production. In this 35-d experiment, 32 Holstein dairy cows were offered 1 of 4 diets: a corn diet (CRN) of 10.0 kg of dry matter (DM)/d of single-rolled corn grain, 1.8 kg of DM/d of canola meal, 0.2 kg of DM/d of minerals, and 11.0 kg of DM/d of chopped alfalfa hay; a wheat diet (WHT) similar to the CRN diet but with the corn replaced by single-rolled wheat; a barley diet (SRB) similar to the CRN diet but with the corn replaced by single rolled barley; and a barley diet (DRB) similar to the CRN diet but with the corn replaced by double-rolled barley. Individual cow feed intakes, milk yields, and milk compositions were measured daily but reported for the last 5 d of the experiment. During the last 5 d of the experiment, individual cow methane emissions were measured using the SF6 tracer technique for all cows, and ruminal fluid pH was continuously measured by intraruminal sensors for 3 cows in each treatment group. The average DM intake of cows offered the CRN, WHT, SRB, and DRB diets was 22.2, 21.1, 22.6, and 22.6 kg/d. The mean energy-corrected milk of cows fed the WHT diet was less than that of cows fed the other diets. This occurred because the milk fat percentage of cows fed the WHT diet was significantly less than that of cows fed the other diets. The mean methane emissions and methane yields of cows fed the WHT diet were also significantly less than those of cows fed the other diets. Indeed, the CRN, SRB, and DRB diets were associated with 49, 73, and 78% greater methane emissions, respectively, compared with the emissions from the WHT diet. Methane yield was found to be most strongly related to the minimum daily ruminal fluid pH. This study showed that although the inclusion of wheat in the diet of dairy cows could be an effective strategy for substantially reducing their methane emissions, it also reduced their milk fat percentage and production of milk fat and energy-corrected milk. PMID- 28711245 TI - Feeding of palm oil fatty acids or rapeseed oil throughout lactation: Effects on energy status, body composition, and milk production in Norwegian dairy goats. AB - The objective of this experiment was to examine how supplements of rapeseed oil or palm oil fatty acids would affect milk production and composition, body lipid stores, and energy balance in 30 multiparous goats of Norwegian dairy goat breed. The experiment lasted 230 d, with 1 to 120 d in milk (DIM) for indoor feeding (P1), 120 to 200 DIM for mountain grazing (P2), and 200 to 230 DIM for indoor feeding (P3). Grass silage was fed according to appetite during indoor feeding periods. After an adjustment period (1-60 DIM) when the control diet was given to the goats, the animals were subdivided into 3 groups of 10 goats. Treatments (60 230 DIM) were (1) basal concentrate (control; no added fat); (2) control concentrate with 8% (added on air-dry basis) hydrogenated palm oil enriched with palmitic acid (POFA); and (3) control concentrate with 8% (added on air-dry basis) rapeseed oil (RSO). Individual energy balances based on energy intake and milk production were estimated on 10, 30, 60, 90, 120, 200, and 230 DIM. At the same times, body weight (BW), body condition score (BCS), body mass index, and body tissue stores using computed tomography were monitored. Silage intake was depressed by POFA throughout the experimental period. Reduced BW and body mass index were observed in the POFA and RSO groups, whereas no effect on BCS or body composition was observed throughout lactation. Generally, a minor decrease in BW was observed from 10 to 120 DIM (only 0.6 kg on average) and the total amount of body lipid was reduced by 4.4 kg. During the mountain grazing period, a further reduction in body lipid stores (2.7 kg) was observed, and BW was reduced by 3.9 kg in the same period. The goats mobilized, on average, 72% of their fat reserves during the first 200 DIM. In this period, dietary fat supplementation did not reduce the mobilization of adipose tissue but resulted in greater milk fat yield (2 kg more, on average, compared with the control group). Milk yield was not affected by POFA or RSO supplementation. Milk fat content was higher in the POFA group than in the control and RSO groups. Milk protein and lactose contents were not affected by lipid supplements. In late lactation, a rapid accumulation of fat deposits followed the intense mobilization during the grazing period. Dietary lipid supplements had no effect on milk fat yield at this stage. Milk production depends heavily on the ability to mobilize body lipid stores, and neither POFA nor RSO supplements at rates used in our study affected this mobilization. PMID- 28711247 TI - Ratio of dietary rumen degradable protein to rumen undegradable protein affects nitrogen partitioning but does not affect the bovine milk proteome produced by mid-lactation Holstein dairy cows. AB - Little is known about the bovine milk proteome or whether it can be affected by diet. The objective of this study was to determine if the dietary rumen degradable protein (RDP):rumen undegradable protein (RUP) ratio could alter the bovine milk proteome. Six Holstein cows (parity: 2.5 +/- 0.8) in mid lactation were blocked by days in milk (80 +/- 43 d in milk) and milk yield (57.5 +/- 6.0 kg) and randomly assigned to treatment groups. The experiment was conducted as a double-crossover design consisting of three 21-d periods. Within each period, treatment groups received diets with either (1) a high RDP:RUP ratio (RDP treatment: 62.4:37.6% of crude protein) or (2) a low RDP:RUP ratio (RUP treatment: 51.3:48.7% of crude protein). Both diets were isonitrogenous and isoenergetic (crude protein: 18.5%, net energy for lactation: 1.8 Mcal/kg of dry matter). To confirm N and energy status of cows, dry matter intake was determined daily, rumen fluid samples were collected for volatile fatty acid analysis, blood samples were collected for plasma glucose, beta-hydroxybutyrate, urea nitrogen, and fatty acid analysis, and total 24-h urine and fecal samples were collected for N analysis. Milk samples were collected to determine the general milk composition and the protein profile. Milk samples collected for high-abundance protein analysis were subjected to HPLC analysis to determine the content of alpha-casein, beta-casein, and kappa-casein, as well as alpha-lactalbumin and beta-lactoglobulin. Samples collected for low-abundance protein analysis were fractionated, enriched using ProteoMiner treatment, and separated using sodium dodecyl sulfate-PAGE. After excision and digestion, the peptides were analyzed using liquid chromatography (LC) tandem mass spectrometry (MS/MS). The LC-MS/MS data were analyzed using PROC GLIMMIX of SAS (version 9.4, SAS Institute Inc., Cary, NC) and adjusted using the MULTTEST procedure. All other parameters were analyzed using PROC MIXED of SAS. No treatment differences were observed in dry matter intake, milk yield, general milk composition, plasma parameters, or rumen volatile fatty acid concentrations, indicating no shift in total energy or protein available. Milk urea N and plasma urea N concentrations were higher in the RDP group, indicating some shift in N partitioning due to diet. A total of 595 milk proteins were identified, with 83% of these proteins known to be involved in cellular processes. Although none of the low-abundance proteins identified by LC-MS/MS were affected by diet, feeding a diet high in RUP decreased beta-casein, kappa-casein, and total milk casein concentration. Further investigations of the interactions between diet and the milk protein profile are needed to manipulate the milk proteome using diet. PMID- 28711246 TI - Temporal and spatial heterogeneity in milk and immune-related gene expression during mammary gland involution in dairy cows. AB - The aim of this study was to investigate heterogeneity in tissue morphology, milk protein and immune-related gene expression, and apoptosis of epithelial cells in the lactating and involuting mammary glands of the dairy cow. Mammary tissue from different regions of the gland (alveolar, cisternal, and peripheral) was collected postmortem from nonpregnant, pasture-fed, Holstein-Friesian primiparous cows in mid-lactation that were killed at different time points postmilking: 0, 6, 12, 18, 24, 36, and 72 h (n = 6 per time point). The CSN1NS1 and LALBA mRNA was decreased in alveolar, cisternal, and peripheral tissue by 12 to 36 h postmilking. In contrast, lactoferrin (LF) and mammary serum amyloid A3 (M-SAA3) mRNA was increased in these regions by 36 to 72 h. During lactation, more variability was present in gene expression in alveolar tissue between cows and between quarters within a cow, than within quarters. Histological analysis indicated the alveolar tissue from lactating cows was mostly uniform in structure; however, in situ hybridization indicated that although most of the alveolar tissue expressed milk proteins, the level of expression varied within and between alveoli. This heterogeneity became more pronounced with involution and with increasing regions of alveoli expressing lactoferrin, indicating that alveoli enter involution asynchronously. The peripheral and cisternal tissue had more variability in gene expression between cows compared with the alveolar tissue. The M-SAA3 signal was more intense in the cisternal tissue and less intense than the peripheral compartment compared with LF particularly in the earlier time points. In addition, between cows within the later time points, differences were observed in tissue morphology, the levels of milk protein and immune-related gene expression, and phosphorylated signal transducer and activator of transcription (STAT) 5-P and STAT3-P proteins, and degree of apoptosis, indicating that involution of the mammary gland occurs at different rates between cows. Understanding the mechanisms initiating the process of involution of the mammary gland provides an opportunity for enhancing milk production of the dairy cow. PMID- 28711248 TI - The effect of source of supplemental dietary calcium and magnesium in the peripartum period, and level of dietary magnesium postpartum, on mineral status, performance, and energy metabolites in multiparous Holstein cows. AB - The objective of this study was to determine the effects of feeding different supplemental sources of Ca and Mg in the peripartum period, and different dietary levels of Mg postpartum, on plasma mineral status, performance, and aspects of energy metabolism in transition dairy cows. Multiparous Holstein cows (n = 41) were used in a completely randomized design with a 2 * 2 factorial arrangement of treatments starting at 28 d before expected parturition. Main effects were source assignments (CS = common sources of supplemental Ca and Mg, or MA = a blend of common and commercial mineral sources with supplemental minerals primarily from a commercial Ca-Mg dolomite source; MIN-AD, Papillon Agricultural Company Inc., Easton, MD) beginning at 21 d before due date; cows were further randomized within source treatments to 1 of 2 levels of Mg supplementation (LM = formulated postpartum diet Mg at 0.30% of dry matter (DM), or HM = formulated postpartum diet Mg at 0.45% of DM) beginning within 1 d after parturition. Final treatment groups included the following: common source, low Mg (CS-LM, n = 11); common source, high Mg (CS-HM, n = 11); MIN-AD, low Mg (MA-LM, n = 10); and MIN-AD, high Mg (MA-HM, n = 9). Treatment diets were fed and data collected through 42 d in milk. Postpartum plasma Mg concentrations tended to be higher for cows fed HM and cows fed CS, but no effects were observed on peripartum plasma Ca concentrations. Peripartum plasma P concentrations were higher for cows fed MA. Dry matter intake (DMI) in the prepartum period was higher for cows fed MA (CS = 15.9 vs. MA = 16.8 kg/d) and postpartum DMI was higher in some groups depending on week. Plasma nonesterified fatty acid concentrations were lower for cows fed MA during both the prepartum and postpartum periods. A source by level interaction was observed for postpartum plasma beta-hydroxybutyrate (BHB) concentrations such that cows fed CS-LM had numerically higher BHB and cows fed MA-LM had numerically lower BHB (geometric means; CS-LM = 7.9, CS-HM = 6.9, MA-LM = 6.3, and MA-HM = 7.3 mg/dL) than cows fed the other 2 treatments. Higher milk fat yield, milk fat content, and fat- and energy-corrected yield during wk 1 for cows fed MA resulted in source by week interactions for these outcomes. This study demonstrated that varying supplemental Ca and Mg sources and feeding rates had minimal effect on plasma Ca status despite differences in plasma Mg and P concentrations. Effects on DMI and plasma energy metabolites suggest an opportunity for strategic use of mineral sources in the transition period to promote metabolic health. PMID- 28711249 TI - Estimating the energetic cost of feeding excess dietary nitrogen to dairy cows. AB - Feeding N in excess of requirement could require the use of additional energy to metabolize excess protein, and to synthesize and excrete urea; however, the amount and fate of this energy is unknown. Little progress has been made on this topic in recent decades, so an extension of work published in 1970 was conducted to quantify the effect of excess N on ruminant energetics. In part 1 of this study, the results of previous work were replicated using a simple linear regression to estimate the effect of excess N on energy balance. In part 2, mixed model methodology and a larger data set were used to improve upon the previously reported linear regression methods. In part 3, heat production, retained energy, and milk energy replaced the composite energy balance variable previously proposed as the dependent variable to narrow the effect of excess N. In addition, rumen degradable and undegradable protein intakes were estimated using table values and included as covariates in part 3. Excess N had opposite and approximately equal effects on heat production (+4.1 to +7.6 kcal/g of excess N) and retained energy (-4.2 to -6.6 kcal/g of excess N) but had a larger negative effect on milk gross energy (-52 to -68 kcal/g of excess N). The results suggest that feeding excess N increases heat production, but more investigation is required to determine why excess N has such a large effect on milk gross energy production. PMID- 28711250 TI - Genetic analysis for quality of frozen embryos produced by Holstein cattle donors in Canada. AB - The number of embryos produced by Holstein donors has been shown to be heritable, so it could be possible to genetically select for this trait to improve the efficiency of the assisted reproductive technology (ART) in dairy cattle. Another important parameter to consider for achieving good results from ART is embryo quality because embryos of good quality have more chance of producing live offspring. The possibility of using genetic selection for increasing the quality of embryo produced from ART has yet to be assessed. The objective of this study was, therefore, to perform a genetic analysis of embryo quality of Holstein donors in Canada using data recorded by Holstein Canada. The data set used was missing quality score data for embryos transferred fresh into a recipient, so the analyses were only performed for frozen embryos. With most traits in the Canadian dairy industry being evaluated with linear models, embryo quality was also evaluated with this class of models. However, considering the categorical nature of embryo quality, a threshold model was also evaluated. Embryo quality data were analyzed with either a univariate linear animal model or a univariate binomial threshold animal model. Genetic parameters estimated from the different models were comparable. A low heritability was found for the donor (0.04 +/- <0.01) and the service sire (0.02 +/- <0.01), but the repeatability estimate for the donor was higher (0.17), indicating that it was worthwhile to use a repeated records model. Overall, considering the low genetic parameters estimated, slow genetic progress is expected for the quality of frozen embryos produced by Canadian Holstein donors. Rank correlations were calculated between breeding values estimated from different models. High correlations were found between all models, indicating that no substantial re-ranking of the animals is expected from the different models. So, even though a threshold model is better suited for the analysis of categorical data, a linear model could be used for the analysis of embryo quality because it is less computationally demanding. PMID- 28711251 TI - Association of candidate gene polymorphisms with milk technological traits, yield, composition, and somatic cell score in Italian Holstein-Friesian sires. AB - Advances in DNA-based marker technology have enabled the identification of genomic regions underlying complex phenotypic traits in livestock species. The incorporation of detected quantitative trait loci into genetic evaluation provides great potential to enhance selection accuracies, hence expediting the genetic improvement of economically important traits. The objective of the present study was to investigate 96 single nucleotide polymorphisms (SNP) located in 53 candidate genes previously reported to have effects on milk production and quality traits in a population of highly selected Holstein-Friesian bulls. A total of 423 semen samples were used to genotype the bulls through a custom oligo pool assay. Forty-five SNP in 32 genes were found to be associated with at least 1 of the tested traits. Most significant and favorable SNP trait associations were observed for polymorphisms located in CCL3 and AGPAT6 genes for fat yield (0.037 and 0.033 kg/d, respectively), DGKG gene for milk yield (0.698 kg/d), PPARGC1A, CSN1S1, and AGPAT6 genes for fat percentage (0.127, 0.113, and 0.093%, respectively), GHR gene for protein (0.064%) and casein percentage (0.053%), and TLR4 gene for fat (0.090%), protein (0.066%), and casein percentage (0.050%). Somatic cell score was favorably affected by GHR (-0.095) and POU1F1 (-0.137), and interesting SNP-trait associations were observed for polymorphisms located in CSN2, POU1F1, and AGPAT6 genes for rennet coagulation time (-0.592, -0.558, and 0.462 min, respectively), and GHR and CSN2 genes for curd firmness 30 min after rennet addition (1.264 and 1.183 mm, respectively). In addition to the influence of individual SNP, the effects of composite genotypes constructed by grouping SNP according to their individual effects on traits considered in the analysis were also examined. Favorable and significant effects on milk traits were observed for 2 composite genotypes, one including 10 SNP and the other 4 SNP. The former was associated with an increase of milk (0.075 kg/d), fat (0.097 kg/d), protein (0.083 kg/d), and casein yields (0.065 kg/d), and the latter was associated with an increase of fat (0.244%), protein (0.071%), and casein percentage (0.047%). Although further research is required to validate the identified SNP loci in other populations and breeds, our results can be considered as a preliminary foundation for further replication studies on gene-assisted selection programs. PMID- 28711252 TI - Ethyl-cellulose rumen-protected methionine enhances performance during the periparturient period and early lactation in Holstein dairy cows. AB - The onset of lactation in dairy cows is characterized by severe negative energy and protein balance. Increasing Met availability during this time may improve milk production, hepatic lipid metabolism, and immune function. The aim of this study was to evaluate the effect of feeding ethyl-cellulose rumen-protected methionine (RPM; Mepron, Evonik Nutrition and Care GmbH, Hanau-Wolfgang, Germany) on the performance of dairy cows during prepartum and early-lactation periods. Sixty multiparous Holstein cows were used in a block design and assigned to either a control or an ethyl-cellulose RPM diet. Ethyl-cellulose RPM was supplied from -28 to 60 d relative to parturition at a rate of 0.09% and 0.10% of dry matter during the prepartum and postpartum periods, respectively. That rate ensured that the ratio of Lys to Met in metabolizable protein was close to 2.8:1. Cows fed ethyl-cellulose RPM had dry matter intakes (DMI) that were 1.2 kg/d greater during the prepartum period and consequently had overall greater cumulative DMI than cows in the control group. Compared with controls, during the fresh period (1-30 d in milk; DIM) feeding ethyl-cellulose RPM increased DMI by 1.7 kg/d, milk yield by 4.1 kg/d, fat yield by 0.17 kg/d, milk protein yield by 0.20 kg/d, 3.5% fat-corrected milk by 4.3 kg/d, and energy-corrected milk by 4.4 kg/d. Although ethyl-cellulose RPM supplementation increased milk protein content by 0.16 percentage units compared with the control during the fresh period, no differences were observed for milk fat, lactose, and milk urea nitrogen concentration. During the high-producing period (31-60 DIM), cows fed ethyl cellulose RPM increased DMI and milk yield by 1.45 and 4.4 kg/d, respectively. Ethyl-cellulose RPM also increased fat yield by 0.19 kg/d, milk protein yield by 0.17 kg/d, 3.5% fat-corrected milk by 4.7 kg/d, and energy-corrected milk by 4.8 kg/d compared with controls. Ethyl-cellulose RPM supplementation reduced plasma fatty acids in the fresh period and decreased gamma-glutamyl transferase, indicating better liver function. In conclusion, when lysine was adequate, feeding ethyl-cellulose RPM to achieve a ratio close to 2.8:1 in metabolizable protein improved dairy cow performance from parturition through 60 DIM. The greater milk production was, at least in part, driven by the greater voluntary DMI and better liver function. PMID- 28711253 TI - The capacity of silage inoculant bacteria to bind aflatoxin B1 in vitro and in artificially contaminated corn silage. AB - The objectives were to examine the aflatoxin B1 (AFB1)-binding capacity of silage bacteria and factors affecting the responses. Experiments 1 and 2 examined the effects of bacterial strain and population on the AFB1-binding capacity of 10 bacteria. When applied at 106 cfu/mL to an in vitro medium, only Lactobacillus plantarum PT5B bound the AFB1 and the binding capacity was low (4%). When applied at 109 cfu/mL, all 10 bacteria bound AFB1, but L. plantarum R2014 (Lp) and EQ12, Lactobacillus buchneri R1102 (Lb), and Pediococcus acidilactici R2142 and EQ01 (Pa) had the greatest capacity (23.9 to 33%). Experiment 3 examined the AFB1 binding capacity of viable and nonviable (HCl-treated) forms of Lp, Lb, and Pa at different pH. Nonviable Lb and Lp, but not Pa, increased AFB1 binding. Binding of AFB1 was greatest at pH 2.5 and least at pH 8. As the nonviable Lb and Lp that bound AFB1 in experiment 3 would not be effective silage inoculants, experiment 4 examined effects of benign versus severe treatments (85 vs. 100 degrees C; pH 2.5 vs. <1) on the viability of Lp, Lb, and Pa. The population of bacteria was reduced from 9 to 4 log cfu/mL by treatment with HCl at pH 2.5 and to 2 log cfu/mL by 85 or 100 degrees C, whereas acidification at pH <1 eliminated the bacteria. Experiment 5 determined the effect of the ensiling duration and benign treatment methods [37 (viable cells) or 85 degrees C (heated cells) or acidification with HCl at pH 2.5 (acid-treated cells)] on binding of AFB1 and silage quality during the fermentation of corn forage. Corn forage was ensiled after treatment with only deionized water (control), AFB1 (30 ug/kg of fresh forage), or a mixture of AFB1 and 109 cfu/g of each of the treated bacteria. Adding AFB1 alone to corn forage reduced the pH decline during the first 3 d of ensiling and increased or tended to increase butyric acid concentration and final pH after ensiling for 21 d. Bacterial inoculation inhibited these negative effects. The fermentation profile of silage treated with Lb and Pa did not differ from those of the control silage. In all silages treated with the toxin, the AFB1 concentration decreased linearly (from 30 to <=0.35 ug/kg) within 3 d of ensiling. Certain silage bacteria can bind AFB1 but the efficacy depends on several factors. PMID- 28711254 TI - Effect of maternal exercise on calf dry matter intake, weight gain, behavior, and cortisol concentrations at disbudding and weaning. AB - The objective of this study was to determine the effect of maternal physical activity during late gestation on calf dry matter intake, weight gain, behavior, and cortisol concentration during disbudding and weaning. Fifty-five Holstein and 5 Jersey * Holstein crossbred calves were enrolled into the study during gestation. Calves were born from pregnant, nonlactating Holstein (n = 58) and Jersey * Holstein crossbred (n = 2) dairy cows. Cows were assigned to either confinement (n = 20 cows; 13 female calves, 7 male calves), exercise (n = 20 cows; 8 female calves, 12 male calves), or pasture (n = 20 cows; 11 female calves, 9 male calves) treatments at dry-off from January to November 2015. Enrollment in treatment was balanced by parity (1.8 +/- 0.9), projected mature equivalent fat-corrected milk (13,831 +/- 2,028 kg/lactation), dam breed, and projected calving date. Cows assigned to confinement remained in the pen throughout the dry period. Cows assigned to exercise were walked 5 times/wk at a targeted 1.5 h at 3.25 km/h. Cows assigned to pasture were turned out 5 times/wk for a targeted 1.5 h/d. Treatments were terminated on the expected due date or at signs of calving. Calves were removed from cows immediately once observed by farm staff and subsequently weighed and moved into a straw deep-bedded hutch. Data loggers were attached to the rear fetlock of each calf -3 d to +6 d relative to disbudding and weaning to monitor changes in lying behavior. Calves were weighed on d -7, -5, -3, -1, 0, 1, 3, 5, and 7, and grain was weighed the 7 d preceding and following disbudding and weaning. Blood was collected 24 h before and 0, 1, and 4 h after disbudding and d -1, 0, 1, and 2 relative to weaning to determine cortisol concentrations. Data were analyzed using mixed linear model in SAS (SAS Institute Inc., Cary, NC). Calf weight gain decreased the day after disbudding and calves tended to have elevated cortisol concentrations 1 h after disbudding, regardless of maternal treatment. Calf weight gain decreased the day of and after weaning; calves had elevated cortisol concentrations the day after weaning, regardless of treatment. Behavior did not differ by treatment at disbudding, but calves from pasture cows lay down for less time compared with confinement and exercise maternal treatments and less frequently than exercise maternal treatments at weaning. More research investigating the significance of lying time and restlessness around stressful events is needed to further understand the implications of such behavioral responses. PMID- 28711255 TI - Short communication: Effect of the addition of Bifidobacterium monocultures on the physical, chemical, and sensory characteristics of fermented goat milk. AB - The aim of the study was to use 3 monocultures of Bifidobacterium (Bifidobacterium animalis ssp. lactis AD600, Bifidobacterium animalis ssp. lactis BB-12, and Bifidobacterium longum AD50) in fermented goat milk to assess the microbial, physicochemical, rheological, and sensory quality of beverages during a 3-wk storage period at 5 degrees C. The results indicated that selected bifidobacteria may be used for production of fermented goat milk because they comply with the minimum standards specified by the Food and Agriculture Organization of the United Nations and the World Health Organization during the entire period of storage. However, goat milk fermented by Bif. longum AD50 had less than 106 cfu/g after 21 d of storage. The acidity, acetaldehyde content, viscosity, and hardness of fermented goat milk beverages depended on the strain and the storage period. Sensory properties were similar and acceptable, with a tendency for the quality to be reduced with an extended storage time. Depending on the monoculture of bifidobacteria used to manufacture fermented goat milk, the product had a different pH value. Titratable acidity in all fermented goat milk increased significantly along with the time of storage. Our study has shown that monocultures of bifidobacteria had a significant effect on the content of acetaldehyde, but the lowest effect over the entire storage period was observed in goat milk fermented by Bif. animalis ssp. lactis BB-12. This sample also had the lowest viscosity values compared with other samples and the best organoleptic properties during a 3-wk storage period. PMID- 28711256 TI - Associations between paratuberculosis ELISA results and test-day records of cows enrolled in the Irish Johne's Disease Control Program. AB - The effect of the Mycobacterium avium ssp. paratuberculosis (MAP) ELISA status on test-day milk performance of cows from Irish herds enrolled in the pilot national voluntary Johne's disease control program during 2013 to 2015 was estimated. A data set comprising 92,854 cows and 592,623 complete test-day records distributed across 1,700 herds was used in this study. The resulting ELISA outcome (negative, inconclusive, and positive) of each cow within each year of the program was used to allocate the cow into different scenarios representing the MAP status. At MAPscenario1, all cows testing ELISA nonnegative (i.e., inconclusive and positive) were assigned a MAP-positive status; at MAPscenario2 only cows testing ELISA-positive were assigned a MAP-positive status; at MAPscenario3 only cows testing ELISA nonnegative (inconclusive or positive) and gathered exclusively from herds where at least 2 further ELISA nonnegative (inconclusive or positive) cows were found were assigned a MAP-positive status; at MAPscenario4 only cows testing ELISA-positive that were gathered exclusively from herds where at least 2 further ELISA-positive cows were found were assigned a MAP-positive status. Milk outputs based on test-day records were standardized for fat and protein contents (SMY) and the effect of MAP ELISA status on the SMY was estimated by a linear mixed effects model structure. The SMY mean difference recorded at test day between cows with a MAP-positive status and those with a MAP-negative status within MAPscenario1 was estimated at -0.182 kg/test day; the mean difference was 0.297 kg/test day for MAPscenario2; for MAPscenario3 mean difference between MAP positive status and MAP test-negative cows was -0.209 kg/test day, and for MAPscenario4, the difference was -0.326 kg/test day. PMID- 28711257 TI - Seasonal and maternal effects on acid-base, l-lactate, electrolyte, and hematological status of 205 dairy calves born to eutocic dams. AB - In this study, we used linear mixed models to determine the effects of season, time of sampling relative to birth (factors), duration of the delivery process, duration of maternal grooming, calf body weight (BW) at birth, and time of day (covariates) on values of venous blood gas, acid-base and electrolyte parameters, and l-lactate concentrations in dairy calves born to eutocic dams in summer (SUM, n = 101) and winter (WIN, n = 104). Neonatal vitality was assessed at 0, 1, and 24 h after delivery in a linear scoring system using muscle tone, erection of the head, muscle reflexes, heart rate, and sucking drive as criteria. Simultaneously with vitality scoring, venous blood samples were collected by jugular venipuncture. Blood was tested for pH, partial pressure of CO2 (pCO2; mmHg) and oxygen (pO2; mmHg), l-lactate (mmol/L), hemoglobin (Hb; g/L), ionized calcium (Ca2+; mmol/L), sodium (Na+; mmol/L), potassium (K+; mmol/L) and chloride (Cl-; mmol/L). Bicarbonate (HCO3-; mmol/L), base excess (BE; mmol/L), total carbon dioxide (TCO2; mmol/L), and anion gap (mmol/L) were calculated. Electrolyte parameters were affected by none of the factors or covariates. Time of day at birth did not affect any of the parameters of interest. Vitality score tended to increase over time and it showed higher values in WIN calves than in SUM calves. Concentrations of HCO3-, BE, and l-lactate indicated a higher degree of metabolic acidosis in SUM calves; however, pH was not affected by season. Concentrations of Hb were higher in SUM calves than in WIN calves; however, covariates did not affect Hb concentrations. Blood pH, concentrations of pO2, HCO3-, and BE decreased, whereas l-lactate concentrations and values of pCO2, TCO2, and anion gap increased with longer duration of delivery. A shift in acid-base balance was also linked to BW of the calf at birth, with lower values of blood pH, HCO3-, and BE in calves with higher BW compared with those with lower BW at birth, whereas TCO2 and l-lactate concentrations increased with higher calf BW at birth. Values of pO2 increased and pCO2 decreased with longer duration of maternal grooming. Blood pH, HCO3-, and BE increased, whereas l-lactate concentrations and anion gap decreased with longer duration of licking the calf. Our results indicate that prolonged delivery can impair acid-base status and can cause slight lactic acidosis, even in calves born from spontaneous or eutocic calvings, and that high BW at birth predisposes calves to acidosis. The positive effect of maternal grooming on neonatal acid-base status should be considered in parturition management. Season, duration of the delivery process, calf BW at birth, and duration of maternal grooming are recommended for consideration in future studies on blood gas and acid-base parameters in dairy calves in the immediate neonatal period. PMID- 28711258 TI - Strains of the Lactobacillus casei group show diverse abilities for the production of flavor compounds in 2 model systems. AB - Cheese flavor development is directly connected to the metabolic activity of microorganisms used during its manufacture, and the selection of metabolically diverse strains represents a potential tool for the production of cheese with novel and distinct flavor characteristics. Strains of Lactobacillus have been proven to promote the development of important cheese flavor compounds. As cheese production and ripening are long-lasting and expensive, model systems have been developed with the purpose of rapidly screening lactic acid bacteria for their flavor potential. The biodiversity of 10 strains of the Lactobacillus casei group was evaluated in 2 model systems and their volatile profiles were determined by gas chromatography-mass spectrometry. In model system 1, which represented a mixture of free AA, inoculated cells did not grow. In total, 66 compounds considered as flavor contributors were successfully identified, most of which were aldehydes, acids, and alcohols produced via AA metabolism by selected strains. Three strains (DPC2071, DPC3990, and DPC4206) had the most diverse metabolic capacities in model system 1. In model system 2, which was based on processed cheese curd, inoculated cells increased in numbers over incubation time. A total of 47 compounds were identified, and they originated not only from proteolysis, but also from glycolytic and lipolytic processes. Tested strains produced ketones, acids, and esters. Although strains produced different abundances of volatiles, diversity was less evident in model system 2, and only one strain (DPC4206) was distinguished from the others. Strains identified as the most dissimilar in both of the model systems could be more useful for cheese flavor diversification. PMID- 28711259 TI - Effect of dairy product environment on the growth of Bacillus cereus. AB - pH is one of the most important parameters to manage bacterial replication in foodstuffs. In this study, the ability of 2 Bacillus cereus strains, 1 clinical human isolate (GPe2) and 1 isolate from a dairy product (D43), were investigated for in vitro growth at different pH values (from 3.5 to 7.5) at 2 temperatures (15 and 37 degrees C), showing their ability to grow from 5.5 to 7.5 and from 5.0 to 7.5, respectively. The ability of spores of these 2 microorganisms to germinate in different typologies of dairy products (unflavored yogurt, Taleggio cheese, mascarpone cheese, and raw and pasteurized milk) was also investigated by inoculating the spores and maintaining the products at 15 degrees C. No growth was observed in yogurt, likely due to the combined effect of low pH (<5) and the presence of natural microflora. An inhibitory action of the natural microflora on the growth of B. cereus was also hypothesized for Taleggio cheese and raw milk, as these substrates were characterized by a high natural lactic acid bacteria population and permissive pH values (5.8/6.8 in Taleggio cheese, >7 in raw milk). In pasteurized milk and mascarpone cheese, where pH was not restrictive for B. cereus growth and where no significant natural microflora was present, growth occurred rapidly up to loads close to 7 log cfu/g. PMID- 28711260 TI - Short communication: Effects of an immunomodulatory feed additive on phagocytic capacity of neutrophils and relative gene expression in circulating white blood cells of transition Holstein cows. AB - High-producing dairy cows typically experience immunosuppression with dysregulated neutrophil function (e.g., compromised phagocytosis) during the transition period (3 wk before to 3 wk after parturition), which is causally associated with increased risk of infections. Enhanced neutrophil immune competence has significant bearing with the wellbeing of transition dairy cattle. In the current study, we investigated the effect of OmniGen-AF (OG; Phibro Animal Health, Quincy, IL) and its dose in modulation of neutrophil function of transition cows. Forty-eight multiparous cows were stratified by parity, somatic cell count, and expected calving date and randomly assigned to 3 treatments: OG fed at 0 g/head per day (CON), 60 g/head per day (OG60; recommended dose), and 90 g/head per day (OG90; 1.5* recommended dose). The OG was added from dry off (61.8 +/- 1.69 d before parturition) to 28 d in milk (DIM), and removed from all treatment groups at 29 to 35 DIM (the last week of the experimental period). Neutrophil phagocytic ability against Staphylococcus aureus and Escherichia coli was improved and tended to be improved, respectively, by OG from d 28 before parturition to 28 DIM. Cows in OG60 had higher neutrophil phagocytic ability against S. aureus and E. coli compared with CON cows from d 28 before parturition to 28 DIM. Neutrophil phagocytosis of S. aureus and E. coli was higher and tended to be higher for OG60 compared with CON on 35 DIM. The relative gene expression of CXCL8 and SELL were upregulated and tended to be upregulated by OG from 60 d before parturition to 28 DIM; this was due to cows in OG60 having greater SELL and CXCL8 gene expression than CON. Expression of SELL in circulating white blood cells of OG60-treated cows was greater than OG90 and the relative expression of CXCL8 gene tended to be greater for OG60 compared with CON on 35 DIM. In conclusion, feeding OG at the recommended dose of 60 g/head per day from dry off was effective in maintaining peripheral blood neutrophil function in transition dairy cows, and it is not necessary to feed OG beyond the recommended dose. PMID- 28711261 TI - The effect of Mycobacterium avium ssp. paratuberculosis infection on clinical mastitis occurrence in dairy cows. AB - Endemic diseases can be counted among the most serious sources of losses for livestock production. In dairy farms in particular, one of the most common diseases is Johne's disease, caused by Mycobacterium avium ssp. paratuberculosis (MAP). Infection with MAP causes direct costs because it affects milk production, but it has also been suspected to increase the risk of clinical mastitis (CM) among infected animals. This might contribute to further costs for farmers. We asked whether MAP infection represents a risk factor for CM and, in particular, whether CM occurrences were more common in MAP-infected animals. Our results, obtained by survival analysis, suggest that MAP-infected cows had an increased probability of experiencing CM during lactation. These results highlight the need to account for the interplay of infectious diseases and other health conditions in economic and epidemiological modeling. In this case, accounting for MAP infected cows having an increased CM occurrence might have nonnegligible effects on the estimated benefit of MAP control. PMID- 28711262 TI - Genetic and nongenetic factors associated with milk color in dairy cows. AB - Milk color is one of the sensory properties that can influence consumer choice of one product over another and it influences the quality of processed dairy products. This study aims to quantify the cow-level genetic and nongenetic factors associated with bovine milk color traits. A total of 136,807 spectra from Irish commercial and research herds (with multiple breeds and crosses) were used. Milk lightness (L^*), red-green index (a^*) and yellow-blue index (b^*) were predicted for individual milk samples using only the mid-infrared spectrum of the milk sample. Factors associated with milk color were breed, stage of lactation, parity, milking-time, udder health status, pasture grazing, and seasonal calving. (Co)variance components for L^*,a^*, and b^* were estimated using random regressions on the additive genetic and within-lactation permanent environmental effects. Greater b^* value (i.e., more yellow color) was evident in milk from Jersey cows. Milk L^* increased consistently with stage of lactation, whereas a^* increased until mid lactation to subsequently plateau. Milk b^* deteriorated until 31 to 60 DIM, but then improved thereafter until the end of lactation. Relative to multiparous cows, milk yielded by primiparae was, on average, lighter (i.e., greater L^*), more red (i.e., greater a^*), and less yellow (i.e., lower b^*). Milk from the morning milk session had lower L^*,a^*, and b^* Heritability estimates (+/-SE) for milk color varied between 0.15 +/- 0.02 (30 DIM) and 0.46 +/- 0.02 (210 DIM) for L^*, between 0.09 +/- 0.01 (30 DIM) and 0.15 +/- 0.02 (305 DIM) for a^*, and between 0.18 +/- 0.02 (21 DIM) and 0.56 +/- 0.03 (305 DIM) for b^* For all the 3 milk color features, the within-trait genetic correlations approached unity as the time intervals compared shortened and were generally <0.40 between the peripheries of the lactation. Strong positive genetic correlations existed between b^* value and milk fat concentration, ranging from 0.82 +/- 0.19 at 5 DIM to 0.96 +/- 0.01 at 305 DIM and confirming the observed phenotypic correlation (0.64, SE = 0.01). Results of the present study suggest that breeding strategies for the enhancement of milk color traits could be implemented for dairy cattle populations. Such strategies, coupled with the knowledge of milk color traits variation due to nongenetic factors, may represent a tool for the dairy processors to reduce, if not eliminate, the use of artificial pigments during milk manufacturing. PMID- 28711263 TI - Robotic milking: Technology, farm design, and effects on work flow. AB - Robotic milking reduces labor demands on dairy farms of all sizes and offers a more flexible lifestyle for farm families milking up to 250 cows. Because milking is voluntary, barn layouts that encourage low-stress access by providing adequate open space near the milking stations and escape routes for waiting cows improve milking frequency and reduce fetching. Because lame cows attend less often, preventing lameness with comfortable stalls, clean alley floors, and effective foot bathing warrants special emphasis in robotic dairies. Variable milking intervals create challenges for foot bathing, sorting and handling, and dealing with special-needs cows. Appropriate cow routing and separation options at the milking stations are needed to address these challenges and ensure that the expected labor savings are realized. Protocols and layout and gating should make it possible for a herd worker to complete all handling tasks alone. Free traffic and guided traffic systems yield similar results when excellent management is applied or when the number of cows is well below capacity. In less ideal circumstances, guided traffic and the use of commitment pens result in longer standing times and stress, particularly for lower ranking cows, and poor management with free traffic results in more labor for fetching. PMID- 28711264 TI - The growth and aflatoxin production of Aspergillus flavus strains on a cheese model system are influenced by physicochemical factors. AB - Traditional cheeses may be contaminated by aflatoxin-producing Aspergillus flavus during the ripening process, which has not been sufficiently taken into account. The objectives of this study were to evaluate the influence of water activity (aw), pH, and temperature on the lag phases, growth, and aflatoxin production of 3 A. flavus strains (CQ7, CQ8, and CG103) on a cheese-based medium. The results showed that the behavior of A. flavus strains was influenced by pH, aw, and temperature conditions. The CQ7 strain showed the maximum growth at pH 5.5, 0.99 aw, and 25 degrees C, whereas for CQ8 and CQ103 strains, no differences were obtained at pH 5.5 and 6.0. In general, low pH, aw, and temperature values increased the latency times and decreased the growth rate and colony diameter, although aw and temperature were the most limiting factors. Maximum aflatoxin production on the cheese-based medium occurred at pH 5.0, 0.95 aw, and 25 or 30 degrees C, depending on the strain. This study shows the effect of pH, aw, and temperature factors on growth and aflatoxin production of 3 aflatoxigenic A. flavus strains on a cheese-based medium. The findings may help to design control strategies during the cheesemaking process and storage, to prevent and avoid aflatoxin contamination by aflatoxigenic molds. PMID- 28711265 TI - Feeding a concentrate rich in rapeseed oil improves fatty acid composition and flavor in Norwegian goat milk. AB - Impaired quality due to a high content of free fatty acids (FFA) and off-flavors has caused challenges in the development of Norwegian goat milk products. The present study aimed to examine the effect of lipid-supplemented concentrates on milk fat content, fatty acid composition, FFA, lipoprotein lipase activity, sensory properties, and size of milk fat globules of goat milk. Thirty goats assigned to 3 experimental groups were fed different concentrates from 60 d in milk (DIM) until late lactation (230 DIM). The diets were (1) control concentrate (no added fat); (2) control concentrate with 8% (added on air-dry basis) hydrogenated palm oil enriched with palmitic acid (POFA); and (3) control concentrate with 8% (added on air-dry basis) rapeseed oil (RSO). The POFA group produced milk with the highest fat content, and fat content was positively correlated with the mean size of milk fat globules. Goats in the RSO group had a higher content of long-chain and unsaturated fatty acids, whereas milk from goats in the POFA group had a higher content of palmitic and palmitoleic acids (C16:0 and C16:1 cis). The control group produced milk with a higher content of short-, medium-, odd-, and branched-chain fatty acids compared with the 2 other groups. The content of FFA in milk was low in early and late lactation and peaked in mid lactation (90 DIM). A high content of FFA was correlated with poor sensory properties (tart/rancid flavor). The RSO group produced milk with lower content of FFA and off-flavors in mid lactation and a higher proportion of unsaturated fatty acids. Therefore, replacement of palm oil with rapeseed oil as a lipid source in dairy goat feed would be favorable. PMID- 28711266 TI - Intravaginal instillation of gonadotropin-releasing hormone analogues with an absorption enhancer induced a surge of luteinizing hormone in lactating dairy cows. AB - Our objectives were to evaluate circulating LH concentrations after intravaginal (IVG) instillation of GnRH analogs in lactating dairy cows. In 2 experiments, lactating Holstein cows (experiment 1: n = 32; experiment 2: n = 47) received the experimental treatments 48 h after the first of 2 PGF2alpha treatments given 12 h apart and 7 d after a modified Ovsynch protocol (GnRH at -7 d, PGF2alpha at -24 h, PGF2alpha at -56 h, GnRH at 0 h). In experiment 1, cows were stratified by parity and randomly allocated to receive the following treatments: 2 mL of saline IVG (SAL, n = 6), 100 ug of gonadorelin (Gon) i.m. (G100-IM, n = 5), and 100 (G100, n = 7), 500 (G500, n = 8), or 1,000 ug of Gon IVG (G1000, n = 7). In experiment 2, treatments were SAL (n = 8), G100-IM (n = 8), G1000 (n = 7), 1,000 ug of Gon plus 10% citric acid (CA) IVG (G1000CA, n = 8), 80 ug of buserelin IVG (B80, n = 8), and 80 ug of buserelin plus 10% CA IVG (B80CA, n = 8). In both experiments, blood was collected every 15 min from -15 min to 4 h, and every 30 min from 4 to 6 h after treatment. Data for area under the curve (AUC), mean LH concentrations, and time to maximum LH concentration were analyzed by ANOVA with (mean LH only) or without repeated measures using PROC MIXED of SAS (version 9.4, SAS Institute Inc., Cary, NC). The proportion of cows with a surge of LH was evaluated with Fisher's exact test using PROC FREQ of SAS. In both experiments, LH concentrations were affected by treatment, time, and the treatment by time interaction. In experiment 1, the AUC for LH and maximum LH concentration were greatest for the G100-IM treatment and were greater for the G1000 than for the SAL and G500 treatments. The proportion of cows with an observed surge of LH was 100 and 0% for cows that received Gon i.m. and IVG, respectively. In experiment 2, the AUC and maximum LH concentrations were greater for the G100-IM, G1000CA, and B80CA treatments than for the other IVG treatments. The proportion of cows with a surge of LH differed by treatment (SAL = 0%, G100-IM = 100%, G1000 = 14%, G1000CA = 88%, B80 = 13%, and B80CA = 100%). For the treatments with a surge of LH, time to maximum concentration of LH was the shortest for the G100-IM treatment, intermediate for the G1000CA treatment, and the longest for cows in the B80CA treatment. In conclusion, Gon (up to 1,000 ug) absorption through intact vaginal epithelium after a single IVG instillation was insufficient to elicit a surge of LH of normal magnitude. Conversely, IVG instillation of 1,000 ug of Gon and 80 ug of buserelin with the addition of citric acid as absorption enhancer resulted in a surge of LH of similar characteristics than that induced after i.m. injection of 100 ug of Gon. PMID- 28711267 TI - A comparative study of the in vitro activity of iodopropynyl butylcarbamate and amphotericin B against Prototheca spp. isolates from European dairy herds. AB - The objective of this study was to assess the in vitro effect of iodopropynyl butylcarbamate (IPBC) and amphotericin B (AMB) on Prototheca zopfii genotype 2 and Prototheca blaschkeae isolates recovered from dairy herds of Belgium, France, Italy, Germany, and Poland. The combination of IPBC with AMB on Prototheca isolates and toxicity of IPBC to the bovine mammary epithelial cells were also evaluated. The in vitro activity of IPBC and AMB against 96 isolates of P. zopfii genotype 2 and 42 isolates of P. blaschkeae was performed. Minimum inhibitory concentrations (MIC) and minimum algicidal concentrations (MAC) of IPBC and AMB were determined. To determine any synergistic, additive, or antagonistic effect of the combination of IPBC and AMB, 2-dimensional checkerboard combination tests were also performed to calculate fractional inhibitory concentrations. Cytotoxicity analysis of IPBC to the bovine mammary epithelial cell line was performed using a 3-(4,5-dimethyl-2-thiazol-2yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. The MIC for 50 and 90% of isolates (MIC50 and MIC90, respectively) for IPBC were 4 and 8 mg/L versus 0.5 and 1 mg/L for AMB, respectively. The MIC profiles differed between P. zopfii genotype 2 and P. blaschkeae, with the latter species being more susceptible to both compounds. The MIC50 and MIC90 of IPBC were 4 and 8 mg/L for P. zopfii genotype 2 and 1 and 2 mg/L for P. blaschkeae, respectively. The MIC50 and MIC90 of AMB were both 1 mg/L for P. zopfii genotype 2 and 0.25 and 1 mg/L for P. blaschkeae, respectively. Both IPBC and AMB exhibited the ability to kill Prototheca spp. The MAC for 90% of isolates of IPBC was twice the MIC90, whereas an 8-fold increase of the MIC90 was algicidal in the case of AMB. Overall, the combined use of IPBC and AMB exhibited an increased algicidal effect, albeit the fractional inhibitory concentration index showed synergistic activity only against 3 P. zopfii genotype 2 isolates. For all the remaining isolates (87.5%), this combination produced only an additive effect. The MTT assay results showed both IPBC and AMB, at the concentrations employed in the study, to be nontoxic to the epithelial mammary gland cells (cell viability >90%). Notably, only IPBC at the highest concentration (i.e., 8 mg/L) exerted a slight cytotoxic effect on the cell line tested (mean cell viability: 88.54 +/- 3.88 and 90.66 +/- 3.0, after 2 and 4 h of MTT treatment, respectively). The anti Prototheca activity of IPBC was here demonstrated for the first time. In addition, the combined use of IPBC with AMB enhanced each other's effect, creating an additive rather than synergistic interaction. Both agents, used at concentrations corresponding to MIC values against Prototheca spp., showed no toxic effect for the mammary epithelial cells. In conclusion, IPBC, used either alone or in combination with AMB, can be considered a promising option in the treatment armamentarium for protothecal mastitis in dairy cows. PMID- 28711268 TI - Short communication: Implementation of a breeding value for heat tolerance in Australian dairy cattle. AB - Excessive ambient temperature and humidity can impair milk production and fertility of dairy cows. Selection for heat-tolerant animals is one possible option to mitigate the effects of heat stress. To enable selection for this trait, we describe the development of a heat tolerance breeding value for Australian dairy cattle. We estimated the direct genomic values of decline in milk, fat, and protein yield per unit increase of temperature-humidity index (THI) using 46,726 single nucleotide polymorphisms and a reference population of 2,236 sires and 11,853 cows for Holsteins and 506 sires and 4,268 cows for Jerseys. This new direct genomic value is the Australian genomic breeding value for heat tolerance (HT ABVg). The components of the HT ABVg are the decline in milk, fat, and protein per unit increase in THI when THI increases above the threshold of 60. These components are weighted by their respective economic values, assumed to be equivalent to the weights applied to milk, fat, and protein yield in the Australian selection indices. Within each breed, the HT ABVg is then standardized to have a mean of 100 and standard deviation (SD) of 5, which is consistent with the presentation of breeding values for many other traits in Australia. The HT ABVg ranged from -4 to +3 SD in Holsteins and -3 to +4 SD in Jerseys. The mean reliabilities of HT ABVg among validation sires, calculated from the prediction error variance and additive genetic variance, were 38% in both breeds. The range in ABVg and their reliability suggests that HT can be improved using genomic selection. There has been a deterioration in the genetic trend of HT, and to moderate the decline it is suggested that the HT ABVg should be included in a multitrait economic index with other traits that contribute to farm profit. PMID- 28711269 TI - Development of an isothermal amplification-based assay for the rapid visual detection of Salmonella bacteria. AB - The efficient and timely detection of pathogens is a major concern worldwide. The aim of this study was to establish a rapid detection method for Salmonella bacteria in food samples to facilitate timely treatment. Widely used detection methods currently include culture-based methods and PCR-based methods. The former are time consuming, requiring 2 to 3 d, whereas the latter have higher accuracy but are typically complicated, requiring expertise and expensive instruments. In this study, a sensitive and rapid approach for the visual and point-of-use detection of Salmonella bacteria based on recombinase polymerase amplification (RPA) and a lateral-flow (LF) nucleic acid strip was established. We designed a pair of primers according to the invA gene of Salmonella bacteria: one was modified with digoxin, and the other was modified with biotin. In the presence of the biotin- and digoxin-modified primers and target DNA, the RPA produced a substantial amount of duplex DNA attached to biotin and digoxin. The products were detected using LF strips through immunoreaction: anti-digoxin antibodies on the gold nanoparticles, digoxin on the duplex, streptavidin on the LF test line, and biotin on the duplex. The developed RPA-LF assay allowed detection of Salmonella genomic DNA in less than 20 min with simple water bath equipment or portable thermal equipment. In addition, the RPA-LF assay was highly sensitive, with a detection limit as low as 20 fg of target DNA or 1.05 * 101 cfu of bacteria in pure culture, and highly specific, exhibiting no cross-reaction with Staphylococcus aureus, Escherichia coli, Listeria monocytogenes, Shigella, Enterobacter aerogenes, or Campylobacter jejuni. Importantly, Salmonella could be detected in milk and chicken breast at concentrations as low as 1.05 * 100 cfu/mL or 1.05 * 100 cfu/g after enrichment for 2 h and in eggs at 1.05 * 100 cfu/g after enrichment for 4 h. Furthermore, RPA was more sensitive than PCR, which requires a thermal cycling device. In summary, this study describes a sensitive, simple, and point-of-use detection method for Salmonella bacteria. PMID- 28711270 TI - Evaluation of the yield, molar mass of exopolysaccharides, and rheological properties of gels formed during fermentation of milk by Streptococcus thermophilus strains St-143 and ST-10255y. AB - The yield and chemical structures of exopolysaccharides (EPS) produced by many strains of Streptococcus thermophilus have been characterized. However, the kinetics (or production profile) for EPS during milk fermentation is not clear. In this study, we investigated whether any differences existed in the yield and molar mass of EPS when milk was fermented at the same acidification rate by 2 strains of S. thermophilus (St-143 and ST-10255y). The type of EPS produced by these 2 strains is different. Milk samples were analyzed for EPS concentration every 30 min during a fermentation period of 270 min (final pH 4.5) by using a modified quantification method, which was faster and validated for its recovery of added EPS. Rheological properties of milks during fermentation were also analyzed using small-strain dynamic oscillatory rheology. For the determination of molar mass, EPS extracts were isolated by ultrafiltration of whey obtained during fermentation of milk to pH values 5.2, 4.9, 4.7, and 4.5, and molar mass was analyzed using size-exclusion chromatography-multi-angle laser light scattering. During fermentation, both strains appeared to start producing significant amounts of EPS after about ~150 min, which corresponded to pH ~5.3, which was close to the point of gelation. During the remainder of the fermentation process (150-270 min), the EPS concentration from strains St-143 and ST-10255y significantly increased from 30 to 72 mg/L and from 26 to 56 mg/L, respectively. The quantity of EPS recovered by our modified method was estimated to represent ~60% of the total EPS added to milk. The molar mass of EPS produced by both strains appeared to slightly decrease during fermentation. At pH 5.2, EPS from St-143 and ST-10255y had molar masses of 2.9 * 106 and 1.4 * 106 g/mol, respectively, which decreased to 1.6 * 106 and 0.8 * 106 g/mol, respectively, when the pH of milk was 4.5. Distinct differences were apparent in the rheological properties of gels fermented by the 2 strains. At the end of fermentation, St-143 fermented milk had weaker gels with storage modulus (G') value at pH 4.6 of 26 Pa, whereas gels made with ST-10255y were stiffer with a G' value at pH 4.6 of 82 Pa. For St-143 gels, maximum loss tangent (LTmax) values were higher (0.50) and occurred earlier (at a higher pH value) than the LTmax values (0.46) for gels from ST-10255y strain. Because the fermentation conditions were identical for both strains, the observed changes in rheological properties could be due to the differences in chemical structures and molar mass of the EPS produced by these 2 S. thermophilus strains. PMID- 28711271 TI - Identification of dipeptidyl peptidase-IV inhibitory peptides from mare whey protein hydrolysates. AB - Inhibition of dipeptidyl peptidase-IV (DPP-IV) activity is a promising strategy for treatment of type 2 diabetes. In the current study, DPP-IV inhibitory peptides were identified from mare whey protein hydrolysates obtained by papain. The results showed that all the mare whey protein hydrolysates obtained at various hydrolysis durations possessed more potent DPP-IV inhibitory activity compared with intact whey protein. The 4-h hydrolysates showed the greatest DPP IV inhibitory activity with half-maximal inhibitory concentration of 0.18 mg/mL. The 2 novel peptides from 4-h hydrolysate fractions separated by successive chromatographic steps were characterized by liquid chromatography-electrospray ionization tandem mass spectrometry. The novel peptides Asn-Leu-Glu-Ile-Ile-Leu Arg and Thr-Gln-Met-Val-Asp-Glu-Glu-Ile-Met-Glu-Lys-Phe-Arg, which corresponded to beta-lactoglobulin 1 f(71-77) and beta-lactoglobulin 1 f(143-155), demonstrated DPP-IV inhibitory activity with half-maximal inhibitory concentrations of 86.34 and 69.84 MUM, respectively. The DPP-IV inhibitory activity of the 2 peptides was retained or even improved after simulated gastrointestinal digestion in vitro. Our findings indicate that mare whey protein derived peptides may possess potential as functional food ingredients in the management of type 2 diabetes. PMID- 28711273 TI - Treatment methods following suicidal self-administration of IV organophosphate: What can additional lipid administration change? AB - Organic phosphor compounds are highly toxic and life-threatening compounds that are widely used in agriculture, households and gardens worldwide. While oral intakes are observed frequently, toxic effects can also be seen through contract or inhalation. However, toxic cases through the parenteral route have rarely been reported. We had three main aims: first, to present a male patient who self administered 2ml of monocrotophos intravenously to commit suicide. Our second goal was to present the current multiple treatment methods, such as fast general support, antidote treatment, lipid emulsion treatment, and plasmapheresis along with the literature. Third, we aimed to emphasize that with these treatments, patients' intensive care needs, intermediate symptoms, and hospitalization periods can be decreased and thus mortality and morbidity increase can be prevented. PMID- 28711272 TI - The infection of Mycoplasma hominis after total knee replacement: Case report and literature review. AB - The Mycoplasma hominis infection is a rare postoperative complication after joint replacement. Based on our knowledge, there were only two cases reported by Korea all over the world currently. A case of postoperative Mycoplasma hominis infection after total knee replacement in our hospital was reported in this article. It was confirmed through mass spectrometer and Mycoplasma cultivation and treated by the first stage debridement, polyethylene insert replacement, and then drainage and irrigation combined with sensitive antibiotics after the operation. We observed that the C reactive protein (CRP) level correlates with the development of disease, while the erythrocyte sedimentation rate (ESR) remains at a high level, indicating the relevance between the Mycoplasma hominis infection caused by knee joint replacement and CRP. This study aims to report the case and review relevant literature. PMID- 28711274 TI - Clinical association: Lyme disease and Guillain-Barre syndrome. AB - Guillain-Barre Syndrome (GBS) is a life-threatening condition in which patients may present to the Emergency Department in respiratory distress leading to death. The early identification and treatment of such a condition is paramount in preventing mortality. While there are many infections associated with GBS, the association with Lyme disease is uncommon. Through our case we aim to highlight Borrelia burgdorferi as an important antecedent infection associated with the development of GBS. In this case we report a 31-year-old male who was diagnosed with Lyme disease and GBS with relevant clinical presentation including progressive numbness and weakness in bilateral hands and feet for the past 1week along with areflexia. Initiation of medical therapy with intravenous immunoglobulin and parenteral ceftriaxone resulted in resolution of his symptoms. The treatment of both diseases early can help prevent further central nervous complications leading to high morbidity and mortality. PMID- 28711275 TI - Chemotherapy induced stroke mimic: 5-Fluorouracil encephalopathy fulfilling criteria for tissue plasminogen activator therapy. AB - Stroke mimics, especially those involving chemotherapy related neurotoxicity, can confound the clinical diagnosis of acute stroke. Here we describe the case of a 63year-old male with a recent history of stage IIIC colon cancer who presented with confusion on the second day of modified FOLFOX6 (5-fluorouracil/oxaliplatin) chemotherapy and subsequently received alteplase, tissue plasminogen activator therapy (tPA), for presumed ischemic stroke. Magnetic resonance imaging scans after tPA administration did not reveal evidence of an infarction and the patients' neurological symptoms resolved completely after discontinuation of 5 fluorouracil (5-FU). Although this patient did not experience any side effects from tPA, fibrinolytic therapy may have been avoided with a better understanding of potential chemotherapy related adverse reactions. Our experience suggests that 5-FU induced reversible encephalopathy can present with acute stroke-like symptoms and emergency medicine personnel evaluating patients for tPA treatment should be aware of this differential diagnosis. PMID- 28711276 TI - Association of clinician burnout and perceived clinician-patient communication. PMID- 28711277 TI - Use of a midstream clean catch mobile application did not lower urine contamination rates in an ED. AB - OBJECTIVES: Urine microscopy is a common test performed in emergency departments (EDs). Urine specimens can easily become contaminated by different factors, including the collection method. The midstream clean-catch (MSCC) collection technique is commonly used to reduce urine contamination. The urine culture contamination rate from specimens collected in our ED is 30%. We developed an instructional application (app) to show ED patients how to provide a MSCC urine sample. We hypothesized that ED patients who viewed our instructional app would have significantly lower urine contamination rates compared to patients who did not. METHODS: We prospectively enrolled 257 subjects with a urinalysis and/or urine culture test ordered in the ED and asked them to watch our MSCC instructional app. After prospective enrollment was complete, we retrospectively matched each enrolled subject to an ED patient who did not watch the instructional app. Controls were matched to cases based on gender, type of urine specimen provided, ED visit date and shift. Urinalysis and urine culture contamination results were compared between the matched pairs using McNemar's test. RESULTS: The overall urine culture contamination rate of the 514 subjects was 38%. The majority of the matched pairs had a urinalysis (63%) or urinalysis plus urine culture (35%) test done. There were no significant differences in our urine contamination rates between the matched pairs overall or when stratified by gender, by prior knowledge of the clean catch process or by type of urine specimen. CONCLUSION: We did not see a lower contamination rate for patients who viewed our instructional app compared to patients who did not. It is possible that MSCC is not effective for decreasing urine specimen contamination. PMID- 28711278 TI - Radon in drinking water: Comparison and evaluation of two ionisation chamber activity measurement methods. AB - In this study the radon activity concentration of water samples from the so called "Thermenlinie" are measured using two different techniques: currents measured with an ionisation chamber setup developed by H. Friedmann are compared with results obtained using a commercially available AlphaGUARD. A fit to compensate for measurements made in non-equilibrium state is applied and the detection limit is estimated. PMID- 28711279 TI - Diagnosis of Duchenne muscular dystrophy in Italy in the last decade: Critical issues and areas for improvements. PMID- 28711280 TI - Unsupervised Extraction of Stable Expression Signatures from Public Compendia with an Ensemble of Neural Networks. AB - Cross-experiment comparisons in public data compendia are challenged by unmatched conditions and technical noise. The ADAGE method, which performs unsupervised integration with denoising autoencoder neural networks, can identify biological patterns, but because ADAGE models, like many neural networks, are over parameterized, different ADAGE models perform equally well. To enhance model robustness and better build signatures consistent with biological pathways, we developed an ensemble ADAGE (eADAGE) that integrated stable signatures across models. We applied eADAGE to a compendium of Pseudomonas aeruginosa gene expression profiling experiments performed in 78 media. eADAGE revealed a phosphate starvation response controlled by PhoB in media with moderate phosphate and predicted that a second stimulus provided by the sensor kinase, KinB, is required for this PhoB activation. We validated this relationship using both targeted and unbiased genetic approaches. eADAGE, which captures stable biological patterns, enables cross-experiment comparisons that can highlight measured but undiscovered relationships. PMID- 28711282 TI - WHO QualityRights: transforming mental health services. PMID- 28711281 TI - CancerGD: A Resource for Identifying and Interpreting Genetic Dependencies in Cancer. AB - Genes whose function is selectively essential in the presence of cancer associated genetic aberrations represent promising targets for the development of precision therapeutics. Here, we present CancerGD, a resource that integrates genotypic profiling with large-scale loss-of-function genetic screens in tumor cell lines to identify such genetic dependencies. CancerGD provides tools for searching, visualizing, and interpreting these genetic dependencies through the integration of functional interaction networks. CancerGD includes different screen types (siRNA, shRNA, CRISPR), and we describe a simple format for submitting new datasets. PMID- 28711284 TI - Financialisation in health care: An analysis of private equity fund investments in Turkey. AB - The 2007-2008 global financial crisis revived interest in the impacts of financial markets and actors on our social and economic life. Nevertheless, research on health care financialisation remains scant. This article presents findings from research on one modality of financial investments in health care: global private equity funds' investments in private hospitals. Adopting a political economy approach, it analyses the drivers and impacts of the upsurge of global private equity investments in the Turkish private hospital sector amid the global financial crisis. The analysis derives from review of research and archival literature, as well as six in-depth interviews held with owners/executive board directors/general managers of the largest private hospital chains in Turkey and the general partners of their PE investors. The interviewing process took place between January and November 2016. All interviews were conducted by the author in Istanbul. The findings point to a mutually reinforcing relationship between neoliberal policies and financialisation processes in health care. The article shows that neoliberal healthcare reforms, introduced under consecutive Justice and Development Party (JDP) governments in Turkey, have been important precursors of private equity investments in healthcare services. These private equity investments, in turn, intensified and broadened the process of marketisation in health care services. Four impacts are identified, through which private equity investments hasten the marketisation of health care services. These relate to the impacts of private equity investments on a) advancing the process of chain formation by large hospital groups, b) spreading financial imperatives into the operations of private hospitals c) fostering internationalisation of capital, and d) augmenting inequities in access to health care services and standards. PMID- 28711283 TI - Common Carotid Artery Flow Measured by 3-D Ultrasonic Vector Flow Imaging and Validated with Magnetic Resonance Imaging. AB - Ultrasound (US) examination of the common carotid artery was compared with a through-plane magnetic resonance imaging (MRI) sequence to validate a recently proposed technique for 3-D US vector flow imaging. Data from the first volunteer examined were used as the training set, before volume flow and peak velocities were calculated for the remaining eight volunteers. Peak systolic velocities (PSVs) and volume flow obtained with 3-D US were, on average, 34% higher and 24% lower than those obtained with MRI, respectively. A high correlation was observed for PSV (r = 0.79), whereas a lower correlation was observed for volume flow (r = 0.43). The overall standard deviations were +/-5.7% and +/-5.7% for volume flow and PSV with 3-D US, compared with +/-2.7% and +/-3.2% for MRI. Finally, the data were re-processed with a change in the parameter settings for the echo-canceling filter to investigate its influence on overall performance. PSV was less affected by the re-processing, whereas the difference in volume flow between 3-D vector flow imaging and MRI was reduced to -9%, and with an improved overall standard deviation of +/-4.7%. The results illustrate the feasibility of using 3-D US for precise and angle-independent volume flow and PSV estimation in vivo. PMID- 28711285 TI - Anti-IL-21 monoclonal antibody combined with liraglutide effectively reverses established hyperglycemia in mouse models of type 1 diabetes. AB - Immunotherapy for type 1 diabetes (T1D) has previously focused on suppressing the autoimmune response against pancreatic beta cells to preserve endogenous insulin production and regulate glucose levels. With increased attention toward combination therapy strategies, studies indicate the multifunctional cytokine interleukin-21 (IL-21) may be a suitable target as an immuno-modulatory arm, while glucagon-like peptide-1 receptor (GLP-1R) agonists may be appropriate as a beta cell protective arm in combination therapy for T1D. We report here that treatment with anti-IL-21 monoclonal antibody delays diabetes onset in the spontaneous non-obese diabetic (NOD) and NOD.scid adoptive transfer models, while its effect in reversing recent-onset hyperglycemia is limited. However, the combination of anti-IL-21 plus the GLP-1R agonist liraglutide is effective in reversing established disease compared to either monotherapy in both the NOD and rat insulin promotor-lymphocytic choriomeningitis virus glycoprotein (RIP-LCMV GP) models of autoimmune diabetes. Enhanced efficacy is particularly evident in severely hyperglycemic mice, with return to normoglycemia remaining stable for the majority of mice even after therapy is withdrawn. Importantly, increased beta cell proliferation does not appear to be the predominant mechanism. In conclusion, combination therapy with anti-IL-21 and liraglutide is able to consistently reverse disease in mouse models of T1D. The observed effects rival the most effective experimental disease-modifying treatments tested in preclinical studies. PMID- 28711286 TI - Novel therapeutic targets for inflammatory bowel disease. AB - Inflammatory bowel disease (IBD), including Crohn's disease (CD) and Ulcerative Colitis (UC), are immune mediated conditions associated with progressive damage of the inflamed gut tissue, and have a considerable impact on the patient's quality of life. The pathogenesis remains uncertain, but it is clear that complex mechanisms associated with host and luminal factors are involved, generating an unbalance between pro- and anti-inflammatory signaling. It is well established that the purpose of an adequate and complete control of the intestinal inflammation measured not only by clinical symptoms, but also with more objective data such as fecal biomarkers (calprotectin) and endoscopy. The treat to target approach possibly correlates with minor risk for complications associated with IBD, specially surgery and cancer. The most studied inflammatory pathway in IBD, is described to be dependent of the pro-inflammatory cytokine tumor necrosis factor-alfa (TNF-alpha), and compose the first line studies for development of biological drugs, in this case, targeting specifically the action of TNF-alpha. Even though, the use of anti-TNFs drugs are associated with improvement of the inflammation in some patients, a great portion do not respond at first or lose response over time. These findings made clear about the possibility of other mechanisms involved in perpetuating the chronic inflammatory state. Many years of intensive research have led to the identification of different inflammatory pathways that form the basis of the intensive drug development that we are experiencing today. These novel drugs include agents that target leukocyte trafficking, Interleukin (IL) 23, Janus kinases (JAK), Sphingosine 1 phosphate (S1P) and Smad7, an inhibitor of the immunosuppressive cytokine transforming growth factor beta1 (TGF-beta1). In this manuscript, we aim to review the most promising late-stage drug candidates for the treatment of IBD. PMID- 28711287 TI - In vivo experience with peroral endoscopic myotomy: An essential activity for developing the technique in humans. AB - INTRODUCTION AND OBJECTIVES: Achalasia is the most widely studied esophageal motility disorder. No treatment has achieved completely satisfactory results. The laparoscopic Heller esophagomyotomy is currently the most accepted technique. With the advent of minimally invasive surgery, the appearance of peroral endoscopic myotomy (POEM) has promising results. The primary aim of our study was to perform peroral endoscopic esophagomyotomy in animal experimentation models to perfect the technique and later apply it to humans. The secondary aims were to evaluate the intraoperative and postoperative complications and to describe the anatomopathologic findings. MATERIALS AND METHODS: An experimental study was conducted on 8 live porcine models that were followed for 30 days to identify postoperative complications. Necropsy was then performed to evaluate the histopathologic findings. The international requirements and regulations for animal experimentation were met. RESULTS: The technique was carried out in all the models. There was one intraoperative death. Pneumothorax was observed in 50% of the units in experimentation and subcutaneous cervical emphysema in 75%, with no significant clinical repercussions. Histologic muscle layer (myotomy) involvement was above the gastroesophageal junction in 87% of the cases and below it in 25%. CONCLUSION: Peroral endoscopic esophagomyotomy is a feasible, albeit complex, procedure that requires advanced training, and thus should be performed in highly specialized centers. Specific skills in advanced therapeutic endoscopic procedures of this type must continue to be developed through continuing education (ideally in in vivo models), to then be performed on humans. PMID- 28711288 TI - Performance and bacterial community structure of a 10-years old constructed mangrove wetland. AB - Constructed mangrove wetland has been used for wastewater treatment but its long term performance has not been reported. One-year monitoring of a 10-years old horizontal subsurface-flow constructed mangrove wetland consisting of three belts, two with mangrove plants and one without, revealed that the system maintained high and stable removal percentages of organic matter and nutrients, and planted belts performed better than unplanted control. Substrates in belts planted with Aegiceras corniculatum or Kandelia obovata had higher abundance of ammonifiers, nitrifiers and denitrifiers but lower total heterotrophic bacteria than unplanted substrate. Denaturing gradient gel electrophoresis showed that microbial diversity in planted substrate was significantly lower than that in unplanted one. The bacteria in substrates, irrespective to belts, were phylogenetically related to Proteobacteria (most dominant), Acidobacteria, Firmicutes, Nitrospirae, Gemmatimonadetes, Chloroflexi and Cyanobacteria. The steady performance of this 10-year old constructed mangrove wetland was affected by the abundance and diversity of bacterial community in substrate. PMID- 28711289 TI - Clinical outcomes in recurrent glioblastoma with bevacizumab therapy: An analysis of the literature. AB - Bevacizumab (BEV) is a common treatment for recurrent glioblastoma (GBM). After progression on BEV, there is no consensus on subsequent therapy, as multiple chemotherapy trials have failed to demonstrate discernible activity for salvage. A previous review (995 patients) estimated a progression free survival (PFS) on BEV of 4.2months (SD+/-2.1) with an overall survival (OS) after progression on BEV at 3.8months (SD+/-1). We endeavored to establish a more rigorous historical control, both as a benchmark for efficacy, and a prognostic tool for clinical practice. A comprehensive literature review was performed utilizing PubMed and societal presentation abstracts. A total 2388 patients from 53 arms of 42 studies were analyzed in three groups: 1) thirty-two studies in which survival post-BEV was determined by subtracting PFS from OS (2045 patients): PFS on BEV=4.38months (95% CI 4.09-4.68); OS post-BEV=3.36months (95% CI 3.12-3.66); 2) two studies (94 patients) in which OS post-BEV is reported: OS=3.26 (95% CI 2.39-4.42); 3) eight studies of salvage therapy after progression on BEV (249 patients): of OS post BEV=4.46months (95% CI 3.68-5.54). These estimates provide a firm historical control for PFS on BEV, as well as OS after disease progression on BEV therapy. PMID- 28711290 TI - Biopsies of pediatric brainstem lesions display low morbidity but strong impact on further treatment decisions. AB - OBJECTIVE: The course of malignant brain stem gliomas in childhood is rarely positive. Because of limited therapeutic options and potentially hazardous biopsies oncologist often relay on MRI diagnoses only for further therapy decisions. In this study we show that brain stem biopsies display a low morbidity rate and neuropathological assessment has a considerable impact on further treatment decision. METHODS: Within 18-months five children with brainstem symptoms and the radiological diagnosis of a malignant brainstem glioma, were identified. From this time point it was possible to analyze all samples with the 450K methylome analysis. Other neuropathological techniques included classical histology with immunohistochemistry. Surgery was performed as biopsy, either microsurgical, frame-guided (Leksell), robot-assisted (ROSA) or navigated (BrainLab, two children). RESULTS: Mean age of the children was 7.5years (range: newborn to 12years). There was no biopsy-related morbidity or mortality. The mean number of taken samples was 12 (range: 1-25). Histologic diagnosis could be established in all children, however, 450K methylome diagnosis was positive in only two out of five patients. CONCLUSION: Despite the technically difficult biopsies, all specimens were sufficient for immunohistochemical diagnosis, however, 450K methylome analysis could only be better established where multiple small samples were taken, instead of few larger ones. Based on the preoperative radiological diagnosis suggesting malignant brainstem glioma, all children would have been treated with combined radiation and temozolomid chemotherapy. Nevertheless, due to the availability of histology and molecular diagnostics, individualized therapy could be performed, preventing in two out of five children from unnecessary radiation and chemotherapy. PMID- 28711291 TI - Clinical value and predictors of subclinical seizures in patients with temporal lobe epilepsy undergoing scalp video-EEG monitoring. AB - The aim of this study was to determine the clinical importance and predictors of SCSs in a large population of patients with temporal epilepsy (TLE) undergoing video electroencephalographic (VEEG) monitoring. We reviewed the VEEG data of 327 consecutive patients with TLE admitted to our epilepsy center between August 2012 and January 2017. Demographic, electro-clinical, and neuroimaging data were recorded and re-analyzed. To our knowledge, this is the first study assessing SCSs recorded by long-term VEEG monitoring in patients with TLE. Twenty-seven of 327 (8.3%) patients exhibited SCSs during VEEG monitoring. Of these patients, 24 had both SCSs and clinical seizures. The mean duration of the SCSs was 23.18s (range: 5-1307s). Of the 27 patients with SCSs, 24 (88.9%) showed localizing value during the diagnostic process. Seventeen patients exhibited colocalization with clinical seizures, 4 showed useless localization related to clinical seizures, and 3 did not have clinical seizures. Sixteen patients (59.3%) experienced their first SCSs within the first 24h of monitoring and one had the first SCSs within 20min. Multivariate logistic regression analysis showed that age <18years at VEEG monitoring (OR=3.272, 95% CI=1.283-8.343, p=0.013) and bilateral IEDs (OR=4.558, 95% CI=1.982-10.477, p<0.001) were independently associated with the presence of SCSs. Thus, SCSs are not uncommon in patients with TLE, particularly those with age <18years or bilateral IEDs, and should be considered of significant clinical relevance during the diagnostic process. PMID- 28711292 TI - Perioperative stroke after cerebral aneurysm clipping: Risk factors and postoperative impact. AB - Stroke is a devastating complication after intracranial aneurysm clipping. Understanding the risk factors that prognosticate perioperative stroke may help to identify patients that would benefit from neuroprotective therapy. This study assesses patient-specific independent predictors of perioperative stroke in relation to surgical aneurysm clipping. Additionally, this study evaluates the postoperative complications of stroke. We performed a retrospective chart review of 437 patients with ruptured and unruptured intracranial aneurysms, which underwent surgical clipping from 2006 to 2013. Multivariate logistical regression was utilized to assess the effect of age, race, gender, subarachnoid hemorrhage, Hunt and Hess (H/H) grade, aneurysm location, and intraoperative somatosensory evoked potentials (SSEPs) changes on the frequency of perioperative stroke. Thirty-five (8.0%) patients developed a stroke within 24h postoperatively. Patients with significant intraoperative SSEP changes were 7.33 (95% confidence interval [CI]: 3.51-15.31) times more likely to develop perioperative strokes. In patients who presented with H/H grade 5, the odds ratio for developing perioperative stroke was 9.21 (95% CI: 1.28-66.13) respectively. In the absence of aneurysm rupture, patients presenting with new-onset stroke were more likely to suffer postoperative complications, stay in the intensive care unit longer, and be discharged to in-patient rehabilitation compared to patients without new onset stroke. This study suggests that severity of subarachnoid hemorrhage based on the patient's clinical condition increases the risk of perioperative stroke in patients with surgical aneurysm clipping. SSEP changes and high-grade H/H scores can serve as independent predictors of perioperative stroke, with the latter having the greatest predictive value. PMID- 28711293 TI - A genetic study of Factor V Leiden (G1691A) mutation in young ischemic strokes with large vessel disease in a South Indian population. AB - Factor V Leiden (FVL) has been, by far, the most investigated gene mutation, with 26 studies to date, on its role in arterial strokes. Overall, a meta-analysis of all these studies taken together showed that carriers of the Factor V Leiden allele were 1.33times more likely to develop arterial strokes when compared to controls. We subjected a highly select subset of young strokes, with large vessel infarcts, to genetic analysis for FVL mutation and compared them with matched healthy controls to look for a statistically significant association. In this prospective study, 6/120 cases (5%) and 2/120 controls (1.6%) were positive for heterozygous FVL (G1691A) mutation. The higher prevalence of FVL mutation in cases (5%) compared to controls (1.6%) did not show statistical significance with a Pearson's Chi square P value of 0.15. The Odds Ratio (OR) for risk of large vessel disease in FVL positive cases was 3.10 (95% CI of 0.61-15.7). FVL mutation (G1691A) in young Indian subjects with ischemic strokes does not seem to be significantly associated with large vessel disease. PMID- 28711294 TI - Clinical management and survival of patients with central nervous system hemangiopericytoma in the National Cancer Database. AB - PURPOSE/OBJECTIVES: Hemangiopericytomas are rare central nervous system (CNS) tumors. We sought to investigate existing clinical management strategies and overall survival (OS) among patients with hemangiopericytomas of the CNS. METHODS/MATERIALS: All patients diagnosed with CNS hemangiopericytoma from 2004 to 2014 in the National Cancer Database were included. Clinical and treatment related characteristics were analyzed for an association with OS following diagnosis using univariable and multivariable analyses. RESULTS: Nine-hundred and eighty-one patients were included (0.22% of all CNS tumors). At diagnosis, 22 patients had spinal tumors (2%), 21 patients had multifocal tumors (2%) 28 had disseminated disease (3%), and the remainder were unifocal intracranial tumors. Patients either underwent surgical resection and radiation (48%), surgery alone (37%), radiation alone (6%), or biopsy alone (9%). Of patients with known extent of resection, 53% underwent gross total resection, and, of patients with known radiation modality, 15% received stereotactic radiosurgery. Among the total cohort, 3 and 10year OS was 87% and 59%, respectively. On multivariable analysis, factors associated with inferior OS included age (HR=1.05, p<0.001), WHO grade (p<0.001), multifocal disease (HR=2.59, p=0.04), disseminated disease (HR=2.67, p=0.01), and chemotherapy (HR=2.66, p=0.01). Patients receiving surgery alone or surgery and radiation demonstrated improved OS compared to biopsy alone (HR=0.45, p=0.01 and HR=0.47, p=0.02, respectively). However radiation utilization did not impact OS (p=0.691). CONCLUSIONS: The present data provide large-scale prognostic information from a contemporary cohort of patients with hemangiopericytoma and support an initial attempt at surgical extirpation. The benefits of ionizing radiation are likely limited to improved local control and neurologic function. PMID- 28711296 TI - Anaerobic digestion of food waste: A review focusing on process stability. AB - Food waste (FW) is rich in biomass energy, and increasing numbers of national programs are being established to recover energy from FW using anaerobic digestion (AD). However process instability is a common operational issue for AD of FW. Process monitoring and control as well as microbial management can be used to control instability and increase the energy conversion efficiency of anaerobic digesters. Here, we review research progress related to these methods and identify existing limitations to efficient AD; recommendations for future research are also discussed. Process monitoring and control are suitable for evaluating the current operational status of digesters, whereas microbial management can facilitate early diagnosis and process optimization. Optimizing and combining these two methods are necessary to improve AD efficiency. PMID- 28711295 TI - Prognostic indicators of adult medullary gliomas after microsurgical treatment - A retrospective analysis of 54 patients. AB - Due to the low incidence of medullary gliomas, the special location, and the function of the gliomas in the medulla oblongata, microsurgical treatment is still challenging for neurosurgeons. The aim of this study was to observe the effect of microsurgical treatment of adult medullary gliomas and to explore the prognostic factors after treatment. The clinical data from 54 patients with adult medullary gliomas who received microsurgical treatment at Beijing Tiantan Hospital (China) from April 2008 to April 2014 was retrospectively analyzed. The factors affecting their prognosis were analyzed with log-rank univariate analysis. The factors that affected prognosis included age, gender, duration of preoperative symptoms, Karnofsky Performance Scale (KPS) score, World Health Organization (WHO) grade, extent of tumor resection, and postoperative complications. Those with statistical significance in the univariate analysis were entered into a multivariate Cox regression analysis. WHO grading showed 7 cases of grade I, 30 cases of grade II, 14 cases of grade III, and 3 cases of grade IV tumors. Univariable analysis showed that postoperative nasogastric feeding (P=0.031), WHO pathological grade (P=0.018), extent of resection (P=0.016), and preoperative involvement of >=3 cranial nerves (CNs) (P=0.014) affected overall survival. The WHO pathological grade of the tumor was an independent risk factor for prognosis. In conclusion, the WHO pathological grade of the tumor was an important prognostic indicator. PMID- 28711297 TI - The nitrogen removal performance and microbial communities in a two-stage deep sequencing constructed wetland for advanced treatment of secondary effluent. AB - The advanced treatment of secondary effluent was conducted in a two-stage deep sequencing constructed wetland (DSCW) which comprised a denitrification chamber (W1) and a nitrification chamber (W2). The results showed that a superior NO3--N removal rate was observed in W1 with a C/N ratio of 6.5, and a high NH4+-N removal rate was obtained when the W2 was operated with 6-h duration of idle. In the long-term operation for 45days, the two-stage DSCW pilot system achieved high and stable removal of TN, NH4+-N and NO3--N, which were 92.9%, 83.7% and 95.6% in average, respectively. The microbial communities between W1 and W2 were significant different. Rich diversity of the microbial community and the high proportion of denitrifying bacteria in the W1 were essential for nitrogen removal in this treatment system. AOB in the W2 played a major role in NH4+-N removal in W2. PMID- 28711298 TI - Synthesis and characterization of slow pyrolysis pine cone bio-char in the removal of organic and inorganic pollutants from aqueous solution by adsorption: Kinetic, equilibrium, mechanism and thermodynamic. AB - Pine cone bio-char was synthesized through slow pyrolysis at 500 degrees C, characterized and used as an effective adsorbent in the removal of organic Methylene Blue (MB) dye and inorganic nickel metal (Ni(II) ions from aqueous phase. Batch adsorption kinetic study was carried out by varying solution pH, dye concentration, temperature, adsorbent dose and contact time. Kinetic and isotherm models indicates that the adsorption of both adsorbates onto pine cone bio-char were mainly by chemisorption. Langmuir maximum adsorption capability was found to be 106.4 and 117.7mg/g for Methylene Blue (MB) and nickel ions (NI(II) respectively. Thermodynamic parameters suggested that the adsorption was an endothermic and spontaneous. These results indicate the applicability of pine cone as a cheap precursor for the sustainable production of cost-effective and environmental friendly bio-char adsorbent. PMID- 28711299 TI - Fracture Risk Assessment in Clinical Practice: Why Do It? What to Do It With? AB - Fracture is the outcome of concern in osteoporosis, and fracture reduction is the primary goal of osteoporosis treatment. Fracture risk assessment is a critical component in osteoporosis management. The earlier approach of deciding on whether to treat solely based on bone mineral density (BMD) T-scores has been supplanted by employing the concept of absolute risk over medium time periods and more encompassing integration of clinical risk factors with or without BMD into robust fracture risk assessment tools. Fracture risk estimation allows for identifying high-risk patient groups not only at a health system and population-based level and thereby allowing allocation of financial resources to the people most at risk, but also at an individual level for the clinician to involve the patient in shared decision-making processes for treatment. The process of fracture risk assessment involves several steps including performing a thorough history and physical examination, assessing BMD, doing radiological assessment for vertebral fractures, and laboratory evaluation to rule out secondary contributors to osteoporosis. The data thus obtained can be input into any one of several fracture risk assessment tools that are now available. The decision on which tool to use can be made on the background of country-specific guidelines, although it is imperative that the physician be aware of the limitations inherent to whichever tool is chosen. This article aims to provide a brief overview of why fracture risk estimation is important and the methods that can be employed for it by the physician in clinical practice. PMID- 28711301 TI - The taxation of unhealthy energy-dense foods (EDFs) and sugar-sweetened beverages (SSBs): An overview of patterns observed in the policy content and policy context of 13 case studies. AB - Taxation of energy-dense foods (EDFs) and sugar-sweetened beverages (SSBs) is increasingly of interest as a novel public health and fiscal policy instrument. However academic interest in policy determinants has remained limited. We address this paucity by comparing the policy content and policy context of EDF/SSB taxes witnessed in 13 case studies, of which we assume the tax is sufficiently high to induce behavioural change. The observational and non-randomized studies published on our case studies seem to indicate that the EDF/SSB taxes under investigation generally had the desired effects on prices and consumption of targeted products. The revenue collection of EDF/SSB taxes is minimal yet significant. Administrative practicalities in tax levying are important, possibly explaining why a drift towards solely taxing SSBs can be noted, as these can be demarcated more easily, with levies seemingly increasing in more recent case studies. Despite the growing body of evidence suggesting that EDF/SSB taxes have the potential to improve health, fiscal needs more often seem to lay their policy foundation rather than public health advocacy. A remarkable amount of conservative/liberal governments have adopted these taxes, although in many cases revenues are earmarked for benefits compensating regressive income effects. Governments voice diverse policy rationales, ranging from explicitly describing the tax as a public health instrument, to solely explicating revenue raising. PMID- 28711300 TI - Raft-dependent endocytic movement and intracellular cluster formation during T cell activation triggered by concanavalin A. AB - Certain food ingredients can stimulate the human immune system. A lectin, concanavalin A (ConA), from Canavalia ensiformis (jack bean) is one of the most well-known food-derived immunostimulants and mediates activation of cell-mediated immunity through T cell proliferation. Generally, T cell activation is known to be triggered by the interaction between T cells and antigen-presenting cells (APCs) via a juxtacrine (contact-dependent) signaling pathway. The mechanism has been well characterized and is referred to as formation of the immunological synapse (IS). We were interested in the mechanism behind the T cell activation by food-derived ConA which might be different from that of T cell activation by APCs. The purpose of this study was to characterize T cell activation by ConA with regard to (i) movement of raft domain, (ii) endocytic vesicular transport, (iii) the cytoskeleton (actin and microtubules), and (iv) cholesterol composition. We found that raft-dependent endocytic movement was important for T cell activation by ConA and this movement was dependent on actin, microtubules, and cholesterol. The T cell signaling mechanism triggered by ConA can be defined as endocrine signaling which is distinct from the activation process triggered by interaction between T cells and APCs by juxtacrine signaling. Therefore, we hypothesized that T cell activation by ConA includes both two-dimensional superficial raft movement on the membrane surface along actin filaments and three dimensional endocytic movement toward the inside of the cell along microtubules. These findings are important for developing new methods for immune stimulation and cancer therapy based on the function of ConA. PMID- 28711302 TI - Potential selection of genetically balanced spermatozoa based on the hypo-osmotic swelling test in chromosomal rearrangement carriers. AB - Chromosomal translocations and other balanced rearrangements, although usually associated with a normal phenotype, can lead to the transmission of an abnormal unbalanced genome to the offspring. Balanced and unbalanced spermatozoa, being indistinguishable, cannot be selected or deselected for prior to IVF and pre implantation genetic diagnosis. Spermatozoa from 16 chromosomal rearrangement carriers were studied. After incubation in a hypo-osmotic solution (hypo-osmotic swelling test, or HOST), spermatozoa were fixed on microscope slides. The chromosomally balanced or unbalanced status corresponding to each observed class of flagellar conformation was evaluated through fluorescent in-situ hybridization (FISH). We show here a specific type of spermatozoa, with a distinct flagellar conformation that was associated with a balanced genetic content. HOST is a simple, low-cost and time-honoured procedure initially developed to distinguish immotile viable from non-viable spermatozoa. We demonstrate that it can also be used to identify genetically balanced spermatozoa in chromosomal rearrangement carriers, with a 96% decrease in the proportion of unbalanced spermatozoa after selection. This may potentially improve reproductive prognosis in affected couples if used prior to pre-implantation genetic diagnosis (PGD), and clinical utility and efficacy should be evaluated in further studies. PMID- 28711303 TI - Measurement techniques of exposure to nanomaterials in the workplace for low- and medium-income countries: A systematic review. AB - Nanotechnology offers many opportunities but there is still considerable uncertainty about the health risks and how to assess these.In the field of risk analysis for workers potentially exposed to nano-objects and their agglomerates and aggregates (NOAA) different methodological approaches to measure airborne NOAA have been proposed.This study proposes a systematic review of scientific literature on occupational exposure to NOAA in the workplace with the aim to identify techniques of exposure measurement to be recommended in low- and medium income countries.We gathered scientific papers reporting techniques of NOAA exposure measurements in the workplace, we summarized the data for each eligible technique according to PRISMA guidelines, and we rated the quality of evidence following an adapted GRADE approach.We found 69 eligible studies to be included in qualitative synthesis: the majority of studies reported a moderate quality and only two studies demonstrated the use of a high quality exposure measurement technique.The review demonstrates that a basic exposure measurement, i.e. evidence for the presence or absence of NOAA in the workplace air, can be achieved with moderate (40 techniques) to high (2 techniques) quality; comprehensive exposure measurement, that allow the quantification of NOAA in the workplace, can be achieved with moderate (11 techniques) to high (2 techniques) quality.The findings of the study also allowed to finalize a list of requirements that must be fulfilled by an effective measurement technique (either basic or comprehensive) and to highlight the main weaknesses that need to be tackled for an effective affordability evaluation of measurement techniques to be recommended in low- and medium-income countries. PMID- 28711304 TI - Comparing REACH Chemical Safety Assessment information with practice-a case-study of polymethylmethacrylate (PMMA) in floor coating in The Netherlands. AB - On June 1st, 2007 the European regulation on Registration, Evaluation and Restriction of Chemical substances (REACH) came into force. Aim of the regulation is safe use of chemicals for humans and for the environment. The core element of REACH is chemical safety assessment of chemicals and communication of health and safety hazards and risk management measures throughout the supply chain. Extended Safety Data Sheets (Ext-SDS) are the primary carriers of health and safety information. The aim of our project was to find out whether the actual exposure to methyl methacrylate (MMA) during the application of polymethylmethacrylate (PMMA) in floor coatings as assessed in the chemical safety assessment, reflect the exposure situations as observed in the Dutch building practice. Use of PMMA flooring and typical exposure situations during application were discussed with twelve representatives of floor laying companies. Representative situations for exposure measurements were designated on the basis of this inventory. Exposure to MMA was measured in the breathing zone of the workers at four construction sites, 14 full shift samples and 14 task based samples were taken by personal air sampling. The task-based samples were compared with estimates from the Targeted Risk Assessment Tool (v3.1) of the European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC-TRA) as supplied in the safety assessment from the manufacturer. For task-based measurements, in 12 out of 14 (86%) air samples measured exposure was higher than estimated exposure. Recalculation with a lower ventilation rate (50% instead of 80%) together with a higher temperature during mixing (40 degrees C instead of 20 degrees C) in comparison with the CSR, reduced the number of underestimated exposures to 10 (71%) samples. Estimation with the EMKG-EXPO-Tool resulted in unsafe exposure situations for all scenarios, which is in accordance with the measurement outcomes. In indoor situations, 5 out of 8 full shift exposures (62%) to MMA were higher than the Dutch occupational exposure limit of 205mg/m3 (8h TWA), which equals the DNEL. For semi-enclosed situations this was 1 out of 6 (17%). Exposures varied from 31 to 367mg/m3. The results emphasize that ECETOC-TRA exposure estimates in poorly controlled situations need better underpinning. PMID- 28711305 TI - Corrigendum to "MicroRNA-17/20a functions to inhibit cell migration and can be used a prognostic marker in oral squamous cell carcinoma" [Oral Oncol. 49(9) (2013) 923-931]. PMID- 28711306 TI - Can the Aviation Industry be Useful in Teaching Oncology about Safety? AB - Healthcare practitioners have long considered aviation as a domain from which much can be learned about safety. Over the past 30 years, attempts have been made to apply aviation safety-related concepts to healthcare. Although some applications have been successful, a few decades later, many healthcare safety experts have learned that the appeal of the aviation-healthcare analogy is an illusion. Both domains are so basically dissimilar that simple adoption of aviation concepts will not be successful. However, what has succeeded is healthcare's adaptation of specific aviation safety concepts. Three concepts, investment in safety, human factors and safety management systems, are described and examples are given of adapted applications to healthcare/clinical oncology. Finally, there is a need to ensure that these concepts are applied systematically throughout healthcare rather than sporadically and without a centralised mandate, to help ensure success and improved patient and provider safety. PMID- 28711307 TI - Medical Error: a Patient's Perspective. PMID- 28711308 TI - The impact of scopolamine pretreatment on 3-iodothyronamine (T1AM) effects on memory and pain in mice. AB - We previously demonstrated that 3-iodothyronamine (T1AM), a by-product of thyroid hormone metabolism, pharmacologically administered to mice acutely stimulated learning and memory acquisition and provided hyperalgesia with a mechanism which remains to be defined. We now aimed to investigate whether the T1AM effect on memory and pain was maintained in mice pre-treated with scopolamine, a non selective muscarinic antagonist expected to induce amnesia and, possibly, hyperalgesia. Mice were pre-treated with scopolamine and, after 20min, injected intracerebroventricularly (i.c.v.) with T1AM (0.13, 0.4, 1.32MUg/kg). 15min after T1AM injection, the mice learning capacity or their pain threshold were evaluated by the light/dark box and by the hot plate test (51.5 degrees C) respectively. Experiments in the light/dark box were repeated in mice receiving clorgyline (2.5mg/kg, i.p.), a monoamine oxidase (MAO) inhibitor administered 10min before scopolamine (0.3mg/kg). Our results demonstrated that 0.3mg/kg scopolamine induced amnesia without modifying the murine pain threshold. T1AM fully reversed scopolamine-induced amnesia and produced hyperalgesia at a dose as low as 0.13MUg/kg. The T1AM anti-amnestic effect was lost in mice pre-treated with clorgyline. We report that the removal of muscarinic signalling increases T1AM pro learning and hyperalgesic effectiveness suggesting T1AM as a potential treatment as a "pro-drug" for memory dysfunction in neurodegenerative diseases. PMID- 28711309 TI - Influence of needle bevel design on injection pain and needle deformation in dental local infiltration anaesthesia - randomized clinical trial. AB - The aims of this in vivo study were to evaluate the impact of needle bevel design on patients' pain perception and the mechanical deformation of the needle tip after the injection. In a prospective single-blinded trial, 150 patients received conventional infiltration anaesthesia for dental treatment by one examiner. Patients were randomized for one out of three different needle bevel types (scalpel-designed bevel needle (SB), n=50; triple bevel needle (TB), n=50; regular bevel needle (RB), n=50). Subjects' self-reported injection pain perception was evaluated using a numeric rating scale (NRS). For each needle tip, deformations after single use were measured using SEM. A significant lower injection pain level was found in SB (mean 2.1+/-1.2) than in TB (mean 3.5+/ 1.6;) and RB (mean 3.4+/-1.0; all P<0.001). A needle deformation was detected in about 97.3% of all needles (SB 50/50, TB 50/50, and RB: 46/50). A higher number of barbs were found in SB (29/50) versus TB (17/50) and RB (19/50). For dental local infiltration anaesthesia, injection needles with a scalpel-designed bevel demonstrated significantly less injection pain. Needle tip deflections after anaesthetic agent infiltration, especially barbed hooks on the non-cutting edge may result in greater soft tissue trauma. PMID- 28711310 TI - Acquired heterotopic ossification of the temporomandibular joint. AB - Although the risk factors and diagnosis of heterotopic ossification (HO) are discussed in the orthopedics literature, the etiology of HO, as well as its prevention and management, remain theoretical. Furthermore, there is a lack of information in the literature regarding HO in temporomandibular joint replacement (TMJR). This article provides a qualitative review of information relative to the etiology, diagnosis, and management of HO to inform and encourage further investigation in TMJR. The orthopedic HO literature considered for this qualitative review was drawn from a comprehensive examination of the subject published previously by one of the authors. Using the key words "heterotopic ossification" or "heterotopic bone", citations in the PubMed database from both the dental and oral and maxillofacial surgery literature were reviewed. Based on this, it appears that the etiology, diagnosis, imaging, laboratory testing, risk factors, prophylaxis, and non-surgical and surgical options available for the management of TMJR-related HO are similar to those for orthopedic HO, but further elucidation is required for TMJR. There is a lack of published information in the literature on TMJR. Therefore, using the literature from this review as a foundation, studies should be developed and reported so that alloplastic TMJ surgeons have evidence-based protocols that will lead to the early detection and potential prevention of HO. PMID- 28711311 TI - Bacterial colonization of penile prosthesis after its withdrawal due to mechanical failure. AB - INTRODUCTION: Prosthetic surgery to treat erectile dysfunction has a risk of infection of up to 3%, but this risk can increase to 18% when the surgery involves replacement. This increased risk of infection is attributed to the bacterial colonization of the prosthesis during the initial surgery. OBJECTIVE: To analyse the presence of germs in the prosthesis that is withdrawn due to mechanical failure (not infection), as well as the surgical results and its progression. MATERIALS AND METHOD: A retrospective study was conducted of all replacements performed between 2013 and 2016 at a single centre. We analysed demographic data, prior type of prosthesis, surgical procedure, microbiological study and follow-up. RESULTS: Of the 12 replacement procedures, a microbiological study of the extracted prosthesis was performed in a total of 10 cases. Of the 10 replacements, the cultures were positive in 5 cases (50%). Staphylococcus epidermidis was the most prevalent germ. All patients underwent a flushing procedure, and an antibiotic-coated prosthesis was implanted. We recorded no infections with the new implanted device after a mean follow-up of 27.33 months (SD 4.13; 95% CI 18.22-36.43). CONCLUSION: In our study population, we observed a high rate of bacterial colonization of the prostheses that were replaced due to mechanical failure. When a flushing procedure was performed during the replacement surgery, there were no more infections than those reported in treatment-naive cases. PMID- 28711312 TI - Radium-223 in the therapeutic sequence of metastatic castration-resistant prostate cancer. AB - CONTEXT: Radium-223 is an ? -particle transmitter with specific action on bone metastases. The Alpharadin in Symptomatic Prostate Cancer Patients (ALSYMPCA) study showed that radium-223 extended overall survival and delayed the onset of bone events in patients with symptomatic castration-resistant prostate cancer with bone metastases (mCRPC) and without visceral metastases, with a good safety profile. OBJECTIVE: To review the new scientific evidence on radium-223 based on prespecified and post-hoc analyses of the ALSYMPCA study and on early-access programs after the publication of the ALSYMPCA study, thereby providing new data on the management of patients with mCRPC. ACQUISITION OF EVIDENCE: We searched for evidence on PubMed and in the abstracts of international urology and oncology congresses, as well as ongoing clinical trials (ClinicalTrials.gov). SYNTHESIS OF THE EVIDENCE: The results of the reviewed studies offer promising results that will broaden the therapeutic benefits of radium-223 to patients with mild symptoms and those with no symptoms. The results also provide preliminary evidence on the benefit of radium-223 treatment after the failure of docetaxel, enzalutamide or abiraterone or the combination of radium-223 with these agents or other therapeutic agents such as bone-targeted agents and immunotherapy. CONCLUSION: Radium-223 can be a treatment option for patients with mild symptoms and can provide a therapeutic benefit after failure of currently available treatments or in combination with these treatments. This evidence should be corroborated in clinical trials before being added to clinical practice. PMID- 28711313 TI - Remote Ischemic Preconditioning in Cardiac Surgery: Is There a Proven Clinical Benefit? PMID- 28711314 TI - Independent Predictors of the Duration and Overall Burden of Postoperative Delirium After Cardiac Surgery in Adults: An Observational Cohort Study. AB - OBJECTIVE: Postoperative delirium (POD) is a common complication after cardiac surgery and is associated with increased patient morbidity and mortality. The objective of this study was to identify risk factors for long duration and overall burden of POD after cardiac surgery. DESIGN: One-year, single-center, retrospective, observational cohort study. SETTING: University hospital. PARTICIPANTS: Adult patients undergoing cardiac surgery with cardiopulmonary bypass in 2013. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients were screened for POD using the Intensive Care Delirium Screening Checklist. The primary outcome measure was the incidence of POD. Secondary outcome measures were the duration of POD and the area under the curve determined using the Intensive Care Delirium Screening Checklist score over time. Independent predictors of POD were estimated in multivariable logistic regression models. Hospital length of stay, medications, and outcome data also were analyzed. Among the 656 patients included in the cohort, 618 were analyzed. The overall incidence of POD was 39%. Older patient age (odds ratio [95% confidence interval]) 1.06 [1.04-1.09] for an increase of 1 year, p < 0.001); low preoperative serum albumin (1.08 [1.03-1.13] for a decrease of 1 g/L, p < 0.001); a history of atrial fibrillation (2.30 [1.30 4.09], p = 0.004); perioperative stroke (6.27 [1.54-43.64], p = 0.008); ascending aortic replacement surgery (2.99 [1.50-6.05], p = 0.002); longer duration of procedure (1.37 [1.16-1.63] for an increase of 1 hour, p < 0.001); and increased postoperative C-reactive protein concentration (2.16 [1.49-3.16] for a 2-fold increase, p < 0.001) were associated with higher odds of POD. Among patients affected by POD, older age, perioperative stroke, longer procedure time, and increased postoperative C-reactive protein were consistently predictive of longer duration of POD and greater area under the curve. CONCLUSIONS: Known risk factors for the development of POD after cardiac surgery also are predictive of prolonged duration and high overall burden of POD. PMID- 28711315 TI - Characterization of mobile genetic elements carrying VIM-1 and KPC-2 carbapenemases in Citrobacter freundii isolates in Madrid. AB - Carbapenemase producing Citrobacter freundii (CPCF) infections are still uncommon in European countries. Here we report a molecular study conducted in a tertiary care facility in southern Madrid, Spain, from 2009 to 2014 to investigate the epidemiology of CPCF. The blaIMP-1,blaIMP-2,blaKPC,blaNDM,blaOXA-48,blaVIM-1 and blaVIM-2 genes were screened by PCR. Molecular typing was carried out by Pulsed field gel electrophoresis analysis (PFGE) and multilocus sequence typing (MLST). Whole genome sequencing (WGS) was performed to characterize the resistome and the mobile genetic elements associated with the carbapenems resistance of CPCF. A total of 11/521 (2.1%) isolates had reduced susceptibility to carbapenems. PCR amplification revealed the presence of blaVIM-1 in 10 isolates and blaKPC-2 in 2 isolates. One C. freundii isolate co-harbored blaVIM-1 and blaKPC-2 genes. PFGE and MLST assigned 10 different clonal, 4 previously reported (ST11, ST18, ST22 and ST64) and 6 new STs (ST89, ST90, ST91, ST92, ST92 and ST94). The blaVIM-1 gene was part of In624 (intI1-blaVIM-1-aacA4-dfrB1-aadA1-catB2-qacEDelta1/sul1). In 3 of these isolates, plasmid-mediated quinolone resistance genes (qnrA1 and qnrB4) were present in its downstream region, taking part of a complex class 1 integron ([In624:ISCR1:qnrB4-blaDHA-1] and [In624:ISCR1:qnrA1]). On the other hand, the blaKPC-2 gene was associated with a Tn3-based transposon. The dissemination of the blaVIM-1 gene among various clones suggests a successful horizontal transfer of integron carrying elements that play a dominant role in the development of multidrug resistance in Enterobacteriaceae. PMID- 28711316 TI - Effect of Gestational Weight Gain and Prepregnancy Body Mass Index in Adolescent Mothers on Weight and Body Mass Index of Adolescent Offspring. AB - PURPOSE: The purpose of the study was to examine the association of the gestational weight gain and prepregnancy body mass index (BMI) of low-income adolescent mothers with the risk of their children being overweight and/or obese in late adolescence. METHODS: Study subjects were low-income, primiparous adolescents (n = 360) who self-identified as black and participated in the New Mothers Study in Memphis, Tennessee, and their children. Gestational weight gain was examined as a continuous variable and also categorized into overgain, recommended gain, and undergain following the 2009 Institute of Medicine guidelines. The effects of maternal prepregnancy BMI percentiles and calculated BMI were also considered. Multivariable logistic and linear regression models were used. The main outcome measures were offspring overweight, obesity, and BMI. RESULTS: Thirty-nine percent of offspring were overweight or obese. Higher maternal gestational weight gain increased the risk for offspring overweight and obesity. There was an interaction between gestational weight gain and prepregnancy BMI: offspring of mothers with a BMI percentile <=76 were at greater risk of obesity with higher maternal weight gain. If mothers with a BMI percentile between the 29th and 83rd percentiles overgained, offspring were at greater risk for overweight. Using calculated BMIs, if a mother's BMI was <=26 kg/m2, offspring risk for obesity was greater with higher gestational weight gain. CONCLUSIONS: High gestational weight gain had a larger effect on offspring overweight and obesity if maternal prepregnancy BMI percentile was <=76. The gestational weight gain of primiparous adolescents who self-identified as black had an effect on offspring weight. PMID- 28711317 TI - Invasion fitness for gene-culture co-evolution in family-structured populations and an application to cumulative culture under vertical transmission. AB - Human evolution depends on the co-evolution between genetically determined behaviors and socially transmitted information. Although vertical transmission of cultural information from parent to offspring is common in hominins, its effects on cumulative cultural evolution are not fully understood. Here, we investigate gene-culture co-evolution in a family-structured population by studying the invasion fitness of a mutant allele that influences a deterministic level of cultural information (e.g., amount of knowledge or skill) to which diploid carriers of the mutant are exposed in subsequent generations. We show that the selection gradient on such a mutant, and the concomitant level of cultural information it generates, can be evaluated analytically under the assumption that the cultural dynamic has a single attractor point, thereby making gene-culture co evolution in family-structured populations with multigenerational effects mathematically tractable. We apply our result to study how genetically determined phenotypes of individual and social learning co-evolve with the level of adaptive information they generate under vertical transmission. We find that vertical transmission increases adaptive information due to kin selection effects, but when information is transmitted as efficiently between family members as between unrelated individuals, this increase is moderate in diploids. By contrast, we show that the way resource allocation into learning trades off with allocation into reproduction (the "learning-reproduction trade-off") significantly influences levels of adaptive information. We also show that vertical transmission prevents evolutionary branching and may therefore play a qualitative role in gene-culture co-evolutionary dynamics. More generally, our analysis of selection suggests that vertical transmission can significantly increase levels of adaptive information under the biologically plausible condition that information transmission between relatives is more efficient than between unrelated individuals. PMID- 28711319 TI - Procalcitonin-guided antibiotic stewardship from newborns to centennials. PMID- 28711318 TI - Procalcitonin-guided decision making for duration of antibiotic therapy in neonates with suspected early-onset sepsis: a multicentre, randomised controlled trial (NeoPIns). AB - BACKGROUND: Up to 7% of term and late-preterm neonates in high-income countries receive antibiotics during the first 3 days of life because of suspected early onset sepsis. The prevalence of culture-proven early-onset sepsis is 0.1% or less in high-income countries, suggesting substantial overtreatment. We assess whether procalcitonin-guided decision making for suspected early-onset sepsis can safely reduce the duration of antibiotic treatment. METHODS: We did this randomised controlled intervention trial in Dutch (n=11), Swiss (n=4), Canadian (n=2), and Czech (n=1) hospitals. Neonates of gestational age 34 weeks or older, with suspected early-onset sepsis requiring antibiotic treatment were stratified into four risk categories by their treating physicians and randomly assigned [1:1] using a computer-generated list stratified per centre to procalcitonin-guided decision making or standard care-based antibiotic treatment. Neonates who underwent surgery within the first week of life or had major congenital malformations that would have required hospital admission were excluded. Only principal investigators were masked for group assignment. Co-primary outcomes were non-inferiority for re-infection or death in the first month of life (margin 2.0%) and superiority for duration of antibiotic therapy. Intention-to-treat and per-protocol analyses were done. This trial was registered with ClinicalTrials.gov, number NCT00854932. FINDINGS: Between May 21, 2009, and Feb 14, 2015, we screened 2440 neonates with suspected early-onset sepsis. 622 infants were excluded due to lack of parental consent, 93 were ineligible for reasons unknown (68), congenital malformation (22), or surgery in the first week of life (3). 14 neonates were excluded as 100% data monitoring or retrieval was not feasible, and one neonate was excluded because their procalcitonin measurements could not be taken. 1710 neonates were enrolled and randomly assigned to either procalcitonin-guided therapy (n=866) or standard therapy (n=844). 1408 neonates underwent per-protocol analysis (745 in the procalcitonin group and 663 standard group). For the procalcitonin group, the duration of antibiotic therapy was reduced (intention to treat: 55.1 vs 65.0 h, p<0.0001; per protocol: 51.8 vs 64.0 h; p<0.0001). No sepsis-related deaths occurred, and 9 (<1%) of 1710 neonates had possible re-infection. The risk difference for non inferiority was 0.1% (95% CI -4.6 to 4.8) in the intention-to-treat analysis (5 [0.6%] of 866 neonates in the procalcitonin group vs 4 [0.5%] of 844 neonates in the standard group) and 0.1% (-5.2 to 5.3) in the per-protocol analysis (5 [0.7%] of 745 neonates in the procalcitonin group vs 4 [0.6%] of 663 neonates in the standard group). INTERPRETATION: Procalcitonin-guided decision making was superior to standard care in reducing antibiotic therapy in neonates with suspected early-onset sepsis. Non-inferiority for re-infection or death could not be shown due to the low occurrence of re-infections and absence of study-related death. FUNDING: The Thrasher Foundation, the NutsOhra Foundation, the Sophia Foundation for Scientific research. PMID- 28711320 TI - Liver stiffness measurement by transient elastography predicts late posthepatectomy outcomes in patients undergoing resection for hepatocellular carcinoma. AB - BACKGROUND: Postoperative hepatic decompensation is a serious complication of liver resection in patients undergoing hepatectomy for hepatocellular carcinoma. Liver fibrosis and clinical significant portal hypertension are well-known risk factors for hepatic decompensation. Liver stiffness measurement is a noninvasive method of evaluating hepatic venous pressure gradient and functional hepatic reserve by estimating hepatic fibrosis. Effectiveness of liver stiffness measurement in predicting persistent postoperative hepatic decompensation has not been investigated. METHODS: Consecutive patients with resectable hepatocellular carcinoma were recruited prospectively and liver stiffness measurement of nontumoral liver was measured using FibroScan. Hepatic venous pressure gradient was measured intraoperatively by direct puncture of portal vein and inferior vena cava. Hepatic venous pressure gradient >=10 mm Hg was defined as clinically significant portal hypertension. Primary outcome was persistent hepatic decompensation defined as the presence of at least one of the following: unresolved ascites, jaundice, and/or encephalopathy >3 months after hepatectomy. RESULTS: One hundred and six hepatectomies, including 22 right hepatectomy (20.8%), 3 central hepatectomy (2.8%), 12 left hepatectomy (11.3%), 11 bisegmentectomy (10.4%), 30 unisegmentectomy (28.3%), and 28 partial hepatectomy (26.4%) were performed in patients for hepatocellular carcinoma (84 men and 22 women with median age of 67.5 years; median model for end-stage liver disease score of 8). Ninety-day mortality was 4.7%. Nine patients (8.5%) developed postoperative hepatic decompensation. Multivariate logistic regression bootstrapped at 1,000 identified liver stiffness measurement (P = .001) as the only preoperative predictor of postoperative hepatic decompensation. Area under receiver operating characteristic curve for liver stiffness measurement and hepatic venous pressure gradient was 0.81 (95% confidence interval, 0.506-0.907) and 0.71 (95% confidence interval, 0.646-0.917), respectively. Liver stiffness measurement >=22 kPa had 42.9% sensitivity and 92.6% specificity and hepatic venous pressure gradient >=10 mm Hg had 28.6% sensitivity and 96.3% specificity. CONCLUSION: In selected patients undergoing liver resection for hepatocellular carcinoma, transient elastography is an easy and effective test to predict persistent hepatic decompensation preoperatively. PMID- 28711321 TI - Importance of positron emission tomography for assessing the response of primary and metastatic lesions to induction treatments in T4 esophageal cancer. AB - BACKGROUND: There is no consensus strategy for treatment of T4 esophageal cancer, and because of this, a better evaluation of treatment response is crucial to establish personalized therapies. This study aimed to establish a useful system for evaluating treatment response in T4 esophageal cancer. METHODS: This study included 130 patients with cT4 esophageal cancer without distant metastasis who underwent 18F-fluorodeoxyglucose-positron emission tomography before and after a series of induction treatments comprising chemoradiation or chemotherapy. We evaluated the maximal standardized uptake value and treatment response. RESULTS: The mean +/- standard deviation of standardized uptake value in the primary tumor before and after induction treatments were 13.8 +/- 4.4 and 5.4 +/- 4.1, respectively, and the mean standardized uptake value decrease was 58.4%. The most significant difference in survival between positron emission tomography-primary tumor responders and nonresponders was at a decrease of 60% standardized uptake value, based on every 10% stepwise cutoff analysis (2-year cause-specific survival: 60.2 vs 23.5%; hazard ratio = 2.705; P < .0001). With this cutoff value, the resectability (P = .0307), pathologic response (P = .0004), and pT stage (P < .0001) were associated with positron emission tomography-primary tumor response. Univariate analysis of 2-year cause-specific survival indicated a correlation between cause-specific survival and clinical stages according to TNM classification, esophageal perforation, positron emission tomography-primary tumor response, lymph node status evaluated by positron emission tomography before and after induction treatments, and operative resection. Multivariate analysis further identified positron emission tomography-primary tumor response (hazard ratio = 2.354; P = .0107), lymph node status evaluated by positron emission tomography after induction treatments (hazard ratio = 1.966; P = .0089), and operative resection (hazard ratio = 2.012; P = .0245) as independent prognostic predictors. CONCLUSION: Positron emission tomography evaluation of the response of primary and metastatic lesions to induction treatments is important to formulate treatment strategies for cT4 esophageal cancer. PMID- 28711322 TI - Intuitive Physics: Current Research and Controversies. AB - Early research in the field of intuitive physics provided extensive evidence that humans succumb to common misconceptions and biases when predicting, judging, and explaining activity in the physical world. Recent work has demonstrated that, across a diverse range of situations, some biases can be explained by the application of normative physical principles to noisy perceptual inputs. However, it remains unclear how knowledge of physical principles is learned, represented, and applied to novel situations. In this review we discuss theoretical advances from heuristic models to knowledge-based, probabilistic simulation models, as well as recent deep-learning models. We also consider how recent work may be reconciled with earlier findings that favored heuristic models. PMID- 28711323 TI - Transapical and transaortic transcatheter aortic valve replacement: Still part of the game and at what cost? PMID- 28711324 TI - Prognostic impact of programmed death-ligand 1 expression in correlation with human leukocyte antigen class I expression status in stage I adenocarcinoma of the lung. AB - OBJECTIVE: The study objective was to investigate the prognostic impact of programmed death-ligand 1 expression in correlation with human leukocyte antigen class I expression on tumor cells in early-stage adenocarcinoma of the lung, because both programmed death-ligand 1 and human leukocyte antigen class I molecules play important roles in cancer immunity. METHODS: Ninety-four patients with completely resected pathologic stage I lung adenocarcinoma were retrospectively reviewed. Programmed death-ligand 1 expression on tumor cells was evaluated with immunohistochemistry in correlation with several clinicopathologic and molecular features, including human leukocyte antigen class I expression on tumor cells. RESULTS: Fifteen patients (16.0%) had tumor with positive programmed death-ligand 1 expression (percentage of tumor cells expressing programmed death ligand 1, >=5%), and the incidence was significantly higher in poorly differentiated tumors. There was no significant correlation between human leukocyte antigen class I expression and programmed death-ligand 1 expression. Programmed death-ligand 1 positivity was a significant factor to predict a poor survival (5-year survival, 66.7% vs 85.9%; P = .049), which was enhanced in tumors with normal human leukocyte antigen class I expression (P = .029) but was not evident in tumors with reduced human leukocyte antigen class I expression (P = .552). CONCLUSIONS: The prognostic impact of programmed death-ligand 1 expression on tumor cells in early-stage lung adenocarcinoma may be distinct according to concurrent human leukocyte antigen class I expression. PMID- 28711325 TI - Improving coronary artery bypass grafting readmission outcomes from 2000 to 2012 in the Medicare population. AB - OBJECTIVE: The study objective was to examine trends in 30-day readmission after coronary artery bypass grafting in the Medicare population over 13 years. METHODS: The study included isolated coronary artery bypass grafting procedures in the Medicare population from January 2000 to November 2012. Comorbidities and causes of readmission were determined using Internal Classification of Diseases, 9th Revision, Clinical Modification diagnostic codes. RESULTS: The cohort included 1,116,991 patients. Readmission rates decreased from 19.5% in 2000 to 16.6% in 2012 (P = .0001). There was significant improvement across all categories of admission status, age, race, gender, and hospital annual coronary artery bypass grafting volume that were analyzed. Adjusted odds of readmission in 2000 compared with 2012 was 1.28 (95% confidence interval, 1.24-1.32). Median length of stay for the readmission episode was 5 days, which improved to 4 days by 2012. Hospital mortality during the readmission episode was 2.8% overall and declined to 2.4% in 2012 (P = .0001). The most common primary readmission diagnoses were heart failure (12.6%), postoperative wound infection/nonhealing wound (8.9%), arrhythmias (6.4%), and pleural effusions (3.7%). Readmission for wound infections/nonhealing wounds decreased significantly over time, from 9.8% to 6.5% (P = .0001). CONCLUSIONS: In a large cohort of Medicare patients undergoing coronary artery bypass grafting over 13 years, there was a significant decrease in 30-day readmission rates, a reduction in readmission for wound infections, and reduced mortality during the readmission episode, despite an increase in patient comorbidities. The improvement in readmission rates was seen regardless of patient variables examined. PMID- 28711326 TI - What a great aortic surgeon would Messer Leonardo have been .... PMID- 28711327 TI - Discussion. PMID- 28711328 TI - Overexpression of microRNA-30a contributes to the development of aortic dissection by targeting lysyl oxidase. AB - OBJECTIVE: To explore the role of microRNA (miR)-30a in the development of aortic dissection. METHODS: Human aortic specimens of aortic dissections and aneurysms were harvested. Aortic specimens from donors for heart transplantation served as controls. Rat aortic vascular smooth muscle cells (VSMCs) were transfected with agomiR-30a or antagomiR-30a, and control cells were incubated with empty vectors. Rats were pretreated with agomiR-30a or antagomiR-30a (5 * 107 transfection units every 3 days for 4 weeks), and empty vectors were infused to controls. Acute aortic dissection was induced by subcutaneous infusion of angiotensin II (1 MUg . kg-1 . min-1 for 24 hours). Protein expressions of lysyl oxidase (LOX) and elastin and gene expression of miR-30a were measured in VSMCs and human and rat aortic specimens by Western blot analysis and quantitative real-time polymerase chain reaction. RESULTS: Gene expression of miR-30a was much higher, and protein abundance of LOX and elastin was significantly lower, in the aortic dissection specimens (P < .05 vs controls). Transfection of agomiR-30a markedly decreased the luciferase activity of LOX in VSMCs of wild type, but not of LOX 3'-UTR mutant (P = .002). In cultured VSMCs, transfection of agomiR-30a dramatically enhanced the gene expression of miR-30a and down-regulated the protein abundance of LOX and elastin (P < .05 vs controls). Pretreatment with agomiR-30a in vivo enhanced miR-30a expression and down-regulated the protein abundance of LOX and elastin in rat aortas (P < .05 vs controls). The rate of dissection was significantly higher in rats pretreated with agomiR-30a (P = .003 vs controls). CONCLUSIONS: Overexpression of miR-30a contributes to the development of aortic dissection, possibly by targeting LOX. PMID- 28711330 TI - Toward a better repair for ischemic mitral regurgitation: Thinking outside the ring. PMID- 28711329 TI - Cardiac reprogramming factor Gata4 reduces postinfarct cardiac fibrosis through direct repression of the profibrotic mediator snail. AB - OBJECTIVE: The administration of a variety of reprogramming factor cocktails has now been shown to reprogram cardiac fibroblasts into induced cardiomyocyte-like cells. However, reductions in ventricular fibrosis observed after reprogramming factor administration seem to far exceed the extent of induced cardiomyocyte-like cell generation in vivo. We investigated whether reprogramming factor administration might primarily play a role in activating antifibrotic molecular pathways. METHODS: Adult rat cardiac fibroblasts were infected with lentivirus encoding the transcription factors Gata4, Mef2c, or Tbx5, all 3 vectors, or a green fluorescent protein control vector. Gene and protein expression assays were performed to identify relevant antifibrotic targets of these factors. The antifibrotic effects of these factors were then investigated in a rat coronary ligation model. RESULTS: Gata4, Mef2c, or Tbx5 administration to rat cardiac fibroblasts in vitro significantly downregulated expression of Snail and the profibrotic factors connective tissue growth factor, collagen1a1, and fibronectin. Of these factors, Gata4 was shown to be the one responsible for the downregulation of the profibrotic factors and Snail (mRNA expression fold change relative to green fluorescent protein for Snail, Gata4: 0.5 +/- 0.3, Mef2c: 1.3 +/- 1.0, Tbx5: 0.9 +/- 0.5, Gata4, Mef2c, or Tbx5: 0.6 +/- 0.2, P < .05). Chromatin immunoprecipitation quantitative polymerase chain reaction identified Gata4 binding sites in the Snail promoter. In a rat coronary ligation model, only Gata4 administration alone improved postinfarct ventricular function and reduced the extent of postinfarct fibrosis. CONCLUSIONS: Gata4 administration reduces postinfarct ventricular fibrosis and improves ventricular function in a rat coronary ligation model, potentially as a result of Gata4-mediated downregulation of the profibrotic mediator Snail. PMID- 28711331 TI - Multilevel data analysis: What? Why? How? PMID- 28711332 TI - Predictors of operating room extubation in adult cardiac surgery. AB - OBJECTIVE: The primary objective of the study was to identify perioperative factors associated with successful immediate extubation in the operating room after adult cardiac surgery. The secondary objective was to derive a simplified predictive scoring system to guide clinicians in operating room extubation. METHODS: All 1518 patients in this retrospective cohort study underwent standardized fast-track cardiac anesthetic protocol during adult cardiac surgery. Perioperative variables between patients who had successful extubation in the operating room versus in the intensive care unit were retrospectively analyzed using both univariate and multivariable logistic regression analyses. A predictive score of successful operating room extubation was constructed from the multivariable results of 800 patients (derivation set), and the scoring system was further tested using a validation set of 398 patients. RESULTS: Younger age, lower body mass index, higher preoperative serum albumin, absence of chronic lung disease and diabetes, less-invasive surgical approach, isolated coronary bypass surgery, elective surgery, and lower doses of intraoperative intravenous fentanyl were independently associated with higher probability of operating room extubation. The extubation prediction score created in a derivation set of patients performed well in the validation set. Patient scores less than 0 had a minimal probability of successful operating room extubation. Operating room extubation was highly predicted with scores of 5 or greater. CONCLUSIONS: Perioperative factors that are independently associated with successful operating room extubation after adult cardiac operations were identified, and an operating room extubation prediction scoring system was validated. This scoring system may be used to guide safe operating room extubation after cardiac operations. PMID- 28711333 TI - B12 deficiency leading to marked poikilocytosis versus true schistocytosis, a pernicious problem. AB - Severe vitamin B12 deficiency is caused most commonly by autoimmune atrophic gastritis leading to loss of intrinsic factor. Vitamin B12 deficiency leading to megaloblastic anemia and demyelinating central nervous system disease is well known; however, a rare presentation of B12 deficiency described as pseudothrombotic microangiopathy is not well known. This complication presents with signs of mechanical hemolysis, elevated lactate dehydrogenase (LDH), thrombocytopenia, and a low reticulocyte count, which can be incorrectly diagnosed as thrombotic thrombocytopenic purpura and managed incorrectly. Decreased reticulocyte count and an LDH >2500IU/L is more commonly seen in B12 deficiency. However, recognizing the differences in marked poikilocytosis can be challenging, as seen with megaloblastic changes and true schistocytosis. To illustrate the challenge in differentiating between megaloblastic changes and true schistocytosis, we present the case of a 27-year-old woman who presented to her physician for symptomatic anemia and complaints of nausea, vomiting, and loose stool. She had a hemoglobin of 5.1g/dL, platelet count of 39*109/L, LDH of 9915IU/L, haptoglobin below assay limit, and a reticulocyte count of 2.5%. Peripheral smear showed macrocytic anemia, rare hypersegmented neutrophils, and schistocytes. Vitamin B12 level was less than 50pg/mL, methylmalonic acid was 0.33MUmol/L, anti-parietal cell antibody was >1:640, and intrinsic factor blocking antibody was positive-confirming the diagnosis of pernicious anemia. While hospitalized, she was treated with vitamin B12 1000MUg intramuscular injections daily and thereafter continued with monthly injections, which ultimately resolved her severe macrocytic anemia. PMID- 28711334 TI - Fully automated, comprehensive knowledge-based planning for stereotactic radiosurgery: Preclinical validation through blinded physician review. AB - PURPOSE: As knowledge-based planning (KBP) attempts to augment and potentially supplant manual treatment planning, it is imperative to ensure any implementation maintains or improves overall plan quality in any disease site. The purpose of this study was to demonstrate the overall quality of KBP-driven automated stereotactic radiosurgery (SRS) treatment planning using blinded physician comparison and determine systematic factors predictive of physician plan preference to guide future KBP refinement. METHODS AND MATERIALS: Automated noncoplanar volume modulated arc therapy KBP routines were developed for 199 plans across 3 clinical SRS scenarios: isolated lesions (isolated), lesions closely abutting (<3 cm) organs at risk (involved), and single-isocenter multiple metastases (multimet). Overall plan quality and preference were assessed via blinded review of the plans by two SRS physicians. Quantitative quality metrics were also compared to determine systematic differences in the treatment plans. Multiple parameters were investigated as predictors of KBP plan selection. RESULTS: For the isolated, involved, and multimet scenarios, the KBP plans were considered to be superior or equivalent to clinical plans 86.7% (91/105), 81.1% (43/53), and 78.1% (32/41) of the time, respectively. All investigated quality metrics were equivalent or indicated more sparing for all KBP plans. The only nondosimetric predictor was planning target volume in the isolated (P = .02) and involved (P = .05) groups. The dosimetric predictors for the isolated group were gradient measure and heterogeneity index (both P < .01). In the multimet category, the only significant dosimetric predictor was interlesion dose (P = .01). CONCLUSIONS: The fully automated KBP SRS plans were equivalent or superior to previously treated plans in 83.4% (166/199) of cases. In clinical implementation, geometric features found to be predictive of KBP performance can be used to identify plans where KBP results might benefit from further refinement, whereas dosimetric predictive features could be used to further refine KBP optimization priorities. PMID- 28711336 TI - Short-term air pollution exposure and cardiovascular events: A 10-year study in the urban area of Como, Italy. AB - BACKGROUND: In the last years several studies have investigated the effects of some air pollutants on cardiovascular diseases (CVD), but the results are not conclusive. Aim of this study was to investigate the association between short term exposure to ambient air pollution and CVD events in a long-term observational period. METHODS: All CVD events (myocardial infarction - MI and ischemic stroke - IS) which occurred in residents of Como between January 2005 and December 2014 were included. Demographics and main vascular risk factors were registered for each patient. Principal meteorological variables and four ambient particles (O3, SO2, NO2, PM10) were recorded. Statistical analysis was performed using linear regression (GLM) and a generalized additive model (GAM) estimating Poisson distribution and adjusted for the main risk factors and ambient meteorological variables. RESULTS: A total of 4110 events were registered with a mild prevalence of MI (51.6%). In GLM analysis we observed a continuative association between CVD events and SO2 (p<0.05), while PM10 was associated with CVD occurrences at two-day lag time (p<0.05). Using GAM we observed a positive association between CVD and PM10 at the same day and at three- and four-day lag time with HRs ranging between 1.025 and 1.039 (p<0.001). These results were observed for both MI and IS, with an earlier effect for MI than for IS. CONCLUSIONS: These data confirm a possible association between some ambient air pollutants and CVD events, precisely MI and IS, with different temporal and cumulative effect. PMID- 28711335 TI - Echocardiographic reference ranges in older children and adolescents in sub Saharan Africa. AB - BACKGROUND: Echocardiographic reference ranges are important to identify abnormalities of cardiac dimensions. Reference ranges for children in sub-Saharan Africa have not been established. The aim of this study was to establish echocardiographic z-score references for Black children in sub-Saharan Africa. METHODS: 282 healthy subjects aged 6-16years (143 [51%] males) with no known history of cardiac disease were enrolled in the study in Harare, Zimbabwe between 2014 and 2016. Standard M-mode echocardiography was performed and nine cardiac chamber dimensions were obtained. Two non-linear statistical models (gamma weighted model and cubic polynomial model) were tested on the data and the best fitting model was used to calculate z-scores of these cardiac chamber measures. The reference ranges are presented on scatter plots against BSA. RESULTS: Normative data for the following cardiac measures were obtained and z-scores calculated: right ventricular diameter at end diastole (RVEDD); left ventricular diameter at end diastole (LVEDD) and systole (LVESD); interventricular septal wall thickness at end diastole (IVSd) and systole (IVSs); left ventricular posterior wall thickness at end diastole (LVPWd) and systole (LVPWs); left atrium diameter at end systole (LA) and tricuspid annular plane systolic excursion (TAPSE). Girls had higher values for BMI and heart rate than boys (p=0.048 and p=0.001, respectively). Mean interventricular septal and left ventricular posterior walls thickness was higher than published normal values in predominantly Caucasian populations. CONCLUSION: These are the first echocardiographic reference ranges for children from sub Saharan Africa and will allow accurate assessment of cardiac dimensions in clinical practice. PMID- 28711337 TI - Is antiarrhythmic medication superior to catheter ablation in suppressing supraventricular ectopic complexes in patients with atrial fibrillation? PMID- 28711339 TI - Imaging department organization in a stroke center and workflow processes in acute stroke. AB - The imaging department is an integral part of the stroke management task force and plays a critical role. Accurate and timely interpretation of images obtained in the emergency department and involvement in decision-making has contributed immensely in stroke care. In fact, the treatment paradigm has changed considerably after the recent positive endovascular clinical trials; and so is the hospital workflow and treatment site. As a result, the imaging department has become the site of maximum activity during an acute stroke protocol. Time management, teamwork and standardized institutional protocols contribute to improve functional outcome. In this review article, we emphasize the critical role an Imaging department's organization plays in a stroke center and the workflow involved in management of acute stroke. PMID- 28711338 TI - In-vitro cytocompatibility of dental resin monomers on osteoblast-like cells. AB - OBJECTIVES: Dental resin-based materials are widely used in modern dentistry. Especially, resin cements enjoy great popularity and are utilized in many applications. Nevertheless, monomers could be released from the resinous matrix, thus interact with surrounding tissues, cause adverse biological reactions and may lead in cases of implant retained restorations to peri-implant bone destruction. Hence, we performed an in-vitro study to determine cytotoxicity of resin monomers on osteoblast-like cells. METHODS: Three permanent osteoblast-like cell lines from tumor origin (MG-63 and Saos-2) as well as immortalized human fetal osteoblasts (hFOB 1.19) were used and treated with different concentrations of the main monomers: BisGMA, UDMA, TEGDMA and HEMA. The impact on cell viability was monitored using three different cytotoxicity tests: alamarBlue, XTT, and LDH assay. Mean+/-SEM were calculated and statistical analysis was performed with GraphPad Prism software. RESULTS: All monomers tested caused concentration dependent cytotoxic effects on the three investigated osteoblast-like cell lines. Although all three cell viability assays showed comparable results in cytotoxic ranking of the monomers (BisGMA > UDMA > TEGDMA > HEMA), higher differences in the absolute values were detected by the various test methods In addition, also a cell line dependent influence on cell viability could be identified with higher impact on the immortalized hFOB 1.19 cells compared to both osteosarcoma cell lines (MG-63, Saos-2). CONCLUSIONS: Monomer concentrations detected in elution studies caused toxic effects in osteoblast-like cells. Although the results from in-vitro studies cannot be directly transferred to a clinical situation our results indicate that released monomers from composite resin cements may cause adverse biological effects and thereby possibly lead to conditions favoring peri implantitis and bone destruction. CLINICAL SIGNIFICANCE: The wide use of composite resin cements especially in implant-prosthetic treatments should be scrutinized to avoid possible clinical implications between eluted resin monomers and bone cells leading to conditions favoring peri-implantitis and bone destruction. PMID- 28711340 TI - Revision Total Hip Arthroplasty Using the Kerboull Acetabular Reinforcement Device and Structural Allograft for Severe Defects of the Acetabulum. AB - BACKGROUND: The purpose of this study is to review our experience with Kerboull reinforcement device combined with bulk allograft for management of severe acetabular defects. METHODS: We investigated the results of revision total hip arthroplasty (THA) in 65 hips of 59 patients (10 male, 49 female) with Paprosky type 3A or 3B acetabular bone defects. Functional outcome was assessed using the Merle d'Aubigne hip score. Post-operative radiographs were examined for evidence of cup loosening. The mean age at revision THA was 59.1 years (23-85) and mean follow-up duration was 11.2 years (2-15). RESULTS: The Merle d'Aubigne hip score improved from 10.6 points (5-15) before surgery to 17.1 points (15-18) (P < .05) at the time of last investigation. In this series, mean coverage of the bone graft was 83.0% (34.6-100) of the loading portion in the horizontal plane on radiography immediately after revision. However, consolidation of the bone graft was completed within 12 months for all cases. There were 4 radiological failures due to acetabular aseptic loosening at a mean of 10.8 years (8-13) after index surgery; all 4 cases demonstrated massive bone loss that no part of the rounded plate could be placed on the host bone. Kaplan-Meier analysis showed that the 15.2-year survival rate was 85.1% (95% confidence interval 71-99) with re revision surgery for any reason as the end point. CONCLUSION: Despite massive bone defects, we achieved favorable results for revision THA using bulk allograft and the Kerboull reinforcement device. PMID- 28711341 TI - Response to Letter to the Editor on "Randomized Prospective Trial Comparing the Use of Intravenous vs Oral Acetaminophen in Total Joint Arthroplasty". PMID- 28711342 TI - Birmingham Hip Resurfacing vs Total Hip Arthroplasty: A Matched-Pair Comparison of Clinical Outcomes. AB - BACKGROUND: Birmingham hip resurfacing (BHR) has proven to be a good alternative for younger patients with osteoarthritis. Some have asserted that BHR may yield outcomes which are superior to total hip arthroplasty (THA), and that some studies which failed to show a difference were plagued by ceiling effects and lack of sensitivity of outcome measures. The purpose of this study is to compare outcomes of BHR and THA using the "Forgotten Joint" Score-12 (FJS), a more sensitive score with lesser vulnerability to the ceiling effect. METHODS: Patients who underwent BHR were matched to patients who underwent posterior THA by computing a propensity score using 5 covariates: age, body mass index, gender, worker's compensation claims, and previous hip surgery. Surgical outcomes were assessed using 6 patient-reported outcome measures, including the FJS, the visual analog scale for pain, and patient satisfaction. RESULTS: There were 42 patients in the BHR group and 18 patients in the THA group. The FJS was 78.0 for the BHR group and 76.0 for the THA group. The Veterans RAND 12-Item Health Survey Mental Component Summary and Short Form 12 Mental Component Summary were significantly higher in the BHR group. No differences were seen between all other patient reported outcomes. CONCLUSION: BHR offers excellent results in young patients that are comparable to THA. As no clinical difference could be shown between BHR and THA, even with the use of the FJS, the choice between BHR and THA should not be based solely on any expectation that either yields superior clinical outcomes compared to the other at short-term follow-up. PMID- 28711343 TI - Innexin expression in electrically coupled motor circuits. AB - The many roles of innexins, the molecules that form gap junctions in invertebrates, have been explored in numerous species. Here, we present a summary of innexin expression and function in two small, central pattern generating circuits found in crustaceans: the stomatogastric ganglion and the cardiac ganglion. The two ganglia express multiple innexin genes, exhibit varying combinations of symmetrical and rectifying gap junctions, as well as gap junctions within and across different cell types. Past studies have revealed correlations in ion channel and innexin expression in coupled neurons, as well as intriguing functional relationships between ion channel conductances and electrical coupling. Together, these studies suggest a putative role for innexins in correlating activity between coupled neurons at the levels of gene expression and physiological activity during development and in the adult animal. PMID- 28711344 TI - Modeling human behavior in economics and social science. AB - The complex interactions between human behaviors and social economic sciences is critically analyzed in this paper in view of possible applications of mathematical modeling as an attainable interdisciplinary approach to understand and simulate the aforementioned dynamics. The quest is developed along three steps: Firstly an overall analysis of social and economic sciences indicates the main requirements that a contribution of mathematical modeling should bring to these sciences; subsequently the focus moves to an overview of mathematical tools and to the selection of those which appear, according to the authors bias, appropriate to the modeling; finally, a survey of applications is presented looking ahead to research perspectives. PMID- 28711345 TI - Working at the intersection of context, culture, and technology: Provider perspectives on antimicrobial stewardship in the emergency department using electronic health record clinical decision support. AB - BACKGROUND: Antibiotic stewardship programs (ASPs) have not been fully developed for the emergency department (ED), in part the result of the barriers characteristic of this setting. Electronic health record-based clinical decision support (EHR CDS) represents a promising strategy to implement ASPs in the ED. We aimed to determine the cultural beliefs and structural barriers and facilitators to implementation of antimicrobial stewardship in the pediatric ED using EHR CDS. METHODS: Interviews and focus groups were conducted with hospital and ED leadership, attending ED physicians, nurse practitioners, physician assistants, and residents at a single health system in Colorado. We reviewed and coded the data using constant comparative analysis and framework analysis until a final set of themes emerged. RESULTS: Two dominant perceptions shaped providers' perspectives on ASPs in the ED and EHR CDS: (1) maintaining workflow efficiency and (2) constrained decision-making autonomy. Clinicians identified structural barriers to ASPs, such as pace of the ED, and various beliefs that shaped patterns of practice, including accommodating the prescribing decisions of other providers and managing parental expectations. Recommendations to enhance uptake focused on designing a simple yet flexible user interface, providing clinicians with performance data, and on-boarding clinicians to enhance buy-in. CONCLUSIONS: Developing a successful ED-based ASP using EHR CDS should attend to technologic needs, the institutional context, and the cultural beliefs of practice associated with providers' antibiotic prescribing. PMID- 28711346 TI - Association of cancer and Alzheimer's disease risk in a national cohort of veterans. AB - INTRODUCTION: To examine the risk of Alzheimer's disease (AD) among cancer survivors in a national database. METHODS: Retrospective cohort of 3,499,378 mostly male US veterans aged >=65 years were followed between 1996 and 2011. We used Cox models to estimate risk of AD and alternative outcomes (non-AD dementia, osteoarthritis, stroke, and macular degeneration) in veterans with and without a history of cancer. RESULTS: Survivors of a wide variety of cancers had modestly lower AD risk, but increased risk of the alternative outcomes. Survivors of screened cancers, including prostate cancer, had a slightly increased AD risk. Cancer treatment was independently associated with decreased AD risk; those who received chemotherapy had a lower risk than those who did not. DISCUSSION: Survivors of some cancers have a lower risk of AD but not other age-related conditions, arguing that lower AD diagnosis is not simply due to bias. Cancer treatment may be associated with decreased risk of AD. PMID- 28711347 TI - Particulate emissions from modern and old technology wood combustion induce distinct time-dependent patterns of toxicological responses in vitro. AB - Toxicological characterisation of combustion emissions in vitro are often conducted with macrophage cell lines, and the majority of these experiments are based on responses measured at 24h after the exposure. The aim of this study was to investigate how significant role time course plays on toxicological endpoints that are commonly measured in vitro. The RAW264.7 macrophage cell line was exposed to PM1 samples (150MUg/ml) from biomass combustion devices representing old and modern combustion technologies for 2, 4, 8, 12, 24 and 32h. After the exposure, cellular metabolic activity, cell membrane integrity, cellular DNA content, DNA damage and production of inflammatory markers were assessed. The present study revealed major differences in the time courses of the responses, statistical differences between the studied samples mostly limiting to differences between modern and old technology samples. Early stage responses consisted of disturbances in metabolic activity and cell membrane integrity. Middle time points revealed increases in chemokine production, whereas late-phase responses exhibited mostly increased DNA-damage, decreased membrane integrity and apoptotic activity. Altogether, these results implicate that the time point of measurement has to be considered carefully, when the toxicity of emission particles is characterised in in vitro study set-ups. PMID- 28711348 TI - Impact of molecular flexibility on the site energy shift of chlorophylls in Photosystem II. AB - Light harvesting from the Sun by antenna complexes surrounding the reaction center of Photosystem II represents the first step of the natural oxygenic photosynthesis performed by plants, algae and cyanobacteria. The excitation energy derived from the sunlight is absorbed by the chlorophylls of the antenna and subsequently conveyed to the reaction center of Photosystem II through resonant energy transfer mechanisms. In the special pair of chlorophylls of the reaction center the charge separation occurs, eventually leading to the oxidation of water molecules into protons, electrons and molecular oxygen. The adsorption properties of the antenna chlorophylls are ad hoc modulated by the protein environment to guarantee fast energy transfer and minimize side and back reactions. At the same time these properties are influenced by the molecular fluctuations occurring at physiological temperature. In the present work, combining classical molecular dynamics simulations with the Charge Density Coupling method, we estimated the impact of the thermal fluctuations on the site energy shift of the chlorophylls embedded in the Photosystem II complex. Our results show how the effect of the molecular fluctuations is not homogeneous throughout the complex, although the symmetry of the homodimer is maintained. Many peripheral chromophores undergo fluctuations larger then 10kJ/mol around the average values. Possible physiological roles of such fluctuations are discussed. PMID- 28711349 TI - Recombinant Bovine herpervirus 5 expressing enhanced green fluorescent protein. PMID- 28711350 TI - Synthesis and biological evaluation of pyrrole-based chalcones as CYP1 enzyme inhibitors, for possible prevention of cancer and overcoming cisplatin resistance. AB - Inhibitors of CYP1 enzymes may play vital roles in the prevention of cancer and overcoming chemo-resistance to anticancer drugs. In this letter, we report synthesis of twenty-three pyrrole based heterocyclic chalcones which were screened for inhibition of CYP1 isoforms. Compound 3n potently inhibited CYP1B1 with an IC50 of ~0.2MUM in SacchrosomesTM and CYP1B1-expressing live human cells. However, compound 3j which inhibited both CYP1A1 and CYP1B1 with an IC50 of ~0.9uM, using the same systems, also potently antagonized B[a]P-mediated induction of AhR signaling in yeast (IC50, 1.5uM), fully protected human cells from B[a]P toxicity and completely reversed cisplatin resistance in human cells that overexpress CYP1B1 by restoring cisplatin's cytotoxicity. Molecular modeling studies were performed to rationalize the observed potency and selectivity of enzyme inhibition by compounds 3j and 3n. PMID- 28711351 TI - Discovery of dual Axl/VEGF-R2 inhibitors as potential anti-angiogenic and anti metastatic drugs for cancer chemotherapy. AB - Axl tyrosine kinase has been shown to be involved in multiple pathways contributing to tumor development, angiogenesis, and metastasis. High Axl expression has been observed in many human tumors where it appears to confer aggressive tumor behavior. Here we present several series of dual Axl-VEGF-R2 kinase inhibitors based on extensive optimization of an acyl diaminotriazole. It was hypothesized that dual inhibition of these two receptor tyrosine kinases may have a synergistic affect in inhibiting tumor angiogenesis and metastasis. One of these molecules, R916562 showed comparable activity to Sunitinib in two mouse tumor xenograft models and a mouse corneal micropocket model. PMID- 28711352 TI - Development of a prodrug of hydantoin based TACE inhibitor. AB - Our research on hydantoin based TNF-alpha converting enzyme (TACE) inhibitors led to fused bi-heteroaryl hydantoin series that demonstrate sub-nanomolar potency (Ki) as well as excellent activity in human whole blood (hWBA). However, lead compound 2 posed some formulation challenges which prevented it for further development. A prodrug approach was investigated to address this issue. The pivalate prodrug 3 can be formulated as stable neutral form and demonstrated improved DMPK properties when compared with parent compound. PMID- 28711353 TI - Synthesis and antibacterial evaluation of novel 11-O-carbamoyl clarithromycin ketolides. AB - A series of novel 11-O-carbamoyl clarithromycin ketolides were designed, synthesized and evaluated for their in vitro antibacterial activity. The results showed that the majority of the target compounds displayed improved activity compared with references against erythromycin-resistant S. pneumoniae A22072 expressing the mef gene, S. pneumoniae B1 expressing the erm gene and S. pneumoniae AB11 expressing the mef and erm genes. In particular, compounds 9, 18, 19 and 22 showed the most potent activity against erythromycin-resistant S. pneumoniae A22072 with the MIC values of 0.5MUg/mL. Furthermore, compounds 11, 18, 19, 24 and 29 were also found to exhibit favorable antibacterial activity against erythromycin-susceptible S. pyogenes with the MIC values of 0.125 1MUg/mL, and moderate activity against erythromycin-susceptible S. aureus ATCC25923 and B. subtilis ATCC9372. PMID- 28711354 TI - The roles of metabolic thermogenesis in body fat regulation in striped hamsters fed high-fat diet at different temperatures. AB - The metabolic thermogenesis plays important roles in thermoregulation, and it may be also involved in body fat regulation. The thermogenesis of brown adipose tissue (BAT) is largely affected by ambient temperature, but it is unclear if the roles in body fat regulation are dependent on the temperature. In the present study, uncoupling protein 1 (ucp1)-based BAT thermogenesis, energy budget and body fat content were examined in the striped hamsters fed high fat diet (HF) at cold (5 degrees C) and warm (30 degrees C) temperatures. The effect of 2, 4 dinitrophenol (DNP), a chemical uncoupler, on body fat was also examined. The striped hamsters showed a notable increase in body fat following the HF feeding at 21 degrees C. The increased body fat was markedly elevated at 30 degrees C, but was significantly attenuated at 5 degrees C compared to that at 21 degrees C. The hamsters significantly increased energy intake at 5 degrees C, but consumed less food at 30 degrees C relative to those at 21 degrees C. Metabolic thermogenesis, indicated by basal metabolic rate, UCP1 expression and/or serum triiodothyronine levels, significantly increased at 5 degrees C, but decreased at 30 degrees C compared to that at 21 degrees C. A significant decrease in body fat content was observed in DNP-treated hamsters relative to the controls. These findings suggest that the roles of metabolic thermogenesis in body fat regulation largely depend on ambient temperature. The cold-induced enhancement of BAT thermogenesis may contribute the decreased body fat, resulting in a lean mass. Instead, the attenuation of BAT thermogenesis at the warm may result in notable obesity. PMID- 28711355 TI - Characterization of the FoxL2 proximal promoter and coding sequence from the common snapping turtle (Chelydra serpentina). AB - Sex is determined by temperature during embryogenesis in snapping turtles, Chelydra serpentina. Previous studies in this species show that dihydrotestosterone (DHT) induces ovarian development at temperatures that normally produce males or mixed sex ratios. The feminizing effect of DHT is associated with increased expression of FoxL2, suggesting that androgens regulate transcription of FoxL2. To test this hypothesis, we cloned the proximal promoter (1.6kb) and coding sequence for snapping turtle FoxL2 (tFoxL2) in frame with mCherry to produce a fluorescent reporter. The tFoxL2-mCherry fusion plasmid or mCherry control plasmid were stably transfected into mouse KK1 granulosa cells. These cells were then treated with 0, 1, 10, or 100nM DHT to assess androgen effects on tFoxL2-mCherry expression. In contrast to the main hypothesis, DHT did not alter expression of the tFoxL2-mCherry reporter. However, normal serum increased expression of tFoxL2-mCherry when compared to charcoal-stripped serum, indicating that the cloned region of tFoxL2 contains cis regulatory elements. We also used the tFoxL2-mCherry plasmid as an expression vector to test the hypothesis that DHT and tFoxL2 interact to regulate expression of endogenous genes in granulosa cells. While tFoxL2-mCherry and DHT had independent effects on mouse FoxL2, FshR, GnRHR, and StAR expression, tFoxL2-mCherry potentiated low concentration DHT effects on mouse aromatase expression. Further studies will be required to determine whether synergistic regulation of aromatase by DHT and FoxL2 also occurs in turtle gonads during the sex-determining period, which would explain the feminizing effect of DHT in this species. PMID- 28711356 TI - Membrane association and localization dynamics of the Ebola virus matrix protein VP40. AB - The Ebola virus matrix protein VP40 is a major structural protein that provides the scaffolding for new Ebola virus particles. For this, VP40 is first trafficked to the lower leaflet of the plasma membrane (PM) in its dimeric form. Once associated with the PM, the VP40 dimers undergo structural rearrangements and oligomerize into hexamers and filaments that make up the virus matrix. Therefore, association of the VP40 dimers and their stabilization at the PM is a crucial step in the Ebola life-cycle. To understand the molecular details of the VP40 dimer-PM interactions, we investigated the dimer association with the inner leaflet of the PM using detailed all-atom molecular dynamics (MD) simulations. The formation of the dimer-PM complex is facilitated by the interactions of the VP40 lysine residues and the anionic lipids POPS, POPI, and PIP2 in the PM. In contrast, the dimer fails to associate with a membrane without POPS, POPI, or PIP2 lipids. We explored the mechanisms of the association and identified important residues and lipids involved in localization and stabilization of VP40 dimers at the PM. MD simulations elucidate the role of a C-terminal alpha-helix alignment parallel to the lipid bilayer surface as well as the creation of membrane defects that allow partial insertion of the hydrophobic residue V276 into the membrane to further stabilize the VP40 dimer-PM complex. Understanding the mechanisms of the VP40 dimer-PM association that facilitate oligomerization can be important for potentially targeting the VP40 for small molecules that can interfere with the virus life-cycle. PMID- 28711357 TI - Effectiveness of the DNA barcoding approach for closely related conifers discrimination: A case study of the Pinus mugo complex. AB - DNA barcoding is a standard and efficient method, frequently used for identification, discrimination and discovery of new species. Although this approach is very useful for classifying the world's biodiversity, little is known about its usefulness in barcoding at lower taxonomic level and its discrimination rate for closely related species, like conifers. In this study, we compared the genetic variation of eight chloroplast DNA barcode regions (matK, rbcL, trnH psbA, trnL-trnF, rpl20-rps18, trnV, ycf1, ycf2) in 17 conifers - three closely related pines from Pinus mugo complex and 14 more distant conifers representing two genera and four sections of the Pinaceae family. The discrimination rate for a single and for multiple DNA barcode regions analyzed in this study was estimated using the Tree-Building and PWG-Distance methods. The usefulness of the DNA barcoding approach for analyzing and resolving taxonomic inconsistency among closely related and more phylogenetically distant conifers was evaluated and discussed. PMID- 28711358 TI - Histidine substitution in the most flexible fragments of firefly luciferase modifies its thermal stability. AB - Molecular dynamics (MD) at two temperatures of 300 and 340 K identified two histidine residues, His461 and His489, in the most flexible regions of firefly luciferase, a light emitting enzyme. We therefore designed four protein mutants H461D, H489K, H489D and H489M to investigate their enzyme kinetic and thermodynamic stability changes. Substitution of His461 by aspartate (H461D) decreased ATP binding affinity, reduced the melting temperature of protein by around 25 degrees C and shifted its optimum temperature of activity to 10 degrees C. In line with the common feature of psychrophilic enzymes, the MD data showed that the overall flexibility of H461D was relatively high at low temperature, probably due to a decrease in the number of salt bridges around the mutation site. On the other hand, substitution of His489 by aspartate (H489D) introduced a new salt bridge between the C-terminal and N-terminal domains and increased protein rigidity but only slightly improved its thermal stability. Similar changes were observed for H489K and, to a lesser degree, H489M mutations. Based on our results we conclude that the MD simulation-based rational substitution of histidines by salt-bridge forming residues can modulate conformational dynamics in luciferase and shift its optimal temperature activity. PMID- 28711359 TI - Interconversion of inactive to active conformation of MARK2: Insights from molecular modeling and molecular dynamics simulation. AB - The Ser/Thr protein kinase MARK2, also known as Par1b, belongs to the highly conserved family of PAR proteins which regulate cell polarity and partitioning through the animal kingdom. In the current study, inactive and active structures of human MARK2 were constructed by modeling and molecular dynamics simulation, based on available incomplete crystal structures in Protein Data Bank, to investigate local structural changes through which MARK2 switches from inactive to active state. None of the MARK2 wild type inactive crystal structures represent the position of activation segment. So, the contribution of this loop to the formation of inactive state is not clear. In the modeled structure of inactive MARK2, activation segment occludes the enzyme active site and assumes a relatively stable position. We also presented a detailed description of the major structural changes occur through the activation process and proposed a framework on how these deviations might be affected by the phosphorylation of Thr208 or existence of the UBA domain. Inspection of protein active state in the presence of Mg-ATP, demonstrated the precise arrangement of the various parts of enzyme around Mg-ATP and the importance of their stability in localization of the resulting complex. The results also confirmed the alleged mild auto-inhibitory role of the UBA domain and suggested a reason for the necessity of this role, based on structural similarities to other related kinases. PMID- 28711360 TI - False Positive STEMI Activations in a Regional Network: Comprehensive Analysis and Clinical Impact. Results From the Catalonian Codi Infart Network. AB - INTRODUCTION AND OBJECTIVES: ST-segment elevation myocardial infarction (STEMI) network activation by a noncardiologist reduces delay times but may increase the rate of false-positive STEMI diagnoses. We aimed to determine the prevalence, predictors, and clinical impact of false-positive activations within the Catalonian STEMI network (Codi Infart). METHODS: From January 2010 through December 2011, all consecutive patients treated within the Codi Infart network were included. Code activations were classified as appropriate if they satisfied both electrocardiogram and clinical STEMI criteria. Appropriate activations were classified as false positives using 2 nonexclusive definitions: a) "angiographic" if a culprit coronary artery was not identified, and b) "clinical" if the discharge diagnosis was other than STEMI. RESULTS: In total, 5701 activations were included. Appropriate activation was performed in 87.8% of the episodes. The rate of angiographic false positives was 14.6%, while the rate of clinical false positives was 11.6%. Irrespective of the definition, female sex, left bundle branch block, and previous myocardial infarction were independent predictors of false-positive STEMI diagnoses. Using the clinical definition, hospitals without percutaneous coronary intervention and patients with complications during the first medical contact also had a false-positive STEMI diagnoses rate higher than the mean. In-hospital and 30-day mortality rates were similar for false-positive and true-positive STEMI patients after adjustment for possible confounders. CONCLUSIONS: False-positive STEMI diagnoses were frequent. Outcomes were similar for patients with a true-positive or false-positive STEMI diagnosis treated within a STEMI network. The presence of any modifiable predictors of a false positive STEMI diagnosis warrants careful assessment to optimize the use of STEMI networks. PMID- 28711361 TI - Does crutch length influence gait parameters after total hip replacement surgery? AB - After total hip replacement surgery, crutches are often prescribed to enable patients to walk independently. Purpose of this study was to evaluate possible crutch length influence on gait performance and symmetry, including spatiotemporal and kinetics parameters. Thirty patients were randomly assigned to elbow flexed (EF) or elbow extended (EE) crutch setup. Subjects were asked to walk on the laboratory path, instrumented with motion tracking system and force platforms. Spatiotemporal gait parameters and ground reaction force (GRF) parameters for both limbs and crutch support were evaluated. In addition, limb symmetry was evaluated for both gait and force parameters using the symmetry index. Variability was quantified for base of support width, stride time and length as the coefficient of variation. Results showed that cadence and walking speed were not significantly different, but stride length significantly decreased and base of support width increased for the EF group when compared to the EE group. Operated limb GRF parameters were significantly decreased for the EF group, while crutch force parameters decreased for the EE group. Furthermore, the EF group showed greater stride length variability and asymmetry of force and spatiotemporal parameters than EE group did. The results of the present study showed that EF and EE setups did not assist patients equally during walking, with EE setup allowing more load bearing on the operated side, reducing load on the crutch and asymmetries in gait parameters when compared to the EF setup. This may help clinicians in rationalizing crutch setup for patients after total hip replacement surgery. PMID- 28711362 TI - Response to Drs. Lahiri and Lyden. PMID- 28711363 TI - Anticoagulant-Free but Dangerous: Perisurgical Consideration. PMID- 28711364 TI - Curcumin and its topical formulations for wound healing applications. AB - Oxidative damage and inflammation have been identified, through clinical and preclinical studies, as the main causes of nonhealing chronic wounds. Reduction of persistent chronic inflammation by application of antioxidant and anti inflammatory agents such as curcumin has been well studied. However, low aqueous solubility, poor tissue absorption, rapid metabolism and short plasma half-life have made curcumin unsuitable for systemic administration for better wound healing. Recently, various topical formulations of curcumin such as films, fibers, emulsion, hydrogels and different nanoformulations have been developed for targeted delivery of curcumin at wounded sites. In this review, we summarize and discuss different topical formulations of curcumin with emphasis on their wound-healing properties in animal models. PMID- 28711365 TI - [How I do... a cylindrical excision for in situ adenocarcinoma of the cervix]. PMID- 28711366 TI - [Contribution of chromosomal microarray analysis by a multidisciplinary prenatal diagnosis center]. AB - OBJECTIVE: Chromosomal analysis by array CGH is a cytogenetic technique that has opened its application to prenatal diagnosis in recent years. The main objective of the study was to analyze the contribution for couples using chromosomal analysis by array CGH in a CPDPN. METHODS: A retrospective cohort study was conducted in 2015 in a CPDPN. All the patients with array CGH analysis were included in the study. The analysis indications were CN>=3.5mm, ultrasound signs, intra-uterine growth retardation and fetal deaths. Data were collected in the prenatal diagnosis and genetic records. RESULTS: In total, 155 patients underwent analysis by array CGH, which corresponds to 36% of patients with invasive sampling indication. Fifteen CGH analysis were positive which represents 9.6% of indications. None of those diagnoses was possible with standard karyotype. These positive results have changed the outcome of pregnancy and what to do for a future pregnancy in 54% of cases. CONCLUSION: Array CGH enables a diagnostic gain despite a delicate interpretation and changes taking care of patients in future pregnancies. These results should be confirmed in a prospective multicenter study. PMID- 28711367 TI - Optimization of a multigene biochip for detection of relapsed and early relapsed colorectal cancer. AB - BACKGROUND: With the recent development of molecular markers, strategies for identifying patients with colorectal cancer (CRC) having a high risk of postoperative early relapse (within 1 y) and relapse have been improved. We previously constructed a multigene biochip with 19 candidate genes. The objective of the present study was to optimize a multigene biochip for detecting the risk of postoperative early relapse and relapse in patients with CRC. METHODS: We included 357 patients with stage I-III CRC who underwent curative resection at a single institution between June 2010 and May 2015. During each follow-up, a postoperative surveillance strategy including the National Comprehensive Cancer Network recommendations and a multigene biochip was used. A statistical algorithm was developed to select candidate biomarkers for an optimal combination. RESULTS: After a 30.9-mo median follow-up, 67 patients (18.8%) had postoperative relapse, of whom 25 (7.0%) relapsed within 1 y after operation and accounted for 37.3% of all relapsed patients. Of the 19 circulating biomarkers, ELAVL4, PTTG1, BIRC5, PDE6D, CHRNB1, MMP13, and PSG2, which presented significant predictive validity, were selected for combination. The expression of the seven-biomarker biochip resulted in area under the receiver operating characteristic curve values of 0.854 (95% confidence interval: 0.756-0.952) for early relapse and 0.884 (95% confidence interval: 0.830-0.939) for relapse. Moreover, the sensitivity, specificity, and predictive accuracy levels were 84.0%, 83.1%, and 83.2% for early relapse and 76.1%, 91.0%, and 88.2% for relapse (P = 0.415, 0.006, and 0.054, respectively). The median lead times before the detection of postoperative early relapse and relapse were 3.8 and 10.4 mo, respectively. CONCLUSIONS: From 19 circulating biomarkers, we optimized seven contemporary circulating biomarkers. The prediction model used for the early and accurate identification of Taiwanese patients with CRC having a high risk of postoperative early relapse and relapse seems to be feasible and comparable. PMID- 28711368 TI - The safety and feasibility of early discharge following ileostomy reversal: a National Surgical Quality Improvement Program analysis. AB - BACKGROUND: This study aimed to compare 30-day clinical outcomes following routine ileostomy reversal between patients that underwent early discharge (<24 h) and standard discharge (postoperative day [POD] 2 or 3). METHODS: A retrospective cohort analysis was conducted between 2005 and 2014 using the American College of Surgeons National Surgical Quality Improvement Program data set. All patients undergoing ileostomy reversal who were discharged on POD 0 or 1 (early discharge group [EDG]) versus POD 2 or 3 (standard discharge group [SDG]) were identified. The primary outcome was the 30-day adverse event rate. The secondary outcome was the 30-day readmission rate. A multivariate analysis was performed to determine the adjusted effect of early discharge as well as the predictors of adverse events and readmissions. RESULTS: The study population consisted of 355 and 5805 patients in the EDG and SDG, respectively. There were 19 (5.4%) 30-day adverse events in the EDG and 341 (5.8%) in the SDG. The EDG had 17 (4.8%) 30-day readmissions and the SDG had 294 (5.1%). The adjusted odds ratio for 30-day adverse events in the EDG was 0.95 (P = 0.83), and for 30-day readmissions, it was 1.01 (P = 0.96). Higher BMI, longer operative time, ASA >=3, chronic steroid use along with a history of bleeding disorder were significant predictors for adverse events and readmissions. CONCLUSIONS: Select patients discharged within 24 h of ileostomy reversal did not have a significantly higher rate of adverse events or readmissions compared to patients discharged on POD 2 or 3 following uncomplicated surgery. Predictors of adverse events and readmissions can guide the selection of patients suitable for early discharge. PMID- 28711369 TI - Predicting failure to rescue after abdominal aortic aneurysm repair in elderly patients. AB - BACKGROUND: We aim to describe trends in failure to rescue (FTR) among elderly patients undergoing elective open aortic aneurysm repair (OAR) and endovascular aortic aneurysm repair (EVAR). MATERIALS AND METHODS: All patients aged >=80 y recorded in the Vascular Quality Initiative database (2002-2014) undergoing nonruptured infrarenal AAA repair were included. Primary outcome was FTR, defined as percentage of deaths in patients who had a complication within 30 d of surgery. Univariable and multivariable statistics were used to identify risk factors for FTR following OAR and EVAR procedures. RESULTS: 975 elderly patients underwent AAA repair during the study period (EVAR = 667, OAR = 308). Overall FTR was 10%, most commonly related to acute kidney injury (62%) and respiratory failure (53%). Independent predictors of FTR included female gender (odds ratio [OR] 1.95), multiple comorbidities (OR 1.98), renal insufficiency (OR 1.97), peripheral vascular disease (OR 2.42), and perioperative vasopressor use (OR 4.49) (all, P < 0.02). Obesity was protective (OR 0.58, P = 0.02). FTR was higher following OAR versus EVAR (14% versus 9%; P = 0.02) on univariable analysis, but there was no significant difference between operative approaches after risk adjustment (OR 1.15, P = 0.60). Comparing elderly versus younger patients (n = 2854), FTR was significantly higher for the elderly for both OAR (OR 2.0, 95% CI 1.36-3.01) and EVAR (OR 1.60, 95% CI 1.07-2.40). CONCLUSIONS: FTR after AAA repair is not uncommon among elderly patients and could explain the higher mortality observed in this group compared to the general population. Overall health status should be carefully considered when weighing the risks versus benefits of performing AAA repair in patients aged >=80 y. PMID- 28711370 TI - Assessing the risk of hypercalcemic crisis in patients with primary hyperparathyroidism. AB - BACKGROUND: Hypercalcemic crisis (HC) is a potentially life-threatening manifestation of primary hyperparathyroidism (PHPT). This study aimed to identify patients with PHPT at greatest risk for developing HC. METHODS: This retrospective cohort study included patients with a preoperative calcium of at least 12 mg/dL undergoing initial parathyroidectomy for PHPT from 11/2000 to 03/2016. We compared those with HC, defined as needing hospitalization for hypercalcemia, to those without HC. RESULTS: The study cohort included 29 patients (15.8%) with HC and 154 patients (84.2%) without HC. Demographics and comorbidities were similar between the groups. Patients with HC were more likely to have a history of kidney stones (31.0% versus 14.3%, P = 0.039), higher preoperative calcium (median 13.8 versus 12.4 mg/dL, P < 0.001), higher parathyroid hormone (PTH) (median 318 versus 160 pg/mL, P = 0.001), and lower vitamin D (median 16 versus 26 ng/mL, P < 0.001) than patients without HC. Cure rates with parathyroidectomy were similar, but nearly double the proportion of patients with HC had multigland disease (24.1 versus 12.3%, P = 0.12). In multivariable analysis, higher preoperative calcium (odds ratio [OR] 1.7, 95% confidence interval [CI] 1.1-2.5), higher PTH (OR 1.0, 95% CI 1.0-1.0), and kidney stones (OR 3.0, 95% CI 1.1-8.2) were independently associated with HC. A Classification and Regression Tree revealed that HC developed in 91% of patients with a calcium >=13.25 mg/dL and a Charlson Comorbidity Index >=4. CONCLUSIONS: These data indicate that calcium, PTH, and kidney stones are important in predicting who are at greatest risk of HC. The Classification and Regression Tree can further help stratify risk for developing HC and allow surgeons to expedite parathyroidectomy accordingly. PMID- 28711371 TI - Extubation to high-flow nasal cannula in critically ill surgical patients. AB - BACKGROUND: High-flow nasal cannula (HFNC) is increasingly used to reduce reintubations in patients with respiratory failure. Benefits include providing positive end expiratory pressure, reducing anatomical dead space, and decreasing work of breathing. We sought to compare outcomes of critically ill surgical patients extubated to HFNC versus conventional therapy. METHODS: A retrospective review was conducted in the surgical intensive care unit of an academic center during August 2015 to February 2016. Data including demographics, ventilator days, oxygen therapy after extubation, reintubation rates, surgical intensive care unit and hospital length of stay, and mortality were collected. Self and palliative extubations were excluded. Characteristics and outcomes, with the primary outcome being reintubation, were compared between those extubated to HFNC versus cool mist/nasal cannula (CM/NC). RESULTS: Of the 184 patients analyzed, 46 were extubated to HFNC and 138 to CM/NC. Mean age and days on ventilation before extubation were 57.8 years and 4.3 days, respectively. Both cohorts were similar in age, sex, and had a similar prevalence of cardiopulmonary diagnoses at admission. Although prior to extubation HFNC had lengthier ventilation requirements (7.1 versus 3.4 days, P < 0.01) and ICU stays (7.8 versus 4.1 days, P < 0.01), the rate of reintubation was similar to CM/NC (6.5% versus 13.8%, P = 0.19). Multivariable analysis demonstrated HFNC to be associated with a lower risk of reintubation (adjusted odds ratio = 0.15, P = 0.02). Mortality rates were similar. CONCLUSIONS: Ventilated patients at risk for recurrent respiratory failure have reduced reintubation rates when extubated to HFNC. Patients with prolonged intubation or those with high-risk comorbidities may benefit from extubation to HFNC. PMID- 28711372 TI - Patient Reported Outcomes in Optimizing Myeloma Patients' Health-Related Quality of Life. AB - OBJECTIVE: To review the current state of evidence for the use of patient reported outcomes (PROs) and health-related quality of life (HRQoL) in optimizing best supportive care for patients with multiple myeloma (MM). DATA SOURCES: Peer reviewed journal articles, research reports, state of the science papers, and clinical guidelines. CONCLUSION: The diagnosis and treatment of MM negatively impacts an individual's HRQoL. Validated self-report tools that assess HRQoL and other PROs provide an insight into how the treatment or disease is impacting the individual, enabling early recognition of physical and emotional concerns. There is a growing body of evidence to support the use of PROs in assessing HRQoL in MM in clinical care. IMPLICATIONS FOR NURSING PRACTICE: There is a clear benefit for nurses to utilize PROs for patients with MM in order to obtain an understanding of how the treatment effects HRQoL. Thoughtful use of PRO measures can enable nurses to individualize supportive care interventions to meet the specific needs of the patient, and facilitate timely access to optimal symptom support. PMID- 28711373 TI - Comparative genomic and phylogenetic analysis of a toxigenic clinical isolate of Corynebacterium diphtheriae strain B-D-16-78 from Malaysia. AB - In this study, we report the comparative genomics and phylogenetic analysis of Corynebacterium diphtheriae strain B-D-16-78 that was isolated from a clinical specimen in 2016. The complete genome of C. diphtheriae strain B-D-16-78 was sequenced using PacBio Single Molecule, Real-Time sequencing technology and consists of a 2,474,151-bp circular chromosome with an average GC content of 53.56%. The core genome of C. diphtheriae was also deduced from a total of 74 strains with complete or draft genome sequences and the core genome-based phylogenetic analysis revealed close genetic relationship among strains that shared the same MLST allelic profile. In the context of CRISPR-Cas system, which confers adaptive immunity against re-invading DNA, 73 out of 86 spacer sequences were found to be unique to Malaysian strains which harboured only type-II-C and/or type-I-E-a systems. A total of 48 tox genes which code for the diphtheria toxin were retrieved from the 74 genomes and with the exception of one truncated gene, only nucleotide substitutions were detected when compared to the tox gene sequence of PW8. More than half were synonymous substitution and only two were nonsynonymous substitutions whereby H24Y was predicted to have a damaging effect on the protein function whilst T262V was predicted to be tolerated. Both toxigenic and non-toxigenic toxin-gene bearing strains have been isolated in Malaysia but the repeated isolation of toxigenic strains with the same MLST profile suggests the possibility of some of these strains may be circulating in the population. Hence, efforts to increase herd immunity should be continued and supported by an effective monitoring and surveillance system to track, manage and control outbreak of cases. PMID- 28711374 TI - The components of shoulder and elbow movements as goals of primary reconstructive operation in obstetric brachial plexus lesions. AB - Most of the cases of obstetric brachial plexus lesions (OBPL) show satisfactory improvement with conservative management, but in about 25% some surgical treatment is indicated. The present paper analyzes the effects of primary reconstructive surgeries in aspect of achieving delineated intraoperatively goals. Children operated before the age of 18 months with follow-up period longer than 1 year were selected. Therapeutic goals established during the operation were identified by analysis of initial clinical status and operative protocols. The elementary movement components in shoulder and elbow joints were classified by assessing range of motion, score in Active Movement Scale and modified British Medical Research Council scale of muscle strength. The effect was considered satisfactory when some antigravity movement was possible, and good when strength exceeded M3 or antigravity movement exceeded half of range of passive movement. In 13 of 19 patients most of established goals were achieved at good level, in 2 at satisfactory level. Remaining 4 patients showed improvement only in some aspects of extremity function. In 2 patients improvement in some movements was accompanied by worsening of other movements. The analysis of results separated into individual components of movements showed that goals were achieved in most of the cases, simultaneously clearly indicating which damaged structures failed to provide satisfactory function despite being addressed intraoperatively. The good results were obtained mainly by regeneration through grafts implanted after resection of neuroma in continuity, which proves that this technique is safe in spite of unavoidable temporary regression of function postoperatively. PMID- 28711375 TI - The prevalence of orodental trauma during epileptic seizures in terms of dental treatment - Survey study. AB - INTRODUCTION: Epilepsy is one of the most common neurological disorders. Seizures that occur during attacks may lead to head injuries. It is crucial to establish proper prophylactic management against trauma occurrence, as nowadays prevention is not sufficient. AIM: Assessment of the frequency of head and intraoral trauma during epileptic seizures and to evaluate factors that may predispose to injuries. MATERIAL AND METHODS: The questionnaire was carried out among 106 patients with epilepsy. Survey conducted questions regarding development of the disease and occurrence of orodental and head trauma. Results were statistically analyzed with the chi-square test (p<0.05). RESULTS: 52.4% of subjects admitted the occurrence of oral trauma during epileptic seizures. The most common were lips, tongue or cheeks injuries. 18% patients suffered from tooth crack and 17% from tooth fracture. 50% of respondents suffered from head trauma during seizures: 41% patients reported bruises, 39% burns, 37% wounds, 10% nose fractures, 7% eye socket trauma and 3% skull crack. 14.1% of respondents experienced dentist refusal to undertake treatment, while 4% of patients had epileptic attack during dental procedures. CONCLUSIONS: Dental trauma is common result of epileptic seizures. It is necessary to implement prophylactic management to prevent hard and soft tissues injuries, for example by using custom made mouthguards. Moreover, specially designed dental programs for this group of patients should be provided. PMID- 28711376 TI - Motor evoked potentials in patients with chronic whiplash-associated disorder grade II. AB - BACKGROUND AND PURPOSE: It is common belief that psychological problems influence the persistence of complains in patients with so-called mild whiplash-associated disorders (WADs). The usefulness of motor evoked potentials (MEPs) is investigated in patients with grade II WAD and remaining complains for more than 6 months. PATIENTS AND METHODS: Twenty consecutive patients, aged between 24 and 58 years, with persistent neck pain for months after a car accident were included. All patients had a magnetic resonance imaging (MRI) of the cervical spine and cord. Central (CMCT) and peripheral motor conduction times (PMCT) were evaluated by registration in the biceps brachii muscle (C5-C6) and in the abductor digiti minimi muscle (C7-C8-Th1). RESULTS: Thirteen patients had prolonged CMCT or/and PMCT compared to 7 with normal values. On MRI discus bulging C5-C6, without abnormal signal changes in the cervical spinal cord was observed in 6 of the patients with disturbed MEPs compared to 3 without. Out of 7 patients, who had repeated MEPs after 6 months, 3 of them had an improvement of their conduction time. The patients with prolonged MEP conduction times were older than those with normal values (p=0.007). CONCLUSIONS: MEP examination has to be performed in all patients with persistent complains even in the absence of objective neurological signs and non-significant changes on imaging. PMID- 28711377 TI - Pancreas exocrine replacement therapy is associated with increased survival following pancreatoduodenectomy for periampullary malignancy. AB - BACKGROUND: Although many patients undergoing pancreatoduodenectomy (PD) for cancer have pancreatic exocrine insufficiency, pancreatic enzyme replacement therapy (PERT) is not routinely used, and effects upon post-operative survival are unclear. METHODS: This review of patients undergoing PD for periampullary malignancy sought to test for an association between PERT and overall survival, with post-hoc subgroup analysis performed after stratifying patients by the year of surgery, pancreatic duct width and tumour type. RESULTS: Some 202/469 (43.1%) patients received PERT. After accounting for pathological variables and chemotherapy, PERT use was found to be independently associated with improved survival on multivariable analysis [HR 0.72 (95% CI: 0.52-0.99), p = 0.044] and on propensity matched analysis (p = 0.009). The effect of PERT upon improved survival was predominantly observed amongst patients with a dilated pancreatic duct (>=3 mm). DISCUSSION: PERT use was independently associated with improved survival following PD for cancer. The validity of this observation is supported by an effect largely confined to those patients with a dilated pancreatic duct. The nutritional status of patients undergoing PD for cancer needs further investigation and the effects of PERT require verification in further clinical studies. PMID- 28711378 TI - Subjective perception of cocaine reward in mice assessed by a single exposure place preference (sePP) paradigm. AB - BACKGROUND: The potential of abused drugs to induce addiction and compulsive drug related behavior is associated with their ability to alter dopamine signaling. Dopamine plays a key role in reward signaling and it has been of great interest to investigate how various drugs of abuse alter reward-related behavior. COMPARISON WITH EXISTING METHODS: In rodents, the rewarding effects of drugs have often been assessed in self-administration or place preference paradigms; both involving repeated drug exposure and weeks of training and testing. NEW METHOD: Our investigation describes a valid approach to assess the initial rewarding effects of cocaine in mice with a single exposure place preference (sePP) paradigm, avoiding repeated drug injections. RESULTS: We present the sePP paradigm with a 3-day protocol to assess the initial rewarding effects of cocaine. Interestingly, only male mice exhibit sePP to cocaine. To assess subsequent drug-related behavior, the protocol was extended by 3days of extinction followed by reinstatement on day 10. CONCLUSION: The sePP paradigm provides a reliable and convenient approach to assess the initial rewarding effects of cocaine, circumventing the need for repeated drug injections. The sePP protocol allows further dissection of the mechanism and influence of initial cocaine exposure on subsequent drug-related behaviors by including extinction and reinstatement. The lack of sePP in female mice may reflect a biologically relevant sex difference in the initial subjective perception of cocaine-induced reward. This could relate to and explain why males and females have been reported to respond differently to cocaine and cocaine-associated cues. PMID- 28711379 TI - The AttentionTrip: A game-like tool for measuring the networks of attention. AB - BACKGROUND: Recognizing that attention is not a unitary system, the Attention Network Test (ANT) and its variants were developed to measure the efficacy of the multiple components of attention. One potential weakness of these tests (ANTs) is that they are unengaging. This poses a problem when particular groups are tested (e.g., young children), when more stable measures of performance are desirable (and can only be achieved in longer testing sessions) and when repeated testing is necessary. NEW METHOD: Here we describe the evolution of a game-like tool, which we call the AttentionTrip(c), that is suitable for investigating three isolable attentional networks (alerting, orienting, and executive functions). RESULTS: Utilizing this tool we were able to generate reasonable network scores for alerting, executive control (from both the flanker and Simon effects), endogenous orienting and, after some motivated modifications, exogenous orienting. COMPARISON WITH EXISTING METHOD(S): Split-half reliabilities of the alerting and executive (flanker) network scores were considerably higher than those reported by MacLeod et al. (2010) in their psychometric review of the ANT. Informal observations (e.g., some participants asking if they could keep doing the task when their session was over) suggesting that the AttentionTrip is considerably more engaging than the traditional ANT have been confirmed in a head to-head comparison (Vallis & Klein, 2016). CONCLUSIONS: The AttentionTrip@ is available now for research purposes. A tablet version, which will have greater clinical utility, is under development. PMID- 28711380 TI - Evaluation of the Glittre-ADL test as an instrument for classifying functional capacity of individuals with cardiovascular diseases. AB - BACKGROUND: The assessment of functional capacity in individuals with cardiovascular disease is closely related to lower limb function. The Glittre-ADL test is a global test to evaluate this patients. OBJECTIVE: We aimed to verify whether the Glittre-ADL test discriminates functional status while evaluating individuals with cardiovascular disease. METHODS: A total of 42 participants were evaluated using the Glittre-ADL test Incremental Shuttle Walking Test (shuttle test), Human Activity Profile, and Duke Activity Status Index. Data from the shuttle test, Human Activity Profile, and DASI were divided into tertiles for statistical analysis. The time required to complete the Glittre-ADL test was compared among tertiles of the shuttle test, Duke Activity Status Index and Human Activity Profile using analysis of variance. RESULTS: There were significant differences between the tertiles of the shuttle test. Tertile 1 was different from tertiles 2 (mean difference, 47.63; 95% CI, 19.86-75.39) and 3 (mean difference, 67.15; 95% CI, 41.25-93.05). For the Duke Activity Status Index there were significant between-group differences. Tertile 1 was different from tertiles 2 (mean difference, 42.45; 95% CI, 8.82-76.09) and 3 (mean difference, 43.56; 95% CI, 13.68-73.44). For the Human Activity Profile there were significant between group differences. Tertile 3 was different from tertiles 1 (mean difference, 51.46; 95% CI, 21.27-81.64) and 2 (mean difference, 33.01; 95% CI, 3.52-62.51). CONCLUSION: The Glittre-ADL test is able to discriminate the functional status in individuals with cardiovascular disease, most of whom have hypertension. The Glittre-ADL test was sensitive to discriminate more functionally affected individuals. PMID- 28711381 TI - Effectiveness assessment of a guideline based protocol for ventilatory support management of COPD exacerbations in an emergency department. AB - OBJECTIVES: To investigate clinical outcomes according to ventilatory support indication in subjects with chronic obstructive pulmonary disease exacerbation in a "real-life" Emergency Department and to analyze potential predictors of successful noninvasive positive pressure ventilation. METHODS: Retrospective cohort performed over an 18-month period, comparing the following patient groups with chronic obstructive pulmonary disease exacerbation: Group A composed of patients initially selected to receive noninvasive positive pressure ventilation without the subsequent need for invasive mechanical ventilation (successful noninvasive positive pressure ventilation); Group B composed of patients transitioning from noninvasive positive pressure ventilation to invasive mechanical ventilation (failed-noninvasive positive pressure ventilation); and Group C composed of patients who presented with immediate need for invasive mechanical ventilation (without prior noninvasive positive pressure ventilation). RESULTS: 117 consecutive chronic obstructive pulmonary disease exacerbation admissions (Group A=96; Group B=13; Group C=8) of candidates for ventilatory support were reviewed. No differences in baseline disease severity and physiological parameters were found between the groups at Emergency Department admission. Nevertheless, Group B had higher intensive care unit admission, length of hospital stay, length of intensive care unit stay, and higher in-hospital mortality compared to Group A. Group C also had worse outcomes when compared to Group A. The only independent variable associated with the successful use of noninvasive positive pressure ventilation were improvement in arterial carbon dioxide pressure after 1h of noninvasive positive pressure ventilation use and its tolerance. CONCLUSION: Our data confirmed in a "real life" Emergency Department cohort that successful management of chronic obstructive pulmonary disease exacerbation with noninvasive positive pressure ventilation showed lower in-hospital mortality and Intensive Care Unit stay when compared to patients transitioning from noninvasive positive pressure ventilation to invasive mechanical ventilation or patients who presented an immediate need for invasive mechanical ventilation. noninvasive positive pressure ventilation tolerance and higher arterial carbon dioxide pressure reduction after 1-h of noninvasive positive pressure ventilation were predictors of successful treatment. These results should be confirmed in a prospective randomized controlled trial. PMID- 28711382 TI - Recreational Physical Activity in Relation to Prostate Cancer-specific Mortality Among Men with Nonmetastatic Prostate Cancer. AB - BACKGROUND: Large prospective cohort studies need to confirm the associations between recreational physical activity (PA), including the most common type walking, and prostate cancer-specific mortality (PCSM) among prostate cancer patients. OBJECTIVE: To investigate the associations of recreational PA, reported before and after diagnosis, with PCSM, overall and by tumor risk category. DESIGN, SETTING, AND PARTICIPANTS: In a prospective cohort study conducted in the USA, men diagnosed with nonmetastatic prostate cancer between 1992/1993 and June 2011 were followed for mortality until 2012. Patients were included in pre- (n=7328) and/or postdiagnosis (n=5319) analyses. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Cox proportional hazards models were used to assess PCSM with recreational PA. RESULTS AND LIMITATIONS: A total of 454 and 261 prostate cancer deaths occurred during pre- and postdiagnosis follow-up, respectively. Prior to diagnosis, engaging in >=17.5 metabolic equivalent hours per week (MET h/wk) of recreational PA, compared with 3.5-<8.75 MET-h/wk, was associated with a significant 37% lower risk of PCSM (hazard ratio: 0.63, 95% confidence interval: 0.43-0.91, p trend=0.03) only among men with lower-risk tumors (Gleason score 2-7 and T1-T2; p interaction=0.02). A similar result was seen for walking but not for other recreational PA. After diagnosis, the same comparison (>=17.5 vs 3.5-<8.75 MET-h/wk) was associated with a significant 31% lower risk of overall PCSM (hazard ratio: 0.69, 95% confidence interval: 0.49-0.95, p trend=0.006), which did not differ by tumor risk category. Postdiagnosis walking had a suggestive inverse association with PCSM (p trend=0.07). These results were observational and may not be generalized to patients with metastatic prostate cancer. Residual confounding due to a higher screening rate among men with lower-risk tumors cannot be ruled out. CONCLUSIONS: The findings provide additional evidence for prostate cancer survivors to adhere to PA recommendations, and support clinical trials of exercise among prostate cancer survivors with progression or mortality as outcomes. PATIENT SUMMARY: In a large follow-up study of men diagnosed with nonmetastatic prostate cancer, those who exercise more after diagnosis had a lower risk of dying from prostate cancer. PMID- 28711383 TI - Gonadotropin-releasing Hormone Agonists, Orchiectomy, and Risk of Cardiovascular Disease: Semi-ecologic, Nationwide, Population-based Study. AB - BACKGROUND: In observational studies, men with prostate cancer treated with gonadotropin-releasing hormone (GnRH) agonists had a higher risk of cardiovascular disease (CVD) compared to men who had undergone orchiectomy. However, selection bias may have influenced the difference in risk. OBJECTIVE: To investigate the association of type of androgen deprivation therapy (ADT) with risk of CVD while minimising selection bias. DESIGN, SETTING, AND PARTICIPANTS: Semi-ecologic study of 6556 men who received GnRH agonists and 3330 men who underwent orchiectomy as primary treatment during 1992-1999 in the Prostate Cancer Database Sweden 3.0. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We measured the proportion of men who received GnRH agonists as primary treatment in 580 experimental units defined by healthcare provider, diagnostic time period, and age at diagnosis. Incident or fatal CVD events in units with high and units with low use of GnRH agonists were compared. Net and crude probabilities were also analysed. RESULTS AND LIMITATIONS: The risk of CVD was similar between units with the highest and units with the lowest proportion of GnRH agonist use (relative risk 1.01, 95% confidence interval [CI] 0.93-1.11). Accordingly, there was no difference in the net probability of CVD after GnRH agonist compared to orchiectomy (hazard ratio 1.02, 95% CI 0.96-1.09). The 10-yr crude probability of CVD was 0.56 (95% CI 0.55-0.57) for men on GnRH agonists and 0.52 (95% CI 0.50 0.54) for men treated with orchiectomy. The main limitation was the nonrandom allocation to treatment, with younger men with lower comorbidity and less advanced cancer more likely to receive GnRH agonists. CONCLUSION: Our data do not support previous observations that GnRH agonists increase the risk of CVD in comparison to orchiectomy. PATIENT SUMMARY: We found a similar risk of cardiovascular disease between medical and surgical treatment as androgen deprivation therapy for prostate cancer. PMID- 28711384 TI - Radical Treatment of Stage II Non-small-cell Lung Cancer With Nonsurgical Approaches: A Multi-institution Report of Outcomes. AB - INTRODUCTION: Standard management of stage II non-small-cell lung cancer (NSCLC) is surgery, often followed by adjuvant chemotherapy. However, some patients do not undergo surgery for various reasons. We examined outcomes in this defined patient group. METHODS: We reviewed the records of patients with stage II NSCLC treated nonsurgically with curative intent from 2002 to 2012 across 3 academic cancer centers. Data collected included demographics, comorbidities, staging, treatments, and survival. The primary endpoint was overall survival (OS). We assessed factors associated with treatment choice and OS. RESULTS: A total of 158 patients were included: the median age was 74 years (range, 50-91 years), 44% were female, and 68% had a performance status of 0 to 1. The stage II groupings of the patients were T2b-T3 N0 in 55% and N1 in 45%. The most common reasons for inoperability were inadequate pulmonary reserve (27%) and medical comorbidities (24%). All patients received radical radiotherapy (RT) (median, 60 Gy [range, 48 75 Gy]). Seventy-three percent received RT alone; 24% received concurrent and 3% sequential chemoradiotherapy (CRT). In multivariate analyses, CRT was less likely in older patients (>= 70 years) (odds ratio [OR], 0.28; 95% confidence interval [CI], 0.11-0.70; P = .006) and in patients with higher (> 5) Charlson comorbidity scores (OR, 0.34; 95% CI, 0.13-0.90; P = .03) or normal (< 10 * 109/L) white blood cell counts (OR, 0.26; 95% CI, 0.09-0.73; P = .01). At the time of our analysis, 74% have died. The median OS was 22.9 months (range, 17.1-26.6 months). Patients who had undergone CRT had a significantly longer median OS than those receiving RT alone (39.1 vs. 20.5 months; P = .0019), confirmed in multivariate analysis (hazard ratio, 0.38; 95% CI, 0.21-0.69; P = .001). CONCLUSION: Nonsurgical approaches to management of stage II NSCLC are varied. Treatment with CRT was associated with significantly longer survival compared with RT alone. A randomized trial may be warranted. PMID- 28711385 TI - Top-down proteomics for the analysis of proteolytic events - Methods, applications and perspectives. AB - Mass spectrometry based proteomics is an indispensable tool for almost all research areas relevant for the understanding of proteolytic processing, ranging from the identification of substrates, products and cleavage sites up to the analysis of structural features influencing protease activity. The majority of methods for these studies are based on bottom-up proteomics performing analysis at peptide level. As this approach is characterized by a number of pitfalls, e.g. loss of molecular information, there is an ongoing effort to establish top-down proteomics, performing separation and MS analysis both at intact protein level. We briefly introduce major approaches of bottom-up proteomics used in the field of protease research and highlight the shortcomings of these methods. We then discuss the present state-of-the-art of top-down proteomics. Together with the discussion of known challenges we show the potential of this approach and present a number of successful applications of top-down proteomics in protease research. This article is part of a Special Issue entitled: Proteolysis as a Regulatory Event in Pathophysiology edited by Stefan Rose-John. PMID- 28711386 TI - Lipofuscin Generated by UVA Turns Keratinocytes Photosensitive to Visible Light. PMID- 28711387 TI - Serotype distribution and antimicrobial susceptibility pattern in children<=5years with invasive pneumococcal disease in India - A systematic review. AB - BACKGROUND: Streptococcus pneumoniae is a leading cause of childhood diseases that result in significant morbidity and mortality in India. Commercially licensed and available pneumococcal conjugate vaccines (PCVs) include ten (PCV 10) and 13 (PCV-13) pneumococcal serotypes. Vaccines with other serotype combinations are under development. Reviewing and reporting trends and distribution of pneumococcal serotypes causing invasive pneumococcal disease in India will be useful for policy making as PCV is being introduced into India's universal immunization program. METHODS: We conducted a systematic literature review of hospital based observational studies (both peer reviewed and gray literature published in English) from India available from January 1990 to December 2016. Studies that documented data on the prevalence of serotype distribution and the antimicrobial resistance pattern of S. pneumoniae in children<=5years of age were included. RESULT: We screened a total number of 116 studies, of which 109 studies were excluded. Final analysis included seven studies. The most frequent pneumococcal serotypes causing invasive disease among children<=5years were 14, 1, 19F, 6B, 5, 6A, 9V and 23F. Serotype 14 and 19A were represented in most of the geographical regions studied in the reviewed articles. Currently available PCV formulations included 67.3-78.4% of all serotypes contributing to IPD among Indian children<=5years. Pneumococcal resistance to trimethoprim/sulfamethoxazole, erythromycin, penicillin, chloramphenicol, levofloxacin and cefotaxime was seen in 81%, 37%, 10%, 8%, 6% and 4% of all pneumococcal isolates respectively, while vancomycin resistance was not reported. CONCLUSION: The present review demonstrates that up to 78.4% of reported invasive pneumococcal disease in children<=5years in India are currently caused by serotypes that are included in the available licensed PCVs. However, sentinel surveillance must be continued in representative parts of the country to assess the changing trends in distribution of pneumococcal serotypes and their implication for vaccine selection and rollout in India. PMID- 28711388 TI - Impact of 13-valent pneumococcal conjugate vaccine on pneumococcal meningitis in children. AB - OBJECTIVES: To evaluate the impact of 13-valent pneumococcal conjugate vaccine on pneumococcal meningitis in children. METHODS: Children younger than 15years of age attending 27 hospitals in the Region of Madrid with confirmed pneumococcal meningitis were identified in a prospective surveillance study, from 2007 to 2015. Clinical data, neurological sequelae, pneumococcal vaccination status, serotyping and antibiotic susceptibility were recorded. RESULTS: One hundred and four cases of pneumococcal meningitis were identified, 63 during the period of routine 7-valent pneumococcal conjugate vaccine immunisation (May 2007-April 2010) and 41 during the period of 13-valent pneumococcal conjugate vaccine immunisation (May 2010-April 2015). When both periods were compared, a 62% (95% CI: 45-75%) decrease in the incidence of pneumococcal meningitis was observed, from 2.19 cases per 100,000 inhabitants in the PCV7 period to 0.81 per 100,000 inhabitants in the PCV13 period (p=0.0001), mainly due to an 83% (95% CI: 30-96%) reduction in cases caused by serotype 19A. Isolates not susceptible to cefotaxime (MIC>0.5MUg/L) decreased from 27% to 8%, (p=0.02). Mean patient ages rose from 28.7months to 38.5months (p<0.05). Case fatality rate across both periods was 5%. An unfavourable outcome (death or neurological sequelae) occurred in 27% of patients, while the rate was similar in both periods. There was no increase in meningitis caused by pneumococcal serotypes not included in 13-valent pneumococcal conjugate vaccine throughout the years of the study. CONCLUSIONS: Immunisation with 13-valent pneumococcal conjugate vaccine has reduced the rate of pneumococcal meningitis in children less than 15years, with a near-elimination of cefotaxime-resistant isolates, but morbidity has remained unchanged. A shift of pneumococcal meningitis towards slightly higher age groups was also observed. PMID- 28711390 TI - Liraglutide preserves renal function in overweight diabetic patients with stage 3 chronic kidney disease. PMID- 28711389 TI - Population genetic structure, antibiotic resistance, capsule switching and evolution of invasive pneumococci before conjugate vaccination in Malawi. AB - INTRODUCTION: Pneumococcal infections cause a high death toll in Sub Saharan Africa (SSA) but the recently rolled out pneumococcal conjugate vaccines (PCV) will reduce the disease burden. To better understand the population impact of these vaccines, comprehensive analysis of large collections of pneumococcal isolates sampled prior to vaccination is required. Here we present a population genomic study of the invasive pneumococcal isolates sampled before the implementation of PCV13 in Malawi. MATERIALS AND METHODS: We retrospectively sampled and whole genome sequenced 585 invasive isolates from 2004 to 2010. We determine the pneumococcal population genetic structure and assessed serotype prevalence, antibiotic resistance rates, and the occurrence of serotype switching. RESULTS: Population structure analysis revealed 22 genetically distinct sequence clusters (SCs), which consisted of closely related isolates. Serotype 1 (ST217), a vaccine-associated serotype in clade SC2, showed highest prevalence (19.3%), and was associated with the highest MDR rate (81.9%) followed by serotype 12F, a non-vaccine serotype in clade SC10 with an MDR rate of 57.9%. Prevalence of serotypes was stable prior to vaccination although there was an increase in the PMEN19 clone, serotype 5 ST289, in clade SC1 in 2010 suggesting a potential undetected local outbreak. Coalescent analysis revealed recent emergence of the SCs and there was evidence of natural capsule switching in the absence of vaccine induced selection pressure. Furthermore, majority of the highly prevalent capsule-switched isolates were associated with acquisition of vaccine-targeted capsules. CONCLUSIONS: This study provides descriptions of capsule-switched serotypes and serotypes with potential to cause serotype replacement post-vaccination such as 12F. Continued surveillance is critical to monitor these serotypes and antibiotic resistance in order to design better infection prevention and control measures such as inclusion of emerging replacement serotypes in future conjugate vaccines. PMID- 28711391 TI - A memorable cause of ST elevation. PMID- 28711392 TI - Corrigendum to "Dietary Lactobacillus acidophilus modulated skin mucus protein profile, immune and appetite gene expression in gold fish (Carassius auratus gibelio)" [Fish Shellfish Immunol. 59C (2016) 149-154]. PMID- 28711393 TI - [Record of participation in a clinical trial in hospital discharge reports]. PMID- 28711394 TI - Exercise prevents IFN-alpha-induced mood and cognitive dysfunction and increases BDNF expression in the rat. AB - Aerobic exercise has marked effects on mood and cognition. Here, we used an interferon-alpha (IFN-alpha) induced depression model to evaluate the potential efficacy of chronic treadmill running on mood and cognition in the rat. IFN-alpha treatment induces behavioral deficits in the forced swim test (FST), open field test and object exploration task. Male han Wistar rats (n=8 per group, 3month old) were injected 3 times weekly with recombinant human IFN-alpha or saline (control) for 4weeks. One group was exercised 3 times (1h treadmill running) per week while the other remained sedentary. Animals were tested for anxiety- and depressive-like behavior in the open field test and FST. Spatial and recognition memory were examined by the object exploration task. Hippocampal and prefrontal cortex brain samples were harvested for analysis of brain-derived neurotrophic factor (BDNF). Treadmill running prevented IFN-alpha-induced decreased central arena exploration in the open field test and decreased immobility in the FST. IFN alpha treated rats had impaired spatial memory in the object exploration task compared to saline controls, which was prevented by treadmill running. Further, treadmill running improved recognition memory in both saline and IFN-alpha treated rats. Treadmill running protected against IFN-alpha induced decreases in expression of BDNF in the hippocampus and prefrontal cortex. Aerobic exercise protects against IFN-alpha induced affective and cognitive dysfunction, which is associated with increased BDNF. Results could have implications for future treatments of depression. PMID- 28711395 TI - Silymarin ameliorates experimentally induced depressive like behavior in rats: Involvement of hippocampal BDNF signaling, inflammatory cytokines and oxidative stress response. AB - Silymarin is a polyphenolic flavonoid of Silybum marianum, exhibited neuroprotection and antidepressant like activity in acute restraint stressed mice. The main objective of the present study is to investigate possible antidepressant like activity of silymarin in experimentally induced depressive behavior in rats. The depressive behaviors were induced in rats by olfactory bulbectomized (OBX) technique. Wistar rats were administered with silymarin at a dose of 100mg/kg and 200mg/kg, by per oral in OBX and sham operated rats. Behavioral (ambulatory and rearing activity and immobility time), neurochemical [serotonin (5-HT), dopamine (DA), norepinephrine (NE) and brain derived neurotrophic factor (BDNF) level], biochemical (MDA formation, IL-6, TNF-alpha and antioxidants) changes in hippocampus and cerebral cortex along with serum corticosterone were investigated. Rats subjected to OBX elicited significant increase in immobility time, ambulatory and rearing behaviors, reduced BDNF level, 5-HT, DA, NE and antioxidant parameters along with increased serum corticosterone, MDA formation, IL-6, and TNF-alpha in hippocampus and cerebral cortex compared to sham operated rats. Administration of with silymarin significantly attenuated immobility time, ambulatory and rearing behaviors, serum corticosterone and improved BDNF expression, 5-HT, DA, NE and antioxidant paradigms in cerebral cortex as well as hippocampus. In addition, silymarin attenuated IL-6, and TNF-alpha significantly in hippocampus and cerebral cortex in OBX rats. Thus, silymarin exhibits anti-depressant-like activity in OBX rats due to alterations in several neurotransmitters, endocrine and immunologic systems, including BDNF, 5-HT, DA, NE, MDA formation, IL-6, and TNF-alpha in hippocampus and cerebral cortex as well as serum corticosterone. PMID- 28711396 TI - Social adversity in pregnancy and trajectories of women's depressive symptoms: A longitudinal study. AB - BACKGROUND: Sound evidence has linked the experience of adversity with depression. Less is known about this association over time. AIM: The aim of this study is to determine whether or not social adversity experienced by pregnant women is associated with their patterns of depressive symptoms over their reproductive life course. METHODS: Data were obtained from a cohort of women collected at their first obstetrical clinic visit of an index pregnancy (time point 1) and at a further six time-points to 27 years following the birth. Latent Class Growth Modelling was used to estimate trajectories of women's depressive symptoms over this time period. Logistic regression modelling determined the prospective association between measures of adversity in pregnancy and 27-year postpartum depression trajectories, controlling for potential confounders. FINDINGS: Experiencing financial problems, housing problems, serious disagreements with partners and with others, and experiencing serious health problems in pregnancy were associated with membership of high and middle depression trajectories over the 27 years. Having someone close die or have a serious illness was associated with the high depression trajectory only. Younger maternal age and low family-income at first clinic visit were also associated with an increased risk of women's membership of both high and middle depression trajectories. CONCLUSIONS: Experiencing adversity during pregnancy predicts subsequent patterns of maternal depression over an extended period of women's reproductive life course. It is not clear whether women's experiences of adversity during pregnancy were causally associated with subsequent depression or whether there are other explanations of the observed association. PMID- 28711397 TI - Birth stories from South Africa: Voices unheard. AB - BACKGROUND: The manner that birth events unfold can have a lasting impact on women. Giving voice to women's experiences is key in the creation of care that embodies humanistic, family-centred service. AIM: The aim of this research was to describe the experiences of women receiving care during childbirth. METHODS: The design was qualitative and descriptive using thematic analysis to analyse women's birth stories. A purposive sample of women (N=12) who had recently given birth in South Africa was selected. Participants were recruited who had delivered across a variety of settings: public, private, and maternity hospital, as well as at home. Data were collected using in-depth interviews and field notes. FINDINGS: Four themes were noted: cocoon of compassionate care, personal regard for shared decision-making, beliefs about birth, and protection. Themes demonstrated both caring and non-caring behaviours including feelings of sadness, loneliness and being unwanted, being scared and uncertain, and overall dissatisfaction with the birth experience. Irrespective of setting, patients felt the absence of shared decision-making; the exception was where care was with midwives in an independent maternity hospital or at home. DISCUSSION: A period of high vulnerability, birth is often met with care perceived as non-caring and lacking in compassion. Many women reported failure to be included as a partner in decision-making where birth occurred in private or public hospital settings. Where a midwifery model of care was in place, experiences were uniformly positive. CONCLUSIONS: Fundamental change is needed in midwifery education and scope of practice, with overhaul of health system resourcing. PMID- 28711398 TI - Comprehensive maternity support and shared care in Switzerland: Comparison of levels of satisfaction. AB - BACKGROUND: According to the woman-centred care model, continuous care by a midwife has a positive impact on satisfaction. Comprehensive support is a model of team midwifery care implemented in the large Geneva University Hospitals in Switzerland, which has organised shared care according to the biomedical model of practice. This model of care insures a follow up by a specific group of midwives, during perinatal period. AIM: The goal of this study was to evaluate the satisfaction and outcomes of the obstetric and neonatal care of women who received comprehensive support during pregnancy, childbirth and the postpartum period, and compare them to women who received shared care. METHODS: This was a prospective comparative study between two models of care in low risk pregnant women. The satisfaction and outcomes of care were evaluated using the French version of the Women's Experiences Maternity Care Scale, two months after giving birth. FINDINGS: In total, 186 women in the comprehensive support group and 164 in the control group returned the questionnaire. After adjustment, the responses of those in the comprehensive support programme were strongly associated with optimal satisfaction, and they had a significantly lower epidural rate. No differences were observed between the two groups in the mode of delivery. The satisfaction relative to this support programme was associated with a birth plan for intrapartum and postnatal care. CONCLUSIONS: Team midwifery had a positive impact on satisfaction, with no adverse effects on the obstetric and neonatal outcomes, when compared to shared care. PMID- 28711399 TI - Restrictive bare stent prevents distal stent graft-induced new entry in endovascular repair of type B aortic dissection. AB - OBJECTIVE: Distal stent graft-induced new entry (SINE) can occur after thoracic endovascular aortic repair (TEVAR) of type B aortic dissection. This study investigated the mechanism of distal SINE and its prevention using a restrictive bare stent (RBS) technique. METHODS: From January 2013 to December 2014, 68 consecutive type B aortic dissection patients received endovascular repair at our center. The RBS technique was used with distal oversizing (between the diameter of the thoracic stent graft and the descending aorta true lumen diameter at the level of the intended distal edge of the thoracic stent graft) >20%. RESULTS: Twenty-three patients received TEVAR with a single thoracic stent graft (TEVAR group, n = 23); the rest received TEVAR combined with the RBS technique (TEVAR + RBS group, n = 45). Four distal SINEs occurred in the TEVAR group. Distal oversizing (69.7% +/- 35.5% vs 31.2% +/- 24.5%; P = .005) and expansion mismatch ratio (132.2% +/- 16.9% vs 106.5% +/- 11.6%; P < .05) were significantly higher in the SINE patients. Compared with standard TEVAR, TEVAR + RBS was associated with significantly lower distal oversizing (TEVAR vs TEVAR + RBS group, 59.8% +/- 24.7% vs 16.7% +/- 7.6%; P < .05), lower expansion mismatch ratio (113.8% +/- 14.6% vs 103.8% +/- 11.7%; P = .012), and lower distal SINE rate (4/23 [17.4%] vs 0/45 [0%]; P = .011). Compared with the TEVAR group, the false lumen was reduced significantly at the level of the RBS distal edge (P = .029). CONCLUSIONS: Excessive distal oversizing and distal expansion mismatch ratio may contribute to the occurrence of distal SINE. The RBS technique reduced the incidence of distal SINE. Based on our midterm and long-term observations, implantation of an RBS may improve aortic remodeling. PMID- 28711400 TI - Thirty-day outcomes after fenestrated endovascular repair are superior to open repair of abdominal aortic aneurysms involving visceral vessels. AB - OBJECTIVE: Although few studies have reported outcomes after branched or fenestrated endovascular aortic aneurysm repair (FEVAR) of abdominal aortic aneurysms involving visceral vessels (AAA-Vs), no multi-institutional study has compared FEVAR with open surgery (OS) for AAA-Vs. Our objective was to compare 30 day outcomes after FEVAR vs OS for AAA-Vs. METHODS: Patients who underwent FEVAR (n = 535) and OS (n = 1207) for elective AAA-Vs were identified from the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) 2008 to 2013 database. Thoracoabdominal aneurysms were excluded. Univariable and multivariable logistic regression analyses were performed. RESULTS: There were more men (82% vs 72%; P < .0001), diabetic patients (16% vs 11%; P = .005), patients with dependent functional status (4% vs 2%; P = .002), and nonsmokers (70% vs 56%; P < .0001) in the FEVAR group vs OS. There was no difference in rates of chronic obstructive pulmonary disease, cardiac history, peripheral artery disease, hypertension, and dialysis (P > .05). FEVAR had fewer major postoperative pulmonary complications (3.0% vs 19.0%; P < .0001), less renal failure requiring dialysis (1.9% vs 6.4%; P < .0001), less frequent cardiac arrest or myocardial infarction (2.2% vs 5.8%; P = .001), less bleeding with major transfusion (17.4% vs 50.2%; P < .0001), and decreased incidence of return to the operating room (4.5% vs 9.6%; P < .0001) and death (2.4% vs 4.7%; P = .02). The median length of stay was also significantly shorter for FEVAR (2 days vs 7 days; P < .0001). On multivariable analyses, OS was associated with higher risk than FEVAR for 30-day death (odds ratio [OR], 2.6; 95% confidence interval [CI], 1.3-5.0), pulmonary complications (OR, 8.8; 95% CI, 5.1-15.0), cardiac complications (OR, 3.4; 95% CI, 1.8-6.6), renal failure needing dialysis (OR, 3.8; 95% CI, 1.9-7.7), and return to the operating room (OR 2.5; 95% CI, 1.6 4.0). CONCLUSIONS: FEVAR is associated with a lower risk for 30-day mortality and adverse events compared with OS for AAA-Vs. PMID- 28711402 TI - Beneficial effects of Angiotensin II receptor blockers in brain disorders. AB - A canonical brain Renin-Angiotensin System (RAS), like the canonical peripheral RAS, has long been proposed as a major regulator of brain function. Because of methodological limitations, however, this system is in urgent need of critical revision. The Angiotensin II AT1 receptors have been confirmed as key factors in the regulation of brain function, and AT1 receptor over activity has been established as a major and early injury factor in the development of many brain diseases. Consequently, Angiotensin Receptor Blockers (ARBs), compounds widely used to treat cardiovascular and metabolic disorders, are excellent candidates for repurposing for the treatment of brain disorders. This review will discuss some of the reasons why revisiting brain RAS is a pressing necessity, will present evidence for a participation of AT1 receptor over activity in the development of major brain disorders, and will present definite evidence of ARBs neuroprotective effects. The review will focus on the beneficial effects of ARB therapy in stroke, neurodegenerative disorders including Alzheimer's and Parkinson's diseases, traumatic brain injury, radiation- induced brain damage, stress and mood disorders. PMID- 28711403 TI - Renin-angiotensin-aldosterone: An inclusive, an invigorative, an interactive and an interminable system. PMID- 28711401 TI - Performance of acoustic radiation force impulse ultrasound imaging for carotid plaque characterization with histologic validation. AB - OBJECTIVE: Stroke is commonly caused by thromboembolic events originating from ruptured carotid plaque with vulnerable composition. This study assessed the performance of acoustic radiation force impulse (ARFI) imaging, a noninvasive ultrasound elasticity imaging method, for delineating the composition of human carotid plaque in vivo with histologic validation. METHODS: Carotid ARFI images were captured before surgery in 25 patients undergoing clinically indicated carotid endarterectomy. The surgical specimens were histologically processed with sectioning matched to the ultrasound imaging plane. Three radiologists, blinded to histology, evaluated parametric images of ARFI-induced peak displacement to identify plaque features such as necrotic core (NC), intraplaque hemorrhage (IPH), collagen (COL), calcium (CAL), and fibrous cap (FC) thickness. Reader performance was measured against the histologic standard using receiver operating characteristic curve analysis, linear regression, Spearman correlation (rho), and Bland-Altman analysis. RESULTS: ARFI peak displacement was two-to-four-times larger in regions of NC and IPH relative to regions of COL or CAL. Readers detected soft plaque features (NC/IPH) with a median area under the curve of 0.887 (range, 0.867-0.924) and stiff plaque features (COL/CAL) with median area under the curve of 0.859 (range, 0.771-0.929). FC thickness measurements of two of the three readers correlated with histology (reader 1: R2 = 0.64, rho = 0.81; reader 2: R2 = 0.89, rho = 0.75). CONCLUSIONS: This study suggests that ARFI is capable of distinguishing soft from stiff atherosclerotic plaque components and delineating FC thickness. PMID- 28711404 TI - Penile Plication With or Without Degloving of the Penis Results in Similar Outcomes. AB - BACKGROUND: Penile plication techniques with or without degloving offer a minimally invasive option for the treatment of penile curvature. AIM: To review the outcomes of penile plication surgery and patient satisfaction with and without degloving of the penis. METHODS: We conducted a retrospective analysis of 52 patients who underwent penile plication for the treatment of Peyronie disease or congenital penile curvature. OUTCOMES: Surgical success rates, complications, and patient satisfaction determined with the Treatment Benefit Scale were compared between groups. RESULTS: The overall surgical success rate was 92.3% at a mean follow-up of 18.84 +/- 23.51 months. There were no intraoperative complications. In the degloving group, 42.6% of patients were greatly satisfied and 42.6% had better outcomes; in the without degloving group, 61.5% of patients were greatly satisfied and 30.8% had better outcomes. Comparison of outcomes was not statistically significant between groups. CLINICAL IMPLICATIONS: The results of the present study indicate the two techniques can be used for penile plication. CONCLUSION: With or without degloving, penile plication is safe and effective and provides high patient satisfaction. Kadirov R, Coskun B, Kaygisiz O, et al. Penile Plication With or Without Degloving of the Penis Results in Similar Outcomes. Sex Med 2017;5:e142-e147. PMID- 28711405 TI - A unique glycan-isoform of transferrin in cerebrospinal fluid: A potential diagnostic marker for neurological diseases. AB - BACKGROUND: Cerebrospinal fluid (CSF) is sequestered from blood by the blood brain barrier and directly communicates with brain parenchymal interstitial fluid, leading to contain specific biomarkers of neurological diseases. SCOPE OF REVIEW: CSF contains glycan isoforms of transferrin (Tf): one appears to be derived from the brain and the other from blood. MAJOR CONCLUSIONS: CSF contains two glycan-isoforms; brain-type Tf and serum-type Tf. Glycan analysis and immunohistochemistry suggest that serum-type Tf having alpha2, 6sialylated glycans is derived from blood whereas brain-type Tf having GlcNAc-terminated glycans is derived from the choroid plexus, CSF producing tissue. The ratio of serum-type/brain-type Tf differentiates Alzheimer's disease from idiopathic normal pressure hydrocephalus, which is an elderly dementia caused by abnormal metabolism of CSF. The ratios in Parkinson's disease (PD) patients were higher than those of controls and did not appear to be normally distributed. Indeed, detrended normal Quantile-Quantile plot analysis reveals the presence of an independent subgroup showing higher ratios in PD patients. The subgroup of PD shows higher levels of CSF alpha-synuclein than the rest, indicating that PD includes two subgroups, which differ in levels of brain-type Tf and alpha synuclein. GENERAL SIGNIFICANCE: Glycosylation in central nervous system appears to be unique. The unique glycan may be a tag for glycoprotein, which is biosynthesized in the central nervous system. This article is part of a Special Issue entitled Neuro-glycoscience, edited by Kenji Kadomatsu and Hiroshi Kitagawa. PMID- 28711406 TI - Glycosylation with ribitol-phosphate in mammals: New insights into the O-mannosyl glycan. AB - BACKGROUND: O-mannosyl glycans have been found in a limited number of glycoproteins of the brain, nerves, and skeletal muscles, particularly in alpha dystroglycan (alpha-DG). Defects in O-mannosyl glycan on alpha-DG are the primary cause of a group of congenital muscular dystrophies, which are collectively termed alpha-dystroglycanopathy. Recent studies have revealed various O-mannosyl glycan structures, which can be classified as core M1, core M2, and core M3 glycans. Although many dystroglycanopathy genes are involved in core M3 processing, the structure and biosynthesis of core M3 glycan remains only partially understood. SCOPE OF REVIEW: This review presents recent findings about the structure, biosynthesis, and pathology of O-mannosyl glycans. MAJOR CONCLUSIONS: Recent studies have revealed that the entire structure of core M3 glycan, including ribitol-5-phosphate, is a novel structure in mammals; its unique biosynthetic pathway has been elucidated by the identification of new causative genes for alpha-dystroglycanopathies and their functions. GENERAL SIGNIFICANCE: O-mannosyl glycan has a novel, unique structure that is important for the maintenance of brain and muscle functions. These findings have opened up a new field in glycoscience. These studies will further contribute to the understanding of the pathomechanism of alpha-dystroglycanopathy and the development of glycotherapeutics. This article is part of a Special Issue entitled Neuro-glycoscience, edited by Kenji Kadomatsu and Hiroshi Kitagawa. PMID- 28711407 TI - Severe neuroimaging anomalies are usually associated with random X inactivation in leucocytes circulating DNA in X-linked dominant Incontinentia Pigmenti. AB - Incontinentia Pigmenti (IP) is a skin disorder with neurological impairment in 30% of cases. The most common disease causing mutation is a deletion of exons 4 10 of the IKBKG gene, located on chromosome Xq28, with skewed X-chromosome inactivation in females, but few cases of random X-inactivation have been reported. We have correlated brain anomalies with X-chromosome inactivation status determined on leucocytes circulating DNA. We reviewed MRI of 18 girls with genetically proven IP. We found three patterns of MRI, normal MRI (n=5), mild white matter abnormalities with cortical and corpus callosum atrophy (n=6), and severe cortical abnormalities suggesting a vascular disease (n=7). Most patients with severe abnormalities had random X-inactivation (6/7,86%), while 80% (4/5) of patients with normal MRI and 100% (6/6) of patients with mild white matter abnormalities had skewed inactivation. These results suggest that skewed chromosome X-inactivation may protect brain from damage, while in case of random inactivation, expression of the mutated IKBKG gene may lead to severe brain lesions. PMID- 28711408 TI - Biochemical characteristics of newborns with carnitine transporter defect identified by newborn screening in California. AB - Carnitine transporter defect (CTD; also known as systemic primary carnitine deficiency; MIM 212140) is due to mutations in the SLC22A5 gene and leads to extremely low carnitine levels in blood and tissues. Affected individuals may develop early onset cardiomyopathy, weakness, or encephalopathy, which may be serious or even fatal. The disorder can be suggested by newborn screening. However, markedly low newborn carnitine levels can also be caused by conditions unrelated to CTD, such as the low carnitine levels often associated with normal pregnancies and some metabolic disorders occurring in the mother. In order to clarify the biochemical characteristics most useful for identification of CTD in newborns, we examined California Department of Public Health newborn screening data for CTD from 2005 to 12 and performed detailed chart reviews at six metabolic centers in California. The reviews covered 14 cases of newborn CTD, 14 cases of maternal disorders (CTD, 6 cases; glutaric aciduria, type 1, 5; medium chain acyl CoA dehydrogenase deficiency, 2; and cobalamin C deficiency, 1), and 154 false-positive cases identified by newborn screening. Our results show that newborns with CTD identified by NBS exhibit different biochemical characteristics, compared to individuals ascertained clinically. Newborns with CTD may have NBS dried blood spot free carnitine near the lower cutoff and confirmatory plasma total and free carnitine levels near the normal lower limit, particularly if obtained within two weeks after birth. These findings raise the concern that true cases of CTD may exist that could have been missed by newborn screening. CTD should be considered as a possible diagnosis in cases with suggestive clinical features, even if CTD was thought to be excluded in the newborn period. Maternal plasma total carnitine and newborn urine total carnitine values are the most important predictors of true CTD in newborns. However, biochemical testing alone does not yield a discriminant rule to distinguish true CTD from low carnitine in newborns due to other causes. Because of this biochemical variability and overlap, molecular genetic testing is imperative to confirm CTD in newborns. Additionally, functional testing of fibroblast carnitine uptake remains necessary for cases in which other confirmatory testing is inconclusive. Even with utilization of all available diagnostic testing methods, confirmation of CTD ascertained by NBS remains lengthy and challenging. Incorporation of molecular analysis as a second tier step in NBS for CTD may be beneficial and should be investigated. PMID- 28711410 TI - A retrospective analysis of the number of therapy visits after distal radius fractures using a new provider-scored clinical severity scale. AB - STUDY DESIGN: Retrospective study. INTRODUCTION: Fractures of the distal radius are common as is a postfracture referral to occupational therapy (OT). This article examines factors that cause greater morbidity and a greater number of OT visits. PURPOSE OF THE STUDY: This study aims to analyze which of 5 common sequelae of the distal radius fracture is most significant for increasing the number of therapy visits. METHODS: Three-hundred Sixty charts were reviewed, and 89 were selected. Multiple regression was used to determine which of our 5 independent variables had the greatest predictive power for the total number of therapy visits. RESULTS: The regression model demonstrated significance at P <= .01. Total active motion (TAM) of the digits (P <= .01) and TAM of the forearm (P <= .01) were the only complications that demonstrated statistical significance and a positive relationship with the number of therapy visits. In addition to this, TAM of the forearm and digits showed a strong correlation with the number of therapy visits. TAM of the wrist, pain, and edema had a weak correlation. Patients with high total group score on the clinical severity scale also had a moderate correlation. DISCUSSION: The results of the study illustrate the importance of digital contractures on a patient's morbidity, function, and their need for OT visits. CONCLUSION: The information from this study is important for the clinician as it identifies patients at risk for increased morbidity and identifies the complications that the clinician may want to stress early in the rehabilitation of that patient. LEVEL OF EVIDENCE: 3. PMID- 28711409 TI - Nortriptyline inhibits aggregation and neurotoxicity of alpha-synuclein by enhancing reconfiguration of the monomeric form. AB - The pathology of Parkinson's disease and other synucleinopathies is characterized by the formation of intracellular inclusions comprised primarily of misfolded, fibrillar alpha-synuclein (alpha-syn). One strategy to slow disease progression is to prevent the misfolding and aggregation of its native monomeric form. Here we present findings that support the contention that the tricyclic antidepressant compound nortriptyline (NOR) has disease-modifying potential for synucleinopathies. Findings from in vitro aggregation and kinetics assays support the view that NOR inhibits aggregation of alpha-syn by directly binding to the soluble, monomeric form, and by enhancing reconfiguration of the monomer, inhibits formation of toxic conformations of the protein. We go on to demonstrate that NOR inhibits the accumulation, aggregation and neurotoxicity of alpha-syn in multiple cell and animal models. These findings suggest that NOR, a compound with established safety and efficacy for treatment of depression, may slow progression of alpha-syn pathology by directly binding to soluble, native, alpha-syn, thereby inhibiting pathological aggregation and preserving its normal functions. PMID- 28711412 TI - Clinical outcomes of patients 80 years of age and older with soft tissue sarcoma. AB - OBJECTIVES: Although soft tissue sarcoma (STS) is rare, its incidence is increasing among older patients. Few studies have compared the outcomes between conservative and surgical treatments for STS patients aged >=80 years. We assessed the outcomes of both treatments in this population and the association between older age and surgical outcome. METHODS: We recruited consecutive patients with STS aged >=80 years treated at our institution between January 2006 and May 2014. We recommended surgical resection for all patients without multiple distant metastases. Overall survival and sarcoma-specific survival were assessed using the Kaplan-Meier method. RESULTS: Of the 39 patients with STS who presented at our institution, 37 were included in this analysis (19 men and 18 women with a median age of 85 [range 80-94] years). Tumors were classified as Stage IB (n = 3), IIA (n = 6), IIB (n = 3) or III (n = 24). Four patients underwent conservative therapy and 33 underwent surgical resection. The most common tumor site was the lower extremity, and the majority of tumors were classified as undifferentiated pleomorphic sarcoma. The follow-up rate was 100%. One-year sarcoma-specific survival rates were 25.0% in the conservative therapy group and 90.9% in the surgical resection group. No associations were found between age >=85 years and perioperative complications or clinical outcome. CONCLUSIONS: Surgical resection had relatively few complications, given the age group, and improved the prognosis of older patients with STS. Surgical resection of STS with curative intent should be considered in older patients. PMID- 28711411 TI - Efficacy of a radial-based thumb metacarpophalangeal-stabilizing orthosis for protecting the thumb metacarpophalangeal joint ulnar collateral ligament. AB - STUDY DESIGN: Basic research (biomechanics). INTRODUCTION: The high degree of motion that occurs at the thumb metacarpophalangeal (MCP) joint must be taken into account when immobilizing a partially torn or repaired thumb ulnar collateral ligament. PURPOSE OF THE STUDY: To determine the efficacy of a radial based thumb MCP-stabilizing orthosis in resisting abduction across the thumb ulnar collateral ligament. METHODS: Ten fresh cadaveric hands were mounted to a custom board. An anteroposterior radiograph of the thumb was obtained with a 2 N preload valgus force applied to the thumb, and the angle between the Kirschner wires was measured as a baseline. Subsequently, 20, 40, 60, 80, and 100 N valgus forces were applied 15 mm distal to the MCP joint. Anteroposterior radiographs of the thumb were obtained after each force was applied. The angle of displacement between the wires was measured and compared with the baseline angle. The angles were measured with an imaging processing tool. A custom radial-based thumb MCP stabilizing orthosis was fashioned for each cadaveric thumb by a certified hand therapist. The aforementioned loading protocol was then repeated. RESULTS: The radial-based thumb MCP-stabilizing orthosis significantly reduced mean abduction angles at each applied load. DISCUSSION: We found that our orthosis, despite being hand-based and leaving the thumb IP and CMC joints free, significantly reduced mean abduction angles at each applied load. CONCLUSIONS: This investigation provides objective evidence that our radial-based thumb MCP stabilizing orthosis effectively reduces the degree of abduction that occurs at the thumb MCP joint up to at least 100 N. LEVEL OF EVIDENCE: n/a (cadaveric). PMID- 28711413 TI - [Hypofractionated stereotactic radiotherapy for brain metastasis: Benefit of additional whole brain radiotherapy?] AB - PURPOSE: To study overall survival, risk of neurological death, local recurrence and development of new brain metastasis in patients treated for brain oligometastases with hypofractionated stereotactic radiotherapy with CyberKnife(r), according to the association or not with an additional whole brain irradiation. PATIENTS AND METHODS: Institutional retrospective study of 102 patients treated for one to three brain metastasis: 76 with exclusive hypofractionated stereotactic radiotherapy and 26 with hypofractionated stereotactic radiotherapy and whole brain irradiation. Objectives were assessed and compared between these two groups according to the Kaplan-Meier method and Cox model. RESULTS: Median follow-up was 18.8 months. There were no difference between exclusive hypofractionated stereotactic radiotherapy and hypofractionated stereotactic radiotherapy with whole brain irradiation for overall survival (respective median 21.5 and 20.1 months), risk of neurological death (respectively 9.2% and 15.4% at one year). At one year: the risk of cerebral progressive disease was greater in the group receiving exclusive hypofractionated stereotactic radiotherapy (respectively 43.4% vs. 26.2%, P=0.043), the risk of local recurrence was 25% versus 17.6% (P=0.28) and the development of new brain metastasis was 23.7% versus 11.5% (P=0.27). After salvage treatments, crude local control was similar in the two groups, respectively 78.6% and 73.5%. Whole brain irradiation has been avoided for 72.4% of patients in the group receving exclusive hypofractionated stereotactic radiotherapy. CONCLUSION: Whole brain irradiation improves local control of brain metastatic disease in addition to hypofractionated stereotactic radiotherapy. Sparing whole brain irradiation for salvage treatments only does not affect overall survival or risk of neurological death in selected patients with favourable prognosis. PMID- 28711414 TI - Reflective practice: Guarded. PMID- 28711415 TI - The experience of facilitators and participants of long term condition self management group programmes: A qualitative synthesis. AB - OBJECTIVE: Our aim was to systematically review the qualitative literature about the experiences of both facilitators and participants in a range of group-based programmes to support the self-management of long-term conditions. METHODS: We searched 7 databases using the terms 'self-management', 'group' and 'qualitative'. Full text articles meeting the inclusion criteria were retrieved for review. A thematic synthesis approach was used to analyse the studies. RESULTS: 2126 articles were identified and 24 were included for review. Group participants valued being with similar others and perceived peer support benefits. Facilitators (HCP and lay) had limited group specific training, were uncertain of purpose and prioritised education and medical conformity over supportive group processes and the promotion of self-management agency and engagement. Overall, studies prioritised positive descriptions. CONCLUSION: Group programmes' medical self-management focus may reduce their ability to contribute to patient-valued outcomes. Further research is needed to explore this disconnect. PRACTICE IMPLICATIONS: This review supports broadening the scope of group-based programmes to foreground shared learning, social support and development of agency. It is of relevance to developers and facilitators of group self-management programmes and their ability to address the burden of long-term conditions. PMID- 28711416 TI - Association of carbohydrate and fat intake with metabolic syndrome. AB - BACKGROUND & AIMS: In Asia, dietary pattern has been changed with increased intake of refined carbohydrates, sugar, and saturated fat, while the prevalence of metabolic syndrome (MetS) is on the rise. However, it remains unclear whether a high-carbohydrate or a high-fat diet is more metabolically harmful, and the optimal amount of carbohydrates and fat has not been determined. The aim of our study was to examine the role of carbohydrate and fat intake in MetS in a Korean population. METHODS: Data were obtained from a large, population-based, cross sectional study (6737 males and 8845 females). The subjects were divided into nine groups based on carbohydrate and fat proportion, and multiple logistic regression analysis was performed after adjusting for confounding variables. RESULTS: Regardless of fat intake, the risk of MetS significantly increased in males with higher carbohydrate proportions (of total energy intake). In females, the risk of MetS was significantly elevated only in those with both the highest carbohydrate proportion and lowest fat proportion. CONCLUSION: A high carbohydrate proportion was associated with a higher prevalence of MetS in males, and a high carbohydrate proportion combined with a low fat proportion was associated with MetS in females. Our results indicate that reduction of excessive carbohydrate intake paired with an adequate fat intake, taking into consideration optimal types of fat, is useful for MetS prevention. Longitudinal studies are needed to clarify the optimal types and amounts of carbohydrate and fat proportions as well as the mechanism underlying these relationships. PMID- 28711417 TI - Food insecurity and cognitive function in older adults: Brief report. AB - OBJECTIVE: We evaluated the specific association between food insecurity and cognitive function among a national sample of the broader U.S. older adult population. METHODS: Data from the 1999-2002 National Health and Nutrition Examination Survey (NHANES) were used to identify 1851 adults, between 60 and 85 years, with complete data on selected study variables. The Food Security Survey Module (FSSM) was administered to assess food insecurity. We used the 10-item U.S. Food Security Survey Module. Based on responses to the FSSM, four mutually exclusive categories were determined: fully food secure (0), marginally food secure (1-2), food insecure without hunger (3-5) and food insecure with hunger (6 10). The DSST (Digit Symbol Substitution Test) was used to assess cognitive functioning. RESULTS: Compared to those who were fully food secure, those who were marginally food secure (beta = -13.4; 95% CI: -17.6, -9.2; P < 0.001), food insecure without hunger (beta = -10.9; 95% CI: -17.6, -4.1; P = 0.003) and food insecure with hunger (beta = -22.2; 95% CI: -28.6, -15.8; P < 0.001) had significantly lower cognitive function. After adjustments, results were attenuated, but remained statistically significant. Older adults who were marginally food secure (betaadjusted = -7.7; 95% CI: -11.9, -3.5; P = 0.001), food insecure without hunger (betaadjusted = -7.0; 95% CI: -11.4, -2.6; P = 0.003) and food insecure with hunger (betaadjusted = -14.4; 95% CI: -23.9, -4.5; P = 0.005) had significantly lower cognitive function. CONCLUSION: In this national sample of older adults, there was an inverse association between food insecurity and cognitive function. PMID- 28711418 TI - Intakes and sources of dietary sugars and their association with metabolic and inflammatory markers. AB - BACKGROUND & AIMS: Associations of dietary sugars with metabolic and inflammatory markers may vary according to the source of the sugars. The aim of this study was to examine the association of dietary sugars from different sources [beverages (liquids), foods (solids), extrinsic (free) or intrinsic (non-free)] with metabolic and inflammatory markers. METHODS: Population-based cross-sectional study of adults in the East of England (n = 9678). Sugar intakes were estimated using food frequency questionnaires. Fasting glycated haemoglobin, glucose, insulin, and C-Reactive Protein (CRP) were measured and indices of metabolic risk were derived (homeostatic model of insulin resistance, HOMA-IR and metabolic risk z-score). RESULTS: In multiple linear regression analyses adjusted for potential confounders including BMI and TEI, sugars from liquids were positively associated with ln-CRP [b-coefficient (95%CI), 0.14 (0.05,0.22) per 10%TEI] and metabolic risk z-score [0.13 (0.07,0.18)]. Free sugars were positively associated with ln HOMA-IR [0.05 (0.03,0.08)] and metabolic risk z-score [0.09 (0.06,0.12)]. Sugars from solids were not associated with any outcome. Among major dietary contributors to intakes (g/d), sugars in fruit, vegetables, dairy products/egg dishes, cakes/biscuits/confectionary and squash/juice drinks were not associated, but sugar added to tea, coffee, cereal was significantly positively associated with all outcomes. Sugars in 100% juice [0.16 (0.06,0.25) per 10%TEI] and other non-alcoholic beverages [0.13 (0.03,0.23)] were positively associated with metabolic risk z-score. CONCLUSION: Higher intakes of sugars from non-alcoholic beverages and sugar added to tea, coffee, cereal were associated with glycaemia and inflammatory markers. Sugars from solids were not associated, irrespective of whether they were intrinsic or extrinsic. Positive associations of free sugars were largely explained by contribution of beverages to intake. PMID- 28711420 TI - [Left-heart catheterization followed by other invasive procedures: Regional comparisons reveal peculiar differences]. AB - BACKGROUND AND AIMS: Diagnostic left heart catheterization (LHC) is recommended if the therapeutic consequences of a bypass operation or percutaneous coronary intervention (PCI) are being considered. The present study examines regional differences in healthcare provision and therapeutic consequences of LHC, differentiated by counties and hospitals of the German federal state of Saxony Anhalt. In addition, it looks at which patient-related factors influence the proportion of follow-up interventions. The relation between the rates of LHC, interventions and hospital discharge due to myocardial infarction is examined. METHODS: The data of 9,791 individuals having statutory health insurance coverage by the AOK Saxony-Anhalt with 10,906 anonymized inpatient cases of LHCs in 2011 were followed until 12/31/2012, and it was examined whether they subsequently received a coronary bypass or PCI. The data was used to compare both the counties of Saxony-Anhalt (according to residence, adjusted for age and sex) and their hospitals. Regression analysis was run to identify determinants of receiving a LHC without consequences. RESULTS: Overall, 54.2 % of the patients with LHC had no invasive follow-up intervention. Regression analysis showed an approximately linear relationship for the counties: the number of LHCs provided correlates with the number of LHCs requiring no PCI or bypass within a period of at least 12 months. Regional LHC rates are not correlated with hospitalizations due to acute myocardial infarction. No bypass or PCI in the follow-up period was reported for 37 to 85 % of the cases, depending on the hospital providing the LHC. Women and younger patients have a higher risk to undergo LHC without therapeutic impact. DISCUSSION: The analysis indicates that there are specific regions in Saxony Anhalt and diagnoses where the indications for LHC should be more conservative. However, more detailed analyses are needed to verify the identified potentials for improving healthcare provision. PMID- 28711419 TI - [Barriers to treatment-seeking among German veterans: expert interviews]. AB - BACKGROUND: The number of service members of the German armed forces suffering from deployment-related mental health problems is increasing. However, less than 50 % seek professional help, and there is little knowledge about the barriers to treatment-seeking. METHODS: The article presents data gathered by the Delphi technique combined with focus groups from 55 health service experts regarding the evaluated barriers to treatment-seeking among German veterans. FINDINGS: According to the interviewed experts, major contextual barriers to treatment seeking include: 1) intimidating processes and structures, 2) actual stigmatization and discrimination, and 3) health service deficits. Major individual barriers to treatment were: 4) health beliefs, self-perception and fear of stigmatization, and 5) avoidance behavior related to psychopathology. In addition, there is another both contextual and individual barrier, i.e., 6) information deficits. INTERPRETATION: Individual internal factors like the soldiers' self-perception and their fear of being stigmatized were considered important barriers to treatment-seeking. The experts' opinion about avoidance behavior related to psychopathology and deficits in health services and information coincides with international findings. Compared to research in other countries, actual stigmatization and discrimination were regarded to be an important barrier in itself. According to our findings daunting/intimidating processes and structures like time-consuming and complex expert medical reports rather seem to be a German phenomenon. PMID- 28711421 TI - Patient safety issues in office-based surgery and anaesthesia in Switzerland: a qualitative study. AB - OBJECTIVES: To identify the spectrum of patient safety issues in office-based surgery and anaesthesia in Switzerland. METHODS: Purposive sample of 23 experts in surgery and anaesthesia and quality and regulation in Switzerland. Data were collected via individual qualitative interviews using a researcher-developed semi structured interview guide between March 2016 and September 2016. Interviews were transcribed and analysed using conventional content analysis. Issues were categorised under the headings "structure", "process", and "outcome". RESULTS: Experts identified two key overarching patient safety and regulatory issues in relation to office-based surgery and anaesthesia in Switzerland. First, experts repeatedly raised the current lack of data and transparency of the setting. It is unknown how many surgeons are operating in offices, how many and what types of operations are being done, and what the outcomes are. Secondly, experts also noted the limited oversight and regulation of the setting. While some standards exists, most experts felt that more minimal safety standards are needed regarding the requirements that must be met to do office-based surgery and what can and cannot be done in the office-based setting are needed, but they advocated a self regulatory approach. CONCLUSION: There is a lack of empirical data regarding the quantity and quality office-based surgery and anaesthesia in Switzerland. Further research is needed to address these research gaps and inform health policy in relation to patient safety in office-based surgery and anaesthesia in Switzerland. PMID- 28711422 TI - Mortality in Evacuating Nursing Home Residents. PMID- 28711423 TI - Randomized Trial of Intelligent Sensor System for Early Illness Alerts in Senior Housing. AB - OBJECTIVES: Measure the clinical effectiveness and cost effectiveness of using sensor data from an environmentally embedded sensor system for early illness recognition. This sensor system has demonstrated in pilot studies to detect changes in function and in chronic diseases or acute illnesses on average 10 days to 2 weeks before usual assessment methods or self-reports of illness. DESIGN: Prospective intervention study in 13 assisted living (AL) communities of 171 residents randomly assigned to intervention (n=86) or comparison group (n=85) receiving usual care. METHODS: Intervention participants lived with the sensor system an average of one year. MEASUREMENTS: Continuous data collected 24 hours/7 days a week from motion sensors to measure overall activity, an under mattress bed sensor to capture respiration, pulse, and restlessness as people sleep, and a gait sensor that continuously measures gait speed, stride length and time, and automatically assess for increasing fall risk as the person walks around the apartment. Continuously running computer algorithms are applied to the sensor data and send health alerts to staff when there are changes in sensor data patterns. RESULTS: The randomized comparison group functionally declined more rapidly than the intervention group. Walking speed and several measures from GaitRite, velocity, step length left and right, stride length left and right, and the fall risk measure of functional ambulation profile (FAP) all had clinically significant changes. The walking speed increase (worse) and velocity decline (worse) of 0.073 m/s for comparison group exceeded 0.05 m/s, a value considered to be a minimum clinically important difference. No differences were measured in health care costs. CONCLUSIONS: These findings demonstrate that sensor data with health alerts and fall alerts sent to AL nursing staff can be an effective strategy to detect and intervene in early signs of illness or functional decline. PMID- 28711424 TI - Conversion and Reversion Rates in Japanese Older People With Mild Cognitive Impairment. AB - OBJECTIVES: Approximately 25% of individuals who are diagnosed with amnestic mild cognitive impairment (aMCI) revert to normal cognition (NC) rather than progressing to Alzheimer disease (AD). However, the prevalence of progression and reversion among older people in Asia remains unclear. DESIGN: A prospective cohort study. SETTING: A community in Japan. PARTICIPANTS: A total of 4153 individuals without dementia aged >=65 years were classified as having NC, aMCI single domain (aMCIs), non-aMCI single domain (naMCIs), aMCI multiple domain (aMCIm), non-aMCI multiple domain (naMCIm), or global cognitive impairment (GCI). MEASUREMENTS: The National Center for Geriatrics and Gerontology-Functional Assessment Tool and the Mini-Mental State Examination were used to conduct cognitive screening. The participants completed baseline (August 2011 to June 2012) and follow-up (August 2015 to June 2016) assessments. We followed up monthly for newly incident AD, as recorded by the Japanese National Health Insurance and Later-Stage Medical Care systems. Multiple imputation was used to adjust for selection bias and loss of information. RESULTS: At 4-year follow-up, the reversion rates to NC in aMCIs, naMCIs, aMCIm, naMCIm, and GCI were 38.7%, 57.0%, 25.7%, 20.9%, and 43.7%, respectively. Of the participants with NC, aMCIs, naMCIs, aMCIm, naMCIm, and GCI at baseline, 4.7%, 4.5%, 13.1%, 20.6%, 21.6%, and 14.3%, respectively, were subsequently diagnosed with AD. We found significant associations between incident AD and naMCIs [hazard ratio (HR) compared to NC: 2.18, 95% confidence interval (CI): 1.45-3.26], and between AD and aMCIm (HR: 4.39, 95% CI: 2.06-9.39) and between AD and naMCIm (HR: 3.60, 95% CI: 2.13-6.08). However, the association between incident AD and aMCIs and between AD and GCI did not reach significance. CONCLUSION: Reversion to NC from MCI and GCI was frequent, and individuals with aMCIs and GCI did not show higher risk of incident AD than those with NC. Older adults with multiple cognitive impairments may be potential targets for preventing dementia. PMID- 28711425 TI - Minerals and Sarcopenia; The Role of Calcium, Iron, Magnesium, Phosphorus, Potassium, Selenium, Sodium, and Zinc on Muscle Mass, Muscle Strength, and Physical Performance in Older Adults: A Systematic Review. AB - INTRODUCTION: Minerals may contribute to prevent and treat sarcopenia, the age related loss of muscle mass, muscle strength, and physical performance. So far, there is no comprehensive review on the impact of minerals on sarcopenia outcomes. The aim of this systematic review is to evaluate the role of calcium, iron, magnesium, phosphorus, potassium, selenium, sodium, and zinc on muscle mass, muscle strength, and physical performance in older adults. METHODS: A systematic search was conducted between March 2016 and July 2016, in the PubMed database using predefined search terms. Articles on the role of dietary mineral intake or mineral serum concentrations on muscle mass, muscle strength, physical performance, and/or the prevalence of sarcopenia in healthy or frail older adults (average age >= 65 years) were selected. Only original research publications were included. The search and data extraction were conducted in duplicate by 2 independent researchers. The Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement was followed in constructing this systematic review. The Effective Public Health Practice Project (EPHPP) Quality Assessment Tool for Quantitative Studies was used to evaluate the quality of the selected articles. RESULTS: From the 3346 articles found, a total of 10 studies met the inclusion criteria. Observational studies showed that serum selenium (n = 1) and calcium intake (n = 1) were significantly associated with muscle mass, and magnesium (n = 1), selenium (n = 1), iron (n = 1), and zinc (n = 1) intake were significantly and positively associated with physical performance in older adults. Furthermore, magnesium (n = 2), selenium (n = 2), calcium (n = 2), and phosphorus (n = 1) intake were associated with the prevalence of sarcopenia. Magnesium supplementation improved physical performance based on one randomized controlled trial. No studies on the role of sodium or potassium on muscle mass, muscle strength, or physical performance were found. CONCLUSION: Minerals may be important nutrients to prevent and/or treat sarcopenia. Particularly, magnesium, selenium, and calcium seem to be most promising. Most of the included studies, however, were observational studies. Therefore, more randomized controlled trials are needed to elucidate the potential benefits of mineral intake to prevent and/or treat sarcopenia and support healthy aging. PMID- 28711426 TI - Chewing lice from wild birds in northern Greece. AB - Greece represents an important area for wild birds due to its geographical position and habitat diversity. Although the bird species in Greece are well recorded, the information about the chewing lice that infest them is practically non-existent. Thus, the aim of the present study was to record the species of lice infesting wild birds in northern Greece and furthermore, to associate the infestation prevalence with factors such as the age, sex, migration and social behaviour of the host as well as the time of the year. In total 729 birds, (belonging to 9 orders, 32 families and 68 species) were examined in 7 localities of northern Greece, during 9 ringing sessions from June 2013 until October 2015. Eighty (11%) of the birds were found to be infested with lice. In 31 different bird species, 560 specimens of lice, belonging to 33 species were recorded. Mixed infestations were recorded in 11 cases where birds were infested with 2-3 different lice species. Four new host-parasite associations were recorded i.e. Menacanthus curuccae from Acrocephalus melanopogon, Menacanthus agilis from Cettia cetti, Myrsidea sp. from Acrocephalus schoenobaenus, and Philopretus citrinellae from Spinus spinus. Moreover, Menacanthus sinuatus was detected on Poecile lugubris, rendering this report the first record of louse infestation in this bird species. The statistical analysis of the data collected showed no association between parasitological parameters (prevalence, mean and median intensity and mean abundance) in two different periods of the year (breeding vs post-breeding season). However, there was a statistically significant difference in the prevalence of infestation between a) migrating and sedentary passerine birds (7.4% vs 13.2%), b) colonial and territorial birds (54.5% vs 9.6%), and c) female and male birds in breeding period (2.6% vs 15.6%). PMID- 28711427 TI - Temporal remodeling of the cell cycle accompanies differentiation in the Drosophila germline. AB - Development of multicellular organisms relies upon the coordinated regulation of cellular differentiation and proliferation. Growing evidence suggests that some molecular regulatory pathways associated with the cell cycle machinery also dictate cell fate; however, it remains largely unclear how the cell cycle is remodeled in concert with cell differentiation. During Drosophila oogenesis, mature oocytes are created through a series of precisely controlled division and differentiation steps, originating from a single tissue-specific stem cell. Further, germline stem cells (GSCs) and their differentiating progeny remain in a predominantly linear arrangement as oogenesis proceeds. The ability to visualize the stepwise events of differentiation within the context of a single tissue make the Drosophila ovary an exceptional model for study of cell cycle remodeling. To describe how the cell cycle is remodeled in germ cells as they differentiate in situ, we used the Drosophila Fluorescence Ubiquitin-based Cell Cycle Indicator (Fly-FUCCI) system, in which degradable versions of GFP::E2f1 and RFP::CycB fluorescently label cells in each phase of the cell cycle. We found that the lengths of the G1, S, and G2 phases of the cell cycle change dramatically over the course of differentiation, and identified the 4/8-cell cyst as a key developmental transition state in which cells prepare for specialized cell cycles. Our data suggest that the transcriptional activator E2f1, which controls the transition from G1 to S phase, is a key regulator of mitotic divisions in the early germline. Our data support the model that E2f1 is necessary for proper GSC proliferation, self-renewal, and daughter cell development. In contrast, while E2f1 degradation by the Cullin 4 (Cul4)-containing ubiquitin E3 ligase (CRL4) is essential for developmental transitions in the early germline, our data do not support a role for E2f1 degradation as a mechanism to limit GSC proliferation or self-renewal. Taken together, these findings provide further insight into the regulation of cell proliferation and the acquisition of differentiated cell fate, with broad implications across developing tissues. PMID- 28711428 TI - [Congenital heart disease mortality in Spain during a 10 year period (2003 2012)]. AB - INTRODUCTION AND OBJECTIVES: Congenital heart disease is a major cause of infant mortality in developed countries. In Spain, there are no publications at national level on mortality due to congenital heart disease. The aim of this study is to analyse mortality in infants with congenital heart disease, lethality of different types of congenital heart disease, and their variation over a ten-year period. METHODS: A retrospective observational study was performed to evaluate mortality rate of children under one year old with congenital heart disease, using the minimum basic data set, from 2003 to 2012. Mortality rate and relative risk of mortality were estimated by Poisson regression. RESULTS: There were 2,970 (4.58%) infant deaths in a population of 64,831 patients with congenital heart disease, with 73.8% of deaths occurring during first week of life. Infant mortality rate in patients with congenital heart disease was 6.23 per 10,000 live births, and remained constant during the ten-year period of the study, representing 18% of total infant mortality rate in Spain. The congenital heart diseases with highest mortality rates were hypoplastic left heart syndrome (41.4%), interruption of aortic arch (20%), and total anomalous pulmonary drainage (16.8%). Atrial septal defect (1%) and pulmonary stenosis (1.1%) showed the lowest mortality rate. CONCLUSIONS: Congenital heart disease was a major cause of infant mortality with no variations during the study period. The proportion of infants who died in our study was similar to other similar countries. In spite of current medical advances, some forms of congenital heart disease show very high mortality rates. PMID- 28711429 TI - [Appropriateness of antibiotic prescribing in paediatric patients in a hospital emergency department]. AB - INTRODUCTION: Antibiotics represent one of the most widely prescribed therapeutic agents in children. It has been estimated that 30-50% of antibiotic prescriptions for this population are inappropriate. In this scenario, analysis of prescription data provides an invaluable source of information as a basis for implementing strategies for improvement in this field. OBJECTIVE: To assess the appropriateness of antibiotic prescriptions in a paediatric population at an emergency department. METHODS: An observational, descriptive, and cross-sectional study was conducted on patients under 14 years who attended the emergency department during 2013. A random sample of 630 patients was selected (confidence level 99%, accuracy 5%). To assess the suitability of antibiotic prescriptions, the clinical practice was compared with an evidence-based guideline especially designed for this study. RESULTS: Antibiotics were prescribed to 16.5% patients (n=104). Antibiotic treatment was inappropriate in 51.9% patients (n=54). Unnecessary treatment was indicated in 40.7%, with wrong antibiotics chosen in 35.2%, and the posology was incorrect in 24.1% of them. The most frequent diseases with incorrectly prescribed antibiotics were: acute otitis media, episodes of wheezing, fever of unknown origin, acute pharyngo-tonsillitis, and community-acquired pneumonia. CONCLUSION: Antibiotic prescribing seems to be inappropriate in up to half of the patients. These data reinforce the need to develop a paediatric antimicrobial stewardship program to decrease the unnecessary use of antimicrobial agents. PMID- 28711430 TI - Implementation of a national bundle care program to reduce catheter-associated urinary tract infection in high-risk units of hospitals in Taiwan. AB - BACKGROUND/PURPOSE: This study was intended to investigate the impact of implementation of catheter-associated urinary tract infection (CA-UTI) bundle care on the incidence of CA-UTI in high-risk units. METHODS: Thirteen high-risk units, including medical (n = 5), surgical (n = 3), cardiac intensive care units (n = 2), respiratory care centers (n = 2), and respiratory care ward (n = 1) were included in this quality-improvement project. This study was divided into pre intervention phase (from January 1 to July 31) and post-intervention phase (from August 1 to October 31) in 2013. RESULTS: The incidence of CA-UTI decreased by 22.7%, from 3.86 to 2.98 per 1000 catheter-days (95% confidence interval, 0.65 0.82; p < 0.0001) before and after the introduction of the CA-UTI bundle. Among 66 episodes of culture-proven CA-UTIs, Candida spp. were the most common pathogens (n = 17, 25.8%), followed by Escherichia coli (n = 10, 15.2%). For the seven elements of the insertion bundle, the compliance was the lowest for cleaning of the perineum, followed by hand hygiene. The overall compliance rates of the insertion bundle were 93.4%, 99.5%, and 96.3% in medical centers, regional hospitals, and district hospital, respectively. For the six elements of the maintenance bundle, the compliance was the lowest for daily review of the need of a Foley catheter. The overall compliance rates of the maintenance bundle were 95.7%, 99.9%, and 99.9% in medical centers, regional hospitals, and district hospital, respectively. CONCLUSIONS: The implementation of CA-UTI bundle care successfully reduced CA-UTI in Taiwanese high-risk units. A process surveillance checklist can be helpful for understanding which parts of the bundle care require improvements. PMID- 28711431 TI - Highly prevalent emmSTG840.0 and emmSTC839.0 types of erythromycin non susceptible group G Streptococcus isolated from bacteremia in southern Taiwan. AB - BACKGROUND/PURPOSE: Group G Streptococcus (GGS) infections in human have increased. Treatment relied on antibiotic therapy, including erythromycin. However, information regarding the dominant strains and erythromycin susceptibility in GGS bacteremia is limited. METHODS: A total of 134 GGS were isolated from patients with bacteremia in a university hospital of southern Taiwan during 1993-2010. The erythromycin susceptibility was determined by disc diffusion and agar dilution assays. The bacterial species was determined by MALDI TOF. The presence of erythromycin-resistant genes and emm types were determined by polymerase chain reaction and sequence. The clonal spreading was analyzed by pulsed-field gel electrophoresis with SmaI or SgrAI digestion. RESULTS: The annual erythromycin non-susceptible rate varied, with an average of 40.3%. All erythromycin non-susceptible strains belonged to the Streptococcus dysgalactiae. No erythromycin non-susceptible strains belong to the anginosus group. The most prevalent erythromycin-resistant gene was mefA (57.4%), followed by ermB (37%), and ermA (3.7%). The N terminal hyper variable region of emm was sequenced to determine the emm type, and only S. dysgalactiae had the emm gene. The most prevalent emm types were emmSTG840.0 (17.2%), emmSTG485.0 (10.4%), and emmSTC839.0 (9.0%). 73% and 47% of the strains with only mefA and ermB belonged to emmSTG840.0 and emmSTC839.0 types, respectively. Pulsed-field gel electrophoresis showed that different clones of emmSTG840.0 and emmSTC839.0 strains were spread in this region during the 18 years of surveillance. CONCLUSION: Our data indicate that there were dominant emm types with erythromycin non-susceptibility in S. dysgalactiae isolated from bacteremia in Taiwan, and thus constant surveillance is warranted. PMID- 28711432 TI - Inactivated Orf-virus shows disease modifying antiviral activity in a guinea pig model of genital herpesvirus infection. AB - BACKGROUND: Inactivated Orf virus (iORFV) has been used as a preventative as well as a therapeutic immunomodulator in veterinary medicine in different species. iORFV elicits strong effects on cytokine secretion in mice and human immune cells leading to an auto-regulated loop of initial up-regulation of inflammatory and Th1-related cytokines followed by Th2-related cytokines that attenuate immunopathology. The therapeutic potential of iORFV has been recognized in several models for difficult-to-treat disease areas such as chronic viral diseases, liver fibrosis or various forms of cancer. METHODS: Guinea pigs were infected with Human Herpesvirus (HSV)-2 strain MS and treated with iORFV, Acyclovir (ACV) or placebo, respectively. Clinical score of herpes lesions and viral shedding was assessed over a period of 40 days. In addition, viral DNA in dorsal root ganglia was quantified at the end of the study. RESULTS: Disease symptoms were minimal or absent in iORFV-treated guinea pigs but tended to be severe in animals treated with either ACV or placebo. The cumulated disease score was significantly reduced in iORFV-treated but not in ACV- or placebo-treated guinea pigs. In addition, treatment with iORFV, but not ACV or placebo, led to significant reduction of viral DNA load in dorsal root ganglia. CONCLUSION: iORFV effectively suppressed recurrences in guinea pigs experimentally infected with HSV. iORFV did not only reduce recurrent disease episodes but was, compared with ACV, more effective in reducing latency as measured by viral DNA detected in dorsal root ganglia of infected animals. PMID- 28711433 TI - Nasal Staphylococcus aureus and methicillin-resistant Staphylococcus aureus carriage among college student athletes in northern Taiwan. AB - Of 259 college students in northern Taiwan surveyed, nasal carriage rate of Staphylococcus aureus and methicillin-resistant S. aureus (MRSA) was 22.4% and 1.54%, respectively and no significant difference was found between athlete students and non-athlete students. Three of four MRSA isolates belonged to sequence type 59, the endemic community clone. PMID- 28711434 TI - An infant with Klebsiella oxytoca septic arthritis. PMID- 28711435 TI - Prevalence and comparative analysis of the type IV secretion system in Aggregatibacter actinomycetemcomitan. AB - BACKGROUD/PURPOSE: Aggregatibacter actinomycetemcomitans has emerged as one of the aetiological agents in periodontal disease. Although Type IV secretion systems (T4SSs) are widely distributed in many bacteria, the genetic features and distribution of T4SSs in A. actinomycetemcomitans remain unclear. In this study, we investigated the prevalence of A. actinomycetemcomitans serotypes and their T4SSs in a Taiwanese population. METHODS: A comparative analysis of 20 A. actinomycetemcomitans genomes and their T4SSs deposited in GenBank was performed. One hundred subjects, including 20 periodontitis and 80 normal subjects, were enrolled and PCR identification of A. actinomycetemcomitans serotypes and T4SS genes were performed. RESULTS: Of 100 subjects, serotypes C (22%) and E (11%) were most common. In addition, T4SSs were distributed in all of the serotypes. The prevalence of T4SSs and their location in plasmids in periodontitis subjects were 1.28-2 fold higher but not significantly different compared to normal subjects. Of 20 A. actinomycetemcomitans genomes, only ten with complete T4SS modules could be detected, which was highly correlated with localized aggressive periodontitis (p < 0.1). Nine of ten T4SS modules were from periodontitis subjects. Phylogenetic analysis of 10 T4SSs in A. actinomycetemcomitans showed that they were clustered into two groups, T4SSAaI and T4SSAaII, with only T4SSAaI appearing in the Taiwanese subjects. CONCLUSION: A. actinomycetemcomitans strains with different serotypes carrying T4SSAaI are widely distributed in a Taiwanese population. This is the first report to show the distribution and detailed comparative genomics of T4SSs in A. actinomycetemcomitans. PMID- 28711436 TI - A simple method for rapid microbial identification from positive monomicrobial blood culture bottles through matrix-assisted laser desorption ionization time-of flight mass spectrometry. AB - BACKGROUND AND PURPOSE: Rapid identification of microbes in the bloodstream is crucial in managing septicemia because of its high disease severity, and direct identification from positive blood culture bottles through matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) can shorten the turnaround time. Therefore, we developed a simple method for rapid microbiological identification from positive blood cultures by using MALDI-TOF MS. METHODS: We modified previously developed methods to propose a faster, simpler and more economical method, which includes centrifugation and hemolysis. Specifically, our method comprises two-stage centrifugation with gravitational acceleration (g) at 600g and 3000g, followed by the addition of a lysis buffer and another 3000g centrifugation. RESULTS: In total, 324 monomicrobial bacterial cultures were identified. The success rate of species identification was 81.8%, which is comparable with other complex methods. The identification success rate was the highest for Gram-negative aerobes (85%), followed by Gram-positive aerobes (78.2%) and anaerobes (67%). The proposed method requires less than 10 min, costs less than US$0.2 per usage, and facilitates batch processing. CONCLUSION: We conclude that this method is feasible for clinical use in microbiology laboratories, and can serve as a reference for treatments or further complementary diagnostic testing. PMID- 28711437 TI - Intestinal parasitic infections: Current status and associated risk factors among school aged children in an archetypal African urban slum in Nigeria. AB - BACKGROUND/PURPOSE: Intestinal parasitic infections (IPIs) among school aged children (SAC) in Nigeria remains endemic, hence the need for regular surveillance to attract the attention of policy makers. This cross-sectional study investigated the current prevalence and factors associated with intestinal parasitic infections among school aged children in an urban slum of Lagos City, Nigeria. METHODS: Single stool samples from 384 school aged children (188 boys and 196 girls) were examined by employing Merthiolate-iodine-formaldehyde concentration (MIFC) and Kato-Katz methods. Demographic characteristics and risk factors were obtained by questionnaires investigation. RESULTS: The overall prevalence was 86.2% in school children, out of them 39.1% had polyparasitism. IPIs showed the highest to the lowest prevalence of 62% (238/384), 25% (97/384), 12.3% (47/384), 11.8% (45/384), 9.9% (38/384), 8.4% (32/384), 3.4% (13/384), and 0.5% (2/384) found in Ascaris lumbricoides, Entamoeba histolytica/dispar, Giardia duodenalis, Endolimax nana, Entamoeba coli, Trichuris trichiura, Blastocystis hominis, and hookworm infections, respectively. MIFC technique showed superiority to Kato-Katz technique in the detection of IPIs (p < 0.0001). Drinking untreated water was a significant risk factor for these school aged children in acquiring protozoan infections after multivariate adjustment (OR = 1.86, 95% CI = 1.08 3.20, p = 0.02). CONCLUSION: Intestinal parasitic infections are very severe among school aged children in the urban slums, thus regular mass de-worming programs, health education, and the provision of safe drinking water is recommended to combat IPIs among the school aged children. PMID- 28711438 TI - Citrobacter freundii bacteremia: Risk factors of mortality and prevalence of resistance genes. AB - BACKGROUND/PURPOSE: Multidrug-resistant strains of Citrobacter have emerged, which carry Amp-C beta-lactamase (Amp-C), broad-spectrum beta-lactamase, extended spectrum beta-lactamase (ESBL), and other resistance mechanisms. These strains are associated with a higher rate of in-hospital mortality. The object of this study is to determine the mortality risk factors, susceptibility pattern to antibiotics, and prevalence of resistance genes in patients with Citrobacter freundii bacteremia. METHODS: From January 2009 to December 2014, blood isolates of C. freundii were collected in MacKay Memorial Hospital, Taipei, Taiwan. PCR technique and sequencing were performed for resistance genes. Pulsed-field gel electrophoresis (PFGE) was done using XbaI restriction enzyme. The clinical characteristics and risk factors for mortality are demonstrated. RESULTS: The 36 blood isolates of C. freundii belonged to 32 different PFGE pulsotypes, and 15 isolates (41.7%) were polymicrobial. The most common source of infection was intra-abdominal origin (61.1%), followed by unknown sources (22.2%), the urinary tract (8.3%), intravascular catheter (5.6%), and soft tissue (2.8%). High degree of antibiotic resistance was noted for cefazolin (100%), cefoxitin (97.2%), and cefuroxime (66.7%). The blaTEM-1 resistance gene was present in 16.7% isolates. 72.2% isolates carried blaAmpC and 5.6% isolates carried ESBL genes (blaSHV-12 or blaCTX-M-15). Multivariate analysis indicated that the independent risk factor for 28-day mortality was carrying the blaTEM-1 resistance gene. CONCLUSION: For patients with C. freundii bacteremia, carrying the blaTEM-1 resistance gene was an independent risk factor for 28-day mortality. Carbapenems, fourth-generation cephalosporins, amikacin, and quinolones are still reliable agents for drug resistant strains. PMID- 28711439 TI - Updates on k13 mutant alleles for artemisinin resistance in Plasmodium falciparum. AB - BACKGROUND: In the fight against malaria caused by Plasmodium falciparum, the successes achieved by artemisinin were endangered by resistance of the parasites to the drug. Whole genome sequencing approach on artemisinin resistant parasite line discovered k13 gene associated with drug resistance. In vitro and in vivo studies indicated mutations in the k13 gene were linked to the artemisinin resistance. METHODOLOGY: The literatures published after April, 2015 up to December, 2016 on k13 mutant alleles for artemisinin resistance in Plasmodium falciparum and relevant literatures were comprehensively reviewed. RESULTS: To date, 13 non-synonymous mutations of k13 gene have been observed to have slow parasite clearance. Worldwide mapping of k13 mutant alleles have shown mutants associated with artemisinin resistance were confined to southeast Asia and China and did not invade to African countries. Although in vitro ring stage survival assay of 0-3 h was a recently developed assay, it was useful for rapid detection of artemisinin resistance associated k13 allelic marker in the parasite. Recently, dissemination of k13 mutant alleles was recommended to be investigated by identity of haplotypes. Significant characteristics of well described alleles in the reports were mentioned in this review for the benefit of future studies. CONCLUSION: According to the updates in the review, it can be concluded artemisinin resistance does not disseminate to India and African countries within short period whereas regular tracking of these mutants is necessary. PMID- 28711440 TI - Prevalence of cervical colonization by Ureaplasma parvum, Ureaplasma urealyticum, Mycoplasma hominis and Mycoplasma genitalium in childbearing age women by a commercially available multiplex real-time PCR: An Italian observational multicentre study. AB - BACKGROUND: Mycoplasmas are frequently isolated from the genital tract. New molecular PCR-based methods for the detection of mycoplasmas can better define the real epidemiology of these microorganisms. The aim of this study was to evaluate the prevalence of mycoplasmas in a population of childbearing age women by means of PCR. METHODS: This 21-month multicentre observational study was conducted at four Italian clinical microbiology laboratories. Women reporting symptoms of vaginitis/cervicitis, or with history of infertility, pregnancy, miscarriage or preterm birth were included. Detection of Ureaplasma parvum, Ureaplasma urealyticum, Mycoplasma hominis, Mycoplasma genitalium was performed from cervical swabs by means of a commercially available multiplex real-time PCR. RESULTS: a total of 1761 women fulfilled the inclusion criteria and were included in the study. The overall prevalence was: U. parvum 38.3%, U. urealyticum 9%, M. hominis 8.6% and M. genitalium 0.6%. The proportion of foreign patients positive for U. parvum was significantly higher compared to Italian patients (37% vs 30.1%, p = 0.007) and also for overall mycoplasma colonization (53.4% vs 45.8%, p = 0.011). The number of symptomatic patients positive for M. hominis was significantly higher than that of negative controls (2.9% vs 1%, p = 0.036). A significant positive trend in mycoplasma colonization was found in relation to the pregnancy week for U. urealyticum (p = 0.015), M. hominis (p = 0.044) and for overall mycoplasma colonization (p = 0.002). CONCLUSION: multiplex RT-PCR can be a valuable tool to evaluate the real epidemiology of cervical mycoplasma colonization. PMID- 28711441 TI - Emergence of carbapenem-resistant Acinetobacter baumannii ST787 in clinical isolates from blood in a tertiary teaching hospital in Northern Taiwan. AB - BACKGROUND/PURPOSE: The purpose of this study is to investigate the predominant clones of carbapenem-resistant Acinetobacter baumannii (CRAB) in our hospital in Taiwan by pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST) technique. METHODS: We collected 108 non-duplicate A. baumannii clinical blood isolates from January 2012 to December 2013 in MacKay Memorial Hospital. PFGE and MLST were used for typing the A. baumannii isolates and for investigation of the predominant clones. Bacteria isolates were screened by polymerase chain reaction for the presence of the carbapenemase-encoding genes. RESULTS: All 108 isolates were classified as 33 pulsotypes by PFGE. The predominant clones were pulsotype 10 (12.04%) in 2012 and pulsotype 8 (16.67%) in 2013, respectively. The 31 predominant pulsotype isolates were typed by MLST, and ST787 (54.84%) and ST455 (45.16%) were identified. All isolates carried blaOXA-51 like genes, and blaOXA-23-like genes was founded in 101 isolates (93.52%). Other identified resistance genes included blaOXA-24-like and blaOXA-IMP. CONCLUSION: To the best of our knowledge, this study is the first to describe the microbiological characteristics of CRAB ST787, which carried high genetic resistance to carbapenem, but remained susceptible to colistin. CRAB ST787 was the predominant clone in our hospital in the study period. PMID- 28711442 TI - Association of EV71 3C polymorphisms with clinical severity. AB - OBJECTIVES: Enterovirus 71 (EV71) may cause neurological and fatal cases. EV71 3C plays an important role on viral replication and possess proteolysis activity. To delineate pathogenesis of EV71 virulence, we studied EV71 3C genetics, protease activity and correlated the results with clinical severity. METHODS: EV71 cases were collected; 3C of EV71 was sequenced and linked with clinical severity. 3C protease activity, viral replication rates of EV71 infectious clones with different 3C and 3C interaction with host proteins were analyzed. RESULTS: The polymorphisms of EV71 3C at the 79th amino acid were associated with clinical severity. About 26% (62/234) patients infected by EV71 with wild-type 3C (T79) had neurological involvement but 78% (25/32) patients infected by EV71 with mutant 3C (T79V) did (p < 0.001). There was no significant difference of protease activity among the different 3C variants. EV71 with mutant 3C (T79V) had the highest viral replication rate and the mutant 3C (T79V) had weaker interaction with TRIM21, a component of antibody-dependent intracellular neutralization, than the other mutants (T79I and T79A). CONCLUSION: We found that 3C polymorphisms were associated with clinical severity and viral replication, which might be related to 3C interaction with important host proteins such as TRIM21. PMID- 28711443 TI - Regional Distribution of Pulmonary Blood Volume with Dual-Energy Computed Tomography: Results in 42 Subjects. AB - RATIONALE AND OBJECTIVES: The noninvasive approach of lung perfusion generated from dual-energy computed tomography acquisitions has entered clinical practice. The purpose of this study was to analyze the regional distribution of iodine within distal portions of the pulmonary arterial bed on dual-source, dual-energy computed tomography examinations in a cohort of subjects without cardiopulmonary pathologies. MATERIALS AND METHODS: The study population included 42 patients without cardiorespiratory disease, enabling quantitative and qualitative analysis of pulmonary blood volume after administration of a 40% contrast agent. Qualitative analysis was based on visual assessment. Quantitative analysis was obtained after semiautomatic division of each lung into 18 areas. RESULTS: The iodine concentration did not significantly differ between the right (R) and left (L) lungs (P = .49), with a mean attenuation of 41.35 Hounsfield units (HU) and 41.14 HU, respectively. Three regional gradients of attenuation were observed between: (a) lung bases and apices (P < .001), linked to the conditions of examination (mean Delta: 6.23 in the R lung; 5.96 in the L lung); (b) posterior and anterior parts of the lung (P < .001) due to gravity (mean Delta: 11.92 in the R lung ; 15.93 in the L lung); and (c) medullary and cortical lung zones (P < .001) (mean Delta: 9.35 in the R lung ; 8.37 in the L lung). The intensity of dependent-nondependent (r = 0.42; P < .001) and corticomedullary (r = 0.58; P < .0001) gradients was correlated to the overall iodine concentration. CONCLUSION: Distribution of pulmonary blood volume is influenced by physiological gradients and scanning conditions. PMID- 28711445 TI - The Fastest Way to the Failing Heart Is Through the Kidneys. PMID- 28711444 TI - Mitochondrial membrane potential. AB - The mitochondrial membrane potential (DeltaPsim) generated by proton pumps (Complexes I, III and IV) is an essential component in the process of energy storage during oxidative phosphorylation. Together with the proton gradient (DeltapH), DeltaPsim forms the transmembrane potential of hydrogen ions which is harnessed to make ATP. The levels of DeltaPsim and ATP in the cell are kept relatively stable although there are limited fluctuations of both these factors that can occur reflecting normal physiological activity. However, sustained changes in both factors may be deleterious. A long-lasting drop or rise of DeltaPsim vs normal levels may induce unwanted loss of cell viability and be a cause of various pathologies. Among other factors, DeltaPsim plays a key role in mitochondrial homeostasis through selective elimination of dysfunctional mitochondria. It is also a driving force for transport of ions (other than H+) and proteins which are necessary for healthy mitochondrial functioning. We propose additional potential mechanisms for which DeltaPsim is essential for maintenance of cellular health and viability and provide recommendations how to accurately measure DeltaPsim in a cell and discuss potential sources of artifacts. PMID- 28711446 TI - Clinical Effectiveness of Hydralazine-Isosorbide Dinitrate in African-American Patients With Heart Failure. AB - OBJECTIVES: This study sought to evaluate the effectiveness of hydralazine isosorbide dinitrate (H-ISDN) in African Americans with heart failure (HF) with reduced ejection fraction (HFrEF). BACKGROUND: Among African-American patients with HFrEF, H-ISDN was found to improve quality of life and lower HF-related hospitalization and mortality rates in the A-HEFT (African-American Heart Failure Trial). Few studies have evaluated the effectiveness of this therapy in clinical practice. METHODS: Veterans Affairs patients with a hospital admission for HF between 2007 and 2013 were screened. Inclusion criteria included African-American race, left ventricular ejection fraction <40%, and receipt of Veterans Affairs medications. Exclusions were documented contraindications to H-ISDN, creatinine >2.0 mg/dl, or intolerance to angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Adjusted hazard ratios were calculated for patients who received H-ISDN 6-months before admission compared with patients who did not receive H-ISDN, by using inverse probability weighting of propensity scores and a time to death analysis for 18 months of follow-up. Propensity scores were generated using patients' characteristics, left ventricular ejection fraction, laboratory values, and hospital characteristics. RESULTS: The final cohort included 5,168 African-American patients with HF (mean age 65.2 years), with 15.2% treated with H-ISDN before index admission. After 18 months, there were 1,275 reported deaths (24.7%). The adjusted mortality rate at 18 months was 22.1% for patients receiving H-ISDN treatment and 25.2% for untreated patients (p = 0.009); adjusted hazard ratio: 0.85 (95% confidence interval: 0.73 to 1.00; p = 0.057). CONCLUSIONS: H-ISDN remains underused in African-American patients with HFrEF. In this cohort, the study found that H-ISDN use was associated with lower mortality rates in African-American patients with HFrEF when controlling for patient selection by using an inverse probability weighting of propensity scores. PMID- 28711448 TI - The Paradox in Demonstrating Hydralazine-Nitrate Efficacy. PMID- 28711447 TI - The Transition From Hypertension to Heart Failure: Contemporary Update. AB - Longstanding hypertension ultimately leads to heart failure (HF), and, as a consequence most patients with HF have a history of hypertension. Conversely, absence of hypertension in middle age is associated with lower risks for incident HF across the remaining life course. Cardiac remodeling to a predominant pressure overload consists of diastolic dysfunction and concentric left ventricular (LV) hypertrophy. When pressure overload is sustained, diastolic dysfunction progresses, filling of the concentric remodeled LV decreases, and HF with preserved ejection fraction ensues. Diastolic dysfunction and HF with preserved ejection fraction are the most common cardiac complications of hypertension. The end stage of hypertensive heart disease results from pressure and volume overload and consists of dilated cardiomyopathy with both diastolic dysfunction and reduced ejection fraction. "Decapitated hypertension" is a term used to describe the decrease in blood pressure resulting from reduced pump function in HF. Progressive renal failure, another complication of longstanding hypertension, gives rise to the cardiorenal syndrome (HF and renal failure). The so-called Pickering syndrome, a clinical entity consisting of flash pulmonary edema and bilateral atheromatous renovascular disease, is a special form of the cardiorenal syndrome. Revascularization of renal arteries is the treatment of choice. Most antihypertensive drug classes when used as initial therapy decelerate the transition from hypertension to HF, although not all of them are equally efficacious. Low-dose, once-daily hydrochlorothiazide should be avoided, but long acting thiazide-like diuretics chlorthalidone and indapamide seem to have an edge over other antihypertensive drugs in preventing HF. PMID- 28711450 TI - Atrial Fibrillation in Heart Failure: A Common and Deadly Combination. PMID- 28711449 TI - Intrarenal Flow Alterations During Transition From Euvolemia to Intravascular Volume Expansion in Heart Failure Patients. AB - OBJECTIVES: The goal of this study was to assess: 1) the intrarenal flow in heart failure (HF) patients during the transition from euvolemia to intravascular volume overload; and 2) the relationship between intrarenal flow and diuretic efficiency. BACKGROUND: Intrarenal blood flow alterations may help to better understand impaired volume handling in HF. METHODS: Resistance index (RI) and venous impedance index (VII) were assessed in 6 healthy subjects, 40 euvolemic HF patients with reduced ejection fraction (HFrEF), and 10 HF patients with preserved ejection fraction (HFpEF). Assessments were performed by using Doppler ultrasonography at baseline, during 3 h of intravascular volume expansion with 1 l of hydroxyethyl starch 6%, and 1 h after the administration of a loop diuretic. Clinical parameters, echocardiography, and biochemistry were assessed. Urine output was collected after 3 and 24 h. RESULTS: In response to volume expansion, VII increased significantly in HFrEF patients (0.4 +/- 0.3 to 0.7 +/- 0.2; p < 0.001) and in HFpEF patients (0.4 +/- 0.3 to 0.7 +/- 0.2; p = 0.002) but not in healthy subjects (0.2 +/- 0.2 to 0.3 +/- 0.1; p = 0.622). This outcome was reversed after loop diuretic administration. In contrast, RI did not change significantly after volume expansion. Echocardiographic-estimated filling pressures did not change significantly. VII during volume expansion was significantly correlated with diuretic response in HF patients independent of baseline renal function (R2 = 0.35; p < 0.001). CONCLUSIONS: In HF patients, intravascular volume expansion resulted in significant blunting of venous flow before a significant increase in cardiac filling pressures could be demonstrated. The observed impaired renal venous flow is correlated with less diuretic efficiency. Intrarenal venous flow patterns may be of interest for evaluating renal congestion. PMID- 28711451 TI - Atrial Fibrillation in Heart Failure With Preserved, Mid-Range, and Reduced Ejection Fraction. AB - OBJECTIVES: The study sought to assess the independent risk factors for, consequences of, and outcomes with atrial fibrillation (AF) compared with sinus rhythm (SR) in heart failure (HF) with preserved ejection fraction (HFpEF) versus HF with mid-range ejection fraction (HFmrEF) versus HF with reduced ejection fraction (HFrEF). BACKGROUND: AF is common in HF, but most data are from HFrEF. The importance of AF in HFpEF and HFmrEF is less well known. METHODS: In patients from 2000 to 2012 in the SwedeHF (Swedish Heart Failure Registry) registry, enriched with patient-level data from national health care registries, the authors assessed prevalence of, associations with, and prognostic impact of AF in HFpEF versus HFmrEF versus HFrEF. RESULTS: Of 41,446 patients, 23% had HFpEF, 22% had HFmrEF, and 55% had HFrEF. The prevalence of AF was 65%, 60%, and 53% in HFpEF, HFmrEF, and HFrEF, respectively. Independent associations with AF were similar in HFpEF, HFmrEF, and HFrEF and included greater age, male, duration of HF, prior myocardial infarction, and prior stroke or transient ischemic attack (TIA). The adjusted hazard ratios for AF versus SR in HFpEF, HFmrEF, and HFrEF were the following: for death, 1.11 (95% confidence interval [CI]: 1.02 to 1.21), 1.22 (95% CI: 1.12 to 1.33), and 1.17 (95% CI: 1.11 to 1.23); for HF hospitalization or death, 1.17 (95% CI: 1.09 to 1.26), 1.29 (95% CI: 1.20 to 1.40), and 1.15 (95% CI: 1.10 to 1.20); and for stroke or TIA or death, 1.15 (95% CI: 1.07 to 1.25), 1.23 (95% CI: 1.13 to 1.34), and 1.19 (95% CI: 1.14 to 1.26). CONCLUSIONS: AF was progressively more common with increasing ejection fraction, but was associated with similar clinical characteristics in HFpEF, HFmrEF, and HFrEF. AF was associated with similarly increased risk of death, HF hospitalization, and stroke or TIA in all ejection fraction groups. In contrast, AF and SR populations were considerably different regarding associated patient characteristics and outcomes. PMID- 28711452 TI - Hematopoietic stem cell transplantation in Algeria. AB - INTRODUCTION: Algeria is a country of 40.4 million inhabitants and half of which is under 30years. In Algeria, Health-care insurance covered, 90% of the population. Health care is free and it is supported by the Ministry of Health. 16 university hospitals exist in Algeria and only two (Algiers and Oran) practicing bone marrow transplant. Adult hematologic malignancies account for 10% (about 4000 new cases/year) of the malignancy affecting in most cases young patients under 65years of age. In 2016, 270 transplants were performed in total (Algiers+Oran), including 149 allografts (related donor transplants: 99%) and 121 autografts. 98% of transplants are done in adults and only 2% in children with cord blood transplants. In summary for the two transplant centers, the predominant types of transplantation performed are allogeneic transplant in 55% and autologous transplant in 45%. The particularity of EHU1st November in Oran, is the use of non-cryopreserved stem cells. Stem cell was mobilized using G-CSF alone and the grafts were kept in a conventional blood bank refrigerator at +4 degrees C until reinfusion on day 0. The outcome with non-cryopreserved stem cells are the same as those with cryopreserved stem cells and we conclude that autologous transplant with non cryopreserved hematopoietic stem cells (HSC) is a simple, effective and safe method and the cryopreservation is not necessary in our work conditions in developing countries. The projects are achieving the autograft in all University Hospitals with non cryopreserved HSC, achieving a center allograft in the east of the country and the development of bone marrow transplantation in children. CONCLUSION: Currently in Algeria, the number of transplantation is insufficient and the development of new transplant centers is essential. In the future, we hope to implement the National Society of Bone Marrow transplant and also the National recipient registry and Donor registry in Algeria. PMID- 28711453 TI - A roadmap for evaluating the use and value of durable ventricular assist device therapy. AB - Heart failure is a disease characterized by profound human suffering with limitations in survival despite treatment with guideline-directed medical therapies. Patients with heart failure frequently progress to advanced stages and often require cardiac transplantation or implantation of left ventricular assist devices (LVADs) to extend survival and improve quality of life. As the number of suitable heart donors, number of experienced medical centers and patient comorbidities place restrictions on the feasibility of cardiac transplantation, implantation of LVADs has emerged as a more frequently applied treatment as either a bridge to transplantation or as permanent therapy. Considerable data have documented improvements in survival, functional status and quality of life offered by LVADs, however, few studies have focused on identifying: (1) determinants of LVAD use across medical centers, (2) the relationship between the determinants of LVAD use and value (defined as quality divided by cost), and (3) how determinants of LVAD use are influenced or impacted by vulnerable populations. We propose a conceptual model that integrates the main determinants of LVAD utilization, which include technology, insurance coverage, market-, provider- and patient-level factors. We propose this paradigm as a necessary prerequisite for understanding LVAD usage and value. This conceptual framework provides a broader view for future studies, which are needed to inform emerging healthcare policies that influence dissemination of this expensive but life prolonging medical therapy. PMID- 28711454 TI - Common Vocal Effects and Partial Glottal Vibration in Professional Nonclassical Singers. AB - OBJECTIVE: To multidimensionally investigate common vocal effects in experienced professional nonclassical singers, to examine their mechanism of production and reproducibility, to demonstrate the existence of partial glottal vibration, and to assess the potential of damage to the voice from nonclassical singing. STUDY DESIGN: Individual cohort study. METHODS: Ten male singers aged between 25 and 46 years (34 +/- 7 years [mean +/- SD]) with different stylistic backgrounds were recruited (five pop/rock/metal, five musical theater). Participants repeatedly presented the usual nonclassical vocal effects and techniques in their repertoire. All performances were documented and analyzed using established instruments (eg, auditory-perceptual assessment, videolaryngostroboscopy, electroglottography, voice function diagnostics). RESULTS: The vocal apparatus of all singers was healthy and capable of high performance. Typical nonclassical vocal effects were breathy voice, creaky voice, vocal fry, grunting, distortion, rattle, belt, and twang. All effects could be easily differentiated from each other. They were intraindividually consistently repeatable and also interindividually produced in a similar manner. A special feature in one singer was the first evidence of partial glottal vibration when belting in the high register. The unintended transition to this reduced voice quality was accompanied by physical fatigue and inflexible respiratory support. CONCLUSION: The long lasting use of the investigated nonclassical vocal effects had no negative impact on trained singers. The possibility of long-term damage depends on the individual constitution, specific use, duration, and extent of the hyperfunction. The incidence of partial glottal vibration and its consequences require continuing research to learn more about efficient and healthy vocal function in nonclassical singing. PMID- 28711455 TI - Recommendations for outpatient parenteral antimicrobial therapy in Brazil. AB - A panel of national experts was convened by the Brazilian Infectious Diseases Society in order to determine the recommendations for outpatient parenteral antimicrobial therapy (OPAT) in Brazil. The following aspects are covered in the document: organization of OPAT programs; patient evaluation and eligibility criteria, including clinical and sociocultural factors; diagnosis of eligibility; venous access and antimicrobial infusion devices; protocols for antimicrobial use and monitoring and cost-effectiveness. PMID- 28711456 TI - A cross-sectional study assessing the pharyngeal carriage of Neisseria meningitidis in subjects aged 1-24 years in the city of Embu das Artes, Sao Paulo, Brazil. AB - Meningococcal carriage is a prerequisite for invasive infection. This cross sectional study assessed the pharyngeal carriage prevalence in healthy subjects aged 1-24 years in Embu das Artes city, Sao Paulo, Brazil. Pharyngeal swabs were examined for the presence of Neisseria meningitidis. The isolates were tested for different serogroups using agglutination and polymerase chain reaction. A logistic regression model assessed any independent association between Neisseria meningitidis carriage and various risk factors. A total of 87/967 subjects (9%, 95% Confidence Interval (CI): 7.3-11.0) tested positive for N. meningitidis: 6.2% (95% CI: 3.8-9.4) in 1-4 years, 8.5% (95% CI: 5.1-13.0) in 5-9 years, 12.5% (95% CI: 7.8-18.6) in 10-14 years, 12.6% (95% CI: 7.4-19.7) in 15-19 years and 9% (95% CI: 4.9-14.9) in 20-24 years age groups. Highest carriage prevalence was observed in adolescents 10-19 years old. Serogroup C was predominant (18.4%) followed by serogroup B (12.6%). The 15-19 years age group showed a significant association between number of household members and carriers of N. meningitidis. This cross sectional study is the first in Brazil to evaluate meningococcal carriage prevalence and associated factors in a wide age range. PMID- 28711457 TI - Comparison of the finger-feeding versus cup feeding methods in the transition from gastric to oral feeding in preterm infants. AB - OBJECTIVES: To assess the finger-feeding technique when compared with the cup feeding method during the early stage of preterm infant feeding transition regarding milk loss, milk ingestion period, and complications. METHODS: Experimental, randomized, prospective study including 53 preterm infants with gestation age<37 weeks, clinically stable, and with a score of >28 points in the Oral Feeding Readiness Assessment Scale. The preterm babies were randomized to be included in the control group, which underwent the feeding transition using a cup or in the experimental group, which used the finger-feeding technique. The analysis of data was performed using Student's t-test to evaluate differences between mean values of the appointed variables, and Fischer's test for categorical variables; the asymmetric variables were assessed by the Kruskal Wallis ANOVA test. RESULTS: When compared with the control group, the experimental group showed lower milk loss, longer milk ingestion time, and a lower frequency of complications during feeding. The significance level was set at 5%, with a confidence interval of 90%. CONCLUSION: The finger-feeding technique was shown to be a better feeding transition method regarding efficacy when compared with cup feeding method, due to lower milk loss and fewer complication episodes. PMID- 28711460 TI - Synchronous parotid and nasopharyngeal Warthin's tumor: case report and literature review. PMID- 28711458 TI - The collaborative work of droplet assembly. AB - Three proteins have been implicated in the assembly of cytoplasmic lipid droplets: seipin, FIT2, and perilipin. This review examines the current theories of seipin function as well as the evidence for the involvement of all three proteins in droplet biogenesis, and ends with a proposal of how they collaborate to regulate the formation of droplets. This article is part of a Special Issue entitled: Recent Advances in Lipid Droplet Biology edited by Rosalind Coleman and Matthijs Hesselink. PMID- 28711459 TI - Influence of the bud neck on nuclear envelope fission in Saccharomyces cerevisiae. AB - Studies have shown that nuclear envelope fission (karyokinesis) in budding yeast depends on cytokinesis, but not distinguished whether this was a direct requirement, indirect, because of cell cycle arrest, or due to bud neck-localized proteins impacting both processes. To determine the requirements for karyokinesis, we examined mutants conditionally defective for bud emergence and/or nuclear migration. The common mutant phenotype was completion of the nuclear division cycle within the mother cell, but karyokinesis did not occur. In the cdc24 swe1 mutant, at the non-permissive temperature, multiple nuclei accumulated within the unbudded cell, with connected nuclear envelopes. Upon return to the permissive temperature, the cdc24 swe1 mutant initiated bud emergence, but only the nucleus spanning the neck underwent fission suggesting that the bud neck region is important for fission initiation. The neck may be critical for either mechanical reasons, as the contractile ring might facilitate fission, or for regulatory reasons, as the site of a protein network regulating nuclear envelope fission, mitotic exit, and cytokinesis. We also found that 77 85% of pairs of septin mutant nuclei completed nuclear envelope fission. In addition, 27% of myo1Delta mutant nuclei completed karyokinesis. These data suggested that fission is not dependent on mechanical contraction at the bud neck, but was instead controlled by regulatory proteins there. PMID- 28711461 TI - Prevalence of Comorbidities in Rheumatoid Arthritis and Evaluation of Their Monitoring in Clinical Practice: The Spanish Cohort of the COMORA Study. AB - OBJECTIVES: To describe the prevalence of comorbidities in patients with RA in Spain and discuss their management and implications using data from the Spanish cohort of the multinational study on COMOrbidities in Rheumatoid Arthritis (COMORA). METHODS: This is a national sub-analysis of the COMORA study. We studied the demographics and disease characteristics of 200 adults patients diagnosed with RA (1987 ACR), and routine practices for screening and preventing the following selected comorbidities: cardiovascular, infections, cancer, gastrointestinal, pulmonary, osteoporosis and depression. RESULTS: Patients had a mean age of 58 years and a mean RA duration of 10 years. Mean DAS28 score was 3.3 and approximately 25% of patients were in remission (DAS28 <2.6). Forty-four (22%) patients had >=1 comorbidity, the most frequent being depression (27%) and obesity (26%). A history of myocardial infarction or stroke was observed in 5% and 1% of patients, respectively, and any solid tumor in 6%. Having a Framingham Risk Score >20% (51%), hypercholesterolemia (46%) or hypertension (41%) and smoking (25%) were the most common CV risk factors. For prostate, colon and skin cancers, only 9%, 10% and 18% of patients, respectively, were optimally monitored. Infections were also inadequately managed, with 7% and 17% of patients vaccinated against influenza and pneumococcal, respectively, as was osteoporosis, with 47% of patients supplemented with vitamin D and 56% with a bone densitometry performed. CONCLUSIONS: In Spain, the prevalence of comorbidities and CV risk factors in RA patients with established and advanced disease is relatively high, and their management in clinical daily practice remains suboptimal. PMID- 28711462 TI - Genetic and evolutionary patterns of innate immune genes in the Pacific oyster Crassostrea gigas. AB - The invertebrate innate immune system functions in immune defence and the stress response. However, knowledge of the genetic and evolutionary patterns of innate immune genes in Mollusca is limited, especially for oysters. Such information would help clarify how oysters adapt to pathogen-rich environments. Here, we characterized the genetic and evolutionary patterns of the innate immune genes in Crassostrea gigas, using population diversity analysis and evolution rates comparison. Innate immune genes have higher median nucleotide diversity than non immune genes. Nucleotide diversity varied with functional regions and different immune-related gene families. Evolutionary analysis of two Crassostrea species showed that the innate immune genes are less conserved and have higher rates of evolution in C. gigas. We also noted a positive association between nucleotide diversity and selective pressures for genes having orthologues. Our findings will help determine the evolutionary patterns of innate immune genes and the association of these genes with mollusc immunity. PMID- 28711463 TI - Modulation of Atlantic salmon miRNome response to sea louse infestation. AB - MicroRNAs are non-coding RNA that plays a crucial role in post-transcriptional regulation and immune system regulation. On other hand, sea lice are prevalent parasites that affect salmon farming, generating different degrees of immune suppression depending on the salmon and sea louse species. Caligus rogercresseyi for example, which affects the salmon industry in Chile, decreases Th1 response, macrophage activation, TLR-mediated response and iron regulation in infected fish. In this study, we explore Atlantic salmon miRNome during infestation by C. rogercresseyi. Using small RNA sequencing, we annotated 1718 miRNAs for skin and head kidney from infected Atlantic salmon. The most abundant families identified were mir-10, mir-21, mir-30, mir-181 and let7. Significant differences were found between tissue, with 1404 annotated miRNA in head kidney and 529 in skin. Differential analysis of transcript expression indicated that at an early stage of infestation miRNA expression was higher in head kidney than in skin tissue, revealing tissue-specific expression patterns. In parallel, miRNA target prediction using 3'UTRs from highly regulated immune-related genes and iron metabolism showed that mir-140-4 and mir-181a-2-5 modulate the expression of TLR22 and Aminolevulinic acid synthase, respectively. This study contributes knowledge about the immune response of Atlantic salmon during infestation with sea lice. PMID- 28711464 TI - Personality and Survival in Older Age: The Role of Lifestyle Behaviors and Health Status. AB - OBJECTIVE: We intended to assess the relationship between personality and survival in an older population and to explore the role of lifestyle behaviors and health status as potential mediators. DESIGN: Population-based cohort study. SETTING: Swedish National Study of Aging and Care in Kungsholmen, Sweden. PARTICIPANTS: 2,298 adults aged 60 or more years, without dementia or depression, followed for 11 years. MEASUREMENTS: Personality (extraversion, neuroticism, and openness) was assessed with a shortened version of the NEO-Five Factor Inventory. We tested whether personality affected mortality and examined the potential mediating effect of health status (body mass index, number of chronic diseases, impairment in instrumental activities of daily living, and C-reactive protein) and lifestyle behaviors (leisure activities, social network, smoking, and alcohol consumption). RESULTS: Over 11 years of follow-up, higher levels of extraversion were associated with a 14% reduction in mortality. Examination of different combinations of personality traits showed that independent of levels of neuroticism and openness, high extraversion were associated with up to 65% lower mortality. Decomposing the effect of extraversion on mortality, we found that the majority (44%) of the beneficial effect was mediated by healthy lifestyle behaviors. Health status accounted for 5% of the association. CONCLUSIONS: Extroverted people, who are characterized by higher optimism and high self efficacy, are prone to healthier behaviors and better health, which may result in longer survival. These results highlight the importance of a healthy lifestyle in survival. PMID- 28711465 TI - Factors that predict consumer acceptance of enriched processed meats. AB - The study aimed to understand predictors of consumers' purchase intention towards processed meat based functional foods (i.e. enriched processed meat). A cross sectional survey was conducted with 486 processed meat consumers in spring 2016. Results showed that processed meats were perceived differently in healthiness, with sausage-type products perceived less healthy than cured meat products. Consumers were in general more uncertain than positive about enriched processed meat but differences existed in terms of the attitudes and purchase intention. Following regression analysis, consumers' purchase intention towards enriched processed meat was primarily driven by their attitudes towards the product concept. Perceived healthiness of existing products and eating frequency of processed meat were also positively associated with the purchase intention. Other factors such as general food choice motives, socio-demographic characteristics, consumer health and the consumption of functional foods and dietary supplements in general, were not significant predictors of the purchase intention for enriched processed meat. PMID- 28711466 TI - Comparative proteomics reveals recruitment patterns of some protein families in the venoms of Cnidaria. AB - Cnidarians are probably the oldest group of animals to be venomous, yet our current picture of cnidarian venom evolution is highly imbalanced due to limited taxon sampling. High-throughput tandem mass spectrometry was used to determine venom composition of the scyphozoan Chrysaora lactea and two cubozoans Tamoya haplonema and Chiropsalmus quadrumanus. Protein recruitment patterns were then compared against 5 other cnidarian venom proteomes taken from the literature. A total of 28 putative toxin protein families were identified, many for the first time in Cnidaria. Character mapping analysis revealed that 17 toxin protein families with predominantly cytolytic biological activities were likely recruited into the cnidarian venom proteome before the lineage split between Anthozoa and Medusozoa. Thereafter, venoms of Medusozoa and Anthozoa differed during subsequent divergence of cnidarian classes. Recruitment and loss of toxin protein families did not correlate with accepted phylogenetic patterns of Cnidaria. Selective pressures that drive toxin diversification independent of taxonomic positioning have yet to be identified in Cnidaria and now warrant experimental consideration. PMID- 28711467 TI - Retrospective study of jellyfish envenomation in emergency wards in Guadeloupe between 2010 and 2016: When to diagnose Irukandji syndrome? AB - BACKGROUND: In Guadeloupe (French West Indies), many marine envenomation cases by jellyfish are observed. Some of them might induce an Irukandji syndrome (IS). The aim of this study was to analyse the clinical features of IS from the envenomation cases in the two public hospitals in Guadeloupe, and to compare them to non-IS stings. METHODS: All jellyfish envenomation cases between the 1st of January 2010 and the 1st of September 2016, from the emergencies data-base, have been extracted. The primary endpoint was the existence of an IS defined by a jellyfish sting followed by one of the symptoms among: severe lumbosacral, thoracic or abdominal pain, muscle cramps of the four limbs, profuse sweating, anxiety, restlessness, nausea, or vomiting. RESULTS: Two hundred and eleven envenomation cases have been extracted, 45.0% of them happened between the 22nd and the 26th day of the lunar phase during a period from June to September. Ninety five patients had an IS. Three of them had Quincke's edema and one a cardiopulmonary failure. Other clinical signs have been associated with IS compared to other sting cases, including hypertension (51.6% vs 18.1%, p < 0.001), tremor (32.6% vs 14.7%, p = 0.0014), paresthesia (20.0% vs. 10.3%, p = 0.049), dyspnea (13.7% vs 3.4%, p = 0.006), and the pain evaluation by the visual analogue pain scale (7.5 +/- 2.6 and 6.0 +/- 2.6, p = 0.001). CONCLUSION: Jellyfish envenomation is frequently associated with IS in Guadeloupean emergency wards. The IS cases were probably due to the species Alatina alata, and their periodicity can be determined according to the cycle of the moon. If patients showed symptoms slightly less severe than those in Australian studies, a case of cardiac decompensation, the first out of the Pacific, was observed. Based on our results, new definition of IS and severe IS are proposed. PMID- 28711470 TI - Looking again at the Look AHEAD study. PMID- 28711468 TI - Effect of initiating use of an insulin pump in adults with type 1 diabetes using multiple daily insulin injections and continuous glucose monitoring (DIAMOND): a multicentre, randomised controlled trial. AB - BACKGROUND: The benefit of initiation of insulin pump therapy (continuous subcutaneous insulin infusion; CSII) in patients with type 1 diabetes using continuous glucose monitoring (CGM) has not been studied. We aimed to assess glycaemic outcomes when switching from multiple daily injections (MDI) to CSII in adults with type 1 diabetes using CGM. METHODS: In this multicentre, randomised controlled trial, 75 adults with type 1 diabetes in the CGM group of the DIAMOND trial were randomly assigned via the study website using a computer-generated sequence to continue MDI or switch to CSII, with continuation of CGM, for 28 weeks. The primary outcome was CGM-measured time in the glucose concentration range of 70-180 mg/dL (3.9-10.0 mmol/L). This study is registered with ClinicalTrials.gov, number NCT02282397. FINDINGS: Between April 14, 2015, and May 5, 2016, 37 participants were randomly assigned to the CGM plus CSII group and 38 participants were randomly assigned to the CGM plus MDI group. The study was completed by 36 (97%) of 37 participants in the CGM plus CSII group and 35 (92%) of 38 participants in the CGM plus MDI group. Mean CGM use was 6.7 days per week (SD 0.8) in the CGM plus CSII group and 6.9 days per week (0.3) in the CGM plus MDI group (p=0.86). No participants in the CGM plus CSII group who completed the trial discontinued CSII. Over the follow-up period, mean time in the glucose concentration range of 70-180 mg/dL (3.9-10.0 mmol/L) was 791 min per day (SD 157) in the CGM plus CSII group and 741 min per day (225) in the CGM plus MDI group (adjusted mean treatment group difference: 83 min, 95% CI 17-149; p=0.01). Participants in the CGM plus CSII group had a greater reduction in CGM-measured mean glucose (p=0.005) and hyperglycaemia (on four metrics: p=0.007 for >180 mg/dL [>10.0 mmol/L], p=0.02 for >250 mg/dL [>13.9 mmol/L], p=0.04 for >300 mg/dL [>16.6 mmol/L], and p=0.02 for the area under the curve for 180 mg/dL [10.0 mmol/L]), but also an increase in CGM-measured hypoglycaemia (p=0.0001 for <70 mg/dL [<3.9 mmol/L], p=0.0002 for <60 mg/dL [<3.3 mmol/L], p=0.0009 for <50 mg/dL [<2.8 mmol/L], p=0.0002 for the area over the curve for 70 mg/dL [3.9 mmol/L]). Mean HbA1c change from baseline to 28 weeks was 0.3% (SD 0.9; 3.3 mmol/mol [SD 9.8]) in the CGM plus CSII group and 0.1% (0.4; 1.1 mmol/mol [4.4]) in the CGM plus MDI group (p=0.32). Severe hypoglycaemia occurred in one participant in the CGM plus MDI group, and diabetic ketoacidosis and severe hyperglycaemia occurred in one participant each in the CGM plus CSII group. INTERPRETATION: Our findings show that glycaemic control measured by time in the glucose range of 70-180 mg/dL (3.9-10.0 mmol/L) is improved by initiation of CSII in adults with type 1 diabetes. However, biochemical hypoglycaemia also was increased in the study, which will be important to consider when incorporating these results into clinical practice. FUNDING: Dexcom. PMID- 28711471 TI - Sensor mightier than pump-the jury is still out. PMID- 28711469 TI - Targeting weight loss interventions to reduce cardiovascular complications of type 2 diabetes: a machine learning-based post-hoc analysis of heterogeneous treatment effects in the Look AHEAD trial. AB - BACKGROUND: The Action for Health in Diabetes (Look AHEAD) trial investigated whether long-term cardiovascular disease morbidity and mortality could be reduced through a weight loss intervention among people with type 2 diabetes. Despite finding no significant reduction in cardiovascular events on average, it is possible that some subpopulations might have derived benefit. In this post-hoc analysis, we test the hypothesis that the overall neutral average treatment effect in the trial masked important heterogeneous treatment effects (HTEs) from intensive weight loss interventions. METHODS: We used causal forest modelling, which identifies HTEs, using a random half of the trial data (the training set). We applied Cox proportional hazards models to test the potential HTEs on the remaining half of the data (the testing set). The analysis was deemed exempt from review by the Columbia University Institutional Review Board, Protocol ID# AAAO3003. FINDINGS: Between Aug 22, 2001, and April 30, 2004, 5145 patients with type 2 diabetes were enrolled in the Look AHEAD randomised controlled trial, of whom 4901 were included in the The National Institute of Diabetes and Digestive and Kidney Diseases Repository and included in our analyses: 2450 for model development and 2451 in the testing dataset. Baseline HbA1c and self-reported general health distinguished participants who differentially benefited from the intervention. Cox models for the primary composite cardiovascular outcome revealed a number needed to treat of 28.9 to prevent 1 event over 9.6 years among participants with HbA1c 6.8% or higher, or both HbA1c less than 6.8% and Short Form Health Survey (SF-36) general health score of 48 or more (2101 [86%] of 2451 participants in the testing dataset; 167 [16%] of 1046 primary outcome events for intervention vs 205 [19%] of 1055 for control, absolute risk reduction of 3.46%, 95% CI 0.21-6.73%, p=0.038) By contrast, participants with HbA1c less than 6.8% and baseline SF-36 general health score of less than 48 (350 [14%] of 2451 participants in the testing data; 27 [16%] of 171 primary outcome events for intervention vs 15 [8%] of 179 primary outcome events for control) had an absolute risk increase of the primary outcome of 7.41% (0.60 to 14.22, p=0.003). INTERPRETATION: Look AHEAD participants with moderately or poorly controlled diabetes (HbA1c 6.8% or higher) and subjects with well controlled diabetes (HbA1c less than 6.8%) and good self-reported health (85% of the overall study population) averted cardiovascular events from a behavioural intervention aimed at weight loss. However, 15% of participants with well controlled diabetes and poor self-reported general health experienced negative effects that rendered the overall study outcome neutral. HbA1c and a short questionnaire on general health might identify people with type 2 diabetes likely to derive benefit from an intensive lifestyle intervention aimed at weight loss. FUNDING: None. PMID- 28711473 TI - Interaction of reelin and stress on immobility in the forced swim test but not dopamine-mediated locomotor hyperactivity or prepulse inhibition disruption: Relevance to psychotic and mood disorders. AB - RATIONALE: Psychotic disorders, such as schizophrenia, as well as some mood disorders, such as bipolar disorder, have been suggested to share common biological risk factors. One such factor is reelin, a large extracellular matrix glycoprotein that regulates neuronal migration during development as well as numerous activity-dependent processes in the adult brain. The current study sought to evaluate whether a history of stress exposure interacts with endogenous reelin levels to modify behavioural endophenotypes of relevance to psychotic and mood disorders. METHODS: Heterozygous Reeler Mice (HRM) and wildtype (WT) controls were treated with 50mg/L of corticosterone (CORT) in their drinking water from 6 to 9weeks of age, before undergoing behavioural testing in adulthood. We assessed methamphetamine-induced locomotor hyperactivity, prepulse inhibition (PPI) of acoustic startle, short-term spatial memory in the Y-maze, and depression-like behaviour in the Forced-Swim Test (FST). RESULTS: HRM genotype or CORT treatment did not affect methamphetamine-induced locomotor hyperactivity, a model of psychosis-like behaviour. At baseline, HRM showed decreased PPI at the commonly used 100msec interstimulus interval (ISI), but not at the 30msec ISI or following challenge with apomorphine. A history of CORT exposure potentiated immobility in the FST amongst HRM, but not WT mice. In the Y maze, chronic CORT treatment decreased novel arm preference amongst HRM, reflecting reduced short-term spatial memory. CONCLUSION: These data confirm a significant role of endogenous reelin levels on stress-related behaviour, supporting a possible role in both bipolar disorder and schizophrenia. However, an interaction of reelin deficiency with dopaminergic regulation of psychosis like behaviour remains unclear. PMID- 28711472 TI - Interactive effects of an N-methyl-d-aspartate receptor antagonist and a nicotinic acetylcholine receptor agonist on mismatch negativity: Implications for schizophrenia. AB - N-methyl-d-aspartate glutamate receptor (NMDAR) hypofunction has been implicated in the pathophysiology of schizophrenia, including auditory processing abnormalities reflected by the mismatch negativity (MMN) event-related potential component. Evidence suggesting cognitive benefits from nicotine administration, together with the high rate of cigarette use in patients with schizophrenia, has stimulated interest in whether nicotine modulates NMDAR hypofunction. We examined the interactive effects of ketamine, an NMDAR antagonist that produces transient schizophrenia-like neurophysiological effects, and nicotine, a nicotinic acetylcholine receptor (nAChR) agonist, in 30 healthy volunteers to determine whether nicotine prevents or attenuates MMN abnormalities. Secondary analyses compared the profile of ketamine and schizophrenia effects on MMN using previously reported data from 24 schizophrenia patients (Hay et al. 2015). Healthy volunteers completed four test days, during which they received ketamine/placebo and nicotine/placebo in a double-blind, counterbalanced design. MMN to intensity, frequency, duration, and frequency+duration double deviant sounds was assessed each day. Ketamine decreased intensity, frequency, and double deviant MMN amplitudes, whereas nicotine increased intensity and double deviant MMN amplitudes. A ketamine*nicotine interaction indicated, however, that nicotine failed to attenuate the decrease in MMN associated with ketamine. Although the present dose of ketamine produced smaller decrements in MMN than those associated with schizophrenia, the profile of effects across deviant types did not differ between ketamine and schizophrenia. Results suggest that while ketamine and schizophrenia produce similar profiles of MMN effects across deviant types, nicotinic agonists may have limited potential to improve these putative NMDAR hypofunction-mediated impairments in schizophrenia. PMID- 28711474 TI - Early trauma and clinical features of schizophrenia cases influenced by the BDNF Val66Met allele. PMID- 28711475 TI - The interaction between subclinical psychotic experiences, insomnia and objective measures of sleep. AB - Investigations into schizophrenia have revealed a high incidence of comorbidity with disturbed sleep and circadian timing. Acknowledging this comorbidity on a dimensional level, we tested prospectively whether subclinical psychotic symptoms are more prevalent in individuals with insomnia. An insomnia group (n=21) and controls (n=22) were recruited on their subjective sleep quality, recorded actigraphically for 3weeks and assessed for psychotic-like experiences with The Prodromal Questionnaire-16. Using multivariate Poisson regression analyses, we found that objective and subjective sleep measures interact to predict the highest risk for psychotic experiences. Objective measures of sleep and statistical modelling are rarely used in either clinical trials or practice for schizophrenia, yet this study highlights their value in these areas. PMID- 28711477 TI - The association between toxoplasma and the psychosis continuum in a general population setting. AB - Toxoplasma gondii infection is associated with increased risk for psychosis. However, the possible association between T. gondii and psychotic-like symptoms in the general adult population is unknown. We investigated whether T. gondii is associated with psychotic-like symptoms and psychosis diagnoses using data from Health 2000, a large cross-sectional health survey of the Finnish general population aged 30 and above. Seropositivity to toxoplasma was defined as a cutoff of 50IU/ml of IgG antibodies. Lifetime psychotic-like symptoms were identified with section G of the Composite International Diagnostic Interview, Munich version (M-CIDI). Symptoms were considered clinically relevant if they caused distress or help-seeking or there were at least three of them. Lifetime psychotic disorders were screened from the sample and were diagnosed with DSM-IV using SCID-I interview and information from medical records. All data were available for 5906 participants. We adjusted for variables related to T. gondii seropositivity (age, gender, education, region of residence, cat ownership, and C reactive protein measuring inflammation) in regression models. We found that T. gondii seropositivity was significantly associated with clinically relevant psychotic-like symptoms (OR 1.77, p=0.001) and with the number of psychotic-like symptoms (IRR=1.55, p=0.001). The association between toxoplasma and diagnosed psychotic disorders did not reach statistical significance (OR 1.45 for schizophrenia). In a large sample representing the whole Finnish adult population, we found that serological evidence of toxoplasma infection predicted psychotic-like symptoms, independent of demographic factors and levels of C reactive protein. Toxoplasma infection may be a risk factor for manifestation of psychotic-like symptoms. PMID- 28711476 TI - Treatment in early psychosis with N-acetyl-cysteine for 6months improves low level auditory processing: Pilot study. AB - Sensory impairments constitute core dysfunctions in schizophrenia. In the auditory modality, impaired mismatch negativity (MMN) has been observed in chronic schizophrenia and may reflect N-methyl-d-aspartate (NMDA) hypo-function, consistent with models of schizophrenia based on oxidative stress. Moreover, a recent study demonstrated deficits in the N100 component of the auditory evoked potential (AEP) in early psychosis patients. Previous work has shown that add-on administration of the glutathione precursor N-acetyl-cysteine (NAC) improves the MMN and clinical symptoms in chronic schizophrenia. To date, it remains unknown whether NAC also improves general low-level auditory processing and if its efficacy would extend to early-phase psychosis. We addressed these issues with a randomized, double-blind study of a small sample (N=15) of early psychosis (EP) patients and 18 healthy controls from whom AEPs were recorded during an active, auditory oddball task. Patients were recorded twice: once prior to NAC/placebo administration and once after six months of treatment. The N100 component was significantly smaller in patients before NAC administration versus controls. Critically, NAC administration improved this AEP deficit. Source estimations revealed increased activity in the left temporo-parietal lobe in patients after NAC administration. Overall, the data from this pilot study, which call for replication in a larger sample, indicate that NAC improves low-level auditory processing in early psychosis. PMID- 28711478 TI - Dosimetric comparison of peripheral NSCLC SBRT using Acuros XB and AAA calculation algorithms. AB - There is a concern for dose calculation in highly heterogenous environments such as the thorax region. This study compares the quality of treatment plans of peripheral non-small cell lung cancer (NSCLC) stereotactic body radiation therapy (SBRT) using 2 calculation algorithms, namely, Eclipse Anisotropic Analytical Algorithm (AAA) and Acuros External Beam (AXB), for 3-dimensional conformal radiation therapy (3DCRT) and volumetric-modulated arc therapy (VMAT). Four dimensional computed tomography (4DCT) data from 20 anonymized patients were studied using Varian Eclipse planning system, AXB, and AAA version 10.0.28. A 3DCRT plan and a VMAT plan were generated using AAA and AXB with constant plan parameters for each patient. The prescription and dose constraints were benchmarked against Radiation Therapy Oncology Group (RTOG) 0915 protocol. Planning parameters of the plan were compared statistically using Mann-Whitney U tests. Results showed that 3DCRT and VMAT plans have a lower target coverage up to 8% when calculated using AXB as compared with AAA. The conformity index (CI) for AXB plans was 4.7% lower than AAA plans, but was closer to unity, which indicated better target conformity. AXB produced plans with global maximum doses which were, on average, 2% hotter than AAA plans. Both 3DCRT and VMAT plans were able to achieve D95%. VMAT plans were shown to be more conformal (CI = 1.01) and were at least 3.2% and 1.5% lower in terms of PTV maximum and mean dose, respectively. There was no statistically significant difference for doses received by organs at risk (OARs) regardless of calculation algorithms and treatment techniques. In general, the difference in tissue modeling for AXB and AAA algorithm is responsible for the dose distribution between the AXB and the AAA algorithms. The AXB VMAT plans could be used to benefit patients receiving peripheral NSCLC SBRT. PMID- 28711479 TI - Identification of the suitable leaf margin for liver stereotactic body radiotherapy with flattening filter-free beams. AB - The purpose of this study is to identify the suitable leaf margin for liver stereotactic body radiotherapy (SBRT) with flattening filter-free (FFF) beams, as compared with that with flattening filter (FF) beams. SBRT treatment planning for 10 patients with liver cancer was performed using 10-MV FFF and FF beams obtained from a Varian TrueBeam (Varian Medical Systems, Palo Alto, CA) linear accelerator. Each plan was generated with the leaf margin to the planning target volume (PTV) ranging from -3 to 5 mm. The prescription dose at D95 (dose covering 95% of the volume) was 48 Gy in 4 fractions to the PTV. The following dosimetric parameters were evaluated quantitatively: homogeneity index (HI), conformity index (CI), gradient index (GI), the normal liver receiving a dose greater than or equal to 20 Gy (V20), and the mean normal liver dose. The HI for FFF and FF beams increased as the leaf margin decreased. The leaf margins that achieved the best CI and GI were 0.1 and -0.3 mm for FFF beams, and 0.1 and -0.9 mm for FF beams. The liver V20 and the mean liver dose reached their minimum values at leaf margins of -0.8 and 0.0 mm for FFF beams, and -0.8 and 0.0 mm for FF beams. The suitable leaf margin for SBRT planning did not differ significantly for FFF and FF beams. Our data showed that, for both FFF and FF beams, a leaf margin of 0 or 1 mm was optimal for liver SBRT planning in terms of both target coverage and normal tissue sparing. PMID- 28711480 TI - Commissioning of small field size radiosurgery cones in a 6-MV flattening filter free beam. AB - This study aimed to describe the commissioning of small field size radiosurgery cones in a 6-MV flattening filter free (FFF) beam and report our measured values. Four radiosurgery cones of diameters 5, 10, 12.5, and 15 mm supplied by Elekta Medical were commissioned in a 6-MV FFF beam from an Elekta Versa linear accelerator. The extraction of a reference signal for measuring small fields in scanning mode is challenging. A transmission chamber was attached to the lower part of the collimators and used for percentage depth dose (PDD) and profile measurements in scanning mode with a stereotactic diode. Tissue-maximum ratios (TMR) and output factors (OF) for all collimators were measured with a stereotactic diode (IBA). TMR and the OF for the largest collimator were also acquired on a polystyrene phantom with a microionization chamber of 0.016 cm3 volume (PTW Freiburg PinPoint 3D). Measured TMR with diode and PinPoint microionization chamber agreed very well with differences smaller than 1% for depths below 20 cm, except for the smaller collimator, for which differences were always smaller than 2%. Calculated TMR were significantly different (up to 7%) from measured TMR. OF measured with diode and chamber showed a difference of 3.5%. The use of a transmission chamber allowed the measurement of the small field dosimetric properties with a simple setup. The commissioning of radiosurgery cones in FFF beams has been performed with essentially the same procedures and recommended detectors used with flattened beams. Good agreement was found between TMR measurements acquired with the IBA stereotactic diode and the PinPoint 3D microionization chamber. The transmission chamber overcomes the problem of extracting a reference signal and is of great help for small-field commissioning. PMID- 28711481 TI - Simultaneous integrated boost (SIB) for treatment of gynecologic carcinoma: Intensity-modulated radiation therapy (IMRT) vs volumetric-modulated arc therapy (VMAT) radiotherapy. AB - The aim of this study was to quantitatively compare dosimetric criteria between intensity-modulated radiation therapy (IMRT) and volumetric-modulated arc therapy (VMAT) plans for patients undergoing radiation treatment of gynecologic carcinoma with a simultaneous integrated boost (SIB) technique. IMRT and VMAT plans were retrospectively analyzed for 20 patients. The elective volume was planned to receive 45 Gy in 25 fractions of 1.8 Gy, with the integrated boost volume (involved nodes) receiving 55 Gy simultaneously. The same dose constraints were employed during the optimization of both techniques. IMRT plans consisted of 9 to 11 fields at equally spaced gantry angles. VMAT plans consisted of 3 full arcs of 360 degrees . A large variety of dose metrics across planning target volume (PTV)45, PTV55, bladder, rectum, sigmoid, bowel, kidneys, and femoral heads were extracted per patient, per plan. Conformity and homogeneity indices were also calculated and compared for each target volume. The total number of monitor units as well as the integral dose was also compared between IMRT and VMAT. The Wilcoxon signed rank test was performed to evaluate any significant differences between parameters, with an applied Bonferroni correction to account for multiple testing (significance level, p < 0.0006). The results demonstrate the equivalence of the 2 planning techniques across all studied parameters, with the exception of the expected decrease in monitor units that VMAT is capable of achieving. The findings of this study suggest that IMRT and VMAT are both acceptable options for applying simultaneous integrated boost techniques for the treatment of gynecologic cancers. The technique of choice will be dependent on departmental resources and should be considered on a case-by-case basis. PMID- 28711482 TI - Is there an Association between beta-Cell Function and Cancer Risk? PMID- 28711485 TI - The effects of female "Thin Ideal" media on men's appearance schema, cognitive performance, and self-evaluations: A self-determination theory approach. AB - Research has primarily focused on the consequences of the female thin ideal on women and has largely ignored the effects on men. Two studies were designed to investigate the effects of a female thin ideal video on cognitive (Study 1: appearance schema, Study 2: visual-spatial processing) and self-evaluative measures in male viewers. Results revealed that the female thin ideal predicted men's increased appearance schema activation and poorer cognitive performance on a visual-spatial task. Constructs from self-determination theory (i.e., global autonomous and controlled motivation) were included to help explain for whom the video effects might be strongest or weakest. Findings demonstrated that a global autonomous motivation orientation played a protective role against the effects of the female thin ideal. Given that autonomous motivation was a significant moderator, SDT is an area worth exploring further to determine whether motivational strategies can benefit men who are susceptible to media body ideals. PMID- 28711483 TI - A Multistage Subunit Vaccine Effectively Protects Mice Against Primary Progressive Tuberculosis, Latency and Reactivation. AB - Adult tuberculosis (TB) is the main cause of TB epidemic and death. The infection results mainly by endogenous reactivation of latent TB infection and secondarily transmitted by exogenous infection. There is no vaccine for adult TB. To this end, we first chose antigens from a potential antigenic reservoir. The antigens strongly recognized T cells from latent and active TB infections that responded to antigens expressed by Mycobacterium tuberculosis cultured under different metabolic states. Fusions of single-stage polyprotein CTT3H, two-stage polyprotein A1D4, and multistage CMFO were constructed. C57BL/6 mice vaccinated with DMT adjuvant ed CMFO (CMFO-DMT) were protected more significantly than by CTT3H-DMT, and efficacy was similar to that of the only licensed vaccine, Bacillus Calmette-Guerin (BCG) and A1D4-DMT in the M. tuberculosis primary infection model. In the setting of BCG priming and latent TB infection, M. tuberculosis in the lung and spleen was eliminated more effectively in mice boosted with CMFO-DMT rather than with BCG, A1D4-DMT, or CTT3H-DMT. In particular, sterile immunity was only conferred by CMFO-DMT, which was associated with expedited homing of interferon-gamma+CD4+ TEM and interleukin-2+ TCM cells from the spleen to the infected lung. CMFO-DMT represents a promising candidate to prevent the occurrence of adult TB through both prophylactic and therapeutic methods, and warrants assessment in preclinical and clinical trials. PMID- 28711486 TI - Assessment of English-French differential item functioning of the Satisfaction with Appearance Scale (SWAP) in systemic sclerosis. AB - The Satisfaction with Appearance Scale (SWAP) has been used to assess body image distress among people with the rare and disfiguring disease systemic sclerosis (SSc); however, it has not been validated across different languages groups. The objective was to examine differential item functioning of the SWAP among 856 Canadian English- or French-speaking SSc patients. Confirmatory factor analysis was used to evaluate the SWAP two-factor structure (Dissatisfaction with Appearance and Social Discomfort). The Multiple-Indicator Multiple-Cause model was utilized to assess differential item functioning. Results revealed that the established two-factor model of the SWAP demonstrated relatively good fit. Statistically significant, but small-magnitude differential item functioning was found for three SWAP items based on language; however, the cumulative effect on SWAP scores was negligible. Findings provided empirical evidence that SWAP scores from Canadian English- and French-speaking patients can be compared and pooled without concern that measurement differences may substantially influence results. PMID- 28711487 TI - Aucubin promotes angiogenesis via estrogen receptor beta in a mouse model of hindlimb ischemia. AB - Aucubin (AU) is an iridoid glycoside that has been shown to display estrogenic properties and has various pharmacological effects. Herein, we described the angiogenic properties of AU. In the study, hindlimb ischemia was induced by ligation of femoral artery on the right leg of ovariectomized mice. AU treatment significantly accelerated perfusion recovery and reduced tissue injury in mice muscle. Quantification of CD31-positive vessels in hindlimb muscles provided evidences that AU promoted angiogenesis in peripheral ischemia. In addition, results from quantitative PCR and western blot suggested AU induced angiogenesis via vascular endothelial cell growth factor (VEGF)/Akt/endothelial nitric oxide synthase (eNOS) signaling pathway. More interestingly, AU's angiogenic effects could be completely abolished in estrogen receptor beta (ERbeta) knockout mice. In conclusion, the underlying mechanisms were elucidated that AU produced pro angiogenic effects through ERbeta-mediated VEGF signaling pathways. These results expand knowledge about the beneficial effects of AU in angiogenesis and blood flow recovery. It might provide insight into the ERbeta regulating neovascularisation in hindlimb ischemia and identify AU as a potent new compound used for the treatment of peripheral vascular disease. PMID- 28711488 TI - Immunomodulatory intervention with Gamma interferon in mice with sepsis. AB - AIMS: Sepsis-triggered immune paralysis including T-cell dysfunction increase susceptibility to infection. Gamma interferon (IFNg) exert beneficial effects in patients with sepsis. Herein, we speculated that IFNg may attenuate T-cell dysfunction induced by sepsis, although the mechanisms remain elusive. To test this hypothesis, we used a model based on cecal ligation and puncture (CLP) to induce sepsis in mice. MAIN METHODS: Male C57BL/6 mice were pretreated with recombinant human IFNg (0.01MUg/g of body weight) before CLP. The immunophenotyping of cell surface receptor expression, and regulatory T cells (CD4+CD25+Foxp3+) were quantified by flow cytometry. Immunohistochemical staining was performed to evaluate the loss of immune effector cells. Formation of IFNg and interleukin 4 (IL-4) in the spleen and plasma levels of TNF-alpha, IL-6, high mobility group box 1 (HMGB1) were determined using enzyme-linked immunosorbent assay. KEY FINDINGS: IFNg markedly inhibited the reduction in cytokine secretion from lipopolysaccharide (LPS)-stimulated splenocytes. IFNg-treated mices had significantly decreased percentages of programmed cell death 1 (PD-1) receptors, increased the percentages of positive costimulatory receptor CD28 on CD4 T cells expressing. IFNg markedly reduced T-cell apoptosis through upregulating the expression of Bcl-2. CLP-induced formation of regulatory T cells in the spleen was abolished in IFNg -treated mices. Moreover, IFNg treatment reduced plasma levels of TNF-alpha, IL-6, HMGB1. SIGNIFICANCE: IFNg can be a powerful regulator of immune function under sepsis conditions. Therefore, targeted immune enhancement with IFNg may be a valid therapeutic approach in sepsis. PMID- 28711489 TI - Time-course microarrays reveal early activation of the immune transcriptome in a choline-deficient mouse model of liver injury. AB - AIMS: Choline-deficient diet is extensively used as a model of nonalcoholic fatty liver disease (NAFLD). In this study, we explored genes in the liver for which the expression changed in response to the choline-deficient (CD) diet. MAIN METHODS: Male CD-1 mice were divided into two groups and fed a CD diet with or without 0.2% choline bitartrate for one or three weeks. Hepatic levels of choline metabolites were analyzed by using liquid chromatography mass spectrometry and hepatic gene expression profiles were examined by DNA microarray analysis. KEY FINDINGS: The CD diet lowered liver choline metabolites after one week and exacerbated fatty liver between one and three weeks. We identified >300 genes whose expression was significantly altered in the livers of mice after consumption of this CD diet for one week and showed that liver gene expression profiles could be classified into six distinct groups. This study showed that STAT1 and interferon-regulated genes was up-regulated after the CD diet consumption and that the Stat1 mRNA level was negatively correlated with liver phosphatidylcholine level. Stat1 mRNA expression was actually up-regulated in isolated hepatocytes from the mouse liver with the CD diet. SIGNIFICANCE: This study provides insight into the genomic effects of the CD diet through the Stat1 expression, which might be involved in NAFLD development. PMID- 28711490 TI - Long-Term Response to Sunitinib Treatment in Metastatic Renal Cell Carcinoma: A Pooled Analysis of Clinical Trials. AB - BACKGROUND: We characterized clinical outcomes of patients with metastatic renal cell carcinoma (mRCC) treated with sunitinib who were long-term responders (LTRs), defined as patients having progression-free survival (PFS) > 18 months. PATIENTS AND METHODS: A retrospective analysis of data from 5714 patients with mRCC treated with sunitinib in 8 phase II/III clinical trials and the expanded access program. Duration on-study and objective response rate (ORR) were compared between LTRs and patients with PFS <= 18 months ("others"). PFS and overall survival (OS) were summarized using Kaplan-Meier methodology. RESULTS: Overall, 898 (15.7%) patients achieved a long-term response and 4816 (84.3%) patients did not achieve long-term response. The median (range) duration on-study was 28.6 (16.8-70.7) months in LTRs and 5.5 (0-68.8) months in others. ORR was 51% in LTRs versus 14% in others (P < .0001). Median PFS in LTRs was 32.11 months and median OS was not reached. LTRs had higher percentage of early tumor shrinkage >= 10% at the first scan (67.1% vs. 51.2%; P = .0018) and greater median maximum on-study tumor shrinkage from baseline (-56.9 vs. -27.1; P < .0001) versus others. White race, Eastern Cooperative Oncology Group performance status 0, time from diagnosis to treatment >= 1 year, clear cell histology, no liver metastasis, lactate dehydrogenase <= 1.5 upper limit of normal (ULN), corrected calcium <= 10 mg/dL, hemoglobin greater than the lower limit of normal, platelets less than or equal to ULN, body mass index >= 25 kg/m2, and low neutrophil-to-lymphocyte ratio were associated with LTR. CONCLUSION: A subset of patients with mRCC treated with sunitinib achieved long-term response. LTRs had improved ORR, PFS, and OS. PMID- 28711491 TI - Copper chaperone ATOX1 regulates pluripotency factor OCT4 in preimplantation mouse embryos. AB - Despite of the importance of copper (Cu) during pregnancy, the roles of Cu binding proteins during early embryonic development are unknown. The Cu chaperone ATOX1 was recently suggested to have additional functions related to transcription and cancer. When we analyzed single-cell RNA transcript data from early mouse embryos, Atox1 transcript levels increased dramatically at the 8-cell stage and, at 16- and 32-cell embryo stages, matched those of Oct4 which expresses a transcription factor essential for pluripotency in the inner cell mass. To explore this, we probed Atox1 expression during the first week of development of mouse embryos. ATOX1 appeared ubiquitously expressed throughout the cells until compaction; in subsequent embryo stages, ATOX1 relocalized to cytoplasmic perinuclear domains in the inner cell mass. Silencing of Oct4 did not affect Atox1 expression, but silencing of Atox1 at the 2-cell stage strongly diminished Oct4 expression in 16-cell embryos. PMID- 28711492 TI - Species-specific real-time RT-PCR analysis of expression of stromal cell genes in a tumor xenotransplantation model in mice. AB - Human tumor xenografts in mice together with the species-specific analysis of expressed genes allow to study the molecular processes driving tumor growth and progression in vivo and help to develop and evaluate anticancer therapies. In the present work, we designed and validated species-specific real-time RT-PCR assays for discrimination and quantitation of expression of human and mouse transcripts in cancer and stromal cells including dipeptidyl peptidase (DPP) 4, DPP8, DPP9, fibroblast activation protein (FAP) and CXC chemokine receptor 4 in mixed human mouse biological samples. Using single species RNA samples and mixed human-mouse RNA samples, we formulated and characterized two-step real-time RT-PCR assays to quantitate expression of the indicated transcripts and described analytical performance of the assays. We also demonstrated the applicability of these assays for species-specific quantitation of transcriptional expression of mouse stromal cell genes including Dpp4, Dpp8, Dpp9, Fap and Cxcr4 in mixed human-mouse RNA samples from human glioma cell-derived tumor xenografts growing in mouse brain. PMID- 28711493 TI - Anti-cancer effect of oncolytic adenovirus-armed shRNA targeting MYCN gene on doxorubicin-resistant neuroblastoma cells. AB - Chemotherapy is one of the few effective choices for patients with neuroblastoma. However, the development of muti-drug resistance (MDR) to chemotherapy is a major obstacle to the effective treatment of advanced or recurrent neuroblastoma. The muti-drug resistance-associated protein (MRP), which encodes a transmembrane glycoprotein, is a key regulator of MDR. The expression of MRP is a close correlation with MYCN oncogene in neuroblastoma. We have recently shown ZD55 shMYCN (oncolytic virus armed with shRNA against MYCN) can down-regulate MYCN to inhibit tumor cells proliferation and induce apoptosis in neuroblastoma. Here we further report ZD55-shMYCN re-sensitized doxorubicin-resistant cells to doxorubicin (as shown by reduced proliferation, increased apoptosis, and inhibited cell migration), and reduced the in vivo growth rate of neuroblastoma xenografts by down-regulation of MRP expression. Sequential therapy with doxorubicin did not affect the replication of ZD55-shMYCN in doxorubicin resistant neuroblastoma cells, but decreased the expression of Bcl-2, Bcl-XL, MMP 1. Thus, this synergistic effect of ZD55-shMYCN in combination with doxorubicin provides a novel therapy strategy for doxorubicin-resistant neuroblastoma, and is a promising approach for further clinical development. PMID- 28711494 TI - Development of membrane ion channels during neural differentiation from human embryonic stem cells. AB - OBJECTIVE: For human embryonic stem cells (hESCs) to differentiate into neurons, enormous changes has to occur leading to trigger action potential and neurotransmitter release. We attempt to determine the changes in expression of voltage gated channels (VGCs) and their electrophysiological properties during neural differentiation. MATERIALS AND METHODS: The relative expressions of alpha subunit of voltage gated potassium, sodium and calcium channels were characterized by qRT-PCR technique. Patch clamp recording was performed to characterize the electrophysiological properties of hESCs during their differentiation into neuron-like cells. RESULTS: Relative expression of alpha subunit of channels changed significantly. 4-AP and TEA sensitive outward currents were observed in all stages, although TEA sensitive currents were recorded once in rosette structure. Nifedipine and QX314 sensitive inward currents were recorded only in neuron-like cells. CONCLUSION: K+ currents were recorded in hESCs and rosette structure cells. Inward currents, sensitive to Nifedipine and QX314, were recorded in neuron-like cells. PMID- 28711495 TI - Evidence for constitutive bone morphogenetic protein-2 secretion by M1 macrophages: Constitutive auto/paracrine osteogenic signaling by BMP-2 in M1 macrophages. AB - Mechanisms mediating vascular calcification recapitulate osteogenic processes encompassing bone formation and imply participation of bone related proteins such as bone morphogenetic protein-2 (BMP-2). Macrophages are amongst the cells that contribute to vascular ossification by releasing cytokines that induce an osteogenic program in vascular smooth muscle cells, and also by becoming themselves osteoclast-like cells. In inflammatory vascular disease, the macrophage population in the vascular wall is diverse, with the M1 or inflammatory, and the M2 or anti-inflammatory macrophage types being dominant. Yet, the osteogenic potential of M1 and M2 macrophages remains unknown. Prompted by recent studies from our laboratory showing that in macrophages the Transient Receptor Potential Canonical 3 (TRPC3) channel contributes to endoplasmic reticulum (ER) stress-induced apoptosis in M1, but not in M2 macrophages, and given the strong relationship between ER stress and vascular calcification, we wished to examine whether TRPC3 would play a role in the osteogenic signaling of polarized macrophages. The findings reported here indicate that a constitutive BMP-2-dependent signaling operates in M1 macrophages, which is not affected by deletion of Trpc3 and is not subject to regulation by ER stress. Our studies suggest operation of an auto/paracrine mechanism by which BMP-2 secreted by M1 macrophages maintains constitutive activation of a BMP-2 receptor/SMAD1/5 signaling axis. PMID- 28711496 TI - Metabolomic profiling reveals potential biomarkers in esophageal cancer progression using liquid chromatography-mass spectrometry platform. AB - Esophageal cancer (EC) is one of the most common malignancies with poor prognosis. Metabolomics has been shown to be a powerful approach to discover the potential biomarkers for cancer diagnosis and prognosis. The goal of this study is to screen potential biomarkers for early diagnosis and prognosis. In this study, 40 tissue samples and the corresponding control samples from the same esophageal squamous cell carcinoma (ESCC) patients were analyzed by liquid chromatography-mass spectrometry (LC-MS)-based metabolomics. 20 potential diagnostic biomarkers were selected. Moreover, 9 metabolites were found to be closely correlated with the pathological feature such as local invasion, lymphatic metastasis and postoperative survival time. Glutamate was correlated with local invasion of tumor, and oleic acid, LysoPC(15:0), uracil, inosine and choline were closely related with the lymphatic metastasis, while glutamine, kynurenine, serine and uracil were related with postoperative survival time. The results indicated that the potential biomarkers discovered by metabolomics could reflect the metabolic characterization of ESCC, and offers a novel approach for early diagnosis, assessment and prognosis of the disease. PMID- 28711497 TI - Theaflavins from black tea affect growth, development, and motility in Dictyostelium discoideum. AB - Theaflavins, flavonoids found in black tea, exhibit a variety of health-promoting activities, but the mechanisms by which they act are not clear. Here, we assess the effects of black tea extract and isolated theaflavins on Dictyostelium discoideum, a model organism exhibiting an unusual life cycle relying on conserved pathways involved in human disease. Dictyostelium has been used to characterize the activities of numerous bioactive small molecules, including catechins, from which theaflavins are produced during the preparation of black tea. We show that theaflavins block growth, development, and motility in Dictyostelium, results that suggest catechins and theaflavins exert similar activities in this organism. PMID- 28711498 TI - Promotion of hair growth by newly synthesized ceramide mimetic compound. AB - Based on the crucial roles of ceramides in skin barrier function, use of ceramides or their structural mimetic compounds, pseudoceramides, as cosmetic ingredients are getting more popular. While currently used pseudoceramides are intended to substitute the structural roles of ceramides in stratum corneum, development of bioactive pseudoceramides has been repeatedly reported. In this study, based on the potential involvement of sphingolipids in hair cycle regulation, we investigated the effects of newly synthesized pseudoceramide, bis oleamido isopropyl alcohol (BOI), on hair growth using cultured human hair follicles and animal models. BOI treatment promoted hair growth in cultured human hair follicles ex vivo and induced earlier conversion of telogen into anagen. Although we did not find a significant enhancement of growth factor expression and follicular cell proliferation, BOI treatment resulted in an increased sphinganine and sphingosine contents as well as increased ceramides contents in cultured dermal papilla (DP) cells. Taken together, our data strongly suggest that biologically active pseudoceramide promotes hair growth by stimulating do novo synthesis of sphingolipids in DP cells. PMID- 28711499 TI - Inhibition of IL-6/STAT3 signaling in human cancer cells using Evista. AB - Persistent activation of IL-6/STAT3 signaling pathway has been frequently detected in human cancer including breast cancer, colon cancer and multiple myeloma. IL-6/STAT3 can be a promising target for cancer prevent and treatment. However, few STAT3 inhibitors with high efficiency, specificity and safety is available for present clinical cancer therapy. Evista (Raloxifene.HCl) is known as selective estrogen receptor modulator which has been used for the prevention and treatment of osteoporosis and was approved for reducing the risk of invasive breast cancer. Our previous study found that Raloxifene inhibited IL-6/GP130 interaction, resulting in blockade of STAT3 phosphorylation. In our present study, we examined the effect on IL-6/GP130/STAT3 signaling pathway and cancer cell viability with Evista. We first demonstrated Evista inhibited constitutive activation of STAT3 in breast cancer cell line MDB-MB-231, colon cancer cell line HCT116 and multiple myeloma cancer cell line U266. Evista also inhibited phosphorylation of STAT3 induced by IL-6 in MCF-7, HT29 and MM.1S cancer cell lines. Induction of apoptosis was exerted in MDA-MB-231, HCT116 and U266 as evidenced by increased caspase-3 cleavage. However, Evista did not inhibit STAT1, STAT2, STAT4 or STAT6 phosphorylation elicited by IFN-alpha, IFN-gamma and IL-4, nor phosphorylation of STAT3 induced by LIF in MCF-7 cell lines. Evista attenuated STAT3 phosphorylation, decreased STAT3 transcriptional activity but much less in pGL3 and AP1 transcriptional luciferase activity, and decreased cell viability in vitro. These results suggest that it may be possible for Evista to emerge as a chemoprevention agent for breast cancer and other cancers such as colon cancer or multiple myeoloma by targeting IL-6/STAT3 signaling. PMID- 28711500 TI - AtVps11 is essential for vacuole biogenesis in embryo and participates in pollen tube growth in Arabidopsis. AB - Vacuoles are multiple functional and essential organelles in plants. Studies in Saccharomyces cerevisiae had identified a tethering factor HOPS (Homotypic Fusion and Vacuolar Protein Sorting) complex that plays a critical role in vacuole biogenesis. The HOPS complex consists of four core subunits (Vps11, Vps16, Vps18 and Vps33) and two special subunits (Vps39 and Vps41). All these subunits were found in Arabidopsis, and our knowledge of the function of Arabidopsis HOPS complex are still limited. In this study, we investigated the function of AtVps11 gene in Arabidopsis, we found that vps11/- lead to embryo lethal, vacuole biogenesis in embryo was impaired. Furthermore, pollen tube growth was arrested by vps11 mutation, however, no obvious vacuole biogenesis defects were found in vps11 pollen tube. Our study indicated that in Arabidopsis, Vps11 is required for vacuole biogenesis in embryo, which is essential for embryogenesis. It also plays a role in pollen tube growth but looks not required for vacuole biogenesis in pollen tube. PMID- 28711501 TI - Comparing the androgenic and estrogenic properties of progestins used in contraception and hormone therapy. AB - Progestins used in endocrine therapies bind to multiple steroid receptors and are associated with several side-effects. It is thus important to understand the relationship between steroid receptor cross-reactivity and the side-effect profile of progestins. In cell lines that express negligible levels of steroid receptors, we report for the first time the binding affinities, potencies and efficacies of selected progestins from different generations determined in parallel. We show that the progestins bind to the androgen receptor (AR) with similar affinities to each other and progesterone, while none bind estrogen receptor (ER)-beta, and only norethisterone acetate, levonorgestrel and gestodene bind ERalpha. Comparative dose-response analysis revealed that progestins from the first three generations display similar androgenic activity to the natural androgen dihydrotestosterone for transactivation, while norethisterone acetate, levonorgestrel and gestodene are ERalpha agonists. We show for the first time that the anti-androgenic properties of progesterone and drospirenone are similar to the well-known AR antagonist hydroxyflutamide, while nomegestrol acetate is more potent and nestorone less potent than both hydroxyflutamide and progesterone. Moreover, we are the first to report that the older progestins, unlike progesterone and the fourth generation progestins, are efficacious ERalpha agonists for transrepression, while the selected progestins from the second and third generation are efficacious AR agonists for transrepression. Considering the progestin potencies and their reported free serum concentrations relative to dihydrotestosterone and estradiol, our results suggest that the progestins are likely to exert AR-, but not ERalpha- or ERbeta-mediated effects in vivo. PMID- 28711502 TI - A small molecule activator of SIRT3 promotes deacetylation and activation of manganese superoxide dismutase. AB - The modulation of protein acetylation network is a promising strategy for life span extension and disease treatment (Sabari et al., 2016; Giblin et al., 2014) [1,2]. A variety of small molecules have been developed to target deacetylases, but extremely few of these molecules are capable of activating the mitochondrial NAD-dependent deacetylase sirtuin-3 (SIRT3) (Gertz and Steegborn, 2016; Scholz et al., 2015) [3,4]. Manganese superoxide dismutase (MnSOD) is the major superoxide scavenger in mitochondria, whose activity is regulated by SIRT3-mediated deacetylation, particularly at the Lys68 site (Chen et al., 2011) [5]. To investigate the influence of Lys68 acetylation on MnSOD activity, we produced a mutant MnSOD protein-bearing N-acetyllysine (AcK) at its Lys68 position through the genetic code expansion approach. We solved the crystal structure of this acetylated MnSOD (MnSODK68AcK), thus revealing the structural and electrostatic basis for the significant activity decrease upon Lys68 acetylation. On the basis of an assay we developed for the SIRT3-mediated deacetylation of MnSODK68AcK, we identified a novel SIRT3 activator, 7-hydroxy-3-(4'-methoxyphenyl) coumarin (C12), which binds to SIRT3 with high affinity and can promote the deacetylation and activation of MnSOD. C12 adds to the current repertoire of extremely few SIRT3 activators, which are potentially valuable for treating a wide array of diseases via modulating the cellular acetylome. PMID- 28711503 TI - Leigh-like syndrome due to OPA1 mutations. PMID- 28711504 TI - Challenges to teaming for pain in primary care. PMID- 28711505 TI - Practice-based research networks add value to evidence-based quality improvement. AB - Background: Evidence-Based Quality Improvement (EBQI) is a systematic, multilevel approach to implementing research evidence into clinical settings. Little is known about EBQI effectiveness in the context of Practice-Based Research Networks (PBRNs), which are themselves designed to foster practice-based change. We evaluated EBQI implementation in a PBRN setting to determine the extent to which the PBRN infrastructure added value. METHODS: We conducted a four-site cluster randomized trial of an EBQI approach to tailoring an evidence-based gender awareness curriculum in the VA Women's Health PBRN (WH-PBRN). After curriculum implementation, site teams identified impacts of the WH-PBRN context on EBQI processes using qualitative methods, including a formal review of project call minutes, post-project debriefing calls, and structured site team input. WH-PBRN site feedback was mapped to the Replicating Effective Programs implementation phases: pre-condition, pre-implementation, implementation, and maintenance/evolution. RESULTS: The pre-condition phase benefited from the existing WH-PBRN research-clinician relationships to facilitate stakeholder engagement and build project buy-in at local sites. During pre-implementation, differences across WH-PBRN sites offered variations in local tailoring of EBQI elements. The WH-PBRN Coordinating Center helped resolve process complexities stemming from local resource differences and the sharing of mid-project adaptations during implementation. Local efforts were amplified in the maintenance phase by WH-PBRN dissemination of findings. Conclusions: The PBRN strengthened multi-site EBQI activities across all implementation phases. Implications: PBRNs contribute to the uptake of evidence into everyday practice, and may serve as an important component of the future implementation of evidence based initiatives. Level of evidence: V. PMID- 28711506 TI - Sodium selenate activated Wnt/beta-catenin signaling and repressed amyloid-beta formation in a triple transgenic mouse model of Alzheimer's disease. AB - Accumulating evidences show that selenium dietary intake is inversely associated with the mortality of Alzheimer's disease (AD). Sodium selenate has been reported to reduce neurofibrillary tangles (NFT) in the tauopathic mouse models, but its effects on the Wnt/beta-catenin signaling pathway and APP processing remain unknown during AD formation. In this paper, triple transgenic AD mice (3*Tg-AD) had been treated with sodium selenate in drinking water for 10month before the detection of hippocampal pathology. Increased Abeta generation, tau hyperphosphorylation and neuronal apoptosis were found in the hippocampus of AD model mouse. Down-regulation of Wnt/beta-catenin signaling is closely associated with the alteration of AD pathology. Treatment with sodium selenate significantly promoted the activity of protein phosphatases of type 2A (PP2A) and repressed the hallmarks of AD. Activation of PP2A by sodium selenate could increase active beta catenin level and inhibit GSK3beta activity in the hippocampal tissue and primarily cultured neurons of AD model mouse, leading to activation of Wnt/beta catenin signaling and transactivation of target genes, including positively regulated genes c-myc, survivin, TXNRD2 and negatively-regulated gene BACE1. Meanwhile, APP phosphorylation was also reduced on the Thr668 residue after selenate treatment, causing the decreases of APP cleavage and Abeta generation. These findings reveal that the Wnt/beta-catenin signaling is a potential target for prevention of AD and sodium selenate may be developed as a new drug for AD treatment. PMID- 28711507 TI - Protective effects of tenuigenin on Staphylococcus aureus-induced pneumonia in mice. AB - Pneumonia is the leading cause of death in infants and young children. Staphylococcus aureus (S.aureus) is one of the most important bacteria that leads to pneumonia. Tenuigenin (TGN), a major active component isolated from the root of the Chinese herb Polygala tenuifolia, has been known to have anti-inflammatory effect. In this study, we aimed to investigate the protective effects of TGN on S.aureus-induced pneumonia in mice. The results showed that TGN significantly attenuated S.aureus-induced lung histopathological changes. TGN also inhibited lung wet/dry (W/D) ratio, and inflammatory cytokines TNF-alpha and IL-1beta production. Furthermore, S.aureus-induced NF-kappaB activation was significantly inhibited by the treatment of TGN. In conclusion, the results of this study showed that TGN protected against S.aureus-induced pneumonia by inhibiting NF kappaB activation. TGN might be a potential agent in the treatment of pneumonia induced by S.aureus. PMID- 28711508 TI - Virulent and pathogenic features on the Cronobacter sakazakii polymyxin resistant pmr mutant strain s-3. AB - Cronobacter sakazakii is a well-known opportunistic pathogen responsible for necrotizing enterocolitis, meningitis and septicaemia in the premature, immunocompromised infants and neonates. This pathogen possesses various virulence factors and regulatory systems, and pmrA/pmrB regulatory system has been identified in a variety of bacterial species. The current study aims to investigate role of pmrA gene in the pathogenicity and virulence characteristics of Cronobacter sakazakii using whole genome sequencing and RNA-seq. Results demonstrated that the absence of pmrA has the potential to affect Cronobacter sakazakii on its pathogenicity, virulence and resistance abilities by regulating expression of numerous related genes, including CusB, CusC, CusR and ESA_pESA3p05434. PMID- 28711509 TI - Listeria monocytogenes PdeE, a phosphodiesterase that contributes to virulence and has hydrolytic activity against cyclic mononucleotides and cyclic dinucleotides. AB - We have identified and partially characterized a putative HD domain hydrolase, LMOf2365_2464, which is highly expressed during listerial intracellular replication. LMOf2365_2464 is annotated as a putative HD domain-containing hydrolase. The ability of an isogenic mutant strain, F2365Delta2464, to adhere, invade and replicate in intestinal epithelial cells (Caco-2) was significantly lower than parent strain F2365. Colonization of mouse liver and spleen by L. monocytogenes F2365 was significantly higher than it was for the mutant. The recombinant protein showed phosphodiesterase activity in the presence of divalent metal ions, indicating its role in nucleotide metabolism. It has activity against several cyclic nucleotides and cyclic dinucleotides, but its strongest activity is against cyclic di-AMP and cyclic AMP. Based on this enzymatic activity, we designated LMOf2365_2464 phosphodiesterase E (PdeE). PMID- 28711510 TI - Serotyping of Brunei pneumococcal clinical strains and the investigation of their capability to adhere and invade a brain endothelium model. AB - INTRODUCTION: Pneumococcal infections have caused morbidity and mortality globally. Streptococcus pneumoniae (pneumococci) are commensal bacteria that colonize the nasopharynx, asymptomatically. From there, pneumococci can spread in the lungs causing pneumonia and disseminate in the bloodstream causing bacteremia (sepsis) and reach the brain leading to meningitis. Endothelial cells are one of the most important components of the blood-brain barrier that separates the blood from the brain and plays the first protective role against pneumococcal entry. Thus this study aimed to investigate on the ability of non-meningitis pneumococcal clinical strains to adhere and invade a brain endothelium model. METHODS: Two pneumococcal Brunei clinical strains were serotyped by multiplex PCR method using oligonucleotide sequences derived from Centers for Disease Control and Prevention. A validated immortalised mouse brain endothelial cell line (bEnd.3) was used as a brain endothelium model for the study of the pneumococcal breach of the blood-brain barrier using an adherence and invasion assay. RESULTS: Both of the pneumococcal clinical strains were found to be serotype 19F, a common circulating serotype in Southeast Asia and globally and possess the ability to adhere and invade the brain endothelial cells. CONCLUSION: In addition, this is the first report on the serotype identification of pneumococci in Brunei Darussalam and their application on a brain endothelium model. Further studies are required to understand the virulence capabilities of the clinical strains. PMID- 28711511 TI - Effects of alliin on LPS-induced acute lung injury by activating PPARgamma. AB - Alliin is a garlic organosulfur compound that possesses various pharmacological properties. In the present study, the protective effects and molecular mechanism of alliin on Lipopolysaccharides (LPS)-induced acute lung injury (ALI) were analyzed. LPS-induced ALI was induced in BALB/c mice by intranasal instillation of LPS. Alliin was administered intraperitoneally to mice 1 h after LPS treatment. The results showed that alliin markedly inhibited lung myeloperoxidase (MPO) activity and wet/dry (W/D) ratio induced by LPS. Alliin also inhibited TNF alpha and IL-1beta in the bronchoalveolar lavage fluid (BALF) induced by LPS. Furthermore, LPS-induced lung pathological injury was attenuated by treatment of alliin. LPS-induced NF-kappaB activation was significantly inhibited by alliin. In addition, the expression of peroxisome proliferator-activated receptor gamma (PPARgamma) was up-regulated by treatment of alliin. Taken together, these results suggested that alliin protected against LPS-induced ALI by activating PPARgamma, which subsequently inhibited LPS-induced NF-kappaB activation and inflammatory response. Alliin might be used as an anti-inflammatory agent in the treatment of ALI. PMID- 28711512 TI - Seasonality in affective disorders. AB - Humans retain neurobiological responses to circadian day-night cycles and seasonal changes in daylength in spite of a life-style usually independent of dawn-dusk signals. Seasonality has been documented in many functions, from mood to hormones to gene expression. Research on seasonal affective disorder initiated the first use of timed bright light as therapy, a treatment since extended to non seasonal major depression and sleep-wake cycle disturbances in many psychiatric and medical illnesses. The growing recognition that sufficient light is important for psychological and somatic well-being is leading to the development of novel lighting solutions in architecture as well as focus on a more conscious exposure to natural daylight. PMID- 28711513 TI - The effectiveness of cognitive-function stress management training in glycemic control in children and in mental health of mother caring for child with type 1 diabetes mellitus. AB - AIM: The study was aimed to evaluate the effectiveness of a training course of cognitive-behavioral stress management in glycaemia regulation in children with type 1 diabetes mellitus as well as in mental health status of their mothers. MATERIALS AND METHODS: Fifty children with type 1 diabetes mellitus and their mothers were selected and randomly assigned into two groups. A group of mothers (n=25; as experimental one besides their children) passed a course, eight 2-h sessions, on the cognitive-behavioral and stress management, and the control group received the usual care. To evaluate the effectiveness of the intervention, before and after holding the course, glycosylated hemoglobin (HbA1C) test was done on both groups of children, and also some information was collected from the mothers through interview and the DASS (depression, anxiety, stress scale) and PSI (parenting stress index) questionnaires. RESULTS: After the intervention, HbA1c level decreased in the experimental group. Feeling of depression, anxiety and stress was significantly lower than the control group. Furthermore, training for parenting stress management positively affected on the sense of demanding, reinforcement, and adaptability in child domain and also on attachment, competence, depression, relationship with spouse and family health in parent domain. CONCLUSION: The intervention program was significantly effective in reducing the amount of HbA1c in diabetic children, and also reduced the intensity of psychosocial problems such as depression, anxiety and stress in the mothers caring for children with type 1 diabetes. PMID- 28711514 TI - Polycystic ovarian syndrome-associated cardiovascular complications: An overview of the association between the biochemical markers and potential strategies for their prevention and elimination. AB - Polycystic ovarian syndrome (PCOS) is associated with multiple cardiovascular risk factors (CVRF) including endothelial dysfunction (ED) and presence of metabolic syndrome (MS). The probable reason suggested for elevated CVRF in PCOS is oxidative stress (OS), which is an integral factor in cardiometabolic complications (CMC) seen in PCOS women. The interrelated mechanisms by which CVRF instigate clinical manifestation plays a crucial role in identification of a strategy to treat different comorbidities in PCOS. The existing treatment for PCOS mostly focuses on management of individual disorders, however, therapeutic strategies or novel targets to address cardiovascular complications in PCOS deserve extensive analysis. PMID- 28711515 TI - Longitudinal changes in visceral and subcutaneous adipose tissue and metabolic syndrome: Results from the Multicultural Community Health Assessment Trial (M CHAT). AB - AIM: Few studies have examined whether longitudinal changes in visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT), independent of each other, are associated with the risk of developing metabolic syndrome (MetS). The objective of this study was to examine the longitudinal effects of VAT and SAT on MetS and metabolic risk factors in a multi-ethnic sample of Canadians followed for 5-years. MATERIALS AND METHODS: In total, 598 adults of the Multicultural Community Health Assessment Trial (M-CHAT) were included in this study. Assessments of body composition using computed tomography (CT) and metabolic risk factors were conducted at baseline, 3-, and 5-years. Mixed-effects logistic regression was used to model the longitudinal effects of VAT and SAT on MetS and metabolic risk factors. RESULTS: There were significant between-person (cross sectional) effects such that for every 10cm2 higher VAT, the odds of MetS, high risk fasting glucose levels and high-risk HDL-C levels significantly increased by 16% (95% CI: 9-24%), 11% (3-20%), and 7% (0-14%) respectively. Significant within person (longitudinal) effects were also found such that for every 10cm2 increase in VAT the odds of MetS and high-risk triglyceride levels significantly increased by 23% (9-39%) and 30% (14-48%), respectively. Cross-sectional or longitudinal changes in SAT were not associated with MetS or metabolic risk factors. CONCLUSIONS: This study found a direct relationship between longitudinal change in VAT and MetS risk independent of changes in SAT. Clinical practice should focus on the reduction of VAT to improve cardiovascular health outcomes. PMID- 28711516 TI - The influence of metabolic syndrome in the outcomes of colorectal cancer patients. AB - AIMS: Determine the influence of metabolic syndrome and its different components in the outcomes of colorectal cancer surgery at 30days. MATERIALS AND METHODS: Prospective study that included all patients submitted to elective colorectal cancer surgery between August 2015 and August 2016 at Hospital de Braga. Clinical and laboratory parameters evaluated pre-operatively were: central obesity, blood pressure, fasting glucose, triglycerides levels and HDL cholesterol levels. Any complications during the first 30-days after surgery were recorded (readmission, reintervention, anastomotic dehiscence, morbimortality). RESULTS: One hundred and thirty-four patients were included. Metabolic syndrome was diagnostic in 40.7% of patients with the ATPIII definition, 67.5% with the AHA definition and 67.0% with the IDF definition. At 30days after colorectal cancer surgery, 73.1% patients don't have any complication, 15.7% have minor complications (grade I/II of Clavien-Dindo classification), 11.1% have major complications (grade III/IV/V of Clavien-Dindo classification) and 1.5% have died from surgical complications (grade V of Clavien-Dindo classification). The statistic analysis didn't reveal any association between MS, or it's different components, and surgical outcomes. CONCLUSION: This study seems to indicate that metabolic syndrome don't have any influence in surgical outcomes of colorectal cancer surgery. PMID- 28711517 TI - Prevention of type 2 diabetes mellitus in polycystic ovary syndrome: A review. AB - Polycystic ovary syndrome (PCOS) is recognized as one of the most common endocrinopathies in women of reproductive age, associated with metabolic sequelae which includes increased risk factors for impaired glucose tolerance (IGT), type 2 diabetes mellitus (DM2) and cardiovascular disease (CVD). The adverse effects of DM2 affects a woman throughout her lifespan. Health care expenditure of DM2 highlights the need for prevention through appropriate screening, diagnosis and intervention. Lifestyle modification (LSM) programs that include diet and/or physical activity are suggested for patients characterized as prediabetic to delay the onset of adult DM2. Diet (i.e. low carbohydrate), combination of aerobic and resistance exercise with high intensity interval training (HIT) 150 to 175min/week with resistance exercise 2 to 3days/week and weight loss may be valuable supporters in the fight against IR, IGT and DM2 associated with PCOS. PMID- 28711518 TI - Antagonism of the 5-HT6 receptor - Preclinical rationale for the treatment of Alzheimer's disease. AB - Antagonism of the 5-HT6 receptor is a promising approach for the symptomatic treatment of Alzheimer's disease (AD). There is compelling preclinical evidence for the procognitive potential of 5-HT6 receptor antagonists and several compounds are in clinical development, as adjunct therapy to acetylcholinesterase inhibitors (AChEIs). This manuscript summarizes the scientific rationale for the use of 5-HT6 receptor antagonists as AD treatment, with some focus on the selective and high-affinity 5-HT6 receptor antagonist idalopirdine (Lu AE58054). The 5-HT6 receptor is enriched in brain regions that mediate cognition, where expression predominates on glutamatergic and GABAergic neurons and subsets of GABAergic interneurons. It is proposed that 5-HT6 receptor antagonism modulates the balance between neuronal excitation (glutamate) and inhibition (GABA), which may have widespread implications for neurotransmission and neuronal activity. This is supported by preclinical studies showing that 5-HT6 receptor antagonists increase concentrations of multiple neurotransmitters, and strengthened by recent evidence that idalopirdine facilitates neuronal oscillations and contributes to the recruitment of several neuronal networks relevant in cognition. Some of these effects are observed with idalopirdine monotherapy, whereas others require concomitant treatment with an AChEI. Several hypotheses for the mechanism underlying the synergistic actions between 5-HT6 receptor antagonists and AChEIs are discussed. Collectively, the current evidence suggests that 5-HT6 receptor antagonism adds a unique, complementary mechanism of action to that of AChEIs. The facilitation of multiple neurotransmitters and neuronal activity in brain regions that mediate cognition, and the synergy with AChEIs, are proposed to mediate the procognitive effects of 5-HT6 receptor antagonists in AD patients. PMID- 28711519 TI - Perspectives on bioeconomy. AB - The insight provided by the authors of this special issue on bioeconomy give a reassuring sign of optimism, vitality and strong will to make bioeconomy a success story. Key to these advances will be inventing and shaping our future and the cooperation of people who will create new scientific and technological discoveries, developments and their implementation into industrial practice. The vibrant global megatrend bioeconomy is developing along various dimensions depending on natural and social conditions, economic development and political objectives. As value chains from producer countries and regions to their corresponding customers are interconnected globally and bioeconomies are diverse, constructive dialogues and agreed social consensus are therefore relevant worldwide. Mapping and engineering the uncharted territories of the molecular transformations, which are key to the bioeconomy, represents a great opportunity for the molecular and engineering sciences to bring in their important contributions. The development of smart bioeconomies needs excellence in science based concepts, long-term support of innovative and mission-oriented research and a subtle equilibrium between science push and market and social pull. On the policy front, coherent and science-based policy decisions embracing bioeconomy and being consistent with each other are needed. From a global perspective, bioeconomy topics should be included in the international and national agendas on sustainable development goals. PMID- 28711520 TI - Exploring substrate specificities of a recombinant Rhizopus oryzae lipase in biodiesel synthesis. AB - The alcoholysis of triolein was used to explore the specific features of a recombinant Rhizopus oryzae lipase (rROL) for biodiesel synthesis. For this purpose, different acylglycerols were compared as substrates in lipase-catalysed transesterification. rROL was shown to exhibit a higher specificity towards 1 monoolein than triolein compared to other R. oryzae lipases, being more than 4 fold more specific; in contrast, rROL did not accept 2-monoolein as substrate, concluding that it is highly 1,3-positional specific. Comparing ethanol and methanol as acyl-acceptors, it was observed that the latter caused more lipase inactivation. Regarding alcohols, it was also demonstrated that acyl migration occurred in moderate alcohol concentrations. PMID- 28711521 TI - A comparison of resetting and nonresetting contingencies in progressive-duration schedules. AB - We compared two progressive schedules of reinforcement in which rats received access to sweetened condensed milk for depressing and holding down a response lever. Duration requirements increased after each reinforcer delivery in a manner similar to progressive-ratio schedules. Under one schedule, any response duration less than that required for reinforcement had no programmed consequences. Under the second schedule, the cumulative duration of all responses could meet the reinforcement criteria. Breaking points were consistently higher when all lever presses, regardless of duration, contributed to meeting the reinforcer requirements. Breaking points under both schedules increased when food deprivation was long enough to result in body-weight reductions, but the sensitivity of the schedules to brief periods of food deprivation was inconsistent. Under both schedules, food deprivation produced an increase in shorter durations, thus reducing the efficiency of responding. PMID- 28711522 TI - Engaging with primary schools: Supporting the delivery of the new curriculum in evolution and inheritance. AB - The official school regulator in England (OFSTED) recently reported that the delivery of science lessons has been significantly diminished in many primary schools. There is concern that the lack of good quality science in school can reduce the recruitment of young scientists, and the level of science literacy among the general public. We believe university scientists and undergraduate students can have a significant impact in the delivery of science in primary schools. However, a relatively small proportion of scientists engage with young children to improve curricular primary school science education. Here, we argue that long term engagement with primary schools can produce significant impact for the scientist's research, schools, and society. As an example, we describe our experience developing teaching materials for the topic of "Evolution and inheritance"; highlighting possible pitfalls and perceived benefits, in hope of encouraging and facilitating other scientists to engage with primary schools. PMID- 28711523 TI - Plant HAK/KUP/KT K+ transporters: Function and regulation. AB - The HAK/KUP/KT family of potassium (K+) transporters belongs to the amino acid polyamine-organocation (APC) superfamily of carriers for secondary active transport and has been widely associated with K+ transport across membranes in bacteria, fungi, and plants. The plant genome contains large number of HAK/KUP/KT transporters, and they show the diverse roles in K+ uptake and translocation, salt tolerance and osmotic potential regulation, as well as in controlling root morphology and shoot phenotyping. Recently, significant progress has been achieved towards uncovering the regulatory mechanisms of HAK/KUP/KT transporters at both transcriptional and post-translational levels. Most of the HAK/KUP/KT genes were regulated at transcriptional level, and such regulation may contribute to the alteration of root cell membrane potential by different growth conditions. At least six transcription factors have been identified as positive or negative regulators of HAK/KUP/KT gene expression in responding to external K+ supply. The HAK/KUP/KT transporter proteins can be phosphorylated by CIPK-CBL complexes for activating their function in K+ uptake and probably signaling. Nevertheless, it is still not known if HAK/KUP/KT transporters are involved in K+-sensing and K+ compartmentation in plant cells. Some orthologues of the HAK/KUP/KT transporters from different species show varied physiological functions and some plant species lack an entire sub-clade of HAK/KUT/KT transporters. We are still a long way from unraveling the molecular mechanism of HAK/KUP/KT involved in K+-sensing and signaling pathways in plants. PMID- 28711524 TI - Strategic disruption of nuclear pores structure, integrity and barrier for nuclear apoptosis. AB - Apoptosis is a programmed cell death playing key roles in physiology and pathophysiology of multi cellular organisms. Its nuclear manifestation requires transmission of the death signals across the nuclear pore complexes (NPCs). In strategic sequential steps apoptotic factors disrupt NPCs structure, integrity and barrier ultimately leading to nuclear breakdown. The present review reflects on these steps. PMID- 28711525 TI - Novel Hsp90 inhibitor platycodin D disrupts Hsp90/Cdc37 complex and enhances the anticancer effect of mTOR inhibitor. AB - Heat shock protein 90 (Hsp90) is a critically conserved molecular chaperone protein and promising therapeutic target for cancer treatment. In this study, platycodin D (PD), a saponin isolated from traditional Chinese herb Platycodonis Radix, was identified as a novel Hsp90 inhibitor. We verified that PD did not affect the ATPase activity of Hsp90. However, PD disrupted the co-chaperone interaction of Hsp90/cell division cycle protein 37 (Cdc37) and subsequently degraded multiple Hsp90 client proteins without the feedback increase of Hsp70. In different genotypes of non-small cell lung cancer cells, co-treatment with the mTOR inhibitor Everolimus and PD enhanced antiproliferation activity and apoptotic effect. The feedback survival signal upon mTOR inhibition was fully terminated by the co-administration with PD through reduced epidermal growth factor receptor (EGFR) and insulin growth factor 1 receptor (IGF1R) expression, suppressed AKT activity, and reinforced 4E-BP1 inhibition. Our results not only identified PD as a novel Hsp90 inhibitor by disrupting the protein-protein interaction of Hsp90/Cdc37 complex, but also provided mechanistic insights into the ineffectiveness of mTOR inhibitors and identified therapeutic strategy for cancer treatment. PMID- 28711526 TI - Xpert HIV-1 point-of-care test for neonatal diagnosis of HIV in the birth testing programme of a maternity hospital: a field evaluation study. AB - BACKGROUND: Point-of-care testing (POCT) among HIV-exposed infants might improve linkage to care relative to laboratory-based testing (LABT). We evaluated HIV-1 POCT at birth in the context of universal LABT in a maternity hospital and describe our implementation experience. METHODS: We did a field evaluation study between Oct 1, 2014, and April 30, 2016, at the urban Rahima Moosa Mother and Child Hospital (RMMCH), Johannesburg, South Africa. We aimed to sample consecutive neonates at birth with POCT (Cepheid Xpert HIV-1 Qualitative test) and compared results with those of LABT (Roche COBAS TaqMan HIV-1 Qualitative test) with respect to performance in terms of sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and Cohen's kappa coefficient, result return, antiretroviral treatment (ART) initiation, and coverage. FINDINGS: 18 268 women delivered livebirths at RMMCH and 4267 (23%) were HIV-positive with 4336 HIV-exposed neonates delivered. Mothers of 4141 (96%) HIV-exposed neonates were offered infant birth testing. Mothers of 4112 (99%) neonates consented. In 78 neonates with consent (2%), a test was not done due to early neonatal death (n=13), mother departing before venesection, or staff unavailability. Among 3970 infants who had LABT, 57 (1%) tested positive, 3906 (99%) tested negative, two (<1%) were indeterminate, and five (<1%) had an error result. 2238 (56%) of these infants had concurrent POCT. POCT detected all 30 HIV infected neonates (sensitivity 100%; 95% CI 88.4-100) with two additional false positive results (specificity 99.9%; 99.7-100). All positive and 96.2% of negative POCT results were returned compared with 88.9% of positive and 52.8% of negative LABT results. Although every POCT required 90 min of instrument time, 2.6 h (IQR 2.3-3.1) elapsed between phlebotomy and result return. In days, median time of result return for POCT was 1 day, significantly earlier than 10 days for LABT (p<0.0001). ART was initiated in 30 neonates (100%) with positive POCT compared with 24 (88.9%, p=0.10) of 27 infants who had LABT only, with initiation occurring a median of 5 days earlier in the POCT group (p<0.0001). POCT implementation required additional staff and weekend cover. INTERPRETATION: Compared with LABT, POCT was associated with good performance, improved rates of result return, and reduced time to ART initiation. Resources needed to integrate POCT into a routine birth testing programme require further evaluation. FUNDING: National Institutes of Health. PMID- 28711527 TI - Paediatric HIV: the unfinished business. PMID- 28711528 TI - Comparison of five methods for isolation of DNA from Mycoplasma cynos. AB - Extraction of DNA from Mycoplasma cultured on agar medium is difficult because the plasticity of these microorganisms enables agar penetration. This eventually causes cell loss during harvesting of colonies from the agar surface. Here, we used the GenEluteTM gel extraction kit, which is usually used to purify polymerase chain reaction products, for extracting DNA from Mycoplasma. We compared the DNA extraction efficiency of the GenEluteTM gel extraction kit from Mycoplasma cynos cultured in agar medium with four other DNA extraction methods. The results were evaluated based on the purity and amount of DNA obtained from one Mycoplasma colony. Eight strains of Mycoplasma cynos isolated from the broncho-alveolar lavage fluid of dogs were used. The GenEluteTM gel extraction protocol was the most efficient among all the methods tested in this study as it yielded the highest amount and the purest quality of DNA (199.3+/-0.744ng/MUl) from a single colony. Among the methods tested, the GenEluteTM gel extraction method is the most rapid, sensitive, and simple method for DNA extraction from Mycoplasma. This procedure may also prove useful for extracting DNA from other Mycoplasma species. PMID- 28711529 TI - Initial Treatment Strategy for Intracranial Mycotic Aneurysms: 2 Case Reports and Literature Review. AB - BACKGROUND: Intracranial mycotic aneurysm (IMA) is a rare neurovascular disease and a well-known complication after infective endocarditis. IMAs potentially carry a high mortality risk resulting from intracranial hemorrhage. Therefore, initial treatment is crucial for IMA patients, but an optimal treatment strategy remains unknown. Herein, we report 1 cases of IMA patients treated with the current usual modalities, and we provide a comprehensive literature review to propose an optimal initial treatment strategy for IMAs. CASE DESCRIPTIONS: Case 1: An 80-year-old man received a diagnosis of ruptured IMA. He immediately underwent trapping surgery and was discharged without neurologic deficit. Case 2: A 36-year-old man with previous aortic root replacement received a diagnosis of ruptured IMA. His general condition was considered too unstable to allow him to undergo direct surgery, and the angiographic access route was limited because of the previous aortic replacement surgery. Therefore, we selected conservative therapy; however, the patient subsequently died after complications from a huge intracerebral hemorrhage during medical treatment. CONCLUSIONS: On the basis of 129 IMA cases across 54 reports published from 2006 to 2016, we propose initial surgical intervention as an optimal treatment for patients with ruptured, and even unruptured, IMAs. Regarding surgical intervention, there was no significant difference in postoperative modified Rankin scale scores between direct surgery and endovascular treatment. By contrast, because antibiotic treatment significantly decreased IMA size in unruptured IMAs, antibiotic treatment might be a reasonable alternative for patients with unruptured IMAs, depending on the patient's situation. PMID- 28711530 TI - Pitfalls of Neuroendoscopic Biopsy of Intraventricular Germ Cell Tumors. AB - OBJECTIVE: A neuroendoscopic biopsy has become common for the diagnosis of ventricular tumors. However, its utility in patients with germ cell tumors (GCTs) has not been well discussed. We examined the usefulness and pitfalls of neuroendoscopic biopsies of intraventricular GCTs at a single institution. METHODS: We retrospectively studied 21 consecutive patients diagnosed with GCTs by a neuroendoscopic biopsy of the ventricular region via the lateral ventricle. We examined the localization of tumors, histologic diagnoses using biopsies, surgical complications, and consistency of the diagnosis at the latest follow-up. RESULTS: Tumor specimens were obtained from a pineal lesion (n = 20), neurohypophysial lesion (n = 5), and lateral ventricular wall lesion (n = 2). In 5 patients, the specimens were obtained from multiple areas. The initial diagnoses were pure germinoma (n = 16), immature teratoma (n = 1), yolk sac tumor (n = 1), and mixed GCT (n = 3). Six of 21 patients needed a second transcranial removal of enhanced residual lesions in the course of the treatment. A discrepancy in the histologic diagnosis between 2 surgeries occurred in 3 patients: All 3 patients had a new diagnosis of teratoma component following transcranial surgery. No postoperative mortality or permanent morbidity related to the neuroendoscopic procedures was noted. CONCLUSION: Neuroendoscopic biopsies are safe and useful for obtaining reliable histologic diagnoses in the management of GCTs. However, for GCTs with mixed histology, biopsies are susceptible to diagnostic errors, especially missing detecting a component of teratoma. PMID- 28711531 TI - Transdural Indocyanine Green Videography for Superficial Temporal Artery-to Middle Cerebral Artery Bypass-Technical Note. AB - BACKGROUND: Neurosurgical application of indocyanine green (ICG) videography before performing a dural opening, known as transdural ICG videography, has been used during surgery of meningiomas associated with venous sinuses as well as cranial and spinal arteriovenous malformations. However, its use for a superficial temporal artery (STA)-to-middle cerebral artery (MCA) bypass has not been reported. METHODS: We performed a retrospective analysis of medical records of patients who underwent transdural ICG videography during STA-MCA bypass performed between January 2012 and March 2015. The primary outcome was visualization of recipient cortical arteries; secondary outcomes were surgical modifications and complications as well as any adverse events associated with transdural ICG videography. RESULTS: We analyzed 29 STA-MCA bypass procedures performed in 30 hemispheres with atherosclerotic steno-occlusive disease and found that the proper recipient was identified in 28 hemispheres. Subsequently modified procedures for those were a tailored dural incision and craniotomy correction. No complications associated with ICG administration were encountered; during the postoperative course, transient aphasia was noted in 1 case, chronic subdural hematoma was noted in 1 case, and subdural effusion was noted in 2 cases. CONCLUSIONS: Transdural ICG videography for atherosclerotic steno occlusive disease facilitates modifications during STA-MCA bypass procedures. Recognition of the proper recipient cortical arteries before a dural incision allows the neurosurgeon to perform a tailored dural incision and extension of the bone window, although the contribution to surgical outcome has yet to be determined. PMID- 28711532 TI - An Intraoperative Look at a Residual/Recurrent Tentorial Dural Arteriovenous Fistula. AB - BACKGROUND: Dural arteriovenous fistulas (dAVFs) often are treated via transarterial or transvenous embolization. Incomplete penetration of the draining vein/occult residual often will become apparent on follow-up angiography, requiring repeat embolization, or at times, surgical resection. CASE DESCRIPTION: A 41-year-old woman presented with cerebellar hemorrhage from a tentorial dAVF treated with transvenous coil embolization. Follow-up angiography disclosed a residual/recurrent fistula treated with transvenous Onyx embolization. After further follow-up angiography demonstrated another occult residual/recurrence, the fistula was disconnected with the tentorial dura excised via a retrosigmoid approach. Six-month follow-up angiography demonstrated no recurrence. CONCLUSIONS: Although endovascular treatment of dAVFs is generally first-line therapy, surgical disconnection of fistulas, particularly high-risk residual/recurrent fistulas, is an excellent option in well-selected cases. PMID- 28711533 TI - Cerebral Vasospasm-Dependent and Cerebral Vasospasm-Independent Cerebral Infarctions Predict Outcome After Nonaneurysmal Subarachnoid Hemorrhage: A Single Center Series with 250 Patients. AB - OBJECTIVE: The number of patients with nonaneurysmal subarachnoid hemorrhage (naSAH) has increased during the last decade. Data regarding infarctions in naSAH are still limited. The aim of this study was to identify the rate of cerebral vasospasm (CVS)-dependent and CVS-independent infarctions and their influence on clinical outcomes. METHODS: Between 1999 and 2015, 250 patients suffering from naSAH were analyzed retrospectively. A delayed infarction was analyzed whether it was associated with CVS (CVS-dependent infarction) or not (CVS-independent). RESULTS: A total of 36 patients (14%) had cerebral infarctions. CVS was detected in 54 patients (22%), and 15 (6%) of them developed infarctions (CVS-dependent). Infarctions without signs of CVS (CVS-independent) occurred in 21 patients (8%). Overall, 86% of the patients had favorable outcome. Patients without cerebral infarctions had the best outcome (91% favorable outcome, 5% mortality rate). Patients with CVS-independent infarctions (57%) as well as patients with CVS dependent infarctions (53%) had a favorable outcome less often. The mortality rate was also significantly greater in patients with CVS-independent (19%) and CVS-dependent infarctions (33%). A further independent predictor was anticoagulative therapy, which increased during study period and was associated with nonperimesencephalic blood distribution. CONCLUSIONS: CVS-dependent and independent infarctions occur in naSAH and contribute to unfavorable outcomes. Whereas CVS-independent infarctions occur in any subgroup, CVS-dependent infarctions seem to be associated with blood pattern (Fisher 3). Anticoagulative therapy seems to be not only a predictor for worse outcome but also for nonperimesencephalic SAH. Accordingly, the proportion of perimesencephalic and nonperimesencephalic SAH changed during the study period (from 2.2:1 to 1:1.7). PMID- 28711534 TI - Primary Intradural Extramedullary Cervical Spinal Cysticercosis. AB - BACKGROUND: Spinal cysticercosis has been reported in 0.7%-3.0% of patients with neurocysticercosis. Most patients with spinal cysticercosis have a coexisting intracranial disease. Most often this intracranial disease manifests as intradural extramedullary lesions involving thoracic and lumbar regions or intramedullary lesions. Intradural extramedullary primary spinal cysticercosis manifesting as cervical myelopathy is extremely rare and has not been reported to date. CASE DESCRIPTION: A 56-year-old man from the northeastern part of India presented with progressive spastic quadriparesis. Magnetic resonance imaging showed a ventrally located intradural extramedullary multiloculated cyst with an enhancing wall in the upper cervical region. Enzyme-linked immunoelectrotransfer blot performed to detect cysticercal antibodies in serum was positive. The patient underwent total excision of the cysts, which were confirmed histologically to be cysticercal cysts. He was also treated with 2 weeks of albendazole therapy after surgery. He had recovered fully 1 year later. CONCLUSIONS: Cysticercosis should be considered in the differential diagnosis in a patient with multiloculated cysts in the spinal subarachnoid space. Surgical exploration and excision of the cysts should be performed not only to establish a diagnosis but also to decompress the cord before medical therapy. PMID- 28711535 TI - Infection or Glioma? The False Dilemma of Primary Central Nervous System Histiocytic Sarcoma. AB - BACKGROUND: Primary central nervous system (CNS) histiocytic sarcoma is an extremely rare lymphoproliferative disorder that affects the CNS and behaves aggressively. Only 27 cases of primary CNS histiocytic sarcoma have been reported. The paucity of literature on this entity has made diagnosis and treatment difficult both for the surgeon and the pathologist. CASE DESCRIPTION: In this case of primary CNS histiocytic sarcoma, a middle-aged woman presented from an outside institution with a supposed cerebellar abscess. Intraoperative frozen pathology was initially interpreted as high-grade glioma; however, final pathology demonstrated histiocytic sarcoma. CONCLUSIONS: This report makes a significant contribution to the literature on this rare malignant disease by outlining a similar presentation among several cases and providing a thorough overview of existing criteria for diagnosis and management. PMID- 28711536 TI - Outcomes of Primary Transsphenoidal Surgery in Cushing Disease: Experience of a Tertiary Center. AB - BACKGROUND: To report the initial and long-term remission rates and related factors, secondary treatments, and outcomes of a series of patients with Cushing disease (CD). METHODS: We included 147 consecutive adult patients with CD who underwent primary transsphenoidal surgery (TSS) between 1998 and 2014 in this study. Eighty-two were followed up in the Cerrahpasa Medical Faculty Endocrinology and Metabolism outpatient clinic. Patients were requested to attend a long-term remission assessment; 55 could be contacted, and data for the remaining 27 patients' last visit to the outpatient clinics were reviewed for early and late remission. Six patients were excluded from the study. Magnetic resonance imaging (MRI) findings and pathologic results including mitosis, Ki-67 levels, and P53 in immunostaining of all patients were evaluated. RESULTS: Data of 82 patients with CD with an average age of 36 years [interquartile range: 29 47] were analyzed with a mean follow-up of 7.5 years [interquartile range: 5-10]. Overall initial remission rates were 72.3% after TSS. Among the 82 patients, 16 patients had Gamma Knife radiosurgery and 7 patients underwent adrenalectomy. After these additional treatments, the long-term remission rate was found as 69.7%. The highest remission rates were with microadenomas. Recurrence was most frequently seen in patients without tumor evidence on MRI. Patients with high Ki 67 levels had higher recurrence rates in long-term follow-up (P = 0.02). CONCLUSION: Life-long follow-up for patients with CD seems essential. Undetectable tumors on MRI before TSS and high Ki-67 immunopositivity were found as risk factors for tumor recurrence. PMID- 28711537 TI - Increased Risk of Anxiety or Depression After Traumatic Spinal Cord Injury in Patients with Preexisting Hyperlipidemia: A Population-Based Study. AB - OBJECTIVE: Anxiety or depression (AD) is a common complication after traumatic spinal cord injury (tSCI). This study sought to investigate the role of preexisting hyperlipidemia in new-onset AD after tSCI using a longitudinal population database. METHODS: This retrospective cohort study used Longitudinal Health Insurance Database data from January 1997 to December 2011. The case and comparison groups were individuals who experienced tSCI and who did and did not have preexisting hyperlipidemia, respectively. Kaplan-Meier curves were plotted, and log-rank test was used to compare the differences between these 2 groups. A Cox regression model was used to estimate the relative risk of AD. RESULTS: A total of 26,892 adult patients were enrolled in this study. After 1:3 matching with age and gender, it showed 1) tSCI patients with preexisting hyperlipidemia have a 1.32-fold adjusted hazard ratio (HR) compared with those without hyperlipidemia (P < 0.05); 2) The Kaplan-Meier plot in tSCI patients with hyperlipidemia were more likely to develop the new-onset AD than those without hyperlipidemia during the follow-up period (P = 0.0003); and 3) the stratified analysis showed the risk of AD among patients with tSCI aged 18-34 years (HR, 3.2; 95% confidence interval (CI) 1.2-8.9), male patients (HR, 1.3; 95% CI 1.1 1.6), and higher Charlson's comorbidity index (CCI) score (CCI > 2; HR, 1.9; 95% CI 1.2-2.9), and those with a history of stroke (HR, 1.7; 95% CI 1.0-2.7). CONCLUSIONS: Preexisting hyperlipidemia is an independent predictor of new-onset AD in patients with tSCI, especially in those who are younger, male, have a higher CCI score, and have stroke. PMID- 28711538 TI - Cerebral Venous Sinus Thrombosis Secondary to Idiopathic Hypertrophic Cranial Pachymeningitis: Case Report and Review of Literature. AB - BACKGOUND AND IMPORTANCE: Idiopathic hypertrophic cranial pachymeningitis (IHCP) is a rare fibrosing inflammatory process involving the dura mater. Currently, there is no consensus on the treatments for IHCP, and the usefulness of immunosuppressive agents as a first-line option remains controversial. Cerebral venous sinus occlusion (CVSO) and cerebral venous sinus thrombosis (CVST) secondary to IHCP, which may cause progressive intracranial hypertension and venous obstructive parenchymal lesions, make the diagnosis and treatment of IHCP more complicated. METHODS: We present a case of IHCP. We also review previous cases of IHCP with secondary CVSO/CVST and then summarize the clinical characteristics of these patients. CLINICAL PRESENTATION: A 52-year-old female patient with IHCP developed secondary CVST. She had a severe headache with a hyperintense lesion on computed tomography, which was considered as subarachnoid hemorrhage. Lumbar tapping with a cerebrospinal fluid test, in addition to gadolinium contrast-enhanced magnetic resonance imaging, suggested IHCP. Secondary CVST was identified by digital subtraction angiography and magnetic resonance venography. Fatal intracranial hypertension with severe neurologic deficits occurred, despite mannitol, furosemide, and corticoid therapy. After administration of intravenous pulse cyclophosphamide, she obtained complete remission. CONCLUSIONS: We experienced a patient with CVST secondary to IHCP, who was successfully treated with cyclophosphamide pulse therapy. Because IHCP with secondary venous obstruction has various differential diagnoses, venography is necessary to avoid misdiagnosis. The use of immunosuppressive agents may be promising but needs further verification. PMID- 28711539 TI - Transventricular Migration of Neurocysticercosis. AB - BACKGROUND: The movements of a neurocysticercosis cyst within the ventricular cavity have been identified rarely. CASE DESCRIPTION: A 22-year old male patient presented with the main symptom of diplopia for about a week. Findings of the neurologic examination revealed bilateral sixth cranial nerve weakness. Investigations during the period showed an intraventricular tumor that migrated from lateral ventricle to the third ventricle and subsequently to the fourth ventricle. The lesion was resected from the fourth ventricle and was identified to be a neurocysticercosis cyst. CONCLUSIONS: Such an intraventricular migration of any kind of tumor has not been recorded in the literature. PMID- 28711540 TI - In-Hospital Complications and Resource Utilization Following Lumbar Spine Surgery in Patients with Parkinson Disease: Evaluation of the National Inpatient Sample Database. AB - BACKGROUND: Previous reports suggest that patients with Parkinson disease (PD) have elevated rates of complications following spine surgery; however, these reports are limited by small patient series. In this study, we used the National Inpatient Sample (NIS) database to compare in-hospital complications following elective lumbar spine surgery in patients with a diagnosis of PD and patients without PD. METHODS: The NIS database was accessed to identify patients with PD and those without PD who underwent lumbar spine surgery. All patients identified had a diagnosis code consistent with degenerative lumbar spine pathology. The patients were evaluated for the presence or absence of PD and divided into 4 lumbar spine procedure groups: decompression alone, lateral fusion, posterior fusion, and anterior fusion technique. Propensity score matching (PSM) was performed for the PD versus non-PD patients in each procedure group to control for confounding demographic variables, and in-hospital complications were compared between the 2 groups. RESULTS: Between 2001 and 2012, a total of 613,522 lumbar spine surgery patient episodes were identified, of which 4492 (0.7%) involved a diagnosis of PD. Following PSM for patient age, sex, and race, the patients with PD were at increased risk for acute postoperative hemorrhagic anemia, increased blood transfusion requirements, and increased genitourinary, neurologic, and cardiac complications compared with the patients without PD. CONCLUSIONS: PSM analysis of the NIS database demonstrated that patients with PD are at increased risk for acute in-hospital complications and greater blood transfusion requirements than those without PD. Surgeons should be aware of the increased risks and differing requirements when treating spinal pathology in patients with PD. PMID- 28711541 TI - Cell Index in the Diagnosis of External Ventricular Drain-Related Infections. AB - BACKGROUND: The use of an external ventricular drain is required for the treatment of many diseases, such as traumatic brain injury and subarachnoid hemorrhage (SAH). Meningitis and ventriculitis are frequent complications arising from the use of external ventricular drain therapy. This study aimed to determine the sensitivity, specificity, and cutoff point for cell index (CI) in patients with traumatic brain injury, SAH, and hemorrhagic stroke. METHODS: Our study population consisted of patients with different underlying diseases and few culture-positive cerebrospinal fluid samples. The diagnosis of infection was based on Centers of Disease Control and Prevention criteria. RESULTS: Overall CI analysis showed an area under the curve (AUC) of 0.982. The cutoff of 2.9 for overall CI provided a sensitivity of 95% and a specificity of 92.9%. In patients with SAH, the AUC was 1.0 for a CI of 2.8; furthermore, sensitivity and specificity were 100%. The relative variation of the CI was also assessed. This analysis revealed an AUC of 0.882, and a 4.33-fold increase was found be indicative of infection (P = 0.002), findings similar to those in the literature. In addition, a heatmap analysis demonstrated that the CI is unlikely to return to normal in patients with meningitis, even after treatment. CONCLUSIONS: Therefore, CI is valuable for the diagnosis of infection, but was inadequate for monitoring treatment. We hope to use the new cutoff point proposed by this study in our institution to improve patient clinical outcome. PMID- 28711542 TI - Symptomatic Intracerebral Hemorrhage Secondary to Ventriculoperitoneal Shunt in Adults without Bleeding Tendency. AB - BACKGROUND: Ventriculoperitoneal shunt (VPS) is a common procedure in daily neurosurgical practice. According to some reports, the rate of intracerebral hemorrhage secondary to VPS in patients with no bleeding tendency can be 43.1%; however, symptomatic intracerebral hemorrhage (SICH) secondary to VPS is rare with only sporadic cases reported in adults. To further elucidate the characteristics, mechanism, management, and prognosis of SICH secondary to VPS, we performed a retrospective study in our institution and a systematic review of the literature. METHODS: A retrospective review of the medical records of patients admitted for VPS was performed. We also performed a systematic PubMed search of published studies. RESULTS: Of 5 patients identified at our institution, 3 experienced a favorable recovery. Including our case series, there were 16 (8 female) patients. The time interval from the termination of VPS procedure to SICH was 4 hours to 15 days. All but 1 patient experienced intracerebral hemorrhage adjacent to cannulation. Of 11 patients in whom a Glasgow Outcome Scale score could be obtained, the score was 5 in 4 patients, 4 in 1 patient, 3 in 1 patient, and 1 in 5 patients. CONCLUSIONS: SICH is a rare complication after VPS in adults without bleeding tendency. The mechanism is obscure, management is challenging, and prognosis is dismal. Future prospective study is anticipated. PMID- 28711543 TI - Clival Defect with Primary CSF Rhinorrhea: A Very Rare Presentation with Challenging Management. AB - BACKGROUND: Primary spontaneous cerebrospinal fluid (CSF) rhinorrhea due to clival defect is an extremely rare presentation, and only 6 cases have been reported in the literature so far17. CASE DESCRIPTION: We present a unique case of a 64-year-old woman who presented with a 2-year history of ongoing CSF rhinorrhea. She had similar episode at the age of 40 years and suffered from meningitis. She underwent magnetic resonance imaging, computed tomography cisternogram, as well as computed tomography of the brain, which showed clival defect with CSF leak into the sphenoid sinus. She underwent transsphenoidal repair of the clival defect with concurrent lumbar drain insertion for CSF drainage. She returned a few months later with recurrent CSF rhinorrhea and meningitis. She was administered broad-spectrum antibiotics and underwent septal reconstruction of clival defect. CONCLUSIONS: Timely endoscopic transnasal, transsphenoidal repair of CSF leaks is the gold standard practice and could prevent devastating complications including repeated episodes of meningitis. PMID- 28711545 TI - Antiulcer properties of fruits and vegetables: A mechanism based perspective. AB - Gastric ulcer is the damage caused to mucosal layer of the stomach under the action of various factors like high levels of acid and pepsin, invasion by Helicobacter pylori, etc. Although most cases have been controlled and the rate of ulcer occurrence has reduced over the last few decades, gastric ulcer still holds a prime concern today. A range of palliative medicines comprising proton pump inhibitors, H2 receptor antagonists, COX-2 inhibitors (coxibs) is widely in use and patients have also been administered with acid suppression therapies. But these remedies aggravate the condition of patients causing severe side effects, or rather impart temporary relief. Therefore, it is highly imperative to develop safe and effective therapies for the treatment of gastric ulcer. Nature provides us various fruits and vegetables that can combat gastric ulcer through multiple mechanisms; predominantly via antioxidant, anti-inflammatory, antisecretory, antimicrobial, anticholinergic and cytoprotective activity, inhibition of small intestinal propulsion etc. Various phytochemicals from fruits and vegetables such as phenolics, flavonoids, tannins and saponins play a vital role in the prevention and cure of gastric ulcer. This review is a compendium of all fruits and vegetables known for their profound antiulcer effect and their underlying mechanisms of action. PMID- 28711544 TI - Concordance of DNA methylation profiles between breast core biopsy and surgical excision specimens containing ductal carcinoma in situ (DCIS). AB - The utility and reliability of assessing molecular biomarkers for translational applications on pre-operative core biopsy specimens assume consistency of molecular profiles with larger surgical specimens. Whether DNA methylation in ductal carcinoma in situ (DCIS), measured in core biopsy and surgical specimens are similar, remains unclear. Here, we compared genome-scale DNA methylation measured in matched core biopsy and surgical specimens from DCIS, including specific DNA methylation biomarkers of subsequent invasive cancer. DNA was extracted from guided 2mm cores of formalin fixed paraffin embedded (FFPE) specimens, bisulfite-modified, and measured on the Illumina HumanMethylation450 BeadChip. DNA methylation profiles of core biopsies exhibited high concordance with matched surgical specimens. Within-subject variability in DNA methylation was significantly lower than between-subject variability (all P<2.20E-16). In 641 CpGs whose methylation was related with increased hazard of invasive breast cancer, lower within-subject than between-subject variability was observed in 92.3% of the study participants (P<0.05). Between patient-matched core biopsy and surgical specimens, <0.6% of CpGs measured had changes in median DNA methylation >15%, and a pathway analysis of these CpGs indicated enrichment for genes related with wound healing. Our results indicate that DNA methylation measured in core biopsies are representative of the matched surgical specimens and suggest that DCIS biomarkers measured in core biopsies can inform clinical decision-making. PMID- 28711546 TI - Evaluation of estrogen receptor alpha activation by glyphosate-based herbicide constituents. AB - The safety, including the endocrine disruptive capability, of glyphosate-based herbicides (GBHs) is a matter of intense debate. We evaluated the estrogenic potential of glyphosate, commercial GBHs and polyethoxylated tallowamine adjuvants present as co-formulants in GBHs. Glyphosate (>=10,000 MUg/L or 59 MUM) promoted proliferation of estrogen-dependent MCF-7 human breast cancer cells. Glyphosate also increased the expression of an estrogen response element luciferase reporter gene (ERE-luc) in T47D-KBluc cells, which was blocked by the estrogen antagonist ICI 182,780. Commercial GBH formulations or their adjuvants alone did not exhibit estrogenic effects in either assay. Transcriptomics analysis of MCF-7 cells treated with glyphosate revealed changes in gene expression reflective of hormone-induced cell proliferation but did not overlap with an ERalpha gene expression biomarker. Calculation of glyphosate binding energy to ERalpha predicts a weak and unstable interaction (-4.10 kcal mol-1) compared to estradiol (-25.79 kcal mol-1), which suggests that activation of this receptor by glyphosate is via a ligand-independent mechanism. Induction of ERE luc expression by the PKA signalling activator IBMX shows that ERE-luc is responsive to ligand-independent activation, suggesting a possible mechanism of glyphosate-mediated activation. Our study reveals that glyphosate, but not other components present in GBHs, can activate ERalpha in vitro, albeit at relatively high concentrations. PMID- 28711547 TI - Interobserver variability for interpretation of DMSA scans in the RIVUR trial. AB - INTRODUCTION: Technetium-99m dimercaptosuccinic acid (DMSA) renal scans are used in the diagnosis of renal scarring. In the Randomized Intervention for Children with Vesicoureteral Reflux (RIVUR) trial that randomized 607 children, DMSA renal scans were used for evaluating the presence and the severity of renal scarring. OBJECTIVE: The aim was to determine interobserver variability in reporting of DMSA renal scans in the RIVUR trial. STUDY DESIGN: We compared DMSA renal scan reports for renal scarring and acute pyelonephritis from all non-reference local radiologists (ALRs) at study sites with adjudicated as well as non-adjudicated reports from two reference radiologists (RRs) of the RIVUR trial. Two-way comparisons of concordant and discrepant responses were analyzed using an unweighted kappa statistic between the ALR and the adjudicated RR interpretations. All analyses were performed using SAS v 9.4 (SAS institute 2015) and significance was determined at the 0.05 level. RESULTS: Of the 2872 kidneys evaluated, adjudicated RR reports had 119 (4%) kidneys with renal scarring compared with 212 (7%) by the ALRs. For 79% kidneys the grading for scarring reported by ALRs was either upgraded (24%) or downgraded (55%) by RRs. For acute pyelonephritis (n = 2924), adjudicated RR reports had 85 (3%) kidneys with pyelonephritis compared with 151 (5%) by the ALRs. For 85% kidneys, the grading for pyelonephritis reported by the ALRs was either upgraded (28%) or downgraded (57%) by the RRs. A three-way comparison revealed that all three (RR1, RR2, and ALR) agreed over presence of renal scarring in 19% cases and two of the three agreed in 80% cases. The respective numbers for pyelonephritis were 13% and 84%. The agreement rate for all DMSA scan reports between the RRs and the ALRs was 93%. DISCUSSION: The study revealed significant interobserver variability in the reporting of abnormal DMSA renal scans compared with the previously published studies. A noteworthy limitation was a lack of uniformity in local reporting of the scans. CONCLUSIONS: Our study highlights the need for optimizing the clinical yield of DMSA renal scans by more specific guidelines, particularly for standardized and uniform interpretation. PMID- 28711548 TI - Experience with specially designed pored polyacetal mold dressing method used in McIndoe-style vaginoplasty. AB - INTRODUCTION: Appropriate postoperative care and prolonged use of the mold are prerequisites for achieving successful results in McIndoe-style vaginoplasty. OBJECTIVE: We introduce a specially designed pored polyacetal mold to maintain the reconstructed vagina, with favorable long-term results allowing drainage of the serous and bloody discharge without removal of the mold, and reduction of infection rate and the chance of skin graft shearing in McIndoe vaginoplasty. METHODS: We retrospectively reviewed data of 10 consecutive patients with Mayer Rokitansky-Kuster-Hauser syndrome who underwent McIndoe vaginoplasty between March 2010 and January 2014. We used a specially designed pored polyacetal mold (Figure) in all reconstructed vaginal wounds. The anatomical surgical success was evaluated by physical examination and functional success, which was defined as satisfaction with sex evaluated by patient self-assessed questionnaire. RESULTS: The follow-up period ranged from 1 to 3.5 years. The postoperative mean vaginal length was 9.5 cm in nine patients who used the mold regularly. In all cases in which a pored polyacetal mold was used, skin engraftment was successfully maintained without partial skin graft loss or infection. The subjective patient self-assessed satisfaction evaluation reported a high satisfaction rate. DISCUSSION: The multi-holed polyacetal vaginal mold was designed to perform vaginal irrigation without removal of the mold, allowing drainage of the serous and bloody discharge. This makes it possible to reduce infection rate and maintain successful skin engraftment by reducing the chance of skin graft shearing. The characteristics of polyacetal make it useful as a vaginal mold material as it is lightweight to use, easy to manufacture in accordance with the dimensions of the neovaginal space, and cost-effective. Although a constant follow-up evaluation is required, the pored polyacetal mold is an attractive vaginal mold dressing material to maximize the initial graft uptake, and it can be individually tailored in patients undergoing McIndoe-style vaginoplasty. CONCLUSIONS: The specially designed vaginal mold made up of pored polyacetal is a proper vaginal mold, which could maximize the initial graft uptake, decrease the risk of wound infection, and, therefore, decrease contracture of the neovagina in patients undergoing McIndoe vaginoplasty. PMID- 28711549 TI - A case of hypocholesterolemia and steatosis in a carrier of a PCSK9 loss-of function mutation and polymorphisms predisposing to nonalcoholic fatty liver disease. AB - We report a new case of hypobetalipoproteinemia in a 44-year-old man of Peruvian origin exhibiting a heterozygous PCSK9 missense mutation (c.946 G>T, p. Gly316Cys). In vitro functional studies demonstrated that this mutation leads to a loss of function of PCSK9 on low-density lipoprotein receptor degradation. This patient exhibited liver steatosis; he was neither diabetic, nor obese or alcoholic, but is a carrier of 2 polymorphisms, p.Ile148Met (rs738409) and p.Glu167Lys (rs58542926) on PNPLA3 and TM6SF2 gene, respectively, previously shown to be associated with nonalcoholic steatosis and fibrosis evolution. These data suggested that if a resistance to hepatic steatosis mediated by the PCSK9 deficiency exists, as demonstrated in mice, it is not sufficient to prevent hepatic fatty accumulation in the case of genetic factors predisposing to nonalcoholic fatty liver disease. PMID- 28711550 TI - Chitosan whisker grafted with oligo(lactic acid) nanoparticles via a green synthesis pathway: Potential as a transdermal drug delivery system. AB - Chitosan whisker (CSWK) grafted with oligo(lactic acid) (OLA) nanoparticles (NPs) in water is developed to aid transferring therapeutic agents through the skin in a transdermal drug delivery system. Although several works in the past have shown grafting of poly(lactic acid) onto chitosan, the present work shows a green grafting system for the first time. The nano-sized CSWK provided effective conjugation of lactic acid even in a heterogeneous water-based system followed by polycondensation to form OLA. The OLA chain length is controlled by the lactic acid content and modulates the lipophilicity of CSWK-OLA. This fine tunes not only the size of the NPs but also the encapsulation efficiency of the hydrophobic drug lidocaine. A detailed chemical structure analysis, including the factors related to the development of NPs, is presented and extends the studies to the model drug encapsulation and delivery. PMID- 28711551 TI - From Evidence Based Medicine to Medicine Based Evidence. AB - Evidence based medicine, using randomized controlled trials and meta-analyses as the major tools and sources of evidence about average results for heterogeneous groups of patients, developed as a reaction against poorly designed observational treatment research and physician reliance on personal experience with other patients as a guide to decision-making about a patient at hand. However, these tools do not answer the clinician's question: "Will a given therapeutic regimen help my patient at a given point in her/his clinical course?" We introduce fine grained profiling of the patient at hand, accompanied by comparative evidence of responses from approximate matches to this patient on whom a contemplated treatment has/has not been administered. This represents medicine based evidence that is tuned to decision-making for the particular patient. PMID- 28711552 TI - 'Landolfi's Sign'-Eyes Don't See What the Mind Does Not Know! PMID- 28711553 TI - Sole-Searing Pain: Classic Kaposi's Sarcoma. PMID- 28711554 TI - Emphysematous Pancreatitis. PMID- 28711555 TI - Diabetes in the Older Patient: A Role for C-Peptide? PMID- 28711556 TI - Medicine Based Evidence for Individualized Decision Making: Case Study of Systemic Lupus Erythematosus. AB - BACKGROUND: To guide management decisions for an index patient, evidence is required from comparisons between approximate matches to the profile of the index case, where some matches contain responses to treatment and others act as controls. METHODS: We describe a method for constructing clinically relevant histories/profiles using data collected but unreported from 2 recent phase 3 randomized controlled trials assessing belimumab in subjects with clinically active and serologically positive systemic lupus erythematosus. Outcome was the Systemic lupus erythematosus Responder Index (SRI) measured at 52 weeks. RESULTS: Among 1175 subjects, we constructed an algorithm utilizing 11 trajectory variables including 4 biological, 2 clinical, and 5 social/behavioral. Across all biological and social/behavioral variables, the proportion of responders based on the SRI whose value indicated clinical worsening or no improvement ranged from 27.5% to 42.3%. Kappa values suggested poor agreement, indicating that each biological and patient-reported outcome provides different information than gleaned from the SRI. CONCLUSION: The richly detailed patient profiles needed to guide decision-making in clinical practice are sharply at odds with the limited information utilized in conventional randomized controlled trial analyses. PMID- 28711557 TI - Postprandial Hypoglycemia: Complication of Peptic Ulcer Surgery. AB - OBJECTIVE: Billroth II procedures (gastrojejunostomy with vagotomy) are seldom performed now but were popular before the advent of histamine 2 receptor blockers and proton pump inhibitors. Such procedures can be a cause of late postprandial hypoglycemia. METHODS: We performed a formal evaluation and discussion of postprandial hypoglycemia. RESULTS: We present a case of an 85-year-old man who presented to the endocrinology clinic with symptoms of "fainting spells after large meals." The patient previously had extensive evaluations by a neurologist and a cardiologist. Because of the history of Billroth II surgery and the description of his fainting spells, a 5-hour glucose tolerance test was performed in the clinic using the foods that uniformly resulted in symptoms. This confirmed that the late dumping syndrome with associated hypoglycemia was the cause of his spells. CONCLUSIONS: Late dumping syndrome manifesting with hypoglycemia should be considered in the workup of patients with a history of gastric surgery and unusual postprandial symptoms. This case highlights the importance of an appropriate workup that can lead to avoidance of unnecessary testing in such patients. PMID- 28711558 TI - Four Cancers and a Rash: Henoch-Schonlein Purpura. PMID- 28711559 TI - Outbreak of colistin-resistant carbapenemase-producing Klebsiella pneumoniae in Tunisia. AB - OBJECTIVES: Mechanisms of colistin and carbapenem resistance among a collection of Klebsiella pneumoniae isolates recovered in a university hospital in Tunisia were studied. METHODS: In vitro antimicrobial susceptibility testing, S1 nuclease pulsed-field gel electrophoresis (S1-PFGE), Southern blotting and PCR-based replicon typing (PBRT) were performed. Extended-spectrum beta-lactamases (ESBLs), carbapenemases, AmpC-type enzymes and mgrB genes were detected by PCR and sequencing. Clonality of isolates was assessed by PFGE and multilocus sequence typing (MLST). RESULTS: Of 940 Enterobacteriaceae isolates recovered from June 2015 to March 2016 in Tahar Sfar Hospital (Mahdia, Tunisia), 220 were identified as K. pneumoniae, among which 29 were carbapenem-resistant. Carbapenem resistance was mostly due to expression of blaOXA-48 or blaOXA-204 in combination with blaCMY-4. Seven isolates carried blaNDM-1, of which two also harboured blaOXA-48, together with blaCMY-16 in one of them. All but two isolates also harboured blaCTX-M-15. All 20 blaOXA-48 genes were part of transposon Tn1999 on an IncL plasmid, whereas blaOXA-204 was found on transposon Tn2016 on an IncA/C plasmid. Finally, all blaNDM-1 genes were located within a Tn125 transposon on an IncFIIk plasmid. Interestingly, 7 (24.1%) of 29 carbapenem-resistant isolates were resistant to colistin, of which 6 were assigned to ST101, had similar PFGE profiles and presented the same 2-kb insertion in the mgrB gene. CONCLUSIONS: This study reports, for the first time in Tunisia, the full molecular characterisation of colistin resistance in K. pneumoniae. There is an urgent need for control measures and prudent use of colistin in treatment of infections with carbapenemase-producing K. pneumoniae. PMID- 28711560 TI - Interaction of carbapenems and beta-lactamase inhibitors towards CTX-M-15 and CTX M-15G238C mutant. AB - OBJECTIVES: The aim of this study was to evaluate the role of residue 238 in CTX M-15 and CTX-M-15G238C mutant with respect to carbapenems and various beta lactamase inhibitors. METHODS: A CTX-M-15G238C laboratory mutant was generated by site-directed mutagenesis from CTX-M-15 enzyme by replacing glycine 238 with cysteine. Thiol titration and p-chloromercuribenzoate (PCMB) inactivation assays were used to ascertain the presence of a disulfide bridge in the active site of CTX-M-15G238C. Kinetic parameters were determined both for CTX-M-15 and CTX-M 15G238C enzymes by analysing either the complete hydrolysis time courses or under initial rate conditions. RESULTS: In CTX-M-15G238C mutant, the two cysteines (C69 and C238) located in the enzyme active site were unable to form a disulfide bridge. CTX-M-15 and thermostable CTX-M-15G238C were used to study the kinetic interaction with carbapenems, which behaved as poor substrates for both enzymes. Meropenem and ertapenem acted as transient inactivators for CTX-M-15 and CTX-M 15G238C, and for these compounds the variation of kobs versus the inactivator concentration was linear. Imipenem behaved as a transient inactivator for CTX-M 15 and as an inactivator (with k+3=0) for CTX-M-15G238C. In any case, the k+2/K values for CTX-M-15G238C were higher than those for CTX-M-15. CONCLUSIONS: Compared with CTX-M-15, CTX-M-15G238C mutant appears to have a more favourable conformation for carbapenem acylation and higher activity against cefotaxime, which could be due to the presence of free -SH groups in the enzyme active site. PMID- 28711561 TI - Sensory processing disorder in preterm infants during early childhood and relationships to early neurobehavior. AB - BACKGROUND: Preterm infants are exposed to a variety of sensory stimuli that they are not developmentally prepared to handle, which puts them at risk for developing a sensory processing disorder. However, the patterns and predictors of sensory processing disorder and their relationship to early behavior at term equivalent age are poorly understood. OBJECTIVES: The aims of the study are to: 1) describe the incidence of sensory processing disorder in preterm infants at four to six years of age, 2) define medical and sociodemographic factors that relate to sensory processing disorder, and 3) explore relationships between early neurobehavior at term equivalent age and sensory processing disorder at age four to six years. METHODS: This study was a prospective longitudinal design. Thirty two preterm infants born <=30weeks gestation were enrolled. Infants had standardized neurobehavioral testing at term equivalent age with the NICU Network Neurobehavioral Scale. At four to six years of age, participants were assessed with the Sensory Processing Assessment for Young Children (SPA). RESULTS: Sixteen children (50%) had at least one abnormal score on the SPA, indicating a sensory processing disorder. There were no identified relationships between medical and sociodemographic factors and sensory processing disorder. More sub-optimal reflexes (p=0.04) and more signs of stress (p=0.02) at term equivalent age were related to having a sensory processing disorder in early childhood. CONCLUSION: Preterm infants are at an increased risk for developing a sensory processing disorder. Medical and sociodemographic factors related to sensory processing disorder could not be isolated in this study, however relationships between sensory processing disorder and early neurobehavior were identified. PMID- 28711562 TI - Early executive function differences in infants born moderate-to-late preterm. AB - Individuals who are born very preterm (<32weeks gestation) show differential development of prefrontal cortex structure, function, and dependent behaviors, including executive function (EF) skills, beginning during late infancy and extending into adulthood. Preschool-aged children born moderate-to-late preterm (PT; 32-36weeks gestation) show smaller discrepancies in EF development, but it is unclear whether these differences first emerge during the early childhood years, when EF is rapidly developing, or if they arise from alterations in complex cognitive skills measurable in late infancy. In the current study, we examined whether differences in complex attention, memory, and inhibition skills (precursor skills to EF) are altered in healthy infants born moderate-to-late PT at 9-months corrected age. Infants born PT demonstrated poorer memory at test following habituation than their full-term peers. Furthermore, lower gestational age at birth was associated with poorer performance on five of the six early EF tasks. Results indicate that even in the context of low medical and environmental risk, performance on the Bayley within the normal range, and no group-level differences in processing speed, infants born moderate-to-late PT show subtle alterations in cognitive skills presumed to be dependent on prefrontal cortex by 9-months of age, likely setting the stage for long-term differences in EF development. PMID- 28711563 TI - Application of neurite orientation dispersion and density imaging or diffusion tensor imaging to quantify the severity of cervical spondylotic myelopathy and to assess postoperative neurologic recovery. AB - BACKGROUND CONTEXT: Surgical outcome and the severity of cervical spondylotic myelopathy (CSM) are unpredictable and cannot be estimated by conventional anatomical magnetic resonance imaging (MRI). The utility of diffusion tensor imaging (DTI) to quantify the severity of CSM and to assess postoperative neurologic recovery has been investigated. However, whether conventional DTI should be applied in a clinical setting remains controversial. Neurite orientation dispersion and density imaging (NODDI) is a recently introduced model based diffusion-weighted MRI technique that quantifies specific microstructural features related directly to neuronal morphology. However, there are as yet few clinical applications of NODDI reported. Indeed, there are no reports to indicate NODDI is useful for diagnosing CSM. STUDY DESIGN: This is a retrospective cohort study using consecutive patients. PURPOSE: The objective of this study was to evaluate the utility of NODDI and conventional DTI for detecting changes in the spinal cord microstructure. In particular, this study aimed to quantify the preoperative severity of CSM and to assess postoperative neurologic recovery from this myelopathy. PATIENT SAMPLE: We included 27 consecutive patients with a nontraumatic cervical lesion from CSM who underwent laminoplasty at a single institution between April 2012 and April 2015. The patients underwent MRI before and approximately 2 weeks after surgery. OUTCOME MEASURES: In addition to conventional DTI metrics, we evaluated the intracellular volume fraction (ICVF) and the orientation dispersion index (ODI), which are metrics derived from NODDI. The 10-second grip and release test and the Japanese Orthopaedic Association scoring system were used before and 1 year after surgery to assess neurologic outcome. MATERIALS AND METHODS: Neurite orientation dispersion and density imaging and conventional DTI values were measured at the C2-C3 intervertebral level (control value) and at the most compressed levels (C3-C7 intervertebral levels) were measured. The changes in these values pre- and postoperative were demonstrated. Correlations between NODDI and conventional DTI values and clinical outcome were determined. RESULTS: Preoperative fractional anisotropy was significantly correlated with the severity of neural damage, but not with postoperative neurologic recovery. No significant correlation could be found between the preoperative ICVF, the ODI, the apparent diffusion coefficient, and the severity of the preoperative neurologic dysfunction. Preoperative ICVF was most strongly correlated with the severity of neurologic dysfunction and postoperative neurologic recovery. CONCLUSIONS: Conventional DTI may be applied clinically to assess the severity of myelopathy. Neurite orientation dispersion and density imaging may be more valuable than conventional DTI to predict outcome following surgery in patients with CSM. PMID- 28711564 TI - Role of estrogen and levodopa in 1-methyl-4-pheny-l-1, 2, 3, 6-tetrahydropyridine (mptp)-induced cognitive deficit in Parkinsonian ovariectomized mice model: A comparative study. AB - Parkinson's disease (PD) is one of the most common neurodegenerative disease found in the aging population. Currently, many studies are being conducted to find a suitable and effective cure for PD, with an emphasis on the use of herbal plants. In this study, the neuroprotective effects of estrogen was evaluated in the 1-methyl-4-phe-nyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD with cognitive deficit and compared to Levodopa (LD), a well reported neuroprotective agent used for treating PD. Twenty-four Swiss albino mice were randomly divided into four groups: Control, MPTP, MPTP+LD and MPTP+estrogen. The behavioral recovery in both LD and estrogen treated mice were investigated using the rotarod, foot printing, narrow beam walking test and hanging tests. Non-motor behavioral recovery in both LD and estrogen treated were investigated using the Y maze and Morris water maze. Furthermore, we performed the biochemical test i.e. catalase, lipid and nitrite in prefrontal cortex as well as nigrostriatal region of mouse brain. We also performed the acetylcholine esterase activity in prefrontal cortex and nigrostriatal region of mice brain. The recovery of dopamine neurons in the substantia nigra (SN) region was estimated by immunostaining of tyrosine hydroxylase (TH). Estrogen treatment restored all the deficits induced by MPTP more effectively than levodopa. Estrogen treatment recovered the number of TH-positive cells in both the SN region. Treatment with Estrogen significantly increased the levels of catalase, decreased the level of lipid and nitite in both region SN as well as prefrontal cortex region. Notably, the effect of estrogen was greater than that elicited by levodopa. Acetylcholine esterase activity was significantly increased in MPTP and it was found to be decreased by the treatment of estrogen as well as levodopa, although decrease in the activity was highly significant in estrogen treated group. Our result suggested that estrogen treatment significantly reduced the MPTP induced neurotoxicity as evident by decrease in oxidative damage, physiological abnormalities and immunohistochemical changes in the Parkinsonian mouse with cognitive deficit as compared to levodopa treatment. PMID- 28711565 TI - New aspects of molecular imaging in prostate cancer. AB - Nowadays several new imaging modalities are available for investigating prostate cancer (PCa) such as magnet resonance imaging (MRI) in the form of whole body MRI and pelvic multiparametric MRI and positron emission tomography (PET) using choline as radiotracers. Nevertheless, these modalities proved sub-optimal accuracy for detecting PCa metastases, particularly in the recurrence setting. A new molecular probe targeting the prostate specific membrane antigen (PSMA) has been recently developed for PET imaging. PSMA, the glutamate carboxypeptidase II, is a membrane bound metallo-peptidase over-expressed in PCa cells. It has been shown that PSMA based imaging offers higher tumor detection rate compared to choline PET/CT and radiological conventional imaging, especially at very low PSA levels during biochemical recurrence. In addition PSMA, as theranostics agent, allows both radiolabeling with diagnostic (e.g. 68Ga, 18F) or therapeutic nuclides (e.g. 177Lu, 225Ac). Initial results show that PSMA-targeted radioligand therapy can potentially delay disease progression in metastatic castrate resistant PCa. Despite still investigational, the bombesin-based radiotracers and antagonist of gastrin releasing-peptide receptor (GRP) (RM2) and anti1-amino-3 18Ffluorocyclobutane-1-carboxylic acid (18F-FACBC) are emerging as possible alternatives for investigating PCa. Considering the wide diffusion of PCa in the Europe and the United States, the presence of these new diagnostic techniques able to detect the disease with high sensitivity and specificity might have a clinical impact on the management of patients. PET/CT imaging with new radiopharmaceuticals can implement the patient management identifying lesion(s) not detectable with conventional imaging procedures. In this review article will be discussed the most promising new PET radiopharmaceuticals (68Ga-PSMA-11, 18F FACBC, 68Ga-RM2) available at the moment, focusing the attention on their accuracy and their impact on treatment strategy. PMID- 28711566 TI - Developmental toxicity of oxidized multi-walled carbon nanotubes on Artemia salina cysts and larvae: Uptake, accumulation, excretion and toxic responses. AB - Using Artemia salina (A. salina) cysts (capsulated and decapsulated) and larvae [instar I (0-24 h), II (24-48 h) and III (48-72 h)] as experimental models, developmental toxicity of oxidized multi-walled carbon nanotubes (O-MWCNTs) was evaluated. Results revealed that hatchability of capsulated and decapsulated cysts was significantly decreased (p < 0.01) following exposure to 600 mg/L for 36 h. Mortality rates were 33.8, 55.7 and 40.7% for instar I, II and III larvae in 600 mg/L. The EC50 values for swimming inhibition of instar I, II and III were 535, 385 and 472 mg/L, respectively. Instar II showed the greatest sensitivity to O-MWCNTs, and followed by instar III, instar I, decapsulated cysts and capsulated cysts. Effects on hatchability, mortality and swimming were accounted for O MWCNTs rather than metal catalyst impurities. Body length was decreased with the concentrations increased from 0 to 600 mg/L. O-MWCNTs attached onto the cysts, gill and body surface, resulting in irreversible damages. Reactive oxygen species, malondialdehyde content, total antioxidant capacity and antioxidant enzymes (superoxide dismutase, catalase and glutathione peroxidase) activities were increased following exposure, indicating that the effects were related to oxidative stress. O-MWCNTs were ingested and distributed in phagocyte, lipid vesicle and intestine. Most of the accumulated O-MWCNTs were excreted by A. salina at 72 h, but some still remained in the organism. Data of uptake kinetics showed that O-MWCNTs contents in A. salina were gradually increased from 1 to 48 h and followed by rapidly decreased from 48 to 72 h with a range from 5.5 to 28.1 mg/g. These results so far indicate that O-MWCNTs have the potential to affect aquatic organisms when released into the marine ecosystems. PMID- 28711567 TI - The trans-continental distributions of pentachlorophenol and pentachloroanisole in pine needles indicate separate origins. AB - The production and use of pentachlorophenol (PCP) was recently prohibited/restricted by the Stockholm Convention on persistent organic pollutants (POPs), but environmental data are few and of varying quality. We here present the first extensive dataset of the continent-wide (Eurasia and Canada) occurrence of PCP and its methylation product pentachloroanisole (PCA) in the environment, specifically in pine needles. The highest concentrations of PCP were found close to expected point sources, while PCA chiefly shows a northern and/or coastal distribution not correlating with PCP distribution. Although long-range transport and environmental methylation of PCP or formation from other precursors cannot be excluded, the distribution patterns suggest that such processes may not be the only source of PCA to remote regions and unknown sources should be sought. We suggest that natural sources, e.g., chlorination of organic matter in Boreal forest soils enhanced by chloride deposition from marine sources, should be investigated as a possible partial explanation of the observed distributions. The results show that neither PCA nor total PCP (SigmaPCP = PCP + PCA) should be used to approximate the concentrations of PCP; PCP and PCA must be determined and quantified separately to understand their occurrence and fate in the environment. The background work shows that the accumulation of airborne POPs in plants is a complex process. The variations in life cycles and physiological adaptations have to be taken into account when using plants to evaluate the concentrations of POPs in remote areas. PMID- 28711568 TI - Is prehypertension more strongly associated with long-term ambient air pollution exposure than hypertension? Findings from the 33 Communities Chinese Health Study. AB - Numerous studies have evaluated the effects of long-term exposure to ambient air pollution on hypertension. However, little information exists regarding its effects on prehypertension, a very common, but understudied cardiovascular indicator. We evaluated data from 24,845 adults (ages 18-74 years) living in three Northeastern Chinese cities in 2009. Blood pressure (BP) was measured by trained observers using a standardized mercuric-column sphygmomanometer. Three year (from 2006 to 2008) average concentrations of particles with an aerodynamic diameter <=10 MUm (PM10), sulfur dioxide (SO2), nitrogen dioxides (NO2), and ozone (O3) were calculated using data from monitoring stations. Effects were analyzed using generalized additive models and two-level regression analyses, controlling for covariates. We found positive associations of all pollutants with prehypertension (e.g. odds ratio (OR) was 1.17 (95% confidence interval (CI), 1.09-1.25) per interquartile range (IQR) of PM10) in a fully adjusted model, as compared to normotensive participants. These associations were stronger than associations with hypertension (e.g. OR was 1.03 (95% CI, 1.00, 1.07) per IQR of PM10). We have also found positive associations of all studied pollutants with systolic and diastolic BP: e.g., associations with PM10 per IQR were 1.24 mmHg (95% CI, 1.03-1.45) for systolic BP and 0.47 mmHg (95% CI, 0.33-0.61) for diastolic BP. Further, we observed that associations with BP were stronger in women and in older participants (systolic BP only). In conclusion, long-term exposure to ambient air pollution was more strongly associated with prehypertension than with hypertension, especially among females and the elderly. Thus, interventions to reduce air pollution are of great significance for preventing future cardiovascular events, particularly among individuals with prehypertension. PMID- 28711570 TI - Anesthetic Management of Reversible Cerebral Vasoconstriction Syndrome: A Case Report. AB - Reversible cerebral vasoconstriction syndrome (RCVS) is a group of disorders characterized by prolonged reversible cerebral vasoconstriction, associated with acute-onset, severe, episodic "thunderclap" headaches with or without other neurologic clinical features. We describe the first reported case, to our knowledge, of a patient with RCVS who was managed under general anesthesia in the field of oral and maxillofacial surgery. A 67-year-old woman with a diagnosis of RCVS made 2 months earlier was scheduled to undergo surgical extraction of the mandibular right third molar. Standard monitoring included noninvasive blood pressure measurement, pulse oximetry, and electrocardiography; a bispectral index (BIS) monitor sensor was placed on her forehead. General anesthesia was induced by target-controlled infusion of propofol to an effect site concentration of 5.0 MUg . mL-1, with remifentanil, 0.50 MUg . kg-1 per minute, and rocuronium, 40 mg. After tracheal intubation, anesthesia was maintained uneventfully with remifentanil, 0.15 to 0.2 MUg . kg-1 per minute, and propofol, 2.0 to 3.0 MUg . mL-1, in oxygen and air. The end-tidal carbon dioxide concentration was maintained at 38 to 42 mm Hg. The BIS reading was 40 to 60. Fentanyl, 0.1 mg, and acetaminophen, 750 mg, were administered before the end of surgery for postoperative analgesia. The postoperative course was uneventful, with no headaches or hypertensive complications. We successfully achieved anesthetic management with no appreciable clinical signs of cerebral ischemia or recurrence in a patient with RCVS. We used propofol as the anesthetic agent with BIS monitoring to detect cerebral ischemia. However, there is no definitive evidence of the utility of these measures for the prevention or diagnosis of RCVS, and further study is needed. PMID- 28711569 TI - The influence of land use on source apportionment and risk assessment of polycyclic aromatic hydrocarbons in road-deposited sediment. AB - The pollution load of urban runoff is boosted due to the washing away of road deposited sediment (RDS). Therefore, a source-oriented mitigation strategy is essential to integrated stormwater management. This study showcases the influence of land use dependent source apportionment and risk assessment of polycyclic aromatic hydrocarbons (PAHs) in RDS. Samples were collected from areas of different land uses, including commercial city centre, highway, residential rural and campus areas. According to the positive matrix factorisation (PMF) receptor model, different primary sources were identified at different land use areas. Generally, potential sources of gasoline- and diesel-powered engine emissions and other pyrogenic sources of biomass, coal, and wood combustions were identified as main sources of PAH content in RDS. The source specific risks posed by PAHs at different land uses were further estimated by the incremental lifetime cancer risk (ILCR). This shows that the mean ILCRs of the total cancer risk for children and adults at the given land uses were lower than the baseline value of an acceptable risk. However, the potential exposure risk to RDS adsorbed PAHs for children was considerably higher than that for adults. Vehicular emissions and wood combustion were the major contributors to the cancer risk with average contributions of 57 and 29%, respectively. PMID- 28711571 TI - Effectiveness of Single-dose Rasburicase in Patients With Lymphoid Malignancies at a High Risk for Tumor Lysis Syndrome. AB - BACKGROUND: Tumor lysis syndrome (TLS) is a life-threatening disorder that occurs mainly in patients with high-tumor burden hemato-oncologic malignancies. It results in metabolic derangements, including hyperuricemia and acute renal failure. The powerful management for TLS is a daily dose of rasburicase for up to 5 days before chemotherapy; however, the optimal dose and duration of rasburicase for TLS prophylaxis have not been standardized for patients at high risk for TLS. Therefore, we evaluated the efficacy of single-dose rasburicase for prophylactic purposes in patients with malignant lymphoma at high risk for TLS. PATIENTS AND MATERIALS: We retrospectively evaluated patients with malignant lymphoma at high risk for TLS treated with a prophylactic single-dose of rasburicase (0.1-0.2 mg/kg) from March 2012 to March 2016. RESULTS: A total of 67 patients treated with a single-dose of rasburicase for prophylaxis were analyzed. A relatively large number of patients (n = 23; 34.3%) had the highly proliferative lymphoblastic lymphoma subtype (n = 14) or Burkitt lymphoma (n = 9) and were at the highest risks of tumor lysis. Two patients were newly diagnosed with TLS; the incidence of TLS after single-dose prophylaxis was 3.0%. Multivariate analysis revealed no predictable risk factors for response to prophylactic rasburicase, though increased level of serum creatinine approached statistical significance in reducing the efficacy of single-dose rasburicase to prevent TLS (odds ratio, 3.61; P = .054). CONCLUSION: Our data indicated that single-dose rasburicase effectively prevented progression of TLS, and, regardless of any risk factors, including increased creatinine, single-dose rasburicase for TLS prophylaxis was useful in patients with lymphoma at a high risk for TLS. PMID- 28711572 TI - Emerging Strategies in Treating Double Hit Lymphomas. AB - Double hit lymphomas (DHLs) are a new category in the World Health Organization newest classification for lymphoid malignancies. DHL encompasses various histologies of lymphomas where the MYC oncogene and either BCL2 or BCL6 oncogenes are present concomitantly. Several observational studies and retrospective series have demonstrated that patients with DHL carry a poor prognosis and respond less and for a shorter duration to standard R-CHOP (rituximab, cyclophosphamide, vincristine, adriamycin, and prednisone). These studies have also proposed that dose intensification (with Burkitt-like regimens such as DA-EPOCH-R [dose adjusted rituximab, etoposide, vincristine, Adriamycin, cyclophosphamide, and prednisone]) might offer patients with DHL better outcomes and improved prognosis. In this timely review, we discuss incidence of DHL, testing implications of MYC translocation, current treatment strategies, and future directions. Understanding this entity and its therapeutic consequences is essential to improve patients' outcomes. PMID- 28711573 TI - Distribution and Impact of Comorbidities on Survival and Leukemic Transformation in Myeloproliferative Neoplasm-Associated Myelofibrosis: A Retrospective Cohort Study. AB - BACKGROUND: We sought to describe the distribution and impact of comorbidities on outcomes in patients with myelofibrosis, a disease characterized by aberrant bone marrow function with eventual fibrosis. Comorbidities were scored using the Adult Comorbidity Evaluation-27 (ACE-27) and the Hematopoietic Cell Transplant Comorbidity Index (HCT-CI), in which a score >= 3 indicates severe comorbidities. PATIENTS AND METHODS: We conducted a retrospective study of 306 patients with a confirmed diagnosis of myelofibrosis. Patients were seen from 1999 to 2014 with a median follow-up of 2 years. Multivariable Cox proportional hazards models were constructed to assess the impact of comorbidities on overall survival and leukemic transformation from the date of presentation to our center. A series of descriptive analyses were performed examining the distribution of comorbidities captured by the scales. RESULTS: On multivariable survival analysis, an ACE-27 score of 3 was associated with an almost twofold increase in the risk of all cause death (hazard ratio [HR] 1.95; 95% confidence interval [CI], 1.06-3.58; P = .03) compared with a lower score of 0 to 1. An HCT-CI score >= 3 was marginally significantly associated with an increased risk of all-cause death (HR 1.60; 95% CI 0.96-2.68; P = .07). ACE-27 captured a greater spectrum of cardiovascular and venous thrombotic disease. No impact of comorbidities on leukemic transformation was observed. CONCLUSIONS: Although the presence of severe comorbidities was lower when assessed by ACE-27 (13%) compared with HCT-CI (23%), and the spectrums of comorbidities captured were different, the overall impact of severe comorbidities as assessed by both scales appears to be similar and associated with a survival disadvantage. PMID- 28711574 TI - Bath Psoralen-ultraviolet A and Narrowband Ultraviolet B Phototherapy as Initial Therapy for Early-stage Mycosis Fungoides: A Retrospective Cohort of 267 Cases at the University of Toronto. AB - BACKGROUND: Phototherapy is used frequently to treat early-stage mycosis fungoides (MF). The effectiveness of bath psoralen-ultraviolet A (bath PUVA) and narrowband ultraviolet B (nbUVB) in MF is well established. However, evidence is limited comparing the effectiveness of the 2 modalities for early-stage MF. The objective of the present study was to compare the responses between the study participants receiving bath PUVA versus nbUVB phototherapy. PATIENTS AND METHODS: The study included a retrospective cohort of stage 1A and 1B MF patients treated with bath PUVA or nbUVB at their initial presentation. The primary outcome was the response to treatment. The secondary outcome was disease-free survival. RESULTS: The cohort included 267 patients (158 treated with bath PUVA and 109 treated with nbUVB) with a mean age of 45.22 years. The mean follow-up period was 59.58 months for bath PUVA and 22.27 months for nbUVB. Overall, 88.61% of the bath PUVA group and 88.07% of the nbUVB group had complete responses (P = .89). The median number of treatments to achieve a complete response was 55 for bath PUVA and 55.5 for nbUVB (P = .63). The median disease-free survival was 43.25 months for bath PUVA and 14.9 months for nbUVB (P < .0001). The study was limited by its retrospective nature. CONCLUSION: Bath PUVA and nbUVB are both effective treatments. The use of bath PUVA resulted in significantly greater disease-free survival. PMID- 28711575 TI - How to Approach a Patient With Limited Stage Hodgkin Lymphoma Who Remains PET Positive at the End of Chemotherapy: Radiation Therapy? AB - The use of 18-F fluorodeoxyglucose (FDG) positron emission tomography (PET) with computed tomography has emerged as a crucial tool for response-adapted therapy in Hodgkin lymphoma (HL). Although more studies have focused on the predictive value of an interim or early PET obtained after 2 cycles of chemotherapy, there are indications that the end of therapy PET might even be more predictive of outcome. The optimal treatment of patients with limited stage HL who are PET-positive after chemotherapy is unknown. Here we review the prognostic significance of end of treatment PET in early stage HL, the role of consolidative radiotherapy in patients who have FDG-PET avidity at the end of chemotherapy, and discuss the place of salvage chemotherapy and autologous transplantation in these patients. PMID- 28711576 TI - Explaining coexistence of nitrogen fixing and non-fixing rhizobia in legume rhizobia mutualism using mathematical modeling. AB - In the mutualism established between legumes and soil bacteria known as rhizobia, bacteria from soil infect plants roots and reproduce inside root nodules where they fix atmospheric N2 for plant nutrition, receiving carbohydrates in exchange. Host-plant sanctions against non N2 fixing, cheating bacterial symbionts have been proposed to act in the legume-Rhizobium symbiosis, to preserve the mutualistic relationship. Sanctions include decreased rhizobial survival in nodules occupied by cheating rhizobia. Previously, a simple population model experimentally based showed that the coexistence of fixing and cheating rhizobia strains commonly found in field conditions is possible, and that the inclusion of sanctions leads to the extinction of cheating strains in soil. Here, we extend the previous model to include other factors that could complicate the sanction scenario, like horizontal transmission of symbiotic plasmids, turning non nodulating strains into nodulating rhizobia, and competition between fixing and cheating strains for nodulation. In agreement with previous results, we show that plant populations persist even in the presence of cheating rhizobia without incorporating any sanction against the cheater populations in the model, under the realistic assumption that plants can at least get some amount of fixed N2 from the effectively mutualistic rhizobia occupying some nodules. Inclusion of plant sanctions leads to the unrealistic extinction of cheater strains in soil. Our results agree with increasing experimental evidence and theoretical work showing that mutualisms can persist in presence of cheating partners. PMID- 28711577 TI - A randomised phase II study of continuous versus stop-and-go S-1 plus oxaliplatin following disease stabilisation in first-line chemotherapy in patients with metastatic gastric cancer. AB - OBJECTIVES: We compared continuous versus stop-and-go chemotherapy after disease stabilisation with induction chemotherapy in the first-line treatment of metastatic gastric cancer (MGC). METHODS: MGC patients who achieved disease control after 6 cycles of S-1/oxaliplatin (SOX) were randomised to receive either continuous SOX until progression (continuous arm) or to have a chemotherapy-free interval followed by SOX reintroduction at progression (stop-and-go arm). The primary end-point was overall survival (OS). RESULTS: Of the 250 patients enrolled, 247 participated in the induction phase. Of these, 121 patients were randomised to the continuous arm (n = 59) or the stop-and-go arm (n = 62). Progression-free survival (PFS) was significantly longer in the continuous arm than in the stop-and-go arm (10.5 versus 7.2 months; hazard ratio [HR] 0.55, 95% CI, 0.37-0.81; P = 0.002). Duration of disease control (DDC) and OS, however, were comparable between the two arms: median DDC, 10.5 versus 11.3 months, HR 0.92 (95% CI, 0.62-1.36; P = 0.674); median OS, 22.6 versus 22.7 months, HR 0.78 (95% CI, 0.50-1.23; P = 0.284). Adverse events including grade >=3 fatigue (28.8% versus 8.1%; P = 0.003) and sensory neuropathy (25.4% versus 9.7%; P = 0.022) occurred more frequently in the continuous arm than in the stop-and-go arm. Quality of life (QOL) including global health status, physical/role functioning and other symptom scores significantly favoured the stop-and-go arm. CONCLUSION: Compared with the stop-and-go strategy, maintenance chemotherapy improved PFS but not DDC and OS and had a negative impact on QOL, suggesting the stop-and-go strategy may be an appropriate option in MGC patients following induction chemotherapy. PMID- 28711579 TI - Classification of eosinophilic granulomatosis with polyangiitis phenotypes and treatment based on phenotypes. PMID- 28711578 TI - Breast cancer in South-Eastern European countries since 2000: Rising incidence and decreasing mortality at young and middle ages. AB - BACKGROUND: Marked variations exist in the incidence and mortality trends of major cancers in South-Eastern European (SEE) countries which have now been detailed by age for breast cancer (BC) to seek clues for improvement. METHODS: We brought together and analysed data from 14 cancer registries (CRs), situated in SEE countries or directly adjacent. Age-standardised rate at world standard (ASRw) and truncated incidence and mortality rates during 2000-2010 by year, and for four age groups, were calculated. Average annual percentage change of rates was estimated using Joinpoint regression. RESULTS: Annual incidence rates increased significantly in countries and age groups, by 2-4% (15-39 years), 2-5% (40-49), 1-4% (50-69) and 1-6% (at 70+). Mortality rates decreased significantly in all age-groups in most countries, but increased up to 5% annually above age 55 in Ukraine, Serbia, Moldova and Cyprus. The BC data quality was evaluated by internationally agreed indicators which appeared suboptimal for Moldova, Bosnia and Herzegovina and Romania. CONCLUSION: The observed variations of incidence trends reflect the influence of risk factors, as well as levels of early detection activities (screening). While mortality rates were mostly decreasing, probably due to improved cancer care and introduction of more effective systemic treatment regimens, the worrying increasing mortality trends in the 55-plus age groups in some countries have to be addressed by health professionals and policymakers. In order to assess and monitor the effects of cancer control activities in the region, the CRs need substantial investments. PMID- 28711580 TI - Lateral rectus muscle resection following maximal recession of the medial rectus muscle in thyroid eye disease. AB - BACKGROUND: Rectus muscle restriction is a common finding in thyroid eye disease (TED). Typically, restricted muscles are recessed to address strabismus and diplopia. However, some patients have residual strabismus following maximal recession of a restricted muscle. The purpose of this study was to report outcomes following resection of the lateral rectus muscle after maximal recession of the medial rectus muscle in patients with TED. METHODS: The medical records of patients with TED who underwent lateral rectus resection between 1998 and 2015 were reviewed retrospectively. Information regarding thyroid disease history and surgical treatment, including history of orbital decompressions, rectus muscle recessions, rectus muscle resections, and pre- and postoperative alignment was collected. Adjustable suture was used in all cases. Success was defined as a postoperative orthotropia with <=2Delta of phoria at distance and a phoria at near. RESULTS: A total of 11 patients were included. Of these, 10 (91%) required postoperative adjustment. A successful outcome was achieved in 10 cases (91%). CONCLUSIONS: Lateral rectus muscle resection to address residual esotropia and diplopia was effective at reducing residual esotropia following medial rectus recession in our study cohort. PMID- 28711581 TI - Reply. PMID- 28711582 TI - A novel Wnt pathway inhibitor, SM04690, for the treatment of moderate to severe osteoarthritis of the knee: results of a 24-week, randomized, controlled, phase 1 study. AB - OBJECTIVE: To assess the safety, pharmacokinetics, and exploratory efficacy of SM04690, a novel Wnt pathway inhibitor, as a potential disease modifying treatment for knee osteoarthritis (OA). DESIGN: Subjects with Kellgren-Lawrence grade 2-3 knee OA were randomized in successive dose-escalation cohorts to receive a knee intra-articular (IA) injection with 0.03, 0.07, or 0.23 mg SM04690, or placebo (PBO) (4:1 ratio). Safety, pharmacokinetics, efficacy (WOMAC Total/Function/Pain, Pain VAS, Physician Global Assessment [MDGA], and OMERACT OARSI Response), OA-related biomarker (P1NP, beta-CTX, and cartilage oligomeric matrix protein [COMP]), and radiographic/imaging data were collected at baseline and during 24-week follow-up. RESULTS: 61 subjects (SM04690 n = 50; PBO n = 11) enrolled. Two dose limiting toxicities (DLTs), increased pain following injection and paroxysmal tachycardia (also the single serious AE), were reported in the 0.07 mg cohort. A total of 72 AEs were reported; Sixteen (occurring in eight subjects) were considered related to study medication. There were three discontinuations; one due to an AE (0.03 mg cohort). Bone marrow edema (BME) remained constant for most subjects. No doses were excluded from further study due to DLT criteria. Plasma levels of SM04690 were below the limit of detection at all time points. At Week 24, improvements from baseline were seen in all cohorts for the exploratory measures WOMAC Total, WOMAC Function, WOMAC Pain, MDGA, Pain VAS, and OMERACT-OARSI response. Joint space width (JSW) improvement was observed in the 0.07 mg cohort (P = 0.02 vs PBO). CONCLUSION: SM04690 appeared safe and well tolerated, with no evidence of systemic exposure. Exploratory efficacy analyses suggested positive trends for measurements of OA pain, function and disease-modifying osteoarthritis drug (DMOAD) properties. CLINICALTRIALS. GOV REGISTRATION: NCT02095548. PMID- 28711583 TI - Incidence of symptomatic osteochondritis dissecans lesions of the knee: a population-based study in Olmsted County. AB - OBJECTIVE: To (1) define population-based incidence of knee Osteochondritis dissecans (OCD) lesions using the population of Olmsted County, (2) examine trends over time, and (3) evaluate rate of surgical management over time. METHOD: Study population included 302 individuals who were diagnosed with knee OCD lesions between January 1, 1976 and December 31, 2014. Complete medical records were reviewed to extract injury and treatment details. Age- and gender-specific incidence rates were calculated and adjusted to the 2010 US population. Poisson regression analyses were performed to examine incidence and surgery trends by age, gender, and calendar period. RESULTS: Overall age- and gender-adjusted incidence annual incidence of knee OCD lesions was 6.09 per 100,000 person-years. The incidence was significantly higher (P < 0.001) in males (8.82, 95% CI 7.63 to 10.00 per 100,000) compared to females (3.32, 95% CI 2.61 to 4.04 per 100,000). Age- and gender-specific incidence was highest in both males and females in the 11-15 years old at 39.06 and 16.15 per 100,000, respectively. In males aged 11-15 years, OCD incidence increased significantly over the study period from 20.68 in 1976-1985 to 48.16 in 2006-2014 (per 100,000). CONCLUSIONS: Overall age- and gender-adjusted annual incidence of knee OCD lesions in the Olmsted Country Population was 6.09 per 100,000 person-years with a significantly higher incidence in males compared to females. The highest incidence for both males and females occurred between the ages 11-15 years. Trends indicate increasing OCD incidence in younger males and decreasing surgical management in females over the last decade. PMID- 28711584 TI - Biomarkers reflect differences in osteoarthritis phenotypes of the lumbar spine: the Johnston County Osteoarthritis Project. AB - OBJECTIVE: To determine differences in biomarker levels between radiographic phenotypes of facet joint osteoarthritis (FOA) only, spine OA only ((disc space narrowing (DSN) and vertebral osteophytes (OST)) or the combination of FOA and spine OA. DESIGN: A cross-sectional analysis of data from 555 participants in the Johnston County Osteoarthritis Project was performed. Lumbar spine levels were graded by severity (OST and DSN) and presence (FOA) of degeneration. Biomarkers included hyaluronan (HA) and type II collagen (CTX-II). Adjusted risk ratios (aRRR) were estimated using multinomial regression, with adjustment for age, race, sex, body mass index (BMI), and radiographic OA (knee, hip, hand). Interactions were tested between sex, race and low back symptoms. RESULTS: FOA only was present in 22.4%, 14.5% had spine OA only, and 34.6% had the combination of FOA and spine OA. Compared to the reference group of neither FOA or spine OA, a one unit higher ln HA level was associated with 31% higher relative risk ratio (RRR = 1.31 (95% 1.03, 1.67)) of having FOA only, while, a one unit higher lnuCTX II level was associated with 84% higher relative risk ratio (RRR = 1.84 (95% CI 1.19, 2.84)) of having spine OA only. No significant interactions were identified. CONCLUSION: Interestingly, OA affecting the synovial facet joint was associated with a marker of inflammation (HA). Spine OA, affecting intervertebral discs that contain collagen type II, was associated with a marker reflecting collagen type II degradation (CTX-II). These findings suggest that biomarkers may reflect the different pathophysiologic processes of lumbar spine OA phenotypes. PMID- 28711586 TI - Achieving safe, effective, and durable Zika virus vaccines: lessons from dengue. AB - Newly proposed candidate Zika virus vaccines might or might not succeed in raising safe, effective, and durable protection against human Zika virus infections or syndromes. Analyses of a clinically tested and licensed dengue vaccine that failed to protect seronegative individuals from breakthrough or enhanced dengue infections suggest that poor T-cell immunity might have contributed to protection failure. Because of the similarity of Zika and dengue viruses, an analogous unwanted outcome might occur with some Zika virus vaccine designs. A successful Zika virus vaccine requires challenge experiments that are done at long intervals after immunisation and that identify protection as the absence of viraemia and the absence of an anamnestic antibody response. T-cell immunity might be an essential component of safe, efficacious, and durable Zika virus vaccines. PMID- 28711587 TI - Mycobacterium chimaera: unraveling a mystery through genomics. PMID- 28711585 TI - Global outbreak of severe Mycobacterium chimaera disease after cardiac surgery: a molecular epidemiological study. AB - BACKGROUND: Since 2013, over 100 cases of Mycobacterium chimaera prosthetic valve endocarditis and disseminated disease were notified in Europe and the USA, linked to contaminated heater-cooler units (HCUs) used during cardiac surgery. We did a molecular epidemiological investigation to establish the source of these patients' disease. METHODS: We included 24 M chimaera isolates from 21 cardiac surgery-related patients in Switzerland, Germany, the Netherlands, and the UK, 218 M chimaera isolates from various types of HCUs in hospitals, from LivaNova (formerly Sorin; London, UK) and Maquet (Rastatt, Germany) brand HCU production sites, and unrelated environmental sources and patients, as well as eight Mycobacterium intracellulare isolates. Isolates were analysed by next-generation whole-genome sequencing using Illumina and Pacific Biosciences technologies, and compared with published M chimaera genomes. FINDINGS: Phylogenetic analysis based on whole-genome sequencing of 250 isolates revealed two major M chimaera groups. Cardiac surgery-related patient isolates were all classified into group 1, in which all, except one, formed a distinct subgroup. This subgroup also comprised isolates from 11 cardiac surgery-related patients reported from the USA, most isolates from LivaNova HCUs, and one from their production site. Isolates from other HCUs and unrelated patients were more widely distributed in the phylogenetic tree. INTERPRETATION: HCU contamination with M chimaera at the LivaNova factory seems a likely source for cardiothoracic surgery-related severe M chimaera infections diagnosed in Switzerland, Germany, the Netherlands, the UK, the USA, and Australia. Protective measures and heightened clinician awareness are essential to guarantee patient safety. FUNDING: Partly funded by the EU Horizon 2020 programme, its FP7 programme, the German Center for Infection Research (DZIF), the Swiss National Science Foundation, the Swiss Federal Office of Public Health, and National Institute of Health Research Oxford Health Protection Research Units on Healthcare Associated Infection and Antimicrobial Resistance. PMID- 28711588 TI - A framework for computational fluid dynamic analyses of patient-specific stented coronary arteries from optical coherence tomography images. AB - The clinical challenge of percutaneous coronary interventions (PCI) is highly dependent on the recognition of the coronary anatomy of each individual. The classic imaging modality used for PCI is angiography, but advanced imaging techniques that are routinely performed during PCI, like optical coherence tomography (OCT), may provide detailed knowledge of the pre-intervention vessel anatomy as well as the post-procedural assessment of the specific stent-to-vessel interactions. Computational fluid dynamics (CFD) is an emerging investigational tool in the setting of optimization of PCI results. In this study, an OCT-based reconstruction method was developed for the execution of CFD simulations of patient-specific coronary artery models which include the actual geometry of the implanted stent. The method was applied to a rigid phantom resembling a stented segment of the left anterior descending coronary artery. The segmentation algorithm was validated against manual segmentation. A strong correlation was found between automatic and manual segmentation of lumen in terms of area values. Similarity indices resulted >96% for the lumen segmentation and >77% for the stent strut segmentation. The 3D reconstruction achieved for the stented phantom was also assessed with the geometry provided by X-ray computed micro tomography scan, used as ground truth, and showed the incidence of distortion from catheter based imaging techniques. The 3D reconstruction was successfully used to perform CFD analyses, demonstrating a great potential for patient-specific investigations. In conclusion, OCT may represent a reliable source for patient specific CFD analyses which may be optimized using dedicated automatic segmentation algorithms. PMID- 28711589 TI - Fixation strength of a polyetheretherketone femoral component in total knee arthroplasty. AB - INTRODUCTION: Introducing polyetheretherketone (PEEK) polymer as a material for femoral components in total knee arthroplasty (TKA) could potentially lead to a reduction of the cemented fixation strength. A PEEK implant is more likely to deform under high loads, rendering geometrical locking features less effective. Fixation strength may be enhanced by adding more undercuts or specific surface treatments. The aim of this study is to measure the initial fixation strength and investigate the associated failure patterns of three different iterations of PEEK OPTIMA(r) implants compared with a Cobalt-Chromium (CoCr) component. METHODS: Femoral components were cemented onto trabecular bone analogue foam blocks and preconditioned with 86,400 cycles of compressive loading (2600 N-260 N at 1 Hz). They were then extracted while the force was measured and the initial failure mechanism was recorded. Four groups were compared: CoCr, regular PEEK, PEEK with an enhanced cement-bonding surface and the latter with additional surface primer. RESULTS: The mean pull-off forces for the four groups were 3814 N, 688 N, 2525 N and 2552 N, respectively. The initial failure patterns for groups 1, 3 and 4 were the same; posterior condylar foam fracture and cement-bone debonding. Implants from group 2 failed at the cement-implant interface. CONCLUSIONS: This study has shown that a PEEK-OPTIMA(r) femoral TKA component with enhanced macro- and microtexture is able to replicate the main failure mechanism of a conventional CoCr femoral implant. The fixation strength is lower than for a CoCr implant, but substantially higher than loads occurring under in-vivo conditions. PMID- 28711590 TI - Improving the detection of evoked responses to periodic stimulation by using bivariate local spectral F-test - Application to EEG during photic stimulation. AB - The spectral local F-test has been applied for detecting evoked responses to rhythmic stimulation that are embedded in the ongoing electroencephalogram (EEG). Based on the sampling distribution of a flat spectrum at the neighbourhood of the stimulation frequency, spectral peaks in an EEG signal that are due to the stimulation may be readily assessed. Nevertheless, the performance of the technique is strongly affected by both the signal-to-noise ratio (SNR) of the responses and the number of data segments used in the estimation. The present work aims at both deriving and evaluating a multivariate extension of local F test by including the EEG collected at a second distinct derivation. The detection rate with this multivariate detector was found to be greater than that using a single channel in case of equal SNR in both signals. Monte Carlo simulation results showed that the probability of detection with this new detector saturates for signal-to-noise ratios above 12 dB and indicated a greater detection rate in practical situations, even when smaller SNR-values are found in the added signal (e.g. 5 dB for 16 neighbouring frequencies used in the estimation). The technique was next applied to the EEG from 12 subjects during intermittent, photic stimulation leading to superior performance in comparison with the univariate local F-test. Since a higher detection rate with the proposed technique is achieved without the need of increasing the number of data segments, it allows evoked responses to be detected faster, once the same detection rate may be accomplished with less segments. This might be useful in clinical practice. PMID- 28711591 TI - Touching the void - First and third person perspectives in two cases of autobiographical amnesia linked to temporal lobe epilepsy. AB - Temporal lobe epilepsy (TLE) can be associated with a marked impairment of autobiographical memory. This is occasionally its presenting feature. We describe two individuals with severe epilepsy-associated autobiographical memory loss. Both MB and PT were reassured initially that their memory was intact on the basis of standard neuropsychological tests. Both have written detailed accounts of their symptoms. The key neuropsychological features of their cases are the relative normality of performance on standard memory tests, with preservation of semantic memory for impersonal information, in contrast to a profound amnesia for salient autobiographical episodes and an impoverishment of imaginative scene construction. First person accounts from these individuals illustrate the importance of autobiographical memory in sustaining a coherent sense of self, informing interpersonal relationships and supporting future thinking and problem solving. These cases contribute to the growing evidence for a distinctive pattern of autobiographical memory loss associated with TLE, and indicate that it can take a severe form affecting both personal semantics and episodic recollection. Defining the phase of memory processing most relevant to this form of amnesia, and the roles of physiological and structural pathology, requires further research. The paper's title refers to the introspective 'void' highlighted by both MB and PT in their reports - in PT's words: 'My primary symptom is the void that is my past'. PMID- 28711592 TI - Producing Amorphous Solid Dispersions via Co-Precipitation and Spray Drying: Impact to Physicochemical and Biopharmaceutical Properties. AB - Many small-molecule active pharmaceutical ingredients (APIs) exhibit low aqueous solubility and benefit from generation of amorphous dispersions of the API and polymer to improve their dissolution properties. Spray drying and hot-melt extrusion are 2 common methods to produce these dispersions; however, for some systems, these approaches may not be optimal, and it would be beneficial to have an alternative route. Herein, amorphous solid dispersions of compound A, a low solubility weak acid, and copovidone were made by conventional spray drying and co-precipitation. The physicochemical properties of the 2 materials were assessed via X-ray diffraction, differential scanning calorimetry, thermal gravimetric analysis, and scanning electron microscopy. The amorphous dispersions were then formulated and tableted, and the performance was assessed in vivo and in vitro. In human dissolution studies, the co-precipitation tablets had slightly slower dissolution than the spray-dried dispersion, but both reached full release of compound A. In canine in vitro dissolution studies, the tablets showed comparable dissolution profiles. Finally, canine pharmacokinetic studies showed that the materials had comparable values for the area under the curve, bioavailability, and Cmax. Based on the summarized data, we conclude that for some APIs, co precipitation is a viable alternative to spray drying to make solid amorphous dispersions while maintaining desirable physicochemical and biopharmaceutical characteristics. PMID- 28711593 TI - Clinical Evaluation of Sepsis-1 and Sepsis-3 in the ICU. AB - BACKGROUND: There has been considerable controversy between sepsis-1 and sepsis-3 criteria. METHODS: Patients with infection meeting two or more systemic inflammatory response syndrome (SIRS) criteria (sepsis-1) or a Sequential Organ Failure Assessment (SOFA) score >= 2 (sepsis-3) on the first day after ICU admission were selected from the Medical Information Mart for Intensive Care-III database, and their outcomes were compared using all-cause death as the end point. Subgroup analysis was also performed based on prior chronic organ dysfunction. RESULTS: There were 21,491 infected patients included. Of those meeting the diagnostic criteria for sepsis-1, 13.42% did not satisfy sepsis-3 criteria, and this population had a 21-day mortality rate of 6.96%. In contrast, 7.00% of the patients meeting sepsis-3 criteria did not meet sepsis-1 criteria, and their 21-day mortality rate was 10.76%. When excluding preexisting organ conditions, 18.41% of patients with sepsis-1 did not meet sepsis-3 criteria, with a 21-day mortality rate of 6.39%, and 6.00% of patients with sepsis-3 did not meet sepsis-1 criteria, with a 21-day mortality rate of 9.11%. When two or more SIRS criteria or SOFA score >= 2 were applied to predict 21-day all-cause mortality in infected patients without prior chronic organ dysfunction, the sensitivity was 96.0% or 91.0%, respectively. Although the areas under the receiver operator curve of both SOFA and SIRS criteria could be used for predicting mortality, SOFA score represented the severity of the condition, whereas SIRS score represented a clinically evident host response to infection. CONCLUSIONS: Sepsis-3 diagnostic criteria narrow the sepsis population at the expense of sensitivity, and the resulting false negatives may delay disease diagnosis. It may be inappropriate to compare the prediction performance of SIRS and SOFA criteria when sepsis-3 is defined. PMID- 28711594 TI - Hepatic mitochondrial bioenergetics in aged C57BL/6 mice exhibit delayed recovery from severe burn injury. AB - Severe burn injuries initiate a cascade of downstream events, culminating in multiple organ dysfunction, sepsis, and even death. The elderly are in particular vulnerable to such outcomes, due primarily to a scarcity of knowledge on trauma progression at the biomolecular level in this population. Mitochondria, the cellular powerhouses, have been increasingly scrutinized recently for their contribution to trauma outcomes. We hypothesized that elderly have a worse outcome compared to adult patients due to failed recovery of hepatic mitochondria. Using a murine model of burn injury, Seahorse respirometry and functional proteomic assays, we demonstrate the impact of thermal trauma on hepatic mitochondrial respiration in adult and aged mice. While the mitochondria in adults rebound from the initial insult within 7days of the injury, the older animals display delayed recovery of mitochondrial bioenergetics accompanied by uncoupling and an oxidative environment. This is associated with a state of increased protein oxidation and nitrosylation, along with increases in circulating mtDNA, a known damage-associated molecular pattern. These findings suggest that hepatic mitochondria fail to normalize after trauma in aged mice and we suggest that this cellular failure is associated with organ damage and subsequently increased morbidity and mortality in elderly burn patients. PMID- 28711597 TI - MicroRNAs and extracellular vesicles in cholangiopathies. AB - : Cholangiopathies encompass a heterogeneous group of disorders affecting biliary epithelial cells (i.e. cholangiocytes). Early diagnosis, prognosis and treatment still remain clinically challenging for most of these diseases and are critical for adequate patient care. In the past decade, extensive research has emphasized microRNAs (miRs) as potential non-invasive biomarkers and tools to accurately identify, predict and treat cholangiopathies. MiRs can be released extracellularly conjugated with lipoproteins or encapsulated in extracellular vesicles (EVs). Research on EVs is also gaining attention since they are present in multiple biological fluids and may represent a relevant source of novel non invasive biomarkers and be vehicles for new therapeutic approaches. This review highlights the most promising candidate miRs and EV-related biomarkers in cholangiopathies, as well as their relevant roles in biliary pathophysiology. This article is part of a Special Issue entitled: Cholangiocytes in Health and Disease edited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen. RESEARCH STRATEGY: PubMed search (April 2017) was done with the following terms: "microRNA", "miRNA", "miR", "extracellular vesicles", "EV", "exosomes", "primary biliary cholangitis", "primary biliary cholangitis", "PBC", "primary sclerosing cholangitis", "PSC", "cholangiocarcinoma", "CCA", "biliary atresia", "BA", "polycystic liver diseases", "PLD", "cholangiopathies", "cholestatic liver disease". Most significant articles in full-text English were selected. The reference lists of selected papers were also considered. PMID- 28711596 TI - The relevance of contact-independent cell-to-cell transfer of TDP-43 and SOD1 in amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease involving the formation of cytoplasmic aggregates by proteins including TDP-43 and SOD1, in affected cells in the central nervous system (CNS). Pathology spreads from an initial site of onset to contiguous anatomical regions. There is evidence that for disease-associated proteins, including TDP-43 and SOD1, non-native protein conformers can promote misfolding of the natively folded counterparts, and cell to-cell transfer of pathological aggregates may underlie the spread of the disease throughout the CNS. A variety of studies have demonstrated that SOD1 is released by neuron-like cells into the surrounding culture medium, either in their free state or encapsulated in extracellular vesicles such as exosomes. Extracellular SOD1 can then be internalised by naive cells incubated in this conditioned medium, leading to the misfolding and aggregation of endogenous intracellular SOD1; an effect that propagates over serial passages. A similar phenomenon has also been observed with other proteins associated with protein misfolding and progressive neurological disorders, including tau, alpha-synuclein and both mammalian and yeast prions. Conditioned media experiments using TDP-43 have been less conclusive, with evidence for this protein undergoing intercellular transfer being less straightforward. In this review, we describe the properties of TDP-43 and SOD1 and look at the evidence for their respective abilities to participate in cell-to-cell transfer via conditioned medium, and discuss how variations in the nature of cell-to-cell transfer suggests that a number of different mechanisms are involved in the spreading of pathology in ALS. PMID- 28711598 TI - iNOS-derived peroxynitrite mediates high glucose-induced inflammatory gene expression in vascular smooth muscle cells through promoting KLF5 expression and nitration. AB - Inducible NO synthase (iNOS) expression and peroxynitrite formation are significantly increased in diabetic vascular tissues. Transcription factor KLF5 activates iNOS gene transcription and is involved in vascular inflammatory injury and remodeling. However, mutual regulation between KLF5, iNOS and peroxynitrite in diabetic vascular inflammation, as well as the underlying mechanisms, remain largely unknown. In this study, we found a marked increase in KLF5 and iNOS expression in vascular smooth muscle cells (VSMC) of diabetic patients. High glucose-induced expression of KLF5 and iNOS was also observed in cultured mouse VSMCs. Further investigation showed that high glucose induced KLF5 nitration by iNOS-mediated peroxynitrite generation, and nitrated KLF5 increased its interaction with NF-kappaB p50 and thus cooperatively activated the expression of inflammatory cytokines TNF-alpha and IL-1beta. Furthermore, we showed that the VSMC-specific knockout of KLF5 dramatically reduced inflammatory cytokine expression in the vascular tissues of diabetic mice. Moreover, 17beta-estradiol (E2) inhibited high glucose-mediated effects in VSMCs, and in the response to E2, estrogen receptor (ER) alpha competed with KLF5 for binding to NF-kappaB p50, which in turn leads to the suppression of inflammatory gene expression in VSMCs. Together, the present findings were the first to show that KLF5 expression and nitration by iNOS-mediated peroxynitrite are necessary for the induction of TNF alpha and IL-1beta expression in VSMCs of diabetic vascular tissues. PMID- 28711595 TI - Abeta truncated species: Implications for brain clearance mechanisms and amyloid plaque deposition. AB - Extensive parenchymal and vascular Abeta deposits are pathological hallmarks of Alzheimer's disease (AD). Besides classic full-length peptides, biochemical analyses of brain deposits have revealed high degree of Abeta heterogeneity likely resulting from the action of multiple proteolytic enzymes. In spite of the numerous studies focusing in Abeta, the relevance of N- and C-terminal truncated species for AD pathogenesis remains largely understudied. In the present work, using novel antibodies specifically recognizing Abeta species N-terminally truncated at position 4 or C-terminally truncated at position 34, we provide a clear assessment of the differential topographic localization of these species in AD brains and transgenic models. Based on their distinct solubility, brain N- and C-terminal truncated species were extracted by differential fractionation and identified via immunoprecipitation coupled to mass spectrometry analysis. Biochemical/biophysical studies with synthetic homologues further confirmed the different solubility properties and contrasting fibrillogenic characteristics of the truncated species composing the brain Abeta peptidome. Abeta C-terminal degradation leads to the production of more soluble fragments likely to be more easily eliminated from the brain. On the contrary, N-terminal truncation at position 4 favors the formation of poorly soluble, aggregation prone peptides with high amyloidogenic propensity and the potential to exacerbate the fibrillar deposits, self-perpetuating the amyloidogenic loop. Detailed assessment of the molecular diversity of Abeta species composing interstitial fluid and amyloid deposits at different disease stages, as well as the evaluation of the truncation profile during various pharmacologic approaches will provide a comprehensive understanding of the still undefined contribution of Abeta truncations to the disease pathogenesis and their potential as novel therapeutic targets. PMID- 28711599 TI - Arachidonic acid sex-dependently affects obesity through linking gut microbiota driven inflammation to hypothalamus-adipose-liver axis. AB - Unraveling the role of dietary lipids is beneficial to treat obesity and metabolic dysfunction. Nonetheless, how dietary lipids affect existing obesity remains unknown. Arachidonic acid (AA), a derivative of linoleic acid, is one of the crucial n-6 fatty acids. The aim of this study was to investigate whether AA affects obesity through associating microbiota-driven inflammation with hypothalamus-adipose-liver axis. Four-week old C57BL/6J mice were fed with a high fat diet (HFD, 45% fat) for 10weeks to induce obesity, and then fed a HFD enriched with 10g/kg of AA or a continuous HFD in the following 15weeks. Systemic adiposity and inflammation, metabolic profiles, gut microbiota composition, short chain fatty acids production, hypothalamic feeding regulators, browning process of adipocytes, hepatosteatosis, and insulin resistance in adipose were investigated. The results indicated that AA aggravates obesity for both genders whereas sex-dependently affects gut microbiota composition. Also, AA favors pro inflammatory microbiota and reduces butyrate production and circulating serotonin, which augments global inflammation and triggers hypothalamic leptin resistance via microglia accumulation in male. AA exacerbates non-alcoholic steatohepatitis along with amplified inflammation through TLR4-NF-kappaB pathway and induces insulin resistance. Reversely, AA alleviates obesity-related disorders via rescuing anti-inflammatory and butyrate-producing microbiota, up regulating GPR41 and GPR109A and controlling hypothalamic inflammation in female. Nevertheless, AA modifies adipocyte browning and promotes lipid mobilization for both genders. We show that AA affects obesity likely through a gut-hypothalamus adipose-liver axis. Our findings formulate recommendations of n-6 fatty acids like AA from dietary intake for obese subjects preferably in a sexually dimorphic way. PMID- 28711600 TI - Double plating as treatment for supracondylar humeral fractures. AB - INTRODUCTION AND OBJECTIVES: Supracondylar humeral fractures represent only about 0.5-1% of all fractures in adults. The objective of this study is to evaluate functional outcome and quality of life in patients treated with open reduction and internal fixation using double plates. MATERIAL AND METHODS: We designed a retrospective descriptive study including 27 supracondylar humeral fractures treated with open reduction and internal fixation using two anatomic plates from January 2005 to September 2012. Mean age was 56 +/- 22.9 years including 14 female and 13 male. All fractures were classified using the AO classification. Average follow-up was of 41 +/- 23.9 months. Fracture union was evaluated with x ray exams and functional outcome using the Mayo Elbow Performance Score (MEPS). Quality of life was evaluated using the Short Form-36 survey. RESULTS: Union at 6 months was achieved in 96% of all fractures. Average range of motion was 102 degrees (70 degrees -140 degrees ) and average MEPS 86 points (60-100). Mean score on SF-36 was 54.87 (8.66-89.22) the older patients had lower scores. Sixty percent of patients (15 of 25) were able to return to previous activity. No infection was reported. Two patients required surgical treatment due to a stiff elbow. CONCLUSIONS: Open reduction and internal fixation using double plates in supracondylar humeral fractures obtains a high union rate allowing excellent functional and radiological outcomes. PMID- 28711602 TI - Contribution of 5-HT2A receptors on diaphragmatic recovery after chronic cervical spinal cord injury. AB - Unilateral C2 spinal cord hemisection (C2Hx) interrupts bulbospinal respiratory pathways innervating ipsilateral phrenic motoneurons, resulting in cessation of ipsilateral diaphragm motor output. Plasticity within the spinal neural circuitry controlling the diaphragm can induce partial recovery of phrenic bursting which correlates with the time-dependent return of spinal serotonin (5-HT) immunoreactivity in the vicinity of phrenic motoneurons. The 5-HT2A receptor subtype is present on phrenic motoneurons and its expression is up-regulated after cervical spinal cord injury; however the functional role of these receptors following injury has not been clearly defined. The present study evaluated the functional role of 5-HT2A receptors by testing the hypothesis that pharmacologic blockade would attenuate diaphragm activity in rats with chronic cervical spinal cord injury. Bilateral diaphragm electromyography (EMG) was performed in vagal intact and spontaneously breathing rats before and after intravenous administration of the 5-HT2A receptor antagonist Ketanserin (1mg/kg). Intravenous ketanserin significantly attenuated ipsilateral diaphragm EMG activity in C2Hx animals but had no impact on diaphragm output in uninjured animals. We conclude that 5-HT2A receptor activation contributes to the recovery of ipsilateral phrenic motor output after chronic cervical spinal cord injury. PMID- 28711601 TI - Catecholaminergic A1/C1 neurons contribute to the maintenance of upper airway muscle tone but may not participate in NREM sleep-related depression of these muscles. AB - Neural mechanisms of obstructive sleep apnea, a common sleep-related breathing disorder, are incompletely understood. Hypoglossal motoneurons, which provide tonic and inspiratory activation of genioglossus (GG) muscle (a major upper airway dilator), receive catecholaminergic input from medullary A1/C1 neurons. We aimed to determine the contribution of A1/C1 neurons in control of GG muscle during sleep and wakefulness. To do so, we placed injections of a viral vector into DBH-cre mice to selectively express the hMD4i inhibitory chemoreceptors in A1/C1 neurons. Administration of the hM4Di ligand, clozapine-N-oxide (CNO), in these mice decreased GG muscle activity during NREM sleep (F1,1,3=17.1, p<0.05); a similar non-significant decrease was observed during wakefulness. CNO administration had no effect on neck muscle activity, respiratory parameters or state durations. In addition, CNO-induced inhibition of A1/C1 neurons did not alter the magnitude of the naturally occurring depression of GG activity during transitions from wakefulness to NREM sleep. These findings suggest that A1/C1 neurons have a net excitatory effect on GG activity that is most likely mediated by hypoglossal motoneurons. However, the activity of A1/C1 neurons does not appear to contribute to NREM sleep-related inhibition of GG muscle activity, suggesting that A1/C1 neurons regulate upper airway patency in a state independent manner. PMID- 28711603 TI - MiR-139-5p inhibits proliferation and promoted apoptosis of human airway smooth muscle cells by downregulating the Brg1 gene. AB - MicroRNAs have emerged as critical regulators in the pathogenesis of asthma. However, the role of microRNAs in asthma needs to be further elucidated. In this study, we found that miR-139-5p was greatly decreased in airway smooth muscle (ASM) cells from asthmatic humans as well as ASM cells stimulated with cytokines. Overexpression of miR-139-5p markedly suppressed ASM cell proliferation and promoted cell apoptosis, whereas knockdown of miR-139-5p had the opposite effect. Further study verified that Brg1, a chromatin remodeling factor, was upregulated in ASM cells treated with cytokines and acted as a direct target of miR-139-5p. Ectopic expression of Brg1 partially reversed the effect of miR-139-5p on cell proliferation and apoptosis. Moreover, overexpression of Brg1 restored miR-139-5p induced downregulation of Akt and p70S6K phosphorylation. Together, these data indicate that miR-139-5p may function as a key regulator of ASM cell proliferation and apoptosis, potentially by targeting the Brg1 gene, and thus suggesting a potential role of miR-139-5p in the pathogenesis of asthma. PMID- 28711604 TI - An animal model of co-existing sarcopenia and osteoporotic fracture in senescence accelerated mouse prone 8 (SAMP8). AB - Sarcopenia and osteoporotic fracture are common aging-related musculoskeletal problems. Recent evidences report that osteoporotic fracture patients showed high prevalence of sarcopenia; however, current clinical practice basically does not consider sarcopenia in the treatment or rehabilitation of osteoporotic fracture. There is almost no report studying the relationship of the co-existing of sarcopenia and osteoporotic fracture healing. In this study, we validated aged senescence accelerated mouse prone 8 (SAMP8) and senescence accelerated mouse resistant 1 (SAMR1) as animal models of senile osteoporosis with/without sarcopenia. Bone mineral density (BMD) at the 5th lumbar and muscle testing of the two animal strains were measured to confirm the status of osteoporosis and sarcopenia, respectively. Closed fracture was created on the right femur of 8 month-old animals. Radiographs were taken weekly post-fracture. MicroCT and histology of the fractured femur were performed at week 2, 4 and 6 post-fracture, while mechanical test of both femora at week 4 and 6 post-fracture. Results showed that the callus of SAMR1 was significantly larger at week 2 but smaller at week 6 post-fracture than SAMP8. Mechanical properties were significantly better at week 4 post-fracture in SAMR1 than SAMP8, indicating osteoporotic fracture healing was delayed in sarcopenic SAMP8. This study validated an animal model of co-existing sarcopenia and osteoporotic fracture, where a delayed fracture healing might be resulted in the presence of sarcopenia. PMID- 28711605 TI - Sentinel lymph node biopsy for external ear melanoma: A 17 year experience with long term survival data. PMID- 28711606 TI - Ovarian aromatase loss-of-function mutant medaka undergo ovary degeneration and partial female-to-male sex reversal after puberty. AB - Although estrogens have been generally considered to play a critical role in ovarian differentiation in non-mammalian vertebrates, the specific functions of estrogens during ovarian differentiation remain unclear. We isolated two mutants with premature stops in the ovarian aromatase (cyp19a1) gene from an N-ethyl-N nitrosourea-based gene-driven mutagenesis library of the medaka, Oryzias latipes. In XX mutants, gonads first differentiated into normal ovaries containing many ovarian follicles that failed to accumulate yolk. Subsequently, ovarian tissues underwent extensive degeneration, followed by the appearance of testicular tissues on the dorsal side of ovaries. In the newly formed testicular tissue, strong expression of gsdf was detected in sox9a2-positive somatic cells surrounding germline stem cells suggesting that gsdf plays an important role in testicular differentiation during estrogen-depleted female-to-male sex reversal. We conclude that endogenous estrogens synthesized after fertilization are not essential for early ovarian differentiation but are critical for the maintenance of adult ovaries. PMID- 28711607 TI - Epigenetics of pituitary tumors: Pathogenetic and therapeutic implications. AB - Genetic mutations involving oncogenes or tumor suppressor genes are relatively uncommon in human sporadic pituitary tumors. Instead, increasing evidence has highlighted frequent epigenetic alterations including DNA methylation, histone modifications, and enhanced miRNA expression. This review covers some of this evidence as it illuminates mechanisms of tumorigenesis and highlights therapeutic opportunities. PMID- 28711608 TI - Do anabolic-androgenic steroids have performance-enhancing effects in female athletes? AB - Doping with anabolic-androgenic steroids (AAS) is common among both male and female athletes and is a growing public health problem. Review of historical data of systematic state-sponsored doping programs implemented by the German Democratic Republic in elite female athletes and from clinical trials of testosterone administration in non-athlete women suggests that AAS have ergogenic effects in women. The use of AAS in female athletes has been associated with adverse effects that include acne, hirsutism, deepening of the voice and menstrual disturbances; life-threatening adverse effects such as cardiac arrhythmias and sudden death have also been reported. Therefore, detection of AAS abuse in female athletes is important to ensure fairness in competition; at the same time, the athletes should be educated regarding the adverse consequences of AAS use. Although administration of exogenous androgens have been associated with ergogenic effects, it remains unclear whether endogenous hyperandrogenism seen in some medical conditions such as disorders of sexual development (DSD), congenital adrenal hyperplasia and polycystic ovary syndrome, confers any competitive advantage. Well-designed studies are needed to determine the effects of endogenous hyperandrogenism on athletic performance in female athletes. PMID- 28711609 TI - The epigenetic landscape of differentiated thyroid cancer. AB - Differentiated thyroid carcinoma of follicular cell-derivation is the most common endocrine neoplasm with a rapidly increasing incidence. The majority represent papillary carcinomas; more rarely, they are follicular carcinomas. The vast majority have indolent behavior, however a significant proportion progress to develop lymph node metastases and a smaller proportion disseminate systemically. While common and frequent genetic events have been described to underlie the development of these neoplasms, the factors contributing to differing behaviors among tumors with similar genetic alterations remain unclear. This review focuses on epigenetic mechanisms targeting major signaling pathways that underlie the spectrum of biological behaviors and that may have potential diagnostic, prognostic and therapeutic value. PMID- 28711610 TI - Night eating among veterans with obesity. AB - The obesity rate is higher among veterans than the general population, yet few studies have examined their eating behaviors, and none have examined the presence of night eating and related comorbidities. This study examines night eating syndrome (NES) among veterans seeking weight management treatment, and relationships between NES and weight, insomnia, disordered eating, and psychological variables. The sample consisted of 110 veterans referred to a weight management program at VA Connecticut Healthcare System. More than one out of ten veterans screened positive for NES, and one-third screened positive for insomnia. Most individuals screening positive for NES also screened positive for insomnia. Night eating was associated with higher BMI, and with higher scores on measures of binge eating, emotional overeating, and eating disorder symptomatology. Veterans screening positive for NES were also significantly more likely to screen positive for depression and PTSD. When controlling for insomnia, only the relationships between night eating and binge and emotional eating remained significant. Those screening positive for PTSD were more likely to endorse needing to eat to return to sleep. Findings suggest that both NES and insomnia are common among veterans seeking weight management services, and that NES is a marker for additional disordered eating behavior, specifically binge eating and overeating in response to emotions. Additional studies are needed to further delineate the relationships among NES, insomnia, and psychological variables, as well as to examine whether specifically addressing NES within behavioral weight management interventions can improve weight outcomes and problematic eating behaviors. PMID- 28711611 TI - Biochemical characterization and stability assessment of Rhizopus oryzae lipase covalently immobilized on amino-functionalized magnetic nanoparticles. AB - Amino-functionalized magnetic nanoparticles (Fe3O4) have been investigated as a support for covalent immobilization of lipase. The nanoparticles were prepared by chemical coprecipitation method and subsequently were coated with 3 aminopropyltriethoxysilane (APTES) via silanization reaction. With glutaraldehyde, as the coupling agent, the lipase from Rhizopus oryzae was successfully immobilized onto the amino-functionalized magnetic nanoparticles. The synthesized support was characterized by transmission electron microscopy and Fourier transform infrared spectroscopy. The results showed that the load of immobilized protein could reach as high as 7mg protein g-1 support. The optimum pH for maximal catalytic activity of the immobilized enzyme was 8.0 at 40 degrees C. The Km values were found as 0.66 and 0.57mgmL-1 for the free and immobilized enzymes, respectively. The Vmax values for the free and immobilized enzymes were calculated as 0.14 and 0.47MUmolmg-1min-1, in turn, when p-nitrophenyl butyrate (pNPB) was used as the substrate. A quick separation of lipase from the reaction mixture was achieved when a magnetically active support was applied. In comparison to the free enzyme, the immobilized enzyme was thermally stable and was reusable for 10 cycles while retaining 64% of its initial activity. PMID- 28711612 TI - Exemestane loaded alginate nanoparticles for cancer treatment: Formulation and in vitro evaluation. AB - Alginate, a biopolymer is most useful for anticancer drug delivery, because of it is biocompatible, nontoxic, biodegradable and exploiting ligand-receptor interaction. Breast cancer is spreading very fast due to the changing food habits and environmental causes. Exemestane (EXE) an oral chemotherapeutic drug was used to treat breast cancer, while loading EXE in alginate nanoparticles, the side effects which was faced during administration are expected to be reduced and control the release of exemestane. Thus, in the present study, an anticancer drug EXE was loaded into the Alginate nanoparticles (ALG-NPs) through simple controlled gelation method and evaluated in vitro to study the performance of ALG NPs in delivering the anticancer drug EXE. The unloaded and loaded formulation was characterized by FT-IR, XRD and SEM studies. The encapsulation of Exemestane was confirmed using FTIR and XRD analysis results. The surface morphology, shape and size of the formulation was studied using SEM analysis and result reveals that the size was in nano size range with rough surface morphology. Encapsulation of EXE was studied by using UV-vis spectrophotometer. In vitro drug release studies implies that ALG-NPs acts as a novel drug delivery system for the effective controlled delivery for cancer treatment. PMID- 28711613 TI - Enzyme activity and expression pattern of intra- and extracellular chitinase and beta-1,3-glucanase of Wickerhamomyces anomalus EG2 using glycol chitin and glucan containing high polymer complex. AB - We investigated cell growth and activity of intra- and extracellular chitinase, beta-1,3-glucanase, and chitin deacetylase with SDS-PAGE by incubating W. anomalus EG2 in PDB and YPD media for 24h in presence of different concentrations (0%, 0.1%, 0.3%, and 0.5%) of colloidal chitin. Maximum cell growth was observed in both PDB and YPD media without colloidal chitin. In the absence of colloidal chitin, maximum extracellular beta-1,3-glucanase activity of 32.96 and 47.28 units/mL was reported at 18h in PDB medium and 6h in YPD medium, respectively. In addition, extracellular chitinase was unaffected by various concentrations of carboxymethyl chitin in both PDB and YPD media. In the absence of colloidal chitin, maximum intracellular chitinase activity was indicated to be 9.82 and 9.86 units/mg protein in PDB and YPD media, respectively. Maximum intracellular beta-1,3-glucanase activity reported was 17.34 units/mg protein in PDB medium containing 0.5% colloidal chitin and 15.0 units/mg protein in YPD medium containing 0.3% colloidal chitin. Five major isozymes, GN1, GN2, GN3, GN4, and GN5, of intracellular beta-1,3-glucanase were detected with glucan-containing high polymer complex as a substrate with or without colloidal chitin. PMID- 28711614 TI - Antioxidant and antibacterial activities of polysaccharides isolated and purified from Diaphragma juglandis fructus. AB - A water-soluble polysaccharide fraction (DJP-2) isolated from Diaphragma juglandis was successfully purified by ion-exchange chromatography (DEAE cellulose) and gel-permeation chromatography (Sephadex G-100). The weight-average molecular weight (Mw) and number-average molecular weight (Mn) of DJP-2 were 4.95 and 3.99kDa, respectively. Monosaccharide component analysis indicated that DJP-2 comprised arabinose, galactose, glucose, xylose, and mannose in a molar ratio of 0.27:0.55:1:0.14:0.08. The evaluation of the antioxidant and antibacterial activities of polysaccharides from Diaphragma juglandis fructus indicated that they could be explored as promising natural antioxidant and bacteriostatic agents in the food and pharmaceutical industries. PMID- 28711615 TI - Water-soluble polysaccharide from Erythronium sibiricum bulb: Structural characterisation and immunomodulating activity. AB - A water-soluble polysaccharide named ESBP2-1 was isolated from Erythronium sibiricum bulb through anion-exchange and size-exclusion chromatography. ESBP2-1 is a neutral polysaccharide fraction with an average molecular weight of 9.4*105Da and is composed of glucose, galactose and arabinose in a ratio of 24.3:1.1:1. Methylation analysis, partial hydrolysis and NMR studies revealed that the backbone of ESBP2-1 primarily consists of repeating ->1)-alpha-d-Glcp-(4 > units where the disaccharide side chains of Arap-(1->6)-alpha-d-Galp-(1-> residue are attached to the O-6 position of Glc. An in vitro assay showed that ESBP2-1 significantly promoted the proliferation and neutral red phagocytosis of RAW 264.7 macrophage cells. In addition, ESBP2-1 stimulated the production of secretory molecules (nitric oxide, TNF-alpha and IL-1beta) of RAW264.7 cells in a dose-dependent manner. These results suggest that ESBP2-1 is a potential immunostimulator. PMID- 28711616 TI - Isolation, screening and characterization of a novel extracellular xylanase from Aspergillus niger (KP874102.1) and its application in orange peel hydrolysis. AB - In the present work, a potent xylanase producing fungal strain Aspergillus niger (KP874102.1) was isolated through cultural and morphological observations from soil sample of Baramura forest, Tripura west, India. 28S rDNA technique was applied for genomic identification of this fungal strain. The isolated strain was found to be phylogenetically closely related to Aspergillus niger. Kinetic constants such as Km and Vmax for extracellular xylanase were determined using various substrate such as beech wood xylan, oat spelt xylan and CM cellulose through Lineweaver-Burk plot. Km, Vmax and Kcat for beech wood xylan are found to be 2.89mg/ml, 2442U and 426178Umlmg-1 respectively. Crude enzyme did not show also CM cellulose activity. The relative efficiency of oat spelt xylan was found to be 0.819 with respect to beech wood xylan. After acid hydrolysis, enzyme was able to produce reducing sugar with 17.7, 35.5, 50.8 and 65% (w/w) from orange peel after 15, 30, 45 and 60min incubation with cellulase free xylanase and maximum reducing sugar formation rate was found to be 55.96MUg/ml/min. Therefore, the Aspergillus niger (KP874102.1) is considered as a potential candidate for enzymatic hydrolysis of orange peel. PMID- 28711617 TI - Highly sensitive immunosensing of prostate specific antigen using poly cysteine caped by graphene quantum dots and gold nanoparticle: A novel signal amplification strategy. AB - A mediator-free electrochemical immunosensor for quantitation of prostate specific antigen (PSA) based on dual signal amplification strategy was fabricated. In this work, PSA-antibody (anti-PSA) was immobilized onto a green and biocompatible nanocomposite containing poly l-cysteine (P-Cys) as conductive matrix and graphene quantum dots (GQDs)/gold nanoparticles (GNPs) as dual signal amplification elements. Therefore, a novel multilayer film based on P-Cys, GQDs, and GNPs was exploited to develop a highly sensitive amperometric immunosensor for detection of PSA. Fully electrochemical methodology was used to prepare a new transducer on a gold surface which provided a high surface area to immobilize a high amount of the anti-PSA. Importantly, GNPs prepared by soft template synthesized method lead to compact morphology was achieved. The surface morphology of electrode surface was characterized by high-resolution field emission scanning electron microscope (FE-SEM) and energy dispersive spectroscopy (EDX). Chemical compositions of the gold nanoparticles were analysed by an EDX. The immunosensor was employed for the detection of PSA in physiological pH. Under optimized condition the calibration curve for PSA concentration was linear up to 2-9pgmL-1 with lower limit of quantification of 1.8pgmL-1. PMID- 28711618 TI - Fabrication of bi-layer scaffold of keratin nanofiber and gelatin-methacrylate hydrogel: Implications for skin graft. AB - Bi-layer scaffold composed of human hair keratin/chitosan nanofiber mat and gelatin methacrylate (GelMA) hydrogel was fabricated by using electrospinning and photopolymerization techniques. To prepare the nanofiber layer, the blend solution of human hair keratin and chitosan (mixture ratio: 5/5) was electrospun using formic acid as a solvent in the presence of poly(ethylene glycol), followed by cross-linking with glutaraldehyde. The tensile strength of the human hair keratin/chitosan nanofiber mat was much higher than that of pure human hair keratin nanofiber mat. Meanwhile, the blend nanofiber mat was relatively more compatible with HaCaT cell proliferation and keratinocyte differentiation than the pure chitosan nanofiber mat. The bi-layer scaffold was prepared by photopolymerization of GelMA under the cross-linked nanofiber mat. To evaluate the feasibility as a skin graft, human fibroblast was encapsulated in the hydrogel layer and HaCaT cells were cultured on the nanofiber layer and they were co-cultured for 10days. As a result, the encapsulated fibroblasts proliferated in the hydrogel matrix and HaCaT cells formed a cell layer on the top of scaffold, mimicking dermis and epidermis of skin tissue. PMID- 28711619 TI - Adsorption of Pb(II) ions from aqueous environment using eco-friendly chitosan schiff's base@Fe3O4 (CSB@Fe3O4) as an adsorbent; kinetics, isotherm and thermodynamic studies. AB - Chitosan and its derivatives can be used to modify magnetic materials to promote the adsorption properties of the magnetic materials for the removal of meal ions. In this study a novel CSB@Fe3O4 was prepared, characterized by XRD, FTIR, SEM, TEM, and VSM analysis and utilized as an adsorbent material for the removal of Pb(II) ions from aqueous solution. Batch studies were performed to evaluate the influences of various experimental parameters like pH, adsorbent dosage, contact time, initial concentration, and the effect of temperature. Optimum conditions for Pb(II) removal were found to be pH 5, adsorbent dosage 0.5g and equilibrium time of 105min. The pseudo-first-order, pseudo-second-order and intraparticle diffusion models were used to analyze kinetic data. The data fit well with the second-order kinetic model. The equilibrium data were analyzed using the Langmuir, and Freundlich isotherm models. The best interpretation for the equilibrium data was given by Langmuir isotherm, and the maximum adsorption capacity was found to be 83.33mg/g for CSB@Fe3O4. The calculated thermodynamic parameters DeltaG degrees (-9.728, -9.034 and -7.883kJ/mol for 303, 313, and 323K), DeltaH degrees (20.39kJ/mol) and DeltaS degrees (0.0947J/molK) showed that the adsorption of Pb(II) ions were feasible, spontaneous and endothermic in nature. PMID- 28711620 TI - Comparison of laccase-catalyzed cross-linking of organosolv lignin and lignosulfonates. AB - Lignin, an underutilized by-product from chemical pulping of wood, can be modified enzymatically through oxidation by laccase. However, little is known about the molecular details surrounding the cross-linking which is a result of the oxidation. To reduce this lack of knowledge, we used oxygen consumption rate data, phenolic content data and molecular weight data together with data from NMR and FTIR spectroscopy to characterize laccase-catalyzed cross-linking of the industrial lignin preparations organosolv lignin and lignosulfonate. The organosolv lignin preparation had a Mn of 780 g/mol, a Mw of 5200 g/mol, and a phenolic content of 1.8 mmol/g. The lignosulfonate preparation had a Mn of 6000 g/mol, a Mw of 19800 g/mol, and a phenolic content of 1.1 mmol/g. Laccase catalyzed oxidation of organosolv lignin was characterized by a relatively slow increase in molecular weight, decreased intensities for aromatic signals and p hydroxycinnamyl groups, and increased intensity for beta-O-4' signals, whereas oxidation of lignosulfonates resulted in a very rapid increase in molecular weight, and strongly decreased intensities for aromatic signals. The data suggest that lignosulfonates cross-linked by couplings to the aromatic ring (e.g. 5-5' and 4-O-5'), whereas beta-O-4' coupling characterized cross-linking of organosolv lignin, probably involving cinnamyl alcohol end-groups. PMID- 28711621 TI - Length of axons expressing the serotonin transporter in orbitofrontal cortex is lower with age in depression. AB - Studies of major depressive disorder (MDD) in postmortem brain tissue report enhanced binding to inhibitory serotonin-1A autoreceptors in midbrain dorsal raphe and reductions in length of axons expressing the serotonin transporter (SERT) in dorsolateral prefrontal cortex. The length density of axons expressing SERT in the orbitofrontal cortex (OFC) was determined in 18 subjects with MDD and 17 age-matched control subjects. A monoclonal antibody was used to immunohistochemically label the SERT in fixed sections of OFC. The 3-dimensional length density of SERT-immunoreactive (ir) axons in layer VI of OFC was estimated. The age of subjects with MDD was negatively correlated with SERT axon length (r=-0.77, p<0.0005). The significant effect of age persisted when removing four depressed subjects with an antidepressant medication present at the time of death, or when removing nine depressed subjects that had a recent prescription for an antidepressant medication. Neither gender, tissue pH, postmortem interval, 5-HTTLPR genotype, time in fixative, nor death by suicide had a significant effect on axon length. The age-related decrease in SERT-ir axon length in MDD may reflect pathology of ascending axons passing through deep white matter hyperintensities. Greater length of axons expressing SERT in younger subjects with MDD may result in a significant deficit in serotonin availability in OFC. PMID- 28711622 TI - Prolonged low-level noise-induced plasticity in the peripheral and central auditory system of rats. AB - Prolonged low-level noise exposure alters loudness perception in humans, presumably by decreasing the gain of the central auditory system. Here we test the central gain hypothesis by measuring the acute and chronic physiologic changes at the level of the cochlea and inferior colliculus (IC) after a 75-dB SPL, 10-20-kHz noise exposure for 5weeks. The compound action potential (CAP) and summating potential (SP) were used to assess the functional status of the cochlea and 16 channel electrodes were used to measure the local field potentials (LFP) and multi-unit spike discharge rates (SDR) from the IC immediately after and one week post-exposure. Measurements obtained immediately post-exposure demonstrated a significant reduction in supra-threshold CAP amplitudes. In contrast to the periphery, sound-evoked activity in the IC was enhanced in a frequency-dependent manner consistent with models of enhanced central gain. Surprisingly, one-week post-exposure supra-threshold responses from the cochlea had not only recovered, but were significantly larger than normal, and thresholds were significantly better than controls. Moreover, sound-evoked hyperactivity in the IC was sustained within the noise exposure frequency band but suppressed at higher frequencies. When response amplitudes representing the neural output of the cochlea and IC activity at one-week post exposure were compared with control animal responses, a central attenuation phenomenon becomes evident, which may play a key role in understanding why low-level noise can sometimes ameliorate tinnitus and hyperacusis percepts. PMID- 28711623 TI - Prioritized cervical or lumbar surgery for coexisting cervical and lumbar stenosis: Prognostic analysis of 222 case. AB - BACKGROUND CONTEXT: Single-stage surgery is usually applied to improving the symptoms of coexisting cervical and lumbar stenosis. In most cases, patients' willingness, surgery affordability, surgical trauma, surgical complications and patients' tolerance to surgery all limit the application of single-stage surgery. For patients who cannot receive single-stage surgery, we hope that we can find out by weighing up merits and flaws of the two surgical sites in order to make decision of prioritize one of the two surgery, so as to bring more benefits to the patients. OBJECTIVE: To confirm which one of prioritized cervical surgery and prioritized lumbar surgery has a better effect in alleviating the symptoms of patients with coexisting cervical and lumbar stenosis. STUDY DESIGN: A retrospective analysis and a cohort study for 15 years. PATIENT SAMPLE: The information of 222 patients who were diagnosed with coexisting cervical and lumbar stenosis over the past 15 years was collected, including 144 patients who underwent prioritized cervical surgery and 78 prioritized lumbar surgery, thereafter the changes in the patients' postoperative neurological functions were evaluated. OUTCOME MEASURES: Primary outcome variables are the clinical diagnosis event and the event of surgical site positioning. Secondary variables are the event of postoperative function changes and the symptom improvement event. METHODS: The information about 222 patients with coexisting cervical and lumbar stenosis who had a follow-up of more than 1 year during January 2000 and December 2014 was collected. The effects of prioritized staged cervical and lumbar surgeries on the prognosis for the above-mentioned patients were respectively evaluated via relevant evaluation indexes. RESULTS: The follow-up time was 18-156 months (58.0 +/- 36.5). The lumbar reoperation rate after prioritized cervical surgery was lower than the cervical reoperation rate after prioritized lumbar surgery (22.91% < 57.69%) (P < 0.01). The JOA score and Nurick grade significantly improved (P < 0.01) and the ODI score improved (P < 0.05) after prioritized cervical surgery. No obvious improvement in the JOA score and Nurick grade (P > 0.05) was shown but the ODI score markedly improved (P < 0.01) after prioritized lumbar surgery. CONCLUSIONS: For patients with coexisting cervical and lumbar stenosis, prioritized cervical surgery is safe and effective and is superior to prioritized lumbar surgery on the improvement of cervical and lumbar symptoms, the postoperative recovery of limb function and the rate of reoperation on another site. PMID- 28711624 TI - Curcumin attenuates oxidative stress induced NFkappaB mediated inflammation and endoplasmic reticulum dependent apoptosis of splenocytes in diabetes. AB - The present study was aimed to determine the curative role of curcumin against diabetes induced oxidative stress and its associated splenic complications. Diabetes was induced in the experimental rats via the intraperitoneal administration of a single dose of STZ (65mgkg-1body weight). Increased blood glucose and intracellular ROS levels along with decreased body weight, the activity of cellular antioxidant enzymes and GSH/GSSG ratio were observed in the diabetic animals. Histological assessment showed white pulp depletion and damaged spleen anatomy in these animals. Oral administration of curcumin at a dose of 100mgkg-1 body weight daily for 8weeks, however, restored these alterations. Investigation of the mechanism of hyperglycemia induced oxidative stress mediated inflammation showed upregulation of inflammatory cytokines, chemokines, adhesion molecules and increased translocation of NFkappaB into the nucleus. Moreover, ER stress dependent cell death showed induction of eIF2alpha and CHOP mediated signalling pathways as well as increment in the expression of GRP78, Caspase-12, Calpain-1, phospho JNK, phospho p38 and phospho p53 in the diabetic group. Alteration of Bax/Bcl-2 ratio; disruption of mitochondrial membrane potential, release of cytochrome-C from mitochondria and upregulation of caspase 3 along with the formation of characteristic DNA ladder in the diabetic animals suggest the involvement of mitochondria dependent apoptotic pathway in the splenic cells. Treatment with curcumin could, however, protect cells from inflammatory damage and ER as well as mitochondrial apoptotic death by restoring the alterations of these parameters. Our results suggest that curcumin has the potential to act as an anti-diabetic, anti-oxidant, anti-inflammatory and anti-apoptotic therapeutic against diabetes mediated splenic damage. PMID- 28711625 TI - Suppressing mPGES-1 expression by sinomenine ameliorates inflammation and arthritis. AB - Recently, microsomal prostaglandin E synthase 1 (mPGES-1) has attracted much attention from pharmacologists as a promising strategy and an attractive target for treating various types of diseases including rheumatoid arthritis (RA), which could preserve the anti-inflammatory effect while reducing the adverse effects often occur during administration of non-steroidal anti-inflammatory drugs (NSAIDs). Here, we report that sinomenine (SIN) decreased prostaglandin (PG)E2 levels without affecting prostacyclin (PG)I2 and thromboxane (TX)A2 synthesis via selective inhibiting mPGES-1 expression, a possible reason of low risk of cardiovascular event compared with NSAIDs. In addition, mPGES-1 protein expression was down-regulated by SIN treatment in the inflamed paw tissues both in carrageenan-induced edema model in rats and the collagen-II induced arthritis (CIA) model in DBA mice. More interestingly, SIN suppressed the last step of mPGES-1 gene expression by decreasing the DNA binding ability of NF-kappaB, paving a new way for drug discovery. PMID- 28711626 TI - Influence of Metabolic Risk Factors on Risk of Hepatocellular Carcinoma and Liver Related Death in Men With Chronic Hepatitis B: A Large Cohort Study. AB - BACKGROUND & AIMS: Little is known about the absolute risk of hepatocellular carcinoma (HCC) and liver-disease related death, in association with metabolic risk factors, for patients with hepatitis B virus (HBV) infection. METHODS: We collected data from 5373 male Taiwanese civil servants who visited Taiwan's Government Employees' Central Clinics and received routine free physical examinations from 1989 through 1992. We obtained information on liver-related morbidity and mortality in HBV carriers, 40-65 years of age (n=1690), with different metabolic risk factors. We compared their medical histories with those of study participants without HBV or HCV infection in the same age range (n=1289). We used patients' baseline data on obesity, diabetes, hypertriglyceridemia, and high blood pressure to assign them to metabolic risk categories. We then performed a case-cohort analysis of the effects of hepatitis B viral factors on risk for HCC, based on metabolic factors and insulin resistance. RESULTS: Over a median follow-up period of 19 years, 158 of the 1690 HBV carriers developed HCC and 126 died from liver-related diseases. Among participants without HBV or HCV infection, only 6 developed HCC or died from liver-related disease. HBV carriers with different metabolic risk factors had significant differences in cumulative incidence of HCC and liver-related death. Patients with 3 or more metabolic risk factors had a substantially higher risk for HCC (10-year cumulative incidence, 13.60%) than patients with a low metabolic risk profile (10-year cumulative incidence, 4.83%; adjusted-hazard ratio, 2.32; 95% CI, 1.18-4.54). Smoking had a significant effect on this association (Pinteraction = .0044). Having 3 or more metabolic risk factors, compared with no factors, significantly increased the risk of HCC (adjusted-hazard ratio, 5.06; 95% CI, 2.23-11.47) and 10-year cumulative incidence of HCC (25.0% in smokers with 3 or more metabolic risk factors vs 3.87% in smokers with none; P < .0001) in smokers, but did not increase risk of HCC in nonsmokers. Metabolic risk factors and insulin resistance had the largest effect on HCC risk in patients with levels of HBV-DNA <10,000 copies/mL. CONCLUSIONS: In a study of men with chronic HBV infection ages 40-65 years in Taiwan, we associated a high burden of metabolic risk factors with increased risk of HCC; smoking has a significant effect on this association. PMID- 28711627 TI - Vasoactive Intestinal Polypeptide and Mast Cells Regulate Increased Passage of Colonic Bacteria in Patients With Irritable Bowel Syndrome. AB - BACKGROUND & AIMS: Irritable bowel syndrome (IBS) is associated with intestinal dysbiosis and symptoms of IBS develop following gastroenteritis. We aimed to study the passage of live bacteria through the colonic epithelium, and determine the role of mast cells (MCs) and vasoactive intestinal polypeptide (VIP) in barrier regulation in IBS and healthy individuals. METHODS: Colon biopsies from 32 women with IBS and 15 age-matched healthy women (controls) were mounted in Ussing chambers; we measured numbers of fluorescently labeled Escherichia coli HS and Salmonella typhimurium that passed through from the mucosal side to the serosal side of the tissue. Some biopsies were exposed to agents that block the VIP receptors (VPAC1 and VPAC2) or MCs. Levels of VIP and tryptase were measured in plasma and biopsy lysates. Number of MCs and MCs that express VIP or VIP receptors were quantified by immunofluorescence. Biopsies from an additional 5 patients with IBS and 4 controls were mounted in chambers and Salmonella were added; we studied passage routes through the epithelium by transmission electron microscopy and expression of tight junctions by confocal microscopy. RESULTS: In colon biopsies from patients with IBS, larger numbers of E coli HS and S typhimurium passed through the epithelium than in biopsies from controls (P < .0005). In transmission electron microscopy analyses, bacteria were found to cross the epithelium via only the transcellular route. Bacterial passage was reduced in biopsies from patients with IBS and controls after addition of antibodies against VPACs or ketotifen, which inhibits MCs. Plasma samples from patients with IBS had higher levels of VIP than plasma samples from controls. Biopsies from patients with IBS had higher levels of tryptase, larger numbers of MCs, and a higher percentage of MCs that express VPAC1 than biopsies from controls. In biopsies from patients with IBS, addition of Salmonella significantly reduced levels of occludin; subsequent addition of ketotifen significantly reversed this effect. CONCLUSIONS: We found that colonic epithelium tissues from patients with IBS have increased translocation of commensal and pathogenic live bacteria compared with controls. The mechanisms of increased translocation include MCs and VIP. PMID- 28711630 TI - Analysis of Liver Offers to Pediatric Candidates on the Transplant Wait List. AB - BACKGROUND & AIMS: Approximately 10% of children on the liver transplant wait list in the United States die every year. We examined deceased donor liver offer acceptance patterns and their contribution to pediatric wait-list mortality. METHODS: We performed a retrospective cohort study of children on the US liver transplant wait-list from 2007 through 2014 using national transplant registry databases. We determined the frequency, patterns of acceptance, and donor and recipient characteristics associated with deceased donor liver organ offers for children who died or were delisted compared with those who underwent transplantation. Children who died or were delisted were classified by the number of donor liver offers (0 vs 1 or more), limiting analyses to offers of livers that were ultimately transplanted into pediatric recipients. The primary outcome was death or delisting on the wait-list. RESULTS: Among 3852 pediatric liver transplant candidates, children who died or were delisted received a median 1 pediatric liver offer (inter-quartile range, 0-2) and waited a median 33 days before removal from the wait-list. Of 11,328 donor livers offered to children, 2533 (12%) were transplanted into children; 1179 of these (47%) were immediately accepted and 1354 (53%) were initially refused and eventually accepted for another child. Of 27,831 adults, 1667 (6.0%; median, 55 years) received livers from donors younger than 18 years (median, 15 years), most (97%) allocated locally or regionally. Of children who died or were delisted, 173 (55%) received an offer of 1 or more liver that was subsequently transplanted into another pediatric recipient, and 143 (45%) died or were delisted with no offers. CONCLUSIONS: Among pediatric liver transplant candidates in the US, children who died or were delisted received a median 1 pediatric liver offer and waited a median of 33 days. Of livers transplanted into children, 47% were immediately accepted and 53% were initially refused and eventually accepted for another child. Of children who died or were delisted, 55% received an offer of 1 or more liver that was subsequently transplanted into another pediatric recipient, and 45% died or were delisted with no offers. Pediatric prioritization in the allocation and development of improved risk stratification systems is required to reduce wait-list mortality among children. PMID- 28711628 TI - Enteric Glia Regulate Gastrointestinal Motility but Are Not Required for Maintenance of the Epithelium in Mice. AB - BACKGROUND & AIMS: When the glial fibrillary acidic protein (GFAP) promoter is used to express cellular toxins that eliminate glia in mice, intestinal epithelial permeability and proliferation increase; this led to the concept that glia are required for maintenance of the gastrointestinal epithelium. Many enteric glia, however, particularly in the mucosa, do not express GFAP. In contrast, virtually all enteric glia express proteolipid protein 1 (PLP1). We investigated whether elimination of PLP1-expressing cells compromises epithelial maintenance or gastrointestinal motility. METHODS: We generated mice that express tamoxifen-inducible Cre recombinase under control of the Plp1 promoter and carry the diptheria toxin subunit A (DTA) transgene in the Rosa26 locus (Plp1CreER;Rosa26DTA mice). In these mice, PLP1-expressing glia are selectively eliminated without affecting neighboring cells. We measured epithelial barrier function and gastrointestinal motility in these mice and littermate controls, and analyzed epithelial cell proliferation and ultrastructure from their intestinal tissues. To compare our findings with those from previous studies, we also eliminated glia with ganciclovir in GfapHSV-TK mice. RESULTS: Expression of DTA in PLP1-expressing cells selectively eliminated enteric glia from the small and large intestines, but caused no defects in epithelial proliferation, barrier integrity, or ultrastructure. In contrast, administration of ganciclovir to GfapHSV-TK mice eliminated fewer glia but caused considerable non-glial toxicity and epithelial cell death. Elimination of PLP1-expressing cells did not reduce survival of neurons in the intestine, but altered gastrointestinal motility in female, but not male, mice. CONCLUSIONS: Using the Plp1 promoter to selectively eliminate glia in mice, we found that enteric glia are not required for maintenance of the intestinal epithelium, but are required for regulation of intestinal motility in females. Previous observations supporting the concept that maintenance of the intestinal epithelium requires enteric glia can be attributed to non-glial toxicity in GfapHSV-TK mice and epithelial-cell expression of GFAP. Contrary to widespread notions, enteric glia are therefore not required for epithelial homeostasis. However, they regulate intestinal motility in a sex dependent manner. PMID- 28711631 TI - Corrigendum to "Osteopontin-metallothionen I/II interactions in experimental autoimmune encephalomyelitis" [Neuroscience 350 (2017) 133-145]. PMID- 28711629 TI - Randomized Comparison of 3 High-Level Disinfection and Sterilization Procedures for Duodenoscopes. AB - BACKGROUND AND AIMS: Duodenoscopes have been implicated in the transmission of multidrug-resistant organisms (MDRO). We compared the frequency of duodenoscope contamination with MDRO or any other bacteria after disinfection or sterilization by 3 different methods. METHODS: We performed a single-center prospective randomized study in which duodenoscopes were randomly reprocessed by standard high-level disinfection (sHLD), double high-level disinfection (dHLD), or standard high-level disinfection followed by ethylene oxide gas sterilization (HLD/ETO). Samples were collected from the elevator mechanism and working channel of each duodenoscope and cultured before use. The primary outcome was the proportion of duodenoscopes with an elevator mechanism or working channel culture showing 1 or more MDRO; secondary outcomes included the frequency of duodenoscope contamination with more than 0 and 10 or more colony-forming units (CFU) of aerobic bacterial growth on either sampling location. RESULTS: After 3 months of enrollment, the study was closed because of the futility; we did not observe sufficient events to evaluate the primary outcome. Among 541 duodenoscope culture events, 516 were included in the final analysis. No duodenoscope culture in any group was positive for MDRO. Bacterial growth of more than 0 CFU was noted in 16.1% duodenoscopes in the sHLD group, 16.0% in the dHLD group, and 22.5% in the HLD/ETO group (P = .21). Bacterial growth or 10 or more CFU was noted in 2.3% of duodenoscopes in the sHLD group, 4.1% in the dHLD group, and 4.2% in the HLD/ETO group (P = .36). MRDOs were cultured from 3.2% of pre-procedure rectal swabs and 2.5% of duodenal aspirates. CONCLUSIONS: In a comparison of duodenoscopes reprocessed by sHLD, dHLD, or HLD/ETO, we found no significant differences between groups for MDRO or bacteria contamination. Enhanced disinfection methods (dHLD or HLD/ETO) did not provide additional protection against contamination. However, insufficient events occurred to assess our primary study end-point. ClinicalTrials.gov no: NCT02611648. PMID- 28711632 TI - To the Editor- Esophageal thermal probes and esophageal lesions during cryoablation. PMID- 28711634 TI - Role of epigenetic modulation in cancer stem cell fate. AB - A sub-population of the tumor micro-environment consists of cancer stem cells (CSCs), which are responsible for the initiation and recurrence of cancer. Recently, epigenetic processes such as DNA methylation, histone modification, and chromatin remodeling have been found to be involved in inducing epigenetic factors in CSCs. Most of these processes, such as DNA methylation, generally occur in the genome that is rich in Cytosine-Guanine repeat sequences, also known as CpG islands, which are distributed throughout the human genome. The Polycomb gene (PcG) complex is a chromatin modifier facilitating the maintenance of embryonic and adult stem cells. Recent evidence suggests that the PcG is also involved in maintaining CSC stemness. We have presented various aspects and examples of how epigenetic modulation may drive or promote tumorigenesis and metastasis by alteration of key transcriptomic programs and signaling pathways in CSCs. PMID- 28711633 TI - Novel measure of autonomic remodeling associated with sudden cardiac arrest in diabetes. AB - BACKGROUND: Diabetes is independently associated with an increased risk of sudden cardiac arrest (SCA), with a need to identify novel methods for risk stratification. Diabetic patients can develop autonomic dysfunction that has been associated with an increased risk of ventricular arrhythmogenesis and manifests as reduced heart rate variability (HRV). However, previously published studies have not accounted for resting heart rate (HR), important from both pathophysiological and prognosticating standpoints. OBJECTIVE: We sought to evaluate autonomic remodeling of the sinus node response in SCA and diabetes while accounting for HR. METHODS: We performed a case-control study in SCA cases (age 35-59 years; 2002-2014) from the ongoing Oregon Sudden Unexpected Death Study (catchment population ~1 million), and archived 12-lead electrocardiograms recorded prior to the SCA event were compared with those of geographic controls. Short-term HRV was calculated from digitized 10-second electrocardiograms by using established methods. We analyzed 313 subjects (mean age 52.0 +/- 5.5 years; 216 men, 69.0%) and compared 4 groups: 111 diabetic (49 cases, 62 controls) and 202 nondiabetic (80 cases, 122 controls) subjects. RESULTS: Analysis of covariance showed an absence of the expected interaction between HRV and HR (HRV HR) in diabetic patients with SCA (regression slope -0.008; 95% confidence interval -0.023 to 0.0071; P = .26). This finding, unique to this population of diabetic patients with SCA, was not detected using traditional HRV measures. CONCLUSION: By incorporating resting HR in this analysis, we observed that this population of diabetic patients with SCA had loss of the expected HRV-HR relationship. This potentially novel noninvasive risk measurement warrants further investigation, especially at the level of the individual patient. PMID- 28711635 TI - Assessing Pain Using the Variation Coefficient of Pupillary Diameter. AB - : Pupillary diameter (PD) varies under the influence of the sympathetic as well as parasympathetic systems, increasing proportionally with pain intensity. Such variations however, should not be confused with pupillary fluctuations, which refer to the fast and permanent PD fluctuations induced by the ongoing interplay between the sympathetic and parasympathetic systems, which we propose to measure using the variation coefficient of PD (VCPD). This study aimed first at correlating PD, PD increase during a contraction, and VCPD, with pain rated using a numeric rating scale (NRS) during obstetrical labor, and then at comparing such correlations with each other. Forty patients were included in the study, and 160 simultaneous ratings (NRS, PD, and VCPD) were taken: 40 in the presence of uterine contractions and 40 in the absence of such contractions, before and 20 minutes after epidural analgesia. VCPD correlates more strongly (r = .77) than PD increase (r = .42) with pain rated using a NRS. The ability of VCPD to predict the occurrence of NRS scores >=4 during obstetrical labor is .97 (confidence interval, .93-1.0). When measured over 10 seconds during contraction, VCPD correlates more strongly than PD increase with pain rated using the NRS. Such stronger correlation allows for an easy assessment of antinociception-nociception balance. PERSPECTIVE: The VCPD allows for an objective assessment of pain in laboring women. It could allow for an easy assessment of pain in noncommunicating patients: newborns or very old patients, patients with serious psychological conditions, assessment during the immediate postoperative period, or in intensive care units. PMID- 28711637 TI - Passive detection and localization of fatigue cracking in aluminum plates using Green's function reconstruction from ambient noise. AB - Recent theoretical and experimental studies have demonstrated that a local Green's function can be retrieved from the cross-correlation of ambient noise field. This technique can be used to detect fatigue cracking in metallic structures, owing to the fact that the presence of crack can lead to a change in Green's function. This paper presents a method of structural fatigue cracking characterization method by measuring Green's function reconstruction from noise excitation and verifies the feasibility of crack detection in poor noise source distribution. Fatigue cracks usually generate nonlinear effects, in which different wave amplitudes and frequency compositions can cause different nonlinear responses. This study also undertakes analysis of the capacity of the proposed approach to identify fatigue cracking under different noise amplitudes and frequency ranges. Experimental investigations of an aluminum plate are conducted to assess the cross-correlations of received noise between sensor pairs and finally to detect the introduced fatigue crack. A damage index is proposed according to the variation between cross-correlations obtained from the pristine crack closed state and the crack opening-closure state when sufficient noise amplitude is used to generate nonlinearity. A probability distribution map of damage is calculated based on damage indices. The fatigue crack introduced in the aluminum plate is successfully identified and oriented, verifying that a fatigue crack can be detected by reconstructing Green's functions from an imperfect diffuse field in which ambient noise sources exist locally. PMID- 28711636 TI - Factors Influencing Long-Term Opioid Use Among Opioid Naive Patients: An Examination of Initial Prescription Characteristics and Pain Etiologies. AB - : The relationships between the initial opioid prescription characteristics and pain etiology with the probability of opioid discontinuation were explored in this retrospective cohort study using health insurance claims data from a nationally representative database of commercially insured patients in the United States. We identified 1,353,902 persons aged 14 years and older with no history of cancer or substance abuse, with new opioid use episodes and categorized them into 11 mutually exclusive pain etiologies. Cox proportional hazards models were estimated to identify factors associated with time to opioid discontinuation. After accounting for losses to follow-up, the probability of continued opioid use at 1 year was 5.3% across all subjects. Patients with chronic pain had the highest probability for continued opioid use followed by patients with inpatient admissions. Patients prescribed doses >=90 morphine milligram equivalents (hazard ratio [HR] = .91; 95% confidence interval [CI], .91-.92), initiated with tramadol (HR = .89; 95% CI, .89-.90) or long-acting opioids (HR = .79; 95% CI, .77-.82) were less likely to discontinue opioids. Increasing days' supply of the first prescription was consistently associated with a lower likelihood of opioid discontinuation (HRs, CIs: 3-4 days' supply = .70, .70-.71; 5-7 days' supply = .48, .47-.48; 8-10 days' supply = .37, .37-.38; 11-14 days' supply = .32, .31 .33; 15-21 days' supply = .29, .28-.29; >=22 days supplied = .20, .19-.20). The direction of this relationship was consistent across all pain etiologies. Clinicians should initiate patients with the lowest supply of opioids to mitigate unintentional long-term opioid use. PERSPECTIVE: This study shows that characteristics of the first opioid prescription, particularly duration of the prescription, are significant predictors of continued opioid use irrespective of the indication for an opioid prescription. These data should encourage prescribers to initiate patients using the minimum effective opioid dose and duration to reduce unintended long-term use and could motivate policies that restrict the initial supply of opioids. PMID- 28711638 TI - The alteration of temoporfin distribution in multicellular tumor spheroids by beta-cyclodextrins. AB - To be effective anticancer drugs must penetrate tissue efficiently, reaching all target population of cancer cells in a concentration sufficient to exert a therapeutic effect. This study aimed to investigate the ability of methyl-beta cyclodextrin (Me-beta-CD) and 2-hydroxypropyl-beta-cyclodextrin (Hp-beta-CD) to alter the penetration and diffusion of temoporfin (mTHPC) in HT29 multicellular tumor spheroids. mTHPC had a nonhomogenous distribution only on the periphery of spheroids. The presence of beta-CDs significantly altered the distribution of mTHPC consisting in the increase of both the depth of photosensitizer penetration and accumulation in HT29 spheroids. We suggest that this improvement is related to the nanoshuttle mechanism of beta-CD action, when beta-CDs facilitate mTHPC transportation to the cells in the inner layers of spheroids. As a result of mTHPC distribution improvement, beta-CDs enhance mTHPC photosensitizing activity towards HT29 multicellular tumor spheroids. The observed effects strongly depend on the type of beta-CD. Thus, varying the type of beta-CD we can finely tune the possibility of using mTHPC for diagnostic (delimitation of tumor margins) or therapeutic purposes. PMID- 28711639 TI - Skin permeability enhancement by Bacillus subtilis alkaline protease: Application to transdermal drug delivery. AB - Enzymes may offer great potentials in topical pharmaceutical applications provided that treatment conditions are controlled for efficacy and safety. In this study, the effect of alkaline protease produced by recombinant Bacillus subtilis cells on the ex-vivo permeability of rabbit ear skin was investigated under different conditions of enzyme activity (5-60 units) and exposure time (15 60min). Data for transepidermal water loss (TEWL) and permeation of a hydrophilic dye, rhodamine B (Rb), indicated biphasic activity-dependent and exposure time dependent skin permeability. Maximum effects were obtained at 20 proteolytic units and 30min exposure. Findings proved consistent with histopathological changes indicating progressive stratum corneum (SC) loss and disruption of the dermo-epidermal junction at 20 units and up to 30min exposure time followed by dermal hyalinization at longer exposure. This was associated with progressive loss of skin hair. Applying the identified pretreatment conditions to transdermal delivery of vardenafil in a gel base across dorsal rat skin indicated a significant increase in plasma levels at 30 and 60min with minimal histopathological changes 5days post enzyme treatment. Accordingly, the recombinant B. subtilis alkaline protease offers promise as a pharmaceutical enzyme for transdermal drug delivery bioenhancement and dermatological applications. PMID- 28711640 TI - Recent advances in TPGS-based nanoparticles of docetaxel for improved chemotherapy. AB - Docetaxel (DTX) is one of the important antitumor drugs, being used in several common chemotherapies to control leading cancer types. Severe toxicities of the DTX are prominent due to sudden parenteral exposure of desired loading dose to maintain the therapeutic concentration. Field of nanotechnology is leading to resist sudden systemic exposure of DTX with more specific delivery to the site of cancer. Further nanometric size range of the formulation aid for prolonged circulation, thereby extensive exposure results better efficacy. In this article, we extensively reviewed the therapeutic benefit of incorporating d-alpha tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS, or simply TPGS) in the nanoparticle (NP) formulation of DTX for improved delivery, tumor control and tolerability. TPGS is well accepted nonionic-ampiphilic polymer which has been identified in the role of emulsifier, stabilizer, penetration enhancer, solubilizer and in protection in micelle. Simultaneously, P-glycoprotein inhibitory activity of TPGS in the multidrug resistant (MDR) cancer cells along with its apoptotic potential are the added advantage of TPGS to be incorporated in nano-chemotherapeutics. Thus, it could be concluded that TPGS based nanoparticulate application is an advanced approach to improve therapeutic efficacy of chemotherapeutic agents by better internalization and sustained retention of the NPs. PMID- 28711641 TI - Tacrolimus loaded biocompatible lecithin-based microemulsions with improved skin penetration: Structure characterization and in vitro/in vivo performances. AB - In order to improve skin penetration of tacrolimus we aimed to develop potentially non-irritant, lecithin-based microemulsions containing ethanol, isopropanol and/or propylene glycol as cosurfactants, varying caprylic/capric triglycerides and propylene glycol monocaprylate as oil phase. The influence of excipients on the size of microemulsion region in pseudo-ternary phase diagrams and their ability to form different types of microemulsions was evaluated. The comprehensive physicochemical characterization of microemulsions and the evaluation of their structure was performed, while the localization of tacrolimus in microemulsions was further investigated using electron paramagnetic resonance spectroscopy. Moreover, stability studies proved no change in tacrolimus content during one year of storage at room temperature. In addition, in vivo skin performance indicated no skin irritation potential of blank microemulsions, whereas in vitro release testing using Franz diffusion cells showed superior release rate of tacrolimus from microemulsions (0.98+/-0.10 and 0.92+/ 0.11MUg/cm2/h for two bicontinuous and 1.00+/-0.24MUg/cm2/h for oil-in-water microemulsion) compared to referent Protopic ointment (0.15+/-0.08MUg/cm2/h). Furthermore, ex vivo penetration assessed through porcine ear skin using tape stripping, confirmed superiority of two microemulsions related to the reference, implying developed microemulsions as promising carriers for dermal delivery of tacrolimus. PMID- 28711642 TI - Transverse vaginal septum identified in a patient requesting second trimester abortion: a case report. AB - A primigravid immigrant woman presented for termination of a 16-week pregnancy. The cervix was obscured by a transverse vaginal septum and was only identifiable by ultrasound. We used mifepristone for cervical preparation before concurrent septoplasty and dilation and evacuation. PMID- 28711643 TI - Contraceptive use and unplanned pregnancy among female sex workers in Zambia. AB - OBJECTIVES: Access to reproductive healthcare, including contraceptive services, is an essential component of comprehensive healthcare for female sex workers (FSW). Here, we evaluated the prevalence of and factors associated with contraceptive use, unplanned pregnancy, and pregnancy termination among FSW in three transit towns in Zambia. STUDY DESIGN: Data arose from the baseline quantitative survey from a randomized controlled trial of HIV self-testing among FSW. Eligible participants were 18 years of age or older, exchanged sex for money or goods at least once in the past month, and were HIV-uninfected or status unknown without recent HIV testing (<3 months). Logistic regression models were used to assess factors associated with contraceptive use and unplanned pregnancy. RESULTS: Of 946 women eligible for this analysis, 84.1% had been pregnant at least once, and among those 61.6% had an unplanned pregnancy, and 47.7% had a terminated pregnancy. Incarceration was associated with decreased odds of dual contraception use (aOR=0.46, 95% CI 0.32-0.67) and increased odds of unplanned pregnancy (aOR=1.75, 95% CI 1.56-1.97). Condom availability at work was associated with increased odds of using condoms only for contraception (aOR=1.74, 95% CI 1.21-2.51) and decreased odds of unplanned pregnancy (aOR=0.63, 95% CI 0.61-0.64). CONCLUSIONS: FSW in this setting have large unmet reproductive health needs. Structural interventions, such as increasing condom availability in workplaces, may be useful for reducing the burden of unplanned pregnancy. PMID- 28711644 TI - NFPRHA commentary on the contraceptive care performance measures. PMID- 28711645 TI - Prostate-specific antigen concentration in vaginal fluid after exposure to semen. AB - OBJECTIVE: Prostate-specific antigen (PSA) is the best established biomarker of semen exposure. PSA in vaginal fluid returns to pre-exposure concentrations within 24-48 h, but the speed of decay during the first 10 h is unknown. We sought to determine how fast PSA concentrations decline during the first 10 h after exposure to semen. STUDY DESIGN: Women in the 50 enrolled couples were intravaginally inoculated with 10, 20, 100 and 200 MUl of their partner's semen and then collected vaginal swabs immediately after, 30 min, 4 h and 10 h after exposure. Forty-seven sets of samples were tested for PSA. Mixed linear models for repeated measures examined the association between log-transformed PSA values and sampling time and semen exposure volume. Sensitivity analyses excluded data from nonabstainers. Fixed-effect estimates from the statistical models were graphed. RESULTS: PSA values were highest at 200 MUl inoculation volumes and at earlier post-exposure time points, then decline steadily. The lowest inoculation volume (10 MUl) corresponded to the smallest concentration of PSA throughout the post-inoculation time points. Average PSA levels return to clinically non detectable levels within 10 h only at the lowest semen exposures. The PSA decay curve assumes a very similar profile across all time points and semen amounts. CONCLUSIONS: The PSA decay curve is similar for varying semen exposure volumes, with average PSA concentrations remaining above clinical thresholds 10 h after exposure at all except the very smallest semen exposure levels. PSA is an objective marker of recent exposure to semen, permitting such detection with high accuracy. IMPLICATIONS: This study clarifies how PSA values vary at different semen exposure levels and time points during the first 10 h post-exposure. Future contraceptive studies that use PSA as a semen biomarker will be better informed about PSA concentrations at different sampling times and exposure amounts. PMID- 28711647 TI - Surgical Training Improves Performance in Minimally Invasive Left Ventricular Assist Device Implantation Without Cardiopulmonary Bypass. AB - OBJECTIVE: We introduced a live animal model for training of minimally invasive implantation of a continuous-flow left ventricular assist device (CF-LVAD) without cardiopulmonary bypass for operator's performance improvement. DESIGN: After watching a videotape of LVAD implantation on the beating heart through the cardiac apex, the surgical team performed implantation of LVADs into 5 pigs during 3 training sessions in a time series. The procedure success rate, operating time, and technical and global performances by self-evaluation and senior evaluation were compared among the sessions. SETTING: Animal Experiment Center in Peking University Third Hospital. PARTICIPANTS: Surgical team comprising a surgical operator, surgical assistant, anesthetist, and scrub nurse performed 3 training sessions in a time series. RESULTS: The urgent situations requiring proper management were myocardial laceration, massive blood loss, and ventricular arrhythmia induced by hemodynamic instability. After practice, the success rate increased to 100% in session 3. The operating times of session 2 (189.80 +/- 14.34min) and session 3 (149.00 +/- 22.85min) were significantly lower than that of session 1 (262.20 +/- 28.26min). The technical and global performances by self-evaluation and senior evaluation were significantly better in session 3 than session 1. CONCLUSION: Simulation training with high-fidelity in vivo model for minimally invasive CF-LVAD implantation improves the surgical team's global performance, success rate, and the ability to manage emergency situations in surgery. PMID- 28711646 TI - Rural Rotations at Core: Rarefied Exposure or Real Experience? AB - OBJECTIVE: Surgical rotations involving rural General Hospitals (rGH) are frequently associated with recruitment challenges, partly because of adverse perceptions regarding distances from social support networks and training opportunities. The aim of this study was to determine the outcomes of core surgical training rotations involving rGHs when compared with urban hospitals in a single UK Deanery. DESIGN: Online Intercollegiate Surgical Curriculum Programme portfolios from 163 core surgical trainees (CST) were examined related to postlocation, operative experience, workplace-based assessments, and academic achievement. Of the 163 CSTs, 27 had completed at least 50% of their 2-year training posts at rGHs and were compared with 136 control CSTs completing rotations in urban general and teaching hospitals (uGH). The primary outcome measures were MRCS pass rate and success at national ST3 selection. SETTING: A core surgical training program serving a single UK Deanery. PARTICIPANTS: Consecutive 177 CSTs appointed to a single UK Deanery between 2010 and 2016. RESULTS: Success at MRCS and national ST3 selection were similar for CSTs from rGH vs uGH rotations-MRCS success: 70.4 vs 72.8% (p = 0.816), and ST3 success: 22.2% vs 27.0% (p = 0.811). Median rGH vs uGH curriculum-based outcomes were operative case load: 378 vs 422 (p = 0.300); workplace-based assessments completed: 79 vs 94 (p = 0.499); audits performed: 4 vs 4 (p = 0.966); learned society communications: 1 vs 2 (p = 0.020); and scientific publications: 0 vs 0 (p = 0.478). CONCLUSION: CST rotations including rGHs produced a different spectrum of training experience compared with uGH rotations but overall primary outcomes were similar. PMID- 28711648 TI - Alteration of PDGFRbeta-Akt-mTOR pathway signaling in fibrosarcomatous transformation of dermatofibrosarcoma protuberans. AB - Dermatofibrosarcoma protuberans (DFSP) is a cutaneous mesenchymal tumor of intermediate malignancy and fibroblastic/myofibroblastic differentiation. Fibrosarcomatous (FS) component is a high-grade component of DFSP. The detailed oncogenic difference between DFSP and FS components is not clear. We thus investigated the Akt-mTOR pathway in both components. We used 65 tumor samples obtained from 65 patients. The phosphorylation of Akt-mTOR pathway proteins (Akt, mTOR, 4EBP1, and S6RP) and PDGFRalpha/beta was assessed by immunohistochemical staining, the results of which were confirmed by Western blotting. The immunohistochemical results were as follows: in ordinary DFSP components, p PDGFRalpha-positive tumors were 41.9% (18/43 cases), p-PDGFRbeta 55.8% (24/43 cases), p-Akt 51.2% (22/43 cases), p-mTOR 39.5% (17/43 cases), p-4EBP1 46.5% (20/43 cases), and p-S6RP 41.8% (18/43 cases); in DFSP components of FS-DFSP, 52.6% (10/19 cases), 47.4% (9/19 cases), 52.6% (10/19 cases), 36.8% (7/19 cases), 52.6% (10/19 cases), and 52.6% (10/19 cases); and in FS components, 45.5% (10/22 cases), 36.4% (8/22 cases), 72.7% (16/22 cases), 54.5% (12/22 cases), 72.7% (16/22 cases), and 68.2% (15/22 cases), respectively. There were significant positive correlations of the phosphorylation of most of the Akt-mTOR pathway proteins (p-Akt, p-mTOR, p-4EBP1, and p-S6RP) with each other (P < .05). Phospho PDGFRbeta was well correlated with the phosphorylation of Akt-mTOR pathway proteins in DFSP components of ordinary and FS-DFSPs, but these correlations were weaker in FS components. This study suggested the association of activation of Akt-mTOR pathway proteins and PDGFR with the progression of DFSP to FS. The Akt mTOR pathway is thus a potential therapeutic target in imatinib-resistant DFSP/FS. PMID- 28711649 TI - Intramucosal colorectal carcinoma with invasion of the lamina propria: a study by the Japanese Society for Cancer of the Colon and Rectum. AB - Cancer invasion of the lamina propria is an important pathological finding. However, the clinicopathologic features and diagnostic accuracy of intramucosal carcinoma assessment in colorectal carcinoma (CRC) are unknown. In this study, intramucosal CRCs were reviewed in institutions affiliated with the Japanese Society for Cancer of the Colon and Rectum, and 32 cases with invasion of the lamina propria were identified. Next, a consensus meeting was held to select cases with a high consensus about the presence of invasion, which were reviewed by one Western pathologist for confirmation. In addition to clinicopathologic evaluation, concordance was assessed for diagnosis and histologic findings. During the consensus meeting, 3 cases were found to show ambiguous features such that it was unclear whether there was intramucosal or submucosal invasion, and 7 cases were judged to have invasion of the lamina propria by more than 75% of the pathologists. A poorly differentiated adenocarcinoma and a signet ring cell carcinoma were diagnosed unanimously. Concordance in diagnosis and detection of characteristics of invasion of the lamina propria proved to be only poor to fair. Single or small clusters of cells and atypical or complex glandular arrangements that are beyond normal mucosal architecture were detected more frequently in the 7 high-consensus tumors. Desmoplasia and marked inflammation were detected more often in cases characterized as ambiguous. Intramucosal CRCs with invasion of the lamina propria constituted 5.1% of the surgically resected high-grade intramucosal epithelial dysplastic/neoplastic lesions, and stromal infiltration of single or small clusters of cells is the best objective criterion of invasion. PMID- 28711650 TI - Role of SATB2 in distinguishing the site of origin in glandular lesions of the bladder/urinary tract. AB - The differential diagnosis of glandular lesions of the bladder/urinary tract can be challenging because of significant morphologic and immunohistochemical overlap between primary lesions and metastasis/direct extension from adjacent organs. Special AT-rich sequence-binding protein 2 (SATB2), encoded on chromosome 2q32 33, is a recently described DNA-binding protein involved in osteoblast lineage commitment and expressed in colorectal and appendiceal neoplasms. In this study, we hypothesized that immunohistochemistry for SATB2 may be of value in distinguishing primary adenocarcinoma of the bladder/urinary tract and urothelial carcinoma with glandular differentiation from gastrointestinal and endocervical primaries. Intensity and distribution of SATB2 nuclear labeling were semiquantitatively scored and compared with those of CDX2. The study included 43 primary adenocarcinomas of the bladder/urinary tract, 20 urothelial carcinomas with glandular differentiation, 26 adenocarcinomas of the uterine cervix, and 22 colorectal adenocarcinomas involving the bladder. Positive SATB2 immunostaining was observed in 21 of 43 (49%) primary bladder/urinary tract adenocarcinomas, in 17 of 22 (77%) colorectal adenocarcinomas, and in the glandular component of 4 of 18 (22%) urothelial carcinomas with glandular differentiation. SATB2 was negative in 25 of 26 endocervical adenocarcinomas and showed focal weak immunostaining (1+) in 1 of 26 (4%). The results were not significantly different from those seen with CDX2. We conclude that SATB2 immunohistochemistry is not useful in supporting urothelial versus gastrointestinal or endocervical origin in the differential diagnosis of glandular lesions of the bladder/urinary tract. PMID- 28711651 TI - Psychometric properties of measures of gait quality and walking performance in young people with Cerebral Palsy: A systematic review. AB - Availability of outcome measures (OMs) with robust psychometric properties is an essential prerequisite for the evaluation of interventions designed to address gait deterioration in young people with Cerebral Palsy (CP). This review evaluates evidence for the reliability, validity and responsiveness of outcome measures of gait quality and walking performance in young people with CP. A systematic search was performed in MEDLINE, CINAHL, PubMed and Scopus. Articles that met the eligibility criteria were selected. Methodological quality of studies was independently rated by two raters using the modified COnsensus-based Standard for the selection of health status Measurement INstruments checklist. Strength of evidence was rated using standardised guidelines. Best evidence synthesis was scored according to Cochrane criteria. Fifty-one articles reporting on 18 distinct OMs were included for review. Best evidence synthesis indicated a moderate to strong evidence for the reliability for OMs of walking performance but conflicting evidence for the reliability of OMs of gait quality. The evidence for responsiveness for all OMs included in this review was rated as 'unknown'. The limitations of using the modified COSMIN scoring for small sample sizes are acknowledged. Future studies of high methodological quality are needed to explore the responsiveness of OMs assessing gait quality and walking performance in young people with CP. PMID- 28711652 TI - Dual-task walking over a compliant foam surface: A comparison of people with transfemoral amputation and controls. AB - People with lower limb amputation are unable to reliably sense ground characteristics due to compromised sensory inputs from the missing limb. As a result, they may rely on compensatory strategies, such as use of cognitive resources, when walking over complex surfaces. This study examined interactions between cognition and walking over a compliant surface in 14 people with transfemoral amputation (TFA) and 14 controls using a dual-task paradigm. Walking was assessed with quantitative motion analysis in both single-task (walking alone) and dual-task (walking while performing a cognitive task) conditions over a compliant foam surface. Outcomes were walking speed, step width, step time asymmetry, step time variability, and the speed and accuracy of cognitive task performance. For each outcome, effects of task (single-task, dual-task) and group (TFA, control) were examined with repeated-measures analysis of variance. No significant group-by-task interactions were observed for cognitive task performance. A significant group-by-task interaction for step time asymmetry indicated that participants with TFA increased temporal asymmetry in dual-task relative to single-task conditions, while control participants maintained symmetrical gait. The addition of a concurrent cognitive task did not differentially affect other aspects of gait between groups. Significant main effects of group for all walking outcomes indicated that participants with TFA walked slower, with wider, more asymmetric, and more variable steps than controls. Results suggest that gait quality degrades in challenging dual-task conditions for people with TFA, but not controls, consistent with the idea that people with TFA may use increased cognitive resources to control walking in complex environments. PMID- 28711654 TI - Involvement of endoplasmic reticulum stress and neurite outgrowth in the model mice of autism spectrum disorder. AB - Neurodevelopmental disorders are congenital impairments, impeding the growth and development of the central nervous system. These disorders include autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder in Diagnostic and Statistical Manual of Mental Disorders-5. ASD is caused by a gene defect and chromosomal duplication. Despite numerous reports on ASD, the pathogenic mechanisms are not clear. The optimal methods to prevent ASD and to treat it are also not clear. Other studies have reported that endoplasmic reticulum (ER) stress contributes to the pathogenesis of neurodegenerative diseases. In this study, we have investigated ER stress condition and neuronal maturation in an ASD mice model employing male ICR mice. An ASD mice model was established by injecting with valproic acid (VPA) into pregnant mice. The offspring born from VPA-treated mothers were subjected to the experiments as the ASD model mice. The cerebral cortex and hippocampus of ASD model mice were found to be under high ER stress. The mRNA levels of Hes1 and Pax6 were decreased in the cerebral cortex of the ASD model mice, but not in the hippocampus. In addition, the mRNA level in Math1 was increased in the cerebral cortex. ER stress inhibited dendrite and axon extension in primary culture derived from the cerebral cortex of E14.5 mice. Furthermore, dendrite outgrowth was suppressed in primary culture derived from the cerebral cortex of ASD model mice by the same method. These results indicated the possibility that ER stress induces abnormal neuronal maturation in the embryonal cerebral cortex of ASD model mice employing male ICR mice. Therefore, ER stress may contribute to the pathogenesis of ASD. PMID- 28711655 TI - Ubiquitination at the mitochondria in neuronal health and disease. AB - The preservation of mitochondrial function is of particular importance in neurons given the high energy requirements of action potential propagation and synaptic transmission. Indeed, disruptions in mitochondrial dynamics and quality control are linked to cellular pathology in neurodegenerative diseases, such as Alzheimer's and Parkinson's disease. Here, we will discuss the role of ubiquitination by the E3 ligases: Parkin, MARCH5 and Mul1, and how they regulate mitochondrial homeostasis. Furthermore, given the role of Parkin and Mul1 in the formation of mitochondria-derived vesicles we give an overview of this area of mitochondrial homeostasis. We highlight how through the activity of these enzymes and MDV formation, multiple facets of mitochondrial biology can be regulated, ensuring the functionality of the mitochondrial network thus preserving neuronal health. PMID- 28711653 TI - Highly conserved intragenic HSV-2 sequences: Results from next-generation sequencing of HSV-2 UL and US regions from genital swabs collected from 3 continents. AB - INTRODUCTION: Understanding the variability in circulating herpes simplex virus type 2 (HSV-2) genomic sequences is critical to the development of HSV-2 vaccines. METHODS: Genital lesion swabs containing >= 107log10 copies HSV DNA collected from Africa, the USA, and South America underwent next-generation sequencing, followed by K-mer based filtering and de novo genomic assembly. Sites of heterogeneity within coding regions in unique long and unique short (UL_US) regions were identified. Phylogenetic trees were created using maximum likelihood reconstruction. RESULTS: Among 46 samples from 38 persons, 1468 intragenic base pair substitutions were identified. The maximum nucleotide distance between strains for concatenated UL_US segments was 0.4%. Phylogeny did not reveal geographic clustering. The most variable proteins had non-synonymous mutations in < 3% of amino acids. CONCLUSIONS: Unenriched HSV-2 DNA can undergo next generation sequencing to identify intragenic variability. The use of clinical swabs for sequencing expands the information that can be gathered directly from these specimens. PMID- 28711656 TI - Upregulation of Cdh1 signaling in the hippocampus attenuates brain damage after transient global cerebral ischemia in rats. AB - Cerebral ischemia is a major cause of brain dysfunction. The E3 ubiquitin ligase anaphase-promoting complex and its coactivator Cdh1 have been reported to be involved in the regulation of neuronal survival, differentiation, axonal growth and synaptic development in the central nervous system. However, its role in the ischemic brain and the underlying mechanisms remain poorly understood. The present study aimed to investigate the effects of Cdh1 overexpression on the ischemic rat brain by direct intra-hippocampal injection of lentivirus-delivered Cdh1 before transient global cerebral ischemia reperfusion. Spatial memory acquisition and retention were assessed using a Morris water maze task. Neuronal damage, glial activation, oxidative stress and the synaptic ultrastructure were also examined. The results indicated that a recombinant Cdh1-encoding lentiviral vector can upregulate the expression of Cdh1 in the rat hippocampus. Cdh1 overexpression increased the survival rates of rats, reversed the abnormal accumulation of cyclin B1, alleviated neuronal death, inhibited glial activation, mitigated oxidative stress, modulated synaptic plasticity and improved neurological deficits caused by ischemia. Our study indicates that targeting the Cdh1 signaling pathway in the hippocampus may provide a promising therapeutic strategy for the clinical treatment of transient global cerebral ischemia. PMID- 28711657 TI - Kaempferol impedes IL-32-induced monocyte-macrophage differentiation. AB - Kaempferol possesses a wide range of therapeutic properties, including antioxidant, anti-inflammatory, and anticancer properties. The present study sought to evaluate the effects and possible pharmacological mechanisms of kaempferol on interleukin (IL)-32-induced monocyte-macrophage differentiation. In this study, we performed flow cytometry assay, immunocytochemical staining, quantitative real-time PCR, enzyme-linked immuno sorbent assay, caspase-1 assay, and Western blotting to observe the effects and underlying mechanisms of kaempferol using the human monocyte cell line THP-1. The flow cytometry, immunocytochemical staining, and real-time PCR results show that kaempferol attenuated IL-32-induced monocyte differentiation to product macrophage-like cells. Kaempferol decreased the production and mRNA expression of pro inflammatory cytokines, in this case thymic stromal lymphopoietin (TSLP), IL 1beta, tumor necrosis factor (TNF)-alpha, and IL-8. Furthermore, kaempferol inhibited the IL-32-induced activation of p38 and nuclear factor-kappaB in a dose dependent manner in THP-1 cells. Kaempferol also ameliorated the lipopolysaccharide-induced production of the inflammatory mediators TSLP, IL 1beta, TNF-alpha, IL-8, and nitric oxide of macrophage-like cells differentiated by IL-32. In brief, our findings may provide new mechanistic insights into the anti-inflammatory effects of kaempferol. PMID- 28711658 TI - Betulinic acid, isolated from the leaves of Syzygium cumini (L.) Skeels, ameliorates the proteinuria in experimental membranous nephropathy through regulating Nrf2/NF-kappaB pathways. AB - Membranous nephropathy (MN) is associated with increased oxidative stress and inflammatory markers in the kidney. Betulinic acid (BA) is a potent antioxidant and anti-inflammatory compound isolated from the leaves of Syzygium cumini (L.) Skeels. In the present study, we investigated the effects of BA on experimental MN in rats and explored the mechanisms by which it enhances antioxidant activities and resolves inflammatory condition in experimental MN. Passive Heymann nephritis (PHN) was induced in Sprague-Dawley rats by a single tail vein injection of anti- Fx1A antiserum. The rats were orally administered BA (25 and 50 mg kg -1 d -1) or dexamethasone (DEX; 0.07 mg kg-1, reference compound) for 4 weeks after the induction of PHN. Blood, urine, and kidney tissue were collected for analysis at the end of the study. Treatment of PHN rats with BA or DEX significantly attenuated renal dysfunction, histopathological alterations and reduced immune complex deposition in the kidneys. Furthermore, BA ameliorated mRNA and protein expression of NF-kappaB, iNOS, TNF-alpha, Nrf2, HO-1 and NQO1 in the kidney. BA also restored malondialdehyde level and antioxidant enzyme activities in the kidney. In a nutshell, the protective effect of BA can be explained by its anti-inflammatory and anti-oxidant activities, which in turn is due to downregulation of NF-kappaB pathway and activation of Nrf2. The results indicated that BA can effectively suppress experimental PHN in rats by regulating Nrf2/NF-kappaB pathways. PMID- 28711659 TI - Exercise initiated after the onset of insulin resistance improves trabecular microarchitecture and cortical bone biomechanics of the tibia in hyperphagic Otsuka Long Evans Tokushima Fatty rats. AB - The present study extends our previous findings that exercise, which prevents the onset of insulin resistance and type 2 diabetes (T2D), also prevents the detrimental effects of T2D on whole-bone and tissue-level strength. Our objective was to determine whether exercise improves bone's structural and material properties if insulin resistance is already present in the Otsuka Long-Evans Tokushima Fatty (OLETF) rat. The OLETF rat is hyperphagic due to a loss-of function mutation in cholecystokinin-1 receptor (CCK-1 receptor), which leads to progressive obesity, insulin resistance and T2D after the majority of skeletal growth is complete. Because exercise reduces body mass, which is a significant determinant of bone strength, we used a body-mass-matched caloric-restricted control to isolate body-mass-independent effects of exercise on bone. Eight-wk old, male OLETF rats were fed ad libitum until onset of hyperglycemia (20weeks of age), at which time they were randomly assigned to three groups: ad libitum fed, sedentary (O-SED); ad libitum fed, treadmill running (O-EX); or, sedentary, mild caloric restriction to match body mass of O-EX (O-CR). Long-Evans Tokushima Otsuka rats served as the normophagic, normoglycemic controls (L-SED). At 32weeks of age, O-SED rats had T2D as evidenced by hyperglycemia and a significant reduction in fasting insulin compared to OLETFs at 20weeks of age. O-SED rats also had reduced total body bone mineral content (BMC), increased C-terminal telopeptide of type I collagen (CTx)/tartrate resistant acid phosphatase isoform 5b (TRAP5b), decreased N-terminal propeptide of type I procollagen (P1NP), reduced percent cancellous bone volume (BV/TV), trabecular number (Tb.N) and increased trabecular separation (Tb.Sp) and structural model index (SMI) of the proximal tibia compared to L-SED. T2D also adversely affected biomechanical properties of the tibial diaphysis, and serum sclerostin was increased and beta catenin, runt-related transcription factor 2 (Runx2) and insulin-like growth factor-I (IGF-I) protein expression in bone were reduced in O-SED vs. L-SED. O-EX or O-CR had greater total body bone mineral density (BMD) and BMC, and BV/TV, Tb.N, Tb.Sp, and SMI compared to O-SED. O-EX had lower CTx and CR greater P1NP relative to O-SED. O-EX, not O-CR, had greater cortical thickness and area, and improved whole-bone and tissue-level biomechanical properties associated with a 4 fold increase in cortical bone beta-catenin protein expression vs. O-SED. In summary, EX or CR initiated after the onset of insulin resistance preserved cancellous bone volume and structure, and EX elicited additional benefits in cortical bone. PMID- 28711661 TI - Mechanisms of action and clinical efficacy of NMDA receptor modulators in mood disorders. AB - Although the biogenic amine models have provided meaningful links between clinical phenomena and pharmacological management of mood disorders (MDs), the onset of action of current treatments is slow and a proportion of individuals fail to adequately respond. A growing number of investigations have focused on the glutamatergic system as a viable target. Herein we review the putative role of N-methyl-d-aspartate (NMDA) signaling in the pathophysiology of MDs. Prompting this focus are several lines of evidence: 1) altered glutamate and NMDA receptor (NMDAR) expression and functioning; 2) antidepressant effects of NMDAR signaling blockers; 3) interaction between conventional therapeutic regimens and NMDAR signaling modulators; 4) biochemical evidence of interaction between monoaminergic system and NMDAR signaling; 5) interaction between neurotrophic factors and NMDAR signaling in mood regulation; 6) cross-talk between NMDAR signaling and inflammatory processes; and 7) antidepressant effects of a number of NMDA modulators in recent clinical trials. Altogether, these studies establish a warrant for the refinement of novel compounds that target glutamatergic mechanisms for the treatment of MDs. PMID- 28711660 TI - A novel deletion involving GNAS exon 1 causes PHP1A and further refines the region required for normal methylation at exon A/B. AB - GNAS exons 1-13 encode the biallelically expressed alpha-subunit of the stimulatory G protein (Galphas). Additional transcripts derived from this locus use alternative first exons that undergo parent-specific methylation, thus allowing transcription only from the non-modified allele. Pseudohypoparathyroidism type Ia (PHP1A) is characterized by Albright's Hereditary Osteodystrophy (AHO) and resistance to multiple hormones; this disorder is caused by maternal inactivating mutations involving Galphas exons. In contrast, pseudohypoparathyroidism type Ib (PHP1B) is characterized mostly by resistance to PTH and often mild TSH resistance, usually without AHO features. The autosomal dominant variant of PHP1B (AD-PHP1B) is caused by maternal deletions in GNAS or STX16 that reduce Galphas expression through loss-of methylation at GNAS exon A/B alone or at multiple differentially methylated regions (DMR). Several large maternal deletions involve not only GNAS exons 1-13, but also one or several GNAS DMRs, thus causing PHP1A combined with apparent GNAS epigenetic changes that are indistinguishable from those observed in PHP1B. Some of these deletions include a large CpG island extending from exon A/B to the intron between GNAS exons 1 and 2, but there is no evidence for parent-specific exon 1 methylation. We now describe a family in which the female proband and her daughter presented with hypocalcemia, elevated PTH levels, shortened metacarpals, and obesity, but without obvious neurocognitive abnormalities. A maternally inherited 2015-bp deletion that includes GNAS exon 1 was identified thereby establishing the diagnosis of PHP1A. The centromeric deletion breakpoint is located 178bp upstream of exon 1, yet no methylation changes were observed at exon A/B. This novel deletion therefore refines further the region between exon A/B and exon 1 that is critical for establishing or maintaining normal methylation at GNAS exon A/B. PMID- 28711662 TI - The clinical and prognostic value of motor abnormalities in psychosis, and the importance of instrumental assessment. AB - Motor abnormalities comprise several clinical signs intrinsic to psychosis. Critically, these features are of prognostic value in individuals at-risk for psychosis, and for those in early stages of psychotic disorders. Motor abnormalities such as tremor, rigidity, and neurological soft signs often go unrecognized. Currently, advances in this area are limited by a paucity of theoretical conceptions categorizing or linking these behaviours to underlying neurobiology affected in psychosis. However, emerging technological advances have significantly improved the ability to detect and assess motor abnormalities with objective instruments in a timely and reliable manner. Further, converging evidence has laid the groundwork for theoretically and empirically derived categorization and conceptualization. This review summarizes these advances, stressing the importance of motor abnormalities for understanding vulnerability across different stages of psychosis and introducing these innovative instrumental approaches. Patients, researchers and clinicians will benefit from these new developments, as better assessment aids the development of targeted interventions to ultimately improve the care for individuals experiencing psychosis. PMID- 28711663 TI - Cognitive workload across the spectrum of cognitive impairments: A systematic review of physiological measures. AB - Our objective was to identify the physiological measures that are sensitive to assessing cognitive workload across the spectrum of cognitive impairments. Three database searches were conducted: PubMed, PsychINFO, and Web of Science. Studies from the last decade that used physiological measures of cognitive workload in older adults (mean age >65 years-old) were reviewed. The cognitive workload of healthy older individuals was compared with the cognitive workload of younger adults, patients with mild cognitive impairment (MCI), and patients with Alzheimer's diseases (AD). The most common measures of cognitive workload included: electroencephalography, magnetoencephalography, functional magnetic resonance imaging, pupillometry, and heart rate variability. These physiological measures consistently showed greater cognitive workload in healthy older adults compared to younger adults when performing the same task. The same was observed in patients with MCI compared to healthy older adults. Behavioral performance declined when the available cognitive resources became insufficient to cope with the cognitive demands of a task, such as in AD. These findings may have implications for clinical practice and future cognitive interventions. PMID- 28711665 TI - Ancient mitochondrial pseudogenes reveal hybridization between distant lineages in the evolution of the Rupicapra genus. AB - Mitochondrial pseudogenes (numts) inserted in the nuclear genome are frequently found in population studies. Its presence is commonly connected with problems and errors when they are confounded with true mitochondrial sequences. In the opposite side, numts can provide valuable phylogenetic information when they are copies of ancient mitochondrial lineages. We show that Rupicapra individuals of different geographic origin from the Cantabrian Mountains to the Apennines and the Caucasus share a nuclear COI fragment. The numt copies are monophyletic, and their pattern of differentiation shows two outstanding features: a long evolution as differentiated true mitochondrial lineage, and a recent integration and spread through the chamois populations. The COI pseudogene is much older than the present day mitochondrial clades of Rupicapra and occupies a basal position within the Rupicapra-Ammotragus-Arabitragus node. Joint analysis of this numt and a cytb pseudogene with a similar pattern of evolution places the source mitochondrial lineage as a sister branch that separated from the Ammotragus Arabitragus lineage 6millionyearsago (Mya). The occurrence of this sequence in the nucleus of chamois suggests hybridization between highly divergent lineages. The integration event seems to be very recent, more recent than the split of the present day mtDNA lineages of Rupicapra (1.9Mya). This observation invites to think of the spread across the genus by horizontal transfer through recent male biased dispersal. PMID- 28711664 TI - Complete genome sequence of Bacillus velezensis S3-1, a potential biological pesticide with plant pathogen inhibiting and plant promoting capabilities. AB - Antagonistic soil microorganisms, which are non-toxic, harmless non-pollutants, can effectively reduce the density of pathogenic species by some ways. Bacillus velezensis strain S3-1 was isolated from the rhizosphere soil of cucumber, and was shown to inhibit plant pathogens, promote plant growth and efficiently colonize rhizosphere soils. The strain produced 13 kinds of lipopeptide antibiotics, belonging to the surfactin, iturin and fengycin families. Here, we presented the complete genome sequence of S3-1. The genome consists of one chromosome without plasmids and also contains the biosynthetic gene cluster that encodes difficidin, macrolactin, surfactin and fengycin. The genome contains 86 tRNA genes, 27 rRNA genes and 57 antibiotic-related genes. The complete genome sequence of B. velezensis S3-1 provides useful information to further detect the molecular mechanisms behind antifungal actions, and will facilitate its potential as a biological pesticide in the agricultural industry. PMID- 28711666 TI - MicroRNAs associated with drought response in the pulse crop common bean (Phaseolus vulgaris L.). AB - Drought stress significantly reduces common bean yields. Recently, some drought related miRNAs were found in various plants. However, reports of miRNAs involved in drought stress in common bean are limited. Here, we obtained four sRNA samples from drought-tolerant and -sensitive cultivars of common bean that experienced with or without drought treatment. A total of 49 novel miRNAs and 120 known miRNAs were detected. Under drought treatment, 9 and 7 known miRNAs were down and up-regulated, respectively, and 5 and 3 of the novel miRNAs were increased and decreased, respectively. Among these miRNAs, four miRNAs shared the same pattern of expression between Long 22-0579 and Naihua. Target genes of these miRNAs included transcription factors, protein kinases, and nuclear transcription factors. Finally, we verified all of the differentially expressed miRNAs by RT qPCR, and we identified 16 miRNAs that are potentially associated with the drought stress response. These miRNAs and target genes will be useful in future basic studies and in applied studies investigating how miRNA regulation can be used to enhance drought resistance in plant species. PMID- 28711667 TI - Identification of three homologous latex-clearing protein (lcp) genes from the genome of Streptomyces sp. strain CFMR 7. AB - Rubber materials have greatly contributed to human civilization. However, being a polymeric material does not decompose easily, it has caused huge environmental problems. On the other hand, only few bacteria are known to degrade rubber, with studies pertaining them being intensively focusing on the mechanism involved in microbial rubber degradation. The Streptomyces sp. strain CFMR 7, which was previously confirmed to possess rubber-degrading ability, was subjected to whole genome sequencing using the single molecule sequencing technology of the PacBio(r) RS II system. The genome was further analyzed and compared with previously reported rubber-degrading bacteria in order to identify the potential genes involved in rubber degradation. This led to the interesting discovery of three homologues of latex-clearing protein (Lcp) on the chromosome of this strain, which are probably responsible for rubber degrading activities. Genes encoding oxidoreductase alpha-subunit (oxiA) and oxidoreductase beta-subunit (oxiB) were also found downstream of two lcp genes which are located adjacent to each other. In silico analysis reveals genes that have been identified to be involved in the microbial degradation of rubber in the Streptomyces sp. strain CFMR 7. This is the first whole genome sequence of a clear-zone-forming natural rubber- degrading Streptomyces sp., which harbours three Lcp homologous genes with the presence of oxiA and oxiB genes compared to the previously reported Gordonia polyisoprenivorans strain VH2 (with two Lcp homologous genes) and Nocardia nova SH22a (with only one Lcp gene). PMID- 28711669 TI - Reply to: Statistical support for Sema3A and multiple sclerosis. PMID- 28711668 TI - Genome-wide characterization and expression analysis of the aldehyde dehydrogenase (ALDH) gene superfamily under abiotic stresses in cotton. AB - In plants, aldehyde dehydrogenases (ALDHs) function as 'aldehyde scavengers' by removing reactive aldehydes and thus play important roles in stress responses. To date, 30 ALDHs have been identified in Gossypium raimondii, whereas ALDHs have not been studied in Gossypium arboreum or in tetraploid cotton. In this study, we identified 30, 59 and 59 aldehyde dehydrogenase (ALDH) genes from G. arboreum, G. hirsutum and G. barbadense, respectively. Gene structure analysis revealed that members of the same family exhibit similar exon-intron structures and structural domains, and all members of the ALDH18 family possess a distinct AA-kinase domain. Synteny analysis showed that segmental and tandem duplications have played an important role in the expansion and evolution of ALDHs in cotton. Phylogenetic and synteny analysis between G. arboreum and G. raimondii demonstrated that all GaALDHs and GrALDHs are orthologous and that most GaALDHs are located in syntenic blocks corresponding to those of G. raimondii, implying that these genes appeared before the divergence of G. arboreum and G. raimondii and that no expansion of the ALDH superfamily has occurred in these two cotton species. Quantitative real-time PCR analysis revealed that the majority of GaALDHs and GhALDHs are up-regulated under conditions of high salinity and drought, indicating that these genes may be stress responsive. The findings of this study, based on genome-wide identification of ALDHs in Gossypium and analysis of their evolution and expression, provide a foundation for further analysis of ALDHs and suggest potential target genes for improving stress resistance in cotton. PMID- 28711670 TI - Evaluation of serum Neuron-specific enolase, S100B, myelin basic protein and glial fibrilliary acidic protein as brain specific proteins in children with autism spectrum disorder. AB - OBJECTIVE: Brain specific-proteins are not found in other tissues and measurement non-invasively in the blood may identify structurally and functionally damaged brain regions and identify the severity and prognosis of neuropsychiatric diseases. For this reason, we aimed to evaluate serum brain-specific protein values as brain damage markers in children with autism spectrum disorder (ASD). METHOD: 35 children with ASD and 31 healthy subjects were included in the study. Sociodemographic form and Childhood Autism Rating Scale (CARS) were applied to each subject. Serum neuron specific enolase (NSE), S100B, Myelin basic protein (MBP) and Glial fibrillary acidic protein (GFAP) values were measured with ELISA. RESULTS: There was no significant difference between the two groups for NSE, MBP and S100B values (p=0.242; p=0.768; p=0.672, respectively). However, GFAP values in the patient group were statistically significantly higher (mean+/-SD: 0.463+/ 0.392ng/ml) than in the healthy control group (mean+/-SD: 0.256+/-0.111ng/ml) (p<0.001). In addition, there was a significant positive correlation between serum GFAP values and CARS score in all subjects and in the patient group (r=0.599; p<0.001 and r=0.380; p=0.024, respectively). CONCLUSIONS: While serum NSE, MBP, and S100B values cannot be considered as biomarkers for ASD, GFAP may be a biomarker and is suggested as a possible indicator of autism severity. PMID- 28711671 TI - Phylogenomic analyses of 539 highly informative loci dates a fully resolved time tree for the major clades of living turtles (Testudines). AB - Accurate time-calibrated phylogenies are the centerpiece of many macroevolutionary studies, and the relationship between the size and scale of molecular data sets and the density and accuracy of fossil calibrations is a key element of time tree studies. Here, we develop a target capture array specifically for living turtles, compare its efficiency to an ultraconserved element (UCE) dataset, and present a time-calibrated molecular phylogeny based on 539 nuclear loci sequenced from 26 species representing the breadth of living turtle diversity plus outgroups. Our gene array, based on three fully sequenced turtle genomes, is 2.4 times more variable across turtles than a recently published UCE data set for an identical subset of 13 species, confirming that taxon-specific arrays return more informative data per sequencing effort than UCEs. We used our genomic data to estimate the ages of living turtle clades including a mid-late Triassic origin for crown turtles and a mid-Carboniferous split of turtles from their sister group, Archosauria. By specifically excluding several of the earliest potential crown turtle fossils and limiting the age of fossil calibration points to the unambiguous crown lineage Caribemys oxfordiensis from the Late Jurassic (Oxfordian, 163.5-157.3Ma) we corroborate a relatively ancient age for living turtles. We also provide novel age estimates for five of the ten testudine families containing more than a single species, as well as several intrafamilial clades. Most of the diversity of crown turtles appears to date to the Paleogene, well after the Cretaceous-Paleogene mass extinction 66mya. PMID- 28711672 TI - The flexible engagement of monitoring processes in non-focal and focal prospective memory tasks with salient cues. AB - Prospective memory (PM) refers to the ability to remember to perform a delayed intention. Here, we aimed to investigate the ability to suspend such an intention and thus to confirm previous findings (Cohen, Gordon, Jaudas, Hefer, & Dreisbach, 2016) demonstrating the ability to flexibly engage in monitoring processes. In the current study, we presented a perceptually salient PM cue (bold and red) to rule out that previous findings were limited to non-salient and, thus, easy to ignore PM cues. Moreover, we used both a non-focal (Experiment 1) and a focal PM (Experiment 2) cue. In both Experiments, three groups of participants performed an Eriksen flanker task as an ongoing task with an embedded PM task (they had to remember to press the F1 key if a pre-specified cue appeared). Participants were assigned to either a control condition (performed solely the flanker task), a standard PM condition (performed the flanker task along with the PM task), or a PM delayed condition (performed the flanker task but were instructed to postpone their PM task intention). The results of Experiment 1 with the non-focal PM cue closely replicated those of Cohen et al. (2016) and confirmed that participants were able to successfully postpone the PM cue intention without additional costs even when the PM cue was a perceptually salient one. However, when the PM cue was focal (Experiment 2), it was much more difficult for participants to ignore it as evidenced by commission errors and slower latencies on PM cue trials. In sum, results showed that the focality of the PM cue plays a more crucial role in the flexibility of the monitoring process whereas the saliency of the PM cue does not. PMID- 28711673 TI - On-line prediction of the glucose concentration of CHO cell cultivations by NIR and Raman spectroscopy: Comparative scalability test with a shake flask model system. AB - In this study, near-infrared (NIR) and Raman spectroscopy were compared in parallel to predict the glucose concentration of Chinese hamster ovary cell cultivations. A shake flask model system was used to quickly generate spectra similar to bioreactor cultivations therefore accelerating the development of a working model prior to actual cultivations. Automated variable selection and several pre-processing methods were tested iteratively during model development using spectra from six shake flask cultivations. The target was to achieve the lowest error of prediction for the glucose concentration in two independent shake flasks. The best model was then used to test the scalability of the two techniques by predicting spectra of a 10l and a 100l scale bioreactor cultivation. The NIR spectroscopy based model could follow the trend of the glucose concentration but it was not sufficiently accurate for bioreactor monitoring. On the other hand, the Raman spectroscopy based model predicted the concentration of glucose in both cultivation scales sufficiently accurately with an error around 4mM (0.72g/l), that is satisfactory for the on-line bioreactor monitoring purposes of the biopharma industry. Therefore, the shake flask model system was proven to be suitable for scalable spectroscopic model development. PMID- 28711674 TI - HPLC-HG-AFS determination of arsenic species in acute promyelocytic leukemia (APL) plasma and blood cells. AB - Arsenic trioxide (ATO) has been successfully used in the treatment of acute promyelocytic leukemia (APL). To clarify the arsenic species in APL patients, high performance liquid chromatography-hydride generation-atomic fluorescence spectrometry (HPLC-HG-AFS) and HG-AFS methods were developed and validated to quantify the plasma concentrations of inorganic arsenic (As(III) and As(V)) and methylated metabolites (MMA and DMA), and the total amounts of arsenic in blood cells and plasma. Blood cells and plasma were digested with mixtures of HNO3H2O2 and analyzed by HG-AFS. For arsenic speciation, plasma samples were prepared with perchloric acid to precipitate protein. The supernatant was separated on an anion exchange column within 6min with isocratic elution using 13mM CH3COONa, 3mM NaH2PO4, 4mM KNO3 and 0.2mM EDTA-2Na. The methods provided linearity range of 0.2 20ng/mL for total arsenic and 2.0-50ng/mL for four arsenic species. The developed methods for total arsenic and arsenic species determination were precise and accurate. The spiked recoveries ranged from 81.2%-108.6% and the coefficients of variation for intra- and inter-batch precision were less than 9.3% and 12.5%, respectively. The developed methods were applied successfully for the assay of total arsenic and arsenic species in 5 APL patients. The HPLC-HG-AFS may be a good alternative for arsenic species determination in APL patients with its simplicity and low-cost in comparison with HPLC-ICP-MS. PMID- 28711675 TI - Molecular dynamics simulations of T-2410 and T-2429 HIV fusion inhibitors interacting with model membranes: Insight into peptide behavior, structure and dynamics. AB - T-2410 and T-2429 are HIV fusion inhibitor peptides (FI) designed to present a higher efficiency even against HIV strains that developed resistance against other FIs. Similar peptides were shown to interact with model membranes both in the liquid disordered phase and in the liquid ordered state. Those results indicated that such interaction is important to function and could be correlated with their effectiveness. Extensive molecular dynamics simulations were carried out to investigate the interactions between both T-2410 and T-2429 with bilayers of pure 1-palmitoyl-2-oleoyl-phosphatidylcholine (POPC) and a mixture of POPC/cholesterol (Chol) (1:1). It was observed that both peptides interact strongly with both membrane systems, especially with the POPC/Chol systems, where these peptides show the highest number of H-bonds observed so far. T-2410 and T 2429 showed higher extent of interaction with bilayers when compared to T-20 or T 1249 in previous studies. This is most notable in POPC/Chol membranes where, although able to form H-bonds with Chol, they do so to a lesser extent than T 1249 does, the latter being the only FI peptide so far that was observed to form H-bonds with Chol. This behavior suggests that interaction of FI peptides with rigid Chol rich membranes may not be as dependent from peptide/Chol H-bond formation as previous results of T-1249 behavior led to believe. As in other similar peptides, the higher ability to interact with membranes shown by T-2410 and T2429 is probably correlated with its higher inhibitory efficiency. PMID- 28711676 TI - Should we consider faecal colonisation with extended-spectrum beta-lactamase producing Enterobacteriaceae in empirical therapy of community-onset sepsis? AB - In patients colonised with extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-E), the preference for carbapenems (CRBs) over non-CRB antibiotics for empirical therapy of sepsis is questionable from an ecologic perspective. Moreover, how well colonisation predicts an ESBL-E aetiology of infection has been poorly investigated. The purpose of this retrospective observational study was to determine the positive predictive value (PPV) of ESBL E faecal colonisation for ESBL-E sepsis aetiology and the impact of empirical therapy on treatment outcome. The study included 653 ESBL-E carriers with community-onset sepsis hospitalised at a single medical centre during a 5-year period. The PPV of ESBL-E colonisation for ESBL-E sepsis aetiology was significantly higher (62.6%) when sepsis originated from a urinary tract infection (UTI) than from a respiratory tract infection (24.5%), other known origins (27.1%) or an unidentified origin (21.4%). Among the 653 patients, 177 (27.1%) received CRBs empirically and 476 received non-CRBs, predominantly beta lactam/beta-lactamase inhibitor combinations. Although univariate analysis suggested a higher 30-day mortality in the non-CRB versus CRB group (26.7% vs. 19.2%; OR = 1.53; P = 0.049), the estimated association was much smaller and was not significant (OR = 1.11, 95% CI 0.66-1.87; P = 0.68) in the multiple regression analysis adjusted for age, sex, Charlson comorbidity index, and severity, origin or aetiology of sepsis. The subgroup of 240 patients with unidentified sepsis aetiology also did not benefit from empirical CRB treatment. In non-critically ill ESBL-E carriers with community-onset sepsis, CRB-sparing empirical therapy seems appropriate, particularly if sepsis originates from a site other than a UTI. PMID- 28711677 TI - Extended spectrum of antibiotic susceptibility for tuberculosis, Djibouti. AB - In the Horn of Africa, there is a high prevalence of tuberculosis that is reported to be partly driven by multidrug-resistant (MDR) Mycobacterium tuberculosis strictu sensu strains. We conducted a prospective study to investigate M. tuberculosis complex species causing tuberculosis in Djibouti, and their in vitro susceptibility to standard anti-tuberculous antibiotics in addition to clofazimine, minocycline, chloramphenicol and sulfadiazine. Among the 118 mycobacteria isolates from 118 successive patients with suspected pulmonary tuberculosis, 111 strains of M. tuberculosis, five Mycobacterium canettii, one 'Mycobacterium simulans' and one Mycobacterium kansasii were identified. Drug susceptibility tests performed on the first 78 isolates yielded nine MDR M. tuberculosis isolates. All isolates were fully susceptible to clofazimine, minocycline and chloramphenicol, and 75 of 78 isolates were susceptible to sulfadiazine. In the Horn of Africa, patients with confirmed pulmonary tuberculosis caused by an in vitro susceptible strain may benefit from anti leprosy drugs, sulfamides and phenicol antibiotics. PMID- 28711678 TI - Linezolid in liver failure: exploring the value of the maximal liver function capacity (LiMAx) test in a pharmacokinetic pilot study. AB - Patients in the intensive care unit frequently require antibiotic treatment. Liver impairment poses substantial challenges for dose selection in these patients. The aim of the present pilot study was to assess the novel maximal liver function capacity (LiMAx test) in comparison with conventional liver function markers as covariates of drug clearance in liver failure using linezolid as a model drug. A total of 28 patients with different degrees of liver failure were recruited. LiMAx test as well as plasma, dialysate and urine sampling were performed under linezolid steady-state therapy (600 mg twice daily). NONMEM(r) was used for a pharmacometric analysis in which the different clearance routes of linezolid were elucidated. Linezolid pharmacokinetics was highly variable in patients with liver failure. The LiMAx score displayed the strongest association with non-renal clearance (CLnon-renal) [ = 4.46?(body weight/57.9) 0.75?(LiMAx/221.5)0.388 L/h], which reduced interindividual variability in CLnon renal from 46.6% to 33.6%, thereby being superior to other common markers of liver function (international normalised ratio, gamma-glutaryl transferase, bilirubin, thrombocytes, alanine aminotransferase, aspartate aminotransferase). For LiMAx < 100 ug/kg/h, 64% of linezolid trough concentrations were above the recommended trough concentration of 8 mg/L, indicating the necessity of therapeutic drug monitoring in these patients. This is the first pilot application of the LiMAx test in a pharmacokinetic (PK) study demonstrating its potential to explain PK variability in linezolid clearance. Further studies with a larger patient collective and further drugs are highly warranted to guide dosing in patients with severe liver impairment. PMID- 28711680 TI - Portraying the oddness of autism: My name is Khan; Indian Sesame street. PMID- 28711679 TI - Reproducibility of studies on text mining for citation screening in systematic reviews: Evaluation and checklist. AB - CONTEXT: Independent validation of published scientific results through study replication is a pre-condition for accepting the validity of such results. In computation research, full replication is often unrealistic for independent results validation, therefore, study reproduction has been justified as the minimum acceptable standard to evaluate the validity of scientific claims. The application of text mining techniques to citation screening in the context of systematic literature reviews is a relatively young and growing computational field with high relevance for software engineering, medical research and other fields. However, there is little work so far on reproduction studies in the field. OBJECTIVE: In this paper, we investigate the reproducibility of studies in this area based on information contained in published articles and we propose reporting guidelines that could improve reproducibility. METHODS: The study was approached in two ways. Initially we attempted to reproduce results from six studies, which were based on the same raw dataset. Then, based on this experience, we identified steps considered essential to successful reproduction of text mining experiments and characterized them to measure how reproducible is a study given the information provided on these steps. 33 articles were systematically assessed for reproducibility using this approach. RESULTS: Our work revealed that it is currently difficult if not impossible to independently reproduce the results published in any of the studies investigated. The lack of information about the datasets used limits reproducibility of about 80% of the studies assessed. Also, information about the machine learning algorithms is inadequate in about 27% of the papers. On the plus side, the third party software tools used are mostly free and available. CONCLUSIONS: The reproducibility potential of most of the studies can be significantly improved if more attention is paid to information provided on the datasets used, how they were partitioned and utilized, and how any randomization was controlled. We introduce a checklist of information that needs to be provided in order to ensure that a published study can be reproduced. PMID- 28711681 TI - Chlorpheniramine dependence presenting as mania. PMID- 28711682 TI - Oral Asenapine overdose leading to Neuroleptic Malignant Syndrome (NMS). PMID- 28711683 TI - Anti-obesogenic effects of WY14643 (PPAR-alpha agonist): Hepatic mitochondrial enhancement and suppressed lipogenic pathway in diet-induced obese mice. AB - Non-alcoholic fatty liver disease (NAFLD) presents with growing prevalence worldwide, though its pharmacological treatment remains to be established. This study aimed to evaluate the effects of a PPAR-alpha agonist on liver tissue structure, ultrastructure, and metabolism, focusing on gene and protein expression of de novo lipogenesis and gluconeogenesis pathways, in diet-induced obese mice. Male C57BL/6 mice (three months old) received a control diet (C, 10% of lipids, n = 10) or a high-fat diet (HFD, 50% of lipids, n = 10) for ten weeks. These groups were subdivided to receive the treatment (n = 5 per group): C, C alpha (PPAR-alpha agonist, 2.5 mg/kg/day mixed in the control diet), HFD and HFD alpha group (PPAR-alpha agonist, 2.5 mg/kg/day mixed in the HFD). The effects were compared with biometrical, biochemical, molecular biology and transmission electron microscopy (TEM) analyses. HFD showed greater body mass (BM) and insulinemia than C, both of which were tackled by the treatment in the HFD-alpha group. Increased hepatic protein expression of glucose-6-phosphatase, CHREBP and gene expression of PEPCK in HFD points to increased gluconeogenesis. Treatment rescued these parameters in the HFD-alpha group, eliciting a reduced hepatic glucose output, confirmed by the smaller GLUT2 expression in HFD-alpha than in HFD. Conversely, favored de novo lipogenesis was found in the HFD group by the increased expression of PPAR-gamma, and its target gene SREBP-1, FAS and GK when compared to C. The treatment yielded a marked reduction in the expression of all lipogenic factors. TEM analyses showed a greater numerical density of mitochondria per area of tissue in treated than in untreated groups, suggesting an increase in beta-oxidation and the consequent NAFLD control. PPAR-alpha activation reduced BM and treated insulin resistance (IR) and NAFLD by increasing the number of mitochondria and reducing hepatic gluconeogenesis and de novo lipogenesis protein and gene expressions in a murine obesity model. PMID- 28711684 TI - Folding of the silver aptamer in a DNAzyme probed by 2-aminopurine fluorescence. AB - The RNA-cleaving Ag10c DNAzyme was recently isolated via in vitro selection and it can bind two Ag+ ions for activity. The Ag10c contains a well-defined Ag+ binding aptamer as indicated by DMS footprinting. Since aptamer binding is often accompanied with conformational changes, we herein used 2-aminopurine (2AP) to probe its folding in the presence of Ag+. The Ag10c was respectively labeled with 2AP at three different positions, both in the substrate strand and in the enzyme strand, one at a time. Ag+-induced folding was observed at the substrate cleavage junction and the A9 position of the enzyme strand, consistent with aptamer binding. The measured Kd at the A9 position was 18 MUM Ag+ with a Hill coefficient of 2.17, similar to those obtained from the previous cleavage activity based assays. However, labeling a 2AP at the A2 position inhibited the activity and folding. Compared to other metal ions, Ag+ has a unique sigmoidal folding profile indicative of multiple silver binding cooperatively. This suggests that Ag+ can induce a local folding in the enzyme loop and this folding is important for activity. This study provides important biophysical insights into this new DNAzyme, suggesting the possibility of designing folding-based biosensors for Ag+. PMID- 28711685 TI - Misunderstandings and controversies about the insulin-secreting properties of antidiabetic sulfonylureas. AB - After 60 years of use in the treatment of type 2 diabetes, hypoglycemic sulfonylureas remain a recommended option in current therapeutic charts. Their binding to sulfonylurea receptor-1, the regulatory subunit of ATP-sensitive potassium channels in the plasma membrane of pancreatic beta-cells, leads to closure of the channels, membrane depolarization and influx of Ca2+ through voltage-gated calcium channels. The resulting increase in cytosolic Ca2+ triggers exocytosis of insulin granules. Sulfonylureas and glucose thus produce the same triggering signal but, unlike sulfonylureas, glucose does so via acceleration of beta-cell metabolism. Glucose metabolism also produces amplifying signals that approximately double the secretory response to triggering Ca2+. One persistent misunderstanding about sulfonylureas is the alleged glucose-independence of their effects. It is correct that high concentrations of these drugs can induce insulin secretion in low glucose and cause hypoglycemic episodes in treated patients. Conversely, that untoward effect is erroneously considered as evidence that their therapeutic action is independent of glucose. Another evolving controversy about the action of sulfonylureas in beta-cells is whether, like glucose, they also produce intracellular amplifying signals able to augment the efficacy of Ca2+ on exocytosis. The aims of this review are to dissipate the misunderstanding and discuss the controversy. Reasons why proposed amplifying effects of sulfonylureas are unlikely to be relevant for their action in vivo will be presented. Possible interactions of sulfonylureas and glucagon-like peptide-1 in beta-cells will be discussed. Mechanisms whereby the ambient glucose concentration modulates the insulin-secreting action of therapeutic concentrations of sulfonylureas will be explained. PMID- 28711687 TI - Methotrexate Therapy for Autoimmune Hepatitis. PMID- 28711688 TI - Cost Effective Therapy for Sphincter of Oddi Dysfunction. PMID- 28711689 TI - Reply. PMID- 28711690 TI - Place of Death and Hospice Utilization Among Patients Who Die From Cirrhosis in the United States. PMID- 28711686 TI - Hydrogel elasticity and microarchitecture regulate dental-derived mesenchymal stem cell-host immune system cross-talk. AB - : The host immune system (T-lymphocytes and their pro-inflammatory cytokines) has been shown to compromise bone regeneration ability of mesenchymal stem cells (MSCs). We have recently shown that hydrogel, used as an encapsulating biomaterial affects the cross-talk among host immune cells and MSCs. However, the role of hydrogel elasticity and porosity in regulation of cross-talk between dental-derived MSCs and immune cells is unclear. In this study, we demonstrate that the modulus of elasticity and porosity of the scaffold influence T lymphocyte-dental MSC interplay by regulating the penetration of inflammatory T cells and their cytokines. Moreover, we demonstrated that alginate hydrogels with different elasticity and microporous structure can regulate the viability and determine the fate of the encapsulated MSCs through modulation of NF-kB pathway. Our in vivo data show that alginate hydrogels with smaller pores and higher elasticity could prevent pro-inflammatory cytokine-induced MSC apoptosis by down regulating the Caspase-3- and 8- associated proapoptotic cascades, leading to higher amounts of ectopic bone regeneration. Additionally, dental-derived MSCs encapsulated in hydrogel with higher elasticity exhibited lower expression levels of NF-kB p65 and Cox-2 in vivo. Taken together, our findings demonstrate that the mechanical characteristics and microarchitecture of the microenvironment encapsulating MSCs, in addition to presence of T-lymphocytes and their pro inflammatory cytokines, affect the fate of encapsulated dental-derived MSCs. STATEMENT OF SIGNIFICANCE: In this study, we demonstrate that alginate hydrogel regulates the viability and the fate of the encapsulated dental-derived MSCs through modulation of NF-kB pathway. Alginate hydrogels with smaller pores and higher elasticity prevent pro-inflammatory cytokine-induced MSC apoptosis by down regulating the Caspase-3- and 8- associated proapoptotic cascade, leading to higher amounts of ectopic bone regeneration. MSCs encapsulated in hydrogel with higher elasticity exhibited lower expression levels of NF-kB p65 and Cox-2 in vivo. These findings confirm that the fate of encapsulated MSCs are affected by the stiffness and microarchitecture of the encapsulating hydrogel biomaterial, as well as presence of T-lymphocytes/pro-inflammatory cytokines providing evidence concerning material science, stem cell biology, the molecular mechanism of dental derived MSC-associated therapies, and the potential clinical therapeutic impact of MSCs. PMID- 28711691 TI - Effects of the 2009 Medical Cannabinoid Legalization Policy on Hospital Use for Cannabinoid Dependency and Persistent Vomiting. AB - BACKGROUND & AIMS: In 2009, the U.S. Department of Justice issued a memo stating that it would not prosecute users and sellers who complied with the state laws allowing for medical use of marijuana. There are growing concerns about legalization of marijuana use and its related public health effects. We performed an interrupted time series analysis to evaluate these effects. METHODS: We collected a representative sample of hospital discharge data from the Healthcare Cost and Utilization Project, from January 1993 to December 2014. We divided the data in to 3 groups: the prelegalization period (1993-2008), the legalization period (2009), and the postlegalization period (2010-2014). The disease variables were International Classification of Disease-Ninth Revision-Clinical Modification 304.30 cannabinoid dependency unspecified (CDU), 536.2 persistent vomiting, and an aggregate of CDU and persistent vomiting. We performed interrupted time series and Poisson-Gamma regression analysis to calculate each year's incidence rate of unspecified and persistent vomiting and CDU per 100,000 hospital discharges. CDU, persistent vomiting, and aggregate of CDU and persistent vomiting were modeled separately to estimate average incidence rate ratio and 95% confidence interval for each study phase. RESULTS: We observed an increasing trend of CDU or an aggregate of CDU and persistent vomiting during the prelegalization period. The legalization of marijuana significantly increased the incidence rate during the legalization period (by 17.9%) and the yearly average increase in rate by 6% after policy implementation, compared to the prelegalization period. The increase in rate of persistent vomiting after policy implementation increased significantly (by about 8%), although there were no significant trends in increase prior to or during marijuana legalization in 2009. CONCLUSIONS: In an interrupted time series analysis of before, during, and after medical marijuana legalization, we estimated levels and rate changes in CDU and persistent vomiting. We found persistent increases in rates of CDU and persistent vomiting during and after legalization of marijuana. PMID- 28711692 TI - Recurrent Jejunal Intussusception Caused by Heterotopic Pancreas Mass. PMID- 28711693 TI - Amyloidosis: An Unusual Cause of Intestinal Pseudo-Obstruction. PMID- 28711694 TI - Normal ultrasonographic reference values for the gastrointestinal tract in developing puppies. AB - Thickness of the individual layers of the wall of the stomach, duodenum, jejunum and colon was assessed by means of ultrasonography in developing puppies at 4, 8 and 16weeks of age. Reference intervals for the thickness of individual ultrasonographic layers of the stomach, duodenum, jejunum and colon at different ages are reported. An increase in wall thickness of all the examined gastro intestinal tracts in relation to age was recorded. The effect of body-weight was stronger on duodenal and jejunal thickness whereas it resulted lesser on stomach and colon. Correlation between duodenal and jejunal mucosal layer thickness and body weight was strong, while correlation between body weight and the other intestinal wall layers of the duodenum, jejunum and colon ranged from moderate to weak. No effects of gender were detected. PMID- 28711695 TI - Identification of a conformational neutralizing epitope on the VP1 protein of type A foot-and-mouth disease virus. AB - Foot-and-mouth disease (FMD) caused by foot-and-mouth disease virus (FMDV), is a highly contagious infectious disease that affects domestic and wild cloven-hoofed animals worldwide. In recent years, outbreaks of serotype A FMD have occurred in many countries. High-affinity neutralizing antibodies against a conserved epitope could provide protective immunity against diverse subtypes of FMDV serotype A and protect against future pandemics. In this study, we generated a serotype A FMDV specific potent neutralizing monoclonal antibody (MAb), 6C9, which recognizes a conformation-dependent epitope. MAb 6C9 potently neutralized FMDV A/XJBC/CHA/2010 with a 50% neutralization titer (NT50) of 4096. Screening of a phage-displayed random 12-mer peptide library revealed that MAb 6C9 bound to phages displaying the consensus motif YxxPxGDLG, which is highly homologous to the 135YxxPxxxxxGDLG147 motif found in the serotype A FMDV virus-encoded structural protein VP1. To further verify the authentic epitope recognized by MAb 6C9, two FMDV A/XJBC/CHA/2010 mutant viruses, P138A and G144A, were generated using a reverse genetic system. Subsequent micro-neutralization assays and double antibody sandwich (DAS) ELISA analyses revealed that the Pro138 and Gly144 residues of the conformational epitope that are recognized by 6C9 are important for MAb 6C9 binding. Importantly, the epitope 135YxxPxxxxxGDLG147 was highly conserved among different topotypes of serotype A FMDV strains in a sequence alignment analysis. Thus, the results of this study could have potential applications in the development of novel epitope-based vaccines and suitable a MAb-based diagnostic method for the detection of serotype A FMDV and the quantitation of antibodies against this serotype. PMID- 28711696 TI - Week-to-week variation of scintigraphic (semi-)quantitative thyroid variables in 14 healthy experimental cats. AB - Although scintigraphy is an important tool for the assessment of thyroid function in cats, time variation of commonly used thyroid variables has not been investigated to this day. The aim of this study was to investigate whether a week to-week variation of scintigraphic variables exists in healthy cats of a magnitude that is clinically relevant, as this could lead to misinterpretation of results. Fourteen adult, healthy, experimental cats were included in the study. At 3 time points, with 7-day intervals, the cats underwent a thyroid pertechnetate scan and blood samples were collected. The scintigraphic variables calculated were the thyroid to salivary gland ratio (T/S), thyroid to background ratio (T/B), percentage technetium uptake in the thyroid glands (%TcUT) and additionally percentage technetium uptake in the salivary glands (%TcUSG). Two thyroid hormones, total thyroxine (TT4) and thyroid stimulating hormone (TSH), were included in the analysis. All scintigraphic variables, with the exception of the %TcUT and T/Bneck ratio, were within the normal reference ranges reported in literature. No clinically relevant week-to-week variation was observed for any of the variables included in this study. PMID- 28711698 TI - Classification of mild cognitive impairment EEG using combined recurrence and cross recurrence quantification analysis. AB - The present study is aimed at the classification of mild cognitive impairment (MCI) EEG by combining complexity and synchronization features based on quantifiers from the common platform of recurrence based analysis. Recurrence rate (RR) of recurrence quantification analysis (RQA) is used for complexity analysis and RR of cross recurrence quantification analysis (CRQA) is used for synchronization analysis. The investigations are carried out on EEG from two states (i) resting eyes closed (EC) and (ii) short term memory task (STM).The results of our analysis show lower levels of complexity and higher levels of inter and intra hemispheric synchronisation in the MCI EEG compared to that of normal controls (NC) as indicated by the statistically significant higher value of RQA RR and CRQA RR. The results also evidence the effectiveness of memory activation task by bringing out the characteristic features of MCI EEG in task specific regions of temporal, parietal and frontal lobes under the STM condition.A new approach of combining complexity and synchronization features for EEG classification of MCI subjects is proposed, based on the geometrical signal separation in a feature space formed by RQA and CRQA RR values. The results of linear classification analysis of MCI and NC EEG also reveals the effectiveness of task state analysis by the enhanced classification efficiency under the cognitive load of STM condition compared to that of EC condition. PMID- 28711697 TI - Role of muscarinic receptors in the contraction of jejunal smooth muscle in the horse: An in vitro study. AB - Nonselective antimuscarinic drugs are clinically useful in several pathologic conditions of horses, but, blocking all muscarinic receptor (MR) subtypes, may cause several side effects. The availability of selective antimuscarinic drugs could improve therapeutic efficacy and safety. We aimed to enlighten the role of different MR subtypes by evaluating the effects of nonselective, and selective M1, M2 and M3 MR antagonists on the contractions of horse jejunum. Segments of circular muscle of equine jejunum, were put into organ baths, connected to isotonic transducers, and the effects on ACh concentration-response curves, and on electrical field stimulation (EFS)-evoked contractions of intestinal preparations, induced by nonselective or selective MR antagonists, compared to pre-drug level, were studied. Atropine (nonselective MR antagonist), pirenzepine (selective M1 antagonist), and p-FHHSiD (selective M3 antagonist) competitively antagonized ACh (pA2=9.78+/-0.21; 7.14+/-0.25 and 7.56+/-0.17, respectively). Methoctramine (selective M2 antagonist) antagonized ACh in a concentration unrelated fashion; however, it competitively antagonized carbachol, a nonselective muscarinic agonist (pA2=6.42+/-0.23). Atropine dose-dependently reduced EFS-evoked contractions, reaching a maximal effect of -45.64+/-6.54%; the simultaneous block of neurokinin receptors, almost completely abolished the atropine-insensitive contractions. p-FHHSiD dose-dependently reduced EFS-induced contractions, while pirenzepine caused a minor decrease. Methoctramine, ineffective up to 10-7M, enhanced the contractions at 10-6M; the block of neurokinin receptors abolished the increase of contraction. Cholinergic contractions of horse jejunum are mainly mediated by M3 receptors; M2 selective antagonists seem to scarcely affect cholinergic, and to enhance neurokininergic contractions of equine jejunum, thus their use entails a lower risk of causing intestinal hypomotility, compared to nonselective drugs. PMID- 28711699 TI - Lower catecholamine activity is associated with greater levels of anger in adults. AB - Previous research has revealed a consistent association between heart rate at rest and during stress and behavioral problems, potentially implicating autonomic nervous system (ANS) functioning in the etiological development of antisocial behavior. A complementary line of research has focused on the potential independent and interactive role of the two subsystems that comprise the ANS, the parasympathetic nervous system (PNS) and the sympathetic nervous system (SNS), on behavioral problems. The current study aims to contribute to the existing literature by examining the influence of heart rate (HR) reactivity, high frequency heart rate variability (HF-HRV) reactivity, and catecholamine activity on a comprehensive measure of anger in a large, nationally-representative sample of adults from the United States. Results from a series of structural equation models (SEMs) revealed that catecholamine activity was most consistently linked to anger, while associations involving HR and HF-HRV reactivity were nonsignificant. Additional analyses revealed that HF-HRV did not significantly moderate the association between catecholamine activity and anger. These findings highlight the importance of SNS activity in the development of more reactive forms of aggression such as anger. PMID- 28711700 TI - The effect of monetary punishment on error evaluation in a Go/No-go task. AB - Little is known about the effects of the motivational significance of errors in Go/No-go tasks. We investigated the impact of monetary punishment on the error related negativity (ERN) and error positivity (Pe) for both overt errors and partial errors, that is, no-go trials without overt responses but with covert muscle activities. We compared high and low punishment conditions where errors were penalized with 50 or 5 yen, respectively, and a control condition without monetary consequences for errors. Because we hypothesized that the partial-error ERN might overlap with the no-go N2, we compared ERPs between correct rejections (i.e., successful no-go trials) and partial errors in no-go trials. We also expected that Pe amplitudes should increase with the severity of the penalty for errors. Mean error rates were significantly lower in the high punishment than in the control condition. Monetary punishment did not influence the overt-error ERN and partial-error ERN in no-go trials. The ERN in no-go trials did not differ between partial errors and overt errors; in addition, ERPs for correct rejections in no-go trials without partial errors were of the same size as in go-trial. Therefore the overt-error ERN and the partial-error ERN may share similar error monitoring processes. Monetary punishment increased Pe amplitudes for overt errors, suggesting enhanced error evaluation processes. For partial errors an early Pe was observed, presumably representing inhibition processes. Interestingly, even partial errors elicited the Pe, suggesting that covert erroneous activities could be detected in Go/No-go tasks. PMID- 28711701 TI - Design, synthesis and biological evaluation of novel 6-substituted pyrrolo [3,2 d] pyrimidine analogues as antifolate antitumor agents. AB - A series of novel 6-substituted pyrrolo[3,2-d]pyrimidine analogues (10a, 11a-13a, 15a, 17a, 18a, 27a and 28a) have been designed and synthesized as antifolate antitumor agents. The anti-proliferative activities of these compounds against HL60, A549, H1299, Hela, HCT116 and HT29 tumor cells were evaluated. Most of the compounds exhibited micromolar anti-proliferative potencies. Compound 15a, the most potent one, has GI50 value of 0.73, 1.72, and 8.92 MUM against A549, H1299 and HL60 cells, respectively. The cell cycle distribution assay displayed that 15a could increase the accumulation of G2/M-phase cells. 15a showed low potency in induction of apoptosis. However, the inhibition of A549 cell colony formation was observed. These indicated that the tumor cell death relied on the irreversible effect of 15a on clonogenicity and cell proliferation. The identification of targeted pathway of 15a implied that the anti-proliferative potencies of 15a probably act through dual inhibition of thymidylate synthase (TS) and dihydrofolate reductase (DHFR). PMID- 28711702 TI - Development of a series of novel 4-anlinoquinazoline derivatives possessing quinazoline skeleton: Design, synthesis, EGFR kinase inhibitory efficacy, and evaluation of anticancer activities in vitro. AB - 4-anilinoquinazoline-based derivatives represent an attractive scaffold for small molecular EGFR-TKIs in the field of medicinal chemistry. A series of novel heterocyclic substituted derivatives have been designed, synthesized and evaluated their antitumor bioactivities as potential EGFR-TKIs. Most of the new compounds exhibited certain efficient inhibition potency for proliferation of a panel of five human cancer cells with IC50 values at the low micromolar level, and some of them possessed good broad-spectrum inhibition activities, compared to Gefitinib. Especially, the IC50 values of compound 21 against HepG2, A549, MCF-7, DU145 and SH-SY5Y cells were 4.61, 9.50, 9.80, 6.79 and 7.77 MUM, respectively, which were much lower than those of Gefitinb. Furthermore, the highlighting compound 21 demonstrated excellent inhibition activity against EGFR-TK with the IC50 value of 3.62 nM, similar to that of Gefitinib(2.21 nM). The results of LDH release assay proved that compound 21 was anti-proliferative rather than cytotoxicity on HepG2 cells. Compound 21 were able to cause HepG2 cells to block in S phase and induce cell death mainly by apoptosis through a mitochondrial dependent pathway. Moreover, the assessment of MMP, the determination of intracellular free Ca2+ concentration, the production of ROS, and the effects on the activity of caspase-3 in a dose-dependent manner demonstrated that compound 21 induced cell apoptosis in HepG2 cells through the Ca2+/ROS-mediated mitochondria/caspase-dependent apoptosis pathway largely. These preliminary results evidenced that compound 21 could be a potential antitumor agent deserving further study. PMID- 28711703 TI - Novel 4-arylaminoquinazoline derivatives with (E)-propen-1-yl moiety as potent EGFR inhibitors with enhanced antiproliferative activities against tumor cells. AB - A series of novel 4-anilinoquinazoline derivatives with (E)-propen-1-yl moiety were designed, synthesized and evaluated for biological activities in vitro. Most compounds exhibited highly antiproliferative activities against all tested tumor cell lines including A431, A549, NCI-H1975 and SW480 cells. Especially, compound 6e not only presented strong antiproliferative activities against the tested four tumor cell lines (IC50 of 1.35, 8.83, 5.53 and 6.08 MUM, respectively) which expressed wild type or L858R/T790M double mutant epidermal growth factor receptor (EGFR), but also showed potent inhibitory activity against wild type EGFR (IC50 = 20.72 nM). The result of molecular docking with EGFR suggested the binding mode of 6e was similar to gefitinib, but different from lapatinib. Additionally, western blot analysis showed that 6e inhibited the phosphorylation of EGFR and its downstream signaling proteins in lung cancer cells. The work could be very useful starting point for developing a new series of tyrosine kinase inhibitors targeting EGFR. PMID- 28711704 TI - Detection of Zika virus RNA in semen of asymptomatic blood donors. AB - OBJECTIVES: Zika virus (ZIKV) transmission through semen donation has never been reported but the risk is supported by the detection of ZIKV in semen and the demonstration of ZIKV sexual transmission. The potential impact of ZIKV on assisted reproductive procedures should be evaluated. METHODS: We tested longitudinally collected semen samples provided by asymptomatic blood donors who tested positive for ZIKV RNA in plasma during ZIKV outbreaks in Puerto Rico and Florida in 2016. RESULTS: Five of the 14 (35.7%) asymptomatic blood donors provided semen samples that tested positive for ZIKV RNA, with ZIKV RNA loads ranging from 8.03 * 103 to 2.55 * 106 copies/mL. Plasma collected at the same time as the semen tested negative for ZIKV RNA for most ZIKV RNA-positive semen collections; all corresponding plasma samples tested positive or equivocal for anti-ZIKV IgG antibodies and all except one tested positive for ZIKV IgM antibodies. The rate of detection of ZIKV RNA in semen in asymptomatic donors is not significantly different from the rate previously reported for symptomatic patients. CONCLUSIONS: Our results that show a high percentage of detection of ZIKV RNA in the semen of asymptomatic men confirm that ZIKV is a new threat for reproductive medicine and should have important implications for assisted reproductive technology. We recommend that semen donations from men at risk for ZIKV infection should be tested for ZIKV RNA, regardless of symptoms of ZIKV infection. PMID- 28711705 TI - BMP15 in catfish testis: Cellular distribution, seasonal variation, and its role in steroidogenesis. AB - Considering the absence of information on testicular growth factors in fishes, present study was aimed to elucidate the existence of BMP15, an important member of TGF-beta superfamily, in the testis of a seasonally breeding freshwater catfish, Clarias batrachus and its role in regulation of testicular activities. The study demonstrated the expression of BMP15 in the somatic cells (Sertoli and interstitial cells) in fish testis. The expression varied with changing testicular activity; the expression was very high in the quiescent and early recrudescing testis coinciding with the renewal of spermatogonial cells. Expression then declined gradually with progression of spermatogenesis and steroidogenesis. Expression of BMP15 showed positive correlation with seasonally changing testicular 17beta-estradiol but negatively with testicular testosterone and 11-ketotestosterone. In vitro treatment of testis with recombinant human BMP15 enhanced the production of estradiol-17beta but concurrently suppressed the production of testosterone and 11-ketotestosterone in testis. Though BMP15 did not alter the expression of StAR protein in the testis, it promoted the expression of 3beta-hydroxysteroid dehydrogenase and aromatase in fish testis. Thus the present study for the first time demonstrates that fish testis is capable of producing BMP15 and is expressed by the somatic cells unlike mammals wherein it is produced exclusively by germ cells. Study also suggests that BMP15 may modulate the testicular steroidogenesis by altering the expression of steroidogenic enzymes. BMP15 also appears to play crucial role in renewal of spermatogial cells by augmenting the testicular production of 17beta-estradiol. PMID- 28711706 TI - Haemolytic activity of formyl- and acetyl-derivatives of bile acids and their gramine salts. AB - Bile acids (lithocholic: LCA, deoxycholic: DCA and cholic: CA) and their formyl- and acetyl-derivatives can be used as starting material in chemical synthesis of compounds with different biological activity strongly depended on their chemical structures. Our previous studies showed that biological activity of bile acids salts with gramine toward human erythrocytes was significantly different from the activity of bile acids alone. Moreover, gramine effectively modified the membrane perturbing activity of other steroids. As a continuation of our work, the haemolytic activity of formyl- and acetyl-substituet bile acids as well as their gramine salts was studied in vitro. The structures of new compounds were confirmed by spectral (NMR, FT-IR) analysis, mass spectrometry (ESI-MS) as well as PM5 semiempirical methods. The results shown that the haemolytic activity of formyl- and acetyl-LCA and DCA was significantly higher in comparison with their native forms at the whole concentration range. At high concentration, formyl derivative of CA was as effective as LCA and DCA derivatives whereas at lower concentration its haemolytic activity was at the level of original acid. The acetyl-CA was not active as membrane perturbing agents. Furthermore, gramine significantly decreased the membrane-perturbing activity of hydrophobic bile acids derivatives. The results obtained with the cellular system are in line with physicochemical calculation. PMID- 28711707 TI - Protecting group-free radical decarboxylation of bile acids: Synthesis of novel steroidal substituted maleic anhydrides and maleimides and evaluation of their cytotoxicity on C6 rat glioma cells. AB - We report the first Barton radical decarboxylation of unprotected bile acids via in situ irradiation of their thiohydroxamic esters in the presence of citraconic anhydride and citracoimide, leading to the synthesis a series of steroidal maleic anhydrides and maleimides as novel hybrid bile acids. The cytotoxic activities were evaluated on C6 rat glioma cells. PMID- 28711709 TI - Isolated erythrocytosis associated with a CALR mutation. PMID- 28711708 TI - Ezetimibe and simvastatin combination inhibits and reverses the pro-inflammatory and pro-atherogenic effects of cream in obese patients. AB - BACKGROUND AND AIMS: Inflammation and postprandial lipemia are associated with increased cardiovascular disease. We investigated whether ezetimibe and simvastatin combination, a lipid lowering combination of simvastatin and ezetimibe, exerts an anti-inflammatory effect in the fasting state and after dairy cream intake. METHODS: Twenty obese patients were randomized to either ezetimibe and simvastatin combination or placebo treatment for 6 weeks. All patients were asked to ingest 33 ml of dairy cream (300 Calories) at the beginning and at the end of intervention. Fasting and post-cream blood samples were obtained. RESULTS: At 0 week, ingestion of cream induced significant increases in MNC expression of IL-1beta (105 +/- 18%), TNFalpha (97 +/- 12%), CD68 (48 +/- 8%), CD16 (141 +/- 39%), MMP-9 (122 +/- 31%), PECAM (66 +/- 10%), TLR-4 (84 +/- 11%) and TLR-2 (67 +/- 9%) and in endotoxin (LPS) concentrations (49 +/- 7%) (p < 0.05). Ezetimibe and simvastatin combination treatment lowered fasting total cholesterol, LDLc and Lp(a) concentrations and Apo B/A1 ratio and suppressed the MNC expression of IL-1beta and CD68 (by 21 +/- 7 and 24 +/- 10, p < 0.05) and the concentrations of LPS, CRP, FFA and IL-18 by 24 +/- 7%, 32 +/- 11%, 19 +/- 8% 15 +/- 4%, respectively, (p < 0.05). Cream-induced increases in the expression of IL-1beta, CD68, CD16, MMP-9, TNFalpha and PECAM were reduced in the ezetimibe and simvastatin combination group by 74 +/- 15%, 68 +/- 13%, 57 +/- 13%, 64 +/- 16%, 67 +/- 14% and 45 +/- 9%, respectively, while those of LPS and MMP-9 concentrations were reduced by 53 +/- 9% and 38 +/- 8%, respectively, compared to the increases at week 0 (p < 0.05). There was a suppression of TLR-2 and TLR-4 expression by 21 +/- 8% and 18 +/- 7%, respectively, compared to 0-h baseline, after cream intake following ezetimibe and simvastatin combination treatment. CONCLUSIONS: Ezetimibe and simvastatin combination exerts a profound anti-inflammatory effect both in the fasting state and acutely after the ingestion of saturated fat. PMID- 28711710 TI - Comparison of the role of metabotropic glutamate receptor subtype 1 in developmental refinement of neuronal connectivity between the cerebellum and the sensory thalamus. AB - Developmental refinement of neuronal connectivity is crucial for proper brain function. In the early phase of development, input fibers arrive at their target areas guided by specific molecular cues and form abundant immature synapses. Then, functionally important synapses are preserved and strengthened by neural activity while unnecessary synapses are eliminated. Afferent synapses in the sensory thalamus, such as from retina to lateral geniculate nucleus, and climbing fiber (CF)-Purkinje cell (PC) synapses in the cerebellum are valuable models for studying this developmental refinement of synaptic connectivity because only a limited number of input fibers innervate a given postsynaptic thalamocortical (TC) neuron or PC. The metabotropic glutamate receptor subtype 1 (mGluR1) is required for the refinement of both afferent-TC neuron and CF-PC synapses. However, mGluR1 functions differently at these synapses. While mGluR1 is critical for elimination of surplus CF-PC synapses in the cerebellum, retinogeniculate synapses require mGluR1 for maintenance of mature connectivity. PMID- 28711711 TI - Three-dimensional kinematic and kinetic analysis of quadrupedal walking in the common marmoset (Callithrix jacchus). AB - The common marmoset has recently gained a great deal of attention as an experimental primate model for biological science and medical research. To use the common marmoset for development of novel treatments and rehabilitation for locomotor disorders, it is crucial to understand fundamental baseline characteristics of locomotion in this species. Therefore, in the present study we performed kinematic and kinetic analyses of quadrupedal locomotion in this animal. A total of 14 common marmosets walking quadrupedally along a walkway were analyzed using synchronized high-speed cameras, with two force platforms set in the walkway. Our results demonstrated that the marmoset uses a lateral sequence walking pattern, in contrast to the macaque and other primates, which usually adopt a diagonal sequence pattern. Furthermore, peak vertical ground reaction force on the forelimb was larger than that on the hindlimb. The rate of energy recovery for quadrupedal walking in the common marmoset was much smaller than that in the macaque, indicating that the marmoset generally utilizes bouncing mechanics in locomotion, even though the duty factor is >0.5. This description of locomotor characteristics of intact marmosets may serve as a basis for comparative analyses of changes in gait due to rehabilitation and regenerative treatments. PMID- 28711712 TI - Ex vivo and in vivo evaluation of microemulsion based transdermal delivery of E. coli specific T4 bacteriophage: A rationale approach to treat bacterial infection. AB - This study is focused on the development and evaluation of transdermal delivery of E. coli-specific T4 bacteriophages both ex-vivo and in-vivo using microemulsion as delivery carrier in eradicating the infection caused by E. coli. Microemulsions were prepared by mixing selected oil, surfactants and aqueous phase containing bacteriophages. The formulations were subjected to physicochemical characterization, ex-vivo and in-vivo permeation, stability studies, histological and immunofluorescence examination. The colloidal system exhibits a uniform size distribution, of finite size (150-320nm). Transmission electron microscopy revealed the encapsulation of bacteriophage in the aqueous globule. Ex-vivo permeation across skin was successfully achieved as 6*106PFU/mL and 6.7*106PFU/mL of T4 permeated from ME 6% and 10%, respectively. ME 6% was found to be thermodynamically stable and in-vivo permeation resulted in 5.49*105PFU/mL of bacteriophages in the blood of the E. coli challenged rats, while 2.48*105PFU/mL was detected in germ free rats, at the end of the study. Infected rats that were treated with bacteriophage were survived while significant mortality was observed in others. Histological and IL-6 immunofluorescence examination of the tissues revealed the efficacy/safety of the therapy. The microemulsion-based transdermal delivery of bacteriophage could be a promising approach to treat the infections caused by antibiotic-resistant bacteria. PMID- 28711713 TI - Surprisingly high stability of the Abeta oligomer eliminating all-d-enantiomeric peptide D3 in media simulating the route of orally administered drugs. AB - The aggregation of the amyloid beta protein (Abeta) plays an important role in the pathology of Alzheimer's disease. Previously, we have developed the all-d enantiomeric peptide D3, which is able to eliminate neurotoxic Abeta oligomers in vitro and improve cognition in a transgenic Alzheimer's disease mouse model in vivo even after oral administration. d-Peptides are expected to be more resistant against enzymatic proteolysis compared to their l-enantiomeric equivalents, and indeed, a pharmacokinetic study with tritiated D3 revealed the oral bioavailability to be about 58%. To further investigate the underlying properties, we examined the stability of D3 in comparison to its corresponding all-l-enantiomeric mirror image l-D3 in media simulating the gastrointestinal tract, blood and liver. Potential metabolization was followed by reversed-phase high-performance liquid chromatography. In simulated gastric fluid, D3 remained almost completely stable (89%) within 24h, while 70% of l-D3 was degraded within the same time period. Notably, in simulated intestinal fluid, D3 also remained stable (96%) for 24h, whereas l-D3 was completely metabolized within seconds. In human plasma and human liver microsomes, l-D3 was metabolized several hundred times faster than D3. The remarkably high stability may explain the high oral bioavailability seen in previous studies allowing oral administration of the drug candidate. Thus, all-d-enantiomeric peptides may represent a promising new compound class for drug development. PMID- 28711714 TI - Review - An update on the use of oral phospholipid excipients. AB - The knowledge and experiences obtained with oral phospholipid excipients is increasing continuously. Nevertheless the present number of oral products using these excipients as essential excipient is very limited. This is remarkable to note, since phospholipids play a significant role in the food uptake mechanisms of the GI tract and these mechanisms could be translated into suitable dosage forms and corresponding drug delivery strategies. In addition, phospholipid excipients are multifunctional biodegradable, non-toxic excipients, which can be used in oral dosage forms as wetting agents, emulsifier, solubilizer and matrix forming excipients. Especially natural phospholipid excipients, made from renewable sources, may be considered as environmentally friendly excipients and as a viable alternative to synthetic phospholipid and non-phospholipid analogues. This review describes 1) essential physico-chemical properties of oral phospholipid excipients 2) the fate of orally administered phospholipids with respect to absorption and metabolism in the GI tract 3) the main dosage forms used for oral administration containing phospholipids. These elements are critically assessed and areas of future research of interest for the use of oral phospholipid excipients are summarized. PMID- 28711715 TI - Novel peptide motifs from lysozyme suppress pro-inflammatory cytokines in macrophages by antagonizing toll-like receptor and LPS-scavenging action. AB - Lysozyme is commonly found in spots where bacterial infections are most likely to enter the body. Earlier we found that lysozyme possesses five antimicrobial peptide motifs in its N-terminal region which can be generated by newborn pepsin. In this study, we explore the role of these peptides in the anti-inflammatory activity of lysozyme. The five peptides, helix1 (H1), helix2 (H2), H1 and H2 connected with a loop (HLH), H2 extended with either 2 beta-strands (H2-S12) or 3 beta-strands (H2-S13), were synthesized and examined for anti-inflammatory action. The five peptides dose-dependently decreased, to different degrees, expression of pro-inflammatory cytokines, TNF-alpha, IL-6 and IL-1beta, in lipopolysaccharide (LPS)- or interferon-gamma (INF-gamma)-stimulated mouse macrophage cells (RAW264.7). The HLH peptide and its individual helices (H1 and H2) were markedly the most potent anti-inflammatory. When macrophage cells were stimulated with live bacteria (E. coli), H1 peptide was the most powerful suppressor of TNF-alpha and IL-6 expression, providing evidence that the peptide is able to antagonize the pathogen-induced inflammatory response. Receptor binding assay and docking simulation provided evidence that H1 peptide bind specifically to the pocket for endotoxin binding of the toll-like receptor 4 (TLR 4) of macrophage. The results demonstrate, for the first time, the molecular basis of anti-inflammatory action of lysozyme that N-terminal helical peptides are the main contributors. This exciting finding offers new classes of therapeutic peptides with potential in the treatment of infection-induced inflammatory diseases. PMID- 28711716 TI - Impact of paroxetine on proximal beta-adrenergic receptor signaling. AB - beta-adrenergic receptors (betaAR) regulate numerous functions throughout the body, however G protein-coupled receptor kinase (GRK)-dependent desensitization of betaAR has long been recognized as a maladaptive process in the progression of various disease states. Thus, the development of small molecule inhibitors of GRKs for the study of these processes and as potential therapeutics has been at the forefront of recent research efforts. Via structural and biochemical analyses, the selective serotonin reuptake inhibitor (SSRI) paroxetine was identified as a GRK2 inhibitor that enhances betaAR-dependent cardiomyocyte and cardiac contractility and reverses cardiac dysfunction and myocardial betaAR expression in mouse models of heart failure. Despite these functional outcomes, consistent with diminished betaAR desensitization, the proximal betaAR signaling mechanisms sensitive to paroxetine have not been reported. In this study, we aimed to determine whether paroxetine prevents classic betaAR desensitization related signaling mechanisms at a molecular level. Therefore, via immunoblotting, radioligand binding, fluorescence resonance energy transfer (FRET) and microscopy assays, we have performed an assessment of the effect of paroxetine on proximal betaAR signaling responses. Indeed, paroxetine treatment inhibited ligand-induced beta2AR phosphorylation in a concentration-dependent manner. Additionally, for both beta1AR and beta2AR, paroxetine decreased ligand-induced betaarrestin2 recruitment and subsequent receptor internalization. Thus, paroxetine inhibits betaAR desensitization mechanisms consistent with GRK2 inhibition and provides a useful pharmacological tool for studying these proximal GPCR signaling responses. PMID- 28711718 TI - Phospholipase D1 is a regulator of platelet-mediated inflammation. AB - Glycoprotein (GP)Ib is not only required for stable thrombus formation but for platelet-mediated inflammatory responses. Phospholipase (PL)D1 is essential for GPIb-dependent aggregate formation under high shear conditions while nothing is known about PLD1-induced regulation of GPIb in platelet-mediated inflammation and the underlying mechanisms. This study aimed to investigate the relevance of PLD1 for platelet-mediated endothelial and leukocyte recruitment and activation in vitro and in vivo. Pld1-/- platelets showed strongly reduced adhesion to TNFalpha stimulated endothelial cells (ECs) under high shear conditions ex vivo. Normal cytoskeletal reorganization of Pld1-/- platelets but reduced integrin activation after adhesion to inflamed ECs confirmed that defective integrin activation is responsible for reduced platelet adhesion to ECs. This, together with significantly reduced CD40L expression on platelets led to reduced chemotactic and adhesive properties of ECs in vitro. Under flow conditions, recruitment of leukocytes to collagen-adherent platelets was reduced. Under inflammatory conditions in vivo, reduced platelet and leukocyte recruitment and arrest to the injured carotid artery was observed in Pld1-/- mice. In a second in vivo model of venous thrombosis, platelet adhesion to activated endothelial cells was reduced while leukocyte recruitment was attenuated in PLD1 deficient mice. Mechanistically, PLD1 modulates PLCgamma2 phosphorylation and integrin activation via Src kinases without affecting vWF binding to GPIb. Thus, PLD1 is important for GPIb-induced inflammatory processes of platelets and might be a promising target to reduce platelet-mediated inflammation. PMID- 28711717 TI - Phosphatidylinositol 4-phosphate 5-kinase alpha contributes to Toll-like receptor 2-mediated immune responses in microglial cells stimulated with lipoteichoic acid. AB - Phosphatidylinositol 4,5-bisphosphate (PIP2) is an important lipid regulator of membrane signaling and remodeling processes. Accumulating evidence indicates a link between PIP2 metabolism and Toll-like receptor (TLR) signaling, a key transducer of immune responses such as inflammation, phagocytosis, and autophagy. Microglia are immune effector cells that serve as macrophages in the brain. Here, we examined the potential role of phosphatidylinositol 4-phosphate 5-kinase alpha (PIP5Kalpha), a PIP2-producing enzyme, in TLR2 signaling in microglial cells. Treatment of BV2 microglial cells with lipoteichoic acid (LTA), a TLR2 agonist, increased PIP5Kalpha expression in BV2 and primary microglial cells, but not in primary cultures from TLR2-deficient mice. PIP5Kalpha knockdown of BV2 cells with shRNA significantly suppressed LTA-induced activation of TLR2 downstream signaling, including the production of proinflammatory cytokines and phosphorylation of NF-kappaB, JNK, and p38 MAP kinase. Such suppression was reversed by complementation of PIP5Kalpha. PIP5Kalpha knockdown lowered PIP2 levels and impaired LTA-induced plasma membrane targeting of TIRAP, a PIP2 dependent adaptor required for TLR2 activation. Besides, PIP5Kalpha knockdown inhibited phagocytic uptake of E. coli particles and autophagy-related vesicle formation triggered by LTA. Taken together, these results support that PIP5Kalpha can positively mediate TLR2-associated immune responses through PIP2 production in microglial cells. PMID- 28711721 TI - "Supporting nursing, midwifery and allied health professional students to raise concerns with the quality of care: A review of the research literature". AB - BACKGROUND: This article reports aspects of a systematic literature review commissioned by the UK Council of Deans of Health. The review collated and analysed UK and international literature on pre-registration healthcare students raising concerns with poor quality care. The research found in that review is summarised here. OBJECTIVE: To review research on healthcare students raising concerns with regard to the quality of practice published from 2009 to the present. DATA SOURCES: In addition to grey literature and Google Scholar a search was completed of the CINAHL, Medline, ERIC, BEI, ASSIA, PsychInfo, British Nursing Index, Education Research Complete databases. REVIEW METHOD: Sandelowski and Barroso's (2007) method of metasynthesis was used to screen and analyse the research literature. The review covered students from nursing, midwifery, health visiting, paramedic science, operating department practice, physiotherapy, chiropody, podiatry, speech and language therapy, orthoptist, occupational therapy, orthotist, prosthetist, radiography, dietitian, and music and art therapy. RESULTS: Twenty three research studies were analysed. Most of the research relates to nursing students with physiotherapy being the next most studied group. Students often express a desire to report concerns, but factors such as the potential negative impact on assessment of their practice hinders reporting. There was a lack of evidence on how, when and to whom students should report. The most commonly used research approach found utilised vignettes asking students to anticipate how they would report. CONCLUSIONS: Raising a concern with the quality of practice carries an emotional burden for the student as it may lead to sanctions from staff. Further research is required into the experiences of students to further understand the mechanisms that would enhance reporting and support them in the reporting process. PMID- 28711720 TI - Onset age of L2 acquisition influences language network in early and late Cantonese-Mandarin bilinguals. AB - Early second language (L2) experience influences the neural organization of L2 in neuro-plastic terms. Previous studies tried to reveal these plastic effects of age of second language acquisition (AoA-L2) and proficiency-level in L2 (PL-L2) on the neural basis of language processing in bilinguals. Although different activation patterns have been observed during language processing in early and late bilinguals by task-fMRI, few studies reported the effect of AoA-L2 and high PL-L2 on language network at resting state. In this study, we acquired resting state fMRI (R-fMRI) data from 10 Cantonese (L1)-Mandarin (L2) early bilinguals (acquired L2: 3years old) and 11 late bilinguals (acquired L2: 6years old), and analyzed their topological properties of language networks after controlling the language daily exposure and usage as well as PL in L1 and L2. We found that early bilinguals had significantly a higher clustering coefficient, global and local efficiency, but significantly lower characteristic path length compared to late bilinguals. Modular analysis indicated that compared to late bilinguals, early bilinguals showed significantly stronger intra-modular functional connectivity in the semantic and phonetic modules, stronger inter-modular functional connectivity between the semantic and phonetic modules as well as between the phonetic and syntactic modules. Differences in global and local parameters may reflect different patterns of neuro-plasticity respectively for early and late bilinguals. These results suggested that different L2 experience influences topological properties of language network, even if late bilinguals achieve high PL-L2. Our findings may provide a new perspective of neural mechanisms related to early and late bilinguals. PMID- 28711722 TI - "Lie to me"-Oxytocin impairs lie detection between sexes. AB - The hormone oxytocin modulates various aspects of social behaviors and even seems to lead to a tendency for gullibility. The aim of the current study was to investigate the effect of oxytocin on lie detection. We hypothesized that people under oxytocin would be particularly susceptible to lies told by people of the opposite sex. After administration of oxytocin or a placebo, male and female participants were asked to judge the veracity of statements from same- vs. other sex actors who either lied or told the truth. Results showed that oxytocin decreased the ability of both male and female participants to correctly classify other-sex statements as truths or lies compared to placebo. This effect was based on a lower ability to detect lies and not a stronger bias to regard truth statements as false. Revealing a new effect of oxytocin, the findings may support assumptions about the hormone working as a catalyst for social adaption. PMID- 28711719 TI - G protein-coupled receptor kinases: Past, present and future. AB - This review is provided in recognition of the extensive contributions of Dr. Robert J. Lefkowitz to the G protein-coupled receptor (GPCR) field and to celebrate his 75th birthday. Since one of the authors trained with Bob in the 80s, we provide a history of work done in the Lefkowitz lab during the 80s that focused on dissecting the mechanisms that regulate GPCR signaling, with a particular emphasis on the GPCR kinases (GRKs). In addition, we highlight structure/function characteristics of GRK interaction with GPCRs as well as a review of two recent reports that provide a molecular model for GRK-GPCR interaction. Finally, we offer our perspective on some future studies that we believe will drive this field. PMID- 28711723 TI - Diurnal cortisol rhythms, fatigue and psychosocial factors in five-year survivors of ovarian cancer. AB - Fatigue is a challenge in ovarian cancer survivorship and greatly impacts quality of life. In other cancer populations, fatigue has been associated with abnormal diurnal cortisol patterns. However, little is known about biological and behavioral factors in 5+-year ovarian cancer survivors and potential mechanisms underlying persistent fatigue have not been investigated in this population. Moreover, relationships between neuroendocrine and psychosocial factors in 5+ year ovarian cancer survivors have not been studied. We addressed these issues by examining relationships between diurnal cortisol rhythms, fatigue, life stress, and social support in 30 survivors of ovarian cancer who were assessed at least 5 years (mean=6.20years) following their primary diagnosis. Flatter diurnal cortisol slopes were associated with higher levels of fatigue, suggesting a role for HPA-axis dysregulation in sustained fatigue experienced by survivors. Moreover, greater cumulative lifetime stressor exposure (p=0.023) and stressor severity (p=0.004) were associated with flatter diurnal cortisol slopes, while higher social attachment (p=0.001) was associated with steeper diurnal cortisol slopes. These findings suggest that ovarian cancer survivors with greater lifetime stress exposure or lower social attachment may be at increased risk for circadian rhythm disruption, which in turn is associated with fatigue. Future research should examine relationships of clinical stage and inflammatory cytokines to cortisol rhythms and fatigue in long-term ovarian cancer survivors, as well as investigating the clinical significance of abnormal diurnal cortisol profiles in this population. PMID- 28711724 TI - Neurotrophic and inflammatory markers in bipolar disorder: A prospective study. AB - Altered neurotrophic signaling is thought to impair neuroplasticity in bipolar disorder (BD). Brain-derived neurotrophic factor (BDNF) is proposed as a neurotrophic marker in BD. However, the current evidence for its use in monitoring disease activity and illness progression is conflicting and an exploration of additional neurotrophic markers is needed. This prospective case control study investigated mood-specific changes in potential neurotrophic markers and their association to inflammatory activity. Patients with BD were included during an acute mood episode, either depressive (n=35) or (hypo)manic (n=32). Fifty-nine patients (88%) and 29 healthy controls (97%) completed the study. Peripheral blood levels of BDNF, vascular endothelial growth factor A (VEGF), soluble fms-like tyrosine kinase-1 (sFlt-1) and tumor necrosis factor alpha (TNF-alpha) were measured at baseline and after 2 months. Biomarker levels in patients were compared to controls and correlated to HDRS-17 and YMRS total scores and the PANSS positive subscale scores. Linear mixed model analysis revealed no significant differences in neurotrophic markers between patients and controls. We found significantly increased TNF-alpha levels in patients and a subsequent normalization during euthymia. None of the biomarkers strongly correlated to mood symptom severity. Despite standardized methodological practices, BDNF and VEGF levels had a wide distribution range. We need a better understanding of methodological aspects influencing the analysis of neurotrophic factors to improve future research on markers for mood state monitoring and illness progression in BD. PMID- 28711725 TI - The cost-effectiveness of a patient centred pressure ulcer prevention care bundle: Findings from the INTACT cluster randomised trial. AB - BACKGROUND: Pressure ulcers are serious, avoidable, costly and common adverse outcomes of healthcare. OBJECTIVES: To evaluate the cost-effectiveness of a patient-centred pressure ulcer prevention care bundle compared to standard care. DESIGN: Cost-effectiveness and cost-benefit analyses of pressure ulcer prevention performed from the health system perspective using data collected alongside a cluster-randomised trial. SETTINGS: Eight tertiary hospitals in Australia. PARTICIPANTS: Adult patients receiving either a patient-centred pressure ulcer prevention care bundle (n=799) or standard care (n=799). METHODS: Direct costs related to the intervention and preventative strategies were collected from trial data and supplemented by micro-costing data on patient turning and skin care from a 4-week substudy (n=317). The time horizon for the economic evaluation matched the trial duration, with the endpoint being diagnosis of a new pressure ulcer, hospital discharge/transfer or 28days; whichever occurred first. For the cost effectiveness analysis, the primary outcome was the incremental costs of prevention per additional hospital acquired pressure ulcer case avoided, estimated using a two-stage cluster-adjusted non-parametric bootstrap method. The cost-benefit analysis estimated net monetary benefit, which considered both the costs of prevention and any difference in length of stay. All costs are reported in AU$(2015). RESULTS: The care bundle cost AU$144.91 (95%CI: $74.96 to $246.08) more per patient than standard care. The largest contributors to cost were clinical nurse time for repositioning and skin inspection. In the cost effectiveness analysis, the care bundle was estimated to cost an additional $3296 (95%CI: dominant to $144,525) per pressure ulcer avoided. This estimate is highly uncertain. Length of stay was unexpectedly higher in the care bundle group. In a cost-benefit analysis which considered length of stay, the net monetary benefit for the care bundle was estimated to be -$2320 (95%CI -$3900, -$1175) per patient, suggesting the care bundle was not a cost-effective use of resources. CONCLUSIONS: A pressure ulcer prevention care bundle consisting of multicomponent nurse training and patient education may promote best practice nursing care but may not be cost-effective in preventing hospital acquired pressure ulcer. PMID- 28711726 TI - If All You Have Is a Hammer...: Transplantation for Myelodysplastic Syndrome after Hypomethylating Agents Fail. PMID- 28711727 TI - A Chemotherapy-Only Regimen of Busulfan, Melphalan, and Fludarabine, and Rabbit Antithymocyte Globulin Followed by Allogeneic T-Cell Depleted Hematopoietic Stem Cell Transplantations for the Treatment of Myeloid Malignancies. AB - We sought to develop a myeloablative chemotherapeutic regimen to secure consistent engraftment of T-cell depleted (TCD) hematopoietic stem cell transplantations (HSCT) without the need for total body irradiation, thereby reducing toxicity while maintaining low rates of graft-versus-host disease (GVHD) and without increasing relapse. We investigated the myeloablative combination of busulfan (Bu) and melphalan (Mel), with the immunosuppressive agents fludarabine (Flu) and rabbit antithymocyte globulin (r-ATG) as cytoreduction before a TCD HSCT. No post-transplantation immunosuppression was administered. Between April 2001 and May 2008, 102 patients (median age, 55 years) with a diagnosis of primary or secondary myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) underwent cytoreduction with Bu/Mel/Flu, followed by TCD grafts. TCD was accomplished by CD34+-selection followed by E-rosette depletion for peripheral blood stem cell grafts and, for bone marrow grafts, by soybean agglutination followed by E-rosette depletion. Donors included matched and mismatched, related and unrelated donors. Risk stratification was by American Society for Blood and Marrow Transplantation risk categorization for patients with primary disease. For patients with secondary/treatment-related MDS/AML, those in complete remission (CR) 1 or with refractory anemia were classified as intermediate risk, and all other patients were considered high risk. Neutrophil engraftment occurred at a median of 11 days in 100 of 101 evaluable patients. The cumulative incidences of grades II to IV acute and chronic GVHD at 1 year were 8.8% and 5.9%, respectively. Overall- and disease-free survival (DFS) rates at 5 years were 50.0% and 46.1%, respectively, and the cumulative incidences of relapse and treatment-related mortality were 23.5% and 28.4%, respectively. Stratification by risk group demonstrated superior DFS for low-risk patients (61.5% at 5 years) compared with intermediate- or high-risk (34.2% and 40.0%, respectively, P = .021). For patients with AML, those in CR1 had superior 5-year DFS compared with those in >=CR2 (60% and 30.6%, respectively, P = .01), without a significant difference in incidence of relapse (17.1% and 30.6%, respectively, P = .209). There were no differences in DFS for other patient, donor, or disease characteristics. In summary, cytoreduction with Bu/Mel/Flu and r-ATG secured consistent engraftment of TCD transplantations. The incidences of acute/chronic GVHD and disease relapse were low, with favorable outcomes in this patient population with high-risk myeloid malignancies. PMID- 28711728 TI - Allogeneic Blood or Marrow Transplantation with Post-Transplantation Cyclophosphamide as Graft-versus-Host Disease Prophylaxis in Multiple Myeloma. AB - Allogeneic blood or marrow transplantation (alloBMT) may lead to long-term disease control in patients with multiple myeloma (MM). However, historically, the use of alloBMT in MM has been limited by its high nonrelapse mortality (NRM) rates, primarily from graft-versus-host disease (GVHD). We previously demonstrated that post-transplantation cyclophosphamide (PTCy) decreases the toxicities of both acute and chronic GVHD after alloBMT. Here, we examine the impact of PTCy in patients with MM undergoing alloBMT at Johns Hopkins Hospital. From 2003 to 2011, 39 patients with MM underwent bone marrow or peripheral blood alloBMT from HLA-matched related/unrelated or haploidentical related donors after either myeloablative or nonmyeloablative conditioning. Post-transplantation GVHD prophylaxis consisted of cyclophosphamide (50 mg/kg) on days +3 and +4 with or without mycophenolate mofetil and tacrolimus. Engraftment was detected in 95% of patients, with neutrophil and platelet recovery at a median of 15 and 16 days, respectively. The cumulative incidences of acute grades 2 to 4 and grades 3 and 4 GVHD were .41 and .08, respectively, and no cases of grade 4 acute GVHD were observed. The cumulative incidence of chronic GVHD was .13. One patient succumbed to NRM. All cases of chronic GVHD involved extensive disease and 60% of these patients received systemic therapy with complete resolution. After alloBMT, the overall response rate was 62% with complete, very good partial, and partial response rates of 26%, 21%, and 15%, respectively. The median progression-free survival was 12 months and was associated with the depth of response but not cytogenetic risk. The estimated cumulative incidence of relapse was .46 (95% confidence interval [CI], .3 to .62) at 1 year and .56 (95% CI, .41 to .72) at 2 years. At last follow-up, 23% of patients remain without evidence of disease at a median follow-up of 10.3 years after alloBMT. The median overall survival was 4.4 years and the 5-year and 10-year overall survival probabilities were 49% (95% CI, 35% to 67%) and 43% (95% CI, 29% to 62%), respectively. The use of PTCy after alloBMT for MM is feasible and results in low NRM and GVHD rates. The safety of this approach may allow the development of novel post-transplantation maintenance strategies to improve long-term disease control. PMID- 28711729 TI - Expanding Roles of PIFs in Signal Integration from Multiple Processes. AB - PHYTOCHROME-INTERACTING FACTORs (PIFs) are members of the basic helix-loop-helix (bHLH) family of transcription factors in Arabidopsis. Since their discovery in phytochrome-mediated light signaling pathways, recent studies have unraveled new functions of PIFs in integrating multiple signaling pathways not only through their role as transcription factors directly targeting gene expression but also by interacting with diverse groups of factors to optimize plant growth and development. These include endogenous (e.g., hormonal) as well as abiotic (light, circadian, and elevated temperature) and biotic (defense responses) pathways. PIFs interact with key factors in each of these pathways and tailor the outcome of the signal integration among these pathways. This review discusses the roles of PIFs as pivotal signal integrators in regulating plant growth and development. PMID- 28711730 TI - Purification and characterization of a long-acting ciliary neurotrophic factor via genetically fused with an albumin-binding domain. AB - Ciliary neurotrophic factor (CNTF) is a promising candidate for the treatment of neurodegenerative or metabolic diseases, but suffers rapid clearance in body. Herein we constructed a new long-acting recombinant human CNTF (rhCNTF) by genetic fusion with an albumin-binding domain (ABD) through a flexible peptide linker, hoping to endow the new molecule prolonged serum circulation time by binding with endogenous human serum albumin (HSA) and then utilizing the naturally long-half-life property of HSA. This fused protein rhCNTF-ABD was expressed in Escherichia coli mainly in the soluble form and purified through a two-step chromatography, with purity of 95% and a high yield of 90-100 mg/L culture. The in vitro binding ability of rhCNTF-ABD with HSA was firstly verified by incubation of the two components together followed by HP-SEC analysis. ABD fused rhCNTF showed similar secondary and tertiary structure as the parent protein. It retained approximately 94.1% of the native bioactivity as demonstrated via CCK-8 cell viability assay analysis. In vivo studies in SD rats were performed and the terminal half-life of 483.89 min for rhCNTF-ABD was determined, which is about 14 folds longer than that of rhCNTF (34.28 min) and comparable with 20 k-40 kDa PEGylated rhCNTFs. The new constructed rhCNTF-ABD represents a potential therapeutic modality, and the proposed strategy may also have useful applications for other long-lasting biopharmaceutics' design. PMID- 28711731 TI - Insulin chains as efficient fusion tags for prokaryotic expression of short peptides. AB - Insulin chains are usually expressed in Escherichia coli as fusion proteins with different tags, including various low molecular weight peptide tags. The objective of this study was to determine if insulin chains could facilitate the recombinant expression of other target proteins, with an emphasis on low molecular weight peptides. A series of short peptides were fused to mini proinsulin, chain B or chain A, and induced for expression in Escherichia coli. All the tested peptides including glucagon-like peptide 1 (GLP-1), a C-terminal extended GLP-1, oxyntomodulin, enfuvirtide, linaclotide, and an unstructured artificial peptide were expressed with reasonable yields, identified by Tricine SDS-PAGE and immunoblotting. All recombinant products were expressed in inclusion bodies. The effective accumulation of products was largely attributed to the insoluble expression induced by fusion with insulin chains, and was confirmed by the fusion expression of transthyretin. Insulin chains thus show promise as efficient fusion tags for mass production of heterologous peptides in prokaryotes. PMID- 28711732 TI - High-level expression and purification of a molluskan endoglucanase from Ampullaria crossean in Pichia pastoris. AB - EG27I is an endogenous glucanase belonging to glycoside hydrolase family (GHF) 45 from the mollusk Ampullaria crossean. In this study, the mature EG27I peptide gene fused to the HFBII secretion signal of Trichoderma reesei was expressed under the GAP promoter of Pichia pastoris in SMD1163 strain. A bioactive EG27I with a molecular weight of 27 kDa was successfully expressed and secreted into our culture medium. The respective final OD600 and hydrolytic activity were 333 and 1.28 U/mL when high-cell-density fermentation of the recombinant P. pastoris was performed in a 7.5 L fermenter through a fed-batch strategy for 132 h. The recombinant protein concentration of the fermentation supernatant was 47.7 mg/L. EG27I was consecutively purified from the fermentation supernatant through ultrafiltration, cation exchange, and hydrophobic interaction. The specific activity of the recombinant EG27I was 26.8 U/mg, and the optimal pH and temperature of the enzyme were 5 and 50 degrees C, respectively. The half-life of the enzyme activity at 100 degrees C could reach 40 min. The N-terminal amino acid sequence analysis of the purified recombinant protein confirmed that the amino terminal sequence was consistent with the natural structure. The high quantity and purity of the EG27I provide a basis for future structural and functional studies. PMID- 28711733 TI - Expression and purification of TAT-NDRG2 recombinant protein and evaluation of its anti-proliferative effect on LNCaP cell line. AB - N-myc downstream regulated gene2 (NDRG2) belongs to tumor suppressor protein family of NDRG. Anti-proliferative and anti-metastasis of NDRG2 overexpression has been demonstrated in a number of tumors. The aim of this study was to fuse the gene of Trans Activator of Transcription (TAT) protein transduction domain with NDRG2 gene and express and purify TAT-NDRG2 fusion protein in order to investigate the effects of TAT-NDRG2 protein on proliferation and apoptosis of LNCaP prostate carcinoma cell line. pET28a-TAT-NDRG2 and pET28a-NDRG2 plasmids were constructed and transformed into E. coli-BL21(DE3). TAT-NDRG2 and NDRG2 proteins were expressed in the bacteria, purified using affinity chromatography and verified using western blotting. The effects of TAT-NDRG2 and NDRG2 protein treatment on LNCaP cells proliferation and apoptosis were evaluated using MTT assay and AnnexinV, 7-AAD flow cytometry assay, respectively. Western blot analysis confirmed the expression and purification of TAT-NDRG2 and NDRG2 proteins. Treatment of LNCaP cells with TAT-NDRG2 protein increased cell death and induced apoptosis significantly (P < 0.05) compared to control and NDRG2 protein-treated cells. These results suggest that TAT-NDRG2 protein can be considered as a therapeutic modality for the treatment of tumors. PMID- 28711734 TI - Immunohistochemical investigations on the expression of programmed cell death ligand 1, human leukocyte antigens G and E, and granzyme B in intraoral mucoepidermoid carcinoma. AB - OBJECTIVE: To identify the expression of nonclassical human leukocyte antigen G and E (HLA-G and -E), programmed cell death ligand-1 (PD-L1) and granzyme B (GB) in intraoral mucoepidermoid carcinomas (MECs), and to assess whether such expressions are related to metastasis, survival, staging, tumor grade and number of GB-positive cells. DESIGN: For this cross-sectional study, samples of MEC (n=30) were selected and classified as low-grade (LG), intermediate-grade (IG) or high-grade (HG), according to the WHO grading system. HLA-G, -E and PD-L1 were identified by immunohistochemistry and quantified as the proportion of positive neoplastic cells. The density of GB+ cells was also evaluated. The Kruskal-Wallis test was used with a 5% significance level. RESULTS: Expressions of HLA-G, -E and PD-L1 were identified in the majority of epidermoid, intermediate and clear cells, but not in the mucous cells of the MECs. The quantitative analysis of the total percentage of positive neoplastic cells showed overexpression of this set of proteins in all MEC samples. The expression of these proteins and histological grading were positively correlated [HLA-G (LG=79% positive cells, IG=96%, HG=99%; p=0.0004), HLA-E (LG=70%, IG=96%, HG=99%; p<0.0001) and PD-L1 (LG=34%, IG=79%, HG=80%; p=0.01)]. No relationship was observed between the immunosuppressive proteins and other clinicopathological parameters. Low GB density was found in all MEC samples. CONCLUSIONS: The augmented expression of HLA-G, -E and PD-L1 in the intraoral MEC might suggest a role of these molecules in the scape of neoplastic cells from immunosurveillance. PMID- 28711735 TI - Transcranial magnetic stimulation of early visual cortex suppresses conscious representations in a dichotomous manner without gradually decreasing their precision. AB - Transcranial magnetic stimulation (TMS) of early visual cortex can suppresses visual perception at early stages of processing. The suppression can be measured both with objective forced-choice tasks and with subjective ratings of visual awareness, but there is lack of objective evidence on how and whether the TMS influences the quality of representations. Does TMS decrease the precision of representations in graded manner, or does it lead to dichotomous, "all-or nothing" suppression. We resolved this question by using a continuous measure of the perceptual error: the observers had to perceive the orientation of a target (Landort-C) and to adjust the orientation of a probe to match that of the target. Mixture modeling was applied to estimate the probability of guess trials and the standard deviation of the non-guess trials. TMS delivered 60-150 ms after stimulus-onset influenced only the guessing rate, whereas the standard deviation (i.e., precision) was not affected. This suggests that TMS suppressed representations dichotomously without affecting their precision. The guessing probability correlated with subjective visibility ratings, suggesting that it measured visual awareness. In a control experiment, manipulation of the stimulus contrast affected the standard deviation of the errors, indicating that contrast has a gradual influence on the precision of representations. The findings suggest that TMS of early visual cortex suppresses perception in dichotomous manner by decreasing the signal-to-noise ratio by increasing the noise level, whereas reduction of the signal level (i.e., contrast) decreases the precision of representations. PMID- 28711736 TI - Two dose investigation of the 5-HT-agonist psilocybin on relative and global cerebral blood flow. AB - Psilocybin, the active compound in psychedelic mushrooms, is an agonist of various serotonin receptors. Seminal psilocybin positron emission tomography (PET) research suggested regional increases in glucose metabolism in frontal cortex (hyperfrontality). However, a recent arterial spin labeling (ASL) study suggests psilocybin may lead to hypo-perfusion in various brain regions. In this placebo-controlled, double-blind study we used pseudo-continuous ASL (pCASL) to measure perfusion changes, with and without adjustment for global brain perfusion, after two doses of oral psilocybin (low dose: 0.160 mg/kg; high dose: 0.215 mg/kg) in two groups of healthy controls (n = 29 in both groups, total N = 58) during rest. We controlled for sex and age and used family-wise error corrected p values in all neuroimaging analyses. Both dose groups reported profound subjective drug effects as measured by the Altered States of Consciousness Rating Scale (5D-ASC) with the high dose inducing significantly larger effects in four out of the 11 scales. After adjusting for global brain perfusion, psilocybin increased relative perfusion in distinct right hemispheric frontal and temporal regions and bilaterally in the anterior insula and decreased perfusion in left hemispheric parietal and temporal cortices and left subcortical regions. Whereas, psilocybin significantly reduced absolute perfusion in frontal, temporal, parietal, and occipital lobes, and bilateral amygdalae, anterior cingulate, insula, striatal regions, and hippocampi. Our analyses demonstrate consistency with both the hyperfrontal hypothesis of psilocybin and the more recent study demonstrating decreased perfusion, depending on analysis method. Importantly, our data illustrate that relative changes in perfusion should be understood and interpreted in relation to absolute signal variations. PMID- 28711737 TI - Subthalamic deep brain stimulation sweet spots and hyperdirect cortical connectivity in Parkinson's disease. AB - OBJECTIVES: Firstly, to identify subthalamic region stimulation clusters that predict maximum improvement in rigidity, bradykinesia and tremor, or emergence of side-effects; and secondly, to map-out the cortical fingerprint, mediated by the hyperdirect pathways which predict maximum efficacy. METHODS: High angular resolution diffusion imaging in twenty patients with advanced Parkinson's disease was acquired prior to bilateral subthalamic nucleus deep brain stimulation. All contacts were screened one-year from surgery for efficacy and side-effects at different amplitudes. Voxel-based statistical analysis of volumes of tissue activated models was used to identify significant treatment clusters. Probabilistic tractography was employed to identify cortical connectivity patterns associated with treatment efficacy. RESULTS: All patients responded well to treatment (46% mean improvement off medication UPDRS-III [p < 0.0001]) without significant adverse events. Cluster corresponding to maximum improvement in tremor was in the posterior, superior and lateral portion of the nucleus. Clusters corresponding to improvement in bradykinesia and rigidity were nearer the superior border in a further medial and posterior location. The rigidity cluster extended beyond the superior border to the area of the zona incerta and Forel-H2 field. When the clusters where averaged, the coordinates of the area with maximum overall efficacy was X = -10(-9.5), Y = -13(-1) and Z = -7(-3) in MNI(AC-PC) space. Cortical connectivity to primary motor area was predictive of higher improvement in tremor; whilst that to supplementary motor area was predictive of improvement in bradykinesia and rigidity; and connectivity to prefrontal cortex was predictive of improvement in rigidity. INTERPRETATION: These findings support the presence of overlapping stimulation sites within the subthalamic nucleus and its superior border, with different cortical connectivity patterns, associated with maximum improvement in tremor, rigidity and bradykinesia. PMID- 28711738 TI - Phase properties of transcranial electrical stimulation artifacts in electrophysiological recordings. AB - Monitoring brain activity during transcranial electric stimulation (tES) is an attractive approach for causally studying healthy and diseased brain activity. Yet, stimulation artifacts complicate electrophysiological recordings during tES. Design and evaluation of artifact removal methods require a through characterization of artifact features, i.e. characterization of the transfer function that defines the relationship between the tES stimulation current and tES artifacts. Here we characterize the phase relationship between stimulation current and tES artifacts in EEG and MEG. We show that stimulation artifacts are not pure in-phase or anti-phase signals, but that non-linear mechanisms induce steady phase deflections relative to the stimulation current. Furthermore, phase deflections of stimulation artifacts are slightly modulated by each heartbeat and respiration. For commonly used stimulation amplitudes, artifact phase deflections correspond to signals several times bigger than normal brain signal. Moreover, the strength of phase deflections varies with stimulation frequency. These phase effects should be accounted for during artifact removal and when comparing recordings with different stimulation frequencies. We summarize our findings in a mathematical model of tES artifacts and discuss how this model can be used in simulations to design and evaluate artifact rejection techniques. To facilitate this research, all raw data of this study is made freely available. PMID- 28711739 TI - Homozygous c.359del variant in MGME1 is associated with early onset cerebellar ataxia. AB - We ascertained a child with early onset cerebellar ataxia and identified a novel frameshift deletion, c.359del [p. (Pro120Leufs*2), NM_052865.2] in exon 2 of MGME1 (mitochondrial genome maintenance exonuclease 1) by exome sequencing. Variations in MGME1 have been reported to cause mitochondrial DNA (mtDNA) depletion syndrome 11 (MIM #615084) in an earlier work. The phenotype included progressive external ophthalmoplegia, emaciation, respiratory failure and late onset progressive ataxia. However, the child presented here has early onset progressive ataxia, speech delay, microcephaly, cerebellar atrophy and fundus albipunctatus. This is the second report of a mutation in MGME1 and describes a more severe phenotype. PMID- 28711740 TI - Early manifestations of epileptic encephalopathy, brain atrophy, and elevation of serum neuron specific enolase in a boy with beta-propeller protein-associated neurodegeneration. AB - Mutations in WDR45 are responsible for beta-propeller protein-associated neurodegeneration (BPAN), which is an X-linked form of neurodegeneration with brain iron accumulation. BPAN mainly affects females and is characterized by seizures and developmental delay or intellectual disability until adolescence or early adulthood, followed by severe dystonia, parkinsonism, and progressive dementia. However, rare male patients have recently been reported with hemizygous germline mutations in WDR45 and severe clinical manifestations, such as epileptic encephalopathies. We report here a 4-year-old boy presenting with profound developmental delay, non-syndromic epileptic encephalopathy, and early brain atrophy. The level of serum neuron specific enolase (NSE) was elevated, but the level of serum phosphorylated neurofilament heavy chain was not detectable. Targeted next-generation sequencing identified a de novo hemizygous splice donor site mutation, c.830+1G > A in WDR45, which resulted in a splicing defect evidenced by reverse transcriptase-PCR. Mutations in WDR45 should be considered as a cause for epileptic encephalopathies in males with profound developmental delay and brain atrophy. Furthermore, elevation of serum NSE may contribute to early diagnosis of BPAN. PMID- 28711741 TI - Confirmation that mutations in DDX59 cause an autosomal recessive form of oral facial-digital syndrome: Further delineation of the DDX59 phenotype in two new families. AB - We report three probands from two unrelated consanguineous families of South Asian origin who all carry the same rare novel homozygous variant within the dead box helicase gene DDX59 in association with features of oral-facial-digital syndrome (OFDS). DDX59 variants have been reported previously in an unclassified, autosomal recessive form of OFDS; clinically associated with features including tongue lobulation, cleft palate, frontal bossing, hypertelorism and postaxial polydactyly. All three probands had lobulated tongues with tongue hamartomas, abnormal tongue tip, developmental delay and microcephaly, with just one proband demonstrating polydactlyly. The novel DDX59 variant was identified through autozygosity studies followed by sequencing of homozygous regions identified. It affects a stop codon, extending the protein product and is therefore predicted to be pathogenic. It is only the third reported DDX59 mutation associated with OFDS reported so far. PMID- 28711742 TI - Microcephaly with simplified gyral pattern, epilepsy and permanent neonatal diabetes syndrome (MEDS). A new patient and review of the literature. AB - Microcephaly with simplified gyration, epilepsy and permanent neonatal diabetes syndrome (MEDS) is a recently described, autosomal recessive-inherited syndrome. We report the case of an infant presenting with lethargy at age five weeks and clinical findings of persistent hyperglycaemia and microcephaly with simplified gyration, suggestive of MEDS. The diagnosis was confirmed by the detection of a known c.233 T > C mutation in the IER3IP1 gene. Only eight cases of MEDS have been reported in the literature. We reviewed these with the aim of better delineating their clinical manifestations, which should allow earlier and more accurate diagnosis and genetic counseling. PMID- 28711743 TI - Is a SIMPLe smartphone application capable of improving biological rhythms in bipolar disorder? AB - BACKGROUND: Biological rhythms (BR) disturbance has been suggested as a potential mediator of mood episodes in Bipolar Disorder (BD). The Biological Rhythms Interview of Assessment in Neuropsychiatry (BRIAN) was designed as an assessment tool to evaluate BR domains comprehensively. In the context of a trial evaluating a smartphone application delivering personalized psychoeducational contents for BD (SIMPLe 1.0), the main aim of this study is to evaluate the potential impact of SIMPLe 1.0 in BR regulation using the BRIAN scale. METHODS: 51 remitted BD patients were asked to use the application for 3 months. Paired t-test analyses were employed to compare baseline and follow-up BRIAN's total and domains scores. The sample was divided into completers and non-completers of the study to evaluate differences between groups regarding BRIAN scores using ANCOVA analyses. RESULTS: The BRIAN's mean total score of the whole sample significantly decreased from baseline to post-intervention (35.89 (SD 6.64) vs. 31.18 (SD 6.33), t = 4.29, p = 0.001). At post-intervention, there was a significant difference between groups regarding the total BRIAN mean score (29.47 (SD 6.21) completers vs. 35.92 (SD 3.90) non-completers, t = 2.50, p = 0.02). This difference was maintained after conducting a one-way ANCOVA controlling for pre-intervention BRIAN scores, F (1, 46) = 10.545, p=0.002. LIMITATIONS: A limited sample, pre post measures, and a short study timeframe could have affected the results. Additional factors affecting BR, such as medication, could not be ruled out. CONCLUSION: Our results suggest that there are potential positive effects of a psychoeducational smartphone application as an adjunctive to treatment as usual on BD patients' BR. PMID- 28711744 TI - Sudden unexpected death in bipolar disorder. PMID- 28711745 TI - Child maltreatment and age of alcohol and marijuana initiation in high-risk youth. AB - INTRODUCTION: Youth with a history of child maltreatment use substances and develop substance use disorders at rates above national averages. Thus far, no research has examined pathways from maltreatment to age of substance use initiation for maltreated youth. We examined the longitudinal impact of maltreatment in early childhood on age of alcohol and marijuana use initiation, and whether internalizing and externalizing behaviors at age 8 mediates the link between maltreatment and age of substance use initiation. MATERIALS AND METHODS: Data were drawn from the Longitudinal Studies of Child Abuse and Neglect (LONGSCAN) at ages 4, 8, 12, and 18. Maltreatment was assessed through reviews of administrative records and youth self-reports. Behavior problems were assessed with the Child Behavior Checklist. Age of substance use initiation was assessed with the Young Adult version of the Diagnostic Interview Schedule for Children. RESULTS: Path analyses indicated mediated effects from a history of maltreatment to age at first alcohol and marijuana use through externalizing behaviors. Considering type of maltreatment, direct effects were found from physical abuse to age of alcohol initiation, and mediated effects were found from sexual abuse and neglect to initial age of alcohol and marijuana use through externalizing behaviors. Direct effects for marijuana use initiation and indirect effects through internalizing behavior problems were not significant for either substance. CONCLUSIONS: Externalizing behavior is one pathway from childhood maltreatment to age of substance use initiation. Services for maltreated youth should incorporate substance use prevention, particularly among those with early externalizing problems. PMID- 28711746 TI - Problematic internet users' skin conductance and anxiety increase after exposure to the internet. AB - INTRODUCTION: To examine the impact of cessation of an internet session on skin conductance responses and anxiety of higher and lower problem internet users, in order to explore possible physiological withdrawal effects. METHOD: Participants were measured in terms of their skin conductance before (15min), during (15min), and after (15min) an internet session, and completed self-report measures of state anxiety and problematic internet use. RESULTS: Higher, but not lower, problem users showed increased skin conductance after internet use was stopped, relative to before their internet session. Higher problem users' GSR scores increased, as the time from internet cessation became longer. Higher problem users also showed increased levels of anxiety, following their internet session, which correlated with their skin conductance scores. CONCLUSIONS: These results suggest that, following termination of an internet session, withdrawal-like effects are seen, both psychologically and physiologically. PMID- 28711747 TI - Hookah use among adolescents: Differential cognitions about hookah and cigarettes. AB - Background Hookah use is prevalent among adolescent and young adult populations. The study assessed how positive cognitions toward cigarettes moderate the impact of positive hookah cognitions on past 30day hookah use among a representative sample of youth. Understanding cognitions about products can contribute to effective interventions. Methods Data from the 2015 Florida Youth Tobacco Survey was used to determine cognitions and use patterns among high school students. Weighted means and proportions were used for demographic comparisons for cognitions about products. t-Tests and chi-square analysis were conducted for differences between users and non-users. Logistic regressions were conducted for the modeling of interaction between hookah and cigarette cognition. Results Nearly one out of ten (9.6%) of adolescents reported current hookah use. Across all cognition measures, positive hookah cognitions were associated with current hookah use. Additionally, there was a pattern of hookah cognitions being more strongly associated with current hookah use among those students that did not endorse the equivalent cognition for traditional cigarettes. Conclusions Hookah cognitions were generally more associated with hookah use among youth who did not endorse positive cognitions for cigarettes compared to those that did endorse positive cognitions for cigarettes. This finding is novel given youth who feel negatively about cigarettes are more influenced by their hookah-specific cognitions. Youth who believe cigarettes pose harm may benefit from messaging about the harms of hookah. Interventions or prevention efforts that draw strong comparisons between cigarettes and hookah may be effective among youth. PMID- 28711748 TI - Do personality traits related to affect regulation predict other tobacco product use among young adult non-daily smokers? AB - INTRODUCTION: Understanding factors that influence non-cigarette tobacco use is important given these products' prevalence and health risks. The goal of this study was to test the hypothesis that personality traits related to affect regulation would be associated with greater frequency of other tobacco product (OTP) use in a sample of young adult non-daily smokers. METHODS: Participants (n=518, 51% male) aged 18-24 were non-daily cigarette smokers recruited from the community for a longitudinal study of tobacco use. Personality characteristics (impulsivity, anhedonia, and negative affectivity) were measured at baseline, and participants reported recent tobacco use at baseline and 3, 6, and 9months later. Assessments were conducted online or via mobile phone. RESULTS: Across the 4 assessments, 33-52% of participants reported recent OTP use, with frequency of use decreasing over time. Longitudinal negative binomial regression models indicated that greater sensation seeking and lack of premeditation were associated with more frequent OTP use (ps<0.05). These effects were consistent over time. CONCLUSIONS: Findings suggest that young adult non-daily cigarette smokers with greater propensity for immediately rewarding behaviors may use OTPs more frequently. Young, non-daily cigarette smokers with high levels of sensation seeking and/or lack of premeditation may be at increased risk for harms related to OTP use and may benefit from prevention and cessation strategies that specifically address affect. PMID- 28711749 TI - Validation of the Korean Version of the Breakthrough Pain Assessment Tool in Cancer Patients. AB - CONTEXT: Breakthrough cancer pain has not been properly evaluated and treated because there are relatively few available measurements. The Breakthrough Pain Assessment Tool (BAT) is currently recognized as a brief, multidimensional, and reliable measurement. OBJECTIVES: The objective of this study was to validate the Korean version of the BAT (BAT-K) in adult cancer patients. METHODS: We conducted a forward-backward translation and cross-cultural equivalence test. The psychometric properties with 120 cancer patients were assessed using factor analysis, reliability, and validity. RESULTS: The Korean translation was well accepted by participants. Factor analysis revealed the presence of two underlying factors: frequency/severity and duration/medication efficacy. Cronbach alpha coefficient was 0.743. Severity, distress, and disruption of normal life showed strong reliability. The intraclass correlation for the test-retest reliability was 0.782 (95% confidence interval 0.694-0.854). The BAT-K had significant correlations with the Brief Pain Inventory, Pain Management Index, and Eastern Cooperative Oncology Group performance status (all P values < 0.05). CONCLUSION: The BAT-K is a valid and reliable measurement of breakthrough cancer pain in Korean cancer patients. PMID- 28711750 TI - Web-Based Tailored Psychoeducation for Breast Cancer Patients at the Onset of the Survivorship Phase: A Multicenter Randomized Controlled Trial. AB - CONTEXT: Many breast cancer patients have unmet informational and psychosocial needs after treatment completion. A psychoeducational intervention may be well suited to support these patients. OBJECTIVES: The purpose of this multicenter randomized controlled trial was to examine the effectiveness of a web-based tailored psychoeducational program (ENCOURAGE) for breast cancer patients, which aims to empower patients to take control over prevailing problems. METHODS: Female breast cancer patients from two hospitals in The Netherlands who recently completed (neo-)adjuvant chemotherapy were randomly assigned to standard care or 12-week access to the ENCOURAGE program providing fully automated information problem-solving strategies, resources, and services for reported problems. At six and 12 weeks, patients completed self-report questions on optimism and control over the future (primary outcome), feelings of being informed, and acceptance of the illness. At baseline and 12 weeks, distress and quality of life questionnaires were completed. RESULTS: About 138 patients were included. Almost all patients (67 of 69) visited ENCOURAGE as requested. No differences between the control and intervention group were observed for primary and secondary outcomes. An unplanned subgroup analysis showed that in clinically distressed patients (N = 57 at baseline; 41%), use of the ENCOURAGE program increased optimism and control over the future at 12 weeks more than in patients in the control group (Cohen's d = 0.65). CONCLUSION: Although the effectiveness was not demonstrated, a subgroup of women treated for breast cancer can probably be supported by the program. The results of the present study are a starting point for further development and use of the program. PMID- 28711751 TI - The Conversion Ratio From Intravenous Hydromorphone to Oral Opioids in Cancer Patients. AB - CONTEXT: The lack of knowledge of the accurate conversion ratio (CR) between intravenous (IV) and oral hydromorphone and opioid rotation ratio (ORR) between IV hydromorphone and oral morphine equivalent daily dose (MEDD) may lead to poorly controlled pain or overdosing in cancer inpatients. OBJECTIVES: We aimed to determine the CR and ORR from IV hydromorphone to oral hydromorphone and MEDD (obtained from oral morphine and oxycodone). METHODS: A total of 4745 consecutive inpatient palliative care consults during 2010-14 were reviewed for conversions from IV hydromorphone to oral hydromorphone, morphine or oxycodone. Patient characteristics, symptoms, and opioid doses were determined in patients successfully discharged on oral opioids without readmission within one week. Linear regression analysis was used to estimate the CR or ORR between the 24 hour IV hydromorphone mg dose before conversion and the oral opioid mg dose used before discharge. RESULTS: Among 394 patients on IV hydromorphone, 147 underwent conversion to oral hydromorphone and 247 underwent rotation to oral morphine (163) or oxycodone (84). The median (interquartile range) CR from IV to PO hydromorphone was 2.5 (2.14-2.75) with correlation of 0.95 (P < 0.0001). The median ORR (interquartile range) from IV hydromorphone to MEDD was 11.46 (9.84 13.00) with correlation of 0.93(P < 0.0001). The median ORR was 11.54 in patients receiving <30 mg of IV hydromorphone/day and 9.86 in patients receiving >=30 mg (P = 0.0004). CONCLUSION: Our study found that 1 mg of IV hydromorphone is equivalent to 2.5 mg of oral hydromorphone and 11.46 mg of MEDD. Hydromorphone at doses >=30 mg/day may require a lower ORR to other opioids. PMID- 28711752 TI - Mind the Mode: Differences in Paper vs. Web-Based Survey Modes Among Women With Cancer. AB - CONTEXT: Researchers administering surveys seek to balance data quality, sources of error, and practical concerns when selecting an administration mode. Rarely are decisions about survey administration based on the background of study participants, although socio-demographic characteristics like age, education, and race may contribute to participants' (non)responses. OBJECTIVES: In this study, we describe differences in paper- and web-based surveys administered in a national cancer survivor study of women with a history of cancer to compare the ability of each survey administrative mode to provide quality, generalizable data. METHODS: We compared paper- and web-based survey data by socio-demographic characteristics of respondents, missing data rates, scores on primary outcome measure, and administrative costs and time using descriptive statistics, tests of mean group differences, and linear regression. RESULTS: Our findings indicate that more potentially vulnerable patients preferred paper questionnaires and that data quality, responses, and costs significantly varied by mode and participants' demographic information. We provide targeted suggestions for researchers conducting survey research to reduce survey error and increase generalizability of study results to the patient population of interest. CONCLUSION: Researchers must carefully weigh the pros and cons of survey administration modes to ensure a representative sample and high-quality data. PMID- 28711753 TI - Psychometric Properties of the Greek Version of the Patient Dignity Inventory in Advanced Cancer Patients. AB - CONTEXT: The patient dignity inventory (PDI) is an instrument to measure dignity distressing aspects at the end of life. OBJECTIVES: The aims of the present study were the translation of the PDI in Greek language as well as to measure its psychometric aspects in a palliative care unit. METHODS: A back-translation method was obtained at the Greek version. One hundred twenty advanced cancer patients completed the Greek version of the PDI, the Greek hospital anxiety and depression scale, the Greek schedule of attitudes toward hastened death (SAHD Gr), and the Greek 12-item short form health survey. RESULTS: Confirmatory factor analysis failed to fit to the original instrument's structure and exploratory factor analysis was conducted revealing five factors ("Psychological Distress," "Body Image and Role Identity," "Self-Esteem," "Physical Distress and Dependency," and "Social Support"). The psychometric analysis of the PDI-Gr demonstrated a good concurrent validity, and the instrument discriminated well between subgroups of patients regarding age differences. Cronbach alpha were between 0.71 and 0.9 showing a good internal consistency. CONCLUSION: The Greek version of the PDI showed good psychometric properties in advanced cancer patients, supported the usefulness of the instrument assessing the sense of dignity distressing aspects of the terminally ill cancer patients. PMID- 28711754 TI - Stability and Priority of Symptoms and Symptom Clusters Among Allogeneic HSCT Patients Within a 5-Year Longitudinal Study. AB - CONTEXT: Due to toxicity and invasiveness, allogeneic hematopoietic stem cell transplantation causes severe and longstanding symptom burden. Longitudinal studies on symptoms and symptom clusters (SC) would be helpful to optimize symptom control but are rare to date. OBJECTIVES: The objective of this study was to investigate stability of symptoms, extract time stable SC, and determine their priority in symptom management. METHODS: In this multicenter study, patients diagnosed with hematologic cancer were assessed before conditioning (T0) and three months (T1), one year (T2), and five years (T3) after transplantation. Symptoms were assessed with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-C30). Symptoms were stable when rated as present at three consecutive time points. Applying factor analysis, stable SC were composed of symptoms loading on the same factor across all time points. Priority in symptom management was derived from a combination of severity and predictive power for quality of life (QoL). RESULTS: Two hundred thirty-nine patients participated at T0, 150 (63%) at T1, 102 (43%) at T2, and 45 (19%) at T3. We identified three stable SC, composed of rest-tired-weak-dyspnea-loss of appetite (exhausted), tense-worried-irritable-depressed (affective), and nausea vomiting (gastrointestinal). Fatigue was most persistent and also most severe and predictive for QoL, both as symptom and in cluster (exhausted). CONCLUSION: Given its high stability, severity, and impact on QoL, fatigue should have priority in symptom management. The treatment of this symptom could be enhanced by also incorporating interventions addressing dyspnea and loss of appetite. PMID- 28711755 TI - Palliative Care Clinicians Caring for Patients Before and After Continuous Flow Left Ventricular Assist Device. AB - Left ventricular assist devices (LVADs) are an available treatment option for carefully selected patients with advanced heart failure. Initially developed as a bridge to transplantation, LVADs are now also offered to patients ineligible for transplantation as destination therapy (DT). Individuals with a DT-LVAD will live the remainder of their lives with the device in place. Although survival and quality of life improve with LVADs compared with medical therapy, complications persist including bleeding, infection, and stroke. There has been increased emphasis on involving palliative care (PC) specialists in LVAD programs, specifically the DT-LVAD population, from the pre-implantation process through the end of life. Palliative care specialists are well poised to provide education, guidance, and support to patients, families, and clinicians throughout the LVAD journey. This article addresses the complexities of the LVAD population, describes key challenges faced by PC specialists, and discusses opportunities for building collaboration between PC specialists and LVAD teams. PMID- 28711756 TI - Meaningful Communication Before Death, but Not Present at the Time of Death Itself, Is Associated With Better Outcomes on Measures of Depression and Complicated Grief Among Bereaved Family Members of Cancer Patients. AB - CONTEXT: Few studies have explored the clinical significance of the family's presence or absence at the moment of a patient's death and meaningful communication (saying "goodbye") in terms of post-bereavement outcomes. OBJECTIVES: To explore the potential association between the family's depression/complicated grief and their presence at the moment of a patient's death and the patient's communication with the family. METHODS: A nationwide questionnaire survey was conducted on 965 family members of cancer patients who had died at palliative care units. RESULTS: More than 90% of family members wished to have been present at the moment of death (agree: 40%, n = 217; strongly agree: 51%, n = 280); 79% (n = 393) thereof were present. Families' presence at death was not significantly associated with the occurrence of depression and complicated grief, but the dying patient's ability to say "goodbye" to the family beforehand was (depression: adjusted odds rate, 0.42; 95% CI, 0.26-0.69 adjusted P = 0.001; complicated grief: adjusted odds rate, 0.53; 95% CI, 0.29-0.94 adjusted P = 0.009). CONCLUSION: Many families wished to be present at the moment of the patient's death; however, meaningful communication (saying "goodbye") between the patient and family members, and not their presence or absence itself, was associated with better outcomes on measures of depression or complicated grief. Health care professionals could consider promoting both mutual communication (relating to preparation for death) between family members and patients before imminent death, as well as the family's presence at the moment of death. PMID- 28711758 TI - Assessing the binding of cholinesterase inhibitors by docking and molecular dynamics studies. AB - In this report we assessed by docking and molecular dynamics the binding mechanisms of three FDA-approved Alzheimer drugs, inhibitors of the enzyme acetylcholinesterase (AChE): donepezil, galantamine and rivastigmine. Dockings by the softwares Autodock-Vina, PatchDock and Plant reproduced the docked conformations of the inhibitor-enzyme complexes within 2A of RMSD of the X-ray structure. Free-energy scores show strong affinity of the inhibitors for the enzyme binding pocket. Three independent Molecular Dynamics simulation runs indicated general stability of donepezil, galantamine and rivastigmine in their respective enzyme binding pocket (also referred to as gorge) as well as the tendency to form hydrogen bonds with the water molecules. The binding of rivastigmine in the Torpedo California AChE binding pocket is interesting as it eventually undergoes carbamylation and breaks apart according to the X-ray structure of the complex. Similarity search in the ZINC database and targeted docking on the gorge region of the AChE enzyme gave new putative inhibitor molecules with high predicted binding affinity, suitable for potential biophysical and biological assessments. PMID- 28711757 TI - CXCR4 and CXCR7 play distinct roles in cardiac lineage specification and pharmacologic beta-adrenergic response. AB - CXCR4 and CXCR7 are prominent G protein-coupled receptors (GPCRs) for chemokine stromal cell-derived factor-1 (SDF-1/CXCL12). This study demonstrates that CXCR4 and CXCR7 induce differential effects during cardiac lineage differentiation and beta-adrenergic response in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Using lentiviral vectors to ablate CXCR4 and/or CXCR7 expression, hiPSC-CMs were tested for phenotypic and functional properties due to gene knockdown. Gene expression and flow cytometry confirmed the pluripotent and cardiomyocyte phenotype of undifferentiated and differentiated hiPSCs, respectively. Although reduction of CXCR4 and CXCR7 expression resulted in a delayed cardiac phenotype, only knockdown of CXCR4 delayed the spontaneous beating of hiPSC-CMs. Knockdown of CXCR4 and CXCR7 differentially altered calcium transients and beta-adrenergic response in hiPSC-CMs. In engineered cardiac tissues, depletion of CXCR4 or CXCR7 had opposing effects on developed force and chronotropic response to beta-agonists. This work demonstrates distinct roles for the SDF-1/CXCR4 or CXCR7 network in hiPSC-derived ventricular cardiomyocyte specification, maturation and function. PMID- 28711759 TI - DFT study of the interaction between DOTA chelator and competitive alkali metal ions. AB - 1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetracetic acid (DOTA) is an important chelator for radiolabeling of pharmaceuticals. The ability of alkali metals found in the body to complex with DOTA and compete with radio metal ions can alter the radiolabeling process. Non-covalent interactions between DOTA complexed with alkali metals Li+, Na+, K+ and Rb+, are investigated with density functional theory using B3LYP and omegaB97XD functionals. Conformational possibilities of DOTA were explored with a varying number of carboxylic pendant arms of DOTA in close proximity to the ions. It is found that the case in which four arms of DOTA are interacting with ions is more stable than other conformations. The objective of this study is to explore the electronic structure properties upon complexation of alkali metals Li+ Na+, K+ and Rb+ with a DOTA chelator. Interaction energies, relaxation energies, entropies, Gibbs free energies and enthalpies show that the stability of DOTA, complexed with alkali metals decreases down the group of the periodic table. Implicit water solvation affects the complexation of DOTA-ions leading to decreases in the stability of the complexes. NBO analysis through the natural population charges and the second order perturbation theory, revealed a charge transfer between DOTA and alkali metals. Conceptual DFT-based properties such as HOMO/LUMO energies, DeltaEHOMO LUMO and chemical hardness and softness indicated a decrease in the chemical stability of DOTA-alkali metal complexes down the alkali metal series. This study serves as a guide to researchers in the field of organometallic chelators, particularly, radiopharmaceuticals in finding the efficient optimal match between chelators and various metal ions. PMID- 28711760 TI - Investigation of the binding free energies of FDA approved drugs against subtype B and C-SA HIV PR: ONIOM approach. AB - Human immune virus subtype C is the most widely spread HIV subtype in Sub-Sahara Africa and South Africa. A profound structural insight on finding potential lead compounds is therefore necessary for drug discovery. The focus of this study is to rationalize the nine Food and Drugs Administration (FDA) HIV antiviral drugs complexed to subtype B and C-SA PR using ONIOM approach. To achieve this, an integrated two-layered ONIOM model was used to optimize the geometrics of the FDA approved HIV-1 PR inhibitors for subtype B. In our hybrid ONIOM model, the HIV-1 PR inhibitors as well as the ASP 25/25' catalytic active residues were treated at high level quantum mechanics (QM) theory using B3LYP/6-31G(d), and the remaining HIV PR residues were considered using the AMBER force field. The experimental binding energies of the PR inhibitors were compared to the ONIOM calculated results. The theoretical binding free energies (?Gbind) for subtype B follow a similar trend to the experimental results, with one exemption. The computational model was less suitable for C-SA PR. Analysis of the results provided valuable information about the shortcomings of this approach. Future studies will focus on the improvement of the computational model by considering explicit water molecules in the active pocket. We believe that this approach has the potential to provide much improved binding energies for complex enzyme drug interactions. PMID- 28711761 TI - Laparoscopic Versus Open Hysterectomy for Benign Disease in Uteri Weighing >1 kg: A Retrospective Analysis on 258 Patients. AB - STUDY OBJECTIVE: To present a large single-center series of hysterectomies for uteri >=1 kg and to compare the laparoscopic and open abdominal approach in terms of perioperative outcomes and complications. DESIGN: A retrospective analysis of prospectively collected data (Canadian Task Force classification II-2). SETTING: An academic research center. PATIENTS: Consecutive women who underwent hysterectomy for uteri >=1 kg between January 2000 and December 2016. Patients with a preoperative diagnosis of uterine malignancy or suspected uterine malignancy were excluded. The subjects were divided according to the intended initial surgical approach (i.e., open or laparoscopic). The 2 groups were compared in terms of intraoperative data and postoperative outcomes. Multivariable analysis was performed to identify possible independent predictors of overall complications. A subanalysis including only obese women was accomplished. INTERVENTIONS: Total laparoscopic versus abdominal hysterectomy (+/ bilateral adnexectomy). MEASUREMENTS AND MAIN RESULTS: Intra- and postoperative surgical outcomes. A total of 258 patients were included; 55 (21.3%) women were initially approached by open surgery and 203 (78.7%) by laparoscopy. Nine (4.4%) conversions from laparoscopic to open surgery were registered. The median operative time was longer in the laparoscopic group (120 [range, 50-360] vs 85 [range, 35-240] minutes, p = .014). The estimated blood loss (150 [range, 0-1700] vs 200 [50-3000] mL, p = .04), postoperative hemoglobin drop, and hospital stay (1 [range, 1-8] vs 3 [range, 1-8] days, p < .001) were lower among patients operated by laparoscopy. No difference was found between groups in terms of intra and postoperative complications. However, the overall rate of complications (10.8% vs. 27.2%, p = .015) and the incidence of significant complications (defined as intraoperative adverse events or postoperative Clavien-Dindo >=2 events, 4.4% vs 10.9%, p = .04) were significantly higher among patients who initially received open surgery. The laparoscopic approach was found to be the only independent predictor of a lower incidence of overall complications (odds ratio = 0.42; 95% confidence interval, 0.19-0.9). The overall morbidity of minimally invasive hysterectomy was lower also in the subanalysis concerning only obese patients. CONCLUSION: In experienced hands and in dedicated centers, laparoscopic hysterectomy for uteri weighing >=1 kg is feasible and safe. Minimally invasive surgery retains its well-known advantages over open surgery even in patients with extremely enlarged uteri. PMID- 28711762 TI - Ogilvie's Syndrome after Robotic-Assisted Radical Hysterectomy for Cervical Cancer. AB - Acute colonic pseudo-obstruction (ACPO), also known as Ogilvie's syndrome, is defined by poor peristaltic activity of the colon that mimics mechanical obstruction in the absence of any mechanical occlusive gut lesion. This case report is the first to be published on ACPO occurring after robotic-assisted radical hysterectomy. Given that robotic-assisted laparoscopic surgery has become the next major stage of advancement for a range of operations, especially in gynecologic oncology surgery, this report emphasizes the importance of recognizing precipitating factors associated with this syndrome, including minimally invasive surgery. PMID- 28711763 TI - Cult membership: What factors contribute to joining or leaving? AB - We assumed that, as in the case of addiction disorders, former cult members exhibit vulnerability and protective factors for cult commitment and membership. Thus, the aim of our study was to identify vulnerability factors that are involved in the commitment and in the retention in the group, as well as protective factors that are involved in the departure. We interviewed 31 former cult members, using semi-structured interviews to evaluate their clinical profile, characteristics of the cultic group and their experience in the group. Cult membership and addictive disorders share some characteristics: persistence despite damage, initial psychological relief, occupation of an exclusive place in the thoughts of members, high psychiatric comorbidity prevalence, high accessibility, leading to social precariousness and the importance of familial support when leaving. Three main axes of improvement were highlighted: regulations concerning cults in order to limit their social presence, which appears to be a vulnerability factor for commitment; social and therapeutic follow-up when a member leaves a group so that social precariousness does not become an obstacle to departure; and familial support to maintain a link with the member, as the intervention of a person from outside of the group is an important protective factor for leaving. PMID- 28711764 TI - The sentence superiority effect revisited. AB - A sentence superiority effect was investigated using post-cued word-in-sequence identification with the rapid parallel visual presentation (RPVP) of four horizontally aligned words. The four words were presented for 200ms followed by a post-mask and cue for partial report. They could form a grammatically correct sentence or were formed of the same words in a scrambled agrammatical sequence. Word identification was higher in the syntactically correct sequences, and crucially, this sentence superiority effect did not vary as a function of the target's position in the sequence. Cloze probability measures for words at the final, arguably most predictable position, revealed overall low values that did not interact with the effects of sentence context, suggesting that these effects were not driven by word predictability. The results point to a level of parallel processing across multiple words that enables rapid extraction of their syntactic categories. These generate a sentence-level representation that constrains the recognition process for individual words, thus facilitating parallel word processing when the sequence is grammatically sound. PMID- 28711765 TI - Functional magnetic resonance imaging response as an early biomarker of cognitive decline in elderly patients with metabolic syndrome. AB - OBJECTIVES: We assessed whether potential changes in brain activation patterns of elderly individuals with metabolic syndrome (MetS) who were cognitively healthy (without mild cognitive impairment or dementia) were associated with cognitive decline in executive function in the short-term. METHOD: We analyzed 43 individuals (23 MetS, 20 controls) using a global geriatric evaluation, a neuropsychological battery, and task-related (attention) fMRI exam. Correlation analysis between the fMRI signal at baseline and cognitive impairment after 1year was based on the voxel-based Pearson coefficient, corrected for multiple comparisons. RESULTS: At baseline, MetS patients showed reduced brain response in frontal and parietal regions compared to controls. After one year, the MetS group also showed a decline in verbal fluency performance. fMRI response in the right dorsolateral prefrontal cortex and bilateral parietal lobes was negatively correlated with verbal fluency decline in the MetS group. DISCUSSION: Our results provide an early biomarker of the possible development of cognitive impairment, particularly in the executive function, of elderly individuals suffering from MetS. These findings also point to an up or down regulation which could be interpreted as compensatory mechanism for possible brain tissue burden caused by MetS. PMID- 28711766 TI - A tool for automated diabetic retinopathy pre-screening based on retinal image computer analysis. AB - AIM: This paper presents a methodology and first results of an automatic detection system of first signs of Diabetic Retinopathy (DR) in fundus images, developed for the Health Ministry of the Andalusian Regional Government (Spain). MATERIAL AND METHODS: The system detects the presence of microaneurysms and haemorrhages in retinography by means of techniques of digital image processing and supervised classification. Evaluation was conducted on 1058 images of 529 diabetic patients at risk of presenting evidence of DR (an image of each eye is provided). To this end, a ground-truth diagnosis was created based on gradations performed by 3 independent ophthalmology specialists. RESULTS: The comparison between the diagnosis provided by the system and the reference clinical diagnosis shows that the system can work at a level of sensitivity that is similar to that achieved by experts (0.9380 sensitivity per patient against 0.9416 sensitivity of several specialists). False negatives have proven to be mild cases. Moreover, while the specificity of the system is significantly lower than that of human graders (0.5098), it is high enough to screen more than half of the patients unaffected by the disease. CONCLUSION: Results are promising in integrating this system in DR screening programmes. At an early stage, the system could act as a pre-screening system, by screening healthy patients (with no obvious signs of DR) and identifying only those presenting signs of the disease. PMID- 28711767 TI - Fully automated subchondral bone segmentation from knee MR images: Data from the Osteoarthritis Initiative. AB - Knee osteoarthritis (OA) progression can be monitored by measuring changes in the subchondral bone structure such as area and shape from MR images as an imaging biomarker. However, measurements of these minute changes are highly dependent on the accurate segmentation of bone tissue from MR images and it is challenging task due to the complex tissue structure and inadequate image contrast/brightness. In this paper, a fully automated method for segmenting subchondral bone from knee MR images is proposed. Here, the contrast of knee MR images is enhanced using a gray-level S-curve transformation followed by automatic seed point detection using a three-dimensional multi-edge overlapping technique. Successively, bone regions are initially extracted using distance regularized level-set evolution followed by identification and correction of leakages along the bone boundary regions using a boundary displacement technique. The performance of the developed technique is evaluated against ground truths by measuring sensitivity, specificity, dice similarity coefficient (DSC), average surface distance (AvgD) and root mean square surface distance (RMSD). An average sensitivity (91.14%), specificity (99.12%) and DSC (90.28%) with 95% confidence interval (CI) in the range 89.74-92.54%, 98.93-99.31% and 88.68-91.88% respectively is achieved for the femur bone segmentation in 8 datasets. For tibia bone, average sensitivity (90.69%), specificity (99.65%) and DSC (91.35%) with 95% CI in the range 88.59-92.79%, 99.50-99.80% and 88.68-91.88% respectively is achieved. AvgD and RMSD values for femur are 1.43 +/- 0.23 (mm) and 2.10 +/- 0.35 (mm) respectively while for tibia, the values are 0.95 +/- 0.28 (mm) and 1.30 +/- 0.42 (mm) respectively that demonstrates acceptable error between proposed method and ground truths. In conclusion, results obtained in this work demonstrate substantially significant performance with consistency and robustness that led the proposed method to be applicable for large scale and longitudinal knee OA studies in clinical settings. PMID- 28711768 TI - Distressed yet empathically sensitive: Preschoolers' responses to infant crying. AB - Using a simulated long bout of progressively intense infant crying, this study demonstrated that preschoolers responded with infant-oriented empathic concern and helping actions despite evidence of self-focused distress. Preschoolers' helping actions were predicted by the interaction between empathic concern and cognitive inquiry. PMID- 28711769 TI - Unmixing hyperspectral data by using signal subspace sampling. AB - This paper demonstrates how Signal Subspace Sampling (SSS) is an effective pre processing step for Non-negative Matrix Factorization (NMF) or Vertex Component Analysis (VCA). The approach allows to uniquely extract non-negative source signals which are orthogonal in at least one observation channel, respectively. It is thus well suited for processing hyperspectral images from X-ray microscopy, or other emission spectroscopies, into its non-negative source components. The key idea is to resample the given data so as to satisfy better the necessity and sufficiency conditions for the subsequent NMF or VCA. Results obtained both on an artificial simulation study as well as based on experimental data from electron microscopy are reported. PMID- 28711770 TI - Multigenerational effects evaluation of the flame retardant tris(2-butoxyethyl) phosphate (TBOEP) using Daphnia magna. AB - Tris(2-butoxyethyl) phosphate (TBOEP) is an organophosphate ester used as substitute following the phase-out of brominated flamed retardants. Because of its high production volume and its use in a broad range of applications, this chemical is now frequently detected in the environment and biota. However, limited information is available on the long-term effects of TBOEP in aquatic organisms. In this study, Daphnia magna were exposed over three 21d generations to an environmentally relevant concentration of TBOEP (10MUg/L) and effects were evaluated at the gene transcription, protein, and life-history (i.e., survival, reproduction and growth) levels. Chronic exposure to TBEOP did not impact survival or reproduction of D. magna but affected the growth output. The mean number of molts was also found to be lower in daphnids exposed to the chemical compared to control for a given generation, however there were no significant differences over the three generations. Molecular responses indicated significant differences in the transcription of genes related to growth, molting, ecdysteroid and juvenile hormone signaling, proteolysis, oxidative stress, and oxygen transport within generations. Levels of mRNA were also found to be significantly different for genes known to be involved in endocrine-mediated mechanisms such as reproduction and growth between generations F0, F1, and F2, indicating effects of parental exposure on offspring. Transcription results were supported by protein analyses with the significant decreased in catalase (CAT) activity in F1 generation, following the decreased transcription of cat in the parental generation. Taken together, these multi-biological level results suggest long term potential endocrine disruption effects of TBOEP in D. magna exposed to an environmentally relevant concentration. This study highlights the importance of using chronic and multigenerational biological evaluation to assess risks of emerging chemicals. PMID- 28711771 TI - Toxicity of organic compounds from unresolved complex mixtures (UCMs) to primary fish hepatocytes. AB - Many environmental matrices contaminated with organic pollutants derived from crude oil or degraded petroleum contain mixtures so complex that they are typically unresolved by conventional analytical techniques such as gas chromatography. The resulting chromatographic features have become known as 'humps' or unresolved complex mixtures (UCMs). These UCMs often dominate the organic contaminants of polluted environmental samples: for example, in oil sands produced water up to 150mgL-1 of 'naphthenic acids' appear as UCMs when examined by gas chromatography as the esters. In oil-contaminated mussels, aromatic hydrocarbon UCMs may comprise almost all of the total toxic hydrocarbons, with over 7000MUgg-1 dry weight reported in some samples. Over the last 25 years, efforts to resolve and thus identify, or at least to produce average structures, for some UCM components, have proved fruitful. Numerous non-polar UCM hydrocarbons and more polar UCM acids have been identified, then synthesised or purchased from commercial suppliers. As UCMs have been proposed to represent a risk to aquatic organisms, the need for assessment of the ecotoxicological effects and characterisation of the mode of action (MoA) of these environmental pollutants has arisen. In the present study, several chemicals with structures typical of those found in some UCMs, were assessed for their potential to disrupt membrane integrity, inhibit metabolic activity, activate the aryl hydrocarbon receptor (AhR), and activate the estrogen receptor (ER) in primary rainbow trout hepatocytes (Oncorhynchus mykiss). These endpoints were determined in order to screen for common toxic modes of action (MoA) in this diverse group of chemicals. The results from the in vitro screening indicated that of the endpoints tested, the predominant toxic MoA was cytotoxicity. EC50 values for cytotoxicity were obtained for 16 compounds and ranged from 77MUM-24mM, whereof aliphatic monocyclic acids, monoaromatic acids, polycyclic monoaromatic acids and alkylnaphthalenes were the most toxic. The observed cytotoxicity of the chemicals correlated well with the hydrophobicity (LogKOW) suggesting that the toxicity was predominantly due to a non-specific MoA. Interestingly, two compounds induced the ER-mediated production of vitellogenin (Vtg) and six compounds induced the AhR mediated Ethoxyresorufin-O-deethylase (EROD) enzymatic activity to >20% of the positive control; by doing so suggesting that they may act as ER or AhR agonists in fish. The heterogeneous group of 'UCM compounds' tested exhibited multiple MoA that may potentially cause adverse effects in fish. Additional studies to determine if these compounds may cause adverse effects in vivo at environmentally relevant concentrations, are warranted to identify if such compounds are indeed of potential environmental concern. PMID- 28711772 TI - Study of the formation of the primary 137Cs vertical profile in the organic matter-rich sediments. AB - A laboratory study of the formation of the primary vertical profile of the 137Cs activity concentration in the anaerobic organic matter-rich sediments was carried out. The incubation was performed using sediment baths method (initial thickness of the water layer over the sediments ~40 cm, initial radiocesium activity concentration in water ~14.53 Bq.L-1). An exponential profile (R2~0.999) with the half-height width of ~0.65 cm was formed after ~32 days of the incubation. A further course of the experiment (sediments were sampled after 64, 130 and 293 days of the incubation) revealed deviations in the form of the radiocesium activity concentration profile related to the appearance of the additional Gauss factor with the increasing half-height width of ~1.2, ~1.3 and ~3 cm, respectively. In spite of the evident growth of the half-height width, the radiocesium migration rate decreased from 0.02 cm.day-1 for the first 32 days of incubation down to 0.009 cm.day-1 at the end of the incubation experiment. Such a time-dependent decrease in the radiocesium migration is possibly related to the beginning of the second radiocesium migration phase depending on the retardation factor. Besides diffusion, the formation of vertical profiles of radiocesium activity concentrations in sediments was additionally induced by effects of buoyancy of the upper sediment layer due to the seepage of the above lying water into sediments. PMID- 28711773 TI - Plants as indicators of tritium concentration in ground water at the Semipalatinsk test site. PMID- 28711774 TI - A rotating-slit-collimator-based gamma radiation mapper. AB - For situations with radioactive material out of control where it may be physically difficult or prohibited to access areas close to the source, measurements from distance may be the only way to assess the radiation environment. Using collimated detectors will provide means to locate the direction of the radiation from the source. To investigate the possibilities of mapping gamma emitting radioactive material in a closed non-enterable area, a tentative system for mapping radioactive materials from a distance was built. The system used a computer controlled cylindrical rotating slit collimator with a high purity germanium detector placed in the cylinder. The system could be placed on a car-towed trailer, with the centre of the detector about 1.4 m above ground. Mapping was accomplished by the use of a specially developed image reconstruction algorithm that requires measurements from two or more locations around the area to be investigated. The imaging capability of the system was tested by mapping an area, 25 by 25 m2, containing three 330 MBq 137Cs point sources. Using four locations outside the area with about 20 min measuring time in each location and applying the image reconstruction algorithm on the deconvoluted data, the system indicated the three source locations with an uncertainty of 1-3 m. The results demonstrated the potential of using collimated mobile gamma radiometry combined with image reconstruction to localize gamma sources inside non-accessible areas. PMID- 28711775 TI - Natural and artificial radionuclides in sludge, sand, granular activated carbon and reverse osmosis brine from a metropolitan drinking water treatment plant. PMID- 28711776 TI - Sleep-wake profiles and circadian rhythms of core temperature and melatonin in young people with affective disorders. AB - While disturbances of the sleep-wake cycle are common in people with affective disorders, the characteristics of these disturbances differ greatly between individuals. This heterogeneity is likely to reflect multiple underlying pathophysiologies, with different perturbations in circadian systems contributing to the variation in sleep-wake cycle disturbances. Such disturbances may be particularly relevant in adolescents and young adults with affective disorders as circadian rhythms undergo considerable change during this key developmental period. This study aimed to identify profiles of sleep-wake disturbance in young people with affective disorders and investigate associations with biological circadian rhythms. Fifty young people with affective disorders and 19 control participants (aged 16-31 years) underwent actigraphy monitoring for approximately two weeks to derive sleep-wake cycle parameters, and completed an in-laboratory assessment including evening dim-light saliva collection for melatonin assay and overnight continuous core body temperature measurement. Cluster analysis based on sleep-wake cycle parameters identified three distinct patient groups, characterised by 'delayed sleep-wake', 'disrupted sleep', and 'long sleep' respectively. The 'delayed sleep-wake' group had both delayed melatonin onset and core temperature nadir; whereas the other two cluster groups did not differ from controls on these circadian markers. The three groups did not differ on clinical characteristics. These results provide evidence that only some types of sleep wake disturbance in young people with affective disorders are associated with fundamental circadian perturbations. Consequently, interventions targeting endogenous circadian rhythms to promote a phase shift may be particularly relevant in youth with affective disorders presenting with delayed sleep-wake cycles. PMID- 28711777 TI - Comment on: "The use of direct oral anticoagulants in 56 patients with antiphospholipid syndrome". PMID- 28711778 TI - The efficacy and associated bleeding complications of recombinant antithrombin supplementation among intensive care unit patients. AB - INTRODUCTION: The aim of this study was to evaluate the efficacy and complications of recombinant antithrombin (rAT) supplementation for adult patients with disseminated intravascular coagulation (DIC) compared with conventional plasma derived AT (pAT) treatment in the intensive care unit. MATERIALS AND METHODS: This study was performed in a single national university hospital in Japan. Adult patients from April 2015 to March 2016 with DIC were divided into two groups based on the type of AT agent used: the pAT group (n=24) and the rAT group (n=21). Patient demographics, medical history, diagnosis, blood tests, various clinical scores, AT activity, complications, and clinical outcome were collected and analyzed retrospectively. RESULTS: Significantly higher SIRS and APACHEII scores were confirmed in the rAT group than the pAT group. The initial dose of AT was significantly higher in the rAT group than in the pAT group. ATIII values before and after initial supplementation and during their ten day clinical course were statistically similar between two groups. During the same period, 10 bleeding adverse events were found and there was no significant difference between both groups. Significantly more cases of the rAT group were administered with recombinant thrombomodulin concomitantly than those of the pAT group. Despite significantly more severe patients in rAT group, the clinical outcomes were the same in each group. CONCLUSIONS: Compared with pAT, the supplementation of rAT indicates clinical effectiveness without increasing the risk of bleeding complications in adult DIC patients with low AT activity. PMID- 28711780 TI - Localised delivery of doxorubicin to prostate cancer cells through a PSMA targeted hyperbranched polymer theranostic. AB - The therapeutic potential of hyperbranched polymers targeted to prostate cancer and loaded with doxorubicin was investigated. Polyethylene glycol hyperbranched polymers were synthesised via RAFT polymerisation to feature glutamate urea targeting ligands for PSMA on the periphery. The chemotherapeutic, doxorubicin, was attached to the hyperbranched polymers through hydrazone formation, which allowed controlled release of the drug from the polymers in vitro endosomal conditions, with 90% release of the drug over 36 h. The polymers were able to target to PSMA-expressing prostate cancer cells in vitro, and demonstrated comparable cytotoxicity to free doxorubicin. The ability of the hyperbranched polymers to specifically facilitate transport of loaded doxorubicin into the cells was confirmed using live cell confocal imaging, which demonstrated that the drug was able to travel with the polymer into cells by receptor mediated internalisation, and subsequently be released into the nucleus following hydrazone degradation. Finally, the ability of the complex to induce a therapeutic effect on prostate cancer cells was investigated through a long term tumour regression study, which confirmed that the DOX-loaded polymers were able to significantly reduce the volume of subcutaneous prostate tumours in vivo in comparison to free doxorubicin and a polymer control, with no adverse toxicity to the animals. This work therefore demonstrates the potential of a hyperbranched polymer system to be utilised for prostate cancer theranostics. PMID- 28711781 TI - The nature of hydrogen-bonding interactions in nonsteroidal anti-inflammatory drugs revealed by polarized IR spectroscopy. AB - The influence of hydrogen-bonding interactions in the solid phase on the IR spectroscopic pattern of the nuOH band of nonsteroidal anti-inflammatory drugs (NSAIDs) was studied experimentally by IR spectroscopy with the use of polarized light at two temperatures (293K and 77K) and in isotopic dilution. The neat and deuterated crystals of (S)-naproxen ((S)-NPX), (R)-flurbiprofen ((R)-FBP), (RS) flurbiprofen ((RS)-FBP) and (RS)-ketoprofen ((RS)-KTP) were obtained by melt crystallization between the two squeezed CaF2 plates. The vibrational spectra of selected alpha-aryl propionic acid derivatives (2APAs) reflected the characteristics of their hydrogen-bond networks, i.e., 2APAs were characterized by the chain ((S)-NPX, (R)-FBP) and by dimeric ((RS)-FBP, (RS)-KTP) arrangement of hydrogen bonds in the crystal lattice. Spectroscopic results showed that the interchain (through-space) exciton coupling, between two laterally-spaced hydrogen bonds, dominates in the crystals of four NSAIDs. The same exciton coupled hydrogen bonds were also responsible for the H/D isotopic recognition mechanism in the crystalline spectra of deuterated 2APAs. The presented spectral results may help to predict the hydrogen bond motifs in the crystalline NSAIDs, which structures are not yet known, based on their IR spectra of hydrogen bond in the crystals. PMID- 28711779 TI - Hyperactive FOXO1 results in lack of tip stalk identity and deficient microvascular regeneration during kidney injury. AB - Loss of the microvascular (MV) network results in tissue ischemia, loss of tissue function, and is a hallmark of chronic diseases. The incorporation of a functional vascular network with that of the host remains a challenge to utilizing engineered tissues in clinically relevant therapies. We showed that vascular-bed-specific endothelial cells (ECs) exhibit differing angiogenic capacities, with kidney microvascular endothelial cells (MVECs) being the most deficient, and sought to explore the underlying mechanism. Constitutive activation of the phosphatase PTEN in kidney MVECs resulted in impaired PI3K/AKT activity in response to vascular endothelial growth factor (VEGF). Suppression of PTEN in vivo resulted in microvascular regeneration, but was insufficient to improve tissue function. Promoter analysis of the differentially regulated genes in KMVECs suggests that the transcription factor FOXO1 is highly active and RNAseq analysis revealed that hyperactive FOXO1 inhibits VEGF-Notch-dependent tip cell formation by direct and indirect inhibition of DLL4 expression in response to VEGF. Inhibition of FOXO1 enhanced angiogenesis in human bio-engineered capillaries, and resulted in microvascular regeneration and improved function in mouse models of injury-repair. PMID- 28711782 TI - The human microbiome. AB - Until recently, human microbiology was based on the identification of single microbes, such as bacteria, fungi and viruses, frequently isolated from patients with acute or chronic infections. Novel culture-independent molecular biochemical analyses (genomics, transcriptomics, proteomics, metabolomics) allow today to detect and classify the diverse microorganisms in a given ecosystem (microbiota), such as the gastrointestinal tract, the skin, the airway system, the urogenital tract and others, and to assess all genomes in these ecosystems (microbiome) as well as their gene products. These analyses revealed that each individual has its own microbiota that plays a role in health and disease. In addition, they greatly contributed to the recent advances in the understanding of the pathogenesis of a wide range of human diseases. It is to be expected that these new insights will translate into diagnostic, therapeutic and preventive measures in the context of personalized/precision medicine. PMID- 28711783 TI - beta-Patchoulene from patchouli oil protects against LPS-induced acute lung injury via suppressing NF-kappaB and activating Nrf2 pathways. AB - beta-Patchoulene (beta-PAE), a tricyclic sesquiterpene isolated from the essential oil of the leaves and stems of Pogostemon cablin (Blanco) Benth., has been reported to have potent anti-inflammatory activity. The aim of this study was to evaluate the potential protective effect of beta-PAE on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice and to illuminate the underlying mechanisms. ALI was induced by intracheal instillation of LPS into lung, and dexamethasone (DEX) was used as a positive control. Results indicated that pretreatment with beta-PAE significantly decreased the mortality rate of mice and lung W/D weight ratio, ameliorated lung pathological changes as compared to model group. Meanwhile, beta-PAE pretreatment markedly inhibited the increase of TNF alpha, IL-6 and IL-1beta secretions in the bronchoalveolar lavage fluid, and prevented LPS-induced elevations of MPO activity and MDA level in the lung. Additionally, beta-PAE pretreatment significantly elevated miR-146a expression and suppressed the LPS-induced activation of NF-kappaB and expression of its mediated genes (TNF-alpha, IL-6 and IL-1beta). beta-PAE was also observed to markedly upregulate the Nrf2 and HO-1 expression and activate the antioxidant genes (NQO-1, GCLC and HO-1). Taken together, beta-PAE possessed protective effect against LPS-induced ALI, which might be associated with its differential regulation of NF-kappaB and Nrf2 activities and up-regulation of expression of miR-146a. The results rendered beta-PAE a promising anti-inflammatory agent worthy of further development into a pharmaceutical drug for the treatment of ALI. PMID- 28711784 TI - Urinary metabolite profiling of flavonoids in Chinese volunteers after consumption of orange juice by UFLC-Q-TOF-MS/MS. AB - The metabolism of flavonoids derived from orange juice in Chinese volunteers has not been well investigated. With the ultra-fast liquid chromatography-quadrupole time-of-flight tandem mass spectrometry (UFLC-Q-TOF-MS/MS) system, orange juice derived flavonoids, as well as metabolites contained in urine collected from healthy Chinese volunteers after consumption of 250mL orange juice, were systematically identified and quantified. Finally, a total of 9 flavonoids and 30 metabolites were detected. Obtained results revealed that flavonoids derived from orange juice underwent extensive phase II metabolism in human, mainly comprising glucuronidation and sulfation. The overall recovery of the primary flavonoid aglycones, i.e., naringenin and hesperetin, were both approximately equivalent 22% of intake, primarily occurred in 4-12h post consumption. Meanwhile, additional 35 phenolic catabolites were identified in urine collected post consumption. However, it is difficult to determine the exact amounts of phenolic catabolites derived from specific flavonoid due to the interference of diets and other flavonoids. This work would be valuable for the clarification of metabolic profiles for flavonoids in Chinese population. PMID- 28711785 TI - A fit-for-purpose LC-MS/MS method for the simultaneous quantitation of ATP and 2,3-DPG in human K2EDTA whole blood. AB - Many hemolytic anemias results in major metabolic abnormalities: two common metabolite abnormalities include increased levels of 2,3-diphosphoglycerate (2,3 DPG) and decreased levels of adenosine triphosphate (ATP). To better monitor the concentration changes of these metabolites, the development of a reliable LC MS/MS method to quantitatively profile the concentrations of 2, 3-DPG and ATP in whole blood is essential to understand the effects of investigational therapeutics. Accurate quantification of both compounds imposes great challenges to bioanalytical scientists due to their polar, ionic and endogenous nature. Here we present an LC-MS/MS method for the reliable quantification of 2,3-DPG and ATP from K2EDTA human whole blood (WB) simultaneously. Whole blood samples were spiked with stable isotope labeled internal standards, processed by protein precipitation extraction, and analyzed using zwitterionic ion chromatography hydrophilic interaction chromatography (ZIC-HILIC) coupled with tandem mass spectrometry. The linear analytical range of the assay was 50-3000MUg/mL. The fit for-purpose method demonstrated excellent accuracy and precision. The overall accuracy was within +/-10.5% (%RE) for both analytes and the intra- and inter assay precision (%CV) were less than 6.7% and 6.2% for both analytes, respectively. ATP and 2,3-DPG were found to be stable in human K2EDTA blood for at least 8h at 4 degrees C, 96days when stored at -70 degrees C and after three freeze/thaw cycles. The assay has been successfully applied to K2EDTA human whole blood samples to support clinical studies. PMID- 28711787 TI - Seed priming and transgenerational drought memory improves tolerance against salt stress in bread wheat. AB - This study was conducted to evaluate the potential of seed priming following terminal drought on tolerance against salt stress in bread wheat. Drought was imposed in field sown wheat at reproductive stage (BBCH growth stage 49) and was maintained till physiological maturity (BBCH growth stage 83). Seeds of bread wheat, collected from crop raised under terminal drought and/or well-watered conditions, were subjected to hydropriming and osmopriming (with 1.5% CaCl2) and were sown in soil-filled pots. After stand establishment, salt stress treatments viz. 10 mM NaCl (control) and 100 mM NaCl were imposed. Seed from terminal drought stressed source had less fat (5%), and more fibers (11%), proteins (22%) and total soluble phenolics (514%) than well-watered seed source. Salt stress reduced the plant growth, perturbed water relations and decreased yield. However, an increase in osmolytes accumulation (4-18%), malondialdehyde (MDA) (27-35%) and tissue Na+ contents (149-332%) was observed under salt stress. The seeds collected from drought stressed crop had better tolerance against salt stress as indicated by better yield (28%), improved water relations (3-18%), osmolytes accumulation (21-33%), and less MDA (8%) and Na contents (35%) than progeny of well-watered crop. Seed priming, osmopriming in particular, further improved the tolerance against salt stress through improvement in leaf area, water relations, leaf proline, glycine betaine and grain yield while lowering MDA and Na+ contents. In conclusion, changed seed composition during terminal drought and seed priming improved the salt tolerance in wheat by modulating the water relations, osmolytes accumulation and lipid peroxidation. PMID- 28711786 TI - EXO1 suppresses double-strand break induced homologous recombination between diverged sequences in mammalian cells. AB - DNA double-strand breaks (DSBs) can be repaired through several mechanisms, including homologous recombination (HR). While HR between identical sequences is robust in mammalian cells, HR between diverged sequences is suppressed by DNA mismatch-repair (MMR) components such as MSH2. Exonuclease I (EXO1) interacts with the MMR machinery and has been proposed to act downstream of the mismatch recognition proteins in mismatch correction. EXO1 has also been shown to participate in extensive DSB end resection, an initial step in the HR pathway. To assess the contribution of EXO1 to HR in mammalian cells, DSB-inducible reporters were introduced into Exo1-/- mouse embryonic stem cells, including a novel GFP reporter containing several silent polymorphisms to monitor HR between diverged sequences. Compared to HR between identical sequences which was not clearly affected, HR between diverged sequences was substantially increased in Exo1-/- cells although to a lesser extent than seen in Msh2-/- cells. Thus, like canonical MMR proteins, EXO1 can restrain aberrant HR events between diverged sequence elements in the genome. PMID- 28711788 TI - Grapevine tissues and phenology differentially affect soluble carbohydrates determination by capillary electrophoresis. AB - Soluble carbohydrates distribution depends on plant physiology and, among other important factors, determines fruit yield and quality. In plant biology, the analysis of sugars is useful for many purposes, including metabolic studies. Capillary electrophoresis (CE) proved to be a powerful green separation technique with minimal sample preparation, even in complex plant tissues, that can provide high-resolution efficiency. Matrix effect refers to alterations in the analytical response caused by components of a sample other than the analyte of interest. Thus, the assessment and reduction of the matrix factor is fundamental for metabolic studies in different matrices. The present study evaluated the source and levels of matrix effects in the determination of most abundant sugars in grapevine tissues (mature and young leaves, berries and roots) at two phenological growth stages. Sucrose was the sugar that showed the least matrix effects, while fructose was the most affected analyte. Based on plant tissues, young leaves presented the smaller matrix effects, irrespectively of the phenology. These changes may be attributed to considerable differences at chemical composition of grapevine tissues with plant development. Therefore, matrix effect should be an important concern for plant metabolomics. PMID- 28711789 TI - Towards a better understanding of protein changes in common bean under drought: A case study of N-glycoproteins. AB - Drought is one of the major abiotic stress conditions limiting crop growth and productivity. Glycosylation of proteins is very important post-translational modification that is involved in many physiological functions and biological pathways. To understand the involvement of N-glycoproteins in the mechanism of drought response in leaves of common bean, a proteomic approach using lectin affinity chromatography, SDS-PAGE and LC-MS/MS was applied. Quantification of N glycoproteins was performed using MaxQuant with a label free quantification approach. Thirty five glycoproteins were changed in abundance in leaves of common bean under drought. The majority of these proteins were classified into functional groups that include cell wall processes, defence/stress related proteins and proteins related to proteolysis. Beta-glucosidase showed the highest increase in abundance among proteins involved in cell wall metabolism, suggesting its role in cell wall modification under drought stress. These results fit with the general concept of the stress response in plants and suggest that drought stress might affect biochemical metabolism in the cell wall. The structures of N glycans were determined manually from spectra, where structures of high mannose, complex and hybrid types of N-glycans were found. The present study provided an insight into the glycoproteins related to drought stress in common bean at the proteome level, which is important for further understanding of molecular mechanisms of drought response in this important legume. PMID- 28711790 TI - Six phenylalanine ammonia-lyases from Camellia sinensis: Evolution, expression, and kinetics. AB - Phenylalanine ammonia-lyase (PAL), the branch point enzyme controlling the flow of primary metabolism into second metabolism, converts the L-phenylalanine (L Phe) to yield cinnamic acid. Based on the sequencing data available from eight transcriptome projects, six PAL genes have been screened out, cloned, and designated as CsPALa-CsPALf. The phylogenetic tree showed that CsPALs were divided into three subgroups, PALa and PALb, PALc and PALd, and PALe and PALf. All six CsPALs exhibited indiscriminate cytosolic locations in epidermis cells and mesophyll cells. Then, the expression profiles of six PAL genes were qualitatively investigated and they displayed tissue-/induced-expression specificity in several tissues or under different exogenous treatments. Furthermore, in vitro enzymatic assays showed that all six recombinant proteins were characterized by the strict substrate specificity toward L-Phe, but no activity toward L-Tyr, and they displayed subtle differences in kinetics and enzymatic properties. These results indicate that CsPALs play both distinct and overlapping roles in plant growth and responses to environmental cues. PMID- 28711792 TI - Regulation of proline biosynthesis and resistance to drought stress in two barley (Hordeum vulgare L.) genotypes of different origin. AB - Drought is considered the main abiotic stress factor that inhibits growth of crop plants (including barley), limiting yield in many regions worldwide. Predicted climate changes show that in future the frequency and intensity of drought events will rise, so crops that are resistant to this stress are in demand. One of the adaptive metabolic responses to drought is the accumulation of proline. The aim of this study was to examine the effect of 10-day drought on tissue dehydration and proline biosynthesis in leaves as well as in roots of barley genotypes of different origin: the Syrian breeding line Cam/B1/CI and the German cultivar Maresi. The involvement of Delta1 pyrroline-5-carboxylate synthetase (P5CS), the expression of the P5CS gene and ABA in proline synthesis under drought were also studied. Finally, we examined the resistance of tested genotypes to applied drought using chlorophyll fluorescence parameters and above-ground dry matter accumulation. Drought caused a gradual decrease of water content and an increase of proline and ABA content in roots and leaves of both genotypes. A statistically significant positive correlation between proline accumulation and activity of P5CS was also revealed. The skyrocketing increase of P5CS activity and proline accumulation was proceeded by transcriptional up-regulation of P5CS. The relationships between changes in P5CS expression, P5CS activity and ABA content show that the latter compound is involved in drought-induced proline synthesis at the transcription and enzyme activity level. The examined barley genotypes were equally resistant to applied moderate drought stress regardless of the differences in the level of proline accumulated. PMID- 28711791 TI - Labeled Azospirillum brasilense wild type and excretion-ammonium strains in association with barley roots. AB - Soil bacteria colonization in plants is a complex process, which involves interaction between many bacterial characters and plant responses. In this work, we labeled Azospirillum brasilense FP2 (wild type) and HM053 (excretion-ammonium) strains by insertion of the reporter gene gusA-kanamycin into the dinitrogenase reductase coding gene, nifH, and evaluated bacteria colonization in barley (Hordeum vulgare). In addition, we determined inoculation effect based on growth promotion parameters. We report an uncommon endophytic behavior of A. brasilense Sp7 derivative inside the root hair cells of barley and highlight the promising use of A. brasilense HM053 as plant growth-promoting bacterium. PMID- 28711795 TI - Significance of pH control in anammox process performance at low temperature. AB - Anaerobic ammonium oxidation (anammox) is an efficient process for biological nitrogen removal from wastewater. Common use of this technology is still limited by relatively high optimal temperature. Temperature and pH influence on the anammox process was widely studied, but the significance of pH control in the anammox performance at low temperature was omitted. Moreover up to now, these two parameters were analyzed separately without looking into the composite effects. Statistical approach was used to conduct an in-depth study of the individual and interactive influence of pH and low temperature on the anammox activity. Optimal pH was observed between 7.0 and 7.5, but results indicate that there is no statistically significant interaction between pH and temperature. However, it was observed that the optimal pH range narrows along with the temperature decrease, which means that the efficiency of the anammox process at low temperatures can be improved by correction and adequate control of pH. PMID- 28711794 TI - Sampling designs for contaminant temporal trend analyses using sedentary species exemplified by the snails Bellamya aeruginosa and Viviparus viviparus. AB - Environmental monitoring typically assumes samples and sampling activities to be representative of the population being studied. Given a limited budget, an appropriate sampling strategy is essential to support detecting temporal trends of contaminants. In the present study, based on real chemical analysis data on polybrominated diphenyl ethers in snails collected from five subsites in Tianmu Lake, computer simulation is performed to evaluate three sampling strategies by the estimation of required sample size, to reach a detection of an annual change of 5% with a statistical power of 80% and 90% with a significant level of 5%. The results showed that sampling from an arbitrarily selected sampling spot is the worst strategy, requiring much more individual analyses to achieve the above mentioned criteria compared with the other two approaches. A fixed sampling site requires the lowest sample size but may not be representative for the intended study object e.g. a lake and is also sensitive to changes of that particular sampling site. In contrast, sampling at multiple sites along the shore each year, and using pooled samples when the cost to collect and prepare individual specimens are much lower than the cost for chemical analysis, would be the most robust and cost efficient strategy in the long run. Using statistical power as criterion, the results demonstrated quantitatively the consequences of various sampling strategies, and could guide users with respect of required sample sizes depending on sampling design for long term monitoring programs. PMID- 28711796 TI - Oxidative stress in the hybrid fish jundiara (Leiarius marmoratus * Pseudoplatystoma reticulatum) exposed to Roundup Original(r). AB - The aim of this study was to investigate the effects of Roundup Original(r), a glyphosate-based herbicide, against biochemical parameters including thiobarbituric acid-reactive substances (TBARS), protein carbonyl, enzymatic and nonenzymatic antioxidant responses and acetylcholinesterase (AChE) of jundiara fish (Leiarius marmoratus * Pseudoplatystoma reticulatum) at a sublethal concentration of 1.357 mg L-1. Fish exposed to the herbicide for different periods (6-96 h) showed a significant increase of both hepatic and muscular TBARS and protein carbonyl. Enzymatic antioxidant activity was decreased in the liver and brain after 48 h of exposure. Glutathione-S-tranferase (GST) had its levels raised in the brain and gills, probably as a toxicity event response. Non protein thiols (GSH) demonstrated a reduction after 6 and 24 h of exposure in the hepatic tissue, followed by an increase at 48 and 96 h in the same tissue. GSH brain levels, however, increased only after 96 h. AChE activity in muscle decreased for all the times tested (26.5, 45, 38 and 14% for 6, 24, 48 and 96 h respectively), but only at 96 h (34%) in the brain. We found that Roundup Original(r) is able to trigger important changes in the biochemical parameters tested, showing it can be a potential threat for the health and survival of fish in the environment. PMID- 28711793 TI - Efficacy and safety of Everolimus and Exemestane in hormone-receptor positive (HR+) human-epidermal-growth-factor negative (HER2-) advanced breast cancer patients: New insights beyond clinical trials. The EVA study. AB - BACKGROUND: The BOLERO-2 trial reported efficacy and safety of Everolimus (EVE) and Exemestane (EXE) combination in HR+ advanced breast cancer (ABC) patients. The BALLET trial further evaluated the safety of EVE-EXE in HR+ ABC patients, without reporting efficacy data. Aim of the EVA real-life study was to collect data of efficacy and safety of EVE-EXE combination in the clinical setting, as well as exploring efficacy according to EVE Dose-Intensity (DI) and to previous treatment with Fulvestrant. PATIENTS AND METHODS: This study aimed to describe the outcome of ABC pts treated with EVE-EXE combination in terms of median duration of EVE treatment and ORR in a real-life setting. RESULTS: From July 2013 to December 2015, the EVA study enrolled 404 pts. Median age was 61 years (33 83). Main metastatic sites were: bone (69.1%), soft tissue (34.7%) and viscera (33.2%). Median number of previous treatments was 2 (1-7). 43.3% of the pts had received Fulvestrant. Median exposure to EVE was 31.0 weeks (15.4-58.3) in the whole population. No difference was observed in terms of EVE exposure duration according to DI (p for trend = 0.27) or type of previous treatments (p = 0.33). ORR and Disease Control Rate (DCR) were observed in 31.6% and 60.7% of the patients, respectively, with the lowest ORRs confined in CHT pre-treated patients or in those who received the lowest DI of EVE. Grade 3-4 adverse events (AEs) were reported in 37.9% of the patients. Main AEs were: stomatitis (11.2%), non infectious pneumonitis - NIP (3.8%), anaemia (3.8%) and fatigue (3.2%). CONCLUSIONS: The EVA study provided new insights in the use of EVE-EVE combination in HR+ ABC pts many years after the publication of the pivotal trial. The combination is safe and the best response could be obtained in patients receiving the full dose of EVE and/or after hormone-therapy as Fulvestrant in ABC. PMID- 28711797 TI - Symptom severity and disability in psychiatric disorders: The U.S. Collaborative Psychiatric Epidemiology Survey. AB - BACKGROUND: While most psychiatric diagnoses are based on simple counts of symptoms, some symptoms may be sign of a more severe mental syndrome than others. This calls for validated estimates of the relative severity specific symptoms imply within a disorder. We focused on four diagnostic disorders: Manic Episode (ME), Major Depressive Episode (MDE), Post-traumatic Stress Disorder (PTSD) and Generalized Anxiety Disorder (GAD). Symptom-specific severity parameters were estimated, and validated by examining their association with levels of self reported disability in daily activities over and above the number of symptoms. METHODS: Data from the cohort study of the U.S. Collaborative Psychiatric Epidemiology Surveys (CPES) was used, which comprises the National Comorbidity Survey Replication, National Survey of American Life, and the National Latino and Asian American Study. The four analytic datasets included respondents who endorsed disorder-specific pre-screening symptoms according to the World Mental Health Survey Initiative's version of the Composite International Diagnostic Interview. Disability was measured using the WHO Disability Assessment Schedule. Item Response Theory and Tobit models were implemented. RESULTS: For ME, PTSD, and GAD (not MDE) symptom severity based on psychometric Item Response Theory predicted disability outcomes after adjusting for symptom count. For PTSD, symptom count was not associated with disability. LIMITATIONS: The analytic sample for each psychiatric disorder was based on a pre-selection stemming from index criteria (e.g. sadness or pleasure loss for MDE), which implies that our results are only generalizable to those individuals at risk rather than for the entire population. Additionally, we acknowledge that the use of unidimensional models is only one of the several options to model psychopathological constructs. CONCLUSIONS: The same number of symptoms may be related to different levels of disability, depending on the specific symptoms from which the person suffers. Diagnostic procedures and treatment decisions may benefit from such additional information without extra costs. PMID- 28711798 TI - Psychotic-like experiences and happiness in the English general population. AB - BACKGROUND: Psychotic-like experiences (PLEs) have been associated with a variety of adverse outcomes but how they affect happiness in individuals with PLE is unknown. Thus, the aim of the study was to assess the association between PLEs and happiness, and the factors that may influence this association. METHODS: Nationally representative data from the 2007 Adult Psychiatric Morbidity Survey including adults aged >= 16 years was analyzed. The Psychosis Screening Questionnaire was used to assess past 12-month PLE. Individuals who endorsed at least one of the following were considered to have any PLE: thought control, paranoia, strange experiences, auditory hallucinations. Happiness (3-point scale) was assessed with a validated question with higher scores indicating lower levels of happiness. The association between PLE and happiness was assessed by multivariable ordinal logistic regression. Mediation analysis was also performed. RESULTS: Among the 7363 individuals included in the analysis, the prevalence of any PLE increased with decreasing levels of happiness [very happy (2.3%), fairly happy (5.4%), not too happy (14.9%)]. This was also shown in the multivariable analysis adjusted for sociodemographic factors and stressful life events (from very happy to not too happy: OR = 2.41; 95%CI = 1.86-3.12). Mediation analysis showed that anxiety disorders explained the largest proportion of the association (38.8%) followed by depressive episode (28.5%), insomnia (21.9%), disability (16.5%), pain (12.5%), social support (10.0%), and physical health conditions (6.0%). LIMITATIONS: The cross-sectional design limits causal inference. CONCLUSION: Interventions to identify and address conditions that may have a negative impact on happiness in individuals with PLE may be important to improve their well-being. PMID- 28711799 TI - Efficient production of d-amino acid oxidase in Escherichia coli by a trade-off between its expression and biomass using N-terminal modification. AB - Native d-amino acid oxidase (DAAO) that is expressed mostly as inclusion body and its toxicity for E. coli hamper efficient heterologous expression. In this study, the soluble expression of DAAO from Rhodosporidium toruloides (RtDAAO) was improved in E. coli through N-terminal modification, but the cell biomass was decreased. Then a trade-off between DAAO expression and biomass was achieved to obtain the highest volumetric activity of DAAO through regulated the number of N terminus histidine residues. When variant 2H3G was fused with three N-terminus histidine residues, the volumetric activity was increased by 3.1 times and the biomass was not significant change compared with the wild type. Finally, the N terminus disordered region of RtDAAO (HSQK) was replaced with HHHG and the variant enzyme activity reached 80.7U/mL (with a 40 percent of inactive DAAO reduced) in a 7.5L fermenter in 24h. PMID- 28711800 TI - Free ammonia offers algal crop protection from predators in dairy wastewater and ammonium-rich media. AB - Cost-effective methods for protecting crops from grazing organisms like rotifers are needed to reduce the risk of pond crashes in mass algal cultures. We present a novel strategy to optimize the exposure time to free ammonia, via control of media pH, in both defined media and dairy anaerobic digester effluent to suppress rotifers and maintain algal productivity. We tested five different free ammonia exposure times (0, 1, 2, 6, and 12h) and found a significant nonlinear effect of exposure time (p<0.0001) but not pH (p>0.9) on rotifer survival. In both media types, 6-12h of elevated free ammonia significantly reduced Brachionus plicatilis rotifer survival with no negative effects on Nannochloropsis oculata, while shorter exposure times were insufficient to inhibit rotifers, leading to severe algal culture crashes. These results suggest that algal crops can be protected from rotifers, without productivity loss, by elevating free ammonia for 6 or more hours. PMID- 28711801 TI - Effect of different nitrogen fertilizer treatments on the conversion of Miscanthus*giganteus to ethanol. AB - Miscanthus*giganteus is a perennial rhizomatous grass which is used as a biofuel crop. Due to its high yields, low production costs, resistance to low temperatures, low soil requirements and, above all, high cellulose content, miscanthus can be a useful resource for ethanol production. The aim of this study was to determine the effect of two fertilization regimes (sewage sludge/mineral NPK) during miscanthus cultivation on the chemical composition of biomass, the content of major lignocellulosic factions and the effectiveness of miscanthus conversion to bioethanol. The results indicate that fertilization treatments influenced biomass yield and the content of major lignocellulosic fractions. Bioethanol production was higher when hydrolysis and fermentation processes were conducted separately than when saccharification and fermentation were conducted simultaneously. Ethanol production increased by 30% and 40% in response to sewage sludge and NPK (equivalent nitrogen content=160kgN/ha) fertilization, respectively, in comparison with unfertilized crops. PMID- 28711802 TI - Two-stage anoxic/oxic combined membrane bioreactor system for landfill leachate treatment: Pollutant removal performances and microbial community. AB - In this study, a laboratory-scale two-stage anoxic/oxic (A/O) combined membrane bioreactor (MBR) was operated for 113d for the treatment of landfill leachate. The average removal of chemical oxygen demand (COD), ammonia (NH4+-N) and total nitrogen (TN) achieved 80.60%, 99.04% and 74.87%, respectively. A mass balance evaluation suggested that the removal of COD, NH4+-N and TN occurred mainly in the second A/O process, and the total removal capacity of COD, NH4+-N and TN were 125.60g/d, 24.35g/d and 22.40g/d, respectively. High-throughput sequencing analysis indicated that the Proteobacteria (44.57-50.36%), Bacteroidetes (22.09 27.25%), Planctomycetes (6.94-8.47%), Firmicutes (3.31-4.53%) and Chloroflexi (3.13-4.80%) were the dominated phyla in the bacterial community during the operation period. At the genus level, Nitrosomonas, Nitrobacter, Planctomyces, Saprospiraceae and Pseudomonas showed relatively high abundance, which played an important role in the removal of pollutants. PMID- 28711804 TI - Effect of iron(III) ion on moso bamboo pyrolysis under microwave irradiation. AB - The effect of iron(III) ion on microwave pyrolysis of moso bamboo was investigated. Hydrofluoric acid washing was used as a pilot process to demineralize moso bamboo in order to eliminate the influences of the other inorganics contained in moso bamboo itself. The results indicated that the addition of iron(III) ion increased the maximal reaction temperatures under microwave condition dependent on the amount of the added iron(III) ion. The production of the non-condensable gases was promoted by the addition of iron(III) ion mainly at the expense of liquid products. Iron(III) ion exhibited the positive effect for syngas production and inhibited the formation of CO2 and CH4. The formation of Fe2O3 and Fe3O4 was found during microwave pyrolysis and the mechanism of the two metallic oxides formation was described in this work. PMID- 28711803 TI - Investigation on the response of anaerobic membrane bioreactor to temperature decrease from 25 degrees C to 10 degrees C in sewage treatment. AB - Anaerobic membrane bioreactor (AnMBR) for sewage treatment was operated for 650days with the decrease of temperature from 25 degrees C to 10 degrees C. At higher temperature >15 degrees C, COD removal was above 94% while sewage treatment efficiency and relevant CH4 production decreased below 15 degrees C. The effluent COD at 10 degrees C was 134mg/L at HRT of 16h. Moreover, low temperature can result in a higher membrane fouling rate due to the microbial self-protection behavior in coping with the temperature decrease by releasing soluble microbial products (SMP) and extracellular polymeric substances (EPS). The contribution of pore blocking to membrane fouling caused by protein from SMP and EPS increased from 17% to 45% and that of cake layer decreased from 81% to 53% at 25 degrees C and 15 degrees C respectively. The inhibition to hydrolysis and acidification process was responsible to the decrease of sewage treatment at lower temperature. PMID- 28711806 TI - Improvement of pig manure compost lignocellulose degradation, organic matter humification and compost quality with medical stone. AB - The present study aimed to investigate the effect of different concentrations (0%, 2.5%, 5.0%, 7.5% and 10.0%) of medical stone (MS) on the lignocellulose degradation and organic matter humification during pig manure (PM) composting. The results indicated that the addition of MS drastically promoted the organic carbon and lignin degradation. Compared to the control, the decomposition rate of hemicellulose and cellulose was increased by 9.64-27.08% and 2.11-12.07% in MS added treatments. Meanwhile, MS amendment significantly improved the humification of composting process, and the humic acid contents in MS added treatments were 5.58-9.75% higher than control. The FTIR and synchronous fluorescence spectra indicated that the aromatization of final compost was promoted with increasing the MS amount. In addition, the application of MS blended composts could significantly improve the biomass and chlorophyll content of pachoi (Brassica chinensis L.). Due to the effective performance of MS, the 10.0% MS was suggested for PM composting. PMID- 28711805 TI - Neural network modeling to support an experimental study of the delignification process of sugarcane bagasse after alkaline hydrogen peroxide pre-treatment. AB - The present study examines the use of Artificial Neural Networks (ANN) as prediction and fault detection tools for the delignification process of sugarcane bagasse via hydrogen peroxide (H2O2). Experimental conditions varied from 25 to 45 degrees C for temperature and from 1.5% to 7.5% (v/v) for H2O2 concentrations. Analytical results for the delignification were obtained by Fourier Transform Infrared (FT-IR) analysis and used for the ANN training and testing steps, allowing for the development of ANN models. The condition experimentally identified as the most suitable for the delignification process was of 25 degrees C with 4.5% (v/v) H2O2, oxidizing 54% of total lignin. An ANN topology was selected for each proposed model, whose performance was evaluated by the correlation coefficient (R2) and error indices (MSE and SSE). The values obtained for R2 and the error indices indicated good agreements of the theoretical and actual data, of close to 1 and close to 0, respectively. PMID- 28711807 TI - Human hair-derived high surface area porous carbon material for the adsorption isotherm and kinetics of tetracycline antibiotics. AB - In this work, a human hair-derived high surface area porous carbon material (HHC) was prepared using potassium hydroxide activation. The morphology and textural properties of the HHC structure, along with its adsorption performance for tetracycline (TC) antibiotics, were evaluated. HHC showed a high surface area of 1505.11m2/g and 68.34% microporosity. The effects of most important variables, such as initial concentration (25-355mg/L), solution pH (3-13), and temperatures (30-50 degrees C), on the HHC adsorption performance were investigated. Isotherm data analysis revealed the favorable application of the Langmuir model, with maximum TC uptakes of 128.52, 162.62, and 210.18mg/g at 30, 40, and 50 degrees C, respectively. The experimental data of TC uptakes versus time were analyzed efficiently using a pseudo-first order model. Porous HHC could be an efficient adsorbent for eliminating antibiotic pollutants in wastewater. PMID- 28711808 TI - Optimization of a novel sequential alkalic and metal salt pretreatment for enhanced delignification and enzymatic saccharification of corn cobs. AB - This study presents a sequential sodium phosphate dodecahydrate (Na3PO4.12H2O) and zinc chloride (ZnCl2) pretreatment to enhance delignification and enzymatic saccharification of corn cobs. The effects of process parameters of Na3PO4.12H2O concentration (5-15%), ZnCl2 concentration (1-5%) and solid to liquid ratio (5 15%) on reducing sugar yield from corn cobs were investigated. The sequential pretreatment model was developed and optimized with a high coefficient of determination value (0.94). Maximum reducing sugar yield of 1.10+/-0.01g/g was obtained with 14.02% Na3PO4.12H2O, 3.65% ZnCl2 and 5% solid to liquid ratio. Scanning electron microscopy (SEM) and Fourier Transform Infrared analysis (FTIR) showed major lignocellulosic structural changes after the optimized sequential pretreatment with 63.61% delignification. In addition, a 10-fold increase in the sugar yield was observed compared to previous reports on the same substrate. This sequential pretreatment strategy was efficient for enhancing enzymatic saccharification of corn cobs. PMID- 28711809 TI - Assessing the impact of hazardous waste on children's health: The exposome paradigm. AB - Assessment of the health impacts related to hazardous waste is a major scientific challenge with multiple societal implications. Most studies related to associations between hazardous waste and public health do not provide established of mechanistic links between environmental exposure and disease burden, resulting in ineffective waste management options. The exposome concept comes to overhaul the nature vs. nurture paradigm and embraces a world of dynamic interactions between environmental exposures, endogenous exposures and genetic expression in humans. In this context, the exposome paradigm provides a novel tool for holistic hazardous waste management. Waste streams and the related contamination of environmental media are not viewed in isolation, but rather as components of the expotype, the vector of exposures an individual is exposed to over time. Thus, a multi-route and multi-pathway exposure estimation can be performed setting a realistic basis for integrated health risk assessment. Waste management practices are thus assessed not only regarding their technological edge and efficacy but also their effects on human health at the individual and community level, considering intra-subject variability in the affected population. The effectiveness of the exposome approach is demonstrated in the case of Athens, the capital of Greece, where the health effects associated to long term and short term exposure to two major waste management facilities (landfill and plastic recycling) are presented. Using the exposome analysis tools, we confirmed that proximity to a landfill is critical for children neurodevelopment. However, this effect is significantly modified by parameters such as parental education level, socioeconomic status and nutrition. Proximity to a plastics recycling plant does not pose significant threats under normal operating conditions; yet, in the case of an accidental fire, release of persistent carcinogenic compounds (dioxins and furans) even for a short period results in increased lifelong risk, especially for breast feeding neonates. PMID- 28711810 TI - Cocaine dependence modulates the effect of HIV infection on brain activation during intertemporal decision making. AB - BACKGROUND: Both HIV infection and chronic cocaine use alter the neural circuitry of decision making, but the interactive effects of these commonly comorbid conditions have not been adequately examined. This study tested how cocaine moderates HIV-related neural activation during an intertemporal decision-making task. METHODS: The sample included 73 participants who differed on cocaine and HIV status (18 COC+/HIV+, 19 COC+/HIV-, 19 COC-/HIV+, 17 COC-/HIV-). Participants made choices between smaller, sooner and larger, delayed rewards while undergoing functional MRI. Choices varied in difficulty based on subjective value: hard (equivalently valued), easy (disparately valued), and control choices. A mixed effects model controlling for education and smoking identified main and interactive effects of HIV and COC during hard relative to easy choices (difficulty contrast). RESULTS: COC+ status was associated with lower activation in bilateral frontal gyri and right insular and posterior parietal cortices. HIV+ status was associated with higher activation in the visual cortex, but lower activation in bilateral prefrontal cortices and cerebellum and left posterior parietal cortex. COC moderated the effects of HIV in several clusters centered in the bilateral prefrontal cortices and cerebellum. In post-hoc analyses, there were significant effects of HIV status on activation for COC+, but not COC-, participants; interaction effects remained after controlling for polysubstance use. CONCLUSION: Cocaine use may diminish the compensatory neural activation often seen among HIV+ samples during decision making. Our results highlight the importance of examining the neuropsychiatric effects of comorbid medical conditions to identify potential neural targets for cognitive remediation interventions. PMID- 28711812 TI - Bullying involvement and adolescent substance use: A multilevel investigation of individual and neighbourhood risk factors. AB - BACKGROUND: Youth involved with school bullying are vulnerable to many negative outcomes, including substance use. Research has yet to examine how this vulnerability operates in the context of other individual and neighbourhood differences. The current study aimed to fill this gap by using multilevel modeling to investigate both the individual and neighbourhood risk factors associated with frequent drunkenness and frequent cannabis use among adolescents. METHODS: Data from the 2010 Canadian Health Behaviours in School-Aged Children (HBSC) survey were analyzed. Participants consisted of 8971 students from 173 neighbourhoods across Canada. Multilevel modeling was used to examine both individual (age, gender, bullying, victimization, peer deviancy, negative affect) and neighbourhood (socioeconomic status, crime, physical neighbourhood disorder, residential instability) risk factors. We tested whether the links between bullying involvement and frequent substance use were mediated by other risk factors. RESULTS: Both individual and neighbourhood risk factors were associated with an increased likelihood of frequent substance use. Specifically, bullying served as a unique risk factor for frequent substance use over and above more traditional risk factors. A cross-level interaction was observed between residential instability and peer deviancy, such that the link between peer deviancy and frequent drunkenness was stronger in more residentially-unstable neighbourhoods. Peer deviancy partially mediated the link between bullying and both types of frequent substance use, whereas both peer deviancy and negative affect mediated the link between victimization and both types of frequent substance use. CONCLUSIONS: Youth who bully others are vulnerable to frequent substance use across peer and neighbourhood contexts. PMID- 28711811 TI - N-Acetylcysteine reduces cocaine-cue attentional bias and differentially alters cocaine self-administration based on dosing order. AB - BACKGROUND: Disrupted glutamate homeostasis is thought to contribute to cocaine use disorder, in particular, by enhancing the incentive salience of cocaine stimuli. n-Acetylcysteine might be useful in cocaine-use disorder by normalizing glutamate function. In prior studies, n-acetylcysteine blocked the reinstatement of cocaine seeking in laboratory animals and reduced the salience of cocaine stimuli and delayed relapse in humans. METHODS: The present study determined the ability of maintenance on n-acetylcysteine (0 or 2400mg/day, counterbalanced) to reduce the incentive salience of cocaine stimuli, as measured by an attentional bias task, and attenuate intranasal cocaine self-administration (0, 30, and 60mg). Fourteen individuals (N=14) who met criteria for cocaine abuse or dependence completed this within-subjects, double-blind, crossover-design study. RESULTS: Cocaine-cue attentional bias was greatest following administration of 0mg cocaine during placebo maintenance, and was attenuated by n-acetylcysteine. Cocaine maintained responding during placebo and n-acetylcysteine maintenance, but the reinforcing effects of cocaine were significantly attenuated across both maintenance conditions in participants maintained on n-acetylcysteine first compared to participants maintained on placebo first. CONCLUSIONS: These results collectively suggest that a reduction in the incentive salience of cocaine related stimuli during n-acetylcysteine maintenance may be accompanied by reductions in cocaine self-administration. These results are in agreement with, and link, prior preclinical and clinical trial results suggesting that n acetylcysteine might be useful for preventing cocaine relapse by attenuating the incentive salience of cocaine cues. PMID- 28711813 TI - Multi-site exploration of sex differences in brain reactivity to smoking cues: Consensus across sites and methodologies. AB - BACKGROUND: Biological sex influences cigarette smoking behavior. More men than women smoke, but women have a harder time quitting. Sex differences in smoking cue (SC) reactivity may underlie such behavioral differences. However, the influence of sex on brain reactivity to SCs has yielded inconsistent findings suggesting the need for continued study. Here, we investigated the effect of sex on SC reactivity across two sites using different imaging modalities and SC stimulus types. METHODS: Pseudo-continuous arterial spin-labeled (pCASL) perfusion functional magnetic resonance imaging (fMRI) was used to assess brain responses to SC versus non-SC videos in 40 smokers (23 females) at the University of Pennsylvania. BOLD fMRI was used to assess brain responses to SC versus non-SC still images in 32 smokers (18 females) at McLean Hospital. Brain reactivity to SCs was compared between men and women and was correlated with SC-induced craving. RESULTS: In both cohorts, males showed higher SC versus non-SC reactivity compared to females in reward-related brain regions (i.e., ventral striatum/ventral pallidum, ventral medial prefrontal cortex). Brain activation during SC versus non-SC exposure correlated positively with SC-induced subjective craving in males, but not females. CONCLUSIONS: The current work provides much needed replication and validation of sex differences in SC-reactivity. These findings also add to a body of literature showing that men have greater reward related brain activation to drug cues across drug classes. Such sex differences confirm the need to consider sex not only when evaluating SC-reactivity but when examining nicotine dependence etiology and treatment. PMID- 28711814 TI - Problem alcohol use and healthcare utilization among persons with cannabis use disorder in the United States. AB - BACKGROUND: The emergency department (ED) and hospital settings represent crucial opportunities for engaging treatment for cannabis use disorder (CUD). Thus, there is a need to identify factors associated with healthcare utilization among persons with CUD to improve screening and intervention approaches. Problematic alcohol use may be a salient risk factor. METHODS: Using data from the 2005-2013 National Surveys on Drug Use and Health, we determined factors, including different patterns of alcohol use, associated with past-year ED admission and inpatient hospitalization among persons aged 12 years or older meeting criteria for CUD in the past year (N=16,757). We also determined the prevalence and correlates of problem alcohol use among persons with CUD to further inform its association with healthcare utilization. RESULTS: Among persons with CUD, 40.15% and 10.04% reported past-year ED admission and inpatient hospitalization, respectively. Severe alcohol use disorder (AUD) (>=6 AUD symptoms), female sex, Black race, low income, major depressive episode (MDE), and other substance use disorders were associated with increased odds of healthcare utilization; current (i.e., last month) alcohol use patterns were not. Persons with CUD that were males, ages 18-25 (vs. ages 12-17), Hispanic (vs. White), and with low income, other drug use disorders, or MDE had increased odds of AUD. CONCLUSIONS: Findings suggest that screening and intervention efforts for improving treatment initiation or engagement for CUD may target cannabis-using women, blacks, low income adults or those with severe AUD in the past year, another substance use disorder, or MDE. PMID- 28711816 TI - Unilateral subthalamotomy in Parkinson's disease: Cognitive, psychiatric and neuroimaging changes. AB - Unilateral subthalamotomy is an effective treatment for the cardinal motor features of Parkinson's disease (PD). However, non-motor changes possibly associated with right or left subthalamotomy remain unknown. Our aim was to assess cognitive, psychiatric and neuroimaging changes after treatment with unilateral subthalamotomy. Fourteen medicated patients with PD were evaluated before and after (mean 6 months after operation) unilateral subthalamotomy (5 right, 9 left). In addition to motor assessments, cognitive (global cognition and executive functions), psychiatric (apathy, depression, anxiety, mania, hypo- and hyperdopaminergic behaviours, impulsivity), quality of life evaluations and volume of lesions were obtained. After surgery, significant improvement of motor signs was observed. Unilateral subthalamotomy improved general cognitive status, but left subthalamotomy reduced semantic verbal fluency compared to the pre operative state. Depression and quality of life were improved with both right and left subthalamotomy. However, hyper-emotionality was present after surgery and right subthalamotomy increased impulsivity and disinhibition (on NeuroPsychiatric Inventory and Ardouin Scale for Behaviour in PD), a result linked to larger lesion volumes. We conclude that unilateral subthalamotomy is effective for treating the cardinal motor features of PD and improves mood. Right subthalamotomy is associated with greater risk of impulsivity and disinhibition, while left subthalamotomy induces further impairment of semantic verbal fluency. PMID- 28711818 TI - The association between second-hand smoke exposure and depressive symptoms among pregnant women. AB - Tobacco smoking and depression are strongly associated, but the possible association between second-hand smoke (SHS) exposure and depression is unclear. This study aimed to examine the possible relation between SHS exposure and depressive symptoms among pregnant women. A cross-sectional survey was conducted in Shenzhen, China, using a multistage sampling method. The univariable and multivariable logistic regression models were used to explore the associations between SHS exposure and depressive symptoms. Among 2176 pregnant women, 10.5% and 2.0% were classified as having probable and severe depressive symptoms. Both binary and multinomial logistic regression revealed that there were significantly increased risks of severe depressive symptoms corresponding to SHS exposure in homes or regular SHS exposure in workplaces using no exposure as reference. In addition, greater frequency of SHS exposure was significantly associated with the increased risk of severe depressive symptoms. Our findings suggest that SHS exposure is positively associated with depressive symptoms in a dose-response manner among the pregnant women. PMID- 28711817 TI - Selection and application of familiar and novel tools in patients with left and right hemispheric stroke: Psychometrics and normative data. AB - Frequently left brain damage (LBD) leads to limb apraxia, a disorder that can affect tool-use. Despite its impact on daily life, classical tests examining the pantomime of tool-use and imitation of gestures are seldom applied in clinical practice. The study's aim was to present a diagnostic approach which appears more strongly related to actions in daily life in order to sensitize applicants and patients about the relevance of the disorder before patients are discharged. Two tests were introduced that evaluate actual tool selection and tool-object application: the Novel Tools (NTT) and the Familiar Tools (FTT) Test (parts of the DILA-S: Diagnostic Instrument for Limb Apraxia - Short Version). Normative data in healthy subjects (N = 82) was collected. Then the tests were applied in stroke patients with unilateral left brain damage (LBD: N = 33), a control right brain damage group (RBD: N = 20) as well as healthy age and gender matched controls (CL: N = 28, and CR, N = 18). The tests showed appropriate interrater reliability and internal consistency as well as concurrent and divergent validity. To examine criterion validity based on the well-known left lateralization of limb apraxia, group comparisons were run. As expected, the LBD group demonstrated a high prevalence of tool-use apraxia (NTT: 36.4%, FTT: 48.5%) ranging from mild to severe impairment and scored worse than their control group (CL). A few RBD patients did demonstrate impairments in tool-use (NTT: 15%, FTT: 15%). On a group level they did not differ from their healthy controls (CR). Further, it was demonstrated that the selection and application of familiar and novel tools can be impaired selectively. Our study results suggest that real tool use tests evaluating tool selection and tool application should be considered for standard diagnosis of limb apraxia in left as well as right brain damaged patients. PMID- 28711815 TI - Geschwind Syndrome in frontotemporal lobar degeneration: Neuroanatomical and neuropsychological features over 9 years. AB - Geschwind Syndrome, a characteristic behavioral syndrome frequently described in patients affected by temporal lobe epilepsy (TLE), consists of the following features: hyper-religiosity, hypergraphia, hyposexuality, and irritability. Here we report the 9-year-clinical course of a case of Geschwind Syndrome that developed as a first and salient clinical expression of right temporal lobe variant of frontotemporal lobar degeneration (FTLD). Only one patient affected by frontotemporal dementia has previously been shown to present with Geschwind Syndrome. MS presented at age 73 with 3 years of personality and behavioral symptoms. Her early symptoms primarily included hyper-religiosity, hypergraphia, and poor emotional regulation (irritability, impulsivity, disinhibition, egocentric behavior). Over nine years, other cognitive functions (word retrieval, memory coding and recall, set-shifting, famous face and building recognition) became affected; however, hyper-religiosity, hypergraphia, and scarce emotional control remained her most prominent deficits. Longitudinal cortical thickness and volumetric analyses revealed early atrophy in the right temporal pole, right amygdala, and right hippocampus, which progressively affected homologous regions in the left hemisphere. The present case describes an unusual clinical picture associated with frontotemporal dementia (FTD), in which the most salient symptoms originated and remained consistent with Geschwind Syndrome. PMID- 28711819 TI - Differentiation potential of synoviocytes derived from joints with cranial cruciate ligament rupture and medial patella luxation in dogs. AB - The objective of this study was to assess the differentiation capability of synoviocytes derived from dogs with inflammatory joint conditions. Cranial cruciate ligament ruptured (CCLr) (n=12) and medial patella luxated (MPL) (n=10) knee joints of the dogs were used to collect the synovial membrane (SM). Synoviocytes were enzymatically released from the SM and analyzed by flow cytometry for specific cellular markers (CD44 and CD90) of mesenchymal stem cells (MSCs), while doing histopathology from another part of SM sections. Under specific culture conditions, synoviocytes were forced to differentiate into chondrogenesis, adipogenesis, osteogenesis and osteoclastogenesis to investigate the multipotency. Upon treatments phenotypes of cell cultures were analyzed by histopathology and by semi-quantitative reverse transcriptase polymerase chain reaction for the expression of each differentiation marker genes. Although flow cytometry showing similar MSCs populations in CCLr and MPL synovium, synovial cells derived from CCLr showed higher multipotency compared to MPL-derived samples. Further, synovial changes such as vascularity, mononuclear cell infiltration and cellular hypertrophy were more pronounced in CCLr-derived synovial tissue than in MPL. Taken together, these findings suggested that the differentiation capability of SM-derived multipotent stem cells varies with inflammatory severity occurring in different joint conditions. PMID- 28711820 TI - Integrated metagenomics and molecular ecological network analysis of bacterial community composition during the phytoremediation of cadmium-contaminated soils by bioenergy crops. AB - Two energy crops (maize and soybean) were used in the remediation of cadmium contaminated soils. These crops were used because they are fast growing, have a large biomass and are good sources for bioenergy production. The total accumulation of cadmium in maize and soybean plants was 393.01 and 263.24MUg pot 1, respectively. The rhizosphere bacterial community composition was studied by MiSeq sequencing. Phylogenetic analysis was performed using 16S rRNA gene sequences. The rhizosphere bacteria were divided into 33 major phylogenetic groups according to phyla. The dominant phylogenetic groups included Proteobacteria, Acidobacteria, Actinobacteria, Gemmatimonadetes, and Bacteroidetes. Based on principal component analysis (PCA) and unweighted pair group with arithmetic mean (UPGMA) analysis, we found that the bacterial community was influenced by cadmium addition and bioenergy cropping. Three molecular ecological networks were constructed for the unplanted, soybean- and maize-planted bacterial communities grown in 50mgkg-1 cadmium-contaminated soils. The results indicated that bioenergy cropping increased the complexity of the bacterial community network as evidenced by a higher total number of nodes, the average geodesic distance (GD), the modularity and a shorter geodesic distance. Proteobacteria and Acidobacteria were the keystone bacteria connecting different co-expressed operational taxonomic units (OTUs). The results showed that bioenergy cropping altered the topological roles of individual OTUs and keystone populations. This is the first study to reveal the effects of bioenergy cropping on microbial interactions in the phytoremediation of cadmium-contaminated soils by network reconstruction. This method can greatly enhance our understanding of the mechanisms of plant-microbe-metal interactions in metal-polluted ecosystems. PMID- 28711821 TI - Endoscopic thyroid surgery in the Caribbean: A case report of the first clinical experience. AB - Minimally invasive surgery is rapidly expanding its role in almost all of the surgical sub-specialties. There is also a growing demand of this service as patients became more and more concerned about cosmesis in addition to their original surgery. Although its role in thyroid surgery has already been proven earlier; but it is not yet accepted as a routine approach amongst many thyroid surgeons. There is no reported case of laparoscopic thyroid surgery in the English literature from the Caribbean. We are reporting our first clinical experience in performing laparoscopic thyroid surgery in the Caribbean with a successful outcome. PMID- 28711822 TI - Extended thymectomy, left pneumonectomy, pericardiectomy and partial pleurectomy for a large thymoma, using only a median sternotomy. AB - We present a case of a large thymoma with invasion to the hilum of the lung and pleural dissemination. A 58-year-old woman was diagnosed with a type B2 thymoma, with suspected pericardium, pulmonary artery and left lung invasion and pleural metastasis (Masaoka-Koga stage IVb). A radical resection was planned after systemic chemotherapy. Through a median sternotomy, we resected the tumour, and after confirmation of pericardium and left lung invasion, we also performed resection of the pericardium, of the lung and of the pleural metastasis. The median sternotomy allowed a safe dissection of pulmonary vessels and main bronchus. PMID- 28711823 TI - Using nitrogen concentration and isotopic composition in lichens to spatially assess the relative contribution of atmospheric nitrogen sources in complex landscapes. AB - Reactive nitrogen (Nr) is an important driver of global change, causing alterations in ecosystem biodiversity and functionality. Environmental assessments require monitoring the emission and deposition of both the amount and types of Nr. This is especially important in heterogeneous landscapes, as different land-cover types emit particular forms of Nr to the atmosphere, which can impact ecosystems distinctively. Such assessments require high spatial resolution maps that also integrate temporal variations, and can only be feasibly achieved by using ecological indicators. Our aim was to rank land-cover types according to the amount and form of emitted atmospheric Nr in a complex landscape with multiple sources of N. To do so, we measured and mapped nitrogen concentration and isotopic composition in lichen thalli, which we then related to land-cover data. Results suggested that, at the landscape scale, intensive agriculture and urban areas were the most important sources of Nr to the atmosphere. Additionally, the ocean greatly influences Nr in land, by providing air with low Nr concentration and a unique isotopic composition. These results have important consequences for managing air pollution at the regional level, as they provide critical information for modeling Nr emission and deposition across regional as well as continental scales. PMID- 28711824 TI - Atmospheric bulk deposition of polycyclic aromatic hydrocarbons in Shanghai: Temporal and spatial variation, and global comparison. AB - Atmospheric deposition leads to accumulation of atmospheric polycyclic aromatic hydrocarbons (PAHs) on urban surfaces and topsoils. To capture the inherent variability of atmospheric deposition of PAHs in Shanghai's urban agglomeration, 85 atmospheric bulk deposition samples and 7 surface soil samples were collected from seven sampling locations during 2012-2014. Total fluxes of 17 PAHs were 587 32,300 ng m-2 day-1, with a geometric mean of 2600 ng m-2 day-1. The deposition fluxes were categorized as moderate to high on a global scale. Phenanthrene, fluoranthene and pyrene were major contributors. The spatial distribution of deposition fluxes revealed the influence of urbanization/industrialization and the relevance of local emissions. Meteorological conditions and more heating demand in cold season lead to a significant increase of deposition rates. Atmospheric deposition is the principal pathway of PAHs input to topsoils and the annual deposition load in Shanghai amounts to ~4.5 tons (0.7 kg km-2) with a range of 2.5-10 tons (0.4-1.6 kg km-2). PMID- 28711825 TI - Autonomous electrochemical biosensors: A new vision to direct methanol fuel cells. AB - A new approach to biosensing devices is demonstrated aiming an easier and simpler application in routine health care systems. Our methodology considered a new concept for the biosensor transducing event that allows to obtain, simultaneously, an equipment-free, user-friendly, cheap electrical biosensor. The use of the anode triple-phase boundary (TPB) layer of a passive direct methanol fuel cell (DMFC) as biosensor transducer is herein proposed. For that, the ionomer present in the anode catalytic layer of the DMFC is partially replaced by an ionomer with molecular recognition capability working as the biorecognition element of the biosensor. In this approach, fuel cell anode catalysts are modified with a molecularly imprinted polymer (plastic antibody) capable of protein recognition (ferritin is used as model protein), inserted in a suitable membrane electrode assembly (MEA) and tested, as initial proof-of-concept, in a non-passive fuel cell operation environment. The anchoring of the ionomer-based plastic antibody on the catalyst surface follows a simple one-step grafting from approach through radical polymerization. Such modification increases fuel cell performance due to the proton conductivity and macroporosity characteristics of the polymer on the TPB. Finally, the response and selectivity of the bioreceptor inside the fuel cell showed a clear and selective signal from the biosensor. Moreover, such pioneering transducing approach allowed amplification of the electrochemical response and increased biosensor sensitivity by 2 orders of magnitude when compared to a 3-electrodes configuration system. PMID- 28711826 TI - Detection principles of biological and chemical FET sensors. AB - The seminal importance of detecting ions and molecules for point-of-care tests has driven the search for more sensitive, specific, and robust sensors. Electronic detection holds promise for future miniaturized in-situ applications and can be integrated into existing electronic manufacturing processes and technology. The resulting small devices will be inherently well suited for multiplexed and parallel detection. In this review, different field-effect transistor (FET) structures and detection principles are discussed, including label-free and indirect detection mechanisms. The fundamental detection principle governing every potentiometric sensor is introduced, and different state-of-the art FET sensor structures are reviewed. This is followed by an analysis of electrolyte interfaces and their influence on sensor operation. Finally, the fundamentals of different detection mechanisms are reviewed and some detection schemes are discussed. In the conclusion, current commercial efforts are briefly considered. PMID- 28711827 TI - Efficient photocatalytic degradation of tetrabromodiphenyl ethers and simultaneous hydrogen production by TiO2-Cu2O composite films in N2 atmosphere: Influencing factors, kinetics and mechanism. AB - TiO2-Cu2O photocatalyst composite film with a heterostructure was synthesized on a copper substrate for 2,2',4,4'-tetrabromodiphenyl ether (BDE47) reduction. First, Cu2O film was synthesized by the electrochemical deposition method, and then TiO2 was coated on the surface of the Cu2O film. The morphology, surface chemical composition and optical characteristics of TiO2-Cu2O film were characterized. The degradation efficiency of BDE47 and hydrogen production by TiO2-Cu2O films was higher than those by pure TiO2 or Cu2O films. The highest BDE47 degradation efficiency of 90% and hydrogen production of 12.7mmolLliq-1 after 150min were achieved by 67%TiO2-Cu2O films. The influencing factors were investigated in terms of film component, solvent condition, and initial pH. A kinetics study demonstrated that BDE47 degradation followed a pseudo-first-order model. Photocatalytic apparent reaction rate constant of BDE47 by TiO2-Cu2O films was 0.0070min-1, which was 3.3 times of that by directly photolysis process. During photocatalytic debrmination process, the photogenerated holes were reserved in the valance band of Cu2O to oxidize methanol. Meanwhile, the partial photogenerated electrons transferred to the conduction band of TiO2 and directly eliminated the ortho-Br of BDE47 and yielded BDE28 and BDE15. The other partial photogenerated electrons reduced protons (H+) to form atomic hydrogen (H degrees ), which could substitute the para-Br of BDE47 and generated BDE17 and produce hydrogen. PMID- 28711828 TI - Thioglycolate-based task-specific ionic liquids: Metal extraction abilities vs acute algal toxicity. AB - We studied the extraction behavior of two thioglycolate-based ionic liquids (ILs), for heavy metals from aqueous solutions; substances of interest were methyltrioctylammonium S-hexyl thioglycolate [N1888][C6SAc] and methyltrioctylphosphonium S-hexyl thioglycolate [P1888][C6SAc]. Theses ILs previously have shown very good extraction abilities towards cadmium and copper, therefore we investigated time-dependent metal removal experiments with aqueous solutions of cobalt(II), nickel(II) and zinc(II). The highest distribution ratio (RIL/Water) was determined for zinc (RIL/Water=2000). Recovery studies for zinc after extraction were performed with different stripping agents showing a successful recycling. Additionally, the two ILs were immobilized on active charcoal, displaying great potential for solid-liquid extraction. Regarding the extraction mechanism, quantum-mechanical calculations were included, which indicate that the metal extraction depends on the stability of the metal-water cluster. Ligands (water as well as ILs) are planar coordinated in nickel complexes but showed a tetrahedral configuration for zinc. As a first estimate of the ecotoxicity of the ILs, in vivo tests toward three freshwater green algae species Tetradesmus obliquus, Desmodesmus armatus and Raphidocelis subcapitata were carried out. The EC50 values (effective concentration after 72 h) confirm high toxicity of all tested ILs to all species, displaying only small differences between the species and EC50ies. PMID- 28711829 TI - Prevalence of antibiotic resistance genes in soils after continually applied with different manure for 30 years. AB - A 30year field experiment with a wheat-soybean cropping system were performed to compare the long-term anthropogenic influence on soil ARGs. Compared with chemical fertilization, the occurrence of 38 ARGs and the abundance of seven ARGs (tetL, tetB(P), tetO, tetW, sul1, ermB, and ermF) were significantly increased by long term exposure of pig manure. However, application of wheat straw and cow manure not substantially affected the abundance of ARGs except cow manure increased the abundance of tetM and tetW to a detectable level. Relative abundance of Firmicutes, Gammaproteobacteria and Bacteroidetes and ARGs observed in the soil were significantly correlated. Integrase gene I1 (intI1) is commonly linked to genes conferring resistance to antibiotics, it was significantly increased in pig manure treated soils and showed a high positive correlation with the abundance of ARGs which were significantly affected by pig manure. Concentrations of Cu, Zn and Pb were also increased in manure treated soil and positive correlated with the relative abundance of intI1 and most of the ARGs. These results indicated that long-term animal manure application to soils has polluted the soil, especially for pig manure, and it should be scrutinized as part of future stewardship programs. PMID- 28711830 TI - Low energy liquid plasma for direct reduction and formation of rGO-aminopyridine hybrid for electrical and environmental applications. AB - The present works demonstrate the formation of reduced graphene oxide (r-GO) and aminopyridine (r-GO-(AmPy)n) hybrid by submerged liquid plasma process. Raman spectra shows the ID/IG ratio of GO, r-GO and r-GO-(AmPy)n are 2.2, 1.91 and 2.0, respectively. The decrease in ID/IG ratio of r-GO clearly indicate the reduction of oxygen functional groups and restoration of sp2 network in r-GO domain. The pyridinic and pyrrolic functional group present in rGO-(AmPy)n hybrids shows a distinct redox peaks in cyclic voltameter at the scan rates of 5, 10 and 25mV/s. The r-GO-(AmPy)n hybrid displayed an excellent electrochemical performance with a high specific capacitance of 418, 400 and 381F/g at the current densities of 0.1, 0.2 and 0.3A/g, respectively. Electro chemical generation of H2O2 at the rGO (AmPy)n surface was evaluated and found to be 0.72mmol for the fixed reaction time of 60min. Similarly, conversion of H2O2 to OH radical with a coated Fe3O4 plate catalyst was found to be 0.15mmol. A H2O2/OH radicals generated in the electrochemical cell was used for the degradation of methyl parathion. During the degradation (7.5mg/L), two intermediates like methylparaoxon, and p-nitrophenol were identified by the Gas Chromatography and Mass Spectrometer analysis. PMID- 28711831 TI - Application of magnetic OMS-2 in sequencing batch reactor for treating dye wastewater as a modulator of microbial community. AB - The potential and mechanism of synthesized magnetic octahedral molecular sieve (Fe3O4@OMS-2) nanoparticles in enhancing the aerobic microbial ability of sequencing batch reactor (SBR) for treating dye wastewater have been revealed in this study. The addition of Fe3O4@OMS-2 of 0.25g/L enhanced the decolorization of SBRs with an operation cycle of 24h by more than 20%. The 16S rRNA gene high throughput sequencing indicated Fe3O4@OMS-2 increased the microbial richness and diversity of SBRs, and more importantly, promoted the potential dye-degrading bacteria. After a series of enriching and screening, four bacterial strains with the considerable decolorizing ability were isolated from SBRs, designating Alcaligenes faecalis FP-G1, Bacillus aryabhattai FP-F1, Escherichia fergusonii FP D1 and Rhodococcus ruber FP-E1, respectively. The growth and decolorization of these pure strains were promoted in the presence of Fe3O4@OMS-2, which agrees with the result of high-throughput sequencing. Monitoring dissolved Fe/Mn ions and investigating the change of oxidation states of Fe/Mn species discovered OMS 2 composition played the critical role in modulating the microbial community. The significant enhancement of Mn-oxidizing/-reducing bacteria suggested microbial Mn redox may be the key action mechanism of Fe3O4@OMS-2, which can provide numerous benefits for the microbial community and decolorization of SBRs. PMID- 28711832 TI - Biodegradation of phenol via meta cleavage pathway triggers de novo TAG biosynthesis pathway in oleaginous yeast. AB - Phenol is reported to be one of the most toxic environmental pollutants present in the discharge of various industrial effluents causing a serious threat to the existing biome. Biodegradation of phenol by oleaginous yeast Rhodosporidium kratochvilovae HIMPA1 was found to degrade 1000mg/l phenol. The pathways for phenol degradation by both ortho and meta-cleavage were proposed by the identification of metabolites and enzymatic assays of ring cleavage enzymes in the cell extracts. Results suggest that this oleaginous yeast degrade phenol via meta-cleavage pathway and accumulates a high quantity of lipid content (64.92%; wt/wt) as compared to control glucose synthetic medium (GSM). Meta-cleavage pathway of phenol degradation leads to formation of pyruvate and acetaldehyde. Both these end products feed as precursors for de novo triacylglycerols (TAG) biosynthesis pathway which causes accumulation of TAG in the lipid droplets (LD) of 6.12+/-0.78MUm grown on phenol while 2.38+/-0.52MUm observed on GSM. This was confirmed by fluorescence microscopic images of BODIPY505-515nm stained live yeast cells. GC-MS analysis of extracted total lipid showed enhanced amount of monounsaturated fatty acid (MUFA) which was as 51.87%, 58.33% and 62.98% in presence of 0.5, 0.75 and 1g/l of phenol. PMID- 28711833 TI - Assessment of nanoparticles release into the environment during drilling of carbon nanotubes/epoxy and carbon nanofibres/epoxy nanocomposites. AB - The risk assessment, exposure and understanding of the release of embedded carbon nanotubes (CNTs) and carbon nanofibers (CNFs) from commercial high performance composites during machining processes are yet to be fully evaluated and quantified. In this study, CNTs and CNFs were dispersed in epoxy matrix through calendaring process to form nanocomposites. The automated drilling was carried out in a specially designed drilling chamber that allowed elimination of background noise from the measurements. Emission measurements were taken using condensed particle counter (CPC), scanning mobility particle sizer (SMPS) and DMS50 Fast Particulate Size Spectrometer. In comparison to the neat epoxy, the study results revealed that the nano-filled samples produced an increase of 102% and 227% for the EP/CNF and EP/CNT sample respectively in average particle number concentration emission. The particle mass concentration indicated that the EP/CNT and EP/CNF samples released demands a vital new perspective on CNTs and CNFs embedded within nanocomposite materials to be considered and evaluated for occupational exposure assessment. Importantly, the increased concentration observed at 10nm aerosol particle sizes measurements strongly suggest that there are independent CNTs being released at this range. PMID- 28711834 TI - Novel reusable porous polyimide fibers for hot-oil adsorption. AB - The development of oil sorbents with high thermal stability, adsorption capacity, reusability and recoverability is of great significance for hot oil leakage protection, especially for oil spillage of oil refinery, petrochemical industry and cars. In our work, highly efficient hot oil adsorption of polyimide (PI) fibers with excellent thermal stability was successfully prepared by a facile electrospinning method followed by post-treatment. The corresponding morphologies, structures and oil adsorption properties of as-prepared PI fibers at different temperatures were analyzed and characterized. Results showed that PI fibers presented a stable morphology and pore structure at 200 degrees C. The oil adsorption capacity of porous PI fibers for hot motor oil (200 degrees C) was about 57.4gg-1, higher than that of PI fibers (32.7gg-1) with non-porous structure for the motor oil at room temperature. Even after ten adsorption cycles, porous PI fibers still maintained a comparable oil sorption capacity (oil retention of 4.2%). The obtained porous PI fibers exhibited excellent hot oil adsorption capacity, reusability and recoverability, which would broaden the application of electrospun fibers in oil spill cleanup and further provide a versatile platform for exploring the technologies of nanofibers in hot oil adsorption field. PMID- 28711835 TI - Synergistic green extraction of nickel ions from electroplating waste via mixtures of chelating and organophosphorus carrier. AB - The discharge of electroplating waste containing nickel ions has led to environmental issues owing to the toxicity problem mainly to the aquatic organisms and humans. Liquid-liquid extraction offers a great potential treatment for nickel removal with several advantages of simple, high efficiency and high separation factor. In this study, a green synergistic liquid-liquid extraction of nickel ions from electroplating waste solution using chelating oxime (LIX63) and organophosphorus (D2EHPA) carriers individually as well as their synergistic mixture has been studied. The result demonstrated that about 83% of nickel ions have been successfully extracted via the mixture system of 0.08M LIX63 +0.02M D2EHPA with the maximum synergistic enhancement factor, Rmax of 29.56. Meanwhile, the back extraction study also revealed that HNO3 was the most suitable stripping agent while the diluent screening also showed that palm oil has high potential to be incorporated as a diluent in the green synergistic liquid-liquid extraction of nickel. PMID- 28711836 TI - One-step in situ hydrothermal fabrication of octahedral CdS/SnIn4S8 nano heterojunction for highly efficient photocatalytic treatment of nitrophenol and real pharmaceutical wastewater. AB - Octahedral CdS/SnIn4S8 nano-heterojunctions were fabricated by a facile and simple one-step in situ hydrothermal method, and the molar ratio of CdS to SnIn4S8 was optimized. The optimal (0.5:1)CdS/SnIn4S8 heterojunctions exhibit the highest visible-light photocatalytic activity with 97.1% degradation efficiency of 2-nitrophenol in 120min, which is much higher than those of individual CdS and SnIn4S8. The enhanced photocatalytic performance could be attributed to the effective separation and transfer of photogenerated charges originating from the well-matched band gap structures. Of special significance is that (0.5:1)CdS/SnIn4S8 can effectively mineralize 2-nitrophenol and real pharmaceutical wastewater. Moreover, CdS/SnIn4S8 nano-heterojunctions show excellent reusability in five cycles due to the stable surface composition and chemical valence state. PMID- 28711837 TI - Fullerol-facilitated transport of copper ions in water-saturated porous media: Influencing factors and mechanism. AB - The environmental safety of carbon nanomaterials (CNMs) has become a hot spot of worldwide research work. The high stability, mobility and adsorption capability of CNMs may give rise to the enhancement of heavy metal transport. However, the understanding of facilitated transport of heavy metal ions by CNMs is still limited. In this research, fullerol nanoparticles (C60(OH)n) were used as a typical CNM to investigate its effect on Cu2+ transport in the water-saturated porous media. Column experiments showed that C60(OH)n could facilitate the transport of Cu2+. Meanwhile, flow velocity showed little impact on the facilitated transport while pH and fullerol concentration played an important role. The mechanism of fullerol-facilitated transport of Cu2+ was mainly due to the much higher adsorption capacity of C60(OH)n than that of the porous media. Besides, the existence of C60(OH)n decreased the adsorption kinetics of Cu2+ on the porous media, which led to a decreasing chance for Cu2+ to be retained and thus enhanced the transport of Cu2+. PMID- 28711839 TI - Variance reduction technique in a beta radiation beam using an extrapolation chamber. AB - This paper aims to show how the variance reduction technique "Geometry splitting/Russian roulette" improves the statistical error and reduces uncertainties in the determination of the absorbed dose rate in tissue using an extrapolation chamber for beta radiation. The results show that the use of this technique can increase the number of events in the chamber cavity leading to a closer approximation of simulation result with the physical problem. There was a good agreement among the experimental measurements, the certificate of manufacture and the simulation results of the absorbed dose rate values and uncertainties. The absorbed dose rate variation coefficient using the variance reduction technique "Geometry splitting/Russian roulette" was 2.85%. PMID- 28711838 TI - Depressive symptoms and correlates among village doctors in China. AB - BACKGROUND: Village doctors are primary care physicians at the grass root-level of rural medical and health institutions in China. Their depression can increase medical errors and affect quality of medical care services. This study aims to examine depressive symptoms and their correlates among Chinese village doctors. METHODS: A total of 616 village doctors were recruited from Zoucheng County of Shandong province. The Center for Epidemiologic Studies Depression Scale (CES-D), the Duke Social Support Index (DSSI) and the Simplified Coping Style Questionnaire (SCSQ) were used to measure depressive symptoms in the last week, social support and coping styles, respectively. Logistic regression model was conducted to identify the associated factors of depressive symptoms among village doctors. RESULTS: The prevalence rate of depressive symptoms was 27.4% (28.54% for males, 24.69% for females). Logistic regression analysis found that body mass index (BMI), poor physical health, low educational level, and negative coping styles were associated with increased risk of depressive symptoms. Positive coping styles were associated with decreased risk of depressive symptoms in village doctors. CONCLUSIONS: Depressive symptoms are prevalent among village doctors in China. They need to adopt more positive coping strategies to respond to negative emotions. More professional and medical trainings may be important to reduce risk of depressive symptoms and improve their quality of healthcare among village doctors in China. PMID- 28711840 TI - A promising protected ascorbic acid-hydroxyapatite nanocomposite as a skin anti ager: A detailed photo-and thermal stability study. AB - A new ascorbic acid (AA) nanocomposite with low toxicity and high photo and thermal stability is constructed for certain dermatological applications in humans. The presented nanocomposite consists of AA, nano-hydroxyapatite (nHAp) and carboxymethyl cellulose (CMC). The physicochemical properties of such CMC nHAp-AA nanocomposite were characterized using X-Ray diffractometery (XRD), Fourier Transform Infra-Red (FTIR), Energy Dispersive X-ray (EDX) and UV-VIS spectroscopies. The size and morphology of the synthesized nanocomposites were characterized by TEM/SEM techniques. A detailed photo and thermal stability studies were performed to examine the stability of AA in the proposed nanocomposite. The AA content showed great stability against sunlight up to 3h or more and against heat up to 100 degrees C, whereas it showed relatively limited stability against laser light up to 10min depending on the laser type. Cytotoxicity endpoints, evaluating the cell viability and IC50 (50% inhibitory concentration) have been performed for the exposed synthesized nanocomposite. There wasn't any effect on the cell viability up to 50MUg/mL of CMC-nHAp-AA nanocomposite. Based on IC50 values, it has been found that after 24h of observation the IC50 of CMC-nHAp-AA nanocomposite was 0.199MUg/mL which depicts high safety profile of the proposed nanocomposite. The produced nanocomposite (CMC-nHAp-AA) is expected to possess great potential in dermatological applications due to its high stability and increased proliferative capacity which lasts longer than AA alone. PMID- 28711841 TI - Free amino acids in the Arctic snow and ice core samples: Potential markers for paleoclimatic studies. AB - The role of oceanic primary production on climate variability has long been debated. Defining changes in past oceanic primary production can help understanding of the important role that marine algae have in climate variability. In ice core research methanesulfonic acid is the chemical marker commonly used for assessing changes in past primary production. However, other organic compounds such as amino acids, can be produced and emitted into the atmosphere during a phytoplankton bloom. These species can be transported and deposited onto the ice cap in polar regions. Here we investigate the correlation between the concentration of chlorophyll-a, marker of marine primary production, and amino acids present in an ice core. For the first time, free l- and d-amino acids in Arctic snow and firn samples were determined by a sensitive and selective analytical method based on liquid chromatography coupled with tandem mass spectrometry. The new method for the determination of free amino acids concentrations was applied to firn core samples collected on April 2015 from the summit of the Holtedahlfonna glacier, Svalbard (N 79'08.424, E 13'23.639, 1120m a.s.l.). The main results of this work are summarized as follows: (1) glycine, alanine and proline, were detected and quantified in the firn core samples; (2) their concentration profiles, compared with that of the stable isotope delta18O ratio, show a seasonal cycling with the highest concentrations during the spring and summer time; (3) back-trajectories and Greenland Sea chlorophyll-a concentrations obtained by satellite measurements were compared with the amino acids profile obtained from ice core samples, this provided further insights into the present results. This study suggests that the amino acid concentrations in the ice samples collected from the Holtedahlfonna glaciers could reflect changes in oceanic phytoplankton abundance. PMID- 28711843 TI - Ecological and environmental transition across the forested-to-open bog ecotone in a west Siberian peatland. AB - Climate change may cause increasing tree cover in boreal peatlands, and the impacts of this encroachment will be noted first at forested-to-open bog ecotones. We investigate key metrics of ecosystem function in five such ecotones at a peatland complex in Western Siberia. Stratigraphic analysis of three cores from one of these transects shows that the ecotone has been dynamic over time with evidence for recent expansion of forested peatland. We observed that the two alternative states for northern boreal peatlands (forested/open) clearly support distinct plant and microbial communities. These in turn drive and respond to a number of feedback mechanisms. This has led to steep ecological gradients across the ecotones. Tree cover was associated with lower water tables and pH, along with higher bulk density, aquatic carbon concentrations, and electrical conductivity. We propose that the conditions found in the forested peatland of Western Siberia make the carbon sink more vulnerable to warmer and drier conditions. PMID- 28711842 TI - Nitrogen deposition has minor effect on soil extracellular enzyme activities in six Chinese forests. AB - Soil extracellular enzymes play a key role in mediating a range of forest ecosystem functions (i.e., carbon and nutrients cycling and biological productivity), particularly in the face of atmospheric N deposition that has been increasing at an unprecedented rate globally. However, most studies have focused only on surface soils in a single ecosystem. In this study, we aimed to determine whether the effect of simulated N deposition on the activities and ratios of soil enzymes changes with soil depth across six forest ecosystems in eastern China. We collected soil samples from three blocks*four soil depths (0-10cm, 10-20cm, 20 40cm and 40-60cm)*three N treatment levels (control, 50 and 100kgNha-1year-1) at each of the six forest ecosystems. We measured the activities of seven soil enzymes involved in C-, N- and P-cycling. We found that 4-5years of N addition had no significant effect on the activities and ratios of these enzymes in most cases. The interactions among N addition, site and soil depth on soil enzyme activities were not significant, except that acid phosphatase activity showed site-specific responses to N addition. Our findings suggest that the activities of soil enzymes involved in C- and N-cycling generally do not track simulated N deposition in the six forest ecosystems. Further work on plant, soil and microbial characteristics is needed to better understand the mechanisms of soil enzyme activities in response to N deposition in forest ecosystems. PMID- 28711844 TI - Application of kinetic modeling to predict the fate of two indoxacarb metabolites and their bound residues in soil. AB - Insecticide indoxacarb metabolites JT333 and MP819 were used as model compounds to assess the utilization of kinetic modeling to elucidate metabolic pathways, determine degradation kinetics of non-extractable residues (NER) and predict the accumulation potential of the released NER in soil. Soil adsorption coefficients and degradation product formation were determined in different soils in laboratory. Inverse kinetic modeling was applied to explore the dynamics of dissipation of parent (P), formation of extractable metabolites (MET), NER and CO2, and to identify their routes of degradation in soil. These two compounds share similar structural characteristics, have high affinity to soil (Koc>5000L/kg), short half-life (DT50 of 4-9days), and significant CO2 formation in soil. However, kinetic modeling showed that they degraded via different pathways. The P-MET-CO2 conversion route was the major degradation pathway for JT333 in aerobic soil. Multiple pathways were involved in MP819 degradation, while the formation of NER was predominant. The time-exposure area under the curves (AUC) for the MET or NER in soils were derived from the time %concentration plots for the evaluation of rate limiting steps in their degradation pathways. In P-MET-CO2 pathway the MET-CO2 conversion is the rate limiting step for both compounds. Higher P-MET conversion/MET-CO2 conversion rate constant ratio resulted in larger MET AUC. The rate of NER degradation appeared much slower compared to the rates of P-MET and MET-CO2 conversions, likely due to the rate-limiting step of NER release from the bound-state, indicating that in this situation the free-state NER would be unlikely to accumulate in soil. The study reported here demonstrates the utility of kinetic modeling to quantify the dynamics of NER formation/dissipation vs. P-MET-CO2 conversion, and the application of kinetic modeling to predict the possibility of free-sate NER accumulation in soil, therefore, reveals the potential for the quantitative NER environmental risk assessment. PMID- 28711845 TI - The impact of synoptic circulation on air quality and pollution-related human health in the Yangtze River Delta region. AB - PM2.5 and O3 pollution are of concern for the Yangtze River Delta (YRD) region due to their adverse impact on human health. In conjunction with a complex distribution of emission sources, the synoptic circulation conditions control the temporal and spatial variability of air pollution levels and hence the pollution related health burdens. In this study, a long-term synoptic circulation catalogue is developed by applying the automated Lamb weather type method to the ECMWF mean sea level pressure reanalysis for the YRD region during 2013-2016. Ten typical circulation types are examined in relation to the transport pathways and diffusion conditions, and then multi-site surface observations of PM2.5 and O3 are composited for different circulation conditions. The results show that each circulation type is characterized with distinct air mass origin, diffusion condition and air quality level. The anticyclonic type (Type A) corresponds to the highest regional PM2.5 concentration (68.5MUg/m3) due to the subsidence flow and long-range transport, while the westerly types (Types SW, W and NW) correspond to the higher regional maximum daily 8-h running average O3 (MDA8 O3) concentration (>100MUg/m3) due to favorable local meteorological conditions. Regional transport causes an east-high and west-low PM2.5 distribution in westerly types but a west-high and east-low PM2.5 distribution in easterly types (Types SE, E and NE). In contrast, nearly all the types show an east-high and west-low O3 distribution, suggesting the predominated impacts of precursor emissions. By using established exposure-response functions, the health impact assessment (HIA) shows that Type W poses the greatest public health risk with mean daily excess mortality of 77.3 (95% CI: 61.9, 92.6) deaths and O3 pollution accounts for approximately 70% of this health burden. PMID- 28711846 TI - Vascular and cardiac autonomic function and PM2.5 constituents among the elderly: A longitudinal study. AB - BACKGROUND: Although epidemiologic studies have shown an association between the total mass of particulate matter <2.5MUm in aerodynamic diameter (PM2.5) and cardiovascular disease, few studies have examined PM2.5 constituents associated with vascular and cardiac autonomic dysfunction. METHODS: In this longitudinal study, we investigated the relationship between PM2.5 constituents and blood pressure (BP), and markers of the autonomic nervous system. In 466 elderly subjects residing in communities in Seoul, Korea, we examined 16 constituents, seven sources, and total mass concentrations of PM2.5. We measured the BP, heart rate (HR), and indices of heart rate variability (HRV), such as the standard deviation of normal-to-normal intervals (SDNN), square root of the mean squared differences of successive NN intervals (rMSSD), and two frequency-domain variables (low frequency [LF] and high frequency [HF]). We used linear mixed effects models to assess the association of PM2.5 constituents and sources with cardiovascular markers. RESULTS: BP, HR, and rMSSD were associated with concentration of total mass of PM2.5. For each increase of the interquartile range in PM2.5 constituents, systolic and diastolic BP, and HR increased by 2.1 3.3mmHg, 1.2-2.3mmHg, and 1.2-1.9bpm, respectively, while the rMSSD, LF, and HF decreased by 8.1-9.3%, 16.6%, and 20.4%, respectively. Particularly, elemental carbon, sulfate, ammonium, lead, and strontium in the PM2.5 constituents and emissions from oil combustion and incineration were associated with increased BP, HR, and decreased HRV. CONCLUSIONS: Our results suggest an association between specific PM2.5 constituents and vascular and cardiac autonomic functions. These findings may provide supportive evidence for developing a pollution reduction plan to prevent cardiovascular diseases. PMID- 28711847 TI - Vertical patterns and controls of soil nutrients in alpine grassland: Implications for nutrient uptake. AB - Vertical patterns and determinants of soil nutrients are critical to understand nutrient cycling in high-altitude ecosystems; however, they remain poorly understood in the alpine grassland due to lack of systematic field observations. In this study, we examined vertical distributions of soil nutrients and their influencing factors within the upper 1m of soil, using data of 68 soil profiles surveyed in the alpine grassland of the eastern Qinghai-Tibet Plateau. Soil organic carbon (SOC) and total nitrogen (TN) stocks decreased with depth in both alpine meadow (AM) and alpine steppe (AS), but remain constant along the soil profile in alpine swamp meadow (ASM). Total phosphorus, Ca2+, and Mg2+ stocks slightly increased with depth in ASM. K+ stock decreased with depth, while Na+ stock increased slightly with depth among different vegetation types; however, SO42- and Cl- stocks remained relatively uniform throughout different depth intervals in the alpine grassland. Except for SOC and TN, soil nutrient stocks in the top 20cm soils were significantly lower in ASM compared to those in AM and AS. Correlation analyses showed that SOC and TN stocks in the alpine grassland positively correlated with vegetation coverage, soil moisture, clay content, and silt content, while they negatively related to sand content and soil pH. However, base cation stocks revealed contrary relationships with those environmental variables compared to SOC and TN stocks. These correlations varied between vegetation types. In addition, no significant relationship was detected between topographic factors and soil nutrients. Our findings suggest that plant cycling and soil moisture primarily control vertical distributions of soil nutrients (e.g. K) in the alpine grassland and highlight that vegetation types in high altitude permafrost regions significantly affect soil nutrients. PMID- 28711848 TI - Long-term litter manipulation alters soil organic matter turnover in a temperate deciduous forest. AB - Understanding soil organic matter (OM) biogeochemistry at the molecular-level is essential for assessing potential impacts from management practices and climate change on shifts in soil carbon storage. Biomarker analyses and nuclear magnetic resonance (NMR) spectroscopy were used in an ongoing detrital input and removal treatment experiment in a temperate deciduous forest in Pennsylvania, USA, to examine how above- and below-ground plant inputs control soil OM quantity and quality at the molecular-level. From plant material to surface soils, the free acyclic lipids and cutin, suberin, and lignin biomarkers were preferentially retained over free sugars and free cyclic lipids. After 20years of above-ground litter addition (Double Litter) or exclusion (No Litter) treatments, soil OM composition was relatively more degraded, as revealed by solid-state 13C NMR spectroscopy. Under Doubled Litter inputs, soil carbon and phospholipid fatty acid (PLFA) concentrations were unchanged, suggesting that the current OM degradation status is a reflection of microbial-mediated degradation that occurred prior to the 20-year sampling campaign. Soil OM degradation was higher in the No Litter treatments, likely due to the decline in fresh, above-ground litter inputs over time. Furthermore, root and root and litter exclusion treatments (No Roots and No Inputs, respectively) both significantly reduced free sugars and PLFAs and increased preservation of suberin-derived compounds. PLFA stress ratios and the low N-acetyl resonances from diffusion edited 1H NMR also indicate substrate limitations and reduced microbial biomass with these treatments. Overall, we highlight that storage of soil carbon and its biochemical composition do not linearly increase with plant inputs because the microbial processing of soil OM is also likely altered in the studied forest. PMID- 28711849 TI - Fertilizer efficiency in wheat is reduced by ozone pollution. AB - Inefficient use of fertilizers by crops increases the risk of nutrient leaching from agro-ecosystems, resulting in economic loss and environmental contamination. We investigated how ground-level ozone affects the efficiency by which wheat used applied nitrogen (N) fertilizer to produce grain protein (NEP, N efficiency with respect to protein yield) and grain yield (NEY, N efficiency with respect to grain yield) across a large number of open-top chamber field experiments. Our results show significant negative ozone effects on NEP and NEY, both for a larger data set obtained from data mining (21 experiments, 70 treatments), and a subset of data for which stomatal ozone flux estimates were available (7 experiments, 22 treatments). For one experiment, we report new data on N content of different above-ground plant fractions as well as grain K and P content. Our analysis of the combined dataset demonstrates that the grain yield return for a certain investment in N fertilizer is reduced by ozone. Results from the experiment with more detailed data further show that translocation of accumulated N from straw and leaves to grains is significantly and negatively affected by ozone, and that ozone decreases fertilizer efficiency also for K and P. As a result of lower N fertilization efficiency, ozone causes a risk of increased N losses from agroecosystems, e.g. through nitrate leaching and nitrous oxide emissions, a hitherto neglected negative effect of ozone. This impact of ozone on the N cycle implies that society is facing a dilemma where it either (i) accepts increased N pollution and counteracts ozone-induced yield reductions by increasing fertilization or (ii) counteracts N pollution under elevated ozone by reducing fertilization, accepting further yield loss adding to the direct effect of ozone on yield. PMID- 28711850 TI - Urinary phthalate metabolites over the first 15months of life and risk assessment - CHECK cohort study. AB - Phthalates are important group of endocrine disruptors. Infants and young children are susceptible to phthalate exposure. However, information on the phthalate exposure during the early stages of life is very limited. This study was conducted to understand the temporal trend of exposure to major phthalates among infants of Korea during the first 15months after birth, and to estimate associated risks. A total of 286 urine samples were collected from 171 children at 3, 9, 12, or 15months of age, with 77 children sampled for two or more times. Four phthalates, i.e., di(2-ethylhexyl) phthalate (DEHP), di-isobutyl phthalate (DiBP), di-n-butyl phthalate (DnBP), and diethyl phthalate (DEP) were chosen, and their major metabolites were analyzed in the urine. The DEHP metabolites were detected in 100% of the urine samples at relatively higher levels compared to those reported in other countries. The levels of mono-ethyl phthalate (MEP) were generally lower. Urinary concentrations of most phthalate metabolites, especially DEHP metabolites, increased as children grew older. Intra-class correlation coefficients (ICCs) calculated for DEHP metabolites over time were high (0.7 0.8), suggesting persistence of consistent exposure sources during this sensitive period of life. Hazard quotient (HQ) and hazard index (HI) were calculated from daily intake estimates divided by recommended toxicity thresholds. Among the study population, 4, 16, and 26% of the children showed HI >1 at 9, 12, and 15months of age, respectively. DEHP exposure explained most of the risk estimates. Considering vulnerability of young children to endocrine disruption, efforts to identify sources of exposure and to develop appropriate mitigation options are warranted. PMID- 28711851 TI - The use of gamma-survey measurements to better understand radon potential in urban areas. AB - Accounting for as much as 14% of all lung cancers worldwide, cumulative radon progeny exposure is the leading cause of lung cancer among never-smokers both internationally and in the United States. To understand the risk of radon progeny exposure, studies have mapped radon potential using aircraft-based measurements of gamma emissions. However, these efforts are hampered in urban areas where the built environment obstructs aerial data collection. To address part of this limitation, this study aimed to evaluate the effectiveness of using in situ gamma readings (taken with a scintillation probe attached to a ratemeter) to assess radon potential in an urban environment: DeKalb County, part of the Atlanta metropolitan area, Georgia, USA. After taking gamma measurements at 402 survey sites, empirical Bayesian kriging was used to create a continuous surface of predicted gamma readings for the county. We paired these predicted gamma readings with indoor radon concentration data from 1351 residential locations. Statistical tests showed the interpolated gamma values were significantly but weakly positively related with indoor radon concentrations, though this relationship is decreasingly informative at finer geographic scales. Geology, gamma readings, and indoor radon were interrelated, with granitic gneiss generally having the highest gamma readings and highest radon concentrations and ultramafic rock having the lowest of each. Our findings indicate the highest geogenic radon potential may exists in the relatively undeveloped southeastern part of the county. It is possible that in situ gamma, in concert with other variables, could offer an alternative to aerial radioactivity measurements when determining radon potential, though future work will be needed to address this project's limitations. PMID- 28711852 TI - Gauging policy-driven large-scale vegetation restoration programmes under a changing environment: Their effectiveness and socio-economic relationships. AB - Large-scale ecological restoration has been widely accepted globally as an effective strategy for combating environmental crises and to facilitate sustainability. Assessing the effectiveness of ecological restoration is vital for researchers, practitioners, and policy-makers. However, few practical tools are available to perform such tasks, particularly for large-scale restoration programmes in complex socio-ecological systems. By taking a "before and after" design, this paper formulates a composite index (Ej) based on comparing the trends of vegetation cover and vegetation productivity to assess ecological restoration effectiveness. The index reveals the dynamic and spatially heterogenic process of vegetation restoration across different time periods, which can be informative for ecological restoration management at regional scales. Effectiveness together with its relationship to socio-economic factors is explored via structural equation modeling for three time periods. The results indicate that the temporal scale is a crucial factor in representing restoration effectiveness, and that the effects of socio-economic factors can also vary with time providing insight for improving restoration effectiveness. A dual-track strategy, which promotes the development of tertiary industry in absorbing the rural labor force together with improvements in agricultural practices, is proposed as a promising strategy for enhancing restoration effectiveness. In this process, timely and long-term ecological restoration monitoring is advocated, so that the success and sustainability of such programmes is ensured, together with more informative decision making where socio-ecological interactions at differing temporal scales are key concerns. PMID- 28711853 TI - Utilization of communities of practice for ongoing learning and knowledge dissemination: Making the case for the Global Alliance for Nursing and Midwifery (GANM). AB - With the growing connectivity among countries and healthcare practitioners, nurses and midwives in low resource settings are connecting digitally to access information through online platforms. Ninety eight percent of adults online report visiting a social network in the past month, and spend almost two hours per day engaged with social media. In an increasingly interconnected world, innovative strategies are needed to translate knowledge into practice. The Global Alliance for Nursing and Midwifery (GANM), part of the Pan American Health Organization (PAHO)/World Health Organization (WHO) Collaborating Center (CC) at the Johns Hopkins University School of Nursing (JHSON) leverages its Knowledge Gateway to facilitate translating knowledge into practice in order to achieve the Sustainable Development Goals (SDGs). This paper explores the concepts of knowledge dissemination, communities of practice, and makes the case for further using the GANM as an exemplary model to build the capacity of nurses and midwives globally. PMID- 28711854 TI - Exploration of the possible effect on survival of lead-time associated with implementation of cancer patient pathways among symptomatic first-time cancer patients in Denmark. AB - BACKGROUND: Implementation of standardised cancer patient pathways (CPPs) has provided faster diagnosis of cancer. Cancer survival has improved during the same time period. Concern has been raised that the faster diagnosis may have introduced lead-time bias by elongating the period from diagnosis to death. AIM: We aimed to analyse the possible effect of lead time on survival due to expedited cancer diagnosis after the implementation of national CPPs among incident cancer patients diagnosed through Danish primary care. MATERIAL AND METHODS: We used actual observed differences in diagnostic intervals to estimate the lead-time effect. We used data from sub-cohorts from the Danish Cancer in Primary Care (CaP) cohort of first-time cancer patients: before and after CPP implementation. To calculate differences in absolute survival, we estimated the survival function after advancing the date of diagnosis in the before cohort to an earlier point in time and hereby adjusting for lead time for nine cancer types and all combined by using Kaplan-Meier analysis. RESULTS: Advancing the date of diagnosis implied that the absolute one-year survival increased from 68.5% to 69.4%. This accounted for 13% of the observed differences in absolute one-year survival from before to after CPPs. CONCLUSION: The lead time caused by shorter diagnostic intervals after implementation of Cancer Patient Pathways seems to explain less than 15% of the observed changes in the one-year survival estimates for cancer patients in Denmark. PMID- 28711856 TI - RNAseq-based transcriptome comparison of Saccharomyces cerevisiae strains isolated from diverse fermentative environments. AB - Transcriptome analyses play a central role in unraveling the complexity of gene expression regulation in Saccharomyces cerevisiae. This species, one of the most important microorganisms for humans given its industrial applications, shows an astonishing degree of genetic and phenotypic variability among different strains adapted to specific environments. In order to gain novel insights into the Saccharomyces cerevisiae biology of strains adapted to different fermentative environments, we analyzed the whole transcriptome of three strains isolated from wine, flor wine or mezcal fermentations. An RNA-seq transcriptome comparison of the different yeasts in the samples obtained during synthetic must fermentation highlighted the differences observed in the genes that encode mannoproteins, and in those involved in aroma, sugar transport, glycerol and alcohol metabolism, which are important under alcoholic fermentation conditions. These differences were also observed in the physiology of the strains after mannoprotein and aroma determinations. This study offers an essential foundation for understanding how gene expression variations contribute to the fermentation differences of the strains adapted to unequal fermentative environments. Such knowledge is crucial to make improvements in fermentation processes and to define targets for the genetic improvement or selection of wine yeasts. PMID- 28711855 TI - Exploiting and engineering hemoproteins for abiological carbene and nitrene transfer reactions. AB - The surge in reports of heme-dependent proteins as catalysts for abiotic, synthetically valuable carbene and nitrene transfer reactions dramatically illustrates the evolvability of the protein world and our nascent ability to exploit that for new enzyme chemistry. We highlight the latest additions to the hemoprotein-catalyzed reaction repertoire (including carbene Si-H and C-H insertions, Doyle-Kirmse reactions, aldehyde olefinations, azide-to-aldehyde conversions, and intermolecular nitrene C-H insertion) and show how different hemoprotein scaffolds offer varied reactivity and selectivity. Preparative-scale syntheses of pharmaceutically relevant compounds accomplished with these new catalysts are beginning to demonstrate their biotechnological relevance. Insights into the determinants of enzyme lifetime and product yield are providing generalizable cues for engineering heme-dependent proteins to further broaden the scope and utility of these non-natural activities. PMID- 28711857 TI - Methotrexate-F127 conjugated mesoporous zinc hydroxyapatite as an efficient drug delivery system for overcoming chemotherapy resistance in osteosarcoma cells. AB - The resistance of cancer cells to chemotherapeutic agents and the poor selectivity of drugs toward tumor cells are regarded as the main impediments in successful cancer therapy. Currently, the design and fabrication of stimulus responsive drug delivery systems with high specificity toward cancer cells are gaining increasing attention and they show a promising potential for clinical applications. In this study, mesoporous zinc-substituted hydroxyapatite has been synthesized and served as a drug delivery vehicle owing to its biocompatibility and high drug loading capacity. The mesoporous nanoparticles were decorated with F127 and subsequently conjugated with methotrexate (MTX) through a stable amide linkage. Since folate receptors are overexpressed on many tumor cell surfaces, MTX on the nanocarrier system plays a dual role as a targeting molecule and a chemotherapeutic drug. The evaluation of the drug release profile revealed that MTX was cleaved from the nanoparticles by a certain type of enzyme under low pH conditions that are meant to simulate the intracellular conditions in the lysosome. Cell viability studies on primary osteosarcoma cells (Saos-2) and MTX resistance cell lines (RSaos-2/MTX) revealed that the drug-loaded nanoparticles possess high antitumor efficacy on both of the cell lines relative to free MTX. It was also found that the inhibition of P-glycoproteins by F127 and the release of Zn2+ ions from the nanoparticles in an acidic environment effectively potentiate the antitumor efficacy of the drug-loaded nanoparticles, leading to caspase-mediated cell death. Based on these data, MTX-F127@ZnHAP nanoparticles are pH-responsive nanocarriers with precise controlled drug release and targeting effect. Therefore, they are considered to be promising candidates capable of overcoming resistance in osteosarcoma cells. PMID- 28711858 TI - Size distribution of extracellular vesicles by optical correlation techniques. AB - Understanding the colloidal properties of extracellular vesicles (EVs) is key to advance fundamental knowledge in this field and to develop effective EV-based diagnostics, therapeutics and devices. Determination of size distribution and of colloidal stability of purified EVs resuspended in buffered media is a complex and challenging issue - because of the wide range of EV diameters (from 30 to 2000nm), concentrations of interest and membrane properties, and the possible presence of co-isolated contaminants with similar size and densities, such as protein aggregates and fat globules - which is still waiting to be fully addressed. We report here a fully detailed protocol for accurate and robust determination of the size distribution and stability of EV samples which leverages a dedicated combination of Fluorescence Correlation Spectroscopy (FCS) and Dynamic Light Scattering (DLS). The theoretical background, critical experimental steps and data analysis procedures are thoroughly presented and finally illustrated through the representative case study of EV formulations obtained from culture media of B16 melanoma cells, a murine tumor cell line used as a model for human skin cancers. PMID- 28711859 TI - Associations between multiple green space measures and birth weight across two US cities. AB - INTRODUCTION: Several measures of green space exposure have been used in epidemiological research, but their relevance to health, and representation of exposure pathways, remains unclear. Here we examine the relationships between multiple urban green space metrics and associations with term birth weight across two diverse US cities. METHODS: We used Vital Statistics data to create a birth cohort from 2005 to 2009 in the cities of Portland, Oregon (n = 90,265) and Austin, Texas (n = 88,807). These cities have similar green space levels but very different population and contextual characteristics. Green space metrics derived from mother's full residential address using multiple buffer distances (50-1000m) included: Landsat Normalized Difference Vegetation Index (NDVI), % tree cover, % green space, % street tree buffering, and access to parks (using US EPA EnviroAtlas Data). Correlation between green space metrics were assessed and mixed models were used to determine associations with term birth weight, controlling for a comprehensive set of individual and neighborhood factors. City specific models were run to determine how contextual and population differences affected green space associations with birth weight. RESULTS: We observed moderate to high degrees of correlation between different green space metrics (except park access), with similar patterns between cities. Unadjusted associations demonstrated consistent protective effects of NDVI, % green space, % tree cover, and % street tree buffering for most buffer sizes on birth weight; however, in fully adjusted models most metrics were no longer statistically significant and no clear patterns remained. For example, in Austin the difference in birth weight for the highest versus lowest quartile of % green space within 50m was 38.3g (95% CI: 30.4, 46.1) in unadjusted and -1.5g (98% CI: -8.8, 6.3) in adjusted models compared to 55.7g (95%CI: 47.9, -63.6) and 12.9g (95% CI: 4.4, 21.4) in Portland. Maternal race, ethnicity and education had the largest impact on reducing green space and birth weight associations. However, consistent positive associations were observed for the high density areas of both cities using several green space metrics at small buffer distances. CONCLUSIONS: This study highlights the importance of understanding the individual and contextual factors that may confound and/or modify green space and birth weight associations. PMID- 28711860 TI - Management of septic myocardial dysfunction in intensive care unit: A survey of French speaking intensivists. PMID- 28711861 TI - Healthcare infrastructure capacity to respond to severe acute respiratory infection (SARI) and sepsis in Vietnam: A low-middle income country. AB - PURPOSE: This study investigated the availability of relevant structural and human resources needed for the clinical management of patients with severe acute respiratory infections and sepsis in critical care units in Vietnam. MATERIAL AND METHODS: A questionnaire survey was conducted by purposive sampling of 128 hospitals (36% of total hospitals in surveyed provinces), including 25 provincial and 103 district level hospitals, from 20 provinces in Vietnam. Data on availability of hospital characteristics, structural resources and health care workers was then analyzed. RESULTS: Most hospitals (>80%) reported having 60% of the relevant structural resources. Significant differences were observed between provincial hospitals when compared to district hospitals in regards to availability of central oxygen piping system (78.3% vs 38.7%, p=0.001) mechanical ventilation (100.0% vs 73.6%, p=0.003), mobile x-rays (80.0% vs 29.8%, p<0.001), carbapenem antibiotic (73.9% vs 17.4%, p<0.001) and norepinephrine (95.8% vs 56.3%, p<0.001). There was a limited availability of arterial blood gas analyzers (13.7%), oseltamivir (42.2%) and N95 respirators (54.6%) across all hospitals surveyed. CONCLUSIONS: The limited availability of relevant structural and human resources in critical care units around Vietnam makes the implementation of quality critical care to patients with SARI and sepsis, according international guidelines, not universally possible. PMID- 28711862 TI - Is acute kidney injury really a detrimental factor of myocardial injury after noncardiac surgery in critical patients? PMID- 28711863 TI - Drivers' social-work relationships as antecedents of unsafe driving: A social network perspective. AB - In order to reduce road accidents rates, studies around the globe have attempted to shed light on the antecedents for unsafe road behaviors. The aim of the current research is to contribute to this literature by offering a new organizational antecedent of driver's unsafe behavior: The driver's relationships with his or her peers, as reflected in three types of social networks: negative relationships network, friendship networks and advice networks (safety consulting). We hypothesized that a driver's position in negative relationship networks, friendship networks, and advice networks will predict unsafe driving. Additionally, we hypothesized the existence of mutual influences among the driver's positions in these various networks, and suggested that the driver's positions interact to predict unsafe driving behaviors. The research included 83 professional drivers from four different organizations. Driving behavior data were gathered via the IVDR (In-Vehicle Data Recorder) system, installed in every truck to measure and record the driver's behavior. The findings indicated that the drivers' position in the team networks predicts safe driving behavior: Centrality in negative relationship networks is positively related to unsafe driving, and centrality in friendship networks is negatively related to unsafe driving, while centrality in advice networks is not related to unsafe driving. Furthermore, we found an interaction effect between negative network centrality and centrality in friendship networks. The relation between negative networks and unsafe behavior is weaker when high levels of friendship network centrality exist. The implications will be presented in the Discussion section. PMID- 28711864 TI - High-Intensity Statin Therapy Is Associated With Improved Survival in Patients With Peripheral Artery Disease. AB - BACKGROUND: The relative benefit of higher statin dosing in patients with peripheral artery disease has not been reported previously. We compared the effectiveness of low- or moderate-intensity (LMI) versus high-intensity (HI) statin dose on clinical outcomes in patients with peripheral artery disease. METHODS AND RESULTS: We reviewed patients with symptomatic peripheral artery disease who underwent peripheral angiography and/or endovascular intervention from 2006 to 2013 who were not taking other lipid-lowering medications. HI statin use was defined as atorvastatin 40-80 mg or rosuvastatin 20-40 mg. Baseline demographics, procedural data, and outcomes were retrospectively analyzed. Among 909 patients, 629 (69%) were prescribed statins, and 124 (13.6%) were treated with HI statin therapy. Mean low-density lipoprotein level was similar in patients on LMI versus HI (80+/-30 versus 87+/-44 mg/dL, P=0.14). Demographics including age (68+/-12 versus 67+/-10 years, P=0.25), smoking history (76% versus 80%, P=0.42), diabetes mellitus (54% versus 48%, P=0.17), and hypertension (88% versus 89%, P=0.78) were similar between groups (LMI versus HI). There was a higher prevalence of coronary artery disease (56% versus 75%, P=0.0001) among patients on HI statin (versus LMI). After propensity weighting, HI statin therapy was associated with improved survival (hazard ratio for mortality: 0.52; 95% confidence interval, 0.33-0.81; P=0.004) and decreased major adverse cardiovascular events (hazard ratio: 0.58; 95% confidence interval 0.37-0.92, P=0.02). CONCLUSIONS: In patients with peripheral artery disease who were referred for peripheral angiography or endovascular intervention, HI statin therapy was associated with improved survival and fewer major adverse cardiovascular events compared with LMI statin therapy. PMID- 28711867 TI - Happy 5th Birthday Biology Open. PMID- 28711865 TI - Enhanced Mitochondrial Transient Receptor Potential Channel, Canonical Type 3 Mediated Calcium Handling in the Vasculature From Hypertensive Rats. AB - BACKGROUND: Mitochondrial Ca2+ homeostasis is fundamental to the regulation of mitochondrial reactive oxygen species (ROS) generation and adenosine triphosphate production. Recently, transient receptor potential channel, canonical type 3 (TRPC3), has been shown to localize to the mitochondria and to play a role in maintaining mitochondrial calcium homeostasis. Inhibition of TRPC3 attenuates vascular calcium influx in spontaneously hypertensive rats (SHRs). However, it remains elusive whether mitochondrial TRPC3 participates in hypertension by increasing mitochondrial calcium handling and ROS production. METHODS AND RESULTS: In this study we demonstrated increased TRPC3 expression in purified mitochondria in the vasculature from SHRs, which facilitates enhanced mitochondrial calcium uptake and ROS generation compared with Wistar-Kyoto rats. Furthermore, inhibition of TRPC3 by its specific inhibitor, Pyr3, significantly decreased the vascular mitochondrial ROS production and H2O2 synthesis and increased adenosine triphosphate content. Administration of telmisartan can improve these abnormalities. This beneficial effect was associated with improvement of the mitochondrial respiratory function through recovering the activity of pyruvate dehydrogenase in the vasculature of SHRs. In vivo, chronic administration of telmisartan suppressed TRPC3-mediated excessive mitochondrial ROS generation and vasoconstriction in the vasculature of SHRs. More importantly, TRPC3 knockout mice exhibited significantly ameliorated hypertension through reduction of angiotensin II-induced mitochondrial ROS generation. CONCLUSIONS: Together, we give experimental evidence for a potential mechanism by which enhanced TRPC3 activity at the cytoplasmic and mitochondrial levels contributes to redox signaling and calcium dysregulation in the vasculature from SHRs. Angiotensin II or telmisartan can regulate [Ca2+]mito, ROS production, and mitochondrial energy metabolism through targeting TRPC3. PMID- 28711866 TI - Identification of apoB-100 Peptide-Specific CD8+ T Cells in Atherosclerosis. AB - BACKGROUND: T cells are found in atherosclerotic plaques, with evidence supporting a potential role for CD8+ T cells in atherogenesis. Prior studies provide evidence of low-density lipoprotein and apoB-100 reactive T cells, yet specific epitopes relevant to the disease remain to be defined. The current study was undertaken to identify and characterize endogenous, antigen-specific CD8+ T cells in atherosclerosis. METHODS AND RESULTS: A peptide fragment of apoB-100 that tested positive for binding to the mouse MHC-I allele H2Kb was used to generate a fluorescent-labeled H2Kb pentamer and tested in apoE-/- mice. H2Kb pentamer(+)CD8+ T cells were higher in apoE-/- mice fed an atherogenic diet compared with those fed a normal chow. H2Kb pentamer (+)CD8+ T cells in atherogenic diet-fed mice had significantly increased effector memory phenotype with a shift in Vbeta profile. H2Kb pentamer blocked lytic activity of CD8+ T cells from atherogenic diet-fed mice. Immunization of age-matched apoE-/- mice with the apoB-100 peptide altered the immune-dominant epitope of CD8+ T cells and reduced atherosclerosis. CONCLUSIONS: Our study provides evidence of a self reactive, antigen-specific CD8+ T-cell population in apoE-/- mice. Immune modulation using the peptide antigen reduced atherosclerosis in apoE-/- mice. PMID- 28711868 TI - Human TTBK1, TTBK2 and MARK1 kinase toxicity in Drosophila melanogaster is exacerbated by co-expression of human Tau. AB - Tau protein is involved in numerous human neurodegenerative diseases, and Tau hyper-phosphorylation has been linked to Tau aggregation and toxicity. Previous studies have addressed toxicity and phospho-biology of human Tau (hTau) in Drosophila melanogaster However, hTau transgenes have most often been randomly inserted in the genome, thus making it difficult to compare between different hTau isoforms and phospho-mutants. In addition, many studies have expressed hTau also in mitotic cells, causing non-physiological toxic effects. Here, we overcome these confounds by integrating UAS-hTau isoform transgenes into specific genomic loci, and express hTau post-mitotically in the Drosophila nervous system. Lifespan and locomotor analyses show that all six of the hTau isoforms elicit similar toxicity in flies, although hTau2N3R showed somewhat elevated toxicity. To determine if Tau phosphorylation is responsible for toxicity, we analyzed the effects of co-expressing hTau isoforms together with Tau-kinases, focusing on TTBK1, TTBK2 and MARK1. We observed toxicity when expressing each of the three kinases alone, or in combination. Kinase toxicity was enhanced by hTau co expression, with strongest co-toxicity for TTBK1. Mutagenesis and phosphorylation analysis indicates that hTau-MARK1 combinatorial toxicity may be due to direct phosphorylation of hTau, while hTau-TTBK1/2 combinatorial toxicity may result from independent toxicity mechanisms. PMID- 28711869 TI - Establishment of a retinal hypoxia organ culture model. AB - Hypoxia plays an important role in several retinal diseases, especially in central retinal artery occlusion (CRAO). Although CRAO has been known for over a hundred years, no cure or sufficient treatment is available. Potential therapies are being evaluated in several in vivo models or primary cultures. However, in vivo models or primary cultures are very time-consuming, expensive, and furthermore several therapies or agents cannot be tested. Therefore, we aimed to develop a standardized organotypic ex vivo retinal hypoxia model. A chamber was developed in which rat retinal explants were incubated for different hypoxia durations. Afterwards, the retinas were adjusted to normal air and incubated for 24, 48 or 72 h under standard conditions. To analyze the retinal explants, and in particular the retinal ganglion cells (RGC) immunohistology, western blot and optical coherence tomography (OCT) measurements were performed. To compare our model to a standardized degeneration model, additional retinal explants were treated with 0.5 and 1 mM glutamate. Depending on hypoxia duration and incubation time, the amount of RGCs decreased and accordingly, the amount of TUNEL-positive RGCs increased. Furthermore, beta-III-tubulin expression and retinal thickness significantly decreased with longer-lasting hypoxia. The reduction of RGCs induced by 75 min of hypoxia was comparable to the one of 1 mM glutamate treatment after 24 h (20.27% versus 19.69%) and 48 h (13.41% versus 14.41%) of incubation. We successfully established a cheap, standardized, easy-to-use organotypic culture model for retinal hypoxia. We selected 75 min of hypoxia for further studies, as approximately 50% of the RGC died compared to the control group after 48 h. PMID- 28711870 TI - Symmetrical retrograde actin flow in the actin fusion structure is involved in osteoclast fusion. AB - The aim of this study was to elucidate the role of the zipper-like structure (ZLS), a podosome-related structure that transiently appears at the cell contact zone, in osteoclast fusion. Live-cell imaging of osteoclasts derived from RAW264.7 cells transfected with EGFP-actin revealed consistent symmetrical retrograde actin flow in the ZLS, but not in the podosome cluster, the podosome ring or the podosome belt. Confocal imaging showed that the distributions of F actin, vinculin, paxillin and zyxin in the ZLS were different from those in the podosome belt. Thick actin filament bundles running outside the ZLS appeared to recruit non-muscle myosin IIA. The F-actin-rich domain of the ZLS contained actin related protein 2/3 complex (Arp2/3). Inhibition of Arp2/3 activity disorganized the ZLS, disrupted actin flow, deteriorated cell-cell adhesion and inhibited osteoclast hypermultinucleation. In contrast, ML-7, an inhibitor of myosin light chain kinase, had little effect on the structure of ZLS and promoted osteoclast hypermultinucleation. These results reveal a link between actin flow in the ZLS and osteoclast fusion. Osteoclast fusion was promoted by branched actin elongation and negatively regulated by actomyosin contraction. PMID- 28711878 TI - Fat Mass Lowers the Response to Tumor Necrosis Factor-alpha Blockers in Patients with Ankylosing Spondylitis. AB - OBJECTIVE: Our main objective was to assess the relationship between body composition (BC) and response to tumor necrosis factor-alpha (TNF-alpha) blocker treatment in patients with ankylosing spondylitis (AS). Our secondary objective was to evaluate the change of BC after treatment, accounting for sex and age. METHODS: All included patients fulfilled the modified New York criteria for AS and were naive to TNF-alpha blocker. They were followed for at least 6 months after the start of etanercept or adalimumab. The Ankylosing Spondylitis Disease Activity Score containing C-reactive protein (ASDAS-CRP) and the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) were reported. BC was assessed by whole body dual-energy X-ray absorptiometry. Body fat percentage (BF%), fat mass index (FMI), and fat free mass index (FFMI) were reported as absolute values and as percentiles. RESULTS: Forty-one patients were included (61% men). The median followup was 14.3 months (interquartile range 8.4-19.4). After multivariate regression analysis, more fat at baseline (BF%, FMI, or FMI percentile) was significantly related with a lower chance of achieving a clinically important improvement of the ASDAS-CRP or BASDAI after treatment. The body composition did not change significantly after treatment, but there was a trend toward muscle recovery in men (FFMI change from 34.0th to 37.4th percentile). CONCLUSION: Higher body fat content at baseline was independently associated with a worse response to treatment with TNF-alpha blockers, measured by ASDAS-CRP and BASDAI change, and might contribute to the lower response rates in female patients. Also, there is a trend toward muscle mass recovery in male patients after treatment. PMID- 28711880 TI - The Relationship Between Synovial Pathobiology and Magnetic Resonance Imaging Abnormalities in Rheumatoid Arthritis: A Systematic Review. AB - OBJECTIVE: Magnetic resonance imaging (MRI) has been increasingly recognized as a critical tool for the assessment of patients with rheumatoid arthritis (RA) and is able to reliably identify synovitis, bone marrow edema, bone erosion, and joint space narrowing (JSN)/cartilage loss. Understanding the exact relationship between each MRI feature and local synovial pathobiology is critical to dissect disease pathogenesis as well as develop future predictive models. METHODS: A systematic review was performed of the current published literature examining the relationship between MRI abnormalities and synovial pathobiology in patients with RA. RESULTS: Eighteen studies were identified; most focused on validation of MRI as a tool to detect and quantify synovitis, with a significant relationship demonstrated. Additionally, from the limited data available, a critical role seems likely for synovial pathways, at least in driving joint damage. However, there was a lack of data examining the relationship between synovial pathobiology and bone marrow abnormalities and JSN. CONCLUSION: Although understanding the interrelationship of these disease biomarkers offers the potential to enhance the predictive validity of modern imaging with concomitant synovial pathobiological analysis, further studies integrating MRI with synovial tissue analysis in well controlled cohorts at distinct disease stages before and after therapeutic intervention are required to achieve this. PMID- 28711879 TI - The Prevalence, Incidence, and Progression of Hand Osteoarthritis in Relation to Body Mass Index, Smoking, and Alcohol Consumption. AB - OBJECTIVE: To estimate the extent that overweight/obesity, smoking, and alcohol are associated with prevalence and longitudinal changes of radiographic hand osteoarthritis (OA). METHODS: Participants from the Osteoarthritis Initiative (n = 1232) were included, of whom 994 had 4-year followup data. In analyses on incident hand OA, only persons without hand OA at baseline were included (n = 406). Our exposure variables were overweight/obesity [body mass index (BMI), waist circumference], smoking (current/former, smoking pack-yrs), and alcohol consumption (drinks/week). Using linear and logistic regression analyses, we analyzed possible associations between baseline exposure variables and radiographic hand OA severity, erosive hand OA, incidence of hand OA, and radiographic changes. Analyses were adjusted for age, sex, and education. RESULTS: Neither overweight nor obesity were associated with hand OA. Current smoking was associated with less hand OA in cross-sectional analyses, whereas longitudinal analyses suggested higher odds of incident hand OA in current smokers (OR 2.20, 95% CI 1.02-4.77). Moderate alcohol consumption was associated with higher Kellgren-Lawrence sum score at baseline (1-3 drinks: 1.55, 95% CI 0.43-2.67) and increasing sum score during 4-year followup (4-7 drinks: 0.33, 95% CI 0.01-0.64). Moderate alcohol consumption (1-7 drinks/week) was associated with 2-fold higher odds of erosive hand OA, which was statistically significant. Additional adjustment for BMI gave similar strengths of associations. CONCLUSION: Overweight/obesity were not associated with hand OA. Contrasting results were observed for smoking and hand OA, suggesting lack of association. Moderate alcohol consumption was associated with hand OA severity, radiographic changes, and erosive hand OA, warranting further investigation. PMID- 28711881 TI - Clinical Utility of YKL-40 in Polymyositis/dermatomyositis-associated Interstitial Lung Disease. AB - OBJECTIVE: Interstitial lung disease (ILD) is involved in polymyositis/dermatomyositis (PM/DM), a disease associated with poor prognoses. Chitinase-3-like-1 protein (YKL-40) has pleiotropic biological activities involved in inflammation, cell proliferation, and tissue remodeling; however, the clinical application of YKL-40 remains limited. We investigated the clinical significance of YKL-40 in PM/DM-ILD. METHODS: Sixty-nine consecutive patients with PM/DM-ILD and 34 healthy controls were analyzed. We measured baseline and followup serum YKL-40 using an ELISA, evaluated the association of YKL-40 with clinical variables and survival, and examined YKL-40 expression in lung specimens from patients with PM/DM-ILD using immunohistochemistry. RESULTS: Serum YKL-40 levels were significantly greater in patients with PM/DM-ILD compared with healthy controls (p < 0.0001). Serum YKL-40 was correlated with arterial oxygen pressure (r = -0.40, p < 0.001) and percent-predicted DLCO (r = -0.41, p = 0.01) in patients with PM/DM-ILD. Multivariate Cox hazard analysis demonstrated that higher serum YKL-40 and lower percent-predicted forced vital capacity were independently associated with a poor prognosis. Immunohistochemistry analysis demonstrated that YKL-40 expression was enhanced in aggregated intraalveolar macrophages and hyperproliferative alveolar epithelial cells in patients with PM/DM-ILD. CONCLUSION: YKL-40 is a promising biomarker for evaluating PM/DM-ILD activity/severity and predicting disease prognosis. Insights into YKL-40 might help elucidate the pathogenesis of PM/DM-ILD. PMID- 28711882 TI - HLA-DRB1 Alleles as Genetic Risk Factors for the Development of Anti-MDA5 Antibodies in Patients with Dermatomyositis. AB - OBJECTIVE: Patients with polymyositis/dermatomyositis (PM/DM) who express anti melanoma differentiation associated protein 5 (anti-MDA5) antibodies frequently present with interstitial lung disease (ILD). The aim of this study was to investigate the association of HLA-DRB1 with anti-MDA5 expression in PM/DM. METHODS: The frequency of DRB1 alleles was compared among 70 patients with PM, 104 patients with DM, and 400 healthy controls in a Han Chinese population. RESULTS: Frequencies of DRB1*04:01 [17.0% vs 1.3%, corrected p value (pc) = 3.8 * 10-8, OR 16.2, 95% CI 6.6-39.7] and *12:02 (42.6% vs 19.3%, pc = 0.008, OR 3.1, 95% CI 1.7-5.7) were significantly higher in anti-MDA5-positive patients with PM/DM compared with the controls. The frequencies of DRB1*04:01 (p = 5.2 * 10-6, OR 17.1, 95% CI 5.3-54.9) and *12:02 (p = 3.8 * 10-4, OR 3.1, 95% CI 1.7-5.7) in anti-MDA5-positive patients with DM-ILD were higher than in the controls, whereas the frequencies of DRB1*04:01 and *12:02 did not differ between the anti-MDA5 negative patients with DM-ILD and controls. No difference in the frequency of DRB1 alleles, other than *04:01, carrying the "shared epitope" (SE), i.e., *01:01, *01:02, *04:05, and *10:01, was observed between the controls and patients with DM stratified by the presence of anti-MDA5 and ILD. CONCLUSION: DRB1*04:01 and *12:02 confer susceptibility to anti-MDA5 antibody production in DM, which cannot be explained by the SE hypothesis. PMID- 28711883 TI - Medical evaluation of efficiency of optimized models for early detection and primary prevention of cardiovascular diseases. AB - INTRODUCTION: Nowadays cardiovascular disease occupies a leading place in the structure of the prevalence, incidence, disability causes and mortality of the adult population in Ukraine and in the whole world. The prevalence of hypertension in the adult population ranges from 25 - 40%, coronary heart disease is almost 20% of people aged 50-59 years while 24.3% of them have a form of silent coronary artery disease. The feasibility of study is justified by the need to perform health institutions Law of Ukraine dated 07.07.2011 year No3611-VI ?On Amendments to the Basic Laws of Ukraine on health care on improvement of care" and MoH of Ukraine from 24.07.2013 No 621/60 "On the system of cardiac care in health facilities of Ukraine" therefore extremely important is to develop an optimized model of early detection and primary prevention of cardiovascular diseases at primary level of health care. The aim of the research is to develop methods and evaluation models optimized for early detection and primary prevention of cardiovascular diseases at a general practitioner of family medicine. MATERIAL AND METHODS: The methodical apparatus is of complex of medical and social research methods that meet the requirements of public health: bibliosemantyc, systematic approach and analysis, statistical, expert evaluations. To determine the effectiveness of medical evaluation was conducted in its 33 clinics of general practice in Poltava region, including 7 urban and 26 rural. In expert opinion is taken 825 patients, of which 175 urban and 650 in rural areas. The results of the study found that 193 patients (23.4%) achieved target blood pressure through the implementation of the recommendations concerning the optimization behavior towards of risk factors, lifestyle. PMID- 28711884 TI - [Comperative characteristics of different organizational approaches to the provision of dental care in Ukraine and Slovakia]. AB - INTRODUCTION: Saving dental health is a priority, which is controlled by the European strategy for the World Health Organization to achieve ?Health for All?. THE AIM: To study and compare organizational approaches to the organization of dental care in Ukraine and Slovakia. MATERIALS AND METHODS: In the course of the work we used statistical, bibliosemantic methods and the method of structural and logical analysis, the data of the statistical branch reporting of Ukraine, Slovakia and the data of the European database ?Health for All? were used. CONCLUSIONS: It is established that the provision of the population with educational institutions for future dentists in Ukraine is one university for 2154566 people, and in Slovakia - one for 676 764 people. Obviously, access to dental education in the Slovak Republic is better than in Ukraine. In the course of the study, we found that the level of provision of dentists for 10 thousand people in Ukraine is 4.56, and in Slovakia-5.75, which is 26% more than in Ukraine. In Slovakia, the level of availability of dentists is 5.75, too, with a reliable difference in the profile of administrative territories Conclusion. Both countries are working to achieve international goals to ensure dental health for the period till 2025. Therefore, the exchange of good experience, which gained in Ukraine and Slovakia for the organization of dental care will improve the performance of dental services of both countries to achieve these goals. PMID- 28711885 TI - [Factors associated with job satisfaction of human resources in healthcare]. AB - INTRODUCTION: Healthcare employee satisfaction is an important criterion for the efficiency of human resource management and prognostic impact factor for high turnover of staff. Furthermore, job satisfaction positively affects patient satisfaction, which is an important indicator for quality of care. AIM: The goal of our study was to identify factors associated with job satisfaction in healthcare organizations in Ukraine. MATERIALS AND METHODS: We conducted sociological and psychological survey of 190 healthcare professionals (81% response rate) in Kherson City Hospital. Job satisfaction and organizational climate was assessed through developed questionnaire, "Test Motype" method of Gerchikov (motivational profile designing) and "Diagnosis Syndrome emotional burnout" method of Boyko. Spearman rank correlation was used for analysis. RESULTS: Job satisfaction positively correlated with personnel age and time record, career prospects, professional development, superior-subordinate, peer-to peer and patient communications (p<0,01 for all), teamwork environment, among executives with achievement and affiliation motivations (r<0,001, accordingly). It negatively correlated with reward-oriented and lumpen-style motivational profile (r<0,001 and <0,01, accordingly). Job satisfaction did not correlate with responsibility of executives, factors for satisfaction of job description, working conditions and range of wages (all p> 0.05). CONCLUSIONS: Based on findings we developed dual job satisfaction-dissatisfaction approach specific for healthcare employee in Ukraine. This model includes internal factors such as work experience, career prospects, professional motivation; external factors such as leadership, governance, work environment, customer satisfaction and preventive factors such as staff role, job description, company policies, salary and benefits. PMID- 28711886 TI - Contribution of mortality from cardiovascular disease to overall mortality. AB - INTRODUCTION: The most significant chronic non-infectious diseases (CVD) are cardiovascular diseases (CVD), oncological, chronic respiratory diseases, diabetes, which together account for 59% of 57 million deaths each year in the world and constitute 46% of the global burden of the disease. AIM: To study the contribution of cardiovascular diseases to the overall mortality of the population of the Poltava region. MATERIALS AND METHODS: For the study, the mortality data of the population of Ukraine and the Poltava region for 2005-2015 were used. Sources of data on the natural movement of the population were forms of state statistical reporting and official data on calculations for primary data of statistical offices. The calculation of intensive death rates by the method of direct standardization according to the world standard (Standard "World"), approved by WHO [19] was carried out. For the analysis of time trends, the JoinPoint software, the Regression Program Statistical Methodology and Applications Branch, the Surveillance Research Program (Electronic Resourse) / National Cancer Institute, was used to analyze population-based piece-wise time trends, as well as the MS EXCEL 2010 office suite. RESULTS: It was shown the increase in the overall mortality of the population of the Poltava region and Ukraine as a whole. In the structure of the causes of death, the first place is occupied by diseases of the cardiovascular system, and in the structure of the Diseases of the blood supply systems, the greatest part is occupied by ischemic heart disease. An increase in mortality and mortality from acute myocardial infarction was noted. CONCLUSIONS: The contribution of diseases of the cardiovascular system plays a leading role among all causes of mortality in the Poltava region and in Ukraine as a whole. There is an increase in overall mortality and in particular from acute myocardial infarction. A significant difference between mortality rates, both general and from myocardial infarction, in Ukraine and the Poltava region was not revealed (p> 0.05). PMID- 28711887 TI - Advertising of medical devices: foreign experience and Ukrainian practice. AB - INTRODUCTION: Chosen European foreign policy vector for Ukraine establishes its obligation to enforce the process of adaptation of the EU law regulations in the internal legal policy. The approximation of Ukrainian law to the European Union (EU) "acquis communautaire" is not only the instrument for deepening our economic cooperation with the European Union, but also the important measure to enhance further development of Ukraine in general. National legislation, which regulate advertising and promotion of medical devices (MD), is not an exception. Some key points on legal regulation of abovementioned sphere is a base of this study. MATERIALS AND METHODS: Ukrainian legislation, European Union's Law Acts, EU's member-states law, WHO Acts and Recommendations, European Medical Technology Industry Association (EUCOMED) Acts. Article is based on dialectical, comparative, analytic, synthetic and comprehensive research methods. DISCUSSION: In accordance with Ukrainian legislation, there is no special law that concerns advertising on MD in Ukraine, this sphere is regulated by general law that named ?About advertisement?, but it doesn't take into account even main characteristics of such a special object as medical devices (MD). Moreover, the law ?About advertisement? contain discrepancies in terms that are used, these contradictions, in our opinion, must be eliminated by appropriate law reforms. CONCLUSION: The advertising and promotion of MD in EU is regulated by a combination of EU and national legislation of EU Member States, national advertising and promotion of MD are not harmonized with the EU MDD for now, resulting in a fragmented legal landscape that differs from one EU Member State to the other. Practice of adopting different codes and guides that regulate advertising, including advertising of MD, is widespread in EU and EU Member States and thus must be used in Ukraine with appropriate reformation of national law. PMID- 28711888 TI - [Comparative analysis of dynamics of health status indexes among school age children of Ukraine in modern conditions]. AB - INTRODUCTION: In the last time, there is a negative dynamics of indicators of the health of the child population in Ukraine in connection with socio-economic problems. AIM: The analysis of the data of the incidence and the prevalence of diseases among the children of the Poltava region in comparison with those of Ukraine for the period 2011-2015. MATERIALS AND METHODS: In our work are used data of State statistics of incidence and prevalence of diseases among the child population of Ukraine. RESULTS: Analysis of the health status of children in the Poltava region and the country as a whole shows that due last 5 years there has been a destabilization of children's health - the incidence and prevalence of diseases, despite the positive trend, remain high. CONCLUSIONS: In the Poltava region for the period of 2011-2015 years there is a steady natural declining of the population (especially among rural residents), which is due to a decreasing in the birth rate and the increase in mortality. The incidence among children in rural areas of the Poltava region is 1000.8 per 1,000 children, which is lower than the average regional rate (1200.4) and significantly lower than the incidence of children in urban areas (1304.7). PMID- 28711889 TI - [Peculiarities of primary health care organization for patients suffering from chronic obstructive pulmonary disease jointly with coronary heart disease]. AB - INTRODUCTION: Combination of chronic obstructive pulmonary disease (COPD) and coronary heart disease (CHD) leads to some difficulties for diagnostics and for prescription of complex differential treatment as well as increasings risk of complications from the illness and drug's side effects. AIM: To develope peculiarities of Primary Health Care (PHC) organisation for patients suffering from COPD jointly with CHD; and to improve the patients surveillance for optimization of early diagnosis of named join pathology and well-timed prescription of appropriate health-promoting treatment. MATERIALS AND METHODS: The COPD and CHD morbidity in Chernivtsi region and prevalence of CHD in 955 hospital cases were analyzed. Health survey of 241 patients of age more than 40 years was conducted according to Questionnaire for COPD primary monitoring on an outpatient basis. RESULTS: The decreasing of COPD detection (-15%) and decreasing of CHD morbidity (-7,7%) were observed in 2015. Primary disablement due to pulmonary diseases across the employable population increased on 28,8%. Analyses of smoking prevalence across the man older 40 years show that 97 (40,2%) of persons are smokers. Risk of COPD symptoms appearance in man older 40 was in more than 6 times bigger for smokers in comparison with non-smoking persons. CHD happens reliably more often (72,5%) in patients suffering from COPD of age 49-50 who smoke comparatively to non-smoking patients (48,7). CONCLUSIONS: An obligatory COPD primary monitoring in population risk groups and well-timed CHD diagnosis are main peculiarities of PHC organization for patients suffering from COPD jointly with CHD on primary health care level. Improvement of the surveillance for patients suffering from COPD jointly with CHD is also important on all population's health care levels. PMID- 28711890 TI - The preexposure prophylaxis of stomatological diseases among the population of ukraine in the practice of the family doctor and the pediatrician. AB - INTRODUCTION: The dental health is one of the direct measures indicators of the population's health, integrated indicator of the nation's health, its invigoration and preservation are the most important medical, social and economic problems. The aim to investigate the position and the role of a family doctor and a pediatrician in the preexposure prophylaxis orthodontic pathology among the population of Ukraine. MATERIALS AND METHODS: The book-semantic analysis of the scientific literature; the content analysis - research of the regulatory and legal framework; the system analysis - analysis of the system of doctors' carrying preexposure prophylaxis of the stomatological diseases. CONCLUSIONS: The health system reforming will allow approaching the preexposure medical aid to the population, providing its quality, a doctor's responsibility for his patients. One of the direction of a pediatrician's and a family doctor's work will be the prevention and early diagnosis of the orthodontic pathology, the advocacy promotion of the health alimentation and the healthy lifestyle for adults and children, saving the dental health in general. PMID- 28711891 TI - [Strategic patient safety action plan for the anesthesiology and intensive care service of Ukraine: basic modules and their components]. AB - INTRODUCTION: In recent years, the problem of patient safety has become top priority in further improvement of national healthcare systems in all developed countries. AIM: To develop a modular structure and a component composition of the strategic patient safety action plan for the anesthesiology and intensive care service of Ukraine as a part of the National Action Plan. MATERIALS AND METHODS: Major domestic priorities, substantiated and made public by the author in previous works, are taken as the basis for the modular structuring of the action plan. Existing foreign prototypes, evaluated for the patient safety effectiveness and the potential for the adaptation to domestic conditions, as well as author's own innovations are offered for a component filling-up of each module. RESULTS: Eight modules - infectious safety, surgical safety, pharmaceutical safety, infrastructural safety, incident monitoring and reporting, education and training, research and awards - have been proposed. Individual components for each of the modules are selected from a variety of foreign prototypes and author's own developments. Inter-modular stratification of the components into short-term perspective tools and long-term perspective tools, depending on the amount of resources needed for their implementation, is carried out. CONCLUSION: The strategic patient safety action plan for the anesthesiology and intensive care service of Ukraine is the embodiment, within a particular specialty, of the wider National Action Plan developed by the First National Congress on Patient Safety (Kiev, 2012) on the initiative of the Council of Europe and aimed at the fulfillment of international obligations of Ukraine in the healthcare sector. Its implementation will contribute to enhancing the safety of anesthesia and intensive care services in Ukraine and further development of the specialty. PMID- 28711892 TI - 3-D bioprinting law regulation perspectives. AB - INTRODUCTION: Achieved level of technical progress moves us closer and closer to practical use of 3-d bioprinting technologies in real life. Such perspective raise a wide variety of crucial legal issues from the acceptable model of regulation of the science and its' societal effects to problems of the commercialization of the technology and potential restrictions of its use. Some key points on concept of legal regulation of abovementioned sphere is a base of this study. MATERIAL AND METHODS: Scientific discussion on 3-D bioprinting, European Union's and US experience in patenting of 3-D bioprinting technologies, European Medicine Agency (EMA) or the US Food and Drug Administration (FDA) regulations, European Medical Technology Industry Association (EUCOMED) Acts. Article is based on dialectical, comparative, analytic, synthetic and comprehensive research methods. DISCUSSION: General debate of last few years comes down to an attempt to resolve hesitation between legal attempts for regulation of 3-D biobrinting and concept of complete prohibition of such activities. An adequate response to the mentioned challenge is a reasonable position between some aspects of prohibition and self-regulation, resulting in a moderate number of regulations and standards for developing and marketing. Such regulations may concern an intellectual property (IP) rights, regulation of distribution, premarket restrictions, control mechanism etc. CONCLUSION: Scientific approach and regulatory settlement of 3-D bioprinting sphere must unite to achieve a fair balance between the interests of humanity and of individuals - on the one hand, and development of science and business benefits for stakeholders - on the other. The main instruments for this must be balanced regulation of intellectual property (IP) rights, regulation of access and distribution, premarket restrictions, control mechanism etc. PMID- 28711893 TI - [Incidence of adverse medical events in the neonatal intensive care unit with the help of a global trigger tool]. AB - INTRODUCTION: Identification and monitoring of the frequency of adverse medical events are important in the organization of the patient's safety system in the intensive care units (ICU). The consistent and accurate identification of adverse events remains a problem for most medical institutions, even in developed countries of the world. AIM: To determine the frequency of adverse medical events in the NICU by using Global and Pediatric Trigger Instruments. MATERIALS AND METHODS: To achieve the goal, the cross-sectional study was conducted in which in retrospect analyzed 160 newborn development records which were treated in the ICU of the newborn in the perinatal center of the M.V. Sklifosovsky Poltava Regional Clinical Hospital in 2016 to identify in them certain neonatal triggers. RESULTS: In 21.3% of newborns, after detecting the triggers of the "Care" module, the hospital infection was confirmed, which we regarded as medical adverse event. The trigger "Infiltration / extravasation" of the same module was detected in 1.9% medical records. Triggers "Glucose less than 3.0 mmol / L after 48 hours from birth", "Increase in creatinine" and trigger "deviation of electrolytes" of the module "Laboratory" were accordingly found in 21.9%, 6.3% and 11.3% medical records of newborns. CONCLUSION: Trigger tool is an effective way to identify adverse events that cause to patient harm. Our results can form the basis for the development of a national neonatal trigger instrument that will effectively monitor the frequency of such events in the ICU of newborn. PMID- 28711894 TI - [Markers of dental children's health in the application of therapeutic orthodontic equipment]. AB - INTRODUCTION: Treatment of teeth anomalies using removable and non-removable orthodontic devices in children leads to complications such as caries, gingivitis, periodontitis, oral mucosa hyperplasia. Etiopathogenetical of these diseases can be associated with biochemical changes in the composition of saliva. AIM: To determine the activity of lysozyme and amylase in oral fluid in children when using a fixed and removable orthodontic devices. MATERIALS AND METHODS: Amylase and lysozyme were studied in oral fluid. Analyzed the biochemical composition of the freshly samples of oral fluid that was obtained in the control, experimental group 1 and 2 (children ages 7-18 years, which were used medical non-removable and removable orthodontic devices). Saliva was collected at the beginning of the therapeutic use of orthodontic devices (the first day of treatment), on 3 and 6 months of treatment. Assessment of lysozyme activity was carried nephelometric method on the ability of lysozyme to dissolve indicator organism Micrococcus lysodeicticus. To construct a calibration graph using dry lysozyme company Sigma. Salivary amylase activity was determined by hydrolysis of starch. The results were subjected to statistical analysis by standard methods. Data processed using software packages applied statistical analysis Statistica 6.0, Microsoft Excel, 2003. RESULTS: The use of a fixed and removable orthodontic equipment led to a decrease in saliva amylase, major changes are observed on the 6th month of treatment. The activity of lysozyme in saliva decreased the mostin patients with a permanent equipment. Major changes were also recorded on the 6th month of treatment. CONCLUSIONS: Complications of orthodontic treatment teeth anomalies in children (caries, gingivitis, periodontitis) caused by changes in the biochemical composition of saliva. For the prevention of the emergence and development of these complications is necessary to control the level of amylase and lysozyme in the mouth. PMID- 28711895 TI - [The dynamics of the incidence of intraventricular hemorrhages and their outcomes among prematurely born children of the poltava region in 2007-2016]. AB - INTRODUCTION: Over the past decade, with the increase in the number of prematurely born babies with very-low-body-weight (VLBW) at birth, the number of intraventricular hemorrhages (IVH), including severe, increases, which leads to an increase in mortality and an increase in the number of posthemorrhagic hydrocephalus (PHH). AIM: To establish epidemiological trends in the IVH frequency, as well as their outcomes (PHH, mortality), among prematurely born children of the Poltava region during 2007-2016. MATERIALS AND METHODS: Information base of the research is formed from materials of statistical reporting of health indicators of newborns for 2007-2016. The morbidity and mortality rates in prematurely born children with severe IVH (grade III-IV) and the incidence of PHH were studied. RESULTS: For 2007-2014 the average frequency of the IVH among children with VLBW was 7.0%, and among children with extremely low-body-weight (ELBW) - 19.3%. There are stable high, with a tendency to increase, indices of the incidence of IVH among children with VLBW (from 5.4% in 2008 to 14.1% in 2014) and among children with ELBW (from 7.8% in 2008 to 45.2% in 2015). The average fatality rate among children with VLBW was 46.0%, and among children with ELBW - 63.2%. There is an increase in the mortality rate among children with ELBW and stable indicators among children with VLBW at birth. The incidence of PHH is 32.8% (20 of 61). This indicator remained stable throughout the study period. CONCLUSIONS: During the 2007-2016 biennium, in the Poltava region there is an increase in the incidence of IVH among prematurely born children, stable values of the mortality rate among children with VLBW and its increase among children with ELBW at birth. PMID- 28711896 TI - Computer-tomographic characteristics of root length incisors and canines of the upper and lower jaws in boys and girls with different craniotypes and physiological bite. AB - INTRODUCTION: In recent years, in world literature appeared research, which focuses on the study of relationships craniotypes with odonto-metric indicators, size, shape of the dental arches and occlusion. However, most of the experts focus on the study of individual features of the structure of the teeth-jaw system in people with different types of faces and aspects of sexual dimorphism and ethnic characteristics. Studies containing information about cranio typological variability of the roots of teeth we did not encounter. The aim is to reveal features length of roots of incisors and canines of the upper and lower jaw, according to the CT scan in boys and girls of different craniotypes with physiological bite, residents Podilskiy region of Ukraine. MATERIAL AND METHODS: The study involved young men with orthognathic bite and their cephalometric performance taken from database from Scientific and Research Center Vinnitsa National Medical University named after Pirogov. To make CT used dental cone beam CT scan - Veraviewepocs 3D, Morita. In the upper and lower incisors and canines were measured vestibular-oral and mesio-distal projection length of the root. The height (length) of the root was measured in the medial (or distal) norm, focusing on border basics crowns (root) and the apex of the tooth root. Established the following distribution craniotype: mesocephalic boys - 16, boys brachycephalic - 19, mesocephalic girls - 16, brachycephalic girls- 26. Statistical analysis of the results was performed using the statistical software package licensed "Statistica 6,0" using non-parametric estimation methods. RESULTS: The peculiarities computed tomographic characteristics of root length incisors and canines of the upper and lower jaws in boys and girls Podilskiy region of Ukraine with different craniotypes and physiological bite have been set. In boys or girls mesocephals majority values of vestibular-oral and mesio-distal projection length of the teeth root, medial and lateral incisors in the upper and lower jaws significantly higher compared to studied similar gender brachycephals. Most values vestibular-oral and mesiodistal projection length of the teeth root, medial and lateral incisors in the upper and lower jaws in boys of total group and brachycephals significantly higher compared with girls of similar comparison groups. In boys mesocephals only value of vestibular-oral projection length of teeth root on the lower jaw was significantly higher compared with girls of the same craniotype. CONCLUSIONS: In mesocephalic boys or girls majority values of vestibular-oral and mesio-distal length projection of the root teeth, medial and lateral incisors on the upper and lower jaws significantly higher compared to similar brachycephalic genders studied. PMID- 28711897 TI - Studying risk factors for skin cancer development. AB - INTRODUCTION: In most countries with a population of mainly European origin, non melanoma skin carcinoma incidence rate has increased over the last decade. Understanding of what is the best way to identify people at high risk for skin cancer development will help to optimize the strategy for prevention and treatment tactics. Aim of the research involves studying risk factors for skin cancer development in patients with cutaneous squamous cell carcinoma and squamous cell carcinoma in situ (cSCC and SCCis correspondingly) and patients with actinic keratosis (AK). MATERIALS AND METHODS: we conducted a survey of patients with cSCC, SCCis and AK who had been under case follow-up at the State Scientific Institution "Scientific and Practical Centre of Preventive and Clinical Medicine" of the State Administration (hereinafter SIS) during 2014 2016.Clinical diagnosis in 100% of cases was confirmed by pathomorphological study. Statistical processing of the obtained data was performed using STATISTICA 7.0 programme. RESULTS: The questionnaire involved 129 patients, including 21(16.3%) patient with cSCC, 40 (31%) patients with SCCis, 57 (44.2%) patients with AK and 11 (8.5%) patients who had mentioned above combined pathology i.e. cSCC, SCCis and AK at the same time. Only two studied risk factors for skin cancer development were found to have influence on the skin pathology: "Not using sun-protection preparation for the skin" and "Burdened family history of thefirst level of relationship". CONCLUSIONS: In forming the risk groups for skin cancer development it is advisable to consider burdened family history and using sun protection preparation for the skin. PMID- 28711898 TI - Professional burnout syndrome in doctors of surgical specialties in Ukraine: causes, consequences, labor optimization ways. AB - INTRODUCTION: The professional burnout syndrome (PBS) affects quality of medical care provision for people, which is acquires the special actuality in terms of reforming the health care system. AIM: To study ways to improve the efficiency of doctors of surgical specialties based on analyzes of PBS and its consequences. MATERIALS AND METHODS: A survey of psychological tests and 62 surgical doctors was carried out. RESULTS: It was found out that the PBS reaches a peak after 11 to 15 years of working experience. Anesthesiologists have high levels of PBS, emotional exhaustion, cynicism, low desire for career growth, frequent misunderstanding with the administration, they prefer 8-hour working day, and relieve stress by sleeping and consuming alcohol. Obstetrician-gynecologists show moderate level of PBS and emotional exhaustion, high degree of cynicism, strong desire for career growth, frequent misunderstandings with patients and their relatives, prefer 8-hour working day, relieve stress by smoking and socializing with family and friends. Traumatic surgeons have moderate level of PBS, emotional exhaustion, high degree of cynicism, strong desire for career growth, frequent misunderstandings with their colleagues of related specialties, prefer the 24 hour working day, and reli eve their stress with alcohol and sports. Surgeons have moderate level of PBS, emotional exhaustion, low degree of cynicism, moderate desire for career growth, frequent misunderstandings with their colleagues of related specialties, prefer the 8-hour working day, and relieve stress by smoking and sleeping. CONCLUSIONS: PBS is most expressed in doctors having working experience of 11 to 15 years and in anesthesiologists. They get professional deformations. These features should be considered in course of organization of working process of medical teams. PMID- 28711899 TI - Intrauterine infections - challenges in the perinatal period (literature review). AB - : The purpose of the study is to summarize the literature data on the state of intrauterine infections that cause antenatal fetal abnormalities. MATERIALS AND METHODS: This article presents the assessment of 25 world literature sources from 2000 to 2016, which discuss the etiology of infectious agents acting on the fetus and causing a variety of pathological conditions. RESULTS: During gestation many researchers refer to the infection as one of the causes of antenatal fetal abnormalities. The etiology of intrauterine infection is diverse and differs between countries with different economic conditions. Detection of an infectious agent makes it possible to promptly carry out preventive measures, to improve hygiene standards in order to reduce the rate of infection transmission from mother to fetus. CONCLUSION: Timely detection of the etiology of intrauterine infections promotes the identification of high-risk groups giving a possibility to provide treatment in order to prevent the transmission of an infectious agent having direct economic benefits, especially in resource-poor countries with low and middle income. PMID- 28711900 TI - [Personal-oriented approach as a pedagogical condition for preparing future doctors to apply health saving tecynologies]. AB - The article considers one of the weighty socially significant results of the future doctors training, namely, his readiness to use health saving technologies, the means of implementation of which should be the appropriate pedagogical conditions on the basis of a person-oriented approach. A detailed analysis of literary sources on the definition of the main provisions of the personality oriented approach is carried out, the term of ?readiness? of future specialists for professional activity is defined. The importance of the personality-oriented approach in shaping the personal qualities of future doctors is revealed. The term of ?health saving? and ?health saving technologies? are considered in the pedagogical aspect. The personal and professional culture of the future doctor is characterized as an important factor in the readiness of future specialists for professional work. PMID- 28711901 TI - Secondary focal form of yersinia enterocolitica infection with prolonged polyarthritis in young caucasian male: a case report. AB - Current issue deals with an interesting clinical case of a rare infectious disease in a Caucasian young male patient, caused by Yersinia enterocolitica. Infection proceeded in the development of secondary focal form, which was accompanied by prolonged polyarthritis. We described a clinical case of secondary focal form with prolonged polyarthritis caused by Y. enterocolitica O:3 serogroup in young patient with the purpose of focusing on the early clinical and laboratory diagnosistics of Yersiniosis that would minimize the role of medical errors in diagnostics made by general practitioners. This case deserves the attention of internal medicine specialists, physicians of the specialty ?general practitioners?, rheumatologists, infectious disease specialists taking into consideration the clinics and immunopathogenesis, as well as a high evidence of a prolonged clinical course and chronicity of this disease. It has accented on the feasibility of early serological diagnostics and etiotropic antibiotic therapy of the disease. PMID- 28711948 TI - Peroxisome Proliferator-Activated Receptor-gamma Coactivator-1alpha (PGC-1alpha) Regulates the Expression of B-Cell Lymphoma/Leukemia-2 (Bcl-2) and Promotes the Survival of Mesenchymal Stem Cells (MSCs) via PGC-1alpha/ERRalpha Interaction in the Absence of Serum, Hypoxia, and High Glucose Conditions. AB - BACKGROUND To study the effect of estrogen-related receptor alpha (ERRalpha) and peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) on mesenchymal stem cells (MSCs) apoptosis, and further investigated its detailed molecular mechanisms in the absence of serum, hypoxia, and high glucose conditions. MATERIAL AND METHODS In our study, we first evaluated the expression rates of CD14, CD34, CD45, CD44, CD29, and Sca-1 surface markers on MSCs by flow cytometry. Then, the ability of osteogenic and fatty differentiation of MSCs was determined by osteogenic differentiation and adipogenesis reagent kit. Next, Annexin V-APC/7-AAD apoptosis kit was used for detecting the apoptosis rate of MSCs. RT-PCR and Western blotting were used for detection of mRNA expression and proteins expression, respectively. RESULTS Our data showed that the MSCs used in our study were capable of self-renewal and differentiating into many cell lineages, such as osteogenic differentiation and adipogenesis. Our results further showed that over-expression of PGC-1alpha could protect MSCs from apoptosis induced by rotenone. We also found that PGC-1alpha over-expression could enhance the expression of anti-apoptotic gene Bcl-2, and inhibit the expression of pro-apoptotic gene Bax in MSCs. In addition, our data demonstrated that PGC-1alpha could induce upregulation of Bcl-2 and further promote the survival of MSCs by interacting with ERRalpha. CONCLUSIONS In the absence of serum, hypoxia and high glucose conditions, PGC-1alpha can regulate the expression of Bcl-2 and promote the survival of MSCs via PGC-1alpha/ERRalpha interaction. PMID- 28711949 TI - Pediatric out-of-hospital cardiopulmonary resuscitation by helicopter emergency medical service, does it has added value compared to regular emergency medical service? AB - PURPOSE: To determine the outcome of out-of-hospital (OOH) cardiopulmonary resuscitation (CPR) and the advanced life support (ALS) procedures provided in pediatrics by the Rotterdam Helicopter Emergency Medical Service (HEMS) METHODS: Retrospective evaluation of all pediatric (0-17 years) OOH cardiopulmonary arrests within a 6-year period and attended by the Rotterdam HEMS team. RESULTS: There were 201 OOH CPRs from October 2008 until October 2014. Endotracheal intubation was performed in 164 cases and done by HEMS in 104 patients (63%), intraosseous/intravenous cannulation 43/27 times, and additional medication given by HEMS in 70 patients (35%). The overall survival rate for OOH CPR was 15%, but in trauma was low. Twenty-seven of the 29 pediatric patients who survived until discharge are neurological well. Although the Dutch nationwide ambulance protocol states intubation, intravenous, or intraosseal excess and medication, in many patients, only HEMS provided additional ALS care. CONCLUSION: The HEMS brings essential medical expertise in the field not provided by regular emergency medical service. HEMS provide a significant quantity of procedures, obviously needed by the OOH CPR of a pediatric patient. PMID- 28711950 TI - Mathematical Models of Electrical Activity in Plants. AB - Electrical activity plays an important role in plant life; in particular, electrical responses can participate in the reception of the action of stressors (local electrical responses and oscillations) and signal transduction into unstimulated parts of the plant (action potential, variation potential and system potential). Understanding the mechanisms of electrical responses and subsequent changes in physiological processes and the prediction of plant responses to stressors requires the elaboration of mathematical models of electrical activity in plant organisms. Our review describes approaches to the simulation of plant electrogenesis and summarizes current models of electrical activity in these organisms. It is shown that there are numerous models of the generation of electrical responses, which are based on various descriptions (from modifications of the classical Hodgkin-Huxley model to detailed models, which consider ion transporters, regulatory processes, buffers, etc.). A moderate number of works simulate the propagation of electrical signals using equivalent electrical circuits, systems of excitable elements with local electrical coupling and descriptions of chemical signal propagation. The transmission of signals from a plasma membrane to intracellular compartments (endoplasmic reticulum, vacuole) during the generation of electrical responses is much less modelled. Finally, only a few works simulate plant physiological changes that are connected with electrical responses or investigate the inverse problem: reconstruction of the type and parameters of stimuli through the analysis of electrical responses. In the conclusion of the review, we discuss future perspectives on the simulation of electrical activity in plants. PMID- 28711951 TI - Optimizing patellar positioning during total knee arthroplasty: an anatomical and clinical study. AB - INTRODUCTION: Optimal positioning of the patellar component is crucial for the success of a total knee arthroplasty (TKA). Usually, the patellar component is placed empirically over the presumed centre of the patellar cut. Medialization of the prosthetic patella has been recommended; however, no evidence-based guidelines have been reported. MATERIAL AND METHOD: This anatomical study aims to quantify a pre-defined optimal location for positioning of the patellar component with regard to the centre of the patellar cut. Intra-operative measurements of the patellar cut of a series of 129 TKA were conducted in order to measure the distance between the optimal centre of prosthetic patella (OCPP) and the centre of the patellar cut, and that over the vertical (proximal-distal) axis and the horizontal axis (medial-lateral). RESULTS: Our results demonstrated that, (a) a significant morphological difference of the patellar cut exists between men and women (P < 0.0001), and (b) with reference to centre of the patellar cut, the OCPP lies superiorly and medially in 89%, inferiorly and medially in 9.4%, laterally and superiorly in 1.6%, and in no case laterally and inferiorly. No anterior pain, dislocation episode or patellar revision has been encountered during a follow-up of 4.5 years. CONCLUSIONS: The placement of the patellar component during TKA differs from one patella to another. Thus, by defining the OCPP on a patient-by-patient basis, the surgeon should be able to reproduce the functional anatomy of the native patella. PMID- 28711952 TI - Polymorphic variants of antioxidative defense enzymes and their gene-gene epistatic interactions in systemic lupus erythematode patients. AB - Systemic lupus erythematosus (SLE) is a chronic autoimmune disease in which pathogenesis oxidative stress has an important role. Single nucleotide polymorphisms (SNPs) in the genes that code enzymes involved in the antioxidative defense are possible factors that are responsible for their decreased activity of antioxidative defense enzymes. Thus, the aim of the study was to examine association of SNPs in these genes with SLE. A total of176 subjects were involved in this study. CAT A-21T (rs7943316), CAT C-262T (rs1001139) and manganese SOD (MnSOD) Ala16Val (rs4880) SNPs were determined using PCR-RFLP method, while GSTT1 and GSTM1 were determined using multiplex PCR. The obtained results showed significant differences in the distribution of genotypes (df = 2; p = 0.001) and alleles (p < 0.001; OR = 2.227; 95% CI = 1.429-3.741) of rs4880 between patients and controls. MnSODValVal genotype showed association with neurologic manifestations (p = 0.016; OR = 6.7; 95% CI = 1.18-37.89), while homozygous GSTT1 showed association with musculoskeletal manifestations of SLE (p = 0.008; OR = 4.168; 95% CI = 1.364-12.737). AlaVal/T+M+ genotype combination is a high-risk genotype for SLE. SNP-SNP interaction model showed positive correlation between CAT A-21T and CAT C-262T SNPs in SLE patients which was not influenced by the linkage disequilibrium (r 2 = 0.005; D' = 0.071). MnSODVal allele is a risk factor for SLE, as well as for SLE with neurologic manifestations, while homozygous GSTT1 genotype is a risk factor for SLE with musculoskeletal manifestations. Catalase SNPs (C-262T and A-21T) show positive correlation in the model of SNP-SNP interaction. PMID- 28711953 TI - Attachment, Mothering and Mental Illness: Mother-Infant Therapy in an Institutional Context. AB - This paper is an ethnographic exploration of how attachment theory underpins therapeutic practices in an Australian institutional context where mothers of infants have been diagnosed and are undergoing treatment for mental illness. We argue that attachment theory in this particular context rests on a series of principles or assumptions: that attachment theory is universally applicable; that attachment is dyadic and gendered; that there is an attachment template formed which can be transferred across generations and shapes future social interactions; that there is understood to be a mental health risk to the infant when attachment is characterised as problematic; and that this risk can be mitigated through the therapeutic practices advocated by the institution. Through an in-depth case study, this paper demonstrates how these assumptions cohere in practice and are used to assess mothering as deficient, to choose therapeutic options, to shape women's behaviour, and to formulate decisions about child placement. PMID- 28711954 TI - Imaging in children with unilateral ureteropelvic junction obstruction: time to reduce investigations? AB - : The objective of the study was the development of an abridged risk-stratified imaging algorithm for the management of children with unilateral ureteropelvic junction obstruction (UPJO). Data on timing, frequency and duration of diagnostic imaging in children with unilateral UPJO was extracted retrospectively. Based on these findings, an abridged imaging algorithm was developed without changing the intended management by the clinicians and the outcome of the individual patient. The potential reduction of imaging studies was analysed and stratified by risk and management groups. The reduction in imaging studies, seen for ultrasound (US) and functional imaging (FI), was 45% each. On average, this is equivalent to 3 US and 1 FI studies less for every patient within the study period. The change was more pronounced in the low-risk groups. Progression of UPJO never occurred after 2 years of age and all secondary surgeries were carried out until the age of 3. CONCLUSIONS: Although our findings need to be validated by further prospective research, the developed imaging algorithm represents a risk-stratified approach towards less imaging studies in children with unilateral UPJO, and a follow-up beyond 3 years of age should be considered only in selected cases at the discretion of the clinician. What is Known: * ultrasound and functional imaging represent an integral part of therapeutic decision-making in children with unilateral ureteropelvic junction obstruction * imaging studies cannot accurately assess which patients are in need of surgical intervention, therefore close, serial imaging is preferred What is New: * a new, risk-stratified imaging algorithm was developed for the first 3 years of life * applying this algorithm could lead to a considerable reduction of imaging studies, and also the associated risks and health-care costs. PMID- 28711955 TI - The effect of early feeding practices on growth indices and obesity at preschool children from four European countries and UK schoolchildren and adolescents. AB - : Not only healthy growth but also childhood obesity partly originate from early life. The current work aimed to examine the association of feeding practices during infancy with growth and adiposity indices in preschool children from four European countries and in UK schoolchildren and adolescents. Existing data from four European birth cohorts (ALSPAC-UK, EDEN-France, EuroPrevall-Greece and Generation XXI-Portugal) were used. Anthropometrics and body composition indices were collected. Parallel multivariate regression analyses were performed to examine the research hypothesis. Overall, the analyses showed that breastfeeding and timing of complementary feeding were not consistently associated with height z-score, overweight/obesity, and body fat mass in children or adolescents. However, breastfeeding duration for less than 6 months was associated with lower height z-scores in 5-year-old French children (P < 0.001) but with higher height z-scores in 4-year-old UK children (P = 0.006). Furthermore, introduction of complementary foods earlier than 4 months of age was positively associated with fat mass levels in 5-year-old French children (P = 0.026). CONCLUSION: Early feeding practices, i.e., any breastfeeding duration and age of introduction of complementary foods, do not appear to be consistently associated with height z score, overweight/obesity, and body fat mass in preschool children from four European countries and in UK schoolchildren and adolescents. What is known? * Healthy growth and childhood obesity partly originate from early life. What is new? * Breastfeeding duration less than 6 months was associated with lower height z-scores in 5-year-old French children, while the opposite was observed in 4-year old British children. * Introduction of complementary foods earlier than 4 months was positively associated with fat mass levels in 5-year-old French children, but not in the other three countries. * Early feeding practices did not appear to be consistently associated with growth and adiposity indices, and as such, no clear influence can be observed. PMID- 28711956 TI - Mapping stripe rust resistance gene YrZH22 in Chinese wheat cultivar Zhoumai 22 by bulked segregant RNA-Seq (BSR-Seq) and comparative genomics analyses. AB - KEY MESSAGE: A stripe rust resistance gene YrZH22 was mapped by combined BSR-Seq and comparative genomics analyses to a 5.92 centimorgan (cM) genetic interval spanning a 4 Mb physical genomic region on wheat chromosome 4BL1. Stripe rust, caused by Puccinia striiformis f. sp. tritici (PST), is one of the most destructive diseases of wheat and severely threatens wheat production worldwide. The widely grown Chinese wheat cultivar Zhoumai 22 is highly resistant to the current prevailing PST race CYR34 (V26). Genetic analysis of F5:6 and F6:7 recombinant inbred line (RIL) populations indicated that adult-plant stripe rust resistance in Zhoumai 22 is controlled by a single gene, temporarily designated YrZH22. By applying bulked segregant RNA-Seq (BSR-Seq), 7 SNP markers were developed and SNP mapping showed that YrZH22 is located between markers WGGB105 and WGGB112 on chromosome arm 4BL. The corresponding genomic regions of the Chinese Spring 4BL genome assembly and physical map of Aegilops tauschii 4DL were selected for comparative genomics analyses to develop nine new polymorphic markers that were used to construct a high-resolution genetic linkage map of YrZH22. YrZH22 was delimited in a 5.92 cM genetic interval between markers WGGB133 and WGGB146, corresponding to 4.1 Mb genomic interval in Chinese Spring 4BL and a 2.2 Mb orthologous genomic region in Ae. tauschii 4DL. The genetic linkage map of YrZH22 will be valuable for fine mapping and positional cloning of YrZH22, and can be used for marker-assisted selection in wheat breeding. PMID- 28711957 TI - An improved protocol for amino acid type-selective isotope labeling in insect cells. AB - An improved expression protocol is proposed for amino acid type-specific [13C], [15N]-isotope labeling of proteins in baculovirus-infected (BV) insect cell cultures. This new protocol modifies the methods published by Gossert et al. (J Biomol NMR 51(4):449-456, 2011) and provides efficient incorporation of isotopically labeled amino acids, with similar yields per L versus unlabeled expression in rich media. Gossert et al. identified the presence of unlabeled amino acids in the yeastolate of the growth medium as a major limitation in isotope labeling using BV-infected insect cells. By reducing the amount of yeastolate in the growth medium ten-fold, a significant improvement in labeling efficiency was demonstrated, while maintaining good protein expression yield. We report an alternate approach to improve isotope labeling efficiency using BV infected insect cells namely by replacing the yeast extracts in the medium with dialyzed yeast extracts to reduce the amount of low molecular weight peptides and amino acids. We report the residual levels of amino acids in various media formulations and the amino acid consumption during fermentation, as determined by NMR. While direct replacement of yeastolate with dialyzed yeastolate delivered moderately lower isotope labeling efficiencies compared to the use of ten-fold diluted undialized yeastolate, we show that the use of dialyzed yeastolate combined with a ten-fold dilution delivered enhanced isotope labeling efficiency and at least a comparable level of protein expression yield, all at a scale which economizes use of these costly reagents. PMID- 28711958 TI - Systematic assessment of urinary hydroxy-oxo-glutarate for diagnosis and follow up of primary hyperoxaluria type III. AB - BACKGROUND: There are currently three distinct autosomal recessive inherited types of primary hyperoxaluria (PH: PHI, PHII, and PHIII), all characterized by the endogenous overproduction of oxalate. The PH type is difficult to differentiate by clinical features alone. In addition to universal general characteristics to all hyperoxaluria subtypes, specific urinary metabolites can be detected: glycolate in PHI, L-glyceric acid in PHII, and hydroxy-oxo-glutarate (HOG) in PHIII. PHIII is considered to be the most benign form and is characterized by severe recurrent urolithiasis in early life, followed by clinical remission in many, but not all patients. We examined urinary HOG (UHOG) excretion as a diagnostic marker and its correlation to progression of the clinical course of PHIII. METHODS: UHOG was analyzed by combined ion chromatography/mass spectrometry (IC/MS) in urine samples from 30 PHIII and 68 PHI/II patients and 79 non-PH hyperoxaluria patients. RESULTS: Mean UHOG excretion was significantly higher in patients with PHIII than in those with PHI/II and in non-PH patients(51.6 vs. 6.61 vs. 8.36 MUmol/1.73 m2/24 h, respectively; p<0.01). CONCLUSIONS: Significantly elevated UHOG excretion was exclusively seen in PHIII patients and showed a 100 % consensus with the results of hydroxy-oxo-glutarate aldolase (HOGA1) mutational analysis in newly diagnosed patients. However, UHOG excretion did not correlate with clinical course on follow-up and could not be used to discriminate between active stone formers and patients with a clinically uneventful follow-up. PMID- 28711959 TI - A Multicentre Study on the Efficacy, Safety and Pharmacokinetics of IqYmune(r), a Highly Purified 10% Liquid Intravenous Immunoglobulin, in Patients with Primary Immune Deficiency. AB - This multicentre, open-label, prospective, single-arm study was designed to evaluate the efficacy, pharmacokinetics, and safety of IqYmune(r), a highly purified 10% polyvalent immunoglobulin preparation for intravenous administration in patients with primary immunodeficiency. IqYmune(r) was administered to 62 patients (aged 2-61 years) with X-linked agammaglobulinemia or common variable immune deficiency at a dose from 0.22 to 0.97 g/kg every 3 to 4 weeks for 12 months with an infusion rate up to 8 mL/kg/h. A pharmacokinetic study was performed at steady state between the 8th and the 9th infusion. A single case of serious bacterial infection was observed, leading to an annualized rate of serious bacterial infections/patient (primary endpoint) of 0.017 (98% CI: 0.000, 0.115). Overall, 228 infections were reported, most frequently bronchitis, chronic sinusitis, nasopharyngitis and upper respiratory tract infection. The mean annualized rate of infections was 3.79/patient. A lower risk of infections was associated with an IgG trough level > 8 g/L (p = 0.01). The mean annualized durations of absence from work or school and of hospitalization due to infections were 1.01 and 0.89 days/patient, respectively. The mean serum IgG trough level before the 6th infusion was 7.73 g/L after a mean dose of IqYmune(r) of 0.57 g/kg. The pharmacokinetic profile of IqYmune(r) was consistent with that of other intravenous immunoglobulins. Overall, 15.5% of infusions were associated with an adverse event occurring within 72 h post infusion. Headache was the most common adverse event. In conclusion, IqYmune(r) was shown to be effective and well tolerated in patients with primary immunodeficiency. PMID- 28711960 TI - Chronic Kidney Disease (CKD): An Observational Study of Etiology, Severity and Burden of Comorbidities. AB - OBJECTIVES: To study the etiology and burden of comorbidities across stages of chronic kidney disease (CKD). METHODS: Children, 2-16 y of age with CKD Stages II IV were recruited over 12 mo. The etiology, clinical presentation and severity of complications were studied. RESULTS: Among 78 children [Stage II (n = 21), Stage III (n = 26), Stage IV (n = 31)], congenital anomalies of the kidney and urinary tract (CAKUT) was the commonest etiology and 28 were newly diagnosed in Stage III /IV. High prevalence of comorbidities was observed with growth retardation (65%), hypertension (59%), hyperphosphatemia (32%), vitamin D deficiency (92%), dyslipidemia (64%), left ventricular hypertrophy (45%) and hyperparathyroidism (56%). While most comorbidities correlated with the estimated glomerular filtration rate and severity of CKD, hypertension, vitamin D deficiency and cardiovascular morbidity were prevalent even in early stages. CONCLUSIONS: CAKUT was the commonest cause of CKD. Late detection and high prevalence of comorbidities even in early stages of CKD were observed. PMID- 28711961 TI - Heat shock protein 70/nitric oxide effect on stretched tubular epithelial cells linked to WT-1 cytoprotection during neonatal obstructive nephropathy. AB - BACKGROUND: Mechanical stress is a key pathogenic driver of apoptosis in the tubular epithelium in obstructive nephropathy. Heat shock protein 70 (Hsp70) and Wilms' tumor (WT-1) have been proposed to represent linked downstream effectors of the cytoprotective properties of NO. In the present study, we sought to evaluate whether the cytoprotective effects of L-arginine in neonatal obstructive nephropathy may be associated with NO-dependent increases in WT-1 and Hsp70 expression. METHODS: Neonatal Wistar-Kyoto rats were submitted to complete unilateral ureteral obstruction (UUO) and treated thereafter with vehicle, L-NAME or L-arginine by daily gavage for 14 days to block or augment NO levels, respectively. Normal rat kidney epithelial cells by NRK-52E were exposed to mechanical stress in vitro in the presence or absence of L-NAME, L-arginine, sodium nitroprusside (SNP), L-arginine + SNP or L-arginine/L-NAME. Induction of apoptosis and the mRNA expression of WT-1 and Hsp70 genes were assessed. RESULTS: WT-1 and Hsp70 genes expression decreased in the presence of L-NAME and following UUO coincident with increased tubular apoptosis. L-arginine treatment increased NO levels, reduced apoptosis and restored expression levels of WT-1 and Hsp70 to control levels. L-arginine treatment in vitro reduced basal apoptotic rates and prevented apoptosis in response to mechanical strain, an effect enhanced by SNP co-incubation. L-NAME increased apoptosis and prevented the anti-apoptotic action of L-arginine. CONCLUSIONS: L-arginine treatment in experimental neonatal UUO reduces apoptosis coincident with restoration of WT-1 and Hsp70 expression levels and directly inhibits mechanical strain-induced apoptosis in an NO-dependent manner in vitro. This potentially implicates an NO-Hsp70-WT-1 axis in the cytoprotective effects of L-arginine. PMID- 28711963 TI - Transfer of Neonates with Critical Congenital Heart Disease Within a Regionalized Network. AB - Regionalization of pediatric cardiac surgical care varies between and within states. In most geographic regions, at least some neonates with critical heart disease are transferred from their birth hospital to a different hospital for surgery. The impact of neonatal transfer for surgery, particularly over a considerable distance (>10 miles), has been largely unexplored. We sought to examine the impact of transferring neonates for cardiac surgery. We queried the New York State Cardiac Surgery database (2005-2014) from a single institution to identify neonates born within the cardiac surgery center and those transferred for surgery. Outcomes were compared between groups, with subgroup analysis of neonates with single ventricle anatomy. 113 surgical neonates were born at the cardiac surgery center, and 268 were transferred to the cardiac surgery center. Median transfer distance was 91 (IQR 73, 94) miles. Age at operation and the need for preoperative ventilation were significantly lower in neonates born at the cardiac surgery center. In addition, single ventricle anatomy was more prevalent among those born at the cardiac surgery center (48.7 vs. 31.3%; p = 0.001). However, postoperative outcomes were the same-30-day survival was similar across groups (birth: 89% vs. transfer: 90%; p = 0.7), and for those with single ventricle palliation (birth: 81% vs. transfer: 81%; p = 0.9). Within our regionalized network, we found no difference in 30-day survival between neonates either born or transferred to a cardiac surgery center, which supports the use of a regionalized network of hospitals to the care of children with congenital heart disease. PMID- 28711962 TI - The relation between hemoglobin variability and carotid intima-media thickness in chronic hemodialysis patients. AB - PURPOSE: Hemoglobin variability is a common problem among hemodialysis patients. We have previously demonstrated an association between Hb variability and left ventricular mass index. In this study, we investigated a possible relation between Hb variability and carotid intima-media thickness (CIMT). METHODS: Twelve month hemoglobin (Hb) values of 135 patients on maintenance hemodialysis were examined retrospectively. The range of 11-12 gr/dl was accepted as normal according to the KDOQI guidelines. Hemoglobin levels were classified as: Hb < 11 gr/dl:Low, Hb = 11-12 gr/dl:Normal and Hb > 12 gr/dl:High. According to 12-month Hb trajectory, the patients were divided into three groups: low-normal (LN), normal-high (NH) and low-high (LH). The CIMT measurements were taken on common carotid arteries bilaterally, and the average of these measurements were taken. The groups were compared in terms of CIMT measurements, demographic and laboratory features. RESULTS: The LN, NH and LH groups were similar in terms of age, gender, incidence of diabetes mellitus, hypertension and cardiovascular diseases. Duration of hemodialysis, hemodialysis adequacy, serum lipids and CaxP products were also similar among the groups. The mean CIMT value was 0.601 +/- 0.107, 0.744 +/- 0.139 and 0.604 +/- 0.134 mm in the LN, LH and NH groups, respectively (p < 0.001). CIMT was significantly higher in LH than in the other two groups. CONCLUSIONS: In our study, when the three groups with similar risk factors for atherosclerosis were examined, we found that the LH group with the highest hemoglobin variability has the highest CIMT. This study is the first study to demonstrate that Hb variability is associated with an increase in CIMT in HD patients. PMID- 28711964 TI - Utility of Echocardiography in Detecting Silent Complications After Pediatric Catheter Ablations. AB - Although transcatheter arrhythmia ablation (TCA) has been performed in children for over two decades, guidelines for routine use of post-ablation transthoracic echocardiography (TTE) are absent. We sought to determine the efficacy of TTE after apparently uneventful TCA procedures in detecting adverse findings and identify predisposing factors. A retrospective review of clinical and procedural data on patients who underwent TCA for supraventricular arrhythmias from 2000 to 2015 was performed. Pre- and post-ablation TTE data were reviewed. All patients were followed at 1 week, 6 and 12 months post-TCA. A repeat TTE was performed at 12 months on patients in whom post-TCA abnormalities were found. Patients were divided into two groups: those with and without adverse TTE findings and comparative analysis between variables was performed. Data on 252 patients, 52% males, mean age 14 +/- 3 years were analyzed. New onset or worsening atrioventricular valve regurgitation occurred in 17 (6.7%), a small pericardial effusion in 3 (1.2%) and worsened ventricular function in 2 patients (0.8%). Patients in the complication group had higher mean number of ablations (22.6 +/- 15.3 vs. 16.8 +/- 9.2, p 0.001) and required longer duration of ablation (sec) (254.6 +/- 256.4 vs. 180.9 +/- 158.9, p < 0.001). TCA location (including coronary sinus), energy source, arrhythmia substrate, and a trans-septal approach were noncontributory to any adverse findings. Routine post-ablation TTE uncovers asymptomatic self-resolving abnormalities that typically do not require any intervention. PMID- 28711965 TI - Efficacy of an Extracellular Matrix in Systemic Loading Conditions in Congenital Heart Surgery. AB - Extracellular matrices (ECM) are commonly used to repair congenital heart defects; however, there is a lack of literature pertaining to outcomes with ECM use in high-pressure conditions. Between 2011 and 2014, a total of 202 patients underwent congenital heart disease repair using the ECM placed in a systemic pressure condition. The operative sites included: defects in the ventricular septum, mitral valve, aortic valve, ascending aorta, and aortic arch. Patients were followed and evaluated for mortality and reoperations due to loss of ECM integrity. Echocardiograms were evaluated for graft malfunction such as aneurysmal dilation, VSD formation, valve malfunction, or outflow tract obstruction. Patients were followed for an average of 1492 days (Median = 1583). Out of the 202 patients, 7 (3.5%) died due to complications unrelated to ECM, and 10 (5%) underwent reoperations due to complications of ECM integrity. Reoperations were as follows: two of 6 patients receiving aortic leaflet replacement required reoperation for leaflet failure; four of 12 patients receiving mitral valve leaflet repairs required reoperation for leaflet failure; and four of 142 patients with VSD repair required reoperation for residual shunting. The average time to reoperation was 208 days. There were no outflow tract obstructions or aneurysmal dilatations observed. This modern case series suggests that the ECM is efficacious and sustainable under systemic conditions in congenital heart defect repair. However, concerns remain about the use of ECM in aortic valve repair and infant mitral valve repair. Further studies are needed to evaluate long-term ECM integrity. PMID- 28711966 TI - Modified Single-Patch Technique Versus Two-Patch Technique for the Repair of Complete Atrioventricular Septal Defect: A Meta-Analysis. AB - Technical selection for surgical repair of complete atrioventricular septal defect (CAVSD) still remains controversial. This meta-analysis aimed to compare the modified single-patch (MP) technique with the two-patch (TP) technique for patients with CAVSD. Relevant studies comparing the MP technique with the TP technique were identified through a literature search using MEDLINE, EMBASE, Google Scholar, Cochrane Library, and the China National Knowledge Infrastructure databases. The variables were ventricular septal defect (VSD) size, cardiopulmonary bypass (CBP) time, aortic cross-clamp (ACC) time, intensive care unit stay, hospital stay, and other outcomes involving mortality, left ventricular outflow tract obstruction, atrioventricular valve regurgitation, residual septal shunt, atrioventricular block, and reoperation. A random effect/fixed-effect model was used to summarize the estimates of mean difference/odds ratio with 95% confidence interval. Subgroup analysis stratified by region was performed. Fifteen publications involving 1034 patients were included. This meta-analysis demonstrated that (1) VSD size in the MP group was significantly smaller; (2) CBP time, ACC time, and hospital stay in the MP group experienced improvement; (3) Other postoperative outcomes showed no significant differences between two groups; and (4) The trends in China and other countries were close. The MP and TP techniques had comparable outcomes; however, the MP technique was performed with significantly shorter CBP and ACC times in patients with smaller VSDs. Given this limitation of data, the results of comparison of the two techniques in patients with larger VSDs remain unknown. Further studies are needed. PMID- 28711967 TI - Fate of Duct-Dependent, Discontinuous Pulmonary Arteries After Arterial Duct Stenting. AB - Significant and balanced PA growth following arterial duct (AD) stenting has already been consistently reported in literature. However, to date, no data are available about the role of this approach as palliation of congenital heart disease with a duct-dependent discontinuous pulmonary artery (dPA). The aim of this study was to evaluate the fate of a dPA of ductal origin following trans catheter AD stabilization. Angiographic PA evaluation was performed in seven patients submitted to neonatal AD stenting as palliative recruitment of dPA. Five patients showed discontinuity of one PA, while two patients had both PAs served by bilateral ducts. PA growth was evaluated as per the Nakata index, McGoon ratio as well as dPA (n = 9) versus heart-dependent PA (hPA; n = 5) size and z-score changes. AD stabilization was performed using coronary stents dilated to 3.2 +/- 0.3 mm (median 3.4), with significant increase of O2 saturation (from 83 +/- 11 to 95 +/- 5%, p < 0.02). Control angiography was performed 5.1 +/- 2.8 months (median 6 months) after duct stenting, showing significant growth of the dPA (from 3.7 +/- 1.0 to 7.6 +/- 2.7 mm, p < 0.001; z-score from -0.7 +/- 1.4 to 1.7 +/- 2.2, p < 0.01). A trend toward better growth of the dPA as compared with the hPA was found (117 +/- 87 vs. 54 +/- 34%, p = NS). The final vessel size was still significantly different between the groups (dPA 7.6 +/- 2.7 vs. hPA 11.9 +/ 3.4 mm, p = 0.02), although the final z-score value did not significantly differ (dPA 1.7 +/- 2.2 vs. hPA 3.8 +/- 0.9 mm, p = NS). In conclusion, percutaneous AD stenting is effective in promoting a significant catch-up growth of duct dependent dPA, being, therefore, advisable as a reliable alternative to surgical palliation. PMID- 28711968 TI - Local and systemic immunity predict survival in patients with pulmonary sarcomatoid carcinoma. AB - Pulmonary sarcomatoid cancer (PSC) is a rare, aggressive subtype of non-small cell lung cancer, and measures of local and systemic immunity as biomarkers are incompletely known. We performed this study to characterize the leukocyte composition within the tumor, stroma, and peripheral blood in patients with PSC and correlated our findings with overall survival. Tissue from 30 patients diagnosed with PSC was evaluated by IHC for the presence of CD3+, CD14+, and CD19+ cells and PD-L1 expression. A lymphocyte-to-monocyte ratio (LMR) was calculated for the tumor microenvironment (TME) and peripheral blood. Survival analyses were performed based on IHC scores or groups defined by receiver operating characteristic curve cutoffs. CD3+ and CD14+ cells were found throughout the TME. CD19+ cells were almost exclusive to the stroma and correlated with superior overall survival (HR 0.40, 95% CI 0.21-0.72, p = 0.003). Most patients expressed PD-L1 on the tumor and/or the infiltrating immune cells, but neither the presence nor PD-L1 expression level impacted survival. A more prolific immune infiltration of the TME was associated with improved survival (HR 0.82, 95% CI 0.70-0.98, p = 0.029). PSC patients with a TME LMR >=1.2 had a median survival of 1598 versus 488 days for a TME LMR <1.2 (p = 0.010). In the peripheral blood, an LMR >=2.3 was associated with improved median survival (1579 vs. 332 days, p < 0.001). Our data demonstrate multiple measures of the local and systemic immunity are associated with patient survival in PSC. PMID- 28711969 TI - Hyperuricemia is associated with an increased prevalence of paroxysmal atrial fibrillation in patients with type 2 diabetes referred for clinically indicated 24-h Holter monitoring. AB - PURPOSE: Several studies have reported an association between hyperuricemia and increased risk of permanent atrial fibrillation (AF) in patients with and without type 2 diabetes mellitus (T2DM). Currently, no published data are available on the relationship between hyperuricemia and risk of paroxysmal AF. METHODS: We retrospectively evaluated 245 T2DM outpatients without pre-existing AF, cancer, cirrhosis and end-stage renal disease, who underwent a 24-h ECG-Holter monitoring for various clinical indications. Hyperuricemia was defined as a serum uric acid level >7 mg/dl for men and >6 mg/dl for women or allopurinol use. The diagnosis of paroxysmal AF was confirmed in affected individuals on the basis of 24-h ECG Holter monitoring by experienced cardiologists. RESULTS: Hyperuricemia was observed in 59 (24.1%) patients, whereas paroxysmal AF was found in 11 (4.5%) patients. The prevalence of paroxysmal AF was higher in patients with hyperuricemia than in those without hyperuricemia (10.2 vs. 2.7%, p = 0.026). Logistic regression analysis showed that hyperuricemia was associated with an increased risk of prevalent paroxysmal AF. This association remained significant even after adjustment for age, metabolic syndrome and chronic kidney disease (adjusted-odds ratio 4.01, 95% CI 1.08-14.9; p = 0.039). Similar results were found when we used serum uric acid levels as a continuous measure. CONCLUSIONS: This study shows for the first time that hyperuricemia is independently associated with an approximately fourfold increased risk of prevalent paroxysmal AF in patients with T2DM. These findings may partly explain the increased risk of permanent atrial fibrillation and cardiovascular death observed among patients with hyperuricemia. PMID- 28711970 TI - Does a male polycystic ovarian syndrome equivalent exist? AB - The occurrence of a genetic background in the etiology of polycystic ovarian syndrome (PCOS) represents the rational basis to postulate the existence of a male PCOS equivalent. Hormonal and metabolic abnormalities have been described in male relatives of women with PCOS. These males also have a higher prevalence of early onset (<35 years) androgenetic alopecia (AGA). Hence, this feature has been proposed as a clinical sign of the male PCOS equivalent. Clinical evidence has shown that men with early onset AGA have hormonal and metabolic abnormalities. Large cohort studies have clearly shown a higher prevalence of type II diabetes mellitus (DM II) and cardiovascular diseases (CVDs) in elderly men with early onset AGA. In addition, prostate cancer, benign prostate hyperplasia (BPH) and prostatitis have been described. These findings support the existence of the male PCOS equivalent, which may represent an endocrine syndrome with a metabolic background, and might predispose to the development of DM II, CVDs, prostate cancer, BPH and prostatitis later in life. Its acknowledgment would be helpful for the prevention of these long-term complications. PMID- 28711971 TI - Innovative technology shows impact of glycaemic control on peripheral retinal vessels in adolescents with type 1 diabetes. AB - AIMS/HYPOTHESIS: Retinal imaging enables non-invasive microvasculature assessment; however, only central retinal vessels have been studied in type 1 diabetes. Peripheral smaller vessels have a major haemodynamic role and may differ from central vessels in their response to the diabetic milieu. We hypothesise that diabetes has a greater impact on peripheral retinal vessels vs central vessels. METHODS: Retinal photographs from adolescents (n = 736; age 12 20 years) with type 1 diabetes were graded (Singapore I Vessel Assessment) with vessel calibres measured in the 'central zone' as central retinal arteriolar and venular equivalents (CRAE and CRVE, respectively) and the 'extended zone' as mean width of arterioles and venules (MWa and MWv, respectively). Multivariable linear regression was used to explore associations between vessel calibres and HbA1c, diabetes duration, sex and BP. RESULTS: Mean +/- SD age was 14.1 +/- 1.5 years, HbA1c was 8.5 +/- 1.3% (69.4 +/- 14.1 mmol/mol) and median diabetes duration was 4.9 years (interquartile range 3.1-7.6 years). Wider MWa was associated with HbA1c (beta 0.01 [95% CI 0.004, 0.03]), longer diabetes duration (0.07 [0.02, 0.13]) and higher systolic BP (0.04 [0.02, 0.05]). MWv was associated with HbA1c (0.02 [0.009, 0.03]) and higher systolic BP (0.04 [0.03, 0.06]). CRAE was associated with longer diabetes duration (0.93 [0.58, 1.28]) and higher systolic BP (-0.28 [-0.37, -0.19]). CRVE was associated with longer diabetes duration (0.91 [0.42, 1.41]) and higher systolic BP (-0.20 [-0.33, -0.07]). Girls had wider vessels (for all four calibre measurements). CONCLUSIONS/INTERPRETATION: In adolescents with type 1 diabetes, higher HbA1c is associated with adverse changes to peripheral smaller retinal vessels but not central vessels. The predictive value of retinal vascular imaging should be evaluated using longitudinal data. PMID- 28711972 TI - The relationship of blood glucose with cardiovascular disease is mediated over time by traditional risk factors in type 1 diabetes: the DCCT/EDIC study. AB - AIMS/HYPOTHESIS: Chronic hyperglycaemia, as measured by HbA1c levels, is a major risk factor for atherosclerosis and cardiovascular disease (CVD) in type 1 diabetes. Our aim was to describe the degree to which the effect of HbA1c on the risk of CVD is mediated by its effect on traditional risk factors over time, and how these mediation pathways change over time. METHODS: The DCCT and its observational follow-up study, the Epidemiology of Diabetes Interventions and Complications (EDIC), followed 1441 participants for a mean of 27 years, with periodic measurement of HbA1c and risk factors over time. We assessed the proportion of the HbA1c effect on risk of CVD that was mediated through its effects on systolic BP (SBP), pulse rate, triacylglycerols and LDL-cholesterol (LDLc) levels, and how the proportion mediated changed over time. RESULTS: The association of HbA1c with CVD outcomes was stable over time, while that of traditional risk factors (SBP, pulse rate, triacylglycerols and LDLc) increased. At 10 years of follow-up, the effect of HbA1c on 10 year CVD risk was minimally mediated by SBP (2.7%), increasing to 26% at 20 years. Likewise, from 10 year follow-up to 20 year follow-up, the proportion of HbA1c effect mediated through pulse rate increased from 6.3% to 29.3%, through triacylglycerols from 2.2% to 22.4%, and through LDLc from 9.2% to 30.7%. CONCLUSIONS/INTERPRETATION: As participants age, the predictive association of mean HbA1c on subsequent CVD events is increasingly mediated by its effect on standard risk factors. Thus, management of traditional non-glycaemic CVD risk factors may have increasing benefits in an ageing type 1 diabetes population with longstanding hyperglycaemia. TRIAL REGISTRATION: ClinicalTrials.gov NCT00360893 and NCT00360815. PMID- 28711974 TI - Erratum to: A new concept and a comprehensive evaluation of SYSMEX UF-1000i flow cytometer to identify culture-negative urine specimens in patients with UTI. PMID- 28711973 TI - PIWI-interacting RNAs as novel regulators of pancreatic beta cell function. AB - AIMS/HYPOTHESIS: P-element induced Wimpy testis (PIWI)-interacting RNAs (piRNAs) are small non-coding RNAs that interact with PIWI proteins and guide them to silence transposable elements. They are abundantly expressed in germline cells and play key roles in spermatogenesis. There is mounting evidence that piRNAs are also present in somatic cells, where they may accomplish additional regulatory tasks. The aim of this study was to identify the piRNAs expressed in pancreatic islets and to determine whether they are involved in the control of beta cell activities. METHODS: piRNA profiling of rat pancreatic islets was performed by microarray analysis. The functions of piRNAs were investigated by silencing the two main Piwi genes or by modulating the level of selected piRNAs in islet cells. RESULTS: We detected about 18,000 piRNAs in rat pancreatic islets, many of which were differentially expressed throughout islet postnatal development. Moreover, we identified changes in the level of several piRNAs in the islets of Goto Kakizaki rats, a well-established animal model of type 2 diabetes. Silencing of Piwil2 or Piwil4 genes in adult rat islets caused a reduction in the level of several piRNAs and resulted in defective insulin secretion and increased resistance of the cells to cytokine-induced cell death. Furthermore, overexpression in the islets of control animals of two piRNAs that are upregulated in diabetic rats led to a selective defect in glucose-induced insulin release. CONCLUSIONS/INTERPRETATION: Our results provide evidence for a role of PIWI proteins and their associated piRNAs in the control of beta cell functions, and suggest a possible involvement in the development of type 2 diabetes. DATA AVAILABILITY: Data have been deposited in Gene Expression Omnibus repository under the accession number GSE93792. Data can be accessed via the following link: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?token=ojklueugdzehpkv&acc=GSE93792 PMID- 28711975 TI - A Delphi study to develop indicators of cancer patient experience for quality improvement. AB - PURPOSE: The purpose of this study was to develop prioritised indicators to measure cancer patient experience and thus guide quality improvement in the delivery of patient care. METHODS: A Delphi study, consisting of two surveys and three workshops, was employed to gather expert opinions on the most important indicators to measure. Survey participants were 149 health professionals, academics/technical experts and consumers. The first survey was based on a literature review which identified 105 elements of care within 14 domains of patient experience. These were rated on a 7-point Likert scale, with '1' representing high importance. Elements with mean ratings between 1.0 and 2.0 were retained for the second survey. The 43 least-important elements were omitted, four elements were revised and nine new elements added. Consensus was defined as at least 70% of participants rating an element '1' or '2'. Multivariate and cluster analyses were used to develop 20 draft indicators, which were presented to 51 experts to refine and prioritise at the three workshops. RESULTS: All elements in the second survey were rated '1' or '2' by 81% of participants. Workshop participants agreed strongly on the four most important indicators: coordinated care, access to care, timeliness of the first treatment, and communication. Other indicators considered highly important were follow-up care for survivors; timeliness of diagnosis; information relating to side effects, pain and medication; comprehensibility of information provided to patients; and needs assessment. CONCLUSIONS: Experts identified priorities with a high level of consensus, providing a rigorous foundation for developing prioritised indicators of quality in cancer patient experience. PMID- 28711976 TI - Assessment of indomethacin oral spray for the treatment of oropharyngeal mucositis-induced pain during anticancer therapy. AB - PURPOSE: The efficacy and safety of indomethacin (IM) oral spray (OS) as a pain control therapy for oropharyngeal mucositis due to anticancer chemo- and radiotherapy were assessed in patients with head and neck carcinomas and haematological tumours. METHOD: We observed 35 patients (male/female, 20/15; 53 +/- 17 years) with oropharyngeal mucositis who were treated with IM-OS preparation for pain relief at University of Tsukuba Hospital, Japan. Analgesic effects were assessed using the six-grade face scale for pain in 28 patients at the start of IM oral spray treatment. Systemic exposure was assessed by determining urinary excretions of IM in seven patients. RESULTS: Pain relief was achieved in 26 (93%) patients at 25 (5-60) min after applying the IM-OS preparation (15.6 +/- 3.4 MUg/kg) and analgesic effects were maintained for 120 (10-360) min. The pain was significantly decreased after using the spray (3.6 +/- 0.7 vs. 2.4 +/- 0.9, p < 0.01). Moreover, urinary IM excretion rates after applying the IM spray preparation were 1.8 +/- 0.8% of the IM oral spray dose (130.5 +/- 77.7 MUg/kg/day), which was markedly lower than that following oral administration of IM (60%). No adverse events were observed following application of the spray. CONCLUSIONS: The present IM spray is an effective and safe preparation for pain relief and can be used as an alternative therapeutic option for oropharyngeal mucositis in cancer patients. PMID- 28711979 TI - Acute kidney injury and critical limb ischaemia associated with the use of the so called "legal high" 3-fluorophenmetrazine. AB - Until the law in the United Kingdom (UK) changed in May 2016 so called "legal highs" or "new psychoactive substances" were freely available in high street shops across the UK. Following prohibition these drugs are still easily purchased illegally via the internet. We report a case of a patient who self-administered 3 fluorophenmetrazine intravenously with catastrophic consequences. Adverse effects were almost immediate with symptoms of malaise and tachycardia. Two days post administration he was transferred to the intensive therapy unit with acute kidney injury and irreversible four limb ischaemia. He required a period of renal replacement therapy and bilateral lower limb amputation. This case highlights the fact that new psychoactive substances have many unintended adverse effect which have not been previously described. Multiple routes of administration are used by people taking these agents including intravenously. Medical practitioners should always consider ingestion of new psychoactive substances in the differential diagnosis of acutely ill patients. PMID- 28711978 TI - The Activity of the Antioxidant Defense System of the Weed Species Senna obtusifolia L. and its Resistance to Allelochemical Stress. AB - Senna obtusifolia L., a common weed in the tropical and subtropical regions of the world, is able to germinate under adverse environmental conditions, suggesting that this species has efficient stress-adaptation strategies. The aims of the present work were to examine the energy metabolism and the antioxidant defense system of the Senna obtusifolia L. during seed germination and initial growth, and the responses to allelochemical-induced stress. Respiratory activity, the activities of alcohol dehydrogenase (ADH), superoxide dismutase (SOD), catalase (CAT),guaicol peroxidase (POD), ascorbate peroxidase (APX), glutathione reductase (GR), lipoxygenase (LOX) and the content of malondialdehyde (MDA) and glutathione (GSSG and GSH) were measured. Shortly after seed imbibition, mitochondrial respiratory activity was active and the presence of SOD, CAT, GR and LOX activity in embryos, along with significant KCN-insensitive respiration, indicated that the production of reactive oxygen species (ROS) is initiated as soon as mitochondrial respiration resumes. Among the fourteen allelochemicals assayed, only coumarin significantly supressed the growth of S. obtusifolia seedlings. Although coumarin reduced the activities of CAT, POD and APX, the GSH, GSSG and MDA levels were not altered. Alpha-pinene, quercetin and ferulic acid did not modify the activity of the antioxidant enzymes or the contents of GSH, GSSH and MDA. Thus the antioxidant defense system of S. obstusifolia may be effective in counteracting the harmful effects of ROS generated during seed germination and initial growth in the presence of toxic allelochemicals. PMID- 28711980 TI - Erratum to: Platelet-rich Plasma and Other Cellular Strategies in Orthopedic Surgery. PMID- 28711981 TI - Universal direct PCR amplification system: a time- and cost-effective tool for high-throughput applications. AB - Taking into account the limits of current genotyping methodologies, we have established a versatile direct PCR method on intact microtissue samples without prior DNA isolation. A simple and standard protocol was developed and validated on a wide range of living organisms including bacterial and fungal strains, plant species and human samples. This allows reliable amplification of target genomic DNA fragment directly from source material using minimal amount of tissue which makes DNA purification irrelevant for a number of biological applications. The direct PCR technique established here represents an excellent alternative to traditional amplification methods used for real-time detection. Since this approach was efficiently and universally applied for high-throughput molecular screening, its implementation will offer new insights for several investigations in human health, biomedical diagnosis, plant biotechnology, as well as in applied environmental and food microbiology. PMID- 28711982 TI - Correlation between the methylation of the FUT1 promoter region and FUT1 expression in the duodenum of piglets from newborn to weaning. AB - Alpha-(1,2)-fucosyltransferase (FUT1) gene has some influence on economically important traits and disease resistance. DNA methylation plays an important role in human diseases but is relatively poorly studied in pigs by regulating the mRNA expression of genes. The aim of this study was to analyze the influence of promoter methylation on the expression of FUT1 gene. We used bisulfite sequencing PCR (BSP) and qPCR to analyze the methylation of the FUT1 5'-flanking region and FUT1 mRNA expression in the duodenum of Sutai piglets from newborn to weaning. FUT1 contains three CpG islands upstream of the start codon, of which two are located in the putative promoter region containing multiple promoter elements and transcription factor binding sites, such as CpG islands, a CAAT box, SP1, and EARLY-SEQ 1. The CpG island between nucleotides -1762 and -580 had a low degree of methylation, and its methylation level was significantly lower in 35-day-old piglets than 8- and 18-day-old piglets (P < 0.05). FUT1 mRNA expression was significantly higher in 35-day-old piglets than 8- and 18-day-old piglets (P < 0.05). Pearson's correlation analysis showed that the methylation of the CpG island between nucleotides -1762 and -580 of FUT1 was significantly, negatively correlated with FUT1 mRNA expression (P < 0.05). These results demonstrate that differential methylation of CpG islands negatively regulates the expression of FUT1 in the porcine duodenum, suggesting a probable influence on the resistance of piglets to infection with ETEC F18. PMID- 28711983 TI - Xanthan gum production using jackfruit-seed-powder-based medium: optimization and characterization. AB - Xanthan gum (XG) production by Xanthomonas campestris NCIM 2961 using jackfruit seed powder (JSP) as a novel substrate was reported. Central composite design (CCD) of response surface method (RSM) was used to evaluate the linear and interaction effects of five medium variables (JSP, peptone, citric acid, K2HPO4 and KH2PO4) for XG production. Maximum XG production (51.62 g/L) was observed at the optimum level of JSP (4 g/L), peptone (0.93 g/L), citric acid (0.26 g/L), K2HPO4 (1.29 g/L) and KH2PO4 (0.5 g/L). K2HPO4 and KH2PO4 were found as significant medium components, which served as buffering agents as well as nutrients for X. campestris growth. The obtained biopolymer was characterized as XG by XRD and FTIR analysis. Results of this study revealed that JSP was found to be a suitable low cost substrate for XG production. PMID- 28711984 TI - Clarithromycin co-administration does not increase irinotecan (CPT-11) toxicity in colorectal cancer patients. AB - PURPOSE: Irinotecan (CPT-11) is used to treat advanced colorectal cancer. The drug is activated by carboxylesterases and rendered inactive by CYP3A4. Recently, the efficacy of combining CPT-11 and anti-epidermal growth factor receptor (EGFR) agents was confirmed in patients with KRAS wild-type metastatic colorectal cancer. Clarithromycin (CAM) is a strong CYP3A inhibitor often used to prevent rash associated with anti-EGFR therapy. The objective of this study was to evaluate the risk of increased neutropenia and diarrhea in combining CPT-11 and CAM. METHODS: Retrospective analyses were conducted at Osaka National Hospital (Osaka, Japan) on the records of colorectal cancer patients treated with a CPT-11 containing regimen between November 2006 and January 2014. The incidence of neutropenia and diarrhea was compared between patients who received CPT-11 and CAM and patients who received CPT-11 without CAM. RESULTS: One-hundred and twenty eight patients were included in this study, of whom 21 were concomitantly treated with CAM and 107 were not. There was no difference in the incidence of grade 3-4 neutropenia between the CAM co-administration group (10%) and the non-CAM group (16%) [Odds ratio: 0.56 (95% confidence interval: 0.12-2.62), p = 0.45]. No difference in the incidence of grade 3-4 diarrhea was found between the CAM co administration group (0%) and the non-CAM group (4%) (p = 0.37). CONCLUSIONS: This study did not identify an increase in CPT-11 toxicity by co-administration with CAM. PMID- 28711985 TI - Higher Rates of DZ Twinning in a Twenty-First Century Birth Cohort. AB - The Colorado Twin Registry is a population based registry initiated in 1984 with the involvement of the Colorado Department of Health, Division of Vital Statistics. Recruitment includes birth cohorts several years prior to 1984 and all subsequent years. As part of a recent evaluation of Colorado birth records for the years 2006 through 2008 we became aware of a shifting trend in the proportion of MZ and DZ twins in the Colorado population. Historically (Bulmer 1970 The biology of twinning in man, Clarendon, Oxford) we have expected a 1/3, 1/3, 1/3 ratio of MZ, same-sex DZ and opposite sex DZ twins in Caucasian populations. An excess of MZ pairs in most studies was assumed to be due to selection bias. Somewhat more recently, Hur et al.(1995 Behav Genet 25, 337-340) provided evidence that the DZ twinning rate was falling and that therefore selection bias was not the reason for higher MZ enrollment in most twin studies. They suggested that twin researchers might consider strategies to over-enroll DZ pairs to maximize statistical power. In contrast, we now find that of the 3217 twin births in Colorado from 2006 to 2008 with identified sex information the MZ rate is estimated at only 22%, and we have corroborating reports from other states of similar estimates. These were calculated applying Weinberg's rule which assumes an equal birth rate for same sex and opposite sex DZ pairs so that the proportion of MZ in a sample is the proportion of same sex (MM + FF) minus the proportion of opposite-sex (MF, FM). We explore factors, such as an increase in the proportion of non-Caucasian parents and an increase in average maternal age, which may contribute to this shift. PMID- 28711986 TI - Single Nucleotide Polymorphisms Associated with Reading Ability Show Connection to Socio-Economic Outcomes. AB - Impairments in reading and in language have negative consequences on life outcomes, but it is not known to what extent genetic effects influence this association. We constructed polygenic scores for difficulties with language and learning to read from genome-wide data in ~6,600 children, adolescents and young adults, and tested their association with health, socioeconomic outcomes and brain structure measures collected in adults (maximal N = 111,749). Polygenic risk of reading difficulties was associated with reduced income, educational attainment, self-rated health and verbal-numerical reasoning (p < 0.00055). Polygenic risk of language difficulties predicted income (p = 0.0005). The small effect sizes ranged 0.01-0.03 of a standard deviation, but these will increase as genetic studies for reading ability get larger. Polygenic scores for childhood cognitive ability and educational attainment were correlated with polygenic scores of reading and language (up to 0.09 and 0.05, respectively). But when they were included in the prediction models, the observed associations between polygenic reading and adult outcomes mostly remained. This suggests that the pathway from reading ability to social outcomes is not only via associated polygenic loads for general cognitive function and educational attainment. The presence of non-overlapping genetic effect is indicated by the genetic correlations of around 0.40 (childhood intelligence) and 0.70 (educational attainment) with reading ability. Mendelian randomization approaches will be important to dissociate any causal and moderating effects of reading and related traits on social outcomes. PMID- 28711988 TI - Emotion recognition based on EEG features in movie clips with channel selection. AB - Emotion plays an important role in human interaction. People can explain their emotions in terms of word, voice intonation, facial expression, and body language. However, brain-computer interface (BCI) systems have not reached the desired level to interpret emotions. Automatic emotion recognition based on BCI systems has been a topic of great research in the last few decades. Electroencephalogram (EEG) signals are one of the most crucial resources for these systems. The main advantage of using EEG signals is that it reflects real emotion and can easily be processed by computer systems. In this study, EEG signals related to positive and negative emotions have been classified with preprocessing of channel selection. Self-Assessment Manikins was used to determine emotional states. We have employed discrete wavelet transform and machine learning techniques such as multilayer perceptron neural network (MLPNN) and k-nearest neighborhood (kNN) algorithm to classify EEG signals. The classifier algorithms were initially used for channel selection. EEG channels for each participant were evaluated separately, and five EEG channels that offered the best classification performance were determined. Thus, final feature vectors were obtained by combining the features of EEG segments belonging to these channels. The final feature vectors with related positive and negative emotions were classified separately using MLPNN and kNN algorithms. The classification performance obtained with both the algorithms are computed and compared. The average overall accuracies were obtained as 77.14 and 72.92% by using MLPNN and kNN, respectively. PMID- 28711987 TI - Getting genetic access to natural adenovirus genomes to explore vector diversity. AB - Recombinant vectors based on the human adenovirus type 5 (HAdV5) have been developed and extensively used in preclinical and clinical studies for over 30 years. However, certain restrictions of HAdV5-based vectors have limited their clinical applications because they are rather inefficient in specifically transducing cells of therapeutic interest that lack the coxsackievirus and adenovirus receptor (CAR). Moreover, enhanced vector-associated toxicity and widespread preexisting immunity have been shown to significantly hamper the effectiveness of HAdV-5-mediated gene transfer. However, evolution of adenoviruses in the natural host is driving the generation of novel types with altered virulence, enhanced transmission, and altered tissue tropism. As a consequence, an increasing number of alternative adenovirus types were identified, which may represent a valuable resource for the development of novel vector types. Thus, researchers are focusing on the other naturally occurring adenovirus types, which are structurally similar but functionally different from HAdV5. To this end, several strategies have been devised for getting genetic access to adenovirus genomes, resulting in a new panel of adenoviral vectors. Importantly, these vectors were shown to have a host range different from HAdV5 and to escape the anti-HAdV5 immune response, thus underlining the great potential of this approach. In summary, this review provides a state-of-the-art overview of one essential step in adenoviral vector development. PMID- 28711990 TI - Assessment of BRAFV600E mutation in pulmonary Langerhans cell histiocytosis in tissue biopsies and bronchoalveolar lavages by droplet digital polymerase chain reaction. AB - The neoplastic nature of pulmonary Langerhans cell histiocytosis (PLCH) is still debated. As the detection of BRAF V600E and MAP2K1 mutations in patients with PCLH is now considered for such assessment, the aim of our study was to evaluate digital droplet polymerase chain reaction (ddPCR) in PCLH diagnosis. We retrospectively analyzed BRAFV600E detection in a cohort of 42 PCLH tissues and 18 bronchoalveolar lavages (BALs) by ddPCR, immunohistochemistry, high-resolution melting PCR (HRM), and next-generation sequencing (NGS). The presence of BRAFV600E mutation was assessed by at least two concordant techniques to further evaluate specificity and sensitivity of each method. The BRAF V600E mutation prevalence was detected in 18 out of 41 cases by ddPCR, 10 out of 36 cases by HRM PCR, and 16 out of 31 cases by NGS. BRAFV600E immunohistochemistry sensitivity was 94%, and specificity was 79%. HRM PCR sensitivity was only 59%, and specificity was 100%. NGS sensitivity and specificity were 100% for interpretable cases (n = 31), but in 11 cases, this technique was non-contributive. The analysis of BAL samples by ddPCR revealed a BRAFV600E mutation both in tissue and in BAL samples in one patient, a wild-type status both in tissue and in BAL samples in two patients, and a wild-type BRAF status in BAL and a BRAFV600E mutation in tissue samples in four patients. The study supports the usefulness of ddPCR for BRAF status assessment in either tissue or BAL samples to increase the accuracy of PLCH diagnosis. PMID- 28711991 TI - One-year efficacy of adjunctive use of Ripasudil, a rho-kinase inhibitor, in patients with glaucoma inadequately controlled with maximum medical therapy. AB - PURPOSE: The aim of this study was to evaluate the one-year efficacy, ability to lower intraocular pressure, and tolerability of ripasudil, a rho-kinase inhibitor, in patients with glaucoma inadequately controlled with maximum medical therapy. METHODS: This prospective, non-comparative, interventional case-series study included 39 patients with primary open-angle glaucoma inadequately controlled with maximum medical therapy before treatment with ripasudil. Ripasudil was administered twice per day as adjunctive therapy to ongoing glaucoma treatment. The primary endpoint was the degree of intraocular pressure reduction after 12 months of treatment; the secondary endpoints were the incidence of adverse events. RESULTS: We examined 39 eyes. The intraocular pressure reduction (given as the relative percentage of intraocular pressure reduction) from baseline was -2.6 mmHg (-15.5%; 95% confidence interval, -1.1 to 3.9 mmHg; P < 0.001) after 12 months of treatment. The adverse events were conjunctival hyperemia (all patients), blepharitis (three), allergic conjunctivitis (two), punctate keratitis (two), and ophthalmalgia (one). CONCLUSIONS: Treatment with ripasudil decreased intraocular pressure in patients with glaucoma that was poorly controlled with maximal medical therapy, and it was well-tolerated. PMID- 28711989 TI - Striking the right immunological balance prevents progression of tuberculosis. AB - INTRODUCTION: Tuberculosis (TB) caused by infection with Mycobacterium tuberculosis (Mtb) is a major burden for human health worldwide. Current standard treatments for TB require prolonged administration of antimycobacterial drugs leading to exaggerated inflammation and tissue damage. This can result in the reactivation of latent TB culminating in TB progression. Thus, there is an unmet need to develop therapies that would shorten the duration of anti-TB treatment and to induce optimal protective immune responses to control the spread of mycobacterial infection with minimal lung pathology. FINDINGS: Granulomata is the hallmark structure formed by the organized accumulation of immune cells including macrophages, natural killer cells, dendritic cells, neutrophils, T cells, and B cells to the site of Mtb infection. It safeguards the host by containing Mtb in latent form. However, granulomata can undergo caseation and contribute to the reactivation of latent TB, if the immune responses developed to fight mycobacterial infection are not properly controlled. Thus, an optimal balance between innate and adaptive immune cells might play a vital role in containing mycobacteria in latent form for prolonged periods and prevent the spread of Mtb infection from one individual to another. CONCLUSION: Optimal and well-regulated immune responses against Mycobacterium tuberculosis may help to prevent the reactivation of latent TB. Moreover, therapies targeting balanced immune responses could help to improve treatment outcomes among latently infected TB patients and thereby limit the dissemination of mycobacterial infection. PMID- 28711992 TI - Oleuropein and hydroxytyrosol inhibit the N-formyl-methionyl-leucyl-phenylalanine induced neutrophil degranulation and chemotaxis via AKT, p38, and ERK1/2 MAP Kinase inhibition. AB - PURPOSE: Oleuropein and hydroxytyrosol are polyphenols that are extracted from olives and are major biological active components of olives and olive oil. Oleuropein and hydroxytyrosol exhibit interesting pharmacological effects on cells, and have been shown to have many health benefits such as anti-inflammatory effects. These effects were mainly attributed to their ability to scavenge the reactive oxygen species (ROS) produced by phagocytes such as neutrophils. The aim of this study was to investigate the effect of oleuropein and hydroxytyrosol on other neutrophil functions. METHODS: Human neutrophils were isolated from healthy donors. ROS production was measured by luminol-amplified chemiluminescence. Degranulation was assessed by measuring myeloperoxidase activity and Western blots. Chemotaxis was assessed by the under-agarose chemotaxis assay. Phosphorylated proteins were assessed by gel electrophoresis and Western blots. RESULTS: We show that in addition to their ROS scavenging effect, oleuropein and hydroxytyrosol significantly inhibited the bacterial peptide N-formyl-methionyl leucyl-phenylalanine (fMLF)-induced degranulation of azurophilic and specific granules as measured by myeloperoxidase and lactoferrin release, respectively. We also show that oleuropein and hydroxytyrosol reduced fMLF-induced neutrophil chemotaxis. Interestingly, both agents impaired the fMLF-induced AKT, p38MAPKinase, and ERK1/2 phosphorylation, signaling molecules that are involved in pathways regulating neutrophil functions. CONCLUSION: Our data suggest that the anti-inflammatory properties of oleuropein and hydroxytyrosol are not only restricted to their ROS scavenging effect, but also involve the inhibition of two other major pro-inflammatory neutrophil functions. PMID- 28711995 TI - Axillary blue sentinel lymph node: an unusual tattoo? PMID- 28711994 TI - [18F]FDG PET/CT features for the molecular characterization of primary breast tumors. AB - PURPOSE: The aim of this study was to evaluate the role of imaging features derived from [18F]FDG-PET/CT to provide in vivo characterization of breast cancer (BC). METHODS: Images from 43 patients with a first diagnosis of BC were reviewed. Images were acquired before any treatment. Histological data were derived from pretreatment biopsy or surgical histological specimen; these included tumor type, grade, ER and PgR receptor status, lymphovascular invasion, Ki67 index, HER2 status, and molecular subtype. Standard parameters (SUVmean, TLG, MTV) and advanced imaging features (histogram-based and shape and size features) were evaluated. Univariate analysis, hierarchical clustering analysis, and exact Fisher's test were used for statistical analysis of data. Imaging derived metrics were reduced evaluating the mutual correlation within group of features as well as the mutual correlation between groups of features to form a signature. RESULTS: A significant correlation was found between some advanced imaging features and the histological type. Different molecular subtypes were characterized by different values of two histogram-based features (median and energy). A significant association was observed between the imaging signature and luminal A and luminal B HER2 negative molecular subtype and also when considering luminal A, luminal B HER2-negative and HER2-positive groups. Similar results were found between the signature and all five molecular subtypes and also when considering the histological types of BC. CONCLUSIONS: Our results suggest a complementary role of standard PET imaging parameters and advanced imaging features for the in vivo biological characterization of BC lesions. PMID- 28711993 TI - Clinical Risk Assessment in the Antiphospholipid Syndrome: Current Landscape and Emerging Biomarkers. AB - PURPOSE OF REVIEW: Laboratory criteria for the classification of antiphospholipid syndrome include the detection of a lupus anticoagulant and/or anticardiolipin and anti-beta2-glycoprotein I antibodies. However, the majority of patients who test positive in these assays do not have thrombosis. Current risk-stratification tools are largely limited to the antiphospholipid antibody profile and traditional thrombotic risk factors. RECENT FINDINGS: Novel biomarkers that correlate with disease activity and potentially provide insight into future clinical events include domain 1 specific anti-beta2GPI antibodies, antibodies to other phospholipids or phospholipid/protein antigens (such as anti-PS/PT), and functional/biological assays such as thrombin generation, complement activation, levels of circulating microparticles, and annexin A5 resistance. Clinical risk scores may also have value in predicting clinical events. Biomarkers that predict thrombosis risk in patients with antiphospholipid antibodies have been long sought, and several biomarkers have been proposed. Ultimately, integration of biomarkers with established assays and clinical characteristics may offer the best chance of identifying patients at highest risk of APS-related complications. PMID- 28711996 TI - The physiological and metabolic changes in sugar beet seedlings under different levels of salt stress. AB - Salinity stress is a major limitation to global crop production. Sugar beet, one of the world's leading sugar crops, has stronger salt tolerant characteristics than other crops. To investigate the response to different levels of salt stress, sugar beet was grown hydroponically under 3 (control), 70, 140, 210 and 280 mM NaCl conditions. We found no differences in dry weight of the aerial part and leaf area between 70 mM NaCl and control conditions, although dry weight of the root and whole plant treated with 70 mM NaCl was lower than control seedlings. As salt concentrations increased, degree of growth arrest became obvious In addition, under salt stress, the highest concentrations of Na+ and Cl- were detected in the tissue of petioles and old leaves. N and K contents in the tissue of leave, petiole and root decreased rapidly with the increase of NaCl concentrations. P content showed an increasing pattern in these tissues. The activities of antioxidant enzymes such as superoxide dismutase, catalase, ascorbate peroxidase and glutathione peroxidase showed increasing patterns with increase in salt concentrations. Moreover, osmoprotectants such as free amino acids and betaine increased in concentration as the external salinity increased. Two organic acids (malate and citrate) involved in tricarboxylic acid (TCA)-cycle exhibited increasing contents under salt stress. Lastly, we found that Rubisco activity was inhibited under salt stress. The activity of NADP-malic enzyme, NADP malate dehydrogenase and phosphoenolpyruvate carboxylase showed a trend that first increased and then decreased. Their activities were highest with salinity at 140 mM NaCl. Our study has contributed to the understanding of the sugar beet physiological and metabolic response mechanisms under different degrees of salt stress. PMID- 28711997 TI - Effects of degradable osteosynthesis plates of MgYREZr alloy on cell function of human osteoblasts, fibroblasts and osteosarcoma cells. AB - The aim was to evaluate the biocompatibility of osteosynthesis plates of the MgYREZr/WE43 alloy by using human cells in vitro. Eluates of degradable magnesium osteosynthesis plates as well as halved plates were used for incubation with human osteoblasts, fibroblasts and osteosarcoma cells. The cell viability was evaluated by using FDA/PI-Staining and LDH analysis. Cell proliferation was assessed by MTT, WST-Test and BrdU-ELISA. Scanning electron microscope was used for investigation of the cell adhesion. The number of devitalized cells in all treatment groups did not significantly deviate from the control group. According to MTT results, the number of metabolically active cells was not significantly affected by the addition of the eluates. The number of metabolically active cells was reduced by 24 to 38% compared to the control on incubation in direct contact with the osteosynthesis plates. The proliferation of the cells was inhibited by the addition of the eluates. While the eluate of the half-hour elution has only a very small effect, the 24 h eluate significantly inhibits proliferation by 23-25% compared to the control. The roughened surface of the magnesium osteosynthesis plate after incubation showed adherent cells. However, some areas of the plates were also free of adherent cells. WE43 based magnesium alloys showed favorable biocompatibility considering the viability of the cells evaluated; however, proliferation rates were reduced in a time dependent manner, especially in fibroblast group. This might be a potential clinical benefit of magnesium osteosynthesis plates and their superiority to titanium, thus the fibroblastic ingrowth might negatively influence the bone-plate contact. PMID- 28711998 TI - Medical history of chemotherapy or immunosuppressive drug treatment and risk of amyotrophic lateral sclerosis (ALS). AB - A recent population-based analysis demonstrated lower risk of the lethal degenerative neuromuscular disease, amyotrophic lateral sclerosis (ALS) associated with history of the use of 'antineoplastic agents' and 'immunosuppressants'. To see if this finding was generalizable to other ALS cohorts, we examined associations between use of these agents and ALS risk in an independent case-control study of n = 414 ALS patients and n = 361 controls in an Eastern US population. Controls were sampled from the general population and among non-neurodegenerative disease patients. A history of chemotherapy treatment was significantly associated with a decreased ALS risk (OR 0.46, 95% CI 0.22 0.89, P = 0.026). We did not observe an association between risk of ALS and immunosuppressant therapy use (OR 0.78, 95% CI 0.50-1.02, P = 0.23). Analyses were adjusted for age, gender, and smoking. Our results support the prior report for chemotherapy treatment and lead to further discussion of the underlying mechanism. PMID- 28711999 TI - Erratum to: Progressive multifocal leukoencephalopathy in patients treated with fumaric acid esters: a review of 19 cases. PMID- 28712000 TI - Predictors of weight loss in early treated Parkinson's disease from the NET-PD LS 1 cohort. AB - Weight loss is a common symptom of Parkinson's disease and is associated with impaired quality of life. Predictors of weight loss have not been studied in large clinical cohorts. We previously observed an association between change in body mass index and change in Unified Parkinson's Disease Rating Scale (UPDRS) motor and total scores. In this study, we performed a secondary analysis of longitudinal data (1-6 years) from 1619 participants in the NINDS Exploratory Trials in PD Long-term Study-1 (NET-PD LS1) to explore predictors of weight loss in a large prospective clinical trial cohort of early treated Parkinson's disease. The NET-PD LS1 study was a double-blind randomized placebo controlled clinical trial of creatine monohydrate 10 gm/day in early treated PD (within 5 years of diagnosis and within 2 years of starting dopaminergic medications). Linear mixed models were used to estimate the effect of baseline clinical covariates on weight change over time. On average, participants lost only 0.6 kg per year. Higher age, baseline weight, female gender, higher baseline UPDRS scores, greater postural instability, difficulty eating and drinking, lower cognitive scores and baseline levodopa use (compared to dopamine agonists) were all associated with weight loss. Surprisingly baseline difficulty swallowing, dyskinesia, depression, intestinal hypomotility (constipation) and self-reported nausea/vomiting/anorexia were not significantly associated with weight loss in this cohort of early treated Parkinson's disease patients. On average, participants with Parkinson's disease experience little weight loss during the first 1-6 years after starting dopaminergic replacement therapy, however levodopa use and postural instability were both predictors of early weight loss. Trial Registration clinicaltrials.gov identifier# NCT00449865. PMID- 28712001 TI - In-hospital ischaemic stroke treated with intravenous thrombolysis or mechanical thrombectomy. AB - Patients with in-hospital strokes (IHS) may be eligible for recanalization therapies. The objective of this study is to compare outcomes in patients with IHS and community-onset strokes (COS) treated by recanalization therapy. We analysed data prospectively collected in consecutive patients treated by thrombolysis, thrombectomy, or both for cerebral ischemia at the Lille University Hospital. We compared four outcomes measures at 3 months in patients with IHS and COS: (1) modified Rankin scale (mRS) 0-1, (2) mRS 0-2, (3) death, and (4) symptomatic intracranial haemorrhage (ECASS 2 definition). Of 1209 patients, 64 (5.3%) had IHS, with an increasing proportion over time (p = 0.001). Their median onset-to-needle time was 128 min vs. 145 in COS (p < 0.001). They were more likely to have had a recent TIA [odds ratio (OR) 30.1; 95% confidence interval (CI) 11.5-78.7], to have been treated by vitamin K antagonist before (OR 4.2; 95% CI 1.4-12.0) and to undergo mechanical thrombectomy (45 vs. 10%, p < 0.001). They were less likely to have a pre-stroke mRS 0-1 (OR 0.22; 95% CI 0.09-0.50). After adjustment, IHS was not associated with any of the four outcome measures. Patients with IHS are treated 17 min earlier than patients with COS, but, taking into account that they were already in the hospital, delays are still too long. Their outcome does not differ from that of patients with COS, suggesting room for improvement if delays can be reduced. IHS being frequent, pre-specified pathways should be organised. PMID- 28712002 TI - Mutations in GFPT1-related congenital myasthenic syndromes are associated with synaptic morphological defects and underlie a tubular aggregate myopathy with synaptopathy. AB - Mutations in GFPT1 (glutamine-fructose-6-phosphate transaminase 1), a gene encoding an enzyme involved in glycosylation of ubiquitous proteins, cause a limb girdle congenital myasthenic syndrome (LG-CMS) with tubular aggregates (TAs) characterized predominantly by affection of the proximal skeletal muscles and presence of highly organized and remodeled sarcoplasmic tubules in patients' muscle biopsies. We report here the first long-term clinical follow-up of 11 French individuals suffering from LG-CMS with TAs due to GFPT1 mutations, of which nine are new. Our retrospective clinical evaluation stresses an evolution toward a myopathic weakness that occurs concomitantly to ineffectiveness of usual CMS treatments. Analysis of neuromuscular biopsies from three unrelated individuals demonstrates that the maintenance of neuromuscular junctions (NMJs) is dramatically impaired with loss of post-synaptic junctional folds and evidence of denervation-reinnervation processes affecting the three main NMJ components. Moreover, molecular analyses of the human muscle biopsies confirm glycosylation defects of proteins with reduced O-glycosylation and show reduced sialylation of transmembrane proteins in extra-junctional area. Altogether, these results pave the way for understanding the etiology of this rare neuromuscular disorder that may be considered as a "tubular aggregates myopathy with synaptopathy". PMID- 28712004 TI - A comparison of perceptions of quality of life among adults with spinal cord injury in the United States versus the United Kingdom. AB - PURPOSE: To identify which aspects of life are most important to adults with spinal cord injury (SCI) and compare perspectives in the United States and the United Kingdom. METHODS: We conducted 20 in-depth interviews with adults with SCI (ten in the US and ten in the UK). Verbatim transcriptions were independently analyzed line-by-line by two coders using an inductive approach. Codes were grouped into themes about factors that constitute and affect quality of life (QOL). RESULTS: Five overarching themes emerged: describing QOL in the context of SCI; functional adjustment; medical care; financial resources; and socio political issues. Twenty subthemes emerged on factors that affect QOL. Participants in both samples identified medical care as a key influence on QOL. The US group talked about a predominantly negative influence (e.g., fragmented primary and specialist care, insurance constraints, bureaucracy), whereas UK interviewees mentioned a predominantly positive influence (e.g., universal provision, including free and continuous care, free wheelchairs and home care, and length of rehabilitation commensurate with level of injury). Functional adjustment, such as physical and mental adjustment post-discharge and aging with SCI, was another important contributor to QOL, and varied by country. Most US interviewees reported poor knowledge about self-care post-discharge and poor quality of home adaptations compared to the UK group. CONCLUSIONS: For adults living with SCI, good QOL is essential for successful rehabilitation. Differences between interviewees from the two countries in perceived medical care and functional adjustment suggest that factors affecting QOL may relate to broader health system characteristics. PMID- 28712003 TI - Association between chronic conditions and health-related quality of life: differences by level of urbanization in Peru. AB - PURPOSE: To evaluate the role of urbanization as an effect modifier for the association between specific chronic conditions and number of conditions with health-related quality of life (QOL). METHODS: We analyzed cross-sectional data from the CRONICAS Cohort Study conducted in Lima (highly urbanized), Tumbes (semi urban), as well as rural and urban sites in Puno. Exposures of interest were chronic bronchitis, depressive mood, hypertension, type 2 diabetes, and a composite variable aggregating the number of chronic conditions (the four exposures plus heart disease and stroke). QOL outcomes were assessed with EuroQol's EQ-5D visual analogue scale (EQ-VAS). We fitted linear regressions with robust variance to evaluate the associations of interest. Study site was assessed as a potential effect modifier using the likelihood-ratio (LR) test. RESULTS: We evaluated data on 2433 subjects: 51.3% were female, mean age was 57.2 years. Study site was found to be an effect modifier only for the association between depressive mood and EQ-VAS score (LR test p < 0.001). Compared to those without depressive mood, participants with depressive mood scored -13.7 points on the EQ VAS in Lima, -7.9 in urban Puno, -11.0 in semi-urban Tumbes, and -2.7 in rural Puno. Study site was not found to be an effect modifier for the association between the number of chronic conditions and EQ-VAS (LR test p = 0.64). CONCLUSION: The impact of depressive mood on EQ-VAS was larger in urban than in rural sites, while site was not an effect modifier for the remaining associations. PMID- 28712005 TI - An overview of the ongoing insights in selenium research and its role in fish nutrition and fish health. AB - In the present review, the ongoing researches about selenium research in fish nutrition have been comprehensively discussed. Selenium research is getting popularity in fish nutrition as it is required for the normal growth and proper physiological and biochemical functions in fish. Its deficiency or surplus amounts create severe problems in fish. It is available as inorganic form, organic form, and nano form. In fish, most of the previous research is about the selenium requirements for fish by using only one selenium source mainly the inorganic one. Selenium shows maximum biological activity and bioavailability when it is supplied in proper form. However, to differentiate the more bioavailable and less toxic form of selenium, sufficient information is needed about the comparative bioavailability of different selenium forms in different fish species. In fish, important data about the new forms of selenoproteins is still scarce. Therefore, it is necessary to focus on the determination and elucidation of the new selenoproteins in fish through the utilization of recent approaches of molecular biology and proteomics. The adaptation of these new approaches will replace the old fashioned methodologies regarding the selenium research in fish nutrition. Moreover, the use of molecular biology and proteomics based new approaches in combination with selenium research will help in optimizing the area of fish nutrition and will improve the feed intake, growth performance, and more importantly the flesh quality which has a promising importance in the consumer market. PMID- 28712007 TI - Erratum to: Microcephalic Osteodysplastic Primordial Dwarfism, Type II: a Clinical Review. PMID- 28712006 TI - An Inframe Trinucleotide Deletion in MTRR Exon 1 is Associated with the Risk of Spina Bifida. AB - Maternal genetic variants of enzymes in folate-homocysteine metabolic network are significantly correlative with the risk of spina bifida. To survey the genetic causality, the genotypes of three women having spina bifida fetuses from two unrelated Chinese families were screened in candidate alleles. Polymerase chain reaction, capillary electrophoresis and Sanger sequencing were employed to recognize the allelic variation. A trinucleotide deletion (c.4_6delAGG) was identified in the first exon of MTRR. All the three women showed the novel clinical variation including one heterozygous and two homozygous. The siblings who had healthy babies from the same families did not harbor the variation. In the unaffected control individuals, the variant was also not observed. Eukaryotic expression and bioinformatics techniques were utilized to explore the molecular pathogenesis of the potential genetic risk of developing spina bifida. Exceptionally, the functional examination revealed that the Arg2del variant kept subcellular localization unaltered with catalytic activity intact, but failed to efficiently activate MTR compared with the wild type. Genetic disorder of folate and homocysteine metabolism during pregnancy is believed to be associated with folate-sensitive neural tube defects. The report highlights that the inframe deletion in MTRR exon 1 could be a high risk factor susceptibility to spina bifida. PMID- 28712009 TI - Analysis of molecular subtypes for the increased HER2 equivocal cases caused by application of the updated 2013 ASCO/CAP HER2 testing guidelines in breast cancer. AB - PURPOSE: Accurate testing of the status of human epidermal growth factor receptor type 2 (HER2) is a prerequisite for HER2-directed therapy. The American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) published joint guideline recommendations for HER2 testing in breast cancer in 2007 and it was updated in 2013. We compared the HER2 gene amplification status based on these two guidelines and analyzed the molecular characteristics of the equivocal cases. PATIENTS AND METHODS: A total of 1894 patient samples were analyzed for both immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). HER2 FISH amplification was examined and re-assessed using 2013 guidelines. RESULTS: According to the 2013 ASCO/CAP recommendations, 763 (40.3%) cases were classified as HER2 positive compared with 729 (38.5%) cases defined by 2007 guidelines. There was a significant increase of 6.1% in the proportion of HER2 FISH equivocal cases that were interpreted using ASCO/CAP 2013 (7.3%) compared with 2007 (1.2%) guidelines (P < 0.001). Of 138 FISH equivocal cases defined by 2013 guidelines, 125 cases were IHC2+ and 13 cases were IHC1+. These 125 cases included 4 double equivocal cases which were defined as equivocal by both 2007 and 2013 guidelines and 121 cases whose status was changed from negative defined by 2007 guidelines to equivocal defined by 2013 guidelines. Compared with luminal A type and luminal B type respectively, these 121 equivocal cases demonstrated no significant difference with luminal B type in T stage and N stage (P = 0.192, P = 0.421). When we divided the luminal B type into two parts that included HER2 negative cases and HER2 positive cases, the equivocal cases also showed no significant difference with these two subtypes in T stage and N stage. CONCLUSIONS: Our study suggested that implementation of the revised ASCO/CAP 2013 guidelines resulted in an increase of 1.7% in overall HER2 positivity rate and of 6.1% in equivocal cases. Pathological analysis revealed that these equivocal cases exhibit similar biological behavior with luminal B type tumors. Clinical utility data on targeted therapy in equivocal patients should be further investigated. PMID- 28712008 TI - Acute lower gastrointestinal haemorrhage: outcomes and risk factors for intervention in 949 emergency cases. AB - PURPOSE: Outcomes of acute lower gastrointestinal haemorrhage (ALGIH) are mostly derived from studies performed in the sub-acute/elective rather than the emergency department (ED) setting. The aims of this study were to determine the incidence and outcomes of patients presenting to a tertiary hospital ED with ALGIH and to identify associated clinicopathological risk factors. METHOD: A retrospective observational cohort study of consecutive patients presenting with ALGIH to a tertiary hospital ED was performed. Primary outcome measures included mortality and hospital (including high dependency [HDU]) admission. Secondary outcome measures included rates of (i) blood transfusion, (ii) radiological/endoscopic investigation(s) and (iii) therapeutic intervention. RESULTS: ALGIH accounted for 949 (512 M, mean age 62.3 years) of 130,262 (0.73%) ED presentations, of which 285 patients (30.1%) were on anti-platelet/coagulant therapy. There were five deaths (0.5%). Hospital admission was required in 498 patients (52.5%), of which 19 (3.8%) required HDU monitoring. Hospital admission was twice as likely in males and four times more likely in patients >75 years old and those taking multiple anti-platelet/coagulant therapy (P < 0.05). Blood product transfusion was required in 172 patients (34.5%), specialist investigations in 230 (46.2%) and therapeutic intervention in 51 (10.2%) (surgery in 24 [4.8%]; endoscopic haemostasis in 20 [4.0%] and angiographic embolisation in 9 [1.8%] patients). CONCLUSION: ALGIH accounts for 1% of all ED presentations, with half requiring hospital admission. Mortality and surgical intervention rates are low and although most patients can be managed supportively, access to interventional radiology/endoscopy is important. PMID- 28712010 TI - The interaction between individualism and wellbeing in predicting mortality: Survey of Health Ageing and Retirement in Europe. AB - The link between greater wellbeing and longevity is well documented. The aim of the current study was to test whether this association is consistent across individualistic and collectivistic cultures. The sample consisted of 13,596 participants from 11 European countries, each of which was assigned an individualism score according to Hofstede et al.'s (Cultures and organizations: software of the mind, McGraw Hill, New York, 2010) cultural dimension of individualism. We tested whether individualism moderated the cross-sectional association between wellbeing and self-rated health or the longitudinal association between wellbeing and mortality risk. Our analysis revealed a significant interaction between individualism and wellbeing such that the association between wellbeing and self-rated health or risk of mortality from cardiovascular disease was stronger in more individualistic countries. However, the interaction between wellbeing and individualism was not significant in analysis predicting all-cause mortality. Further prospective studies are needed to confirm our finding and to explore the factors responsible for this culturally dependent effect. PMID- 28712012 TI - Development of an MR-compatible hand exoskeleton that is capable of providing interactive robotic rehabilitation during fMRI imaging. AB - Following advances in robotic rehabilitation, there have been many efforts to investigate the recovery process and effectiveness of robotic rehabilitation procedures through monitoring the activation status of the brain. This work presents the development of a two degree-of-freedom (DoF) magnetic resonance (MR) compatible hand device that can perform robotic rehabilitation procedures inside an fMRI scanner. The device is capable of providing real-time monitoring of the joint angle, angular velocity, and joint force produced by the metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints of four fingers. For force measurement, a custom reflective optical force sensor was developed and characterized in terms of accuracy error, hysteresis, and repeatability in the MR environment. The proposed device consists of two non magnetic ultrasonic motors to provide assistive and resistive forces to the MCP and PIP joints. With actuation and sensing capabilities, both non-voluntary passive movements and active-voluntary movements can be implemented. The MR compatibility of the device was verified via the analysis of the signal-to-noise ratio (SNR) of MR images of phantoms. SNR drops of 0.25, 2.94, and 11.82% were observed when the device was present but not activated, when only the custom force sensor was activated, and when both the custom force sensor and actuators were activated, respectively. PMID- 28712011 TI - FGF21 Attenuates High-Fat Diet-Induced Cognitive Impairment via Metabolic Regulation and Anti-inflammation of Obese Mice. AB - Accumulating studies suggest that overnutrition-associated obesity may lead to development of type 2 diabetes mellitus and metabolic syndromes (MetS). MetS and its components are important risk factors of mild cognitive impairment, age related cognitive decline, vascular dementia, and Alzheimer's disease. It has been recently proposed that development of a disease-course modification strategy toward early and effective risk factor management would be clinically significant in reducing the risk of metabolic disorder-initiated cognitive decline. In the present study, we propose that fibroblast growth factor 21 (FGF21) is a novel candidate for the disease-course modification approach. Using a high-fat diet (HFD) consumption-induced obese mouse model, we tested our hypothesis that recombinant human FGF21 (rFGF21) administration is effective for improving obesity-induced cognitive dysfunction and anxiety-like behavior, by its multiple metabolic modulation and anti-pro-inflammation actions. Our experimental findings support our hypothesis that rFGF21 is protective to HFD-induced cognitive impairment, at least in part by metabolic regulation in glucose tolerance impairment, insulin resistance, and hyperlipidemia; potent systemic pro inflammation inhibition; and improvement of hippocampal dysfunction, particularly by inhibiting pro-neuroinflammation and neurogenesis deficit. This study suggests that FGF21 might be a novel molecular target of the disease-course-modifying strategy for early intervention of MstS-associated cognitive decline. PMID- 28712013 TI - A novel approach to an automated needle insertion in brachytherapy procedures. AB - One of the most challenging phases in interstitial brachytherapy is the placement of the needles. In these medical procedures, the needles are inserted inside the tissue to guide the positioning of the radioactive sources. The low-dose-rate radioactive sources are placed inside the tissue permanently, whereas a radioactive source in the high-dose-rate brachytherapy is temporarily placed in the desired positions so that the delivery of the prescription dose to the clinical targets can be achieved. Consequently, the precise needle placement directly influences the radiation dose delivery and the treatment outcomes of patients. Any deviation from the desired position of the radioactive sources can cause a suboptimal dose distribution and inadequate tumor coverage. Therefore, it is of significant importance to develop a robust and sophisticated tool that can perform the automatic needle placement with a high level of accuracy for different medical procedures and conditions. In this study, we propose a novel concept for the automatic needle insertion using a new miniature automated robotic system. The mathematical model of this system was presented in detail, allowing the implementation of the model predictive control that can be used to govern the mechanism. The purpose of this approach was to minimize the lateral components of the generalized reactive force which is responsible for the tissue displacement and, consequently, for the needle deflection. The proposed approach was designed to predict and to compensate for the unmeasured disturbances, such as needle deflection or tissue resistance and reactive force, and it was capable of correcting them without waiting until the effect appears at the output of the system causing the needle deviation from the desired positions. The extensive simulation of the system was presented to evaluate the feasibility of the method and the parameters of interest including displacements, system errors and system responses to the change in the environmental conditions. PMID- 28712014 TI - Do you see what I see? Mobile eye-tracker contextual analysis and inter-rater reliability. AB - Mobile eye-trackers are currently used during real-world tasks (e.g. gait) to monitor visual and cognitive processes, particularly in ageing and Parkinson's disease (PD). However, contextual analysis involving fixation locations during such tasks is rarely performed due to its complexity. This study adapted a validated algorithm and developed a classification method to semi-automate contextual analysis of mobile eye-tracking data. We further assessed inter-rater reliability of the proposed classification method. A mobile eye-tracker recorded eye-movements during walking in five healthy older adult controls (HC) and five people with PD. Fixations were identified using a previously validated algorithm, which was adapted to provide still images of fixation locations (n = 116). The fixation location was manually identified by two raters (DH, JN), who classified the locations. Cohen's kappa correlation coefficients determined the inter-rater reliability. The algorithm successfully provided still images for each fixation, allowing manual contextual analysis to be performed. The inter-rater reliability for classifying the fixation location was high for both PD (kappa = 0.80, 95% agreement) and HC groups (kappa = 0.80, 91% agreement), which indicated a reliable classification method. This study developed a reliable semi-automated contextual analysis method for gait studies in HC and PD. Future studies could adapt this methodology for various gait-related eye-tracking studies. PMID- 28712016 TI - A Survey of Pesticide Accumulation in a Specialist Feeder, the Koala (Phascolarctos cinereus). AB - To maintain profitability in Australia's agricultural and urban landscapes pesticides are used throughout the range of koala habitats. The koala is a specialist feeder, reliant on metabolic enzyme capacities to utilise a toxic diet of eucalypt leaves and is potentially prone to adverse effects when xenobiotic interactions between dietary and anthropogenic xenobiotics occur. The aim of this study was to investigate accumulation of frequently used pesticides in wild koalas in 4 areas of New South Wales and Queensland. Liver samples of 57 deceased koalas were collected from care facilities and analysed using a modified QuEChERS extraction method followed by GCMSMS, HRLCMS and LCMSMS. No accumulation of any of the 166 investigated pesticides was found. Data indicate hepatic accumulation of pesticides in this species is uncommon even with close interactions with intensive land use. Despite the lack of hepatic bioaccumulation, this study cannot exclude a direct effect on hepatocellular metabolic pathways. PMID- 28712015 TI - Mechanisms contributing to reduced knee stiffness during movement. AB - The ability to modulate the mechanical properties of our limbs contributes to our ability to interact with the physical world in a consistent and predictable manner. An individual joint's contributions to whole limb mechanics can be quantified by its joint impedance, which characterizes the torque generated about a joint in response to external perturbations of position. A number of studies have estimated joint impedance during movement and have shown that it can be much lower than it is during posture. However, the mechanisms contributing to these differences remain unknown partly because conditions known to affect impedance, including muscle activation and joint angles, have not been carefully controlled across studies. The goal of this study was to contrast knee impedance during continuous volitional movements with that during maintained postures spanning a similar range of joint angles and muscle activations and to explore physiological mechanisms likely to contribute to the observed differences. We found that knee impedance was substantially lower during movement than during matched postural tasks, even for matched muscle activations. At times, the impedance during movement was even lower than that measured during isometric tasks with no volitional muscle activity. These decreases in impedance could be attributed in part to reduced stretch reflexes during movement and to an effect of movement itself on reducing knee impedance. PMID- 28712017 TI - The distribution of infection with Propionibacterium acnes is equal in patients with cervical and lumbar disc herniation. AB - BACKGROUND: Cervical and back pains are important clinical problems affecting human populations globally. It is suggested that Propionibacterium acnes (P. acnes) is associated with disc herniation. The aim of this study is to evaluate the distribution of P. acnes infection in the cervical and lumbar disc material obtained from patients with disc herniation. METHODS AND MATERIAL: A total of 145 patients with mean age of 45.21 +/- 11.24 years who underwent micro-discectomy in cervical and lumbar regions were enrolled into the study. The samples were excited during the operation and then cultured in the anaerobic incubations. The cultured P. acnes were detected by 16S rRNA-based polymerase chain reaction. RESULTS: In this study, 145 patients including 25 cases with cervical and 120 cases with lumbar disc herniation were enrolled to the study. There was no significant difference in the age of male and female patients (p = 0.123). P. acnes infection was detected in nine patients (36%) with cervical disc herniation and 46 patients (38.3%) with lumbar disc herniation and no significant differences were reported in P. acnes presence according to the disc regions (p = 0.508.). Moreover, there was a significant difference in the presence of P. acnes infection according to the level of lumbar disc herniation (p = 0.028). CONCLUSION: According to the results, the presence of P. acnes is equal in patients with cervical and lumbar disc herniation. There was a significant difference in the distribution of P. acnes infection according to level of lumbar disc herniation. LEVEL OF EVIDENCE: II. PMID- 28712018 TI - Laparoscopic implantation of electrodes for bilateral neuromodulation of the pudendal nerves and S3 nerve roots for treating pelvic pain and voiding dysfunction. AB - INTRODUCTION AND HYPOTHESIS: The objective of this video is to describe the technique for laparoscopic implantation of electrodes for bilateral neuromodulation of S3 and pudendal nerves. We report a successful case of a 48 year-old woman with spina bifida occulta referred with a 14-year history of intense acyclic pelvic pain, urinary hesitancy, and intermittent flow refractory to various conservative measures. METHODS: The procedure began with the removal of two previously placed InterStims. A quadripolar electrode was then laparoscopically inserted into Alcock's canal and attached to the pelvic pectineal line. Another lead was placed juxtaneurally to S3. Lead contacts were then exteriorized, and the peritoneum closed. The same procedure was then performed on the contralateral side. The leads were connected to a 16-pole rechargeable pulse generator. Postoperatively, the patient developed an acute dissection and partial thrombosis of the external iliac artery, which was treated endovascularly. RESULTS: Complete pain resolution was observed with simultaneous S3 and pudendal stimulation, with pudendal stimulation turned off for voiding. CONCLUSIONS: We conclude that laparoscopic implantation of neuromodulation electrodes allows simultaneous stimulation of S3 and pudendal nerves, providing more programming options and possibly increasing success rates in complex pelvic floor dysfunction cases. PMID- 28712019 TI - Maternal body mass index before pregnancy as a risk factor for ADHD and autism in children. AB - The risk of attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorders (ASD) may be influenced by environmental factors such as maternal obesity before pregnancy. Previous studies investigating those associations have found divergent results. We aim to investigate in a large birth cohort this association further in children with ADHD, ASD and comorbid ADHD and ASD. Our study population consisted of 81,892 mother-child pairs participating in the Danish National Birth Cohort (DNBC). Information about pre-pregnancy weight and height was collected in week 16 of pregnancy; the analysis was divided into groups based on BMI. Children with a clinical diagnosis of ADHD and/or ASD were identified in the Danish health registries at an average age of 13.3 years. Hazard ratios (HRs) were estimated using time-to-event analysis. Compared to normal weight mothers, the risk of having a child with ADHD was significantly increased if the mother was overweight (HR = 1.28 [95% CI 1.15;1.48]), obese (HR = 1.47 [95% CI 1.26;1.71]) or severely obese (HR = 1.95 [95% CI 1.58;2.40]). The same pattern was seen for the combined ADHD and ASD group. Regarding ASD, an increased risk was observed in underweight (HR = 1.30 [95% CI 1.01;1.69]) and obese (HR = 1.39 [95% CI 1.11;1.75]) mothers. Subgroup analysis revealed that the association in the ADHD group could mostly be attributable to the hyperactive group. Maternal obesity before pregnancy is a risk factor for ADHD in children. Maternal obesity as well as underweight may also be associated with an increased risk for ASD. PMID- 28712020 TI - Considering Weight Loss Programs and Public Health Partnerships in American Evangelical Protestant Churches. AB - The obesity epidemic is a critical public health threat facing the USA. With the advent of American Evangelical Protestant (AEP) weight loss guides and narratives, AEP churches could potentially aid public health agencies in combatting obesity, and some scholars have called for investment in partnerships between public health agencies and religious institutions. This paper examines the theological and social underpinnings of AEP weight loss programs and considers the potential benefits and risks of public health partnerships with AEP churches to combat obesity. While AEP churches may be successful at empowering people to lose weight, AEP weight loss also carries several risks. These risks include reinforcing gendered bodily norms, stigmatizing both overweight bodies and unhealthy behaviors deemed to be sinful (for example, overeating), and failing to acknowledge social factors that promote obesity. These risks must be assessed and minimized to create appropriate public health weight loss partnerships with AEP communities. PMID- 28712021 TI - The State of Essential Newborn Care by Delivery Location in Bangladesh. AB - Introduction Essential newborn care (ENC) around the time of birth is critical in improving neonatal survival. There is currently a gap in our knowledge of the use of ENC by place of delivery in Bangladesh. This study assesses the provision of ENC and examines the odds of newborns receiving ENC by different levels of delivery care in Bangladesh. Methods Descriptive statistics and logistic regressions were performed on ENC practices from the 2011 Bangladesh Demographic and Health Survey dataset. ENC practices included nonapplication of substances to the cord; application of antiseptic to the cord; drying newborn within 5 min; wrapping newborn within 5 min; delaying first bath until the first 72 h; and breastfeeding within 1 h. Key predictors included home delivery with a lay attendant, delivery with primary healthcare services and delivery with higher level healthcare services. Results Coverage of ENC practices was low. Women who delivered with primary and higher-level healthcare services generally reported greater odds of their newborns receiving recommended ENC than women who had home delivery with a lay attendant, the referent category. However, the odds of delayed first bath until 72 h and breastfeeding within 1 h were not statistically different for newborns who were delivered with primary healthcare services. Discussion These findings have significant public health implications as primary healthcare facilities are the first point of entry into the healthcare system. Provision of ENC, particularly delayed first bath until 72 h and breastfeeding within 1 h, should be encouraged for all healthy mother-newborn pairs in Bangladesh. PMID- 28712022 TI - Effects of Dietary Lactobacillus plantarum on Growth Performance, Digestive Enzymes and Gut Morphology of Litopenaeus vannamei. AB - A 15-day feeding trial was conducted to investigate the effect of dietary Lactobacillus plantarum on growth performance, digestive enzyme activities and gut morphology of juvenile Pacific white shrimp, Litopenaeus vannamei (initial body weight = 7.96 +/- 0.59 g). Four microbound diets were formulated to contain fermentation supernatant (FS), live bacteria (LB), dead bacteria (DB), and cell free extract (CE) of L. plantarum. Results indicated that final weight was significantly higher in FS, DB, and CE group in comparison to the control group (P < 0.05). The maximum weight gain rate (WGR) and specific growth rate (SGR) of the CE diet group were significantly higher than that of other groups (P < 0.05). The FCR of CE diet group was lower than that of the control, LB, DB, and FS diets groups (P < 0.05). The highest digestive enzyme activities (amylase, lipase, and pepsin activity) in the hepatopancreas and gut of shrimp were observed in the CE diet group. Histological study revealed that dietary CE diet could significantly increase the enterocytes height of shrimp. The administration of cell-free extract of L. plantarum could effectively improve the growth performance of L. vannamei via the improvement of digestive enzyme activities and the enterocytes height of shrimp. The results of this study will be essential to promote application of probiotics in shrimp aquaculture. PMID- 28712023 TI - Selection of Potential Probiotic Lactobacillus with Inhibitory Activity Against Salmonella and Fecal Coliform Bacteria. AB - Three hundred and sixty presumptive lactic acid bacteria (LAB) isolated from pregnant sows, newborn, suckling, and weaned piglets were preliminarily screened for anti-Salmonella activity. Fifty-eight isolates consisting of Lactobacillus reuteri (n = 32), Lactobacillus salivarius (n = 10), Lactobacillus mucosae (n = 8), Lactobacillus johnsonii (n = 5), and Lactobacillus crispatus (n = 3) were selected and further characterized for probiotic properties including production of antimicrobial substances, acid and bile tolerance, and cell adherence to Caco 2 cells. Eight isolates including Lact. johnsonii LJ202 and Lact. reuteri LR108 were identified as potential probiotics. LJ202 was selected for further use in co culture studies of two-bacterial and multiple-bacterial species to examine its inhibitory activity against Salmonella enterica serovar Enteritidis DMST7106 (SE7106). Co-culture of LJ202 and SE7106 showed that LJ202 could completely inhibit the growth of SE7106 in 10 h of co-culture. In co-culture of multiple bacterial species, culturable fecal bacteria from pig feces were used as representative of multiple-bacterial species. The study was performed to examine whether interactions among multiple-bacterial species would influence antagonistic activity of LJ202 against SE7106 and fecal coliform bacteria. Co culture of SE7106 with different combinations of fecal bacteria and probiotic (LJ202 and LR108) or non-probiotic (Lact. mucosae LM303) strains revealed that the growth of SE7106 was completely inhibited either in the presence or in the absence of probiotic strains. Intriguingly, LJ202 exhibited notable inhibitory activity against fecal coliform bacteria while LR108 did not. Taken together, the results of co-culture studies suggested that LJ202 is a good probiotic candidate for further study its inhibitory effects against pathogen infections in pigs. PMID- 28712024 TI - Knee hyperextension does not adversely affect dynamic in vivo kinematics after anterior cruciate ligament reconstruction. AB - PURPOSE: To evaluate the effect of knee hyperextension on dynamic in vivo kinematics after anterior cruciate ligament reconstruction (ACL-R). METHODS: Forty-two patients underwent unilateral ACL-R. Twenty-four months after surgery, subjects performed level walking and downhill running on a treadmill while dynamic stereo radiographs were acquired at 100 (walking) and 150 Hz (running). Tibiofemoral motion was determined using a validated model-based tracking process, and tibiofemoral translations/rotations were calculated. The range of tibiofemoral motions from 0 to 10% of the gait cycle (heel strike to early stance phase) and side-to-side difference (SSD) were calculated. Maximum knee extension angle of ACL-reconstructed knees during walking was defined as active knee extension angle in each subject. Correlations between maximum knee extension angle and tibiofemoral kinematics data were evaluated using Spearman's rho (P < 0.05). RESULTS: No significant correlation was observed between maximum knee extension angle and the range of anterior tibial translation during functional activities in the ACL-R knees. Maximum knee extension angle was weakly correlated with internal tibial rotation range in ACL-R knee during running (rho = 0.376, P = 0.014); however, maximum extension angle was not correlated with SSD of internal tibial rotation. SSD of internal tibial rotation was -0.4 degrees +/- 1.9 degrees (walking), -1.6 degrees +/- 3.1 degrees (running), indicating ACL R restored rotatory knee range of motion during functional movements. CONCLUSION: Knee hyperextension was not significantly correlated with greater SSD of anterior translation and internal rotation. The clinical relevance is that knee hyperextension does not adversely affect kinematic outcomes after ACL-R and that physiologic knee hyperextension can be restored after ACL-R when knee hyperextension is present. LEVEL OF EVIDENCE: III. PMID- 28712025 TI - Side-to-side asymmetries in landing mechanics from a drop vertical jump test are not related to asymmetries in knee joint laxity following anterior cruciate ligament reconstruction. AB - PURPOSE: Asymmetries in knee joint biomechanics and increased knee joint laxity in patients following anterior cruciate ligament reconstruction (ACLR) are considered risk factors for re-tear or early onset of osteoarthritis. Nevertheless, the relationship between these factors has not been established. The aim of the study was to compare knee mechanics during landing from a bilateral drop vertical jump in patients following ACLR and control participants and to study the relationship between side-to-side asymmetries in landing mechanics and knee joint laxity. METHODS: Seventeen patients following ACLR were evaluated and compared to 28 healthy controls. Knee sagittal and frontal plane kinematics and kinetics were evaluated using three-dimensional motion capture (200 Hz) and two synchronized force platforms (1000 Hz). Static anterior and internal rotation knee laxities were measured for both groups and legs using dedicated arthrometers. Group and leg differences were investigated using a mixed model analysis of variance. The relationship between side-to-side differences in sagittal knee power/energy absorption and knee joint laxities was evaluated using univariate linear regression. RESULTS: A significant group-by-leg interaction (p = 0.010) was found for knee sagittal plane energy absorption, with patients having 25% lower values in their involved compared to their non-involved leg (1.22 +/- 0.39 vs. 1.62 +/- 0.40 J kg-1). Furthermore, knee sagittal plane energy absorption was 18% lower at their involved leg compared to controls (p = 0.018). Concomitantly, patients demonstrated a 27% higher anterior laxity of the involved knee compared to the non-involved knee, with an average side-to-side difference of 1.2 mm (p < 0.001). Laxity of the involved knee was also 30% higher than that of controls (p < 0.001) (leg-by-group interaction: p = 0.002). No relationship was found between sagittal plane energy absorption and knee laxity. CONCLUSIONS: Nine months following surgery, ACLR patients were shown to employ a knee unloading strategy of their involved leg during bilateral landing. However, this strategy was unrelated to their increased anterior knee laxity. Side-to-side asymmetries during simple bilateral landing tasks may put ACLR patients at increased risk of second ACL injury or early-onset osteoarthritis development. Detecting and correcting asymmetric landing strategies is highly relevant in the framework of personalized rehabilitation, which calls for complex biomechanical analyses to be applied in clinical routine. LEVEL OF EVIDENCE: III. PMID- 28712026 TI - Posterior cruciate ligament is twisted and flat structure: new prospective on anatomical morphology. AB - PURPOSE: This cadaveric study aimed to elucidate PCL morphology by observing the anatomical relationship with other structures and the fibre layers of the PCL in cross section for remnant preserving PCL reconstruction. METHODS: Seventeen fresh frozen cadaveric knees were studied, using the clock-face method to analyse the anatomical relationship between the PCL and Humphrey's ligament. The width and thickness of the PCL, Humphrey's and Wrisberg's ligaments were measured. The PCL was cut sharply perpendicular to the tibia shaft, and the fibre layers were observed in cross section. RESULTS: The PCL was located between 12 and 4 o'clock in the right knee (8 and 12 o'clock in the left), while Humphrey's ligament was located between 2 and 4 o'clock in the right knee (8 and 10 o'clock in the left). Humphrey's ligament at femoral insertion, midsubstance and lateral meniscus insertion averaged 8.7 +/- 2.3, 5.9 +/- 2.1 and 6.1 +/- 2.0 mm, respectively, while the thickness at each level averaged 2.0 +/- 1.2, 1.6 +/- 0.6 and 1.9 +/- 0.6 mm. The width of the PCL at midsubstance and at medial meniscus level averaged 13.3 +/- 2.0 and 11.0 +/- 1.6 mm, respectively, while the thickness of the PCL averaged 5.4 +/- 0.8 and 5.5 +/- 1.4 mm. In cross section, multiple, interconnected layers were observed which could not be divided. The main layers at each level were aligned from the posterolateral to the anteromedial aspect and formed a C-shape at the medial meniscus level. CONCLUSION: The PCL at midsubstance is flat. PCL appears as a twisted ribbon composed of many small fibres without clearly separate bundles. When remnant preserving PCL reconstruction is performed, it is necessary to take account of not only PCL morphology but also the ligaments of Humphrey and Wrisberg. These findings may affect the PCL footprint and the graft shape in the future remnant preserving PCL reconstruction. PMID- 28712027 TI - Concomitant meniscal injury in anterior cruciate ligament reconstruction does not lead to poorer short-term post-operative outcomes. AB - PURPOSE: The main objective was to compare post-operative outcomes in patients undergoing anterior cruciate ligament (ACL) reconstruction both with and without concomitant meniscus injury at a mean follow-up of 3.5 years. The secondary objective was to study the effect of different meniscal injury sites and treatment modalities on post-operative outcomes (PROS). METHODS: This is a retrospective analysis of a prospectively maintained database of patients undergoing ACL reconstruction at our tertiary institution between 2009 and 2012. Age, sex, graft type, graft fixation modality, location of meniscal tear and treatment (meniscal repair or meniscectomy) were recorded in the database. PROS used included the Tegner activity scale and the Lysholm score. RESULTS: There were no significant differences between patients with or without meniscal injury in terms of age, BMI or preoperative PROS. There was no significant difference in the post-operative outcome scores between patients with or without meniscal injury at a mean follow-up of 3.5 years. Regardless of the location of meniscal injury, the post-operative scores improved as compared to preoperative scores. CONCLUSION: Concomitant meniscal injury in cases of ACL reconstruction is not associated with poorer short-term post-operative PROS (mean follow-up time: 3.5 years). These findings may influence management decisions and help in preoperative counselling. LEVEL OF EVIDENCE: IV. PMID- 28712028 TI - Internal femoral component rotation adversely influences load transfer in total knee arthroplasty: a cadaveric navigated study using the Verasense device. AB - PURPOSE AND HYPOTHESIS: Correct femoral component rotation at knee arthroplasty influences patellar tracking and may determine function at extremes of movement. Additionally, such malrotation may deleteriously influence flexion/extension gap geometry and soft tissue balancing kinematics. Little is known about the effect of subtle rotational change upon load transfer across the tibiofemoral articulation. Our null hypothesis was that femoral component rotation would not influence load across this joint in predictable manner. METHODS: A cadaveric study was performed to examine load transfer using the orthosensor device, respecting laxity patterns in 6 degrees of motion, to examine load across the medial and lateral compartments across a full arc of motion. Mixed-effect modelling allowed for quantification of the effect upon load with internal and external femoral component rotation in relation to a datum in a modern single radius cruciate-retaining primary knee design. RESULTS: No significant change in maximal laxity was found between different femoral rotational states. Internal rotation of the femoral component resulted in significant increase in medial compartment load transfer for knee flexion including and beyond 60 degrees . External rotation of the femoral component within the limits studied did not influence tibiofemoral load transfer. CONCLUSIONS: Internal rotation of the femoral component will adversely influence medial compartment load transfer and could lead to premature polyethylene wear on the medial side. PMID- 28712030 TI - Predictive modelling of eutrophication in the Pozon de la Dolores lake (Northern Spain) by using an evolutionary support vector machines approach. AB - Eutrophication is a water enrichment in nutrients (mainly phosphorus) that generally leads to symptomatic changes and deterioration of water quality and all its uses in general, when the production of algae and other aquatic vegetations are increased. In this sense, eutrophication has caused a variety of impacts, such as high levels of Chlorophyll a (Chl-a). Consequently, anticipate its presence is a matter of importance to prevent future risks. The aim of this study was to obtain a predictive model able to perform an early detection of the eutrophication in water bodies such as lakes. This study presents a novel hybrid algorithm, based on support vector machines (SVM) approach in combination with the particle swarm optimization (PSO) technique, for predicting the eutrophication from biological and physical-chemical input parameters determined experimentally through sampling and subsequent analysis in a certificate laboratory. This optimization technique involves hyperparameter setting in the SVM training procedure, which significantly influences the regression accuracy. The results of the present study are twofold. In the first place, the significance of each biological and physical-chemical variables on the eutrophication is presented through the model. Secondly, a model for forecasting eutrophication is obtained with success. Indeed, regression with optimal hyperparameters was performed and coefficients of determination equal to 0.90 for the Total phosphorus estimation and 0.92 for the Chlorophyll concentration were obtained when this hybrid PSO-SVM-based model was applied to the experimental dataset, respectively. The agreement between experimental data and the model confirmed the good performance of the latter. PMID- 28712029 TI - Good clinical results but moderate osseointegration and defect filling of a cell free multi-layered nano-composite scaffold for treatment of osteochondral lesions of the knee. AB - PURPOSE: The aim of this retrospective study was to evaluate the clinical and radiological results of a nano-composite multi-layered three-dimensional biomaterial scaffold for treatment of osteochondral lesions (OCL) of the knee. It was a particular radiological interest to analyse the osseointegration, filling of the defects and the bone tracer uptake (BTU), and it was hypothesised that this scaffold, which was created to mimic the entire osteo-cartilaginous unit, is integrated within the bone 12 months postoperatively and comes along with improved patients symptoms and function. METHODS: Fourteen patients (male:female = 11:3, mean age +/- SD 33.1 +/- 10.7 years) treated for OCL (size 1.0-3.5 cm2) were clinically and radiologically evaluated at 1 year postoperatively. The data were prospectively collected including SPECT/CT, Tegner and Lysholm scores. BTU was anatomically localised and volumetrically quantified in SPECT/CT. Defect filling was analysed in CT. Spearman's rho and Wilcoxon test were used for correlation of BTU in SPECT/CT and clinical scores (p < 0.05). RESULTS: A significant improvement in Lysholm knee score (p < 0.001) and slight deterioration in Tegner score were found (p < 0.01). A complete filling of the defect was shown in 14%, a partial filling in 14% and only minor filling was seen in 72%. A significant correlation (p < 0.001) was found between location of osteochondral lesions and increased BTU. At the lesion sites pre- and postoperative BTU was markedly increased and did not show any decrease at 12 month follow-up. Median Tegner and mean Lysholm scores did not correlate with BTU at any time. CONCLUSIONS: Treatment of OCL in the knee joint with a nano composite multi-layered three-dimensional biomaterial scaffold resulted in a significant clinical improvement at 1-year follow-up. However, osseointegration was still ongoing at 12-month follow-up. LEVEL OF EVIDENCE: Case series, Level IV. PMID- 28712031 TI - Human skeletal muscle type 1 fibre distribution and response of stress-sensing proteins along the titin molecule after submaximal exhaustive exercise. AB - Early responses of stress-sensing proteins, muscle LIM protein (MLP), ankyrin repeat proteins (Ankrd1/CARP and Ankrd2/Arpp) and muscle-specific RING finger proteins (MuRF1 and MuRF2), along the titin molecule were investigated in the present experiment after submaximal exhaustive exercise. Ten healthy men performed continuous drop jumping unilaterally on a sledge apparatus with a submaximal height until complete exhaustion. Five stress-sensing proteins were analysed by mRNA measurements from biopsies obtained immediately and 3 h after the exercise from exercised vastus lateralis muscle while control biopsies were obtained from non-exercised legs before the exercise. Decreased maximal jump height and increased serum creatine kinase activities as indirect markers for muscle damage and HSP27 immunostainings on muscle biopsies as a direct marker for muscle damage indicated that the current exercised protocol caused muscle damage. mRNA levels for four (MLP, Ankrd1/CARP, MuRF1 and MuRF2) out of the five studied stress sensors significantly (p < 0.05) increased 3 h after fatiguing exercise. The magnitude of MLP and Ankrd2 responses was related to the proportion of type 1 myofibres. Our data showed that the submaximal exhaustive exercise with subject's own physical fitness level activates titin-based stretch-sensing proteins. These results suggest that both degenerative and regenerative pathways are activated in very early phase after the exercise or probably already during the exercise. Activation of these proteins represents an initial step forward adaptive remodelling of the exercised muscle and may also be involved in the initiation of myofibre repair. PMID- 28712032 TI - Copper stressed anaerobic fermentation: biogas properties, process stability, biodegradation and enzyme responses. AB - The effect of copper (added as CuCl2) on the anaerobic co-digestion of Phragmites straw and cow dung was studied in pilot experiments by investigating the biogas properties, process stability, substrate degradation and enzyme activities at different stages of mesophilic fermentation. The results showed that 30 and 100 mg/L Cu2+ addition increased the cumulative biogas yields by up to 43.62 and 20.77% respectively, and brought forward the daily biogas yield peak, while 500 mg/L Cu2+ addition inhibited biogas production. Meanwhile, the CH4 content in the 30 and 100 mg/L Cu2+-added groups was higher than that in the control group. Higher pH values (close to pH 7) and lower oxidation-reduction potential (ORP) values in the Cu2+-added groups after the 8th day indicated better process stability compared to the control group. In the presence of Cu2+, the degradation of volatile fatty acids (VFAs) and other organic molecules (represented by chemical oxygen demand, COD) generated from hydrolysis was enhanced, and the ammonia nitrogen (NH4+-N) concentrations were more stable than in the control group. The contents of lignin and hemicellulose in the substrate declined in the Cu2+-added groups while the cellulose contents did not. Neither the cellulase nor the coenzyme F420 activities could determine the biogas producing efficiency. Taking the whole fermentation process into account, the promoting effect of Cu2+ addition on biogas yields was mainly attributable to better process stability, the enhanced degradation of lignin and hemicellulose, the transformation of intermediates into VFA, and the generation of CH4 from VFA. PMID- 28712033 TI - Oncolytic immunotherapy: unlocking the potential of viruses to help target cancer. AB - Oncolytic immunotherapy is a research area of cancer immunotherapy investigating the use of modified viruses to target cancer cells. A variety of different viral backbones (e.g., adenovirus, reovirus) with a diverse range of genetic modifications are currently being investigated for the treatment of a variety of cancers. The oncolytic virus that has advanced the furthest in clinical development is talimogene laherparepvec, a recombinant HSV-1 virus expressing granulocyte-macrophage colony-stimulating factor (GM-CSF). In a phase 3 study in patients with unresectable metastatic melanoma, intralesional talimogene laherparepvec treatment resulted in a higher durable response rate compared with subcutaneous GM-CSF treatment (16.3 versus 2.1%; P < 0.001). Notably, responses were observed at uninjected lesions including visceral lesions, indicating a systemic antitumor response had occurred. Studies evaluating combination treatments involving oncolytic viruses and immunologic agents are ongoing. This review focuses on the mechanisms of action for oncolytic viruses and highlights select agents and combinations currently in development. PMID- 28712035 TI - Ginsenoside improves physicochemical properties and bioavailability of curcumin loaded nanostructured lipid carrier. AB - The aim of this study was to develop a ginsenoside-modified nanostructured lipid carrier (G-NLC) dispersion containing curcumin. The NLC was prepared by melt emulsification with slight modification process. Different G-NLC dispersion systems were prepared using lipid carrier matrix composed of ginsenoside, phosphatidylcholine, lysophosphatidylcholine, and hydrogenated bean oil. TEM image of the nanoparticles in the NLC dispersion showed core/shell structure, and there was corona-like layer surrounding the particles in the G-NLC. The mean particle size of G-NLC dispersion was in the range of about 300-500 nm and stayed submicron size up to 12 months. The in vitro release of curcumin was faster in pH 1.2 compared to pH 6.8 and it showed linear release pattern after lag time of 1 h. When the G-NLC dispersion was orally administered to rats, Cmax of the free curcumin was 15.2 and 32.3 ng/mL at doses of 50 and 100 mg/kg, respectively, while it was below quantification limit when curcumin was administered as of dispersion in distilled water. Based on these results, it is certain that ginsenoside modulated the NLC dispersion, leading to enduring shelf-life of the dispersion system and enhanced bioavailability. These results strongly suggest that ginsenoside holds a promising potential as a pharmaceutical excipient in the pharmaceutical industries to increase the utility of various bioactives. PMID- 28712034 TI - Recurrence of acute lymphoblastic leukemia manifesting as serous retinal detachments and optic disc swelling. AB - PURPOSE: The aim of this case report is to describe a patient with acute lymphoblastic leukemia (ALL) who developed bilateral serous retinal detachments and unilateral optic disc swelling. METHODS: A 23-year-old woman with ALL presented to the ophthalmology clinic with bilateral subacute visual loss. RESULTS: Ophthalmologic examination revealed bilateral serous retinal detachments and unilateral optic disc swelling. Magnetic resonance imaging for differential diagnosis was inconclusive; however, cerebrospinal fluid sampling demonstrated leukemic involvement of the central nervous system. The patient's vision improved and fundus findings resolved with the institution of systemic and intrathecal chemotherapy. CONCLUSIONS: Serous retinal detachment and optic disc swelling are unusual ocular manifestations of ALL. They may occur due to leukemic infiltration of ocular structures and may indicate extramedullary recurrence of the disease. Early recognition and treatment is crucial to improve prognosis. PMID- 28712036 TI - Synchronization to metrical levels in music depends on low-frequency spectral components and tempo. AB - Previous studies have found relationships between music-induced movement and musical characteristics on more general levels, such as tempo or pulse clarity. This study focused on synchronization abilities to music of finely-varying tempi and varying degrees of low-frequency spectral change/flux. Excerpts from six classic Motown/R&B songs at three different tempos (105, 115, and 130 BPM) were used as stimuli in this experiment. Each was then time-stretched by a factor of 5% with regard to the original tempo, yielding a total of 12 stimuli that were presented to 30 participants. Participants were asked to move along with the stimuli while being recorded with an optical motion capture system. Synchronization analysis was performed relative to the beat and the bar level of the music and four body parts. Results suggest that participants synchronized different body parts to specific metrical levels; in particular, vertical movements of hip and feet were synchronized to the beat level when the music contained large amounts of low-frequency spectral flux and had a slower tempo, while synchronization of head and hands was more tightly coupled to the weak flux stimuli at the bar level. Synchronization was generally more tightly coupled to the slower versions of the same stimuli, while synchronization showed an inverted u-shape effect at the bar level as tempo increased. These results indicate complex relationships between musical characteristics, in particular regarding metrical and temporal structure, and our ability to synchronize and entrain to such musical stimuli. PMID- 28712037 TI - Introduction of sample tubes with sodium azide as a preservative for ethyl glucuronide in urine. AB - Ethyl glucuronide (EtG) is a direct alcohol marker, which is widely used for clinical and forensic applications, mainly for abstinence control. However, the instability of EtG in urine against bacterial degradation or the post collectional synthesis of EtG in contaminated samples may cause false interpretation of EtG results in urine samples. This study evaluates the potential of sodium azide in tubes used for urine collection to hinder degradation of ethyl glucuronide by bacterial metabolism taking place during growth of bacterial colonies. The tubes are part of a commercial oral fluid collection device. The sampling system was tested with different gram-positive and gram-negative bacterial species previously observed in urinary tract infections, such as Escherichia coli, Staphylococcus aureus, Enterecoccus faecalis, Staphylococcus epidermidis, Klebsiella pneumoniae, Enterobacter cloacae, and Pseudomonas aeruginosa. Inhibition of bacterial growth by sodium azide, resulting in lower numbers of colony forming units compared to control samples, was observed for all tested bacterial species. To test the prevention of EtG degradation by the predominant pathogen in urinary tract infection, sterile filtered urine and deficient medium were spiked with EtG, and inoculated with E. coli prior to incubation for 4 days at 37 degrees C in tubes with and without sodium azide. Samples were collected every 24 hours, during four consecutive days, whereby the colony forming units (CFU) were counted on Columbia blood agar plates, and EtG was analyzed by LC-MS/MS. As expected, EtG degradation was observed when standard polypropylene tubes were used for the storage of contaminated samples. However, urine specimens collected in sodium azide tubes showed no or very limited bacterial growth and no EtG degradation. As a conclusion, sodium azide is useful to reduce bacterial growth of gram-negative and gram-positive bacteria. It inhibits the degradation of EtG by E. coli and can be used for the stabilization of EtG in urine samples. PMID- 28712038 TI - Binding mode prediction and MD/MMPBSA-based free energy ranking for agonists of REV-ERBalpha/NCoR. AB - The knowledge of the free energy of binding of small molecules to a macromolecular target is crucial in drug design as is the ability to predict the functional consequences of binding. We highlight how a molecular dynamics (MD) based approach can be used to predict the free energy of small molecules, and to provide priorities for the synthesis and the validation via in vitro tests. Here, we study the dynamics and energetics of the nuclear receptor REV-ERBalpha with its co-repressor NCoR and 35 novel agonists. Our in silico approach combines molecular docking, molecular dynamics (MD), solvent-accessible surface area (SASA) and molecular mechanics poisson boltzmann surface area (MMPBSA) calculations. While docking yielded initial hints on the binding modes, their stability was assessed by MD. The SASA calculations revealed that the presence of the ligand led to a higher exposure of hydrophobic REV-ERB residues for NCoR recruitment. MMPBSA was very successful in ranking ligands by potency in a retrospective and prospective manner. Particularly, the prospective MMPBSA ranking-based validations for four compounds, three predicted to be active and one weakly active, were confirmed experimentally. PMID- 28712040 TI - The Effect of Targeted Therapy for Genitourinary Malignancies on Sexual Function and Fertility. AB - PURPOSE OF REVIEW: Targeted therapy for genitourinary cancer is being used at an increasing rate. These medications show great survival benefit but are relatively lacking in long-term adverse effect data. With increasing survivability, measures to improve quality of life must be considered for GU cancer and a large proponent of this is sexual function. RECENT FINDINGS: mTOR inhibitors have shown an effect on testosterone levels and may have a link to abnormal semen parameters. Tyrosine kinase inhibitors (TKIs) have shown no adverse sexual outcomes in the literature. There are laboratory links to tyrosine kinases having a beneficial effect on erectile and sexual function. Possible sexual side effects must be discussed with patients receiving a diagnosis of cancer. Further research is required to determine the exact mechanisms and outcomes of sexual function with new and emerging targeted therapy. PMID- 28712042 TI - Erratum to: Effects of atomoxetine on attention in Wistar rats treated with the neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4). PMID- 28712041 TI - Nightmares in the general population: identifying potential causal factors. AB - BACKGROUND: Nightmares are inherently distressing, prevent restorative sleep, and are associated with a number of psychiatric problems, but have rarely been the subject of empirical study. Negative affect, linked to stressful events, is generally considered the key trigger of nightmares; hence nightmares have most often been considered in the context of post-traumatic stress disorder (PTSD). However, many individuals with heightened negative affect do not have nightmares. The objective of this study was to identify mechanistically plausible factors, beyond negative affect, that may explain why individuals experience nightmares. METHOD: 846 participants from the UK general population completed an online survey about nightmare occurrence and severity (pre-occupation, distress, and impairment), negative affect, worry, depersonalisation, hallucinatory experiences, paranoia, alcohol use, sleep duration, physical activity levels, PTSD symptoms, and stressful life events. Associations of nightmares with the putative predictive factors were tested controlling for levels of negative affect. Analyses were also repeated controlling for levels of PTSD and the recent occurrence of stressful life events. RESULTS: Nightmare occurrence, adjusting for negative affect, was associated with higher levels of worry, depersonalisation, hallucinatory experiences, paranoia, and sleep duration (odds ratios 1.25-1.45). Nightmare severity, controlling for negative affect, was associated with higher levels of worry, depersonalisation, hallucinatory experiences, and paranoia (R 2s: 0.33-0.39). Alcohol use and physical activity levels were not associated with nightmares. DISCUSSION: The study identifies a number of potential predictors of the occurrence and severity of nightmares. Causal roles require testing in future longitudinal, experimental, and treatment studies. PMID- 28712043 TI - Effects of fibre digestibility and level of roughage on performance and rumen fermentation of finishing beef cattle. AB - The objective was to evaluate effects of neutral detergent fibre (NDF) digestibility and level of fresh sugarcane on intake, body fatness, carcass characteristics, and rumen kinetics and fermentation of beef cattle. Forty-eight Nellore young bulls were used in a complete randomized block design with a 2 * 2 factorial arrangement of treatments. Eight rumen-cannulated Nellore steers were used in a replicated 4 * 4 Latin square design. Two sugarcane genotypes divergent for stalk NDF digestibility (NDFD) were used. Experimental diets were formulated with 20 or 40% of sugarcane on a dry matter (DM) basis. High-NDFD genotype associated with the lower level of roughage in the diet promoted greater DM intake, resulting in greater body gain. Sugarcane with high-NDFD increased final body weight, hot carcass weight, and back-fat thickness. Animals receiving the genotype with high NDFD had greater rump-fat thickness only with 40% sugarcane in the diet. Animals receiving the low-NDFD genotype at 20% of the diet had lower NDF passage rate. Rumen pH was greater for diets with greater NDF content. There was greater proportion of butyrate in the rumen of animals receiving diets with greater NDF content. In conclusion, high-NDFD sugarcane increased final body and carcass weight, HCW, and fat thickness. When associated with lower inclusion of roughage in the diet, it can also increase DM intake and body weight gain of beef cattle. PMID- 28712044 TI - Is it time to revise linezolid dose in elderly patients? PMID- 28712039 TI - Cutaneous Manifestations of Scleroderma and Scleroderma-Like Disorders: a Comprehensive Review. AB - Scleroderma refers to an autoimmune connective tissue fibrosing disease, including three different subsets: localized scleroderma, limited cutaneous systemic sclerosis, and diffuse cutaneous systemic sclerosis with divergent patterns of organ involvement, autoantibody profiles, management, and prognostic implications. Although systemic sclerosis is considered the disease prototype that causes cutaneous sclerosis, there are many other conditions that can mimic and be confused with SSc. They can be classified into immune mediated/inflammatory, immune-mediated/inflammatory with abnormal deposit (mucinoses), genetic, drug-induced and toxic, metabolic, panniculitis/vascular, and (para)neoplastic disorders according to clinico-pathological and pathogenetic correlations. This article reviews the clinical presentation with emphasis on cutaneous disease, etiopathogenesis, diagnosis, and treatment options available for the different forms of scleroderma firstly and for scleroderma-like disorders, including scleromyxedema, scleredema, nephrogenic systemic fibrosis, eosinophilic fasciitis, chronic graft-versus-host disease, porphyria cutanea tarda, diabetic stiff-hand syndrome (diabetic cheiroartropathy), and other minor forms. This latter group of conditions, termed also scleroderma mimics, sclerodermiform diseases, or pseudosclerodermas, shares the common thread of skin thickening but presents with distinct cutaneous manifestations, skin histology, and systemic implications or disease associations, differentiating each entity from the others and from scleroderma. The lack of Raynaud's phenomenon, capillaroscopic abnormalities, or scleroderma-specific autoantibodies is also important diagnostic clues. As cutaneous involvement is the earliest, most frequent and characteristic manifestation of scleroderma and sclerodermoid disorders, dermatologists are often the first-line doctors who must be able to promptly recognize skin symptoms to provide the affected patient a correct diagnosis and appropriate management. PMID- 28712045 TI - Dynamics of Soil Bacterial Communities Over a Vegetation Season Relate to Both Soil Nutrient Status and Plant Growth Phenology. AB - Soil microorganisms regulate element cycling and plant nutrition, mediate co existence of neighbors, and stabilize plant communities. Many of these effects are dependent upon environmental conditions and, in particular, on nutrient quality and availability in soils. In this context, we set up a pot experiment in order to examine the combined effects of soil nutrient availability and microbial communities on plant-soil interactions and to investigate assemblage rules for soil bacterial communities under changed nutrient conditions. Four gamma sterilized soils, strongly differing in their nutrient contents, were obtained from different fertilization treatments of a centenary field experiment and used to grow communities of grassland plants. The sterilized soils were either self- or cross-inoculated with microbial consortia from the same four soils. Molecular fingerprinting analyses were carried out at several time points in order to identify drivers and underlying processes of microbial community assemblage. We observed that the bacterial communities that developed in the inoculated sterilized soils differed from those in the original soils, displaying dynamic shifts over time. These shifts were illustrated by the appearance of numerous OTUs that had not been detected in the original soils. The community patterns observed in the inoculated treatments suggested that bacterial community assembly was determined by both niche-mediated and stochastic-neutral processes, whereby the relative impacts of these processes changed over the course of the vegetation season. Moreover, our experimental approach allowed us not only to evaluate the effects of soil nutrients on plant performance but also to recognize a negative effect of the microbial community present in the soil that had not been fertilized for more than 100 years on plant biomass. Our findings demonstrate that soil inoculation-based approaches are valid for investigating plant-soil microbe interactions and for examining rules that shape soil microbial community assemblages under variable ecological conditions. PMID- 28712046 TI - The Healthy Worker Survivor Effect: Target Parameters and Target Populations. AB - PURPOSE OF REVIEW: We offer an in-depth discussion of the time-varying confounding and selection bias mechanisms that give rise to the healthy worker survivor effect (HWSE). RECENT FINDINGS: In this update of an earlier review, we distinguish between the mechanisms collectively known as the HWSE and the statistical bias that can result. This discussion highlights the importance of identifying both the target parameter and the target population for any research question in occupational epidemiology. Target parameters can correspond to hypothetical workplace interventions; we explore whether these target parameters' true values reflect the etiologic effect of an exposure on an outcome or the potential impact of enforcing an exposure limit in a more realistic setting. If a cohort includes workers hired before the start of follow-up, HWSE mechanisms can limit the transportability of the estimates to other target populations. We summarize recent publications that applied g-methods to control for the HWSE, focusing on their target parameters, target populations, and hypothetical interventions. PMID- 28712047 TI - Shaped graft for aneurysmal bone cyst of upper limb bones. AB - The optimal treatment of aneurysmal bone cyst remains challenging. The aim of this prospective study was to evaluate the results of using bone grafts shaped to the defects caused by aneurysmal bone cysts of upper limb bones. Fifteen patients (12 males and 3 females) with an average age of 12 years (range 6-16 years) were treated for aneurysmal bone cysts of upper limb bones by intralesional resection, argon beam coagulation and shaped bone graft. The grafts were harvested from 14 patients (11 fibulas and 3 iliac bones) and from the mother of one patient (proximal fibula). Osteosynthesis was required to stabilize the graft in four cases. The modified Enneking's scoring system was used for functional evaluation. One patient developed partial recurrence at 6 months and required reoperation. Superficial wound infection was encountered in one patient. Shortening of the humeral segment was seen in two patients (1 and 1.5 cm) but without angular deformity. After a mean follow-up of 45 months (range 24-68 months), the mean functional score was 97.3%. This technique proved to be reliable in obtaining a well reconstructed and growing bone with no or minimal deformity and good function. PMID- 28712048 TI - Photobiomodulation therapy improves both inflammatory and fibrotic parameters in experimental model of lung fibrosis in mice. AB - Lung fibrosis (LF) is a chronic and progressive lung disease characterized by pulmonary parenchyma progressive lesion, inflammatory infiltration, and interstitial fibrosis. It is developed by excessive collagen deposition and other cellular matrix components, resulting in severe changes in the alveolar architecture. Considering the absence of effective treatment, the aim of this study was to investigate the effect of photobiomodulation therapy (PBMT) on the development of PF. For this purpose, we used C57BL6 mice subjected to induction of LF by bleomycin administration (1.5 U/kg) by orotracheal route and, after 14 days of the induction, mice were treated with PBMT applied to the thorax 1*/day for 8 days (wavelength 660 +/- 20 nm, power 100 mW, radiant exposure 5 J/cm2, irradiance 33.3 mW/cm2, spot size 2.8cm2, total energy 15 J, time of irradiation: 150 s) and inflammatory and fibrotic parameters were evaluated with or without PBMT. Our results showed that PBMT significantly reduced the number of inflammatory cells in the alveolar space, collagen production, interstitial thickening, and static and dynamic pulmonary elastance. In addition, we observed reduced levels of IL-6 e CXCL1/KC released by pneumocytes in culture as well as reduced level of CXCL1/KC released by fibroblasts in culture. We can conclude that the PBMT improves both inflammatory and fibrotic parameters showing a promising therapy which is economical and has no side effects. PMID- 28712049 TI - Ginkgolide B Suppresses Methamphetamine-Induced Microglial Activation Through TLR4-NF-kappaB Signaling Pathway in BV2 Cells. AB - Accumulating evidence suggests that microglial cells have altered morphology and proliferation in different brain regions of methamphetamine (Meth) abusers and Meth-abusing animal models. However, the possible mechanisms underlying Meth induced microglial activation remain poorly understood. Meanwhile, Toll-like receptor4 (TLR4) is closely associated with inflammation. Therefore the aim of the present study was to assess whether Meth treatment affects TLR4 expression; in addition, we evaluated the effects of ginkgolide B (GB), a diterpene lactone extracted from Ginkgo biloba, on Meth-mediated inflammation. BV2 cells were treated with Meth. Interestingly, Meth treatment significantly increased TLR4 expression, activated the NF-kappaB signaling pathway, and promoted TNF-alpha, IL 6 and IL-1beta excretion. These effects, however, were partially attenuated by GB pre-treatment. To further confirm the role of TLR4 in Meth-mediated inflammation, the siRNA technology was applied to knock down TLR4, which resulted in hampered Meth-mediated inflammatory responses, confirming the important role of TLR4 in this process. Taken together, our findings suggested that Meth exposure results in BV2 cell activation, in association with TLR4 upregulation. GB could attenuate Meth-induced inflammation, at least partially through TLR4-NF-kappaB signaling pathway, therefore, targeting TLR4 may constitute a potential intervention strategy for Meth mediated neuroinflammation. PMID- 28712050 TI - Spatiotemporal Expression of Bcl-2/Bax and Neural Cell Apoptosis in the Developing Lumbosacral Spinal Cord of Rat Fetuses with Anorectal Malformations. AB - Fecal incontinence and constipation still remain the major complications after procedures for anorectal malformations (ARMs). Previous studies have demonstrated a decrease of neural cell in lumbosacral spinal cord of ARMs patients and rat models. However, the underlying mechanism remains elusive. In this study, the neural cell apoptosis and Bcl-2/Bax expression were explored during lumbosacral spinal cord development in normal and ARMs fetuses. ARMs rat fetuses were induced by treating pregnant rats with ethylenethiourea on embryonic day 10. TUNEL staining was performed to identify apoptosis, and the expression of Bcl-2/Bax was confirmed with immunohistochemical staining, RT-qPCR and Western blot analysis on E16, E17, E19 and E21. Apoptosis index (AI) in the ARMs group was significantly higher compared to normal group. Our results showed that TUNEL-positive cells were mainly localized in the ventral horn, which is the location of neural cells controlling defecation. And the expression of Bcl-2 decreased, whereas the level of Bax increased in the ARMs fetuses. In addition, there was a significantly negative correlation between protein expression of Bcl-2/Bax ratio and AI in the ARMs group. Abnormal apoptosis might be a fundamental pathogenesis for the number decrease of neural cells in lumbosacral spinal cord, which leads to complications after procedures for ARMs. The negative correlation between the ratio of Bcl 2/Bax and AI manifested that Bcl-2/Bax pathway might be the mechanism for neural cell apoptosis in ARMs. PMID- 28712051 TI - A Carbazole-Fused-RhodamineProbe for Detection of HOCl in Living Cells. AB - A novel fluorescent probe CR-ClO for detection of HOCl based on a carbazole fused rhodamine was designed and synthesized. The probe utilized a HOCl-promoted oxidation reaction, which lead to the ring opening of the compound with a strong enhancement of the fluorescent emission at about 587 nm.The new probe CR-ClO has excellent selectivity and high sensitivity to ClO-,whose detection limit to ClO- is 1.16 * 10-6 M. Furthermore, the new probe has been successfully applied in living cells for detection of ClO-. PMID- 28712053 TI - Soy isoflavone consumption and age at pubarche in adolescent males. AB - PURPOSE: Isoflavones have estrogenic properties that may adversely affect pubertal development of boys. We examined if soy isoflavone consumption is associated with age at pubarche (first onset of pubic hair) in a male population with a wide range of soy intake. METHODS: Boys aged 12-18 years (n = 248) who attended schools around Adventist universities in Southern California and Michigan self-reported their age at pubarche. Intake of soy isoflavones was assessed using a validated Web-based food frequency questionnaire; consumption levels were designated as low, moderate, and high. Descriptives, time-to-event analysis, and Cox proportional hazards regression that controlled for confounders were performed. RESULTS: Energy-adjusted mean intakes were 0.8-54.9 mg/d for total isoflavones, 0.4-22.1 mg/d for daidzein, and 0.4-28.0 mg/d for genistein. Moderate and high total soy isoflavone intake were significantly associated with earlier adjusted median age at pubarche: 12.58 years [RR (95% CI): 1.58 (1.06, 2.36)] for moderate and 12.50 years [RR (95% CI): 1.63 (1.03, 2.60)] for high vs. 13.00 years for low consumers. Similarly, daidzein and genistein consumption was also significantly associated with age at pubarche. No significant associations were found for facial hair for any of the isoflavones. CONCLUSIONS: Age at pubarche in this male population widely exposed to soy is within the reported range for boys' pubarcheal age; moderate/high consumers tend to have it earlier compared to low consumers. Further studies are needed to ascertain that substantial exposure to soy isoflavones does not adversely affect pubertal development of boys. PMID- 28712052 TI - Pharmacotherapy for Pediatric Neurogenic Bladder. AB - Neurogenic bladder (NB) is a nonspecific term that may describe conditions ranging from areflectic noncontractile bladder to detrusor overactivity. The most common cause of NB in children is the presence of dysraphic malformations. Urodynamic evaluations make it possible to describe bladder dysfunctions and to plan a therapeutic strategy for each patient. In a child with NB there are two major dangerous functional problems seen in urodynamic investigations: high intravesical pressure in the storage phase and high pressure during urination. The basic goals of urologic treatment for a child with NB are the protection of the urinary tract from complications and improvement of continence. Treatment for a child with NB is usually conservative, and focuses on achieving safe bladder pressures during storage with reliable emptying, via voiding or catheterization. The two most important forms of conservative treatment are clean intermittent catheterization and pharmacological treatment of functional disorders. Some drugs are used in the treatment of functional disorders in children with NB, but none of the drugs are officially approved for small children and babies. PMID- 28712056 TI - The crescent sign in pneumatic reduction of intussusception. PMID- 28712054 TI - Alcohol exposure promotes DNA methyltransferase DNMT3A upregulation through reactive oxygen species-dependent mechanisms. AB - Abundant evidence has accumulated showing that fetal alcohol exposure broadly modifies DNA methylation profiles in the brain. DNA methyltransferases (DNMTs), the enzymes responsible for DNA methylation, are likely implicated in this process. However, their regulation by ethanol exposure has been poorly addressed. Here, we show that alcohol exposure modulates DNMT protein levels through multiple mechanisms. Using a neural precursor cell line and primary mouse embryonic fibroblasts (MEFs), we found that ethanol exposure augments the levels of Dnmt3a, Dnmt3b, and Dnmt3l transcripts. We also unveil similar elevation of mRNA levels for other epigenetic actors upon ethanol exposure, among which the induction of lysine demethylase Kdm6a shows heat shock factor dependency. Furthermore, we show that ethanol exposure leads to specific increase in DNMT3A protein levels. This elevation not only relies on the upregulation of Dnmt3a mRNA but also depends on posttranscriptional mechanisms that are mediated by NADPH oxidase-dependent production of reactive oxygen species (ROS). Altogether, our work underlines complex regulation of epigenetic actors in response to alcohol exposure at both transcriptional and posttranscriptional levels. Notably, the upregulation of DNMT3A emerges as a prominent molecular event triggered by ethanol, driven by the generation of ROS. PMID- 28712055 TI - Potential of Casein as a Carrier for Biologically Active Agents. AB - Casein is the collective name for a family of milk proteins. In bovine milk, casein comprises four peptides: alphaS1, alphaS2, beta, and kappa, differing in their amino acid, phosphorus and carbohydrate content but similar in their amphiphilic character. Hydrophilic and hydrophobic regions of casein show block distribution in the protein chain. Casein peptides carry negative charge on their surface as a result of phosphorylation and tend to bind nanoclusters of amorphous calcium phosphate. Due to these properties, in suitable conditions, casein molecules agglomerate into spherical micelles. The high content of casein in milk (2.75 %) has made it one of the most popular proteins. Novel research techniques have improved understanding of its properties, opening up new applications. However, casein is not just a dietary protein. Its properties promise new and unexpected applications in science and the pharmaceutical and functional food industries. One example is an encapsulation of health-related substances in casein matrices. This review discusses gelation, coacervation, self-assembly and reassembly of casein peptides as means of encapsulation. We highlight information on encapsulation of health-related substances such as drugs and dietary supplements inside casein micro- and nanoparticles. PMID- 28712057 TI - Phrygian cap. PMID- 28712058 TI - Reliance on medicinal plant therapy among cancer patients in Jamaica. AB - PURPOSE: Patients' perspective of their treatment regime plays a vital role in its success. Recognizing the high prevalence of medicinal plant usage among Jamaicans at large, we investigated the engagement of such remedies by cancer patients, with the aim of uncovering self-medicating habits, perceptions and details of utilized plants. METHODS: A structured, interviewer-based questionnaire was administered to 100 patients attending the oncology and urology clinics at the University Hospital of the West Indies in Kingston, Jamaica. A method of convenience sampling was employed and the data were analyzed using summary statistics and statistical significance tests. RESULTS: A large proportion (n = 80, 80%) of interviewed patients, engaged medicinal plants in their treatment regimes. Such habits were independent of person's education, economic status and were higher among the 55-74 age groups (p < 0.05) compared with younger patients. The use of herbs was hinged on the patient's strong sense of tradition and positive perspective of herbal efficacy (88%), fueled by anecdotal accounts from fellow patients. Majority of such users (74.7%) were under concomitant treatment with a prescription medicine, and worryingly, only 15% of patients made their oncologists aware. Annona muricata L. and Petiveria alliacea L. were the most commonly used plants for treating breast and prostate cancers, respectively. CONCLUSION: A large proportion of Jamaican cancer patients use medicinal plants in self-medicating practices and their perceptions and habits need to be considered by physicians, in the design of safe and effective care regimes. PMID- 28712059 TI - A Combination of Testosterone and White Blood Cell Count as a Predictive Factor of Overall Survival in Localized Prostate Cancer. AB - BACKGROUND: It has been shown that neutrophil count or an elevated neutrophil-to lymphocyte ratio (NLR) as well as testosterone levels are separately associated with increased mortality in patients with localized prostate cancer. OBJECTIVE: We tested a combination of testosterone levels and white blood cell (WBC) counts to predict overall survival (OS) in a prospective cohort of patients treated with radiotherapy for localized prostate cancer. PATIENTS AND METHODS: The 381 patients included in this study were prospectively enrolled in phase 2 or 3 studies. Multivariate Cox proportional hazards models were used to analyze the influence of WBC count and testosterone level on biochemical recurrence and OS. Cutoff levels of <=10.4 nmol/L (300 ng/dL) for testosterone and a median value of 6.2 (*109/L) for WBC count were used. RESULTS: The median follow-up for biochemical recurrence and OS were 72 and 78 months, respectively. A WBC count of >=6.2 alone was not associated with OS (hazard ratio [HR] 0.66; 95% confidence interval [CI] 0.30-1.46). When combined with a testosterone level of >10.3 nmol/L, a WBC count of >=6.2 was associated with increased mortality (HR 2.96; 95% CI 1.45-6.06) when compared with a WBC count of <6.2 (p-interaction = 0.01). The HR for biochemical recurrence for patients with a testosterone level >10.3 nmol/L combined with a lymphocyte level above or equal to the median was nearly identical to the HR of a testosterone level >10.3 nmol/L with a WBC above or equal to the median. There was no association between testosterone level and the NLR. CONCLUSIONS: A high WBC and lymphocyte count combined with normal testosterone levels increases the overall mortality of patients treated with radiotherapy for localized prostate cancer within the first 6-7 years post treatment. Validation in larger cohorts is necessary. PMID- 28712061 TI - Introduction to Mammalian Genome Special Issue: Genome Editing. PMID- 28712060 TI - Abnormal social behavior in mice with tyrosinemia type I is associated with an increase of myelin in the cerebral cortex. AB - Hereditary tyrosinemia type I (HT1) is caused by mutations in the fumarylacetoacetate hydrolase (FAH) gene, the template for the final enzyme in the tyrosine catabolism pathway. If left untreated this deficiency of functional FAH leads to a buildup of toxic metabolites that can cause liver disease, kidney dysfunction and high mortality. The current treatment with the drug NTBC prevents the production of these metabolites and has consequently increased the survival rate in HT1 children. As a result of this increased survival, long term complications of HT1 are now being observed, including slower learning, impaired cognition and altered social behavior. We studied a mouse model of HT1 to gain insight into the effects of HT1 and treatment with NTBC on social behavior in mice. We showed that mice with HT1 display abnormal social behavior in that they spend more time in the absence of another mouse and do not discriminate between a novel mouse and an already familiar mouse. This altered behavior was due to HT1 and not treatment with NTBC. Quantification of cerebral cortex myelin in mice with HT1 showed a two to threefold increase in myelin expression. Our findings suggest that absence of FAH expression in the brain produces an altered brain biochemistry resulting in increased expression of myelin. This increase in myelination could lead to abnormal action potential velocity and altered neuronal connections that provide a mechanism for the altered learning, social behavior and cognitive issues recently seen in HT1. PMID- 28712063 TI - Resisting Sleep Pressure: Impact on Resting State Functional Network Connectivity. AB - In today's 24/7 society, sleep restriction is a common phenomenon which leads to increased levels of sleep pressure in daily life. However, the magnitude and extent of impairment of brain functioning due to increased sleep pressure is still not completely understood. Resting state network (RSN) analyses have become increasingly popular because they allow us to investigate brain activity patterns in the absence of a specific task and to identify changes under different levels of vigilance (e.g. due to increased sleep pressure). RSNs are commonly derived from BOLD fMRI signals but studies progressively also employ cerebral blood flow (CBF) signals. To investigate the impact of sleep pressure on RSNs, we examined RSNs of participants under high (19 h awake) and normal (10 h awake) sleep pressure with three imaging modalities (arterial spin labeling, BOLD, pseudo BOLD) while providing confirmation of vigilance states in most conditions. We demonstrated that CBF and pseudo BOLD signals (measured with arterial spin labeling) are suited to derive independent component analysis based RSNs. The spatial map differences of these RSNs were rather small, suggesting a strong biological substrate underlying these networks. Interestingly, increased sleep pressure, namely longer time awake, specifically changed the functional network connectivity (FNC) between RSNs. In summary, all FNCs of the default mode network with any other network or component showed increasing effects as a function of increased 'time awake'. All other FNCs became more anti-correlated with increased 'time awake'. The sensorimotor networks were the only ones who showed a within network change of FNC, namely decreased connectivity as function of 'time awake'. These specific changes of FNC could reflect both compensatory mechanisms aiming to fight sleep as well as a first reduction of consciousness while becoming drowsy. We think that the specific changes observed in functional network connectivity could imply an impairment of information transfer between the affected RSNs. PMID- 28712064 TI - Comment on "The effect of septoplasty surgery on serum oxidative stress levels". PMID- 28712062 TI - Genome editing and genetic engineering in livestock for advancing agricultural and biomedical applications. AB - Genetic modification of livestock has a longstanding and successful history, starting with domestication several thousand years ago. Modern animal breeding strategies predominantly based on marker-assisted and genomic selection, artificial insemination, and embryo transfer have led to significant improvement in the performance of domestic animals, and are the basis for regular supply of high quality animal derived food. However, the current strategy of breeding animals over multiple generations to introduce novel traits is not realistic in responding to the unprecedented challenges such as changing climate, pandemic diseases, and feeding an anticipated 3 billion increase in global population in the next three decades. Consequently, sophisticated genetic modifications that allow for seamless introgression of novel alleles or traits and introduction of precise modifications without affecting the overall genetic merit of the animal are required for addressing these pressing challenges. The requirement for precise modifications is especially important in the context of modeling human diseases for the development of therapeutic interventions. The animal science community envisions the genome editors as essential tools in addressing these critical priorities in agriculture and biomedicine, and for advancing livestock genetic engineering for agriculture, biomedical as well as "dual purpose" applications. PMID- 28712065 TI - Erratum to: Stochastic phenotypic interconversion in tumors can generate heterogeneity. PMID- 28712066 TI - Effect of pH and ionic strength on the binding strength of anti-PF4/polyanion antibodies. AB - Antibodies against the chemokine platelet factor 4 (PF4) in complex with heparin cause the prothrombotic adverse drug reaction heparin-induced thrombocytopenia (HIT). The current dilemma for laboratory diagnosis of HIT is that only about 50% of these antibodies are pathogenic, but the widely available enzyme immunosorbent assays (EIA), used for diagnosis in the clinical laboratory cannot differentiate between non-pathogenic- and pathogenic (platelet activating) antibodies. It would be highly desirable to improve diagnosis for HIT. Here, we use single-molecule force spectroscopy to identify conditions at which non-pathogenic antibodies show a different reactivity pattern compared to pathogenic antibodies. At physiological conditions (pH 7.4, 150 mM NaCl), non-pathogenic antibodies bound to PF4/heparin complexes with weaker binding forces than pathogenic ones. Binding forces measured over a wide range of pH or ionic strength show that non pathogenic antibodies are not significantly affected by environmental changes, whereas pathogenic antibodies are. Based on the dissimilar behavior of these antibodies at 500 mM salt, we performed a PF4/heparin EIA at this condition and observed that optical density of non-pathogenic antibodies slightly reduced while it drastically reduced for pathogenic antibodies. Our results suggest that the specificity of anti-PF4/heparin EIAs for clinically relevant antibodies can be improved by changing test conditions. PMID- 28712067 TI - RNAi-mediated resistance to whitefly (Bemisia tabaci) in genetically engineered lettuce (Lactuca sativa). AB - RNA interference (RNAi)-based transgenic technologies have evolved as potent biochemical tools for silencing specific genes of plant pathogens and pests. The approach has been demonstrated to be useful in silencing genes in insect species. Here, we report on the successful construction of RNAi-based plasmid containing an interfering cassette designed to generate dsRNAs that target a novel v-ATPase transcript in whitefly (Bemisia tabaci), an important agricultural pest in tropical and sub-tropical regions. The presence of the transgene was confirmed in T0 and T1 generations of transgenic lettuce lines, segregating in a Mendelian fashion. Seven lines were infested with whiteflies and monitored over a period of 32 days. Analysis of mortality showed that within five days of feeding, insects on transgenic plants showed a mortality rate of 83.8-98.1%. In addition, a reduced number of eggs (95 fold less) was observed in flies feeding on transgenic lettuce plants than insects on control lines. Quantitative reverse transcription PCR showed decreased expression level of endogenous v-ATPase gene in whiteflies feeding on transgenic plants. This technology is a foundation for the production of whitefly-resistant commercial crops, improving agricultural sustainability and food security, reducing the use of more environmentally aggressive methods of pest control. PMID- 28712068 TI - Qualitative angiographic and quantitative myocardial perfusion assessment using fluorescent cardiac imaging during graded coronary artery bypass stenosis. AB - Intraoperative graft assessment in coronary artery bypass (CAB) grafting is important to avoid early graft failure. This study aimed to evaluate the accuracy of fluorescent cardiac imaging (FCI) for intraoperative qualitative angiographic and quantitative myocardial perfusion assessment during graded CAB stenosis compared to coronary angiography (CA). After CAB grafting to the left anterior descending coronary artery, graded distal bypass stenoses were created in ten pigs by 25, 50, 75, and 100% flow reduction assessed by transit-time flow measurement (TTFM). Visual angiographic assessment was performed by FCI and CA during baseline and graded bypass stenoses. Altered myocardial perfusion was assessed by quantitative intraoperative fluorescence intensity (QIFI) derived from FCI and correlated to TTFM. Patent bypass grafts and graft occlusion were visualized successfully by FCI and CA, while discrimination between various graded bypass stenosis was possible in 73.3%. The degree of CAB stenosis was overestimated in 16.7% and underestimated in 10.0% by FCI compared to CA. Graded CAB stenosis reduced regional myocardial perfusion quantified by decreased QIFI value (p < 0.001). Mean QIFI value was 76.8 (95% CI 67.2-86.3) during baseline, 55.6 (95% CI 45.3-65.9) during 25% flow-reduction, 30.6 (95% CI 22.3-39.0) during 50% flow-reduction, 20.3 (95% CI 15.4-25.3) during 75% flow-reduction, and 0 during CAB occlusion (p < 0.001) with a significant correlation to TTFM (r = 0.955; p < 0.0001). Solely visual assessment of CAB quality using FCI is limited as compared to CA. Additional QIFI assessment identified graded CAB stenosis and occlusion with a significant correlation to TTFM. PMID- 28712071 TI - Ultrasound detection of normal parathyroid glands: a preliminary study. AB - OBJECTIVE: No previous prospective study has investigated the detection of normal parathyroid glands (PTGs) and their features using real-time ultrasound (US). This study aimed to assess the preoperative US detection of normal PTGs in patients who underwent hemithyroidectomy. METHODS: Between August and October 2016, 44 patients underwent hemithyroidectomy using a low-collar incision, and 5 were excluded from the study. A single radiologist performed the preoperative US examination in all patients, and the surgical data for the PTGs were obtained by a single surgeon. Based on the surgical findings of PTGs, the preoperative US detection of PTGs was determined. RESULTS: Of the 39 patients, 3 had no surgical data for PTG (n = 2) and the presence of parathyroid hyperplasia (n = 1). In the 36 remaining patients, in 3 patients, US identification of a normal PTG was corroborated by surgical findings, whereas in 2 patients, US findings differed from surgical findings, and in 31 patients, US did not detect a normal PTG. The successful US detection rate of normal PTG was only 8.3% (3/36). CONCLUSIONS: US cannot be used for identification of normal PTGs. PMID- 28712070 TI - Flow-diverter in radiation-induced skull base carotid blowout syndrome: do not write it off! AB - Post-radiotherapy carotid blowout syndrome (CBS) of the skull base is a rare but often catastrophic complication of head and neck malignancies. The existing literature on the treatment of this condition with flow-diverting devices (FDD) is extremely limited and disappointing. We present a case of impending CBS in a patient previously irradiated for nasopharyngeal cancer that was successfully treated with use of multiple FDDs, adjunctive endonasal packing and delayed reinforcement with pedicled naso-septal flap, yielding an excellent outcome at 14 months follow-up. Notwithstanding the discouraging results in literature, our anecdotal experience suggests that endovascular reconstruction using FDD could be an option with long-term viability in post-radiotherapy CBS involving the skull base when reinforced with a vascularised naso-septal flap. PMID- 28712069 TI - Left atrial dysfunction as a determinant of pulmonary hypertension in patients with severe aortic stenosis and preserved left ventricular ejection fraction. AB - In patients with severe aortic stenosis (AS), the presence of pulmonary hypertension (PH) has been linked to a poor prognosis. We aimed to assess the main determinants of PH in patients with severe AS and preserved left ventricular ejection fraction (LVEF). We prospectively enrolled 108 consecutive patients with isolated severe AS (indexed aortic valve area <0.6 cm2/m2) and LVEF >50%, in sinus rhythm. Left atrial (LA) function was assessed using longitudinal deformation parameters (by speckle tracking echocardiography). PH (defined as systolic pulmonary artery pressure >40 mmHg) was present in 20 patients. Patients with severe AS and PH were older (p = 0.05), had higher BNP values (p = 0.05) and a greater degree of LV diastolic dysfunction: higher E/e' and E/A ratios and lower EDT values (p < 0.03 for all) compared to patients without PH. There were no differences between groups regarding AS severity and LV systolic function parameters. Patients with PH had a more impaired LA function: lower septal and lateral late diastolic peak velocity a' (p < 0.001 and p = 0.04 respectively) and lower LA peak longitudinal strain and strain rate parameters (p <= 0.005 for all). In multivariable analysis, LA late diastolic longitudinal strain rate was the only independent correlate of PH in our patients (p = 0.04). Patients with isolated severe AS, preserved LVEF and PH had larger LA volumes, a more impaired LA function, and higher LV filling pressures compared to those without PH. LA booster pump function, reflected by late diastolic longitudinal strain rate, emerged as an independent correlate of PH in these patients. PMID- 28712072 TI - Clinical role of guidance by C-arm CT for 125I brachytherapy on pulmonary tumors. AB - PURPOSE: To evaluate the clinical value of C-arm CT (CACT)-guided interstitial iodine-125 (125I) brachytherapy on pulmonary tumors. MATERIALS AND METHODS: 30 patients with 40 solid pulmonary tumors were enrolled to undergo CACT-guided interstitial 125I brachytherapy between November 2011 and November 2014. The needle path was planned on a CACT virtual navigation and real-time fluoroscopy system. Technical success, puncture score, procedure time, local control rate (LCR), radiation exposure, complications and survival were investigated. RESULTS: The technical success of interstitial 125I brachytherapy under CACT guidance was 40/40 (100%). The performance score was 4.7 +/- 0.5 with a mean total procedure time of 17.7 +/- 5.6 min. LCR in small (<=2.0 cm), intermediate (2.1-4.9 cm) and large (>=5.0 cm) pulmonary tumors was 100, 89.5 and 72.7% at the 4-month follow up, respectively. The mean effective dose was 10.1 +/- 2.8 mSv. Major complications occurred in four patients (13.3%). The mean survival time was 28.4 +/- 2.3 months. CONCLUSION: CACT can provide virtual navigation and real-time fluoroscopy synchronously for interstitial 125I seed implantation on pulmonary tumors. PMID- 28712073 TI - Association between ACE and AGT polymorphism and cardiovascular risk in acromegalic patients. AB - PURPOSE: Whether the renin-angiotensin-aldosterone system plays a role or not in the development of cardiovascular morbidity in acromegaly patients is unknown. The aim of the study was to investigate the association between ACE (I/D) and AGT (M235T) gene polymorphisms and cardiovascular and metabolic disorders in the acromegaly. METHODS: The study included one hundred and seventeen acromegalic patients (62 F/55 M, age: 50.2 +/- 12.3 years) and 106 healthy controls (92 F/14 M, age: 41.4 +/- 11.3 years). PCR method was used to evaluate the prevalence of ACE and AGT genotype. RESULTS: The genotypes of ACE polymorphism in acromegalic patients were distributed as follows; 41.0% (n: 48) for DD, 44.4% (n: 52) for ID and 14.5% (n: 17) for II genotype. The control group had significantly different distribution of the ACE polymorphism [48.1% (n: 51) for DD, 25.5% (n: 27) for ID and 26.4% (n: 28) for II genotype]compared to acromegalic group. Regarding AGT polymorphism, AGT-MT genotype was seen in 88.9% of the acromegalic patients while MM and TT genotype (9.4% and 1.7%, respectively) were present in the rest. The controls had similar distribution of the AGT genotype with the acromegaly group (80.2% MT genotype, 15.1% MM genotype and 4.7% TT genotype). Due to the small number of patients with TT allele (n: 2), T carriers for AGT genotype (AGT-MT+TT) were subgrouped and compared to those with AGT-MM group. ACE-DD, ID and II groups had similar anthropometric measures, blood pressure values and baseline GH and IGF-1 levels. Significantly higher baseline GH levels were found in AGT-MM group compared to T allele carriers [40 (16-60) vs. 12 (5-36) ug/L, p < 0.05]. The compared groups in both polymorphisms had similar fasting plasma glucose levels. Patients with ACE-II genotype had significantly higher HDL-C levels compared to those with ACE-DD and ACE-ID polymorphisms (p < 0.05) whereas there was no significant difference in lipid profile between AGT-MM group and AGT-T allele carriers. Moreover, the compared groups in both polymorphisms had similar distribution of hyperlipidemia, hypertension, impaired glucose metabolism (prediabetes or type 2 diabetes mellitus) and coronary artery disease. In terms of echocardiographic parameters, systolic and diastolic function was similar among the groups in ACE and AGT genotypes. Interestingly, AGT-MM group had higher mitral inflow Apeak values than T allele carriers (0.94 +/- 0.46 vs. 0.73 +/- 0.20; p = 0.051). No significant difference was observed in LV mass index values in acromegalic patients among the groups in both polymorphisms. CONCLUSIONS: Both ACE (I/D) and AGT (M235T) gene polymorphisms do not seem to have a significant effect on the development of clinical properties or cardiovascular comordities of acromegalic patients. PMID- 28712075 TI - Erratum to: Dye removal of AR27 with enhanced degradation and power generation in a microbial fuel cell using bioanode of treated clinoptilolite-modified graphite felt. PMID- 28712074 TI - Efficacy and Safety of SHP465 Mixed Amphetamine Salts in the Treatment of Attention-Deficit/Hyperactivity Disorder in Adults: Results of a Randomized, Double-Blind, Placebo-Controlled, Forced-Dose Clinical Study. AB - OBJECTIVE: The objective of this randomized, double-blind, placebo-controlled study was to evaluate the efficacy and safety of SHP465 mixed amphetamine salts (MAS) in adults with attention-deficit/hyperactivity disorder (ADHD). METHODS: Eligible adults [aged 18-55 years; meeting the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition ADHD criteria; baseline ADHD Rating Scale with Adult Prompts (ADHD-RS-AP) total scores >=28] were randomized 1:1:1 to placebo or forced-dose SHP465 MAS (12.5 or 37.5 mg/day) for 4 weeks. The ADHD-RS-AP total score change from baseline to week 4 (primary endpoint) and Clinical Global Impressions-Improvement score at week 4 (key secondary endpoint) were assessed using linear mixed-effects models for repeated measures. Other efficacy endpoints were changes from baseline to week 4 on the ADHD-RS-AP hyperactivity/impulsivity and inattentiveness subscales and the percentage of participants categorized as improved on the dichotomized Clinical Global Impressions-Improvement. Safety and tolerability assessments were treatment-emergent adverse events, vital sign and weight changes, Columbia-Suicide Severity Rating Scale responses, and electrocardiogram results. RESULTS: Of 369 screened participants, 275 were randomized (placebo, n = 91; 12.5 mg/day of SHP465 MAS, n = 92; 37.5 mg/day of SHP465 MAS, n = 92) and 236 completed the study (placebo, n = 80; 12.5 mg/day of SHP465 MAS, n = 80; 37.5 mg/day of SHP465 MAS, n = 76). Least-squares mean (95% confidence interval) treatment differences at week 4 significantly favored SHP465 MAS over placebo for the ADHD-RS-AP total score change from baseline [12.5 mg/day: -8.1 (-11.7, -4.4), effect size = 0.67; 37.5 mg/day: -13.4 (-17.1, -9.7), effect size = 1.11; both p < 0.001] and Clinical Global Impressions-Improvement score [12.5 mg/day: -0.8 (-1.1, -0.4), effect size = 0.68; 37.5 mg/day: -1.2 ( 1.6, -0.9), effect size = 1.11; both p < 0.001]. Treatment differences for the change from baseline at week 4 favored 12.5 and 37.5 mg/day of SHP465 MAS, respectively, over placebo on the ADHD-RS-AP hyperactivity/impulsivity (both nominal p < 0.001; effect size = 0.56 and 0.91) and inattentiveness (both nominal p < 0.001; effect size = 0.70 and 1.19) subscales. At the final on-treatment assessment, the percentage of participants categorized as improved on Clinical Global Impressions-Improvement was higher with both SHP465 MAS doses than with placebo (both nominal p < 0.001). Treatment-emergent adverse events reported (>5%) with SHP465 MAS were decreased appetite, dry mouth, insomnia, headache, anxiety, initial insomnia, irritability, and bruxism. Severe treatment-emergent adverse events and treatment-emergent adverse events leading to discontinuation, respectively, were reported by 8 and 12 participants (placebo, n = 2 and 0; 12.5 mg/day SHP465 MAS, n = 1 and 7; 37.5 mg/day SHP465 MAS, n = 5 and 5). At the final on-treatment assessment, mean +/- standard deviation increases from baseline were observed with 12.5 and 37.5 mg/day of SHP465 MAS for pulse (3.3 +/- 10.52 and 7.1 +/- 11.48 bpm) and blood pressure (systolic 0.2 +/- 7.24 and 1.7 +/ 9.99 mmHg; diastolic 1.0 +/- 7.46 and 2.8 +/- 7.90 mmHg) and decreases were observed for weight (-0.97 +/- 1.523 and -1.65 +/- 2.333 kg), body mass index ( 0.33 +/- 0.519 and -0.56 +/- 0.777 kg/m2), and Fridericia corrected QT interval ( 3.0 +/- 10.72 and -1.6 +/- 13.70 ms). No participant in any treatment group had a positive response for on-study Columbia-Suicide Severity Rating Scale assessments. CONCLUSIONS: SHP465 MAS was superior to placebo in reducing ADHD symptoms, with a safety profile consistent with other long-acting stimulants. ClinicalTrials.gov Registry Number: NCT02604407. PMID- 28712076 TI - Nickel stressed responses of rice in Ni subcellular distribution, antioxidant production, and osmolyte accumulation. AB - Nickel has been found a key pollutant in farmlands of central and south China, and understanding of Ni toxicity in rice is of great significance in safety production of rice and remediation of Ni polluted paddy soils. The present study aimed to investigate the uptake and subcellular distribution of Ni, antioxidant production, and osmolyte accumulation of rice (Oryza sativa L., cv. yangliangyou 6) plants exposed to excessive Ni concentrations to gain an insight into Ni induced phytotoxicity. Results revealed that exposure of rice seedlings to high Ni concentrations resulted a decline in root and shoot lengths and fresh weight (FW) and dry weight (DW) of rice plants, which are in connection with the depletion of the contents of photosynthetic pigments. Measurement of Ni concentrations in the roots and shoots showed that Ni was mainly accumulated in roots followed by shoots. Moreover, Ni was mainly deposited in soluble fraction and cell wall, than cell organelle, which suggests that both compartments act as crucial defensive barriers against Ni toxicity in rice plants. Ni also induced its toxicity by damaging oxidative metabolism, as indicated by increased level of hydrogen peroxide and malondialdehyde content. Furthermore, Ni stress also showed a desynchronized antioxidant system by increasing the activities of catalase, peroxidase, and the contents of ascorbic acid and glutathione, whereas decreasing the activity of superoxide dismutase in the roots and shoots of rice plants. Ni stress also triggered the rate of proline accumulation and decreasing the contents of soluble protein and soluble sugar. In crux, our results suggests that excessive Ni inhibited rice growth and induced oxidative stress through inducing ROS formation, while stimulated enzymatic and non-enzymatic antioxidants system appeared as adaptive mechanisms of rice plants against Ni-induced oxidative stress. Furthermore, majority of Ni was located in soluble fraction and modulation in osmolyte accumulation under Ni stress seemed to provide additional defense against oxidative stress. PMID- 28712077 TI - Insecticidal effect and impact of fitness of three diatomaceous earths on different maize hybrids for the eco-friendly control of the invasive stored product pest Prostephanus truncatus (Horn). AB - Diatomaceous earths (DEs) are able to successfully protect grain commodities from noxious stored-product insect and mite infestations; however, their effectiveness may be moderated by the grain hybrid or variety they are applied to. There is a gap of information on the comparison of the efficacy of different DEs when are applied on different maize hybrids against Prostephanus truncatus (Horn). Therefore, here we tested three commercially available DEs (DEA-P at 75 and 150 ppm, Protect-It at 500 ppm, and PyriSec at 500 ppm) on five different maize hybrids (Calaria, Doxa, Rio Grande, Sisco, and Studio) for the control of P. truncatus adults in terms of mortality (at 7 and 14 days), progeny production, properties of the infested maize hybrids (number and weight of kernels with or without holes, number of holes per kernel) and the adherence level of the tested DEs to the kernels. DEA-P was very effective at 75 ppm while a considerable proportion of the exposed P. truncatus adults was still alive after 14 days of exposure on all maize hybrids treated with 500 ppm of Protect-It or PyriSec, even though it was 3.3 times higher than the maximal application tested dose of DEA-P. Apart from parental mortality, DEA-P was able to reduce P. truncatus progeny production in all hybrids contrary to Protect-It or PyriSec. The adherence ratios were always higher for DEA-P than Protect-It or PyriSec to all maize hybrids. The highest numbers of kernels (or weight of kernels) without holes were noticed after their treatment with DEA-P. Doxa and Sisco performed better than Calaria, Rio Grande, or Studio based on the differences found concerning the numbers of kernels without holes at treatments with DEA-P and Protect-It. Overall, the findings of our study indicate the high potentiality of DEA-P as protectant of different maize hybrids to P. truncatus infestations at low doses, a fact that could help the eco-friendly management of this noxious species in the stored product environment. PMID- 28712078 TI - Effects-based spatial assessment of contaminated estuarine sediments from Bear Creek, Baltimore Harbor, MD, USA. AB - Estuarine sediments in regions with prolonged histories of industrial activity are often laden to significant depths with complex contaminant mixtures, including trace metals and persistent organic pollutants. Given the complexity of assessing risks from multi-contaminant exposures, the direct measurement of impacts to biological receptors is central to characterizing contaminated sediment sites. Though biological consequences are less commonly assessed at depth, laboratory-based toxicity testing of subsurface sediments can be used to delineate the scope of contamination at impacted sites. The extent and depth of sediment toxicity in Bear Creek, near Baltimore, Maryland, USA, was delineated using 10-day acute toxicity tests with the estuarine amphipod Leptocheirus plumulosus, and chemical analysis of trace metals and persistent organic pollutants. A gradient of toxicity was demonstrated in surface sediments with 21 of 22 tested sites differing significantly from controls. Effects were most pronounced (100% lethality) at sites proximate to a historic industrial complex. Sediments from eight of nine core samples to depths of 80 cm were particularly impacted (i.e., caused significant lethality to L. plumulosus) even in locations overlain with relatively non-toxic surface sediments, supporting a conclusion that toxicity observed at the surface (top 2 cm) does not adequately predict toxicity at depth. In seven of nine sites, toxicity of surface sediments differed from toxicity at levels beneath by 28 to 69%, in five instances underestimating toxicity (28 to 69%), and in two instances overestimating toxicity (44 to 56%). Multiple contaminants exceeded sediment quality guidelines and correlated positively with toxic responses within surface sediments (e.g., chromium, nickel, polycyclic aromatic hydrocarbon (PAH), total petroleum hydrocarbon). Use of an antibody-based PAH biosensor revealed that porewater PAH concentrations also increased with depth at most sites. This study informs future management decisions concerning the extent of impact to Bear Creek sediments, and demonstrates the benefits of a spatial approach, relying primarily on toxicity testing to assess sediment quality in a system with complex contaminant mixtures. PMID- 28712080 TI - Elemental and isotopic determination of lead (Pb) in particulate matter in the Brazilian city of Goiania (GO) using ICP-MS technique. AB - The toxic metal lead (Pb) can be harmful to human health in various manners, but is also considered as a distinguished tracer of environmental pollution since the relative abundance of its four stable isotopes with the atomic masses of 204, 206, 207, and 208 varies with the emission source. This study is focused on the Pb concentrations and isotope ratios in the particulate matter of the Brazilian city of Goiania in order to determine the main Pb emission sources. Particulate matter samples were collected on clean Teflon filters during rainy and dry season in 2014 in the center of Goiania city near main roads with a high traffic volume. Pb concentrations as well as stable Pb isotope ratios of the particulate matter samples were analyzed by inductively coupled plasma-mass spectrometry. To apply this analytical technique successfully, it was necessary to optimize parameters in case of acquisition time, detector dead time, and mass discrimination, which affect the measurement accuracy and precision. Results showed that Pb concentrations in Goiania were different between rainy and dry season. Pb concentrations showed higher values and less variation in dry season than in rainy season. Pb isotope ratios demonstrated significant variations between dry and rainy season. An enrichment of 206Pb isotopes related to 207Pb and 208Pb isotopes was observed in dry season. However, the comparison of the obtained isotopic Pb signature with data of potential Pb sources from previous studies indicated that traffic-related sources should be considered as main Pb source in the particulate matter of Goiania. These assumptions were incorporated by the calculation of the contribution factor of Pb coming from traffic-related sources by applying binary mixing equations. PMID- 28712079 TI - Aryl hydrocarbon receptor gene transitions (c.-742C>T; c.1661G>A) and idiopathic male infertility: a case-control study with in silico and meta-analysis. AB - Aryl hydrocarbon receptor (AHR) is responsible for crucial events in male reproductive biology. Here, the association of the AHR transitions c.-742C>T and c.1661G>A with idiopathic male infertility was investigated in a case-control study, which is followed by a meta-analysis and a bioinformatic investigation. Blood and semen samples were obtained from a total of 135 idiopathic infertile men and 130 healthy controls. Participants were genotyped for the transitions using a PCR-RFLP method. A meta-analysis of five sets of data evaluated the association of c.1661G>A with male infertility, and using an in silico analysis, the possible molecular effects of the transitions predicted. Genotypes and alleles of AHR-c.-742C>T and c.1661G>A polymorphisms were not associated with the risk of male infertility significantly. However, the frequency of C/A haplotype was significantly associated with the increased risk of male infertility, and T/A haplotype was higher among controls significantly. Also, the frequencies of combined genotypes CT/GG, CT/GA and TT/GG were significantly associated with decreased risk of infertility. And, the meta-analysis showed that the AA versus GA/GG recessive model is associated with decreased risk of male infertility among the Iranian population. In silico analysis predicted that c.-742C>T does not alter the binding sites of the proposed transcription factors, but c.1661G>A poses a tolerable structural disturbance in AHR protein. In conclusion, these results showed that AHR c.-742C>T and c.1661G>A transitions separately could not be nominated as a risk or protective factor for male infertility. However, some combined models could affect infertility risk, especially among Iranian men. PMID- 28712081 TI - Survey on awareness and attitudes of secondary school students regarding plastic pollution: implications for environmental education and public health in Sharjah city, UAE. AB - Since the industrial revolution in the 1800s, plastic pollution is becoming a global reality. This study aims to assess knowledge and attitude about plastic pollution among secondary school students in Sharjah city, United Arab Emirates. A cross-sectional study was conducted among 400 students in 6 different secondary schools in Sharjah city. Self-administered questionnaires were distributed through probability stratified random sampling method between February and April 2016. Majority of the population understands how harmful plastic wastes are to the environment (85.5%). However, the students' mean knowledge score was 53%, with females (P < 0.01), grades 11 and 12 (P = 0.024), and students whose mothers were more educated (P = 0.014) being more knowledgeable and inclined towards pro environmental behavior. Yet, all students showed tendency to be involved in the fighting against this dilemma. Strategies which address deficiencies, provide incentives for change, and assure governmental support along with environmental education are needed to bridge the information gap and enhance opportunities to adopt pro-environmental behaviors. PMID- 28712082 TI - Biological nutrient recovery from culturing of pearl gourami (Trichogaster leerii ) by cherry tomato (Solanum lycopersicum) in aquaponic system. AB - The possibility of using different densities of cherry tomato as a bio-filter in a simple media-based aquaponic system to recycle nutrients from pearl gourami intensive culture wastewater was evaluated. Water quality parameters including total ammonia nitrogen (TAN), nitrite (NO2-), nitrate (NO3-), phosphate (PO43-), pH, and dissolved oxygen (DO) were determined in outlet of the aquaponic system during a 60-day experimental period. Cherry tomato was planted at four densities of 0 (control), 3 (T1), 6 (T2), and 9 (T3) plants per aquaponic unit with a constant fish stock density. Each treatment was equipped with aquaponic systems containing fish tank and plant growing bed. Productivity of the system was measured by recording the fish and plant growth indices. The potential in removing nitrogen of the water was the highest in T3 (with nine plants) compared to other treatments (p < 0.05). The highest concentrations of TAN (6.59 +/- 0.241 mg/L), nitrite (0.42 +/- 0.005 mg/L), nitrate (0.45 +/- 0.162 mg/L), and phosphate (30.47 +/- 0.371 mg/L) were obtained in control group, while the lowest concentrations of TAN (0.05 +/- 0.091 mg/L), NO2- (0.11 +/- 0.008 mg/L), NO3- (29.77 +/- 0.205 mg/L), and phosphate (18.59 +/- 0.185 mg/L) were detected in T3 (p < 0.05). The maximum fish weight gain was recorded in T3 (26 +/- 0.014%) with 1.26 +/- 0.059 FCR, and the lowest fish weight gain was measured in the control group (15 +/- 0.024%) with 2.19 +/- 0.446 FCR (p < 0.05). Total plant length gain was reached at the maximum value in T3 (74.70 +/- 1.153 cm) in comparison to other groups (p < 0.05). It was concluded that small-scale aquaponic growing bed system can be created a sustainable ecosystem which both the plant and fish can thrive and suitable for home-made production system. PMID- 28712083 TI - Predictive statistical modelling of cadmium content in durum wheat grain based on soil parameters. AB - Regulatory limits on cadmium (Cd) content in food products are tending to become stricter, especially in cereals, which are a major contributor to dietary intake of Cd by humans. This is of particular importance for durum wheat, which accumulates more Cd than bread wheat. The contamination of durum wheat grain by Cd depends not only on the genotype but also to a large extent on soil Cd availability. Assessing the phytoavailability of Cd for durum wheat is thus crucial, and appropriate methods are required. For this purpose, we propose a statistical model to predict Cd accumulation in durum wheat grain based on soil geochemical properties related to Cd availability in French agricultural soils with low Cd contents and neutral to alkaline pH (soils commonly used to grow durum wheat). The best model is based on the concentration of total Cd in the soil solution, the pH of a soil CaCl2 extract, the cation exchange capacity (CEC), and the content of manganese oxides (Tamm's extraction) in the soil. The model variables suggest a major influence of cadmium buffering power of the soil and of Cd speciation in solution. The model successfully explains 88% of Cd variability in grains with, generally, below 0.02 mg Cd kg-1 prediction error in wheat grain. Monte Carlo cross-validation indicated that model accuracy will suffice for the European Community project to reduce the regulatory limit from 0.2 to 0.15 mg Cd kg-1 grain, but not for the intermediate step at 0.175 mg Cd kg 1. The model will help farmers assess the risk that the Cd content of their durum wheat grain will exceed regulatory limits, and help food safety authorities test different regulatory thresholds to find a trade-off between food safety and the negative impact a too strict regulation could have on farmers. PMID- 28712084 TI - Effluent trading in river systems through stochastic decision-making process: a case study. AB - The objective of this paper is to provide an efficient framework for effluent trading in river systems. The proposed framework consists of two pessimistic and optimistic decision-making models to increase the executability of river water quality trading programs. The models used for this purpose are (1) stochastic fallback bargaining (SFB) to reach an agreement among wastewater dischargers and (2) stochastic multi-criteria decision-making (SMCDM) to determine the optimal treatment strategy. The Monte-Carlo simulation method is used to incorporate the uncertainty into analysis. This uncertainty arises from stochastic nature and the errors in the calculation of wastewater treatment costs. The results of river water quality simulation model are used as the inputs of models. The proposed models are used in a case study on the Zarjoub River in northern Iran to determine the best solution for the pollution load allocation. The best treatment alternatives selected by each model are imported, as the initial pollution discharge permits, into an optimization model developed for trading of pollution discharge permits among pollutant sources. The results show that the SFB-based water pollution trading approach reduces the costs by US$ 14,834 while providing a relative consensus among pollutant sources. Meanwhile, the SMCDM-based water pollution trading approach reduces the costs by US$ 218,852, but it is less acceptable by pollutant sources. Therefore, it appears that giving due attention to stability, or in other words acceptability of pollution trading programs for all pollutant sources, is an essential element of their success. PMID- 28712085 TI - Long-term spatiotemporal trends and health risk assessment of oyster arsenic levels in coastal waters of northern South China Sea. AB - Long-term spatiotemporal trends and health risk assessment of oyster arsenic levels in the coastal waters of northern South China Sea were investigated in order to help improve the quality and safety control and sustainable aquaculture for mollusks in China. Cultured oysters (Crassostrea rivularis) collected from the waters of 23 bays, harbors, and estuaries along the coast of northern South China Sea from 1989 to 2012 were examined for spatial patterns and long-term temporal trends of oyster arsenic levels. Single-factor index and health risk assessment were used to quantify arsenic exposure to human health through oyster consumption. Overall, arsenic was detected in 97.4% of the oyster samples, and oyster arsenic levels were non-detectable-2.51 mg/kg with an average of 0.63 +/- 0.54 mg/kg. Oyster arsenic levels in the coastal waters of northern South China Sea showed an overall decline from 1989 to 2012, remained relatively low since 2005, and slightly increased after 2007. Oyster arsenic levels in Guangdong coastal waters were much higher with more variation than in Guangxi and Hainan coastal waters, and the long-term trends of oyster arsenic levels in Guangdong coastal waters dominated the overall trends of oyster arsenic levels in the coastal waters of northern South China Sea. Within Guangdong Province, oyster arsenic levels were highest in east Guangdong coastal waters, followed by the Pearl River estuary and west Guangdong coastal waters. Single-factor index ranged between 0.27 and 0.97, and average health risk coefficient was 3.85 * 10-5, both suggesting that oyster arsenic levels in northern South China Sea are within the safe range for human consumption. However, long-term attention should be given to seafood market monitoring in China and the risk of arsenic exposure to human health through oyster consumption. PMID- 28712086 TI - Pilot study investigating ambient air toxics emissions near a Canadian kraft pulp and paper facility in Pictou County, Nova Scotia. AB - Air toxics are airborne pollutants known or suspected to cause cancer or other serious health effects, including certain volatile organic compounds (VOCs), prioritized by the US Environmental Protection Agency (EPA). While several EPA designated air toxics are monitored at a subset of Canadian National Air Pollution Surveillance (NAPS) sites, Canada has no specific "air toxics" control priorities. Although pulp and paper (P&P) mills are major industrial emitters of air pollutants, few studies quantified the spectrum of air quality exposures. Moreover, most NAPS monitoring sites are in urban centers; in contrast, rural NAPS sites are sparse with few exposure risk records. The objective of this pilot study was to investigate prioritized air toxic ambient VOC concentrations using NAPS hourly emissions data from a rural Pictou, Nova Scotia Kraft P&P town to document concentration levels, and to determine whether these concentrations correlated with wind direction at the NAPS site (located southwest of the mill). Publicly accessible Environment and Climate Change Canada data (VOC concentrations [Granton NAPS ID: 31201] and local meteorological conditions [Caribou Point]) were examined using temporal (2006-2013) and spatial analytic methods. Results revealed several VOCs (1,3-butadiene, benzene, and carbon tetrachloride) routinely exceeded EPA air toxics-associated cancer risk thresholds. 1,3-Butadiene and tetrachloroethylene were significantly higher (p < 0.05) when prevailing wind direction blew from the northeast and the mill towards the NAPS site. Conversely, when prevailing winds originated from the southwest towards the mill, higher median VOC air toxics concentrations at the NAPS site, except carbon tetrachloride, were not observed. Despite study limitations, this is one of few investigations documenting elevated concentrations of certain VOCs air toxics to be associated with P&P emissions in a community. Findings support the need for more research on the extent to which air toxics emissions exist in P&P towns and contribute to poor health in nearby communities. PMID- 28712088 TI - Erratum to Expression of Inflammatory Mediators in Induced Sputum: Comparative Study in Asthma and COPD. PMID- 28712087 TI - Toxicity of cypermethrin and deltamethrin insecticides on embryos and larvae of Physalaemus gracilis (Anura: Leptodactylidae). AB - It is important to establish the toxicity pesticides against non-target species, especially those pesticides used in commercial formulations. Pyrethroid insecticides are widely used in agriculture despite their toxicity to aquatic animals. In this study, we determine the toxicity of commercial formulation of two pyrethroid insecticides, cypermethrin and deltamethrin, in two life stages of Physalaemus gracilis, a frog that breeds in agricultural ecosystems and has potential contact with pyrethroid pesticides. The acute toxicity test (96 h) was carried out with embryos of stage 17:18 and larvae of stages 24:25. Embryos were more resistant to both pesticides than larvae. In embryo mobility assays, we found that both pesticides caused spasmodic contractions, suggestive of neurological effects. In acute toxicity assays, we found that P. gracilis is more resistant to these insecticides than other studied species. PMID- 28712089 TI - Increased recruitment of cognitive control in the presence of traumatic stimuli in complex PTSD. AB - A neurocircuitry model of post-traumatic stress disorder (PTSD) suggests increased amygdala responses to emotional stimuli, coupled with hypoactivation of prefrontal regions associated with cognitive control. However, results are heterogenous across different subsamples of PTSD as well as different paradigms. We investigated cognitive control in a classic and emotional Stroop task in 28 female patients with complex PTSD (cPTSD), 28 female trauma-exposed healthy controls (TCs) and 28 female non-trauma-exposed healthy controls (HCs) using functional neuroimaging. Afterwards, we assessed memory function in a spontaneous free recall and recognition task. Patients with cPTSD displayed significantly greater Stroop interference with trauma-related words (as reflected in slower reaction times and increased errors) compared to the other conditions and compared to the TC and HC groups. Moreover, patients with cPTSD showed increased activation in the context of trauma-related words in brain regions associated with cognitive control (dlPFC, vmPFC, dACC) compared to both control groups, and a trend for increased activation in the insula compared to the HC group. Increased recruitment of regions contributing to cognitive control in patients with cPTSD, together with a lack of amygdala response may point to efforts to compensate for emotional distraction caused by the trauma-related words. PMID- 28712090 TI - Does prior traumatization affect the treatment outcome of CBT for panic disorder? The potential role of the MAOA gene and depression symptoms. AB - Although cognitive behavioral therapy (CBT) is highly effective in the treatment of anxiety disorders, many patients still do not benefit. This study investigates whether a history of traumatic event experience is negatively associated with outcomes of CBT for panic disorder. The moderating role of the monoamine oxidase A (MAOA) gene and depression symptoms as well as the association between trauma history and fear reactivity as a potential mechanism are further analyzed. We conducted a post-hoc analysis of 172 male and 60 female patients with panic disorder treated with CBT in a multi-center study. Treatment outcome was assessed at post-treatment using self-report and clinician rating scales. Fear reactivity before treatment was assessed via heart rate and self-reported anxiety during a behavioral avoidance test. Among females, we did not find any differences in treatment response between traumatized and non-traumatized individuals or any two way interaction trauma history * MAOA genotype. There was a significant three-way interaction trauma history * MAOA genotype * depression symptoms on all treatment outcomes indicating that in traumatized female patients carrying the low-activity allele, treatment effect sizes decreased with increasing depression symptoms at baseline. No such effects were observed for males. In conclusion, we found no evidence for a differential treatment response in traumatized and non-traumatized individuals. There is preliminary evidence for poorer treatment outcomes in a subgroup of female traumatized individuals carrying the low-active variant of the MAOA gene. These patients also report more symptoms of depression symptomatology and exhibit a dampened fear response before treatment which warrants further investigation. PMID- 28712091 TI - Contribution of Genetic Factors to Lower DHEAS in Patients with Rheumatoid Arthritis. AB - OBJECTIVE: Lower production of adrenal androgens has been confirmed in females with rheumatoid arthritis (RA); however, the mechanisms of this finding are not completely understood. The aim of our study was to assess the contribution of genetic factors associated with variability of dehydroepiandrosterone sulfate (DHEAS) levels to lower DHEAS in female RA patients. METHODS: 448 RA and 648 healthy controls were genotyped for single-nucleotide polymorphisms (SNPs) in genes ZKSCAN5 (rs11761528), SULT2A1 (rs2637125), HHEX (rs2497306), and ARPC1A (rs740160). Serum DHEAS concentrations were measured in 112 RA patients and 91 healthy women. RESULTS: The allele frequencies in DHEAS-related loci were similar in RA and controls. RA patients had significantly lower serum DHEAS concentrations compared to healthy women. The cumulative number of alleles associated with lower DHEAS within genes ZKSCAN5, SULT2A1, HHEX, and ARPC1A present in each individual negatively correlated with DHEAS levels in RA patients, but not in controls. Linear regression analysis showed significant effect of polymorphisms in genes ZKSCAN5 and ARPC1A on serum DHEAS levels in female RA patients but not in the control group. CONCLUSION: Our findings suggest that complex interactions exist between genotype and adrenal androgen hypofunction in RA. PMID- 28712092 TI - Favorable Impact on Stress-Related Behaviors by Modulating Plasma Butyrylcholinesterase. AB - In the last decade, it has become clear that the neuropeptide "ghrelin" and its principal receptor have a large impact on anxiety and stress. Our recent studies have uncovered a link between plasma butyrylcholinesterase (BChE) and ghrelin. BChE actually turns out to be the key regulator of this peptide. This article reviews our recent work on manipulating ghrelin levels in mouse blood and brain by long term elevation of BChE, leading to sustained decrease of ghrelin. That effect in turn was found to reduce stress-induced aggression in group caged mice. Positive consequences were fewer bite wounds and longer survival times. No adverse effects were observed. Further exploration may pave the way for BChE based treatment of anxiety in humans. PMID- 28712093 TI - Neurobiological effect of selective brain cooling after concussive injury. AB - The search for effective treatment facilitating recovery from concussive injury, as well as reducing risk for recurrent concussion is an ongoing challenge. This study aimed to determine: a) feasibility of selective brain cooling to facilitate clinical symptoms resolution, and b) biological functions of the brain within athletes in acute phase of sports-related concussion. Selective brain cooling for 30 minutes using WElkins sideline cooling system was administered to student athletes suffering concussive injury (n=12; tested within 5+/-3 days) and those without history of concussion (n=12). fMRI and ASL sequences were obtained before and immediately after cooling to better understanding the mechanism by which cooling affects neurovascular coupling. Concussed subjects self-reported temporary relief from physical symptoms after cooling. There were no differences in the number or strength of functional connections within Default Mode Network (DMN) between groups prior to cooling. However, we observed a reduction in the strength and number of connections of the DMN with other ROIs in both groups after cooling. Unexpectedly, we observed a significant increase in cerebral blood flow (CBF) assessed by ASL after selective cooling in the concussed subjects compared to the normal controls. We suggest that compromised neurovascular coupling in acute phase of injury may be temporarily restored by cooling to match CBF with surges in the metabolic demands of the brain. Upon further validation, selective brain cooling could be a potential clinical tool in the minimization of symptoms and pathological changes after concussion. PMID- 28712094 TI - Different Mutations of Gap Junction Connexin 47 Lead to Discrepant Activation of Unfolded Protein Response Pathway in Pelizaeus-Merzbacher-Like Disease. PMID- 28712095 TI - Jeffrey Vacirca on How the COA Advocates for Community Oncology Practices and Patients. PMID- 28712096 TI - Myeloproliferative Neoplasms: Translating New Discoveries Into Better Outcomes, Better Quality of Life. AB - Despite the identification of JAK mutations and the development of targeted inhibitors, there remain significant unmet needs for patients with myeloproliferative neoplasms. Identification of the myeloproliferative neoplasm populations not currently benefiting from JAK inhibitor therapy highlights the therapeutic deficits still present in this heterogeneous stem cell malignancy. While JAK inhibition has provided significant benefits for patients with intermediate-2 or high-risk myelofibrosis and in patients with polycythemia vera in the second-line setting, JAK inhibitor monotherapy is not approved and not appropriate for all patients with myeloproliferative neoplasms. Continued investigation into additional JAK inhibitors, combination therapy, and novel pathway therapeutics remains key to improving outcomes for all patients with myeloproliferative neoplasms. While therapeutic advances in the JAK inhibitor arena or involving alternative pathways are crucial to improving outcomes in myeloproliferative neoplasms, it is also important to reconsider the role of constitutional symptoms in affected patients as an indication for treatment with agents, such as JAK inhibitors, that can mitigate these debilitating symptoms. In this review, we demonstrate the evolving landscape of clinical investigations that address the important therapeutic needs of patients with myeloproliferative neoplasms. PMID- 28712097 TI - Fertility Preservation in Young Adult Patients With Cancer. AB - More than 60,000 young adults are diagnosed with cancer each year in the United States. Many will not have started or completed their families at the time of diagnosis, and reproductive concerns are common. Practice guidelines from a number of professional organizations, including the American Society of Clinical Oncology, highlight the need for oncology clinicians to address fertility with their at-risk patients by discussing options for fertility preservation. Fertility preservation options for men include sperm banking (through manual stimulation, electroejaculation, and testicular sperm extraction) and testicular shielding. Fertility preservation options for women include egg and embryo freezing, ovarian tissue freezing, ovarian transposition, and ovarian suppression. This article highlights several practical strategies for integrating fertility preservation discussions into daily clinical practice and ensuring that oncology professionals are able to refer interested patients to appropriate reproductive specialists. PMID- 28712098 TI - Precision Medicine in Metastatic Colorectal Cancer: Relevant Carcinogenic Pathways and Targets-PART 1: Biologic Therapies Targeting the Epidermal Growth Factor Receptor and Vascular Endothelial Growth Factor. AB - The survival of patients with metastatic colorectal cancer has improved dramatically in recent years, with overall survival exceeding 3 years in large randomized clinical trials. There are now several treatment options for patients with metastatic colorectal cancer. In addition to chemotherapy backbones utilizing fluoropyrimidine, oxaliplatin, and irinotecan combinations, biologic agents that target specific oncogenic pathways have contributed to the improved survival observed in this patient population. This class of medications includes epidermal growth factor receptor (EGFR)-targeted drugs (cetuximab and panitumumab) and vascular endothelial growth factor (VEGF)-targeted therapies (bevacizumab, ramucirumab, ziv-aflibercept, and regorafenib). Bevacizumab remains the only VEGF-targeted agent approved by the US Food and Drug Administration in the first-line metastatic setting. EGFR-directed treatment should be restricted to patients with extended RAS and BRAF wild-type tumors. Tumor sidedness may be a more powerful prognostic and predictive biomarker than tumor mutational profile. Patients with left-sided primary tumors derive greater benefit from EGFR-targeted therapies whereas patients with right-sided primary tumors benefit more from bevacizumab. Herein we review drugs that target the EGFR and VEGF pathways, focusing on patient selection, drug toxicities, and how to choose agents for first-line therapy. PMID- 28712099 TI - Don't Be Fooled by DCIS. PMID- 28712100 TI - The Role of Genomic Techniques in Predicting Response to Radiation Therapy. AB - The understanding of the relationship between genetic variation and an individual patient's response to radiation therapy (RT) has gained significant ground over the past several years. Genetic markers have been identified that could ultimately serve as the foundation for predictive models in clinical practice, and that hold the potential to revolutionize the delivery of precision medicine in oncology. Single nucleotide polymorphisms, single genes, and/or gene signatures could ultimately serve as the basis for patient stratification in prospective clinical trials. Currently, molecular markers relevant to breast, lung, and head and neck cancers have been integrated into clinical practice and serve as predictive tools to guide systemic therapy. In the future, the use of predictive models based on genomic determinants may become standard practice in radiation oncology, offering the potential to further personalize the delivery of RT and optimize the therapeutic ratio. PMID- 28712101 TI - Molecular Profiling in the Practice of Radiation Oncology. PMID- 28712102 TI - Precision Medicine in Metastatic Colorectal Cancer: Relevant Carcinogenic Pathways and Targets-PART 2: Approaches Beyond First-Line Therapy, and Novel Biologic Agents Under Investigation. AB - A frequent quandary for oncologists is the selection of chemotherapy and biologic therapy for patients with metastatic colorectal cancer in second-line and higher treatment settings. While not approved by the US Food and Drug Administration (FDA) in the first-line setting, the vascular endothelial growth factor (VEGF) targeting agents ziv-aflibercept and ramucirumab are appropriate treatment options in the second-line setting, as is continuation of first-line bevacizumab. Tumor RAS mutational status is helpful to determine which patients may benefit from epidermal growth factor receptor (EGFR)-directed therapies, and other novel biomarkers (BRAF, HER2, and mismatch repair deficiency) allow us to select patients who may benefit from biologic therapies that are FDA-approved for other malignancies. Maintenance therapy for patients with stable disease following first-line therapy is a unique clinical situation that warrants special attention. Immunotherapy has thus far been ineffective for patients with mismatch repair-proficient tumors, but novel combination strategies are being studied to break through this treatment barrier. Finally, several new biologic therapies with novel targets are under development and will likely contribute to the growing arsenal of treatment options for patients with metastatic colorectal cancer. PMID- 28712103 TI - Randomised controlled trial of analgesic effectiveness of three different techniques of single-shot interscalene brachial plexus block using 20 mL of 0.5% ropivacaine for shoulder arthroscopy. AB - BACKGROUND: Shoulder arthroscopic procedures impose a challenge to anaesthesiologists in terms of postoperative analgesia. Proper pain management after arthroscopic procedures improves patient satisfaction and facilitates early rehabilitation. METHODS: We performed a randomized, prospective clinical study to assess the influence of anthropometric parameters and IBPB technique on the quality of postoperative analgesia. A total of 106 randomly selected patients of ASA I-III status scheduled for elective shoulder arthroscopy. Reasons for exclusion were neurological deficit in the upper arm, allergies to amide-type local anesthetics, coagulopathy, and pregnancy.The patients received 20 mL of 0.5% ropivacaine for an ultrasound-guided interscalene brachial plexus block (IBPB) (group U), peripheral nerve stimulation (PNS)-confirmed IBPB (group N), or ultrasound-guided, PNS-confirmed IBPB (dual guidance; group NU). RESULTS: We observed that the three groups did not differ in mean time of sensory and motor block terminations. In individual cases in each group, sensory block lasted up to 890-990 minutes, providing satisfactory long lasting postoperative analgesia in patients receiving IBPB. We observed a negative correlation between body mass index and termination of motor block (P = 0.037, Pearson's correlation coefficient) and a positive correlation between age and termination of sensory block (P = 0.0314, Pearson's correlation coefficient) in group U compared to the other two groups. We found a positive correlation between male gender and termination of motor block (P = 0.0487, Pearson's correlation coefficient) in group N compared to the other two groups. CONCLUSION: In our study, patients received satisfactory analgesia in the postoperative period regardless of technique used, age, gender, or potentially uncommon anthropometry. PMID- 28712104 TI - Do bacteria isolated from ICU patients 'ESKAPE' antibiotic treatment? In vitro susceptibility of the Enterobacteriaceae family to tigecycline. AB - BACKGROUND: Enterobacteriaceae are currently causing the majority of healthcare associated infections (HAI) and simultaneously expressing increasing levels of antibiotic resistance. The purpose of this study is to assess the in vitro sensitivity of MDR strains from the family Enterobacteriaceae to tigecycline in relation to their origin from patients hospitalized in intensive care units (ICUs) and non-ICUs. METHODS: The study involved 156 clinically significant strains of the Enterobacteriaceae family isolated from patients with complicated intraabdominal infections (cIAIs) and/or complicated skin and skin structure infections (cSSSIs) hospitalized in ICUs and other surgical departments. Tigecycline MICs were determined by Etest. RESULTS: The highest percentage of tigecycline non-susceptible (intermediate + resistant strains) in vitro strains among the Enterobacteriaceae species were observed for Serratia spp. 77.3%, followed by Citrobacter spp. (76.9%) and Enterobacter spp. (70%); whereas K. pneumoniae and E. coli showed 73-73.8% tigecycline susceptibility rates. CONCLUSION: Tigecycline demonstrates a high level of antimicrobial in vitro activity when tested against E. coli and K. pneumoniae, even those with the ESBL phenotype. Tigecycline retained activity against merely 22-30% of Enterobacter, Citrobacter and Serratia genera. PMID- 28712105 TI - Evaluation of a low-cost, 3D-printed model for bronchoscopy training. AB - BACKGROUND: Flexible bronchoscopy is a fundamental procedure in anaesthesia and critical care medicine. Although learning this procedure is a complex task, the use of simulation-based training provides significant advantages, such as enhanced patient safety. Access to bronchoscopy simulators may be limited in low resource settings. We have developed a low-cost 3D-printed bronchoscopy training model. METHODS: A parametric airway model was obtained from an online medical model repository and fabricated using a low-cost 3D printer. The participating physicians had no prior bronchoscopy experience. Participants received a 30 minute lecture on flexible bronchoscopy and were administered a 15-item pre-test questionnaire on bronchoscopy. Afterwards, participants were instructed to perform a series of predetermined bronchoscopy tasks on the 3D printed simulator on 4 consecutive occasions. The time needed to perform the tasks and the quality of task performance (identification of bronchial anatomy, technique, dexterity, lack of trauma) were recorded. Upon completion of the simulator tests, participants were administered the 15-item questionnaire (post-test) once again. Participant satisfaction data on the perceived usefulness and accuracy of the 3D model were collected. A statistical analysis was performed using the t-test. Data are reported as mean values (+/- standard deviation). RESULTS: The time needed to complete all tasks was 152.9 +/- 71.5 sec on the 1st attempt vs. 98.7 +/- 40.3 sec on the 4th attempt (P = 0.03). Likewise, the quality of performance score improved from 8.3 +/- 6.7 to 18.2 +/- 2.5 (P < 0.0001). The average number of correct answers in the questionnaire was 6.8 +/- 1.9 pre-test and 13.3 +/- 3.1 post-test (P < 0.0001). Participants reported a high level of satisfaction with the perceived usefulness and accuracy of the model. CONCLUSIONS: We developed a 3D-printed model for bronchoscopy training. This model improved trainee performance and may represent a valid, low-cost bronchoscopy training tool. PMID- 28712106 TI - Sensitivity and specificity of urinalysis samples in critically ill patients. AB - BACKGROUND: Pre-emptive screening of urine for patients admitted to an intensive care unit can result in the misinterpretation of data and over- or under treatment of urinary tract infection. METHODS: Data were studied from 169 consecutive patients admitted to the neurologic or burn intensive care unit at Shands Hospital at the University of Florida. All patients had a urinary catheter in place at the time of admission. Urinalysis and urine culture were sent for analysis. Data included leukocyte esterase, urine nitrate, urine protein, pyuria or urine white blood cell count, and culture. RESULTS: Leukocyte esterase and pyuria were the most sensitive indicators of a positive urine culture at 87.5% (95% CI: 71.3-100%) and 73.3% (95% CI: 51.0-95.7%), respectively; urine nitrate was specific at 100%. More than half of the patients (56.3%) with positive cultures did not initially receive antibiotics. CONCLUSION: The combination of leukocyte esterase and urine nitrate provides the best indicator for the initiation of antibiotic coverage for urinary tract infection prior to culture availability. PMID- 28712107 TI - An iron rod restricting access to airway: an unusual presentation. AB - . PMID- 28712108 TI - Tramadol addict: a rare but real challenge for the anaesthesiologist. PMID- 28712109 TI - Therapeutic effect of capsaicin nasal treatment in patients with mixed rhinitis unresponsive to intranasal steroids. AB - Literature is convincing regarding the efficacy of capsaicin nasal treatment in idiopathic rhinitis (IR). However, up to 50% of IR patients do not meet the strict inclusion criteria of the trials conducted so far. As a consequence, the efficacy of capsaicin is unknown in a significant number of IR patients that do not meet the strict inclusion/exclusion criteria (J Allergy Clin Immunol. 2014;133:1332, J Allergy Clin Immunol. 2017; [Epub ahead of print]). "Mixed rhinitis" (MR) patients have more than one major etiologic factor involved in the mucosal pathology. We have no idea about the efficacy of capsaicin nasal spray in these patients nor about the time interval to seek a second application. We report here that capsaicin nasal spray is effective in a broader group of IR than the purely selected ones described before, that subjective nasal hyper-reactivity is a good predictor of positive outcome, and that the time interval for seeking a second treatment is likely to be shorter in MR patients than in the strictly selected IR patients. PMID- 28712110 TI - Assessing attitudes and actions of pediatric dentists toward childhood obesity and sugar-sweetened beverages. AB - OBJECTIVES: Childhood obesity is a major US health concern, and oral health professionals have opportunities to participate in an interprofessional effort to intervene owing to their access to young patients and their abilities in addressing obesity-related dietary habits like consumption of sugar-sweetened beverages (SSBs). This study determined attitudes, behaviors, future intentions, and perceived barriers of pediatric dentists regarding efforts to prevent childhood obesity and reduce children's consumption of SSBs. METHODS: The American Academy of Pediatric Dentistry conducted an online electronic survey with a convenience sample of approximately 7,450 pediatric dentists and pediatric dental residents during spring 2016. RESULTS: Over 17 percent of pediatric dentists offer childhood obesity interventions. Of those not providing interventions, 67 percent were interested in offering obesity-prevention services. Nearly 94 percent of pediatric dentists offer information or other interventions on consumption of SSBs. Statistically significant barriers to providing healthy weight interventions were fear of offending parents, appearing judgmental, or creating parent dissatisfaction and a lack of parental acceptance of guidance about weight management from a dentist. Significant barriers to SSB interventions were sufficient time and health professional education. CONCLUSIONS: More pediatric dentists stated they offer childhood obesity interventions than in previous surveys reporting 6 percent, but respondents suggested that a child's weight is seen as a medical rather than dental issue. Most pediatric dentists provide interventions related to consumption of SSBs, perceiving the issue as integral to their care of children. PMID- 28712111 TI - Long-term outcomes and transmission rates in hepatitis C virus-positive donor to hepatitis C virus-negative kidney transplant recipients: Analysis of United States national data. AB - The use of kidneys from hepatitis C virus (HCV)-positive (D+) deceased donors for HCV-negative recipients (R-) might increase the donor pool. We analyzed the national Organ Procurement and Transplant Network (OPTN) registry from 1994 to 2014 to compare the outcomes of HCV D+/R- (n = 421) to propensity-matched HCV negative donor (D-)/R- kidney transplants, as well as with waitlisted patients who never received a transplant, in a 1:5 ratio (n = 2105, per matched group). Both 5-year graft survival (44% vs 66%; P < .001) and patient survival (57% vs 79%; P < .001) were inferior for D+/R- group compared to D-/R-. Nevertheless, 5 year patient survival from the time of wait listing was superior for D+/R- when compared to waitlisted controls (68% vs 43%; P < .001). Of the 126 D+/R- with available post-transplant HCV testing, HCV seroconversion was confirmed in 62 (49%), likely donor-derived. Five-year outcomes were similar between D+/R- that seroconverted vs D+/R- that did not (n = 64). Our analysis shows inferior outcomes for D+/R- patients although detailed data on pretransplant risk factors was not available. Limited data suggest that HCV transmission occurred in half of HCV D+/R- patients, although this might not have been the primary factor contributing to the poor observed outcomes. PMID- 28712112 TI - Socioeconomic differences in the cost, availability and quality of healthy food in Sydney. AB - OBJECTIVE: To compare the cost of a basket of staple foods, together with the availability and quality of fresh fruit and vegetables, by supermarket store type in high and low socioeconomic suburbs of Sydney. METHODS: A food basket survey was undertaken in 100 supermarkets in the 20 highest and 20 lowest socioeconomic suburbs of Sydney. We assessed the cost of 46 foods, the range of 30 fresh fruit and vegetables and the quality of ten fresh fruit and vegetables. Two major supermarket retailers, a discount supermarket chain and independent grocery stores were surveyed. RESULTS: The food basket was significantly cheaper in low compared to high socioeconomic suburbs ($177 vs $189, p<0.01). Discount supermarkets were at least 30% cheaper than other supermarket stores. There were fewer varieties and poorer quality fruit and vegetables in stores in low socioeconomic suburbs. CONCLUSIONS: Food basket prices and the availability and quality of fruit and vegetables varied significantly by store type and socioeconomic status of suburb. Implications for public health: A nationwide food and nutrition surveillance system is required to inform public health policy and practice initiatives. In addition to the food retail environment, these initiatives must address the underlying contributors to inequity and food insecurity for disadvantaged groups. PMID- 28712113 TI - Nutritional status is the major factor affecting grip strength of African HIV patients before and during antiretroviral treatment. AB - OBJECTIVES: Low grip strength is a marker of frailty and a risk factor for mortality among HIV patients and other populations. We investigated factors associated with grip strength in malnourished HIV patients at referral to ART, and at 12 weeks and 2-3 years after starting ART. METHODS: The study involved HIV infected Zambian and Tanzanian participants recruited to the NUSTART trial when malnourished (body mass index <18.5 kg/m2 ) and requiring ART. The relationship of grip strength to nutritional, infectious and demographic factors was assessed by multivariable linear regression at referral for ART (n = 1742) and after 12 weeks (n = 778) and 2-3 years of ART (n = 273). RESULTS: In analyses controlled only for sex, age and height, most nutrition and infection-related variables were associated with grip strength. However, in multivariable analyses, consistent associations were seen for fat-free mass index, mid-upper arm circumference, haemoglobin and systolic blood pressure, and a variable association with fat mass index in men. C-reactive protein and CD4 count had limited independent effects on grip strength, while receiving tuberculosis treatment was associated with weaker grip strength. CONCLUSIONS: In this population of originally malnourished HIV patients, poor grip strength was more strongly and independently associated with nutritional than with infection and inflammation variables. Programmes to improve health and survival of HIV patients should incorporate nutritional assessment and management and could use grip strength as a functional indicator of improving nutrition. PMID- 28712114 TI - Comparative evaluation of human heat stress indices on selected hospital admissions in Sydney, Australia. AB - OBJECTIVE: To find appropriate regression model specifications for counts of the daily hospital admissions of a Sydney cohort and determine which human heat stress indices best improve the models' fit. METHODS: We built parent models of eight daily counts of admission records using weather station observations, census population estimates and public holiday data. We added heat stress indices; models with lower Akaike Information Criterion scores were judged a better fit. RESULTS: Five of the eight parent models demonstrated adequate fit. Daily maximum Simplified Wet Bulb Globe Temperature (sWBGT) consistently improved fit more than most other indices; temperature and heatwave indices also modelled some health outcomes well. Humidity and heat-humidity indices better fit counts of patients who died following admission. CONCLUSIONS: Maximum sWBGT is an ideal measure of heat stress for these types of Sydney hospital admissions. Simple temperature indices are a good fallback where a narrower range of conditions is investigated. Implications for public health: This study confirms the importance of selecting appropriate heat stress indices for modelling. Epidemiologists projecting Sydney hospital admissions should use maximum sWBGT as a common measure of heat stress. Health organisations interested in short-range forecasting may prefer simple temperature indices. PMID- 28712115 TI - Expression of interferon regulatory factor 7 correlates with the expression of Epstein-Barr Virus latent membrane protein 1 and cervical lymph node metastasis in nasopharyngeal cancer. AB - Interferon regulatory factor 7 (IRF7) has oncogenic properties in several malignancies such as Epstein-Barr virus (EBV)-associated lymphoma. However, there is no evidence whether IRF7 is associated with the oncogenesis of nasopharyngeal cancer (NPC), the pathogenesis of which is closely associated with EBV. Herein, we report that expression of IRF7 was increased in normal nasopharyngeal cells that expressed the EBV principal oncoprotein, latent membrane protein 1 (LMP1). In addition, IRF7 was mainly expressed in the nucleus in both normal nasopharyngeal cells and nasopharyngeal cancer cells that expresses LMP1. On immunohistochemical analysis, IRF7 was predominantly localized in the nucleus in biopsy samples of NPC tissues. In total, IRF7 expression was detected with 36 of 49 specimens of these tissues. Furthermore, the expression score of IRF7 correlated with the expression score of LMP1. Moreover, the expression score of IRF7 is associated with cervical lymph-node metastasis, which reflects the highly metastatic nature of this cancer. Taken together, our results suggest that expression of IRF7 is one of the metastatic effectors of LMP1 signalling in EBV associated NPC. PMID- 28712116 TI - Multi-century tree-ring precipitation record reveals increasing frequency of extreme dry events in the upper Blue Nile River catchment. AB - Climate-related environmental and humanitarian crisis are important challenges in the Great Horn of Africa (GHA). In the absence of long-term past climate records in the region, tree-rings are valuable climate proxies, reflecting past climate variations and complementing climate records prior to the instrumental era. We established annually resolved multi-century tree-ring chronology from Juniperus procera trees in northern Ethiopia, the longest series yet for the GHA. The chronology correlates significantly with wet-season (r = .64, p < .01) and annual (r = .68, p < .01) regional rainfall. Reconstructed rainfall since A.D. 1811 revealed significant interannual variations between 2.2 and 3.8 year periodicity, with significant decadal and multidecadal variations during 1855-1900 and 1960 1990. The duration of negative and positive rainfall anomalies varied between 1-7 years and 1-8 years. Approximately 78.4% (95%) of reconstructed dry (extreme dry) and 85.4% (95%) of wet (extreme wet) events lasted for 1 year only and corresponded to historical records of famine and flooding, suggesting that future climate change studies should be both trend and extreme event focused. The average return periods for dry (extreme dry) and wet (extreme wet) events were 4.1 (8.8) years and 4.1 (9.5) years. Extreme-dry conditions during the 19th century were concurrent with drought episodes in equatorial eastern Africa that occurred at the end of the Little Ice Age. El Nino and La Nina events matched with 38.5% and 50% of extreme-dry and extreme-wet events. Equivalent matches for positive and negative Indian Ocean Dipole events were weaker, reaching 23.1 and 25%, respectively. Spatial correlations revealed that reconstructed rainfall represents wet-season rainfall variations over northern Ethiopia and large parts of the Sahel belt. The data presented are useful for backcasting climate and hydrological models and for developing regional strategic plans to manage scarce and contested water resources. Historical perspectives on long-term regional rainfall variability improve the interpretation of recent climate trends. PMID- 28712117 TI - Climate warming: a loss of variation in populations can accompany reproductive shifts. AB - The most documented response of organisms to climate warming is a change in the average timing of seasonal activities (phenology). Although we know that these average changes can differ among species and populations, we do not know whether climate warming impacts within-population variation in phenology. Using data from five study sites collected during a 13-year survey, we found that the increase in spring temperatures is associated with a reproductive advance of 10 days in natural populations of common lizards (Zootoca vivipara). Interestingly, we show a correlated loss of variation in reproductive dates within populations. As illustrated by a model, this shortening of the reproductive period can have significant negative effects on population dynamics. Consequently, we encourage tests in other species to assess the generality of decreased variation in phenological responses to climate change. PMID- 28712118 TI - Farm injury hospitalisations in New South Wales (2010 to 2014). AB - OBJECTIVE: To examine gender differences in the characteristics, treatment costs and health outcomes of farm injuries resulting in hospitalisation of New South Wales (NSW) residents. METHOD: A population-based study of individuals injured on a farm and admitted to hospital using linked hospital admission and mortality records from 1 January 2010 to 30 June 2014 in NSW. Health outcomes, including injury severity, hospital length of stay (LOS), 28-day readmission and 30-day mortality were examined by gender. RESULTS: A total of 6,270 hospitalisations were identified, with males having a higher proportion of work-related injuries and injuries involving motorbikes compared to females. Females had a higher proportion of equestrian-related injuries. There were no differences in injury severity, with around 20% serious injuries, in mean LOS or 28-day hospital re admission. Treatment costs totalled $42.7 million, with males accounting for just under 80% of the total. CONCLUSIONS: There are some gender differences in the characteristics of farm injury-related hospitalisations. Farm injury imposes modest, but nonetheless relatively considerable, financial costs on hospital services in NSW. Implications for public health: Continued efforts to ameliorate these injuries in a farm environment, which are mainly preventable, will have personal and societal benefits. PMID- 28712120 TI - What would Dr. James Parkinson think today? The 21st Annual Congress of the International Parkinson's disease and movement disorders society. PMID- 28712119 TI - Circulating Activin A predicts survival in cancer patients. AB - BACKGROUND: Several experimental evidences pinpoint the possible role of Activin A (ActA) as a driver of cancer cachexia. Supporting this hypothesis, we showed recently that human cancer cachexia is associated with high ActA levels. Moreover, ActA levels were correlated with body weight loss and skeletal muscle density, two prognostic factors in cancer patients. Our goal was therefore to investigate the value of ActA to predict survival in cancer patients. METHODS: Patients with colorectal or lung cancer were prospectively enrolled at the time of diagnosis or relapse between January 2012 and March 2014. At baseline, patients had clinical, nutritional, and functional assessment. Body composition and skeletal muscle density were measured by CT scan, and plasma ActA concentrations were determined. Overall survival (OS) was analysed since inclusion to 24 months later. RESULTS: Survival data were available for 149 patients out of 152. Patients with high ActA (>=408 pg/mL) had lower OS than those with low levels, regardless the type of cancer (OS in colorectal cancer, 50% vs. 79%, P < 0.05; and in lung cancer, 27% vs. 67%, P = 0.001). The multivariable analysis confirmed the prognostic value of ActA independently of tumour stage or inflammatory markers, particularly in lung cancer. Low muscularity was also an independent prognostic factor. CONCLUSIONS: Our study demonstrates that high ActA level is an independent prognosis factor of survival in cancer patients. More than a basic marker of the severity of the neoplastic disease or of the inflammatory process, ActA seems to influence survival by contributing to the development of cachexia and loss of skeletal muscle mass. PMID- 28712121 TI - Motor-symptom laterality affects acquisition in Parkinson's disease: A cognitive and functional magnetic resonance imaging study. AB - BACKGROUND AND OBJECTIVES: Asymmetric onset of motor symptoms in PD can affect cognitive function. We examined whether motor-symptom laterality could affect feedback-based associative learning and explored its underlying neural mechanism by functional magnetic resonance imaging in PD patients. METHODS: We recruited 63 early-stage medication-naive PD patients (29 left-onset medication-naive patients, 34 right-onset medication-naive patients) and 38 matched normal controls. Subjects completed an acquired equivalence task (including acquisition, retention, and generalization) and resting-state functional magnetic resonance imaging scans. Learning accuracy and response time in each phase of the task were recorded for behavioral measures. Regional homogeneity was used to analyze resting-state functional magnetic resonance imaging data, with regional homogeneity lateralization to evaluate hemispheric functional asymmetry in the striatum. RESULTS: Left-onset patients made significantly more errors in acquisition (feedback-based associative learning) than right-onset patients and normal controls, whereas right-onset patients performed as well as normal controls. There was no significant difference among these three groups in the accuracy of either retention or generalization phase. The three groups did not show significant differences in response time. In the left-onset group, there was an inverse relationship between acquisition errors and regional homogeneity in the right dorsal rostral putamen. There were no significant regional homogeneity changes in either the left or the right dorsal rostral putamen in right-onset patients when compared to controls. CONCLUSIONS: Motor-symptom laterality could affect feedback-based associative learning in PD, with left-onset medication naive patients being selectively impaired. Dysfunction in the right dorsal rostral putamen may underlie the observed deficit in associative learning in patients with left-sided onset.(c) 2016 International Parkinson and Movement Disorder Society. PMID- 28712122 TI - Clinical features and treatment response of cutaneous leishmaniasis in North-West Ethiopia. AB - OBJECTIVE: Cutaneous leishmaniasis (CL) receives far less attention than visceral leishmaniasis. Nevertheless, CL is predominantly caused by a unique species in Ethiopia (L. aethiopica), which is known to cause severe forms such as diffuse (DCL) and mucocutaneous leishmaniasis (MCL). We report on the number and type of CL cases diagnosed, the clinical features, the treatments and treatment outcomes in North-West Ethiopia. METHODS: This is a retrospective chart record analysis of CL patients treated at the Leishmania Research and Treatment Center (LRTC) of the University of Gondar, Ethiopia. RESULTS: From 178 CL patients seen between January 2014 and December 2015, a total of 154 chart records were retrieved. These included 80 localised CL (LCL), 7 DCL and 67 MCL. The median age was 23 years; 71.4% were male. Most (n = 121, 78.6%) of the lesions were on the face. The median time since onset was 12 months (6-24 months), and 28.6% presented after a trial of traditional medicine. The treatment of all forms of CL mainly consisted of 30 days of IM antimonial injections. Of these, 51/133 (38.3%) required treatment extension or change due to nonresponse. Three cases were treated with liposomal amphotericin B or miltefosine (two received the combination), of which two responded well. CONCLUSION: CL was found to be complicated and difficult to treat. MCL was common, and patients presented after long delays. There is an urgent need to look for better treatment options for CL and improve access to care. PMID- 28712123 TI - Substance misuse intervention research in remote Indigenous Australian communities since the NHMRC 'Roadmap'. AB - OBJECTIVE: Describe program theories of substance misuse interventions with Aboriginal and Torres Strait Islander (Indigenous) Australians funded by the National Health and Medical Research Council (NHMRC) since the 'Roadmap' for Indigenous health. METHODS: Projects funded 2003-2013 were categorised by intervention strategies. Realist concepts informed the program theory: intended resources and responses; influence of context on outcomes; explicit and implicit program assumptions. RESULTS: Seven interventions were included. Three randomised controlled trials targeted tobacco using psychosocial interventions in primary health centres using the program theory: "Local Indigenous health workers extend and sustain the effects of conventional clinical brief intervention by engendering social and cultural resources". Four pragmatic trials of multiple component, community-based interventions using controlled, semi-controlled or before-and-after designs used the program theory: "Discrete intervention components targeting locally defined substance misuse issues will activate latent capacities to create an environment that favours cessation." Publications did not report clear effect, implementation fidelity or explicit mechanisms affecting participant thinking. CONCLUSIONS: Rigorous intervention designs built on 'Roadmap' principles neither reduced substance use in the populations studied nor identified transferable mechanisms for behaviour change. Implications for public health: Substance misuse impacts among Indigenous Australians remain severe. Theoretical mechanisms of behaviour change may improve intervention design. PMID- 28712124 TI - Sexual violence associated with poor mental health in women attending Australian general practices. AB - OBJECTIVE: Sexual violence (SV) against adult women is prevalent and associated with a range of mental health issues. General practitioners could potentially have a role in responding, however, there is little information to help guide them. Data around prevalence of all forms of adult SV (not just rape) is inconsistent, particularly in clinical samples, and the links between other forms of SV and mental health issues are not well supported. This study aimed to address these gaps in the knowledge base. METHODS: A descriptive, cross-sectional study was conducted in Australian general practice clinics. Two hundred and thirty adult women completed an anonymous iPad survey while waiting to see the doctor. RESULTS: More than half the sample had experienced at least one incident of adult SV. Most commonly, women reported public harassment or flashing, unwanted groping and being coerced into sex. Women who had experienced adult SV were more likely to experience anxiety than women who had not, even after controlling for other factors. Women who had experienced adult SV were more likely to feel down, depressed or hopeless than women who had not; however, this association disappeared after controlling for childhood sexual abuse. CONCLUSIONS: The findings support the association between SV and poor mental health, even when 'lesser' incidents have occurred. Implications for public health: General practitioners should consider an experience of SV as a possible factor in otherwise unexplained anxiety and depressive symptoms in female patients. PMID- 28712125 TI - Oral Contraceptive Pill Alters Acute Dietary Protein-Induced Thermogenesis in Young Women. AB - OBJECTIVE: There is much interest in the role of dietary protein for weight control. However, there remains a need to characterize individual determinants of the thermogenic effects of protein. This study aimed to investigate the influence of menstrual cycle phase and the combined, monophasic oral contraceptive pill on the thermogenic response to a standardized high-protein (HP) versus normal protein (NP) meal. METHODS: Following an overnight fast, resting energy expenditure (EE) was measured in 16 healthy young women (8 taking and 8 not taking the pill) and 8 men for 30 minutes pre ingestion and 3 hours post ingestion of a NP (11%) or HP (24%) meal. RESULTS: There was no effect of menstrual phase or contraceptive pill use on fasting EE or NP response. However, HP increased EE significantly more than NP in women not taking the oral contraceptive pill and in men, but not in women taking the pill. CONCLUSIONS: This study shows an absence of the greater thermic effect of HP versus NP in women taking the oral contraceptive pill and has important implications regarding the effectiveness of HP for body weight regulation in women. With current obesity treatment/prevention strategies remaining largely ineffective, understanding the relationship between oral contraceptive pill use and protein-induced thermogenesis may enable the successful recalibration of existing dietary recommendations. PMID- 28712126 TI - Evidence of an abnormal epithelial barrier in active, untreated and corticosteroid-treated eosinophilic esophagitis. AB - BACKGROUND: Eosinophilic esophagitis (EoE) is a chronic, immune/antigen-mediated disease characterized by symptoms related to esophageal dysfunction and an eosinophil-predominant inflammation. This study has aimed to investigate whether the recently observed sensitization to Candida albicans in patients with EoE is owing to pre-existing disease and its underlying abnormal epithelial barrier or, alternatively, is linked to corticosteroid (CS) therapy. METHODS: Medical histories, as well as serum and tissue samples of 60 patients with EoE (15 CS naive, 45 with current or previous CS therapy) and 20 controls, stored in the Swiss Eosinophilic Esophagitis Database (SEED) and Biobank, were analyzed. We applied ImmunoCAP to measure IgE levels and immunofluorescence techniques to examine epithelial barrier components. RESULTS: Patients with EoE had higher total IgE levels and were more frequently sensitized to C. albicans than controls. In EoE tissue specimens, increased numbers of eosinophils and mast cells, a higher expression levels of thymic stromal lymphopoietin (TSLP), cathelicidin, proteases, that is, the kallikreins (KLK)-5 and KLK-7, were observed as compared with controls, while reduced expression of lympho-epithelial Kazal-type-related inhibitor (LEKTI), filaggrin, E-cadherin, claudin, occludin, desmoglein-1 was found, independent of CS therapy. In CS-treated EoE, significantly lower numbers of CD1a+ cells and cathelicidin expression were noted as compared to CS-naive EoE. CONCLUSION: This study provides further evidence that EoE is associated with an abnormal epithelial barrier and postulates that CS therapy, by reducing innate immune mechanisms, may promote C. albicans colonization and likely subsequent sensitization. PMID- 28712127 TI - Mapping progress in chronic hepatitis B: geographic variation in prevalence, diagnosis, monitoring and treatment, 2013-15. AB - OBJECTIVE: To measure progress towards Australia's National Hepatitis B Strategy 2014-17 targets, and assess geographic variation in disease burden and access to care for those living with chronic hepatitis B (CHB). METHODS: Data were generated from routinely collected sources, including risk-group prevalence and population data, infectious diseases notifications, Medicare records, and immunisation registry data, and assessed nationally and according to geographic area for 2013-15. RESULTS: CHB prevalence in 2015 was 239,167 (1.0%), with 62% of those affected having been diagnosed (target 80%). Treatment uptake was 6.1% (target 15%), and only 15.3% of people with CHB received guideline-based care. CHB prevalence ranged within Australia's 31 Primary Health Networks (PHNs) from 1.77% (NT) to 0.56% (Grampians & Barwon South West VIC). No PHN reached the 15% treatment target, with uptake highest in South Western Sydney (13.7%). Immunisation coverage reached the 95% target in three PHNs. CONCLUSIONS: The CHB burden in Australia is significant and highly geographically focused, with notable disparities in access to care across Australia. Implications for public health: Efforts to improve progress toward National Strategy targets should focus on priority areas where the prevalence of CHB is substantial but access to treatment and care remains low. PMID- 28712128 TI - Where to start when treating COPD? PMID- 28712129 TI - Lactobacillus reuteri DSM 17938 and a placebo both significantly reduced symptoms in children with functional abdominal pain. AB - AIM: Lactobacillus reuteri is a Gram-positive bacterium that naturally inhabits the human intestinal tract. This study assessed how effectively the probiotic L. reuteri DSM 17938 managed childhood functional abdominal pain (FAP). METHODS: We recruited 54 children with a mean age 9.1 +/- 3.8 years, who were diagnosed with FAP in the outpatient clinics of three university hospitals in Greece, Slovenia and Poland, according to the Rome III criteria, from January 2013 to December 2015. They were randomly assigned to receive either 2 * 108 colony-forming units of L. reuteri (n = 27) or a placebo (n = 27) for four weeks. RESULTS: Both L. reuteri and the placebo significantly reduced the frequency and intensity of abdominal pain episodes at four and eight weeks compared to baseline (all p < 0.001). L. reuteri decreased the use of pain relieving drugs at four weeks and the number of child school and adult work absences at four and eight weeks, unlike the placebo, which achieved nonsignificant results. However, the difference between the groups did not reach significance. No side effects were recorded. CONCLUSION: Both L. reuteri and the placebo were effective in alleviating pain in children with FAP, but only L. reuteri improved the child's and family's normal activities. PMID- 28712130 TI - The role of protected areas in land use/land cover change and the carbon cycle in the conterminous United States. AB - Protected areas (PAs) cover about 22% of the conterminous United States. Understanding their role on historical land use and land cover change (LULCC) and on the carbon cycle is essential to provide guidance for environmental policies. In this study, we compiled historical LULCC and PAs data to explore these interactions within the terrestrial ecosystem model (TEM). We found that intensive LULCC occurred in the conterminous United States from 1700 to 2005. More than 3 million km2 of forest, grassland and shrublands were converted into agricultural lands, which caused 10,607 Tg C release from land ecosystems to atmosphere. PAs had experienced little LULCC as they were generally established in the 20th century after most of the agricultural expansion had occurred. PAs initially acted as a carbon source due to land use legacies, but their accumulated carbon budget switched to a carbon sink in the 1960s, sequestering an estimated 1,642 Tg C over 1700-2005, or 13.4% of carbon losses in non-PAs. We also find that PAs maintain larger carbon stocks and continue sequestering carbon in recent years (2001-2005), but at a lower rate due to increased heterotrophic respiration as well as lower productivity associated to aging ecosystems. It is essential to continue efforts to maintain resilient, biodiverse ecosystems and avoid large-scale disturbances that would release large amounts of carbon in PAs. PMID- 28712131 TI - A novel antibacterial peptide derived from Crocodylus siamensis haemoglobin hydrolysate induces membrane permeabilization causing iron dysregulation, oxidative stress and bacterial death. AB - AIMS: A novel antibacterial peptide from Crocodylus siamensis haemoglobin hydrolysate (CHH) was characterized for antimicrobial activity. METHODS AND RESULTS: CHHs were hydrolysed for 2 h (2 h-CHH), 4 h (4h-CHH), 6 h (6 h-CHH) and 8 h (8 h-CHH). The 8 h-CHH showed antibacterial activity against Escherichia coli, Staphylococcus aureus, Klebsiella pneumoniae and Pseudomonas aeruginosa at concentrations of 20, 20, 20 and 10 mg ml-1 (w/v) respectively. Fluorescent microscopy revealed that the 8 h-CHH had bactericidal activity against E. coli and P. aeruginosa. beta-galactosidase assay supported by RT-qPCR demonstrated that the 8 h-CHH resulted in differential expression of genes involved in iron homeostasis (ftnA and bfd) and oxidative stress (sodA, soxR and oxyR). Siderophore assay indicated that the 8 h-CHH also impaired siderophore production with diminished expression of pvdF. This pattern of gene expression suggests that the 8 h-CHH triggers the release of free ferric ions in the cytoplasm. However, decreased expression of genes associated with the SOS response (recA and lexA) in combination with neutral comet revealed that no DNA damage was caused by 8 h-CHH. Membrane permeabilization assay indicated that 8 h-CHH caused membrane leakage thought to mediate the antibacterial and iron-stress responses observed, due to loss of regulated iron transport. The novel active peptide from 8 h-CHH was determined as QAIIHNEKVQAHGKKVL (QL17), with 41% hydrophobicity and +2 net charge. CONCLUSIONS: The QAIIHNEKVQAHGKKVL fragment of C. siamensis haemoglobin is antibacterial via a mechanism that likely relies on iron dysregulation and oxidative stress which results in bacterial death. SIGNIFICANCE AND IMPACT OF THE STUDY: We have described for the first time, a novel peptide derived from C. siamensis haemoglobin hydrolysate that has the potential to be developed as a novel antimicrobial peptide. PMID- 28712132 TI - Impact of lipoprotein apheresis with dextran-sulfate adsorption on the expression of genes involved in cardiovascular health in the blood of patients with homozygous familial hypercholesterolemia. AB - Lipoprotein apheresis (LA) with dextran sulfate adsorption (DSA) is a reliable method to decrease LDL-cholesterol (C) concentrations in patients with homozygous familial hypercholesterolemia (HoFH). The objective of the present study was to investigate the impact of LA with DSA on the mRNA expression of genes associated with cardiovascular health in the whole blood of HoFH patients. Blood samples were collected before and after LA treatment with DSA in 9 HoFH patients. Microarray analyses were performed to measure the whole blood expression of >30 000 annotated genes pre- and post-LA. Concomitant reductions in LDL-C (median 73.8%, range: -55.9 to -82.0, P = .0001) and lipoprotein (a) concentrations (median -74.1%, range -65.6 to -84.1, P = .003) were induced with LA treatment. LA with DSA did not impact the whole blood mRNA expression of most key genes involved in cardiovascular health, including those associated with cholesterol, fatty acid and lipoprotein metabolism. However, LA with DSA significantly upregulated the whole blood expression of early growth response protein (EGR)1 (1.94-fold, P = .02), EGR3 (1.56-fold, P = .0008) and B-cell lymphoma 3-encoded protein (BCL3; 1.25-fold, P = .03). In conclusion, this study demonstrated that a single LA treatment with DSA has very limited impact on the whole blood expression of a broad spectrum of genes associated with cardiovascular health. Our results suggest that contact between blood cells and the primary membrane or extracorporeal circulation could upregulate the expression of EGR1, EGR3, BCL3, and MMP9 in blood cells. PMID- 28712133 TI - Aquatic export of young dissolved and gaseous carbon from a pristine boreal fen: Implications for peat carbon stock stability. AB - The stability of northern peatland's carbon (C) store under changing climate is of major concern for the global C cycle. The aquatic export of C from boreal peatlands is recognized as both a critical pathway for the remobilization of peat C stocks as well as a major component of the net ecosystem C balance (NECB). Here, we present a full year characterization of radiocarbon content (14 C) of dissolved organic carbon (DOC), carbon dioxide (CO2 ), and methane (CH4 ) exported from a boreal peatland catchment coupled with 14 C characterization of the catchment's peat profile of the same C species. The age of aquatic C in runoff varied little throughout the year and appeared to be sustained by recently fixed C from the atmosphere (<60 years), despite stream DOC, CO2 , and CH4 primarily being sourced from deep peat horizons (2-4 m) near the mire's outlet. In fact, the 14 C content of DOC, CO2 , and CH4 across the entire peat profile was considerably enriched with postbomb C compared with the solid peat material. Overall, our results demonstrate little to no mobilization of ancient C stocks from this boreal peatland and a relatively large resilience of the source of aquatic C export to forecasted hydroclimatic changes. PMID- 28712134 TI - Phenotypic and genotypic characterization of clinically relevant bacteria isolated from dental waste and waste workers' hands, mucosas and coats. AB - : Infectious wastes are potential sources of pathogenic micro-organisms, which may represent a risk to the professionals who manage them. In this study, we aimed to characterize the infectious bacteria present in dental waste and waste workers. The dental waste produced over 24 h was collected and waste workers were sampled by swabbing. Isolate resistance profiles were characterized by Vitek(r) and PCR and biofilm formation by Congo Red agar, string test and microtitre assay. To assess similarity between the waste and the workers' samples, a random amplified polymorphic DNA test was used. Twenty-eight bacteria were identified as clinically relevant. The most frequent gene was blaTEM present in five Gram negative micro-organisms, and one blaSHV in Klebsiella pneumoniae. All Pseudomonas aeruginosa were positive to extracellular polymeric substances formation, except one isolated from a worker. Klebsiella pneumoniae had negative results for the string test. Pseudomonas aeruginosa showed better adherence at 25 degrees C after 48 h of incubation and K. pneumonia had the best biofilm formation at the same temperature, after 24 h. The similarity between P. aeruginosa recovered from dental waste and from workers was low, however, it is important to note that a pathogen was found on a worker's hands and that improvements in biosafety are required. SIGNIFICANCE AND IMPACT OF THE STUDY: Infectious dental waste can contain clinically relevant bacteria with important resistance and biofilm profiles. These micro-organisms could be transmitted to waste workers, other professionals and patients if the principles of biosafety measures are neglected. To our knowledge, no study has ever evaluated the microbial characterization and the potential contamination risk of dental infectious waste and waste handlers. The presence of clinically relevant bacteria in the hands and nasal mucosa of waste workers highlights the need for studies in this field to clarify the risk of these pathogens in dental healthcare services, and to stress the need for an efficient waste management. PMID- 28712135 TI - Long-term changes in abundances of Sonoran Desert lizards reveal complex responses to climatic variation. AB - Understanding how climatic variation affects animal populations and communities is essential for addressing threats posed by climate change, especially in systems where impacts are projected to be high. We evaluated abundance dynamics of five common species of diurnal lizards over 25 years in a Sonoran Desert transition zone where precipitation decreased and temperature increased across time, and assessed hypotheses for the influence of climatic flux on spatiotemporal variation in abundances. We repeatedly surveyed lizards in spring and summer of each year at up to 32 sites, and used hierarchical mixture models to estimate detection probabilities, abundances, and population growth rates. Among terrestrial species, abundances of a short-lived, winter-spring breeder increased markedly by an estimated 237%-285% across time, while two larger spring summer breeders with higher thermal preferences declined by up to 64%. Abundances of two arboreal species that occupy shaded and thus sheltered microhabitats fluctuated but did not decline systematically. Abundances of all species increased with precipitation at short lag times (1-1.5 years) likely due to enhanced food availability, but often declined after periods of high precipitation at longer lag times (2-4 years) likely due to predation and other biotic pressures. Although rising maximum daily temperatures (Tmax ) are expected to drive global declines of lizards, associations with Tmax were variable and weak for most species. Instead, abundances of all species declined with rising daily minimum temperatures, suggesting degradation of cool refugia imposed widespread metabolic or other costs. Our results suggest climate warming and drying are having major impacts on lizard communities by driving declines in species with traits that augment exposure to abiotic extremes and by modifying species interactions. The complexity of patterns we report indicates that evaluating and responding to the influence of climate change on biodiversity must consider a broad array of ecological processes. PMID- 28712136 TI - The built environment and sexual and reproductive health. PMID- 28712137 TI - What Indigenous Australian clients value about primary health care: a systematic review of qualitative evidence. AB - OBJECTIVE: To synthesise client perceptions of the unique characteristics and value of care provided in Aboriginal Community Controlled Health Organisations (ACCHOs) compared to mainstream/general practitioner services, and implications for improving access to quality, appropriate primary health care for Indigenous Australians. METHOD: Standardised systematic review methods with modification informed by ethical and methodological considerations in research involving Indigenous Australians. RESULTS: Perceived unique valued characteristics of ACCHOs were: 1) accessibility, facilitated by ACCHOs welcoming social spaces and additional services; 2) culturally safe care; and 3) appropriate care, responsive to holistic needs. CONCLUSION: Provider-client relationships characterised by shared understanding of clients' needs, Indigenous staff, and relationships between clients who share the same culture, are central to ACCHO clients' perceptions of ACCHOs' unique value. The client perceptions provide insights about how ACCHOs address socio-economic factors that contribute to high levels of chronic disease in Indigenous communities, why mainstream PHC provider care cannot substitute for ACCHO care, and how to improve accessibility and quality of care in mainstream providers. Implications for public health: To increase utilisation of PHC services in Indigenous Australian communities, and help close the gaps between the health status of Indigenous and non-Indigenous Australians, Indigenous community leaders and Australian governments should prioritise implementing effective initiatives to support quality health care provision by ACCHOs. PMID- 28712138 TI - Hematologic reference intervals and age effect in European Strigiformes. AB - BACKGROUND: The clinical importance of hematologic testing in avian veterinary medicine is reflected in the increasing number of studies for the establishment of hematologic RIs of Strigiformes and other species. Age is an important physiologic factor in birds and the effect on hematology variable should be understood. OBJECTIVES: The objective of this study was to determine baseline data of hematologic variables in 5 species of Iberian Strigiformes in different age classes. METHODS: Nocturnal birds of prey were sampled at Wildlife Health Centers. Packed cell volume was determined by the microhematocrit centrifugation method, and RBC and WBC counts were determined using the direct hemocytometer count method with Natt and Herrick solution. Hemoglobin concentration was measured spectrophotometrically. The MCV, MCHC, and MHC were calculated using the standard formulas. The differential WBC count was performed by the routine microscopic evaluation of 200 cells on a blood smear manually stained with Wright stain. Thrombocyte blood count estimate was obtained from the blood film. RESULTS: No differences were observed between juveniles and adults for any variable evaluated in Tawny owl, Little owl, Scops owl, Long-eared owl, and Barn owl. In addition, PCV, RBC, and HGB of chicks were statistically significantly lower than in juveniles and adults, and total WBC was significantly higher in Tawny owl, Little owl, Scops owl, and Long-eared owl. CONCLUSIONS: Our findings provide evidence that laboratory data from chicks of Strigiformes are different compared to juveniles and adults; therefore, separate RIs were defined. PMID- 28712140 TI - Pregnancy and immune stimulation: re-imagining the fetus as parasite to understand age-related immune system changes in US women. AB - OBJECTIVES: Pregnancy can increase production of Immunoglobulin E (IgE), an immune response more often directed towards parasite infections. An absence of parasitism makes the US population ideal to test the hypothesis that the maternal immune system recognizes a fetus as a parasite. We predict that total IgE levels are positively associated with a history of pregnancy across all ages of adult women, mirroring patterns of IgE in parasitized populations. METHODS: Reproductive-aged women (n = 2201) from the National Health and Nutrition Examination Survey 2005-2006 were analyzed in a cross-sectional design using complex survey regression and multiple imputation to evaluate associations between total IgE levels, pregnancy history, and interactions between age and pregnancy. RESULTS: Women with a history of pregnancy have significantly higher IgE levels and a significantly shallower slope of IgE levels across ages (P = .031). CONCLUSIONS: This research supports the hypothesis that maternal immune systems respond to prior pregnancies as they do to macro-parasitic exposures, and may modify the expected linear declines of IgE levels in women that accompanies aging. These finding have implications for understanding the evolution of internal gestation in mammals. PMID- 28712139 TI - Warming drives a front of white spruce establishment near western treeline, Alaska. AB - Regional warming has led to increased productivity near the boreal forest margin in Alaska. To date, the effects of warming on seedling recruitment have received little attention, in spite of forecasted forest expansion. Here, we used stand structure and environmental data from 95 white spruce (Picea glauca) plots sampled across a longitudinal gradient in southwest Alaska to explore factors influencing spruce establishment and recruitment near western treeline. We used total counts of live seedlings, saplings, and trees, representing five life stages, to evaluate whether geospatial, climate, and measured plot covariates predicted abundance, using current abundance distributions as a surrogate for climate conditions in the past. We used generalized linear models to test the null hypothesis that conditions favorable for recruitment were similar along the environmental gradient represented by longitude, by exploring relationships between per-plot counts of each life stage and the covariates hypothesized to affect abundance. We also examined the relationship between growing degree days (GDD) and seedling establishment over a period of three decades using tree-ring chronologies obtained from cores taken at a subset of our sites (n = 30). Our results indicated that seedling, sapling, and tree abundance were positively correlated with temperature across the study area. The response to longitude was mixed, with earlier life stages (seedlings, saplings) most abundant at the western end of the gradient, and later life stages (trees) most abundant to the east. The differential relationship between longitude and life-stage abundance suggests a moving front of white spruce establishment through time, driven by changes in environmental conditions near the species' western range limit. Likewise, we found a positive relationship between periods of seedling establishment and GDD, suggesting that longer summers and/or greater heat accumulation might enhance establishment, consistent with the positive relationship we found between life-stage abundance and temperature. PMID- 28712141 TI - Carrying capacity in a heterogeneous environment with habitat connectivity. AB - A large body of theory predicts that populations diffusing in heterogeneous environments reach higher total size than if non-diffusing, and, paradoxically, higher size than in a corresponding homogeneous environment. However, this theory and its assumptions have not been rigorously tested. Here, we extended previous theory to include exploitable resources, proving qualitatively novel results, which we tested experimentally using spatially diffusing laboratory populations of yeast. Consistent with previous theory, we predicted and experimentally observed that spatial diffusion increased total equilibrium population abundance in heterogeneous environments, with the effect size depending on the relationship between r and K. Refuting previous theory, however, we discovered that homogeneously distributed resources support higher total carrying capacity than heterogeneously distributed resources, even with species diffusion. Our results provide rigorous experimental tests of new and old theory, demonstrating how the traditional notion of carrying capacity is ambiguous for populations diffusing in spatially heterogeneous environments. PMID- 28712142 TI - Influenza vaccination of Australian healthcare workers: strategies to achieve high uptake. PMID- 28712143 TI - Reliability of the EchoMRI Infants System for Water and Fat Measurements in Newborns. AB - OBJECTIVE: The precision and accuracy of a quantitative magnetic resonance (EchoMRI Infants) system in newborns were determined. METHODS: Canola oil and drinking water phantoms (increments of 10 g to 1.9 kg) were scanned four times. Instrument reproducibility was assessed from three scans (within 10 minutes) in 42 healthy term newborns (12-70 hours post birth). Instrument precision was determined from the coefficient of variation (CV) of repeated scans for total water, lean mass, and fat measures for newborns and the mean difference between weight and measurement for phantoms. In newborns, the system accuracy for total body water (TBW) was tested against deuterium dilution (D2 O). RESULTS: In phantoms, the repeatability and accuracy of fat and water measurements increased as the weight of oil and water increased. TBW was overestimated in amounts >200 g. In newborns weighing 3.14 kg, fat, lean mass, and TBW were 0.52 kg (16.48%), 2.28 kg, and 2.40 kg, respectively. EchoMRI's reproducibility (CV) was 3.27%, 1.83%, and 1.34% for total body fat, lean mass, and TBW, respectively. EchoMRI TBW values did not differ from D2 O; mean difference, -1.95 +/- 6.76%, P = 0.387; mean bias (limits of agreement), 0.046 kg (-0.30 to 0.39 kg). CONCLUSIONS: The EchoMRI Infants system's precision and accuracy for total body fat and lean mass are better than established techniques and equivalent to D2 O for TBW in phantoms and newborns. PMID- 28712144 TI - Frailty is an independent prognostic marker in elderly patients with myocardial infarction. AB - BACKGROUND: Acute coronary syndrome (ACS) patients are increasingly older. Conventional prognostic scales include chronological age but do not consider vulnerability. In elderly patients, a frail phenotype represents a better reflection of biological age. HYPOTHESIS: This study aims to determine the prevalence of frailty and its influence on patients age >=75 years with ACS. METHODS: Patients age >=75 years admitted due to type 1 myocardial infarction were included in 2 tertiary hospitals, and clinical data were collected prospectively. Frailty was defined at admission using the previously validated Survey of Health Ageing and Retirement in Europe Frailty Index (SHARE-FI) tool. The primary endpoint was the combination of death or nonfatal myocardial reinfarction during a follow-up of 6 months. Major bleeding (hemoglobin decrease >=3 g/dL or transfusion needed) and readmission rates were also explored. RESULTS: A total of 234 consecutive patients were included. Frail patients (40.2%) had a higher-risk profile, based on higher age and comorbidities. On multivariate analysis, frailty was an independent predictor of the combination of death or nonfatal myocardial reinfarction (adjusted hazard ratio [aHR]: 2.54, 95% confidence interval [CI]: 1.12-5.79), an independent predictor of the combination of death, nonfatal myocardial reinfarction, or major bleeding (aHR: 2.14, 95% CI: 1.13-4.04), and an independent predictor of readmission (aHR: 1.80, 95% CI: 1.00 3.22). CONCLUSIONS: Frailty phenotype at admission is common among elderly patients with ACS and is an independent predictor for severe adverse events. It should be considered in future risk-stratification models. PMID- 28712145 TI - Resolution rate of pulmonary sarcoidosis and its related factors in a Japanese population. AB - BACKGROUND AND OBJECTIVE: A number of previous studies have reported on the rate of resolution of pulmonary sarcoidosis and its associated factors. However, most of the studies were conducted several decades ago and no similar surveys have been conducted in recent years. The aim of this study was to evaluate the rate of resolution of pulmonary sarcoidosis and its related factors in recently diagnosed patients, and to compare the results with those from previous studies. METHODS: This study included 306 patients who had been newly diagnosed with pulmonary sarcoidosis between 2000 and 2009 in Sapporo, Japan. Chest radiographical findings were assessed at the initial visit and at the 2- or 5-year observation points. The rates of resolution on chest radiographs and the association with clinical manifestations were evaluated. RESULTS: The resolution rates were 17.9% at the 2-year and 29.9% at the 5-year observation point. These rates were lower than those reported in the earlier surveys. Younger subjects (aged <40 years) showed resolution more often (P < 0.05). The absence of extra-pulmonary organ involvement was associated with resolution at 5 years (P < 0.05). CONCLUSION: The clinical course of pulmonary sarcoidosis may be changing, showing a tendency not to resolve. At least in part, this may be due to the ageing of the Japanese population. PMID- 28712147 TI - Journey from the oocyte to embryo... and beyond! PMID- 28712146 TI - A reversal of the shift towards earlier spring phenology in several Mediterranean reptiles and amphibians during the 1998-2013 warming slowdown. AB - Herps, especially amphibians, are particularly susceptible to climate change, as temperature tightly controls many parameters of their biological cycle-above all, their phenology. The timing of herps' activity or migration period-in particular the dates of their first appearance in spring and first breeding-and the shift to earlier dates in response to warming since the last quarter of the 20th century has often been described up to now as a nearly monotonic trend towards earlier phenological events. In this study, we used citizen science data opportunistically collected on reptiles and amphibians in the northern Mediterranean basin over a period of 32 years to explore temporal variations in herp phenology. For 17 common species, we measured shifts in the date of the species' first spring appearance-which may be the result of current changes in climate-and regressed the first appearance date against temperatures and precipitations. Our results confirmed the expected overall trend towards earlier first spring appearances from 1983 to 1997, and show that the first appearance date of both reptiles and amphibians fits well with the temperature in late winter. However, the trend towards earlier dates was stopped or even reversed in most species between 1998 and 2013. We interpret this reversal as a response to cooling related to the North Atlantic Oscillation (NAO) in the late winter and early spring. During the positive NAO episodes, for certain species only (mainly amphibians), the effect of a warm weather, which tends to advance the phenology, seems to be counterbalanced by the adverse effects of the relative dryness. PMID- 28712148 TI - Influence of kidney offer acceptance behavior on metrics of allocation efficiency. AB - We investigated associations of deceased donor kidney offer acceptance with likelihood of the kidney being discarded, cold ischemia time at transplant (CIT), and likelihood of the kidney being exported outside the donation service area (DSA). We used kidney offers from donors in the Scientific Registry of Transplant Recipients July 1, 2015-June 30, 2016, and a stratified logistic regression to estimate odds ratios of acceptance for candidates wait-listed in a DSA. We estimated associations between these ratios and likelihood of discard or export and CIT at transplant. Approximately 0.50 kidneys were discarded per donor; lower DSA-specific offer acceptance ratios were associated with more discards (R=-0.20; P=0.006). For a median donor, the DSA with the highest acceptance ratio would place 0.12 more kidneys per donor than the DSA with the lowest ratio. Low acceptance ratios were associated with higher CIT (R=-0.23; P<0.001). For the median donor, CIT was 2.9 hours shorter for the DSA with the highest versus lowest acceptance ratio. Low acceptance ratios were associated with more exports (R=-0.43; P<0.001); the probability was 15% higher for a median donor in the DSA with the lowest versus highest acceptance ratio. Improving lower-than-expected offer acceptance would likely reduce discards, CIT, and exports. PMID- 28712149 TI - Occurrence, genetic diversity and antibiotic resistance of Arcobacter sp. in a dairy plant. AB - AIMS: The aim of this study was to evaluate the occurrence, diversity and resistance to antibiotics of Arcobacter sp. in a dairy plant samples. METHODS AND RESULTS: A total of 75 samples from dairy plant surfaces and materials and several food products collected in different steps of the cheese production process were analysed by culture, under aerobic and microaerobic atmospheric conditions, and by enrichment molecular detection. Isolates were identified and genotyped by ERIC-PCR, and their susceptibility to nine antibiotics was evaluated by agar dilution. Global prevalence of Arcobacter sp. was 42.7%, where 20 of the 42 food samples analysed were positive for A. butzleri by both culture and molecular detection, one for A. marinus by culture and one for A. cryaerophilus by molecular detection only; 10 of the 30 analysed materials and plant surfaces were positive for A. butzleri. All A. butzleri isolates were resistant to nalidixic acid and showed high resistance rates to ampicillin (56.2%) and cefotaxime (97.9%), being all strains susceptible to gentamicin and erythromycin. CONCLUSIONS: Contamination of dairy plant environment with A. butzleri and its progression along cheese production process were observed, however, the cheese ripening process may have a relevant role in the reduction of the contamination. SIGNIFICANCE AND IMPACT OF THE STUDY: This study showed the presence of Arcobacter sp. in a dairy plant, displaying its high prevalence and genetic diversity and highlighting its high resistance rates. The data obtained could contribute to further acknowledge the Arcobacter food contamination as a potential health hazard. PMID- 28712150 TI - The effect of young children's faeces disposal practices on child growth: evidence from 34 countries. AB - OBJECTIVE: To characterize the relationship between child faeces disposal and child growth in low- and middle-income countries. METHODS: We analysed caregiver responses and anthropometric data from Demographic and Health Surveys (2005-2014) for 202 614 children under five and 82 949 children under two to examine the association between child faeces disposal and child growth. RESULTS: Child faeces disposal in an improved toilet was associated with reduced stunting for children under five [adjusted prevalence ratio (aPR) = 0.90, 95% confidence interval (CI) 0.89-0.92] and a 0.12 increase in height-for-age z-score (HAZ; 95% CI: 0.10-0.15) among all households. Among households with improved sanitation access, practicing improved child faeces disposal was still associated with a decrease in stunting (aPR = 0.94, 95% CI: 0.91-0.96) and a 0.09 increase in HAZ (95% CI: 0.06 0.13). Improved child faeces disposal was also associated with reductions in underweight and wasting, and an increase in weight-for-age z-score (WAZ), but not an increase in weight-for-height z-score (WHZ). Community coverage level of improved child faeces disposal was also associated with stunting, with 75-100% coverage associated with the greatest reduction in stunting. Child faeces disposal in an unimproved toilet was associated with reductions in underweight and wasting, but not stunting. CONCLUSIONS: Improved child faeces disposal practices could achieve greater reductions in child undernutrition than improving toilet access alone. Additionally, the common classification of child faeces disposal as 'safe' regardless of the type of toilet used for disposal may underestimate the benefits of disposal in an improved toilet and overestimate the benefits of disposal in an unimproved toilet. PMID- 28712151 TI - The incidence of public sector hospitalisations due to dog bites in Australia 2001-2013. AB - OBJECTIVE: To estimate the incidence of dog bite-related injuries requiring public sector hospitalisation in Australia during the period 2001-13. METHODS: Summary data on public sector hospitalisations due to dog bite-related injuries with an ICD 10-AM W54.0 coding were sourced from the Australian Institute of Health and Welfare for the study period 2001-2013. RESULTS: In Australia, on average, 2,061 persons were hospitalised each year for treatment for dog bite injuries at an annual rate of 12.39 (95%CI 12.25-12.53) per 100,000 during 2001 13. The highest annual rates of 25.95 (95%CI 25.16-26.72) and 18.42 (95%CI 17.75 19.07) per 100,000 were for age groups 0-4 and 5-9 years respectively. Rates of recorded events increased over the study period and reached 16.15 (95%CI 15.78 16.52) per 100,000 during 2011-13. CONCLUSION: Dog bites are a largely unrecognised and growing public health problem in Australia. Implications for public health: There is an increasing public sector burden of hospitalisations for injuries from dog bites in Australia. PMID- 28712152 TI - Teeth bleaching with low concentrations of hydrogen peroxide (6%) and catalyzed by LED blue (450 +/- 10 nm) and laser infrared (808 +/- 10 nm) light for in office treatment: Randomized clinical trial 1-year follow-up. AB - OBJECTIVES: The aim of this study was to evaluate color longevity after a year of in-office bleaching with gel (6% hydrogen peroxide HP, LED blue/laser infrared activation system) compared to a 35% control concentration in a split-mouth study model. MATERIALS AND METHODS: Thirty-one patients were initially treated. The bleaching procedure with 6% or 35% gel HP was performed randomly in the upper half arcade of each patient. The color was measured at baseline and at 1 week, 1 month, and 1 year using the spectrophotometer Vita Easyshade, Vita Bleached, and Vita classical Shade guide organized by value. During the 1-year recall, the color was assessed before and after dental prophylaxis. RESULTS: Only 27 patients were assessed in the 1-year recall. There was a significant difference in the DeltaE between the two groups at all times assessed (P < .011). The DeltaL, Deltaa, and Deltab showed significant difference between both groups at all assessed times (P < .038). There was no significant difference between the DeltaSGU at all times (P > .05) except for the Vita bleachedguide postprophylaxis comparison (P < .05). CONCLUSION: The two compounds remained effective at 1 year. When objectively evaluated, color difference between groups was found, not seen when subjectively determined. CLINICAL SIGNIFICANCE: A low concentration hydrogen peroxide bleaching agent can reach good clinical results at 1 year of follow-up. PMID- 28712153 TI - Proteomic analysis reveals the enhancement of human serum apolipoprotein A-1(APO A-1) in individuals infected with multiple dengue virus serotypes. AB - OBJECTIVES: Human serum protein profiling of the individual infected with multiple dengue virus serotypes for identifying the potential biomarkers and to investigate the cause for the severity of dengue virus infection. METHODS: Dengue virus NS1-positive serum samples were pooled into two groups (S2 and S3) based on the molecular serotyping and number of heterotypic infections. The pooled serum samples were subjected to two-dimensional gel electrophoresis (2DGE) to identify the differentially expressed proteins. The peptide masses of upregulated protein were detected by matrix-assisted laser desorption-ionisation time-of-flight MALDI TOF mass spectrometry and analysed by MASCOT search engine. The results were compared with the control group (S1). The commonly upregulated protein was validated by quantitative ELISA and compared with control as well as single serotypic infected samples. RESULTS: Based on 2DGE, total thirteen proteins were differentially upregulated in S2 and S3 groups as compared to control. Some of the upregulated proteins were involved in mediating the complement activation of immune response. The apolipoprotein A-1 (APO A-1) was upregulated in S2 and S3 groups. Upon validation, APO A-1 levels were increased in line with the number of heterotypic infection of dengue viruses. CONCLUSION: Heterotypic infection of dengue viruses upregulate the serum proteins involved in the complement pathway in the early phase of infection. There was a significant increase in the level of APO A-1 in three different serotypic infections of dengue virus as compared to control. Further, the role of APO-A1 can be explored in elucidating the mechanism of dengue pathogenesis. PMID- 28712154 TI - A longitudinal study of cognitive and educational outcomes of those born small for gestational age. AB - AIM: This study examined the long-term cognitive and educational outcomes of being born small for gestational age (SGA) and assessed whether the family's attitude towards education modified the effect of being born SGA on educational attainment. METHODS: We used anonymised data on 9598 individuals from the Stockholm Birth Cohort. This study focused on babies born in 1953 in the Stockholm metropolitan area, who were followed up for 50 years, and included educational data at the age of 13 and 48. Ordinary least squares regression analyses, modification analyses and logistic regression analyses were conducted. RESULTS: The findings suggested that individuals who were born SGA (n = 798) had lower mean verbal, spatial and numerical test scores than those born appropriate for gestational age (AGA) (n = 7364) and large for gestational age (n = 1436). The SGA/AGA differences were small, but statistically significant, and the effects of being born SGA on the test scores was modified by the family's attitude towards education. The findings also suggested that attaining higher education was largely, but not entirely, explained by the family's attitude towards education. CONCLUSION: The detrimental effects of being born SGA were limited on cognitive and educational outcomes, but may have been reduced by positive family attitudes. PMID- 28712155 TI - Economic activity and patterns of infant growth in a high altitude district of Peru. AB - OBJECTIVES: Changing economic activities bring significant cultural, epidemiological, and nutritional transitions. Infancy represents a critical period when rapid growth and metabolic programming occur, making infants particularly vulnerable to long-lasting biological changes due to such transitions. This paper examines the relationship between residence in distinct economic production zones (urban, herding, and dairy) and early growth in a highland district of Peru. METHODS: The length, weight, body mass index, and triceps skinfold of 93 infants (55 boys and 38 girls, aged 2 to 24 months) from 3 economic zones were measured at two time points 6 months apart. Z-scores were calculated based on the WHO Growth Reference for children under 5 years of age. Comparisons were made to the reference group and between economic zones to examine the impacts of different economic activities on infant growth. RESULTS: Female infants had significantly higher height-for-age z-scores (HAZ) than males (P < 0.05). Across zones, dairying infants had the highest HAZ scores and the lowest prevalence of stunting. There was a significant association between zone and HAZ at baseline. While these associations were attenuated in measurements, taken 6 months later, longitudinal growth monitoring revealed differential patterns of weight gain and adiposity deposition across the zones with herding infants showing consistent high adiposity and urban infants gaining both weight and adiposity between rounds. DISCUSSION: Changes in economic activity are bringing about nutritional and epidemiological transitions in the Nunoa district. Economic activity is a key factor influencing early growth with distinct longitudinal growth patterns in each economic zone. PMID- 28712156 TI - 'Unfit for human consumption': a study of the contamination of formula milk fed to young children in East Java, Indonesia. AB - OBJECTIVES: To examine levels of bacterial contamination in formula feeding bottles in Sidoarjo, East Java, and to assess the preparation practices that may have been responsible. METHODS: A cross-sectional study was conducted among 92 randomly selected households with children under the age of two who were bottle fed formula. In each household, we carried out video observation of mothers/caregivers preparing bottles, and examined samples of formula for coliform bacteria and Escherichia coli (E. coli). In-depth interviews were conducted with a subsample of 20 mothers. RESULTS: A total of 88% of the formula feeds were contaminated with total coliforms at a level >10 MPN/ml, and 45% contained E. coli. These feeds were defined as 'unfit for human consumption'. In the video observations, none of the mothers complied with all five WHO recommended measures of hygienic formula feed preparation. Only two mothers washed their hands with soap prior to formula preparation. Most mothers also failed to clean or sterilise the bottle and clean the preparation area. In-depth interviews confirmed that such suboptimal hygiene practices were common. CONCLUSION: The high levels of contamination found highlight that bottles are an important faecal-oral exposure pathway resulting from poor hygiene practices during bottle preparation. PMID- 28712157 TI - Training and proficiency in endobronchial ultrasound-guided transbronchial needle aspiration: A systematic review. AB - Endobronchial ultrasound (EBUS)-guided transbronchial needle aspiration (TBNA) is currently the modality of choice for evaluation of mediastinal lymphadenopathy. However, there is still uncertainty regarding the training methodology and the number of procedures required to attain proficiency in EBUS. Herein, we performed a systematic review of studies selected from PubMed, EmBase and Scopus databases describing the training and assessment of proficiency during EBUS, specifically studies investigating various methods for training, its outcome and the number of procedures required to overcome the learning curve for EBUS. Twenty-seven (simulator-based learning (n = 8), tools for assessing competence in EBUS-TBNA (n = 5) and threshold numbers needed to attain proficiency in EBUS-TBNA (n = 16)) studies were identified. An EBUS simulator accurately stratified individuals based on the level of experience in performing EBUS. Training received on a simulator was comparable with traditional apprentice-based training. Importantly, skills acquired on a simulator could be transferred to real-world patients. The number needed to overcome the initial learning curve of EBUS varied from 10 to 100 in individual studies with a mean of 37-44 procedures. Tools such as EBUS STAT (EBUS skill and task assessment tool) and EBUSAT (EBUS skill and assessment tool) were effective in evaluating the EBUS trainees. We conclude that an EBUS simulator or EBUS assessment tools can objectively assess the training of an EBUS trainee. Simulator-based training is a useful modality in EBUS training. The number of procedures needed to overcome the initial learning curve is about 40. Centres involved in EBUS training could incorporate simulator-based training in their curriculum before allowing operators to perform EBUS on patients. PMID- 28712158 TI - Towards a harmonised approach to reducing quad-related fatal injuries in Australia and New Zealand: a cross-sectional comparative analysis. AB - OBJECTIVE: This study compares the patterns of quad-related fatal injuries between Australia and New Zealand (NZ). METHOD: Fatal injuries from July 2007 to June 2012 involving a quad (quad bike or all-terrain vehicle) were identified from coronial files. Data described the socio-demographic, injury, vehicle and environment factors associated with incidents. Injury patterns were compared between countries. RESULTS: A total of 101 quad-related fatalities were identified: 69 in Australia and 32 in NZ (7.3 and 8.0 annual fatalities per 100,000 vehicles). Of these, 95 closed cases were examined in detail and factors in common included fatalities occurring mainly in males, on farms, involving a rollover and resulting in crush injuries to the head and thorax. Helmet use and alcohol/drug involvement were infrequent. Differences were observed with regard to age, season of fatal incident and the presence of a slope. CONCLUSIONS: Fatality patterns are broadly similar. The few differences could be attributed to differing agricultural commodity mix, demographics and topography. IMPLICATIONS: This study's findings support harmonised cross-country injury prevention efforts primarily focused on safe design and engineering principles to reduce this injury burden. PMID- 28712159 TI - Association of the Cardiometabolic Staging System with Individual Engagement and Quality of Life in the US Adult Population. AB - OBJECTIVE: The aim of this study was to examine the relationships of Cardiometabolic Disease Staging (CMDS), a validated five-stage system for assessing risk for diabetes, cardiovascular mortality, and all-cause mortality, with measures of individual engagement and health-related quality of life (HRQOL) in the US adult population. METHODS: Data from the 2011-2014 National Health and Nutrition Examination Survey were used to derive the CMDS stages, five participant engagement measures, and four HRQOL measures among adult participants >= 40 years of age. Analyses accounted for the complex sampling design and sample weights. RESULTS: Higher CMDS was associated with greater participant awareness of cardiometabolic risk, but after adjusting for covariates, only Stage 4 remained significant (odds ratio: 5.08; 95% CI: 3.25, 7.94). Higher CMDS was associated with receiving recommendations to engage in a healthy lifestyle, not meeting 2008 physical activity guidelines, and fewer leisure time moderate activities after controlling for covariates. For HRQOL measures, Stage 4 was associated with a higher likelihood of perceiving health as fair or poor (odds ratio: 4.85; 95% CI: 2.42, 9.73). CONCLUSIONS: Higher CMDS was associated with greater individual awareness of risk, less leisure time physical activity, and worse self-rated health. CMDS is a clinically practical method for identifying individuals for targeted preventive strategies. PMID- 28712161 TI - A Health Behavior Score is Associated with Hypertension and Obesity Among Australian Adults. AB - OBJECTIVE: To investigate associations between a health behavior score and prevalence of hypertension and overweight/obesity. METHODS: Adults (n = 4,609; 19 85 years) were included from the cross-sectional Australian National Nutrition and Physical Activity Survey. A health behavior score was derived based on individuals meeting recommendations for diet quality, smoking, physical activity, sedentary time, and sleep. Poisson regression estimated the prevalence ratio (PR) of hypertension and overweight/obesity by health behavior score. RESULTS: Individuals meeting three (PR: 0.67, 95% CI: 0.54-0.86; P = 0.001), four (PR: 0.76, 95% CI: 0.59-0.96; P = 0.024), or five (PR: 0.63, 95% CI: 0.43-0.94; P = 0.024) health behavior recommendations had a lower hypertension PR compared with those meeting zero or one recommendation. The PR of overweight/obesity was lower in individuals meeting three (PR: 0.98, 95% CI: 0.95-1.02; P = 0.019), four (PR: 0.95, 95% CI: 0.91-0.99; P = 0.019), or five (PR: 0.94, 95% CI: 0.90-0.99; P = 0.022) recommendations compared with those meeting zero or one. CONCLUSIONS: Hypertension and overweight/obesity prevalence were lower in individuals who had above-average diet quality, never smoked, were physically active, spent less time sedentary, and got adequate sleep. These findings support a holistic approach to public health recommendations. PMID- 28712162 TI - BCG Vaccine An Innovation For Diabetes Treatment In Pakistan? PMID- 28712160 TI - Perspectives on childhood resilience among the Aboriginal community: an interview study. AB - OBJECTIVE: To describe Aboriginal community members' perspectives on the outcomes and origins of resilience among Aboriginal children. METHODS: Face-to-face interviews were conducted with 36 Aboriginal adults (15 health service professionals, 8 youth workers and 13 community members) at two urban and one regional Aboriginal Community Controlled Health Service in New South Wales. Interviews were transcribed and analysed thematically. RESULTS: We identified six themes: withstanding risk (displaying normative development, possessing inner fortitude); adapting to adversity (necessary endurance, masking inner vulnerabilities); positive social influences (secure family environments, role modelling healthy behaviours and relationships); instilling cultural identity (investing in Aboriginal knowledge, building a strong cultural self-concept); community safeguards (offering strategic sustainable services, holistic support, shared responsibility, providing enriching opportunities); and personal empowerment (awareness of positive pathways, developing self-respect, fostering positive decision making). CONCLUSIONS: Community members believed that resilient Aboriginal children possessed knowledge and self-belief that encouraged positive decision making despite challenging circumstances. A strong sense of cultural identity and safe, stable and supportive family environments were thought to promote resilient behaviours. Implications for public health: Many Aboriginal children continue to face significant adversity. More sustainable, Aboriginal-led programs are needed to augment positive family dynamics, identify at-risk children and provide safeguards during periods of familial adversity. PMID- 28712163 TI - Molecular Characterization Of Fecal Microbiota Of Healthy Chinese Tobacco Smoker Subjects In Shaanxi Province, Xi'an China. AB - BACKGROUND: Tobacco Smoking, most commonly, can cause the diseases affecting the lungs and heart. Human gut microbiota plays a key role to decide the health status of the host. Current study aimed to characterize the gut microbiota of healthy Chinese tobacco smokers and to study the alteration in diversity and similarity of gut microbiota, with comparison of healthy non-smokers. METHODS: Fecal samples were collected from fourteen healthy tobacco smokers and six from healthy non-smoker individuals. PCR-denaturing gradient gel electrophoresis, with universal primers focusing V3 region of the 16S rRNA gene, was done to characterize the overall gut microbial composition of healthy tobacco smokers in comparison with healthy non-smoker subjects and some strongly dominant gel bands were excised for sequencing. Real time PCR was also performed to evaluate the copy numbers of some dominant bacteria of intestinal flora. RESULTS: The results indicated that gut microbial diversity in tobacco smoker group was lower than non smoker controls. Furthermore, similarity index comparison also indicated that it was lower in inter-group than intra-group, which showed that gut microbial composition was changed in tobacco smoker group. Sequencing results also indicated a change in bacterial composition between both groups. We also observed that in tobacco smoker group, there was a significant reduction in Bifidobacterium and non-significant increase in Bacteroides vulgatus, while nonsignificant decrease in Lactobacillus and clostridium leptum sub group, respectively. CONCLUSIONS: It can be concluded that in healthy Chinese tobacco smoker group, there is a notable alteration in the molecular characterization of gut microbiota. PMID- 28712164 TI - Efficacy And Toxicity Of Carboplatin/Paclitaxel Based Chemoradiation For Localized Oesophageal Cancer. AB - BACKGROUND: The management of Oesophageal and Gastroesophageal junction cancers is challenging. Multimodality therapy with carboplatin/paclitaxel based chemoradiation (CRT) and surgery shows improved efficacy. In this study, we wanted to establish the efficacy and safety of CRT for neoadjuvant and radical treatment of localized oesophageal cancer. METHODS: Patients with oesophageal cancer, registered between September 2013 and October 2014 were reviewed retrospectively. Toxicity and efficacy analysis in the form of radiological response rate, R0 resection rate, Progression free survival (PFS) and overall survival (OS) was performed on 102 patients who received radical carbo/pacli induction chemotherapy followed by CRT. Impact of Surgery was seen on PFS and OS. RESULTS: Males and females were 71 (51.1%) and 68 (48.9%) respectively, with squamous cell carcinoma being the predominant histology (92%). Majority of patient belonged to T3/4 and N1 stage. Grade III/IV thrombocytopenia, neutropenia, anaemia, febrile neutropenia requiring hospitalisation, non hematologic toxicities were noted in 13 (12.8%), 18 (17.7%), 18 (17.7%), 1 (1%), 1 (1%), patients respectively. Complete Radiological response, partial response, Stable disease, progressive disease was seen in 6 (5.9%), 51 (50%), 23 (22.5%) 8 (8.7%), respectively. Resection was done in 29 (28.4%). Complete and partial pathological response were seen 19 (65.5%), 10 (34.4%), respectively. PFS at 40 and 80 weeks was 90%, 73%, respectively and OS at 80 weeks was 86%. PFS at 40 and 80 weeks was 100% and 90.5%, respectively with resection, while it was 86% and 65%, without resection (P value 0.015). OS at 40 and 80 weeks was 100% (both) with resection, while it was 96% and 79.5% weeks without resection. (p-value 0.034). CONCLUSIONS: Carbo/pacli based CRT is effective with acceptable toxicity profile in treating localised oesophageal cancer as both as Radical CRT and as a part of multimodality therapy. For definitive results, long term follow up and prospective analysis are required. PMID- 28712165 TI - Effectiveness Of A School-Based Multicomponent Intervention On Nutritional Status Among Primary School Children In Bangkok, Thailand. AB - BACKGROUND: Childhood obesity has become a major public health issue today. The prevalence of obesity and overweight is increasing in both adults and children. Childhood obesity in Thailand has more than doubled since the 1960s and a recent study reported that overweight and obesity in Thais is the 5th highest in Asia. The present study objective was to evaluate the effectiveness of a life-skills, multicomponent, school-based intervention on child nutritional status. METHODS: A quasi-experimental design was conducted in two-groups (control and intervention schools) on 453 students attending grade levels 4-5 in Bangkok. Two schools were selected for control, and two schools for intervention groups. The interventions included education, diet, physical activity (PA), food-environment, school builtenvironment, and life-skills components. Subjects were measured at baseline and at 6 months post-treatment. RESULTS: The intervention group had significant differences in overall healthy practices (+1.5 mean difference, p=0.048), dietary habits, physical activity, lower total cholesterol (TC) levels (-2.43 mean, p=0.019) and higher high density lipoprotein cholesterol (HDL-C) levels (+4.06 p=0.028) as compared to the control. A higher reduction of overweight individuals among the intervention group over the intervention period was observed. Physical activity and consumption of vegetables increased while consumption of high caloric snacks and fast foods decreased in children after the intervention. CONCLUSIONS: This study indicated that a multidisciplinary approach in school based interventions is most likely to be effective in preventing children from becoming overweight in the long term. More research should be conducted on school based interventions with longer intervention periods and higher sustainability. PMID- 28712166 TI - Quality Of Life Through Listening Music Among Elderly People In Semi-Urban Area, Thailand. AB - BACKGROUND: Aging is one of the biggest problems in Southeast Asia due to their rapidly growing population of the older person. Old aging population is usually confined to their homes resulting in poor quality of life (QOL). Music has been found to be the great activity for older peoples with physical, emotional and social disorders hence, it affects on quality of their life. This study explored the music preference among elderly people and their quality of life in the semi urban of Thailand. METHODS: A cross-sectional study was conducted by interviewing 353 elderly individuals living in the semi-urban area of Thailand. A validated, reliable world health organization quality of life (WHOQOL-OLD) tool was adapted for this study. Logistic regression analysis was performed to identify the factors associated with QOL and its six domains with adjusted covariates, and the potential factors including chronic disease, community participation, traditional event participation, the experiences of music listening, and the types of music preference were entered in the model. RESULTS: Findings revealed that more than half of respondents were married female with an average age of 68.92+/-6.99. Around (80.7%) suffered from chronic diseases and the hypertension was found the highest (66.32%). The quality of life among the elderly was found at the moderate level with the total QOL score of 83.41+/-SD=10.32. Respondents with chronic diseases have the total QOL score (OR=0.95, 95% CI 0.93-0.98). Respondents who preferred to listen to Look Krung (Thai popular classic music) type have the total QOL score (OR=1.03, 95% CI 1.01-1.05), Autonomy Facet(AUT) score (OR=1.11, 95% CI 1.02-1.21), and Intimacy facet(INT) score (OR=1.14, 95% CI 1.05-1.24) as compared to those who did not listen the music. CONCLUSIONS: The study highlights the relationship between the QOL among aging people and the listening of music in the semi-urban area of Thailand. PMID- 28712167 TI - Exploration Of The Contralateral Groin In Paediatric Inguinal Hernia Or Hydrocele Based On Ultrasound Findings - Is It Justified? AB - BACKGROUND: Routine exploration of contralateral side in cases of unilateral inguinal hernia or hydrocele is a highly debatable topic because of various reasons. The purpose of this study was to analyse whether the contralateral groin exploration in unilateral inguinal hernia/ hydrocele is justified or not, based on ultrasonographic measurements of the inguinal ring diameter. METHODS: This cross-sectional study was conducted at two naval hospitals, PNS Rahat and PNS Shifa in Karachi, Pakistan, from June 2007 to Aug 2012. Children presenting with unilateral inguinal hernia or hydrocele were included in the study. Ultrasound examination of the contralateral, apparently normal, groin was carried out using a high-resolution 7.5-11 MHz linear array with the patients in supine position. Surgical exploration of the contralateral groin was carried out in those children in whom the diameter of the inguinal canal at the internal ring was 4.5 mm or greater. All those children in whom the contralateral exploration was not done were followed up to 2 years. RESULTS: A total of 287 patients completed the study, including 264 (92%) boys and 23 (8%) girls. In 242 (84%) cases, the mean diameter of internal ring on contralateral (clinically uninvolved) side was 3.5+/ 0.4 mm, considered negative. Out of these 13 (5.4%) cases, however, proved to be false negative after a follow up of two year. There were 45 (16%) cases that underwent contralateral exploration on basis on positive ultrasound findings; 25 (55.6%) were hernias and 14 (31.1%) were hydroceles. In the remaining 6 (13.3%) cases surgical exploration failed to demonstrate hernia or PPV. CONCLUSIONS: Contralateral exploration in children with unilateral inguinal hernia or hydrocele, based on ultrasonographic findings, is not only cost effective but can also prevent unnecessary routine contralateral explorations and complications related to inguinal hernias. PMID- 28712168 TI - Justification For Re-Look Cystoscopy After Posterior Urethral Valve Fulguration. AB - BACKGROUND: Posterior urethral valve (PUV) is life-threatening congenital anomaly of the urinary tract that results in vesicoureteric reflux, recurrent UTI, voiding dysfunction and renal insufficiency if not treat timely. Endoscopic ablation of posterior urethral valves using cold knife or laser is the current gold standard therapy. Many urologists go for repeat cystoscopy to see residual valve or stricture while others repeat VCUG to measure the posterior to anterior urethral ratio for residual obstruction. In this study, we have standardized by regularly doing re-look cystoscopy at 3 months whether the child is symptomatic or not to see justification for re-look cystoscopy after PUV ablation. METHODS: In this prospective study, first 50 cases that underwent posterior urethral valve fulguration were included. Diagnosis of posterior urethral valve was made by voiding symptoms, ultrasonography and confirmed by voiding cysto-urethrogram (VCUG). All children were treated by endoscopic fulguration of posterior urethral valves (PUV) using cold knife as urethral valvotome and were followed clinically for voiding symptoms and with ultrasonography and laboratory test at 3 and 6 months. All patients underwent re-look cystoscopy at three months to see residual valves irrespective of their clinical improvement. RESULTS: Mean age at presentation was 4.9+/-3.2 years. The most common symptoms were poor stream (76%), straining at voiding (72%), dribbling of urine (54%), fever (42%) and urinary retention (14%). Residual valves on re-look cystoscopy were seen in 78%. Four (8%) patients had urethral stricture on re-look cystoscopy. CONCLUSIONS: We suggest routine re-look cystoscopy after primary fulguration of PUV to pick more residual obstructive valves. PMID- 28712169 TI - Analytic Study In Patients Presenting To A Tertiary Care Hospital Regarding The Artemether-Lumefantrine Induced Qtc Interval Changes In ECG. AB - BACKGROUND: Malaria is one of the most common causes of morbidity and mortality in our part of the world. Artemether-Lumefantrine (AL) Combination therapy is widely used for the treatment of malaria both in outpatients and inpatients hospital settings. Some of the previous anti-malarial were associated with prolongation of QTc interval. Similar query was raised about AL therapy. This study was conducted to determine the risk of QTc interval prolongation in ECG of patients with Falciparum malaria using oral Artemether-Lumefantrine (AL) combination therapy. METHODS: The venue of this analytical, quasi-experimental study was Medical Unit A, Khyber Teaching Hospital Peshawar, spanning 1st August 2015 to 31st July 2016. The study sample included male and female patients, having Plasmodium falciparum rings in their peripheral smear. These patients were treated with oral Artemether- Lumefantrine (AL) combination for 3 consecutive days in recommended doses. Electrocardiography (ECG) profile before and after 72 hours' treatment with AL was noted for discernable QTc interval changes. The calculated prolongation of the QTc interval between these two study points was analyzed using Paired samples t-test. The statistically significant P value for this study was 0.05. SPSS version 23 was used for statistical analysis. RESULTS: Amongst 200 cases, the QTc interval was noted to be normal before the start of the treatment in all. There was no significant prolongation of QTc interval following the treatment (p-value=0.119) in the treated patients. It appears that cardiotoxicity is a remote adverse effect of AL combination therapy and that its use is safe in patients with Falciparum malaria. CONCLUSIONS: It can thus be concluded that AL is a safe drug combination for the treatment of falciparum malaria with negligible cardiotoxic adverse effects. PMID- 28712170 TI - Characteristics And Outcomes Of Anaplastic Large Cell Lymphoma Patients-A Single Centre Experience. AB - BACKGROUND: Anaplastic large cell lymphoma (ALCL) is the second most common T cell lymphoma and 2% of all non-hodgkin lymphoma (NHL). It is an aggressive lymphoma with three subtypes, primary cutaneous ALCL, primary systemic ALK +ve ALCL and primary systemic ALK-ve ALCL depending upon rearrangement of Anaplastic Lymphoma Kinase (ALK) gene into ALK +ve and ALK -ve ALCL. Purpose of study is to determine the outcome of patients with ALCL treated at our institute. METHODS: In this retrospective analysis, 49 patients with ALCL from 2000 to 2012 were included. Their base line IPI score, stage at presentation, bone marrow involvement, type of chemotherapy, ALK status, extra nodal sites and outcome were recorded. RESULTS: Median age was 34 years (range 20-72 years), with males' predominance, i.e., 75.5%. At presentation, 7 (14.3%), 12 (24.5%), 14 (28.6%) and 16 (32.7%) were in stage I-IV, respectively. According to IPI risk categorization, there were 27 (55.1%) in low risk, 12 (24.5%) in low intermediate risk, 8 (16.3%) in high intermediate risk and 2 (4%) in high risk. Seventeen patients (34.7%) were ALK +ve while 21 patients (43%) were ALK +ve and 11 patients (22.4%) had unknown status. Kaplan Meir overall survival (OS) at 5 years was 49.9%. Five-year OS in ALK +ve tumour was 67.4% compared to 39.7% in ALK -ve, p=0.05. CONCLUSIONS: Based on our study results, ALCL is common in males with a trend towards better outcome in Alk+ disease. The majority of patients are in advanced stage of disease at the time of presentation. PMID- 28712171 TI - Neonatal Pain And Preventive Strategies: An Experience In A Tertiary Care Unit. AB - BACKGROUND: Little is known about neonatal pain in Pakistan. So, to know about neonatal pain, its scoring and the effectiveness of oral dextrose in neonatal pain management we carried this study in neonatal intensive care unit (NICU) of military hospital (MH) Rawalpindi. METHODS: This randomized control trial was carried out in NICU of MH, Rawalpindi from Jan to Dec 2013. Total of 252 babies were enrolled in the study. We assessed neonatal pain by using Modified Behavioural Pain Scale (MBPS). Babies were given 10% dextrose and sterile water two minutes before a painful procedure and pain assessment was done after the procedure. The different painful procedures included, heel prick, nasogastric (NG) tube insertion, cannulation, catheterization and venepuncture for blood sampling. RESULTS: A total of 252 babies were enrolled in the study. Of these 139 (55%) were male and 113 (45%) were female babies. Painful procedures included heel lancing 120 (48%), I/V cannulations 60 (24%), venepuncture 40 (16%), NG insertion 26 (10%) and Foley catheterization 6 (2%). Mean MBPS score with 10% dextrose and sterile water were 4.31 and 6.26 respectively and the difference between two was significant statically. CONCLUSIONS: Oral dextrose is a cheap and easily available solution and can be used in neonatal pain management during various painful procedures. PMID- 28712172 TI - Laparoscopic Sleeve Gastrectomy - A Prospective Follow Up Of 30 Patients. AB - BACKGROUND: Morbid obesity has become a surgically treatable problem. Laparoscopic sleeve gastrectomy is becoming a popular choice both for surgeons and patients due to effectiveness and low complication rates. METHODS: It was a prospective case series spanning over 6 years. Patient enrolment started from January 2009 and data collection completed in January 2015. Patient with BMI (weight in kilogram/height in meter square) of more than 35 were included in the study. Follow up was at 2 weeks, 1 month, 6 months and 12 months. Success was defined as 25% of excess weight loss at 1 year. Paired t-test was used as a test of significance. RESULTS: A total of 34 patients were included in the study over a 6-year period, 3 were lost to follow up and one patient died of cardiac arrest. Data of 30 patients is considered for final analysis. Mean age was 39.5+/-10 years, while mean BMI 45.8+/-6.3 (range 37.1-62.2). Average weight of the patients preoperatively was 129.9+/-20.8 kg while mean excess weight was 70.3+/ 20.8 kg. Average weight loss at two weeks was 8.9+/-2.9 kg, at one month 14.7+/ 4.6 kg, at 6 months 25.0+/-7.6 kg and at twelve months was 31.4+/-6.8 kg. Mean percentage of excess weight loss after 2 weeks was 13.5+/-4.6%, at one month 22.0+/-6.1%, at six months 37.6+/-12.0% and at twelve months 47.3+/-10.1%. CONCLUSIONS: Laparoscopic sleeve gastrectomy is an effective weight loss surgery with minimal complications. On average weight loss of about 30 kg at one year was achieved which equals to almost half of excess body weight. PMID- 28712173 TI - Surgical Site Infection In Orthopaedic Implants And Its Common Bacteria With Their Sensitivities To Antibiotics, In Open Reduction Internal Fixation. AB - BACKGROUND: Surgical site infection in orthopaedic implants is a major problem, causing long hospital stay, cost to the patient and is a burden on health care facilities. It increases rate of nonunion, osteomyelitis, implant failure, sepsis, multiorgan dysfunction and even death. Surgical site infection is defined as pain, erythema, swelling and discharge from wound site. Surgical site infection in orthopaedic implants is more challenging to the treating orthopaedic surgeon as the causative organism is protected by a biofilm over the implant's surface. Antibiotics cannot cross this film to reach the bacteria's, causing infection. METHODS: This descriptive case series study includes 132 patients of both genders with ages between 13-60 years conducted at Orthopaedic Unit, Ayub Medical College, Abbottabad from 1st October 2015 to 31st March 2016. Patients with close fractures of long bones were included in the study to determine the frequency of surgical site infection in orthopaedic implants and the type of bacteria involved and their sensitivity to various antibiotics. All implants were of stainless steel. The implants used were Dynamic hip screws, Dynamic compression screws, plates, k-wires, Interlocking nails, SIGN nails, Austin Moore prosthesis and tension band wires. Pre-op and post-op antibiotics used were combination of Sulbactum and Cefoperazone which was given 1 hour before surgery and continued for 72 hours after surgery. Patients were followed up to 4 weeks. Pus was taken on culture stick, from those who developed infection. Results were entered in the pro forma. RESULTS: A total of 132 patients of long bone fractures, who were treated with open reduction and internal fixation, were studied. Only 7 patients developed infection. Staphylococcus Aureus was isolated from all 7 patients. Staphylococcus aureus was sensitive to Linezolid, Fusidic Acid, and vancomycin. Cotrimoxazole, tetracycline, Gentamycin and Clindamycin were partially effective. CONCLUSIONS: Surgical Site Infection is common in orthopaedic implants, occurring in 5.30% cases. Staphylococcus aureus is the common bacteria, causing it. PMID- 28712174 TI - Arthrocentesis For Temporomandibular Joint Pain Dysfunction Syndrome. AB - BACKGROUND: Temporomandibular joint (TMJ) dysfunction is painful condition of facial musculoskeletal system. Arthrocentesis is less invasive treatment of TMJ dysfunctions. It has been used to treat variety of TMJ disorders. The objective of this study was to determine the success of arthrocentesis in TMJPDS patients where conservative treatment had failed. METHODS: This descriptive case study of 45 patients was completed in 6 months at Outpatient Department of Oral and Maxillofacial Surgery, Mayo hospital Lahore. TMJPDS Patients who were unresponsive to conservative treatment were included in this study. The study consisted of a single arthrocentesis procedure performed by a single oral surgeon per patient. Visual Analogue Scale was used to record pain while maximum mouth opening was measured by the interincisal distance in millimetres, at 1 month and 2 months after the treatment. Success was measured two months after arthrocentesis. RESULTS: Thirty (66.7%) patients had no pain and 15 (33.3%) patients had mild pain. Similarly, 16 (35.5%) patients had maximum mouth opening more than 30mm and 29 (64.5%) patients had less than 30 mm mouth opening, two months after arthrocentesis procedure. CONCLUSIONS: Arthrocentesis is very effective in patients suffering from TMPDS by reducing pain and discomfort and increase in mouth opening. This procedure should be considered in TMPDS patients who do not respond to conservative treatment. PMID- 28712175 TI - Corneal Complications And Visual Impairment In Vernal Keratoconjunctivitis Patients. AB - BACKGROUND: Vernal kerato-conjunctivitis (VKC) is an infrequent but serious form of allergic conjunctivitis common in warm and humid areas where air is rich in allergens. It affects both eyes asymmetrically. Although VKC is a self-limiting disease but visions affecting corneal complications influence the quality of life in school children. The aim of this study was to list the corneal complications due to this condition and to find out the extent of visual impairment among VKC patients. METHODS: This cross-sectional study was conducted in the department of Ophthalmology, Benazir Bhutto Shaheed Hospital on 290 eyes of diagnosed cases of VKC. The diagnosis of VKC was made on the basis of history and examination. Visual acuity was recorded using Snellen's notation and visual impairment was classified according to World Health Organization classification for visual disabilities. RESULTS: The mean age of presentation was 10.83+/-6.13 years. There were 207 (71.4%) males and 83 (28.6%) females. Corneal scarring was observed in 59 (20.3%) eyes. Keratoconus was found to be in 17 (5.9%) eyes. Shield ulcer was detected in 09 (3.1%) eyes while 07 (2.4%) eyes had corneal neovascularization. Majority of the patients with visual loss had corneal scarring and the complication that led to severe visual loss in most of the eyes was Keratoconus. CONCLUSIONS: Vernal kerato-conjunctivitis in the presence of corneal complications is a sight threatening disease and can lead to severe visual impairment. PMID- 28712176 TI - ECG Abnormalities In Patients With Chronic Kidney Disease. AB - BACKGROUND: Chronic kidney disease (CKD) is associated with increased risk of cardiovascular disease. Electrocardiographic (ECG) abnormalities are common in CKD patients. However, there is variation in literature regarding frequency of ECG abnormalities in CKD patients and limited information in local population. METHODS: The study design was cross-sectional in nature. All patients between ages of 20-80 years with CKD not previously on renal replacement therapy who were admitted to nephrology ward at a tertiary care facility over a 6-month period were included. All patients underwent 12 lead electrocardiograms (ECG). ECG abnormalities were defined based on accepted standard criteria. RESULTS: Total number of patients included in the study was 124. Mean age of all patients was 49.9+/-13.8 years, 106 (84.8%) had hypertension, 84 (70%) had diabetes mellitus, and 35 (29.9%) had known cardiovascular disease. Mean serum creatinine was 7.2+/ 3.4 mg/dl, mean eGFR was 10.6+/-9.2 ml/min/1.73 m2. Overall 78.4% of all CKD patients have one or more ECG abnormality. Left ventricular hypertrophy (40%), Q waves (27.2%), ST segment elevation or depression (23.4%), prolonged QRS duration (19.2%), tachycardia (17.6%) and left and right atrial enlargement (17.6%) were the most common abnormalities. CONCLUSIONS: ECG abnormalities are common in hospitalized CKD patients in local population. All hospitalized CKD patients should undergo ECG to screen for cardiovascular disease. PMID- 28712177 TI - Analysis Of Two Years Cases Of Ectopic Pregnancy. AB - BACKGROUND: Ectopic pregnancy is the leading cause of pregnancy related deaths in the first trimester. The aim of this study was to evaluate the frequency of risk factors, clinical presentation, diagnostic methods and site of ectopic pregnancy. METHODS: This descriptive cross sectional study was conducted in Gynaecology and Obstetrical Unit-A of Ayub Teaching Hospital Abbottabad from 1st October 2013 to 31st October 2015. All women diagnosed with ectopic pregnancy were included in the study. A predesigned proforma was used to record the details about demographic features, risk factors, clinical features at presentation, diagnostic methods and site of ectopic pregnancy. RESULTS: Out of total 6675 patients admitted during the study period, 45 cases of ectopic pregnancy were diagnosed with frequency of ectopic pregnancy to be 0.65%. Mean age of the patients was 28.98+/-5.525. Majority of patients were primigravida14 (31.3%), 9 (20.0%) gravida 2, 5 (11.1%) gravida 3, 4 (8.8%) gravida 4, 7 (15.5%) gravida 5, 6 (13.3%) found grand multi out of total 45 ectopic pregnancies, 45% of the patients had no identifiable risk factors, however history of infertility 20 (22.22%), history of Pelvic inflammatory disease (PID) 10 (22.22%), previous ectopic 2 (4.44%) and previous abdominal pelvic surgery 3 (6.67%) were identified as common risk factors of 45 ectopic pregnancies. Out of total 45 sufferers 23 (51.11%) were clinically diagnosed, 20 (44.44%) through abdominal ultrasound and 2 (4.44%) through transvaginal ultrasound. The most frequent clinical presentation was amenorrhea 30 (66.67%) followed by abdominal pain 28 (62.22%), irregular vaginal bleeding 18 (40.00%), asymptomatic patients with routine ultrasound 18 (40.0%) and 10 (22.22%) presented in shock. Twenty-eight (62.2%) of the ectopic pregnancies were found in right sided fallopian tube and 17(37.8%) were found in left sided fallopian tube. The commonest site of ectopic pregnancy was ampulla 29 (64.44%) followed by 11 (24.44%) Isthmus, 4 (8.89%) fimbrial end and 1 (2.22%) were rudimentary horn of uterus out of total 45 ectopic pregnancies. Evidence of 32 (71.1%) patients with ruptured ectopic was recorded. Thirteen (28.9%) were unruptured ectopic. CONCLUSIONS: Amenorrhea and abdominal pain are the most consistent features of ectopic pregnancy. PMID- 28712178 TI - Cognitive Potential And Its Predictors In Children From A Rural District Of Pakistan. AB - BACKGROUND: Effective interventions are available to reduce cognitive deficit currently estimated to affect more than 200 million children under 5 years of age in developing countries. However, developing world's investment is negligible in this regard mainly because of non-existent global indicators to monitor progress with respect to the childhood cognitive development. Intelligence Quotient (IQ) or Full Scale Intelligence Quotient (FSIQ) is an indicator of the cognitive development. This study was designed to assess cognitive potential of 6-7 years old children from a rural district of Pakistan by calculating their FSIQ. Predictors of the FSIQ were also determined. METHODS: This cross-sectional research was carried out in 40 rural Union Councils (UCs) of 2 subdistricts in district Rawalpindi utilizing simple random sampling technique. Wechsler Pre school and Primary Scale of Intelligence (WPPSI-IV) was administered to 6-7 years old children (n=300) for measuring their FSIQ. RESULTS: FSIQ of rural Pakistani children, relative to the normative sample, was found to be in the category of low-average. Findings of multiple regression analysis concluded grade/class of the child as the most influential predictor of the FSIQ followed by the level of mother's and then father's education. CONCLUSIONS: FSIQ of the rural Pakistani children, relative to the normative sample, was found to be in the category of low-average. Predictors of the FSIQ, seen in this research, were school grades and non-educated parents of the children warranting future research on the contribution of environmental influences to the variability in cognitive potential. PMID- 28712179 TI - Clinical Spectrum Of Solitary Rectal Ulcer In Children Presenting With Per-Rectal Bleed. AB - BACKGROUND: Solitary rectal ulcer syndrome (SRUS) is a benign and chronic disorder well known in young adults and less common in children. The objective of this study was to determine the frequency and clinical spectrum of solitary rectal ulcer in children with bleeding per rectum. METHODS: This study was conducted in the Department of Paediatric Gastroenterology Hepatology& Nutrition; The Children's Hospital & The Institute of Child Health, Lahore, from January December 2015. Total 187 children presenting with per-rectal bleeding who underwent colonoscopy were entered in the study. Demographic and presenting clinical features; colonoscopy and histopathology findings were recorded. Data was analysed using SPSS-20. RESULTS: Out of a total of 187 children with bleeding per rectum, 21 (11.23%) were diagnosed with solitary rectal ulcer. Males were 15 (71.43%) and females were 6 (28.57%) with age range 8-12 years. Mucus in stool 14 (66.7%), constipation 12 (57.1%) and tenesmus 10 (47.6%) were the most common clinical presentations. Colonoscopic finding are solitary erythmatous ulcerative lesion was seen in 8 (38.09%) children, multiple ulcerative lesions in colon 6 (28.57%), multiple ulcerative lesions in rectum 5 (23.81%), polypoidal growth in colon and hyperaemic rectal mucosa in 1 (4.76%) each. Histopathological findings were consistent with SRUS in all the cases. CONCLUSIONS: The frequency of SRUS was high (19.6%) in patients with per-rectal bleed. Mucus in stool, constipation and tenesmus were the most common clinical presentations. Colonoscopic and histopathological findings were helpful in the confirmation of the underlying aetiology. PMID- 28712180 TI - Causes Of Chronic Non-Infectious Diarrhoea In Infants Less Than 6 Months Of Age: Rarely Recognized Entities. AB - BACKGROUND: Non-infectious causes of chronic diarrhoea are important and easily missed. The study was done with the objectives to identify different causes of chronic non-infectious diarrhoea in infants less than 6 months of age. METHODS: All patients less than 6 months of age presenting for the first time to a Paediatric Gastroenterology tertiary care centre with a history of chronic diarrhoea and negative stool cultures were enrolled over a period of 8 months. Demographical profile and various factors under observation were recorded in this observational study. Collected data was analysed using SPSS version 20. Chi square test was applied as a test of significance for any qualitative variable, p value (p<0.05) was taken as significant. RESULTS: Among 72 enrolled patients, female to male ratio was1.05:1. Age at onset of symptoms was between 15 days to 6 months. Aetiology found was Cow's milk protein allergy (CMPA) in 58 (80.6%), Primary intestinal lymphangiectasia (PIL) 6 (8.3%), Cystic fibrosis (CF) 3 (4.2%), Immunodeficiency (SCID) 2 (2.8%), 1 (1.4%) for each Abetalipoproteinemia (ABL), Glucose galactose malabsorption (GGM) and Congenital chloride diarrhoea (CCD). CONCLUSIONS: Among noninfectious causes of chronic diarrhoea in early infancy, cow's milk protein allergy is most common followed by Primary intestinal lymphangiectasia and Cystic fibrosis. PMID- 28712181 TI - Comparison Of Lipid Lowering Effect Of Extra Virgin Olive Oil And Atorvastatin In Dyslipidaemia In Type 2 Diabetes Mellitus. AB - BACKGROUND: Extra virgin olive oil (EVOO) is fruit oil with rich source of monounsaturated fats and powerful antioxidants. It acts as hypolipidemic agent and significant decrease of plasma lipids level was observed with EVOO use. Atorvastatin is hypolipidemic drug commonly used for treatment of hyperlipidaemia. The purpose of this study was to determine & compare the lipid lowering effect of EVOO with atorvastatin in type 2 diabetic dyslipidaemia which is leading cause of microvascular diseases. METHODS: This randomised controlled trial was conducted on 60 already diagnosed cases of type 2 diabetes mellitus with dyslipidaemia. All sixty subjects were divided randomly into 2 groups. Atorvastatin 40 mg was given to Group One and two tablespoons of extra virgin olive oil orally per day was given to Group Two. Blood was collected for estimation of plasma lipids level at base line, 4th week, and 6th weeks in two groups and was compared statistically. RESULTS: The present study demonstrated 20 40% lipid lowering effect of atorvastatin on plasma lipids level with 9-16% increase in HDL while extra virgin olive oil showed 14-25% reduction in plasma lipids with 8-12% increase in HDL-cholesterol level. CONCLUSIONS: This study concludes that both atorvastatin and extra virgin olive oil are effective in reducing plasma lipids level in type 2 diabetic dyslipidaemia with more prominent effect of atorvastatin than EVOO. PMID- 28712182 TI - Trend Of Irrational Medication Among The Students Of Department Of Pharmacy Abbottabad University Of Science And Technology In Common Cold And Flu. AB - BACKGROUND: Common cold and flu are mostly of viral pathogenesis with symptoms in upper respiratory tract. It is highly contagious and close inter-individual contact in winter season increase the spread spectrum. Mis-interpretation with bacterial cause leads to irrationality in its medication. METHODS: A cross sectional study was conducted among pharmacy department students in February March 2016. Data were collected through self-administered questionnaire and expressed as percentage frequency. RESULTS: Total 180 students were provided with questionnaire to fill the desired data. 66 out of them were reported as patients of common cold and flu. Trend of medication after compilation and analyzing data reveal that: 60.60% (n=40/66) students got irrational medication, 4.54% (n=3/66) students presents with other disease, so were declared of complex nature and 9.1% (n=6/66) patients, presented only with symptoms were counseled accordingly to the standard therapy by Health Protection Agency-UK (Management of infection guidance for primary care for consultation and local adaptation, 2013), and Columbia University Medical Center (Guidelines for the empiric use of antibiotics in adult patients - Feb, 2005) and all of them were followed for their entire therapy time. All of the counseled patients recovered successfully. Total 25.76% (n=17/66) other than that of counseled group students also got rational medication. CONCLUSIONS: Use of medicine by students in study was found irrational. National and international awareness programs about such viral disease should be designed and arranged to promote information in the community and limit the irrational medication. It also need an active health regulatory authority in undeveloped and less developed countries specially to limit the availability of prescription drugs without physician advise through availability of qualified person in pharmacies. PMID- 28712183 TI - Association Of Abo And Rh Blood Group Types To Hepatitis B, Hepatitis C, Hiv And Syphilis Infection, A Five Year' Experience In Healthy Blood Donors In A Tertiary Care Hospital. AB - BACKGROUND: Aim of the study: The aim of the study was to find out the frequency of Hepatitis B Hepatitis C, Syphilis, HIV and malaria in apparently healthy blood donors and to find out any association between ABO and Rh blood groups. METHODS: It was a descriptive study carried out at Rehman Medical Institute laboratory. All blood donors who volunteered for blood donation from Jan 2008 to Dec 2014 were reviewed for blood groups and screening tests. Those who were eligible were then screened for Hepatitis B, Hepatitis C, HIV, syphilis and malaria on Architect 8200i through chemiluminescent immunoassay whereas malaria was screened by a thin film. Blood group was determined by both forward and reverse grouping. Statistical analysis was carried out using SPSS software and expressed as frequencies. RESULTS: A total of 41033 apparently healthy donors were included in the study. All of them were voluntary donors. Their age ranged from 18-70 years with a mean age of 38+/-10.5years. Out of these 41033, 40245 (98.3%) were males and 788 (1.9%) were females. The most frequent blood group was B positive followed by O positive. Out of 41033 donors 961 (2.30%) had Hepatitis B, 566 (1.30%) had Hepatitis C, 363 (0.90%) had syphilis, 311 (0.76%) had malaria and 30 (0.07%) had HIV. There is a significant association between A blood group and HIV and hepatitis B. Donors with blood group O had no significant association with any blood transmitted infection. CONCLUSIONS: Blood group O may have some influence in protecting against blood transmitted infection. People having Blood group A are more prone to get Hepatitis B and HIV. PMID- 28712184 TI - Service Quality Of Diagnostic Fine Needle Aspiration Cytology In A Tertiary Care Hospital Of Lahore (Process Measure As Patient's Perspective). AB - BACKGROUND: Quality of any service is the most important aspect for the manufacturer as well as the consumer. The primary objective of any nation's health system is to provide supreme quality health care services to its patients. The objective of this study was to assess the quality of diagnostic fine needle aspiration cytology service in a tertiary care hospital. As Patient's perspectives provide valuable information on quality of process, therefore, patient's perception in terms of satisfaction with the service was measured. METHODS: In this cross sectional analytical study, 291 patients undergoing fine needle aspiration cytology in Mayo Hospital were selected by systematic sampling technique. Information regarding satisfaction of patients with four dimensions of service quality process, namely "procedure, sterilization, conduct and competency of doctor" was collected through interview on questionnaire. The questionnaire was developed on SERVQUAL model, a measurement tool, for quality assessment of services provided to patients. All items were assessed on 2- point likert scale (0=dissatisfied, 1=satisfied). Frequencies and percentages of satisfied and dissatisfied patients were recorded for each item and all items in each dimension were scored. If the percentage of sum of all item scores of a dimension was >=60, the dimension was 'good quality'. Whereas <60% was 'poor quality' dimension. Data was analysed using epi-info-3.5.1. Fisher test was applied to check statistical significance. (p-value <0.05). RESULTS: Out of the 4 dimensions of service quality process, Procedure (48.8%), Sterilization (51.5%) and practitioner conduct (50.9%) were perceived as 'poor' by the patients. Only practitioner competency (67.4%) was perceived as 'good'. Comparison of dimensions of service quality scoring with overall level of patient satisfaction revealed that all 4 dimensions were significantly related to patient dissatisfaction (p<.05). CONCLUSIONS: The study suggests that service quality of therapeutic and diagnostic procedures in public hospitals should be routinely monitored from the patients' point of view as most aspects of service quality in public hospitals of Pakistan, require improvements. In this manner patient's satisfaction regarding use of services in public hospitals can be made better. PMID- 28712185 TI - Effect Of Midazolam Premedication On Doses Of Propofol For Laryngeal Mask Airway Insertion In Children. AB - BACKGROUND: Propofol is a widely-accepted medication for the successful insertion of laryngeal mask airway (LMA). When propofol is used alone, larger doses are required which can lead to cardiorespiratory distress resulting in hypotension and prolonged apnoea. The objective of this study was to evaluate the effect of premedication of midazolam on different doses of propofol for LMA insertion. METHODS: In this randomized clinical trial, eighty-six (86) patients who were scheduled to undergo elective surgery is supine position not requiring the need for tracheal intubation from September 2015 to 6 March 2016 were included. In group I (n=43), the LMA was introduced after induction of anaesthesia with Propofol alone. In Group II (n=43, the patient was premeditated with midazolam (0.05 mg/kg) before induction of anaesthesia with propofol. Each group was divided into three subgroups depending upon the dose of propofol used for LMA insertion. RESULTS: In this study, there were 53.5% females in group I and 48.8% females in group II. The mean age of Children in group I was 7.30+/-2.55 years and 7.47+/-2.46 years in group II. Incidence of incomplete Jaw relaxation, coughing and limb movements was significantly high in in Group I patients (pvalues <0.001, <0.001 and <0.001 respectively). Effectiveness of anaesthesia was compared among different subgroups. On comparison of subgroup Ia and IIa, the effectiveness rate was significantly high in subgroup IIa 50% versus only 7.1% in subgroup Ia (p-value 0.012). Similarly, in subgroup IIb effectiveness was achieved in 100% patients as compared to only 64.3% patients in subgroup IIb (p value 0.014). There was no significant difference in effectiveness rate in subgroup Ic and IIc (p-value 0.309). CONCLUSIONS: With midazolam premedication, the dose of propofol for LMA insertion is decreased. The incidence of adverse events during LMA insertion is also low with midazolam premedication. PMID- 28712186 TI - Glycaemic Control Of Type 2 Diabetic Patients During Ramazan Fasting. AB - BACKGROUND: Among five main pillars of Islam Fasting is one of the key elements, all healthy adult Muslims have to observe fast from dawn till dusk during the holy month of Ramadan. According to a 2009 demographic study, Islam has 1.57 billion believers, making up 23% of the world population of 6.8 billion, and is growing by 3% per year. EPIDIAR (epidemiology of diabetes and Ramadan) study showed that 43% patients with type 1 and 79% patients with type2 diabetes observe fast during the month of Ramadan. Whereas those people who are suffering from diabetes and are fasting may be at risk of adverse outcomes and the risks may rise with longer fasting periods. Ideal management of diabetic patients who wish to fast during Ramadan needs to be done to avoid the complications. The purpose of this study was to observe the effect of fasting on glycaemic control in type 2 diabetic patients during the month of Ramadan. METHODS: This was an observational cross sectional study; it was conducted at outpatient department Jinnah institute of diabetes and endocrinology Jinnah hospital Lahore during the month of Ramadan. Patients were advised to monitor blood sugar levels for two days before and after three meals (lunch, breakfast and dinner) before Ramadan and then during Ramadan blood sugar levels were monitored for four days in first Ashra before and two hours after Sehari, for four days at noon during second Ashra and then for four days pre and two hours after Iftar in last Ashra of Ramadan. Patients were educated Pre-Ramadan about glucose monitoring and drug dosage adjustments were done along with dietary counselling. RESULTS: Blood glucose levels two days before and during Ramadan fell within range of mean glucose level of 150-187 mg/dl showing no extreme fluctuations in blood glucose levels only one patient reported symptomatic and biochemical hypoglycaemia severe enough to break the fast at noon. CONCLUSIONS: We concluded that in Ramadan fasting, type 2 diabetic patients with proper education, dietary counselling and drug dosage adjustments glycaemic control can remain in safe acceptable range preventing any life threatening complication. PMID- 28712187 TI - Utility Of Heart Type Fatty Acid Binding Protein (H-Fabp) Point Of Care Test In The Early Hours Of Stemi Compared With Troponin-I In Pakistani Population. AB - BACKGROUND: Acute coronary syndrome remains a dominant cause of high morbidity and mortality despite advancements in treatment This study was conducted to examine the utility of point-of-care test of heart-type fatty-acid binding protein (h-FABP) and compare it with the point-of-care test of cardiac troponin I (cTnI) in the first 06 hours of STEMI. METHODS: This cross-sectional, comparative study which was conducted in Rawalpindi institute of cardiology, Rawalpindi, Pakistan, from January to June 2015. Serum samples of 125 patients with the diagnosis of STEMI, presenting with chest pain of less than 6 hours' duration, were analysed for quantitative and qualitative determination of h-FABP and cardiac troponin I (cTnI) using rapid immunochromatographic technique in the emergency department. Samples were taken at presentation and after 12 hours. RESULTS: Out of 125 patients, 112 were males and 13 were females with a mean age of 54.26+/-9.53 years. The average symptom-to-sample time was 3.19+/-1.44 hours (median 3 hours). Mean h-FABP levels were significantly higher than the mean cTnI levels (29.10+/-30.66 vs 0.94+/-2.02; p=0.000). Overall, HFABP was more sensitive than cTnI (72% vs 26.4%). The sensitivity of cTnI within 0-2, 2-4, and 4-6 hours of symptom onset was calculated to be 0%, 17.7%, and 75.9%, whereas sensitivity of HFABP was 35.3%, 79.03% and 100% respectively. There was not a single patient who was cTnI positive and H-FABP negative as compared to 57 patients who were FABP positive and cTnI negative. CONCLUSIONS: h-FABP is a promising cardiac biomarker for the early identification of myocardial ischemia and infarction. It could be a superior biomarker for earlier detection of ACS and screening of patients with non-cardiac chest pain. PMID- 28712188 TI - A Novel Link Between Adipokines And Lipoprotein (A) To Contemplate Their Diagnostic Role In Patients With Stemi And Nstemi. AB - BACKGROUND: Early detection of cardiac events allow better and cost-effective triage and welltimed management of these patients. Study was conducted to evaluate the prognostic significance of plasma adiponectin, resistin and lipoprotein (a) in a group of patients with ST segment elevation myocardial infarction and non-ST-segment elevation myocardial infarction. These parameters were also compared with other predictors like troponin T, troponin I and CK-MB. METHODS: Present study was based on the 100 patients with AMI of whom 52 had a diagnosis of STEMI, and 48 had NSTEMI. Duration of study was January to June 2015. Patients having chest pain that was indicative of myocardial ischemia within first 12 hours after the onset of symptoms were included in the study. Adiponectin, Lp (a), resistin, troponin T and troponin I were estimated using ELISA method. Level of CK-MB was measured by Auto-analyser using standard kit of Merck. RESULTS: Mean age of patients with STEMI was 52.32 years and with NSTEMI it was 48.17 years. Mean value of BMI of patients with STEMI was 28.33 and with NSTEMI was 25.22 Kg/m2. Duration of chest pain in patients with STEMI was 8.64 and patients with NSTEMI it was 16.52hours with highly significant difference (p<0.001). History of smoking in patients with STEMI was more as compared to the patients with NSTEMI. Level of CPK, adiponectin and lipoprotein (a) was raised in patients with STEMI as compared to patients with NSTEMI but significant difference was only found in levels of CPK (p<0.001) and in adiponectin (p<0.05). Level of serum CK-MB, TnT, TnI and resistin was raised in patients with NSTEMI as compared to patients with STEMI but significant difference (p<0.001) was only observed in serum troponin I concentration. CONCLUSIONS: It is concluded that the incidence of STEMI and NSTEMI is similar in our patients. However, the markers of STEMI are increased level of adiponectin and Lp(a) and the markers of NSTEMI are troponins especially troponin I, resistin and CKMB. PMID- 28712189 TI - Maternal Mortality In Pakistan: Is There Any Metamorphosis Towards Betterment? AB - BACKGROUND: Every year more than half million mother die due to pregnancy related preventable causes like haemorrhage, hypertensive disorders, sepsis, and obstructed labour and unsafe abortion. Among these deaths 99% occur in developing countries. The study was conducted to assess the maternal death rate and to analyse its trends over a period of 20 years in tertiary care hospital in Sindh Province Pakistan. METHODS: A retrospective analysis of maternal mortality records were carried out for a period of 20 years from 1986-1995 and 2011-2015 at the Department of Obstetrics and gynaecology Liaquat University of Medical and Health Sciences Hyderabad Sindh Pakistan. The record retrieved was categorized into four 5 yearly periods 1986- 1990, 1991-995, 2006-2010 and 2011-2015 for comparison of trends. RESULTS: The cumulative maternal mortality ratio (MMR) was 1521.5 per 100,000 live births. The comparison of first 5 years' period (1986 1990) and last 5 years (2011-2015) showed downward trend in maternal mortality rate from 2368.6-1265.1. Direct causes of death have accounted for 2820 (84.78%) of total maternal death. Sepsis was the major cause of death for first 5 years accounted for 196(35.1%) of maternal death while in the last 5 years' eclampsia causes 284 (27.84%) of direct maternal deaths. CONCLUSIONS: The reduction in the maternal deaths has been very slow. The direct causes were still the main reasons for obstetrical deaths. PMID- 28712190 TI - Anxiety And Depression In Medical Students Of A Private Medical College. AB - BACKGROUND: Depression and anxiety are the common mental disorders with a prevalence of 10-44% in developing countries and is the fourth leading cause of morbidity. Undergraduate medical studies are generally perceived to be more stressful for the students as compared to other undergraduate programs as students have to undergo strenuous curriculum and evaluation which may lead to many emotional stresses that may end with psychiatric disorders like depression and anxiety. This study aimed to determine the frequency of anxiety and depression in medical students of Foundation University Medical College (FUMC), Islamabad. METHODS: In this cross-sectional study, Beck Depressive Inventory and Beck Anxiety Scales were used to assess anxiety and depression at three different times of the Academic year. All five-year students were included in the study. RESULTS: Out of a sample of 150 students, mild depression was seen in 37.46% and moderate to severe depression was observed in 14% students. About 19% of the students had moderate to severe anxiety. In Second year students time of assessment was significantly related to depression and anxiety (p-0.000). Females had higher association with depression in final year (p-0.037). CONCLUSIONS: High Psychiatric morbidity found needs to be identified and treated at the earliest; otherwise it can lead to serious consequences such as suicidal ideation and burnout. PMID- 28712192 TI - Journey From Black To Pink Gums: Management Of Melanin Induced Physiological Gingival Hyper Pigmentation. AB - Smile is an expression of happiness, self-confidence, kindness and beauty. Along with teeth and lips, gingiva is also a vital component of smile. Melanin induced gingival hyper pigmentation may appear un-aesthetic especially when it is associated with high smile line, upper anterior labial segment and is uneven in appearance. It affects individuals from all races. Generally, it is believed that melanin induced gingival hyper pigmentation is confined to individuals from dark races. But studies have shown that Iranian, Indian, Italian, Arabian, Greek. German, French, Japanese, Chinese, Jewish, Thai, Malaysian and other ethnic groups also display clinical gingival pigmentation.1 Gingival hyper pigmentation may result in psychological distress especially when the appearance is of utmost importance for the individuals. This article aims to focus on the physiology, clinical appearance and treatment options available for the melanin induced gingival hyper pigmentation along with the reported recurrence in the light of current literature. PMID- 28712191 TI - Assessing The Role Of Education In Adult Women's Knowledge And Awareness Of Human Papillomavirus And Human Papillomavirus Vaccine. AB - BACKGROUND: Awareness and knowledge of Human Papillomavirus (HPV) and HPV vaccine among women are not satisfactory in developing countries. The aim of this study was to assess the role of education in adult women about knowledge and awareness of human papillomavirus (HPV) and HPV vaccine. METHODS: This cross-sectional study was carried out in women aged 19- 50 years attending the out-patient waiting area of a tertiary care hospital in Karachi from August 2014 to August 2015. Convenience sampling was applied. After their written consent, a selfadministered questionnaire was used to obtain information regarding role of education and awareness, knowledge of human papillomavirus (HPV) and HPV vaccine. A total of 600 women completed the questionnaire. RESULTS: Mean age of the study participants was 39+/-10.7 years. About 68% (n=405) had an education level intermediate or less, while 33% (n=195) had a bachelors or higher degree. A total of 56.3% (n=338) women were aged less than 40 years. CONCLUSIONS: Awareness among women varies with the level of education acquired. As shown by results, a lesser proportion of undergraduate women were aware about HPV and its related diseases as compared women at graduate level. Moreover, our study identifies significant gaps in knowledge about sexually transmitted infections, HPV, cervical cancer and its prevention. There is an urgent need to develop public awareness programs targeting the adolescent and young adult women of our country. PMID- 28712193 TI - Autoimmune Disease Presenting As Acute Abdomen. AB - Mesenteric vasculitis and resultant bowel ischemia is rare but serious complication of autoimmune disorders. Early detection and treatment is the key to avoid potentially fatal outcomes of bowel perforation and peritonitis. In this series, we present patients presenting with acute abdominal pain and having CT imaging features of bowel ischemia who responded well to immunosuppressive therapy. The aim of this work is to familiarize health professionals with possibility and imaging features of mesenteric vasculitis. PMID- 28712194 TI - Blocked Coronary Artery Due To Coronary Spasm Treated With Stent Insertion: A Sub Optimal Result? AB - Myocardial infarction (MI) is an extremely common cause of chest pain. MI can be acute with ST elevation (STEMI) or non-STEMI (NSTEMI). Coronary artery spasm can be severe enough to cause occlusion of the coronary arteries particularly with an exaggerated response in regions of coronary atheroma and plaque ulceration. It is not uncommon for coronary spasm to be mistaken with acute thrombotic occlusion of the coronary artery. We describe a case of a 42-year old man with known cardiac risk factors presents with chest pain for few hours to a tertiary centre hospital. A coronary angiogram showed occlusion of the right epicardial coronary artery with a severe spasm at the level of the atheroma. The initial coronary stent which was deformed because of intense pressure of spasm required another stent to be placed within the first stent. Diltiazem and Nitrates were started as secondary prevention treatment to reduce effect of coronary spasm. The patient made an uneventful recovery and was discharged home with no sequelae over the next 3 years follow up. PMID- 28712195 TI - Giant Cementoblastoma Of Left Maxilla Involving A Deciduous Molar. AB - Cementoblastoma is a relatively rare benign tumour. The clinicopathologic features, radiological findings, treatment and prognosis are reported here in a 10-year-old girl who presented to us from Afghanistan. The tumor was managed surgically and the histopathology confirmed the diagnosis of cementoblastoma. There was no evidence of recurrence at one year of follow up. PMID- 28712196 TI - Small Gut Volvulus, A Rare Twist, In The Setting Of An Even Rarer Entity; Multiple Giant Jejuno Ileal Diverticula. AB - Small gut volvulus with multiple Jejuno-ileal diverticulosis is an unusual pathology of the small intestine with a scarce number of cases reported so far. It usually goes unnoticed because it is often asymptomatic but complications like diverticulitis, perforation, bleeding or intestinal obstruction can occur in 10 30% of the cases. Mechanical obstruction, if it occurs, can be caused by adhesions or stenosis due to diverticulitis, intussusception at the site of the diverticulum and volvulus of the segment containing the diverticula. Acute volvulus of the small bowel is a serious abdominal emergency that poses a difficulty in diagnosis and delayed operative intervention can lead to dire consequences. We herein report the case of a 42-yearold man presented at the emergency department with acute abdominal pain, absolute constipation and vomiting. Preoperative investigations followed by laparotomy revealed small gut volvulus and multiple giant jejunal and ileal diverticula. PMID- 28712197 TI - Ipsilateral Renal Agenesis With Megaureter, Blind End Proximal Ureter And Ureterocele In An Adult. AB - We reporting unilateral renal agenesis with ipsilateral ureterocoele, mega ureter and blind end proximal ureter in same patient first time as case report and has not been so far reported in local or international literature. Ultrasound, CT scan and intravenous pyelography performed which confirm the case. Patient presented with left lumber and pelvic pain on and off and history of recurrent urinary tract infection. PMID- 28712198 TI - Pancreatic Duct Stones. AB - pancreatitis appears to exist in the presence of such calculi upon radiology. Having said that, pancreatic ductal stone due to biliary causes (origin), in face of acute pancreatitis, is rare. To the best of our knowledge this was the first case of its kind presented to our hospital in recent past. A 25-year-old female presented to the emergency department of our hospital with an acute episode of pancreatitis. Computerized tomography (CT) scan, endoscopic retrograde cholangiopancreatography (ERCP) & magnetic resonance cholangiopancreatography (MRCP) concluded acute pancreatitis (AP) with dilated main pancreatic duct left side branches and intra ductal calculi. The findings were not suggestive of any chronic pancreatitis. Conservative treatment was given for the episodic attack of AP. After the episode resolved, an exploration and extraction of the pancreatic ductal calculus was performed successfully. The pancreatic duct stones were removed by lateral pancreaticojejunostomy (partington-rochelle procedure). The patient made a remarkable recovery after the procedure and was perfectly healthy and well-oriented in time and space at 4-months follow up. Acute pancreatitis is an inflammatory condition of pancreas, when, associated with pancreatic duct stones a lateral pancreaticojejunostomy is done, which, results in better outcomes decreasing the mortality and morbidity. Acute pancreatitis due to ductal calculi is rare for which extraction is safe after resolution of the episode of AP. Studies need to be carried out to look for the outcome and the effectiveness of the procedure, when, specifically and specially done for this condition. PMID- 28712199 TI - Multimodality Imaging Approach For The Early Diagnosis Boerhaave Syndrome. AB - Boerhaave's syndrome is a spontaneous transmural rupture or perforation of the oesophagus or post-emesis oesophageal rupture. Boerhaave's syndrome has a high risk of morbidity and mortality, and early, definitive diagnosis leading to prompt management improves outcomes. Definitive diagnosis of this syndrome is made with imaging, including x-ray, USG and computed tomography Scan. This is a case of a 50-year male with history of sudden onset of epigastric pain after an episode of forceful emesis was referred for Ultrasound (USG) abdomen. His USG examination demonstrated fluid collection with internal free floating and linear echoes in left pleural cavity consistent with hemo-pneumothorax his further imaging workup was done with suspicious of Boerhaave's Syndrome which conformed the suspected diagnosis. PMID- 28712200 TI - Pregnancy With Bilateral Metastatic Ovarian Tumour. AB - Metastatic ovarian tumours are extremely rare. The commonest primary site is usually stomach and the metastasis from this site is termed as krukenberg tumour. It accounts for 1-2% of malignant ovarian tumours. We present a case of 14 weeks' pregnancy with metastatic bilateral malignant ovarian tumour is presented. Diagnosis was made on ultrasound. Tumour markers were insignificant. Patient underwent staging laparotomy with total abdominal hysterectomy and bilateral salpingo oophorectomy and partial omentectomy. She also had haematemesis. Endoscopy revealed suspicious growth in stomach, but biopsy report excluded it. Case was handed over to the oncologist for further management. PMID- 28712201 TI - Case Of Xanthogranulomatous Oophoritis. AB - Xanthogranulomatous inflammation is characterized by destruction of the tissues of the organ involved and replacement by chronic inflammatory cells such as lymphocytes, plasma cells, occasional neutrophils with or without multinucleated or Touton giant cells. Exact aetiology is not known but the theory of infection with organisms like Proteus, E coli, and Bacteroides fragilis is most popular. Xanthogranulomatous inflammation of the female genital tract is not common and usually involves the endometrium; however, xanthogranulomatous inflammation of the ovaries is a rare entity. PMID- 28712202 TI - Stillbirths: What Can Be Done To Confront An Invisible Public Health Problem In Pakistan? AB - Pakistan has been ranked highest and appears worst in stillbirths' rate according to the recent global estimates. Reasons could be manifold; socio-cultural, health system related country specific, and some of these of course deja vu, i.e., the biomedical causes. Yet, a fresh stocktaking is necessary to understand the complex phenomenon in a country, awfully affected by this menace. Maternal, neonatal and child health program needs to be informed and geared up toward addressing the actual reasons behind this heavy toll of stillbirths in Pakistan. Maternal health indicators would never be improved, if the issue of stillbirths is not stalled at the earliest. Besides known medical reasons, this account attempts to document the health systems related factors, and more so the social determinants behind the whole scenario, so that appropriate and customized interventions could be suggested, developed and implemented. This paper will be a piece of evidence for policy corridors, program managers, development partners, non-governmental organizations, public health institutions, students, and researchers to enhance their understanding of a major public health problem, and to recognize the strengths and opportunities in the health system of Pakistan to cope with this challenge. PMID- 28712203 TI - Now Or Never: "Public Health Issues Requiring Urgent Attention". AB - Pakistan is a developing country and most of its population is based in rural areas. Over the last two decades' significant changes have occurred in the health system in an attempt to improve the health care in general with a particular emphasis in the health of people living in rural areas. Despite these efforts, significant development and planning is required to improve the health of nation. Undoubtedly ministry of health has taken practical steps in tacking some serious health issues such as polio. However, the fact remains that there are a number of public health issues which if not addressed on an urgent basis, there is a great danger that the implications would be huge with unbearable consequences. Among various issues, only those are discussed here which are in a dire need of attention of government, ministry of health, department of public health, disaster management authorities, health education authorities, health institutions and health professionals. PMID- 28712204 TI - Middle East Respiratory Syndrome Corona Virus Alert Verification In Mirpur, Azad Kashmir. AB - BACKGROUND: Middle East Respiratory-Corona virus (MERS-CoV), SARS like virus, identified in September 2012 in Middle-East. February 2013, an elderly man, who visited Pakistan and KSA, was confirmed as MRS-CoV in UK. A team visited Mirpur to assess current and past SARI trends in major indoor facilities, to explore possible contact of the patient with known or suspected SARI case during his stay in Pakistan and enlist close contacts. METHODS: Review of indoor records in hospitals, interviews with relatives & physicians and active contact tracing using operational case definition. RESULTS: Arrived on 16th December 2012, mostly stayed at daughter's house, visited by relatives, on 19th January, left for KSA accompanied by daughter, developed fever with chills and body aches on 23rd January. On 28th January, arrived London, admitted at City Hospital, Birmingham, subsequently shifted to Manchester Hospital on 6th February 2013, diagnosed as MERS-CoV, expired on 19th February. His son having underlying condition, confirmed as MERS-CoV on 13th February, and expired on 17th February. Daughter developed mild respiratory symptoms, confirmed as MERS-CoV on 16th Feb and recovered. Both have been infected by the Index case. The review of indoor record did not reveal any significant change in SARI trends, the cumulative number of cases for the January -February 2012 and 2013 was 291 and 294 respectively indicating no difference. During his stay in Pakistan, he didn't meet any suspected/ill person. Close contacts were observed and investigated for MERS-CoV, all remained healthy. CONCLUSIONS: The available evidence does not suggest any MERS-CoV transmission to, or from the patient in Pakistan. PMID- 28712205 TI - Cologuard test: A Possible Alternate To Colonoscopy? PMID- 28712206 TI - Spectrum Of Brain Abnormalities Detected On Whole Body F-18 FDG PET/CT Scan. AB - Positron emission tomography (PET) with integrated computed tomography (CT) is a unique modality to noninvasively scan the whole body for diagnosing, staging and assessing response to therapy in various benign and malignant diseases. 18F fluorodeoxyglucose (FDG) is the most commonly used radiotracer for PET/CT imaging in cancer patients. FDG is a glucose analogue which is the predominant substrate for brain metabolism. As the brain cells are obligate glucose consumers, the knowledge of physiologic radiotracer uptake within the brain is imperative for correct interpretation of abnormal sites of metabolism. Over 10,000 PET/CT scans have been performed at our centre in a 5 years' period. A spectrum of brain abnormalities, both benign and malignant, detected in cancer patients undergoing whole body 18F FDG PET/CT imaging has been compiled. PMID- 28712207 TI - Malignant Melanoma Of Oral Cavity. PMID- 28712208 TI - Crimean Congo Hemorrhagic Fever: A Looming Threat. PMID- 28712209 TI - Localization Of Accessory Pathway In Patients With Wolff-Parkinson-White Syndrome From Surface Ecg Using Arruda Algorithm. AB - BACKGROUND: To ablate accessory pathway successfully and conveniently, accurate localization of the pathway is needed. Electrophysiologists use different algorithms before taking the patients to the electrophysiology (EP) laboratory to plan the intervention accordingly. In this study, we used Arruda algorithm to locate the accessory pathway. The objective of the study was to determine the accuracy of the Arruda algorithm for locating the pathway on surface ECG. METHODS: It was a cross-sectional observational study conducted from January 2014 to January 2016 in the electrophysiology department of Hayat Abad Medical Complex Peshawar Pakistan. A total of fifty nine (n=59) consecutive patients of both genders between age 14-60 years presented with WPW syndrome (Symptomatic tachycardia with delta wave on surface ECG) were included in the study. Patient's electrocardiogram (ECG) before taking patients to laboratory was analysed on Arruda algorithm. Standard four wires protocol was used for EP study before ablation. Once the findings were confirmed the pathway was ablated as per standard guidelines. RESULTS: A total of fifty nine (n=59) patients between the age 14-60 years were included in the study. Cumulative mean age was 31.5 years+/ 12.5 SD. There were 56.4% (n=31) males with mean age 28.2 years+/-10.2 SD and 43.6% (n=24) were females with mean age 35.9 years+/-14.0 SD. Arruda algorithm was found to be accurate in predicting the exact accessory pathway (AP) in 83.6% (n=46) cases. Among all inaccurate predictions (n=9), Arruda inaccurately predicted two third (n=6; 66.7%) pathways towards right side (right posteroseptal, right posterolateral and right antrolateral). CONCLUSIONS: Arruda algorithm was found highly accurate in predicting accessory pathway before ablation. PMID- 28712210 TI - In-Vitro Comparison Of Micro-Leakage Between Nanocomposite And Microhybrid Composite In Class V Cavities Treated With The Self-Etch Technique. AB - BACKGROUND: When a light cure composite resin is used to restore a class V lesion, certain stresses are generated at the tooth-restoration interface. If these stresses exceed the bond strength of the restorative material, microscopic gaps are formed which eventually cause micro-leakage at the tooth-restoration interface. The objective of the present study was to compare the micro-leakage values at the tooth-restoration interface using dye penetration method between a Nano filled and a Micro hybrid light cured composite resin in class V cavities using the self-etch technique. METHODS: Sixty class V cavities were made coronal to the cemento-enamel junction in the extracted premolars. These were then randomly divided into two study groups. Group A: Self-etch; filled with P-60 (microhybrid) n=30. Group B: Self-etch; filled with Z-350 (nano-filled) n=30. Specimens were subjected to thermo-cycling at 5-55 degrees C+/-2 degrees C with a 30 seconds dwell time. After which they were stained with 2% methylene blue. Later, sectioned bucco-lingually and examined using a stereo microscope (magnification X4) at the occlusal, axial and gingival surfaces. Micro-leakage around the toothrestoration interface was assessed by using the degree of dye penetration in millimetres. RESULTS: There was 100% micro leakage seen at both the occlusal and gingival surfaces when using the P-60 composite. With the Z-350 composite 84% occlusal and 88% of the gingival surfaces exhibited microleakage.. CONCLUSIONS: With respect to micro-leakage in class V cavities, Z-350 was found to be a superior restorative material compared to P-60 on the occlusal surface. Overall, there is no statistically significant difference in the micro-leakage exhibited by the two restorative materials in class V preparations subjected to self-etch protocol. PMID- 28712211 TI - Deep Bite Malocclusion: Exploration Of The Skeletal And Dental Factors. AB - BACKGROUND: Correction of deep bite is crucial for maintenance of dental hard and soft tissue structures and for prevention of temporomandibular joint disorders. Exploration of underlying skeletal and dental factors is essential for efficient and individualized treatment planning. To date etiological factors of dental and skeletal deep bite have not been explored in Pakistani orthodontic patients. The objectives of this study were to explore frequencies of dental and skeletal etiological factors in deep bite patients and to determine correlations amongst dental and skeletal etiological factors of deep bite. METHODS: The study included a total of 113 subjects (males=35; females=78) with no craniofacial syndromes or prior orthodontic treatment. Pre-treatment orthodontic records were used to evaluate various dental and skeletal parameters. Descriptive statistics of each parameter were calculated. The various study parameters were correlated using Pearson's Correlation. RESULTS: Deep curve of Spee was most frequently seen factor of dental deep bite (72.6%), followed by increased coronal length of upper incisors (28.3%), retroclined upper incisors (17.7%), retroclined lower incisors (8%) and increased coronal length of lower incisors (5.3%). Decreased gonial angle was most commonly found factor of skeletal deep bite (43.4%), followed by decreased mandibular plane angle (27.4%) and maxillary plane's clockwise rotation (26.5%). Frankfort mandibular plane angle and gonial angle showed a strong positive correlation (r=0.66, p=0.000). CONCLUSIONS: Reduced gonial angle is most frequently seen skeletal factor, signifying the importance of angulation and growth of ramus in development of deep bite. Deep curve of Spee is most frequently seen dental etiological component in deep bite subjects, hence signifying the importance of intruding the lower anterior teeth. PMID- 28712212 TI - Comparison Of Efficacy Of Phenytoin And Levetiracetam For Prevention Of Early Post Traumatic Seizures. AB - BACKGROUND: The incidence of early post-traumatic seizures after civilian traumatic brain injury ranges 4-25%. The control of early post-traumatic seizure is mandatory because these acute insults may add secondary damage to the already damaged brain with poor outcome. Prophylactic use of anti-epileptic drugs have been found to be have variable efficacy against early post-traumatic seizures. The objective of this study was to compare the efficacy of Phenytion and Levetiracetam in prevention of early post-traumatic seizures in moderate to severe traumatic brain injury. METHODS: This randomized controlled trial was conducted in department of Neurosurgery, Ayub Medical College, Abbottabad from March, 2012 to March 2013. The patients with moderate to severe head injury were randomly allocated in two groups. Patients in group A were given phenytoin and patients in group B were given Levetiracetam. Patients were followed for one week to detect efficacy of drug in terms of early post traumatic seizures. RESULTS: The 154 patients included in the study were equally divided into two groups. Out of 154 patients 115 (74.7%) were male while 29 (25.3%) were females. Age of patients ranges from 7-48 (24.15+/-9.56) years. Ninety one (59.1%) patients had moderate head injury while 63 (40.9%) patients had severe head injury. Phenytoin was effective in preventing early post traumatic seizures in 73 (94.8%) patients whereas Levetiracetam effectively controlled seizures in 70 (90.95%) cases (p value of .348). CONCLUSIONS: There is no statistically significant difference in the efficacy of Phenytoin and Levetiracetam in prophylaxis of early posttraumatic seizures in cases of moderate to severe traumatic brain injury. PMID- 28712213 TI - Laparoscopy In Unexplained Abdominal Pain: Surgeon's Perspective. AB - BACKGROUND: Unexplained abdominal pain is a common but difficult presenting feature faced by the clinicians. Such patients can undergo a number of investigations with failure to reach any diagnosis. The objective of this study was to evaluate the use of laparoscopy in the diagnosis and management of patients with unexplained abdominal pain. METHODS: This cross-sectional study was conducted at Pakistan Institute of Medical Sciences Islamabad from January 2009 to December 2013. This study included 91 patients of unexplained abdominal pain not diagnosed by routine clinical examination and investigations. These patients were subjected to diagnostic laparoscopy for evaluation of their conditions and to confirm the diagnosis. These patients presented 43% of patients undergoing investigations for abdominal pain. Patients diagnosed with gynaecological problems were excluded to see surgeon's perspective. The findings and the outcomes of the laparoscopy were recorded and data was analyzed. RESULTS: Unexplained abdominal pain is common in females than in males. The most common laparoscopic findings were abdominal tuberculosis followed by appendicitis. Ninety percent patients achieved pain relief after laparoscopic intervention. CONCLUSIONS: Laparoscopy is both beneficial and safe in majority of patients with unexplained abdominal pain. General surgeons should acquire training and experience in laparoscopic surgery to provide maximum benefit to these difficult patients. PMID- 28712214 TI - Early Onset Diabetes - Genetic And Hormonal Analysis In Pakistani Population. AB - BACKGROUND: Mitochondrial DNA mutation and hormonal imbalance is involved in the pathogenesis of early onset diabetes but data is lacking in Pakistani population. The study was planned to delineate the clinical presentation of early onset diabetes with possible hormonal and genetic etiological factors and aascertain the possible etiological role of insulin and glucagon in these patients either on oral hypoglycaemic or subcutaneous insulin therapy. METHODS: Retrospective, analytical case control study with conventional sampling technique carried at Centre for Research in Experimental and Applied Medicine (CREAM) affiliated with the department of Biochemistry and Molecular Biology, Army Medical College Rawalpindi from Dec 2006 to July 2011. Study included the patients (20-35 years of age) with early onset diabetes on oral hypoglycemic (n=240), insulin therapy (n=280), and compared with non-diabetic healthy controls (n=150). A fragment surrounding tRNALeu (UUR) gene was amplified by AmpliTaq from mtDNA which was extracted from peripheral blood leucocytes. Then it was subjected to restriction endonucleases, ApaI for A3242G mutation and HaeIII for G3316A mutation detection. Plasma glucose, glycosylated Hb, osmolality, insulin and glucagon levels along with ABGs analysis was also done. RESULTS: Non diabetic controls comprised of 51% males and 49% females, diabetics on oral hypoglycemic 60% males and 40 % females and on insulin therapy 54% males and 46% females. Insulin dependent diabetics had statistically significant hyperglucagonemia, acidemia and bicarbonate deficit. MtDNA A3242G and G3316A mutations were not detected. CONCLUSIONS: relative hyperglucagonemia and acidemia in Insulin dependent diabetics was a potent threat leading to DKA. The absence of two mtDNA mutations in ND1 gene rules out the possibility of involvement of these mutations in early onset diabetes in Pakistani population. PMID- 28712215 TI - Effect Of Internal Mammary Artery Harvesting With And Without Pleurotomy On Respiratory Complications In Patients Undergoing Coronary Artery Bypass Grafting. AB - BACKGROUND: Respiratory problems are one of the major issues faced by cardiovascular surgeons, which increase morbidity and mortality among patients undergoing coronary artery bypass grafting (CABG). It is possible to harvest the left internal mammary artery (LIMA) without opening the left pleura; however this cannot be reliably achieved in all cases due to intimate anatomical relationship. This study was designed to evaluate the effect of internal mammary artery harvesting with and without pleurotomy on respiratory complications in patients undergoing coronary artery bypass grafting. METHODS: In this observational study 90 patients who underwent coronary artery bypass surgery were included by review of records. Patients were stratified into two groups according to surgical procedures, i.e., Internal Mammary artery harvesting with pleurotomy; (WP Group) (n=45) and with extra pleural harvesting technique; (EP Group) (n=45). Inclusion criteria were elective coronary artery bypass grafting, age over 18 years, willingness to be randomly assigned, provision of informed consent. Exclusion criteria were chronic obstructive pulmonary disease (COPD) or skeletal abnormalities that caused pulmonary restriction. Only the first 30 days postoperative outcome was studied. Data was analysed using SPSS version 21. RESULTS: The demographic characteristics in terms of age and gender were comparable in study groups. The preoperative clinical presentation and medical history were also found similar. The hospital stay was significantly longer in WP Group than EP Group patients (7.2 vs 6.1 days, p<0.005). Moreover, post-operative morbidity was more prevalent in WP group 10 (22.2%) than EP Group 3 (66%) (p<0.03). In WP Group more respiratory complications were observed; 2 (4.4%) patients had dry cough and atelectasis, 1 (2.2%) patient experienced pleural effusion, 3 (6.6%) had bronchospasm while 1 (2.2%) patient each had sternal dehiscence and bleeding, however, these did not differ significantly among study groups. CONCLUSIONS: Respiratory complications were more frequent in patients undergoing Internal Mammary artery harvesting with pleurotomy compared to those managed extra pleural harvesting. PMID- 28712216 TI - Role Of Clamping Tube Thoracostomy Prior To Removal In Non-Cardiac Thoracic Trauma. AB - BACKGROUND: The frequently encountered thoracic trauma in surgical emergencies is a major cause of mortality and morbidity. Eighty percent of thoracic trauma can be managed by simple insertion of tube thoracostomy. Though guidelines for insertion are comprehensively explained in literature, an ideal algorithm for discontinuation is not available. A standard and safe defined protocol would eliminate hesitancy in confident removal among general surgeons. The objective of this study was to determine role of clamping trial prior to removal in terms of frequency of recurrent pneumothorax. METHODS: This study was conducted in department of Surgery Combined military hospital/Military Hospital Rawalpindi from April 2013 to March 2014. Total 180 patients with blunt or penetrating thoracic trauma were included in the study. Chest tube (28-36 Fr) was inserted in Trauma centre under strict asepsis. Tubes were then connected to under water seal for minimum six hours. Patients were randomly divided in two equal groups (90 in each). In Group A, Clamping trial was given before attempting removal while in Group B, tube was removed immediately without clamping trial. Patients of both groups were observed two hourly for development of recurrent pneumothorax. Data was analysed using SPSS-18. RESULTS: The comparison of frequency of recurrent pneumothorax in Group A (9 patients, 10%) and in Group B (4 patients, 4.5%) was not found to be statistically significant. (p-value 2.073). CONCLUSIONS: Clamping trial is unnecessary prior to removal of tube thoracostomy in blunt and penetrating non-cardiac thoracic trauma in terms of recurrent pneumothorax. PMID- 28712217 TI - Bacterial Profile And Antibiogram Of Otitis Media Among Children In Yemen. AB - BACKGROUND: Otitis media is a worldwide disease and is higher in developing countries, particularly among the low socioeconomic levels of the society. The aim of the study is to identify the bacterial etiologic agents of otitis media (OM) and their antibiotics sensitivity patterns among children in Specialized Sam Paediatric Centre (SSPC) and Al-Mamoon Diagnostic Medical Centre (AMDC), in Sana'a city. METHODS: A cross-sectional study was done in SSPC and AMDC from January to October 2015. A total of 150 patients who had ear pus discharge and clinically diagnosed as OM were included in this study. Samples of ear discharge were collected, bacteriologically tested by standard methods and bacterial strains were identified using biochemical testes. Questionnaire was administered on patients or parents that cover the age, gender and the duration of symptoms. RESULTS: A total of 150 children with OM, their age ranged from below 1-15 years (85 males and 65 females). Children less than 5 years of age were 100 and 50 with age ranged from 6-15 years. Bacterial isolates were Staphylococcus aureus (44%), Pseudomonas aeruginosa (12.67%), Enterococcus species (12.67%), and Streptococcus pneumonia (10%). Bacterial culture revealed that, Staphylococcus aureus sensitivity to cefotaxime and azithromycin was 98%, to amoxicillin-clavulanic acid was 92% and it was 85% to gentamicin. Pseudomonas aeruginosa sensitivity to cefotaxime was 100%, to azithromycin and gentamicin was 98% and it was 80% to cefaclor. Enterococcus sensitivity to amoxicillin-clavulanic acid was 85%, to azithromycin was 80%, and it was 75% to cefotaxime, and gentamicin. CONCLUSIONS: The most common microorganism isolated was Staphylococcus aureus followed by Pseudomonas, Enterococcus species, and then Streptococcus pneumonia. The most effective antibiotics were cefotaxime, amoxicillin-clavulanic acid, azithromycin and gentamicin. Therefore, knowledge of antimicrobial susceptibility test is essential for guiding appropriate antibacterial therapy. PMID- 28712218 TI - Predictive Value Of Ocular Trauma Score In Open Globe Combat Eye Injuries. AB - BACKGROUND: Prediction of final visual outcome in ocular injuries is of paramount importance and various prognostic models have been proposed to predict final visual outcome. The objective of this study was to validate the predictive value of ocular trauma score (OTS) in patients with combat related open globe injuries and to evaluate the factors affecting the final visual outcome. METHODS: Data of 93 patients admitted in AFIO Rawalpindi between Jan 2010 to June 2014 with combat related open globe ocular injuries was analysed. Initial and final best corrected visual acuity (BCVA) was categorized as No Light Perception (NLP), Light Perception (LP) to Hand Movement (HM), 1/200-19/200, 20/200-20/50, and >=20/40. OTS was calculated for each eye by assigning numerical raw points to six variables and then scores were stratified into five OTS categories. RESULTS: Mean age of study population was 28.77+/-8.37 years. Presenting visual acuity was <20/200 (6/60) in 103 (96.23%) eyes. However, final BCVA of >=20/40 (6/12) was achieved in 18 (16.82%) eyes, while 72 (67.28%) eyes had final BCVA of <20/200 (6/60). Final visual outcome in our study were similar to those in OTS study, except for NLP in category 1 (81% vs. 74%) and >=20/40 in category 3 (30% vs. 41%). The OTS model predicted visual survival (LP or better) with a sensitivity of 94.80% and predicted no vision (NLP) with a specificity of 100%. CONCLUSIONS: OTS is a reliable tool for assessment of ocular injuries and predicting final visual outcome at the outset. PMID- 28712219 TI - Association Of Surfactant Protein-D With Obesity. AB - BACKGROUND: Obesity is associated with inflammatory diseases and obese individual's poses high risk for infections. Surfactant protein D (SP-D) is an important regulator of immunity and inflammation. Latest studies have suggested that it is also involved in lipid homeostasis and obese subjects have decrease concentration of SP-D as compared to normal weight peoples. The aim of the current study was to elucidate the relationship among serum SP-D and BMI. METHODS: This cross sectional study was performed at Dow University of health sciences (DUHS), Karachi. We analysed 90 obese and non-obese subjects for serum SP-D concentration. SP-D was estimated by ELISA. Data was analysed by SPSS 16. Mean SP-D level and demographical variables between the groups were compared by t test, Associations of SP-D with BMI investigated by regression analysis. RESULTS: obese subjects have significant lower levels of Serum SP-D than non-obese and negatively associated with BMI in both genders (p=0.000). CONCLUSIONS: This study concluded that obese subjects have lower concentration of SP-D as compare to non obese and there is an inverse association between the SP-D and BMI. PMID- 28712220 TI - Effect Of Medical Waste Management Trainings On Behavior Change Among Doctors Versus Nurses And Paramedical Staff In Pakistan. AB - BACKGROUND: Healthcare waste management is a neglected issue in hospitals of developing countries due to poor practices among health staff. This study was aimed to determine the differences in knowledge, attitude and practices of physicians versus nursing and paramedical staff about standard health care waste management (HCWM). METHODS: This quasi-experimental study was conducted among healthcare workers of the two tertiary care hospitals in Rawalpindi. A total of 138 hospital workers in intervention and 137 in control hospital were given training on HCWM. Subjects were followed up at one year and after 18 months of the intervention. RESULTS: We found that nursing and paramedical staff was more knowledgeable and compliant with the HCWM standards, knowledge and practices as compared to physicians. A higher proportion of nursing and paramedical staff was able to retain more of high level of knowledge but more of the doctors had achieved and retained positive attitudes towards HCWM standards after the training. More of nursing and paramedical staff also had good HCWM practices; both at first as well as second follow up. CONCLUSIONS: As nursing and paramedical staff was more knowledgeable and practiced optimum standards they needed to be rewarded adequately and given further regular trainings to help them maintain their knowledge and best practices about HCWM. As HCWM and patient safety standards keep on changing regularly, the hospital workers especially doctors need to be focused to comply with the standard practices in hospitals. PMID- 28712221 TI - Frequency And Pattern Of Bone Marrow Involvement Among Patients With Non Hodgkin Lymphoma. AB - BACKGROUND: Non-Hodgkin lymphoma (NHLs) are a heterogeneous group of lymphoid neoplasms, characterized by an irregular pattern of spread and may present with extranodal involvement This study was conducted to determine the frequency and pattern of Bone marrow involvement on trephine biopsy in cases of Non-Hodgkin lymphoma (NHL). METHODS: This cross sectional study was conducted in Pathology department of Fauji Foundation Hospital (FFH)/Foundation University medical college (FUMC) Rawalpindi, from14th December 2010 to 14th December 2011. One hundred and six patients with histopathologically confirmed Non-Hodgkin lymphoma on lymph node (LN) biopsy, who had not received any chemotherapy were selected and Bone Marrow (BM) trephine biopsies for staging were performed on them. RESULTS: Out of one hundred and six patients, forty five (42.5%) were diagnosed to have Bone Marrow involvement on staging. The most common pattern was diffuse, i.e., 44.44%, followed by the interstitial infiltrate in 28.89%, focal and mixed constituted 11.11% each, and paratrabecular pattern was found in 4.44%. CONCLUSIONS: This study highlights the high incidence of involvement and diffuse pattern in the Bone marrow biopsies of newly diagnosed Non-Hodgkin lymphoma, both of which indicate poor prognosis.. PMID- 28712222 TI - Effectiveness And Acceptability Of Ready-To-Use Therapuetic Foods Among Malnourished Children In A Tertiary Care Hospital. AB - BACKGROUND: Ready-to-use-therapeutic foods (RUTF) are an important component of the effective outpatient treatment of severe wasting because most of the child deaths in the world especially in developing countries is due to malnutrition. The objective of the study was to evaluate the effectiveness and acceptability of ready to use therapeutic food among malnourished children in a tertiary care hospital. METHODS: An observational exploratory study based on sixty subjects with 3-120 months of age, malnourished children were chosen by universal sampling from Children Hospital Lahore, Pakistan, during the time period 1st September 2012 to 30th November 2012 with the approval of ethical committee. The study tool for investigation was a well-structured questionnaire. RESULTS: The highest proportion of malnourished children belonged to urban areas (71.67%) and age group <24 months (65%).The effect of RUTF on weight for height and weight for age Z score from baseline to the end of follow-up was statistically significant (Paired sample t-test) (p=0.000, 0.000) but there was no significant effect of RUTF on height for age (p-value=0.14).The acceptance of food among patients was good, the proportion of patient was higher who consumed ready to use therapeutic food easily (70%), percentage of vomiting (16.7%) and complaints of diarrhoea (46.7%) after taking RUTF was less in patients. All mothers were satisfied from ready to use therapeutic foods (100%). CONCLUSIONS: Malnourished children gained weight after the short term supplementation of ready to use therapeutic food but had no significant effect on height of the patients. Its acceptability in term of taste, amount consumes and demand was good. Mother's perception was also satisfactory regarding these foods. PMID- 28712223 TI - Detrimental Complications Of Meconium Aspiration Syndrome And Their Impact On Outcome. AB - BACKGROUND: Meconium aspiration syndrome (MAS) is respiratory distress in an infant born through meconium stained amniotic fluid (MSAF) whose signs cannot be otherwise explained. MAS is associated with different complications. Many studies have been conducted in developed world to find the outcome associated with MAS but data from developing countries is lacking. Present study was conducted to determine the impact of chemical pneumonitis, pulmonary hypertension (PHN) and air leak on outcome of new-borns with MAS. METHODS: This cross sectional descriptive study was conducted in a tertiary care Neonatology unit. The babies diagnosed with MAS were included in the study. All patients were monitored for development of complications. Outcome in terms of mortality was recorded. Outcome was compared by chisquare test and p-value <0.05 is considered significant. RESULTS: Seventy two babies were included in the study. Mean gestation was 37+/ 0.56 weeks and birth weight was 2.87+/-0.49 kg. Male to female ratio was 1.57:1 and mean age of admission was 9.59+/-5.27 hours. Chemical pneumonitis, PHN and chemical pneumonitis with PHN were observed in 23.6%, 20.8% and 26.4% neonates respectively. Mortality rate was 19.44%. The mortality was highest in babies having chemical pneumonitis with PHN (p-value=0.013) followed by chemical pneumonitis group (p-value=0.02) and PHN group (p-value=0.032). CONCLUSIONS: About three fourth babies with MAS developed one or more complications. Mortality is significantly increases with the development of complications so as more the complications more is the mortality. PMID- 28712224 TI - Forecasting Health Indicators Of Pakistan. AB - BACKGROUND: Forecasting of health indicators is of great importance for health policy makers. This study is aimed to forecast some important health indicators like crude death rate (CDR), crude birth rate (CBR), and infant mortality rate (IMR) and total fertility rate (TFR) of Pakistan. METHODS: In this retrolective study, annual data of these indicators for years 1984-2010 have been used. The simple linear regression model with time as independent variable has been used to forecast these health indicators. RESULTS: The within-sample forecast results are close enough to the actual values. All the forecast values of the stated indicators tend to decrease with time. The forecast values of CDR, CBR, IMR and TFR for year 2020 are 12.85, 5.61, 43.61 and 0.93, respectively. CONCLUSIONS: Although the forecast values show an improvement in health indicators of Pakistan but the IMR is expected to remain high even in 2020, a concern for the health policy makers. PMID- 28712225 TI - Histopathological Pattern Of Soft Tissues Tumors And Tumour Like Lesions In The Pathology Department Of Lady Reading Hospital Peshawar, Pakistan. AB - BACKGROUND: Soft tissues tumours are tumours of mesenchymal origin excluding epithelial, skeletal tissue, reticuloendothelial system, brain coverings and solid viscera of the body. The objective of this study was to know the histopathological pattern of soft tissues tumours in the Pathology Department of Lady Reading Hospital Peshawar Khyber Pakhtunkhwa Pakistan. METHODS: This descriptive study was conducted on retrospective data from January 2009 to December 2013. All the soft tissues biopsy specimens were received in 10% formalin, labelled, gross performed, sections processed in alcohol, xylene, wax, block prepared, frozen, microtome sections taken and processed for H&E staining, mounted and reported by a Histopathologist. The inclusion criteria were any sufficient soft tissue tumour biopsy specimen of any age, sex, location in body whereas the exclusion criteria were autolysed biopsy specimen. A minimum of four and maximum of eight sections and 5 micron thick were taken from each specimen. RESULTS: A total of 267 soft tissues tumours biopsy specimens were received in the pathology laboratory with age range of 1-75 years, with mean age of 30.68+/ 17.71 years. Male to female ratio was 1.13:1. Amongst the total, benign tumours were 176 (65.91%). Haemangioma, 73 (27.3%) was the commonest tumours followed by lipomas 41 (15.4%) cases. Amongst the total malignant tumours, i.e., 91 (34.08%), rhabdomyosarcoma, 35 (13.1%) was the commonest tumour followed by angiosarcoma 14 (5.2%) cases. CONCLUSIONS: Haemangioma is the commonest benign tumour and rhabdomyosarcoma is the commonest malignant tumour in this study. PMID- 28712226 TI - Spontaneous Perforation Of Bile Duct, Clinical Presentation, Laboratory Work Up, Treatment And Outcome. AB - BACKGROUND: Spontaneous perforation of bile duct (SPBD) is a rare and often misdiagnosed entity. Though rare, it is the second most common surgical cause of jaundice in infants, after biliary atresia. This study was planned to determine the clinical presentation, study different diagnostic modalities, treatment and outcome of patients with spontaneous perforation of bile duct. METHODS: This descriptive case series, comprising 22 patients with spontaneous perforation of bile duct over a period of 24 months. Clinical presentation, biochemical abnormalities, imaging details, treatment options and outcome were studied. RESULTS: Total 22 patients (12 Males and 10 Females) between ages of 1.5-36 months were studied. Associated anatomical defects included choledochal cyst in 7 (31.8%) while acquired biliary atresia in 1 (4.5%). Elevated liver enzymes (ALT and AST) were present in 16 patients (72.7%) and 5 (22.7%) had bilirubin above 3 mg/dl. Coagulopathy was seen in 8 (36.6%) patients. Abdominal USG showed presence of ascites in all 22 (100%), hydrocele in 2 (9.0%), inguinal hernia in 1 (4.5%), choledochal cyst in 7 (31.8%) and atretic gall bladder suggestive of acquired biliary atresia in one (4.5%) patient. HIDA scan was diagnostic in all 17 (77.27%) in which it was performed. MRCP was done in 3 (13.6%) patients. Mortality frequency was 3/22 (13.6%); one died of post-surgical sepsis second one was cirrhotic at time of presentation and didn't make It. Two were lost to follow up one which died at home while we lost contact with fourth patient. CONCLUSIONS: Spontaneous perforation of bile duct can present and should be suspected as an important cause of neonatal biliary ascites or peritonitis. Most patients can be managed with intravenous antibiotics, percutaneous drainage and ttube insertion while patients with choledochal cysts required cholecystectomy with roux en y choledochjejunostomy. Timely recognition and intervention is associated with favourable outcome. PMID- 28712227 TI - Knowledge, Attitude And Practice Of Common Cold And Its Management Among Doctors Of Pakistan. AB - BACKGROUND: Antibiotic misuse for upper respiratory tract infections such as the common cold is widespread in clinical practice. Excessive prescription of antibiotics by doctors has resulted in increased antimicrobial resistance. This led to our objective of determining the percentage of doctors in Pakistan prescribing antibiotics for the treatment of common cold and to know about their knowledge in preventing the spread of this disease. METHODS: It was a cross sectional descriptive study, conducted in 9 cities of Pakistan including Rawalpindi, Islamabad, Peshawar, Lahore, Karachi, Faisalabad, Sargodha, Multan and D.G. Khan over a period of 03 months -from October to December, 2013. Questionnaire regarding the disease spread and its treatment was distributed among 300 randomly selected doctors in nine cities of Pakistan from both public and private sector. RESULTS: Eighteen percent of the doctors prescribe antibiotics for common cold. Only 113 (37.7%) doctors correctly responded that mean incubation period for common cold was 1-2 days. Two hundred and nine (69.7%) answered correctly that cold weather increases susceptibility to common cold. Only 84 (28%) responded correctly by choosing that regular and frequent hand washing with good quality soaps was the most effective way to prevent spread of this disease in day-to-day life. CONCLUSIONS: Antibiotics are being prescribed for treatment of common cold by a large proportion of doctors. There is insufficient knowledge among our doctors regarding the factors which aggravate or alleviate common cold symptoms as well as the methods by which these infections can be prevented. PMID- 28712228 TI - Frequency Of Common Bacteria And Their Antibiotic Sensitivity Pattern In Diabetics Presenting With Foot Ulcer. AB - BACKGROUND: Foot ulcers are one of the most important complications of diabetes mellitus and often lead to lower limb amputation. Diabetic foot ulcers are susceptible to infection. The objective of this study was to determine the frequency of common bacteria infecting these ulcers and their antibiotic sensitivity pattern. METHODS: This descriptive cross-sectional study was performed in the Departments of Medicine and Surgery, Khyber Teaching Hospital, Peshawar from April, 2011 to February, 2012. Specimens collected from ulcers of 131 patients were inoculated on Blood Agar and MacConkey Agar, and antibiotic sensitivity was tested using standard disc diffusion method. RESULTS: Out of 131, specimens from 120 patients yielded 176 bacteria. Sixty-six patients had monomicrobial infection while polymicrobial growth was obtained in 54 patients. Overall, Staphylococcus aureus (38.6%) was the most common isolate followed by Pseudomonas aeruginosa (27.3%). Staphylococcus aureus was most often sensitive to Moxifloxacin, Imipenem/Meropenem, Vancomycin and Linezolid while it showed varying sensitivity to Penicillins and Cephalosporins. 47.1% isolates of Staphylococcus aureus were resistant to Methicillin. Most of the gram negative rods were sensitive to Imipenem/Meropenem, Piperacillin-Tazobactam and Ticarcillin-Clavulanate. Majority of gram negative bacteria were found resistant to Cephalosporins and Moxifloxacin except Pseudomonas which showed variable sensitivity to Ceftriaxone, Ceftazidime and Moxifloxacin. CONCLUSIONS: Majority of isolates were found resistant to the commonly used antibiotics. Most commonly isolated bacterium, Staphylococcus aureus was most often sensitive to Moxifloxacin, Imipenem/Meropenem, Vancomycin and Linezolid, while majority isolated gram negative rods were sensitive to Imipenem/Meropenem, Piperacillin Tazobactam and Ticarcillin-Clavulanate. PMID- 28712229 TI - Insulin Sensitivity To Trace Metals (Chromium, Manganese) In Type 2 Diabetic Patients And Non Diabetic Individuals. AB - BACKGROUND: Diabetes mellitus constitutes one of the most important problems in developing and non-developing countries. The purpose of the study to estimate the concentrations of Chromium and Manganese in diabetic and non-diabetic population of Hazara division. The cross sectional comparative study was carried out on one hundred blood samples of Type 2 Diabetic patients collected non-randomly from Ayub Teaching Hospital and one hundred normal healthy controls from Women Medical College Abbottabad from September 2014 to April 2015. METHODS: The study included two hundred subjects. Among them 100 were diabetic and 100 non diabetic respectively. The blood samples were collected from Ayub Medical College, Abbottabad. The serum Chromium and Manganese levels were determined by Atomic Absorption spectrophotometer. RESULTS: Serum Chromium and Manganese levels were decreased in diabetic and increased in non-diabetic patients. CONCLUSIONS: Low serum level of Chromium and manganese were found in diabetic patients as compare to non-diabetic individuals. PMID- 28712230 TI - Association Of Serum Total Bilirubin Level With Diabetic Retinopathy In Type 2 Diabetes Mellitus. AB - BACKGROUND: Serum bilirubin has anti-inflammatory, antioxidant and immunological properties. It is considered a protective substance against atherosclerotic and microvascular complications of diabetes mellitus (DM). This study was designed to find the association between total serum bilirubin concentration and diabetic retinopathy (DR). METHODS: This case control study was conducted in the Department of Endocrinology, Diabetes and Metabolic Diseases, Hayatabad Medical Complex, Peshawar. Type-2 DM patients more than 18 years of age of either gender with duration of T2DM more than 6 months were included and sub categorized in two groups. Cases (DM with DR) and Controls (DM without DR) while patients with acute and chronic liver diseases, haemolytic anaemia, history of chronic alcohol consumption, use of hepatotoxic drugs (anti-tuberculous, anti-epileptic), women on oral contraceptive pills were excluded. All participants underwent ophthalmic examination at diabetic retinopathy screening clinic followed by pre designed set of investigations. RESULTS: A total of 152 patients, 76 cases and 76 controls were included. Serum bilirubin concentration was found inversely and independently (p 0.000) associated and inversely co related (r -0.345and p 0.000) with prevalence of DR. Cases were concentrated in the lower quartiles of serum bilirubin concentration and vice versa. Low haemoglobin (p 0.00) and longer duration of DM (0.003) were independently and directly associated with prevalence of DR. CONCLUSIONS: Serum bilirubin concentration is inversely and independently associated and inversely correlated with the prevalence of DR and may predict progression of DR over time. PMID- 28712231 TI - Early Experience Of Pneumatic Lithoclast For The Management Of Ureteric Stones At Peshawar. AB - BACKGROUND: Pakistan lies in the Afro-Asia stone belt. Ureteric calculi are common occurrence and a major burden on health care facilities in Pakistan. The objective of this study was to assess the efficacy and safety of pneumatic lithoclast in the management of ureteric calculi. METHODS: Case series study Department of Urology at Institute of Kidney Diseases Hayatabad Peshawar, from 1st Oct 2010 to 1st Oct 2011. One-hundred adult patients with ureteric calculi >= 0.7 cm were evaluated by history, physical examination, routine blood and urine examination after taking their written informed consent and approval of ethical committee. Ultrasound and X-ray KUB were done with IVU if required. All patients underwent ureteroscopy within intracorporeal lithotripsy and JJ stenting. Patients were followed up with post-op X-ray KUB at 24 hours and then weekly intervals till they became stone free. Following parameters were assessed: stone size, site, laterality, degree of fragmentation, success rate, stone migration and complications. Inability to reach the calculus with URS, proximal migration of stone or requirement of another/auxiliary procedure was considered failure. RESULTS: One hundred and ten patients were enrolled with a mean age of 38+/-10 years. There were 72 males and 28 females. Fifty-eight calculi were on right and 42 on left side. 24, 24 and 52 stones were in upper, middle and lower ureter respectively. Forty stones measured 7-10 mm, 52 measured 11-15 mm and 8 measured 16-20 mm in size. 98 stones were broken while 2 calculi migrated proximally. Overall success rate was 90% (Efficiency Quotient =78.95). Success rate in upper, middle and lower ureter was 83.3%, 83.3% and 96.1% respectively. 10 and 2 patients required ESWL and open ureterolithotomy, respectively, as additional treatment. Mean operative time was 33.5 minutes. There were no major complications.. CONCLUSIONS: Pneumatic lithoclast with URS is effective and safe in the management of the ureteric calculi with some limitations in the upper ureter. PMID- 28712232 TI - Understanding Health Seeking Behavior Of Health Care Professionals In Tertiary Care Hospitals In Pakistan. AB - BACKGROUND: Health seeking behaviour refers to the behaviour of people towards seeking their own health through provided health services. The medical professionals are at a higher risk of avoiding health seeking behaviour because they believe they are aware of the diseases and their symptoms as well as the pharmaceutical management of the disease. The aim of this study was to understand the healthcare seeking behaviour of nurses and doctors as well as the factors affecting it in hospitals of a major city in a developing country. METHODS: A cross-sectional study was designed and a self-report questionnaire was distributed to healthcare workers at four tertiary care hospitals from July, 2012 to December, 2014. A total of 1015 participants responded. There were 234 (23%) doctors, 664 (65%) nurses, 60 (6%) pharmacist and 57 (6%) paramedical staff. RESULTS: The doctors 194 (83%) had a greater access to medical facilities compared to nurses 278 (42%) (p<0.001). Doctors 176 (75%) compared to nurses 262 (39%) were utilizing healthcare service more often (p<0.001). Majority of the nurses 494 (74%) never visited a doctor for any complaint over a period of one year compared to doctors 132 (56%) (p=0.002). Doctors 234 (100%) and nurses 662 (99.7%) equally self -medicated themselves (p=0.401). Nurses 134 (20%) were less aware of the organization policies offered for employees ill-health compared to doctors 102 (44%) (p<0.001). Nurses 530 (80%) were also less aware of the significance of regular health check-ups compared to doctor 234 (100%) (p<0.001). CONCLUSIONS: Among the healthcare workers, doctors have greater access to healthcare facilities. Majority of nurses do not seek healthcare when they get sick. Self-medication is common in both groups. PMID- 28712233 TI - Panoramic View Of Challenges And Opportunities For Primary Healthcare Systems In Pakistan. AB - BACKGROUND: Pakistan has a broad system of primary health care facilities to achieve mission of "Health for all". Over the last seven years health expenditure by government of Pakistan has been increased to attain this goal. This study was conducted with the aim to assess all blocks of service readiness (basic equipment, basic amenities, laboratory capacity, standard precautions and essential medicines) in public-primary health care facilities of tehsil Rawalpindi, Pakistan. METHODS: A cross-sectional survey was carried out utilizing two separate structured questionnaires for basic health units and rural health centres. Information was collected from administrative heads along with other staff where required, of all public-primary health care facilities of Tehsil Rawalpindi. Data were analysed by using SPSS version.17. RESULTS: A total of 26 health facilities were assessed; only 56% BHUs had a sign board that was available in readable form. BHUs with women medical officer as administrative head constituted 52%. Backup for electricity and toilet were the most neglected areas. Basic amenities, standard precautions and laboratory capacity of Basic Health Units (BHUs) showed a clear deviation from standards and is thus a challenge for Pakistan's Primary Health care (PHC). On the other hand for Rural Health Centres (RHCs), most were on the way to meet expectations. CONCLUSIONS: Pakistan's government is undoubtedly putting efforts in order to achieve targets of primary healthcare but it needs better mainstreaming of political, institutional and social commitments with modified standards for PHC. PMID- 28712234 TI - Anti-Infective Potential Of A Medicinal Plant Pimpenella Stewartii Used Traditionally In Hazara. AB - BACKGROUND: Medicinal plants have been used since long as folk medicines and also in Ayuvedic and Unani systems of treatment. They have importance to save human and animal lives because of their utilization in the herbal medicines. In all over the word plants are in constant use for curing of various kinds of diseases. The herbal medicines are effective due to presence of bioactive compounds along with vitamins and minerals in them. Moreover, plants produce photo-chemicals mainly secondary metabolites which have significant pharmaceutical activities like antioxidant, antimicrobial, pesticidal and anti-tumour activity. They are very effective and have little or no side effects. METHODS: Five microbial strains including three fungal and two bacterial species were tested for the efficacy of plant materials by Agar diffusion method. The fungal species were Aspergilus flavus, Aspergilus niger and Alternaria alternata while bacterial species included Arvenia caratovora and Xanthomans spp. RESULTS: Results obtained for methanolic extracts of Pimpenella stewartii against Aspergilus flavus, Aspergilus niger and Alternaria alternata showed significant antifungal activity. The antibacterial screening of Methanolic extracts of Pimpenella stewartii were evaluated against Arvenia caratovora and Xanthomans spp. The best zone of inhibition was found against Xanthomans spp (97.33+/-2 mm) at 250 ppm concentration followed by Arvenia caratovora (49.7+/-14 mm) at same concentration. PMID- 28712235 TI - Recurrent Laryngeal Nerve Injury In Total Versus Subtotal Thyroidectomy. AB - BACKGROUND: Both Total and Subtotal Thyroidectomy are correct treatment options for symptomatic Euthyroid Multinodular Goitre. The choice depends upon surgeon's preference due to consideration of disadvantages like permanent hypothyroidism in Total Thyroidectomy and high chances of recurrence in Subtotal Thyroidectomy. Many surgeons believe that there is a higher incidence of Recurrent Laryngeal nerve injury in Total Thyroidectomy which affects their choice of surgery. This study aimed to compare the incidence of recurrent laryngeal nerve injury in total versus subtotal thyroidectomy. METHODS: This non randomized controlled trial was carried out at Department of Surgery and ENT of Ayub Teaching Hospital Abbottabad, and Combined Military Hospital Rawalpindi from 1st September 2013 to 30th August 2014. During the period of study, patients presenting in surgical outpatient department with euthyroid multinodular goitre having pressure symptoms requiring thyroidectomy were divided into two groups by convenience sampling with 87 patients in group 1 and 90 patients in group 2. Group-1 was subjected to total thyroidectomy and Group -2 underwent subtotal thyroidectomy. All the patients had preoperative Indirect Laryngoscopy examination and it was repeated postoperatively to check for injury to the recurrent laryngeal nerve. RESULTS: A total of 177 patients were included in the study. Out of these, 87 patients underwent total thyroidectomy (Group-1). Two of these patients developed recurrent laryngeal nerve injury (2.3%). In group-2 subjected to subtotal thyroidectomy, three of the patients developed recurrent laryngeal nerve injury (3.3%). The p-value was 0.678. The overall risk of injury to this nerve in both surgeries combined was 2.8%. CONCLUSIONS: There is no significant difference in the risk of recurrent laryngeal nerve damage in patients undergoing total versus subtotal thyroidectomy. PMID- 28712236 TI - Impact Of Socio-Economic Status On Determinants Of Medical Career. AB - BACKGROUND: Research on determinants of Medical profession has established some constant factors with universal impact and appeal. However, the dramatic changes in the dynamics of medical profession and medical education over the past years have necessitated a revisiting of the established conclusions. The knowledge of impact of economic status on these determinants would pave way to greater interest and research on the subject, especially in Hazara Division where it is practically nonexistent. METHODS: This exploratory research followed deductive inductive approach and was conducted upon 550 respondents from four public and private colleges in Hazara Division. Extensive study of related literature yielded 20 broad determinants of medical career. Pre-research pilot testing verified the reliability of a self-designed instrument. The data collection method adopted was a single shot survey. Personal data of respondents was collected during administration of the instrument. The sample was extracted through systematic random sampling technique giving due weight to proportional representation of each college as well as to the gender distribution. RESULTS: The results revealed a significant difference in the impact of reassuring social perceptions and social status and prestige of medical profession between upper middle class and lower middle class. The results also showed that the students of upper middle class faced significantly greater domestic and familial pressure to enter the medical profession than those from lower middle class. CONCLUSIONS: The findings showed that the upper middle class is under greater influence of societal forces and wider impressions about the medical profession. The students hailing from upper middle class enter the Medical career motivated by urge for social status and prestige and are most compelled by domestic and familial pressures to enter medicine. PMID- 28712238 TI - Antimicrobial Resistance Patterns In Community Acquired Urinary Tract Infections. AB - BACKGROUND: Urinary tract infection (UTI) is the most frequent disease for which patients seek medical care. The antimicrobial agents causing UTI and their sensitivity patterns have remarkably changed throughout the world over the past few years. Hence, the present study was designed to explore the uropathogens and their susceptibility to various molecules in our region. METHODS: This descriptive cross sectional study was conducted at Medical C Unit of Ayub Teaching Hospital, Abbottabad from January 2015 to January 2016. Patients with clinical features of UTI were evaluated using Urine R/E and Urine culture and sensitivity. Ten antibiotics were checked for susceptibility. Results were analysed using SPSS 17. RESULTS: A total of 630 patients presented with urinary complaints. Of these, 236 patients had more than 8-10 pus cells on urine R/E. They were further evaluated using culture and sensitivity and positive culture was obtained in 75 patients. Of these 34 (45.3%) were males and 41 (54.7%) were females. E Coli was the predominant isolate being present in 49 (65.3%) patients. This was followed by Klebsiella in 9 (12%) patients. Tazobactam-piperacillin and cefoperazone-sulbactam were the most sensitive drugs having overall sensitivity of 96% and 93.3% respectively. The isolates were highly resistant to Fluoroquinolones 77.3% followed by Penicillins 72% and TMP-SMX 69.3%. CONCLUSIONS: Antibiotic sensitivity patterns have enormously changed over the past decade. Newer agents are quite efficacious but their use should be highly judicious to prevent the development of resistance to these molecules. PMID- 28712237 TI - Antimicrobial Susceptibility Of Intra-Abdominal Infection Isolates From A Tertiary Care Hospital In Karachi. AB - BACKGROUND: Intra-abdominal infections are associated with significant morbidity and mortality. The most frequent pathogens involved are the gastrointestinal flora which can cause poly-microbial infections. Microbiological diagnosis is required to determine the aetiology and antimicrobial susceptibility of the organisms involved. Prompt initiation of antimicrobials is essential for improving patient's outcome. Knowledge of local trends of antimicrobial resistance in nosocomial isolates is essential for empiric therapy. METHODS: A total of 190 clinical isolates collected from intra-abdominal infections during July 2013 to July 2014 were included in the study. Organism identification and Antimicrobial sensitivity testing using standard biochemical tests and CLSI recommended criteria was carried out. RESULTS: Of the total 190 isolates from abdominal infection sources 52% were from fluid sources (peritoneal & ascitic fluid), 41% were from gall bladder and 6.5% were from other abdominal sources. E. coli (46.8%) was the most frequently isolated gram negative and Enterococcus (13.1%) was the most frequently isolated gram positive organism. Carbapenem (imipenem) was the most active agent against enterobacteraceae exhibiting, 94.4% and 91.3% sensitivity against E. coli and Klebsiella respectively. While vancomycin was the most active agent against gram positive organisms. Eighty-four percent of the Enterococci isolated were sensitive to vancomycin. Most isolates exhibited resistance to one or more antibiotics. CONCLUSIONS: Continuous evolution of antimicrobial resistance patterns in bacteria necessitates updating of local data on antimicrobial susceptibility profiles to ensure the safety and efficacy of pathogen specific antimicrobial therapies. PMID- 28712240 TI - Hepatorenal Syndrome In Patients With Cirrhosis Of Liver According To 2007 International Ascites Club Criteria. AB - BACKGROUND: Heptorenal syndrome is a complication of cirrhosis of liver and is characterized by progressive renal failure. This study was done to determine the frequency of hepatorenal syndrome according to 2007 international ascites club criteria among patients of cirrhosis attending Medical Units of Civil hospital Karachi. METHODS: This is a cross-sectional study conducted on the hospitalized patients in the Department of Medicine-Civil Hospital Karachi from 01-04-2014 to 30-09-2014 where total 265 patients of either gender, age >18 years & <60 years & diagnosed case of CLD were included. Patients with shock, SIRS, sepsis, known cases of intrinsic renal diseases, or history of diabetes mellitus, Hypertension or connective tissue diseases were excluded. Mean+/-SD were expressed for continuous variable like, age, duration of CLD. Frequency & percentages of other categorical variables, i.e., gender, residence were expressed. Effect modification was tested through Chi-square with p-value <0.05 significant. RESULTS: The mean+/-SD age of patient was 48.23+/-7.87 years with range 18-60 years. Mean+/-SD duration of chronic liver disease was 5.60+/-1.92 years with a range of 3-12 years. More than 155 (58%) participants in this study were male and females were 110 (41.51%). More than 36 (13%) were of age less than and equal to 40 years; 121 (45.67%) were from 41-50 years, while 108 (40.75%) were from age 51 60 years. More than 176 (66.41%) belonged to rural areas while only 89 (33.58%) belonged to urban areas. The study observed that according to IAC 2007 criteria of diagnosis of hepatorenal syndrome 15.09% of patients with cirrhosis were found to have HRS. CONCLUSIONS: Hepatorenal syndrome represents the end stage of a sequence of reduction of renal perfusion induced by advanced liver failure. Almost every seventh patient of Cirrhosis can develop hepatorenal Syndrome. This should be looked up at an early stage so that it can be prevented. PMID- 28712239 TI - Cryptosporidiosis Among Children Of District Skardu, Pakistan. AB - BACKGROUND: Cryptosporidiosis is a common cause of persistent diarrhoea in children in developing countries. Previously it was thought to be a major pathogenic organism in immuno-compromised children, but recent studies have shown it to be a common infectious agent in immune-competent children as well. METHODS: This descriptive case-series was carried out at Combined Military Hospital Skardu, Pakistan from August 2014 to June 2015. Fifty-three children aged 12 months to 12 years with history of persistent watery diarrhoea for more than 2 weeks, with no blood or mucous in it and no other systemic findings, were included in the study. RESULTS: We examined 53 stool specimens from children with persistent diarrhoea for the presence of cryptosporidium as well other pathogenic organisms. There were 22 (41.5%) females and 31 (58.5%) males. Out of 53 samples, 11 (20.8%) samples were found to be positive for cryptosporidium. Twenty-seven (50.9%) samples were found to be negative for any intestinal pathogen. CONCLUSIONS: It is concluded from this study that cryptosporidium is a very common infectious organism of persistent diarrhoea in this part of the country. PMID- 28712242 TI - Out Come Of Trial Of Scar In Patients With Previous Caesarean Section. AB - BACKGROUND: Patients who had one caesarean section were previously not given a trial of scar due to fear of increased morbidity. However, recently there has been a trend to give a trial of labour to patients with a previous caesarean section for a non-recurrent cause. Medical evidence indicates that 60-80% of women can achieve vaginal delivery after a previous lower segment caesarean section. Proper selection of patients for trial of scar and vigilant monitoring during labour will achieve successful maternal and perinatal outcome. The objective of our study is to establish the fact that vaginal delivery after one caesarean section has a high success rate in patients with previous one caesarean section for non-recurrent cause. METHODS: The study was conducted in Ayub Teaching Abbottabad, Gynae-B Unit. All labouring patients, during the study period of five years, with previous one caesarean section and between 37 weeks to 41 weeks of gestation for a non-recurrent cause were included in the study. Data was recorded on special pro forma designed for the purpose. Patients who had previous classical caesarean section, more than one caesarean section, and previous caesarean section with severe wound infection, transverse lie and placenta previa in present pregnancy were excluded. Foetal macrosomia (wt>4 kg) and severe IUGR with compromised blood flow on Doppler in present pregnancy were also not considered suitable for the study. Patients who had any absolute contraindication for vaginal delivery were also excluded. RESULTS: There were 12505 deliveries during the study period. Total vaginal deliveries were 8790 and total caesarean sections were 3715. Caesarean section rate was 29.7%. Out of these 8790 patients, 764 patients were given a trial of scar and 535 patients delivered successfully vaginally (70%). Women who presented with spontaneous onset of labour were more likely to deliver vaginally (74.8%) as compared to induction group (27.1%). CONCLUSIONS: Trial of vaginal birth after caesarean (VBAC) in selected cases has great importance in the present era of the rising rate of primary caesarean section. PMID- 28712241 TI - Hospitalized Patients' Awareness Of Their Rights-A Cross Sectional Survey In A Public And Private Tertiary Care Hospitals Of Punjab, Pakistan. AB - BACKGROUND: The awareness of patient's rights is negligible in developing countries where no legal framework is present to protect these rights and Pakistan is no exception. Not only is there an absence of legal structure for protection of patients' rights, but the enforcement and implementation for existing law is also questionable. Pakistan has an Islamic Charter of Medical and Health Ethics which includes the medical behaviour and physician's rights and duties towards the patients. Despite all these charters on patients' rights, there is little to no awareness regarding these rights and their practice remains low in healthcare system of Pakistan. This assessment of awareness among patients about their rights will guide in formulating recommendations to improve the existing system of healthcare delivery in the country. METHODS: This descriptive cross-sectional comparative study was conducted in two hospitals in Lahore, each belonging to public and private sector. A structured questionnaire was used to collect data from patients. A total of 220 patients were selected to participate in the study, 110 belonging to each private and public hospital. RESULTS: The findings indicate that most of the patients (64%) were not aware of their rights. The awareness level was better in patients seeking care from private hospital than those from public hospital. Education, monthly income and type of hospital utilized were found to be positively associated with the level of awareness. Most of the patients were not satisfied with the practices of their rights, especially in public hospitals. CONCLUSIONS: The lack of awareness regarding the rights of a patient was more common in patients of public/government hospitals compared to private hospitals. A nation-wide healthcare education program is needed to increase awareness and practice of patients' rights in the country. PMID- 28712243 TI - Preferences Of Doctors For Working In Rural Islamabad Capital Territory, Pakistan: A Qualitative Study. AB - BACKGROUND: Developing countries are faced with acute shortages of human resources in rural/remote areas. Decisions of human resources for health to work in rural areas are influenced by many financial and non-financial factors. This study focused on preferences of doctors for working in rural and resource constrained areas of Pakistan. METHODS: The study was based on qualitative research techniques. Focus group discussions (FGDs) were conducted with final year medical students and house officers and In-depth Interviews (IDIs) with senior health managers of Islamabad Capital Territory (ICT). Results were analyzed using qualitative content analysis technique to present the findings. RESULTS: The results showed that quality of facilities; career development, lack of incentives, quality of life, and lack of connectivity between rural and urban health facilities, transportation services and governance issues are some of the main factors identified by young doctors of ICT that contribute in their decision of choosing a certain job or not in rural areas. CONCLUSIONS: Study results show the indepth detail of deciding factors for attracting and retaining health workforce in rural areas. These can be used for designing DCE (Discrete Choice Experiment) questionnaire to further analyze the preference incentive packages for attracting doctors to work in rural Islamabad. PMID- 28712244 TI - Obesity, An Emerging Epidemic In Pakistan-A Review Of Evidence. AB - BACKGROUND: In Pakistan, the disease pattern is facing a huge changeover from acute and communicable diseases to the non-communicable diseases. Moreover, an emerging epidemic of obesity is still under recognized in Pakistan. A detailed review and dissemination of the existing knowledge to determine the extent of burden of obesity can help understand this important public health issue. METHODS: A detailed literature review was conducted through PubMed search engines, regarding obesity burden in Pakistan. The original peer reviewed research articles, reports of WHO in English language, non-government organizations reports were included in the review. "Obesity AND Pakistan" were used as a search terms. RESULTS: Pakistan is suffering from epidemic of obesity, affecting all age groups. Urban population, particularly women shows considerable higher burden of obesity as compared to men and women from rural population. However, among children and adolescents there is variation in prevalence of obesity. Girls from all age groups are predominantly more obese as compared to boys. Most of the studies have estimated child obesity among school going children of different age groups and need careful interpretation. CONCLUSIONS: Pakistan is currently suffering from an emerging epidemic of obesity. The rising burden of obesity is widespread among adults (man and women) and children. The burden of obesity is higher among females in all age groups as compare to males. Effective interventions are required at population level to prevent and control this emerging public health issue. PMID- 28712245 TI - Analysis Of The Health Care System Of Pakistan: Lessons Learnt And Way Forward. AB - BACKGROUND: Pakistani health care system is in progress and since last year, Pakistan has tried to make much improvement in its health care delivery system and has brought out many reforms. METHODS: A systematic search of national and international literature was looked from peerreviewed databases form MEDLINE, CINAHL, and PubMed. RESULTS: There is little strength in health care delivery system in Pakistan like making health policies, participating in Millennium Development Goals program, initiating vertical programs and introducing Public Private Partnership, improving human resource development and infrastructure by making Basic Health Unit and Rural Health Centres. However, these all programs are very limited in its scope and that is the reason that Pakistan's healthcare system is still not very efficient. There are numerous weaknesses like poor governance, lack of access and unequal resources, poor quality of Health Information Management System, corruption in health system, lack of monitoring in health policy and health planning and lack of trained staff. CONCLUSIONS: Pakistan is improving very slowly in the health sector for the last five decades as is evident by its health indicators and above mentioned strengths and weaknesses. Therefore, the Government needs to take strong initiatives to change the current health care system. PMID- 28712246 TI - Primary Empty Sella Syndrome Presenting With Severe Hyponatremia And Minimal Salt Wasting. AB - A 41 year old Jordanian gentleman known case of osteogenesis imperfecta presented with vomiting, decreased oral intake followed by confusion. At presentation he was found to have signs of hypogonadism with severe hyponatremia. The hyponatremia responded to intravenous steroid replacement .This alerted the physicians to search for other pituitary hormone deficiencies. Our patient had pneumonia with respiratory failure. He was intubated and mechanically ventilated. Subsequent tracheostomy was done because of failure of weaning. His GCS remained very low despite treatment of infection and correction of electrolyte imbalance. He had multiple hormone deficiencies. He was found to be severely hypothyroid, replacement of thyroxine caused gradual improvement of GCS over a period of six to eight weeks. In the absence of history pituitary adenoma, pituitary, irradiation or surgery, a diagnosis of primary empty Sella syndrome with anterior pituitary dysfunction was made. PMID- 28712247 TI - Filariasis Presenting As Bone Marrow Suppression. AB - Lymphatic filariasis is caused by most commonly Wuchereria bancrofti in India. The diagnosis is made by demonstration of microfilariae in the peripheral blood, body fluids, fine needle aspirates and in bronchial brushings. Presence of microfilariae in the bone marrow is unusual and not been reported frequently. We are reporting here a case of a young male who had pancytopenia and was found to have microfilariae in the bone marrow. PMID- 28712249 TI - Sweat Gland Carcinoma With Lymphadenopathy. AB - Sweat gland carcinoma is a rare tumour, being almost 1% of primary skin lesions. The tumour has tendency to spread to regional lymph nodes and distant metastases has also been reported. Their exact incidence in Pakistan is not known. Treatment options are also not clearly defined though surgery is the initial treatment approach as adjuvant treatment has not been properly explored. We report a case of sweat gland carcinoma with lymphadenopathy. PMID- 28712248 TI - One Stage Bilateral Knee And Hip Arthroplasties In 42 Years Old Female. AB - Knee and hip joint replacement surgeries are the mainstay of treatment in patients having grade 3 or grade 4 arthritis either due to degenerative process, rheumatoid disease or due to some other disease process. The main aims of these surgeries are to decrease the morbidity, early rehabilitation and decrease management costs of such patients. We report the first case in which bilateral total knee and total hip replacement surgery were done in single anaesthesia in 42 years old female patient suffering from Rheumatoid Arthritis. PMID- 28712250 TI - Spinal Cord Compression By Metastatic Thoracic Spine Paraganglioma. AB - Paragangliomas are rare neuroendocrine tumours most commonly located in the adrenal glands. The overall incidence of paragangliomas is 0.8 per 100,000 persons, but the incidence of malignant paraganglioma was found to be 93 cases out of 400 million persons in United States. We present a case of 50 year old male who came to the hospital with back pain and progressive bilateral lower limb weakness for the past 6 months. Imaging studies revealed enhancing lesions on dorsal spines. Bone scintigraphy showed increased tracer uptake at multiple sites. Bone biopsy and immune-histochemical staining proved metastatic paraganglioma. After a thorough literature search only few cases of metastatic spine paraganglioma causing spinal cord compression have been reported to date. PMID- 28712251 TI - Pleomorphic Adenoma Of Minor Salivary Glands. AB - Pleomorphic adenoma is the most common benign tumour of salivary glands which is Known for its wide pleomorphic architecture. It accounts for 45-75% of all salivary gland neoplasm. It can involve major as well as minor salivary glands. Among minor salivary glands (5-10% of cases) the palate lip, nasal cavity, pharynx, larynx and trachea are the most common sites. Diagnosis is made with biopsy along with histopathology. Wide excision with biopsy and removal of underlying extension of tumour is the treatment of choice. Sixty years old farmer presented with painless swelling in the upper lip for the last 8 years. History revealed recurrent mass in the midline of upper lip with no other complaints. He was operated 3 times for this complaint in the past. Belonging to poor socioeconomic status no biopsy records were found. On examination 3*4 cm hard and mobile mass was found. Lymph nodes of head and neck and parotid gland revealed no enlargement. Surgery by wide excision was planned. After baseline investigation surgery was done and the mass sent for histopathology. Biopsy reports showed pleomorphic adenoma on unusual site. Dissection of salivary gland tumour is important as they have propensity to metastasize. Wide local excision along with biopsy is the method of choice. Proper surgical techniques are required to avoid recurrence. PMID- 28712252 TI - Omental Infarction In A Child. AB - Omental infarction is a rare cause of acute abdomen in children. Typical findings on imaging establish the diagnosis. We present case of a 7 years old boy who presented with acute right iliac fossa pain with diagnosis of omental infarction on imaging and findings confirmed on laparotomy. Sound knowledge regarding this infrequent cause of acute abdomen in children is necessary for timely diagnosis. PMID- 28712253 TI - Traumatic Right Diaphragmatic Hernia; A Delayed Presentation. AB - Diaphragmatic rupture following blunt or penetrating thoraco-abdominal trauma is frequently missed. It presents years later with herniation of abdominal viscera. Surgical treatment should be sought for when diagnosed. A 56 year old female presented to emergency with traumatic right diaphragmatic hernia, road traffic accident 8 years ago when she sustained multiple rib fractures on the right side. Upon diagnosis, successful primary hernia repair was performed. Non-specific clinical and radiological features of diaphragmatic hernia (diminished breath sounds, respiratory distress, orthopnoea, dyspnoea, hydro-pneumothorax, and mediastinal shift and lung collapse) lead to delayed or missed diagnosis. Patients present months to years later with complications. By including it in the differentials while managing a trauma patient along with collaboration of the radiology department, the chances of missing this finding would be lowered substantially. PMID- 28712254 TI - Identification And Endodontic Treatment Of Threecanalled Maxillary First Premolar. AB - Maxillary premolars exhibit variable root canal morphology, but it is quite rare to find three canals in their root system. The aim of this case report is to present the diagnosis and clinical management of a patient with anatomical variation of having three root canals in the maxillary first premolar. Three canalled maxillary premolars are quite an endodontic challenge. A discussion is provided here to facilitate the early recognition of these canals, access cavity modifications for better intra-canal preparation and obturation procedures. Clinicians are required to be aware of the anatomical variations they may encounter when dealing with maxillary premolars and should be trained to apply this knowledge in the clinical scenario. PMID- 28712255 TI - Pediatric Oxygen Therapy: A Clinical Update. AB - Oxygen therapy is a life-saving, medical intervention in the management of hospitalized children. The goal of oxygen therapy is to prevent or treat tissue hypoxia. Oxygen should be prescribed according to the principles of drug prescription, however, use of oxygen in clinical practice is often inappropriate without knowledge of its potential risks and benefits. This article summarizes practical aspects of clinical use of oxygen in terms of indication, administration, and monitoring, weaning, discontinuation and oxygen toxicity to rationalize therapy and achieve maximum benefits. PMID- 28712256 TI - Zika Virus Infection: Important Concern. PMID- 28712257 TI - Oral Pemphigus Vulgaris In A Pediatric Patient. PMID- 28712258 TI - Case Of Debakey Class I Aortic Dissection. PMID- 28712260 TI - Effects of an Integrated Health Care Program for Children. AB - PURPOSE: This study examined the effects of an integrated health care program in elementary school students. METHODS: The integrated program comprised exercises (3-4 times/week) and six sessions on nutritional and psychological education. Anthropometric measurements were recorded before the intervention. Additionally, physical fitness, dietary habits, nutrition knowledge, and psychological changes were assessed before and after the program. RESULTS: In total, 29% of the subjects were overweight and obese before the intervention (32% boys and 26% girls). There was a significant increase in flexibility, endurance, and cardiovascular endurance after the implementation of the program. Additionally, as a result of the program, participants showed improvement in nutrition knowledge and dietary habits. After the training, children tended to exhibit increased self-efficacy and lower stress, but the findings were not statistically significant. CONCLUSION: Implementation of an integrated health care program for the prevention and treatment of obesity could have a positive impact on children's health. It is hoped that continued research on the long-term effects of such programs is conducted along with the development of various programs. PMID- 28712259 TI - Four-week "living high training low" program enhances 3000-m and 5000-m time trials by improving energy metabolism during submaximal exercise in athletes. AB - PURPOSE: This study aimed to determine the effect of a 4-week living high training low (LHTL) versus a living low training low (LLTL) program on energy metabolism during submaximal exercise and 3000-m and 5000-m time trial (TT) in athletes. METHODS: Male athletes (n = 20) were randomly assigned to the LLTL (n = 10, living at 1000 m and training at 700-1330 m) and LHTL (n = 10, living at simulated 3000 m and training at 700-1330 m) groups. We compared energy metabolisms during submaximal exercise on a treadmill and aerobic exercise performance (3000 m and 5000 m TT) before and after 4 weeks of training. RESULTS: As expected, the LHTL group demonstrated enhanced energy metabolism during submaximal exercise via significant interaction (time * group) in heart rate, oxygen consumption, and carbon dioxide excretion; these variables were significantly decreased in the LHTL group compared with the LLTL group. Additionally, both training groups revealed significantly decreased blood lactate levels during submaximal exercise, 3000 m TT, and 5000 m TT but significant interactions (time * group) in the 3000 m and 5000 m TT. Thus, the LHTL group demonstrated greater improvements in 3000 m and 5000 m TT than the LLTL group via significant interactions. CONCLUSION: Our results suggest that 4-week LHTL intervention enhances 3000 m and 5000 m TT by improving energy metabolism during submaximal exercise. The proposed LHTL intervention in this study is a novel and effective method for improving aerobic exercise performance in male athletes. PMID- 28712261 TI - Application of "living high-training low" enhances cardiac function and skeletal muscle oxygenation during submaximal exercises in athletes. AB - PURPOSE: The aim of this study was to determine the efficiency of the application of living high-training low (LHTL) on cardiac function and skeletal muscle oxygenation during submaximal exercises compared with that of living low-training low (LLTL) in athletes. METHODS: Male middle- and long-distance runners (n = 20) were randomly assigned into the LLTL group (n = 10, living at 1000-m altitude and training at 700-1330-m altitude) and the LHTL group (n = 10, living at simulated 3000-m altitude and training at 700-1330-m altitude). Their cardiac function and skeletal muscle oxygenation during submaximal exercises at sea level before and after training at each environmental condition were evaluated. RESULTS: There was a significant interaction only in the stroke volume (SV); however, the heart rate (HR), end-diastolic volume (EDV), and end-systolic volume (ESV) showed significant main effects within time; HR and SV significantly increased during training in the LHTL group compared with those in the LLTL group. EDV also significantly increased during training in both groups; however, the LHTL group had a higher increase than the LLTL group. ESV significantly increased during training in the LLTL group. There was no significant difference in the ejection fraction and cardiac output. The skeletal muscle oxygen profiles had no significant differences but improved in the LHTL group compared with those in the LLTL group. CONCLUSION: LHTL can yield favorable effects on cardiac function by improving the HR, SV, EDV, and ESV during submaximal exercises compared with LLTL in athletes. PMID- 28712262 TI - Evaluation of efforts in untrained Wistar rats following exercise on forced running wheel at maximal lactate steady state. AB - PURPOSE: We aimed to examine the effect of running speed on metabolic responses associated with maximal lactate steady state (MLSS) in rats during forced running wheel (FRW) exercise. METHODS: Forty male adult Wistar rats were divided into seven groups. The blood lactate threshold and peak running speed were determined for an incremental power test group. Five groups participated in constant power tests at intensities 10, 13, 14.5, 16, and 17.5 m/min to determine MLSS and a non exercise group was chosen as the control. Animals were euthanized immediately after constant power tests and their corticosterone, non-esterified fatty acid (NEFA), blood glucose, and creatine kinase (CK) levels analyzed. The differences among groups were identified by one-way analysis of variance (p < 0.05). RESULTS: Blood lactate threshold corresponded a running intensity of 15 m/min, while MLSS was determined to be 16 m/min. Serum corticosterone concentrations were significantly higher in 14.5, 16, and 17.5 m/min groups (298.8+/-62, 338.3+/-65, and 354+/-26 nM, respectively) as compared to that in the control group (210.6+/ 16 nM). Concentrations of NEFA observed in groups 13, 14.5, 16, and 17.5 m/min (662.8+/-24, 702.35+/-69, 718.4+/-34, and 752.8+/-77 MUM, respectively) were significantly higher than those in 10 m/min and control groups (511.1+/-53 and 412.1+/-56 MUM, respectively). The serum CK concentration recorded for group 17.5 m/min (372.4+/-56 U/L) was higher than those recorded for other groups. CONCLUSION: The speed above 16 m/min on FRW resulted in increased physiological demands and muscle damage in untrained healthy Wistar rats. PMID- 28712263 TI - Effects of colostrum serum on the serotonergic system in the dorsal raphe nuclei of exercised rats. AB - PURPOSE: The central fatigue hypothesis suggests that exhaustion, or the maximum level of exercise, induces excessive stress and increases serotonin concentrations in the brain, which in turn decreases central nervous system (CNS) function and induces fatigue. Our aim was to determine the effects of colostrum serum on the serotonergic system in the dorsal raphe nuclei during exhaustive exercise. METHODS: Animals were randomly divided into five groups: control, exercise, exercise and treatment with 50, 100, and 200 mg/kg of colostrum serum. The rats in the colostrum serum treatment groups were fed colostrum serum at three different doses of 50, 100, and 200 mg/kg per day for seven days. The rats in the control and exercise groups received water by oral gavage once per day for seven days. RESULTS: The time to exhaustion in response to treadmill running increased after treatment with colostrum serum. These results show that exhaustive exercise led to over activation of the serotonergic system in the dorsal raphe nuclei, and that treatment with colostrum serum suppressed of the exercise-induced expression of tryptophan hydroxylase (TPH) and serotonin (5-HT). The results also indicated that exhaustive exercise induced 5-HT1A autoreceptor and serotonin transporter (5-HTT) overexpression in the dorsal raphe nuclei, and that colostrum serum treatment suppressed exhaustive exercise-induced 5-HT1A and 5-HTT expression in the dorsal raphe nuclei. The most effective dose of colostrum serum was 100 mg/kg. CONCLUSION: Overall, our study suggests that colostrum serum has positive effects on exercise performance and recovery by increasing the resistance to fatigue. PMID- 28712265 TI - Jaeumganghwa-Tang, a traditional herbal formula, improves muscle function and attenuates muscle loss in aged mice. AB - PURPOSE: Jaeumganghwa-Tang (JGT), a traditional herbal formula composed of 12 medicinal herbs, is used for the treatment of age-related diseases. In the present study, we investigated the effects of JGT on muscle mass and function in aged mice. METHODS: Young (5-month-old) and old (19-month-old) male C57BL/6 mice were divided into two groups each; one group received JGT (75 mg/d) and the other group received the vehicle for 6 weeks. At the end of the experimental period, muscle strength was examined using the wire hang test, and the tibialis anterior and gastrocnemius muscles were weighed. Muscle samples were further used for histological analysis to assess muscle damage, and the expression of transforming growth factor-beta was investigated via western blotting and immunohistochemistry. RESULTS: Our results showed that treatment of old mice with JGT improved muscle strength, increased skeletal muscle mass, alleviated muscle damage, and suppressed intramuscular expression of transforming growth factor beta. CONCLUSION: In conclusion, JGT has beneficial effects on age-related loss of muscle mass and function. Thus, it might serve as a potential therapeutic agent for sarcopenia. PMID- 28712266 TI - Use of ustekinumab in five psoriatic patients with hepatitis B virus infection. PMID- 28712264 TI - Treadmill exercise ameliorates the regulation of energy metabolism in skeletal muscle of NSE/PS2mtransgenic mice with Alzheimer's disease. AB - PURPOSE: Alzheimer's disease (AD) is classified as a progressive neurological disorder, which not only causes cognitive impairment but also abnormal weight loss, with a reduction of muscle mass related to the accumulation of amyloid-beta (Abeta) in skeletal muscle. Thus, we investigated the effect of treadmill exercise on Abeta deposition, and p-AMPK, p-ACC, BDNF, and GLUT4 protein levels the regulation of muscle energy metabolism using an AD mouse. METHODS: At 13 months of age, NSE/PS2m mice (Tg) and control mice (non-Tg) were assigned to non exercise control (Con) and exercise groups (Exe). The four groups were as follows: non-Tg Con, non-Tg Exe, Tg Con, and Tg Exe. The treadmill exercise was carried out for 12 weeks. RESULTS: The highest levels of Abeta expression in the skeletal muscle were in the Tg Con group. Abeta expression was significantly reduced in the Tg Exe group, compared to the Tg Con group. Congo red staining showed remarkable diffuse red amyloid deposition in the Tg Con group, while Abeta deposition in the skeletal was reduced with muscle exercise in the Tg Exe group. Exercise also increased AMPK and ACC phosphorylation and BDNF and GLUT4 expression in the skeletal muscle of non-Tg and Tg mice. CONCLUSION: Treadmill exercise reduces Abeta-deposition in the skeletal muscle and improves the regulation of energy metabolism. Thus, collectively, these results suggest that exercise could be a positive therapeutic strategy for skeletal muscle dysfunction in AD patients. PMID- 28712267 TI - Use of topical ephedrine and naphazoline in the treatment of a keratoacanthoma. PMID- 28712268 TI - The anti-inflammatory and antioxidant properties of 1,2-decanediol and willow bark extract in lipopolysaccharide-stimulated keratinocytes. AB - BACKGROUND: The 1,2-decanediol (S-Mal) is an organic compound belonging to the 1,2- alkanediol family, with two hydroxyl groups located on the first and second carbon of the alkane chain, probably responsible for the enhanced anti-bacterial efficacy. The willow bark total extract (W-Mal) has been used since thousands of years as an herbal remedy for its antipyretic, analgesic, anti-inflammatory and anti-microbial activities. S-Mal is used in cosmetic preparations, whether W- Mal can be topically or systemically administered. Aim of our study was to evaluate in vitro the anti-inflammatory and antioxidant properties of S-Mal and W-Mal, singularly or in combination, in LPS-stimulated keratinocytes. METHODS: The possible toxic effect of S-Mal and W-Mal was assessed through analysis of cell viability 24h after treatment. The anti-inflammatory and antioxidant activities were evaluated by measuring IL-8, TNF-alpha and IL-1beta production as well as cellular antioxidants (GSH and NADPH) consumption, respectively, 24 and 48h after LPS stimulation. RESULTS: Both substances resulted able to: i) increase cell viability (P < 0.05), ii) decrease the release of inflammatory mediators (IL-8, TNF-alpha and IL-1beta) (P < 0.05- P < 0.001), and iii) limit the depletion of cellular antioxidants (GSH and NADPH) (P < 0.001). CONCLUSIONS: S-Mal and W-Mal have shown a potential cytoprotective activity when used together, and good anti inflammatory and antioxidant effects when used either singularly or in combination. In light of our results, S-Mal and W-Mal could represent effective and safe options in the management of bacterial-induced or aggravated skin conditions. PMID- 28712269 TI - Acne fulminans following isotretinoine therapy. PMID- 28712270 TI - Folliculitis caused by Staphylococcus epidermidis? PMID- 28712271 TI - Ectopic extramammary Paget's disease on the scalp. PMID- 28712272 TI - Quality of life among dermatology patients: a systematic review of investigations using qualitative methods. AB - INTRODUCTION: Quality of life may be assessed using quantitative or qualitative methods. Quantitative methods are commonly used in research settings; however, they may fail to capture the full range of patient experiences and impact on quality of life. Qualitative methods may be used to address this limitation. In this systematic review, we aim to synthesize data from articles utilizing qualitative methods to assess quality of life in dermatology patients. EVIDENCE ACQUISITION: We performed a systematic review search using the MEDLINE, EMBASE, and SCOPUS databases. The search was conducted using the following search criteria: ("Dermatology" [MeSH]) AND ("Quality of Life" [MeSH]), AND ("Qualitative Research" [MeSH]), searching literature spanning from January 1, 1946- October 5, 2016. EVIDENCE SYNTHESIS: The systematic review of 15 articles included 533 dermatology patients. Patients expressed frustration over the unpredictability of disease symptoms and having to compensate for the subsequent limitations by altering their daily routines. Patients also reported profound helplessness due to chronic skin disease and social isolation in an effort to hide their disease. Patients noted the patient-provider relationship as a source of support and information exchange, with the goal to form easy to use treatment plans that met both physician and patient expectations. CONCLUSIONS: Qualitative assessment of patient quality of life can provide new insights into the patient experience and the impact of their skin disease. Qualitative methodology may capture meaningful information that may be overlooked by quantitative methods, and it should be included in quality of life research. PMID- 28712273 TI - Effect of time interval between capecitabine intake and radiotherapy on local recurrence-free survival in preoperative chemoradiation for locally advanced rectal cancer. AB - PURPOSE: The concentration of capecitabine peaks at 1-2 hours after administration. We therefore assumed that proper timing of capecitabine administration and radiotherapy would maximize radiosensitization and influence survival among patients with locally advanced rectal cancer. MATERIALS AND METHODS: We retrospectively reviewed 223 patients with locally advanced rectal cancer who underwent preoperative chemoradiation, followed by surgery from January 2002 to May 2006. All patients underwent pelvic radiotherapy (50 Gy/25 fractions) and received capecitabine twice daily at 12-hour intervals (1,650 mg/m2/day). Patients were divided into two groups according to the time interval between capecitabine intake and radiotherapy. Patients who took capecitabine 1 hour before radiotherapy were classified as Group A (n = 109); all others were classified as Group B (n = 114). RESULTS: The median follow-up period was 72 months (range, 7 to 149 months). Although Group A had a significantly higher rate of good responses (44% vs. 25%; p = 0.005), the 5-year local recurrence-free survival rates of 93% in Group A and 97% in Group B did not differ significantly (p = 0.519). The 5-year disease-free survival and overall survival rates were also comparable between the groups. CONCLUSIONS: Despite the better pathological response in Group A, the time interval between capecitabine and radiotherapy administration did not have a significant effect on survivals. Further evaluations are needed to clarify the interaction of these treatment modalities. PMID- 28712274 TI - Stereotactic body radiation therapy for liver oligo-recurrence and oligo progression from various tumors. AB - PURPOSE: To evaluate the outcomes of stereotactic body radiation therapy (SBRT) for patients with liver oligo-recurrence and oligo-progression from various primary tumors. MATERIALS AND METHODS: Between 2002 and 2013, 72 patients with liver oligo-recurrence (oligo-metastasis with a controlled primary tumor) and oligo-progression (contradictory progression of a few sites of disease despite an overall tumor burden response to therapy) underwent SBRT. Of these, 9 and 8 patients with uncontrollable distant metastases and patients immediate loss to follow-up, respectively, were excluded. The total planning target volume was used to select the SBRT dose (median, 48 Gy; range, 30 to 60 Gy, 3-4 fractions). Toxicity was evaluated using the Common Toxicity Criteria for Adverse Events v4.0. RESULTS: We evaluated 55 patients (77 lesions) treated with SBRT for liver metastases. All patients had controlled primary lesions, and 28 patients had stable lesions at another site (oligo-progression). The most common primary site was the colon (36 patients), followed by the stomach (6 patients) and other sites (13 patients). The 2-year local control and progression-free survival rates were 68% and 22%, respectively. The 2- and 5-year overall survival rates were 56% and 20%, respectively. The most common adverse events were grade 1-2 fatigue, nausea, and vomiting; no grade >=3 toxicities were observed. Univariate analysis revealed that oligo-progression associated with poor survival. CONCLUSION: SBRT for liver oligo-recurrence and oligo-progression appears safe, with similar local control rates. For liver oligo-progression, criteria are needed to select patients in whom improved overall survival can be expected through SBRT. PMID- 28712275 TI - Predictive factors of symptomatic radiation pneumonitis in primary and metastatic lung tumors treated with stereotactic ablative body radiotherapy. AB - PURPOSE: Although stereotactic ablative body radiotherapy (SABR) is widely used therapeutic technique, predictive factors of radiation pneumonitis (RP) after SABR remain undefined. We aimed to investigate the predictive factors affecting RP in patients with primary or metastatic lung tumors who received SABR. MATERIALS AND METHODS: From 2012 to 2015, we reviewed 59 patients with 72 primary or metastatic lung tumors treated with SABR, and performed analyses of clinical and dosimetric variables related to symptomatic RP. SABR was delivered as 45-60 Gy in 3-4 fractions, which were over 100 Gy in BED when the alpha/beta value was assumed to be 10. Tumor volume and other various dose volume factors were analyzed using median value as a cutoff value. RP was graded per the Common Terminology Criteria for Adverse Events v4.03. RESULTS: At the median follow-up period of 11 months, symptomatic RP was observed in 13 lesions (12 patients, 18.1%), including grade 2 RP in 11 lesions and grade 3 in 2 lesions. Patients with planning target volume (PTV) of <=14.35 mL had significantly lower rates of symptomatic RP when compared to others (8.6% vs. 27%; p = 0.048). Rates of symptomatic RP in patients with internal gross tumor volume (iGTV) >4.21 mL were higher than with <=4.21 mL (29.7% vs. 6.1%; p = 0.017). CONCLUSIONS: The incidence of symptomatic RP following treatment with SABR was acceptable with grade 2 RP being observed in most patients. iGTV over 4.21 mL and PTV of over 14.35 mL were significant predictive factors related to symptomatic RP. PMID- 28712277 TI - Moderate hypofractionated image-guided thoracic radiotherapy for locally advanced node-positive non-small cell lung cancer patients with very limited lung function: a case report. AB - Patients with locally advanced lung cancer and very limited pulmonary function (forced expiratory volume in 1 second [FEV1] <= 1 L) have dismal prognosis and undergo palliative treatment or best supportive care. We describe two cases of locally advanced node-positive non-small cell lung cancer (NSCLC) patients with very limited lung function treated with induction chemotherapy and moderate hypofractionated image-guided radiotherapy (Hypo-IGRT). Hypo-IGRT was delivered to a total dose of 45 Gy to the primary tumor and involved lymph nodes. Planning was based on positron emission tomography-computed tomography (PET/ CT) and four dimensional computed tomography (4D-CT). Internal target volume (ITV) was defined as the overlap of gross tumor volume delineated on 10 phases of 4D-CT. ITV to planning target volume margin was 5 mm in all directions. Both patients showed good clinical and radiological response. No relevant toxicity was documented. Hypo-IGRT is feasible treatment option in locally advanced node-positive NSCLC patients with very limited lung function (FEV1 <= 1 L). PMID- 28712276 TI - Optimal dose and volume for postoperative radiotherapy in brain oligometastases from lung cancer: a retrospective study. AB - PURPOSE: To evaluate intracranial control after surgical resection according to the adjuvant treatment received in order to assess the optimal radiotherapy (RT) dose and volume. MATERIALS AND METHODS: Between 2003 and 2015, a total of 53 patients with brain oligometastases from non-small cell lung cancer (NSCLC) underwent metastasectomy. The patients were divided into three groups according to the adjuvant treatment received: whole brain radiotherapy (WBRT) +/- boost (WBRT +/- boost group, n = 26), local RT/Gamma Knife surgery (local RT group, n = 14), and the observation group (n = 13). The most commonly used dose schedule was WBRT (25 Gy in 10 fractions, equivalent dose in 2 Gy fractions [EQD2] 26.04 Gy) with tumor bed boost (15 Gy in 5 fractions, EQD2 16.25 Gy). RESULTS: The WBRT +/- boost group showed the lowest 1-year intracranial recurrence rate of 30.4%, followed by the local RT and observation groups, at 66.7%, and 76.9%, respectively (p = 0.006). In the WBRT +/- boost group, there was no significant increase in the 1-year new site recurrence rate of patients receiving a lower dose of WBRT (EQD2) <27 Gy compared to that in patients receiving a higher WBRT dose (p = 0.553). The 1-year initial tumor site recurrence rate was lower in patients receiving tumor bed dose (EQD2) of >=42.3 Gy compared to those receiving <42.3 Gy, although the difference was not significant (p = 0.347). CONCLUSIONS: Adding WBRT after resection of brain oligometastases from NSCLC seems to enhance intracranial control. Furthermore, combining lower-dose WBRT with a tumor bed boost may be an attractive option. PMID- 28712278 TI - In vivo dosimetry and acute toxicity in breast cancer patients undergoing intraoperative radiotherapy as boost. AB - PURPOSE: To report the results of a correlation analysis of skin dose assessed by in vivo dosimetry and the incidence of acute toxicity. This is a phase 2 trial evaluating the feasibility of intraoperative radiotherapy (IORT) as a boost for breast cancer patients. MATERIALS AND METHODS: Eligible patients were treated with IORT of 20 Gy followed by whole breast irradiation (WBI) of 46 Gy. A total of 55 patients with a minimum follow-up of 1 month after WBI were evaluated. Optically stimulated luminescence dosimeter (OSLD) detected radiation dose delivered to the skin during IORT. Acute toxicity was recorded according to the Common Terminology Criteria for Adverse Events v4.0. Clinical parameters were correlated with seroma formation and maximum skin dose. RESULTS: Median follow-up after IORT was 25.9 weeks (range, 12.7 to 50.3 weeks). Prior to WBI, only one patient developed acute toxicity. Following WBI, 30 patients experienced grade 1 skin toxicity and three patients had grade 2 skin toxicity. Skin dose during IORT exceeded 5 Gy in two patients: with grade 2 complications around the surgical scar in one patient who received 8.42 Gy. Breast volume on preoperative images (p = 0.001), ratio of applicator diameter and breast volume (p = 0.002), and distance between skin and tumor (p = 0.003) showed significant correlations with maximum skin dose. CONCLUSIONS: IORT as a boost was well-tolerated among Korean women without severe acute complication. In vivo dosimetry with OSLD can help ensure safe delivery of IORT as a boost. PMID- 28712279 TI - The role of adjuvant external beam radiation therapy for papillary thyroid carcinoma invading the trachea. AB - PURPOSE: To evaluate the effect of adjuvant external beam radiation therapy (EBRT) on local failure-free survival rate (LFFS) for papillary thyroid cancer (PTC) invading the trachea. MATERIALS AND METHODS: Fifty-six patients with locally advanced PTC invading the trachea were treated with surgical resection. After surgery, 21 patients received adjuvant EBRT and radioactive iodine therapy (EBRT group) and 35 patients were treated with radioactive iodine therapy (control group). RESULTS: The age range was 26-87 years (median, 56 years). The median follow-up period was 43 months (range, 4 to 145 months). EBRT doses ranged from 50.4 to 66 Gy (median, 60 Gy). Esophagus invasion and gross residual disease was more frequent in the EBRT group. In the control group, local recurrence developed in 9 (9/35, 26%) and new distant metastasis in 2 (2/35, 6%) patients, occurring 4 to 68 months (median, 37 months) and 53 to 68 months (median, 60 months) after surgery, respectively. Two patients had simultaneous local recurrence and new distant metastasis. There was one local failure in the EBRT group at 18 months after surgery (1/21, 5%). The 5-year LFFS was 95% in the EBRT group and 63% in the control group (p = 0.103). In the EBRT group, one late grade 2 xerostomia was developed. CONCLUSION: Although, EBRT group had a higher incidence of esophagus invasion and gross residual disease, EBRT group showed a better 5-year LFFS. Adjuvant EBRT may have contributed to the better LFFS in these patients. PMID- 28712281 TI - Extraordinary radiation super-sensitivity accompanying with sorafenib combination therapy: what lies beneath? AB - Primary liver tumor, especially hepatocellular carcinoma (HCC), is a common cause of cancer death worldwide. The incidence is generally higher in Asian countries than in western countries. Carcinogenesis of HCC is often associated with hepatitis viral infections. Current standard treatment of HCC is surgical resection or transplantation in patients with early stage disease. However, the patient with advanced stage disease, surgical resection is often limited. Sorafenib or other treatment modalities are not so effective as well. We report a case of unusual radiation super-sensitivity in advanced stage HCC, and review the literature. PMID- 28712280 TI - Radiation for persistent or recurrent epithelial ovarian cancer: a need for reassessment. AB - PURPOSE: The role of radiotherapy (RT) was largely deserted after the introduction of platinum-based chemotherapy, but still survival rates are disappointingly low. This study focuses on assessing the clinical efficacy of RT in relation to chemotherapy resistance. MATERIALS AND METHODS: From October 2002 to January 2015, 44 patients were diagnosed with epithelial ovarian cancer (EOC) and treated with palliative RT for persistent or recurrent EOC. All patients received initial treatment with optimal debulking surgery and adjuvant platinum based chemotherapy. The biologically effective dose (BED) was calculated with alpha/beta set at 10. Ninety-four sites were treated with RT with a median BED of 50.7 Gy (range 28.0 to 79.2 Gy). The primary end-point was the in-field local control (LC) interval, defined as the time interval from the date RT was completed to the date any progressive or newly recurring disease within the RT field was detected on radiographic imaging. RESULTS: The median follow-up duration was 52.3 months (range 7.7 to 179.0 months). The 1-year and 2-year in field LC rates were 66.0% and 55.0%, respectively. Comparisons of percent change of in-field tumor response showed similar distribution of responses among chemoresistant and chemosensitive tumors. On multivariate analysis of predictive factors for in-field LC analyzed by sites treated, BED >= 50 Gy (hazard ratio, 0.4; confidence interval, 0.2-0.9; p = 0.025) showed better outcomes. CONCLUSION: Regardless of resistance to platinum-based chemotherapy, RT can be a feasible treatment modality for patients with persistent of recurrent EOC. The specific role of RT using updated approaches needs to be reassessed. PMID- 28712282 TI - Deformable image registration in radiation therapy. AB - The number of imaging data sets has significantly increased during radiation treatment after introducing a diverse range of advanced techniques into the field of radiation oncology. As a consequence, there have been many studies proposing meaningful applications of imaging data set use. These applications commonly require a method to align the data sets at a reference. Deformable image registration (DIR) is a process which satisfies this requirement by locally registering image data sets into a reference image set. DIR identifies the spatial correspondence in order to minimize the differences between two or among multiple sets of images. This article describes clinical applications, validation, and algorithms of DIR techniques. Applications of DIR in radiation treatment include dose accumulation, mathematical modeling, automatic segmentation, and functional imaging. Validation methods discussed are based on anatomical landmarks, physical phantoms, digital phantoms, and per application purpose. DIR algorithms are also briefly reviewed with respect to two algorithmic components: similarity index and deformation models. PMID- 28712283 TI - Stereotactic radiotherapy of the prostate: fractionation and utilization in the United States. AB - PURPOSE: To analyze the utilization and fractionation of extreme hypofractionation via stereotactic body radiotherapy (SBRT) in the treatment of prostate cancer. MATERIALS AND METHODS: Data was analyzed on men diagnosed with localized prostate cancer between 2004-2012 and treated with definitive-intent radiation therapy, as captured in the National Cancer Database. This database is a hospital-based registry that collects an estimated 70% of all diagnosed malignancies in the United States. RESULTS: There were 299,186 patients identified, of which 4,962 (1.7%) were identified as receiving SBRT as primary treatment. Of those men, 2,082 had low risk disease (42.0%), 2,201 had intermediate risk disease (44.4%), and 679 had high risk disease (13.7%). The relative utilization of SBRT increased from 0.1% in 2004 to 4.0% in 2012. Initially SBRT was more commonly used in academic programs, though as time progressed there was a shift to favor an increased absolute number of men treated in the community setting. Delivery of five separate treatments was the most commonly utilized fractionation pattern, with 4,635 patients (91.3%) receiving this number of treatments. The most common dosing pattern was 725 cGy * 5 fractions (49.6%) followed by 700 cGy * 5 fractions (21.3%). CONCLUSIONS: Extreme hypofractionation via SBRT is slowly increasing acceptance. Currently 700-725 cGy * 5 fractions appears to be the most commonly employed scheme. As further long term data regarding the safety and efficacy emerges, the relative utilization of this modality is expected to continue to increase. PMID- 28712285 TI - Freeze-Thaw Sample Preparation Method Improves Detection of Volatile Compounds in Insects Using Headspace Solid-Phase Microextraction. AB - Headspace solid-phase microextraction (HS-SPME) coupled with gas chromatography mass spectrometry (GC-MS) is commonly used in analyzing insect volatiles. To improve the detection of volatiles in insects, a freeze-thaw method was applied to insect samples before the HS-SPME-GC-MS analysis. Insect samples were first frozen at -80 degrees C for 10 min and then thawed at 25 degrees C for 5 min before SPME extraction was performed. The freeze-thaw method clearly improved the detection of volatile compounds for all six tested insect species, including red imported fire ants, Solenopsis invicta Buren, black imported fire ants, Solenopsis richteri Forel, little black ants, Monomorium minimum (Buckley), pharaoh ants, Monomorium pharaonis (Linnaeus), eastern subterranean termites, Reticulitermes flavipes (Kollar), and spotted lady beetles, Coleomegilla maculate De Geer. This method helped identify various volatile compounds in the tested insects which have never been reported previously. This improved method may facilitate the identification of insect derived volatiles such as insect semiochemicals. PMID- 28712284 TI - Mn(II) Oxidation by the Multicopper Oxidase Complex Mnx: A Binuclear Activation Mechanism. AB - The bacterial protein complex Mnx contains a multicopper oxidase (MCO) MnxG that, unusually, catalyzes the two-electron oxidation of Mn(II) to MnO2 biomineral, via a Mn(III) intermediate. Although Mn(III)/Mn(II) and Mn(IV)/Mn(III) reduction potentials are expected to be high, we find a low reduction potential, 0.38 V (vs Normal Hydrogen Electrode, pH 7.8), for the MnxG type 1 Cu2+, the electron acceptor. Indeed the type 1 Cu2+ is not reduced by Mn(II) in the absence of molecular oxygen, indicating that substrate oxidation requires an activation step. We have investigated the enzyme mechanism via electronic absorption spectroscopy, using chemometric analysis to separate enzyme-catalyzed MnO2 formation from MnO2 nanoparticle aging. The nanoparticle aging time course is characteristic of nucleation and particle growth; rates for these processes followed expected dependencies on Mn(II) concentration and temperature, but exhibited different pH optima. The enzymatic time course is sigmoidal, signaling an activation step, prior to turnover. The Mn(II) concentration and pH dependence of a preceding lag phase indicates weak Mn(II) binding. The activation step is enabled by a pKa > 8.6 deprotonation, which is assigned to Mn(II)-bound H2O; it induces a conformation change (consistent with a high activation energy, 106 kJ/mol) that increases Mn(II) affinity. Mnx activation is proposed to decrease the Mn(III/II) reduction potential below that of type 1 Cu(II/I) by formation of a hydroxide-bridged binuclear complex, Mn(II)(MU-OH)Mn(II), at the substrate site. Turnover is found to depend cooperatively on two Mn(II) and is enabled by a pKa 7.6 double deprotonation. It is proposed that turnover produces a Mn(III)(MU OH)2Mn(III) intermediate that proceeds to the enzyme product, likely Mn(IV)(MU O)2Mn(IV) or an oligomer, which subsequently nucleates MnO2 nanoparticles. We conclude that Mnx exploits manganese polynuclear chemistry in order to facilitate an otherwise difficult oxidation reaction, as well as biomineralization. The mechanism of the Mn(III/IV) conversion step is elucidated in an accompanying paper . PMID- 28712286 TI - Calibration-Free Electrochemical Biosensors Supporting Accurate Molecular Measurements Directly in Undiluted Whole Blood. AB - The need to calibrate to correct for sensor-to-sensor fabrication variation and sensor drift has proven a significant hurdle in the widespread use of biosensors. To maintain clinically relevant (+/-20% for this application) accuracy, for example, commercial continuous glucose monitors require recalibration several times a day, decreasing convenience and increasing the chance of user errors. Here, however, we demonstrate a "dual-frequency" approach for achieving the calibration-free operation of electrochemical biosensors that generate an output by using square-wave voltammetry to monitor binding-induced changes in electron transfer kinetics. Specifically, we use the square-wave frequency dependence of their response to produce a ratiometric signal, the ratio of peak currents collected at responsive and non- (or low) responsive square-wave frequencies, which is largely insensitive to drift and sensor-to-sensor fabrication variations. Using electrochemical aptamer-based (E-AB) biosensors as our test bed, we demonstrate the accurate and precise operation of sensors against multiple drugs, achieving accuracy in the measurement of their targets of within better than 20% across dynamic ranges of up to 2 orders of magnitude without the need to calibrate each individual sensor. PMID- 28712287 TI - Observation and Simulation of Transient Anion Oligomers (LiClO4)n- (n = 1-4) in Diethyl Carbonate LiClO4 Solutions. AB - NMR measurements show that diethyl carbonate (DEC, a solvent with a low dielectric constant) solutions of LiClO4 contain (LiClO4)n oligomers. The reduction of these species by solvated and presolvated electrons is followed by picosecond pulse radiolysis measurements. The data analysis shows that several anions absorbing in the near-infrared (NIR) and visible range are formed after the 7 ps electron pulse. In contrast with tetrahydrofuran (THF) solutions of LiClO4, the anionic monomer (LiClO4)- is not observed in DEC solutions. This is due to the fact that DEC is a nonpolar solvent favoring the clustering of monomers in the nonirradiated solution, as shown by NMR results, and also due to the instability of the anionic monomer. The absorption spectra of the anionic dimer (LiClO4)2-, trimer (LiClO4)3-, and tetramer (LiClO4)4- are clearly observed in NIR and visible ranges. Compared to the results obtained for the same system in THF and in agreement with simulated absorption spectra, the experimental results show that the absorption bands are shifted to the blue end of the spectrum when n increases. The kinetics recorded for the molar LiClO4 solution indicates that the solute is only in the form of oligomers (LiClO4)n with a large n value and that the reduced species absorb weakly in the visible region. Lastly, and contrary to what is known for well-separated ions in polar solvents, it is shown that the (LiClO4)n- anions are not stable with respect to self-reduction, leading to the decomposition of perchlorate anions. In this reaction, the perchlorate anion ClO4- is reduced by the Li atom into a chlorate anion ClO3-. This is proved by the presence of ClO3- and chlorinated species detected by mass spectrometry measurements in irradiated DEC solutions containing LiClO4. PMID- 28712288 TI - Role of Orbital Interactions and Activation Strain (Distortion Energies) on Reactivities in the Normal and Inverse Electron-Demand Cycloadditions of Strained and Unstrained Cycloalkenes. AB - The Diels-Alder reactivities of a series of cycloalkenes, from the highly strained cyclopropene to the unstrained cyclohexene, have been studied with density functional theory using the M06-2X functional. The normal electron-demand Diels-Alder reactions with cyclopentadiene and the inverse electron-demand Diels Alder reactions with 3,6-bis(trifluoromethyl)tetrazine were analyzed using the distortion/interaction-activation strain model. Previous studies showed that activation strain computed from the distorted reactants in the transition structures are larger for unstrained than strained cycloalkenes, and that most of the activation energy differences are accounted for by this difference. We have now analyzed the strain and interaction energy curves for the series of cycloalkenes along the reaction coordinate. Our analyses reveal that the strain curves associated with the distortion of the reactants in the Diels-Alder reactions are nearly identical and that the reactivity differences originate from differences in interaction energies. Analysis of the diene-dienophile interactions reveal that the reactivity trends result from differences in the strength of the primary and secondary orbital interactions. PMID- 28712289 TI - Comprehensive Proteomic Analysis of PGC7-Interacting Proteins. AB - Primordial germ cell 7 (PGC7), a maternal factor essential for early development, plays a critical role in the regulation of DNA methylation, transcriptional repression, chromatin condensation, and cell division and the maintenance of cell pluripotentiality. Despite the fundamental roles of PGC7 in these cellular processes, only a few molecular and functional interactions of PGC7 have been reported. Here, a streptavidin-biotin affinity purification technique combined with LC-MS/MS was used to analyze potential proteins that interact with PGC7. In total, 291 potential PGC7-interacting proteins were identified. Through an in depth bioinformatic analysis of potential interactors, we linked PGC7 to critical cellular processes including translation, RNA processing, cell cycle, and regulation of heterochromatin structure. To better understand the functional interactions of PGC7 with its potential interactors, we constructed a protein protein interaction network using the STRING database. In addition, we discussed in detail the interactions between PGC7 and some of its newly validated partners. The identification of these potential interactors of PGC7 expands our knowledge on the PGC7 interactome and provides a valuable resource for understanding the diverse functions of this protein. PMID- 28712290 TI - High-Affinity-Assisted Nanoscale Alloys as Remarkable Bifunctional Catalyst for Alcohol Oxidation and Oxygen Reduction Reactions. AB - A key challenge in developing fuel cells is the fabrication of low-cost electrocatalysts with high activity and long durability for the two half reactions, i.e., the methanol/ethanol oxidation reaction (MOR/EOR) and the oxygen reduction reaction (ORR). Herein, we report a conductivity-enhanced bifunctional electrocatalyst of nanoscale-coated Pt-Pd alloys on both tin-doped indium (TDI) and reduced graphene oxide (rGO), denoted as Pt-Pd@TDI/rGO. The mass activities of Pt in the Pt-Pd@TDI/rGO hybrid toward MOR, EOR, and ORR are 2590, 1500, and 2690 mA/mg, respectively. The ORR Pt specific activity and mass activity of the electrocatalyst are 17 and 28 times larger, respectively, than commercial Pt/C catalysts. All these remarkable catalytic performances are attributed to the role of TDI in enhancing the catalytic activity by protecting Pt from oxidation as well as rapid mass/charge transfer due to the synergistic effect between surface Pt-Pd alloys and TDI/rGO. PMID- 28712291 TI - Programming Cell Adhesion for On-Chip Sequential Boolean Logic Functions. AB - Programmable remodelling of cell surfaces enables high-precision regulation of cell behavior. In this work, we developed in vitro constructed DNA-based chemical reaction networks (CRNs) to program on-chip cell adhesion. We found that the RGD functionalized DNA CRNs are entirely noninvasive when interfaced with the fluidic mosaic membrane of living cells. DNA toehold with different lengths could tunably alter the release kinetics of cells, which shows rapid release in minutes with the use of a 6-base toehold. We further demonstrated the realization of Boolean logic functions by using DNA strand displacement reactions, which include multi input and sequential cell logic gates (AND, OR, XOR, and AND-OR). This study provides a highly generic tool for self-organization of biological systems. PMID- 28712292 TI - Crystal Structure of Cocosin, A Potential Food Allergen from Coconut (Cocos nucifera). AB - Coconut (Cocos nucifera) is an important palm tree. Coconut fruit is widely consumed. The most abundant storage protein in coconut fruit is cocosin (a likely food allergen), which belongs to the 11S globulin family. Cocosin was crystallized near a century ago, but its structure remains unknown. By optimizing crystallization conditions and cryoprotectant solutions, we were able to obtain cocosin crystals that diffracted to 1.85 A. The cocosin gene was cloned from genomic DNA isolated from dry coconut tissue. The protein sequence deduced from the predicted cocosin coding sequence was used to guide model building and structure refinement. The structure of cocosin was determined for the first time, and it revealed a typical 11S globulin feature of a double layer doughnut-shaped hexamer. PMID- 28712293 TI - Spectroscopic Study of Thiophene-Pyrrole-Containing S,N-Heteroheptacenes Compared to Acenes and Phenacenes. AB - In this study, we report a detailed spectroscopic study concerning the energy levels and vibrational structure of thiophene-pyrrole-containing S,N heteroacenes. The aim of the study is first, to understand the differences in the photoluminescence (PL) efficiencies in this structurally similar series and second, to compare the electronic structure of S,N-heteroacenes to that of linear acenes and phenacenes, with a view to derive guidelines for the design of singlet fission materials. For S,N-heteroacenes comprising seven fused heterocyclic rings, we observe a higher PL quantum yield for derivatives with terminal thienothiophene units than for thienopyrrole-capped ones. This is assigned to a stronger tendency of the thienopyrrole-capped derivatives to form nonemissive associates in dilute solution, producing emissive excimers at higher concentration. By conducting time-resolved PL studies at 77 K, we further determine the lowest singlet and triplet energies for the S,N-heteroacenes with three, five, and seven fused rings. We show that their energies evolve with oligomer length analogously to those of phenacenes, yet in a fundamentally different way from that of linear acenes. This difference in evolution is attributed to the increasingly biradical character in acenes with increasing chain length in contrast to the S,N-heteroacenes and phenacenes. PMID- 28712294 TI - Giant Pickering Droplets: Effect of Nanoparticle Size and Morphology on Stability. AB - The interaction between a pair of millimeter-sized nanoparticle-stabilized n dodecane droplets was analyzed using a high-speed video camera. The droplets were grown in the presence of either poly(glycerol monomethacrylate)-poly(benzyl methacrylate) (PGMA-PBzMA) diblock copolymer spheres or poly(glycerol monomethacrylate)-poly(2-hydroxypropyl methacrylate)-poly(benzyl methacrylate) (PGMA-PHPMA-PBzMA) triblock copolymer worms prepared by polymerization-induced self-assembly. The effect of nanoparticle morphology on droplet coalescence was analyzed by comparing 22 nm spheres to highly anisotropic worms with a mean worm width of 26 nm and comparable particle contact angle. Both morphologies lowered the interfacial tension, providing direct evidence for nanoparticle adsorption at the oil-water interface. At 0.03 w/v % copolymer, an aging time of at least 90 s was required to stabilize the n-dodecane droplets in the presence of the worms, whereas no aging was required to produce stable droplets when using the spheres, suggesting faster diffusion of the latter to the surface of the oil droplets. The enhanced stability of the sphere-coated droplets is consistent with the higher capillary pressure in this system as the planar interfaces approach. However, the more strongly adsorbing worms ultimately also confer stability. At lower copolymer concentrations (<=0.01 w/v %), worm adsorption promoted droplet stability, whereas the spheres were unable to stabilize droplets even after longer aging times. The effect of mean sphere diameter on droplet stability was also assessed while maintaining an approximately constant particle contact angle. Small spheres of either 22 or 41 nm stabilized n-dodecane droplets, whereas larger spheres of either 60 or 91 nm were unable to prevent coalescence when the two droplets were brought into contact. These observations are consistent with the greater capillary pressure stabilizing the oil-water interfaces coated with the smaller spheres. Addition of an oil-soluble polymeric diisocyanate cross linker to either the 60 or the 91 nm spheres produced highly stable colloidosomes, thus confirming adsorption of these nanoparticles. PMID- 28712295 TI - Closing the Mass Balance on Fluorine on Papers and Textiles. AB - Papers and textiles that are treated with per- and polyfluoroalkyl substances (PFASs) are sources of human and environmental exposure. Data for individual PFASs, such as perfluorooctanesulfonate (PFOS) and perfluorooctanoate (PFOA), are not placed into the context of total fluorine for papers and textiles. Gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) were used to quantify volatile and ionic PFASs, respectively, and the total oxidizable precursor (TOP) assay was used to quantify precursors that form perfluoroalkyl carboxylates. Molar sums of PFASs obtained by GC-MS, LC-MS/MS, and precursors were compared to total fluorine (nmol F/cm2) determined by particle-induced gamma ray emission (PIGE) spectroscopy, measured before and after extraction. Volatile and ionic PFASs and unknown precursors accounted for 0-2.2%, 0-0.41%, and 0.021-14%, respectively, of the total nmol F/cm2 determined by PIGE. After extraction, papers and textiles retained 64 +/- 28% to 110 +/- 30% of the original nmol F/cm2 as determined by PIGE, indicating that the majority of fluorine remains associated with the papers and textiles. The sum of PFASs in the volatile, ionic, and precursor fraction, and total fluorine after extraction indicate that mass balance was achieved (within analytical error) of the initial total fluorine measured by PIGE. PMID- 28712296 TI - Competing Annulene and Radialene Structures in a Single Anti-Aromatic Molecule Studied by High-Resolution Atomic Force Microscopy. AB - According to Huckel theory, an anti-aromatic molecule possessing (4n)pi-electrons becomes unstable. Although the stabilization has been demonstrated by radialene type structures-fusing aromatic rings to anti-aromatic rings-in solution, such molecules have never been studied at a single molecular level. Here, we synthesize a cyclobutadiene derivative, dibenzo[b,h]biphenylene, by an on-surface intramolecular reaction. With a combination of high-resolution atomic force microscopy and density functional theory calculations, we found that a radialene structure significantly reduces the anti-aromaticity of the cyclobutadiene core, extracting pi-electrons, while the small four-membered cyclic structure keeps a high density of the total charge. PMID- 28712297 TI - Photocatalytic Conversion of Nitrogen to Ammonia with Water on Surface Oxygen Vacancies of Titanium Dioxide. AB - Ammonia (NH3) is an essential chemical in modern society. It is currently manufactured by the Haber-Bosch process using H2 and N2 under extremely high pressure (>200 bar) and high-temperature (>673 K) conditions. Photocatalytic NH3 production from water and N2 at atmospheric pressure and room temperature is ideal. Several semiconductor photocatalysts have been proposed, but all suffer from low efficiency. Here we report that a commercially available TiO2 with a large number of surface oxygen vacancies, when photoirradiated by UV light in pure water with N2, successfully produces NH3. The active sites for N2 reduction are the Ti3+ species on the oxygen vacancies. These species act as adsorption sites for N2 and trapping sites for the photoformed conduction band electrons. These properties therefore promote efficient reduction of N2 to NH3. The solar-to chemical energy conversion efficiency is 0.02%, which is the highest efficiency among the early reported photocatalytic systems. This noble-metal-free TiO2 system therefore shows a potential as a new artificial photosynthesis for green NH3 production. PMID- 28712298 TI - The Fragment Network: A Chemistry Recommendation Engine Built Using a Graph Database. AB - The hit validation stage of a fragment-based drug discovery campaign involves probing the SAR around one or more fragment hits. This often requires a search for similar compounds in a corporate collection or from commercial suppliers. The Fragment Network is a graph database that allows a user to efficiently search chemical space around a compound of interest. The result set is chemically intuitive, naturally grouped by substitution pattern and meaningfully sorted according to the number of observations of each transformation in medicinal chemistry databases. This paper describes the algorithms used to construct and search the Fragment Network and provides examples of how it may be used in a drug discovery context. PMID- 28712299 TI - Evaluation of Efficacy and Toxicity of Exfoliated Silicate Nanoclays as a Feed Additive for Fumonisin Detoxification. AB - The efficacy of nanosilicate clay platelets (NSCP), exfoliated silicates from natural montmorillonites, as a feed additive for ameliorating fumonisin B1 (FB1) toxicosis was evaluated. Toxicological mechanisms by NSCP were examined through proteomic and biochemical analyses. Dietary supplementation with NSCP at a low level of 40 mg/kg of feed improved growth performances in chickens with respect to FB1 toxicosis. Other issues of ameliorated symptoms including serum and/or hepatic aspartate aminotransferase activity, oxidative stress indicators, and sphinganine/sphingosine ratio, a hallmark of FB1 toxicosis, were considered. Chickens with NSCP inclusion alone at 1000 mg/kg of feed exhibited no changes in hepatic histology, oxidative status, and serum parameters and even had a higher feed intake. Proteomic analysis with liver tissues identified 45 distinct proteins differentially affected by FB1 and/or NSCP, in which proteins involved in thiol metabolism and redox regulation, glycolysis, carcinogenesis, and detoxification by glutathione S-transferase were promoted by FB1, whereas NSCP caused differential changes of protein abundances related to methionine/cysteine and choline/glycine interconversion for glutathione synthesis, redox regulation by peroxiredoxin, toxin/metabolite delivery by albumin, glycolysis, tricarboxylic acid cycle, adenosine triphosphate (ATP) synthesis, and chaperon escort for endoplasmic reticulum stress relief. Functional analyses confirmed the enhancement of hepatic metabolic processes for ATP and NAD(P)H production to meet the need for detoxification, antioxidative defense, and toxin/metabolite clearance by FB1 or NSCP ingestion. On the basis of the amelioration of FB1 toxicosis, global profile of hepatic protein expressions, and validated toxicological mechanisms, NSCP were concluded as a safe and effective agent for FB1 detoxification. PMID- 28712302 TI - Overcoming the Hydrolytic Lability of a Reaction Intermediate in Production of Protein/Drug Conjugates: Conjugation of an Acyclic Nucleoside Phosphonate to a Model Carrier Protein. AB - Acquired immunodeficiency syndrome (AIDS) remains one of the most serious public health challenges and a significant cause of mortality for certain populations. Despite the large number of antiretrovirals developed in the past two decades, the inability of small molecule therapeutics to target HIV reservoirs directly creates a significant obstacle to their effective utilization. Indeed, achieving the desired therapeutic outcome in the absence of an effective means of targeted delivery must rely on dosage escalation, which frequently causes severe toxicity. This problem may be solved by conjugation of antiretroviral agents to endogenous proteins that are specifically recognized by HIV reservoirs (such as macrophages) for internalization and catabolism. However, conjugation of a large class of antiretroviral agents (acyclic nucleoside phosphonates, such as adefovir, tenofovir, and cidofovir) to a protein is challenging due to rapid degradation of the activated form of the drug (e.g., adefovir phosphonoimidazolide) in an aqueous environment. A novel synthetic strategy introduced in this work overcomes the instability of the activated form of adefovir by emulating the first step of its metabolic pathway (phosphorylation), making it highly reactive toward primary amine groups of proteins and, at the same time, less prone to hydrolysis by water. Efficient conjugation of the phosphorylated form of adefovir to a protein following activation with EDC (1-ethyl-3-(3-(dimethylamino)propyl)carbodiimide hydrochloride) and imidazole was demonstrated using a model protein. Mass spectrometry (MS) was used to identify conditions that favor formation of conjugates with minimal side products, and online ion exchange chromatography/MS analysis of the products revealed the presence of multiple positional isomers within the 1:1 protein/drug conjugates. Both liquid chromatography/MS data and the analysis of ions produced upon top-down fragmentation of the 1:1 conjugates suggest that conjugation of phosphorylated adefovir to the protein occurs not only at primary amines but also at hydroxyl groups. The new conjugation protocol can be used to attach adefovir and other acyclic nucleoside phosphonates to proteins recognized by the cell surface receptors specific to macrophages (such as the haptoglobin/hemoglobin complex), enabling targeted drug delivery directly to HIV reservoirs. PMID- 28712300 TI - Continuous Intestinal Absorption Model Based on the Convection-Diffusion Equation. AB - Prediction of the rate and extent of drug absorption upon oral dosing needs models that capture the complexities of both the drug molecule and intestinal physiology. We report here the development of a continuous intestinal absorption model based on the convection-diffusion equation. The model includes explicit enterocyte apical membrane and intracellular lipid radial compartments along the length of the intestine. Physiologic functions along length x are built into the model and include velocity, diffusion, surface areas, and pH of the intestine. Also included are expression levels of the intestinal active uptake transporter OATP2B1 and efflux transporter P-gp. Oral dosing of solution as well as solid (with a dissolution function) was modeled for several drugs. The fraction absorbed (FA) and concentration-time (C-t) profiles were predicted and compared with clinical data. Overall, FA was well predicted upon oral (n = 21) or colonic dosing (n = 11), with four outliers. The overall accuracy (prediction of the correct bin) was 81% with outliers and 90% without outliers. Of the nine solution dosing data sets, six drugs were very well predicted with an exposure overlap coefficient (EOC) > 0.9 and predicted Cmax and Tmax values similar to those observed. Of the six solid dose formulations evaluated, the EOC values were > 0.9 for all drugs except budesonide. The observed precipitation of nifedipine at high doses was predicted by the model. Most of the poor predictions were for drugs that are known to be transporter substrates. As proof of concept, incorporating OATP2B1 and P-gp markedly improved the EOC and predicted Cmax and Tmax for fexofenadine. Finally, the continuous intestinal model accurately recapitulated the known relationships between drug absorption and permeability, solubility, and particle size. Together, these results indicate that this preliminary intestinal absorption model offers a simple and straightforward framework to build in complexities such as drug permeability, lipid partitioning, solubility, metabolism, and transport for improved prediction of the rate and extent of drug absorption. PMID- 28712303 TI - Mn(II) Oxidation by the Multicopper Oxidase Complex Mnx: A Coordinated Two-Stage Mn(II)/(III) and Mn(III)/(IV) Mechanism. AB - The bacterial manganese oxidase MnxG of the Mnx protein complex is unique among multicopper oxidases (MCOs) in carrying out a two-electron metal oxidation, converting Mn(II) to MnO2 nanoparticles. The reaction occurs in two stages: Mn(II) -> Mn(III) and Mn(III) -> MnO2. In a companion study , we show that the electron transfer from Mn(II) to the low-potential type 1 Cu of MnxG requires an activation step, likely forming a hydroxide bridge at a dinuclear Mn(II) site. Here we study the second oxidation step, using pyrophosphate (PP) as a Mn(III) trap. PP chelates Mn(III) produced by the enzyme and subsequently allows it to become a substrate for the second stage of the reaction. EPR spectroscopy confirms the presence of Mn(III) bound to the enzyme. The Mn(III) oxidation step does not involve direct electron transfer to the enzyme from Mn(III), which is shown by kinetic measurements to be excluded from the Mn(II) binding site. Instead, Mn(III) is proposed to disproportionate at an adjacent polynuclear site, thereby allowing indirect oxidation to Mn(IV) and recycling of Mn(II). PP plays a multifaceted role, slowing the reaction by complexing both Mn(II) and Mn(III) in solution, and also inhibiting catalysis, likely through binding at or near the active site. An overall mechanism for Mnx-catalyzed MnO2 production from Mn(II) is presented. PMID- 28712305 TI - From Donor to Recipient: Considerations for Blood Transfusion Outcomes Research. AB - Donated blood can be broken down into blood components for use in patient care. This article focuses primarily on packed red blood cells (PRBCs), as they experience breakdown during storage that may adversely impact patient outcomes. Patients require PRBC transfusions for a number of clinical reasons. Although transfusions of PRBCs provide some clinical benefit, they are also associated with increased morbidity and mortality across multiple patient populations, albeit the mechanisms underlying this relationship remain unclear. With an aging, more acutely ill population requiring aggressive treatment and a lack of transfusion alternatives, research focused on PRBCs has gained momentum. Proper interpretation of research findings on the part of clinicians depends on accurate data collection that includes aspects of both the transfused blood components and the recipients. The purpose of this article is to examine stored PRBC factors, blood-donor characteristics, transfusion-specific factors, and patient-specific characteristics as they relate to patient outcomes research. Challenges associated with performing and interpreting outcomes of transfusion-related research are presented. Implications of current evidence for patient care, such as awareness of benefits as well as risks associated with blood component transfusion, are also provided. PMID- 28712307 TI - Deaf: A Concept Analysis From a Cultural Perspective Using the Wilson Method of Concept Analysis Development. AB - The purpose of this article is to provide an analysis of the concept Deaf to increase health care provider (HCP) understanding from a cultural perspective. Deaf signers, people with hearing loss who communicate primarily in American Sign Language (ASL), generally define the term Deaf as a cultural heritage. In the health care setting, the term deaf is most often defined as a pathological condition requiring medical intervention. When HCPs are unaware that there are both cultural and pathological views of hearing loss, significant barriers may exist between the HCP and the Deaf individual. The concept of Deaf is analyzed using the Wilsonian method. Essential elements of the concept "Deaf" from a cultural perspective include a personal choice to communicate primarily in ASL and identify with the Deaf community. Resources for HCPs are needed to quickly identify Deaf signers and provide appropriate communication. PMID- 28712306 TI - Targeting intrinsic apoptosis and other forms of cell death by BH3-mimetics in glioblastoma. AB - INTRODUCTION: Novel approaches to treat malignant brain tumors are necessary since these neoplasms still display an unfavorable prognosis. Areas covered: In this review, the authors summarize and analyze recent preclinical data that suggest that targeting intrinsic apoptosis may be a suitable strategy for the treatment of malignant gliomas. They focus on the anti-apoptotic Bcl-2 family members of proteins and the recent drug developments in that field with a special focus on BH3-mimetics. With the discovery of BH3-mimetics that interfere with anti-apoptotic Bcl-2 family members in the low nanomolar range significant excitement has been generated towards these class of inhibitors, such as ABT-737, ABT-263 and the most recent successor, ABT-199 which is most advanced with respect to clinical application. The authors discuss the more recent selective inhibitors of Bcl-xL and Mcl-1. Concerning Mcl-1, these novel classes of inhibitors have the potential to impact malignant gliomas since these tumors reveal increased levels of Mcl-1. Expert opinion: The recent development of certain small molecules raises significant hope that intrinsic apoptosis might soon be efficiently targetable for malignancies of the central nervous system. That being said, additional studies are necessary to determine which of the BH3 mimetics might be most suitable. PMID- 28712308 TI - Erratum. AB - Wu R, An DA, Hu J, et al. The apparent diffusion coefficient is strongly correlated with extracellular volume, a measure of myocardial fibrosis, and subclinical cardiomyopathy in patients with systemic lupus erythematosus. Acta Radiol 2017. DOI: 10.1177/0284185117717763. In the above-referenced article, the corresponding author was wrongly listed as "Lian-Ming Wu" in the initial OnlineFirst version. The online and print versions have been updated to reflect the correct corresponding author, "Jian-Rong Xu." PMID- 28712304 TI - Regulation of Cellular Redox Signaling by Matricellular Proteins in Vascular Biology, Immunology, and Cancer. AB - SIGNIFICANCE: In contrast to structural elements of the extracellular matrix, matricellular proteins appear transiently during development and injury responses, but their sustained expression can contribute to chronic disease. Through interactions with other matrix components and specific cell surface receptors, matricellular proteins regulate multiple signaling pathways, including those mediated by reactive oxygen and nitrogen species and H2S. Dysregulation of matricellular proteins contributes to the pathogenesis of vascular diseases and cancer. Defining the molecular mechanisms and receptors involved is revealing new therapeutic opportunities. Recent Advances: Thrombospondin-1 (TSP1) regulates NO, H2S, and superoxide production and signaling in several cell types. The TSP1 receptor CD47 plays a central role in inhibition of NO signaling, but other TSP1 receptors also modulate redox signaling. The matricellular protein CCN1 engages some of the same receptors to regulate redox signaling, and ADAMTS1 regulates NO signaling in Marfan syndrome. In addition to mediating matricellular protein signaling, redox signaling is emerging as an important pathway that controls the expression of several matricellular proteins. CRITICAL ISSUES: Redox signaling remains unexplored for many matricellular proteins. Their interactions with multiple cellular receptors remains an obstacle to defining signaling mechanisms, but improved transgenic models could overcome this barrier. FUTURE DIRECTIONS: Therapeutics targeting the TSP1 receptor CD47 may have beneficial effects for treating cardiovascular disease and cancer and have recently entered clinical trials. Biomarkers are needed to assess their effects on redox signaling in patients and to evaluate how these contribute to their therapeutic efficacy and potential side effects. Antioxid. Redox Signal. 27, 874-911. PMID- 28712311 TI - Feasibility and efficacy of an attachment-based intervention in a maltreatment sample in residential care: A pilot study. AB - The effects of the Video-feedback Intervention to promote Positive Parenting and Sensitive Discipline on improving maternal sensitivity and sensitive discipline were investigated using a randomized control design in a pilot sample of mothers at high risk of maltreatment. The study included 12 mothers and their 10- to 36 month-old children placed in parental residential care, due to a guardianship order issued by the Youth Court. Both at pretest and post-test, maternal sensitivity and sensitive discipline were assessed during mother-child interaction via observational measures. Mothers who received the intervention showed a significant reduction in dysfunctional strategies of maternal discipline. Results highlight the usefulness and feasibility of a brief residential care-based intervention in such a risk sample, with promising implications for the prevention of child maltreatment. PMID- 28712310 TI - Primary Cutaneous Peripheral T-Cell Lymphoma in a Sporotrichoid Pattern: A Case Report. AB - We present the extraordinary case of a 72-year-old man with a history of primary cutaneous peripheral T-cell lymphoma not otherwise specified (pcPTCL-NOS) previously controlled with topical agents who developed tumours in a sporotrichoid pattern. Culture of the tumours was negative, and histopathology showed findings consistent with recurrent pcPTCL. The tumours were successfully treated with localised radiation therapy. Sporotrichoid lesions are an extremely rare and atypical presentation of cutaneous lymphoma, with only 2 other cases reported in the literature. Our case reinforces the need to include cutaneous lymphoma in the differential diagnosis of nodules on the extremities spreading in a sporotrichoid pattern. Clinical recognition of this atypical presentation of cutaneous lymphoma allows for prompt, effective treatment, which might include localised radiation therapy. PMID- 28712312 TI - Near Full-Length Genome Sequence of a Novel HIV-1 Second-Generation Recombinant Form (CRF01_AE/CRF07_BC) Detected Among Blood Donors in North China. AB - In this study, a novel CRF01_AE/07_BC HIV-1 recombinant form, with five breakpoints in the pol, vpr, env, and nef gene regions, was identified from a voluntary blood donor in North China. Our study showed that this HIV-1 recombinant form might be a second-generation recombinant form from two predominant strains in the men who have sex with men (MSM) population, with the CRF07_BC fragments belonging to a CRF07_BC lineage specific to Chinese MSM and the CRF01_AE fragments belonging to the CRF01_AE lineage 5 common among MSM in northern China. Our findings supported the high-risk blood donation behaviors of MSM, implied the increasing complexity of the HIV-1 epidemic among the Chinese MSM population, and called more attention to the effectiveness of the screening test for the growing number of new HIV-1 recombinant forms. PMID- 28712313 TI - Compulsory military service as a measure of later physical and cognitive performance in male survivors of childhood cancer. AB - BACKGROUND: Compromised physical fitness and cognitive difficulties have been reported as late effects of cancer treatment during childhood. To assess this issue, the military rankings of cancer survivors in medical checkups at call-up, and conscripts' physical and cognitive performance during the first weeks of compulsory military education were compared to those of matched population controls without a history of cancer. MATERIAL AND METHODS: A total of 1680 male patients born between 1960 and 1992 with a malignancy diagnosed before the age of 16 who were alive at the call-up age (18 years) were identified using the Finnish Cancer Registry, and five age, sex and place of residence matched controls for each patient using the Population Register Centre. Data on military service were gathered from Finnish Defense Forces. A conditional logistic regression analysis, the GEE-method with the cumulative logit link function, the chi-square test, the chi-square test for trend and a one-way analysis of variance were used in different analyses. RESULTS: Cancer survivors were exempted from military service more often than the controls (p < .001). The fit-for-service frequency was highest for survivors of kidney tumors (68%) and lowest after irradiated brain tumors (19%). In service, the results of the 12-min running test were poorer than those of controls for leukemia/non-Hodgkin lymphoma (p = .03) and brain tumor (p = .01) survivors. Interestingly, the standing long-jump test was the only muscle test for which survivor groups performed worse than controls. Performance on cognitive tests only differed from controls in brain tumor survivors. CONCLUSIONS: Exemption from service is still common under the current guidelines, but fit-for-service survivors do well in military education. These results can be used for reassuring survivors that completion of military service is possible for those fulfilling the national general guidelines for military fitness. PMID- 28712315 TI - Debate on the value of end-of-treatment FDG-PET response evaluation in follicular lymphoma. PMID- 28712314 TI - Angiogenesis inhibitors and symptomatic anal ulcers in metastatic colorectal cancer patients *. AB - BACKGROUND: Angiogenesis inhibitors are a standard first-line treatment for metastatic colorectal cancer. Anal canal pain is a common adverse event, but its cause has never been described. The aim of the study was to evaluate the association between the use of angiogenesis inhibitors and symptomatic anal ulcer development. METHODS: This retrospective cohort study included all 601 consecutive metastatic colorectal cancer patients undergoing first line treatment from January 2010 to June 2016 at the Veneto Institute of Oncology. Details about patient characteristics, treatment and proctology reports were retrieved and compared. Vascularization of the anal canal was evaluated with contrast MRI. RESULTS: Fifty out of 601 patients reported perianal complaints during treatment and underwent proctologic evaluation. Among those, 16 were found to have an anal ulcer. Symptomatic anal ulcers occurred only in patients receiving bevacizumab (4.2% vs. 0% with other regimens, p = .009). The peak incidence was 4-8 weeks after treatment start. Vascularization of anal canal was significantly lower in patients treated with bevacizumab (p = .03). Hypertension and hemorrhoids were associated with a lower risk of anal ulcer occurrence (p = .009 and p = .036). Pain intensity was severe. All attempts at symptomatic treatment only led to transient benefit. The absence of symptomatic ulcers was protective against earlier permanent discontinuation of treatment (HR = .22, 95%CI: 0.04-0.62). CONCLUSIONS: The development of symptomatic anal ulcers in patients receiving angiogenesis inhibitor is a common adverse event which can compromise the continuation of cancer therapy. We recommend an early proctologic evaluation in case of anal symptoms with the aim to prevent and timely manage such complication. PMID- 28712309 TI - Improving miRNA Delivery by Optimizing miRNA Expression Cassettes in Diverse Virus Vectors. AB - The RNA interference pathway is an evolutionary conserved post-transcriptional gene regulation mechanism that is exclusively triggered by double-stranded RNA inducers. RNAi-based methods and technologies have facilitated the discovery of many basic science findings and spurred the development of novel RNA therapeutics. Transient induction of RNAi via transfection of synthetic small interfering RNAs can trigger the selective knockdown of a target mRNA. For durable silencing of gene expression, either artificial short hairpin RNA or microRNA encoding transgene constructs were developed. These miRNAs are based on the molecules that induce the natural RNAi pathway in mammals and humans: the endogenously expressed miRNAs. Significant efforts focused on the construction and delivery of miRNA cassettes in order to solve basic biology questions or to design new therapy strategies. Several viral vectors have been developed, which are particularly useful for the delivery of miRNA expression cassettes to specific target cells. Each vector system has its own unique set of distinct properties. Thus, depending on the specific application, a particular vector may be most suitable. This field was previously reviewed for different viral vector systems, and now the recent progress in the field of miRNA-based gene-silencing approaches using lentiviral vectors is reported. The focus is on the unique properties and respective limitations of the available vector systems for miRNA delivery. PMID- 28712316 TI - Disturbed bovine mitochondrial lipid metabolism: a review. AB - In mammals, excess energy is stored primarily as triglycerides, which are mobilized when energy demands arise and cannot be covered by feed intake. This review mainly focuses on the role of long chain fatty acids in disturbed energy metabolism of the bovine species. Long chain fatty acids regulate energy metabolism as ligands of peroxisome proliferator-activated receptors. Carnitine acts as a carrier of fatty acyl groups as long-chain acyl-CoA derivatives do not penetrate the mitochondrial inner membrane. There are two different types of disorders in lipid metabolism which can occur in cattle, namely the hypoglycaemic hypoinsulinaemic and the hyperglycaemic-hyperinsulinaemic type with the latter not always associated with ketosis. There is general agreement that fatty acid beta-oxidation capability is limited in the liver of (ketotic) cows. In accord, supplemental L-carnitine decreased liver lipid accumulation in periparturient Holstein cows. Of note, around parturition concurrent oxidation of fatty acids in skeletal muscle is highly activated. Also peroxisomal beta-oxidation in liver of dairy cows may be part of the hepatic adaptations to a negative energy balance (NEB) to break down fatty acids. An elevated blood concentration of nonesterified fatty acids is one of the indicators of NEB in cattle among others like increased beta-hydroxy butyrate concentration, and decreased concentrations of glucose, insulin, and insulin-like growth factor-I. Assuming that liver carnitine concentrations might limit hepatic fatty acid oxidation capacity in dairy cows, further study of the role of acyl-CoA dehydrogenases and/or riboflavin in bovine ketosis is warranted. PMID- 28712317 TI - Genetic variation of the land-locked freshwater shrimp Caridina pseudodenticulata (Decapoda: Atyidae: Caridina) in Taiwan. AB - Caridina pseudodenticulata is a land-locked freshwater shrimp, which is endemic to North and West Taiwan. It is listed as Vulnerable under criteria A1ce in the IUCN Red List. Our study used mitochondrial DNA fragment sequences of the cytochrome oxidase subunit I (COI) gene to examine its genetic structure. In total, 204 sequences were analyzed from 22 populations, and all 39 haplotypes were identified. Our study (1) found that the genetic diversity within population of this species was similar to that of other land-locked freshwater prawn in Taiwan; (2) displayed that during glaciation, the Taiwan Strait was largely above water, an event which created opportunities for colonization Taiwan and dispersal widely; (3) showed that although the phylogenetic analysis showed the lack of a population genetic structure, the AMOVA and haplotypes distribution pattern revealed geographically divided; (4) indicated that C. pseudodenticulata could across to neighbor rivers through the mouths of rivers, which confluent with each other during floods. PMID- 28712318 TI - Phylogenetic studies and comparative chloroplast genome analyses elucidate the basal position of halophyte Nitraria sibirica (Nitrariaceae) in the Sapindales. AB - Nitraria sibirica is a halophyte and belongs to the family Nitrariaceae. The chloroplast genome of Nitraria sibirica (159,466 bp) has a quadripartite structure, which consists of a large single-copy (87,914 bp) region, a small single-copy (18,316 bp) region, and a pair of inverted repeats (26,618 bp). Sequencing analyses indicate that the chloroplast genome contains 113 distinct genes, including 79 peptide-coding genes, 30 transfer RNA genes, and 4 ribosomal RNA genes. We also identified 105 perfect simple sequence repeats, 12 most divergent non-coding regions, and 6 most divergent coding regions when compared to the chloroplast genomes of the Sapindales plants. Phylogenetic analyses using the concatenated amino acid sequences of 58 protein-coding genes from 48 species suggest that the 'basal' position of Nitraria sibirica belongs to the Sapindales clade. We also found that the inverted repeat expansion resulted in a duplication of rps19 in Nitraria sibirica when comparing its chloroplast genome structure with Theobroma cacao, Vitis vinifera, Eucalyptus erythrocorys and Arabidopsis thaliana. The duplication of rps19 gene was consistent with that in Zanthoxylum piperitum, Azadirachta indica, Sapindus mukorossi and Citrus sinensis, all of which belong to the order Sapindales, but different from most Rosids plants. In summary, the analyses of Nitraria sibirica chloroplast genome not only provide insights into comparative genome analysis, but also pave the way for a better understanding of the phylogenetic relationships within the Sapindales. PMID- 28712319 TI - Primary liver cancer genome sequencing: translational implications and challenges. AB - INTRODUCTION: The prognosis of primary liver cancer (PLC) remains poor and is explained by the slow progress in understanding the molecular pathways driving tumorigenesis, therapeutic resistance and relapse. For early PLCs, complete surgical resection is the only effective treatment, with sorafenib and, more recently, regorafenib prolonging overall survival by a few months. Areas covered: Application of next-generation sequencing (NGS), including targeted NGS (tNGS), whole-exome sequencing (WES), whole-genome sequencing (WGS) and RNA sequencing (RNAseq), on clinical samples from patients with hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) could aid in comprehending tumorigenesis, genetic and genomic heterogeneity, as well as developing molecular classifications for specialized targeted therapy. Expert commentary: Despite the many overenthusiastic original and opinion reports, we have critically reviewed available NGS studies, with focus on the challenges to achieve clinical implications. Based on the recommendations for valid identification of clinically crucial genomic alterations (GAs) by NGS, we propose NGS integration into appropriately designed clinical trials. Furthermore, valid detection of genomic heterogeneity enables the conduction of clinical trials investigating the efficacy both of GAs as prognostic and predictive tools, as well as the discovery of novel oncotargets, on the basis of an early drug development strategy. PMID- 28712320 TI - Certolizumab Pegol treatment in Behcet's disease with different organ involvement: A multicenter retrospective observational study. AB - OBJECTIVES: The purpose of the present study was to describe our experience with the recombinant Fab' antibody fragment against TNF-alpha Certolizumab Pegol (CZP) in patients with Behcet's disease (BD) refractory to standardized therapies and previous biologic agents. METHODS: Retrieved data including demographic characteristics, clinical manifestations, and previous treatments were collected in three different specialized Rheumatologic Units in Italy. In order to evaluate disease activity, the BD current activity form (BDCAF) has been used before starting CZP therapy and at each visit during treatment. RESULTS: Thirteen BD patients (mean age 42.6 +/- 8.8 years) with a disease duration of 8.80 +/- 6.9 years, underwent CZP treatment for 6.92 +/- 3.52 months. Six patients (46.15%) experienced a worsening of symptoms after 4.16 +/- 1.21 months, whereas a satisfactory response was achieved in seven patients (53.84%) who were still on CZP therapy at the last follow-up visit (after 9.28 +/- 3.03 months of treatment). The mean decrease of BDCAF between the first and last visit was 0.308 +/- 1.84 without reaching significant difference (mean 8.3 +/- 1.3 and 8 +/- 2.08, respectively; p= .51). During the whole study period, CZP was well tolerated in all patients except one who developed a generalized cutaneous reaction after the third administration. CONCLUSIONS: These results suggest that despite an improvement of clinical manifestations has been observed in more than half of the patients, it is not possible to draw firm conclusions about the effectiveness of CZP in BD and further studies with larger cohorts of patients are warranted. Whether the increase of CZP dosage may ensure a better clinical response remains an unsolved issue that needs to be considered. PMID- 28712321 TI - Assessing the effectiveness of mitochondrial COI and 16S rRNA genes for DNA barcoding of farmland spiders in China. AB - DNA barcoding has been widely used to identify and discover new species in a wide range of taxa. In order to assess the effectiveness of COI (cytochrome C oxidase subunit I) and 16S (16S ribosomal RNA) in the discrimination of spiders, we have generated 289 barcodes for a total of 56 farmland spider species from 14 different families for the first time in China. Our results reveal that the standard barcoding marker COI can be used to distinguish the farmland spiders both in species and family level by NJ tree-based method, despite the absence of a barcode gap between the intra- and inter-specific genetic divergences. 16S has a lower species identification success as compared with COI. However, almost 98% of the species can be correctly distinguished for both COI and 16S when a threshold of 3% nucleotide divergence was used for species discrimination. Our study significantly improves the barcode reference sequence library for Chinese farmland spiders, and will be very useful in pest management and eco environmental monitoring and protection. PMID- 28712322 TI - Is now the time for molecular driven therapy for diffuse large B-cell lymphoma? AB - INTRODUCTION: Recent genetic and molecular discoveries regarding alterations in diffuse large B-cell lymphoma (DLBCL) deeply changed the approach to this lymphoproliferative disorder. Novel additional predictors of outcomes and new therapeutic strategies are being introduced to improve outcomes. Areas covered: This review aims to analyse the recent molecular discoveries in DLBCL, the rationale of novel molecular driven treatments and their impact on DLBCL prognosis, especially in ABC-DLBCL and High Grade B Cell Lymphoma. Pre-clinical and clinical evidences are reviewed to critically evaluate the novel DLBCL management strategies. Expert commentary: New insights in DLBCL molecular characteristics should guide the therapeutic approach; the results of the current studies which are investigating safety and efficacy of novel 'X-RCHOP' will probably lead, in future, to a cell of origin (COO) based upfront therapy. Moreover, it is necessary to identify early patients with DLBCL who carried MYC, BCL2 and/or BCL6 rearrangements double hit lymphomas (DHL) because they should not receive standard R-CHOP but high intensity treatment as reported in many retrospective studies. New prospective trials are needed to investigate the more appropriate treatment of DHL. PMID- 28712324 TI - The role of carbonyl reductase 1 in drug discovery and development. AB - INTRODUCTION: Carbonyl reductase 1 (CBR1) plays a critical role in drug metabolism of ketones and aldehydes. CBR1 has broad substrate specificity and is involved in metabolizing a number of clinically important drugs. Areas covered: The impact of CBR1 in drug metabolism and disposition are discussed. The CBR1 enzyme is covered in detail including discussion on topics such as tissue distribution, species difference, individual variability, the effect of genetic polymorphism and disease state, iGnducibility and drug-drug interaction potential. The structure and function of CBR1 and CBR3 are also compared. In addition, the formation of chiral alcohols from CBR1 reduction and MIST coverage are reviewed. Expert Opinion: As CBR1 is an emerging enzyme in drug discovery and development, much research is needed to further understand its role in drug metabolism and disposition. In vitro-in vivo correlation for CBR1-mediated clearance is mostly unknown. Selective CBR1 inhibitors and substrates are not well enough characterized for reaction phenotyping of the CBR1 pathway. Multiple pathways appear to be involved in the regulation of CBR1. Future investigation will also help reveal their impact on drug-drug interaction potentials and the influence of individual variability. PMID- 28712323 TI - Management of cutaneous Merkel cell carcinoma. AB - PURPOSE: To report the outcomes of patients with previously untreated cutaneous Merkel cell carcinoma (MCC) managed with curative intent. MATERIAL AND METHODS: Between December 1984 and August 2015, 59 patients with previously untreated cutaneous MCC were managed with curative intent with surgery and adjuvant radiotherapy (54 patients) or radiotherapy alone (5 patients) at the University of Florida. Primary sites included head and neck (45 patients), extremities (11 patients) and trunk (3 patients). Adjuvant chemotherapy was employed in 14 patients. Patients were staged according to the AJCC staging system: stage I, 25 patients; stage IIA, 7 patients; and, stage III, 27 patients. No patients had distant metastases. Median follow-up for all patients was 3.2 years (range, 0.3 20.9 years). Median follow-up for survivors was 6.7 years (range, 1.6-20.9 years). RESULTS: The 5-year outcomes were as follows: local control, 91%; regional control, 79%; local-regional control, 77%; disease metastasis-free survival, 60%; cause-specific survival, 53%; and overall survival, 39%. The 5 year outcomes for patients with stage I-IIA versus stage-III disease were the following: local-regional control, 90% versus 57% (p = .0115); distant metastasis free survival, 78% versus 36% (p = .0002); cause-specific survival, 68% versus 35% (p = .0050); and overall survival, 48% versus 27% (p = .0377). Local-regional recurrences occurred in 12 patients; no patients were successfully salvaged. Severe late complications were observed in four patients. CONCLUSIONS: Although radiotherapy alone or combined with surgery results in a relatively high likelihood of local-regional control, the majority of recurrences are distant and approximately half of patients are cured. Patients with regional disease at diagnosis have significantly worse outcomes. PMID- 28712325 TI - Pharmacodynamics of combined estrogen-progestin oral contraceptives: 2. effects on hemostasis. AB - INTRODUCTION: The pharmacodynamic effects of various combined oral estrogen progestin combinations (COC) are examined for their components alone or in the various combined formulations. Special emphasis is given to products containing natural estrogens. Areas covered: Recent information on the effect of androgens, estrogens, progestins, as well as various COC combinations on the coagulation cascade will be reviewed aiming at providing an updated picture. The present article reviews hemostatic changes occurring during use of classic and modern combinations of estrogens (ethinyl estradiol, estradiol, estradiol valerate and estetrol) and new progestins (desogestrel, gestodene, dienogest, drospirenone, nomegestrol acetate), compared to classic compounds, such as levonorgestrel. Both pro- and anti-coagulatory effects of COC in healthy women are detailed and possible links with incidence of thromboembolic events are discussed. Expert commentary: Overall, the picture is reassuring: the use of natural estrogens and of new generation progestins has reduced pro-coagulatory changes in healthy subjects, although the observed differences in the risk of venous thromboembolism between second and third generation progestins is still incompletely understood. At the same time, there still is a need for large comparative and surveillance studies before firm conclusions can be drawn. At any rate, available evidence indicates that hemostatic effects of the newer COC, especially those utilizing natural estrogens, are minimal and often remain with the normal range. PMID- 28712326 TI - Calcium phosphate nanoparticles as a new generation vaccine adjuvant. AB - INTRODUCTION: Adjuvants are essential components in vaccine formulations to induce robust immunity against pathogens. The most widely used adjuvants in human vaccines are aluminum salts, that can effectively elicit a T helper type-2 (Th2) biased humoral immune response for producing a high antibody titer but with a limited cellular immune response. Biocompatible calcium phosphate nanoparticles (CaP-NPs) with tunable characteristics have potentials to function as adjuvants for inducing more balanced T helper type-1 (Th1) and Th2 immune responses. Areas covered: Here we review the preparation procedures and characteristics of CaP NPs. The process can be well-controlled and readily scaled up. Antigen loading can take place as encapsulation during the particle formation or as passive adsorption post particle formation. Different modalities of immunogens were tested with CaP-NPs as adjuvants. The possible mechanisms of the CaP-NP-based adjuvants are discussed. Expert commentary: With good adjuvant effects and safety profiles, CaP-NPs have the potentials to be a new generation vaccine adjuvant. A more in-depth understanding of the mechanisms of their adjuvanticity could facilitate the process optimization for making adjuvants with preferred characteristics. Interdisciplinary collaborations are essential for testing the biocompatible CaP-NPs in human vaccines for clinical development and eventually for use in marketed vaccines. PMID- 28712327 TI - Genetic diversity and phylogenetic relationships of seven Amorphophallus species in southwestern China revealed by chloroplast DNA sequences. AB - Plants species in the genus Amorphophallus are of great economic importance, as they are the only plants known to produce glucomannan. Although southwestern China has been recognized as one of the origin centres of Amorphophallus, only a few studies assessing its genetic diversity have been reported. To aid in the utilization and conservation of Amorphophallus species, we evaluated the genetic diversity and phylogenetic relationships among seven edible Amorphophallus species using three chloroplast DNA regions (rbcL, trnL and trnK-matK). The results showed that the genetic diversity at the population level was relatively low, with over half of the populations harbouring only one haplotype. The widely scattered species, A. konjac, had the largest genetic diversity, while the narrow endemic species, A. yuloensis, possessed only one haplotype. Phylogeny analysis identified three well-supported major lineages. Our study suggested that habitat fragmentation might be a driver of the genetic variation patterns within and between populations of Amorphophallus. A conservation strategy consisting of in situ conservation and germplasm collection is recommended. PMID- 28712328 TI - Knowledge of hypertension and its management among hypertensive patients on chronic medicines at primary health care public sector facilities in South Africa; findings and implications. AB - BACKGROUND: There are high growing prevalence rates of hypertension in South Africa. Consequently, there is a need to assess knowledge and management among hypertensive patients receiving chronic medication from primary health care (PHC) facilities in South Africa as a basis for improving future management. This is important as South Africa seeks to improve its management of chronic diseases. METHODS: Descriptive, quantitative study amongst chronic hypertensive patients in the chronic disease programme. Patients were interviewed face-to-face by trained pharmacists using a structured questionnaire. Data analysis included descriptive and inferential statistics. RESULTS: Half (53.7%) of the patients had uncontrolled blood pressure (BP). Less than a third of patients (27.7%) knew what hypertension is, the meaning of recorded BP numbers (4.5%), and what normal BP should be (19.9%). All patients who knew the meaning of BP numbers had formal education (p = 0.047). Only 15.6% of the 56.0% patients, who received hypertension information, received it on antihypertensive medicines specifically. CONCLUSIONS: The majority of the patients lacked hypertension specific knowledge and only half had controlled BP. Interventions to improve the control of high BP should be targeted at closing knowledge gaps as part of the current chronic treatment initiatives in South Africa to ensure the benefits of increased access to care are realized. PMID- 28712329 TI - Organotypic cultures of cerebellar slices as a model to investigate demyelinating disorders. AB - INTRODUCTION: Demyelinating disorders, characterized by a chronic or episodic destruction of the myelin sheath, are a leading cause of neurological disability in young adults in western countries. Studying the complex mechanisms involved in axon myelination, demyelination and remyelination requires an experimental model preserving the neuronal networks and neuro-glial interactions. Organotypic cerebellar slice cultures appear to be the best alternative to in vivo experiments and the most commonly used model for investigating etiology or novel therapeutic strategies in multiple sclerosis. Areas covered: This review gives an overview of slice culture techniques and focuses on the use of organotypic cerebellar slice cultures on semi-permeable membranes for studying many aspects of axon myelination and cerebellar functions. Expert opinion: Cerebellar slice cultures are probably the easiest way to faithfully reproduce all stages of axon myelination/demyelination/remyelination in a three-dimensional neuronal network. However, in the cerebellum, neurological disability in multiple sclerosis also results from channelopathies which induce changes in Purkinje cell excitability. Cerebellar cultures offer easy access to electrophysiological approaches which are largely untapped and we believe that these cultures might be of great interest when studying changes in neuronal excitability, axonal conduction or synaptic properties that likely occur during multiple sclerosis. PMID- 28712330 TI - The role of abnormalities in the corpus callosum in social cognition deficits after Traumatic Brain Injury. AB - The corpus callosum (CC) is vulnerable to severe traumatic brain injury (TBI). Social cognition requires integration of non-verbal and verbal information in order to understand social behaviour and may be compromised if the CC is damaged. 17 adults with severe, chronic TBI and 17 control participants underwent structural MRI and Diffusion Tensor Imaging. A region of interest analysis examined fractional anisotropy (FA) and mean diffusivity (MD) across regions of the CC. Performance on The Awareness of Social Inference Test (TASIT): part 1 (emotion recognition) and parts 2 and 3 (social inference), was examined in relation to FA and MD. Across participants, higher genu FA values were related to higher TASIT part 3 scores. Increased splenium FA was associated with better performance for TASIT parts 1-3. There was no association between DTI values and TASIT in the controls alone. In the TBI group, FA of the genu and splenium was correlated with TASIT part 3. The pattern of performance was similar when controlling for non-social cognitive ability. In conclusion, social information is complex and multi-modal requiring inter-hemispheric connection. People with TBI, regardless of focal grey matter injury, may lose social cognitive ability due to trauma related changes to the corpus callosum. PMID- 28712331 TI - Feasibility and Efficacy of Mat Pilates on People with Mild-to-Moderate Parkinson's Disease: A Preliminary Study. AB - This pilot study aimed at assessing the feasibility and efficacy of a Mat Pilates program in people with mild-to-moderate Parkinson's disease (PD). The participants carried out a Mat Pilates program twice a week for 12 weeks. The Senior Fitness Test battery and the 39-item PD Questionnaire were used to assess the effects of the program on the participants' fitness level and quality of life. A total of 16 patients with mild-to-moderate PD volunteered for and finished the study. The Mat Pilates program proved to be feasible. Adherence to the program was excellent, and no adverse effects were observed. The program had a positive effect on the participants' fitness levels, except for shoulder range of motion and dynamic balance, and on their quality of life. Assessments at follow-up indicated a regression in the improvements obtained by the end of the intervention, even though the sample still showed higher levels of fitness and quality of life than those tested at baseline. Mat Pilates is feasible and may be a beneficial rehabilitation strategy to improve fitness and quality of life in people with mild-to-moderate PD. Future randomized controlled trials might determine the extent of such benefits. PMID- 28712332 TI - Comparison of commercial baker's yeast versus bacteria-based membrane bioreactors for landfill leachate treatment. AB - This study compares the performance of the membrane bioreactor (MBR) inoculated with commercial baker's yeast (Saccharomyces cerevisiae) (MBRy) versus one inoculated with bacterial sludge (MBRb) for treatment of landfill leachate. The MBRb and MBRy were operated with a hydraulic retention time of 48 h, solids retention time of 60 d, and specific air demand based on membrane area of 0.6 m3 h-1 m-2. The MBRy was more efficient in removing chemical oxygen demand (COD) (68 +/- 12%), color (79 +/- 8%), ammoniacal nitrogen (58 +/- 18%), and phosphorus (62 +/- 19%) compared to MBRb, which showed removal efficiencies of 44 +/- 18%, 46 +/ 20%, 45 +/- 17%, and 29 +/- 15% for COD, color, ammoniacal nitrogen, and phosphorus. Furthermore, the MBRy had lower production of soluble microbial products, which are the main cause of membrane fouling, and so a lower membrane fouling potential. The average hydraulic permeability of the MBRy (32.23 L m-2 h 1 bar-1) was about four times higher than that of the MBRb (8.34 L m-2 h-1 bar 1). Thus using commercial baker's yeasts as a MBR inoculum can enhance pollutants' removal and membrane performance. PMID- 28712334 TI - Retraction Notice. PMID- 28712333 TI - Retraction Notice. PMID- 28712335 TI - Retraction Notice. PMID- 28712336 TI - Clinical and Histological Studies of Suborbital Wrinkles Treated with Fractional Bipolar Radiofrequency. AB - Fractional bipolar radiofrequency (FRF) has been well established for facial rejuvenation, but there is no report showing its efficacy for the treatment of suborbital wrinkles. The aim of this study was to investigate and objectively evaluate the clinical efficacy and side effects of FRF for the treatment of suborbital wrinkles, including observation of histological changes of the suborbital skin along the therapy. Thirty-two female patients with suborbital wrinkles underwent three sessions of FRF at 3-week intervals with a follow-up period of 6 months after treatment. Two independent dermatologists with standardized photographs evaluated improvement grade. Most patients improved according to photographic assessments and the differences between results at 1 and 6 months were not statistically significant (p > 0.05). The median score of pain rated by patients using a visual analog scale (0-10 points) was 4.4 +/- 1.2. Most patients rated themselves as satisfied (68.8%) and very satisfied (9.4%). Ten subjects (31.3%) experienced hyperpigmentation in 24 of all together 96 treatments (25.0%). Skin biopsies of three patients were routinely obtained, processed, and stained, and the histological changes had shown that 1-month after the end of the treatment, both the collagen and normal elastic fibers increased in accordance with the clinical efficacy. The study suggested that FRF is a safe and effective method to treat suborbital wrinkles. PMID- 28712337 TI - Overall effect of carbon production and nutrient release in sludge holding tank on mainstream biological nutrient removal efficiency. AB - The potential of hydrolysis/fermentation of activated sludge in sludge holding tank (SHT) to produce additional carbon for the biological nutrient removal (BNR) process was investigated. The study was conducted in anaerobic batch tests using the BNR sludge (from a full-scale Westside process) and the mixture of BNR sludge with conventional non-BNR activated sludge (to have higher biodegradable particulate chemical oxygen demand (bpCOD) in sludge). The BioWin 4.1 was used to simulate the anaerobic batch test of the BNR sludge. Also, the overall effect of FCOD production and nutrient release on BNR efficiency of the Westside process was estimated. The experimental results showed that the phosphorous uptake of sludge increased during hydrolysis/ fermentation condition up to the point when poly-P was completely utilized; afterwards, it decreased significantly. The BioWin simulation could not predict the loss of aerobic phosphorous uptake after poly-P was depleted. The results showed that in the case of activated sludge with relatively higher bpCOD (originating from plants with short sludge retention time or without primary sedimentation), beneficial effect of SHT on BNR performance is feasible. In order to increase the potential of SHT to enhance BNR efficiency, a relatively low retention time and high sludge load is recommended. PMID- 28712338 TI - Medial prefrontal cortex stimulation modulates irony processing as indexed by the N400. AB - In this study, we investigated whether the ERP responses observed during a verbal irony comprehension task might represent the cortical manifestation of the Medial Prefrontal Cortex (MPFC) activity. We performed a tDCS-EEG study in which we analyzed the effects of tDCS polarities (anode, cathode, sham) over the MPFC during a verbal irony task. We presented visual short stories portraying everyday situations followed by written statements in either an ironic or literal condition, whose meaning was referred to in the previous context. We manipulated the valence of the stimuli by presenting positive sentences or negative sentences in the ironic and literal conditions. The results revealed that the participants who received the anodal stimulation showed no differences in the N400 amplitude in response to the literal and the ironic condition. This could suggest that anodal stimulation has modulatory effects on N400 responses during irony comprehension. Our results indicated that the MPFC might be critical in accessing ironic information at the initial stage of irony comprehension. Finally, we found that the ironic compliments were more difficult to understand compared to the literal ones, suggesting that irony comprehension is affected by the valence of the information presented. PMID- 28712339 TI - The role of bariatric surgery in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. AB - INTRODUCTION: Nonalcoholic fatty liver disease (NAFLD) affects between 25% and 33% of the population, is more common in obese individuals, and is the most common cause of chronic liver disease in the United States. However, despite rising prevalence, effective treatments remain limited. Areas covered: We performed a literature search across multiple databases (Pubmed, Medline, etc.) to identify significant original research and review articles to provide an up-to date and concise overview of disease pathogenesis and diagnostic evaluation and to expand on available treatment options with a specific focus on the potential role of bariatric surgery. Here we provide the most comprehensive review of bariatric surgery for the management of NAFLD, noting benefits from different procedures and multiple reports showing improvements in steatosis, inflammation and fibrosis over the duration of follow-up. Expert commentary: The morbidity of NAFLD is significant as it may become the most common indication for liver transplantation within the next 5 years. In addition to known benefits of weight loss and diabetes resolution, bariatric surgery has the potential to halt and reverse disease progression and future controlled trials should be performed to further define its benefit in the treatment of NAFLD in morbidly obese patients. PMID- 28712340 TI - Deep sequencing reveals the mitochondrial DNA variation landscapes of breast-to brain metastasis blood samples. AB - Breast-to-brain metastasis (BBM) often represents a terminal event, due to the inability of many systemic treatments to cross the blood-brain barrier (BBB), rendering the brain a sanctuary site for tumour cells. Identifying genetic variations that can predict the patients who will develop BBM would allow targeting of adjuvant treatments to reduce risk while disease bulk is minimal. Germ-line genetic variations may contribute to whether a BBM forms by influencing the primary tumour subtype that presents, or by influencing the host response to the tumour or treatment regimen, or by facilitating transition of tumour cells across the BBB and establish a viable brain metastasis. The role of mitochondrial DNA (mtDNA) variants specifically in BBM is underexplored. Consequently, using a sensitive deep sequencing approach, we characterized the mtDNA variation landscapes of blood samples derived from 13 females who were diagnosed with early onset breast cancer and later went on to develop BBM. We also predicted the potential pathogenic significance of variations identified in all mtDNA-encoded oxidative phosphorylation (OXPHOS) proteins using 3D protein structural mapping and analysis, to identify variations worthy of follow-up. From the 70 variations found in protein coding regions, we reveal novel links between three specific mtDNA variations and altered OXPHOS structure and function in 23% of the BBM samples. Further studies are required to confirm the origin of mtDNA variations, and whether they correlate with (1) the predicted alterations in mitochondrial function and (2) increased risk of developing breast-to-brain metastasis using a much larger cohort of samples. PMID- 28712341 TI - Genetic analysis of Bactrocera zonata (Diptera: Tephritidae) populations from India based on cox1 and nad1 gene sequences. AB - The peach fruit fly, Bactrocera zonata, is among the most serious and polyphagous insect pest of fruit crops in many parts of the world under genus Bactrocera. In the present study, the genetic structure, diversity and demographic history of B. zonata in India were inferred from mitochondrial cytochrome oxidase 1 (cox1) and NADH dehydrogenase 1 (nad1) sequences. The efficiency of DNA barcodes for identification of B. zonata was also tested. Genetic diversity indices [number of haplotypes (H), haplotype diversity (Hd), nucleotide diversity (pi) and average number of nucleotide differences (k)] of B. zonata populations across India maintain high level of genetic diversity without isolation by distance among the geographic regions. Non-significant negative correlation between pairwise Fst and geographic distance suggests a high level of gene flow among studied populations of B. zonata. The possibility of sudden expansion of B. zonata revealed through mismatch distribution analysis as well as negative Tajima's D and Fu's Fs values further supported by star-like network of haplotypes. DNA barcoding analysis suggests that B. zonata specimens can be clearly differentiated from other species with 100% accuracy of identification. Therefore, cytochrome oxidase 1 (cox1) barcode sequences generated in the present study could be a valuable source for the rapid identification and global population genetic study of B. zonata. PMID- 28712342 TI - Anterior Cerebral Artery Territory Infarction-Related Resolution of Chronic Lower Back Pain. PMID- 28712343 TI - Overload From Anxiety: A Non-Motor Cause for Gait Impairments in Parkinson's Disease. AB - Threatening situations lead to observable gait deficits in individuals with Parkinson's disease (PD) who suffer from high trait anxiety levels. The specific characteristics of gait that are affected appear to be similar to behaviors observed while walking during a dual-task (DT) condition. Yet, it remains unclear whether anxiety is similar to a cognitive load. If it were, then those with PD who have high trait anxiety might be expected to be more susceptible to DT interference during walking. Thus, the overall aim of this study was to evaluate whether trait anxiety influences gait during single-task (ST) and DT walking. Seventy participants (high-anxiety PD [HA-PD], N=26; low-anxiety PD [LA-PD], N=26; healthy control [HC], N=18) completed three ST and three DT walking trials on a data-collecting carpet. The secondary task consisted of digit monitoring while walking. Results showed that during both ST and DT gait, the HA-PD group demonstrated significant reductions in walking speed and step length, as well as increased step length variability and step time variability compared with healthy controls and the LA-PD group. Notably, ST walking in the HA-PD group resembled (i.e., it was not significantly different from) the gait behaviors seen during a DT in the LA-PD and HC groups. These results suggest that trait anxiety may consume processing resources and limit the ability to compensate for gait impairments in PD. PMID- 28712344 TI - Interaction of graphene oxide nano-sheets and landfill leachate bacterial culture. AB - The interaction of graphene oxide (GO) and municipal landfill leachate bacterial culture was investigated. In aerobic conditions, stepwise addition of GO concentration to 60 mg/L increased the oxygen uptake rate coefficient. However, increasing the GO concentration to 100 mg/L slightly decreased the oxygen uptake rate coefficient. When anoxic conditions developed, GO suspensions decreased the total bacterial activity and the substrate consumption. Raman spectroscopy confirmed the chemical reduction of GO during exposure to bacteria; nonetheless, the extent of reduction in anoxic conditions was more than that in aerobic conditions. The chemical composition of landfill leachate showed to be able to also slightly reduce the GO after 10 days exposure, but the role of bacterial activity in the reduction process seemed to be dominant. As far as it could be seen under a light microscope, while the gram-positive bacteria were more vulnerable in anoxic assays, GO suspension did not affect the morphology and size of active cultures in the aerobic atmosphere. PMID- 28712345 TI - Post-processing optimization of electrospun submicron poly(3-hydroxybutyrate) fibers to obtain continuous films of interest in food packaging applications. AB - Polyhydroxyalkanoates (PHAs) are one of the most researched family of biodegradable polymers based on renewable materials due to their thermoplastic nature and moisture resistance. The present study was targeted to investigate the preparation and characterization of poly(3-hydroxybutyrate) (PHB) films obtained through the electrospinning technique. To convert them into continuous films and then to increase their application interest in packaging, the electrospun fiber mats were subsequently post-processed by different physical treatments. Thus, the effect of annealing time and cooling method on morphology, molecular order, thermal, optical, mechanical, and barrier properties of the electrospun submicron PHB fibers was studied. Annealing at 160 degrees C, well below the homopolyester melting point, was found to be the minimum temperature at which homogeneous transparent films were produced. The film samples that were cooled slowly after annealing showed the lowest permeability to oxygen, water vapor, and limonene. The optimally post-processed electrospun PHB fibers exhibited similar rigidity to conventional compression-molded PHA films, but with enhanced elongation at break and toughness. Films made by this electrospinning technique have many potential applications, such as in the design of barrier layers, adhesive interlayers, and coatings for fiber- and plastic-based food packaging materials. PMID- 28712346 TI - A model averaging approach for estimating propensity scores by optimizing balance. AB - Many approaches, including traditional parametric modeling and machine learning techniques, have been proposed to estimate propensity scores. This paper describes a new model averaging approach to propensity score estimation in which parametric and nonparametric estimates are combined to achieve covariate balance. Simulation studies are conducted across different scenarios varying in the degree of interactions and nonlinearities in the treatment model. The results show that, based on inverse probability weighting, the proposed propensity score estimator produces less bias and smaller standard errors than existing approaches. They also show that a model averaging approach with the objective of minimizing the average Kolmogorov-Smirnov statistic leads to the best performing IPW estimator. The proposed approach is also applied to a real data set in evaluating the causal effect of formula or mixed feeding versus exclusive breastfeeding on a child's body mass index Z-score at age 4. The data analysis shows that formula or mixed feeding is more likely to lead to obesity at age 4, compared to exclusive breastfeeding. PMID- 28712347 TI - Cultural competence: a framework for promoting voluntary medical male circumcision among VaRemba communities in Zimbabwe. AB - Almost a decade after the formal introduction of voluntary medical male circumcision (VMMC) as an important technology for HIV prevention, its implementation is still fraught with acceptability challenges. This is especially true among ethnic groups where male circumcision is conducted as a rite of passage into adulthood. In this article we question why VMMC is being met with resistance despite widespread awareness of its promise to reduce HIV incidence in a culturally circumcising community in Zimbabwe. In-depth and key informant interviews were conducted with selected VaRemba initiation graduates and surgeons respectively in Mposi area in Mberengwa to explore why VMMC has not been readily accepted in their community. Findings suggest that male circumcision among VaRemba is not only the removal of prepuce but comprises a secretive and rich curriculum rooted in their culture and identity. Such a conceptualisation renders some social and programmatic impediments for VMMC uptake. To scale up VMMC uptake among VaRemba, we argue for a reorganisation and adaptation of VMMC services in a culturally competent way that accounts for local conceptions of circumcision and respect for the cultural beliefs and practices of VaRemba communities. PMID- 28712348 TI - An Exploratory Study of Fatigue and Physical Activity in Canadian Thyroid Cancer Patients. AB - BACKGROUND: Fatigue is common among cancer survivors, but fatigue in thyroid cancer (TC) survivors may be under-appreciated. This study investigated the severity and prevalence of moderate and severe fatigue in TC survivors. Potential predictive factors, including physical activity, were explored. METHODS: A cross sectional, written, self-administered TC patient survey and retrospective chart review were performed in an outpatient academic Endocrinology clinic in Toronto, Canada. The primary outcome measure was the global fatigue score measured by the Brief Fatigue Inventory (BFI). Physical activity was evaluated using the International Physical Activity Questionnaire-7 day (IPAQ-7). Predictors of BFI global fatigue score were explored in univariate analyses and a multivariable linear regression model. RESULTS: The response rate was 63.1% (205/325). Three quarters of the respondents were women (152/205). The mean age was 52.5 years, and the mean time since first TC surgery was 6.8 years. The mean global BFI score was 3.5 (standard deviation 2.4) out of 10 (10 is worst). The prevalence of moderate-severe fatigue (global BFI score 4.1-10 out of 10) was 41.4% (84/203). Individuals who were unemployed or unable to work due to disability reported significantly higher levels of fatigue compared to the rest of the study population, in uni-and multivariable analyses. Furthermore, increased physical activity was associated with reduced fatigue in uni- and multivariable analyses. Other socio-demographic, disease, or biochemical variables were not significantly associated with fatigue in the multivariable model. CONCLUSIONS: Moderate or severe fatigue was reported in about 4/10 TC survivors. Independent predictors of worse fatigue included unemployment and reduced physical activity. PMID- 28712350 TI - Defining Peer Roles and Status Among Community Health Workers and Peer Support Specialists in Integrated Systems of Care. AB - Current strategies for integrating general medical and behavioral health services focus primarily on improving the coordination of care and expanding team-based services. Absent from most discussion has been a focus on the workforces that provide the bulk of community-based outreach, engagement, activation, motivational support, and self-management: community health workers (CHWs) and peer support specialists (PSSs). CHWs have primarily been deployed in general medical care and PSSs in behavioral health care. Understanding the unique contributions that CHWs and PSS provide for health promotion and wellness and improved population health outcomes is an important challenge. This Open Forum reviews the key elements of peer status as a way to help illustrate the differences between these workforces and the best deployment strategies for each workforce. A framework is proposed that outlines key support roles provided by the CHW and PSS workforces. PMID- 28712349 TI - A Community-Partnered, Participatory, Cluster-Randomized Study of Depression Care Quality Improvement: Three-Year Outcomes. AB - OBJECTIVE: Community Partners in Care, a community-partnered, cluster-randomized trial with depressed clients from 93 Los Angeles health and community programs, examined the added value of a community coalition approach (Community Engagement and Planning [CEP]) versus individual program technical assistance (Resources for Services [RS]) for implementing depression quality improvement in underserved communities. CEP was more effective than RS in improving mental health-related quality of life, reducing behavioral health hospitalizations, and shifting services toward community-based programs at six months. At 12 months, continued evidence of improvement was found. This study examined three-year outcomes. METHODS: Among 1,004 participants with depression who were eligible for three year follow-up, 600 participants from 89 programs completed surveys. Multiple regression analyses estimated intervention effects on poor mental health-related quality of life and depression, physical health-related quality of life, behavioral health hospital nights, and use of services. RESULTS: At three years, no differences were found in the effects of CEP versus RS on depression or mental health-related quality of life, but CEP had modest effects in improving physical health-related quality of life and reducing behavioral health hospital nights, and CEP participants had more social- and community-sector depression visits and greater use of mood stabilizers. Sensitivity analyses with longitudinal modeling reproduced these findings but found no significant differences between groups in change from baseline to three years. CONCLUSIONS: At three years, CEP and RS did not have differential effects on primary mental health outcomes, but CEP participants had modest improvements in physical health and fewer behavioral health hospital nights. PMID- 28712351 TI - Bringing Recovery and Consumers' Views Into the Mainstream of Mental Health Quality Measurement. AB - Health policies in the United States and elsewhere are moving to increase accountability of health care systems and providers for providing high-quality, efficient care and driving application of evidence-based improvement strategies. To support these efforts, a "quality measurement industrial complex" has been created to develop, endorse, and apply quality measures that incentivize these behaviors. Parallel to this development in mental health care is an emerging commitment to include recovery orientation approaches in treating serious mental illness. However, consumers have been only tangentially involved in quality assessment and improvement strategies of the mental health services that they are receiving. This Open Forum aims to advance the conversation about how to integrate recovery into mental health care quality assessment cohesively and how to involve consumers in this process in a more meaningful way. PMID- 28712352 TI - National Overview of Medication-Assisted Treatment for American Indians and Alaska Natives With Substance Use Disorders. AB - OBJECTIVE: American Indians and Alaska Natives (AI/ANs) experience higher rates of substance use disorders and less access to high-quality care compared with other racial-ethnic groups. The objective of this study was to better understand the use of medication-assisted treatment (MAT) of substance use disorders for AI/ANs and barriers to broader implementation. METHODS: Representatives of 192 substance abuse treatment programs completed a survey about their use of MAT. On the basis of implementation science frameworks, the authors examined survey items about program structure, workforce, and other services provided in order to develop logistic regression models that explored significant associations between workforce and program characteristics and use of MAT. RESULTS: Of the 192 programs, 28% reported implementing MAT. Multivariate logistic regression models indicated that programs with staff that perceived MAT to be consistent with their program's treatment approach and philosophy and programs reporting that MAT fit with staff expertise and training were more likely to implement MAT. Programs with nurses on staff and those reporting a perceived gap in the use of evidence based treatments (EBTs) were less likely to implement MAT. CONCLUSIONS: Low rates of MAT implementation suggest racial disparities in access to MAT among AI/ANs, a population with historically high rates of substance use disorders. Study findings also highlight the important role of treatment culture and organizational fit in the implementation of MAT in treatment programs serving AI/AN populations. Results also speak to the importance of adapting existing EBTs in a culturally competent way to best serve the needs of the AI/AN community. PMID- 28712354 TI - Using a Continuum-Based Framework for Behavioral Health Integration Into Primary Care in New York State. AB - Behavioral health integration with primary care has long been shown to be an essential part of improving health care and, more recently, of achieving the "triple aim" as part of national reform. Many states are promoting integration activities as part of Medicaid reform, using different models and strategies. The purpose of this column is to describe a framework developed to support behavioral health integration into primary care settings in New York State and how it is specifically linked to key policy initiatives. The framework is designed to be adaptable to practices of varying sizes and with various resources and organizational structures. Its use in groundbreaking New York State integration initiatives is discussed. PMID- 28712353 TI - Cost-Effectiveness of a PTSD Intervention Tailored for Individuals With Severe Mental Illness. AB - OBJECTIVE: This study examined the cost-effectiveness of a cognitive-behavioral therapy (CBT) intervention for posttraumatic stress disorder (PTSD) that is tailored for adults with a co-occurring severe mental illness. METHODS: Data were from a randomized trial involving 183 adult clients of two outpatient clinics and three partial hospitalization programs. All had a severe mental illness diagnosis (major mood disorder, schizophrenia, or schizoaffective disorder) and severe PTSD. Participants were randomly assigned to the tailored 12- to 16-session CBT intervention for PTSD (CBT-P) or a three-session breathing retraining and psychoeducation intervention (BRF). Cost estimates included intervention costs for training, supervision, fidelity assessment, personnel, and overhead and related mental health care costs for outpatient, inpatient, and emergency department services and for medications. The incremental cost-effectiveness ratio comparing CBT-P with BRF measured the added cost or savings per remission from PTSD at 12 months postintervention. Generalized linear models were used to estimate intervention effects on annual mental health care costs and the likelihood of a remission from PTSD. Ten thousand bootstrap replications were used to assess uncertainty. RESULTS: Annual mean mental health care costs were $25,539 per client (in 2010 dollars) for BRF participants and $29,530 per client for CBT-P participants, a nonsignificant difference. The mean incremental cost effectiveness ratio was $36,893 per additional PTSD remission yielded by CBT-P compared with BRF (95% confidence interval=-$33,523 to $158,914). Remissions were associated with improvements in quality of life and functioning. CONCLUSIONS: An effective CBT intervention tailored for adults with severe mental illness and PTSD was not found to be more cost-effective than a brief three-session intervention. PMID- 28712355 TI - Using Digital Media Advertising in Early Psychosis Intervention. AB - OBJECTIVE: Identifying and engaging youth with early-stage psychotic disorders in order to facilitate timely treatment initiation remains a major public health challenge. Although advertisers routinely use the Internet to directly target consumers, limited efforts have focused on applying available technology to proactively encourage help-seeking in the mental health community. This study explores how one might take advantage of Google AdWords in order to reach prospective patients with early psychosis. METHODS: A landing page was developed with the primary goal of encouraging help-seeking individuals in New York City to contact their local early psychosis intervention clinic. In order to provide the best opportunity to reach the intended audience, Google AdWords was utilized to link more than 2,000 selected search terms to strategically placed landing page advertisements. The campaign ran for 14 weeks between April 11 and July 18, 2016 and had a total budget of $1,427. RESULTS: The ads appeared 191,313 times and were clicked on 4,350 times, at a per-click cost of $.33. Many users took additional help-seeking steps, including obtaining psychosis-specific information/education (44%), completing a psychosis self-screener (15%), and contacting the local early treatment program (1%). CONCLUSIONS: Digital ads appear to be a reasonable and cost-effective method to reach individuals who are searching for behavioral health information online. More research is needed to better understand the many complex steps between online search inquiries and making first clinical contact. PMID- 28712357 TI - Medicare Accountable Care Organizations and Antidepressant Use by Patients With Depression. AB - OBJECTIVE: This study examined whether Medicare accountable care organization (ACO) programs were associated with early changes in antidepressant use or adherence among beneficiaries with depression. METHODS: A difference-in difference design was used to compare claims from Medicare fee-for-service beneficiaries (2009-2013) and ACO patients with those from local control groups. Outcome measures were total antidepressant days supplied, filling one or more antidepressant prescriptions, and proportion of days covered (PDC) by supply among antidepressant users (adherence). RESULTS: Among antidepressant users, ACO contracts were associated with slight differential increases in PDC (.4-.8 percentage point, p<=.03), depending on ACO program and entry year. The proportion of patients with one or more prescriptions was unchanged or decreased slightly for ACO patients with depression, such that total supply did not consistently increase. CONCLUSIONS: Medicare ACO programs were associated with early modest increases in antidepressant adherence but not with increases in the proportion of patients with depression who received antidepressants. PMID- 28712356 TI - Discontinuing Psychiatric Medications: A Survey of Long-Term Users. AB - OBJECTIVE: Individuals undergoing long-term psychiatric treatment frequently choose to stop taking psychiatric medications. To enhance service user choice and prevent undesirable outcomes, this first U.S. survey of a large sample of longer term users sought to increase knowledge about users' experience of medication discontinuation. METHODS: A sample of 250 U.S. adults with a diagnosis of serious mental illness and a recent goal to stop up to two prescribed psychiatric medications, which they had taken for at least nine months, completed a web-based survey about experiences, strategies, and supports during discontinuation. RESULTS: About half (54%) met their goal of completely discontinuing one or more medications; 46% reported another outcome (use was reduced, use increased, or use stayed the same). Concerns about medications' effects (for example, long-term effects and side effects) prompted the decision to discontinue for 74% of respondents. They used various strategies to cope with withdrawal symptoms, which 54% rated as severe. Self-education and contact with friends and with others who had discontinued or reduced medications were most frequently cited as helpful. Although more than half rated the initial medication decision with prescribers as largely collaborative, only 45% rated prescribers as helpful during discontinuation. Of respondents who completely discontinued, 82% were satisfied with their decision. CONCLUSIONS: Discontinuing psychiatric medication appears to be a complicated and difficult process, although most respondents reported satisfaction with their decision. Future research should guide health care systems and providers to better support patient choice and self-determination regarding the use and discontinuation of psychiatric medication. PMID- 28712359 TI - Resource implications of preparing individual participant data from a clinical trial to share with external researchers. AB - BACKGROUND: Demands are increasingly being made for clinical trialists to actively share individual participant data (IPD) collected from clinical trials using responsible methods that protect the confidentiality and privacy of clinical trial participants. Clinical trialists, particularly those receiving public funding, are often concerned about the additional time and money that data sharing activities will require, but few published empirical data are available to help inform these decisions. We sought to evaluate the activity and resources required to prepare anonymised IPD from a clinical trial in anticipation of a future data-sharing request. METHODS: Data from two UK publicly funded clinical trials were used for this exercise: 2437 participants with epilepsy recruited from 90 hospital outpatient clinics in the SANAD trial and 146 children with neuro-developmental problems recruited from 18 hospitals in the MENDS trial. We calculated the time and resources required to prepare each anonymised dataset and assemble a data pack ready for sharing. RESULTS: The older SANAD trial (published 2007) required 50 hours of staff time with a total estimated associated cost of L3185 whilst the more recently completed MENDS trial (published 2012) required 39.5 hours of staff time with total estimated associated cost of L2540. CONCLUSIONS: Clinical trial researchers, funders and sponsors should consider appropriate resourcing and allow reasonable time for preparing IPD ready for subsequent sharing. This process would be most efficient if prospectively built into the standard operational design and conduct of a clinical trial. Further empirical examples exploring the resource requirements in other settings is recommended. TRIAL REGISTRATION: SANAD: International Standard Randomised Controlled Trials Registry: ISRCTN38354748 . Registered on 25 April 2003. MENDS: EU Clinical Trials Register Eudract 2006-004025-28 . Registered on 16 May 2007. International Standard Randomised Controlled Trials Registry: ISRCTN05534585 /MREC 07/MRE08/43. Registered on 26 January 2007. PMID- 28712362 TI - Letter to the Editor: Measuring and defining: the double role of the DSM criteria for psychiatric disorders. PMID- 28712363 TI - Overlapping and disease specific trait, response, and reflection impulsivity in adolescents with first-episode schizophrenia spectrum disorders or attention deficit/hyperactivity disorder. AB - BACKGROUND: Schizophrenia and attention-deficit/hyperactivity disorder (ADHD) are developmental disorders with shared clinical characteristics such as cognitive impairments and impulsivity. Impulsivity is a core feature of ADHD and an important factor in aggression, violence, and substance use in schizophrenia. Based on the hypothesis that schizophrenia and ADHD represent a continuum of neurodevelopmental impairments, the aim was to identify overlapping and disease specific forms of impulsivity. METHODS: Adolescents between 12 and 17 years of age were assessed with the Schedule for Affective Disorders and Schizophrenia for School-aged Children - Present and Lifetime Version. Subjects with early-onset, first-episode schizophrenia spectrum disorders (EOS) (N = 29) or ADHD (N = 29) and healthy controls (N = 45) were compared on two performance measures (Information Sampling Task, Stop Signal Task) and a subjective personality trait measure of impulsivity (Barratt Impulsiveness Scale, Version 11 (BIS-11)). RESULTS: Significantly increased reflection impulsivity was observed in ADHD but not in the EOS group. No significant response inhibition deficits (stop signal reaction time) were found in the two clinical groups. The ADHD and the EOS group showed significantly increased motor, attentional, and non-planning subtraits of impulsivity. CONCLUSIONS: Impaired pre-decisional information gathering appeared to be specific for ADHD while the information gathering was not significantly reduced in subjects with EOS. Neither the ADHD nor EOS group showed impaired response inhibition but shared increased personality subtraits of attentional, non-planning, and motor impulsivity although the latter was significantly more pronounced in ADHD. These increased subtraits of impulsivity may reflect diagnostic non-specific neurodevelopmental impairments in ADHD and EOS in adolescence. PMID- 28712360 TI - Resisting and tolerating P. falciparum in pregnancy under different malaria transmission intensities. AB - BACKGROUND: Resistance and tolerance to Plasmodium falciparum can determine the progression of malaria disease. However, quantitative evidence of tolerance is still limited. We investigated variations in the adverse impact of P. falciparum infections among African pregnant women under different intensities of malaria transmission. METHODS: P. falciparum at delivery was assessed by microscopy, quantitative PCR (qPCR) and placental histology in 946 HIV-uninfected and 768 HIV infected pregnant women from Benin, Gabon, Kenya and Mozambique. Resistance was defined by the proportion of submicroscopic infections and the levels of anti parasite antibodies quantified by Luminex, and tolerance by the relationship of pregnancy outcomes with parasite densities at delivery. RESULTS: P. falciparum prevalence by qPCR in peripheral and/or placental blood of HIV-uninfected Mozambican, Gabonese and Beninese women at delivery was 6% (21/340), 11% (28/257) and 41% (143/349), respectively. The proportion of peripheral submicroscopic infections was higher in Benin (83%) than in Mozambique (60%) and Gabon (55%; P = 0.033). Past or chronic placental P. falciparum infection was associated with an increased risk of preterm birth in Mozambican newborns (OR = 7.05, 95% CI 1.79 to 27.82). Microscopic infections were associated with reductions in haemoglobin levels at delivery among Mozambican women (-1.17 g/dL, 95% CI -2.09 to -0.24) as well as with larger drops in haemoglobin levels from recruitment to delivery in Mozambican (-1.66 g/dL, 95% CI -2.68 to -0.64) and Gabonese (-0.91 g/dL, 95% CI 1.79 to -0.02) women. Doubling qPCR-peripheral parasite densities in Mozambican women were associated with decreases in haemoglobin levels at delivery (-0.16 g/dL, 95% CI -0.29 to -0.02) and increases in the drop of haemoglobin levels ( 0.29 g/dL, 95% CI -0.44 to -0.14). Beninese women had higher anti-parasite IgGs than Mozambican women (P < 0.001). No difference was found in the proportion of submicroscopic infections nor in the adverse impact of P. falciparum infections in HIV-infected women from Kenya (P. falciparum prevalence by qPCR: 9%, 32/351) and Mozambique (4%, 15/417). CONCLUSIONS: The lowest levels of resistance and tolerance in pregnant women from areas of low malaria transmission were accompanied by the largest adverse impact of P. falciparum infections. Exposure dependent mechanisms developed by pregnant women to resist the infection and minimise pathology can reduce malaria-related adverse outcomes. Distinguishing both types of defences is important to understand how reductions in transmission can affect malaria disease. TRIAL REGISTRATION: ClinicalTrials.gov NCT00811421 . Registered 18 December 2008. PMID- 28712361 TI - Plasmodium knowlesi: a superb in vivo nonhuman primate model of antigenic variation in malaria. AB - Antigenic variation in malaria was discovered in Plasmodium knowlesi studies involving longitudinal infections of rhesus macaques (M. mulatta). The variant proteins, known as the P. knowlesi Schizont Infected Cell Agglutination (SICA) antigens and the P. falciparum Erythrocyte Membrane Protein 1 (PfEMP1) antigens, expressed by the SICAvar and var multigene families, respectively, have been studied for over 30 years. Expression of the SICA antigens in P. knowlesi requires a splenic component, and specific antibodies are necessary for variant antigen switch events in vivo. Outstanding questions revolve around the role of the spleen and the mechanisms by which the expression of these variant antigen families are regulated. Importantly, the longitudinal dynamics and molecular mechanisms that govern variant antigen expression can be studied with P. knowlesi infection of its mammalian and vector hosts. Synchronous infections can be initiated with established clones and studied at multi-omic levels, with the benefit of computational tools from systems biology that permit the integration of datasets and the design of explanatory, predictive mathematical models. Here we provide an historical account of this topic, while highlighting the potential for maximizing the use of P. knowlesi - macaque model systems and summarizing exciting new progress in this area of research. PMID- 28712365 TI - Psychoneurometric assessment of dispositional liabilities for suicidal behavior: phenotypic and etiological associations. AB - BACKGROUND: Can core genetic liabilities for suicidal behavior be indexed using psychological and neural indicators combined? The current work addressed this question by examining phenotypic and genetic associations of two biobehavioral traits, threat sensitivity (THT) and disinhibition (DIS) - operationalized as psychoneurometric variables (i.e., composites of psychological-scale and neurophysiological measures) - with suicidal behaviors in a sample of adult twins. METHODS: Participants were 444 identical and fraternal twins recruited from an urban community. THT was assessed using a psychological-scale measure of fear/fearlessness combined with physiological indicators of reactivity to aversive pictures, and DIS was assessed using scale measures of disinhibitory tendencies combined with indicators of brain response from lab performance tasks. Suicidality was assessed using items from structured interview and questionnaire protocols. RESULTS: THT and DIS each contributed uniquely to prediction of suicidality when assessed psychoneurometrically (i.e., as composites of scale and neurophysiological indicators). In addition, these traits predicted suicidality interactively, with participants high on both reporting the greatest degree of suicidal behaviors. Biometric (twin-modeling) analyses revealed that a high percentage of the predictive association for each psychoneurometric trait (83% for THT, 68% for DIS) was attributable to genetic variance in common with suicidality. CONCLUSIONS: Findings indicate that psychoneurometric assessments of biobehavioral traits index genetic liability for suicidal behavior, and as such, can serve as innovative targets for research on core biological processes contributing to severe psychopathology, including suicidal proclivities and actions. PMID- 28712366 TI - Letter to the Editor: Exposure to nitrous oxide and intrusive memory formation in psychological trauma. PMID- 28712364 TI - The structure of schizotypal personality traits: a cross-national study. AB - BACKGROUND: Schizotypal traits are considered a phenotypic-indicator of schizotypy, a latent personality organization reflecting a putative liability for psychosis. To date, no previous study has examined the comparability of factorial structures across samples originating from different countries and cultures. The main goal was to evaluate the factorial structure and reliability of the Schizotypal Personality Questionnaire (SPQ) scores by amalgamating data from studies conducted in 12 countries and across 21 sites. METHOD: The overall sample consisted of 27 001 participants (37.5% males, n = 4251 drawn from the general population). The mean age was 22.12 years (s.d. = 6.28, range 16-55 years). The SPQ was used. Confirmatory factor analysis (CFA) and Multilevel CFA (ML-CFA) were used to evaluate the factor structure underlying the SPQ scores. RESULTS: At the SPQ item level, the nine factor and second-order factor models showed adequate goodness-of-fit. At the SPQ subscale level, three- and four-factor models displayed better goodness-of-fit indices than other CFA models. ML-CFA showed that the intraclass correlation coefficients values were lower than 0.106. The three-factor model showed adequate goodness of fit indices in multilevel analysis. The ordinal alpha coefficients were high, ranging from 0.73 to 0.94 across individual samples, and from 0.84 to 0.91 for the combined sample. CONCLUSIONS: The results are consistent with the conceptual notion that schizotypal personality is a multifaceted construct and support the validity and utility of SPQ in cross-cultural research. We discuss theoretical and clinical implications of our results for diagnostic systems, psychosis models and cross national mental health strategies. PMID- 28712367 TI - The effects of vitamin and mineral supplementation on symptoms of schizophrenia: a systematic review and meta-analysis - CORRIGENDUM. PMID- 28712368 TI - Inferring genetic parameters on latent variables underlying milk yield and quality, protein composition, curd firmness and cheese-making traits in dairy cattle. AB - We studied the genetics of cheese-related latent variables (factors; Fs) for application in dairy cattle breeding. In total, 26 traits, recorded in 1264 Brown Swiss cows, were analyzed through multivariate factor analysis (MFA). Traits analyzed were descriptors of milk quality and yield (including protein fractions) and measures of coagulation, curd firmness (CF), cheese yields (%CY) and nutrient recoveries in the curd (REC). A total of 10 Fs (mutual orthogonal with a varimax rotation) were obtained. To assess the practical use of the Fs into breeding, we inferred their genetic parameters using single and bivariate animal models under a Bayesian framework. Heritability estimates (intra-herd) varied between 0.11 and 0.72 (F3: Yield and F7: kappa-beta-CN, respectively). The Fs underlined basic characteristics of the cheese-making process, milk components and udder health, while retaining 74% of the original variability. The first two Fs were indicators of the CY percentage (F1: %CY) and the CF process (F2: CF t ), and presented similar heritability estimates: 0.268 and 0.295, respectively. The third factor was associated with the yield of milk and solids (F3: Yield) characterized by a low heritability (0.108) and the fourth with the cheese nitrogen (N) (F4: Cheese N) that conversely appeared to be characterized by a high heritability (0.618). Three Fs were associated with the proportion of the basic milk caseins on total milk protein (F5: as1-beta-CN, F7: kappa-beta-CN, F8: as2-CN), also highly heritable (0.565, 0.723 and 0.397, respectively) and 1 factor with the phosphorylated form of the as1-CN (F9: as1-CN-Ph; 0.318). Moreover, 1 factor was linked to the whey protein alpha-LA (F10: alpha-LA; 0.147). An indicator factor of a cow's udder health (F6: Udder health) was also obtained and showed a moderate heritability (0.204). Although the Fs were phenotypically uncorrelated, considerable additive genetic correlations existed among them, with highest values observed between F10: alpha-LA and F6: Udder health (-0.67) as well as between F9: as1-CN-Ph and F3: Yield (-0.60). Our results show the usefulness of MFA in dairy cattle breeding. The ability to replace a large number of variables with a few latent indicators of the same biological meaning marks MFA as a valuable tool for developing breeding strategies to improve cow's cheese-related traits. PMID- 28712369 TI - A hospital-based matched case-control study to identify risk factors for clinical infection with OXA-48-producing Klebsiella pneumoniae in rectal carriers. AB - Asymptomatic colonisation of the gastrointestinal tract by carbapenemase producing Enterobacteriaceae is an important reservoir for transmission, which may precede infection. This retrospective observational case-control study was designed to identify risk factors for developing clinical infection with OXA-48 producing Klebsiella pneumoniae in rectal carriers during hospitalisation. Case patients (n = 76) had carbapenemase-producing K. pneumoniae (CPKP) infection and positive rectal culture for CPKP. Control patients (n = 174) were those with rectal colonisation with CPKP but without CPKP infection. Multivariate analysis identified the presence of a central venous catheter (OR 4.38; 95% CI 2.27-8.42; P = 0.008), the number of transfers between hospital units (OR 1.27; 95% CI (1.06 1.52); P < 0.001) and time at risk (OR 1.02 95% CI 1.01-1.03; P = 0.01) as independent risk factors for CPKP infection in rectal carriers. Awareness of these risk factors may help to identify patients at higher risk of developing CPKP infection. PMID- 28712370 TI - Beyond scoring systems: usefulness of morphometry considering demographic variables, to evaluate neck and overall obesity in Andalusian horses. AB - Morphometry has proven to be a useful tool, both for the clinician and horse owners, for evaluating the body condition in equids due to its objectivity, easiness and capacity for detection of important metabolic disturbances. However, limited information is available on the use of morphometric ratios to characterize regional and overall adiposity and much less about their application in different genders, ages and horses with different levels of obesity. The objectives were to evaluate body and neck absolute measurements and ratios; factors affecting them such as the influence of gender, age, appearance of the neck crest and overall body condition and; relationships among these measurements. A total of 154 Andalusian horses classified according to their gender, age, body score status and cresty neck condition were evaluated in this cross-sectional study. Two evaluators assigned a body condition score (BCS, 1 to 9) and a cresty neck score (CNS, 0 to 5) to each horse. Horses were divided into males and females; young (2 to 5 years) and adults (6 to 15 years); obese (BCS?7) and non-obese (BCS<7); cresty neck (CNS?3) and non-cresty neck horses (CNS<3). Morphometric measurements (cm) included were: height at the withers (HW); body length (BL), girth (GC) and waist (WC) circumferences; neck length (NL); three neck circumferences (NCs), over the first (NC25%), the second (NC50%) and the third part (NC75%) of the NL and neck crest height (NCH). These measurements were also used to calculate the following ratios: GC : HW, WC : HW, GC : BL, WC : BL, NC25% : HW, NC50% : HW, NC75% : HW, NC25% : BL, NC50% : BL, NC75% : BL, NC25% : NL, NC50% : NL, NC75% : NL, NC25% : NCH, NC50% : NCH and NC75% : NCH. The results showed that most of the absolute measurements and ratios were greater than those described in other light breeds. In addition, most neck ratios were higher (P<0.050) in males than in females, however, all body ratios were greater (P<0.001) in females. Among the absolute measurements, WC in obese horses and NC25% and NC75% in cresty neck horses highlighted as higher. Either GC : HW or WC : HW and NC75% : BL were alternative surrogates for the appraisal of overall and regional adiposity in Andalusians. Several interactions were observed between the gender and adiposity scoring systems affecting the morphometric evaluation. This study establishes absolute morphometric measurements and ratios in Andalusian horses. It also highlights the variability of morphometric values and how the outcome of these can be influenced by demographic variables and the breed analyzed. Further studies are necessary to set morphometric reference values in other breeds. PMID- 28712372 TI - Segmenting Microscopy Images of Multi-Well Plates Based on Image Contrast. AB - Image segmentation is a key process in analyzing biological images. However, it is difficult to detect the differences between foreground and background when the image is unevenly illuminated. The unambiguous segmenting of multi-well plate microscopy images with various uneven illuminations is a challenging problem. Currently, no publicly available method adequately solves these various problems in bright-field multi-well plate images. Here, we propose a new method based on contrast values which removes the need for illumination correction. The presented method is effective enough to distinguish foreground and therefore a model organism (Caenorhabditis elegans) from an unevenly illuminated microscope image. In addition, the method also can solve a variety of problems caused by different uneven illumination scenarios. By applying this methodology across a wide range of multi-well plate microscopy images, we show that our approach can consistently analyze images with uneven illuminations with unparalleled accuracy and successfully solve various problems associated with uneven illumination. It can be used to process the microscopy images captured from multi-well plates and detect experimental subjects from an unevenly illuminated background. PMID- 28712371 TI - Visual systemizing preference in children with autism: A randomized controlled trial of intranasal oxytocin. AB - Several studies have suggested that the neuropeptide oxytocin may enhance aspects of social communication in autism. Little is known, however, about its effects on nonsocial manifestations, such as restricted interests and repetitive behaviors. In the empathizing-systemizing theory of autism, social deficits are described along the continuum of empathizing ability, whereas nonsocial aspects are characterized in terms of an increased preference for patterned or rule-based systems, called systemizing. We therefore developed an automated eye-tracking task to test whether children and adolescents with autism spectrum disorder (ASD) compared to matched controls display a visual preference for more highly organized and structured (systemized) real-life images. Then, as part of a randomized, double-blind, placebo-controlled crossover study, we examined the effect of intranasal oxytocin on systemizing preferences in 16 male children with ASD, compared with 16 matched controls. Participants viewed 14 slides, each containing four related pictures (e.g., of people, animals, scenes, or objects) that differed primarily on the degree of systemizing. Visual systemizing preference was defined in terms of the fixation time and count for each image. Unlike control subjects who showed no gaze preference, individuals with ASD preferred to fixate on more highly systemized pictures. Intranasal oxytocin eliminated this preference in ASD participants, who now showed a similar response to control subjects on placebo. In contrast, control participants increased their visual preference for more systemized images after receiving oxytocin versus placebo. These results suggest that, in addition to its effects on social communication, oxytocin may play a role in some of the nonsocial manifestations of autism. PMID- 28712373 TI - Impact of animal density on cattle nutrition in dry Mediterranean rangelands: a faecal near-IR spectroscopy-aided study. AB - In the context of determining the sustainable carrying capacity of dry Mediterranean herbaceous rangelands, we examined the effect of animal density on cattle nutrition, which is fundamental to animal performance and welfare. The effects on dietary components of low (0.56 cows/ha; L) and high (1.11 cows/ha; H) animal densities were monitored for three consecutive years in grazing beef cows. In the dry season (summer and early autumn), cows had free access to N-rich poultry litter (PL) given as a dietary supplement. In each season, near-IR spectroscopy (NIRS) was used to predict the chemical composition of herbage samples (ash, NDF, CP, in vitro dry matter digestibility (IVDMD) and metabolizable energy (ME) content from IVDMD). Near-IR spectroscopy was applied also to faecal samples to determine the chemical composition of the diet selected by the animal, as well as the contents of ash, NDF and CP in the faeces themselves. A faecal-NIRS equation was applied to estimate the dietary proportion of PL. Seasonal categories were green, dry without PL supplementation and dry with it. We found no effects of animal density on nutrition during the green season but effects were apparent when cows consumed dry pasture. Ash content predicted by faecal NIRS was higher in the diet than in plant samples clipped from pasture, which infers that cows ingested soil. Dietary and faecal ash contents were higher (P<0.05) at the H, implying greater soil intake in these animals. During the dry period, dietary contents of ME were higher in L than in H (P<0.05). Poultry litter supplementation was associated with a marked increase (P<0.01) in dietary and faecal CP contents. Poultry litter represented 0.45 and 0.59 of the diet in treatments L and H, respectively (P<0.05). Consequently, treatment H had higher faecal protein (P<0.05). A tendency of higher dietary protein (P=0.08) and lower dietary NDF (P=0.10) in treatment H was probably related to greater PL ingestion. Given that high and sustained rates of poultry litter consumption are detrimental to animal health, the above results cast doubts on the long-term sustainability of the higher of the animal densities tested. Although it may be sustainable vis-a-vis the vegetation, treatment H may have exceeded the boundaries of what is acceptable for cow health. Chemical information revealed with NIRS can be used to evaluate whether animal densities are compatible with animal health and welfare standards and can play a role in determining the carrying capacity of Mediterranean rangelands. PMID- 28712374 TI - Parthenogenetic activation and somatic cell nuclear transfer of porcine oocytes activated by an electric pulse and AZD5438 treatment. AB - We examined the in vitro developmental competence of parthenogenetic activation (PA) oocytes activated by an electric pulse (EP) and treated with various concentrations of AZD5438 for 4 h. Treatment with 10 uM AZD5438 for 4 h significantly improved the blastocyst formation rate of PA oocytes in comparison with 0, 20, or 50 uM AZD5438 treatment (46.4% vs. 34.5%, 32.3%, and 24.0%, respectively; P 0.05). Furthermore, 66.67% of blastocysts derived from these AZD5438-treated PA oocytes had a diploid karyotype. The blastocyst formation rate of PA and somatic cell nuclear transfer (SCNT) embryos was similar between oocytes activated by an EP and treated with 2 mM 6-dimethylaminopurine for 4 h and those activated by an EP and treated with 10 uM AZD5438 for 4 h (11.11% vs. 13.40%, P > 0.05). In addition, the level of maturation-promoting factor (MPF) was significantly decreased in oocytes activated by an EP and treated with 10 uM AZD5438 for 4 h. Finally, the mRNA expression levels of apoptosis-related genes (Bax and Bcl-2) and pluripotency-related genes (Oct4, Nanog, and Sox2) were checked by RT-PCR; however, there were no differences between the AZD5438-treated and non-treated control groups. Our results demonstrate that porcine oocyte activation via an EP in combination with AZD5438 treatment can lead to a high blastocyst formation rate in PA and SCNT experiments. PMID- 28712375 TI - Imputation of non-genotyped sheep from the genotypes of their mates and resulting progeny. AB - Accurate genomic analyses are predicated on access to a large quantity of accurately genotyped and phenotyped animals. Because the cost of genotyping is often less than the cost of phenotyping, interest is increasing in generating genotypes for phenotyped animals. In some instances this may imply the requirement to genotype older animals with greater phenotypic information content. Biological material for these older informative animals may, however, no longer exist. The objective of the present study was to quantify the ability to impute 11 129 single nucleotide polymorphism (SNP) genotypes of non-genotyped animals (in this instance sires) from the genotypes of their progeny with or without including the genotypes of the progenys' dams (i.e. mates of the sire to be imputed). The impact on the accuracy of genotype imputation by including more progeny (and their dams') genotypes in the imputation reference population was also quantified. When genotypes of the dams were not available, genotypes of 41 sires with at least 15 genotyped progeny were used for the imputation; when genotypes of the dams were available, genotypes of 21 sires with at least 10 genotyped progeny were used for the imputation. Imputation was undertaken exploiting family and population level information. The mean and variability in the proportion of genotypes per individual that could not be imputed reduced as the number of progeny genotypes used per individual increased. Little improvement in the proportion of genotypes that could not be imputed was achieved once genotypes of seven progeny and their dams were used or genotypes of 11 progeny without their respective dam's genotypes were used. Mean imputation accuracy per individual (depicted by both concordance rates and correlation between true and imputed) increased with increasing progeny group size. Moreover, the range in mean imputation accuracy per individual reduced as more progeny genotypes were used in the imputation. If the genotype of the mate of the sire was also used, high accuracy of imputation (mean genotype concordance rate per individual of 0.988), with little additional benefit thereafter, was achieved with seven genotyped progeny. In the absence of genotypes on the dam, similar imputation accuracy could not be achieved even using genotypes on up to 15 progeny. Results therefore suggest, at least for the SNP density used in the present study, that it is possible to accurately impute the genotypes of a non-genotyped parent from the genotypes of its progeny and there is a benefit of also including the genotype of the sire's mate (i.e. dam of the progeny). PMID- 28712376 TI - Grape pomace improves performance, antioxidant status, fecal microbiota and meat quality of piglets. AB - In the present study, grape pomace (GP) was used as feed additive in the diet of weaned piglets in order to develop innovative feedstuffs and to investigate their potential beneficial effects on welfare, productivity and meat quality. For examining the antioxidant capacity of the experimental feeds, 24 piglets of 20 days old were assigned to two experimental groups receiving standard or experimental diet for 30 days. Blood and tissues collections were performed at four different time-points, 2, 20, 35 and 50 days post birth. The collected tissues were brain, heart, kidney, liver, lung, quadriceps muscle, pancreas, spleen and stomach. The following oxidative stress markers were assessed: reduced glutathione (GSH), catalase activity, total antioxidant capacity (TAC), thiobarbituric acid reactive substances (TBARS), protein carbonyls (CARB) and H2O2 decomposition activity. The effect on bacterial growth was assessed by examining microbial populations in piglets' fecal microbiota. Furthermore, the average daily gain (ADG) was calculated and the fatty acid profile of quadriceps muscle was assessed. The results showed that piglets fed with the diet supplemented with GP, had significantly increased antioxidants mechanisms in almost all the tissues as shown by increases in GSH, H2O2 decomposition activity and TAC compared with control group. Piglets fed with the experimental diet exhibited decreased oxidative stress-induced damage to lipids and proteins as shown by decreases in TBARS and CARB in GP group compared with control. In addition, the experimental diet increased significantly ADG (by 23.65%) (P<0.05) and enhanced the growth of facultative probiotic bacteria (by up to 1.2 log colony forming units (CFU)/g) (P<0.05) and lactic acid bacteria (by up to 2.0 log CFU/g) (P<0.05) in GP group compared with the control group. GP supplementation inhibited the growth of pathogen populations such as Enterobacteriacae (by up to 1.8 log CFU/g) (P<0.05) and Campylobacter jejuni (by up to 1.0 log CFU/g) (P<0.05). Regarding fatty acid composition of meat, GP inclusion in piglets' diet increased significantly n-3 fatty acids (EPA; C20 : 5n-3, DHA; C22 : 6n-3, alpha linolenic acid; C18 : 3n-3) and decreased significantly n-6/n-3 ratio compared with control (P<0.05). The results suggested that dietary GP supplementation may have a beneficial impact on piglets' welfare and may improve productivity as well as meat quality. PMID- 28712377 TI - Breed of cow and herd productivity affect milk nutrient recovery in curd, and cheese yield, efficiency and daily production. AB - Little is known about cheese-making efficiency at the individual cow level, so our objective was to study the effects of herd productivity, individual herd within productivity class and breed of cow within herd by producing, then analyzing, 508 model cheeses from the milk of 508 cows of six different breeds reared in 41 multi-breed herds classified into two productivity classes (high v. low). For each cow we obtained six milk composition traits; four milk nutrient (fat, protein, solids and energy) recovery traits (REC) in curd; three actual % cheese yield traits (%CY); two theoretical %CYs (fresh cheese and cheese solids) calculated from milk composition; two overall cheese-making efficiencies (% ratio of actual to theoretical %CYs); daily milk yield (dMY); and three actual daily cheese yield traits (dCY). The aforementioned phenotypes were analyzed using a mixed model which included the fixed effects of herd productivity, parity, days in milk (DIM) and breed; the random effects were the water bath, vat, herd and residual. Cows reared in high-productivity herds yielded more milk with higher nutrient contents and more cheese per day, had greater theoretical %CY, and lower cheese-making efficiency than low-productivity herds, but there were no differences between them in terms of REC traits. Individual herd within productivity class was an intermediate source of total variation in REC, %CY and efficiency traits (10.0% to 17.2%), and a major source of variation in milk yield and dCY traits (43.1% to 46.3%). Parity of cows was an important source of variation for productivity traits, whereas DIM affected almost all traits. Breed within herd greatly affected all traits. Holsteins produced more milk, but Brown Swiss cows produced milk with higher actual and theoretical %CYs and cheese making efficiency, so that the two large-framed breeds had the same dCY. Compared with the two large-framed breeds, the small Jersey cows produced much less milk, but with greater actual and theoretical %CYs, similar efficiencies and a slightly lower dCY. Compared with the average of the specialized dairy breeds, the three dual-purpose breeds (Simmental and the local Rendena and Alpine Grey) had, on average, similar dMY, lower actual and theoretical %CY, similar fat and protein REC, and slightly greater cheese-making efficiency. PMID- 28712378 TI - Treatment of allicin improves maturation of immature oocytes and subsequent developmental ability of preimplantation embryos. AB - Allicin (AL) regulates the cellular redox, proliferation, viability, and cell cycle of different cells against extracellular-derived stress. This study investigated the effects of allicin treatment on porcine oocyte maturation and developmental competence. Porcine oocytes were cultured in medium supplemented with 0 (control), 0.01, 0.1, 1, 10 or 100 MUM AL, respectively, during in vitro maturation (IVM). The rate of polar body emission was higher in the 0.1 AL treated group (74.5% +/- 2.3%) than in the control (68.0% +/- 2.6%) (P < 0.1). After parthenogenetic activation, the rates of cleavage and blastocyst formation were significantly higher in the 0.1 AL-treated group than in the control (P < 0.05). The reactive oxygen species level at metaphase II did not significantly differ among all groups. In matured oocytes, the expression of both BAK and CASP3, and BIRC5 was significantly lower and higher, respectively, in the 0.1 AL treated group than in the control. Similarly, the expression of BMP15 and CCNB1, and the activity of phospho-p44/42 mitogen-activated protein kinase (MAPK), significantly increased. These results indicate that supplementation of oocyte maturation medium with allicin during IVM improves the maturation of oocytes and the subsequent developmental competence of porcine oocytes. PMID- 28712379 TI - Mental health difficulties and academic attainment: Evidence for gender-specific developmental cascades in middle childhood. AB - We present a developmental cascade model of the longitudinal relationships between internalizing symptoms, externalizing problems, and academic performance in middle childhood, utilizing a large sample (N = 1,771) from the United Kingdom in a 3-year, cross-lag design. Three hypotheses were tested: adjustment erosion, academic incompetence, and (cumulative) shared risk. In addition, we sought to examine whether developmental cascade pathways varied across gender, while also statistically exploring indirect, mediation pathways. Structural equation models that accounted for within-time covariance, data nesting, and temporal stability provided evidence of gender-specific effects as follows: externalizing-attainment adjustment erosion pathways were found only in boys, while attainment internalizing/externalizing academic incompetence pathways were found only in girls. Analysis of mediation pathways provided further support for these gender specific longitudinal profiles. Protective longitudinal internalizing externalizing and externalizing-internalizing pathways were found for both boys and girls. Finally, while it improved model fit for both genders, the influence of cumulative shared risk on the aforementioned pathways was relatively meager, substantively affecting only one (externalizing-attainment adjustment erosion pathway in boys). The implications of these findings are discussed, and study limitations noted. PMID- 28712380 TI - Influence of para-aminohippuric acid analysis on net portal-drained viscera flux of nutrients in pigs. AB - In nutrition studies, para-aminohippuric acid (PAH) is a marker frequently used to measure blood flow in pigs, which is essential for estimating portal-drained viscera (PDV) flux of nutrients. The aim of this study was to evaluate the PAH analytical method by means of qualimetric statistical procedures to estimate the matrix effect and the accuracy and limits of quantitation of the method. Net PDV flux of nutrients was determined in five multi-catheterized pigs using water, plasma or commercial serum as standard matrix. A proportional systematic error due to matrix effect was found for plasma and serum. Mean recovery was 99.4%, and intra- and inter-day precision of the method was 2.4% and 3.8% relative standard deviation, respectively. The limit of quantification was 0.22 mg PAH/l. Use of water for the PAH standard curves underestimated portal blood flow compared with PAH standards prepared with plasma or commercial serum (706, 954 and 927 ml/min; P<0.05, respectively). Consequently, PDV O2 consumption, glucose and amino acids fluxes were underestimated by 33% (P<0.001). In conclusion, our results stress the importance of using plasma from pigs not infused with PAH or alternatively commercial pig serum to prepare PAH standards to determine blood flow in pigs to avoid underestimation of blood flow. PMID- 28712381 TI - Parental feeding styles, young children's fruit, vegetable, water and sugar sweetened beverage consumption, and the moderating role of maternal education and ethnic background. AB - OBJECTIVE: To examine the associations between parental feeding styles and children's dietary intakes and the modifying effect of maternal education and children's ethnicity on these associations. DESIGN: Cross-sectional study of parental feeding styles, assessed by the Parental Feeding Style Questionnaire, and children's dietary intakes. Multiple regression analyses were carried out to assess the associations between the parental feeding styles studied ('control', 'emotional feeding', 'encouragement to eat' and 'instrumental feeding') and children's dietary intakes (consumption of fruit, vegetables, water and sugar sweetened beverages (SSB)). The modifying effect of maternal education and children's ethnicity on these associations was explored. SETTING: North-western part of the Netherlands. SUBJECTS: Children aged 3-7 years (n 5926). RESULTS: Both 'encouragement' and 'control' were associated with higher consumption of vegetables and lower consumption of SSB, but only 'encouragement' was positively associated with fruit and water intakes. 'Instrumental feeding' showed a positive association with SSB and negative associations with fruit, vegetable and water consumption. No significant associations were found for 'emotional feeding'. Maternal educational level and children's ethnicity moderated some associations; for example, 'control' was beneficial for vegetable intake in all subgroups, whereas the association with SSB was beneficial only in highly educated mothers. CONCLUSIONS: The study shows that both encouraging and controlling feeding styles may improve children's dietary behaviour, while 'instrumental feeding' may have a detrimental effect. Furthermore, maternal educational level and children's ethnicity influence these associations. The study's findings could provide a basis for development of interventions to improve parental feeding styles. PMID- 28712382 TI - Design and Fabrication of a Three-Dimensional In Vitro System for Modeling Vascular Stenosis. AB - Vascular stenosis, the abnormal narrowing of blood vessels, arises from defective developmental processes or atherosclerosis-related adult pathologies. Stenosis triggers a series of adaptive cellular responses that induces adverse remodeling, which can progress to partial or complete vessel occlusion with numerous fatal outcomes. Despite its severity, the cellular interactions and biophysical cues that regulate this pathological progression are poorly understood. Here, we report the design and fabrication of a three-dimensional (3D) in vitro system to model vascular stenosis so that specific cellular interactions and responses to hemodynamic stimuli can be investigated. Tubular cellularized constructs (cytotubes) were produced, using a collagen casting system, to generate a stenotic arterial model. Fabrication methods were developed to create cytotubes containing co-cultured vascular cells, where cell viability, distribution, morphology, and contraction were examined. Fibroblasts, bone marrow primary cells, smooth muscle cells (SMCs), and endothelial cells (ECs) remained viable during culture and developed location- and time-dependent morphologies. We found cytotube contraction to depend on cellular composition, where SMC-EC co-cultures adopted intermediate contractile phenotypes between SMC- and EC-only cytotubes. Our fabrication approach and the resulting artery model can serve as an in vitro 3D culture system to investigate vascular pathogenesis and promote the tissue engineering field. PMID- 28712383 TI - Retrospective genomic analysis of Vibrio cholerae O1 El Tor strains from different places in India reveals the presence of ctxB-7 allele found in Haitian isolates. AB - A total of 45 strains of Vibrio cholerae O1 isolated from 10 different places in India where they were associated with cases of cholera between the years 2007 and 2008 were examined by molecular methods. With the help of phenotypic and genotypic tests the strains were confirmed to be O1 El Tor biotype strains with classical ctxB gene. Polymerase chain reaction (PCR) analysis by double - mismatch amplification mutation assay PCR showed 16 of these strains carried the ctxB-7 allele reported in Haitian strains. Sequencing of the ctxB gene in all the 45 strains revealed that in 16 strains the histidine at the 20th amino acid position had been replaced by asparagine and this single nucleotide polymorphism did not affect cholera toxin production as revealed by beads enzyme-linked immunosorbent assay. This study shows that the new ctxB gene sequence was circulating in different places in India. Seven representatives of these 45 strains analysed by pulsed - field gel electrophoresis showed four distinct Not I digested profiles showing that multiple clones were causing cholera in 2007 and 2008. PMID- 28712384 TI - The epidemiology of invasive pneumococcal disease in older adults in the post-PCV era. Has there been a herd effect? AB - The 7 and 13-valent pneumococcal conjugate vaccines (PCVs) have reduced the incidence of invasive pneumococcal disease (IPD) in children in many countries. The objective of this work was to assess the impact of PCVs and potential herd protection in older adults in Ireland. IPD notification and typing data from adults ?65 years of age from July 2007 to June 2016 was assessed using national surveillance data. There was a 94% reduction in PCV7 serotypes from 2007-2008 to 2015-2016, incidence rate ratio (IRR 0.05, P < 0.0001). However, there was no decline in the additional PCV13 (PCV13-7) serotypes over the same period (IRR 0.90) nor in comparison with the pre-PCV13 period 2009-2010 (IRR 0.92). The incidence of serotypes in the 23-valent pneumococcal polysaccharide vaccine only (PPV23-PCV13) and non-vaccine types (NVTs) increased significantly (IRR 2.17, P = 0.0002 and IRR 3.43, P = 0.0001 respectively). Consequently, the overall IPD incidence rate in adults has remained relatively unchanged (from 28.66/100 000 to 28.88/100 000, IRR 1.01, P = 0.9477). Serotype 19A and NVTs were mainly responsible for penicillin resistance in recent years. The decline of PCV7 serotypes indicate that the introduction of PCV7 resulted in herd-protection for adults. However, increases in PPV23-PCV13 and NVTs suggest that changes in vaccination strategy amongst older adults are needed to build on the success of PCVs in children. PMID- 28712385 TI - Pregnant with HIV before age 25: data from a large national study in Italy, 2001 2016. AB - Young pregnant women with HIV may be at significant risk of unplanned pregnancy, lower treatment coverage, and other adverse pregnancy outcomes. In a large cohort of pregnant women with HIV in Italy, among 2979 pregnancies followed in 2001 2016, 9.0% were in women <25 years, with a significant increase over time (2001 2005: 7.0%; 2006-2010: 9.1%; 2011-2016: 12.2%, P < 0.001). Younger women had a lower rate of planned pregnancy (23.2% vs. 37.7%, odds ratio (OR) 0.50, 95% confidence interval (CI) 0.36-0.69), were more frequently diagnosed with HIV in pregnancy (46.5% vs. 20.9%, OR 3.29, 95% CI 2.54-4.25), and, if already diagnosed with HIV before pregnancy, were less frequently on antiretroviral treatment at conception (<25 years: 56.3%; ?25 years: 69.0%, OR 0.58, 95% CI 0.41-0.81). During pregnancy, treatment coverage was almost universal in both age groups (98.5% vs. 99.3%), with no differences in rate of HIV viral suppression at third trimester and adverse pregnancy outcomes. The data show that young women represent a growing proportion of pregnant women with HIV, and are significantly more likely to have unplanned pregnancy, undiagnosed HIV infection, and lower treatment coverage at conception. During pregnancy, antiretroviral treatment, HIV suppression, and pregnancy outcomes are similar compared with older women. Earlier intervention strategies may provide additional benefits in the quality of care for women with HIV. PMID- 28712386 TI - Neuropeptide Y improves cisplatin-induced bone marrow dysfunction without blocking chemotherapeutic efficacy in a cancer mouse model. AB - Cisplatin is the most effective and widely used chemotherapeutic agent for many types of cancer. Unfortunately, its clinical use is limited by its adverse effects, notably bone marrow suppression leading to abnormal hematopoiesis. We previously revealed that neuropeptide Y (NPY) is responsible for the maintenance of hematopoietic stem cell (HSC) function by protecting the sympathetic nervous system (SNS) fibers survival from chemotherapy-induced bone marrow impairment. Here, we show the NPY-mediated protective effect against bone marrow dysfunction due to cisplatin in an ovarian cancer mouse model. During chemotherapy, NPY mitigates reduction in HSC abundance and destruction of SNS fibers in the bone marrow without blocking the anticancer efficacy of cisplatin, and it results in the restoration of blood cells and amelioration of sensory neuropathy. Therefore, these results suggest that NPY can be used as a potentially effective agent to improve bone marrow dysfunction during cisplatinbased cancer therapy. [BMB Reports 2017; 50(8): 417-422]. PMID- 28712387 TI - SRSF2 directly inhibits intron splicing to suppresses cassette exon inclusion. AB - SRSF2, a Serine-Arginine rich (SR) protein, is a splicing activator that mediates exon inclusion and exclusion events equally well. Here we show SRSF2 directly suppresses intron splicing to suppress cassette exon inclusion in SMN premRNA. Through a serial mutagenesis, we demonstrate that a 10 nt RNA sequence surrounding the branch-point (BP), is important for SRSF2-mediated inhibition of cassette exon inclusion through directly interacting with SRSF2. We conclude that SRSF2 inhibits intron splicing to promote exon exclusion. [BMB Reports 2017; 50(8): 423-428]. PMID- 28712389 TI - Rescuing p53 from mdm2 by a pre-structured motif in intrinsically unfolded SUMO specific protease 4. AB - Many intrinsically unstructured/unfolded proteins (IUPs) contain transient local secondary structures even though they are "unstructured" in a tertiary sense. These local secondary structures are named "pre-structured motifs (PreSMos)" and in fact are the specificity determinants for IUP-target binding, i.e., the active sites in IUPs. Using high-resolution NMR we have delineated a PreSMo active site in the intrinsically unfolded mid-domain (residues 201-300) of SUMO-specific protease 4 (SUSP4). This 29-residue motif which we termed a p53 rescue motif can protect p53 from mdm2 quenching by binding to the p53-helix binding pocket in mdm2(3-109). Our work demonstrates that the PreSMo approach is quite effective in providing a structural rationale for interactions of p53-mdm2- SUSP4 and opens a novel avenue for designing mdm2- inhibiting anticancer compounds. [BMB Reports 2017; 50(10): 485-486]. PMID- 28712388 TI - RING E3 ligases: key regulatory elements are involved in abiotic stress responses in plants. AB - Plants are constantly exposed to a variety of abiotic stresses, such as drought, heat, cold, flood, and salinity. To survive under such unfavorable conditions, plants have evolutionarily developed their own resistant-mechanisms. For several decades, many studies have clarified specific stress response pathways of plants through various molecular and genetic studies. In particular, it was recently discovered that ubiquitin proteasome system (UPS), a regulatory mechanism for protein turn over, is greatly involved in the stress responsive pathways. In the UPS, many E3 ligases play key roles in recognizing and tethering poly-ubiquitins on target proteins for subsequent degradation by the 26S proteasome. Here we discuss the roles of RING ligases that have been defined in related to abiotic stress responses in plants. [BMB Reports 2017; 50(8): 393-400]. PMID- 28712390 TI - [The oxLDL/beta2GPI/beta2GPI-Ab complex promotes the migration and the expression of inflammatory cytokines in human umbilical vein endothelial cells]. AB - Objective To study the effects of the complex of oxidized low density lipoprotein/beta2-glycoprotein I/beta2-glycoprotein I antibodies (oxLDL/beta2GPI/beta2GPI-Ab) on the migration of human umbilical vein endothelial cells (HUVECs) and the expression of inflammatory cytokines, and their underlying Toll-like receptor (TLR4) pathway. Methods HUVECs were treated with oxLDL, oxLDL/beta2GPI complex, oxLDL/beta2GPI-Ab complex, oxLDL/beta2GPI/beta2GPI-Ab complex, or lipopolysaccharide (LPS) for a period of time in their corresponding groups. The migration of HUVECs was observed by the wound-healing assay. The mRNA and protein levels of TLR4 in HUVECs were detected by real-time quantitative PCR (qRT-PCR) and Western blotting, respectively. The cells were pretreated with or without TAK-242 (the inhibitor of TLR4) 2 hours before stimulated by corresponding stimulus as described above. Then, the contents of monocyte chemotactic protein-1 (MCP-1), interleukin 1beta (IL-1beta) and IL-6 in cell culture supernatant were determined by ELISA, and their mRNAs were detected by qRT-PCR. Results The oxLDL/beta2GPI/beta2GPI-Ab complex promoted the migration of HUVECs effectively, and increased the expression of TLR4. The oxLDL/beta2GPI/beta2GPI-Ab complex increased the expressions of MCP-1, IL-1beta, and IL-6. TAK-242 could reduce the effects of oxLDL/beta2GPI/beta2GPI-Ab complex. Conclusion The oxLDL/beta2GPI/anti-beta2GPI-Ab complex can promote the migration of HUVECs and the expression of related inflammatory cytokines, and TLR4 may be involved in this process. PMID- 28712391 TI - [Hepatic stellate cells inhibit the proliferation and invasion of HepG2 hepatocellular carcinoma via activating gammadelta T cells]. AB - Objective To investigate the effects of gammadelta T cells co-cultured with human hepatic stellate cells (HSCs) on the proliferation and invasion of hepatocellular carcinoma (HCC) cells. Methods Peripheral gammadelta T cells of healthy volunteers and HCC patients were separated and collected by density gradient centrifugation and flow cytometry. TranswellTM chambers were used to co-culture LX-2 cells and gammadelta T cells. The concentration of IFN-gamma in gammadelta T cell supernatant was detected by ELISA. The proliferation of HepG2 cells was analyzed by CCK-8 assay, and the invasion ability of HepG2 cells was evaluated by TranswellTM chamber assay. Results After co-cultured with LX-2 cells, the IFN gamma secretion in gammadelta T cells increased obviously, and the level of IFN gamma was higher in healthy volunteer group than in HCC patient group. The inhibitory effects of gammadelta T cells on the proliferation and invasion of HepG2 cells were enhanced after the co-culture, and the enhancement of inhibitory abilities was more obvious in healthy volunteer group than in HCC patient group. Conclusion HSC could activate gammadelta T cells and promote IFN-gamma secretion of gammadelta T cells, thus enhancing the inhibitory effects of gammadelta T cells on the proliferation and invasion of hepatoma cells. PMID- 28712392 TI - [Protection of Rho-associated protein kinase inhibitor Y-27632 in MRL/lpr mice]. AB - Objective To investigate the immunological effect of Rho-associated protein kinase inhibitor Y-27632 on MRL/lpr mice and explore its underlying mechanisms. Methods The study collected 10 wild-type C57BL/6 mice as normal controls and 20 MRL/lpr mice that were randomly assigned to MRL/lpr group and 5 mg/kg Y-27632 treated MRL/lpr group, with 10 mice in each group. Superoxide dismutase (SOD), methane dicarboxylic aldehyde (MDA), interleukin 6 (IL-6), IL-1beta and tumor necrosis factor alpha (TNF-alpha) in the serum or spleen were detected by ELISA. The protein levels of thioredoxin-interacting protein/thioredoxin (Txnip/Trx), MAPK-associated protein ERK, JNK, p38 and NF-kappaB were detected by Western blot analysis. T lymphocytes were isolated and cultured from the groups, and then subjected to Western blotting for evaluating the levels of Txnip/Trx, MAPK, NF kappaB proteins and to ELISA for determining the levels of IL-6, IL-1beta, TNF alpha in the supernatants. Results Compared with the MRL/lpr group, the level of SOD increased and MDA decreased in the serum and spleen; the levels of IL-6, IL 1beta, TNF-alpha were reduced in the serum, spleen and the supernatant of T cells from the spleen; the protein levels of Txnip/Trx, MAPK, NF-kappaB from the spleen were inhibited and the level of Trx in the spleen was raised in MRL/lpr mice treated with Y-27632. Conclusion Ros kinase inhibitor Y-27632 has protective effects on MRL/lpr lupus mice. PMID- 28712393 TI - [VCAM-1-mediated migration of CD34+VLA-4+ bone marrow derived cells into myocardial tissues in mice with acute viral myocarditis]. AB - Objective To analyze the migration and expression of CD34+VLA-4+ cells under the induction of vascular cell adhesion molecule-1 (VCAM-1) in a murine model of acute viral myocarditis (VMC). Methods Frequency of CD34+VLA-4+ cells in the myocardial tissues and peripheral blood were examined by flow cytometry. The mRNA and protein of VCAM-1 in the myocardial tissues were analyzed by real-time quantitative PCR and Western blotting. Results In the acute VMC mice, CD34+VLA-4+ cell population in the myocardial tissues significantly increased at day 3, peaked at day 7, and then decreased, but it was still higher than that in the control group at day 14 and 28. It decreased in the peripheral blood at day 3, and then increased to the peak at day 7, thereafter it decreased, but was still higher than that in the control group at day 14 and 28. We found a high expression of VCAM-1 in the myocardial tissues of the acute VMC mice, paralleling the mobilization of CD34+VLA-4+ cells in the myocardial tissues. Conclusion VCAM 1 promotes CD34+VLA-4+ cell mobilization into the damaged myocardial tissues. PMID- 28712394 TI - [Human rhinovirus infection promotes mast cell apoptosis and increases the release of inflammatory cytokines]. AB - Objective To investigate the regulation of innate immune response of HMC-1 mast cells to human rhinovirus (HRV) infection. Methods Virus replication in HMC-1 cells was quantified by real-time quantitative PCR (qRT-PCR). Cell viability and apoptosis were assessed by flow cytometry. The levels of tumor necrosis factor alpha (TNF-alpha), interferon alpha (IFN-alpha), interleukin 6 (IL-6) and IL-8 produced by HMC-1 cells were measured using ELISA. Results After HRV infected HMC 1 cells, the copy numbers of virus RNA and apoptotic cells increased obviously over time, what's more, the release of TNF-alpha, IFN-alpha, IL-6 and IL-8 from HMC-1 cells ascended significantly compared with control groups. Conclusion HRV infection can promote mast cell apoptosis and enhance the release of inflammatory cytokines from mast cells. PMID- 28712395 TI - [Inhibitory effect of bispecific antibody targeting IL-12 p40 and TNF-alpha simultaneously on psoriasis in mice]. AB - Objective To construct bispecific antibodies, which can block interleukin 12 (IL 12)/IL-23 p40 subunit and tumor necrosis factor alpha (TNF-alpha) simultaneously, and identify their biological function and inhibitory effect on psoriasis formation in mice. Methods Based on the sequences of adalimumab and ustekinumab, three kinds of bispecific antibodies were designed, named BiAU003, BiAU022 and BiAU023. The specificity and binding capacity of bispecific antibodies were determined by ELISA. After co-treated with bispecific antibodies and TNF-alpha, the level of endothelial leukocyte adhesion molecule-1 (ELMA-1) labeled with fluorescein isothiocyanate (FITC) in human umbilical vein endothelial cells (HUVECs) were examined by flow cytometry. Human peripheral blood mononuclear cells (PBMCs) were purified and cultured in the medium containing IL-2 and IL-12 in the absence or presence of bispecific antibodies. Commercial ELISA kit was used to detect interferon gamma (IFN-gamma) concentration in the supernatant. BALB/c mice were used for psoriasis model construction through injection of IL-12 and TNF-alpha subcutaneously. Then they were treated with the bispecific antibodies. Psoriasic skin was measured in thickness and scale under microscopy after H&E staining. Results The three kinds of bispecific antibodies could specifically recognize IL-12/23 p40 and TNF-alpha protein, and inhibit IFN-gamma secretion and the expression of ELAM-1 protein. Data also indicated that bispecific antibodies inhibited the formation of psoriasic skin, and showed an equal or superior effect to control antibody drug. Conclusion The novel bispecific antibodies, BiAU003, BiAU022 and BiAU023, can serve as an antagonist of TNF-alpha and IL-12/23 p40, and have a blocking effect on mouse psoriasis formation. PMID- 28712396 TI - [Response surface methodology for optimizing the technology of induction and isolation of dendritic cells by multiple cytokines]. AB - Objective To promote the induction and separation efficiency of bone marrow derived dendritic cells (BMDCs) in vitro through optimizing the inducing and isolating process by multiple cytokines. Methods The factors to be optimized in single factor tests included recombinant mouse granulocyte macrophage-colony stimulating factor (rmGM-CSF), recombinant mouse interleukine 4 (rmIL-4), lipopolysaccharide (LPS), recombinant mouse tumor necrosis factor alpha (rmTNF alpha) and inducing time. The numbers of immature dendritic cells (imDCs) and mature dendritic cells (mDCs) were investigated as the indicators. Box-Behnken experimental design-response surface methodology was used to analyze and verify the data. Morphological changes were observed using the inverted microscopy and the transmission electron microscopy. Surface molecules including CD11c and CD86 were detected using the flow cytometry. Results The optimum inducing conditions for imDCs were obtained as follows: rmGM-CSF was 46 ng/mL, rmIL-4 was 24 ng/mL, inducing time was 6 days, and the number of imDCs was (4.58+/-0.28)*106 cells, and the relative deviation was 4.00%. The optimum inducing conditions for mDCs were as follows: LPS was 1.4 MUg/mL, rmTNF-alpha was 30 ng/mL, inducing time was 1 day, and the number of mDCs was (4.21+/-0.15)*106 cells, and the relative deviation was 3.80%. Sufficient typical imDCs and mDCs were obtained within 5-7 days of induction in vitro. Also, flow cytometry showed that the amplified imDCs had a high expression of CD11c (68.62%+/-2.3%) and a low expression of CD86 (37.95%+/-1.8%), and the mDCs had high expressions of both CD86 (90.34%+/-1.4%) and CD11c (82.05%+/-1.6%). Conclusion The combination of single factor tests and Box-Behnken design -response surface methodology could optimize the inducing and isolating method for DCs in vitro by multiple cytokines rapidly and efficiently, which provided basic experiment materials for further studies. PMID- 28712397 TI - [Stem cell factor enhances invasive ability of BxPC-3 cells via hypoxia-inducible factor 1alpha (HIF-1alpha)]. AB - Objective To investigate the effect of stem cell factor (SCF)/c-KIT system on the invasion of BxPC-3 pancreatic cancer cells and the role of hypoxia-inducible factor 1 alpha (HIF-1alpha) in this effect. Methods BxPC-3 cells were cultured in normoxia and hypoxia. The cells cultured in normoxia were treated with SCF. Real time quantitative PCR and Western blotting were used to investigate the expressions of HIF-1alpha mRNA and protein, respectively. Small interference RNA of HIF-1alpha (siHIF-1alpha) was designed and synthesized, and then transfected into BxPC-3 cells. The expressions of matrix metalloproteinase-2 (MMP2), MMP9, and urokinase type plasminogen activator (uPA) were detected by real-time quantitative PCR and Western blotting in BxPC-3 cells after treated with SCF or siHIF-1alpha. The effects of SCF/c-KIT and HIF-1alpha knockdown on BxPC-3 cell invasion were examined by TranswellTM assay. Results Either SCF or hypoxia could induce the protein expression of HIF-1alpha. The siHIF-1alpha down-regulated the expression of HIF-1alpha specifically in BxPC-3 cells. SCF up-regulated the mRNA and protein expressions of MMP2, MMP9 and uPA, while siHIF-1alpha down-regulated the expressions of these genes. The invasive ability of BxPC-3 cells were enhanced by SCF, while siHIF-1alpha played an opposite role. Conclusion SCF/c-KIT system up-regulates the mRNA and protein expressions of MMP2, MMP9 and uPA through HIF-1alpha, which enhances the invasive ability of pancreatic cancer cells. And siHIF-1alpha can effectively inhibit these effects. PMID- 28712399 TI - [Expressions of stem cell factor and hypoxia inducible factor 1 alpha in pancreatic cancer cells and related mechanism]. AB - Objective To study the correlation between the expressions of stem cell factor (SCF) and hypoxia inducible factor 1 alpha (HIF-1alpha) in pancreatic cancer, and investigate the mechanism by which SCF regulates the expression of HIF-1alpha. Methods Immunohistochemistry was used to detect the expressions of SCF and HIF 1alpha in pancreatic cancer specimens and to analyze the correlation between SCF and HIF-1alpha expressions. Pancreatic cancer PANC-1 cells were treated with different doses of SCF (0, 1, 10, 100 ng/mL) alone or combined with c-KIT inhibitor Gleevec (5 MUmol/L). Real-time fluorescent quantitative PCR (qRT-PCR) was performed to detect the level of HIF-1alpha mRNA, and Western blotting to detect the HIF-1alpha protein level, the phosphorylation levels of ERK1/2 and AKT. Results SCF and HIF-1alpha were up-regulated in pancreatic cancer samples and they had an obvious positive correlation. In PANC-1 cells, SCF didn't affect the expression of HIF-1alpha mRNA, but up-regulated the expression of HIF-1alpha protein in a dose-dependent manner. Gleevec inhibited the SCF-induced up regulation of HIF-1alpha protein, but did not affect the mRNA. And Gleevec blocked the phosphorylation of AKT and ERK1/2. Conclusion SCF/c-KIT can up regulate the protein expression of HIF-1alpha by activating AKT and ERK signaling pathways in pancreatic cancer cells. PMID- 28712398 TI - [Fasudil attenuates mitochondrial injury and apoptosis in rat model of myocardial ischemia/reperfusion injury]. AB - Objective To observe the changes of mitochondria fusion protein 2 (Mfn2) and dynamin-related protein 1 (Drp1) in the cardioprotection of fasudil, and analyze the significance. Methods Hearts isolated from male Sprague-Dawley rats were subjected to ischemia for 30 minutes (occlusion of left anterior descending artery), and continuously perfusion for 120 minutes to establish myocardial ischemia/reperfusion (I/R) injury model. The rats were divided into 3 groups: sham group, I/R group and fasudil group. The left ventricular hemodynamics were continuously recorded; lactate dehydrogenase (LDH) content was measured during reperfusion; myocardial ultrastructure was observed by electron microscopy; the protein expression of phosphorylated protein phosphatase 1 regulatory subunit 12A (p-PPP1R12A/p-MYPT1) was detected by immunohistochemistry; and the protein expressions of Mfn2, Drp1 and cleaved caspase-3 (c-caspase-3) were detected by Western blot analysis. Results Compared with the sham group, the left ventricular systolic and diastolic function was weakened, and LDH release was promoted in the other two groups during reperfusion. Compared with the I/R group, fasudil improved left ventricular systolic and diastolic function and reduced LDH release. Electron microscopy and immunohistochemical results showed that myofibril and mitochondria were damaged obviously, and p-MYPT1 protein expression was enhanced in the I/R group. Compared with the I/R group, fasudil attenuated the damage of myofibril and mitochondria, and decreased p-MYPT1 protein expression. Western blotting showed that, compared with the sham group, Mfn2 protein expression decreased, Drp1 and c-caspase-3 protein expressions increased in the I/R group. Compared with I/R group, there was no obvious change in Mfn2 protein expression, while Drp1 and c-caspase 3 protein expressions decreased in the fasudil group. Conclusion Fasudil can protect against myocardial I/R damage through inhibiting Rho kinase, which has no clear correlation with Mfn2 protein expression, but may be related with decreasing Drp1 protein expression and reducing mitochondrial injury, thereby inhibiting apoptosis. PMID- 28712400 TI - [Dopamine inhibits glutamate-uptake ability of astrocytes via TAAR1-EAAT2 pathway]. AB - Objective To investigate the effect of dopamine (DA) on the glutamate (Glu) uptake ability of astrocytes, and the role of trace amine-associated receptor 1 excitatory amino acid transporter 2 (TAAR1-EAAT2) signaling pathway in Glu uptake by astrocytes. Methods In the primary cultured astrocytes pretreated with DA, extracellular Glu levels were measured by the Amplex Red glutamic acid assay kit. The levels of TAAR1 and EAAT2 transcriptions were detected by reverse transcription PCR and their protein levels were analyzed by Western blotting. After TAAR1 plasmid and TAAR1 siRNA were separately transfected into the primary astrocytes pretreated by DA, Western blotting was performed to determine the level of EAAT2 and Amplex Red glutamic acid assay kit was used to analyze Glu uptake in primary cultured astrocyte supernatants. Results The expression of EAAT2 in the primary cultured astrocytes significantly decreased in response to DA, and the level of TAAR1 increased. DA significantly enhanced the Glu uptake in primary cultured astrocyte supernatants. After TAAR1 siRNA transfection, EAAT2 expression was upregulated by DA treatment and Glu content in the supernatants was downregulated. On the contrary, after TAAR1 plasmid transfection, EAAT2 expression descended and Glu level ascended in the supernatants. Conclusion DA reduces the Glu-uptake ability of astrocytes through TAAR1-EAAT2 signaling pathway, causes extracellular Glu accumulation, and ultimately destroys the function of astrocytes. PMID- 28712402 TI - [Xinfeng Capsule improves lung function by regulating Notch/Jagged-HES axis of type II alveolar epithelial cells in adjuvant arthritis rats]. AB - Objective To observe the effect of Xinfeng Capsule (XFC) on Notch/Jagged-HES of type II alveolar epithelial cells (AECII). Methods Rats were divided for four groups: normal control (NC) group, model control (MC) group, leflunomide (LEF) group, XFC group, with 10 rats in each group. Complete Freund's adjuvant (CFA) was injected in the right foot plantar skin of each rat except for the NC group. After adjuvant arthritis was successfully induced, LEF group was given LEF (0.5 mg/100 g), and XFC group was treated with XFC (0.034 g/100 g), once a day from the 13th day to the 42th day. The NC and MC groups were given normal saline instead. Swelling degree (SD), arthritis index (AI) and pulmonary function were observed. AECII was observed by transmission electron microscopy (TEM). The expressions of transforming growth factor beta1 (TGF-beta1), Notch1, Notch3, Jagged1 and HES1 proteins in AECII were detected by Western blotting. Results The pulmonary function parameters such as forced expiratory volume in 1 second (FEV1), maximum expiratory flow rate at 50% FVC (FEF50), instantaneous flow at 75% of expired volume (FEF75), peak expiratory flow (PEF) in the MC group were significantly lower than those in the NC group, and the expressions of TGF-beta1, Notch1, Notch3, Jagged1 and HES1 in AECII increased. The ultrastructure of AECII was damaged. Compared with the MC group, FEV1, FEF50, FEF75 and PEF increased, and TGF-beta1, Notch1, Notch3, Jagged1 and HES1 decreased in the XFC group. Compared with LEF group, the lung function was better in XFC group. Conclusion XFC can inhibit pulmonary fibrosis and improve pulmonary function by down regulating TGF-beta1, Notch1, Notch3, Jagged1 and HES1 in rats with adjuvant arthritis. PMID- 28712401 TI - [Fisetin alleviates hypoxia/reoxygenation injury in rat hepatocytes via modulation of TLR4/NF-kappaB signaling pathway]. AB - Objective To investigate the protective effect of fisetin (FIS) against hypoxia/reoxygenation (H/R) injury in rat hepatocytes and its mechanism. Methods H/R injury model of BRL-3A cells was established and the cells were pretreated with FIS. Survival rate was detected by CCK-8 assay. Cell apoptosis was measured by flow cytometry. The levels of ALT and AST were determined by microplate assay. The production of TNF-alpha and IL-1beta were detected by ELISA. The mRNA and protein levels of TLR4 and NF-kappaBp65 were analyzed by quantitative real-time PCR and Western blotting, respectively. Results After subjected to H/R, cell survival rate decreased and the apoptosis level increased. The levels of ALT and AST in cell supernatant were elevated, so were the production of TNF-alpha and IL 1beta. FIS pretreatment increased the cell survival rate and inhibited apoptosis. The levels of ALT, AST and the production of TNF-alpha and IL-1beta were reduced significantly. Moreover, FIS inhibited the increasing expression levels of TLR4 and NF-kappaBp65 induced by H/R. Conclusion FIS alleviates the hepatocyte injury induced by H/R via modulation of TLR4/NF-kappaB signaling pathway. PMID- 28712403 TI - [Serum soluble HLA-G, soluble CD30 is correlated to the time after transplantation in renal transplant recipients]. AB - Objective To investigate the expressions of serum soluble human leukocyte antigen G (sHLA-G) and soluble CD30 (sCD30) in renal transplant recipients at different time after transplantation, and explore the relationship between the expressions of serum sHLA-G, sCD30 and the time after renal transplantation. Methods Eleven kidney transplant recipients and 10 healthy donors were selected, in which the dynamic changes of serum sHLA-G and sCD30 were detected by ELISA before transplantation and 1 year after transplantation; 33 kidney transplant recipients with normal renal graft were selected and divided into three groups: 1-5 years, 5 10 years and 10 years post-transplantation. The expressions of serum sHLA-G and sCD30 in the recipients were tested over one year after transplantation. Results The level of serum sHLA-G before transplantation was not significantly different from that of the control group. There was no significant difference between pre transplantation, 1 week and 1 month after transplantation. Serum sHLA-G level of renal transplant recipients at 3 months after transplantation was higher than that 1 month after transplantation. There was no significant change in serum sHLA G level among 3, 6 and 12 months after transplantation. The level of serum sHLA-G in the group of transplant time >10 years was significantly higher than that in the group of transplant time <=5 years. The serum sHLA-G level was significantly associated with the time after renal transplantation. The level of serum sCD30 before transplantation was higher than that in the control group and decreased in 1 week after transplantation. There were no significant differences in sCD30 level between 1, 3, 6, and 12 months after transplantation, and similarly, there were also no significant differences between the groups of transplant time <=5 years, 5-10 years and 10 years after transplantation. The level of sCD30 was significantly associated with the time within 1 month after renal transplantation. Conclusion The serum sHLA-G in kidney transplant recipients with normal renal graft increased with the time after renal transplantation, while the serum sCD30 level was reduced within 1 month after renal transplantation. PMID- 28712404 TI - [Polymorphisms of TLR7 rs3853839 and rs179010 are associated with susceptibility to and severity of hand, foot and mouth disease caused by enterovirus 71 in male children]. AB - Objective To investigate whether the polymorphisms of TLR7/MyD88 signaling pathway is associated with the susceptibility to and severity of hand, foot and mouth disease (HFMD) caused by enterovirus 71 (EV71) in children. Methods We collected 180 EV71 HFMD cases and 201 healthy controls from both the Second Affiliated Hospital of Xi'an Jiaotong University and Xi'an Children's Hospital. The genotypes including rs3853839, rs179010 of TLR7, and rs7744 of MyD88 were detected in the 381 samples by SNPscan kit. Results The susceptibility risk (OR=2.343, 95%CI:1.516-3.621) and severity risk (OR=1.939, 95%CI: 1.064-3.521) of TLR7 rs3853839 allele C significantly increased in the male children with EV71 HFMD. Also, the susceptibility risk (OR=1.701, 95%CI: 1.142-2.535) and severity risk (OR=1.852, 95%CI: 1.038-3.305) of TLR7 rs179010 allele T significantly increased in the male children with EV71 HFMD. But there was no significant difference in the distribution of TLR7 rs179010 and rs3853839 genes between female children with EV71 HFMD and female controls. There was no correlation between the genetic polymorphisms of MyD88 rs7744 and the susceptibility to and severity of EV71 HFMD in the children. Conclusion Polymorphisms of TLR7 rs3853839 and rs179010 are correlated to the susceptibility to and severity of EV71 HFMD in male children. PMID- 28712405 TI - [Changes of monocyte and monocyte-platelet aggregates in different subgroups of thrombotic events in patients with acute myocardial infarction during PCI]. AB - Objective To investigate the impact of thrombotic events on the alterations of monocyte and monocyte-platelet aggregates (MPAs) in patients with acute myocardial infarction (AMI) during percutaneous coronary intervention (PCI). Methods Blood was collected before PCI for flow cytometry. Monocyte subsets and MPAs were detected by four-color platform (CDl4-APC, CDl6-PE-Cy7, CD86-PE and CD41-Alexa FluorR488). According to the expression of the platelet surface marker CD41, the number of monocyte subsets and MPAs was analyzed using the fluorescent microspheres of absolute counting tube. The Wilcoxon rank sum test and receiver operating characteristic (ROC) curve analysis were performed. Results CD14+CD16++ monocytes in intraprocedural thrombotic events (IPTE) group were significantly fewer than those in non-IPTE group, and the percentage in total mononuclear cells decreased. Compared with non-IPTE group, MPA binding ratio and monocyte subset MPA binding ratio were significantly higher in IPTE group. ROC analysis showed that MPA binding ratio and subgroup MPA binding ratio had a better predictive value for IPTE in patients with AMI. Conclusion The CD14+CD16++ monocytes in IPTE group were significantly fewer than those in the non-IPTE group. MPA binding ratio and MPA binding ratio of monocyte subsets were significantly higher in the IPTE group than in the non-IPTE group, so they have a good predictive value for IPTE in patients with AMI. PMID- 28712406 TI - [Increased expressions of substance P and neurokinin/tachykinin receptor 1 in eosinophils of patients with psoriasis]. AB - Objective To investigate the expressions of substance P (SP) and its receptor neurokinin/tachykinin receptor 1 (NK1R) in peripheral blood eosinophils of patients with psoriasis. Methods The levels of SP and NK1R in the peripheral blood of both patients with psoriasis and healthy people were detected by flow cytometry. This method was again used to detect the levels of SP and NK1R in the peripheral blood eosinophils of patients with psoriasis after stimulated with the crude extracts of Artemisia pollen, dust mite and Platanus pollen (all at concentrations of 0.1 and 1.0 MUg/mL). Results Compared with the healthy controls, the percentages of SP+ and NK1R+ eosinophils in psoriasis patients increased up to 2.7 and 0.5 folds, respectively. Moreover, the mean fluorescence intensity (MFI) of SP+ and NK1R+ eosinophils of psoriasis patients were elevated by 1.5 and 0.2 folds, respectively. The percentage of SP+ eosinophils in psoriasis were down-regulated by 60% after the stimulation with Platanus pollen extract (1 MUg/mL), while 0.1 MUg/mL Platanus pollen extract induced a 0.6-fold increase in the percentage of NK1R+ eosinophis. Conclusion The expressions of SP and NK1R are up-regulated in peripheral blood eosinophils of patients with psoriasis. PMID- 28712407 TI - [Detection and clinical significance of PML protein expression of acute promyelocytic leukemia cells]. AB - Objective To study the expression patterns of promyelocytic leukemia (PML) protein at different stages of acute promyelocytic leukemia (APL) and investigate the effects that the arsenical, all-trans retinoic acid (ATRA) and chemotherapeutic drugs on PML protein expression patterns. Methods The bone marrow cells of 42 APL patients, NB4 cells and MR2 cells were collected and treated separately with 1 MUmol/L arsenic trioxide (As2O3), 1 MUmol/L tetra arsenic tetra-sulfide (As4S4), 1 MUmol/L ATRA, 10 mg/L cytosine arabinoside, and 1 mg/L homoharringtonine. The changes of fluorescent signals before and after the treatment were detected by indirect immunofluorescence technique. Results The 87.5% of initial onset APL cases showed small fluorescent signals (fluorescent signals in the nucleus look like a starry sky, more than 30 fluorescent light dots per cell); 91.67% of complete remission APL cases manifested large fluorescent signals (fluorescent signals in the nucleus are larger, fewer than 30 fluorescent light dots per cell); and 83.33% of relapse APL cases presented small fluorescent signals. Compared with control group without medication, the PML protein expression of APL cells in initial onset cases had larger fluorescent signals in the ATRA group, As2O3 group and As4S4 group, whereas there were no significant changes in the arabinoside cytosine group and the homoharringtonine group. In addition, ATRA transformed the PML protein expression of NB4 cells from small fluorescent signals into large ones, but did not change small fluorescent signals of the PML protein expression in MR2 cells. Also, As2O3 and As4S4 turned the PML protein expression of NB4 and MR2 cells from small fluorescent signals into large ones. Conclusion Detection of PML protein expression patterns of APL cells has practical application values for evaluating the prognosis of APL and making a rational choice of drugs. PMID- 28712408 TI - [Dectection of G3BP and CD44v6 in the tissues of laryngeal squamous cell carcinoma and their clinical significance]. AB - Objective To study the expressions of RNA-binding Ras-GAP SH3 binding protein (G3BP) and tumor stem cell marker CD44v6 in laryngeal squamous cell carcinoma and their correlations with angiogenesis. Methods We collected the cancer tissues and corresponding paracancerous tissues from 56 patients with laryngeal squamous cell carcinoma. The expressions of G3BP and CD44v6 proteins were detected by Western blotting in cancer tissues and corresponding paracancerous tissues; the expressions of G3BP, CD44v6 and vascular endothelial growth factor A (VEGF-A) were tested by immunohistochemistry. Thereafter, we compared the positive expression rates of G3BP and CD44v6 between in cancer tissues and in normal tissues, analyzed the correlations between the expressions of G3BP, CD44v6 and the laryngeal squamous cell carcinoma features as well as their correlations with microvessel density (MVD) that was determined by FVIIIAg immunohistochemistry. Results Western blotting showed that the expressions of G3BP and CD44v6 proteins in the laryngeal squamous cell carcinoma were higher than those in the paracancerous tissues. Immunohistochemistry showed that compared with the paracancerous tissues, G3BP, CD44v6 and VEGF-A expressions (the positive rates are 58.9%, 53.6%, 46.4%, respectively) were higher in cancer tissues. The positive rates of G3BP and CD44v6 in cancer tissues were related with the clinical stage, recurrence or metastasis, and lymph node metastasis of laryngeal squamous cell carcinoma, but had nothing to do with patients' age and tumor size. Pearson correlation analysis showed the expressions of both G3BP and CD44v6 were positively correlated with VEGF-A (r=0.741, r=0.756). MVD values were significantly higher in the G3BP and CD44v6 positive cases than in paracancerous tissues, but there was no difference in MVD between those without G3BP and CD44v6 positive expressions and the paracancerous tissues. Conclusion The positive expression rates of G3BP and CD44v6 in laryngeal squamous cell carcinoma tissues are very high, and they have a close relationship with the clinical prognosis. They may raise the VEGF-A expression so as to promote angiogenesis, and then accelerate the development of the laryngeal squamous cell carcinoma. PMID- 28712409 TI - [Preparation and identification of monoclonal antibodies against chicken interleukin 4]. AB - Objective To prepare and characterize the monoclonal antibodies (mAbs) against chicken interleuikin-4 (ChIL-4). Methods Using lymphocyte hybridoma technique, 8 week-old BALB/c mice were immunized with purified recombinant ChIL-4 (rChIL-4) with GST tag (GST-ChIL-4), and rChIL-4 with histidine tag (His-ChIL-4) was utilized to set up an indirect ELISA to screen positive hybridomas. Limited dilution methods were used to generate hybridoma cell lines stably secreting mAbs against ChIL-4. The specificity of the mAbs was identified by indirect ELISA, immunofluorescent assay (IFA) and Western blot. Results Four mAbs against rChIL-4 were obtained and named 6A8, 18F12, 19F1 and 20G3. ELISA titers of the 4 mAbs were (1.6~6.4)*104. ELISA, IFA and Western blot showed that the 4 mAbs could only react with rChIL-4, but not with the other proteins like bovine IL-4 (BovIL-4), chicken IFN-gamma (ChIFN-gamma). Conclusion The mAbs against rChIL-4 were successfully obtained. PMID- 28712410 TI - Achieving self-sufficiency: training Australia's future medical workforce. AB - There is an oversupply of Australian junior doctors, but significant training bottlenecks are developing, and geographical maldistribution in rural and remote areas remains. Last year, the Federal Minister for Immigration rejected a Department of Health recommendation for the removal of 41 health roles from the Skilled Occupation List after concerns that rural and regional communities would be left without access to medical services in areas currently serviced by international medical graduates. In an effort to achieve workforce self sufficiency, Australia must ensure access to high-quality vocational training places in rural and regional settings while managing immigration of overseas trained health professionals. PMID- 28712411 TI - Calcium-sensing receptor (CASR) is involved in porcine in vitro fertilisation and early embryo development. AB - It has been demonstrated that extracellular calcium is necessary in fertilisation and embryo development but the mechanism is still not well understood. The present study mainly focussed on the extracellular calcium effector called the calcium-sensing receptor (CASR) and examined its expression in porcine gametes and embryos and its function during fertilisation and early embryo development. By using reverse transcription polymerase chain reaction, CASR was found to be expressed in porcine oocytes, spermatozoa and embryos at different developmental stages. Functionally, medium supplementation with a CASR agonist or an antagonist during in vitro fertilisation (IVF) and in vitro culture (IVC) was tested. During fertilisation, the presence of a CASR agonist increased sperm penetration rate and decreased polyspermy rate leading to an increased normal fertilisation rate. During embryo development, for the IVF embryos, agonist treatment during IVC significantly increased cleavage rate and blastocyst formation rate compared with the control group. Furthermore, parthenogenetically activated embryos showed similar results with lower cleavage and blastocyst formation rates in the antagonist group than in the other groups. It was concluded that CASR, as the effector of extracellular calcium, modulates porcine fertilisation and early embryo development. PMID- 28712412 TI - The relationship between levels of salivary and serum interleukin-6 and oral lichen planus: A systematic review and meta-analysis. AB - BACKGROUND: The relationship between levels of salivary and serum interleukin (IL)-6 and oral lichen planus (OLP) is not understood fully. The authors conducted a systematic review and meta-analysis to compare levels of salivary and serum IL-6 among people with OLP and healthy control participants. METHODS: The authors searched the literature for studies whose investigators had evaluated the relationships between IL-6 and OLP before treatment. The authors used meta analysis to compare the standardized mean differences (SMD) of the levels of salivary and serum IL-6 between people who had OLP and people who did not have OLP and between patients with erosive OLP and patients with nonerosive OLP. RESULTS: The results of separate meta-analyses, which included 5 studies each, indicated that the levels of salivary and serum IL-6 were significantly higher among patients with OLP than among healthy control participants (SMD, 2.35; 95% confidence interval [CI], 0.50 to 4.19; P = .01; and SMD, 2.03; 95% CI, 0.74 to 3.33; P = .002; respectively). The results of a meta-analysis of 4 studies indicated that the levels of IL-6 were not significantly different between patients with erosive OLP and patients with nonerosive OLP (SMD, 1.37; 95% CI, 0.26 to 3.00; P = .10). There was significant heterogeneity among the studies (P < .00001). CONCLUSIONS: Through the results of this meta-analysis, the authors found significant differences in the levels of IL-6 in saliva and serum between patients with OLP and healthy control participants. The authors found no differences in the levels of serum IL-6 between patients with erosive OLP and patients with nonerosive OLP. These results should be considered with caution because there was a high degree of heterogeneity among studies. PRACTICAL IMPLICATIONS: Levels of IL-6 in saliva and serum may be potential biomarkers for OLP. However, additional research is needed to confirm findings of this meta analysis. PMID- 28712415 TI - The role of incongruence between the perceived functioning by patients and clinicians in the detection of psychological distress among functional and motor digestive disorders. AB - OBJECTIVES: Previous research on gastrointestinal and other medical conditions has shown the presence of incongruence between self- and clinician-reported functioning and its relation with psychopathology. The main objective of this study was to test whether inconsistencies between clinician- and self-assessed functionality can be used to detect psychopathology among patients diagnosed of motor or functional gastrointestinal disorders. METHODS: One hundred and three patients from a gastroenterology inpatient unit were included in this study. All patients underwent clinical assessment, including intestinal manometry, Rome III criteria for functional gastrointestinal disorders, and psychological and psychiatric evaluation. Patients with suspected gastroparesis underwent a scintigraphic gastric emptying test. Definitive diagnoses were made at discharge. RESULTS: Patients with higher levels of incongruence differed in various sociodemographic (age, educational level, work activity and having children) and psychopathological (all SCL-90-R subscales except anxiety and hostility) characteristics. Using general lineal models, incongruence was found to be the variable with stronger relations with psychopathology even when controlling for diagnosis. Interactions were found between incongruence and diagnosis reflecting a pattern in which patients with functional disorders whose subjective evaluation of functioning is not congruent with that of the clinician, have higher levels of psychopathology than patients with motor disorders. CONCLUSIONS: Incongruence between clinician and self-reported functionality seems to be related to higher levels of psychopathology in patients with functional disorders. These findings underscore the need for routine psychosocial assessment among these patients. Gastroenterologists could use the concept of incongruence and its clinical implications, as a screening tool for psychopathology, facilitating consultation liaison processes. PMID- 28712414 TI - Anxiety during pregnancy and autonomic nervous system activity: A longitudinal observational and cross-sectional study. AB - OBJECTIVES: To assess the longitudinal change in autonomic nervous system (ANS) activity during pregnancy and the association between anxiety during pregnancy and ANS activity. METHODS: Pregnant Japanese women with a singleton fetus and normal pregnancy were recruited (n=65). ANS activity and anxiety were measured using a self-rating questionnaire at approximately 20, 30, and 36weeks of gestation. Very low (VLF) and high (HF) frequency bands of heart rate variability spectrums were used. Anxiety was assessed using the Japanese version of the State Trait Anxiety Inventory. A score of 45 or more on trait-anxiety and the other represent the trait-anxiety group and the non- trait-anxiety group, respectively. The state-anxiety group and the non-state-anxiety group were defined in the same manner. RESULTS: Longitudinal observation of individual pregnant women indicated the significant increasing trend (p=0.002) of VLF power and the significant decreasing trend (p<0.001) of HF power during 20 to 36 gestation weeks. Compared with the non-trait-anxiety group, the trait-anxiety group had significantly lower VLF values at 20 gestational weeks (p=0.033) and had significantly lower HF values at 30 and 36 gestational weeks (p=0.015 and p=0.044, respectively). The increasing rate of VLF from 20 to 36 gestational weeks was higher among the trait anxiety group. The same associations were observed between the state-anxiety and non-state-anxiety groups at 20 gestational weeks. CONCLUSIONS: Anxiety during pregnancy decreased heart rate variability. Anxiety in second trimester pregnancy promoted a subsequent increase in sympathetic activity. PMID- 28712413 TI - Sleep disturbance and kynurenine metabolism in depression. AB - OBJECTIVE: Although the interrelationships between sleep disturbance, inflammation, and depression have been found, molecular mechanisms that link these conditions are largely unknown. Kynurenine metabolism is hypothesized to be a key mechanism that links inflammation and depression. Inflammation activates the kynurenine pathway, leading to increases in 3-hydroxykynurenine (3HK) and quinolinic acid (QA), potentially neurotoxic metabolites, and decreases in kynurenic acid (KynA), a potentially neuroprotective compound. This relative neurotoxic shift in the balance of kynurenine metabolites has been associated with depression, but never been examined regarding sleep disturbance. We tested the association between sleep disturbance and this relative neurotoxic shift in 68 currently depressed, 26 previously depressed, and 66 never depressed subjects. METHODS: Sleep disturbance was assessed using the Pittsburgh Sleep Quality Index. Serum concentrations of kynurenine metabolites were measured using high performance liquid chromatography. Putative neuroprotective indices reflecting the relative activity of neuroprotective and neurotoxic kynurenine metabolites were calculated as KynA/QA and KynA/3HK (primary outcomes). RESULTS: Sleep disturbance was associated with reduced KynA/QA in the currently depressed group only (unadjusted beta -0.43, p<0.001). This association remained significant even after controlling for age, sex, analysis batch, body-mass index, and depressive symptoms in currently depressed subjects (adjusted beta -0.30, p=0.02). There was no significant association between sleep disturbance and KynA/3HK in any of the groups. Sleep disturbance was associated with increased C-reactive protein in currently depressed subjects only (unadjusted beta 0.38, p=0.007; adjusted beta 0.33, p=0.02). CONCLUSION: These data support the hypothesis that altered kynurenine metabolism may molecularly link sleep disturbance and depression. PMID- 28712416 TI - Biopsychosocial risk factors of persistent fatigue after acute infection: A systematic review to inform interventions. AB - OBJECTIVES: Fatigue is a prevalent and debilitating symptom, preceded by an acute infectious episode in some patients. This systematic review aimed to identify risk factors for the development of persistent fatigue after an acute infection, to develop an evidence-based working model of post-infectious fatigue. METHODS: Electronic databases (Medline, PsycINFO and EMBASE) were searched, from inception to March 2016, for studies which investigated biopsychosocial risk factors of on going fatigue after an acute infection. Inclusion criteria were: prospective design; biological, psychological or social risk factors; standardised measure of post-infectious fatigue (self-report scales or clinical diagnosis). Studies were excluded if the sample had a pre-existing medical condition, infection was conceptualised as 'vaccination' or they were intervention trials. A narrative synthesis was performed. RESULTS: Eighty-one full texts were screened, of which seventeen were included in the review. Over half included glandular fever populations. Other infections included dengue fever, 'general'/'viral' and Q fever. Risk factors were summarised under biological, social, behavioural, cognitive and emotional subthemes. Patients' cognitive and behavioural responses to the acute illness, and pre-infection or baseline distress and fatigue were the most consistent risk factors for post-infectious fatigue. CONCLUSION: An empirical summary model is provided, highlighting the risk factors most consistently associated with persistent fatigue. The components of the model, the possible interaction of risk factors and implications for understanding the fatigue trajectory and informing preventative treatments are discussed. PMID- 28712417 TI - Holding the body in mind: Interoceptive awareness, dispositional mindfulness and psychological well-being. AB - : Objective Recent dialogue between Western and Eastern traditions has stimulated novel explorations of the relationship between mind and body. Many of these cross cultural, mind-body dialogues have proven productive in identifying more adaptive forms of embodiment. Prior studies suggest that dispositional mindfulness (DM) and interoceptive awareness (IA) are associated but distinct, key constructs in mind-body approaches that are conceptualized in a variety of ways with imprecisely characterized relationship. The current study is a secondary data analysis that explores the relationship between scores on measures of IA and DM, examining multivariate networks of association between these constructs and addressing their relationship with scores on a measure of psychological well being. METHOD: Participants (n=478) were American adults completing measures of interoceptive awareness (as measured by the Multidimensional Assessment of Interoceptive Awareness; MAIA), dispositional mindfulness (as measured by the Five Facet Mindfulness Questionnaire; FFMQ), and psychological well-being (as measure by the Scales of Psychological Well-Being; SPWB) online. The average participant age was 36.44 (S.D.=12.17), and 57% were female. RESULTS: Correlational results from his study indicated that the IA scales and DM facets form two associative clusters. Canonical correlation analysis supported this finding, revealing that two primary networks of association exist between IA and DM, a Regulatory Awareness cluster and an Acceptance in Action cluster. Finally, hierarchical linear regression demonstrated that the self-report measures of IA and DM shared considerable variance, but also explained unique portions of the variance in psychological well-being. CONCLUSION: This psychometric investigation demonstrates that IA and DM are tightly interwoven, partly overlapping constructs. Indeed, greater DM is strongly linked with greater IA. Additionally, both IA and DM appear to be independently associated with enhanced psychological well-being. Future research should investigate how mindfulness practices moderate IA for therapeutic implications. PMID- 28712418 TI - The cross-sectional relation between medically unexplained physical symptoms (MUPS) and the Cortisol Awakening Response. AB - OBJECTIVES: We aimed to assess the cross-sectional relation between levels of cortisol and specific symptom clusters, symptom severity and duration of symptoms in patients with medically unexplained physical symptoms (MUPS). METHODS: Baseline data of a cohort of MUPS patients were used. We chose the Cortisol Awakening Response (CAR) as a cortisol parameter, using saliva samples. We used confirmatory factor analysis for the identification of 4 specific symptom clusters: (1) gastro-intestinal symptoms; (2) pain; (3) cardio-pulmonary symptoms; and (4) fatigue. For this factor analysis we used the Physical Symptom Questionnaire (PSQ), which assesses the occurrence and frequency of 51 physical symptoms. Symptom severity was measured with the Patient Health Questionnaire-15 (PHQ-15). Duration of symptoms was based on self-reported duration of top 3 symptoms. We performed multiple linear regression to assess relations between CAR and individual factor scores on symptom clusters, symptom severity and duration of symptoms. RESULTS: Data from 296 patients (76% female) were included in the analyses. The majority of patients suffered from symptoms in multiple organ systems. Factor analysis confirmed that the model with 4 symptom clusters fitted our data. For the total study population, we found no significant relation between CAR and participants' factor scores on any of the symptom clusters. We also found no significant relations between CAR and severity or duration of symptoms. CONCLUSION: Our results suggest that within a heterogeneous MUPS population there is no relation between CAR and symptom severity and duration. However, more studies are needed to confirm our findings. PMID- 28712419 TI - The relationship between childhood adversities and fibromyalgia in the general population. AB - BACKGROUND: Fibromyalgia is a syndrome characterized by widespread pain and a variety of somatic symptoms. The international prevalence of fibromyalgia is 2 5%, but its current prevalence in Finland is unclear. Various adversities are linked to the onset of fibromyalgia. However, there is need for more data regarding the association between childhood physical abuse and fibromyalgia. Further, the association of childhood emotional stressors and fibromyalgia is disputed. The aim of the current study is to produce more information about that relationship using data from the Health and Social Support (HeSSup) Study. METHODS: HeSSup is a postal study consisting of a random sample of the Finnish population. The study setting is cross-sectional. Participants in the study were asked if they have been diagnosed with fibromyalgia. Those responding affirmatively were classified as fibromyalgia patients. Six childhood adversities were enquired, and the relationship between fibromyalgia and these events were analysed by cross tabulation and logistic regression. RESULTS: There were associations between examined adversities and fibromyalgia before and after adjustments for demographic features and depression (being afraid of a family member: odds ratio after adjustment 1.60, 95% CI 1.28-2.01; long-lasting financial difficulties 1.45, 1.18-1.77; serious conflicts in the family 1.40, 1.14-1.72; parental divorce 1.34, 1.05-1.72; serious or chronic illnesses in the family 1.27, 1.05-1.55; alcohol problems in the family 1.25, 1.02-1.53). CONCLUSION: All six enquired adversities were associated with fibromyalgia after adjustments. These findings emphasize the importance of preventing adverse childhood experiences. PMID- 28712420 TI - The role of trait mindfulness in quality of life and asthma control among adolescents with asthma. AB - OBJECTIVE: The current study focused on the role of trait mindfulness in asthma related quality of life (QoL) and asthma control in adolescent asthma patients. Furthermore, potential underlying mechanisms (general and asthma-specific stress) of this relationship were investigated. METHODS: In this cross-sectional study, questionnaire data of 94 adolescents with asthma that were prescribed daily asthma medication were included. Two Structural Equation Models (SEMs), a direct model and an indirect model, were tested. RESULTS: We found that trait mindfulness was directly related to asthma-related QoL, but not to asthma control. The relationship between trait mindfulness and asthma-related QoL was explained by asthma-specific, but not by general stress. Furthermore, an indirect relation from mindfulness to asthma control via asthma-specific stress was found. CONCLUSIONS: Cross-sectional evidence for a relation between mindfulness and asthma-related QoL is found. These findings may point to the possibility that an intervention aimed at increasing mindfulness could be a promising tool to improve asthma-related QoL in adolescents via a decrease in asthma-specific stress. PMID- 28712422 TI - Torturing personification of chronic pain among torture survivors. AB - BACKGROUND: Consistent with the human tendency to anthropomorphize objects, events, and situations, individuals might ascribe human characteristics to physical symptoms and illnesses. This manuscript presents an examination of chronic pain personification in torture survivors. Specifically, it was hypothesized that torture survivors personify chronic pain as a torturing sensation. It was further hypothesized that PTSD mediates the effect of past torture on torturing pain personification. METHODS: Fifty-nine Israeli ex prisoners of war (ex-POWs), who experienced severe torture in captivity, and 44 matched controls completed self-administered questionnaires at 18, 30, and 35years post captivity. RESULTS: Whereas ex-POWs exhibit higher torturing personification than controls, no differences were found in concrete description of chronic pain. PTSD trajectories were implicated in different levels of torturing personification. Finally, sequential mediation analysis revealed that PTSD at T2 and T3 mediated the association between torture and torturing personification. CONCLUSIONS: The findings suggest that trauma shapes the way individuals relate to and experience their bodily sensations. PMID- 28712421 TI - Number of recent stressful life events and incident cardiovascular disease: Moderation by lifetime depressive disorder. AB - OBJECTIVE: We investigated whether number of recent stressful life events is associated with incident cardiovascular disease (CVD) and whether this relationship is stronger in adults with a history of clinical depression. METHODS: Prospective data from 28,583 U.S. adults (mean age=45years) initially free of CVD who participated in Waves 1 (2001-2002) and 2 (2004-2005) of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) were examined. Number of past-year stressful life events (Wave 1), lifetime depressive disorder (Wave 1), and incident CVD (Wave 2) were determined by structured interviews. RESULTS: There were 1069 cases of incident CVD. Each additional stressful life event was associated with a 15% increased odds of incident CVD [Odds Ratio (OR)=1.15, 95% Confidence Interval (CI): 1.11, 1.19]. As hypothesized, a stressful life events by lifetime depressive disorder interaction was detected (P=0.003). Stratified analyses indicated that stressful life events had a stronger association with incident CVD among adults with (OR=1.18, 95% CI: 1.10, 1.27, n=4908) versus without (OR=1.10, 95% CI: 1.07, 1.14, n=23,675) a lifetime depressive disorder. CONCLUSION: Our findings suggest that a greater number of recent stressful life events elevate the risk of new-onset CVD and that this risk is potentiated in adults with a history of clinical depression. PMID- 28712423 TI - Anxiety and depression in patients three months after myocardial infarction: Association with markers of coagulation and the relevance of age. AB - OBJECTIVE: Anxiety and depression are associated with an activation of coagulation and an impairment of fibrinolysis, which may contribute to the increased cardiovascular risk associated with the two disorders. However, very few studies have examined the impact of psychological distress on coagulation factors in coronary artery disease patients. The aim of this study was to assess the correlation between anxiety/depression and factors of coagulation and fibrinolysis in patients who had suffered an acute MI three months prior. METHODS: In 148 patients, anxiety and depression were assessed by the Hospital Anxiety and Depression Scale (HADS) shortly after MI and three months later. At the second time of assessment, plasma levels of fibrinogen, factor VII, factor VIII, von Willebrand factor, prothrombin-fragment 1 and 2, tissue-plasminogen activator, plasminogen activator inhibitor-1, D-dimer, and homocysteine were measured. RESULTS: In 32% of the patients, elevated levels of anxiety and depression were found three months after a MI. Multiple regression analyses showed that coagulation and fibrinolysis markers were not significantly associated with HADS anxiety and depression scores. We found that age, gender, BMI, and smoking status were significant predictors for haemostasis factors. A higher age was associated with a higher coagulability but lower anxiety levels. CONCLUSION: We measured parameters of coagulation and fibrinolysis in patients three months after MI and found no predictive value of HADS anxiety and depression scores shortly after MI or at the time of blood sampling. The effects of age on the relationship between anxiety and haemostasis should be further investigated. PMID- 28712424 TI - Determinants and incidence of depression in multiple sclerosis: A prospective cohort study. AB - OBJECTIVE: To estimate the incidence and explore potential determinants of incidence of depression in MS. METHODS: A prospective cohort study used a sample of 192 patients from the southern Alberta MS clinic registry. Participants completed baseline risk factor assessment questionnaires using either online, mail or telephone surveys, and completed the Patient Health Questionnaire every 2weeks for 6months to assess depressive symptoms in real time. Risk factors assessed included biopsychosocial variables such as socioeconomic status, illness related factors, childhood risk factors, psychosocial factors, and health behaviors. Cox proportional hazard models were fit to estimate predictors of incidence. RESULTS: 2-week incidence of depression for females was 0.019 (95% CI 0.013-0.029) and for males was 0.044 (0.026-0.074). Strongest predictor of depression incidence risk included fatigue impact, low mobility, resiliency, self esteem, self-efficacy, and coping style. CONCLUSION: Depression in MS exhibits a risk factor profile similar to that of depression in the general population, with the additional impact of MS illness-related factors. Potentially modifiable risk factors, such as coping with stress and resiliency, present opportunities for focus of further research in depression in MS treatment and prevention efforts. Some differences in determinants of incidence were found compared to the prevalence risk factors, highlighting the danger of using cross-sectional data to make assumptions about risk. For example, the finding that depression incidence was higher for men is opposite to the higher depression prevalence estimates found for women as well as the consensus in the literature. PMID- 28712425 TI - Telomere length is inversely correlated with urinary stress hormone levels in healthy controls but not in un-medicated depressed individuals-preliminary findings. AB - OBJECTIVE: Leukocyte telomere length (LTL) is a biomarker of cellular aging affected by chronic stress. The relationship of LTL to the stress hormones, cortisol and catecholamines, is unclear, as are possible differences between healthy controls (HC) and individuals with Major Depressive Disorder (MDD). This small pilot study is the first to examine the relationship between cortisol, catecholamines and LTL specifically in un-medicated MDD in comparison with HC. METHODS: Participants included 16 un-medicated MDD subjects and 15 HC for assay of LTL, 12-hour overnight urinary free cortisol and catecholamine levels. RESULTS: LTL, cortisol and catecholamine levels did not significantly differ between groups. In HC, a hierarchical regression analysis indicated that higher levels of cortisol were correlated with shorter LTL (p=0.003) above and beyond age and sex. Higher catecholamine levels were nearly-significant with shorter LTL (p=0.055). Neither hormone was correlated with shorter LTL in MDD (p's>0.28). To assess a possible cumulative effect of stress hormone activation, a summary score was calculated for each subject based on the number of stress hormone levels above the median for that group (HC or MDD). A significant inverse graded relationship was observed between LTL and the number of activated systems in HC (p=0.001), but not in MDD (p=0.96). CONCLUSION: This pilot study provides preliminary evidence that stress hormone levels, especially cortisol, are inversely related to LTL in HC, but not in un-medicated MDD. Clarification of these relationships in larger samples could aid in understanding differential mechanisms underlying stress-related cellular aging in healthy and depressed populations. PMID- 28712426 TI - Negative affect is unrelated to fluctuations in hormone levels across the menstrual cycle: Evidence from a multisite observational study across two successive cycles. AB - BACKGROUND: Female sex hormones may play a crucial role in the occurrence of cycle-related mood disorders. However, the literature is inconsistent and methodologically stringent observational studies on the relationship between sex hormones and negative affect are lacking. METHODS: In this longitudinal multisite study from Hannover, Germany, and Zurich, Switzerland, we examined oestrogen, progesterone, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone serum levels in association with negative affect as measured with the Positive and Negative Affect Schedule (PANAS). Negative affect and hormone assays were collected at four consecutive time points comprising menstrual, pre ovulatory, mid-luteal and premenstrual phase across two cycles (n=87 and n=67 for the first and second cycles). The Beck Depression Inventory (BDI) was assessed once prior to the first cycle and included as a secondary measure. RESULTS: Mean negative affect scores did not significantly fluctuate across both cycles and there was in particular no symptom increase premenstrually. No sex hormone consistently related to repeated measures of negative affect across two consecutive cycles. The BDI sum-score assessed at baseline was not related to hormone levels across the first cycle. CONCLUSIONS: This is the first multisite longitudinal study on the association between negative affect and sex hormone levels encompassing two consecutive menstrual cycles. Negative affect did not fluctuate across the cycle and there was no direct and uniform association between sex hormones and self-reported negative affect. These findings suggest that moderators such as personality traits and epigenetics should be considered in future research. PMID- 28712427 TI - Depression, inflammation, and epidermal growth factor receptor (EGFR) status in metastatic non-small cell lung cancer: A pilot study. AB - OBJECTIVE: Patients with stage IV non-small cell lung cancer (NSCLC) have high risk for depressive symptoms and major depressive disorder (MDD); however, those with epidermal growth factor receptor (EGFR) mutations may have decreased risk. The biological underpinning of this relationship is unknown. We examined differences in depression severity and MDD in patients with newly diagnosed stage IV NSCLC based on EGFR mutation status, and examined proinflammatory cytokines and growth factors known to play a role in cancer progression and depression. METHODS: Fifty-five patients with newly diagnosed stage IV NSCLC completed self report and clinician-administered depression assessments prior to receiving results of tumor genotyping. We measured serum levels of circulating biological markers of inflammation: IL-1beta, IL-6, TGF-alpha, and TNF-alpha. We examined differences in depression severity, MDD, and inflammatory biomarkers in patients with and without EGFR mutations. RESULTS: Patients with EGFR mutations (n=10) had lower depression severity (t[43]=2.38, p=0.03) than those without EGFR mutations (n=38) and fewer patients with EGFR mutations had concurrent MDD (2.08%) relative to those without mutations (27.08%). Patients with MDD had higher levels of TNF alpha than those without MDD (t[40]=2.95, p=0.005). Those with EGFR mutations exhibited higher levels of TNF-alpha relative to those without EGFR mutations (t[35]=2.17, p=0.04). CONCLUSIONS: Patients with stage IV NSCLC harboring an EGFR mutation exhibited elevated proinflammatory marker TNF-alpha, yet had lower depression severity than patients without EGFR mutations. More work is warranted to examine the interaction between tumor genotyping and inflammatory cytokines in the context of depression. PMID- 28712428 TI - Association between all-cause mortality and severity of depressive symptoms in patients with type 2 diabetes: Analysis from the Japan Diabetes Complications Study (JDCS). AB - OBJECTIVE: The aims of this study are to confirm whether the excess mortality caused by depressive symptoms is independent of severe hypoglycemia in patients with type 2 diabetes mellitus (T2DM) and to evaluate the association between all cause mortality and degrees of severity of depressive symptoms in Japanese patients with T2DM. METHODS: A total of 1160 Japanese patients with T2DM were eligible for this analysis. Participants were followed prospectively for 3years and their depressive states were evaluated at baseline by the Center for Epidemiologic Studies Depression Scale (CES-D). Cox proportional hazards model was used to evaluate the relative risk of all-cause mortality and was adjusted by possible confounding factors, including severe hypoglycemia, all of which are known as risk factors for both depression and mortality. RESULTS: After adjustment for severe hypoglycemia, each 5-point increase in the CES-D score was significantly associated with excess all-cause mortality (hazard ratio 1.69 [95% CI 1.26-2.17]). The spline curve of HRs for mortality according to total CES-D scores showed that mortality risk was slightly increased at lower scores but was sharply elevated at higher scores. CONCLUSION: A high score on the CES-D at baseline was significantly associated with all-cause mortality in patients with T2DM after adjusting for confounders including severe hypoglycemia. However, only a small effect on mortality risk was found at relatively lower levels of depressive symptoms in this population. Further research is needed to confirm this relationship between the severity of depressive symptoms and mortality in patients with T2DM. PMID- 28712429 TI - The association between multiple chemical sensitivity and mental illness: Evidence from a nationally representative sample of Canadians. AB - OBJECTIVE: The goal of the present study was to investigate the association between multiple chemical sensitivity (MCS) and major depressive disorder (MDD), generalized anxiety disorder (GAD), MDD and GAD comorbidity (MDD+GAD), severe distress, and positive mental wellbeing. METHODS: This cross-sectional investigation was carried out using the 2012 Canadian Community Health Survey - Mental Health Component. The study population consisted of 21,977 individuals aged 20 and older, from Canada's ten provinces. Odds ratios were computed using multinomial logistic regression to calculate estimates of the association between MCS and mental illness. All analyses were weighted to take into account the complex survey design. RESULTS: Individuals with MCS had 2.37 (1.55, 3.64) times greater odds of MDD, 3.09 (1.80, 5.30) times greater odds of MDD+GAD, and 2.60 (1.67, 4.07) times greater odds of severe distress. No association between MCS and GAD was observed. A sex difference was observed with males with MCS having lower odds of positive mental wellbeing, whereas no association was observed in females. CONCLUSIONS: The present study findings supported an association between MCS and mental illness. The causal mechanism supporting this association remains unclear. PMID- 28712430 TI - Social networks and patterns of health risk behaviours over two decades: A multi cohort study. AB - OBJECTIVE: To determine the associations between social network size and subsequent long-term health behaviour patterns, as indicated by alcohol use, smoking, and physical activity. METHODS: Repeat data from up to six surveys over a 15- or 20-year follow-up were drawn from the Finnish Public Sector study (Raisio-Turku cohort, n=986; Hospital cohort, n=7307), and the Health and Social Support study (n=20,115). Social network size was determined at baseline, and health risk behaviours were assessed using repeated data from baseline and follow up. We pooled cohort-specific results from repeated-measures log-binomial regression with the generalized estimating equations (GEE) method using fixed effects meta-analysis. RESULTS: Participants with up to 10 members in their social network at baseline had an unhealthy risk factor profile throughout the follow-up. The pooled relative risks adjusted for age, gender, survey year, chronic conditions and education were 1.15 for heavy alcohol use (95% CI: 1.06 1.24), 1.19 for smoking (95% CI: 1.12-1.27), and 1.25 for low physical activity (95% CI: 1.21-1.29), as compared with those with >20 members in their social network. These associations appeared to be similar in subgroups stratified according to gender, age and education. CONCLUSIONS: Social network size predicted persistent behaviour-related health risk patterns up to at least two decades. PMID- 28712431 TI - The mediating role of sleep-related metacognitive processes in trait and pre sleep state hyperarousal in insomnia disorder. AB - OBJECTIVE: Trait predisposition to hyperarousal and pre-sleep state hyperarousal are considered key factors in insomnia, but research also supports the role of cognitive and metacognitive processes. Therefore, the aim of this study was to evaluate the relationship between unhelpful sleep-related beliefs, sleep-related metacognition and trait/pre-sleep state arousal in insomnia disorder. METHOD: Sixty-eight subjects with insomnia disorder (DSM-5) and 36 good sleepers were evaluated with a set of questionnaires that included Dysfunctional Beliefs about Sleep scale (DBAS), Metacognitions Questionnaire - Insomnia (MCQI), Arousal Predisposition Scale (APS), and Pre-sleep Arousal Scale (PSAS). The statistical analyses included univariate, multivariate regression and mediation analyses. RESULTS: Subjects with insomnia reported higher scores on the DBAS, MCQI, APS, and PSAS (p's<0.001) compared to good sleepers. In the insomnia group, trait hyper-arousal was best determined by insomnia-related metacognition (p=0.02). Pre sleep cognitive arousal was determined by insomnia-related metacognition (p=0.001) and trait hyperarousal (p<0.0001) after controlling for years of insomnia. Insomnia-metacognitive activity mediated the association between trait hyperarousal and cognitive arousal (p=0.01, p=0.002) and the bidirectional association between pre-sleep cognitive and somatic arousal (p=0.002, p=0.04). CONCLUSION: This study suggests that a broad range of cognitive and metacognitive processes may be involved in the development of sleep-related arousal among people with insomnia. Insomnia metacognitive activity may influence trait factors and pre-sleep state factors depending on insomnia duration. Both insomnia evaluation and treatment may also be focused on insomnia metacognitive processes especially in subject with a long history of insomnia. PMID- 28712433 TI - Two-year prognosis after acute coronary syndrome in younger patients: Association with feeling depressed in the prior year, and BDI-II score and Endothelin-1. AB - OBJECTIVE: To examine the effects of depressive symptoms and Endothelin (ET)-1 on 2-year prognosis in younger patients with acute coronary syndrome (ACS). Depression is associated with poor post-ACS prognosis; however, few investigations have focused on younger patients. Importantly, the studies that did emphasize younger patients suggested that the influence of depression on prognosis could be more robust in younger subgroups. The particular links between depression and poor prognosis in younger patients have yet to be definitively determined. ET-1 is a potent endogenous vasoconstrictor that has been previously linked to adverse post-ACS outcomes. METHODS: The sample (n=153) included male (age<=50years) and female (age<=55years) ACS patients. Blood samples for ET-1 assessment were collected within 2-3h of ACS hospital admission. Depressive symptoms were assessed with the Beck Depression Inventory (BDI) II within 2-5days of admission. The primary outcome was defined as a composite of major adverse cardiovascular events (MACE), including recurrent myocardial infarction, emergent coronary revascularization, and all-cause mortality within 2years after index admission. RESULTS: During the follow-up period, 23 patients experienced MACE. Neither the BDI-II score nor ET-1 predicted MACE in unadjusted analyses or in analyses adjusted for demographic characteristics, comorbidities and troponin levels. In the supplementary analyses, feeling depressed in the year preceding ACS predicted MACE. CONCLUSIONS: In this cohort of younger ACS patients, feeling depressed in the year preceding ACS admission predicted MACE in the 2years after baseline ACS event, while neither the BDI-II score, nor circulating ET-1 level predicted this outcome. PMID- 28712434 TI - Does vital exhaustion increase the risk of type 2 diabetes? A prospective study. AB - BACKGROUND: There is evidence that both stress and depression have a causal relationship with type 2 diabetes suggesting that vital exhaustion (VE) too could be a risk factor. The association between VE and type 2 diabetes has, however, not been investigated prospectively. AIM: To prospectively investigate whether VE is associated with an increased risk of type 2 diabetes in a Danish population. METHODS: A prospective cohort study based on the Copenhagen City Heart Study (1991-1993). The degree of VE was measured among 9075 participants without type 1 or 2 diabetes at baseline. To detect type 2 diabetes in the follow-up period, two different approaches were used: In the first substudy, type 2 diabetes was defined based on blood samples and questionnaires from a follow-up study in 2001 2003 (N=4708). The second substudy was register-based, and the study population was linked to the Danish Hospital Discharge Register to detect registrations with type 2 diabetes until 2014. RESULTS: A high degree of VE was associated with an increased risk of developing type 2 diabetes in both substudies. In the first substudy, the OR for developing type 2 diabetes was 2.56 (95% CI, 1.53; 4,29, P<0,001) among the quartile of participants reporting the highest degree of VE. In the second substudy, the OR was 1.31 (95% CI, 0.99; 1.72, P=0.053) for this group. CONCLUSION: The results indicate that VE may be a useful measure in clinical practice in order to discover individuals at risk of type 2 diabetes. PMID- 28712432 TI - Alexithymia in eating disorders: Systematic review and meta-analyses of studies using the Toronto Alexithymia Scale. AB - OBJECTIVE: The aim of this review was to synthesise the literature on the use of the Toronto Alexithymia Scale (TAS) in eating disorder populations and Healthy Controls (HCs) and to compare TAS scores in these groups. METHOD: Electronic databases were searched systematically for studies using the TAS and meta analyses were performed to statistically compare scores on the TAS between individuals with eating disorders and HCs. RESULTS: Forty-eight studies using the TAS with both a clinical eating disorder group and HCs were identified. Of these, 44 were included in the meta-analyses, separated into: Anorexia Nervosa; Anorexia Nervosa, Restricting subtype; Anorexia Nervosa, Binge-Purge subtype, Bulimia Nervosa and Binge Eating Disorder. For all groups, there were significant differences with medium or large effect sizes between the clinical group and HCs, with the clinical group scoring significantly higher on the TAS, indicating greater difficulty with identifying and labelling emotions. CONCLUSION: Across the spectrum of eating disorders, individuals report having difficulties recognising or describing their emotions. Given the self-report design of the TAS, research to develop and evaluate treatments and clinician-administered assessments of alexithymia is warranted. PMID- 28712435 TI - Are modern health worries associated with medical conspiracy theories? AB - This study was concerned with whether Medical Conspiracy Theories (MCTs), along with other variables (demographics, ideology and health perceptions) are associated with Modern Health Worries (MHWs). MCTs were significantly associated with MHWs over and above all other variables. Older individuals, with more religious and right-wing beliefs had higher MHWs. In addition, those who used Complementary and Alternative Medicine (CAM) and individuals who perceived their mental health as worse than their peers were also more likely to display higher MHWs. Implications for helping health professions understand their patients' health-related beliefs and choices were discussed. PMID- 28712436 TI - Association of symptoms of insomnia and sleep parameters among kidney transplant recipients. AB - OBJECTIVE: Insomnia complaints are frequent among kidney transplant (kTx) recipients and are associated with fatigue, depression, lower quality of life and increased morbidity. However, it is not known if subjective insomnia symptoms are associated with objective parameters of sleep architecture. Thus, we analyze the association between sleep macrostructure and EEG activity versus insomnia symptoms among kTx recipients. METHODS: Participants (n1=100) were selected from prevalent adult transplant recipients (n0=1214) followed at a single institution. Insomnia symptoms were assessed by the Athens Insomnia Scale (AIS) and standard overnight polysomnography was performed. In a subgroup of patients (n2=56) sleep microstructure was also analyzed with power spectral analysis. RESULTS: In univariable analysis AIS score was not associated with sleep macrostructure parameters (sleep latency, total sleep time, slow wave sleep, wake after sleep onset), nor with NREM and REM beta or delta activity in sleep microstructure. In multivariable analysis after controlling for covariables AIS score was independently associated with the proportion of slow wave sleep (beta=0.263; CI: 0.026-0.500) and REM beta activity (beta=0.323; CI=0.041-0.606) (p<0.05 for both associations). CONCLUSIONS: Among kTx recipients the severity of insomnia symptoms is independently associated with higher proportion of slow wave sleep and increased beta activity during REM sleep but not with other parameters sleep architecture. The results suggest a potential compensatory sleep protective mechanism and a sign of REM sleep instability associated with insomnia symptoms among this population. PMID- 28712437 TI - The long term effects of "Consumer-Directed" health plans on preventive care use. AB - "Consumer-Directed" Health Plans (CDHPs), those with high deductibles and personal medical accounts, have been shown to reduce health care spending. The impact of CDHPs on preventive care is unclear. On the one hand CDHPs might increase use of preventive care as such care is exempt from the deductible. However, CDHPs also decrease visits to physicians which might results in less screening. Prior research has found conflicting results. In this study, using data from 37 employers we examine the effects of CDHPs on the use of cancer screenings up to three years after the initial CDHP offering with ITT and LATE approaches. Being offered a CDHP or enrolling in a CDHP had little or no effect on cancer screening rates but individuals increase screenings prior to enrolling in a CDHP. Our findings suggest the importance of examining CDHP effects on periodic care over the longer-term and carefully controlling for anticipatory stockpiling. PMID- 28712439 TI - ? PMID- 28712438 TI - Granuloma Annulare Possibly Secondary to Oral Treatment With Topiramate. PMID- 28712440 TI - [Social inequalities in health, missions of a regional healthcare agency]. AB - The presence of social inequalities in health requires a multi-faceted intervention, focusing on the social determinants as well as the provision of care and prevention strategies. Regional health agencies have important levers at their disposal, as illustrated by the example of the Ile-de-France region. PMID- 28712441 TI - [Social inequalities in health, challenges for nursing care]. AB - The main factors of social inequalities in health lie outside the healthcare system. In a context centred on curative care, the influence of social determinants on people's health is a challenge facing nursing care and highlights the need to reinforce cross-sector action. PMID- 28712442 TI - [Addressing the needs of the most disadvantaged in our health care system]. AB - The improvement in the quality of health care for the most disadvantaged people is dependent on the conditions of their existence being addressed. It also means understanding the factors influencing their relationship with health and care. PMID- 28712443 TI - [The role of professionals in reducing social inequalities in health]. AB - Inequalities in health stem from social mechanisms which for the most part operate outside the health care sector. By being aware of these inequalities and understanding them from the perspective of a gradient of resources, health professionals can intervene to improve equality in this field. PMID- 28712444 TI - [The obstacles to accessing care for the most disadvantaged, the view of Samusocial de Paris]. AB - Samusocial de Paris works daily with disadvantaged people. It has identified a number of obstacles which prevent access to care for these people: notably prejudices, the complexity of access to rights, congestion within the accommodation system, a lack of interpreters and health care mediators, as well as failures in the legal system. PMID- 28712445 TI - [Sociological aspects of health service access points]. AB - The work of health service access points highlights the process of exclusion through marginalisation, the phenomenon of precarity and anthropological tensions between hospitality and inhospitality or between the desirable and undesirable. PMID- 28712446 TI - [Role and mission of health service access points]. AB - Part of the health and social care landscape since 1998, health service access points (in French, permanences d'acces aux soins de sante) were set up in response to a health and social care problem. The objective is to help disadvantaged people integrate the healthcare pathway. The ultimate aim is to ensure everyone has access to the appropriate care at a fair price. PMID- 28712447 TI - [Raising student nurses' awareness of precarity and volunteer work]. AB - An optional teaching unit on precarity and volunteering can be offered to student nurses. It encourages reflection on facilitating access to care for the most disadvantaged. PMID- 28712448 TI - [Private practice nurse faced with inequalities in health]. AB - The private practice nurse can be confronted with patients living in situations of extreme poverty. During her home visits, she is sometimes reminded of the lack of prevention and the difficulties of accessing care. In her daily practice, she plays an important role faced with these inequalities in health. PMID- 28712449 TI - [Nurses and inequalities in health across the world]. AB - The nursing profession must be actively involved, across the world, in the fight against inequalities in accessing care. The nurse plays a critical role in ensuring that each individual has the right to enjoy the best health possible. PMID- 28712450 TI - ? PMID- 28712451 TI - ? PMID- 28712452 TI - ? PMID- 28712453 TI - [On overview of social inequalities in health in France]. AB - Health is dependent on the living conditions and the socioeconomic environment of populations. The healthcare system tends to underestimate these aspects and thereby maintain, and even aggravate, the resulting social inequalities in health. It is essential that this situation is improved by adopting a global and interdisciplinary vision of healthcare and its social determinants. PMID- 28712454 TI - CRISPR/Cas9-Mediated Scanning for Regulatory Elements Required for HPRT1 Expression via Thousands of Large, Programmed Genomic Deletions. AB - The extent to which non-coding mutations contribute to Mendelian disease is a major unknown in human genetics. Relatedly, the vast majority of candidate regulatory elements have yet to be functionally validated. Here, we describe a CRISPR-based system that uses pairs of guide RNAs (gRNAs) to program thousands of kilobase-scale deletions that deeply scan across a targeted region in a tiling fashion ("ScanDel"). We applied ScanDel to HPRT1, the housekeeping gene underlying Lesch-Nyhan syndrome, an X-linked recessive disorder. Altogether, we programmed 4,342 overlapping 1 and 2 kb deletions that tiled 206 kb centered on HPRT1 (including 87 kb upstream and 79 kb downstream) with median 27-fold redundancy per base. We functionally assayed programmed deletions in parallel by selecting for loss of HPRT function with 6-thioguanine. As expected, sequencing gRNA pairs before and after selection confirmed that all HPRT1 exons are needed. However, HPRT1 function was robust to deletion of any intergenic or deeply intronic non-coding region, indicating that proximal regulatory sequences are sufficient for HPRT1 expression. Although our screen did identify the disruption of exon-proximal non-coding sequences (e.g., the promoter) as functionally consequential, long-read sequencing revealed that this signal was driven by rare, imprecise deletions that extended into exons. Our results suggest that no singular distal regulatory element is required for HPRT1 expression and that distal mutations are unlikely to contribute substantially to Lesch-Nyhan syndrome burden. Further application of ScanDel could shed light on the role of regulatory mutations in disease at other loci while also facilitating a deeper understanding of endogenous gene regulation. PMID- 28712456 TI - Announcing Advances in Pharmacy Practice. PMID- 28712455 TI - The properties of the unique age-associated B cell subset reveal a shift in strategy of immune response with age. AB - In aged mice, conventional naive B cells decrease and a new population of age associated B cells (ABC)3 develops. When aged unprimed mice are infected with influenza virus, there is a reduced generation of helper CD4 T cell subsets and germinal center B cells, leading to limited production of IgG Ab and less generation of conventional long-lived plasma cells, compared to young. However, we find an enhanced non-follicular (GL7-) ABC response that is helper T cell independent, but requires high viral dose and pathogen recognition pathways. The infection-induced ABC (iABC) include IAV-specific Ab-secreting cells, some of which relocate to the bone marrow and lung, and persist for >4wk., suggesting they may provide significant protection. We also speculate there is a shift with increased age to dependence on TLR-mediated pathogen-recognition in both B and CD4 T cell responses. PMID- 28712457 TI - APhA2017 house of delegates: Opportunities for collaboration. PMID- 28712458 TI - APhA2017 House of Delegates: Opportunities for collaboration: Moving forward through meaningful involvement and engagement. PMID- 28712459 TI - APhA2017 House of Delegates: Opportunities for collaboration: The impact of science and research on pharmacy practice. PMID- 28712460 TI - Treat the patient and not the number: A call to care. PMID- 28712461 TI - 2017 Remington Honor Medal Address: Blessings and dreams. PMID- 28712462 TI - 2017 Prescott Lecture: Bridging the intersection between pharmacy, advocacy, and value-based care. PMID- 28712463 TI - Vaccines in development for the primary prevention of Clostridium difficile infection. PMID- 28712464 TI - Ocrelizumab, edaravone, and valbenazine. PMID- 28712465 TI - Pharmacist impact on patient activation-a key to success. PMID- 28712466 TI - Hepatic encephalopathy: Manganese also shines in T1. PMID- 28712467 TI - Children disassociate from antisocial in-group members. AB - Extensive research has demonstrated that children show a robust in-group bias and, concurrently, are highly attuned to the prosocial and antisocial behavior of others. The limited research investigating the capacity for antisocial behavior to attenuate children's in-group bias has, however, returned mixed findings. Moreover, no research has examined how this might interact with perceived group permeability. Thus, the current study aimed to provide a more complete understanding of the relationship between in-group bias and antisocial behavior, how this interacts with perceptions of out-group behavior, and how group context (permeability) influences these responses. Children at age 4 and 5years and age 7 and 8years were assigned to a group randomly or based on their performance of a task. They then watched videos of in-groups and out-groups behaving prosocially and antisocially, in differing combinations, with the key experimental conditions focusing on an antisocial in-group paired with either a prosocial or antisocial out-group. In-group preference was then determined using liking ratings, resource allocation, and perceived similarity to the in-group. For older children, but not younger children, antisocial behavior, but not group permeability, was found to attenuate in-group bias for measures of liking and association. Interestingly, no effect was identified for children's own resource allocation behavior. This indicates that although there is a robust effect of antisocial behavior on in group judgments, it does not extend so far as to influence children to behave antisocially themselves. PMID- 28712468 TI - The impact of counter-perceptual testimony on children's categorization after a delay. AB - When preschoolers are presented with a label for an entity that conflicts with its appearance, they sometimes rely on the new label rather than on the entity's appearance to categorize the entity and to infer its properties. We examined whether children's learning from such claims is short-lived or long-lasting and whether the persistence of their learning depends on the degree of fit between those claims and the available perceptual evidence. Children aged 3-5years (N=71) were asked to categorize hybrids. These hybrids combined 75% of the features from one animal or object with 25% of the features from a different animal or object. After categorizing each hybrid, children heard an informant provide a contrary label. Immediately after they were provided with this new label, children often recategorized the entities accordingly, especially when the label matched the hybrid's predominant features. Children's endorsement of the informant's label proved to be long-lasting when it matched the hybrid's predominant features, typically persisting even after 5weeks. In contrast, children's endorsement often faded over time when the informant's label did not match the hybrid's predominant features. Overall, children were more skeptical of testimony that was more discrepant with the perceptual evidence available to them, and they were less likely to continue endorsing it after a delay. The findings have implications for our understanding of how children eventually come to represent and believe in counter-perceptual and counterintuitive concepts. PMID- 28712469 TI - Subcortical Contributions to Motor Speech: Phylogenetic, Developmental, Clinical. AB - Vocal learning is an exclusively human trait among primates. However, songbirds demonstrate behavioral features resembling human speech learning. Two circuits have a preeminent role in this human behavior; namely, the corticostriatal and the cerebrocerebellar motor loops. While the striatal contribution can be traced back to the avian anterior forebrain pathway (AFP), the sensorimotor adaptation functions of the cerebellum appear to be human specific in acoustic communication. This review contributes to an ongoing discussion on how birdsong translates into human speech. While earlier approaches were focused on higher linguistic functions, we place the motor aspects of speaking at center stage. Genetic data are brought together with clinical and developmental evidence to outline the role of cerebrocerebellar and corticostriatal interactions in human speech. PMID- 28712470 TI - Field proteomics of Populus alba grown in a heavily modified environment - An example of a tannery waste landfill. AB - Tannery waste is highly toxic and dangerous to living organisms because of the high heavy metal content, especially chromium [Cr(III)]. This study analysed the proteomic response of the Populus alba L. clone 'Villafranca' grown for 4years on a tannery waste landfill. In this extremely hostile environment, the plants struggled with continuous stress, which inhibited growth by 54%, with a 67% decrease in tree height and diameter at breast height compared to those of the forest reference plot, respectively. The leaves and roots of the tannery landfill grown plants produced strong proteomic stress signals for protection against reactive oxygen species (ROS) and repair to ROS-damaged proteins and DNA as well as signals for protection of the photosynthetic apparatus. The content of HSP80 was also high. However, primary metabolic pathways were generally unaffected, and signals of increased protein protection, but not turnover, were found, indicating mechanisms of adaptation to long-term stress conditions present at the landfill. A proteomic tool, two-dimensional electrophoresis coupled with tandem mass spectrometry, was successfully applied in this environmental in situ study of distant plots (280km apart). PMID- 28712471 TI - Early Pliocene anuran fossils from Kanapoi, Kenya, and the first fossil record for the African burrowing frog Hemisus (Neobatrachia: Hemisotidae). AB - Isolated amphibian bones from the early Pliocene of Kanapoi (West Turkana, Kenya) help to improve the scarce fossil record of the late Neogene and Quaternary amphibians from East Africa. All currently available 579 bones are referable exclusively to the Anura (frogs and toads). More than half of the remains (366) are identified as Hemisus cf. Hemisus marmoratus, an extant species that still inhabits Kenya, but apparently not the northwest of the country and the Turkana area in particular. The rest of the remains are identified simply as Anura indet. because of poor preservation or non congruence with the relatively few African extant taxa whose osteology is known in detail. The Hemisus material represents the first fossil record for Hemisotidae, an endemic African family of peculiar, head-first burrowing frogs, whose sister taxon relationships indicate a divergence from brevicipitids in the Late Cretaceous or early Paleocene. The ecological requirements of extant H. marmoratus suggest that the Kanapoi area surrounding the fluvial and deltaic settings, from where the fossil remains of vertebrates were buried, was likely a grassland or relatively dry, open low tree shrub savanna. PMID- 28712472 TI - Emotional intelligence in heart failure nursing. PMID- 28712473 TI - Implementation of Acupuncture Therapy in the Care of Patients with Breast Cancer. PMID- 28712474 TI - Postherpetic Neuralgia: Practical Experiences Return to Traditional Chinese Medicine. AB - Post-herpetic neuralgia (PHN) is a complication of herpes zoster that can cause different types of pain in the affected area. It often occurs mainly in severe cases of herpes zoster. The problem is defined as a persisting pain for 90-120 days after relieving of acute phase of herpes lesions. This complication causes suffering in patients and reduces the quality of life. In western medicine's viewpoints, PHN is due to disturbance in local and dermatomal nerves. There are several topical and systemic drugs that are used to manage the pain relief. In traditional medicine (TM), PHN is mostly due to incomplete heat and damp clearing in liver and spleen meridians, qi and toxic pathogens stagnation, accumulation of yin (blood stagnation in microcapillary), internal fire, and heat and obstruction of meridians. Acupuncture works based on the eradication of wind, clearing of heat, and destroying of damp by regulating qi and blood movement. In clinics, several methods of TM are used to relief PHN, such as simultaneous needling, surrounding needling, acupuncture, electro acupuncture, moxibustion, wet cupping or hijamat, and herbal medicine. In this review, we discussed all these methods and their role in reducing PHN and pain. PMID- 28712475 TI - Effectiveness of Acupuncture Therapy on Stress in a Large Urban College Population. AB - This study is a randomized controlled clinical trial to study the effectiveness of acupuncture on the perception of stress in patients who study or work on a large, urban college campus. The hypothesis was that verum acupuncture would demonstrate a significant positive impact on perceived stress as compared to sham acupuncture. This study included 111 participants with high self-reported stress levels who either studied or worked at a large, urban public university in the southwestern United States. However, only 62 participants completed the study. The participants were randomized into a verum acupuncture or sham acupuncture group. Both the groups received treatment once a week for 12 weeks. The Cohen's global measure of perceived stress scale (PSS-14) was completed by each participant prior to treatment, at 6 weeks, at 12 weeks, and 6 weeks and 12 weeks post-treatment completion. While participants of both the groups showed a substantial initial decrease in perceived stress scores, at 12 weeks post treatment, the verum acupuncture group showed a significantly greater treatment effect than the sham acupuncture group. This study indicates that acupuncture may be successful in decreasing the perception of stress in students and staff at a large urban university, and this effect persists for at least 3 months after the completion of treatment. PMID- 28712476 TI - Comparative Assessment of the Heart's Functioning by Using the Akabane Test and Classical Methods of Instrumental Examination. AB - Acupuncture physicians have studied the application of reflexotherapy to cardiology. However, no one has investigated the connection of ancient Chinese diagnostic methods with modern tools. A total of 102 patients (54 men and 48 women) with heart pathology, namely, sick-sinus syndrome, Wolff-Parkinson-White syndrome, and atrioventricular blockade, were studied using the usual instrumental methods (transesophageal electrophysiological study of the heart, echocardiography), after which they underwent Akabane thermopuncture testing as in traditional Chinese medicine. The results of cardio examination from one side of the Akabane test with that from the other side were compared by means of a multiple stepwise regression analysis. We revealed the effects on the characteristic pattern of acupuncture channel lesions inherent in a definite heart pathology, i.e., the most vulnerable acupuncture channel (AC), of such factors as disturbances of the contractile, conductive, or automatic heart functions, and changes in the chambers' size or circulation volume. Shanges in the indices of the left and the right branches of these channels usually reflect the opposing natures of the changes in these indicators, which should be considered in reflexotherapy. The main value of the Akabane test along with the use of mathematical analysis lies in early, quick, and inexpensive detection of the above-mentioned heart disturbances. PMID- 28712477 TI - Phytochemical Analysis and Cytotoxicity Evaluation of Kelussia odoratissima Mozaff. AB - BACKGROUND: Kelussia odoratissima Mozaff. (Apiaceae) is an edible, indigenous, and ethnomedicinal plant that grows only in Iran. Although antioxidant and anti inflammatory properties of K. odoratissima have been reported, cytotoxic activity of this plant has not been investigated previously. OBJECTIVE: This study aims to evaluate the cytotoxicity of K. odoratissima leaf extract against a panel of human cancer cell lines. A secondary aim was to perform a phytochemical analysis of the plant's leaf oil. METHODS: To extract the plant oil, dried leaves were subjected to hydrodistillation using a Clevenger-type apparatus for up to 3 hours. For the phytochemical analysis, essential oil was subjected to gas chromatography/mass spectrometry. Plant extraction was performed by macerating leaf powder of K. odoratissima (50 g) in 70% methanol (500 mL) at room temperature (25-28 degrees C) for 24 hours. To perform cytotoxicity assays, methanolic extract of K. odoratissima was tested against a panel of cell lines including MDA-MB468 (human breast cancer cell line), K562 (human leukemia cell line), SKOV3 (human ovarian cancer cell line), Y79 (human eye cancer cell line), A549 (lung cancer cell line), and HEK 293 (normal human embryonic kidney cell line). RESULTS: Gas chromatography/mass spectrometry analysis revealed that sesquiterpens are dominant volatile components of the plant, followed by phthalides comprising 3-butyldine phthalide and 3-n-butyl phthalide, the latter compound being the major component of the leaf oil (25.1%). The leaf extract showed selective and dose-dependent cytotoxicity against MDA-MB468, K562, SKOV3, Y79, and A549 cancer cell lines with IC50 values (concentration that inhibits cell growth by 50%) of 85 MUg/mL, 70 MUg/mL, 120 MUg/mL, 82 MUg/mL, and145 MUg/mL, respectively. CONCLUSIONS: The present results suggest a direct cytotoxic activity of K. odoratissima leaf extract against human cancer cell lines. This activity of K. odoratissima may find application in combination with traditional herbal medicines to develop a new anticancer pharmacopuncture therapy. PMID- 28712478 TI - Comparison of Effects of Local Anesthesia and Two-Point Acupressure on the Severity of Venipuncture Pain Among Hospitalized 6-12-Year-Old Children. AB - The aim of the present study was to compare the effects of topical anesthesia and acupressure at the Yintang (Extra 1) and the Laogong (P-8) points on the severity of venipuncture pain among hospitalized 6-12-year-old children. A sample (n = 120) of 6-12-year-old hospitalized children was recruited from two teaching hospitals located in Rafsanjan, Iran. The children were allocated to the topical anesthesia, acupressure, and control groups. For children in the topical anesthesia and the acupressure groups, eutectic mixture of local anesthetic (EMLA) cream and two-point acupressure were used, respectively, prior to performing venipuncture, whereas children in the control group only received routine prevenipuncture care. The severity of venipuncture pain was evaluated 5 minutes after performing venipuncture by using the Face, Leg, Activity, Cry, and Consolability behavioral pain assessment scale. The findings revealed that pain severity in both experimental groups was significantly lower than that in the control group, whereas there was no significant difference between the experimental groups regarding pain severity. Although acupressure was as effective as topical anesthesia cream in alleviating children's venipuncture pain, nurses are recommending to use acupressure instead of pharmacological pain management agents because of its greater safety, cost-effectiveness, and applicability. PMID- 28712479 TI - Antiplatelet Aggregation Activity of Walnut Hull Extract via Suppression of Reactive Oxygen Species Generation and Caspase Activation. AB - Walnut hull (wal hull) is an agricultural by-product that is widely used in traditional medicine for alleviating pain and treating skin diseases, however, recently it has gained much attention in modern pharmacology due to its antioxidant properties. The current study was aimed to determine the total phenolic, flavonoid, and tannin content of Persian wal hull extract and evaluate its biological effects on platelet function. Experimental data showed that acetone extract of wal hulls has a high content of polyphenolic compounds and antioxidant properties. The analytical study of crude extract by gas chromatography-mass spectrometry demonstrated different types of high- and low molecular-weight compounds that are basically and biologically important. Moreover, an in vitro study revealed that wal hull extract at a concentration of 50 MUg/mL inhibited thrombin-induced platelet aggregation and protein secretion by 50%, without any cytotoxic effects on platelets. The examined extract suppressed reactive oxygen species generation and also caspase activation in thrombin-stimulated platelets. Identically, N-acetylcysteine inhibited the increase of reactive oxygen species level induced by thrombin in platelets, and supported a link between cellular redox status and caspase activation in activated platelets. Presumably, the antiplatelet activity of wal hull extract is related to its polyphenolic compounds and their antioxidant properties. Therefore, wal hulls can be considered as a candidate for thrombotic disorders. PMID- 28712480 TI - Bee Venom Acupuncture Reduces Interleukin-6, Increases Interleukin-10, and Induces Locomotor Recovery in a Model of Spinal Cord Compression. AB - Spinal cord injuries (SCIs) initiate a series of molecular and cellular events in which inflammatory responses can lead to major neurological dysfunctions. The present study aims to investigate whether bee venom (BV) acupuncture applied at acupoints ST36 (Zusanli) and GV3 (Yaoyangquan) could minimize locomotor deficits and the magnitude of neural tissue losses, and change the balance between pro- and anti-inflammatory cytokines after an SCI by compression. Wistar rats were subjected to an SCI model by compression in which a 2-French Fogarty embolectomy catheter was inflated in the extradural space. The effects of BV acupuncture, in which 20 MUL of BV diluted in saline (0.08 mg/kg) was injected at acupoints GV3 and ST36 [BV(ST36+GV3)-SCI] was compared with BV injected at nonacupoints [BV(NP) SCI] and with no treatment [group subjected only to SCI (CTL-SCI)]. The BV(ST36+GV3)-SCI group showed a significant improvement in the locomotor performance and a decrease of lesion size compared with the controls. BV acupuncture at the ST36 + GV3 increased the expression of interleukin-10 (anti inflammatory) at 6 hours and reduced the expression of interleukin-6 (proinflammatory) at 24 hours after SCI compared with the controls. Our results suggest that BV acupuncture can reduce neuroinflammation and induce recovery in the SCI compression model. PMID- 28712481 TI - Korean Sa-Ahm Acupuncture for Treating Canine Oral Fibrosarcoma. AB - A nine-year-old male neutered Golden Retriever presented with oral fibrosarcoma. Sa-Ahm Traditional Korean acupuncture was provided along with medicinal herb treatment. Based on Sa-Ahm's theory, the constitution of this case was hypoactive Large-Intestine (LI) meridian qi. The acupuncture treatment was focused on reinforcing LI meridian qi along with reinforcing Small-Intestine and Liver meridian qi. The necrosis of the tumor started from 8 months after treatments and was completely necrotized around 1 month after initiation of tumor necrosis. Karnofsky Performance Status score was 80 to 100 % throughout the treatment except during the active stage of tumor necrosis having KPS of 50%. In this study, oral fibrosarcoma was managed well by both Sa-Ahm acupuncture and medicinal herb treatment. The result suggested that Sa-Ahm acupuncture along with herbal treatment could be a potential medical option for canine oral FSA therapy. PMID- 28712482 TI - Ultrasonography in Acupuncture-Uses in Education and Research. AB - This study aims to explore the potential use of ultrasound in locating the second posterior sacral foramen acupuncture point, quantifying depth of insertion and describing surrounding anatomical structures. We performed acupuncture needle insertion on a study team member. There were four steps in our experiment. First, the acupuncturist located the acupuncture point by palpation. Second, we used an ultrasound machine to visualize the structures surrounding the location of the acupuncture point and measure the depth required for needle insertion. Third, the acupuncturist inserted the acupuncture needle into the acupuncture point at an angle of 30 degrees . Fourth, we performed another ultrasound scan to ensure that the needle was in the desired location. Results suggested that ultrasound could be used to locate the acupuncture point and estimate the depth of needle insertion. The needle was inserted to a depth of 4.0 cm to reach the surface of the sacral foramen. Based on Pythagoras theorem, taking a needle insertion angle of 30 degrees and a needle insertion depth of 4.0 cm, the estimated perpendicular depth is 1.8 cm. An ultrasound scan corroborated the depth of 1.85 cm. The use of an ultrasound-guided technique for needle insertion in acupuncture practice could help standardize the treatment. Clinicians and students would be able to visualize and measure the depth of the sacral foramen acupuncture point, to guide the depth of needle insertion. This methodological guide could also be used to create a standard treatment protocol for research. A similar mathematical guide could also be created for other acupuncture points in future. PMID- 28712483 TI - Corrigendum to "Improvements in Scrotal Thermoregulation in Patients with Varicoceles Treated by Using Traditional Korean Medicine: Two Case Reports" [J Acupunct Meridian Stud 9 (3) (2016) 156-160]. PMID- 28712484 TI - Relevance of DNA damage repair in the management of prostate cancer. AB - Recent insights into the genomic aberrations that underlie and drive prostate cancer have redoubled efforts to molecularly stratify treatments based on predictive markers. Approximately 23% of patients with metastatic castration resistant prostate cancer exhibit somatic or germline aberrations in genes implicated in DNA repair, such as BRCA2, BRCA1, ATM, CHEK2, and PALB2, as well as mismatch repair genes. At least 10% of men with advanced disease have germline mutations in DNA-repair genes (DRG). The enrichment of DRG defects in metastatic disease compared with localized, primary tumors suggests a possible role in carcinogenesis, disease progression, and potentially accounts for a more aggressive phenotype. Germline BRCA2-mutant prostate cancer is more likely to present with advanced disease, higher Gleason score, and exhibit poorer survival than noncarriers. Very little is currently known about the clinicopathological features of prostate cancer associated with rarer DRG variants. It is currently unknown whether germline carriers of DRG mutations would benefit from additional screening strategies or more intensive treatment of localized prostate cancer. Defective DNA repair may have profound therapeutic implications for advanced disease, conferring tumor-specific vulnerability to poly(ADP-ribose) polymerase inhibitors, platinum chemotherapy, or immunotherapy that can be exploited for clinical benefit. Pertinent issues regarding cancer risk, screening recommendations and risk reduction strategies for carriers of poorly characterized DRG variants remains to be defined. We review the prevalence and potential clinical implications of DNA damage repair defects in prostate cancer. The broader promise and challenge of implementing this knowledge into clinical practice is also discussed. PMID- 28712485 TI - Memorial address to Dr. Isabelle Rapin. PMID- 28712486 TI - Myoclonic epilepsy in infancy with preceding or concurrent afebrile generalized tonic-clonic seizures in Chinese children. AB - OBJECTIVE: To investigate the general characteristics and the category of myoclonic epilepsy in infancy (MEI) with or without afebrile generalized tonic clonic seizures (GTCS). METHODS: Thirty-three children were retrospectively recruited from approximately 42,814 video-electroencephalogram (VEEG) recordings monitored in our department over last nearly 10years. Myoclonic seizures (MS) must be identified by VEEG in all patients. The clinical, EEG features and outcome were analyzed among these patients. RESULTS: The 33 patients (25 boys and 8 girls) were divided into three groups: 11 patients with typical MEI; 16 patients with MEI experienced afebrile GTCS before MS onset; and 6 patients with MEI presented afebrile GTCS occurring concurrently with MS. No significant differences were found among the three groups, including gender distribution, family history, personal history of febrile seizures, the age at seizure onset and control, the duration of MS, the interval between age at onset and seizure control, the age at EEG normalization, the interval between seizure onset age and EEG normalization age and normal psychomotor development at the end of follow-up. More patients in group two and group three were controlled by two or three kinds of antiepileptic drugs compared with those in group one. CONCLUSIONS: In this study, three groups of patients had similar clinical, EEG features and outcome. Afebrile GTCS was associated with a stronger cortical hyperexcitability. It was worth considering whether MEI with preceding or concurrent afebrile GTCS should be recognized as subgroups or different epileptic syndromes independent of MEI. PMID- 28712487 TI - Real time PI-backstepping induction machine drive with efficiency optimization. AB - This paper describes a robust and efficient speed control of a three phase induction machine (IM) subjected to load disturbances. First, a Multiple-Input Multiple-Output (MIMO) PI-Backstepping controller is proposed for a robust and highly accurate tracking of the mechanical speed and rotor flux. Asymptotic stability of the control scheme is proven by Lyapunov Stability Theory. Second, an active online optimization algorithm is used to optimize the efficiency of the drive system. The efficiency improvement approach consists of adjusting the rotor flux with respect to the load torque in order to minimize total losses in the IM. A dSPACE DS1104 R&D board is used to implement the proposed solution. The experimental results released on 3kW squirrel cage IM, show that the reference speed as well as the rotor flux are rapidly achieved with a fast transient response and without overshoot. A good load disturbances rejection response and IM parameters variation are fairly handled. The improvement of drive system efficiency reaches up to 180% at light load. PMID- 28712488 TI - Staged reconstruction of diaphyseal fractures with segmental defects: Surgical and patient-reported outcomes. AB - INTRODUCTION: Two-stage limb reconstruction is an option for patients with critical size segmental bone defects following acute trauma or non-union. Reconstruction is technically demanding and associated with a high complication rate. Current protocols for limb reconstruction have well-documented challenges, and no study has reported on patient outcomes using a validated questionnaire. In this study, we aimed to examine the clinical and patient-centered outcomes following our surgical protocol for two-stage limb reconstruction following critical size segmental defects. PATIENTS AND METHODS: A single surgeon performed reconstruction of long bone defects using antibiotic impregnated cement spacers and intramedullary cancellous bone autograft. A retrospective chart review was performed. Three reviewers independently measured time to union based on radiographs. The Lower Extremity Functional Scale (LEFS) survey was administered to patients after most recent follow-up. RESULTS: Ten limbs representing nine patients were included. All patients sustained a lower extremity injury, and one patient had bilateral lower extremity injuries. Average clinical follow-up was 18.3 months (range 7-33) from final surgical intervention, and follow-up to questionnaire administration was 28 months (range 24-37). The mean time between stages was 3.1 months. Average time to unrestricted weight-bearing was 7.9 months from Stage 1 (range 3.4-15.9) and 4.5 months from Stage 2 (range 1.1-11.6). Average time to full union was 16.7 months from Stage 1 (range 6.4-28.6) and 13.5 months from Stage 2 (range 1.8-27). Eight patients (nine limbs) participated in the LEFS survey, the average score was 53.1 (range 30-67), equating to 66% of full functionality (range 38%-84%). Complications included 5 infections, 3 non unions, and one amputation. There was a moderate positive correlation between infection at any time point and non-union (R=0.65, p=0.03). DISCUSSION AND CONCLUSIONS: Outcomes in this small patient cohort were good despite risks of complication. There is an association between infection and non-union. Further studies addressing clinical and functional outcomes will help to guide expectations for future surgeons and patients. PMID- 28712489 TI - Plant-made virus-like particles bearing influenza hemagglutinin (HA) recapitulate early interactions of native influenza virions with human monocytes/macrophages. AB - INTRODUCTION: Plant-made virus-like particles (VLP) bearing influenza virus hemagglutinins (HA) are novel vaccine candidates that induce cross-reactive humoral and poly-functional T cell responses. To better understand the mechanisms that underlie this broad immunogenicity we studied early interactions of VLPs bearing either H1 (A/California/07/2009 (H1N1)) or H5 (A/Indonesia/05/2005 (H5N1)) with a human monocytoid cell line (U-937 cells) and human monocyte derived macrophages (MDMs) as model antigen-presenting cells (APC). METHODS AND RESULTS: Using Vibrio cholerae sialidase and lectins that target alpha2,6- (Sambucus nigra lectin) or alpha2,3-linked sialic acids (Maackia amurensis lectin I), we demonstrated that VLPs bind to these APCs in a sialic acid-dependent manner. Using lysosomal markers and DiD-labelled VLPs, we found that attachment to the cell surface leads to internalization, trafficking to acidic cell compartments and fusion of the VLP lipid envelope with endosomal membranes. Incubation of MDMs with H1- but not H5-VLPs induced proliferation of autologous peripheral blood mononuclear cells suggesting antigen processing and stimulation of a memory T cell response. CONCLUSIONS: Plant-made VLPs bearing influenza HA not only mimic the structure of influenza virions to some degree but also recapitulate key features of the initial virus-APC interaction. These observations may help to explain the balanced humoral and cellular responses to plant-made VLP vaccines. PMID- 28712491 TI - Glaucoma Progression in the Unaffected Fellow Eye of Glaucoma Patients who Developed Unilateral Branch Retinal Vein Occlusion. PMID- 28712490 TI - Pneumococcal vaccination for splenectomized patients with thalassemia major in Indonesia. AB - INTRODUCTION: Streptococcus pneumoniae is a capsulated bacterium that can cause severe infection in patients with thalassemia major, particularly those who have undergone splenectomy. The absence of the spleen as well as zinc deficiency in splenectomized patients with thalassemia major increases the possibility of developing invasive pneumococcal infection. The aims of this study are to evaluate pneumococcal IgG levels following PCV and PPV immunizations and the effect of zinc supplementation on qualitative specific immune responses in splenectomized patients with thalassemia. METHODS: Splenectomized patients with thalassemia major were administered a PCV pneumococcal vaccine (Prevenar 13(r)) at the start of the trial, after which they were randomly assigned to 2 groups (zinc and placebo group). After 8weeks, the patients received a PPV pneumococcal vaccine (Pneumovax(r)). Zinc syrup was provided to the zinc group at a dose of 1.5mg/kg/day (maximum of 50mg/day). Pneumococcal IgG examinations were conducted at the start of the trial and after 12weeks. RESULTS: In the group without PPV, the median initial pneumococcal IgG value was 315 (ranging from 65 to 1419) mU/mL for the zinc group and 338.5 (ranging from 82 to 1648) mU/mL for the placebo group. The median final pneumococcal IgG value was 1812.5 (ranging from 834 to 2444) mU/mL for the zinc group and 2857.5 (ranging from 834 to 2624) for the placebo group. The increase in the pneumococcal IgG value between the two groups was comparable (p=0.642). In the group with previous PPV, the median initial pneumococcal IgG value was 1333 (ranging from 793 to 2031) mU/mL for the zinc group and 880 (ranging from 74 to 1686) mU/mL for the placebo group. The median final pneumococcal IgG value was 1487 (ranging from 635 to 1757) mU/mL for the zinc group and 1012 (ranging from 292 to 1732) mU/mL for the placebo group. The increase in the pneumococcal IgG value between the two groups was comparable (p=0.528). CONCLUSION: There is no difference in the increase in pneumococcal IgG level in splenectomized patients with thalassemia major prior to and after receiving PPV. There were no differences observed in the development of pneumococcal IgG following zinc supplementation. PMID- 28712492 TI - Genome Engineering and Agriculture: Opportunities and Challenges. AB - In recent years, plant biotechnology has witnessed unprecedented technological change. Advances in high-throughput sequencing technologies have provided insight into the location and structure of functional elements within plant DNA. At the same time, improvements in genome engineering tools have enabled unprecedented control over genetic material. These technologies, combined with a growing understanding of plant systems biology, will irrevocably alter the way we create new crop varieties. As the first wave of genome-edited products emerge, we are just getting a glimpse of the immense opportunities the technology provides. We are also seeing its challenges and limitations. It is clear that genome editing will play an increased role in crop improvement and will help us to achieve food security in the coming decades; however, certain challenges and limitations must be overcome to realize the technology's full potential. PMID- 28712493 TI - CRISPR/Cas9-Enabled Multiplex Genome Editing and Its Application. AB - The CRISPR/Cas9 system is a prevalent and versatile genome-editing tool of choice for basic and applied biological research. An exchange of a 20-bp spacer sequence in the gRNA can easily reprogram Cas9 to target a different DNA site. By expressing or providing multiple gRNAs, the system also enables multiplex genome editing at high efficiencies. Current approaches for providing multiple gRNAs in vivo include the use of multigene cassettes to express several gRNAs, Csy4-based excision, arrays of crRNAs, ribozyme-flanked gRNAs, tRNA-dependent cleavage of gRNAs, and direct introduction of Cas9 proteins preloaded with different gRNAs. By simultaneously targeting multiple DNA sequences, multiplex genome editing can be used to knockout multiple genes or delete chromosomal fragments. Off-target risk can also be reduced by Cas9-dimers that require the simultaneous expression of two gRNAs. With multiple gRNAs, specific gene expression or methylation status can be efficiently controlled by dCas9 fused to activators, repressors, methyltransferase, demethylase, or other functional domains. As a result, multiplex genome editing is expected to accelerate functional discovery of plant genes as well as genetic improvement of agricultural crops. PMID- 28712494 TI - CRISPR/Cas9-Based Genome Editing in Plants. AB - Recently, genome editing technologies have shown great potential in plants. The newly developed clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system is a new generation of genome editing tool rapidly replacing the earlier zinc finger nucleases and transcription activator-like effector nucleases systems. Indeed, due to its advantages of simplicity and high efficiency, the CRISPR/Cas9-based genome editing system is becoming a powerful tool in plant science research. Here, we introduce the technical features of the plant CRISPR/Cas9-based genome editing system and its applications in plant functional genomics studies and genetic improvement. PMID- 28712495 TI - On Improving CRISPR for Editing Plant Genes: Ribozyme-Mediated Guide RNA Production and Fluorescence-Based Technology for Isolating Transgene-Free Mutants Generated by CRISPR. AB - CRISPR/Cas9-mediated genome editing technology has been used to successfully edit numerous genes in various organisms including plants. There are still two major challenges in using CRISPR/Cas9 technology for gene editing in plants. First, there are very limited choices of promoters that are suitable for in vivo production of single-guide RNAs (sgRNAs), which is complementary to the target sequence and which guides Cas9 to generate double-strand breaks at the target site. It is especially difficult to produce sgRNA molecules with temporal and spatial precision. Second, there is a lack of efficient methods for identifying plants that (1) contain heritable and stable mutations generated by CRISPR/Cas9, and (2) no longer harbor the CRISPR/Cas9 construct and other transgenes. In this chapter, we describe the development of a ribozyme-based strategy that enables the production of sgRNA molecules from any chosen promoter. More importantly, the ribozyme-based technology makes it feasible to produce sgRNAs with temporal and spatial precision, greatly expanding the scope and applications of CRISPR/Cas9 technology. We also developed a fluorescence-based technology that allows us to efficiently and reliably isolate Cas9-free stable Arabidopsis mutants. Thus, we provide effective protocols to overcome two important obstacles in using CRISPR/Cas9 for editing genes in plants. PMID- 28712496 TI - Engineering Molecular Immunity Against Plant Viruses. AB - Genomic engineering has been used to precisely alter eukaryotic genomes at the single-base level for targeted gene editing, replacement, fusion, and mutagenesis, and plant viruses such as Tobacco rattle virus have been developed into efficient vectors for delivering genome-engineering reagents. In addition to altering the host genome, these methods can target pathogens to engineer molecular immunity. Indeed, recent studies have shown that clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated 9 (Cas9) systems that target the genomes of DNA viruses can interfere with viral activity and limit viral symptoms in planta, demonstrating the utility of this system for engineering molecular immunity in plants. CRISPR/Cas9 can efficiently target single and multiple viral infections and confer plant immunity. Here, we discuss the use of site-specific nucleases to engineer molecular immunity against DNA and RNA viruses in plants. We also explore how to address the potential challenges encountered when producing plants with engineered resistance to single and mixed viral infections. PMID- 28712497 TI - Use of CRISPR/Cas9 for Symbiotic Nitrogen Fixation Research in Legumes. AB - Nitrogen-fixing rhizobia have established a symbiotic relationship with the legume family through more than 60 million years of evolution. Hundreds of legume host genes are involved in the SNF (symbiotic nitrogen fixation) process, such as recognition of the bacterial partners, nodulation signaling and nodule development, maintenance of highly efficient nitrogen fixation within nodules, regulation of nodule numbers, and nodule senescence. However, investigations of SNF-related gene functions and dissecting molecular mechanisms of the complicated signaling crosstalk on a genomic scale were significantly restricted by insufficient mutant resources of several representative model legumes. Targeted genome-editing technologies, including ZFNs, TALENs, and CRISPR-Cas systems, have been developed in recent years and rapidly revolutionized biological research in many fields. These technologies were also applied to legume plants, and significant progress has been made in the last several years. Here, we summarize the applications of these genome-editing technologies, especially CRISPR-Cas9, toward the study of SNF in legumes, which should greatly advance our understanding of the basic mechanisms underpinning the legume-rhizobia interactions and guide the engineering of the SNF pathway into nonlegume crops to reduce the dependence on the use of nitrogen fertilizers for sustainable development of modern agriculture. PMID- 28712498 TI - Safety, Security, and Policy Considerations for Plant Genome Editing. AB - Genome editing with engineered nucleases (GEEN) is increasingly used as a tool for gene discovery and trait development in crops through generation of targeted changes in endogenous genes. The development of the CRISPR-Cas9 system (clustered regularly interspaced short palindromic repeats with associated Cas9 protein), in particular, has enabled widespread use of genome editing. Research to date has not comprehensively addressed genome-editing specificity and off-target mismatches that may result in unintended changes within plant genomes or the potential for gene drive initiation. Governance and regulatory considerations for bioengineered crops derived from using GEEN will require greater clarity as to target specificity, the potential for mismatched edits, unanticipated downstream effects of off-target mutations, and assurance that genome reagents do not occur in finished products. Since governance and regulatory decision making involves robust standards of evidence extending from the laboratory to the postcommercial marketplace, developers of genome-edited crops must anticipate significant engagement and investment to address questions of regulators and civil society. PMID- 28712499 TI - Use of CRISPR/Cas9 for Crop Improvement in Maize and Soybean. AB - CRISPR/Cas enables precise improvement of commercially relevant crop species by transgenic and nontransgenic methodologies. We have used CRISPR/Cas with or without DNA repair template in both corn and soybean for a range of applications including enhancing drought tolerance, improving seed oil composition, and endowing herbicide tolerance. Importantly, by pairing CRISPR/Cas technology with recent advances in plant tissue culture, these changes can be introduced directly into commercially relevant genotypes. This powerful combination of technologies enables advanced breeding techniques for introducing natural genetic variations directly into product relevant lines with improved speed and quality compared with traditional breeding methods. Variation generated through such CRISPR/Cas enabled advanced breeding approaches can be indistinguishable from naturally occurring variation and therefore should be readily accessible for commercialization. The precision, reach, and flexibility afforded by CRISPR/Cas promise an important role for genome editing in future crop improvement efforts. PMID- 28712500 TI - Use of Zinc-Finger Nucleases for Crop Improvement. AB - Over the past two decades, new technologies enabling targeted modification of plant genomes have been developed. Among these are zinc-finger nucleases (ZFNs) which are composed of engineered zinc-finger DNA-binding domains fused with a nuclease, generally the FokI nuclease. The zinc-finger domains are composed of a series of four to six 30 amino acid domains that can bind to trinucleotide sequences giving the entire DNA-binding domain specificity to 12-18 nucleotides. Since the FokI nuclease functions as a dimer, pairs of zinc-finger domains are designed to bind upstream and downstream of the cut site which increases the specificity of the complete ZFN to 24-36 nucleotides. The ability of these engineered nucleases to create targeted double-stranded breaks at designated locations throughout the genome has enabled precise deletion, addition, and editing of genes. These techniques are being used to create new genetic variation by deleting or editing endogenous gene sequences and enhancing the efficiency of transgenic product development through targeted insertion of transgenes to specific genomic locations and to sequentially add and/or delete transgenes from existing transgenic events. PMID- 28712501 TI - Gene Editing in Polyploid Crops: Wheat, Camelina, Canola, Potato, Cotton, Peanut, Sugar Cane, and Citrus. AB - Polyploid crops make up a significant portion of the major food and fiber crops of the world and include wheat, potato, cotton, apple, peanut, citrus, and brassica oilseeds such as rape, canola, and Camelina. The presence of three sets of chromosomes in triploids, four sets in tetraploids, and six sets in hexaploids present significant challenges to conventional plant breeding and, potentially, to efficient use of rapidly emerging gene and genome-editing systems such as zinc finger nucleases, single-stranded oligonucleotides, TALE effector nucleases, and clustered regularly interspaced short palindromic repeats (CRISPR/Cas9). However, recent studies with each of these techniques in several polyploid crops have demonstrated facile editing of some or all of the genes targeted for modification on homeologous chromosomes. These modifications have allowed improvements in food nutrition, seed oil composition, disease resistance, weed protection, plant breeding procedures, and food safety. Plants and plant products exhibiting useful new traits created through gene editing but lacking foreign DNA may face reduced regulatory restrictions. Such plants can be obtained either by simply selecting for null segregants that have lost their editing transgenes during plant breeding or, even more attractively, by delivery of biodegradable Cas9/sgRNA ribonucleoprotein complexes (i.e., no DNA) into plant cells where they are expressed only transiently but allow for efficient gene editing-a system that has been recently demonstrated in at least two polyploid crops. Such systems that create precise mutations but leave no transgene footprint hold potential promise for assisting with the elimination or great diminution of regulatory processes that presently burden approvals of conventional transgenic crops. PMID- 28712502 TI - Gene Editing With TALEN and CRISPR/Cas in Rice. AB - Engineered, site-specific nucleases induce genomic double-strand DNA breaks and break repair processes enable genome editing in a plethora of eukaryotic genomes. TALENs (transcription activator-like effector nucleases) and CRISPR/Cas (clustered regularly interspaced short palindromic repeats and CRISPR-associated proteins) are potent biotechnological tools used for genome editing. In rice, species-tailored editing tools have proven to be efficient and easy to use. Both tools are capable of generating DNA double-strand breaks (DSBs) in vivo and such breaks can be repaired either by error-prone NHEJ (nonhomologous end joining) that leads to nucleotide insertions or deletions or by HDR (homology-directed repair) if an appropriate exogenous DNA template is provided. NHEJ repair often results in gene knockout, while HDR results in precise nucleotide sequence or gene replacement. In this review, we revisit the molecular mechanisms underlying DSB repair in eukaryotes and review the TALEN and CRISPR technologies (CRISPR/Cas9, CRISPR/Cpf1, and Base Editor) developed and utilized for genome editing by scientists in rice community. PMID- 28712503 TI - Genome Editing to Improve Abiotic Stress Responses in Plants. AB - Targeted modification of specific genes via genome editing is now used routinely to modify plant genomes. In developing new mutations in plant genomes using the widely used CRISPR/Cas9 system, it is important for further use in plant molecular studies and crop breeding that the mutations generated are heritable. To date, several improvements to increase efficiency and specificity have been developed to generate heritable mutations in various plant species. In this chapter, we focus on strategies to improve genome editing technology to increase heritability in plants, and summarize the process used to generate new mutant alleles of environmental stress response genes in plants. Such studies suggest further applications in molecular breeding to improve plant function using optimized plant CRISPR/Cas9 systems. PMID- 28712504 TI - Preface. PMID- 28712505 TI - Long-term evaluation of single-puncture temporomandibular joint arthrocentesis in patients with unilateral temporomandibular disorders. AB - The purpose of this study was to evaluate the long-term effects of the single puncture arthrocentesis (SPA) technique. Forty-two patients with unilateral temporomandibular joint disorders (TMDs) were treated by SPA. Thirty-eight of these patients completed 1-24 months of follow-up (short-term group) and 21 completed 11 months or longer of follow-up (long-term group). The two groups were evaluated statistically for pain (visual analogue scale), maximum mouth opening, lateral excursion, and protrusion. Both follow-up duration groups showed significant improvements when compared to baseline levels for almost all of the outcome variables (P<0.05). Single puncture temporomandibular joint arthrocentesis is an effective treatment method over both the short and long term. PMID- 28712506 TI - VDAC1 functions in Ca2+ homeostasis and cell life and death in health and disease. AB - In the outer mitochondrial membrane (OMM), the voltage-dependent anion channel 1 (VDAC1) serves as a mitochondrial gatekeeper, controlling the metabolic and energy cross-talk between mitochondria and the rest of the cell. VDAC1 also functions in cellular Ca2+ homeostasis by transporting Ca2+ in and out of mitochondria. VDAC1 has also been recognized as a key protein in mitochondria mediated apoptosis, contributing to the release of apoptotic proteins located in the inter-membranal space (IMS) and regulating apoptosis via association with pro and anti-apoptotic members of the Bcl-2 family of proteins and hexokinase. VDAC1 is highly Ca2+-permeable, transporting Ca2+ to the IMS and thus modulating Ca2+ access to Ca2+ transporters in the inner mitochondrial membrane. Intra mitochondrial Ca2+ controls energy metabolism via modulating critical enzymes in the tricarboxylic acid cycle and in fatty acid oxidation. Ca2+ also determines cell sensitivity to apoptotic stimuli and promotes the release of pro-apoptotic proteins. However, the precise mechanism by which intracellular Ca2+ mediates apoptosis is not known. Here, the roles of VDAC1 in mitochondrial Ca2+ homeostasis are presented while emphasizing a new proposed mechanism for the mode of action of pro-apoptotic drugs. This view, proposing that Ca2+-dependent enhancement of VDAC1 expression levels is a major mechanism by which apoptotic stimuli induce apoptosis, position VDAC1 oligomerization at a molecular focal point in apoptosis regulation. The interactions of VDAC1 with many proteins involved in Ca2+ homeostasis or regulated by Ca2+, as well as VDAC-mediated control of cell life and death and the association of VDAC with disease, are also presented. PMID- 28712507 TI - A unity of the self or a multiplicity of locations? How the graphesthesia task sheds light on the role of spatial perspectives in bodily self-consciousness. AB - Integrating multisensory stimuli from a self-centred perspective is crucial for the unity of the self. On the other hand, understanding external space and communicating spatial knowledge with others necessitate the adoption of decentred perspectives. How do we juggle these two requirements? In this article, we review those studies that have used the graphesthesia task in order to investigate the perspectives that people adopt when interpreting ambiguous tactile symbols (e.g., b, d, p, and q). With such ambiguous symbols, self-centred and decentred perspectives conflict with one another. The results reviewed here reveal that the perspectives adopted vary significantly with spatial, personal, and interpersonal factors. Such findings suggest that the self can adopt a multiplicity of spatial locations. However, the unity of the self can partly be explained by the predominance of a head-centred perspective. On the other hand, perspective-taking abilities contribute to the distinction between self and others, reinforcing self consciousness. PMID- 28712508 TI - Health care importance of Treponema pallidum, Chagas' disease and Human immunodeficiency virus 1 among Amerindians of Argentina: an observational study. AB - The objective of this study was to estimate the prevalence of Treponema pallidum, Trypanosoma cruzi and Human immunodeficiency virus 1 (HIV-1) in five Amerindian populations of Argentina. A retrospective study was conducted among 857 Amerindian populations (112 Kollas, 298 Mbya-guaranies, 79 Sagua Huarpes, 368 Wichis) from 2007 to 2010. Screening and confirmation of T. pallidum, T. cruzi and HIV-1 were performed. T. pallidum and T. cruzi infections were detected in all communities with an overall prevalence rate of 4.2% and 16.8%, respectively. Although HIV was not detected, syphilis and Chagas' disease represent a challenge for the health care system and the reinforcement of public health strategies is necessary considering the socioeconomic isolation of these populations. PMID- 28712509 TI - Genetic diversity of thermotolerant Campylobacter spp. isolates from different stages of the poultry meat supply chain in Argentina. AB - The objective of this study was to investigate a clonal relationship among thermotolerant Campylobacter spp. isolates from different stages of the poultry meat supply chain in Argentina. A total of 128 thermotolerant Campylobacter spp. (89 C. jejuni and 39 C. coli) isolates from six poultry meat chains were examined. These isolates were from: a) hens from breeder flocks, b) chickens on the farm (at ages 1 wk and 5 wk), c) chicken carcasses in the slaughterhouse, and d) chicken carcasses in the retail market. Chickens sampled along each food chain were from the same batch. Campylobacter spp. isolates were analyzed using pulsed field gel electrophoresis to compare different profiles according to the source. Clustering of C. jejuni isolates resulted in 17 profiles, with four predominant genotypes and many small profiles with just a few isolates or unique patterns, showing a very high degree of heterogeneity among the C. jejuni isolates. Some clusters included isolates from different stages within the same chain, which would indicate a spread of strains along the same poultry meat chain. Moreover, twenty-two strains of C. coli clustered in seven groups and the remaining 17 isolates exhibited unique profiles. Evidence for transmission of thermotolerant Campylobacter spp. through the food chain and cross contamination in the slaughterhouses were obtained. This collective evidence should be considered as the scientific basis to implement risk management measures to protect the public health. PMID- 28712510 TI - Narrow-band imaging with 4K technology in the head and neck: preliminary experience and technical settings. PMID- 28712511 TI - Re: Medical students' understanding of oral and maxillofacial surgery: an Irish perspective. PMID- 28712512 TI - Higher pain level and lower functional capacity are associated with the number of altered kinematics in women with patellofemoral pain. AB - This study investigated whether women with patellofemoral pain (PFP) present kinematic alterations in proximal, local, and distal factors simultaneously, and determined the association between the number of kinematic alterations, pain level, and functional status. A three-dimensional motion analysis system was used to analyze the peak hip adduction, peak knee flexion, and peak rearfoot eversion, addressing the proximal, local, and distal factors, respectively, in fifty women. Functional status and pain level were assessed using the anterior knee pain scale (AKPS) and a visual analogic scale. Receiver operating characteristic curves were calculated to identify participants with and without kinematic alterations and the number of them was obtained for each participant. Associations between the number of kinematic alterations, pain level, and AKPS score were determined by the Pearson correlation. Results showed that 52% of women with PFP presented at least two kinematic alterations of which 24% were local/proximal, 16% local/distal, and 12% proximal/distal. Three kinematic alterations were found in 48% of the women with PFP. A strong positive correlation was found between the number of kinematic alterations and pain (r=0.78; p<0.001). A strong negative correlation was found between the number of altered kinematics and functional status (r=-0.79; p<0.001). Findings revealed that women with PFP presented at least two kinematic alterations and a higher number of kinematic alterations was associated with higher pain levels and lower functional status. Clinicians should carefully assess movement pattern of women with PFP as it could indicate a more severe condition, which is associated with a poor prognosis. PMID- 28712513 TI - NCI oncologists excluded from some US insurance networks. PMID- 28712515 TI - Questions over the import of radionuclides after Brexit. PMID- 28712514 TI - TERT mutations in urine could predict bladder cancer recurrence. PMID- 28712516 TI - Online Master of Education Program: Academic Outcomes. PMID- 28712517 TI - Comparison of Oropharyngeal and Nasopharyngeal Swab Specimens for the Detection of Mycoplasma pneumoniae in Children with Lower Respiratory Tract Infection. AB - The oropharyngeal swab specimen was superior to the nasopharyngeal swab specimen for the detection of Mycoplasma pneumoniae in children with lower respiratory tract infection. The oropharyngeal loop-mediated isothermal amplification had 100% sensitivity and specificity compared with polymerase chain reaction testing, whereas the oropharyngeal rapid antigen detection test using immunochromatographic assay had relatively low sensitivity (66%) and reasonable specificity (90.7%). PMID- 28712518 TI - Subclinical Atherosclerosis in Youth: Relation to Obesity, Insulin Resistance, and Polycystic Ovary Syndrome. PMID- 28712519 TI - Contemporary Outcomes of Infants with Gastroschisis in North America: A Multicenter Cohort Study. AB - OBJECTIVE: To quantify outcomes and analyze factors predictive of morbidity and mortality in infants with gastroschisis. STUDY DESIGN: Clinical data regarding neonates with gastroschisis born between 2009 and 2014 were prospectively collected at 175 North American centers. Multivariate regression was used to assess risk factors for mortality and length of stay (LOS). RESULTS: Gastroschisis was diagnosed in 4420 neonates with median birth weight 2410 g (IQR 2105-2747). Survival (discharge home or alive in hospital at 1 year) was 97.8% with a 37 day median LOS (IQR 27-59). Sepsis, defined by positive blood or cerebrospinal fluid culture, was the only significant independent predictor of mortality (P = .04). Significant independent determinants of LOS and the percentage of neonates affected were as follows: bowel resection (9.8%, P < .0001), sepsis (8.6%, P < .0001), presence of other congenital anomalies (7.6%, including 5.8% with intestinal atresias, P < .0001), necrotizing enterocolitis (4.5%, P < .0001), and small for gestational age (37.3%, P = .0006). Abdominal surgery in addition to gastroschisis repair occurred in 22.3%, with 6.4% receiving gastrostomy or jejunostomy tubes and 6.3% requiring ostomy creation. At discharge, 57.0% were less than the 10th percentile weight for age. The mode of delivery (52.4% cesarean delivery) was not associated with any differences in outcome. CONCLUSIONS: Although neonates with gastroschisis have excellent overall survival they remain at risk for death from sepsis, prolonged hospitalization, multiple abdominal operations, and malnutrition at discharge. Outcomes appear unaffected by the use of cesarean delivery. Further opportunities for quality improvement include sepsis prevention and enhanced nutritional support. PMID- 28712520 TI - Rear-Facing Car Safety Seat Use for Children 18 Months of Age: Prevalence and Determinants. AB - OBJECTIVE: To examine the prevalence and potential determinants of rear-facing car safety seat use among children approximately 18 months of age born at a university hospital. STUDY DESIGN: We administered a telephone survey to caregivers of children 17-19 months of age who were born between November 2013 and May 2014. The survey was designed to assess the prevalence of rear-facing car safety seat use and estimate the likelihood of rear-facing car safety seat use, compared with forward-facing car seat use, in reference to hypothesized determinants. aORs and 95% CIs were calculated using multivariable logistic regression. RESULTS: In total, 56% of potentially eligible caregivers (491/877) completed the survey; 62% of these reported rear-facing car safety seat use. Race, education, rurality, and household income were associated with rear-facing car safety seat use after controlling for potential confounders. Additionally, caregivers who reported having discussed car seats with their child's provider (aOR 1.7; 95% CI 1.1-2.6); receiving their child's primary care in pediatrics compared with family practice clinics (aOR 2.4; 95% CI 1.1-2.6); and being aware of the American Academy of Pediatrics rear-facing recommendation (aOR 2.8; 95% CI 1.8-4.1) were significantly more likely to report rear-facing car safety seat use. Conversely, caregivers who previously used a car seat with another child were less likely to have their child rear facing at 18 months of age (aOR 0.6; 95% CI 0.4-0.9). CONCLUSIONS: A large proportion of children were forward facing at 18 months of age. Future efforts focused on encouraging providers to discuss car seats during patient visits, increasing awareness of the American Academy of Pediatrics' rear-facing recommendation, and targeting high-risk populations may improve the prevalence of children who remain rear facing until 2 years of age. PMID- 28712521 TI - Subclinical Kidney Injury in Children Receiving Nonsteroidal Anti-Inflammatory Drugs After Cardiac Surgery. AB - OBJECTIVE: To investigate the association of nonsteroidal anti-inflammatory drug (NSAID) administration with urinary neutrophil gelatinase-associated lipocalin (NGAL) levels in children following cardiopulmonary bypass (CPB) who did not develop acute kidney injury (AKI). STUDY DESIGN: In this prospective observational study, urinary NGAL levels were investigated in 210 children who underwent cardiothoracic surgery requiring CPB. Children with clinical AKI (defined as an increase in serum creatinine >=50% from baseline within 72 hours of CPB) were excluded from the analysis. NSAIDs were administered no sooner than 24 hours after CPB. NGAL levels were compared between children who received NSAIDs (n = 146) and those who did not receive NSAIDs (n = 64). RESULTS: The median age was 3.2 years in the children who received NSAIDs and 2.5 years in those who did not receive NSAIDs (P = .05). Before NSAID administration at 24 hours following CPB, the median NGAL level was 15 ng/mL in both groups (P = .92). Following NSAID administration, the median urinary NGAL level increased to 83 ng/mL (IQR, 45-95 ng/mL) at 72 hours after CPB in those receiving NSAIDs (P < .001). In contrast, the median NGAL level decreased to 10 ng/mL (IQR, 5.4-15.9 ng/mL) at 72 hours after CPB in those who did not receive NSAIDs (P = .01). In multivariable analysis, children receiving NSAIDs demonstrated a 5-fold elevation of urinary NGAL levels at 60-72 hours following CPB compared with those who did not receive NSAIDs (P < .001). CONCLUSION: NSAID administration was associated with a significant increase in urinary NGAL in children who did not develop clinical AKI following CPB. This indicates that NGAL can detect NSAID-induced subclinical kidney injury in this population. PMID- 28712522 TI - Comparison of the origin and coupling interval between ectopy with and without atrial fibrillation initiation. AB - BACKGROUND: Differentiation of atrial fibrillation (AF) trigger ectopy from other ectopy is often difficult. The purpose of this study was to compare the origin and coupling intervals (CI) between AF-trigger and non-AF-trigger ectopy. METHODS: This study consisted of 120 patients with AF who underwent an initial ablation. Isoproterenol was infused up to 20MUg/min to provoke ectopy and AF. We measured the CI of all ectopy provoked by an isoproterenol infusion. The %CI was calculated as the CI of the ectopy/P-P interval of the preceding 2 beats. RESULTS: A total of 117 patients had at least one ectopy, and AF was induced in 56 (47%) patients. Of the 276 ectopies observed in this study, 211 (76%) originated from pulmonary veins and 77 (28%) were AF-trigger ectopy. AF-trigger ectopy more frequently originated from pulmonary veins (PVs) (74 vs. 3, p<0.001) and had a significantly shorter CI (201+/-70ms vs. 365+/-147ms, p<0.001) and lower %CI (29+/-11% vs. 55+/-14%, p<0.001) than that of non-AF-trigger ectopy. A receiver operating characteristics analysis revealed that a %CI of 40% was the best cut-off value for differentiating whether it was an AF-trigger or not. The identified trigger group, including patients with provoked AF-trigger ectopy or ectopy with a low %CI (<40%), had a significantly better AF recurrence-free survival rate than the other group (88% vs. 65%, p=0.004). CONCLUSIONS: AF trigger ectopy predominantly originated from PVs and had a short CI. These findings may be useful for estimating whether ectopies are an AF-trigger or not. PMID- 28712523 TI - West Nile Encephalitis in the Emergency Department: Prevalence and Recognition. PMID- 28712524 TI - The Unexpected Death of a Child and The Experience of Emergency Service Personnel. AB - INTRODUCTION: In 2013, 55,000 infants and children, aged 0 to 14, died in the United States. Nearly 7,000 of those deaths were attributed to traumatic causes. A child's death significantly affects emergency service personnel (ESP) caring for children and families. This study explores the lived experience of ESP involved in unsuccessful pediatric resuscitation efforts and how this experience affects them professionally and personally. METHODS: A phenomenologic approach guided this study. Using an open-ended format, an interview was conducted with a purposive sample of ESP who experienced unexpected pediatric death. Eight ESP participated in semistructured, face-to-face interviews, ranging in length from 35 to 75 minutes. The research question asked: "What is it like for you when a child dies after an unsuccessful resuscitation attempt?" Data were analyzed using thematic analysis. RESULTS: Van Manen's 4 existentials guided this study, and 10 subthemes emerged that included: "what if," "dying before my eyes," "team," "what if it was were my child?/being a parent," "the environment," "being trapped," "wounded healer," "education," "anger," and "coping." DISCUSSION: This study explores the experience of ESP involved in unsuccessful pediatric resuscitation that resulted in unexpected pediatric death and ESP's perceptions of this experience: thoughts of loss, a sense of anger, and a lack of preparation to cope with unexpected pediatric death and the unknowns of life. PMID- 28712525 TI - An 85-Year-Old Woman with Acute Onset Visual Hallucinations. PMID- 28712526 TI - Occupational Disappointment: Why Did I Even Become a Nurse? AB - INTRODUCTION: The aim of this study was to identify patterns of feelings and behavior of ED RNs who have experienced verbal workplace violence. METHODS: Twenty-eight registered nurses from across the state of California were recruited. Data were collected, using in-depth interviews, and were recorded. The tapes were transcribed and analyzed using Glaserian grounded-theory methodology. RESULTS: The main experiences of participants included occupational disappointment, peer support, lack of preparation by mandatory violence prevention classes, and unrealistic patient expectations. DISCUSSION: These findings can help staff, managers, and future educators of ED RNs examine feelings, mitigate the profound and pervasive effects of VWPV, and improve patient care. Contribution to Emergency Practice. PMID- 28712527 TI - Clinical Presentation to the Emergency Department Predicts Subarachnoid Hemorrhage-Associated Myocardial Injury. AB - INTRODUCTION: Aneurysmal subarachnoid hemorrhage (aSAH) is frequently seen in emergency departments. Secondary injury, such as subarachnoid hemorrhage associated myocardial injury (SAHMI), affects one third of survivors and contributes to poor outcomes. SAHMI is not attributed to ischemia from myocardial disease but can result in hypotension and arrhythmias. It is important that emergency nurses recognize which clinical presentation characteristics are predictive of SAHMI to initiate proper interventions. The aim of this study was to determine whether patients who present to the emergency department with clinical aSAH are likely to develop SAHMI, as defined by troponin I >=0.3 ng/mL. METHODS: This was a prospective descriptive study. SAHMI was defined as troponin I >=0.3 ng/mL. Predictors included demographics and clinical characteristics, severity of injury, admission 12-lead electrogardiogram (ECG), initial emergency department vital signs, and pre-hospital symptoms at time of aneurysm rupture. RESULTS: Of 449 patients, 126 (28%) had SAHMI. Patients with SAHMI were more likely to report seizures and unresponsiveness with significantly lower Glasgow coma score and higher proportion of Hunt and Hess grades 3 to 5 and Fisher grades III and IV (all P < .05). Patients with SAHMI had higher atrial and ventricular rates and longer QTc intervals on initial ECG (P < .05). On multivariable logistic regression, poor Hunt and Hess grade, report of prehospital unresponsiveness, lower admission Glasgow coma score, and longer QTc interval were significantly and independently predictive of SAHMI (P < .05). DISCUSSION: Components of the clinical presentation of subarachnoid hemorrhage to the emergency department predict SAHMI. Identifying patients with SAHMI in the emergency department can be helpful in determining surveillance and care needs and informing transfer unit care. Contribution to Emergency Nursing Practice. PMID- 28712528 TI - Breast cancer in the 21st century: from early detection to new therapies. AB - The analysis of the causes that have given rise to a change in tendency in the incidence and mortality rates of breast cancer in the last few decades generates important revelations regarding the role of breast screening, the regular application of adjuvant therapies and the change of risk factors. The benefits of early detection have been accompanied by certain adverse effects, even in terms of an excessive number of prophylactic mastectomies. Recently, several updates have been published on the recommendations in breast cancer screening at an international level. On the other hand, the advances in genomics have made it possible to establish a new molecular classification of breast cancer. Our aim is to present an updated overview of the epidemiological situation of breast cancer, as well as some relevant issues from the point of view of diagnosis, such as molecular classification and different strategies for both population-based and opportunistic screening. PMID- 28712529 TI - Dynamic simulation of knee-joint loading during gait using force-feedback control and surrogate contact modelling. AB - The aim of this study was to perform multi-body, muscle-driven, forward-dynamics simulations of human gait using a 6-degree-of-freedom (6-DOF) model of the knee in tandem with a surrogate model of articular contact and force control. A forward-dynamics simulation incorporating position, velocity and contact force feedback control (FFC) was used to track full-body motion capture data recorded for multiple trials of level walking and stair descent performed by two individuals with instrumented knee implants. Tibiofemoral contact force errors for FFC were compared against those obtained from a standard computed muscle control algorithm (CMC) with a 6-DOF knee contact model (CMC6); CMC with a 1-DOF translating hinge-knee model (CMC1); and static optimization with a 1-DOF translating hinge-knee model (SO). Tibiofemoral joint loads predicted by FFC and CMC6 were comparable for level walking, however FFC produced more accurate results for stair descent. SO yielded reasonable predictions of joint contact loading for level walking but significant differences between model and experiment were observed for stair descent. CMC1 produced the least accurate predictions of tibiofemoral contact loads for both tasks. Our findings suggest that reliable estimates of knee-joint loading may be obtained by incorporating position, velocity and force-feedback control with a multi-DOF model of joint contact in a forward-dynamics simulation of gait. PMID- 28712530 TI - Regulation of unregistered birth workers in Australia: Homebirth and public safety. AB - BACKGROUND: Australian midwives are regulated under the National Registration and Accreditation Scheme. Unregistered birth workers may provide midwifery services at homebirths without any regulatory oversight. To address this issue, several states have passed legislation enabling prohibition orders to be made (negative licensing) against unregistered health practitioners who fail to comply with a statutory code of conduct developed for those not covered by the National Scheme. AIM: To explore the consequences for the availability of birth choices for women that arise from the introduction of negative licensing. DISCUSSION: An analysis of the regulatory framework and recent cases of unregistered birth workers attending homebirths reveals problems with equitable access to homebirth support, arising from issues with professional indemnity insurance, geography, and poor integration with hospitals and the wider healthcare system. These problems contribute to women choosing to employ the services of unregistered birth workers. CONCLUSION: Negative licensing provides a useful additional tool for improving the safety of homebirths for mothers and babies, but it does not address the issues leading expectant parents to choose an unregistered birth worker to attend their births, and may contribute to an increase in high-risk behaviours, such as freebirthing. PMID- 28712531 TI - The role of tryptophan metabolism and food craving in the relationship between obesity and bipolar disorder. AB - BACKGROUND & AIMS: Individuals with bipolar disorder (BD) have a significantly increased risk of obesity-related conditions. The imbalance between food intake and energy expenditure is assumed to be a major risk factor for obesity in BD. This study analyzed food craving in relation to anthropometric, metabolic, and neurobiological parameters in a well-characterized cohort of euthymic individuals with BD. METHODS: One-hundred-thirty-five patients completed the Food-Craving Inventory assessing four categories of food craving (fat, fast-food, sweets and carbohydrate craving). Additionally, clinical, metabolic and anthropometric parameters were assessed. RESULTS: Higher levels of fat craving were observed in males, versus females, with BD. High levels of carbohydrate craving positively correlated with kynurenine and the kynurenine-to-tryptophan ratio. Higher serum nitrite and neopterin levels were related to fat craving. Parameters of fat metabolism (triglycerides, high-density lipoprotein) were associated with fat and fast-food craving. Anthropometric measures of obesity (e.g. body mass index, waist-to-hip-ratio) were not related to food craving. CONCLUSIONS: Overweight/obese individuals with BD show an increased driving of tryptophan down the kynurenine pathways, as indicated by an increase in the serum kynurenine-to tryptophan ratio. The driving of tryptophan down the kynurenine pathway is mediated by immune-inflammatory activity and stress. The correlation of increased kynurenine with food craving, especially carbohydrate craving, probably indicates a regulatory deficit in the maintenance of chronic inflammatory processes in obesity and BD. Food craving seems to be of clinical importance in the treatment of metabolic disturbances in BD, although not associated with anthropometric measures of obesity. Rather, food craving correlates with blood metabolic parameters and an increased activation of the kynurenine pathway, both of which are linked to higher affective symptomatology and the development of cardiovascular diseases. PMID- 28712532 TI - Influence of different intravenous lipid emulsions on growth, development and laboratory and clinical outcomes in hospitalised paediatric patients: A systematic review. AB - BACKGROUND & AIMS: Fats in the form of lipid emulsions (LEs) are an integral part of intravenous nutrition. The fatty acid composition of different LEs varies. The exact composition of a LE may influence cell and tissue function and clinical outcome. Currently, it is not clear which LE might be best for paediatric patients. We conducted a systematic review of the effects of different intravenous LEs in hospitalised paediatric patients. METHODS: Randomised controlled trials published in a peer reviewed journal, written in the English language, and comparing two or more different intravenous LEs in hospitalised paediatric patients were included. Data on outcomes of relevance (growth, development, laboratory and clinical outcomes) were extracted, collated and interpreted. RESULTS: Thirty-one articles involving 1522 infants or children were included. Most outcomes were not affected by the nature of the LE used. LEs containing fish oil, a source of omega-3 fatty acids, improved outcome of retinopathy of prematurity, decreased liver cholestasis and increased blood omega 3 fatty acid levels. LEs containing olive oil increased blood oleic acid level and had a cholesterol lowering effect. CONCLUSION: Blood fatty acids are influenced by the nature of the intravenous LE used in hospitalised paediatric patients. Most studies suggest limited differences in relevant laboratory or clinical outcomes or in growth in paediatric patients receiving different LEs, although several studies do find benefits from including fish oil or olive oil. There is a need for larger trials to fully evaluate the effects of the available LE types in hospitalised paediatric patients. PMID- 28712533 TI - Dose-volume toxicity modeling for de-intensified chemo-radiation therapy for HPV positive oropharynx cancer. AB - BACKGROUND AND PURPOSE: The aim is to determine the radiobiological parameters of four popular normal tissue complication probability (NTCP) models that describe the dose-response relations of salivary glands and pharyngeal constrictors to the severity of patient reported xerostomia and dysphagia, respectively 6 and 12months post chemo-radiotherapy, furthermore, to evaluate the goodness-of-fit of the NTCP models for different combinations of glands and constrictors. MATERIAL AND METHODS: Forty-three patients were treated on a prospective multi institutional phase II study (ClinicalTrials.gov, NCT01530997) assessing the efficacy of de-intensified chemoradiotherapy in patients with favorable risk, HPV associated oropharyngeal squamous cell carcinoma. All patients received 60Gy intensity modulated radiotherapy with concurrent weekly intravenous cisplatinum. All patients reported severity of their xerostomia and dysphagia (pre- and post treatment) using the patient reported outcome version of the CTCAE (PRO-CTCAE). A change in severity (from baseline) of >=2 was considered clinically meaningful. The Lyman-Kutcher-Burman (LKB), Relative Seriality (RS), Logit, and Relative Seriality Logit (RSL) NTCP models were used to fit the patients' dose/volume data to changes in PRO-CTCAE severity of xerostomia and dysphagia (from baseline to 6 and 12months post-treatment). The correlation of the models with the patient outcomes was performed for different combinations of salivary glands and different sections of pharyngeal constrictors. The goodness-of-fit of the different models was assessed through the area under the receiver operating characteristic curve (AUC), maximum of the log-likelihood function, normal error distribution and Akaike information criterion (AIC). RESULTS: The dose/volume metrics of the combined contralateral (parotid+submandibular) glands appear to correlate best with xerostomia, at both 6- and 12-months. Among the different sections of pharyngeal constrictors, the dose/volume metrics of the superior pharyngeal constrictors appear to correlate best with dysphagia at 6months. The AUC values ranged from 0.72 to 0.85 in the case of xerostomia and 0.73 to 0.74 in the case of dysphagia over the different models. The four NTCP models showed similar goodness-of-fit. The differences in AIC between the different models were less than 2 and ranged within 0.7 and 0.8 in the cases of xerostomia and dysphagia, respectively. The calculated parameters of the LKB model were D50=26.9Gy, m=0.63, n=1.0 for the combined contralateral glands at 12months and D50=62.0Gy, m=0.10, n=0.49 for the superior pharyngeal constrictors at 6months. CONCLUSIONS: The values of the parameters of four NTCP models were determined for salivary glands and pharyngeal constrictors. All four models could fit the clinical data equally well. The NTCP predictions of the combined contralateral glands and superior pharyngeal constrictors showed the best correlation with the patient reported outcomes of xerostomia and dysphagia, respectively. PMID- 28712534 TI - Effect of Isoniazid Resistance on the Tuberculosis Treatment Outcome. PMID- 28712535 TI - The UN adopts treaty to ban the use of nuclear weapons. PMID- 28712536 TI - Gene therapy for RPE65-mediated inherited retinal dystrophy completes phase 3. PMID- 28712538 TI - Lessons From the Lives of Celebrated Musicians: What Armstrong, Cash, Dylan, Ellington, Fitzgerald, and Sinatra Can Teach Us About Creative Resilience and Aging. AB - For a decade the author has delivered presentations using techniques from the humanities, principally biography, to elucidate themes of creative resilience and aging in the lives of well-known musicians, illustrated with excerpted images, audio clips, and videos. The goal has been to stimulate discussions about the potential for creative growth in later years, even in the face of the professional and personal setbacks inevitable in the course of life, with implications for clinical work with older adults and for ourselves as we age. This summary describes key take-home points that have recurred across these varied artists' stories and the interactions they have sparked with audiences and colleagues. PMID- 28712537 TI - Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial. AB - BACKGROUND: Phase 1 studies have shown potential benefit of gene replacement in RPE65-mediated inherited retinal dystrophy. This phase 3 study assessed the efficacy and safety of voretigene neparvovec in participants whose inherited retinal dystrophy would otherwise progress to complete blindness. METHODS: In this open-label, randomised, controlled phase 3 trial done at two sites in the USA, individuals aged 3 years or older with, in each eye, best corrected visual acuity of 20/60 or worse, or visual field less than 20 degrees in any meridian, or both, with confirmed genetic diagnosis of biallelic RPE65 mutations, sufficient viable retina, and ability to perform standardised multi-luminance mobility testing (MLMT) within the luminance range evaluated, were eligible. Participants were randomly assigned (2:1) to intervention or control using a permuted block design, stratified by age (<10 years and >=10 years) and baseline mobility testing passing level (pass at >=125 lux vs <125 lux). Graders assessing primary outcome were masked to treatment group. Intervention was bilateral, subretinal injection of 1.5 * 1011 vector genomes of voretigene neparvovec in 0.3 mL total volume. The primary efficacy endpoint was 1-year change in MLMT performance, measuring functional vision at specified light levels. The intention to-treat (ITT) and modified ITT populations were included in primary and safety analyses. This trial is registered with ClinicalTrials.gov, number NCT00999609, and enrolment is complete. FINDINGS: Between Nov 15, 2012, and Nov 21, 2013, 31 individuals were enrolled and randomly assigned to intervention (n=21) or control (n=10). One participant from each group withdrew after consent, before intervention, leaving an mITT population of 20 intervention and nine control participants. At 1 year, mean bilateral MLMT change score was 1.8 (SD 1.1) light levels in the intervention group versus 0.2 (1.0) in the control group (difference of 1.6, 95% CI 0.72-2.41, p=0.0013). 13 (65%) of 20 intervention participants, but no control participants, passed MLMT at the lowest luminance level tested (1 lux), demonstrating maximum possible improvement. No product related serious adverse events or deleterious immune responses occurred. Two intervention participants, one with a pre-existing complex seizure disorder and another who experienced oral surgery complications, had serious adverse events unrelated to study participation. Most ocular events were mild in severity. INTERPRETATION: Voretigene neparvovec gene replacement improved functional vision in RPE65-mediated inherited retinal dystrophy previously medically untreatable. FUNDING: Spark Therapeutics. PMID- 28712539 TI - Chronic treatment with angiotensin-converting enzyme inhibitor increases cardiac fibrosis in young rats submitted to early ovarian failure. AB - BACKGROUND: We investigated whether the treatment with enalapril maleate, combined with aerobic physical training, promotes positive effects on the autonomic balance, the morphology and the cardiac function in female rats submitted to early ovarian failure. METHODS: Thirty-five female Wistar rats, ovariectomized at 10weeks of age, were assigned into Ovariectomized rats (OVX) and Ovariectomized rats treated with enalapril maleate (OVX-EM, 10mg-1.kg-1.d-1) Each group was subdivided into sedentary and trained (aerobic swimming training for 10weeks). All animals were submitted to a) double pharmacological autonomic blockade, b) study of morphology and cardiac function by echocardiography, and c) analysis of cardiac fibrosis. RESULTS: The OVX-EM sedentary group showed a significant increase in cardiac fibrosis, relative heart weight, interventricular septum thickness and increased sympathetic participation and reduced participation of the vagal tone in the determination of the basal heart rate when compared to the OVX sedentary group. Physical training reduced cardiac fibrosis in both groups, however, with less intensity in the OVX-EM group. It also increased the absolute and relative heart weight and the end-systolic volume. Finally, the OVX-EM trained group showed higher values for left ventricular end systolic volume and lower values for ejection fraction and shortening fraction than the sedentary OVX-EM group. CONCLUSION: Enalapril maleate exacerbated cardiac fibrosis and increased sympathetic participation in the basal heart rate determination, without significantly affecting the cardiac function. Aerobic physical training did not change the cardiac autonomic control, but reduced cardiac fibrosis and had little effect on the cardiac function. PMID- 28712540 TI - Aqueous humor tyrosinase activity is indicative of iris melanocyte toxicity. AB - Antibiotics such as fluoroquinolones (FQLs) are commonly used to treat ocular infections but are also known to cause dermal melanocyte toxicity. The release of dispersed pigments from the iris into the aqueous humor has been considered a possible ocular side effect of the systemic administration of FQLs such as Moxifloxacin, and this condition is known as bilateral acute iris transillumination (BAIT). Bilateral acute depigmentation of iris (BADI) is a similar condition, with iris pigment released into the aqueous, but it has not been reported as a side effect of FQL. Iris pigments are synthesized by the melanogenic enzyme tyrosinase (TYR) and can be detected but not quantified by using slit-lamp biomicroscopy. The correlation between dispersed pigments in the aqueous and the extent of melanocyte toxicity due to topical antibiotics in vivo is not well studied. Here, we aimed to study the effect of topical FQLs on iris tissue, the pigment release in the aqueous humor and the development of clinically evident iris atrophic changes. We evaluated this process by measuring the activity of TYR in the aqueous humor of 82 healthy eyes undergoing cataract surgery following topical application of FQLs such as Moxifloxacin (27 eyes, preservative-free) or Ciprofloxacin (29 eyes, with preservative) or the application of non-FQL Tobramycin (26 eyes, with preservative) as a control. In addition, the patients were questioned and examined for ocular side effects in pre- and post-operative periods. Our data showed a significantly higher mean TYR activity in the aqueous humor of Ciprofloxacin-treated eyes compared to Moxifloxacin- (preservative free, p < 0.0001) or Tobramycin-treated eyes (p < 0.0001), which indicated that few quinolones under certain conditions are toxic to the iris melanocytes. However, the reduced TYR activity in the aqueous of Moxifloxacin-treated eyes was possibly due to the presence of a higher drug concentration, which inhibits TYR activity. Consistently, immunoblotting analysis of the aqueous humor from both Ciprofloxacin- and Moxifloxacin-treated eyes showed the presence of soluble TYR enzyme, thus reflecting its toxicity to iris melanocytes and corresponding to its activity in the aqueous humor. Intriguingly, none of these patients developed any clinically appreciable ocular side effects characteristic of BAIT or BADI. Overall, our results suggest that topical antibiotics cause different levels of iris melanocyte toxicity, releasing dispersed pigments into the aqueous humor, which can be measured through TYR enzyme activity. Hence, we conclude that topical FQLs may cause subclinical toxicity to the iris melanocytes but may not be the sole cause of the development of BAIT or BADI. PMID- 28712541 TI - Mechanical demands on the lower back in patients with non-chronic low back pain during a symmetric lowering and lifting task. AB - : There is limited information in the literature related to the lower back loading in patients with LBP, particularly those with non-chronic LBP. Toward addressing such a research gap, a case-control study was conducted to explore the differences in lower back mechanical loads between a group of females (n=19) with non-chronic, non-specific LBP and a group of asymptomatic females (n=19). The differences in lower back mechanical loads were determined when participants completed one symmetric lowering and lifting of a 4.5kg load at their preferred cadence. The axial, shearing, and moment components of task demand at the time of peak moment component as well as measures of peak trunk kinematics were analyzed. Patient vs. asymptomatic group performed the task with smaller peak thoracic rotation and peak lumbar flexion. While no differences in the moment component of task demand on the lower back between the patients and controls were found, the shearing (40-50 age group) and axial components of task demand were, respectively, larger and smaller in patients vs. CONTROLS: Whether alterations in lower back loads in patients with non-chronic LBP are in response to pain or preceded the pain, the long-term exposure to abnormal lower back mechanics may adversely affect spinal structure and increase the likelihood of further injury or pain. Therefore, the underlying reason(s) as well as the potential consequence(s) of such altered lower back mechanics in patients with non-chronic LBP should to be further investigated. PMID- 28712542 TI - Investigating the effect of cell substrate on cancer cell stiffness by optical tweezers. AB - The mechanical properties of cells are influenced by their microenvironment. Here we report cell stiffness alteration by changing the cell substrate stiffness for isolated cells and cells in contact with other cells. Polydimethylsiloxane (PDMS) is used to prepare soft substrates with three different stiffness values (173, 88 and 17kPa respectively). Breast cancer cells lines, namely HBL-100, MCF-7 and MDA MB-231 with different level of aggressiveness are cultured on these substrates and their local elasticity is investigated by vertical indentation of the cell membrane. Our preliminary results show an unforeseen behavior of the MDA-MB-231 cells. When cultured on glass substrate as isolated cells, they are less stiff than the other two types of cells, in agreement with the general statement that more aggressive and metastatic cells are softer. However, when connected to other cells the stiffness of MDA-MB-231 cells becomes similar to the other two cell lines. Moreover, the stiffness of MDA-MB-231 cells cultured on soft PDMS substrates is significantly higher than the stiffness of the other cell types, demonstrating thus the strong influence of the environmental conditions on the mechanical properties of the cells. PMID- 28712543 TI - Influence of overlapping pattern of multiple overlapping uncovered stents on the local mechanical environment: A patient-specific parameter study. AB - BACKGROUND: Multiple overlapping uncovered stents (MOUS) system has shown potentials in managing complex aortic aneurysms with side branches involvement. It promotes the development of thrombus by modulating local flow pattern that reduces the wall tension, while maintaining patency of side branches. However the modulation of local hemodynamic parameters depends on various factors that have not been assessed comprehensively. METHODS: Aneurysm 3D geometry was reconstructed based on CT images. One-way fluid-structure interaction analysis was performed to quantify structural stress concentration in the wall, and changes of blood velocity, wall shear stress (WSS), oscillatory shear index (OSI), relative residence time (RRT) and pressure in the sac due to the stent deployment. RESULTS: High structural stress concentration due to stent deployment was found in the landing zone and it increased linearly with the number of stents deployed. The wall tension in the sac was unaffected by the stent deployment. Stress within the wall was insensitive to the different overlapping pattern. After one stent was deployed, the mean flow velocity in the sac reduced by 36.4%. The deployment of the 2nd stent further reduced the mean sac velocity by 10%. WSS decreased while both OSI and RRT increased after stent deployment, however pressure in the sac remained nearly unchanged. Except for the cases with complete stents struts alignment, different overlapping pattern had little effect on flow parameters. CONCLUSIONS: Mechanical parameters modulated by the MOUS are insensitive to different overlapping pattern suggesting that endovascular procedure can be performed with less attention to the overlapping pattern. PMID- 28712544 TI - The effect of leg dominance and landing height on ACL loading among female athletes. AB - Female athletes are more prone to anterior cruciate ligament (ACL) injury. A neuromuscular imbalance called leg dominance may provide a biomechanical explanation. Therefore, the purpose of this study was to compare the side-to-side lower limb differences in movement patterns, muscle forces and ACL forces during a single-leg drop-landing task from two different heights. We hypothesized that there will be significant differences in lower limb movement patterns (kinematics), muscle forces and ACL loading between the dominant and non-dominant limbs. Further, we hypothesized that significant differences between limbs will be present when participants land from a greater drop-landing height. Eight recreational female participants performed dominant and non-dominant single-leg drop landings from 30 to 60cm. OpenSim software was used to develop participant specific musculoskeletal models and to calculate muscle forces. We also predicted ACL loading using our previously established method. There were no significant differences between dominant and non-dominant leg landing except in ankle dorsiflexion and GMED muscle forces at peak GRF. Landing from a greater height resulted in significant differences among most kinetics and kinematics variables and ACL forces. Minimal differences in lower-limb muscle forces and ACL loading between the dominant and non-dominant legs during single-leg landing may suggest similar risk of injury across limbs in this cohort. Further research is required to confirm whether limb dominance may play an important role in the higher incidence of ACL injury in female athletes with larger and sport-specific cohorts. PMID- 28712545 TI - Viscoelasticity of multicellular surfaces. AB - Various modeling approaches have been applied to describe viscoelasticity of multicellular surfaces. The viscoelasticity is considered within three time regimes: (1) short time regime for milliseconds to seconds time scale which corresponds to sub-cellular level; (2) middle time regime for several tens of seconds to several minutes time scale which corresponds to cellular level; and (3) long time regime for several tens of minutes to several hours time scale which corresponds to supra-cellular level. Short and middle time regimes have been successfully elaborated in the literature, whereas long time viscoelasticity remains unclear. Long time regime accounts for collective cell migration. Collective cell migration could induce uncorrelated motility which has an impact to energy storage and dissipation during cell surface rearrangement. Uncorrelated motility influences: (1) volume fraction of migrating cells, (2) distribution of migrating cells, (3) shapes of migrating cell groups. These parameters influence mechanical coupling between migrating and resting subpopulations and consequently the constitutive model for long time regime. This modeling consideration indicates that additional experimental work is needed to confirm the feasibility of constitutive models which have been applied in literature for long time regime as: (1) relaxation of stress and strain, (2) storage and loss moduli as the function of time, (3) distribution of migrating cells. PMID- 28712546 TI - A Novel Target Antigen for the Treatment of Acute Myeloid Leukemia by CAR T Cells. PMID- 28712547 TI - Pilot study to determine whether microbial contamination levels in hospital washrooms are associated with hand-drying method. PMID- 28712548 TI - Excess mortality between 2007 and 2014 among patients with Clostridium difficile infection: a French health insurance database analysis. AB - BACKGROUND: The impact of Clostridium difficile infection (CDI) on mortality is controversial. AIM: To assess excess mortality due to CDI in France. METHOD: Two cohorts of patients with CDI and a cohort of matched controls were extracted from a 1% representative sample of subjects covered by the general health insurance system in France (Echantillon Generaliste de Beneficiaires database, 660,000 patients). The CDI patients were hospitalized with CDI as a principal diagnosis or an associated diagnosis between 2007 and 2014, but not in 2006. Controls were patients hospitalized between 2007 and 2014 but not hospitalized with CDI between 2006 and 2014. The one-year incidence of deaths between 2007 and 2014 was estimated and compared with that of a propensity score (PS)-matched control group with no CDI (two controls per case). The PS was calculated with the following variables: age; sex; Charlson Comorbidity Index score; duration of stay; year of index stay; and main comorbidities. Cox and Poisson models were used to estimate the increased risk of death while adjusting for PS. Sensitivity analyses (timeframe, diarrhoea, recurrent hospitalization for CDI) were used to explore the robustness of the results. FINDINGS: In total, 482 patients who had been infected with C. difficile were matched with 964 controls. A significantly higher risk of death was observed among the subjects with CDI, with a non-adjusted hazard ratio of 1.65 [95% confidence interval (CI) 1.33-2.04] and an adjusted ratio of 1.58 (95% CI 1.27-1.97). The adjusted relative risk of death was 1.78 (95% CI 1.18-2.70]) at 28 days, 1.52 (95% CI 1.17-1.98) at three months, 1.52 (95% CI 1.20-1.93) at six months and 1.64 (95% CI 1.32-2.03) at 12 months. Sensitivity analyses produced similar results; the hazard ratio ranged from 1.53 to 1.86, and was always statistically significant. CONCLUSION: CDI is responsible for excess mortality after taking age, sex, comorbidities and length of hospital stay into account. PMID- 28712549 TI - Determination of trace amounts of G-type nerve agents in aqueous samples utilizing "in vial" instantaneous derivatization and liquid chromatography-tandem mass spectrometry. AB - A methodology for sensitive determination of sarin (GB), soman (GD) and cyclosarin (GF) chemical warfare agents in aqueous media was developed. The method incorporates direct derivatization with 2-[(dimethylamino)methyl]phenol (2 DMAMP), a commercially available, water-soluble reagent, followed by LC-ESI-MS/MS analysis in the positive ion mode. Five derivatization agents were characterized for their MS/MS fragmentation pattern, and their reaction time, temperature and derivatization-reagent amount were optimized. The developed derivatization reaction is simple, fast (1min) and proceeds at ambient temperature. Sample preparation consists of only the addition of the reagent directly into an injection vial prior to LC-ESI(+)-MS/MS analysis. All 2-DMAMP derivatives were stable for at least 48h and had unique tandem mass spectra characterized by common product ions at m/z 230 and 185. Compared with conventional GC-MS or LC-MS methods, simplicity, better sensitivity and informative MS/MS spectra were achieved by this method. Limits of detection (LODs), identification (LOIs), and quantification (LOQs) were determined in tap water and found to be 1pg/ml, 4pg/ml and 4pg/ml respectively. The proposed methodology is appropriate for routine evaluation of contaminated water supplies and has the advantage of a simultaneous analysis of both derivatized G-nerve agents and their intact hydrolysis products within a single LC-MS analysis. PMID- 28712550 TI - Towards an automatic lab-on-valve-ion mobility spectrometric system for detection of cocaine abuse. AB - A lab-on-valve miniaturized system integrating on-line disposable micro-solid phase extraction has been interfaced with ion mobility spectrometry for the accurate and sensitive determination of cocaine and ecgonine methyl ester in oral fluids. The method is based on the automatic loading of 500MUL of oral fluid along with the retention of target analytes and matrix clean-up by mixed-mode cationic/reversed-phase solid phase beads, followed by elution with 100MUL of 2 propanol containing (3% v/v) ammonia, which are online injected into the IMS. The sorptive particles are automatically discarded after every individual assay inasmuch as the sorptive capacity of the sorbent material is proven to be dramatically deteriorated with reuse. The method provided a limit of detection of 0.3 and 0.14MUgL-1 for cocaine and ecgonine methyl ester, respectively, with relative standard deviation values from 8 till 14% with a total analysis time per sample of 7.5min. Method trueness was evaluated by analyzing oral fluid samples spiked with cocaine at different concentration levels (1, 5 and 25MUgL-1) affording relative recoveries within the range of 85+/-24%. Fifteen saliva samples were collected from volunteers and analysed following the proposed automatic procedure, showing a 40% cocaine occurrence with concentrations ranging from 1.3 to 97MUgL-1. Field saliva samples were also analysed by reference methods based on lateral flow immunoassay and gas chromatography-mass spectrometry. The application of this procedure to the control of oral fluids of cocaine consumers represents a step forward towards the development of a point-of care cocaine abuse sensing system. PMID- 28712551 TI - Facile synthesis of thiol-polyethylene glycol functionalized magnetic titania nanomaterials for highly efficient enrichment of N-linked glycopeptides. AB - As protein N-glycosylation involved in generation and development of various cancers and diseases, it is vital to capture glycopeptides from complex biological samples for biomarker discovery. In this work, by taking advantages of the interaction between titania and thiol groups, thiol-polyethylene glycol functionalized magnetic titania nanomaterials (denoted as Fe3O4@TiO2@PEG) were firstly fabricated as an excellent hydrophilic adsorbent of N-linked glycopeptides. On one hand, the special interaction of titanium-thiol makes the synthetic manipulation simple and provides a new idea for design and synthesis of novel nanomaterials; on the other hand, strong magnetic response could realize rapid separation and the outstanding hydrophilicity of polyethylene glycol makes Fe3O4@TiO2@PEG nanomaterials show superior performance for glycopeptides enrichment with ultralow limit of detection (0.1mol/MUL) and high selectivity (1:100). As a result, 24 and 33 glycopeptides enriched from HRP and IgG digests were identified respectively by MALDI-TOF MS, and 300 glycopeptides corresponding to 106 glycoproteins were recognized from merely 2MUL human serum, indicating a great potential of Fe3O4@TiO2@PEG nanomaterials for glycoproteomic research. PMID- 28712552 TI - Insights into head-column field-amplified sample stacking: Part II. Study of the behavior of the electrophoretic system after electrokinetic injection of cationic compounds across a short water plug. AB - Part I on head-column field-amplified sample stacking comprised a detailed study of the electrokinetic injection of a weak base across a short water plug into a phosphate buffer at low pH. The water plug is converted into a low conductive acidic zone and cationic analytes become stacked at the interface between this and a newly formed phosphoric acid zone. The fundamentals of electrokinetic processes occurring thereafter were studied experimentally and with computer simulation and are presented as part II. The configuration analyzed represents a discontinuous buffer system. Computer simulation revealed that the phosphoric acid zone at the plug-buffer interface becomes converted into a migrating phosphate buffer plug which corresponds to the cationically migrating system zone of the phosphate buffer system. Its mobility is higher than that of the analytes such that they migrate behind the system zone in a phosphate buffer comparable to the applied background electrolyte. The temporal behaviour of the current and the conductivity across the water plug were monitored and found to reflect the changes in the low conductivity plug. Determination of the buffer flow in the capillary revealed increased pumping caused by the mismatch of electroosmosis within the low conductivity plug and the buffer. This effect becomes elevated with increasing water plug length. For plug lengths up to 1% of the total column length the flow quickly drops to the electroosmotic flow of the buffer and simulations with experimentally determined current and flow values predict negligible band dispersion and no loss of resolution for both low and large molecular mass components. PMID- 28712553 TI - Implications of phase ratio for maximizing peak capacity in comprehensive two dimensional gas chromatography time-of-flight mass spectrometry. AB - The relationship between the phase ratio, beta, of the primary (1D) and secondary (2D) separation dimensions of comprehensive two-dimensional (2D) gas chromatography (GC*GC) separations, and the implications of beta on realization of maximal 2D peak capacity, nc,2D, are examined. A GC*GC chromatographic system with time-of-flight mass spectrometry, TOFMS, was otherwise held constant for the separation of a multi-component test mixture spanning a range of chemical functionalities, while only the beta of the two analytical columns were changed, 1beta for 1D and 2beta for 2D. Six column sets were studied using common, commercially available beta values. The beta ratio, betaR=1beta/2beta, is defined as a quantitative metric to facilitate this study. It is demonstrated that betaR plays a key role in maximizing nc,2D. Overall, betaR substantially affected nc,2D by influencing retention factors on the 2D column, 2k, and thereby changing the modulation period, PM, necessary for proper 2D column separations. The necessary changes to PM modify the modulation ratio, MR, which affects the 1D column peak widths and 1nc due to the impact of undersampling. Through changes to 1beta, the range of 2k can be controlled, with subsequent effects to both 2nc and 1nc. These effects were opposite in direction, such that improvements to 2nc may result in declines in 1nc. It is observed that due to the pseudo-isothermal nature of the 2D separation, there are diminishing returns to extending the 2nc at the cost of 1nc. In this particular study, column set 3 (1D: 20m length, 250MUm i.d., 0.25MUm film; 2D: 2m, 180MUm i.d., 0.2MUm film; betaR=1.11) with a PM of 3s provided the highest theoretical nc,2D of ~8200, though this was at a relatively low MR of ~1.8. Column set 2 (1D: 20m length, 250MUm i.d., 0.5MUm film; 2D: 2m, 180MUm i.d., 0.2MUm film; betaR=0.56) with a PM of 1.5s provided a high theoretical nc,2D of ~5800, at a much higher MR of ~3.7. Though column set 2 had a lesser total peak capacity than column set 3, its higher MR suggests that by improving the 1D column efficiency (i.e., narrowing the 1D column peak widths) to improve 1nc, can result in an increased theoretical nc,2D. PMID- 28712554 TI - Improved coverage of naphthenic acid fraction compounds by comprehensive two dimensional gas chromatography coupled with high resolution mass spectrometry. AB - This study reports the first application of comprehensive two-dimensional gas chromatography coupled to a high-resolution quadrupole time-of-flight mass spectrometer (GC*GC/HRQTOF-MS) for the characterization of naphthenic acid fraction compounds (NAFCs) from the Alberta Oil Sands. High resolution mass spectrometry (HRMS) significantly increased the coverage of NAFCs in the mixture and allowed the differentiation of NAFCs from several chemical classes. It was demonstrated that GC*GC, in combination with the high mass accuracy and precision of the HRQTOF-MS, could distinguish chemical species with the C3 vs SH4 mass split at a much lower resolving power than required with direct infusion experiments. Mass defect plots were useful for visualizing the complex datasets generated by GC*GC/HRQTOF-MS and led to the identification of 1105 chemical species with unique elemental compositions (<5ppm mass accuracy). Mass defect plots were shown to be a powerful screening tool and enabled the detection of extensive isomer series from the SO2 chemical class, some of which have not been previously reported in oil sands related samples. The GC*GC/HRQTOF-MS approach is expected to improve NAFC monitoring programs since the technique allows the qualitative analysis of individual NAFCs and provides unique fingerprints via isomer distributions which may assist in future fingerprinting studies. PMID- 28712555 TI - Space charge effects and aberrations on electron pulse compression in a spherical electrostatic capacitor. AB - The effects of space charge, aberrations and relativity on temporal compression are investigated for a compact spherical electrostatic capacitor (alpha-SDA). By employing the three-dimensional (3D) field simulation and the 3D space charge model based on numerical General Particle Tracer and SIMION, we map the compression efficiency for a wide range of initial beam size and single-pulse electron number and determine the optimum conditions of electron pulses for the most effective compression. The results demonstrate that both space charge effects and aberrations prevent the compression of electron pulses into the sub ps region if the electron number and the beam size are not properly optimized. Our results suggest that alpha-SDA is an effective compression approach for electron pulses under the optimum conditions. It may serve as a potential key component in designing future time-resolved electron sources for electron diffraction and spectroscopy experiments. PMID- 28712556 TI - Serosurvey for Crimean-Congo hemorrhagic fever virus infections in ruminants in Katanga province, Democratic Republic of the Congo. AB - Crimean-Congo hemorrhagic fever virus (CCHFV) has been detected in many African countries. Unfortunately, little is known about the current CCHFV situation in most of those countries including the Democratic Republic of the Congo (DRC). In over 50 years, three human CCHF cases have been detected in DRC but no seroepidemiological investigation was performed so far. To determine the prevalence of CCHFV-specific antibodies we tested 838 serum samples of cattle, goat and sheep from the southern province Katanga, DRC. The detected seroprevalence in ruminants was 1.6% ranging from 0.4% to 3.4% between the two sampling sites, Kamina and Lubumbashi. The low prevalence indicates only sporadic introduction of CCHFV into this part of the country. DRC is a very large country and the study was performed only at two locations in one province; therefore, the investigations can be only a starting point for further epidemiological activities. PMID- 28712557 TI - Age modulates the relationship between platelet-to-lymphocyte ratio and coronary artery disease. AB - BACKGROUND: Thrombocytosis and inflammation are vital elements in the pathogenesis of atherosclerosis. The platelet-to-lymphocyte ratio (PLR) is a novel biomarker that combines these parameters and has been shown to be associated with cardiovascular disease (CVD). This study aimed to determine whether PLR correlates with coronary artery disease (CAD) in high-risk patients, and if the relationship is affected by age. METHODS: Consecutive patients referred for coronary angiogram were evaluated (n=822). with 608 patients demonstrating CAD, compared to 214 patients with normal coronary arteries. Patients were stratified into premature CAD (age<55) and non-premature CAD (age>=55). High and low PLR groups were defined as admission PLR in the highest (>=146.7) and lower two tertiles (<146.7) respectively. Multivariate logistic regression was undertaken to adjust for traditional cardiovascular risk factors. RESULTS: In univariate analysis, high PLR negatively correlated with premature CAD (OR 0.45, 95%CI 0.23-0.87, P=0.017), while its association with CAD in older patients did not reach statistical significance (OR 1.32, 95%CI 0.89-1.97, P=0.170). After adjustment for traditional risk factors, high PLR was significantly associated with increased CAD in older patients (OR 2.22, 95%CI 1.28-3.82, P=0.004) but decreased premature CAD (OR 0.31, 95%CI 0.11-0.87, P=0.026). CONCLUSIONS: There is an age-related effect on the correlation between PLR and CAD. While high PLR was an independent marker of CAD in older high-risk patients, it was negatively correlated with premature CAD in younger patients. PLR is widely available and inexpensive, and could be used in highlighting patients at high risk for CAD. PMID- 28712558 TI - Catheter ablation of accessory pathway: 14-year trends in utilization and complications in adults in the United States. AB - BACKGROUND: The aim of this study was to determine the temporal trends in utilization of catheter ablation of accessory pathways in the United States. METHODS: All patients from the Nationwide Inpatient Sample (NIS) >=18years of age with a primary diagnosis of anomalous atrioventricular excitation syndrome (International Classification of Diseases, Ninth Edition, Clinical Modification [ICD-9-CM] code 426.7) were included in the study. Patients who underwent catheter ablation were identified using ICD-9-CM procedure code 37.34. Patients with a concomitant diagnosis of atrial fibrillation, atrial flutter, atrial tachycardia or ventricular arrhythmias were excluded from the analysis. Annual hospital volume was identified using unique hospital identification number and was divided into tertiles for further analysis. RESULTS: A total of 11,601 catheter ablations for anomalous atrioventricular excitation syndrome were studied from 1998 to 2011. The mean length of stay was 1.8days (median 1day). The utilization trends of accessory pathway ablation have steadily declined from 3.9 ablation procedures/million US population in 1998-1999 to 2.5 ablation procedures/million US population in 2010-2011. The second tertile (adjusted OR 0.41; 95% CI 0.20-0.83, p=0.01) and third tertile (adjusted OR 0.39; 95% CI 0.18 0.85, p=0.02) of hospital volume were associated with reduction in cardiac complications as compared to first tertile of hospital volume. Advanced age (OR 1.02, 95% CI 1.01-1.04, p=0.002) was independent predictor of cardiac complications. There were no in-hospital deaths. CONCLUSION: Despite decline in ablation trends, it still remains a relatively safe procedure associated with low morbidity and no mortality. PMID- 28712559 TI - Impact of percutaneous mitral valvuloplasty on left ventricular function in patients with mitral stenosis assessed by 3D echocardiography. AB - BACKGROUND: The status of intrinsic left ventricular (LV) contractility in patients with isolated rheumatic mitral stenosis (MS) has been debated. The acute changes in loading conditions after percutaneous mitral valvuloplasty (PMV) may affect LV performance. We aimed to examine the acute effects of PMV on LV function and identify factors associated with LV ejection fraction (LVEF) changes, and determinants of long-term events following the procedure. METHODS: One hundred and forty-two patients who underwent PMV for symptomatic rheumatic MS (valve area of 0.99+/-0.3cm2) were prospectively enrolled. LV volumes and LVEF were measured by three-dimensional (3D) echocardiography. Long-term outcome was a composite endpoint of death, mitral valve (MV) replacement, repeat PMV, new onset of atrial fibrillation, and stroke. RESULTS: The mean age was 42.3+/-12.1years, and 125 patients were women (88%). After PMV, LVEF increased significantly (51.4 vs 56.5%, p<0.001), primary due to a significant increase in LV end-diastolic volume (65.8mL vs 67.9mL, p=0.002), and resultant increase in the stroke volume (33.9mL vs 39.6mL, p<0.001). Changes in cardiac index and systolic pulmonary artery pressure were associated with LVEF changes after PMV. During a mean follow up period of 30.8months, 28 adverse clinical events were observed. Postprocedural mitral regurgitation, MV area, and mean gradient were independent predictors of composite endpoints. CONCLUSIONS: In patients with rheumatic MS, PMV resulted in a significant improvement in LV end-diastolic volume, stroke volume and consequently increased in LVEF. Changes in cardiac index and systolic pulmonary artery pressure were associated with LVEF changes after PMV. The predictors of long-term adverse events following PMV were post-procedural variables, including mitral regurgitation, valve area, and mean gradient. PMID- 28712560 TI - Relation between severity of myocardial bridge and vasospasm. AB - BACKGROUND: Myocardial bridge (MB) has been reported to induce cardiac complications including coronary vasospasm. Although MB has some anatomical and morphological variations, the association of these variations with vasospasm is unclear. The aim of this study was to investigate the relation between morphological severity of MB and vasospasm induced by acetylcholine (ACh) provocation test. METHODS: A total of 392 patients without coronary stent in the left anterior descending artery (LAD) undergoing intracoronary ACh provocation test were included. Angiographic coronary artery vasospasm was defined as total or subtotal occlusion induced by ACh provocation. MB was identified on coronary angiography as a milking effect. Total bridged length and maximum percent systolic compression of MB in the LAD were analyzed quantitatively. RESULTS: MBs in the LAD were identified in 140 patients (36%), mostly in the mid segment. Patients with MB in the LAD had greater number of provoked vasospasm in the LAD and positive ACh provocation test compared to those without. The bridged length positively correlated with percent systolic compression of MB (r=0.37, p<0.001). In the receiver operating characteristic curve analysis, both bridged length and percent systolic compression of MB significantly predicted the provoked LAD spasm (AUC 0.74, p<0.001, and AUC 0.68, p<0.001). Multivariate regression analysis demonstrated these factors as independent predictors for provoked LAD spasm. CONCLUSION: MB, especially morphologically severe MB, may induce greater coronary vasospasm. PMID- 28712561 TI - Head to head comparison of intact and C-terminal fibroblast growth factor 23 in heart failure patients with reduced ejection fraction. PMID- 28712562 TI - Abnormal right atrial performance in repaired tetralogy of Fallot: A CMR feature tracking analysis. AB - BACKGROUND: We hypothesized that right atrial (RA) performance is abnormal in repaired tetralogy of Fallot (TOF). METHODS: TOF patients were prospectively enrolled for cardiovascular magnetic resonance (CMR), echocardiography and exercise stress following a standardized 14-center protocol. Peak RA longitudinal strain (RALS) and right ventricular longitudinal strain (RVLS) were measured using CMR feature tracking (FT) and correlated to RA and RV end diastolic volumes (EDVi) and ejection fraction (EF). RESULTS: The cohort had 311 subjects: 171 TOF (94 male, age 18.2+/-8years) and 140 healthy controls (69 male, 16.4+/-11years). RAEDVi, RALS, RVEDVi, RVLS, RAEF, and RVEF in TOF were 60.8+/-17.1ml/m2, 13.6+/ 5.7%, 120.3+/-30.3ml/m2, 12.3+/-4.2%, 32.5+/-9.9% and 51.2+/-8.4% and differed from respective indices in controls: 51.7+/-15.7ml/m2, 27+/-10.1%, 74+/ 19.0ml/m2, 18.5+/-5.3%, 54+/-8% and 62.5+/-5.5% (p<0.001). RAEDVi and RALS correlated with RVLS (p=0.004, <0.001, r=0.2,0.3). RAEDVi was higher in older TOF, while RALS did not increase with age. RAEDVi but not RALS correlated with RV systolic pressure(r=0.2, 0). Neither RAEDVi nor RALS was associated with tricuspid regurgitation grade or peak oxygen uptake (r=0.1, 0). Positive correlation was observed for RVEDVi with RAEDVi (p=0.035, r=0.2) and a trend toward negative correlation with RALS (p=0.09, r=0.1). CONCLUSION: RALS, RAEDVi and RAEF are abnormal in TOF. Reduced RALS indicates decreased RA reservoir function. Because they correlate with other functional RV indices, these abnormalities may represent RA diastolic burden from chronic RV dysfunction in TOF. The young cohort age might explain the absence of RALS correlation to tricuspid regurgitation and peak oxygen uptake. PMID- 28712563 TI - Trends in comorbidity in patients hospitalised for cardiovascular disease. AB - BACKGROUND: We determined trends over time in cardiovascular and non cardiovascular comorbidity in patients hospitalised for cardiovascular disease (CVD). METHODS: The Dutch nationwide hospital register was used to identify patients hospitalised for CVD during 2000-2010. Comorbidity was defined as a previous hospital admission for CVD other than the index CVD, cancer, diabetes, musculoskeletal and connective tissue disorders, respiratory disorders, thyroid gland disorders, kidney disorders and dementia in the five years previous to hospital admittance for the index CVD. Trends were calculated in strata of age and sex and for different types of CVD: coronary heart disease (CHD), cerebrovascular disease (CVA), heart failure (HF) and peripheral arterial disease (PAD). RESULTS: We identified 2,397,773 admissions for CVD between 2000 and 2010. Comorbidity was present in 38%. In HF, PAD, CHD and CVA this was 54%, 46%, 40%, and 32%, respectively. Between 2000 and 2010, the percentage of patients with comorbidity increased (+1.1%), this increase was most pronounced in patients >=75years (+3.0%). Cardiovascular disease was the most frequent comorbid condition, though became less prevalent over time (men -5%; women: -2%), whereas non-cardiovascular comorbidity increased in men (+4%), and remained similar in women (-1%). Cancer was the most common non-cardiovascular comorbid condition and increased in men and women (men: +5%; women: +4%). CONCLUSIONS: Comorbid conditions are highly prevalent in patients hospitalised for CVD, especially HF and PAD patients. In older patients, prevalences increased over time. Cardiovascular diseases were the most common comorbid condition, though the prevalence decreased over the study period whereas the prevalence of cancer increased. PMID- 28712564 TI - Autonomic dysfunction plays a decisive role in the arrhythmia initiation, whereas metabolic disorders facilitate further atrial remodeling in antipsychotic-related atrial fibrillation. PMID- 28712565 TI - Circadian Clock Involvement in Zooplankton Diel Vertical Migration. AB - Biological clocks are a ubiquitous ancient and adaptive mechanism enabling organisms to anticipate environmental cycles and to regulate behavioral and physiological processes accordingly [1]. Although terrestrial circadian clocks are well understood, knowledge of clocks in marine organisms is still very limited [2-5]. This is particularly true for abundant species displaying large scale rhythms like diel vertical migration (DVM) that contribute significantly to shaping their respective ecosystems [6]. Here we describe exogenous cycles and endogenous rhythms associated with DVM of the ecologically important and highly abundant planktic copepod Calanus finmarchicus. In the laboratory, C. finmarchicus shows circadian rhythms of DVM, metabolism, and most core circadian clock genes (clock, period1, period2, timeless, cryptochrome2, and clockwork orange). Most of these genes also cycle in animals assessed in the wild, though expression is less rhythmic at depth (50-140 m) relative to shallow-caught animals (0-50 m). Further, peak expressions of clock genes generally occurred at either sunset or sunrise, coinciding with peak migration times. Including one of the first field investigations of clock genes in a marine species [5, 7], this study couples clock gene measurements with laboratory and field data on DVM. While the mechanistic connection remains elusive, our results imply a high degree of causality between clock gene expression and one of the planet's largest daily migrations of biomass. We thus suggest that circadian clocks increase zooplankton fitness by optimizing the temporal trade-off between feeding and predator avoidance, especially when environmental drivers are weak or absent [8]. PMID- 28712567 TI - Perceived Object Trajectory Is Influenced by Others' Tracking Movements. AB - In social interactions, it is highly salient to us where other people are looking. The ability to recover this information is critical to typical social development, helping us to coordinate our attention and behavior with others and understand their intentions and mental states [1-3]. The depth and direction in which another individual is fixating are specified jointly by their head position, eye deviation, and binocular vergence [4, 5]. It is hereto unknown, however, whether this dynamic visual information about others' focus of attention affects how we ourselves see the world. Here we show that the perceived depth and movement of physical objects in our environment are influenced by others' tracking behavior. This effect occurred even in the presence of conflicting size cues to object location and generalized to the context of apparent motion displays [6] and judgments about causal interactions between moving objects [7]. Perceived object trajectory was modulated primarily by the object-level motion of the tracking agent (e.g., the head), with less-pronounced effects of eye motion and low-level motion. Interestingly, comparable perceptual effects were induced by non-face objects that displayed similar tracking behavior, indicating a mechanism of distal coupling between the motion of the target and an appropriately moving inducer. These results demonstrate that social information can have a fundamental effect on our vision, such that the visual reality constructed in each brain is determined in part by what others see. PMID- 28712566 TI - Left Habenular Activity Attenuates Fear Responses in Larval Zebrafish. AB - Fear responses are defensive states that ensure survival of an organism in the presence of a threat. Perception of an aversive cue causes changes in behavior and physiology, such as freezing and elevated cortisol, followed by a return to the baseline state when the threat is evaded [1]. Neural systems that elicit fear behaviors include the amygdala, hippocampus, and medial prefrontal cortex. However, aside from a few examples, little is known about brain regions that promote recovery from an aversive event [2]. Previous studies had implicated the dorsal habenular nuclei in regulating fear responses and boldness in zebrafish [3 7]. We now show, through perturbation of its inherent left-right (L-R) asymmetry at larval stages, that the dorsal habenulo-interpeduncular (dHb-IPN) pathway expedites the return of locomotor activity following an unexpected negative stimulus, electric shock. Severing habenular efferents to the IPN, or only those from the left dHb, prolongs the freezing behavior that follows shock. Individuals with a symmetric, right-isomerized dHb also exhibit increased freezing. In contrast, larvae that have a symmetric, left-isomerized dHb, or in which just the left dHb-IPN projection is optogenetically activated, rapidly resume swimming post shock. In vivo calcium imaging reveals a neuronal subset, predominantly in the left dHb, whose activation is correlated with resumption of swimming. The results demonstrate functional specialization of the left dHb-IPN pathway in attenuating the response to fear. PMID- 28712568 TI - The Discovery of Wild Date Palms in Oman Reveals a Complex Domestication History Involving Centers in the Middle East and Africa. AB - For many crops, wild relatives constitute an extraordinary resource for cultivar improvement [1, 2] and also help to better understand the history of their domestication [3]. However, the wild ancestor species of several perennial crops have not yet been identified. Perennial crops generally present a weak domestication syndrome allowing cultivated individuals to establish feral populations difficult to distinguish from truly wild populations, and there is frequently ongoing gene flow between wild relatives and the crop that might erode most genetic differences [4]. Here we report the discovery of populations of the wild ancestor species of the date palm (Phoenix dactylifera L.), one of the oldest and most important cultivated fruit plants in hot and arid regions of the Old World. We discovered these wild individuals in remote and isolated mountainous locations of Oman. They are genetically more diverse than and distinct from a representative sample of Middle Eastern cultivated date palms and exhibit rounded seed shapes resembling those of a close sister species and archeological samples, but not modern cultivars. Whole-genome sequencing of several wild and cultivated individuals revealed a complex domestication history involving the contribution of at least two wild sources to African cultivated date palms. The discovery of wild date palms offers a unique chance to further elucidate the history of this iconic crop that has constituted the cornerstone of traditional oasis polyculture systems for several thousand years [5]. PMID- 28712569 TI - Extensive Farming in Estonia Started through a Sex-Biased Migration from the Steppe. AB - The transition from hunting and gathering to farming in Europe was brought upon by arrival of new people carrying novel material culture and genetic ancestry. The exact nature and scale of the transition-both material and genetic-varied in different parts of Europe [1-7]. Farming-based economies appear relatively late in Northeast Europe, and the extent to which they involve change in genetic ancestry is not fully understood due to the lack of relevant ancient DNA data. Here we present the results from new low-coverage whole-genome shotgun sequence data from five hunter-gatherers and five first farmers of Estonia whose remains date to 4,500 to 6,300 years before present. We find evidence of significant differences between the two groups in the composition of autosomal as well as mtDNA, X chromosome, and Y chromosome ancestries. We find that Estonian hunter gatherers of Comb Ceramic culture are closest to Eastern hunter-gatherers, which is in contrast to earlier hunter-gatherers from the Baltics, who are close to Western hunter-gatherers [8, 9]. The Estonian first farmers of Corded Ware culture show high similarity in their autosomes with European hunter-gatherers, Steppe Eneolithic and Bronze Age populations, and European Late Neolithic/Bronze Age populations, while their X chromosomes are in addition equally closely related to European and Anatolian and Levantine early farmers. These findings suggest that the shift to intensive cultivation and animal husbandry in Estonia was triggered by the arrival of new people with predominantly Steppe ancestry but whose ancestors had undergone sex-specific admixture with early farmers with Anatolian ancestry. PMID- 28712570 TI - Electron Microscopic Reconstruction of Functionally Identified Cells in a Neural Integrator. AB - Neural integrators are involved in a variety of sensorimotor and cognitive behaviors. The oculomotor system contains a simple example, a hindbrain neural circuit that takes velocity signals as inputs and temporally integrates them to control eye position. Here we investigated the structural underpinnings of temporal integration in the larval zebrafish by first identifying integrator neurons using two-photon calcium imaging and then reconstructing the same neurons through serial electron microscopic analysis. Integrator neurons were identified as those neurons with activities highly correlated with eye position during spontaneous eye movements. Three morphological classes of neurons were observed: ipsilaterally projecting neurons located medially, contralaterally projecting neurons located more laterally, and a population at the extreme lateral edge of the hindbrain for which we were not able to identify axons. Based on their somatic locations, we inferred that neurons with only ipsilaterally projecting axons are glutamatergic, whereas neurons with only contralaterally projecting axons are largely GABAergic. Dendritic and synaptic organization of the ipsilaterally projecting neurons suggests a broad sampling from inputs on the ipsilateral side. We also observed the first conclusive evidence of synapses between integrator neurons, which have long been hypothesized by recurrent network models of integration via positive feedback. PMID- 28712571 TI - Hierarchical Status Predicts Behavioral Vulnerability and Nucleus Accumbens Metabolic Profile Following Chronic Social Defeat Stress. AB - Extensive data highlight the existence of major differences in individuals' susceptibility to stress [1-4]. While genetic factors [5, 6] and exposure to early life stress [7, 8] are key components for such neurobehavioral diversity, intriguing observations revealed individual differences in response to stress in inbred mice [9-12]. This raised the possibility that other factors might be critical in stress vulnerability. A key challenge in the field is to identify non invasively risk factors for vulnerability to stress. Here, we investigated whether behavioral factors, emerging from preexisting dominance hierarchies, could predict vulnerability to chronic stress [9, 13-16]. We applied a chronic social defeat stress (CSDS) model of depression in C57BL/6J mice to investigate the predictive power of hierarchical status to pinpoint which individuals will exhibit susceptibility to CSDS. Given that the high social status of dominant mice would be the one particularly challenged by CSDS, we predicted and found that dominant individuals were the ones showing a strong susceptibility profile as indicated by strong social avoidance following CSDS, while subordinate mice were not affected. Data from 1H-NMR spectroscopy revealed that the metabolic profile in the nucleus accumbens (NAc) relates to social status and vulnerability to stress. Under basal conditions, subordinates show lower levels of energy related metabolites compared to dominants. In subordinates, but not dominants, levels of these metabolites were increased after exposure to CSDS. To the best of our knowledge, this is the first study that identifies non-invasively the origin of behavioral risk factors predictive of stress-induced depression-like behaviors associated with metabolic changes. PMID- 28712572 TI - Centriolar Satellites Control GABARAP Ubiquitination and GABARAP-Mediated Autophagy. AB - Autophagy maintains cellular health and homeostasis during stress by delivering cytosolic material captured by autophagosomes to lysosomes for degradation. Autophagosome formation is complex: initiated by the recruitment of autophagy (Atg) proteins to the formation site, it is sustained by activation of Atg proteins to allow growth and closure of the autophagosome. How Atg proteins are translocated to the forming autophagosome is not fully understood. Transport of the ATG8 family member GABARAP from the centrosome occurs during starvation induced autophagosome biogenesis, but how centrosomal proteins regulate GABARAP localization is unknown. We show that the centriolar satellite protein PCM1 regulates the recruitment of GABARAP to the pericentriolar material. In addition to residing on the pericentriolar material, GABARAP marks a subtype of PCM1 positive centriolar satellites. GABARAP, but not another ATG8 family member LC3B, binds directly to PCM1 through a canonical LIR motif. Loss of PCM1 results in destabilization of GABARAP, but not LC3B, through proteasomal degradation. GABARAP instability is mediated through the centriolar satellite E3 ligase Mib1, which interacts with GABARAP through its substrate-binding region and promotes K48-linked ubiquitination of GABARAP. Ubiquitination of GABARAP occurs in the N terminus, a domain associated with ATG8-family-specific functions during autophagosome formation, on residues absent in the LC3 family. Furthermore, PCM1 GABARAP-positive centriolar satellites colocalize with forming autophagosomes. PCM1 enhances GABARAP/WIPI2/p62-positive autophagosome formation and flux but has no significant effect on LC3B-positive autophagosome formation. These data suggest a mechanism for how centriolar satellites can specifically regulate an ATG8 ortholog, the centrosomal GABARAP reservoir, and centrosome-autophagosome crosstalk. PMID- 28712574 TI - Black tongue. PMID- 28712575 TI - Editorial: 63rd International Congress of Meat Science and Technology (63rd ICoMST), Cork, Ireland, 13-18th August 2017. PMID- 28712573 TI - VE-Cadherin Phosphorylation Regulates Endothelial Fluid Shear Stress Responses through the Polarity Protein LGN. AB - Fluid shear stress due to blood flow on the vascular endothelium regulates blood vessel development, remodeling, physiology, and pathology [1, 2]. A complex consisting of PECAM-1, VE-cadherin, and vascular endothelial growth factor receptors (VEGFRs) that resides at endothelial cell-cell junctions transduces signals important for flow-dependent vasodilation, blood vessel remodeling, and atherosclerosis. PECAM-1 transduces forces to activate src family kinases (SFKs), which phosphorylate and transactivate VEGFRs [3-5]. By contrast, VE-cadherin functions as an adaptor that interacts with VEGFRs through their respective cytoplasmic domains and promotes VEGFR activation in flow [6]. Indeed, shear stress triggers rapid increases in force across PECAM-1 but decreases the force across VE-cadherin, in close association with downstream signaling [5]. Interestingly, VE-cadherin cytoplasmic tyrosine Y658 can be phosphorylated by SFKs [7], which is maximally induced by low shear stress in vitro and in vivo [8]. These considerations prompted us to address the involvement of VE-cadherin cytoplasmic tyrosines in flow sensing. We found that phosphorylation of a small pool of VE-cadherin on Y658 is essential for flow sensing through the junctional complex. Y658 phosphorylation induces dissociation of p120ctn, which allows binding of the polarity protein LGN. LGN is then required for multiple flow responses in vitro and in vivo, including activation of inflammatory signaling at regions of disturbed flow, and flow-dependent vascular remodeling. Thus, endothelial flow mechanotransduction through the junctional complex is mediated by a specific pool of VE-cadherin that is phosphorylated on Y658 and bound to LGN. PMID- 28712576 TI - Comparing effectiveness and outcomes in asthma and cystic fibrosis. AB - As technology yields new treatments, pediatric pulmonologists need determine how best to use them and how to decide which ones are best for any specific group or individual patient. Physicians have always customized therapies based upon patient response, but the new concept of "Personalized (or precision) medicine" focuses attention to a greater degree on the individual needs of patients based on their genetic, biomarker, phenotypic, or psychosocial characteristics. The newly developed biologics for treatment of asthma and CFTR modulators for treatment of cystic fibrosis (CF) highlight this newer approach. As we have more treatments available, new approaches to testing efficacy and effectiveness of these new therapies is necessary in order to efficiently bring them to market and compare their benefits in real world practice. While comparative effectiveness can be tested in pragmatic clinic trials, the most common approaches make use of observational data such as administrative databases and patient registries but their use for this is fraught with pitfalls that may or may not be methodologically surmountable. Once new therapies have been shown to be efficacious and effective, it is important to be cognizant of methods for ensuring that all patients actually receive the treatments that will be best for them. Comparisons of the effectiveness of clinical practice in the form of benchmarking is helpful for this, and consideration of costs and cost effectiveness is essential to judging the best treatment for patients in a real world setting. PMID- 28712577 TI - Bacterial adherence to graft tissues in static and flow conditions. AB - BACKGROUND: Various conduits and stent-mounted valves are used as pulmonary valve graft tissues for right ventricular outflow tract reconstruction with good hemodynamic results. Valve replacement carries an increased risk of infective endocarditis (IE). Recent observations have increased awareness of the risk of IE after transcatheter implantation of a stent-mounted bovine jugular vein valve. This study focused on the susceptibility of graft tissue surfaces to bacterial adherence as a potential risk factor for subsequent IE. METHODS: Adhesion of Staphylococcus aureus, Staphylococcus epidermidis, and Streptococcus sanguinis to bovine pericardium (BP) patch, bovine jugular vein (BJV), and cryopreserved homograft (CH) tissues was quantified under static and shear stress conditions. Microscopic analysis and histology were performed to evaluate bacterial adhesion to matrix components. RESULTS: In general, similar bacteria numbers were recovered from CH and BJV tissue surfaces for all strains, especially in flow conditions. Static bacterial adhesion to the CH wall was lower for S sanguinis adhesion (P < .05 vs BP patch). Adhesion to the BJV wall, CH wall, and leaflet was decreased for S epidermidis in static conditions (P < .05 vs BP patch). Bacterial adhesion under shear stress indicated similar bacterial adhesion to all tissues, except for lower adhesion to the BJV wall after S sanguinis incubation. Microscopic analysis showed the importance of matrix component exposure for bacterial adherence to CH. CONCLUSIONS: Our data provide evidence that the surface composition of BJV and CH tissues themselves, bacterial surface proteins, and shear forces per se are not the prime determinants of bacterial adherence. PMID- 28712578 TI - Outcomes, readmissions, and costs in transfemoral and alterative access transcatheter aortic valve replacement in the US Medicare population. AB - OBJECTIVE: To comprehensively evaluate and compare utilization, outcomes, and especially costs of transfemoral (TF), transapical (TA), and transaortic (TAO) transcatheter aortic valve replacement (TAVR). METHODS: All Medicare fee-for service patients undergoing TF (n = 4065), TA (n = 691), or TAO (n = 274) TAVR between January 1, 2011, and November 30, 2012, were identified using Health Care Procedure Classification Codes present on Medicare claims. Hospital charges from Medicare claims were converted to costs using hospital-specific Medicare cost-to charge ratios. RESULTS: TA and TAO patients were similar in age, race, and common comorbidities. Compared with TF patients, TA and TAO patients were more likely to be female and to have peripheral vascular disease, chronic lung disease, and renal failure. Thirty-day mortality rates were higher among TA and TAO patients than among TF patients (TA, 9.6%; TAO, 8.0%; TF, 5.0%; P < .001). Adjusted mortality beyond 1 year did not differ by access. TA patients were more likely to require cardiopulmonary bypass (CPB). Increased adjusted mortality was associated with CPB (hazard ratio, 2.13; P < .01) and increased 30-day cost ($62,000 [interquartile range (IQR)], $45,100-$86,400 versus $48,800 [IQR, $38,100 $62,900]; P < .01). Cost at 30 days was lowest for TF ($48,600) compared with TA ($49,800; P < .01) and TAO ($53,200; P = .03). CONCLUSIONS: For patients ineligible to receive TF TAVR, TAO and TA approaches offer similar clinical outcomes at similar cost with acceptable operative and 1-year survival, except for higher rates of CPB use in TA patients. CPB was associated with worse survival and increased costs. PMID- 28712579 TI - The importance of capillary density-stroke work mismatch for right ventricular adaptation to chronic pressure overload. AB - OBJECTIVE: Mechanisms of right ventricular (RV) adaptation to chronic pressure overload are not well understood. We hypothesized that a lower capillary density (CD) to stroke work ratio would be associated with more fibrosis and RV maladaptive remodeling. METHODS: We induced RV chronic pressure overload over a 20-week period in 2 piglet models of pulmonary hypertension; that is, a shunt model (n = 5) and a chronic thromboembolic pulmonary hypertension model (n = 5). We assessed hemodynamic parameters and RV remodeling as well as RV CD, fibrosis, and angiogenic factors expression. RESULTS: Although RV was similarly hypertrophied in both models, maladapted RV remodeling with impaired systolic function was only seen in chronic thromboembolic pulmonary hypertension group members who had lower CD (484 +/- 99 vs 1213 +/- 74 cap/mm2; P < .01), lower CD to stroke work ratio (0.29 +/- 0.07 vs 0.82 +/- 0.16; P = .02), higher myocardial fibrosis (15.4% +/- 3.8% vs 8.0% +/- 2.5%; P < .01), as well as a higher angiogenic and fibrosis factors expression. CONCLUSIONS: The RV adaptive response to chronic pressure overload differs between 2 different piglet models of PH. Mismatch between angiogenesis and workload (CD to stroke work ratio) was associated with greater degree of myocardial fibrosis and RV dysfunction and could be a promising index of RV maladaptation. Further studies are needed to understand the underlying mechanisms. PMID- 28712580 TI - WITHDRAWN: Single-dose del Nido cardioplegia in minimally invasive aortic valve surgery. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our business/policies/article-withdrawal. PMID- 28712581 TI - Cost and contribution margin of transcatheter versus surgical aortic valve replacement. AB - OBJECTIVE: To compare the cost of and payments for transcatheter aortic valve replacement (TAVR), a novel and expensive technology, and surgical aortic valve replacement (SAVR). METHODS: Medicare claims provided hospital charges, payments, and outcomes between January and December 2012. Hospital costs and charges were estimated using hospital-specific cost-to-charge ratios. Costs and payments were examined in propensity score- matched TAVR and SAVR patients. RESULTS: Medicare spent $215,770,200 nationally on 4083 patients who underwent TAVR in 2012. Hospital costs were higher for TAVR patients (median, $50,200; interquartile range [IQR], $39,800-$64,300) than for propensity-matched SAVR patients ($45,500; IQR, $34,500-$63,300; P < .01), owing largely to higher estimated medical supply costs, including the implanted valve prosthesis. Postprocedure hospital length of stay (LOS) length was shorter for TAVR patients (median, 5 days [IQR, 4-8 days] vs 7 days [IQR, 5-9 days]; P < .01), as was total intensive care unit (ICU) LOS (median, 2 days [IQR, 0-5 days] vs 3 days [IQR, 1-6 days]; P < .01). Medicare payments were lower for TAVR hospitalizations (median, $49,500; IQR, $36,900 $64,600) than for SAVR (median, $50,400; IQR, $37,400-$65,800; P < .01). The median of the differences between payments and costs (contribution margin) was $3380 for TAVR hospitalizations and $2390 for SAVR hospitalizations (P < .01). CONCLUSIONS: TAVR accounted for $215 million in Medicare payments in its first year of clinical use. Among SAVR Medicare patients at a similar risk level, TAVR was associated with higher hospital costs despite shorter ICU LOS and hospital LOS. Overall and/or medical device cost reductions are needed for TAVR to have a net neutral financial impact on hospitals. PMID- 28712582 TI - To stent or not to stent? That is the question. PMID- 28712583 TI - Discussion. PMID- 28712584 TI - The advantage of early plication in children diagnosed with diaphragm paresis. AB - BACKGROUND: In this single-center study, we sought to determine the frequency of phrenic nerve injury leading to diaphragm paresis (DP) in children following open cardiac surgery over the last 10 years, and to identify possible variables that predict the need for plication and associated clinical outcomes. METHODS: Patients diagnosed with DP were identified from departmental databases and a review of clinical diaphragm ultrasound images. A cohort was analyzed for predictors of diaphragm plication and associations with clinical outcomes. Cumulative proportion graphs modeled the association between plication and length of stay. RESULTS: DP was diagnosed in 161 of 6448 patients (2.5%) seen between January 2002 and December 2012. All diagnoses but 1 were confirmed by ultrasound. Plication of the diaphragm was performed in 30 patients (19%); compared with patients who did not undergo plication, these patients were younger (median age, 10 days vs 138 days; P < .001), more likely to have undergone deep hypothermic circulatory arrest (47% vs 18%; P = .005), had a longer duration of positive pressure ventilation (median, 15 days vs 7 days; P < .001), and had longer lengths of stay in both the intensive care unit (median, 23 days vs 8 days; P < .0001) and the hospital (median, 37 days vs 15 days; P < .0001). Early plication was associated with reduction in all intervals of care. CONCLUSIONS: Early plication should be considered for patients with diaphragm paresis requiring prolonged respiratory support after cardiac bypass surgery. Longer follow-up evaluation is required to better define the long-term implications of plication. PMID- 28712585 TI - Conduction disturbance after isolated surgical aortic valve replacement in degenerative aortic stenosis. AB - OBJECTIVE: Conduction disturbances are common in patients with aortic stenosis. We investigated the incidence, reversibility, and prognosis of conduction disorders requiring permanent pacemaker implantation in patients with degenerative aortic stenosis after isolated aortic valve replacement. METHODS: This was a retrospective study conducted at a tertiary care center. We evaluated the incidence of conduction disturbances in patients who underwent isolated surgical aortic valve replacement for aortic stenosis between January 2005 and May 2015. Relevant clinical information was obtained from the patients' medical records. RESULTS: We reviewed results of 663 patients with pathologically proven degenerative aortic stenosis (bicuspid aortic valve, n = 285 [43.0%]) who underwent isolated aortic valve replacement (mechanical valve, n = 310 [46.8%]). Patients' mean age was 67.1 +/- 8.1 years, and 362 were male (54.6%). Immediate postoperative intraventricular conduction disorders occurred in 56 patients (8.4%), and atrioventricular block occurred in 68 patients (10.3%). Ten patients with symptomatic second-degree or third-degree atrioventricular block underwent permanent pacemaker implantation within 30 days of aortic valve replacement. During the mean follow-up period of 1288 +/- 1122 days, 64 patients (9.7%) developed irreversible conduction disorders (bundle branch block n = 24 and first degree atrioventricular block n = 42). Of the 10 patients requiring permanent pacemakers, 4 remained depend on the permanent pacemaker during follow-up. Beyond 30 days after aortic valve replacement, 1 patient underwent permanent pacemaker implantation for de novo conduction disturbance 44 months postoperatively. CONCLUSIONS: After isolated aortic valve replacement, permanent pacemaker implantation for conduction disturbance is rare (n = 10/663, 1.5%). Isolated aortic valve replacement for degenerative aortic stenosis has a low risk of conduction disturbances during long-term follow-up. PMID- 28712586 TI - Platelet testing to guide aspirin dose adjustment in pediatric patients after cardiac surgery. AB - OBJECTIVES: Thrombosis is associated with increased morbidity and mortality in pediatric patients undergoing cardiac surgery. Although aspirin commonly is used for thromboprophylaxis, the utility of laboratory-based tests that assess aspirin efficacy have not been evaluated. We sought to determine the relationship between platelet aggregation testing and aspirin dose adjustment on thrombosis rates in this population. METHODS: Pediatric patients undergoing cardiac surgery who received aspirin and underwent platelet testing were studied retrospectively. Patients were excluded if they were treated with multiple agents or experienced thrombosis before the initiation of aspirin. Thrombosis events within 30 days after initiation of aspirin were recorded. Associations between aspirin responsiveness and thrombosis rate and aspirin dose adjustment and thrombosis rate were assessed with the use of multivariable logistic regression analysis. RESULTS: Suboptimal platelet response to aspirin was detected in 64 of 430 patients (15%) and thrombosis was detected in 11 patients (2.6%). Lack of aspirin responsiveness on initial testing was a significant risk factor for thrombosis (P < .001) independent of age, weight, diagnosis, and initial aspirin dose. Dose escalation based on aspirin testing was performed in 40 of 64 patients, and significantly lower rate of thrombosis was observed in patients who underwent dose escalation compared with those without dose escalation (0/40 vs 9/24, P < .001). By multivariable analysis, the only significant independent risk factor for thrombosis was failure to increase aspirin dose after initial unresponsiveness (P < .001). CONCLUSIONS: Current practice of weight-based aspirin dosing may lead to subtherapeutic platelet inhibition in some children. Aspirin unresponsiveness is associated with increased risk of thrombosis after specific pediatric cardiac surgical procedures. Aspirin dose increase in unresponsive patients is associated with reduced risk of thrombosis. PMID- 28712587 TI - Clinical implications of donor age: A single-institution analysis spanning 3 decades. AB - BACKGROUND: We sought to clarify the effect of donor age as a continuous variable on morbidity and mortality in a single-institution experience. METHODS: From 1986 to 2016, 882 adult lung transplants were performed, including 396 in the lung allocation score era. Kaplan-Meier curves and Cox proportional hazards models were used to evaluate the association of donor age with overall survival and bronchiolitis obliterans syndrome (BOS) score >=1-free survival. Logistic regression was used to evaluate the association with primary graft dysfunction grade 3. Natural cubic splines were used to explore donor age in a continuous fashion to allow for nonlinear relationships. RESULTS: In the lung allocation score era, unadjusted 5-year survival was not significantly different between 3 a priori-defined donor age groups: age <40, 40 to 54, and age >=55 years (64%, 61%, and 69%, P = .8). Unadjusted 5-year freedom from BOS >=1 was not significantly different (34%, 20%, and 33%, respectively, P = .1). After we adjusted for comorbidities, cubic spline analysis demonstrated no effect between donor age as a continuous variable and hazard for mortality at 5 years. Similarly, no interaction was seen between donor age and risk of BOS or primary graft dysfunction 3. Adjusted analysis of all 882 transplants pre- and postinception of the lung allocation score also showed no effect of age on 10-year survival. CONCLUSIONS: Long-term survival of lung transplant recipients was not affected by the age of the donor. These findings support the notion that donor age could be relaxed. PMID- 28712588 TI - Retraction notice to "Anti-diabetic activity of Swertia corymbosa (Griseb.) Wight ex C.B. Clarke aerial parts extract in streptozotocin induced diabetic rats" [J. Ethnopharmacol. 151/3 (2014) 1175-1183]. PMID- 28712589 TI - Exposure to a contextually neutral stressor potentiates fear conditioning in juvenile rainbow trout, Oncorhynchus mykiss. AB - Organisms faced with stressors deploy a suite of adaptive responses in the form of behavioral, physiological and cognitive modifications to overcome the challenge. Interactive effects of these responses are known to influence learning and memory processes and facilitation is thought to be dependent, in part, upon contextual relevance of the stressor to the learning task. Predation is one such stressor for prey animals, and their ability to manage reliable information about predators is essential for adaptive antipredator strategies. Here, we investigated (i) the influence cortisol has on the ability of juvenile rainbow trout to learn and retain conditioned antipredator responses to predatory cues, and (ii) whether conditioned behavioral and physiological responses to predator cues are fixed or deployed in a threat-sensitive manner. Trout were fed cortisol coated pellets minutes prior to a conditioning event where they were exposed to novel predator odor paired with chemical alarm cues (unconditioned stimulus). We tested for conditioned responses by exposing trout to predator cues after 2, 4 or 10days and subsequently documented physiological and behavioral responses. Both control and cortisol-fed trout learned the predator odor and responded 2 and 4days post conditioning. However, at 10days only cortisol-fed trout maintained strong behavioral responses to predator cues. Interestingly, we failed to find conditioned physiological responses to predator odor despite the presence of threat-sensitive cortisol responses to the unconditioned stimulus. Our findings suggest cortisol exposure prior to predator-learning may enhance retention of conditioned responses, even without a contextual link between stressor source and learning task. PMID- 28712590 TI - Intelligence Is Associated With Voluntary Disclosure in Child Sexual Abuse Victims. AB - PURPOSE: The purpose of this study was (1) to determine whether intelligence level is associated with the pattern of the disclosure and (2) to elucidate which, between the verbal and performance intelligence, better reflect the pattern of disclosure in child and adolescent sexual abuse victims. METHODS: Data were collected on 162 participants who visited a public center for sexually abused children and adolescents between January 2013 and December 2014. Demographic information, case characteristics, and disclosure pattern as well as intelligence quotients (IQs) of subjects were gathered. Intelligence was analyzed as level, full scale IQ, and the verbal and performance IQ. RESULTS: Eighty-one subjects (50.0%) voluntarily disclosed that they have been sexually abused. In regression analysis, intellectual level, age, and the number of perpetrators were associated with disclosure pattern. Full scale IQ was associated with the disclosure pattern (odds ratio = .983, 95% confidence interval = .968-.997, p = .017). When intelligence was divided into verbal and performance IQ, verbal IQ affected the pattern of disclosure (odds ratio = .973, 95% confidence interval = .956-.991, p = .003) with linear correlation (p = .001). CONCLUSIONS: We found that IQ was associated with the disclosure pattern. The intelligence, especially in verbal domain, is linearly correlated with the probability of voluntary disclosure. We suggest that special legal assistance and social concern are required for children and adolescent victims below normal intelligence to make them disclose the sexual abuse. PMID- 28712591 TI - Normalizing Ovulation Rate by Preferential Reduction of Hepato-Visceral Fat in Adolescent Girls With Polycystic Ovary Syndrome. AB - PURPOSE: Polycystic ovary syndrome (PCOS) is an increasingly prevalent disorder in adolescent girls, commonly presenting with hirsutism/oligomenorrhea, commonly treated with an oral contraceptive (OC), and commonly followed by oligoanovulatory subfertility. We tested whether an intervention targeting the reduction of hepato-visceral adiposity is followed by a higher ovulation rate than OC treatment. METHODS: This randomized, open-label, single-center, pilot proof-of-concept study (12 months on treatment, then 12 months off) was performed in adolescent girls with hirsutism and oligomenorrhea (PCOS by National Institutes of Health; no sexual activity; N = 36; mean age 16 years, body mass index 23.5 kg/m2; 94% study completion). Compared treatments were OC (ethinylestradiol-levonorgestrel) versus low-dose combination of spironolactone 50 mg/d, pioglitazone 7.5 mg/d, and metformin 850 mg/d (SPIOMET). Primary outcome was post-treatment ovulation rate inferred from menstrual diaries and salivary progesterone (12 + 12 weeks). Secondary outcomes included body composition (dual X-ray absorptiometry), abdominal fat (magnetic resonance imaging), insulinemia (oral glucose tolerance test), and androgenemia (liquid chromatography - tandem mass spectrometry). RESULTS: SPIOMET was followed by a 2.5-fold higher ovulation rate than OC (p <= .001) and by a 6-fold higher normovulatory fraction (71% vs. 12%; p <= .001); oligoanovulation risk after SPIOMET was 65% lower (95% confidence interval, 40%-89%) than after OC. Higher post-treatment ovulation rates related to more on-treatment loss of hepatic fat (r2 = .27; p < .005). Visceral fat and insulinemia normalized only with SPIOMET; androgenemia normalized faster with OC but rebounded more thereafter. Body weight, lean mass, and abdominal subcutaneous fat mass remained stable in both groups. CONCLUSIONS: Early SPIOMET treatment for PCOS normalized post-treatment ovulation rates more than OC. Focusing PCOS treatment on early reduction of hepato-visceral fat may prevent part of later oligoanovulatory subfertility. PMID- 28712592 TI - Risk Factors for Youth E-Cigarette "Vape Trick" Behavior. AB - PURPOSE: Some adolescent users of e-cigarettes and other electronic vaping products (EVPs) report performing "vape tricks" (exhaling aerosol to make shapes). However, little is known about this behavior. We examined the frequency of performing and watching vape tricks and the characteristics of those most likely to perform vape tricks among a sample of adolescent EVP users. METHODS: We used social media ads to recruit a national convenience sample of U.S. adolescents (n = 1,729) to participate in an online survey in September 2016. Inclusion criteria required participants to be aged 15-17 years and to have used EVPs at least once in the past 30 days. RESULTS: The majority of EVP-using adolescents reported trying (77.8%) and watching vape tricks in person (83.7%) or online (74.0%). Risk factors for performing tricks included using advanced vaping devices, vaping every day, white race, moderate levels of seeing and sharing vaping information on social media, and believing that EVP use is more normative among peers. Likelihood of trying vape tricks decreased as beliefs about the harmfulness of EVPs increased. CONCLUSIONS: Vape tricks pose a potential threat to adolescent health if they encourage nonusers to initiate or current EVP users to use more frequently or switch to advanced devices that produce more harmful chemical emissions. Further research should examine the possible health effects of performing vape tricks, and future public health campaigns should be informed by an understanding of the appeal of this activity for adolescents. PMID- 28712593 TI - Access to Tobacco Among California High School Students: The Role of Family Members, Peers, and Retail Venues. AB - PURPOSE: The purpose of the study was to determine from whom and where adolescents obtained tobacco, including cigarettes, e-cigarettes, and hookah. METHODS: California adolescents (N = 772; 63.19% female; mean age = 16.13 years, SD = 1.61; 26.44% white, 22.12% Asian/Pacific Islander, 36.65% Hispanic, and 14.79% other) were surveyed about their access to different tobacco products. RESULTS: Adolescents were significantly more likely to obtain tobacco from friends (54.9%) than family members or direct purchasing (p < .001). Smoke shops were the most common purchase location across products (44.3%), with adolescents significantly more likely to purchase hookah and e-cigarettes from smoke shops than gas stations, liquor stores, or drug stores (p < .02). CONCLUSIONS: The effective characterization of tobacco access patterns is critical to the development of comprehensive tobacco control. By demonstrating peers and smoke shops as the primary social and retail outlets, this study identifies targets for the optimization of regulation and messaging aimed at reducing adolescents' access to tobacco. PMID- 28712594 TI - An Age-Stratified Longitudinal Study of Primary Spontaneous Pneumothorax. AB - PURPOSE: The objective of this study was to determine the age-stratified incidence, frequency, and duration of recurrence of primary spontaneous pneumothorax (PSP). METHODS: This study analyzed the epidemiology of PSP among hospitalized patients using the National Health Research Institutes of Taiwan database. The incidence of PSP was determined from a cohort of 19,562 deidentified individuals with PSP between 2001 and 2013. The insurants consisted of 99% of the Taiwan population of about 23 million people. A 5- to 12-year long term recurrence analysis was based on data from 11,190 patients with PSP between 2001 and 2008. RESULTS: The incidence of PSP in in-patients increased from 5.05 to 7.18/100,000 in a 13-year analysis. The age group at highest risk was 15-22 years with incidence rates >11/100,000 and readmission rates of 17%-31%. About 20% of patients had more than one attack based on long-term follow-ups. About .8% of patients had more than three hospital admissions. Only 3.9% of patients had repeated or recurrent attacks after more than 4 years. All patients who had been admitted on more than four occasions were adolescents, except for four patients who were aged between 20 and 24 years old. CONCLUSIONS: Adolescents with PSP had a higher incidence of attacks and more frequent and longer periods of vulnerability to recurrence. The majority of patients experienced recurrence during the first 4 years after the first attack. PMID- 28712595 TI - Health-Related Issues in Latina Youth: Racial/Ethnic, Gender, and Generational Status Differences. AB - PURPOSE: Few studies have examined the early development of a broad range of health issues of importance in adolescence in Latina (female) youth, despite their being potentially a vulnerable group. This study compared suicide and depressive symptoms, substance use, violence exposure, injury prevention, obesity, and health-related quality of life among Latina, African-American, and white females as well as Latino (male) youth in fifth grade, as well as differences related to immigrant generational status for Latinas. METHODS: Data were from the Healthy Passages study, including 3,349 African-American, Latina, and white females as well as Latino male fifth graders in three U.S. metropolitan areas. Self-report items and scales were used to compare status on health-related issues. Generational status was classified based on the parent report of birth location. Logistic and linear regression analyses were conducted, including adjustment for sociodemographic differences. RESULTS: Latinas showed higher vulnerability than white females for several health issues, whereas few remained after adjustments for sociodemographic differences (higher obesity, lower bike helmet use, and lower physical health-related quality of life). Latina's lower vulnerability compared with African-American females generally persisted after adjustments. Third generation Latinas, after adjustments, reported lower prevalence of alcohol use and fewer friends using alcohol, yet higher future intentions of alcohol use, than first and second generation Latinas. There were few differences between Latina and Latino youth. CONCLUSIONS: Latina youth generally report low vulnerability across health issues in preadolescence. To the extent they appear at higher vulnerability than white females, this may be related to their disadvantaged sociodemographic status. PMID- 28712596 TI - Factors Associated With Contraceptive Method Choice and Initiation in Adolescents and Young Women. AB - PURPOSE: The purpose of the study was to identify factors associated with uptake of contraceptive implants or intrauterine devices (IUDs) by adolescents and young women. METHODS: For this prospective cohort study, we recruited English-speaking female contraceptive initiators aged 14-24 years attending a Title X-supported, youth-focused clinic. Immediately prior to their visits, participants completed surveys assessing demographic and reproductive characteristics and awareness of, interest in, and intent to initiate specific contraceptive methods. Participants also answered questions about their social contacts' contraceptive experiences. Following the visit, participants reported the method initiated and the perceived importance of provider counseling. We used a multivariable regression model to ascertain factors associated with initiation of an IUD, an implant, or a short acting reversible method. RESULTS: We enrolled 1,048 contraceptive initiators: 277 initiated short-acting methods, 384 IUDs, and 387 implants. High previsit personal acceptability of the method was associated with choosing that method for both implants and IUDs. Knowing someone who uses a specific method and likes it was predictive of personal acceptability of that method (IUD adjusted odds ratio: 10.9, 95% confidence interval: 3.8-31.1; implant adjusted odds ratio: 7.0, 95% confidence interval: 2.3-21.0). However, 10.4% of those initiating IUDs and 14.2% of those initiating implants had never heard of the method before their appointment. Even women with previsit intent to initiate a specific method found importance in contraceptive counseling. CONCLUSIONS: Previsit personal acceptability, which was associated with social contacts' experiences, was the strongest predictor of specific method uptake in our study. However, counseling informed the decisions of those with low previsit awareness and supported patients with formed intent. PMID- 28712597 TI - Comparative lifecycle assessment of alternatives for waste management in Rio de Janeiro - Investigating the influence of an attributional or consequential approach. AB - The environmental impacts from three management alternatives for organic fraction of municipal solid waste were compared using lifecycle assessment methodology. The alternatives (sanitary landfill, selective collection of organic waste for anaerobic digestion and anaerobic digestion after post-separation of organic waste) were modelled applying an attributional as well as consequential approach, in parallel with the aim of identifying if and how these approaches can affect results and conclusions. The marginal processes identified in the consequential modelling were in general associated with higher environmental impacts than average processes modelled with an attributional approach. As all investigated waste management alternatives result in net-substitution of energy and in some cases also materials, the consequential modelling resulted in lower absolute environmental impacts in five of the seven environmental impact categories assessed in the study. In three of these, the chosen modelling approach can alter the hierarchy between compared waste management alternatives. This indicates a risk of underestimating potential benefits from efficient energy recovery from waste when applying attributional modelling in contexts in which electricity provision historically has been dominated by technologies presenting rather low environmental impacts, but where projections point at increasing impacts from electricity provision in coming years. Thus, in the present case study, the chosen approach affects both absolute and relative results from the comparison. However, results were largely related to the processes identified as affected by investigated changes, and not merely the chosen modelling approach. The processes actually affected by future choices between different waste management alternatives are intrinsically uncertain. The study demonstrates the benefits of applying different assumptions regarding the processes affected by investigated choices - both for provision of energy and materials substituted by waste management processes in consequential LCA modelling, in order to present outcomes that are relevant as decision support within the waste management sector. PMID- 28712598 TI - Technical assessment of discarded tires gasification as alternative technology for electricity generation. AB - Concern about contamination associated with the disposal of tires has led to the search for technologies to reuse discarded tires, which include the use of Tire Derived Fuel (TDF) as fuel in advanced thermal-conversion processes, this allows the energy use of these wastes at affordable costs and reduces the environmental impact on scrap tires disposal. A theoretical assessment of the technical viability of TDF gasification for electric and thermal power generation, from the producer gas combustion in an internal combustion engine and in a gas turbine, was performed. The combustion of producer gas derived from the gasification of TDF in an internal combustion engine driving a generator (ICE-G) appears as the more efficient route for electricity generation when compared with the efficiency obtained with the use of gas turbine (GT-G). A higher global efficiency, considering the electric and thermal generation efficiency can be expected with the use of TDF producer gas in GT-G, where is expected an overall efficiency of 77.49%. The assessment shows that is possible produces up to 7.67MJ and 10.62MJ of electric and thermal energy per kilogram of TDF gasified using an ICE-G and up to 6.06MJ and 13.03MJ of electric and thermal energy respectively per kilogram of gasified TDF using a GT-G. PMID- 28712599 TI - Effects of woody peat and superphosphate on compost maturity and gaseous emissions during pig manure composting. AB - This study investigated the effect of calcium superphosphate on compost maturity and gaseous emissions during pig manure composting with woody peat as the bulking agent. Two treatments were conducted with or without the addition of calcium superphosphate (10% dry weight of the composting mass), which were denoted as the control and superphosphate-amended treatment, respectively. Results show that the composting temperature of both treatments was higher than 50 degrees C for more than 5days, which is typically required for pathogen destruction during manure composting. Compared to the control treatment, the superphosphate-amended treatment increased the emission of nitrogen oxide, but reduced the emission of methane, ammonia and hydrogen sulfide by approximately 35.5%, 37.9% and 65.5%, respectively. As a result, the total greenhouse gas (GHG) emission during manure composting was reduced by nearly 34.7% with the addition of calcium superphosphate. The addition of calcium superphosphate increased the content of humic acid (indicated by E4/E6 ratio). Nevertheless, the superphosphate-amended treatment postponed the biological degradation of organic matter and produced the mature compost with a higher electrical conductivity in comparison with the control treatment. PMID- 28712600 TI - MYC rearrangement in aggressive B-cell lymphomas: A major therapeutic challenge. PMID- 28712601 TI - The effects of uvulopalatal flap operation on speech nasalance and the acoustic parameters of the final nasal consonants. AB - OBJECTIVE: The acoustic characteristics of voice are determined by the source of the sound and shape of the vocal tract. Various anatomical changes after uvulopalatal flap (UPF) operation can change nasalance and/or other voice characteristics. Our aim was to explore the possible effects of UPF creation on speech nasalance and the resonatory features of the final nasal consonants, and thus voice characteristics. METHODS: A total of 30 patients (26 males, 4 females) with obstructive sleep apnea who underwent UPF operation were recruited. A Nasometer II 3.4 instrument was used to assess nasalance pre- and post operatively; the patients read standard Korean passages and the readings were recorded in Computer Speech Laboratory for later spectral analysis. Praat software was used to identify frequency bands affecting perioperative nasalance scores. Minima, maxima, and slopes were analyzed. RESULTS: We found no significant correlation between nasalance scores (any passage) and the respiratory distress index or body mass index. No significant perioperative change in any nasalance score. The moment variations in the final consonants /m/ and /n/ did not change significantly postoperatively. However, the postoperative moment variation of the final consonant /ng/ differed significantly in the third formant (F3) and second bandwidth (BW2). CONCLUSION: Few significant changes in nasal resonance speech quality were apparent after UPF operation. However, a postoperative acoustic change in the final sound /ng/ may be sustained. Patients may be preoperatively advised that the risk of voice change is very low, but not absent. PMID- 28712602 TI - Anaplerotic therapy in propionic acidemia. AB - BACKGROUND: Propionic acidemia is a rare metabolic disorder caused by a deficiency of propionyl- CoA carboxylase, the enzyme converting propionyl-CoA to methylmalonyl-CoA that subsequently enters the citric acid cycle as succinyl-CoA. Patients with propionic acidemia cannot metabolize propionic acid, which combines with oxaloacetate to form methylcitric acid. This, with the defective supply of succinyl-CoA, may lead to a deficiency in citric acid cycle intermediates. PURPOSE: The objective of this study was to determine whether supplements with glutamine (400mg/kg per day), citrate (7.5mEq/kg per day), or ornithine alpha ketoglutarate (400mg/kg per day) (anaplerotic agents that could fill up the citric acid cycle) would affect plasma levels of glutamine and ammonia, the urinary excretion of Krebs cycle intermediates, and the clinical outcome in 3 patients with propionic acidemia. METHODS: Each supplement was administered daily for four weeks with a two week washout period between supplements. The supplement that produced the most favorable changes was supplemented for 30 weeks following the initial study period and then for a 2 year extension. RESULTS: The urinary excretion of the Krebs cycle intermediates, alpha-ketoglutarate, succinate, and fumarate increased significantly compared to baseline during citrate supplementation, but not with the other two supplements. For this reason, citrate supplements were continued in the second part of the study. The urinary excretion of methylcitric acid and 3-hydroxypropionic acid did not change with any intervention. No significant changes in ammonia or glutamine levels were observed with any supplement. However, supplementation with any anaplerotic agents normalized the physiological buffering of ammonia by glutamate, with plasma glutamate and alanine levels significantly increasing, rather than decreasing with increasing ammonia levels. No significant side effects were observed with any therapy and safety labs (blood counts, chemistry and thyroid profile) remained unchanged. Motor and cognitive development was severely delayed before the trial and did not change significantly with therapy. Hospitalizations per year did not change during the trial period, but decreased significantly (p<0.05) in the 2years following the study (when citrate was continued) compared to the 2years before and during the study. CONCLUSIONS: These results indicate that citrate entered the Krebs cycle providing successful anaplerotic therapy by increasing levels of the downstream intermediates of the Krebs cycle: alpha ketoglutarate, succinate and fumarate. Citrate supplements were safe and might have contributed to reduce hospitalizations in patients with propionic acidemia. PMID- 28712603 TI - What Elements Suggest Infectious Mononucleosis? PMID- 28712604 TI - "Sometimes You Feel Like the Freak Show": A Qualitative Assessment of Emergency Care Experiences Among Transgender and Gender-Nonconforming Patients. AB - STUDY OBJECTIVE: Transgender, gender-variant, and intersex (trans) people have decreased access to care and poorer health outcomes compared with the general population. Little has been studied and documented about such patients' emergency department (ED) experiences and barriers to care. Using survey and qualitative research methods, this study aims to identify specific areas for improvement and generate testable hypotheses about the barriers and challenges for trans individuals needing acute care. METHODS: A survey and 4 focus groups were conducted with trans individuals older than 18 years who had been to an ED in the last 5 years. Participants were recruited by trans e-mail listservs; outreach to local trans organizations; and lesbian, gay, bisexual, and transgender periodical advertisements. The interview guide was reviewed by qualitative research and trans health content experts. Deidentified participant demographic information was collected with a standardized instrument. All discussions were captured on digital audio recorders and professionally transcribed. Interview coding and thematic analysis were conducted with a grounded theory approach. RESULTS: Among 32 participants, 71.9% were male identified and 78.1% were white. Nearly half (43.8%) reported avoiding the ED when they needed acute care. The factors that had the greatest influence on ED avoidance were fear of discrimination, length of wait, and negative previous experiences. There were 4 overarching discussion themes: system structure, care competency, discrimination and trauma, and avoidance of emergency care. Improvement recommendations focused on staff and provider training about gender and trans health, assurance of private gender identity disclosure, and accurate capture of sex, gender, and sexual orientation information in the electronic medical record. CONCLUSION: Efforts to improve trans ED experiences should focus on provider competency and communication training, electronic medical record modifications, and assurance of private means for gender disclosure. Future research directions include quantifying the frequency of care avoidance, the effect of avoidance on trans patient morbidity and mortality, and comparing ED patient outcomes by gender identity. Further research with increased inclusion of transwomen and people of color is needed to identify themes that may not have been raised in this preliminary investigation. PMID- 28712605 TI - Do Intravenous Benzodiazepines or Benzodiazepines by an Alternative Route (Nonintravenous) Abort Seizures Faster? PMID- 28712606 TI - Effectiveness of Apneic Oxygenation During Intubation: A Systematic Review and Meta-Analysis. AB - STUDY OBJECTIVE: We conduct a systematic review and meta-analysis to evaluate the effectiveness of apneic oxygenation during emergency intubation. METHODS: We searched Ovid MEDLINE, Ovid EMBASE, Ovid CENTRAL, and Scopus databases for randomized controlled trials and observational studies from 2006 until July 2016, without language restrictions. Gray literature, clinicaltrials.gov, and reference lists of articles were hand searched. We conducted a meta-analysis with random effects models to evaluate first-pass success rates, incidence of hypoxemia, and lowest peri-intubation SpO2 between apneic oxygenation and standard oxygenation cases. RESULTS: A total of 1,386 studies were screened and 77 selected for full text review. A total of 14 studies were included for qualitative analysis, and 8 studies (1,837 patients) underwent quantitative analysis. In the meta-analysis of 8 studies (1,837 patients), apneic oxygenation was associated with decreased hypoxemia (odds ratio [OR] 0.66; 95% confidence interval [CI] 0.52 to 0.84), but was not associated with decreased severe hypoxemia (6 studies; 1,043 patients; OR 0.86; 95% CI 0.47 to 1.57) or life-threatening hypoxemia (5 studies; 1,003 patients; OR 0.90; 95% CI 0.52 to 1.55). Apneic oxygenation was associated with increased first-pass success rate (6 studies; 1,658 patients; OR 1.59; 95% CI 1.04 to 2.44) and increased lowest peri-intubation SpO2 (6 studies; 1,043 patients; weighted mean difference 2.2%; 95% CI 0.8% to 3.6%). CONCLUSION: In this meta-analysis, apneic oxygenation was associated with increased peri intubation oxygen saturation, decreased rates of hypoxemia, and increased first pass intubation success. PMID- 28712607 TI - Patients' Perspectives on Outcomes of Care After Discharge From the Emergency Department: A Qualitative Study. AB - STUDY OBJECTIVE: Much effort has been expended to understand what care experiences patients value in the emergency department (ED), yet little is known about which outcomes patients value after ED care. Our goal is to define outcomes of ED care that are valued by patients discharged from the ED, with the goal of informing the development of a patient-reported outcome measure for ED care. METHODS: We conducted qualitative semistructured interviews with patients recruited during their care at 1 of 2 EDs and interviewed in either English or French 1 to 9 days after their visit. Patients who were hospitalized were excluded. Interviews focused on perceived outcomes of care since the ED visit and expectations of care before the ED visit. We identified themes with standard descriptive content analysis techniques and a modified version of the constant comparative method, drawing on grounded theory methods. RESULTS: We interviewed 46 patients in English (n=38) or French (n=8). Participants with diverse reasons for seeking care appeared to value common outcomes from ED care that centered around 4 themes: understanding the cause and expected trajectory of their symptoms; reassurance; symptom relief; and having a plan to manage their symptoms, resolve their issue, or pursue further medical care. These themes were also reflected in the expectations participants recalled having when they decided to seek care in the ED. CONCLUSION: The 4 outcomes defined constitute areas for improvement and will inform the development of an ED patient-reported outcome questionnaire. Consideration should be given to measuring patient-reported outcomes separately from patient experience. PMID- 28712609 TI - Is Early Goal-Directed Therapy or Standard Therapy More Effective in Decreasing Mortality Among Patients With Sepsis? PMID- 28712608 TI - A Custom-Developed Emergency Department Provider Electronic Documentation System Reduces Operational Efficiency. AB - STUDY OBJECTIVE: Electronic health record implementation can improve care, but may also adversely affect emergency department (ED) efficiency. We examine how a custom, ED provider, electronic documentation system (eDoc), which replaced paper documentation, affects operational performance. METHODS: We analyzed retrospective operational data for 1-year periods before and after eDoc implementation in a single ED. We computed daily operational statistics, reflecting 60,870 pre- and 59,337 postimplementation patient encounters. The prespecified primary outcome was daily mean length of stay; secondary outcomes were daily mean length of stay for admitted and discharged patients and daily mean arrival time to disposition for admitted patients. We used a prespecified multiple regression model to identify differences in outcomes while controlling for prespecified confounding variables. RESULTS: The unadjusted change in length of stay was 8.4 minutes; unadjusted changes in secondary outcomes were length of stay for admitted patients 11.4 minutes, length of stay for discharged patients 1.8 minutes, and time to disposition 1.8 minutes. With a prespecified regression analysis to control for variations in operational characteristics, there were significant increases in length of stay (6.3 minutes [95% confidence interval 3.5 to 9.1 minutes]) and length of stay for discharged patients (5.1 minutes [95% confidence interval 1.9 to 8.3 minutes]). There was no statistically significant change in length of stay for admitted patients or time to disposition. CONCLUSION: In our single-center study, the isolated implementation of eDoc was associated with increases in overall and discharge length of stay. Our findings suggest that a custom-designed electronic provider documentation may negatively affect ED throughput. Strategies to mitigate these effects, such as reducing documentation requirements or adding clinical staff, scribes, or voice recognition, would be a valuable area of future research. PMID- 28712610 TI - The HIQA's Health Technology Assessment of Breast Screening: Highlighting Some of the Challenges Posed by Evaluations of Screening Programs. AB - A review of the Health Information and Quality Authority's (HIQA) assessment of breast cancer surveillance cancer criticized how the results were presented and interpreted. The health technology assessment (HTA) investigated surveillance options for women aged less than 50 years who were at elevated risk of breast cancer. Surveillance strategies using digital mammography, magnetic resonance imaging, or a combination of the two modalities were modeled on the basis of diagnostic test accuracy. The HTA faced a number of issues, including the use of diagnostic test accuracy as a surrogate for long-term outcomes; modeling interventions that were not considered acceptable to clinicians; and extrapolating for screening intervals and age ranges not directly supported by available evidence. The evaluation of screening programs gives rise to challenges in terms of balancing an adequate exploration of the possible options while also being cognizant of what is appropriately supported by evidence. In this article, the authors of the HIQA report discuss the challenges posed by this particular HTA. PMID- 28712612 TI - Patient-Reported Outcome and Observer-Reported Outcome Assessment in Rare Disease Clinical Trials: An ISPOR COA Emerging Good Practices Task Force Report. AB - BACKGROUND: Rare diseases (RDs) affect a small number of people within a population. About 5000 to 8000 distinct RDs have been identified, with an estimated 6% to 8% of people worldwide suffering from an RD. Approximately 75% of RDs affect children. Frequently, these conditions are heterogeneous; many are progressive. Regulatory incentives have increased orphan drug designations and approvals. OBJECTIVE: To develop emerging good practices for RD outcomes research addressing the challenges inherent in identifying, selecting, developing, adapting, and implementing patient-reported outcome (PRO) and observer-reported outcome (ObsRO) assessments for use in RD clinical trials. GOOD PRACTICES FOR OUTCOMES RESEARCH: This report outlines the challenges and potential solutions in determining clinical outcomes for RD trials. It follows the US Food and Drug Administration Roadmap to Patient-Focused Outcome Measurement in Clinical Trials. The Roadmap consists of three columns: 1) Understanding the Disease or Condition, 2) Conceptualizing Treatment Benefit, and 3) Selecting/Developing the Outcome Measure. Challenges in column 1 include factors such as incomplete natural history data and heterogeneity of disease presentation and patient experience. Solutions include using several information sources, for example, clinical experts and patient advocacy groups, to construct the condition's natural history and understand treatment patterns. Challenges in column 2 include understanding and measuring treatment benefit from the patient's perspective, especially given challenges in defining the context of use such as variations in age or disease severity/progression. Solutions include focusing on common symptoms across patient subgroups, identifying short-term outcomes, and using multiple types of COA instruments to measure the same constructs. Challenges in column 3 center around the small patient population and heterogeneity of the condition or study sample. Few disease-specific instruments for RDs exist. Strategies include adapting existing instruments developed for a similar condition or that contain symptoms of importance to the RD patient population, or using a generic instrument validated for the context of use. CONCLUSIONS: This report provides state-of-the-art solutions to patient-reported outcome (PRO) and observer reported outcome (ObsRO) assessments challenges in clinical trials of patients with RDs. These recommended solutions are both pragmatic and creative and posed with clear recognition of the global regulatory context used in RD clinical development programs. PMID- 28712613 TI - Patient-Reported Outcome and Observer-Reported Outcome Assessment in Rare Disease Trials. PMID- 28712614 TI - What Is Real-World Data? A Review of Definitions Based on Literature and Stakeholder Interviews. AB - BACKGROUND: Despite increasing recognition of the value of real-world data (RWD), consensus on the definition of RWD is lacking. OBJECTIVES: To review definitions publicly available for RWD to shed light on similarities and differences between them. METHODS: A literature review and stakeholder interviews were used to compile data from eight groups of stakeholders. Data from documents and interviews were subjected to coding analysis. Definitions identified were classified into four categories: 1) data collected in a non-randomized controlled trial setting, 2) data collected in a non-interventional/non-controlled setting, 3) data collected in a non-experimental setting, and 4) others (i.e., data that do not fit into the other three categories). The frequency of definitions identified per category was recorded. RESULTS: Fifty-three documents and 20 interviews were assessed. Thirty-eight definitions were identified: 20 out of 38 definitions (53%) were category 1 definitions, 9 (24%) were category 2 definitions, 5 (13%) were category 3 definitions, and 4 (11%) were category 4 definitions. Differences were identified between, and within, definition categories. For example, opinions differed on the aspects of intervention with which non-interventional/non-controlled settings should abide. No definitions were provided in two interviews or identified in 33 documents. CONCLUSIONS: Most of the definitions defined RWD as data collected in a non-randomized controlled trial setting. A considerable number of definitions, however, diverged from this concept. Moreover, a significant number of authors and stakeholders did not have an official, institutional definition for RWD. Persisting variability in stakeholder definitions of RWD may lead to disparities among different stakeholders when discussing RWD use in decision making. PMID- 28712615 TI - Predicting Real-World Effectiveness of Cancer Therapies Using Overall Survival and Progression-Free Survival from Clinical Trials: Empirical Evidence for the ASCO Value Framework. AB - OBJECTIVES: To measure the relationship between randomized controlled trial (RCT) efficacy and real-world effectiveness for oncology treatments as well as how this relationship varies depending on an RCT's use of surrogate versus overall survival (OS) endpoints. METHODS: We abstracted treatment efficacy measures from 21 phase III RCTs reporting OS and either progression-free survival or time to progression endpoints in breast, colorectal, lung, ovarian, and pancreatic cancers. For these treatments, we estimated real-world OS as the mortality hazard ratio (RW MHR) among patients meeting RCT inclusion criteria in Surveillance and Epidemiology End Results-Medicare data. The primary outcome variable was real world OS observed in the Surveillance and Epidemiology End Results-Medicare data. We used a Cox proportional hazard regression model to calibrate the differences between RW MHR and the hazard ratios on the basis of RCTs using either OS (RCT MHR) or progression-free survival/time to progression surrogate (RCT surrogate hazard ratio [SHR]) endpoints. RESULTS: Treatment arm therapies reduced mortality in RCTs relative to controls (average RCT MHR = 0.85; range 0.56-1.10) and lowered progression (average RCT SHR = 0.73; range 0.43-1.03). Among real-world patients who used either the treatment or the control arm regimens evaluated in the relevant RCT, RW MHRs were 0.6% (95% confidence interval -3.5% to 4.8%) higher than RCT MHRs, and RW MHRs were 15.7% (95% confidence interval 11.0% to 20.5%) higher than RCT SHRs. CONCLUSIONS: Real-world OS treatment benefits were similar to those observed in RCTs based on OS endpoints, but were 16% less than RCT efficacy estimates based on surrogate endpoints. These results, however, varied by tumor and line of therapy. PMID- 28712616 TI - Aripiprazole Lauroxil Compared with Paliperidone Palmitate in Patients with Schizophrenia: An Indirect Treatment Comparison. AB - BACKGROUND: Aripiprazole lauroxil (AL) is a long-acting injectable atypical antipsychotic recently approved for treatment of schizophrenia on the basis of a large-scale trial of two doses of AL versus placebo. There are no direct comparison studies with paliperidone palmitate (PP; long-acting antipsychotic used most often in acute settings) for the acute psychotic episode. OBJECTIVES: To indirectly compare efficacy and safety of the pivotal AL study with all PP studies meeting indirect comparison criteria. METHODS: Systematic searches of MEDLINE, Embase, Cochrane CENTRAL, PsycINFO, ClinicalTrials.gov, International Clinical Trials Registry Platform, and gray literature were performed to identify randomized controlled trials of PP with similar designs to the AL trial. Bayesian network meta-analysis compared treatments with respect to symptom response and tolerability issues including weight gain, akathisia, parkinsonism, and likelihood of treatment-emergent adverse events. RESULTS: Three appropriate PP studies were identified for indirect comparison. Both doses of AL (441 mg and 882 mg monthly) were used and compared with two efficacious doses of PP (156 mg and 234 mg monthly). All four active-treatment conditions were associated with comparable reductions in acute symptoms (Positive and Negative Syndrome Scale) versus placebo and were of similar magnitude (range of mean difference -8.12 to 12.01, with overlapping 95% credible intervals). Between-group comparisons of active-treatment arms were associated with summary estimates of magnitude near 0. No clinically meaningful differences in selected safety or tolerability parameter incidence were found between active treatments. CONCLUSIONS: These results suggest that both AL and PP are effective for treatment of adults experiencing acute exacerbation of schizophrenia. PMID- 28712617 TI - Cost-Effectiveness Analysis of an Automated Medication System Implemented in a Danish Hospital Setting. AB - OBJECTIVES: To evaluate the cost-effectiveness of an automated medication system (AMS) implemented in a Danish hospital setting. METHODS: An economic evaluation was performed alongside a controlled before-and-after effectiveness study with one control ward and one intervention ward. The primary outcome measure was the number of errors in the medication administration process observed prospectively before and after implementation. To determine the difference in proportion of errors after implementation of the AMS, logistic regression was applied with the presence of error(s) as the dependent variable. Time, group, and interaction between time and group were the independent variables. The cost analysis used the hospital perspective with a short-term incremental costing approach. The total 6 month costs with and without the AMS were calculated as well as the incremental costs. The number of avoided administration errors was related to the incremental costs to obtain the cost-effectiveness ratio expressed as the cost per avoided administration error. RESULTS: The AMS resulted in a statistically significant reduction in the proportion of errors in the intervention ward compared with the control ward. The cost analysis showed that the AMS increased the ward's 6-month cost by ?16,843. The cost-effectiveness ratio was estimated at ?2.01 per avoided administration error, ?2.91 per avoided procedural error, and ?19.38 per avoided clinical error. CONCLUSIONS: The AMS was effective in reducing errors in the medication administration process at a higher overall cost. The cost effectiveness analysis showed that the AMS was associated with affordable cost effectiveness rates. PMID- 28712618 TI - Would a Large tPA Trial for Those 4.5 to 6.0 Hours from Stroke Onset Be Good Value for Information? AB - OBJECTIVES: To quantify the potential value of new research in patients treated with thrombolytic treatment (tissue-type plasminogen activator [tPA]) in the 4.5- to 6.0-hour time window after stroke onset and to determine the optimal size of a future trial using value of information analysis. METHODS: Expected value of partial perfect and sample information (EVPPI and EVSI) analyses were conducted using a probabilistic Markov model. Data for modified Rankin Scale (mRS) distributions in patients 4.5 to 6.0 hours since stroke onset for tPA (n = 576) and placebo (n = 543) were obtained from pooled randomized controlled trials. EVSI was quantified with net monetary benefit (assuming willingness to pay for health as $100,000/QALY). We calculated discounted population-level EVSI by multiplying per-person EVSI by the annual number of eligible patients with stroke in the United States and assuming a 10-year time frame of treatment use. Study costs were based on administrative costs and the costs of tPA. RESULTS: The base case lifetime cost-effectiveness analysis showed that tPA was dominated by placebo in this patient group. EVPPI for mRS distributions was $1003 per person. On the basis of EVSI, the optimal sample size of a new trial collecting data on tPA efficacy in these patients would be 5600 across study arms with expected population-level societal returns (EVSI minus study costs) of $68.7 million. CONCLUSIONS: Expanding research attention to the 4.5- to 6.0-hour time window for tPA treatment of patients with acute ischemic stroke is justified because the expected returns are substantial. Even a relatively large trial in which more information on treatment efficacy on the basis of mRS scores is collected would represent good value for information. PMID- 28712619 TI - Ethics of Informed Consent for Pragmatic Trials with New Interventions. AB - OBJECTIVES: Pragmatic trials evaluate the comparative benefits, risks, and burdens of health care interventions in real-world conditions. Such studies are now recognized as valuable to the perimarketing stage of drug development and evaluation, with early pragmatic trials (EPTs) being explored as a means to generate real-world evidence at the time of regulatory market approval. In this article, we present an analysis of the ethical issues involved in informed consent for EPTs, in light of the generally recognized concern that traditional ethical rules governing randomized clinical trials, such as lengthy informed consent procedures, could threaten the "real world" nature of such trials. Specifically, we examine to what extent modifications (waivers or alterations) to regulatory consent for EPTs would be ethical. METHODS: We first identify broadly accepted necessary conditions for modifications of informed consent (namely, the research involves no more than minimal risk of harm, the research is impracticable with regulatory consent, and the alternative to regulatory consent does not violate legitimate patient expectations) and then apply those criteria to the premarket and early postmarket contexts. RESULTS AND CONCLUSIONS: The analysis shows that neither waivers nor alterations of regulatory consent for premarket EPTs will be ethically permissible. For postmarket EPTs with newly approved interventions, waivers of consent will be ethically problematic, but some studies might be conducted in an ethical manner with alterations to regulatory consent. PMID- 28712620 TI - A Review of Empirical Analyses of Disinvestment Initiatives. AB - BACKGROUND: Disinvesting in low-value health care services provides opportunities for investment in higher value care and thus an increase in health care efficiency. OBJECTIVES: To identify international experience with disinvestment initiatives and to review empirical analyses of disinvestment initiatives. METHODS: We performed a literature search using the PubMed database to identify international experience with disinvestment initiatives. We also reviewed empirical analyses of disinvestment initiatives. RESULTS: We identified 26 unique disinvestment initiatives implemented across 11 countries. Nineteen addressed multiple intervention types, six addressed only drugs, and one addressed only devices. We reviewed 18 empirical analyses of disinvestment initiatives: 7 reported that the initiative was successful, 8 reported that the initiative was unsuccessful, and 3 reported that findings were mixed; that is, the study considered multiple services and reported a decrease in the use of some but not others. Thirty-seven low-value services were evaluated across the 18 empirical analyses, for 14 (38%) of which the disinvestment initiative led to a decline in use. Six of the seven studies that reported the disinvestment initiative to be successful included an attempt to promote the disinvestment initiative among participating clinicians. CONCLUSIONS: The success of disinvestment initiatives has been mixed, with fewer than half the identified empirical studies reporting that use of the low-value service was reduced. Our findings suggest that promotion of the disinvestment initiative among clinicians is a key component to the success of the disinvestment initiative. PMID- 28712621 TI - Dealing with Uncertainty and Accounting for Social Value Judgments in Assessments of Orphan Drugs: Evidence from Four European Countries. AB - OBJECTIVES: To better understand the reasons for differences in reimbursement decisions for orphan drugs in four European countries that were not readily apparent from health technology assessment (HTA) reports and operating procedures. METHODS: Semistructured interviews with representatives of HTA bodies in England, Scotland, Sweden, and France were conducted. An interview topic guide was developed on the basis of findings from a systematic comparison of HTA decisions for 10 orphan drugs. Qualitative thematic data analysis was applied to the interview transcripts using the framework approach. RESULTS: Eight representatives from the four HTA bodies were interviewed between March and June 2015. Evidentiary requirements and approaches to dealing with imperfect or incomplete evidence were explored, including trial design and duration, study population and subgroups, comparators, and end points. Interviewees agreed that decisions regarding orphan drugs are made in a context of lower quality evidence, and the threshold of acceptable uncertainty varied by country. Some countries imposed higher evidentiary standards for greater clinical claims, which may be more challenging for orphan diseases. The acceptability of surrogate end points was not consistent across countries nor were the validation requirements. The most common social value judgments identified related to innovation, disease severity, and unmet need. Differences were seen in the way these concepts were defined and accounted for across countries. CONCLUSIONS: Although agreement was seen in evidentiary requirements or preferences, there were subtle differences in the circumstances in which uncertain evidence may be considered acceptable, possibly explaining differences in HTA recommendations across countries. PMID- 28712622 TI - Pharmaceutical Pricing in Germany: How Is Value Determined within the Scope of AMNOG? AB - OBJECTIVES: To analyze how value is determined within the scope of the German Pharmaceutical Restructuring Act, which came into effect in 2011. METHODS: Using data from all pharmaceuticals that had undergone assessment, appraisal, and price negotiations in Germany before June 30, 2016, we applied generalized linear model regression to analyze the impact of added benefit on the difference between negotiated prices and the prices of comparators. Data were extracted from the Federal Joint Committee's appraisals and price databases. We specified added benefit in various ways. In all models, we controlled for additional criteria such as size of patient population, European price levels, and whether the comparators were generic. RESULTS: Our regression results confirmed the descriptive results, with price premiums reflecting the extent of added benefit as appraised by the Federal Joint Committee. On the substance level, an added benefit was associated with an increase in price premium of 227.2% (P < 0.001) compared with no added benefit. Moreover, we saw increases in price premium of 377.5% (P < 0.001), 90.0% (P < 0.001), and 336.8% (P < 0.001) for added benefits that were "considerable," "minor," and "not quantifiable," respectively. Beneficial effects on mortality were associated with the greatest price premium (624.3%; P < 0.001), followed by such effects on morbidity (174.7%; P < 0.001) and adverse events (93.1%; P = 0.019). CONCLUSIONS: Price premiums, or "value," are driven by health gain, the share of patients benefiting from a pharmaceutical, European price levels, and whether comparators are generic. No statement can be made, however, about the appropriateness of the level of price premiums. PMID- 28712623 TI - Valid Outcome Measures in Care for Older People: Comparing the ASCOT and the ICECAP-O. AB - BACKGROUND: Limited health care budgets and population aging result in a need to compare care services on their benefits and costs. Because services for older people often aim to improve multiple life aspects, valid measures are needed to examine their benefits on individuals' health and well-being simultaneously. Two measures may meet this end: the Adult Social Care Outcomes Toolkit (ASCOT) and the ICEpop CAPability measure for Older people (ICECAP-O). OBJECTIVES: To compare the validity of both measures, the ASCOT and the ICECAP-O. METHODS: A sampling agency gathered cross-sectional data in May 2015. Using exploratory factor analysis, the underlying factor structure of the ASCOT and the ICECAP-O was examined for the first time. Convergent and discriminant validity in relation to health measures (five-level EuroQol five-dimensional questionnaire, EuroQol Visual Analogue Scale, Barthel Index, and Geriatric Depression Scale-15) and well being measures (Older People's Quality of Life Questionnaire-13, Satisfaction with Life Scale, and Cantril's Ladder) were tested using Spearman rank correlations and variance analysis. RESULTS: The ASCOT and the ICECAP-O tapped into a shared factor, whereas both measures also loaded on two separate factors. The ASCOT and the ICECAP-O correlated highly with the health and well-being measures, but the correlation with the physical health measure Barthel Index was moderate. Both measures discriminated between subgroups of respondents. CONCLUSIONS: The ASCOT and the ICECAP-O seem promising measures to evaluate well being among older people, whereby the ASCOT seems more specific to social care related outcomes. The performance of both measures in other respondent groups and countries, and their relation to physical health, need to be further examined before their use in economic evaluations can be recommended. PMID- 28712624 TI - Less Is More: Cross-Validation Testing of Simplified Nonlinear Regression Model Specifications for EQ-5D-5L Health State Values. AB - BACKGROUND: The conventional method for modeling of the five-level EuroQol five dimensional questionnaire (EQ-5D-5L) health state values in national valuation studies is an additive 20-parameter main-effects regression model. Statistical models with many parameters are at increased risk of overfitting-fitting to noise and measurement error, rather than the underlying relationship. OBJECTIVES: To compare the 20-parameter main-effects model to simplified, nonlinear, multiplicative regression models in terms of how accurately they predict mean values of out-of-sample health states. METHODS: We used data from the Spanish, Singaporean, and Chinese EQ-5D-5L valuation studies. Four models were compared: an 8-parameter model with single parameter per dimension, multiplied by cross dimensional parameters for levels 2, 3, and 4; 9- and 11-parameter extensions with handling of differences in the wording of level 5; and the "standard" additive 20-parameter model. Fixed- and random-intercept variants of all models were tested using two cross-validation methods: leave-one-out at the level of valued health states, and of health state blocks used in EQ-5D-5L valuation studies. Mean absolute error, Lin concordance correlation coefficient, and Pearson R between observed health state means and out-of-sample predictions were compared. RESULTS: Predictive accuracy was generally best using random intercepts. The 8-, 9-, and 11-parameter models outperformed the 20-parameter model in predicting out-of-sample health states. CONCLUSIONS: Simplified nonlinear regression models look promising and should be investigated further using other EQ-5D-5L data sets. To reduce the risk of overfitting, cross validation is recommended to inform model selection in future EQ-5D valuation studies. PMID- 28712625 TI - Impact of Survey Administration Mode on the Results of a Health-Related Discrete Choice Experiment: Online and Paper Comparison. AB - BACKGROUND: Electronic data collection is increasingly being used for discrete choice experiments (DCEs). OBJECTIVES: To study whether paper or electronic administration results in measurement effects. METHODS: Respondents were drawn from the same sample frame (an Internet panel) and completed a nearly identical DCE survey either online or on paper during the same period. A DCE on preferences for basic health insurance served as a case study. We used panel mixed logit models for the analysis. RESULTS: In total, 898 respondents completed the survey: 533 respondents completed the survey online, whereas 365 respondents returned the paper survey. There were no significant differences with respect to sociodemographic characteristics between the respondents in both samples. The median response time was shorter for the online sample than for the paper sample, and a smaller proportion of respondents from the online sample were satisfied with the number of choice sets. Although some willingness- to-pay estimates were higher for the online sample, the elicited preferences for basic health insurance characteristics were similar between both modes of administration. CONCLUSIONS: We find no indication that online surveys yield inferior results compared with paper-based surveys, whereas the price per respondent is lower for online surveys. Researchers might want to include fewer choice sets per respondent when collecting DCE data online. Because our findings are based on a nonrandomized DCE that covers one health domain only, research in other domains is needed to support our findings. PMID- 28712626 TI - Public Preferences for Lung Cancer Screening Policies. AB - BACKGROUND: Because early detection of lung cancer can substantially improve survival, there is increasing attention for lung cancer screening. OBJECTIVES: To estimate public preferences for lung cancer screening and to identify subgroups in preferences. METHODS: Seven important attributes were selected using the literature, interviews, and a panel session. Preferences were elicited using a swing weighting questionnaire. The resulting attribute weights indicate the relative importance of swings from the worst to the best level between attributes. Hierarchical clustering was used to identify subgroups with different attribute weights. RESULTS: One thousand thirty-four respondents from a representative Dutch panel aged between 40 and 80 years were included. The identified attributes were location of screening (weight = 0.18 +/- 0.16), mode of screening (weight = 0.17 +/- 0.14), sensitivity (weight = 0.16 +/- 0.13) and specificity (weight = 0.13 +/- 0.12) of the screening modality, waiting time until results (weight = 0.13 +/- 0.12), radiation burden (weight = 0.13 +/- 0.12), and duration of screening procedure (weight = 0.10 +/- 0.09). Most respondents preferred breath analysis (45%) to giving blood samples (31%) or going through a scanner (24%) as screening modality; 59% preferred screening at the general practitioner's office instead of at the hospital. There was a significant difference in education between the five identified preference subgroups (P < 0.01). CONCLUSIONS: There is considerable variation in how people value attributes of lung cancer screening. Different screening policies and implementation strategies may be appropriate for particular preference subgroups. Our results indicate that people prefer breath analysis and that they are more likely to attend screening modalities that can be used at a primary care facility. PMID- 28712627 TI - Testing the External Validity of a Discrete Choice Experiment Method: An Application to Latent Tuberculosis Infection Treatment. AB - OBJECTIVES: To explore the external validity and predictive power of stated preferences obtained from a discrete choice experiment (DCE) by comparing the predicted behavior of respondents to their actual choices at an individual level. METHODS: A DCE was performed in patients before being offered treatment for latent tuberculosis infection. A mixed logit model was estimated using hierarchical Bayes. The individual-specific preference coefficients were used to calculate the expected probability of choosing the treatment by each patient. The predicted choice using this probability was compared with their actual decision. We used a receiver-operating characteristic curve and different thresholds to convert probabilities into the predicted choices. The comparability of different distributions for the random parameters was also examined. RESULTS: Our results identified significant heterogeneity in preferences for all attributes among respondents. The best model correctly predicted actual treatment decisions for 83% of the participants. The results from using different thresholds and a receiver-operating characteristic curve also confirmed the compatibility between predicted and actual choices. We showed that individual-specific coefficients reflected respondents' actual choices more closely compared with the aggregate level estimates. CONCLUSIONS: The results of this study provided support for the external validity of DCEs on the basis of their power to predict actual behavior in this setting. Future investigations are, however, required to establish the external validity of DCEs in different settings. PMID- 28712629 TI - The Prime Diabetes Model: Novel Methods for Estimating Long-Term Clinical and Cost Outcomes in Type 1 Diabetes Mellitus. AB - BACKGROUND: Recent publications describing long-term follow-up from landmark trials and diabetes registries represent an opportunity to revisit modeling options in type 1 diabetes mellitus (T1DM). OBJECTIVES: To develop a new product independent model capable of predicting long-term clinical and cost outcomes. METHODS: After a systematic literature review to identify clinical trial and registry data, a model was developed (the PRIME Diabetes Model) to simulate T1DM progression and complication onset. The model runs as a patient-level simulation, making use of covariance matrices for cohort generation and risk factor progression, and simulating myocardial infarction, stroke, angina, heart failure, nephropathy, retinopathy, macular edema, neuropathy, amputation, hypoglycemia, ketoacidosis, mortality, and risk factor evolution. Several approaches novel to T1DM modeling were used, including patient characteristics and risk factor covariance, a glycated hemoglobin progression model derived from patient-level data, and model averaging approaches to evaluate complication risk. RESULTS: Validation analyses comparing modeled outcomes with published studies demonstrated that the PRIME Diabetes Model projects long-term patient outcomes consistent with those reported for a number of long-term studies. Macrovascular end points were reliably reproduced across five different populations and microvascular complication risk was accurately predicted on the basis of comparisons with landmark studies and published registry data. CONCLUSIONS: The PRIME Diabetes Model is product-independent, available online, and has been developed in line with good practice guidelines. Validation has indicated that outcomes from long-term studies can be reliably reproduced. The model offers new approaches to long-standing challenges in diabetes modeling and may become a valuable tool for informing health care policy. PMID- 28712628 TI - Estimating Health-State Utility Values in Kidney Transplant Recipients and Waiting-List Patients Using the EQ-5D-5L. AB - OBJECTIVES: To report health-state utility values measured using the five-level EuroQol five-dimensional questionnaire (EQ-5D-5L) in a large sample of patients with end-stage renal disease and to explore how these values vary in relation to patient characteristics and treatment factors. METHODS: As part of the prospective observational study entitled "Access to Transplantation and Transplant Outcome Measures," we captured information on patient characteristics and treatment factors in a cohort of incident kidney transplant recipients and a cohort of prevalent patients on the transplant waiting list in the United Kingdom. We assessed patients' health status using the EQ-5D-5L and conducted multivariable regression analyses of index scores. RESULTS: EQ-5D-5L responses were available for 512 transplant recipients and 1704 waiting-list patients. Mean index scores were higher in transplant recipients at 6 months after transplant surgery (0.83) compared with patients on the waiting list (0.77). In combined regression analyses, a primary renal diagnosis of diabetes was associated with the largest decrement in utility scores. When separate regression models were fitted to each cohort, female gender and Asian ethnicity were associated with lower utility scores among waiting-list patients but not among transplant recipients. Among waiting-list patients, longer time spent on dialysis was also associated with poorer utility scores. When comorbidities were included, the presence of mental illness resulted in a utility decrement of 0.12 in both cohorts. CONCLUSIONS: This study provides new insights into variations in health state utility values from a single source that can be used to inform cost effectiveness evaluations in patients with end-stage renal disease. PMID- 28712630 TI - How to Compare the Length of Stay of Two Samples of Inpatients? A Simulation Study to Compare Type I and Type II Errors of 12 Statistical Tests. AB - BACKGROUND: Although many researchers in the field of health economics and quality of care compare the length of stay (LOS) in two inpatient samples, they often fail to check whether the sample meets the assumptions made by their chosen statistical test. In fact, LOS data show a highly right-skewed, discrete distribution in which most of the observations are tied; this violates the assumptions of most statistical tests. OBJECTIVES: To estimate the type I and type II errors associated with the application of 12 different statistical tests to a series of LOS samples. METHODS: The LOS distribution was extracted from an exhaustive French national database of inpatient stays. The type I error was estimated using 19 sample sizes and 1,000,000 simulations per sample. The type II error was estimated in three alternative scenarios. For each test, the type I and type II errors were plotted as a function of the sample size. RESULTS: Gamma regression with log link, the log rank test, median regression, Poisson regression, and Weibull survival analysis presented an unacceptably high type I error. In contrast, the Student standard t test, linear regression with log link, and the Cox models had an acceptable type I error but low power. CONCLUSIONS: When comparing the LOS for two balanced inpatient samples, the Student t test with logarithmic or rank transformation, the Wilcoxon test, and the Kruskal Wallis test are the only methods with an acceptable type I error and high power. PMID- 28712631 TI - Remembering a Giant in Economics: Kenneth J. Arrow (1922-2017). PMID- 28712632 TI - Fracture Resistance of Endodontically Treated Teeth Restored with 2 Different Fiber-reinforced Composite and 2 Conventional Composite Resin Core Buildup Materials: An In Vitro Study. AB - INTRODUCTION: The purpose of this in vitro study was to comparatively evaluate the fracture resistance of endodontically treated teeth restored with 2 fiber reinforced composite resins and 2 conventional composite resin core buildup materials. METHODS: Sixty noncarious unrestored human maxillary premolars were collected, endodontically treated (except group 1, negative control), and randomly divided into 5 groups (n = 10). Group 2 was the positive control. The remaining 40 prepared teeth were restored with various direct core buildup materials as follows: group 3 teeth were restored with dual-cure composite resin, group 4 with posterior composite resin, group 5 with fiber-reinforced composite resin, and group 6 with short fiber-reinforced composite resin. Fracture strength testing was performed using a universal testing machine. The results were statistically analyzed by 1-way analysis of variance and the post hoc Tukey test. Fracture patterns for each sample were also examined under a light microscope to determine the level of fractures. RESULTS: The mean fracture resistance values (in newtons) were obtained as group 1 > group 6 > group 4 > group 3 > group 5 > group 2. Group 6 showed the highest mean fracture resistance value, which was significantly higher than the other experimental groups, and all the fractures occurred at the level of enamel. CONCLUSIONS: Within the limitations of this study, a short fiber-reinforced composite can be used as a direct core buildup material that can effectively resist heavy occlusal forces against fracture and may reinforce the remaining tooth structure in endodontically treated teeth. PMID- 28712633 TI - Association of End-stage Renal Disease with Radiographically and Clinically Diagnosed Apical Periodontitis: A Hospital-based Study. AB - INTRODUCTION: The present study aimed to evaluate the prevalence of apical periodontitis (AP) and endodontic treatment in patients with end-stage renal disease (ESRD) as compared with patients with no history of ESRD. METHODS: In this cross-sectional study, 40 patients diagnosed with nondiabetic ESRD were included. The control group consisted of 40 age-matched and sex-matched healthy individuals. Digital panoramic radiographs were exposed on patients in both the experimental and control groups. The number of remaining teeth and the prevalence of nonsurgical and/or surgical root canal treatment were evaluated. Also, the presence of AP in all teeth and endodontically treated teeth (ETT) was recorded using the periapical index. Logistic regression was used to determine the possible association between ESRD and AP. RESULTS: AP in at least 1 tooth was found in 29 of the patients with ESRD (73%) and in 16 of the control patients (40%) (odds ratio [OR] = 3.9, P < .05). In 21 (52%) patients with ESRD in the experimental group, at least 1 ETT was diagnosed with AP. In the control group, 11 (28%) individuals had AP affecting at least 1 of the ETT (OR = 2.9, P < .05). Adjusted for the number of teeth and endodontic treatment, ESRD was significantly associated with the presence of AP (P < .05; OR = 2.6; 95% confidence interval, 1.43-4.8). Also, the number of teeth with AP was significantly associated with the urea serum level in the experimental group (P < .05, beta coefficient = 4.35). CONCLUSION: AP was significantly more prevalent in the experimental group. This may suggest that ESRD could possibly alter the pathogenesis of AP. However, these findings do not confirm the presence of any cause-and-effect relationship between these conditions. Also, considering the modifying effect of AP on urea serum level, the treatment of AP could be incorporated in the treatment planning of patients with ESRD. PMID- 28712634 TI - Management of Dens Invaginatus Type II Associated with Immature Apex and Large Periradicular Lesion Using Platelet-rich Fibrin and Biodentine. AB - Dens invaginatus (DI) poses peculiar challenges in endodontic treatment of teeth because of distortion of pulpal space. A case of Oehlers type II DI with open apex and large periapical lesion is reported. The case was managed using cone beam computed tomography (CBCT), operating microscope, platelet-rich fibrin (PRF), and Biodentine. A 15-year-old male patient presented with palatal swelling. Pulp sensibility testing of right maxillary lateral incisor was negative. Intraoral periapical digital radiograph revealed an Oehlers type II DI with open apex and periapical radiolucency. A CBCT scan was performed to study the anatomy, determine the true extent of the periapical lesion, and form a treatment plan. A diagnosis of Oehlers type II DI with pulp necrosis and acute periapical abscess was made. Two-visit endodontic treatment was performed. In the first visit, the invaginated central mass was removed under operating microscope, chemo-mechanical preparation was done, and double antibiotic paste dressing was placed. In the second visit, the canal was sealed with apical matrices of PRF and Biodentine as filling material. The patient was asymptomatic and radiographs revealed continued healing of the osseous defect at follow-up visits. A CBCT scan at 30 months showed complete continuity of periodontal ligament space, healing of labial and palatal cortical plates, and formation of intercortical bone. The advances in endodontic armamentarium and technology, like CBCT and operating microscope, have made successful treatment of challenging cases possible. PRF and Biodentine as apical matrices and filling material, respectively, proved to be effective in the present case. PMID- 28712635 TI - Efficacy of XP-Endo Finisher in the Removal of Triple Antibiotic Paste from Immature Root Canals. AB - INTRODUCTION: The aim of this study was to evaluate and compare the effectiveness of the XP-Endo Finisher (FKG Dentaire, La Chaux-de-Fonds, Switzerland) with passive ultrasonic irrigation (PUI) and needle irrigation in the removal of triple antibiotic paste (TAP) from the straight immature root canals of extracted teeth. METHODS: Thirty-four freshly extracted single-rooted teeth were used. All canals were prepared up to the ProTaper F5 file (Dentsply Maillefer, Ballaigues, Switzerland). Apices were drilled to simulate teeth with immature apices. The canals were filled with TAP, sealed, and incubated at 37 degrees C and 100% humidity for 1 month. Samples were randomly assigned to 3 experimental groups according to the method used for TAP removal: XP-Endo Finisher, PUI, and needle irrigation (n = 10). Then, the roots were split into 2 halves. The amount of TAP residue in the apical portion of each segment was evaluated using a scanning electron microscopy and scored. RESULTS: The amount of remaining TAP was significantly lower in the XP-Endo Finisher group compared with the needle irrigation and PUI groups (P < .05). Between the needle irrigation and PUI groups, there were no statistically significant differences (P > .05). CONCLUSIONS: Within the limitations of this study, the XP-Endo Finisher removed significantly more TAP than needle irrigation and PUI. PMID- 28712636 TI - Human Exoproteome in Acute Apical Abscesses. AB - INTRODUCTION: An acute apical abscess is a severe response of the host to massive invasion of the periapical tissues by bacteria from infected root canals. Although many studies have investigated the microbiota involved in the process, information on the host factors released during abscess formation is scarce. The purpose of this study was to describe the human exoproteome in samples from acute apical abscesses. METHODS: Fourteen pus samples were obtained by aspiration from patients with an acute apical abscess. Samples were subjected to protein digestion, and the tryptic peptides were analyzed using a mass spectrometer and ion trap instrument. The human proteins identified in this analysis were classified into different functional categories. RESULTS: A total of 303 proteins were identified. Most of these proteins were involved in cellular and metabolic processes. Immune system proteins were also very frequent and included immunoglobulins, S100 proteins, complement proteins, and heat shock proteins. Polymorphonuclear neutrophil proteins were also commonly detected, including myeloperoxidases, defensins, elastases, and gelatinases. Iron-sequestering proteins including transferrin and lactoferrin/lactotransferrin were found in many samples. CONCLUSIONS: The human exoproteome included a wide variety of proteins related to cellular processes, metabolism, and immune response. Proteins involved in different mechanisms against infection, tissue damage, and protection against tissue damage were identified. Knowledge of the presence and function of these proteins using proteomics provides an insight into the complex host pathogen relationship, the host antimicrobial strategies to fight infections, and the disease pathogenesis. PMID- 28712637 TI - Treatment Options for Failing Regenerative Endodontic Procedures: Report of 3 Cases. AB - INTRODUCTION: Regenerative treatments in necrotic immature teeth are suggested as alternatives to conventional multiple or single-step apexification procedures. Although case reports and case series provide promising results, the treatment protocol is not yet fully established and regenerative procedure might fail. Once failure is encountered, the apexification treatment options still remain. METHODS: Repetition of the regenerative procedure after initial revitalization failure has not been suggested yet. Here, 3 cases of failing regenerative endodontic procedures are reported. All 3 cases had been initially treated by single-step disinfection/revascularization procedures. In different time intervals, all cases showed signs of recurrent disease. The first case was managed with renegotiation and apical mineral trioxide aggregate plug placement; the second case was managed with renegotiation and conventional root canal treatment; and the third case was managed with renegotiation, long-term calcium hydroxide disinfection, and repetition of the regenerative endodontic procedure. RESULTS: Two years after the second intervention, all cases were considered successful. CONCLUSIONS: Repetition of failed regenerative treatment procedures might be a viable alternative to conventional apexification procedures. PMID- 28712638 TI - Canal Transportation, Unprepared Areas, and Dentin Removal after Preparation with BT-RaCe and ProTaper Next Systems. AB - INTRODUCTION: This study compared the shaping ability of ProTaper Next (Dentsply Sirona, Tulsa, OK) and BT-RaCe (FKG Dentaire, La Chaux-de-Fonds, Switzerland) instrument systems in the mesial canals of mandibular molars using micro-computed tomographic (micro-CT) imaging. METHODS: A total of 17 type IV mesial roots of extracted first mandibular molars were scanned using micro-CT imaging before and after root canal preparation with the 2 instrument systems. Both systems were used in the same root but alternating the mesial canals from root to root. The following parameters were analyzed: root canal volume, surface area, unprepared surface areas, transportation, canal/root width ratio, and preparation time. RESULTS: There were no statistically significant differences between the 2 systems for all evaluated parameters (P > .05). The unprepared surface areas for the full canal length and the apical 5-mm segment were 33% and 14% for BT-RaCe and 31% and 14% for ProTaper Next, respectively. After preparation, all root canals had a diameter that was not larger than 35% of the root diameter at the coronal and middle segments. CONCLUSIONS: The 2 systems showed no differences in any of the evaluated shaping parameters. None of the tested systems put the roots at risk of fracture because of excessive dentin removal. PMID- 28712639 TI - Reduction in Fracture Resistance of the Root with Aging. AB - INTRODUCTION: The incidence of vertical root fracture in endodontically treated teeth increases with patient age. This study evaluated the microstructure, chemical composition, and mechanical properties of radicular dentin as a function of aging. METHODS: Single-rooted teeth were obtained from adult donors ranging from age 15 to older than 80 years. Beams were extracted from the middle third of the root and subjected to 4-point flexure to failure to evaluate strength of dentin in terms of donor age. Based on the strength distribution, the fatigue strength of root tissue from young (<=30 years) and old (>=55 years) donor teeth was evaluated via cyclic flexure loading. The microstructure and chemical composition of radicular dentin from the 2 groups were evaluated as a function of distance from the root apex using microscopy and Raman spectroscopy, respectively. RESULTS: The strength decreased with age by approximately 25 MPa per decade, which resulted in a significant difference (P <= .0001) between the young (199 +/- 36 MPa) and old (122 +/- 11 MPa) groups. There was also a significant difference (P <= .0001) in fatigue strength between the young and old age groups. Both the mineral-to-collagen ratio and degree of cross-linking increased with age, with the largest changes identified in the apical and middle thirds, respectively. CONCLUSIONS: There is a reduction in the damage tolerance of radicular dentin with increasing age. This degradation appears to result from changes in the microstructure, corresponding chemical composition, and increase in collagen cross-linking with age, and is most severe near the root apex. PMID- 28712641 TI - Late onset postpartum preeclampsia 3 months after delivery. AB - Preeclampsia is defined by the American College of Obstetrics and Gynecology (ACOG) as "the occurrence of new onset hypertension plus new-onset proteinuria" [1]. Up-to-Date elaborates a little further on this by defining preeclampsia as "the new onset of hypertension and proteinuria, or hypertension and end-organ dysfunction with or without proteinuria, after 20 weeks of gestation in a previously normotensive woman. It may also develop postpartum. Severe hypertension or signs/symptoms of end-organ injury represent the severe end of the disease spectrum" [2] In 2013, the American College of Obstetricians and Gynecologists removed proteinuria as a key component in the diagnosis of preeclampsia. They also removed massive proteinuria (previously, 5 g/24 hours) and fetal growth restriction as possible features of severe disease. They found that were was a poor correlation in many outcomes between massive proteinuria and fetal growth restriction when managed similarly, with or without preeclampsia as a diagnosis. Oliguria was also removed as a characteristic of severe disease. [3] There have been several cases reported in the literature as well as by Obstetricians citing the incidence of preeclampsia occurring upwards of 6 to even 12 weeks postpartum. We hope to demonstrate what we believe to be a case of postpartum preeclampsia at 89 days postpartum. PMID- 28712640 TI - Resident Calmodulin Primes NMDA Receptors for Ca2+-Dependent Inactivation. AB - N-methyl-d-aspartate (NMDA) receptors are glutamate- and glycine-gated channels that flux Na+ and Ca2+ into postsynaptic neurons during synaptic transmission. The resulting intracellular Ca2+ transient is essential to physiological and pathological processes related to synaptic development, plasticity, and apoptosis. It also engages calmodulin (CaM) to reduce subsequent NMDA receptor activity in a process known as Ca2+-dependent inactivation (CDI). Here, we used whole-cell electrophysiology to measure CDI and computational modeling to dissect the sequence of events that underlies it. With these approaches, we estimate that CaM senses NMDA receptor Ca2+ influx at ~9 nm from the channel pore. Further, when we controlled the frequency of Ca2+ influx through individual channels, we found that a kinetic model where apoCaM associates with channels before their activation best predicts the measured CDI. These results provide, to our knowledge, novel functional evidence for CaM preassociation to NMDA receptors in living cells. This particular mechanism for autoinhibitory feedback reveals strategies and challenges for Ca2+ regulation in neurons during physiological synaptic activity and disease. PMID- 28712642 TI - Febrile abdominal pain revealing Horton's disease. AB - BACKGROUND: Horton's disease is a systemic inflammatory vasculitis, usually found in persons over 50years old. It affects medium and large-sized arteries stemming from the external carotid, especially the superficial temporal arteries. It can affect extracranial large vessels but only rarely the aorta. Diagnosis of aortitis is difficult and its incidence is probably underestimated. CASE PRESENTATION: A 68-year-old Caucasian woman consulted in an emergency department for febrile abdominal pain with inflammatory syndrome. Abdomen was soft with right-side flank sensitivity. A contrast-enhanced CT scan showed aortitis from the descending aorta to the iliac arteries without complication. Because of age, clinical presentation and aortitis, Horton disease was suspected. The temporal artery biopsy showed a histological aspect of degenerative endarteritis with intimal thickening and luminal stenosis. High-dose corticosteroid therapy was introduced which improved clinical conditions and resulted in the amendment of the pain. DISCUSSION: In the present case, this patient had Horton's disease, based on 3 criteria of The American College of Rheumatology (age, temporal artery abnormalities and inflammatory syndrome) associated with aortitis. However, aortitis is a rare complication of Horton disease and is a major cause of mortality inasmuch as it can be complicated by aneurysm and dissection. It is unusual to diagnose Horton's disease from aortitis symptoms without complications. The aorta represents the most severe localization of Horton's disease. It should not be ignored in etiological hypotheses regarding febrile abdominal pain in the elderly. Corticosteroids should be started rapidly at high doses and temporal artery biopsy should be planned. PMID- 28712643 TI - Emergency geriatric assessment: A novel comprehensive screen tool for geriatric patients in the emergency department. PMID- 28712644 TI - Capsaicin topical in emergency department treatment of cannabinoid hyperemesis syndrome. PMID- 28712645 TI - Comparison of QSOFA score and SIRS criteria as screening mechanisms for emergency department sepsis. AB - OBJECTIVES: The Quick Sequential [Sepsis-related] Organ Failure Assessment (qSOFA) score has been shown to accurately predict mortality in septic patients and is part of recently proposed diagnostic criteria for sepsis. We sought to ascertain the sensitive of the score in diagnosing sepsis, as well as the diagnostic timeliness of the score when compared to traditional systemic inflammatory response syndrome (SIRS) criteria in a population of emergency department (ED) patients treated in the ED, admitted, and subsequently discharged with a diagnosis of sepsis. METHODS: Electronic health records of 200 patients who were treated for suspected sepsis in our ED and ultimately discharged from our hospital with a diagnosis of sepsis were randomly selected for review from a population of adult ED patients (N=1880). Data extracted included the presence of SIRS criteria and the qSOFA score as well as time required to meet said criteria. RESULTS: In this cohort, 94.5% met SIRS criteria while in the ED whereas only 58.3% met qSOFA. The mean time from arrival to SIRS documentation was 47.1min (95% CI: 36.5-57.8) compared to 84.0min (95% CI: 62.2-105.8) for qSOFA. The median ED "door" to positive SIRS criteria was 12min and 29min for qSOFA. CONCLUSIONS: Although qSOFA may be valuable in predicting sepsis-related mortality, it performed poorly as a screening tool for identifying sepsis in the ED. As the time to meet qSOFA criteria was significantly longer than for SIRS, relying on qSOFA alone may delay initiation of evidence-based interventions known to improve sepsis-related outcomes. PMID- 28712646 TI - Live births after embryo selection using morphokinetics versus conventional morphology: a retrospective analysis. AB - The increasing corpus of clinical studies using time-lapse imaging for embryo selection demonstrates considerable variation in study protocols and only limited sized study cohorts. Outcome measures are based on implantation or clinical pregnancy; some predict blastulation from early cleavage-stage data, and few have evaluated live birth. Erroneously, most studies treat the embryos as independent variables and do not include patient or treatment variables in the statistical analyses. In this study, cohort size was 14,793 patients and 23,762 cycles. The incidence of live birth (n = 973 deliveries) after embryo selection by objective morphokinetic algorithms was compared with conventional embryology selection parameters (n = 6948 deliveries). A 19% increase in the incidence of live birth was observed when morphokinetic data were used to select embryos for the patient cohort aged younger than 38 years (OR 1.19 with 95% CI 1.06 to 1.34) using their own eggs, and an increase of 37% for oocyte recipients aged over 37 years (OR 1.370; 95% Cl 0.763 to 2.450). This is the largest study of the prospective use of time-lapse imaging algorithms in IVF reporting on live birth outcome, although the nature of purely a closed system versus standard incubation could not be assessed. PMID- 28712648 TI - Elucidating biochemical features and biological roles of Streptomyces proteins recognizing crystalline chitin- and cellulose-types and their soluble derivatives. AB - Pioneering biochemical, immunological, physiological and microscopic studies in combination with gene cloning allowed uncovering previously unknown genes encoding proteins of streptomycetes to target crystalline chitin and cellulose as well as their soluble degradation-compounds via binding protein dependent transporters. Complementary analyses provoked an understanding of novel regulators governing transcription of selected genes. These discoveries induced detecting close and distant homologues of former orphan proteins encoded by genes from different bacteria. Grounded on structure-function-relationships, several researchers identified a few of these proteins as novel members of the growing family for lytic polysaccharides monooxygenases. Exemplary, the ecological significance of the characterized proteins including their role to promote interactions among organisms is outlined and discussed. PMID- 28712647 TI - Perinatal exposure to 2,2',4'4' -Tetrabromodiphenyl ether induces testicular toxicity in adult rats. AB - Since 1965, polybrominated diphenyl ethers (PBDEs) have been used internationally as flame-retardant additives. PBDEs were recently withdrawn from commerce in North America and Europe due to their environmental persistence, bioaccumulative properties and endocrine-disrupting effects. Generations exposed perinatally to the highest environmental doses of PBDE account for one-fifth of the total United States population. While, toxicity of PBDE for the male reproductive system has been demonstrated in several human and animal studies, the long-lasting effects of perinatal exposures on male reproduction are still poorly understood. In this study, pregnant Wistar rats were exposed to 0.2mg/kg 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) from gestation day 8 until postnatal day 21. Male reproductive outcomes were analyzed on postnatal day 120 in offspring. Exposed animals had significantly smaller testes, displayed decreased sperm production per testis weight, had significantly increased percentage of morphologically abnormal spermatozoa, and showed an increase in spermatozoa head size. Perinatal BDE-47 exposure led to significant changes in testes transcriptome, including suppression of genes essential for spermatogenesis and activation of immune response genes. In particular, we observed a 4-fold average decrease in expression of protamine and transition protein genes in testes, suggesting that histone-protamine exchange may be dysregulated during spermatogenesis, resulting in an aberrant sperm epigenome. The possibility of long-lasting effects of developmental PBDE exposures calls for additional studies to build a foundation for the development of preventive and protective interventions against the environmentally-induced decline in fertility. PMID- 28712649 TI - Foreword for Pediatric Rehabilitation Medicine. PMID- 28712650 TI - Response to a letter to the editor. PMID- 28712651 TI - The association between red cell distribution width and poor outcomes in hospitalized patients with influenza: Methodological issues. PMID- 28712652 TI - Serotonergic Modulation Enables Pathway-Specific Plasticity in a Developing Sensory Circuit in Drosophila. AB - How experiences during development cause long-lasting changes in sensory circuits and affect behavior in mature animals are poorly understood. Here we establish a novel system for mechanistic analysis of the plasticity of developing neural circuits by showing that sensory experience during development alters nociceptive behavior and circuit physiology in Drosophila larvae. Despite the convergence of nociceptive and mechanosensory inputs on common second-order neurons (SONs), developmental noxious input modifies transmission from nociceptors to their SONs, but not from mechanosensors to the same SONs, which suggests striking sensory pathway specificity. These SONs activate serotonergic neurons to inhibit nociceptor-to-SON transmission; stimulation of nociceptors during development sensitizes nociceptor presynapses to this feedback inhibition. Our results demonstrate that, unlike associative learning, which involves inputs from two sensory pathways, sensory pathway-specific plasticity in the Drosophila nociceptive circuit is in part established through feedback modulation. This study elucidates a novel mechanism that enables pathway-specific plasticity in sensory systems. VIDEO ABSTRACT. PMID- 28712654 TI - Activity-Dependent Gating of Parvalbumin Interneuron Function by the Perineuronal Net Protein Brevican. AB - Activity-dependent neuronal plasticity is a fundamental mechanism through which the nervous system adapts to sensory experience. Several lines of evidence suggest that parvalbumin (PV+) interneurons are essential in this process, but the molecular mechanisms underlying the influence of experience on interneuron plasticity remain poorly understood. Perineuronal nets (PNNs) enwrapping PV+ cells are long-standing candidates for playing such a role, yet their precise contribution has remained elusive. We show that the PNN protein Brevican is a critical regulator of interneuron plasticity. We find that Brevican simultaneously controls cellular and synaptic forms of plasticity in PV+ cells by regulating the localization of potassium channels and AMPA receptors, respectively. By modulating Brevican levels, experience introduces precise molecular and cellular modifications in PV+ cells that are required for learning and memory. These findings uncover a molecular program through which a PNN protein facilitates appropriate behavioral responses to experience by dynamically gating PV+ interneuron function. PMID- 28712653 TI - Neural Circuit-Specialized Astrocytes: Transcriptomic, Proteomic, Morphological, and Functional Evidence. AB - Astrocytes are ubiquitous in the brain and are widely held to be largely identical. However, this view has not been fully tested, and the possibility that astrocytes are neural circuit specialized remains largely unexplored. Here, we used multiple integrated approaches, including RNA sequencing (RNA-seq), mass spectrometry, electrophysiology, immunohistochemistry, serial block-face-scanning electron microscopy, morphological reconstructions, pharmacogenetics, and diffusible dye, calcium, and glutamate imaging, to directly compare adult striatal and hippocampal astrocytes under identical conditions. We found significant differences in electrophysiological properties, Ca2+ signaling, morphology, and astrocyte-synapse proximity between striatal and hippocampal astrocytes. Unbiased evaluation of actively translated RNA and proteomic data confirmed significant astrocyte diversity between hippocampal and striatal circuits. We thus report core astrocyte properties, reveal evidence for specialized astrocytes within neural circuits, and provide new, integrated database resources and approaches to explore astrocyte diversity and function throughout the adult brain. VIDEO ABSTRACT. PMID- 28712655 TI - Insulin Regulation of Proteostasis and Clinical Implications. AB - Maintenance and modification of the cellular proteome are at the core of normal cellular physiology. Although insulin is well known for its control of glucose homeostasis, its critical role in maintaining proteome homeostasis (proteostasis) is less appreciated. Insulin signaling regulates protein synthesis and degradation as well as posttranslational modifications at the tissue level and coordinates proteostasis at the organism level. Here, we review regulation of proteostasis by insulin in postabsorptive, postprandial, and diabetic states. We present the effects of insulin on amino acid flux in skeletal muscle and splanchnic tissues, the regulation of protein quality control, and turnover of mitochondrial protein pools in humans. We also review the current evidence for the mechanistic control of proteostasis by insulin and insulin-like growth factor 1 receptors based on preclinical studies. Finally, we discuss irreversible posttranslational modifications of the proteome in diabetes and how future investigations will provide new insights into mechanisms of diabetic complications. PMID- 28712656 TI - Treatments for Ocular Adnexal Lymphoma: A Report by the American Academy of Ophthalmology. AB - PURPOSE: To review the literature to determine the efficacy of available treatments for ocular adnexal lymphoma (OAL) and to evaluate the outcomes and complications of treatments in patients older than 13 years. METHODS: A literature search was conducted last in March 2017 in the PubMed and Cochrane Library databases for English-language original research investigations that evaluated treatment outcomes for OAL. The searches identified 307 unique citations, and 27 studies were selected according to the criteria outlined for this assessment. RESULTS: The 27 studies reviewed comprised 2009 patients. Seventy-five percent of the cases reported were extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT). Twenty-five studies reported results using radiotherapy with or without chemotherapy or surgery. The local control rate of MALT lymphomas with treatments involving radiotherapy averaged 95.9%. Distant and local relapses can occur, and in studies reporting only on MALT lymphomas (884 patients), the 5-year and 10-year disease-free survival rates were reported to be 86.4% and 78.7%, respectively. However, overall survival in patients receiving radiotherapy remained very good, with the 5-year and 10-year survival rates reported to be 93.8% and 84.9%, respectively. Studies that included data on multiple histologic subtypes of lymphoma or non-MALT lymphomas (988 patients) reported local control rates to be 93.1%; 5-year and 10-year disease-free survival rates to be 75.7% and 71.0%, respectively; and 5-year and 10-year overall survival rates to be 78.9% and 73.5%, respectively. Studies on the use of doxycycline for MALT lymphomas (137 patients) reported complete responses of between 4.4% and 13%. Complete and partial responses combined were between 26.7% and 65%. Disease-free survival was not reported for these 2 studies, although progression-free survival was reported to be between 55% and 60.9%. The most frequently reported complications of treatment were cataracts (12.1%) and dry eye (8.5%). CONCLUSIONS: For MALT lymphomas, local control, disease-free survival, and overall survival are good with radiation treatment. The results of treatment of non-MALT lymphomas using radiotherapy also were good, but they were not as favorable as the treatment results of MALT lymphomas. PMID- 28712658 TI - Is YouTube an accurate and reliable source of yellow fever information during outbreaks? PMID- 28712659 TI - Pre-travel care for immunocompromised and chronically ill travellers: A retrospective study. AB - BACKGROUND: Immunocompromised and chronically ill travellers (ICCITs) are susceptible to travel related diseases. In ICCITs, pre-travel care regarding vaccinations and prophylactics is complex. We evaluated the protection level by preventive measures in ICCITs by analysing rates of vaccination protection, antibody titres, and the prescription of standby antibiotics. METHODS: We analysed, and reported according to STROBE guidelines, pre-travel care data for ICCITs visiting the medical pre-travel clinic at the Academic Medical Centre, The Netherlands from 2011 to 2016. RESULTS: We analysed 2104 visits of 1826 ICCITs. Mean age was 46.6 years and mean travel duration 34.5 days. ICCITs on immunosuppressive treatment (29.7%), HIV (17.2%) or diabetes mellitus (10.2%) comprised the largest groups. Most frequently visited countries were Suriname, Indonesia, and Ghana. Most vaccination rates were >90%. Of travellers in high need of hepatitis A and B protection, 56.6 and 75.7%, underwent titre assessments, respectively. Of ICCITs with a respective indication, 50.6% received a prescription for standby antibiotics. CONCLUSION: Vaccination rates in our study population were overall comparable to those of healthy travellers studied previously in our centre. However, regarding antibody titre assessments and prescription of standby antibiotics, this study demonstrates that uniform pre travel guidelines for ICCITs are highly needed. PMID- 28712660 TI - Numerical investigation of dispersive behaviors for helical thread waveguides using the semi-analytical isogeometric analysis method. AB - In this paper, we propose a semi-analytical isogeometric analysis(S-IGA) approach in the twist space to investigate the dispersive properties in helical thread waveguides, which combines the advantages of the spectral approach and IGA. The convergence and accuracy of the proposed method are discussed, by comparing S-IGA results with reference solutions. Additionally, the analytical expression of axial offset wavenumbers is derived to explain the difference of spectrograms between the Cartesian and twisted systems. In order to illustrate the effectiveness of the proposed method, some dispersion curves of elastic wave propagation in helical thread waveguides are presented for a wide range of thicknesses and tortuosities. PMID- 28712661 TI - Managing Incidentalomas Safely: Do Computed Tomography Requisitions Tell Us What We Need to Know? AB - PURPOSE: Technological advancements and the ever-increasing use of computed tomography (CT) have greatly increased the detection of incidental findings, including tiny pulmonary nodules. The management of many "incidentalomas" is significantly influenced by a patient's history of cancer. The study aim is to determine if CT requisitions include prior history of malignancy. METHODS: Requisitions for chest CTs performed at our adult tertiary care hospital during April 2012 were compared to a cancer history questionnaire, administered to patients at the time of CT scan. Patients were excluded from the study if the patient questionnaire was incomplete or if the purpose of the CT was for cancer staging or cancer follow-up. RESULTS: A total of 569 CTs of the chest were performed. Of the 327 patients that met inclusion criteria, 79 reported a history of cancer. After excluding patients for whom a history of malignancy could not be confirmed through a chart review and excluding nonmelanoma skin cancer, dysplasia, and in situ neoplasm, 68 patients were identified as having a history of malignancy. We found 44% (95% confidence interval [0.32-0.57]) of the chest CT requisitions for these 68 patients did not include the patient's history of cancer. Of the malignancies that were identified by patient questionnaire but omitted from the clinical history provided on the requisitions, 47% were malignancies that commonly metastasize to the lung. CONCLUSIONS: A significant number of requisitions failed to disclose a history of cancer. Without knowledge of prior malignancy, radiologists cannot comply with current guidelines regarding the reporting and management of incidental findings. PMID- 28712663 TI - Rectal swabs: a diagnostic alternative in paediatric gastroenteritis? PMID- 28712657 TI - Prevalence of Age-Related Macular Degeneration in Europe: The Past and the Future. AB - PURPOSE: Age-related macular degeneration (AMD) is a frequent, complex disorder in elderly of European ancestry. Risk profiles and treatment options have changed considerably over the years, which may have affected disease prevalence and outcome. We determined the prevalence of early and late AMD in Europe from 1990 to 2013 using the European Eye Epidemiology (E3) consortium, and made projections for the future. DESIGN: Meta-analysis of prevalence data. PARTICIPANTS: A total of 42 080 individuals 40 years of age and older participating in 14 population based cohorts from 10 countries in Europe. METHODS: AMD was diagnosed based on fundus photographs using the Rotterdam Classification. Prevalence of early and late AMD was calculated using random-effects meta-analysis stratified for age, birth cohort, gender, geographic region, and time period of the study. Best corrected visual acuity (BCVA) was compared between late AMD subtypes; geographic atrophy (GA) and choroidal neovascularization (CNV). MAIN OUTCOME MEASURES: Prevalence of early and late AMD, BCVA, and number of AMD cases. RESULTS: Prevalence of early AMD increased from 3.5% (95% confidence interval [CI] 2.1% 5.0%) in those aged 55-59 years to 17.6% (95% CI 13.6%-21.5%) in those aged >=85 years; for late AMD these figures were 0.1% (95% CI 0.04%-0.3%) and 9.8% (95% CI 6.3%-13.3%), respectively. We observed a decreasing prevalence of late AMD after 2006, which became most prominent after age 70. Prevalences were similar for gender across all age groups except for late AMD in the oldest age category, and a trend was found showing a higher prevalence of CNV in Northern Europe. After 2006, fewer eyes and fewer >=80-year-old subjects with CNV were visually impaired (P = 0.016). Projections of AMD showed an almost doubling of affected persons despite a decreasing prevalence. By 2040, the number of individuals in Europe with early AMD will range between 14.9 and 21.5 million, and for late AMD between 3.9 and 4.8 million. CONCLUSION: We observed a decreasing prevalence of AMD and an improvement in visual acuity in CNV occuring over the past 2 decades in Europe. Healthier lifestyles and implementation of anti-vascular endothelial growth factor treatment are the most likely explanations. Nevertheless, the numbers of affected subjects will increase considerably in the next 2 decades. AMD continues to remain a significant public health problem among Europeans. PMID- 28712662 TI - Enteropathogen detection in children with diarrhoea, or vomiting, or both, comparing rectal flocked swabs with stool specimens: an outpatient cohort study. AB - BACKGROUND: Enteropathogen detection traditionally relies on diarrhoeal stool samples, but these are inconvenient to collect if they are not immediately available, leading to suboptimum return rates of samples and delayed or missed diagnostic opportunities. We sought to compare the enteropathogen yields of rectal swabs and stool specimens in children with diarrhoea or vomiting, or both. METHODS: The Alberta Provincial Pediatric EnTeric Infection TEam (APPETITE) did a study in three outpatient cohorts in Calgary and Edmonton (AB, Canada)-children enrolled in the Pediatric Emergency Research Canada emergency departments, children receiving routine vaccinations at a Calgary health clinic, and symptomatic children who met criteria for treatment at home. Eligible participants were children younger than 18 years, with at least three episodes of vomiting or diarrhoea in the preceding 24 h and fewer than 7 days of symptoms. After excluding those enrolled within the previous fortnight, unable to follow up, or having psychiatric illness, neutropenia, or requiring emergent care, we attempted to collect rectal swabs and stool from all participants. Specimens were tested with the multianalyte assay Luminex xTAG Gastrointestinal Pathogen Panel, an in-house five-virus panel and bacterial culture. Primary outcomes were comparative yield (calculated as the proportion of submitted paired specimens only in which at least one pathogen was identified) and overall yield (which calculated the proportion of study participants in whom at least one pathogen was identified in all specimens, where unsubmitted specimens were analysed as negative). We used McNemar's test to do pathogen-specific analyses, and generalised estimating equations (GEE) for the global (ie, any) pathogen analyses, with adjustments made for the presence of diarrhoea, location, and their interactions with specimen type. FINDINGS: Between Dec 12, 2014, and Aug 31, 2016, we studied 1519 eligible participants, 1147 (76%) of whom provided stool specimens and 1514 (>99%) provided swab specimens. 871 (76%) of 1147 stool specimens and 1024 (68%) of 1514 swabs were positive for any pathogen (p<0.0001). Comparative yield adjusted odds ratios (ORs) for stool specimens relative to swabs were 1.24 (95% CI 1.11-1.38) in children with diarrhoea at presentation and 1.76 (1.47-2.11) in children without diarrhoea. GEE analysis identified an interaction between the presence of diarrhoea and specimen type (p=0.0011) and collection location (p=0.0078). In an overall yield analysis, pathogen yield was 57% (871 of 1519 children) for stool specimens and 67% (1024 of 1519 children) for rectal swabs, with an unadjusted OR of 0.65 (95% CI 0.59-0.72) for stool relative to swab. INTERPRETATION: Rectal swabs should be done when enteropathogen identification and rapid detection are needed, appropriate molecular diagnostic technology is available, and a stool specimen is not immediately available. In view of their high yield, we urge that the recommendation against the use of rectal swabs as diagnostic specimens be reconsidered. FUNDING: Alberta Innovates Health Solutions Team Collaborative Research Innovation Opportunity. PMID- 28712664 TI - GSK3 and its interactions with the PI3K/AKT/mTOR signalling network. AB - Glycogen Synthase Kinase-3 (GSK3 or GSK-3) is a promiscuous protein kinase and its phosphorylation of its diverse substrates has major influences on many areas of physiology and pathology, including cellular metabolism, lineage commitment and neuroscience. GSK3 was one of the first identified substrates of the heavily studied oncogenic kinase AKT, phosphorylation by which inhibits GSK3 activity via the formation of an autoinhibitory pseudosubstrate sequence. This has led to investigation of the role of GSK3 inhibition as a key component of the cellular responses to growth factors and insulin, which stimulate the class I PI 3-Kinases and in turn AKT activity and GSK3 phosphorylation. GSK3 has been shown to phosphorylate several upstream and downstream components of the PI3K/AKT/mTOR signalling network, including AKT itself, RICTOR, TSC1 and 2, PTEN and IRS1 and 2, with the potential to apply feedback control within the network. However, it has been clear for some time that functionally distinct, insulated pools of GSK3 exist which are regulated independently, so that for some GSK3 substrates such as beta-catenin, phosphorylation by GSK3 is not controlled by input from PI3K and AKT. Instead, as almost all GSK3 substrates require a priming phosphorylated residue to be 4 amino acids C-terminal to the Ser/Thr phosphorylated by GSK3, the predominant form of regulation of the activity of GSK3 often appears to be through control over these priming events, specific to individual substrates. Therefore, a major role of GSK3 can be viewed as an amplifier of the electrostatic effects on protein function which are caused by these priming phosphorylation events. Here we discuss these different aspects to GSK3 regulation and function, and the functions of GSK3 as it integrates with signalling through the PI3K-AKT-mTOR signalling axis. PMID- 28712665 TI - Isospora belli. PMID- 28712666 TI - Molecular surveillance of measles and rubella in the WHO European Region: new challenges in the elimination phase. AB - BACKGROUND: The WHO European Region (EUR) has adopted the goal of eliminating measles and rubella but individual countries perform differently in achieving this goal. Measles virus spread across the EUR by mobile groups has recently led to large outbreaks in the insufficiently vaccinated resident population. As an instrument for monitoring the elimination process and verifying the interruption of endemic virus transmission, molecular surveillance has to provide valid and representative data. Irrespective of the country's specific situation, it is required to ensure the functionality of the laboratory surveillance that is supported by the WHO Global Measles and Rubella Laboratory Network. AIMS: To investigate whether the molecular surveillance in the EUR is adequate for the challenges in the elimination phase, we addressed the quality assurance of molecular data, the continuity and intensity of molecular monitoring, and the analysis of transmission chains. SOURCES: Published articles, the molecular External Quality Assessment Programme of the WHO, the Centralized Information System for Infectious Diseases of the WHO EUR and the WHO Measles and Rubella Nucleotide Surveillance databases served as information sources. CONTENT: Molecular proficiency testing conducted by the WHO in 2016 has shown that the expertise for measles and rubella virus genotyping exists in all parts of the EUR. The analysis of surveillance data reported nationally to the WHO in 2013 2016 has revealed some countries with outbreaks but not sufficiently representative molecular data. Long-lasting supranational MV transmission chains were identified. IMPLICATIONS: A more systematic molecular monitoring and recording of the transmission pattern for the whole EUR could help to create a meaningful picture of the elimination process. PMID- 28712667 TI - Antibiotic stewardship in low- and middle-income countries: the same but different? AB - BACKGROUND: Antibiotic resistance (ABR) is a quickly worsening problem worldwide, also in low- and middle-income countries (LMICs). Appropriate antibiotic use in humans and animals, i.e. antibiotic stewardship (ABS), is one of the cornerstones of the World Health Organization's global action plan for ABR. Many LMICs are in the process of developing stewardship programs. AIMS: We highlight challenges for ABS initiatives in LMICs, give an outline of (inter)national recommendations and demonstrate examples of effective, contextualized stewardship interventions. SOURCES: We searched PubMed for articles on ABS interventions in humans in LMICs. Relevant websites and experts were consulted for additional sources. CONTENT: Evidence on effective and feasible stewardship interventions in LMICs is limited, and challenges for implementation of interventions are numerous. Nevertheless, several initiatives at the international and local levels in Latin America, Africa and Asia have shown that ABS effective interventions are feasible in LMICs, although contextualization is essential. IMPLICATIONS: Specific guidance for setting up antimicrobial stewardship programs in LMICs should be developed. Strategic points might need to be progressively addressed in LMICs, such as (a) ensuring availability of diagnostic testing, (b) providing dedicated education in ABR both for healthcare workers and the general public, (c) creating or strengthening (inter)national agencies towards better regulations and audit on production, distribution and dispensing of drugs, (d) strengthening healthcare facilities, (e) exploring a broader synergism between policy makers, academia, professional bodies and civil society and (f) designing and studying easy and scalable ABS interventions for both hospital and community settings. PMID- 28712668 TI - Treatment outcomes of multidrug-resistant tuberculosis patients in Zhejiang, China, 2009-2013. AB - OBJECTIVES: To examine treatment outcomes and factors associated with poor outcome of multidrug-resistant (MDR) tuberculosis (TB) in China. METHODS: We conducted a prospective observational cohort study including consecutive patients with MDR-TB between 2009 and 2013 in six regions of Zhejiang province. Patients were prescribed treatments by infectious disease specialists, and treatment outcomes were recorded. Sociodemographic characteristics were obtained through a structured questionnaire. The primary endpoint was poor treatment outcomes, defined as treatment failure based on microbiologic persistence, default (lost to follow-up) or death at 24 months. We assessed risk factors for poor treatment outcomes using a Cox proportional hazards model. RESULTS: A total of 820 MDR-TB patients were observed, and 537 with known treatment outcomes were included in our study. Overall, the treatment success rate was 40.2 per 100 years (374/537 participants, 69.6%), while treatment failure, death and default rates were 10.0 per 100 years (101 participants, 18.8%), 3.4 per 100 years (36 participants, 6.7%) and 2.7 per 100 years (26 participants, 4.8%) respectively. Independent predictors of poor treatment outcomes included age >60 years (hazard ratio (HR) 2.3, 95% confidence interval (CI) 1.2-4.2), patients registered as experiencing relapse (HR 2.2, 95% CI 1.1-4.4), patients registered as receiving treatment after failure (HR 2.4, 95% CI 1.2-4.9), use of standardized MDR-TB regimens (HR 0.6, 95% CI 0.4-1.0), cavitary disease (HR 4.9, 95% CI 2.8-8.6) and adverse events (HR 2.5, 95% CI 1.2-5.5). CONCLUSIONS: Under well-designed treatment and management scheme, high treatment success rates were achieved in a high-MDR-TB burden country. Antimicrobial susceptibility testing for all second-line drugs should be conducted to further assist in the treatment of MDR-TB. PMID- 28712669 TI - Use of interferon-gamma release assay and tuberculin skin test in diagnosing tuberculosis in Lithuanian adults: A comparative analysis. AB - BACKGROUND AND OBJECTIVE: Lithuania belongs to the group of countries with a high incidence of tuberculosis (TB). Some scientific studies show that the interferon gamma release assay is more accurate and correlates more highly with TB exposure as compared to the tuberculin skin test (TST). This study aimed at comparing the efficacy between the T SPOT TB and TST for diagnosing TB among Lithuanian adults. MATERIALS AND METHODS: Individuals with diagnosed TB, healthcare workers with known risk for TB and individuals without any known risk for TB underwent clinical examinations, interviews about their history of TB exposure and chest radiography. Then the TST and the T SPOT TB were performed on patients. RESULTS: A positive T SPOT TB was more common in the group with diagnosed TB compared to healthcare workers and the low risk for TB groups (97.5%, 36.4%, and 0%, respectively, P<0.01). Positive TST results did not differ between the groups with diagnosed TB and the healthcare workers (92.5% vs. 95.5%, P>0.05). Agreement between TST and T SPOT TB was poor (kappa 0.14, P>0.05). T SPOT TB had higher specificity and sensitivity compared to TST (area under the ROC 0.9+/-0.04, P<0.01, vs. 0.5+/-0.06, P>0.05). CONCLUSIONS: The T SPOT TB showed greater accuracy in diagnosing TB than TST did. Positive T SPOT TB result but not the TST was more common in patients with diagnosed TB. PMID- 28712670 TI - Production and regulation of interleukin-1 family cytokines at the materno-fetal interface. AB - IL-1 family members regulate innate immune responses, are produced by gestation associated tissues, and have a role in healthy and adverse pregnancy outcomes. To better understand their role at the materno-fetal interface we used a human tissue explant model to map lipopolysaccharide (LPS)-stimulated production of IL 1alpha, IL-1beta, IL-18, IL-33, IL-1Ra, IL-18BPa, ST2 and IL-1RAcP by placenta, choriodecidua and amnion. Caspase-dependent processing of IL-1alpha, IL-1beta, IL 18, and IL-33 and the ability of IL-1alpha, IL-1beta, IL-18, and IL-33 to regulate the production of IL-1RA, IL-18BPa, ST2 and IL-1RAcP was also determined. LPS acted as a potent inducer of IL-1 family member expression especially in the placenta and choriodecidua with the response by the amnion restricted to IL-1beta. Caspases-1, 4 and 8 contributed to LPS-stimulated production of IL-1beta and IL-18, whereas calpain was required for IL-1alpha production. Exogenous administration of IL-1alpha, IL-1beta, IL-18, and IL-33 lead to differential expression of IL-1Ra, IL-18BPa, ST2 and IL-1RAcP across all tissues examined. Most notable were the counter-regulatory effect of LPS on IL 1beta and IL-1Ra in the amnion and the broad responsiveness of the amnion to IL-1 family cytokines for increased production of immunomodulatory peptides and soluble receptors. The placenta and membranes vary not only in their output of various IL-1 family members but also in their counter-regulatory mechanisms through endogenous inhibitory peptides, processing enzymes and soluble decoy receptors. This interactive network of inflammatory mediators likely contributes to innate defence mechanisms at the materno-fetal interface to limit, in particular, the detrimental effects of microbial invasion. PMID- 28712671 TI - Analysis of stereotactic biopsies performed on suspicious calcifications identified within 24 months after completion of breast conserving surgery and radiation therapy for early breast cancer: Can biopsy be obviated? AB - BACKGROUND: To determine the cancer yield of stereotactic biopsy of suspicious calcifications identified within 24 months after breast conservation therapy (BCT). METHODS: Retrospective review of stereotactic biopsies performed during 2009-2013 for suspicious calcifications in the ipsilateral breast of patients who completed BCT. RESULTS: 94/2773 (3.4%) had stereotactic biopsies for suspicious calcifications in the ipsilateral breast; 7/94 (7.4%) had DCIS (6) or invasive (1) cancer; 5/7 occurred in the same breast quadrant as the primary. All 7 originally had negative surgical margins (>=2 mm); 6 received whole breast irradiation, and 2 received adjuvant chemotherapy + endocrine therapy. Median time to detection was 11 months (range, 6-20 months). There was a strong association between calcification morphology (particularly pleomorphic) and likelihood of malignancy (p = 0.008). CONCLUSIONS: Stereotactic biopsy of calcifications identified within 24 months post-BCT has a 7% cancer yield. Tissue biopsy should be performed rather than imaging followup alone when breast calcifications have suspicious morphology. PMID- 28712673 TI - Extract critical factors affecting the length of hospital stay of pneumonia patient by data mining (case study: an Iranian hospital). AB - MOTIVATION: Pneumonia is a prevalent infection of lower respiratory tract caused by infected lungs. Length of stay (LOS) in hospital is one of the simplest and most important indicators in hospital activity that is used for different purposes. The aim of this study is to explore the important factors affecting the LOS of patients with pneumonia in hospitals. METHODS: The clinical data set for the study were collected from 387 patients in a specialized hospital in Iran between 2009 and 2015. Patients discharge summary includes their demographic details, reasons for admission, prescribed medications for the patient, the result of laboratory tests, and length of treatment. RESULTS AND CONCLUSIONS: The proposed model in the study demonstrates the way various scenarios of data processing impact on the scale efficiency model, which points to the significance of the pre-processing in data mining. In this article, some methods were utilized; it is noteworthy that Bayesian boosting method led to better results in identifying the factors affecting LOS (accuracy 95.17%). In addition, it was found that 58% of patients younger than 15 years old and 74% of the elderly within the age range of 74-88 were more vulnerable to pneumonia disease. Also, it was found that the Meropenem is a relatively more effective medicine compared to other antibiotics which are used to treat pneumonia in the majority of age groups. Regardless of the impact of various laboratory findings (including CRP, ESR, WBC, NA, K), the patients LOS decreased as a result of Meropenem. PMID- 28712672 TI - Noise-induced cochlear synaptopathy in rhesus monkeys (Macaca mulatta). AB - Cochlear synaptopathy can result from various insults, including acoustic trauma, aging, ototoxicity, or chronic conductive hearing loss. For example, moderate noise exposure in mice can destroy up to ~50% of synapses between auditory nerve fibers (ANFs) and inner hair cells (IHCs) without affecting outer hair cells (OHCs) or thresholds, because the synaptopathy occurs first in high-threshold ANFs. However, the fiber loss likely impairs temporal processing and hearing-in noise, a classic complaint of those with sensorineural hearing loss. Non-human primates appear to be less vulnerable to noise-induced hair-cell loss than rodents, but their susceptibility to synaptopathy has not been studied. Because establishing a non-human primate model may be important in the development of diagnostics and therapeutics, we examined cochlear innervation and the damaging effects of acoustic overexposure in young adult rhesus macaques. Anesthetized animals were exposed bilaterally to narrow-band noise centered at 2 kHz at various sound-pressure levels for 4 h. Cochlear function was assayed for up to 8 weeks following exposure via auditory brainstem responses (ABRs) and otoacoustic emissions (OAEs). A moderate loss of synaptic connections (mean of 12-27% in the basal half of the cochlea) followed temporary threshold shifts (TTS), despite minimal hair-cell loss. A dramatic loss of synapses (mean of 50-75% in the basal half of the cochlea) was seen on IHCs surviving noise exposures that produced permanent threshold shifts (PTS) and widespread hair-cell loss. Higher noise levels were required to produce PTS in macaques compared to rodents, suggesting that primates are less vulnerable to hair-cell loss. However, the phenomenon of noise-induced cochlear synaptopathy in primates is similar to that seen in rodents. PMID- 28712674 TI - The Ebbinghaus illusion in the gray bamboo shark (Chiloscyllium griseum) in comparison to the teleost damselfish (Chromis chromis). AB - This is the first study to comparatively assess the perception of the Ebbinghaus Titchener circles and variations of the Delboeuf illusion in four juvenile bamboo sharks (Chiloscyllium griseum) and five damselfish (Chromis chromis) using identical training paradigms. We aimed to investigate whether these two species show similarities in the perceptual integration of local elements into the global context. The Ebbinghaus-Titchener circles consist of two equally sized central test circles surrounded by smaller or larger circles of different size, number and/or distance. During training, sharks and damselfish learned to distinguish a large circle from a small circle, regardless (i) of its gray level and (ii) of the presence of surrounding circles arranged along an outer semi-circle. During the subsequent transfer period, individuals were presented with variations of the Ebbinghaus-Titchener circles and the Delboeuf illusion. Similar to adult humans, dolphins, or some birds, damselfish tended to judge the test circle surrounded by smaller inducers as larger than the one surrounded by larger inducers (contrast effect). However, sharks significantly preferred the overall larger figure or chose indifferently between both alternatives (assimilation effect). These contrasting responses point towards potential differences in perceptual processing mechanisms, such as 'filling-in' or '(a)modal completion', 'perceptual grouping', and 'local' or 'global' visual perception. The present study provides intriguing insights into the perceptual abilities of phylogenetically distant taxa separated in evolutionary time by 200 million years. PMID- 28712675 TI - Ejaculates are not used as nuptial gifts in simultaneously hermaphroditic snails. AB - Promoted by sexual selection, males usually adopt different ways to increase their fertilization chances. In many insect taxa males donate nuptial gifts, together with sperm, which represent a valuable additional nutrient source that females can use to provision eggs. This has also been suggested to occur in simultaneous hermaphrodites, organisms with both sex functions. In theory, donation of nuptial gifts or extra nutrients might work in hermaphrodites that mate unilaterally (one-way donation of ejaculates), but will not be effective when these organisms mate reciprocally (mutual exchange of ejaculates), since on average each partner would receive the amount it also transfers. Hence, for the latter the net amount gained would be zero, and when considering the non-trivial costs of metabolic conversion the energy balance of this exchange ends up negative. To test this prediction, we measured the material (dry weight) and resource (carbon and nitrogen content) investment into ejaculates of the unilaterally mating freshwater snail Lymnaea stagnalis and spermatophores of the reciprocally mating land snail Cornu aspersum. When compared to eggs, our measurements indicate that the investment is low for ejaculates and spermatophores, neither of which represent a significant contribution to egg production. Importantly, during reciprocal matings, couples exchanged similar amounts of material and resources, thus a gain of extra substances seems irrelevant. Hence, caution is needed when generalizing functions of male reproductive strategies across mating systems. Although digestion of ejaculates does not provide extra material and resources in simultaneous hermaphrodites, their absorption could still be important to eliminate an excess of received sperm and to select sperm via cryptic female choice. PMID- 28712676 TI - First observations on the behavior of the flightless anomalure (Zenkerella insignis). AB - The sole extant representative of the ancient family Zenkerellidae, the flightless anomalure (Zenkerella insignis), is one of the world's least studied mammals. No first-hand observations of its behavior and live appearance have been published to date. I report an observation of Z. insignis behavior, live appearance and habitat in the Central African Republic. PMID- 28712677 TI - Extracorporeal membrane oxygenation following lung transplantation: indications and survival. AB - BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is employed to rescue patients with early graft dysfunction after lung transplantation (LTx). Rates of post-LTx ECMO and subsequent outcomes have been limited to single-center reports. METHODS: UNOS registry was queried for LTx recipients from March 2015 to March 2016; 2,001 recipients were identified and stratified by need for post-LTx ECMO. Logistic regression was used to determine variables associated with post-LTx ECMO. Cox proportional hazards modeling identified factors associated with survival. Kaplan-Meier analysis with log-rank testing was employed for survival analysis. RESULTS: Of 2,001 recipients identified, 107 required post-LTx ECMO (5.1%). Recipients requiring ECMO were younger (56 vs 60 years, p = 0.007) and had higher body mass index (27.2 vs 25.8, p = 0.012). Recipients requiring post LTx ECMO were more likely to have required mechanical ventilation before transplant (9.3% vs 4.9%, p = 0.049) and were more likely to have required pre transplant ECMO (15% vs 3.7%, p < 0.001). On multivariable analysis, pre transplant ECMO and increasing ischemic time were associated with post-LTx ECMO. Six-month survival for recipients requiring ECMO was 62.2%. On multivariable analysis, need for post-transplant dialysis was associated with mortality. Six month survival for recipients requiring ECMO with and without dialysis was 25.8% and 86.7% (p < 0.001). CONCLUSIONS: In a nationally representative database, ischemic time and pre-transplant ECMO and/or ventilator requirement were associated with need for post-LTx ECMO. Need for post-transplant dialysis was associated with mortality in patients requiring post-LTx ECMO. These data may permit improved prediction of graft dysfunction. Strategies to minimize renal toxicity in the perioperative phase may lead to improved early survival post-LTx. PMID- 28712678 TI - Impact of the 18th birthday on waitlist outcomes among young adults listed for heart transplant: A regression discontinuity analysis. AB - BACKGROUND: Patients listed for heart transplant after their 18th birthday purportedly wait longer to receive a donor heart compared with patients listed before their 18th birthday. It is unclear whether there is an actual difference in wait times and whether any difference in wait time is associated with lower likelihood of transplant and/or higher risk of mortality. METHODS: Organ procurement and transplant network data were used to identify all patients listed for heart transplant between 2006 and 2014 within a 1-year period before and after their 18th birthday. The primary study end-point was the waiting time to receive a donor heart. Secondary end-points included the probability of transplant and waitlist mortality. Regression discontinuity analysis was used to analyze the effect of age on either side of the sharp cut-off value of age 18 years (6,574 days of life), when allocation of donor hearts transitions from the pediatric to adult allocation system. RESULTS: A total of 360 patients met the study inclusion criteria, including 207 (57.5%) listed during the 12-month period before their 18th birthday under the pediatric allocation system, and 153 (42.5%) listed during the 12 months after their 18th birthday under the adult allocation system. The pediatric cohort was more likely to be listed Status 1A. Otherwise, the 2 groups shared similar baseline characteristics. Overall, patients listed after their 18th birthday waited 8.5 months longer to receive a transplant than adolescents listed before their 18th birthday (p = 0.01) and had a 47% lower probability of receiving a transplant (p = 0.001), but there was no difference in waitlist mortality (p = 0.37). CONCLUSIONS: Patients listed for heart transplant shortly after their 18th birthday have significantly longer wait-times compared with patients listed shortly before their 18th birthday and a lower probability of transplant, but no significant difference in waitlist mortality. For medically fragile adolescents at high risk of death, birth date may be a relevant factor in the timing of heart transplant listing. PMID- 28712679 TI - The molecular biology in wound healing & non-healing wound. AB - The development of molecular biology and other new biotechnologies helps us to recognize the wound healing and non-healing wound of skin in the past 30 years. This review mainly focuses on the molecular biology of many cytokines (including growth factors) and other molecular factors such as extracellular matrix (ECM) on wound healing. The molecular biology in cell movement such as epidermal cells in wound healing was also discussed. Moreover many common chronic wounds such as pressure ulcers, leg ulcers, diabetic foot wounds, venous stasis ulcers, etc. usually deteriorate into non-healing wounds. Therefore the molecular biology such as advanced glycation end products (AGEs) and other molecular factors in diabetes non-healing wounds were also reviewed. PMID- 28712680 TI - [Omental infarction: An unusual cause of acute abdomen]. PMID- 28712681 TI - [Effectiveness of individual supported employment for people with severe mental disorders]. AB - OBJECTIVE: To assess the effectiveness of an individual placement and support (IPS) strategy in people with severe mental disorders in Tenerife Island (Spain). METHODS: Patients of Community Mental Health Services with severe mental disorders were randomly assigned to two groups. One of them received IPS (n=124), and the control group (n=75) was advised in the usual job search. Patients were followed up for an average of 3.4 years and an analysis was made of how many patients worked at least one day, working hours, wages, the number of contracts and the number of hospital admissions. Non-parametric methods were used to compare the results (Mann-Whitney U test). RESULTS: The percentage of patients who worked at least one day was 99% in the IPS group compared with 75% in the control group; they worked on average 30.1 weeks per year vs 7.4; the monthly salary was ? 777.9 vs ? 599.9; the number of contracts per person was 3.89 vs 4.85, and hospital admissions were 0.19 vs 2.1. CONCLUSIONS: The IPS strategy is effective for the labour integration of people with severe mental illness getting them to work longer, have higher wages and fewer hospital admissions. PMID- 28712682 TI - Adherence to nutritional recommendations in vending machines at secondary schools in Madrid (Spain), 2014-2015. AB - OBJECTIVE: To describe the nutritional content of products offered in food and drink vending machines at secondary schools in the Madrid Autonomous Community (Spain), and to evaluate these items' adherence to the nutritional recommendations of the National Health System Consensus Document on School Food. METHODS: Cross-sectional study of a sample of 330 secondary schools in Madrid across the period 2014-2015. Secondary school vending machines were identified by telephone interview. The products offered in a representative sample of six machines were identified by inspection in situ, and their nutritional composition was obtained from the labelling. RESULTS: A total of 94.5% of the 55 products on offer failed to comply with at least one nutritional criterion of the Consensus Document on School Food. The recommendation relating to sugar content registered the highest level of non-compliance, with 52.7% of products, followed by the recommendations relating to energy (47.3%) and fats (45.5%). The mean number of unmet criteria was 2.2, with this figure being higher in foods than in drinks (2.8 versus 1; p <0.01). CONCLUSION: Almost all the products on display in secondary school vending machines in Madrid were in breach of the Consensus Document on School Food, mainly due to an excess of calories, sugars and fats. Compulsory nutritional criteria and a procedure for monitoring adherence should be established, specifying those responsible for performing this task and the corrective measures to be applied in the event of non-compliance. PMID- 28712683 TI - [Stratification of thoracic pain with modified HEART score and its relationship to short term cardiovascular events]. AB - OBJECTIVE: Chest pain is a major reason for emergency room care worldwide. The relationship between the Modified Heart Score and the presence of major cardiac events at 30 days after emergency admission was evaluated. METHODS: Retrospective, observational study in a single centre on patients older than 18 years, who were treated for chest pain. The Modified HEART Score was applied at admission and related to the presence of major cardiac events (myocardial infarction, death, hospital re-admission due to cardiac causes, and percutaneous or surgical coronary revascularisation) at 30 days of follow-up. RESULTS: Of 158 patients analysed, 17 (10.8%) adverse events were found at follow-up. The modified HEART score could predict adverse events in 4%; 21.4%, and 100% of patients with scores 0-3; 4-6, and 7-10, respectively (P=.0001). A modified HEART score greater than or equal to 4 was associated with more adverse events (OR: 4.52; 95% CI 2.76-7.39) with a sensitivity of 70% and specificity of 84%. CONCLUSIONS: The application of the modified HEART score is useful for stratifying patients with chest pain into low, moderate, and high risk of cardiovascular complications, which should help the emergency units to improve their protocols for triage and diagnosis of acute coronary syndromes. PMID- 28712684 TI - Cerebellar perineuronal nets in cocaine-induced pavlovian memory: Site matters. AB - One of the key mechanisms for the stabilization of synaptic changes near the end of critical periods for experience-dependent plasticity is the formation of specific lattice extracellular matrix structures called perineuronal nets (PNNs). The formation of drug memories depends on local circuits in the cerebellum, but it is unclear to what extent it may also relate to changes in their PNN. Here, we investigated changes in the PNNs of the cerebellum following cocaine-induced preference conditioning. The formation of cocaine-related preference memories increased expression of PNN-related proteins surrounding Golgi inhibitory interneurons as well as that of cFos in granule cells at the apex of the cerebellar cortex. In contrast, the expression of PNNs surrounding projection neurons in the medial deep cerebellar nucleus (DCN) was reduced in all cocaine treated groups, independently of whether animals expressed a preference for cocaine-related cues. Discriminant function analysis confirmed that stronger PNNs in Golgi neurons and higher cFos levels in granule cells of the apex might be considered as the cerebellar hallmarks of cocaine-induced preference conditioning. Blocking the output of cerebellar granule cells in alpha6Cre Cacna1a mutant mice prevented re-acquisition, but not acquisition, of cocaine induced preference conditioning. Interestingly, this impairment in consolidation was selectively accompanied by a reduction in the expression of PNN proteins around Golgi cells. Our data suggest that PNNs surrounding Golgi interneurons play a role in consolidating drug-related memories. PMID- 28712686 TI - Using Touch Surgery to Improve Surgical Education in Low- and Middle-Income Settings: A Randomized Control Trial. AB - BACKGROUND/OBJECTIVE: There is a severe surgical workforce shortage in Rwanda. Innovative educational tools must be introduced to train more residents and increase surgical capacity. Touch Surgery (TS) is a smartphone application that offers trainees the opportunity to practice operations; however, its effect is unknown in low- and middle-income countries. Our objectives were to determine the training effect of TS and its feasibility for use in surgery education in a low resource setting. DESIGN: We performed a randomized control trial of University of Rwanda surgical residents. Participants were blocked by postgraduate year and randomized to textbook or TS for learning tendon repair surgical technique. After the learning period, participants performed a tendon repair simulation, evaluated by blinded expert raters. Presimulation and postsimulation questionnaires tested their knowledge of tendon repair. SETTING: The study was conducted at the simulation center of the University Teaching Hospital of Kigali, a tertiary referral and teaching hospital. PARTICIPANTS: The study included University of Rwanda surgery residents. A total 27 of 51 surgery residents (52.94%) were enrolled. Participating residents represented the following specialties: general surgery (51.85%), orthopedics (40.74%), and urology (7.41%). RESULTS: TS users scored 89.7% on tendon repair simulation, compared to textbook users who scored 63.4% (p < 0.001). Postsimulation questionnaires showed a significant improvement in cognitive scores for TS users (38.6%, p < 0.001), as compared to nonsignificant improvement for textbook users (15.9%, p = 0.304). About 92.3% of TS users reported that TS represents a useful training tool, and 61.5% reported that it would be a good or very good required part of the curriculum. CONCLUSIONS: TS is a useful tool to improve both technical skills and knowledge of tendon repair procedure steps; however, its role may be limited to a supplemental tool as it does not improve the theoretical knowledge. TS has the potential to be implemented in a surgical academic curriculum in low- and middle income countries. PMID- 28712685 TI - Emergency Medical Services Perspectives on Identifying and Reporting Victims of Elder Abuse, Neglect, and Self-Neglect. AB - BACKGROUND: Emergency Medical Services (EMS) providers, who perform initial assessments of ill and injured patients, often in a patient's home, are uniquely positioned to identify potential victims of elder abuse, neglect, or self neglect. Despite this, few organized programs exist to ensure that EMS concerns are communicated to or further investigated by other health care providers, social workers, or the authorities. OBJECTIVE: To explore attitudes and self reported practices of EMS providers surrounding identification and reporting of elder mistreatment. METHODS: Five semi-structured focus groups with 27 EMS providers. RESULTS: Participants reported believing they frequently encountered and were able to identify potential elder mistreatment victims. Many reported infrequently discussing their concerns with other health care providers or social workers and not reporting them to the authorities due to barriers: 1) lack of EMS protocols or training specific to vulnerable elders; 2) challenges in communication with emergency department providers, including social workers, who are often unavailable or not receptive; 3) time limitations; and 4) lack of follow-up when EMS providers do report concerns. Many participants reported interest in adopting protocols to assist in elder protection. Additional strategies included photographically documenting the home environment, additional training, improved direct communication with social workers, a dedicated location on existing forms or new form to document concerns, a reporting hotline, a system to provide feedback to EMS, and community paramedicine. CONCLUSIONS: EMS providers frequently identify potential victims of elder abuse, neglect, and self neglect, but significant barriers to reporting exist. Strategies to empower EMS providers and improve reporting were identified. PMID- 28712687 TI - Assessing Residents' Readiness for OR Autonomy: A Qualitative Descriptive Study of Expert Surgical Teachers' Best Practices. AB - PURPOSE: Providing resident autonomy in the operating room (OR) is one of the major challenges for surgical educators today. The purpose of this study was to explore what approaches expert surgical teachers use to assess residents' readiness for autonomy in the OR. We particularly focused on the assessments that experts make prior to conducting the surgical time-out. METHODS: We conducted semistructured in-depth interviews with expert surgical teachers from March 2016 to September 2016. Purposeful sampling and snowball sampling were applied to identify and recruit expert surgical teachers from general surgery residency programs across the United States to represent a range of clinical subspecialties. All interviews were audio-recorded, deidentified, and transcribed. We applied the Framework Method of content analysis, discussed and reached final consensus on the themes. RESULTS: We interviewed 15 expert teachers from 9 institutions. The majority (13/15) were Program or Associate Program Directors; 47% (7/15) primarily performed complex surgical operations (e.g., endocrine surgery). Five themes regarding how expert surgical teachers determine residents' readiness for OR autonomy before the surgical time-out emerged. These included 3 domains of evidence elicited about the resident (resident characteristics, medical knowledge, and beyond the current OR case), 1 variable relating to attending characteristics, and 1 variable composed of contextual factors. Experts obtained one or more examples of evidence, and adjusted residents' initial autonomy using factors from the attending variable and the context variable. CONCLUSIONS: Expert surgical teachers' assessments of residents' readiness for OR autonomy included 5 key components. Better understanding these inputs can contribute to both faculty and resident development, enabling increased resident autonomy and preparation for independent practice. PMID- 28712688 TI - The Role of the Operating Room in Medical Student Education: Differing Perspectives of Learners and Educators. AB - OBJECTIVE: The surgical clerkship is an integral part of third-year medical student education. The operating room (OR) is a heavily used setting, but it is unclear whether this setting is as effective as possible. To determine the role of the OR and potential improvements, it is necessary to analyze the perspectives of those involved, including surgeons, residents, and medical students. DESIGN: An electronic survey was distributed to the surgeons, surgical residents, and third-year medical students associated with Rutgers New Jersey Medical School. The questions were a combination of 5-point Likert scale questions and qualitative responses. The questions assessed the role of the OR, the information taught in the OR, the quality of the teaching and environment, and potential improvements. RESULTS: Attending surgeons and residents generally rated the OR more positively than medical students did. Medical students desired more hands-on participation and a greater focus on learning technical skills. In addition, most medical students rated the feedback and direct instruction in the OR as "poor." Furthermore, the attending surgeons and medical students disagreed about the main roles of the OR as well as the effectiveness of teaching in the OR. The medical students reported experiencing anxiety and intimidation in the OR and suggested several improvements, such as decreasing the length of the surgical clerkship. CONCLUSIONS: There is significant disagreement between the surgeons and residents and the medical students regarding the roles and effectiveness of learning in the OR. This may help explain the reported medical student dissatisfaction and frustrations with the surgical clerkship. PMID- 28712690 TI - Gallstone disease: Optimal timing of treatment. PMID- 28712689 TI - Enhancing Medical Curricula: The Role of a 1-Day Plastic Surgery Course as an Educational Adjunct for Medical Students. AB - INTRODUCTION: Plastic surgery is underrepresented in medical school curricula. The St George's Surgical Society hosted a 1-day undergraduate course in plastic surgery. Our aim was to introduce students to plastic surgery and teach basic plastic surgical skills. METHODOLOGY: The skills day consisted of lectures from consultants and a core trainee followed by registrar-taught workshops in suturing, tendon repair, and local flap design. Precourse and postcourse questionnaires assessed perceptions of plastic surgery, confidence in performing basic plastic surgical skills, and usefulness of course components. RESULTS: Many perceptions of plastic surgery saw statistically significant changes. The belief that plastic surgery covers a wide range of specialties increased by 36% (p = 0.01). A -32% change (p = 0.00) was seen in the perception of plastic surgery only being pursued as a career for financial gain. Delegates reported greater confidence in all components of basic plastic surgical skills. The most useful activity was reported as performing surgical skills on real tissue. CONCLUSION: A 1-day course can significantly increase positive perceptions of plastic surgery, dispel preconceived false stereotypes, while improving student confidence in performing basic plastic surgery skills. It is important that university surgical societies provide opportunities for student education, to aid informed decisions about future careers. PMID- 28712691 TI - Biliary bile acids in hepatobiliary injury - What is the link? AB - The main trigger for liver injury in acquired cholestatic liver disease remains unclear. However, the accumulation of bile acids (BAs) undoubtedly plays a role. Recent progress in deciphering the pathomechanisms of inborn cholestatic liver diseases, decoding mechanisms of BA-induced cell death, and generating modern BA derived drugs has improved the understanding of the regulation of BA synthesis and transport. Now is the appropriate time to reassess current knowledge about the specific role of BAs in hepatobiliary injury. PMID- 28712692 TI - Volumetric parameters of 2-deoxy-2-[18F]fluoro-d-glucose positron emission tomography/computed tomography can predict histopathologic treatment response after neoadjuvant chemoradiotherapy in pancreatic adenocarcinoma. AB - PURPOSE: The purpose of this study was to investigate the clinical potential of 2 deoxy-2-[18F]fluoro-d-glucose positron emission tomography/computed tomography (FDG PET/CT) to evaluate histopathologic effects of preoperative chemoradiotherapy (CRT) in pancreatic adenocarcinoma, with particular focus on volumetric PET/CT parameters. MATERIAL AND METHODS: This study included 25 patients with pancreatic adenocarcinoma who underwent radical surgery after gemcitabine- and S-1-based preoperative-CRT. The extent of residual tumor was graded using the Evans grading systems, and patients with more than 50% destruction of tumor cells were defined as responder. Peak SUV corrected for lean body mass (SULpeak), metabolic tumor volume (MTV) with a threshold of SUV=2.0, total lesion glycolysis (TLG) of pre- and post-CRT, and reduction rates of SULpeak in those parameters were assessed by PET/CT. These parameters were compared using the student's t-test between responder and non-responder. The treatment effect was also assessed by contingency table analysis divided with median value of each parameter using chi-square tests. RESULTS: Eight patients (32%) showed histopathologic poor response (Evans grade I), 11 cases (44%) had mild response (Evans grade IIa), and six cases (24%) had moderate response (Evans grade IIb); therefore, six cases (24%) were assigned to responders and others 19 cases (76%) were non-responders. With regards to volumetric PET parameters, post CRT SULpeak of responders was significantly lower than that of non-responders (p=0.013). Post-CRT MTV and TLG were negative for all six cases of responders. There were significant differences between responder and non-responder on the contingency table analysis of post-CRT MTV and TLG status (p=0.014 for both). CONCLUSIONS: This study demonstrated that the volumetric PET/CT parameters, higher post-treatment SULpeak and positive MTV/TLG could predict the unfavorable histopathological effects of CRT in patients with pancreatic adenocarcinoma. PMID- 28712693 TI - Diagnostic performance of contrast-enhanced CT-scan in sinusoidal obstruction syndrome induced by chemotherapy of colorectal liver metastases: Radio pathological correlation. AB - PURPOSE: Sinusoidal obstruction syndrome (SOS) is a likely side effect of colorectal liver metastases (CRLM) chemotherapy. This study aimed to assess computed tomography scan (CT-scan) performance for SOS diagnosis for patients receiving neoadjuvant chemotherapy (NC) prior to CRLM surgery, comparing obtained results with pathological gold standard. METHODS: Preoperative CT-scans of 67 patients who had received a NC prior to liver resection for CRLM from 2011 to 2016 were retrospectively analysed. Positive diagnosis and severity of SOS were established after consensual review of the slides by three pathologists. Preoperative CT-scans were separately interpreted by two radiologists and evocative signs of SOS were sought, defined according to a literature review and operators experience. In order to identify SOS predictors, univariate analysis and multivariate logistic regression were used to study CT-scan signs and pathological results correlation. RESULTS: Twenty-nine patient (43%) had an SOS, 22 (33%) were low-grade and 7 (10%) were high-grade. All patient had received a median of 6 cures (3-27) containing Oxaliplatin for 53 (79%) of them. In univariate analysis, hepatic heterogeneity (p<0.001), puddle-like or micronodular appearance (p<0.001), peripheral distribution of heterogeneity (p=0.085), clover like sign (p=0.02), splenomegaly (p=0.0026), spleen volume increase >=30% (p=0.04) or splenic length increase >=15% (p=0.04), as well as the subjective impression of the observer (P<0.001) were significantly associated with SOS diagnosis. In multivariate analysis, clover-like sign (OR 1.87, 95% CI 1.18-2.95, p=0.0081), increase in spleen volume >=30% (OR 1.29, 95% CI 1.01-1.64, p=0.04), and the peripheral distribution of heterogeneity (OR 1.53, 95% CI 1.21-1.94, p<0.001) were independent SOS predictors. The area under the ROC curve was 0.804. The inter-observer agreement for SOS diagnosis was moderate (Kappa=0.546). CONCLUSION: CT-scan can detect suggestive signs of SOS in patients receiving chemotherapy for CRLM. By integrating clinical and biological information into CT scan data, it may be fruitful to create a positive diagnostic and severity score for chemotherapy-induced SOS. PMID- 28712694 TI - Imaging pearls of pediatric Behcet's disease. AB - OBJECTIVE: To emphasize the diverse diagnostic imaging findings of pediatric Behcet's disease and to define the fundamental imaging clues for pulmonary, vascular, gastrointestinal and central nervous system involvements of Behcet's disease in pediatric age group. We also aim to list the major imaging differences of Behcet's disease in childhood and adulthood. CONCLUSION: The diagnosis of pediatric Behcet's disease is challenging. Imaging can narrow the differential diagnosis by using some substantial clues and prevent diagnostic delays. PMID- 28712695 TI - Endoleaks after endovascular aortic aneurysm repair: Improved detection with noise-optimized virtual monoenergetic dual-energy CT. AB - PURPOSE: To assess image quality and diagnostic performance of a noise-optimized algorithm to reconstruct virtual monoenergetic images (VMI+) for the detection of endoleaks after endovascular abdominal aortic aneurysm repair (EVAR) using dual energy CT angiography (DE-CTA). MATERIALS AND METHODS: Seventy-five patients (42 men; 66.2+/-11.7years) underwent DE-CTA following EVAR. Arterial phase images were acquired in dual-energy mode for the reconstruction of standard linearly blended M_0.5, VMI+ and traditional monoenergetic images (VMI) at 40-100keV in 10 keV intervals. Contrast-to-noise ratios (CNR) were calculated for the area of leakage in patients with endoleaks. Diagnostic accuracy for endoleak detection was evaluated by three blinded radiologists using the objectively best series for each reconstruction technique. RESULTS: Thirty-four out of 75 patients showed endoleaks. Quantitative image parameters were highest at 40-keV VMI+ (CNR, 21.3+/ 11.1), compared to M_0.5 (CNR, 10.9+/-5.5) and all VMI series that showed highest values at 70keV (CNR, 13.5+/-6.6; all P<0.001). ROC analysis for endoleak detection revealed an area under the curve (AUC) of 0.992 for 40-keV VMI+ series, which was significantly higher (P<=0.039) compared to 70-keV VMI (0.914) and M_0.5 series (0.916). CONCLUSIONS: Noise-optimized VMI+ series at 40keV improve diagnostic accuracy for the detection and rule-out of endoleaks after EVAR. PMID- 28712696 TI - The value of ultrasound in the preoperative diagnosis of muscle herniation: A comparison with magnetic resonance imaging. AB - OBJECTIVES: To evaluate the clinic value of ultrasound (US) in the diagnosis of muscle herniation. METHODS: This retrospective study was performed on 26 patients with muscle herniation confirmed by surgery. All patients were examined by US and magnetic resonance imaging (MRI) preoperatively. The final histopathologic findings were retrospectively compared with the results of US and MRI. RESULTS: The accuracy of ultrasonography and MRI were 92.3%(24/26) and 84.6%(22/26) respectively. There was no significant difference between two methods (chi2=0.25, P>0.05). CONCLUSIONS: US can be used to observe the shape, size, location, internal echo and fascial defect of the mass of muscle herniation in a dynamical way. Ultrasound is a convenient method with high accuracy, it can be used as the first choice of imaging modality for the diagnosis of muscle herniation. PMID- 28712697 TI - Hepatic steatosis in participants in a program of low-dose CT screening for lung cancer. AB - OBJECTIVE: Determine the frequency of moderate-to-severe hepatic steatosis (HS) in asymptomatic participants in a low-dose CT (LDCT) screening program for lung cancer, to identify risk factors, and develop recommendations. METHODS: Baseline LDCT scans of the chest of 170 participants in an IRB-approved study between August 2011 and April 2016 were reviewed. Demographic variables, comorbidities, and liver function tests were documented. Hepatic and splenic attenuation values hounsfield unit (HU) were measured. Regression analyses were performed. RESULTS: Average liver attenuation was 57.6HU (standard deviation (SD) 9.3) and average liver/spleen (L/S) ratio was 1.3 (SD 0.3). Liver attenuation was <40HU for 9 (5.3%), liver/spleen (L/S) ratio <0.8 for 6 (3.5%), and either <40HU or L/S ratio <0.8 for 9 (5.3%). Male sex (p=0.004), diabetes (p=0.0005), emphysema (p=0.03), and high BMI (p=0.0006) were significant predictors of HS. Aspartate aminotransferase (p=0.0018) and alanine aminotransferase (p=0.012) were negatively correlated with liver attenuation. Reduced serum levels of alpha-1 antitrypsin may be a common factor of emphysema and HS. CONCLUSION: LDCT can detect HS in asymptomatic participants with frequencies similar to previous reports. If liver attenuation is below 40HU and/or L/S ratio below 0.8, further evaluation of HS to the primary care physician or liver specialist is recommended. PMID- 28712698 TI - Preoperative breast MR Imaging in patients with primary breast cancer has the potential to decrease the rate of repeated surgeries. AB - PURPOSE: The impact of preoperative MRI on re-excisions and mastectomy rate is discussed controversially in the literature. Aim of this study was to evaluate the effect of preoperative breast MRI on the surgical procedure and rate of repeated surgeries. MATERIAL AND METHODS: A total of 991 consecutive patients in the years 2009 and 2010 with 1036 primary breast cancers were retrospectively analyzed. Sixty percent (599 patients with 626 cancers) received preoperative breast MRI. Planned surgical procedures before and after MRI and numbers of repeated surgeries in patients with (MR+ ) and without preoperative MRI (MR-) were compared. RESULTS: The result of preoperative MRI changed the surgical procedure in 25% (157/626) of the cases. In 81% (127/157), MRI was beneficial for the patients, as otherwise occult carcinomas were removed (n=122) or further biopsy could be prevented (n=5). Mastectomy rates did not differ between MR+ and MR- group (39% vs. 39%). On multiple regression analysis, the MR+ group had a lower chance for repeated surgery (p<0.05). CONCLUSION: Preoperative MRI could lower the chance for repeated surgery in patients with primary breast cancer. The rate of mastectomy did not differ between patients undergoing preoperative MRI and those who did not. PMID- 28712699 TI - CT-scout based, semi-automated vertebral morphometry after digital image enhancement. AB - INTRODUCTION: Radiographic diagnosis of osteoporotic vertebral fracture is necessary to reduce its substantial associated morbidity. Computed tomography (CT) scout has recently been demonstrated as a reliable technique for vertebral fracture diagnosis. Software assistance may help to overcome some limitations of that diagnostics. We aimed to evaluate whether digital image enhancement improved the capacity of one of the existing software to detect fractures semi automatically. METHODS: CT scanograms of patients suffering from osteoporosis, with or without vertebral fractures were analyzed. The original set of CT scanograms were triplicated and digitally modified to improve edge detection using three different techniques: SHARPENING, UNSHARP MASKING, and CONVOLUTION. RESULTS: The manual morphometric analysis identified 1485 vertebrae, 200 of which were classified as fractured. Unadjusted morphometry (AUTOMATED with no digital enhancement) found 63 fractures, 33 of which were true positive (i.e., it correctly identified 52% of the fractures); SHARPENING detected 57 fractures (30 true positives, 53%); UNSHARP MASKING yielded 30 (13 true positives, 43%); and CONVOLUTION found 24 fractures (9 true positives, 38%). The intra-reader reliability for height ratios did not significantly improve with image enhancement (kappa ranged 0.22-0.41 for adjusted measurements and 0.16-0.38 for unadjusted). Similarly, the inter-reader agreement for prevalent fractures did not significantly improve with image enhancement (kappa 0.29-0.56 and -0.01 to 0.23 for adjusted and unadjusted measurements, respectively). CONCLUSIONS: Our results suggest that digital image enhancement does not improve software-assisted vertebral fracture detection by CT scout. PMID- 28712700 TI - Radiomic analysis of DCE-MRI for prediction of response to neoadjuvant chemotherapy in breast cancer patients. AB - OBJECTIVES: To enhance the accurate prediction of the response to neoadjuvant chemotherapy (NAC) in breast cancer patients by using a quantitative analysis of dynamic enhancement magnetic resonance imaging (DCE-MRI). MATERIALS AND METHODS: A dataset of 57 cancer patients with breast DCE-MR images acquired before NAC was used. Among them, 47 patients were Responders, and 10 patients were non Responders based on the RECIST criteria. The breast regions were segmented on the MR images, and a total of 158 radiomic features were computed to represent the morphologic, dynamic, and the texture of the tumors as well as the background parenchymal features. The optimal subset of features was selected using evolutionary based Wrapper Subset Evaluator. The classifier was trained and tested using a leave-one-out cross-validation (LOOCV) method to classify Responder and non-Responder cases. The area under a receiver operating characteristic curve (AUC) was computed to assess the classifier performance. An additional independent dataset with 46 patients was also included to validate the results. RESULTS: The evolutionary algorithm (EA)-based method identified optimal subsets comprising 12 image features that were fit for classification for the main cohort. Following the same feature selection procedure, the independent validation dataset produced 11 image features, 7 of which were identical to those from the main cohort. The classifier based on the features yield a LOOCV AUC of 0.910 and 0.874 for the main and the reproducibility study cohort, respectively. If the optimal features in the main cohort were utilized to test performance on the reproducibility cohort, the classifier generated an AUC of 0.713. While the features developed in the reproducibility cohort were applied to test the main cohort, the classifier achieved an AUC of 0.683. The AUC of the averaged receiver operating characteristic (ROC) curve for the two data cohort was 0.703. CONCLUSIONS: This study demonstrated that quantitative analyses of radiomic features from pretreatment breast DCE-MRI data could be used as valuable image markers that are associated with tumor response to NAC. PMID- 28712701 TI - Impact of advanced modeled iterative reconstruction on interreader agreement in coronary artery measurements. AB - OBJECTIVES: To evaluate the influence of advanced modeled iterative reconstruction (ADMIRE) on coronary artery computed tomography angiography (cCTA) measurements in comparison to filtered back projection (FBP). MATERIAL AND METHODS: Phantom scans and coronary CTA studies of 27 patients were acquired with a third generation dual-source CT scanner. Images were reconstructed using FBP and ADMIRE. Phantom measurements were used as reference standard. In patient studies, representative axial slices of each coronary artery segment without (n=308) and with coronary plaques (n=40) were assessed in identical positions for comparison of FBP and ADMIRE reconstructions. Image analyses included quality assessment, phantom and coronary artery measurements, plaque analysis, and interreader agreement of two independent and blinded readers. RESULTS: Mean image noise was lower on ADMIRE reconstructions with 31.3+/-9.9 HU compared to 55.9+/ 15.7 HU on FBP reconstructions (p<0.001). Measurement precision and interreader agreement of both observers were assessed satisfactorily on phantom images in comparison to the full width half maximum method. In patients, correlation of lumen diameters of both observers improved using ADMIRE with a Pearson's r=0.987 (95% confidence interval [CI], 0.983-0.989; p<0.001) compared to FBP images with r=0.939 (95% CI, 0.924-0.951; p<0.001). Applying ADMIRE, agreement of both observers for lumen diameter measurements significantly increased (p<0.001). This was also observed for the degree of stenosis (p<0.001) with r=0.560 using FBP (95% CI, 0.301-0.742) and with r=0.818 using ADMIRE (95% CI, 0.680-0.900). Plaque density measurements correlated closely with a Pearson's r of 0.951 in FBP (95% CI, 0.909-0.974) and 0.967 in ADMIRE (95% CI, 0.939-0.983). CONCLUSIONS: Advanced modeled iterative reconstruction significantly improves coronary artery assessment in coronary CTA in comparison to FBP by improved image quality due to image noise removal. This renders improved interobserver agreement for coronary lumen diameter and degree of stenosis measurements without influencing mean plaque attenuation. PMID- 28712702 TI - Clinical usefulness of F-18 FDG PET in lymphoepithelioma-like gastric carcinoma. AB - PURPOSE: Lymphoepithelioma-like carcinoma (LELC) is a rare type of gastric cancer. We evaluated the clinical usefulness of F-18 FDG positron emission tomography/computed tomography (PET/CT) in LELC of stomach. MATERIALS AND METHODS: A total of 28 patients (mean age=59years) who underwent preoperative F 18 FDG PET/CT were enrolled retrospectively. Nine patients underwent follow-up F 18 FDG PET/CT. Pathologic information was obtained through gastrectomy and the association with Epstein-Barr virus (EBV) was investigated in 26 patients. RESULTS: PET/CT detected 85.0% (17/20) of advanced gastric cancers (AGC) and 12.5% (1/8) of early gastric cancers (EGC). Most tumors (23/26, 88.5%) were EBV associated. The maximum standardized uptake value of FDG-avid tumors was 7.5+/ 3.0. The sensitivity and specificity of PET/CT for the presence of lymph node metastasis was 47.8% (11/23) and 100.0% (13/13), respectively. PET/CT also detected a hepatic sarcomatoid carcinoma in one patient. The specificity of PET/CT for distant metastasis or second malignancy was 96.3%. Follow-up PET/CT detected malignant lesions in 3 of 9 patients; a liver metastasis, recurrent hepatic sarcomatoid carcinomas and a metachronous cholangiocarcinoma. PET/CT correctly excluded recurrence in the rest of the patients (6/6). The sensitivity and specificity of PET/CT for detecting recurrence or second malignancy was 100% and 100%, respectively. CONCLUSION: F-18 FDG PET/CT would be a useful tool in evaluating distant metastasis or recurrence in patients with gastric LELC. PMID- 28712703 TI - Role of semi-quantitative dynamic contrast-enhanced MR imaging in characterization and grading of prostate cancer. AB - OBJECTIVE: The study retrospectively assessed the diagnostic value of semi quantitative dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) in characterization and grading of prostate cancer, with correlation to histopathological analysis. MATERIALS AND METHODS: 161 consecutive patients with prostate cancer underwent DCE MRI. 430 lesions, including 200 cancers with Gleason grade (GG) of 6 (n=25), 7 (n=112) and 8 or higher (n=63); 80 benign hyperplasia; and 150 healthy tissues were assessed using a histology-MRI correlation. Time-intensity curve types between two radiologists and kinetic parameters (Cpeak, time to peak, wash-in and wash-out) were compared in the different tissue types and GGs. Receiver operating characteristic curve analysis was performed to assess for each parameter to differentiate cancer from benign hyperplasia or healthy tissue, and GG 8 or higher from GG 6 or 7. RESULTS: Type 2 was the prevalent assigned curve type. Inter-radiologist agreement for the curve types was excellent. Cancer and GG 8 or higher significantly showed a higher Cpeak and faster wash-in compared to healthy tissue and GG 6. Only wash-in significantly differentiated cancer from healthy tissue, and GG 8 or higher from GG 6, having an area under the curve (AUC) of 0.755 and 0.815 respectively. Wash in for the combined parameters revealed AUCs of 0.791 and 0.839 in two (Cpeak) parameters, and AUCs of 0.862 and 0.891 in three (Cpeak and wash-out) parameters. CONCLUSION: Semi-quantitative parameters can differentiate cancer from benign hyperplasia and healthy tissue. Wash-in is the most accurate differentiation parameter of cancer foci and GG 8 or higher. PMID- 28712704 TI - Impact of Perioperative Voice Therapy on Outcomes in the Surgical Management of Vocal Fold Cysts. AB - INTRODUCTION: Vocal fold cysts are benign mid-membranous lesions of the true vocal fold, classified as mucus retention or epidermal inclusion cysts. Treatment is surgical excision with or without postoperative voice therapy. METHODS: A retrospective review was performed of the demographics, treatment approach, and outcomes of patients treated for vocal fold cysts between 2009 and 2014. Voice Handicap Index (VHI)-10 scores before and after treatment were compared using the Wilcoxon Rank-Sum test and the two-tailed Student's t test. Videostroboscopy examinations were reviewed for posttreatment changes in vibratory characteristics of the vocal folds. RESULTS: Twenty-five patients were identified, and one was excluded for incomplete records. Mean age was 41.9 years (66.7% female), and mean follow-up time was 5.58 months. Microflap excision was pursued by 21/24 (87.5%) patients, with 14 patients (58.3%) undergoing perioperative voice therapy. One cyst recurred. Two patients elected for observation, and their cysts persisted. VHI-10 decreased from 23.8 to 6.6 (P < 0.001) overall. There was a statistically significant reduction in VHI-10 in patients undergoing surgery with and without postoperative voice therapy (P < 0.004 and 0.001), but there was no significant difference between these two groups. Mucosal wave was classified as normal or improved in the majority. Cysts were characterized as mucus retention cysts in 19/21 (90%) and as epidermal inclusion cysts in 2/21 (10%). CONCLUSIONS: Vocal fold cysts impact mucosal wave and glottic closure. Surgical excision resulted in low rates of recurrence, and in improvement in the mucosal wave and VHI-10. Perioperative voice therapy did not offer a significant benefit. Mucus retention cysts were the majority, in contrast to other published studies. PMID- 28712705 TI - Engineering of global regulators and cell surface properties toward enhancing stress tolerance in Saccharomyces cerevisiae. AB - Microbial cell factories are subject to various stresses, leading to the reductions of metabolic activity and bioproduction efficiency. Therefore, the development of stress-tolerant microorganisms is important for improving bio production efficiency. Recently, modifications of cell surface properties and master regulators have been shown to be effective approaches for enhancing stress tolerance. The cell surface is an attractive target owing to its interactions with the environment and its role in transmitting environmental information. Cell surface engineering in yeast has enabled the convenient modification of cell surface properties. Displaying random peptide libraries and subsequent screening can successfully improve stress tolerance. Furthermore, master regulators including transcription factors are also promising target to be engineered because stress tolerance is determined by many cooperative factors and modification of master regulators can simultaneously affect the expression of multiple downstream genes. The key single amino acid mutations in transcription factors have been identified by analyzing tolerant yeasts that were isolated by adaptive evolution under stress conditions. This enabled the reconstruction of stress-tolerant yeast without burdening cells by introducing the identified mutations. Therefore, for the construction of stress-tolerant yeast from any strains, these two approaches are promising alternatives to conventional overexpression and deletion of stress-related genes. PMID- 28712706 TI - Discovery of novel 2-(4-aryl-2-methylpiperazin-1-yl)-pyrimidin-4-ones as glycogen synthase kinase-3beta inhibitors. AB - We herein describe the results of further evolution of glycogen synthase kinase (GSK)-3beta inhibitors from our promising compounds containing a 3 methylmorpholine moiety. Transformation of the morpholine moiety into a piperazine moiety resulted in potent GSK-3beta inhibitors. SAR studies focused on the nitrogen atom of the piperazine moiety revealed that a phenyl group afforded potent inhibitory activity toward GSK-3beta. Docking studies indicated that the phenyl group on the piperazine nitrogen atom and the methyl group on the piperazine make cation-pi and CH-pi interactions with GSK-3beta respectively. 4 Methoxyphenyl analogue 29 showed most potent inhibitory activity toward GSK-3beta with good in vitro and in vivo pharmacokinetic profiles, and 29 demonstrated a significant decrease in tau phosphorylation after oral administration in mice. PMID- 28712707 TI - Discovery of a potent angiotensin converting enzyme inhibitor via virtual screening. AB - Prompted by the prominent role of angiotensin converting enzyme (ACE) in hypertension, heart failures, myocardial infarction and diabetic nephropathy, we have attempted to discover novel ACE inhibitors through ligand-based virtual screening. Molecular docking method and rigorously validated model was utilized to search a natural compounds database. Finally, 36 compounds were randomly selected and subjected to in vitro ACE kinase inhibitory assay using fluorescence assays method. The results showed that three compounds (Licochalcone A, Echinatin and EGCG) have strong potential to be developed as a new class of ACE inhibitors. Further chemical modification via fragment modifications guided by structure and ligand-based computational methodologies can lead to discover better agents as potential clinical candidates. PMID- 28712708 TI - Discovery of novel 2-(3-phenylpiperazin-1-yl)-pyrimidin-4-ones as glycogen synthase kinase-3beta inhibitors. AB - We herein describe the results of further evolution of glycogen synthase kinase (GSK)-3beta inhibitors from our promising compounds containing a 2 phenylmorpholine moiety. Transformation of the morpholine moiety into a piperazine moiety resulted in potent GSK-3beta inhibitors. SAR studies focused on the phenyl moiety revealed that a 4-fluoro-2-methoxy group afforded potent inhibitory activity toward GSK-3beta. Based on docking studies, new hydrogen bonding between the nitrogen atom of the piperazine moiety and the oxygen atom of the main chain of Gln185 has been indicated, which may contribute to increased activity compared with that of the corresponding phenylmorpholine analogues. Effect of the stereochemistry of the phenylpiperazine moiety is also discussed. PMID- 28712709 TI - Synthesis and biological evaluation of novel 1,2,3-triazole derivatives as anti tubercular agents. AB - A library of seventeen novel 1,2,3-triazole derivatives were efficiently synthesized in excellent yields by the popular 'click chemistry' approach and evaluated in vitro for their anti-tubercular activity against Mycobacterium tuberculosis H37Ra (ATCC 25177 strain). Among the series, six compounds exhibited significant activity with minimum inhibitory concentration (MIC) values ranging from 3.12 to 0.78MUg/mL and along with no significant cytotoxicity against MBMDMQs (mouse bone marrow derived macrophages). Molecular docking of the target compounds into the active site of DprE1 (Decaprenylphosphoryl-beta-d-ribose-2' epimerase) enzyme revealed noteworthy information on the plausible binding interactions. PMID- 28712710 TI - beta-TCP bone substitutes in tibial plateau depression fractures. AB - BACKGROUND: The use of beta-tricalciumphospate (beta-TCP, Cerasorb(r)) ceramics as an alternative for autologous bone-grafting has been outlined previously, however with no study focusing on both clinical and histological outcomes of beta TCP application in patients with multi-fragment tibial plateau fractures. The aim of this study was to analyze the long-term results of beta-TCP in patients with tibial plateau fractures. METHODS: 52 patients were included in this study. All patients underwent open surgery with beta-TCP block or granulate application. After a mean follow-up of 36months (14-64months), the patients were reviewed. Radiography and computed-tomography were performed, while the Rasmussen score was obtained for clinical outcome. Furthermore, seven patients underwent biopsy during hardware removal, which was subsequently analyzed by histology and backscattered electron microscopy (BSEM). RESULTS: An excellent reduction with two millimeters or less of residual incongruity was achieved in 83% of the patients. At follow-up, no further changes occurred and no nonunions were observed. Functional outcome was good to excellent in 82%. Four patients underwent revision surgery due to reasons unrelated to the bone substitute material. Histologic analyses indicated that new bone was built around the beta TCP-grafts, however a complete resorption of beta-TCP was not observed. DISCUSSION: beta-TCP combined with internal fixation represents an effective and safe treatment of tibial plateau depression fractures with good functional recovery. While its osteoconductivity seems to be successful, the biological degradation and replacement of beta-TCP is less pronounced in humans than previous animal studies have indicated. PMID- 28712711 TI - Specificity and putative mode of action of a mosquito larvicidal toxin from the bacterium Xenorhabdus innexi. AB - Reduction of mosquito-borne diseases relies, in part, on the use of synthetic pesticides to control pest mosquitoes. This reliance has led to genetic resistance, environmental contamination and the nondiscriminatory elimination of both pest and non-pest species. To expand our options for control, we screened entomopathogenic bacteria for potential larvicidal activity. A lipopeptide from the bacterium, Xenorhabdus innexi, was discovered that displayed potent larvicidal activity. The LC50s of the lipopeptide towards Aedes aegypti, Culex pipiens and Anopheles gambiae larvae were 1.81, 1.25 and 1.86 parts-per-million, respectively. No mortality was observed in other insect species tested. The putative mode of action of the lipopeptide suggested that after orally ingestion, it bound to the apical membrane of anterior midgut cells and created pores in the cellular membranes. The rapid neutralization of midgut pH suggested the pores disabled the H+-V-ATPase on the basal membrane and led to epithelial cell death. Specificity and toxicity towards mosquito larvae and the unique mode of action makes this lipopeptide a potentially attractive bacterial insecticide for control of mosquitoes. PMID- 28712712 TI - Author Reply. PMID- 28712713 TI - Editorial Comment. PMID- 28712714 TI - Spinning slithole collimation for high-sensitivity small animal SPECT: Design and assessment using GATE simulation. AB - PURPOSE: While traditional collimations are widely used in preclinical SPECT imaging, they usually suffer from possessing a low system sensitivity leading to noisy images. In this study, we are aiming at introducing a novel collimator, the slithole, offering a superior resolution-sensitivity tradeoff for small animal SPECT. METHODS: The collimator was designed for a molecular SPECT scanner, the HiReSPECT. The slithole is a knife-edge narrow long aperture extended across long axis of the camera's head. To meet the data completeness requirement, the collimator-detector assembly spins at each regular SPECT angle. The collimator was modeled within GATE Monte Carlo simulator and the data acquisition was performed for NEMA Image Quality (IQ) phantom. In addition, a dedicated 3D iterative reconstruction algorithm based upon plane-integral projections was also developed. RESULTS: The mean sensitivity of the slithole is 285cps/MBq while the current parallel-hole collimator holds a sensitivity of 36cps/MBq at a 30mm distance. The slithole collimation gives rise to a tomographic resolution of 1.8mm compared to a spatial resolution of~1.7mm for the parallel-hole one (even after resolution modeling). A 1.75 reduction factor in the noise level was observed when the current parallel-hole collimator is replaced by the slithole. Furthermore, quantitative analysis proves that 3 full-iterations of our dedicated image reconstruction lead to optimal image quality. For the largest rod in the NEMA IQ phantom, a recovery coefficient of~0.83 was obtained. CONCLUSION: The slithole collimator outperforms the current parallel-hole collimation by exhibiting a better resolution-sensitivity compromise for preclinical SPECT studies. PMID- 28712715 TI - Split-VMAT technique to control the expiratory breath-hold time in liver stereotactic body radiation therapy. AB - PURPOSE: In this study, we demonstrate the feasibility of using split-arcs in volumetric modulated arc therapy (VMAT), tailored for expiratory breath-hold in stereotactic body radiation therapy (SBRT) for liver tumors. We compare it with three-dimensional conformal radiation therapy (3D-CRT) and continuous-VMAT, for ten randomly selected hepatocellular carcinoma cases. METHODS: Four coplanar and four non-coplanar beams were used for the 3D-CRT plans. A pair of partial arcs, chosen using a back-and-forth rotating motion, were used for the continuous-VMAT plans. Split-VMAT plans were created using the same arc range as the continuous VMAT plans, but were split into smaller arcs (<90 degrees ), to simulate an expiratory breath hold of <15s. The dose distribution, treatment delivery efficiency, and patient specific quality assurance of the split-VMAT, were verified to ensure that the outcomes were equal, or better than, those for 3D-CRT and continuous-VMAT. The prescription was 48Gy/4 fractions, to 95% of the PTV, using 10MV FFF X-ray beams. RESULTS: The mean dose of the liver-GTV was lower in the split-VMAT compared with that of 3D-CRT. Split-VMAT was more conformal compared with 3D-CRT. The total treatment time for split-VMAT was shorter than that of 3D-CRT. Similar dosimetric indices were observed for split-VMAT and continuous-VMAT. All VMAT plans passed the gamma acceptance test. CONCLUSIONS: Split-VMAT designed to accommodate an expiratory breath-hold period of 15s is a feasible and efficient use of liver SBRT, because it does not compromise the quality of the plan, when compared with 3D-CRT or continuous-VMAT. PMID- 28712716 TI - Differentiation of glioma malignancy grade using diffusion MRI. AB - Modern diffusion MR protocols allow one to acquire the multi-shell diffusion data with high diffusion weightings in a clinically feasible time. In the present work we assessed three diffusion approaches based on diffusion and kurtosis tensor imaging (DTI, DKI), and neurite orientation dispersion and density imaging (NODDI) as possible biomarkers for human brain glioma grade differentiation based on the one diffusion protocol. We used three diffusion weightings (so called b values) equal to 0, 1000, and 2500s/mm2 with 60 non-coplanar diffusion directions in the case of non-zero b-values. The patient groups of the glioma grades II, III, and IV consist of 8 subjects per group. We found that DKI, and NODDI scalar metrics can be effectively used as glioma grade biomarkers with a significant difference (p<0.05) for grading between low- and high-grade gliomas, in particular, for glioma II versus glioma III grades, and glioma III versus glioma IV grades. The use of mean/axial kurtosis and intra-axonal fraction/orientation dispersion index metrics allowed us to obtain the most feasible and reliable differentiation criteria. For example, in the case of glioma grades II, III, and IV the mean kurtosis is equal to 0.31, 0.51, and 0.90, and the orientation dispersion index is equal to 0.14, 0.30, and 0.59, respectively. The limitations and perspectives of the biophysical diffusion models based on intra-/extra-axonal compartmentalisation for glioma differentiation are discussed. PMID- 28712717 TI - Radiobiological evaluation of prostate cancer IMRT and conformal-RT plans using different treatment protocols. AB - The purpose of this study is to evaluate the clinical efficacy of both step-and shoot IMRT and 3D-Conformal Radiation Therapy modalities (CRT) in treating prostate cancer using radiobiological measures. Another aim was to estimate the risks for developing secondary malignancies in bladder and rectum due to radiotherapy from the corresponding modalities. The treatment plans of ten prostate cancer patients were developed using IMRT and CRT. For the IMRT plans, two beam energies and two treatment protocols were used (the RTOG 0415 and a most restrictive one proposed by Fox Chase Cancer Center (FCCC)). For the evaluation of these plans, the complication-free tumor control probability, the total probability of injury, the total probability of control/benefit, and the biologically effective uniform dose were employed. Furthermore, based on the dosimetric data of IMRT and CRT, the risk for secondary malignancies was calculated for bladder and rectum. The average risk for secondary malignancy was lower for the bladder (0.37%) compared to the rectum (0.81%) based on all the treatment plans of the ten prostate cancer patients. The highest average risk for secondary malignancy for bladder and rectum was for the CRT-6X modality (0.46% and 1.12%, respectively) and the lowest was for the IMRT RTOG-18X modality (0.33% and 0.56%, respectively). The >= Grade 2 LENT/SOMA response probability was lower for the bladder than for the rectum in all the plans. For the bladder the highest average value was for the IMRT RTOG-18X (0.9%) and the lowest was for the CRT-18X modality (0.1%). For the rectum, the highest average value was for the IMRT RTOG 6X (11.9%) and the lowest was for the IMRT FCCC-18X modality (2.2%). By using radiobiological measures it is shown that the IMRT FCCC plans had the lowest risks for normal tissue complications, whereas the IMRT RTOG had the highest. Regarding the risk for secondary malignancies, the CRT plans showed the highest values for both bladder and rectum. PMID- 28712718 TI - Young Adults with Multiple Myeloma. AB - OBJECTIVE: To identify the salient issues of young adults (YAs) diagnosed with multiple myeloma (MM), a hematologic disease of older adults, that is rare in patients 19-40 years of age. DATA SOURCES: Peer-reviewed journal articles, case reports, single-institution series, and national guidelines. CONCLUSION: Compared to older adults with MM, YAs live longer and are at higher risk for survivorship related issues, which include treatment adherence, infertility, reproductive concerns, risk of second primary cancers, treatment-related cardiotoxicity, and higher risk of non-cancer-related mortality. IMPLICATIONS FOR NURSING PRACTICE: In addition to understanding disease biology, the oncology nurse should have an understanding of the unique developmental, psychosocial, and medical and psychosocial needs of the young adult with MM. The oncology nurse will then be able to provide targeted education about the disease, its treatment trajectory, and supportive care issues, as well as advocate for therapies, and based on response, toxicities, while taking into consideration patient-centered needs. PMID- 28712719 TI - AGEs, RAGEs and s-RAGE; friend or foe for cancer. AB - Impaired awareness of glycation biology in cancer initiation and progression is one of the fundamental reasons for its meticulous investigation of the molecules involved in signalling pathway. Glycation of biological macromolecules results in the progression of advanced glycation end-products (AGEs) that proliferates the process of carcinogenesis by activation of transcription factors and release of cytokines. The receptor for advanced glycation end-products (RAGEs) with the binding of its different ligands like; AGEs, HMGB1 and S100 activate the signalling arrays. The activation of downstream signalling pathway ultimately leads to the pathophysiological conditions of diabetes, ageing, neurological disorders and cancers as well as a result of the activation of transcription factors which is discussed in the main body text of this review. However, there might be a likelihood of the positive effect of the HMGB1 and S100 proteins in cancer. Still, some untouched mechanisms might be responsible for the establishment of the function of AGE-RAGE or AGE-sRAGE axis activation that leads to the friend-foe association with the cancers. The levels of RAGE and s-RAGE may be a useful biomarker of ligand-RAGE pathway activation and cancer. Thus, the possibility of providing a potential complement to carcinogenesis is very high which might be an interesting target for therapeutic interventions. This article is an insightful assessment on AGE, RAGE and s-RAGE for its possible role in cancer onset and progression. The novel therapeutic targets for cancer prevention or inhibition are also explained in brief in relation to AGE and RAGE. PMID- 28712720 TI - Manual Aspiration Thrombectomy in Patients with Acute Stroke-Related Calcified Cerebral Emboli. AB - OBJECTIVE: The aim of this study was to evaluate the effectiveness of mechanical aspiration thrombectomy (MAT) in patients with acute ischemic stroke from calcified cerebral emboli. METHODS: Procedural results were reviewed for acute stroke patients with clinically neurological deficits who underwent recanalization from October 2012 through September 2015. Initial imaging studies and cerebral angiography were analyzed. RESULTS: Of the total number of patients with acute stroke, 5 patients were confirmed to have acute ischemic stroke by calcified cerebral emboli. On initial brain computed tomographic imaging, all patients showed small, dense single calcifications in the middle cerebral artery with no definitive ischemic low-density lesions (M1: 3, M2: 2, mean size: 4.8 mm). All patients had angiographic findings of filling defects from calcified emboli. Four patients had good collateral flow and two had continuous distal flow. All patients underwent MAT using a Penumbra catheter (Penumbra Inc., Alameda, CA). MAT did not remove calcified emboli in all patients. Two patients with good collateral flow had favorable functional outcomes (modified Rankin Scale score <=2). Four patients had diffuse calcification in the aortic arch, carotid artery, and aortic valve. CONCLUSIONS: Cerebral angiography supports a diagnosis of stroke when calcified cerebral emboli have contrast-filling defects and a degree of vascular occlusion. However, in this study, MAT was not an effective treatment for patients with calcified cerebral emboli because of hardness of the calcified plaque and packing into the arterial lumen. PMID- 28712721 TI - Comprehensive Cost of Illness of Three Major Diseases in Japan. AB - OBJECTIVE: The purpose of this study was to calculate the burden of 3 major diseases (cancer, heart disease, and cerebrovascular disease [CVD]) using the cost of illness (COI) method. METHODS: As a modification of the original COI method developed by Rice, the estimated comprehensive COI (C-COI) of cancer, heart disease, and CVD were redefined. C-COI consists of medical direct, morbidity, and mortality costs (MtCs; components of the original COI); long-term care (LTC) direct cost (DC); and family burden (FB). LTC DC is an insurance benefit, and FB is the unpaid care cost incurred by the family, relatives, and friends for in-home and in-community medical expenses (opportunity cost). All costs for 2008-2014 were calculated using official statistics of the Japanese government. RESULTS: The C-COI of cancer, heart disease, and CVD in 2014 amounted to 9815 billion Japanese yen (JPY), 4461 billion JPY, and 6501 billion JPY, respectively. As for the composition of the C-COI, the MtC accounted for the largest portion of medical expenses for treatment of cancer (63.5%) and heart disease (50.6%), but the DC (LTC) accounted for the largest portion of medical expenses for CVD (26.7%). CONCLUSIONS: This study, based on government statistics, demonstrated that C-COI, including LTC DC and FB, could be estimated, and the latter was found to be a major cost component in CVD, whereas long-term disability is a salient feature of the disease. PMID- 28712722 TI - Cell Polarity Regulates Biased Myosin Activity and Dynamics during Asymmetric Cell Division via Drosophila Rho Kinase and Protein Kinase N. AB - Cell and tissue morphogenesis depends on the correct regulation of non-muscle Myosin II, but how this motor protein is spatiotemporally controlled is incompletely understood. Here, we show that in asymmetrically dividing Drosophila neural stem cells, cell intrinsic polarity cues provide spatial and temporal information to regulate biased Myosin activity. Using live cell imaging and a genetically encoded Myosin activity sensor, we found that Drosophila Rho kinase (Rok) enriches for activated Myosin on the neuroblast cortex prior to nuclear envelope breakdown (NEB). After NEB, the conserved polarity protein Partner of Inscuteable (Pins) sequentially enriches Rok and Protein Kinase N (Pkn) on the apical neuroblast cortex. Our data suggest that apical Rok first increases phospho-Myosin, followed by Pkn-mediated Myosin downregulation, possibly through Rok inhibition. We propose that polarity-induced spatiotemporal control of Rok and Pkn is important for unequal cortical expansion, ensuring correct cleavage furrow positioning and the establishment of physical asymmetry. PMID- 28712723 TI - Msp1 Is a Membrane Protein Dislocase for Tail-Anchored Proteins. AB - Mislocalized tail-anchored (TA) proteins of the outer mitochondrial membrane are cleared by a newly identified quality control pathway involving the conserved eukaryotic protein Msp1 (ATAD1 in humans). Msp1 is a transmembrane AAA-ATPase, but its role in TA protein clearance is not known. Here, using purified components reconstituted into proteoliposomes, we show that Msp1 is both necessary and sufficient to drive the ATP-dependent extraction of TA proteins from the membrane. A crystal structure of the Msp1 cytosolic region modeled into a ring hexamer suggests that active Msp1 contains a conserved membrane-facing surface adjacent to a central pore. Structure-guided mutagenesis of the pore residues shows that they are critical for TA protein extraction in vitro and for functional complementation of an msp1 deletion in yeast. Together, these data provide a molecular framework for Msp1-dependent extraction of mislocalized TA proteins from the outer mitochondrial membrane. PMID- 28712724 TI - Acylglycerol Kinase Mutated in Sengers Syndrome Is a Subunit of the TIM22 Protein Translocase in Mitochondria. AB - Mutations in mitochondrial acylglycerol kinase (AGK) cause Sengers syndrome, which is characterized by cataracts, hypertrophic cardiomyopathy, and skeletal myopathy. AGK generates phosphatidic acid and lysophosphatidic acid, bioactive phospholipids involved in lipid signaling and the regulation of tumor progression. However, the molecular mechanisms of the mitochondrial pathology remain enigmatic. Determining its mitochondrial interactome, we have identified AGK as a constituent of the TIM22 complex in the mitochondrial inner membrane. AGK assembles with TIMM22 and TIMM29 and supports the import of a subset of multi spanning membrane proteins. The function of AGK as a subunit of the TIM22 complex does not depend on its kinase activity. However, enzymatically active AGK is required to maintain mitochondrial cristae morphogenesis and the apoptotic resistance of cells. The dual function of AGK as lipid kinase and constituent of the TIM22 complex reveals that disturbances in both phospholipid metabolism and mitochondrial protein biogenesis contribute to the pathogenesis of Sengers syndrome. PMID- 28712725 TI - Dynamic Organization of Chromatin Domains Revealed by Super-Resolution Live-Cell Imaging. AB - The eukaryotic genome is organized within cells as chromatin. For proper information output, higher-order chromatin structures can be regulated dynamically. How such structures form and behave in various cellular processes remains unclear. Here, by combining super-resolution imaging (photoactivated localization microscopy [PALM]) and single-nucleosome tracking, we developed a nuclear imaging system to visualize the higher-order structures along with their dynamics in live mammalian cells. We demonstrated that nucleosomes form compact domains with a peak diameter of ~160 nm and move coherently in live cells. The heterochromatin-rich regions showed more domains and less movement. With cell differentiation, the domains became more apparent, with reduced dynamics. Furthermore, various perturbation experiments indicated that they are organized by a combination of factors, including cohesin and nucleosome-nucleosome interactions. Notably, we observed the domains during mitosis, suggesting that they act as building blocks of chromosomes and may serve as information units throughout the cell cycle. PMID- 28712726 TI - Sengers Syndrome-Associated Mitochondrial Acylglycerol Kinase Is a Subunit of the Human TIM22 Protein Import Complex. AB - Acylglycerol kinase (AGK) is a mitochondrial lipid kinase that catalyzes the phosphorylation of monoacylglycerol and diacylglycerol to lysophosphatidic acid and phosphatidic acid, respectively. Mutations in AGK cause Sengers syndrome, which is characterized by congenital cataracts, hypertrophic cardiomyopathy, skeletal myopathy, exercise intolerance, and lactic acidosis. Here we identified AGK as a subunit of the mitochondrial TIM22 protein import complex. We show that AGK functions in a kinase-independent manner to maintain the integrity of the TIM22 complex, where it facilitates the import and assembly of mitochondrial carrier proteins. Mitochondria isolated from Sengers syndrome patient cells and tissues show a destabilized TIM22 complex and defects in the biogenesis of carrier substrates. Consistent with this phenotype, we observe perturbations in the tricarboxylic acid (TCA) cycle in cells lacking AGK. Our identification of AGK as a bona fide subunit of TIM22 provides an exciting and unexpected link between mitochondrial protein import and Sengers syndrome. PMID- 28712727 TI - Error-Prone Splicing Controlled by the Ubiquitin Relative Hub1. AB - Accurate pre-mRNA splicing is needed for correct gene expression and relies on faithful splice site recognition. Here, we show that the ubiquitin-like protein Hub1 binds to the DEAD-box helicase Prp5, a key regulator of early spliceosome assembly, and stimulates its ATPase activity thereby enhancing splicing and relaxing fidelity. High Hub1 levels enhance splicing efficiency but also cause missplicing by tolerating suboptimal splice sites and branchpoint sequences. Notably, Prp5 itself is regulated by a Hub1-dependent negative feedback loop. Since Hub1-mediated splicing activation induces cryptic splicing of Prp5, it also represses Prp5 protein levels and thus curbs excessive missplicing. Our findings indicate that Hub1 mediates enhanced, but error-prone splicing, a mechanism that is tightly controlled by a feedback loop of PRP5 cryptic splicing activation. PMID- 28712728 TI - HEXIM1 and NEAT1 Long Non-coding RNA Form a Multi-subunit Complex that Regulates DNA-Mediated Innate Immune Response. AB - The DNA-mediated innate immune response underpins anti-microbial defenses and certain autoimmune diseases. Here we used immunoprecipitation, mass spectrometry, and RNA sequencing to identify a ribonuclear complex built around HEXIM1 and the long non-coding RNA NEAT1 that we dubbed the HEXIM1-DNA-PK-paraspeckle components ribonucleoprotein complex (HDP-RNP). The HDP-RNP contains DNA-PK subunits (DNAPKc, Ku70, and Ku80) and paraspeckle proteins (SFPQ, NONO, PSPC1, RBM14, and MATRIN3). We show that binding of HEXIM1 to NEAT1 is required for its assembly. We further demonstrate that the HDP-RNP is required for the innate immune response to foreign DNA, through the cGAS-STING-IRF3 pathway. The HDP-RNP interacts with cGAS and its partner PQBP1, and their interaction is remodeled by foreign DNA. Remodeling leads to the release of paraspeckle proteins, recruitment of STING, and activation of DNAPKc and IRF3. Our study establishes the HDP-RNP as a key nuclear regulator of DNA-mediated activation of innate immune response through the cGAS-STING pathway. PMID- 28712729 TI - Gene by cognition interaction on stress-induced attention bias for food: Effects of 5-HTTLPR and ruminative thinking. AB - INTRODUCTION: Stress is often found to increase the preference and intake of high caloric foods. This effect is known as emotional eating and is influenced by cognitive as well as biological stress vulnerabilities. An S-allele of the 5 HTTLPR gene has been linked to decreased (brain) serotonin efficiency, leading to decreased stress resilience and increased risks for negative affect and eating related disturbances. Recently it has been proposed that a cognitive ruminative thinking style can further exacerbate the effect of this gene by prolonging the already increased stress response, thereby potentially increasing the risk of compensating by overeating high palatable foods. OBJECTIVE: This study was aimed at investigating whether there is an increased risk for emotional eating in high ruminative S/S-allele carriers reflected by an increased attention bias for high caloric foods during stress. METHODS: From a large (N=827) DNA database, participants (N=100) were selected based on genotype (S/S or L/L) and ruminative thinking style and performed an eye-tracking visual food-picture probe task before and after acute stress exposure. A significant Genotype x Rumination x Stress-interaction was found on attention bias for savory food; indicating that a stress-induced attention bias for specifically high-caloric foods is moderated by a gene x cognitive risk factor. CONCLUSION: Both a genetic (5-HTTLPR) and cognitive (ruminative thinking) stress vulnerability may mutually increase the risk for stress-related abnormal eating patterns. PMID- 28712730 TI - Social processing in early adolescence: Associations between neurophysiological, self-report, and behavioral measures. AB - Peer relationships play a major role in adolescent development, but few methods exist for measuring social processing at the neurophysiological level. This study extends our pilot study of Island Getaway, a task for eliciting event-related potentials (ERPs) to peer feedback. We differentiated ERPs using principal components analysis (PCA) and examined associations with behavioral and self report measures in young adolescents (N=412). PCA revealed an early negativity in the ERP enhanced for rejection feedback, followed by a series of positivities (consistent with reward positivity [RewP], P300, and late positive potential) that were enhanced for acceptance feedback. Greater self-reported task engagement correlated with a larger RewP to acceptance and lower rates of rejecting peers. Youth higher in depressive symptoms exhibited a blunted RewP to social acceptance and reported lower engagement. Results highlight ERP components sensitive to peer feedback that may inform understanding of social processes relevant to typical and atypical development. PMID- 28712731 TI - Cervical dystonia patients display subclinical gait changes. AB - INTRODUCTION: Gait disorders in cervical dystonia (CD) are reported in patients under DBS or in severe cases complicated with spinal deformities. OBJECTIVE: to assess walking motor pattern in CD patients without DBS and not presenting scoliosis. METHODS: Computerized gait analysis (CGA) was performed in CD patients, before and after botulinum toxin (BoNT) injections, and in healthy controls (HC). Spatiotemporal (ST) parameters were compared between CD and HC groups. Correlation analysis was conducted between ST parameters and clinical features of CD patients. RESULTS: CD patients demonstrated a significant reduction of velocity, stride length, % of swing phase, and dynamic stability index while stride and swing time were increased. No significant effect of BoNT was detected. A significant inverse correlation was found between TWSTRS and stride length. CONCLUSION: CD patients may have a slow gait with subclinical evidence. Our data suggest this alteration might be an endophenotipic feature of CD. PMID- 28712732 TI - Burn center care reduces acute health care utilization after discharge: A population-based analysis of 1,895 survivors of major burn injury. AB - BACKGROUND: Improvements in survival after burns have resulted in more patients being discharged home after severe injury. However, the postdischarge health care needs of burn survivors are not well understood. We aimed to determine the rate and causes of unplanned presentation to acute care facilities in the 5 years after major burn injury. METHODS: Data derived from several population-based administrative databases were used to conduct a retrospective cohort study. All patients aged >=16 years who survived to discharge after a major burn injury in 2003-2013 were followed for 1-5 years. All emergency department visits and unplanned readmissions were identified and classified by cause. Factors associated with emergency department visits were modeled using negative binomial generalized estimating equations. Factors associated with readmission were modeled using multivariable competing risk regression. RESULTS: We identified 1,895 patients who survived to discharge; 68% of patients had at least one emergency department visit and 30% had at least one readmission. Five-year mortality was 10%. The most common reason for both emergency department visits and readmissions was traumatic injury. After risk adjustment, patients who received their index care in a burn center experienced significantly less need for subsequent unplanned acute care, fewer emergency department visits (relative risk 0.61, 95% confidence interval, 0.52-0.72), and fewer hospital readmissions (hazard ratio 0.77, 95% confidence interval, 0.65-0.92). CONCLUSION: Acute health care utilization is frequent after burn injury and is most commonly related to traumatic injuries. Burn-related events are uncommon beyond 30 days after discharge, suggesting low rates of burn recidivism. Patients treated at burn centers have significantly reduced unplanned health care utilization after their injury. PMID- 28712733 TI - Long-term outcomes after autogenous versus synthetic lower extremity bypass in patients on hemodialysis. AB - BACKGROUND: Hemodialysis dependence confers unique physiologic conditions. Prior reports of outcomes after infrainguinal open bypass operations in patients on hemodialysis have been based on relatively small sample institutional series. In this study, we evaluate long-term outcomes after open bypass operations in a large contemporary population-based cohort of hemodialysis patients. We studied all hemodialysis patients who underwent infrainguinal open operation using autogenous versus prosthetic conduits in the United States Renal Data System between January 2007 and December 2011. METHODS: Univariate methods (chi2, analysis of variance) were used to compare the characteristics of the patient and type of bypass. Kaplan-Meier, univariate and multivariate logistic, and Cox regression analyses were used to evaluate 30-day postoperative outcomes as well as patency, limb salvage, and mortality in the long term. RESULTS: There were 9,739 (autogenous: 59%, prosthetic: 49%) infrainguinal open bypass operations performed in this cohort. Of these, 4,717 (48%) were femoral-popliteal, 3,321 (34%) were femoral-tibial, and 1,701 (18%) were popliteal-tibial bypasses. Bypass operations were performed most commonly for critical limb ischemia (72%). Primary patency was 18% for both types of conduits at 5 years (P = .16). Comparing autogenous versus prosthetic conduits, primary-assisted patency was 23% vs 20% at 5 years (P = .98), while secondary patency was 30% for both conduits at 5 years (P = .05). Limb salvage was 35% vs 41% at 5 years (P < .001). Multivariable analyses demonstrated greater patency (adjusted hazard ratio [aHR]: 1.16; 95% confidence interval, 1.05-1.28; P = .003) and limb salvage (aHR: 1.12; 95% confidence interval, 1.01-1.24; P = .03) for autogenous compared to prosthetic bypasses. The advantage conferred by autogenous conduits was most clinically relevant for femoral-tibial (aHR: 1.34; 95% confidence interval, 1.17-1.55; P < .001) and popliteal-tibial (aHR: 1.55; 95% confidence interval, 1.09-2.21; P = .014) configurations. CONCLUSION: This large study evaluated the long-term outcomes of open bypass operations in patients on hemodialysis. The data confirm the long-term benefits of autogenous conduits compared with prosthetic conduits in this high-risk population of patients, especially for the treatment of distal lesions. Individual patient life expectancy, availability of adequate autogenous conduit options, indication for operation, level of disease, as well as potential need for future options for additional access for dialysis should be taken into consideration when deciding to construct an open bypass in a hemodialysis patient. PMID- 28712734 TI - Combined direct and indirect traumatic carotid-cavernous fistula (CCF): Case report and review of the literature. AB - BACKGROUND: Within the current Barrow classification system, there are no categorical descriptions or reports in the literature of cavernous carotid fistulas (CCFs) with both a direct component (type A) and separate indirect contribution (type B, C, or D). We report the first definitive case of a combined simultaneous traumatic direct and indirect CCF, and review the literature on the similar existing entity of traumatic indirect CCFs presenting delayed and subsequent to the treatment of traumatic, direct CCFs. METHODS: We report a case of simultaneous direct type A CCF with a traumatic indirect CCF component and a review of the relevant literature. RESULTS: An 18year-old female presented after a motor vehicle collision. A diagnostic cerebral angiogram confirmed the diagnosis of CCF, with contribution both directly from the ICA and indirectly via branches of the ECA. The direct component of the CCF was first treated in 3 stages via both transarterial and transvenous coil embolization, followed by a final 4th stage of parent vessel sacrifice in order to treat the residual direct component, with transarterial embolization to treat residual indirect CCF activity. CONCLUSIONS: To our knowledge, this is the first report of a traumatic CCF with simultaneous direct (type A) and indirect via the ECA (type C) contributions. PMID- 28712735 TI - Spontaneous regression of post-traumatic syringomyelia: A case report and literature review. AB - Syringomyelia defines a condition in which myelopathy develops secondary to the formation of a cyst or cavity within the spinal cord parenchyma known as a syrinx. Although there is a significant volume of studies analysing the underlying mechanisms behind their formation, the management of such cavities remains an ongoing topic of debate. Aside from conservative approach, a range of surgical options exist, however long term outcomes are poor and a literature search reveals that the overall benefits are questionable. We present a 31-year old man with an incidental finding of a syrinx on MRI following a traumatic spinal cord injury. Following a decompression and 360 degrees fusion at the C6/7 level for a fracture-dislocation, the patient developed a delayed syrinx (54mm*11mm*8mm), and was managed conservatively. Over 2-year follow-up, the volume of the syrinx spontaneously reduced (46*5*5). Conservative treatment including careful observation is advisable as the first line therapy in patients with a post-traumatic syrinx. Surgery may be indicated in patients with progressive neurological symptoms, however there is a distinct lack of robust evidence on the long-term efficacy of surgery. PMID- 28712736 TI - Multivariable analysis of factors affecting length of stay and hospital charges after single-level corpectomy. AB - Anterior cervical corpectomy and fusion (ACCF) is commonly employed for treating myelopathy, deformity, and a variety of other cervical pathologies. Limited data are available on factors associated with longer hospitalization and higher hospital charges following ACCF. The purpose of this study was to evaluate the pre-, intra-, and postoperative variables that are associated with length of hospital stay and hospital charges for patients undergoing single-level anterior cervical corpectomy and fusion in a retrospective case series. We retrospectively identified from a clinical database 69 patients who underwent single-level ACCF at a single institution from 2010 through 2014. Demographic variables, clinical information, and intraoperative data were analyzed with respect to length of hospitalization and hospital charges. T-test and Chi-squared testing as well as univariate and multivariable analysis were performed with p<0.05 considered significant. On multivariable analysis, polytrauma, postoperative complications, lower postoperative hematocrit, and two-staged procedures were significantly associated with longer lengths of stay. Length of stay, postoperative complications, and two-staged procedures were significantly associated with higher hospital charges. Patients undergoing a two-staged procedure and those having postoperative complications experience a longer postoperative length of stay and incur higher hospital charges. Avoidance of postoperative anemia may help to reduce length of stay following ACCF. PMID- 28712737 TI - Pharmacists can help prevent lipoid pneumonia: Two case reports. AB - OBJECTIVES: To report 2 cases of lipoid pneumonia. SUMMARY: Lipoid pneumonia is an inflammatory process in the lower airways due to the presence of lipid molecules in the alveoli. Exogenous lipoid pneumonia is due to the inhalation or aspiration of fat-containing substances. Historically, mineral oil is the most common medication cause but there have also been several reports of lipoid pneumonia associated with petroleum jelly, medicated vapor rub, and lip glosses. Two case reports are presented to illustrate the importance of identifying risk factors for lipoid pneumonia. RESULTS: Use of the Naranjo algorithm suggested that both cases of lipoid pneumonia were "possibly" due to aspiration of lipid containing over-the-counter agents. The first case was associated with aspiration of mentholated topical ointment applied intranasally, whereas the second case was attributed to probable aspiration of mineral oil for management of chronic constipation. CONCLUSION: Pharmacists in many practice settings can play an integral role in preventing this condition and screening for patients who may warrant a diagnostic workup. During medication reconciliation, pharmacists should identify all prescription and nonprescription medications used by patients. Patients should specifically be asked about lipid-based over-the-counter products and cosmetic agents. PMID- 28712738 TI - A technology-supported collaboration between a health plan and a community pharmacy to improve blood pressure control. AB - OBJECTIVES: To assess the impact of a health plan and community pharmacy partnership to improve blood pressure control. SETTING: A midwestern health plan and a regional community pharmacy chain. PRACTICE INNOVATION: Health plan members with a hypertension diagnosis and attributed to the pharmacy chain based on prescription claims were invited to participate. Interested patients enrolled in the program at their pharmacies and were assigned a "smart card" for use with a blood pressure kiosk in the pharmacy. When the card was used at the kiosk, individual patient readings were linked directly to their electronic pharmacy record and an online patient portal. Pharmacists intervened with patients and prescribers as necessary to address adherence issues and adjust therapy as needed. EVALUATION: Before and after blood pressure readings were assessed to determine the impact of patient self-monitoring and pharmacist intervention for patients with 1) uncontrolled blood pressure at first reading and 2) multiple readings throughout the pilot period. RESULTS: Fifty-six of 276 eligible patients (20%) were enrolled in the program. Fourteen patients qualified for before and after assessments, having uncontrolled blood pressure on initial reading and multiple readings throughout the pilot. These patients demonstrated a mean reduction in systolic blood pressure of 12 mm Hg and diastolic blood pressure of 8 mm Hg. Nine of 16 eligible pharmacy locations enrolled patients at their sites. Challenges faced in the initiative included gaining adequate pharmacist and patient engagement. CONCLUSION: The pilot demonstrated promising early results in a model that has potential to improve blood pressure monitoring and management in a community pharmacy setting. PMID- 28712740 TI - Aspects of adhesion tests on resin-glass ceramic bonding. AB - OBJECTIVES: This study aimed to compare and contrast two resin-ceramic bond strength tests, the tensile bond strength and the four-point bending tests. The effects of hydrofluoric acid (HF) etching time and storage condition on bond strength were also studied. METHODS: Ceramic beams (N=480) with the dimensions of 2.00*2.00*12.45mm3 were sectioned from lithium disilicate ceramic ingots (IPS e.max CAD), then polished and fired for final crystallization. The joint surfaces were etched with HF gel (IPS Ceramic etching gel) for 20s, 40s, or 60s of each group (n=160). Then, a silane coupling agent (Vitasil(r)) was applied in a single application on the HF etched surfaces, left for 60s before air-drying. Two beams were bonded together with resin composite cement (Variolink II(r)) in a tailored mold (2.00*2.00*25.00mm3) to control cement thickness to 0.10mm and then light cured on both sides. The bonded specimens were further divided into two groups (n=40): (1) tested one day after luting (dry); and (2) tested after storage in 37 degrees C distilled water for 4 weeks. Two mechanical tests were used (n=20): the tensile bond strength and four-point bending tests. Bond strength results were subjected to two-way AoV, and Weibull statistics with alpha=0.05. Fracture surfaces were examined visually and verified using light microscopy. RESULTS: The four-point bending test showed a higher consistency than the tensile bond strength test using Weibull statistics (p<0.01). The effect of HF etching time on the flexural strength was significant, with longer HF etching times decreasing the flexural strength (p<0.01). Storage also had a significant effect on the flexural strength (p<0.01). However, HF etching time did not have a significant effect on the tensile bond strengths (p>0.05) and the influence of the storage time was marginally significant (p<0.05). More than 75% of specimens failed adhesively in the four-point bend test while a mixture of adhesive, cohesive and mixed failures was observed in the tensile bond test. SIGNIFICANCE: The four point bending test might be a better approach to evaluate bond strengths. Increased HF etching time and a longer storage period resulted in a decrease in the flexural bond strength. However, both HF etching time and storage time had no significant effect on the tensile bond strengths. PMID- 28712739 TI - Biocompatibility and bond degradation of poly-acrylic acid coated copper iodide adhesives. AB - OBJECTIVE: To investigate the effect of poly-acrylic acid (PAA) copper iodide (CuI) adhesives on bond degradation, tensile strength, and biocompatibility. METHODS: PAA-CuI particles were incorporated into Optibond XTR, Optibond Solo and XP Bond in 0.1 and 0.5mg/ml. Clearfil SE Protect, an MDPB-containing adhesive, was used as control. The adhesives were applied to human dentin, polymerized and restored with composite in 2mm-increments. Resin-dentin beams (0.9+/-0.1mm2) were evaluated for micro-tensile bond strength after 24h, 6 months and 1year. Hourglass specimens (10*2*1mm) were evaluated for ultimate tensile strength (UTS). Cell metabolic function of human gingival fibroblast cells exposed to adhesive discs (8*1mm) was assessed with MTT assay. Copper release from adhesive discs (5*1mm) was evaluated with UV-vis spectrophotometer after immersion in 0.9% NaCl for 1, 3, 5, 7, 10, 14, 21 and 30 days. SEM, EDX and XRF were conducted for microstructure characterization. RESULTS: XTR and Solo did not show degradation when modified with PAA-CuI regardless of the concentration. The UTS for adhesives containing PAA-CuI remained unaltered relative to the controls. The percent viable cells were reduced for Solo 0.5mg/ml and XP 0.1 or 0.5mg/ml PAA-CuI. XP demonstrated the highest ion release. For all groups, the highest release was observed at days 1 and 14. SIGNIFICANCE: PAA-CuI particles prevented the bond degradation of XTR and Solo after 1year without an effect on the UTS for any adhesive. Cell viability was affected for some adhesives. A similar pattern of copper release was demonstrated for all adhesives. PMID- 28712741 TI - Epithelial-mesenchymal transition of human lung adenocarcinoma A549 cells up regulates cytokine production upon LPS stimulation. PMID- 28712744 TI - Response. PMID- 28712742 TI - Analyses of Treatment Outcome According to Age in Patients With Chronic Myeloid Leukemia Receiving Front-line Imatinib Therapy. AB - BACKGROUND: Previous studies have indicated that the effect of age at the diagnosis of chronic myeloid leukemia (CML) is minimized in patients treated with imatinib. The treatment response and survival rates were similar for younger and elderly patients. The aim of the present study was to evaluate the effect of age on the treatment outcomes in patients with CML receiving front-line imatinib therapy. PATIENTS AND METHODS: Using age, 101 patients were divided into 3 groups: young (age, 18-44 years; YP), middle-age (age, 45-64 years; MP), and elderly (age, >= 65 years; EP). The patients' clinical features, treatment responses, survival, and adverse events were evaluated. RESULTS: The complete cytogenetic response rates were similar in all 3 groups (81.8% in YP, 86.8% in MP, and 76.7% in EP; P = .328). However, the major molecular response rate was greatest in the MP group (84.2% vs. 63.6% in the YP and 60.0% in the EP group; P < .001). Most of the nonhematologic adverse events (all grades) were in the EP group (40.0% vs. 27.3% in the YP and 21.1% in the MP group; P = .005). The estimated 6-year event-free survival in the MP group (75.5%) was significantly greater than that in the YP group (58.6%) or EP group (43.4%). Also, the estimated 6-year overall survival rate in the EP group (73.5%) was significantly lower than that in the YP group (90.8%) and MP group (86.4%) (P < .001 for all). CONCLUSION: Our results have shown that middle-age patients have the best clinical outcomes, with the greatest rates of an optimal therapeutic response, longer event-free survival, and longer overall survival. PMID- 28712743 TI - Is pancreaticogastrostomy safer than pancreaticojejunostomy after pancreaticoduodenectomy? A meta-regression analysis of randomized clinical trials. AB - OBJECTIVE: To evaluate the clinically relevant POPF rate between Pancreatogastrostomy (PG) and pancreaticojejunostomy (PJ) after pancreaticoduodenectomy (PD). To evaluate the confounding factors affecting meta analytic results. METHODS: A systematic literature search of randomized clinical trials (RCTs) comparing PG to PJ with an International Study Group of Pancreatic Fistula (ISGPF) definition of postoperative pancreatic fistula (POPF). Risk difference (RD) and number needed to treat or harm (NNT and NNH) were used. Fixed and random-effect models were applied. Impact of confounding covariates on the meta-analytic results was evaluated using meta-regression analysis, reporting beta coefficient +/- standard error (SE). RESULTS: Seven RCTs were identified involving 1184 patients: 603 PG and 581 PJ. RD in the fixed model of clinically relevant POPFs suggested that PG was superior to PJ (RD-0.07; 95% CI: -0.11 to 0.03) with an NNT of 14 (95% CI: 9 to 33). In random model, PG was not superior to PJ (RD-0.06; 95% CI: -0.13 to 0.01) with an NNT of 17 and a possibility of harm in some cases (NNH = 100). Meta-regression suggested that the increase in the proportion of "soft pancreas" in the PG arm corresponded to a more positive value of RD (beta = 0.47 +/- 0.19; P value: 0.045 +/- 0.003). CONCLUSION: A PG could be slightly superior to PJ in the prevention of clinically relevant POPF. The presence of high risk pancreatic remnant remains the main limitation of PG. PMID- 28712745 TI - The Ligand Binding Landscape of Diacylglycerol Kinases. AB - Diacylglycerol kinases (DGKs) are integral components of signal transduction cascades that regulate cell biology through ATP-dependent phosphorylation of the lipid messenger diacylglycerol. Methods for direct evaluation of DGK activity in native biological systems are lacking and needed to study isoform-specific functions of these multidomain lipid kinases. Here, we utilize ATP acyl phosphate activity-based probes and quantitative mass spectrometry to define, for the first time, ATP and small-molecule binding motifs of representative members from all five DGK subtypes. We use chemical proteomics to discover an unusual binding mode for the DGKalpha inhibitor, ritanserin, including interactions at the atypical C1 domain distinct from the ATP binding region. Unexpectedly, deconstruction of ritanserin yielded a fragment compound that blocks DGKalpha activity through a conserved binding mode and enhanced selectivity against the kinome. Collectively, our studies illustrate the power of chemical proteomics to profile protein-small molecule interactions of lipid kinases for fragment-based lead discovery. PMID- 28712746 TI - Formation of an Angular Aromatic Polyketide from a Linear Anthrene Precursor via Oxidative Rearrangement. AB - Bacterial aromatic polyketides are a group of natural products synthesized by polyketide synthases (PKSs) that show diverse structures and biological activities. They are structurally subclassified into linear, angular, and discoid aromatic polyketides, the formation of which is commonly determined by the shaping and folding of the poly-beta-keto intermediates under the concerted actions of the minimal PKSs, cyclases and ketoreductases. Murayaquinone, found in several streptomycetes, possesses an unusual tricyclic angular aromatic polyketide core containing a 9,10-phenanthraquinone. In this study, genes essential for murayaquinone biosynthesis were identified, and a linear anthraoxirene intermediate was discovered. A unique biosynthetic model for the angular aromatic polyketide formation was discovered and confirmed through in vivo and in vitro studies. Three oxidoreductases, MrqO3, MrqO6, and MrqO7, were identified to catalyze the conversion of the linear aromatic polyketide intermediate into the final angularly arranged framework, which exemplifies a novel strategy for the biosynthesis of angular aromatic polyketides. PMID- 28712748 TI - CHI: A contemporaneous health index for degenerative disease monitoring using longitudinal measurements. AB - In this paper, we develop a novel formulation for contemporaneous patient risk monitoring by exploiting the emerging data-rich environment in many healthcare applications, where an abundance of longitudinal data that reflect the degeneration of the health condition can be continuously collected. Our objective, and the developed formulation, is fundamentally different from many existing risk score models for different healthcare applications, which mostly focus on predicting the likelihood of a certain outcome at a pre-specified time. Rather, our formulation translates multivariate longitudinal measurements into a contemporaneous health index (CHI) that captures patient condition changes over the course of progression. Another significant feature of our formulation is that, CHI can be estimated with or without label information, different from other risk score models strictly based on supervised learning. To develop this formulation, we focus on the degenerative disease conditions, for which we could utilize the monotonic progression characteristic (either towards disease or recovery) to learn CHI. Such a domain knowledge leads us to a novel learning formulation, and on top of that, we further generalize this formulation with a capacity to incorporate label information if available. We further develop algorithms to mitigate the challenges associated with the nonsmooth convex optimization problem by first identifying its dual reformulation as a constrained smooth optimization problem, and then, using the block coordinate descent algorithm to iteratively solve the optimization with a derived efficient projection at each iteration. Extensive numerical studies are performed on both synthetic datasets and real-world applications on Alzheimer's disease and Surgical Site Infection, which demonstrate the utility and efficacy of the proposed method on degenerative conditions that include a wide range of applications. PMID- 28712747 TI - Selectivity and Kinetic Requirements of HDAC Inhibitors as Progranulin Enhancers for Treating Frontotemporal Dementia. AB - Frontotemporal dementia (FTD) arises from neurodegeneration in the frontal, insular, and anterior temporal lobes. Autosomal dominant causes of FTD include heterozygous mutations in the GRN gene causing haploinsufficiency of progranulin (PGRN) protein. Recently, histone deacetylase (HDAC) inhibitors have been identified as enhancers of PGRN expression, although the mechanisms through which GRN is epigenetically regulated remain poorly understood. Using a chemogenomic toolkit, including optoepigenetic probes, we show that inhibition of class I HDACs is sufficient to upregulate PGRN in human neurons, and only inhibitors with apparent fast binding to their target HDAC complexes are capable of enhancing PGRN expression. Moreover, we identify regions in the GRN promoter in which elevated H3K27 acetylation and transcription factor EB (TFEB) occupancy correlate with HDAC-inhibitor-mediated upregulation of PGRN. These findings have implications for epigenetic and cis-regulatory mechanisms controlling human GRN expression and may advance translational efforts to develop targeted therapeutics for treating PGRN-deficient FTD. PMID- 28712750 TI - Is there an association between mesenteric panniculitis and lymphoma? A case control analysis. AB - AIM: To determine the prevalence and association of mesenteric panniculitis (MP) in a group of patients with non-Hodgkin's lymphoma (NHL) compared to control group. MATERIALS AND METHODS: We retrospectively evaluated computed tomography (CT) and combined positron-emission tomography (PET) with CT examinations of a total of 166 patients who were diagnosed with NHL over a period of 5 years (2008 2013). The control group consisted of 332 subjects who were matched for gender and age at the time period the examinations were performed on the study group. A combination of radiological signs and absence of 2-[18F]-fluoro-2-deoxy-d-glucose (FDG)-uptake was used to establish the diagnosis of MP and distinguish it from the involvement of mesentery by lymphoma. RESULTS: MP was identified in three patients (prevalence 1.8%) from the study group as compared to seven subjects out of 332 (2.1%) in the control group (p=0.556). During the course of follow-up no changes in the imaging features of MP were seen in either group. Additionally, 27 (16.2%) patients from the study group were found to have changes in the mesentery, which were attributed to the involvement of the mesentery in the primary disease. CONCLUSION: The prevalence of MP among patients with NHL was found to be 1.8%, which corresponds to the range of its prevalence in the general population. This is contrary to the proposition that MP is associated with NHL. PMID- 28712749 TI - Nicotine- and cocaine-triggered methamphetamine reinstatement in female and male Sprague-Dawley rats. AB - Preclinical studies have demonstrated a return to methamphetamine (meth)-seeking behavior (reinstatement) induced by injections of meth administered by the experimenter (drug-prime). Notably, females tend to be more sensitive to drug prime; often displaying more reinstatement behavior when compared to males. While meth-primed reinstatement of meth-seeking behavior has been established, little is known about the ability of other drugs of abuse to substitute for meth during drug-primed reinstatement; nicotine and cocaine were the focus of the present work. We also examined if self-administration and/or reinstated meth-seeking behavior was affected by repeated nicotine administration. Male and female Sprague-Dawley rats were trained to self-administer meth during daily sessions. During this self-administration phase, rats were placed into 1 of 2 groups: saline or repeated nicotine exposure. Rats in the repeated nicotine group received nicotine injections 4h after meth self-administration sessions, whereas the remaining rats received saline. Following self-administration was extinction in which meth was no longer available and nicotine was no longer administered. After extinction, rats were tested to determine if 0 (saline), 0.2, and 0.4mg/kg nicotine reinstated meth-seeking behavior. Three days of re-extinction followed nicotine testing. Finally, rats received reinstatement tests with 0 (saline), 5, and 10mg/kg cocaine. Nicotine and cocaine reinstated meth-seeking behavior in male and female rats with no difference between the sexes. Repeated nicotine administration potentiated meth reinstatement following the 0.4mg/kg nicotine prime. While females may be more sensitive to reinstatement triggered with the original self-administration drug, this effect may not generalize to priming with other drugs of abuse. PMID- 28712752 TI - Asymptomatic Scattered Pigmented Flat Lesions in the Esophagus. PMID- 28712751 TI - Melena in a Patient With a Metastasized Neuroendocrine Tumor. PMID- 28712753 TI - Diffuse Small Intestine Erosions and Ulcers in an Immunocompromised Host. PMID- 28712754 TI - An Unusual Rectal Mass. PMID- 28712755 TI - A Surprising Granulomatous Cheilitis. PMID- 28712756 TI - An Unusual Cause of a Solid-Cystic Pancreatic Lesion. PMID- 28712757 TI - Hematochezia Caused by a Colon Disease With Unusual Presentation. PMID- 28712758 TI - A Rare But Curable Cause of Iron Deficiency Anemia. PMID- 28712759 TI - An Elderly Woman With Upper Abdominal Pain and a 60-Pound Weight Loss. PMID- 28712760 TI - Rodeo, Anyone? PMID- 28712761 TI - Detection, Diagnosis, and Resection of Sessile Serrated Adenomas and Polyps. PMID- 28712762 TI - Acute Epigastric Abdominal Pain Post-Gastric Polypectomy. PMID- 28712763 TI - Unusual Cause of Dysphagia. PMID- 28712764 TI - Nucleocytoplasmic transport in cells with progerin-induced defective nuclear lamina. AB - Recent data indicate that nuclear lamina (NL) plays a relevant role in many fundamental cellular functions. The peculiar role of NL in cells is dramatically demonstrated by the Hutchinson-Gilford progeria syndrome (HGPS), an inherited laminopathy that causes premature, rapid aging shortly after birth. In HGPS, a mutant form of Lamin A (progeria) leads to a dysmorphic NL structure, but how this perturbation is transduced into cellular changes is still largely unknown. Owing to the close structural relationship between NL and the Nuclear Pore Complex (NPC), in this work we test whether HGPS affects passive and active nucleo-cytoplasmic shuttling of cargoes by means of an established model based of fluorescence recovery after photobleaching. Our findings clearly demonstrate that dysmorphic NL is decoupled from the dynamic characteristics of passive and active transport towards and from the nucleus, as well as from the binding affinity of transport protein mediators. PMID- 28712765 TI - Losartan reverses COX-2-dependent vascular dysfunction in offspring of hyperglycaemic rats. AB - AIMS: This study examined whether chronic treatment with losartan, an angiotensin II type 1 receptor (AT1R) antagonist, might reverse COX-2-mediated vascular dysfunction in mesenteric resistance arteries (MRA) from offspring of hyperglycaemic rats. MATERIALS AND METHODS: Male 12-month-old offspring of hyperglycaemic (O-DR) and normoglycaemic (O-CR) rats were treated with losartan (15mg.kg.day-1) during 2months. Third order MRA of untreated and losartan-treated O-DR and O-CR were mounted in wire myograph for isometric tension measurements. COX-2 expression was analyzed by Western blot; TxA2, PGE2 and PGF2alpha release was measured using commercial kits. KEY FINDINGS: O-DR showed increased blood pressure, impaired acetylcholine-induced vasodilation and increased noradrenaline induced vasoconstriction than O-CR. All these parameters were normalized by losartan in O-DR. Pre-incubation of MRA with indomethacin (COX-1/2 inhibitor), NS 398 (COX-2 inhibitor) or tempol (superoxide dismutase mimetic) increased relaxation to acetylcholine and reduced contraction to noradrenaline only in O DR. COX-2 expression, TxA2, PGE2 and PGF2alpha release were increased in O-DR. In losartan-treated O-DR, NS-398, indomethacin or tempol failed to produce any effect on acetylcholine or noradrenaline responses. Losartan treatment reduced COX-2 expression, TxA2, PGE2 and PGF2alpha release in O-DR. SIGNIFICANCE: The present results reveal that chronic losartan administration in O-DR normalizes endothelial function in MRA by correcting the existing COX-2 overexpression and the imbalance between endothelium-derived relaxing and contracting factors. These findings not only support the beneficial effects of AT1 receptor antagonist in O DR, but also suggest the implication of angiotensin II as a putative mediator of hyperglycemia-programmed vascular dysfunction in rats. PMID- 28712766 TI - "A call for a clear assignment" - A focus group study of the ambulance service in Sweden, as experienced by present and former employees. AB - AIM: The aim was to explore the ambulance service as experienced by present and former employees. BACKGROUND: Over the last decade, the number of ambulance assignments has increased annually by about 10%, and as many as 50% of all ambulance assignments are considered non-urgent. This raises questions about which assignments the Ambulance Service (AS) is supposed to deal with. DESIGN/METHOD: Data were collected from three focus group interviews with a total of 18 present and former employees of the Swedish AS. An inductive qualitative analysis method developed by Krueger was chosen. RESULTS: Five themes emerged in the analysis: "Poor guidance for practice", "An unclear assignment", "Being a gate keeper", "From saving lives to self-care" and "Working in no man's land", which together constitute the AS. CONCLUSION: Present and former employees of the AS in Sweden describe their mission as unclear and recognize the lack of consensus and a clearly developed mission statement. Furthermore, expectations and training mainly focus on emergency response, which is contrary to the reality of the ambulance clinicians' everyday work. PMID- 28712767 TI - Corrigendum to "The Starting Treatment for Ethanol in Primary care Trials (STEP Trials): Protocol for three parallel multi-site stepped care effectiveness studies for unhealthy alcohol use in HIV-positive patients" [Contemp. Clin. Trials 52 (2017) 80-90]. PMID- 28712769 TI - Clam bioaccumulation of Alkylphenols and Polyciclic aromatic hydrocarbons in the Venice lagoon under different pressures. AB - Biota-Sediment Accumulation Factors (BSAFs) of nonylphenols (NPs) and polycyclic aromatic hydrocarbons (PAHs) in Ruditapes philippinarum from the Venice Lagoon (Italy) were determined with the aim to verify whether the routine biomonitoring studies are reliable in contaminated sites. Clams and sediments were collected in field campaigns (October 2003 to June 2004) in three sites of the Venice Lagoon. Results showed that Marghera and Campalto sediments were more contaminated by NPs and PAHs than Poveglia. Different trends were observed in the contamination of clams with the highest BSAFs found at Poveglia. BSAF trend appeared to be inversely related to the contaminant pressure on the sites. These results suggest that clam bioaccumulation is not always representative of the chemical pressure on aquatic biota. The direct correlation between sediment and biota concentrations in contaminated sites can be lost as a function of the site specific conditions such as sediment toxicity and food availability. PMID- 28712768 TI - Neutralizing Antibodies Against a Specific Human Immunodeficiency Virus gp41 Epitope are Associated With Long-term Non-progressor Status. AB - Antibodies (Abs) play a central role in human immunodeficiency virus (HIV) protection due to their multiple functional inhibitory activities. W614A-3S Abs recognize a specific form of a highly conserved motif of the gp41 envelope protein and can elicit viral neutralization to protect CD4+ T cells. Here, we describe in detail the neutralizing profile of W614A-3S Abs in untreated long term non-progressor (LTNP) HIV-infected patients. W614A-3S Abs were detected in 23.5% (16/68) of untreated LTNP patients compared with <5% (5/104) of HIV-1 progressor patients. The W614A-3S Abs had efficient neutralizing activity that inhibited transmitted founder primary viruses and exhibited Fc-mediated inhibitory functions at low concentrations in primary monocyte-derived macrophages. The neutralizing capacity of W614A-3S Abs was inversely correlated with viral load (r=-0.9013; p<0.0001), viral DNA (r=-0.7696; p=0.0005) and was associated the preservation of high CD4+ T-cell counts and T-cell responses. This study demonstrates that W614A-3S neutralizing Abs may confer a crucial advantage to LTNP patients. These results provide insights for both pathophysiological research and the development of vaccine strategies. PMID- 28712770 TI - Determination of trace metals and analysis of arsenic species in tropical marine fishes from Spratly islands. AB - Trace metal contents in 38 species of tropical marine fishes harvested from the Spratly islands of China were determined by microwave digestion and inductively coupled plasma mass spectrometry analysis. Arsenic species were determined by high-performance liquid chromatography and inductively coupled plasma mass spectrometry analysis. The average levels of Al, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, As, Se, Mo, Cd, Pb, and U in the fish samples were 1.683, 0.350, 0.367, 2.954, 36.615, 0.087, 0.319, 1.566, 21.946, 20.845, 2.526, 3.583, 0.225, 0.140, and 0.061mg.kg-1, respectively; Fe, Zn, and As were found at high concentrations. The trace metals exhibited significant positive correlation between each other, with r value of 0.610-0.852. Further analysis indicated that AsB (8.560-31.020mg.kg-1) was the dominant arsenic species in the fish samples and accounted for 31.48% to 47.24% of the total arsenic. As(III) and As(V) were detected at low concentrations, indicating minimal arsenic toxicity. PMID- 28712771 TI - Characterization and ecological risk of polycyclic aromatic hydrocarbons (PAHs) and n-alkanes in sediments of Shadegan international wetland, the Persian Gulf. AB - The distribution and sources of PAHs and n-alkanes were determined in the surface sediments from 202 locations in Shadegan international wetland with 537,700ha. The concentrations of total n-alkanes and PAHs ranged from 395.3 to 14933.46MUgg 1dw and 593.74 to 53393.86ngg-1dw, respectively. Compared with other worldwide surveys, the concentration and contamination of sedimentary hydrocarbons were classified very high. A common petrogenic hydrocarbon source was strongly suggested in all sites by n-alkanes' profile with a Cmax at n-C20, Pr/Ph and CPI ratios<1 in all sites, and high percentage of UCM. Typical profile of petrogenic PAHs with alkyl-substituted naphthalenes and phenanthrenes predominance, various PAH ratios and multivariate analysis indicated that PAHs were mainly derived from petrogenic source. Naphthalene-derived compounds in all sites were significantly above their ERL, and adversely affected benthic biota. 92% of the sites had mean ERM values<0.1, indicating high ecological risk on the wildlife of the wetland. PMID- 28712772 TI - Spatio-temporal variations in bloom of the red-tide dinoflagellate Karenia mikimotoi in Imari Bay, Japan, in 2014: Factors controlling horizontal and vertical distribution. AB - A massive bloom of the dinoflagellate Karenia mikimotoi appeared in 2014 in Imari Bay, Japan. Bloom dynamics and hydrographical conditions were examined by field survey. The bloom initially developed in the eastern area of Imari Bay, subsequently after rainfall during the neap tides, cell density exceeded over 10,000cellsml. Vertical distribution of K. mikimotoi was primarily controlled by the light intensity and secondarily by the water quality during the daytime. Almost all cell-density maxima occurred in depths with weak daytime light intensities of <300MUmolm-2s-1. In some cases of weak light intensity, cell density maxima occurred in depths with favorable hydrodynamic conditions for the growth. Spatially classified areas were identified by cluster analysis using the growth rate calculated from seawater temperature and salinity. This study quantitatively evaluated the environmental factors of the eastern area, where the bloom initially occurred, during the development of the bloom. PMID- 28712773 TI - Spatial distribution and seasonal variation of phthalate esters in the Jiulong River estuary, Southeast China. AB - The spatial distribution and seasonal variation of 16 phthalate esters (PAEs) in water, suspended particulate matter (SPM) and sediment were investigated in the Jiulong River estuary, Fujian, Southeast China. Of the 16 PAE congeners analyzed, only six PAEs, including dimethyl phthalate (DMP), diethyl phthalate (DEP), diisobutyl phthalate (DIBP), di-n-butyl phthalate (DBP), di(2-ethylhexyl) phthalate (DEHP) and diisononyl phthalate (DINP), were identified and quantified. The total concentrations of the six PAEs (?6PAEs) detected for all seasons ranged from 3.01 to 26.4MUg/L in water, 1.56 to 48.7mg/kg in SPM, and 0.037 to 0.443MUg/kg in sediment. DEHP, DIBP and DBP were the most abundant PAE congeners in all of the water, SPM and sediment phases. The spatial distributions of PAEs in the estuary were controlled not only by the riverine runoff, seasons, hydrodynamic condition and human activities but also the physicochemical properties of PAEs. PMID- 28712774 TI - Characterization of NPHS2 gene polymorphisms associated to steroid resistance nephrotic syndrome in Indian children. AB - Nephrotic syndrome (NS) is the common glomerular disease in children. These children are treated with steroids, depending upon their behavior. They are either steroid sensitive (SSNS) or steroid resistant (SRNS). NPHS2 gene mutants are linked to the risk of autosomal recessive SRNS and in some cases to SSNS. The present study has been performed to screen single nucleotide polymorphisms (SNPs) of the NPHS2 gene in a group of 90 Indian children suffering with NS (30 SSNS, 30 SRNS and 30 Controls) by PCR method followed by direct exon sequencing. Effect of SNPs on fold expression changes at transcript level of podocin was checked using quantitative real time PCR (qRT-PCR). SNPs identified through sequencing helps to carry out in-silico analysis. Overall 17 SNPs were identified in NPHS2 gene where 6 were found novel. Three missense SNPs p.R299Q, p.P20L and p.G35D were also identified in this population where SNP, p.G35D was found novel. In addition to sequencing analysis, results of in silico analysis shows that a mutant with these three missense SNPs has least ligand binding efficiency compared to native model. Moreover the significant observation of this study included two intronic SNPs c.451+23C>T and c.451+58A>T present in SRNS group of patients. These SNPs has shown high level of clinical significance within genomic and allelic frequency along with haplotypes and linkage disequilibrium count. The qRT-PCR analysis shows, down expression of podocin protein at transcript level in SRNS patients compared to SSNS patients. All these results support the fact that SNPs present in this population could affect the protein structural stability. Thus it is concluded that the polymorphisms predicted in this study might be disease causing in the NPHS2 gene and may have influence on the therapeutic response of NS patients. PMID- 28712775 TI - Simple sequence repeats showing 'length preference' have regulatory functions in humans. AB - Simple sequence repeats (SSRs), simple tandem repeats (STRs) or microsatellites are short tandem repeats of 1-6 nucleotide motifs. They are twice as abundant as the protein coding DNA in the human genome and yet little is known about their functional relevance. Analysis of genomes across various taxa show that despite the instability associated with longer stretches of repeats, few SSRs with specific longer repeat lengths are enriched in the genomes indicating a positive selection. This conserved feature of length dependent enrichment hints at not only sequence but also length dependent functionality for SSRs. In the present study, we selected 23 SSRs of the human genome that show specific repeat length dependent enrichment and analysed their cis-regulatory potential using promoter modulation, boundary and barrier assays. We find that the 23 SSR sequences, which are mostly intergenic and intronic, possess distinct cis-regulatory potential. They modulate minimal promoter activity in transient luciferase assays and are capable of functioning as enhancer-blockers and barrier elements. The results of our functional assays propose cis-gene regulatory roles for these specific length enriched SSRs and opens avenues for further investigations. PMID- 28712776 TI - Clonal evolution in paired endometrial intraepithelial neoplasia/atypical hyperplasia and endometrioid adenocarcinoma. AB - Endometrial intraepithelial neoplasia (EIN) and atypical endometrial hyperplasia (AH) are histomorphologically defined precursors to endometrioid adenocarcinoma, which are unified as EIN/AH by the World Health Organization. EIN/AH harbors a constellation of molecular alterations similar to those found in endometrioid adenocarcinoma. However, the process of clonal evolution from EIN/AH to carcinoma is poorly characterized. To investigate, we performed next-generation sequencing, copy number alteration (CNA) analysis, and immunohistochemistry for mismatch repair protein expression on EIN/AH and endometrioid adenocarcinoma samples from 6 hysterectomy cases with spatially distinct EIN/AH and carcinoma. In evaluating all samples, EIN/AH and carcinoma did not differ in mutational burden, CNA burden, or specific genes mutated (all P>.1). All paired EIN/AH and carcinoma samples shared at least one identical somatic mutation, frequently in PI(3)K pathway members. Large CNAs (>10 genes in length) were identified in 83% of cases; paired EIN/AH and carcinoma samples shared at least one identical CNA in these cases. Mismatch repair protein expression matched in all paired EIN/AH and carcinoma samples. All paired EIN/AH and carcinoma samples had identical The Cancer Genome Atlas subtype, with 3 classified as "copy number low endometrioid" and 3 classified as "microsatellite instability hypermutated." Although paired EIN/AH and carcinoma samples were clonal, private mutations (ie, present in only one sample) were identified in EIN/AH and carcinoma in all cases, frequently in established cancer-driving genes. These findings indicate that EIN/AH gives rise to endometrioid adenocarcinoma by a complex process of subclone evolution, not a linear accumulation of molecular events. PMID- 28712777 TI - Reproducibility for histologic parameters in peritoneal mesothelioma. AB - Histologic subtype is recognized as a prognostic factor in malignant pleural mesothelioma. Specifically, epithelial morphology is associated with a better prognosis than other subtypes, and the same association is observed in peritoneal malignant mesothelioma. Recently, prognostic differences based on morphologic subtypes of epithelial peritoneal malignant mesothelioma were reported. Herein, we report the interobserver variability across four pathologists at three institutions. The authors independently reviewed 67 cases of malignant peritoneal epithelioid mesotheliomas and subclassified them according to their epithelial subtype: papillary, tubulopapillary, trabecular, micropapillary, solid and/or pleomorphic. The cases were also evaluated by each author for several other histopathologic parameters including depth of invasion, nuclear grade, lymphocytic host response, mitotic count/index, presence of lymphovascular invasion, and stromal desmoplasia. The interobserver agreement for histopathologic parameters was highest for mitotic rate (kappa=0.36) and primary epithelial subtype (kappa=0.32). The interobserver variability for solid subtype pattern was moderate (kappa=0.49). We found that the interobserver variability for most histopathologic parameters is poor. PMID- 28712778 TI - Hydrothermal carbonization for the preparation of hydrochars from glucose, cellulose, chitin, chitosan and wood chips via low-temperature and their characterization. AB - In this work, the hydrothermal carbonization of glucose, cellulose, chitin, chitosan and wood chips at 200 degrees C at processing times between 6 and 48h was studied. The carbonization degree of wood chips, cellulose and chitosan obviously increases as function of time. The heating value of glucose increases to 88% upon carbonization for 48h, while it is only 5% for chitin. It is calculated to be between 44 and 73% for wood chips, chitosan and cellulose. Glucose yielded complete formation of spherical hydrochar structures at a shorter processing time, as low as 12h. However, carbon spheres with narrow size (~560nm) distribution were obtained upon 48h of residence time. Cellulose and wood chips yielded a similar morphology with an irregular size distribution. Chitin seemed not to undergo hydrothermal carbonization, whereas densely aggregated spheres of a uniform size around 42nm were obtained from chitosan after 18h. PMID- 28712779 TI - Fabrication of engineered biochar from paper mill sludge and its application into removal of arsenic and cadmium in acidic water. AB - An engineered biochar was fabricated via paper mill sludge pyrolysis under CO2 atmosphere, and its adsorption capability for As(V) and Cd(II) in aqueous solution was evaluated in a batch mode. The characterization results revealed that the biochar had the structure of complex aggregates containing solid minerals (FeO, Fe3O4 and CaCO3) and graphitic carbon. Adsorption studies were carried out covering various parameters including pH effect, contact time, initial concentrations, competitive ions, and desorption. The adsorption of As(V) and Cd(II) reached apparent equilibrium at 180min, and followed the pseudo-second order kinetics. The highest equilibrium uptakes of As(V) and Cd(II) were 22.8 and 41.6mgg-1, respectively. The adsorption isotherms were better described by Redlich-Peterson model. The decrease in As(V) adsorption was apparent with the increase in PO43- concentration, and a similar inhibition effect was observed for Cd(II) adsorption with Ni(II) ion. The feasibility of regeneration was demonstrated through desorption by NaOH or HCl. PMID- 28712780 TI - A review of biochar-based catalysts for chemical synthesis, biofuel production, and pollution control. AB - This review addresses the use of biochar as a green and versatile catalyst support for emerging high-end applications beyond soil remediation, including chemical synthesis and biodiesel production from biomass, and pollutant degradation in the environment. Their catalytic performances are comparable or even superior to the conventional resin-, silica-, or carbon-based catalysts, owing to the favourable intrinsic features of biochar (various functional groups, intricate network of structures, etc.). Yet, distinctive active sites are needed for different applications. It is highlighted that the active site accessibility for substrates critically determines the performance, which is associated with the biochar physicochemical characteristics (-SO3H site density, pore size distribution, surface area, etc.). They show varying significance depending on the catalytic sites on biochar, which may be controlled via novel pre-/post synthesis modifications. This review elucidates the links among catalytic performances, physicochemical properties, and pyrolysis/modification-induced features, advising the tailored production of application-oriented biochar-based catalyst in the future. PMID- 28712781 TI - Pressurized Microcystis can help to remove nitrate from eutrophic water. AB - The aim of this study was to investigate the feasibility of using harmful cyanobacterium Microcystis to help remove nitrate from eutrophic water. The results showed that after treatment by pressurization at 0.4MPa, Microcystis quickly sank to the bottom. Pressurization did not significantly affect the viability of Microcystis and this cyanobacterium maintained high viability over three days under dark/anoxic conditions. Meanwhile, the amount of dissolved organic carbon (DOC) secreted from living Microcystis cells reached 2.48mgCmg-1 Chl a, and a significant enhancement of pressurized Microcystis on nitrate removal at the sediment-water interface was observed, with a 2.85-fold increase in the specific NOX--N removal rate. The results of this study support the novel idea that harmful Microcystis could be converted to a carbon source for removing nitrate from eutrophic water by a simple pressurization measure. PMID- 28712782 TI - Cu removal and response mechanisms of periphytic biofilms in a tubular bioreactor. AB - This work studied Cu removal and response mechanisms of periphytic biofilms in a tubular bioreactor. Periphytic biofilms immobilized in a tubular bioreactor were used to remove Cu from wastewater with different Cu concentrations. Results showed that periphytic biofilms had a high removal efficiency (max. 99%) at a hydraulic retention time (HRT) of 12h under initial Cu concentrations of 2.0 and 10.0mgL-1. Periphyton quickly adapted to Cu stress by regulating the community composition. Species richness, evenness and carbon metabolic diversity of the periphytic community increased when exposed to Cu. Diatoms, green algae, and bacteria (Gammaproteobacteria and Bacteroidia) were the dominant microorganisms and responsible for Cu removal. This study indicates that periphytic biofilms are promising in Cu removal from wastewater due to their strong adaptation capacity to Cu toxicity and also provides valuable information for understanding the relationships between microbial communities and heavy metal stress. PMID- 28712783 TI - Discovery and engineering of a 1-butanol biosensor in Saccharomyces cerevisiae. AB - The present study aimed to develop a universal methodology for the discovery of biosensors sensitive to particular stresses or metabolites by using a transcriptome analysis, in order to address the need for in vivo biosensors to drive the engineering of microbial cell factories. The method was successfully applied to the discovery of 1-butanol sensors. In particular, the genome-wide transcriptome profiling of S. cerevisiae exposed to three similar short-chain alcohols, 1-butanol, 1-propanol, and ethanol, identified genes that were differentially expressed only under the treatment of 1-butanol. From these candidates, two promoters that responded specifically to 1-butanol were characterized in a dose-dependent manner and were used to distinguish differences in production levels among different 1-butanol producer strains. This strategy opens up new opportunities for the discovery of promoter-based biosensors and can potentially be used to identify biosensors for any metabolite that causes cellular transcriptomic changes. PMID- 28712784 TI - Effects of interventions with therapeutic suits (clothing) on impairments and functional limitations of children with cerebral palsy: a systematic review. AB - BACKGROUND: Therapeutic suits or clothing whether associated with intensive protocols or not, became popular in the rehabilitation of children with cerebral palsy. Studies have reported positive effects of these suits on children's posture, balance, motor function and gait. A summary of current literature may help guide therapeutic actions. OBJECTIVE: To evaluate the available evidence on the effects of interventions based on the use of therapeutic suits in the treatment of impairments and functional limitations of children with cerebral palsy. METHOD: Three independent reviewers searched for experimental studies on MEDLINE, SciELO, BIREME, LILACS, PEDro and CENTRAL databases, between October and December 2015 and updated in May 2016. The reviewers evaluated the methodological quality of selected studies using the Checklist for Measuring Quality. The Grading of Recommendations Assessment, Development and Evaluation was used to synthesize the quality of evidence and strength of recommendation. RESULTS: From the 13 studies, two evaluated the Full Body Suit, two tested the Dynamic Elastomeric Fabric Orthose, three evaluated TheraTogs and six tested the TheraSuit/AdeliSuit protocols. The quality of evidence for the Full Body Suit, the Dynamic Elastomeric Fabric Orthose and the TheraSuit/AdeliSuit protocols was very low for body structure and function outcomes, while the evidence for TheraTogs was low quality. Regarding the activity outcomes, the Full Body Suit and TheraSuit showed very low quality evidence while the evidence for TheraSuit/AdeliSuit protocols were of low quality. CONCLUSION: Enthusiasm with new therapeutic approaches that argue modifications in the neuromusculoskeletal impairments and functional limitations of children with cerebral palsy need to be guided by scientific evaluation. The low quality of evidence suggests caution in recommending the use of these therapeutic suits. New studies could change the findings of this review. PMID- 28712785 TI - Development of the cerebellum in turbot (Psetta maxima): Analysis of cell proliferation and distribution of calcium binding proteins. AB - The morphogenesis, cell proliferation and neuronal differentiation of the turbot (Psetta maxima) cerebellum has been studied using conventional histological techniques and immunohistochemical methods for proliferating cell nuclear antigen and calcium binding proteins. As in other vertebrates, the cerebellar anlage emerges as proliferative plates of neural tissue during the embryonic period. The anlage of the cerebellum persists without morphological changes until the end of the larval life when the mantle zone is differentiated. The major ontogenetic changesthat drive the formation of the cerebellar subdivisions begin in late premetamorphic larvae when cerebellar plates growth and merge medially. This transformation is accomplished by the reorganization of proliferative zones as well as by the onset of cell differentiation. The cerebellum becomes fully differentiated during metamorphosis when parvalbumin and calretinin were detected in Purkinje and eurydendroid cells. Sustained proliferation is maintained in all subdivisions of the cerebellum and this support the robust growth of this part of the brain that takes place during the metamorphic and juvenile periods.The location and histological organization of the proliferative activity in the turbot mature cerebellum are described and their functional significance was analyzed in light of the information available for other teleosts. PMID- 28712787 TI - Untethering physiolysis for delta phalanx (longitudinally bracketed diaphysis) combined with free fat interposition graft. AB - We report the results of physiolysis of the epiphyseal bracket combined with free fat grafting for the treatment of delta phalanx. Thirteen cases (five patients) were included. Mean patient age was 6.6years (range, 4-9). The patients underwent physiolysis in which the epiphyseal bracket was cut and replaced with a free fat graft. The angle between the long axis of the proximal and distal phalanges and the ratio between the width and length of the affected middle phalanx were evaluated on plain radiographs. The range of motion in the fingers was also evaluated. The mean follow-up period was 42.2months (range, 25-61). The mean correction angle was 17.1 degrees (range; 13-23). The mean width-to-length ratio of the affected phalanx was improved from 0.6 to 0.47. The range of motion was maintained at the previous level. Physiolysis by untethering the bracketing epiphysis and free fat grafting can alleviate the angulation of clinodactyly, especially in growing children. It also allows catch-up growth in the middle phalanx. PMID- 28712786 TI - The Relationship between Hot Flashes and Testosterone Recovery after 12 Months of Androgen Suppression for Men with Localised Prostate Cancer in the ASCENDE-RT Trial. AB - AIMS: This study describes the proportion of men who experienced hot flashes (flashes), and the testosterone level at onset, peak frequency and cessation of flashes after 12 months of androgen deprivation therapy (ADT) in men undergoing curative-intent external beam radiation therapy (+/- brachytherapy boost). We also aimed to characterise testosterone recovery in this population. MATERIALS AND METHODS: This was a pre-specified secondary analysis of the ASCENDE-RT clinical trial. Three hundred and ninety-eight men were randomised. All received 12 months of ADT. The presence and frequency of flashes were patient reported. Cessation of flashes was defined as the first date a patient reported resolution of this symptom. Testosterone recovery was defined as any single serum testosterone above the threshold of 5, 7.5 or 10 nmol/l. RESULTS: The median age and follow-up were 68 years and 6.1 years. Flashes were reported in 93% of men. Flashes began and reached peak frequency at a median time of 4.0 months from the first luteinizing hormone-releasing hormone injection when testosterone levels had fallen to castrate. The median time to cessation of flashes was 7.6 months after the cessation of ADT (last injection + 3 months), when the median testosterone had risen to 5.7 nmol/l. A resolution of flashes was reported in 99% of patients. Baseline testosterone was available in 338 patients (85%). The median baseline testosterone was 13.2 nmol/l. The median (95% confidence interval) time of testosterone recovery to thresholds of 5 nmol/l, 7.5 nmol/l and 10 nmol/l were 9 (9-10) months, 13 (10-15) months and 18 (17-19) months from the cessation of ADT. At the time of censor, 96, 94 and 91% of patients had recovered testosterone to thresholds of 5, 7.5 and 10 nmol/l. CONCLUSION: Flashes occur at castrate levels of testosterone, with cessation of hot flashes antedating full recovery of testosterone in most patients. Rates of testosterone recovery after 12 months of ADT exceed 90%, although it can be delayed. PMID- 28712788 TI - Antimalarial agent artesunate protects Concanavalin A-induced autoimmune hepatitis in mice by inhibiting inflammatory responses. AB - The anti-malarial drug artesunate (ARS) has been shown to possess anti inflammatory activity. Its effect on autoimmune hepatitis remains unclear. Concanavalin A (Con A)-induced hepatitis was used in this study to reveal the potential action of ARS and the related mechanism. Mice were pretreated with ARS followed by Con A challenge. Con A caused obvious hepatic injury with higher levels of liver enzymes, elevated pro-inflammatory cytokines and activation of nuclear factor-kappaB (NF-kappaB) and mitogen activated protein kinase (MAPK) signaling pathways. However, ARS pretreatment notably inhibited Con A-induced liver injury with remarkable reduction of liver enzymes, and dramatically suppressed the expression of inflammatory cytokines including interferon (IFN) gamma, tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6 and IL-17, and increased anti-inflammatory cytokines IL-10. In line with cytokines, the phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinases (p38), nuclear factor kappaBalpha (IkappaBalpha) and NF-kappaB p65 was also significantly inhibited by ARS pretreatment. As a contrast, the specific inhibitor of NF-kappaB pyrrolidine dithiocarbamate (PDTC) achieved similar repressive effects as ARS on phosphorylation of p65 and IkappaBalpha, and serum levels of aminotransferases. Taken together, these data highlight that ARS has facilitating to make a better understanding of ARS against acute autoimmune hepatitis, and indicating a promising therapy candidate for autoimmune hepatitis. PMID- 28712789 TI - The role of lymph node dissection in the contemporary management of renal cell carcinoma: A critical appraisal of the evidence. AB - The role of lymph node dissection (LND) in the management of renal cell carcinoma has been controversial. Older studies provided initial support to a potential survival benefit in resection of lymph node metastases, and several predictive models were developed to identify patients with lymph node involvement. However, the only randomized trial on the subject did not report a survival benefit to LND in the nonmetastatic setting. Several studies have recently reexplored the therapeutic benefit of LND. In both nonmetastatic and metastatic settings, LND does not appear to be associated with a survival benefit. Moreover, it does not appear that LND confers a survival advantage to patients at increased risk of lymph node metastases, such as those with preoperative radiographic lymphadenopathy or across increasing probability of lymph node disease. Among patients with clinically isolated lymph node metastases, the majority develop disease progression following surgical resection, suggesting a high prevalence of occult systemic disease. Lymph node metastases appear to have prognostic value in both nonmetastatic and metastatic settings. LND may, therefore, have an increasingly important staging role in the management of renal cell carcinoma. PMID- 28712790 TI - Prognostic factors for tumor recurrence in patients with clinical stage I seminoma undergoing surveillance-A systematic review. AB - OBJECTIVE: To systematically evaluate evidence on prognostic factors for tumor recurrence in patients with clinical stage I seminoma undergoing surveillance. METHODS: Systematic literature search conducted of Medline, Web of Science, Cochrane Library, and the conference proceedings of the ASCO, AUA, and EAU meetings (last search: October 2016), according to our prospectively registered protocol (PROSPERO registration number CRD42014009434). Identified records were reviewed according to the Cochrane Method Group of Prognosis Reviews recommendations and the PRISMA reporting guideline. Study quality was appraised with the Quality in Prognosis Studies (QUIPS) tool. RESULTS: Nineteen studies reporting on 26 potential prognostic factors were included in our analysis. Among the most frequently reported factors, tumor size (continuous or dichotomized) was significantly associated with relapse in 10/14 studies with a hazard ratio (HR) ranging from 1.33 (95% confidence interval [CI]: 1.14-1.56) to 3.17 (95% CI: 1.08 9.26). Rete testis invasion was significantly associated with relapse in only 4/13 studies with a HR ranging from 1.18 (95% CI: 0.92-1.51) to 1.36 (95% CI: 0.81-2.28). Lymphovascular invasion, young age, and preoperative HCG level had no association with relapse. Our findings are limited by heterogeneity of study designs, potential reporting bias, and moderate-to-poor study quality. CONCLUSION: In stage I seminoma, tumor size is the most valuable prognostic factor on which to base relapse risk and to counsel patients about adjuvant treatment. Large tumor size was defined quite inhomogenously among the included studies, so no distinct cutoff value for tumor size can be recommended. Other potential prognostic factors including rete testis invasion play a minor role in stage I seminoma. PMID- 28712791 TI - Radiotherapy for stage I and II testicular seminomas: Secondary malignancies and survival. AB - INTRODUCTION: Testicular seminoma affects relatively young men with excellent survival outcomes. There has been increasing concern that radiotherapy (RT) leads to secondary malignant neoplasms (SMNs) and subsequent mortality. We evaluated the effect of RT on incidence of SMNs and quantified cancer-related mortality and other causes of death for patients with stage I and II testicular seminoma. MATERIAL AND METHODS: A national sample of men (1988-2013) diagnosed with stage IA/IB/IS/IIA/IIB/IIC testicular seminomas from Surveillance, Epidemiology, and End Results were evaluated. Use of RT over time and survival curves (5/10/15 year) was stratified by stage. Log-binomial regression determined relative risk of developing SMNs. Incidence rate ratios (IRR) and age-adjusted Cox proportional hazards models compared overall, cancer-specific survival (CSS), and other cancer specific survival. Competing-risks regression generated cumulative incidence functions. Prevalence ratios explored excess deaths owing to specific causes. RESULTS: A total of 16,463 men were included with 9,126 (55.4%) undergoing RT with markedly decreased use for stage I seminoma in recent years (<20%) and ~50% for stage IIA. RT increased risk of SMNs (relative risk = 1.84 [95% CI: 1.61 2.10, P<0.01]). Survival rates were excellent (15-year CSS for stage I [>=99%], stage IIA [98.1%], stage IIB-C [96%-97%]). RT was associated with improved CSS for stage IB and IIA, but demonstrated less benefit for stage IA (IRR = 0.63 [95% CI: 0.35-1.14, P = 0.10]) with worse other cancer-specific survival (IRR = 1.80 [95% CI: 0.97-3.59, P = 0.05]). Gastrointestinal, respiratory, urinary, and hematologic malignances accounted for 84% of SMN deaths. CONCLUSIONS: RT offers excellent CSS for men with stage I/II seminoma and an increased risk of SMN later in life. Future studies should better evaluate risk-stratification for stage IB patients. PMID- 28712792 TI - Seasonal plasticity of song behavior relies on motor and syntactic variability induced by a basal ganglia-forebrain circuit. AB - : The plasticity of nervous systems allows animals to quickly adapt to a changing environment. In particular, seasonal plasticity of brain structure and behavior is often critical to survival or mating in seasonal climates. Songbirds provide striking examples of seasonal changes in neural circuits and vocal behavior and have emerged as a leading model for adult brain plasticity. While seasonal plasticity and the well-characterized process of juvenile song learning may share common neural mechanisms, the extent of their similarity remains unclear. Especially, it is unknown whether the basal ganglia (BG)-forebrain loop which implements song learning in juveniles by driving vocal exploration participates in seasonal plasticity. To address this issue, we performed bilateral lesions of the output structure of the song-related BG-forebrain circuit (the magnocellular nucleus of the anterior nidopallium) in canaries during the breeding season, when song is most stereotyped, and just after resuming singing in early fall, when canaries sing their most variable songs and may produce new syllable types. Lesions drastically reduced song acoustic variability, increased song and phrase duration, and decreased syntax variability in early fall, reverting at least partially seasonal changes observed between the breeding season and early fall. On the contrary, lesions did not affect singing behavior during the breeding season. Our results therefore indicate that the BG-forebrain pathway introduces acoustic and syntactic variability in song when canaries resume singing in early fall. We propose that BG-forebrain circuits actively participate in seasonal plasticity by injecting variability in behavior during non-breeding season. SIGNIFICANCE STATEMENT: The study of seasonal plasticity in temperate songbirds has provided important insights into the mechanisms of structural and functional plasticity in the central nervous system. The precise function and mechanisms of seasonal song plasticity however remain poorly understood. We show here that a basal ganglia-forebrain circuit involved in the acquisition and maintenance of birdsong is actively inducing song variability outside the breeding season, when singing is most variable, while having little effect on the stereotyped singing during the breeding season. Our results suggest that seasonal plasticity reflects an active song-maintenance process akin to juvenile learning, and that basal ganglia-forebrain circuits can drive plasticity in a learned vocal behavior during the non-injury-induced degeneration and reconstruction of the neural circuit underlying its production. PMID- 28712793 TI - [Endometriosis and miscarriage: Systematic review]. AB - OBJECTIVES: In spontaneous pregnancies, endometriosis appears to be a risk factor of miscarriage. The aim of this study is to evaluate the association between endometriosis and miscarriage in spontaneous pregnancy. METHODS: We searched the Cochrane Library, Medline of eligible studies from inception to December 2016, without any restriction. We selected studies that compared endometriosis-affected pregnant women to disease-free pregnant women. To ensure the quality of the methodology, the PRISMA criteria have been met at all stages of the development of this meta-analysis. The primary adverse pregnancy outcomes studied was miscarriage. Three reviewers independently extracted the studies' characteristics and outcome data. RESULTS: Of 225 identified abstracts, 4 primary studies met our inclusion criteria by comparing spontaneous pregnant patients with endometriosis to disease-free women. Miscarriage rate was higher in the endometriosis group (OR 1.77 [CI 95% 1.13-2.78]). CONCLUSION: In spontaneous pregnancies, endometriosis appears to be a risk factor of miscarriages (almost 80% increased risk). Further prospective studies are needed to confirm these results in order to establish the exact impact of endometriosis on spontaneous pregnancy course. PMID- 28712794 TI - The Use of Opportunistic Salpingectomy at the Time of Benign Hysterectomy. AB - STUDY OBJECTIVE: To delineate the use of opportunistic salpingectomy over the study period, to examine factors associated with its use, and to evaluate whether salpingectomy was associated with perioperative complications. DESIGN: A retrospective cross-sectional study (Canadian Task Force classification II-2). SETTING: The Michigan Surgical Quality Collaborative. PATIENTS: Women undergoing ovarian-conserving hysterectomy for benign indications from January 2013 through April 2015. INTERVENTIONS: The primary outcome was the performance of opportunistic salpingectomy with ovarian preservation during benign hysterectomy. The change in the rate of salpingectomy was examined at 4-month intervals to assess a period effect over the study period. Multivariate logistic regression was performed to evaluate independent effects of patient, operative, and period factors. Perioperative outcomes were compared using propensity score matching. MEASUREMENTS AND MAIN RESULTS: There were 10 676 (55.9%) ovarian-conserving hysterectomies among 19 090 benign hysterectomies in the Michigan Surgical Quality Collaborative in the study period. The rate of opportunistic salpingectomy was 45.8% (n = 4890). Rates of opportunistic salpingectomy increased over the study period from 27.5% to 61.6% (p < .001), demonstrating a strong period effect in the consecutive 4-month period analysis. Salpingectomy was more likely with the laparoscopic approach (odds ratio = 3.48; 95% confidence interval, 3.15-3.85) and among women younger than 60 years of age (odds ratio = 1.60; 95% CI, 1.34-1.92). There was substantial variation in salpingectomy across hospital sites, ranging from 3.6% to 79.9%. Salpingectomy was associated with a 12-minute increase in operative time (p < .001), but there were no differences in the estimated blood loss or perioperative complications. CONCLUSION: The rates of salpingectomy increased significantly over the study period. The laparoscopic approach and younger age are associated with an increased probability of salpingectomy. Salpingectomy is not associated with increased blood loss or perioperative complications. PMID- 28712795 TI - Transcatheter Arterial Embolization for Severe Secondary Hemorrhage after Hysterectomy. AB - Four of 1237 patients who underwent abdominal, laparoscopic, and vaginal hysterectomy between October 2013 and May 2015 had severe secondary hemorrhage after hysterectomy (2 conventional multiport total laparoscopic hysterectomies, 1 single-port access hysterectomy, and 1 total abdominal hysterectomy). The median time interval between hysterectomy and secondary hemorrhage was 28.4 days (range, 16-52 days). All 4 cases were treated with transcatheter arterial embolization (TAE), all of whom required blood transfusions to maintain vital functions before TAE. The mean operative time was 90 minutes. The median length of hospital stay after TAE was 12 days (range, 4-24 days), and the patients were discharged without complications or additional surgery. These cases show the value of minimally invasive TAE for patients experiencing severe secondary hemorrhage after hysterectomy. PMID- 28712796 TI - Electrosurgery Induced Damage to Ti-6Al-4V and CoCrMo Alloy Surfaces in Orthopedic Implants In Vivo and In Vitro. AB - BACKGROUND: Recent observations of specific metal damage patterns on retrieved total joint implants implied a cellular origin and was termed inflammatory cell induced (ICI) corrosion. Although ICI corrosion continues to present a potential damage source for metallic biomaterials surfaces, an alternate source of some damage patterns may arise from electrosurgery instruments in total joint arthroplasty. METHODS: To characterize electrosurgically-induced damage patterns on metal implants, a model system of highly polished CoCrMo and Ti-6Al-4V disks and commercial electrosurgical generator was evaluated in various modes and power settings using monopolar and bipolar configurations. Surfaces were tested dry, wet with phosphate-buffered saline, or covered with known thicknesses of hydrated 5% agarose hydrogel. RESULTS: In all cases, surface damage was generated on both alloy surfaces, directly resulting from plasma discharge interacting with the metal. Direct surface contact caused pitting and oxide buildup at the contact area. Damage was produced through 3 mm thickness of hydrogel on the surface and across metal-metal junctions representing modular tapers. Damage patterns on wetted surfaces were highly consistent with damage patterns observed on retrieved total joint implants; circular, ruffled areas with centralized pits, occasionally presenting trail- and weld-like features. CONCLUSION: Surgeons using electrosurgical systems in proximity to metallic implants should exercise caution. Discharge of electrical energy through implants can induce localized surface damage and may result in other adverse outcomes. Although these results show some damage reported to be ICI corrosion is indeed the result of electrosurgery, there remains damage observed in retrievals not explained by this process. PMID- 28712797 TI - Evaluation of a Patient Decision Aid for Unicompartmental or Total Knee Arthroplasty for Medial Knee Osteoarthritis. AB - BACKGROUND: Many patients with isolated medial compartment osteoarthritis are candidates for either unicompartmental knee arthroplasty (UKA) or total knee arthroplasty (TKA). A novel patient decision aid (PDA) was developed to educate patients on both interventions and prepare them for making the decision with their surgeon. The study objective was to evaluate the acceptability and usefulness of a PDA for informing and helping patients reach a surgical preference without increasing decisional conflict. METHODS: A PDA was developed in accordance with the criteria listed by Ottawa Decision Support Framework and prospectively tested in UKA and TKA patients, who were mailed the PDAs to complete at home along with outcome measures before surgeon consultation. Of 50 patients who consented to participate, 45 patients (26 men, 19 women) used the PDA. Quantitative analysis of acceptability, decisional conflict, knowledge, and preferred surgical option was then performed. RESULTS: Mean patient age was 64.6 years (range, 50-80 years). Patients rated the PDA as acceptable: 84.4% indicated balanced presentation of information and 77.8% asserted that PDA helped them to make decisions between UKA and TKA. Mean knowledge score was 86.6% and total decisional conflict was 19.7 out of 100. Of 45, 33 stated a preferred option (24 UKA; 9 TKA; 12 unsure). CONCLUSION: Patients understood the majority of the benefits and risks for each surgical option without increasing decisional conflict. The decision aid for advanced medial compartment osteoarthritis is shown to be acceptable and useful for choosing between UKA and TKA. PMID- 28712798 TI - Region and Insurance Plan Type Influence Discharge Disposition After Hip and Knee Arthroplasty: Evidence From the Privately Insured US Population. AB - BACKGROUND: Little is known about regional variation in the use of postacute care services after elective procedures, such as total hip or knee arthroplasty (THA/TKA), and how insurance type may influence it. The goal of this study is to assess the influence of region and insurance arrangements on discharge disposition. METHODS: A representative sample of the privately insured US population with THA or TKA in 2009 or 2010 was obtained from the MarketScan database applying individual-level weights from the Medical Expenditure Panel Survey. Multivariate logistic regression was used to predict the odds of being discharged to an extended care facility (ECF) compared with being discharged home. The model adjusted for region, insurance plan type, sociodemographic characteristics, comorbidities, and length of stay. RESULTS: Large variability was observed in ECF use across the US. Patients in the Northeast were 2.5 times more likely to receive care at an ECF compared with patients in the South (odds ratio [OR] = 2.51, 95% confidence interval [CI]: 1.97-3.19). Enrollees in noncapitated plans such as fee-for-service plans or exclusive provider organizations were less likely to be discharged to an ECF compared with health maintenance organizations/preferred provider organizations with capitation enrollees (OR = 0.74, 95% CI: 0.57-0.94; OR = 0.49, 95% CI: 0.34-0.74, respectively). CONCLUSION: Region and private insurance plan arrangements are related to extended care use among THA and TKA patients. Understanding regional variation in discharge disposition provides policy makers with important information as to where to focus new tests of hip and knee procedures such as same day arthroplasty. PMID- 28712799 TI - Diagnosing Periprosthetic Joint Infection: And the Winner Is? AB - BACKGROUND: Diagnosis of periprosthetic joint infection (PJI) remains a challenge despite a wide variety of available diagnostic tests. The question that arises is which of these tests has a better performance for diagnosing PJI. Diagnostic odds ratio (DOR) has been described as the best indicator for test performance. METHODS: To compare the performance of the standard diagnostic tests, the DOR of serum erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), synovial fluid (SF) white blood cell (WBC) count, SF polymorphonuclear (PMN%), and leukocyte esterase (LE) were calculated. RESULTS: We obtained 4662 ESRs, 4392 CRPs, 836 SF WBC, 804 SF PMN%, and 659 LE results. LE had the highest DOR for diagnosing PJI: 30.06 (95% confidence interval [CI]: 17.8-50.7). The rest of the DORs in the descending order were SF WBC: 29.4 (95% CI: 20.2-42.8), CRP: 25.6 (95% CI: 19.5-33.7), SF PMN%: 25.5 (95% CI: 17.5-37.0), and ESR: 14.6 (95% CI: 11.5-18.6). CONCLUSION: Based on our findings, it appears that among the minor diagnostic criteria, LE has the best performance. PMID- 28712800 TI - Hip Arthroplasty After Surgical Treatment of Intertrochanteric Hip Fractures. AB - BACKGROUND: Although use of intramedullary hip screws (IMHS) for intertrochanteric (IT) hip fractures has become more common, limited data have suggested difficulties in conversion to hip arthroplasty. The present study investigates whether conversion of failed IT fracture fixation with an intramedullary vs extramedullary device leads to different rates or types of complications or decreased arthroplasty survivorship. METHODS: One hundred eleven patients were converted to hip arthroplasty after previous surgical treatment of an IT fracture from 2000 to 2010. Seventy hips had been treated with an extramedullary fixation device (EFD) and 41 with an IMHS. RESULTS: Length of hospital stay and operative times were similar (6 days and 206 minutes for EFD vs 6 days and 208 minutes for IMHS; P > .7). The presence of a Trendelenburg gait at last clinical follow-up was similar between groups (37% in EFD group and 38% in IMHS group). Five-year survivorship free of revision was 95% in the EFD group and 94% in the IMHS group (P = 1.0). The overall complication rate was similar (21% for EFD vs 27% for IMHS; P = .51) between groups. The most common complication was late periprosthetic fracture in the EFD patients (6% vs 0% in IMHS; P = .29) and intraoperative femoral fracture in the IMHS patients (12% vs 1% in EFD; P = .02). CONCLUSION: The short-term survivorship of conversion hip arthroplasty after surgical treatment of an IT fracture is excellent regardless of original fracture fixation method. If early complications, particularly periprosthetic fractures, can be minimized, the likelihood of a successful outcome is high. The risk of intraoperative femoral fracture was greater during conversion from an IMHS compared to an EFD. PMID- 28712801 TI - The Effect of Pelvic Tilt and Femoral Head Size on Hip Range-of-Motion to Impingement. AB - BACKGROUND: About 50%-70% of dislocators have cups placed within so-called "safe zones." It has been postulated that factors such as femoral head size and pelvic tilt, obliquity, or rotation may influence postoperative stability. Therefore, we assessed varying degrees of pelvic tilt and head sizes on the range of motion (ROM) to impingement. METHODS: A hip simulator was used to import models of 10 subjects who performed object pickup, squatting, and low-chair rising. Parameters were set for pelvic tilt, stem version, and the specific motions as defined by the subjects. Femur-to-pelvis relative motions were determined for abduction/adduction, internal/external rotation, and flexion/extension. Varying tilt angles were tested. Thirty-two millimeter and 36-mm head with a standard cup and 42-mm dual mobility cup were tested. Cup orientations for abduction and anteversion combinations were chosen, and computations of minimum clearances or impingement between components were made. RESULTS: The ROM to impingement varied with the different pelvic tilts and femoral head sizes and with the different motions. The larger the head size, the larger the impingement-free ROM. Negative 10 degrees of pelvic tilt led to the largest impingement-free zone, whereas 10 degrees of forward tilt was associated with fewer impingement-free cup anteversion and abduction angle combinations. Variations in pelvic tilt had the greatest influence on object pickup and affected the impingement-free "safe zone." CONCLUSION: Targets for impingement-free motion may be smaller when considering varying pelvic tilts and femoral head sizes, particularly for certain activities, such as object pickup. These findings may indicate the need for more individualized patient planning. PMID- 28712802 TI - Efficacy of a Pelvic Lateral Positioner With a Mechanical Cup Navigator Based on the Anatomical Pelvic Plane in Total Hip Arthroplasty. AB - BACKGROUND: The acetabular component orientation in total hip arthroplasty (THA) is of critical importance to the good clinical results. However, traditional widely used cup alignment guides for cup placement are reported to be relatively unreliable. The present study aims at comparing a novel cup alignment guide, which can be attached to our anatomical pelvic plane (APP) pelvic lateral positioner for reducing discrepancies in sagittal pelvic tilt and indicate a targeted cup angle based on the APP, with a conventional cup alignment guide. METHODS: The subjects were 136 hips of 136 patients who underwent unilateral THA using the APP positioner. The procedure was performed with the conventional cup alignment guide (conventional group; 60 hips) and with the novel cup navigator (mechanical navigator group; 76 hips). Postoperative cup angles and discrepancies of postoperative cup angles (inclination and anteversion angles) from the targeted angles were compared between the 2 groups to evaluate the usefulness of these navigators. RESULTS: The mean cup angles in the conventional group were 39.0 degrees +/- 5.3 degrees for the inclination angle and 21.7 degrees +/- 6.4 degrees for the anteversion angle, whereas those in the mechanical navigator group were 40.6 degrees +/- 3.2 degrees and 18.3 degrees +/- 4.6 degrees , respectively (P = .018, P < .0001). The discrepancies from the targeted angles were 3.5 degrees +/- 3.1 degrees for the inclination angle and 4.6 degrees +/- 3.4 degrees for the anteversion angle in the conventional group and 2.3 degrees +/- 2.3 degrees and 3.2 degrees +/- 2.7 degrees , respectively, in the mechanical navigator group (P = .020, P = .012). CONCLUSION: The mechanical cup navigator easily attachable to the APP positioner is a tool that can improve the accuracy of cup placement in a simple, economical, and noninvasive manner in THA via the lateral position. PMID- 28712803 TI - Maternal asthma severity and control during pregnancy and risk of offspring asthma. AB - BACKGROUND: Severe and uncontrolled asthma during pregnancy has been linked to several unfavorable perinatal outcomes. However, current knowledge on the association between the severity and control of maternal asthma and offspring asthma is sparse. OBJECTIVE: We sought to investigate the extent to which offspring asthma is influenced by maternal asthma severity and control during pregnancy. METHODS: We performed a prospective population-based cohort study. Using linkage of Danish national registers, we constructed a cohort of 675,379 singletons, of which 15,014 children were born to asthmatic mothers. Among them, 7,188 children were born to mothers with active asthma during pregnancy. We categorized mothers with active asthma into 4 groups based on dispensed antiasthma prescriptions and on use of medical services: mild controlled, mild uncontrolled, moderate-to-severe controlled, and moderate-to-severe uncontrolled asthma. The outcomes were offspring early-onset transient, early-onset persistent, and late-onset asthma. We estimated prevalence ratios (PRs) of each phenotype of asthma using a log-binomial model with 95% CIs. RESULTS: Higher prevalence of early-onset persistent asthma was observed among children of asthmatic mothers with mild uncontrolled (PR, 1.19; 95% CI, 1.05-1.35), moderate to-severe controlled (PR, 1.33; 95% CI, 1.09-1.63), and moderate-to-severe uncontrolled asthma (PR, 1.37; 95% CI, 1.17-1.61) compared with those of mothers with mild controlled asthma. A borderline increased prevalence of early-onset transient asthma was observed among children of mothers with uncontrolled asthma. CONCLUSION: Maternal uncontrolled asthma increases the risk of early-onset persistent and transient asthma. If replicated, this could suggest that maintaining asthma control in pregnancy is an area for possible prevention of specific phenotypes of offspring asthma. PMID- 28712804 TI - Identifying cell populations with scRNASeq. AB - Single-cell RNASeq (scRNASeq) has emerged as a powerful method for quantifying the transcriptome of individual cells. However, the data from scRNASeq experiments is often both noisy and high dimensional, making the computational analysis non-trivial. Here we provide an overview of different experimental protocols and the most popular methods for facilitating the computational analysis. We focus on approaches for identifying biologically important genes, projecting data into lower dimensions and clustering data into putative cell populations. Finally we discuss approaches to validation and biological interpretation of the identified cell-types or cell-states. PMID- 28712805 TI - Direct Spectroscopic Detection of ATP Turnover Reveals Mechanistic Divergence of ABC Exporters. AB - We have applied high-field (W-band) pulse electron-nuclear double resonance (ENDOR) and electron-electron double resonance (ELDOR)-detected nuclear magnetic resonance (EDNMR) to characterize the coordination sphere of the Mn2+ co-factor in the nucleotide binding sites (NBSs) of ABC transporters. MsbA and BmrCD are two efflux transporters hypothesized to represent divergent catalytic mechanisms. Our results reveal distinct coordination of Mn2+ to ATP and transporter residues in the consensus and degenerate NBSs of BmrCD. In contrast, the coordination of Mn2+ at the two NBSs of MsbA is similar, which provides a mechanistic rationale for its higher rate constant of ATP hydrolysis relative to BmrCD. Direct detection of vanadate ion, trapped in a high-energy post-hydrolysis intermediate, further supports the notion of asymmetric hydrolysis by the two NBSs of BmrCD. The integrated spectroscopic approach presented here, which link energy input to conformational dynamics, can be applied to a variety of systems powered by ATP turnover. PMID- 28712807 TI - SNX16 Regulates the Recycling of E-Cadherin through a Unique Mechanism of Coordinated Membrane and Cargo Binding. AB - E-Cadherin is a major component of adherens junctions on cell surfaces. SNX16 is a unique member of sorting nexins that contains a coiled-coil (CC) domain downstream of the PX domain. We report here that SNX16 regulates the recycling trafficking of E-cadherin. We solved the crystal structure of PX-CC unit of SNX16 and revealed a unique shear shaped homodimer. We identified a novel PI3P binding pocket in SNX16 that consists of both the PX and the CC domains. Surprisingly, we showed that the PPII/alpha2 loop, which is generally regarded as a membrane insertion loop in PX family proteins, is involved in the E-cadherin binding with SNX16. We then proposed a multivalent membrane binding model for SNX16. Our study postulates a new mechanism for coordinated membrane binding and cargo binding for SNX family proteins in general, and provide novel insights into recycling trafficking of E-cadherin. PMID- 28712806 TI - Structures of Human A1 and A2A Adenosine Receptors with Xanthines Reveal Determinants of Selectivity. AB - The adenosine A1 and A2A receptors belong to the purinergic family of G protein coupled receptors, and regulate diverse functions of the cardiovascular, respiratory, renal, inflammation, and CNS. Xanthines such as caffeine and theophylline are weak, non-selective antagonists of adenosine receptors. Here we report the structure of a thermostabilized human A1 receptor at 3.3 A resolution with PSB36, an A1-selective xanthine-based antagonist. This is compared with structures of the A2A receptor with PSB36 (2.8 A resolution), caffeine (2.1 A), and theophylline (2.0 A) to highlight features of ligand recognition which are common across xanthines. The structures of A1R and A2AR were analyzed to identify the differences that are important selectivity determinants for xanthine ligands, and the role of T2707.35 in A1R (M2707.35 in A2AR) in conferring selectivity was confirmed by mutagenesis. The structural differences confirmed to lead to selectivity can be utilized in the design of new subtype-selective A1R or A2AR antagonists. PMID- 28712808 TI - Structural Insight into the Activation of PknI Kinase from M. tuberculosis via Dimerization of the Extracellular Sensor Domain. AB - Protein kinases play central roles in the survival of Mycobacterium tuberculosis within host. Here we report the individual high-resolution crystal structures of the sensor domain (in both monomer and dimer forms) and the kinase domain of PknI, a transmembrane protein member of the serine/threonine protein kinases (STPKs) family. PknI is the first STPK identified whose sensor domain exists in a monomer-dimer equilibrium. Inspection of the two structures of the sensor domain (PknI_SD) revealed conformational changes upon dimerization, with an arm region of critical importance for dimer formation identified. Rapamycin-induced dimerization of unphosphorylated fusions of PknI juxtamembrane and the kinase domain, intended to mimic the dimerization effect presumably imposed by PknI_SD, was observed to be able to activate auto-phosphorylation activity of the kinase domain. In vivo experiments using an M. bovis model suggested PknI functions as a dimer in the regulation of M. tuberculosis growth. PMID- 28712809 TI - Near-Atomic Resolution Structure of a Plant Geminivirus Determined by Electron Cryomicroscopy. AB - African cassava mosaic virus is a whitefly-transmitted geminivirus which forms unique twin particles of incomplete icosahedra that are joined at five-fold vertices, building an unusual waist. How its 22 capsomers interact within a half capsid or across the waist is unknown thus far. Using electron cryo-microscopy and image processing, we determined the virion structure with a resolution of 4.2 A and built an atomic model for its capsid protein. The inter-capsomer contacts mediated by the flexible N termini and loop regions differed within the half capsids and at the waist, explaining partly the unusual twin structure. The tip of the pentameric capsomer is sealed by a plug formed by a turn region harboring the evolutionary conserved residue Y193. Basic amino acid residues inside the capsid form a positively charged pocket next to the five-fold axis of the capsomer suitable for binding DNA. Within this pocket, density most likely corresponding to DNA was resolved. PMID- 28712811 TI - Empty Vein Technique: Can Perivenous Tumescent Compression Help? PMID- 28712810 TI - Conformational Heterogeneity in the Activation Mechanism of Bax. AB - Bax is known for its pro-apoptotic role within the mitochondrial pathway of apoptosis. However, the mechanism for transitioning Bax from cytosolic to membrane-bound oligomer remains elusive. Previous nuclear magnetic resonance (NMR) and electron paramagnetic resonance (EPR) studies defined monomeric Bax as conformationally homogeneous. Yet it has recently been proposed that monomeric Bax exists in equilibrium with a minor state that is distinctly different from its NMR structure. Here, we revisited the structural analysis of Bax using methods uniquely suited for unveiling "invisible" states of proteins, namely, NMR paramagnetic relaxation enhancements and EPR double electron-electron resonance (DEER). Additionally we examined the effect of glycerol, the co-solvent of choice in DEER studies, on the structure of Bax using NMR chemical-shift perturbations and residual dipolar couplings. Based on our combined NMR and EPR results, Bax is a conformationally homogeneous protein prior to its activation. PMID- 28712812 TI - Peroxynitrite Footprint in Circulating Neutrophils of Abdominal Aortic Aneurysm Patients is Lower in Statin than in Non-statin Users. AB - OBJECTIVES: Extensive reactive oxygen and nitrogen species (also reactive species) production is a mechanism involved in abdominal aortic aneurysm (AAA) development. White blood cells (WBCs) are a known source of reactive species. Their production may be decreased by statins, thereby reducing the AAA growth rate. Reactive species production in circulating WBCs of AAA patients and the effect of statins on their production was investigated. METHODS: This observational study investigated reactive species production in vivo and ex vivo in circulating WBCs of AAA patients, using venous blood from patients prior to elective AAA repair (n = 34; 18 statin users) and from healthy volunteers (n = 10). Reactive species production was quantified in circulating WBCs using immunofluorescence microscopy: nitrotyrosine (footprint of peroxynitrite, a potent reactive nitrogen species) in snap frozen blood smears; mitochondrial superoxide and cytoplasmic hydrogen peroxide (both reactive oxygen species) by live cell imaging. Neutrophils, lymphocytes, and monocytes were examined individually. RESULTS: In AAA patients using statins, the median nitrotyrosine level in neutrophils was 646 (range 422-2059), in lymphocytes 125 (range 74-343), and in monocytes 586 (range 291-663). Median levels in AAA patients not using statins were for neutrophils 928 (range 552-2095, p = .03), lymphocytes 156 (101 273, NS), and for monocytes 536 (range 535-1635, NS). The statin dose tended to correlate negatively with nitrotyrosine in neutrophils (Rs -0.32, p = .06). The median levels in controls were lower for neutrophils 466 (range 340-820, p < .01) and for monocytes 191 (range 102-386, p = .03), but similar for lymphocytes 99 (range 82-246) when compared to the AAA patients. There were no differences in mitochondrial superoxide and cytoplasmic hydrogen peroxide between statin and non statin users within AAA patients. CONCLUSIONS: It was found that the peroxynitrite footprint in circulating neutrophils and monocytes of AAA patients is higher than in controls. AAA patients treated with statins had a lower peroxynitrite footprint in neutrophils than non-statin users. PMID- 28712813 TI - Factors affecting operative time and outcome of carotid endarterectomy in the Vascular Quality Initiative. AB - OBJECTIVE: Prior studies have suggested a relationship between operative (Op) time and outcome after major vascular procedures. This study analyzed factors associated with Op time and outcome after carotid endarterectomy (CEA) in the Vascular Quality Initiative (VQI) registry. METHODS: Elective, primary CEAs without high anatomic risk or concomitant procedures from 2012 to 2015 in the VQI were analyzed (N = 26,327, performed by 1188 surgeons from 249 centers). Multivariable analysis was used to identify patient, procedure, and surgeon factors associated with Op time and major adverse events (MAEs), categorized as either technical (ipsilateral stroke, cranial nerve injury, reoperation) or cardiac (myocardial infarction, congestive heart failure, dysrhythmia requiring treatment, surgical site infection, and death). RESULTS: The mean CEA Op time in the VQI was 114 minutes, with the mean Op time for individual surgeons ranging from 37 to 305 minutes. Procedural factors and the surgeon's volume were responsible for much of the variation in overall Op time (patient factors that reflected demographics and comorbidities each added 5.9 to 6.8 minutes; procedural factors, such as patch angioplasty and completion duplex ultrasound, each added 5.5 to 16.4 minutes; the lowest quartile of the surgeon's annual case volume added 24 minutes). Chi-pie analysis demonstrated that patient factors accounted for 17% of variability in Op time; procedural factors, 44%; and the surgeon's annual volume, 39%. Increasing Op time was highly associated with increased rates of MAEs (P < .001 for cardiac, technical, and death rates). Based on hierarchical multiple logistic regression, cardiac complications were independently associated with increased Op time (comparing surgeons in highest quartile of Op time with those in the lowest: odds ratio, 2.16 for cardiac MAE; 95% confidence interval, 1.59-2.95; P < .001) but not with the surgeon's annual volume. Technical complications were independently associated with a surgeon's low volume (comparing surgeons with the highest annual case volume by quartile against the lowest: odds ratio, 1.25 for technical MAE; 95% confidence interval, 1.06-1.48; P < .001) but not with Op time. CONCLUSIONS: Op time for elective, primary CEAs varies substantially across surgeons in the VQI. Increased Op time is associated with a surgeon's lower annual CEA volume in addition to patient variables and techniques employed. Cardiac complications after CEA are associated with longer Op time, whereas technical complications are associated with a surgeon's low annual volume. PMID- 28712814 TI - Safety and efficacy of rivaroxaban compared with warfarin in patients undergoing peripheral arterial procedures. AB - OBJECTIVE: Rivaroxaban is a United States Food and Drug Administration-approved oral anticoagulant for venous thromboembolic disease; however, there is no information regarding the safety and its efficacy to support its use in patients after open or endovascular arterial interventions. We report the safety and efficacy of rivaroxaban vs warfarin in patients undergoing peripheral arterial interventions. METHODS: This single-institution retrospective study analyzed all sequential patients from December 2012 to August 2014 (21 months) who were prescribed rivaroxaban or warfarin after a peripheral arterial procedure. Our study population was then compared using American College of Chest Physicians guidelines with patients then stratified as low, medium, or high risk for bleeding complications. Statistical analyses were performed using the Student t test and chi2 test to compare demographics, readmissions because of bleeding, and the need for secondary interventions. Logistic regression models were used for analysis of variables associated with bleeding complications and secondary interventions. The Fisher exact test was used for power analysis. RESULTS: There were 44 patients in the rivaroxaban group and 50 patients in the warfarin group. Differences between demographics and risk factors for bleeding between groups or reintervention rate were not statistically significant (P = .297). However, subgroup evaluation of the safety profile suggests that patients who were aged <=65 years and on warfarin had an overall higher incidence of major bleeding (P = .020). Patients who were aged >65 years, undergoing open operation, had a significant risk for reintervention (P = .047) when they received rivaroxaban. CONCLUSIONS: Real-world experience using rivaroxaban and warfarin in patients after peripheral arterial procedures suggests a comparable safety and efficacy profile. Subgroup analysis of those requiring an open operation demonstrated a decreased bleeding risk when rivaroxaban was used (in those aged <65 years) but an increased risk for secondary interventions. Further studies with a larger cohort are required to validate our results. PMID- 28712815 TI - Asymptomatic carotid stenosis is associated with cognitive impairment. AB - BACKGROUND: Cerebrovascular risk factors (eg, hypertension, coronary artery disease) and stroke can lead to vascular cognitive impairment. The Asymptomatic Carotid Stenosis and Cognitive Function study evaluated the isolated impact of asymptomatic carotid stenosis (no prior ipsilateral or contralateral stroke or transient ischemic attack) on cognitive function. Cerebrovascular hemodynamic and carotid plaque characteristics were analyzed to elucidate potential mechanisms affecting cognition. METHODS: There were 82 patients with >=50% asymptomatic carotid stenosis and 62 controls without stenosis but matched for vascular comorbidities who underwent neurologic, National Institutes of Health Stroke Scale, and comprehensive neuropsychological examination. Overall cognitive function and five domain-specific scores were computed. Duplex ultrasound with Doppler waveform and B-mode imaging defined the degree of stenosis, least luminal diameter, plaque area, and plaque gray-scale median. Breath-holding index (BHI) and microembolization were measured using transcranial Doppler. We assessed cognitive differences between stenosis patients and control patients and of stenosis patients with low vs high BHI and correlated cognitive function with microembolic counts and plaque characteristics. RESULTS: Stenosis and control patients did not differ in vascular risk factors, education, estimated intelligence, or depressive symptoms. Stenosis patients had worse composite cognitive scores (P = .02; Cohen's d = 0.43) and domain-specific scores for learning/memory (P = .02; d = 0.42) and motor/processing speed (P = .01; d = 0.65), whereas scores for executive function were numerically lower (P = .08). Approximately 49.4% of all stenosis patients were impaired in at least two cognitive domains. Precisely 50% of stenosis patients demonstrated a reduced BHI. Stenosis patients with reduced BHI performed worse on the overall composite cognitive score (t = -2.1; P = .02; d = 0.53) and tests for learning/memory (t = 2.7; P = .01; d = 0.66). Cognitive function did not correlate with measures of plaque burden (degree of stenosis, least luminal diameter, and plaque area) or with plaque gray-scale median. CONCLUSIONS: Asymptomatic carotid stenosis is associated with cognitive impairment independent of known vascular risk factors for vascular cognitive impairment. Approximately 49.4% of these patients demonstrate impairment in at least two neuropsychological domains. The deficit is driven primarily by reduced motor/processing speed and learning/memory and is mild to moderate in severity. The mechanism for impairment is likely to be hemodynamic as evidenced by reduced cerebrovascular reserve and the likely result of hypoperfusion from a pressure drop across the stenosis in the presence of inadequate collateralization. PMID- 28712816 TI - Enhanced startle reflexivity during presentation of visual nurture cues in young adults who experienced parental divorce in early childhood. AB - Adverse childhood experiences (ACE) may influence stress and affective processing in adulthood. Animal and human studies show enhanced startle reflexivity in adult participants with ACE. This study examined the impact of one of the most common ACE, parental divorce, on startle reflexivity in adulthood. Affective modulation of acoustically-elicited startle eye blink was assessed in a group of 23 young adults with self-reported history of parental divorce, compared to an age- and sex-matched control group (n=18). Foreground pictures were either aversive (e.g. mutilation and injury), standard appetitive (e.g. erotic, recreational sport), or nurture pictures (e.g. related to early life, parental care), intermixed with neutral pictures (e.g. household objects), and organized in three valence blocks delivered in a balanced, pseudo-randomized sequence. During picture viewing startle eye blinks were elicited by binaural white noise bursts (50ms, 105 dB) via headphones and recorded at the left orbicularis oculi muscle via EMG. A significant interaction of group*picture valence (p=0.01) was observed. Contrast with controls revealed blunted startle responsiveness of the ACE group during presentation of aversive pictures, but enhanced startle during presentation of nurture-related pictures. No group differences were found during presentation of standard appetitive pictures. ACE participants rated nurture pictures as more arousing (p=0.02) than did control participants. Results suggest that divorce in childhood led to altered affective context information processing in early adulthood. When exposed to unpleasant (vs. neutral) pictures participants with ACE showed less startle potentiation than controls. Nurture context, however, potentiated startle in ACE participants, suggesting visual cuing to activate protective behavioral responses. PMID- 28712817 TI - Clinical features and dynamic ordinary laboratory tests differentiating dengue fever from other febrile illnesses in children. AB - BACKGROUND: Dengue fever is not easily to be diagnosed before presentation of the classic symptoms. The study aimed to investigate the clinical features and dynamic laboratory tests in pediatric patients to facilitate dengue diagnosis. METHODS: This retrospective study examined the medical records of all pediatric patients who were clinically suspected to have dengue from June to December 2014. Laboratory-positive dengue cases were confirmed by detecting non-structural protein NS1, reverse transcription-polymerase chain reaction of dengue virus, and dengue-specific IgM seroconversion. RESULTS: Of the 317 pediatric cases clinically suspected of dengue, 205 were laboratory-positive and 112 were laboratory-negative. In laboratory-positive cases, the most common clinical manifestation was skin rash in 156 (76.1%). Leukopenia occurred on days 1-5; thrombocytopenia, on days 2-7; prolonged activated partial thromboplastin time (aPTT), on days 1-4; and elevated transaminase levels, on days 3-11; and low CRP, on days 0-14. The specificity and positive predictive value (PPV) of combining of rash, itching and petechiae increased up to 100%. The PPV of combining of leukopenia, thrombocytopenia, and elevated transaminase levels reached 100% on day 2 as well as days 6-8. CONCLUSION: Leukopenia, thrombocytopenia, elevated aPTT, elevated transaminase levels, and low CRP could be used to differentiate dengue fever from other febrile illnesses. During dengue epidemics, combinations of the symptoms and laboratory findings are helpful to physicians for accurate diagnosis of dengue fever. PMID- 28712818 TI - Systemic lupus erythematosus and thyroid disease - Experience in a single medical center in Taiwan. AB - BACKGROUND: To investigate the association of systemic lupus erythematosus (SLE) with thyroid diseases in a medical center in central Taiwan. METHODS: This is a retrospective cohort of 2796 SLE patients in a tertiary referral medical center from 2000 to 2013. We screened SLE by catastrophic illness registration from national insurance bureau; and thyroid diseases by ICD 9 codes, then confirmed by thyroid function test, auto-antibody, medical and/or surgical intervention. We compared the rate of hyperthyroidism, hypothyroidism and autoimmune thyroid disease (AITD) in SLE patients and the 11,184 match controls. We calculated the rate of these thyroid diseases and positive antibodies to thyroglobulin (ATGAb), thyroid peroxidase (TPOAb) in SLE patients grouped by the presence of overlap syndrome and anti-dsDNA antibody. We also compared the association of thyroid diseases to severe SLE conditions, including renal, central nervous system (CNS) involvement, and thrombocytopenia. RESULTS: Compared to the matched controls, the cumulative incidence of thyroid disease, including hyperthyroidism, hypothyroidism and AITD, were all higher in SLE patients (p < 0.0001). The average age of SLE patients with thyroid diseases patients were older than those without thyroid diseases (p = 0.002). Those had euthyroid AITD were younger than other patients with thyroid diseases (p = 0.02). Up to 30.3% SLE patients had overlap syndrome and had higher relative risk of thyroid diseases than those without overlap syndrome, in terms of hypothyroidism and AITD, but not hyperthyroidism. SLE patients with thyroid diseases also carry higher risk for severe complications such as renal involvement (p = 0.024) central nervous system involvement (p < 0.0001). CONCLUSION: SLE patients had significantly higher rate of hyperthyroidism, hypothyroidism, and AITD than the matched control. Among lupus patients, the risks of thyroid diseases are even higher in the presence of overlap syndrome. SLE patients with thyroid diseases had higher risk of renal and CNS involvement. PMID- 28712819 TI - Clinical characteristics, radiologic findings, risk factors and outcomes of serum galactomannan-negative invasive pulmonary aspergillosis. AB - BACKGROUND: The sensitivity of galactomannan (GM) assay is suboptimal for detecting invasive pulmonary aspergillosis (IPA) in serum samples. However, the clinical characteristics, radiologic findings, and outcomes in patients with GM negative IPA have not been fully elucidated. METHODS: Over a 7-year period, adult patients with proven or probable IPA by the EORTC/MSG definition were retrospectively enrolled. Patients with negative GM results and positive Aspergillus spp. cultures from sputum or bronchoalveolar lavage were classified into GM-negative IPA group. GM-positive and culture-negative IPA cases were selected at a 1:2 ratio. RESULTS: Thirty-four patients with GM-negative IPA were compared to 68 randomly selected patients from 158 patients with GM-positive and culture-negative IPA. Patients with diabetes mellitus, chronic kidney disease, and steroid use were more common but those with hematologic malignancy, prior receipt of mold-active antifungal drugs, and neutropenia were less common in GM negative IPA than in GM-positive IPA. Regarding radiologic findings, angioinvasive aspergillosis was less common in GM-negative IPA than in GM positive IPA. The median number of days from diagnosis to appropriate antifungal therapy was higher in GM-negative IPA than in GM-positive IPA. Multivariate analysis indicated that neutropenia (adjusted odds ratio [aOR], 0.10) and prior receipt of mold-active antifungal drugs (aOR, 0.12) were inversely associated with GM-negative IPA. The 30-day and 90-day mortality were similar between the two groups. CONCLUSION: Neutropenia and prior receipt of mold-active antifungal drugs before GM assay were independently associated with GM positivity among patients with proven/probable IPA. Angioinvasive aspergillosis was less common in GM-negative IPA than in GM-positive IPA. PMID- 28712820 TI - Routine CD4 monitoring in HIV patients with viral suppression: Is it really necessary? A Portuguese cohort. AB - PURPOSE: CD4 cell-count has been regarded as the key surrogate marker for prognostic staging and therapeutic monitoring of HIV-infected individuals. Our purpose was to assess the probability of maintaining a CD4 count >200 cells/MUL in patients with continuous viral suppression and CD4 cell counts >200 cells/MUL. METHODS: Retrospective cohort study of HIV-infected patients, treatment naive, who started antiretroviral therapy between 2007 and 2011. We estimated the probability of maintaining CD4 counts >200 cells/MUL during continuous viral suppression using the Kaplan-Meier method. The hazard ratios of a CD4 count <200 cells/MUL were estimated and compared using Cox proportional hazards regression. RESULTS: 401 patients were included: 70.1% men; median age 37 years; 98.8% HIV-1 infected. The median duration of continuous viral suppression with CD4 counts >200 cells/MUL was 40.5 months. Ninety-three percent of patients maintained CD4 counts >=200 cells/MUL during the period of continuous viral suppression. Compared with those with an initial CD4 count >=350 cells/MUL, patients with initial CD4 count <300 cells/MUL had a significantly higher risk of a CD4 count <200 cells/MUL. Patients with viral suppression and CD4 counts >=350 cells/MUL had a 97.1% probability of maintaining CD4 cell counts >=200 cells/MUL for 48 months. CONCLUSIONS: The probability of a CD4 count <200 cells/MUL in an HIV infected patient with viral suppression and CD4 >=350 cells/MUL was very low. These data suggests less frequent monitoring of CD4 counts in these patients. PMID- 28712821 TI - Appropriate anthropometric indices of obesity and overweight for diagnosis of metabolic syndrome and its relationship with oxidative stress. AB - AIMS: this study aimed to determine the most appropriate anthropometric indices for diagnosis of metabolic syndrome (MetS) and its relationship with oxidative stress markers. MATERIAL AND METHODS: This cross-sectional study was conducted in 2015 on 108 employees working in Shahroud University of Medical Sciences. Demographics, anthropometric indices (BMI: Body mass index; WC: Waist circumference, WHR: Waist hip ratio, WHtR: Waist-to-height Ratio), Mets: and Then oxidative stress markers (total antioxidant capacity; TAC, Malondialdehyde; MDA, serum superoxide dismutase; SOD, catalase; Cat) were measured. All analyses were performed at a significant level of 0.05, using the SPSS Statistics 21 and Stata 12 software. RESULT: The mean age of the participants was 41.4+/-7.8years. the mean values of different anthropometric indices in patients with metabolic syndrome were higher than those in subjects without MetS and this difference was significant. According to ROC curve the best marker for diagnosis of Mets was WHtR (Waist-to-height Ratio) and its cut off point was 0.54.Also, there was a positive correlation between WHtR and MDA serum levels. In addition, there was a negative correlation between WHtR and the levels of TAC, SOD, and CAT but it was not significant. CONCLUSIONS: It seems that WHtR can be a valuable marker for predicting metabolic disorders and related diseases; moreover, it can be used for evaluation of oxidative stress level. Finally, the formula WC=height*0.54 as a simple tool for prevention of metabolic diseases can be used in university personnel. PMID- 28712822 TI - Association study of HNF1A polymorphisms with metabolic syndrome in the Moroccan population. AB - AIMS: Variants in Hepatocyte Nuclear Factor 1 alpha (HNF1A) gene are associated with Metabolic Syndromeand its components independently. In this study, we aimed to assess the statistical association of the rs1169288, rs2464196 and rs735396 variants and haplotypes of HNF1A gene with metabolic syndrome (MS) and its components in a Moroccan population sample. METHODS: Three variants in the HNF1A gene were genotyped, rs1169288 A>C, rs2464196 G>A and rs735396 T>C in cases and controls from Moroccan population using KASPar(r) technology (KBioscience, UK). Anthropometric and biochemical parameters were assessed. MS was defined according to the international Diabetes Federation (IDF). The effects of HNF1A polymorphisms and constructed haplotypes on MS were estimated using logistic regression analyses. RESULTS: The HNF1A gene, rs1169288 and rs2464196 variants conferred an increased risk to MS (OR=2.08, 95%CI=1.38-3.14, P=0.0005 and OR=1.52, 95%IC=1.05-2.20, P=0.03, respectively) when adjusted for BMI, sex and age. We found that the C allele of the variant rs735396 was associated with an increased triglycerides level (p-value=0.04434) among patients and high weist circumference (P=0.02005) and total cholesterol (P=0.03227) amount among controls. The haplotype AAT (OR=5.656, P<0.00001) was the most significantly associated with susceptibility to metabolic syndrome. CONCLUSION: The present study demonstrated that SNPs rs1169288 and rs2464196 of HNF1A gene were significantly associated with metabolic syndrome in a Morrocan population. Furthermore, the CAC, AAC, AAT and AGT haplotypes of these SNPs and rs735396 were significantly associated with metabolic syndrome. PMID- 28712823 TI - An overview on biological functions and emerging therapeutic roles of apelin in diabetes mellitus. AB - Type 2 diabetes mellitus is a common type of diabetes and considered as multifactorial disease. Apelin is an adipokine which secreted from white adipose tissue and involved in various functions such as insulin sensitivity and food intake. Many studies showed that apelin has a crucial role in diabetes and its concentration will change in relation with insulin resistance. In this review, we will discuss the roles of apelin in energy metabolism and pathogenesis of diabetes and explain why apelin can be a good candidate adipokine to promoting insulin sensitivity. PMID- 28712824 TI - Full-coverage spatial distribution of epibenthic communities in the south-eastern North Sea in relation to habitat characteristics and fishing effort. AB - Full-coverage spatial data of occurrence and a detailed description of habitat requirements of epibenthic communities are needed in many conservation and management contexts. In the North Sea the focus has so far been on small benthic infauna, whereas structure and ecosystem functions of larger epifaunal communities have been largely ignored. This study provides a comprehensive analysis of epibenthic community structure in the south-eastern North Sea, including a detailed inventory of species, diversity and spatially contiguous distribution of communities. Data from nearly 400 stations were compiled for the study, enabling us to describe epibenthic community structure at unprecedented spatial resolution. Eight distinct epibenthic communities were found in the south eastern North Sea by using multivariate analysis. Distribution modelling with eight environmental variables (bottom temperature and salinity, temperature differences between summer and winter, mud content of sediments, maximum bottom shear stress, stratification, water depth and annual primary production) and one human pressure (fishing effort) was used to extrapolate probable spatial distributions and to identify associated habitat characteristics of the communities in the south-eastern North Sea. Three large epibenthic communities "Coast", "Oysterground" and "Tail End" reflect a gradual habitat change from the coast towards offshore regions, expressed in gradients of bottom salinity, seasonal temperature differences and stratification as the dominant environmental factors. Five smaller communities ("Amrum Bank", "Frisian Front", "Deeps", "Dogger Bank" and "Dogger Slope") outline specific habitats in the south-eastern North Sea. The "Dogger Slope" community has not been recognized before, but has a predicted spatial extent of 7118 km2. Due to the high occurrence of long-lived, sessile species such as sponges this community is very sensitive to demersal fishing. PMID- 28712825 TI - Use of biomarkers to evaluate the effects of environmental stressors on Mytilus galloprovincialis sampled along the Moroccan coasts: Integrating biological and chemical data. AB - A biomonitoring study using wild Mytilus galloprovincialis mussels sampled from six sites along the Moroccan coasts evaluated whether select biomarkers are suitable for identifying and quantifying pollution-induced stress syndrome in mussels. Lysosomal membrane stability was confirmed to be a highly sensitive biological parameter, and acetylcholinesterase activity was found a suitable biomarker of neurotoxicity. Metallothionein concentrations were in line with heavy metal concentrations detected in mussel tissues. However, malondialdehyde was not sensitive, suggesting the need for alternative biomarkers of oxidative stress. Three different approaches were used for biomarker and chemical data integration. The Integrated Biomarker Response (IBR) was suitable for classifying the stress response but did not allow to evaluate the level of stress in the organisms. The Mussel Expert System (MES) was suitable for ranking the biological effects of pollutants, also providing an indication of the evolution of the stress syndrome in the animals. Finally, the use of Principal Component Analysis (PCA) provided indication of the inorganic chemicals contributing to the detrimental biological effects. PMID- 28712826 TI - Induction of skeletal abnormalities and autophagy in Paracentrotus lividus sea urchin embryos exposed to gadolinium. AB - Gadolinium (Gd) concentration is constantly increasing in the aquatic environment, becoming an emergent environmental pollutant. We investigated the effects of Gd on Paracentrotus lividus sea urchin embryos, focusing on skeletogenesis and autophagy. We observed a delay of biomineral deposition at 24 hours post fertilization (hpf), and a strong impairment of skeleton growth at 48 hpf, frequently displayed by an asymmetrical pattern. Skeleton growth was found partially resumed in recovery experiments. The mesodermal cells designated to biomineralization were found correctly migrated at 24 hpf, but not at 48 hpf. Western blot analysis showed an increase of the LC3-II autophagic marker at 24 and 48 hpf. Confocal microscopy studies confirmed the increased number of autophagolysosomes and autophagosomes. Results show the hazard of Gd in the marine environment, indicating that Gd is able to affect different aspects of sea urchin development: morphogenesis, biomineralization, and stress response through autophagy. PMID- 28712827 TI - Physiological responses to ocean acidification and warming synergistically reduce condition of the common cockle Cerastoderma edule. AB - The combined effect of ocean acidification and warming on the common cockle Cerastoderma edule was investigated in a fully crossed laboratory experiment. Survival of the examined adult organisms remained high and was not affected by elevated temperature (+3 degrees C) or lowered pH (-0.3 units). However, the morphometric condition index of the cockles incubated under high pCO2 conditions (i.e. combined warming and acidification) was significantly reduced after six weeks of incubation. Respiration rates increased significantly under low pH, with highest rates measured under combined warm and low pH conditions. Calcification decreased significantly under low pH while clearance rates increased significantly under warm conditions and were generally lower in low pH treatments. The observed physiological responses suggest that the reduced food intake under hypercapnia is insufficient to support the higher energy requirements to compensate for the higher costs for basal maintenance and growth in future high pCO2 waters. PMID- 28712828 TI - Food availability and predation risk drive the distributional patterns of two pulmonate gastropods in a mangrove-saltmarsh transitional habitat. AB - The pulmonate gastropods, Phallomedusa solida (Martens, 1878) and Ophicardelus ornatus (Ferussac, 1821), exhibit characteristic distributional patterns at the upper intertidal zones in estuarine mangrove and saltmarsh habitats on the eastern Australian coast. Past studies suggested inundation condition, soil salinity, and percent of vegetation cover were responsible for these patterns. In this study, the role of environmental parameters, food availability, physical stress, and predation pressure in determining the distributional patterns of these gastropods was evaluated along transects spanning saltmarsh, mangrove, and the ecotone habitats. For both species, the maximum population abundance occurred in the upper saltmarsh and the ecotone between mangrove and saltmarsh at 361.0 and 358.0 ind.m-2, respectively, which was four times that of the lower saltmarsh. Mangroves were evaluated as the optimal habitat for the pulmonates in terms of the environmental parameters moisture content and food availability. However, due to its longer inundation duration within each tidal cycle, use of the mangrove habitat by the pulmonates was impeded because of difficulties in oxygen acquisition under submerged conditions. Laboratory experiments revealed the oxygen intake of the pulmonates dropped abruptly to 4.3-9.0% of aerial rates when submerged. This result indicated that mangroves were not the optimal habitat for the pulmonates. Furthermore, the visiting frequency of predators (yellowfin bream Acanthopagrus australis and toadfishes, Tetraodontidae) was 1.3 times higher in the mangrove compared to those in the ecotone and upper saltmarsh habitats. Underwater video recording also suggested high mortality of these gastropods at 31.7-88.9% in mangrove and 0.80-0.98 times higher than that in saltmarsh, resulting from the predators preying in the mangrove habitat during high tides. Despite the abiotic factors facilitating the distribution of the pulmonates in the mangrove, the higher predation risk restricted the occurrence of P. solida and O. ornatus in the mangrove areas. More than verifying that the distributional pattern of macrobenthos is a complex outcome from environmental factors and interaction with predators, our study also indicated that the influencing strength of the biotic and abiotic factors on the pulmonates distribution might be spatially changeable within a geographically small-scale continuum. PMID- 28712829 TI - Influence of ontogeny and environmental exposure on mercury accumulation in muscle and liver of male Round Stingrays. AB - Mercury tissue distribution and its dynamics are poorly understood in elasmobranchs. Total mercury was measured in liver and muscle of male Round Stingrays (Urobatis halleri) from Seal Beach, California, an anthropogenically impacted site, and from the offshore island of Santa Catalina, a less impacted site. Stable isotope analysis was also performed on the muscle and red blood cells (RBCs) of a subset of rays over a range of age classes to investigate mercury accumulation with respect to trophic ecology. Mercury in both tissues was found to be significantly greater in adults than juveniles in mainland rays; however, liver mercury accumulation drastically increased after maturity and was significantly greater in mainland adult rays than Catalina rays. There were no patterns in delta15N or delta13C with size in muscle; however, there were indications of seasonal changes in RBC delta15N, suggesting short term shifts in diet or behavior is likely linked to reproductive status as is mercury accumulation. PMID- 28712830 TI - Antioxidant defenses in polar cod (Boreogadus saida) and responsiveness toward dietary crude oil exposure. AB - Increasing anthropogenic activities in the Arctic pose the risk for accidental oil spills but our knowledge of ecotoxicological effects is still limited for Arctic organisms. This study aimed to provide insights in baseline levels of antioxidants in polar cod (Boreogadus saida) from different Arctic locations and investigate the susceptibility of this species to oxidative stress during a 32 day dietary crude oil exposure. Baseline levels of individual antioxidants and total oxyradical scavenging capacity (TOSC) varied among different Arctic fjords. Upon crude oil exposure, dose- and time-dependent polycyclic aromatic hydrocarbons (PAHs) biotransformation was evident through hepatic ethoxyresorufine-O-deethylase activity, glutathione S-transferase mRNA expression and biliary PAH metabolites. Changes in the activity of individual antioxidants and TOSC was, however, slight and transient upon exposure. In conclusion, biotransformation was clearly induced by the sub-lethal levels of crude oil in polar cod, while the antioxidant defense responded with high variability. PMID- 28712831 TI - Maternal Prepregnancy Weight and Children's Behavioral and Emotional Outcomes. AB - INTRODUCTION: This study investigated associations between maternal prepregnancy BMI and child behaviors at ages 9-11 years and examine interaction by race and gender. METHODS: The National Longitudinal Survey of Youth and the Children and Young Adults surveys are U.S.-based, ongoing longitudinal studies, initiated in 1979 and 1986, respectively. Mothers (n=2,952) reported pregnancy and child (n=5,660) developmental information at multiple time points. Child total, internalizing, and externalizing problems at ages 9-11 years were assessed using the Behavior Problems Index (BPI), collected biennially until 2012. Associations between prepregnancy BMI and child BPI outcomes were examined, as well as two- and three-way interactions by race and gender. Analyses were conducted in 2017. RESULTS: Boys whose mothers had higher prepregnancy weights exhibited higher total BPI and externalizing scores at ages 9-11 years versus those with normal weight mothers. Boys with severely obese mothers had higher total BPI (mean difference=7.99, 95% CI=3.53, 12.46) and externalizing (mean difference=5.77, 95% CI=1.50, 10.04) scores. Prepregnancy underweight was associated with boys' higher total BPI (mean difference=2.34, 95% CI=0.02, 4.66) and externalizing (mean difference=3.30, 95% CI=0.69, 5.91); these associations were not significant in sensitivity analyses. No associations emerged for girls or internalizing problems. Two-way interactions by race and three-way interactions by race and gender were not significant. CONCLUSIONS: Maternal prepregnancy weight was associated with BPI level among boys. Boys with severely obese mothers exhibited markedly higher behavioral problems at ages 9-11 years versus those with normal weight mothers, regardless of race. Maintaining healthy prepregnancy weight may be important for preventing boys' deleterious behavior outcomes in middle childhood. PMID- 28712832 TI - Enhanced Pru p 3 IgE-binding activity by selective free fatty acid-interaction. PMID- 28712833 TI - Transitioning to Independent Practice: A Successful Fourth-Year Radiology Resident Curriculum. PMID- 28712834 TI - Use of Multisource Feedback to Improve Interdisciplinary Care Among Oncologists. PMID- 28712835 TI - Biological impact of advanced glycation endproducts on estrogen receptor-positive MCF-7 breast cancer cells. AB - Diabetes mellitus potentiates the risk of breast cancer. We have previously described the pro-tumorigenic effects of advanced glycation endproducts (AGEs) on estrogen receptor (ER)-negative MDA-MB-231 breast cancer cell line mediated through the receptor for AGEs (RAGE). However, a predominant association between women with ER-positive breast cancer and type 2 diabetes mellitus has been reported. Therefore, we have investigated the biological impact of AGEs on ER positive human breast cancer cell line MCF-7 using in vitro cell-based assays including cell count, migration, and invasion assays. Western blot, FACS analyses and quantitative real time-PCR were also performed. We found that AGEs at 50 100MUg/mL increased MCF-7 cell proliferation and cell migration associated with an enhancement of pro-matrix metalloproteinase (MMP)-9 activity, without affecting their poor invasiveness. However, 200MUg/mL AGEs inhibited MCF-7 cell proliferation through induction of apoptosis indicated by caspase-3 cleavage detected using Western blotting. A phospho-protein array analysis revealed that AGEs mainly induce the phosphorylation of extracellular-signal regulated kinase (ERK)1/2 and cAMP response element binding protein-1 (CREB1), both signaling molecules considered as key regulators of AGEs pro-tumorigenic effects. We also showed that AGEs up-regulate RAGE and ER expression at the protein and transcript levels in MCF-7 cells, in a RAGE-dependent manner after blockade of AGEs/RAGE interaction using neutralizing anti-RAGE antibody. Throughout the study, BSA had no effect on cellular processes. These findings pave the way for future studies investigating whether the exposure of AGEs-treated ER-positive breast cancer cells to estrogen could lead to a potentiation of breast cancer development and progression. PMID- 28712836 TI - Tapia syndrome plus: A new entity or a variant of Tapia syndrome? PMID- 28712837 TI - Folinic acid is ineffective for treating kearns-sayre syndrome. PMID- 28712838 TI - Status dissociatus: The most extreme expression of state dissociation. PMID- 28712839 TI - Congenital myasthenia and congenital disorders of glycosylation caused by mutations in the DPAGT1 gene. PMID- 28712840 TI - Current validity of diagnosis of permanent vegetative state: A longitudinal study in a sample of patients with altered states of consciousness. AB - INTRODUCTION: Altered states of consciousness have traditionally been associated with poor prognosis. At present, clinical differences between these entities are beginning to be established. METHOD: Our study included 37 patients diagnosed with vegetative state/unresponsive wakefulness syndrome (UWS) and 43 in a minimally conscious state (MCS) according to the Coma Recovery Scale-Revised (CRS R). All patients were followed up each month for at least 6 months using the CRS R. We recorded the time points when vegetative state progressed from 'persistent' to 'permanent' based on the cut-off points established by the Multi-Society-Task Force: 12 months in patients with traumatic injury and 3 months in those with non traumatic injury. A logistic regression model was used to determine the factors potentially predicting which patients will emerge from MCS. RESULTS: In the UWS group, 23 patients emerged from UWS but only 9 emerged from MCS. Of the 43 patients in the MCS group, 26 patients emerged from that state during follow-up. Eight of the 23 patients (34.7%) who emerged from UWS and 17 of the 35 (48.6%) who emerged from MCS recovered after the time points proposed by the Multi Society-Task-Force. According to the multivariate regression analysis, aetiology (P<.01), chronicity (P=.01), and CRS-R scores at admission (P<.001) correctly predicted emergence from MCS in 77.5% of the cases. CONCLUSIONS: UWS and MCS are different clinical entities in terms of diagnosis and outcomes. Some of the factors traditionally associated with poor prognosis, such as time from injury and likelihood of recovery, should be revaluated. PMID- 28712841 TI - Long-term impact of subthalamic stimulation on cognitive function in patients with advanced Parkinson's disease. AB - OBJECTIVE: The aim of this study was to evaluate the effects of deep brain stimulation of the subthalamic nucleus (DBS-SN) on cognitive function in patients with Parkinson's disease (PD) 5 years after surgery. MATERIAL AND METHODS: We conducted a prospective study including 50 patients with PD who underwent DBS-SN (62.5% were men; mean age of 62.2+/-8.2 years; mean progression time of 14.1+/ 6.3 years). All patients were assessed before the procedure and at one year after surgery; 40 patients were further followed up until the 5-year mark. Follow-up assessments included the following neuropsychological tests: Mini-Mental State Examination (MMSE), Mattis Dementia Rating Scale (MDRS), letter-number sequencing of the WAIS-III (WAIS-III-LN), clock-drawing test, Rey auditory verbal learning test (RAVLT), Benton Visual Retention Test (BVRT), Judgment of Line Orientation (JLO) test, FAS Phonemic Verbal Fluency Test, Stroop test, and the Montgomery Asberg Depression Rating Scale (MADRS). RESULTS: Patients were found to score lower on the MMSE (-0.89%), clock-drawing test (-2.61%), MDRS (-1.72%), and especially phonemic (-13.28%) and sematic verbal fluency tests (-12.40%) at one year after surgery. Delayed recall on the RAVLT worsened one year after the procedure (-10.12%). At 5 years, impairment affected mainly verbal fluency; scores decreased an additional 16.10% and 16.60% in semantic and phonemic verbal fluency, respectively. Moderate decreases were observed in immediate recall ( 16.87%), WAIS-III-LN (-16.67%), and JLO test (-11.56%). DISCUSSION: In our sample, DBS-SN did not result in global cognitive impairment 5 years after surgery. Verbal function was found to be significantly impaired one year after the procedure. Impaired learning and visuospatial function may be attributed to degeneration associated with PD. PMID- 28712842 TI - Intracranial hypertension syndrome in a patient with psoriasis receiving ustekinumab. PMID- 28712843 TI - Orthostatic tremor as the only manifestation of thyrotoxicosis following cerebral angiography. PMID- 28712844 TI - New cases of star anise poisoning: Are we providing enough information? PMID- 28712845 TI - Dual inhibitors of the human blood-brain barrier drug efflux transporters P glycoprotein and ABCG2 based on the antiviral azidothymidine. AB - The brain provides a sanctuary site for HIV due, in part, to poor penetration of antiretroviral agents at the blood-brain barrier. This lack of penetration is partially attributed to drug efflux transporters such as P-glycoprotein (P-gp) and ABCG2. Inhibition of both ABCG2 and P-gp is critical for enhancing drug accumulation into the brain. In this work, we have developed a class of homodimers based on the HIV reverse transcriptase inhibitor azidothymidine (AZT) that effectively inhibits P-gp and ABCG2. These agents block transporter mediated efflux of the P-gp substrate calcein-AM and the ABCG2 substrate mitoxantrone. The homodimers function by interacting with the transporter drug binding sites as demonstrated by competition studies with the photo-affinity agent and P-gp/ABCG2 substrate [125I]iodoarylazidoprazosin. As such, these dual inhibitors of both efflux transporters provide a model for the future development of delivery vehicles for antiretroviral agents to the brain. PMID- 28712846 TI - Reactive Astrocytes Promote ALS-like Degeneration and Intracellular Protein Aggregation in Human Motor Neurons by Disrupting Autophagy through TGF-beta1. AB - Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly progressing motor neuron disease. Astrocytic factors are known to contribute to motor neuron degeneration and death in ALS. However, the role of astrocyte in promoting motor neuron protein aggregation, a disease hallmark of ALS, remains largely unclear. Here, using culture models of human motor neurons and primary astrocytes of different genotypes (wild-type or SOD1 mutant) and reactive states (non-reactive or reactive), we show that reactive astrocytes, regardless of their genotypes, reduce motor neuron health and lead to moderate neuronal loss. After prolonged co cultures of up to 2 months, motor neurons show increased axonal and cytoplasmic protein inclusions characteristic of ALS. Reactive astrocytes induce protein aggregation in part by releasing transforming growth factor beta1 (TGF-beta1), which disrupts motor neuron autophagy through the mTOR pathway. These results reveal the important contribution of reactive astrocytes in promoting aspects of ALS pathology independent of genetic influences. PMID- 28712847 TI - Pluri-IQ: Quantification of Embryonic Stem Cell Pluripotency through an Image Based Analysis Software. AB - Image-based assays, such as alkaline phosphatase staining or immunocytochemistry for pluripotent markers, are common methods used in the stem cell field to assess pluripotency. Although an increased number of image-analysis approaches have been described, there is still a lack of software availability to automatically quantify pluripotency in large images after pluripotency staining. To address this need, we developed a robust and rapid image processing software, Pluri-IQ, which allows the automatic evaluation of pluripotency in large low-magnification images. Using mouse embryonic stem cells (mESC) as a model, we combined an automated segmentation algorithm with a supervised machine-learning platform to classify colonies as pluripotent, mixed, or differentiated. In addition, Pluri-IQ allows the automatic comparison between different culture conditions. This efficient user-friendly open-source software can be easily implemented in images derived from pluripotent cells or cells that express pluripotent markers (e.g., OCT4-GFP) and can be routinely used, decreasing image assessment bias. PMID- 28712848 TI - A Short Region of Connexin43 Reduces Human Glioma Stem Cell Migration, Invasion, and Survival through Src, PTEN, and FAK. AB - Connexin43 (CX43), a protein that forms gap junction channels and hemichannels in astrocytes, is downregulated in high-grade gliomas. Its relevance for glioma therapy has been thoroughly explored; however, its positive effects on proliferation are counterbalanced by its effects on migration and invasion. Here, we show that a cell-penetrating peptide based on CX43 (TAT-Cx43266-283) inhibited c-Src and focal adhesion kinase (FAK) and upregulated phosphatase and tensin homolog in glioma stem cells (GSCs) derived from patients. Consequently, TAT Cx43266-283 reduced GSC motility, as analyzed by time-lapse microscopy, and strongly reduced their invasive ability. Interestingly, we investigated the effects of TAT-Cx43266-283 on freshly removed surgical specimens as undissociated glioblastoma blocks, which revealed a dramatic reduction in the growth, migration, and survival of these cells. In conclusion, a region of CX43 (amino acids 266-283) exerts an important anti-tumor effect in patient-derived glioblastoma models that includes impairment of GSC migration and invasion. PMID- 28712852 TI - Osteonecrosis of the jaws: a review and update in etiology and treatment. AB - INTRODUCTION: Osteonecrosis of the jaws can result either from radiation, used in radiotherapy for treatment of malignant tumors, or medications used for bone remodeling and anti-angiogenesis such as bisphosphonates. These conditions can be associated with triggering factors such as infection, trauma and decreased vascularity. The management of patients with osteonecrosis of the jaws requires caution since there is no specific treatment that acts isolated and decidedly. However, different treatment modalities can be employed in an associated manner to control and stabilize lesions. OBJECTIVE: To review the current knowledge on etiology and management of osteonecrosis of the jaws, both radio-induced and medication-related, aiming to improve knowledge of professionals seeking to improve the quality of life of their patients. METHODS: Literature review in PubMed as well as manual search for relevant publications in reference list of selected articles. Articles in English ranging from 1983 to 2017, which assessed osteonecrosis of the jaws as main objective, were selected and analyzed. RESULTS: Infections, traumas and decreased vascularity have a triggering role for osteonecrosis of the jaws. Prophylactic and/or stabilizing measures can be employed in association with therapeutic modalities to properly manage osteonecrosis of the jaws patients. CONCLUSION: Selecting an appropriate therapy for osteonecrosis of the jaws management based on current literature is a rational decision that can help lead to a proper treatment plan. PMID- 28712849 TI - Structure, function, and mechanism of proline utilization A (PutA). AB - Proline has important roles in multiple biological processes such as cellular bioenergetics, cell growth, oxidative and osmotic stress response, protein folding and stability, and redox signaling. The proline catabolic pathway, which forms glutamate, enables organisms to utilize proline as a carbon, nitrogen, and energy source. FAD-dependent proline dehydrogenase (PRODH) and NAD+-dependent glutamate semialdehyde dehydrogenase (GSALDH) convert proline to glutamate in two sequential oxidative steps. Depletion of PRODH and GSALDH in humans leads to hyperprolinemia, which is associated with mental disorders such as schizophrenia. Also, some pathogens require proline catabolism for virulence. A unique aspect of proline catabolism is the multifunctional proline utilization A (PutA) enzyme found in Gram-negative bacteria. PutA is a large (>1000 residues) bifunctional enzyme that combines PRODH and GSALDH activities into one polypeptide chain. In addition, some PutAs function as a DNA-binding transcriptional repressor of proline utilization genes. This review describes several attributes of PutA that make it a remarkable flavoenzyme: (1) diversity of oligomeric state and quaternary structure; (2) substrate channeling and enzyme hysteresis; (3) DNA binding activity and transcriptional repressor function; and (4) flavin redox dependent changes in subcellular location and function in response to proline (functional switching). PMID- 28712850 TI - Ex vivo instability of glycated albumin: A role for autoxidative glycation. AB - Ex vivo protein modifications occur within plasma and serum (P/S) samples due to prolonged exposure to the thawed state-which includes temperatures above -30 degrees C. Herein, the ex vivo glycation of human serum albumin from healthy and diabetic subjects was monitored in P/S samples stored for hours to months at -80 degrees C, -20 degrees C, and room temperature, as well as in samples subjected to multiple freeze-thaw cycles, incubated at different surface area-to-volume ratios or under different atmospheric compositions. A simple dilute-and-shoot method utilizing trap-and-elute LC-ESI-MS was employed to determine the relative abundances of the glycated forms of albumin-including forms of albumin bearing more than one glucose molecule. Significant increases in glycated albumin were found to occur within hours at room temperature, and within days at -20 degrees C. These increases continued over a period of 1-2 weeks at room temperature and over 200 days at -20 degrees C, ultimately resulting in a doubling of glycated albumin in both healthy and diabetic patients. It was also shown that samples stored at lower surface area-to-volume ratios or incubated under a nitrogen atmosphere experienced less rapid glucose adduction of albumin-suggesting a role for oxidative glycation in the ex vivo glycation of albumin. PMID- 28712851 TI - IRF6 rs2235375 single nucleotide polymorphism is associated with isolated non syndromic cleft palate but not with cleft lip with or without palate in South Indian population. AB - INTRODUCTION: Transcription factors are very diverse family of proteins involved in activating or repressing the transcription of a gene at a given time. Several studies using animal models demonstrated the role of transcription factor genes in craniofacial development. OBJECTIVE: We aimed to investigate the association of IRF6 intron-6 polymorphism in the non-syndromic cleft lip with or without palate in a South Indian population. METHODS: 173 unrelated nonsyndromic cleft lip with or without cleft palate patients and 176 controls without clefts patients were genotyped for IRF6 rs2235375 variant by allele-specific amplification using the KASPar single nucleotide polymorphism genotyping system. The association between interferon regulatory factor-6 gene intron-6 dbSNP208032210:g.G>C (rs2235375) single nucleotide polymorphism and non-syndromic cleft lip with or without palate risk was investigated by chi-square test. RESULTS: There were significant differences in genotype or allele frequencies of rs2235375 single nucleotide polymorphism between controls and cases with non syndromic cleft lip with or without palate. IRF6 rs2235375 variant was significantly associated with increased risk of non-syndromic cleft lip with or without palate in co-dominant, dominant (OR: 1.19; 95% CI 1.03-2.51; p=0.034) and allelic models (OR: 1.40; 95% CI 1.04-1.90; p=0.028). When subset analysis was applied significantly increased risk was observed in cleft palate only group (OR dominant: 4.33; 95% CI 1.44-12.97; p=0.005). CONCLUSION: These results suggest that IRF6 rs2235375 SNP play a major role in the pathogenesis and risk of developing non-syndromic cleft lip with or without palate. PMID- 28712853 TI - Short-term evaluation of tegumentary changes of the nose in oral breathers undergoing rapid maxillary expansion. AB - INTRODUCTION: Rapid maxillary expansion is an orthodontic and orthopedic procedure that can change the form and function of the nose. The soft tissue of the nose and its changes can influence the esthetics and the stability of the results obtained by this procedure. OBJECTIVE: The objective of this study was to assess the changes in nose dimensions after rapid maxillary expansion in oral breathers with maxillary atresia, using a reliable and reproducible methodology through computed tomography. METHODS: A total of 30 mouth-breathing patients with maxillary atresia were analyzed and divided into a treatment group who underwent rapid maxillary expansion (20 patients, 10 of which were male and 10 female, with a MA of 8.9 years and a SD of 2.16, ranging from 6.5 to 12.5 years) and a Control Group (10 patients, 5 of which were male and 5 female, with a MA of 9.2 years, SD of 2.17, ranging from 6.11 to 13.7 years). In the treatment group, multislice computed tomography scans were obtained at the start of the treatment (T1) and 3 months after expansion (T2). The patients of the control group were submitted to the same exams at the same intervals of time. Four variables related to soft tissue structures of the nose were analyzed (alar base width, alar width, height of soft tissue of the nose and length of soft tissue of the nose), and the outcomes between T1 and T2 were compared using Osirix MD software. RESULTS: In the TG, the soft tissues of the nose exhibited significant increases in all variables studied (p<0.05), whereas, changes did not occur in the control group (p>0.05). In the treatment group, mean alar base width increased by 4.87% (p=0.004), mean alar width increased by 4.04% (p=0.004), mean height of the soft tissues of the nose increased by 4.84% (p=0.003) and mean length of the soft tissues of the nose increased by 4.29% (p=0.012). CONCLUSION: In short-term, rapid maxillary expansion provided a statistically significant increase in the dimensions of the soft tissues of the nose. PMID- 28712854 TI - C5 nephritic factors drive the biological phenotype of C3 glomerulopathies. AB - C3 Glomerulopathies, which include Dense Deposit Disease and C3 Glomerulonephritis, are associated with genetic and acquired dysregulation of the C3 convertase alternative pathway of complement. The potential role of the activation of the C5 convertase has not been studied extensively. Here we analyzed IgG samples from patients with C3 Glomerulopathies to identify circulating autoantibodies that stabilize the C3 alternative pathway (C3 Nephritic Factors) as well as C5 convertases (C5 Nephritic Factors), thus preventing decay of these enzyme complexes. Rare variants in alternative pathway genes were found in 28 of 120 tested patients. C3 and C5 Nephritic Factors were found in 76 of 101 (75%) and 29 of 59 (49%) of the patients, respectively. Therefore, we compared the results of the assays for the C3 and C5 nephritic factors functional activity: 29% were positive for C3 Nephritic Factors alone, 39% were positive for both C3 and C5 Nephritic Factors, and 10% were positive for C5 Nephritic Factors alone. We found that the addition of properdin-enhanced stabilization of C3 convertase in the presence of IgG doubly positive for both Nephritic Factors, while it did not modify the stabilization mediated by IgG solely positive for C3 Nephritic Factors. Both C3 and C5 Nephritic Factors correlated with C3 consumption, while only C5 Nephritic Factors correlated with sC5b9 levels. C5 Nephritic Factors-positive patients were more likely to have C3 Glomerulonephritis than Dense Deposit Disease. Thus, dysregulation of the C5 convertase contributes to C3 Glomerulopathies inter-disease differences and may have direct therapeutic implications. PMID- 28712856 TI - Lung cancer-moving in the right direction. PMID- 28712855 TI - Plasma high-sensitivity troponin T predicts end-stage renal disease and cardiovascular and all-cause mortality in patients with type 1 diabetes and diabetic nephropathy. AB - High-sensitivity troponin T (hsTnT) is a marker of cardiovascular disease (CVD) and in type 2 diabetes also a marker of renal events, but has not been evaluated in type 1 diabetics. We therefore reviewed a type 1 diabetes cohort of 442 without and 458 with diabetic nephropathy. Baseline samples were analyzed for hsTnT levels. Cox regression analyses assessed predictive value in relation to the development of end-stage renal disease (ESRD) in 99 patients, all-cause mortality in 178, and CVD events in 134 after up to 12 years of follow-up. To assess if hsTnT improved risk prediction beyond traditional clinical risk markers, we calculated c statistics and relative integrated discrimination improvement. HsTnT was significantly higher in patients with diabetic nephropathy compared to normoalbuminuria (median 8.9 vs 3.1 ng/L). For a doubling in hsTnT levels, and after adjustment for well-known risk factors, including NT-proBNP and hsCRP, the hazard ratio for ESRD at 1.26 was not significant in the diabetic nephropathy group, but there was a significant association with GFR decline after adjustment during follow-up (2.9 ml/min/1.73 m2 annual decline per doubling in hsTnT). The unadjusted and adjusted hazard ratios for mortality (1.64 and 1.32, respectively) were significant in patients with, but not for patients without, nephropathy. Adjusted hazard ratios for fatal and non-fatal CVD events were significant for the whole cohort (1.13), and those with nephropathy (1.14), but not significant for normoalbuminuria (1.06). Addition of hsTNT to traditional risk factors significantly increased the area under the curve by 0.01 in a receiver-operating characteristic curve for mortality. The relative integrated discrimination improvement was increased 15.7% for mortality, 6.3% for CVD, and 1.9% for ESRD (all significant). Thus, higher hsTnT is an independent predictor of renal decline and cardiovascular events in patients with type 1 diabetes and diabetic nephropathy. PMID- 28712857 TI - Reply from Authors re: Mikkel Fode, Jens Sonksen. Towards a Greater Understanding of Underactive Bladder. Eur Urol 2017;72:408-9. PMID- 28712858 TI - Reply to Paolo Capogrosso, Francesco Montorsi, and Andrea Salonia's Letter to the Editor re: Philipp Mandel, Felix Preisser, Markus Graefen, et al. High Chance of Late Recovery of Urinary and Erectile Function Beyond 12 Months After Radical Prostatectomy. Eur Urol 2017;71:848-50. Late Recovery of Erectile Function After Radical Prostatectomy: Should We Modify the Way of Assessment? PMID- 28712859 TI - Tyr42 phosphorylation of RhoA GTPase promotes tumorigenesis through nuclear factor (NF)-kappaB. AB - Dysregulation of reactive oxygen species (ROS) levels is implicated in the pathogenesis of several diseases, including cancer. However, the molecular mechanisms for ROS in tumorigenesis have not been well established. In this study, hydrogen peroxide activated nuclear factor-kappaB (NF-kappaB) and RhoA GTPase. In particular, we found that hydrogen peroxide lead to phosphorylation of RhoA at Tyr42 via tyrosine kinase Src. Phospho-Tyr42 (p-Tyr42) residue of RhoA is a binding site for Vav2, a guanine nucleotide exchange factor (GEF), which then activates p-Tyr42 form of RhoA. P-Tyr42 RhoA then binds to IkappaB kinase gamma (IKKgamma), leading to IKKbeta activation. Furthermore, RhoA WT and phospho-mimic RhoA, RhoA Y42E, both promoted tumorigenesis, whereas the dephospho-mimic RhoA, RhoA Y42F suppressed it. In addition, hydrogen peroxide induced NF-kappaB activation and cell proliferation, along with expression of c-Myc and cyclin D1 in the presence of RhoA WT and RhoA Y42E, but not RhoA Y42F. Indeed, levels of p Tyr42 Rho, p-Src, and p-65 are significantly increased in human breast cancer tissues and show correlations between each of the two components. Conclusively, the posttranslational modification of as RhoA p-Tyr42 may be essential for promoting tumorigenesis in response to generation of ROS. PMID- 28712860 TI - Tolerance and outcomes of sorafenib in elderly patients treated for advanced hepatocellular carcinoma. AB - INTRODUCTION: Use of sorafenib remains debated in elderly patients treated for advanced hepatocellular carcinoma (HCC). METHODS: This was a bicentric retrospective study including all patients >=75years and treated with sorafenib for advanced HCC between January 2010 and March 2014. RESULTS: Of the 51 patients included (median age: 78 years, range: 75-92; performance status (PS) 0-1: 98%; cirrhosis: 88.2%; Child-Pugh A: 95.6%) all experienced at least one adverse event (AE). About 2/3 of them (66.7%) had grade 3-4 toxicities, including fatigue (43.1%), hand foot skin syndrome (11.8%), anorexia (9.8%) or diarrhea (9.8%). After adjustment for arterial hypertension, heart failure, other(s) cardiovascular history(ies), and sorafenib dose at baseline, only patients >=80 years were associated with severe AE (OR: 13.3; p=0.009). Discontinuation for toxicity was reported in 31 (60.8%) patients, mainly within the 3rd months, especially in those who had PS >=1 at baseline (OR: 10.4; p=0.01), or other cardiovascular histories (OR: 30.9; p=0.016). In this setting, overall survival was significantly reduced (HR: 4.5; p<0.0001). CONCLUSION: Tolerance of Sorafenib seems to be low in elderly, especially for patients aged >=80 years or with PS >=1. Starting with reduced dose of sorafenib does not seem to impact results. Some of these patients may truly benefit from the treatment in terms of survival. PMID- 28712861 TI - A novel Golgi-Cox staining method for detecting and characterizing roles of the hepatic stellate cells in liver injury. AB - The aim of this study was to investigate the utility of the Golgi-Cox method to characterize the distribution and morphological changes of the hepatic stellate cells (HSCs) in CCl4 liver damaged rats. Six-week-old male Wistar rats were injected with CCl4 for ten weeks. The livers were processed with the Golgi-Cox method, reticuline, and Massons Trichrome stains, and analyzed under light microscopy. Histological evaluation of livers was made through the METAVIR score. In normal livers, the HSCs show stellate form with abundant thin cytoplasmic processes, distributed into hepatic lobule, mainly in zone 1. In addition, an intricate and broad network of fibers with radial distribution from the central vein to the periphery of the hepatic lobule was observed. In CCl4 damaged livers, with METAVIR score I and II, HSCs showed a moderate increase in the soma size, in the cytoplasmic processes and in density, distributed in zone 2 and 3; changes associated with a decrease in network fibers. In livers with METAVIR score III and IV, the morphology changes of the HSCs consisted of a significant increase in the soma size, cut and fraying appearance of the emerging cytoplasmic processes, and a decrease in HSCs density, distributed mainly in zone 3, with a significant depletion of network fibers. Results show that Golgi-Cox stain is able to impregnate the HSCs and could be an additional tool to study the morphological changes of the HSCs in the different experimental pathological conditions of the liver. PMID- 28712862 TI - Determination of 7Be and 22Na activity in air and rainwater samples by gamma-ray spectrometry. AB - Natural radionuclides, such as short lived radon daughters and 7Be, have been analyzed in aerosols at the Nuclear Engineering Department of the National Technical University of Athens (NED-NTUA) since many years, with high accuracy and precision. During this research, an effort to detect 22Na and determine 7Be/22Na ratio in aerosols is presented. In order to study the role of precipitation in surface air 7Be and 22Na activity concentration, a procedure for collecting and analyzing rainwater was developed. With this technique 22Na was detected in air samples, although with relatively high uncertainties. PMID- 28712863 TI - Harnessing the CD1 restricted T cell response for leukemia adoptive immunotherapy. AB - Disease recurrence following chemotherapy and allogeneic hematopoietic cell transplantation is the major unmet clinical need of acute leukemia. Adoptive cell therapy (ACT) with allogeneic T lymphocytes can control recurrences at the cost of inducing detrimental GVHD. Targeting T cell recognition on leukemia cells is therefore needed to overcome the problem and ensure safe and durable disease remission. In this review, we discuss adoptive cells therapy based on CD1 restricted T cells specific for tumor associated self-lipid antigens. CD1 molecules are identical in every individual and expressed essentially on mature hematopoietic cells and leukemia blasts, but not by parenchymatous cells, while lipid antigens are enriched in malignant cells and unlike to mutate upon immune mediated selective pressure. Redirecting T cells against self-lipids presented by CD1 molecules can thus provide an appealing cell therapy strategy for acute leukemia that is patient-unrestricted and can minimize risks for GVHD, implying potential prognostic improvement for this cancer. PMID- 28712864 TI - Thermal comfort zone of the hands, feet and head in males and females. AB - INTRODUCTION: The present study compared the thermal comfort zones (TCZ) of the hands, feet and head in eight male and eight female participants, assessed with water-perfused segments (WPS). METHODS: On separate occasions, and separated by a minimum of one day, participants were requested to regulate the temperature of three distal skin regions (hands, feet and head) within their TCZ. On each occasion they donned a specific water-perfused segment (WPS), either gloves, socks or hood for assessing the TCZ of the hands, feet and head, respectively. In the absence of regulation, the temperature of the water perfusing the WPS changed in a saw-tooth manner from 10 to 50 degrees C; by depressing a switch and reversing the direction of the temperature at the limits of the TCZ, each participant defined the TCZ for each skin region investigated. RESULTS: The range of regulated temperatures (upper and lower limits of the TCZ) did not differ between studied skin regions or between genders. Participants however maintained higher head (35.7+/-0.4 degrees C; p?0.001) skin temperature (Tsk) compared to hands (34.5+/-0.8 degrees C) and feet (33.8+/-1.1 degrees C). CONCLUSIONS: When exposed to normothermic conditions, distal skin regions do not differ in ranges of temperatures, perceived as thermally comfortable. PMID- 28712865 TI - Stearic acid suppresses mammary gland development by inhibiting PI3K/Akt signaling pathway through GPR120 in pubertal mice. AB - It has been demonstrated that dietary high fat diet negatively affects the pubertal mammary gland development. The aim of the present study was to investigate the effects of stearic acid (SA), an 18-carbon chain saturated fatty acid, on mammary gland development in pubertal mice and to explore the underlying mechanism. Our results demonstrated that dietary supplementation of 2% SA suppressed mammary duct development, with significant reduction of terminal end bud (TEB) number and ductal branch. In accord, the expression of proliferative marker Cyclin D1 was markedly decreased by dietary SA. Furthermore, dietary SA led to increase of G protein-coupled receptor 120 (GPR120) expression and inhibition of PI3K/Akt signaling pathway in mammary gland of pubertal mice. In good agreement with the in vivo findings, the in vitro results showed that 40 MUM SA significantly suppressed proliferation of mouse mammary epithelial cell HC11 by regulating mRNA and/or protein expression of proliferative markers such as Cyclin D1/3, p21, and PCNA. Meanwhile, SA activated GPR120 and inhibited PI3K/Akt signaling pathway in a GPR120-dependent manner. In addition, SA-induced inhibition of PI3K/Akt signaling pathway, suppression of HC11 proliferation, and alteration of proliferative markers expression were abolished by knockdown of GPR120 with siRNA. Collectively, these findings showed that SA suppressed mammary gland development of pubertal mice, which was coincident with the SA-inhibited HC11 proliferation, and was associated with inhibition of PI3K/Akt signaling pathway through activation of GPR120. These data provided new insights into the regulation of mammary gland development by dietary fatty acids. PMID- 28712867 TI - WITHDRAWN: Anti-inflammatory and anti-oxidant effects of apigetrin on LPS-induced acute lung injury by regulating Nrf2 and AMPK pathways. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our business/policies/article-withdrawal. PMID- 28712866 TI - Cell-free methemoglobin drives platelets to apoptosis via mitochondrial ROS mediated activation of JNK and p38 MAP kinase. AB - Cell-free hemoglobin (Hb), a well-known marker of intravascular hemolysis, is eventually oxidized to methemoglobin (MtHb). Elevated levels of MtHb have been noted, alongside depleted levels of platelets, in several hemolytic diseases. The current study aims to probe the possible role of MtHb in platelet death, based on the facts that it is a pro-inflammatory and pro-apoptotic agent, as well as the sensitive nature of platelets and their tendency to undergo apoptosis under oxidative stress. An attempt is made to establish the link between hemolysis and thrombocytopenia, by deciphering the underlying molecular signaling pathways. The results of this study demonstrate that MtHb, not Hb exerts oxidative stress on platelets, which triggers their death via ROS-mediated mitochondrial apoptotic pathway. It was further established that the MtHb-induced platelet apoptotic events mediate through JNK and p38 MAPK activation. Thus, the study presents a mechanistic insight into the previous studies that reported the incidence of thrombocytopenia in hemolytic diseases. This study highlights the fate of platelets in intravascular hemolytic conditions, which demands the need for a specific treatment strategy considering the risks associated with thrombocytopenia during severe hemolytic diseases. PMID- 28712868 TI - Salicylates promote mitochondrial biogenesis by regulating the expression of PGC 1alpha in murine 3T3-L1 pre-adipocytes. AB - Mitochondrial dysfunction has been associated with insulin resistance and diabetes. Decreased mitochondrial density and mitochondrial copy numbers have been found in insulin-resistant individuals. Restoration of the number of mitochondria and normal mitochondrial function has become an important therapeutic target of diabetes. Salicylate, the main active ingredient in aspirin, has been in medicinal use since ancient times. Little information regarding the effects of salicylate on mitochondrial function has been reported. In this study, we assessed the effects of salicylate on the peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) signaling pathway and mitochondrial biogenesis in pre-adipocytes. Our findings demonstrate that treatment with salicylate promoted the expression of PGC-1alpha and its downstream targets nuclear respiratory factor 1 (NRF1) and mitochondrial transcription factor A (TFAM). Importantly, salicylate treatment significantly increased the number of mDNA, citrate synthase activity, expression of respiratory chain complex I, and mitochondrial mass, which were suppressed by the specific AMPK inhibitor Compound C. Indeed, salicylate treatment induced the phosphorylation of AMPK, which was involved in the induction of PGC-1alpha, NRF1, and TFAM. Importantly, inhibition of PGC-1alpha expression using PGC-1alpha small RNA interference abolished the effects of salicylate on mitochondrial biogenesis. These results suggest that salicylate has a potential therapeutic capacity against mitochondrial dysfunction in diabetes. PMID- 28712869 TI - Evaluation of human platelet lysate and dimethyl sulfoxide as cryoprotectants for the cryopreservation of human adipose-derived stem cells. AB - Cryopreservation provides an effective technique to maintain the functional properties of human adipose-derived stem cells (ASCs). Dimethylsulfoxide (DMSO) and fetal bovine serum (FBS) are frequently used as cryoprotectants for this purpose. However, the use of DMSO can result in adverse effects and toxic reactions and FBS can introduce risks of viral, prion, zoonose contaminations and evoke immune responses after injection. It is therefore crucial to reduce DMSO concentrations and use serum-free solution in the cryopreservation process. Human platelet lysate (PL) is a promising candidate for use as an alternative to DMSO and FBS. Therefore, in this study, with an aim to identify a cryoprotective agent for ASC cryopreservation, we determined the viability, proliferation potential, phenotype, and differentiation potential of fresh ASCs and ASCs cryopreserved using different combinations of three cryoprotective agents: fetal bovine serum (FBS), dimethylsulfoxide (DMSO), and human platelet lysate (PL). The viability of the ASCs cryopreserved with 90% FBS and 10% DMSO, 95% FBS and 5% DMSO, and 97% PL and 3% DMSO was >80%, and the proliferation potentials, cell phenotypes, and differentiation potentials of these groups were similar to those of fresh ASCs. Together, our findings suggest that a combination of 97% PL and 3% DMSO is an ideal cryoprotective agent for the efficient cryopreservation of human ASCs. PMID- 28712871 TI - Inhibition of phosphatidylinositide 3-kinase ameliorates antiproliferation by benzyl isothiocyanate in human colon cancer cells. AB - In the present study, we clarified the role of phosphatidylinositide 3-kinase (PI3K) in antiproliferation induced by benzyl isothiocyanate (BITC) in human colorectal cancer cells. BITC simultaneously activated the PI3K/Akt/forkhead box O (FoxO) pathway, whereas it significantly inhibited the proliferation in human colorectal cancer cells. Inhibitory experiments using a PI3K selective inhibitor, LY294002 or NVP-BEZ235, significantly enhanced the BITC-induced antiproliferation and apoptotic cell population with the attenuation of the BITC-induced activation of the PI3K/Akt/FoxO survival pathway. Furthermore, BITC enhanced the insulin activated PI3K/Akt/FoxO pathway, possibly through its inhibition of the protein tyrosine phosphatase 1B enzymatic activity. Taken together, these results suggested that the PI3K/Akt/FoxO pathway negatively regulates the BITC-induced antiproliferation in human colorectal cancer cells. PMID- 28712870 TI - Tissue factor pathway inhibitor attenuates ER stress-induced inflammation in human M2-polarized macrophages. AB - Endoplasmic reticulum (ER) stress has been shown to play a key role during the initiation and clinical progression of the cardiovascular diseases, such as atherosclerosis. We have recently shown that expression of tissue factor pathway inhibitor (TFPI) in human monocyte-derived macrophages (MDMs) was induced by cholesterol crystals (CC). In the present study we aimed to determine the role of TFPI under ER stress conditions using human MDMs. qRT-PCR and immunohistochemistry analysis were performed to determine the presence of the ER stress marker CCAAT/enhancer binding protein homologous protein (CHOP) and TFPI in human carotid plaque material and also in human MDMs polarized into pro inflammatory M1 or anti-inflammatory M2 populations. CHOP mRNA levels were upregulated in the plaques compared to healthy vessels, and CHOP protein was localized in the same area as TFPI in the plaques. Both CHOP and TFPI mRNA levels were upregulated after CC treatment, especially in the M2 phenotype, and the ER stress inhibitor 4-phenylbutyric acid (PBA) reversed this effect. Furthermore, CC treatment increased the levels of the pro-inflammatory cytokines TNF-alpha, IL-6, and IL-8, which for TNF-alpha and IL-8 was inhibited by PBA, and reduced the levels of the anti-inflammatory cytokine IL-10 in M2-polarized macrophages. Knockdown of TFPI prior to CC treatment exacerbated TNF-alpha and IL-6 levels, but reduced IL-8 and IL-10 levels. Our results show that CC induce TFPI and cytokine expression in M2-polarized macrophages through activation of the ER stress pathway and that TFPI has a protective effect against TNF-alpha and IL-6 mediated inflammation. These mechanisms may have implications for the pathogenesis of atherosclerosis. PMID- 28712872 TI - Suppression of CD36 attenuates adipogenesis with a reduction of P2X7 expression in 3T3-L1 cells. AB - Adipogenesis is a process of differentiation from preadipocyte into adipocyte, and is regulated by several transcription factors, including the peroxisome proliferator-activated receptor gamma (PPARgamma) and the CCAAT-enhancer-binding protein alpha (C/EBPalpha). CD36 is a membrane protein which contributes to the metabolic disorders such as obesity. Although the previous study demonstrated CD36 participated in the progression of adipogenesis, the mechanism is still unclear. We report here that knockdown of CD36 expression by CD36 small interfering RNA (siRNA) resulted in a reduction of adipocyte differentiation and adipogenic protein expression. In addition, purinergic receptor P2X, ligand-gated ion channel 7 (P2X7) was downregulated in CD36-knockdown 3T3-L1 cells, suggesting that the suppression of CD36 attenuates adipogenesis via the P2X7 pathway in 3T3 L1 cells. PMID- 28712873 TI - The effect of oil sands tailings pond sediments on embryo-larval walleye (Sander vitreus). AB - Walleye (Sander vitreus) are a commercially important North American fish species that inhabit the Athabasca River. This river flows through the Athabasca oil sands where natural sources of bitumen erode from the McMurray formation. Little information is available on responses of walleye embryos to oil sands tailings pond sediments in a laboratory setting. The current study describes the design and implementation of a daily-renewal bioassay to assess the potential effects of tailings pond sediments from the Athabasca oil sands area on walleye development. Developing walleye embryos were exposed to increasing concentrations of two tailings pond sediments (collected in the Athabasca oil sands area) until the completion of yolk absorption in control fish. Sediments from the tailings pond represent a mixture of polycyclic aromatic hydrocarbons (PAHs) and alkylated PAHs. During the 31 day exposure, the walleye were examined for mortalities, weight, length and developmental abnormalities to provide an initial evaluation of the effects of the oil sands tailings pond sediments. Walleye embryo survival differed between the tailings pond sediments, and survival decreased with increasing sediment concentration. Alkylated PAH content differed between the two tailings pond sediments and lower embryo survival corresponded to higher total and alkylated PAH content. Tailings pond sediment-exposed walleye exhibited a delay in development, as well as increased percentages of larvae with heart and yolk sac edema, and cranial and spinal malformations. These abnormalities in development are often associated with PAH and alkylated PAH exposure. This study provides an exposure design that can be used to assess sediment toxicity to early developmental stages of a fish species not commonly tested in the lab, and lays the groundwork for future studies with this and other difficult-to-culture species. These results offer information on the potential effects of tailings pond sediments containing PAH/alkylated PAH mixtures on walleye development and survival. PMID- 28712874 TI - An easy method to define the cervical borders during postpartum hysterectomy. PMID- 28712875 TI - Apical constriction in distal visceral endoderm cells initiates global, collective cell rearrangement in embryonic visceral endoderm to form anterior visceral endoderm. AB - The behavior of visceral endoderm cells was examined as the anterior visceral endoderm (AVE) formed from the distal visceral endoderm (DVE) using the mouse lines R26-H2B-EGFP and R26-PHA7-EGFP to visualize cell nuclei and adherens junction, respectively. The analysis using R26-H2B-EGFP demonstrated global cell rearrangement that was not specific to the DVE cells in the monolayer embryonic visceral endoderm sheet; each population of the endoderm cells moved collectively in a swirling movement as a whole. Most of the AVE cells at E6.5 were not E5.5 DVE cells but were E5.5 cells that were located caudally behind them, as previously reported (Hoshino et al., 2015; Takaoka et al., 2011). In the rearrangement, the posterior embryonic visceral endoderm cells did not move, as extraembryonic visceral endoderm cells did not, and they constituted a distinct population during the process of anterior-posterior axis formation. The analysis using R26-PHA7-EGFP suggested that constriction of the apical surfaces of the cells in prospective anterior portion of the DVE initiated the global cellular movement of the embryonic visceral endoderm to drive AVE formation. PMID- 28712876 TI - Drosophila SCE/dRING E3-ligase inhibits apoptosis in a Dp53 dependent manner. AB - The Polycomb group (PcG) of proteins control developmental gene silencing and are highly conserved between flies and mammals. PcG proteins function by controlling post-translational modification of histones, such as ubiquitylation, which impacts chromatin compaction and thus gene transcription. Changes in PcG cellular levels have drastic effects on organismal development and are involved in the generation of human pathologies such as cancer. However, the mechanisms controlling their levels of expression and their physiological effects are only partially understood. In this work we describe the effects of modulating levels of SCE/dRING, a conserved E3 ubiquitin ligase and member of the PcG known to mono ubiquitylate histone H2A. We find that inactivation of Sce induces apoptosis, an effect that is decreased in the absence of Dp53 function. However, over expression of SCE produce no developmental effects but inhibits DP53-induced apoptosis. Thus, Sce functions as a Dp53-dependent apoptosis inhibitor. The SCE inhibition of DP53-induced apoptosis requires dRYBP, an ubiquitin binding protein and member of the PcG. Moreover, this inhibition of apoptosis involves the reduction of DP53 protein levels. Finally, high levels of SCE inhibit X-ray induced apoptosis as well as the apoptosis associated with tumor growth. We propose that SCE, together with dRYBP, inhibits apoptosis either by epigenetically regulating Dp53 transcription or by controlling the stabilization of DP53 protein levels thus promoting its ubiquitylation for proteaosomal degradation. This function may generate a homeostatic balance between apoptosis and proliferation during development that provides cell survival during the initiation and progression of disease processes. PMID- 28712877 TI - Bone mass, microarchitecture and strength are influenced by race/ethnicity in young adult men and women. AB - : Lower rates of fracture in both Blacks compared to Whites, and men compared to women are not completely explained by differences in bone mineral density (BMD). Prior evidence suggests that more favorable cortical bone microarchitecture may contribute to reduced fracture rates in older Black compared to White women, however it is not known whether these differences are established in young adulthood or develop during aging. Moreover, prior studies using high-resolution pQCT (HR-pQCT) have reported outcomes from a fixed-scan location, which may confound sex- and race/ethnicity-related differences in bone structure. PURPOSE: We determined differences in bone mass, microarchitecture and strength between young adult Black and White men and women. METHODS: We enrolled 185 young adult (24.2+/-3.4yrs) women (n=51 Black, n=50 White) and men (n=34 Black, n=50 White) in this cross-sectional study. We used dual-energy X-ray absorptiometry (DXA) to determine areal BMD (aBMD) at the femoral neck (FN), total hip (TH) and lumbar spine (LS), as well as HR-pQCT to assess bone microarchitecture and failure load by micro-finite element analysis (MUFEA) at the distal tibia (4% of tibial length). We used two-way ANOVA to compare bone outcomes, adjusted for age, height, weight and physical activity. RESULTS: The effect of race/ethnicity on bone outcomes did not differ by sex, and the effect of sex on bone outcomes did not differ by race/ethnicty. After adjusting for covariates, Blacks had significantly greater FN, TH and LS aBMD compared to Whites (p<0.05 for all). Blacks also had greater cortical area, vBMD, and thickness, and lower cortical porosity, with greater trabecular thickness and total vBMD compared to Whites. MUFEA-estimated FL was significantly higher among Blacks compared to Whites. Men had significantly greater total vBMD, trabecular thickness and cortical area and thickness, but greater cortical porosity than women, the net effects being a higher failure load in men than women. CONCLUSION: These findings demonstrate that more favorable bone microarchitecture in Blacks compared to Whites and in men compared to women is established by young adulthood. Advantageous bone strength among Blacks and men likely contributes to their lower risk of fractures throughout life compared to their White and women counterparts. PMID- 28712878 TI - Antidepressants are cytotoxic to rat primary blood brain barrier endothelial cells at high therapeutic concentrations. AB - Antidepressants are commonly employed for the treatment of major depressive disorders and other psychiatric conditions. We investigated the relatively acute cytotoxic effects of three commonly prescribed antidepressants: fluoxetine, sertraline, and clomipramine on rat primary blood brain barrier endothelial cells over a concentration range of 0.1-100MUM. At therapeutic concentrations (0.1MUM) no significant cytotoxicity was observed after 4, 24, or 48h. At high therapeutic to overdose concentrations (1-100MUM), antidepressants reduced cell viability in proportion to their concentration and exposure duration. At 1MUM, antidepressants significantly reduced mitochondrial membrane potential. At drug concentrations producing ~50% inhibition of cell viability, all drugs significantly reduced cellular oxygen consumption rates, activities of mitochondrial complexes I and III, and triggered a significant increase of lactate production. Fluoxetine (6.5MUM) and clomipramine (5.5MUM) also significantly lowered transcellular transport of albumin. The mechanism of cellular cytotoxicity was evaluated and at high concentrations all drugs significantly increased the production of reactive oxygen species, and significantly increased the activity of the pro-apoptotic caspases-3, 8, and 9. Comet assays revealed that all drugs were genotoxic. Pre incubation of cells with glutathione significantly ameliorated antidepressant induced cytotoxicity, indicating the potential benefit of treatment of overdosed patients with antioxidants. PMID- 28712879 TI - Comet assay on thawed embryos: An optimized technique to evaluate DNA damage in mouse embryos. AB - : Our objective was to optimize the CA technique on mammal embryos. MATERIALS AND METHODS: 1000 frozen 2-cell embryos from B6CBA mice were used. Based on a literature review, and after checking post-thaw embryo viability, the main outcome measures included: 1) comparison of the embryo recovery rate between 2 CA protocols (2 agarose layers and 3 agarose layers); 2) comparison of DNA damage by the CA on embryos with (ZP+) and without (ZP-) zona pellucida; and 3) comparison of DNA damage in embryos exposed to 2 genotoxic agents (H2O2 and simulated sunlight irradiation (SSI)). DNA damage was quantified by the % tail DNA. RESULTS: 1) The recovery rate was 3,3% (n=5/150) with the 2 agarose layers protocol and 71,3% (n=266/371) with the 3 agarose layers protocol. 2) DNA damage did not differ statistically significantly between ZP- and ZP+ embryos (12.60+/ 2.53% Tail DNA vs 11.04+/-1.50 (p=0.583) for the control group and 49.23+/-4.16 vs 41.13+/-4.31 (p=0.182) for the H2O2 group); 3) H2O2 and SSI induced a statistically significant increase in DNA damage compared with the control group (41.13+/-4.31% Tail DNA, 36.33+/-3.02 and 11.04+/-1.50 (p<0.0001)). The CA on mammal embryos was optimized by using thawed embryos, by avoiding ZP removal and by the adjunction of a third agarose layer. PMID- 28712880 TI - The role of oxidative stress in antipsychotics induced ovarian toxicity. AB - This study tested the hypothesis that oxidative stress could be an underlying mechanism for APs-induced ovarian cytotoxicity and reproductive dysfunction. Rat ovarian theca interstitial cells (TICs) were isolated and treated with four APs [chlorpromazine (CPZ), haloperidol (HAL), risperidone (RIS) and clozapine (CLZ)]. MTT assay was used to test the effects of these antipsychotics on TICs viability and to estimate their 50% inhibitory concentrations (IC50s). The effects of APs (IC50s and 1MUM concentrations) on the activities of caspases-3, -8 and -9, reactive oxygen species (ROS) production, total intracellular glutathione and lipid peroxidation (LPO) in TICs were assessed. The effect of antioxidants (reduced glutathione (GSH) and quercetin) on the APs-induced cytotoxicity on TICs was investigated. MTT assay showed all APs to reduce TICs viability. CPZ, HAL and CLZ significantly increased the activity of caspases-3, -8 and -9 (P<0.0001, <0.0001 and <0.01, respectively). All APs at IC50s significantly (P<0.0001) increased ROS production, decreased total intracellular glutathione and increased LPO. MTT assay in the presence of antioxidants (reduced GSH (5mM) or quercetin (50mM)) showed each antioxidant to significantly inhibit the effects of APs at their IC50s on TICs viability. In conclusion, oxidative stress seems to be a possible mechanism for APs-induced ovarian and reproductive toxicity. PMID- 28712881 TI - A systematic review of the influence of burying or not burying Kirschner wires on infection rates following fixation of upper extremity fractures. PMID- 28712882 TI - Perfusion of muscle flaps independent of the anatomical vascular pedicle: Pedicle autonomy. AB - INTRODUCTION: Free muscle flaps are being used more commonly for complex lower limb reconstruction. Up to 33% of flaps used to reconstruct lower limb trauma will require an orthopaedic procedure after reconstruction. To date there have been only case reports detailing the variable survival of muscle flaps after actual or simulated pedicle injury and the process and timeframe of neovascularisation remains undefined. We aim to show that perfusion of a muscle flap is possible after injury to its anatomical vascular pedicle. METHODS: Pedicled muscle flaps were raised and transposed to a cutaneous inset on the chest wall in a rodent model. Each flap was subjected to simulated pedicle injury at a variable time. Allocation was by computer randomisation. Flap perfusion was assessed before and after pedicle injury followed 48 h later by sacrifice of the animal and static angiography of the flaps. RESULTS: By the 21st day after inset, all flaps survived simulated pedicle injury. Prior to this, flap survival was significantly lower (p = 0.017, Fisher's Exact Test). Clinical signs at the time of pedicle injury did not predict flap survival. Most new vessels form at the distal part of the inset (p < 0.01, ANOVA). The total number does not change with time (p = 0.82, ANOVA). New vessels anastomose preferentially with skin. The fall in perfusion after pedicle ligation was significant for all groups except the day 35 group (p = 0.53). CONCLUSIONS: Muscle flaps can perfuse after an injury to the anatomical vascular pedicle through neovascularisation at the inset. These new vessels are evident early but may not function adequately to perfuse the flap. Regional variations in neovascularisation suggest that a gradient of ischaemia drives this process. Inset at the cutaneous level is important, which has implications for buried muscle flaps. The correlation between change in flap perfusion after pedicle injury and flap necrosis suggests a role for the former in determining the capacity of a muscle flap to tolerate a pedicle injury and thereby the approach to re-raising it. PMID- 28712883 TI - Comparing oncoplastic breast conserving surgery with mastectomy and immediate breast reconstruction: Case-matched patient reported outcomes. AB - BACKGROUND: Oncoplastic breast conserving surgery (OBCS) allows women who may otherwise have mastectomy and immediate reconstruction (MxIR) the choice to conserve their breast yet avoid deformity. We compared the outcome of these options. METHODS: Two cohorts meeting study criteria were identified from prospectively audited series of women undergoing OBCS or MxIR. After case matching for age, tumour size and date of surgery, stratification by breast size and controlling for radiotherapy; body image scale (BIS) scores of psychosocial function and patient reported outcome measures (PROMs) for breast appearance and return to function were analysed. RESULTS: A total of 567 women (286 treated by OBCS and 281 by MxIR) fulfilled inclusion criteria. Demographics were similar between the two unmatched cohorts, except for radiotherapy, age and tumour size (all p < 0.001). Overall, BIS score (p = 0.002), self-rated breast appearance, return to work and function (all p < 0.001) significantly favoured OBCS. Case matched women with larger breasts treated by OBCS reported better BIS scores (mean 3.30 vs. 5.37, p = 0.011) and self-rated breast appearance score (p < 0.001) than MxIR, whereas no significant difference was observed for smaller breasts. BIS and appearance favoured OBCS, regardless of whether radiotherapy would have been avoided if treated by MxIR. CONCLUSION: OBCS offers suitable women the option to avoid MxIR while providing faster recovery. Better psychosocial and self-rated satisfaction with breast appearance is achieved for OBCS in all groups, regardless of the need for radiotherapy, apart from those women with smaller breasts for whom the results are comparable. PMID- 28712884 TI - The supraorbital region revisited: An anatomic exploration of the neuro-vascular bundle with regard to frontal migraine headache. AB - BACKGROUND: Recent findings on the pathogenesis of frontal migraine headache support, besides a central vasogenic cause, an alternative peripheral mechanism involving compressed craniofacial nerves. This is further supported by the efficiency of botulinum toxin injections as a new treatment option in frontal migraine headache patients. METHODS: The supraorbital regions of 22 alcohol glycerine-embalmed facial halves of both sexes were dissected. Both the supratrochlear and supraorbital nerves (STN and SON, respectively) were identified, and their relationship with the corrugator supercilii muscle (CSM) was investigated by dissection and ultrasound. The course of both nerves was defined, and the interaction between the supraorbital artery (SOA) and SON was determined. RESULTS: We discovered a new possible compression point of the STN passing through the orbital septum and verified previously described compression points of both STN and SON. Osteofibrous channels used by the STN and SON were found constantly. We described the varying topography of the STN and CSM, the SON and CSM, and the SON and SOA. Further, we provide an algorithm for the ultrasound visualization of the supraorbital neurovascular bundle. CONCLUSION: Our data support the hypothesis of a peripheral mechanism for frontal migraine headache because of following potential irritation points: first, the CSM is constantly perforated by the SON and frequently by the STN; second, the topographic proximity between SOA and SON and the osteofibrous channels is used by the SON and STN; and third, the STN passes through the orbital septum. PMID- 28712885 TI - Detection of CFTR function and modulation in primary human nasal cell spheroids. AB - BACKGROUND: Expansion of CFTR modulators to patients with rare/undescribed mutations will be facilitated by patient-derived models quantifying CFTR function and restoration. We aimed to generate a personalized model system of CFTR function and modulation using non-surgically obtained nasal epithelial cells (NECs). METHODS: NECs obtained by curettage from healthy volunteers and CF patients were expanded and grown in 3-dimensional culture as spheroids, characterized, and stimulated with cAMP-inducing agents to activate CFTR. Spheroid swelling was quantified as a proxy for CFTR function. RESULTS: NEC spheroids recapitulated characteristics of pseudostratified respiratory epithelia. When stimulated with forskolin/IBMX, spheroids swelled in the presence of functional CFTR, and shrank in its absence. Spheroid swelling quantified mutant CFTR restoration in F508del homozygous cells using clinically available CFTR modulators. CONCLUSIONS: NEC spheroids hold promise for understanding rare CFTR mutations and personalized modulator testing to drive evaluation for CF patients with common, rare or undescribed mutations. Portions of this data have previously been presented in abstract form at the 2016 meetings of the American Thoracic Society and the 2016 North American Cystic Fibrosis Conference. PMID- 28712886 TI - Impacts of Abstinence Time on Semen Parameters in a Large Population-based Cohort of Subfertile Men. AB - OBJECTIVE: To assess the effects of abstinence time on semen parameters in normozoospermic and oligozoospermic men using a large cohort of subfertile men. MATERIALS AND METHODS: From 2002 to 2013, we retrospectively reviewed data from 15,623 patients seen at our fertility clinic. Data on patient age and semen parameters were extracted along with abstinence time. Abstinence time was categorized into 4 groups (<=2 days; >2 and <=5 days; >5 and <=7 days; and >7 days). Semen samples were further categorized as normozoospermic or oligozoospermic based on concentration. Age-adjusted linear mixed effect regression models were used to test the effect of abstinence categories on semen parameters. RESULTS: Data from 11,782 encounters (10,095 patients) were used for the final analysis after excluding patients <18 years old, azoospermic samples, and those missing all semen parameters. Mean age was 32.4 (standard deviation: 6.5) and median abstinence time was 4.0 days. There were 9840 normozoospermic and 1939 oligozoospermic samples. In normozoospermic men, longer abstinence was associated with increases in ejaculate volume, concentration, total sperm count, and total motile sperm count. However, in oligozoospermic men, longer abstinence time was not associated with improvements in semen parameters except ejaculate volume. CONCLUSION: The effects of abstinence are different on semen parameters in normozoospermic and oligozoospermic patients. Longer abstinence does not improve most semen parameters in oligozoospermic samples. The World Health Organization recommendations for 2-7 days of abstinence may not be beneficial for subfertile patients when timing is a factor. PMID- 28712887 TI - Prostatic Ductal Adenocarcinoma-A Rare Entity With Radiological Dilemma Demanding Endoscopic Biopsy. AB - This is a rare case of a prostatic ductal adenocarcinoma. A 75-year-old gentleman presented with complaints of lower urinary tract symptoms, constipation, and occasional hematuria. The clinical and radiological differentiations from other retroperitoneal soft cystic lesion were difficult, and fine needle aspiration cytology from the papillary solid components of the cyst was required to reach diagnosis. Transrectal ultrasound-guided biopsy was performed in view of the raised serum prostate-specific antigen (>100 ng/mL); however, the cyst was ruptured without yielding any tissue for biopsy. In such difficult situations, a cystourethroscopic view, biopsy of the cyst, and immunohistochemical analysis can help in diagnosing and confirming the prostatic ductal adenocarcinoma. PMID- 28712888 TI - Is Concealed Epispadias a Rare Variant? AB - OBJECTIVE: To present our experience with concealed epispadias and to estimate its actual share in the isolated male epispadias cases and its effect on the surgical outcome. MATERIALS AND METHODS: Consecutive patients with isolated male epispadias treated in our center between 2008 and 2015 were classified into concealed and classic epispadias. The 2 groups were compared regarding age at presentation, meatal location, incontinence, dorsal curvature, success rate, and complications. RESULTS: Out of 51 patients with isolated male epispadias, 11 (21.6%) were concealed: 7 balanic and 4 penile shaft epispadias. Concealed epispadias cases were found to have significantly delayed age at presentation, more distal meatal location, and less incontinence rate than classic epispadias cases. None of the surgical outcome parameters showed significant difference between the 2 groups. CONCLUSION: Concealed epispadias represents about one-fifth of isolated male epispadias cases. Impediment and delay of diagnosis are its main clinical impacts, with insignificant effect on the surgical outcome. PMID- 28712889 TI - The Adjustable Transobturator Male System in Stress Urinary Incontinence After Transurethral Resection of the Prostate. AB - OBJECTIVE: To investigate the efficacy and safety of the Adjustable Transobturator Male System (ATOMS) in men with stress urinary incontinence after transurethral resection of the prostate (TURP). MATERIALS AND METHODS: From a large international prospectively administrated ATOMS register, we identified 49 patients with an ATOMS device as a result of persistent stress urinary incontinence after TURP. For evaluation, the men were divided into standard transurethral resection of the prostate (sTURP) and palliative transurethral resection of the prostate (pTURP) in radiated patients. Baseline and follow-up measurements included continence parameters, urodynamics, quality-of-life surveys (Patient Global Impression-Improvement and International Consultation on Incontinence Questionnaire-Short Form), and pain ratings. The dry rate (0-1 security pad/<10 mL urine loss), the success rate (overall improvement), removals, complications, and treatment failures were recorded. A P value of <.05 was considered statistically significant. RESULTS: After a median of 34 and 22 months' follow-up and 2-3 adjustments, the sTURP and pTURP cohorts had 58% and 50% dry rates and 90% and 87% success rates. Hence, no improvement was seen in 10% and 13%. The removal rate was higher in pTURP (50% vs 10%, P = .0171) and infection was the most common side effect (50%) observed. Neither intraoperative nor Clavien-Dindo 4 and 5 adverse events were recorded. In sTURP and pTURP, the median daily pad count and the pad test improved significantly (all P <.001), and quality-of-life parameters shifted to a high satisfaction level (P <.001 and P = .001). Urodynamics remained unchanged and postoperative pain was not an issue. CONCLUSION: The ATOMS device shows promising treatment outcomes in patients after TURP and a similar efficacy as in postprostatectomy incontinence. There is no difference in continence outcome between sTURP and pTURP; however, a higher removal rate was found after pTURP, which may be important for patient counseling. PMID- 28712890 TI - Amburana cearensis seed extract protects brain mitochondria from oxidative stress and cerebellar cells from excitotoxicity induced by glutamate. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Amburana cearensis (Allemao) A.C.Sm. is a medicinal plant of the Brazilian Caatinga reported to present antioxidant and anti-inflammatory activity. This study aimed to evaluate the neuroprotective effect of the extracts obtained from the seeds of A. cearensis in primary cultures of cerebellar cells subjected to excitotoxicity induced by glutamate and brain mitochondria submitted to oxidative stress. MATERIALS: and methods: Primary cultures of cerebellar cells were treated with the ethanol (ETAC), hexane (EHAC), dichloromethane (EDAC) and ethyl acetate (EAAC) extracts of the seeds of A.cearensis and subjected to excitotoxicity induced by glutamate (10uM). Mitochondria isolated from rat brains were submitted to oxidative stress and treated with ETAC. RESULTS: Only the EHAC extract reduced cell viability by 30% after 72h of treatment. Morphological analyses by Immunofluorescence showed positive staining for glutamine synthetase, beta-III tubulin, GFAP and IBA1 similar to control cultures, indicating a better preservation of astrocytes, neurons and microglia, after excitotoxic damage induced by glutamate in cerebellar cultures treated with the extracts. The ETAC extract also protected mitochondria isolated from rat brains from oxidative stress, reducing the swelling, dissipation of the membrane potential, ROS production and calcium influx. CONCLUSION: Thus, this study suggests that the seed extracts from A. Cearensis exhibit neuroprotective potential against oxidative stress and excitotoxicity induced by glutamate and can be considered a potential therapeutic agent in the treatment of neurodegenerative diseases. PMID- 28712891 TI - Corneo-scleral contact lenses in an uncommon case of keratoconus with high hyperopia and astigmatism. AB - PURPOSE: To analyse the visual quality achieved by fitting corneo-scleral contact lenses (CScL) in an uncommon case of bilateral keratoconus, high hyperopia and astigmatism. METHODS: A 45-year-old man presented for eye examination due to the unsatisfactory quality of his vision wearing soft toric contact lenses. He presented high hyperopia and astigmatism with bilateral keratoconus. He was fitted with CScL to correct his irregular astigmatism and ocular aberrations. A diagnostic trial set was used in the fitting process and he was assessed according to standardised fitting methodology. Visual acuity, corneal topography, biometry and ocular aberrations were evaluated. The follow-up period was 1year. RESULTS: The best spectacle-corrected visual acuity was 20/32 with +8.00/-4.50*30 degrees for the right eye (RE) and 20/25 with +7.75/-2.25*120 degrees for the left eye (LE). After CScL fitting, visual acuity was improved to 20/20 and 20/16 for the RE and LE, respectively. The patient wore these contact lenses an average of 13h a day. The total high order aberrations decreased by approximately 79% in the RE (2.37-0.50MUm) and 47% in the LE (1.04-0.55MUm) after CScL fitting. Visual quality and wearing time were maintained after 1year wearing CScL. In addition, no adverse ocular effects were found during this period. CONCLUSION: The present case report describes how the patient had CScL fitted successfully for management of keratoconus with high hyperopia and astigmatism. They provided optimal visual quality, along with prolonged use times and no adverse effects to the cornea. PMID- 28712892 TI - Discontinuation of long term orthokeratology lens wear and subsequent refractive surgery outcome. AB - PURPOSE: To report a case of lens discontinuation in a long term orthokeratology (OK) lens wearer and describe regression in refraction, corneal topography, and corneal thickness over 408days after lens discontinuation. Furthermore, the outcome of subsequent LASIK treatment is also reported. CASE REPORT: A 41year old Caucasian female who had been previously wearing OK lenses for 13 years discontinued lens wear in the left eye to consider refractive surgery in that eye. The greatest changes in subjective and objective refractions, corneal topography and thickness occurred during the first 28days after lens discontinuation. Subjective refraction did not reach baseline values, but corneal topography parameters returned to pre-OK values after 408days of no lens wear. The patient then received successful refractive surgery treatment in that eye, achieving uncorrected visual acuity of 0.00 LogMAR units, and residual refractive error within +/-0.50D of emmetropia. CONCLUSION: The period of lens discontinuation required for long term OK lens wearers before refractive surgery is likely to vary between individuals and the patient described in this case report required a significant period of lens discontinuation of at least one year before being considered suitable for refractive surgery. PMID- 28712893 TI - The glucagon-like peptide-1 analogue liraglutide promotes autophagy through the modulation of 5'-AMP-activated protein kinase in INS-1 beta-cells under high glucose conditions. AB - Glucagon-like peptide-1 (GLP-1) is a potent therapeutic agent for the treatment of diabetes and has been proven to protect pancreatic beta-cells from glucotoxicity; however, its mechanisms of action are not entirely understood. Autophagy is a dynamic lysosomal degradation process that can protect organisms against metabolic stress. Studies have shown that autophagy plays a protective role in the survival of pancreatic beta-cells under high glucose conditions. In the present study, we explored the role of autophagy in GLP-1-induced protection of pancreatic beta-cells exposed to high glucose. We demonstrated that the GLP-1 analogue liraglutide increased autophagy in rat INS-1 beta-cells, and inhibition of autophagy abated the anti-apoptosis effect of liraglutide under high glucose conditions. Our results also showed that activation of 5'-AMP-activated protein kinase (AMPK) reduced liraglutide-induced autophagy enhancement and inhibited liraglutide-induced protection of INS-1 beta-cells from high glucose. These data suggest that GLP-1 may protect beta-cells from glucotoxicity through promoting autophagy by the modulation of AMPK. Deeper insight into the molecular mechanisms linking autophagy and GLP-1-induced beta-cell protection may reveal novel therapeutic targets to preserve beta-cell mass. PMID- 28712895 TI - Parent and Child Balloon Technique for Navigating Guide Catheters During Neurointerventions. AB - BACKGROUND: The stabilization of a guide catheter is an important factor for performing successful neurointerventional procedures. We present our technique for navigating guide catheters using parent and child balloons. METHODS: In 9 patients with severe atherosclerosis or anatomic variations such as a bovine arch, 8-9-F balloon-mounted guide catheters were navigated using balloon-attached guidewires. Both balloons were used complementarily for flow navigation and vessel fixation at the appropriate positions and times. RESULTS: In all cases, the balloon guide catheter could be inserted up to the required positions, and the procedures were completed without any complications. CONCLUSIONS: The parent and child balloon technique is useful for inserting guide catheters in hostile vascular anatomies. PMID- 28712894 TI - Antimicrobial and immunomodulatory activity of host defense peptides, clavanins and LL-37, in vitro: An endodontic perspective. AB - Endodontic treatment is mainly based on root canal disinfection and its failure may be motivated by microbial resistance. Endodontic therapy can be benefitted by host defense peptides (HDPs), which are multifunctional molecules that act against persistent infection and inflammation. This study aimed to evaluate the antimicrobial, cytotoxic and immunomodulatory activity of several HDPs, namely clavanin A, clavanin A modified (MO) and LL-37, compared to intracanal medication Ca(OH)2. HDPs and Ca(OH)2 were evaluated by: (1) antimicrobial assays against Candida albicans and Enterococcus faecalis, (2) cytotoxicity assays and (3) cytokine tumor necrosis factor (TNF)-alpha, monocyte chemoattractant protein (MCP)-1, interleukin (IL)-1alpha, IL-6, IL-10 and IL-12 and nitric oxide (NO) production by RAW 264.7 cells incubated with or without heat-killed (HK) C. albicans or E. faecalis combined or not with interferon-gamma. The minimum inhibitory concentration (MIC) was established only for E. faecalis (LL-37, 57MUM). Considering cytotoxicity, clavanin MO was able to reduce cell viability in many groups and demonstrated lowest LC50. The Ca(OH)2 up-regulated the production of MCP-1, TNF-alpha, IL-12 and IL-6 and down-regulated IL-1alpha, IL 10 and NO. Clavanins up-regulated the TNF-alpha and NO and down-regulated IL-10 production. LL-37 demonstrated up-regulation of IL-6 and TNF-alpha production and down-regulation in IL-10 and NO production. In conclusion, LL-37 demonstrated better antibacterial potential. In addition, Ca(OH)2 demonstrated a proinflammatory response, while the HDPs modulated the inflammatory response from non-interference with the active cytokines in the osteoclastogenesis process, probably promoting the health of periradicular tissues. PMID- 28712896 TI - Prospective Evaluation of Noninvasive HeadSense Intracranial Pressure Monitor in Traumatic Brain Injury Patients Undergoing Invasive Intracranial Pressure Monitoring. AB - BACKGROUND: Currently, intracranial pressure (ICP) is measured by invasive methods with a significant risk of infectious and hemorrhagic complications. Because of these high risks, there is a need for a noninvasive ICP (nICP) monitor with an accuracy similar to that of an invasive ICP (iICP) monitor. OBJECTIVE: We sought to assess prospectively the accuracy and precision of an nICP monitor compared with iICP measurement in severe traumatic brain injury (TBI) patients. METHODS: Participants were ICP-monitored patients who had sustained TBI. In parallel with the standard invasive ICP measurements, nICP was measured by the HeadSense HS-1000, which is based on sound propagation. The device generated an acoustic signal using a small transmitter, placed in the patient's ear, and picked up by an acoustic sensor placed in the other ear. The signal is then analyzed using proprietary algorithms, and the ICP value is calculated in millimeter of mercury (mm Hg). RESULTS: Analysis of 2911 paired iICP and nICP measurements from 14 severe TBI patients showed a good accuracy of the nICP monitor indicated by a mean difference of 0.5 mm Hg. The precision was also good with a standard deviation of 3.9 mm Hg. The Pearson r correlation was 0.604 (P < 0.001). CONCLUSIONS: The HeadSense HS-1000 nICP monitor seems sufficiently accurate to measure the ICP in severe TBI patients, is patient friendly, and has minimal risk of complications. PMID- 28712897 TI - Safety and Efficacy of a 600-mg Loading Dose of Clopidogrel 24 Hours Before Pipeline Embolization Device Treatment. AB - BACKGROUND: Clopidogrel/aspirin antiplatelet therapy routinely is administered 7 10 days before pipeline aneurysm treatment. Our study assessed the safety and efficacy of a 600-mg loading dose of clopidogrel 24 hours before Pipeline Embolization Device (PED) treatment. METHODS: We performed a retrospective cohort study involving patients treated with pipeline from October 2010 to May 2016. A total of 39.7% (n = 158) of patients were dispensed a loading dose of 650 mg of aspirin plus at least 600 mg of clopidogrel 24 hours preceding PED deployment; 60.3% (n = 240) received 81-325 mg of aspirin daily for 10 days with 75 mg of clopidogrel daily preprocedurally. The mean follow-up was 15.8 months (standard deviation [SD] 12.4 months). modified Rankin Scale (mRS) was registered before the discharge and at each follow-up visit. To control confounding, we used multivariable logistic regression and propensity score conditioning. RESULTS: Of 398 patients, the proportion of female patients was ~16.5% (41/240) in both groups and shared the same mean of age ~56.46 years. Similarly, ~12.2% (mean = 0.09; SD = 0.30) had a subarachnoid hemorrhage. A total of 92% (mean = 0.29; SD = 0.70) from the pretreatment group and 85.7% (mean = 0.44; SD = 0.91) of the bolus group had a mRS <=2. In a multivariate analysis, bolus did not affect the mRS score, P = 0.24. Seven patients had a long-term recurrence, 2 (0.83%; mean = 0.01; SD = 0.10) from the pretreatment group. In a multivariable logistic regression, bolus was not associated with a long-term recurrence rate (odds ratio [OR] 1.91; 95% confidence interval [CI] 0.27-13.50; P = 0.52) neither with thromboembolic accidents (OR 0.99; 95% CI 0.96-1.03; P = 0.83) nor with hemorrhagic events (OR 1.00; 95% CI 0.97-1.03; P = 0.99). Three patients died: 1 who received a bolus had an acute subarachnoid hemorrhage. The mean mortality rate was parallel in both groups ~0.25 (SD = 0.16). Bolus was not associated with mortality (OR 1.11; 95% CI 0.26-4.65; P = 0.89). The same associations were present in propensity score-adjusted models. CONCLUSIONS: In a cohort receiving PED, a 600-mg loading dose of clopidogrel should be safe and efficacious in those off the standard protocol or showing <30% platelet inhibition before treatment. PMID- 28712899 TI - Iatrogenic Ascending Pharyngeal Artery Injury by Predilation Balloon Inflation During Carotid Artery Stenting with Flow Reversal. AB - BACKGROUND: The ascending pharyngeal artery (APA) may rarely arise from the common carotid artery bifurcation. We report an injury to the APA as an unusual complication of predilation balloon inflation during carotid artery stenting (CAS) with flow reversal. CASE DESCRIPTION: A 73-year-old man presented with symptomatic severe left cervical internal carotid artery stenosis. The left APA arose from the common carotid artery bifurcation. We performed CAS with flow reversal to decrease the risk of distal embolization. When we attempted to catheterize the internal carotid artery under roadmap guidance for predilation, we did not notice that the balloon catheters had advanced into the APA owing to the absence of an anterograde angiogram, and the APA was injured when the balloon catheters were inflated. CONCLUSIONS: Our case emphasizes the importance of performing a detailed anatomic assessment before CAS and ensuring adequate angiographic visualization during the procedure under flow reversal when the origin of the APA is in the vicinity of the origin of the internal carotid artery. PMID- 28712898 TI - Iatrogenic Vertebral Artery Injury During Anterior Cervical Spine Surgery: A Systematic Review. AB - BACKGROUND: Iatrogenic vertebral artery injury (VAI) during anterior cervical surgery is rare but potentially catastrophic. METHODS: Causes, presentation, diagnosis, management, prognosis, and prevention of VAI were reviewed following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. English language studies and case reports published from 1980 to 2017 were retrieved. Data on diagnosis, surgical procedures and approach, site and cause of VAI, management, outcomes, and vertebral artery (VA) status were extracted. RESULTS: In 25 articles including 54 patients, VAI was diagnosed during or after surgery commonly indicated for cervical degenerative diseases (64%), tumors (14%), and trauma (9%). The incidence of VAI for each side was similar regardless of approach. Common presentations were unexpected copious surgical bleeding, delayed hemorrhage of pseudoaneurysm with neck swelling, dyspnea, hypotension, and cervical bruits caused by arteriovenous fistula. Causes included drilling (61%), instrumentation (16%), and soft tissue retraction (8%). Direct exposure or angiography confirmed VAI. Ten patients had VA anomalies; collateral status was verified in 9 before definitive treatment. Tamponade was adopted for urgent hemostasis in most cases but with a high incidence of pseudoaneurysm (48%). Unknown VA status increased occlusion risk and neurologic sequelae (41%). VA repair and stent placement had excellent outcomes. CONCLUSIONS: Extensive lateral decompression, loss of landmarks, and anatomic variations or pathologic status of VA increased VAI risk. Evaluation of collateral vessels before definitive treatment helped determine appropriate management and avoid neurologic sequelae. Tamponade was not recommended as definitive treatment. Meticulous preoperative evaluation, cautious intraoperative manipulation, and real-time radiographic guidance reduced VAI risk. PMID- 28712900 TI - Surgical Treatment of Thoracolumbar Segmental Spinal Dysgenesis: Optimal Type of Fusion. AB - OBJECTIVES: We sought to evaluate long-term results of surgical treatment of thoracolumbar segmental spinal dysgenesis (SSD). METHODS: We analyzed 8 patients with thoracolumbar SSD treated in our institution. Each case was evaluated for specific clinical and radiologic criteria and types and outcomes of treatment. RESULT: The average age of primary surgery was 3.4 years (median 3.4 years, range 1.7-7 years). The average correction of kyphosis was 49.3 degrees (mean 45 degrees , from 25 degrees -75 degrees ) and scoliosis 10.6 degrees (mean 10 degrees , from 0 degrees -25 degrees ). Average follow-up time was 3.2 years (mean 2.6 years, from 1.8-5.6 years). Neurologic improvement was also achieved in all patients. The Japanese Orthopaedic Association scale score (Benzel's modification) was increased by 2.5 points on average (mean 2.5 points, from 2-5 points). One patient had complications: pseudarthrosis and rod fracture followed by refusion. CONCLUSIONS: Our treatment strategy provides favorable deformity correction and neurologic improvement. It is limited by immature vertebral structures in newborns and infants, who should be carefully monitored from birth with braces until they reach the age when a fixing tool can be used. PMID- 28712901 TI - Henry II of France (1519-1559) and His Death From Meningoencephalitis Following Cranial Trauma. AB - This historical review summarizes the most significant theories regarding the cause of death of King Henry II of France (1519-1559) and the circumstances under which it occurred. Although the historical testimonies are inconclusive and vague, postmortem analysis has shown that the King died of meningoencephalitis, caused by hematoma of a cerebral contusion, with effusion in the cerebral laminae and its surrounding tissue initiated by a periorbital fracture. PMID- 28712902 TI - Design-Based Comparison of Spine Surgery Simulators: Optimizing Educational Features of Surgical Simulators. AB - BACKGROUND: Simulation-based education has made its entry into surgical residency training, particularly as an adjunct to hands-on clinical experience. However, one of the ongoing challenges to wide adoption is the capacity of simulators to incorporate educational features required for effective learning. The aim of this study was to identify strengths and limitations of spine simulators to characterize design elements that are essential in enhancing resident education. METHODS: We performed a mixed qualitative and quantitative cohort study with a focused survey and interviews of stakeholders in spine surgery pertaining to their experiences on 3 spine simulators. Ten participants were recruited spanning all levels of training and expertise until qualitative analysis reached saturation of themes. Participants were asked to perform lumbar pedicle screw insertion on 3 simulators. Afterward, a 10-item survey was administrated and a focused interview was conducted to explore topics pertaining to the design features of the simulators. RESULTS: Overall impressions of the simulators were positive with regards to their educational benefit, but our qualitative analysis revealed differing strengths and limitations. Main design strengths of the computer-based simulators were incorporation of procedural guidance and provision of performance feedback. The synthetic model excelled in achieving more realistic haptic feedback and incorporating use of actual surgical tools. DISCUSSION: Stakeholders from trainees to experts acknowledge the growing role of simulation based education in spine surgery. However, different simulation modalities have varying design elements that augment learning in distinct ways. Characterization of these design characteristics will allow for standardization of simulation curricula in spinal surgery, optimizing educational benefit. PMID- 28712903 TI - Multimodality Treatment of Posterior Inferior Cerebellar Artery Aneurysms. AB - OBJECTIVE: Posterior inferior cerebellar artery (PICA) aneurysms are heterogeneous, uncommon lesions that can be treated in many fashions. Many previous series have focused on a specific aneurysm subset or treatment paradigm. The aim of this study was to present a comprehensive approach for all PICA aneurysms and analyze outcomes by PICA location. METHODS: All PICA aneurysms treated from 2012 until present were reviewed retrospectively and classified by location. Angiographic and clinical outcome were assessed. RESULTS: We identified 30 patients (average age 56 years, female 76.7%, subarachnoid hemorrhage 83.3%) with 30 aneurysms (saccular 50.0%) who underwent 36 treatments. Locations included the vertebral artery-PICA junction: 8; anterior medullary (AM): 7; lateral medullary: 3; tonsillomedullary: 1; telovelotonsillar: 5; and cortical: 6. Treatments included clipping: 6; trapping: 2; coiling: 13; balloon-assisted coiling: 1; stent-assisted coiling: 1; flow diversion: 1; and endovascular parent vessel occlusion: 6. There were 3 procedural complications. Recurrence and retreatment rates were 23.3% and 20.0%, respectively. Retreatments included coiling: 1; clipping: 4; and bypass: 1. Seven patients had an associated cerebellar arteriovenous malformation, of whom 5 have undergone resection. Good clinical outcome was achieved in 43.3% at discharge and 84.6% at follow-up (average 10.7 months). Aneurysms distal to the AM segment were more likely to occur in older patients (P = 0.007), with cerebellar arteriovenous malformations (P = 0.031), and to be treated with parent vessel occlusion (P = 0.001). Recurrences were more common for AM segment aneurysms (P = 0.016). Poor outcome was associated with poor SAH grade (P = 0.010), not aneurysm morphology (P = 0.356), location (P = 0.867), or treatment type (P = 0.365). CONCLUSIONS: Our 5 year modern experience highlights the diversity of PICA aneurysms and the need for multimodality paradigms to treat them successfully. The AM segment has the greatest rate of recurrence. Aggressive management is warranted given that the majority of patients can have a good neurologic outcome. PMID- 28712905 TI - Endoscopic Endonasal Transsphenoidal Approach for the Removal of Optochiasmatic Cavernoma: Case Report and Literature Review. AB - BACKGROUND: Cavernoma of the optic chiasm is a rare disease, and the most common clinical presentation is chiasmal apoplexy. Almost all the cases reported in the literature were treated surgically with craniotomy. CASE DESCRIPTION: We report a case of optochiasmatic cavernoma successfully resected via an endoscopic endonasal transsphenoidal approach (EETA). CONCLUSIONS: Rapid diagnosis and complete resection of a symptomatic optochiasmatic cavernoma are helpful in improving visual dysfunction. EETA is an alternative, minimally invasive technique for resecting this type of lesion. PMID- 28712904 TI - Pitfalls in Diagnosis and Management of Testicular Choriocarcinoma Metastatic to the Brain: Report of 2 Cases and Review of Literature. AB - INTRODUCTION: Pure choriocarcinoma of the testes is a rare, aggressive germ cell tumor that can metastasize to the brain. Although its prognosis has improved with the development of cisplatin-based chemotherapy regimens, cerebral metastases are prone to hemorrhage and associated with high morbidity. Here, we present 2 cases of testicular choriocarcinoma with cerebral metastasis and discuss potential pitfalls in their diagnosis and management. We also review cases in the literature that feature these rare lesions. METHODS: Medline was searched for all publications including the terms "testicular choriocarcinoma" and "cerebral metastasis" or "brain metastasis." Articles that included patients with tumors classified as a mix of choriocarcinoma and other germ cell tumor subtypes were excluded. RESULTS: A total of 15 cases from the literature and our own 2 cases were included in the analysis. The mean age at presentation was 25.5 years. Neurologic symptoms accounted for the initial presentation of 9 patients (60%). Outcomes were predominantly poor, with 10 patients (67%) expiring shortly after their initial diagnosis. Three of these deaths were related to mass effect from metastasis-related hemorrhages. Two patients underwent emergent decompressive craniectomies, and both died from cerebral herniation. CONCLUSION: The potentially catastrophic nature of choriocarcinoma-related cerebral hemorrhages underscores the need for prompt, accurate diagnosis and aggressive surgical management of these lesions. Their highly vascular nature and lack of findings on cerebral angiography may cause them to be confused with occult vascular malformations. PMID- 28712906 TI - A Comparison of Pharmacologic Therapeutic Agents Used for the Reduction of Intracranial Pressure After Traumatic Brain Injury. AB - OBJECTIVE: In neurotrauma care, a better understanding of treatments after traumatic brain injury (TBI) has led to a significant decrease in morbidity and mortality in this population. TBI represents a significant medical problem, and complications after TBI are associated with the initial injury and postevent intracranial processes such as increased intracranial pressure and brain edema. Consequently, appropriate therapeutic interventions are required to reduce brain tissue damage and improve cerebral perfusion. We present a contemporary review of literature on the use of pharmacologic therapies to reduce intracranial pressure after TBI and a comparison of their efficacy. METHODS: This review was conducted by PubMed query. Only studies discussing pharmacologic management of patients after TBI were included. This review includes prospective and retrospective studies and includes randomized controlled trials as well as cohort, case control, observational, and database studies. Systematic literature reviews, meta analyses, and studies that considered conditions other than TBI or pediatric populations were not included. RESULTS: Review of the literature describing the current pharmacologic treatment for intracranial hypertension after TBI most often discussed the use of hyperosmolar agents such as hypertonic saline and mannitol, sedatives such as fentanyl and propofol, benzodiazepines, and barbiturates. Hypertonic saline is associated with faster resolution of intracranial hypertension and restoration of optimal cerebral hemodynamics, although these advantages did not translate into long-term benefits in morbidity or mortality. In patients refractory to treatment with hyperosmolar therapy, induction of a barbiturate coma can reduce intracranial pressure, although requires close monitoring to prevent adverse events. CONCLUSIONS: Current research suggests that the use of hypertonic saline after TBI is the best option for immediate decrease in intracranial pressure. A better understanding of the efficacy of each treatment option can help to direct treatment algorithms during the critical early hours of trauma care and continue to improve morbidity and mortality after TBI. PMID- 28712907 TI - Skeletal Muscle as a Factor Contributing to Better Stratification of Older Patients with Traumatic Brain Injury: A Retrospective Cohort Study. AB - BACKGROUND: Traumatic brain injury (TBI) in older patients is becoming an increasing problem, and methods that help predict outcomes in this population are needed. The objective of this study was to evaluate skeletal muscle mass as a predictive marker for TBI outcome in older patients. METHODS: Older patients (age >=60 years) with TBI were included in this study. Clinical outcomes were assessed using the Glasgow Outcome Scale (GOS) at 6 months postinjury. Patients were classified according to their GOS score as having a good outcome (GOS 3-5) or a poor outcome (GOS 1 OR 2). Skeletal muscle mass was estimated, and the relationship with outcome was analyzed. A multivariable logistic regression model was used to quantify the independent effects of sarcopenia on the risk of poor outcome. RESULTS: Seventy-four patients (median age, 74 years; 53 males) were included. Outcomes at 6 months postinjury were good in 38 patients and poor in 36 patients. The skeletal muscle area was significantly larger in the good outcome group compared with the poor outcome group (57.3 cm2 vs. 47.6 cm2; P < 0.001). The rate of poor outcome was significantly higher in the patients with sarcopenia compared with those without sarcopenia (0.70 vs. 0.24; relative risk, 2.98; 95% confidence interval [CI], 1.57-5.64). The difference was statistically significant, and the odds ratio was 3.88 (95% CI, 1.14-13.2; P = 0.031). CONCLUSION: Reduced skeletal muscle mass was associated with poorer outcome after TBI in our cohort of older patients. Our results suggest that identifying patients with low muscularity may contribute to better stratification in this population. PMID- 28712908 TI - Patient Expectations and Preferences in the Spinal Surgery Clinic. AB - BACKGROUND: Managing patient expectations is essential in the treatment of patients undergoing spinal surgery. Patient satisfaction is associated with improved clinical outcomes and can be improved when patient and surgeon expectations are aligned and patient preferences are met. METHODS: Patients presenting to clinic for management of spinal disease were asked to complete a questionnaire assessing demographics, current pain, reason for visit, and expectations and preferences surrounding the clinic experience. Variables were compared with chi2 tests to determine factors associated with patient expectations. Subsets of new patients and returning patients were compared by the use of matched pair tests. One-way analysis of variance was used to compare means of clinic expectations in patients depending on their level of education. RESULTS: A total of 240 patients were included. New patient evaluation was the most common reason for evaluation (26.6%), and pain relief was the most common chief concern (39.3%). Patients preferred their surgeon wash their hands in the room instead of before entering (P < 0.001) and wear professional attire over scrubs (P < 0.001). Patients believe their wait time will be longer than it should be (P = 0.002), they will spend longer in clinic than they should (P = 0.03), and they will get less face-to-face time with their surgeon than they should (P < 0.01) but also that the surgeon is not getting paid enough for the clinic visit (P = 0.02). CONCLUSIONS: Because spine surgery is largely elective, patients often seek treatment to improve quality of life and alleviate subjective symptoms. Understanding patient expectations is critical to ensure that patients and physicians are working toward similar goals. PMID- 28712910 TI - Key Aspects in Foramen Magnum Meningiomas: From Old Neuroanatomical Conceptions to Current Far Lateral Neurosurgical Intervention. AB - Foramen magnum meningiomas represent a challenge for neurosurgeons. These tumors require careful surgical manipulation as they are often located in proximity to critical neurovascular structures and the cranial nerves. The far lateral approach is considered the safest neurosurgical approach for excising foramen magnum lesions. It facilitates the access to the anterior foramen magnum and reduces the retraction of vital structures. We describe key historical, epidemiological, genetic, epigenetic, clinical, and neurosurgical aspects of foramen magnum meningiomas. We emphasize the far lateral approach for lesions arising in the foramen magnum, as well as the most appropriate patient positioning for such approach. Caring for these aspects will be rewarded with the best perioperative neurosurgical outcomes. PMID- 28712909 TI - Comparison of Grading Scales Regarding Perioperative Complications and Clinical Outcomes of Brain Arteriovenous Malformations After Endovascular Therapy Multicenter Study. AB - OBJECTIVES: Several scales have been proposed for risk assessment and outcome determination in brain arteriovenous malformations treated by endovascular therapy. We aim to validate and compare the efficacy of these scales in predicting perioperative complications and clinical outcomes. METHODS: We retrospectively reviewed brain arteriovenous malformations patients who underwent endovascular therapy at 4 centers in China from January 2012 to December 2015. The primary outcomes were complications, unfavorable outcome (mRS >= 3), and complete obliteration. Each patient was assessed using the Spetzler-Martin grading system (SM), Puerto Rico scale, Buffalo score, and arteriovenous malformation embocure score (AVMES). Correlation analysis was performed between primary outcomes incidence rate and the grades of each scale. The area under the receiver operating characteristic curve of these scales was calculated. Pairwise comparison of receiver operating characteristic curves was performed to compare the efficacy of the scales. RESULTS: A total of 270 patients were included. Correlation analysis demonstrated that the complication rate increased with increasing grade in SM (P = 0.002), Puerto Rico scale (P = 0.014), and Buffalo score (P = 0.001); complete obliteration rate decreased with increasing grade in AVMES (P = 0.017); unfavorable outcome rate increased with increasing grade in the Puerto Rico scale (P = 0.005). The area under the receiver operating characteristic curve analysis showed statistical differences between the Puerto Rico score and SM (P = 0.047) in predicting complications and between the Puerto Rico score and SM (P = 0.008) in predicting unfavorable outcomes. The area under the curve of the AVMES in predicting complete obliteration was 0.757. CONCLUSIONS: The Puerto Rico score predicts complications and unfavorable outcomes better than the SM. The AVMES scale has medium efficacy in predicting complete obliteration. PMID- 28712911 TI - Intramedullary Spinal Cord Metastasis from Ovarian Cancer in a 50-Year-Old Female. AB - Intramedullary spinal cord metastasis (ISCM) from ovarian cancer is rare. Here we report a case of a 50-year-old female with ISCM from ovarian cancer. PMID- 28712912 TI - MultiXplore: Visual exploration platform for multimodal neuroimaging data. AB - BACKGROUND: Construction of brain functional and structural networks by neuroimaging methods facilitates inter-modal studies. These type of studies often demand exploration tools to carry out functional-structural discoveries and answer questions regarding the anatomical basis of brain networks. NEW METHOD: This paper describes the design and development of a software module for interactive visualization and exploration of dual-modal brain networks. Our objective was to equip the user with a research tool to investigate brain connectivity matrices while visualizing relevant anatomical landmarks within a 3D volumetric view. In order to create this view, MultiXplore was designed to load data from both structural and diffusion MRI and connectivity matrices. RESULTS: Once user starts to select desired cells through an interactive matrix unit, associated axonal fiber pathways and grey matter regions are generated and displayed. Integration and visualization of functional and structural networks in this 3D interactive framework was successfully implemented and tested. COMPARISON WITH EXISTING METHOD(S): MultiXplore contributes to the transition of connectivity visualization techniques from node-link format to an anatomically more realistic graphical form and assists scientists in relating connectivity matrices to their anatomical correlates. This module also benefits from additional novel functionalities to annotate and differentiate fibers in a large bundle. Unlike traditional graph displays, interactive functionality helps in the inspection and visualization of relevant structures without cluttering the scene with excessive items. CONCLUSION: This module was designed and developed as a plugin to 3D Slicer imaging platform and is accessible for neuroimaging researchers through NITRC (http://www.nitrc.org/projects/multixplore/). PMID- 28712913 TI - Acute Ochratoxin A exposure induces inflammation and apoptosis in human embryonic kidney (HEK293) cells. AB - Ochratoxin A (OTA), a common contaminant of grain and fruit and known carcinogen, has been linked to impaired antioxidant response and cellular repair. The effect of OTA on inflammation in cells has not been explored. This study investigated OTA's influence on inflammatory mediators using a range of OTA concentrations (0.5 MUM (sub-IC50), 1.2 MUm (IC50) and 2 MUm (supra-IC50)) on human embryonic kidney (HEK293) cells over 24hr. The markers of inflammation in HEK293 cells were evaluated using the following techniques: western blotting (phosphorylated (p )NFkappaB (Ser536), p-IKK (Ser176/180) and p-p53 (Ser392), total NFkappaB, IKK, IkappaBalpha and p53), luminometry (caspases 1, 3/7, 8, 9, ATP) and ELISA to determine IL-1beta levels. The results indicate increased activation of the inflammatory pathway in the sub-IC50 concentration, evidenced by significant increases in p-NFkappaB (p = 0.0006). The IC50 concentration indicates decreased inflammatory induction supported by decreased levels of IL-1beta and caspase 1 (p = 0.0186 and p = 0.0068 respectively) with decreased IKK and increased IkappaBalpha (p = 0.0046 and p = 0.0006 respectively). Furthermore, a decrease in inflammatory pathway activation was seen in O3 (increased IkappaBalpha, p < 0.05) coupled with increased apoptosis via elevated caspase 3/7 (p = 0.0002), 8 (p = 0.0011) and 9 activity (p = 0.0002); as well as decreased ATP levels. This data suggests a new mechanism of OTA toxicity and its involvement in inflammation, kidney disease and fibrosis. PMID- 28712914 TI - IgE cross-reactivity of phospholipase A2 and hyaluronidase of Apis dorsata (Giant Asian Honeybee) and Apis mellifera (Western Honeybee) venom: Possible use of A. mellifera venom for diagnosis of patients allergic to A. dorsata venom. AB - Diagnostic and therapeutic reagents are unavailable for anaphylaxis arising from stings by Apis dorsata. Venom profiles and cross-reactivity of A. dorsata and Apis mellifera were compared, to ascertain whether venom of A. mellifera can be used for diagnosis in A. dorsata allergy. Both venom profiles were similar by High Performance Liquid Chromatography and SDS-PAGE. Sera of 29 of 30 (96.7%) patients with anaphylaxis to A. dorsata stings had IgE to the phospholipase-2 (PLA2) doublet (15 and 16 kDa) of A. dorsata venom by immunoblot, compared to 26 of 30 (86.7%) with the PLA2 of A. mellifera and a purified preparation of PLA2. Twelve patients (40%) with severe anaphylaxis had IgE reactivity to a 39 kDa protein band of venom of both species, a third band, identified in immunoblot as hyaluronidase. The cross-reactivity of PLA2 and hyaluronidase of A. dorsata and A. mellifera were further confirmed by immunoblot inhibition results. Twenty five of 30 (83.3%) of our patients had positive venom specific IgE (>0.35 KUA/L) reactivity to Phadia ImmunoCAPs of A. mellifera venom. The observed IgE cross reactivity suggests the possibility of using A. mellifera venom as a diagnostic test for A. dorsata venom allergy. PMID- 28712915 TI - Comparative analyses and implications for antivenom serotherapy of four Moroccan scorpion Buthus occitanus venoms: Subspecies tunetanus, paris, malhommei, and mardochei. AB - Temporary passive immunity such as serotherapy against venoms requires the full knowledge of all venom's components. Here, four venoms from Moroccan common yellow scorpions belonging to Buthus occitanus, subspecies tunetanus, paris, malhommei, and mardochei, all collected in four different restricted areas, were analysed in deep. They were fractionated by reversed-phase high-performance liquid chromatography (RP-HPLC) and their molecular masse profile determined by off-line MALDI-TOF mass spectrometry. Characterisation of their main components was achieved by enzyme-linked immunosorbent assay (ELISA) using specific antisera against the major lethal scorpion toxins identified so far, i.e. voltage-gated sodium channels (Nav) modulators alpha- and beta-toxins, as well as diverse potassium channel pore blocker toxins. For fractions with identical RP-HPLC retention times, we observe that their relative quantities show large differences. Moreover, identical masses present simultaneously in the four venoms are infrequent. ELISAs show that the majority of the RP-HPLC compounds cross react with the antiserum against the "alpha-like" toxin Bot I, which has been previously identified in the Algerian Buthus occitanus tunetanus venom. Moreover, minor fractions were recognised by the antiserum against the highly lethal "classical" alpha-toxin of reference AaH II from the Androctonus australis venom. As such, our results bring new sights for further improving scorpion venom serotherapy in Morocco. PMID- 28712916 TI - Targeting lipodisks enable selective delivery of anticancer peptides to tumor cells. AB - Issues concerning non-specificity, degradation and hemolysis severely hamper the development of membranolytic amphiphilic peptides into safe and efficient anticancer agents. To increase the therapeutic potential, we have previously developed a strategy based on formulation of the peptides in biocompatible nanosized lipodisks. Studies using melittin as model peptide show that the proteolytic degradation and hemolytic effect of the peptide are substantially reduced upon loading in lipodisks. Here, we explored the possibilities to increase the specificity and boost the cytotoxicity of melittin to tumor cells by use of targeting lipodisk. We demonstrate that small (~20 nm) EGF-targeted lipodisks can be produced and loaded with substantial amounts of peptide (lipid/peptide molar ratio >7) by means of a simple and straightforward preparation protocol. In vitro cell studies confirm specific binding of the peptide-loaded disks to tumor cells and suggest that cellular internalization of the disks results in a significantly improved cell-killing effect. PMID- 28712917 TI - Amphotericin B releasing topical nanoemulsion for the treatment of candidiasis and aspergillosis. AB - The present study was designed to develop a nanoemulsion formulation of Amphotericin B (AmB) for the treatment of skin candidiasis and aspergillosis. Several ingredients were selected on the basis of AmB solubility and compatibility with skin. The formulation that exhibited the best properties was selected from the pseudo-ternary phase diagram. After physicochemical characterization its stability was assessed. Drug release and skin permeation studies were also accomplished. The antifungal efficacy and skin tolerability of developed AmB nanoemulsion was demonstrated. Finally, our results showed that the developed AmB formulation could provide an effective local antifungal effect without theoretical systemic absorption, based on its skin retention capacity, which might avoid related side effect. These results suggested that the nanoemulsion may be an optimal therapeutic alternative for the treatment of skin fungal infections with AmB. PMID- 28712918 TI - Topical nitric oxide releasing nanoparticles are effective in a murine model of dermal Trichophyton rubrum dermatophytosis. AB - Systemic therapies are preferred for treating dermal dermatophytosis due to inadequate penetration of topical agents. However, systemic antifungals are associated with off-target effects and limited tissue penetration, and antimicrobial resistance is a growing concern. To address this, we investigated topical nitric oxide-releasing nanoparticles (NO-np), which have been used against superficial fungal infections and bacterial abscesses. In addition to enhanced penetration and permeation conferred by nanoparticles, nitric oxide, a broad-spectrum multi-mechanistic antimicrobial agent, offers decreased likelihood of resistance development. In the current study, NO-np inhibited Trichophyton rubrum in vitro, as well as in a murine model of dermal dermatophytosis. In mice, NO-np reduced fungal burden after three days, with complete clearance after seven. Furthermore, NO-np decreased tissue IL-2, 6, 10 and TNFalpha, indicating earlier attenuation of the host inflammatory response and decreased tissue morbidity. Thus, topical NO-np represent an attractive alternative to systemic therapy against dermal T. rubrum infection. PMID- 28712919 TI - An innovative MWCNTs/DOX/TC nanosystem for chemo-photothermal combination therapy of cancer. AB - Chemotherapy and photothermal therapy can be efficiently integrated to achieve enhanced antitumor efficacy by using carbon nanotubes (CNTs) which are super in delivering drug and converting near infrared radiation (NIR) into heat. We previously developed an innovative TAT-chitosan functionalized MWCNTs (MWCNTs/TC) based drug delivery system for doxorubicin (DOX) and preliminarily investigated its release profile and antitumor effect. In the present study, the application potential of MWCNTs/DOX/TC in chemo-photothermal combination therapy was further explored. The in vitro drug release, photothermal effect, cellular uptake and cytotoxicity were assessed. The in vivo anti-tumor effect of MWCNTs/DOX/TC was further evaluated by noninvasive bioluminescence imaging. It was demonstrated that this innovative drug delivery system not only realized a conspicuously sustained release of DOX, but also retained the optical properties of MWCNTs for a high photothermal effect upon NIR irradiation, and exhibited remarkably enhanced anti-tumor efficacy through the synergistic function of chemotherapy and photothermal ablation. PMID- 28712920 TI - Amelioration of cirrhotic portal hypertension by targeted cyclooxygenase-1 siRNA delivery to liver sinusoidal endothelium with polyethylenimine grafted hyaluronic acid. AB - Portal hypertension (PH), a leading cause of mortality in cirrhosis, lacks effective clinical therapeutic strategies. The increased thromboxane A2 (TXA2), derived primarily from the upregulation of cyclooxygenase-1 (COX-1) in cirrhotic liver sinusoidal endothelial cells (LSECs), is responsible for hepatic endothelial dysfunction and PH. Thus, blocking the COX-1 pathway in cirrhotic LSECs may benefit the treatment of PH. In this study, hyaluronate-graft polyethylenimine (HA-PEI) was synthesized for the targeted delivery of COX-1 siRNA to LSECs. Compared to non-targeted PEI, HA-PEI mediated much more efficient siRNA delivery, which resulted in potent targeted gene silencing in LSECs. In vivo, HA-PEI notably increased the accumulation of siRNA along the sinusoidal lining of the liver, inhibited over-activation of the COX-1/TXA2 pathway in LSECs, and successfully reduced portal pressure in cirrhotic mice. These results highlight the potential of HA-PEI complexed siRNA to serve as a LSECs-specific nanomedical system for effective gene therapy in PH. PMID- 28712921 TI - Selective regulation of biological processes by vitamin D based on the spatio temporal cistrome of its receptor. AB - The transcription factor vitamin D receptor (VDR) is the exclusive nuclear target of the biologically active form of vitamin D (1,25(OH)2D3). In THP-1 human monocytes we obtained a highly accurate VDR cistrome after 2 and 24h ligand stimulation comprising >11,600 genomic loci, 78% of which were detected exclusively after 24h. In contrast, a group of 510 persistent VDR sites occurred at all conditions and some 2100 VDR loci were only transiently occupied. Machine learning and statistical analysis as well as a comparison with the re-analyzed B cell VDR cistrome indicated a subgroup of 339 highly conserved persistent VDR sites that were suited best for describing vitamin D-triggered gene regulatory scenarios. The 1,25(OH)2D3-dependent transcriptome of THP-1 cells comprised 587 genes, 311 of which were primary targets with main functions in the immune system. More than 97% of the latter genes were located within 1,25(OH)2D3 modulated topologically associated domains (TADs). The number of persistent and transient VDR sites was found to be the main discriminator for sorting these TADs into five classes carrying vitamin D target genes involved in distinct biological processes. In conclusion, specific regulation of biological processes by vitamin D depends on differences in time-dependent VDR binding. PMID- 28712922 TI - Utilization of Manipulative Treatment for Spine and Shoulder Conditions Between Different Medical Providers in a Large Military Hospital. AB - OBJECTIVE: To describe the use of manipulative treatment for shoulder and spine conditions among various provider types. DESIGN: Retrospective observational cohort. SETTING: Single military hospital. PARTICIPANTS: Consecutive sample of patients (N=7566) seeking care for an initial spine or shoulder condition from January 1 to December 31, 2009. INTERVENTIONS: Manipulative treatment (eg, manual therapy, spinal and joint manipulation). MAIN OUTCOME MEASURE: Manipulation treatment was identified with procedure billing codes in the medical records. Spine and shoulder conditions were identified by using the International Classification of Diseases, 9th Revision codes. All data were abstracted from the Department of Defense Military Health System Management and Analysis Tool. RESULTS: Of 7566 total patients seeking care, 2014 (26.6%) received manipulative treatment at least once, and 1870 of those received this treatment in a military facility (24.7%). Manipulative treatment was used most often for thoracic conditions and least often for shoulder conditions (50.8% and 24.2% of all patients). There was a total of 6706 unique medical visits with a manipulative treatment procedure (average of 3.3 manipulative treatment procedure visits per patient). CONCLUSIONS: Manipulative treatment utilization rates for shoulder and spine conditions ranged from 26.6% to 50.2%. Chiropractors used manipulation the most and physical therapists the least. PMID- 28712923 TI - Key players in the immune response to biomaterial scaffolds for regenerative medicine. AB - The compatibility of biomaterials is critical to their structural and biological function in medical applications. The immune system is the first responder to tissue trauma and to a biomaterial implant. The innate immune effector cells, most notably macrophages, play a significant role in the defense against foreign bodies and the formation of a fibrous capsule around synthetic implants. Alternatively, macrophages participate in the pro-regenerative capacity of tissue derived biological scaffolds. Research is now elucidating the role of the adaptive immune system, and T cells in particular, in directing macrophage response to synthetic and biological materials. Here, we review basic immune cell types and discuss recent research on the role of the immune system in tissue repair and its potential relevance to scaffold design. We will also discuss new emerging immune cell types relevant to biomaterial responses and tissue repair. Finally, prospects for specifically targeting and modulating the immune response to biomaterial scaffolds for enhancing tissue repair and regeneration will be presented. PMID- 28712924 TI - Advanced methodologies for cocrystal synthesis. AB - Pharmaceutical cocrystals are multicomponent systems composed of two or more molecules and held together by H-bonding. Currently, cocrystals provide exciting opportunities in the pharmaceutical industry for the development and manufacturing of new medicines by improving poor physical properties of Active Pharmaceutical Ingredients (APIs) such as processability, solubility, stability and bioavailability. According to the recent reclassification, cocrystals are considered as drug polymorph rather a new API which has a significant impact on drug development, regulatory submissions and intellectual property protection. This review summarizes recent trends and advances in synthesis, manufacturing and scale - up of cocrystals. The operational principles of several cocrystals manufacturing technologies are discussed including their advantages and disadvantages in terms of crystal quality, purity stability, throughput and limitations in large scale production. PMID- 28712925 TI - Borderline ER-Positive Primary Breast Cancer Gains No Significant Survival Benefit From Endocrine Therapy: A Systematic Review and Meta-Analysis. AB - Endocrine responsiveness of primary breast cancers with borderline estrogen receptor expression (ER+ [1%-9%]) remains unclear. We aimed at investigating differences in endocrine responsiveness, prognosis, and clinicopathological characteristics between the ER+ (1%-9%) cohort and the ER- cohort or ER+ (>=10%) cohort. Eligible literature published from inception to November 20, 2016 was retrieved from the PubMed database on the basis of Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Data on survival outcomes were extracted and pooled odds ratios (ORs), 95% confidence intervals (CIs), and 2 tailed P values are reported. P values of the chi2 test for comparison of clinicopathological characteristics among included patients in the ER+ (1%-9%) cohort and the other 2 cohorts were calculated respectively. The analysis included 6 studies with 16,606 patients. Significant differences were detected between the ER+ (1%-9%) cohort and the other 2 cohorts on the basis of clinicopathological characteristics respectively. When taking all of the patients into analysis without consideration of treatment modality, the ER+ (1%-9%) cohort presented better prognosis than the ER- group in terms of 5-year disease-free survival (OR, 1.47; P = .046) and 5-year overall survival (OR, 1.23; P = .046). However, patients with ER+ (1%-9%) breast cancer who received endocrine therapy seemed to have a prognosis similar to those without any endocrine therapy (P = .684) and those with ER- carcinoma who received endocrine therapy (P = .145). Patients with ER+ (>=10%) tumors had better endocrine responsiveness compared with their ER+ (1%-9%) counterparts (OR, 0.52; P = .034, ER+ [1%-9%] vs. ER+ [>=10%]). Our results indicate that primary breast cancer patients with ER+ (1% 9%) expression gained no significant survival benefit from endocrine therapy, but manifested overall better prognosis than those with ER- cancer. PMID- 28712926 TI - Glenohumeral arthritis after Latarjet procedure: Progression and it's clinical significance. AB - BACKGROUND: The risk factors of glenohumeral arthritis after the Latarjet procedure remain relatively unexplored. The purposes of this study are to evaluate the clinical significance of glenohumeral arthritis after the Latarjet procedure, and to investigate risk factors associated with arthritis progression. METHODS: We evaluated 110 patients (110 shoulders) who underwent the Latarjet procedure for recurrent anterior shoulder instability. Patients had a mean age of 23.8 years (range, 14-52 years) at the time of the operation, and the mean duration of follow-up was 31 months (range, 24-111 months). RESULTS: At the last follow-up, the mean Visual Analog Scale (VAS), Rowe and University of California at Los Angeles (UCLA) scores significantly improved from 3.1, 36.5 and 23.6 points preoperatively to 1.6, 87.6 and 32.6 points (all P < 0.05, respectively). The postoperative rate of recurrence was 5.4%. Among the 14 shoulders with preoperative arthritis, 8 (57.1%) showed progression of arthritis at the last follow up. New occurrence or progression of arthritis after the Latarjet procedure was in 20 shoulders (18.2%). At the final, overall prevalence of arthritis was 23.6% (26 shoulders). The non-arthritis group showed significantly better functional outcomes (VAS score: 0.9, Rowe Score: 89.3, UCLA score: 33.5) than the arthritis group (2.1, 84.9, 29.2; all P < 0.05, respectively). Preoperative generalized laxity and lateral overhang were associated with glenohumeral arthritis progression after surgery. (all P < 0.05, retrospectively). CONCLUSION: The Latarjet procedure yielded satisfactory functional outcomes with low recurrent rate at mid-term follow-up. Development or progression of arthritis was observed in 18.2% of patients, postoperatively. Glenohumeral arthritis after the Latarjet procedure had an adverse effect on clinical outcome. Generalized laxity and lateral overhang should be considered as risk factors of progression to glenohumeral arthritis after the Latarjet procedure. PMID- 28712927 TI - Role of hepatic Annexin A6 in fatty acid-induced lipid droplet formation. AB - Annexin A6 (AnxA6) has been implicated in the regulation of endo-/exocytic pathways, cholesterol transport, and the formation of multifactorial signaling complexes in many different cell types. More recently, AnxA6 has also been linked to triglyceride storage in adipocytes. Here we investigated the potential role of AnxA6 in fatty acid (FA) - induced lipid droplet (LD) formation in hepatocytes. AnxA6 was associated with LD from rat liver and HuH7 hepatocytes. In oleic acid (OA) -loaded HuH7 cells, substantial amounts of AnxA6 bound to LD in a Ca2+ independent manner. Remarkably, stable or transient AnxA6 overexpression in HuH7 cells led to elevated LD numbers/size and neutral lipid staining under control conditions as well as after OA loading compared to controls. In contrast, overexpression of AnxA1, AnxA2 and AnxA8 did not impact on OA-induced lipid accumulation. On the other hand, incubation of AnxA6-depleted HuH7 cells or primary hepatocytes from AnxA6 KO-mice with OA led to reduced FA accumulation and LD numbers. Furthermore, morphological analysis of liver sections from A6-KO mice revealed significantly lower LD numbers compared to wildtype animals. Interestingly, pharmacological inhibition of cytoplasmic phospholipase A2alpha (cPLA2alpha)-dependent LD formation was ineffective in AnxA6-depleted HuH7 cells. We conclude that cPLA2alpha-dependent pathways contribute to the novel regulatory role of hepatic AnxA6 in LD formation. PMID- 28712928 TI - Bone marrow-derived mesenchymal stem cells propagate immunosuppressive/anti inflammatory macrophages in cell-to-cell contact-independent and -dependent manners under hypoxic culture. AB - Immunosuppressive/anti-inflammatory macrophage (Mphi), M2-Mphi that expressed the typical M2-Mphis marker, CD206, and anti-inflammatory cytokine, interleukin (IL) 10, is beneficial and expected tool for the cytotherapy against inflammatory diseases. Here, we demonstrated that bone marrow-derived lineage-positive (Lin+) blood cells proliferated and differentiated into M2-Mphis by cooperation with the bone marrow-derived mesenchymal stem cells (MSCs) under hypoxic condition: MSCs not only promoted proliferation of undifferentiated M2-Mphis, pre-M2-Mphis, in the Lin+ fraction via a proliferative effect of the MSCs-secreted macrophage colony-stimulating factor, but also promoted M2-Mphi polarization of the pre-M2 Mphis through cell-to-cell contact with the pre-M2-Mphis. Intriguingly, an inhibitor for intercellular adhesion molecule (ICAM)-1 receptor/lymphocyte function-associated antigen (LFA)-1, Rwj50271, partially suppressed expression of CD206 in the Lin+ blood cells but an inhibitor for VCAM-1 receptor/VLA-4, BIO5192, did not, suggesting that the cell-to-cell adhesion through LFA-1 on pre M2-Mphis and ICAM-1 on MSCs was supposed to promoted the M2-Mphi polarization. Thus, the co-culture system consisting of bone marrow-derived Lin+ blood cells and MSCs under hypoxic condition was a beneficial supplier of a number of M2 Mphis, which could be clinically applicable to inflammatory diseases. PMID- 28712929 TI - Exosomes from Osteosarcoma and normal osteoblast differ in proteomic cargo and immunomodulatory effects on T cells. AB - BACKGROUND: Canine osteosarcoma (OSA) is the most common cancer of the appendicular skeleton and is associated with high metastatic rate to the lungs and poor prognosis. Recent studies have shown the impact of malignant-derived exosomes on immune cells and the facilitation of immune evasion. In the current study, we have characterized the proteomic profile of exosomes derived from healthy osteoblasts and osteosarcoma cell lines. We investigated the direct impact of these exosomes on healthy T cells. RESULTS: Proteomic cargo of the malignant exosomes was markedly different from osteoblastic exosomes and contained immunosuppressive proteins including TGF-beta, alpha fetoprotein and heat shock proteins. OSA exosomes directly attenuated the rate of T cell proliferation, increased a regulatory (FoxP3+) CD4+ phenotype and diminished the expression of the activation marker CD25+ on CD8+ cells. Exosomes of osteoblasts also demonstrated a direct impact on T cells, but to a lesser degree. CONCLUSIONS: Osteosarcoma-derived exosomes compared to normal osteoblasts contain an immunomodulatory cargo, which reduced the rate of T cell proliferation and promoted T regulatory phenotype. Osteoblast-derived exosomes can also reduce T cell activity, but to lesser degree compared to OSA exosomes and without promoting a T regulatory phenotype. PMID- 28712930 TI - Disseminated Mycobacterium kansasii infection with cutaneous lesions in an immunocompetent patient. AB - A case of disseminated Mycobacterium kansasii infection involving the skin and soft tissue in a 57-year-old male farmer who presented with recurrent fever, respiratory syndromes, and skin lesions is reported. The positive findings of syndromes, laboratory examinations, and identification of M. kansasii in puncture fluid indicated the diagnosis of disseminated M. kansasii infection involving the skin and soft tissue, lungs, and mediastinal lymph nodes. After applying the standard HRE regimen (isoniazid 300mg/day, rifampicin 600mg/day, and ethambutol 750mg/day), the patient's temperature normalized and his symptoms improved gradually. No notable adverse drug reactions occurred and the skin lesions had healed after 4 months of follow-up. Disseminated M. kansasii infections occur mainly in immunocompromised patients. Moreover, disseminated infections with skin lesions is rare in immunocompetent patients. Following a review of the literature, only eight similar cases were identified as of disseminated M. kansasii infection with cutaneous lesions, and thecase presented here appears to be the second involving an immunocompetent individual. Special attention should be paid to a persistent and chronic rash following a chronic respiratory syndrome in order to exclude skin disease caused by non-tuberculous mycobacteria. PMID- 28712931 TI - Genome-wide Association Study Reveals that the Aquaporin NIP1;1 Contributes to Variation in Hydrogen Peroxide Sensitivity in Arabidopsis thaliana. AB - Hydrogen peroxide (H2O2) is a reactive oxygen species that affects cell signaling in various plant defense responses and induces programmed cell death. To identify the new components associated with H2O2 signaling and tolerance, we conducted a genome-wide association study (GWAS) on the root growth of 133 Arabidopsis thaliana accessions grown in the presence of toxic H2O2 levels. The most significant SNPs were associated with a cluster of chromosome 4 genes encoding an aquaporin NODULIN 26-LIKE INTRINSIC PROTEIN 1; 1 (NIP1;1), an NB-ARC domain containing disease resistance protein (AT4G19050), and a putative membrane lipoprotein (AT4G19070). The expression level of NIP1;1 was relatively high in A. thaliana accessions sensitive to H2O2. Additionally, overexpression of NIP1;1 in a tolerant accession (e.g., Col-0) increased the sensitivity of transgenic plants to H2O2. An in planta beta-glucuronidase reporter assay revealed that variations in the NIP1;1 promoter were responsible for the differences of its expression level in H2O2-tolerant and -sensitive accessions. Cell death was extensive and H2O2 levels were high in the roots of H2O2-sensitive and NIP1;1-overexpressing accessions. Together, our results indicate that the aquaporin NIP1;1 is a key determinant of the sensitivity of A. thaliana to H2O2, and contributes to the phenotypic variations detected by our GWAS. PMID- 28712932 TI - Pyrrolidine dithiocarbamate (PDTC) inhibits inflammatory signaling via expression of regulator of calcineurin activity 1 (RCAN1): Anti-inflammatory mechanism of PDTC through RCAN1 induction. AB - Pyrrolidine dithiocarbamate (PDTC) is a thiol compound that elicits anti inflammatory effects by inhibiting NF-kappaB signaling. In this study, we report that regulator of calcineurin activity 1 (RCAN1) expression is induced by PDTC treatment and that increased RCAN1 expression is dependent on the generation of reactive oxygen species (ROS) and activation of p38 MAPK and JNK signaling. We also report that the ability of PDTC to induce RCAN1 is mediated by activator protein-1 (AP-1)-dependent gene transcription, and identified a functional AP-1 binding site in the RCAN1 promoter by producing mutations and conducting chromatin immunoprecipitation (ChIP) analyses. Moreover, we show that the PDTC mediated inhibitory effect on NF-kappaB signaling is significantly perturbed by knocking out RCAN1. Our data provide the first evidence that PDTC prevents in vivo expression of pro-inflammatory cytokines by inducing RCAN1 expression. PMID- 28712933 TI - Measuring drug absorption improves interpretation of behavioral responses in a larval zebrafish locomotor assay for predicting seizure liability. AB - INTRODUCTION: Unanticipated effects on the central nervous system are a concern during new drug development. A larval zebrafish locomotor assay can reveal seizure liability of experimental molecules before testing in mammals. Relative absorption of compounds by larvae is lacking in prior reports of such assays; having those data may be valuable for interpreting seizure liability assay performance. METHODS: Twenty-eight reference drugs were tested at multiple dose levels in fish water and analyzed by a blinded investigator. Responses of larval zebrafish were quantified during a 30min dosing period. Predictive metrics were calculated by comparing fish activity to mammalian seizure liability for each drug. Drug level analysis was performed to calculate concentrations in dose solutions and larvae. Fifteen drug candidates with neuronal targets, some having preclinical convulsion findings in mammals, were tested similarly. RESULTS: The assay has good predictive value of established mammalian responses for reference drugs. Analysis of drug absorption by larval fish revealed a positive correlation between hyperactive behavior and pro-convulsive drug absorption. False negative results were associated with significantly lower compound absorption compared to true negative, or true positive results. The predictive value for preclinical toxicology findings was inferior to that suggested by reference drugs. DISCUSSION: Disproportionately low exposures in larvae giving false negative results demonstrate that drug exposure analysis can help interpret results. Due to the rigorous testing commonly performed in preclinical toxicology, predicting convulsions in those studies may be more difficult than predicting effects from marketed drugs. PMID- 28712934 TI - Donor Lymphocyte Infusions Used to Treat Mixed-Chimeric and High-Risk Patient Populations in the Relapsed and Nonrelapsed Settings after Allogeneic Transplantation for Hematologic Malignancies Are Associated with High Five-Year Survival if Persistent Full Donor Chimerism Is Obtained or Maintained. AB - Mixed chimerism (MC), a persistent or increasing number of host cells after allogeneic hematopoietic stem cell transplantation (HSCT), is a predictor of disease relapse. Donor lymphocyte infusions (DLI) have the potential to enhance the graft-versus-malignancy (GVM) effect, reducing the risk of relapse in patients with MC. Hence, in addition to utilizing DLI in the relapsed setting, there is a motivation to pursue pre-emptive DLI for patients in complete remissions after HSCT. To assess the safety and efficacy of DLI, records of 86 patients who received DLI between 2003 and 2015 at a single institution were studied retrospectively. Patients who received DLI included 50 patients with relapsed/residual (RR) disease, 29 patients with emerging MC without detectable disease, and 7 patients in an "other" cohort who had neither RR disease nor emerging MC after HSCT. DLI were administered using a dose-escalation protocol. After DLI, 93% of MC patients converted to full donor chimerism (FDC). Nonrelapsed patients (MC and other) reported high overall survival (OS) at 1 and 5 years (83% at 1 year, 70% at 5 years for MC; 86% at 1 year, 69% at 5 years for other) and was statistically superior to 5-year OS for RR patients (nonrelapsed 69% versus RR 28%; P = .00032). Improved survival correlated with successful conversion to FDC after DLI for RR and MC cohorts: 71% 2-year OS for patients converted to FDC versus 13% for patients who failed to achieve FDC (P < .0001). DLI for nonrelapsed patients was associated with a superior 5-year progression free survival (PFS) of 71% compared with 18% 5-year PFS in the RR group (P < .0001). Relapse/progressive disease was the most frequent cause of death (41%). Seven MC (24%), 2 other (29%), and 39 RR patients (78%) relapsed or did not respond after DLI. Overall, 6 patients (7%) died of graft-versus-host disease after DLI. Our results demonstrate a successful dose-escalation approach for nonrelapsed patients that correlated with high survival and a high rate of achieving FDC in MC and RR populations. DLI remain a viable option to boost the GVM effect in the relapsed setting and may pre-emptively protect against relapse in MC populations after HSCT. PMID- 28712935 TI - Phase II Study of Sequential Infusion of Donor Lymphocyte Infusion and Cytokine Induced Killer Cells for Patients Relapsed after Allogeneic Hematopoietic Stem Cell Transplantation. AB - Seventy-four patients who relapsed after allogeneic stem cell transplantation were enrolled in a phase IIA study and treated with the sequential infusion of donor lymphocyte infusion (DLI) followed by cytokine-induced killer (CIK) cells. Seventy-three patients were available for the intention to treat analysis. At least 1 infusion of CIK cells was given to 59 patients, whereas 43 patients received the complete cell therapy planned (58%). Overall, 12 patients (16%) developed acute graft-versus-host disease (aGVHD) of grades I to II in 7 cases and grades III to IV in 5). In 8 of 12 cases, aGVHD developed during DLI treatment, leading to interruption of the cellular program in 3 patients, whereas in the remaining 5 cases aGVHD was controlled by steroids treatment, thus allowing the subsequent planned administration of CIK cells. Chronic GVHD (cGVHD) was observed in 11 patients (15%). A complete response was observed in 19 (26%), partial response in 3 (4%), stable disease in 8 (11%), early death in 2 (3%), and disease progression in 41 (56%). At 1 and 3 years, rates of progression-free survival were 31% and 29%, whereas rates of overall survival were 51% and 40%, respectively. By multivariate analysis, the type of relapse, the presence of cGVHD, and a short (<6 months) time from allogeneic hematopoietic stem cell transplantation to relapse were the significant predictors of survival. In conclusion, a low incidence of GVHD is observed after the sequential administration of DLI and CIK cells, and disease control can be achieved mostly after a cytogenetic or molecular relapse. PMID- 28712936 TI - Prognostic and diagnostic potential of suPAR levels in pleural effusion. PMID- 28712937 TI - Returning ex-patriot Chinese to Guangdong, China, increase the risk for local transmission of Zika virus. AB - OBJECTIVES: Fast expansion and linkage to microcephaly and Guillain Barre syndrome have made Zika virus (ZIKV) track attention of global health authority concerns. The epidemiology, virological characteristics and genetic evolution of introduced ZIKV to Guangdong, China, were investigated. METHODS: Analyses of the epidemiological characteristics and genetic diversity of ZIKV isolates were performed. RESULTS: A total of twenty-eight confirmed ZIKV infection cases were imported into China in 2016, of which 19 were imported into Guangdong, China from Venezuela (16), the Samoa Islands (1), Suriname (1) and Guatemala (1). Serial sampling studies of the cases indicated longer shedding times of ZIKV particles from urine and saliva samples than from serum and conjunctiva swab samples. Seven ZIKV strains were successfully isolated from serum, urine and conjunctiva swab samples using cell culture and neonatal mouse injection methods. Genomic analysis indicated that all viruses belonged to the Asian lineage but had different evolutionary transmission routes with different geographic origins. The molecular clock phylogenetic analysis of the ZIKV genomes indicated independent local transmission that appeared to have been previously established in Venezuela and Samoa. Additionally, we found 7 unique non-synonymous mutations in the genomes of ZIKV that were imported to China. The mutations may indicate that ZIKV has undergone independent evolutionary history not caused by sudden adaptation to Chinese hosts. CONCLUSION: The increasing number of ex-patriot Chinese returning from ZIKV hyper-endemic areas to Guangdong combined with the presence of a variety of Aedes species indicate the potential for autochthonous transmission of ZIKV in Guangdong. PMID- 28712938 TI - ASCL1 Reorganizes Chromatin to Direct Neuronal Fate and Suppress Tumorigenicity of Glioblastoma Stem Cells. AB - Glioblastomas exhibit a hierarchical cellular organization, suggesting that they are driven by neoplastic stem cells that retain partial yet abnormal differentiation potential. Here, we show that a large subset of patient-derived glioblastoma stem cells (GSCs) express high levels of Achaete-scute homolog 1 (ASCL1), a proneural transcription factor involved in normal neurogenesis. ASCL1hi GSCs exhibit a latent capacity for terminal neuronal differentiation in response to inhibition of Notch signaling, whereas ASCL1lo GSCs do not. Increasing ASCL1 levels in ASCL1lo GSCs restores neuronal lineage potential, promotes terminal differentiation, and attenuates tumorigenicity. ASCL1 mediates these effects by functioning as a pioneer factor at closed chromatin, opening new sites to activate a neurogenic gene expression program. Directing GSCs toward terminal differentiation may provide therapeutic applications for a subset of GBM patients and strongly supports efforts to restore differentiation potential in GBM and other cancers. PMID- 28712939 TI - Rituximab biosimilars: introduction into clinical practice. PMID- 28712940 TI - Efficacy, pharmacokinetics, and safety of the biosimilar CT-P10 compared with rituximab in patients with previously untreated advanced-stage follicular lymphoma: a randomised, double-blind, parallel-group, non-inferiority phase 3 trial. AB - BACKGROUND: Studies in patients with rheumatoid arthritis have shown that the rituximab biosimilar CT-P10 (Celltrion, Incheon, South Korea) has equivalent efficacy and pharmacokinetics to rituximab. In this phase 3 study, we aimed to assess the non-inferior efficacy and pharmacokinetic equivalence of CT-P10 compared with rituximab, when used in combination with cyclophosphamide, vincristine, and prednisone (CVP) in patients with newly diagnosed advanced-stage follicular lymphoma. METHODS: In this ongoing, randomised, double-blind, parallel group, active-controlled study, patients aged 18 years or older with Ann Arbor stage III-IV follicular lymphoma were assigned 1:1 to CVP plus intravenous infusions of 375 mg/m2 CT-P10 or rituximab on day 1 of eight 21-day cycles. Randomisation was done by the investigators using an interactive web or voice response system and a computer-generated randomisation schedule, prepared by a clinical research organisation. Randomisation was balanced using permuted blocks and was stratified by country, gender, and Follicular Lymphoma International Prognostic Index score (0-2 vs 3-5). Study teams from the sponsor and clinical research organisation, investigators, and patients were masked to treatment assignment. The study was divided into two parts: part 1 assessing equivalence of pharmacokinetics (in the pharmacokinetics subset), and part 2 assessing efficacy in all randomised patients (patients from the pharmacokinetics subset plus additional patients enrolled in part 2). Equivalence of pharmacokinetics was shown if the 90% CIs for the geometric mean ratio of CT-P10 to rituximab in AUCtau and CmaxSS were within the bounds of the equivalence margin of 80% and 125%. Non-inferiority of response was shown if the one-sided 97.5% CI lay on the positive side of the -7% margin, using a one-sided test done at the 2.5% significance level. The primary efficacy endpoint was the proportion of patients who had an overall response over eight cycles and was assessed in the efficacy population (all randomised patients). The primary pharmacokinetic endpoints were area under the serum concentration-time curve at steady state (AUCtau) and maximum serum concentration at steady state (CmaxSS) at cycle 4, assessed in the pharmokinetic population. This trial is registered with ClinicalTrials.gov, number NCT02162771. FINDINGS: Between July 28, 2014, and Dec 29, 2015, 140 patients were enrolled. Here we report data for the eight-cycle induction period, up to week 24. The proportion of patients with an overall response in the efficacy population was 64 (97.0%) of 66 patients in the CT-P10 treatment group and 63 (92.6%) of 68 patients in the rituximab treatment group (4.3%; one-sided 97.5% CI -4.25), which lay on the positive side of the predefined non-inferiority margin. The ratio of geometric least squares means (CT-P10/rituximab) was 102.25% (90% CI 94.05-111.17) for AUCtau and 100.67% (93.84-108.00) for CmaxSS, with all CIs within the bioequivalence margin of 80-125%. Treatment-emergent adverse events were reported for 58 (83%) of 70 patients in the CT-P10 treatment group and 56 (80%) of 70 in the rituximab treatment group. The most common grade 3 or 4 treatment-emergent adverse event in each treatment group was neutropenia (grade 3, 15 [21%] of 70 patients in the CT-P10 group and seven [10%] of 70 patients in the rituximab group). The proportion of patients who experienced at least one treatment-emergent serious adverse event was 16 (23%) of 70 patients in the CT P10 group and nine (13%) of 70 patients in the rituximab group. INTERPRETATION: In this study, we show that CT-P10 exhibits non-inferior efficacy and pharmacokinetic equivalence to rituximab. The safety profile of CT-P10 was comparable to that of rituximab. CT-P10 might represent a new therapeutic option for advanced-stage follicular lymphoma. FUNDING: Celltrion, Inc. PMID- 28712942 TI - Structure-based discovery of clinically approved drugs as Zika virus NS2B-NS3 protease inhibitors that potently inhibit Zika virus infection in vitro and in vivo. AB - Zika virus (ZIKV) infection may be associated with severe complications in fetuses and adults, but treatment options are limited. We performed an in silico structure-based screening of a large chemical library to identify potential ZIKV NS2B-NS3 protease inhibitors. Clinically approved drugs belonging to different drug classes were selected among the 100 primary hit compounds with the highest predicted binding affinities to ZIKV NS2B-NS3-protease for validation studies. ZIKV NS2B-NS3 protease inhibitory activity was validated in most of the selected drugs and in vitro anti-ZIKV activity was identified in two of them (novobiocin and lopinavir-ritonavir). Molecular docking and molecular dynamics simulations predicted that novobiocin bound to ZIKV NS2B-NS3-protease with high stability. Dexamethasone-immunosuppressed mice with disseminated ZIKV infection and novobiocin treatment had significantly (P < 0.05) higher survival rate (100% vs 0%), lower mean blood and tissue viral loads, and less severe histopathological changes than untreated controls. This structure-based drug discovery platform should facilitate the identification of additional enzyme inhibitors of ZIKV. PMID- 28712941 TI - Rituximab biosimilar and reference rituximab in patients with previously untreated advanced follicular lymphoma (ASSIST-FL): primary results from a confirmatory phase 3, double-blind, randomised, controlled study. AB - BACKGROUND: GP2013 is a rituximab biosimilar developed to stringent development guidelines, including non-clinical and preclinical investigations and clinical trials in rheumatoid arthritis and follicular lymphoma. We aimed to compare the efficacy, safety, tolerability, pharmacokinetics, and pharmacodynamics of GP2013 plus cyclophosphamide, vincristine, and prednisone (GP2013-CVP) with rituximab CVP (R-CVP) in patients with follicular lymphoma. METHODS: In this phase 3, multinational, double-blind, randomised, controlled trial, adults (aged 18 years or older) with previously untreated, advanced stage (Ann Arbor stage III or IV) follicular lymphoma of WHO histological grades 1, 2, or 3a were randomly assigned (1:1) using interactive response technology to eight cycles of GP2013-CVP or R CVP (combination phase), followed by monotherapy maintenance in responders for a 2-year period. Randomisation was stratified by Follicular Lymphoma International Prognostic Index risk group and geographic region. The primary endpoint was comparability in overall response, with equivalence concluded if the entire 95% CI was within a margin of -12% to 12%. The primary endpoint was analysed using the per-protocol set, which included all patients who received at least one (partial or complete) dose of investigational treatment and who did not have any major protocol deviations. The trial is registered with ClinicalTrials.gov, number NCT01419665, and is ongoing. FINDINGS: Between Dec 1, 2011, and Jan 15, 2015, 858 patients were screened for eligibility. 314 patients were randomly assigned to GP2013, of whom 312 were given GP2013, and 315 were assigned to reference rituximab. Median follow-up was 11.6 months (IQR 5.8-18.2) for the primary analysis. The primary endpoint, equivalence of overall response, was met (271 [87%] of 311 patients with GP2013 and 274 [88%] of 313 patients with reference rituximab achieved an overall response; difference -0.40% [95% CI -5.94 to 5.14]). Occurrence of adverse events and serious adverse events was similar between the treatment groups (289 [93%] of 312 patients in the GP2013-CVP group had an adverse event and 71 [23%] of 312 patients had a serious adverse event; 288 [91%] of 315 patients in the R-CVP group had an adverse event and 63 [20%] had a serious adverse event). The most common adverse event was neutropenia (80 [26%] of 312 patients in the GP2013-CVP group and 93 [30%] of 315 patients in the R-CVP group in the combination phase and 23 [10%] of 231 patients in the GP2013 CVP group and 13 [6%] of 231 patients in the R-CVP group in the maintenance phase). The most common grade 3 or 4 adverse event during the combination and maintenance phase was neutropenia (55 [18%] of 312 patients in the GP2013-CVP group and 65 [21%] of 315 patients in the R-CVP group in the combination phase and 17 [7%] of 231 patients in the GP2013-CVP group and nine [4%] of 231 patients in the R-CVP group in the maintenance phase). The occurrence of anti-drug antibodies was similar in the treatment groups (five [2%] of 268 patients in the GP2013-CVP; three [1%] in the R-CVP group). INTERPRETATION: Our results show that GP2013 represents a viable rituximab biosimilar candidate for patients with previously untreated advanced follicular lymphoma. The introduction of biosimilars provides additional therapeutic options with potential to increase access to effective and life-saving biological therapies such as rituximab. FUNDING: Hexal. PMID- 28712943 TI - Sex- and brain region- specific effects of prenatal stress and lead exposure on permissive and repressive post-translational histone modifications from embryonic development through adulthood. AB - Developmental exposure to prenatal stress (PS) and lead (Pb) can affect brain development and adversely influence behavior and cognition. Epigenetic-based gene regulation is crucial for normal brain development and mis-regulation, in any form, can result in neurodevelopmental disorders. Post-translational histone modifications (PTHMs) are an integral and dynamic component of the epigenetic machinery involved in gene regulation. Exposures to Pb and/or PS may alter PTHM profiles, promoting lifelong alterations in brain function observed following Pb+/-PS exposure. Here we examined the effects of Pb+/-PS on global levels of activating marks H3K9Ac and H3K4Me3 and repressive marks H3K9Me2 and H3K27Me3 at different developmental stages: E18, PND0, PND6 and PND60. Dams were exposed to 0 or 100ppm Pb beginning 2 months prior to breeding followed by no PS (NS) or PS resulting in 4 offspring treatment groups per sex: 0-NS (control), 0-PS, 100-NS and 100-PS. Global levels of PTHMs varied from E18 through adulthood even in control mice, and were influenced by sex and brain-region. The developmental trajectory of these PTHM levels was further modified by Pb+/-PS in a sex-, brain region- and age-dependent manner. Females showed a preferential response to Pb alone in frontal cortex (FC) and differentially to PS alone and combined Pb+PS in hippocampus (HIPP). In males, PS-induced increases in PTHM levels in FC, whereas PS produced reductions in HIPP. Pb+/-PS-based changes in PTHM levels continued to be observed in adulthood (PND60), demonstrating the lasting effect of these early life environmental events on these histone marks. These results indicate that epigenetic consequences of Pb+/-PS and their contribution to mechanisms of toxicity are sex dependent. Additional studies will assist in understanding the functional significance of these changes in PTHM levels on expression of individual genes, functional pathways, and ultimately, their behavioral consequences. PMID- 28712944 TI - A Fe3O4@Au-basedpseudo-homogeneous electrochemical immunosensor for AFP measurement using AFP antibody-GNPs-HRP as detection probe. AB - In this study, a Fe3O4@Au-based pseudo-homogeneous electrochemical immunosensor was prepared for detection of alpha fetoprotein (AFP), a well-known hepatocellular carcinoma biomarker. The primary antibody (Ab1) was immobilized on Fe3O4@Au NPs as the capture probe. Horseradish peroxidase (HRP) and secondary antibody (Ab2) were conjugated on gold nanoparticles (GNPs) through electrostatic adsorption to form signal-amplifying labels. In the presence of AFP, a sandwich immunocomplex was formed via specific recognition of antigen-antibody in a Fe3O4@Au-basedpseudo-homogeneousreaction system. After the immunocomplex was captured to the surface of magnetic glassy carbon electrode (MGCE), the labeling HRP catalyzed the decomposition of H2O2, resulting in a substantial current for the quantitative detection of AFP. The amperometric (i-t) method was employed to record the response signal of the immunosensor based on the catalysis of the immobilized HRP toward the reduction of H2O2 with hydroquinone (HQ) as the redox mediator. Under the optimal conditions, the amperometric current response presented a linear relationship with AFP concentration over the range of 20 ng/mL 100 ng/mLwith a correlation coefficient of 0.9940, and the detection limit was 0.64 ng/mL at signal/noise [S/N] = 3. Moreover, the electrochemical immunosensor exhibited higher anti-interference ability, acceptable reproducibility and long term stability for AFP detection. PMID- 28712945 TI - Intestinal and Extraintestinal Cancers Associated With Inflammatory Bowel Disease. AB - Inflammatory bowel disease (IBD) with its 2 most common entities, ulcerative colitis and Crohn's disease, causes an increased risk of developing intestinal cancers. In fact, malignancies are the second most common cause of death after cardiovascular diseases in both sexes of patients with IBD. Risk factors for colorectal cancer in IBD correlate with the duration of the disease, extent of disease, the association with primary sclerosing cholangitis, family history, and early age at onset. Patients with IBD also have an increased risk for developing a variety of extraintestinal malignancies. In particular, lymphomas, mostly non Hodgkin lymphomas and skin cancers, are more frequently observed in IBD patients. Longstanding inflammation and the degree of immunosuppression as a result of IBD treatment appear to be the main driving factors for IBD-related carcinogenesis. This review provides an update on the clinical and pathological features of IBD related intestinal and extraintestinal malignancies. PMID- 28712946 TI - Dissociation between decision-making under risk and decision-making under ambiguity in premanifest and manifest Huntington's disease. AB - We investigated decision-making under ambiguity (DM-UA) and decision making under risk (DM-UR) in individuals with premanifest and manifest Huntington's disease (HD). Twenty individuals with premanifest HD and 23 individuals with manifest HD, on one hand, and 39 healthy individuals divided into two control groups, on the other, undertook a modified version of the Iowa Gambling Task (IGT), an adaptation of a DM-UA task, and a modified version of the Game of Dice Task (GDT), an adaptation of a DM-UR task. Participants also filled in a questionnaire of impulsivity and responded to cognitive tests specifically designed to assess executive functions. Compared to controls, individuals with premanifest HD were unimpaired in performing executive tests as well as in decision-making tasks, except for the Stroop task. In contrast, individuals with manifest HD were impaired in both the IGT and executive tasks, but not in the GDT. No sign of impulsivity was observed in individuals with premanifest or manifest HD. Our results suggest that the progression of HD impairs DM-UA without affecting DM-UR, and indicate that decision-making abilities are preserved during the premanifest stage of HD. PMID- 28712947 TI - Cortical dynamics of emotional autobiographical memory retrieval differ between women and men. AB - Retrieval of autobiographical memories entails periods of search, access, and elaboration. Women's reports of their memories feature more detail and emotional content relative to men's. A key question is how these gender differences relate to unfolding changes in cortical activity during retrieval. We recorded EEG activity from 32 scalp electrodes as women and men were cued to retrieve positive, negative, and neutral autobiographical memories. Alpha (9-12Hz) oscillations were prominent at all EEG channels. Alpha coherence between channels was calculated as a measure of ms-level cortical synchrony. Across participants and memory types, a frontal cluster showed pronounced decreases in coherence with other channels during the first second of autobiographical retrieval. In the following second, a left parietal-centered cluster showed increased coherence with other channels. This effect strengthened and spread in the third second of retrieval, perhaps reflecting trace elaboration and/or evaluation of the memory. Although women and men gave similar subjective ratings of their memories, the second-by-second pattern of alpha coherence during autobiographical retrieval differed by gender and memory type. Specifically, women sustained the increased pattern of left-parietal coherence throughout the trial, whereas for men, alpha coherence in this cluster returned to baseline by second two for neutral memories and by second three for emotional memories. Examination of the temporal dynamics of cortical oscillations provides novel insight into autobiographical memory retrieval processes and to gendered retrieval in particular, suggesting that women may persist with elaboration and/or evaluation to a greater extent than men. PMID- 28712948 TI - When pain really matters: A vicarious-pain brain marker tracks empathy for pain in the romantic partner. AB - In a previous study (Krishnan, 2016) we identified a whole-brain pattern, the Vicarious Pain Signature (VPS), which predicts vicarious pain when participants observe pictures of strangers in pain. Here, we test its generalization to observation of pain in a close significant other. Participants experienced painful heat (Self-Pain) and observed their romantic partner in pain (Partner Pain). We measured whether (i) the VPS would respond selectively to Partner-Pain and (ii) the Neurologic Pain Signature (NPS), a measure validated to track somatic pain, would selectively respond to Self-Pain, despite the high interpersonal closeness between partners. The Partner-Pain condition activated the VPS (t = 4.71, p = 0.00005), but not the NPS (t = -1.03, p = 0.308). The Self Pain condition activated the NPS (t = 13.70, p < .00005), but not the VPS (t = 1.03 p = 0.308). Relative VPS-NPS response differences strongly discriminated Partner-Pain vs. Self-Pain (cross-validated accuracy=97%, p < .000001). Greater interpersonal closeness between partners predicted greater VPS responses during Partner-Pain (r = 0.388, p = 0.050) and greater unpleasantness when observing the romantic partner in pain (r = 0.559, p = 0.003). The VPS generalizes across empathy paradigms and to an interactive social setting, and strongly activates when observing a close significant other in pain. VPS responses may be modulated by relevant interpersonal relationship factors. Self-Pain and Partner-Pain evoke non-overlapping large-scale neural representations. PMID- 28712950 TI - Predictors of laparoscopic simulation performance among practicing obstetrician gynecologists. AB - BACKGROUND: While simulation training has been established as an effective method for improving laparoscopic surgical performance in surgical residents, few studies have focused on its use for attending surgeons, particularly in obstetrics and gynecology. Surgical simulation may have a role in improving and maintaining proficiency in the operating room for practicing obstetrician gynecologists. OBJECTIVE: We sought to determine if parameters of performance for validated laparoscopic virtual simulation tasks correlate with surgical volume and characteristics of practicing obstetricians and gynecologists. STUDY DESIGN: All gynecologists with laparoscopic privileges (n = 347) from 5 academic medical centers in New York City were required to complete a laparoscopic surgery simulation assessment. The physicians took a presimulation survey gathering physician self-reported characteristics and then performed 3 basic skills tasks (enforced peg transfer, lifting/grasping, and cutting) on the LapSim virtual reality laparoscopic simulator (Surgical Science Ltd, Gothenburg, Sweden). The association between simulation outcome scores (time, efficiency, and errors) and self-rated clinical skills measures (self-rated laparoscopic skill score or surgical volume category) were examined with regression models. RESULTS: The average number of laparoscopic procedures per month was a significant predictor of total time on all 3 tasks (P = .001 for peg transfer; P = .041 for lifting and grasping; P < .001 for cutting). Average monthly laparoscopic surgical volume was a significant predictor of 2 efficiency scores in peg transfer, and all 4 efficiency scores in cutting (P = .001 to P = .015). Surgical volume was a significant predictor of errors in lifting/grasping and cutting (P < .001 for both). Self-rated laparoscopic skill level was a significant predictor of total time in all 3 tasks (P < .0001 for peg transfer; P = .009 for lifting and grasping; P < .001 for cutting) and a significant predictor of nearly all efficiency scores and errors scores in all 3 tasks. CONCLUSION: In addition to total time, there was at least 1 other objective performance measure that significantly correlated with surgical volume for each of the 3 tasks. Higher volume physicians and those with fellowship training were more confident in their laparoscopic skills. By determining simulation performance as it correlates to active physician practice, further studies may help assess skill and individualize training to maintain skill levels as case volumes fluctuate. PMID- 28712949 TI - Role of early second-trimester uterine artery Doppler screening to predict small for-gestational-age babies in nulliparous women. AB - BACKGROUND: Trophoblastic invasion of the uterine spiral arteries substantially increases compliance to accommodate increased blood flow to the placenta. Failure of this process impedes uterine artery blood flow, and this may be detected by uterine artery Doppler flow studies. However, the clinical utility of uterine artery Doppler flow studies in the prediction of adverse pregnancy outcomes in a general population remains largely unknown. OBJECTIVE: We sought to determine the utility of early second-trimester uterine artery Doppler studies as a predictor of small-for-gestational-age neonates. STUDY DESIGN: Nulliparous women with a viable singleton pregnancy were recruited during their first trimester into an observational prospective cohort study at 8 institutions across the United States. Participants were seen at 3 study visits during pregnancy and again at delivery. Three indices of uterine artery Doppler flow (resistance index, pulsatility index, and diastolic notching) were measured in the right and left uterine arteries between 16 weeks 0 days' and 22 weeks 6 days' gestation. Test characteristics for varying thresholds in the prediction of small for gestational age (defined as birthweight <5th percentile for gestational age [Alexander growth curve]) were evaluated. RESULTS: Uterine artery Doppler indices, birthweight, and gestational age at birth were available for 8024 women. Birthweight <5th percentile for gestational age occurred in 358 (4.5%) births. Typical thresholds for the uterine artery Doppler indices were all associated with birthweight <5th percentile for gestational age (P < .0001 for each), but the positive predictive values for these cutoffs were all <15% and areas under receiver operating characteristic curves ranged from 0.50-0.60. Across the continuous scales for these measures, the areas under receiver operating characteristic curves ranged from 0.56-0.62. Incorporating maternal age, early pregnancy body mass index, race/ethnicity, smoking status prior to pregnancy, chronic hypertension, and pregestational diabetes in the prediction model resulted in only modest improvements in the areas under receiver operating characteristic curves ranging from 0.63-0.66. CONCLUSION: In this large prospective cohort, early second trimester uterine artery Doppler studies were not a clinically useful test for predicting small-for-gestational-age babies. PMID- 28712951 TI - RA-Induced Transcriptional Silencing of Checkpoint Kinase-2 through Promoter Methylation by Dnmt3b Is Required for Neuronal Differentiation of P19 Cells. AB - In a previous study, we identified several novel targets of Dnmt3b using a chromatin library from retinoic acid (RA)-treated P19 cells. The present study describes the regulation of expression and function of checkpoint kinase (Chk2), which was one of the target genes of Dnmt3b. Chromatin immunoprecipitation followed by quantitative PCR analysis showed that recruitment of Dnmt3b on Chk2 promoter is induced following RA treatment of P19 cells. Both bisulfite genomic sequence and COBRA analyses showed that the methylation level of Chk2 promoter is progressively increased during RA-induced neuronal differentiation of P19 cells. Concomitantly, both mRNA and protein expression of Chk2 are reduced as determined by real-time PCR and Western blot analysis, respectively. Suppression of Dnmt3b expression by lentiviral-mediated shRNA resulted in increased expression and reduced methylation of Chk2, which clearly showed that Dnmt3b is responsible for transcriptional silencing of Chk2 gene in RA-treated P19 cells. Neuronal differentiation of P19 cells was inhibited upon enforced Chk2 expression in P19 cells, which showed that the decrease in endogenous expression of Chk2 is essential for normal differentiation. Ectopic Chk2 expression also negatively regulated cell cycle arrest and apoptosis following RA treatment, which could also contribute to impaired neuronal differentiation. Together, this study described the regulation of Chk2 expression through promoter methylation and also presented a novel role of Chk2 during neuronal differentiation, which is independent of its previously known function in DNA damage response. PMID- 28712952 TI - A robust high-throughput fungal biosensor assay for the detection of estrogen activity. AB - Estrogenic active compounds are present in a variety of sources and may alter biological functions in vertebrates. Therefore, it is crucial to develop innovative analytical systems that allow us to screen a broad spectrum of matrices and deliver fast and reliable results. We present the adaptation and validation of a fungal biosensor for the detection of estrogen activity in cow derived samples and tested the clinical applicability for pregnancy diagnosis in 140 mares and 120 cows. As biosensor we used a previously engineered genetically modified strain of the filamentous fungus Aspergillus nidulans, which contains the human estrogen receptor alpha and a reporter construct, in which beta galactosidase gene expression is controlled by an estrogen-responsive-element. The estrogen response of the fungal biosensor was validated with blood, urine, feces, milk and saliva. All matrices were screened for estrogenic activity prior to and after chemical extraction and the results were compared to an enzyme immunoassay (EIA). The biosensor showed consistent results in milk, urine and feces, which were comparable to those of the EIA. In contrast to the EIA, no sample pre-treatment by chemical extraction was needed. For 17beta-estradiol, the biosensor showed a limit of detection of 1ng/L. The validation of the biosensor for pregnancy diagnosis revealed a specificity of 100% and a sensitivity of more than 97%. In conclusion, we developed and validated a highly robust fungal biosensor for detection of estrogen activity, which is highly sensitive and economic as it allows analyzing in high-throughput formats without the necessity for organic solvents. PMID- 28712953 TI - Physical activity levels in children with sensory problems: Cross-sectional analyses from the Millennium Cohort Study. AB - BACKGROUND: Hearing and vision impairments/problems are associated with increased risk of premature mortality in adulthood. One potential pathway explaining this association is reduced levels of physical activity. Reductions in activity levels due to sensory impairments may commence earlier in life; however, associations between sensory impairments/problems and activity levels in childhood are not well understood. OBJECTIVE: The objective of this study was to examine associations between hearing and vision problems and objectively measured activity levels in a representative sample of British children. METHODS: Data were drawn from sweep 4 of the Millennium Cohort Study, a prospective cohort study among children aged 7. Child hearing and vision problems were reported by parents in a postal survey. Children were also invited to have their physical activity measured objectively via accelerometry. A total of 6410 children had valid accelerometry data accompanied by complete survey data on the variables of interest. The main outcomes were objectively measured moderate-to-vigorous physical activity, steps and sedentary time. Adjusted linear regression was used to examine associations between vision and hearing problems and objectively measured activity levels. RESULTS: In this sample of 7-year old children, 16.7% (n = 1068) had a reported vision problem and 11.6% (n = 745) had a hearing problem. Reported vision problems in both eyes, but not one eye, was associated with 2 fewer minutes of moderate-to-vigorous physical activity per day (B = -2.1 95% Confidence Intervals [CI] -3.9 to -0.4) and almost 200 fewer steps per day (B = -198.4 95% CI, -398.4 to 1.6). Hearing problems were not associated with activity levels in either one or both ears. CONCLUSION: Children with visual problems affecting both eyes, but not one eye, are likely to have lower levels of physical activity. Strategies to promote physical activity in children with visual problems are warranted. PMID- 28712954 TI - Social Media Platforms and Heart Failure. AB - With the pervasive use of the internet and social media, the potential applicability toward patients with heart failure (HF) remains understudied. Here, we outline the general use of social media and some early work with the use of social media as well as data from our own Mayo Clinic Center for Social Media experience. Both enterprise-wide social media data as well as those specific to HF-related pages and posts appear to support the preferential use of Facebook and Youtube for potential benefit in patients with HF. Large-scale prospective studies are needed to confirm these anecdotal results, and to ensure we can optimally, yet safely, engage our patients with HF to improve their care. PMID- 28712955 TI - Clinical Impact of Changes in Hemodynamic Indices of Contractile Function During Treatment of Acute Decompensated Heart Failure. AB - BACKGROUND: The objective of this work was to determine the impact of improving right ventricular versus left ventricular stroke work indexes (RVSWI vs LVSWI) during therapy for acute decompensated heart failure (ADHF). METHODS AND RESULTS: Cox proportional hazards regression and logistic regression were used to analyze key factors associated with outcomes in 175 patients (mean age 56.7 +/- 13.6 years, 29.1% female) with hemodynamic data from the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness trial. In this cohort, 28.6% and 69.7%, respectively, experienced the outcomes of death, transplantation, or ventricular assist device implantatation (DVADTX) and DVADTX or HF rehospitalization (DVADTXHF) during 6 months of follow-up. Increasing RVSWI (DeltaRVSWI) from baseline to discharge was associated with a decrease in DVADTXHF (hazard ratio [HR] 0.923, 95% confidence interval [CI] 0.871 0.979) per 0.1 mm Hg?L?m-2 increase); however, increasing LVSWI (DeltaLVSWI) had only a nonsignificant association with decreased DVADTXHF (P = .11) In a multivariable model, patients with DeltaRVSWI <=1.07 mm Hg?L?m-2 and DeltaLVSWI <=4.57 mm Hg?L?m-2 had a >2-fold risk of DVADTXHF (HR 2.05, 95% CI 1.23-3.41; P = .006). CONCLUSION: Compared with left ventricular stroke work, increasing right ventricular stroke work during treatment of ADHF was associated with better outcomes. The results promise to inform optimal hemodynamic targets for ADHF. PMID- 28712957 TI - Secretory expression of beta-mannanase from Bacillus circulans NT 6.7 in Lactobacillus plantarum. AB - The beta-mannanase gene of Bacillus circulans NT 6.7 was successfully cloned in Lactobacillus plantarum WCFS1 using the pSIP403 expression vector and secreted to the supernatant rather than accumulated in the cells. The highest activity was achieved by controlling the pH at 6 during cultivation. Maximum mannanase activities detected in the supernatant and cell-free extract of 200 ml MRS broth were 8.2 and 0.86 U/ml, respectively. Enzyme activity in the supernatant increased to 27 U/ml by fermentation in a 5-L bioreactor with automatic pH control. The optimum temperature of recombinant beta-mannanase was 50 degrees C and stable between 30 and 50 degrees C. The optimum pH was 6 with stability in the range 5-7. Enzyme activity slightly increased with Co2+ but was strongly inhibited by EDTA. The enzyme exhibited high specificity to galactomannan substrates. The main products of copra meal and locust bean gum hydrolysis were manno-oligosaccharides. Therefore, recombinant beta-mannanase produced from a food grade host, L. plantarum WCFS1, showed potential for use in manno oligosaccharides production and other food-related applications. PMID- 28712956 TI - Refolding of a novel cholesterol oxidase from Pimelobacter simplex reveals dehydrogenation activity. AB - Cholesterol oxidases, which catalyze the degradation of cholesterol to cholest-4 en-3-one, are widely used in the pharmaceutical and food processing industries. The cholesterol oxidase from Pimelobacter simplex (PsChO3) was transformed into E. coli BL21(DE3), but it was expressed mainly as inclusion bodies, and any soluble PsChO3 failed to bind to Ni-NTA resin. To overcome this obstacle, we devised a simple yet efficient purification and refolding process using 8 M urea for the solubilization of PsChO3 and achieved a high yield of the enzyme in its active form. Column-bound PsChO3 was refolded in situ through a gradient of successively decreased urea concentrations and purified using Ni-affinity chromatography, ionic exchange and gel filtration. This treatment converted the denatured PsChO3 into a soluble protein exhibiting an unexpected dehydrogenation activity amounting to 9.27 U/mg - an activity not reported for enzymes with noncovalently-linked FAD to date. The product, cholest-5-en-3-one, was confirmed using TLC, GC-MS and NMR. Structural analysis revealed a distinct binding mode in both FAD and substrate domain, which may explain the enzyme's unusual catalytic behavior. PMID- 28712958 TI - Enhancing oxidative stress resistance in Bifidobacterium thermophilum using a novel overexpression vector and transformation protocol. AB - Bifidobacterium thermophilum is encountered in the GI-tract of pigs and infants. Here we provide a transformation protocol for B. thermophilum and a novel expression vector for this species. The protocol resulted in transformation rates of 1*103 transformed cells per MUg DNA. Transformation was shown to be dependent on the presence of fructo-oligosaccharides during growth, polyethylene glycol in the electroporation buffer, and on methylation of the vector. The Escherichia coli - B. thermophilum shuttle vector pLFB1012 for heterologous gene expression was constructed harbouring the glyceraldehyde 3-phosphate dehydrogenase promoter from Bifidobacterium longum (Pgap). Activity of the beta-glucoronidase gene gusA under control of Pgap could be detected at a 20-fold higher rate compared to the wild type, showing activity of the promoter in B. thermophilum. Thereafter, the B. longum gene bl_1404, previously proposed to be involved in oxidative stress resistance, was cloned under control of the Pgap. The wild type cell numbers of B. thermophilum RBL 67 decreased at least 9 log after a 20-mM H2O2 treatment for 60min whereas the mutant strain expressing bl_1404 showed an increased survival of 2 logs compared to the wild type strain. To our knowledge this is the first report on transformation of B. thermophilum. Further, it is shown that pLFB1002 is suitable for engineering B. thermophilum and that bl_1404 from B. longum is involved in peroxide resistance in bifidobacteria. PMID- 28712960 TI - MRTF-A mediated FN and ICAM-1 expression in AGEs-induced rat glomerular mesangial cells via activating STAT5. AB - Advanced glycation end products (AGEs), formed at an accelerated rate under diabetes, play a role in inflammation and fibrosis in mesangial areas in diabetic nephropathy (DN). However, the transcriptional modulator that mediates the cellular response to AGEs remains largely obscure. Our goal was to determine whether myocardin-related transcription factor (MRTF)-A, a key protein involved in the transcriptional regulation of smooth muscle cell phenotype, was responsible for the glomerular mesangial cells (GMCs) injury by AGEs, and, if so, how MRTF-A promoted mesangial dysfunction initiated by AGEs. In this study, MRTF A was activated by AGEs in terms of protein expression and nuclear translocation in rat GMCs. MRTF-A overexpression synergistically enhanced the induction of FN and ICAM-1 by AGEs. In contract, depletion of MRTF-A abrogated the pathogenic program triggered by AGEs. Then, by interfering with MRTF-A, STAT1, STAT3 and STAT5 nuclear translocation were observed and we screened out STAT5, which was decreased obviously when MRTF-A depleted. Further investigation showed that MRTF A interacted with STAT5 and promoted its nuclear accumulation and transcriptional activity. Therefore, our present findings suggested a role of MRTF-A in AGEs induced GMCs injury, and further revealed that the underlying molecular mechanism was related to activating the nuclear factor STAT5. PMID- 28712961 TI - Disruption in "Nonanastomotic Section" of an Axillofemoral Bypass: A Thorough Critical Review of the Literature. AB - This work is a thorough nonsystematic critical review (PubMed/MEDLINE 1950 September 2016) of "disruption in nonanastomotic section of an axillofemoral bypass." Fourteen cases were selected (including that provided by the authors of this publication) dating from 1963 to 2016 (53 years). This type of disruption is a very unusual complication in the axillofemoral bypass. The cases described reveal that this disorder is more frequent in unifemoral bypass (9 cases), in ringed polytetrafluorethylene, in blunt trauma, and at costal level especially on the left side. The mean age of the patients was 65.2 (38-83) years, and the men:women ratio was 2:2. The usual symptom was a false aneurysm (10 cases). Although the imaging diagnosis of the first cases was done by arteriography, computed tomography is currently more used. The usual treatment (7 cases) consisted in the resection of the affected segment and the interposition of the new prosthesis. Furthermore, 2 cases treated with coated stent have been described, as well as 1 case of femorofemoral bypass, 1 of suture, and 1 of exeresis without revascularization. One patient refused surgery, and there was as a case where the treatment was unknown. The evolution in the short term is satisfactory, with no perioperative mortality registered. PMID- 28712959 TI - Associations between long-term exposure to air pollution, glycosylated hemoglobin and diabetes. AB - BACKGROUND: Air pollution exposures have been shown to adversely impact health through a number of biological pathways associated with glucose metabolism. However, few studies have evaluated the associations between air pollution and glycosylated hemoglobin (HbA1c) levels. Further, no studies have evaluated these associations in US populations or investigated whether associations differ in diabetic as compared to non-diabetic populations. To address this knowledge gap, we investigated the associations between airborne fine particulate matter (PM2.5) and nitrogen dioxide (NO2) and HbA1c levels in both diabetic and non-diabetic older Americans. We also examined the impact of PM2.5 and NO2 on prevalent diabetes mellitus (DM) in this cohort. METHODS: We used multilevel logistic and linear regression models to evaluate the association between long-term average air pollutant levels and prevalence of DM and HbA1c levels, respectively, among 4121 older (57+ years) Americans enrolled in the National Social Life, Health, and Aging Project between 2005 and 2011. All models adjusted for age, sex, body mass index, smoking status, race, household income, education level, neighborhood socioeconomic status, geographic region, urbanicity and diabetic medication use. We estimated participant-specific exposures to PM2.5 on a six-kilometer grid covering the conterminous U.S. using spatio-temporal models, and to NO2 using nearest measurements from the Environmental Protection Agency's Air Quality System. HbA1c levels were measured for participants in each of two data collection waves from dried blood spots and log-transformed prior to analysis. Participants were considered diabetic if they had HbA1c values>=6.5% or reported taking diabetic medication. RESULTS: The prevalence of diabetes at study entry was 22.2% (n=916) and the mean HbA1c was 6.0+/-1.1%. Mean one-year moving average PM2.5 and NO2 exposures were 10.4+/-3.0MUg/m3 and 13.1+/-7.0 ppb, respectively. An inter-quartile range (IQR, 3.9MUg/m3) increase in one-year moving average PM2.5 was positively associated with increased diabetes prevalence (prevalence odds ratio, POR 1.35, 95% CI: 1.19, 1.53). Similarly, an IQR (8.6 ppb) increase in NO2 was also significantly associated with diabetes prevalence (POR 1.27, 95% CI: 1.10, 1.48). PM2.5 (1.8%+/-0.6%, p<0.01) and NO2 (2.0%+/-0.7%, p<0.01) exposures were associated with higher HbA1c levels in diabetic participants, while only NO2 was significantly associated with HbA1c in non-diabetic participants (0.8%+/-0.2%, p<0.01). Significant dose response relationships were identified for both pollutants in diabetic participants and for NO2 in non diabetic participants. CONCLUSIONS/INTERPRETATIONS: In a cohort of older men and women in the United States, PM2.5 and NO2 exposures were significantly associated with prevalence of DM and increased HbA1c levels among both non-diabetic and diabetic participants. These associations suggest that air pollution could be a key risk factor for abnormal glucose metabolism and diabetes in the elderly. PMID- 28712962 TI - Fenestrated Endograft as a New Perspective for the Treatment of Infrarenal Abdominal Aortic Aneurysm with a Congenital Pelvic Kidney-A Case Report and Review of Literature. AB - The coexistence of abdominal aortic aneurysm (AAA) and congenital pelvic kidney is infrequent. Various treatment modalities have been reported in literature for the treatment of the aforementioned condition. We report a complete endovascular modality for the treatment of this association, especially for high-risk patients. Only one such treatment has been reported before. Compared with this previously reported case, we would like to share our experience with additional prototype testing, before surgery, which provided us with more detailed information about the planning and deployment of the branched endograft. An incidental 7-cm infra renal AAA with the presence of right pelvic kidney was detected on magnetic resonance imaging performed for back pain in a 75-year-old male patient with a history of 2 previous myocardial infarctions and a radical prostatectomy for prostate cancer. He was unfit for open surgery. We report a custom-made fenestrated endograft with prior prototype information used for the repair of a large aneurysm with right pelvic kidney. This procedure is less invasive than any other reported treatment modalities such as open surgery or hybrid procedures. This procedure has an added advantage in that there is no renal ischemia, and recovery is significantly faster. PMID- 28712964 TI - On the Use of Nonsteroidal Anti-Inflammatory Drugs as Rheology Modifiers for Surfactant Solutions. AB - Surfactant molecules can give rise to different morphological structures, depending on numerous parameters such as temperature, surfactant concentration, and salinity. Specifically, the salt content can be easily tuned in a way to induce morphological transitions and modulate the rheological response. It is shown that nonsteroidal anti-inflammatory drugs can be used in the same way as classical binding salts in changing the rheological properties of the resulting gel-like system. On the one hand, the experimental results show that by tuning small details in the molecular conformation of the drug and its concentration in the micellar solution, it is possible to obtain the desired mechanical response. On the other hand, the results prove that rheology can be considered as a powerful tool to detect the drug release content, with obvious consequences on possible applications. PMID- 28712963 TI - Anti-quorum sensing activity of Pistacia atlantica against Pseudomonas aeruginosa PAO1 and identification of its bioactive compounds. AB - Pseudomonas aeruginosa is a multidrug resistant opportunistic pathogen and an important cause of nosocomial infections. Quorum-sensing (QS) is a process in which bacterial cell-cell communication can regulates production of many virulence factors including pigment formation and the ability to form biofilm which is essential for establishment of chronic infections. We examined the inhibitory effect of Pistacia atlantica (Anacardiaceae) methanolic leaf extract and its bioactive components on biofilm formation and pigment production by P. aeruginosa PAO1. Fractionation of the methanolic leaf extract was carried out using HPLC based activity profiling. Identification of the active compounds was carried out by the integrated approach of HPLC-DAD and LC-MS followed by molecular docking analysis. Pistacia atlantica crude extract at 2 and 1 mg/mL, inhibited 92% and 79% biofilm formation, respectively. Minimum biofilm inhibitory concentration (MBIC) determined by microbroth dilution was 0.25 mg/mL with 39% inhibition. Pyocyanin production measured by spectrophotometry showed 100% and 83% inhibition at 2 and 1 mg/mL and minimum inhibitory concentration (MIC) was 0.5 mg/mL with 40% inhibition. Four active HPLC fractions (11, 15, 16 and 19) showed MBIC values of 0.06, 0.16, 0.10, 0.15 mg/mL, and MICs for pyocyanin production of 0.49, 0.31, 0.76, >0.30 mg/mL, respectively. The active compounds were identified as rutin (1), myricetin, 3-O-rutinoside (2) and kaempferol-3-O rutinoside (4), all belonging to the flavonoid family. Molecular docking simulation of the active compounds showed that all had high affinity for LasR protein which is an important quorum-sensing signal receptor. The results of this study suggest that the active components of P. atlantica have high anti-QS activities and may have the potential for treatment of chronic infections caused by Pseudomonas aeruginosa. PMID- 28712966 TI - Positive symptoms and social cognition impairment affect severity of suicidal ideation in schizophrenia. PMID- 28712965 TI - Trial exclusion criteria and their impact on the estimation of antipsychotic drugs effect: A case study using the SOHO database. AB - OBJECTIVES: To explore the impact upon estimation of drug effect as a result of applying exclusion criteria in randomized-controlled trials (RCT) measuring the efficacy of antipsychotics (AP) in schizophrenia. METHODS: Three characteristics which may act as effect-modifiers of AP, while also common exclusion criteria in RCTs, were identified through literature review: schizophrenia duration, substance use disorder and poor adherence. The SOHO cohort was used to estimate the effect of initiating antipsychotic drugs "A", "B" or "C" (pooled) upon symptom evolution at 3months from baseline (CGI-S scale). "Estimated effectiveness" and "estimated efficacy" were drawn from the "SOHO" and "RCT-like" (patients with none of the above-listed exclusion criteria) samples, respectively. Effect-modification and impact of each exclusion criterion on AP effect estimates were explored using non-adjusted statistics. RESULTS: The "SOHO sample" included 8250 patients initiating drug A, B or C at baseline, whose AP "estimated effectiveness" was DeltaCGI-S=-0.78 (95% CI=-0.80, -0.76). The "RCT like" sub-sample included 5348 (65%) patients whose AP "estimated efficacy" was DeltaCGI-S=-0.73 (95% CI=-0.75, -0.70). Patients with short illness duration (<=3years since first AP; n=2436) experienced significant symptom improvement (DeltaCGI-S=-0.89; 95%CI=-0.93, -0.85) compared to patients with duration >3years (mean DeltaCGI-S=-0.73; 95%CI=-0.76, -0.71). Excluding patients with short illness duration led to a change in AP effect estimates but this was not the case for substance use disorder or poor adherence. CONCLUSION: Using certain exclusion criteria in RCTs may impact the drug's effect estimate, particularly when exclusion criteria are AP effect-modifiers representing frequent characteristics among patients with schizophrenia. PMID- 28712967 TI - Clinical utility of the Calgary Depression Scale for Schizophrenia in individuals at ultra-high risk of psychosis. AB - There is a pressing need for reliable and valid rating scales to assess and measure depression in individuals at ultra-high risk (UHR) of psychosis. The aim of this study was to examine the clinical utility of the Calgary Depression Scale for Schizophrenia (CDSS) in individuals at UHR of psychosis. 167 individuals at UHR of psychosis were included as participants in this study. The Structured Clinical Interview for DSM-IV Axis I Disorders, CDSS, Beck Anxiety Inventory and Global Assessment of Functioning were administered. A receiver operating characteristic (ROC) curve analysis and factor analyses were performed. Cronbach's alpha was computed. Correlations between CDSS factor scores and other clinical variables were examined. The median CDSS total score was 5.0 (IQR 1.0 9.0). The area under ROC curve was 0.886 and Cronbach's alpha was 0.855. A score of 7 on the CDSS yielded the highest sensitivity and specificity in detecting depression in UHR individuals. Exploratory factor analysis of the CDSS yielded two factors: depression-hopelessness and self depreciation-guilt, which was confirmed by confirmatory factor analysis. Further analysis showed that the depression-hopelessness factor predicted functioning; whereas the self depreciation-guilt factor was related to the severity of the attenuated psychotic symptoms. In conclusion, the CDSS demonstrates good psychometric properties when used to evaluate depression in individuals at UHR of psychosis. Our study results also support a two-factor structure of the CDSS in UHR individuals. PMID- 28712968 TI - Treatment of social cognition in schizophrenia: Current status and future directions. AB - Efforts to develop psychosocial interventions that specifically target social cognition in schizophrenia spectrum disorders began nearly two decades ago. The field has matured considerably since then and has engendered a great deal of optimism about this treatment approach. Indeed, the efficacy of social cognitive interventions, especially those that address multiple domains of social cognition, has received substantial support. This article critically evaluates the current evidence for social cognitive interventions, identifies limitations and open questions, and suggests priorities and directions for further research. Limitations of available studies include a frequent lack of methodological rigor, suboptimal selection of endpoints, and sparse evidence for generalization to functional improvements. We highlight several emerging psychosocial and non psychosocial approaches that may enhance the efficacy of social cognitive interventions and promote generalization to improvements in real world functioning. We conclude that cautious optimism is warranted as the field moves forward into the next wave of social cognitive treatment studies. PMID- 28712969 TI - The role of self-disturbances and cognitive biases in the relationship between traumatic life events and psychosis proneness in a non-clinical sample. AB - BACKGROUND: Traumatic life events have been established as an environmental risk factor for psychosis. However, the exact mechanisms by which traumatic life events increase risk for psychosis are unknown. In the present study we tested an integrative model of traumatic life events being related to psychosis proneness via self-disturbances and cognitive biases. METHODS: The sample consisted of 653 healthy people. Traumatic life events, self-disturbances, cognitive biases and psychosis proneness were assessed with self-report questionnaires. The direct and an indirect model of the relationship between traumatic life events and psychosis proneness were compared using path analyses with structural equation modelling in a cross-sectional study. RESULTS: There was a significant direct effect of traumatic life events on psychosis proneness. However, path analysis suggested better fit of the indirect model including paths from trauma to psychosis proneness via cognitive biases and self-disturbances. There were significant paths from traumatic life events to cognitive biases and self-disorders. Self disorders significantly predicted cognitive biases. Finally, cognitive biases and self-disorders significantly predicted psychosis proneness. Exclusion of any paths, apart from direct path in the model, significantly reduced model fitness. DISCUSSION: The results revealed that a direct relationship between trauma and psychosis proneness became insignificant when taking into account the influence of self-disorders and cognitive biases. This suggests that the interactions between disrupted self-experience, impaired information processing and traumatic life events are of importance in psychosis proneness. This model should be further tested in a longitudinal study on a clinical sample. PMID- 28712970 TI - Cortical responses to tone and phoneme mismatch as a predictor of dyslexia? A systematic review. AB - Evidence from event-related-potential (ERP) studies has repeatedly shown differences in the perception and processing of auditory stimuli in children with dyslexia compared to control children. The mismatch negativity (MMN) - an ERP component reflecting passive auditory change detection ability - has been found to be reduced, not only in children with a diagnosis of dyslexia, but also in infants and preschool children at risk of developing dyslexia. However, the results are controversial due to the different methods, age of the children and stimuli used. The aim of the present review is to summarize and evaluate the MMN research about at-risk children in order to identify risk factors that discriminate between children with and without dyslexia risk and to analyze if the MMR (the abbreviation refers to positive and negative mismatch responses) correlates with later reading and spelling ability. A literature search yielded 17 studies reporting MMR to speech or non-speech stimuli in children at risk of dyslexia. The results of the studies were inconsistent. Studies measuring speech MMR often found attenuated amplitudes in the at-risk group, but mainly in very young children. The results for older children (6-7years) and for non-speech stimuli are more heterogeneous. A moderate positive correlation of MMR amplitude size with later reading and spelling abilities was consistently found. Overall, the findings of this review indicate that the MMR can be a valuable part of early dyslexia identification, which can enable efficient support and intervention for a child before the first problems appear. PMID- 28712971 TI - Drug repurposing in cancer. AB - Cancer is a major health issue worldwide, and the global burden of cancer is expected to increase in the coming years. Whereas the limited success with current therapies has driven huge investments into drug development, the average number of FDA approvals per year has declined since the 1990s. This unmet need for more effective anti-cancer drugs has sparked a growing interest for drug repurposing, i.e. using drugs already approved for other indications to treat cancer. As such, data both from pre-clinical experiments, clinical trials and observational studies have demonstrated anti-tumor efficacy for compounds within a wide range of drug classes other than cancer. Whereas some of them induce cancer cell death or suppress various aspects of cancer cell behavior in established tumors, others may prevent cancer development. Here, we provide an overview of promising candidates for drug repurposing in cancer, as well as studies describing the biological mechanisms underlying their anti-neoplastic effects. PMID- 28712972 TI - Arenobufagin inhibits prostate cancer epithelial-mesenchymal transition and metastasis by down-regulating beta-catenin. AB - Epithelial-mesenchymal transition (EMT) plays an important role in prostate cancer (PCa) metastasis; thus, developing EMT inhibitors may be a feasible treatment for metastatic PCa. Here, we discovered that arenobufagin and four other bufadienolides suppressed PC3 cell EMT. These compounds modulated EMT marker expression with elevating E-cadherin and reducing ZEB1, vimentin and slug expression, and attenuated the migration and invasion of PC3 cells. Among these five compounds, arenobufagin exhibited the most potent activity. We found that the mRNA and protein expression of beta-catenin and beta-catenin/TCF4 target genes, which are related to tumor invasion and metastasis, were down-regulated after arenobufagin treatment. Overexpression of beta-catenin in PC3 cells antagonized the EMT inhibition effect of arenobufagin, while silencing beta catenin with siRNA enhanced the inhibitory effect of arenobufagin on EMT. In addition, arenobufagin restrained xenograft tumor EMT, as demonstrated by decreased mesenchymal marker expression and increased epithelial marker expression, and reduced the tumor metastatic foci in lung. This study demonstrates a novel anticancer activity of arenobufagin, which inhibits PC3 cell EMT by down-regulating beta-catenin, thereby reducing PCa metastasis. In addition, it also provides new evidence for the development of arenobufagin as a treatment for metastatic prostate cancer. PMID- 28712973 TI - Occurrence of Lutzomyia longipalpis Lutz & Neiva 1912 and Cerdocyon thous Linnaeus 1977, in a visceral leishmaniasis endemic area in Brazil. AB - Cerdocyon thous presents a wide geographic distribution in Brazil and its role as a possible Leishmania infantum reservoir in a visceral leishmaniasis (VL) transmission cycle regardless of dogs (Canis familiaris) has been discussed. From this perspective, this work describes the occurrence and use of the habitat by Cerdocyon thous in a Lutzomyia longipalpis occurrence area Teresina (Piaui - Brazil), VL endemic region. Three specimens of C. thous were monitored with the use of radio telemetry and trails and footprints, seeking to find possible natural dens in order to collect the sanflies from the site. Luminous CDC and Damasceno traps were simultaneously installed at the visited sites, where two specimens of L. longipalpis and one L. termitophila were captured. The identification of the dens and trails, allows us to infer that the dens are not used only by the C. thous. Finding the VL vector in natural C. thous natural dens, reinforces the hypothesis of transmission of Le. infantum in the outskirts of the large urban centers, in a cycle that independs from dogs. PMID- 28712974 TI - Diversity and altitudinal distribution of phlebotomine sand flies (Diptera: Psychodidae) in visceral leishmaniasis endemic areas of northwest Ethiopia. AB - BACKGROUND: The Leishmaniases are caused by the protozoan parasites of the genus Leishmania and are transmitted to humans by the bite of infected female phlebotomine sand flies. Both visceral and cutaneous leishmaniases are widely distributed in different parts of Ethiopia. The aim of this study was to determine the diversity and altitudinal distribution of phlebotomine sand flies from Kafta Humera to Gondar town in northwest Ethiopia. METHODS: Seven localities were selected with distinct altitudinal variations between 550m above sea level (m a.s.l) and 2300m a.s.l. In each locality, sand flies were collected using standard CDC light traps and sticky traps during the active sand fly season from December 2012 to May 2013. Shannon-Weiner species diversity index and Jaccard's coefficient were used to estimate species diversity and similarity between altitudes and localities, respectively. RESULTS: A total of 89,044 sand flies (41,798 males and 47, 246 females) were collected from the seven localities/towns throughout the study period. Twenty-two species belonging to 11 species in the genus Phlebotomus and 11 species in the genus Sergentomyia were documented. Of these, Sergentomyia clydei (25.87%), S. schwetzi (25.21%), S. africana (24.65%), S. bedfordi (8.89%), Phlebotomus orientalis (6.43%), and S. antennata (4.8%) were the most prevalent species. The remaining 10 Phlebotomus species and six Sergentomyia were less frequent catches. In CDC light trap and sticky trap, higher species diversity and richness for both male and female sand flies was observed at low altitude ranging from 550 to 699m a.s.l in Adebay village in Kafta Humera district whereas low species richness and high evenness of both sexes were also observed in an altitude 1950-2300m a.s.l. CONCLUSION: The results revealed that the presence of leishmaniasis vectors such as P. orientalis, P. longipes, P. papatasi, and P. duboscqi in different altitudes in northwest Ethiopia. P. orientalis a vector of L. donovani, occurred between altitude 500 1100m a.s.l, the area could be at high risk of VL. P. longipes a vector of L. aethiopica, was recorded in the highland area in Tikil-Dingay and Gondar town, implicating the possibility of CL transmission. Hence, further investigation into vector competence in relation to leishmaniasis (VL and CL) in the region is very vital. PMID- 28712975 TI - FTO genotype and weight status among preadolescents: Assessing the mediating effects of obesogenic appetitive traits. AB - Polymorphisms in the Fat Mass and Obesity Associated (FTO) gene are robustly associated with overweight and obesity among children, although the underlying mechanisms are poorly understood. We tested if appetitive traits partially mediated the association between FTO genotype and increased BMI among a sample of US preadolescents. Data were from 178 unrelated 9-10 year olds who participated in an experimental study between 2013 and 2015. Children's DNA was isolated from buccal swabs, and the rs9939609 SNP in the FTO gene was genotyped. Children's age and sex-adjusted BMI z-scores were computed using height and weight measured at the laboratory. Parents completed the Child Eating Behavior Questionnaire that includes three validated scales of habitual appetitive traits related to drive and regulation: satiety responsiveness, enjoyment of food and food responsiveness. Structural equation modeling was used to assess if those traits mediated the relationship between FTO and BMI z-score. The sample of children was 48.9% male and 91.0% non-Hispanic white. FTO distribution was in Hardy Weinberg equilibrium, and 16.3% of participants were homozygous for the high-risk allele. Mean BMI z-score was greatest among those with the high-risk genotype (ANOVA P < 0.01). In separate structural equation models adjusted for the child's sex and maternal education, decreased satiety responsiveness and increased food responsiveness each partially mediated the positive association between the high risk genotype and increased BMI z-score (P-value for each indirect effect <0.05). Continued research is needed to better understand how other known genetic obesity risk factors may impact appetitive traits among children. PMID- 28712976 TI - Repetitive eating questionnaire [Rep(eat)-Q]: Enlightening the concept of grazing and psychometric properties in a Portuguese sample. AB - BACKGROUND/OBJECTIVE: Grazing has been associated with poor weight loss or weight regain in obese patients undergoing bariatric surgery, but research remains scarce and complicated by the use of different non-validated measures. The aim of this paper is to describe the validation of the Rep(eat)-Q, a self-report measure developed to assess grazing, and investigates its relationship with BMI and psychopathology. SUBJECTS/METHODS: 1223 university students and community participants (non-clinical; Study A) and 154 pre-bariatric and 84 post-bariatric patients (Study B) completed a set of self-report measures, including the Rep(eat)-Q (worded in Portuguese), to assess disordered eating, depression, anxiety, stress and impulsivity. Exploratory and confirmatory factor analyses tested the factor structure; internal consistency construct, convergent and divergent validity were also tested. RESULTS: The Rep(eat)-Q scales showed good internal consistency (alpha >= 0.849) and temporal stability (rsp = 0.824, p < 0.000). Factor analyses generated two subscales: compulsive grazing and repetitive eating. Significant correlations (p < 0.05) were found between the Rep(eat)-Q and BMI in the non-clinical population and weight loss and weight regain in the bariatric sample. Generally, the correlations with psychological distress were weak (rsp < 0.4). Strong and significant (rsp>=0.4; p's < 0.05) correlations were found between compulsive grazing and eating disorder psychopathology. Repetitive eating subscale was inversely correlated with cognitive restraint (rsp -0.321, p < 0.05) and directly correlated with uncontrolled eating and emotional eating (rsp = 0.754; rsp = 0.691; p < 0.05). DISCUSSION/CONCLUSION: The Rep(eat)-Q is a valid measure to assess grazing in non clinical and in bariatric surgery populations. Grazing can be conceptualized on the spectrum of disordered eating behavior, and appears associated with loss of control over eating. Considering the link between grazing and weight outcomes, the Rep(eat)-Q represents a necessary strategy for the systematic screening of grazing. PMID- 28712977 TI - Food marketing with movie character toys: Effects on young children's preferences for unhealthy and healthier fast food meals. AB - This study aimed to test whether movie tie-in premiums (MTIPs) accompanying unhealthy and healthier fast food meals influenced children's meal preferences and their perceptions of these meals. Nine hundred and four Grade 1 and 2 students (aged 5-9 years) from Melbourne, Australia participated in a between subjects online experiment comprising the following conditions: (A) unhealthy and healthier meals with no MTIP (control); (B) unhealthy and healthier meals with MTIP (current situation in Australia); (C) unhealthy meals with MTIP and healthier meals without MTIP; (D) unhealthy meals without MTIP and healthier meals with MTIP. The latter condition tested a potential regulatory model restricting premiums to healthier meals. Participants were shown a trailer for a current children's movie followed by an advertisement for an associated McDonald's Happy Meal(r) (conditions B-D) or an advertisement for a children's leisure activity (condition A). They were then shown four McDonald's Happy Meal(r) options on screen and asked to select their preferred meal before completing detailed meal ratings. Overall, children showed a preference for unhealthy meals over healthier ones. Children were significantly more likely to select a healthier meal over an unhealthy meal when only the healthier meals were accompanied by a MTIP (condition D) compared to the other three conditions. When healthier meals were accompanied by a MTIP, children reported the meal looked better, would taste better, they would be more likely to ask their parents for this meal, and they would feel happier if their parents bought them this meal, compared to when the healthier meal was not accompanied by a MTIP. Results suggest that modifying the food marketing environment to restrict MTIPs to healthier meals should encourage healthier fast food meal choices by children. PMID- 28712978 TI - Local Radiotherapy Intensification for Locally Advanced Non-small-cell Lung Cancer - A Call to Arms. AB - Chemoradiotherapy, the standard of care for locally advanced non-small-cell lung cancer (NSCLC), often fails to eradicate all known disease. Despite advances in chemotherapeutic regimens, locally advanced NSCLC remains a difficult disease to treat, and locoregional failure remains common. Improved radiographic detection can identify patients at significant risk of locoregional failure after definitive treatment, and newer methods of escalating locoregional treatment may allow for improvements in locoregional control with acceptable toxicity. This review addresses critical issues in escalating local therapy, focusing on using serial positron emission tomography-computed tomography to select high-risk patients and employing stereotactic radiotherapy to intensify treatment. We further propose a clinical trial concept that incorporates the review's findings. PMID- 28712980 TI - Association of Selective Serotonin Reuptake Inhibitors and Bone Mineral Density in Elderly Women. AB - Depression and osteoporosis are 2 common comorbidities in geriatric patients. There are concerns about the deleterious effects of selective serotonin reuptake inhibitor (SSRI) antidepressant use on bone mineral density (BMD). We examined the association between SSRI use and BMD in elderly women (>=65 yr) referred to a geriatric osteoporosis clinic for bone health evaluation. Cross-sectional analyses using the general linear model were performed on data collected retrospectively from August 2010 to April 2015. A total of 250 women were seen during the study period. Of these, 140 women had complete data on BMD measurements: 22 (15.7%) used an SSRI and 118 (84.3%) did not. The 2 groups, SSRI users and SSRI nonusers, did not differ significantly across any of the covariates tested (age, ethnicity, body mass index, and past and present osteoporosis treatment medications). After adjusting for covariates, there was no difference in the BMDs at the femoral neck (p = 0.887) or the spine (p = 0.275) between the 2 groups. Similarly, no difference was seen in the T-scores between SSRI users and nonusers at the femoral neck (p = 0.924) or at the spine level (p = 0.393). Our study did not show an association between SSRI use and BMD among elderly women referred for bone health evaluation. Other studies in the literature have been inconclusive, and therefore, robust longitudinal studies are needed to further assess the interaction between SSRI use and predictors of fracture such as BMD, bone turnover markers, and genes involved in bone turnover. Until then, clinicians should closely monitor the bone health of long-term SSRI users. PMID- 28712979 TI - Clinical Implications of the T790M Mutation in Disease Characteristics and Treatment Response in Patients With Epidermal Growth Factor Receptor (EGFR) Mutated Non-Small-Cell Lung Cancer (NSCLC). AB - BACKGROUND: The secondary T790M mutation accounts for more than 50% of acquired tyrosine kinase inhibitor (TKI) resistance in patients with EGFR-mutated non small-cell lung cancer (NSCLC). Recent reports suggest this resistance mutation may be more common among patients with longer progression-free survival (PFS) on first-line TKI therapy, but much is still unknown. MATERIALS AND METHODS: Our group collected medical records from patients who underwent a biopsy for T790M mutation testing while screening for clinical trials involving the drug rociletinib (CO-1686), a T790M mutation-specific TKI. Medical records were retrospectively analyzed for demographic data, PFS, and best response to previous therapies. RESULTS: Our patient cohort included 69 T790M+ patients and 28 T790M- patients. Patients who later developed a T790M mutation had a longer PFS on first line TKI therapy (12.0 vs. 9.0 months, P = .021), but overall response rate (ORR) was the same (75.0% vs. 81.0%, P = .76). There was no difference in PFS on TKI rechallenge (4.0 vs. 3.0 months, P = .94), although there was a trend toward higher ORR in T790M+ patients (22.2% vs. 0%, P = .12). T790M+ patients had a longer PFS on initial chemotherapy treatment (5.0 vs. 4.0 months, P = .025) and a trend toward higher ORR (40.0% vs. 21.4%, P = .31). CONCLUSION: Our study confirms that tumors expressing T790M have a more indolent progression of disease compared with their T790M- counterparts when treated with both first-line TKI and cytotoxic chemotherapy. PMID- 28712981 TI - Judo Practice in Early Age Promotes High Level of Bone Mass Acquisition of Growing Boys' Skeleton. AB - The current study aimed to exhibit effects of judo training for at least 2 yr on bone mass parameters in growing boys. Our population was composed of one hundred and thirty boys in tanner stage 1 and aged 10.52 +/- 0.86 yr. Eleven judo players were therefore, excluded from the study because they do not have participate regularly to the judo training sessions during the last 2 yr. The resting sample was divided into two groups: 50 judo players (JU group) and 69 controls (C group). Bone mineral density (BMD), bone mineral content (BMC), and bone area (BA) were evaluated by using dual-photon X-ray absorptiometry on weight-bearing sites: the whole body, lumbar spine (L2-L4), legs, femoral necks and hips and on the non-weight bearing sites: arms and radiuses. Our findings displayed that judo participation was markedly associated with greater values of bone mass parameters in young judo players than control group. Accordingly, the BMD and BA results exhibited significant differences in the whole body, legs, dominant total hip, arms and both whole radiuses in addition to the dominant femoral neck, the non dominant total hip and except the non-dominant whole radius for the BMC parameter. Additionally, data of the subject within t test has shown significant differences of bone mass parameters only in the non weight-bearing sites in the judo players without any obvious variation in the controls. Differences of BMD observed on the dominant arm and whole radius in addition to the increased BMC values showed in the dominant whole radius compared with their contra-lateral sites in judo players without any marked variation of BA parameters in all sites in both groups. In growing boys, judo practice was obviously associated with osteogenic effects in specific sites. PMID- 28712982 TI - Fracture Risk Prediction Modeling and Statistics: What Should Clinical Researchers, Journal Reviewers, and Clinicians Know? AB - Fractures are binary events (they either occur or they do not), and predicting whether fractures may occur involves assigning probabilities of one or more of those events occurring over time to populations and to individuals. Fracture risk prediction has become central to the management of osteoporosis and fracture prevention in clinical practice, and the ultimate clinical usefulness of the prediction tools used to estimate these risks depends, at a minimum, on the validity and accuracy of those tools. In this paper, we will describe how fracture prediction models are developed and validated, and how their performance characteristics are assessed. We will provide a checklist by which clinicians, clinical researchers, and reviewers of journal submissions can judge whether a fracture prediction tool meets basic requirements of good performance. We will further describe how the incremental predictive value of additional diagnostic tools, such as bone mass measurement technologies, is assessed. PMID- 28712983 TI - Older Age and Higher Body Mass Index Are Associated With a More Degraded Trabecular Bone Score Compared to Bone Mineral Density. AB - Trabecular bone score (TBS) may detect subjects with a more degraded microarchitecture but whose bone mineral density (BMD) reflects normal or osteopenia. The purpose of this study was to evaluate whether age and body sizes were associated with the discordance between BMD and TBS. We analyzed BMD and TBS in 1505 Korean women over 40 yr of age who had no history of osteoporotic fractures or conditions that affect bone metabolism. We considered 3 groups to have TBS values that reflected a more degraded TBS than their BMD values: (1) normal BMD but partially degraded TBS, (2) normal BMD but degraded TBS, and (3) osteopenia but degraded TBS. We compared subjects in these 3 groups with other subjects in terms of age and body sizes, and used multivariable logistic regression to analyze the odds ratios (ORs) for the occurrence of a more degraded TBS than their BMD level using age and body mass index (BMI). One hundred sixty subjects (10.6%) were found to have a more degraded TBS than their BMD level; these subjects were older, heavier, and had higher BMIs than the other subjects. Age (OR: 1.038, 95% confidence interval: 1.020-1.057, p <0.001) and BMI (OR: 1.223, 95% confidence interval: 1.166-1.283, p <0.001) were statistically significant in the multivariable analysis for the occurrence of this feature. Women with a more degraded TBS than their BMD level are older and have higher BMIs than the other subjects. It may be helpful to consider the possibility of trabecular bone degradation when clinically evaluating fracture risk in patients who are older or who have high BMIs with normal BMD or osteopenia. PMID- 28712984 TI - Quantitative Computed Tomography-Current Status and New Developments. AB - This review focuses on new developments and current controversies in the field of quantitative computed tomography. Recent positions of the International Society for Clinical Densitometry acknowledged the clinical value of quantitative computed tomography of the spine and the hip using clinical whole-body computed tomography (CT) scanners. Opportunistic screening summarizes a number of new approaches describing the dual use of clinical CT scans. For example, CT scans may have been taken for tumor diagnosis but may also be used for the prediction of high or low fracture risks as an additional benefit for the patient. The assessment of the cortical parameters is another topic of current research. In CT images of the spine and the hip, a number of techniques have been developed to determine the thickness, mass, and bone density of the cortex. In higher-spatial resolution peripheral CT images of the radius and tibia obtained from special purpose scanners, 1 focus is the measurement of cortical porosity. Two different approaches, one based on the direct segmentation of the pores and one based on cortical density, will be reviewed. PMID- 28712985 TI - An Ill-Defined Upper Abdominal Mass. PMID- 28712986 TI - The Effectiveness of Distraction as Procedural Pain Management Technique in Pediatric Oncology Patients: A Meta-analysis and Systematic Review. AB - CONTEXT: Diagnostic tests and treatment regimens for pediatric cancers involve invasive and painful procedures. Effective management of such pain has been shown to be suboptimal in many parts of the world, often because of the cost and limited availability of appropriate medications. Current evidence suggests that distraction (a relatively low-cost technique) is a promising intervention for procedural pain management. There is, however, limited evidence demonstrating its effectiveness in pediatric oncology patients. OBJECTIVES: A systematic review was conducted to ascertain the effectiveness of distraction as a procedural pain management technique in pediatric oncology patients. METHODS: Using a comprehensive search strategy, MEDLINE, PsycINFO, Cochrane Library, AMED, CINAHL, Web of Science, and EMBASE electronic databases were searched for studies comparing distraction techniques to standard care/any intervention. Using the selected studies, a systematic review and meta-analysis of randomized controlled trials was conducted. RESULTS: Two hundred ninety-nine studies were identified, with seven randomized control trials identified as eligible for inclusion. Pain was assessed using self-report, observer-report, and physiological measures. A meta-analysis of four studies showed distraction as effective in reducing procedural pain, based on self-reported pain. A meta-analysis of three studies, based on pulse rates, demonstrated similar results. For observer-reported pain, limited evidence supported the effectiveness of distraction. CONCLUSION: This systematic review demonstrates that distraction is a promising intervention for procedural pain. Future research should assess effectiveness of distraction in varied populations, to explore evidence of cultural influences on pain expression, measurement, and management approaches. PMID- 28712987 TI - The Trial of Ascertaining Individual Preferences for Loved Ones' Role in End-of Life Decisions (TAILORED) Study: A Randomized Controlled Trial to Improve Surrogate Decision Making. AB - CONTEXT: Patients with terminal illnesses often require surrogate decision makers. Prior research has demonstrated high surrogate stress, and that despite standards promoting substituted judgment, most patients do not want their surrogates to make pure substituted judgments for them. It is not known how best to help loved ones fulfill the surrogate role. OBJECTIVES: To test the effectiveness of an intervention to help surrogate decision makers. METHODS: One hundred sixty-six patients (41% with amyotrophic lateral sclerosis and 59% with gastrointestinal cancers) and their surrogates at two university medical centers were randomized to an intensive nurse-directed discussion of the end-of-life decision control preferences of the patient (TAILORED) or a discussion of nutrition (CONTROL); 163 completed baseline interviews and underwent the intervention. RESULTS: Twelve patients died during follow-up and 137 dyads completed the study. Post-intervention, using all available data, TAILORED patients and surrogates became more likely to endorse mutual surrogate decision making, that is, a balance of their own wishes and what the surrogate thinks best (adjusted odds compared with baseline for patients = 1.78, P = 0.04; adjusted odds for surrogates = 2.05, P = 0.03). CONTROL patients became 40% less likely to endorse mutual surrogate decision making (P = 0.08), and CONTROL surrogates did not change significantly from baseline (adjusted odds = 1.44, P = 0.28). Stress levels decreased for TAILORED surrogates (impact of events scale = 23.1 +/- 14.6 baseline, 20.8 +/- 15.3 f/u, P = 0.046), but not for CONTROL (P = 0.85), and post intervention stress was lower for TAILORED than CONTROL (P = 0.04). Surrogates' confidence was uniformly high at baseline and did not change. Caregiver burden (Zarit) increased from 12.5 +/- 6.5 to 14.7 +/- 8.1 for TAILORED (P < 0.01), while not changing for CONTROL, yet satisfaction with involvement in decision making was higher at follow-up for TAILORED than for CONTROL (71% vs. 52%, P = 0.03). CONCLUSION: TAILORED patients and surrogates who completed the study adopted a more mutual decision-making style, balancing their own wishes with what the surrogate thinks would be best for them. Surrogates reported less stress and more satisfaction. Confidence was high at baseline and did not change. There was a modest increase in caregiver burden. These findings suggest that interventions like TAILORED might positively impact surrogate decision making. PMID- 28712989 TI - Is amputation a viable treatment option in lower extremity trauma? AB - INTRODUCTION: There is currently no consensus on how to treat patients with lower extremity trauma. Should amputation be performed early on to avoid complications or should the limb be saved at any price? The goal of this study was to show that early amputation is a viable treatment option in lower extremity trauma cases. MATERIAL AND METHODS: Twenty patients who underwent early amputation and 16 patients who underwent limb-salvage were included with a minimum follow-up of 1year. The main endpoints were the Mangled Extremity Severity Score (MESS) used to predict amputation, complications, sequelae, bone union and functional outcomes. RESULTS: The amputees had a higher MESS score than those treated conservatively (7.8 vs. 4.9, P<0.00001), had a shorter hospital stay (P<0.022) and had fewer postoperative complications (P<0.003), especially infection-related (P<0.001). The prevalence of infection in limb-salvage patients was 61%. There was no significant difference between the two groups in terms of quality of life. DISCUSSION: In cases of lower extremity trauma, early amputation and limb-sparing treatment each have their advantages and disadvantages. Early amputation seems to be better in cases of complications, despite similar quality of life in the two groups in the long-term. It is a viable treatment option in cases of lower extremity trauma. Amputation must not be considered as a failure, but a deliberate choice due to the functional impact of complications that occur after limb-salvage. LEVEL OF EVIDENCE: Level IV study. PMID- 28712988 TI - The Spanish Adaptation of the Palliative Performance Scale (Version 2) Among Cancer Patients at the End of Life: Psychometric Properties. AB - BACKGROUND: Palliative Performance Scale (PPS) is a reliable tool to assess performance status in cancer patients receiving palliative care (PC). Spanish validated and culturally adapted tools are needed. OBJECTIVES: The objectives are to develop PPS translation and cross-cultural adaptation into Spanish and to assess its psychometric properties. DESIGN: Translation process with cross cultural adaptation to produce Spanish Palliative Performance Scale (PPS SPANISH). SETTINGS: PC Team at one University hospital in Spain. PARTICIPANTS: Fifteen advanced cancer patients (60 assessments) were included for PPS translation and validation and 250 patients for cross-sectional analysis. All participants were recruited at oncology ward, emergency area, and outpatient clinic by PC team professionals. Informed consent was given. Average age was 66.4 +/- 13 years (60% men). METHODS: The process is designed in three steps. In Step 1, PPS translation and reverse translation into Spanish (three bilingual speakers) and linguistic complexity measurement were performed. In Step 2, readability and intelligibility assessment was carried out. In Step 3, a pilot study was conducted to assess test-retest reliability followed by a cross sectional study to measure internal consistency. Inclusion criteria were the same for two samples. Demographic data were also analyzed by descriptive statistics. RESULTS: Following cultural, linguistic, and grammatical adaptation, PPS-SPANISH was readable and reliable. The analysis of the test-retest reliability after 48 hours showed intraclass correlations >0.60. Cronbach's alpha coefficient was 0.99 (0.988-0.992). There was high agreement with other functional assessment tools (Barthel Index and Karnofsky Performance Status Index). CONCLUSIONS: PPS-SPANISH showed reliability and validity, and it is suitable to assess performance status in cancer patients receiving PC. PMID- 28712990 TI - Supervoxel-based statistical analysis of diffusion tensor imaging in schizotypal personality disorder. AB - To study white matter changes in schizotypal personality disorder (SPD), we developed a new statistical analysis method based on supervoxels for diffusion tensor imaging. Twenty patients with SPD and eighteen healthy controls were recruited from a pool of 3000 first-year university undergraduates, and underwent MRI using a 3T scanner. Diffusion tensors were first normalized into ICBM-152 space followed by a supervoxel segmentation based on graph clustering to segment white matter tensors into diffusion homogeneous supervoxels. Fractional anisotropy (FA) values in supervoxels were compared between SPD and healthy controls using permutation test. Suprathreshold cluster size test was used to correct multiple comparison. At last, fibers with significant differences were extracted from supervoxel clusters with significance level P < 0.05. Results showed that FA values in genu of corpus callosum were significantly reduced (P = 0.012) in patients with SPD (FA = 0.565) compared with healthy controls (FA = 0.593). In summary, this study proposed a novel supervoxel segmentation method for diffusion tensor imaging using graph-based clustering, and extended permutation test and suprathreshold cluster size test to supervoxels for detection of white matter changes. PMID- 28712992 TI - Proton and multinuclear magnetic resonance spectroscopy in the human brain at ultra-high field strength: A review. AB - Magnetic Resonance Spectroscopy (MRS) allows for a non-invasive and non-ionizing determination of in vivo tissue concentrations and metabolic turn-over rates of more than 20 metabolites and compounds in the central nervous system of humans. The aim of this review is to give a comprehensive overview about the advantages, challenges and advances of ultra-high field MRS with regard to methodological development, discoveries and applications from its beginnings around 15 years ago up to the current state. The review is limited to human brain and spinal cord application at field strength of 7T and 9.4T and includes all relevant nuclei (1H, 31P, 13C). PMID- 28712991 TI - Low-beta cortico-pallidal coherence decreases during movement and correlates with overall reaction time. AB - Beta band oscillations (13-30 Hz) are a hallmark of cortical and subcortical structures that are part of the motor system. In addition to local population activity, oscillations also provide a means for synchronization of activity between regions. Here we examined the role of beta band coherence between the internal globus pallidus (GPi) and (motor) cortex during a simple reaction time task performed by nine patients with idiopathic dystonia. We recorded local field potentials from deep brain stimulation (DBS) electrodes implanted in bilateral GPi in combination with simultaneous whole-head magneto-encephalography (MEG). Patients responded to visually presented go or stop-signal cues by pressing a button with left or right hand. Although coherence between signals from DBS electrodes and MEG sensors was observed throughout the entire beta band, a significant movement-related decrease prevailed in lower beta frequencies (~13-21 Hz). In addition, patients' absolute coherence values in this frequency range significantly correlated with their median reaction time during the task (r = 0.89, p = 0.003). These findings corroborate the recent idea of two functionally distinct frequency ranges within the beta band, as well as the anti-kinetic character of beta oscillations. PMID- 28712993 TI - Decoding the orientation of contrast edges from MEG evoked and induced responses. AB - Visual gamma oscillations have been proposed to subserve perceptual binding, but their strong modulation by diverse stimulus features confounds interpretations of their precise functional role. Overcoming this challenge necessitates a comprehensive account of the relationship between gamma responses and stimulus features. Here we used multivariate pattern analyses on human MEG data to characterize the relationships between gamma responses and one basic stimulus feature, the orientation of contrast edges. Our findings confirmed we could decode orientation information from induced responses in two dominant frequency bands at 24-32 Hz and 50-58 Hz. Decoding was higher for cardinal than oblique orientations, with similar results also obtained for evoked MEG responses. In contrast to multivariate analyses, orientation information was mostly absent in univariate signals: evoked and induced responses in early visual cortex were similar in all orientations, with only exception an inverse oblique effect observed in induced responses, such that cardinal orientations produced weaker oscillatory signals than oblique orientations. Taken together, our results showed multivariate methods are well suited for the analysis of gamma oscillations, with multivariate patterns robustly encoding orientation information and predominantly discriminating cardinal from oblique stimuli. PMID- 28712994 TI - Recognition of white matter bundles using local and global streamline-based registration and clustering. AB - Virtual dissection of diffusion MRI tractograms is cumbersome and needs extensive knowledge of white matter anatomy. This virtual dissection often requires several inclusion and exclusion regions-of-interest that make it a process that is very hard to reproduce across experts. Having automated tools that can extract white matter bundles for tract-based studies of large numbers of people is of great interest for neuroscience and neurosurgical planning. The purpose of our proposed method, named RecoBundles, is to segment white matter bundles and make virtual dissection easier to perform. This can help explore large tractograms from multiple persons directly in their native space. RecoBundles leverages latest state-of-the-art streamline-based registration and clustering to recognize and extract bundles using prior bundle models. RecoBundles uses bundle models as shape priors for detecting similar streamlines and bundles in tractograms. RecoBundles is 100% streamline-based, is efficient to work with millions of streamlines and, most importantly, is robust and adaptive to incomplete data and bundles with missing components. It is also robust to pathological brains with tumors and deformations. We evaluated our results using multiple bundles and showed that RecoBundles is in good agreement with the neuroanatomical experts and generally produced more dense bundles. Across all the different experiments reported in this paper, RecoBundles was able to identify the core parts of the bundles, independently from tractography type (deterministic or probabilistic) or size. Thus, RecoBundles can be a valuable method for exploring tractograms and facilitating tractometry studies. PMID- 28712996 TI - Optimization of de-esterified tragacanth microcapsules by computational fluid dynamic and the Taguchi design with purpose of the cell encapsulation. AB - This work presents the development of the new De-Esterified Tragacanth (DET) microcapsules (MCs). Co-flow extrusion method was applied for producing the MCs; the processing parameters were optimized by the Taguchi design to obtain the smallest and the most spherical MCs. Computational Fluid Dynamic (CFD) modeling was accomplished to show the formation of droplets at different airflows, and finally, betaTC3 pancreatic cells were encapsulated in the MCs. The optimum MCs had 214.58MUm size and 60.75% sphericality. The air pressure and the cross linking reaction of DET were the most influential parameter in size and the sphericality of MCs, respectively. CFD showed two velocity vortices with rotational flow formed in the chamber, which caused changing the droplet moving direction. The encapsulated cells were proliferated, and cell viability was not reduced during six days. These phenomena make DET MCs a potential candidate for the cell encapsulation. PMID- 28712995 TI - Investigations into within- and between-subject resting-state amplitude variations. AB - The amplitudes of spontaneous fluctuations in brain activity may be a significant source of within-subject and between-subject variability, and this variability is likely to be carried through into functional connectivity (FC) estimates (whether directly or indirectly). Therefore, improving our understanding of amplitude fluctuations over the course of a resting state scan and variation in amplitude across individuals is of great relevance to the interpretation of FC findings. We investigate resting state amplitudes in two large-scale studies (HCP and UK Biobank), with the aim of determining between-subject and within-subject variability. Between-subject clustering distinguished between two groups of brain networks whose amplitude variation across subjects were highly correlated with each other, revealing a clear distinction between primary sensory and motor regions ('primary sensory/motor cluster') and cognitive networks. Within subjects, all networks in the primary sensory/motor cluster showed a consistent increase in amplitudes from the start to the end of the scan. In addition to the strong increases in primary sensory/motor amplitude, a large number of changes in FC were found when comparing the two scans acquired on the same day (HCP data). Additive signal change analysis confirmed that all of the observed FC changes could be fully explained by changes in amplitude. Between-subject correlations in UK Biobank data showed a negative correlation between primary sensory/motor amplitude and average sleep duration, suggesting a role of arousal. Our findings additionally reveal complex relationships between amplitude and head motion. These results suggest that network amplitude is a source of significant variability both across subjects, and within subjects on a within-session timescale. Future rfMRI studies may benefit from obtaining arousal-related (self report) measures, and may wish to consider the influence of amplitude changes on measures of (dynamic) functional connectivity. PMID- 28712997 TI - Novel characteristics of horseradish peroxidase immobilized onto the polyvinyl alcohol-alginate beads and its methyl orange degradation potential. AB - Herein, we report the immobilization of in-house isolated horseradish peroxidase (HRP) from Armoracia rusticana with novel characteristics. The HRP was immobilized onto the self-fabricated polyvinyl alcohol-alginate (PVA-alginate) beads using sodium nitrate as a cross-linker. The PVA-alginate beads (2.0mm size) developed using 10% PVA and 1.5% sodium alginate showed maximal immobilization yield. The surface morphologies of the PVA-alginate (control) and immobilized-HRP were characterized by scanning electron microscopy (SEM). The immobilized-HRP retained 64.14% of its initial activity after 10 consecutive substrate-oxidation cycles as compared to the free counterpart. Simultaneously, the thermal stability of the immobilized-HRP was significantly enhanced as compared to the free HRP. The enzyme leakage (EL) assay was performed by storing the immobilized-HRP in phosphate buffer solution for 30days. Evidently, the leakage of immobilized-HRP was recorded to be 6.98% and 14.82% after 15 and 30days of incubation, respectively. Finally, the immobilized-HRP was used for methyl orange (MO) dye degradation in a batch mode. A noticeable decline in spectral shift accompanied by no appearance of a new peak demonstrated the complete degradation of MO. The degraded fragments of MO were scrutinized by ultra-performance liquid chromatography coupled with mass spectrometry (UPLC-MS). A plausible degradation pathway for MO was proposed based on the identified intermediates. In conclusion, the study portrays the PVA-alginate-immobilized-HRP as a cost-effective and industrially desirable green catalyst, for biotechnological at large and industrial in particular, especially for the treatment of textile dyes or dye containing industrial waste effluents. PMID- 28712998 TI - Brain Natriuretic Peptide mediates the prognostic role of renal function toward 10-year cardiovascular mortality in patients with Acute Coronary Syndrome: the HHF study (2006-2016). AB - BACKGROUND/INTRODUCTION: Risk stratification in chronic heart failure (HF) remains a challenge. Renal function and B-natriuretic peptide (BNP) might confer predictive value towards long-term mortality in HF patients after an acute coronary syndrome (ACS). METHODS: From May 2006 to March 2009, 1,000 consecutive patients who were hospitalized with ACS diagnosis were enrolled in the study. In 2016, the 10-year follow-up (2006 -2016) was performed in 745 participants. GFR was evaluated through the MDRD formula. HF phenotype was defined according to baseline ejection fraction (EF); HF with reduced EF (i.e. <40%) (HFrEF), preserved EF (i.e. >=50%) (HFpEF) and mid-range EF (i.e. 40 -49%) (HFmrEF). RESULTS: 10-year mortality was 21%. Deceased patients presented significantly lower GFR and higher BNP values at the baseline, compared with their alive counterparts (p <0.001 for both). By multivariable logistic regression analysis, GFR independently predicted all-cause mortality (OR = 0.98, p = 0.04). After adjusting for baseline BNP, GFR lost its predictive role while BNP was independently associated with 10-year mortality (OR = 1.39 for a 2-fold increase, p = 0.001). A significant interaction was observed between EF and BNP levels on the tested outcome (p for interaction < 0.001). In stratified analysis, BNP predicted all cause death only in HFmrEF (OR=1.43, p = 0.04) and in HFpEF (OR=1.80, p = 0.01). CONCLUSION: BNP mediates the predictive role of GFR towards long-term mortality in ACS-induced HF patients with retained systolic performance of the left ventricle (HFmrEF and HFpEF). PMID- 28712999 TI - Dynamic changes in calprotectin and its correlation with traditional markers of oxidative stress in patients with acute ischemic stroke. PMID- 28713000 TI - Discrete particle modeling and micromechanical characterization of bilayer tablet compaction. AB - A mechanistic particle scale model is proposed for bilayer tablet compaction. Making bilayer tablets involves the application of first layer compaction pressure on the first layer powder and a second layer compaction pressure on entire powder bed. The bonding formed between the first layer and the second layer particles is crucial for the mechanical strength of the bilayer tablet. The bonding and the contact forces between particles of the first layer and second layer are affected by the deformation and rearrangement of particles due to the compaction pressures. Our model takes into consideration the elastic and plastic deformations of the first layer particles due to the first layer compaction pressure, in addition to the mechanical and physical properties of the particles. Using this model, bilayer tablets with layers of the same material and different materials, which are commonly used pharmaceutical powders, are tested. The simulations show that the strength of the layer interface becomes weaker than the strength of the two layers as the first layer compaction pressure is increased. The reduction of strength at the layer interface is related to reduction of the first layer surface roughness. The reduced roughness decreases the available bonding area and hence reduces the mechanical strength at the interface. In addition, the simulations show that at higher first layer compaction pressure the bonding area is significantly less than the total contact area at the layer interface. At the interface itself, there is a non-monotonic relationship between the bonding area and first layer force. The bonding area at the interface first increases and then decreases as the first layer pressure is increased. These results are in agreement with findings of previous experimental studies. PMID- 28713001 TI - Comparison of the properties of implantable matrices prepared from degradable and non-degradable polymers for bisphosphonate delivery. AB - The aim of the present study was the development of directly compressed tablets for implantable delivery of risedronate sodium for osteoporosis treatment and the comparison of the mechanism and kinetics of drug release from biogradable (chitosan) and non-degradable (PVC) polymer matrices. The compositions and process parameters were optimized in accordance to a mixed 2 and 3 level full factorial design. Critical Quality Attributes (CQA), such as diametral breaking hardness, porosity and speed of drug dissolution were investigated. The results revealed significant differences between the behaviours of the two polymers. Chitosan exhibited poor compressibility, which resulted in poor mechanical properties and the fast disintegration of chitosan based tablets. Nevertheless, despite the fast disintegration, the chitosan based matrices exhibited one-week long continuous drug release, which can be due to a strong drug-carrier interaction. The presence of intermolecular hydrogen bonds was confirmed with FT IR and NIR measurements. In contrast, PVC based compositions exhibited excellent compressibility, good tablet hardness and low porosity. The tablets remained intact during the dissolution and exhibited a slower release rate than what was measured in the case of chitosan based matrices. There was no sign of intermolecular association on NIR spectra, suggesting that the dissolution rate is basically determined by the porosity of tablets, but FT-IR measurements revealed some details of the molecular background of drug release mechanism. PMID- 28713002 TI - Photo-stimulation of persistent luminescence nanoparticles enhances cancer cells death. AB - Persistent luminescence nanoparticles made of ZnGa1.995Cr0.005O4 (ZGO-NPs) are innovative nanomaterials that emit photons during long periods of time after the end of the excitation, allowing their use as diagnosis probes for in vivo optical imaging. During the excitation process, a part of the energy is stored in traps to further emit photons over long time. However, we observed in this study that some of the energy reduces molecular oxygen to produce reactive oxygen species (ROS). Following this observation, theoxidative stress induction and cytotoxic effects of these NPs were investigated on human breast cancer cells. The results indicate that ROS production was stimulated by exposition of the hydroxylated ZGO NPs to UV or visible light, and the oxidative stress induced in cells after internalization can be directly correlated to their dose-dependent inhibition of cell viability. On the contrary, PEGylated ZGONPs were not uptaken by cells and have no effect on the production of ROS. Thus, the cell viability was not altered by these nanoparticles. This study reveals the importance of considering light irradiation and surface coating of luminescent nanoparticles toxicity which open new perspectives for their use in photodynamic therapy. PMID- 28713003 TI - Reassessing the utility of routine urine culture with urodynamics: UTI incidence and risk factors. AB - INTRODUCTION: There is no consensus regarding use of periprocedural antibiotics or routine urine cultures during urodynamics study (UDS) in children. At our hospital, we historically have obtained urine cultures during UDS. However, even with positive cultures, few patients require treatment. Most are successfully managed with increased hydration and frequent bladder emptying. PURPOSE: To evaluate clinical characteristics, antibiotic treatment, and outcomes in patients undergoing UDS to identify (1) risk factors for urinary tract infection (UTI) after UDS, and (2) patients who may benefit from routine urine culture. STUDY DESIGN: Retrospective review of 769 patients who underwent 1057 UDS between January 2013 and January 2015. Positive urine culture was defined as >=104 colony forming units/ml. Afebrile UTI was defined as new symptoms within 7 days. Febrile UTI was new symptoms with fever (>=38.5 degrees C). Fisher's exact test was used for comparative analyses. RESULTS: Nearly all patients had a urine culture taken immediately prior to UDS (94%, 993/1057). Patients on clean intermittent catheterization (CIC) were more likely to be on pre-UDS antibiotics, 22.8% (106/464) vs. 17.9% of those not on CIC (106/593) (p = 0.04). Of patients who had a urine culture, it was positive in 40% (402/993) with more positive cultures in patients on CIC vs. not (72.0%, 316/439 vs. 15.5%, 86/554, p < 0.0001). Factors significantly associated with clinical/possible post-UDS UTI included clinical UTI within 30 days before UDS, immunosuppression, overnight Foley catheter use, febrile UTI as indication, and symptoms on day of procedure (Table). Fifteen patients (1.4%, 95% confidence interval 0.7-2.1%) developed a clinical/possible post-UDS UTI, of which 40% (6/15) were febrile, with one requiring hospitalization. Of patients with post-UDS UTIs, 33% (5/15) had negative cultures at the time of UDS. DISCUSSION: If urine cultures were obtained selectively based on our study findings, 78% of pre-UDS urine cultures could be eliminated, while "missing" clinically relevant cultures in only 0.4% (4/1057). Study limitations include the retrospective design. However, prospective data collection will now be possible by using standardized, templated UDS and post-UDS follow-up notes with extractable data elements that automatically populate a database. CONCLUSION: Post-UDS UTI is uncommon (1.4%), even in the setting of bacteriuria. This finding calls into question the utility of routine pre-UDS urine culture. Data from this study and a future prospective study will be used to refine a new working protocol, with the goal of targeting future urine cultures to a high-risk subset of patients. PMID- 28713004 TI - Results of a prospective randomized control trial comparing hydrophilic to uncoated catheters in children with neurogenic bladder. AB - INTRODUCTION: Children with neurogenic bladder (NGB) often require a lifetime of clean intermittent catheterization (CIC), typically using uncoated catheters (UCs). Hydrophilic catheters (HCs) have lower friction than UCs with reported less damage to the urethra. The purpose of this study is to compare outcomes between these catheters. METHODS: An investigator-initiated, prospective, randomized clinical trial was conducted to compare HCs versus UCs. Children aged 2-17 years with NGB on CIC were enrolled for 1 year. Block randomization was used. Dexterity scores were obtained in those who perform self-catheterization. Outcomes were UTI, difficulty passing the catheter, urethral injury, and patient satisfaction. RESULTS: Demographic data is presented in the Table. Seventy-eight patients were enrolled. Age and gender were similar between the groups. Fifteen patients in each group performed CIC via an abdominal wall stoma. Eight and 15 patients withdrew from the UC and HC groups, respectively. The HC group overall had more problems with the catheter, mainly difficulty with handling. There were no differences for passing the catheter, pain, hematuria, or urethral injuries. There were two urinary tract infections (UTIs) in two HC patients and 17 UTIs in seven UC patients (p = 0.003). Patients with UTIs in the HC group went from 16% in the previous year to 5% during the study. Three children in the HC group had three or more UTIs in the year before enrollment and none during the study. The patients that completed the study with HC were overall satisfied and many requested to continue with the HC. CONCLUSIONS: HCs may decrease the risk of UTI in children with NGB. Urethral complications were low in both groups. Most HC patients were pleased but some found the slippery coating difficult to handle. PMID- 28713005 TI - Steroid 5-alpha-reductase type 2 (SRD5A2) gene V89L polymorphism and hypospadias risk: A meta-analysis. AB - BACKGROUND: Hypospadias is a common congenital malformation in males, in which the urethral orifice is found on the ventral side of the penis as a result of incomplete fusion of urethral folds. The etiology of hypospadias is poorly understood, and may be multifactorial, including genetic, endocrine and environmental factors. The steroid 5-alpha-reductase type 2 (SRD5A2) gene, which is mainly expressed in the ventral side of the urethra in the process of male genital development, plays an important role in urethral shaping. OBJECTIVE: To investigate, with database searches of related published papers, whether SRD5A2 gene V89L polymorphism has an association with hypospadias risk. METHODS: The following databases were searched for relevant papers, and all published case control studies of hypospadias were used to perform a meta-analysis: PubMed, Embase, Springer Link, Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang, and Weipu. A quality assessment was performed using the Newcastle-Ottawa scale of a case-control study. To assess the strength of the association under various genetic models, odds ratio (OR) and its 95% confidence interval (CI) were calculated using fixed-effect or random-effects model according to the heterogeneity. Overall and stratified subgroup analyses, including ethnicity, source of controls, sample for DNA extraction, and hypospadias classification, were performed. All data were analyzed using Review Manager 5.3. RESULTS: This analysis included six eligible case-control studies with 1130 cases and 1279 controls. Overall, there was a statistically significant association between hypospadias risk and V89L polymorphism for allele contrast (C vs G: OR 1.91, 95% CI 1.13-3.23), P = 0.02), codominant model (CC vs GG: OR 2.97, 95% CI 1.25-7.04, P = 0.01; GC vs GG: OR 2.36, 95% CI 1.35-4.13, P = 0.003), dominant model (GC + CC vs GG: OR 2.46, 95% CI 1.28-4.72, P = 0.007), and recessive model (CC vs GC + GG: OR 1.91, 95% CI 1.00-3.66, P = 0.05). Moreover, there was also a statistically significant association in some subgroups. The positive results are shown in the Summary Table. CONCLUSION: This meta-analysis suggested that the V89L polymorphism definitely increases the risk of hypospadias, and the C allele is a genetic risk factor for hypospadias occurrence. PMID- 28713006 TI - Ultrasonographic findings in the epididymis of pediatric patients with testicular torsion. AB - INTRODUCTION: Although grayscale ultrasound and color Doppler ultrasound characteristics of the torsed testis are well established in the literature, less is known about its anatomic partner: the epididymis. OBJECTIVE: The purpose of this study was to describe the ultrasound characteristics of the epididymis in pediatric patients with testicular torsion, and to describe their potential role as prognostic criteria for testicular salvage outcomes. STUDY DESIGN: During a retrospective review of 217 pediatric patients with acute testicular torsion during 2009-2016, morphological features of the epididymis from scrotal ultrasounds (size, parenchymal characteristics, and vascular flow of both epididymis heads), as well as patient demographics, time duration, surgical outcomes, histopathology results, and follow-up periods were analyzed. RESULTS: Mean epididymis size and twisting degree were significantly higher in the torsed testes than in the contralateral epididymis (P < 0.001) (Summary table). Cystic structures in the epididymis were identified: a higher number of cysts was associated with testicular non-viability (P = 0.025) and higher twisting degree (P = 0.017). Histopathologic examination showed that these spaces were infiltrated connective tissue most likely formed by venous congestion and vessel rupture. DISCUSSION: Scrotal ultrasound can provide information on testicular morphology and viability, as well as morphological changes in the epididymis over time in pediatric patients with testicular torsion. These findings may provide potential prognostic information regarding testicular viability, as a higher number of cystic spaces in the epididymis was associated with a higher rate of testicular non-viability and a higher twisting degree. In addition, the epididymis size (volume) can change during the time course of the ischemic state. CONCLUSIONS: This was the first study to describe and analyze epididymis ultrasound findings in pediatric patients with testicular torsion and to correlate them with testicular salvage outcomes. Further prospective studies are needed to determine the role of epididymis ultrasound findings as a potential pre operative prognostic tool. PMID- 28713007 TI - Future fertility for individuals with differences of sex development: Parent attitudes and perspectives about decision-making. AB - BACKGROUND: Children, adolescents, and young adults (children/youth) with differences/disorders of sex development (DSD) face challenges related to future fertility; this may be due to variations in gonadal development, and, for some, gonadectomy performed to reduce the risk of malignancy. Childhood may be the only time for preservation of biological fertility potential for children/youth who undergo gonadectomy or have early gonadal failure. Fertility-related decision making for these patients is particularly complicated, due to the need for parental proxy decision-making, potential discordance between gender identity and gonadal type, and uncertain future assisted reproductive technologies. OBJECTIVE: This study aimed to assess: (1) attitudes regarding future fertility, and (2) healthcare needs for fertility-related decision-making among parents of children/youth with DSD. STUDY DESIGN: Semi-structured qualitative interviews about future fertility were conducted with parents of children/youth with DSD. Parents who had never discussed fertility with a healthcare provider were excluded. Grounded theory methodology was used to identify emergent themes and patterns. Demographics and clinical characteristics were assessed via survey and medical chart review. RESULTS: Nineteen parents were interviewed (participation rate: 60%, 14 mothers/5 fathers, median patient age at diagnosis 6 months (range 0-192), eight DSD diagnoses). The most common emergent themes are summarized in the Summary Table. Most parents identified fertility as a key concern, both at time of diagnosis and throughout development. Parents expressed difficulty with timing of disclosure about potential infertility to their children. Multiple preferences related to medical decision-making about future fertility and fertility preservation were expressed, including: a desire for step-by-step decision-making, and use of medically vetted information and research to guide decisions. DISCUSSION: This qualitative study provided new information about the perspectives of parents of children/youth with DSD regarding future fertility. Previous studies have suggested that the possibility of biological parenthood is important to many individuals with DSD. This study provided an in-depth parental perspective. This is important because many decisions that affect future fertility are made in childhood, and require parents to make decisions on behalf of their children. The study sample was limited in its geographic diversity. Strengths of the study included diversity in age of the child/youth, ethnic backgrounds, and the DSD diagnoses that were represented. CONCLUSIONS: Future fertility was a concern for many parents of children/youth with DSD. Parents expressed multiple priorities and preferences related to making difficult fertility-related medical decisions for their children. Many of the study findings could be incorporated into future best practices for discussions about fertility with families of children/youth with DSD. PMID- 28713008 TI - Determining myeloperoxidase activity and protein concentration in a single assay: Utility in biomarker and therapeutic studies. AB - Myeloperoxidase (MPO) is predominantly expressed by neutrophils and is an important enzyme used by the immune system for the neutralisation of bacteria and other microorganisms. The strong oxidative activity of MPO has been linked to pro inflammatory responses in surrounding cells and tissues with implication in the pathophysiology of cardiovascular, neuroscience and inflammatory diseases. This broad disease association has made MPO an attractive biomarker and therapeutic target. Here we describe the construction and validation of a single combined MPO activity and protein concentration assay using commercially available reagents. This method offers the investigative laboratory the ability to generate results from blood plasma samples in a single analytical run using the same sample aliquot. PMID- 28713009 TI - Aeromonas hydrophila-induced alterations in cytosolic calcium activate pro apoptotic cPKC-MEK1/2-TNFalpha axis in infected headkidney macrophages of Clarias gariepinus. AB - Alterations in intracellular-calcium (Ca2+)i homeostasis is critical to Aeromonas hydrophila-induced headkidney macrophages (HKM) apoptosis of Clarias gariepinus, though the implications are poorly understood. Here, we describe the role of intermediate molecules of Ca2+-signaling pathway that are involved in HKM apoptosis. We observed phosphoinositide-3-kinase/phospholipase C is critical for (Ca2+)i release in infected HKM. Heightened protein kinase-C (PKC) activity and phosphorylation of MEK1/2-ERK1/2 was noted which declined in presence of 2-APB, Go6976 and PD98059, inhibitors to IP3-receptor, conventional PKC isoforms (cPKC) and MEK1/2 respectively implicating Ca2+/cPKC/MEK-ERK1/2 axis imperative in A. hydrophila-induced HKM apoptosis. Significant tumor necrosis factor-alpha (TNFalpha) production and its subsequent reduction in presence of MEK-ERK1/2 inhibitor U0126 suggested TNFalpha production downstream to cPKC-mediated signaling via MEK1/2-ERK1/2 pathway. RNAi and inhibitor studies established the role of TNFalpha in inducing caspase-8-mediated apoptosis of infected HKM. We conclude, alterations in A. hydrophila-induced (Ca2+)i alterations activate cPKC MEK1/2-ERK1/2-TNFalpha signaling cascade triggering HKM apoptosis. PMID- 28713010 TI - Hemolectin expression reveals functional heterogeneity in honey bee (Apis mellifera) hemocytes. AB - The identification of molecular markers considerably facilitated the classification and functional analysis of blood cell types. Apis mellifera hemocytes have been classified by morphological criteria and lectin binding properties; however, the use of molecular markers has been minimal. Here we describe a monoclonal antibody to a non-phagocytic subpopulation of A. mellifera hemocytes and to a constituent of the hemolymph clot. We demonstrate that the antibody identifies the A. mellifera hemolectin, a protein carrying human von Willebrand factor homology domains, characteristic of proteins involved in blood coagulation and platelet aggregation in mammals. Hemolectin expressing A. mellifera hemocytes contain the protein as cytoplasmic granules and contribute to the formation of a protein matrix, building up around foreign particles. Consequently, hemolectin as a marker molecule reveals a clear functional heterogeneity of hemocytes, allowing for the analytical separation of hemocyte classes, and could promote the molecular identification of hemocyte lineages in A. mellifera. PMID- 28713012 TI - Authors' Response. PMID- 28713011 TI - The genomic and transcriptomic analyses of serine proteases and their homologs in an endoparasitoid, Pteromalus puparum. AB - In insects, serine proteases (SPs) and serine protease homologs (SPHs) constitute a large family of proteins involved in multiple physiological processes such as digestion, development, and immunity. Here we identified 145 SPs and 38 SPHs in the genome of an endoparasitoid, Pteromalus puparum. Gene duplication and tandem repeats were observed in this large SPs/SPHs family. We then analyzed the expression profiles of SP/SPH genes in response to different microbial infections (Gram-positive bacterium Micrococcus luteus, Gram-negative bacterium Escherichia coli, and entomopathogenic fungus Beauveria bassiana), as well as in different developmental stages and tissues. Some SPs/SPHs also displayed distinct expression patterns in venom gland, suggesting their specific physiological functions as venom proteins. Our finding lays groundwork for further research of SPs and SPHs expressed in the venom glands. PMID- 28713013 TI - Questioning the Definition of Sustainable Agriculture. PMID- 28713014 TI - A recombinant type 2 porcine reproductive and respiratory syndrome virus between NADC30-like and a MLV-like: Genetic characterization and pathogenicity for piglets. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) is an economically important pathogen for swine industry worldwide. The recombination occurring among PRRSV strains has been recognized as one of important molecular mechanisms for the evolution of PRRSV. Current prevalence of PRRSV NADC30-like causing clinical disease outbreaks is highly concerned in China. In the present study, the genetic characterization of a recombinant type 2 PRRSV (designated TJnh1501) was analyzed and its pathogenicity for piglets was examined. Our study showed that each region of TJnh1501 genome had 96.67-100% nucleotide and 96.5-100% amino acid identities with a Chinese highly pathogenic PRRSV-derived modified-live virus (MLV)-like except for its nonstructural protein 2 (nsp2)-coding region; while its nsp2-coding region shared higher nucleotide (84.44-85.85%) and amino acid (82.44-84.79%) identities with NADC30 and NADC30-like CHsx1401, and in particular, the highly variable region of nsp2 exhibited characteristic 131-aa deletion identical to NADC30 and NADC30-like CHsx1401. Meanwhile, we identified two recombination breakpoints located in the nt1737 and nt3506 of nsp2-coding region, which had higher nucleotide homology with NADC30 and NADC30-like CHsx1401. Moreover, TJnh1501 infection could cause persistent fever, moderate respiratory clinical signs, higher viremia, and obvious gross and microscopic lung lesions in piglets. The virus was shown to have lower pathogenicity than HP PRRSV JXwn06, but higher than NADC30-like CHsx1401 for piglets. Our findings reveal that TJnh1501 is a recombinant type 2 PRRSV from the recombinant event between NADC30-like and MLV-like derived from the Chinese highly pathogenic PRRSV, and it exhibits intermediate virulence for pigs. This study adds valuable evidence for understanding the role of genomic recombination in the evolution of PRRSV. PMID- 28713015 TI - Folate-conjugated and pH-responsive polymeric micelles for target-cell-specific anticancer drug delivery. AB - : In this study, we developed a folate (FA)-conjugated and pH-responsive active targeting micellar system for anti-cancer drug delivery. In this system, FA was attached to the terminal of the hydrophilic segment of poly(lactic acid)-poly(L lysine) (PLA-PLL), and PLL was modified by a citric acid group. The FA receptor mediated active targeting and electrostatic interaction between micelles and cell membrane due to a negative-to-positive charge reversal was combined in one micellar anti-cancer drug delivery system to enhance the tumour targeting and cellular internalisation of micelles. In vitro and in vivo anti-cancer studies demonstrated that the doxorubicin-loaded, FA-conjugated and pH-responsive polymeric micelles possess an enhanced and effective cancer efficiency. STATEMENT OF SIGNIFICANCE: Negatively charged nano-carriers prolonged anti-cancer drugs' blood circulation. However it is difficult to be internalised. Therefore, a negative-to-positive charged micelle surface could improve selectivity for tumour cells and increase uptake chance. In this study, we developed a folate (FA) conjugated and pH-responsive active targeting micellar system for anti-cancer drug delivery. The FA receptor-mediated active targeting and electrostatic interaction between micelles and cell membrane due to a negative-to-positive charge reversal was combined in one micellar anti-cancer drug delivery system to enhance the tumour targeting and cellular internalisation of micelles. In vitro and in vivo anti-cancer studies demonstrated that the doxorubicin-loaded, FA conjugated and pH-responsive polymeric micelles possess an enhanced and effective cancer efficiency. PMID- 28713016 TI - A conducive bioceramic/polymer composite biomaterial for diabetic wound healing. AB - : Diabetic wound is a common complication of diabetes. Biomaterials offer great promise in inducing tissue regeneration for chronic wound healing. Herein, we reported a conducive Poly (caprolactone) (PCL)/gelatin nanofibrous composite scaffold containing silicate-based bioceramic particles (Nagelschmidtite, NAGEL, Ca7P2Si2O16) for diabetic wound healing. NAGEL bioceramic particles were well distributed in the inner of PCL/gelatin nanofibers via co-electrospinning process and the Si ions maintained a sustained release from the composite scaffolds during the degradation process. The nanofibrous scaffolds significantly promoted the adhesion, proliferation and migration of human umbilical vein endothelial cells (HUVECs) and human keratinocytes (HaCaTs) in vitro. The in vivo study demonstrated that the scaffolds distinctly induced the angiogenesis, collagen deposition and re-epithelialization in the wound sites of diabetic mice model, as well as inhibited inflammation reaction. The mechanism for nanofibrous composite scaffolds accelerating diabetic wound healing is related to the activation of epithelial to mesenchymal transition (EMT) and endothelial to mesenchymal transition (EndMT) pathway in vivo and in vitro. Our results suggest that the released Si ions and nanofibrous structure of scaffolds have a synergetic effect on the improved efficiency of diabetic wound healing, paving the way to design functional biomaterials for tissue engineering and wound healing applications. STATEMENT OF SIGNIFICANCE: In order to stimulate tissue regeneration for chronic wound healing, a new kind of conducive nanofibrous composite scaffold containing silicate-based bioceramic particles (Nagelschmidtite, NAGEL, Ca7P2Si2O16) were prepared via co-electrospinning process. Biological assessments revealed that the NAGEL bioceramic particles could active epithelial to mesenchymal transition (EMT) and endothelial to mesenchymal transition (EndMT) pathway in vitro and in vivo. The new composite scaffold had potential as functional biomaterials for tissue engineering and wound healing applications. The strategy of introducing controllable amount of therapeutic ions instead of loading expensive drugs/growth factors on nanofibrous composite scaffold provides new options for bioactive biomaterials. PMID- 28713017 TI - Intracellular co-delivery of Sr ion and phenamil drug through mesoporous bioglass nanocarriers synergizes BMP signaling and tissue mineralization. AB - : Inducing differentiation and maturation of resident multipotent stem cells (MSCs) is an important strategy to regenerate hard tissues in mal-calcification conditions. Here we explore a co-delivery approach of therapeutic molecules comprised of ion and drug through a mesoporous bioglass nanoparticle (MBN) for this purpose. Recently, MBN has offered unique potential as a nanocarrier for hard tissues, in terms of high mesoporosity, bone bioactivity (and possibly degradability), tunable delivery of biomolecules, and ionic modification. Herein Sr ion is structurally doped to MBN while drug Phenamil is externally loaded as a small molecule activator of BMP signaling, for the stimulation of osteo/odontogenesis and mineralization of human MSCs derived from dental pulp. The Sr-doped MBN (85Si:10Ca:5Sr) sol-gel processed presents a high mesoporosity with a pore size of ~6nm. In particular, Sr ion is released slowly at a daily rate of ~3ppm per mg nanoparticles for up to 7days, a level therapeutically effective for cellular stimulation. The Sr-MBN is internalized to most MSCs via an ATP dependent macropinocytosis within hours, increasing the intracellular levels of Sr, Ca and Si ions. Phenamil is loaded maximally ~30% into Sr-MBN and then released slowly for up to 7days. The co-delivered molecules (Sr ion and Phenamil drug) have profound effects on the differentiation and maturation of cells, i.e., significantly enhancing expression of osteo/odontogenic genes, alkaline phosphatase activity, and mineralization of cells. Of note, the stimulation is a result of a synergism of Sr and Phenamil, through a Trb3 dependent BMP signaling pathway. This biological synergism is further evidenced in vivo in a mal-calcification condition involving an extracted tooth implantation in dorsal subcutaneous tissues of rats. Six weeks post operation evidences the osseous-dentinal hard tissue formation, which is significantly stimulated by the Sr/Phenamil delivery, based on histomorphometric and micro computed tomographic analyses. The bioactive nanoparticles releasing both Sr ion and Phenamil drug are considered to be a promising therapeutic nanocarrier platform for hard tissue regeneration. Furthermore, this novel ion/drug co delivery concept through nanoparticles can be extensively used for other tissues that require different therapeutic treatment. STATEMENT OF SIGNIFICANCE: This study reports a novel design concept in inorganic nanoparticle delivery system for hard tissues - the co-delivery of therapeutic molecules comprised of ion (Sr) and drug (Phenamil) through a unique nanoparticle of mesoporous bioactive glass (MBN). The physico-chemical and biological properties of MBN enabled an effective loading of both therapeutic molecules and a subsequently sustained/controlled release. The co-delivered Sr and Phenamil demonstrated significant stimulation of adult stem cell differentiation in vitro and osseous/dentinal regeneration in vivo, through BMP signaling pathways. We consider the current combination of Sr ion with Phenamil is suited for the osteo/odontogenesis of stem cells for hard tissue regeneration, and further, this ion/drug co-delivery concept can extend the applications to other areas that require specific cellular and tissue functions. PMID- 28713018 TI - Effect of increased surface hydrophobicity via drug conjugation on the clearance of inhaled PEGylated polylysine dendrimers. AB - PEGylated polylysine dendrimers are attractive and well tolerated inhalable drug delivery platforms that have the potential to control the release, absorption kinetics and lung retention time of conjugated drugs. The clinical application of these systems though, would likely require partial substitution of surface PEG groups with drug molecules that are anticipated to alter their lung clearance kinetics and clearance pathways. In the current study, we therefore evaluated the impact of increased surface hydrophobicity via substitution of 50% surface PEG groups with a model hydrophobic drug (alpha-carboxyl OtButylated methotrexate) on the lung clearance of a Generation 5 PEGylated polylysine dendrimer in rats. PEG substitution with OtBu-methotrexate accelerated lung clearance of the dendrimer by increasing polylysine scaffold catabolism, improving systemic absorption of the intact dendrimer and low molecular weight products of scaffold catabolism, and enhancing mucociliary clearance. These results suggest that the conjugation of hydrophobic drug on the surface of a PEGylated dendrimer is likely to accelerate lung clearance when compared to a fully PEGylated dendrimer. PMID- 28713019 TI - Glioma sensitive or chemoresistant to temozolomide differentially modulate macrophage protumor activities. AB - BACKGROUND: Glioblastomas are the most devastating brain tumor characterized by chemoresistance development and poor prognosis. Macrophages are a component of tumor microenvironment related to glioma malignancy. The relation among inflammation, innate immunity and cancer is accepted; however, molecular and cellular mechanisms mediating this relation and chemoresistance remain unresolved. OBJECTIVE: Here we evaluated whether glioma sensitive or resistant to temozolomide (TMZ) modulate macrophage polarization and inflammatory pathways associated. The impact of glioma-macrophage crosstalk on glioma proliferation was also investigated. METHODS: GL261 glioma chemoresistance was developed by exposing cells to increasing TMZ concentrations over a period of 6months. Mouse peritoneal macrophages were exposed to glioma-conditioned medium or co-cultured directly with glioma sensitive (GL) or chemoresistant (GLTMZ). Macrophage polarization, in vitro and in vivo glioma proliferation, redox parameters, ectonucleotidase activity and ATP cytotoxicity were performed. RESULTS: GLTMZ cells were more effective than GL in induce M2-like macrophage polarization and in promote a strong immunosuppressive environment characterized by high IL-10 release and increased antioxidant potential, which may contribute to glioma chemoresistance and proliferation. Interestingly, macrophage-GLTMZ crosstalk enhanced in vitro and in vivo proliferation of chemoresistant cells, decreased ectonucleotidase activities, which was followed by increased macrophage sensitivity to ATP induced death. CONCLUSIONS: Results suggest a differential macrophage modulation by GLTMZ cells, which may favor the maintenance of immunosuppressive tumor microenvironment and glioma proliferation. GENERAL SIGNIFICANCE: The induction of immunosuppressive environment and macrophage education by chemoresistant gliomas may be important for tumor recovery after chemotherapy and could be considered to overcome chemoresistance development. PMID- 28713020 TI - Pneumolysin-induced autophagy contributes to inhibition of osteoblast differentiation through downregulation of Sp1 in human osteosarcoma cells. AB - BACKGROUND INFORMATION: The 53kDa protein pneumolysin (PLY) is the main virulence factor of Streptococcus pneumoniae, a leading cause of invasive pneumococcal diseases. PLY forms pores in cholesterol-containing membranes, thereby interfering with the function of cells. Bone destruction is a serious matter in chronic inflammatory diseases such as septic arthritis and osteomyelitis. S. pneumoniae is increasingly being recognized as a common cause of septic arthritis, but its pathogenesis is poorly defined. METHOD: We examined the effect of PLY on osteoblast differentiation and its mechanisms of action. The effect of PLY on osteoblast differentiation was evaluated by qRT-PCR, ALP activity assay, flow cytometric analysis, and Western blotting. We also examined the role of PLY induced autophagy in osteoblast differentiation using RNA interference analysis. RESULTS: PLY inhibited osteoblast differentiation by decreasing the expression of osteoblast marker genes such as Runx2 and OCN, along with ALP activity. ROS production was increased by PLY during osteoblast differentiation. PLY induced autophagy through ROS-mediated regulation of AMPK and mTOR, which downregulated the expression of Sp1 and subsequent inhibition of differentiation. Treatment with autophagy inhibitors or Atg5 siRNA alleviated the PLY-induced inhibition of differentiation. CONCLUSION: The results suggest that PLY inhibits osteoblast differentiation by downregulation of Sp1 accompanied by induction of autophagy through ROS-mediated regulation of the AMPK/mTOR pathway. GENERAL SIGNIFICANCE: This study proposes a molecular mechanism for inhibition of osteoblast differentiation in response to PLY. PMID- 28713021 TI - The path to the genetic code. AB - In December of 1966 the last nucleotide triplet in the genetic code has been assigned (Brenner et al., 1967 [1]) thus completing years of studies aimed at deciphering the nature of the relationship between the sequences of genes and proteins. The end product, the table of the genetic code, was a crowning achievement of the quest to unravel the basic mechanisms underlying functioning of all living organisms on the molecular level. PMID- 28713023 TI - An extended mathematical model of tumor growth and its interaction with the immune system, to be used for developing an optimized immunotherapy treatment protocol. AB - BACKGROUND: Chemotherapy is usually known as the main modality for cancer treatment. Nevertheless, most of chronic cancers could not be treated with chemotherapy alone. Immunotherapy is a new modality for cancer treatment that is effective for early stages of cancer and it has fewer side effects compared to chemotherapy, specifically for those types of cancer that are resistant to it. METHOD: This work presents an extended mathematical model to depict interactions between cancerous and adaptive immune system in mouse. We called the model an extended model, because we embedded all those compartments that have important roles in response to tumor in one model. The model includes tumor cells, natural killers, naive and mature cytotoxic T cells, naive and mature helper T cells, regulatory T cells, dendritic cells and interleukin 2 cytokine. Whole cycle of cell division program of immune cells is also considered in the model. We also optimized protocol of immunotherapy with DC vaccine based on the proposed mathematical model. RESULT: Simulation results of the proposed model are in conformity with the experimental data recorded from mouse in immunology department of Tehran University of Medical Science as well as what has been explained in the literature. Our results explain dynamics of the immune cells from the first day of cancer growth and progression. Simulation result shows that reducing intervals between immunotherapy injections, efficacy of the treatment will be increased because CD8+ cells are boosted more rapidly. Optimized protocol for immunotherapy suggests that if the effect of DC vaccines on increasing number of anti-tumor immune cells be just before the maximum number of CD8+ cells, the effect of treatment will be maximized. PMID- 28713022 TI - Resveratrol inhibits phorbol ester-induced membrane translocation of presynaptic Munc13-1. AB - BACKGROUND: Resveratrol (1) is a naturally occurring polyphenol that has been implicated in neuroprotection. One of resveratrol's several biological targets is Ca2+-sensitive protein kinase C alpha (PKCalpha). Resveratrol inhibits PKCalpha by binding to its activator-binding C1 domain. Munc13-1 is a C1 domain-containing Ca2+-sensitive SNARE complex protein essential for vesicle priming and neurotransmitter release. METHODS: To test if resveratrol could also bind and inhibit Munc13-1, we studied the interaction of resveratrol and its derivatives, (E)-1,3-dimethoxy-5-(4-methoxystyryl)benzene, (E)-5,5'-(ethene-1,2 diyl)bis(benzene-1,2,3-triol), (E)-1,2-bis(3,4,5-trimethoxyphenyl)ethane, and (E) 5-(4-(hexadecyloxy)-3,5-dihydroxystyryl)benzene-1,2,3-triol with Munc13-1 by studying its membrane translocation from cytosol to plasma membrane in HT22 cells and primary hippocampal neurons. RESULTS: Resveratrol, but not the derivatives inhibited phorbol ester-induced Munc13-1 translocation from cytosol to membrane in HT22 cells and primary hippocampal neurons, as evidenced by immunoblot analysis and confocal microscopy. Resveratrol did not show any effect on Munc13 1H567K, a mutant which is not sensitive to phorbol ester. Binding studies with Munc13-1 C1 indicated that resveratrol competes with phorbol ester for the binding site. Molecular docking and dynamics studies suggested that hydroxyl groups of resveratrol interact with phorbol-ester binding residues in the binding pocket. CONCLUSIONS AND SIGNIFICANCE: This study characterizes Munc13-1 as a target of resveratrol and highlights the importance of dietary polyphenol in the management of neurodegenerative diseases. PMID- 28713025 TI - For cryoballoon ablation, time to effect is time well spent. PMID- 28713024 TI - To retrieve, or not to retrieve: System revisions with the Micra transcatheter pacemaker. AB - BACKGROUND: Early experience with leadless pacemakers has shown a low rate of complications. However, little is known about system revision in patients with these devices. OBJECTIVE: The purpose of this study was to describe the system revision experience with the Micra Transcatheter Pacing System (TPS). METHODS: Patients with implants from the Pre-market Micra Transcatheter Pacing Study and the Micra Transcatheter Pacing System Continued Access Study (N = 989) were analyzed and compared with 2667 patients with transvenous pacemakers (TVPs). Revisions included TPS retrieval/explant, repositioning, replacement, or electrical deactivation (with or without prior attempt at retrieval, generally followed by TVP implant) for any reason. Kaplan-Meier revision rates were calculated to account for varying follow-up duration and were compared using a Fine-Gray competing risk model. RESULTS: The actuarial rate for revision at 24 months postimplant was 1.4% for the TPS group (11 revisions in 10 patients), 75% (95% confidence interval 53%-87%; P < .001) lower than the 5.3% for the TVP group (123 revisions in 117 patients). TPS revisions occurred 5-430 days postimplant for elevated pacing thresholds, need for alternate therapy, pacemaker syndrome, and prosthetic valve endocarditis; none were due to device dislodgment or device related infection. TPS was disabled and left in situ in 7 cases, 3 were retrieved percutaneously (range 9-406 days postimplant), and 1 was surgically removed during aortic valve surgery. CONCLUSION: The overall system revision rate for patients with TPS at 24 months was 1.4%, 75% lower than that for patients with TVPs. TPS was disabled and left in situ in 64% of revisions, and percutaneous retrieval was successful as late as 14 months postimplant. PMID- 28713026 TI - Cardiac magnetic resonance imaging to guide ventricular tachycardia ablation: Are we there? PMID- 28713027 TI - An "on-matrix" digestion procedure for AP-MS experiments dissects the interplay between complex-conserved and serotype-specific reactivities in Dengue virus human plasma interactome. AB - : The interactions between the four Dengue virus (DENV) serotypes and plasma proteins are crucial in the initial steps of viral infection to humans. Affinity purification combined with quantitative mass spectrometry analysis, has become one of the most powerful tools for the investigation on novel protein-protein interactions. Using this approach, we report here that a significant number of bait-interacting proteins do not dissociate under standard elution conditions, i.e. acid pH and chaotropic agents, and that this problem can be circumvented by using the "on-matrix" digestion procedure described here. This procedure enabled the identification of 16 human plasma proteins interacting with domain III from the envelope protein of DENV serotypes 1, 3 and 4 that would have not been detected otherwise and increased the known DIIIE interactors in human plasma to 59 proteins. Selected Reaction Monitoring analysis evidenced DENV interactome in human plasma is rather conserved although significant differences on the reactivity of viral serotypes with specific proteins do exist. A comparison between the serotype-dependent profile of reactivity and the conservation pattern of amino acid residues suggests an evolutionary selection of highly conserved interactions with the host and other interactions mediated for surface regions of higher variability. SIGNIFICANCE: False negative results on the identification of interacting proteins in pull-down experiments compromise the subsequent interpretation of results and the formulation of a working hypothesis for the derived future work. In this study we demonstrate the presence of bait interacting proteins reluctant to dissociate under elution conditions of acid pH and presence of chaotropics. We propose the direct proteolytic digestion of proteins while still bound to the affinity matrix ("on-matrix" digestion) and evaluate the impact of this methodology in the comparative study of the interactome of the four serotypes of Dengue virus mediated by the domain III of the viral envelope glycoprotein. Fifty nine proteins were identified as putative interaction partners of Dengue virus (IPs) either due to direct binding or by co isolation with interacting proteins. Collectively the IPs identified from the pull-down with the recombinant domain III proteins representing the four viral serotypes, 29% were identified only after "on-matrix" digestion which demonstrate the usefulness of this method of recovering bait-bound proteins. Results highlight a particular importance of "on-matrix" digestion procedure for comparative studies where a stronger interaction with one of the interest baits could prevent a bound protein to elute under standard conditions thus leading to misinterpretation as absent in the interactome of this particular bait. The analysis of the Interaction Network indicates that Dengue virus interactome mediated by the domain III of the envelope protein is rather conserved in the viral complex suggesting a key role of these interactions for viral infection thus making candidates to explore for potential biomarkers of clinical outcome in DENV-caused disease. Interestingly, some particular IPs exhibit significant differences in the strength of the interaction with the viral serotypes representing interactions that involve more variable regions in the surface of the domain III. Since such variable regions are the consequence of the interaction with antibodies generated by human immune response; this result relates the interaction with proteins from human plasma with the interplay of the virus and the human immune system. PMID- 28713028 TI - The effect of Fusarium culmorum infection and deoxynivalenol (DON) application on proteome response in barley cultivars Chevron and Pedant. AB - Fusarium head blight (FHB) disease adversely affects grain quality and final yield in small-grain cereals including barley. In the present study, the effect of an artificial infection with Fusarium culmorum and an application of deoxynivalenol (DON) on barley spikes of cultivars Chevron and Pedant during flowering was investigated at grain mid-dough stage (BBCH 73) 10days after pathogen inoculation (10 dai). Proteomic analysis using a two-dimensional differential gel electrophoresis (2D-DIGE) technique coupled with LC-MS/MS investigated 98 protein spots revealing quantitative or qualitative differences between the experimental variants. Protein functional annotation of 93 identified protein spots revealed that most affected functional groups represent storage proteins (globulins, hordeins), followed by proteins involved in carbohydrate metabolism (alpha-amylase inhibitor, beta-amylase, glycolytic enzymes), amino acid metabolism (aminotransferases), defence response (chitinase, xylanase inhibitor, serpins, SGT1, universal stress protein USP), protein folding (chaperones, chaperonins), redox metabolism (ascorbate-glutathione cycle), and proteasome-dependent protein degradation. The obtained results indicate adverse effects of infection on plant proteome as well as an active plant response to pathogen as shown by enhanced levels of several inhibitors of pathogen-produced degradation enzymes (alpha-amylase inhibitor, xylanase inhibitor, serpins), chaperones, and other stress-related proteins (SGT1, USP). Genotypic differences were found in hordein abundance between Chevron and Pedant. PMID- 28713030 TI - Paintings discrimination by mice: Different strategies for different paintings. AB - C57BL/6 mice were trained on simultaneous discrimination of paintings with multiple exemplars, using an operant chamber with a touch screen. The number of exemplars was successively increased up to six. Those mice trained in Kandinsky/Mondrian discrimination showed improved learning and generalization, whereas those trained in Picasso/Renoir discrimination showed no improvements in learning or generalization. These results suggest category-like discrimination in the Kandinsky/Mondrian task, but item-to-item discrimination in the Picasso/Renoir task. Mice maintained their discriminative behavior in a pixelization test with various paintings; however, mice in the Picasso/Renoir task showed poor performance in a test that employed scrambling processing. These results do not indicate that discrimination strategy for any Kandinsky/Mondrian combinations differed from that for any Picasso/Monet combinations but suggest the mice employed different strategies of discrimination tasks depending upon stimuli. PMID- 28713029 TI - Successive odor matching- and non-matching-to-sample in rats: A reversal design. AB - There is a growing body of research on matching- and non-matching-to-sample (MTS, NMTS) relations with rats using olfactory stimuli; however, the specific characteristics of this relational control are unclear. In the current study we examine MTS and NMTS in rats with an automated olfactometer using a successive (go, no-go) procedure. Ten rats were trained to either match- or non-match-to sample with common scents (apple, cinnamon, etc.) as olfactory stimuli. After matching or non-matching training with four odorants, rats were tested for transfer twice with four new odorants on each test. Most rats trained on MTS showed immediate transfer to new stimuli, and most rats trained on NMTS showed full transfer by the second set of new odors. After meeting criterion on the second transfer test, the contingencies were reversed with four new odor stimuli such that subjects trained on matching were shifted to non-matching and vice versa. Following these reversed contingencies, the effects of the original training persisted for many trials with new odorants. These data extend previous studies on same-different concept formation in rats, showing strong generalization requiring few exemplars. The critical role of olfactory stimuli is discussed. PMID- 28713031 TI - An LC-MS/MS based candidate reference method for the quantification of carbamazepine in human serum. AB - A validated LC-MS/MS-based candidate reference measurement procedure for the quantification of carbamazepine is presented in order to be used for standardization and harmonization of routine assays applied for therapeutic drug monitoring. Sample preparation was based on protein precipitation using acetonitrile followed by sample dilution. Since the previously listed certified reference material (CRM) SRM 1599 (anticonvulsant drug level assay standard) is no longer available, an ISO certified calibration material was used in this assay. As internal standards deuterated analyte congeners were applied. The method allows the measurement of carbamazepine, carbamazepine-10,11-epoxide and 10-hydroxy-10,11-dihydrocarbamazepine in the concentration range of 0.1 to 22.0MUg/ml with LODs and LOQs of <0.1MUg/ml and 0.1MUg/ml, respectively. Comparative measurement of 105 native patient samples using the here presented method showed a good agreement between two independent laboratories with a mean bias of 0.6%. PMID- 28713032 TI - Psychosocial rehabilitation after war trauma with adaptive disclosure: Design and rationale of a comparative efficacy trial. AB - BACKGROUND: Posttraumatic stress disorder (PTSD) from warzone exposure is associated with chronic and disabling social and occupational problems. However, functional impairment is rarely assessed or targeted directly in PTSD treatments, which instead focus on symptom reduction. Trauma-related contributors to diminished functioning, including guilt, shame, and anger resulting from morally compromising or loss-based war experiences, are also underemphasized. The goal of this clinical trial is to fill a substantial gap in the treatment of military related PTSD by testing a modified Adaptive Disclosure (AD) therapy for war related PTSD stemming from moral injury and traumatic loss focused on improving psychosocial functioning AD. METHOD AND DESIGN: This paper describes the rationale and design of a multi-site randomized controlled trial comparing AD to Present-Centered Therapy (PCT). We will recruit 186 veterans with PTSD, who will be assessed at baseline, post-treatment, and 3- and 6-months post-treatment. Primary outcomes are functional changes (i.e., functioning/disability and quality of life). Secondary outcomes are mental health variables (i.e., PTSD, depression, guilt, shame). We hypothesize that veterans treated with AD will experience greater improvements in all outcomes compared to those treated with PCT. DISCUSSION: This trial will advance knowledge in rehabilitation research by testing the first therapy specifically designed to address psychosocial functioning among veterans with war-related PTSD. The results may improve the quality of mental health care for veterans by offering an ecologically sound treatment for experiences that are uniquely impactful for war veterans. PMID- 28713033 TI - Corrections. PMID- 28713034 TI - Marc Tardieu: the interface man. PMID- 28713036 TI - Intracerebral gene therapy for mucopolysaccharidosis type IIIB syndrome. PMID- 28713035 TI - Intracerebral gene therapy in children with mucopolysaccharidosis type IIIB syndrome: an uncontrolled phase 1/2 clinical trial. AB - BACKGROUND: Mucopolysaccharidosis type IIIB syndrome (also known as Sanfilippo type B syndrome) is a lysosomal storage disease resulting in progressive deterioration of cognitive acquisition after age 2-4 years. No treatment is available for the neurological manifestations of the disease. We sought to assess the safety and efficacy of a novel intracerebral gene therapy. METHODS: Local regulatory authorities in France allowed inclusion of up to four children in this phase 1/2 study. Treatment was 16 intraparenchymal deposits (four in the cerebellum) of a recombinant adenoassociated viral vector serotype 2/5 (rAAV2/5) encoding human alpha-N-acetylglucosaminidase (NAGLU) plus immunosuppressive therapy. We assessed tolerance, neurocognitive progression, brain growth, NAGLU enzymatic activity in CSF, and specific anti-NAGLU immune response for 30 months after surgery. This trial is registered with EudraCT, number 2012-000856-33, and the International Standard Clinical Trial Registry, number ISRCTN19853672. FINDINGS: Of seven eligible children, the four youngest, from France (n=2), Italy (n=1), and Greece (n=1), aged 20, 26, 30, and 53 months, were included between February, 2012, and February, 2014. 125 adverse events were recorded, of which 117 were treatment emergent and included six classified as severe, but no suspected unexpected serious adverse drug reactions were seen. Vector genomes were detected in blood for 2 days after surgery. Compared with the natural history of mucopolysaccharidosis type III syndromes, neurocognitive progression was improved in all patients, with the youngest patient having function close to that in healthy children. Decrease in developmental quotient was -11.0 points in patient one, -23.0 in patient two, -29.0 in patient three, and -17.0 in patient four, compared with -37.7 in the natural history of the disease. NAGLU activity was detected in lumbar CSF and was 15-20% of that in unaffected children. Circulating T lymphocytes that proliferated and produced tumour necrosis factor alpha upon ex-vivo exposure to NAGLU antigens were detectable at 1-12 months and 3-12 months, respectively, but not at 30 months in three of four patients. INTERPRETATION: Intracerebral rAVV2/5 was well tolerated and induced sustained enzyme production in the brain. The initial specific anti-NAGLU immune response that later subsided suggested acquired immunological tolerance. The best results being obtained in the youngest patient implies a potential window of opportunity. Longer follow-up is needed to further assess safety outcomes and persistence of improved cognitive development. FUNDING: Association Francaise Contre les Myopathies, Vaincre les Maladies Lysosomales, Institut Pasteur, and UniQure. PMID- 28713037 TI - Systematic flexion-based approach for patients with radiological signs of lumbar spinal stenosis: Myth or reality? A retrospective study. PMID- 28713038 TI - Assessment of sexual function in women with neurological disorders: A review. AB - BACKGROUND: Although the rehabilitation of sexual function has been identified as a top priority among women presenting neurological conditions, sexual function is rarely assessed in this clinical group. OBJECTIVES: To review published assessment tools of sexual dysfunction in women with neurological conditions including multiple sclerosis (MS), spinal cord injury (SCI), Parkinson disease, stroke, traumatic brain injury. METHODS: A systematic literature review was conducted with Medline via PubMed, PubMed Central, and Medline databases. RESULTS: There are three reliable methods to assess sexual dysfunctions in women with neurological conditions: physiological assessments of reflexes and perineal sensitivity testing, self-reporting questionnaires on sexual function and sexual satisfaction, and electrophysiological assessments. Physiological assessments of sacral and thoracolumbar reflexes have mainly been conducted among women with SCI. When performed, they reveal the existence of a psychogenic and/or reflex sexual potential in those women. Other forms of physiological assessments include vulvar sensitivity testing in women with SCI, quantitative sensory testing and pudendal somatosensory evoked potentials in MS populations. A few validated self reporting measures are also available to assess sexual potential and sexual satisfaction, although mostly in women with SCI and MS. CONCLUSION: Despite high prevalence rates and important clinical implications, sexual dysfunction is not systematically assessed in women presenting various neurological conditions. Several well-validated tools exist for such assessments, which could be used for sexual rehabilitation in these patients. The implementation of systematic assessments of sexual potential is feasible and renewed efforts should be made to do so in clinical practice. PMID- 28713039 TI - Efficacy of ankle foot orthoses types on walking in children with cerebral palsy: A systematic review. AB - BACKGROUND: Ankle foot orthoses (AFOs) are orthotic devices that can be used to normalize the walking pattern of children with cerebral palsy (CP). One of the aims of orthotic management is to produce a more normal gait pattern by positioning joints in the proper position to reduce pathological reflex or spasticity. OBJECTIVE: To conduct a systematic review of the literature and establish the effect of treatment with various types of AFOs on gait patterns of children with CP. METHODS: PubMed, Scopus, ISI Web of knowledge, Cochrane Library, EMBASE and Google Scholar were searched for articles published between 2007 and 2015 of studies of children with CP wearing the following AFOs: hinged (HAFO), solid (SAFO), floor reaction (FRO), posterior leaf spring (PLS) and dynamic (DAFO). Studies that combined treatment options were excluded. Outcomes investigated were a change in gait pattern and subsequent walking ability. The PEDro scale used to assess the methodological quality of relevant studies. RESULTS: We included 17 studies investigating a total of 1139 children with CP. The PEDro score was poor for most studies (3/10). Only 4 studies, of 209 children in total, were randomized controlled trials, for a good PEDro score (5, 7, 9/10) and an appropriate level of evidence. One study used a case-based series and the remainder a cross-sectional design. In general, the use of AFOs improved speed and stride length. The HAFO was effective for improving gait parameters and decreasing energy expenditure with hemiplegic CP as compared with the barefoot condition. It also improved stride length, speed of walking, single limb support and gait symmetry with hemiplegic CP. The plastic SAFO and FRO were effective in reducing energy expenditure with diplegic CP. With diplegic CP, the HAFO and SAFO improved gross motor function. CONCLUSION: For children with CP, use of specific types of AFOs improved gait parameters, including ankle and knee range of motion, walking speed and stride length. AFOs reduced energy expenditure in children with spastic CP. However, further studies with good PEDro scores are required for more conclusive evidence regarding the effectiveness of AFOs in children with CP. PMID- 28713040 TI - Watching the gorilla and questioning delivery dogma. PMID- 28713041 TI - Chains of magnetosomes with controlled endotoxin release and partial tumor occupation induce full destruction of intracranial U87-Luc glioma in mice under the application of an alternating magnetic field. AB - Previous studies showed that magnetic hyperthermia could efficiently destroy tumors both preclinically and clinically, especially glioma. However, antitumor efficacy remained suboptimal and therefore required further improvements. Here, we introduce a new type of nanoparticles synthesized by magnetotactic bacteria, called magnetosomes, with improved properties compared with commonly used chemically synthesized nanoparticles. Indeed, mice bearing intracranial U87-Luc glioma tumors injected with 13MUg of nanoparticles per mm3 of tumor followed by 12 to 15 of 30min alternating magnetic field applications displayed either full tumor disappearance in 40% of mice or no tumor regression using magnetosomes or chemically synthesized nanoparticles, respectively. Magnetosome superior antitumor activity could be explained both by a larger production of heat and by endotoxins release under alternating magnetic field application. Most interestingly, this behavior was observed when magnetosomes occupied only 10% of the whole tumor volume, which suggests that an indirect mechanism, such as an immune reaction, takes part in tumor regression. This is desired for the treatment of infiltrating tumors, such as glioma, for which whole tumor coverage by nanoparticles can hardly be achieved. PMID- 28713042 TI - Implementation of the universal BLS termination of resuscitation rule in a rural EMS system. AB - BACKGROUND: Emergency Medical Services (EMS) are often the first medical providers to begin resuscitation of out-of-hospital cardiac arrest (OHCA) victims. The universal Basic Life Support Termination of Resuscitation (BLS-TOR) rule is a validated clinical prediction tool used to identify patients in which continued resuscitation efforts are futile. OBJECTIVE: The primary aim is to compare the rate of transport of OHCA cases before and after the implementation of a BLS-TOR protocol and to determine the compliance rate of EMS personnel with the new protocol in a largely volunteer, rural system. METHODS: A retrospective cohort study was conducted using the statewide EMS electronic patient care report system. Cases were identified by searching for any incident that had a primary impression of "cardiac arrest" or a primary symptom of "cardiorespiratory arrest" or "death." Data were collected from the two years prior to and following implementation of the BLS-TOR rule from January 1, 2012 through March 31, 2016. RESULTS: There were 702 OHCA cases were identified, with 329 cases meeting inclusion criteria. The transport rate was 91.1% in the pre-intervention group compared with 69.4% in the post-intervention group (chi2=24.8; p<0.001). EMS compliance rate with the BLS-TOR rule was 66.7%. Of the 265 patients transported during the study, 87 patients met (post-intervention group; n=22) or retrospectively met (pre-intervention group; n=65) the BLS-TOR requirements for field termination of resuscitation. None of these patients survived to hospital discharge. CONCLUSION: Rural EMS systems may benefit from implementation and utilization of the universal BLS-TOR rule. PMID- 28713043 TI - Auditory discrimination improvement predicts awakening of postanoxic comatose patients treated with targeted temperature management at 36 degrees C. AB - BACKGROUND: Outcome prognostication in postanoxic comatose patients is more accurate in predicting poor than good recovery. Using electroencephalography recordings in patients treated with targeted temperature management at 33 degrees C (TTM 33), we have previously shown that improvement in auditory discrimination over the first days of coma predicted awakening. Given the increased application of a 36 degrees C temperature target (TTM 36), here we aimed at validating the predictive value of auditory discrimination in the TTM 36 setting. METHODS: In this prospective multicenter study, we analyzed the EEG responses to auditory stimuli from 60 consecutive patients from the first and second coma day. A semiautomatic decoding analysis was applied to single patient data to quantify discrimination performance between frequently repeated and deviant sounds. The decoding change from the first to second day was used for predicting patient outcome. RESULTS: We observed an increase in auditory discrimination in 25 out of 60 patients. Among them, 17 awoke from coma (68% positive predictive value; 95% confidence interval: 0.46-0.85). By excluding patients with electroencephalographic epileptiform features, 15 of 18 exhibited improvement in auditory discrimination (83% positive predictive value; 95% confidence interval: 0.59-0.96). Specificity of good outcome prediction increased after adding auditory discrimination to EEG reactivity. CONCLUSION: These results suggest that tracking of auditory discrimination over time is informative of good recovery independent of the temperature target. This quantitative test provides complementary information to existing clinical tools by identifying patients with high chances of recovery and encouraging the maintenance of life support. PMID- 28713044 TI - Reply letter to: Economic evaluations of clinician training - make your research meaningful to decision makers. PMID- 28713045 TI - Cortisol elevation post-hatch affects behavioural performance in zebrafish larvae. AB - Maternal cortisol is essential for cortisol stress axis development and de novo production of this steroid commences only after hatch in zebrafish (Danio rerio). However, very little is known about the effect of elevated cortisol levels, during the critical period of stress axis activation, on larval performance. We tested the hypothesis that elevated cortisol levels post-hatch affect behavioural performance and this is mediated by glucocorticoid receptor (GR) activation in zebrafish larvae. The behavioural response included measuring larval activity in response to alternating light and dark cycles, as well as thigmotaxis. Zebrafish larvae at 3days post-fertilization were exposed to waterborne cortisol for 24h to mimic a steroid response to an early-life stressor exposure. Also, larvae were exposed to waterborne RU-486 (a GR antagonist) either in the presence or absence of cortisol to confirm GR activation. Co-treatment with RU-486 completely abolished the upregulation of cortisol-induced 11beta-hydroxysteroid dehydrogenase type 2 transcript abundance, confirming GR signalling. Cortisol exposed larvae displayed increased locomotor activity irrespective of light condition, but showed no changes in thigmotaxis. This cortisol-mediated behavioural response was not affected by co-treatment with RU-486. Cortisol exposure also did not modify the transcript abundances of GR and mineralocorticoid receptor (MR) in zebrafish larvae. Altogether, cortisol stress axis activation post-hatch increases locomotor activity in zebrafish larvae. Our results suggest that GR signalling may not be involved in this behavioural response, leading to the proposal that cortisol action via MR signalling may influence locomotor activity in zebrafish larvae. PMID- 28713046 TI - A 90-day oral toxicity study of glycolipids from Dacryopinax spathularia in Beagle dogs. AB - The subchronic toxicity of glycolipids from Dacryopinax spathularia (herein referred to as "AM-1") was studied in male and female Beagle dogs administered AM 1 by oral capsule at doses of 150, 500 or 1000 mg/kg/day for 90 days. AM-1 was well tolerated at all dosages and there were no test article-related effects on survival, clinical observations, neurological screening (functional observational battery) parameters, clinical pathology parameters, organ weights, macroscopic or microscopic evaluations. Test article-related changes were limited to minimal effects on food consumption and body weight changes in the 1000 mg/kg/day group females. Therefore, the no-observed-adverse-effect level (NOAEL) was considered to be 1000 mg/kg/day, the highest dosage level tested. These results add to the safety database for these naturally derived jelly mushroom glycolipids with potential for use as a food ingredient. PMID- 28713047 TI - Evidence against an involvement of aryl hydrocarbon receptor (AhR) in polyphenol inhibition of benzo[a]pyrene-induced oxidative stress and neoplastic transformation. PMID- 28713048 TI - Phytochemical analysis and effects on ingestive behaviour of a Caralluma fimbriata extract. AB - Caralluma fimbriata Wall. is currently used as a "natural slimming" food supplement, likely due to its content in pregnane glycosides. In the present study, a commercially available Caralluma fimbriata extract (Slimaluma(r); CFE, 100 mg/kg) has been evaluated for its ability to affect the ingestive behaviour in female rats, also with reference to the modulation of the brain neuropeptides NPY and ORX.The interference of CFE with alpha-amylase and lipase enzymes has been investigated in vitro, as possible peripheral mechanism of action. Also, the chemical composition of CFE has been assessed by NMR and spectrophotometric analysis. Results from in vivo study showed that CFE induced effects neither on blood parameters, nor on liver and gut histomorphology. Interestingly, a reduction in body weight gain with an increase in water intake and hypothalamic levels of NPY and ORX peptides were found. Phytochemical analysis, showed CFE contained about 12% of pregnane glycosides and 1.3% of polyphenols. Present results suggest possible effects of C. fimbriata on ingestive behaviour, likely mediated by central and peripheral mechanisms. PMID- 28713049 TI - Patient-reported outcomes after surgical stabilization of spinal tumors: symptom based validation of the Spinal Instability Neoplastic Score (SINS) and surgery. AB - BACKGROUND CONTEXT: Neoplastic spinal instability is movement-related pain or neurologic compromise under physiologic loads with the Spinal Instability Neoplastic Score (SINS) developed to facilitate diagnosis. There is a paucity of evidence that mechanical instability correlates with patient-reported symptoms and that surgical stabilization significantly improves these patient-reported outcomes (PROs). PURPOSE: The objective of this study was to determine if SINS correlates with patient-reported preoperative pain and disability, and if surgical stabilization significantly improves PRO. STUDY DESIGN: A single institution prospective cohort study was carried out. PATIENT SAMPLE: A total of 131 patients who underwent stabilization for metastatic spinal tumor treatment between July 2014 and August 2016 were included. OUTCOMES MEASURES: Preoperative baseline and mean difference in perioperative PROs as assessed by the Brief Pain Inventory (BPI) and MD Anderson Symptom Inventory (MDASI) were the outcome measures. METHODS: The SINS was analyzed as a continuous, ordinal, and categorical variable (Stable: 0-6, Indeterminate: 7-12, Unstable: 13-18). Statistical analysis was performed using Spearman rank coefficient (rho), the Kruskal-Wallis test, and an extension of the Cochran-Armitage trend test. The SINS and association between the mean differences in post- and preoperative PRO scores was analyzed using the Wilcoxon signed-rank test. RESULTS: There was a statistically significant positive correlation between increasing SINS and severity of preoperative pain with BPI average pain (rho=0.20; p=.03) and MDASI pain (rho=0.19; p=.03). Increasing SINS correlated with severity of preoperative disability with BPI walking (rho=0.19; p=.04), MDASI activity (rho=0.24; p=.006), and MDASI walking (rho=0.20; p=.03). Similar associations were noted when SINS was analyzed as an ordinal categorical variable. Stabilization significantly improved nearly all PRO measures for patients with indeterminate and unstable SINS. Significant correlations persisted when controlling for neurologic status and were not affected based on the technique of surgical stabilization used. CONCLUSIONS: Patient-related outcome-based validation of SINS confirms this scoring system for diagnosing neoplastic spinal instability and provides surgeons with a tool to determine which patients will benefit from stabilization. Surgical stabilization of cancer patients with SINS consistent with mechanical instability provides significant reduction in pain and improves patient mobility independent of neurologic status and stabilization technique. PMID- 28713051 TI - WITHDRAWN: 3D visualization and pathological characteristics of cartilage and subchondral bone changes in the lumbar facet joint of an Ovariectomized mouse model. AB - The Publisher regrets that this article is an accidental duplication of an article that has already been published, http://dx.doi.org/10.1016/j.spinee.2017.11.009. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal. PMID- 28713050 TI - The biomechanical impact of facet tropism on the intervertebral disc and facet joints in the cervical spine. AB - BACKGROUND CONTEXT: Facet tropism is defined as the angular difference between the left and the right facet orientation. Facet tropism was suggested to be associated with the disc degeneration and facet degeneration in the lumbar spine. However, little is known about the relationship between facet tropism and pathologic changes in the cervical spine and the mechanism behind. PURPOSE: This study was conducted to investigate the biomechanical impact of facet tropism on the intervertebral disc and facet joints. STUDY DESIGN: A finite element analysis study. METHODS: The computed tomography (CT) scans of a 28-year-old male volunteer was used to construct the finite element model. First, a symmetrical cervical model from C2 to C7 was constructed. The facet orientations at each level were simulated using the data from our previously published study. Second, the facet orientations at the C5-C6 level were altered to simulate facet tropism with respect to the sagittal plane. The angular difference of the moderate facet tropism model was set to be 7 degrees, whereas the severe facet tropism model was set to be 14 degrees. The inferior of the C7 vertebra was fixed. A 75 N follower loading was applied to simulate the weight of the head. A 1.0 N?m moments was applied on the odontoid process of the C2 to simulate flexion, extension, lateral bending, and axial rotation. RESULTS: The intradiscal pressure (IDP) at the C5-C6 level of the severe facet tropism model increased by 49.02%, 57.14%, 39.06%, and 30.67%, under flexion, extension, lateral bending, and axial rotation moments, in comparison with the symmetrical model. The contact force of the severe facet tropism model increased by 35.64%, 31.74%, 79.26%, and 59.47% from the symmetrical model under flexion, extension, lateral bending, and axial rotation, respectively. CONCLUSIONS: Facet tropism with respect to the sagittal plane at the C5-C6 level increased the IDP and facet contact force under flexion, extension, lateral bending, and axial rotation. The results suggested that facet tropism might be the anatomic risk factor of the development of cervical disc degeneration or facet degeneration. Future clinical studies are in need to verify the biomechanical impact of facet tropism on the development of degenerative changes in the cervical spine. PMID- 28713052 TI - Advice for acute low back pain: a comparison of what research supports and what guidelines recommend. AB - BACKGROUND: Advice is widely considered an effective treatment for acute low back pain (LBP); however, details on what and how to deliver this intervention is less clear. PURPOSE: We assessed and compared clinical trials that test advice for acute LBP with practice guidelines for their completeness of reporting and concordance on the content, method of delivery, and treatment regimen of advice interventions. DESIGN/SETTING: Systematic review. METHODS: Advice randomized controlled trials were identified through a systematic search. Guidelines were taken from recent overviews of guidelines for LBP. Completeness of reporting was assessed using the Template for Intervention Description and Replication checklist. Thematic analysis was used to characterize advice interventions into topics across the aspects of content, method of delivery, and regimen. Concordance between clinical trials and guidelines was assessed by comparing the number of trials that found a statistically significant treatment effect for an intervention that included a specific advice topic with the number of guidelines recommending that topic. RESULTS: The median (interquartile range) completeness of reporting for clinical trials and guidelines was 8 (7-9) and 3 (2-4) out of nine items on the Template for Intervention Description and Replication checklist, respectively. Guideline recommendations were discordant with clinical trials for 50% of the advice topics identified. CONCLUSION: Completeness of reporting was less than ideal for randomized controlled trials and extremely poor for guidelines. The recommendations made in guidelines of advice for acute LBP were often not concordant with the results of clinical trials. Taken together, these findings mean that the potential clinical value of advice interventions for patients with acute LBP is probably not being realized. PMID- 28713053 TI - Perils of intraoperative neurophysiological monitoring: analysis of "false negative" results in spine surgeries. AB - BACKGROUND CONTEXT: Although some authors have published case reports describing false negatives in intraoperative neurophysiological monitoring (IONM), a systematic review of causes of false-negative IONM results is lacking. PURPOSE: The objective of this study was to analyze false-negative IONM findings in spine surgery. STUDY DESIGN: This is a retrospective cohort analysis. PATIENT SAMPLE: A cohort of 109 patients with new postoperative neurologic deficits was analyzed for possible false-negative IONM reporting. OUTCOME MEASURES: The causes of false negative IONM reporting were determined. MATERIALS AND METHODS: From a cohort of 62,038 monitored spine surgeries, 109 consecutive patients with new postoperative neurologic deficits were reviewed for IONM alarms. RESULTS: Intraoperative neurophysiological monitoring alarms occurred in 87 of 109 surgeries. Nineteen patients with new postoperative neurologic deficits did not have an IONM alarm and surgeons were not warned. In addition, three patients had no interpretable IONM baseline data and no alarms were possible for the duration of the surgery. Therefore, 22 patients were included in the study. The absence of IONM alarms during these 22 surgeries had different origins: "true" false negatives where no waveform changes meeting the alarm criteria occurred despite the appropriate IONM (7); a postoperative development of a deficit (6); failure to monitor the pathway, which became injured (5); the absence of interpretable IONM baseline data which precluded any alarm (3); and technical IONM application issues (1). CONCLUSIONS: Overall, the rate of IONM method failing to predict the patient's outcome was very low (0.04%, 22/62,038). Minimizing false negatives requires the application of a proper IONM technique with the limitations of each modality considered in their selection and interpretation. Multimodality IONM provides the most inclusive information, and although it might be impractical to monitor every neural structure that can be at risk, a thorough preoperative consideration of available IONM modalities is important. Delayed development of postoperative deficits cannot be predicted by IONM. Absent baseline IONM data should be treated as an alarm when inconsistent with the patient's preoperative neurologic status. Alarm criteria for IONM may need to be refined for specific procedures and deserves continued study. PMID- 28713054 TI - Aggregation-induced emission probes for cancer theranostics. AB - Conventional cancer therapy usually suffers from poor treatment efficiency and adverse effects. To improve the treatment efficiency, it is critical to precisely diagnose specific cancer types and monitor the therapy process in situ. Fluorescence imaging has the advantages of high sensitivity and easy operation, but conventional fluorophores suffer from aggregation-caused quenching (ACQ), and therefore, their applications for imaging or diagnosis are severely impeded. By contrast, aggregation-induced emission (AIE) probes have significant advantages in terms of excellent photostability and a lack of self-quenching, and can be conveniently incorporated into theranostic platforms by combining them with various therapeutic modalities. Here, we discuss and summarize the recent advances in the development of AIE probes for cancer theranostics. PMID- 28713055 TI - Anterior and nasal transposition of inferior oblique muscle in cases of superior oblique palsy. AB - PURPOSE: To report long-term outcome of inferior oblique anterior and nasal transposition in superior oblique palsy. METHODS: The medical records of patients with superior oblique palsy who underwent inferior oblique anterior nasal transposition were reviewed retrospectively. A comprehensive ophthalmic evaluation, including prism bar cover test and measurement of torsion, was performed for all cases. One-year postoperative results were evaluated for alignment in primary gaze, contralateral gaze, and upgaze; reduction in inferior oblique overaction and changes in fundus torsion to assess long-term outcome of the procedure. RESULTS: A total of 12 patients were included. Three cases also underwent horizontal muscle surgery. Mean age at the time of surgery was 20.6 years. The median preoperative hypertropia was 21.5Delta (range, 12Delta 36Delta), corrected to 4.5Delta (range, 2Delta-10Delta) at 12 months postoperatively (P = 0.002). Median inferior oblique overaction decreased from +3 (range, +1 to +4) to 0 (range, -1 to +1). Preoperative fundus extorsion was 19.2 degrees +/- 6.7 degrees ; postoperative, 0.58 degrees +/- 1.8 degrees (P < 0.001). No consecutive hypotropia or underaction in elevation was observed in 10patients; 1 patient complained of torsional diplopia in upgaze. Extorsion was eliminated and head tilt improved in all patients. CONCLUSIONS: Inferior oblique anterior and nasal transposition resulted in good long-term outcomes in our patients with superior oblique palsy presenting with hypertropia, inferior oblique overaction, and extorsion in primary gaze. PMID- 28713056 TI - Peters anomaly in PHACE syndrome. AB - PHACE syndrome is a rare neurocutaneous disorder, with a complex pathogenesis. It presents with a large facial hemangioma associated with anomalies of the posterior fossa of the brain, arterial anomalies, cardiac anomalies, coarctation of the aorta, and eye anomalies. Ocular abnormalities are rare. We report the first published case of an infant with PHACE syndrome and Peters anomaly. PMID- 28713057 TI - Spontaneous closure of traumatic macular hole in a pediatric patient. AB - We present the case of a 14-year-old boy with ocular trauma and the complete eye tracking OCT imaging follow-up of the development and later spontaneous closure of a secondary macular hole. PMID- 28713059 TI - Congenital ptosis repair with a frontalis silicon sling: comparison between Fox's single pentagon technique and a modified Crawford double triangle technique. AB - PURPOSE: To compare the results of two different frontalis sling surgery techniques with silicon rod for ptosis: Fox's single pentagon technique and a modification of Crawford's double triangle technique. METHODS: In a randomized clinical trial, 52 eyes of 50 patients with severe ptosis and poor levator function (<=4 mm) were randomly assigned to the Fox group or the modified Crawford group. Cosmetic outcome, functional success, and lagophthalmos were compared. RESULTS: The patients achieved a fair to good cosmetic outcome by subjective grading and a fair outcome by objective grading in both groups. The intergroup difference was not statistically significant (P > 0.05). However, patients with preoperative lateral droop had better cosmetic outcome in the modified Crawford group. Mean increase in marginal reflex distance 1 (MRD-1) was 4.0 +/- 1.7 mm in the Fox group and 3.7 +/- 1.1 mm in the modified Crawford group. Change in MRD-1 within groups was significant (P < 0.0001); however, the difference in the groups was not (P = 0.44). The mean lagophthalmos in the Fox group was 1.3 +/- 0.7 mm versus 0.6 +/- 0.7 mm in the modified Crawford group at final follow-up. This intergroup difference in lagophthalmos was statistically significant (P = 0.001). CONCLUSIONS: Both techniques were effective in reducing the amount of blepharoptosis and achieving a natural appearing cosmetic outcome. In cases with predominant lateral droop, the modified Crawford's technique seems to produce better results, although the small number of cases does not permit statistical comparison. PMID- 28713058 TI - Regression of unusual optic disk neovascularization after adalimumab in a case of juvenile idiopathic arthritis-related uveitis. AB - We report the case of a 9-year-old girl with a severe and uncommon presentation of juvenile idiopathic arthritis-related posterior uveitis, with neovessels at the optic disk associated with peripheral vasculitis. After two failed bevacizumab intravitreal injections, uveitis responded to systemic adalimumab administration, with a complete and long-term remission of ocular inflammation. PMID- 28713060 TI - A standardized imaging protocol for the endoscopic prediction of dysplasia within sessile serrated polyps (with video). AB - BACKGROUND AND AIMS: Dysplasia within sessile serrated polyps (SSPs) is difficult to detect and may be mistaken for an adenoma, risking incomplete resection of the background serrated tissue, and is strongly implicated in interval cancer after colonoscopy. The use of endoscopic imaging to detect dysplasia within SSPs has not been systematically studied. METHODS: Consecutively detected SSPs >=8 mm in size were evaluated by using a standardized imaging protocol at a tertiary-care endoscopy center over 3 years. Lesions suspected as SSPs were analyzed with high definition white light then narrow-band imaging. A demarcated area with a neoplastic pit pattern (Kudo type III/IV, NICE type II) was sought among the serrated tissue. If this was detected, the lesion was labeled dysplastic (sessile serrated polyp with dysplasia); if not, it was labeled non-dysplastic (sessile serrated polyp without dysplasia). Histopathology was reviewed by 2 blinded specialist GI pathologists. RESULTS: A total of 141 SSPs were assessed in 83 patients. Median lesion size was 15.0 mm (interquartile range 10-20), and 54.6% were in the right side of the colon. Endoscopic evidence of dysplasia was detected in 36 of 141 (25.5%) SSPs; of these, 5 of 36 (13.9%) lacked dysplasia at histopathology. Two of 105 (1.9%) endoscopically designated non-dysplastic SSPs had dysplasia at histopathology. Endoscopic imaging, therefore, had an accuracy of 95.0% (95% confidence interval [CI], 90.1%-97.6%) and a negative predictive value of 98.1% (95% CI, 92.6%-99.7%) for detection of dysplasia within SSPs. CONCLUSIONS: Dysplasia within SSPs can be detected accurately by using a simple, broadly applicable endoscopic imaging protocol that allows complete resection. Independent validation of this protocol and its dissemination to the wider endoscopic community may have a significant impact on rates of interval cancer. (Clinical trial registration number: NCT03100552.). PMID- 28713061 TI - Extent of unnecessary surgery for benign rectal polyps in the Netherlands. AB - BACKGROUND AND AIMS: Minimally invasive techniques are available to safely and efficaciously remove even the largest rectal polyps. This study aimed to investigate the magnitude of cases still referred for radical rectal surgery and the reasons for these referrals and to perform a re-evaluation of cases potentially suitable for endoscopic therapy. METHODS: A retrospective analysis of data from the Dutch Pathology Registry (Pathologic Anatomic Nationwide Automated Archive) was performed using the records of patients who underwent major surgical treatment for a histologically proven benign rectal polyp between 2005 and 2014 in the Netherlands. In a representative subset of 7 hospitals, detailed analysis was performed. An expert panel of 3 endoscopists reassessed all patient data to judge whether endoscopic treatment would have been a reasonable alternative. RESULTS: In the last decade 575 patients, and 56 patients in the subset of hospitals, were referred for major rectal surgery for a benign rectal polyp in the Netherlands. The number of radical resections declined over the years but stabilized in the last years. The main reasons for surgery were polyp size (34%), suspicion of malignancy (34%), and transanal endoscopic microsurgery failures (20%). In community hospitals, referrals for surgery were relatively more prevalent compared with academic hospitals (P < .01). Thirty-nine percent of patients had perioperative adverse events, and 1 patient (1.8%) died. Seventy three percent of cases were assessed as "probably feasible" for endoscopic therapy. CONCLUSIONS: Over the last 10 years the rate of radical rectal surgery for a benign polyp declined. However, a significant subgroup of patients was still referred for invasive surgery at the cost of high morbidity and mortality. Referral to an expert endoscopist may avoid unnecessary surgery in most cases. PMID- 28713062 TI - A prospective study on second-generation colon capsule endoscopy to detect mucosal lesions and disease activity in ulcerative colitis (with video). AB - BACKGROUND AND AIMS: Mucosal healing is the goal for ulcerative colitis (UC) therapy, but it needs to be confirmed via colonoscopy. Colon capsule endoscopy (CCE) is a noninvasive technique for colon investigation. Our study investigated the accuracy of second-generation CCE (CCE-2) in assessing mucosal lesions and disease activity in UC. METHODS: In this prospective study, CCE-2 and conventional colonoscopy were performed on the same day. CCE-2 reviewers and colonoscopists used the Mayo endoscopic subscore (MES) and the Ulcerative Colitis Endoscopic Index of Severity (UCEIS) to assess disease activity, and they were blinded to each other's findings. Diagnostic parameters of CCE-2 for identifying mucosal lesions were evaluated by using colonoscopy as the reference. RESULTS: A total of 150 patients were enrolled. Of the 150 patients, 108 were included for per-patient analysis. CCE-2 and colonoscopy showed substantial agreement in measuring MES (intraclass correlation coefficient [ICC] 0.69; 95% confidence interval [CI], 0.46-0.81; P < .001) and UCEIS (ICC 0.64; 95% CI, 0.38-0.78; P < .001). CCE-2 had a sensitivity of 97% and 94% to detect mucosal inflammation (MES >0) and moderate to severe inflammation (MES >1), respectively. In per-segment analysis, the negative predictive values of CCE-2 to detect mucosal inflammation, including vascular pattern loss, bleeding, and erosions reached 94% to 95%. Interobserver agreement between 2 independent CCE-2 readers for both scoring systems was good (ICC > .80). The sensitivity and specificity of CCE-2 in detecting postinflammatory polyps were 100% and 91%, respectively. CCE-2 was better tolerated and preferred by patients than was colonoscopy. CONCLUSIONS: CCE 2 yields high accuracy in detecting mucosal lesions and determining disease severity in UC. It represents a well-tolerated and reliable tool for disease monitoring in UC. (Clinical trial registration number: NCT02469103.). PMID- 28713063 TI - Radiofrequency ablation for the treatment of weight regain after Roux-en-Y gastric bypass surgery. AB - BACKGROUND AND AIMS: Roux-en-Y gastric bypass (RYGB) surgery is an established modality for the treatment of morbid obesity. However, approximately one-quarter of patients experience weight regain after initially successful weight loss. Endoscopic therapy targeting the gastric remnant pouch represents a novel potential strategy to re-induce weight loss in this population. We performed a pilot trial of radiofrequency ablation (RFA) of the gastric remnant pouch after RYGB to determine feasibility, safety, and efficacy for weight loss. METHODS: We identified patients who had undergone RYGB, achieved >40% excess body weight loss (EBWL), and then regained >25% of lost weight. RFA was applied to the gastrojejunal anastomosis and the entire surface area of the gastric remnant pouch. Treatment was repeated at 4 and 8 months if patients did not meet specified weight loss targets. Weekly weights were obtained for 12 months. The primary efficacy outcome was percent EBWL at 12 months, compared with baseline. RESULTS: Twenty-five patients were enrolled at 4 centers. Mean (+/- standard deviation [SD]) age was 45.4 +/- 9.1 years, and 84% (21/25) were female. Mean (+/ SD) baseline body mass index was 40.2 +/- 7.8. Twenty-two of 25 patients completed 12 months of follow-up. At 12 months, median (+/- SD) EBWL was 18.4% (interquartile ratio 10.8, 33.7; P < .0001). Significant weight loss was seen at 3.5 months (P < .0001) and at 7.5 months (P < .0001), with a significant trend for continued weight loss over the 12-month period (P = .013). Two patients had serious adverse events requiring hospitalization. CONCLUSIONS: RFA of the gastric remnant pouch in patients with weight regain after RYGB resulted in significant reductions in excess body weight with an acceptable safety profile. Continued weight loss was observed after each RFA treatment. Further clinical trials in well-selected populations are warranted to determine the optimal number and frequency of RFA treatments and to assess durability of weight loss. (Clinical trial registration number: NCT01910688.). PMID- 28713064 TI - Novel risk stratification for metachronous recurrence after curative endoscopic submucosal dissection for early gastric cancer. AB - BACKGROUND AND AIMS: This study stratified the risk of developing metachronous gastric cancer (MGC) after curative endoscopic submucosal dissection (ESD) of early gastric cancer (EGC) to enable customization of endoscopic surveillance for MGC. METHODS: A total of 1115 patients who underwent curative ESD based on the expanded criteria for differentiated EGC from 2005 to 2014 at a single tertiary hospital were enrolled in this retrospective cohort study. They were followed up with annual endoscopy for a median of 50.1 months. Helicobacter pylori and histologic intestinal metaplasia (IM) were evaluated. The Kaplan-Meier method and Cox regression analysis were used for risk stratification. RESULTS: Three risk groups were identified: group 1 comprised patients with a synchronous neoplasm; group 2 comprised male patients with corpus IM; and group 3 comprised male patients without corpus IM or female patients. The 5- and 7-year cumulative risks (95% confidence interval [CI]) for metachronous recurrence were 15.1% (95% CI, 7.7-22.5) and 26.1% (95% CI, 14.9-37.3), respectively, in group 1; 5.6% (95% CI, 3.1-8.1) and 9.3% (95% CI, 5.4-13.2), respectively, in group 2; and 3.8% (95% CI, 1.6-6.0) and 4.9% (95% CI, 2.4-7.4), respectively, in group 3 (P < .001 by log rank test). The incidence of MGCs increased constantly even after 5 years in groups 1 and 2 but not in group 3. There was not enough evidence to show an association between H pylori eradication and metachronous recurrence in the data. CONCLUSIONS: Meticulous annual endoscopic surveillance for MGC for more than 5 years is recommended for patients with synchronous neoplasm. Endoscopic surveillance may also be extended beyond 5 years in male patients with corpus IM. PMID- 28713065 TI - Incidental giardiasis diagnosed during transduodenal EUS-FNA. PMID- 28713066 TI - Approaches for stricture prevention after esophageal endoscopic resection. AB - BACKGROUND AND AIMS: Endoscopic resection of extensive esophageal lesions has become more common as endoscopic resection techniques and equipment have developed. However, extensive esophageal endoscopic resections can cause postoperative esophageal strictures, which have a negative impact on the quality of life of patients. We aimed to review current treatments and innovative approaches to prevent esophageal strictures after widespread endoscopic resection of esophageal lesions. METHODS: We performed a comprehensive literature search from 2000 to 2016 using predetermined search terms to identify relevant articles and summarized their results as a narrative review. RESULTS: A total of 21 original articles and case series were identified. A circumferential mucosal defect involving more than three fourths of the esophageal luminal circumference was the primary risk factor for developing an esophageal stricture after endoscopic resection. Oral and injectable steroid therapy demonstrated promise in preventing post-endoscopic submucosal dissection esophageal strictures, with both strategies significantly reducing the number of required endoscopic balloon dilations. More data are needed on prophylactic self-expandable metal stents, local botulinum toxin injection, and oral tranilast as a strategy to prevent post endoscopic submucosal dissection esophageal strictures. Although preliminary studies of tissue-shielding resection sites with polyglycolic acid sheets and fibrin glue and autologous cell sheet transplantation have demonstrated promising results, additional larger validation studies are needed. CONCLUSIONS: Oral and locally injected/administered steroids are first-line options for the prevention of esophageal strictures, but additional innovative solutions are being developed. PMID- 28713067 TI - EUS-guided drainage of peripancreatic fluid collections with lumen-apposing metal stents and plastic double-pigtail stents: comparison of efficacy and adverse event rates. AB - BACKGROUND AND AIMS: Transmural drainage with double-pigtail plastic stents (DPPSs) was the mainstay of endoscopic therapy for symptomatic peripancreatic fluid collections (PPFCs) until the introduction of lumen-apposing covered self expanding metal stents (LAMSs). Currently, there are limited data regarding the efficacy and adverse event rate of LAMSs compared with DPPSs. METHODS: A retrospective analysis of EUS-guided PPFC drainage at a single tertiary care center between 2008 and 2015 was performed. Patients were classified based on drainage method: DPPSs and LAMSs. Adverse event rates, unplanned endoscopic procedures/necrosectomies, and PPFC resolution within 6 months were recorded. Significant bleeding was defined as necessitating transfusion or requiring endoscopic treatment/radiographic embolization. Subsequent endoscopic procedures were defined as unplanned procedures; stent removals were excluded. RESULTS: A total of 103 patients met inclusion criteria (84 DPPSs, 19 LAMSs). PPFCs were classified as walled-off necrosis (WON) in 23 (14 DPPSs, 9 LAMSs). There were significantly more bleeding episodes in the LAMS group (4 [19%]: 2 splenic artery pseudo-aneurysms, 1 collateral vessel bleed, 1 intracavitary variceal bleed; P = .0003) than in the DPPS group (1 (1%]: stent erosion into the gastric wall). One perforation occurred in the DPPS group. Unplanned repeat endoscopy was more frequent in the LAMS group (10% vs 26%, P = .07). Among retreated LAMS patients in with WON, 5 (56%) had obstruction by necrotic debris. In patients for whom follow-up was available, 67 of 70 (96%) with DPPSs and 16 of 17 (94%) with LAMSs had resolution of PPFCs within 6 months (P = .78). CONCLUSIONS: DPPSs and LAMSs are effective methods for treatment of PPFCs. In our cohort, use of LAMSs was associated with significantly higher rates of procedure-related bleeding and greater need for repeat endoscopic intervention. PMID- 28713068 TI - Implementation of Good Laboratory Practices (GLP) in basic scientific research: Translating the concept beyond regulatory compliance. AB - The principles of Good Laboratory Practices (GLPs) are mainly intended for the laboratories performing studies for regulatory compliances. However, today GLP can be applied to broad disciplines of science to cater to the needs of the experimental objectives, generation of quality data and assay reproducibility. Considering its significance, it can now be applied in academics; industries as well as government set ups throughout the world. GLP is the best way to promote the reliability, reproducibility of the test data and hence facilitates the international acceptability. Now it is high time to translate and implement the concept of GLP beyond regulatory studies. Thus, it can pave the way for better understanding of scientific problems and help to maintain a good human and environmental health. Through this review, we have made an attempt to explore the uses of GLP principles in different fields of science and its acceptability as well as looking for its future perspectives. PMID- 28713069 TI - Bilateral capitato-hamato-trapezoidal synostosis. PMID- 28713070 TI - The Role of CD200 and CD43 Expression in Differential Diagnosis between Chronic Lymphocytic Leukemia and Mantle Cell Lymphoma. AB - OBJECTIVE: Atypical chronic lymphocytic leukemia (CLL) is most frequently confused with mantle cell lymphoma (MCL). Several markers may contribute to the diagnosis of CLL. However, there is no consensus on which markers are needed to be used in flow cytometry for the diagnosis of CLL. The aim of the present study was to investigate the role of CD43 and CD200 markers in the differential diagnosis between CLL and MCL. MATERIALS AND METHODS: To address this issue, 339 consecutive patients with CLL and MCL were included in the flow cytometry lymphoproliferative disease panel for evaluation of CD43 and CD200 expressions, but not in the Matutes scoring system. RESULTS: CD200 was expressed in 97.3% of atypical CLL cases, whereas it was dimly expressed in only 6.1% of MCL cases. CD43 expression was 95.7% in atypical CLL cases. In the MCL cases, its expression rate was 39.4%. CONCLUSION: CD43 and CD200 were found to be more valuable markers than CD22, CD79b, and FMC7. CD43 and CD200 could also be considered as definitive markers in atypical CLL patients, for whom the Matutes scoring system remains ineffective. PMID- 28713071 TI - Association of Interleukin-2-330T/G and Interleukin-10-1082A/G Genetic Polymorphisms with B-Cell Non-Hodgkin Lymphoma in a Cohort of Egyptians. AB - OBJECTIVE: Polymorphisms in the interleukin (IL)-2 and IL-10 genes are known to be associated with susceptibility to different immune-dysregulated disorders and cancers such as non-Hodgkin lymphoma (NHL). To explore the possible association between IL-2-330T/G and IL-10-1082A/G single-nucleotide polymorphisms and the susceptibility to B-cell NHL (B-NHL) in Egyptians, we conducted a case-control study. MATERIALS AND METHODS: Genotyping of the studied genetic variations was done for 100 B-NHL patients as well as 100 age- and sex-matched healthy controls. RESULTS: The IL-2 variant allele occurred at a significantly higher rate in patients than controls and was associated with susceptibility to B-NHL [odds ratio (OR): 1.91, 95% confidence interval (CI): 1.28-2.85]. It was also associated with advanced performance status score. IL-2 polymorphism conferred an almost threefold increased risk of diffuse large B-cell lymphoma (OR: 2.64, 95% CI: 1.35-5.15) and a fourfold increased risk of indolent subtypes (OR: 4.34, 95% CI: 1.20-15.7). The distribution of IL-10-1082A/G genotypes in our patients was close to that of the controls. Co-inheritance of the variant genotypes of IL-2 and the common genotype of IL-10 conferred an almost sixfold increased risk (OR: 5.75, 95% CI: 1.39-23.72), while co-inheritance of the variant genotypes of IL-2 and IL-10 conferred fivefold increased risk of B-NHL (OR: 5.43, 95% CI: 1.44 20.45). The variant genotypes of IL-2-330T/G and IL-10-1082A/G had no effect on the disease-free survival of B-NHL patients. CONCLUSION: The present study highlights the possible involvement of the IL-2-330T/G genetic polymorphism in the susceptibility to B-NHL in Egypt, especially indolent subtypes. Moreover, IL 10-1082A/G is not a molecular susceptibility marker for B-NHL in Egyptians. PMID- 28713072 TI - Link Worker social prescribing to improve health and well-being for people with long-term conditions: qualitative study of service user perceptions. AB - OBJECTIVES: To describe the experiences of patients with long-term conditions who are referred to and engage with a Link Worker social prescribing programme and identify the impact of the Link Worker programme on health and well-being. DESIGN: Qualitative study using semistructured interviews with thematic analysis of the data. INTERVENTION: Link Worker social prescribing programme comprising personalised support to identify meaningful health and wellness goals, ongoing support to achieve agreed objectives and linkage into appropriate community services. SETTING: Inner-city area in West Newcastle upon Tyne, UK (population n=132 000) ranked 40th most socioeconomically deprived in England, served by 17 general practices. PARTICIPANTS: Thirty adults with long-term conditions, 14 female, 16 male aged 40-74 years, mean age 62 years, 24 white British, 1 white Irish, 5 from black and minority ethnic communities. RESULTS: Most participants experienced multimorbidity combined with mental health problems, low self confidence and social isolation. All were adversely affected physically, emotionally and socially by their health problems. The intervention engendered feelings of control and self-confidence, reduced social isolation and had a positive impact on health-related behaviours including weight loss, healthier eating and increased physical activity. Management of long-term conditions and mental health in the face of multimorbidity improved and participants reported greater resilience and more effective problem-solving strategies. CONCLUSIONS: Findings suggest that tackling complex and long-term health problems requires an extensive holistic approach not possible in routine primary care. This model of social prescribing, which takes into account physical and mental health, and social and economic issues, was successful for patients who engaged with the service. Future research on a larger scale is required to assess when and for whom social prescribing is clinically effective and cost-effective. PMID- 28713073 TI - Dementia-friendly interventions to improve the care of people living with dementia admitted to hospitals: a realist review. AB - OBJECTIVES: To identify features of programmes and approaches to make healthcare delivery in secondary healthcare settings more dementia-friendly, providing a context-relevant understanding of how interventions achieve outcomes for people living with dementia. DESIGN: A realist review conducted in three phases: (1) stakeholder interviews and scoping of the literature to develop an initial programme theory for providing effective dementia care; (2) structured retrieval and extraction of evidence; and (3) analysis and synthesis to build and refine the programme theory. DATA SOURCES: PubMed, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Cochrane Library, NHS Evidence, Scopus and grey literature. ELIGIBILITY CRITERIA: Studies reporting interventions and approaches to make hospital environments more dementia-friendly. Studies not reporting patient outcomes or contributing to the programme theory were excluded. RESULTS: Phase 1 combined findings from 15 stakeholder interviews and 22 publications to develop candidate programme theories. Phases 2 and 3 identified and synthesised evidence from 28 publications. Prominent context-mechanism outcome configurations were identified to explain what supported dementia friendly healthcare in acute settings. Staff capacity to understand the behaviours of people living with dementia as communication of an unmet need, combined with a recognition and valuing of their role in their care, prompted changes to care practices. Endorsement from senior management gave staff confidence and permission to adapt working practices to provide good dementia care. Key contextual factors were the availability of staff and an alignment of ward priorities to value person-centred care approaches. A preoccupation with risk generated responses that werelikely to restrict patient choice and increase their distress. CONCLUSIONS: This review suggests that strategies such as dementia awareness training alone will not improve dementia care or outcomes for patients with dementia. Instead, how staff are supported to implement learning and resources by senior team members with dementia expertise is a key component for improving care practices and patient outcomes. TRIAL REGISTRATION NUMBER: CRD42015017562. PMID- 28713074 TI - Barriers and facilitators to adherence to secondary stroke prevention medications after stroke: analysis of survivors and caregivers views from an online stroke forum. AB - OBJECTIVE: To identify barriers and facilitators of medication adherence in patients with stroke along with their caregivers. DESIGN: Qualitative thematic analysis of posts about secondary prevention medications, informed by Perceptions and Practicalities Approach. SETTING: Posts written by the UK stroke survivors and their family members taking part in the online forum of the Stroke Association, between 2004 and 2011. PARTICIPANTS: 84 participants: 49 stroke survivors, 33 caregivers, 2 not stated, identified using the keywords 'taking medication', 'pills', 'size', 'side-effects', 'routine', 'blister' as well as secondary prevention medication terms. RESULTS: Perceptions reducing the motivation to adhere included dealing with medication side effects, questioning doctors' prescribing practices and negative publicity about medications, especially in regard to statins. Caregivers faced difficulties with ensuring medications were taken while respecting the patient's decisions not to take tablets. They struggled in their role as advocates of patient's needs with healthcare professionals. Not experiencing side effects, attributing importance to medications, positive personal experiences of taking tablets and obtaining modification of treatment to manage side effects were facilitators of adherence. Key practical barriers included difficulties with swallowing tablets, dealing with the burden of treatment and drug cost. Using medication storage devices, following routines and getting help with medications from caregivers were important facilitators of adherence. CONCLUSIONS: An online stroke forum is a novel and valuable resource to investigate use of secondary prevention medications. Analysis of this forum highlighted significant barriers and facilitators of medication adherence faced by stroke survivors and their caregivers. Addressing perceptual and practical barriers highlighted here can inform the development of future interventions aimed at improving adherence to secondary prevention medication after stroke. PMID- 28713075 TI - Association of Parental Obesity and Diabetes Mellitus With Circulating Adipokines in Nonobese Nondiabetic Offspring. AB - BACKGROUND: Adipokines are implicated in the development of obesity-related traits. We hypothesized that nonobese participants without diabetes mellitus (DM) whose parents were obese or had DM would have altered circulating adipokines compared with those without parental history of these conditions. METHODS AND RESULTS: Participants in the community-based Framingham Third Generation cohort who were not obese (body mass index <30) and not diabetic with both parents in the Framingham Offspring cohort were included in this analysis (n=2034, mean age 40 years, 54% women). Circulating concentrations of fetuin A, RBP4 (retinol binding protein 4), FABP4 (fatty acid binding protein 4), leptin, LEP-R (leptin receptor), and adiponectin were assayed. Parental DM was defined as occurring before age 60 years, and obesity was defined as body mass index >=30 before age 60 years. General estimating equations were used to compare concentrations of adipokines among participants with 0, 1, or 2 parents affected by obesity or DM (separate analyses for each), adjusting for known correlates of adipokines. Overall, 44% had at least 1 parent who was obese and 15% had parents with DM. Parental obesity was associated with higher serum levels of FABP4 and LEP-R in their offspring (P=0.02 for both). Parental DM was associated with lower adiponectin but higher RBP4 concentrations in offspring (P<=0.02 for both). CONCLUSIONS: In our community-based sample, a parental history of DM or obesity was associated with an altered adipokine profile in nonobese nondiabetic offspring. Additional studies are warranted to evaluate whether such preclinical biomarker alterations presage future risk of disease. PMID- 28713077 TI - [Burnout syndrome among physiotherapists]. AB - BACKGROUND: Burnout is a syndrome of emotional exhaustion, depersonalization, and a reduced sense of personal accomplishment. Symptoms of burnout include mental and physical exhaustion, accompanied by psychosomatic disorders and emotional problems. Burnout occurs most often in people employed in occupations requiring working with people (human services) as a result of coping with stress and experience numerous failures at work. The aim of the research is the analysis of burnout among physiotherapists and demographic factors and conditions that may contribute to the burnout. MATERIAL AND METHODS: 212 (137 woman and 75 man) physiotherapists completed an anonymous questionnaire to assess burnout created by Owczarek and Olczyk. The age of respondents ranged between 20 to 56 years, with work experience from several months to more than 30 years. RESULTS: Total score of burnout was 115,66 (SD 21,78). On the scale of attitude to work 36,82 was achieved, workload - 34,76, contact with the patient - 27,54, and an attitude towards stress - 16,54, which means that the result obtained fit in the lower zone including average results concerning the level of burnout. Women had a higher level of professional burnout than men. Respondents who reported that their working conditions are not conducive to achieving therapeutic success (quality of equipment, size of treatment rooms, treatment technologies), exhibited a higher level of burnout. The average result of the level of burnout among physiotherapists is lower than all the results obtained in other occupational groups of health care workers, lead with the same diagnostic tool. CONCLUSIONS: Burnout syndrome among practicing physiotherapists require further study, taking into account the type and quality of jobs, but also the level of referral among professional physiotherapists. PMID- 28713076 TI - Prospective Relation of Circulating Adipokines to Incident Metabolic Syndrome: The Framingham Heart Study. AB - BACKGROUND: Adipokines are elaborated by adipose tissue and are associated with glycemic, lipid, and vascular traits. We hypothesized that in a cross-sectional analysis circulating adipokines are altered among subsets of obesity stratified by presence versus absence of metabolic syndrome (MetS) and prospectively predict the incidence of MetS. METHODS AND RESULTS: Participants in the community-based Framingham Third Generation Cohort who attended examination cycle 1 were included in the study (2002-2005; N=3777, mean age, 40 years; 59% women). Circulating adiponectin, leptin, leptin receptor, fetuin-A, fatty acid-binding protein 4, and retinol binding protein 4 were assayed and related to incident MetS in follow-up (mean 6 years). The adipokines were compared among individuals with excess body weight (body mass index >=25 kg/m2) and prevalent MetS, excess body weight without MetS (metabolically healthy obese), and normal-weight with MetS (metabolically obese, normal-weight) with normal-weight participants without MetS as a referent. Metabolically healthy obese individuals (n=1467) had higher circulating levels of fetuin-A and fatty acid-binding protein 4 but lower levels of leptin, leptin receptor, and adiponectin (P<0.001 for all). The adipokine panel was associated with incident MetS (263 new-onset cases; P=0.002). Higher circulating concentrations of retinol-binding protein 4 and fetuin-A were associated with incidence of MetS (odds ratio per 1-SD increment log marker, 1.21; 95% CI, 1.03-1.41 [P=0.02] and 1.17; 95% CI, 1.01-1.34 [P=0.03], respectively). CONCLUSIONS: In our community-based sample of young to middle-aged adults, metabolically healthy obese individuals demonstrated an adverse adipokine profile. Higher circulating levels of retinol-binding protein 4 and fetuin-A marked future cardiometabolic risk. PMID- 28713078 TI - [The influence of pain aliments and vertebral mobility in patients after whole body cryotherapy]. AB - INTRODUCTION: The motive efficiency depends from many factors, in this currently also form the state of health. The change in grounds of vertebral column causing the limitations of mobility and pain can significance worsen the functional state, motive efficiency and quality of patient's life. The leadership of active mode of life complying to recommendations the preventive style of life as well as the using with interventions of physical medicine influences on improvement significance the state of health. MATERIAL AND METHODS: It the examination groups were 42 patients (21 women and 21 men) in age from 45-65 years with low back pain about different etiology. All studied were thirty interventions of whole body cryotherapy and then practices kinesitherapy exercises by 30 minutes subjected on gymnastic room. To evaluation of stepping pain ailments was the scale VAS executed, mobility of lumbar spine with help of Schober test as well as was executed. All results were statistical analysis subjected. RESULTS: After whole body cryotherapy the pain ailments in scale VAS were statistical significant in men group. The decrease of pain ailments influenced on improvement column mobility vertebral spine with use a Schober test (p<0,05). The statistical analysis were not significant in women group of pain ailments and the opinion of mobility of vertebral column spine (p > 0,05). CONCLUSIONS: Whole body cryotherapy reduced significance pain ailments and mobility of lumbar spine in men group. In women group the got results were not statistical significant. PMID- 28713079 TI - [Acceptance of the disease and tendency to pay higher health insurance fee by patients with lung cancer]. AB - INTRODUCTION: Thanks to knowledge on the relationship between acceptance of disease and the willingness to co-pay for treatment in patients with lung cancer we can try to assess whether their introduction would be justified and acceptable. THE AIM: The purpose of the study was to examine the propensity of patients with lung cancer to pay higher rate of health insurance depending on their acceptance of the disease. MATERIALS AND METHODS: The study was conducted in 2016 at the Oncology Center in Bydgoszcz and the Kujawsko-Pomorskie Pulmonology Center in Bydgoszcz. The study involved the same group of 87 patients before and after surgery because of lung cancer. The original questionnaire and the Acceptance of Illness Scale were used in the study. RESULTS: Men accounted for 75% of the respondents, 65% of them were 50-69 years old. Before the surgery 34 (39.1%) patients stated that they are willing to pay a higher rate for health insurance, and 65 (74.7%) patients after the surgery (p <0.001). Among the 34 (39%) patients who were willing to pay a higher premium, before the surgery the most of them 21 (61.8%) by 10% higher, while least 2 (5.9%) by 100% higher. In contrast, after the surgery among the 65 (74.7%) patients 30 (46.2%) expressed a willingness to pay premiums by 10%, while the lowest 9 (13.8%) by 25% higher. Before the surgery 34 patients were willing to pay health insurance by 26% higheron average while 65 patients had an average increase of 36.5%. CONCLUSIONS: Patients with lower acceptance of the disease, living in the city, with secondary education and undergone surgeryare more likely to pay higher health insurance. More than half of the patients with lower acceptance of the disease are willing to pay higher premiums on health insurance by an average of 36%. PMID- 28713080 TI - Clinical and psychopathological characteristics of the autoagressive behavior in patients with the first psychotic episode with considering circadian rhythms. AB - INTRODUCTION: The high rate of autoagressive action in patients with psychotic symptoms manifested during the beginning of active psychopharmatherapy, and they are often the reason for psychiatric help. The continuous growth of autoagressive behavior indicates the number of unsolved problems in clinical suicidology. AIM: The aim of this research was to explore the clinical and psychopathological characteristics of the autoagressive behavior in patients with the first psychotic episode with considering circadian rhythms. MATERIAL AND METHODS: There was a research in regional clinical psychiatric hospital and 130 patients were involved in the research with autoagressive behavior during the first psychotic episodes. Clinical and psychopathological, psychodiagnostic and statistical methods were used. Characteristic clinical manifestations of first psychotic episode is determined by PANSS [1986] and BPRS [1962], level of suicidal risk is determined by Lyuban-Plotstsa's scale [2000], characteristics of biological rhythms is established by Estberg's questionnaire [1986]. RESULTS: Certain psychiatric symptoms were associated with the level of suicide risk in the first episode of psychosis, such as ?tension", ?hostility", ?mannerisms and posturing, ?excitement?, ?suspiciousness?, ?somatic concern?, ?anxiety?, ?depression?, ?guilt?. Circadian rhythms include the level of risk occurrence and severity autoagressive behavior such as clearly and dimly expressed evening types of daily activity. CONCLUSIONS: Therefore, further research of autoagression during the first psychotic episode with considering the influence of biological rhythms is a given area of current research in psychiatry aimed to improve the prevention, treatment and rehabilitation. PMID- 28713081 TI - Gene polymorphism of xenobiotic detoxification in children with bronchial asthma. AB - INTRODUCTION: Children are the most susceptible to harmful external factors due to the incomplete development of all functional body systems. The ecological situation the problem of influence of genetic and environmental factors on the pathogenesis of chronic respiratory diseases in children and its investigation is very impotent today. Among it the bronchial asthma is a leader among bronchial and pulmonary diseases caused by the influence of pneumotropic pollutants. The aim of our research was to study the phenotypic characteristics of asthma in Pre Carpathian children with different types of allelic gene polymorphism of the first phase of xenobiotic detoxification of microsomal epoxide hydrolases (mEPHX1). MATERIAL AND METHODS: The phenotypic peculiarities of bronchial asthma in 94 children from Ivano-Frankivsk region with different types of allelic gene polymorphism of the first phase of xenobiotic detoxification - mEPXH1 have been investigated. The material of genetic investigations was DNA isolated from leukocytes of patients' peripheral blood. Isolation and purification of DNA was carried out using commercial kits DIAtom TM DNA Prep200, GenePak DNA PCR test (LLC "Laboratory IzoGen") according to the manufacturer's recommendations. The association between polymorphism of gene mEPXH1 and susceptibility to occurrence and severity of BA in children have been described. RESULTS: It has been established that the manifestation of asthma as eco-determined pathology is affected by individual types of metabolic activity of genes of xenobiotic detoxification. It has been proved that patients with uncontrolled asthma have genotypes CC and GG (p <0.05) much more often. Children with asthma often have high enzymatic activity of a gene mEPHX1 (polymorphic variants of AG and AA-TT TT). A "slow" functional state of gene mEPHX1 corresponding to homo- and hetero zygotes for the mutant alleles: SS-AA and TS-AA is also a frequent phenomenon. CONCLUSIONS: It has been established that bronchial asthma as eco-determined pathology is affected by individual variants of metabolic activity of genes of xenobiotic detoxification. PMID- 28713082 TI - Morphological and immunohistochemical characteristics of human trigeminal ganglion neurons in the prenatal period of development. AB - INTRODUCTION: Data related to the amount, size and morphological characteristics of cell elements of sensory ganglia at different stages of prenatal development has not been fully elucidated in recent scientific publications. At the same time publications considering the study of cell structure of trigeminal ganglion in the postnatal period confirm heterogeneity of its neurons. The aim of the research was to study morphological and immunohistochemical characteristics of human trigeminal ganglion neurons at 12-14 weeks of prenatal development. MATERIAL AND METHODS: The study was made on 24 trigeminal ganglions of 12 human fetuses at 12 to 14 weeks of prenatal development after abortion made on social and medical indications. RESULTS: At the studied period of the intrauterine development nerve cells of the trigeminal ganglion significantly differed in size, tinctorial properties and degree of argentophility of the perikaryon. At the same time, the number of small nerve cells with an average diameter of less than 15 MUm prevailed. Immunohistochemical study allowed detecting the apparent Bcl-2 expression in the overwhelming number of small neurons; the expression of this marker has been observed in 50% of cells of the medium-sized neurons. No Bcl 2 expression has been found in most of the large neurons. Almost all the neurons, regardless of the size, showed moderate Ki-67 expression, protein S-100. VEGF expression has also occurred in the vast majority of the nerve cells of all size groups. CONCLUSIONS: 1. Human trigeminal ganglion neurons both at 12-14 weeks of prenatal development and in postnatal period are represented by heterogeneous population. 2. Polymorphism of trigeminal ganglion neurons has been found by all applied techniques. 3. Detected polymorphism is the evidence of processes of maturation and differentiation of neurons in human trigeminal ganglion at 12-14 weeks of prenatal development. PMID- 28713083 TI - Regional features of the microbial landscape of urine and comparative evaluation of antimicrobial therapy in children with cystitis. AB - INTRODUCTION: Growing resistance of pathogens to antibiotics, including cross resistance to other antimicrobial classes that are used in the treatment of recurrent infections of the lower urinary system in children demands constant control of issues of regional antibiotic resistance. In the present days, in the empirical treatment of such patients physicians still choose medications with preserved activity in relation to E. coli. The aim of our study was to investigate the regional features of microbial landscape of urine in children with cystitis and study the efficacy of 7-day administration of Furamag medicinal drug for the treatment of recurrent episodes of this disease in children. MATERIAL AND METHODS: 65 children aged 5 to 16 years underwent clinical and laboratory examinations. The patients in Group I (33 children) received Furamag as an antimicrobial therapy; the comparison group consisted of patients (32 children) who received cefuroxime axetil. The both therapies course duration was 7 days. RESULTS: Bacteriological examination results were indicative of prevalence of gram-negative opportunistic microflora; in particular, E. coli prevailed in the structure of isolated causative agents (61.9%). Analysis of detected pathogens susceptibility to antimicrobial agents showed a high level of E.coli resistance to ampicillin, amoxicillin/clavulanate and gentamicin (in 97.4% of cases), and in 50% of cases the E.coli were resistant to cefotaxime, ceftriaxone and cefuroxime. High rates of resistance of Enterococcus spp. (100%) and Enterobacter spp. (96.7%) to cefuroxime, cefotaxime and ceftriaxone were recorded. Furamag demonstrated significantly higher bacteriological efficacy vs. cefuroxime axetil as for eradication of the most clinically significant causative agents of cystitis identified in the Poltava region (93.9% and 68.8%, respectively, p <0.05). During the follow-up study, anti-relapse efficacy of Furamag appeared to be 1.5 times higher as compared to the reference drug in the children examined (p <0.05). PMID- 28713084 TI - Evalution of the effectiveness of multimodal approach to the management of cervical vertigo. AB - INTRODUCTION: Vertigo is one of the most common complaints among patients consulting neurologists and general practitioners - family medicine. A special form of dizziness is cervical vertigo. However, the presence of chronic vertigo and imbalance in this group of patients makes it possible to include the treatment of vestibular rehabilitation in the program. AIM: Evalution of the effectiveness of multimodal approach to the management of cervical vertigo. MATERIAL AND METHODS: 109 patients aged from 18 to 45 with vertigo together with myofascial pain syndrome of neck and shoulder area were examined. The survey included a sample of Dix-Hallpike, neurological and otoneurological examinations, Doppler ultrasound of the main arteries of the head and neck, brain MRI, functional spondylography of the cervical spine. For quantitive evaluation of the impact of vertigo on daily life the questionnaire DHI (Dizziness Handicap Inventory) was used. Testing was performed in two stages - before treatment and in 2 weeks' time. Patients were randomly divided into 3 groups which differ in their therapeutic tactics. RESULTS: In all three groups the normalization of the biomechanical pattern and elimination of musculo-tonic disorders accompanied by a decrease of a pain syndrome and a decrease in the severity or complete regression of dizziness and postural instability. At the same time, in groups 2 and 3, in which in addition to manual therapy, patients received acupuncture, there was a distinct positive dynamics of a pain syndrome according to VAS, Neck Disability Index and the Dizziness Handicap Inventory. A marked regression of vertigo and postural instability can be observed in patients in which the treatment along with manual therapy and acupuncture, a complex of vestibular rehabilitation was used. CONCLUSIONS: The multimodal approach using manual therapy in combination with acupuncture and vestibular rehabilitation showed the maximum therapeutic effect on elimination of musculo-tonic disorders, reduction of a pain syndrome with a complete regression of vertigo and postural instability. PMID- 28713085 TI - [The dependence of the marginal adaptation of composite fillings in caries cavities of class ii by black, on the state of oral hygiene and intensity of caries]. AB - INTRODUCTION: The problem of treatment of dental caries by fillings in dentistry is the key point in dentistry. Thus the main issue is the long-term functioning of the restorations. Particularly acute, this problem in the reduction of cavities class II according to Black, where the pressure on the filling is sufficiently high. MATERIALS AND METHODS: It was examined and treated 87 patients with different levels of oral hygiene of oral cavity and caries of varying intensity and whom 186 defects of hard tissues of teeth class II Black were fitted. All patients were divided into 3 groups depending on the type of filling material selected. Each group was in turn divided into two groups depending on the type of the prepared cavity. In a subgroup (1) the preparation was carried out without additional primary cavity retention elements. In a subgroup (2) the preparation was carried out with the main cavity in the form of retention elements as extra place on the chewing surface. RESULTS: Analyzing the quality of edge adjacent of fillings and restorations in the long-term period (24 months) depending on the intensity of caries and oral hygiene, we found that the best results were obtained in patients with low intensity of caries, and in patients with a high level of oral hygiene of patients in all study groups. CONCLUSION: The best results in the short and long-term periods were obtained in II and III groups. It should be noted that these groups the particularity of preparation has no influence on the quality of the restoration. According to restorations of group I where the restorative material was composite material as chemical hardening"Charisma PPF" ( "Heraeus Kulser"), this relation takes place. The best results in the short and long-term periods shown those restorations, under which created at preparing retention elements in the form of extra place. PMID- 28713086 TI - Intensifying approach to the therapy of patients with constellation of the diseases: chronic obstructive pulmonary disease and osteoarthritis. AB - INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is one of 21st century. About 210 million people all over the world are suffering with COPD, and annually 3 million people die of it. Under the influence of different factors, such as smoking, air prolusion, evaporation of chemicals, poisoning effect of chemical firings, inflammation processes take place in lungs, and if it is prolonged and take place simultaneously with morphological changes in the lungs, it it provide the de4velopment of the systemic inflammation process. At present systemic inflammation is regarded to be an essential component of COPD pathogeneses capable to become risk factor in developing and progressing multiple complications of the disease. The development of osteoporoses as the basis for the development of osteoarthritis (OA) is often considered one of a great amount of COPD complications and systemic effects. In the course of complex approach to treating patients for COPD, especially in the case when it is accompanied with OA, resolving therapy is more and more often referred to nowadays, namely, to the use of fenspirid hydrochloride. The aim of the article is to depict the results of the study of the effectiveness of fenspirid hydrochloride (EurespalR, ?Servier? France) included in complex therapy in treating patients for COPD accompanied with OA. MATERIALS AND METHODS: Hospitalized in the Pulmonology Department of Poltava regional clinical hospital named after N.V. Sklifosovsky served as the bases for the research, the investigation being carried out in the Institute of genetic and immune studies of development of pathology and pharmocogenetics of Ukrainian Higher State Educational Establishment "Ukrainian Medical Stomatological Academy of Poltava". Under investigation there were 33 patients (the average age of them was 54.4+/-3.1) suffering from exacerbation of COPD (clinic group B-GOPDII), accompanied with OA - basic group. Patients of the basic group were divided into two representative subgroups - A and B. The patients of A subgroup were restricted to basic therapy COPD according to the running protocol, while in B subgroup the basic therapy was accompanied with fenspirid hydrochloride hydrochloride per 80 mg twice a day 12 days running. Check group included 25 practically healthy people of the identical age. Results obtained showed that regress of the illness (cough decreasing) among the patients of the subgroup with COPD accompanied with OA, who were given fenspirid hydrochloride together with the basic therapy, 2.9+/-0.4 days earlier, dyspnoea 2.3+/-0.33 comparing to another subgroup ( p<0.05), the quality of the patients' life was getting better, the ability to endue more physical assignment increased. By the end of the treatment the sharpened forced exhalation FEV1level within the A subgroup patients equaled 57.1 +/-4.2% (before the treatment it was 53.4+/-3.9 %), while within the B subgroup patients it became 59.9 +/-3.9 (before the treatment it was 53.9+/-4.0 %). Repayments of bronchial obstruction in both groups became a bit higher- in A subgroup by 3.2+/-0.7%, and in B subgroup - by 3.6+/-0.5%. Concentration of IL-1beta in blood serum of basic group patients was 14.6 times higher than that of practically healthy people. After the therapy the level of IL-1beta within the A subgroup patients became 1.7 times lower (p < 0.01). After the basic therapy being accompanied with fenspirid hydrochloride to B subgroup patients the level of lowering was more vivid, and equelled 2.8 times ( p < 0.001). Decrease of the concentration of other mediators of inflammatory process under the influence of fenspirid hydrochloride was evident in other researches as well. Strong negative correlation ( r = -0.812; p < 0.05) between the level of IL-1beta in blood serum of basic group patients and their sharpened forced inhalation/exhalation. Forced expiratory volume (FEV)1 level before the treatment became moderately negative within the patients of A subgroup ( r= - 0.681; p < 0.05) and week within the patients of B subgroup ( r= -0.475; p <0.05). The term of treatment of A subgroup patients was 14.3 +/- 0.4 days, and that of B subgroup patients it was a bit less, namely, 12.9 +/- 0.5 days. An important result of the therapy with additional use of fenspirid hydrochloride was determining the periods between the case when next COPD exacerbation occurs because it is the frequency of the disease exacerbation that predicts the disease. Within A subgroup this time was 10.3+/-0.9 months, and within B subgroup it was 15.7+/-1.1 months. CONCLUSION: All this made it possible to draw the conclusion that usage of fenspirid hydrochloride hydrochloride in addition to complex therapy essentially reduces the level of IL-1beta in blood serum in compereson to the cases when only basic remedy was used, favours reduction of cases and intensity of systemic inflammations associated with increasing the duration of remission within this type/constellation of patients. PMID- 28713087 TI - Clinical factors related to post-stroke fatigue within the first 3 month after acute cerebrovascular events. AB - INTRODUCTION: Post-stroke fatigue (PSF) is a common stroke complication with long term negative consequences. AIM: Assess the rates of certain PSF domains within first 3 months after different acute cerebrovascular events (ACE) and identify clinical factors associated with each PSF domain. MATERIAL AND METHODS: There were examined 285 patients (195 with ischemic strokes, 39 with hemorrhagic strokes and 51 with transient ischemic attacks (TIA)) consequently at hospital stay, in 1 month and in 3 months after ACE. Global PSF and certain PSF domains were measured by multidimensional fatigue inventory-20 scale. RESULTS: In 1 month and in 3 months after stroke, in comparison with TIA, it has been identified the significant prevalence of only such PSF aspects that are just related to physical activity (physical PSF and activity-related PSF). In multivariate logistic regression analysis the majority of clinical variables as for ischemic strokes (subtype, affected cerebral arterial region, affected cerebral hemisphere, recurrent stroke, post-stroke urinary tract infection, pyrexia, stroke severity according to NIHSS score) and for hemorrhagic strokes (affected cerebral hemisphere, stroke severity according to NIHSS score) were not significantly associated with any PSF domain at any time point after each ACE. On the other hand, in stroke patients it had been found reliable associations between risk of global PSF, activity-related PSF during hospital stay and presence of post-stroke pneumonia, between risk of global PSF, mental PSF in 1 months after stroke and MRS score, between risk of physical PSF in 3 months after stroke and MRS score. CONCLUSION: Active prevention of post-stroke pneumonia and early post-stroke rehabilitation probably may be helpful for PSF prevention within first 3 months after stroke. PMID- 28713088 TI - [Pathogenic factors of regulatory mechanisms of organism adaptation to conditions with a high level of psychoemotional load]. AB - INTRODUCTION: The urgency of the issue is determined by the value of the stress impact of environmental conditions on workers of the operator personnel contingent, because the deterioration of their health and well-being is a factor in dangerous situations. However, the search for early diagnostic markers forming diseases, with a view to their prevention, is still a challenge. The aim was to establish the most important (among studied) pathogenetic factors of status of regulatory mechanisms of adaptation of individuals with a high level of psychoemotional load that is conditional upon profession. MATERIALS AND METHODS: The research is based on the results of the survey of transport operators (114 professional drivers of city passenger electrotransport) and 27 people who had high-level of mental and emotional load due to professional conditions. RESEARCH METHODS: general clinical; psychological (evaluation of psycho-emotional stability, level of anger, S. Muddy viability test , WHO well-being scale; Beck depression self-rating scale). laboratory (leukogram; cytochemical (the total amount of catecholamines blood; biochemical (cortisol saliva); instrumental (sardiointervalography); determination of the cellular adaptive responses; mathematic. RESULTS: The common data set survey was analyzed by factor analysis- 33 survey criteria, that showed status of health and pathogenic (emotional, behavioral, autonomic, neurohumoral, immune, and cellular) factors of regulatory mechanisms of adaptation of operators to conditions of high psycho-emotional stress. The results established that the main pathogenetic mechanisms of adaptation in drivers of passenger electric transport is possible to consider by four main factors: the integrated mechanisms of autonomic regulation with a predominance of trophotropic effects of parasympathetic; mobilizing influence of the sympathetic nervous system in regulatory mechanisms of adaptation and the level of centralization of heart rate control; state of regulation of systemic hemodynamics, mental health and level of depression for the current period. CONCLUSION: By factor analysis the framework of indicators was formed and they can be considered as the expression of the major pathogenetic mechanisms of regulatory mechanisms of adaptation to conditions with a high level of emotional stress in drivers of passenger transport. PMID- 28713090 TI - [The teaching of medical ethics in medical school]. AB - Medical ethics constitutes some kind of core, which enables the physicians to decide in complicated clinical situations. This subject is taught during medical studies through only one semester. Number of teaching hours designed for this crucial in later physician's practice subject is insufficient. Additional problem in teaching process is inconsistence between the Law and the Code of Medical Ethics. As a result it causes alarmingly weak preparation of students to take practical decisions according to ethical and moral values of the Code of Medical Ethics. What is also important, in 2012 a medical studies schedule was changed, which in author's opinion had very negative effect on medical ethics teaching. In our opinion it is vital to increase number of teaching hours spent on medical ethics, create a model of gradual ethical knowledge transfer to students on every year of studies, which should be based on clinical subjects in master-student relations. Authors of this article discuss in a complex way problems of medical ethics teaching at medical studies supporting their thesis with author's survey carried out on large group of students of Medical University of Silesia in Katowice. PMID- 28713089 TI - [Peculiarities of clinical psychopathological phenomenology of chronic neuropathies]. AB - INTRODUCTION: The study of psycho-emotional reactions associated with chronic neuropathies, is an important factor of the integrated solution to the problem of treatment and prevention of disorders of the peripheral nervous system. The aim of the research is to study clinical psychopathological phenomenology and personality characteristics of patients suffering from chronic neuropathies. MATERIAL AND METHODS: We examined 115 patients with chronic neuropathies in comparison with 60 healthy persons using a clinical conversation method, shortened multivariable personality questionnaire, The Zung Self-Rating Depression Scale, Spilberger's scale of trait and state anxiety and Symptom Check List-90-Revised questionnaire. RESULTS: Patients with chronic neuropathies are characterized by multiple complaints from the psycho-emotional sphere, the most common of which are depressed mood (72.2%), fatigue (76.5%) and sleep disorders (77.4%). Elevated levels of somatization (2,35 +/- 0,66 points), interpersonal sensitivity (1,83 +/- 0,80 points), depression (2,82 +/- 1,05 points), anxiety (2,08 +/- 1, 28 points) were revealed in patients. The level of depression on the The Zung Self-Rating Depression Scale in patients corresponded to mild depression of situational or neurotic genesis (54,45 +/- 9,93 points), and trait and state anxiety to an increased level (respectively 45,17 +/- 11,19 points and 45,14 +/- 9,89 points). Specific personality traits in the form of persistent depressive tendencies combined with hypochondriacal symptoms, an increase in trait and state anxiety, decreased general reactivity and manifestations of chronic fatigue and exhaustion correspond to somatic predisposition and provide ground to consider them as signs of persistent neuroticism with hypochondriacal personality development and accentuation on hypothymic (dysthymic) type. CONCLUSIONS: The study revealed a wide range of psychopathological phenomena of a polymorphic character. The main psychopathological construct of unfavourable changes in the psycho-emotional sphere of patients with neuropathies are depressive and anxiodepressive symptoms and auxiliary ones are somatization, emotional lability, increased interpersonal sensitivity and the phenomenon of asthenia. PMID- 28713091 TI - [S100A4 , MACC - 1 , REG - 4 - promising biomarkers of metastasis in cancers]. AB - Metastasis is one of the key steps in cancer, which is exposed to a large group of patients diagnosed with malignancy. Initiating the process of metastasis is to move the epithelial - mesenchymal cells wherein the cancer cells by blood and lymph vessels, penetrate to distant sites of the body to form secondary foci. Cancer biomarkers are group of molecules (typically proteins) secreted mainly by tumor cells themselves having use in diagnosis of cancer, determining the length of survival in patients or in the assessment of the body's response to treatment. Studies on the search for new cancer biomarkers are conducted nowadays more intensively. Examples of such molecules include S100A4, MACC1 or REG4, proteins, where elevated level in the body is associated primarily with the process of metastasis. Article briefly characterized above particles, presenting the most important functions performed by them in the body, thus drawing attention to the potential therapeutic use of these proteins. PMID- 28713092 TI - [Communicative competence and physician - patient relationship in aboriginal health care]. AB - Modern society consists of people from all walks of life. This melting pot of cultures might be considered both enriching and problematic. In order to communicate successfully, society members should acquire some social skills specific to a given community or, in other words, develop their communicative competence. The aim of this paper is to examine the way extralinguistic knowledge can influence physician - patient relationship in Aboriginal Australian communities. The paper is concerned with not only reviewing fundamental principles of ethnography and communicative competence but also identifying the main cultural differences that may affect the quality of healthcare services. PMID- 28713093 TI - Legal regulation of the production and trade of medical devices and medical equipment in the EU and US: experience for Ukraine. AB - INTRODUCTION: The need for effective legal regulation of production and sale of medical products in Ukraine due to its social effect is obvious and requires a high level of clarity. The experience of more advanced countries in this area, given the way chosen by Ukraine to harmonize our laws with EU legislation, is certainly could be a useful source of information. The urgency of issues need further intensification of national legal reforms. Some key points on concept of legal regulation of abovementioned sphere is a base of this study. MATERIAL AND METHODS: Legislation of Ukraine, European Union, United States of America, Guidelines, developed by European Commission & Food and Drug Administration's (FDA), recommendations represented by international voluntary group and scientific works. This article is based on dialectical, comparative, analytic, synthetic and comprehensive research methods. DISCUSSION: This study provide a possibility to state that main difference of regulatory systems in EU and US is that the legal framework of the EU is more flexible. This flexibility is grounded on main principle that only basic quality requirements for medical devices is defined by legislative acts however more detailed requirements are defined in standards, technical regulations, specifications, which are discretionary in nature. Contractors are free to choose any technical solution that provides compliance with the essential requirements, they can choose among different conformity assessment procedures and between accredited conformity assessment bodies to which they want to apply. The contractors themselves is interested to pass the conformity assessment procedure and have the right to put a conformity mark on their medical device because it will give them a real competitive advantage. In contrast, US State regulatory system provides strict control over business entities and law act establishes the quality requirements of medical products. The only body that can authorize the introduction of medical products and perform post-market monitoring is Food and Drug Administration (FDA), which has almost unlimited competence in this sphere. CONCLUSION: Taking into account further deepening of the European integration process of Ukraine, establishing of the regulatory system as much similar to that of the EU as possible is a main goal of legal reforms in abovementioned sphere. On the one hand, such system allows to implement effective control of contractors in the sphere of production and sale of medical products and provide safety of medical devices that are introduced, on the other hand, it does not afflict contractors with excessive and total control, allowing them to choose behavior that is most acceptable, understandable and user-specific. However, US's experience also has some positive characteristics, which could be taken into account. Therefore, such complex symbiosis of approaches from our point of view will balance controversial interest of manufacturers, sellers and consumers of medical devices. PMID- 28713094 TI - The use of various models of chronic immobilization stress in experimental studies. AB - INTRODUCTION: Stress is defined as a complex of protective and disturbing responses of the organism, generated in the process of the evolution, which occur as a result of neuroendocrine and metabolic alterations in response to the impact of emergency or pathological factors. Hence, stress is an important link of the adaptive mechanism; however, its adverse course can contribute to pathogenesis of many diseases. The problem of stress, which has been under study for years, is still a relevant topic to be investigated. AIM: The paper was aimed at comparison of various models of chronic immobilization stress based on the published data and findings from our own research. MATERIALS AND METHODS: The comparative analysis of the various techniques of chronic immobilization stress simulation in rats has been carried out on the basis of published data and findings of our own studies. RESULTS: It has been shown that the model, proposed by the investigators from the Ukrainian Medical Stomatological Academy aids in reducing the time of experimental study, does not require sophisticated equipment and the use of additional stressors, at night time, in particular, as well as enables animals' restraint in the convenient morning time. CONCLUSIONS: This technique is easy-to use and can be applied while studying the influence of the immobilization stress on the body. PMID- 28713095 TI - Rotavirus infection in children as of today (literature review). AB - INTRODUCTION: Urgency of the issue of rotavirus infection (RV) is stipulated by a special place in the structure of morbidity and mortality among young children. According to the data provided by WHO, 180 million diarrheal diseases with rotavirus etiology are registered every year. The aim of this article is to examine of current views on diagnosis and management of rotavirus infection in children. MATERIAL AND METHODS: The data of scientific literatures with the use of bibliosemantic method of study became the material for research. REVIEW: The urgent approaches to diagnosis and management of rotavirus infection in children is reflected in the article. CONCLUSIONS: The specific prophylaxis is recommended in order to prevent these infection. Apply monovalent vaccine, which has cross protection against different strains (G1, G2, G3, G4 and G9), and use pentavalent liquid vaccine containing G serotypes are recommended. It has cross-protection against different strains. PMID- 28713096 TI - The directions of development of legal regulation of patenting the methods of treatment in Ukraine considering the European and world experience. AB - INTRODUCTION: the current state of patenting legal regulation of medical treatment in Ukraine and in the world is analyzed, the directions for the further development are determined. The author defines "non-industrial medical" and socio ethical theories in the field of medical treatment patent protection. The existence of exclusively formal "monopoly" of the patent owner is noted, as well as the inapplicability of the majority of the patented achievements in this field in Ukraine. AIM: the purpose of this article is to investigate the current state of patenting legal regulation of medical treatment in Ukraine and in the world, to analyze the limitation of patent protection basic conception in the medical field and to determine the tendencies and perspectives of the legal protection mechanism of further development in this field in Ukraine, considering the European and world regulation experience. MATERIAL AND METHODS: this study is based on Ukrainian regulation acts, The European Patent Convention, The Code of Laws of the United States of America, judgments, scientific works and opinions of progressive-minded people in this sphere. Such methods as dialectical, comparative, analytic, synthetic and comprehensive are used in the article. CONCLUSION: The experience analysis of the medical treatment patenting regulation in EU and in other countries of the word made it possible to substantiate the tendencies of development the patenting legal regulation of treatment methods mechanism, based on the needs of creation conditions for the availability of the recent treatment developments and technics for citizens, without increasing the cost of such treatment through license fees. PMID- 28713097 TI - [Drug-induced changes in adrenal cortex function]. AB - Glucocorticoids, commonly used in the treatment of various disorders, particularly if administered at high doses, may lead to the development of iatrogenic Cushing's syndrome, being by far the most common iatrogenic disorder of the adrenal gland. In some cases, however, adrenal cortex function may be affected by other drugs and risk of the development of various clinical entities is dependent on the drug, its dose, as well as on the duration of the treatment. This risk is also related to the baseline function of this gland. Because little is known about the influence of non-hormonal drugs on adrenal cortex function, many physicians are unaware of the existence of these disorders, which, if not detected in the early stages, can pose serious health risk. Although distinguishing endogenous from exogenous adrenal cortex disorders is usually straightforward and based on the patient's history, in rare cases the investigation and differentiation of iatrogenic adrenal cortex disorders may be diagnostically challenging. This article raises awareness of the association between drugs other than adrenal cortex hormones and the function of this gland, and provide the reader with recommendations concerning the diagnosis and treatment of iatrogenic adrenal cortex disorders. PMID- 28713098 TI - [New physical methods in osteoarthritis treatment]. AB - Osteoarthritis is a chronic disease in which the pathological processes start from the catabolism of cartilage extracellular matrix and next extend on the whole joint. Therefore, it is important to diagnose the disease and determining treatment, selecting individually for each patient. The main health problems presents by every patients is pain, which decreases the everyday functioning and quality of life. The paper presents the definition of the disease and new therapeutic methods which improve the quality of life, as well as reduce intensity of pain. PMID- 28713099 TI - [Giving medico-legal opinions in cases with suspicion of medical mistake.part 1. between medicine and justice.] AB - Creating medico-legal opinion is a sophisticated investigative, analytical, decision-making and creative process. Forensic medicine specialist in cooperation with clinical medicine consultants, on the basis of evidence analysis, which was gathered during procedures and contained in the acts has to create an objective and essential opinion. This opinion is a vital, very important and irreplaceable proof in every case. Judicial body consults with forensic medicine specialist or specialists if there are circumstances for settlement of which there is a need of classified informations - art. 193 of Penalty Code. Forensic medicine specialists face many difficulties which may have effect on quality, positiveness of opinion, compliance with the deadline, increasing expectancy of judicial body or sides. It is very difficult to find clinical specialists which except their clinical knowledge have basic knowledge about law, the role and duties of an court expert. In this article we discuss creating-opinion problems, role and position of court expert in confrontation with expectations of judicial body and the Justice with particular emphasis on medical mistakes and assessment of medical proceedings. We show the complexity of creating of medical opinions, especially these institutional. PMID- 28713100 TI - [Dermatological and rheumatic symptoms in neoplasmas]. AB - Some of the symptoms that occur in neoplasmas are not directly related to tumor mass or metastasis. These may be an expression of paraneopastic syndromes and occur simultaneously or during neoplastic disease, but it is extremely important that they can precede the first symptoms of malignancy by several months or years. The clinical picture of paraneopastic syndromes often includes symptoms of defined disease or symptoms which resemble them. The association of neoplasmas and certain dermatological or rheumatic diseases is complex. Most of them are more likely to occur as primary diseases, therefore it is important for dermatologist and rheumatologist have an oncological awareness, especially in cases which are not routinely treated. PMID- 28713101 TI - [Extracorporeal shock waves (ESW) as an alternative treatment method for improving the limb muscles' spasticity after cerebral stroke - a systematic review of the literature]. AB - Extracorporeal shock wave (ESW) is a physical factor, of which the clinical use is observed in a wide range of disorders, particularly musculoskeletal dysfunctions. Recently, one can observe that the list of indications for ESW treatment is continuously growing and adapting the increasingly different systemic diseases in terms of etiology and pathomechanism. Nevertheless, it should be remembered that the potential biological mechanisms of ESW stimulation conditioning advantageous and desirable therapeutic effects are not clearly explained. In the world of science is the lack of irrefutable evidence, supported by advanced research in the field of observation and recording biophysical mechanisms under the influence of ESW stimulation in a number of neurological disorders, especially in patients after stroke suffer from the damage of upper motor neuron (UMN). The aim of this paper is to provide an overview of current research reports evaluating the efficacy and safety of ESW in reducing a post stroke spasticity of limbs and recover a motor finctions in stroke patients. A number of 8 research articles were qualified into review, only in English, which appeared in the years 2005 - 2015. The following summary includes a total group of 83 patients with spasticity of the lower limbs and 79 in the upper limbs. Review of scientific reports were based on international medical databases. All classified papers were characterized in detail, taking into account the methodology of research, patient characteristics, establish treatment parameters, as well as the results obtained on the basis of subjective and objective indicators. Despite a promising effectiveness of ESW therapy, the results of which have been described so far in several pilot studies, there is a legitimate need for further verification of this subject of research in terms of clinical application. PMID- 28713102 TI - [Contemporary use of radiosynoviorthesis in chronic polyarthrtitis]. AB - Radiosynoviorthesis is used for local treatment of recurrent joint effusions, leads to necrosis of inflamed synovium due to beta radiation energy served after intraarticular radionuclide administration. The aim of the therapy is destruction and fibrosis of abnormal, hypertrophic synovial membrane and then full recovery of its normal function after local corticosteroids and systemic modifying drugs failure. Radiosynoviorthesis is effective in different type of peripheral arthritis like rheumatoid arthritis, inflammatory spondyloarthtropaties, gout, chondrocalcinosis, pigmented villo-nodular synovitis, recurrent knee effusion after total joint replacement, idiopathic knee joint effusion, osteoarthritis and secondary prevention of intraarticular bleeding in haemophilia. The absolute contraindications are: pregnancy and breastfeeding, uncontrolled coagulation disorders in haemophilic patients, septic skin changes around area of joint puncture, septic arthritis, raptured Baker's cyst. The commonly used radioisotypes in Europe are: 90Yttrium, 186Rhenium, 169Erbium. The favourable results could be reached on average in 60-80% of treated joints regardless of radionuclide used. The efficacy of radiosynoviorthesis is comparable with surgical synovectomy and in some selected situations both methods could be combined. If the primary failure of radiosynoviorthesis appeared procedure could be repeated, good results are obtained very frequently regardless of poor primary effect. Radiosynoviorthesis is safe, effective, simple and patient-friendly procedure, working fast in different type of arthtritis. The team consisted of rheumatologist, orthopedic surgeon and nuclear medicine specialist is essential for proper indications for local radiation therapy. PMID- 28713104 TI - Oral Health Hazards of Water Pipe Smoking: Current Evidence. AB - Water pipe smoking (WPS) has been a traditional habit in the Middle Eastern Society for hundreds of years. The WPS users have a false sense of safety due to its casual use in social gatherings. It was estimated that about 70% of WPS users believe it to be a safe alternative to cigarette smoking.1 Further, the use of flavored tobacco has led to its growing popularity, especially among youngsters. PMID- 28713103 TI - [Listeriosis of central nervous system in patients with ulcerative colitis - case study]. AB - In the recently an increase morbidity inflammatory bowel disease, including ulcerative colitis was observed. The use of purine analogs and their metabolites are associated with a higher incidence of infections in this group of patients. Listeriosis is an infectious disease caused by a relatively anaerobic gram positive bacteria - Listeria monocytogenes. Common symptoms include fever, nausea, vomiting and diarrhea, but these pathogens can also cause myocarditis, central nervous system infections, including brain abscesses and sepsis. Since the incidence of Listeria monocytogenes is higher in patients with inflammatory bowel disease than in the general population, it is important to pay special attention to this group of patients (in prophylaxis as well as treatment) as these infections are serious and often fatal among them. PMID- 28713105 TI - Evaluation of the Current Techniques and Introduction of a Novel Approach for Estimating Maxillary Anterior Teeth Dimensions. AB - INTRODUCTION: Several techniques and methods have been proposed to estimate the anterior teeth dimensions in edentulous patients. However, this procedure remains challenging especially when preextraction records are not available. Therefore, the purpose of this study is to evaluate some of the existing extraoral and intraoral methods for estimation of anterior tooth dimensions and to propose a novel method for estimation of central incisor width (CIW) and length (CIL) for Saudi population. MATERIALS AND METHODS: Extraoral and intraoral measurements were recorded for a total of 236 subjects. Descriptive statistical analysis and Pearson's correlation tests were performed. Association was evaluated between combined anterior teeth width (CATW) and interalar width (IAW), intercommisural width (ICoW) and interhamular notch distance (IHND) plus 10 mm. Evaluation of the linear relationship between central incisor length (CIL) with facial height (FH) and CIW with bizygomatic width (BZW) was also performed. RESULTS: Significant correlation was found between the CATW and ICoW and IAW (p-values <0.0001); however, no correlation was found relative to IHND plus 10 mm (p-value = 0.456). Further, no correlation was found between the FH and right CIL and BZW and right CIW (p-values = 0.255 and 0.822). The means of CIL, CIW, incisive papillae-fovea palatinae (IP-FP), and IHND were used to estimate the central incisor dimensions: CIL = FP-IP distance/4.45, CIW = IHND/4.49. CONCLUSION: It was concluded that the ICoW and IAW measurements are the only predictable methods to estimate the initial reference value for CATW. A proposed intraoral approach was hypothesized for estimation of CIW and CIL for the given population. CLINICAL SIGNIFICANCE: Based on the results of the study, ICoW and IAW measurements can be useful in estimating the initial reference value for CATW, while the proposed novel approach using specific palatal dimensions can be used for estimating the width and length of central incisors. These methods are crucial to obtain esthetic treatment results within the parameters of the given population. PMID- 28713106 TI - Prevalence of Dental Anomalies in Odisha Population: A Panoramic Radiographic Study. AB - AIM: The aim of this study was to evaluate the prevalence of dental anomalies (DAs) in Odisha population using panoramic radiographs. MATERIALS AND METHODS: In this study, 1,080 panoramic radiographs were evaluated for DAs. Dental records were reviewed for diagnostic confirmation. Anomalies related to the shape, size, position of teeth, and number of roots (supernumerary roots) were evaluated. RESULTS: The study results showed the prevalence of DAs to be 35.27%. The most prevalent was dilaceration, which was seen in 46.71% cases followed by peg laterals in 20.99%. CONCLUSION: Dental anomalies were present in more than one third of the study group, which was mostly related to shape of the teeth. Early diagnosis of these DAs helps in avoiding complications. CLINICAL SIGNIFICANCE: Identification of DAs requires proper examination and thereby subsequent correct diagnosis. These anomalies can pose complications in normal functioning of orofacial complex. The knowledge of the prevalence of such anomalies aids dental practitioners for a proper treatment plan. PMID- 28713107 TI - Study on Personality Types of Dentists in different Disciplines of Dentistry. AB - AIM: The purpose of this study was to determine the most common personality type among dentists in seven selected clinical dentistry specialties using the Myers Briggs Type Indicator (MBTI) and to compare between these different types of personalities. MATERIALS AND METHODS: A survey containing the MBTI and demographic and practice questions was used to assess the personality styles of 243 dental specialists in Riyadh, Saudi Arabia. The survey results were analyzed using descriptive statistics. RESULTS: The results of the MBTI for 243 specialist dentists revealed, generally, a higher percentage of scoring for introversion (I) with an average of 65% than extroversion (E). The study identified 10 common personality types among these specialists: ISTJ, ISFJ, INFJ, ISTP, INFP, INTP, ENFP, ENTP, ENFJ, and ENTJ (extraversion-introversion (E-I), sensing-intuition (S N), thinking-feeling (T-F), and judging-perception (J-P)). The dominant personality type in all seven clinical specialties in dentistry was ISTJ, with an average of 54%. CONCLUSION: The personality types showed variation among the seven clinical dentistry specialties. However, among these seven clinician's specialties in dentistry, more than 50% of the individuals shared one common type of personality (ISTJ). CLINICAL SIGNIFICANCE: The identification of the personality type might help in their association with coworkers, students, and patients as well as knowing the individual preferences toward different specialties in dentistry. PMID- 28713108 TI - Current prescribing Practices for Antibiotic Prophylaxis: A Survey of Dental Practitioners. AB - AIM: Antibiotic prophylaxis guidelines have been developed for health care and dentistry. The authors examined whether dentists were following the 2007 American Heart Association (AHA) and the 2012 American Association of Orthopaedic Surgeons (AAOS) recommendations for antibiotic prophylaxis. MATERIALS AND METHODS: A survey was sent to 600 dentists in the south-central region of the United States. The survey examined dentists' prescribing practices for patients with cardiac and prosthetic joint replacements, antibiotic regimen prescribed, confidence in their prescription decisions, and dentistry's contribution to antibiotic resistance. RESULTS: The response rate was 28.7% (n = 172). Dentists followed the 2007 AHA guidelines for patients with a history of infective endocarditis (95%), and cardiac valves repaired with prosthetic materials (76%) or animal/donor tissue (61%). For prosthetic joint replacement, 72% prescribed antibiotic prophylaxis within the first 2 years after placement and 58% continued to prescribe after 2 years. Amoxicillin was the most frequently prescribed antibiotic for cardiac conditions (92%) and prosthetic joint replacements (77%). No significant differences were found in relation to dentists' gender (p = 0.75), year of graduation (p = 0.71), scope of practice (p = 0.30), and their confidence in their prescription decisions; 73% believed taking multiple doses of antibiotics leads to antibiotic resistance. CONCLUSION: The majority of dentists were following the 2007 AHA guidelines. Confusion regarding the 2012 AAOS guidelines for prosthetic joint replacement was evident. CLINICAL SIGNIFICANCE: Keeping current with changing antibiotic prophylaxis guidelines ensures dentists are providing the best evidence-based dentistry for their patients. PMID- 28713109 TI - Comparative Evaluation of Neem Mouthwash on Plaque and Gingivitis: A Double-blind Crossover Study. AB - AIM: The present study aimed at evaluating the impact of neem-containing mouthwash on plaque and gingivitis. MATERIALS AND METHODS: This randomized, double-blinded, crossover clinical trial included 40 participants aged 18 to 35 years with washout period of 1 week between the crossover phases. A total of 20 participants, each randomly allocated into groups I and II, wherein in the first phase, group I was provided with 0.2% chlorhexidine gluconate and group II with 2% neem mouthwash. After the scores were recorded, 1-week time period was given to the participants to carry over the effects of the mouthwashes and then the second phase of the test was performed. The participants were instructed to use the other mouthwash through the second test phase. RESULTS: There was a slight reduction of plaque level in the first phase as well as in the second phase. When comparison was made between the groups, no statistically significant difference was seen. Both the groups showed reduction in the gingival index (GI) scores in the first phase, and there was a statistically significant difference in both groups at baseline and after intervention (0.005 and 0.01 respectively). In the second phase, GI scores were reduced in both groups, but there was a statistically significant difference between the groups only at baseline scores (0.01). CONCLUSION: In the present study, it has been concluded that neem mouthwash can be used as an alternative to chlorhexidine mouthwash based on the reduced scores in both the groups. CLINICAL SIGNIFICANCE: Using neem mouthwash in maintaining oral hygiene might have a better impact in prevention as well as pervasiveness of oral diseases as it is cost-effective and easily available. PMID- 28713110 TI - An Innovative Approach to Retention: Thermoplastic Retainer. AB - AIM: The aim of this study was to design and introduce a retainer that overcomes the common shortcomings seen in other retainers. MATERIALS AND METHODS: Hard thermoplastic sheet of 0.5 mm thickness is vacuum or pressure-molded onto the patient cast. Lingual portion of the retainer is trimmed according to the contours of the anterior teeth. Contact points between the maxillary and mandibular anterior teeth are marked on the retainer and reduced. Punch cut holes are placed on the retainer for the exit of flash and air bubbles while fixation. The retainer is bonded onto the lingual surface of the anterior teeth using composite. RESULTS: A 1-month review of the retainer showed no patient discomfort, occlusal interference, or bond failure. The aim of the article was found to have been achieved. CONCLUSION: Initial evaluation has shown positive findings. Long-term clinical findings will determine the overall success of this new retainer. CLINICAL SIGNIFICANCE: As compared with other retainers, thermoplastic retainer has shown reduced tendency to debond from occlusal forces, decreased patient discomfort, and occlusal interference. PMID- 28713111 TI - Effect of Hydrogen and Carbamide Peroxide in Bleaching, Enamel Morphology, and Mineral Composition: In vitro Study. AB - AIM: The aim of the study was to evaluate the bleaching effect, morphological changes, and variations in calcium (Ca) and phosphate (P) in the enamel with hydrogen peroxide (HP) and carbamide peroxide (CP) after the use of different application regimens. MATERIALS AND METHODS: Four groups of five teeth were randomly assigned, according to the treatment protocol: HP 37.5% applied for 30 or 60 minutes (HP30, HP60), CP 16% applied for 14 or 28 hours (CP14, CP28). Changes in dental color were evaluated, according to the following formula: DeltaE = [(La-Lb)2+(aa-ab)2 + (ba-bb)2]1/2. Enamel morphology and Ca and P compositions were evaluated by confocal laser scanning microscope and environmental scanning electron microscopy. RESULTS: DeltaE HP30 was significantly greater than CP14 (10.37 +/- 2.65/8.56 +/- 1.40), but not between HP60 and CP28. HP60 shows greater morphological changes than HP30. No morphological changes were observed in the groups treated with CP. The reduction in Ca and P was significantly greater in HP60 than in CP28 (p < 0.05). CONCLUSION: Both formulations improved tooth color; HP produced morphological changes and Ca and P a gradual decrease, while CP produced no morphological changes, and the decrease in mineral component was smaller. CLINICAL SIGNIFICANCE: CP 16% applied during 2 weeks could be equally effective and safer for tooth whitening than to administer two treatment sessions with HP 37.5%. PMID- 28713112 TI - Effect of Casein Phosphopeptide-Amorphous Calcium Phosphate and Three Calcium Phosphate on Enamel Microhardness. AB - AIM: This study aims to investigate the effect of casein phos-phopeptide amorphous calcium phosphate and three calcium phosphate (CPP-ACP and TCP) on increasing the microhardness of human enamel after induction of erosion. MATERIALS AND METHODS: A total of 26 healthy human-impacted third molar teeth were chosen, and their hardness measured using a microhardness testing machine. The samples were immersed in Coca Cola (pH = 4.7) for 8 minutes. Then, micro hardness was measured again, and these samples were randomly divided into four groups (two control groups and two experimental groups). (1) Negative control group: Artificial saliva was used for 10 minutes, (2) positive control group: Fluoride gel was used for 10 minutes, (3) beta-TCP group: TCP was used for 10 minutes, (4) CCP-ACP group: CCP-ACP was used for 10 minutes. The final microhardness of those samples was measured, and the changes in microhardness of teeth within group and between groups were analyzed using the paired and analysis of variance tests respectively. Results were considered statistically significant at a level of p < 0.05. RESULTS: No significant difference was observed in microhard-ness between CPP-ACP group and TCP group (p = 0.368) during the time microhardness significantly dropped after soaking in soda. CONCLUSION: Casein phosphopeptide-amorphous calcium phosphate and TCP increased the microhardness of teeth. The increase in hardness in the TCP group was higher than in the CPP-ACP group, but this difference was not significant (p = 0.36). CLINICAL SIGNIFICANCE: Casein phosphopeptide-amorphous calcium phosphate and TCP can affect the remineralization of erosive lesions. PMID- 28713113 TI - Assessment of the Effect of Orthodontic Treatment on the Periodontal Health of Endodontically Restored Tooth. AB - : Intorduction: Patients usually undergo orthodontic treatment for achieving ideal interocclusal relationship between the dental tissue and bony tissue along with improving the speech, mastication, and facial esthetic appearance. Literature quotes paucity in the studies evaluating the effect of orthodontic treatment on the periodontal health of endodontically treated teeth. Hence, we planned the present study to assess the effect of orthodontic treatment on the periodontal health of endodonti-cally restored tooth. MATERIALS AND METHODS: The present study included assessment of 80 patients who underwent orthodontic treatment. All the patients were divided broadly into two study groups: groups I and II. Group I included patients with the absence of endodontically treated teeth, while group II included patients which maxillary central incisors were resorted endodontically. Examination of the periodontal health of the patients was done using the community periodontal index of treatment need (CPITN) around the selected teeth. All the values were recorded during the preorthodontic time, postorthodontic time, and after the first 6 months of starting of the orthodontic treatment. All the results were recorded separately and analyzed. RESULTS: In the groups I and II, 28 and 25 patients respectively, had score of 1, while 10 patients in group I and 12 patients in group II had score of 2. Nonsignificant results were obtained while comparing the CPITN score in between the two study groups when measured at the pre-, intra-, and postortho time. CONCLUSION: In patients undergoing orthodontic treatment, having endodontically resorted teeth, no difference exists in relation to the periodontal health. CLINICAL SIGNIFICANCE: Orthodontic treatment can be safely carried in patients with endodontically restored teeth. PMID- 28713114 TI - Retrospective Assessment of Healing Outcome of Endodontic Treatment for Mandibular Molars with C-shaped Root Canal. AB - INTRODUCTION: A thorough knowledge of the anatomic morphology of the root canal system is necessary for the long-term success of the root canal therapy. The occurrence of C-shaped root canal configuration is one such variation. Achievement of favorable prognosis after commencing root canal therapy in such teeth is one of the challenges imposed on the endodontist. Hence, we evaluated the healing occurring after endodontic therapy in patients with C-shaped root canals in mandibular molars. MATERIALS AND METHODS: The present study was conducted in the Department of Conservative Dentistry of the institution and included assessment of all the patients who underwent root canal treatment of the mandibular first and second molars. Endodontic therapy was performed in all the cases by experienced endodontist. Final postoperative radiographs were taken. Recording of the data of the personal and clinical details of a total of 250 patients was done. All the clinical and radiographic details of the patients, such as tooth location in the jaw, presence or absence of C-shaped canals, status of the pulp tissue, presence or absence of the fractures, and other details of the patients were recorded. Radiographic and clinical examination of the tooth of the patients was done during the baseline visit and further during the follow-up visits. The presence of C-shaped root canals was confirmed using the radiographs. Periapical index (PI) scoring system was used. Categories defined for enlisting the healing after the root canal treatment with the assessment of the PI score. All the results were analyzed by Statistical Package for the Social Sciences software. RESULTS: Vital pulp tissue was encountered in majority of the cases. C shaped root canal configuration was observed in 40% of the cases included in the present study. After completion of the endodontic therapy, complete crown placement was done in only 22% of the cases. In cases of vital teeth with C shaped root canals configuration, most of the teeth showed complete healing. Significant results were obtained while comparing the complete coverage crown parameter in relation to the healing process in teeth with C-shaped root canals. CONCLUSION: In the present study, no significant effect of the C-shaped root canal configuration was found on the healing rate of the endodontic therapy in mandibular molars. CLINICAL SIGNIFICANCE: Meticulous endodontic therapy with special techniques should be done while preparing teeth with C-shaped root canals. PMID- 28713116 TI - Therapeutic Evaluation of Cervical Dysfunction in Patients with Myofascial Pain Dysfunction Syndrome: A Prospective Study. AB - AIM: The aim of this study was to find out the therapeutic correlation between cervical dysfunction and myofascial pain dysfunction syndrome (MPDS). MATERIALS AND METHODS: The study included 46 patients out of which 23 had MPDS with cervical pain (group I), and 23 patients had only MPDS (group II). Detailed history and examination of the patients were carried out, and the factors taken into consideration were pain and tenderness of muscles of mastication and neck muscles, maximum comfortable mouth opening, and cervical range of motion. All the patients were randomly divided and advised physical exercises, light amplification by stimulated emission of radiation (LASER) therapy, and the combination of both exercise and LASER. Patients were assessed for the relief of signs and symptoms of myofascial pain and cervical pain posttreatment, every month for 2 months. RESULTS: Both the groups showed a similar response to all the different treatment modalities. In group I, the patients also had relief in their cervical pain although the treatment was directed for MPDS. Patients from both the groups who were advised LASER and combination of both exercise and LASER showed better response in terms of reduction in visual analog scale, number of tender muscles, and increased maximum comfortable mouth opening posttreatment and during the follow-up, as compared with the patients who were advised only exercise. CONCLUSION: Patients having cervical pain showed significant improvement comparable with patients having no cervical pain. Hence, the conclusion drawn was that there is a positive interrelationship between MPDS and cervical (neck) pain; MPDS may act as a catalyst for precipitating cervical pain. CLINICAL SIGNIFICANCE: Cervical pain showed significant improvement to physiotherapy in the form of exercise, LASER, and combination treatment, though the effective modality was LASER and combination of exercise and LASER therapy. PMID- 28713115 TI - Association between Cheiloscopic Patterns and ABO Blood Groups among South Indian Population. AB - BACKGROUND: Human beings have few characteristics that are unique from others. Lip prints are one of such feature. They are not changed throughout the life and are not influenced by injuries, diseases, or environmental changes. According to the various antigen-antibody reactions in the bloodstream, different individuals have specific blood groups. AIM: To study the distribution of lip print patterns among individuals with different ABO and Rh blood groups and also to know the relation between their characters and blood groups. MATERIALS AND METHODS: In the present study, lip prints were collected randomly from 85 individuals, and their blood group matching was performed. This is to identify the most common lip print type and to know any association between lip print types and blood groups. Tsuchihashi's classification of lip prints was used to compare with the ABO and Rh blood grouping systems. RESULTS: It was observed that in individuals with B+, A+, and O- blood groups, predominant pattern was Type IV and individuals having blood group O+ and AB+ common lip print pattern was Type II. CONCLUSION: This study showed strong association between lip print patterns and ABO blood groups as some blood groups were not included in statistical analysis; further studies including larger sample are essential to substantiate the results. CLINICAL SIGNIFICANCE: Correlating lip print with blood group helps in identification of the suspects. Along with lip prints, another biological record that remains unchanged throughout the lifetime of a person is the blood group. Determining the blood group of a person from the samples obtained at the site of crime and also recovering lip prints from site can help identify a person. PMID- 28713117 TI - Alteration in Taste Perception among Young Children during the use of Removable Orthodontic Appliance Therapy. AB - BACKGROUND: The sense of smell is very influential in the taste of foods. If the smell pleases us, we anticipate the taste of the food with a great deal of relish. If our sense of smell is impaired, so is our taste. The effect of appliance on taste perceptions has always had a controversial subject. MATERIALS AND METHODS: The present study was designed to analyze the change in taste perception in children using removable orthodontic appliances. All the selected volunteers were given different taste stimuli and were asked to score as per their perception. The verbal score was calculated based on the correct and incorrect taste stimuli given to them. Visual analog scale was used to assess intensity and hedonic (palatability) estimation of the volunteers. RESULTS: The volunteers from both study and control groups scored different values for taste stimuli. The majority of stimuli were estimated correctly by both groups. There was no statistically significant difference between the study and control groups. CONCLUSION: In different testing sessions, the scoring of the volunteers was nearly constant, indicating that an appliance does not play a major role in the alteration of taste stimuli. CLINICAL SIGNIFICANCE: The appliance brings about transient change in taste perception, we should educate the patient before delivering the appliance about the transient change in taste perception and encourage full-time wear of the appliance, including during meals, without fear of affecting taste sensations. PMID- 28713118 TI - Preserving the Bone Profile in Anterior Maxilla using an Equine Cortical Bone Membrane and an Equine Enzyme-treated Bone Graft: A Case Report with 5-year Follow-up. AB - AIM: This study aimed to report a well-succeeded use of equine enzyme-deantigenic cortical membrane and bone granules for guided bone regeneration (GBR) in the esthetic zone concomitant with implant placement. BACKGROUND: In the anterior maxilla, where patients typically have the highest expectations for implant supported restorations, bone resorption in the wake of tooth loss often leads to a lack of soft tissue support and ultimately to unsatisfactory esthetic results. Buccal bone augmentation at the time of implant placement has thus become common. This is usually accomplished following GBR principles and employing membranes made from various materials to serve as a barrier between the soft tissue and graft material. One of the more recently introduced membrane materials is made from thin, flexible equine cortical bone, i.e., rendered nonantigenic in an enzymatic process that preserves native bone collagen. CASE REPORT: This report describes the treatment of a patient who received an equine enzyme-deantigenic graft and membrane in conjunction with placement of an implant in the right maxillary lateral incisor site. CONCLUSION: After 5 years of follow-up, the patient was very satisfied with her appearance. A cone-beam computed tomography scan showed that the peri-implant bone levels and ridge thickness had been maintained, and the cortical layer in the pristine ridge had also undergone remodeling. CLINICAL SIGNIFICANCE: Guided bone regeneration with the concomitant use of enzyme-deantigenic membrane and graft is a valuable and suitable option for effective implant-supported prosthetic rehabilitation in the esthetic zone. PMID- 28713119 TI - Adhesive Bonding to Computer-aided Design/ Computer-aided Manufacturing Esthetic Dental Materials: An Overview. AB - AIM: To review the adhesive bonding to different computer-aided design/computer aided manufacturing (CAD/CAM) esthetic restorative materials. BACKGROUND: The use of CAD/CAM esthetic restorative materials has gained popularity in recent years. Several CAD/ CAM esthetic restorative materials are commercially available. Adhesive bonding is a major determinant of success of CAD/ CAM restorations. Review result: An account of the currently available bonding strategies are discussed with their rationale in various CAD/ CAM materials. CONCLUSION: Different surface treatment methods as well as adhesion promoters can be used to achieve reliable bonding of CAD/CAM restorative materials. Selection of bonding strategy to such material is determined based on its composition. Further evidence is required to evaluate the effect of new surface treatment methods, such as nonthermal atmospheric plasma and self-etching ceramic primer on bonding to different dental ceramics. CLINICAL SIGNIFICANCE: An understanding of the currently available bonding strategies to CA/CAM materials can help the clinician to select the most indicated system for each category of materials. PMID- 28713120 TI - Sealing Ability of Esthetic Post and Core Systems. AB - AIM: To review the literature on the sealing ability of esthetic post systems with different cementation techniques. BACKGROUND: An important factor for successful root canal treatment is the development of a coronal seal to the treated root canal system. Review result: The current literature describes promising results using fiber posts with a dual-cure, self-etch resin cement system. However, none of the published results describe a post system or cementation technique that achieved a homogeneous and tight coronal seal. CONCLUSION: Fiber post systems appear to be favorable alternatives to metallic or ceramic post systems. Furthermore, dual-cure, self-etch resin cement systems represent superior alternatives to other cement systems. CLINICAL SIGNIFICANCE: The clinician should be aware of the differences between various post systems and different cement systems to select and apply the most appropriate post and cement in each clinical situation. PMID- 28713121 TI - Youth Giving Voice in Research Ethics. PMID- 28713122 TI - Engaging the Disengaged Community: Opportunities, Strategies and Lessons Learned Working with African American Males. PMID- 28713123 TI - Engagement and Quality of Life in Under-represented Older Adults: A Community Based Participatory Research Project. PMID- 28713124 TI - A Belgian Story of CBPR Among People with a Migration Background. PMID- 28713125 TI - Developing Trust, Multiple Identities, and Participatory Research: Select Examples. PMID- 28713127 TI - Editors' Note. PMID- 28713128 TI - Introduction: Community-Academic Partnerships in Research and Public Health. AB - This symposium includes twelve personal narratives from individuals and teams who have been engaged in community-academic partnerships in research and public health. This issue also includes four commentaries on these narratives by experts in patient and research subject advocacy, healthcare and biomedical ethics, social science, and health education funding. While much has been written about community-academic partnerships, what appears in the literature does not include in-depth, personal reflection on the challenges and obstacles faced in these partnerships. With this symposium, we aim to stimulate reflection and discussion about creative approaches to community-academic partnerships in order to guide those who are both new to and experienced in community-engaged work. PMID- 28713126 TI - Advance Care Planning for the Homeless: A Community Collaboration. PMID- 28713129 TI - Two Steps Forward, One Step Back: Dancing Toward Equitable Collaboration. PMID- 28713130 TI - Full Collection of Personal Narratives. PMID- 28713131 TI - Research Partnership Rather than Research on the Amish. PMID- 28713132 TI - We Really Do Have the Same Goals: The Push and Pull of One Community-Academic Partnership to Support Congolese Refugee Women. PMID- 28713133 TI - Dual Relationships in Specialty Care: Reflections from the Field. PMID- 28713134 TI - A Storied Community: Piloting a Patient/Student Narrative Workshop at a Community Health Center. PMID- 28713135 TI - Community-Academic Partnerships to Improve Hispanic Immigrant Health: Perspectives from a Doctoral Student. PMID- 28713136 TI - Reflections on Cultivating Community-based Participatory Research Partnerships with the Afghan Immigrant Community. PMID- 28713137 TI - Be Careful What You Wish for: A Community-Academic Student Partnership Story. PMID- 28713139 TI - Stigma as a Facet of Community-Academic Partnership. PMID- 28713138 TI - The Power of The Personal: Breaking Down Stereotypes and Building Human Connections. PMID- 28713140 TI - The Engaged Dissertation-Conducting Community-Based Participatory Research with Rural Indigenous Communities as a Graduate Student. PMID- 28713142 TI - A Deep Dive into Community Engagement. AB - Community engagement offers opportunities to enhance the value of health research. Through engaging with community partners, researchers can pursue projects that produce meaningful benefits for study populations. At the same time, engagement presents challenges for everyone involved. High-quality engagement requires attending to the choice of community partners, the ethics of engagement, education for researchers and community partners, project planning, and the distinct knowledge that experienced research subjects can contribute to engagement activities. PMID- 28713141 TI - A Community-Developed, Culturally-Based Palliative Care Program for African American and White Rural Elders with a Life-Limiting Illness: A Program By The Community for the Community. PMID- 28713143 TI - The Common Denominator. AB - Despite the best of intentions, researchers and subjects can fall into mindsets of "Us vs. Them", focusing on the different characteristics of their roles, skillsets and agendas. This commentary looks at the commonalities of the investigators and community members in these narratives, and the ways these shared human traits and experiences become the basis for merged social unit that moves productively toward relevant research goals. PMID- 28713144 TI - Toward an Ethics of Community-Academic Partnership. AB - Community-academic partnerships, which often form unexpectedly, can be time consuming, tedious, and sometimes awkward alliances, yet they arise out of perceived needs and can be fruitful. Putting aside hierarchy to explore such partnerships as communities themselves that seek to capitalize on the strengths, knowledge, and life experiences of each stakeholder can offer a fresh perspective for thinking about the ethics of community-academic partnerships. This commentary explores the partnerships detailed in the symposia through the lens of ethnography. PMID- 28713145 TI - Reciprocal Relationships: Something for Everyone. AB - Reciprocal relationships based on mutual goals, respect and trust are key to maintaining working relationships and getting reliable research results. Yet relationship building is not a concept taught in academia. These skills are often learned the hard way, with singular solutions found for case-by-case scenarios. Several journeys to identify the components, barriers and rewards of reciprocal relationships are discussed. PMID- 28713146 TI - "Being Persistent without Being Pushy": Student Reflections on Vaccine Hesitancy. AB - Our goal as pediatric educators is to graduate physicians who have witnessed effective approaches and have grasped the nuances of communication strategies between vaccine-hesitant families and health care providers. We identified vaccine hesitancy as a recurring topic in 19 of 304 medical student reflective narratives addressing an issue in professionalism or systems-based practice. We conducted content analysis on the narratives in order to gain a better understanding of student perceptions of visits in which they observed a provider discussing vaccine hesitancy with a parent. We identified four major themes: perceived effectiveness of provider-family communication, student reaction to the encounter, physician approach to vaccine hesitancy, and gaps in students' own knowledge. Most students described communication positively, despite only 4 of 19 observing eventual vaccine acceptance. Information regarding vaccines, vaccine delivery, and approaches to vaccine hesitancy needs to be introduced and enhanced in the educational curriculum of providers at all levels, including medical students, resident physicians, and attending physicians, in order to ensure that providers possess the comprehension and communication skills to ethically optimize vaccine uptake among patients. PMID- 28713147 TI - To Enroll or Not to Enroll?: A Researcher Struggles with the Decision to Involve Study Participants in a Clinical Trial That Could Save Their Lives. AB - Hundreds of thousands of clinical trials are conducted annually around the world, working to further scientific knowledge and expand medical treatment. At the same time, clinical trials also present novel challenges to researchers who have access to large pools of research participants and are routinely approached by pharmaceutical companies seeking to recruit subjects for clinical trials. This case study discusses the ethical dilemmas faced by a community health investigator who received an invitation to enroll people who inject drugs (PWID) into a clinical trial of a drug that promised a new treatment option for Hepatitis C. The author elaborates on the ethical tensions that he confronted between "doing good" and "avoiding harm. The paper suggests that issues of distributive justice should also be considered, particularly when the drugs being tested might eventually command prices that place them out of reach of the population enrolled in the trial. This case does not attempt to provide an ethical road map to assist researchers in similar circumstances, but rather to illustrate some of the considerations involved in making a decision about whether or not to participate in clinical trials research. PMID- 28713148 TI - Sometimes Those Hoofbeats Are Zebras: A Narrative Analysis. AB - The case of BB, an 11-year-old girl who was hospitalized because of sudden odd seizure-like symptoms and catatonic affect, highlights several ethical issues and communication problems. The correct diagnosis was initially missed, partly because physicians are trained to think of the most common explanation for a patient's symptoms; the medical education truism "when you hear hoofbeats, think horses, not zebras" was not helpful in BB's case. The common habit of medical professionals to not revisit a diagnosis once one is established also led to missed opportunities to provide appropriate care for this young patient. The difficulty nurses and/or family members have in questioning a diagnosis and treatment plan are also discussed. PMID- 28713149 TI - Reframing Medical Appropriateness: A Case Study Concerning the Use of Life Sustaining Technologies for a Patient With Profoundly Diminished Quality of Life. AB - This case study considers the clinical ethics issues of medical appropriateness and quality of life for patients who are critically ill. The case involves a terminally ill cancer patient with a profoundly diminished quality of life and an extremely poor prognosis; his spouse desires to bring him home, where she will arrange to keep him alive for as long as possible via life-sustaining interventions. The analysis engages with the complicated notion of medical appropriateness, both in general and as it pertains to life-sustaining interventions in a critical care setting, and considers the ethical implications of the various ways in which one might understand this concept. It also addresses the significance of quality-of-life determinations, emphasizing the role of individualized values in determining the importance of quality of life for clinical decision-making. The discussion concludes with a description of the two strategies employed by the ethics team in helping to alleviate the medical team's concerns about this case. PMID- 28713150 TI - A Jehovah's Witness Adolescent in the Labor and Delivery Unit: Should Patient and Parental Refusals of Blood Transfusions for Adolescents Be Honored? AB - A 15-year-old was admitted to the labor and delivery unit for induction of a 41 week-gestation pregnancy. Her parents, members of Jehovah's Witnesses, and the patient, who had been studying the religion but had not yet been baptized, were adamant that no blood transfusions would be accepted even if a life-threatening hemorrhage were to occur. In our analysis, we examine the underlying ethical conflict and issues raised by this case. We considered two important ethical questions in analyzing the dilemma: first, whether adolescents are capable of providing autonomous and authentic refusals for lifesaving interventions; and second, whether parents can refuse such interventions for their adolescent children based on their religious beliefs. We provided justifications for not considering the adolescent's refusal as autonomous and for overruling the parental refusal, concluding that there was ethical support for providing potentially lifesaving transfusions should they become clinically indicated. We also suggested strategies to avoid blood loss and the need for transfusions in order to respect the stated values and preferences of the patient and her family to the greatest degree possible. In order to protect the privacy of the patient and her family, details in this case have been changed and no identifiable information has been used. PMID- 28713151 TI - Trifluoperazine Inhibits Mesangial Cell Proliferation by Arresting Cell Cycle Dependent Mechanisms. AB - BACKGROUND It has been reported that trifluoperazine (TFP) inhibits proliferation of cancer cells, however, the effects of TFP in renal proliferation diseases are still unclear. This study examined the effects of TFP on proliferation of human renal mesangial cells and analyzed the underlying mechanisms. MATERIAL AND METHODS Cell proliferation in vivo was determined by HE staining, immunohistochemistry of proliferating cell nuclear antigen (PCNA), and Western blot analysis (Ki-67 and PCNA). Effects of different TFP concentrations and treatment duration on cell proliferation and cell cycle were analyzed using the MTT assay and flow cytometry. Expression of G0/G1 phase cell cycle-related proteins and TFP-induced MAPK and PI3K/AKT signaling pathways was estimated with Western blot analysis. RESULTS Our findings suggest that TFP inhibits cell proliferation in a dose- and time-dependent manner and decreased PCNA and Ki-67 levels in lupus MRL/lpr mice. TFP arrested the cell cycle in the G0/G1 phase, down-regulating cyclin D1, CDK2, and CDK4, and up-regulating p21 expression in a dose-dependent manner. In addition, TFP inhibited p-AKT and p-JNK, possibly by suppressing the activation of PI3K/AKT and JNK/MAPK signaling pathways. TFP treatment remarkably reduced the levels of serum creatinine (Cr) in lupus mice. CONCLUSIONS TFP exhibits inhibitory activity against mesangial cells in vivo and in vitro, which is associated with G1 cell cycle arrest by inactivation of PI3K/AKT and JNK/MAPK signaling pathways. These results suggest the potential of TFP in treatment of mesangial proliferative diseases. PMID- 28713152 TI - Metastatic Anaplastic Lymphoma Kinase-1 (ALK-1)-Rearranged Inflammatory Myofibroblastic Sarcoma to the Brain with Leptomeningeal Involvement: Favorable Response to Serial ALK Inhibitors: A Case Report. AB - BACKGROUND ALK gene rearrangements as oncogenic drivers have been described in many cancers, including inflammatory myofibroblastic sarcoma (IMS). The first generation ALK inhibitor was limited in its ability to cross the blood-brain barrier to treat brain metastasis. Drug-resistance invariably develops over time in ALK-rearranged tumors, which leads to disease progression. The newer generations of ALK inhibitors are designed to have higher potency in ALK inhibition and improved CNS penetration. CASE REPORT We report a rare case of pulmonary IMS with ALK-1 gene rearrangement and multiple brain metastases as initial presentation. After the primary lung tumor and the larger brain metastases were resected, control of residual CNS disease and subsequent progression and CNS spread was achieved with favorable clinical response by all three generations of ALK inhibitors. CONCLUSIONS ALK inhibitors may be an effective therapy for this rare and unusual form of ALK-1-rearranged cancer, even in the presence of multifocal CNS metastases with leptomeningeal involvement. PMID- 28713153 TI - Non-coding RNA: A protective role for TERRA at telomeres. PMID- 28713155 TI - Hypoxia induces universal but differential drug resistance and impairs anticancer mechanisms of 5-fluorouracil in hepatoma cells. AB - Hepatocellular carcinoma (HCC) is one of the most refractory cancers. The mechanisms by which hypoxia further aggravates therapeutic responses of advanced HCC to anticancer drugs remain to be clarified. Here, we report that hypoxia (1% O2) caused 2.55-489.7-fold resistance to 6 anticancer drugs (sorafenib, 5 fluorouracil [5-FU], gemcitabine, cisplatin, adriamycin and 6-thioguanine) in 3 HCC cell lines (BEL-7402, HepG2 and SMMC-7721). Among the 6 drugs, sorafenib, the sole one approved for HCC therapy, inhibited proliferation with little influence from hypoxia and displayed the smallest variation among the 3 HCC cell lines tested. By contrast, the inhibition of proliferation by 5-FU, which has been extensively tested in clinical trials but has not been approved for HCC therapy, was severely affected by hypoxia and showed a large variation among these cell lines. In 5-FU-treated HCC cells, hypoxia reduced the levels of basal thymidylate synthase (TS) and functional TS, leading to decreased dTMP synthesis and DNA replication. Hypoxia also affected the accumulation of FdUTP and its misincorporation into DNA. Consequently, both single-strand breaks and double strand breaks in DNA were reduced, although hypoxia also inhibited DNA repair. In 5-FU-treated HCC cells, hypoxia further abated S-phase arrest, alleviated the loss of mitochondrial membrane potential, diminished the activation of caspases, and finally resulted in reduced induction of apoptosis. Thus, hypoxia induces universal but differential drug resistance. The extensive impacts of hypoxia on the anticancer mechanisms of 5-FU contributes to its hypoxia-induced resistance in HCC cells. We propose that hypoxia-induced drug resistance and interference of hypoxia with anticancer mechanisms could be used as candidate biomarkers in selecting and/or developing anticancer drugs for improving HCC therapy. PMID- 28713154 TI - Legionella and Coxiella effectors: strength in diversity and activity. AB - Legionella pneumophila and Coxiella burnetii are two evolutionarily related intracellular pathogens that use the Dot/Icm type IV secretion system to translocate effectors into host cells. These effectors are essential for the establishment of membrane-bound compartments known as replication vacuoles, which enable the survival and replication of bacteria inside host cells. The effectors interfere with diverse signalling pathways to co-opt host processes, such as vesicle trafficking, ubiquitylation, gene expression and lipid metabolism, to promote pathogen survival. In this Review, we explore Dot/Icm effectors from L. pneumophila and C. burnetii as key virulence factors, and we examine the biochemical and cell biological functions of these effectors and their roles in our understanding of bacterial virulence. PMID- 28713156 TI - Discovery of a novel calcium-sensitive fluorescent probe for alpha-ketoglutarate. AB - alpha-Ketoglutarate (alpha-KG), a pivotal metabolite in energy metabolism, has been implicated in nonalcoholic fatty liver disease (NAFLD) and several cancers. It is recently proposed that plasma alpha-KG is a surrogate biomarker of NAFLD. Here, we report the development of a novel "turn-on" chemosensor for alpha-KG that contains a coumarin moiety as a fluorophore. Using benzothiazole-coumarin (BTC) as inspiration, we designed a probe for calcium ion recognition that possesses a unique fluorophore compared with previously reported probes for alpha KG measurement. This chemosensor is based on the specific Schiff base reaction and the calcium ion recognition property of the widely used calcium indicator BTC. The probe was synthesized, and a series of parallel experiments were conducted to optimize the chemical recognition process. Compared to the initial weak fluorescence, a remarkable 7.6-fold enhancement in fluorescence intensity (I/I0 at 495 nm) was observed for the conditions in which the probe (1 MUmol/L), alpha-KG (50 MUmol/L), and Ca2+ (100 MUmol/L) were incubated at 30 degrees C in EtOH. The probe displayed good selectivity for alpha-KG even in an environment with an abundance of amino acids and other interfering species such as glutaric acid. We determined that the quantitative detection range of alpha-KG in EtOH was between 5 and 50 MUmol/L. Finally, probe in serum loaded with alpha-KG (10 mmol/L) showed a 7.4-fold fluorescence enhancement. In summary, a novel probe for detecting the biomarker alpha-KG through a typical Schiff base reaction has been discovered. With further optimization, this probe may be a good alternative for detecting the physiological metabolite alpha-KG. PMID- 28713157 TI - Population pharmacokinetics of moxifloxacin and its concentration-QT interval relationship modeling in Chinese healthy volunteers. AB - Moxifloxacin (MX) is an 8-methoxyquinolone antimicrobial drug, which is often used as a positive control in thorough QT (TQT) studies. In the present study we established the population pharmacokinetics model of MX and the relationship of MX concentrations with the QT and various corrected QT (QTc) intervals, and compared the results with other ethnicities. The MX data used for modeling were obtained from a published TQT interval prolongation study of antofloxacin with MX as the positive control. In this four-period crossover study, 24 adult Chinese healthy volunteers received either 200 or 400 mg of oral antofloxacin once daily, 400 mg of MX, or a placebo. Population concentration-effect models were used to investigate the relationship between MX concentrations and QT interval prolongation, baseline-adjusted QTc (DeltaQTc), or DeltaQTc adjusted with time matched placebo corrections (DeltaDeltaQTc). The influencing factors of MX PK and the concentration-QTc relationship were determined through covariate screening. Simulation studies were conducted in R2.30 by using the final model with the estimated population mean and intra-individual and inter-individual variability. The estimated pharmacokinetic parameters and the estimated slope of the MX concentration-QT/DeltaQTc/DeltaDeltaQTc relationship were described using models and were compared to results for other ethnicities from the literature. We showed that the population pharmacokinetic parameter estimates for total plasma clearance (CL/F), the volume of distribution of central compartment (Vc/F), the distributional clearance in plasma (Q), the volume of distribution of peripheral compartment (Vp/F), and the absorption rate constant (Ka) were 8.22 L/h, 104 L, 3.98 L/h, 37.7 L, and 1.81 1/h, respectively. There was no significant covariate included in the final model. QT interval prolongation of MX estimates ranging from 9.77 to 12.91 ms at the mean average maximum concentration of MX (4.36 MUg/mL) and a mean slope ranging from 2.33 to 2.96 ms per MUg/mL. In conclusion, no ethnic differences were observed for the MX pharmacokinetic parameters and QT interval prolongation. PMID- 28713159 TI - Co-delivery of docetaxel and silibinin using pH-sensitive micelles improves therapy of metastatic breast cancer. AB - Breast cancer is the most vicious killer for women, and tumor metastasis is one of the leading causes of breast cancer therapy failure. In this study, a new pH sensitive polymer (polyethylene glycol-block-poly[(1,4-butanediol)-diacrylate beta-N,N-diisopropylethylenediamine], BDP) was synthesized. Based on BDP, docetaxel/silibinin co-delivery micelles (DSMs) was constructed. DSM had a well defined spherical shape under the transmission electron microscope with average hydrodynamic diameter of 85.3+/-0.4 nm, and were stable in the bloodstream but could dissociate to release the chemotherapeutic agents in the low pH environment of the endo/lysosomes in the tumor cells. Compared with free drugs, DSM displayed greatly enhanced cellular uptake, higher cytotoxicity and a stronger anti metastasis effect against mouse breast cancer cell line 4T1. In 4T1 tumor-bearing mice treated with DSM (twice a week for 3 weeks), the inhibition rate on tumor growth and metastasis reached 71.9% and 80.1%, respectively. These results reveal that DSM might be a promising drug delivery system for metastatic breast cancer therapy. PMID- 28713161 TI - Functional expression of the Ca2+ signaling machinery in human embryonic stem cells. AB - Emerging evidence suggests that Ca2+ signals are important for the self-renewal and differentiation of human embryonic stem cells (hESCs). However, little is known about the physiological and pharmacological properties of the Ca2+-handling machinery in hESCs. In this study we used RT-PCR and Western blotting to analyze the expression profiles of genes encoding Ca2+-handling proteins; we also used confocal Ca2+ imaging and pharmacological approaches to determine the contribution of the Ca2+-handling machinery to the regulation of Ca2+ signaling in hESCs. We revealed that hESCs expressed pluripotent markers and various Ca2+ handling-related genes. ATP-induced Ca2+ transients in almost all hESCs were inhibited by the inositol-1,4,5-triphosphate receptor (IP3R) blocker 2-APB or xestospongin C. In addition, Ca2+ transients were induced by a ryanodine receptor (RyR) activator, caffeine, in 10%-15% of hESCs and were blocked by ryanodine, whereas caffeine and ATP did not have additive effects. Moreover, store-operated Ca2+ entry (SOCE) but not voltage-operated Ca2+ channel-mediated Ca2+ entry was observed. Inhibition of sarco/endoplasmic reticulum (ER) Ca2+-ATPase (SERCA) by thapsigargin induced a significant increase in the cytosolic free Ca2+ concentration ([Ca2+]i). For the Ca2+ extrusion pathway, inhibition of plasma membrane Ca2+ pumps (PMCAs) by carboxyeosin induced a slow increase in [Ca2+]i, whereas the Na+/Ca2+ exchanger (NCX) inhibitor KBR7943 induced a rapid increase in [Ca2+]i. Taken together, increased [Ca2+]i is mainly mediated by Ca2+ release from intracellular stores via IP3Rs. In addition, RyRs function in a portion of hESCs, thus indicating heterogeneity of the Ca2+-signaling machinery in hESCs; maintenance of low [Ca2+]i is mediated by uptake of cytosolic Ca2+ into the ER via SERCA and extrusion of Ca2+ out of cells via NCX and PMCA in hESCs. PMID- 28713162 TI - ABT-263 induces G1/G0-phase arrest, apoptosis and autophagy in human esophageal cancer cells in vitro. AB - Both the anti- and pro-apoptotic members of the Bcl-2 family are regulated by a conserved Bcl-2 homology (BH3) domain. ABT-263 (Navitoclax), a novel BH3 mimetic and orally bioavailable Bcl-2 family inhibitor with high affinity for Bcl-xL, Bcl 2 and Bcl-w has entered clinical trials for cancer treatment. But the anticancer mechanisms of ABT-263 have not been fully elucidated. In this study we investigated the effects of ABT-263 on human esophageal cancer cells in vitro and to explore its anticancer mechanisms. Treatment with ABT-263 dose-dependently suppressed the viability of 3 human esophageal cancer cells with IC50 values of 10.7+/-1.4, 7.1+/-1.5 and 8.2+/-1.6 MUmol/L, in EC109, HKESC-2 and CaES-17 cells, respectively. ABT-263 (5-20 MUmol/L) dose-dependently induced G1/G0-phase arrest in the 3 cancer cell lines and induced apoptosis evidenced by increased the Annexin V-positive cell population and elevated levels of cleaved caspase 3, cleaved caspase 9 and PARP. We further demonstrated that ABT-263 treatment markedly increased the expression of p21Waf1/Cip1 and decreased the expression of cyclin D1 and phospho-Rb (retinoblastoma tumor suppressor protein) (Ser780) proteins that contributed to the G1/G0-phase arrest. Knockdown of p21Waf1/Cip1 attenuated ABT-263-induced G1/G0-phase arrest. Moreover, ABT-263 treatment enhanced pro-survival autophagy, shown as the increased LC3-II levels and decreased p62 levels, which counteracted its anticancer activity. Our results suggest that ABT-263 exerts cytostatic and cytotoxic effects on human esophageal cancer cells in vitro and enhances pro-survival autophagy, which counteracts its anticancer activity. PMID- 28713163 TI - Microbiota or short-chain fatty acids: which regulates diabetes? PMID- 28713160 TI - Pathogenic roles of microvesicles in diabetic retinopathy. AB - Diabetic retinopathy (DR) is a common complication of diabetes and has been recognized as the leading cause of blindness in adults. Several interrelated molecular pathways are involved in the development of DR. Microvesicles (MVs) are cell membrane vesicles, which carry many biologic molecules, such as mRNAs, microRNAs, transcription factors, membrane lipids, membrane receptors, and other proteins. They may be involved in intercellular communication that can promote inflammation, angiogenesis, and coagulation. Recent studies have indicated that changes in the number and composition of MVs may reflect the pathologic conditions of DR. At present, MVs are well recognized as being involved in the pathophysiological conditions of tumors and cardio-metabolic diseases. However, the roles of MVs in DR have yet to be investigated. In this review, we provide an overview of DR-induced microvascular injury that is caused by MVs derived from endothelial and circulating cells, and discuss the possible mechanisms by which MVs can lead to endothelial dysfunction, coagulation and inflammation. In addition, the protective effects of preconditioned MVs and stem cell-derived MVs are also described . Understanding the involvement of MVs in the pathophysiological conditions of DR may provide insight into the disease mechanisms and may suggest novel therapeutic strategies for DR in the future. PMID- 28713165 TI - Fatty is not that bad: feeding short-chain fatty acids to restrain autoimmunity. PMID- 28713164 TI - Human immunodeficiency virus type-1 induces a regulatory B cell-like phenotype in vitro. AB - Individuals infected with human immunodeficiency virus type-1 (HIV-1) usually show a general dysregulation and hyper-activation of the immune system. A direct influence of HIV-1 particles on B-cell phenotypes and functions has been previously described. However, the consequences of B-cell dysregulation are still poorly understood. We evaluated the phenotypic changes in primary B cells after direct contact with HIV-1 particles in comparison with different types of stimuli. The functionality of treated B cells was challenged in co-culture experiments with autologous CD4+ and CD8+ T cells. We demonstrated that HIV-1 induces a phenotypic change in B cells towards a regulatory B-cell phenotype, showing a higher level of IL-10, TGF-beta1, EBI3 or IL-12(p35) mRNA expression and acquiring an immunosuppressive profile. The acquisition of a Breg phenotype was confirmed by co-culture experiments where HIV-treated B cells reduced the proliferation and the TNFalpha production of CD4+ or CD8+ T cells. This suppressive ability of HIV-treated B cells was dependent on cell-to-cell contact between these B cells and effector cells. To our knowledge, these data provide the first evidence that HIV-1 can directly induce a regulatory B cell-like immunosuppressive phenotype, which could have the ability to impair specific immune responses. This dysregulation could constitute one of the mechanisms underlying unsuccessful efforts to develop an efficient vaccine against HIV 1.Cellular &Molecular Immunology advance online publication, 17 July 2017; doi:10.1038/cmi.2017.48. PMID- 28713166 TI - Infection: Impeding UPEC gut colonization. PMID- 28713167 TI - Cell biology: Connexin connections in GN. PMID- 28713158 TI - Amyloid beta: structure, biology and structure-based therapeutic development. AB - Amyloid beta peptide (Abeta) is produced through the proteolytic processing of a transmembrane protein, amyloid precursor protein (APP), by beta- and gamma secretases. Abeta accumulation in the brain is proposed to be an early toxic event in the pathogenesis of Alzheimer's disease, which is the most common form of dementia associated with plaques and tangles in the brain. Currently, it is unclear what the physiological and pathological forms of Abeta are and by what mechanism Abeta causes dementia. Moreover, there are no efficient drugs to stop or reverse the progression of Alzheimer's disease. In this paper, we review the structures, biological functions, and neurotoxicity role of Abeta. We also discuss the potential receptors that interact with Abeta and mediate Abeta intake, clearance, and metabolism. Additionally, we summarize the therapeutic developments and recent advances of different strategies for treating Alzheimer's disease. Finally, we will report on the progress in searching for novel, potentially effective agents as well as selected promising strategies for the treatment of Alzheimer's disease. These prospects include agents acting on Abeta, its receptors and tau protein, such as small molecules, vaccines and antibodies against Abeta; inhibitors or modulators of beta- and gamma-secretase; Abeta degrading proteases; tau protein inhibitors and vaccines; amyloid dyes and microRNAs. PMID- 28713168 TI - Creative Destruction and Subjective Well-Being. AB - In this paper we analyze the relationship between turnover-driven growth and subjective wellbeing. Our model of innovation-led growth and unemployment predicts that: (i) the effect of creative destruction on expected individual welfare should be unambiguously positive if we control for unemployment, less so if we do not; (ii) job creation has a positive and job destruction has a negative impact on wellbeing; (iii) job destruction has a less negative impact in US Metropolitan Statistical Areas (MSA) within states with more generous unemployment insurance policies; (iv) job creation has a more positive effect on individuals that are more forward-looking. The empirical analysis using cross sectional MSA-level and individual-level data provide empirical support to these predictions. PMID- 28713171 TI - Comfrey and Buttercup Eaters: Wild Vegetables of the Imereti Region in Western Georgia, Caucasus. PMID- 28713169 TI - The Long-Run Impact of Cash Transfers to Poor Families. AB - We estimate the long-run impact of cash transfers to poor families on children's longevity, educational attainment, nutritional status, and income in adulthood. To do so, we collected individual-level administrative records of applicants to the Mothers' Pension program-the first government-sponsored welfare program in the United States (1911-1935)-and matched them to census, WWII, and death records. Male children of accepted applicants lived one year longer than those of rejected mothers. They also obtained one-third more years of schooling, were less likely to be underweight, and had higher income in adulthood than children of rejected mothers. PMID- 28713170 TI - Sexual behaviour in early adolescence: a cross-national comparison of Australian and United States youth. AB - OBJECTIVE: This study used matched samples from schools in the states of Victoria, Australia and Washington, United States (US), to compare sexual behaviour in early adolescence. It was hypothesised that the contrasting dominant policy objectives of harm minimisation in Australia and abstinence in the US would result in state differences for markers of sexual risk, mirroring prior cross-national findings in substance use. METHOD: A two-stage cluster sampling approach was used to recruit students from the two states. Self-reported sexual behaviour was examined for 1,596 students in annual surveys from Grade 7 in 2002 to Grade 9 in 2004. Prevalence estimates were derived for each measure of sexual behaviour, and comparisons were made between gender groups in each state. RESULTS: State differences were found for girls' first sex, with significantly more girls in Washington than Victoria having had sex by Grade 7. By Grade 9, significantly more girls in Victoria reported sex in the last year and more sexual partners than girls in Washington. A large proportion of Grade 9 students across both states reported inconsistent contraception use. CONCLUSIONS: Contradicting the abstinence policy objective, first sex by Grade 7 was more prevalent in Washington than Victoria. Whilst sexual behaviour was more prevalent in Grade 9 in Victoria, the sexually active showed no clear cross-national differences in markers of risk such as contraception use and pregnancy outcomes. Findings demonstrate few cross-national differences in adolescent sexual behaviour despite the different policy contexts of Victoria, Australia and Washington, US. PMID- 28713172 TI - POxylation as an alternative stealth coating for biomedical applications. AB - Polyethylene glycol (PEG) polymers are currently used in a variety of medical formulations to reduce toxicity, minimize immune interactions and improve pharmacokinetics. Despite its widespread use however, the presence of anti-PEG antibodies indicates that this polymer has the potential to be immunogenic and antigenic. Here we present an alternative polymer, poly(2-oxazoline) (POx) for stealth applications, specifically shielding of a proteinaceous nanoparticle from recognition by the immune system. Tobacco mosaic virus (TMV) was used as our testbed due to its potential for use as a nanocarrier for drug delivery and molecular imaging applications. PMID- 28713173 TI - A Standard Mammography Unit - Standard 3D Ultrasound Probe Fusion Prototype: First Results. AB - AIM: The combination of different imaging modalities through the use of fusion devices promises significant diagnostic improvement for breast pathology. The aim of this study was to evaluate image quality and clinical feasibility of a prototype fusion device (fusion prototype) constructed from a standard tomosynthesis mammography unit and a standard 3D ultrasound probe using a new method of breast compression. MATERIALS AND METHODS: Imaging was performed on 5 mastectomy specimens from patients with confirmed DCIS or invasive carcinoma (BI RADS TM 6). For the preclinical fusion prototype an ABVS system ultrasound probe from an Acuson S2000 was integrated into a MAMMOMAT Inspiration (both Siemens Healthcare Ltd) and, with the aid of a newly developed compression plate, digital mammogram and automated 3D ultrasound images were obtained. RESULTS: The quality of digital mammogram images produced by the fusion prototype was comparable to those produced using conventional compression. The newly developed compression plate did not influence the applied x-ray dose. The method was not more labour intensive or time-consuming than conventional mammography. From the technical perspective, fusion of the two modalities was achievable. CONCLUSION: In this study, using only a few mastectomy specimens, the fusion of an automated 3D ultrasound machine with a standard mammography unit delivered images of comparable quality to conventional mammography. The device allows simultaneous ultrasound - the second important imaging modality in complementary breast diagnostics - without increasing examination time or requiring additional staff. PMID- 28713175 TI - A Model of Pressure and Flow Distribution in Branching Networks. AB - The objective of this work is to provide a mechanical description of steady-state flow of Newtonian fluid in a branching network that consists of rigid vessels of different diameters. Solution of this problem is of importance for better understanding of the mechanics of blood flow within the microcirculation. The developed branching network model predicts a wide distribution of the hydrodynamic pressure and flow in the vessels of the same caliber (flow heterogeneity). The obtained results are compared with predictions of a simple series-parallel network model. It is shown that this model provides an accurate approximation to the values of the mean pressure and flow given by the branching network model. PMID- 28713174 TI - Fusing multiple neuroimaging modalities to assess group differences in perception action coupling. AB - In the last few decades, non-invasive neuroimaging has revealed macro-scale brain dynamics that underlie perception, cognition and action. Advances in non-invasive neuroimaging target two capabilities; 1) increased spatial and temporal resolution of measured neural activity, and 2) innovative methodologies to extract brain-behavior relationships from evolving neuroimaging technology. We target the second. Our novel methodology integrated three neuroimaging methodologies and elucidated expertise-dependent differences in functional (fused EEG-fMRI) and structural (dMRI) brain networks for a perception-action coupling task. A set of baseball players and controls performed a Go/No-Go task designed to mimic the situation of hitting a baseball. In the functional analysis, our novel fusion methodology identifies 50ms windows with predictive EEG neural correlates of expertise and fuses these temporal windows with fMRI activity in a whole-brain 2mm voxel analysis, revealing time-localized correlations of expertise at a spatial scale of millimeters. The spatiotemporal cascade of brain activity reflecting expertise differences begins as early as 200ms after the pitch starts and lasting up to 700ms afterwards. Network differences are spatially localized to include motor and visual processing areas, providing evidence for differences in perception-action coupling between the groups. Furthermore, an analysis of structural connectivity revealed that the players have significantly more connections between cerebellar and left frontal/motor regions, and many of the functional activation differences between the groups are located within structurally defined network modules that differentiate expertise. In short, our novel method illustrates how multimodal neuroimaging can provide specific macro-scale insights into the functional and structural correlates of expertise development. PMID- 28713176 TI - In the Shadow of a Giant: Medicare's Influence on Private Physician Payments. AB - We analyze Medicare's influence on private insurers' payments for physicians' services. Using a large administrative change in reimbursements for surgical versus medical care, we find that private prices follow Medicare's lead. A $1.00 increase in Medicare's fees increases corresponding private prices by $1.16. A second set of Medicare fee changes, which generates area-specific payment shocks, has a similar effect on private reimbursements. Medicare's influence is strongest in areas with concentrated insurers and competitive physician markets, consistent with insurer-doctor bargaining. By echoing Medicare's pricing changes, these payment spillovers amplify Medicare's impact on specialty choice and other welfare-relevant aspects of physician practices. PMID- 28713177 TI - Nitsche's Method For Helmholtz Problems with Embedded Interfaces. AB - In this work, we use Nitsche's formulation to weakly enforce kinematic constraints at an embedded interface in Helmholtz problems. Allowing embedded interfaces in a mesh provides significant ease for discretization, especially when material interfaces have complex geometries. We provide analytical results that establish the well-posedness of Helmholtz variational problems and convergence of the corresponding finite element discretizations when Nitsche's method is used to enforce kinematic constraints. As in the analysis of conventional Helmholtz problems, we show that the inf-sup constant remains positive provided that the Nitsche's stabilization parameter is judiciously chosen. We then apply our formulation to several 2D plane-wave examples that confirm our analytical findings. Doing so, we demonstrate the asymptotic convergence of the proposed method and show that numerical results are in accordance with the theoretical analysis. PMID- 28713178 TI - Glucose transporter-4 in white blood cells of young and old sled dogs: a model for human biomarker development. AB - The insulin responsive glucose transporter, GLUT4 is found predominantly in muscle and adipose cells. Maratou and others (2007) reported that there is GLUT4 in white blood cells (WBC) collected from human subjects in response to insulin activation. This study was designed to validate the presence of GLUT4 in white blood cells of sled dogs and furthermore to investigate whether changes in levels of the GLUT4 protein might be associated with aging. Additionally, we examined the blood insulin concentration of two populations of dogs, young and old, before and after a meal to observe their insulin response. It is documented in skeletal muscle that GLUT4 expression is increased as a result of conditioning, making sled dogs an excellent model in the circumpolar north for studying the effects of exercise, nutrition and diabetes (Felsburg 2002; Kararli 2006). Blood was withdrawn from 11 healthy sled dogs: 6 young (1-5 years) and physically fit, conditioned for racing and 5 old (7-13 years), retired from racing. The insulin response was determined using blood plasma and ELISA. The buffy coat (containing WBC) was collected with a glass pipette after centrifugation and washed and suspended in 1x phosphate buffer. GLUT4 was measured using ELISA kits (USCN Life Sciences). The results validate that GLUT4 is present in white blood cells in sled dogs. Age had no significant effect in the concentration of GLUT4 between the populations of old and young dogs. A significant difference in insulin levels pre and post meal in young (0.13 +/- 0.03 ng/mL (pre), 0.22 +/- 0.04 ng/mL (post), p < 0.05) and old (0.13 +/- 0.02 ng/mL (pre), 0.22 +/- 0.03 ng/mL (post), p < 0.05) dogs was observed, displaying the typical postprandial insulin spike. No significant difference was found in insulin concentration comparing old versus young dogs. Our data shows that white blood cells in young (40.4 +/- 2.4 ng/mL) and old (35.3 +/- 8.8 ng/mL) sled dogs have quantifiable but non-significant different GLUT4 levels (p > 0.05). Detecting GLUT4 via an ELISA in white blood cells, opens up minimally invasive avenues for studying the underlying molecular mechanisms associated with insulin resistance in more complex, dynamic and physiological systems. This project was the first step in developing a protocol for this simple, technique with a potential clinical application for diagnosing insulin resistance. PMID- 28713179 TI - The Student-Teacher Relationship Quality of Abused Children. AB - Considering the association between children's quality of relationships with teachers and their academic adjustment, information pertaining to how abused children are functioning in their relationships with teachers could be useful in promoting their academic success- yet there has been limited research in this area. The purpose of this study was to use cluster analyses to explore within group differences in relational schemas and quality of student-teacher relationships for 70 abused children. Two clusters of abused children emerged, and as hypothesized, there were significant differences in student-teacher relationships for the two clusters. The cluster with more positive relational schemas had less conflict and less dependency reported by their teachers compared to the cluster with negative relational schemas. However, there were no differences between the clusters in terms of closeness with teachers. Implications for practice in schools is discussed. PMID- 28713180 TI - Global observations of magnetospheric high-m poloidal waves during the 22 June 2015 magnetic storm. AB - We report global observations of high-m poloidal waves during the recovery phase of the 22 June 2015 magnetic storm from a constellation of widely spaced satellites of five missions including Magnetospheric Multiscale (MMS), Van Allen Probes, Time History of Events and Macroscale Interactions during Substorm (THEMIS), Cluster, and Geostationary Operational Environmental Satellites (GOES). The combined observations demonstrate the global spatial extent of storm time poloidal waves. MMS observations confirm high azimuthal wave numbers (m ~ 100). Mode identification indicates the waves are associated with the second harmonic of field line resonances. The wave frequencies exhibit a decreasing trend as L increases, distinguishing them from the single-frequency global poloidal modes normally observed during quiet times. Detailed examination of the instantaneous frequency reveals discrete spatial structures with step-like frequency changes along L. Each discrete L shell has a steady wave frequency and spans about 1 RE , suggesting that there exist a discrete number of drift-bounce resonance regions across L shells during storm times. PMID- 28713181 TI - Neophilia Ranking of Scientific Journals. AB - The ranking of scientific journals is important because of the signal it sends to scientists about what is considered most vital for scientific progress. Existing ranking systems focus on measuring the influence of a scientific paper (citations)-these rankings do not reward journals for publishing innovative work that builds on new ideas. We propose an alternative ranking based on the proclivity of journals to publish papers that build on new ideas, and we implement this ranking via a text-based analysis of all published biomedical papers dating back to 1946. In addition, we compare our neophilia ranking to citation-based (impact factor) rankings; this comparison shows that the two ranking approaches are distinct. Prior theoretical work suggests an active role for our neophilia index in science policy. Absent an explicit incentive to pursue novel science, scientists underinvest in innovative work because of a coordination problem: for work on a new idea to flourish, many scientists must decide to adopt it in their work. Rankings that are based purely on influence thus do not provide sufficient incentives for publishing innovative work. By contrast, adoption of the neophilia index as part of journal-ranking procedures by funding agencies and university administrators would provide an explicit incentive for journals to publish innovative work and thus help solve the coordination problem by increasing scientists' incentives to pursue innovative work. PMID- 28713182 TI - The transition from affective to linguistic meaning. AB - This paper reports a transition from affective to linguistic meaning in 15-month old infants. Behaviour regulation in the context of a social referencing procedure is used as a measure of the meaning of stimulus messages for infants. Of particular interest is the extent to which receptive vocabulary predicts behaviour regulation by language and paralanguage. Approving and disapproving lexical content was completely crossed with approving and disapproving facial and vocal paralanguage to produce stimulus messages. At the group level, the behaviour of 15-month-olds was better regulated by paralanguage than by lexical content. However, receptive vocabulary was a significant predictor of the relative primacy of language and paralanguage: infants who understood the lexical content of stimulus messages were better regulated by lexical content than by paralanguage. These data suggest a transition from affective to linguistic meaning in comprehension that parallels the transition from affective expression to expression that integrates affect and language. PMID- 28713183 TI - Signs of Fascism Rising: A European Americanist Looks at Recent Political Trends in the U.S. and Europe. AB - This paper's central concern is with signs of fascism in recent political developments in a number of European countries and the United States. It takes the reader back to earlier periods in European and American history when this same anguished question was raised. Thus a longer intellectual history of concerns about the viability of democratic systems is drawn to guide us in our current political evaluations. PMID- 28713184 TI - Childhood IQ and survival to 79: Follow-up of 94% of the Scottish Mental Survey 1947. AB - OBJECTIVE: To extend previous literature that suggests higher IQ in youth is associated with living longer. Previous studies have been unable to assess reliably whether the effect differs across sexes and ages of death, and whether the effect is graded across different levels of IQ. METHODS: We test IQ-survival associations in 94% of the near-entire population born in Scotland in 1936 who took an IQ test at age 11 (n = 70,805) and were traced in a 68-year follow-up. RESULTS: Higher IQ at age 11 years was associated with a lower risk of death (HR = 0.80, 95% CI = 0.79, 0.81). The decline in risk across categories of IQ scores was graded across the full range with the effect slightly stronger in women (HR = 0.79, 95% CI = 0.77, 0.80) than in men (HR = 0.82, 95% CI = 0.81, 0.84). Higher IQ had a significantly stronger association with death before and including age 65 (HR = 0.76, 95% CI = 0.74, 0.77) than in those participants who died at an older age (HR = 0.79, 95% CI = 0.78, 0.80). CONCLUSIONS: Higher childhood IQ is associated with lower risk of all-cause mortality in both men and women. This is the only near-entire population study to date that examines the association between childhood IQ and mortality across most of the human life course. PMID- 28713185 TI - Can having internal locus of control insure against negative shocks? Psychological evidence from panel data. AB - We investigate whether the intensity of emotional pain following a negative shock is different across the distribution of a person's locus of control - the extent to which individuals believe that their actions can influence future outcomes. Using panel data from Australia, we show that individuals with strong internal locus of control are psychologically insured against own and others' serious illness or injury, close family member detained in jail, becoming a victim of property crime and death of a close friend, but not against the majority of other life events. The buffering effects vary across gender. Our findings thus add to the existing literature on the benefits of internal locus of control. PMID- 28713186 TI - Happy People Have Children: Choice and Self-Selection into Parenthood. AB - There is mixed evidence in the existing literature on whether children are associated with greater subjective well-being, with the correlation depending on which countries and populations are considered. We here provide a systematic analysis of this question based on three different datasets: two cross-national and one national panel. We show that the association between children and subjective well-being is positive only in developed countries, and for those who become parents after the age of 30 and who have higher income. We also provide evidence of a positive selection into parenthood, whereby happier individuals are more likely to have children. PMID- 28713187 TI - Structural representations: causally relevant and different from detectors. AB - This paper centers around the notion that internal, mental representations are grounded in structural similarity, i.e., that they are so-called S representations. We show how S-representations may be causally relevant and argue that they are distinct from mere detectors. First, using the neomechanist theory of explanation and the interventionist account of causal relevance, we provide a precise interpretation of the claim that in S-representations, structural similarity serves as a "fuel of success", i.e., a relation that is exploitable for the representation using system. Then, we discuss crucial differences between S-representations and indicators or detectors, showing that-contrary to claims made in the literature-there is an important theoretical distinction to be drawn between the two. PMID- 28713188 TI - What are cultural attractors? AB - Concepts from cultural attractor theory are now used in domains far from their original home in anthropology and cultural evolution. Yet these concepts have not been consistently characterised. I here distinguish four ways in which the cultural attractor concept has been used and identify three kinds of factors of attraction typically appealed to. Clarifying these explanatory concepts identifies problems and ambiguities in the work of cultural epidemiologists and commentators alike. PMID- 28713189 TI - The animal sensorimotor organization: a challenge for the environmental complexity thesis. AB - Godfrey-Smith's environmental complexity thesis (ECT) is most often applied to multicellular animals and the complexity of their macroscopic environments to explain how cognition evolved. We think that the ECT may be less suited to explain the origins of the animal bodily organization, including this organization's potentiality for dealing with complex macroscopic environments. We argue that acquiring the fundamental sensorimotor features of the animal body may be better explained as a consequence of dealing with internal bodily-rather than environmental complexity. To press and elucidate this option, we develop the notion of an animal sensorimotor organization (ASMO) that derives from an internal coordination account for the evolution of early nervous systems. The ASMO notion is a reply to the question how a collection of single cells can become integrated such that the resulting multicellular organization becomes sensitive to and can manipulate macroscopic features of both the animal body and its environment. In this account, epithelial contractile tissues play the central role in the organization behind complex animal bodies. In this paper, we relate the ASMO concept to recent work on epithelia, which provides empirical evidence that supports central assumptions behind the ASMO notion. Second, we discuss to what extent the notion applies to basic animal architectures, exemplified by sponges and jellyfish. We conclude that the features exhibited by the ASMO are plausibly explained by internal constraints acting on and within this multicellular organization, providing a challenge for the role the ECT plays in this context. PMID- 28713190 TI - Rumination about Social Stress Mediates the Association between Peer Victimization and Depressive Symptoms during Middle Childhood. AB - Although prior research has established a link between exposure to peer victimization and depressive symptoms, relatively little is known about the processes underlying this association. This study examined whether maladaptive responses to a novel social stressor - specifically, lower levels of problem solving or higher levels of rumination - mediate this association. Data were gathered from 130 children (64 boys, 66 girls; M age = 9.46, SD = .33) who participated in a laboratory social stressor task with an unfamiliar peer. Results indicated that prior exposure to peer victimization in the school context was associated with ruminative responses to the novel stressor, which mediated the association between victimization and depressive symptoms. These results indicate that ruminative responses to social stress outside of the victimization context may serve as one process explaining the association between victimization and heightened depressive symptoms. PMID- 28713191 TI - Long-term Recovery in Stroke Accompanied by Aphasia: A Reconsideration. AB - BACKGROUND: This work focuses on the twenty-six individuals who provided data to AphasiaBank on at least two occasions, with initial testing between 6 months and 5.8 years post-onset of aphasia. The data are archival in nature and were collected from the extensive database of aphasic discourse in AphasiaBank. AIMS: The aim is to furnish data on the nature of long-term changes in both the impairment of aphasia as measured by the Western Aphasia Battery-Revised (WAB-R) and its expression in spoken discourse. METHODS AND PROCEDURES: AphasiaBank's demographic database was searched to discover all individuals who were tested twice at an interval of at least a year with either: 1) the AphasiaBank protocol; or 2) the AphasiaBank protocol at first testing, and the Famous People Protocol (FPP) at second testing. The Famous People Protocol is a measure developed to assess the communication strategies of individuals whose spoken language limitations preclude full participation in the AphasiaBank protocol. The 26 people with aphasia (PWA) who were identified had completed formal speech therapy before being seen for AphasiaBank. However, all were participants in aphasia centers where at least three hours of planned activities were available, in most cases, twice weekly. WAB-R Aphasia Quotient scores (AQ) were examined, and in those cases where AQ scores improved, changes were assessed on a number of measures from the AphasiaBank discourse protocol. OUTCOMES AND RESULTS: Sixteen individuals demonstrated improved WAB-R AQ scores, defined as positive AQ change scores greater than the WAB-R AQ standard error of the mean (WAB-SEM); seven maintained their original WAB quotients, defined as AQ change scores that were not greater than the WAB-SEM; and the final three showed negative WAB-R change scores, defined as a negative WAB-R AQ change score greater than the WAB-SEM. Concurrent changes on several AphasiaBank tasks were also found, suggesting that the WAB-R improvements were noted in more natural discourse as well. CONCLUSIONS: These data are surprising, since conventional wisdom suggests that spontaneous improvement in language is unlikely to occur beyond one year. Long-term improvement or maintenance of early test scores, such as that shown here, has seldom been demonstrated in the absence of formal treatment. Speculations about why these PWA improved, maintained or declined in their scores are considered. PMID- 28713193 TI - In Vitro Synthesis of Connectin in an Extract of Chicken Embryo Muscles. AB - Incorporation of 35S-methionine into connectin during protein synthesis in an extract from chicken embryo muscles was detected by autoradiography after immunoprecipitation with anti-connectin antibodies followed by SDS gel electrophoresis. Any radioactivity of peptides smaller than connectin but larger than actin was not detected with anti-connectin antibodies reacted samples. On the other hand, incorporation of radioactive methionine into nebulin was not observed. PMID- 28713192 TI - FOXP3 Allelic Variants and Haplotype Structures Are Associated with Aggressive Breast Cancer Subtypes. AB - FOXP3 genetic polymorphisms have been associated with cancer development and prognosis. In this context, the present study aimed to evaluate the g.10403A>G (rs2232365) polymorphisms and g.8048A>C (rs3761548), in aggressive breast cancer (BC) subtypes, including, Luminal B HER2+ (LB), HER2-enriched (HER2+), and triple negative (TN). Polymerase chain reaction followed by enzymatic restriction was performed to genotyping 117 BC samples and 300 controls. A significant association of AA genotype (g.10403A>G) in relation to BC susceptibility (OR = 1.93; 95% CI = 1.01-3.66; p = 0.046) was observed. The GG (g.10403A>G) genotype was correlated with higher proliferation index (Ki-67) in HER2+ subtype (tau = 0.47; p = 0.019) and advanced TNM staging in TN (tau = 0.23; p = 0.032). A correlation of AA genotype (g.8048A>C) with higher Ki-67 (tau = -0.47; p = 0.018) and lower histological grade (tau = 0.39; p = 0.026) in HER2+ was also found. GA haplotype was correlated with lower histological grade (tau = -0.15; p = 0.009) and higher Ki-67 (tau = 0.43; p = 0.036) in HER2+ and advanced staging in TN (tau = 0.29; p = 0.044). On the other hand, AC haplotype was correlated with lower Ki 67 (tau = -0.54; p = 0.005) and staging (tau = -0.29; p = 0.027) in HER2+ and TN respectively. Results showed that FOXP3 influence regarding clinical outcome depends greatly on the BC subtype and indicated this transcription factor as a promising marker in aggressive BC subtypes. PMID- 28713194 TI - Drought priming improves subsequent more severe drought in a drought-sensitive cultivar of olive cv. Chetoui. AB - Drought is a major factor limiting crop production worldwide. The objective of this study was to test whether pre-exposure to drought can enhance the subsequent drought response of a drought-sensitive variety of olive cv. Chetoui. Seven months old olive plants were grown in a controlled conditions and divided into control plants (irrigated daily), primed plants (PP, primed by exposure to drought for 21 days, re-watered for 60 days and then exposed to water depletion for 30 days) and non-primed plants (NPP, well watered for 81 days and immediately followed by intermediate drought as PP). Compared to the non-primed plants, primed plants showed an improvement in biomass production and healthy values of photosynthesis parameters with a higher accumulation of photosynthetic pigments. Additionally, the data of chlorophyll fluorescence were significantly similar to those of control, implying that no photodamage was occurred. Moreover, primed plants exhibited high accumulation of total sugar and proline which lead to the better water status maintenance. The lower level of oxidative status measured in term of hydrogen peroxide (H2O2), malondiadehyde (MDA) and electrolyte leakage (EC) in primed plants confirmed the alleviation of oxidative stress. Furthermore, the primed plants possessed more effective oxygen scavenging systems as exemplified by the increased activities of CAT, SOD, GP and high accumulation of polyphenols, resulting in a better maintenance in homeostasis of ROS production. Our investigation is indicative of the result of the benefit memory effects caused by stress pre-exposure in young olive plants cv.'Chetoui' to overcome subsequent stress. PMID- 28713195 TI - Work-Education Mismatch: An Endogenous Theory of Professionalization. AB - We model the education-workforce pipeline and offer an endogenous theory of professionalization and ever-higher degree attainment. We introduce two mechanisms that act on the education enterprise, causing the number of educated people to increase dramatically with relatively short-term changes in the job market. Using our illustrative dynamic model, we argue that the system is susceptible to small changes and the introduced self-driving growth engines are adequate to over-incentivize degree attainment. We also show that the mechanisms magnify effects of short-term recessions or technological changes, and create long-term waves of mismatch between workforce and jobs. The implication of the theory is degree inflation, magnified pressures on those with lower degrees, underemployment, and job market mismatch and inefficiency. PMID- 28713196 TI - Morulustatin, A Disintegrin that Inhibits ADP-Induced Platelet Aggregation, Isolated from the Mexican Tamaulipan Rock Rattlesnake (Crotalus lepidus morulus). AB - The Tamaulipan rock rattlesnake (Crotalus lepidus morulus) is a montane snake that occurs in the humid pine-oak forest and the upper cloud forest of the Sierra Madre Oriental in southwestern Tamaulipas, central Nuevo Leon, and southeastern Coahuila in Mexico. Venom from this rattlesnake was fractionated by High Performance Liquid Chromatography for the purpose of discovering disintegrin molecules. Disintegrins are non-enzymatic, small molecular weight peptides that interfere with cell-cell and cell-matrix interactions by binding to various cell receptors. Eleven fractions were collected by anion exchange chromatography and pooled into six groups (I, II, III, IV, V, and VI). Proteins of the six groups were analyzed by SDS-PAGE and western blot using antibodies raised against a disintegrin. The antibodies recognized different protein bands in five (II, III, IV, V, and VI) of six groups in a molecular mass range of 7 to 105 kDa. Western blot analysis revealed fewer protein bands in the higher molecular mass range and two bands in the disintegrin weight range in group II compared with the other four groups. Proteins in group II were further separated into nine fractions using reverse phase C18 chromatography. Fraction 4 inhibited platelet aggregation and was named morulustatin, which exhibited a single band with a molecular mass of approximately 7 kDa. Mass spectrometry analysis of fraction 4 revealed the identification of disintegrin peptides LRPGAQCADGLCCDQCR (MH+ 2035.84) and AGEECDCGSPANCCDAATCK (MH+ 2328.82). Morulustatin inhibited ADP-induced platelet aggregation in human whole blood and was concentration-dependent with an IC50 of 89.5 nM +/- 12. PMID- 28713197 TI - Detecting paralinguistic events in audio stream using context in features and probabilistic decisions. AB - Non-verbal communication involves encoding, transmission and decoding of non lexical cues and is realized using vocal (e.g. prosody) or visual (e.g. gaze, body language) channels during conversation. These cues perform the function of maintaining conversational flow, expressing emotions, and marking personality and interpersonal attitude. In particular, non-verbal cues in speech such as paralanguage and non-verbal vocal events (e.g. laughters, sighs, cries) are used to nuance meaning and convey emotions, mood and attitude. For instance, laughters are associated with affective expressions while fillers (e.g. um, ah, um) are used to hold floor during a conversation. In this paper we present an automatic non-verbal vocal events detection system focusing on the detect of laughter and fillers. We extend our system presented during Interspeech 2013 Social Signals Sub-challenge (that was the winning entry in the challenge) for frame-wise event detection and test several schemes for incorporating local context during detection. Specifically, we incorporate context at two separate levels in our system: (i) the raw frame-wise features and, (ii) the output decisions. Furthermore, our system processes the output probabilities based on a few heuristic rules in order to reduce erroneous frame-based predictions. Our overall system achieves an Area Under the Receiver Operating Characteristics curve of 95.3% for detecting laughters and 90.4% for fillers on the test set drawn from the data specifications of the Interspeech 2013 Social Signals Sub-challenge. We perform further analysis to understand the interrelation between the features and obtained results. Specifically, we conduct a feature sensitivity analysis and correlate it with each feature's stand alone performance. The observations suggest that the trained system is more sensitive to a feature carrying higher discriminability with implications towards a better system design. PMID- 28713198 TI - Analysis of engagement behavior in children during dyadic interactions using prosodic cues. AB - Child engagement is defined as the interaction of a child with his/her environment in a contextually appropriate manner. Engagement behavior in children is linked to socio-emotional and cognitive state assessment with enhanced engagement identified with improved skills. A vast majority of studies however rely solely, and often implicitly, on subjective perceptual measures of engagement. Access to automatic quantification could assist researchers/clinicians to objectively interpret engagement with respect to a target behavior or condition, and furthermore inform mechanisms for improving engagement in various settings. In this paper, we present an engagement prediction system based exclusively on vocal cues observed during structured interaction between a child and a psychologist involving several tasks. Specifically, we derive prosodic cues that capture engagement levels across the various tasks. Our experiments suggest that a child's engagement is reflected not only in the vocalizations, but also in the speech of the interacting psychologist. Moreover, we show that prosodic cues are informative of the engagement phenomena not only as characterized over the entire task (i.e., global cues), but also in short term patterns (i.e., local cues). We perform a classification experiment assigning the engagement of a child into three discrete levels achieving an unweighted average recall of 55.8% (chance is 33.3%). While the systems using global cues and local level cues are each statistically significant in predicting engagement, we obtain the best results after fusing these two components. We perform further analysis of the cues at local and global levels to achieve insights linking specific prosodic patterns to the engagement phenomenon. We observe that while the performance of our model varies with task setting and interacting psychologist, there exist universal prosodic patterns reflective of engagement. PMID- 28713199 TI - Isothermal Crystallization Kinetics and Time-Temperature-Transformation of the Conjugated Polymer: Poly(3-(2'-ethyl)hexylthiophene). AB - Thermal annealing strongly impacts the nano- and microstructure of conjugated polymers. Despite the fundamental importance for the resulting optoelectronic behavior of this class of materials, the underlying crystallization processes have not received the same attention that is encountered in other disciplines of materials science. The question arises whether classical treatment of nucleation and growth phenomena is truly applicable to conjugated polymers? Here, the isothermal crystallization behavior of the conjugated polymer poly(3-(2' ethyl)hexylthiophene) (P3EHT) is monitored with differential scanning calorimetry (DSC). Avrami analysis reveals growth- and nucleation-limited temperature regimes that are separated by the maximum rate of crystallization. The molecular weight of the polymer is found to strongly influence the absolute rate of crystallization at the same degree of undercooling relative to the melting temperature. A combination of optical microscopy and grazing-incidence wide-angle X-ray scattering (GIWAXS) confirms that the resulting nano- and microstructure strongly correlate with the selected isothermal annealing temperature. Hence, this work establishes that classical nucleation and growth theory can be applied to describe the solidification behavior of the semicrystalline conjugated polymer P3EHT. PMID- 28713200 TI - Spatio-temporal precipitation climatology over complex terrain using a censored additive regression model. AB - Flexible spatio-temporal models are widely used to create reliable and accurate estimates for precipitation climatologies. Most models are based on square root transformed monthly or annual means, where a normal distribution seems to be appropriate. This assumption becomes invalid on a daily time scale as the observations involve large fractions of zero observations and are limited to non negative values. We develop a novel spatio-temporal model to estimate the full climatological distribution of precipitation on a daily time scale over complex terrain using a left-censored normal distribution. The results demonstrate that the new method is able to account for the non-normal distribution and the large fraction of zero observations. The new climatology provides the full climatological distribution on a very high spatial and temporal resolution, and is competitive with, or even outperforms existing methods, even for arbitrary locations. PMID- 28713201 TI - Language-dependent changes in pitch-relevant neural activity in the auditory cortex reflect differential weighting of temporal attributes of pitch contours. AB - There remains a gap in our knowledge base about neural representation of pitch attributes that occur between onset and offset of dynamic, curvilinear pitch contours. The aim is to evaluate how language experience shapes processing of pitch contours as reflected in the amplitude of cortical pitch-specific response components. Responses were elicited from three nonspeech, bidirectional (falling rising) pitch contours representative of Mandarin Tone 2 varying in location of the turning point with fixed onset and offset. At the frontocentral Fz electrode site, Na-Pb and Pb-Nb amplitude of the Chinese group was larger than the English group for pitch contours exhibiting later location of the turning point relative to the one with the earliest location. Chinese listeners' amplitude was also greater than that of English in response to those same pitch contours with later turning points. At lateral temporal sites (T7/T8), Na-Pb amplitude was larger in Chinese listeners relative to English over the right temporal site. In addition, Pb-Nb amplitude of the Chinese group showed a rightward asymmetry. The pitch contour with its turning point located about halfway of total duration evoked a rightward asymmetry regardless of group. These findings suggest that neural mechanisms processing pitch in the right auditory cortex reflect experience dependent modulation of sensitivity to weighted integration of changes in acceleration rates of rising and falling sections and the location of the turning point. PMID- 28713202 TI - Toward mosquito control with a green alga: Expression of Cry toxins of Bacillus thuringiensis subsp. israelensis (Bti) in the chloroplast of Chlamydomonas. AB - We are developing Chlamydomonas strains that can be used for safe and sustainable control of mosquitoes, because they produce proteins from Bacillus thuringiensis subsp. israelensis (Bti) in the chloroplast. Chlamydomonas has a number of advantages for this approach, including genetic controls that are not generally available with industrial algae. The Bti toxin has been used for mosquito control for > 30 years and does not engender resistance; it contains three Cry proteins, Cry4Aa (135 kDa), Cry4Ba (128 kDa) and Cry11Aa (72 kDa), and Cyt1Aa (25 kDa). To express the Cry proteins in the chloroplast, the three genes were resynthesized and cry4Aa was truncated to the first 700 amino acids (cry4Aa700 ); also, since they can be toxic to host cells, the inducible Cyc6:Nac2-psbD expression system was used. Western blots of total protein from the chloroplast transformants showed accumulation of the intact polypeptides, and the relative expression level was Cry11Aa > Cry4Aa700 > Cry4Ba. Quantitative western blots with purified Cry11Aa as a standard showed that Cry11Aa accumulated to 0.35% of total cell protein. Live cell bioassays in dH20 demonstrated toxicity of the cry4Aa700 and cry11Aa transformants to larvae of Aedes aegypti and Culex quinquefasciatus. These results demonstrate that the Cry proteins that are most toxic to Aedes and Culex mosquitoes, Cry4Aa and Cry11Aa, can be successfully expressed in the chloroplast of Chlamydomonas. PMID- 28713203 TI - Solvatochromic fluorescent probes for recognition of human serum albumin in aqueous solution: Insights into structure-property relationship. AB - Human serum albumin (HSA) as the most abundant protein in human blood plasma, serves many physiological functions. The dysregulation of HSA in serum or in urine is associated with various diseases, such as cirrhosis of liver, multiple myeloma, and cardiovascular disease. Therefore, to quantify HSA in body fluids with high selectivity and sensitivity is of great significance for disease diagnosis and preventive medicine. We herein developed a series of amide functionalized flavonoids probes, 1-3, for recognition of human serum albumin. All flavonoids could be easily prepared by a Claisen-Schmidt condensation and Algar-Flynn-Oyamada reaction, and showed positive solvatochromism on their dual emissions. The chemical structure of flavonoids played an important role on their HSA-sensing abilities. Among three probes, the compound 1 showed the highest sensitivity, the remarkable selectivity, and the quantitive response for HSA in aqueous solution. Together with its high tolerance of environmental pH, anti interference properties, and time-insensitivity, thus it provides a promising sensing method for HSA. PMID- 28713204 TI - Efficient NH3-SCR removal of NOx with highly ordered mesoporous WO3(chi)-CeO2 at low temperatures. AB - To eliminate nitrogen oxides (NOx), a series of highly ordered mesoporous WO3(chi)-CeO2 nanomaterials (chi represents the mole ratio of W/Ce) were synthesized by using KIT-6 as a hard template, which was used for selective catalytic reduction (SCR) to remove NOx with NH3 at low temperatures. Moreover, the nanomaterials were characterized by TEM, XRD, Raman, XPS, BET, H2-TPR, NH3 TPD and in situ DRIFTS. It can be found that all of the prepared mesoporous WO3(chi)-CeO2 (chi = 0, 0.5, 0.75, 1 and 1.25) showed highly ordered mesoporous channels. Furthermore, mesoporous WO3(1)-CeO2 exhibited the best removal efficiency of NOx, and its NOx conversion ratio could reach 100% from 225 degrees C to 350 degrees C with a gas hourly space velocity of 30 000 h-1, which was due to higher Ce3+ concentrations, abundant active surface oxygen species and Lewis acid sites based on XPS, H2-TPR, NH3-TPD and in situ DRIFTS. In addition, several key performance parameters of mesoporous WO3(1)-CeO2, such as superior water resistance, better alkali metal resistance, higher thermal stability and N2 selectivity, were systematically studied, indicating that the synthesized mesoporous WO3(1)-CeO2 has great potential for industrial applications. PMID- 28713205 TI - KHF2, a mild and selective desilylating agent for phenol t-butyldimethylsilyl (TBDMS) ethers. AB - TBDMS (t-BuMe2Si, t-butyldimethylsilyl) ethers of a variety of phenols have been deprotected with KHF2 in MeOH, at room temperature. Carboxylic ester and labile phenolic acetate were unaffected under these conditions. In competition reactions between TBDMS ethers of a phenol and two primary benzylic alcohols, the phenolic ether underwent cleavage whereas the alcohol ethers remained intact. From a substrate containing both a phenolic hydroxyl group and a secondary, doubly benzylic hydroxyl group protected as TBDMS ethers, the phenol was rapidly and selectively released. Cleavage of TBDMS, TBDPS, and TIPS ethers of a phenol was also compared. TBDMS and TBDPS ethers underwent cleavage at room temperature within 30 min, whereas removal of the TIPS ether required 2.5 hours. Ease of cleavage appears to be TBDMS ~ TBDPS > TIPS. At 60 degrees C, TBDMS ethers of primary benzylic, allylic, and unactivated alcohols can be efficiently desilylated over a prolonged period (13-17 h). Thus, KHF2 proves to be a mild and effective reagent for the selective desilylation of phenol TBDMS ethers at room temperature. PMID- 28713206 TI - The Astrocytic S100B Protein with Its Receptor RAGE Is Aberrantly Expressed in SOD1G93A Models, and Its Inhibition Decreases the Expression of Proinflammatory Genes. AB - Neuroinflammation is one of the major players in amyotrophic lateral sclerosis (ALS) pathogenesis, and astrocytes are significantly involved in this process. The astrocytic protein S100B can be released in pathological states activating the receptor for advanced glycation end products (RAGE). Different indications point to an aberrant expression of S100B and RAGE in ALS. In this work, we observed that S100B and RAGE are progressively and selectively upregulated in astrocytes of diseased rats with a tissue-specific timing pattern, correlated to the level of neurodegeneration. The expression of the full-length and soluble RAGE isoforms could also be linked to the degree of tissue damage. The mere presence of mutant SOD1 is able to increase the intracellular levels and release S100B from astrocytes, suggesting the possibility that an increased astrocytic S100B expression might be an early occurring event in the disease. Finally, our findings indicate that the protein may exert a proinflammatory role in ALS, since its inhibition in astrocytes derived from SOD1G93A mice limits the expression of reactivity-linked/proinflammatory genes. Thus, our results propose the S100B-RAGE axis as an effective contributor to the pathogenesis of the disease, suggesting its blockade as a rational target for a therapeutic intervention in ALS. PMID- 28713207 TI - A MULTIVARIATE GAUSSIAN PROCESS FACTOR MODEL FOR HAND SHAPE DURING REACH-TO-GRASP MOVEMENTS. AB - We propose a Multivariate Gaussian Process Factor Model to estimate low dimensional spatio-temporal patterns of finger motion in repeated reach-to-grasp movements. Our model decomposes and reduces the dimensionality of variation of the multivariate functional data. We first account for time variability through multivariate functional registration, then decompose finger motion into a term that is shared among replications and a term that encodes the variation per replication. We discuss variants of our model, estimation algorithms, and we evaluate its performance in simulations and in data collected from a non-human primate executing a reach-to-grasp task. We show that by taking advantage of the repeated trial structure of the experiments, our model yields an intuitive way to interpret the time and replication variation in our kinematic dataset. PMID- 28713208 TI - Visible-Light Initiated Free-Radical/Cationic Ring-Opening Hybrid Photopolymerization of Methacrylate/Epoxy: Polymerization Kinetics, Crosslinking Structure, and Dynamic Mechanical Properties. AB - The effects of polymerization kinetics and chemical miscibility on the crosslinking structure and mechanical properties of polymers cured by visible light initiated free-radical/cationic ring-opening hybrid photopolymerization are determined. A three-component initiator system is used and the monomer system contains methacrylates and epoxides. The photopolymerization kinetics is monitored in situ by Fourier transform infrared-attenuated total reflectance. The crosslinking structure is studied by modulated differential scanning calorimetry and dynamic mechanical analysis. X-ray microcomputed tomography is used to evaluate microphase separation. The mechanical properties of polymers formed by hybrid formed by free-radical polymerization. These investigations mark the first time that the benefits of the chain transfer reaction between epoxy and hydroxyl groups of methacrylate, on the crosslinking network and microphase separation during hybrid visible-light initiated photopolymerization, have been determined. PMID- 28713209 TI - A more accurate half-discrete Hardy-Hilbert-type inequality with the logarithmic function. AB - By means of the weight functions, the technique of real analysis and Hermite Hadamard's inequality, a more accurate half-discrete Hardy-Hilbert-type inequality related to the kernel of logarithmic function and a best possible constant factor is given. Moreover, the equivalent forms, the operator expressions, the reverses and some particular cases are also considered. PMID- 28713210 TI - Variance Reduction in Stochastic Gradient Langevin Dynamics. AB - Stochastic gradient-based Monte Carlo methods such as stochastic gradient Langevin dynamics are useful tools for posterior inference on large scale datasets in many machine learning applications. These methods scale to large datasets by using noisy gradients calculated using a mini-batch or subset of the dataset. However, the high variance inherent in these noisy gradients degrades performance and leads to slower mixing. In this paper, we present techniques for reducing variance in stochastic gradient Langevin dynamics, yielding novel stochastic Monte Carlo methods that improve performance by reducing the variance in the stochastic gradient. We show that our proposed method has better theoretical guarantees on convergence rate than stochastic Langevin dynamics. This is complemented by impressive empirical results obtained on a variety of real world datasets, and on four different machine learning tasks (regression, classification, independent component analysis and mixture modeling). These theoretical and empirical contributions combine to make a compelling case for using variance reduction in stochastic Monte Carlo methods. PMID- 28713211 TI - Early extubation in pediatric heart surgery across a spectrum of case complexity: Impact on hospital length of stay and chest tube days. AB - Early extubation is increasingly common in congenital heart surgery, but there are limited outcomes data across the spectrum of case complexity. We performed a retrospective review of 201 pediatric operations using cardiopulmonary bypass between 2012 and 2014. Patients extubated in the operating room or immediately on arrival to the ICU were compared to those extubated by traditional protocols. In hospital mortality, major complications, need for re-intubation, hospital length of stay, and chest-tube days were compared between groups and by Society of Thoracic Surgeons-European Association for Cardiothoracic Surgery Congenital Heart Surgery (STAT) mortality category. Outcome measures of hospital length of stay and chest tube days were analyzed using multivariable regression modeling. Early extubation subjects were older, weighed more, had shorter bypass and aortic cross-clamp time, more often received caudal anesthesia, and had shorter hospital length of stay and fewer chest tube days. Subjects not extubated early had more chromosomal abnormalities, more preoperative co-morbidities, and had more major complications. Inhospital death, major complications, and re-intubation were rare outcomes for both groups across all STAT categories. Multivariable regression analysis showed that cardiopulmonary bypass time was a significant predictor of hospital length of stay and chest tube days. Hospital LOS and chest tube days were significantly lower for the early extubation group in both the unadjusted and adjusted analyses. Early extubation can be performed safely in congenital heart surgery across a spectrum of case complexity. No increased early mortality or re-intubation was observed with early extubation although there were important differences between the groups that merits further study. The potential benefits of early extubation include decreased hospital length of stay and fewer chest tube days, particularly in young children and patients with long bypass times. PMID- 28713212 TI - Family Structure, Transitions and Psychiatric Disorders Among Puerto Rican Children. AB - This paper examines whether family structure and its transitions are associated with internalizing and externalizing psychiatric disorders among Puerto Rican origin children. It uses longitudinal data (three waves) from the Boricua Youth Study, which includes probability samples of children in the South Bronx (New York) and San Juan (Puerto Rico) (n = 2,142). We also examine factors which may explain how family structure and transitions may be related to child psychiatric disorders. Our results show that for both internalizing and externalizing disorders there were no significant differences between children of cohabiting (biological or step) parents or of single parents compared to children of married biological parents. In Puerto Rico only, transitioning once from a two-parent family to a single-parent family was related to child internalizing disorders. Family transitions were not associated with externalizing disorders at either site. Context may be an important factor shaping the risk that family dissolution is followed by an internalizing disorder among children. PMID- 28713213 TI - Secondary motion in three-dimensional branching networks. AB - A major aim of the present work is to understand and thoroughly document the generation, the three-dimensional distribution, and the evolution of the secondary motion as the fluid progresses downstream through a branched network. Six generations (G0-G5) of branches (involving 63 straight portions and 31 bifurcation modules) are computed in one go; such computational challenges are rarely taken in the literature. More than 30 * 106 computational elements are employed for high precision of computed results and fine quality of the flow visualization diagrams. The study of co-planar vis-a-vis non-planar space-filling configurations establishes a quantitative evaluation of the dependence of the fluid dynamics on the three-dimensional arrangement of the same individual branches. As compared to the secondary motion in a simple curved pipe, three distinctive features, viz., the change of shape and size of the flow-cross section, the division of non-uniform primary flow in a bifurcation module, and repeated switchover from clockwise to anticlockwise curvature and vice versa in the flow path, make the present situation more complex. It is shown that the straight portions in the network, in general, attenuate the secondary motion, while the three-dimensionally complex bifurcation modules generate secondary motion and may alter the number, arrangement, and structure of vortices. A comprehensive picture of the evolution of quantitative flow visualizations of the secondary motion is achieved by constructing contours of secondary velocity [Formula: see text], streamwise vorticity [Formula: see text], and [Formula: see text] iso-surfaces. It is demonstrated, for example, that for in-plane configuration, the vortices on any plane appear in pair (i.e., for each clockwise rotating vortex, there is an otherwise identical anticlockwise vortex), whereas the vortices on a plane for the out-of-plane configuration may be dissimilar, and there may even be an odd number of vortices. We have formulated three new parameters (ES/P , [Formula: see text], and [Formula: see text]) for a quantitative description of the overall features of the secondary flow field. [Formula: see text] represents a non-uniformity index of the secondary flow in an individual branch, ES/P represents the mass-flow-averaged relative kinetic energy of the secondary motion in an individual branch, and [Formula: see text] provides a measure of the non-uniformity of the secondary flow between various branches of the same generation Gn. The repeated enhancement of the secondary kinetic energy in the bifurcation modules is responsible for the occurrence of significant values of ES/P even in generation G5. For both configurations, it is found that for any bifurcation module, the value of ES/P is greater in that daughter branch in which the mass-flow rate is greater. Even though the various contour plots of the complex secondary flow structure appear visually very different from one another, the values of [Formula: see text] are found to lie within a small range ([Formula: see text]) for the six-generation networks studied. It is shown that [Formula: see text] grows as the generation number Gn increases. It is established that the out-of-plane configuration, in general, creates more secondary kinetic energy (higher ES/P ), a similar level of non-uniformity in the secondary flow in an individual branch (similar [Formula: see text]), and a significantly lower level of non-uniformity in the distribution of secondary motion among various branches of the same generation (much lower [Formula: see text]), as compared to the in-plane arrangement of the same branches. PMID- 28713214 TI - First-principles equation-of-state table of beryllium based on density-functional theory calculations. AB - Beryllium has been considered a superior ablator material for inertial confinement fusion (ICF) target designs. An accurate equation-of-state (EOS) of beryllium under extreme conditions is essential for reliable ICF designs. Based on density-functional theory (DFT) calculations, we have established a wide-range beryllium EOS table of density rho = 0.001 to 500 g/cm3 and temperature T = 2000 to 108 K. Our first-principle equation-of-state (FPEOS) table is in better agreement with the widely used SESAME EOS table (SESAME 2023) than the average atom INFERNO and Purgatorio models. For the principal Hugoniot, our FPEOS prediction shows ~10% stiffer than the last two models in the maximum compression. Although the existing experimental data (only up to 17 Mbar) cannot distinguish these EOS models, we anticipate that high-pressure experiments at the maximum compression region should differentiate our FPEOS from INFERNO and Purgatorio models. Comparisons between FPEOS and SESAME EOS for off-Hugoniot conditions show that the differences in the pressure and internal energy are within ~20%. By implementing the FPEOS table into the 1-D radiation-hydrodynamic code LILAC, we studied the EOS effects on beryllium-shell-target implosions. The FPEOS simulation predicts higher neutron yield (~15%) compared to the simulation using the SESAME 2023 EOS table. PMID- 28713215 TI - A high spatial resolution synchrotron Mossbauer study of the Tazewell IIICD and Esquel pallasite meteorites. AB - Metallic phases in the Tazewell IIICD iron and Esquel pallasite meteorites were examined using 57Fe synchrotron Mossbauer spectroscopy. Spatial resolution of ~10 20 MUm was achieved, together with high throughput, enabling individual spectra to be recorded in less than 1 h. Spectra were recorded every 5-10 MUm, allowing phase fractions and hyperfine parameters to be traced along transects of key microstructural features. The main focus of the study was the transitional region between kamacite and plessite, known as the "cloudy zone." Results confirm the presence of tetrataenite and antitaenite in the cloudy zone as its only components. However, both phases were also found in plessite, indicating that antitaenite is not restricted exclusively to the cloudy zone, as previously thought. The confirmation of paramagnetic antitaenite as the matrix phase of the cloudy zone contrasts with recent observations of a ferromagnetic matrix phase using X-ray photoemission electron spectroscopy. Possible explanations for the different results seen using these techniques are proposed. PMID- 28713216 TI - Prenatal Motherese? Newborn Speech Perception May Be Enhanced by Having a Young Sibling. AB - Prenatal experience with infant- and child-directed speech (IDS/CDS) may affect newborns' speech perception. We examined this possibility using an existing neonatal database from a recent cross-language study (Moon, Lagercrantz, & Kuhl, 2011). Seventy-three American and Swedish neonates (Mage = 32.58 hr, SD = 13.58 hr) were retrospectively coded as either having High (n = 32) or Low (n = 41) prenatal IDS/CDS exposure based on whether there were any children younger than 4 years old in the household during pregnancy. We compared the mean sucks for contingent presentations of prototypes and nonprototypes of vowel stimuli (native or foreign) among groups. A mixed 3-way ANOVA revealed a significant interaction: Neonates responded to prototypes and nonprototypes differently in the High IDS/CDS group, whereas there was a lack of differential responses in the Low IDS/CDS group. Future research with well-controlled measurement of prenatal speech is warranted. PMID- 28713218 TI - Developmental changes in sensitivity to vocal paralanguage. AB - Developmental changes in children's sensitivity to the role of acoustic variation in the speech stream in conveying speaker affect (vocal paralanguage) were examined. Four-, 7- and 10-year-olds heard utterances in three formats: low-pass filtered, reiterant, and normal speech. The availability of lexical and paralinguistic information varied across these three formats in a way that required children to base their judgments of speaker affect on different configurations of cues in each format. Across ages, the best performance was obtained when a rich array of acoustic cues was present and when there was no competing lexical information. Four-year-olds performed at chance when judgments had to be based solely on speech prosody in the filtered format and they were unable to selectively attend to paralanguage when discrepant lexical cues were present in normal speech. Seven-year-olds were significantly more sensitive to the paralinguistic role of speech prosody in filtered speech than were 4-year olds and there was a trend toward greater attention to paralanguage when lexical and paralinguistic cues were inconsistent in normal speech. An integration of the ability to utilize prosodic cues to speaker affect with attention to paralanguage in cases of lexical/paralinguistic discrepancy was observed for 10-year-olds. The results are discussed in terms of the development of a perceptual bias emerging out of selective attention to language. PMID- 28713217 TI - The Burden of Illness Related to Chronic Obstructive Pulmonary Disease Exacerbations in Quebec, Canada. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) prevalence in Canada has risen over time. COPD-related exacerbations contribute to the increased health care utilization (HCU) in this population. This study investigated the impact of exacerbations on COPD-related HCU. METHODS: This retrospective observational cohort study used patient data from the Quebec provincial health insurance databases. Eligible patients with a new HCU claim with a diagnostic billing for COPD during 2001-2010 were followed until March 31, 2011. Exacerbation rates and time to first exacerbation were assessed. Unadjusted analyses and multivariable models compared the rate of HCU by exacerbation classification (any [moderate/severe], moderate, or severe). RESULTS: The exacerbation event rate in patients with an exacerbation was 34.3 events/100 patient-years (22.7 for moderate exacerbations and 11.6 for severe exacerbations). Median time to first exacerbation of any classification was 37 months. In unadjusted analyses, COPD related HCU significantly increased with exacerbation severity. In the multivariable, HCU rates were significantly higher after exacerbation versus before exacerbation (p < 0.01) for patients with an exacerbation or moderate exacerbations. For severe exacerbations, general practitioner, respiratory specialist, emergency room, and hospital visits were significantly higher after exacerbation versus before exacerbation (p < 0.001). CONCLUSIONS: Exacerbations were associated with increased HCU, which was more pronounced for patients with severe exacerbations. Interventions to reduce the risk of exacerbations in patients with COPD may reduce disease burden. PMID- 28713219 TI - Spectroscopic and Computational Investigation of Low-Spin Mn(III) Bis(scorpionate) Complexes. AB - Six-coordinate MnIII complexes are typically high-spin (S = 2), however, the scorpionate ligand, both in its traditional, hydridotris(pyrazolyl)borate form, Tp- and Tp*- (the latter with 3,5-dimethylpyrazole substituents) and in an aryltris(carbene)borate (i.e., N-heterocyclic carbene, NHC) form, [Ph(MeIm)3B]-, (MeIm = 3-methylimidazole) lead to formation of bis(scorpionate) complexes of MnIII with spin triplet ground states; three of which were investigated herein: [Tp2Mn]SbF6 (1SBF6), [Tp*2Mn]SbF6 (2SBF6), and [{Ph(MeIm)3B}2Mn]CF3SO3 (3CF3SO3). These trigonally symmetric complexes were studied experimentally by magnetic circular dichroism (MCD) spectroscopy (the propensity of 3 to oxidize to MnIV precluded collection of useful MCD data) including variable temperatures and fields (VTVH-MCD) and computationally by ab initio CASSCF/NEVPT2 methods. These combined experimental and theoretical techniques establish the 3A2g electronic ground state for the three complexes, and provide information on the energy of the "conventional" high-spin excited state (5Eg) and other, triplet excited states. These results show the electronic effect of pyrazole ring substituents in comparing 1 and 2. The tunability of the scorpionate ligand, even by perhaps the simplest change (from pyrazole in 1 to 3,5-dimethylpyrazole in 2) is quantitatively manifested through perturbations in ligand-field excited-state energies that impact ground-state zero-field splittings. The comparison with the NHC donor is much more dramatic. In 3, the stronger sigma-donor properties of the NHC lead to a quantitatively different electronic structure, so that the lowest lying spin triplet excited state, 3Eg, is much closer in energy to the ground state than in 1 or 2. The zero-field splitting (zfs) parameters of the three complexes were calculated and in the case of 1 and 2 compare closely to experiment (lower by < 10%, < 2 cm-1 in absolute terms); for 3 the large magnitude zfs is reproduced, although there is ambiguity about its sign. The comprehensive picture obtained for these bis(scorpionate) MnIII complexes provides quantitative insight into the role played by the scorpionate ligand in stabilizing unusual electronic structures. PMID- 28713220 TI - Parallel responses of human epidermal keratinocytes to inorganic SbIII and AsIII. AB - SbIII and AsIII are known to exhibit similar chemical properties, but the degree of similarity in their effects on biological systems merits further exploration. Present work compares the responses of human epidermal keratinocytes, a known target cell type for arsenite-induced carcinogenicity, to these metalloids after treatment for a week at environmentally relevant concentrations. Previous work with these cells has shown that arsenite and antimonite have parallel effects in suppressing differentiation, altering levels of several critical enzymes and maintaining colony forming ability. More globally, protein profiling now reveals parallels in SbIII and AsIII effects. The more sensitive technique of transcriptional profiling also shows considerable parallels. Thus, gene expression changes were almost entirely in the same directions for the two treatments, although the degree of change was sometimes significantly different. Inspection of the changes revealed that RYR1 and LRIG1 were among the genes strongly suppressed, consistent with reduced calcium-dependent differentiation and maintenance of EGF-dependent proliferative potential. Moreover, levels of miRNAs in the cells were altered in parallel, with nearly 90% of the 198 most highly expressed ones being suppressed. Among these was miR-203, which is known to decrease proliferative potential. Finally, both SbIII and AsIII were seen to attenuate bone morphogenetic protein 6 induction of dual specificity phosphatases 2 and 14, consistent with maintaining epidermal growth factor receptor signaling. These findings raise the question whether SbIII, like AsIII, could act as a human skin carcinogen. PMID- 28713221 TI - Heritability of the affective response to exercise and its correlation to exercise behavior. AB - OBJECTIVES: Individual differences in adolescent exercise behavior are strongly influenced by genetic factors. The affective response to exercise is a potential source of these genetic influences. To test its role in the motivation to exercise, we estimated the heritability of the affective responses during and after exercise and the overlap with the genetic factors influencing regular voluntary exercise behavior. DESIGN: 226 twin pairs and 38 siblings completed two submaximal exercise tests on a cycle ergometer and a treadmill and a maximal exercise test on a cycle ergometer. Affective responses were assessed by the Feeling Scale (FS), Borg's Rating of Perceived Exertion (RPE) and the Activation Deactivation Adjective Checklist (AD ACL). METHODS: Multivariate structural equation modeling was used to estimate heritability of the affective responses during and after submaximal and maximal exercise and the (genetic) correlation with self-reported regular voluntary exercise behavior over the past year. RESULTS: Genetic factors explained 15% of the individual differences in FS responses during the cycle ergometer test, as well as 29% and 35% of the individual differences in RPE during the cycle ergometer and treadmill tests, respectively. For the AD ACL scales, heritability estimates ranged from 17% to 37% after submaximal exercise and from 12% to 37% after maximal exercise. Without exception, more positive affective responses were associated with higher amounts of regular exercise activity (.15 < r < .21) and this association was accounted for by an overlap in genetic factors influencing affective responding and exercise behavior. CONCLUSIONS: We demonstrate low to moderate heritability estimates for the affective response during and after exercise and significant (genetic) associations with regular voluntary exercise behavior. These innate individual differences in the affective responses to exercise should be taken into account in interventions aiming to motivate adolescents to adopt and maintain regular exercise. PMID- 28713222 TI - Young Children Prefer and Remember Satisfying Explanations. AB - Research with preschool children shows that explanations are important to them in that they actively seek explanations in their conversations with adults. But, what sorts of explanations do they prefer, and what, if anything, do young children learn from the explanations they receive? Following a preliminary study with adults (N=67) to establish materials for use with children, we addressed this question using a semi-naturalistic methodology. 4- and 5-year-olds (N=69) were dissatisfied when receiving non-explanations to their explanatory questions, but satisfied when receiving explanations, and their satisfaction varied appropriately across several levels of explanatory information. Moreover, using recall as a measure of learning, whereas children typically failed to recall non explanations, their recall of explanatory information was consistently high and also varied appropriately across differing levels of information provided. These results confirm that children not only actively seek informative explanations in their everyday conversational interactions with adults, they selectively retain the answers they receive. PMID- 28713223 TI - SHARE: Spreading Health Awareness with Resources and Education -- Librarians' role in patient education, a case study. PMID- 28713224 TI - Low frequency aeration of pig slurry affects slurry characteristics and emissions of greenhouse gases and ammonia. AB - Low frequency aeration of slurries may reduce ammonia (NH3) and methane (CH4) emissions without increasing nitrous oxide (N2O) emissions. The aim of this study was to quantify this potential reduction and to establish the underlying mechanisms. A batch experiment was designed with 6 tanks with 1 m3 of pig slurry each. After an initial phase of 7 days when none of the tanks were aerated, a second phase of 4 weeks subjected three of the tanks to aeration (2 min every 6 h, airflow 10 m3 h-1), whereas the other three tanks remained as a control. A final phase of 9 days was established with no aeration in any tank. Emissions of NH3, CH4, carbon dioxide (CO2) and N2O were measured. In the initial phase no differences in emissions were detected, but during the second phase aeration increased NH3 emissions by 20% with respect to the controls (8.48 vs. 7.07 g m-3 [slurry] d-1, P < 0.05). A higher pH was found in the aerated tanks at the end of this phase (7.7 vs. 7.0 in the aerated and control tanks, respectively, P < 0.05). CH4 emissions were 40% lower in the aerated tanks (2.04 vs. 3.39 g m-3 [slurry] d-1, P < 0.05). These differences in NH3 and CH4 emissions remained after the aeration phase had finished. No effect was detected for CO2, and no relevant N2O emissions were detected during the experiment. Our results demonstrate that low frequency aeration of stored pig slurry increases slurry pH and increases NH3 emissions. PMID- 28713225 TI - HIV-transmission-related risk behavior in HIV+ African American men: Exploring biological, psychological, cognitive, and social factors. AB - OBJECTIVES: To identify factors associated with HIV-transmission-related risk behavior among HIV+ African American men. METHOD: We examined biological, psychological, cognitive, and social factors and recent HIV-transmission-related risk behavior (i.e., needle sharing, unprotected sex, exchange sex) among a sample of HIV+ African American men. RESULTS: A binary logistic regression showed that individuals under age 50 (OR=4.2), with clinically-elevated masochism scores (OR=3.9) on the Millon Clinical Multiaxial Inventory-III (MCMI-III), current substance abuse/dependence (OR=2.6), and higher sensation-seeking (OR=1.3) were more likely to report recent risk behavior. CONCLUSIONS: Reducing substance use, addressing self-defeating attitudes, and improving self-control may be avenues for future prevention and intervention research among HIV+ African American men engaging in HIV-transmission-related risk behavior. PMID- 28713226 TI - Psychosocial Correlates of Medication Adherence among HIV-Positive, Cognitively Impaired Individuals. AB - Although cognitive impairment has been shown to adversely affect antiviral medication adherence, a subset of cognitively impaired adults nonetheless are able to adequately adhere to their medication regimen. However, little is known about factors that serve as buffers against suboptimal adherence among the cognitively impaired. This study consisted of 160 HIV-positive, cognitively impaired adults (Global Deficit Score >= 0.50) whose medication adherence was monitored over 6-months using an electronic monitoring device (MEMS caps). Logistic regressions were run to determine psychosocial variables associated with medication adherence. Higher self-efficacy and treatment related support, a stable medication regimen, stable stress levels, and absence of current stimulant use were predictive of optimal adherence. A distinct array of psychosocial factors was found that buffer against the adverse effects of cognitive impairment on medication adherence. Assessment and interventions targeting these factors may improve adherence rates among cognitively impaired adults. PMID- 28713227 TI - Design of 3-D Printed Concentric Tube Robots. AB - Concentric tube surgical robots are minimally invasive devices with the advantages of snake-like reconfigurability, long and thin form factor, and placement of actuation outside the patient's body. These robots can also be designed and manufactured to acquire targets in specific patients for treating specific diseases in a manner that minimizes invasiveness. We propose that concentric tube robots can be manufactured using 3-D printing technology on a patient- and procedure-specific basis. In this paper, we define the design requirements and manufacturing constraints for 3-D printed concentric tube robots and experimentally demonstrate the capabilities of these robots. While numerous 3 D printing technologies and materials can be used to create such robots, one successful example uses selective laser sintering to make an outer tube with a polyether block amide and uses stereolithography to make an inner tube with a polypropylene-like material. This enables a tube pair with precurvatures of 0.0775 and 0.0455 mm-1, which can withstand strains of 20% and 5.5% for the outer and inner tubes, respectively. PMID- 28713228 TI - Exploring the Catalytic Promiscuity of Phenolic Acid Decarboxylases: Asymmetric, 1,6-Conjugate Addition of Nucleophiles Across 4-Hydroxystyrene. AB - The catalytic promiscuity of a ferulic acid decarboxylase from Enterobacter sp. (FDC_Es) and phenolic acid decarboxylases (PADs) for the asymmetric conjugate addition of water across the C=C bond of hydroxystyrenes was extended to the N-, C- and S-nucleophiles methoxyamine, cyanide and propanethiol to furnish the corresponding addition products in up to 91% ee. The products obtained from the biotransformation employing the most suitable enzyme/nucleophile pairs were isolated and characterized after optimizing the reaction conditions. Finally, a mechanistic rationale supported by quantum mechanical calculations for the highly (S)-selective addition of cyanide is proposed. PMID- 28713229 TI - Slippery Liquid-Infused Porous Surfaces that Prevent Microbial Surface Fouling and Kill Non-Adherent Pathogens in Surrounding Media: A Controlled Release Approach. AB - Many types of slippery liquid-infused porous surfaces (or 'SLIPS') can resist adhesion and colonization by microorganisms. These 'slippery' materials thus offer new approaches to prevent fouling on a range of commercial and industrial surfaces, including biomedical devices. However, while SLIPS can prevent fouling on surfaces to which they are applied, they can currently do little to prevent the proliferation of non-adherent (planktonic) organisms, stop them from colonizing other surfaces, or prevent them from engaging in other behaviors that could lead to infection and associated burdens. Here, we report an approach to the design of multi-functional SLIPS that addresses these issues and expands the potential utility of slippery surfaces in antimicrobial contexts. Our approach is based on the incorporation and controlled release of small-molecule antimicrobial agents from the porous matrices used to host infused slippery oil phases. We demonstrate that SLIPS fabricated using nanoporous polymer multilayers can prevent short- and longer-term colonization and biofilm formation by four common fungal and bacterial pathogens (Candida albicans, Pseudomonas aeruginosa, Escherichia coli, and Staphylococcus aureus), and that the polymer and oil phases comprising these materials can be exploited to load and sustain the release of triclosan, a model hydrophobic and broad-spectrum antimicrobial agent, into surrounding media. This approach both improves the inherent anti-fouling properties of these materials and endows them with the ability to efficiently kill planktonic pathogens. Finally, we show that this approach can be used to fabricate dual-action SLIPS on complex surfaces, including the luminal surfaces of flexible catheter tubes. This strategy has the potential to be general; we anticipate that the materials, strategies, and concepts reported here will enable new approaches to the design of slippery surfaces with improved anti-fouling properties and open the door to new applications of slippery liquid-infused materials that host or promote the release of a variety of other active agents. PMID- 28713230 TI - In Vivo Micro-CT Imaging of Human Mesenchymal Stem Cells Labeled with Gold-Poly-L Lysine Nanocomplexes. AB - Developing in vivo cell tracking is an important prerequisite for further development of cell-based therapy. So far, few computed tomography (CT) cell tracking studies have been described due to its notoriously low sensitivity and lack of efficient labeling protocols. We present a simple method to render human mesenchymal stem cells (hMSCs) sufficiently radiopaque by complexing 40 nm citrate-stabilized gold nanoparticles (AuNPs) with poly-L-lysine (PLL) and rhodamine B isothiocyanate (RITC). AuNP-PLL-RITC labeling did not affect cellular viability, proliferation, or downstream cell differentiation into adipocytes and osteocytes. Labeled hMSCs could be clearly visualized in vitro and in vivo with a micro-CT scanner, with a detection limit of approximately 2*104 cells/MUl in vivo. Calculated HU values were 2.27 /pg of intracellular Au as measured with inductively coupled plasma mass spectrophotometry (ICP-MS), and were linear over a wide range of cell concentrations. This linear CT attenuation was observed for both naked AuNPs and those that were taken up by hMSCs, indicating that the number of labeled cells can be quantified similar to the use of radioactive or fluorine tracers. This approach for CT cell tracking may find applications in CT image-guided interventions and fluoroscopic procedures commonly used for the injection of cellular therapeutics. PMID- 28713231 TI - Grip Force and 3D Push-Pull Force Estimation Based on sEMG and GRNN. AB - The estimation of the grip force and the 3D push-pull force (push and pull force in the three dimension space) from the electromyogram (EMG) signal is of great importance in the dexterous control of the EMG prosthetic hand. In this paper, an action force estimation method which is based on the eight channels of the surface EMG (sEMG) and the Generalized Regression Neural Network (GRNN) is proposed to meet the requirements of the force control of the intelligent EMG prosthetic hand. Firstly, the experimental platform, the acquisition of the sEMG, the feature extraction of the sEMG and the construction of GRNN are described. Then, the multi-channels of the sEMG when the hand is moving are captured by the EMG sensors attached on eight different positions of the arm skin surface. Meanwhile, a grip force sensor and a three dimension force sensor are adopted to measure the output force of the human's hand. The characteristic matrix of the sEMG and the force signals are used to construct the GRNN. The mean absolute value and the root mean square of the estimation errors, the correlation coefficients between the actual force and the estimated force are employed to assess the accuracy of the estimation. Analysis of variance (ANOVA) is also employed to test the difference of the force estimation. The experiments are implemented to verify the effectiveness of the proposed estimation method and the results show that the output force of the human's hand can be correctly estimated by using sEMG and GRNN method. PMID- 28713232 TI - Detection of Movement Related Cortical Potentials from EEG Using Constrained ICA for Brain-Computer Interface Applications. AB - The movement related cortical potential (MRCP), a slow cortical potential from the scalp electroencephalogram (EEG), has been used in real-time brain-computer interface (BCI) systems designed for neurorehabilitation. Detecting MPCPs in real time with high accuracy and low latency is essential in these applications. In this study, we propose a new MRCP detection method based on constrained independent component analysis (cICA). The method was tested for MRCP detection during executed and imagined ankle dorsiflexion of 24 healthy participants, and compared with four commonly used spatial filters for MRCP detection in an offline experiment. The effect of cICA and the compared spatial filters on the morphology of the extracted MRCP was evaluated by two indices quantifying the signal-to noise ratio and variability of the extracted MRCP. The performance of the filters for detection was then directly compared for accuracy and latency. The latency obtained with cICA (-34 +/- 29 ms motor execution (ME) and 28 +/- 16 ms for motor imagery (MI) dataset) was significantly smaller than with all other spatial filters. Moreover, cICA resulted in greater true positive rates (87.11 +/- 11.73 for ME and 86.66 +/- 6.96 for MI dataset) and lower false positive rates (20.69 +/- 13.68 for ME and 19.31 +/- 12.60 for MI dataset) compared to the other methods. These results confirm the superiority of cICA in MRCP detection with respect to previously proposed EEG filtering approaches. PMID- 28713233 TI - The Role of the Interplay between Stimulus Type and Timing in Explaining BCI Illiteracy for Visual P300-Based Brain-Computer Interfaces. AB - Visual P300-based Brain-Computer Interface (BCI) spellers enable communication or interaction with the environment by flashing elements in a matrix and exploiting consequent changes in end-user's brain activity. Despite research efforts, performance variability and BCI-illiteracy still are critical issues for real world applications. Moreover, there is a quite unaddressed kind of BCI illiteracy, which becomes apparent when the same end-user operates BCI-spellers intended for different applications: our aim is to understand why some well performers can become BCI-illiterate depending on speller type. We manipulated stimulus type (factor STIM: either characters or icons), color (factor COLOR: white, green) and timing (factor SPEED: fast, slow). Each BCI session consisted of training (without feedback) and performance phase (with feedback), both in copy-spelling. For fast flashing spellers, we observed a performance worsening for white icon-speller. Our findings are consistent with existing results reported on end-users using identical white*fast spellers, indicating independence of worsening trend from users' group. The use of slow stimulation timing shed a new light on the perceptual and cognitive phenomena related to the use of a BCI-speller during both the training and the performance phase. We found a significant STIM main effect for the N1 component on P z and PO7 during the training phase and on PO8 during the performance phase, whereas in both phases neither the STIM*COLOR interaction nor the COLOR main effect was statistically significant. After collapsing data for factor COLOR, it emerged a statistically significant modulation of N1 amplitude depending to the phase of BCI session: N1 was more negative for icons than for characters both on P z and PO7 (training), whereas the opposite modulation was observed for PO8 (performance). Results indicate that both feedback and expertise with respect to the stimulus type can modulate the N1 component and that icons require more perceptual analysis. Therefore, fast flashing is likely to be more detrimental for end-users' performance in case of icon-spellers. In conclusion, the interplay between stimulus type and timing seems relevant for a satisfactory and efficient end user's BCI-experience. PMID- 28713234 TI - Leftward Deviation and Asymmetric Speed of Egocentric Judgment between Left and Right Visual Fields. AB - The egocentric reference frame is essential for body orientation and spatial localization of external objects. Recent neuroimaging and lesion studies have revealed that the right hemisphere of humans may play a more dominant role in processing egocentric information than the left hemisphere. However, previous studies of egocentric discrimination mainly focused on assessing the accuracy of egocentric judgment, leaving its timing unexplored. In addition, most previous studies never monitored the subjects' eye position during the experiments, so the influence of eye position on egocentric judgment could not be excluded. In the present study, we systematically assessed the processing of egocentric information in healthy human subjects by measuring the location of their visual subjective straight ahead (SSA) and their manual reaction time (RT) during fixation (monitored by eye tracker). In an egocentric discrimination task, subjects were required to judge the position of a visual cue relative to the subjective mid-sagittal plane and respond as quickly as possible. We found that the SSA of all subjects deviated to the left side of the body mid-sagittal plane. In addition, all subjects but one showed the longest RT at the location closest to the SSA; and in population, the RTs in the left visual field (VF) were longer than that in the right VF. These results might be due to the right hemisphere's dominant role in processing egocentric information, and its more prominent representation of the ipsilateral VF than that of the left hemisphere. PMID- 28713236 TI - Modulation of Calcitonin, Parathyroid Hormone, and Thyroid Hormone Secretion by Electrical Stimulation of Sympathetic and Parasympathetic Nerves in Anesthetized Rats. AB - The thyroid and parathyroid glands are dually innervated by sympathetic (cervical sympathetic trunk [CST]) and parasympathetic (superior laryngeal nerve [SLN]) nerve fibers. We examined the effects of electrical stimulation of efferent or afferent nerve fibers innervating the thyroid and parathyroid glands on the secretion of immunoreactive calcitonin (iCT), parathyroid hormone (iPTH), 3,3',5 triiodothyronine (iT3), and thyroxine (iT4) from the thyroid and parathyroid glands. In anesthetized and artificially ventilated rats, thyroid venous blood was collected. The rate of hormone secretion from the glands was calculated from plasma hormone levels, measured by ELISA, and the flow rate of thyroid venous plasma. SLNs or CSTs were stimulated bilaterally with rectangular pulses with a 0.5-ms width. To define the role of unmyelinated nerve fibers (typically efferent), the cut peripheral segments were stimulated at various frequencies (up to 40 Hz) with a supramaximal intensity to excite all nerve fibers. The secretion of iCT, iT3, and iT4 increased during SLN stimulation and decreased during CST stimulation. iPTH secretion increased during CST stimulation, but was not affected by SLN stimulation. To examine the effects of selective stimulation of myelinated nerve fibers (typically afferent) in the SLN, intact SLNs were stimulated with a subthreshold intensity for unmyelinated nerve fibers. iCT, iT3, and iT4 secretion increased during stimulation of intact SLNs at 40 Hz. These results suggest that excitation of myelinated afferents induced by low intensity and high frequency stimulation of intact SLNs promotes secretion of CT and thyroid hormones from the thyroid gland, potentially via reflex activation of parasympathetic efferent nerve fibers in the SLN. PMID- 28713235 TI - Connecting the Brain to Itself through an Emulation. AB - Pilot clinical trials of human patients implanted with devices that can chronically record and stimulate ensembles of hundreds to thousands of individual neurons offer the possibility of expanding the substrate of cognition. Parallel trains of firing rate activity can be delivered in real-time to an array of intermediate external modules that in turn can trigger parallel trains of stimulation back into the brain. These modules may be built in software, VLSI firmware, or biological tissue as in vitro culture preparations or in vivo ectopic construct organoids. Arrays of modules can be constructed as early stage whole brain emulators, following canonical intra- and inter-regional circuits. By using machine learning algorithms and classic tasks known to activate quasi orthogonal functional connectivity patterns, bedside testing can rapidly identify ensemble tuning properties and in turn cycle through a sequence of external module architectures to explore which can causatively alter perception and behavior. Whole brain emulation both (1) serves to augment human neural function, compensating for disease and injury as an auxiliary parallel system, and (2) has its independent operation bootstrapped by a human-in-the-loop to identify optimal micro- and macro-architectures, update synaptic weights, and entrain behaviors. In this manner, closed-loop brain-computer interface pilot clinical trials can advance strong artificial intelligence development and forge new therapies to restore independence in children and adults with neurological conditions. PMID- 28713237 TI - Behavioral and Neural Correlates of Executive Function: Interplay between Inhibition and Updating Processes. AB - This study investigated the interaction between two executive function processes, inhibition and updating, through analyses of behavioral, neurophysiological, and effective connectivity metrics. Although, many studies have focused on behavioral effects of executive function processes individually, few studies have examined the dynamic causal interactions between these two functions. A total of twenty participants from a local university performed a dual task combing flanker and n back experimental paradigms, and completed the Operation Span Task designed to measure working memory capacity. We found that both behavioral (accuracy and reaction time) and neurophysiological (P300 amplitude and alpha band power) metrics on the inhibition task (i.e., flanker task) were influenced by the updating load (n-back level) and modulated by working memory capacity. Using independent component analysis, source localization (DIPFIT), and Granger Causality analysis of the EEG time-series data, the present study demonstrated that manipulation of cognitive demand in a dual executive function task influenced the causal neural network. We compared connectivity across three updating loads (n-back levels) and found that experimental manipulation of working memory load enhanced causal connectivity of a large-scale neurocognitive network. This network contains the prefrontal and parietal cortices, which are associated with inhibition and updating executive function processes. This study has potential applications in human performance modeling and assessment of mental workload, such as the design of training materials and interfaces for those performing complex multitasking under stress. PMID- 28713238 TI - Targeting Cognitive Impairment in Multiple Sclerosis-The Road toward an Imaging based Biomarker. AB - Multiple Sclerosis (MS) is a neuro-degenerative and -inflammatory disease leading to physical and cognitive impairment, pathological fatigue and depression, and affecting patients' quality of life and employment status. The combination of inflammation, demyelination, and neurodegeneration leads to the emergence of MS lesions, reduced white and gray matter brain volumes, a reduced conduction velocity and microstructural changes in the so-called Normal Appearing White Matter (NAWM). Currently, there are very limited options to treat cognitive impairment and its origin is only poorly understood. Therefore, several studies have attempted to relate clinical scores with features calculated either using T1 and/or FLAIR weighted MR images or using neurophysiology. The aim of those studies is not only to provide an improved understanding of the processes that underlie the different symptoms, but also to develop a biomarker-sensitive to therapy induced change-that could be used to speed up therapeutic developments (e.g., cognitive training/drug discovery/...). Here, we provide an overview of studies that have established relationships between either neuro-anatomical or neurophysiological measures and cognitive outcome scores. We discuss different avenues that may help to improve the prediction of cognitive impairment, and how well we can expect them to predict cognitive scores. PMID- 28713239 TI - Increased White Matter Inflammation in Aging- and Alzheimer's Disease Brain. AB - Chronic neuroinflammation, which is primarily mediated by microglia, plays an essential role in aging and neurodegeneration. It is still unclear whether this microglia-induced neuroinflammation occurs globally or is confined to distinct brain regions. In this study, we investigated microglia activity in various brain regions upon healthy aging and Alzheimer's disease (AD)-related pathology in both human and mouse samples. In purified microglia isolated from aging mouse brains, we found a profound gene expression pattern related to pro-inflammatory processes, phagocytosis, and lipid homeostasis. Particularly in white matter microglia of 24-month-old mice, abundant expression of phagocytic markers including Mac-2, Axl, CD16/32, Dectin1, CD11c, and CD36 was detected. Interestingly, in white matter of human brain tissue the first signs of inflammatory activity were already detected during middle age. Thus quantification of microglial proteins, such as CD68 (commonly associated with phagocytosis) and HLA-DR (associated with antigen presentation), in postmortem human white matter brain tissue showed an age-dependent increase in immunoreactivity already in middle-aged people (53.2 +/- 2.0 years). This early inflammation was also detectable by non-invasive positron emission tomography imaging using [11C]-(R)-PK11195, a ligand that binds to activated microglia. Increased microglia activity was also prominently present in the white matter of human postmortem early-onset AD (EOAD) brain tissue. Interestingly, microglia activity in the white matter of late-onset AD (LOAD) CNS was similar to that of the aged clinically silent AD cases. These data indicate that microglia-induced neuroinflammation is predominant in the white matter of aging mice and humans as well as in EOAD brains. This white matter inflammation may contribute to the progression of neurodegeneration, and have prognostic value for detecting the onset and progression of aging and neurodegeneration. PMID- 28713240 TI - The Coordinated Action of Calcineurin and Cathepsin D Protects Against alpha Synuclein Toxicity. AB - The degeneration of dopaminergic neurons during Parkinson's disease (PD) is intimately linked to malfunction of alpha-synuclein (alphaSyn), the main component of the proteinaceous intracellular inclusions characteristic for this pathology. The cytotoxicity of alphaSyn has been attributed to disturbances in several biological processes conserved from yeast to humans, including Ca2+ homeostasis, general lysosomal function and autophagy. However, the precise sequence of events that eventually results in cell death remains unclear. Here, we establish a connection between the major lysosomal protease cathepsin D (CatD) and the Ca2+/calmodulin-dependent phosphatase calcineurin. In a yeast model for PD, high levels of human alphaSyn triggered cytosolic acidification and reduced vacuolar hydrolytic capacity, finally leading to cell death. This could be counteracted by overexpression of yeast CatD (Pep4), which re-installed pH homeostasis and vacuolar proteolytic function, decreased alphaSyn oligomers and aggregates, and provided cytoprotection. Interestingly, these beneficial effects of Pep4 were independent of autophagy. Instead, they required functional calcineurin signaling, since deletion of calcineurin strongly reduced both the proteolytic activity of endogenous Pep4 and the cytoprotective capacity of overexpressed Pep4. Calcineurin contributed to proper endosomal targeting of Pep4 to the vacuole and the recycling of the Pep4 sorting receptor Pep1 from prevacuolar compartments back to the trans-Golgi network. Altogether, we demonstrate that stimulation of this novel calcineurin-Pep4 axis reduces alphaSyn cytotoxicity. PMID- 28713241 TI - Cold Temperature Encoding by Cutaneous TRPA1 and TRPM8-Carrying Fibers in the Mouse. AB - Previous research identified TRPM8 and TRPA1 cold transducers with separate functions, one being functional in the non-noxious range and the second one being a nociceptive transducer. TRPM8-deficient mice present overt deficits in the detection of environmental cool, but not a lack of cold avoidance and TRPA1 deficient mice show clear deficits in some cold nocifensive assays. The extent of TRPA1's contribution to cold sensing in vivo is still unclear, because mice lacking both TRPM8 and TRPA1 (DKO) were described with unchanged cold avoidance from TRPM8-/- based on a two-temperature-choice assay and by c-fos measurement. The present study was designed to differentiate how much TRPM8 alone and combined TRPA1 and TRPM8 contribute to cold sensing. We analyzed behavior in the thermal ring track assay adjusted between 30 and 5 degrees C and found a large reduction in cold avoidance of the double knockout mice as compared to the TRPM8-deficient mice. We also revisited skin-nerve recordings from saphenous-nerve skin preparations with regard to nociceptors and thermoreceptors. We compared the frequency and characteristics of the cold responses of TRPM8-expressing and TRPM8 negative C-fiber nociceptors in C57BL/6J mice with nociceptors of TRPM8-deficient and DKO mice and found that TRPM8 enables nociceptors to encode cold temperatures with higher firing rates and larger responses with sustained, static component. In TRPM8-/-, C-fiber cold nociceptors were markedly reduced and appeared further reduced in DKO. Nevertheless, the remaining cold responses in both knockout strains were similar in their characteristics and they were indifferent from the TRPM8-negative cold responses found in C57BL/6J mice. TRPM8 had a comparably essential role for encoding cold in thermoreceptors and lack of TRPM8 reduced response magnitude, peak and mean firing rates and the incidence of thermoreceptors. The encoding deficits were similar in the DKO strain. Our data illustrate that lack of TRPA1 in TRPM8-deficient mice results in a disproportionately large reduction in cold avoidance behavior and also affects the incidence of cold encoding fiber types. Presumably TRPA1 compensates for lack of TRPM8 to a certain extent and both channels cooperate to cover the entire cold temperature range, making cold-temperature encoding by TRPA1-although less powerful-synergistic to TRPM8. PMID- 28713242 TI - The Distance between N and C Termini of Tau and of FTDP-17 Mutants Is Modulated by Microtubule Interactions in Living Cells. AB - The microtubule (MT)-associated protein Tau is a natively unfolded protein, involved in a number of neurodegenerative disorders, collectively called tauopathies, aggregating in neurofibrillary tangles (NFT). It is an open question how the conversion from a MT bound molecule to an aggregation-prone Tau species occurs and, also, if and how tauopathy-related mutations affect its behavior in the cell. To address these points, we exploited a genetically encoded FRET sensor based on the full length Tau protein, to monitor in real time Tau conformational changes in different conditions in live cells. By studying the FRET signal we found that soluble Tau molecules, detached from MTs, display an unfolded structure. On the contrary, we observed an increased FRET signal generated by Tau monomers bound to MT, indicating that the association with MTs induced a folding of Tau protein, decreasing the distance between its N and C termini. We exploited the FRET sensor to investigate the impact of FTDP-17 mutations and of phosphorylation-site mutations on Tau folding and mobility in live cells. We demonstrated that the FTDP-17 Tau mutations weaken the interaction of Tau with cellular MTs, shifting the equilibrium towards the soluble pool while, conversely, phosphorylation site mutations shift the equilibrium of Tau towards the MT-bound state and a more closed conformation. PMID- 28713243 TI - Synaptic Interactome Mining Reveals p140Cap as a New Hub for PSD Proteins Involved in Psychiatric and Neurological Disorders. AB - Altered synaptic function has been associated with neurological and psychiatric conditions including intellectual disability, schizophrenia and autism spectrum disorder (ASD). Amongst the recently discovered synaptic proteins is p140Cap, an adaptor that localizes at dendritic spines and regulates their maturation and physiology. We recently showed that p140Cap knockout mice have cognitive deficits, impaired long-term potentiation (LTP) and long-term depression (LTD), and immature, filopodia-like dendritic spines. Only a few p140Cap interacting proteins have been identified in the brain and the molecular complexes and pathways underlying p140Cap synaptic function are largely unknown. Here, we isolated and characterized the p140Cap synaptic interactome by co immunoprecipitation from crude mouse synaptosomes, followed by mass spectrometry based proteomics. We identified 351 p140Cap interactors and found that they cluster to sub complexes mostly located in the postsynaptic density (PSD). p140Cap interactors converge on key synaptic processes, including transmission across chemical synapses, actin cytoskeleton remodeling and cell-cell junction organization. Gene co-expression data further support convergent functions: the p140Cap interactors are tightly co-expressed with each other and with p140Cap. Importantly, the p140Cap interactome and its co-expression network show strong enrichment in genes associated with schizophrenia, autism, bipolar disorder, intellectual disability and epilepsy, supporting synaptic dysfunction as a shared biological feature in brain diseases. Overall, our data provide novel insights into the molecular organization of the synapse and indicate that p140Cap acts as a hub for postsynaptic complexes relevant to psychiatric and neurological disorders. PMID- 28713244 TI - Regulatory Roles of Long Non-Coding RNAs in the Central Nervous System and Associated Neurodegenerative Diseases. AB - Accumulating studies have revealed that the human genome encodes tens of thousands of long non-coding RNAs (lncRNAs), which participate in multiple biological networks modulating gene expression via transcriptional, post transcriptional and epigenetic regulation. Strikingly, a large fraction of tissue specific lncRNAs are expressed in the Central Nervous System (CNS) with precisely regulated temporal and spatial expression patterns. These brain-specific lncRNAs are also featured with the cell-type specificity, the highest signals of evolutionary conservation, and their preferential location adjacent to brain expressed protein-coding genes. Mounting evidence has indicated dysregulation or mutations in lncRNA gene loci are associated with a variety of CNS-associated neurodegenerative disorders, such as Alzheimer's, Parkinson's, Huntington's diseases, Amyotrophic Lateral Sclerosis and others. However, how lncRNAs contribute to these disorders remains to be further explored and studied. In this review article, we systematically and comprehensively summarize the current studies of lncRNAs, demonstrate the specificity of lncRNAs expressed in the brain, their functions during neural development and expression profiles in major cell types of the CNS, highlight the regulatory mechanisms of several studied lncRNAs that may play essential roles in the pathophysiology of neurodegenerative diseases, and discuss the current challenges and future perspectives of lncRNA studies involved in neurodegenerative and other diseases. PMID- 28713246 TI - Differential Contribution of Ca2+-Dependent Mechanisms to Hyperexcitability in Layer V Neurons of the Medial Entorhinal Cortex. AB - Temporal lobe epilepsy is characterized by recurrent seizures in one or both temporal lobes of the brain; some in vitro models show that epileptiform discharges initiate in entorhinal layer V neurons and then spread into other areas of the temporal lobe. We previously found that, in the presence of GABAA receptor antagonists, stimulation of afferent fibers, terminating both at proximal and distal dendritic locations, initiated hyperexcitable bursts in layer V medial entorhinal neurons. We investigated the differential contribution of Ca2+-dependent mechanisms to the plateaus underlying these bursts at proximal and distal synapses. We found that the NMDA glutamatergic antagonist D,L-2-amino-5 phosphonovaleric acid (APV; 50 MUM) reduced both the area and duration of the bursts at both proximal and distal synapses by about half. The L-type Ca2+ channel blocker nimodipine (10 MUM) and the R- and T-type Ca2+ channel blocker NiCl2 (200 MUM) decreased the area of the bursts to a lesser extent; none of these effects appeared to be location-dependent. Remarkably, the perfusion of flufenamic acid (FFA; 100 MUM), to block Ca2+-activated non-selective cation currents (ICAN) mediated by transient receptor potential (TRP) channels, had a location-dependent effect, by abolishing burst firing and switching the suprathreshold response to a single action potential (AP) for proximal stimulation, but only minimally affecting the bursts evoked by distal stimulation. A similar outcome was found when FFA was pressure-applied locally around the proximal dendrite of the recorded neurons and in the presence of a selective blocker of melastatin TRP (TRPM) channels, 9-phenanthrol (100 MUM), whereas a selective blocker of canonical TRP (TRPC) channels, SKF 96365, did not affect the bursts. These results indicate that different mechanisms might contribute to the initiation of hyperexcitability in layer V neurons at proximal and distal synapses and could shed light on the initiation of epileptiform activity in the entorhinal cortex. PMID- 28713247 TI - Divergent Roles of Central Serotonin in Adult Hippocampal Neurogenesis. AB - The central serotonin (5-HT) system is the main target of selective serotonin reuptake inhibitors (SSRIs), the first-line antidepressants widely used in current general practice. One of the prominent features of chronic SSRI treatment in rodents is the enhanced adult neurogenesis in the hippocampus, which has been proposed to contribute to antidepressant effects. Therefore, tremendous effort has been made to decipher how central 5-HT regulates adult hippocampal neurogenesis. In this paper, we review how changes in the central serotonergic system alter adult hippocampal neurogenesis. We focus on data obtained from three categories of genetically engineered mouse models: (1) mice with altered central 5-HT levels from embryonic stages, (2) mice with deletion of 5-HT receptors from embryonic stages, and (3) mice with altered central 5-HT system exclusively in adulthood. These recent findings provide unique insights to interpret the multifaceted roles of central 5-HT on adult hippocampal neurogenesis and its associated effects on depression. PMID- 28713245 TI - Multifaceted Roles of Metzincins in CNS Physiology and Pathology: From Synaptic Plasticity and Cognition to Neurodegenerative Disorders. AB - The extracellular matrix (ECM) and membrane proteolysis play a key role in structural and functional synaptic plasticity associated with development and learning. A growing body of evidence underscores the multifaceted role of members of the metzincin superfamily, including metalloproteinases (MMPs), A Disintegrin and Metalloproteinases (ADAMs), A Disintegrin and Metalloproteinase with Thrombospondin Motifs (ADAMTSs) and astacins in physiological and pathological processes in the central nervous system (CNS). The expression and activity of metzincins are strictly controlled at different levels (e.g., through the regulation of translation, limited activation in the extracellular space, the binding of endogenous inhibitors and interactions with other proteins). Thus, unsurprising is that the dysregulation of proteolytic activity, especially the greater expression and activation of metzincins, is associated with neurodegenerative disorders that are considered synaptopathies, especially Alzheimer's disease (AD). We review current knowledge of the functions of metzincins in the development of AD, mainly the proteolytic processing of amyloid precursor protein, the degradation of amyloid beta (Abeta) peptide and several pathways for Abeta clearance across brain barriers (i.e., blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB)) that contain specific receptors that mediate the uptake of Abeta peptide. Controlling the proteolytic activity of metzincins in Abeta-induced pathological changes in AD patients' brains may be a promising therapeutic strategy. PMID- 28713249 TI - CRISPR/Cas9-Mediated Zebrafish Knock-in as a Novel Strategy to Study Midbrain Hindbrain Boundary Development. AB - The midbrain-hindbrain boundary (MHB) acts as an organizer and controls the fate of neighboring cells to develop into either mesencephalic (midbrain) or metencephalic (hindbrain) cells by secreting signaling molecules like Wnt1 and Fgf8. The zebrafish is an excellent vertebrate model for studying MHB development due to the ease of gene manipulation and the possibility of following cellular dynamics and morphogenetic processes using live imaging. Currently, only very few reporter and/or Cre-driver lines are available to study gene expression at the MHB, hampering the understanding of MHB development, and traditional transgenic technologies using promoter/enhancer fragments or bacterial artificial chromosome (BAC)-mediated transgenesis often do not faithfully recapitulate endogenous expression patterns. In contrast, CRISPR/Cas9-mediated genome editing technology now provides a great opportunity to efficiently knock-in or knock-out genes. We have generated four CRISPR/Cas9-based knock-in fluorescent reporter lines for two crucial genes involved in MHB development, namely otx2 and pax2a. The coding sequences of the reporters were knocked-in upstream of the corresponding ATG and are, thus, under the control of the endogenous promoter/enhancer elements. Interestingly, this strategy does not disturb endogenous gene expression. Using the fast maturing fluorescent protein reporter, Venus, enabled us to follow MHB development using cell tracking and live imaging. In addition, we show that these reporter lines label various neuronal and glial cell types in the adult zebrafish brain, making them highly suitable for investigating embryonic and adult midbrain, hindbrain, and MHB development. PMID- 28713248 TI - Deep Brain Magnetic Stimulation Promotes Neurogenesis and Restores Cholinergic Activity in a Transgenic Mouse Model of Alzheimer's Disease. AB - Alzheimer's disease (AD) is characterized by progressive decline of memory and cognitive functions. Deep magnetic stimulation (DMS), a noninvasive and nonpharmacological brain stimulation, has been reported to alleviate stress related cognitive impairment in neuropsychiatric disorders. Our previous study also discovered the preventive effect of DMS on cognitive decline in an AD mouse model. However, the underlying mechanism must be explored further. In this study, we investigated the effect of DMS on spatial learning and memory functions, neurogenesis in the dentate gyrus (DG), as well as expression and activity of the cholinergic system in a transgenic mouse model of AD (5XFAD). Administration of DMS effectively improved performance in spatial learning and memory of 5XFAD mice. Furthermore, neurogenesis in the hippocampal DG of DMS-treated 5XFAD mice was clearly enhanced. In addition, DMS significantly raised the level of acetylcholine and prevented the increase in acetylcholinesterase activity as well as the decrease in acetyltransferase activity in the hippocampus of 5XFAD mice. These findings indicate that DMS may be a promising noninvasive tool for treatment and prevention of AD cognitive impairment by promoting neurogenesis and enhancing cholinergic system function. PMID- 28713250 TI - Impaired In Vivo Gamma Oscillations in the Medial Entorhinal Cortex of Knock-in Alzheimer Model. AB - The entorhinal cortex (EC) has bidirectional connections with the hippocampus and plays a critical role in memory formation and retrieval. EC is one of the most vulnerable regions in the brain in early stages of Alzheimer's disease (AD), a neurodegenerative disease with progressive memory impairments. Accumulating evidence from healthy behaving animals indicates gamma oscillations (30-100 Hz) as critical for mediating interactions in the circuit between EC and hippocampus. However, it is still unclear whether gamma oscillations have causal relationship with memory impairment in AD. Here we provide the first evidence that in vivo gamma oscillations in the EC are impaired in an AD mouse model. Cross-frequency coupling of gamma (30-100 Hz) oscillations to theta oscillations was reduced in the medial EC of anesthetized amyloid precursor protein knock-in (APP-KI) mice. Phase locking of spiking activity of layer II/III pyramidal cells to the gamma oscillations was significantly impaired. These data indicate that the neural circuit activities organized by gamma oscillations were disrupted in the medial EC of AD mouse model, and point to gamma oscillations as one of possible mechanisms for cognitive dysfunction in AD patients. PMID- 28713252 TI - Effect of Postural Control Demands on Early Visual Evoked Potentials during a Subjective Visual Vertical Perception Task in Adolescents with Idiopathic Scoliosis. AB - Subjective visual vertical (SVV) judgment and standing stability were separately investigated among patients with adolescent idiopathic scoliosis (AIS). Although, one study has investigated the central mechanism of stability control in the AIS population, the relationships between SVV, decreased standing stability, and AIS have never been investigated. Through event-related potentials (ERPs), the present study examined the effect of postural control demands (PDs) on AIS central mechanisms related to SVV judgment and standing stability to elucidate the time-serial stability control process. Thirteen AIS subjects (AIS group) and 13 age-matched adolescents (control group) aged 12-18 years were recruited. Each subject had to complete an SVV task (i.e., the modified rod-and-frame [mRAF] test) as a stimulus, with online electroencephalogram recording being performed in the following three standing postures: feet shoulder-width apart standing, feet together standing, and tandem standing. The behavioral performance in terms of postural stability (center of pressure excursion), SVV (accuracy and reaction time), and mRAF-locked ERPs (mean amplitude and peak latency of the P1, N1, and P2 components) was then compared between the AIS and control groups. In the behavioral domain, the results revealed that only the AIS group demonstrated a significantly accelerated SVV reaction time as the PDs increased. In the cerebral domain, significantly larger P2 mean amplitudes were observed during both feet shoulder-width-apart standing and feet together standing postures compared with during tandem standing. No group differences were noted in the cerebral domain. The results indicated that (1) during the dual-task paradigm, a differential behavioral strategy of accelerated SVV reaction time was observed in the AIS group only when the PDs increased and (2) the decrease in P2 mean amplitudes with the increase in the PD levels might be direct evidence of the competition for central processing attentional resources under the dual-task postural control paradigm. PMID- 28713251 TI - Age-related Changes in Lateral Entorhinal and CA3 Neuron Allocation Predict Poor Performance on Object Discrimination. AB - Age-related memory deficits correlate with dysfunction in the CA3 subregion of the hippocampus, which includes both hyperactivity and overly rigid activity patterns. While changes in intrinsic membrane currents and interneuron alterations are involved in this process, it is not known whether alterations in afferent input to CA3 also contribute. Neurons in layer II of the lateral entorhinal cortex (LEC) project directly to CA3 through the perforant path, but no data are available regarding the effects of advanced age on LEC activity and whether these activity patterns update in response to environmental change. Furthermore, it is not known the extent to which age-related deficits in sensory discrimination relate to the inability of aged CA3 neurons to update in response to new environments. Young and aged rats were pre-characterized on a LEGO(c) object discrimination task, comparable to behavioral tests in humans in which CA3 hyperactivity has been linked to impairments. The cellular compartment analysis of temporal activity with fluorescence in situ hybridization for the immediate early gene Arc was then used to identify the principal cell populations that were active during two distinct epochs of random foraging in different environments. This approach enabled the extent to which rats could discriminate two similar objects to be related to the ability of CA3 neurons to update across different environments. In both young and aged rats, there were animals that performed poorly on the LEGO object discrimination task. In the aged rats only, however, the poor performers had a higher percent of CA3 neurons that were active during random foraging in a novel environment, but this is not related to the ability of CA3 neurons to remap when the environment changed. Afferent neurons to CA3 in LEC, as identified with the retrograde tracer choleratoxin B (CTB), also showed a higher percentage of cells that were positive for Arc mRNA in aged poor performing rats. This suggests that LEC contributes to the hyperactivity seen in CA3 of aged animals with object discrimination deficits and age-related cognitive decline may be the consequence of dysfunction endemic to the larger network. PMID- 28713253 TI - On the Keyhole Hypothesis: High Mutual Information between Ear and Scalp EEG. AB - We propose and test the keyhole hypothesis-that measurements from low dimensional EEG, such as ear-EEG reflect a broadly distributed set of neural processes. We formulate the keyhole hypothesis in information theoretical terms. The experimental investigation is based on legacy data consisting of 10 subjects exposed to a battery of stimuli, including alpha-attenuation, auditory onset, and mismatch-negativity responses and a new medium-long EEG experiment involving data acquisition during 13 h. Linear models were estimated to lower bound the scalp-to ear capacity, i.e., predicting ear-EEG data from simultaneously recorded scalp EEG. A cross-validation procedure was employed to ensure unbiased estimates. We present several pieces of evidence in support of the keyhole hypothesis: There is a high mutual information between data acquired at scalp electrodes and through the ear-EEG "keyhole," furthermore we show that the view-represented as a linear mapping-is stable across both time and mental states. Specifically, we find that ear-EEG data can be predicted reliably from scalp EEG. We also address the reverse view, and demonstrate that large portions of the scalp EEG can be predicted from ear-EEG, with the highest predictability achieved in the temporal regions and when using ear-EEG electrodes with a common reference electrode. PMID- 28713254 TI - Short-Term Effects of Thoracic Spine Manipulation on the Biomechanical Organisation of Gait Initiation: A Randomized Pilot Study. AB - Speed performance during gait initiation is known to be dependent on the capacity of the central nervous system to generate efficient anticipatory postural adjustments (APA). According to the posturo-kinetic capacity (PKC) concept, any factor enhancing postural chain mobility and especially spine mobility, may facilitate the development of APA and thus speed performance. "Spinal Manipulative Therapy High-Velocity, Low-Amplitude" (SMT-HVLA) is a healing technique applied to the spine which is routinely used by healthcare practitioners to improve spine mobility. As such, it may have a positive effect on the PKC and therefore facilitate gait initiation. The present study aimed to investigate the short-term effect of thoracic SMT-HVLA on spine mobility, APA and speed performance during gait initiation. Healthy young adults (n = 22) performed a series of gait initiation trials on a force plate before ("pre-manipulation" condition) and after ("post-manipulation" condition) a sham manipulation or an HVLA manipulation applied to the ninth thoracic vertebrae (T9). Participants were randomly assigned to the sham (n = 11) or the HVLA group (n = 11).The spine range of motion (ROM) was assessed in each participant immediately after the sham or HVLA manipulations using inclinometers. The results showed that the maximal thoracic flexion increased in the HVLA group after the manipulation, which was not the case in the sham group. In the HVLA group, results further showed that each of the following gait initiation variables reached a significantly lower mean value in the post-manipulation condition as compared to the pre-manipulation condition: APA duration, peak of anticipatory backward center of pressure displacement, center of gravity velocity at foot-off, mechanical efficiency of APA, peak of center of gravity velocity and step length. In contrast, for the sham group, results showed that none of the gait initiation variables significantly differed between the pre- and post-manipulation conditions. It is concluded that HVLA manipulation applied to T9 has an immediate beneficial effect on spine mobility but a detrimental effect on APA development and speed performance during gait initiation. We suggest that a neural effect induced by SMT-HVLA, possibly mediated by a transient alteration in the early sensory-motor integration, might have masked the potential mechanical benefits associated with increased spine mobility. PMID- 28713255 TI - The Impact of Aerobic Exercise on Fronto-Parietal Network Connectivity and Its Relation to Mobility: An Exploratory Analysis of a 6-Month Randomized Controlled Trial. AB - Impaired mobility is a major concern for older adults and has significant consequences. While the widely accepted belief is that improved physical function underlies the effectiveness of targeted exercise training in improving mobility and reducing falls, recent evidence suggests cognitive and neural benefits gained through exercise may also play an important role in promoting mobility. However, the underlying neural mechanisms of this relationship are currently unclear. Thus, we hypothesize that 6 months of progressive aerobic exercise training would alter frontoparietal network (FPN) connectivity during a motor task among older adults with mild subcortical ischemic vascular cognitive impairment (SIVCI)-and exercise-induced changes in FPN connectivity would correlate with changes in mobility. We focused on the FPN as it is involved in top-down attentional control as well as motor planning and motor execution. Participants were randomized either to usual-care (CON), which included monthly educational materials about VCI and healthy diet; or thrice-weekly aerobic training (AT), which was walking outdoors with progressive intensity. Functional magnetic resonance imaging was acquired at baseline and trial completion, where the participants were instructed to perform bilateral finger tapping task. At trial completion, compared with AT, CON showed significantly increased FPN connectivity strength during right finger tapping (p < 0.05). Across the participants, reduced FPN connectivity was associated with greater cardiovascular capacity (p = 0.05). In the AT group, reduced FPN connectivity was significantly associated with improved mobility performance, as measured by the Timed-Up-and-Go test (r = 0.67, p = 0.02). These results suggest progressive AT may improve mobility in older adults with SIVCI via maintaining intra-network connectivity of the FPN. PMID- 28713256 TI - Baseline Performance Predicts tDCS-Mediated Improvements in Language Symptoms in Primary Progressive Aphasia. AB - Primary Progressive Aphasia (PPA) is a neurodegenerative condition characterized by insidious irreversible loss of language abilities. Prior studies suggest that transcranial direct current stimulation (tDCS) directed toward language areas of the brain may help to ameliorate symptoms of PPA. In the present sham-controlled study, we examined whether tDCS could be used to enhance language abilities (e.g., picture naming) in individuals with PPA variants primarily characterized by difficulties with speech production (non-fluent and logopenic). Participants were recruited from the Penn Frontotemporal Dementia Center to receive 10 days of both real and sham tDCS (counter-balanced, full-crossover design; participants were naive to stimulation condition). A battery of language tests was administered at baseline, immediately post-tDCS (real and sham), and 6 weeks and 12 weeks following stimulation. When we accounted for individuals' baseline performance, our analyses demonstrated a stratification of tDCS effects. Individuals who performed worse at baseline showed tDCS-related improvements in global language performance, grammatical comprehension and semantic processing. Individuals who performed better at baseline showed a slight tDCS-related benefit on our speech repetition metric. Real tDCS may improve language performance in some individuals with PPA. Severity of deficits at baseline may be an important factor in predicting which patients will respond positively to language-targeted tDCS therapies. Clinicaltrials.gov ID: NCT02928848. PMID- 28713257 TI - Language, Paleoneurology, and the Fronto-Parietal System. PMID- 28713258 TI - Relationship of Topology, Multiscale Phase Synchronization, and State Transitions in Human Brain Networks. AB - How the brain reconstitutes consciousness and cognition after a major perturbation like general anesthesia is an important question with significant neuroscientific and clinical implications. Recent empirical studies in animals and humans suggest that the recovery of consciousness after anesthesia is not random but ordered. Emergence patterns have been classified as progressive and abrupt transitions from anesthesia to consciousness, with associated differences in duration and electroencephalogram (EEG) properties. We hypothesized that the progressive and abrupt emergence patterns from the unconscious state are associated with, respectively, continuous and discontinuous synchronization transitions in functional brain networks. The discontinuous transition is explainable with the concept of explosive synchronization, which has been studied almost exclusively in network science. We used the Kuramato model, a simple oscillatory network model, to simulate progressive and abrupt transitions in anatomical human brain networks acquired from diffusion tensor imaging (DTI) of 82 brain regions. To facilitate explosive synchronization, distinct frequencies for hub nodes with a large frequency disassortativity (i.e., higher frequency nodes linking with lower frequency nodes, or vice versa) were applied to the brain network. In this simulation study, we demonstrated that both progressive and abrupt transitions follow distinct synchronization processes at the individual node, cluster, and global network levels. The characteristic synchronization patterns of brain regions that are "progressive and earlier" or "abrupt but delayed" account for previously reported behavioral responses of gradual and abrupt emergence from the unconscious state. The characteristic network synchronization processes observed at different scales provide new insights into how regional brain functions are reconstituted during progressive and abrupt emergence from the unconscious state. This theoretical approach also offers a principled explanation of how the brain reconstitutes consciousness and cognitive functions after physiologic (sleep), pharmacologic (anesthesia), and pathologic (coma) perturbations. PMID- 28713259 TI - Transcallosal Inhibition during Motor Imagery: Analysis of a Neural Mass Model. AB - The EEG rhythmic activities of the somato-sensory cortex reveal event-related desynchronization (ERD) or event-related synchronization (ERS) in beta band (14 30 Hz) as subjects perform certain tasks or react to specific stimuli. Data reported for imagination of movement support the hypothesis that activation of one sensorimotor area (SMA) can be accompanied by deactivation of the other. In order to improve our understanding of beta ERD/ERS generation, two neural mass models (NMM) of a cortical column taken from Wendling et al. (2002) were interconnected to simulate the transmission of information from one cortex to the other. The results show that the excitation of one cortex leads to inhibition of the other and vice versa, enforcing the Theory of Inhibition. This behavior strongly depends on the initial working point (WP) of the neural populations (between the linear and the upper saturation region of a sigmoidal function) and on how the cortical activation or deactivation can move the WP in the upper saturation region ERD or in the linear region ERS, respectively. PMID- 28713260 TI - Automated Detection of Epileptic Biomarkers in Resting-State Interictal MEG Data. AB - Certain differences between brain networks of healthy and epilectic subjects have been reported even during the interictal activity, in which no epileptic seizures occur. Here, magnetoencephalography (MEG) data recorded in the resting state is used to discriminate between healthy subjects and patients with either idiopathic generalized epilepsy or frontal focal epilepsy. Signal features extracted from interictal periods without any epileptiform activity are used to train a machine learning algorithm to draw a diagnosis. This is potentially relevant to patients without frequent or easily detectable spikes. To analyze the data, we use an up to-date machine learning algorithm and explore the benefits of including different features obtained from the MEG data as inputs to the algorithm. We find that the relative power spectral density of the MEG time-series is sufficient to distinguish between healthy and epileptic subjects with a high prediction accuracy. We also find that a combination of features such as the phase-locked value and the relative power spectral density allow to discriminate generalized and focal epilepsy, when these features are calculated over a filtered version of the signals in certain frequency bands. Machine learning algorithms are currently being applied to the analysis and classification of brain signals. It is, however, less evident to identify the proper features of these signals that are prone to be used in such machine learning algorithms. Here, we evaluate the influence of the input feature selection on a clinical scenario to distinguish between healthy and epileptic subjects. Our results indicate that such distinction is possible with a high accuracy (86%), allowing the discrimination between idiopathic generalized and frontal focal epilepsy types. PMID- 28713261 TI - Age-Related Decline in the Variation of Dynamic Functional Connectivity: A Resting State Analysis. AB - Normal aging is typically characterized by abnormal resting-state functional connectivity (FC), including decreasing connectivity within networks and increasing connectivity between networks, under the assumption that the FC over the scan time was stationary. In fact, the resting-state FC has been shown in recent years to vary over time even within minutes, thus showing the great potential of intrinsic interactions and organization of the brain. In this article, we assumed that the dynamic FC consisted of an intrinsic dynamic balance in the resting brain and was altered with increasing age. Two groups of individuals (N = 36, ages 20-25 for the young group; N = 32, ages 60-85 for the senior group) were recruited from the public data of the Nathan Kline Institute. Phase randomization was first used to examine the reliability of the dynamic FC. Next, the variation in the dynamic FC and the energy ratio of the dynamic FC fluctuations within a higher frequency band were calculated and further checked for differences between groups by non-parametric permutation tests. The results robustly showed modularization of the dynamic FC variation, which declined with aging; moreover, the FC variation of the inter-network connections, which mainly consisted of the frontal-parietal network-associated and occipital-associated connections, decreased. In addition, a higher energy ratio in the higher FC fluctuation frequency band was observed in the senior group, which indicated the frequency interactions in the FC fluctuations. These results highly supported the basis of abnormality and compensation in the aging brain and might provide new insights into both aging and relevant compensatory mechanisms. PMID- 28713262 TI - Effects of Strength Training and Anabolic Steroid in the Peripheral Nerve and Skeletal Muscle Morphology of Aged Rats. AB - Thirty male 20-month-old Wistar rats were divided into groups: IC-initial control (n = 6), FC-final control (n = 6), AC-anabolic hormone control (n = 6), ST strength trained (n = 6) and STA-strength trained with anabolic hormone (n = 6). All groups were submitted to adaptation, familiarization and maximum load carrying test (MLCT). Strength training (6-8*/session with loads of 50%-100% MLCT, 3*/week and pause of 120 s) was performed in ladder climbing (LC) for 15 weeks. The administration of testosterone propionate (TP) was performed 2*/week (10 mg/kg) in animals in the AC and STA groups. After the experimental period, animals were euthanized and the tibial nerve and plantaris muscle removed and prepared for electron transmission and histochemistry. To compare the groups we used one-way ANOVA (post hoc Bonferroni), student's t-tests for pre vs. post (dependent and independent variables) comparisons and significance level set at p <= 0.05. The following significant results were found: (a) aging decreased the number of myelinated axon fibers; (b) use of isolated TP increased the diameter of myelinated fibers, along with increased thickness of myelin sheath; (c) ST increased area of myelinated and unmyelinated fibers, together with the myelin sheath. These changes made it possible to increase the area occupied by myelinated fibers keeping their quantity and also reduce the interstitial space; and (d) association of anabolic steroid and ST increased the area of unmyelinated axons and thickness of the myelin sheath. Compared to ST, both strategies have similar results. However, Schwann cells increased significantly only in this strategy. PMID- 28713263 TI - The Frequency-Dependent Aerobic Exercise Effects of Hypothalamic GABAergic Expression and Cardiovascular Functions in Aged Rats. AB - A decline in cardiovascular modulation is a feature of the normal aging process and associated with cardiovascular diseases (CVDs) such as hypertension and stroke. Exercise training is known to promote cardiovascular adaptation in young animals and positive effects on motor and cognitive capabilities, as well as on brain plasticity for all ages in mice. Here, we examine the question of whether aerobic exercise interventions may impact the GABAergic neurons of the paraventricular nucleus (PVN) in aged rats which have been observed to have a decline in cardiovascular integration function. In the present study, young (2 months) and old (24 months) male Wistar rats were divided into young control (YC), old sedentary, old low frequency exercise (20 m/min, 60 min/day, 3 days/week, 12 weeks) and old high frequency exercise (20 m/min, 60 min/day, 5 days/week, 12 weeks). Exercise training indexes were obtained, including resting heart rate (HR), blood pressure (BP), plasma norepinephrine (NE), and heart weight (HW)-to-body weight (BW) ratios. The brain was removed and processed according to the immunofluorescence staining and western blot used to analyze the GABAergic terminal density, the proteins of GAD67, GABAA receptor and gephyrin in the PVN. There were significant changes in aged rats compared with those in the YC. Twelve weeks aerobic exercise training has volume-dependent ameliorated effects on cardiovascular parameters, autonomic nervous activities and GABAergic system functions. These data suggest that the density of GABAergic declines in the PVN is associated with imbalance in autonomic nervous activities in normal aging. Additionally, aerobic exercise can rescue aging-related an overactivity of the sympathetic nervous system and induces modifications the resting BP and HR to lower values via improving the GABAergic system in the PVN. PMID- 28713264 TI - White Matter Changes-Related Gait and Executive Function Deficits: Associations with Age and Parkinson's Disease. AB - Background: White matter changes (WMC) are a common finding among older adults and patients with Parkinson's disease (PD), and have been associated with, e.g., gait deficits and executive dysfunction. How the factors age and PD influence WMC related deficits is, to our best knowledge, not investigated to date. We hypothesized that advanced age and presence of PD leads to WMC-related symptoms while practicing tasks with a low complexity level, and low age and absence of PD leads to WMC-related symptoms while practicing tasks with a high complexity level. Methods: Hundred and thirty-eight participants [65 young persons without PD (50-69 years, yPn), 22 young PD patients (50-69 years, yPD), 36 old persons without PD (70-89 years, oPn) and 15 old PD patients (70-89 years, oPD)] were included. Presence and severity of WMC were determined with the modified Fazekas score. Velocity of walking under single and dual tasking conditions and the Trail Making Test (TMT) were used as gait and executive function parameters. Correlations between presence and severity of WMC, and gait and executive function parameters were tested in yPn, yPD, oPn, and oPD using Spearman's rank correlation, and significance between groups was evaluated with Fisher's z transformed correlation coefficient. Results: yPn and yPD, as well as oPn and oPD did not differ regarding demographic and clinical parameters. Severity of WMC was not significantly different between groups. yPn and yPD displayed significant correlations of WMC with executive function parameters at low levels of task complexity, oPn at intermediate, and oPD at high complexity levels. Conclusion: This study argues for a relevant association of age and PD-related brain pathology with WMC-related gait and executive function deficits. PMID- 28713265 TI - A Comparison of Reimbursement Recommendations by European HTA Agencies: Is There Opportunity for Further Alignment? AB - Introduction: In Europe and beyond, the rising costs of healthcare and limited healthcare resources have resulted in the implementation of health technology assessment (HTA) to inform health policy and reimbursement decision-making. European legislation has provided a harmonized route for the regulatory process with the European Medicines Agency, but reimbursement decision-making still remains the responsibility of each country. There is a recognized need to move toward a more objective and collaborative reimbursement environment for new medicines in Europe. Therefore, the aim of this study was to objectively assess and compare the national reimbursement recommendations of 9 European jurisdictions following European Medicines Agency (EMA) recommendation for centralized marketing authorization. Methods: Using publicly available data and newly developed classification tools, this study appraised 9 European reimbursement systems by assessing HTA processes and the relationship between the regulatory, HTA and decision-making organizations. Each national HTA agency was classified according to two novel taxonomies. The System taxonomy, focuses on the position of the HTA agency within the national reimbursement system according to the relationship between the regulator, the HTA-performing agency, and the reimbursement decision-making coverage body. The HTA Process taxonomy distinguishes between the individual HTA agency's approach to economic and therapeutic evaluation and the inclusion of an independent appraisal step. The taxonomic groups were subsequently compared with national HTA recommendations. Results: This study identified European national reimbursement recommendations for 102 new active substances (NASs) approved by the EMA from 2008 to 2012. These reimbursement recommendations were compared using a novel classification tool and identified alignment between the organizational structure of reimbursement systems (System taxonomy) and HTA recommendations. However, there was less alignment between the HTA processes and recommendations. Conclusions: In order to move forward to a more harmonized HTA environment within Europe, it is first necessary to understand the variation in HTA practices within Europe. This study has identified alignment between HTA recommendations and the System taxonomy and one of the major implications of this study is that such alignment could support a more collaborative HTA environment in Europe. PMID- 28713267 TI - Epoxyeicosatrienoic Acid Analog Decreases Renal Fibrosis by Reducing Epithelial to-Mesenchymal Transition. AB - Renal fibrosis, which is a critical pathophysiological event in chronic kidney diseases, is associated with renal epithelial-to-mesenchymal transition (EMT). Epoxyeicosatrienoic acids (EETs) are Cyp epoxygenase arachidonic acid metabolites that demonstrate biological actions that result in kidney protection. Herein, we investigated the ability of 14,15-EET and its synthetic analog, EET-A, to reduce kidney fibrosis induced by unilateral ureter obstruction (UUO). C57/BL6 male mice underwent sham or UUO surgical procedures and were treated with 14,15-EET or EET A in osmotic pump (i.p.) for 10 days following UUO surgery. UUO mice demonstrated renal fibrosis with an 80% higher kidney-collagen positive area and 70% higher alpha-smooth muscle actin (SMA) positive renal areas compared to the sham group. As a measure of collagen content, kidney hydroxyproline content was also higher in UUO (6.4 +/- 0.5 MUg/10 mg) compared to sham group (2.5 +/- 0.1 MUg/10 mg). Along with marked renal fibrosis, UUO mice had reduced renal expression of EET producing Cyp epoxygenase enzymes. Endogenous 14,15-EET or EET-A demonstrated anti-fibrotic action in UUO by reducing kidney-collagen positive area (50-60%), hydroxyproline content (50%), and renal alpha-SMA positive area (85%). In UUO mice, renal expression of EMT inducers, Snail1 and ZEB1 were higher compared to sham group. Accordingly, renal epithelial marker E-cadherin expression was reduced and mesenchymal marker expression was elevated in the UUO compared to sham mice. Interestingly, EET-A reduced EMT in UUO mice by deceasing renal Snail1 and ZEB1 expression. EET-A treatment also opposed the decrease in renal E cadherin expression and markedly reduced several prominent renal mesenchymal/myofibroblast markers in UUO mice. Overall, our results demonstrate that EET-A is a novel anti-fibrotic agent that reduces renal fibrosis by decreasing renal EMT. PMID- 28713268 TI - Sitagliptin, An Anti-diabetic Drug, Suppresses Estrogen Deficiency-Induced OsteoporosisIn Vivo and Inhibits RANKL-Induced Osteoclast Formation and Bone Resorption In Vitro. AB - Postmenopausal osteoporosis is a disease characterized by excessive osteoclastic bone resorption. Some anti-diabetic drugs were demonstrated for anti-osteoclastic bone-loss effects. The present study investigated the skeletal effects of chronic administration of sitagliptin, a dipeptidyl peptidase IV (DPP IV) inhibitor that is increasingly used for type 2 diabetes treatments, in an estrogen deficiency induced osteoporosis and elucidated the associated mechanisms. This study indicated that sitagliptin effectively prevented ovariectomy-induced bone loss and reduced osteoclast numbers in vivo. It was also indicated that sitagliptin suppressed receptor activator of nuclear factor-kappaB ligand (RANKL)-mediated osteoclast differentiation, bone resorption, and F-actin ring formation in a manner of dose-dependence. In addition, sitagliptin significantly reduced the expression of osteoclast-specific markers in mouse bone-marrow-derived macrophages, including calcitonin receptor (Calcr), dendrite cell-specific transmembrane protein (Dc-stamp), c-Fos, and nuclear factor of activated T-cells cytoplasmic 1 (Nfatc1). Further study indicated that sitagliptin inhibited osteoclastogenesis by suppressing AKT and ERK signaling pathways, scavenging ROS activity, and suppressing the Ca2+ oscillation that consequently affects the expression and/or activity of the osteoclast-specific transcription factors, c Fos and NFATc1. Collectively, these findings suggest that sitagliptin possesses beneficial effects on bone and the suppression of osteoclast number implies that the effect is exerted directly on osteoclastogenesis. PMID- 28713269 TI - The Emerging Role for Zinc in Depression and Psychosis. AB - Zinc participation is essential for all physiological systems, including neural functioning, where it participates in a myriad of cellular processes. Converging clinical, molecular, and genetic discoveries illuminate key roles for zinc homeostasis in association with clinical depression and psychosis which are not yet well appreciated at the clinical interface. Intracellular deficiency may arise from low circulating zinc levels due to dietary insufficiency, or impaired absorption from aging or medical conditions, including alcoholism. A host of medications commonly administered to psychiatric patients, including anticonvulsants, oral medications for diabetes, hormones, antacids, anti inflammatories and others also impact zinc absorption. Furthermore, inefficient genetic variants in zinc transporter molecules that transport the ion across cellular membranes impede its action even when circulating zinc concentrations is in the normal range. Well powered clinical studies have shown beneficial effects of supplemental zinc in depression and it important to pursue research using zinc as a potential therapeutic option for psychosis as well. Meta-analyses support the adjunctive use of zinc in major depression and a single study now supports zinc for psychotic symptoms. This manuscript reviews the biochemistry and bench top evidence on putative molecular mechanisms of zinc as a psychiatric treatment. PMID- 28713270 TI - Evaluation of Selected CYP51A1 Polymorphisms in View of Interactions with Substrate and Redox Partner. AB - Cholesterol is essential for development, growth, and maintenance of organisms. Mutations in cholesterol biosynthetic genes are embryonic lethal and few polymorphisms have been so far associated with pathologies in humans. Previous analyses show that lanosterol 14alpha-demethylase (CYP51A1) from the late part of cholesterol biosynthesis has only a few missense mutations with low minor allele frequencies and low association with pathologies in humans. The aim of this study is to evaluate the role of amino acid changes in the natural missense mutations of the hCYP51A1 protein. We searched SNP databases for existing polymorphisms of CYP51A1 and evaluated their effect on protein function. We found rare variants causing detrimental missense mutations of CYP51A1. Some missense variants were also associated with a phenotype in humans. Two missense variants have been prepared for testing enzymatic activity in vitro but failed to produce a P450 spectrum. We performed molecular modeling of three selected missense variants to evaluate the effect of the amino acid substitution on potential interaction with its substrate and the obligatory redox partner POR. We show that two of the variants, R277L and especially D152G, have possibly lower binding potential toward obligatory redox partner POR. D152G and R431H have also potentially lower affinity toward the substrate lanosterol. We evaluated the potential effect of damaging variants also using data from other in vitro CYP51A1 mutants. In conclusion, we propose to include damaging CYP51A1 variants into personalized diagnostics to improve genetic counseling for certain rare disease phenotypes. PMID- 28713266 TI - Significance of Microbiota in Obesity and Metabolic Diseases and the Modulatory Potential by Medicinal Plant and Food Ingredients. AB - Metabolic syndrome is a cluster of three or more metabolic disorders including insulin resistance, obesity, and hyperlipidemia. Obesity has become the epidemic of the twenty-first century with more than 1.6 billion overweight adults. Due to the strong connection between obesity and type 2 diabetes, obesity has received wide attention with subsequent coining of the term "diabesity." Recent studies have identified unique contributions of the immensely diverse gut microbiota in the pathogenesis of obesity and diabetes. Several mechanisms have been proposed including altered glucose and fatty acid metabolism, hepatic fatty acid storage, and modulation of glucagon-like peptide (GLP)-1. Importantly, the relationship between unhealthy diet and a modified gut microbiota composition observed in diabetic or obese subjects has been recognized. Similarly, the role of diet rich in polyphenols and plant polysaccharides in modulating gut bacteria and its impact on diabetes and obesity have been the subject of investigation by several research groups. Gut microbiota are also responsible for the extensive metabolism of polyphenols thus modulating their biological activities. The aim of this review is to shed light on the composition of gut microbes, their health importance and how they can contribute to diseases as well as their modulation by polyphenols and polysaccharides to control obesity and diabetes. In addition, the role of microbiota in improving the oral bioavailability of polyphenols and hence in shaping their antidiabetic and antiobesity activities will be discussed. PMID- 28713271 TI - Luminally Acting Agents for Constipation Treatment: A Review Based on Literatures and Patents. AB - Constipation is one of the most frequently reported gastrointestinal (GI) disorders that negatively impacts quality of life and is associated with a significant economic burden to the patients and society. Traditional treatments including lifestyle modification and laxatives are often ineffective in the more severe forms of constipation and over the long term. New medications targeting at intestinal chloride channels and colonic serotonin receptors have been demonstrated effective in recent years. Emerging agents focusing on improving intestinal secretion and/or colonic motility have been shown effective in animal models and even in clinical trials. Recognization of the role of cystic fibrosis transmembrane regulator (CFTR) and calcium-activated chloride channels (CaCCs) in intestine fluid secretion and motility modulation makes CFTR and CaCCs promising molecule targets for anti-constipation therapy. Although there are multiple choices for constipation treatment, there is still a recognized need for new medications in anti-constipation therapy. The present review covers the discovery of luminally acting agents for constipation treatment described in both patents (2011-present) and scientific literatures. PMID- 28713272 TI - Anticancer Potential of Citrus Juices and Their Extracts: A Systematic Review of Both Preclinical and Clinical Studies. AB - Background: During the last decades, a huge body of evidence has been accumulated suggesting that Citrus fruits and their juices might have a role in preventing many diseases including cancer. Objective: To summarize the numerous evidences on the potential of Citrus juices and their extracts as anticancer agents. Data sources: A systematic review of articles written in English using MEDLINE (1946 present), EMBASE (1974-present) and Web of Sciences (1970-present) was performed independently by two reviewers. Search terms included Citrus, Citrus aurantifolia, Citrus sinensis, Citrus paradisi, Citrus fruits, Citrus fruits extract, cancer, neoplasm, neoplasia, tumor, metastasis, carcinogenesis, proliferation. The last search was performed on March 16th, 2017. Study selection: Study selection and systematic review were carried out in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Prior to the beginning of the review, Authors defined a checklist for inclusion criteria, thus including articles which meet the following: (i) published on peer-reviewed scientific journals; (ii) Citrus juice used alone; (iii) extracts derived from Citrus juice; (iii) for preclinical studies, an exposure time to Citrus juices and their extracts more than 24 h. Reviews, meta-analyses, conference abstracts and book chapters were excluded. Data extraction: Three reviewers independently performed the extraction of articles. Data synthesis: 22 papers met our inclusion criteria and were eligible for inclusion in the final review. According to the kind of study, the selected ones were further divided in preclinical (n = 20) and observational (n = 2) studies. Conclusion: The studies discussed in this review strongly corroborate the role of Citrus juices and their derivatives as potential resource against cancer. PMID- 28713273 TI - Inhibition of 6-phosphogluconate Dehydrogenase Reverses Cisplatin Resistance in Ovarian and Lung Cancer. AB - Cisplatin (DDP) is currently one of the most commonly used chemotherapeutic drugs for treating ovarian and lung cancer. However, resistance to cisplatin is common and it often leads to therapy failure. In addition, the precise mechanism of cisplatin resistance is still in its infancy. In this study, we demonstrated that the oxidative pentose phosphate pathway enzyme 6-phosphogluconate dehydrogenase (6PGD) promotes cisplatin resistance. We showed that cisplatin-resistant cancer cells (C13* and A549DDP), had higher levels of 6PGD compared to their cisplatin sensitive counterparts (OV2008 and A549). Furthermore, ovarian and lung cancer patients with higher 6PGD levels have worse survival outcomes relative to patients with lower 6PGD expression. Interestingly, we found that the upregulation of 6PGD in cisplatin-resistant cells was due to the decreased expression of miR-206 and miR-613, which we found to target this enzyme. We further demonstrate that suppressing 6PGD using shRNA, inhibitor or miR-206/miR 613, either as single agents or in combination, could sensitize cisplatin resistant cancer cells to cisplatin treatment and thereby improving the therapeutic efficacy of cisplatin. Taken together, our results suggest that 6PGD serves as a novel potential target to overcome cisplatin resistance. PMID- 28713274 TI - Stimulation of Adenosine A2B Receptor Inhibits Endothelin-1-Induced Cardiac Fibroblast Proliferation and alpha-Smooth Muscle Actin Synthesis Through the cAMP/Epac/PI3K/Akt-Signaling Pathway. AB - Background and Purpose: Cardiac fibrosis is characterized by an increase in fibroblast proliferation, overproduction of extracellular matrix proteins, and the formation of myofibroblast that express alpha-smooth muscle actin (alpha SMA). Endothelin-1 (ET-1) is involved in the pathogenesis of cardiac fibrosis. Overstimulation of endothelin receptors induced cell proliferation, collagen synthesis, and alpha-SMA expression in cardiac fibroblasts. Although adenosine was shown to have cardioprotective effects, the molecular mechanisms by which adenosine A2 receptor inhibit ET-1-induced fibroblast proliferation and alpha-SMA expression in cardiac fibroblasts are not clearly identified. Experimental Approach: This study aimed at evaluating the mechanisms of cardioprotective effects of adenosine receptor agonist in rat cardiac fibroblast by measurement of cell proliferation, and mRNA and protein levels of alpha-SMA. Key results: Stimulation of adenosine subtype 2B (A2B) receptor resulted in the inhibition of ET-1-induced fibroblast proliferation, and a reduction of ET-1-induced alpha-SMA expression that is dependent on cAMP/Epac/PI3K/Akt signaling pathways in cardiac fibroblasts. The data in this study confirm a critical role for Epac signaling on A2B receptor-mediated inhibition of ET-1-induced cardiac fibrosis via PI3K and Akt activation. Conclusion and Implications: This is the first work reporting a novel signaling pathway for the inhibition of ET-1-induced cardiac fibrosis mediated through the A2B receptor. Thus, A2B receptor agonists represent a promising perspective as therapeutic targets for the prevention of cardiac fibrosis. PMID- 28713275 TI - Probiotics Supplementation Therapy for Pathological Neonatal Jaundice: A Systematic Review and Meta-Analysis. AB - Background: Neonatal jaundice is a relatively prevalent disease and affects approximately 2.4-15% newborns. Probiotics supplementation therapy could assist to improve the recovery of neonatal jaundice, through enhancing immunity mainly by regulating bacterial colonies. However, there is limited evidence regarding the effect of probiotics on bilirubin level in neonates. Therefore, this study aims at systematically evaluating the efficacy and safety of probiotics supplement therapy for pathological neonatal jaundice. Methods: Databases including PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), Wan Fang Database (Wan Fang), Chinese Biomedical Literature Database (CBM), VIP Database for Chinese Technical Periodicals (VIP) were searched and the deadline is December 2016. Randomized controlled trials (RCTs) of probiotics supplementation for pathological neonatal jaundice in publications were extracted by two reviewers. The cochrane tool was applied to assessing the risk of bias of the trials. The extracted information of RCTs should include efficacy rate, serum total bilirubin level, time of jaundice fading, duration of phototherapy, duration of hospitalization, adverse reactions. The main outcomes of the trials were analyzed by Review Manager 5.3 software. The relative risks (RR) or mean difference (MD) with a 95% confidence interval (CI) was used to measure the effect. Results: 13 RCTs involving 1067 neonatal with jaundice were included in the meta-analysis. Probiotics supplementation treatment showed efficacy [RR: 1.19, 95% CI (1.12, 1.26), P < 0.00001] in neonatal jaundice. It not only decreased the total serum bilirubin level after 3day [MD: 18.05, 95% CI (-25.51, -10.58), P < 0.00001], 5day [MD: -23.49, 95% CI (-32.80, 14.18), P < 0.00001], 7day [MD: -33.01, 95% CI (-37.31, -28.70), P < 0.00001] treatment, but also decreased time of jaundice fading [MD: -1.91, 95% CI (-2.06, 1.75), P < 0.00001], as well as the duration of phototherapy [MD: -0.64, 95% CI ( 0.84, -0.44), P < 0.00001] and hospitalization [MD: -2.68, 95% CI (-3.18, -2.17), P < 0.00001], when compared with the control group. Additionally, no serious adverse reaction was reported. Conclusion: This meta-analysis shows that probiotics supplementation therapy is an effective and safe treatment for pathological neonatal jaundice. PMID- 28713276 TI - Structure-Activity Relationships of Pentacyclic Triterpenoids as Potent and Selective Inhibitors against Human Carboxylesterase 1. AB - Human carboxylesterase 1 (hCE1), one of the most important serine hydrolases distributed in liver and adipocytes, plays key roles in endobiotic homeostasis and xenobiotic metabolism. This study aimed to find potent and selective inhibitors against hCE1 from phytochemicals and their derivatives. To this end, a series of natural triterpenoids were collected and their inhibitory effects against human carboxylesterases (hCEs) were assayed using D-Luciferin methyl ester (DME) and 6,8-dichloro-9,9-dimethyl-7-oxo-7,9-dihydroacridin-2-yl benzoate (DDAB) as specific optical substrate for hCE1, and hCE2, respectively. Following screening of a series of natural triterpenoids, oleanolic acid (OA), and ursolic acid (UA) were found with strong inhibitory effects on hCE1 and relative high selectivity over hCE2. In order to get the highly selective and potent inhibitors of hCE1, a series of OA and UA derivatives were synthesized from OA and UA by chemical modifications including oxidation, reduction, esterification, and amidation. The inhibitory effects of these derivatives on hCEs were assayed and the structure-activity relationships of tested triterpenoids as hCE1 inhibitors were carefully investigated. The results demonstrated that the carbonyl group at the C-28 site is essential for hCE1 inhibition, the modifications of OA or UA at this site including esters, amides and alcohols are unbeneficial for hCE1 inhibition. In contrast, the structural modifications on OA and UA at other sites, such as converting the C-3 hydroxy group to 3-O-beta-carboxypropionyl (compounds 20 and 22), led to a dramatically increase of the inhibitory effects against hCE1 and very high selectivity over hCE2. 3D-QSAR analysis of all tested triterpenoids including OA and UA derivatives provide new insights into the fine relationships linking between the inhibitory effects on hCE1 and the steric electrostatic properties of triterpenoids. Furthermore, both inhibition kinetic analyses and docking simulations demonstrated that compound 22 was a potent competitive inhibitor against hCE1-mediated DME hydrolysis. All these findings are very helpful for medicinal chemists to design and develop highly selective and more potent hCE1 inhibitors for biomedical applications. PMID- 28713277 TI - Does the Strategy of Risk Group Testing for Hepatitis C Hit the Target? AB - In the European Union, it is estimated that there are 5.5 million individuals with chronic infection of hepatitis C. Intravenous drug abuse is undoubtedly the key source of the hepatitis C epidemic in Europe and the most efficient mode of transmission of HCV infections (primarily due to short incubation time, but also because the virus is introduced directly into the blood stream with the infected needle). Potentially high-risk and vulnerable populations in Europe (and the world) include immigrants, prisoners, sex workers, men having sex with men, individuals infected with HIV, psychoactive substance users etc. Since there is a lack of direct evidence of clinical benefits of HCV testing, decisions related to testing are made based on indirect evidence. Clinical practice has shown that HCV antibody tests are mostly adequate for identification of HCV infection, but the problem is that this testing strategy does not hit the target. As a result of this health care system strategy, a large number of infected patients remain undetected or they are diagnosed late. There is only a vague link between screening and treatment outcomes since there is a lack of evidence on transmission risks, multiple causes, risk behavior, ways of reaching screening decisions, treatment efficiency, etc. According to results of limited number of studies it can be concluded that there is a need to develop targeted programmes for detection of HCV and other infections, but there also a need to decrease potential harms. PMID- 28713278 TI - The Neuroanatomical, Neurophysiological and Psychological Basis of Memory: Current Models and Their Origins. AB - This review aims to classify and clarify, from a neuroanatomical, neurophysiological, and psychological perspective, different memory models that are currently widespread in the literature as well as to describe their origins. We believe it is important to consider previous developments without which one cannot adequately understand the kinds of models that are now current in the scientific literature. This article intends to provide a comprehensive and rigorous overview for understanding and ordering the latest scientific advances related to this subject. The main forms of memory presented include sensory memory, short-term memory, and long-term memory. Information from the world around us is first stored by sensory memory, thus enabling the storage and future use of such information. Short-term memory (or memory) refers to information processed in a short period of time. Long-term memory allows us to store information for long periods of time, including information that can be retrieved consciously (explicit memory) or unconsciously (implicit memory). PMID- 28713280 TI - Editorial: Computational and Experimental Approaches in Multi-target Pharmacology. PMID- 28713279 TI - Antiepileptogenic and Neuroprotective Effects of Pergularia daemia on Pilocarpine Model of Epilepsy. AB - In this study, we investigated antiepileptogenic and neuroprotective effects of the aqueous extract of Pergularia daemia roots (PDR) using in vivo and in vitro experimental models. In in vivo studies, status epilepticus caused by pilocarpine injection triggers epileptogenesis which evolves during about 1-2 weeks. After 2 h of status epilepticus, mice were treated during the epileptogenesis period for 7 days with sodium valproate and vitamin C (standards which demonstrated to alter epileptogenesis), or Pergularia daemia. The animals were then, 1 week after status epilepticus, challenged with acute pentylenetetrazole (PTZ) administration to test behaviorally the susceptibility to a convulsant agent of animals treated or not with the plan extract. Memory was assessed after PTZ administration in the elevated plus maze and T-maze paradigms at 24 and 48 h. Antioxidant and acetylcholinesterase activities were determined in the hippocampus after sacrifice, in vitro studies were conducted using embryonic rat primary cortical cultures exposed to L-glutamate. Cell survival rate was measured and apoptotic and necrotic cell death determined. The results showed that chronic oral administration of PDR significantly and dose-dependently increased the latency to myoclonic jerks, clonic seizures and generalized tonic-clonic seizures, and the seizure score. In addition, PDR at all doses (from 4.9 to 49 mg/kg) significantly decreased the initial and retention transfer latencies in the elevated plus maze. Interestingly PDR at the same doses significantly increased the time spent and the number of entries in T-maze novel arm. PDR significantly increased the activities of acetylcholinesterase and antioxidant enzymes superoxide dismutase, catalase, and total glutathione and proteins, and decreased malondialdehyde level. Furthermore, PDR increased viability rate of primary cortical neurons after L-glutamate-induced excitotoxicity, in a dose dependent manner. Altogether these results suggest that PDR has antiepileptogenic and neuroprotective effects, which could be mediated by antioxidant and antiapoptotic activities. PMID- 28713282 TI - The N-Terminal Region of the Ryanodine Receptor Affects Channel Activation. AB - Mutations in the cardiac ryanodine receptor (RyR2), the ion channel responsible for release of calcium ions from intracellular stores into cytoplasm, are the cause of several inherited cardiac arrhythmias. At the molecular level, disease symptoms can be mimicked by domain peptides from mutation-prone regions of RyR2 that bind to RyR2 and activate it. Here we show that the domain peptide DPcpvtN2, corresponding to the central helix of the N-terminal region of RyR2, activates the RyR2 channel. Structural modeling of interaction between DPcpvtN2 and the N terminal region of RyR2 in the closed and open conformation provided three plausible structures of the complex. Only one of them could explain the dependence of RyR2 activity on concentration of DPcpvtN2. The structure of the complex was at odds with the previously proposed "domain switch" mechanism of competition between domain peptides and ryanodine receptor domains. Likewise, in structural models of the N-terminal region, the conformational changes induced by DPcpvtN2 binding were different from those induced by mutation of central helix amino acids. The activating effect of DPcpvtN2 binding and of mutations in the central helix could be explained by their similar effect on the transition energy between the closed and open conformation of RyR2. PMID- 28713283 TI - Excitatory Modulation of the preBotzinger Complex Inspiratory Rhythm Generating Network by Endogenous Hydrogen Sulfide. AB - Hydrogen Sulfide (H2S) is one of three gasotransmitters that modulate excitability in the CNS. Global application of H2S donors or inhibitors of H2S synthesis to the respiratory network has suggested that inspiratory rhythm is modulated by exogenous and endogenous H2S. However, effects have been variable, which may reflect that the RTN/pFRG (retrotrapezoid nucleus, parafacial respiratory group) and the preBotzinger Complex (preBotC, critical for inspiratory rhythm generation) are differentially modulated by exogenous H2S. Importantly, site-specific modulation of respiratory nuclei by H2S means that targeted, rather than global, manipulation of respiratory nuclei is required to understand the role of H2S signaling in respiratory control. Thus, our aim was to test whether endogenous H2S, which is produced by cystathionine-beta-synthase (CBS) in the CNS, acts specifically within the preBotC to modulate inspiratory activity under basal (in vitro/in vivo) and hypoxic conditions (in vivo). Inhibition of endogenous H2S production by bath application of the CBS inhibitor, aminooxyacetic acid (AOAA, 0.1-1.0 mM) to rhythmic brainstem spinal cord (BSSC) and medullary slice preparations from newborn rats, or local application of AOAA into the preBotC (slices only) caused a dose-dependent decrease in burst frequency. Unilateral injection of AOAA into the preBotC of anesthetized, paralyzed adult rats decreased basal inspiratory burst frequency, amplitude and ventilatory output. AOAA in vivo did not affect the initial hypoxia-induced (10% O2, 5 min) increase in ventilatory output, but enhanced the secondary hypoxic respiratory depression. These data suggest that the preBotC inspiratory network receives tonic excitatory modulation from the CBS-H2S system, and that endogenous H2S attenuates the secondary hypoxic respiratory depression. PMID- 28713281 TI - Effectiveness of Traditional Strength vs. Power Training on Muscle Strength, Power and Speed with Youth: A Systematic Review and Meta-Analysis. AB - Numerous national associations and multiple reviews have documented the safety and efficacy of strength training for children and adolescents. The literature highlights the significant training-induced increases in strength associated with youth strength training. However, the effectiveness of youth strength training programs to improve power measures is not as clear. This discrepancy may be related to training and testing specificity. Most prior youth strength training programs emphasized lower intensity resistance with relatively slow movements. Since power activities typically involve higher intensity, explosive-like contractions with higher angular velocities (e.g., plyometrics), there is a conflict between the training medium and testing measures. This meta-analysis compared strength (e.g., training with resistance or body mass) and power training programs (e.g., plyometric training) on proxies of muscle strength, power, and speed. A systematic literature search using a Boolean Search Strategy was conducted in the electronic databases PubMed, SPORT Discus, Web of Science, and Google Scholar and revealed 652 hits. After perusal of title, abstract, and full text, 107 studies were eligible for inclusion in this systematic review and meta-analysis. The meta-analysis showed small to moderate magnitude changes for training specificity with jump measures. In other words, power training was more effective than strength training for improving youth jump height. For sprint measures, strength training was more effective than power training with youth. Furthermore, strength training exhibited consistently large magnitude changes to lower body strength measures, which contrasted with the generally trivial, small and moderate magnitude training improvements of power training upon lower body strength, sprint and jump measures, respectively. Maturity related inadequacies in eccentric strength and balance might influence the lack of training specificity with the unilateral landings and propulsions associated with sprinting. Based on this meta-analysis, strength training should be incorporated prior to power training in order to establish an adequate foundation of strength for power training activities. PMID- 28713284 TI - Greater Progression of Age-Related Aortic Stiffening in Adults with Poor Trunk Flexibility: A 5-Year Longitudinal Study. AB - Purpose: Having a low level of physical fitness, especially cardiorespiratory fitness, appears to accelerate age-related aortic stiffening. Whereas, some studies have reported that trunk flexibility is a component of physical fitness, it is also negatively associated with arterial stiffening independent of cardiorespiratory fitness in cross-sectional studies. However, no long-term longitudinal study has determined whether poor trunk flexibility accelerates the progression of age-related aortic stiffening. We examined trunk flexibility and aortic stiffness progression in a 5-year longitudinal study. Methods and Results: A total of 305 apparently healthy men and women participated in this study (49.6 +/- 9.5 years of age). Trunk flexibility was measured using a sit-and-reach test. Aortic stiffness was assessed using carotid-femoral pulse wave velocity (cfPWV) at baseline and after 5 years. Analysis of covariance (ANCOVA) was used to assess the association of the annual rate of cfPWV across flexibility levels (low, middle, high). There were no significant differences in baseline cfPWV among the three groups (835 +/- 164, 853 +/- 140, 855 +/- 2.68 cm/s; P = 0.577). Annual DeltacfPWV was significantly higher in the low-flexibility group than in the high flexibility group (P = 0.009). ANCOVA revealed an inverse relationship between flexibility level and annual DeltacfPWV (14.41 +/- 2.73, 9.79 +/- 2.59, 2.62 +/- 2.68 cm/s/year; P for trend = 0.011). Multiple regression analysis revealed that baseline sit and reach (beta = -0.12, -0.70 to -0.01) was independently correlated with DeltacfPWV following adjustment for baseline peak oxygen uptake, age, sex, body fat, heart rate, and cfPWV. The 5-year change in cfPWV was not significantly correlated with 5-year change in sit-and-reach performance (P = 0.859). Conclusion: Poor trunk flexibility is associated with greater progression of age-related aortic stiffening in healthy adults. However, we failed to confirm a significant association between 5-year change in aortic stiffness and 5-year change in trunk flexibility. The association between increased age-related increase in aortic stiffness and deterioration in flexibility due to age may require observation for more than 5 years. PMID- 28713285 TI - Amiloride Improves Endothelial Function and Reduces Vascular Stiffness in Female Mice Fed a Western Diet. AB - Obese premenopausal women lose their sex related cardiovascular disease protection and develop greater arterial stiffening than age matched men. In female mice, we have shown that consumption of a Western diet (WD), high in fat and refined sugars, is associated with endothelial dysfunction and vascular stiffening, which occur via activation of mineralocorticoid receptors and associated increases in epithelial Na+ channel (ENaC) activity on endothelial cells (EnNaC). Herein our aim was to determine the effect that reducing EnNaC activity with a very-low-dose of amiloride would have on decreasing endothelial and arterial stiffness in young female mice consuming a WD. To this end, we fed female mice either a WD or control diet and treated them with or without a very low-dose of the ENaC-inhibitor amiloride (1 mg/kg/day) in the drinking water for 20 weeks beginning at 4 weeks of age. Mice consuming a WD were heavier and had greater percent body fat, proteinuria, and aortic stiffness as assessed by pulse wave velocity than those fed control diet. Treatment with amiloride did not affect body weight, body composition, blood pressure, urinary sodium excretion, or insulin sensitivity, but significantly reduced the development of endothelial and aortic stiffness, aortic fibrosis, aortic oxidative stress, and mesenteric resistance artery EnNaC abundance and proteinuria in WD-fed mice. Amiloride also improved endothelial-dependent vasodilatory responses in the resistance arteries of WD-fed mice. These results indicate that a very-low-dose of amiloride, not affecting blood pressure, is sufficient to improve endothelial function and reduce aortic stiffness in female mice fed a WD, and suggest that EnNaC inhibition may be sufficient to ameliorate the pathological vascular stiffening effects of WD-induced obesity in females. PMID- 28713286 TI - Mechanism of Action for rTMS: A Working Hypothesis Based on Animal Studies. AB - Experiments in rodents have elucidated some of the molecular mechanisms underlying repetitive transcranial magnetic stimulation (rTMS). These studies may be useful in a translational perspective so that future TMS studies in rodents can closely match human TMS protocols designed for therapeutic purposes. In the present work we will review the effects of rTMS on glutamate neurotransmission which in turn induce persistent changes in synaptic activity. In particular, we will focus on the role of NMDA and non-NMDA transmission and on the permissive role of BDNF-TrKB interaction in the rTMS induced after-effects. PMID- 28713288 TI - Commentary: Autonomic Modulation in Patients with Heart Failure Increases Beat-to Beat Variability of Ventricular Action Potential Duration. PMID- 28713287 TI - Vitamin A Affects Flatfish Development in a Thyroid Hormone Signaling and Metamorphic Stage Dependent Manner. AB - Vitamin A (VA) and retinoid derivatives are known morphogens controlling vertebrate development. Despite the research effort conducted during the last decade, the precise mechanism of how VA induces post-natal bone changes, and particularly those operating through crosstalk with the thyroid hormones (THs) remain to be fully understood. Since effects and mechanisms seem to be dose and time-dependent, flatfish are an interesting study model as they undergo a characteristic process of metamorphosis driven by THs that can be followed by external appearance. Here, we studied the effects of VA imbalance that might determine Senegalese sole (Solea senegalensis) skeletogenetic phenotype through development of thyroid follicles, THs homeostasis and signaling when a dietary VA excess was specifically provided during pre-, pro- or post-metamorphic stages using enriched rotifers and Artemia as carriers. The increased VA content in enriched live prey was associated to a higher VA content in fish at all developmental stages. Dietary VA content clearly affected thyroid follicle development, T3 and T4 immunoreactive staining, skeletogenesis and mineralization in a dose and time-dependent fashion. Gene expression analysis showed that VA levels modified the mRNA abundance of VA- and TH-specific nuclear receptors at specific developmental stages. Present results provide new and key knowledge to better understand how VA and TH pathways interact at tissue, cellular and nuclear level at different developmental periods in Senegalese sole, unveiling how dietary modulation might determine juvenile phenotype and physiology. PMID- 28713290 TI - Advanced Maternal Age Worsens Postpartum Vascular Function. AB - The age at which women experience their first pregnancy has increased throughout the decades. Pregnancy has an important influence on maternal short- and long term cardiovascular outcomes. Pregnancy at an advanced maternal age increases maternal risk of gestational diabetes, preeclampsia, placenta previa and caesarian delivery; complications which predict worsened cardiovascular health in later years. Aging also independently increases the risk of cardiovascular disease; therefore, combined risk in women of advanced maternal age may lead to detrimental cardiovascular outcomes later in life. We hypothesized that pregnancy at an advanced maternal age would lead to postpartum vascular dysfunction. We used a reproductively aged rat model to investigate vascular function in never pregnant (virgin), previously pregnant (postpartum) and previously mated but never delivered (nulliparous) rats at approximately 13.5 months of age (3 months postpartum or equivalent). Nulliparous rats, in which pregnancy was spontaneously lost, demonstrated significantly reduced aortic relaxation responses (methylcholine [MCh] Emax: 54.2 +/- 12.6%) vs. virgin and postpartum rats (MCh Emax: 84.8 +/- 3.5% and 84.7 +/- 3.2% respectively); suggesting pregnancy loss causes a worsened vascular pathology. Oxidized LDL reduced relaxation to MCh in aorta from virgin and postpartum, but not nulliparous rats, with an increased contribution of the LOX-1 receptor in the postpartum group. Further, in mesenteric arteries from postpartum rats, endothelium-derived hyperpolarization (EDH)-mediated vasodilation was reduced and a constrictive prostaglandin effect was apparent. In conclusion, aged postpartum rats exhibited vascular dysfunction, while rats which had pregnancy loss demonstrated a distinct vascular pathology. These data demonstrate mechanisms which may lead to worsened outcomes at an advanced maternal age; including early pregnancy loss and later life cardiovascular dysfunction. PMID- 28713291 TI - An Expanding World of Novel Psychoactive Substances: Opioids. AB - The abuse of novel psychoactive substances (NPS) has been increasing dramatically worldwide since late 2000s. By the end of 2015, more than 560 NPS had been reported to the European Monitoring Centre for Drugs and Drug Addiction. Although the most popular compounds are synthetic cannabinoids and psychostimulatory derivatives of cathinone (so-called beta-keto-amphetamines), novel synthetic opioids have recently emerged on the recreational drug market. They include fentanyl (a potent narcotic analgesic) and its analogs (e.g., acetylfentanyl, acryloylfentanyl, carfentanil, alpha-methylfentanyl, 3-methylfentanyl, furanylfentanyl, 4-fluorobutyrylfentanyl, 4-methoxybutyrylfentanyl, 4 chloroisobutyrylfentanyl, 4-fluoroisobutyrylfentanyl, tetrahydrofuranylfentanyl, cyclopentylfentanyl, and ocfentanil) and compounds with different chemical structures, such as AH-7921, MT-45, and U-47700. This survey provides an overview of the pharmacological properties, pattern of use, and desired and unwanted effects of the above-listed novel opioids. Special emphasis is given to cases of non-fatal and lethal intoxication involving these compounds. PMID- 28713289 TI - Mitochondrial VDAC1: A Key Gatekeeper as Potential Therapeutic Target. AB - Mitochondria are the key source of ATP that fuels cellular functions, and they are also central in cellular signaling, cell division and apoptosis. Dysfunction of mitochondria has been implicated in a wide range of diseases, including neurodegenerative and cardiac diseases, and various types of cancer. One of the key proteins that regulate mitochondrial function is the voltage-dependent anion channel 1 (VDAC1), the most abundant protein on the outer membrane of mitochondria. VDAC1 is the gatekeeper for the passages of metabolites, nucleotides, and ions; it plays a crucial role in regulating apoptosis due to its interaction with apoptotic and anti-apoptotic proteins, namely members of the Bcl 2 family of proteins and hexokinase. Therefore, regulation of VDAC1 is crucial not only for metabolic functions of mitochondria, but also for cell survival. In fact, multiple lines of evidence have confirmed the involvement of VDAC1 in several diseases. Consequently, modulation or dysregulation of VDAC1 function can potentially attenuate or exacerbate pathophysiological conditions. Understanding the role of VDAC1 in health and disease could lead to selective protection of cells in different tissues and diverse diseases. The purpose of this review is to discuss the role of VDAC1 in the pathogenesis of diseases and as a potentially effective target for therapeutic management of various pathologies. PMID- 28713292 TI - Cognitive Attachment Model of Voices: Evidence Base and Future Implications. AB - There is a robust association between hearing voices and exposure to traumatic events. Identifying mediating mechanisms for this relationship is key to theories of voice hearing and the development of therapies for distressing voices. This paper outlines the Cognitive Attachment model of Voices (CAV), a theoretical model to understand the relationship between earlier interpersonal trauma and distressing voice hearing. The model builds on attachment theory and well established cognitive models of voices and argues that attachment and dissociative processes are key psychological mechanisms that explain how trauma influences voice hearing. Following the presentation of the model, the paper will review the current state of evidence regarding the proposed mechanisms of vulnerability to voice hearing and maintenance of voice-related distress. This review will include evidence from studies supporting associations between dissociation and voices, followed by details of our own research supporting the role of dissociation in mediating the relationship between trauma and voices and evidence supporting the role of adult attachment in influencing beliefs and relationships that voice hearers can develop with voices. The paper concludes by outlining the key questions that future research needs to address to fully test the model and the clinical implications that arise from the work. PMID- 28713293 TI - Predicting Future High-Cost Schizophrenia Patients Using High-Dimensional Administrative Data. AB - BACKGROUND: The burden of serious and persistent mental illness such as schizophrenia is substantial and requires health-care organizations to have adequate risk adjustment models to effectively allocate their resources to managing patients who are at the greatest risk. Currently available models underestimate health-care costs for those with mental or behavioral health conditions. OBJECTIVES: The study aimed to develop and evaluate predictive models for identification of future high-cost schizophrenia patients using advanced supervised machine learning methods. METHODS: This was a retrospective study using a payer administrative database. The study cohort consisted of 97,862 patients diagnosed with schizophrenia (ICD9 code 295.*) from January 2009 to June 2014. Training (n = 34,510) and study evaluation (n = 30,077) cohorts were derived based on 12-month observation and prediction windows (PWs). The target was average total cost/patient/month in the PW. Three models (baseline, intermediate, final) were developed to assess the value of different variable categories for cost prediction (demographics, coverage, cost, health-care utilization, antipsychotic medication usage, and clinical conditions). Scalable orthogonal regression, significant attribute selection in high dimensions method, and random forests regression were used to develop the models. The trained models were assessed in the evaluation cohort using the regression R2, patient classification accuracy (PCA), and cost accuracy (CA). The model performance was compared to the Centers for Medicare & Medicaid Services Hierarchical Condition Categories (CMS-HCC) model. RESULTS: At top 10% cost cutoff, the final model achieved 0.23 R2, 43% PCA, and 63% CA; in contrast, the CMS-HCC model achieved 0.09 R2, 27% PCA with 45% CA. The final model and the CMS-HCC model identified 33 and 22%, respectively, of total cost at the top 10% cost cutoff. CONCLUSION: Using advanced feature selection leveraging detailed health care, medication utilization features, and supervised machine learning methods improved the ability to predict and identify future high-cost patients with schizophrenia when compared with the CMS-HCC model. PMID- 28713294 TI - Screening for Adult Attention-Deficit/Hyperactivity Disorder in a Psychiatric Outpatient Population with Specific Focus on Sex Differences. AB - BACKGROUND/AIMS: Attention-deficit/hyperactivity disorder (ADHD) is often overlooked in adults; moreover, the problem seems to be even more critical in women. In the present, observational screening study, a clinical, particularly adult outpatient population was examined regarding frequency and severity of a likely ADHD, whereby sex differences were of particular interest. METHODS: 224 participants, 146 men and 78 women, were included. Based on data recorded with the self-rating WHO screening instrument Adult ADHD Self-Report Scale (ASRS v1.1), it was examined how many participants were conspicuous for adult ADHD by exceeding a predefined cutoff value (COV) (COV >= 4 for ASRS-6, and >=12 for ASRS 18). To examine frequency distributions, chi2 tests were conducted. For the inferential statistical comparison of means, t-tests for independent samples or Mann-Whitney U tests were calculated. RESULTS: 34.4% of the sample was screened positive in the ASRS-v1.1 screener short version, ASRS-6, while 17.4% were conspicuous in the symptom checklist, ASRS-18. There were indeed more men screened positive, but the difference in the frequency between the sexes was not statistically significant, indicating a balanced sex ratio. Further, severity of ADHD core symptoms inattention and hyperactivity/impulsivity was examined by comparing ASRS-18 symptom subscale scores. In concordance with the hypothesis, men and women did not differ in severity of symptoms. CONCLUSION: Results indicate that women might be affected by ADHD in a comparable manner as men; this emphasizes the importance for the awareness of ADHD in both sexes in clinical practice. PMID- 28713295 TI - Women's Reasons for Leaving the Engineering Field. AB - Among the different Science, Technology, Engineering, and Math fields, engineering continues to have one of the highest rates of attrition (Hewlett et al., 2008). The turnover rate for women engineers from engineering fields is even higher than for men (Frehill, 2010). Despite increased efforts from researchers, there are still large gaps in our understanding of the reasons that women leave engineering. This study aims to address this gap by examining the reasons why women leave engineering. Specifically, we analyze the reasons for departure given by national sample of 1,464 women engineers who left the profession after having worked in the engineering field. We applied a person-environment fit theoretical lens, in particular, the Theory of Work Adjustment (TWA) (Dawis and Lofquist, 1984) to understand and categorize the reasons for leaving the engineering field. According to the TWA, occupations have different "reinforcer patterns," reflected in six occupational values, and a mismatch between the reinforcers provided by the work environment and individuals' needs may trigger departure from the environment. Given the paucity of literature in this area, we posed research questions to explore the reinforcer pattern of values implicated in women's decisions to leave the engineering field. We used qualitative analyses to understand, categorize, and code the 1,863 statements that offered a glimpse into the myriad reasons that women offered in describing their decisions to leave the engineering profession. Our results revealed the top three sets of reasons underlying women's decision to leave the jobs and engineering field were related to: first, poor and/or inequitable compensation, poor working conditions, inflexible and demanding work environment that made work-family balance difficult; second, unmet achievement needs that reflected a dissatisfaction with effective utilization of their math and science skills, and third, unmet needs with regard to lack of recognition at work and adequate opportunities for advancement. Implications of these results for future research as well as the design of effective intervention programs aimed at women engineers' retention and engagement in engineering are discussed. PMID- 28713296 TI - Affective and Engagement Issues in the Conception and Assessment of a Robot Assisted Psychomotor Therapy for Persons with Dementia. AB - The interest in robot-assisted therapies (RAT) for dementia care has grown steadily in recent years. However, RAT using humanoid robots is still a novel practice for which the adhesion mechanisms, indications and benefits remain unclear. Also, little is known about how the robot's behavioral and affective style might promote engagement of persons with dementia (PwD) in RAT. The present study sought to investigate the use of a humanoid robot in a psychomotor therapy for PwD. We examined the robot's potential to engage participants in the intervention and its effect on their emotional state. A brief psychomotor therapy program involving the robot as the therapist's assistant was created. For this purpose, a corpus of social and physical behaviors for the robot and a "control software" for customizing the program and operating the robot were also designed. Particular attention was given to components of the RAT that could promote participant's engagement (robot's interaction style, personalization of contents). In the pilot assessment of the intervention nine PwD (7 women and 2 men, M age = 86 y/o) hospitalized in a geriatrics unit participated in four individual therapy sessions: one classic therapy (CT) session (patient- therapist) and three RAT sessions (patient-therapist-robot). Outcome criteria for the evaluation of the intervention included: participant's engagement, emotional state and well-being; satisfaction of the intervention, appreciation of the robot, and empathy-related behaviors in human-robot interaction (HRI). Results showed a high constructive engagement in both CT and RAT sessions. More positive emotional responses in participants were observed in RAT compared to CT. RAT sessions were better appreciated than CT sessions. The use of a social robot as a mediating tool appeared to promote the involvement of PwD in the therapeutic intervention increasing their immediate wellbeing and satisfaction. PMID- 28713297 TI - A Multiple Identity Approach to Gender: Identification with Women, Identification with Feminists, and Their Interaction. AB - Across four studies, we examine multiple identities in the context of gender and propose that women's attitudes toward gender group membership are governed by two largely orthogonal dimensions of gender identity: identification with women and identification with feminists. We argue that identification with women reflects attitudes toward the content society gives to group membership: what does it mean to be a woman in terms of group characteristics, interests and values? Identification with feminists, on the other hand, is a politicized identity dimension reflecting attitudes toward the social position of the group: what does it mean to be a woman in terms of disadvantage, inequality, and relative status? We examine the utility of this multiple identity approach in four studies. Study 1 showed that identification with women reflects attitudes toward group characteristics, such as femininity and self-stereotyping, while identification with feminists reflects attitudes toward the group's social position, such as perceived sexism. The two dimensions are shown to be largely independent, and as such provide support for the multiple identity approach. In Studies 2-4, we examine the utility of this multiple identity approach in predicting qualitative differences in gender attitudes. Results show that specific combinations of identification with women and feminists predicted attitudes toward collective action and gender stereotypes. Higher identification with feminists led to endorsement of radical collective action (Study 2) and critical attitudes toward gender stereotypes (Studies 3-4), especially at lower levels of identification with women. The different combinations of high vs. low identification with women and feminists can be thought of as reflecting four theoretical identity "types." A woman can be (1) strongly identified with neither women nor feminists ("low identifier"), (2) strongly identified with women but less so with feminists ("traditional identifier"), (3) strongly identified with both women and feminists ("dual identifier"), or (4) strongly identified with feminists but less so with women ("distinctive feminist"). In sum, by considering identification with women and identification with feminists as multiple identities we aim to show how the multiple identity approach predicts distinct attitudes to gender issues and offer a new perspective on gender identity. PMID- 28713298 TI - Linear Relationship between Resilience, Learning Approaches, and Coping Strategies to Predict Achievement in Undergraduate Students. AB - The aim of the present research was to analyze the linear relationship between resilience (meta-motivational variable), learning approaches (meta-cognitive variables), strategies for coping with academic stress (meta-emotional variable) and academic achievement, necessary in the context of university academic stress. A total of 656 students from a southern university in Spain completed different questionnaires: a resiliency scale, a coping strategies scale, and a study process questionnaire. Correlations and structural modeling were used for data analyses. There was a positive and significant linear association showing a relationship of association and prediction of resilience to the deep learning approach, and problem-centered coping strategies. In a complementary way, these variables positively and significantly predicted the academic achievement of university students. These results enabled a linear relationship of association and consistent and differential prediction to be established among the variables studied. Implications for future research are set out. PMID- 28713299 TI - Effects of Direct Instruction and Strategy Modeling on Upper-Primary Students' Writing Development. AB - Strategy-focused instruction is one of the most effective approaches to improve writing skills. It aims to teach developing writers strategies that give them executive control over their writing processes. Programs under this kind of instruction tend to have multiple components that include direct instruction, modeling and scaffolded practice. This multi-component nature has two drawbacks: it makes implementation challenging due to the amount of time and training required to perform each stage, and it is difficult to determine the underlying mechanisms that contribute to its effectiveness. To unpack why strategy-focused instruction is effective, we explored the specific effects of two key components: direct teaching of writing strategies and modeling of strategy use. Six classes (133 students) of upper-primary education were randomly assigned to one of the two experimental conditions, in which students received instruction aimed at developing effective strategies for planning and drafting, or control group with no strategy instruction: Direct Instruction (N = 46), Modeling (N = 45), and Control (N = 42). Writing performance was assessed before the intervention and immediately after the intervention with two tasks, one collaborative and the other one individual to explore whether differential effects resulted from students writing alone or in pairs. Writing performance was assessed through reader-based and text-based measures of text quality. Results at post-test showed similar improvement in both intervention conditions, relatively to controls, in all measures and in both the collaborative and the individual task. No statistically significant differences were observed between experimental conditions. These findings suggest that both components, direct teaching and modeling, are equally effective in improving writing skills in upper primary students, and these effects are present even after a short training. PMID- 28713300 TI - New Technologies Smart, or Harm Work-Family Boundaries Management? Gender Differences in Conflict and Enrichment Using the JD-R Theory. AB - Background: The relationship between technology-assisted supplemental work and well-being outcomes is a recent issue in scientific literature. Whether the use of technology for work purpose in off-work time may have a positive or negative impact on work-family balance remains an open question and the role of gender in this relationship is poorly understood. Aim: According to the JD-R theory, this study aimed to investigate the relationship between off-work hours technology assisted job demand (off-TAJD) and both work-family conflict (WFC) and work family enrichment (WFE). Moreover, it considered two general job demands, workload and emotional dissonance, and one job resource, supervisory coaching. Method: The hypotheses were tested with a convenience sample of 671 workers. Data were collected with a self-report questionnaire and analyzed with SPSS 23 and through multi-group structural equation model (SEM) (Mplus 7). Results: The estimated SEM [Chi-square (510) = 1041.29; p < 0.01; CFI = 0.95; TLI = 0.95; RMSEA = 0.06 (0.05, 0.06); SRMR = 0.05. M = 319/F = 352] showed that off-TAJD was positively related to WFC in both subsamples; off-TAJD was positively related also to WFE only in the Male group. Workload was positively related to WFC in both Male and Female subsamples. Emotional dissonance was positively related to WFC in both subsamples and was negatively related to WFE. Supervisory coaching was strongly, positively related to WFE in both groups, and only in the Male subsample presented a low negative relationship with WFC. Conclusion: This study contributes to the literature on new challenges in work-life interface by analyzing the association between off-TAJD and WFC and Enrichment. Our findings suggest it is important to pay attention to gender differences in the study of the impact of supplemental work carried out during off-work hours using technology on the work-life interface. In fact, employee perception of Company demands of being available during off-work time, with the use of technology, may have different consequences for men and women, indicating potential differences in the centrality of the working role. Practical implications, at both cultural and organizational levels, should address the use of technology during leisure time. PMID- 28713301 TI - Understanding the Impact of Expertise in Joint and Solo-Improvisation. AB - Joint-improvisation is not only an open-ended creative action that two or more people perform together in the context of an artistic performance (e.g., theatre, music or dance). Joint-improvisation also takes place in daily life activities when humans take part in collective performance such as toddlers at play or adults engaged in a conversation. In the context of this article, joint improvisation has been looked at from a social motor coordination perspective. In the literature, the nature of the social motor coordination characteristics of joint-improvisation for either the creative aspect or daily life features of this motor performance remains unclear. Additionally, both solo-improvisation and joint-improvisation need to be studied conjointly to establish the influence of the social element of improvisation in the emergence of multi-agent motor coordination. In order to better understand those two types of improvisation, we compared three level of expertise - novice, intermediate and professional in dance improvisation to identify movement characteristics for each of the groups. Pairs of the same level were asked to improvise together. Each individual was also asked to perform an improvisation on his/her own. We found that each of the three groups present specific movement organization with movement complexity increasing with the level of expertise. Experts performed shorter movement duration in conjunction with an increase range of movement. The direct comparison of individual and paired Conditions highlighted that the joint-improvisation reduced the complexity of the movement organization and those for all three levels while maintaining the differences between the groups. This direct comparison amongst those three distinct groups provides an original insight onto the nature of movement patterns in joint-improvisation situation. Overall, it reveals the role of both individual and collective properties in the emergence of social coordination. PMID- 28713302 TI - Evaluating the Effect of Labeled Benchmarks on Children's Number Line Estimation Performance and Strategy Use. AB - Some authors argue that age-related improvements in number line estimation (NLE) performance result from changes in strategy use. More specifically, children's strategy use develops from only using the origin of the number line, to using the origin and the endpoint, to eventually also relying on the midpoint of the number line. Recently, Peeters et al. (unpublished) investigated whether the provision of additional unlabeled benchmarks at 25, 50, and 75% of the number line, positively affects third and fifth graders' NLE performance and benchmark-based strategy use. It was found that only the older children benefitted from the presence of these benchmarks at the quartiles of the number line (i.e., 25 and 75%), as they made more use of these benchmarks, leading to more accurate estimates. A possible explanation for this lack of improvement in third graders might be their inability to correctly link the presented benchmarks with their corresponding numerical values. In the present study, we investigated whether labeling these benchmarks with their corresponding numerical values, would have a positive effect on younger children's NLE performance and quartile-based strategy use as well. Third and sixth graders were assigned to one of three conditions: (a) a control condition with an empty number line bounded by 0 at the origin and 1,000 at the endpoint, (b) an unlabeled condition with three additional external benchmarks without numerical labels at 25, 50, and 75% of the number line, and (c) a labeled condition in which these benchmarks were labeled with 250, 500, and 750, respectively. Results indicated that labeling the benchmarks has a positive effect on third graders' NLE performance and quartile-based strategy use, whereas sixth graders already benefited from the mere provision of unlabeled benchmarks. These findings imply that children's benchmark-based strategy use can be stimulated by adding additional externally provided benchmarks on the number line, but that, depending on children's age and familiarity with the number range, these additional external benchmarks might need to be labeled. PMID- 28713303 TI - Investigating Thematic Roles through Implicit Learning: Evidence from Light Verb Constructions. AB - The syntactic structure of a sentence is usually a strong predictor of its meaning: Each argument noun phrase (i.e., Subject and Object) should map onto exactly one thematic role (i.e., Agent and Patient, respectively). Some constructions, however, are exceptions to this pattern. This paper investigates how the syntactic structure of an utterance contributes to its construal, using ditransitive English light verb constructions, such as "Nils gave a hug to his brother," as an example of such mismatches: Hugging is a two-role event, but the ditransitive syntactic structure suggests a three-role event. Data from an eye tracking experiment and behavioral categorization data reveal that listeners learn to categorize sentences according to the number of thematic roles they convey, independent of their syntax. Light verb constructions, however, seem to form a category of their own, in which the syntactic structure leads listeners down an initial incorrect assignment of thematic roles, from which they only partly recover. These results suggest an automatic influence of syntactic argument structure on semantic interpretation and event construal, even in highly frequent constructions. PMID- 28713304 TI - Eye Behavior Associated with Internally versus Externally Directed Cognition. AB - What do our eyes do when we are focused on internal representations such as during imagination or planning? Evidence from mind wandering research suggests that spontaneous shifts from externally directed cognition (EDC) to internally directed cognition (IDC) involves oculomotor changes indicative of visual disengagement. In the present study, we investigated potential differences in eye behavior between goal-directed forms of IDC and EDC. To this end, we manipulated the focus of attention (internal versus external) in two demanding cognitive tasks (anagram and sentence generation). IDC was associated with fewer and longer fixations and higher variability in pupil diameter and eye vergence compared to EDC, suggesting reduced visual scanning and higher spontaneous eye activity. IDC was further related to longer blinks, lower microsaccade frequency, and a lower angle of eye vergence. These latter changes appear conducive to attenuate visual input and thereby shield ongoing internal processes from external distraction. Together, these findings suggest that IDC is accompanied by characteristic eye behavior that reflects a decoupling of attention from external events and serves gating out visual input. PMID- 28713305 TI - Sequential Modulations in a Combined Horizontal and Vertical Simon Task: Is There ERP Evidence for Feature Integration Effects? AB - In the Simon task, participants respond faster when the task-irrelevant stimulus position and the response position are corresponding, for example on the same side, compared to when they have a non-corresponding relation. Interestingly, this Simon effect is reduced after non-corresponding trials. Such sequential effects can be explained in terms of a more focused processing of the relevant stimulus dimension due to increased cognitive control, which transfers from the previous non-corresponding trial (conflict adaptation effects). Alternatively, sequential modulations of the Simon effect can also be due to the degree of trial to-trial repetitions and alternations of task features, which is confounded with the correspondence sequence (feature integration effects). In the present study, we used a spatially two-dimensional Simon task with vertical response keys to examine the contribution of adaptive cognitive control and feature integration processes to the sequential modulation of the Simon effect. The two-dimensional Simon task creates correspondences in the vertical as well as in the horizontal dimension. A trial-by-trial alternation of the spatial dimension, for example from a vertical to a horizontal stimulus presentation, generates a subset containing no complete repetitions of task features, but only complete alternations and partial repetitions, which are equally distributed over all correspondence sequences. In line with the assumed feature integration effects, we found sequential modulations of the Simon effect only when the spatial dimension repeated. At least for the horizontal dimension, this pattern was confirmed by the parietal P3b, an event-related potential that is assumed to reflect stimulus-response link processes. Contrary to conflict adaptation effects, cognitive control, measured by the fronto-central N2 component of the EEG, was not sequentially modulated. Overall, our data provide behavioral as well as electrophysiological evidence for feature integration effects contributing to sequential modulations of the Simon effect. PMID- 28713306 TI - Parenting with PTSD: A Review of Research on the Influence of PTSD on Parent Child Functioning in Military and Veteran Families. AB - Posttraumatic stress disorder (PTSD) is strongly associated with exposure to war related trauma in military and veteran populations. In growing recognition that PTSD may influence and be influenced by social support and family systems, research has begun to explore the effects that war related trauma and the ensuing PTSD may have on varied aspects of close relationship and family functioning. Far less research, however, has examined the influence of war-related PTSD on parent child functioning in this population. This paper provides a timely review of emergent literature to examine the impacts that PTSD may have on parenting behaviors and children's outcomes with a focus on studies of military and veterans of international conflicts since post-9/11. The review sheds light on the pathways through which PTSD may impact parent-child relationships, and proposes the cognitive-behavioral interpersonal theory of PTSD as a theoretical formulation and extends this to parenting/children. The review identifies the strengths and limitations in the extant research and proposes directions for future research and methodological practice to better capture the complex interplay of PTSD and parenting in military and veteran families. PMID- 28713307 TI - Posttraumatic Growth and Dyadic Adjustment among War Veterans and their Wives. AB - The controversy regarding the nature of posttraumatic growth includes two main competing claims: one which argues that posttraumatic growth reflects authentic positive changes and the other which argues that posttraumatic growth reflects illusory defenses. While the former might suggest that posttraumatic growth enhances intimacy and close relationships, the latter might imply that posttraumatic growth hinders interpersonal relations. The present study aimed to test these claims by investigating the association between posttraumatic growth and dyadic adjustment over time at both the individual and dyadic levels, and the potential role of posttraumatic stress symptoms. Former prisoners of war and comparable war veterans and their wives (n = 229) were assessed twice, 30-31 (T1) and 35-38 (T2) years after the 1973 Yom Kippur War in Israel, with regard to posttraumatic growth, posttraumatic stress symptoms and dyadic adjustment. Results indicated that posttraumatic growth was associated with both elevated posttraumatic stress symptoms and low dyadic adjustment among both husbands and wives. Posttraumatic stress symptoms at T1 and T2 mediated the association between posttraumatic growth and dyadic adjustment. Wives' posttraumatic growth at T1 predicted posttraumatic growth and dyadic adjustment of the husbands at T2. The higher the wives' posttraumatic growth, the higher the posttraumatic growth and the lower the dyadic adjustment of the husbands in the subsequent measure. The findings suggest that posttraumatic growth reflects defensive beliefs which undermine marital relationships and that posttraumatic growth might be transmitted between spouses and implicated in the deterioration of the marital relationship over time. PMID- 28713308 TI - Predictive Relation between Early Numerical Competencies and Mathematics Achievement in First Grade Portuguese Children. AB - Early numerical competencies (ENC) (counting, number relations, and basic arithmetic operations) have a central position in the initial learning of mathematics, and their assessment is useful for predicting later mathematics achievement. Using a regression model, this study aims to analyze the correlational and predictive evidence between ENC and mathematics achievement in first grade Portuguese children (n = 123). The children's ENC were examined at the point of school entry. Three criterion groups (low, moderate, and high ENC) were formed based on the results of the early numerical brief screener and mathematics achievement measured at the end of first grade. The following hypotheses were tested: children who started first grade with low numerical competencies remained low mathematics achievement at the end of first grade; and children who started with high numerical competencies, finished the first grade with high mathematics achievement. The results showed that ENC contributed to a significant amount of explained variance in mathematics achievement at the end of the first grade. Children with low numerical competencies performed lower than children with moderate and high numerical competencies. Findings suggest that ENC are meaningful for predicting first-grade mathematics difficulties. PMID- 28713309 TI - Associations among Different Internet Access Time, Gender and Cyberbullying Behaviors in Taiwan's Adolescents. AB - With the increasing convenience of social networking sites and their interconnectedness with human interaction, verbal and image bullying have turned digital, making cyberbullying a new form of bullying attracting the attention of researchers, social workers, and schools. This study focuses on the status quo of attitude toward cyberbullying and cyberbullying behavior, explores associations of attitude toward behavior on cyberbullying behavior in gender and different internet access times. In a cross-sectional survey, adolescents were surveyed through self-report questionnaires, 13,864 respondents were received among 150 high schools in Taiwan. Statistical analyses were performed using structural equation modeling (SEM). The study revealed that attitude toward cyberbullying has a direct effect on cyberbullying behavior; among the greatest direct impact were when students use the Internet during the time frame 10:00-14:00. Parents and schoolteachers pay special attention to students using the Internet during this time frame 10:00-14:00 and give guidance, express care, and help those being bullied to communicate and use the Internet in a correct manner. Among genders, male student attitude toward behavior has a greater effect than those of female students. Both male and female students know what cyberbullying is and have witnessed, heard of, or personally encountered cyberbullying behavior. We recommend students talk to parents or teachers or other people who care to reduce the negative effects of cyberbullying. We hopeful that the conceptualization model presented in this study serves as an activator for researches on attitude toward cyberbullying and cyberbullying behavior, and serves a guide and a call to attract more researches in this area. PMID- 28713310 TI - An Examination of the Four-Part Theory of the Chinese Self: The Differentiation and Relative Importance of the Different Types of Social-Oriented Self. AB - Because culture has a deep and far-reaching influence, individuals who grew up within different cultures tend to develop different basic self-constructions. With respect to the Chinese under the influence of Chinese culture, Yang proposed the concepts of individual-oriented self and social-oriented self. He argued that, besides the individual-oriented self, the social-oriented self of the Chinese contains three types of self: the relationship-oriented self, the familistic (group)-oriented self, and the other-oriented self. The theory proposed that the Chinese self is appropriately covered only through this four part theory of the Chinese self. However, this remains to be tested; whether these three types of sub-level "selves" can be effectively triggered, along with their relative importance. This study examines the four-part theory of the Chinese self. Through photo priming, Experiment 1 shows that the three types of social-oriented self are differentiated from each other and can be individually triggered. In Experiment 2, the importance of the three types of self was investigated, adopting the concept of limited self-regulation resources to design scenarios. The participants were asked to make counterarguments about the notion of each of the three types of self, with performance in the subsequent task serving as the main dependent variable. In Experiment 3, the relative importance of the three types of self was examined by investigating the choices made by individuals within the context of conflict under the three orientations of the social-oriented self. Overall, results of the experiments showed that the Chinese have a four-part self with the importance of the other-oriented self as the most remarkable. PMID- 28713311 TI - Validation of Spanish Language Evaluation Instruments for Body Dysmorphic Disorder and the Dysmorphic Concern Construct. AB - Dysmorphic concern (DC) refers to excessive preoccupation with a slight or imagined defect in physical appearance with social avoidance and behavior directed at controlling the defect in appearance. This study attempted to adapt the factor structure of two instruments that cover the DC construct, the Dysmorphic Concern Questionnaire (DCQ) and the Body Dysmorphic Disorder Examination Self-Report (BDDE-SR), to Spanish and establish their psychometric properties. A total of 920 subjects (62.7% women, Mage = 32.44 years) participated. Exploratory and Confirmatory Factor Analysis of both scales found adequate goodness of fit indices. A one-dimensional structure was found for the DCQ and two first-order factors (dissatisfaction/preoccupation with body image (BI) and BI avoidance behavior) were identified for the BDDE-SR. The psychometric test-retest reliability and validity properties (content, convergent, and discriminant) were satisfactory. It is suggested that the DC construct includes both cognitive and behavioral aspects and may represent a continuum of severity with Body Dysmorphic Disorder at the end. PMID- 28713312 TI - Neural Temporal Dynamics of Facial Emotion Processing: Age Effects and Relationship to Cognitive Function. AB - This study used event-related potentials (ERPs) to investigate the effects of age on neural temporal dynamics of processing task-relevant facial expressions and their relationship to cognitive functions. Negative (sad, afraid, angry, and disgusted), positive (happy), and neutral faces were presented to 30 older and 31 young participants who performed a facial emotion categorization task. Behavioral and ERP indices of facial emotion processing were analyzed. An enhanced N170 for negative faces, in addition to intact right-hemispheric N170 for positive faces, was observed in older adults relative to their younger counterparts. Moreover, older adults demonstrated an attenuated within-group N170 laterality effect for neutral faces, while younger adults showed the opposite pattern. Furthermore, older adults exhibited sustained temporo-occipital negativity deflection over the time range of 200-500 ms post-stimulus, while young adults showed posterior positivity and subsequent emotion-specific frontal negativity deflections. In older adults, decreased accuracy for labeling negative faces was positively correlated with Montreal Cognitive Assessment Scores, and accuracy for labeling neutral faces was negatively correlated with age. These findings suggest that older people may exert more effort in structural encoding for negative faces and there are different response patterns for the categorization of different facial emotions. Cognitive functioning may be related to facial emotion categorization deficits observed in older adults. This may not be attributable to positivity effects: it may represent a selective deficit for the processing of negative facial expressions in older adults. PMID- 28713314 TI - When Advisors' True Intentions Are in Question. How Do Bank Customers Cope with Uncertainty in Financial Consultancies? AB - When making financial decisions bank customers are confronted with two types of uncertainty: first, return on investments is uncertain and there is a risk of losing money. Second, customers cannot be certain about their financial advisor's true intentions. This might decrease customers' willingness to cooperate with advisors. However, the uncertainty management model and fairness heuristic theory predict that in uncertain situations customers are willing to cooperate with financial advisors when they perceive fairness. In the current study, we investigated how perceived fairness in the twofold uncertain situations increased people's intended future cooperation with an advisor. We asked customers of financial consultancies about their experienced uncertainty regarding both the investment decision and the advisor's intentions. Moreover, we asked them about their perceived fairness, as well as their intention to cooperate with the advisor in the future. A three-way moderation analysis showed that customers who faced high uncertainty regarding the investment decision and high uncertainty regarding the advisor's true intentions indicated the lowest intended cooperation with the advisor but high fairness increased their cooperation. Interestingly, when people were only uncertain about the advisor's intentions (but certain about the decision) they indicated less cooperation than when they were only uncertain about the decision (but certain about the advisor's intentions). A mediated moderation analysis revealed that this relationship was explained by customers' lower trust in their advisors. PMID- 28713313 TI - The Burden of Binge and Heavy Drinking on the Brain: Effects on Adolescent and Young Adult Neural Structure and Function. AB - Introduction: Adolescence and young adulthood are periods of continued biological and psychosocial maturation. Thus, there may be deleterious effects of consuming large quantities of alcohol on neural development and associated cognition during this time. The purpose of this mini review is to highlight neuroimaging research that has specifically examined the effects of binge and heavy drinking on adolescent and young adult brain structure and function. Methods: We review cross sectional and longitudinal studies of young binge and heavy drinkers that have examined brain structure (e.g., gray and white matter volume, cortical thickness, white matter microstructure) and investigated brain response using functional magnetic resonance imaging (fMRI). Results: Binge and heavy-drinking adolescents and young adults have systematically thinner and lower volume in prefrontal cortex and cerebellar regions, and attenuated white matter development. They also show elevated brain activity in fronto-parietal regions during working memory, verbal learning, and inhibitory control tasks. In response to alcohol cues, relative to controls or light-drinking individuals, binge and heavy drinkers show increased neural response mainly in mesocorticolimbic regions, including the striatum, anterior cingulate cortex (ACC), hippocampus, and amygdala. Mixed findings are present in risky decision-making tasks, which could be due to large variation in task design and analysis. Conclusions: These findings suggest altered neural structure and activity in binge and heavy-drinking youth may be related to the neurotoxic effects of consuming alcohol in large quantities during a highly plastic neurodevelopmental period, which could result in neural reorganization, and increased risk for developing an alcohol use disorder (AUD). PMID- 28713315 TI - The Moderating Effect of Psychological Contract Violation on the Relationship between Narcissism and Outcomes: An Application of Trait Activation Theory. AB - We use trait activation and psychological contracts theories to build the argument that narcissism is a personality trait that will manifest itself in the form of exit and neglect when employees experience psychological contract violation. To test our hypotheses, we surveyed 262 employees from a wide array of industries working in different organizations at two points in time. Our results indicate that violation moderated the relationship between narcissism and exit such that narcissistic employees who experienced high levels of violation had higher levels of exit. However, we did not find support for our prediction regarding neglect. The findings suggest that the importance of narcissism at work may be contingent on the situation. Our study contributes to research on narcissism in the workplace, trait activation theory, and the role that individual differences play in shaping employee responses to psychological contract violation. PMID- 28713316 TI - Leader Humility and Team Innovation: Investigating the Substituting Role of Task Interdependence and the Mediating Role of Team Voice Climate. AB - Leadership has been found to be linked with team innovation. Based on social information processing theory and substitutes for leadership theory, this paper examines the influence of leader humility on team innovation. Results from 90 teams showed that leader humility will enhance team innovation by fostering team voice climate. Further, task interdependence substitutes the effect of leader humility on team innovation through an indirect way via team voice climate. This study discussed the theoretical and practical implementations of these observations. PMID- 28713317 TI - Personality and Cognition: Sociability Negatively Predicts Shoal Size Discrimination Performance in Guppies. AB - Evidence from a growing number of organisms suggests that individuals show consistent performance differences in cognitive tasks. According to empirical and theoretical studies, these cognitive differences might be at least partially related to personality. We tested this hypothesis in the guppy, Poecilia reticulata, by comparing individuals with different degree of sociability in the discrimination of shoals formed by a different number of conspecifics. We found that individual guppies show repeatability of sociability as expected for personality traits. Furthermore, individuals with higher sociability showed poorer shoal size discrimination performance and were less efficient in choosing the larger shoal compared to individuals with low sociability. As choosing the larger shoal is an important strategy of defense against predators for guppies, we discuss this relationship between personality and cognition in the light of its fitness consequences. PMID- 28713318 TI - The Bidirectional Relationship between Positive Mental Health and Social Rhythm in College Students:A Three-Year Longitudinal Study. AB - Social rhythm refers to the general regularity of engaging in basic social activities during the week, and was found to be associated with individuals' positive mental health. The present study investigated the relationship between social rhythm and emotional well-being in a cohort of 2,031 college students over 3 years with a cross-lagged longitudinal panel design. Results revealed that regularity of social rhythm positively predicted emotional well-being in the following year, and vice versa, when the level of both factors in the previous year was controlled. Our study provides evidence of a longitudinal positive reciprocal relationship between social rhythm and positive mental health in younger adult populations. PMID- 28713319 TI - Neuropsychological Predictors of Trauma Centrality in OIF/OEF Veterans. AB - This study examined whether reduced performance on two neuropsychological tasks, cognitive flexibility and working memory, were associated with higher levels of trauma centrality. A growing body of research has shown that trauma centrality, the extent to which a person believes a potentially traumatic event has become central to their self-identity and life story, is associated with post-traumatic stress disorder (PTSD). Furthermore, PTSD is often associated with alterations in neuropsychological functioning. The relationship between neuropsychological processes and trauma centrality, however, has yet to be explored. OEF/OIF combat veterans (N = 41) completed the Post-traumatic Diagnostic Scale (PDS), the Beck Depression Inventory-II (BDI-II), the Centrality of Event Scale (CES), and on line measures of cognitive flexibility and working memory assessed via WebNeuro. Bivariate Pearson correlations showed that CES scores were positively correlated with PDS and BDI scores, and negatively correlated with cognitive flexibility and working memory. Linear regressions revealed that working memory significantly predicted CES when controlling for depression and PTSD severity while cognitive flexibility approached significance when controlling for these same variables. This study employed a cross-sectional design, precluding causality. The small sample size, entirely male sample, and use of an online neuropsychological assessment warrant follow-up research. Although numerous studies have found an association between CES and PTSD, this is the first to suggest that neuropsychological processes underlie the construct of trauma centrality. Given the importance of maladaptive cognitive processes underlying the pathogenesis of PTSD, these data suggest that future studies aimed at examining the link between neuropsychological processes and maladaptive cognitive processes, such as trauma centrality, may help to characterize and treat PTSD. PMID- 28713320 TI - Social Media Membership, Browsing, and Profile Updating in a Representative U.S. Sample: Independent and Interdependent Effects of Big Five Traits and Aging and Social Factors. AB - Guided by cybernetic perspectives on personality, the present work used a representative sample of U.S. adults (N = 992) to examine Big Five personality traits and social and aging factors as predictors of social media network membership and past-month browsing/searching and profile updating among members. The results showed adults who were less extraverted and less neurotic and who reported greater physical limitations were less likely to be members. Moreover, extraverted adults without partners were more likely to be members than introverted adults without partners. Among members, the results showed extraverted and emotionally stable younger and older adults reported a similar frequency of profile updating. In contrast, older adults with all other combinations of extraversion and neuroticism showed a reduced frequency of profile updating compared to younger adults. The findings are discussed in terms of social media involvement as a response of a self-regulatory system of personality adaptation. PMID- 28713321 TI - Multi-Level Family Factors and Affective and Behavioral Symptoms of Oppositional Defiant Disorder in Chinese Children. AB - Given the important role of family environment in children's psychological development, the objective of this study was to examine the linkages between family factors at the whole, dyadic, and individual levels and two dimensions (affective and behavioral) of Oppositional Defiant Disorder (ODD) symptoms in Chinese children. Participants comprised of 80 father-child dyads and 169 mother child dyads from families with ODD children. The results indicated that multilevel family factors were differently associated with children's affective and behavioral ODD symptoms. All the family factors at the dyadic and individual levels were significantly associated with child affective ODD symptoms. However, only the most proximal factors (parent-child relationship and child emotion regulation, which were directly related to child) were significantly related to child behavioral ODD symptoms. The present study extends the current knowledge regarding the relationships between family factors and two dimensions of child ODD symptoms by testing the comprehensive multilevel family factors model. This study also recommends that future interventions for ODD children should consider the multi-level family factors to enhance intervention efficacy. PMID- 28713322 TI - Age-Differential Effects of Job Characteristics on Job Attraction: A Policy Capturing Study. AB - Based on an integration of job design and lifespan developmental theories, Truxillo et al. (2012) proposed that job characteristics interact with employee age in predicting important work outcomes. Using an experimental policy-capturing design, we investigated age-differential effects of four core job characteristics (i.e., job autonomy, task variety, task significance, and feedback from the job) on job attraction (i.e., individuals' rating of job attractiveness). Eighty-two employees between 19 and 65 years (Mage = 41, SD = 14) indicated their job attraction for each of 40 hypothetical job descriptions in which the four job characteristics were systematically manipulated (in total, participants provided 3,280 ratings). Results of multilevel analyses showed that the positive effects of task variety, task significance, and feedback from the job were stronger for younger compared to older employees, whereas we did not find significant age differential effects of job autonomy on job attraction. These findings are only partially consistent with propositions of Truxillo et al.'s (2012) lifespan perspective on job design. PMID- 28713323 TI - Model of Illusions and Virtual Reality. AB - In Virtual Reality (VR) it is possible to induce illusions in which users report and behave as if they have entered into altered situations and identities. The effect can be robust enough for participants to respond "realistically," meaning behaviors are altered as if subjects had been exposed to the scenarios in reality. The circumstances in which such VR illusions take place were first introduced in the 80's. Since then, rigorous empirical evidence has explored a wide set of illusory experiences in VR. Here, we compile this research and propose a neuroscientific model explaining the underlying perceptual and cognitive mechanisms that enable illusions in VR. Furthermore, we describe the minimum instrumentation requirements to support illusory experiences in VR, and discuss the importance and shortcomings of the generic model. PMID- 28713324 TI - Color Vision Losses in Autism Spectrum Disorders. AB - Autism spectrum disorders (ASDs) are neurodevelopmental conditions characterized by impairments in social/communication abilities and restricted behaviors. The present study aims to examine color vision discrimination in ASD children and adolescents without intellectual disability. The participants were also subdivided in order to compare color vision thresholds of autistic participants and those who achieved diagnostic criteria for Asperger Syndrome (AS). Nine subjects with autism, 11 participants with AS and 36 typically developing children and adolescents participated in the study. Color vision was assessed by the Cambridge Color Test (CCT). The Trivector protocol was administered to determine color discrimination thresholds along the protan, deutan, and tritan color confusion lines. Data from ASD participants were compared to tolerance limits for 90% of the population with 90% probability obtained from controls thresholds. Of the 20 ASD individuals examined, 6 (30%) showed color vision losses. Elevated color discrimination thresholds were found in 3/9 participants with autism and in 3/11 AS participants. Diffuse and tritan deficits were found. Mechanisms for chromatic losses may be either at the retinal level and/or reflect reduced cortical integration. PMID- 28713325 TI - Editorial: The Role of the Distinctions between Identification/Production and Perceptual/Conceptual Processes in Implicit Memory: Findings from Cognitive Psychology, Neuroscience and Neuropsychology. PMID- 28713326 TI - The Glare Effect Test and the Impact of Age on Luminosity Thresholds. AB - The glare effect (GE) is an illusion in which a white region appears self luminous when surrounded by linearly decreasing luminance ramps. It has been shown that the magnitude of the luminosity effect can be modulated by manipulating the luminance range of the gradients. In the present study we tested the thresholds for the GE on two groups of adults: young (20-30 years old) and elderly (60-75 years old). Purpose of our perspective study was to test the possibility of transforming the GE into a test that could easily measure thresholds for luminosity and discomfort glare. The Glare Effect Test (GET) consisted in 101 printed cards that differed from each other for the range of luminance ramps. Participants were assessed with GET and a battery of visual tests: visual acuity, contrast sensitivity, illusion of length perception, and Ishihara test. Specifically in the GET, participants were required to classify cards on the basis of two reference cards (solid black-no gradient; full range black to white gradient). PSEs of the GE show no correlation with the other visual tests, revealing a divergent validity. A significant difference between young and elderly was found: contrary to our original expectations, luminosity thresholds of GE for elderly were higher than those for young, suggesting a non direct relationship between luminosity perception and discomfort glare. PMID- 28713327 TI - IL-2/Anti-IL-2 Complex Attenuates Inflammation and BBB Disruption in Mice Subjected to Traumatic Brain Injury. AB - Traumatic brain injury (TBI) induces the excessive inflammation and disruption of blood-brain barrier, both of which are partially mediated by the activation of microglia and release of inflammatory cytokines. Previous reports showed that administration of regulatory T cells (Tregs) could suppress inflammation and promote neurological function recovery, and that the IL-2/anti-IL-2 complex (IL 2C) could increase the number of Tregs. Thus, we hypothesized that IL-2C-mediated expansion of Tregs would be beneficial in mice subjected to TBI. In this study, mice received an intraperitoneal injection of IL-2C for three consecutive days. We observed that IL-2C dose-dependently increased Tregs without affecting the populations of CD4, CD8, or natural killer cells. IL-2C could improve the neurological recovery and reduce brain edema, tissue loss, neutrophils infiltration, and tight junction proteins degradation. Furthermore, this complex could also reduce the expression of CD16/32, IL-1beta, or TNF-alpha, and elevate the expression of CD206, arginase 1, or TGF-beta. These results suggest that IL 2C could be a potential therapeutic method to alleviate excessive inflammation and maintain blood vessel stability after TBI. PMID- 28713328 TI - Recovery from Unrecognized Sleep Loss Accumulated in Daily Life Improved Mood Regulation via Prefrontal Suppression of Amygdala Activity. AB - Many modern people suffer from sleep debt that has accumulated in everyday life but is not subjectively noticed [potential sleep debt (PSD)]. Our hypothesis for this study was that resolution of PSD through sleep extension optimizes mood regulation by altering the functional connectivity between the amygdala and prefrontal cortex. Fifteen healthy male participants underwent an experiment consisting of a baseline (BL) evaluation followed by two successive interventions, namely, a 9-day sleep extension followed by one night of total sleep deprivation (TSD). Tests performed before and after the interventions included a questionnaire on negative mood and neuroimaging with arterial spin labeling MRI for evaluating regional cerebral blood flow (rCBF) and functional connectivity. Negative mood and amygdala rCBF were significantly reduced after sleep extension compared with BL. The amygdala had a significant negative functional connectivity with the medial prefrontal cortex (FCamg-MPFC), and this negative connectivity was greater after sleep extension than at BL. After TSD, these indices reverted to the same level as at BL. An additional path analysis with structural equation modeling showed that the FCamg-MPFC significantly explained the amygdala rCBF and that the amygdala rCBF significantly explained the negative mood. These findings suggest that the use of our sleep extension protocol normalized amygdala activity via negative amygdala-MPFC functional connectivity. The resolution of unnoticed PSD may improve mood by enhancing frontal suppression of hyperactivity in the amygdala caused by PSD accumulating in everyday life. PMID- 28713329 TI - Prevalence, Incidence, Prognosis, Early Stroke Risk, and Stroke-Related Prognostic Factors of Definite or Probable Transient Ischemic Attacks in China, 2013. AB - The epidemiological characteristics of transient ischemic attacks (TIAs) in China are unclear. In 2013, we conducted a nationally representative, door-to-door epidemiological survey on TIA in China using a complex, multistage, probability sampling design. Results showed that the weighted prevalence of TIA in China was 103.3 [95% confidence interval (CI): 83.9-127.2] per 100,000 in the population, 92.4 (75.0-113.8) per 100,000 among men, and 114.7 (87.2-151.0) per 100,000 among women. The weighted incidence of TIA was 23.9 (17.8-32.0) per 100,000 in the population, 21.3 (14.3-31.5) per 100,000 among men, and 26.6 (17.0-41.7) per 100,000 among women. No difference in average prognosis was found between TIA and stroke in the population. Weighted risk of stroke among TIA patients was 9.7% (6.5-14.3%), 11.1% (7.5-16.1%), and 12.3% (8.4-17.7%) at 2, 30, and 90 days, respectively. The risk of stroke was higher among male patients with a history of TIA than among female patients with a history of TIA (OR: 2.469; 95% CI: 1.172 5.201; P = 0.018), and higher among TIA patients with hypertension than among TIA patients without hypertension (OR: 2.671; 1.547-4.613; P < 0.001). It can be concluded that there are an estimated 1.35 million TIA patients nationwide, with 0.31 million new cases of TIA annually in China. TIA patients were not better managed prior to a stroke event. Early risk of stroke among TIA patients is high. Sex and hypertension may be stroke-associated prognostic factors among TIA patients. TIA clinics and surveillance should be integrated into the national health-care system. PMID- 28713330 TI - Access to Thrombolysis for Non-Resident and Resident Stroke Patients-A Registry Based Comparative Study from Berlin. AB - OBJECTIVES: Stroke can happen to people away from home. It is unknown whether non resident and resident stroke patients have equal access to thrombolysis. MATERIALS AND METHODS: Consecutive patients cared for by the Stroke Emergency Mobile between 2011 and 2016 after prompting suspicion of acute stroke during the emergency call were included in our registry. Patients were categorized as residents or non-residents based on their main address. Clinical characteristics, thrombolysis rates, and time intervals from symptom onset/last seen well to alarm and to thrombolysis were compared between groups adjusting for age, pre-stroke modified Rankin Scale (mRS) score, and National Institutes of Health Stroke Scale (NIHSS) score. RESULTS: Of 4,254 patients for whom a stroke dispatch was activated, 2,451 had ischemic or hemorrhagic strokes, including 73 non-residents. Non-resident stroke patients were younger (median 69.4 vs. 76.6 years, p < 0.001), had less pre-stroke disability (mRS >= 2:17.8 vs. 47.5%, p < 0.001) and less severe strokes (median NIHSS 4 vs. 5, p = 0.02). Thrombolysis rates were higher in non-residents (30.9 vs. 22.0% of ischemic stroke patients, p = 0.04) and emergency calls were made faster (symptom onset/last-seen-well-to-alarm time 35 vs. 144 min, p = 0.04). A lower proportion of non-residents had unknown time of symptom onset (21.9 vs. 46.4%, p < 0.001). For patients with known time of symptom onset, thrombolysis rates, and prehospital delays were similar among non residents and residents. CONCLUSION: In this study, non-resident stroke patients had higher rates of thrombolysis than residents. This may be explained by a lower proportion of patients with unknown time of symptom onset. PMID- 28713332 TI - Childhood Maltreatment Is an Independent Risk Factor for Prediabetic Disturbances in Glucose Regulation. AB - AIMS: Childhood maltreatment (CM) is shown to be associated with obesity and depression. However, the relationship of CM to prediabetic state is much less studied. We tested the hypothesis that CM increases the risk for prediabetic state due to glucose intolerance, reduced insulin sensitivity, and beta cell function. METHODS: Oral glucose tolerance test (OGTT)-derived metabolic parameters of glucose tolerance, insulin sensitivity, and beta cell function were measured in 121 participants aged 19-60 years. CM exposure was measured using the Childhood Trauma Questionnaire. Blood samples were collected to measure the inflammatory factors. RESULTS: After controlling for age, race, gender, education, and depression, about 15% higher glucose area under the OGTT curve was observed in the CM group. CM individuals also exhibited impaired insulin sensitivity manifested by the Matsuda index and homeostasis model assessment of insulin resistance, which were correlated with CM severity after adjusting for depression. CM group showed approximately 50% lower disposition index. C-reactive protein and tumor necrosis factor-alpha levels were greater in the CM group vs. the non-CM group, and both were correlated with CM severity (r = 0.21, 0.23, respectively, both p < 0.05). Multiple regression analyses revealed that CM contributed to reduced insulin sensitivity and lower disposition index independent of depression and visceral fat mass. CONCLUSION: These data suggest an important relationship between CM and increased risk for prediabetic state due to glucose intolerance, impaired insulin sensitivity, and beta cell function. Our findings indicate that CM appears to be an independent risk factor for developing prediabetes. PMID- 28713331 TI - Thyroid-Stimulating Hormone Receptor Antibodies in Pregnancy: Clinical Relevance. AB - Graves' disease is the most common cause of thyrotoxicosis in women of childbearing age. Approximately 1% of pregnant women been treated before, or are being treated during pregnancy for Graves' hyperthyroidism. In pregnancy, as in not pregnant state, thyroid-stimulating hormone (TSH) receptor (TSHR) antibodies (TRAbs) are the pathogenetic hallmark of Graves' disease. TRAbs are heterogeneous for molecular and functional properties and are subdivided into activating (TSAbs), blocking (TBAbs), or neutral (N-TRAbs) depending on their effect on TSHR. The typical clinical features of Graves' disease (goiter, hyperthyroidism, ophthalmopathy, dermopathy) occur when TSAbs predominate. Graves' disease shows some peculiarities in pregnancy. The TRAbs disturb the maternal as well as the fetal thyroid function given their ability to cross the placental barrier. The pregnancy-related immunosuppression reduces the levels of TRAbs in most cases although they persist in women with active disease as well as in women who received definitive therapy (radioiodine or surgery) before pregnancy. Changes of functional properties from stimulating to blocking the TSHR could occur during gestation. Drug therapy is the treatment of choice for hyperthyroidism during gestation. Antithyroid drugs also cross the placenta and therefore decrease both the maternal and the fetal thyroid hormone production. The management of Graves' disease in pregnancy should be aimed at maintaining euthyroidism in the mother as well as in the fetus. Maternal and fetal thyroid dysfunction (hyperthyroidism as well as hypothyroidism) are in fact associated with several morbidities. Monitoring of the maternal thyroid function, TRAbs measurement, and fetal surveillance are the mainstay for the management of Graves' disease in pregnancy. This review summarizes the biochemical, immunological, and therapeutic aspects of Graves' disease in pregnancy focusing on the role of the TRAbs in maternal and fetal function. PMID- 28713333 TI - Algevir: An Expression System for Microalgae Based on Viral Vectors. AB - The use of recombinant algae for the production of valuable compounds is opening promising biotechnological applications. However, the development of efficient expression approaches is still needed to expand the exploitation of microalgae in biotechnology. Herein, the concept of using viral expression vectors in microalgae was explored for the first time. An inducible geminiviral vector leading to Rep-mediated replication of the expression cassette allowed the production of antigenic proteins at high levels. This system, called Algevir, allows the production of complex viral proteins (GP1 from Zaire ebolavirus) and bacterial toxin subunits (B subunit of the heat-labile Escherichia coli enterotoxin), which retained their antigenic activity. The highest achieved yield was 1.25 mg/g fresh biomass (6 mg/L of culture), which was attained 3 days after transformation. The Algevir system allows for a fast and efficient production of recombinant proteins, overcoming the difficulties imposed by the low yields and unstable expression patterns frequently observed in stably transformed microalgae at the nuclear level; as well as the toxicity of some target proteins. PMID- 28713334 TI - Quantification of Salmonella Survival and Infection in an In vitro Model of the Human Intestinal Tract as Proxy for Foodborne Pathogens. AB - Different techniques are available for assessing differences in virulence of bacterial foodborne pathogens. The use of animal models or human volunteers is not expedient for various reasons; the use of epidemiological data is often hampered by lack of crucial data. In this paper, we describe a static, sequential gastrointestinal tract (GIT) model system in which foodborne pathogens are exposed to simulated gastric and intestinal contents of the human digestive tract, including the interaction of pathogens with the intestinal epithelium. The system can be employed with any foodborne bacterial pathogens. Five strains of Salmonella Heidelberg and one strain of Salmonella Typhimurium were used to assess the robustness of the system. Four S. Heidelberg strains originated from an outbreak, the fifth S. Heidelberg strain and the S. Typhimurium strain originated from routine meat inspections. Data from plate counts, collected for determining the numbers of surviving bacteria in each stage, were used to quantify both the experimental uncertainty and biological variability of pathogen survival throughout the system. For this, a hierarchical Bayesian framework using Markov chain Monte Carlo (MCMC) was employed. The model system is able to distinguish serovars/strains for in vitro infectivity when accounting for within strain biological variability and experimental uncertainty. PMID- 28713335 TI - A Novel Regulatory Cascade Involving BluR, YcgZ, and Lon Controls the Expression of Escherichia coli OmpF Porin. AB - In Escherichia coli, OmpF is an important outer membrane protein, which serves as a passive diffusion pore for small compounds including nutrients, antibiotics, and toxic compounds. OmpF expression responds to environmental changes such as temperature, osmolarity, nutrients availability, and toxic compounds via complex regulatory pathways involving transcriptional and post-transcriptional regulation. Our study identified a new regulatory cascade that controls the expression of OmpF porin. This pathway involves BluR, a transcriptional regulator repressing the expression of the ycgZ-ymgABC operon. We showed that BluR was responsible for the temperature-dependent regulation of the ycgZ-ymgABC operon. Furthermore, our results showed that independent expression of YcgZ led to a decreased activity of the ompF promoter, while YmgA, YmgB, and YmgC expression had no effect. We also determined that YcgZ accumulates in the absence of the Lon protease. Thus, mutation in bluR leads to de-repression of ycgZ-ymgABC transcription. With a second mutation in lon, YcgZ protein accumulates to reach levels that do not allow increased expression of OmpF under growth conditions that usually would, i.e., low temperature. With BluR responding to blue-light and temperature, this study sheds a new light on novel signals able to regulate OmpF porin. PMID- 28713336 TI - Development and Use of a Real-Time Quantitative PCR Method for Detecting and Quantifying Equol-Producing Bacteria in Human Faecal Samples and Slurry Cultures. AB - This work introduces a novel real-time quantitative PCR (qPCR) protocol for detecting and quantifying equol-producing bacteria. To this end, two sets of primers targeting the dihydrodaidzein reductase (ddr) and tetrahydrodaidzein reductase (tdr) genes, which are involved in the synthesis of equol, were designed. The primers showed high specificity and sensitivity when used to examine DNA from control bacteria, such as Slackia isoflavoniconvertens, Slackia equolifaciens, Asaccharobacter celatus, Adlercreutzia equolifaciens, and Enterorhabdus mucosicola. To demonstrate the validity and reliability of the protocol, it was used to detect and quantify equol-producing bacteria in human faecal samples and their derived slurry cultures. These samples were provided by 18 menopausal women under treatment of menopause symptoms with a soy isoflavone concentrate, among whom three were known to be equol-producers given the prior detection of the molecule in their urine. The tdr gene was detected in the faeces of all these equol-producing women at about 4-5 log10 copies per gram of faeces. In contrast, the ddr gene was only amplified in the faecal samples of two of these three women, suggesting the presence in the non-amplified sample of reductase genes unrelated to those known to be involved in equol formation and used for primer design in this study. When tdr and ddr were present in the same sample, similar copy numbers of the two genes were recorded. However, no significant increase in the copy number of equol-related genes along isoflavone treatment was observed. Surprisingly, positive amplification for both tdr and ddr genes was obtained in faecal samples and derived slurry cultures from two non equol producing women, suggesting the genes could be non-functional or the daidzein metabolized to other compounds in samples from these two women. This novel qPCR tool provides a technique for monitoring gut microbes that produce equol in humans. Monitoring equol-producing bacteria in the human gut could provide a means of evaluating strategies aimed at increasing the endogenous formation of this bioactive compound. PMID- 28713338 TI - Investigation of OCH1 in the Virulence of Candida parapsilosis Using a New Neonatal Mouse Model. AB - Candida parapsilosis is an opportunistic human fungal pathogen that poses a serious threat to low birth weight neonates, particularly at intensive care units. In premature infants, the distinct immune responses to Candida infections are not well understood. Although several in vivo models exist to study systemic candidiasis, only a few are available to investigate dissemination in newborns. In addition, the majority of related studies apply intraperitoneal infection rather than intravenous inoculation of murine infants that may be less efficient when studying systemic invasion. In this study, we describe a novel and conveniently applicable intravenous neonatal mouse model to monitor systemic C. parapsilosis infection. Using the currently developed model, we aimed to analyze the pathogenic properties of different C. parapsilosis strains. We infected 2 days-old BALB/c mouse pups via the external facial vein with different doses of C. parapsilosis strains. Homogenous dissemination of yeast cells was found in the spleen, kidney, liver and brain of infected newborn mice. Colonization of harvested organs was also confirmed by histological examinations. Fungal burdens in newborn mice showed a difference for two isolates of C. parapsilosis. C. parapsilosis CLIB infection resulted in higher colonization of the spleen, kidney and liver of neonatal mice compared to the C. parapsilosis GA1 strain at day 2 after the infection. In a comprehensive study with the adult mice infection, we also presented the attenuated virulence of a C. parapsilosis cell wall mutant (OCH1) in this model. Significantly less och1Delta/Delta null mutant cells were recovered from the spleen, kidney and liver of newborn mice compared to the wild type strain. When investigating the cytokine response of neonatal mice to C. parapsilosis infection, we found elevated TNFalpha, KC, and IL-1beta expression levels in all organs examined when compared to the uninfected control. Furthermore, all three measured cytokines showed a significantly elevated expression when newborn mice were infected with och1Delta/Delta cells compared to the wild type strain. This result further supported the inclusion of OCH1 in C. parapsilosis pathogenicity. To our current knowledge, this is the first study that uses a mice neonatal intravenous infection model to investigate C. parapsilosis infection. PMID- 28713337 TI - The S-layer Associated Serine Protease Homolog PrtX Impacts Cell Surface-Mediated Microbe-Host Interactions of Lactobacillus acidophilus NCFM. AB - Health-promoting aspects attributed to probiotic microorganisms, including adhesion to intestinal epithelia and modulation of the host mucosal immune system, are mediated by proteins found on the bacterial cell surface. Notably, certain probiotic and commensal bacteria contain a surface (S-) layer as the outermost stratum of the cell wall. S-layers are non-covalently bound semi porous, crystalline arrays of self-assembling, proteinaceous subunits called S layer proteins (SLPs). Recent evidence has shown that multiple proteins are non covalently co-localized within the S-layer, designated S-layer associated proteins (SLAPs). In Lactobacillus acidophilus NCFM, SLP and SLAPs have been implicated in both mucosal immunomodulation and adhesion to the host intestinal epithelium. In this study, a S-layer associated serine protease homolog, PrtX (prtX, lba1578), was deleted from the chromosome of L. acidophilus NCFM. Compared to the parent strain, the PrtX-deficient strain (DeltaprtX) demonstrated increased autoaggregation, an altered cellular morphology, and pleiotropic increases in adhesion to mucin and fibronectin, in vitro. Furthermore, DeltaprtX demonstrated increased in vitro immune stimulation of IL-6, IL-12, and IL-10 compared to wild-type, when exposed to mouse dendritic cells. Finally, in vivo colonization of germ-free mice with DeltaprtX led to an increase in epithelial barrier integrity. The absence of PrtX within the exoproteome of a DeltaprtX strain caused morphological changes, resulting in a pleiotropic increase of the organisms' immunomodulatory properties and interactions with some intestinal epithelial cell components. PMID- 28713339 TI - Concurrent Methane Production and Oxidation in Surface Sediment from Aarhus Bay, Denmark. AB - Marine surface sediments, which are replete with sulfate, are typically considered to be devoid of endogenous methanogenesis. Yet, methanogenic archaea are present in those sediments, suggesting a potential for methanogenesis. We used an isotope dilution method based on sediment bag incubation and spiking with 13C-CH4 to quantify CH4 turnover rates in sediment from Aarhus Bay, Denmark. In two independent experiments, highest CH4 production and oxidation rates (>200 pmol cm-3 d-1) were found in the top 0-2 cm, below which rates dropped below 100 pmol cm-3 d-1 in all other segments down to 16 cm. This drop in overall methane turnover with depth was accompanied by decreasing rates of organic matter mineralization with depth. Molecular analyses based on quantitative PCR and MiSeq sequencing of archaeal 16S rRNA genes showed that the abundance of methanogenic archaea also peaked in the top 0-2 cm segment. Based on the community profiling, hydrogenotrophic and methylotrophic methanogens dominated among the methanogenic archaea in general, suggesting that methanogenesis in surface sediment could be driven by both CO2 reduction and fermentation of methylated compounds. Our results show the existence of elevated methanogenic activity and a dynamic recycling of CH4 at low concentration in sulfate-rich marine surface sediment. Considering the common environmental conditions found in other coastal systems, we speculate that such a cryptic methane cycling can be ubiquitous. PMID- 28713340 TI - Distinct Network Interactions in Particle-Associated and Free-Living Bacterial Communities during a Microcystis aeruginosa Bloom in a Plateau Lake. AB - Particle-associated bacteria (PAB) and free-living bacteria (FLB) from aquatic environments during phytoplankton blooms differ in their physical distance from algae. Both the interactions within PAB and FLB community fractions and their relationship with the surrounding environmental properties are largely unknown. Here, by using high-throughput sequencing and network-based analyses, we compared the community and network characteristics of PAB and FLB from a plateau lake during a Microcystis aeruginosa bloom. Results showed that PAB and FLB differed significantly in diversity, structure and microbial connecting network. PAB communities were characterized by highly similar bacterial community structure in different sites, tighter network connections, important topological roles for the bloom-causing M. aeruginosa and Alphaproteobacteria, especially for the potentially nitrogen-fixing (Pleomorphomonas) and algicidal bacteria (Brevundimonas sp.). FLB communities were sensitive to the detected environmental factors and were characterized by significantly higher bacterial diversity, less connectivity, larger network size and marginal role of M. aeruginosa. In both networks, covariation among bacterial taxa was extensive (>88% positive connections), and bacteria potentially affiliated with biogeochemical cycling of nitrogen (i.e., denitrification, nitrogen-fixation and nitrite-oxidization) were important in occupying module hubs, such as Meganema, Pleomorphomonas, and Nitrospira. These findings highlight the importance of considering microbial network interactions for the understanding of blooms. PMID- 28713341 TI - Prevalence, Host Range, and Comparative Genomic Analysis of Temperate Ochrobactrum Phages. AB - Ochrobactrum and Brucella are closely related bacteria that populate different habitats and differ in their pathogenic properties. Only little is known about mobile genetic elements in these genera which might be important for survival and virulence. Previous studies on Brucella lysogeny indicated that active phages are rare in this genus. To gain insight into the presence and nature of prophages in Ochrobactrum, temperate phages were isolated from various species and characterized in detail. In silico analyses disclosed numerous prophages in published Ochrobactrum genomes. Induction experiments showed that Ochrobactrum prophages can be induced by various stress factors and that some strains released phage particles even under non-induced conditions. Sixty percent of lysates prepared from 125 strains revealed lytic activity. The host range and DNA similarities of 19 phages belonging to the families Myoviridae, Siphoviridae, or Podoviridae were determined suggesting that they are highly diverse. Some phages showed relationship to the temperate Brucella inopinata phage BiPB01. The genomic sequences of the myovirus POA1180 (41,655 bp) and podovirus POI1126 (60,065 bp) were analyzed. Phage POA1180 is very similar to a prophage recently identified in a Brucella strain isolated from an exotic frog. The POA1180 genome contains genes which may confer resistance to chromate and the ability to take up sulfate. Phage POI1126 is related to podoviruses of Sinorhizobium meliloti (PCB5), Erwinia pyrifoliae (Pep14), and Burkholderia cenocepacia (BcepIL02) and almost identical to an unnamed plasmid of the Ochrobactrum intermedium strain LMG 3301. Further experiments revealed that the POI1126 prophage indeed replicates as an extrachromosomal element. The data demonstrate for the first time that active prophages are common in Ochrobactrum and suggest that atypical brucellae also may be a reservoir for temperate phages. PMID- 28713342 TI - NF-kappaBp50 and HDAC1 Interaction Is Implicated in the Host Tolerance to Infection Mediated by the Bacterial Quorum Sensing Signal 2-Aminoacetophenone. AB - Some bacterial quorum sensing (QS) small molecules are important mediators of inter-kingdom signaling and impact host immunity. The QS regulated small volatile molecule 2-aminoacetophenone (2-AA), which has been proposed as a biomarker of Pseudomonas aeruginosa colonization in chronically infected human tissues, is critically involved in "host tolerance training" that involves a distinct molecular mechanism of host chromatin regulation through histone deacetylase (HDAC)1. 2-AA's epigenetic reprogramming action enables host tolerance to high bacterial burden and permits long-term presence of P. aeruginosa without compromising host survival. Here, to further elucidate the molecular mechanisms of 2-AA-mediated host tolerance/resilience we investigated the connection between histone acetylation status and nuclear factor (NF)-kappaB signaling components that together coordinate 2-AA-mediated control of transcriptional activity. We found increased NF-kappaBp65 acetylation levels in 2-AA stimulated cells that are preceded by association of CBP/p300 and increased histone acetyltransferase activity. In contrast, in 2-AA-tolerized cells the protein-protein interaction between p65 and CBP/p300 is disrupted and conversely, the interaction between p50 and co-repressor HDAC1 is enhanced, leading to repression of the pro-inflammatory response. These results highlight how a bacterial QS signaling molecule can establish a link between intracellular signaling and epigenetic reprogramming of pro-inflammatory mediators that may contribute to host tolerance training. These new insights might contribute to the development of novel therapeutic interventions against bacterial infections. PMID- 28713343 TI - The Bacterial Ecosystem of Mother's Milk and Infant's Mouth and Gut. AB - The progressive building of the infants' gut microbiota is pivotal for educating their immune system. Human breast milk is among the first sources of microbes for the assembly of the infant's microbiota, but research struggles to give a demonstration for the origin of bacteria in milk. Aiming at contributing to the knowledge on assembly of the mother's milk and infant's microbiome, here we characterized the oral, gut and milk ecosystems in a homogeneous cohort of 36 healthy mother-infants pairs, by 16S rRNA next-generation sequencing. A limited number of operational taxonomic units (OTUs) was shared among the three ecosystems, including not only OTUs assigned to the well-known immune-modulating Bifidobacterium genus, but also specific Streptococcus and Staphylococcus OTUs, which were dominant in the infant's mouth ecosystem. The high conservation of these OTUs among the three ecosystems seems to call for a worth exploring ecological role through targeted and/or culture-dependent techniques. Notwithstanding the limitations of a 16S rRNA gene-based molecular characterization, we might hypothesize that the baby's mouth, being the transition point for the milk to reach the intestine, could play a role in both the gut microbiota assembly, via deglutition, and mother's milk duct colonization, during suction. PMID- 28713344 TI - Outer Membrane Proteome of Veillonella parvula: A Diderm Firmicute of the Human Microbiome. AB - Veillonella parvula is a biofilm-forming commensal found in the lungs, vagina, mouth, and gastro-intestinal tract of humans, yet it may develop into an opportunistic pathogen. Furthermore, the presence of Veillonella has been associated with the development of a healthy immune system in infants. Veillonella belongs to the Negativicutes, a diverse clade of bacteria that represent an evolutionary enigma: they phylogenetically belong to Gram-positive (monoderm) Firmicutes yet maintain an outer membrane (OM) with lipopolysaccharide similar to classic Gram-negative (diderm) bacteria. The OMs of Negativicutes have unique characteristics including the replacement of Braun's lipoprotein by OmpM for tethering the OM to the peptidoglycan. Through phylogenomic analysis, we have recently provided bioinformatic annotation of the Negativicutes diderm cell envelope. We showed that it is a unique type of envelope that was present in the ancestor of present-day Firmicutes and lost multiple times independently in this phylum, giving rise to the monoderm architecture; however, little experimental data is presently available for any Negativicutes cell envelope. Here, we performed the first experimental proteomic characterization of the cell envelope of a diderm Firmicute, producing an OM proteome of V. parvula. We initially conducted a thorough bioinformatics analysis of all 1,844 predicted proteins from V. parvula DSM 2008's genome using 12 different localization prediction programs. These results were complemented by protein extraction with surface exposed (SE) protein tags and by subcellular fractionation, both of which were analyzed by liquid chromatography tandem mass spectrometry. The merging of proteomics and bioinformatics results allowed identification of 78 OM proteins. These include a number of receptors for TonB-dependent transport, the main component of the BAM system for OM protein biogenesis (BamA), the Lpt system component LptD, which is responsible for insertion of LPS into the OM, and several copies of the major OmpM protein. The annotation of V. parvula's OM proteome markedly extends previous inferences on the nature of the cell envelope of Negativicutes, including the experimental evidence of a BAM/TAM system for OM protein biogenesis and of a complete Lpt system for LPS transport to the OM. It also provides important information on the role of OM components in the lifestyle of Veillonella, such as a possible gene cluster for O-antigen synthesis and a large number of adhesins. Finally, many OM hypothetical proteins were identified, which are priority targets for further characterization. PMID- 28713345 TI - Experimental Study and ANN Dual-Time Scale Perturbation Model of Electrokinetic Properties of Microbiota. AB - The electrokinetic properties of the rumen microbiota are involved in cell surface adhesion and microbial metabolism. An in vitro study was carried out in batch culture to determine the effects of three levels of special surface area (SSA) of biomaterials and four levels of surface tension (ST) of culture medium on electrokinetic properties (Zeta potential, xi; electrokinetic mobility, MUe), fermentation parameters (volatile fatty acids, VFAs), and ST over fermentation processes (ST-a, gamma). The obtained results were combined with previously published data (digestibility, D; pH; concentration of ammonia nitrogen, c(NH3 N)) to establish a predictive artificial neural network (ANN) model. Concepts of dual-time series analysis, perturbation theory (PT), and Box-Jenkins Operators were applied for the first time to develop an ANN model to predict the variations of the electrokinetic properties of microbiota. The best dual-time series Radial Basis Functions (RBR) model for xi of rumen microbiota predicted xi for >30,000 cases with a correlation coefficient >0.8. This model provided insight into the correlations between electrokinetic property (zeta potential) of rumen microbiota and the perturbations of physical factors (specific surface area and surface tension) of media, digestibility of substrate, and their metabolites (NH3-N, VFAs) in relation to environmental factors. PMID- 28713346 TI - Distribution of 2,4-Diacetylphloroglucinol Biosynthetic Genes among the Pseudomonas spp. Reveals Unexpected Polyphyletism. AB - Fluorescent pseudomonads protecting plant roots from phytopathogens by producing 2,4-diacetylphloroglucinol (DAPG) are considered to form a monophyletic lineage comprised of DAPG+Pseudomonas strains in the "P. corrugata" and "P. protegens" subgroups of the "Pseudomonas fluorescens" group. However, DAPG production ability has not been investigated for many species of these two subgroups, and whether or not the DAPG+Pseudomonas are truly monophyletic remained to be verified. Thus, the distribution of the DAPG biosynthetic operon (phlACBD genes) in the Pseudomonas spp. was investigated in sequenced genomes and type strains. Results showed that the DAPG+Pseudomonas include species of the "P. fluorescens" group, i.e., P. protegens, P. brassicacearum, P. kilonensis, and P. thivervalensis, as expected, as well as P. gingeri in which it had not been documented. Surprisingly, they also include bacteria outside the "P. fluorescens" group, as exemplified by Pseudomonas sp. OT69, and even two Betaproteobacteria genera. The phl operon-based phylogenetic tree was substantially congruent with the one inferred from concatenated housekeeping genes rpoB, gyrB, and rrs. Contrariwise to current supposition, ancestral character reconstructions favored multiple independent acquisitions rather that one ancestral event followed by vertical inheritance. Indeed, based on synteny analyses, these acquisitions appeared to vary according to the Pseudomonas subgroup and even the phylogenetic groups within the subgroups. In conclusion, our study shows that the phl+Pseudomonas populations form a polyphyletic group and suggests that DAPG biosynthesis might not be restricted to this genus. This is important to consider when assessing the ecological significance of phl+ bacterial populations in rhizosphere ecosystems. PMID- 28713347 TI - Generic Amplicon Deep Sequencing to Determine Ilarvirus Species Diversity in Australian Prunus. AB - The distribution of Ilarvirus species populations amongst 61 Australian Prunus trees was determined by next generation sequencing (NGS) of amplicons generated using a genus-based generic RT-PCR targeting a conserved region of the Ilarvirus RNA2 component that encodes the RNA dependent RNA polymerase (RdRp) gene. Presence of Ilarvirus sequences in each positive sample was further validated by Sanger sequencing of cloned amplicons of regions of each of RNA1, RNA2 and/or RNA3 that were generated by species specific PCRs and by metagenomic NGS. Prunus necrotic ringspot virus (PNRSV) was the most frequently detected Ilarvirus, occurring in 48 of the 61 Ilarvirus-positive trees and Prune dwarf virus (PDV) and Apple mosaic virus (ApMV) were detected in three trees and one tree, respectively. American plum line pattern virus (APLPV) was detected in three trees and represents the first report of APLPV detection in Australia. Two novel and distinct groups of Ilarvirus-like RNA2 amplicon sequences were also identified in several trees by the generic amplicon NGS approach. The high read depth from the amplicon NGS of the generic PCR products allowed the detection of distinct RNA2 RdRp sequence variant populations of PNRSV, PDV, ApMV, APLPV and the two novel Ilarvirus-like sequences. Mixed infections of ilarviruses were also detected in seven Prunus trees. Sanger sequencing of specific RNA1, RNA2, and/or RNA3 genome segments of each virus and total nucleic acid metagenomics NGS confirmed the presence of PNRSV, PDV, ApMV and APLPV detected by RNA2 generic amplicon NGS. However, the two novel groups of Ilarvirus-like RNA2 amplicon sequences detected by the generic amplicon NGS could not be associated to the presence of sequence from RNA1 or RNA3 genome segments or full Ilarvirus genomes, and their origin is unclear. This work highlights the sensitivity of genus specific amplicon NGS in detection of virus sequences and their distinct populations in multiple samples, and the need for a standardized approach to accurately determine what constitutes an active, viable virus infection after detection by molecular based methods. PMID- 28713348 TI - Engineering Strategies to Decode and Enhance the Genomes of Coral Symbionts. AB - Elevated sea surface temperatures from a severe and prolonged El Nino event (2014 2016) fueled by climate change have resulted in mass coral bleaching (loss of dinoflagellate photosymbionts, Symbiodinium spp., from coral tissues) and subsequent coral mortality, devastating reefs worldwide. Genetic variation within and between Symbiodinium species strongly influences the bleaching tolerance of corals, thus recent papers have called for genetic engineering of Symbiodinium to elucidate the genetic basis of bleaching-relevant Symbiodinium traits. However, while Symbiodinium has been intensively studied for over 50 years, genetic transformation of Symbiodinium has seen little success likely due to the large evolutionary divergence between Symbiodinium and other model eukaryotes rendering standard transformation systems incompatible. Here, we integrate the growing wealth of Symbiodinium next-generation sequencing data to design tailored genetic engineering strategies. Specifically, we develop a testable expression construct model that incorporates endogenous Symbiodinium promoters, terminators, and genes of interest, as well as an internal ribosomal entry site from a Symbiodinium virus. Furthermore, we assess the potential for CRISPR/Cas9 genome editing through new analyses of the three currently available Symbiodinium genomes. Finally, we discuss how genetic engineering could be applied to enhance the stress tolerance of Symbiodinium, and in turn, coral reefs. PMID- 28713349 TI - The Gut Microbiota of Healthy Chilean Subjects Reveals a High Abundance of the Phylum Verrucomicrobia. AB - The gut microbiota is currently recognized as an important factor regulating the homeostasis of the gastrointestinal tract and influencing the energetic metabolism of the host as well as its immune and central nervous systems. Determining the gut microbiota composition of healthy subjects is therefore necessary to establish a baseline allowing the detection of microbiota alterations in pathologic conditions. Accordingly, the aim of this study was to characterize the gut microbiota of healthy Chilean subjects using 16S rRNA gene sequencing. Fecal samples were collected from 41 young, asymptomatic, normal weight volunteers (age: 25 +/- 4 years; ?:48.8%; BMI: 22.5 +/- 1.6 kg/m2) with low levels of plasma (IL6 and hsCRP) and colonic (fecal calprotectin) inflammatory markers. The V3-V4 region of the 16S rRNA gene of bacterial DNA was amplified and sequenced using MiSeq Illumina system. 109,180 +/- 13,148 sequences/sample were obtained, with an alpha-diversity of 3.86 +/- 0.37. The dominant phyla were Firmicutes (43.6 +/- 9.2%) and Bacteroidetes (41.6 +/- 13.1%), followed by Verrucomicrobia (8.5 +/- 10.4%), Proteobacteria (2.8 +/- 4.8%), Actinobacteria (1.8 +/- 3.9%) and Euryarchaeota (1.4 +/- 2.7%). The core microbiota representing the genera present in all the subjects included Bacteroides, Prevotella, Parabacteroides (phylum Bacteroidetes), Phascolarctobacterium, Faecalibacterium, Ruminococcus, Lachnospira, Oscillospira, Blautia, Dorea, Roseburia, Coprococcus, Clostridium, Streptococcus (phylum Firmicutes), Akkermansia (phylum Verrucomicrobia), and Collinsella (phylum Actinobacteria). Butyrate-producing genera including Faecalibacterium, Roseburia, Coprococcus, and Oscillospira were detected. The family Methanobacteriaceae was reported in 83% of the subjects and Desulfovibrio, the most representative sulfate-reducing genus, in 76%. The microbiota of the Chilean individuals significantly differed from those of Papua New Guinea and the Matses ethnic group and was closer to that of the Argentinians and sub-populations from the United States. Interestingly, the microbiota of the Chilean subjects stands out for its richness in Verrucomicrobia; the mucus-degrading bacterium Akkermansia muciniphila is the only identified member of this phylum. This is an important finding considering that this microorganism has been recently proposed as a hallmark of healthy gut due to its anti-inflammatory and immunostimulant properties and its ability to improve gut barrier function, insulin sensitivity and endotoxinemia. These results constitute an important baseline that will facilitate the characterization of dysbiosis in the main diseases affecting the Chilean population. PMID- 28713350 TI - Biphenyl Modulates the Expression and Function of Respiratory Oxidases in the Polychlorinated-Biphenyls Degrader Pseudomonas pseudoalcaligenes KF707. AB - Pseudomonas pseudoalcaligenes KF707 is a soil bacterium which is known for its capacity to aerobically degrade harmful organic compounds such as polychlorinated biphenyls (PCBs) using biphenyl as co-metabolite. Here we provide the first genetic and functional analysis of the KF707 respiratory terminal oxidases in cells grown with two different carbon sources: glucose and biphenyl. We identified five terminal oxidases in KF707: two c(c)aa3 type oxidases (Caa3 and Ccaa3), two cbb3 type oxidases (Cbb31 and Cbb32), and one bd type cyanide insensitive quinol oxidase (CIO). While the activity and expression of both Cbb31 and Cbb32 oxidases was prevalent in glucose grown cells as compared to the other oxidases, the activity and expression of the Caa3 oxidase increased considerably only when biphenyl was used as carbon source in contrast to the Cbb32 oxidase which was repressed. Further, the respiratory activity and expression of CIO was up-regulated in a Cbb31 deletion strain as compared to W.T. whereas the CIO up regulation was not present in Cbb32 and C(c)aa3 deletion mutants. These results, together, reveal that both function and expression of cbb3 and caa3 type oxidases in KF707 are modulated by biphenyl which is the co-metabolite needed for the activation of the PCBs-degradation pathway. PMID- 28713351 TI - A Genome-Wide Association Study to Identify Diagnostic Markers for Human Pathogenic Campylobacter jejuni Strains. AB - Campylobacter jejuni is a leading human enteric pathogen worldwide and despite an improved understanding of its biology, ecology, and epidemiology, limited tools exist for identifying strains that are likely to cause disease. In the current study, we used subtyping data in a database representing over 24,000 isolates collected through various surveillance projects in Canada to identify 166 representative genomes from prevalent C. jejuni subtypes for whole genome sequencing. The sequence data was used in a genome-wide association study (GWAS) aimed at identifying accessory gene markers associated with clinically related C. jejuni subtypes. Prospective markers (n = 28) were then validated against a large number (n = 3,902) of clinically associated and non-clinically associated genomes from a variety of sources. A total of 25 genes, including six sets of genetically linked genes, were identified as robust putative diagnostic markers for clinically related C. jejuni subtypes. Although some of the genes identified in this study have been previously shown to play a role in important processes such as iron acquisition and vitamin B5 biosynthesis, others have unknown function or are unique to the current study and warrant further investigation. As few as four of these markers could be used in combination to detect up to 90% of clinically associated isolates in the validation dataset, and such markers could form the basis for a screening assay to rapidly identify strains that pose an increased risk to public health. The results of the current study are consistent with the notion that specific groups of C. jejuni strains of interest are defined by the presence of specific accessory genes. PMID- 28713352 TI - Use of Native Yeast Strains for In-Bottle Fermentation to Face the Uniformity in Sparkling Wine Production. AB - The in-bottle fermentation of sparkling wines is currently triggered by few commercialized Saccharomyces cerevisiae strains. This lack of diversity in tirage yeast cultures leads to a prevalent uniformity in sensory profiles of the end products. The aim of this study has been to exploit the natural multiplicity of yeast populations in order to introduce variability in sparkling wines throughout the re-fermentation step. A collection of 133 S. cerevisiae strains were screened on the basis of technological criteria (fermenting power and vigor, SO2 tolerance, alcohol tolerance, flocculence) and qualitative features (acetic acid, glycerol and H2S productions). These activities allowed the selection of yeasts capable of dominating the in-bottle fermentation in actual cellar conditions: in particular, the performances of FX and FY strains (isolated in Franciacorta area), and OX and OY strains (isolated in Oltrepo Pavese area), were compared to those of habitually used starter cultures (IOC18-2007, EC1118, Lalvin DV10), by involving nine wineries belonging to the two Consortia of Appellation of Origin. The microbiological analyses of samples have revealed that the indigenous strains showed an increased latency period and a higher cultivability along the aging time than the commercial starter cultures do. Results of chemical analyses and sensory evaluation of the samples after 18 months sur lies have shown that significant differences (p < 0.05) were present among the strains for alcoholic strength, carbon dioxide overpressure and pleasantness, whereas they were not observed for residual sugars content, titratable acidity or volatile acidity. Indigenous S. cerevisiae exhibited comparable values respect to the commercial starter cultures. The ANOVA has also proven that the base wine formulation is a key factor, by significantly affecting (p < 0.01) some oenological parameters of wine, like alcoholic strength, volatile acidity, carbon dioxide overpressure, titratable acidity and dry extract. The use of native yeast strains for the re fermentation step can be considered a convenient way for introducing differentiation to the final product without modifying the traditional technology. In a perspective of "precision enology," where the wine is designed on specific vine cultivars and microorganisms, this work underlines that exploring yeast biodiversity is a strategic activity to improve the production. PMID- 28713353 TI - Functional Characterization of Novel Faecalibacterium prausnitzii Strains Isolated from Healthy Volunteers: A Step Forward in the Use of F. prausnitzii as a Next-Generation Probiotic. AB - Faecalibacterium prausnitzii is a major member of the Firmicutes phylum and one of the most abundant bacteria in the healthy human microbiota. F. prausnitzii depletion has been reported in several intestinal disorders, and more consistently in Crohn's disease (CD) patients. Despite its importance in human health, only few microbiological studies have been performed to isolate novel F. prausnitzii strains in order to better understand the biodiversity and physiological diversity of this beneficial commensal species. In this study, we described a protocol to isolate novel F. prausnitzii strains from feces of healthy volunteers as well as a deep molecular and metabolic characterization of these isolated strains. These F. prausnitzii strains were classified in two phylogroups and three clusters according to 16S rRNA sequences and results support that they would belong to two different genomospecies or genomovars as no genome sequencing has been performed in this work. Differences in enzymes production, antibiotic resistance and immunomodulatory properties were found to be strain-dependent. So far, all F. prausnitzii isolates share some characteristic such as (i) the lack of epithelial cells adhesion, plasmids, anti microbial, and hemolytic activity and (ii) the presence of DNAse activity. Furthermore, Short Chain Fatty Acids (SCFA) production was assessed for the novel isolates as these products influence intestinal homeostasis. Indeed, the butyrate production has been correlated to the capacity to induce IL-10, an anti inflammatory cytokine, in peripheral blood mononuclear cells (PBMC) but not to the ability to block IL-8 secretion in TNF-alpha-stimulated HT-29 cells, reinforcing the hypothesis of a complex anti-inflammatory pathway driven by F. prausnitzii. Altogether, our results suggest that some F. prausnitzii strains could represent good candidates as next-generation probiotic. PMID- 28713354 TI - Microbial Populations of Stony Meteorites: Substrate Controls on First Colonizers. AB - Finding fresh, sterilized rocks provides ecologists with a clean slate to test ideas about first colonization and the evolution of soils de novo. Lava has been used previously in first colonizer studies due to the sterilizing heat required for its formation. However, fresh lava typically falls upon older volcanic successions of similar chemistry and modal mineral abundance. Given enough time, this results in the development of similar microbial communities in the newly erupted lava due to a lack of contrast between the new and old substrates. Meteorites, which are sterile when they fall to Earth, provide such contrast because their reduced and mafic chemistry commonly differs to the surfaces on which they land; thus allowing investigation of how community membership and structure respond to this new substrate over time. We conducted 16S rRNA gene analysis on meteorites and soil from the Nullarbor Plain, Australia. We found that the meteorites have low species richness and evenness compared to soil sampled from directly beneath each meteorite. Despite the meteorites being found kilometers apart, the community structure of each meteorite bore more similarity to those of other meteorites (of similar composition) than to the community structure of the soil on which it resided. Meteorites were dominated by sequences that affiliated with the Actinobacteria with the major Operational Taxonomic Unit (OTU) classified as Rubrobacter radiotolerans. Proteobacteria and Bacteroidetes were the next most abundant phyla. The soils were also dominated by Actinobacteria but to a lesser extent than the meteorites. We also found OTUs affiliated with iron/sulfur cycling organisms Geobacter spp. and Desulfovibrio spp. This is an important finding as meteorites contain abundant metal and sulfur for use as energy sources. These ecological findings demonstrate that the structure of the microbial community in these meteorites is controlled by the substrate, and will not reach homeostasis with the Nullarbor community, even after ca. 35,000 years. Our findings show that meteorites provide a unique, sterile substrate with which to test ideas relating to first-colonizers. Although meteorites are colonized by microorganisms, the microbial population is unlikely to match the community of the surrounding soil on which they fall. PMID- 28713355 TI - Respiratory Pathways Reconstructed by Multi-Omics Analysis in Melioribacter roseus, Residing in a Deep Thermal Aquifer of the West-Siberian Megabasin. AB - Melioribacter roseus, a representative of recently proposed Ignavibacteriae phylum, is a metabolically versatile thermophilic bacterium, inhabiting subsurface biosphere of the West-Siberian megabasin and capable of growing on various substrates and electron acceptors. Genomic analysis followed by inhibitor studies and membrane potential measurements of aerobically grown M. roseus cells revealed the activity of aerobic respiratory electron transfer chain comprised of respiratory complexes I and IV, and an alternative complex III. Phylogeny reconstruction revealed that oxygen reductases belonged to atypical cc(o/b)o3 type and canonical cbb3 -type cytochrome oxidases. Also, two molybdoenzymes of M. roseus were affiliated either with Ttr or Psr/Phs clades, but not with typical respiratory arsenate reductases of the Arr clade. Expression profiling, both at transcripts and protein level, allowed us to assign the role of the terminal respiratory oxidase under atmospheric oxygen concentration for the cc(o/b)o3 cytochrome oxidase, previously proposed to serve for oxygen detoxification only. Transcriptomic analysis revealed the involvement of both molybdoenzymes of M. roseus in As(V) respiration, yet differences in the genomic context of their gene clusters allow to hypothesize about their distinct roles in arsenate metabolism with the 'Psr/Phs'-type molybdoenzyme being the most probable candidate respiratory arsenate reductase. Basing on multi-omics data, the pathways for aerobic and arsenate respiration were proposed. Our results start to bridge the vigorously increasing gap between homology-based predictions and experimentally verified metabolic processes, what is especially important for understudied microorganisms of novel lineages from deep subsurface environments of Eurasia, which remained separated from the rest of the biosphere for several geological periods. PMID- 28713356 TI - A Genotypic Analysis of Five P. aeruginosa Strains after Biofilm Infection by Phages Targeting Different Cell Surface Receptors. AB - Antibiotic resistance constitutes one of the most serious threats to the global public health and urgently requires new and effective solutions. Bacteriophages are bacterial viruses increasingly recognized as being good alternatives to traditional antibiotic therapies. In this study, the efficacy of phages, targeting different cell receptors, against Pseudomonas aeruginosa PAO1 biofilm and planktonic cell cultures was evaluated over the course of 48 h. Although significant reductions in the number of viable cells were achieved for both cases, the high level of adaptability of the bacteria in response to the selective pressure caused by phage treatment resulted in the emergence of phage resistant variants. To further investigate the genetic makeup of phage-resistant variants isolated from biofilm infection experiments, some of these bacteria were selected for phenotypic and genotypic characterization. Whole genome sequencing was performed on five phage-resistant variants and all of them carried mutations affecting the galU gene as well as one of pil genes. The sequencing analysis further revealed that three of the P. aeruginosa PAO1 variants carry large deletions (>200 kbp) in their genomes. Complementation of the galU mutants with wild-type galU in trans restored LPS expression on the bacterial cell surface of these bacterial strains and rendered the complemented strains to be sensitive to phages. This provides unequivocal evidence that inactivation of galU function was associated with resistance to the phages that uses LPS as primary receptors. Overall, this work demonstrates that P. aeruginosa biofilms can survive phage attack and develop phage-resistant variants exhibiting defective LPS production and loss of type IV pili that are well adapted to the biofilm mode of growth. PMID- 28713357 TI - Extensively Drug-Resistant Klebsiella pneumoniae Causing Nosocomial Bloodstream Infections in China: Molecular Investigation of Antibiotic Resistance Determinants, Informing Therapy, and Clinical Outcomes. AB - The rise in diversity of antimicrobial resistance phenotypes seen in Klebsiella pneumoniae is becoming a serious antibiotic management problem. We sought to investigate the molecular characteristics and clinical implications of extensively drug-resistant (XDR) K. pneumoniae isolated from different nosocomial bloodstream infections (BSIs) patients from July 2013 to November 2015. Even in combination treatment, meropenem did not protect against mortality of BSIs patients (P = 0.015). In contrast, tigecycline in combination with other antimicrobial agents significantly protected against mortality (P = 0.016). Antimicrobial susceptibility tests, molecular detection of antibiotic resistance determinants, conjugation experiments, multilocus sequence typing (MLST), S1 PFGE, Southern blot, SDS-PAGE, immunoblot analysis, and pulsed-field gel electrophoresis (PFGE) were used to characterize these isolates. These XDR K. pneumoniae strains were resistant to conventional antimicrobials except tigecycline and polymyxin B and co-harbored diverse resistance determinants. rmtB, blaKPC-2 as well as blaCTX-M-9 were located on a transferable plasmid of ~54.2 kb and the most predominant replicon type was IncF. 23 of the 35 isolates belonging the predominant clone were found to incorporate the globally disseminated sequence type ST11, but others including a unique, previously undiscovered lineage ST2281 (allelic profile: 4-1-1-22-7-4-35) were also found and characterized. The porins OmpK35 and OmpK36 were deficient in two carbapenemase-negative carbapenem-resistant strains, suggesting decreased drug uptake as a mechanism for carbapenem resistance. This study highlights the importance of tracking hospital acquired infections, monitoring modes of antibiotic resistance to improve health outcomes of BSIs patients and to highlight the problems of XDR K. pneumoniae dissemination in healthcare settings. PMID- 28713358 TI - Aquarium Viromes: Viromes of Human-Managed Aquatic Systems. AB - An aquarium ecosystem is home to many animal species providing conditions similar to native aquatic habitats but under highly controlled management. With a growing interest in understanding the interaction of microbiomes and resident animal health within aquarium environments, we undertook a metagenomic survey of viromes in seven aquarium systems with differing physicochemical and resident animal profiles. Our results show that a diverse array of viruses was represented in aquarium viromes, many of which were widespread in different aquarium systems (27 common viral families in all of the aquarium systems). Most viromes were dominated by DNA phages of the order Caudovirales as commonly found in other aquatic environments with average relative abundance greater than 64%. The composition and structure of aquarium viromes were associated with controlled system parameters, including nitrate, salinity, and temperature as well as resident animal profiles, indicating the close interaction of viromes with aquarium management practices. Furthermore, finding human associated viruses in a touch exhibit suggested that exposure of aquarium systems to human contact may lead to introduction of human cutaneous viruses into aquaria. This is consistent with the high abundance of skin microflora on the palms of healthy individuals and their detection in recreational waters, such as swimming pools. Lastly, assessment of antibiotic resistance genes (ARGs) in aquarium viromes revealed a unique signature of ARGs in different aquarium systems with trimethoprim being the most common. This is the first study to provide vital information on viromes and their unique relationships with management practices in a human-built and controlled aquarium environment. PMID- 28713359 TI - Exploring the Diversity of Field Strains of Brucella abortus Biovar 3 Isolated in West Africa. AB - Brucellosis is one of the most widespread bacterial zoonotic diseases in the world, affecting both humans and domestic and wild animals. Identification and biotyping of field strains of Brucella are of key importance for a better knowledge of the epidemiology of brucellosis, for identifying appropriate antigens, for managing disease outbreaks and for setting up efficient preventive and control programmes. Such data are required both at national and regional level to assess potential threats for public health. Highly discriminative genotyping methods such as the multiple locus variable number of tandem repeats analysis (MLVA) allow the comparison and assessment of genetic relatedness between field strains of Brucella within the same geographical area. In this study, MLVA biotyping data retrieved from the literature using a systematic review were compared using a clustering analysis and the Hunter-Gaston diversity index (HGDI). Thus, the analysis of the 42 MLVA genotyping results found in the literature on West Africa [i.e., from Ivory Coast (1), Niger (1), Nigeria (34), The Gambia (3), and Togo (3)] did not allow a complete assessment of the actual diversity among field strains of Brucella. However, it provided some preliminary indications on the co-existence of 25 distinct genotypes of Brucella abortus biovar 3 in this region with 19 genotypes from Nigeria, three from Togo and one from Ivory Coast, The Gambia, and Niger. The strong and urgent need for more sustainable molecular data on prevailing strains of Brucella in this sub-region of Africa and also on all susceptible species including humans is therefore highlighted. This remains a necessary stage to allow a comprehensive understanding of the relatedness between field strains of Brucella and the epidemiology of brucellosis within West Africa countries. PMID- 28713360 TI - Cyanobacterial Diversity in Microbial Mats from the Hypersaline Lagoon System of Araruama, Brazil: An In-depth Polyphasic Study. AB - Microbial mats are complex, micro-scale ecosystems that can be found in a wide range of environments. In the top layer of photosynthetic mats from hypersaline environments, a large diversity of cyanobacteria typically predominates. With the aim of strengthening the knowledge on the cyanobacterial diversity present in the coastal lagoon system of Araruama (state of Rio de Janeiro, Brazil), we have characterized three mat samples by means of a polyphasic approach. We have used morphological and molecular data obtained by culture-dependent and -independent methods. Moreover, we have compared different classification methodologies and discussed the outcomes, challenges, and pitfalls of these methods. Overall, we show that Araruama's lagoons harbor a high cyanobacterial diversity. Thirty-six unique morphospecies could be differentiated, which increases by more than 15% the number of morphospecies and genera already reported for the entire Araruama system. Morphology-based data were compared with the 16S rRNA gene phylogeny derived from isolate sequences and environmental sequences obtained by PCR-DGGE and pyrosequencing. Most of the 48 phylotypes could be associated with the observed morphospecies at the order level. More than one third of the sequences demonstrated to be closely affiliated (best BLAST hit results of >=99%) with cyanobacteria from ecologically similar habitats. Some sequences had no close relatives in the public databases, including one from an isolate, being placed as "loner" sequences within different orders. This hints at hidden cyanobacterial diversity in the mats of the Araruama system, while reinforcing the relevance of using complementary approaches to study cyanobacterial diversity. PMID- 28713361 TI - Exposure to Umbelliferone Reduces Ralstonia solanacearum Biofilm Formation, Transcription of Type III Secretion System Regulators and Effectors and Virulence on Tobacco. AB - Ralstonia solanacearum is one of the most devastating phytopathogens and causes bacterial wilt, which leads to severe economic loss due to its worldwide distribution and broad host range. Certain plant-derived compounds (PDCs) can impair bacterial virulence by suppressing pathogenic factors of R. solanacearum. However, the inhibitory mechanisms of PDCs in bacterial virulence remain largely unknown. In this study, we screened a library of coumarins and derivatives, natural PDCs with fused benzene and alpha-pyrone rings, for their effects on expression of the type III secretion system (T3SS) of R. solanacearum. Here, we show that umbelliferone (UM), a 7-hydroxycoumarin, suppressed T3SS regulator gene expression through HrpG-HrpB and PrhG-HrpB pathways. UM decreased gene expression of six type III effectors (RipX, RipD, RipP1, RipR, RipTAL, and RipW) of 10 representative effector genes but did not alter T2SS expression. In addition, biofilm formation of R. solanacearum was significantly reduced by UM, though swimming activity was not affected. We then observed that UM suppressed the wilting disease process by reducing colonization and proliferation in tobacco roots and stems. In summary, the findings reveal that UM may serve as a plant derived inhibitor to manipulate R. solanacearum T3SS and biofilm formation, providing proof of concept that these key virulence factors are potential targets for the integrated control of bacterial wilt. PMID- 28713362 TI - Biocontrol Agents Increase the Specific Rate of Patulin Production by Penicillium expansum but Decrease the Disease and Total Patulin Contamination of Apples. AB - Synthetic fungicides are commonly employed for the control of postharvest diseases of fruits. However, due to health concerns about the use of these chemicals, alternative control methods including biocontrol based on antagonistic yeasts are gaining in popularity. In this study, we investigated the effects of two biocontrol yeasts, Rhodotorula mucilaginosa strain 3617 and Rhodotorula kratochvilovae strain LS11, on blue mold and patulin (PAT) contamination caused by Penicillium expansum strains PY and FS7 in artificially inoculated Fuji apples stored at 20 degrees C for 9 days. To correlate the development of the P. expansum strains in yeast-treated and untreated apples with PAT production, we quantified their biomass in the infected fruits using a recently published quantitative real-time polymerase chain reaction method based on specific primers for patF, a gene from P. expansum that is involved in PAT biosynthesis. Both yeasts significantly reduced the disease incidence caused by the two strains of P. expansum up to 5-7 days of incubation, and lowered their biomass and the progression of symptoms up to 9 days. Interestingly, both yeasts strains increased the rate of PAT production (expressed as ng patulin/MUg fungal DNA) by the two pathogenic strains. Nevertheless, both biocontrol agents reduced the total PAT contamination, especially in the case of P. expansum strain FS7, the higher PAT producer of the two tested P. expansum strains. Comparing between the yeast strains, R. kratochvilovae LS11 was more effective than R. mucilaginosa 3617 for the control of P. expansum. PMID- 28713363 TI - Geographic Distribution of Ammonia-Oxidizing Archaea along the Kuril Islands in the Western Subarctic Pacific. AB - Community composition and abundance of ammonia-oxidizing archaea (AOA) in the ocean were affected by different physicochemical conditions, but their responses to physical barriers (such as a chain of islands) were largely unknown. In our study, geographic distribution of the AOA from the surface photic zone to the deep bathypelagic waters in the western subarctic Pacific adjacent to the Kuril Islands was investigated using pyrosequencing based on the ammonia monooxygenase subunit A (amoA) gene. Genotypes of clusters A and B dominated in the upper euphotic zone and the deep waters, respectively. Quantitative PCR assays revealed that the occurrence and ammonia-oxidizing activity of ammonia-oxidizing archaea (AOA) reached their maxima at the depth of 200 m, where a higher diversity and abundance of actively transcribed AOA was observed at the station located in the marginal sea exposed to more terrestrial input. Similar community composition of AOA observed at the two stations adjacent to the Kuril Islands maybe due to water exchange across the Bussol Strait. They distinct from the station located in the western subarctic gyre, where sub-cluster WCAII had a specific distribution in the surface water, and this sub-cluster seemed having a confined distribution in the western Pacific. Habitat-specific groupings of different WCB sub-clusters were observed reflecting the isolated microevolution existed in cluster WCB. The effect of the Kuril Islands on the phylogenetic composition of AOA between the Sea of Okhotsk and the western subarctic Pacific is not obvious, possibly because our sampling stations are near to the Bussol Strait, the main gateway through which water is exchanged between the Sea of Okhotsk and the Pacific. The vertical and horizontal distribution patterns of AOA communities among stations along the Kuril Islands were essentially determined by the in situ prevailing physicochemical gradients along the two dimensions. PMID- 28713364 TI - Immunomodulatory Activities of a Fungal Protein Extracted from Hericium erinaceus through Regulating the Gut Microbiota. AB - A single-band protein (HEP3) was isolated from Hericium erinaceus using a chemical separation combined with pharmacodynamic evaluation methods. This protein exhibited immunomodulatory activity in lipopolysaccharide-activated RAW 264.7 macrophages by decreasing the overproduction of tumor necrosis factor alpha, interleukin (IL)-1beta, and IL-6, and downregulating the expression of inducible nitric oxide synthase and nuclear factor-kappaB p65. Further researches revealed that HEP3 could improve the immune system via regulating the composition and metabolism of gut microbiota to activate the proliferation and differentiation of T cells, stimulate the intestinal antigen-presenting cells in high-dose cyclophosphamide-induced immunotoxicity in mice, and play a prebiotic role in the case of excessive antibiotics in inflammatory bowel disease model mice. Aided experiments also showed that HEP3 could be used as an antitumor immune inhibitor in tumor-burdened mice. The results of the present study suggested that fungal protein from H. erinaceus could be used as a drug or functional food ingredient for immunotherapy because of its immunomodulatory activities. PMID- 28713365 TI - What's Normal? Immune Profiling of Human Milk from Healthy Women Living in Different Geographical and Socioeconomic Settings. AB - Human milk provides a very wide range of nutrients and bioactive components, including immune factors, human milk oligosaccharides, and a commensal microbiota. These factors are essential for interconnected processes including immunity programming and the development of a normal infant gastrointestinal microbiome. Newborn immune protection mostly relies on maternal immune factors provided through milk. However, studies dealing with an in-depth profiling of the different immune compounds present in human milk and with the assessment of their natural variation in healthy women from different populations are scarce. In this context, the objective of this work was the detection and quantification of a wide array of immune compounds, including innate immunity factors (IL1beta, IL6, IL12, INFgamma, TNFalpha), acquired immunity factors (IL2, IL4, IL10, IL13, IL17), chemokines (IL8, Groalpha, MCP1, MIP1beta), growth factors [IL5, IL7, epidermal growth factor (EGF), granulocyte colony-stimulating factor, granulocyte macrophage colony-stimulating factor, TGFbeta2], and immunoglobulins (IgA, IgG, IgM), in milk produced by healthy women of different ethnicities living in different geographic, dietary, socioeconomic, and environmental settings. Among the analyzed factors, IgA, IgG, IgM, EGF, TGFbeta2, IL7, IL8, Groalpha, and MIP1beta were detected in all or most of the samples collected in each population and, therefore, this specific set of compounds might be considered as the "core" soluble immune factors in milk produced by healthy women worldwide. This approach may help define which immune factors are (or are not) common in milk produced by women living in various conditions, and to identify host, lifestyle, and environmental factors that affect the immunological composition of this complex biological fluid. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT02670278. PMID- 28713366 TI - Intratumoral Lentivector-Mediated TGF-beta1 Gene Downregulation As a Potent Strategy for Enhancing the Antitumor Effect of Therapy Composed of Cyclophosphamide and Dendritic Cells. AB - Vaccination with dendritic cells (DCs) stimulated with tumor antigens can induce specific cellular immune response that recognizes a high spectrum of tumor antigens. However, the ability of cancer cells to produce immunosuppressive factors drastically decreases the antitumor activity of DCs. The main purpose of the study was to improve the effectiveness of DC-based immunotherapy or chemoimmunotherapy composed of cyclophosphamide (CY) and DCs by application of lentivectors (LVs)-encoding short hairpin RNA specific for TGF-beta1 (shTGFbeta1 LVs). We observed that s.c. inoculation of both MC38 cells with silenced expression of TGF-beta1 (MC38/shTGF-beta1) and direct intratumoral application of shTGFbeta1 LVs contributed to reduction of suppressor activity of myeloid cells and Tregs in tumor. Contrary to expectations, in mice bearing wild tumor, the application of shTGFbeta1 LVs prior to vaccination with bone marrow-derived DC stimulated with tumor antigens (BMDC/TAg) did not influence myeloid-derived suppressor cell (MDSC) infiltration into tumor. As a result, we observed only minor MC38 tumor growth inhibition (TGI) accompanied by systemic antitumor response activation comparable to that obtained for negative control (shN). However, when the proposed scheme was complemented by pretreatment with a low dose of CY, we noticed high MC38 TGI together with decreased number of MDSCs in tumor and induction of Th1-type response. Moreover, in both schemes of treatment, LVs (shTGFbeta1 as well as shN) induced high influx of CTLs into tumor associated probably with the viral antigen introduction into tumor microenvironment. Concluding, the application of shTGFbeta1 LVs alone or in combination with DC based vaccines is not sufficient for long-lasting elimination of suppression in tumor. However, simultaneous reduction of TGF-beta1 in tumor microenvironment and its remodeling by pretreatment with a low dose of CY facilitates the settlement of peritumorally inoculated DCs and supports them in restoration and activation of a potent antitumor response. PMID- 28713368 TI - The SpTransformer Gene Family (Formerly Sp185/333) in the Purple Sea Urchin and the Functional Diversity of the Anti-Pathogen rSpTransformer-E1 Protein. AB - The complex innate immune system of sea urchins is underpinned by several multigene families including the SpTransformer family (SpTrf; formerly Sp185/333) with estimates of ~50 members, although the family size is likely variable among individuals of Strongylocentrotus purpuratus. The genes are small with similar structure, are tightly clustered, and have several types of repeats in the second of two exons and that surround each gene. The density of repeats suggests that the genes are positioned within regions of genomic instability, which may be required to drive sequence diversification. The second exon encodes the mature protein and is composed of blocks of sequence called elements that are present in mosaics of defined element patterns and are the major source of sequence diversity. The SpTrf genes respond swiftly to immune challenge, but only a single gene is expressed per phagocyte. Many of the mRNAs appear to be edited and encode proteins with altered and/or missense sequence that are often truncated, of which some may be functional. The standard SpTrf protein structure is an N-terminal glycine-rich region, a central RGD motif, a histidine-rich region, and a C terminal region. Function is predicted from a recombinant protein, rSpTransformer E1 (rSpTrf-E1), which binds to Vibrio and Saccharomyces, but not to Bacillus, and binds tightly to lipopolysaccharide, beta-1,3-glucan, and flagellin, but not to peptidoglycan. rSpTrf-E1 is intrinsically disordered but transforms to alpha helical structure in the presence of binding targets including lipopolysaccharide, which may underpin the characteristics of binding to multiple targets. SpTrf proteins associate with coelomocyte membranes, and rSpTrf-E1 binds specifically to phosphatidic acid (PA). When rSpTrf-E1 is bound to PA in liposome membranes, it induces morphological changes in liposomes that correlate with PA clustering and leakage of luminal contents, and it extracts or removes PA from the bilayer. The multitasking activities of rSpTrf-E1 infer multiple and perhaps overlapping activities for the hundreds of native SpTrf proteins that are produced by individual sea urchins. This likely generates a flexible and highly protective immune system for the sea urchin in its marine habitat that it shares with broad arrays of microbes that may be pathogens and opportunists. PMID- 28713369 TI - Sestrin2 Suppresses Classically Activated Macrophages-Mediated Inflammatory Response in Myocardial Infarction through Inhibition of mTORC1 Signaling. AB - Myocardial infarction (MI) triggers an intense inflammatory response that is essential for dead tissue clearance but also detrimental to cardiac repair. Macrophages are active and critical players in the inflammatory response after MI. Understanding the molecular mechanisms by which macrophage-mediated inflammatory response is regulated is important for designing new therapeutic interventions for MI. In the current study, we examined the role of Sestrin2, which is a stress-inducible protein that regulate metabolic homeostasis, in the regulation of inflammatory response of cardiac macrophages after MI. We found that cardiac macrophages upregulated Sestrin2 expression in a mouse MI model. Using a lentiviral transduction system to overexpress Sestrin2 in polarized M1 and M2 macrophages, we revealed that Sestrin2 predominantly functioned on M1 rather than M2 macrophages. Sestrin2 overexpression suppressed inflammatory response of M1 macrophages both in vitro and in vivo. Furthermore, in the mouse MI model with selective depletion of endogenous macrophages and adoptive transfer of exogenous Sestrin2-overexpressing macrophages, the anti-inflammatory and repair-promoting effect of Sestrin2-overexpressing macrophages was demonstrated. Furthermore, Sestrin2 significantly inhibited mTORC1 signaling in M1 macrophages. Taken together, our study indicates the importance of Sestrin2 for suppression of M1 macrophage-mediated cardiac inflammation after MI. PMID- 28713367 TI - Nanobodies As Tools to Understand, Diagnose, and Treat African Trypanosomiasis. AB - African trypanosomes are strictly extracellular protozoan parasites that cause diseases in humans and livestock and significantly affect the economic development of sub-Saharan Africa. Due to an elaborate and efficient (vector) parasite-host interplay, required to complete their life cycle/transmission, trypanosomes have evolved efficient immune escape mechanisms that manipulate the entire host immune response. So far, not a single field applicable vaccine exists, and chemotherapy is the only strategy available to treat the disease. Current therapies, however, exhibit high drug toxicity and an increased drug resistance is being reported. In addition, diagnosis is often hampered due to the inadequacy of current diagnostic procedures. In the context of tackling the shortcomings of current treatment and diagnostic approaches, nanobodies (Nbs, derived from the heavy chain-only antibodies of camels and llamas) might represent unmet advantages compared to conventional tools. Indeed, the combination of their small size, high stability, high affinity, and specificity for their target and tailorability represents a unique advantage, which is reflected by their broad use in basic and clinical research to date. In this article, we will review and discuss (i) diagnostic and therapeutic applications of Nbs that are being evaluated in the context of African trypanosomiasis, (ii) summarize new strategies that are being developed to optimize their potency for advancing their use, and (iii) document on unexpected properties of Nbs, such as inherent trypanolytic activities, that besides opening new therapeutic avenues, might offer new insight in hidden biological activities of conventional antibodies. PMID- 28713370 TI - Persistence of Activated and Adaptive-Like NK Cells in HIV+ Individuals despite 2 Years of Suppressive Combination Antiretroviral Therapy. AB - Innate immune dysfunction persists in HIV+ individuals despite effective combination antiretroviral therapy (cART). We recently demonstrated that an adaptive-like CD56dim NK cell population lacking the signal transducing protein FcRgamma is expanded in HIV+ individuals. Here, we analyzed a cohort of HIV+ men who have sex with men (MSM, n = 20) at baseline and following 6, 12, and 24 months of cART and compared them with uninfected MSM (n = 15) to investigate the impact of cART on NK cell dysfunction. Proportions of NK cells expressing markers of early (CD69+) and late (HLA-DR+/CD38+) activation were elevated in cART-naive HIV+ MSM (p = 0.004 and 0.015, respectively), as were FcRgamma- NK cells (p = 0.003). Using latent growth curve modeling, we show that cART did not reduce levels of FcRgamma- NK cells (p = 0.115) or activated HLA-DR+/CD38+ NK cells (p = 0.129) but did reduce T cell and monocyte activation (p < 0.001 for all). Proportions of FcRgamma- NK cells were not associated with NK cell, T cell, or monocyte activation, suggesting different factors drive CD56dim FcRgamma- NK cell expansion and immune activation in HIV+ individuals. While proportions of activated CD69+ NK cells declined significantly on cART (p = 0.003), the rate was significantly slower than the decline of T cell and monocyte activation, indicating a reduced potency of cART against NK cell activation. Our findings indicate that 2 years of suppressive cART have no impact on CD56dim FcRgamma- NK cell expansion and that NK cell activation persists after normalization of other immune parameters. This may have implications for the development of malignancies and co-morbidities in HIV+ individuals on cART. PMID- 28713371 TI - Regulation of Subunit-Specific Germinal Center B Cell Responses to the HIV-1 Envelope Glycoproteins by Antibody-Mediated Feedback. AB - The regulation of germinal center (GC) B cell responses to single epitopes is well investigated. How monoclonal B cells are regulated within the polyclonal B cell response to protein antigens is less so. Here, we investigate the primary GC B cell response after injection of mice with HIV-1 envelope glycoproteins. We demonstrate that single GCs are seeded by a diverse number of B cell clones shortly after a single immunization and that the presence of Env-specific antibodies can inhibit the development of early GC B cells. Importantly, the suppression was dependent on the GC B cells and the infused antibodies to target the same subunit of the injected HIV-1 envelope glycoproteins. An affinity dependent antibody feedback has previously been shown to regulate GC B cell development. Here, we propose that this antibody-based feedback acts on GC B cells only if they target the same or overlapping epitopes. This study provides important basic information of GC B cell regulation, and for future vaccine designs with aim to elicit neutralizing antibodies against HIV-1. PMID- 28713372 TI - Nanoparticle-Formulated Curcumin Prevents Posttherapeutic Disease Reactivation and Reinfection with Mycobacterium tuberculosis following Isoniazid Therapy. AB - Curcumin, the bioactive component of turmeric also known as "Indian Yellow Gold," exhibits therapeutic efficacy against several chronic inflammatory and infectious diseases. Even though considered as a wonder drug pertaining to a myriad of reported benefits, the translational potential of curcumin is limited by its low systemic bioavailability due to its poor intestinal absorption, rapid metabolism, and rapid systemic elimination. Therefore, the translational potential of this compound is specifically challenged by bioavailability issues, and several laboratories are making efforts to improve its bioavailability. We developed a simple one-step process to generate curcumin nanoparticles of ~200 nm in size, which yielded a fivefold enhanced bioavailability in mice over regular curcumin. Curcumin nanoparticles drastically reduced hepatotoxicity induced by antitubercular antibiotics during treatment in mice. Most interestingly, co treatment of nanoparticle-formulated curcumin along with antitubercular antibiotics dramatically reduced the risk for disease reactivation and reinfection, which is the major shortfall of current antibiotic treatment adopted by Directly Observed Treatment Short-course. Furthermore, nanoparticle-formulated curcumin significantly reduced the time needed for antibiotic therapy to obtain sterile immunity, thereby reducing the possibility of generating drug-resistant variants of the organisms. Therefore, adjunct therapy of nano-formulated curcumin with enhanced bioavailability may be beneficial to treatment of tuberculosis and possibly other diseases. PMID- 28713373 TI - 15-Deoxy-Delta-12,14-Prostaglandin J2 Inhibits Lung Inflammation and Remodeling in Distinct Murine Models of Asthma. AB - 15-deoxy-Delta-12,14-prostaglandin J2 (15d-PGJ2) has been described as an anti inflammatory lipid mediator in several in vitro and in vivo studies, but its effect on allergic pulmonary inflammation remains elusive. The aim of this study was to investigate the therapeutic potential of 15d-PGJ2 based on distinct murine models of allergic asthma triggered by either ovalbumin (OVA) or house dust mite extract (HDM). Characteristics of lung inflammation, airway hyper-reactivity (AHR), mucus exacerbation, and lung remodeling in sensitized A/J mice treated or not with 15d-PGJ2 were assessed. 15d-PGJ2 treatments were carried out systemically or topically given via subcutaneous injection or intranasal instillation, respectively. Analyses were carried out 24 h after the last allergen provocation. Irrespective of the route of administration, 15d-PGJ2 significantly inhibited the peribronchial accumulation of eosinophils and neutrophils, subepithelial fibrosis and also mucus exacerbation caused by either OVA or HDM challenge. The protective effect of 15d-PGJ2 occurred in parallel with inhibition of allergen-induced AHR and lung tissue production of pro-inflammatory cytokines, such as interleukin (IL)-5, IL-13, IL-17, and TNF-alpha. Finally, 15d PGJ2 was found effective in inhibiting NF-kappaB phosphorylation upon HDM challenge as measured by Western blotting. In conclusion, our findings suggest that 15d-PGJ2 can reduce crucial features of asthma, including AHR, lung inflammation, and remodeling in distinct murine models of the disease. These effects are associated with a decrease in lung tissue generation of pro inflammatory cytokines by a mechanism related to downregulation of NF-kappaB phosphorylation. PMID- 28713374 TI - The Selective Phosphoinoside-3-Kinase p110delta Inhibitor IPI-3063 Potently Suppresses B Cell Survival, Proliferation, and Differentiation. AB - The class I phosphoinoside-3-kinases (PI3Ks) are important enzymes that relay signals from cell surface receptors to downstream mediators driving cellular functions. Elevated PI3K signaling is found in B cell malignancies and lymphocytes of patients with autoimmune disease. The p110delta catalytic isoform of PI3K is a rational target since it is critical for B lymphocyte development, survival, activation, and differentiation. In addition, activating mutations in PIK3CD encoding p110delta cause a human immunodeficiency known as activated PI3K delta syndrome. Currently, idelalisib is the only selective p110delta inhibitor that has been FDA approved to treat certain B cell malignancies. p110delta inhibitors can suppress autoantibody production in mouse models, but limited clinical trials in human autoimmunity have been performed with PI3K inhibitors to date. Thus, there is a need for additional tools to understand the effect of pharmacological inhibition of PI3K isoforms in lymphocytes. In this study, we tested the effects of a potent and selective p110delta inhibitor, IPI-3063, in assays of B cell function. We found that IPI-3063 potently reduced mouse B cell proliferation, survival, and plasmablast differentiation while increasing antibody class switching to IgG1, almost to the same degree as a pan-PI3K inhibitor. Similarly, IPI-3063 potently inhibited human B cell proliferation in vitro. The p110gamma isoform has partially overlapping roles with p110delta in B cell development, but little is known about its role in B cell function. We found that the p110gamma inhibitor AS-252424 had no significant impact on B cell responses. A novel dual p110delta/gamma inhibitor, IPI-443, had comparable effects to p110delta inhibition alone. These findings show that p110delta is the dominant isoform mediating B cell responses and establish that IPI-3063 is a highly potent molecule useful for studying p110delta function in immune cells. PMID- 28713375 TI - Interferon-Lambda: A Potent Regulator of Intestinal Viral Infections. AB - Interferon-lambda (IFN-lambda) is a recently described cytokine found to be of critical importance in innate immune regulation of intestinal viruses. Endogenous IFN-lambda has potent antiviral effects and has been shown to control multiple intestinal viruses and may represent a factor that contributes to human variability in response to infection. Importantly, recombinant IFN-lambda has therapeutic potential against enteric viral infections, many of which lack other effective treatments. In this mini-review, we describe recent advances regarding IFN-lambda-mediated regulation of enteric viruses with important clinical relevance including rotavirus, reovirus, and norovirus. We also briefly discuss IFN-lambda interactions with other cytokines important in the intestine, and how IFN-lambda may play a role in regulation of intestinal viruses by the commensal microbiome. Finally, we indicate currently outstanding questions regarding IFN lambda control of enteric infections that remain to be explored to enhance our understanding of this important immune molecule. PMID- 28713377 TI - Th1 and Th17 Cells and Associated Cytokines Discriminate among Clinically Isolated Syndrome and Multiple Sclerosis Phenotypes. AB - Multiple sclerosis (MS) is a chronic, inflammatory, and demyelinating disease of the central nervous system. It is a heterogeneous pathology that can follow different clinical courses, and the mechanisms that underlie the progression of the immune response across MS subtypes remain incompletely understood. Here, we aimed to determine differences in the immunological status among different MS clinical subtypes. Blood samples from untreated patients diagnosed with clinically isolated syndrome (CIS) (n = 21), different clinical forms of MS (n = 62) [relapsing-remitting (RRMS), secondary progressive, and primary progressive], and healthy controls (HCs) (n = 17) were tested for plasma levels of interferon (IFN)-gamma, IL-10, TGF-beta, IL-17A, and IL-17F by immunoanalysis. Th1 and Th17 lymphocyte frequencies were determined by flow cytometry. Our results showed that IFN-gamma levels and the IFN-gamma/IL-10 ratio were higher in CIS patients than in RRMS patients and HC. Th1 cell frequencies were higher in CIS and RRMS than in progressive MS, and RRMS had a higher Th17 frequency than CIS. The Th1/Th17 cell ratio was skewed toward Th1 in CIS compared to MS phenotypes and HC. Receiver operating characteristic statistical analysis determined that IFN-gamma, the IFN gamma/IL-10 ratio, Th1 cell frequency, and the Th1/Th17 cell ratio discriminated among CIS and MS subtypes. A subanalysis among patients expressing high IL-17F levels showed that IL-17F and the IFN-gamma/IL-17F ratio discriminated between disease subtypes. Overall, our data showed that CIS and MS phenotypes displayed distinct Th1- and Th17-related cytokines and cell profiles and that these immune parameters discriminated between clinical forms. Upon validation, these parameters might be useful as biomarkers to predict disease progression. PMID- 28713376 TI - Myristoylation: An Important Protein Modification in the Immune Response. AB - Protein N-myristoylation is a cotranslational lipidic modification specific to the alpha-amino group of an N-terminal glycine residue of many eukaryotic and viral proteins. The ubiquitous eukaryotic enzyme, N-myristoyltransferase, catalyzes the myristoylation process. Precisely, attachment of a myristoyl group increases specific protein-protein interactions leading to subcellular localization of myristoylated proteins with its signaling partners. The birth of the field of myristoylation, a little over three decades ago, has led to the understanding of the significance of protein myristoylation in regulating cellular signaling pathways in several biological processes especially in carcinogenesis and more recently immune function. This review discusses myristoylation as a prerequisite step in initiating many immune cell signaling cascades. In particular, we discuss the hitherto unappreciated implication of myristoylation during myelopoiesis, innate immune response, lymphopoiesis for T cells, and the formation of the immunological synapse. Furthermore, we discuss the role of myristoylation in inducing the virological synapse during human immunodeficiency virus infection as well as its clinical implication. This review aims to summarize existing knowledge in the field and to highlight gaps in our understanding of the role of myristoylation in immune function so as to further investigate into the dynamics of myristoylation-dependent immune regulation. PMID- 28713378 TI - The Impact of Gut Microbiota on Gender-Specific Differences in Immunity. AB - Males and females are known to have gender-specific differences in their immune system and gut microbiota composition. Whether these differences in gut microbiota composition are a cause or consequence of differences in the immune system is not known. To investigate this issue, gut microbiota from conventional males or females was transferred to germ-free (GF) animals of the same or opposing gender. We demonstrate that microbiota-independent gender differences in immunity are already present in GF mice. In particular, type I interferon signaling was enhanced in the intestine of GF females. Presumably, due to these immune differences bacterial groups, such as Alistipes, Rikenella, and Porphyromonadaceae, known to expand in the absence of innate immune defense mechanism were overrepresented in the male microbiota. The presence of these bacterial groups was associated with induction of weight loss, inflammation, and DNA damage upon transfer of the male microbiota to female GF recipients. In summary, our data suggest that microbiota-independent gender differences in the immune system select a gender-specific gut microbiota composition, which in turn further contributes to gender differences in the immune system. PMID- 28713379 TI - OP9 Feeder Cells Are Superior to M2-10B4 Cells for the Generation of Mature and Functional Natural Killer Cells from Umbilical Cord Hematopoietic Progenitors. AB - Adoptive natural killer (NK) cell therapy relies on the acquisition of large numbers of mature and functional NK cells. An option for future immunotherapy treatments is to use large amounts of NK cells derived and differentiated from umbilical cord blood (UCB) CD34+ hematopoietic stem cells (HSCs), mainly because UCB is one of the most accessible HSC sources. In our study, we compared the potential of two stromal cell lines, OP9 and M2-10B4, for in vitro generation of mature and functional CD56+ NK cells from UCB CD34+ HSC. We generated higher number of CD56+ NK cells in the presence of the OP9 cell line than when they were generated in the presence of M2-10B4 cells. Furthermore, higher frequency of CD56+ NK cells was achieved earlier when cultures were performed with the OP9 cells than with the M2-10B4 cells. Additionally, we studied in detail the maturation stages of CD56+ NK cells during the in vitro differentiation process. Our data show that by using both stromal cell lines, CD34+ HSC in vitro differentiated into the terminal stages 4-5 of maturation resembled the in vivo differentiation pattern of human NK cells. Higher frequencies of more mature NK cells were reached earlier by using OP9 cell line than M2-10B4 cells. Alternatively, we observed that our in vitro NK cells expressed similar levels of granzyme B and perforin, and there were no significant differences between cultures performed in the presence of OP9 cell line or M2-10B4 cell line. Likewise, degranulation and cytotoxic activity against K562 target cells were very similar in both culture conditions. The results presented here provide an optimal strategy to generate high numbers of mature and functional NK cells in vitro, and point toward the use of the OP9 stromal cell line to accelerate the culture procedure to obtain them. Furthermore, this method could establish the basis for the generation of mature NK cells ready for cancer immunotherapy. PMID- 28713380 TI - Targeting the Human T-Cell Inducible COStimulator Molecule with a Monoclonal Antibody Prevents Graft-vs-Host Disease and Preserves Graft vs Leukemia in a Xenograft Murine Model. AB - BACKGROUND: Graft-vs-host disease (GVHD) is a major complication of allogenic bone marrow transplantation (BMT). Targeting costimulatory molecules with antagonist antibodies could dampen the excessive immune response that occurs, while preserving the beneficial graft vs leukemia (GVL) of the allogeneic response. Previous studies using a mouse model of GVHD have shown that targeting the T-cell Inducible COStimulator (ICOS, CD278) molecule is beneficial, but it is unclear whether the same applies to human cells. METHODS: Here, we assessed whether a monoclonal antibody (mAb) to human ICOS was able to antagonize the costimulatory signal delivered in vivo to human T cells. To test this hypothesis, we used a xenogeneic model of GVHD where human peripheral blood mononuclear cells were adoptively transferred in immunocompromised NOD.SCID.gc-null mice (NSG). RESULTS: In this model, control mice invariably lost weight and died by day 50. In contrast, 65% of the mice receiving a single injection of the anti-hICOS mAb survived beyond 100 days. Moreover, a significant improvement in survival was obtained in a curative xeno-GVHD setting. Mechanistically, administration of the anti-hICOS mAb was associated with a strong reduction in perivascular infiltrates in liver and lungs and reduction in frequencies and numbers of human T cells in the spleen. In addition, the mAb prevented T-cell expansion in the blood during xeno-GVHD. Importantly, GVHD-protected mice retained the ability to control the P815 mastocytoma cell line, mimicking GVL in humans. CONCLUSION: A mAb-targeting human ICOS alleviated GVHD without impairing GVL in a xenograft murine model. Thus, ICOS represents a promising target in the management of BMT, preventing GVHD while preserving GVL. PMID- 28713381 TI - Key Features of Gamma-Delta T-Cell Subsets in Human Diseases and Their Immunotherapeutic Implications. AB - The unique features of gamma-delta (gammadelta) T cells, related to their antigen recognition capacity, their tissue tropism, and their cytotoxic function, make these cells ideal candidates that could be targeted to induce durable immunity in the context of different pathologies. In this review, we focus on the main characteristics of human gammadelta T-cell subsets in diseases and the key mechanisms that could be explored to target these cells. PMID- 28713382 TI - Recent Advances on Nutrition in Treatment of Acute Pancreatitis. AB - Acute pancreatitis (AP) is a common abdominal acute inflammatory disorder and the leading cause of hospital admission for gastrointestinal disorders in many countries. Clinical manifestations of AP vary from self-limiting local inflammation to devastating systemic pathological conditions causing significant morbidity and mortality. To date, despite extensive efforts in translating promising experimental therapeutic targets in clinical trials, disease-specific effective remedy remains obscure, and supportive care has still been the primary treatment for this disease. Emerging evidence, in light of the current state of pathophysiology of AP, has highlighted that strategic initiation of nutrition with appropriate nutrient supplementation are key to limit local inflammation and to prevent or manage AP-associated complications. The current review focuses on recent advances on nutritional interventions including enteral versus parenteral nutrition strategies, and nutritional supplements such as probiotics, glutamine, omega-3 fatty acids, and vitamins in clinical AP, hoping to advance current knowledge and practice related to nutrition and nutritional supplements in clinical management of AP. PMID- 28713384 TI - Intact CD100-CD72 Interaction Necessary for TCR-Induced T Cell Proliferation. AB - Targeting CD100 by antibody blockade is a potential therapeutic strategy for cancers, but the functional effects on T cells following blockade of this immune activating molecule are rarely considered. Indeed, CD100 is highly expressed in T cells and anti-CD100 antibodies play a role during T cell proliferation; however, the outcome varies from different studies and the underlying mechanism is still unclear. To address this, monoclonal antibody clones directed against CD100 were evaluated. In their soluble form, four of these antibodies significantly reduced the expansion of T cells in the presence of bead-bound anti-CD3/CD28, either in total peripheral blood mononuclear cell or purified T cell culture systems. Similar inhibition was seen when blocking CD100-CD72 interaction by soluble anti CD72 instead of anti-CD100 antibodies. Conversely, restoring the interaction by CD72-Fc eliminated the soluble anti-CD100-induced inhibitory effect. Taken together, these results reveal that T cell proliferation is regulated by CD100 via interaction with CD72. They further establish an in vitro system to evaluate the inhibitory effect of anti-CD100 antibodies on T cells, to which attention should be paid in clinical trials in order to avoid potential side effects. PMID- 28713385 TI - Tumor-Associated Tertiary Lymphoid Structures: Gene-Expression Profiling and Their Bioengineering. AB - Tertiary lymphoid structures (TLSs) have been identified in the parenchyma and/or in the peripheral margins of human solid tumors. Uncovering the functional nature of these structures is the subject of much intensive investigation. Studies have shown a direct correlation of the presence of human tumor-localized TLS and better patient outcome (e.g., increase in overall survival) in certain solid tumor histologies, but not all. We had identified a tumor-derived immune gene expression signature, encoding 12 distinct chemokines, which could reliably identify the presence of TLSs, of different degrees, in various human solid tumors. We are focused on understanding the influence of TLSs on the tumor microenvironment and leveraging this understanding to both manipulate the antitumor immune response and potentially enhance immunotherapy applications. Moreover, as not all human solid tumors show the presence of these lymphoid structures, we are embarking on bioengineering approaches to design and build "designer" TLSs to address, and potentially overcome, an unmet medical need in cancer patients whose tumors lack such lymphoid structures. PMID- 28713386 TI - Impairment of Granzyme B-Producing Regulatory B Cells Correlates with Exacerbated Rheumatoid Arthritis. AB - Hyperactivated B cells have been demonstrated the contribution to the development of rheumatoid arthritis (RA). While the recognition of the negative regulatory function of B cells further promoted our understanding of their pathogenic role in RA. Recently, a new population of granzyme B (GrB)-producing B cells was identified, which was proved to be involved in cancer and infectious diseases. However, their characteristics and roles in RA remain to be elucidated. In the present study, we aim to further characterize whether B cells could produce GrB and reveal their potential role in the pathogenesis of RA. Here, we further demonstrated peripheral blood B cells from healthy individuals could produce and secrete GrB, which could be enhanced by IL-21 and/or anti-B-cell receptor stimulation. These cells could negatively regulate Th1 and Th17 cells partly via downregulating TCR zeta chain and inducing T cell apoptosis, which might be termed as GrB-producing regulatory B cells (Bregs). These GrB-producing Bregs were significantly decreased under RA circumstance concomitant of lower levels of IL-21 receptor, with impaired regulatory functions on Th1 and Th17 cells. Moreover, the frequencies of these cells were negatively correlated with RA patient disease activity and clinical features. After effective therapy with disease remission in RA, these GrB-producing Bregs could be recovered. Therefore, our data revealed that B cells could produce GrB with immunosuppressive functions, and the impairment of this Breg subset was correlated with RA pathogenesis. PMID- 28713387 TI - Human CD6 Down-Modulation following T-Cell Activation Compromises Lymphocyte Survival and Proliferative Responses. AB - Available evidence indicates that the CD6 lymphocyte surface receptor is involved in T-cell developmental and activation processes, by facilitating cell-to-cell adhesive contacts with antigen-presenting cells and likely modulating T-cell receptor (TCR) signaling. Here, we show that in vitro activation of human T cells under different TCR-ligation conditions leads to surface downregulation of CD6 expression. This phenomenon was (i) concomitant to increased levels of soluble CD6 (sCD6) in culture supernatants, (ii) partially reverted by protease inhibitors, (iii) not associated to CD6 mRNA down-regulation, and (iv) reversible by stimulus removal. CD6 down-modulation inversely correlated with the upregulation of CD25 in both FoxP3- (Tact) and FoxP3+ (Treg) T-cell subsets. Furthermore, ex vivo analysis of peripheral CD4+ and CD8+ T cells with activated (CD25+) or effector memory (effector memory T cell, CD45RA-CCR7-) phenotype present lower CD6 levels than their naive or central memory (central memory T cell, CD45RA-CCR7+) counterparts. CD6lo/- T cells resulting from in vitro T-cell activation show higher apoptosis and lower proliferation levels than CD6hi T cells, supporting the relevance of CD6 in the induction of proper T-cell proliferative responses and resistance to apoptosis. Accordingly, CD6 transfectants also showed higher viability when exposed to TCR-independent apoptosis-inducing conditions in comparison with untransfected cells. Taken together, these results provide insight into the origin of sCD6 and the previously reported circulating CD6-negative T-cell subset in humans, as well as into the functional consequences of CD6 down-modulation on ongoing T-cell responses, which includes sensitization to apoptotic events and attenuation of T cell proliferative responses. PMID- 28713383 TI - The Toxicological Mechanisms of Environmental Soot (Black Carbon) and Carbon Black: Focus on Oxidative Stress and Inflammatory Pathways. AB - The environmental soot and carbon blacks (CBs) cause many diseases in humans, but their underlying mechanisms of toxicity are still poorly understood. Both are formed after the incomplete combustion of hydrocarbons but differ in their constituents and percent carbon contents. For the first time, "Sir Percival Pott" described soot as a carcinogen, which was subsequently confirmed by many others. The existing data suggest three main types of diseases due to soot and CB exposures: cancer, respiratory diseases, and cardiovascular dysfunctions. Experimental models revealed the involvement of oxidative stress, DNA methylation, formation of DNA adducts, and Aryl hydrocarbon receptor activation as the key mechanisms of soot- and CB-induced cancers. Metals including Si, Fe, Mn, Ti, and Co in soot also contribute in the reactive oxygen species (ROS) mediated DNA damage. Mechanistically, ROS-induced DNA damage is further enhanced by eosinophils and neutrophils via halide (Cl- and Br-) dependent DNA adducts formation. The activation of pulmonary dendritic cells, T helper type 2 cells, and mast cells is crucial mediators in the pathology of soot- or CB-induced respiratory disease. Polyunsaturated fatty acids (PUFAs) were also found to modulate T cells functions in respiratory diseases. Particularly, telomerase reverse transcriptase was found to play the critical role in soot- and CB-induced cardiovascular dysfunctions. In this review, we propose integrated mechanisms of soot- and CB-induced toxicity emphasizing the role of inflammatory mediators and oxidative stress. We also suggest use of antioxidants and PUFAs as protective strategies against soot- and CB-induced disorders. PMID- 28713388 TI - Exploiting Natural Cross-reactivity between Human Immunodeficiency Virus (HIV)-1 p17 Protein and Anti-gp41 2F5 Antibody to Induce HIV-1 Neutralizing Responses In Vivo. AB - Anti-p17 antibodies are able to neutralize human immunodeficiency virus (HIV) entry in a mouse model. In this study, we identified a region of sequence similarity between the epitopes of anti-p17 neutralizing antibodies and anti-gp41 neutralizing 2F5 antibody and verified cross-reactivity between p17 and 2F5 in vitro. The p17 sequence was modified to increase sequence identity between the p17 and 2F5 epitopes, which resulted in enhanced cross-reactivity in vitro. Immunogenicity of wild-type and modified p17 was characterized in a rabbit model. Both wild-type and mutated p17 induced anti-gp41 responses in rabbits; sera from these animals reacted with gp41 from different HIV clades. Moreover, introduction of the 2F5 sequence in p17 resulted in induction of antibodies with partially neutralizing activity. Based upon these data, we suggest that the natural cross reactivity between HIV-1 p17 protein and 2F5 antibody can be exploited to induce antibodies with neutralizing activity in an animal model. PMID- 28713389 TI - Non-Steroidal Anti-inflammatory Drugs As Host-Directed Therapy for Tuberculosis: A Systematic Review. AB - Lengthy, antimicrobial therapy targeting the pathogen is the mainstay of conventional tuberculosis treatment, complicated by emerging drug resistances. Host-directed therapies, including non-steroidal anti-inflammatory drugs (NSAIDs), in contrast, target host factors to mitigate disease severity. In the present Systematic Review, we investigate whether NSAIDs display any effects as therapy of TB and discuss possible mechanisms of action of NSAIDs as adjunctive therapy of TB. Ten studies, seven preclinical studies in mice and three clinical trials, were included and systematically reviewed. Our results point toward a beneficial effect of NSAIDs as adjunct to current TB therapy regimens, mediated by decreased lung pathology balancing host-immune reaction. The determination of the best timing for their administration in order to obtain the potential beneficial effects needs further investigation. Even if the preclinical evidence requires clinical evaluation, NSAIDs might represent a potential safe, simple, and cheap improvement in therapy of TB. PMID- 28713390 TI - Hematopoietic Stem Cell Transplantation in an Infant with Immunodeficiency, Centromeric Instability, and Facial Anomaly Syndrome. AB - Immunodeficiency, centromeric instability, and facial anomaly (ICF) syndrome is a rare autosomal recessive genetic condition with severe immunodeficiency, which leads to lethal infections if not recognized and treated in early childhood. Up to-date treatment regimens consist of prophylactic and supportive treatment of the recurrent infections. Here, we report the case of a 1-year-old boy of Moroccan consanguineous parents, who was diagnosed at 4 months of age with ICF syndrome with a homozygous missense mutation in the DNMT3B gene. He was initially admitted to the hospital with recurrent pulmonary infections from the opportunistic pathogen Pneumocystis jirovecii (PJ). Further immunological workup revealed agammaglobulinemia in the presence of B cells. After successful recovery from the PJ pneumonia, he underwent hematopoietic stem cell transplantation (HSCT) from the HLA-matched healthy sister using a chemotherapeutic conditioning regimen consisting of treosulfan, fludarabine, and thiotepa. Other than acute chemotherapy-associated side effects, no serious adverse events occurred. Six months after HSCT immune-reconstitution, he had a stable chimerism with 2.9% autologous portion in the peripheral blood and a normal differential blood cell count, including all immunoglobulin subtypes. This is one of the first cases of successful HSCT in ICF syndrome. Early diagnosis and subsequent HSCT can prevent severe opportunistic infections and cure the immunodeficiency. Centromeric instability and facial anomaly remain unaffected. Although the long-term patient outcome and the neurological development remain to be seen, this curative therapy for immunodeficiency improves life expectancy and quality of life. This case is meant to raise physicians awareness for ICF syndrome and highlight the consideration for HSCT in ICF syndrome early on. PMID- 28713391 TI - Apoptosis Induced via Gamma Delta T Cell Antigen Receptor "Blocking" Antibodies: A Cautionary Tale. AB - Mechanistic studies contribute greatly to our understanding of gammadelta T cell (gammadeltaTc) biology, aiding development of these cells as immunotherapeutic agents. The antibody blocking assay is an accepted method to determine the receptors involved in gammadeltaTc killing of tumor targets. Effectors and/or targets are preincubated with microgram quantities of monoclonal antibodies (mAb), often described by commercial sources to be useful for blocking assays. We and others have used such assays extensively in the past, correlating decreases in cytotoxicity against specific targets with involvement of the blocked receptor(s). However, we wondered whether other mechanisms might be at play beyond cytotoxicity inhibition. Indeed, administration of certain "blocking" mAb to the gammadelta T cell antigen receptor (gammadeltaTCR) induced gammadeltaTc death. Upon further investigation, we discovered that gammadeltaTc underwent apoptosis triggered by incubation with mAb to the gammadeltaTCR. This effect was specific, as no apoptosis was observed when alphabeta T cells (alphabetaTc) were incubated with these mAb. Apoptosis was further potentiated by the presence of interleukin (IL)-2, often included in cytotoxicity assays; however, exogenous interleukin-2 (IL-2) did not contribute significantly to gammadeltaTc cytotoxicity against breast cancer cell lines. Here, we have investigated the usefulness of four mAb for use in blocking assays by assessing blocking properties in conjunction with their propensity to induce apoptosis in cultured primary human gammadeltaTc. We found that the 5A6.E9 clone was usually a better alternative to the commonly used B1 (or B1.1) and 11F2 clones; however, some variability in susceptibility to apoptosis induction was observed among donor cultures. Thus, viability assessment of primary effector cells treated with mAb alone should be undertaken in parallel with cytotoxicity assays employing blocking antibodies, to account for cytotoxicity reduction caused by effector cell death. Previous findings should be reassessed in this light. PMID- 28713392 TI - IL-15 Harnesses Pro-inflammatory Function of TEMRA CD8 in Kidney-Transplant Recipients. AB - The involvement of TEMRA CD8 is evident in a large array of immunological conditions ranging from auto- to allo-immunity. Nevertheless, the factors leading to their accumulation and activation remain ill-defined and, efficient therapeutics to control their inflammatory response is lacking. Here, we show that IL-15-stimulated TEMRA from kidney-transplant (KT) recipients promote inflammation by inducing the expression of CX3CL1 by endothelial cells in an IFN gamma- and TNF-alpha-dependent manner. The responsiveness of TEMRA to IL-15 is not restricted to chronic stimulation, as TEMRA from healthy volunteers respond earlier and faster when compared to effector memory (EM). IL-15 induces antiapoptotic signals and promotes proliferation dependent of PI3K/Akt, MAPK, and ERK pathways. Without ex vivo stimulation, TEMRA cells are metabolically more active than naive and EM, as shown by their high ATP reservoir and a high expression of genes involved in glycolysis, glutaminolysis, and the Pentose Phosphate Pathway. Upon stimulation, TEMRA adapt their metabolism by sustaining an increased mitochondrial respiration and glycolysis. Finally, we show that the inhibition of glycolysis is highly effective in preventing endothelial inflammation induced by TEMRA from KT recipients. Together, our findings highlight the metabolic fitness that tightly regulates the immune function of TEMRA in physiological and pathogenic situations. PMID- 28713393 TI - The Complete Chloroplast Genome of Chinese Bayberry (Morella rubra, Myricaceae): Implications for Understanding the Evolution of Fagales. AB - Morella rubra (Myricaceae), also known as Chinese bayberry, is an economically important, subtropical, evergreen fruit tree. The phylogenetic placement of Myricaceae within Fagales and the origin of Chinese bayberry's domestication are still unresolved. In this study, we report the chloroplast (cp) genome of M. rubra and take advantage of several previously reported chloroplast genomes from related taxa to examine patterns of evolution in Fagales. The cp genomes of three M. rubra individuals were 159,478, 159,568, and 159.586 bp in length, respectively, comprising a pair of inverted repeat (IR) regions (26,014-26,069 bp) separated by a large single-copy (LSC) region (88,683-88,809 bp) and a small single-copy (SSC) region (18,676-18,767 bp). Each cp genome encodes the same 111 unique genes, consisting of 77 different protein-coding genes, 30 transfer RNA genes and four ribosomal RNA genes, with 18 duplicated in the IRs. Comparative analysis of chloroplast genomes from four representative Fagales families revealed the loss of infA and the pseudogenization of ycf15 in all analyzed species, and rpl22 has been pseudogenized in M. rubra and Castanea mollissima, but not in Juglans regia or Ostrya rehderiana. The genome size variations are detected mainly due to the length of intergenic spacers rather than gene loss, gene pseudogenization, IR expansion or contraction. The phylogenetic relationships yielded by the complete genome sequences strongly support the placement of Myricaceae as sister to Juglandaceae. Furthermore, seven cpDNA markers (trnH-psbA, psbA-trnK, rps2-rpoC2, ycf4-cemA, petD-rpoA, ndhE-ndhG, and ndhA intron) with relatively high levels of variation and variable cpSSR loci were identified within M. rubra, which will be useful in future research characterizing the population genetics of M. rubra and investigating the origin of domesticated Chinese bayberry. PMID- 28713394 TI - A Novel NAC Transcription Factor, PbeNAC1, of Pyrus betulifolia Confers Cold and Drought Tolerance via Interacting with PbeDREBs and Activating the Expression of Stress-Responsive Genes. AB - NAC (NAM, ATAF, and CUC) transcription factors are important regulator in abiotic stress and plant development. However, knowledge concerning the functions of plant NAC TFs functioning in stress tolerance and the underlying molecular basis are still limited. In this study, we report functional characterization of the NAC TF, PbeNAC1, isolated from Pyrus betulifolia. PbeNAC1 were greatly induced by cold and drought, while salt stress had little effect on expression. PbeNAC1 was localized in the nuclei showed transactivation activity. Overexpression of PbeNAC1 conferred enhanced tolerance to multiple stresses, including cold and drought, as supported by lower levels of reactive oxygen species, higher survival rate, higher activities of enzymes, relative to wild-type (WT). In addition, steady-state mRNA levels of 15 stress-responsive genes coding for either functional or regulatory proteins were higher levels in the transgenic plants relative to the WT with drought or cold treatment. yeast two-hybrid (Y2H) and bimolecular fluorescence complementation (BiFC) assays showed that PbeNAC1 protein can physically interact with PbeDREB1 and PbeDREB2A. Taken together, these results demonstrate that pear PbeNAC1 plays an important role in improving stress tolerance, possibly by interacting with PbeDREB1 and PbeDREB2A to enhance the mRNA levels of some stress-associated genes. PMID- 28713395 TI - Economic and Environmental Assessment of Seed and Rhizome Propagated Miscanthus in the UK. AB - Growth in planted areas of Miscanthus for biomass in Europe has stagnated since 2010 due to technical challenges, economic barriers and environmental concerns. These limitations need to be overcome before biomass production from Miscanthus can expand to several million hectares. In this paper, we consider the economic and environmental effects of introducing seed based hybrids as an alternative to clonal M. x giganteus (Mxg). The impact of seed based propagation and novel agronomy was compared with current Mxg cultivation and used in 10 commercially relevant, field scale experiments planted between 2012 and 2014 in the United Kingdom, Germany, and Ukraine. Economic and greenhouse gas (GHG) emissions costs were quantified for the following production chain: propagation, establishment, harvest, transportation, storage, and fuel preparation (excluding soil carbon changes). The production and utilization efficiency of seed and rhizome propagation were compared. Results show that new hybrid seed propagation significantly reduces establishment cost to below L900 ha-1. Calculated GHG emission costs for the seeds established via plugs, though relatively small, was higher than rhizomes because fossil fuels were assumed to heat glasshouses for raising seedling plugs (5.3 and 1.5 kg CO2 eq. C Mg [dry matter (DM)]-1), respectively. Plastic mulch film reduced establishment time, improving crop economics. The breakeven yield was calculated to be 6 Mg DM ha-1 y-1, which is about half average United Kingdom yield for Mxg; with newer seeded hybrids reaching 16 Mg DM ha-1 in second year United Kingdom trials. These combined improvements will significantly increase crop profitability. The trade-offs between costs of production for the preparation of different feedstock formats show that bales are the best option for direct firing with the lowest transport costs (L0.04 Mg-1 km-1) and easy on-farm storage. However, if pelleted fuel is required then chip harvesting is more economic. We show how current seed based propagation methods can increase the rate at which Miscanthus can be scaled up; ~*100 those of current rhizome propagation. These rapid ramp rates for biomass production are required to deliver a scalable and economic Miscanthus biomass fuel whose GHG emissions are ~1/20th those of natural gas per unit of heat. PMID- 28713396 TI - System-Level and Granger Network Analysis of Integrated Proteomic and Metabolomic Dynamics Identifies Key Points of Grape Berry Development at the Interface of Primary and Secondary Metabolism. AB - Grapevine is a fruit crop with worldwide economic importance. The grape berry undergoes complex biochemical changes from fruit set until ripening. This ripening process and production processes define the wine quality. Thus, a thorough understanding of berry ripening is crucial for the prediction of wine quality. For a systemic analysis of grape berry development we applied mass spectrometry based platforms to analyse the metabolome and proteome of Early Campbell at 12 stages covering major developmental phases. Primary metabolites involved in central carbon metabolism, such as sugars, organic acids and amino acids together with various bioactive secondary metabolites like flavonols, flavan-3-ols and anthocyanins were annotated and quantified. At the same time, the proteomic analysis revealed the protein dynamics of the developing grape berries. Multivariate statistical analysis of the integrated metabolomic and proteomic dataset revealed the growth trajectory and corresponding metabolites and proteins contributing most to the specific developmental process. K-means clustering analysis revealed 12 highly specific clusters of co-regulated metabolites and proteins. Granger causality network analysis allowed for the identification of time-shift correlations between metabolite-metabolite, protein- protein and protein-metabolite pairs which is especially interesting for the understanding of developmental processes. The integration of metabolite and protein dynamics with their corresponding biochemical pathways revealed an energy linked metabolism before veraison with high abundances of amino acids and accumulation of organic acids, followed by protein and secondary metabolite synthesis. Anthocyanins were strongly accumulated after veraison whereas other flavonoids were in higher abundance at early developmental stages and decreased during the grape berry developmental processes. A comparison of the anthocyanin profile of Early Campbell to other cultivars revealed similarities to Concord grape and indicates the strong effect of genetic background on metabolic partitioning in primary and secondary metabolism. PMID- 28713397 TI - Fitness Outcomes Related to Glyphosate Resistance in Kochia (Kochia scoparia): What Life History Stage to Examine? AB - A fast-spreading weed, kochia (Kochia scoparia), has developed resistance to the widely-used herbicide, glyphosate. Understanding the relationship between the occurrence of glyphosate resistance caused by multiple EPSPS gene copies and kochia fitness may suggest a more effective way of controlling kochia. A study was conducted to assess fitness cost of glyphosate resistance compared to susceptibility in kochia populations at different life history stages, that is rate of seed germination, increase in plant height, days to flowering, biomass accumulation at maturity, and fecundity. Six kochia populations from Scott, Finney, Thomas, Phillips, Wallace, and Wichita counties in western Kansas were characterized for resistance to field-use rate of glyphosate and with an in vivo shikimate accumulation assay. Seed germination was determined in growth chambers at three constant temperatures (5, 10, and 15 C) while vegetative growth and fecundity responses were evaluated in a field study using a target-neighborhood competition design in 2014 and 2015. One target plant from each of the six kochia populations was surrounded by neighboring kochia densities equivalent to 10 (low), 35 (moderate), or 70 (high) kochia plants m-2. In 2015, neighboring corn densities equivalent to 10 and 35 plants m-2 were also evaluated. Treatments were arranged in a randomized complete block design with at least 7 replications. Three kochia populations were classified as glyphosate-resistant (GR) [Scott (SC R), Finney (FN-R), and Thomas (TH-R)] and three populations were classified as glyphosate-susceptible (GS) [Phillips (PH-S), Wallace (WA-S) and Wichita (WI-S)]. Of the life history stages measured, fitness differences between the GR and GS kochia populations were consistently found in their germination characteristics. The GR kochia showed reduced seed longevity, slower germination rate, and less total germination than the GS kochia. In the field, increases in plant height, biomass accumulation, and fecundity were not clearly different between GR and GS kochia populations (irrespective of neighbor density). Hence, weed management plans should integrate practices that take advantage of the relatively poor germination characteristics of GR kochia. This study suggests that evaluating plant fitness at different life history stages can increase the potential of detecting fitness costs. PMID- 28713399 TI - Metabolite Profiling Reveals Developmental Inequalities in Pinot Noir Berry Tissues Late in Ripening. AB - Uneven ripening in Vitis vinifera is increasingly recognized as a phenomenon of interest, with substantial implications for fruit and wine composition and quality. This study sought to determine whether variation late in ripening (~Modified Eichhorn-Lorenz stage 39) was associated with developmental differences that were observable as fruits within a cluster initiated ripening (veraison). Four developmentally distinct ripening classes of berries were tagged at cluster veraison, sampled at three times late in ripening, and subjected to untargeted HPLC-MS to measure variation in amino acids, sugars, organic acids, and phenolic metabolites in skin, pulp, and seed tissues separately. Variability was described using predominantly two strategies. In the first, multivariate analysis (Orthogonal Projections to Latent Structures-Discriminant Analysis, OPLS DA) was used to determine whether fruits were still distinguishable per their developmental position at veraison and to identify which metabolites accounted for these distinctions. The same technique was used to assess changes in each tissue over time. In a second strategy and for each annotated metabolite, the variance across the ripening classes at each time point was measured to show whether intra-cluster variance (ICV) was growing, shrinking, or constant over the period observed. Indeed, berries could be segregated by OPLS-DA late in ripening based on their developmental position at veraison, though the four ripening classes were aggregated into two larger ripening groups. Further, not all tissues were dynamic over the period examined. Although pulp tissues could be segregated by time sampled, this was not true for seed and only moderately so for skin. Ripening group differences in seed and skin, rather than the time fruit was sampled, were better able to define berries. Metabolites also experienced significant reductions in ICV between single pairs of time points, but never across the entire experiment. Metabolites often exhibited a combination of ICV expansion, contraction and persistence. Finally, we observed significant differences in the abundance of some metabolites between ripening classes that suggest the berries that initiated ripening first remained developmentally ahead of the lagging fruit even late in the ripening phase. This presents a challenge to producers who would seek to harvest at uniformity or at a predefined level of variation. PMID- 28713398 TI - A HOPS Protein, MoVps41, Is Crucially Important for Vacuolar Morphogenesis, Vegetative Growth, Reproduction and Virulence in Magnaporthe oryzae. AB - The homotypic fusion and protein sorting protein complex (HOPS) is the first known tether complex identified in the endocytic system that plays a key role in promoting homotypic vacuolar fusion, vacuolar biogenesis and trafficking in a wide range of organisms, including plant and fungi. However, the exact influence of the HOPS complex on growth, reproduction and pathogenicity of the economically destructive rice blast fungus has not been investigated. In this study, we identified M. oryzae vacuolar protein sorting 41 (MoVps41) an accessory subunit of HOPS complex and used targeted gene deletion approach to evaluate its contribution to growth, reproduction and infectious life cycle of the rice blast fungus. Corresponding results obtained from this study showed that MoVps41 is required for optimum vegetative development of M. oryzae and observed that MoVps41 deletion mutant displayed defective vegetative growth. Our investigation further showed that MoVps41 deletion triggered vacuolar fragmentation, compromised membrane integrity and pathogenesis of the DeltaMovps41 mutant. Our studies also showed for the first time that MoVps41 plays an essential role in the regulation of sexual and asexual reproduction of M. oryzae. In summary, our study provides insight into how MoVps41 mediated vacuolar fusion and biogenesis influences reproduction, pathogenesis, and vacuolar integrity in M. oryzae and also underscores the need to holistically investigate the HOPS complex in rice blast pathogen. PMID- 28713400 TI - Overexpression of E3 Ubiquitin Ligase Gene AdBiL Contributes to Resistance against Chilling Stress and Leaf Mold Disease in Tomato. AB - Ubiquitination is a common regulatory mechanism, playing a critical role in diverse cellular and developmental processes in eukaryotes. However, a few reports on the functional correlation between E3 ubiquitin ligases and reactive oxygen species (ROS) or reactive nitrogen species (RNS) metabolism in response to stress are currently available in plants. In the present study, the E3 ubiquitin ligase gene AdBiL (Adi3 Binding E3 Ligase) was introduced into tomato line Ailsa Craig via Agrobacterium-mediated method. Transgenic lines were confirmed for integration into the tomato genome using PCR. Transcription of AdBiL in various transgenic lines was determined using real-time PCR. Evaluation of stress tolerance showed that T1 generation of transgenic tomato lines showed only mild symptoms of chilling injury as evident by higher biomass accumulation and chlorophyll content than those of non-transformed plants. Compared with wild-type plants, the contents of AsA, AsA/DHA, GSH and the activity of GaILDH, gamma-GCS and GSNOR were increased, while H2O2, [Formula: see text], MDA, NO, SNOs, and GSNO accumulations were significantly decreased in AdBiL overexpressing plants in response to chilling stress. Furthermore, transgenic tomato plants overexpressing AdBiL showed higher activities of enzymes such as G6PDH, 6PGDH, NADP-ICDH, and NADP-ME involved in pentose phosphate pathway (PPP). The transgenic tomato plants also exhibited an enhanced tolerance against the necrotrophic fungus Cladosporium fulvum. Tyrosine nitration protein was activated in the plants infected with leaf mold disease, while the inhibition could be recovered in AdBiL gene overexpressing lines. Taken together, our results revealed a possible physiological role of AdBiL in the activation of the key enzymes of AsA-GSH cycle, PPP and down-regulation of GSNO reductase, thereby reducing oxidative and nitrosative stress in plants. This study demonstrates an optimized transgenic strategy using AdBiL gene for crop improvement against biotic and abiotic stress factors. PMID- 28713401 TI - Genome-Wide Association Study Reveals Natural Variations Contributing to Drought Resistance in Crops. AB - Crops are often cultivated in regions where they will face environmental adversities; resulting in substantial yield loss which can ultimately lead to food and societal problems. Thus, significant efforts have been made to breed stress tolerant cultivars in an attempt to minimize these problems and to produce more stability with respect to crop yields across broad geographies. Since stress tolerance is a complex and multi-genic trait, advancements with classical breeding approaches have been challenging. On the other hand, molecular breeding, which is based on transgenics, marker-assisted selection and genome editing technologies; holds great promise to enable farmers to better cope with these challenges. However, identification of the key genetic components underlying the trait is critical and will serve as the foundation for future crop genetic improvement. Recently, genome-wide association studies have made significant contributions to facilitate the discovery of natural variation contributing to stress tolerance in crops. From these studies, the identified loci can serve as targets for genomic selection or editing to enable the molecular design of new cultivars. Here, we summarize research progress on this issue and focus on the genetic basis of drought tolerance as revealed by genome-wide association studies and quantitative trait loci mapping. Although many favorable loci have been identified, elucidation of their molecular mechanisms contributing to increased stress tolerance still remains a challenge. Thus, continuous efforts are still required to functionally dissect this complex trait through comprehensive approaches, such as system biological studies. It is expected that proper application of the acquired knowledge will enable the development of stress tolerant cultivars; allowing agricultural production to become more sustainable under dynamic environmental conditions. PMID- 28713402 TI - Unmanned Aerial Vehicle Remote Sensing for Field-Based Crop Phenotyping: Current Status and Perspectives. AB - Phenotyping plays an important role in crop science research; the accurate and rapid acquisition of phenotypic information of plants or cells in different environments is helpful for exploring the inheritance and expression patterns of the genome to determine the association of genomic and phenotypic information to increase the crop yield. Traditional methods for acquiring crop traits, such as plant height, leaf color, leaf area index (LAI), chlorophyll content, biomass and yield, rely on manual sampling, which is time-consuming and laborious. Unmanned aerial vehicle remote sensing platforms (UAV-RSPs) equipped with different sensors have recently become an important approach for fast and non-destructive high throughput phenotyping and have the advantage of flexible and convenient operation, on-demand access to data and high spatial resolution. UAV-RSPs are a powerful tool for studying phenomics and genomics. As the methods and applications for field phenotyping using UAVs to users who willing to derive phenotypic parameters from large fields and tests with the minimum effort on field work and getting highly reliable results are necessary, the current status and perspectives on the topic of UAV-RSPs for field-based phenotyping were reviewed based on the literature survey of crop phenotyping using UAV-RSPs in the Web of ScienceTM Core Collection database and cases study by NERCITA. The reference for the selection of UAV platforms and remote sensing sensors, the commonly adopted methods and typical applications for analyzing phenotypic traits by UAV-RSPs, and the challenge for crop phenotyping by UAV-RSPs were considered. The review can provide theoretical and technical support to promote the applications of UAV-RSPs for crop phenotyping. PMID- 28713403 TI - Time-Dependent Trapping of Pollinators Driven by the Alignment of Floral Phenology with Insect Circadian Rhythms. AB - Several evolutionary lineages in the early divergent angiosperm family Annonaceae possess flowers with a distinctive pollinator trapping mechanism, in which floral phenological events are very precisely timed in relation with pollinator activity patterns. This contrasts with previously described angiosperm pollinator traps, which predominantly function as pitfall traps. We assess the circadian rhythms of pollinators independently of their interactions with flowers, and correlate these data with detailed assessments of floral phenology. We reveal a close temporal alignment between patterns of pollinator activity and the floral phenology driving the trapping mechanism (termed 'circadian trapping' here). Non-trapping species with anthesis of standard duration (c. 48 h) cannot be pollinated effectively by pollinators with a morning-unimodal activity pattern; non-trapping species with abbreviated anthesis (23-27 h) face limitations in utilizing pollinators with a bimodal circadian activity; whereas species that trap pollinators (all with short anthesis) can utilize a broader range of potential pollinators, including those with both unimodal and bimodal circadian rhythms. In addition to broadening the range of potential pollinators based on their activity patterns, circadian trapping endows other selective advantages, including the possibility of an extended staminate phase to promote pollen deposition, and enhanced interfloral movement of pollinators. The relevance of the alignment of floral phenological changes with peaks in pollinator activity is furthermore evaluated for pitfall trap pollination systems. PMID- 28713405 TI - Vegetable Grafting as a Tool to Improve Drought Resistance and Water Use Efficiency. AB - Drought is one of the most prevalent limiting factors causing considerable losses in crop productivity, inflicting economic as well as nutritional insecurity. One of the greatest challenges faced by the scientific community in the next few years is to minimize the yield losses caused by drought. Drought resistance is a complex quantitative trait controlled by many genes. Thus, introgression of drought resistance traits into high yielding genotypes has been a challenge to plant breeders. Vegetable grafting using rootstocks has emerged as a rapid tool in tailoring plants to better adapt to suboptimal growing conditions. This has induced changes in shoot physiology. Grafting applications have expanded mainly in Solanaceous crops and cucurbits, which are commonly grown in arid and semi arid areas characterized by long drought periods. The current review gives an overview of the recent scientific literature on root-shoot interaction and rootstock-driven alteration of growth, yield, and fruit quality in grafted vegetable plants under drought stress. Further, we elucidate the drought resistance mechanisms of grafted vegetables at the morpho-physiological, biochemical, and molecular levels. PMID- 28713404 TI - Genome-Wide Identification and Analysis of Genes, Conserved between japonica and indica Rice Cultivars, that Respond to Low-Temperature Stress at the Vegetative Growth Stage. AB - Cold stress is very detrimental to crop production. However, only a few genes in rice have been identified with known functions related to cold tolerance. To meet this agronomic challenge more effectively, researchers must take global approaches to select useful candidate genes and find the major regulatory factors. We used five Gene expression omnibus series data series of Affymetrix array data, produced with cold stress-treated samples from the NCBI Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo/), and identified 502 cold inducible genes common to both japonica and indica rice cultivars. From them, we confirmed that the expression of two randomly chosen genes was increased by cold stress in planta. In addition, overexpression of OsWRKY71 enhanced cold tolerance in 'Dongjin,' the tested japonica cultivar. Comparisons between japonica and indica rice, based on calculations of plant survival rates and chlorophyll fluorescence, confirmed that the japonica rice was more cold-tolerant. Gene Ontology enrichment analysis indicate that the 'L-phenylalanine catabolic process,' within the Biological Process category, was the most highly overrepresented under cold-stress conditions, implying its significance in that response in rice. MapMan analysis classified 'Major Metabolic' processes and 'Regulatory Gene Modules' as two other major determinants of the cold-stress response and suggested several key cis-regulatory elements. Based on these results, we proposed a model that includes a pathway for cold stress-responsive signaling. Results from our functional analysis of the main signal transduction and transcription regulation factors identified in that pathway will provide insight into novel regulatory metabolism(s), as well as a foundation by which we can develop crop plants with enhanced cold tolerance. PMID- 28713406 TI - Ultrastructural and Cytological Studies on Mycosphaerella pinodes Infection of the Model Legume Medicago truncatula. AB - Ascochyta (Mycosphaerella) blight on cultivated peas is primarily caused by infection through asexual spores (pycnospores) of Mycosphaerella pinodes (Berk. et Blox.) Vestergren [recently renamed Peyronellaea pinodes (Berk. & A. Bloxam) Aveskamp, Gruyter & Verkley]. Using a model pathosystem involving Medicago truncatula and Mycosphaerella pinodes strain OMP-1, we examined the histology and ultrastructure of early infection events and fungal development including penetration by appressoria, vegetative growth of infection hyphae, and host responses. On the susceptible ecotype R108-1, pycnospores germinated and grew over the surface of the epidermis, then formed an appressoria and penetrated the cuticle. Beneath the cuticle, the infection peg expanded into a hyphae that grew within the outer wall of the epidermis. Subsequently, the hyphae penetrated down within mesophyll cells and proliferated vigorously, eventually, forming asexual fruiting bodies (pycnidia). In contrast, successful penetration and subsequent growth of infection hyphae were considerably restricted in the ecotype Caliph. Detected by its reaction with cerium chloride (CeCl3) to generate electron-dense cerium perhydroxides in transmission electron micrographs, hydrogen peroxide (H2O2) accumulated in epidermal and mesophyll cells of Caliph challenged with pycnospores of M. pinodes. This intracellular localization was confirmed by energy-dispersive X-ray spectroscopy. Our observations thus indicate that the oxidative burst reaction leading to the generation of reactive oxygen species is associated with a local host defense response in Caliph, since no clear H2O2 accumulation was detectable in susceptible R108-1. Indeed, aberrant hyphae such as intrahyphal hyphae and dead hyphae, probably due to a local defense elicited by the fungus, were abundant in Caliph but not in R108-1. Our results on the cellular interactions between the fungus and host cells provide additional insights to understand foliar infection by M. pinodes on cultivated peas. PMID- 28713407 TI - Biorhizome: A Biosynthetic Platform for Colchicine Biomanufacturing. AB - Colchicine is one of the oldest plant-based medicines used to treat gout and one of the most important alkaloid-based antimitotic drugs with anticancer potential, which is commercially extracted from Gloriosa superba. Clinical trials suggest that colchicine medication could prevent atrial fibrillation recurrence after cardiac surgery. In addition, therapeutic colchicine is undergoing clinical trials to treat non-diabetic metabolic syndrome and diabetic nephropathy. However, the industrial-scale biomanufacturing of colchicine have not yet been established. Clearly, further studies on detailed biorhizome-specific transcriptome analysis, gene expression, and candidate gene validation are required before uncover the mechanism of colchicine biosynthesis and biorhizome based colchicine biomanufacturing. Annotation of 32312 assembled multiple-tissues transcripts of G. superba represented 15088 unigenes in known plant specific gene ontology. This could help understanding colchicine biosynthesis in G. superba. This review highlights the biorhizomes, rhizome specific genes or gene what expressed with high level in rhizomes, and deep fluid dynamics in a bioreactor specifically for the biomanufacture of colchicine. PMID- 28713408 TI - Transcriptome Analyses Shed New Insights into Primary Metabolism and Regulation of Blumeria graminis f. sp. tritici during Conidiation. AB - Conidia of the obligate biotrophic fungal pathogen Blumeria graminis f. sp. tritici (Bgt) play a vital role in its survival and rapid dispersal. However, little is known about the genetic basis for its asexual reproduction. To uncover the primary metabolic and regulatory events during conidiation, we sequenced the transcriptome of Bgt epiphytic structures at 3 (vegetative hyphae growth), 4 (foot cells initiation), and 5 (conidiophore erection) days post-inoculation (dpi). RNA-seq analyses identified 556 and 404 (combined 685) differentially expressed genes (DEGs) at 4 and 5 dpi compared with their expression levels at 3 dpi, respectively. We found that several genes involved in the conversion from a variety of sugars to glucose, glycolysis, the tricarboxylic acid cycle (TAC), the electron transport chain (ETC), and unsaturated fatty acid oxidation were activated during conidiation, suggesting that more energy supply is required during this process. Moreover, we found that glucose was converted into glycogen, which was accumulated in developing conidiophores, indicating that it could be the primary energy storage molecule in Bgt conidia. Clustering for the expression profiles of 91 regulatory genes showed that calcium (Ca2+), H2O2, and phosphoinositide (PIP) signaling were involved in Bgt conidiation. Furthermore, a strong accumulation of H2O2 in developing conidiophores was detected. Application of EGTA, a Ca2+ chelator, and trifluoperazine dihydrochloride (TFP), a calmodulin (CaM) antagonist, markedly suppressed the generation of H2O2, affected foot cell and conidiophore development and reduced conidia production significantly. These results suggest that Ca2+ and H2O2 signaling play important roles in conidiogenesis and a crosslink between them is present. In addition to some conidiation-related orthologs known in other fungi, such as the velvet complex components, we identified several other novel B. graminis-specific genes that have not been previously found to be implicated in fungal conidiation, reflecting a unique molecular mechanism underlying asexual development of cereal powdery mildews. PMID- 28713409 TI - Phylogenetic Resolution in Juglans Based on Complete Chloroplast Genomes and Nuclear DNA Sequences. AB - Walnuts (Juglans of the Juglandaceae) are well-known economically important resource plants for the edible nuts, high-quality wood, and medicinal use, with a distribution from tropical to temperate zones and from Asia to Europe and Americas. There are about 21 species in Juglans. Classification of Juglans at section level is problematic, because the phylogenetic position of Juglans cinerea is disputable. Lacking morphological and DNA markers severely inhibited the development of related researches. In this study, the complete chloroplast genomes and two nuclear DNA regions (the internal transcribed spacer and ubiquitin ligase gene) of 10 representative taxa of Juglans were used for comparative genomic analyses in order to deepen the understanding on the application value of genetic information for inferring the phylogenetic relationship of the genus. The Juglans chloroplast genomes possessed the typical quadripartite structure of angiosperms, consisting of a pair of inverted repeat regions separated by a large single-copy region and a small single-copy region. All the 10 chloroplast genomes possessed 112 unique genes arranged in the same order, including 78 protein-coding, 30 tRNA, and 4 rRNA genes. A combined sequence data set from two nuclear DNA regions revealed that Juglans plants could be classified into three branches: (1) section Juglans, (2) section Cardiocaryon including J. cinerea which is closer to J. mandshurica, and (3) section Rhysocaryon. However, three branches with a different phylogenetic topology were recognized in Juglans using the complete chloroplast genome sequences: (1) section Juglans, (2) section Cardiocaryon, and (3) section Rhysocaryon plus J. cinerea. The molecular taxonomy of Juglans is almost compatible to the morphological taxonomy except J. cinerea (section Trachycaryon). Based on the complete chloroplast genome sequence data, the divergence time between section Juglans and section Cardiocaryon was 44.77 Mya, while section Rhysocaryon diverged from other sections in the genus Juglans was 47.61 Mya. Eleven of the 12 small inversions in the chloroplast genomes provided valuable phylogenetic information for classification of walnut plants at section and species levels. Our results are valuable for future studies on Juglans genetic diversity and will enhance the understanding on the phylogenetic evolution of Juglandaceae. PMID- 28713410 TI - Isolation of an ABA Transporter-Like 1 Gene from Arachis hypogaea That Affects ABA Import and Reduces ABA Sensitivity in Arabidopsis. AB - Abscisic acid (ABA) transporters are essential for the transport of ABA from its sites of synthesis to its multiple sites of action within plants and are key players in plant stress responses. Despite their importance, there is limited information on ABA transporters in crop plants. In this study, we isolated and characterized an ABA transporter-like 1 (AhATL1) gene from peanut (Arachis hypogaea L.) whose cognate protein, AhATL1, is a member of the ATP-binding cassette transporter G subfamily and localizes to the plasma membrane. The expression of both the AhATL1 transcript and the corresponding protein were upregulated by water stress and treatment with exogenous ABA. Overexpression of AhATL1 in ecotype Columbia (Col) Arabidopsis (AhATL1-OX) plants reduced ABA sensitivity. When AhATL1-OX and Arabidopsis Col plants were subjected to dehydration stress, the expression of 9-cis-epoxycarotenoid dioxygenase 3 (AtNCED3) and responsive to desiccation 29 A (AtRD29A) accumulated rapidly in rosette leaves of both lines. In contrast, while expression of ATP-binding cassette G 40 (AtABCG40) was increased in Col rosette leaves, there was no change in expression of AtABCG40 in AhATL1-OX leaves. Similarly, water loss from detached leaves of AhATL1-OX plants was more rapid than from Col leaves. Therefore, we suggest that the function of AhATL1 is probably to modulate ABA sensitivity by specifically influencing ABA import into cells. PMID- 28713411 TI - Physiological, Biochemical, Epigenetic and Molecular Analyses of Wheat (Triticum aestivum) Genotypes with Contrasting Salt Tolerance. AB - Abiotic stress exerts significant impact on plant's growth, development, and productivity. Productivity of crop plants under salt stress is lagging behind because of our limited knowledge about physiological, biochemical, epigenetic, and molecular mechanisms of salt tolerance in plants. This study aimed to investigate physio-biochemical, molecular indices and defense responses of selected wheat cultivars to identify the most contrasting salt-responsive genotypes and the mechanisms associated with their differential responses. Physio biochemical traits specifically membrane stability index, antioxidant potential, osmoprotectants and chlorophyll contents, measured at vegetative stage, were used for multivariate analysis to identify the most contrasting genotypes. Genetic and epigenetic analyses indicated the possible mechanisms associated with differential response of the wheat genotypes under salt stress. Better antioxidant potential, membrane stability, increased accumulation of osmolytes/phytophenolics, and higher K+/Na+ ratio under 200 mM NaCl stress identified Kharchia-65 to be the most salt-tolerant cultivar. By contrast, increased MDA level, reduced soluble sugar, proline, total chlorophyll, total phenolics contents, and lower antioxidant potential in HD-2329 marked it to be sensitive to the stress. Genetic and bioinformatics analyses of HKT1;4 of contrasting genotypes (Kharchia-65 and HD-2329) revealed deletions, transitions, and transversions resulting into altered structure, loss of conserved motifs (Ser Gly-Gly-Gly and Gly-Arg) and function in salt-sensitive (HD-2329) genotype. Expression analysis of HKTs rationalized the observed responses. Epigenetic variations in cytosine methylation explained tissue- and genotype-specific differential expression of HKT2;1 and HKT2;3. PMID- 28713412 TI - The Emerging Oilseed Crop Sesamum indicum Enters the "Omics" Era. AB - Sesame (Sesamum indicum L.) is one of the oldest oilseed crops widely grown in Africa and Asia for its high-quality nutritional seeds. It is well adapted to harsh environments and constitutes an alternative cash crop for smallholders in developing countries. Despite its economic and nutritional importance, sesame is considered as an orphan crop because it has received very little attention from science. As a consequence, it lags behind the other major oil crops as far as genetic improvement is concerned. In recent years, the scenario has considerably changed with the decoding of the sesame nuclear genome leading to the development of various genomic resources including molecular markers, comprehensive genetic maps, high-quality transcriptome assemblies, web-based functional databases and diverse daft genome sequences. The availability of these tools in association with the discovery of candidate genes and quantitative trait locis for key agronomic traits including high oil content and quality, waterlogging and drought tolerance, disease resistance, cytoplasmic male sterility, high yield, pave the way to the development of some new strategies for sesame genetic improvement. As a result, sesame has graduated from an "orphan crop" to a "genomic resource-rich crop." With the limited research teams working on sesame worldwide, more synergic efforts are needed to integrate these resources in sesame breeding for productivity upsurge, ensuring food security and improved livelihood in developing countries. This review retraces the evolution of sesame research by highlighting the recent advances in the "Omics" area and also critically discusses the future prospects for a further genetic improvement and a better expansion of this crop. PMID- 28713415 TI - Repeated Stand-Replacing Crown Fires Affect Seed Morphology and Germination in Aleppo pine. AB - Post-fire reproductive niche of Aleppo pine (Pinus halepensis) is deeply interlaced with fire products. Indeed, the high pH and low osmotic potentials of ash beds under burnt crowns constitute the main constraints to seed germination. In this study, we aim to investigate whether fire recurrence, through the physico chemical constraints imposed by the ash beds, affects the reproduction ability of P. halepensis at the germination stage. To this aim, Aleppo pine seeds were collected in neighboring even-aged stands subjected to 0, 1, or 2 fires (namely fire cohorts), and seed morphology and germination performance, in terms of cumulative germination and germination kinetics, were studied under increasing osmotic potentials (from 0.0 to -1.2 MPa) and pH (from 6 to 11). Besides fire history, the role of ontogenetic age of mother plants on seed morphology and germination was also investigated. Differences in seed morphology among the three cohorts have been highlighted in a multivariate context, with anisotropic enlargement of the seeds produced by pine stands experiencing repeated fires. The patterns of seed germination varied primarily in relation to the fire cohort, with seeds from the pine stand experiencing repeated fires exhibiting enhanced tolerance to pH stress. Conversely, germination performances under osmotic constraints mainly depends on tree ontogenetic stage, with an involvement of fire history especially in the timing of seed germination. Our results suggest that, at least in the short term, fire recurrence does not constrain the reproduction ability of Aleppo pine. These results highlight the need for further research to elucidate the mechanisms behind these responses to recurrent fires. PMID- 28713413 TI - Identification of Conserved and Novel MicroRNAs in Blueberry. AB - MicroRNAs (miRNAs) are a class of small endogenous RNAs that play important regulatory roles in cells by negatively affecting gene expression at both transcriptional and post-transcriptional levels. There have been extensive studies aiming to identify miRNAs and to elucidate their functions in various plant species. In the present study, we employed the high-throughput sequencing technology to profile miRNAs in blueberry fruits. A total of 9,992,446 small RNA tags with sizes ranged from 18 to 30 nt were obtained, indicating that blueberry fruits have a large and diverse small RNA population. Bioinformatic analysis identified 412 conserved miRNAs belonging to 29 families, and 35 predicted novel miRNAs that are likely to be unique to blueberries. Among them, expression profiles of five conserved miRNAs were validated by stem loop qRT-PCR. Furthermore, the potential target genes of conserved and novel miRNAs were predicted and subjected to Gene Ontology (GO) annotation. Enrichment analysis of the GO-represented biological processes and molecular functions revealed that these target genes were potentially involved in a wide range of metabolic pathways and developmental processes. Particularly, anthocyanin biosynthesis has been predicted to be directly or indirectly regulated by diverse miRNA families. This study is the first report on genome-wide miRNA profile analysis in blueberry and it provides a useful resource for further elucidation of the functional roles of miRNAs during fruit development and ripening. PMID- 28713416 TI - The Detection and Characterization of QoI-Resistant Didymella rabiei Causing Ascochyta Blight of Chickpea in Montana. AB - Ascochyta blight (AB) of pulse crops (chickpea, field pea, and lentils) causes yield loss in Montana, where 1.2 million acres was planted to pulses in 2016. Pyraclostrobin and azoxystrobin, quinone outside inhibitor (QoI) fungicides, have been the choice of farmers for the management of AB in pulses. However, a G143A mutation in the cytochrome b gene has been reported to confer resistance to QoI fungicides. A total of 990 isolates of AB-causing fungi were isolated and screened for QoI resistance. Out of these, 10% were isolated from chickpea, 81% were isolated from field peas, and 9% isolated from lentil. These were from a survey of grower's fields and seed lots (chickpea = 17, field pea = 131, and lentil = 21) from 23 counties in Montana sent to the Regional Pulse Crop Diagnostic Laboratory, Bozeman, MT, United States for testing. Fungicide resistant Didymella rabiei isolates were found in one chickpea seed lot each sent from Daniels, McCone and Valley Counties, MT, from seed produced in 2015 and 2016. Multiple alignment analysis of amino acid sequences showed a missense mutation that replaced the codon for amino acid 143 from GGT to GCT, introducing an amino acid change from glycine to alanine (G143A), which is reported to be associated with QoI resistance. Under greenhouse conditions, disease severity was significantly higher on pyraclostrobin-treated chickpea plants inoculated with QoI-resistant isolates of D. rabiei than sensitive isolates (p-value = 0.001). This indicates that where resistant isolates are located, fungicide failures may be observed in the field. D. rabiei-specific polymerase chain reaction primer sets and hydrolysis probes were developed to efficiently discriminate QoI- sensitive and - resistant isolates. PMID- 28713414 TI - Divergent Evolutionary Patterns of NAC Transcription Factors Are Associated with Diversification and Gene Duplications in Angiosperm. AB - NAC (NAM/ATAF/CUC) proteins constitute one of the biggest plant-specific transcription factor (TF) families and have crucial roles in diverse developmental programs during plant growth. Phylogenetic analyses have revealed both conserved and lineage-specific NAC subfamilies, among which various origins and distinct features were observed. It is reasonable to hypothesize that there should be divergent evolutionary patterns of NAC TFs both between dicots and monocots, and among NAC subfamilies. In this study, we compared the gene duplication and loss, evolutionary rate, and selective pattern among non-lineage specific NAC subfamilies, as well as those between dicots and monocots, through genome-wide analyses of sequence and functional data in six dicot and five grass lineages. The number of genes gained in the dicot lineages was much larger than that in the grass lineages, while fewer gene losses were observed in the grass than that in the dicots. We revealed (1) uneven constitution of Clusters of Orthologous Groups (COGs) and contrasting birth/death rates among subfamilies, and (2) two distinct evolutionary scenarios of NAC TFs between dicots and grasses. Our results demonstrated that relaxed selection, resulting from concerted gene duplications, may have permitted substitutions responsible for functional divergence of NAC genes into new lineages. The underlying mechanism of distinct evolutionary fates of NAC TFs shed lights on how evolutionary divergence contributes to differences in establishing NAC gene subfamilies and thus impacts the distinct features between dicots and grasses. PMID- 28713417 TI - Foliar Phenolic Compounds in Norway Spruce with Varying Susceptibility to Chrysomyxa rhododendri: Analyses of Seasonal and Infection-Induced Accumulation Patterns. AB - Secondary phenolic metabolites are involved in plant responses to various biotic stress factors, and are apparently important for the defense against fungal pathogens. In this study, we investigated their role in defense against the rust Chrysomyxa rhododendri in Norway spruce. The fungal pathogen undergoes a seasonal lifecycle with host shift; after overwintering in rhododendron shrubs, it attacks the sprouting current-year spruce needles and causes needle fall in autumn. Repeated infections lead to reduced timber yield and severe problems with rejuvenation in subalpine Norway spruce forests. Trees with varying susceptibility to infection by C. rhododendri were selected and foliar phenolic composition was assessed using UHPLC-MS. We report on seasonal accumulation patterns and infection-related changes in the concentrations of 16 metabolites, including flavonoids, stilbenes, simple phenylpropanoids and the precursor shikimic acid, and their correlation with the infection degree of the tree. We found significant variation in the phenolic profiles during needle development: flavonoids were predominant in the first weeks after sprouting, whereas stilbenes, picein and shikimic acid increased during the first year. Following infection, several flavonoids and resveratrol increased up to 1.8 fold in concentration, whereas picein and shikimic acid were reduced by about 70 and 60%, respectively. The constitutive and early stage infection-induced concentrations of kaempferol, quercetin and taxifolin as well as the late stage infection induced concentrations of stilbenes and picein were negatively correlated with infection degree. We conclude that a combination of constitutive and inducible accumulation of phenolic compounds is associated with the lower susceptibility of individual trees to C. rhododendri. The potentially fungicidal flavonoid aglycones may limit hyphal growth and prevent development of infection symptoms, and high levels of stilbenes may impede the infection of older needles. The presented results underline a highly compound-specific seasonal accumulation and defense response of Norway spruce and may facilitate the selection of promising trees for breeding programs. PMID- 28713418 TI - Editorial: How Plants Deal with Stress: Exploration through Proteome Investigation. PMID- 28713419 TI - Population Structure, Genetic Diversity, and Evolutionary History of Kleinia neriifolia (Asteraceae) on the Canary Islands. AB - Kleinia neriifolia Haw. is an endemic species on the Canarian archipelago, this species is widespread in the coastal thicket of all the Canarian islands. In the present study, genetic diversity and population structure of K. neriifolia were investigated using chloroplast gene sequences and nuclear SSR (simple sequence repeat). The differentiation among island populations, the historical demography, and the underlying evolutionary scenarios of this species are further tested based on the genetic data. Chloroplast diversity reveals a strong genetic divergence between eastern islands (Gran Canaria, Fuerteventura, and Lanzarote) and western islands (EI Hierro, La Palma, La Gomera, Tenerife), this west-east genetic divergence may reflect a very beginning of speciation. The evolutionary scenario with highest posterior probabilities suggests Gran Canaria as oldest population with a westward colonization path to Tenerife, La Gomera, La Palma, and EI Hierro, and eastward dispersal path to Lanzarote through Fuerteventura. In the western islands, there is a slight decrease in the effective population size toward areas of recent colonization. However, in the eastern islands, the effective population size increase in Lanzarote relative to Gran Canaria and Fuerteventura. These results further our understanding of the evolution of widespread endemic plants within Canarian archipelago. PMID- 28713420 TI - Modeling the Metabolism of Arabidopsis thaliana: Application of Network Decomposition and Network Reduction in the Context of Petri Nets. AB - Motivation:Arabidopsis thaliana is a well-established model system for the analysis of the basic physiological and metabolic pathways of plants. Nevertheless, the system is not yet fully understood, although many mechanisms are described, and information for many processes exists. However, the combination and interpretation of the large amount of biological data remain a big challenge, not only because data sets for metabolic paths are still incomplete. Moreover, they are often inconsistent, because they are coming from different experiments of various scales, regarding, for example, accuracy and/or significance. Here, theoretical modeling is powerful to formulate hypotheses for pathways and the dynamics of the metabolism, even if the biological data are incomplete. To develop reliable mathematical models they have to be proven for consistency. This is still a challenging task because many verification techniques fail already for middle-sized models. Consequently, new methods, like decomposition methods or reduction approaches, are developed to circumvent this problem. Methods: We present a new semi-quantitative mathematical model of the metabolism of Arabidopsis thaliana. We used the Petri net formalism to express the complex reaction system in a mathematically unique manner. To verify the model for correctness and consistency we applied concepts of network decomposition and network reduction such as transition invariants, common transition pairs, and invariant transition pairs. Results: We formulated the core metabolism of Arabidopsis thaliana based on recent knowledge from literature, including the Calvin cycle, glycolysis and citric acid cycle, glyoxylate cycle, urea cycle, sucrose synthesis, and the starch metabolism. By applying network decomposition and reduction techniques at steady-state conditions, we suggest a straightforward mathematical modeling process. We demonstrate that potential steady-state pathways exist, which provide the fixed carbon to nearly all parts of the network, especially to the citric acid cycle. There is a close cooperation of important metabolic pathways, e.g., the de novo synthesis of uridine-5 monophosphate, the gamma-aminobutyric acid shunt, and the urea cycle. The presented approach extends the established methods for a feasible interpretation of biological network models, in particular of large and complex models. PMID- 28713421 TI - Analyses of Genomic tRNA Reveal Presence of Novel tRNAs in Oryza sativa. AB - Transfer rRNAs are important molecules responsible for the translation event during protein synthesis. tRNAs are widespread found in unicellular to multi cellular organisms. Analysis of tRNA gene family members in Oryza sativa revealed the presence of 750 tRNA genes distributed unevenly in different chromosomes. The length of O. sativa tRNAs genes were ranged from 66 to 91 nucleotides encoding 52 isoacceptor in total. tRNASer found in chromosome 8 of O. sativa encoded only 66 nucleotides which is the smallest tRNA of O. sativa and to our knowledge, this is the smallest gene of eukaryotic lineage reported so far. Analyses revealed the presence of several novel/pseudo tRNA genes in O. sativa which are reported for the first time. Multiple sequence alignment of tRNAs revealed the presence of family specific conserved consensus sequences. Functional study of these novel tRNA and family specific conserved consensus sequences will be crucial to decipher their importance in biological events. The rate of transition of O. sativa tRNA was found to be higher than the rate of transversion. Evolutionary study revealed, O. sativa tRNAs were evolved from the lineages of multiple common ancestors. Duplication and loss study of tRNAs genes revealed, majority of the O. sativa tRNA were duplicated and 17 of them were found to be undergone loss during the evolution. Orthology and paralogy study showed, the majority of O. sativa tRNA were paralogous and only a few of tRNASer were found to contain orthologous tRNAs. PMID- 28713422 TI - Computational Analysis of Lifespan Experiment Reproducibility. AB - Independent reproducibility is essential to the generation of scientific knowledge. Optimizing experimental protocols to ensure reproducibility is an important aspect of scientific work. Genetic or pharmacological lifespan extensions are generally small compared to the inherent variability in mean lifespan even in isogenic populations housed under identical conditions. This variability makes reproducible detection of small but real effects experimentally challenging. In this study, we aimed to determine the reproducibility of C. elegans lifespan measurements under ideal conditions, in the absence of methodological errors or environmental or genetic background influences. To accomplish this, we generated a parametric model of C. elegans lifespan based on data collected from 5,026 wild-type N2 animals. We use this model to predict how different experimental practices, effect sizes, number of animals, and how different "shapes" of survival curves affect the ability to reproduce real longevity effects. We find that the chances of reproducing real but small effects are exceedingly low and would require substantially more animals than are commonly used. Our results indicate that many lifespan studies are underpowered to detect reported changes and that, as a consequence, stochastic variation alone can account for many failures to reproduce longevity results. As a remedy, we provide power of detection tables that can be used as guidelines to plan experiments with statistical power to reliably detect real changes in lifespan and limit spurious false positive results. These considerations will improve best practices in designing lifespan experiment to increase reproducibility. PMID- 28713423 TI - Discovering the Unexpected with the Utilization of NGS in Diagnostics of Non syndromic Hearing Loss Disorders: The Family Case of ILDR1-Dependent Hearing Loss Disorder. AB - Sensorineural hearing loss (SNHL) is a heterogeneous family of hearing disabilities with congenital (including genetic) as well as acquired etiology. Congenital SNHL of genetic etiology is further sub-divided into autosomal dominant, autosomal recessive and X-linked SNHL. More than 60 genes are involved in the etiology of autosomal recessive non-syndromic hearing loss (ARNSHL) commonly manifesting as heterogeneous pre-lingual profound to severe non progressive clinical phenotype. ILDR1-dependent ARNSHL (DFNB42, OMIM: # 609646) is a very rare sub-type of hearing disability, with unknown prevalence, caused by function-damaging genetic variants in ILDR1 gene reported in families of Middle Eastern origin. ILDR1 (Immunoglobulin-Like Domain-containing Receptor 1) is involved in the development of semicircular canal, tricellular tight junction and auditory hair cells. An apparently non-consanguineous family of European ancestry with two affected siblings with profound progressive hearing loss characterized in their infancy and successfully treated with cochlear implants (CI) is presented. Genetic analysis of common ARNSHL genetic causes in the population of origin was negative, thus the next-generation sequencing (NGS) and family segregation analysis to identify underlying causative genetic variant was performed. Unexpectedly and atypical for the population of origin a homozygous non-sense variant ILDR1 c.942C > A (p.Cys314Ter) inherited from both heterozygous parents was identified in both patients. Contrary to the commonly reported phenotype, indices of a progressive hearing loss and potential compensatory mechanism of vestibular function were revealed with the analysis of clinical data. The utilization of NGS was demonstrated as an invaluable tool for the detection of atypical rare variants in diagnostics of unidentified hearing loss disorders. PMID- 28713424 TI - Prolonged Survival of Subcutaneous Allogeneic Islet Graft by Donor Chimerism without Immunosuppressive Treatment. AB - The aim of this study was to investigate whether tolerance-induced protection of islets in the renal subcapsular space can also prevent subcutaneous allogeneic islets from being rejected. We used bone marrow stem cells from C57BL/6 (H2b) mice to construct donor chimerism in conditioned diabetic BALB/c (H2d) mice and investigated the effect of donor chimerism on engraftment and survival of subcutaneously transplanted allogeneic islets in streptozotocin-induced diabetic mice. We also studied the anti-inflammatory effect of mesenchymal stem cell on islet engraftment. Full but not low-grade or no donor chimerism was associated with successful engraftment of allogeneic islets and restoration of normoglycemia in the treated diabetic mice. The temporary hyperglycemia was 11 +/- 1 versus 19 +/- 5 days (p < 0.05) for the mice with full donor chimerism with transplanted islets in the renal subcapsular space versus the subcutaneous space, respectively. Cotransplantation of mesenchymal stem cell did not enhance alloislet engraftment. Full multilineage donor chimerism was associated with a higher transient expansion of CD11b+ and Gr-1+ myeloid progenitor cells and effector memory CD4 and CD8 T cells. In conclusion, full donor chimerism protected both renal subcapsular and subcutaneous allogeneic islets in this rodent transplantation model. PMID- 28713425 TI - Periapical Status and Quality of Root Canal Fillings in a Moroccan Subpopulation. AB - AIM: The aim of the study was to assess the prevalence of apical periodontitis (AP) and quality of root canal fillings in an adult Moroccan subpopulation. METHODS: In the study 508 patients were included, attending the Conservative Dentistry Clinic at the Faculty of Dentistry of Casablanca. 508 panoramic and 709 periapical radiographs were observed. The periapical status of all teeth (with the exception of third molars) was examined according to Orstavik's periapical index. The statistical analysis was performed with the software Epi Info Version 6.04dfr, April 2001. RESULTS: A total of 12719 teeth were examined. 45.3% of patients had apical periodontitis. 4.2% of teeth were treated endodontically and 70.4% of these treatments were inadequate. 91,5% with inadequate endodontic treatment presented apical periodontitis, while only 8,2% with adequate endodontic treatment had apical periodontitis. The lower molars and the upper premolars were the most affected teeth. The presence of apical periodontitis was correlated significantly with insufficient root canal fillings (p < 0.05). CONCLUSIONS: The present study found a high prevalence of apical periodontitis in this Moroccan population. Inadequate root canal fillings were associated with an increased prevalence of apical periodontitis. PMID- 28713426 TI - 3D Morphology Analysis of TMJ Articular Eminence in Magnetic Resonance Imaging. AB - PURPOSE: The objective of this study was to evaluate the computational reconstruction of the articular eminence of the temporomandibular joint (TMJ) based on magnetic resonance imaging (MRI) and semiautomatic volumetric segmentation techniques for morphological classification of the TMJ structure. MATERIALS AND METHODS: A total of 36 MRI scans of TMJ individuals were selected and formatted by using the ITK-SNAP software, consisting of MRI segmentation and generation of 3D models. The TMJ articular eminences were also classified according to the morphology analysis of the articular eminence in 3D reconstructions. Two independent trained and calibrated investigators performed the image analysis, which was repeated after thirty days. RESULTS: There was no association between sex and eminence shape (p = 0.456). Fisher's test revealed no statistically significant association between disc classification and eminence shape on both sides (p = 0.629). Chi-square test showed a significant statistically association between disc classification and disc displacement (p = 0.000). Intra- and interrater correlation coefficients showed excellent reproducibility values. CONCLUSIONS: Anatomical variability of the sample investigated was found, with predominantly round shape and presence of correlation between this shape and normal disc position. The correlation of flattened and convex shapes with disc position reduction indicated that type of disc derangement is more prevalent. PMID- 28713427 TI - A Three-Year Retrospective Study on Survival of Ceramic-Veneered Zirconia (Y-TZP) Fixed Dental Prostheses Performed in Private Practices. AB - OBJECTIVES: The aim of this retrospective study was to evaluate the three-year clinical outcome for ceramic-veneered zirconia fixed dental prostheses (FDPs). METHODS: All patients who were treated with ceramic-veneered zirconia FDPs, in three private practices in Sweden, during the period June 2003 to April 2007 were included. Case records from 151 patients, treated with a total of 184 zirconia FDPs (692 units), were analysed for clinical data. All complications noted in the charts were registered and compared to definitions for success and survival and statistical analysis was performed using the Kaplan-Meier method and a Cox regression model. RESULTS: In total, 32 FDPs in 31 patients experienced some type of complication (17.4% of FDPs, 20.5% of patients). Core fractures occurred in two (1.1%) FDPs. Two (1.1%) FDPs or 0.6% of units showed adhesive veneer fractures. Cohesive veneer fractures occurred in 10 (5.4%) FDPs (1.6% of units). The three-year cumulative success and survival rates (CSR) were 82.3% and 95.2%, respectively. CONCLUSIONS: Ceramic-veneered zirconia is a promising alternative to metal-ceramic FDPs, even in the posterior area. However, the higher survival rate of metal-ceramic FDPs should be noted and both dentists and patients must be aware of the risks of complications. PMID- 28713428 TI - Clinically Apparent Arterial Thrombosis in Persons with Systemic Vasculitis. AB - OBJECTIVE: To estimate the incidence rate of clinically apparent arterial thrombotic events and associated comorbidities in patients with primary systemic vasculitis. METHODS: Using large cohort administrative data from Quebec, Canada, we identified patients with vasculitis, including polyarteritis nodosa (PAN) and granulomatosis with polyangiitis (GPA). Incident acute myocardial infarctions (AMIs) and cerebrovascular accidents (CVAs) after the diagnosis of vasculitis were ascertained in the PAN and GPA group via billing and hospitalization data. These were compared to rates of a general population comparator group. The incidences of comorbidities (type 2 diabetes mellitus, dyslipidemia, and hypertension) were also collected. RESULTS: Among the 626 patients identified with vasculitis, 19.7% had PAN, 2.9% had Kawasaki disease, 23.8% had GPA, 52.4% had GCA, and 1.3% had Takayasu arteritis. The AMI rate was substantially higher in males aged 18-44 with PAN, with rates up to 268.1 events per 10,000 patient years [95% CI 67.1-1070.2], approximately 30 times that in the age- and sex matched control group. The CVA rate was also substantially higher, particularly in adults aged 45-65. Patients with vasculitis had elevated incidences of diabetes, dyslipidemia, and hypertension versus the general population. CONCLUSION: Atherothrombotic rates were elevated in patients identified as having primary systemic vasculitis. While incident rates of cardiovascular comorbidities were also increased, the substantial elevation in AMIs seen in young adults suggests a disease-specific component which requires further investigation. PMID- 28713429 TI - Treatment of Severe Refractory Hematuria due to Radiation-Induced Hemorrhagic Cystitis with Dexamethasone. AB - Treatment of pelvic neoplasms with radiotherapy may develop sequelae, especially RHC. An 85-year-old male patient was admitted to a hospital emergency with gross hematuria leading to urinary retention and was diagnosed with RHC. The urinary bladder was probed, unobstructed, and maintained in continuous three-way saline irrigation. During 45 days of hospitalization, the patient underwent two cystoscopic procedures for urinary bladder flocculation, whole blood transfusions, and one platelet apheresis. None of these interventions led to clinical resolution. As the patient hematological condition was deteriorating, dexamethasone (4 mg i.v., bolus of 6/6, 12/12, and 24 h during five days) and epoetin alpha (1000 IU, 1 ml, s.c., for four weeks) were administered which led to the remission of the urinary bleeding. Dexamethasone therapy may be considered for RHC, when conventional treatments are not effective or are not possible, avoiding more aggressive interventions such as cystectomy. PMID- 28713430 TI - Incidental Thrombus in Transit Causing Embolic Stroke. AB - Thrombus in transit leading to paradoxical systemic arterial embolism is a rare echocardiographic finding in patients presenting with embolic stroke. We present a case of a patient who had an atrial thrombus in transit discovered incidentally and later suffered a fatal stroke. Etiologies of cardioembolic stroke and the use of echocardiography in diagnosis and management are briefly discussed. PMID- 28713431 TI - An Unexpected Cause of Bradycardia in a Patient with Bacterial Meningitis. AB - Sinus bradycardia which is a sinus rhythm with a resting heart rate of less than 60 bpm is caused by intrinsic cardiac disorders like sick sinus syndrome or inferior myocardial infarction, metabolic and environmental causes (such as hypothyroidism and electrolyte disorders), medications (such as beta-blockers and amiodarone), infection (such as myocarditis), increased intracranial pressure, and toxic exposure, while it can sometimes be a normal phenomenon, especially during sleep, in athletes, and during pregnancy. Symptomatic sinus bradycardia should warrant a thorough work-up in order to identify any reversible causes; otherwise, placement of a permanent pacemaker could be needed. We present the case of a patient who was admitted due to confusion and fever and was found to have pneumococcal meningitis and bacteremia, and during his hospital stay he developed symptomatic sinus bradycardia that was of intractable cause and persistent. Placement of a permanent pacemaker was chosen until the night staff of the hospital discovered by chance the neglected cause of his bradycardia. PMID- 28713432 TI - Haematological Profile and Intensity of Urogenital Schistosomiasis in Ghanaian Children. AB - BACKGROUND: Urogenital schistosomiasis is a widely contracted parasitic helminth infection often associated with haematological abnormalities. AIM: We investigated the relationship between the haematological profile and the intensity of schistosomiasis among children in the Yeji district. MATERIALS AND METHODS: A total of 100 participants comprising 50 Schistosoma haematobium (S. haematobium) infected and 50 noninfected controls aged 6-17 years matched for age and sex were recruited into the study. Blood and urine samples were collected and haematological profile and presence of S. haematobium eggs were assessed using standard protocols. RESULTS: Haemoglobin (HGB) (P < 0.0001), haematocrit (HCT) (P < 0.0001), mean cell volume (MCV) (P = 0.0053), mean cell haemoglobin (MCH) (P < 0.0001), and mean cell haemoglobin concentration (MCHC) (P = 0.005) levels were reduced in cases compared to controls. Mixed cell percentage (MXD) (P = 0.018) and red blood cell distribution width (RDW-CV) (P = 0.012) were significantly elevated among cases as compared to controls. Haematuria was a clinical characteristic of heavy infection. CONCLUSION: S. haematobium infection creates an imbalance in the haematological profile. We found low HGB, HCT, MCV, MCH, and MCHC levels coupled with increased % MXD count and RDW-CV. Also, low MCV, MCH, and MCHC and high % MXD count are independently associated with S. haematobium infection among our study participants. PMID- 28713434 TI - First Insight into a Nationwide Genotypic Diversity of Mycobacterium tuberculosis among Previously Treated Pulmonary Tuberculosis Cases in Benin, West Africa. AB - BACKGROUND: Molecular studies on tuberculosis (TB) are rare in low-resource countries like Benin, where data on molecular study on previously treated TB cases is unavailable. MATERIALS AND METHODS: From January to December 2014, all smear- and culture-positive previously treated pulmonary TB patients from all TB clinics were systematically recruited. Drug susceptibility testing and spoligotyping were performed on all isolates. RESULTS: Of the 100 patients recruited, 71 (71.0%) were relapse cases and 24 (24.0%) were failure cases, while 5 (5.0%) were default cases. Resistance rate to any first-line drug was 40.0%, while 12.0% of strains were multidrug-resistant (MDR) and no strain was extensively drug-resistant (XDR). A total of 40 distinct spoligotypes were found to be corresponding to a genotypic diversity of 40.0%. ST61 was the most predominant spoligotype with prevalence of 33.0%. In all, 31 single spoligotypes and nine clusters were observed with 2 to 33 strains per cluster giving a clustering rate of 69.0%. Euro-American (Lineage 4) was the most prevalent lineage (74.0%) and Lineage 2 was associated with resistance to streptomycin. CONCLUSION: This first insight into genetic diversity of previously treated pulmonary TB patients in Benin showed a relatively high genetic diversity of Mycobacterium tuberculosis. PMID- 28713435 TI - Comparative Efficacy and Toxicity of Different Species of Sargassum in Haizao Yuhu Decoction in PTU-Induced Goiter Rats. AB - BACKGROUND: Haizao Yuhu Decoction has been widely used to treat thyroid-related diseases especially goiter with few side effects in traditional Chinese medicine (TCM), including herb pair Sargassum (HZ) and Glycyrrhizae Radix et Rhizoma (GC), as one of "eighteen antagonistic medicaments." The two different species of Sargassum, Sargassum fusiforme (Sf) and Sargassum pallidum (Sp), are not clearly differentiated in clinical use, so that herb pair Sf-GC and Sp-GC could show different effect and toxicity. METHODS: We investigated the antigoitrous effect and toxicity and clarified the potential underlying mechanism of the two different species of Sargassum in HYD (HYDf and HYDp) in PTU-reduced goiter rats. RESULTS: The results demonstrated that both HYDf and HYDp could exhibit antigoitrous effect through alterations in hypothalamus-pituitary-thyroid (HPT) axis and inhibition of the TPO gene expression; there is no difference in the antigoitrous effects between the two different species of Sargassum application in HYD. CONCLUSION: This study evaluated the safety and efficacy of herb pair HZ GC applied in HYD in goiter rats at molecular, cellular, and whole level and compared the two species of Sargassum further. We provide a reliable way to clarify the possible mechanism of the antagonistic medicament herb pair HZ-GC for its application. PMID- 28713433 TI - Black Tea Source, Production, and Consumption: Assessment of Health Risks of Fluoride Intake in New Zealand. AB - In countries with fluoridation of public water, it is imperative to determine other dietary sources of fluoride intake to reduce the public health risk of chronic exposure. New Zealand has one of the highest per capita consumption rates of black tea internationally and is one of the few countries to artificially fluoridate public water; yet no information is available to consumers on the fluoride levels in tea products. In this study, we determined the contribution of black tea as a source of dietary fluoride intake by measuring the fluoride content in 18 brands of commercially available products in New Zealand. Fluoride concentrations were measured by potentiometric method with a fluoride ion selective electrode and the contribution of black tea to Adequate Intake (AI) and Tolerable Upper Intake Level (UL) was calculated for a range of consumption scenarios. We examined factors that influence the fluoride content in manufactured tea and tea infusions, as well as temporal changes in fluoride exposure from black tea. We review the international evidence regarding chronic fluoride intake and its association with chronic pain, arthritic disease, and musculoskeletal disorders and provide insights into possible association between fluoride intake and the high prevalence of these disorders in New Zealand. PMID- 28713436 TI - The Traditional Chinese Medicine and Relevant Treatment for the Efficacy and Safety of Atopic Dermatitis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. AB - BACKGROUND: Atopic dermatitis (AD) has become a common skin disease that requires systematic and comprehensive treatment to achieve adequate clinical control. Traditional Chinese medicines and related treatments have shown clinical effects for AD in many studies. But the systematic reviews and meta-analyses for them are lacking. OBJECTIVE: The systematic review and meta-analysis based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement were conducted to evaluate the efficacy and safety of traditional Chinese medicines and related treatments for AD treatment. METHODS: Randomized controlled trials (RCTs) were searched based on standardized searching rules in eight medical databases from the inception up to December 2016 and a total of 24 articles with 1,618 patients were enrolled in this meta-analysis. RESULTS: The results revealed that traditional Chinese medicines and related treatments did not show statistical differences in clinical effectiveness, SCORAD amelioration, and SSRI amelioration for AD treatment compared with control group. However, EASI amelioration of traditional Chinese medicines and related treatments for AD was superior to control group. CONCLUSION: We need to make conclusion cautiously for the efficacy and safety of traditional Chinese medicine and related treatment on AD therapy. More standard, multicenter, double-blind randomized controlled trials (RCTs) of traditional Chinese medicine and related treatment for AD were required to be conducted for more clinical evidences providing in the future. PMID- 28713438 TI - Looking to the Future of Work and Family Theory and Research: Some Reflections. PMID- 28713437 TI - Astragalus Extract Mixture HT042 Increases Longitudinal Bone Growth Rate by Upregulating Circulatory IGF-1 in Rats. AB - Astragalus extract mixture HT042 is a standardized ingredient of health functional food approved by Korean FDA with a claim of "height growth of children." HT042 stimulates bone growth rate and increases local IGF-1 expression in growth plate of rats which can be considered as direct stimulation of GH and its paracrine/autocrine actions. However, it remains unclear whether HT042 stimulates circulatory IGF-1 which also plays a major role to stimulate bone growth. To determine the effects on circulatory IGF-1, IGF-1 and IGFBP-3 expressions and phosphorylation of JAK2/STAT5 were evaluated in the liver after 10 days of HT042 administration. HT042 upregulated liver IGF-1 and IGFBP-3 mRNA expression, IGF-1 protein expression, and phosphorylation of JAK2/STAT5. HT042 also increased bone growth rate and proliferative zonal height in growth plate. In conclusion, HT042 stimulates bone growth rate via increment of proliferative rate by upregulation of liver IGF-1 and IGFBP-3 mRNA followed by IGF-1 protein expression through phosphorylation of JAK2/STAT5, which can be regarded as normal functioning of GH-dependent endocrine pathway. PMID- 28713439 TI - Predicting future biomass yield in Miscanthus using the carbohydrate metabolic profile as a biomarker. AB - In perennial energy crop breeding programmes, it can take several years before a mature yield is reached when potential new varieties can be scored. Modern plant breeding technologies have focussed on molecular markers, but for many crop species, this technology is unavailable. Therefore, prematurity predictors of harvestable yield would accelerate the release of new varieties. Metabolic biomarkers are routinely used in medicine, but they have been largely overlooked as predictive tools in plant science. We aimed to identify biomarkers of productivity in the bioenergy crop, Miscanthus, that could be used prognostically to predict future yields. This study identified a metabolic profile reflecting productivity in Miscanthus by correlating the summer carbohydrate composition of multiple genotypes with final yield 6 months later. Consistent and strong, significant correlations were observed between carbohydrate metrics and biomass traits at two separate field sites over 2 years. Machine-learning feature selection was used to optimize carbohydrate metrics for support vector regression models, which were able to predict interyear biomass traits with a correlation (R) of >0.67 between predicted and actual values. To identify a causal basis for the relationships between the glycome profile and biomass, a 13C-labelling experiment compared carbohydrate partitioning between high- and low-yielding genotypes. A lower yielding and slower growing genotype partitioned a greater percentage of the 13C pulse into starch compared to a faster growing genotype where a greater percentage was located in the structural biomass. These results supported a link between plant performance and carbon flow through two rival pathways (starch vs. sucrose), with higher yielding plants exhibiting greater partitioning into structural biomass, via sucrose metabolism, rather than starch. Our results demonstrate that the plant metabolome can be used prognostically to anticipate future yields and this is a method that could be used to accelerate selection in perennial energy crop breeding programmes. PMID- 28713440 TI - Investigating the physical stability of repackaged medicines stored into commercially available multicompartment compliance aids (MCAs). AB - BACKGROUND: Compliance aids are devices which have been developed and are currently used to assist individuals in their medicines management. The use of compliance aids involves the transfer of medicines from the manufacturers' original packaging and repackaged into an multicompartment compliance aid (MCA). MCAs do not guarantee the same level of protection compared to manufacturer's original packaging. OBJECTIVE: The aim of this study was to investigate the stability profile of atenolol, aspirin and lansoprazole dosage forms repackaged together in two different commercially available MCAs. METHODS: In a laboratory in the United Kingdom, the physical stability of the formulations repackaged into two commercially available brands of MCAs was evaluated. After 8 weeks of storage (under controlled ambient conditions), changes in the disintegration (tablets only) and dissolution properties (all formulations) were examined in accordance with British Pharmacopoeia (BP) specifications. KEY FINDINGS: Findings from this study confirm that changes in solid-dosage form quality are observed when repackaged into MCAs compared to manufacturers packaging resulting in differences in in-vitro dissolution performance. However, even with these changes, overall product performance was acceptable and within BP specifications. CONCLUSION: There is a need for greater collaboration in this area between manufacturers, hospital and community pharmacists, academics and policymakers to increase the data available on the physical stability and in turn performance of medicines repackaged into MCAs. PMID- 28713441 TI - Analysis of Raw Biofluids by Mass Spectrometry Using Microfluidic Diffusion-Based Separation. AB - Elucidation and monitoring of biomarkers continues to expand because of their medical value and potential to reduce healthcare costs. For example, biomarkers are used extensively to track physiology associated with drug addiction, disease progression, aging, and industrial processes. While longitudinal analyses are of great value from a biological or healthcare perspective, the cost associated with replicate analyses is preventing the expansion of frequent routine testing. Frequent testing could deepen our understanding of disease emergence and aid adoption of personalized healthcare. To address this need, we have developed a system for measuring metabolite abundance from raw biofluids. Using a metabolite extraction chip (MEC), based upon diffusive extraction of small molecules and metabolites from biofluids using microfluidics, we show that biologically relevant markers can be measured in blood and urine. Previously it was shown that the MEC could be used to track metabolic changes in real-time. We now demonstrate that the device can be adapted to high-throughput screening using standard liquid chromatography mass spectrometry instrumentation (LCMS). The results provide insight into the sensitivity of the system and its application for the analysis of human biofluids. Quantitative analysis of clinical predictors including nicotine, caffeine, and glutathione are described. PMID- 28713442 TI - Overdiagnosis: An Unrecognised and Growing Worldwide Problem in Healthcare. AB - Overdiagnosis is the diagnosis of deviations, abnormalities, risk factors, and pathologies that in themselves would never cause symptoms (this applies only to risk factors and pathology), would never lead to morbidity, and would never be the cause of death. Therefore, treating an overdiagnosed condition (deviation, abnormality, risk factor, pathology) cannot, by definition, improve the patient's prognosis, and can therefore only be harmful. Overdiagnosis is an extremely harmful and big problem all over the world, and the problem is increasing. This is especially the case in high-income countries, where more sensitive tests, more testing, more screening and earlier diagnosis is in focus, and more of the same will be implemented in the future. Moreover, disease definitions have been and are still being widened, plus thresholds for treating, e.g. risk factors, have been and are still being lowered. Finally, disease mongering is growing, because it is cheaper and faster to invent new "diseases" than new pharmaceutical drugs. From the definition of overdiagnosis it can be reasoned that a patient who has been correctly diagnosed and a person who has been overdiagnosed can have the same kind of pathologies. Therefore, at the level of the individual person or patient it can never be verified whether he or she has in fact been correctly diagnosed or overdiagnosed. Therefore, the complexity, dilemmas and pitfalls in understanding what overdiagnosis really is so succinctly captured by this quote from the Danish philosopher S?ren Kirkegaard (1813-55): 'Life can only be understood backwards; but it must be lived forwards'. PMID- 28713443 TI - E-healthcare for Diabetes Mellitus Type 2 Patients - A Randomised Controlled Trial in Slovenia. AB - BACKGROUND: Telemonitoring and web-based interventions are increasingly used in primary-care practices in many countries for more effective management of patients with diabetes mellitus (DM). A new approach in treating patients with diabetes mellitus in family practices, based on ICT use and nurse practitioners, has been introduced and evaluated in this study. METHOD: Fifteen Slovene family practices enrolled 120 DM patients treated only with a diet regime and/or tablets into the study. 58 of them were included into the interventional group, and the other 62 DM patients into the control group, within one-year-long interventional, randomised controlled trial. Patients in the control group had conventional care for DM according to Slovenian professional guidelines, while the patients in the interventional group were using also the eDiabetes application. Patients were randomised through a balanced randomisation process. RESULTS: Significant reductions of glycated haemoglobin (HbA1c) values were found after 6 and 12 months among patients using this eDiabetes application (p<0.05). Among these patients, a significant correlation was also found between self-monitored blood pressure and the final HbA1c values. Diabetic patients' involvement in web-based intervention had only transient impact on their functional health status. CONCLUSION: This eDiabetes application was confirmed to be an innovative approach for better self-management of DM type 2 patients not using insulin. Both a significant reduction of HbA1c values and a significant correlation between the average self-measured blood pressure and the final HbA1c values in the interventional group were found. Nurse practitioners - as diabetes care coordinators - could contribute to better adherence in diabetes e-care. PMID- 28713444 TI - Smoking Behaviors in Kosova: Results of Steps Survey. AB - INTRODUCTION: Tobacco use continues to be the leading global cause of preventable death. Most of these deaths occur in low and middle-income countries, and this trend is expected to widen further over the next several decades. The overall objective of the study is to describe and analyse the smoking behaviours of adults in Kosova. METHODS: According to the STEPs methodology, 6,400 respondents, aged 15 - 64 years, are selected randomly within each sex and 10-year age-group. Out of 6,400 participants, 6,117 were selected, which is approximately 95.6%. RESULTS: The prevalence of smoking was higher among males (37.4%) compared with females (19.7%). In all age groups, the prevalence of smoking was higher among males compared with females. Regarding the age group of 15 - 24 years, the prevalence of smoking was 16.0%, but in the age group of 25 - 34 years, it nearly doubled to the rate of 31.9%. We have a smaller increase in the age group of 35 - 44 years, and after the age of 45, it falls gradually. CONCLUSIONS: The prevalence of smoking in Kosova is high compared with other countries in Eastern Europe. In future decades, Kosova will face a high probability of an increased burden of smoking-related diseases. PMID- 28713445 TI - The Role of Attitudes to, and the Frequency of, Domestic Violence Encounters in the Healthcare Professionals' Handling of Domestic Violence Cases. AB - BACKGROUND: Domestic violence is recognized as a public health problem with a high prevalence in the general population. Healthcare professionals play an important role in the recognition and treatment of domestic violence. Hence, conducting research on factors that facilitate or inhibit appropriate actions by healthcare professionals is of the upmost importance. The objective of the study was to examine the relationship between healthcare professionals' attitudes toward the acceptability of domestic violence and their responses when dealing with victims of domestic violence. METHODS: The sample consisted of 322 healthcare professionals (physicians, dentists, nursing staff and other healthcare workers; 85.2% female), who completed a questionnaire, assessing their attitudes towards domestic violence, experience, behaviour and perceived barriers in recognizing and treating domestic violence in the health care sector. The study was cross-sectional and used availability sampling. RESULTS: The results showed no significant differences in domestic violence acceptability attitudes when comparing groups of healthcare professionals who reported low or high frequency of domestic violence cases encounters. Furthermore, we found that domestic violence acceptability attitudes were negatively associated with action taking when the frequency of encounters with domestic violence cases was high and medium. However, the attitudes were not associated with action taking when the frequency of encounters with domestic violence cases was low. CONCLUSIONS: The results highlight the important role of attitudes in action taking of healthcare professionals when it comes to domestic violence. This indicates the need for educational interventions that specifically target healthcare professionals' attitudes towards domestic violence. PMID- 28713446 TI - Nasopharyngeal Carriage of Streptococcus Pneumoniae and Serotypes Indentified among Nursing Home Residents in Comparison to the Elderly and Patients Younger than 65 Years Living in Domestic Environment. AB - INTRODUCTION: In Slovenia, there is little data available on pneumococcal vaccination rates and no data on asymptomatic NPCR and serotypes in the population of nursing home residents in comparison to the elderly living in domestic environment, therefore the goal was to gain these data. METHODS: A cross sectional epidemiological study was performed. Nasopharyngeal swabs from 151 nursing home residents, 150 elderly living in domestic environment, and 38 adults less than 65 years old were collected twice (in two consecutive years). The swabs were analysed for pneumococcal identification and serotyping. Patient data were collected from medical files and medical history. RESULTS: No statistically significant differences in NPCR were seen between compared groups in two consecutive years. An average NPCR in two consecutive years in nursing home residents was 1.45%, in the elderly living in domestic environment 0.85%, and in adults less than 65 years old 7.05%. Serotypes identified among nursing home residents were 6B and 9N, among the group of elderly living in domestic environment, 6A and among adults less than 65 years old, 35F, 18C and 3. Pneumococcal vaccination rates were low (3.3% in nursing home residents, 6% in the elderly from domestic environment and 0% in the group of adults less than 65 years old). CONCLUSIONS: Our data suggests that NPCR and the proportion of people vaccinated with pneumococcal vaccine among the elderly are low. We identified different serotypes in all groups, only one person was a chronic carrier (serotype 35F). PMID- 28713447 TI - Knowledge about Blood-borne Pathogens and the Prevalence of Needle Stick Injuries among Medical Students in Serbia. AB - INTRODUCTION: Medical students are mainly exposed to needle stick and sharp object injuries in the course of their clinical activities during studying. They are at high risk due to their undeveloped skills, restricted clinical experience, lack of knowledge and risk perception. The objectives of this study were to determine the prevalence of needle stick injuries of the fourth and final year medical students, and to estimate their knowledge about blood-borne pathogens disease transmission and standard precautions. METHODS: This cross-sectional study was conducted at the Faculty of Medicine, in February 2014. The students were invited to self-administer a questionnaire of 26 closed questions prepared for this study. RESULTS: The questionnaire was filled in and returned by 637 students. The prevalence of needle sticks and sharp object injuries was 29.5%. Needle stick injuries were the most common type of accidents, more frequent among the fourth compared to the sixth year students (p=0.002). The majority of accidents occurred in patient rooms (53%) and the emergency department (15%). 54% of participants reported an accident to the responsible person. Students without accidents had a significantly better perception of risk (3.79 vs. 3.35; p<0.05). Out of the total participating students, only 16.6% (106/637) received all three doses of Hepatitis B vaccination, while 16.2% were partially vaccinated. CONCLUSIONS: There is a need for additional theoretical and practical education of our students on blood exposure via accidents, raising the awareness of the necessity of hepatitis B vaccination, and introducing the unique/comprehensive procedure for accident reporting for students and healthcare workers in the entire country. PMID- 28713448 TI - Survival of Node-negative Breast Cancer Patients Treated at the University Medical Centre Maribor in the Period 2000-2009. AB - INTRODUCTION: Breast cancer is increasingly diagnosed in the early stages without regional nodal involvement. The aim of the present study was to determine the 5 year overall (OS) and breast cancer specific survival (BCSS) for patients with node-negative breast cancer treated at the University Medical Centre Maribor, and compare it with survival at the national level. METHODS: Medical records were searched for information on patients with lymph node-negative invasive breast cancer who received primary treatment at the University Medical Centre Maribor in the period 2000-2009. Information on all Slovenian node-negative breast cancer patients diagnosed in the same period was obtained from the Cancer Registry of Republic of Slovenia. Time trends in survival were assessed by comparing the periods 2000-2004 and 2005-2009. RESULTS: The 5-year OS and BCSS of patients treated in Maribor in the period 2000-2009 were 92.3% (95% CI, 90.5%- 94.1%) and 96.4% (95% CI, 95.2%-97.6%), respectively, and did not differ from the corresponding OS and BCSS for Slovenian patients. Although the improvement in OS for patients from Maribor diagnosed in the period 2005-2009 compared to 2000-2004 did not reach statistical significance (HR 0.73; 95% CI, 0.51-1.05; p=0.086), BCSS significantly improved over the same time periods (HR 0.53; 95% CI, 0.30 0.94; p=0.028). CONCLUSIONS: Survival of node-negative breast cancer patients treated at the University Medical Centre Maribor is comparable to survival of corresponding patients at the national level. The rising number of long-term breast cancer survivors places additional importance on survivorship care. PMID- 28713449 TI - Understanding Racial and Ethnic Disparities in Arrest: The Role of Individual, Home, School, and Community Characteristics. AB - Contact with the justice system can lead to a range of poor health and social outcomes. While persons of color are disproportionately represented in both the juvenile and criminal justice systems, reasons for these patters remain unclear. This study sought to examine the extent and sources of differences in arrests during adolescence and young adulthood among blacks, whites, and Hispanics in the USA. Multilevel cross-sectional logistic regression analyses were conducted using data from waves I and IV of the National Longitudinal Study of Adolescent to Adult Health (n = 12,752 respondents). Results showed significantly higher likelihood of having ever been arrested among blacks, when compared to whites, even after controlling for a range of delinquent behaviors (odds ratio = 1.58, 95 % confidence interval = 1.27, 1.95). These black-white disparities were no longer present after accounting for racial composition of the neighborhood, supporting the growing body of research demonstrating the importance of contextual variables in driving disproportionate minority contact with the justice system. PMID- 28713450 TI - Generalized Benford's Law as a Lie Detector. AB - The first significant (leftmost nonzero) digit of seemingly random numbers often appears to conform to a logarithmic distribution, with more 1s than 2s, more 2s than 3s, and so forth, a phenomenon known as Benford's law. When humans try to produce random numbers, they often fail to conform to this distribution. This feature grounds the so-called Benford analysis, aiming at detecting fabricated data. A generalized Benford's law (GBL), extending the classical Benford's law, has been defined recently. In two studies, we provide some empirical support for the generalized Benford analysis, broadening the classical Benford analysis. We also conclude that familiarity with the numerical domain involved as well as cognitive effort only have a mild effect on the method's accuracy and can hardly explain the positive results provided here. PMID- 28713451 TI - Words That Move Us. The Effects of Sentences on Body Sway. AB - According to the embodied cognition perspective, cognitive systems and perceptuo motor systems are deeply intertwined and exert a causal effect on each other. A prediction following from this idea is that cognitive activity can result in subtle changes in observable movement. In one experiment, we tested whether reading various sentences resulted in changes in postural sway. Sentences symbolized various human activities involving high, low, or no physical effort. Dutch participants stood upright on a force plate, measuring the body center of pressure, while reading a succession of sentences. High physical effort sentences resulted in more postural sway (greater SD) than low physical effort sentences. This effect only showed up in medio-lateral sway but not anterio-posterior sway. This suggests that sentence comprehension was accompanied by subtle motoric activity, likely mirroring the various activities symbolized in the sentences. We conclude that semantic processing reaches the motor periphery, leading to increased postural activity. PMID- 28713452 TI - Training of Visual-Spatial Working Memory in Preschool Children. AB - Working memory, the ability to store and manipulate information is of great importance for scholastic achievement in children. In this study, we report four studies in which preschoolers were trained on a visual-spatial working memory span task, namely the Corsi Block Task. Across all four studies, we found significant training effects for the intervention groups compared to active control groups. Confirming recent research, no transfer effects to other working memory tasks were found. Most importantly, our training effects were mainly brought about by children performing below the median in the pretest and those showing median performance, thereby closing the gap to children performing above the median (compensation effect). We consider this finding of great interest to ensure comparable starting conditions when entering school with a relatively short intervention. PMID- 28713453 TI - Yellow Fever and Traveling Athletes: Is Competing in Brazil Safe? PMID- 28713454 TI - Balance, Basic Anthropometrics and Performance in Young Alpine Skiers; Longitudinal Analysis of the Associations During two Competitive Seasons. AB - Balance is hypothesized to be important in alpine skiing, while it is known that balance depends on anthropometric indices. The aim of this investigation was to explore the association between balance, anthropometrics and skiing-results over two competitive seasons among youth alpine-skiers. Eighty-one skiers (40 females) participated in this study. The participants were tested twice over two competitive seasons: when they were 12-13 years old (U14) and when they were 14 15 years old (U16). The variables consisted of anthropometrics (body height and body mass) and three balance indexes (medio-lateral-, anterio-posterior- and overall-stability-index). Additionally, skiing results in U14 and U16 were evaluated. The balance status did not change significantly over the observed period of time regardless of the significant changes in body mass and height. The relationships between balance and skiing results were higher in the U14 (Pearson's r = 0.45-0.54) than in the U16 (Pearson's r = 0.05-0.28). The relationships between anthropometrics and competitive results were generally stronger in girls (Pearson's r = 0.39-0.88) than in boys (Pearson's r = 0.26 0.58). After clustering athletes into three achievement groups on a basis of their competitive performance, discriminant canonical analysis showed that relationships between balance and skiing results decreased, while the relationships between anthropometrics and skiing results increased over the two observed seasons. This study highlighted the importance of balance in youth alpine skiing in the age range of 11-14 years. PMID- 28713455 TI - A Pilot Study of the Effect of Outsole Hardness on Lower Limb Kinematics and Kinetics during Soccer Related Movements. AB - The purpose of this study was to investigate the effect of different outsole hardness of turf cleats shoes on the lower limb kinematics and kinetics of soccer players playing on artificial turf. The participants were required to complete tasks of straight running and 45 degrees left sidestep cutting movements, respectively, at the speed of 4.5 +/- 0.2 m/s on artificial turf. They were asked to randomly select turf cleats shoes with a soft outsole (SO), medium hardness outsole (MO) and hard outsole (HO). During the stance phase of straight running, peak pressure and force-time integral in medial forefoot (MFF) of players wearing cleats shoes with MO were significantly higher than those wearing cleats shoes with SO. During the stance phase of a 45 degrees cutting maneuver, players wearing cleats shoes with SO showed significantly higher peak knee flexion and abduction angles than the HO group. Players wearing cleats shoes with SO also showed higher ankle dorsiflexion and inversion angles compared with those wearing cleats shoes with HO. The vertical average loading rate (VALR) as well as peak pressure and force-time integral in the heel (H) and lateral forefoot (LFF) regions of players wearing cleats shoes with HO were significantly higher than those wearing shoes with SO. On the contrary, peak pressure and force-time integral of players wearing shoes with SO were significantly higher than those wearing shoes with HO in MFF. A higher vertical loading rate and plantar pressure of some areas may increase the potential risk of metatarsal stress fractures and plantar fasciitis. Therefore, this finding about turf cleats shoes could give some theoretic support for the design of turf cleats shoes and material optimization in the future. PMID- 28713456 TI - Post Activation Potentiation of the Plantarflexors: Implications of Knee Angle Variations. AB - Flexing the knee to isolate the single joint soleus from the biarticular gastrocnemius is a strategy for investigating individual plantarflexor's post activation potentiation (PAP). We investigated the implications of testing plantarflexor PAP at different knee angles and provided indirect quantification of the contribution of gastrocnemius potentiation to the overall plantarflexor enhancements post conditioning. Plantarflexor supramaximal twitches were measured in ten male power athletes before and after a maximal isometric plantarflexion (MVIC) at both flexed and extended knee angles. Mean torque and soleus (SOLRMS) and medial gastrocnemius (MGRMS) activity were measured during the MVIC. The mean torque and MGRMS of the MVIC were lower (by 33.9 and 42.4%, respectively) in the flexed compared to the extended position, with no significant difference in SOLRMS. After the MVIC, twitch peak torque (PT) and the rate of torque development (RTR) potentiated significantly more (by 17.4 and 14.7% respectively) in the extended as compared to the flexed knee position, but only immediately (5 s) after the MVIC. No significant differences were found in the twitch rate of torque development (RTD) potentiation between positions. It was concluded that knee joint configuration should be taken into consideration when comparing studies of plantarflexor PAP. Furthermore, results reflect a rather brief contribution of the gastrocnemius potentiation to the overall plantarflexor twitch enhancements. PMID- 28713457 TI - Personal and Social Responsibility among Athletes: the Role of Self Determination, Achievement Goals and Engagement. AB - The purpose of this study was to assess the relationship between motivation, engagement and personal and social responsibility among athletes. Based on the literature, a survey was conducted including measures of motivation, considering task orientation and ego orientation, intrinsic and extrinsic motivation, and amotivation. We also measured the components of engagement (dedication, confidence, vigor and enthusiasm) and the components of personal and social responsibility. A total of 517 athletes from different types of sports participated in the study. The results gathered through a structural equation model revealed that task orientation had the strongest relationship with personal responsibility and social responsibility, followed by engagement. Self determination levels were not associated with personal and social responsibility. These results suggest that monitoring of task orientation and engagement levels should be performed by coaches as a strategy to develop personal and social responsibility among their athletes. Moreover, findings from this study provide scholars with a tool to aid them in managing athletes' levels of personal and social responsibility. PMID- 28713458 TI - Trunk Strength Characteristics of Elite Alpine Skiers - a Comparison with Physically Active Controls. AB - Core muscle imbalances and weak trunk strength are relevant for injury prevention and performance. Information regarding core strength requirements and ideal flexion/extension ratios in alpine skiing is limited. We aimed to compare trunk strength capacities in elite alpine skiers with those of a matched control group. The concentric maximal trunk flexion and extension of 109 elite skiers and 47 active controls were measured at 150 degrees /s in a ballistic mode using the CON TREX(r) TP 1000 test system. The relative flexion peak torque was higher in male ski racers (p = 0.003; 2.44 +/- 0.30 Nm/kg) than in the controls (2.32 +/- 0.42 Nm/kg). The relative peak torque for extension was 4.53 +/- 0.65 Nm/kg in ski racers and 4.11 +/- 0.52 Nm/kg in the controls (p = 0.001). Female athletes were significantly stronger in both, relative flexion force (p = 0.006; skiers 2.05 +/ 0.22 Nm/kg; controls 1.74 +/- 0.28 Nm/kg) and relative extension force (p = 0.001; skiers 3.55 +/- 0.53 Nm/kg; controls 3.14 +/- 0.48 Nm/kg). No significant differences were found in the ratios of flexion to extension forces in females and males. Ski racers are engaged in extensive strength training for both leg and trunk muscles, which explains the higher peak values. Both groups indicated a low ratio from 0.54-0.59, which represents high trunk extensor muscles strength relative to flexor muscles. PMID- 28713459 TI - The Effects of Bench Press Variations in Competitive Athletes on Muscle Activity and Performance. AB - The aim of the study was to compare the EMG activity performing 6RM competition style bench press (flat bench-wide grip) with 1) medium and narrow grip widths on a flat bench and 1) inclined and declined bench positions with a wide grip. Twelve bench press athletes competing at national and international level participated in the study. EMG activity was measured in the pectoralis major, anterior and posterior deltoid, biceps brachii, triceps brachii and latissimus dorsi. Non-significant differences in activation were observed between the three bench positions with the exception of 58.5-62.6% lower triceps brachii activation, but 48.3-68.7% greater biceps brachii activation in the inclined bench compared with the flat and declined bench position. Comparing the three grip widths, non-significant differences in activations were observed, with the exception of 25.9-30.5% lower EMG activity in the biceps brachii using a narrow grip, compared to the medium and wide grip conditions. The 6-RM loads were 5.8 11.1% greater using a medium and wide grip compared to narrow grip width and 18.5 21.5% lower in the inclined bench position compared with flat and declined. Comparing the EMG activity during the competition bench press style with either the inclined and declined bench position (wide grip) or using a narrow and medium grip (flat bench), only resulted in different EMG activity in the biceps- and triceps brachii. The 6RM loads varied with each bench press variation and we recommend the use of a wide grip on a flat bench during high load hypertrophy training to bench press athletes. PMID- 28713460 TI - Effects of an Elastic Hamstring Assistance Device During Downhill Running. AB - The purpose of this study was to determine the appropriateness of using an elastic hamstring assistance device to reduce perceived levels of soreness, increase isometric strength, increase passive range of motion, and decrease biomarkers of muscle damage after eccentric exercise, specifically, downhill running This study was conducted in a university exercise physiology laboratory placing sixteen apparently healthy males (X = 21.6 +/- 2.5 years) into two groups using a pre-test/post-test design. Pre-intervention measures taken included participants' body height, body mass, body fat, capillary blood samples, VO2max, isometric hamstring strength at 45 and 90 degrees of flexion and passive hamstring range of motion. Post-intervention measures included blood biomarkers, passive range of motion, the perceived level of soreness and isometric strength. An analysis of normality of data was initially conducted followed by multivariate analysis of variance (MANOVA) of hamstring strength at 45 and 90 degrees of flexion, blood myoglobin and passive range of motion of the hamstrings. Statistically significant changes were noted in subject-perceived muscle soreness and isometric strength at 90 degrees at the 24-hour post-exercise trial measure between the two groups. Results would suggest the findings could be explained by the decrease in muscle soreness from utilizing the device during the exercise trial. Further research should be conducted to address sample size issues and to determine if the results are comparable on different surfaces. PMID- 28713462 TI - The Effect of Foam Rolling on Recovery Between two Eight Hundred Metre Runs. AB - With the increased popularity of foam rolling as a means of recovery, it is important to establish the exact manner in which the practice is useful. The purpose of this study was to examine the impact of foam rolling on recovery between two 800 m runs. Sixteen trained males (mean +/- sd; age, 20.5 +/- .5 yr; average 800 m treadmill run time, 145.2 +/- 1.8 s) participated in the study, using a randomized, crossover design. The subjects completed two 800 m runs on a treadmill, separated by a 30 min rest, during which time a foam rolling protocol or passive rest period was performed. The speed of each run was as fast as possible. Subjects had access to speed controls, but were blinded to the actual speed. Blood lactate concentration and [Formula: see text]CO2 were measured prior to and following each run. Stride length, 800 m run time, and hip extension were measured during each run. [Formula: see text]CO2, stride length, 800 m run time, and hip extension were not significantly different between conditions (p > .05). For blood lactate, no statistical interaction was found between condition and time (p > .05). Foam rolling between two 800 m runs separated by 30 min performed by trained male runners does not alter performance. PMID- 28713461 TI - The Effects of Maximal Intensity Exercise on Cognitive Performance in Children. AB - High intensity physical exercise has previously been found to lead to a decline in cognitive performance of adults. The aim of this study was to determine the effects of maximal intensity exercise on cognitive performance of children. Using a repeated-measures design, 20 children and adolescents aged 8-17 years completed a battery of tests measuring memory and attention. Forward and Backward Digit Span tests, the Rey Auditory-Verbal Learning Test (RAVLT) and the Digit Symbol Substitution Test (DSST) were performed at baseline, immediately after, and one hour after a maximal cardiopulmonary exercise test. Forward and Backward Digit Span scores significantly improved post-recovery compared with baseline measurements. There was a significant decrease in RAVLT scores post-exercise, which returned to baseline values after recovery. The DSST test scores were mildly elevated from post-exercise to after recovery. Maximal intensity exercise in children and adolescents may result in both beneficial and detrimental cognitive effects, including transient impairment in verbal learning. Cognitive functions applying short term memory improve following a recovery period. Parents, educators and coaches should consider these changes in memory and attention following high-intensity exercise activities in children. PMID- 28713463 TI - Cardiopulmonary Performance During Maximal Exercise in Soccer Players with Alterations in Renal Function. AB - The aim of this study was to evaluate the curves of cardiorespiratory variables during cardiopulmonary exercise testing (CPET) in soccer players who had acute alterations in the glomerular filtration rate (GFR) after performing the pre season training protocol. Sixteen male professional soccer players (25 +/- 3 years; 179 +/- 2 cm; and 77 +/- 6 kg) were evaluated for oxygen uptake (VO2), heart rate (HR) and pulse relative oxygen (relative O2 Pulse) curves with intervals corresponding to 10% of the total duration of CPET. Athletes were grouped according to the GFR and classified as decreased GFR (dGFR; n = 8) and normal GFR (nGFR; n = 8). Athletes from the dGFR group exhibited lower VO2 values (p < 0.05) when 90% (dGFR 49.8 +/- 4.0 vs. nGFR 54.4 +/- 6.1 ml.kg-1.min-1) and 100% (dGFR 52.6 +/- 4.1 vs. nGFR 57.4 +/- 5.9 ml.kg-1.min-1) of the test was complete; HR high values (p < 0.05) when 90% (dGFR 183.7 +/- 5.1 vs. nGFR 176.6 +/- 4.8 bpm-1) and 100% (dGFR 188.1 +/- 5.0 vs. nGFR 180.8 +/- 4.8 bpm-1) of the test was complete; and lower relative O2 Pulse values (p < 0.05) when 70% (dGFR 25.6 +/- 8.4 vs. nGFR 27.9 +/- 9.7 ml.beat-1.kg-1), 80% (dGFR 26.6 +/- 8.8 vs. nGFR 29.1 +/- 10.0 ml.beat-1.kg-1), 90% (dGFR 27.1 +/- 9.0 vs. nGFR 30.8 +/- 10.6 ml.beat-1.kg-1) and 100% (dGFR 28 +/- 9.2 vs. nGFR 31.8 +/- 10.9 ml.beat-1.kg-1) of the test was complete. A correlation was found (r = -0.66, R2 = 0.44, p = 0.00) between lower VO2 peak and elevated levels of urinary protein excretion. In conclusion, soccer players with reduced kidney function after performing the pre season training protocol also presented alterations in cardiopulmonary variables. We suggest that monitoring of renal function may be used to identify less conditioned soccer players. PMID- 28713464 TI - A Rapidly-Incremented Tethered-Swimming test for Defining Domain-Specific Training Zones. AB - The purpose of this study was to investigate whether a tethered-swimming incremental test comprising small increases in resistive force applied every 60 seconds could delineate the isocapnic region during rapidly-incremented exercise. Sixteen competitive swimmers (male, n = 11; female, n = 5) performed: (a) a test to determine highest force during 30 seconds of all-out tethered swimming (Favg) and the DeltaF, which represented the difference between Favg and the force required to maintain body alignment (Fbase), and (b) an incremental test beginning with 60 seconds of tethered swimming against a load that exceeded Fbase by 30% of DeltaF followed by increments of 5% of DeltaF every 60 seconds. This incremental test was continued until the limit of tolerance with pulmonary gas exchange (rates of oxygen uptake and carbon dioxide production) and ventilatory (rate of minute ventilation) data collected breath by breath. These data were subsequently analyzed to determine whether two breakpoints defining the isocapnic region (i.e., gas exchange threshold and respiratory compensation point) were present. We also determined the peak rate of O2 uptake and exercise economy during the incremental test. The gas exchange threshold and respiratory compensation point were observed for each test such that the associated metabolic rates, which bound the heavy-intensity domain during constant-work-rate exercise, could be determined. Significant correlations (Spearman's) were observed for exercise economy along with (a) peak rate of oxygen uptake (rho = .562; p < 0.025), and (b) metabolic rate at gas exchange threshold (rho = -.759; p < 0.005). A rapidly-incremented tethered-swimming test allows for determination of the metabolic rates that define zones for domain-specific constant-work-rate training. PMID- 28713465 TI - A Comparison of GPS Workload Demands in Match Play and Small-Sided Games by the Positional Role in Youth Soccer. AB - The external demands of small-sided games (SSGs) according to the positional role are currently unknown. Using a Catapult Minimax X3 5 Hz GPS, with a 100 Hz tri axial accelerometer, we compared the accumulated tri-axial player workload per min (PLacc.min-1) during friendly youth match play (MP) (11 vs. 11) and SSGs (2 vs. 2, 3 vs. 3, and 4 vs. 4). Significant differences existed between all SSGs and MP for PLacc.min-1 (F = 21.91, p < 0.001, eta2 = 0.38), and individual X (F = 27.40, p < 0.001, eta2 = 0.43), Y (F = 14.50, p < 0.001, eta2 = 0.29) and Z (F = 19.28, p < 0.001, eta2 = 0.35) axis loads. Across all conditions, mean PLacc.min 1 was greater for midfielders (p = 0.004, CI: 0.68, 4.56) and forwards (p = 0.037, CI: 0.08, 3.97) than central defenders. In all conditions, greater Y axis values existed for wide defenders (p = 0.024, CI: 0.67, 1.38), midfielders (p = 0.006, CI: 0.18, 1.50) and forwards (p = 0.007, CI: 0.17, 0.15) compared to central defenders. Midfielders reported greater Z axis values compared to central defenders (p = 0.002, CI: 0.40, 2.23). We concluded that SSGs elicited greater external loads than MP, and previous studies may have underestimated the demands of SSGs. PMID- 28713466 TI - Intra-Subject Variability of 5 km Time Trial Performance Completed by Competitive Trained Runners. AB - Time-trials represent an ecologically valid approach to assessment of endurance performance. Such information is useful in the application of testing protocols and estimation of sample sizes required for research/magnitude based inference methods. The present study aimed to investigate the intra-subject variability of 5 km time-trial running performance in trained runners. Six competitive trained male runners (age = 33.8 +/- 10.1 years; stature = 1.78 +/- 0.01 m; body mass = 69.0 +/- 10.4 kg, [Formula: see text]O2max = 62.6 +/- 11.0 ml.kg.min-1) completed an incremental exercise test to volitional exhaustion followed by 5 x 5 km time trials (including a familiarisation trial), individually spaced by 48 hours. The time taken to complete each trial, heart rate, rating of perceived exertion and speed were all assessed. Intra-subject absolute standard error of measurement and the coefficient of variance were calculated for time-trial variables in addition to the intra-class correlation coefficient for time taken to complete the time trial. For the primary measure time, results showed a coefficient of variation score across all participants of 1.5 +/- 0.59% with an intra-class correlation coefficient score of 0.990. Heart rate, rating of perceived exertion and speed data showed a variance range between 0.8 and 3.05%. It was concluded that when compared with related research, there was observed low intra-subject variability in trained runners over a 5 km distance. This supports the use of this protocol for 5 km time-trial performance for assessment of nutritional strategies, ergogenic aids or training interventions on endurance running performance. PMID- 28713467 TI - Quality versus Quantity Debate in Swimming: Perceptions and Training Practices of Expert Swimming Coaches. AB - The debate over low-volume, high-intensity training versus high-volume, low intensity training, commonly known as Quality versus Quantity, respectively, is a frequent topic of discussion among swimming coaches and academics. The aim of this study was to explore expert coaches' perceptions of quality and quantity coaching philosophies in competitive swimming and to investigate their current training practices. A purposeful sample of 11 expert swimming coaches was recruited for this study. The study was a mixed methods design and involved each coach participating in 1 semi-structured interview and completing 1 closed-ended questionnaire. The main findings of this study were that coaches felt quality training programmes would lead to short term results for youth swimmers, but were in many cases more appropriate for senior swimmers. The coaches suggested that quantity training programmes built an aerobic base for youth swimmers, promoted technical development through a focus on slower swimming and helped to enhance recovery from training or competition. However, the coaches continuously suggested that quantity training programmes must be performed with good technique and they felt this was a misunderstood element. This study was a critical step towards gaining a richer and broader understanding on the debate over Quality versus Quantity training from an expert swimming coaches' perspective which was not currently available in the research literature. PMID- 28713468 TI - A Model for Determining the Effect of the Wind Velocity on 100 m Sprinting Performance. AB - This paper introduces an equation for determining instantaneous and final velocity of a sprinter in a 100 m run completed with a wind resistance ranging from 0.1 to 4.5 m/s. The validity of the equation was verified using the data of three world class sprinters: Carl Lewis, Maurice Green, and Usain Bolt. For the given constant wind velocity with the values + 0.9 and + 1.1 m/s, the wind contribution to the change of sprinter velocity was the same for the maximum as well as for the final velocity. This study assessed how the effect of the wind velocity influenced the change of sprinting velocity. The analysis led to the conclusion that the official limit of safely neglecting the wind influence could be chosen as 1 m/s instead of 2 m/s, if the velocity were presented using three, instead of two decimal digits. This implies that wind velocity should be rounded off to two decimal places instead of the present practice of one decimal place. In particular, the results indicated that the influence of wind on the change of sprinting velocity in the range of up to 2 m/s and was of order of magnitude of 10-3 m/s. This proves that the IAAF Competition Rules correctly neglect the influence of the wind with regard to such velocities. However, for the wind velocity over 2 m/s, the wind influence is of order 10-2 m/s and cannot be neglected. PMID- 28713469 TI - Anthropometric Profile in Different Event Categories of Acrobatic Gymnastics. AB - There is a specific anthropometric profile for each sport, which may be differentiated even in relation to the position, role or event category within each sport discipline. However, there are few studies on acrobatic gymnastics, and the goal of this work was to determine the anthropometric profile depending on the event category, as well as factors that predisposed to performance in these categories. The sample consisted of 150 gymnasts from Spain, divided into 8 groups according to the event category and the role played. The kinanthropometric measurements were taken through the procedures established by the International Society for the Advancement of Kineantropometry. The anthropometric characteristics, including body mass index, somatotype, body composition and proportionality using the Phantom stratagem were analyzed, and the results obtained from the different groups were compared. A regression analysis was performed with particular groups of gymnasts. No significant differences (p < 0.05) were observed between groups of female tops or male bases, although differences were found between female group bases and female pair bases. It could be suggested that higher values of body height, sitting height, the minimum abdominal circumference, percentage of fat and low biliocristal breadth predispose female bases to work in pairs rather than in groups. The conclusion is that the anthropometric measurements are not decisive when guiding a gymnast toward choosing one event category or another, except for female bases. PMID- 28713470 TI - Differences in Anthropometry, Biological Age and Physical Fitness Between Young Elite Kayakers and Canoeists. AB - The aim of this study was to determine the anthropometric and physical characteristics of youth elite paddlers and to identify the differences between kayakers and canoeists. A total of 171 male paddlers (eighty-nine kayakers and eighty-two canoeists), aged 13.69 +/- 0.57 years (mean +/- SD) volunteered to participate in this study. The participants completed basic anthropometric assessments (body mass, stretch stature, sitting height, body mass index, maturity level, sum of 6 skinfolds and fat mass percentage) as well as a battery of physical fitness tests (overhead medicine ball throw, counter movement jump, sit-and-reach and 20 m multi-stage shuttle run tests). The anthropometric results revealed a significantly larger body size (stretch stature and sitting height) and body mass in the kayakers (p < 0.01) as well as a more mature biological status (p = 0.003). The physical fitness level exhibited by the kayakers was likewise significantly greater than that of the canoeists, both in the counter movement jump and estimated VO2max (p < 0.05), as well as in the overhead medicine ball throw and sit-and-reach test (p < 0.01). These findings confirm the more robust and mature profile of youth kayakers that might be associated with the superior fitness level observed and the specific requirements of this sport discipline. PMID- 28713471 TI - Assessment of Specificity of the Badcamp Agility test for Badminton Players. AB - The Badcamp agility test was created to evaluate agility of badminton players. The Badcamp is a valid and reliable test, however, a doubt about the need for the use of this test exists as simpler tests could provide similar information about agility in badminton players. Thus, the aim of this study was to examine the specificity of the Badcamp, comparing the performance of badminton players and athletes from other sports in the Badcamp and the shuttle run agility test (SRAT). Sixty-four young male and female athletes aged between 14 and 16 years participated in the study. They were divided into 4 groups of 16 according to their sport practices: badminton, tennis, team sport (basketball and volleyball), and track and field. We compared the groups in both tests, the Badcamp and SRAT. The results revealed that the group of badminton players was faster compared to all other groups in the Badcamp. However, in the SRAT there were no differences among groups composed of athletes from open skill sports (e.g., badminton, tennis, and team sports), and a considerable reduction of the difference between badminton players and track and field athletes. Thus, we concluded that the Badcamp test is a specific agility test for badminton players and should be considered in evaluating athletes of this sport modality. PMID- 28713472 TI - Performance Trends in Master Butterfly Swimmers Competing in the FINA World Championships. AB - Performance trends in elite butterfly swimmers are well known, but less information is available regarding master butterfly swimmers. We investigated trends in participation, performance and sex differences in 9,606 female and 13,250 male butterfly race times classified into five-year master groups, from 25 29 to 90-94 years, competing in the FINA World Masters Championships between 1986 and 2014. Trends in participation were analyzed using linear regression analysis. Trends in performance changes were investigated using mixed-effects regression analyses with sex, distance and a calendar year as fixed variables. We also considered interaction effects between sex and distance. Participation increased in master swimmers older than ~30-40 years. The men-to-women ratio remained unchanged across calendar years and master groups, but was lower in 200 m compared to 50 m and 100 m. Men were faster than women from 25-29 to 85-89 years (p < 0.05), although not for 90-94 years. Sex and distance showed a significant interaction in all master groups from 25-29 to 90-94 years for 200m (p < 0.05). For 50 m and 100 m, a significant sex * distance interaction was observed from 25 29 to 75-79 years (p < 0.05), but not in the older groups. In 50 m, women reduced the sex difference in master groups 30-34 to 60-64 years (p < 0.05). In 100 m, women decreased the gap to men in master groups 35-39 to 55-59 years (p < 0.05). In 200 m, the sex difference was reduced in master groups 30-34 to 40-44 years (p < 0.05). In summary, women and men improved performance at all distances, women were not slower compared to men in the master group 90-94 years; moreover, women reduced the gap to men between ~30 and ~60 years, although not in younger or older master groups. PMID- 28713473 TI - Home Advantage in Judo: Analysis by the Combat Phase, Penalties and the Type of Attack. AB - Previous studies indicate positive home advantage in judo; however, the factors that influence home advantage have yet to be fully explored. This study investigated the potential differences in technical-tactical variables between home and visiting athletes. A total of 1411 video recorded matches were analyzed (123 home, 1288 away) from 36 international judo competitions contested in 2011 12. The matches were analyzed by the following criteria: combat phases (approach, gripping, attack, defense, groundwork and pause), penalties (by the athlete or the opponent) and the types of attacks (with or without a score). Elite judo athletes competing in their home country attacked more frequently using trunk/leg couple techniques (p < 0.011) and scored more frequently with arm/leg couple techniques (p < 0.001), while visiting judo athletes received fewer scores from penalties (p < 0.001) and engaged in more frequent pauses during competition (p < 0.01). The results of this study provide an outline of technical-tactical differences that may contribute to home advantage in judo. PMID- 28713475 TI - Perceived Hindrances Experienced by Sport Coaches in South Africa. AB - The purpose of this study was to examine perceived hindrances encountered by sport coaches in the Gauteng Province of South Africa. A total of 224 sport coaches (122 males and 102 females) were purposively recruited to participate in this study. An exploratory factor analysis was used to assess the factor structure of the Perceived Hindrance Scale. The results of this study indicated the following as major hindrances encountered by sport coaches: "Lack of support systems for women players", "Lack of support for women coaches from superiors", "Low salary", "Lack of opportunities for promotion", "Difficulties with parents/spectators" and "Lack of job security". Recommendations on strategies to overcome these perceived hindrances are discussed. PMID- 28713474 TI - Plantar Pressure Differences between Nordic Walking Techniques. AB - High plantar pressure has been associated with increased risk of injury. The characteristics of each physical activity determine the load on the lower limbs. The influence of Nordic Walking (NW) technique on plantar pressure is still unknown. The aim of this study was to analyze the differences between plantar pressure during NW with the Diagonal technique (DT) versus Alpha technique (AT) and compare them with the pressure obtained during normal walking (W). The normality and sphericity of the plantar pressure data were checked before performing a two-way repeated measures ANOVA in order to find differences between speeds (preferred, fast) and the gait (NW, W) as within-subject factors. Then, a t-test for independent measures was used to identify the specific differences between NW techniques. The strength of the differences was calculated by means of the effect size (ES). The results demonstrated that during NW with AT at preferred speed the pressure was lower under the Calcaneus, Lateral Metatarsal and Toes compared to the DT group (p = 0.046, ES = 1.49; p = 0.015, ES = 1.44; p = 0.040, ES = 1.20, respectively). No differences were found at the fast speed (p > 0.05). Besides the increase in walking speed during NW (p < 0.01), both technique groups showed lower pressure during NW compared to W under the Hallux and Central Metatarsal heads (F = 58.321, p = 0.000, ES = 2.449; F = 41.917, p = 0.012, ES = 1.365, respectively). As a practical conclusion, the AT technique may be the most effective of the NW techniques at reducing plantar pressure while allowing NW practitioners to achieve the physiological benefits of NW. PMID- 28713476 TI - The Relationship between Perceived Coaching Behaviours, Motivation and Self Efficacy in Wrestlers. AB - The current study aimed to determine the relationship between perceived coaching behaviours, motivation, self-efficacy and general self-efficacy of wrestlers who competed in the Super National Wrestling League. The sample consisted of 289 wrestlers. The Self-Efficacy Scale was used to measure self-efficacy perception, the Sports Motivation Scale to measure the motivation of the athletes, the Leadership Scale for Sport to determine perceived leadership behaviours, and the General Self-Efficacy Scale to determine the general self-efficacy perceptions of the athletes. For data analyses, SPSS 17.0 software was used. According to the results of the regression analyses performed with the enter method, it was found that perceived training and instruction behaviour along with perceived social support behaviour significantly explained self-efficacy (adjusted R2_ = .03), intrinsic motivation (adjusted R2 = .04) and amotivation (adjusted R2 = .05). Also, perceived training and instruction behaviour (beta = .51), autocratic behaviour (beta = -.17) and social support behaviour (beta = -.27) significantly contributed to athletes' general self-efficacy (adjusted R2 = .10). In light of these findings, it may be argued that perceived training and instruction behaviour may be beneficial for self-efficacy, general self-efficacy, intrinsic motivation, and amotivation. On the other hand, it could be stated that perceived autocratic behaviour may be detrimental for general self-efficacy of the athletes. As for social support behaviour, it may be suggested that it is negatively related to self-efficacy, general self-efficacy and intrinsic motivation. Lastly, a positive relationship was observed between perceived social support behaviour and amotivation in wrestlers. The results reveal the specific characteristics of wrestlers and suggest some implications for wrestling coaches. PMID- 28713477 TI - MOPSA: A microfluidics-optimized particle simulation algorithm. AB - Computer simulation plays a growing role in the design of microfluidic chips. However, the particle tracers in some existing commercial computational fluid dynamics software are not well suited for accurately simulating the trajectories of particles such as cells, microbeads, and droplets in microfluidic systems. To address this issue, we present a microfluidics-optimized particle simulation algorithm (MOPSA) that simulates the trajectories of cells, droplets, and other particles in microfluidic chips with more lifelike results than particle tracers in existing commercial software. When calculating the velocity of a particle, MOPSA treats the particle as a two-dimensional rigid circular object instead of a single point. MOPSA also checks for unrealistic interactions between particles and channel walls and applies an empirical correcting function to eliminate these errors. To validate the performance of MOPSA, we used it to simulate a variety of important features of microfluidic devices like channel intersections and deterministic lateral displacement (DLD) particle sorter chips. MOPSA successfully predicted that different particle sizes will have different trajectories in six published DLD experiments from three research groups; these DLD chips were used to sort a variety of different cells, particles, and droplets. While some of these particles are not actually rigid or spherical, MOPSA's approximation of these particles as rigid spheres nonetheless resulted in lifelike simulations of the behaviors of these particles (at least for the particle sizes and types shown here). In contrast, existing commercial software failed to replicate these experiments. Finally, to demonstrate that MOPSA can be extended to simulate other properties of particles, we added support for simulating particle density to MOPSA and then used MOPSA to simulate the operation of a microfluidic chip capable of sorting cells by their density. By enabling researchers to accurately simulate the behavior of some types of particles in microfluidic chips before fabricating the chips, MOPSA should accelerate the development of new microfluidic devices for important applications. PMID- 28713478 TI - An integrated microfluidic system for the isolation and detection of ovarian circulating tumor cells using cell selection and enrichment methods. AB - Gynecological cancer is difficult to be diagnosed at early stages. The relatively high mortality rate has been a serious issue accordingly. We herein reported a diagnosis method by using circulating tumor cells (CTCs) which have been extensively explored as a potential tool for diagnostics and prognostics of ovarian cancers. Nonetheless, the detection of CTCs still remains a challenge because of the difficulty in isolating them from whole blood samples since they are shed into the vasculature from primary tumors and circulate irregularly in the bloodstream in extremely low concentrations. In this work, we reported a new, integrated microfluidic system capable of (1) red blood cells lysis, (2) white blood cell (WBC) depletion via a negative selection process, and (3) capture of target cancer cells from whole blood samples using aptamer-binding technology. Furthermore, this is the first time that an aptamer was used to capture ovarian cancer cells owing to its high affinity. The new microfluidic chip could efficiently perform the entire process in one hour without human intervention at a high recovery rate and a low false positive detection rate when compared with antibody-based systems. A high recovery rate for the isolation of CTCs within a short period of time has been reported when compared to the traditional negative or positive selection approach by using traditional antibody biomarkers. More importantly, "false positive" results from WBCs could be significantly alleviated due to the high specificity of the cancer cell-specific aptamers. The developed integrated microfluidic system could be promising for the isolation and detection of CTCs, which could be used for early diagnosis and prognosis of cancers. PMID- 28713479 TI - Automated selection of aptamers against cholangiocarcinoma cells on an integrated microfluidic platform. AB - An integrated microfluidic system capable of automatically identifying aptamers specific to cholangiocarcinoma (CCA) cells was developed herein. The developed system was capable of performing cell-based systematic evolution of ligands via an exponential enrichment (Cell-SELEX) process on-chip, and only six rounds of Cell-SELEX were required to identify high specificity aptamers; this represents a significant improvement in speed over conventional SELEX, in which 15-20 rounds are typically required. Using the microfluidic chip developed, three aptamers specific to CCA cells (one for SNU-478 cells and two for HuCCT-1 cells) were successfully screened. This automated system could be modified to uncover aptamer probes against other cancer cells, thereby allowing for earlier diagnosis and consequently a potentially improved prognosis. PMID- 28713480 TI - Impact of Exercise Programs on Hospital Readmission Following Hospitalization for Heart Failure: A Systematic Review. AB - Given persistently high 30-day readmission rates among patients hospitalized for heart failure, there is an ongoing need to identify new interventions to reduce readmissions. Although exercise programs can improve outcomes among ambulatory heart failure patients, it is not clear whether this benefit extends to reducing readmissions following heart failure hospitalization. We therefore conducted a systematic review of the literature to identify randomized controlled trials examining the impact of exercise programs on hospital readmissions among patients recently hospitalized for heart failure. We searched Ovid MEDLINE, EMBASE, and the Wiley Cochrane Library for studies that fulfilled pre-defined criteria, including that the exercise program pre-specify activity type and exercise frequency, duration, and intensity. Exercise interventions could occur at any location including within the hospital, at an outpatient facility, or at home. Among 1213 unique publications identified, only one study fulfilled inclusion criteria. This study was a single-site randomized controlled trial that consisted of a 12-week exercise program in a cohort of 105 patients with a principal diagnosis of HF at a metropolitan hospital in Australia. This study revealed a reduction in 12-month all-cause and cardiovascular-related hospitalization rates. However, inferences were limited by its single-site study design, small sample size, premature termination, and high risk for selection, performance, and detection bias. As no studies have built upon the findings of this study, it remains unknown whether exercise programs can improve readmission rates among patients recently hospitalized for heart failure, a significant gap in the literature. PMID- 28713481 TI - Gerontechnologies for Older Patients with Heart Failure: What is the Role of Smartphones, Tablets, and Remote Monitoring Devices in Improving Symptom Monitoring and Self-Care Management? AB - Older adults with heart failure have multiple chronic conditions and a large number and range of symptoms. A fundamental component of heart failure self-care management is regular symptom monitoring. Symptom monitoring can be facilitated by cost-effective, easily accessible technologies that are integrated into patients' lives. Technologies that are tailored to older adults by incorporating gerontological design principles are called gerontechnologies. Gerontechnology is an interdisciplinary academic and professional field that combines gerontology and technology with the goals of improving prevention, care, and enhancing the quality of life for older adults. The purpose of this article is to discuss the role of gerontechnologies, specifically the use of mobile applications available on smartphones and tablets as well as remote monitoring systems, for outpatient disease management among older adults with heart failure. While largely unproven, these rapidly developing technologies have great potential to improve outcomes among older persons. PMID- 28713482 TI - Comparative Therapeutic Effects of Minocycline Treatment and Bone Marrow Mononuclear Cell Transplantation following Striatal Stroke. AB - We explored the comparative effects of minocycline treatment and intrastriatal BMMC transplantation after experimental striatal stroke in adult rats. Male Wistar adult rats were divided as follows: saline-treated (N = 5), minocycline treated (N = 5), and BMMC-transplanted (N = 5) animals. Animals received intrastriatal microinjections of 80 pmol of endothelin-1 (ET-1). Behavioral tests were performed at 1, 3, and 7 days postischemia. Animals were treated with minocycline (50 mg/kg, i.p.) or intrastriatal transplants of 106 BMMCs at 24 h postischemia. Animals were perfused at 7 days after ischemic induction. Coronal sections were stained with cresyl violet for gross histopathological analysis and immunolabeled for the identification of neuronal bodies (NeuN), activated microglia/macrophages (ED1), and apoptotic cells (active caspase-3). BMMC transplantation and minocycline reduced the number of ED1+ cells (p < 0.05, ANOVA Tukey), but BMMC afforded better results. Both treatments afforded comparable levels of neuronal preservation compared to control (p > 0.05). BMMC transplantation induced a higher decrease in the number of apoptotic cells compared to control and minocycline treatment. Both therapeutic approaches improved functional recovery in ischemic animals. The results suggest that BMMC transplantation is more effective in modulating microglial activation and reducing apoptotic cell death than minocycline, although both treatments are equally efficacious on improving neuronal preservation. PMID- 28713483 TI - The Treadmill Exercise Protects against Dopaminergic Neuron Loss and Brain Oxidative Stress in Parkinsonian Rats. AB - Parkinson's disease (PD), a progressive neurological pathology, presents motor and nonmotor impairments. The objectives were to support data on exercise benefits to PD. Male Wistar rats were distributed into sham-operated (SO) and 6 OHDA-lesioned, both groups without and with exercise. The animals were subjected to treadmill exercises (14 days), 24 h after the stereotaxic surgery and striatal 6-OHDA injection. Those from no-exercise groups stayed on the treadmill for the same period and, afterwards, were subjected to behavioral tests and euthanized for neurochemical and immunohistochemical assays. The data, analyzed by ANOVA and Tukey post hoc test, were considered significant for p < 0.05. The results showed behavioral change improvements in the 6-OHDA group, after the treadmill exercise, evaluated by apomorphine rotational behavior, open field, and rota rod tests. The exercise reduced striatal dopaminergic neuronal loss and decreased the oxidative stress. In addition, significant increases in BDNF contents and in immunoreactive cells to TH and DAT were also observed, in striata of the 6-OHDA group with exercise, relatively to those with no exercise. We conclude that exercise improves behavior and dopaminergic neurotransmission in 6-OHDA-lesioned animals. The increased oxidative stress and decreased BDNF contents were also reversed, emphasizing the importance of exercise for the PD management. PMID- 28713484 TI - Moderate Autophagy Inhibits Vascular Smooth Muscle Cell Senescence to Stabilize Progressed Atherosclerotic Plaque via the mTORC1/ULK1/ATG13 Signal Pathway. AB - In order to investigate the effects of autophagy induced by rapamycin in the development of atherosclerosis plaque we established murine atherosclerosis model which was induced in ApoE-/- mice by high fat and cholesterol diet (HFD) for 16 weeks. Rapamycin and 3-Methyladenine (MA) were used as autophagy inducer and inhibitor respectively. The plaque areas in aortic artery were detected with HE and Oil Red O staining. Immunohistochemical staining were applied to investigate content of plaque respectively. In contrast to control and 3-MA groups, rapamycin could inhibit atherosclerosis progression. Rapamycin was able to increase collagen content and a-SMA distribution relatively, as well as decrease necrotic core area. Then we used MOVAS and culture with ox-LDL for 72 h to induce smooth muscle-derived foam cell model in vitro. Rapamycin and 3-MA were cultured together respectively. Flow cytometry assay and SA-beta-Gal staining experiments were performed to detect survival and senescence of VSMCs. Western blot analysis were utilized to analyze the levels of protein expression. We found that rapamycin could promote ox-LDL-induced VSMCs autophagy survival and alleviate cellular senescence, in comparison to control and 3-MA groups. Western blot analysis showed that rapamycin could upregulate ULK1, ATG13 and downregulate mTORC1 and p53 protein expression. PMID- 28713486 TI - Concurrent Aerobic and Resistance Training Has Anti-Inflammatory Effects and Increases Both Plasma and Leukocyte Levels of IGF-1 in Late Middle-Aged Type 2 Diabetic Patients. AB - Type 2 diabetes (T2D) is an age-related chronic disease associated with metabolic dysregulation, chronic inflammation, and activation of peripheral blood mononuclear cells (PBMC). The aim of this study was to assess the effects of a concurrent exercise training program on inflammatory status and metabolic parameters of T2D patients. Sixteen male patients (age range 55-70) were randomly assigned to an intervention group (n = 8), which underwent a concurrent aerobic and resistance training program (3 times a week; 16 weeks), or to a control group, which followed physicians' usual diabetes care advices. Training intervention significantly improved patients' body composition, blood pressure, total cholesterol, and overall fitness level. After training, plasma levels of adipokines leptin (-33.9%) and RBP4 (-21.3%), and proinflammatory markers IL-6 ( 25.3%), TNF-alpha (-19.8%) and MCP-1 (-15.3%) decreased, whereas anabolic hormone IGF-1 level increased (+16.4%). All improvements were significantly greater than those of control patients. Plasma proteomic profile of exercised patients showed a reduction of immunoglobulin K light chain and fibrinogen as well. Training also induced a modulation of IL-6, IGF-1, and IGFBP-3 mRNAs in the PBMCs. These findings confirm that concurrent aerobic and resistance training improves T2D related metabolic abnormalities and has the potential to reduce the deleterious health effects of diabetes-related inflammation. PMID- 28713487 TI - Moringa oleifera Seeds Attenuate Vascular Oxidative and Nitrosative Stresses in Spontaneously Hypertensive Rats. AB - Moringa oleifera (MOI) is a tree currently used in traditional medicine in tropical Africa, America, and Asia for therapeutic applications in several disorders including arterial hypertension. We previously described a cardiac protective role of a treatment with MOI seeds in spontaneously hypertensive rats (SHR). Here, we investigated the effects of this treatment on oxidative and nitrosative vascular stresses in SHR, with normotensive Wistar Kyoto rats used as controls. Oxidative and nitrosative stresses detected in SHR aortas using the fluorescent dye dihydroethidine and protein nitrotyrosine staining were reduced in MOI-treated SHR aortas. This was associated with a decrease of free 8 isoprostane circulating level, vascular p22phox and p47phox expressions, and SOD2 upregulation. Moreover, circulating nitrites and C-reactive protein, increased in SHR, were both reduced in SHR receiving MOI. This was associated to decrease iNOS and NF-kappaB protein expressions after MOI treatment. In functional studies, the endothelium-dependent carbachol-induced relaxation was improved in MOI-treated SHR resistance arteries. Oral administration of MOI seeds demonstrates vascular antioxidant, anti-inflammatory, and endothelial protective effects in SHR. Our data support the use of MOI seeds in diet against cardiovascular disorders associated with oxidative stress and inflammation such as hypertension, scientifically validating the use of these seeds in Malagasy traditional medicine. PMID- 28713485 TI - MicroRNAs and Autophagy: Fine Players in the Control of Chondrocyte Homeostatic Activities in Osteoarthritis. AB - Osteoarthritis (OA) is a debilitating degenerative disease of the articular cartilage with a multifactorial etiology. Aging, the main risk factor for OA development, is associated with a systemic oxidative and inflammatory phenotype. Autophagy is a central housekeeping system that plays an antiaging role by supporting the clearance of senescence-associated alterations of macromolecules and organelles. Autophagy deficiency has been related to OA pathogenesis because of the accumulation of cellular defects in chondrocytes. Microribonucleic acids (microRNAs or miRs) are a well-established class of posttranscriptional modulators belonging to the family of noncoding RNAs that have been identified as key players in the regulation of cellular processes, such as autophagy, by targeting their own cognate mRNAs. Here, we present a state-of-the-art literature review on the role of miRs and autophagy in the scenario of OA pathogenesis. In addition, a comprehensive survey has been performed on the functional connections of the miR network and the autophagy pathway in OA by using "microRNA," "autophagy," and "osteoarthritis" as key words. Discussion of available evidence sheds light on some aspects that need further investigation in order to reach a more comprehensive view of the potential of this topic in OA. PMID- 28713488 TI - Dietary Polyphenol Intake, but Not the Dietary Total Antioxidant Capacity, Is Inversely Related to Cardiovascular Disease in Postmenopausal Polish Women: Results of WOBASZ and WOBASZ II Studies. AB - The aim of the study was to assess the relationship between the dietary polyphenol intake (DPI) and the dietary total antioxidant capacity (DTAC) and the prevalence of cardiovascular disease (CVD) in postmenopausal women. Participants were 916 postmenopausal women diagnosed with CVD and 1683 postmenopausal women without history of CVD, who took part in the population-based studies carried out in Poland: WOBASZ (2003-2005) and WOBASZ II (2013-2014). Nutritional data were collected using a single 24-hour dietary recall. DPI and DTAC in the CVD women were significantly lower and accounted for 1766.39 mg/d and 10.84 mmol/d, respectively, versus 1920.57 mg/d and 11.85 mmol/d in the women without CVD, but these differences disappeared after the standardization for energy input. Also, in the multiple-adjustment model, higher DPI, but not DTAC, was associated with the reduced odds ratio for the prevalence of CVD. Beverages, mainly coffee and tea, contributed in more than 40% to DPI and in more than a half to DTAC. In this study, higher dietary polyphenol intake, but not the dietary total antioxidant capacity, was inversely associated with CVD in postmenopausal women, which points to the health benefits of increased polyphenol intake from food sources for these women. PMID- 28713489 TI - The Inhibitory Effect of WenxinKeli on H9C2 Cardiomyocytes Hypertrophy Induced by Angiotensin II through Regulating Autophagy Activity. AB - OBJECTIVES: We investigated the role of cardiomyocyte autophagy and its regulatory mechanisms by WenxinKeli (WXKL) in cells subjected to hypertrophy. METHODS: H9C2 cardiomyocytes were divided into 8 groups. Cytoskeletal proteins as well as endogenously expressed autophagy marker proteins were studied by confocal imaging. Western blotting was used to assess the levels of light chain-3 (LC3) and mechanistic target of rapamycin (mTOR). The cell viability assay was used to detect the content of ATP. Flow cytometry was used to detect apoptotic cardiomyocytes. RESULTS: (1) Compared with the control group, the length and width of cells in the Angiotensin II (AngII) group were significantly increased, while those in the 3-methyladenine (3-MA) and the WXKL groups were decreased. (2) Compared with AngII group, the expression of LC3 II/I protein in the 3-MA and WXKL groups was downregulated, while the expression of mTOR protein was upregulated. (3) Compared with the AngII group, the cardiomyocytes in the WXKL group showed increased ATP and decreased apoptosis rate and number of autophagosome. CONCLUSIONS: We propose a novel role of WXKL as a likely inhibitor of cardiac hypertrophy by regulation of pathological autophagy. PMID- 28713490 TI - Picroside II Shows Protective Functions for Severe Acute Pancreatitis in Rats by Preventing NF-kappaB-Dependent Autophagy. AB - Picroside II, from the herb Picrorhiza scrophulariiflora Pennell, has antioxidant and anti-inflammatory activities. However, its function on severe acute pancreatitis (SAP) and molecular mechanism remains unknown. The effects of picroside II on the SAP induced by cerulean were investigated. SAP rats were treated with picroside II (25 mg/kg). The severity of SAP was evaluated by using biochemical and histological analyses. Pancreatic cancer cell PANC-1 was transfected with ptfLC3 (an indicator of autophagic activity), pcDNA3.1-NF-kappaB (nuclear factor kappa B), and pTZU6+1-NF-kappaB-shRNA and then treated with picroside II. Relative molecules related with NF-kappaB-dependent autophagy were detected by using Western blot. Autophagic activities were observed by phase contrast and fluorescent microscopes. Acetylated LC3 was detected by immunoprecipitation. The results showed that picroside II treatment reduced the level of ALT, AST, NF-kappaB, IL-1beta, IL-6, TNF-alpha, and SIRT1 (NAD+ dependent deacetylase) and increased the level of SOD and GSH. The autophagic activity was reduced when NF-kappaB was silenced, and the levels of TNF-alpha and SIRT1 were reduced. In contrast, the overexpression of NF-kappaB increased autophagic activity and the level of TNF-alpha, which activated SIRT1. SIRT1 deacetylated LC3 and increased autophagic activities. Picroside II ameliorates SAP by improving antioxidant and anti-inflammtory activities of SAP models via NF kappaB-dependent autophagy. PMID- 28713492 TI - Salvianolic Acid Exerts Cardioprotection through Promoting Angiogenesis in Animal Models of Acute Myocardial Infarction: Preclinical Evidence. AB - Radix Salviae miltiorrhizae, danshen root (danshen), is one of the widely used Chinese herbal medicines in clinics, containing rich phenolic compounds. Salvianolic acid is the main active compound responsible for the pharmacologic effects of danshen. Here, we aimed to evaluate the effects of salvianolic acid on cardioprotection through promoting angiogenesis in experimental myocardial infarction. Studies of salvianolic acid in animal models of myocardial infarction were obtained from 6 databases until April 2016. The outcome measures were vascular endothelium growth factor (VEGF), blood vessel density (BVD), and myocardial infarct size. All the data were analyzed using Rev-Man 5.3 software. Ultimately, 14 studies were identified involving 226 animals. The quality score of studies ranged from 3 to 6. The meta-analysis of six studies showed significant effects of salvianolic acid on increasing VEGF expression compared with the control group (P < 0.01). The meta-analysis of the two salvianolic acid A studies and three salvianolic acid B studies showed significantly improving BVD compared with the control group (P < 0.01). The meta-analysis of five studies showed significant effects of salvianolic acid for decreasing myocardial infarct size compared with the control group (P < 0.01). In conclusion, these findings demonstrated that salvianolic acid can exert cardioprotection through promoting angiogenesis in animal models of myocardial infarction. PMID- 28713491 TI - Mulberry Anthocyanin Extract Ameliorates Oxidative Damage in HepG2 Cells and Prolongs the Lifespan of Caenorhabditis elegans through MAPK and Nrf2 Pathways. AB - Mulberry anthocyanins possess many pharmacological effects including liver protection, anti-inflammation, and anticancer. The aim of this study was to evaluate whether mulberry anthocyanin extract (MAE) exerts beneficial effects against oxidative stress damage in HepG2 cells and Caenorhabditis elegans. In vitro, MAE prevented cytotoxicity, increased glucose consumption and uptake, and eliminated excessive intracellular free radicals in H2O2-induced cells. Moreover, MAE pretreatment maintained Nrf2, HO-1, and p38 MAPK stimulation and abolished upregulation of p-JNK, FOXO1, and PGC-1alpha that were involved in oxidative stress and insulin signalling modulation. In vivo, extended lifespan was observed in C. elegans damaged by paraquat in the presence of MAE, while these beneficial effects were disappeared in pmk-1 and daf-16 mutants. PMK-1 and SKN-1 were activated after exposure to paraquat and MAE suppressed PMK-1 activation but enhanced SKN-1 stimulation. Our findings suggested that MAE recovered redox status in HepG2 cells and C. elegans that suffered from oxidative stress, which might be by targeting MAPKs and Nrf2. PMID- 28713493 TI - A new strategy in neurocritical care nurse continuing stroke education: A hybrid simulation pilot study. AB - INTRODUCTION: High-fidelity simulation is frequently utilized in medical education. Its use in the neurosciences is limited by the inherent limitations of the manikin to simulate neurological changes. We report here the use of a hybrid simulation - a combination of lecture and high-fidelity manikin - in the education of neurosciences nurses, involved in care of neurocritical care patients. METHODS: Neurosciences nurses from at the University of Missouri, Columbia, MO, USA, which is an academic, tertiary-care medical center participated in the simulation during Spring of 2016. The simulation involved a patient presenting with acute intracerebral hemorrhage (ICH) who neurologically deteriorated to brain death. Pre- and post-simulation questionnaires were administered using a questionnaire with five-point Liker scale. RESULTS: Seventy two responses were returned. The majority had 0-5 years of nursing experience with 83.8% having prior critical care experience. Pre-simulation, the majority of nurses (85.7%) agreed or strongly agreed with managing patients with ICH. When the responses of "agree" were compared to "strongly agree", a significant improvement (p<0.001) in all responses except confidence in speaking with other healthcare providers was found. CONCLUSION: Nurses reported significant improvement in understanding and managing patients with acute ICH and neurological deterioration after participating in a neurocritical care hybrid simulation. This study shows the benefit of using hybrid simulation in the education of neurocritical care nurses. PMID- 28713494 TI - Caspase 3 role and immunohistochemical expression in assessment of apoptosis as a feature of H1N1 vaccine-caused Drug-Induced Liver Injury (DILI). AB - BACKGROUND: Drug-Induced Liver Injury (DILI) changes, occur post exposure to natural or chemical compounds including apoptosis. AIM: To assess the H1N1 vaccine-caused DILI by histochemical and immunohistochemical methods. METHODS: This 2014's experimental study was conducted on 70 albino rats. They were given ArepanrixTM H1N1 vaccine and were divided into 7 groups; 10 mice each, as control (non-vaccinated), vac2 and vac4 injected with 1st and 2nd doses of vaccine (suspension only) and euthanized after 3 weeks each, vac5 euthanized 6 weeks after 2nd dose, mix2 and mix4 injected with 1st and 2nd doses of vaccine (mixture of suspension and adjuvant) and euthanized after 3 weeks each, mix5 and euthanized 6 weeks after 2nd dose. Histopathological evaluation and histochemical assessment of metabolic protein, glycogen and collagen changes using PAS, bromophenol blue, Mallory's trichrome and immunohistochemistry for caspase 3 on liver tissue paraffin sections were done. Image analysis system Leica QIIN 500 was used. Data were analyzed by SPSS software, using descriptive statistics and ANOVA. RESULTS: Histopathological changes ranging from subtle up to necrosis were noticed, mainly in mix groups. Metabolic protein and glycogen changes were the maximum in mix5 group (p<0.01). Collagen deposition in sinusoids was higher in mix groups, and maximally in vac5 and mix5. Apoptotic hepatocytes expressing diffuse strong nuclear and cytoplasmic caspase 3 were the highest in mix5. CONCLUSION: H1N1 vaccine can cause DILI by either direct toxic or idiosyncratic metabolic type reactions rather than immunologic hypersensitivity type. It ranges from subtle changes up to necrosis. Caspase 3 is pivotal in liver damage etiology, apoptosis induction and processing. Follow up for at least 2 months after the 2nd dose of H1N1 vaccine is recommended to rule out H1N1-induced DILI. PMID- 28713495 TI - Awareness of epidural analgesia among pregnant women in Jeddah, Saudi Arabia. AB - BACKGROUND AND OBJECTIVE: Labor pain is one of the most severe forms of pain that women experience throughout their lifetime. Many pregnant women decide to have an epidural anesthesia to cope with labor pain. This study has focused on general awareness about epidural anesthesia among pregnant women in Jeddah, Saudi Arabia. METHODS: This was a cross-sectional hospital-based study using a self administered questionnaire, conducted in King Faisal Specialist Hospital and Research Center and International Medical Centre. The study was carried out from July to September 2016 and included all pregnant women who were having a routine antenatal care. They were asked about four main topics that tapped their knowledge on epidural anesthesia. A total of 384 questionnaires were returned and analyzed. Data were analyzed by SPSS version 21 using chi-square and multivariate logistic regression. RESULTS: According to multivariate logistic regression, women aged between 21-35 years were more likely to opt for an epidural anesthesia (EPA) than those aged less than 20 years, but women aged >35 years were less likely to select EPA, compared with women < 20 years old. Women who were previously exposed to EPA were 2.14 times more likely to prefer EPA during their current pregnancy than those who were not previously exposed (O.R 95% C.I: 1.123 3.66, p=0.006). Those who believed that EPA was commonly used by other women in the Kingdom were also 1.41 times more likely to report their preference to EPA (O.R 95% C.I: 1.15-1.74, p=0.001). CONCLUSION: This study demonstrates a lack of knowledge about EPA in certain countries but is better than in some other countries. In an aim to fill this gap, it is recommended that information about EPA must be given to all women during the antenatal visit either by the obstetrician, anesthetist, or through flyers and brochures. PMID- 28713496 TI - Effect of denture cleaning on abrasion resistance and surface topography of polymerized CAD CAM acrylic resin denture base. AB - BACKGROUND: The application of computer-aided design computer-aided manufacturing (CAD CAM) technology in the fabrication of complete dentures, offers numerous advantages as it provides optimum fit and eliminates polymerization shrinkage of the acrylic base. Additionally, the porosity and surface roughness of CAD CAM resins is less compared to conventionally processed resins which leads to a decrease in the adhesion of bacteria on the denture base, which is associated with many conditions including halitosis and aspiration pneumonia in elderly denture wearers. AIM: To evaluate the influence of tooth brushing with dentifrices on CAD CAM resin blocks in terms of abrasion resistance, surface roughness and scanning electron photomicrography. METHODS: This experimental study was carried out at the Faculty of Dentistry of King Abdulaziz University during 2016. A total of 40 rectangular shaped polymerized CAD CAM resin samples were subjected to 40.000 and 60.000 brushing strokes under a 200-gram vertical load simulating three years of tooth brushing strokes using commercially available denture cleaning dentifrice. Data were analyzed by SPSS version 20, using descriptive statistics and ANOVA. RESULTS: ANOVA test revealed a statistical significant weight loss of CAD CAM acrylic resin denture base specimens following 40.000 and 60.000 brushing strokes as well as a statistical significant change (p=0.0.5) in the surface roughness following brushing. The CAD CAM resin samples SEM baseline imaging revealed a relatively smooth homogenous surface, but following 40,000 and 60,000 brushing strokes, imaging displayed the presence of small scratches on the surface. CONCLUSION: CAD CAM resin displayed a homogenous surface initially with low surface roughness that was significantly affected following simulating three years of manual brushing, but despite the significant weight loss, the findings are within the clinically acceptable limits. PMID- 28713497 TI - Study on attitudes of students of Islamic Azad University Tehran Medical Branch toward food safety, 2016. AB - BACKGROUND: Given the importance of high-quality healthy food for humans, contamination control is the most important concern for healthy staff. AIM: To determine the attitudes of students at Islamic Azad University (Tehran Medical Branch) toward food safety. METHODS: This cross-sectional and analytic descriptive study was conducted on 326 students of Azad University of Medical Sciences in 2016. A self-made questionnaire consisting of 40 questions was used. The reliability of the questionnaire was confirmed using internal consistency method (Cronbach's alpha coefficient of 0.80). After collecting data, we use descriptive statistical indexes (mean and standard deviation) among demographic variables and the level of knowledge to describe and analyze the data. The participants' attitudes and operation are measured by Spearman tests, and the analytical results are given using SPSS version 20. RESULTS: According to the findings, 55.3, 30 and 14.7 percent of students had high, moderate and low attitude scores toward food safety, respectively. In addition, male and female students had equal attitudes toward food safety, and no significant relationship between sex and attitude was observed a significant difference (p>0.05), but between educational levels (p=0.008) and ages (p=0.001) of students significance was a positive correlation. CONCLUSIONS: Due to the low attitudes score of about half of the students of Islamic Azad University Tehran Medical Branch toward food safety, it can be claimed, food safety training in this community is required. PMID- 28713498 TI - Identical twins with Pierre Robin syndrome; unusual encounter. AB - New born babies could suffer from multiple craniofacial abnormalities, such as Pierre Robin syndrome, which consists of micrognathia and relative macroglossia with or without cleft palate. Although Pierre Robin syndrome is well described in literature, only a few have mentioned its occurrence in identical twins. This paper presents a rare incident of full-term twin babies born with the sequence of Pierre Robin syndrome, which consists of micrognathia, cleft palate, and glossoptosis. Although it is a rare coincidence, Pierre Robin syndrome still can occur in identical twin babies. The treatment is a step-by-step approach, but all procedures are mainly directed to widening the pharyngeal space. PMID- 28713499 TI - Relationship among mammographic findings with histopathologic type of breast cancer and human epidermal growth factor receptor 2 (HER2) in young women. AB - INTRODUCTION: Radiological measures to diagnose breast cancer, including mammographic and ultrasound assessments in young women, are associated with restrictions affecting the use of this tool. No adequate information is available on mammography view in young people with breast cancer and its relationship with pathologic type and epidermal growth factor receptor 2 (HER2) as a prognostic marker, especially in the Iranian race. This study was conducted to examine the relationship between mammographic findings of young women with breast cancer with diagnosed histopathologic type and HER2 marker status. METHODS: This retrospective cross-sectional study was carried out on women with breast cancer referred to Omid Hospital in Mashhad, Iran. Inclusion criteria were age less than 45 years and definitive diagnosis of breast cancer documented in the patient record. Information on mammographic findings such as mass, asymmetry, microcalcification, tissue distortion, nipple retraction, and skin thickening was collected from patient medical records. In addition, the type of pathology diagnosed based on biopsy samples and HER2 examination results were collected. The chi-square test and SPSS software were used to analyze the relationship among qualitative variables. RESULTS: This study was performed on 153 patients with a mean age of 39.3+/-2.5 years (minimum 20 years and maximum 45 years). The mammographic finding was reported normal in 41 patients (26.7%). The evidence of malignant mass was observed in 48 patients (31.3%). The microcalcification was found in 31 patients (20.3%). The retraction or thickening of breast tissue was seen in 39 patients (25.5%). The distortion of breast stroma was found in 41 patients (26.8%). The HER2 marker in 76 patients (49.7%) was positive in study subjects. There was no statistically significant association between mammographic findings and pathologic type. Among the mammographic findings, only the presence of microcalcification had significant association with HER2 results (p=0.008). CONCLUSION: It seems that a significant relationship could not be found between mammographic features in patients with breast cancer and type of pathology diagnosed. However, the presence of calcification in mammography is associated with positive HER2. PMID- 28713500 TI - The social network among the elderly and its relationship with quality of life. AB - INTRODUCTION: Attention to the needs of the elderly is a social necessity, and it seems that evaluating the social network and quality of life of the elderly can be useful in a better understanding of their needs. This study was performed to determine the relationship between the social network and the quality of life of the elderly in the city of Bojnoord in Iran. METHODS: In this cross-sectional study, 201 elderly people aged 60 years or more were selected by continuous and consecutive sampling method in Bojnoord, Iran in 2014. Data were collected using demographic questionnaire, Lubben social network scale and LEIPAD elderly quality of life questionnaire. Data were analyzed by SPSS 16 and using descriptive statistics and independent-samples t-test, ANOVA and Pearson product-moment coefficient. RESULTS: The results showed that 30.3% of elderly people studied, were subjected to a high risk of isolation. The highest mean in social network dimensions was in the family (19.68%), friends (12.01%) and the neighbors (9.90%), respectively. The mean score for quality of life of the elderly was as moderate to high (63.90+/-13.73), and among the quality of life dimensions, the highest mean was related to the self-care dimension (15.59%), and the lowest mean was related to the sexual functioning dimension (1.53%). The findings suggested a positive and significant relationship between social network and quality of life in the elderly who were studied (p<0.000, r=0.468). CONCLUSION: This study was a step toward understanding the social network status and quality of life of the elderly. It is necessary to say that health care professionals, especially nurses, display a significant role in the community to help people in this regard. PMID- 28713501 TI - Removal of Acid Orange 7 dye from aqueous solutions by adsorption onto Kenya tea pulps; granulated shape. AB - BACKGROUND AND AIM: Water resources pollution control is one of the main challenges of our time for researchers. Colored wastewater discharges caused by textile industry activities has added to the concern. In this study, removal of Acid Orange 7 dye (AO7) using Kenya Tea residue absorbent (granular) has been studied. METHODS: This cross-sectional study was conducted in 2016. In this work, initially, tea residue was prepared in three forms of raw, treated with concentrated phosphoric acid, and carbonated, at temperatures of 350, 450 and 500 degrees C in the chemistry laboratory of Gonabad University of Medical Sciences. Then, efficiency of the above absorbents in the removal of Acid Orange 7 dye in initial concentrations of dye as 50-500 mg/l from water samples in terms of pH 2 10 and 1-10 g/l of adsorbent dose within 20 to 300 minutes was investigated. In addition, their subordination from Langmuir and Freundlich absorption isotherms was also determined. Concentration changes in Acid Orange 7 dye at a wavelength of 483 nm was determined by spectrophotometry and results were reported using descriptive statistics. RESULTS: Results showed that efficiency of Acid Orange 7 dye removal is higher in acidic pH and higher adsorbent dosage. The highest efficiency of Acid Orange 7 dye removal was 98.41% by raw tea residue absorbent at pH 2, reaction time was 120 minutes and initial concentration of dye was 50 mg/l, which was obtained at adsorbent dosage of 10 g/l. It was determined that the mechanism of absorption acceptably follows Freundlich absorption isotherm (R2=0.97). CONCLUSION: Due to the availability and very low price, optimal performance of Kenya tea raw residue (granular) in Acid Orange 7 dye removal, it can be used as an efficient surface absorber in an absorber from colored wastewater. PMID- 28713502 TI - The effect of personality traits on undergraduate dental students' performance in multiple mini interviews. AB - BACKGROUND: Multiple mini interviews (MMI) is a structured student selection method where applicants rotate around a series of stations that do not require previously learned knowledge. The Big Five Inventory (BFI) is a tool often used to measure personality traits commonly used in applicant selection. OBJECTIVE: The aim of the current study was to assess the effect of personality traits using the BFI on undergraduate dental students' performance in MMI. METHODS: This research was conducted at The Faculty of Dentistry, King Abdulaziz University, Jeddah, Saudi Arabia. All undergraduates applying to the dental program at King Abdulaziz University, Faculty of Dentistry (KAUFD) in two academic years [(2014 2015) and (2015-2016)] undertook the MMI held at KAUFD and completed the BFI inventory with a total number of 350 students. The MMI consisted of five stations while the BFI contained forty-four items. Data were analysed by SPSS version 20, using independent-samples t-test, Mann-Whitney U test, Spearman's rho correlation coefficient and Chi-square test. RESULTS: female students scored higher than their male counterparts but scores were only significant in the empathy station (p<0.001) in the first year, and in both empathetic skills and team work abilities (p<0.05) in the second. BFI results indicate that male students scored higher on agreeableness (p<0.003) and lower on neuroticism (p<0.001) in the first year while female students scored higher on agreeableness and conscientiousness (p<0.001) in the second year. Students of private schools had higher total MMI scores compared to those of public schools (p<0.05). CONCLUSION: MMI combined with the Big Five Inventory can be a useful tool in the admission process. PMID- 28713503 TI - Drinking water in traditional Persian medicine: Do's and don'ts. AB - Water is the main component of our body and its balance is vital for maintaining normal physiology. Accordingly, adequate fluid intake in the daily diet is very important for a healthy life. Nevertheless, there is a controversy about what the suitable amount of water that we need to drink is. In this paper, we aimed to discuss this important issue based on the doctrine of traditional Persian medicine (TPM) and our clinical experience in a practical manner. PMID- 28713504 TI - Strategic thinking and its related factors in a medical science university in Iran. AB - BACKGROUND: Having strategic thinking is necessary in order to anticipate future changes and make strategic decisions. This study was carried out to assess the strategic thinking level in managers and personnel of Ahvaz Jundishapour University of Medical Science (AJUMS) - a public university in Iran. METHODS: It was a cross-sectional and analytical study and all managers (50) as well as a sample of personnel (200) from AJUMS participated in it. A researcher-made questionnaire was used in order to measure four dimensions of strategic thinking, including system thinking, futurism, conceptual thinking, and intelligent opportunism along with demographic and organizational characteristics of respondents. Statistical analysis was done by Freedman ranking test, one-way ANOVA, and Independent-samples t-test in SPSS software version 16. RESULTS: Strategic thinking in managers (5.62+/-0.51) and personnel (5.22+/-0.4), was evaluated at a somewhat high level. The maximum score among strategic thinking dimensions in managers (5.62+/-0.42) and personnel (5.52+/-0.43) was related to conceptual thinking that was in "good" level. A significant relationship was seen between intelligent opportunism dimension with job location in managers and education degree in personnel (p<=0.005). Also, there was a significant relationship between future dimension in managers and personnel with education degrees (p<=0.005). There was a significant difference between managers and employees in future dimension (p=0.018). CONCLUSION: It seems that the participants have acceptable strategic thinking levels, although there is still room for improvement. Therefore, considering the factors such as educational development of managers and personnel can be very useful in this regard. PMID- 28713505 TI - Risk factors associated with musculoskeletal disorders of the neck and shoulder in the personnel of Kerman University of Medical Sciences. AB - BACKGROUND: Musculoskeletal disorders (MSDs) of the neck and shoulder are the most common and most influential factors causing disorder in the performance and absenteeism of work in administrative personnel. AIM: To identify risk factors which affect musculoskeletal disorders of neck and shoulder areas in headquarters staff of Kerman University of Medical Sciences. METHODS: The present cross sectional study was conducted in 2015 on 282 headquarters personnel of Kerman University of Medical Sciences (Kerman, Iran). The desired headquarters staff were selected from seven Deputy Vice-Chancellors of Kerman University of Medical Sciences, including Deputy of Health; Deputy of Treatment; Deputy of Education; Deputy of Students and Cultural Affairs; Deputy of Food and Drugs; Deputy of Management Development and Resource Planning; Deputy of Research and Technology, and data were gathered by using a standard Nordic musculoskeletal questionnaire NMQ (Nordic) and were analyzed by using SPSS version 16. The impact of various factors on the most common complications (neck and shoulder pains) was analyzed separately through logistic regression analysis and detailed Odds Ratio (OR) was calculated for each individual. RESULTS: The occurrence of neck and shoulder pains in headquarters staff were 42.14% and 40.71%, respectively. In the prevalence of neck pain variables such as marital status (single than married p=0.01, OR=0.24), work experience (p=0.03, OR=1.07 ), education (bachelor's degree and lower than master's degree and higher p=0.003, OR=2.69), right / left handedness (left than right p=0.03, OR=0.33), weight (p=0.04, OR=1.04), place of work (p<0.05); as well as in the prevalence of shoulder pain variables such as marital status (single than married p=0.04, OR=0.48), work experience (p=0.01, OR=1.20), education (bachelor and lower than master and higher p=0.04, OR=1.97), right / left handedness (left than right p=0.01, OR=0.42), age (p=0.02, OR=1.05), and gender (male than female p=0.03, OR=0.65) affected. CONCLUSION: The results of this study showed that the prevalence of neck and shoulder pains is influenced by various risk factors and some of which were identified and an amount of their influence in this study was found. Therefore, it is suggested by considering the risk factors and planning control programs, a major step is taken in reducing the musculoskeletal disorders of office staff. PMID- 28713506 TI - Women's perceptions and experiences of the challenges in the process of male infertility treatment: A qualitative study. AB - BACKGROUND: Despite the fact that both men and women are equally subject to infertility, it is usually women who bear the burden of treatment and its consequences, even in cases of male infertility. Therefore, it is more necessary to recognize their health problems in order to help them. AIM: To explore women's perceptions and experiences of the challenges they face in the process of male infertility treatment. METHODS: This qualitative study was conducted during 2014 2015 using content analysis. Thirty semi-structured interviews were conducted with women whose husbands suffered from male infertility. Purposive sampling was conducted until data saturation was achieved. All interviews were recorded, transcribed and analyzed using conventional content analysis adopted by Graneheim and Lundman. RESULTS: From data analysis, the major category of "treatment related stresses" and four subcategories of "high treatment expenses", "inefficiency of healthcare system", "being captive in the infertility treatment" and "treatment failure" emerged. CONCLUSION: Experiences of women who face male infertility indicate their various concerns in the process of treatment. Therefore, it is required to develop emotional and financial support for the clients and to promote their quality of healthcare services. In addition, awareness of treatment challenges of these women can assist proper planning to promote the quality of services they need. PMID- 28713507 TI - Multi-arrhythmias detection with an XML rule-based system from 12-Lead Electrocardiogram. AB - BACKGROUND: The computer-aided detection of cardiac arrhythmias stills a crucial application in medical technologies. The rule based systems RBS ensure a high level of transparency and interpretability of the obtained results. AIM: To facilitate the diagnosis of the cardiologists and to reduce the uncertainty made in this diagnosis. METHODS: In this research article, we have realized a classification and automatic recognition of cardiac arrhythmias, by using XML rules that represent the cardiologist knowledge. Thirteen experiments with different knowledge bases were realized for improving the performance of the used method in the detection of 13 cardiac arrhythmias. In the first 12 experiments, we have designed a specialized knowledge base for each cardiac arrhythmia, which contains just one arrhythmia detection rule. In the last experiment, we applied the knowledge base which contains rules of 12 arrhythmias. We used, for the experiments, an international data set with 279 features and 452 records characterizing 12 leads of ECG signal and social information of patients. The data sets were constructed and published at Bilkent University of Ankara, Turkey. In addition, the second version of the self-developed software "XMLRULE" was used; the software can infer more than one class and facilitate the interpretability of the obtained results. RESULTS: The 12 first experiments give 82.80% of correct detection as the mean of all experiments, the results were between 19% and 100% with a low rate in just one experiment. The last experiment in which all arrhythmias are considered, the results of correct detection was 38.33% with 90.55% of sensibility and 46.24% of specificity. It was clearly show that in these results the good choice of the classification model is very beneficial in terms of performance. The obtained results were better than the published results with other computational methods for the mono class detection, but it was less in multi-class detection. CONCLUSION: The RBS is the most transparent method for cardiac arrhythmias detection and multi arrhythmias detection. It improves an exceptional recognition of arrhythmias, but due to conflicts between rules, multi-arrhythmias and uncertainty of measures, the rate of correct classification was less than the other methods. PMID- 28713508 TI - Presence and seasonal variation of trihalomethanes (THMs) levels in drinking tap water in Mostaganem Province in northwest Algeria. AB - BACKGROUND: The use of chlorine to disinfect water, produces various disinfection byproducts such as trihalomethanes (THMs). These compounds are formed when free available chlorine reacts with natural organic matter in raw water during water disinfection. Epidemiologic studies have shown an association between long-term exposure to THMs and an increased risk of cancer, all of them are suspected of having carcinogenic effects. AIM: The aim of this study was to determine the presence of THMs in the drinking tap water of Mostaganem Province (Algeria) in order to assess the seasonal variation in trihalomethane levels in tap water and to identify the season of high risk to the consumer. METHODS: This analytical study was conducted in Mostaganem Province, Algeria in March, July, September and December 2015. Primarily, we proceeded to collect 30 samples from different areas of Mostaganem Province which were marked with a higher level of residual chlorine for the year 2015; secondly, we utilised the HS-SPME method for determination of trihalomethanes in drinking tap water over a period of four months. For comparison of trihalomethanes values, we used ANOVA. RESULTS: The results obtained show variability in total THM concentrations from one district to another, with a maximum of 198 MUg/l recorded in the Achaacha district during July, but the lowest value 07.84 MUg/l is noted at Salamandre city during the same period, noting that these values decrease progressively during the winter period. CONCLUSION: Our drinking tap water samples include a large quantity of THMs with different concentrations, where the dibromochloromethane and the bromoform constitute the major portion of THMs. PMID- 28713509 TI - Mechanical ventilation practice in Egyptian pediatric intensive care units. AB - INTRODUCTION: Mechanical ventilation is one of the indispensable tools in pediatric intensive care units. Few studies addressed the epidemiology of pediatric patients on mechanical ventilation and the frequently used modes of ventilation. This is the first study to describe the practice of mechanical ventilation (MV) in Egyptian pediatric intensive care units (PICUs). METHODS: This prospective observational study was conducted from January 2014 to December 2014 in two pediatric intensive care units at Cairo University Pediatric Hospital. The study included all children who were intubated and mechanically ventilated for more than 12 hours of admission. Pre-coded data was entered into the SPSS version 21 for data analysis. Comparison between groups was performed using Mann Whitney test for quantitative variables and Chi square with Fisher's exact test for qualitative ones. Multivariate logistic regression model was conducted to explore the significant predictors for PICU mortality. RESULTS: In total, 893 children were admitted and 293 were mechanically ventilated. The incidence of utilizing MV in children was 32.8%. Neurologic causes were the most common reasons for initiation of MV, with 114 (38.9%) cases. The most commonly preferred mode for initiation of MV is SIMV with PS. Complication occurred in 117 (39.9%) of the cases. The most commonly preferred method of weaning was PS with CPAP in 115/154 (74.7%) cases. Mortality occurred in 134/293 (45.7%) of patients. Duration of mechanical ventilation was significantly longer with neuromuscular diseases, and with the occurrence of complications (p<0.001). There was a significant relationship between mortality and higher PRISM III score, cardiovascular cases, sepsis, multiple organ dysfunction syndrome (MODS), ventilator-associated pneumonia (VAP), and with barotrauma. CONCLUSIONS: In our practice, MV is used oftentimes with almost a third of admissions requiring intubation for different reasons. Most children are ventilated due to neurologic causes. This study paves the way for improving our knowledge of MV with avoiding the fatal complications. PMID- 28713510 TI - Color doppler indices of proximal and distal parts of middle cerebral artery in fetuses with intrauterine growth restriction. AB - INTRODUCTION: Intrauterine growth restriction (IUGR) is a major clinical issue for pregnant women. The purpose of this study was to evaluate color Doppler indices of the proximal and distal parts of the middle cerebral artery (MCA) of the fetus. METHODS: In this cross-sectional study, 350 pregnant patients, with gestation age of 32-40 who were suspected to have intrauterine growth restriction, participated. The patients were referred for color Doppler sonography at the Imam Reza Hospital (Kermanshah, Iran) from May 2011 to September 2012. The following indices were measured for the proximal and distal part of the MCA: pulsatility index (PI), resistive index (RI), fetal heart rate (FHR), systolic to diastolic (S/D) ratio, and peak systolic velocity (PSV). The data were analyzed applying Tukey's-test, Paired-Samples t-test, and simple linear regression analysis using SPSS 19. RESULTS: Average age of the mother, the frequency of pregnancy, and fetus gestational age were 27.79+/-0.17 years, 2.09+/ 1.3, and 34.19+/-2.52 weeks, respectively. For gestation age of <36weeks, all Doppler indices of the distal part of the fetus MCA were significantly different from those of proximal part (p<0.05). Comparing indices of gestation age <36 weeks with those of >36 weeks, significant difference was found between the Doppler indices of the proximal parts as well as for the distal parts (p<0.05). CONCLUSION: Measurement of fetus MCA indices may depend to the sampling location; however, this needs further investigation in order to find a clear probe location. PMID- 28713511 TI - Accuracy of densitometry of two cone beam computed tomography equipment in comparison with computed tomography. AB - BACKGROUND: The use of oral implants has been growing, and cone beam computerized tomography (CBCT) has become the method of choice for oral and maxillofacial radiology. OBJECTIVE: To assess the accuracy of bone densitometry in two different CBCT devices in comparison with MDCT (multi-detector CT). METHODS: Different concentrations of urografin, including 2.5%, 5%, 7.5%, 10%, 12.5%, were prepared, and the Hounsfield unit of these solution was measured by two CBCT devices (SORDEX CRANEX 3D and NEWTOM 5G) and one spiral CT device (SOMATOM SENSATION). Difference of output Hounsfield units in each concentration was compared in three devices. Correlation of devices with increase of urografin dose also was evaluated. Statistical analyses of the data were performed using SPSS18 and Kruskal-Wallis and Mann-Whitney U tests, along with Spearman's correlation coefficient. RESULTS: The range of gray density for NEWTOM 5G CBCT, SORDEX 3D CBCT, and SOMATOM CT imaging systems was from 781 to 2311, 427 to 1464, and 222 to 994, respectively. There was significant difference between devices in the Hounsfield unit in all urografin concentrations (p<0.001). Also there was a significant correlation between three devices with increasing the urografin dose (p<0.05; r>0.95). CONCLUSION: Our findings indicated a high correlation and linear relationship between different studied imaging systems. Although utilizing CBCT in the assessment of bone density is useful according to its lower emitted dose and less cost, clinicians should be aware of the issue that the voxel value in CBCT is not as perfect as CT. PMID- 28713512 TI - Laboratory evaluation of the effect of unfilled resin after the use of self-etch and total-etch dentin adhesives on the Shear Bond Strength of composite to dentin. AB - BACKGROUND: Based on the frequent application of composite resins as tooth colored fillings, this method is considered a viable alternative to dental amalgam. However, this method has the low bond strength of the composite to dentin. To solve this issue, various dental adhesive systems with different characteristics have been developed by dentistry experts. AIM: To assess the effect of an additional layer of unfilled resin in self-etch and total-etch dentin adhesives on the shear bond strength (SBS) of composite to dentin. Moreover, we assessed the effects of sample storage in artificial saliva on the SBS of composite to dentin. METHODS: Methods: This experimental study was conducted on 160 freshly extracted human first or second premolar teeth, which were randomly divided into 16 groups. The teeth were prepared from Mashhad University of Medical Sciences, Mashhad, Iran (2008-2009). Scotchbond Multi purpose (SBMP), single bond (SB), Clearfil SE Bond, and Clearfil S3 Bond were applied to dentin surface with or without the placement of hydrophobic resin (Margin Bond) in accordance with the instructions of the manufacturers. To expose the coronal dentin, the teeth were abraded with 600 grit SiC paper. Immediately after restoration, half of the samples were tested in terms of SBS, while the other samples were evaluated in terms of SBS after three months of storage in artificial saliva. SBS rates of dental composites evaluated by universal testing machine and samples were studied by optical stereomicroscopy to verify the failure type. Data analysis was performed in SPSS V.16 using Kolmogorov-Smirnov test, independent-samples t-test, ANOVA, and Duncan's logistic regression test. RESULTS: In this study, a significant reduction was observed in the SBS rates of SB and S3 bond adhesive systems after storage with and without hydrophobic resin (p>0.000). Without storage in normal saline, a significant increase was observed in the SBS rate of the SE bond (p=0.013). In addition, SBS rate of SBMP significantly increased after storage with hydrophobic resin (p=0.001). Finally, the highest and lowest rates of SBS were observed in the SE and S3 bonds in all the experimental groups, respectively. CONCLUSION: The effects of using a hydrophobic resin layer on shear bond strength values seem to be effective. The mild self-etch adhesive exhibited the best resin-dentine bond strength after aging. PMID- 28713513 TI - The prevalence and risk factors of group B streptococcus colonization in Iranian pregnant women. AB - BACKGROUND: Group B Streptococcus (GBS) is a leading cause of serious neonatal infections. Although great progress has been made in preventing prenatal GBS, its colonization rate in different regions of Iran remains unknown. AIM: To determine GBS colonization prevalence and its risk factors among Iranian pregnant women. METHODS: This prospective cross-sectional study was performed on 186 pregnant women, who attended Boo-Ali hospital which is affiliated with Islamic Azad University in Tehran, Iran, from March 2014 to June 2015. The demographic, obstetric and gynecological data were gathered. A recto-vaginal culture was taken from each patient, with a sterile swab, in lithotomy position without using speculum, and vaginal pH was measured. Patients with positive GBS received IV antibiotic therapy during labor (penicillin G 3 gram at first dose then 1.5 gram Q/4h until delivery). Data were analyzed by statistical software SPSS version 21. Statistical tests for differences were performed by Chi-square test. Potential confounding was assessed by logistic regression. Level of significance was set at p<0.05. RESULTS: Twenty-two (11.8%) patients had positive recto-vaginal colonization. No significant differences between colonized and GBS-negative women with regard to age, obstetrics history and socio-economic factor were noticed. In contrast, smoking, history of previous infection with HPV, presence of vulvitis and a vaginal pH>4.5 were associated with GBS colonization (p<=0.05). CONCLUSIONS: With a relatively low prevalence and few significantly correlated factors, it is hardly possible to define a high risk group of pregnant women for GBS colonization. Therefore, thorough measures should be taken in order to prevent infection complications in mothers and neonates in the Iranian population. PMID- 28713514 TI - Detection of eight foodborne bacterial pathogens by oligonucleotide array hybridization. AB - BACKGROUND: Simultaneous and rapid detection of multiple foodborne bacterial pathogens is important for the prevention of foodborne illnesses. OBJECTIVE: The aim of this study was to evaluate the use of 16S rDNA and 23S rDNA sequences as targets for simultaneous detection of eight foodborne bacterial pathogens. METHODS: Nineteen bacterial oligonucleotide probes were synthesized and applied to nylon membranes. Digoxygenin labeled 16S rDNA and 23S rDNA from bacteria were amplified by PCR using universal primers, and the amplicons were hybridized to the membrane array. Hybridization signals were visualized by NBT/BCIP color development. RESULTS: The eight intestinal bacterial pathogens including Salmonella enterica, Escherichia coli, Bacillus cereus, Vibrio cholerae, Shigella dysenteriae, Staphylococcus aureus, Listeria monocytogenes, and Enterococcus faecalis were appropriately detected in a panel of oligonucleotide array hybridization. The experimental results showed that the method could discriminate the bacterial pathogens successfully. The sensitivity of oligonucleotide array was 103 CFU/ml. CONCLUSION: This study showed that 16S rDNA and 23S rDNA genes had sufficient sequence diversity for species identification and were useful for monitoring the populations of foodborne pathogenic bacteria. Furthermore, results obtained in this study revealed that oligonucleotide array hybridization had a powerful capability to detect and identify the bacterial pathogens simultaneously. PMID- 28713515 TI - Effectiveness of methylphenidate and PUFA for the treatment of patients with ADHD: A double-blinded randomized clinical trial. AB - BACKGROUND: In some children with ADHD, sub-optimal levels of various nutrients including PUFA especially omega-3 has been observed, and contradictory reports exist on the results of studies conducted on the positive therapeutic effects of PUFA in patients with ADHD. OBJECTIVE: The aim of this study was to investigate the effectiveness of methylphenidate and PUFA on treatment of patients with ADHD in Zahedan, Iran. METHODS: In this clinical trial, 40 children between 6 and 12 years of age with ADHD were investigated in Zahedan in 2014. Patients were randomly divided into two groups of methylphenidate plus PUFA and methylphenidate plus placebo. ADHD rating scale was filled before and after the study for patients of both groups. Finally, data were analyzed using SPSS18, paired-samples t-test and chi-square. RESULTS: Mean age of patients was 2.9+/-1.8 years. Thirty three children (82.5%) were boys and seven children (17.5%) were girls. Mean severity of signs in the group under methylphenidate plus PUFA treatment was 39.9+/-4.9 before treatment and 20.1+/-6.0 after 8 weeks of treatment (p<0.001). Mean severity of signs in the group under methylphenidate plus placebo treatment was 41.2+/-2.7 before treatment and 26.1+/-9.0 after 8 weeks of treatment (p<0.001). Mean reduction in the severity of symptoms in the group under methylphenidate therapy was 19.7+/-5.9 and in PUFA and placebo group it was 15.1+/-9.3 (p<0.067). Response to treatment (a reduction of at least 25% in the signs) in the group taking methylphenidate plus PUFA was 90% (18 patients) and in methylphenidate plus placebo group, it was 60% (12 patients) (p=0.028). CONCLUSION: This study shows that PUFA is an efficient nutrient to treat ADHD and it can be used to treat patients. However, definitive conclusion requires repeating the study with a larger sample and longer study period. TRIAL REGISTRATION: The trial was registered at the Iranian Registry of Clinical Trials (http://www.irct.ir) with the Irct ID: IRCT2015092724209N2. FUNDING: The authors received no financial support for the research, authorship, and/or publication of this article. PMID- 28713516 TI - Sequential compression pump effect on hypotension due to spinal anesthesia for cesarean section: A double blind clinical trial. AB - BACKGROUND: Spinal anesthesia (SA) is a standard technique for cesarean section. Hypotension presents an incident of 80-85% after SA in pregnant women. OBJECTIVE: To determine the effect of intermittent pneumatic compression of lower limbs on declining spinal anesthesia induced hypotension during cesarean section. METHODS: This double-blind clinical prospective study was conducted on 76 non-laboring parturient patients, aged 18-45 years, with the American Society of Anesthesiologist physical status I or II who were scheduled for elective cesarean section at Razi Hospital, Ahvaz, Iran from December 21, 2015 to January 20, 2016. Patients were divided into treatment mechanical pump (Group M) or control group (Group C) with simple random sampling. Fetal presentation, birth weight, Apgar at 1 and 5 min, time taken for pre-hydration (min), pre-hydration to the administration of spinal anesthesia (min), initiation of spinal to the delivery (min) and total volume of intravenous fluids, total dose of ephedrine and metoclopramide were recorded. Data were analyzed by SPSS version 19, using repeated measures of ANOVA and Chi square test. RESULTS: Heart rate, MPA, DAP and SAP changes were significantly higher in off-pump group in the baseline and 1st minute (p<0.05), and in the other times, this change was significantly different with control groups. CONCLUSION: This research showed the suitability of the use of Sequential Compression Device (SCD) in reducing hypotension after spinal anesthesia for cesarean section, also this method can cause reducing vasopressor dosage for increased blood pressure, but the approval of its effectiveness requires repetition of the study with a larger sample size. TRIAL REGISTRATION: The trial was registered at the Iranian Registry of Clinical Trials (http://www.irct.ir) with the IRCT ID: IRCT2015011217742N3. FUNDING: The authors received no financial support for the research, authorship, and/or publication of this article. PMID- 28713517 TI - Developing the concept of caring in nursing education. AB - BACKGROUND: Caring is a value-based concept in the nursing field and in education. Exact understanding of caring in education and developing this concept in nursing will result in the evolution of the position of nursing science and profession. AIM: The aim of this study was to attempt to develop the concept of caring in nursing education. METHODS: This qualitative study was conducted in 2016 using directed content analysis. Participants were thirteen subjects (6 instructors and 7 senior and junior nursing students) who were selected using purposeful sampling method. Research environment was the Faculty of Nursing and Midwifery in Mashhad. Data collection method was semi-structured interviews for thirty to ninety minutes and sampling continued until data saturation. Interviews were conducted in Persian language and they were immediately transcribed and analyzed using MAXDA10 software. The text of interviews was reviewed several times. First, open codes were extracted, and after several reviews based on similarity in meaning, they were classified into subcategories and finally, similar subcategories were placed in main classes based on meaning. RESULTS: Results of this study led to the identification of four themes: 1, ethical and religious commitment, 2, development of knowing and cultural sensitivity, 3, soft assertion, 4, clear describing of objectives, expectations, and educational rules for students. CONCLUSION: Results of this study showed that the cultural and religious background of instructors affects their interaction with students. Instructors' commitment and compliance to values in interacting with students and other educational colleagues has an origin beyond ethical and human subjects and it is originated from their religious education and training. PMID- 28713518 TI - Examining non-structural retrofitting status of teaching hospitals in Kerman against disasters. AB - BACKGROUND AND OBJECTIVE: Continuous services provision of a hospital before and after a disaster is one of the most prominent issues that all people, especially the authorities must take into huge consideration. Concerning the experiences of previous earthquakes, the role and importance of nonstructural components becomes increasingly clear in the uninterrupted services of hospitals. In this study, non structural retrofitting status of Kerman teaching hospitals was evaluated against natural disasters. METHODS: This cross-sectional study was carried out in the second half of 2014 on the teaching hospitals in Kerman (Iran). The study population consisted of all Kerman teaching hospitals. The research instrument was World Health Organization/Pan American Health Organization (WHO/PAHO) standard checklist. Data analysis was carried out using descriptive statistics through SPSS 19. RESULTS: One hospital had a low retrofitting level, two hospitals had an average level and one had a high level. In the examined hospitals in this study, the medical gas section had the lowest preparedness against natural disasters, while the office, warehouse and furniture section had the highest resistance. Generally, the non-structural retrofitting status was 50% in one hospital and was between 65% and 85% in other hospitals. CONCLUSIONS: Generally, the retrofitting status of hospitals was not at the ideal condition, most hospitals were in average condition. Concerning the high risk of hospitals in disasters, it is necessary that senior executives and managers of Kerman Province and Kerman University of Medical Sciences take some measures to retrofit these buildings and to reduce the risk of vulnerability. PMID- 28713519 TI - Common solvents for making extraction of allergenic proteins from plants' pollens for prick tests and related factors: a technical review. AB - Collecting information on influencing factors in developing consistent and high quality extracts results in accurate diagnosis and effective treatment of type I allergy (IgE mediated). Furthermore, considering that a large number of allergens are currently in practice, any attempt to develop a more effective procedure for preparing extract may be useful. Nowadays, different saline solvents, temperature, incubation time, and PH are being incorporated for preparing allergen extracts. The objective of the current study was to clear and address the commonest of solvent buffers and allied conditions for making extracts of pollens of grasses, trees, and weeds. The literature review was done in Jan 2016 on PubMed and Google Scholar medical search engines without any time limitation. After reading abstracts of 87 articles, finally 37 relevant papers were selected and their full texts were retrieved. In conclusion, 24 full-text papers were recognized appropriate and chosen. The extracted information for papers has been described fully in the text. On the basis of these data, PBS buffer with PH 7.4, temperature of 4 degrees C and with overnight incubation time, may be the optimized condition in order to have a proper extract for carrying out skin prick tests. PMID- 28713520 TI - Decisional balance and self-efficacy of physical activity among the elderly in Rasht in 2013 based on the transtheoretical model. AB - BACKGROUND: Regular physical activity has been considered as health promotion, and identifying different effective psycho-social variables on physical has proven to be essential. OBJECTIVE: To identify the relationship between decisional balance and self-efficacy in physical activities using the transtheoretical model in the members of a retirement center in Rasht, Guillen. METHODS: A descriptive cross-sectional study was conducted in 2013 by using convenient sampling on 262 elderly people who are the members of retirement centers in Rasht. Data were collected using Stages of change, Decisional balance, Self-efficacy and Physical Activity Scale for the Elderly (PASE). Data was analyzed using SPSS-16 software, descriptive and analytic statistic (Pearson correlation, Spearman, ANOVA, HSD Tukey, linear and ordinal regression). RESULTS: The majority of participants were in maintenance stage. Mean and standard deviation physical activity for the elderly was 119.35+/-51.50. Stages of change and physical activities were significantly associated with decisional balance and self-efficacy (p<0.0001); however, cons had a significant and reverse association. According to linear and ordinal regression the only predicator variable of physical activity behavior was self-efficacy. CONCLUSION: By increase in pros and self-efficacy on doing physical activity, it can be benefited in designing appropriate intervention programs. PMID- 28713521 TI - Nurses views on accepting the creation of a nurses' health monitoring system. AB - BACKGROUND: Nurses' health is often accompanied by various dangers due to the nature of their career. Therefore, it is required to monitor their health. Based on designing any system, users' views should be investigated relative to the usefulness, necessity and acceptance of the system. Then, a designing and implementing process is conducted. OBJECTIVE: To investigate nurses' views on accepting the creation of a Nurses' Health Monitoring System. METHODS: This cross sectional study was conducted in 2015. Sample size was 586 nurses of Shahid Beheshti University of Medical Sciences. Sampling was conducted using multi-stage random sampling method. Research tool was a two-section researcher-made questionnaire. In the first section, demographic data were studied and in the second section, a twelve-item questionnaire was presented based on technology acceptance model. Five-item questions were regulated on perceived usefulness (PU) and perceived ease of use (PEU) and views towards creating this system. Validity of the questionnaire was approved by content validity and content validity index and its reliability was approved by Cronbach's alpha. Data were analyzed using SPSS16 and descriptive statistics (frequency distribution, percentage, mean). RESULTS: The majority of participants (75.3%) were females between 25-35 years of age (44.4%) and (58.2%) were married. Mean work experience was 11.5+/-8.19. Mean perceived usefulness (PU) (17.36+/-2.66) and perceived ease of use (PEU) (16.75+/ 2.65) and views towards using a Nurses' Health Monitoring System was (16.220+/ 3.05). CONCLUSION: Over two-thirds of nurses demonstrated perceived usefulness and perceived ease of use as well as positive views towards creating a nurses' health monitoring system. It is recommended to design and implement a nurses' health monitoring system based on local culture of Iranian nurses using IT in the health sector. PMID- 28713522 TI - The effect of motivational interviewing-based intervention using self determination theory on promotion of physical activity among women in reproductive age: A randomized clinical trial. AB - BACKGROUND: Physical activity (PA) prevents chronic diseases. Self-determination theory (SDT) provides a useful framework to understand the nature of motivational interviewing (MI). OBJECTIVE: This study aimed to determine the effect of MI based intervention using SDT on the promotion of PA among women in reproductive age. METHODS: Seventy women in reproductive age were selected by clustering sampling method for this randomized controlled trial. The questionnaire included the variables of physical fitness test, SDT, and global physical activity questionnaire (GPAQ). The validity of the questionnaires was approved using content validity ratio (CVR) and index (CVI). The reliability and internal consistency of the questionnaires and measures was approved using test-retest method and Cronbach's alpha test, respectively. The intervention group (n=35) received four MI sessions through theory and one standard education session about PA. The control group (n=35) received a standard education session about PA. RESULTS: Four months after the intervention, an increase in the mean scores of total PA (p<0.001, ES=4.77), physical fitness tests including flexibility (p<0.001, ES=1.59), muscular endurance (p<0.001, ES=2.0), cardiorespiratory endurance (p<0.001, ES=0.51), and a decrease in mean scores of agility test (p<0.001, ES= - 0.51) and sedentary behavior (p<0.01, ES=- 0.74) was observed in the intervention group compared to the control group. The intervention group reported an increase in the scores of intrinsic motivation (p<0.001, ES=3.34), identified regulation (p<0.001, ES= 1.28), perceptions of competence (p<0.001, ES=0.81) and autonomy (p<0.001, ES=2.01), enjoyment (p<0.001, ES=0.98) and health motives (p<0.01, ES=0.19), health care climate (p<0.001, ES=4.6), and a decreased score of external regulation (p<0.01, ES=-0.55) and amotivation (p<0.01, ES= 0.56) over time, compared to the control group. CONCLUSION: MI-based intervention using SDT was effective on the promotion of PA. TRIAL REGISTRATION: The Trial was registered at the Iranian Registry of Clinical Trial (http://www.irct.ir) with the Irct ID: IRCT2015101924592N1. PMID- 28713523 TI - Cementless One-Stage Bilateral Total Hip Arthroplasty in Osteoarthritis Patients: Functional Outcomes and Complications. AB - Total hip arthroplasty (THA) is one of the successful and cost-benefit surgical treatments. One-stage bilateral THA (BTHA) has a large number of advantages, although there are concerns about the higher complications in this procedure. Aim of our study was to evaluate the complications and outcomes of cementless one stage BTHA in osteoarthritis patients. A total of 147 patients from 2009 till 2012, underwent one-stage BTHA in Milad and Erfan hospitals, Tehran, Iran. A prospective analysis of the functional outcomes and complications of one-stage BTHA through Hardinge approach in patients with osteoarthritis was performed. We evaluated all patients clinically and radiologically with serial followups. A clinical hip score based upon the modified Harris Hip Score (MHHS) was performed preoperatively and again postoperatively. During the period of study 89 men (60.5%) and 58 women (39.4%) with a mean age of 54.67+/-7.08 years at the time of presentation were recruited. The mean surgical time was 2.8+/-0.25 hrs. The mean hospital stay was 3.83+/-0.65 days. Hemoglobin level decreased significantly after operation (P=0.038). There was two deep venous thromboses, one superficial infection and one temporal proneal palsy but no pulmonary embolism, dislocation, periprosthetic fracture or heterotrophic ossification. The mean preoperative MHHS score was 41.64+/-5.42 in patients. MHHS score improved to 89.26+/-4.68 in the last followup (P=0.0001). Our results recommended the use of cementless one-stage BTHA through Hardinge approach in patients with bilateral hip osteoarthritis. PMID- 28713524 TI - Forced-Air Warming Discontinued: Periprosthetic Joint Infection Rates Drop. AB - Several studies have shown that the waste heat from forced-air warming (FAW) escapes near the floor and warms the contaminated air resident near the floor. The waste heat then forms into convection currents that rise up and contaminate the sterile field above the surgical table. It has been shown that a single airborne bacterium can cause a periprosthetic joint infection (PJI) following joint replacement surgery. We retrospectively compared PJI rates during a period of FAW to a period of air-free conductive fabric electric warming (CFW) at three hospitals. Surgical and antibiotic protocols were held constant. The pooled multicenter data showed a decreased PJI rate of 78% following the discontinuation of FAW and a switch to air-free CFW (n=2034; P=0.002). The 78% reduction in joint implant infections observed when FAW was discontinued suggests that there is a link between the waste FAW heat and PJIs. PMID- 28713525 TI - Orthopedic In-Training Examination Question Metrics and Resident Test Performance. AB - First administered in November 1963, the orthopedic in-training examination (OITE) is now distributed to more than 4000 residents in over 20 countries and has become important for evaluation of resident fund of knowledge. Several studies have assessed the effect of didactic programs on resident performance, but only recently has it become possible to assess detailed testtaking metrics such as time spent per question. Here, we report the first assessment of resident OITE performance utilizing this full electronic dataset from two large academic institutions. Full 2015 OITE score reports for all orthopedic surgery residents at two institutions were anonymized and compiled. For every question answered by each resident, the resident year, question content or domain, question result (correct or incorrect), and answer speed were recorded. Data were then analyzed to determine whether resident year, result, or domain affected answer speed and whether performance in each subspecialty domain varied based on resident year in training. Data was available for 46 residents and 12,650 questions. Mean answer speed for questions answered correctly, 54.0+/-48.1 s, was significantly faster than for questions answered incorrectly, 72.2+/-61.2 s (P<0.00001). When considering both correct and incorrect answers, PGY-1s were slower than all other years (P<0.02). Residents spent a mean of nearly 80 seconds on foot and ankle and shoulder and elbow questions, compared to only 40 seconds on basic science questions (P<0.05). In education, faster answer speed for questions is often considered a sign of mastery of the material and more confidence in the answer. Though faster answer speed was strongly associated with correct answers, this study demonstrates that answer speed is not reliably associated with resident year. While answer speed varies between domains, it is likely that the majority of this variation is due to question type as opposed to confidence. Nevertheless, it is possible that in domains with more tiered experience such as shoulder, answer speed correlates strongly with resident year and percentage correct. PMID- 28713526 TI - Recent Developments in the Treatment of Spinal Epidural Abscesses. AB - Spinal epidural abscess (SEA) is a serious condition that can be challenging to diagnose due to nonspecific symptomology and delayed presentation. Despite this, it requires prompt recognition and management in order to prevent permanent neurologic sequelae. Several recent studies have improved our understanding of SEA. Herein, we summarize the recent literature from the past 10 years relevant to SEA diagnosis, management and outcome. While surgical care remains the mainstay of treatment, a select subset of SEA patients may be managed without operative intervention. Multidisciplinary management involves internal medicine, infectious disease, critical care, and spine surgeons in order to optimize care. PMID- 28713527 TI - Comparison of Continuous Femoral Nerve Block with and Without Combined Sciatic Nerve Block after Total Hip Arthroplasty: A Prospective Randomized Study. AB - In association with the growing interests in pain management, several modalities to control postoperative pain have been proposed and examined for the efficacy in the recent studies. Various modes of peripheral nerve block have been proposed and the effectiveness and safety have been examined for each of those techniques. We have described our clinical experiences, showing that continuous femoral nerve block could provide a satisfactory analgesic effect after total hip arthroplasty (THA) procedure. In this study, we compared the effectiveness and safety of continuous femoral nerve block with and without sciatic nerve blockade on pain control after THA. Forty patients scheduled for THA were included in the study and randomly divided into 2 groups. Postoperative analgesic measure was continuous femoral nerve block alone, while the identical regimen of continuous femoral nerve block was combined with sciatic nerve block. The amount of postoperative pain was evaluated in the immediate postoperative period, 6 hours, and 12 hours after surgery. Moreover, postoperative complications as well as requirement of supplemental analgesics during the initial 12 hours after surgery were reviewed in the patient record. The obtained study results showed that the supplemental sciatic nerve blockade provided no significant effect on arrival at the postoperative recovery room, while the NRS pain score was significantly reduced by the combined application of sciatic nerve blockade at 6 and 12 hours after surgery. In the investigation of postoperative analgesiarelated complications, no major complication was encountered without significant difference in complication rate between the groups. PMID- 28713528 TI - The Double-Transforaminal Lumbar Interbody Fusion: An Innovative One-Stage Surgical Technique for Posterior Kyphosis Correction. AB - Posttraumatic deformities after vertebral fractures are challenging for orthopedic surgeons in the non-operative and operative field. Especially osteoporotic fractures may cause a hyperkyphosis resulting in segmental or global sagittal imbalance and chronic back pain. Different vertebral osteotomies are potent to restore sagittal profile but show a very high perioperative risk including neurological and soft tissue complications. In addition, some of these extensive operations require a two-step procedure including posterior and anterior approaches. Therefore, these established techniques may be contraindicated in elderly or multimorbide patients suffering from concomitant diseases. The authors describe the double transforaminal lumbar interbody fusion (TLIF) osteotomy (DTO) as an innovative one-stage and low-invasive surgical technique to correct a fixed posttraumatic kyphosis in the thoracolumbar junction. The procedure includes posterior release (laminectomy, facettectomy, nucleotomy) combined with two expandable TLIF implants (sandwich technique) and posterior instrumentation and is illustrated by a case of a multimorbide 78-year old female. PMID- 28713529 TI - Somatoform Dissociation, Fatigue Severity and Pain Behavior Compared in Patients with Migraine Headache and in Healthy Individuals. AB - The prevalence of migraine in the world is about 15 and 7% among women and men, respectively. The purpose of this study was comparison of somatoform dissociation, fatigue severity and pain behavior in patients with migraine headache and its relationship with coping strategies. This descriptive analytical study has been done on 120 patients with migraine headache and 120 healthy subjects were selected randomly. Data collected by somatoform dissociation questionnaire (SDQ-20), fatigue severity scale, pain behavior scale and coping strategies scale. For data analysis we used SPSS.19. The means of the somatoform dissociation, pain behavior scale, help searching subscale and pain compliant in migraine and healthy subjects were statistically significant. There was not significant difference in avoidance subscales between the two groups. Comparison of fatigue severity in patients with migraine and control group was meaningful. There was significant positive correlation between all four scales and coping strategies. It seems that these symptoms can play an important role in this disease; thus, their careful evaluation in the treatment of migraine headache is essential. PMID- 28713530 TI - Are Cerebrospinal Fluid Protein Levels and Plasma Neutrophil/Lymphocyte Ratio Associated with Prognosis of Guillain Barre Syndrome? AB - Guillain Barre syndrome (GBS) is a post-infectious acute autoimmune polyradiculopathy. Cerebrospinal fluid (CSF) total protein level and plasma neutrophil/lymphocyte ratio (NLR) are related with autoimmune response. We aimed to reach a prognostic indicator for GBS by using electrophysiological findings, protein level of CSF, and plasma NLR based on Medical Research Council (MRC) sum score data. Cases who met diagnostic criteria of GBS and followed at least six months were enrolled in the study. Nerve conduction study (NCS) and lumbar puncture were performed one week after symptom onset. Routine CSF findings and complete blood count were recorded. Plasma NLR was calculated as the ratio of neutrophil cell count to lymphocyte cell count. All patients received intravenous immunoglobulin. MRC sum scores were calculated on administration time (1st) and six months later (2nd) for evaluation of recovery. Mean values of baseline CSF protein level, NCS parameters and NLR were compared with mean scores of MRC1st and MRC2nd. Increased CSF protein levels showed negative correlation with MRC2nd scores but no correlation with NCS. Increased NLR levels were positively correlated with age, MRC2nd scores and NCS. Facial diplegia was observed in 42% of patients. A positive correlation was found between high level of NLR and MRC1st, and there was no relationship with MRC2nd. Regression analyses showed that only CSF protein level was an independent factor on both MRC1st and MRC2nd. A positive association was found between baseline data included young age high plasma NLR, low level of CSF protein and good prognosis in our study. Also a positive correlation was found between high level of NLR and baseline disability in GBS cases with facial diplegia. Calculation of NLR is an easy and inexpensive method. On the other hand it may be influenced by age and immunotherapy. Our results showed that CSF protein level is still a liable parameter for prognosis. NLR could be a candidate prognostic marker of GBS cases. Further investigations including more cases are needed. PMID- 28713531 TI - The Effects of Fasting During Ramadan on the Concentration of Serotonin, Dopamine, Brain-Derived Neurotrophic Factor and Nerve Growth Factor. AB - Neurotransmitters and neurotrophic factors are signaling molecules that play a crucial role in cell proliferation, differentiation, survival and functions of neurons. It is believed that caloric restriction could help the health of the nervous system by affecting the synthesis of neurotrophins and neurotransmitter and oxygen radical metabolism. The objective was to investigate the plasma levels of serotonin, dopamine, brain-derived neurotrophic factor (BDNF), and nerve growth factor (NGF) in 29 healthy fasted subjects (22 women and 7 men) during the month of fasting in Ramadan. The levels of these factors were measured (using ELISA method) three times, 2 days before the fasting month as a control, on the 14th and 29th day of Ramadan as test groups. In addition, these factors were investigated in the group of women only. According to our investigation, the plasma levels of serotonin, BDNF and NGF were significantly increased during fasting month of Ramadan. In detail, the levels of these factors were increased in 14th and 29th day test groups compared to controls (P<0.05). Moreover, these levels were significantly increased on the 29th day compared to the 14th day test groups, but there were no differences between dopamine levels in all groups. Furthermore, the results obtained in women's groups were the same as those obtained in previous groups. Our findings suggest that plasma levels of serotonin, BDNF and NGF were significantly increased during fasting month of Ramadan. PMID- 28713532 TI - Bilateral Cavernous Sinus Thrombosis as First Manifestation of Primary Burkitt Lymphoma of the Thyroid Gland. AB - Cavernous sinus thrombosis (CST) is a rare condition that is usually associated with infections, pregnancy, vasculitis and some types of medication, such as the contraceptive pill and paraneoplastic. Primary Burkitt lymphoma (PBL) of the thyroid gland is very uncommon and the clinical description of such cases has been largely limited to case reports. In this paper, we present a case of CST as the first manifestation of PBL of the thyroid gland. To the best of our knowledge, our patient is the first case report of PBL of the thyroid gland that presents with bilateral CST. PMID- 28713534 TI - Low-Load High-Velocity Resistance Exercises Improve Strength and Functional Capacity in Diabetic Patients. AB - This study investigated the effects of low-load high-velocity resistance exercises on neuromuscular and functional outcomes in patients with Type 2 diabetes (T2D) during the early-phase of resistance training. Thirty participants with T2D performed 18 training sessions (6 weeks - 3x week) in one of two groups: low-load high-velocity exercises (LLHV, n=15, 62.1+/-10.5 years) or recreational activities (RA, n=15 56.7 +/- 19.4 years). LLHV performed resistance exercises with 3x 8reps as fast as possible with 50-60% 1RM. RA performed light activities. Strength, power, and functional tests were assessed. There was significant increasing in the knee extension peak-torque at 60 degrees /s (7.6%) and 180 degrees /s (12.2%), rate of force development in the LLHV group (P<0.05), whereas there were no changes in the RA group. Significant increases in functional test were observed in the LLHV group (P<0.01) with no changes in the RA group. In conclusion, the LLHV induced marked improvements in neuromuscular parameters, as well as in the functional capacity of participants with T2D. PMID- 28713533 TI - Photonics and plasmonics go viral: self-assembly of hierarchical metamaterials. AB - Sizing and shaping of mesoscale architectures with nanoscale features is a key opportunity to produce the next generation of higher-performing products and at the same time unveil completely new phenomena. This review article discusses recent advances in the design of novel photonic and plasmonic structures using a biology-inspired design. The proteinaceous capsids from viruses have long been discovered as platform technologies enabling unique applications in nanotechnology, materials, bioengineering, and medicine. In the context of materials applications, the highly organized structures formed by viral capsid proteins provide a 3D scaffold for the precise placement of plasmon and gain materials. Based on their highly symmetrical structures, virus-based nanoparticles have a high propensity to self-assemble into higher-order crystalline structures, yielding hierarchical hybrid materials. Recent advances in the field have led to the development of virus-based light harvesting systems, plasmonic structures for application in high-performance metamaterials, binary nanoparticle lattices, and liquid crystalline arrays for sensing or display technologies. There is still much that could be explored in this area, and we foresee that this is only the beginning of great technological advances in virus based materials for plasmonics and photonics applications. PMID- 28713535 TI - Strength Training with Repetitions to Failure does not Provide Additional Strength and Muscle Hypertrophy Gains in Young Women. AB - This study investigated the effects of a 10-week resistance training to failure on neuromuscular adaptations in young women. Eighty-nine active young women were randomly assigned to one of three groups: 1) repetitions to failure (RF; three sets of repetitions to failure); 2) repetitions not to failure with equalized volume (RNFV; four sets of 7 repetitions); and 3) repetitions not to failure (RNF; three sets of 7 repetitions). All groups performed the elbow flexor exercise (bilateral biceps curl) and trained 2 days per week using 70% of 1RM. There were significant increases (p<0.05) in muscle strength after 5 (15.9% for RF, 18.4% for RNF, and 19.9% for RNFV) and 10 (28.3% for RF, 26.8% for RNF, and 28.3% for RNFV) weeks of training, with no significant differences between groups. Additionally, muscular endurance increased after 5 and 10 weeks, with no differences between groups. However, peak torque (PT) increased significantly at 180 degrees .s-1 in the RNFV (13.7%) and RNF (4.1%) groups (p<0.05), whereas no changes were observed in the RF group (-0.5%). Muscle thickness increased significantly (p<0.05) in the RF and RNFV groups after 5 (RF: 8.4% and RNFV: 2.3%) and 10 weeks of training (RF: 17.5%, and RNFV: 8.5%), whereas no significant changes were observed in the RNF group (3.9 and 2.1% after 5 and 10 weeks, respectively). These data suggest that short-term training of repetitions to failure do not yield additional overall neuromuscular improvements in young women. PMID- 28713536 TI - Neuromuscular Taping Application in Counter Movement Jump: Biomechanical Insight in a Group of Healthy Basketball Players. AB - Kinesiologic elastic tape is widely used for both clinical and sport applications although its efficacy in enhancing agonistic performance is still controversial. Aim of the study was to verify in a group of healthy basketball players whether a neuromuscular taping application (NMT) on ankle and knee joints could affect the kinematic and the kinetic parameters of the jump, either by enhancing or inhibiting the functional performance. Fourteen healthy male basketball players without any ongoing pathologies at upper limbs, lower limbs and trunk volunteered in the study. They randomly performed 2 sets of 5 counter movement jumps (CMJ) with and without application of Kinesiologic tape. The best 3 jumps of each set were considered for the analysis. The Kinematics parameters analyzed were: knees maximal flexion and ankles maximal dorsiflexion during the push off phase, jump height and take off velocity. Vertical ground reaction force and maximal power expressed in the push off phase of the jump were also investigated. The NMT application in both knees and ankles showed no statistically significant differences in the kinematic and kinetic parameters and did not interfere with the CMJ performance. Bilateral NMT application in the group of healthy male basketball players did not change kinematics and kinetics jump parameters, thus suggesting that its routine use should have no negative effect on functional performance. Similarly, the combined application of the tape on both knees and ankles did not affect in either way jump performance. PMID- 28713538 TI - 2017Spring PaduaMuscleDays, roots and byproducts. AB - The second 2017 issue of EJTM volume 27 contains the collection of abstracts from the 2017Spring PaduaMuscleDays conference, that was held March 23-25 in Montegrotto, Euganei Hills, Padova, Italy. In addition to a brief history of the Padova Myology Meetings held during the last 30 years, the present and the future of the PaduaMuscleDays conference are discussed with special reference to new media and the options they offer to spread to a larger audience the results of the many workshops held in the Hotel Augustus conference hall and in the Aula Guariento of the Accademia Galileiana di Scienze, Lettere ed Arti, one of the hidden treasures of the medioeval Padua, Italy. Preliminary announcements of the 2017 and 2018 events, in particular of the Giovanni Salviati Memorial, will follow. PMID- 28690828 TI - Culture and identification of Borrelia spirochetes in human vaginal and seminal secretions. AB - Background: Recent reports indicate that more than 300,000 cases of Lyme disease are diagnosed yearly in the USA. Preliminary clinical, epidemiological and immunological studies suggest that infection with the Lyme disease spirochete Borrelia burgdorferi (Bb) could be transferred from person to person via intimate human contact without a tick vector. Detecting viable Borrelia spirochetes in vaginal and seminal secretions would provide evidence to support this hypothesis. Methods: Patients with and without a history of Lyme disease were selected for the study after informed consent was obtained. Serological testing for Bb was performed on all subjects. Semen or vaginal secretions were inoculated into BSK-H medium and cultured for four weeks. Examination of genital cultures and culture concentrates for the presence of spirochetes was performed using light and darkfield microscopy, and spirochete concentrates were subjected to Dieterle silver staining, anti-Bb immunohistochemical staining, molecular hybridization and PCR analysis for further characterization. Immunohistochemical and molecular testing was performed in three independent laboratories in a blinded fashion. Positive and negative controls were included in all experiments. Results: Control subjects who were asymptomatic and seronegative for Bb had no detectable spirochetes in genital secretions by PCR analysis. In contrast, spirochetes were observed in cultures of genital secretions from 11 of 13 subjects diagnosed with Lyme disease, and motile spirochetes were detected in genital culture concentrates from 12 of 13 Lyme disease patients using light and darkfield microscopy. Morphological features of spirochetes were confirmed by Dieterle silver staining and immunohistochemical staining of culture concentrates. Molecular hybridization and PCR testing confirmed that the spirochetes isolated from semen and vaginal secretions were strains of Borrelia, and all cultures were negative for treponemal spirochetes. PCR sequencing of cultured spirochetes from three couples having unprotected sex indicated that two couples had identical strains of Bb sensu stricto in their semen and vaginal secretions, while the third couple had identical strains of B. hermsii detected in their genital secretions. Conclusions: The culture of viable Borrelia spirochetes in genital secretions suggests that Lyme disease could be transmitted by intimate contact from person to person. PMID- 28713537 TI - What Can be Learned from the Time Course of Changes in Low-Frequency Stimulated Muscle? PMID- 28698795 TI - Semi-automated Modular Program Constructor for physiological modeling: Building cell and organ models. AB - The Modular Program Constructor (MPC) is an open-source Java based modeling utility, built upon JSim's Mathematical Modeling Language (MML) ( http://www.physiome.org/jsim/) that uses directives embedded in model code to construct larger, more complicated models quickly and with less error than manually combining models. A major obstacle in writing complex models for physiological processes is the large amount of time it takes to model the myriad processes taking place simultaneously in cells, tissues, and organs. MPC replaces this task with code-generating algorithms that take model code from several different existing models and produce model code for a new JSim model. This is particularly useful during multi-scale model development where many variants are to be configured and tested against data. MPC encodes and preserves information about how a model is built from its simpler model modules, allowing the researcher to quickly substitute or update modules for hypothesis testing. MPC is implemented in Java and requires JSim to use its output. MPC source code and documentation are available at http://www.physiome.org/software/MPC/. PMID- 28690828 TI - Culture and identification of Borrelia spirochetes in human vaginal and seminal secretions. AB - Background: Recent reports indicate that more than 300,000 cases of Lyme disease are diagnosed yearly in the USA. Preliminary clinical, epidemiological and immunological studies suggest that infection with the Lyme disease spirochete Borrelia burgdorferi (Bb) could be transferred from person to person via intimate human contact without a tick vector. Failure to detect viable Borrelia spirochetes in vaginal and seminal secretions would argue against this hypothesis. Methods: Patients with and without a history of Lyme disease were selected for the study after informed consent was obtained. Serological testing for Bb was performed on all subjects. Semen or vaginal secretions were inoculated into BSK-H medium and cultured for four weeks. Examination of genital cultures and culture concentrates for the presence of spirochetes was performed using light and darkfield microscopy, and spirochete concentrates were subjected to Dieterle silver staining, anti-Bb immunohistochemical staining, molecular hybridization and PCR analysis for further characterization. Immunohistochemical and molecular testing was performed in three independent laboratories in a blinded fashion. Positive and negative controls were included in all experiments. Results: Control subjects who were asymptomatic and seronegative for Bb had no detectable spirochetes in genital secretions by PCR analysis. In contrast, spirochetes were observed in cultures of genital secretions from 11 of 13 subjects diagnosed with Lyme disease, and motile spirochetes were detected in genital culture concentrates from 12 of 13 Lyme disease patients using light and darkfield microscopy. Morphological features of spirochetes were confirmed by Dieterle silver staining and immunohistochemical staining of culture concentrates. Molecular hybridization and PCR testing confirmed that the spirochetes isolated from semen and vaginal secretions were strains of Borrelia, and all cultures were negative for treponemal spirochetes. PCR sequencing of cultured spirochetes from three couples having unprotected sex indicated that two couples had identical strains of Bb sensu stricto in their semen and vaginal secretions, while the third couple had identical strains of B. hermsii detected in their genital secretions. Conclusions: The culture of viable Borrelia spirochetes in genital secretions suggests that Lyme disease could be transmitted by intimate contact from person to person. Further studies are needed to evaluate this hypothesis. PMID- 28698795 TI - Semi-automated Modular Program Constructor for physiological modeling: Building cell and organ models. AB - The Modular Program Constructor (MPC) is an open-source Java based modeling utility, built upon JSim's Mathematical Modeling Language (MML) ( http://www.physiome.org/jsim/) that uses directives embedded in model code to construct larger, more complicated models quickly and with less error than manually combining models. A major obstacle in writing complex models for physiological processes is the large amount of time it takes to model the myriad processes taking place simultaneously in cells, tissues, and organs. MPC replaces this task with code-generating algorithms that take model code from several different existing models and produce model code for a new JSim model. This is particularly useful during multi-scale model development where many variants are to be configured and tested against data. MPC encodes and preserves information about how a model is built from its simpler model modules, allowing the researcher to quickly substitute or update modules for hypothesis testing. MPC is implemented in Java and requires JSim to use its output. MPC source code and documentation are available at http://www.physiome.org/software/MPC/. PMID- 28713543 TI - GeneBreak: detection of recurrent DNA copy number aberration-associated chromosomal breakpoints within genes. AB - Development of cancer is driven by somatic alterations, including numerical and structural chromosomal aberrations. Currently, several computational methods are available and are widely applied to detect numerical copy number aberrations (CNAs) of chromosomal segments in tumor genomes. However, there is lack of computational methods that systematically detect structural chromosomal aberrations by virtue of the genomic location of CNA-associated chromosomal breaks and identify genes that appear non-randomly affected by chromosomal breakpoints across (large) series of tumor samples. 'GeneBreak' is developed to systematically identify genes recurrently affected by the genomic location of chromosomal CNA-associated breaks by a genome-wide approach, which can be applied to DNA copy number data obtained by array-Comparative Genomic Hybridization (CGH) or by (low-pass) whole genome sequencing (WGS). First, 'GeneBreak' collects the genomic locations of chromosomal CNA-associated breaks that were previously pinpointed by the segmentation algorithm that was applied to obtain CNA profiles. Next, a tailored annotation approach for breakpoint-to-gene mapping is implemented. Finally, dedicated cohort-based statistics is incorporated with correction for covariates that influence the probability to be a breakpoint gene. In addition, multiple testing correction is integrated to reveal recurrent breakpoint events. This easy-to-use algorithm, 'GeneBreak', is implemented in R ( www.cran.r-project.org) and is available from Bioconductor ( www.bioconductor.org/packages/release/bioc/html/GeneBreak.html). PMID- 28713544 TI - Heterogeneous ensembles for predicting survival of metastatic, castrate-resistant prostate cancer patients. AB - Ensemble methods have been successfully applied in a wide range of scenarios, including survival analysis. However, most ensemble models for survival analysis consist of models that all optimize the same loss function and do not fully utilize the diversity in available models. We propose heterogeneous survival ensembles that combine several survival models, each optimizing a different loss during training. We evaluated our proposed technique in the context of the Prostate Cancer DREAM Challenge, where the objective was to predict survival of patients with metastatic, castrate-resistant prostate cancer from patient records of four phase III clinical trials. Results demonstrate that a diverse set of survival models were preferred over a single model and that our heterogeneous ensemble of survival models outperformed all competing methods with respect to predicting the exact time of death in the Prostate Cancer DREAM Challenge. PMID- 28713545 TI - 2017 Outstanding Contributions to ISCB Award: Fran Lewitter. AB - The Outstanding Contributions to the International Society for Computational Biology (ISCB) Award was launched in 2015 to recognize individuals who have made lasting and valuable contributions to the Society through their leadership, service, and educational work, or a combination of these areas. Fran Lewitter is the 2017 winner of the Outstanding Contributions to ISCB Award and will be recognized at the 2017 Intelligent Systems for Molecular Biology (ISMB)/European Conference on Computational Biology, meeting in Prague, Czech Republic being held from July 21-25, 2017. PMID- 28713547 TI - 2017 ISCB Innovator Award: Aviv Regev. AB - 2017 marks the second year of the International Society for Computational Biology (ISCB) Innovator Award, which recognizes an ISCB scientist who is within two decades of having completed his or her graduate degree and has consistently made outstanding contributions to the field. The 2017 winner is Dr. Aviv Regev, Professor of Biology at the Massachusetts Institute of Technology (MIT), a Core Member and Chair of the Faculty of the Broad Institute of MIT and Harvard, and an HHMI Investigator. Regev will receive her award and deliver a keynote address during International Conference on Intelligent Systems for Molecular Biology/European Conference on Computational Biology (ISMB/ECCB) 2017 in Prague, Czech Republic (July 21 - 25, 2017). PMID- 28713546 TI - 2017 ISCB Overton Prize: Christoph Bock. AB - The International Society for Computational Biology (ISCB) each year recognizes the achievements of an early to mid-career scientist with the Overton Prize. This prize honors the untimely death of Dr. G. Christian Overton, an admired computational biologist and founding ISCB Board member. Winners of the Overton Prize are independent investigators who are in the early to middle phases of their careers and are selected because of their significant contributions to computational biology through research, teaching, and service. ISCB is pleased to recognize Dr. Christoph Bock, Principal Investigator at the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences in Vienna, Austria, as the 2017 winner of the Overton Prize. Bock will be presenting a keynote presentation at the 2017 International Conference on Intelligent Systems for Molecular Biology/European Conference on Computational Biology (ISMB/ECCB) in Prague, Czech Republic being held during July 21-25, 2017. PMID- 28713548 TI - 2017 ISCB Accomplishment by a Senior Scientist Award: Pavel Pevzner. AB - The International Society for Computational Biology ( ISCB) recognizes an established scientist each year with the Accomplishment by a Senior Scientist Award for significant contributions he or she has made to the field. This award honors scientists who have contributed to the advancement of computational biology and bioinformatics through their research, service, and education work. Pavel Pevzner, PhD, Ronald R. Taylor Professor of Computer Science and Director of the NIH Center for Computational Mass Spectrometry at University of California, San Diego, has been selected as the winner of the 2017 Accomplishment by a Senior Scientist Award. The ISCB awards committee, chaired by Dr. Bonnie Berger of the Massachusetts Institute of Technology, selected Pevzner as the 2017 winner. Pevzner will receive his award and deliver a keynote address at the 2017 Intelligent Systems for Molecular Biology-European Conference on Computational Biology joint meeting ( ISMB/ECCB 2017) held in Prague, Czech Republic from July 21-July 25, 2017. ISMB/ECCB is a biennial joint meeting that brings together leading scientists in computational biology and bioinformatics from around the globe. PMID- 28713549 TI - Where are aphasia theory and management "headed"? AB - The sequelae of post-stroke aphasia are considerable, necessitating an understanding of the functional neuroanatomy of language, cognitive processes underlying various language tasks, and the mechanisms of recovery after stroke. This knowledge is vital in providing optimal care of individuals with aphasia and counseling to their families and caregivers. The standard of care in the rehabilitation of aphasia dictates that treatment be evidence-based and person centered. Promising techniques, such as cortical stimulation as an adjunct to behavioral therapy, are just beginning to be explored. These topics are discussed in this review. PMID- 28713552 TI - Case Report: Diagnosis of hypogeusia after oral exposure to commercial cleaning agent and considerations for clinical taste testing. AB - Few reports in the literature document acute taste disturbance following exposure to toxic chemicals. We describe the case of a 54-year-old man who presented with primary complaint of tongue numbness and persistent problems with taste 1.5 years following oral exposure to a commercial cleaning agent. A test of olfaction revealed normosmia for age and gender. Lingual tactile two-point discrimination testing showed reduced somatosensation. Taste threshold testing using a 3-drop method demonstrated severe hypogeusia, though the patient was able to discriminate tastants at lower concentrations with a whole mouth swish and spit test. We conclude that clinical evaluation of dysgeusia can be performed using a number of previously published testing methods, however, determining causative factors may be confounded by duration since exposure, lack of knowledge of baseline taste function, and medications. Although many testing options exist, basic taste testing can be performed with minimal expertise or specialized equipment, depending on the patient history and goals of evaluation. PMID- 28713551 TI - Case Report: Intramammary lymph node metastasis of an unknown primary, probably occult breast, undifferentiated carcinoma. AB - Little is known about the clinical importance of intramammary lymph node metastasis of breast cancer, even though it is not rare. In the present paper, the authors present an unusual, rare case of an intramammary lymph node metastasis of an unknown primary, probably occult breast cancer, and its management. The patient was submitted to various staging exams and surgical procedures and a definitive diagnosis was not established. From a multidisciplinary context, it was assumed that the patient had a breast triple negative primary with axillary involvement. This decision lead to adjuvant chemo and radiotherapy. Challenging cases like the one described here, should always be managed within the multidisciplinary team context and recorded in the institution's database. PMID- 28713550 TI - A community proposal to integrate proteomics activities in ELIXIR. AB - Computational approaches have been major drivers behind the progress of proteomics in recent years. The aim of this white paper is to provide a framework for integrating computational proteomics into ELIXIR in the near future, and thus to broaden the portfolio of omics technologies supported by this European distributed infrastructure. This white paper is the direct result of a strategy meeting on 'The Future of Proteomics in ELIXIR' that took place in March 2017 in Tubingen (Germany), and involved representatives of eleven ELIXIR nodes. These discussions led to a list of priority areas in computational proteomics that would complement existing activities and close gaps in the portfolio of tools and services offered by ELIXIR so far. We provide some suggestions on how these activities could be integrated into ELIXIR's existing platforms, and how it could lead to a new ELIXIR use case in proteomics. We also highlight connections to the related field of metabolomics, where similar activities are ongoing. This white paper could thus serve as a starting point for the integration of computational proteomics into ELIXIR. Over the next few months we will be working closely with all stakeholders involved, and in particular with other representatives of the proteomics community, to further refine this paper. PMID- 28713553 TI - The evolution of medulloblastoma therapy to personalized medicine. AB - Recent advances in cancer genomics have revolutionized the characterization and classification of medulloblastomas. According to the current WHO guidelines, medulloblastomas are now classified into the following molecularly defined groups: Wnt signaling pathway (WNT)-activated, sonic hedgehog signaling pathway (SHH)-activated and tumor suppressor protein p53 (TP53)-mutant, SHH-activated and TP53-wildtype, and non-WNT/non-SHH (i.e. group 3 and group 4). Importantly, genomic, epigenomic, and proteomic advances have created a potential paradigm shift in therapeutic options. The challenge now is to (i) translate these observations into new therapeutic approaches and (ii) employ these observations in clinical practice, utilizing the classification following a molecular analysis for diagnosis and application of new subgroup-specific targeted therapeutics. PMID- 28713555 TI - Case Report: Using ultrasound to prevent a broken catheter from migrating to the heart. AB - Peripheral intravenous (IV) catheters can break off while still in the patient, with possible detrimental effects such as upstream migration to the heart. These catheters have probably been damaged by the needle during a difficult insertion. A peripheral IV catheter was removed in a 90 year old patient and only half of the catheter was retrieved. By using ultrasound examination the remaining part of the IV catheter was identified, and retrieved surgically, before it could migrate towards the heart. This case report suggests that ultrasound should not only be used for difficult placement of a peripheral IV catheter, but can also be used when removal is complicated. PMID- 28713554 TI - Growth hormone receptor antagonism with pegvisomant in insulin resistant non diabetic men: A phase II pilot study. AB - Background: Growth hormone (GH) is known to affect insulin and glucose metabolism. Blocking its effects in acromegalic patients improves diabetes and glucose metabolism. We aimed to determine the effect of pegvisomant, a GH receptor antagonist, on insulin resistance, endogenous glucose production (EGP) and lipolysis in insulin resistant non-diabetic men. Methods: Four men between the ages of 18-62 with a BMI of 18-35kg/m 2, with insulin resistance as defined by a HOMA-IR > 2.77, were treated for four weeks with pegvisomant 20 mg daily. Inpatient metabolic assessments were performed before and after treatment. The main outcome measurements were: change after pegvisomant therapy in insulin sensitivity as measured by hyperinsulinemic euglycemic clamp; and EGP and lipolysis assessed by stable isotope tracer techniques. Results: Insulin like growth factor-1 (IGF-1) concentrations decreased from 134.0 +/- 41.5 (mean +/- SD) to 72.0 +/- 11.7 ng/mL (p = 0.04) after 4 weeks of therapy. Whole body insulin sensitivity index (M/I 3.2 +/- 1.3 vs. 3.4 +/- 2.4; P = 0.82), as well as suppression of EGP (89.7 +/- 26.9 vs. 83.5 +/- 21.6%; p = 0.10) and Ra glycerol (59.4 +/- 22.1% vs. 61.2 +/- 14.4%; p = 0.67) during the clamp were not changed significantly with pegvisomant treatment. Conclusions: Blockade of the GH receptor with pegvisomant for four weeks had no significant effect on insulin/glucose metabolism in a small phase II pilot study of non-diabetic insulin resistant participants without acromegaly. PMID- 28713556 TI - Electrocortical correlations between pairs of isolated people: A reanalysis. AB - A previously reported experiment collected electrocortical data recorded simultaneously in pairs of people separated by distance. Reanalysis of those data confirmed the presence of a time-synchronous, statistically significant correlation in brain electrical activity of these distant "sender-receiver" pairs. Given the sensory shielding employed in the original experiment to avoid mundane explanations for such a correlation, this outcome is suggestive of an anomalous intersubjective connection. PMID- 28713558 TI - The ABCs of finding a good antibody: How to find a good antibody, validate it, and publish meaningful data. AB - Finding an antibody that works for a specific application can be a difficult task. Hundreds of vendors offer millions of antibodies, but the quality of these products and available validation information varies greatly. In addition, several studies have called into question the reliability of published data as the primary metric for assessing antibody quality. We briefly discuss the antibody quality problem and provide best practice guidelines for selecting and validating an antibody, as well as for publishing data generated using antibodies. PMID- 28713559 TI - Draft genome sequencing of the sugarcane hybrid SP80-3280. AB - Sugarcane commercial cultivar SP80-3280 has been used as a model for genomic analyses in Brazil. Here we present a draft genome sequence employing Illumina TruSeq Synthetic Long reads. The dataset is available from NCBI BioProject with accession PRJNA272769. PMID- 28713557 TI - Yin and yang of interleukin-17 in host immunity to infection. AB - The interleukin-17 (IL-17) family cytokines, such as IL-17A and IL-17F, play important protective roles in host immune response to a variety of infections such as bacterial, fungal, parasitic, and viral. The IL-17R signaling and downstream pathways mediate induction of proinflammatory molecules which participate in control of these pathogens. However, the production of IL-17 can also mediate pathology and inflammation associated with infections. In this review, we will discuss the yin-and-yang roles of IL-17 in host immunity to pathogens. PMID- 28713560 TI - Massive open online courses in health sciences from Latin American institutions: A need for improvement? AB - Background: Massive open online courses (MOOCs) have undergone exponential growth over the past few years, offering free and worldwide access to high-quality education. We identified the characteristics of MOOCs in the health sciences offered by Latin American institutions (LAIs). Methods: We screened the eight leading MOOCs platforms to gather their list of offerings. The MOOCs were classified by region and subject. Then, we obtained the following information: Scopus H-index for each institution and course instructor, QS World University Ranking(r) 2015/16 of LAI, and official language of the course. Results: Our search identified 4170 MOOCs worldwide. From them, 205 MOOCs were offered by LAIs, and six MOOCs were health sciences related. Most of these courses (n = 115) were offered through Coursera. One health science MOOC was taught by three instructors, of which only one was registered in Scopus (H-index = 0). The remaining five health science MOOCs had solely one instructor (H-index = 4 [0 17]). The Latin American country with the highest participation was Brazil (n = 11). Conclusion: The contribution of LAI to MOOCs in the health sciences is low. PMID- 28713561 TI - Case Report: Lupoid cutaneous leishmaniasis mimicking verruca plana. AB - Cutaneous leishmaniasis (CL) is an infectious disease caused by various species of leishmania protozoan parasites. Lupoid CL is a rare form of CL that has a stunning similarity to other granulomatous cutaneous conditions of infectious or inflammatory origin. Verruca plana, also known as a "flat wart", is a benign proliferation of the skin resulting from infection with human papilloma virus (HPV). Herein, we presented a case of lupoid CL mimicking verruca plana on the face. PMID- 28713562 TI - Epithelial spindle orientation diversities and uncertainties: recent developments and lingering questions. AB - Mitotic spindle orientation is a conserved, dynamic, and highly complex process that plays a key role in dictating the cleavage plane, fate, and positioning of cells within a tissue, therefore laying the blueprint for tissue structure and function. While the spindle-positioning pathway has been extensively studied in lower-model organisms, research over the past several years has highlighted its relevance to mammalian epithelial tissues. Although we continue to gain critical insights into the mechanisms underlying spindle positioning, many uncertainties persist. In this commentary, we will review the protein interactions that modulate spindle orientation and we will present important recent findings that underscore epithelial tissue-specific requirements and variations in this important pathway, as well as its potential relevance to cancer. PMID- 28713563 TI - Recent advances in the treatment of venous thromboembolism in the era of the direct oral anticoagulants. AB - The direct oral anticoagulants (DOACs) have now supplanted vitamin K antagonists (VKAs) for the treatment of venous thromboembolism (VTE). The DOACs include dabigatran, which inhibits thrombin, and rivaroxaban, apixaban, and edoxaban, which inhibit factor Xa. The DOACs are as effective for the prevention of recurrence as conventional VTE treatment, consisting of a parenteral anticoagulant followed by a VKA, and are associated with less bleeding. Because of these properties and the convenience of fixed dosing without the need for routine coagulation monitoring, guidelines now recommend DOACs over VKAs for VTE treatment in patients without active cancer. This paper examines the increasing role of the DOACs for VTE treatment. PMID- 28713564 TI - Recent advances in methods to assess the activity of the kinome. AB - Protein and lipid kinases are deregulated in most, if not all, cancers and are among the most valuable therapeutic targets in these diseases. Despite the introduction of dozens of effective kinase inhibitors into clinical practice, the development of drug resistance remains a major barrier to treatment because of adaption of cellular signaling pathways to bypass targeted kinases. So that the basal and adaptive responses of kinases in cancer can be better understood, new methods have emerged that allow simultaneous and unbiased measurement of the activation state of a substantial fraction of the entire kinome. Here, we discuss such kinome-profiling methodologies, emphasizing the relative strengths and weaknesses of each approach. PMID- 28713565 TI - Chronic postoperative pain: recent findings in understanding and management. AB - Chronic postoperative pain is a poorly recognized potential outcome from surgery. It affects millions of patients every year, with pain lasting for months to years, resulting in patient suffering and ensuing economic consequences. The operations with the highest incidence of chronic postoperative pain are amputations, thoracotomies, cardiac surgery, and breast surgery. Other risk factors include preoperative pain, psychological factors, demographics, and the intensity of acute postoperative pain. Attempts to prevent chronic postoperative pain have often led to debatable results. This article presents data from recently published studies examining the incidence, risk factors, mechanisms, treatment options, and preventive strategies for chronic postoperative pain in adults. In summary, many of the previously identified risk factors for chronic postoperative pain have been confirmed and some novel ones discovered, such as the importance of the trajectory of acute pain and the fact that catastrophizing may not always be predictive. The incidence of chronic postoperative pain hasn't changed over time, and there is limited new information regarding an effective preventive therapy. For example, pregabalin may actually cause more harm in certain surgeries. Further research is needed to demonstrate whether multimodal analgesic techniques have the best chance of significantly reducing the incidence of chronic postoperative pain and to determine which combination of agents is best for given surgical types and different patient populations. PMID- 28713566 TI - Controlled nanogel and macrogel structures from self-assembly of a stimuli responsive amphiphilic block copolymer. AB - RAFT polymerization was utilized to prepare an amphiphilic block copolymer containing both hydrophilic and hydrophobic segments. The self-assembly behavior of the block copolymer into nano-scale particulate structures was studied in both water and polar organic solvents. Uniform micelle assemblies were stabilized by reaction within the hydrophobic core, which contained pendant azide groups, through copper-catalyzed azide-alkyne cycloaddition (CuAAC) click chemistry with a dialkyne crosslinker. The reaction preceded efficiently with negligible residual azide functionality and resulted in core-shell nanogel structures that were analyzed by a variety of techniques including light scattering, electron microscopy and the ability to take up hydrophobic molecules. Both thermo- and pH responsive character of the nanogels and the linear polymers from which they were made were studied through cloud point testing at different pH levels. It was found that these nanogel dispersions in water exhibited the highest cloud point temperatures indicating a highly stable nanogel structure. The solvent-dispersed nanogels were used as building blocks to form extended polymer networks through the inter- as well as intra-particle reaction between hydroxyl groups within the hydrophilic domain of the nanogel shell by crosslinking with a diisocyanate. It was found that as little as 10 wt% nanogel dispersions in solvent reached the percolation threshold to yield highly porous macroscopic networks; while 50 wt% concentrations achieved densely packed and interdigitated nanogels to afford relatively homogeneous structures. PMID- 28713568 TI - Gauging Change in Australian Aid: Stakeholder Perceptions of the Government Aid Program. AB - In this article, we use data from the 2013 and 2015 Australian Aid Stakeholder Surveys to gauge the extent of the changes to the Australian Government Aid Program since the 2013 federal election. The two surveys targeted the same set of stakeholders of the aid program, and both gathered data on a wide range of aspects of its functioning. As we assess the findings that emerged from the surveys, we situate our work amongst recent academic studies that have looked at the post-2013 aid changes in Australia. Our key findings are that the post-2013 changes to Australian aid have had wide-ranging impacts and have led to deteriorating overall aid quality. However, changes have not affected all aspects of the aid program equally, and some changes are starting to be reversed. In discussion, we examine what these developments mean for the future of Australian aid. PMID- 28713567 TI - Genetically engineered bananas resistant to Xanthomonas wilt disease and nematodes. AB - Banana is an important staple food crop feeding more than 100 million Africans, but is subject to severe productivity constraints due to a range of pests and diseases. Banana Xanthomonas wilt caused by Xanthomonas campestris pv. musacearum is capable of entirely destroying a plantation while nematodes can cause losses up to 50% and increase susceptibility to other pests and diseases. Development of improved varieties of banana is fundamental in order to tackle these challenges. However, the sterile nature of the crop and the lack of resistance in Musa germplasm make improvement by traditional breeding techniques either impossible or extremely slow. Recent developments using genetic engineering have begun to address these problems. Transgenic banana expressing sweet pepper Hrap and Pflp genes have demonstrated complete resistance against X. campestris pv. musacearum in the field. Transgenic plantains expressing a cysteine proteinase inhibitors and/or synthetic peptide showed enhanced resistance to a mixed species population of nematodes in the field. Here, we review the genetic engineering technologies which have potential to improve agriculture and food security in Africa. PMID- 28713569 TI - KCTD12 modulation of GABA(B) receptor function. AB - The molecular composition and functional diversity of native GABAB receptors (GABABR) are still poorly understood, thus hindering development of selective GABABR ligands. Potassium channel tetramerization domain-containing protein (KCTD) 12 is a GABABR auxiliary subunit and mouse KCTD12 can alter GABABR function. In this study, we sought to characterize the effects of human KCTD12 on GABABR kinetics and pharmacology, using an automated electrophysiological assay. Seizure susceptibility and ethanol consumption were also investigated in a KCTD12 knockout mouse model. Human KCTD12 co-expression altered the kinetics of GABABR mediated GIRK channels, speeding rates of both activation and desensitization. Analysis of concentration-response curves showed that KCTD12 coexpression did not alter effects of the agonists GABA or baclofen on GABABR. KCTD12 coexpression enhanced the potentiating effects of the positive allosteric modulator CGP7930, and its effects on GABABR activation and desensitization. The function of KCTD12 in vivo was examined, using the KCTD12 knockout mouse model. The knockout mice were more resistant to a pentylenetetrazole proconvulsant challenge suggesting reduced seizure susceptibility. In the two bottle preference test, KCTD12 knockout mice demonstrated a reduced consumption at high ethanol concentrations. In summary, human KCTD12 accelerated the kinetics of GABABR in vitro, in a manner possibly sensitive to allosteric pharmacological modulation. This study also provides novel in vivo evidence that the interaction between KCTD12 and GABABR is of physiological significance, and may be a mechanism to more selectively modulate GABABR. PMID- 28713570 TI - Reduced first-phase insulin secretion increases postprandial lipidemia in subjects with impaired glucose tolerance. AB - OBJECTIVE: It is not clear which phase of insulin secretion is more important to regulate lipoprotein lipase (LPL) activity. After a meal, insulin is released and acts as a major regulator of LPL activity. Postprandial hyperlipidemia is a common comorbidity in subjects with insulin resistance (IR). Therefore this study aimed to evaluate the role of the first-phase insulin secretion (FPIS) on postprandial lipidemia in subjects with IR and impaired glucose tolerance (IGT). RESEARCH DESIGN AND METHODS: This is a cross-sectional, observational and comparative study. We included male and female subjects between 40 and 60 years with a body mass index (BMI) between 23 and 30 kg/m2. Then, patients were divided into three groups. Group 1 consisted of control subjects with normal glucose tolerance and preserved FPIS. Group 2 included patients with IGT and a reduced FPIS. Group 3 consisted of subjects with IGT but normal FPIS. Both groups were paired by age and BMI with subjects in the control group. Subjects underwent an intravenous glucose tolerance test to classify each case, and then a load with a mixed meal load to measure postprandial lipidemia. RESULTS: A total of 32 subjects were evaluated: 10 were control subjects, 8 subjects with IGT with a reduced FPIS and 14 subjects with IGT and preserved FPIS. After administration of a standardized meal, group 2 showed a greater glucose area under the curve (AUC) at 30 and 120 min (p=0.001, for both). This group also showed a statistically significant increase (p<0.001) in triglyceride AUC. CONCLUSIONS: A reduced FPIS is significantly and independently associated with a larger postprandial hyperlipidemia in subjects with IGT. PMID- 28713571 TI - EYA1 expression and subcellular localization in neuroblastoma and its association with prognostic markers. AB - Neuroblastoma, the most frequently occurring extracranial solid tumor of childhood, arises from neural crest-derived cells that are arrested at an early stage of differentiation in the developing sympathetic nervous system. There is an urgent need to identify clinically relevant biomarkers for better prognosis and treatment of this aggressive malignancy. Eyes Absent 1 (EYA1) is an essential transcriptional coactivator for neuronal developmental programs during organogenesis. Whether or not EYA1 is implicated in neuroblastoma and subcellular localization of EYA1 is relevant to clinical behaviour of neuroblastoma is not known. We studied EYA1 expression and subcellular localization by immunohistochemistry in tissue microarrays containing tumor specimens from 98 patients, 66 of which were characterized by known clinical prognostic markers of neuroblastoma. Immunostaining results were evaluated and statistically correlated with the degree of histologic differentiation and with neuroblastoma risk stratification group characteristics, including stage of disease, patient age, tumor histology and mitosis-karyorrhexis index (MKI), respectively. We found that EYA1 levels were significantly higher in neuroblastomas than in ganglioneuromas and ganglioneuroblastomas. EYA1 was more highly expressed in stage 1,2,3 or 4S tumors as compared to stage 4 tumors (P<0.01). Tumors with high levels of nuclear EYA1 were more frequently associated with high nuclear MYCN levels. These results suggest that modulation of expression and intracellular localization of EYA1 in neural crest cells may provide a novel direction for therapeutic strategies. PMID- 28713572 TI - A transcriptome analysis of two grapevine populations segregating for tendril phyllotaxy. AB - The shoot structure of cultivated grapevine Vitis vinifera L. typically exhibits a three-node modular repetitive pattern, two sequential leaf-opposed tendrils followed by a tendril-free node. In this study, we investigated the molecular basis of this pattern by characterizing differentially expressed genes in 10 bulk samples of young tendril tissue from two grapevine populations showing segregation of mutant or wild-type shoot/tendril phyllotaxy. One population was the selfed progeny and the other one, an outcrossed progeny of a Vitis hybrid, 'Roger's Red'. We analyzed 13 375 expressed genes and carried out in-depth analyses of 324 of them, which were differentially expressed with a minimum of 1.5-fold changes between the mutant and wild-type bulk samples in both selfed and cross populations. A significant portion of these genes were direct cis-binding targets of 14 transcription factor families that were themselves differentially expressed. Network-based dependency analysis further revealed that most of the significantly rewired connections among the 10 most connected hub genes involved at least one transcription factor. TCP3 and MYB12, which were known important for plant-form development, were among these transcription factors. More importantly, TCP3 and MYB12 were found in this study to be involved in regulating the lignin gene PRX52, which is important to plant-form development. A further support evidence for the roles of TCP3-MYB12-PRX52 in contributing to tendril phyllotaxy was the findings of two other lignin-related genes uniquely expressed in the mutant phyllotaxy background. PMID- 28713574 TI - Preliminary study of ectoparasites of horses in the western highlands of Cameroon. AB - To evaluate the prevalence of infestation of ectoparasites of horses, a total of 894 horses (367 males and 527 females), aged 1-7 years old were examined. Horses were groomed for collection of ectoparasites. Out of the horses examined, 164 came from Fundong, 80 from Acha, 30 from Fongo-Tongo, 30 from Fokoue and 17 from Dschang, all of which were infested with ectoparasites. Five hundred and seventy three (573) horses came from Banso and 99.48% were infested by ectoparasites. From the results obtained, three species of hard ticks (Boophilus decoloratus, Amblyomma hebraeum and Hyalomma rufipes) and one species of biting lice (Bovicola equi) were identified. Boophilus decoloratus (66%) had the highest prevalence per locality, followed by A. hebraeum (18%), H. rufipes (11%) and B. equi (5%). Boophilus decoloratus infested horses of all ages, sex or colour. Meanwhile, A. hebraeum and H. rufipes had a higher prevalence in adult male horses. Mono parasitic infestation (69%) was more common than poly-parasitic infestation (31%). Only three horses were free from infestation with ectoparasites. Understanding the biology, epidemiology and economic impact on the equine industry is important for public health and disease prevention programmes. PMID- 28713573 TI - A monograph proposing the use of canine mammary tumours as a model for the study of hereditary breast cancer susceptibility genes in humans. AB - Canines are excellent models for cancer studies due to their similar physiology and genomic sequence to humans, companion status and limited intra-breed heterogeneity. Due to their affliction to mammary cancers, canines can serve as powerful genetic models of hereditary breast cancers. Variants within known human breast cancer susceptibility genes only explain a fraction of familial cases. Thus, further discovery is necessary but such efforts have been thwarted by genetic heterogeneity. Reducing heterogeneity is key, and studying isolated human populations have helped in the endeavour. An alternative is to study dog pedigrees, since artificial selection has resulted in extreme homogeneity. Identifying the genetic predisposition to canine mammary tumours can translate to human discoveries - a strategy currently underutilized. To explore this potential, we reviewed published canine mammary tumour genetic studies and proposed benefits of next generation sequencing canine cohorts to facilitate moving beyond incremental advances. PMID- 28713575 TI - Wildlife hosts for OIE-Listed diseases: considerations regarding global wildlife trade and host-pathogen relationships. AB - The expanding international wildlife trade, combined with a lack of surveillance for key animal diseases in most countries, represents a potential pathway for transboundary disease movement. While the international wildlife trade represents over US $300 billion per year industry involving exchange of billions of individual animals, animal products, and plants as traditional medicines, meat from wild animals, trophies, live exotic pets, commercial products and food, surveillance and reporting of OIE-Listed diseases in wildlife are often opportunistic. We reviewed peer-reviewed literature for reports of 73 OIE-Listed terrestrial animal diseases in wild animals and found 528 possible wild animal hosts using our methodology. Not all host-pathogen relationships indicate that a particular species serves an epidemiologically significant role in the transmission of disease, but improved reporting of infections in wild animals along with clinical and pathological findings would contribute to improved One Health risk assessments. PMID- 28713576 TI - Seroprevalence and risk factor analysis for exposure to equine encephalosis virus in Israel, Palestine and Jordan. AB - Equine encephalosis virus (EEV) is an orbivirus transmitted by Culicoides species. Most infected horses show mild clinical signs and mortality is usually very low. EEV is closely related and similarly transmitted to other, more pathogenic and economically important, orbiviruses such as African horse sickness virus (AHSV), bluetongue virus (BTV) and epizootic haemorrhagic disease viruses (EHDV), and may serve as an indicator for possible transmission of the latter. Israel has been reported to be endemic for EEV since 2001. This study was initiated to re-evaluate the current seroprevalence and risk factors for EEV exposure in Israel, and to assess, for the first time, the seroprevalence of EEV in Palestine and Jordan. Three hundred and sixteen serum samples were collected from apparently healthy horses at 21 farms in Israel, 66 horses at nine farms in Palestine and 100 horses at three farms in Jordan. The presence of EEV antibodies was detected by a serum neutralization assay. Seroprevalence of EEV was 58.2% (184/316 horses) in Israel, 48.5% (32/66 horses) in Palestine and 2% (2/100 horses) in Jordan. Seroprevalence in Jordan was significantly lower than in Israel and Palestine (P < 0.001). The farm (P < 0.001) and horse age (P = 0.003) were found as significant risk factors for EEV exposure in Israel in multivariable statistical analysis. The results of this study further demonstrate that EEV is no longer limited to South Africa and is endemic in both Israel and Palestine and horses in Jordan were also exposed to this virus emphasizing the potential of pathogens to invade new ecological niches. PMID- 28713577 TI - Seroprevalence of spotted fever group (SFG) rickettsiae infection in domestic ruminants in Khartoum State, Sudan. AB - Spotted fever group (SFG) rickettsiosis is caused by obligatory intracellular Gram-negative bacteria that belong to the genus Rickettsia. Ticks belonging to the family Ixodidae can act as vectors, reservoirs or amplifiers of SFG rickettsiae. This study was conducted to estimate the seroprevalence of SFG rickettsioses in cattle, sheep and goats from Khartoum State, Sudan. Blood samples were collected from a total of 600 animals (sheep, goats and cattle) from 32 different farms distributed in three locations in Khartoum State during the period January to December 2012. Sera were tested for antibodies against SFG rickettsiae using IFAT. The prevalence of seropositivity was 59.3% in sheep, 60.1% in goats and 64.4% in cattle. Season was significantly (P < 0.05) associated with seroprevalence of SFG rickettsiae in cattle during winter. The SFG rickettsiae antibodies prevalence was significantly higher in female compared with male in sheep, but there were no significant differences between male and female in either cattle or goats. The prevalence was significantly higher in adult animals compared with young in both sheep and goats. With regard to management system, there was a significant difference in the prevalence in cattle raised in closed system compared with those raised in semi-intensive system. In contrast, there was significant difference in the seroprevalence of SFG in sheep where the prevalence was higher in the sheep raised in semi-intensive system compared with those raised in close system. There was no significant difference in the seroprevalence in goats with regard to management systems. The unexpected high prevalence of SFG rickettsia antibodies in domestic ruminants sera suggest that the veterinary and public health impact of these agents in Sudan need further evaluation especially in humans. PMID- 28713578 TI - Retrospective evaluation of pimobendan and sildenafil therapy for severe pulmonary hypertension due to lung disease and hypoxia in 28 dogs (2007-2013). AB - Pulmonary hypertension (PH) is the persistent abnormal increase in pulmonary artery (PA) pressure and in dogs is usually secondary to congenital disease causing pulmonary over circulation, chronic respiratory disease and elevated left atrial pressure. Sildenafil (SF) is a phosphodiesterase (PDE) V inhibitor that causes pulmonary artery (PA) vasodilation by increasing pulmonary vascular concentrations of cyclic guanosine monophosphate which subsequently increases the activity of endogenous nitric oxide. Pimobendan (PB) is a PDE III inhibitor with calcium sensitizing effects thereby exerting positive inotropy and vasodilation. The purpose of this retrospective study was to evaluate the long-term survival of dogs with severe PH treated with SF and PB compared to SF alone. The use of PB in combination with SF did not result in a statistically significant increase in survival times in dogs with pulmonary hypertension secondary to chronic respiratory disease compared to SF alone. PMID- 28713579 TI - Ring trial 2016 for Bluetongue virus detection by real-time RT-PCR in France. AB - Since the unexpected emergence of BTV-8 in Northern Europe and the incursion of BTV-8 and 1 in France in 2006-2007, molecular diagnosis has considerably evolved. Several real-time RT-PCR (rtRT-PCR) methods have been developed and published, and are currently being used in many countries across Europe for BTV detection and typing. In France, the national reference laboratory (NRL) for orbiviruses develops and validates 'ready-to-use' kits with private companies for viral RNA detection. The regional laboratories network that was set up to deal with a heavy demand for analyses has used these available kits. From 2007, ring tests were organized to monitor the performance of the French laboratories. This study presents the results of 63 regional laboratories in the ring trial organized in 2016. Blood samples were sent to the laboratories. Participants were asked to use the rtRT-PCR methods in place in their laboratory, for detection of all BTV serotypes and specifically BTV-8. The French regional laboratories are able to detect and genotype BTV in affected animals. Despite the use of several methods (i.e. RNA extraction and different commercial rtRT-PCRs), the network is homogeneous. The ring trial demonstrated that the French regional veterinary laboratories have reliable and robust BTV diagnostic tools for BTV genome detection. PMID- 28713580 TI - Severe hypothermia in transported pullets: case study of its occurrence, diagnosis and treatment using active external rewarming technique. AB - Sixty pullets, aged 17 weeks, were presented when presumed to be 'dead' after being exposed to wet-cold weather transportation. The birds appeared unconscious and their feathers were soaking wet, and with a body rigid and cold to touch. The aim of the study was to resuscitate the hypothermic pullets. Blood samples were obtained and core body temperature recorded before and after rewarming. The birds were resuscitated using active external rewarming technique. Blood samples revealed significant (P < 0.05) decreases in the concentrations of serum electrolytes of Na, Cl, K, Ca and P; and renal function and activities of the serum enzymes of AST, ALT, ALP and CRT decreased compared to baseline reference normal values. Colonic temperature, recorded through the cloacae, revealed a temperature of 29 +/- 0.4 degrees C. The presumptive diagnosis was severe hypothermia. Treatment of the pullets using active external rewarming technique for 7 to 10 h resulted in successful restoration of all the behavioural, biochemical and colonic temperature responses to normal values. The treatment resulted in a complete recovery of all the birds with no signs of illness at 4 week follow-up. To the best of our knowledge, this study is one of the first reports to evaluate the behavioural and biochemical responses of pullets accidentally exposed to severe hypothermia, and successful treatment of the birds using active external rewarming technique. PMID- 28713581 TI - Short term elevation in dietary protein intake does not worsen insulin resistance or lipids in older adults with metabolic syndrome: a randomized-controlled trial. AB - BACKGROUND: There is a great deal of controversy as to whether higher protein intake improves or worsens insulin sensitivity in humans. The purpose of the study was to determine the influence of a short-term elevation in dietary protein on hepatic and peripheral insulin sensitivity in twelve older subjects (51-70 yrs) with metabolic syndrome. METHODS: Individuals were randomly assigned to one of the dietary groups: recommended protein intake (RPI, 10% of daily calorie intake) or elevated protein intake (EPI, 20% of daily calorie intake) for 4 weeks. Prior to and immediately following the dietary intervention, subjects were studied with primed continuous infusion of [6,6-2H2]glucose and [1-3C]glucose dissolved in drink during the dual tracer oral glucose tolerance test (DT OGTT) to determine hepatic and peripheral insulin sensitivity. Plasma lipids were measured pre- and post-dietary intervention. RESULTS: In both intervention groups: 1) hepatic insulin sensitivity as assessed by the endogenous glucose rate of appearance (glucose Ra), 2) peripheral insulin sensitivity as assessed by the metabolic clearance rate of glucose normalized to plasma glucose concentration (MCR) and/or the rate of glucose utilization (Rd) or 3) glucose/insulin AUC were unaffected by the diets. Moreover, fasting lipid was not affected by RPI or EPI. CONCLUSION: Our findings suggest that a short-term elevation in EPI with correspondingly higher branched chain amino acid (BCAA) contents has no detrimental impact on hepatic and peripheral insulin sensitivity or plasma lipid parameters in older adults with metabolic syndrome. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02885935; This trial was registered retrospectively (Study start date, April 01, 2013, date of registration, August 26, 2016). PMID- 28713582 TI - Distance learning strategies for weight management utilizing online social networks versus group phone conference call. AB - OBJECTIVE: The increase in technology and online social networks (OSNs) may present healthcare providers with an innovative modality for delivering weight management programmes that could have an impact on health care at the population level. The objective of this study was to evaluate the feasibility and efficacy of using an OSN to deliver a weight loss programme to inform future, large-scale trials. METHODS: Seventy individuals (age = 47 +/- 12.4, minority = 24.3%) with obesity (BMI = 36.2 +/- 4.0) completed a 6-month weight loss intervention and were randomized to either a conference call or OSN delivery group. Weight loss was achieved by reducing energy intake by 500-700 kcal.d-1 below estimated total daily energy expenditure and progressing physical activity to 300 min/week. Behavioural weight loss strategies were delivered weekly throughout the intervention. RESULTS: Conference call and OSN groups produced clinically meaningful weight loss of >=5% from baseline to 6 months (phone = -6.3 +/- 6.4%, OSN = -5.8 +/- 6.7%). There was no significant difference in weight change between groups (p = 0.765). CONCLUSION: The phone and OSN groups met the American Heart Association/American College of Cardiology/The Obesity Society's Guidelines by reducing baseline weight by 5-10% within 6 months. OSNs appear to be a viable delivery platform for weight loss interventions; however, larger scale adequately powered trials are needed. PMID- 28713583 TI - Effects of supervised and unsupervised physical activity programmes for weight loss. AB - OBJECTIVES: Physical activity is important for weight management. However, it remains unclear what type of physical activity prescription/programme is optimal for increasing physical activity during a standard behavioural weight loss intervention. This study examined changes in physical activity after a 12-week supervised programme prescribed in minutes per week (SUP-PA), an unsupervised programme prescribed in minutes per week (UNSUP-PA) and an unsupervised programme prescribed in steps per day (STEP). METHODS: Fifty-two adults who were overweight or obese (age: 43.5 +/- 10.1 years, BMI: 31.5 +/- 3.5 kg.m-2) were randomized to STEP (n = 18), UNSUP-PA (n = 17) and SUP-PA (n = 17). Subjects attended weekly in person group intervention sessions and were prescribed a calorie-restricted diet (1,200-1,800 kcals.day-1) combined with increased physical activity (150 min.week 1 or 10,000 steps.day-1 with 2,500 brisk steps.day-1). RESULTS: All three groups significantly increased moderate-to-vigorous physical activity (STEP: 80.6 +/- 218.5 min.week-1, UNSUP-PA: 112.9 +/- 180.4 min.week-1 and SUP-PA: 151.1 +/- 174.0 min.week-1, p < 0.001) with no differences between groups (p = 0.94) or group by time interaction (p = 0.81). In addition, there were no significant differences in weight loss between the groups (p = 0.81). CONCLUSIONS: In this short-term study, all three physical activity programmes increased physical activity and elicited modest weight loss when combined with a standard behavioural weight loss intervention. PMID- 28713584 TI - Fitness adjusted racial disparities in central adiposity among women in the USA using quantile regression. AB - OBJECTIVE: This study comprehensively explores racial/ethnic disparities in waist circumference (WC) after adjusting for cardiorespiratory fitness (CRF), among both adult and adolescent women, across WC percentiles. METHODS: Analysis was conducted using data from the 1999 to 2004 National Health and Nutrition Examination Survey. Female participants (n = 3,977) aged 12-49 years with complete data on CRF, height, weight and WC were included. Quantile regression models, stratified by age groups (12-15, 16-19 and 20-49 years), were used to assess the association between WC and race/ethnicity adjusting for CRF, height and age across WC percentiles (10th, 25th, 50th, 75th, 90th and 95th). RESULTS: For non-Hispanic (NH) Black, in both the 16-19 and 20-49 years age groups, estimated WC was significantly greater than for NH White across percentiles above the median with estimates ranging from 5.2 to 11.5 cm. For Mexican Americans, in all age groups, estimated WC tended to be significantly greater than for NH White particularly for middle percentiles (50th and 75th) with point estimates ranging from 1.9 to 8.4 cm. CONCLUSIONS: Significant disparities in WC between NH Black and Mexican women, as compared to NH White, remain even after adjustment for CRF. The magnitude of the disparities associated with race/ethnicity differs across WC percentiles and age groups. PMID- 28713585 TI - Associations of centrally acting ACE inhibitors with cognitive decline and survival in Alzheimer's disease. AB - BACKGROUND: Cognitive improvement has been reported in patients receiving centrally acting angiotensin-converting enzyme inhibitors (C-ACEIs). AIMS: To compare cognitive decline and survival after diagnosis of Alzheimer's disease between people receiving C-ACEIs, non-centrally acting angiotensin-converting enzyme inhibitors (NC-ACEIs), and neither. METHOD: Routine Mini-Mental State Examination (MMSE) scores were extracted in 5260 patients receiving acetylcholinesterase inhibitors and analysed against C-/NC-ACEI exposure at the time of Alzheimer's disease diagnosis. RESULTS: In the 9 months after Alzheimer's disease diagnosis, MMSE scores significantly increased by 0.72 and 0.19 points per year in patients on C-ACEIs and neither respectively, but deteriorated by 0.61 points per year in those on NC-ACEIs. There were no significant group differences in score trajectories from 9 to 36 months and no differences in survival. CONCLUSIONS: In people with Alzheimer's disease receiving acetylcholinesterase inhibitors, those also taking C-ACEIs had stronger initial improvement in cognitive function, but there was no evidence of longer-lasting influence on dementia progression. DECLARATION OF INTEREST: R.S. has received research funding from Pfizer, Lundbeck, Roche, Janssen and GlaxoSmithKline. COPYRIGHT AND USAGE: (c) The Royal College of Psychiatrists 2017. This is an open access article distributed under the terms of the Creative Commons Non Commercial, No Derivatives (CC BY-NC-ND) license. PMID- 28713586 TI - Formal thought disorder in people at ultra-high risk of psychosis. AB - BACKGROUND: Formal thought disorder is a cardinal feature of psychosis. However, the extent to which formal thought disorder is evident in ultra-high-risk individuals and whether it is linked to the progression to psychosis remains unclear. AIMS: Examine the severity of formal thought disorder in ultra-high-risk participants and its association with future psychosis. METHOD: The Thought and Language Index (TLI) was used to assess 24 ultra-high-risk participants, 16 people with first-episode psychosis and 13 healthy controls. Ultra-high-risk individuals were followed up for a mean duration of 7 years (s.d.=1.5) to determine the relationship between formal thought disorder at baseline and transition to psychosis. RESULTS: TLI scores were significantly greater in the ultra-high-risk group compared with the healthy control group (effect size (ES)=1.2), but lower than in people with first-episode psychosis (ES=0.8). Total and negative TLI scores were higher in ultra-high-risk individuals who developed psychosis, but this was not significant. Combining negative TLI scores with attenuated psychotic symptoms and basic symptoms predicted transition to psychosis (P=0.04; ES=1.04). CONCLUSIONS: TLI is beneficial in evaluating formal thought disorder in ultra-high-risk participants, and complements existing instruments for the evaluation of psychopathology in this group. DECLARATION OF INTERESTS: None. COPYRIGHT AND USAGE: (c) The Royal College of Psychiatrists 2017. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) license. PMID- 28713587 TI - Predictive model of thrombospondin-1 and vascular endothelial growth factor in breast tumor tissue. AB - Angiogenesis, the formation of new blood capillaries from pre-existing vessels, is a hallmark of cancer. Thus far, strategies for reducing tumor angiogenesis have focused on inhibiting pro-angiogenic factors, while less is known about the therapeutic effects of mimicking the actions of angiogenesis inhibitors. Thrombospondin-1 (TSP1) is an important endogenous inhibitor of angiogenesis that has been investigated as an anti-angiogenic agent. TSP1 impedes the growth of new blood vessels in many ways, including crosstalk with pro-angiogenic factors. Due to the complexity of TSP1 signaling, a predictive systems biology model would provide quantitative understanding of the angiogenic balance in tumor tissue. Therefore, we have developed a molecular-detailed, mechanistic model of TSP1 and vascular endothelial growth factor (VEGF), a promoter of angiogenesis, in breast tumor tissue. The model predicts the distribution of the angiogenic factors in tumor tissue, revealing that TSP1 is primarily in an inactive, cleaved form due to the action of proteases, rather than bound to its cellular receptors or to VEGF. The model also predicts the effects of enhancing TSP1's interactions with its receptors and with VEGF. To provide additional predictions that can guide the development of new anti-angiogenic drugs, we simulate administration of exogenous TSP1 mimetics that bind specific targets. The model predicts that the CD47 binding TSP1 mimetic dramatically decreases the ratio of receptor-bound VEGF to receptor-bound TSP1, in favor of anti-angiogenesis. Thus, we have established a model that provides a quantitative framework to study the response to TSP1 mimetics. PMID- 28713588 TI - Genomic landscape of high-grade meningiomas. AB - High-grade meningiomas frequently recur and are associated with high rates of morbidity and mortality. To determine the factors that promote the development and evolution of these tumors, we analyzed the genomes of 134 high-grade meningiomas and compared this information with data from 587 previously published meningiomas. High-grade meningiomas had a higher mutation burden than low-grade meningiomas but did not harbor any statistically significant mutated genes aside from NF2. High-grade meningiomas also possessed significantly elevated rates of chromosomal gains and losses, especially among tumors with monosomy 22. Meningiomas previously treated with adjuvant radiation had significantly more copy number alterations than radiation-induced or radiation-naive meningiomas. Across serial recurrences, genomic disruption preceded the emergence of nearly all mutations, remained largely uniform across time, and when present in low grade meningiomas, correlated with subsequent progression to a higher grade. In contrast to the largely stable copy number alterations, mutations were strikingly heterogeneous across tumor recurrences, likely due to extensive geographic heterogeneity in the primary tumor. While high-grade meningiomas harbored significantly fewer overtly targetable alterations than low-grade meningiomas, they contained numerous mutations that are predicted to be neoantigens, suggesting that immunologic targeting may be of therapeutic value. PMID- 28713589 TI - Super-resolution imaging in a multiple layer EPID. AB - A new portal imager consisting of four vertically stacked conventional electronic portal imaging device (EPID) layers has been constructed in pursuit of improved detective quantum efficiency (DQE). We hypothesize that super-resolution (SR) imaging can also be achieved in such a system by shifting each layer laterally by half a pixel relative to the layer above. Super-resolution imaging will improve resolution and contrast-to-noise ratio (CNR) in megavoltage (MV) planar and cone beam computed tomography (MV-CBCT) applications. Simulations are carried out to test this hypothesis with digital phantoms. To assess planar resolution, 2 mm long iron rods with 0.3 * 0.3 mm2 square cross-section are arranged in a grid pattern at the center of a 1 cm thick solid water. For measuring CNR in MV-CBCT, a 20 cm diameter digital phantom with 8 inserts of different electron densities is used. For measuring resolution in MV-CBCT, a digital phantom featuring a bar pattern similar to the GammexTM phantom is used. A 6 MV beam is attenuated through each phantom and detected by each of the four detector layers. Fill factor of the detector is explicitly considered. Projections are blurred with an estimated point spread function (PSF) before super-resolution reconstruction. When projections from multiple shifted layers are used in SR reconstruction, even a simple shift-add fusion can significantly improve the resolution in reconstructed images. In the reconstructed planar image, the grid pattern becomes visually clearer. In MV-CBCT, combining projections from multiple layers results in increased CNR and resolution. The inclusion of two, three and four layers increases CNR by 40%, 70% and 99%, respectively. Shifting adjacent layers by half a pixel almost doubles resolution. In comparison, using four perfectly aligned layers does not improve resolution relative to a single layer. PMID- 28713590 TI - Effect of Preoperative Intravitreal Bevacizumab on the Surgical Outcome of Neovascular Glaucoma at Different Stages. AB - PURPOSE: To evaluate the effect of preoperative intravitreal bevacizumab (IVB) injection on the surgical outcome of Ahmed glaucoma valve (AGV) implantation according to the angle status in neovascular glaucoma (NVG) eyes. MATERIALS AND METHODS: This retrospective study included 70 NVG patients who underwent AGV implantation and were followed up for at least 12 months. An IVB injection before AGV implantation was administered to 45 eyes (IVB group), while it was not administered to 25 eyes (control group). Subgroup analyses were done at different stages in terms of the extent of peripheral anterior synechiae (PAS). RESULTS: Mean follow-up period after AGV implantation was 27 +/- 15 months. The IVB group showed higher prevalence of the eyes with less than 50% of PAS than that of the control group (78% versus 44%). The overall success rate 1 year postoperatively was 80% and 64% for the IVB and control groups, respectively (P = 0.142). When PAS extent was less than 50%, preoperative IVB had a marginally positive effect on surgical outcome (HR = 0.39, P = 0.064, per 1-time IVB injection). CONCLUSIONS: Preoperative IVB may enhance the success rate of AGV implantation in NVG eyes, before PAS has extensively formed. Further prospective randomized studies controlling the extent of PAS are warranted. PMID- 28713591 TI - The Effect of Partnership Care Model on Mental Health of Patients with Thalassemia Major. AB - BACKGROUND: Thalassemia major has become a public health problem worldwide, particularly in developing and poor countries, while the role of educating the family and community has not been considered enough in patients' care. OBJECTIVES: This study examines the impact of partnership care model on mental health of patients with beta-thalassemia major. MATERIALS AND METHODS: This experimental study, with pretest and posttest design, was performed on patients with beta-thalassemia major in Jiroft city. 82 patients with beta-thalassemia major were allocated randomly into two groups of intervention (41 patients) and control (n = 41) groups. Mental health of the participants was measured using the standard questionnaire GHQ-28 before and after intervention in both groups. The intervention was applied to the intervention group for 6 months, based on the partnership care model. RESULTS: There were significant differences between the scores of mental health and its subscales between two groups after the intervention (P < 0.05). CONCLUSIONS: The findings of the study revealed the efficacy and usefulness of partnership care model on mental health of patients with beta-thalassemia major; thus, implementation of this model is suggested for the improvement of mental health of patients with beta-thalassemia major. PMID- 28713592 TI - Clinicodemographic Profile of Children with Seizures in a Tertiary Care Hospital: A Cross-Sectional Observational Study. AB - Seizures are one of the common causes for hospital admissions in children with significant mortality and morbidity. This study was conducted to study the prevalence and clinicodemographic profile of children with seizures in a tertiary care hospital of western Nepal. This prospective cross-sectional study conducted over a period of 2 years included all admitted children (2 months-16 years) with seizures. Among 4962 admitted children, seizures were present in 3.4% (n = 168) of children, with male preponderance. 138 (82.1%) children had generalized tonic clonic seizures (GTCS) and 30 (17.9%) children had partial seizures. GTCS were more common than partial seizures in both sexes (male = 82.7%; female = 81.2%) and age groups. There was no statistical significance in the distribution of seizures (GTCS and partial seizures) with sexes (P = 0.813) and age groups (P = 0.955). Mean ages of children having GTCS and partial seizures were 8.2 +/- 4.6 years and 8.2 +/- 4.2 years, respectively. Loss of consciousness (55.4%), fever (39.9%), vomiting (35.1%), and headache (16.1%) were common complaints in seizure patients. Significant number of GTCS cases had fever (P = 0.041) and neurocysticercosis (n = 72; 43%) was the most common etiology in seizure patients. Idiopathic epilepsy (38 (22.6%)), meningoencephalitis (26 (15.5%)), and febrile convulsions (14 (8.33%)) were other leading disorders in children with seizures. PMID- 28713593 TI - Synthesis and Evaluation of In Vitro Antibacterial and Antitumor Activities of Novel N,N-Disubstituted Schiff Bases. AB - To get inside the properties of N,N-disubstituted Schiff bases, we synthesized three high-yielding benzaldehyde Schiff bases. We used the reaction between salicylaldehyde and different diamine compounds, including diamine, ethanediamine, and o-phenylenediamine, determining the structure of obtained molecules by nuclear magnetic resonance spectroscopy and electrospray ionization mass spectroscopy. We thus evaluated the microbicidal and antitumor activity of these compounds, showing that salicylaldehyde-hydrazine hydrate Schiff base (compound 1a) significantly inhibited the growth of S. aureus; salicylaldehyde-o phenylenediamine Schiff base (compound 1c) displayed a strong capability to inhibit the proliferation of leukemia cell lines K562 and HEL. Moreover, we observed that the antibacterial action of 1a might be associated with the regulation of the expression of key virulence genes in S. aureus. Compound 1c resulted in a strong apoptotic activity against leukemia cells, also affecting the cell cycle distribution. Overall, our novel N,N-disubstituted Schiff bases possess unique antibacterial or antitumor activities that exhibit the potent application prospect in prophylactic or therapeutic interventions, providing new insights for developing new antibacterial and anticancer chemical agents. PMID- 28713595 TI - Fatty Acid Profiles of Stipe and Blade from the Norwegian Brown Macroalgae Laminaria hyperborea with Special Reference to Acyl Glycerides, Polar Lipids, and Free Fatty Acids. AB - A thorough analysis of the fatty acid profiles of stipe and blade from the kelp species Laminaria hyperborea is presented. Lipid extracts were fractionated into neutral lipids, free fatty acids, and polar lipids, prior to derivatization and GC-MS analysis. A total of 42 fatty acids were identified and quantified, including the n-3 fatty acids alpha-linolenic acid, stearidonic acid, and eicosapentaenoic acid. The fatty acid amounts are higher in blade than in stipe (7.42 mg/g dry weight and 2.57 mg/g dry weight, resp.). The highest amounts of n 3 fatty acids are found within the neutral lipid fractions with 590.6 ug/g dry weight and 100.9 ug/g dry weight for blade and stipe, respectively. The amounts of polyunsaturated fatty acids are 3.4 times higher in blade than stipe. The blade had the highest PUFA/SFA ratio compared to stipe (1.02 versus 0.76) and the lowest n-6/n-3 ratio (0.8 versus 3.5). This study highlights the compositional differences between the lipid fractions of stipe and blade from L. hyperborea. The amount of polyunsaturated fatty acids compared to saturated- and monounsaturated fatty acids is known to influence human health. In the pharmaceutical, food, and feed industries, this can be of importance for production of different health products. PMID- 28713596 TI - Discharge against Medical Advice in Surgical Patients with Posttraumatic Stress Disorder: A Case Report Series Illustrating Unique Challenges. AB - Discharge against medical advice (DAMA) can have detrimental effects on patient outcomes. Recently, the diagnosis of posttraumatic stress disorder (PTSD) has been linked with DAMA in the mental health setting. However, PTSD as a risk factor for DAMA in surgical patients has not received much consideration, although such patients may be at risk for triggering or amplification of PTSD symptoms perioperatively. We present the first case report series of three surgical patients with PTSD who left the hospital AMA. These cases differ markedly from DAMA in non-PTSD patients. In all three subjects, the stress of feeling misunderstood by clinicians and the distress of public detainment by hospital security in the setting of chronic PTSD led to aggressive and risky behavior. All three subjects represented a risk to themselves and to others at the time of DAMA. Finally, all three subjects were difficult to contact for follow-up or medical care and missed appointments. PMID- 28713594 TI - Small Molecule, Big Prospects: MicroRNA in Pregnancy and Its Complications. AB - MicroRNAs are small, noncoding RNA molecules that regulate target gene expression in the posttranscriptional level. Unlike siRNA, microRNAs are "fine-tuners" rather than "switches" in the regulation of gene expression; thus they play key roles in maintaining tissue homeostasis. The aberrant microRNA expression is implicated in the disease process. To date, numerous studies have demonstrated the regulatory roles of microRNAs in various pathophysiological conditions. In contrast, the study of microRNA in pregnancy and its associated complications, such as preeclampsia (PE), fetal growth restriction (FGR), and preterm labor, is a young field. Over the last decade, the knowledge of pregnancy-related microRNAs has increased and the molecular mechanisms by which microRNAs regulate pregnancy or its associated complications are emerging. In this review, we focus on the recent advances in the research of pregnancy-related microRNAs, especially their function in pregnancy-associated complications and the potential clinical applications. Here microRNAs that associate with pregnancy are classified as placenta-specific, placenta-associated, placenta-derived circulating, and uterine microRNA according to their localization and origin. MicroRNAs offer a great potential for developing diagnostic and therapeutic targets in pregnancy-related disorders. PMID- 28713597 TI - Ketamine Use for Successful Resolution of Post-ERCP Acute Pancreatitis Abdominal Pain. AB - We report a case in which a patient with intractable pain secondary to post endoscopic retrograde cholangiopancreatography (ERCP) acute pancreatitis is successfully treated with a subanesthetic ketamine infusion. Shortly after ERCP, the patient reported severe stabbing epigastric pain. She exhibited voluntary guarding and tenderness without distension. Amylase and lipase levels were elevated. Pain persisted for hours despite hydromorphone PCA, hydromorphone boluses, fentanyl boluses, and postprocedure anxiolytics. Pain management was consulted and a ketamine infusion was trialed, leading to a dramatic reduction in pain. This case suggests that ketamine may be a promising option in treating intractable pain associated with ERCP acute pancreatitis. PMID- 28713598 TI - Development of New Deep Venous Thrombosis While on Apixaban. AB - The efficacy of novel oral anticoagulants (NOACs) in preventing deep venous thrombosis (DVT) has been established in large multicenter trials. Predictable pharmacokinetics, avoidance of routine laboratory monitoring, and lesser drug interactions have made NOACs safer and more tolerable treatment option in comparison to warfarin. However, cases of treatment failure mainly due to interindividual variation in plasma drug levels can be seen rarely. In this report we describe a case of acute DVT of right lower extremity in a patient who was on apixaban for prevention of venous thromboembolism (VTE) due to underlying nonvalvular atrial fibrillation (NVAF). PMID- 28713599 TI - Lyme Carditis Buried Beneath ST-Segment Elevations. AB - Lyme disease is caused by the spirochete Borrelia burgdorferi and is carried to human hosts by infected ticks. There are nearly 30,000 cases of Lyme disease reported to the CDC each year, with 3-4% of those cases reporting Lyme carditis. The most common manifestation of Lyme carditis is partial heart block following bacterial-induced inflammation of the conducting nodes. Here we report a 45-year old gentleman that presented to the hospital with intense nonradiating chest pressure and tightness. Lab studies were remarkable for elevated troponins. EKG demonstrated normal sinus rhythm with mild ST elevations. Three weeks prior to hospital presentation, patient had gone hunting near Madison. One week prior to admission, he noticed an erythematous lesion on his right shoulder. Because of his constellation of history, arthralgias, and carditis, he was started on ceftriaxone to treat probable Lyme disease. This case illustrates the importance of thorough history taking and extensive physical examination when assessing a case of possible acute myocardial infarction. Because Lyme carditis is reversible, recognition of this syndrome in young patients, whether in the form of AV block, myocarditis, or acute myocardial ischemia, is critical to the initiation of appropriate antibiotics in order to prevent permanent heart block, or even death. PMID- 28713600 TI - Periodontics, Implantology, and Prosthodontics Integrated: The Zenith-Driven Rehabilitation. AB - A customized treatment plan is important to reach results that will satisfy the patient providing esthetics, function, and long-term stability. This type of oral rehabilitation requires professionals from different dental specialties where communication is a major key point. Digital Smile Design allows the practitioners to plan and discuss the patient's condition to establish the proper treatment plan, which must be driven by the desired zenith position. The ideal gingival position will guide the professionals and determine the need to perform surgical procedures or orthodontic movement before placing the final restorations. In this article, the zenith-driven concept is discussed and a challenging case is presented with 4-year follow-up where tooth extraction, immediate implant placement, bone regeneration, and a connective tissue graft were performed. PMID- 28713601 TI - Resin Nanoceramic CAD/CAM Restoration of the Primary Molar: 3-Year Follow-Up Study. AB - This case report presents the clinical use of a resin nanoceramic CAD/CAM restoration of a primary second molar without successor in the form of a permanent second premolar tooth in a patient. Three-year follow-up of the case revealed that resin nanoceramic CAD/CAM restoration of the primary molar without successor achieved both aesthetics and function. Despite the high cost of treatment, this type of restoration should be considered if the retained tooth is expected to maintain functionality over the long term. PMID- 28713602 TI - Treatment of Nonclassic 11-Hydroxylase Deficiency with Ashwagandha Root. AB - An elderly woman presented with acne and male pattern alopecia, which upon diagnostic evaluation was found to be due to nonclassic 11-hydroxylase deficiency. We previously reported that Ashwagandha root ameliorates nonclassic 3 beta-ol dehydrogenase and aldosterone synthase deficiencies. This is the first report of its use being associated with amelioration of nonclassic 11-hydroxylase deficiency, where its apparent effects appear to be dose-related. PMID- 28713603 TI - Adrenal Ganglioneuroblastoma in Adults: A Case Report and Review of the Literature. AB - Incidentally discovered adrenal masses are very common given the increased number of imaging studies performed in recent years. We here report a clinical case of a 20-year-old woman who presented with left flank pain. Ultrasound examination revealed a contralateral adrenal mass, which was confirmed at computed tomography (CT) scan. Hormonal hypersecretion was excluded. Given the size (11 * 10 * 7 cm) and the uncertain nature of the mass, it was surgically removed and sent for pathological analyses. Conclusive diagnosis was ganglioneuroblastoma. Ganglioneuroblastoma is an uncommon malignant tumor, extremely rare in adults, particularly in females. This neoplasm is frequently localized in adrenal gland. PMID- 28713604 TI - Metastatic Renal Cell Carcinoma Presenting as Gastric Ulcer: Case Report and Literature Review. AB - Renal cell carcinoma (RCC) accounts for approximately 3% of all adult malignancies. True gastrointestinal metastases, specifically to gastric wall, have been rarely observed. Herein we describe a case of delayed metastasis to gastric wall occurring more than a decade after previously curative nephrectomy for RCC. A 67-year-old male with history of right radical nephrectomy in 2001 for RCC was found to have an asymptomatic right lower lobe solitary lung mass upon routine follow-up in 2011, with final biopsy results showing metastatic RCC for which he was treated accordingly. In 2014, patient was evaluated for dyspepsia with microcytic anemia and underwent an esophagogastroduodenoscopy and colonoscopy. EGD revealed a solitary one-centimeter atypical ulcer in the posterior mid gastric body with biopsy results being consistent with metastatic RCC. Our literature review has yielded thirty-six reported cases of RCC in association with gastric wall metastases. PMID- 28713605 TI - Diarrhea as a Presenting Symptom of Disseminated Toxoplasmosis. AB - Disseminated toxoplasmosis is uncommon in both immunocompetent and immunocompromised hosts with gastrointestinal involvement being rarely described. We report a case of disseminated gastrointestinal toxoplasmosis in an immunocompromised man who presented with one month of diarrhea and abdominal pain. Imaging showed thickening of the ascending colon and cecum. Esophagogastroduodenoscopy and colonoscopy biopsies revealed Toxoplasma gondii, confirmed by immunostain. Symptoms completely resolved following treatment with pyrimethamine, sulfadiazine, and leucovorin. This case highlights the importance of including toxoplasmosis in the differential diagnosis of any immunocompromised individual presenting with gastrointestinal symptoms. PMID- 28713606 TI - Autologous Concentrated Bone Marrow Grafting for the Treatment of Osteonecrosis of the Humeral Head: A Report of Five Shoulders in Four Cases. AB - Five shoulders in four patients affected by advanced osteonecrosis of the humeral head were treated with autologous concentrated bone marrow grafting. Bone marrow sample was aspirated from the iliac crests, concentrated by a centrifugation technique, and injected into the necrotic site. The shoulders were evaluated radiologically with X-ray scoring and clinically with measurement of range of motion and pain score (visual analogue scale, VAS). The mean follow-up period was 49.4 (range, 24-73) months. The concentration ratio of nucleated cells was calculated and the number of transplanted mesenchymal stem cells (MSC) was estimated by a colony-forming assay. All four shoulders with stage 3 disease achieved joint sparing. One shoulder with stage 4 disease required replacement surgery. Clinical evaluation of the spared joints showed improvement in range of motion in two cases and deterioration in two cases. VAS scores were 0 after surgery in three cases. The mean concentration ratio was 2.73, and the mean number of transplanted MSC was 1125. The outcomes of autologous concentrated bone marrow grafting for advanced osteonecrosis of the humeral head were varied. Further research is needed to determine the effectiveness and the indications of the present surgery. PMID- 28713607 TI - Primary Osteosarcoma of the Breast Arising in an Intraductal Papilloma. AB - INTRODUCTION: Primary osteosarcoma of the breast is extremely rare, and an osteosarcoma arising from an intraductal papilloma is exceptional. CASE PRESENTATION: A 72-year-old Saudi Arabian woman presented with a solid, bone containing breast mass that was diagnosed as primary osteosarcoma of the breast on biopsy. She had a history of untreated intraductal papilloma. Treatment was completed with a modified mastectomy after excluding extramammary metastases. However, she subsequently developed multiple recurrent lesions at the same site. CONCLUSION: Primary osteogenic sarcomas of the breast are very rare. Although the main treatment is resection the optimal management remains uncertain and prognosis is poor. PMID- 28713608 TI - Posttraumatic Progressive Vertebral Hemangioma Induced by a Fracture. AB - The authors present an extremely rare case of an aggressive and progressive vertebral capillary hemangioma of the lumbar spine secondary to a trauma. A 40 year-old man who complained of back and leg pain due to a hemangioma of L1 that had begun a year after the fracture of the same vertebra was subsequently operated on. Due to the profuse bleeding, only a subtotal removal was possible. Histopathological diagnosis of the lesion revealed a capillary hemangioma. Postoperative control MRI taken at eight months showed that the lesion and destruction of the L1 vertebra were progressive. A second embolization procedure was performed and this time the hemangioma was totally removed via an anterior approach and corpectomy. Fusion was achieved by Th12-L2 graft and plaque. In the fourteenth year of follow-up, he was symptom-free and radiologically clear of this lesion. We propose that progressive hemangioma is extremely rare and that its cure is possible by total surgical removal of the lesion. This case is the second extradural capillary hemangioma secondary to spinal trauma ever to have been documented in English literature. The emergence of a hemangioma in a fractured vertebra suggests that its pathogenesis can be related to the deviation of the angiogenetic pathways from the normal healing process. PMID- 28713610 TI - Study of sexual dimorphism of Malaysian crania: an important step in identification of the skeletal remains. AB - Sex determination is one of the main steps in the identification of human skeletal remains. It constitutes an initial step in personal identification from the skeletal remains. The aim of the present study was to provide the population specific sex discriminating osteometric standards to aid human identification. The present study was conducted on 87 (174 sides) slices of crania using postmortem computed tomography in 45 males and 42 females, aged between 18 and 75 years. About 22 parameters of crania were measured using Osirix software 3-D Volume Rendering. Results showed that all parameters were significantly higher in males than in females except for orbital height of the left eye by independent t test (P<0.01). By discriminant analysis, the classification accuracy was 85.1%, and by regression, the classification accuracy ranged from 78.2% to 86.2%. In conclusion, cranium can be used to distinguish between males and females in the Malaysian population. The results of the present study can be used as a forensic tool for identification of unknown crania. PMID- 28713609 TI - The molecular mechanism for nuclear transport and its application. AB - Transportation between the cytoplasm and the nucleoplasm is critical for many physiological and pathophysiological processes including gene expression, signal transduction, and oncogenesis. So, the molecular mechanism for the transportation needs to be studied not only to understand cell physiological processes but also to develop new diagnostic and therapeutic targets. Recent progress in the research of the nuclear transportation (import and export) via nuclear pore complex and four important factors affecting nuclear transport (nucleoporins, Ran, karyopherins, and nuclear localization signals/nuclear export signals) will be discussed. Moreover, the clinical significance of nuclear transport and its application will be reviewed. This review will provide some critical insight for the molecular design of therapeutics which need to be targeted inside the nucleus. PMID- 28713611 TI - Vascular foramina of navicular bone: a morphometric study. AB - The navicular bone is supplied by more than one artery. The knowledge about the vascular foramina is important to understand the pathogenesis and management of navicular fractures. The objective of the present study is to analyze the morphology and morphometry of vascular foramina of dried human navicular bone in Indian population. The study was carried out by using 100 navicular bones (50 right and 50 left) collected from our institute and other medical institutes in and around Puducherry. The bones were macroscopically studied for vascular foramina with respect to its location, number, size, and shape. The data collected were statistically analyzed. The vascular foramina were present on dorsal, plantar, medial, and lateral surfaces of navicular bone. Kruskal-Wallis test followed by series of Mann-Whitney test for post hoc analysis showed the number of nutrient foramina observed on dorsal surface were significantly greater than those observed on the plantar (U=2,755, P=0.001), medial (U=43, P=0.001), and lateral (U=626.5, P=0.001) surfaces of the navicle. About 97.6% of foramina were circular and 2.5% were oval in appearance. About 96.7% of vascular foramina were <1 mm in size and 3.3% were >=1 mm in size. Spearman's rank correlation coefficient done showed a strong, positive correlation between vascular foramina of <1 mm size and circular shape, which was statistically significant (rs =0.981, P=0.001). We believe the present study has provided additional information on the vascular foramina of navicular bone and useful to surgeons in foot surgeries. PMID- 28713613 TI - The use of human mature cystic ovarian teratoma as a model to study the development of human lymphatics. AB - The angiogenic theory to the development of human lymphatics is not clear. The objective of this study was to investigate the development of human lymphatics. Semi-thin and thin paraffin sections from human mature cystic ovarian teratoma tissues were studied using light and electron microscopy. Lymphatics were formed by the differentiation of mesenchymal cells that gradually acquired morphological features of endothelial cells. It is suggested that in human mature cystic ovarian teratoma the lymphatic endothelium develops from mesenchymal cells, and not from cells derived from mature endothelium of a preexisting vein or lymphatic. PMID- 28713612 TI - In vivo magnetic resonance imaging morphometry of the patella bone in South Indian population. AB - Racial differences exist in the dimensions of structures and the commercially available prostheses are designed based on the Caucasians. In this context, the goal of the present investigation was to determine the gender wise measurements of patella bone in South Indians. The present study included axial magnetic resonance images of the knee joint from 140 South Indian adults (70 males, 70 females; aged between 20-70 years). The angle, width, thickness, lateral facet width, facet thickness, ratio of the lateral facet, the relative thickness and ratio of facet thickness were measured in the patella by using the digital ruler. The statistical analysis was performed by using the SPSS software. The dimensions exhibited statistically highly significant sexual dimorphism (P<=0.001). The mean value was higher in males than females except for the ratio of patellar lateral facet and patellar facet thickness ratio. It was observed that the males exhibit more variability than females in all the measurements of patella except patellar thickness, patellar facet thickness, patellar relative thickness, and patellar facet thickness ratio. The present study of the in vivo morphometry of patella bone from the South Indians can provide a population and gender specific database for the morphometric measurements of the patella. We believe that the data of the present study will be useful to the orthopaedician during the procedures like arthroplasty of the total knee, patellofemoral arthroplasty, resurfacing of patella, and designing the prosthetic implant. PMID- 28713614 TI - Condition medium of cerebrospinal fluid and retinoic acid induces the transdifferentiation of human dental pulp stem cells into neuroglia and neural like cells. AB - Cerebrospinal fluid (CSF) contains several molecules which are essential for neurogenesis. Human dental pulp stem cells (hDPSCs) are putatively neural crest cell-derived that can differentiate into neurons and glial cells under appropriate neurotrophic factors. The aim of this study was to induce differentiation of hDPSCs into neuroglial phenotypes using retinoic acid (RA) and CSF. The hDPSCs from an impacted third molar were isolated by mechanical and digestion and cultured. The cells have treated by 10-7 uM RA (RA group) for 8 days, 10% CSF (CSF group) for 8 days and RA with CSF for 8 days (RA/CSF group). Nestin, microtubule-associated protein 2 (MAP2), and glial fibrillary acidic protein immunostaining were used to examine the differentiated cells. Axonal outgrowth was detected using Bielschowsky's silver impregnation method and Nissl bodies were stained in differentiated cells by Cresyl violet. The morphology of differentiated cells in treated groups was significantly changed after 3-5 days. The results of immunocytochemistry showed the presence of neuroprogenitor marker nestin was seen in all groups. However, the high percentage of nestin positive cells and MAP2, as mature neural markers, were observed at the pre-induction and induction stage, respectively. Nissl bodies were detected as dark-blue particles in the cytoplasm of treated cells. Our findings showed the RA as pre-inducer and CSF as inducer for using in vitro differentiation of neuron-like cells and neuroglial cells from hDPSCs. PMID- 28713615 TI - Effects of radiofrequency exposure emitted from a GSM mobile phone on proliferation, differentiation, and apoptosis of neural stem cells. AB - Due to the importance of neural stem cells (NSCs) in plasticity of the nervous system and treating neurodegenerative diseases, the main goal of this study was to evaluate the effects of radiofrequency radiation emitted from a GSM 900-MHz mobile phone with different exposure duration on proliferation, differentiation and apoptosis of adult murine NSCs in vitro. We used neurosphere assay to evaluate NSCs proliferation, and immunofluorescence assay of neural cell markers to examine NSCs differentiation. We also employed alamarBlue and caspase 3 apoptosis assays to assess harmful effects of mobile phone on NSCs. Our results showed that the number and size of resulting neurospheres and also the percentage of cells differentiated into neurons decreased significantly with increasing exposure duration to GSM 900-MHz radiofrequency (RF)-electromagnetic field (EMF). In contrast, exposure to GSM 900-MHz RF-EMF at different durations did not influence cell viability and apoptosis of NSCs and also their astrocytic differentiation. It is concluded that accumulating dose of GSM 900-MHz RF-EMF might have devastating effects on NSCs proliferation and neurogenesis requiring more causations in terms of using mobile devices. PMID- 28713616 TI - Baicalein, wogonin, and Scutellaria baicalensis ethanol extract alleviate ovalbumin-induced allergic airway inflammation and mast cell-mediated anaphylactic shock by regulation of Th1/Th2 imbalance and histamine release. AB - Asthma is characterized by chronic inflammation, goblet cell hyperplasia, the aberrant production of the Th2 cytokines, and eosinophil infiltration into the lungs. In this study, we examined the effects of baicalein, wogonin, and Scutellaria baicalensis ethanol extract on ovalbumin (OVA)-induced asthma by evaluating Th1/Th2 cytokine levels, histopathologic analysis, and compound 48/80 induced systemic anaphylaxis and mast cell activation, focusing on the histamine release from rat peritoneal mast cells. Baicalein, wogonin, and S. baicalensis ethanol extract also decreased the number of inflammatory cells especially eosinophils and downregulated peribronchial and perivascular inflammation in the lungs of mice challenged by OVA. Baicalein, wogonin, and S. baicalensis ethanol extract significantly reduced the levels of tumor necrosis factor alpha, interleukin (IL)-1beta, IL-4, IL-5 and the production of OVA-specific IgE and IgG1, and upregulated the level of interferon-gamma and OVA-specific IgG2a. In addition, oral administration of baicalein, wogonin, and S. baicalensis ethanol extract inhibited compound 48/80-induced systemic anaphylaxis and plasma histamine release in mice. Moreover, baicalein, wogonin, and S. baicalensis ethanol extract suppressed compound 48/80-induced mast cell degranulation and histamine release from rat peritoneal mast cells. Conclusively, baicalein and wogonin as major flavonoids of S. baicalensis may have therapeutic potential for allergic asthma through modulation of Th1/Th2 cytokine imbalance and histamine release from mast cells. PMID- 28713617 TI - Age-related change of Iba-1 immunoreactivity in the adult and aged gerbil spinal cord. AB - In the present study, we examined change of ionized calcium-binding adapter molecule 1 (Iba-1) in the adult and aged gerbil spinal cords. Significant change of morphological feature and neuronal cell loss were not observed in both adult and aged spinal cords of gerbil after NeuN immunohistochemistry and Fluoro-Jade B histofluoresce staining. Iba-1-immunoreactive microglia broadly distributed in the spinal cord. Most of Iba-1-immunoreactive microglia showed ramified forms in the adult gerbil cervical and lumbar spinal cords. However, morphological changes of Iba-1-immunoreactive microglia were observed in the cervical and lumbar regions of the aged gerbil spinal cord. These microglia were showed a hypertrophied body with shortened swollen processes which was characteristic of activated microglia. In addition, Iba-1 protein level significantly higher in aged cervical and lumbar spinal cords than those in the adult gerbil. The present study showed an increase of activated forms of Iba-1-immunoreactive microglia and its protein level without marked changes in morphological features and neuronal loss in the aged spinal cord compared to those in the adult gerbil spinal cord. This result suggests that the increase of Iba-1 expression in the aged spinal cord may be closely associated with age-related changes in aged gerbil spinal cord. PMID- 28713619 TI - Functional and clinical importance of a large sized ostium secundum defect in a middle aged female cadaver: a case report. AB - Atrial septal defect (ASD) is one of the common congenital anomalies of the heart in humans. Its complications depend on the size of the defect and can manifest at any age. The common symptoms of ASD include dyspnea and fatigue. Most of the ASDs are associated with morbidity and mortality, Earlier the treatment, it is better to the patient. I saw a large ostium secundum defect in the heart of an adult female cadaver during dissection classes for undergraduate medical students. The interatrial septum had large defect at the region where fossa ovalis should have been located. It was about 1.25 inches in diameter and oval in shape. This type of large septal defect might result in cyanosis, stroke or death of the patient at any age. PMID- 28713618 TI - Vanillin and 4-hydroxybenzyl alcohol attenuate cognitive impairment and the reduction of cell proliferation and neuroblast differentiation in the dentate gyrus in a mouse model of scopolamine-induced amnesia. AB - 4-Hydroxy-3-methoxybenzaldehyde (vanillin) and 4-hydroxybenzyl alcohol (4-HBA) are natural phenolic compounds, which present in many plants and have diverse biological properties. In this study, we examined effects of vanillin and 4-HBA on learning and memory function, cell proliferation, and neuroblast differentiation in the hippocampal dentate gyrus in a mouse model of scopolamine induced amnesia. Scopolamine (SCO; 1 mg/kg/day, intraperitoneally), vanillin, and 4-HBA (40 mg/kg/day, orally) were administered for 28 days. Treatment with scopolamine alone impaired learning and memory function in the Morris water maze and passive avoidance tests, in addition, the treatment significantly reduced cell proliferation and neuroblast differentiation in the dentate gyrus, which were examined by immunohistochemistry for Ki-67 (a classic marker for cell proliferation) and doublecortin (a marker for neuroblasts). However, treatment with vanillin or 4-HBA significantly attenuated SCO-induced learning and memory impairment as well as the reduction of cell proliferation and neuroblast differentiation in the dentate gyrus. These results indicate that vanillin and 4 HBA may be helpful in improving cognitive function and in increasing endogenous neuronal proliferation in the brain. PMID- 28713620 TI - Supernumerary lumbar ribs: a rare occurrence on an adult African male skeleton. AB - Supernumerary lumbar ribs are usually asymptomatic and discovered incidentally during routine diagnostic radiography. During a routine inventory of the research skeletal repository at the University of the Witwatersrand, a rare case of bilateral supernumerary ribs on the first lumbar vertebra was observed. The skeletal specimen belonged to a 70-year-old African male whose recorded cause of death was esophageal carcinoma. Plain radiography revealed bilateral joint cavities between the transverse processes of the first lumbar vertebra and the supernumerary ribs. Clinically, supernumerary lumbar ribs may present with pain of the renal angle, cause confusion during enumeration of the vertebral levels on radiographs, and may be misinterpreted as fractures, kissing osteophytes, and/or calcification of abdominal vasculature. PMID- 28713621 TI - Surgical and radiological importance of a rare cysto-duodeno-colic peritoneal fold. AB - It is quite common to see abnormal peritoneal folds in the abdominal cavity. Some of them might compress or strangulate the viscera and others might determine the direction of the flow of peritoneal fluid, pus or blood. Many unusual clinically important peritoneal folds such as Ladd's band, cysto-gastro-colic fold, omento cystic fold, and cysto-colic fold have been reported earlier. Knowledge of these folds is important for radiologists, gastroenterologists, and surgeons. We report an unusual cysto-duodeno-colic fold observed during our dissection classes. The fold was seen to compress the duodenum and colon. The fold extended from the descending part of the duodenum and the transverse colon to the gallbladder. It enclosed the entire gallbladder. A case similar to this has not been reported yet. It is important for the gastroenterologists and laparoscopic surgeons to be aware of this fold to avoid misdiagnosis and iatrogenic injuries. PMID- 28713622 TI - Erratum to: Evaluation of sHLA-G levels in serum of patients with prostate cancer identify as a potential of tumor marker. AB - [This corrects the article on p. 69 in vol. 50, PMID: 28417057.]. PMID- 28713623 TI - Bistability and oscillations in co-repressive synthetic microbial consortia. AB - Synthetic microbial consortia are conglomerations of multiple strains of genetically engineered microbes programmed to cooperatively bring about population-level phenotypes. By coordinating their activity, the constituent strains can display emergent behaviors that are difficult to engineer into isogenic populations. To do so, strains are engineered to communicate with one another through intercellular signaling pathways. As a result, the regulatory networks that control gene transcription throughout the population are sensitive to the extracellular concentration of the signaling molecules, and hence the relative densities of constituent strains. Here, we use computational modeling to examine how the behavior of a synthetic microbial consortium results from the interplay between the population dynamics governed by cell growth and the internal transcriptional dynamics governed by cell-to-cell signaling. Specifically, we examine a synthetic microbial consortium in which two strains each produce signals that down-regulate transcription in the other. Within a single strain this regulatory topology is called a "co-repressive toggle switch" and can lead to bistability. We find that in a two-strain synthetic microbial consortium the existence and stability of different states depends on the population-level dynamics of the interacting strains. As the two strains passively compete for space within the colony, their relative fractions can fluctuate and thus alter the strengths of intercellular signals. These fluctuations can drive the consortium to alternative equilibria. Additionally, if the growth rates of the strains depend on their transcriptional states, an additional feedback loop is created that can generate relaxation oscillations. These findings demonstrate that the dynamics of microbial consortia cannot be predicted from their regulatory topologies alone, but also is determined by interactions between the strains. PMID- 28713624 TI - Temporal gradients limit the accumulation of neutrophils towards sources of chemoattractant. AB - Neutrophil trafficking during inflammation is a highly orchestrated process, coordinating neutrophil recruitment, sterilization of the wound, and inflammation resolution. Although the chemotactic signals guiding neutrophil recruitment to sites of inflammation are relatively well understood, mechanisms controlling cessation of neutrophil recruitment and return to normal tissue physiology remain undefined. To gain insights into these processes, we designed a microfluidic device with an array of chemoattractant reservoirs, which mimics the microenvironment in infected tissues, when multiple clusters of microbes are present. We monitored the temporal dynamics of neutrophil recruitment towards the chemoattractant reservoirs at single cell resolution, for 3 hours. We observed robust neutrophil recruitment that reached a plateau after 1.5 hours, despite the continuous presence of robust chemoattractant gradients around the reservoirs. The timing of the plateau was dependent on the geometry of the devices and was independent from the number of neutrophils. Based on these observations, we ruled out sub-population sensitivity, chemoattractant scavenging, and production of a self-limiting stop signal as potential mechanisms underpinning the plateau in neutrophil recruitment. We found a strong correlation between the temporal stabilization of concentration changes and the plateau in neutrophils recruitment. These results suggest that dynamic aspects of chemoattractant gradients are key for maximizing recruitment during the acute phase of infections and limiting the accumulation of neutrophils as soon as the infection is contained. PMID- 28713625 TI - Delayed cerebral ischemia after subarachnoid hemorrhage: Comparing and integrating classification systems. PMID- 28713626 TI - Recurrent hemorrhage in hemangioblastoma involving the posterior fossa: Case report. AB - BACKGROUND: Hemangioblastomas (HGBs) are the most common primary intra-axial posterior fossa tumor in adults. Although spontaneous hemorrhage of these tumors is exceedingly rare, despite their vascular nature, we describe a case of recurrent hemorrhage with associated tonsillar herniation, and demonstrate that a surgical approach can provide a suitable outcome. CASE DESCRIPTION: A 54-year-old female with von Hippel-Lindau (VHL) syndrome presented with acute loss of consciousness and Glasgow Coma Scale (GCS) was 4. Computed tomographic (CT) images demonstrated large volume subarachnoid hemorrhage of the posterior fossa with intraventricular extension and intraparenchymal hemorrhage involving the right cerebellar tonsil. Magnetic resonance imaging (MRI) displayed three lesions in the posterior fossa, two near the hemorrhage site. Patient underwent suboccipital craniectomy with a decent recovery followed by radiosurgery as she refused resection. A second hemorrhage occurred ultimately prompting surgical resection of the three posterior fossa lesions, with a reasonable postoperative course. CONCLUSION: Hemorrhage of HGBs of the posterior fossa can present in conjunction of tonsillar herniation. Re-hemorrhage appears to be likely if prior acute hemorrhage has occurred. A stepwise approach of surgical decompression and resection may provide the best outcome. PMID- 28713627 TI - Spinal epidural capillary hemangioma: A rare case report with a review of literature. AB - BACKGROUND: Purely epidural capillary hemangiomas are very rare. There are only 6 such reports. CASE DESCRIPTION: A 50-year-old male presented with a progressive lower extremity paraparesis. Magnetic resonance imaging demonstrated a purely epidural lesion at the L1-L2 level without any bony involvement. Following an L1 L2 laminectomy for total excision of the lesion, the patient showed significant improvement. The histopathology was consistent with a pure capillary hemangioma. CONCLUSION: The radiological presentation of purely epidural capillary hemangiomas are often similar to those of schwannomas and meningiomas. Surgical confirmation of the pathology, and gross total excision of these lesions is recommended. PMID- 28713628 TI - Outcomes of post-neurosurgical ventriculostomy-associated infections. AB - BACKGROUND: Ventriculostomy-associated infection (VAI) is a major concern to physicians. Limited studies have looked at the outcomes of external ventricular drain (EVD) infection and predictors of unfavorable outcomes. In this study, we assessed the outcomes of EVD infection and predictors of unfavorable outcomes. METHODS: This was a retrospective medical chart review, conducted at the Aga Khan University Hospital. All the patients irrespective of age and gender, fulfilling the diagnostic criteria of VAI were included. Patients with preexisting bacterial meningitis or ventriculitis were excluded from the study. Outcome assessment was based on Glasgow outcome scale (GOS) at 1 and 3 months after procedure. Other outcomes included 30-day mortality and total length of hospital stay. RESULTS: We included 256 patients in the study. 66 patients (25.8%) developed VAI. EVD was the primary procedure in 21 (31.8%) cases. Most patients, 24 (36.4%), had EVD as a secondary procedure for tumor surgery. Median interval between EVD placement and diagnosis of infection was 3 days. Mean length of stay in VAI patients was 31.85 +/- 20.53 days. Seven patients required ICU care. Ten patients (15.2%) expired during hospital stay or within 30 days of discharge and further four had GOS of 2 or 3. A total of 52 patients had a favorable outcome after 6 months. CONCLUSIONS: Rate of VAI in this cohort was high. VAI is associated with increased morbidity, mortality, and prolonged hospital stay. PMID- 28713630 TI - Primary calvarial tuberculosis. AB - BACKGROUND: Tuberculosis is a very common disease in India. Its prevalence, capacity to affect every other organ, and atypical presentations make it an important part of the differential diagnosis for cases presenting in the rural setup. Primary tuberculous caries of the calvarium is a rare manifestation of this common entity. CASE DESCRIPTION: A young lady presented with headache and discharging sinus of the scalp. Imaging revealed epidural abscess with midline shift. She underwent surgery, and histopathological diagnosis of tuberculous etiology was made. The pre and intraoperative images, radiological images, and histopathological images are reported and discussed. CONCLUSION: Tuberculosis should be included in the differential diagnosis of the osteolytic lesions of skull with discharging sinus. A high degree of suspicion, especially in patients from low socioeconomic status, is warranted in managing such cases. PMID- 28713629 TI - Abducent nerve palsy after microballoon compression of the trigeminal ganglion: Case report. AB - BACKGROUND: Trigeminal neuralgia (TN) is the most common type of facial neuralgia with incidence of 26.8/100,000 person year. In general, this scenario is characterized by a lancinating, unilateral, paroxysmal pain in the area of the fifth cranial nerve. Several treatment methods, including the injection of ethyl alcohol or butyl alcohol into the ganglion, the glycerol injection into the trigeminal cistern, peripheral nerve divisions, the radiofrequency thermocoagulation of the preganglionic fibers, and radiosurgery has been used for TN. CASE DESCRIPTION: A case of a 74-year-old woman patient who undergone a treatment of TN through a compression of Meckel cave and developed a transient abducent palsy is presented. Complication regarding to a palsy of abducent nerve is discussed as well as the analysis of presumable evolving physiopathology. A critical review of literature was performed. CONCLUSIONS: Among the procedures, we mean that percutaneous microballoon compression (PMC) is the best choice for elderly frail patients, because it had a very low associated mortality-morbidity rate and does not damage permanent the Gasserian ganglion. PMID- 28713631 TI - Percutaneous cervical laser diskectomy, thermoannuloplasty, and thermonucleoplasty; comparable results without surgery. AB - BACKGROUND: Utilizing the literature, the results of three different minimally invasive surgery (MIS) anterior cervical percutaneous operations for neck/mild radicular pain and magnetic resonance (MR)-documented "contained" (not extruded/sequestrated) discs were evaluated. Results were compared with patients treated nonsurgically for comparable/greater neurological compromise, and even more severe cervical disc disease. METHODS: There were three MIS percutaneous anterior cervical discectomy procedures. Anterior cervical laser discectomy ablated and vaporized disc tissue. The thermoannuloplasty used heat to contract collagen fibers to reduce disc volume. Thermonucleoplasty employed a low temperature resister probe to promote disintegration and evacuation of small volumes of disc (e.g., some studies cited an average of just 0.09 mL of disc removed). These results were compared to those for the nonsurgical management of patients with comparable/greater neurological deficits, and more severe cervical disc herniations. RESULTS: The three MIS anterior cervical operations resulted in 80-90%+ improvement using Macnab's criteria. However, although the literature demonstrated similar 80-90+% improvement without cervical surgery, the latter patients were more neurologically compromised. CONCLUSIONS: For patients with pain alone/mild radiculopathy and "contained" discs on MR, three MIS percutaneous anterior cervical disc operations resulted in 80-90%+ improvement. Notably, similar 80-90%+ improvement was observed for comparable/more neurologically impaired patients with even larger cervical disc herniations treated nonsurgically. With such findings, where is the "value added" for these three MIS cervical operations? PMID- 28713632 TI - Radiographic Assessment of the presigmoid retrolabyrinthine approach. AB - BACKGROUND: Lesions of the petroclival fissure are difficult to access surgically. Both retrosigmoid and presigmoid retrolabyrinthine approaches have been described to successfully treat these complex tumors. The retrosigmoid approach offers quick and familiar access, whereas the presigmoid retrolabyrinthine approach reduces the operative distance and the need for cerebellar retraction. The presigmoid retrolabyrinthine approach, however, is constrained by anatomical limits that can be subject to patient variation. We sought to characterize the surgically relevant variation to guide preoperative assessment. METHODS: One hundred and seventy-seven high-resolution computed tomography scans of the head (without preexisting pathology) were reviewed. Three hundred and fifty-four temporal bone scans were analyzed for level of aeration, size of Trautmann's triangle dura, and petrous slope. Petrous slope is the angle between the anterior sigmoid sinus and the petroclival fissure at the level of the internal acoustic canal. RESULTS: Trautmann's triangle area had a mean of 185.15 mm2 (range 71.4-426.7 mm2). Petrous slope had a mean value of 149 degrees (range 106-178 degrees ). Increasing aeration was found to be correlated with decreasing petrous slope and decreasing Trautmann's triangle area. CONCLUSION: The presigmoid retrolabyrinthine approach is uniquely confined. Variations in temporal bone anatomy can have dramatic impacts on the operative time, risk profile, and final exposure. Preoperative assessment is critical in guiding the surgeon on the appropriateness of approach. Preoperative measurement of Trautmann's triangle, petrous slope, and aeration can help to reduce surgical morbidity. PMID- 28713633 TI - The floating anchored craniotomy. AB - BACKGROUND: The "floating anchored" craniotomy is a technique utilized at our tertiary neurosurgery institution in which a traditional decompressive craniectomy has been substituted for a floating craniotomy. The hypothesized advantages of this technique include adequate decompression, reduction in the intracranial pressure, obviating the need for a secondary cranioplasty, maintained bone protection, preventing the syndrome of the trephined, and a potential reduction in axonal stretching. METHODS: The bone plate is re-attached via multiple loosely affixed vicryl sutures, enabling decompression, but then ensuring the bone returns to its anatomical position once cerebral edema has subsided. RESULTS: From the analysis of 57 consecutive patients analyzed at our institution, we have found that the floating anchored craniotomy is comparable to decompressive craniectomy for intracranial pressure reduction and has some significant theoretical advantages. CONCLUSIONS: Despite the potential advantages of techniques that avoid the need for a second cranioplasty, they have not been widely adopted and have been omitted from trials examining the utility of decompressive surgery. This retrospective analysis of prospectively collected data suggests that the floating anchored craniotomy may be applicable instead of decompressive craniectomy. PMID- 28713634 TI - Pedicle screw placement accuracy impact and comparison between grading systems. AB - BACKGROUND: Pedicle screw instrumentation is widely used for spinal stabilization. However, the accuracy for free-hand screw placement ranges from 69% to 94%. This study assesses the value of the existing classification systems, and investigates their impact on the ability to assess the accuracy of free-hand screw placement. METHODS: Data were collected retrospectively from the medical records of 34 patients who received 224 pedicle screws placed utilizing a free hand technique. Screw placement was evaluated employing the 2-mm increment and Zdichavsky et al. classification systems. Kappa coefficient and Landis and Koch interpretations were employed for statistical analysis. RESULTS: The 2-mm increment classification system resulted in a total of 18 (8.03%) misplaced screws. Lateral screw misplacement was observed in 13 (5.8%) instances, with medial pedicle wall penetration being noted in 5 (2.23%). Of the 18 misplaced screws, 4 (22.22%) were classified as minor (<=2 mm), 12 (66.67%) as moderate (2 4 mm), and 2 (11.11%) as severe (>4 mm) (K = 0.882). The Zdichavsky et al. grading system categorized 208 (92.84%) pedicle screws as Ia, 10 (4.46%) as Ib, 1 (0.45%) as IIa, 2 (0.90%) as IIb, 2 (0.90%) as IIIa, and 1 (0.45%) as IIIb grade; this resulted in a total of 16 (7.14%) misplaced screws (K = 0.980). One patient exhibited a new postoperative radiculopathy attributed to poor screw placement. There were no additional early or late postsurgical complications attributed to screw misplacement. CONCLUSION: The free-hand pedicle screw placement technique is both safe and effective. Postoperative computed tomography studies; however, are useful to confirm the accuracy of screw placement. Although, the available grading systems proved reliable, easy to use, and clearly reflected the individual surgeon's skills, they do not clearly document whether screws are safely placed. PMID- 28713635 TI - Fibrous encapsulation of the peritoneal catheter in peritoneal shunt: Case report. AB - BACKGROUND: The authors report a case of fibrous encapsulation of the peritoneal catheter, which caused peritoneal shunt malfunction, and has not previously been researched well as a complication of peritoneal shunts. CASE DESCRIPTION: A 69 year-old woman who had undergone a lumboperitoneal (LP) shunt for communicative hydrocephalus following subarachnoid hemorrhage caused by a ruptured aneurysm was identified with malfunction of the LP shunt system by dementia and gait disturbance. Hydrocephalus was revealed on computed tomography (CT). Under a laparoscopy, the intraabdominal peritoneal catheter was observed to be obstructed by fibrous encapsulation covering it like a long white stocking. Although the fibrous encapsulating tissue was excised by laparoscopy forceps, a ventriculoperitoneal shunt device was replaced with a new peritoneal catheter. The histopathological diagnosis of the surgically resected encapsulating tissue was the fibrous tissue with a few inflammation cells and a layer of lining cells surrounding some part of it. In the immunohistochemical study, a layer of lining cells surrounding the fibrous tissue showed immunohistochemically positive staining for calretinin. CONCLUSION: The fibrous encapsulation would be formed by peritoneal reaction to a peritoneal catheter as a foreign body by these histopathological and immunohistochemical analyses. PMID- 28713636 TI - Ranking Causal Anomalies via Temporal and Dynamical Analysis on Vanishing Correlations. AB - Modern world has witnessed a dramatic increase in our ability to collect, transmit and distribute real-time monitoring and surveillance data from large scale information systems and cyber-physical systems. Detecting system anomalies thus attracts significant amount of interest in many fields such as security, fault management, and industrial optimization. Recently, invariant network has shown to be a powerful way in characterizing complex system behaviours. In the invariant network, a node represents a system component and an edge indicates a stable, significant interaction between two components. Structures and evolutions of the invariance network, in particular the vanishing correlations, can shed important light on locating causal anomalies and performing diagnosis. However, existing approaches to detect causal anomalies with the invariant network often use the percentage of vanishing correlations to rank possible casual components, which have several limitations: 1) fault propagation in the network is ignored; 2) the root casual anomalies may not always be the nodes with a high-percentage of vanishing correlations; 3) temporal patterns of vanishing correlations are not exploited for robust detection. To address these limitations, in this paper we propose a network diffusion based framework to identify significant causal anomalies and rank them. Our approach can effectively model fault propagation over the entire invariant network, and can perform joint inference on both the structural, and the time-evolving broken invariance patterns. As a result, it can locate high-confidence anomalies that are truly responsible for the vanishing correlations, and can compensate for unstructured measurement noise in the system. Extensive experiments on synthetic datasets, bank information system datasets, and coal plant cyber-physical system datasets demonstrate the effectiveness of our approach. PMID- 28713637 TI - Regenerative Rehabilitation: An Innovative and Multifactorial Approach to Recovery From Stroke and Brain Injury. AB - There is currently a dearth of treatment options for stroke or traumatic brain injury that can restore cognitive and motor function. Regenerative and translational medicine have ushered forth promising new methods for mediating recovery in the central nervous system, the most salient of which are rehabilitation and stem cell therapies that, when combined, result in more pronounced recovery than one approach alone. PMID- 28713638 TI - Neurovascular Cell Sheet Transplantation in a Canine Model of Intracranial Hemorrhage. AB - Cell-based therapy for intracerebral hemorrhage (ICH) has a great therapeutic potential. However, methods to effectively induce direct regeneration of the damaged neural tissue after cell transplantation have not been established, which, if done, would improve the efficacy of cell-based therapy. In this study, we aimed to develop a cell sheet with neurovasculogenic potential and evaluate its usefulness in a canine ICH model. We designed a composite cell sheet made of neural progenitors derived from human olfactory neuroepithelium and vascular progenitors from human adipose tissue-derived stromal cells. We also generated a physiologic canine ICH model by manually injecting and then infusing autologous blood under arterial pressure. We transplanted the sheet cells (cell sheet group) or saline (control group) at the cortex over the hematoma at subacute stages (2 weeks from ICH induction). At 4 weeks from the cell transplantation, cell survival, migration, and differentiation were evaluated. Hemispheric atrophy and neurobehavioral recovery were also compared between the groups. As a result, the cell sheet was rich in extracellular matrices and expressed neurotrophic factors as well as the markers for neuronal development. After transplantation, the cells successfully survived for 4 weeks, and a large portion of those migrated to the perihematomal site and differentiated into neurons and pericytes (20% and 30% of migrated stem cells, respectively). Transplantation of cell sheets alleviated hemorrhage-related hemispheric atrophy (p = 0.042) and showed tendency for improving functional recovery (p = 0.062). Therefore, we concluded that the cell sheet transplantation technique might induce direct regeneration of neural tissue and might improve outcomes of intracerebral hemorrhage. PMID- 28713639 TI - A Prospective, Nonrandomized, no Placebo-Controlled, Phase I/II Clinical Trial Assessing the Safety and Efficacy of Intramuscular Injection of Autologous Adipose Tissue-Derived Mesenchymal Stem Cells in Patients With Severe Buerger's Disease. AB - Buerger's disease is a rare and severe disease affecting the blood vessels of the limbs. Adipose tissue-derived mesenchymal stem cells (ADSCs) have the potential to cure Buerger's disease when developed as a stem cell drug. In the present study, we conducted a prospective, nonrandomized, no placebo-controlled, phase I/II clinical trial with a 2-year follow-up questionnaire survey. A total of 17 patients were intramuscularly administered autologous ADSCs at a dose of 5 million cells/kg. The incidence of adverse events (AEs), adverse drug reaction (ADR), and serious adverse events (SAEs) was monitored. No ADRs and SAEs related to stem cell treatment occurred during the 6-month follow-up. In terms of efficacy, the primary endpoint was increase in total walking distance (TWD). The secondary endpoint was improvement in rest pain, increase in pain-free walking distance (PFWD), toe-brachial pressure index (TBPI), transcutaneous oxygen pressure (TcPO2), and arterial brachial pressure index (ABPI). ADSCs demonstrated significant functional improvement results including increased TWD, PFWD, and rest pain reduction. No amputations were reported during the 6-month clinical trial period and in the follow-up questionnaire survey more than 2 years after the ADSC injection. In conclusion, intramuscular injection of ADSCs is very safe and is shown to prompt functional improvement in patients with severe Buerger's disease at a dosage of 300 million cells per 60 kg of body weight. However, the confirmatory therapeutic efficacy and angiogenesis need further study. PMID- 28713640 TI - Human Adipose-Derived Mesenchymal Stem Cells Respond to Short-Term Hypoxia by Secreting Factors Beneficial for Human Islets In Vitro and Potentiate Antidiabetic Effect In Vivo. AB - Adipose-derived mesenchymal stem cells (ASCs) release factors beneficial for islets in vitro and protect against hyperglycemia in rodent models of diabetes. Oxygen tension has been shown to induce metabolic changes and alter ASCs' release of soluble factors. The effects of hypoxia on the antidiabetic properties of ASCs have not been explored. To investigate this, we incubated human ASCs for 48 h in 21% (normoxia) or 1% O2 (hypoxia) and compared viability, cell growth, surface markers, differentiation capability, and soluble factors in the conditioned media (CM). Human islets were exposed to CM from ASCs incubated in either normoxia or hypoxia, and islet function and apoptosis after culture with or without proinflammatory cytokines were measured. To test hypoxic preconditioned ASCs' islet protective effects in vivo, ASCs were incubated for 48 h in normoxia or hypoxia before being injected into Balb/c Rag 1-/- immunodeficient mice with streptozotocin-induced insulitis. Progression of diabetes and insulin content of pancreas were measured. We found that incubation in hypoxia was well tolerated by ASCs and that levels of VEGF-A, FGF-2, and bNGF were elevated in CM from ASCs incubated in hypoxia compared to normoxia, while levels of HGF, IL-8, and CXCL1 were reduced. CM from ASCs incubated in hypoxia significantly improved human islet function and reduced apoptosis after culture, and reduced cytokine-induced apoptosis. In our mouse model, pancreas insulin content was higher in both groups receiving ASCs compared to control, but the mice receiving preconditioned ASCs had lower random and fasting blood glucose, as well as improved oral glucose tolerance compared to untreated mice. In conclusion, our in vitro results indicate that the islet protective potential of ASCs improves in hypoxia, and we give insight into factors involved in this. Finally we show that hypoxic preconditioning potentiates ASCs' antidiabetic effect in vivo. PMID- 28713641 TI - Higher Serum Alanine Transaminase Levels in Male Urokinase-Type Plasminogen Activator-Transgenic Mice Are Associated With Improved Engraftment of Hepatocytes but not Liver Sinusoidal Endothelial Cells. AB - The effects of sex on the degree of liver damage and human cell engraftment were investigated in immunodeficient urokinase-type plasminogen activator-transgenic (uPA-NOG) mice. Liver damage, measured by serum alanine transaminase (ALT) levels, was compared in male and female uPA-NOG mice of different ages. Male mice had significantly higher ALT levels than females with a median of 334 versus 158 U/L in transgenic homozygous mice, respectively. Mice were transplanted with human adult hepatocytes or fetal liver cells and analyzed for any correlation of engraftment of hepatocytes, liver sinusoidal endothelial cells (LSECs), and hematopoietic cells with the degree of liver damage. Hepatocyte engraftment was measured by human albumin levels in the mouse serum. Higher ALT levels correlated with higher hepatocyte engraftment, resulting in albumin levels in male mice that were 9.6 times higher than in females. LSEC and hematopoietic cell engraftment were measured by flow cytometric analysis of the mouse liver and bone marrow. LSEC and hematopoietic engraftment did not differ between male and female transplant recipients. Thus, the sex of uPA-NOG mice affects the degree of liver damage, which is reflected in the levels of human hepatocyte engraftment. However, the high levels of LSEC engraftment observed in uPA-NOG mice are not further improved among male mice, suggesting that a lower threshold of liver damage is sufficient to enhance endothelial cell engraftment. Previously described sex differences in human hematopoietic stem cell engraftment in immunodeficient mice were not observed in this model. PMID- 28713642 TI - Synthetic and Computational Studies on the Rhodium-Catalyzed Hydroamination of Aminoalkenes. AB - The influence of ligand structure on rhodium-catalyzed hydroamination has been evaluated for a series of phosphinoarene ligands. These catalysts have been evaluated in a set of catalytic intramolecular Markovnikov hydroamination reactions. The mechanism of hydroamination catalyzed by the rhodium(I) complexes in this study was examined computationally, and the turnover-limiting step was elucidated. These computational studies were extended to a series of theoretical hydroamination catalysts to compare the electronic effects of the ancillary ligand substituents. The relative energies of intermediates and transition states were compared to those of intermediates in the reaction catalyzed by the unsubstituted catalyst. The experimental difference in the reactivities of electron-rich and electron-poor catalysts was compared to the computational results, and it was found that the activity for the electron-poor catalysts predicted from the reaction barriers was overestimated. Thus, the analysis of the catalysts in this study was expanded to include the binding preference of each ligand, in comparison to that of the unsubstituted ligand. This information accounts for the disparity between observed reactivity and the calculated overall reaction barrier for electron-poor ligands. The ligand-binding preferences for new ligand structures were calculated, and ligands that were predicted to bind strongly to rhodium generated catalysts for the experimental catalytic reactions that were more reactive than those predicted to bind more weakly. PMID- 28713643 TI - Solvent Polarity-Induced Pore Selectivity in H-ZSM-5 Catalysis. AB - Molecular-sized micropores of ZSM-5 zeolite catalysts provide spatial restrictions around catalytic sites that allow for shape-selective catalysis. However, the fact that ZSM-5 has two main pore systems with different geometries is relatively unexploited as a potential source of additional shape selectivity. Here, we use confocal laser-scanning microscopy to show that by changing the polarity of the solvent, the acid-catalyzed furfuryl alcohol oligomerization can be directed to selectively occur within either of two locations in the microporous network. This finding is confirmed for H-ZSM-5 particles with different Si/Al ratios and indicates a general trend for shape-selective catalytic reactions. PMID- 28713644 TI - Kinetic Modeling of the Nickel-Catalyzed Esterification of Amides. AB - Nickel-catalyzed coupling reactions provide exciting tools in chemical synthesis. However, most methodologies in this area require high catalyst loadings, which commonly range from 10-20 mol % nickel. Through an academic-industrial collaboration, we demonstrate that kinetic modeling can be used strategically to overcome this problem, specifically within the context of the Ni-catalyzed conversion of amides to esters. The successful application of this methodology to a multigram-scale coupling, using only 0.4 mol % Ni, highlights the impact of this endeavor. PMID- 28713645 TI - Effects of A Novel Disc Formulation on Dry Mouth Symptoms and Enamel Remineralization in Patients With Hyposalivation: An In Vivo Study. AB - BACKGROUND: The goal of this study was to identify the in vivo effects in patients with hyposalivation of a novel slowly dissolving adhering test disc upon on enamel remineralization, oral biofilm, salivary production, pH and buffering, gingival health, and on self-evaluation of oral well-being. METHODS: Five subjects with xerostomia wore custom made retainers carrying 5 demineralized enamel chips for periods of 1 week each. In 1 study arm, subjects used the test agent plus oral hygiene self-care; in the other they used oral hygiene self-care only, with a 1 week washout in between arms. The treatment sequence was randomized. Before and after each study arm Plaque Index (PI), Gingival Index (GI) and Sulcus Bleeding Index (mSBI) were recorded. Clinical plaque staining was quantified using digital image analysis. Saliva production, pH and buffering capacity were recorded. Subjects completed a self-evaluation questionnaire for oral comfort. Enamel samples underwent standardized Knoop microhardness testing to quantify mineralization status. RESULTS: Plaque presence and clinical Plaque Indices decreased significantly with test agent use (p<0.05). Five-minute saliva production almost doubled 10 and 40 minutes after oral test disc insertion (significant, p<0.05). Salivary pH buffering improved in 4/5 subjects with disc use. All demineralized tooth samples re-hardened intraorally (p>0.05). The discs favorably impacted eating problems and dental sensitivity. Subjects were positive about disc flavor and mouth feel. CONCLUSION: Using established in vivo techniques, the effects of a novel product in xerostomic patients were evaluated and quantified. The adhering disc facilitated eating, reduced dental sensitivity, improved saliva production and buffering capacity, reduced plaque, and alleviated xerostomia symptoms. CLINICAL RELEVANCE: Xerostomia management is challenging. A novel dry mouth disc was effective in alleviating dry mouth symptoms. PMID- 28713646 TI - Progression of Local Glaucomatous Damage Near Fixation as Seen with Adaptive Optics Imaging. AB - PURPOSE: Deep glaucomatous defects near fixation were followed over time with an adaptive optics-scanning light ophthalmoscope (AO-SLO) to better understand the progression of these defects and to explore the use of AO-SLO in detecting them. METHODS: Six eyes of 5 patients were imaged with an AO-SLO from 2 to 4 times for a range of 14.6 to 33.6 months. All eyes had open-angle glaucoma with deep defects in the superior visual field (VF) near fixation as defined by 10-2 VFs with 5 or more points less than -15 dB; two of the eyes had deep defects in the inferior VF as well. AO-SLO images were obtained around the temporal edge of the disc. RESULTS: In 4 of the 6 eyes, the edge of the inferior-temporal disc region of the retinal nerve fiber (RNF) defect seen on AO-SLO moved closer to fixation within 10.6 to 14.7 months. In 4 eyes, RNF bundles in the affected region appeared to lose contrast and/or disappear. CONCLUSIONS: Progressive changes in RNF bundles associated with deep defects on 10-2 VFs can be seen within about 1 year with AO-SLO imaging. These changes are well below the spatial resolution of the 10-2 VF. On the other hand, subtle thinning of regions with RNF bundles is not easy to see with current AO-SLO technology, and may be better followed with OCT. TRANSLATIONAL RELEVANCE: AO-SLO imaging may be useful in clinical trials designed to see very small changes in deep defects. PMID- 28713647 TI - Evaluation of Two Systems for Fundus-Controlled Scotopic and Mesopic Perimetry in Eye with Age-Related Macular Degeneration. AB - PURPOSE: The purpose of this study was to evaluate and compare the MP-1S (Nidek Technologies, Padova, Italy) and the S-MAIA (CenterVue, Padova, Italy) for mesopic and scotopic fundus-controlled perimetry (FCP) in age-related macular degeneration (AMD). METHODS: Eleven eyes from 11 patients underwent mesopic and, after 30 minutes of dark adaptation, scotopic (MP-1S: Goldmann V, 200 ms, background luminance 0.0032 cd/m2; S-MAIA: Goldman III, 200 ms, background luminance <0.0001 cd/m2) FCP. For the S-MAIA device, cyan (505 nm) and red (627 nm) scotopic FCP were performed. For both devices, a grid of 56 stimulus points covering 16 degrees of the central macula was used. Examination time, fixation stability, and threshold values were analyzed. RESULTS: The upper end of the dynamic range (<=4 dB of lowest threshold) was frequently reached by the MP-1S for mesopic testing (median 34 of 56 stimuli), while threshold values within the lower 4 dB of the dynamic range were occasionally found with the S-MAIA for scotopic testing (median 3 for cyan, median 2 for red). After correction of the stimulus intensity for the S-MAIA results, the median difference for all stimuli between both devices for mesopic testing was -2.0 dB (interquartile range [-4;0], range -14 to 6). CONCLUSIONS: The results indicate that robust testing of mesopic and scotopic function is feasible with both devices in patients with AMD, although both devices are susceptible to floor and ceiling effects. TRANSLATIONAL RELEVANCE: The interpretation and particularly the comparison of both scotopic and mesopic FCP results between the MP-1S and the S-MAIA in AMD eyes need to consider variable susceptibility of floor and ceiling effects. Further software updates are desirable as FCP captures visual functional loss that is not noted with best-corrected central visual acuity and is important for clinical trials in AMD. PMID- 28713648 TI - Interfacial reactions at Fe/topological insulator spin contacts. AB - The authors study the composition and abruptness of the interfacial layers that form during deposition and patterning of a ferromagnet, Fe on a topological insulator (TI), Bi2Se3, Bi2Te3, and SiOx/Bi2Te3. Such structures are potentially useful for spintronics. Cross-sectional transmission electron microscopy, including interfacial elemental mapping, confirms that Fe reacts with Bi2Se3 near room temperature, forming an abrupt 5 nm thick FeSe0.92 single crystalline binary phase, predominantly (001) oriented, with lattice fringe spacing of 0.55 nm. In contrast, Fe/Bi2Te3 forms a polycrystalline Fe/TI interfacial alloy that can be prevented by the addition of an evaporated SiOx separating Fe from the TI. PMID- 28713649 TI - Accurate external localization of the left frontal cortex in dogs by using pointer based frameless neuronavigation. AB - BACKGROUND: In humans, non-stereotactic frameless neuronavigation systems are used as a topographical tool for non-invasive brain stimulation methods such as Transcranial Magnetic Stimulation (TMS). TMS studies in dogs may provide treatment modalities for several neuropsychological disorders in dogs. Nevertheless, an accurate non-invasive localization of a stimulation target has not yet been performed in this species. HYPOTHESIS: This study was primarily put forward to externally locate the left frontal cortex in 18 healthy dogs by means of a human non-stereotactic neuronavigation system. Secondly, the accuracy of the external localization was assessed. ANIMALS: A total of 18 healthy dogs, drawn at random from the research colony present at the faculty of Veterinary Medicine (Ghent University), were used. METHODS: Two sets of coordinates (X, Y, Z and X", Y", Z") were compared on each dog their tomographical dataset. RESULTS: The non stereotactic neuronavigation system was able to externally locate the frontal cortex in dogs with accuracy comparable with human studies. CONCLUSION AND CLINICAL IMPORTANCE: This result indicates that a non-stereotactic neuronavigation system can accurately externally locate the left frontal cortex and paves the way to use guided non-invasive brain stimulation methods as an alternative treatment procedure for neurological and behavioral disorders in dogs. This technique could, in analogy with human guided non-invasive brain stimulation, provide a better treatment outcome for dogs suffering from anxiety disorders when compared to its non-guided alternative. PMID- 28713650 TI - The fossil Osmundales (Royal Ferns)-a phylogenetic network analysis, revised taxonomy, and evolutionary classification of anatomically preserved trunks and rhizomes. AB - The Osmundales (Royal Fern order) originated in the late Paleozoic and is the most ancient surviving lineage of leptosporangiate ferns. In contrast to its low diversity today (less than 20 species in six genera), it has the richest fossil record of any extant group of ferns. The structurally preserved trunks and rhizomes alone are referable to more than 100 fossil species that are classified in up to 20 genera, four subfamilies, and two families. This diverse fossil record constitutes an exceptional source of information on the evolutionary history of the group from the Permian to the present. However, inconsistent terminology, varying formats of description, and the general lack of a uniform taxonomic concept renders this wealth of information poorly accessible. To this end, we provide a comprehensive review of the diversity of structural features of osmundalean axes under a standardized, descriptive terminology. A novel morphological character matrix with 45 anatomical characters scored for 15 extant species and for 114 fossil operational units (species or specimens) is analysed using networks in order to establish systematic relationships among fossil and extant Osmundales rooted in axis anatomy. The results lead us to propose an evolutionary classification for fossil Osmundales and a revised, standardized taxonomy for all taxa down to the rank of (sub)genus. We introduce several nomenclatural novelties: (1) a new subfamily Itopsidemoideae (Guaireaceae) is established to contain Itopsidema, Donwelliacaulis, and Tiania; (2) the thamnopteroid genera Zalesskya, Iegosigopteris, and Petcheropteris are all considered synonymous with Thamnopteris; (3) 12 species of Millerocaulis and Ashicaulis are assigned to modern genera (tribe Osmundeae); (4) the hitherto enigmatic Aurealcaulis is identified as an extinct subgenus of Plenasium; and (5) the poorly known Osmundites tuhajkulensis is assigned to Millerocaulis. In addition, we consider Millerocaulis stipabonettiorum a possible member of Palaeosmunda and Millerocaulis estipularis as probably constituting the earliest representative of the (Todea-)Leptopteris lineage (subtribe Todeinae) of modern Osmundoideae. PMID- 28713651 TI - Amphibian population genetics in agricultural landscapes: does viniculture drive the population structuring of the European common frog (Rana temporaria)? AB - Amphibian populations have been declining globally over the past decades. The intensification of agriculture, habitat loss, fragmentation of populations and toxic substances in the environment are considered as driving factors for this decline. Today, about 50% of the area of Germany is used for agriculture and is inhabited by a diverse variety of 20 amphibian species. Of these, 19 are exhibiting declining populations. Due to the protection status of native amphibian species, it is important to evaluate the effect of land use and associated stressors (such as road mortality and pesticide toxicity) on the genetic population structure of amphibians in agricultural landscapes. We investigated the effects of viniculture on the genetic differentiation of European common frog (Rana temporaria) populations in Southern Palatinate (Germany). We analyzed microsatellite data of ten loci from ten breeding pond populations located within viniculture landscape and in the adjacent forest block and compared these results with a previously developed landscape permeability model. We tested for significant correlation of genetic population differentiation and landscape elements, including land use as well as roads and their associated traffic intensity, to explain the genetic structure in the study area. Genetic differentiation among forest populations was significantly lower (median pairwise FST = 0.0041 at 5.39 km to 0.0159 at 9.40 km distance) than between viniculture populations (median pairwise FST = 0.0215 at 2.34 km to 0.0987 at 2.39 km distance). Our analyses rejected isolation by distance based on roads and associated traffic intensity as the sole explanation of the genetic differentiation and suggest that the viniculture landscape has to be considered as a limiting barrier for R. temporaria migration, partially confirming the isolation of breeding ponds predicted by the landscape permeability model. Therefore, arable land may act as a sink habitat, inhibiting genetic exchange and causing genetic differentiation of pond populations in agricultural areas. In viniculture, pesticides could be a driving factor for the observed genetic impoverishment, since pesticides are more frequently applied than any other management measure and can be highly toxic for terrestrial life stages of amphibians. PMID- 28713652 TI - Fungi associated with mesophotic macroalgae from the 'Au'au Channel, west Maui are differentiated by host and overlap terrestrial communities. AB - Mesophotic coral ecosystems are an almost entirely unexplored and undocumented environment that likely contains vast reservoirs of undescribed biodiversity. Twenty-four macroalgae samples, representing four genera, were collected from a Hawaiian mesophotic reef at water depths between 65 and 86 m in the 'Au'au Channel, Maui, Hawai'i. Algal tissues were surveyed for the presence and diversity of fungi by sequencing the ITS1 gene using Illumina technology. Fungi from these algae were then compared to previous fungal surveys conducted in Hawaiian terrestrial ecosystems. Twenty-seven percent of the OTUs present on the mesophotic coral ecosystem samples were shared between the marine and terrestrial environment. Subsequent analyses indicated that host species of algae significantly differentiate fungal community composition. This work demonstrates yet another understudied habitat with a moderate diversity of fungi that should be considered when estimating global fungal diversity. PMID- 28713653 TI - Frail phenotype might herald bone health worsening among end-stage renal disease patients. AB - BACKGROUND: Frailty exhibits a high prevalence in end-stage renal disease (ESRD) patients and is associated with adverse health-related outcomes, including falls and fractures. Available studies do not address whether frailty is associated with temporal changes in BMD. We evaluated this issue by analyzing the follow-up dual energy X-ray absorptiometry (DXA) results in an ESRD cohort. METHODS: In 2015, we enrolled forty-three ESRD patients, divided into frail, pre-frail, and robust ones based on a validated simple FRAIL scale, all receiving DXA at baseline. After one year of follow-up, survivors received another DXA, and we calculated the absolute and percentage changes in area, bone mineral density (BMD), T-, and Z-scores of lumbar spine and femoral neck (FN) between baseline and follow-up examinations. RESULTS: Among all, frail individuals with ESRD had significantly lower average lumbar spine area, lower L4, FN, and total BMD and T scores, lower FN and total Z-scores than non-frail ones, without differences in gender, body mass index, dialysis duration, and comorbidities. Furthermore, we discovered frail ESRD patients had significantly more prominent decrease in average lumbar spine area, percentage changes in L1 Z-scores and average lumbar spine area, and a trend toward more prominent decrease in L4 area than non-frail ones after one year of follow-up. CONCLUSIONS: Baseline frailty might be associated with deteriorating bone health, including shrinking L-spine areas and a more rapid decrease in L-spine Z scores, among ESRD patients. This frailty-bone association should be highlighted during our care of frail individuals with ESRD. PMID- 28713654 TI - Predator-prey interactions between native brine shrimp Artemia parthenogenetica and the alien boatman Trichocorixa verticalis: influence of salinity, predator sex, and size, abundance and parasitic status of prey. AB - Trichocorixa verticalis (T. verticalis), native to North America and the Caribbean islands, is an invasive waterboatman species (Corixidae) in the southwest of the Iberian Peninsula. Previous studies in the native range have suggested that predation by T. verticalis can regulate the abundance of Anostracan and Cladoceran zooplankton in saline ecosystems, causing increases in phytoplankton through a trophic cascade. In this experimental study, we tested the predator-prey relationship between the native brine shrimp Artemia parthenogenetica, and T. verticalis from the Odiel salt ponds in SW Spain. In three experiments, we investigated (1) the effects of Artemia life stage (metanauplii, juveniles, and adults), (2) abundance (three, six, and 12 adult Artemia) and (3) parasitic status (Artemia infected with avian cestodes or uninfected) on predation rates by T. verticalis. We also considered how predation rates in all three experiments were influenced by the sex of T. verticalis and by different salinities (25 and 55 g l-1). Experiment 1 showed that predation rates were highest for metanauplii, possibly because their photophilic behavior makes them more prone to predation. In Experiment 2, we found that predation rate was higher for female T. verticalis and the higher salinity, although the strength of the sex effect varied between treatments. Experiment 3 showed that T. verticalis selectively predated adult Artemia infected with cestodes (red in color), as previously reported for predation by avian final hosts. Collectively, these results indicate that T. verticalis are important predators in their introduced range, and are likely to reduce the abundance of Artemia in more salt ponds as they expand their range, thus increasing phytoplankton abundance through trophic cascades. PMID- 28713655 TI - Differential effect of Platelet Endothelial Cell Adhesion Molecule-1 (PECAM-1) on leukocyte infiltration during contact hypersensitivity responses. AB - BACKGROUND: 2'-4' Dinitrofluorobenzene (DNFB) induced contact hypersensitivity is an established model of contact sensitivity and leukocyte migration. Platelet Endothelial Cell Adhesion Molecule-1 (PECAM-1) deficient mice were used to examine the role of PECAM-1 in the migration capacity of several different leukocyte populations after primary and secondary application. RESULTS: gammadelta T lymphocytes, granulocytes, and Natural Killer cells were most affected by PECAM-1 deficiency at the primary site of application. gammadelta T lymphocytes, granulocytes, DX5+ Natural Killer cells, and, interestingly, effector CD4+ T lymphocytes were most affected by the loss of PECAM-1 at the secondary site of application. CONCLUSIONS: PECAM-1 is used by many leukocyte populations for migration, but there are clearly differential effects on the usage by each subset. Further, the overall kinetics of each population varied between primary and secondary application, with large relative increases in gammadelta T lymphocytes during the secondary response. PMID- 28713657 TI - 290 metagenome-assembled genomes from the Mediterranean Sea: a resource for marine microbiology. AB - The Tara Oceans Expedition has provided large, publicly-accessible microbial metagenomic datasets from a circumnavigation of the globe. Utilizing several size fractions from the samples originating in the Mediterranean Sea, we have used current assembly and binning techniques to reconstruct 290 putative draft metagenome-assembled bacterial and archaeal genomes, with an estimated completion of >=50%, and an additional 2,786 bins, with estimated completion of 0-50%. We have submitted our results, including initial taxonomic and phylogenetic assignments, for the putative draft genomes to open-access repositories for the scientific community to use in ongoing research. PMID- 28713656 TI - Methodological considerations in assessment of language lateralisation with fMRI: a systematic review. AB - The involvement of the right and left hemispheres in mediating language functions has been measured in a variety of ways over the centuries since the relative dominance of the left hemisphere was first known. Functional magnetic resonance imaging (fMRI) presents a useful non-invasive method of assessing lateralisation that is being increasingly used in clinical practice and research. However, the methods used in the fMRI laterality literature currently are highly variable, making systematic comparisons across studies difficult. Here we consider the different methods of quantifying and classifying laterality that have been used in fMRI studies since 2000, with the aim of determining which give the most robust and reliable measurement. Recommendations are made with a view to informing future research to increase standardisation in fMRI laterality protocols. In particular, the findings reinforce the importance of threshold independent methods for calculating laterality indices, and the benefits of assessing heterogeneity of language laterality across multiple regions of interest and tasks. This systematic review was registered as a protocol on Open Science Framework: https://osf.io/hyvc4/. PMID- 28713658 TI - Morphological variation of Aphidius ervi Haliday (Hymenoptera: Braconidae) associated with different aphid hosts. AB - BACKGROUND: Parasitoids are frequently used in biological control due to the fact that they are considered host specific and highly efficient at attacking their hosts. As they spend a significant part of their life cycle within their hosts, feeding habits and life history of their host can promote specialization via host race formation (sequential radiation). The specialized host races from different hosts can vary morphologically, behaviorally and genetically. However, these variations are sometimes inconspicuous and require more powerful tools in order to detect variation such as geometric morphometrics analysis. METHODS: We examined Aphidius ervi, an important introduced biological control agent in Chile associated with a great number of aphid species, which are exploiting different plant hosts and habitats. Several combinations (biotypes) of parasitoids with various aphid/host plant combinations were analyzed in order to obtain measures of forewing shape and size. To show the differences among defined biotypes, we chose 13 specific landmarks on each individual parasitoid wing. The analysis of allometric variation calculated in wing shape and size over centroid size (CS), revealed the allometric changes among biotypes collected from different hosts. To show all differences in shape of forewings, we made seven biotype pairs using an outline-based geometric morphometrics comparison. RESULTS: The biotype A. pis_pea (Acyrthosiphon pisum on pea) was the extreme wing size in this study compared to the other analyzed biotypes. Aphid hosts have a significant influence in the morphological differentiation of the parasitoid forewing, splitting biotypes in two groups. The first group consisted of biotypes connected with Acyrthosiphon pisum on legumes, while the second group is composed of biotypes connected with aphids attacking cereals, with the exception of the R. pad_wheat (Rhopalosiphum padi on wheat) biotype. There was no significant effect of plant species on parasitoid wing size and shape. DISCUSSION: Although previous studies have suggested that the genotype of parasitoids is of greater significance for the morphological variations of size and shape of wings, this study indicates that the aphid host on which A. ervi develops is the main factor to alter the structure of parasitoid forewings. Bigger aphid hosts implied longer and broader forewings of A. ervi. PMID- 28713659 TI - A Descriptive Report of Early Mobilization for Critically Ill Ventilated Patients with Cancer. AB - BACKGROUND: Early mobilization protocols have been successfully implemented to improve function in critically ill patients; however, no study has focused on the oncology population. OBJECTIVES: To investigate the feasibility of early mobilization and describe the rehabilitation interventions and discharge outcomes in a cohort of critically ill patients with cancer. DESIGN: Retrospective review. METHODS: A retrospective analysis of patients with cancer who participated in occupational and physical therapy while on mechanical ventilation utilizing an institutional early mobilization protocol from June 2010 - July 2011, was completed. Demographic and clinical variables were abstracted, as well as occupational and physical therapy interventions. RESULTS: A cohort of 42 cancer patients on mechanical ventilation in the mixed medical/surgical intensive care unit of a comprehensive cancer center received early mobilization during the study period. The majority of participants demonstrated improved cognitive and functional status from the intensive care unit to hospital discharge. There were no reported adverse events during the occupational and physical therapy sessions. Among the 30 hospital survivors, 53% required continued rehabilitation services in their home environment and 40% were transferred to a rehabilitation facility. LIMITATIONS: Due to the small sample size, these findings are not generalizable to all critically ill cancer patients. There was no post-acute care follow-up of cognitive and physical functional performance. CONCLUSION: Early mobilization appears feasible in addressing the cognitive and functional needs of oncology patients in the intensive care unit. PMID- 28713660 TI - A Cross-Sectional Pharmacoepidemiological Study of the Utilization Pattern of Pre Anesthetic Medications in Major Surgical Procedures in a Tertiary Care Hospital. AB - OBJECTIVE : A study of the utilization pattern of pre-anesthetic medications in major surgical procedures. MATERIAL AND METHODS : A cross-sectional, pharmacoepidemiological study was conducted among patients undergoing surgical procedures in routine or emergency conditions under general anesthesia. The utilization of pre-anesthetic medicines in all patients was reported. RESULTS: A total of 110 patients (mean age - 42.36 years; 57.27% males) were enrolled. The major (>10%) indications for surgery were carcinoma/tumor - 25 (22.73%), perforation peritonitis - 20 (18.18%), and intestinal obstruction - 11 (10%). All patients received ranitidine plus metoclopramide. Injections of ondansetron, midazolam, pentazocin, anticholinergic agents, and fentanyl were used in 103 (93.64%), 103 (93.64%), 92 (83.64%), 84 (76.36%), and 23 (20.91%) patients, respectively. The dosage of ondansetron was 4 mg in 95 patients (86.36%), while 89.09% patients received 1 mg of midazolam. In 86 patients (78.18%), pentazocine was used in a 15 mg dose. Among the anticholinergic agents, glycopyrrolate was used in 76 patients (69.09%). Glycopyrrolate was used in a 0.2 mg dose in 74 patients (97.37%). The major indications for the use of fentanyl were carcinoma - 8 (34.8%), perforation peritonitis - 4 (17.4%), and surgery for intestinal obstruction - 3 (13%). CONCLUSION: The administration of ondansetron, midazolam, and pentazocin is very common (>80% patients) as pre-anesthetic medication. Glycopyrrolate was the preferred anticholinergic agent. In cancer patients, the use of fentanyl is common. PMID- 28713661 TI - Pre-surgical Provisional Prosthesis for Immediate Non-occlusal-loaded Flapless Implant. AB - A 49-year-old patient reported for immediate replacement of missing maxillary anterior teeth with implant-retained prosthesis. Elevation of flap alters the mucosal level, causes discomfort, and delays the restorative procedure. To maintain the esthetics, flapless surgery was planned. Since placement of an implant is pre-planned in a predetermined site, fabrication of the prostheses before commencement of the surgery, especially when replacing the teeth in the anterior region, could be a viable option. This case report explains the method of fabrication of the provisional restoration for flapless surgery in the presurgical phase. The technique would avoid any micromotion and implant instability caused due to abutment preparation and impression procedure postsurgically. PMID- 28713662 TI - Subacute Sclerosing Panencephalitis in a Child Suffering from Human Immunodeficiency Virus on "Highly Active Antiretroviral Therapy" - Can This be Another Instance of Immune Reconstitution Inflammatory Syndrome? AB - We report a 12-year-old boy with human immunodeficiency virus (HIV) who presented with rapidly progressive difficulty in ambulation. The symptoms started to worsen when he was put on antiretroviral therapy (ART). Our findings show that the dynamics of HIV-related immune suppression and highly active antiretroviral therapy (HAART) have an impact on the clinical course of Subacute sclerosing panencephalitis (SSPE). Slow progression is expected in children on HAART but in our case, we observe a complex interaction of the virus with the immune system and modification of disease course of SSPE with ART. The child we discuss in this case report developed rapidly progressive SSPE on HAART regime; so the possibility of SSPE to be labeled as immune reconstitution inflammatory syndrome (IRIS) should be considered. PMID- 28713663 TI - Correlation between Glycated Hemoglobin and Triglyceride Level in Type 2 Diabetes Mellitus. AB - CONTEXT: Dyslipidemia is quite prevalent in non-insulin dependent diabetes mellitus. Maintaining tight glycemic along with lipid control plays an essential role in preventing micro- and macro-vascular complications associated with diabetes. PURPOSE: The main purpose of the study was to highlight the relationship between glycosylated hemoglobin (HbA1c) and triglyceride levels. This may in turn help in predicting the triglyceride status of type 2 diabetics and therefore identifying patients at increased risk from cardiovascular events. Hypertriglyceridemia is one of the common risk factors for coronary artery disease in type 2 diabetes mellitus (DM). Careful monitoring of the blood glucose level can be used to predict lipid status and can prevent most of the complications associated with the disease. METHOD: This is a cross-sectional study using data collected from the outpatient diabetic clinic of Jinnah Postgraduate Medical Centre (JPMC) Karachi, Pakistan. Patients of age 18 years and above were recruited from the clinic. A total of consenting 509 patients of type 2 diabetes mellitus were enrolled over a period of 11 months. For statistical analysis, SPSS Statistics for Windows, Version 17.0 ( IBM Corp, Armonk, New York) was used and Chi-square and Pearson's correlation coefficient was used to find the association between triglyceride and HbA1c. The HbA1c was dichotomized into four groups on the basis of cut-off. Chi-square was used for association between HbA1c with various cut-off values and high triglyceride levels. Odds-ratio and its 95% confidence interval were calculated to estimate the level of risk between high triglyceride levels and HbA1c groups. The p-value < 0.05 was considered statistically significant for all the tests applied for significance. RESULT: The association of high triglyceride was evaluated in four different groups of HbA1c, with a cut-off seven, eight, nine and 10 respectively. With HbA1c cut-off value of 7%, 74% patients had high triglycerides and showed a significant association with high triglyceride levels at p < 0.001 and odds ratio was 2.038 (95% confidence interval: 1.397 - 2.972). Logistic regression models were adjusted for demographic factors (age, race, gender), lifestyle factors (smoking, body mass index, lifestyle) and health status factors (blood pressure, physician-rated health status). CONCLUSION: After adjusting for relevant covariates, glycated hemoglobin was positively correlated with high triglyceride. Hence, HbA1c can be an indicator of triglyceride level and can be one of the predictors of cardiovascular risk factors in type 2 diabetes mellitus. PMID- 28713665 TI - Neuromodulation Treatments for Schizophrenia. AB - Schizophrenia is a psychiatric disorder that causes great suffering and debilitation worldwide. We have a multitude of medications that are effective for psychosis. However, these have not been successful in treating the negative and cognitive symptom domains of schizophrenia. These symptoms are responsible for the larger part of functional impairments that result from schizophrenia. In addition, there are many patients for whom no significant improvement is achieved even in the positive symptom domain. Hence, other treatment modalities have been explored to help these patients. Electroconvulsive therapy and transcranial magnetic stimulation are two of the most promising adjunct treatment methods for medication resistant schizophrenia. Electroconvulsive therapy is the gold standard treatment for catatonias whether associated with schizophrenia, mood disorders or other non-psychiatric disorders. Although not effective for negative symptoms, electroconvulsive therapy provides substantial augmentation to antipsychotic medications in improving positive symptoms and overall severity. Electroconvulsive therapy should be considered more often in patients with inadequate response to antipsychotic medications even when they do not have prominent affective symptoms. Transcranial magnetic stimulation has emerged as a promising useful therapeutic tool in targeting medication resistant auditory hallucinations and negative symptoms. Transcranial magnetic stimulation has proven to be very safe and well-tolerated by the patients in spite of its labor intensiveness. The incorporation of transcranial magnetic stimulation to routine clinical use awaits further studies to substantiate its efficacy and to optimize and customize treatment parameters to individual patients and their symptom patterns. Moreover, combining transcranial magnetic stimulation with electroconvulsive therapy to synergize their likely different mechanisms of action is another exciting possibility. PMID- 28713664 TI - CDK inhibitors for muscle stem cell differentiation and self-renewal. AB - Regeneration of muscle is undertaken by muscle stem cell populations named satellite cells which are normally quiescent or at the G0 phase of the cell cycle. However, upon signals from damaged muscle, satellite cells lose their quiescence, and enter the G1 cell cycle phase to expand the population of satellite cell progenies termed myogenic precursor cells (MPCs). Eventually, MPCs stop their cell cycle and undergo terminal differentiation to form skeletal muscle fibers. Some MPCs retract to quiescent satellite cells as a self-renewal process. Therefore, cell cycle regulation, consisting of satellite cell activation, proliferation, differentiation and self-renewal, is the key event of muscle regeneration. In this review, we summarize up-to-date progress on research about cell cycle regulation of myogenic progenitor cells and muscle stem cells during embryonic myogenesis and adult muscle regeneration, aging, exercise and muscle diseases including muscular dystrophy and muscle fiber atrophy, especially focusing on cyclin-dependent kinase inhibitors (CDKIs). PMID- 28713666 TI - Gramene Database: Navigating Plant Comparative Genomics Resources. AB - Gramene (http://www.gramene.org) is an online, open source, curated resource for plant comparative genomics and pathway analysis designed to support researchers working in plant genomics, breeding, evolutionary biology, system biology, and metabolic engineering. It exploits phylogenetic relationships to enrich the annotation of genomic data and provides tools to perform powerful comparative analyses across a wide spectrum of plant species. It consists of an integrated portal for querying, visualizing and analyzing data for 44 plant reference genomes, genetic variation data sets for 12 species, expression data for 16 species, curated rice pathways and orthology-based pathway projections for 66 plant species including various crops. Here we briefly describe the functions and uses of the Gramene database. PMID- 28713667 TI - Absent congenital cervical pedicle nearly misdiagnosed as a facet dislocation: A case report. AB - BACKGROUND: Cervical spinal injury encompasses up to 1.5% of all pediatric injuries. Children, and more specifically infants, are a difficult subset of patients to obtain neurological exam in the setting of trauma, thus necessitating the use of cervical X-rays, CT scans, and MRI imaging. CASE DESCRIPTION: A healthy, 15-month-old boy had an unwitnessed fall down a flight of stairs and received a CT scan of the head and cervical spine in the emergency department due to cephalohematoma and mechanism of injury. The patient was initially diagnosed with a unilateral facet dislocation but after additional imaging and rigorous interdisciplinary discussions, the patient was correctly diagnosed with a congenitally absent left C5 pedicle. Surgical intervention was not pursued and the patient was discharged home with close follow up. CONCLUSION: In the acute trauma setting, congenital absent cervical pedicle can be difficult to differentiate from unilateral facet dislocation and may require the use of advanced imaging and close communication between the neurosurgery and radiology departments. Given the high morbidity and mortality involved in the repair of facet dislocation in a child, it is crucial to maintain high degree of clinical suspicion for absent spinal pedicle. In this case, the patient nearly underwent surgical intervention, but was ultimately able to be discharged home with no symptoms or deficits after correct diagnosis. PMID- 28713668 TI - What's the good of education on our overall quality of life? A simultaneous equation model of education and life satisfaction for Australia. AB - Many economists and educators favour public support for education on the premise that education improves the overall quality of life of citizens. However, little is known about the different pathways through which education shapes people's satisfaction with life overall. One reason for this is because previous studies have traditionally analysed the effect of education on life satisfaction using single-equation models that ignore interrelationships between different theoretical explanatory variables. In order to advance our understanding of how education may be related to overall quality of life, the current study estimates a structural equation model using nationally representative data for Australia to obtain the direct and indirect associations between education and life satisfaction through five different adult outcomes: income, employment, marriage, children, and health. Although we find the estimated direct (or net) effect of education on life satisfaction to be negative and statistically significant in Australia, the total indirect effect is positive, sizeable and statistically significant for both men and women. This implies that misleading conclusions regarding the influence of education on life satisfaction might be obtained if only single-equation models were used in the analysis. PMID- 28713669 TI - The promise of emerging developments and concepts in mesothelioma. PMID- 28713670 TI - In vitro experimental models of mesothelioma revisited. AB - Malignant pleural mesothelioma (MPM) is a biologically unusual, highly aggressive cancer that defies current multimodality treatments. Epidemiologic data suggest that this malignancy has not abated despite increasingly strict environmental regulations on asbestos, the putative causative agent for sporadic cases. An incomplete understanding of all the factors mechanistically driving mesothelioma is largely responsible for the current lack of curative treatments. Many approaches have been employed to ascertain the step-by-step molecular events involved in mesothelioma oncogenesis including in vitro, small animal in vivo, and human experimental models; though clearly defined, druggable mechanisms still are elusive. Importantly, the foundation of the latest accepted model of tumor initiation is derived from in vitro systems. A thorough review of in vitro mesothelioma oncogenesis models may suggest further opportunities for discovery. PMID- 28713671 TI - Diagnostic and prognostic biomarkers for malignant mesothelioma: an update. AB - Malignant mesothelioma (MM) is an aggressive and lethal cancer, mostly related to inhalation of asbestos and erionite fibers. MM is associated with poor prognosis, because of its resistance to current therapies, even if higher survival occurs in patients diagnosed and treated when at stage I of the disease. However, these do not exceed 5% of the total number of cases, due to the inadequacy of the existing biomarkers for early and accurate diagnosis. Therefore, new effective biomarkers are needed for MM detection at earlier stages and to develop tailored therapies. Here we review the most promising biomarkers in MM to date: mesothelin, soluble mesothelin-related peptides (SMRPs), megakaryocyte potentiating factor (MPF), Osteopontin (OPN), Fibulin-3, high mobility group B1 (HMGB1), microRNAs (miRNAs), multiplex protein signatures. The validation of these biomarkers will allow their use, alone or in combination, for monitoring individuals from cohorts at risk of MM and attaining early detection of MM that is instrumental in improving patient survival. PMID- 28713672 TI - BAP1, a tumor suppressor gene driving malignant mesothelioma. AB - Like cancer generally, malignant mesothelioma (MM) is a genetic disease at the cellular level. DNA copy number analysis of mesothelioma specimens has revealed a number of recurrent sites of chromosomal loss, including 3p21.1, 9p21.3, and 22q12.2. The key inactivated driver genes located at 9p21.1 and 22q12.2 were discovered two decades ago as being the tumor suppressor loci CDKN2A and NF2, respectively. Only relatively recently was the BAP1 gene determined to be the driver gene at 3p21.1 that is somatically inactivated. In 2011, we reported germline mutations in BAP1 in two families with a high incidence of mesothelioma and other cancers such as uveal melanoma (UM). As a result of a flurry of research activity over the last 5-6 years, the BAP1 gene is now firmly linked causally to a novel tumor predisposition syndrome (TPDS) characterized by increased susceptibility to mesothelioma, UM, cutaneous melanoma (CM) and benign melanocytic tumors, as well as several other cancer types. Moreover, results from recent in vivo studies with genetically engineered Bap1-mutant mouse models and new functional studies have provided intriguing biological insights regarding BAP1's role in tumorigenesis. These and other recent findings offer new possibilities for novel preventative and therapeutic strategies for MM patients. PMID- 28713673 TI - Intraoperative near-infrared imaging of mesothelioma. AB - Though difficult to achieve, complete resection of malignant pleural mesothelioma is paramount to improving patient survival. Surgeons have traditionally been limited to using visual inspection and manual palpation to locate and remove cancerous tissue. However, intraoperative molecular imaging (IMI) is a promising new technology in surgery. Molecular imaging utilizes a fluorescent tracer that selectively accumulates in cancer cells. An imaging device is then used to detect and augment the fluorescent signal emitted from the fluorescent cancer cells. Our group and others have demonstrated that molecular imaging with either indocyanine green (ICG) or a folate receptor alpha (FRalpha) targeted fluorophore can accurately identify a number of intrathoracic malignancies. Early studies of intraoperative imaging have suggested its efficacy for malignant pleural mesothelioma. In a murine model of mesothelioma, intraoperative imaging was found to have sensitivity of 87% and specificity of 83%. In a pilot human study, eight patients with biopsy-proven epithelial malignant pleural mesothelioma were administered 5 mg/kg of intravenous ICG injection 24 h prior to resection. The following day, a near-infrared (NIR) imaging device was used to detect tumor fluorescence intraoperatively. After what was believed to be complete tumor excision, the wound bed was re-imaged for residual fluorescence indicative of retained tumor. When residual fluorescence was detected, additional tissue was resected, if feasible, and specimens were sent for pathologic correlation. In all cases, intraoperative fluorescence localized to mesothelioma deposits which were confirmed on final pathology. Following resection, fluorescence was confirmed ex vivo with a mean tumor-to-background ratio (TBR) of 3.2 (IQR: 2.9-3.4). It is hoped that this technology will improve outcomes for mesothelioma patients by allowing for a more complete oncologic resection. PMID- 28713674 TI - Intraoperative adjuncts for malignant pleural mesothelioma. AB - Malignant pleural mesothelioma (MPM) is a rapidly fatal disease. Multimodality surgically based therapies may extend survival in select patients, however, local relapse after resection is common. Novel intraoperative adjunctive therapies including heated intraoperative chemotherapy (HIOC), heated intraoperative povidone-iodine (PVP-I), and photodynamic therapy (PDT) target micrometastatic disease and aim to improve local control. This review details the most recent studies and trials of HIOC, heated intraoperative PVP-I, and PDT, this aims to provide an update on some of the most promising intraoperative adjuncts for patients with MPM. PMID- 28713676 TI - Immunotherapy for malignant pleural mesothelioma: current status and future directions. AB - Malignant pleural mesothelioma (MPM) has been marked historically by poor prognosis. Current standard of care for this deadly disease results in sub optimal improvements in overall survival (OS), which has prompted researchers to explore innovative treatment alternatives. Immunotherapy is an emerging therapeutic modality that harnesses the power of the human immune system. In this review, we summarize the different methods of immunotherapy for malignant pleural mesothelioma. Using ClinicalTrials.gov we searched the terms "immunotherapy" and "immune therapy" combined with "pleural mesothelioma". Our search yielded 75 trials, among which 37 trials met our specific criteria. Our search identified immune checkpoint blockade, immunotoxin therapy, anticancer vaccines, oncolytic viral therapy, and adoptive cell therapy as the most common and pertinent methods of immunotherapy currently being assessed in clinical trials. We have reviewed the most up-to-date clinical trials involving immunotherapeutic approaches for the treatment of malignant pleural mesothelioma. In addition to highlighting some of the successes of immunotherapy, we also have identified limitations that must be overcome to improve the efficacy of these therapies. PMID- 28713677 TI - Radio-immunotherapy and chemo-immunotherapy as a novel treatment paradigm in malignant pleural mesothelioma. AB - Malignant pleural mesothelioma (MPM) is an aggressive neoplasm with poor outcome. Novel radical radiation techniques using intensity modulated radiation therapy (IMRT) have become an important component of therapy in mesothelioma. Immunotherapy also provides new therapeutic options. However, how best to integrate immunotherapy with standard therapy such as radiation, chemotherapy and surgery remains unknown. A change of paradigm from adjuvant normofractionation to induction accelerated hypofractionated hemithoracic radiation could provide a platform to combine immunotherapy due to the potential benefit of short course high dose radiation on the immune system. Immunotherapy can also be combined with chemotherapy. Although chemotherapy is generally considered immunosuppressive, some chemotherapeutic agents do induce cell death that can be immunogenic and stimulate a specific immune response against the tumor. Immunotherapy could also be used in between cycles of chemotherapy to limit tumor cell repopulation and optimize the results of both treatments. The integration of immunotherapy into a multimodality approach is opening new avenue of treatment for mesothelioma. PMID- 28713678 TI - Drug development against the hippo pathway in mesothelioma. AB - Advances in the treatments for malignant pleural mesothelioma (MPM) have been disappointing until recently. Conventional cytotoxic drugs fail in MPM in part because they do not address the cancer stem cell population or stem cell pathways that drive tumor resistance and resurgence following treatment. The Hippo stem cell pathway regulates cell contact inhibition with tumor suppressor genes such as NF2 (Neurofibromatosis 2) upstream controlling YAP (Yes-associated protein 1) oncogenes. NF2 is mutated in 40-50% of all MPM and downstream YAP is constitutively active in greater than 70% of MPM, making the downstream YAP/TEAD (transcriptional enhancer associate domain) complex the ultimate target. Novel small molecule YAP inhibitors are showing promising results in preclinical studies and may prove to be effective chemotherapy drugs in MPM. PMID- 28713675 TI - Novel systemic therapy against malignant pleural mesothelioma. AB - Malignant pleural mesothelioma is an aggressive tumor of the pleura with an overall poor prognosis. Even with surgical resection, for which only a subset of patients are eligible, long term disease free survival is rare. Standard first line systemic treatment consists of a platinum analog, an anti-metabolite, and sometimes anti-angiogenic therapy, but there is currently no well-established standard therapy for refractory or relapsed disease. This review focuses on efforts to develop improved systemic therapy for the treatment of malignant pleural mesothelioma (MPM) including cytotoxic systemic therapy, a variety of tyrosine kinase inhibitors and their downstream effector pathways, pharmacologic targeting of the epigenome, novel approaches to target proteins expressed on mesothelioma cells (such as mesothelin), arginine depletion therapy, and the emerging role of immunotherapy. Overall, these studies demonstrate the challenges of improving systemic therapy for MPM and highlight the need to develop therapeutic strategies to control this disease. PMID- 28713679 TI - Targeting eukaryotic protein translation in mesothelioma. AB - The default mechanism for protein translation in eukaryotes involves activation of the eIF4 complex at the 5' end of mRNA. This activity is upregulated in cancers, resulting in the expression of a variety of proteins necessary for the development and maintenance of the neoplastic state. Not surprisingly, mesothelioma demonstrates this same reliance on activation of 5' cap mediated translation. Efforts are ongoing to target and exploit our knowledge of this key molecular switch for cancer therapy. Agents targeting the critical eIF4E cap binding protein, disruption of the eIF4 complex, and exploitation for oncolytic virotherapy are some of the important areas of current research in mesothelioma protein translational research. PMID- 28713681 TI - The use of TCP based EUD to rank and compare lung radiotherapy plans: in-silico study to evaluate the correlation between TCP with physical quality indices. AB - BACKGROUND: To apply the equivalent uniform dose (EUD) radiobiological model to estimate the tumor control probability (TCP) scores for treatment plans using different radiobiological parameter settings, and to evaluate the correlation between TCP and physical quality indices of the treatment plans. METHODS: Ten radiotherapy treatment plans for lung cancer were generated. The dose distributions were calculated using anisotropic analytical algorithm (AAA). Dose parameters and quality indices derived from dose volume histograms (DVH) for target volumes were evaluated. The predicted TCP was computed using EUD model with tissue-specific parameter (a=-10). The assumed radiobiological parameter setting for adjuvant therapy [tumor dose to control 50% of the tumor (TCD50) =36.5 Gy and gamma50=0.72] and curative intent (TCD50=51.24 Gy and gamma50=0.83) were used. The bootstrap method was used to estimate the 95% confidence interval (95% CI). The coefficients (rho) from Spearman's rank test were calculated to assess the correlation between quality indices with TCP. Wilcoxon paired test was used to calculate P value. RESULTS: The 95% CI of TCP were 70.6-81.5 and 46.6 64.7, respectively, for adjuvant radiotherapy and curative intent. The TCP outcome showed a positive and good correlation with calculated dose to 95% of the target volume (D95%) and minimum dose (Dmin). Consistently, TCP correlate negatively with heterogeneity indices. CONCLUSIONS: This study confirms that more relevant and robust radiobiological parameters setting should be integrated according to cancer type. The positive correlation with quality indices gives chance to improve the clinical out-come by optimizing the treatment plans to maximize the Dmin and D95%. This attempt to increase the TCP should be carried out with the respect of dose constraints for organs at risks. However, the negative correlation with heterogeneity indices shows that the optimization of beam arrangements could be also useful. Attention should be paid to obtain an appropriate optimization of initial plans, when comparing and ranking radiotherapy plans using TCP models, to avoid over or underestimated for TCP outcome. PMID- 28713680 TI - Targeting the epigenome in malignant pleural mesothelioma. AB - Malignant pleural mesotheliomas (MPM) are notoriously refractory to conventional treatment modalities. Recent insights regarding epigenetic alterations in MPM provide the preclinical rationale for the evaluation of novel combinatorial regimens targeting the epigenome in these neoplasms. PMID- 28713682 TI - Predictive biomarkers of immunotherapy for non-small cell lung cancer: results from an Experts Panel Meeting of the Italian Association of Thoracic Oncology. AB - Unleashing the potential of immune system to fight cancer has become one of the main promising treatment modalities for advanced non-small cell lung cancer (NSCLC). The knowledge of numerous factors that come into play in the cancer immunity cycle provide a wide range of potential therapeutic targets, including monoclonal antibodies that inhibits the programmed death-1 (PD-1) checkpoint pathway. Over the last two years, nivolumab, pembrolizumab and atezolizumab received approval for treatment of pretreated advanced NSCLC, and more recently, immunotherapy with pembrolizumab is the new standard of care as first-line in patients with high levels of programmed death-ligand 1 (PD-L1) expression. Selection of patients is mandatory and PD-L1 is the only biomarker currently available in clinical practice. However, PD-L1 staining is an imperfect marker, whose negativity does not exclude a response to immunotherapy, as well as the roughly half of patients are "not-responders" despite high tumor PD-L1 levels. The right cut-off, the differences among various immune checkpoint inhibitors and among various antibody clones, and a not trivial activity reported even in PD-L1 negative tumors are questions still open. New biomarkers beyond to PD-L1 assays as well as new strategies, including combination of immune checkpoint inhibitors are under investigation. PMID- 28713683 TI - Do we really care about incidental lung nodules?-Review of atypical lung carcinoid and a proposal for systematic patient follow up. AB - Atypical lung carcinoids are intermediate-grade neuroendocrine tumors (NETs) with malignant potential. They are often detected incidentally on imaging done for non related causes, as the patients are frequently asymptomatic. Histopathology is required to confirm the diagnosis with immunohistochemistry (IHC). Due to their indolent nature, these are often diagnosed only in the advanced stages. Treatment options include chemoradiation for widespread disease versus surgery for local or minimally invasive disease. This article describes a nonsmoker female with enlarging solitary pulmonary nodule who was initially lost to follow up, subsequently operated and with final pathology revealing atypical lung carcinoid. This case stress on the schematic follow up of these incidentally detected pulmonary nodules. Inspired from the mandatory lay mammography report letters recommended by ACR, this article proposes sending lay letters to patients for pulmonary nodule follow up, directly from the Radiology Department to reinforce the importance of timely follow up, which will complement the information provided to the patient from their primary care physician or pulmonologist's office. PMID- 28713684 TI - Combination MET- and EGFR-directed therapy in MET-overexpressing non-small cell lung cancers: time to move on to better biomarkers? PMID- 28713686 TI - Development of an instrument to measure patients' attitudes towards involuntary hospitalization. AB - AIM: To construct and assess the psychometric properties of an instrument to measure patients' attitudes towards involuntary hospitalization. METHODS: This is a two phase study. In the first phase, based on comprehensive literature review, a twenty one item scale to measure patients' attitudes to involuntary admission was constructed. Forensic and inpatient Psychiatrists, patients' advocates and legal experts (n = 15) were invited to participate in the validation process of the written instrument, by formally rating each item of the instrument for its relevancy in measuring patients' attitudes to involuntary admission. In the second phase of the project, the instrument was administered to a sample of eighty consecutive patients, who were admitted involuntarily to an acute psychiatric unit of a teaching hospital. All patients completed the constructed attitudes towards involuntary admission scale, and the client satisfaction questionnaire. RESULTS: Responses from psychiatry and advocacy experts provided evidence for face and content validity for the constructed instrument. The internal consistency reliability of the instrument is 0.84 (Chronbach' alpha), factor analysis resulted in three correlated, and theoretically meaningful factors. There was evidence for content, convergent, and concurrent validity. CONCLUSION: A reliable twenty one item instrument scale to measure patients' attitudes to involuntary admission was developed. The developed instrument has high reliability, there is strong evidence for validity, and it takes ten minutes to complete. PMID- 28713685 TI - Understanding the pathophysiology of postpartum psychosis: Challenges and new approaches. AB - Postpartum psychosis is a severe psychiatric condition which affects 1-2 of every 1000 mothers shortly after childbirth. Whilst there is convincing evidence that the condition is precipitated by a complex combination of biological and environmental factors, as yet the pathophysiological mechanisms remain extremely poorly defined. Here, I critically review approaches that have been, or are being, employed to identify and characterise such mechanisms; I also review a recent animal model approach, and describe a novel biological risk model that it suggests. Clarification of biological risk mechanisms underlying disorder risk should permit the identification of relevant predictive biomarkers which will ensure that "at risk" subjects receive prompt clinical intervention if required. PMID- 28713687 TI - Group psychological intervention for maternal depression: A nested qualitative study from Karachi, Pakistan. AB - AIM: To understand the experience of maternal depression, the factors implicated in accessing health, and the acceptability of the psychosocial intervention. METHODS: The participants were recruited from the paediatrics outpatient department of Civil Hospital Karachi, Pakistan. The study started in December 2009 and completed in December 2010. Women with maternal depression, aged 18-44 years with children aged 0-30 mo who had received nutritional supplements, and participated in the intervention programme [called Learning through Play (LTP) plus] were included in the study. Qualitative interviews were conducted with 8 participants before the intervention and 7 participants after the intervention. A semi structured topic guide was used to conduct the interviews. RESULTS: Framework analysis procedures were used to analyse the qualitative data. Four themes emerged: (1) the women's contextual environment: Interpersonal conflicts, lack of social support and financial issues being the major barriers in assessing healthcare; (2) women's isolation and powerlessness within the environment: Sense of loneliness was identified as a restricting factor to access healthcare; (3) the impact of the intervention (LTP-Plus): Women felt "listened to" and seemed empowered; and (4) empowered transformed women within the same contextual environment: The facilitator provided a "gardening role" in nurturing the women resulting in a positive transformation within the same environment. The women's homes seemed to be more happy homes and there was a positive change in their behaviour towards their children. CONCLUSION: Findings informed the further development and testing of culturally-appropriate psychosocial intervention (LTP+) for addressing maternal depression. PMID- 28713688 TI - Childhood trauma and factors associated with depression among inpatients with cardiovascular disease. AB - AIM: To identify factors associated with depressive symptoms among inpatients with cardiovascular disease (CVD). METHODS: This is a cross-sectional study performed in a subsample of a large cross-sectional research that investigated affective disorders and suicide behaviour among inpatients hospitalized in non surgical wards of the University Hospital of the Federal University of Minas Gerais from November 2013 to October 2015. Sociodemographic and clinical data were obtained through a structured interview and medical record review. Depression was assessed by the depression subscale of the Hospital Anxiety and Depression Scale, with scores >= 8 considered as positive screening for depression. We used the Fagestrom Test for Nicotine Dependence to characterize nicotine dependence. For assessing resilience and early-life trauma, we used the raw scores of the Wagnild and Young Resilience Scale and Childhood Trauma Questionnaire, respectively. RESULTS: At endpoint, we included 137 subjects. Thirty-eight (27.7%) subjects presented depressive symptoms and nine (23.7%) of those were receiving antidepressant treatment during hospitalization. The female sex; a lower mean educational level; a greater prevalence of previous suicide attempts; a higher level of pain; a higher prevalence of family antecedents of mental disorders; a lower resilience score; and higher childhood trauma score were the factors significantly associated with screening positive for major depression (P < 0.05). Multivariate analysis demonstrated that the factors independently associated with the depressive symptoms were a higher childhood trauma severity (OR = 1.06; P = 0.004); moderate to severe nicotine dependence (OR = 8.58; P = 0.008); and the number of previous hospital admissions (OR = 1.11; P = 0.034). The obtained logistic model was considered valid, indicating that the three factors together distinguished between having or not depressive symptoms, and correctly classified 74.6% of individuals in the sample. CONCLUSION: Our results demonstrate that inpatients presenting both CVD and a positive screening for depression are more prone to have antecedents of childhood trauma, nicotine dependence and a higher number of previous hospitalizations. PMID- 28713690 TI - Three-dimensional stereotactic surface projection in the statistical analysis of single photon emission computed tomography data for distinguishing between Alzheimer's disease and depression. AB - AIM: To evaluate usefulness of single photon emission computed tomography (SPECT) with three-dimensional stereotactic surface projection (3D-SSP) in distinguishing between Alzheimer's disease (AD) and depression. METHODS: We studied 43 patients who presented with both depressive symptoms and memory disturbance. Each subject was evaluated using the following: (1) the Minimal Mental State Examination; (2) the Hamilton Rating Scale for Depression; (3) Clinical Global Impression-Severity scale (CGI-S); and (4) SPECT imaging with 3D-SSP. RESULTS: The MMSE scores correlated significantly with the maximum Z-scores of AD-associated regions. CGI S scores correlated significantly with the maximum Z-scores of depression associated regions. Factor analysis identified three significant factors. Of these, Factor 1 could be interpreted as favouring a tendency for AD, Factor 2 as favouring a tendency for pseudo-dementia, and Factor 3 as favouring a depressive tendency. CONCLUSION: We investigated whether these patients could be categorized as types: Type A (true AD), Type B (pseudo-dementia), Type C (occult AD), and Type D (true depression). The factor scores in factor analysis supported the validity of this classification. Our results suggest that SPECT with 3D-SSP is highly useful for distinguishing between depression and depressed mood in the early stage of AD. PMID- 28713689 TI - Relation of binge eating disorder with impulsiveness in obese individuals. AB - AIM: To investigate the levels of impulsiveness, and the relationship between the binge eating disorder (BED) and the levels of impulsiveness in obese individuals. METHODS: Two hundred and forty-one obese patients who were included in the study and candidate for bariatric surgery (weight loss surgery) were clinically interviewed to identify the BED group, and patients were divided into two groups: Those with BED and those without BED. The comorbidity rate of groups was determined by using structured clinical interview for DSM-IV (SCID-I). A sociodemographic data form including the story of previous psychiatric treatment, structured clinical interview for DSM-IV (SCID-I), Beck Anxiety Inventory, Beck Depression Inventory (BDI) and Barratt Impulsiveness Scale-11 were applied to both of the groups. RESULTS: In regard to 241 obese individuals included in the study, total score and score of attention subscale for BED (+) group were significantly high (P < 0.05). In addition, suicide attempt, story of psychiatric consultation, and score for BDI were again significantly high in the BED (+) group (P < 0.05). CONCLUSION: In assessment of obese individuals, assessment of associated psychopathology such as impulsive characteristics and suicide attempt in addition to disrupted eating behaviors will allow to have a more extensive view. PMID- 28713691 TI - Cognitive correlates of neuroimaging abnormalities in the onset of schizophrenia: A case report. AB - Increasing evidence shows that cognitive impairment and brain abnormalities can appear early in the first episodes of schizophrenia, but it is currently debated how brain changes can correlate with clinical presentation of schizophrenic patients. Of note, this report describes the case of a young schizophrenic male presenting parietal magnetic resonance/positron emission tomography abnormalities and cognitive impairment, documented by specific neuropsychological tests. In our knowledge only few studies have investigated if neuropsychological abnormalities could be concomitant with both structural and functional neuroimaging. This case shows that impairment in specific cognitive domains is associated with structural/functional brain abnormalities in the corresponding brain areas (frontal and parietal lobes), supporting the hypothesis of disconnectivity, involving a failure to integrate anatomical and functional pathways. Future research would define the role of cognitive impairment and neurodegeneration in psychiatric nosography and, in particular, their role in the early phases of illness and long-term outcome of schizophrenic patients. PMID- 28713692 TI - Overview of robotic thyroidectomy. AB - With the advancement and adaptation of technology, there has been a tremendous evolution in the surgical approaches for thyroidectomy. Robotic thyroidectomy has become increasingly popular worldwide attracting both surgeons and patients searching for new and innovative techniques for thyroidectomy with a superior cosmetic result when compared to the conventional open procedures. In this review, we describe the following surgical approaches for robotic thyroidectomy: transaxillary, retroauricular (facelift) and transoral. The advantages and disadvantages as well as limitations of each approach are examined, and future directions of robotic thyroidectomy are discussed. PMID- 28713693 TI - Gasless trans-axillary robotic thyroidectomy: the introduction and principle. AB - A historic review of the main stages of evolution of the minimally-invasive techniques in thyroid surgery. The endoscopic era is divided into direct and indirect approaches. Examples are the minimally invasive video-assisted thyroidectomy (MIVAT) and the minimally invasive lateral approach. The indirect approach is divided into transaxillary and chest/breast incisions. A brief historic review of the advent of robots to the medical and mainly surgical field. And finally, an introduction to transaxillary robotic thyroidectomy. PMID- 28713694 TI - Gasless trans-axillary robotic thyroidectomy: the technique and evidence. AB - Robot assisted thyroid surgery has the advantage of a superior field vision and technical advancements of robotic technology that have permitted novel remote access thyroid surgical approaches. Gasless trans-axillary robot-assisted thyroidectomy has been proved to be among the most current feasible approaches. This approach offers an excellent cosmetic outcome, with comparable outcomes to conventional surgical approaches. This review aims to provide details of this specific remote access technique for thyroid resection with most recent evidences in the literature. PMID- 28713695 TI - Robotic modified radical neck dissection with bilateral axillo-breast approach. AB - Bilateral axillo-breast approach (BABA) robotic thyroidectomy has been performed since 2008, and the indications of the BABA robotic operation has been widened to the robotic modified radical neck dissection (MRND). The indication for BABA robotic MRND is suspicious lateral neck metastasis of well-differentiated thyroid carcinoma, and the contraindication is far advanced carcinoma such as encasement of common carotid artery. Surgical procedures start from flap formation as a routine BABA robotic thyroidectomy and the lateral neck dissection is performed from level IV and Vb to level III and IIA. The procedures are very similar to those of open MRND. Comparison between robotic MRND and open MRND in mean age, sex, body mass index, and tumor size were not different significantly. There was no statistically significant difference in the number of retrieved lymph nodes, metastatic lymph nodes or stimulated thyroglobulin level between the groups. The operation time was longer in the robotic group. BABA robotic MRND can be safe and feasible method to treat lateral neck metastasis of well differentiated thyroid carcinoma. More prospective, controlled, multicenter studies are required to establish robotic MRND as an alternative standard and to justify additional costs beyond the cosmetic advantages. PMID- 28713696 TI - Bilateral axillo-breast approach robotic thyroidectomy: review of evidences. AB - The bilateral axillo-breast approach (BABA) is one of the most popular contemporary remote-access thyroidectomy techniques. While the initial experiences with BABA endoscopic thyroidectomy (ET) were associated with some technical challenges and safety concerns, many limitations of the technique could now be substantially overcome by BABA robotic thyroidectomy (RT). In this review, the current literature evidences of BABA RT were analyzed. Data regarding the patient selection, the learning curve, and the comparison with open thyroidectomy (OT) and BABA ET were examined. Careful case selection for BABA RT should be undertaken according to factors related to the patient and the thyroid pathology. The learning curve of BABA RT was about 40 cases. Comparing to OT, BABA RT was comparable to OT for the complication profiles and most perioperative outcomes. But it was associated with longer operative time, higher cost and possibly inferior oncological control with lower number of central lymph node (LN) retrieved. When compared to BABA ET, BABA RT was comparable for most perioperative outcomes except longer operative time and higher cost. Yet, BABA RT was superior to BABA ET for better oncological control. BABA RT is a safe and effective procedure for most benign thyroid conditions and low-risk differentiated thyroid cancers (DTC). PMID- 28713697 TI - Safe implementation of retroauricular robotic and endoscopic neck surgery in South America. AB - In the last three decades, otolaryngology and head and neck oncological surgery have shown remarkable progress with the development of several modalities of endoscopic-assisted minimally invasive surgeries. More recently, the Da Vinci robotic surgery system has promoted the development of several surgical approaches with less morbidity and better cosmetic results, including the transaxillary and retroauricular approaches for thyroid surgery and neck dissections. In South America, there are several shortcomings regarding financial resources as well as the lack of support for innovation leading to a significant delay in adoption of numerous technological advances in medical practice. Despite these obstacles, we obtained training in transoral robotic surgery and neck procedures, and then decided to implement neck endoscopic and robotic surgery at our institution. We developed a collaborative training program with Yonsei University that, together with several local measures, allowed for a safe implementation. From June 2014 to December 2016, we have performed a total of 121 retroauricular neck surgeries, of which 65 were robotic-assisted and 56 were endoscopic assisted procedures, with a complication rate that seems to be comparable to conventional procedures in our experience and a smooth learning curve. Safety compliance has been continuously assessed. Aiming to develop and disseminate these techniques, we have ongoing collaborative work with Yonsei University faculty, to continue increasing our clinical experience, and we are now preparing the group and infrastructure to establish a local training program for South American surgeons. We have been presenting our results at national and international medical meetings and started to publish the preliminary results in peer reviewed medical journals. The emphasis is that a retroauricular approach is a therapeutic option to be considered, especially for young patients. Media exposure has been avoided so far. As expected, resistance by our peers is still present and much more work is needed to overcome it, including the generation of data on the outcomes and a critical analysis of the advantages and disadvantages of endoscopic and robotic neck surgery. PMID- 28713698 TI - Robotic retroauricular thyroidectomy: initial experience from India. AB - Robotic thyroidectomy is getting accepted worldwide, but, majority of the literature is from South Korea. The purpose of this paper is to review the early experiences with robotic retroauricular (RA) thyroidectomy from India. The rationale for robotic thyroidectomy, its advantages and disadvantages are reviewed. The reasons for selecting the RA approach and the criteria used for selecting the patients are discussed. The early experience and outcomes of 29 patients, from three centres across India is presented. Robotic approaches score above endoscopic methods. RA approach may have some technical advantages for the head and neck surgeons. Sufficient cadaver and preclinical training should be undertaken. Standardized and formal teaching for robotic surgical skill is necessary. Case selection is important especially in the initial phases of the learning curve. Our early experience with robotic thyroidectomy was encouraging. PMID- 28713699 TI - Transoral thyroidectomy: why is it needed? AB - Transoral thyroidectomy (TOT) represents reasonably the desirable minimally invasive approach to the gland due to the scarless non-visible incisions, the limited distance between the gland and the access that minimize tissue dissection and respect of the surgical anatomical planes. Patients are routinely selected according to an extensive inclusion criteria: (I) ultrasonographically (US) estimated thyroid diameter not larger than 10 cm; (II) US gland volume <=45 mL; (III) nodule size <=50 mm; (IV) a benign tumor, such as a thyroid cyst, single nodular goiter, or multinodular goiter; (V) follicular neoplasm; (VI) papillary microcarcinoma without lymph node metastasis. The operation is realized through median, central approach which allows bilateral exploration of the thyroid gland and central compartment. TOT is succeed both endoscopically adopting ordinary endoscopic equipments or robotically. In detail three ports are placed at the inferior oral vestibule: one 10-mm port for 30 degrees endoscope and two 5-mm ports for dissecting, coagulating and neuromonitoring instruments. Low CO2 insufflation pressure is set at 6 mmHg. An anterior cervical subplatysmal space is created from the oral vestibule down to the sternal notch, laterally to the sterncleidomuscles similar to that of conventional thyroidectomy. TOT is now reproducible in selective high volume endocrine centers. PMID- 28713700 TI - Transoral endoscopic thyroidectomy using vestibular approach: updates and evidences. AB - Recently, natural orifice transluminal endoscopic surgery (NOTES) has been applied in thyroid surgery with transoral access. The benefit of transoral endoscopic thyroidectomy is the potential for scar-free surgery. However, there are many concerns over some aspects, such as infection, recurrent laryngeal nerve injury, and oncological outcome. In this paper, we have reviewed the development history and the current clinical evidence of this innovative surgery. We conclude that the transoral endoscopic thyroidectomy vestibular approach (TOETVA) is feasible and can be considered no longer an experimental operation. PMID- 28713701 TI - Transoral robotic thyroidectomy (TORT): procedures and outcomes. AB - Remote-access approaches to the thyroid gland have seen a rapid evolution recently with the development of various techniques to minimize the cosmetic and quality-of-life impact of a visible scar. Most approaches have required significantly more tissue dissection and have been limited in their extent to treat contralateral disease. The transoral approach is the most recent iteration of "scarless" thyroidectomy and offers various advantages over other techniques including less tissue dissection, equal access to both sides of the neck, and a superb midline view of the anatomy. Transoral thyroidectomy may be performed with either laparoscopic or robotic technology, each with various advantages and disadvantages. Herein, we discuss our experience with transoral robotic thyroidectomy (TORT). PMID- 28713702 TI - Evidence-Based Efficacy of Autologous Grated Cartilage in Primary and Secondary Rhinoplasty. AB - BACKGROUND: There are numerous methods to mold and shape cartilage grafts for use in rhinoplasty. Each technique has advantages and disadvantages. We are going to introduce a new method for cartilage shaping with long lasting effects confirmed by follow up examination and pathologic evaluation. METHODS: Grated cartilage was used in 483 patients. For 89 cases, it was wrapped in fascia and in 394 patients, used as a filler per se or in contiguity with solid structural grafts. In 51 patients, the operation was primary rhinoplasty and 432 cases, underwent secondary rhinoplasty. Postoperatively, there was a mean follow up of 2.8 years. Graft viability, and capability to maintain almost original volume, and general durability were assessed. RESULTS: Out of 483 patients, only 23 cases (4.7%) needed later correction. In 11 cases (2%), it was due to overcorrection and some minor imperfections. In the rest 12 cases (2%), there was a need for more augmentation probably due to some degree of graft resorption. Three cases of these 12 patients, were corrected by outpatient shaved cartilage injection. CONCLUSION: According to the very low revision rate (less than 5%), we strongly recommend our grated cartilage graft for use in primary and secondary rhinoplasty. Our study showed that patient and surgeon's satisfaction can be achieved with a high degree of confidence. PMID- 28713703 TI - Comparative Perfusion Analysis of Free Muscle-Sparing Versus Pedicle Transverse Rectus Abdominis Myocutaneous (TRAM) Flaps in Vivo in the Peri-Operative and Late Post-Operative Periods. AB - BACKGROUND: Current teaching suggests increased perfusion in free transverse rectus abdominis myocutaneous (TRAM) flaps over pedicled TRAM flaps, broadening indications for its use in high risk patients. This study compared perfusion analysis of free muscle-sparing versus pedicle TRAM flaps in vivo in the peri operative and late post-operative periods. METHODS: The SPY-Elite system using indocyanine green dye was used to analyze flap perfusion intra-operatively and at 1 week and 3 months post-operatively. Image analysis was completed by evaluating the perfusion maps from the SPY- Elite system with Image J software calculate maximum, minimum, and average luminescence over the surface area of the flaps. Student's T-test was used for statistical analysis. RESULTS: Intra-operatively, we found a 73.4% greater perfusion in the free muscle-sparing as compared to the pedicled TRAM. This increase in free muscle-sparing TRAM perfusion was not evident 1 week post-operatively, due to a relative increase in pedicle flap perfusion that coincided with a revision of the pedicled flap due to distal flap necrosis. At 3 months, the free muscle-sparing TRAM flap once again showed superior perfusion with a 15.7% increase over the pedicled flap. CONCLUSION: We showed superior free muscle-sparing TRAM perfusion in the early peri-operative period which coincided with the time framein which flap loss was most common. Local swelling, pedicle rotation, tunneling, and dominance of the deep inferior epigastric circulation were potential causes of initial decreased pedicled TRAM perfusion. This analysis adds more objective data to the question of indications and relative strengths between free and pedicled TRAM flaps. PMID- 28713704 TI - The Anterior Interosseus Artery Perforator Flap: Anatomical Dissections and Clinical Study. AB - BACKGROUND: Reconstruction of upper extremity deformities continues to be a challenge to the reconstructive surgeon. Various loco regional, distant and free flaps are available for reconstruction. However, each has its own set of advantages and disadvantages. Of the commonly performed local flaps, radial artery forearm flap, and the posterior interosseus artery flap stand out prominently. Recently, perforator propeller flaps have been used for resurfacing the upper extremity. The anterior interosseus artery perforator flap is an uncommonly used and described flap. METHODS: This study was divided into anatomical study and clinical application in a IV level of evidence. In the anatomical study, five upper extremities were studied. Clinically, 12 patients underwent reconstruction using the anterior interosseus artery perforator flap. Flaps were performed by a single surgeon. A retrospective review of these cases from November 2008 to May 2014 is presented. RESULTS: The anterior interosseus artery perforator was identified in four out of five cadaver limbs. The septocutaneous perforator was in the fifth extensor compartment around 4 cm proximal to the wrist joint. Of the twelve flaps, there was complete necrosis in one flap, and partial necrosis in one flap. The patient with complete necrosis underwent skin grafting at a later date. The wound healed secondarily in case of partial flap necrosis. CONCLUSION: Anterior interosseus artery perforator flap must be considered as an important reconstructive option in the armamentarium of the plastic surgeon, while managing hand and wrist defects. PMID- 28713705 TI - Body Image Coping Strategies among Aesthetic Surgery Patients in Iran. AB - BACKGROUND: Aesthetic surgery procedures have been performed at dramatically increased rates in recent years in Iran. Few researches exist documenting the usage of body image coping strategies and its relationship in seeking surgery. METHODS: The present research examined data from 90 aesthetic surgery participants (30 Subjects each in invasive, minimally-invasive, and control groups). Assessed subjects on body image coping strategies inventory (avoidance, appearance fixing and positive rational acceptance) provided dysfunctional usage of its variables among Iranian clients. RESULTS: Between the three groups, on variables of body image coping strategies, there was a significant difference. There was a significant difference on avoidance variable in three groups. On positive rational acceptance variable, there was a significant difference for invasive group with minimally-invasive and control groups. No significant difference was found on appearance fixing variable. CONCLUSION: The study emphasizes on the role of psychological problems of aesthetic surgery clients that surgeons should be aware of them, which could inhibit the positive effects of aesthetic surgery. These results have implications for pre-surgical assessment along with psychological interventions at first step rather than invasive medical interventions. PMID- 28713706 TI - Complications of Internal Continuous and Perforating External Osteotomy in Primary Rhinoplasty. AB - BACKGROUND: Osteotomy is one of the major steps in rhinoplasty. The aim of study was to compare edema and ecchymosis after external and internal lateral osteotomy in patients who underwent rhinoplasty. METHODS: Based on a prospective randomized clinical trial, 168 osteotomies were performed through an external route in a perforating fashion and internal route in a continuous fashion at right or left side respectively in any patient. Subjective scoring system was applied to evaluate edema and ecchymosis on 1st, 3rd, 7th, and 30th days after surgery. RESULTS: Edema and ecchymosis were the same in both types of osteotomies. CONCLUSION: Regarding edema and ecchymosis, there was not any significant difference between external and internal osteotomies in rhinoplasty. PMID- 28713707 TI - Epidemiology of Acid-Burns in a Major Referral Hospital in Tehran, Iran. AB - BACKGROUND: Most of the acid- burns are due to assault or accidental. The epidemiology of burns is diverse across the world and within a country. We evaluated the epidemiology and outcome of acid-burns in tertiary health care center in Tehran, Iran. METHODS: This study was retrospective descriptive among patients referred for acid-burn injury that was done in a referral Burn Care Center in Tehran, Iran, during a ten-year period since 2005 to 2014. Patient's data collected by a specially designed check list. The subjects included 37 consecutive patients with various causes of acid burn injury. Descriptive statistics (means with standard deviations or frequency distribution) of sociodemographic variables were computed. RESULTS: The patients' mean age was 31.97+/-11.02 years. The mean hospitalization period was 18.08+/-15.25 days. The grade of burn was III in 75.7% patients. Among the acid-burn patients, 64.8% suffered from <20% of total body surface area burn. Most affected part of the body was Head /face/neck 17 (45.9%). Most of the acid-burn occurred from attack (67.6%). Burns mortality rate for this study was identified 8.1% (N=3). CONCLUSION: The results of this study showed high acid attacks rates. Prevention strategies must be coordinated at national level. So acid-burn patients have to receive the best medical care possible, first locally and then in a specialized center. PMID- 28713708 TI - The Healing Effect of Grape Seed Oil Enema with or without Sesame Oil in Acetic Acid Induced Ulcerative Colitis of Rats. AB - BACKGROUND: Inflammatory bowel diseases contain two digestive system diseases, ulcerative colitis (UC) and Crohn's disease with unclear causes. The aim of present study was to investigate the therapeutic effects of administration of the Sesame oil (SO) and grape seed oil (GSO) as enema route in rats suffering from experimental acetic acid induced UC. METHODS: Eighty male rats were randomly allocated into 8 equal groups as health control (HC1) without any disease treated with 1 ml of normal saline as enema; HC2 received SO; HC3 received GSO; negative control (NC) with induced UC receiving 1 ml of normal saline as enema; and positive control (PC) with induced UC treated by asacol. All treatments were performed identically with 4 mg/kg of medication except for asacol that was 100 mg/kg for 7 days. The weight changes was recorded after seven days. The serum levels of malondialdehyde (MDA), total antioxidant capacity (TAC), interleukin-6, and c-reactive protein (CRP) were measured. Colon macroscopic and microscopic histological changes were also measured at the end of 7th day. RESULTS: No significant changes were detected in weight in neither groups on day 0 nor at the end of study. No beneficial effects were seen for all treatments regarding healing process and the decrease in inflammation. Between treatment groups, the lowest MDA (7.40+/-0.98 U/ml), CRP (83.20+/-10.01 mg/l) and IL-6 levels (130.86+/ 10.70 mU/ml) and highest TAC (1.91+/-0.43 mmol/l) belonged to GSO group. CONCLUSION: GSO enema alone can be considered as a treatment of choice for UC due to its antioxidant properties. PMID- 28713709 TI - High Quality of Infant Chondrocytes in Comparison with Adult Chondrocytes for Cartilage Tissue Engineering. AB - BACKGROUND: Tissue engineering is used for the treatment of many diseases, and the ideal cell source for cartilage tissue engineering is chondrocytes. The main limitation of chondrocyte is the low number of cells in cartilage tissue engineering. This study investigated a suitable cell source with high proliferation rate to obtain a large number of chondrocytes. METHODS: Adult cartilage tissue samples were obtained from adult patients undergoing surgical procedure, and infant cartilage tissue samples were obtained from polydactyly surgical waste. After isolation and expansion of chondrocytes, the proliferation rate was evaluated by calculating population doubling time (PDT) and MTT assay for both types of cells. Cartilage film was prepared with sheets of over confluent chondrocytes. The cartilage tissue film from infant and adult chondrocytes were evaluated histologically and by immunefluorescent staining collagen type 2. RESULTS: PDT and MTT assays revealed that the growth rate of the infant chondrocytes was significantly higher than adult chondrocytes. Histological findings showed that sheets were thicker in the cartilage film of infant chondrocytes and they had more extracellular matrix between the sheets of cells than the cartilage film of adult chondrocytes. The findings of the immunofluorescent staining of cartilage film indicated that collagen type II film of polyductily was more positive than adult chondrocytes. CONCLUSION: The recent study presented a new cell source to overcome the limitation of low number of chondrocytes for cell therapy of cartilage defects in adults and also sheets of cells able to overcome the problems of scaffolds. PMID- 28713710 TI - The Healing Effect of Conditioned Media and Bone Marrow-Derived Stem Cells in Laryngotracheal Stenosis: A Comparison in Experimental Dog Model. AB - BACKGROUND: Differences in causes, severities, areas of stenosis, and the association with swallowing and phonation of larynx and trachea can result into Laryngotracheal stenosis (LTS).This study evaluated the healing effect of bone marrow stem cells (BMSCs) in experimentally induced LTS dog model. METHODS: Seven dogs were enrolled. BMSCs were isolated from proximal humerus and shoulder of a dog and cultured in media containing alpha minimal essential medium, fetal bovine serum, penicillin and streptomycin, and L-glutamine. BMSCs were characterized morphologically, by RT-PCR, and osteogenic induction. Karyotyping was undertaken for chromosomal stability. Mechanical trauma to laryngeal mucosa was identically conducted by Tru-cut punch forceps in right and left vocal folds. Two milliliter of conditioned media or BMSCs (2*106) were injected in the right site of the tissue and the left side was considered as control after LTS induction. The larynx was visualized 2, 4 and 6 weeks after treatment. Six weeks post-treatment, the larynges were evaluated histologically. RESULTS: BMSCs were adhered to culture flasks, spindle shape and positive for mesenchymal marker and negative for hematopoietic markers. Osteogenic induction was verified by Alizarin red staining. Karyotype was normal. A complete epithelialization and minimal chronic inflammatory cell infiltration were noted in submucosa of both left (control) and right (cases) vocal folds. The healing effect of conditioned media and BMSCs in comparison to the control group was more prominent. CONCLUSION: As thickness of fibrosis in cases were less than control group, conditioned media and BMSCs were shown to be good choices in healing of LTS. PMID- 28713711 TI - The Role of Human Adult Peripheral and Umbilical Cord Blood Platelet-Rich Plasma on Proliferation and Migration of Human Skin Fibroblasts. AB - BACKGROUND: Wound healing is a complex and dynamic process following damage in tissue structures. Due to extensive skin damage caused by burn injuries, this study determined the role of human adult peripheral and umbilical cord blood platelet-rich plasma on proliferation and migration in human skin fibroblasts. METHODS: Platelet-rich plasma (5, 10, 15, 20 and 50% PRP) from human umbilical cord blood and adult peripheral blood were provided and added to fibroblasts cultured from a human skin sample. Migration and proliferation of fibroblasts were assessed in comparison to 10% FBS and by the fibroblast responses to a concentration gradient. RESULTS: All components of the umbilical cord blood PRP significantly stimulated the growth of fibroblasts when compared to the negative control. Fibroblast growth was enhanced in a dose dependent manner. All fibroblast cultures retained normal morphology. No significant difference was noted between umbilical cord blood and adult peripheral blood PRP preparations regarding cell proliferation and migration, but the difference to 10% FBS was significant. 1% and 50% PRP reduced cellular proliferation. The 20% umbilical cord blood PRP and 10% adult peripheral blood PRP had a significant stimulatory effect on the migration of the skin fibroblast cells in comparison with 10% FBS. CONCLUSION: As PRP could promote the migration and proliferation of dermal fibroblasts, it can be safely added in cultures when treatment of chronic wounds without triggering the immune response is needed. PMID- 28713712 TI - Management of Gigantomastia: Outcomes of Superomedial Pedicle with Vertical Scar or Wise Pattern Skin Excision. AB - BACKGROUND: Gigantomastia is a rare condition characterized by excessive breast growth and can be physically and psychosocially disabling for the patient. Regarding management of gigantomastia, this study evaluates the outcomes of superomedial pedicle with vertical scar or wise pattern skin excision. METHODS: A total of 425 patients who underwent reduction mammoplasty in our institution were reviewed. Forty eight reduction mammoplasty patients with resection weights greater than 1 kg per breast and treated with superomedial dermoglandular pedicle technique combined with vertical or wise-pattern skin excision were included. RESULTS: The patients were between 19 and 66 years old, with an average of 41 years. Total weight of resection was between 1000 and 2600 g, with an average of 1384 grams for right breast and between 1000 and 3000g, with an average of 1434 grams for left breast. The secondary revisions and wound healing complications were extremely high in vertical scar group compared to wise pattern group (87,5% and 12,5%, respectively). CONCLUSION: The authors concluded that superomedial dermoglandular pedicle in the addition of a wise pattern is an appropriate, safe and reliable method when dealing with significantly larger breasts (>1000g). PMID- 28713713 TI - Reverse Peroneal Artery Flap for Large Heel and Sole Defects: A Reliable Coverage. AB - BACKGROUND: Large soft tissue defects of ankle and foot always have been challenging to reconstruct. Reverse sural flaps, free flaps have been used for this problem with variable success. Reverse peroneal artery flap is an option to use with reliability without microvascular repair. Connections of peroneal artery around talus and ankle joint are deep and reliable with anterior tibial and posterior tibial artery. Arterial inflow and venous drainage improved with including short saphenous vein and reverse sural artery in the flap. METHODS: Ten patients with large defects around heel underwent reconstruction with (RPAF) reverse peroneal artery flap (pedicled) over a period of 2 years. Final inset given after 18-21 days of primary surgery. The mean age of these patients was 45 years. RESULTS: Of the 10 flaps, all showed complete survival without even marginal necrosis. Two patients had minor donor site problems that settled with conservative management. CONCLUSION: RPAF is a very reliable flap for the coverage of large soft tissue defects of the heel and sole. Large defects can be reconstructed without microvascular surgery and without compromising major vessel of foot region. If some experience with perforator flaps and free fibula is there then RPAF is easy to execute with reliability. PMID- 28713714 TI - Fibular Bone Graft for Nasal Septal Reconstruction: A Case Report. AB - Although various techniques have been described for treatment of severe nose deformities, these problems have high revision rates. Conventional nasal septal surgery may not be adequate for all cases. A 21-year-old male patient with nose deformity underwent a nasal surgery. Patient had both functional and aesthetic nasal problems. Rigid fibular bone graft was used for corrective nasal surgery. Duration of the operation was three hours. Patient recovered without problems. Aesthetic and functional results of the operation were acceptable. Fibular bone graft may offer a long lasting support in treatment of severe nose deformity. PMID- 28713715 TI - Hand Injuries by the Killer Kite Manja and Their Management. AB - Although hand injuries due to kite strings seem to be trivial, these injuries could be serious enough to lose the function of hand. This case series in the division of Plastic and Reconstructive Surgery of our institution from August 2014 to January 2016 evaluated the clinic-etiological profile, severity and management of hand injuries due to kite strings assessed clinically and radiologically. Eleven patients reported kite related injuries during two years, and 5 presented during 17 months. Of 11 patients, 8 were male and 3 were female with a M:F ratio of 2.66:1. The majority of patients presented with the mean age of 19.9+/-4.27 years. Eight patients presented acutely to the emergency while 3 believed the injury to be trivial and had delayed presentation. Injuries in the right hand were 8 and 3 in the left hand. Seven patients had injuries in zone II of the hand while 4 presented with zone III injuries. Total number of injured digits was 14 (1.4+/-1.11), total number of injured tendons was 26 (2.36+/-2.18), only one patient had nerve injury (mean=0.09), and no patient had any major vessel injury. So strict attention to safety measures and parental/guardian supervision while flying kites can avoid many preventable injuries to life and limb and also let the sport be an enjoyable and safe. PMID- 28713716 TI - Urethroplasty Using A Turnover Flap for Correction of Problematic Urethrocutaneous Fistula: A Case Report. AB - Urethral fistula formation after urethroplasty for hypospadias is a frequent complication. Repeated failures can occur even after multiple attempts at repair. A surgical procedure is described for a problematic resistant urethrocutaneous fistula (UF) with the transverse turnover flap using the Buck's fascia of the corpus cavernosum. A 23-year-old male was admitted to our hospital with recurrent coronal UF. We placed a suprapubic catheter in the bladder and operated the patient with the flap technique combined with glanuloplasty. In 3rd month follow up, the patient had no fistula with normal voiding. PMID- 28713717 TI - Reconstructive and Oncoplastic Surgery for Giant Phyllodes Tumors: A Single Center's Experience. AB - Phyllodes tumors are biphasic fibroepithelial neoplasms of the breast. While the surgical management of these relatively uncommon tumors has been addressed in the literature, few reports have commented on the surgical approach to tumors greater than ten centimetres in diameter - the giant phyllodes tumor. We report a case of giant breast tumors and discuss the techniques utilized for pre-operative diagnosis, tumor removal, and breast reconstruction. A review of the literature on the surgical management of phyllodes tumors was performed. Management of the large phyllodes tumors presents the surgeon with unique challenges. The majority of these tumors can be managed by simple mastectomy but reconstruction and even oncoplastic conservative management is for selective consideration. PMID- 28713718 TI - Ergonomics and Biogeometry of Perforator/Propeller Flaps in the Lower Limb Reconstruction. PMID- 28713719 TI - Stacked PAP Flaps for Two-Stage Immediate Bilateral Breast Reconstruction: A Case Report. PMID- 28713720 TI - A Rare Case of Extra Gigantic Digit of Sole. PMID- 28713721 TI - Giant Palmar Lipoma: A Rare Presentation. PMID- 28713722 TI - Using Pericardium Allograft in Closing Tracheal Fistula after Removing Tracheotomy Tube. PMID- 28713723 TI - The Effect of Aloe Vera Gel and Nitrofurazone on Dressing Related Pain of Superficial Burn Wounds. PMID- 28713724 TI - An Innovative Method of Repeated Tie over Dressing for Fixation of skin Graft. PMID- 28713725 TI - Orange and Sunlight: A Recipe for Blisters. PMID- 28713726 TI - Mirror Hand: An Uncommon Neglected Case Managed with Pollicisation. PMID- 28713727 TI - Global Surgery and the Sustainable Goals 2030: Implications for Craniomaxillofacial Surgery. PMID- 28713728 TI - Identifying Complications in Distraction Osteogenesis. PMID- 28713729 TI - Piezosurgery versus Rotatory Osteotomy in Mandibular Impacted Third Molar Extraction. AB - AIM: The aim of this study is to compare piezoelectric surgery versus rotatory osteotomy technique in removal of mandibular impacted third molar. MATERIALS AND METHODS: Sample size of 30 patients 18 males, 12 females with a mean age of 27.43 +/- 5.27. Bilateral extractions were required in all patients. All the patients were randomly allocated to two groups in one group, namely control group, surgical extraction of mandibular third molar was done using conventional rotatory osteotomy and in the other group, namely test group, extraction of lower third molar was done using Piezotome. RESULTS: Parameters assessed in this study were - mouth opening (interincisal opening), pain (visual analog scale VAS score), swelling, incidence of dry socket, paresthesia and duration of surgery in both groups at baseline, 1st, 3rd, and 7th postoperative day. Comparing both groups pain scores with (P < 0.05) a statistically significant difference was found between two groups. Mean surgical time was longer for piezosurgery group (51.40 +/- 17.9) minutes compared to the conventional rotatory group with a mean of (37.33 +/- 15.5) minutes showing a statistically significant difference (P = 0.002). CONCLUSION: The main advantages of piezosurgery include soft tissue protection, optimal visibility in the surgical field, decreased blood loss, less vibration and noise, increased comfort for the patient, and protection of tooth structures. Therefore, the piezoelectric device was efficient in decreasing the short-term outcomes of pain and swelling although taking longer duration than conventional rotatory technique it significantly reduces the associated postoperative sequelae of third molar surgery. PMID- 28713730 TI - Application of Orthodontic Immediate Force on Dental Implants: Histomorphologic and Histomorphometric Assessment. AB - AIMS: Application of force to implants is helpful, especially in orthodontic implant therapies. The aim of this study was a histomorphologic and histomorphometric evaluation of peri-implant bone after immediate orthodontic and orthopedic forces comparing them with a control group. MATERIALS AND METHODS: Eighteen dental titanium implants were inserted in the premolar region of three dogs. Implants were divided into three groups: (1) group with immediate orthodontic force of 300 NC, (2) group with immediate orthopedic force of 600 NC, and (3) control group. Implants were explanted with adequate amount of surrounding bone after 3 months and bone-implant contact (BIC), amount of lamellar bone (LB), amount of woven bone (WB), amount of inflammatory connective tissue, and the rate of the movement were investigated. ANOVA, t-test, paired t test, and Pearson's test were used to analyze the data using SPSS software version 16 at a significant level of 0.05. RESULTS: Based on BIC, amount of lamellar and WB and the amount of inflammatory connective tissue, there was no significant difference between the three groups (300 centinewton (CN), 600-CN, and control group) (P > 0.05). In the 300-CN and 600-CN groups, the rate of movement was reported 0.41 and 0.94 with no significant differences (P = 0.38). CONCLUSION: 300-CN and 600-CN immediate static loads do not interfere with osseointegration phenomenon and it does not decrease the amount of BIC and LB. Implants can be moved by preserving osseointegration, and this movement is in direct relation with the amount of applied force. PMID- 28713731 TI - Magnetic Field Effects on Bone Repair after Calcium Phosphate Cement Implants: Histometric and Biochemistry Evaluation. AB - OBJECTIVE: This work evaluated histologic and biochemically the effect of magnetic field buried in bone repair after autogenous bone graft and calcium phosphate cement implants. METHODOLOGY: Bone defects with 5,0 mm of diameter in the cranium of Wistar mice were used to analyse. These mice were submitted to different interventions: autogenous bone graft and calcium phosphate cement implants, both with and without magnetic stimulation. Longitudinal and transversal histometric and biochemistry analysis were made in times of 15, 30 and 60 post-operative days. RESULTS: The histometric transversal analysis did not show significant differences in the bone repair between groups. Longitudinally, significant difference were found in the quantity of neoformed bone between the times 15 and 60 post-operative days in the autogenous bone graft group under magnetic stimulation. The alkaline phosphatase enzyme presented a higher activity in 30 post-operative days and the groups under magnetic stimulation presented reduced enzymatic activity in comparison to the other groups. CONCLUSION: The permanent and static magnetic field promoted significant differences in the neoformed bone in the groups autogenous bone graft. PMID- 28713732 TI - Effect of Low-intensity Pulsed Ultrasound on Postorthognathic Surgery Healing Process. AB - BACKGROUND: Orthognathic surgery can cause discomforts such as pain, inflammation, and edema. One of the challenges is bone regeneration at surgery area. The aim of this study is to evaluate the effect of low-intensity pulsed ultrasound (LIPUS) therapy on bone regeneration and pain relief after surgery. MATERIALS AND METHODS: Following mandibular surgery of nine patients, LIPUS treatment was applied to the left or right side for 3 weeks and 20 min/day. The other side was treated with sham-LIPUS as the control group. Digital panoramic radiographies were obtained immediately after surgery and 3 weeks later. Bone density at surgery site was assessed using Digora version 2.8 software. The data were analyzed with one-sample Kolmogorov-Smirnov and t-paired test. Postoperation pain was evaluated by means of visual analog scale. RESULTS: Increase in bone density at border and medulla was 23 and 28.33 for experimental group and 13 and 13.55 units in control group, respectively. The differences are statistically significant (P < 0.01). Variance analysis showed that decrease in experienced pain during 3 weeks after surgery was significantly different between groups (P < 0.01). CONCLUSION: LIPUS can be an effective way to increase bone modeling and decrease pain following orthognathic surgeries. PMID- 28713733 TI - Effectiveness of Preoperative Lymphoscintigraphy for the Detection of Cervical Lymph Node Metastasis in Patients with Oral Squamous Cell Carcinoma. AB - BACKGROUND: Oral squamous cell carcinoma (OSCC) is one of the most common malignant tumor. OSCC is the malignancy of squamous epithelium of oral cavity, which is the sixth most common malignancy reported worldwide and one with highest mortality rate among all malignancies. AIMS: The aims of this study is to assess the diagnostic performance of lymphoscintigraphy (LSG) for the detection of cervical lymph node metastasis in patients with OSCC. MATERIALS AND METHODS: This was a prospective study done in Oral and Maxillofacial Surgery Department and National Institute of Nuclear Medicine and Allied Science, Bangabandhu Sheikh Mujib Medical University during July 2015-June 2016. Thirty-six patients with OSCC were included in this study. Radioisotope technique was used in the detection of cervical metastases in patients with histologically proven OSCC. Patients were assessed by LSG after diagnosis of OSCC, and then, it was compared with postoperative histopathology report. RESULTS: Lymphoscintigraphically out of 36 patients, 23 had lymphatic channel obstruction where histologically 20 patients had lymph node metastasis. There were 20 true positive cases, 13 true negative cases, and 3 false positive cases but no false negative case was found. The test of validity result reveals that sensitivity 100.0%, specificity 81.25%, accuracy 96.66%, positive predictive value 86.96%, and negative predictive value 100.0%. CONCLUSION: LSG for the detection of cervical lymph node metastasis has an important role for the management of OSCC. It is also cost-effective and decreases the morbidity. PMID- 28713734 TI - Treatment of Micrognathia by Intraoral Distraction Osteogenesis: A Prospective Study. AB - PURPOSE: Maxillofacial deformities are always psychologically and physically distressing to the patients and is also challenging to the treating surgeons. The term Micrognathia means a "small jaw". True micrognathia, where the maxilla or the mandibular skeleton does not grow to the full size can be congenital or acquired. Distraction osteogenesis also called as callus distraction or callostasis or osteodistraction or distraction histogenesis is a biological process of regenerating newly formed bone and adjacent soft tissue by a gradual and controlled traction of surgically separated bone segments. The purpose of this prospective study was to assess the versatility of distraction osteogenesis in the treatment of micrognathia. MATERIALS AND METHODS: Four patients (three males and one female) with micrognathia of mandible were included in this prospective study. The patients were between the age group of 10-20 years. Facial asymmetry was the chief complaint of all the patients. In all the patients following treatment protocol was carried out, Osteotomy and placement of intraoral distraction device under general anaesthesia, latency phase (5-7 days), activation period-rate 1.5 mm per day, consolidation period of 8 weeks, removal of distraction device under local anaesthesia. The parameters assessed were ramus height, body length, hyo mental distance, posterior pharyngeal airway space, chin projection, facial symmetry occlusion, mid line shift pre and post operatively. RESULTS: The mean increase in ramus height achieved was 9.2 + 2.17 mm and the mandibular body length achieved was 10.4+1.67 mm. There was an average increase in hyo-mental distance of 2.75 cm +0.9 cm postoperatively showing a definitive improvement in the airway. The posterior pharyngeal space measured from the lateral cephalogram preoperatively ranged from 3-6 mm and post operatively from 6 9 mm.Intraorally there was a shift in occlusion to class I molar relation in three patients and there was posterior open bite in one patient. Marked correction of facial asymmetry was noticed in all cases both clinically and in PA cephalogram. There was a restoration of dental as well as lip midline and improved lip competence. There was a significant improvement in chin projection and occlusal cant however further chin correction was needed in one case by means of advancement genioplasty. CONCLUSION: A definite improvement in all parameters such as body length,ramus height,chin projection,occlusal cant was observed in all patients. Moreover the patients were subjectively satisfied with the outcome of the results. Distraction Osteogenesis is definitely a boon to the oral and maxillofacial surgeons in treating large deficiencies of mandible in terms of stability. PMID- 28713735 TI - An Assessment of Factors Influencing the Difficulty in Third Molar Surgery. AB - BACKGROUND AND OBJECTIVES: Surgical removal of a mandibular impacted third molar is one among the most common oral surgical procedures. The objective of this study was to assess and identify risk indicators influencing extended operation time in relation to the surgical removal of mesioangular impacted mandibular third molar, position A, Class I and to evaluate the incidence of postoperative swelling, trismus, and pain. MATERIALS AND METHODS: A prospective cohort was implemented and the patients who presented for mandibular third molar removal which were impacted in position A, Class I were enlisted for the study. During 1 year between July 2014 and June 2015, a total of 40 patients were enrolled in the study. The evaluation of patient variables and radiographic variables was done preoperatively. Depending on the duration of time taken for an operation, patients were divided into three groups: Group I, Group II, and Group III. Postoperative complications such as swelling, trismus, and pain were assessed in each of the patients. STATISTICAL ANALYSIS: The statistical analysis was done among the groups using Chi-square test, and ANOVA. RESULTS: Among the six variables studied in this study including patient variables and radiographic variables, maximum interincisal opening, external oblique ridge, and root morphology were found to be dependent factors which influence the operating time. Moreover, other variables such as the crown root width ratio and the number of roots were independent factors. Swelling, trismus, and pain were statistically significant among groups and were directly related to operating time. CONCLUSION: We consider that the outcome of surgical removal of mandibular impacted third molar, position A, Class I depends significantly on relevant patients characteristics and radiographic variables which should be evaluated preoperatively as they are predetermined factors to avoid postoperative morbidity. PMID- 28713736 TI - Using Carnoy's Solution in Treatment of Keratocystic Odontogenic Tumor. AB - AIM: The aim of this study was to assess the treatment of keratocystic odontogenic tumor using enucleation and Carnoy's solution with peripheral ostectomy. MATERIALS AND METHODS: Twenty-nine patients (14 females and 15 males) with age range from 12 to 62 years were included in this study and followed up for 7 years; all the patients were treated in the Department of Oral and Maxillofacial Surgery of the Specialized Surgeries Teaching Hospital (Al-Shaheed Ghazi Al-Hariri Hospital-Medical City, Baghdad, Iraq). Enucleation followed by peripheral ostectomy and the application of Carnoy's solution is the standardized method of treatment. RESULTS: This study showed (32.7%) unilocular radiolucency for the lesions (19.9%) as multilocular radiolucency. Furthermore, it showed that the recurrence rate by this method was 0% with a minimum neurosensory disturbance. CONCLUSION: The complications and morbidity originating from the application of Carnoy's solution occurred less frequently and were less serious than those associated with resection while the recurrence rate is 0% which is equal to the recurrence rate of resection. PMID- 28713737 TI - Maxillary Distraction Osteogenesis in Unilateral Cleft Lip and Palate Patients with Rigid External Distraction System. AB - AIM: Distraction osteogenesis (DO) is a treatment option for patients with maxillary hypoplasia secondary to cleft lip and palate (CLP). PURPOSE: The aim of this study is to present a technique for maxillary DO using Le Fort I osteotomy with rigid external distraction (RED) system. SUBJECTS AND METHODS: The patient presented in this paper was an Asian female with CLP aged 13 years and 6 months. She presented with severe midfacial deficiency with a Class III dental malocclusion with a negative overjet and concave facial profile. Cone-beam computed tomography images were recorded preoperatively and the operation performed involved a high Le Fort I osteotomy. The appliance fabricated was banded to upper first molars used for anchorage of the RED system. Distraction of the maxilla was initiated after 7-day latency period. RESULTS: Postoperative cephalometric analysis showed maxillary advancement anteriorly and superiorly, the total distraction treatment period was 10 days. The maxillary advancement was 10.5 mm and the SNA angle increased from 67.5 degrees to 77.9 degrees . Furthermore, the ANB angle changed from -9.8 degrees to 1.6 degrees and the occlusion changed from Class III to Class I. The profile of the face changed from concave to convex and a much better esthetic result was achieved. CONCLUSION: The study suggests RED system to be a reliable alternative procedure for the treatment of midfacial hypoplasia with or without cleft. Furthermore, it minimizes the risk of the surgical procedure and shortens the operating time. PMID- 28713738 TI - Three-dimensional Planning and Reconstruction of the Mandible in Children with Craniofacial Microsomia Type III Using Costochondral Grafts. AB - BACKGROUND: In craniofacial microsomia (CFM) Type III patients, autogenous costochondral grafts (CCG) are conventionally used for the reconstruction of the ramus and condyle. The aim of this study was to describe the use of CCG in children with CFM in terms of outcomes, growth patterns, and complications. MATERIALS AND METHODS: This is a retrospective study of nine, aged 4-12 years, patients with CFM Type III, who underwent reconstruction of the mandibular ramus condyle unit by CCG. Seven patients had right-sided CFM and two had left-sided CFM. The rationale for this choice was to utilize the potential growth of the CCG, providing length to the ramus, and the joint by acting as a growth center; to control the repositioning of the chin center; and to improve child compliance by undergoing only one operation. The surgical treatment plan was determined preoperatively, based on measurements of mandibular vertical and horizontal deficiency and analysis of the mandibular posterior and anterior angulation. The mandibular planes and axis were defined by a three-dimensional simulation software program to perform a "mock surgery", by creating a prototype model. Clinical follow-up included measurements of the maximal opening, observation of the facial symmetry, and recording of complications, such as reankylosis. RESULTS: There were no serious postoperative complications, infections, or graft rejections. Successful postoperative occlusal cants were noted and measured in five patients and acceptable results were obtained in three patients. In one case, the CCG underwent distraction osteogenesis to improve the facial symmetry. In one patient, the graft continued to grow and the chin started to deviate into the opposite side. Measuring and calculating the ratio of the ramus height on the panoramic X-ray revealed a good relation between the healthy contralateral and the reconstructed ipsilateral ramus. Postoperative mean mouth opening was 34.3 mm, with minimal midline deviation of 2.6 mm in occlusion. Mean follow-up was 51.7 months. The mean postoperative occlusal cant analysis for eight patients was 3.66 degrees . CONCLUSION: CCG is useful in treating CFM Type III. The growth potential of the CCG makes it the ideal choice for children. The advantages of this graft are its biological compatibility, workability, functional adaptability, and minimal additional detriment to the patient. The use of a stereolithographic model preoperatively improved intraoperative precision by clearly displaying detailed anatomy of the patient undergoing craniofacial surgery. The surgeon can plan the length of the CCG before surgery and use the printed template while harvesting without waiting for the exact measurements to be provided by the facial surgical team. PMID- 28713739 TI - A Retrospective Analysis of Dentofacial Deformities and Orthognathic Surgeries. AB - BACKGROUND: Information regarding the prevalence of surgical osteotomies used for the correction of dentofacial deformities in Iran is lacking. MATERIALS AND METHODS: This retrospective cross-sectional study assessed the distribution of orthognathic surgeries performed (2011-2015) at major University hospital in Iran. Records of 103 orthognathic surgery patients were assessed (58 female, 45 males, aged = 23.47 [6.44] years). RESULTS: Class III malocclusion (incisor classification, 45.6%) and Class II skeletal pattern (based on ANB angle, 51.5%) were the most prevalent type. Overall, 4.8%, 51.5%, and 43.7% of subjects had Class I, II, and III sagittal skeletal patterns, respectively. The most prevalent (66%) osteotomy was the bimaxillary osteotomy. The frequencies of reported and corrected asymmetries in the lower third of the face (35%) were similar among patients with different malocclusions (chi2 = 4.134, P = 0.127) or sagittal skeletal patterns (chi2 = 2.133, P = 0.344), as well as between Class II and III malocclusions (P = 0.125) or sagittal skeletal patterns (P = 0.149). CONCLUSION: Compared to Class II subjects, Class III (malocclusions or sagittal skeletal patterns) subjects had more bimaxillary osteotomies, indicating the higher prevalence of skeletal discrepancies affecting both jaws in Class III subjects. PMID- 28713740 TI - The Effects of Platelet-Rich Fibrin Membrane on Secondary Healing After Pleomorphic Adenoma Excision in the Hard Palate: A Preliminary Study. AB - AIM: This study aims to evaluate the effects of platelet-rich fibrin (PRF) membrane on secondary healing after pleomorphic adenoma (PA) excision in the hard palate. MATERIALS AND METHODS: PRF membranes were laid over mucosal defects which occurred following PA excision in the hard palate. The secondary healing process was monitored in the patients by follow-up examinations on postoperative days 5, 10, 15, 20, 25, 30, 35, and 40. RESULTS: In this preliminary study, epithelialization was observed to have completed on the 30th day of follow-up in the first patient and on the 35th day in the second and third patients. No bleeding or infection was seen in any of the three patients. CONCLUSIONS: PRF membrane as a new method in the secondary healing after PA excision in the hard palate provided rapid healing and reduced complications such as bleeding and infection. PMID- 28713741 TI - Reconstruction of Drug-induced Cleft Palate Using Bone Marrow Mesenchymal Stem Cell in Rodents. AB - BACKGROUND: Triamcinolone acetonide (TAC) (Kenacort*) is a commonly used synthetic glucocorticoid in today's medical practice. The drug is also a potential agent in inducing cleft palates in rats. This drug has been used to induce cleft palate in the fetus of the pregnant rats to bring out a suitable animal model for human cleft lip and palate. The drug was given intraperitoneally to induce congenital cleft palate in pregnant mother rats. AIM: The aim of this study is to induce congenital cleft palate in pregnant Wister albino rats and reconstruct the defect with bone marrow mesenchymal stem cells (BMSCs) isolated from the same species along with PLGA (poly lactic co glycolic acid) scaffold. METHODS: Twenty female animals were divided into two groups. Each group contains 10 animals. The animals were allowed to mate with male rat during the esterase period and the day, in hich vaginal plug was noticed was taken to be day 0. The pregnant rats were given triamcinolone acetonide (Kenacort* 10 mg/1 ml intramuscularly/intravenous [IM/IV] injections) injection intraperitoneally at two different dosages as the existing literature. The injection was given on the 10, 12, and 14th day of gestation. The clinical changes observed were recorded, and the change in the body weight was noted carefully. Group 1 which received 0.5 mg/kg body weight of TAC had many drug toxic effects. Group 2 which received 0.05 mg/kg body weight produced cleft palate in rat pups. The pups were divided into three groups. Group A control group without cell transplant, the cleft was allowed to close by itself. Group B containing palate reconstructed with plain PLGA scaffold (Bioscaffold, Singapore) without BMSC, Group C containing BMSC and PLGA scaffold (Bioscaffold, Singapore), Group C operated for the cleft palate reconstruction using BMSCs and PLGA scaffold. There was faster and efficient reconstruction of bone in the cleft defect in Group C while there was no defect closure in Group A and B. RESULTS: There was complete reconstruction of the cleft palate in the group of rat pups which received BMSCs along with PLGA scaffold. Bone growth in the cleft defect was faster; complete fusion of the defect was achieved. CONCLUSION: The dosage of drug used for inducing cleft palate was standardized in rodents for a definitive congenital cleft palate model. The cleft palate induced was reconstructed using BMSCs and PLGA scaffold. This was compared with a control group and the other group with plain PLGA used for reconstruction of the palate. This study will invite future research in the effect of the drug on human beings, especially on pregnant mothers. PMID- 28713742 TI - Conservative Surgical Approach to Restore Necrotic Columella in Patients Undergoing Neonatal Usage of Nasogastric Tube. AB - CONTEXT: A common complication, related to the use of nasogastric tube during the 1st day of life, is the necrosis of the columella. Esthetic damage in the early age typically leads to a healing request with very high result expectations. AIMS: We aimed to develop and use an innovative surgical technique. SETTINGS AND DESIGN: We used our technique in four cases. SUBJECTS AND METHODS: Our technique requires two flaps designed with two paramedian release incisions. The two flaps will be sutured to what remains of the fibrous septum; finally, the two flaps will be sutured together in the medial region. RESULTS: Postoperative course was devoid of any complication. All patients gained esthetic improvements and an increase in the volume of the columella on the sagittal and frontal planes. CONCLUSIONS: This technique allows a conservative approach with low donor site morbidity and rapid postoperative course. PMID- 28713743 TI - Bone Ring Augmentation Around Immediate Implants: A Clinical and Radiographic Study. AB - PURPOSE: The purpose of this study was to evaluate the efficacy of bone ring augmentation technique for three-dimensional augmentation of severely defective sockets along with placement of immediate dental implants. MATERIALS AND METHODS: A clinical study was conducted on 14 patients with 15 defective sockets requiring extractions and immediate implant placement. Following extraction, bone ring with an implant osteotomy, harvested from chin, was sculptured and fitted into the extraction socket. The bone apical to the socket was prepared for implant through the central osteotomy of the ring. Implant was then placed through the ring into the apical bone. After 6 months, prosthesis was placed. Clinical and radiographic examination was done to evaluate the soft tissue and crestal bone level around implants immediate postoperatively and at 1st, 3rd, 6th, and 9th month postoperatively. RESULTS: Out of 15 grafted sockets, 14 showed an evidence of bone healing with no significant crestal bone resorption. One ring showed soft tissue dehiscence which underwent severe resorption at 6th month postoperative visit. CONCLUSION: The bone ring augmentation technique is an effective method for three-dimensional augmentation of severely defective sockets. This technique helps in reducing the overall treatment time by allowing grafting and placement of implant simultaneously in a single visit. However, longer observation periods are needed to draw more definite conclusions on the success of bone ring augmentation technique. PMID- 28713744 TI - Access Osteotomy in the Maxillofacial Skeleton. AB - Surgical accesses for the facial skeleton are based on the concept of modular osteotomies. Various techniques and combination of osteotomies facilitate access to the most inaccessible tumors of craniomaxillofacial region. Most appropriate surgical access is determined by considering size, location, extension of the tumor, and experience of the surgical team. These are primarily used for tumors in the nasopharynx or the skull base. The aim of this paper is to review surgical accesses that aid in removal of inaccessible tumors of craniomaxillofacial region with series of cases operated in the Department of Oral and Maxillofacial Surgery, Armed Forces Medical College, Pune, India, between July 2008 and June 2010. The surgical approaches constituted of transfacial, transoral, lip-split mandibulotomy and modified osteotomy of the orbital rim in cases of juvenile nasoangiofibroma, squamous cell carcinoma of the base of the tongue, orbital floor tumour respectively. Only 3 cases (33.33%) reported with postoperative paresthesia of the infraorbital region and mandibular symphysis region which resolved in 6 months. None of the patients presented with occlusal discrepancy, neuromotor deficit or sign of recurrence in the follow up period of one year. PMID- 28713745 TI - Recovering Breathing and Feeding of a Newborn with Pierre Robin Sequence. AB - Pierre Robin sequence (PRS) is characterized by the triad micrognathia, glossoptosis, and airway obstruction, commonly associated with cleft palate. This study reports the case of a patient with characteristics consistent with the diagnosis of PRS in the 1st week of life. To stabilize the airway, oro-tracheal intubation was performed without success, followed by tracheostomy and glossopexy and after a small improvement in symptoms, it was decided to perform the mandibular distraction osteogenesis (MDO). At the age of 6, her maxillofacial development was within expectations, with patent airway, the presence of deciduous teeth, and without neurological impairment. The MDO described in this case allowed patient's respiratory and feeding improvement, thus avoiding episodes of cyanosis, allowing timely removal of the tracheostomy and glossopexy, and execution of palatoplasty at the right time. While it is uncertain whether MDO will replace the possible need for future orthognathic surgery, treatment greatly improved the quality of life of the patient. PMID- 28713746 TI - Unicoronal Craniosynostosis and Plagiocephaly Correction with Fronto-orbital Bone Remodeling and Advancement. AB - The standard surgical treatment for unilateral coronal synostosis is fronoto orbital advancement. The technique is known for its high recurrence rate and established plagiocephaly remains a challenge. In this case report, the management of a 5-year-old with unicoronal plagiocephaly correction with fronto orbital bone remodeling and advancement is presented. The previous surgery done at 6 months of age resulted in failure with establishment of hypertelorism and sudden progressive diminishing vision. Furthermore, temporal hallowing was evident in the imaging technique. As the child is in the active growing phase, only one end of the bandeau was secured with plates and screws while the other end was welded with ultrasonic waves. This ensured that the plate was held in position while bone remodeling will ensure normal healing and establish regular sutural growth. The child recovered well with regaining of vision. The report also discusses the possible reason for failures and the effectiveness of modification of the standard technique for growing child. PMID- 28713747 TI - The Surgical Management of Skeletal Disproportion with Lingual Orthodontics and Three-dimensional Planning. AB - This case report describes the successful treatment of a 26-year-old Caucasian male with skeletal and dental Class III malocclusion associated with mild maxillary and mandibular crowding. The patient had anteroposterior and transverse discrepancies with a reverse overjet and bilateral posterior crossbites. The nonextraction treatment plan included aligning and leveling of the teeth in both arches, Le Fort I and bilateral sagittal split osteotomies, and postsurgical correction of the malocclusion. Orthodontic treatment was initiated with custom lingual appliances followed by orthognathic surgery planned with virtual surgical planning. Treatment was concluded with detailed orthodontic finishing, achieving optimum esthetics and function. PMID- 28713748 TI - Closure of Oroantral Communication Using Platelet-rich Fibrin: A Report of Two Cases. AB - Oroantral communication (OAC) is an abnormal connection between the maxillary sinus and oral cavity. It is mostly formed after the extraction of the first and second upper molars. Platelet-rich fibrin (PRF) created by Choukroun's protocol concentrates most platelets and leukocytes from a blood harvest to a single autologous fibrin biomaterial. It has been used widely in oral and maxillofacial surgery. However, no data are available concerning the use of PRF alone as a clot and a membrane for the closure of OACs. Two clinical cases presented with OAC, created after extraction of tooth #16 in two patients, were closed with PRF as a clot and a membrane and monitored until the epithelization of the sockets was ended successfully. Two months postclosure, the sockets were evaluated clinically and on waters' view radiography. The results of these case reports showed that PRF can be successfully applied for the closure of OACs. PMID- 28713749 TI - Mucormycosis of the Frontal Sinus: A Rare Case Report and Review. AB - Mucormycosis of the frontal sinus are rarely seen in day to day clinical practice. Although this fungus is commonly found in the environment, the disease is usually prevented by the immune system and is hence rare. Well-recognized risk factors for the disease include diabetes mellitus, leukemia, aplastic anemia, myelodysplastic syndrome, blood dyscrasias, and immunosuppressive therapy in organ transplantation, renal disease, sepsis, and severe burns. The disease is primarily found in those who are immunocompromised, but it may also manifest in immuno competent persons. Current therapy for the invasive disease includes early surgical debridement, antifungal therapy management of underlying predisposing factors. Early recognition of the disease and treating the underlying cause of mucormycosis, such as diabetes, are key to improving outcomes. The antifungal treatment of choice for mucormycosis is amphotericin B, although very high doses are required because of the relative resistance of the fungus to the drug. Here, we present a case of rhinocerebral mucormycosis of frontal sinus in a diabetic patient, who was managed by systemic antifungals, surgical debridement, and obliteration procedures. PMID- 28713750 TI - Comminuted Laryngeal Fracture Following Blunt Trauma: A Need for Strict Legislation on Roads! AB - Laryngeal fracture is a rare condition with potential life-long implications related to airway patency, voice quality, and swallowing. Rarity of the condition leads to lack of consensus on the most suitable way to manage this injury. The mode of injury can be prevented by strict legislation on the roads. We report a case of a 28-year-old Indian male who sustained a comminuted displaced fracture of the thyroid cartilage with disruption of anterior commissure due to blunt trauma caused by the metallic side rod of a ladder projecting from the rear of a vehicle in front of the bike on which he was riding. He presented with breathing difficulty, change in voice, surgical emphysema, and pneumomediastinum, but without any skin changes over the neck. His airway could be restored due to early tracheostomy and open reduction with internal fixation with sutures along with laryngeal stenting. He has no significant swallowing or breathing problem and reasonably good voice 6 months after surgery. This case highlights the need for strict legislation on roads in India and the importance of high level of suspicion for laryngeal fracture in acute trauma patient. Early identification and timely internal fixation not only restore the airway but also improve long term voice and airway outcomes. PMID- 28713751 TI - Parotid Duct Repair with Intubation Tube: Technical Note. AB - The parotid duct can be damaged in traumatic injuries and surgical interventions. Early diagnosis and treatment of a duct injury is of great importance because complications such as sialocele and salivary gland fistula may develop if the duct is not surgically repaired. We think the cuff of an intubation tube is an ideal material in parotid duct repair, because of its technical characteristics, easiness of availability, and low-cost. In this paper, we described the use of the cuff cannula of an intubation tube for the diagnosis and treatment of parotid duct laceration, as a low-cost and easy to access material readily available in every operating room. PMID- 28713752 TI - Largest De Novo Parapharyngeal Pleomorphic Adenoma: A Rare Case Removed Via Minimal Access Approach. AB - Parapharyngeal tumors are relatively rare tumors of head and neck. In general, pleomorphic adenoma is one of the most common benign tumor of the parapharyngeal region. Various approaches have been described in the literature for removal of parapharyngeal tumor with mandibulotomy generally carried out for large tumors. Here, we describe removal of a large parapharyngeal pleomorphic adenoma transcervically without mandibulotomy which subsequently turned out to be one of the largest ever reported in the literature and describe how large tumors of parapharyngeal can be removed with minimal invasive approach with mandibulotomy kept as a backup thereby avoiding complications associated with mandibulotomy. PMID- 28713753 TI - Removal of Multiple Keratocystic Odontogenic Tumors in a Nonsyndromic Patient. AB - Multiple keratocystic odontogenic tumors are one of the key features of Gorlin Goltz syndrome. A 15-year-old nonsyndromic female child presented with multiple keratocystic odontogenic tumors. The presence of the tumors was observed in immunological examinations. The images led to the suspicion of Gorlin-Goltz syndrome which was discarded after analyzing the patient's medical history and complementary examinations. Le Fort I osteotomy was opted to access the maxillary tumors favoring visibility and allowing simultaneous bilateral accesses. A sagittal vestibular incision in the lower rim was performed to access the mandibular lesions. After 3 months, the patient underwent a bilateral myotomy to reduce the volume of the masseter muscles. The occurrence of nonsyndromic multiple keratocystic odontogenic tumors is rare. Clinicians facing this situation shall seek for other known features of the Gorlin-Goltz syndrome and follow up closely these patients for the possibility of occurrence of basal cell carcinoma. PMID- 28713754 TI - A Rare Report of Two Cases: Ancient Schwannoma of Infratemporal Fossa and Verocay Schwannoma of Buccal Mucosa. AB - Schwannoma is a benign tumor that originates from Schwann cells of the peripheral nerve. Occurring as a common tumor in the head and neck region, its intraoral presentation is rare which accounts for only 1%. They are solitary, slow-growing, smooth-surfaced, usually asymptomatic, and encapsulated tumor. This paper comprises two case reports, both of which presented with an intraoral soft tissue swelling which turned out to be schwannoma of buccal mucosa and infratemporal fossa with extension into the oral cavity, respectively. The treatment was done with complete surgical excision. Soft tissue tumors of the oral cavity can present with similar clinical feature, which can make it difficult to distinguish one lesion from the other. Thus, final diagnosis for such lesions can only be rendered based on complete analysis of clinical, radiological, surgical, and histopathological findings. PMID- 28713755 TI - Tumor-induced Osteomalacia: A Sherlock Holmes Approach to Diagnosis and Management. AB - Tumor-induced osteomalacia (TIO) is a subtype of paraneoplastic syndrome associated with hypophosphatemia due to renal phosphate wasting in adults. The humoral factor responsible for clinical picture known as fibroblast growth factor 23 (FGF23) is most often secreted by benign yet elusive mesenchymal tumors, difficult to localize, access, and excise completely; rarely, they are multiple and malignant. Paradoxical inappropriately normal or low levels of 1,25 dihydroxyvitamin D in the setting of hypophosphatemia is due to suppressive effect of FGF23. The following case report describes a 31-year-old male with symptoms of multiple fractures and severe muscle weakness, hypophosphatemia with elevated tubular maximum reabsorption of phosphate/glomerular filtration rate with low active Vitamin D, prompted assay for C-terminal FGF23, which was elevated multifold. The tumor was localized with whole body 68-Gadolinium DOTANOC positron emission tomography-computed tomography fusion scan in the left nasal cavity with ipsilateral maxillary antrum. It was excised through transnasal approach and found to be mesenchymal tumor on histopathology. At 1 week of follow up, serum phosphate became normalized without supplementation. The patient is in follow-up for further measurement of FGF23 level and signs of recurrence. Because the occurrence of such a condition is rare and most often misdiagnosed or mismanaged for years, it is important to recognize this condition in differential diagnosis as potential curative surgical option is a reality. PMID- 28713756 TI - Dental Invasion by Adenoid Cystic Carcinoma of the Oral Cavity. AB - Cancer progression through the mandible bone is still questioned. Once the tumor has eroded the cortex, it can extend vertically and laterally. It usually spreads in the medullary spaces and finally affects the alveolar nerve. The presence of the teeth has been considered as a relative barrier to cancer infiltration until now. Herein, we report an uncommon case of dental root invasion by adenoid cystic carcinoma of the floor of the mouth. PMID- 28713757 TI - Epidermoid Cyst: Clinical and Surgical Case Report. AB - The epidermoid cyst is a development cyst, skin, filled with keratin and imprisoned by stratified squamous epithelium similar to skin. They are more frequent in males. Clinically presenting as flabby, prevalent over the face, neck and back. They are usually asymptomatic and its etiology is directly linked to trauma, as well as the imprisonment of epithelial rests during embryonic fusion. This study aims to present a case report of a patient 54 years old, with an epidermal cyst in the face, which was treated surgically. PMID- 28713758 TI - Two Concurrent Large Epidermoid Cysts in Sublingual and Submental Region Resembling Plunging Ranula: Report of a Rare Case. AB - An elderly female patient presented to surgical outpatient clinic with complaint of gradual onset of painless submental and sublingual midline swellings for 6 months of duration. The swellings were noncompressible, nontranslucent, nonpulsatile, and nontender on palpation. Clinical diagnosis was plunging ranula or dermoid cysts. Ultrasound examination of sublingual swelling showed cystic lesion with particulate content. Submental swelling showed cystic swelling with few echogenic floating lobules inside suggesting possibility of epidermoid/dermoid cyst. Magnetic resonance imaging of the face showed homogeneous fluid content within the sublingual cystic lesion and heterogeneous fluid content with few floating nodules within submental swelling. Both cystic lesions were noncommunicative and were showing diffusion restriction and no fat signal. Radiological diagnosis was sublingual and submental epidermoid cysts. She was operated under general anesthesia, and two separate cystic masses were excised with intact capsule. Histopathological diagnosis of masses confirms epidermoid cyst. Several literature have reported isolated sublingual or submandibular epidermoid cyst. However, concurrent sublingual and submental epidermoid cysts with different imaging appearance are rarely reported. PMID- 28713759 TI - Retraction: 6-0 Nylon Versus 6-0 Vicrylrapide in Chieloplasty. AB - [This retracts the article on p. 272 in vol. 6, PMID: 28299270.]. PMID- 28713760 TI - Prosthetic Consideration in Implant-supported Prosthesis: A Review of Literature. AB - Modern dentistry has changed tremendously with implant therapy. For the successful implant therapy, making a proper treatment plan considering both surgical and prosthetic part in mind is the key of success. Often practitioners tend to create a treatment plan overlooking the basic principles of prosthetic part. This present review has discussed various prosthetic consideration of implant-supported prosthesis. A step-by-step detailed prosthetic option with their indications has been discussed to help all dental implant practitioners in making of an optimal treatment plan for each case. PMID- 28713761 TI - Measurement of Lingual Cortical Plate Thickness and Lingual Position of Lower Third Molar Roots Using Cone Beam Computed Tomography. AB - OBJECTIVE: The objective of the study was to determine the potential risk of tooth/root displacement into the soft tissue during the third molar surgery. While performing third molar surgeries, one of the many complications is displacement of the tooth into the soft tissues. This can be due perforation of the lingual cortical bone during surgery or the position of the tooth root which may be close to the lingual bone. MATERIALS AND METHODS: Retrospective samples of 251 patients were collected who had undergone cone-beam computed tomography (CBCT) for various reasons. Measurements were performed independently and recorded twice by one surgeon and one radiologist; the average of the two measurements was calculated and evaluated using MyRay CBCT. RESULTS: On the right and the left side, the average distances in males for AL were 3.31 and 2.96 mm, respectively, whereas in females was found to be 3.98 and 3.56 mm which were statistically significant. On the right and left side, the average distances in males for RL were 2.03 and 1.78 mm, respectively, whereas in females, it was 2.41 and 1.99 mm, respectively, with the significant P value in the right side. CONCLUSION: Despite the sample size being of 251 patients, a large number of root of the third molar (95.62%) were not in contact with lingual cortical bone, but still practitioner should be careful during surgery as there might be the risk for displacement of the tooth. The images used were of impacted molar used in this study and these teeth were not subjected to surgery. Hence, the results can be only correlated theoretically, i.e., there would be a risk of displacement of the tooth during extraction. PMID- 28713762 TI - Comparison of the Shaping Ability of WaveOne Reciprocating Files with or without Glide Path in Simulated Curved S-shaped Root Canals. AB - OBJECTIVES: The aim was to compare the shaping ability of WaveOne reciprocating files with or without glide path in simulated curved S-shaped root canals. MATERIALS AND METHODS: Forty ISO #15, 0.02 taper, clear resin Endo Training Bloc S blocks were studied. The simulated curved S-shaped canals were dyed using ink, preinstrumentation images were scanned, and resin blocks were prepared and divided into Group A: PathFile and WaveOne and Group B: WaveOne. All canals were postoperatively scanned. Pre- and postoperative images were superimposed and evaluated at 12 defined measuring points. The efficacy of the systems was compared based on the amount and direction of canal transportation, centering ability, amount of material removed, and presence of canal aberrations. Mann Whitney U-test and independent t-test were used for statistical comparison. RESULTS: Both systems produced transportation at all levels and straightened the curved S-shaped canals. No significant differences in the amount and direction of transportation and amount of material removed were observed between the groups at each level (P > 0.05). However, Group A had significantly greater centering ability at the coronal straight zone (P = 0.018) and apical curvature (P = 0.014) levels than did Group B. Moreover, Group B showed more canal aberrations than did Group A. CONCLUSION: Within the limitations of the present study, the creation of a glide path with the PathFile system improved the centering ability of the WaveOne reciprocating file in the apical and straight coronal portions of the simulated curved S-shaped root canals and reduced the incidence of canal aberrations. PMID- 28713763 TI - Evaluation of Three Different Processing Techniques in the Fabrication of Complete Dentures. AB - AIMS AND OBJECTIVES: The objective of the present study is to compare the effectiveness of three different processing techniques and to find out the accuracy of processing techniques through number of occlusal interferences and increase in vertical dimension after denture processing. MATERIALS AND METHODS: A cross-sectional study was conducted on a sample of 18 patients indicated for complete denture fabrication was selected for the study and they were divided into three subgroups. Three processing techniques, compression molding and injection molding using prepolymerized resin and unpolymerized resin, were used to fabricate dentures for each of the groups. After processing, laboratory remounted dentures were evaluated for number of occlusal interferences in centric and eccentric relations and change in vertical dimension through vertical pin rise in articulator. Data were analyzed using statistical test ANOVA and SPSS software version 19.0 by IBM was used. RESULTS: Data obtained from three groups were subjected to one-way ANOVA test. After ANOVA test, results with significant variations were subjected to post hoc test. Number of occlusal interferences with compression molding technique was reported to be more in both centric and eccentric positions as compared to the two injection molding techniques with statistical significance in centric, protrusive, right lateral nonworking, and left lateral working positions (P < 0.05). Mean vertical pin rise (0.52 mm) was reported to more in compression molding technique as compared to injection molding techniques, which is statistically significant (P < 0.001). CONCLUSIONS: Within the limitations of this study, injection molding techniques exhibited less processing errors as compared to compression molding technique with statistical significance. There was no statistically significant difference in processing errors reported within two injection molding systems. PMID- 28713764 TI - Assessing Prevalence of Temporomandibular Disorders among University Students: A Questionnaire Study. AB - AIM: The aim of this study is to assess the prevalence of temporomandibular disorders (TMDs) among university students. OBJECTIVES: The etiology of TMD is of multifactorial, and our study is designed to assess the prevalence of TMD in an institution within a university. Various parameters including trauma, malocclusion, stress assessment - its correlation with the timing, the duration of TMD in meeting the deadlines, and examinations have been assessed. MATERIALS AND METHODS: A standard questionnaire-based study with modified Fonseca anamnestic index is used. The questionnaire study was conducted with a statistically calculated sample size of 402 students within a university. The data were analyzed statistically for significance and correlations. Statistical analysis was performed using SPSS for Windows release 14.0 (SPSS Inc., Chicago, IL, USA). Differences at the 5% level were accepted as being statistically significant. RESULTS: TMD and its associated symptoms are frequent among students of health and science studies. Female predominance is seen. There was also an increased prevalence of symptoms in people who described themselves as being tense. The relationship between orthodontic therapy and TMDs were also evaluated, and the duration of therapy is found to be significant. There was a significant association between history of trauma and presence of TMDs. CONCLUSIONS: TMD and its associated symptoms are frequent among students of health and science studies. A simple anamnestic index is of use in identifying and classifying temporomandibular joint and TMD symptoms in patients according to the severity of the disorder. Females showed a greater prevalence of signs and symptoms of TMD than males. Longitudinal studies are recommended to identify and follow-up the prevalence and health-care needs of patients with TMDs. PMID- 28713765 TI - Prevalence of Periodontal Pathogens in a Group of Participants from the Middle East and North Africa Geographic Region with Minimal Periodontal Disease. AB - AIM AND OBJECTIVES: To assess the prevalence of the three putative periodontal pathogens such as Aggregatibacter actinomycetemcomitans (A. a), Porphyromonas gingivalis (P. g), and Prevotella intermedia (P. i) in a group of Arab participants from the Middle East and North Africa (MENA) region who had minimal periodontal disease and no history of periodontal treatment and further to analyze the association among these three microorganisms. MATERIALS AND METHODS: Eighty-four participants of varied demographics and oral/dental care habits were screened for this study. Twenty-one participants who eventually gave their consent to fully participate in the study provided a balanced representation of the screened universe. RESULTS: Seventy-eight microbiological samples were taken from the deepest pockets. Twenty-three percent of all samples were found to be A. a positive and so were 79% for P. g and 82% for P. i. A highly remarkable association was observed between the presence of P. i along with P. g (P < 0.00l; Fisher's exact test). Of all samples, merely six cases were P. i positive but not P. g and eight cases were vice versa. There was a statistically significant association between A. a and P. g (P = 0.016). No significant relationship was detected between P. i and A. a. CONCLUSIONS: This qualitative study shows very high frequency of the three periodontal pathogens (A. a, P. g, and P. i) in a group of Arab nationals with minimal periodontal disease. The lack of oral hygiene, minimal use of antimicrobial drugs and antiseptics, and the absence of dental care may partly explain the high prevalence of periodontal pathogens. PMID- 28713766 TI - Comparative Evaluation of Antiplaque Efficacy between Essential Oils with Alcohol Based and Chlorhexidine with Nonalcohol-Based Mouthrinses. AB - AIM AND OBJECTIVES: The aim of this study is to compare the antiplaque efficacy of alcohol-based mouthwash with essential oils and nonalcohol-based chlorhexidine mouthrinse in 4 days plaque re-formation study. MATERIALS AND METHODS: The current research paper is double-blinded, parallel designed clinical trial that was conducted in the Department of Periodontics and Oral Implantology, Kalinga Institute of Dental Sciences, Bhubaneswar. This included ninety dental students of Bachelor of Dental Surgery curriculum (in the age range from 20 to 24 years) Professional cleaning with scaling and polishing was carried out to acquire a zero plaque and gingival index (GI) for all ninety patients at baseline. Ninety patients were randomly divided into three groups with thirty patients in each group named as Group A, B, and C, respectively. Two commercially available mouthrinses, one containing alcohol (labeled as Solution (A) and one without alcohol (labeled as Solution (B) were placed in identical bottles and distributed to Group A and Group B patients. Whereas, the Group C patientswere instructed to use warm saline mouth rinse. The statistical analysis was performed using the Statistical Package for the Social Sciences software (Version 18). RESULTS: Essential oils with an alcohol-based and chlorhexidine (CHX) alcohol-free mouthrinse (0.2%) groups compared to normal saline showed significant reductions in GI and PI scores.(P < 0.0001). CONCLUSION: The antiplaque efficacy of both alcohol-based mouthwash with essential oils and nonalcohol based CHX mouthwash were found to be equally effective in 4 days of plaque re-formation. PMID- 28713767 TI - Validated Questionnaire of Maternal Attitude and Knowledge for Predicting Caries Risk in Children: Epidemiological Study in North Jakarta, Indonesia. AB - AIMS AND OBJECTIVES: Predicting caries risk in children can be done by identifying caries risk factors. It is an important measure which contributes to best understanding of the cariogenic profile of the patient. Identification could be done by clinical examination and answering the questionnaire. We arrange the study to verify the questionnaire validation for predicting caries risk in children. MATERIALS AND METHODS: The study was conducted on 62 pairs of mothers and their children, aged between 3 and 5 years. The questionnaire consists of 10 questions concerning mothers' attitude and knowledge about oral health. The reliability and validity test is based on Cronbach's alpha and correlation coefficient value. RESULTS: All question are reliable (Cronbach's alpha = 0.873) and valid (Corrected item-total item correlation >0.4). CONCLUSIONS: Five questionnaires of mother's attitude about oral health and five questionnaires of mother's knowledge about oral health are reliable and valid for predicting caries risk in children. PMID- 28713768 TI - Dental Implants Placed in Patients with Mechanical Risk Factors: A Long-term Follow-up Retrospective Study. AB - OBJECTIVES: Risk factors in oral implantology are defined as local or systemic conditions that increase failure rates. The purpose of this paper is to evaluate the long-term survival rate of dental implants placed in patients presenting mechanical risk factors. MATERIALS AND METHODS: This retrospective study was conducted only with patients presenting at least one of the following risk factors were included: Bruxism; crown-to-implant (C/I) ratio <0.8; abutment angulation. The overall implant survival was estimated using Kaplan-Meier analyses. Risk factors for implant failure were identified using the Cox proportional hazard regression models. RESULTS: Eighty-nine eligible patients were enrolled in this study: They were both male (n = 56, 62.92%) and female (n = 33, 37.08%), with an average age of 53.24 (23-76 years), with 227 dental implants inserted. The mean follow-up was 13.6 years (range: 10-16 years). The overall 10 year Kaplan-Meier survival estimate with associated 95% confidence intervals was 86.34% (82.8, 87.1). Bruxism was the only variable that showed a statistically significant association with implant failure (P < 0.05) and a hazard ratio of 2.9, while both Crown to-implant and abutment angulations reported lower values of failure (P > 0.05). CONCLUSIONS: Within the limitations of this study, can be concluded that data suggested an evident relationship between bruxism and dental implant failure but further studies, with a larger sample and a different design are required to assess this relationship. PMID- 28713769 TI - Fracture Fragment Reattachment Using Projectors and Anatomic everstick PostTM: An Ultraconservative Approach. AB - Traumatized anterior teeth require quick functional and esthetic repair. Tooth fragment reattachment is a simple and conservative clinical procedure to restore fractured anterior teeth. Different techniques of reattachment include enamel beveling, "v-" shaped internal enamel and dentin grooves, external chamfer, over contouring, and by placing fiber post, all of which were invasive methods. This article describes a novel technique of reattachment using canal projectors for stabilizing fractured fragments followed by endodontic therapy and internal reinforcement with custom fiber post (everStick PostTM, GC Corporation, Tokyo, Japan). PMID- 28713770 TI - Prognostic Impact of AJCC/UICC 8th Edition New Staging Rules in Oropharyngeal Squamous Cell Carcinoma. AB - INTRODUCTION: The purpose of this study was to test whether the 8th edition of the AJCC/UICC TNM staging system (UICC) precisely differentiates between stages and reflects disease outcome in human papilloma virus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC). PATIENTS AND METHODS: OPSCC patients that were diagnosed between 2000 and 2016 were included in this analysis and HPV status was determined by combined DNA and p16 testing. Stratification was done according to 7th and 8th UICC staging rules. Incidence trends of HPV associated tumorigenesis, 5-year overall survival (OS) according to tumor stages as well as the influence of therapy and prognostic factors toward the outcome were calculated using Kaplan-Meier method and Cox proportional-hazards model. RESULTS: A significant increase [2000; n = 8/39 (21%)-2015; n = 17/32 (53%); p = 0.002] in HPV-associated OPSCC was seen in the observation period. Together, 150/599 (25.0%) of the patients had HPV-driven OPSCC and 64.7% of curative treatments in all OPSCC patients included upfront surgery of the primary and the neck. 7th edition staging rules led to no discrimination in all respective four UICC stages in HPV OPSCC underlining the need for new staging rules. However, only discrimination between stages I vs. II and III vs. IV was significant in our patients with HPV-OPSCC (94.4 vs. 77.5%; p = 0.031 and 63.9 vs. 25.0%; p = 0.013), and stages II vs. III did not differ in OS rates (p = 0.257), when applying the new staging rules. For HPV-negative OPSCC, significant outcome differences were only seen between UICC stages III vs. IV (57.6 vs. 35.2%; p = 0.012). DISCUSSION: While the 7th edition of UICC shows invalid discrimination between stages, the 8th edition is more suitable for HPV-associated carcinoma. Due to lack of differentiation between stages II and III further adaption is essential. PMID- 28713771 TI - Integrating Hyperthermia into Modern Radiation Oncology: What Evidence Is Necessary? AB - Hyperthermia (HT) is one of the hot topics that have been discussed over decades. However, it never made its way into primetime. The basic biological rationale of heat to enhance the effect of radiation, chemotherapeutic agents, and immunotherapy is evident. Preclinical work has confirmed this effect. HT may trigger changes in perfusion and oxygenation as well as inhibition of DNA repair mechanisms. Moreover, there is evidence for immune stimulation and the induction of systemic immune responses. Despite the increasing number of solid clinical studies, only few centers have included this adjuvant treatment into their repertoire. Over the years, abundant prospective and randomized clinical data have emerged demonstrating a clear benefit of combined HT and radiotherapy for multiple entities such as superficial breast cancer recurrences, cervix carcinoma, or cancers of the head and neck. Regarding less investigated indications, the existing data are promising and more clinical trials are currently recruiting patients. How do we proceed from here? Preclinical evidence is present. Multiple indications benefit from additional HT in the clinical setting. This article summarizes the present evidence and develops ideas for future research. PMID- 28713772 TI - Harnessing Neutrophil Survival Mechanisms during Chronic Infection by Pseudomonas aeruginosa: Novel Therapeutic Targets to Dampen Inflammation in Cystic Fibrosis. AB - More than two decades after cloning the cystic fibrosis transmembrane regulator (CFTR) gene, the defective gene in cystic fibrosis (CF), we still do not understand how dysfunction of this ion channel causes lung disease and the tremendous neutrophil burden which persists within the airways; nor why chronic colonization by Pseudomonas aeruginosa develops in CF patients who are thought to be immunocompetent. It appears that the microenvironment within the lung of CF patients provides favorable conditions for both P. aeruginosa colonization and neutrophil survival. In this context, the ability of bacteria to induce hypoxia, which in turn affects neutrophil survival is an additional level of complexity that needs to be accounted for when controlling neutrophil fate in CF. Recent studies have underscored the importance of neutrophils in innate immunity and their functions appear to extend far beyond their well-described role in antibacterial defense. Perhaps a disturbance in neutrophil reprogramming during the course of an infection severely modulates the inflammatory response in CF. Furthermore there is an emerging concept that the CFTR itself may be an immune modulator and stimulating CFTR function in CF patients could promote neutrophil and macrophages antimicrobial function. Fostering the resolution of inflammation by favoring neutrophil apoptosis could preserve their microbicidal activities but decrease their proinflammatory potential. In this context, triggering neutrophil apoptosis with roscovitine may be a potential therapeutic option and this is currently being evaluated in CF patients. In the present review we discuss how neutrophils functions are disturbed in CF and how this may relate to chronic infection with P. aeuginosa and we propose novel research directions aimed at modulating neutrophil survival, dampening lung inflammation and ultimately leading to an amelioration of the lung disease. PMID- 28713773 TI - The Cytolethal Distending Toxin Subunit CdtB of Helicobacter hepaticus Promotes Senescence and Endoreplication in Xenograft Mouse Models of Hepatic and Intestinal Cell Lines. AB - Cytolethal distending toxins (CDTs) are common among pathogenic bacteria of the human and animal microbiota. CDTs exert cytopathic effets, via their active CdtB subunit. No clear description of those cytopathic effects has been reported at the cellular level in the target organs in vivo. In the present study, xenograft mouse models of colon and liver cell lines were set up to study the effects of the CdtB subunit of Helicobacter hepaticus. Conditional transgenic cell lines were established, validated in vitro and then engrafted into immunodeficient mice. After successful engraftment, mice were treated with doxycyclin to induce the expression of transgenes (red fluorescent protein, CdtB, and mutated CdtB). For both engrafted cell lines, results revealed a delayed tumor growth and a reduced tumor weight in CdtB-expressing tumors compared to controls. CdtB-derived tumors showed gamma-H2AX foci formation, an increase in apoptosis, senescence, p21 and Ki-67 nuclear antigen expression. No difference in proliferating cells undergoing mitosis (phospho-histone H3) was observed. CdtB intoxication was also associated with an overexpression of cytokeratins in cells at the invasive front of the tumor as well as an increase in ploidy. All these features are hallmarks of endoreplication, as well as aggressiveness in cancer. These effects were dependent on the histidine residue at position 265 of the CdtB, underlying the importance of this residue in CdtB catalytic activity. Taken together, these data indicate that the CdtB triggers senescence and cell endoreplication leading to giant polyploid cells in these xenograft mouse models. PMID- 28713775 TI - Salivary Tick Cystatin OmC2 Targets Lysosomal Cathepsins S and C in Human Dendritic Cells. AB - To ensure successful feeding tick saliva contains a number of inhibitory proteins that interfere with the host immune response and help to create a permissive environment for pathogen transmission. Among the potential targets of the salivary cystatins are two host cysteine proteases, cathepsin S, which is essential for antigen- and invariant chain-processing, and cathepsin C (dipeptidyl peptidase 1, DPP1), which plays a critical role in processing and activation of the granule serine proteases. Here, the effect of salivary cystatin OmC2 from Ornithodoros moubata was studied using differentiated MUTZ-3 cells as a model of immature dendritic cells of the host skin. Following internalization, cystatin OmC2 was initially found to inhibit the activity of several cysteine cathepsins, as indicated by the decreased rates of degradation of fluorogenic peptide substrates. To identify targets, affinity chromatography was used to isolate His-tagged cystatin OmC2 together with the bound proteins from MUTZ-3 cells. Cathepsins S and C were identified in these complexes by mass spectrometry and confirmed by immunoblotting. Furthermore, reduced increase in the surface expression of MHC II and CD86, which are associated with the maturation of dendritic cells, was observed. In contrast, human inhibitor cystatin C, which is normally expressed and secreted by dendritic cells, did not affect the expression of CD86. It is proposed that internalization of salivary cystatin OmC2 by the host dendritic cells targets cathepsins S and C, thereby affecting their maturation. PMID- 28713776 TI - Modulation of Trehalose Dimycolate and Immune System by Rv0774c Protein Enhanced the Intracellular Survival of Mycobacterium smegmatis in Human Macrophages Cell Line. AB - Mycobacterium tuberculosis Rv0774c protein was reported previously to express under stress conditions. Therefore, Rv0774c gene was cloned and expressed in Mycobacterium smegmatis, a surrogate host, to determine its role in bacterial persistence and immune modulation in natural environment. The bacterial colonies expressing Rv0774c (Ms_rv0774c) were larger, smoother, more moist, and flatter than the control ones (Ms_ve). Enhanced survival of Ms_rv0774c after treatment with streptomycin was observed when compared with control. The cell envelope of Ms_rv0774c was demonstrated to have more trehalose di-mycolate (TDM) and lesser amount of mycolylmannosylphosphorylheptaprenol (Myc-PL) in comparison to control. Higher intracellular survival rate was observed for Ms_rv0774c as compared to Ms_ve in the THP-1 cells. This could be correlated to the reduction in the levels of reactive NO and iNOS expression. Infection of macrophages with Ms_rv0774c resulted in significantly increased expression of TLR2 receptor and IL-10 cytokines. However, it lowered the production of pro-inflammatory cytokines such as IL-12, TNF-alpha, IFN-gamma, and MCP-1 in Ms_rv0774c infected macrophages in comparison to the control and could be associated with decreased phosphorylation of p38 MAPK. Though, predicted with high antigenicity index bioinformatically, extracellular in nature and accessible to host milieu, Rv0774c was not able to generate humoral response in patient samples. Overall, the present findings indicated that Rv0774c altered the morphology and streptomycin sensitivity by altering the lipid composition of M. smegmatis as well as modulated the immune response in favor of bacterial persistence. PMID- 28713774 TI - Epic Immune Battles of History: Neutrophils vs. Staphylococcus aureus. AB - Neutrophils are the most abundant leukocytes in human blood and the first line of defense after bacteria have breached the epithelial barriers. After migration to a site of infection, neutrophils engage and expose invading microorganisms to antimicrobial peptides and proteins, as well as reactive oxygen species, as part of their bactericidal arsenal. Ideally, neutrophils ingest bacteria to prevent damage to surrounding cells and tissues, kill invading microorganisms with antimicrobial mechanisms, undergo programmed cell death to minimize inflammation, and are cleared away by macrophages. Staphylococcus aureus (S. aureus) is a prevalent Gram-positive bacterium that is a common commensal and causes a wide range of diseases from skin infections to endocarditis. Since its discovery, S. aureus has been a formidable neutrophil foe that has challenged the efficacy of this professional assassin. Indeed, proper clearance of S. aureus by neutrophils is essential to positive infection outcome, and S. aureus has developed mechanisms to evade neutrophil killing. Herein, we will review mechanisms used by S. aureus to modulate and evade neutrophil bactericidal mechanisms including priming, activation, chemotaxis, production of reactive oxygen species, and resolution of infection. We will also highlight how S. aureus uses sensory/regulatory systems to tailor production of virulence factors specifically to the triggering signal, e.g., neutrophils and defensins. To conclude, we will provide an overview of therapeutic approaches that may potentially enhance neutrophil antimicrobial functions. PMID- 28713777 TI - A Novel Chimeric Endolysin with Antibacterial Activity against Methicillin Resistant Staphylococcus aureus. AB - Cysteine/histidine-dependent amidohydrolase/peptidase (CHAP) and amidase are known as catalytic domains of the bacteriophage-derived endolysin LysK and were previously reported to show lytic activity against methicillin-resistant Staphylococcus aureus (MRSA). In the current study, the in silico design and analysis of chimeric CHAP-amidase model was applied to enhance the stability and solubility of protein, which was achieved through improving the properties of primary, secondary and tertiary structures. The coding gene sequence of the chimeric CHAP-amidase was synthesized and subcloned into the pET-22(+) expression vector, and the recombinant protein was expressed in E. coli BL21 (DE3) strain. Subsequent affinity-based purification yielded ~12 mg soluble protein per liter of E. coli culture. Statistical analysis indicated that concentrations of >=1 MUg/mL of the purified protein have significant antibacterial activity against S. aureus MRSA252 cells. The engineered chimeric CHAP-amidase exhibited 3.2 log reduction of MRSA252 cell counts at the concentration of 10 MUg/mL. A synergistic interaction between CHAP-amidase and vancomycin was detected by using checkerboard assay and calculating the fractional inhibitory concentration (FIC) index. This synergistic effect was shown by 8-fold reduction in the minimum inhibitory concentration of vancomycin. The chimeric CHAP-amidase displayed strong antibacterial activity against S. aureus, S. epidermidis, and enterococcus. However, it did not indicate any significant antibacterial activity against E. coli and Lactococcus lactis. Taken together, these findings suggest that our chimeric CHAP-amidase might represent potential to be used for the development of efficient antibacterial therapies targeting MRSA and certain Gram positive bacteria. PMID- 28713778 TI - Tick-Virus Interactions: Toll Sensing. AB - Ticks are important vectors of viruses that infect and cause disease in man, livestock, and companion animals. The major focus of investigation of tick-borne viruses has been the interaction with the mammalian host, particularly the mechanisms underlying disease and the development of vaccines to prevent infection. Only recently has research begun to investigate the interaction of the virus with the tick host. This is striking when considering that the virus spends far more time infecting the tick vector relative to the vertebrate host. The assumption has been that the tick host and virus have evolved to reach an equilibrium whereby virus infection does not impede the tick life cycle and conversely, the tick does not restrict virus replication and through blood feeding on vertebrates, disseminates the virus. The development and application of new technologies to tick-pathogen interactions has been fuelled by a number of developments in recent years. This includes the release of the first draft of a tick genome, that of Ixodes scapularis, and the availability of tick-cell lines as convenient models to investigate interactions. One of the by-products of these investigations has been the observation of familiar proteins in new situations. One such protein family is Toll and Toll-like receptors that in vertebrates play a key role in detection of microorganisms, including viruses. But does Toll signaling play a similar role in detection of virus infection in ticks, and if it does, how does this affect the maintenance of viruses within the tick? PMID- 28713779 TI - IFITM3 Rs12252-C Variant Increases Potential Risk for Severe Influenza Virus Infection in Chinese Population. AB - Background: Interferon Inducible Transmembrane 3 (IFITM3) is a key factor in interferon pathway and it involves host's immune response against multiple viruses. IFITM3 rs12252-C was associated with severe influenza virus infection in several studies, however whether this association is universal to all types of influenza virus or diverse ethnic populations remain controversial. Method: A case-control genetic association study was performed from September 2013 to April 2014 and September 2014 to April 2015. All samples were tested for influenza using RT-PCR, and genotyped by High Resolution Melting assay. Results: A total of 65 healthy people, 165 mild influenza-like illness (ILI) cases and 315 severe acute respiratory infection (SARI) cases were enrolled in this study. The frequency of CC genotype was much higher in SARI cases with IVI than that in ILI cases with IVI (61.59 vs. 27.16%), leading a 4.67-fold greater risk for severe IVI than other two genotypes. Moreover, the risk of IFITM3 rs12252-C variant for severe IVI was specific for both influenza A and influenza B. Conclusion:IFITM3 rs12252 CC genotype was associated with severity rather than susceptibility of IVI in Chinese population, and this strong effect was observed in all subtypes of seasonal influenza infection. PMID- 28713780 TI - Tumor Targeting by Fusobacterium nucleatum: A Pilot Study and Future Perspectives. AB - Colorectal adenocarcinoma (CRC) is a common tumor with high mortality rates. Interestingly, CRC was found to be colonized by the oral anaerobic bacteria Fusobacterium nucleatum, which accelerates tumor progression and enables immune evasion. The CRC-specific colonization by fusobacteria is mediated through the recognition of tumor displayed Gal-GalNAc moieties by the fusobacterial Fap2 Gal GalNAc lectin. Here, we show high Gal-GalNAc levels in additional adenocarcinomas including those found in the stomach, prostate, ovary, colon, uterus, pancreas, breast, lung, and esophagus. This observation coincides with recent reports that found fusobacterial DNA in some of these tumors. Given the tumorigenic role of fusobacteria and its immune evasion properties, we suggest that fusobacterial elimination might improve treatment outcome of the above tumors. Furthermore, as fusobacteria appears to specifically home-in to Gal-GalNAc-displaying tumors, it might be engineered as a platform for treating CRC and the above common, lethal, adenocarcinomas. PMID- 28713781 TI - The Metalloprotease, Mpr1, Engages AnnexinA2 to Promote the Transcytosis of Fungal Cells across the Blood-Brain Barrier. AB - Eukaryotic pathogens display multiple mechanisms for breaching the blood-brain barrier (BBB) and invading the central nervous system (CNS). Of the fungal spp., that cause disease in mammals, only some cross brain microvascular endothelial cells which constitute the BBB, and invade the brain. Cryptococcus neoformans, the leading cause of fungal meningoencephalitis, crosses the BBB directly by transcytosis or by co-opting monocytes. We previously determined that Mpr1, a secreted fungal metalloprotease, facilitates association of fungal cells to brain microvascular endothelial cells and we confirmed that the sole expression of CnMPR1 endowed S. cerevisiae with an ability to cross the BBB. Here, the gain of function conferred onto S. cerevisiae by CnMPR1 (i.e., Sc strain) was used to identify targets of Mpr1 that might reside on the surface of the BBB. Following biotin-labeling of BBB surface proteins, Sc-associated proteins were identified by LC-MS/MS. Of the 62 proteins identified several were cytoskeleton-endocytosis-associated including AnnexinA2 (AnxA2). Using an in vitro model of the human BBB where AnxA2 activity was blocked, we found that the lack of AnxA2 activity prevented the movement of S. cerevisiae across the BBB (i.e., transcytosis of Sc strain) but unexpectedly, TEM analysis revealed that AnxA2 was not required for the association or the internalization of Sc. Additionally, the co-localization of AnxA2 and Sc suggest that successful crossing of the BBB is dependent on an AxnA2-Mpr1-mediated interaction. Collectively the data suggest that AnxA2 plays a central role in fungal transcytosis in human brain microvascular endothelial cells. The movement and exocytosis of Sc is dependent on membrane trafficking events that involve AnxA2 but these events appear to be independent from the actions of AnxA2 at the host cell surface. We propose that Mpr1 activity promotes cytoskeleton remodeling in brain microvascular endothelial cells and thereby engages AnxA2 in order to facilitate fungal transcytosis of the BBB. PMID- 28713782 TI - Characterization and Differentiation of Mycobacterium avium subsp. paratuberculosis from Other Mycobacteria Using Matrix Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry. AB - Mycobacterium avium subsp. paratuberculosis (MAP), the causative agent of Johne's disease in cattle, is responsible for significant economic losses to the US dairy industry. The pathogen has also been associated with chronic human diseases like Crohn's disease, type 1 diabetes and multiple sclerosis. Determining causation requires rapid characterization and source tracking the pathogen. Here, we used matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry to characterize and differentiate strains of MAP from 14 other species of Mycobacterium from bovine, human, and environmental sources. Lysates from cells disrupted by bead beating in TFA-acetonitrile solution were analyzed by MALDI-TOF. MAP strains were differentiated by mass spectral profiles that are distinct from each other and from other Mycobacterium species. Cluster analysis of spectral profiles indicates two distinct clusters, one dominated by the members of avium complex and a second group dominated by members of fortuitum and parafortuitum complexes. We believe that MALDI-TOF methods can be used to differentiate and source-track MAP strains. PMID- 28713783 TI - Streptococcus pyogenes Phospholipase A2 Induces the Expression of Adhesion Molecules on Human Umbilical Vein Endothelial Cells and Aorta of Mice. AB - The Streptococcus pyogenes phospholipase A2 (SlaA) gene is highly conserved in the M3 serotype of group A S. pyogenes, which often involves hypervirulent clones. However, the role of SlaA in S. pyogenes pathogenesis is unclear. Herein, we report that SlaA induces the expression of intercellular adhesion molecule 1 (ICAM1) and vascular cell adhesion molecule 1 (VCAM1) via the arachidonic acid signaling cascade. Notably, recombinant SlaA induced ICAM1 and VCAM1 expression in human umbilical vein endothelial cells (HUVECs), resulting in enhanced adhesion of human monocytic leukemia (THP-1) cells. However, C134A, a variant enzyme with no enzymatic activity, did not induce such events. In addition, culture supernatants from S. pyogenes SSI-1 enhanced the adhesion of THP-1 cells to HUVECs, but culture supernatants from the DeltaslaA isogenic mutant strain had limited effects. Aspirin, a cyclooxygenase 2 inhibitor, prevented the adhesion of THP-1 cells to HUVECs and did not induce ICAM1 and VCAM1 expression in HUVECs treated with SlaA. However, zileuton, a 5-lipoxygenase inhibitor, did not exhibit such effects. Furthermore, pre-administration of aspirin in mice intravenously injected with SlaA attenuated the transcriptional abundance of ICAM1 and VCAM1 in the aorta. These results suggested that SlaA from S. pyogenes stimulates the expression of adhesion molecules in vascular endothelial cells. Thus, SlaA contributes to the inflammation of vascular endothelial cells upon S. pyogenes infection. PMID- 28713784 TI - Identification of Novel and Efficacious Chemical Compounds that Disturb Influenza A Virus Entry in vitro. AB - Influenza A virus is a negative RNA stranded virus of the family Orthomyxoviridae, and represents a major public health threat, compounding existing disease conditions. Influenza A virus replicates rapidly within its host and the segmented nature of its genome facilitates re-assortment, whereby whole genes are exchanged between influenza virus subtypes during replication. Antiviral medications are important pharmacological tools in influenza virus prophylaxis and therapy. However, the use of currently available antiviral is impeded by sometimes high levels of resistance in circulating virus strains. Here, we identified novel anti-influenza compounds through screening of chemical compounds synthesized de novo on human lung epithelial cells. Computational and experimental screening of extensive and water soluble compounds identified novel influenza virus inhibitors that can reduce influenza virus infection without detectable toxic effects on host cells. Interestingly, the indicated active compounds inhibit viral replication most likely via interaction with cell receptors and disturb influenza virus entry into host cells. Collectively, screening of new synthesis chemical compounds on influenza A virus replication provides a novel and efficacious anti-influenza compounds that can inhibit viral replication via disturbing virus entry and indicates that these compounds are attractive candidates for evaluation as potential anti-influenza drugs. PMID- 28713785 TI - Inactivation of Heat Adapted and Chlorine Adapted Listeria Monocytogenes ATCC 7644 on Tomatoes Using Sodium Dodecyl Sulphate, Levulinic Acid and Sodium Hypochlorite Solution. AB - The effectiveness of sodium dodecyl sulphate (SDS), sodium hypochlorite solution and levulinic acid in reducing the survival of heat adapted and chlorine adapted Listeria monocytogenes ATCC 7644 was evaluated. The results against heat adapted L. monocytognes revealed that sodium hypochlorite solution was the least effective, achieving log reduction of 2.75, 2.94 and 3.97 log colony forming unit (CFU)/mL for 1, 3 and 5 minutes, respectively. SDS was able to achieve 8 log reduction for both heat adapted and chlorine adapted bacteria. When used against chlorine adapted L. monocytogenes sodium hypochlorite solution achieved log reduction of 2.76, 2.93 and 3.65 log CFU/mL for 1, 3 and 5 minutes, respectively. Using levulinic acid on heat adapted bacteria achieved log reduction of 3.07, 2.78 and 4.97 log CFU/mL for 1, 3, 5 minutes, respectively. On chlorine adapted bacteria levulinic acid achieved log reduction of 2.77, 3.07 and 5.21 log CFU/mL for 1, 3 and 5 minutes, respectively. Using a mixture of 0.05% SDS and 0.5% levulinic acid on heat adapted bacteria achieved log reduction of 3.13, 3.32 and 4.79 log CFU/mL for 1, 3 and 5 minutes while on chlorine adapted bacteria it achieved 3.20, 3.33 and 5.66 log CFU/mL, respectively. Increasing contact time also increased log reduction for both test pathogens. A storage period of up to 72 hours resulted in progressive log reduction for both test pathogens. Results also revealed that there was a significant difference (P<=0.05) among contact times, storage times and sanitizers. Findings from this study can be used to select suitable sanitizers and contact times for heat and chlorine adapted L. monocytogenes in the fresh produce industry. PMID- 28713786 TI - Development of a Method to Extract and Amplify the Complete Mitogenome of Some Sparidae Species. AB - Previous studies showed that fish mitochondrial DNA (mtDNA) is set up by a closed circular molecule of 16-17 kilobases (kb), comprising 2 ribosomal RNA genes (rRNA), 22 transfer RNA genes (tRNA), 13 protein-coding genes and 2 non-coding regions. The analysis of single mtDNA genes, such as Cytb, COI, 16S and 12S, or short segment of them, has been widely used against species substitution in both fresh and processed fish products. The analysis of the complete mitochondrial genome of fishery products allows to better study and characterise fish species. The aim of this research was to extract and amplify the complete mtDNA of some fish species of commercial interest belonging to the Sparidae family. The studied species were Dentex dentex, Dentex gibbosus, Dentex nufar, Pagellus acarne and Pagellus erythrinus. The entire mitogenome was obtained by gene amplification using long polymerase chain reactions. The analysis of the complete mitochondrial sequences will allow to gain further insights on these species and to find polymorphic sites that assess the degree of genetic variability of the species belonging to the family Sparidae. PMID- 28713787 TI - Consumers' Preferences for a Local Food Product: The Case of a New Carnaroli Rice Product in Lombardy. AB - Italy, with a cultivated area of 218,000 ha, is a European leader of rice production. In particular Lombardy region accounts for 40% of total rice cultivation and the case study in object accounts for 3.2% of Lombardy total rice area (2773 ha). Starting from 2012, through a regional project titled Buono, Sano e Vicino (good, healthy and close), Riso e Rane rural district supported local rice farmers in developing innovation in rice production and promoting an alternative supply chain to increase farmers bargaining power and promote new market strategies. More specifically, the innovation introduced is a new biotech method for variety certification, named DNA controllato (DNA tested). In the first step of the project, the attention was focused on an Italian traditional variety of rice: Carnaroli rice. Thanks to a commercial agreement with one of the most important large retailers in Lombardy, the Riso e Rane rice is offered for sale both in the traditional and wholegrain version. In this context, this work aims to evaluate the determinants of consumer's quality perception of this product, through a preference study of the commercial rice package. Preliminary results reveal that consumers perceive information about origin, local food system and tradition more easily than DNA tested certification. In conclusion, this work contributes to evaluate the role of bio economy applications to the food sector and offers new insights for the debate about the relationships between tradition and innovation. PMID- 28713788 TI - Microorganisms of the Intestinal Microbiota of Oncorhynchus Mykiss Produce Antagonistic Substances Against Bacteria Contaminating Food and Causing Disease in Humans. AB - The objective was to analyse the antibacterial ability of members of the intestinal microbiota of Oncorhynchus mykiss specimens on several bacterial target strains that contaminate food and cause disease in humans. Bacterial colonies from an intestinal portion of the 20 specimens of O. mykiss were obtained in different culture media. Several of the colonies showed antibacterial action on different target strains. The bacterial species with the highest antagonistic capacity were Hafnia alvei and Lactococcus lactis and the more susceptible target strains were Aeromonas hydrophila, Listeria monocytogenes and Escherichia coli. Moreover, it was shown that all the antibacterial substances were susceptible to the action of various proteolytic enzymes. The detection of substances of a proteinaceous nature, possibly bacteriocins produced by bacteria of the intestinal microbiota of O. mykiss, allows further study of these products to establish biotechnological developments in the area of health protection and food biopreservation. PMID- 28713789 TI - Screening of Oxalate Degrading Lactic Acid Bacteria of Food Origin. AB - A screening for oxalate degrading abilities was initially carried on within Lactic Acid Bacteria cultures of different food origin. Seventy-nine strains were drop-inoculated onto MRS agar plates containing calcium oxalate. By comparing colonies diameters, 31 strains were used to inoculate, in parallel, MRS and MRS modified by sodium oxalate addition. Differences in the strains' growth were assessed by colony forming unit counts. For two strains, the growth in oxalate enriched medium was significantly higher; while, for eleven strains an opposite behaviour was recorded. Two strains - probiotic Lactobacillus rhamnosus LbGG and Enterococcus faecalis 59 - were chosen. The first strain appeared to be able to metabolize oxalate more efficiently than the other tested cultures, while strain 59 appeared unable to gather advantage by oxalates and, indeed, appeared to be inhibited by the salt presence in the medium. Outcomes revealed that higher glucose concentrations may favour oxalates utilization. In MRS with oxalate, but without glucose, citrate was completely metabolized. Evaluation along time confirmed that the oxalate degradation is more significant in presence of glucose. Outcomes may represent a good start for the development of a safe and even probiotic culture able to lower the oxalates content of food. PMID- 28713790 TI - Preliminary Study on Physicochemical and Biochemical Stress Markers at Poultry Slaughterhouse. AB - Pre-slaughter stress can result in variations in the glycogen storage and metabolic changes of muscle, responsible for quality poultry meat. Aim of this study was to investigate, as pre-slaughter stress markers and quality meat, physicochemical (pH), biochemical (muscle glycogen content), and chemical (super oxides free radicals) parameters. The carcass quality, as incidence of individual carcass defects, was also evaluated. Twenty broilers were processed with two different electrical stunning: high (250 Hz; 640 mA; 60V) (Lot C or control) and low (150 Hz; 360 mA; 60 V) (Lot A) frequency and intensity, using sinusoidal alternating current. As preliminary results, the use of low frequency and intensity induced faster pH decline post mortem and adequate acidification of pH at 3 hours (6.49 Lot C; 6.37 Lot A), better muscle glycogen reserve (0.770 MUL/50 mL Lot C; 1.497 MUL/50mL Lot A), and lightly more rapid muscle oxidation (IDF: 0.109 Lot C; 0.122 Lot A), (FOX: 0.131 MeqO2/kg Lot C; 0.140 MeqO2/kg Lot A). The incidence of individual carcass defects sufficient to cause downgrading or rejection, both in Lot C and Lot A, was generally low. In a multidisciplinary approach, to assess animal welfare and quality poultry meat, additional and feasible parameters should be implemented. Monitoring of pH, muscle glycogen reserve and superoxide free radical production measurements might be markers easier to use, routinely, in practice at abattoir. Further studies are needed to evaluate the usefulness of these parameters. PMID- 28713791 TI - Detection of Sulfites in Fresh Meat Preparation Commercialised at Retail in Lazio Region. AB - In Europe sulfur dioxide (SO2) and sulfites in foods and beverages at concentrations of more than 10 mg kg-1 or 10 mg L-1 expressed as SO2 equivalents are subject to mandatory labelling. In fresh meats the addition of sulfites is not admitted because of their unlawful use to give the product a more attractive appearance. Aim of the study was to detect sulfites in meat product sampled in 19 commercial shops of Lazio Region. In n=12 samples, sulfites were present at different concentrations and no indication for them was reported on the label. Sulfites concentrations ranged from 13.3 to 1278.9 mg kg-1. The results of the present investigation underline the need for better controls by operators, not only under the food information but also in the consumers' health perspective. PMID- 28713792 TI - Shiga Toxin-Producing Escherichia Coii in Slaughtered Pigs and Pork Products. AB - During the years 2015-2016, 83 faecal samples were collected at slaughter from pigs reared in farms located in Central-Northern Italy. During the years 2014 2016 a total of 562 pork products [465 not-readyto-eat (NRTE) and 97 ready-to-eat (RTE) products] were collected from retail outlets, large retailers and processing plants. The samples were analysed according to ISO TS 13136:2012. Out of 83 swine faecal samples, 77 (92.8%) resulted stx-positive by real time polymerase chain reaction (PCR), 5 stx2+ and 1 stx1+ Shiga toxin-producing Escherichia coli (STEC) strains were isolated. Among the 465 NRTE samples, 65 (14.0%) resulted stx-positive by real time PCR and 7 stx2+ STEC strains were isolated. The stx2 gene was detected more frequently than the stx1 gene both in faecal samples (90.4 vs 8.4%) and in NRTE pork products (13.3 vs 1.3%). All the RTE samples included in the analysis resulted stx-negative. Among the samples resulted positive for stx and eae genes, serogroup-associated genes were detected at high frequency: O26 resulted the most frequent in faecal samples (81.3%) and O145 in pork products (88.1%). The O157 serogroup resulted positive in 83.3 and 78.1% of pork products and faecal samples, respectively. Despite the frequent detection by real time PCR of genes indicating the possible presence of STEC strains belonging to the six serogroups, the bacteriological step did not confirm the isolation of any such strains. PMID- 28713793 TI - Phenotypic Antimicrobial Resistance Profile of Isolates Causing Clinical Mastitis in Dairy Animals. AB - Mastitis is the most frequent and costly disease of lactating animals and is associated with a significant reduction in milk yield, increased cost and culling. Early and specific antibiotic based treatment reduces the severity of the disease. Over the years the extensive use of antimicrobials has led to increase antimicrobial resistance. The present study was designed to investigate the prevalence of microorganisms responsible for mastitis and their antimicrobial resistance pattern. A total of 282 milk samples were collected from different animal species (sheep, cows and goats) with clinical mastitis. Antimicrobial resistance was evaluated for Streptococcus spp. and Staphylococcus spp. In cow samples Streptococcus spp. represented the most frequently isolated genus (33.84%), while Staphylococcus spp. was the most prevalent genus in sheep and goat samples (44.4 and 73.86%, respectively). Gentamicin and chloramphenicol were found to be the most effective drugs against the tested isolates, while the highest resistance rates were observed for amoxicillin, ampicillin, tetracycline, trimethoprim-sulfamethoxazole. PMID- 28713794 TI - Correction: Occurrence of Harmful Algal Species and Shellfish Toxicity in Sardinia (Italy). AB - [This corrects the article on p. 6095 in vol. 5, PMID: 28058244.]. PMID- 28713795 TI - A New Approach to Predict the Fish Fillet Shelf-Life in Presence of Natural Preservative Agents. AB - Three data sets concerning the behaviour of spoilage flora of fillets treated with natural preservative substances (NPS) were used to construct a new kind of mathematical predictive model. This model, unlike other ones, allows expressing the antibacterial effect of the NPS separately from the prediction of the growth rate. This approach, based on the introduction of a parameter into the predictive primary model, produced a good fitting of observed data and allowed characterising quantitatively the increase of shelf-life of fillets. PMID- 28713797 TI - Health-Related Quality of Life after Pediatric Liver Transplantation: A Qualitative Analysis of the Perspectives of Health Care Providers. AB - With improved survival outcomes after pediatric liver transplantation (LT), health-related quality of life (HRQoL) is an important outcome metric. Understanding the elements contributing to HRQoL after LT in children would enable more targeted strategies towards optimizing best outcomes. This qualitative study aimed to explore health care providers (HCP) perceptions about HRQoL after pediatric LT. Thirteen experienced HCP participated in two focus group discussions. Data analysis via a thematic analysis approach revealed 4 major themes: "LT as a facilitator of better HRQoL," "coping and adapting to LT," "living with a transplanted liver," and "the family context." HCP identified elements that both enhance (improved physical health, peer relationship, and activities of daily living) and challenge (need for immunosuppression, transplant follow-up, and restrictions) the multidimensional domains of HRQoL. HCP perceived LT to be a stressful life-changing event for children and their families. Patients and their parents' ability to cope and adjust positively to LT was perceived as a key contributor to better HRQoL. HCP perspective highlights the importance of promoting psychosocial support and a family-centered care delivery model towards the overarching goal of optimizing durable outcomes. PMID- 28713796 TI - Multimodal Imaging in Focal Therapy Planning and Assessment in Primary Prostate Cancer. AB - PURPOSE: There is increasing interest in focal therapy (male lumpectomy) of localized low-intermediate risk prostate cancer. Focal therapy is typically associated with low morbidity and provides the possibility of retreatment. Imaging is pivotal in stratification of men with localized prostate cancer for active surveillance, focal therapy or radical intervention. This article provides a concise review of focal therapy and the evolving role of imaging in this clinical setting. METHODS: We performed a narrative and critical literature review by searching PubMed/Medline database from January 1997 to January 2017 for articles in the English language and the use of search keywords "focal therapy", "prostate cancer", and "imaging". RESULTS: Most imaging studies are based on multiparametric magnetic resonance imaging. Transrectal ultrasound is inadequate independently but multiparametric ultrasound may provide new prospects. Positron emission tomography with radiotracers targeted to various underlying tumor biological features may provide unprecedented new opportunities. Multimodal Imaging appears most useful in localization of intraprostatic dominant index lesions amenable to focal therapy, in early assessment of therapeutic efficacy and potential need for additional focal treatments or transition to whole-gland therapy, and in predicting short-term and long-term outcomes. CONCLUSION: Multimodal imaging is anticipated to play an increasing role in the focal therapy planning and assessment of low-intermediate risk prostate cancer and thereby moving this form of treatment option forward in the clinic. PMID- 28713798 TI - Incidence and Severity of Prescribing Errors in Parenteral Nutrition for Pediatric Inpatients at a Neonatal and Pediatric Intensive Care Unit. AB - OBJECTIVES: Pediatric inpatients are particularly vulnerable to medication errors (MEs), especially in highly individualized preparations like parenteral nutrition (PN). Aside from prescribing via a computerized physician order entry system (CPOE), we evaluated the effect of cross-checking by a clinical pharmacist to prevent harm from PN order errors in a neonatal and pediatric intensive care unit (NICU/PICU). METHODS: The incidence of prescribing errors in PN in a tertiary level NICU/PICU was surveyed prospectively between March 2012 and July 2013 (n = 3,012 orders). A pharmacist cross-checked all PN orders prior to preparation. Errors were assigned to seven different error-type categories. Three independent experts from different academic tertiary level NICUs judged the severity of each error according to the National Coordinating Council for Medication Error Reporting and Prevention (NCC MERP) Index (categories A-I). RESULTS: The error rate was 3.9% for all 3,012 orders (118 prescribing errors in 111 orders). 77 (6.0%, 1,277 orders) errors occurred in the category concentration range, all concerning a relative overdose of calcium gluconate for peripheral infusion. The majority of all events (60%) were assigned to categories C and D (without major harmful consequences) while 28% could not be assigned due to missing majority decision. Potential harmful consequences requiring interventions (category E) could have occurred in 12% of assessments. CONCLUSION: Next to systematic application of clinical guidelines and prescribing via CPOE, order review by a clinical pharmacist is still required to effectively reduce MEs and thus to prevent minor and major adverse drug events with the aim to enhance medication safety. PMID- 28713800 TI - Strategies for Meaningful Engagement between Community-Based Health Researchers and First Nations Participants. AB - The Baby Teeth Talk Study (BTT) is a partnership-based research project looking at interventions to prevent early childhood caries (ECC) in First Nations populations in Canada. Community-based researchers (CBRs) conducted preventive and behavioral interventions that targeted expectant mothers and their newborns, over a 3-year period. The work of the CBRs requires a great deal of training and skills to administer the interventions. It also requires a broad set of strategies to meaningfully engage participants to make health-promoting changes in their behavior to prevent ECC in their children. After implementing the intervention, BTT CBRs participated in interviews to explore the strategies they employed to engage participants in the prevention of ECC. CBRs perceived two key strategies as essential for meaningful engagement with BTT participants. First, CBRs indicated that their shared experiences through motherhood, First Nations identity, age, and childhood experience provided a positive foundation for dialog with participants that lead to build trust and rapport. Second, supportive interpersonal and culturally based communication skills of the CBR provided further foundation to engage with participants from a strength-based approach. For example, the CBRs knew how to effectively communicate in ways such as being gentle, non-intrusive, and avoiding any perception of judgment when discussing oral health behavior. In First Nations health research, CBRs can provide an essential link in engaging participants and the community for improvements in health. Researchers should carefully consider characteristics such as shared experience and ability to understand cultural communication styles when hiring CBRs in order to build a solid foundation of trust with research participants. PMID- 28713799 TI - The Use of Ambulatory Blood Pressure Monitoring As Standard of Care in Pediatrics. AB - Hypertension (HTN) is a significant global health problem, responsible for 7.5 million deaths each year worldwide. The prevalence of HTN is increasing in the pediatric population likely attributed to the increase in childhood obesity. Recent work has also shown that blood pressure (BP) tends to track from childhood to adulthood including BP-related target organ damage. In the last 25-30 years, pediatric use of ambulatory blood pressure monitoring (ABPM) has been expanding mainly in the setting of initial elevated BP measurement evaluation, HTN therapy efficacy follow-up, and renal disease. However, there are many clinical areas where ABPM could potentially be used but is currently underutilized. This review summarizes the current knowledge and the uses of pediatric ABPM and explores clinical areas where it can be very useful both to detect HTN and its longitudinal follow-up. And thus, ABPM could serve as a critical tool to potentially prevent early cardiovascular mortality and morbidity in wide variety of populations. With solid data to support ABPM's superiority over clinic BP measurements and these clinical areas for its expansion, ABPM should now be part of standard of care in BP evaluation and management in pediatrics. PMID- 28713801 TI - An Evaluation of a Train-the-Trainer Workshop for Social Service Workers to Develop Community-Based Family Interventions. AB - INTRODUCTION: Evaluation studies on train-the-trainer workshops (TTTs) to develop family well-being interventions are limited in the literature. The Logic Model offers a framework to place some important concepts and tools of intervention science in the hands of frontline service providers. This paper reports on the evaluation of a TTT for a large community-based program to enhance family well being in Hong Kong. METHODS: The 2-day TTT introduced positive psychology themes (relevant to the programs that the trainees would deliver) and the Logic Model (which provides a framework to guide intervention development and evaluation) for social service workers to guide their community-based family interventions. The effectiveness of the TTT was examined by self-administered questionnaires that assessed trainees' changes in learning (perceived knowledge, self-efficacy, attitude, and intention), trainees' reactions to training content, knowledge sharing, and benefits to their service organizations before and after the training and then 6 months and 1 year later. Missing data were replaced by baseline values in an intention-to-treat analysis. Focus group interviews were conducted approximately 6 months after training. RESULTS: Fifty-six trainees (79% women) joined the TTT. Forty-four and 31 trainees completed the 6-month and 1 year questionnaires, respectively. The trainees indicated that the workshop was informative and well organized. The TTT-enhanced trainees' perceived knowledge, self-efficacy, and attitudes toward the application of the Logic Model and positive psychology constructs in program design. These changes were present with small to large effect size that persisted to the 1 year follow-up. The skills learned were used to develop 31 family interventions that were delivered to about 1,000 families. Qualitative feedback supported the quantitative results. CONCLUSION: This TTT offers a practical example of academic-community partnerships that promote capacity among community social service workers. Goals included sharing basic tools of intervention development and evaluation, and the TTT offered, therefore, the potential of learning skills that extended beyond the lifetime of a single program. CLINICAL TRIAL REGISTRATION: The research protocol was registered at the National Institutes of Health (identifier number: NCT01796275). PMID- 28713802 TI - Developing a Mentorship Program in Laos. AB - Skills strengthening and capacity building for maternal and newborn health (MNH) providers are essential to ensure quality care for mothers and newborns. There is, however, limited research regarding what constitutes an effective model in low-income countries. The Lao People's Democratic Republic (Laos) has some of the region's worst outcomes for neonatal and maternal mortality. Moreover, with a 23 year hiatus in midwifery training, which ended approximately 7 years ago, there is a cadre of new and inexperienced midwives in practice without support systems, skills, or continuing professional development opportunities. Traditional didactic teaching methodologies prevail in Laos, but with little evidence of efficacy. As an alternative model, Save the Children International has been implementing a mentorship approach for MNH providers in two provinces in northern Laos since January 2016, with technical guidance and funding from the United States Agency for International Development-supported global Maternal Child Survival Program. This community case study will describe and reflect on the approach by highlighting the need and rationale for mentorship, followed by a description of the program's core components and the results observed so far. Lessons learned and the application of the approach to different contexts and health-care professionals, considering both constraints and opportunities, will be discussed. PMID- 28713803 TI - The Institute for Global Orthopedics and Traumatology: A Model for Academic Collaboration in Orthopedic Surgery. AB - In 2006, surgeons at the University of California, San Francisco (UCSF) established the Institute for Global Orthopedics and Traumatology (IGOT), an initiative within the department of orthopedic surgery. The principal aim of IGOT is to create long-term, sustainable solutions to the growing burden of musculoskeletal injury in low- and middle-income countries (LMICs) through academic partnership. IGOT currently has relationships with teaching hospitals in Ghana, Malawi, Tanzania, Nicaragua, and Nepal. The organizational structure of IGOT is built on four pillars: Global Surgical Education (GSE), Global Knowledge Exchange (GKE), Global Research Initiative (GRI), and Global Leadership and Advocacy. GSE focuses on increasing surgical knowledge and technical proficiency through hands-on educational courses. The GKE facilitates the mutual exchange of surgeons and trainees among IGOT and its partners. This includes a global resident elective that allows UCSF residents to complete an international rotation at one of IGOT's partner sites. The GRI strives to build research capacity and sponsor high-quality clinical research projects that address questions relevant to local partners. The fourth pillar, Global Leadership and Advocacy aims to increase awareness of the global impact of musculoskeletal injury through national and international courses and events, such as the Bay Area Global Health Film Festival. At the core of each tenet is the collaboration among IGOT and its international partners. Over the last decade, IGOT has experienced tremendous growth and maturation in its partnership model based on cumulative experience and the needs of its partners. PMID- 28713804 TI - Facilitating and Inhibiting Factors of Sexual Behavior among Migrants in Transition from Mexico to the United States. AB - INTRODUCTION: Human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) is one of the most prevalent infectious diseases in the border region of Mexico due to the flow of migrants under desperate conditions, encouraging casual and unprotected sex. Since this has become a binational public health problem, it is important to understand the factors that predict these sexual behaviors. The aim of the current study was to investigate the facilitators and inhibitors of transition in the sexual behavior of migrants from two border regions on the Mexico-United States (US) border. METHODS: This was a predictive and cross-sectional study. A sample of 256 migrants in shelters for migrants on the border between Mexico and US were selected through systematic random sampling. Predictor variables investigated for effect on the safe sexual behavior (SSB) of the migrant were reasons for having sex; sexual attitudes; sexual machismo; knowledge about HIV; access to health services; and social discrimination. RESULTS: The sample was predominantly male (89.5%), with 46.1% reporting being single. The average age was 33.38 years (SD = 9.73) and the average number of years of education reported was 8.05 (SD = 3.37). A permissive sexual attitude and sexual machismo both correlated with condom use (rs = 0.130, p < 0.01 and rs = -0.174, p < 0.01, respectively). Regression analysis showed that a permissive sexual attitude decreased the practice of safe sex (beta = 0.17, t = 4.16, p < 0.001), as did sexual machismo (beta = -0.28, t = -4.83, p < 0.001) and HIV knowledge (beta = -0.11, t = -2.62, p = 0.006). DISCUSSION: It was found that access to health services did not influence the SSB of migrants, as suggested by the literature. However, a permissive sexual attitude, sexual machismo, and HIV knowledge were all variables capable of predicting SSB. It is recommended that the study is extended to study migrant populations from other parts of the border, as well undertaking as a qualitative approach to explore new variables. PMID- 28713805 TI - The Benefits and Challenges of Managing Asthma in Hispanic Families in South Texas: A Mixed-Methods Study. AB - BACKGROUND: Understanding the experience of Hispanic parents of children diagnosed with asthma can be useful in the delivery of effective and meaningful asthma education. In order to assess the needs of Hispanic families with asthmatic children in South Texas, investigators utilized a combination of qualitative and quantitative research methods. OBJECTIVES: This study aimed (1) to assess the impact of asthma in the quality of life of Hispanic children and their families and (2) to identify barriers and challenges to asthma management as perceived by parents of children diagnosed with asthma. METHODS: A mixed methods study included a quality-of-life survey and focus group discussions. The Children's Health Survey for Asthma (CHSA) was completed by 90 parents of children with asthma. Three focus groups were conducted with 15 low-income, Hispanic parents of asthmatic children to assess their needs and experience in managing the disease. RESULTS: Results from the CHSA showed that asthma significantly affects the quality of life of children with asthma and their families, particularly the emotional dimensions and the child's physical health. Fifty-three percent of the children had visited the emergency room, and 51% had been hospitalized due to asthma. One out of five parents had missed work, and 27% of children had missed school in the past 2 weeks due to the child's asthma. In the focus group discussions, the key themes emerging included lack of asthma knowledge, the burden of disease for asthmatic children and their families, and the importance of asthma education and self-management behaviors for asthma control. CONCLUSION: One of the main challenges faced by Hispanic families with asthmatic children is the lack of asthma-related knowledge to help understand and control their children's disease. Lack of knowledge and self-management skills lead to significant stress and anxiety among children with asthma and their parents. Results highlight that while asthma has an effect on the quality of life of children and their families, particularly on the emotional health domain, a wide dissemination of asthma management education in different settings might help prevent asthma attacks and improve symptom control among those suffering from this disease along the US-Mexico border. PMID- 28713806 TI - Ventanillas de Salud: A Collaborative and Binational Health Access and Preventive Care Program. AB - While individuals of Mexican origin are the largest immigrant group living in the U.S., this population is also the highest uninsured. Health disparities related to access to health care, among other social determinants, continue to be a challenge for this population. The government of Mexico, in an effort to address these disparities and improve the quality of life of citizens living abroad, has partnered with governmental and non-governmental health-care organizations in the U.S. by developing and implementing an initiative known as Ventanillas de Salud Health Windows-(VDS). The VDS is located throughout the Mexican Consular network and aim to increase access to health care and health literacy, provide health screenings, and promote healthy lifestyle choices among low-income and immigrant Mexican populations in the U.S. PMID- 28713807 TI - The Development of a Postgraduate Orthopaedic Manual Therapy Residency Program in Nairobi, Kenya. AB - INTRODUCTION: There are very few opportunities for long-term, comprehensive postgraduate education in developing countries because of fiscal and human resource constraints. Therefore, physiotherapists have little opportunity following graduation to advance their skills through the improvement of clinical reasoning and treatment planning and application. BACKGROUND: To address the need for sustainable advanced instruction in physiotherapy within the country, a postgraduate Residency program was initiated in Nairobi, Kenya in 2012. The mission of the program is to graduate advanced orthopedic practitioners who can lead their communities and local profession in the advancement of clinical care and education. Since its inception, six cohorts have been initiated for a total of 90 resident participants. In addition, six program graduates are being trained to continue the Residency program and are serving as teaching assistants for the on campus modules. This training will result in a self-sustaining program by 2020. DISCUSSION: The manual therapy Residency education model allowed for advancement of the participating physiotherapists professional development utilizing evidence-based practice. This was done without altering the current education system within the country, or accessing expensive equipment. CONCLUDING REMARKS: The Residency program was developed and established with the cooperation of a local education institution and a non-profit corporation in the United States. This collaboration has facilitated the advancement of orthopedic clinical standards in the country and will, hopefully, one day serve an as a template for future programs. PMID- 28713808 TI - Children's Autonomic Nervous System Reactivity Moderates the Relations between Family Adversity and Sleep Problems in Latino 5-Year Olds in the CHAMACOS Study. AB - Sleep problems are common for young children especially if they live in adverse home environments. Some studies investigate if young children may also be at a higher risk of sleep problems if they have a specific biological sensitivity to adversity. This paper addresses the research question, does the relations between children's exposure to family adversities and their sleep problems differ depending on their autonomic nervous system's sensitivity to challenges? As part of a larger cohort study of Latino, low-income families, we assessed the cross sectional relations among family demographics (education, marital status), adversities [routines, major life events (MLE)], and biological sensitivity as measured by autonomic nervous system (ANS) reactivity associated with parent rated sleep problems when the children were 5 years old. Mothers were interviewed in English or Spanish and completed demographic, family, and child measures. The children completed a 15-min standardized protocol while continuous cardiac measures of the ANS [respiratory sinus arrhythmia (RSA), preejection period (PEP)] were collected during resting and four challenge conditions. Reactivity was defined as the mean of the responses to the four challenge conditions minus the first resting condition. Four ANS profiles, co-activation, co-inhibition, reciprocal low RSA and PEP reactivity, and reciprocal high RSA and PEP reactivity, were created by dichotomizing the reactivity scores as high or low reactivity. Logistic regression models showed there were significant main effects for children living in families with fewer daily routines having more sleep problems than for children living in families with daily routines. There were significant interactions for children with low PEP reactivity and for children with the reciprocal, low reactivity profiles who experienced major family life events in predicting children's sleep problems. Children who had a reciprocal, low reactivity ANS profile had more sleep problems if they also experienced MLE than children who experienced fewer MLE. These findings suggest that children who experience family adversities have different risks for developing sleep problems depending on their biological sensitivity. Interventions are needed for young Latino children that support family routines and reduce the impact of family adversities to help them develop healthy sleep practices. PMID- 28713809 TI - A Perspective on Reagent Diversity and Non-covalent Binding of Reactive Carbonyl Species (RCS) and Effector Reagents in Non-enzymatic Glycation (NEG): Mechanistic Considerations and Implications for Future Research. AB - This perspective focuses on illustrating the underappreciated connections between reactive carbonyl species (RCS), initial binding in the nonenzymatic glycation (NEG) process, and nonenzymatic covalent protein modification (here termed NECPM). While glucose is the central species involved in NEG, recent studies indicate that the initially-bound glucose species in the NEG of human hemoglobin (HbA) and human serum albumin (HSA) are non-RCS ring-closed isomers. The ring opened glucose, an RCS structure that reacts in the NEG process, is most likely generated from previously-bound ring-closed isomers undergoing concerted acid/base reactions while bound to protein. The generation of the glucose RCS can involve concomitantly-bound physiological species (e.g., inorganic phosphate, water, etc.); here termed effector reagents. Extant NEG schemes do not account for these recent findings. In addition, effector reagent reactions with glucose in the serum and erythrocyte cytosol can generate RCS (e.g., glyoxal, glyceraldehyde, etc.). Recent research has shown that these RCS covalently modify proteins in vivo via NECPM mechanisms. A general scheme that reflects both the reagent and mechanistic diversity that can lead to NEG and NECPM is presented here. A perspective that accounts for the relationships between RCS, NEG, and NECPM can facilitate the understanding of site selectivity, may help explain overall glycation rates, and may have implications for the clinical assessment/control of diabetes mellitus. In view of this perspective, concentrations of ribose, fructose, Pi, bicarbonate, counter ions, and the resulting RCS generated within intracellular and extracellular compartments may be of importance and of clinical relevance. Future research is also proposed. PMID- 28713810 TI - A Biomechanical Comparison of Proportional Electromyography Control to Biological Torque Control Using a Powered Hip Exoskeleton. AB - BACKGROUND: Despite a large increase in robotic exoskeleton research, there are few studies that have examined human performance with different control strategies on the same exoskeleton device. Direct comparison studies are needed to determine how users respond to different types of control. The purpose of this study was to compare user performance using a robotic hip exoskeleton with two different controllers: a controller that targeted a biological hip torque profile and a proportional myoelectric controller. METHODS: We tested both control approaches on 10 able-bodied subjects using a pneumatically powered hip exoskeleton. The state machine controller targeted a biological hip torque profile. The myoelectric controller used electromyography (EMG) of lower limb muscles to produce a proportional control signal for the hip exoskeleton. Each subject performed two 30-min exoskeleton walking trials (1.0 m/s) using each controller and a 10-min trial with the exoskeleton unpowered. During each trial, we measured subjects' metabolic cost of walking, lower limb EMG profiles, and joint kinematics and kinetics (torques and powers) using a force treadmill and motion capture. RESULTS: Compared to unassisted walking in the exoskeleton, myoelectric control significantly reduced metabolic cost by 13% (p = 0.005) and biological hip torque control reduced metabolic cost by 7% (p = 0.261). Subjects reduced muscle activity relative to the unpowered condition for a greater number of lower limb muscles using myoelectric control compared to the biological hip torque control. More subjects subjectively preferred the myoelectric controller to the biological hip torque control. CONCLUSION: Myoelectric control had more advantages (metabolic cost and muscle activity reduction) compared to a controller that targeted a biological torque profile for walking with a robotic hip exoskeleton. However, these results were obtained with a single exoskeleton device with specific control configurations while level walking at a single speed. Further testing on different exoskeleton hardware and with more varied experimental protocols, such as testing over multiple types of terrain, is needed to fully elucidate the potential benefits of myoelectric control for exoskeleton technology. PMID- 28713811 TI - Reducing the Impact of Shoulder Abduction Loading on the Classification of Hand Opening and Grasping in Individuals with Poststroke Flexion Synergy. AB - Application of neural machine interface in individuals with chronic hemiparetic stroke is regarded as a great challenge, especially for classification of the hand opening and grasping during a functional upper extremity movement such as reach-to-grasp. The overall accuracy of classifying hand movements, while actively lifting the paretic arm, is subject to a significant reduction compared to the accuracy when the arm is fully supported. Such a reduction is believed to be due to the expression of flexion synergy, which couples shoulder abduction (SABD) with elbow/wrist and finger flexion, and is common in up to 60% of the stroke population. Little research has been done to develop methods to reduce the impact of flexion synergy on the classification of hand opening and grasping. In this study, we proposed a novel approach to classify hand opening and grasping in the context of the flexion synergy using a wavelet coherence-based filter. We first identified the frequency ranges where the coherence between the SABD muscle and wrist/finger flexion muscles is significant in each participant, and then removed the synergy-induced electromyogram (EMG) component with a subject specific and muscle-specific coherence-based filter. The new approach was tested in 21 stroke individuals with moderate to severe motor impairments. Employing the filter, 14 participants gained improvement in classification accuracy with a range of 0.1 to 14%, while four showed 0.3 to 1.2% reduction. The remaining three participants were excluded from comparison due to the lack of significant coherence, thus no filters were applied. The improvement in classification accuracy is significant (p = 0.017) when the SABD loading equals 50% of the maximal torque. Our findings suggest that the coherence-based filters can reduce the impact of flexion synergy by removing the synergy-induced EMG component and have the potential to improve the overall classification accuracy of hand movements in individuals with poststroke flexion synergy. PMID- 28713813 TI - Incidental Finding of an Aorto-Right Atrial Fistula in a Patient Undergoing Repair of a Sinus of Valsalva Aneurysm. AB - A sinus of Valsalva aneurysm is a rare malformation of the aortic root that can fistulize to another cardiac structure such as the right atrium. Although transthoracic echocardiography and computed tomography angiography have demonstrated utility for the diagnosis of a sinus of Valsalva-to-right atrial fistula, there are few cases where a misdiagnosis may occur. Intraoperative transesophageal echocardiography may be an essential imaging tool for the diagnosis and management of incidental findings such as a sinus of Valsalva-to right atrial fistula during cardiac surgery and should be used routinely. PMID- 28713814 TI - Application of Artificial Neural Network and Support Vector Machines in Predicting Metabolizable Energy in Compound Feeds for Pigs. AB - BACKGROUND: In the nutrition literature, there are several reports on the use of artificial neural network (ANN) and multiple linear regression (MLR) approaches for predicting feed composition and nutritive value, while the use of support vector machines (SVM) method as a new alternative approach to MLR and ANN models is still not fully investigated. METHODS: The MLR, ANN, and SVM models were developed to predict metabolizable energy (ME) content of compound feeds for pigs based on the German energy evaluation system from analyzed contents of crude protein (CP), ether extract (EE), crude fiber (CF), and starch. A total of 290 datasets from standardized digestibility studies with compound feeds was provided from several institutions and published papers, and ME was calculated thereon. Accuracy and precision of developed models were evaluated, given their produced prediction values. RESULTS: The results revealed that the developed ANN [R2 = 0.95; root mean square error (RMSE) = 0.19 MJ/kg of dry matter] and SVM (R2 = 0.95; RMSE = 0.21 MJ/kg of dry matter) models produced better prediction values in estimating ME in compound feed than those produced by conventional MLR (R2 = 0.89; RMSE = 0.27 MJ/kg of dry matter). CONCLUSION: The developed ANN and SVM models produced better prediction values in estimating ME in compound feed than those produced by conventional MLR; however, there were not obvious differences between performance of ANN and SVM models. Thus, SVM model may also be considered as a promising tool for modeling the relationship between chemical composition and ME of compound feeds for pigs. To provide the readers and nutritionist with the easy and rapid tool, an Excel(r) calculator, namely, SVM_ME_pig, was created to predict the metabolizable energy values in compound feeds for pigs using developed support vector machine model. PMID- 28713812 TI - The Biology of Eosinophils and Their Role in Asthma. AB - This review will describe the structure and function of the eosinophil. The roles of several relevant cell surface molecules and receptors will be discussed. We will also explore the systemic and local processes triggering eosinophil differentiation, maturation, and migration to the lungs in asthma, as well as the cytokine-mediated pathways that result in eosinophil activation and degranulation, i.e., the release of multiple pro-inflammatory substances from eosinophil-specific granules, including cationic proteins, cytokines, chemokines growth factors, and enzymes. We will discuss the current understanding of the roles that eosinophils play in key asthma processes such as airway hyperresponsiveness, mucus hypersecretion, and airway remodeling, in addition to the evidence relating to eosinophil-pathogen interactions within the lungs. PMID- 28713815 TI - Bioinformatic Prediction of Possible Targets and Mechanisms of Action of the Green Tea Compound Epigallocatechin-3-Gallate Against Breast Cancer. AB - Epigallocatechin-3-gallate (EGCG), a bioactive compound in green tea, is the most abundant and biologically active catechin, and it exerts multiple effects in humans through mechanisms that remain to be clarified. The present study used bioinformatics to identify possible mechanisms by which EGCG reduces risk of breast cancer. Possible human protein targets of EGCG were identified in the PubChem database, possible human gene targets were identified in the NCBI database, and then both sets of targets were analyzed using Ingenuity Pathway Analysis to predict molecular networks affected by EGCG in breast cancer. The results suggest that signaling proteins affected by EGCG in breast cancer, which include JUN, FADD, NFKB1, Bcl-2, GNAO1, and MMP14, are involved primarily in cell death and survival; DNA replication, recombination and repair; and the cell cycle. The main networks affected by EGCG are predicted to involve the cell cycle; cellular assembly and organization; DNA replication, recombination and repair; and cell death and survival. These results identify several specific proteins and pathways that may be affected by EGCG in breast cancer, and they illustrate the power of integrative bioinformatics and chemical fragment analysis for focusing mechanistic studies. PMID- 28713816 TI - Effect of the Camelid's Seminal Plasma Ovulation-Inducing Factor/beta-NGF: A Kisspeptin Target Hypothesis. AB - Female mammals are classified into spontaneous and induced ovulators based on the mechanism eliciting ovulation. Ovulation in spontaneous species (e.g., human, sheep, cattle, horse, pigs, and most rodents) occurs at regular intervals and depends upon the circulating estradiol. However, in induced ovulators (e.g., rabbits, ferrets, cats, and camelids), ovulation is associated with coitus. In the later, various factors have been proposed to trigger ovulation, including auditory, visual, olfactory, and mechanic stimuli. However, other studies have identified a biochemical component in the semen of induced ovulators responsible for the induction of ovulation and named accordingly ovulation-inducing factor (OIF). In camelids, intramuscular or intrauterine administration of seminal plasma (SP) was shown to induce the preovulatory luteinizing hormone (LH) surge followed by ovulation and subsequent formation of corpus luteum. Recently, this OIF has been identified from SP as a neurotrophin, the beta subunit of nerve growth factor (beta-NGF). beta-NGF is well known as promoting neuron survival and growth, but in this case, it appears to induce ovulation through an endocrine mode of action. Indeed, beta-NGF may be absorbed through the endometrium to be conveyed, via the blood stream, to the central structures regulating the LH preovulatory surge. In this review, we provide a summary of the most relevant results obtained in the field, and we propose a working hypothesis for the central action of beta-NGF based on our recent demonstration of the presence of neurons expressing kisspeptin, a potent stimulator of GnRH/LH, in the camel hypothalamus. PMID- 28713817 TI - Generation of Monoclonal Antibodies against Ag85A Antigen of Mycobacterium tuberculosis and Application in a Competitive ELISA for Serodiagnosis of Bovine Tuberculosis. AB - The Ag85 complex functions as the main secretory protein of Mycobacterium tuberculosis (M. tuberculosis) and BCG. This complex is composed of the proteins, Ag85A, Ag85B, and Ag85C, with Ag85A thought to play the largest role within the complex. However, the lack of commercially available monoclonal antibodies (mAbs) against Ag85A still hinders the biological and applicative research on this protein. In this study, we developed and identified anti-Ag85A mAbs, and five hybridoma cells were established. Using the indirect immunofluorescence test, we found that two anti-Ag85A mAbs did not cross-react with Ag85B and/or Ag85C. In addition, we showed that all of the mAbs tested in this study are able to react with endogenous Ag85A protein in BCG and rBCG:Ag85A using indirect ELISA and Western blot analyses. A competitive ELISA (cELISA) based on mAb 3B8 was developed, the analyses of clinic serum samples from cattle with bovine tuberculosis (TB) and healthy cattle demonstrated that the sensitivity of the cELISA was 54.2% (26/48) and the specificity was 83.5% (167/200). This study demonstrated that the mAbs against Ag85A will provide useful reagents for further investigation into the function of the Ag85 complex and can be used for serodiagnosis of bovine TB. PMID- 28713819 TI - Differential Analysis of Genetic, Epigenetic, and Cytogenetic Abnormalities in AML. AB - Acute myeloid leukemia (AML) is a haematological malignancy characterized by the excessive proliferation of immature myeloid cells coupled with impaired differentiation. Many AML cases have been reported without any known cytogenetic abnormalities and carry no mutation in known AML-associated driver genes. In this study, 200 AML cases were selected from a publicly available cohort and differentially analyzed for genetic, epigenetic, and cytogenetic abnormalities. Three genes (FLT3, DNMT3A, and NPMc) are found to be predominantly mutated. We identified several aberrations to be associated with genome-wide methylation changes. These include Del (5q), T (15; 17), and NPMc mutations. Four aberrations Del (5q), T (15; 17), T (9; 22), and T (9; 11)-are significantly associated with patient survival. Del (5q)-positive patients have an average survival of less than 1 year, whereas T (15; 17)-positive patients have a significantly better prognosis. Combining the methylation and mutation data reveals three distinct patient groups and four clusters of genes. We speculate that combined signatures have the better potential to be used for subclassification of AML, complementing cytogenetic signatures. A larger sample cohort and further investigation of the effects observed in this study are required to enable the clinical application of our patient classification aided by DNA methylation. PMID- 28713820 TI - Antioxidant Properties of "Natchez" and "Triple Crown" Blackberries Using Korean Traditional Winemaking Techniques. AB - This research evaluated blackberries grown in Oklahoma and wines produced using a modified traditional Korean technique employing relatively oxygen-permeable earthenware fermentation vessels. The fermentation variables were temperature (21.6 degrees C versus 26.6 degrees C) and yeast inoculation versus wild fermentation. Wild fermented wines had higher total phenolic concentration than yeast fermented wines. Overall, wines had a relatively high concentration of anthocyanin (85-320 mg L-1 malvidin-3-monoglucoside) and antioxidant capacity (9776-37845 umol Trolox equivalent g-1). "Natchez" berries had a higher anthocyanin concentration than "Triple Crown" berries. Higher fermentation temperature at the start of the winemaking process followed by the use of lower fermentation/storage temperature for aging wine samples maximized phenolic compound extraction/retention. The Korean winemaking technique used in this study produced blackberry wines that were excellent sources of polyphenolic compounds as well as being high in antioxidant capacity as measured by the Oxygen Radical Absorbance Capacity (ORAC) test. PMID- 28713818 TI - Atrazine Exposure and Reproductive Dysfunction through the Hypothalamus-Pituitary Gonadal (HPG) Axis. AB - Endocrine disrupting chemicals (EDC) are exogenous agents that alter endogenous hormone signaling pathways. These chemicals target the neuroendocrine system which is composed of organs throughout the body that work alongside the central nervous system to regulate biological processes. Of primary importance is the hypothalamic-pituitary-gonadal (HPG) axis which is vital for maintaining proper reproductive function. Atrazine (2-chloro-4-ethylamino-6-isopropylamino-1,3,5 triazine) is a pre-emergent herbicide used to prevent the growth of weeds on various crops. This herbicide is reported to widely contaminate potable water supplies everywhere it is applied. As such, the European Union banned the use of atrazine in 2004. Currently the United States Environmental Protection Agency regulates atrazine at 3 parts per billion (ppb; MUg/L) in drinking water, while the World Health Organization recently changed their drinking water guideline to 100 ppb. Atrazine is implicated to be an EDC that alters reproductive dysfunction by targeting the HPG axis. However, questions remain as to the human health risks associated with atrazine exposure with studies reporting mixed results on the ability of atrazine to alter the HPG axis. In this review, the current findings for atrazine's effects on the HPG axis are examined in mammalian, anuran, and fish models and in epidemiological studies. PMID- 28713821 TI - Comparative Analysis of the Cell Fates of Induced Schwann Cells from Subcutaneous Fat Tissue and Naive Schwann Cells in the Sciatic Nerve Injury Model. AB - PURPOSE: The fate and function of the induced Schwann cells (iSCs) like cells from adipose tissue have not been critically evaluated in vivo after transplantation. The objective of this study is to compare the fate of iSCs with naive SCs (nSCs) after transplantation into the lesion sites of sciatic nerve, respectively. METHODS: Adipose-derived stem cells from eGFP-expressing transgenic rat's subcutaneous fat were induced to iSCs in vitro. iSCs were injected to the sciatic nerve lesion area after crush injury and the cells fate was comparatively analyzed with that of nSCs from the same rat. RESULTS: At 12 weeks after transplantation, nSCs were detected only in the restricted area of cell transplantation site but iSCs were widely distributed all over the sciatic nerve. Based on double fluorescence observations, both iSCs and naive ones were colocalized with P0-expressing myelin sheath, outbound by laminin-expressing basal membrane, and terminated at contactin-associated protein-expressing doublets. However, some of iSCs were also differentiated to the fibrocyte/fibroblast-like cells. In the histological analysis of repaired sciatic nerves, axon density was higher in iSC-received group than in the nSCs group and normal sciatic nerve. CONCLUSION: iSCs induced from subcutaneous fat tissues have higher engraftment and migration capacity than nSCs. PMID- 28713822 TI - Bone Marrow Mesenchymal Stem Cells Inhibit the Function of Dendritic Cells by Secreting Galectin-1. AB - This study aimed to investigate whether bone marrow-derived mesenchymal stem cells (BM-MSCs) can inhibit function of dendritic cells (DCs) by secreting Galectin-1 (Gal-1). BM-MSCs have been shown to inhibit the maturation and function of DCs, further inhibiting the activation and proliferation of T cells. However, the detailed mechanism remains unknown. In this current study, MSCs and DCs derived from mouse bone marrow were cocultured using Transwell culture plates under different in vitro conditions. The results showed that as the ratio of MSC to DC of the coculture system increased and the coculture time of the two cells prolonged, the concentrations of Gal-1, interleukin- (IL-) 10, and IL-12 in the supernatants were increased and the protein expression of Gal-1 on and within DCs was also enhanced. The phosphorylation of extracellular signal-regulated kinase (ERK) pathway in DCs was boosted, whereas p38 mitogen-activated protein kinase (MAPK) pathway phosphorylation was weakened. Meanwhile, the expression of costimulatory molecules on the surface of DCs was decreased, and the proliferative effect of DCs on allogeneic T cells was also decreased. Therefore, this present study indicated that Gal-1 secreted from MSCs upregulated expression of Gal-1 and stimulated formation of tolerance immunophenotype on DCs, where the underlying mechanism was the regulation of the MAPK signaling pathway in DCs, thereby inhibiting the function of DCs. PMID- 28713823 TI - Intracardiac Hemostasis and Fibrinolysis Parameters in Patients with Atrial Fibrillation. AB - AIMS: To identify intracardiac hemostasis or fibrinolysis abnormalities, which are associated with atrial fibrillation (AF) and increase the risk of thromboembolism. PATIENTS AND METHODS: Patient group consisted of 24 patients with AF and control group included 14 individuals with other supraventricular tachycardia undergoing transcatheter radiofrequency ablation. Blood samples were drawn from the femoral vein (FV), left atrium (LA), and left atrial appendage (LAA) before the ablation procedure. Fibrinogen, factor VIII (FVIII) and factor XIII activity, von Willebrand factor (VWF) antigen, thrombin-antithrombin (TAT) complex, quantitative fibrin monomer (FM), plasminogen, alpha2-plasmin inhibitor, plasmin-alpha2-antiplasmin (PAP) complex, PAI-1 activity, and D-dimer were measured from all samples. RESULTS: Levels of FVIII and VWF were significantly elevated in the FV and LA of AF patients as compared to controls. TAT complex, FM, PAP complex, and D-dimer levels were significantly elevated in the LA as compared to FV samples in case of both groups, indicating a temporary thrombotic risk associated with the catheterization procedure. CONCLUSIONS: None of the investigated hemostasis or fibrinolysis parameters showed significant intracardiac alterations in AF patients as compared to non-AF controls. AF patients have elevated FVIII and VWF levels, most likely due to endothelial damage, presenting at both intracardiac and systemic level. PMID- 28713824 TI - Effects of Hyperglycemia on Vascular Smooth Muscle Ca2+ Signaling. AB - Diabetes is a complex disease that is characterized with hyperglycemia, dyslipidemia, and insulin resistance. These pathologies are associated with significant cardiovascular implications that affect both the macro- and microvasculature. It is therefore important to understand the effects of various pathologies associated with diabetes on the vasculature. Here we directly test the effects of hyperglycemia on vascular smooth muscle (VSM) Ca2+ signaling in an isolated in vitro system using the A7r5 rat aortic cell line as a model. We find that prolonged exposure of A7r5 cells to hyperglycemia (weeks) is associated with changes to Ca2+ signaling, including most prominently an inhibition of the passive ER Ca2+ leak and the sarcoplasmic reticulum Ca2+-ATPase (SERCA). To translate these findings to the in vivo condition, we used primary VSM cells from normal and diabetic subjects and find that only the inhibition of the ER Ca2+ leaks replicates in cells from diabetic donors. These results show that prolonged hyperglycemia in isolation alters the Ca2+ signaling machinery in VSM cells. However, these alterations are not readily translatable to the whole organism situation where alterations to the Ca2+ signaling machinery are different. PMID- 28713825 TI - The Serum Analysis of Dampness Syndrome in Patients with Coronary Heart Disease and Chronic Renal Failure Based on the Theory of "Same Syndromes in Different Diseases". AB - AIM: To analyze the serum metabolites in patients with coronary heart disease (CHD) showing dampness syndrome and patients with chronic renal failure (CRF) showing dampness syndrome and to seek the substance that serves as the underlying basis of dampness syndrome in "same syndromes in different diseases." Methods. Metabolic spectrum by GC-MS was performed using serum samples from 29 patients with CHD showing dampness syndrome and 32 patients with CRF showing dampness syndrome. The principal component analysis and statistical analysis of partial least squares were performed to detect the metabolites with different levels of expression in patients with CHD and CRF. Furthermore, by comparing the VIP value and data mining in METLIN and HMDB, we identified the common metabolites in both patient groups. RESULTS: (1) Ten differential metabolites were found in patients with CHD showing dampness syndrome when compared to healthy subjects. Meanwhile, nine differential metabolites were found in patients with CRF showing dampness syndrome when compared to healthy subjects. (2) There were 9 differential metabolites identified when the serum metabolites of the CHD patients with dampness syndrome were compared to those of CRF patients with dampness syndrome. There were 4 common metabolites found in the serums of both patient groups. PMID- 28713826 TI - Characterization of Oral Microbiota in Removable Dental Prosthesis Users: Influence of Arterial Hypertension. AB - INTRODUCTION: Studies have described the possible relation between oral infections and atherosclerotic events. OBJECTIVE: To characterize the oral microbiota of normotensive and hypertensive users of dental prostheses. METHODS: The sample consisted of 41 complete dental prosthesis users, divided into groups: 21 participants with systemic arterial hypertension and 20 normotensive participants. The data collection included the characteristics of the sociodemographic variables and the determination of the microbial load in the saliva. For the descriptive analyses, Statistical Package for the Social Sciences was used. The description of the proportional differences between the groups was based on the application of Mann-Whitney's statistical test. Statistical significance was set at 5% (p < 0.05). RESULTS: The analysis of the oral microbiota showed the vast growth of aerobic microorganisms in all samples from both groups. The microbial load of streptococci and staphylococci was significantly higher among hypertensive participants. Candida yeasts were detected in the saliva culture of most samples. The hypertensive participants rank in the category of very high colonization index/high risk of infection related to this microorganism. CONCLUSIONS: The mouth of dental prosthesis users, especially when hypertensive, can constitute an important reservoir of pathogens, indicating an established inflammatory or infectious condition or risk for developing this condition. PMID- 28713827 TI - Retracted: Estimation of Response Functions Based on Variational Bayes Algorithm in Dynamic Images Sequences. AB - [This retracts the article DOI: 10.1155/2016/4851401.]. PMID- 28713828 TI - The Effect of Small Sample Size on Measurement Equivalence of Psychometric Questionnaires in MIMIC Model: A Simulation Study. AB - Evaluating measurement equivalence (also known as differential item functioning (DIF)) is an important part of the process of validating psychometric questionnaires. This study aimed at evaluating the multiple indicators multiple causes (MIMIC) model for DIF detection when latent construct distribution is nonnormal and the focal group sample size is small. In this simulation-based study, Type I error rates and power of MIMIC model for detecting uniform-DIF were investigated under different combinations of reference to focal group sample size ratio, magnitude of the uniform-DIF effect, scale length, the number of response categories, and latent trait distribution. Moderate and high skewness in the latent trait distribution led to a decrease of 0.33% and 0.47% power of MIMIC model for detecting uniform-DIF, respectively. The findings indicated that, by increasing the scale length, the number of response categories and magnitude DIF improved the power of MIMIC model, by 3.47%, 4.83%, and 20.35%, respectively; it also decreased Type I error of MIMIC approach by 2.81%, 5.66%, and 0.04%, respectively. This study revealed that power of MIMIC model was at an acceptable level when latent trait distributions were skewed. However, empirical Type I error rate was slightly greater than nominal significance level. Consequently, the MIMIC was recommended for detection of uniform-DIF when latent construct distribution is nonnormal and the focal group sample size is small. PMID- 28713829 TI - Experimental Verification of CAPN1 and CAST Gene Polymorphisms in Different Generations of Da-Heng Broilers. AB - The micromolar calcium activated neutral protease (CAPN1) and calpastatin (CAST) have been widely regarded as genes related to muscle growth and meat tenderness. The objective of this study was to verify the association of SNPs of CAPN1 and CAST genes with carcass and tenderness traits and search the possible change patterns of SNPs in CAPN1 and CAST genes in six generations of broiler breeding process for growth rate, efficiency, and reproduction, during the third generation and the ninth generation, respectively. We found that, for CAPN1, genetic effects between SNPs (G3535A, C7198A) and meat tenderness were similar in different generations, while SNP3 (G7324A) was a novel polymorphism and had significant association with carcass and tenderness traits (P < 0.05) in this study. Furthermore, there was significant association between SNP4 (G9950A) and carcass indexes instead of tenderness traits (P < 0.05) which was consistent in the two generations. Moreover, although SNP6 (G37868A) of CAST had no relevance to carcass traits or tenderness traits in the third generation, it showed significant association with LW and CW in the ninth generation (P < 0.05). PMID- 28713830 TI - The Prevalence and Replication Capacity of a Tibetan Dominant HBV Strain, C/D Recombinant. AB - This study aimed to estimate the distribution of hepatitis B virus (HBV) C/D recombinant in Han and Tibet patients with chronic hepatitis B (CHB) and then learn such strain's replication capacity in vivo. A total of 331 serum samples were collected from Han outpatients from Sichuan Province and Tibetan outpatients from Tibet. Viral genotypes in these samples were identified. An HBV replicative plasmid of C/D recombinant was constructed with selected genome. Sequentially, HBV replicative mouse models were established and the replication capacity of the viral strain was studied in vivo. In the 314 Han patients, 66% (207) were infected by genotype B strain while 31% (96) were by genotype C strain. Only 1% (3) were by C/D recombinant. In the 17 Tibetan patients, 41% (7) were by genotype D and 35% (6) by C/D recombinant. A plasmid with 1.3 copies of C/D recombinant genome was constructed. And its replication intermediates were found at similar levels to that of genotype D strain. Thus, C/D recombinant, the dominant viral strain in Tibet, was rather rare in the genotype B predominated Han patients from Sichuan Province. And the C/D recombinant replicated at a similar level to viral strain of genotype D in vivo. PMID- 28713831 TI - New Mydriasis-Free Electroretinogram Recorded with Skin Electrodes in Healthy Subjects. AB - PURPOSE: To evaluate the reproducibility and consistency of the new mydriasis free electroretinogram (ERG) with a skin electrode (RETeval) device, to determine the normative values of parameters, and to clarify the usefulness of pupil records to colored-light stimulus. METHODS: A total of 100 eyes of 50 healthy subjects (mean age, 21.4 years) were enrolled. The diagnostic parameters obtained by the RETeval device were examined under the following conditions. The reproducibility was determined with the coefficient of variation (CV). The consistency was examined by intraclass correlation coefficients (ICCs). The mean value and the normal range were analyzed with a 95% confidence interval as the normative values of parameters. The correlation of parameters to pupil records (area ratio, constriction ratio) and flicker ERG was also examined in the diabetic retinopathy assessment protocol. RESULTS: From the CV for each of the two measurements, the amplitude has a low reproducibility compared with the implicit time. Generally good consistency was obtained with both ERG parameters (ICCs = 0.48-0.92). Moderate correlations were found for the white-, red-, and blue-light stimulus in the area ratio and the constriction ratio, respectively (r = 0.44-0.62; P = 0.010-<0.0001). No correlation was observed between pupil and flicker parameters (r = 0.06-0.34; P = 0.646-0.051). CONCLUSIONS: The RETeval device was suggested as a possible screening device to detect the visual afferent diseases by evaluating in combination with the ERG recording and the colored light pupil response. PMID- 28713832 TI - Postnatal Growth in a Cohort of Sardinian Intrauterine Growth-Restricted Infants. AB - Recent studies have shown that infants with intrauterine growth restriction (IUGR) undergo catch-up growth during infancy. The aim of our study was to evaluate the postnatal growth in a cohort of IUGR infants born in a tertiary level Obstetric University Hospital of Northern Sardinia. An observational retrospective study was conducted on 12 IUGR (group A) and 12 control infants (group B) by measuring the anthropometric parameters of weight (W), length (L) and head circumference (HC) from birth to the 3rd postnatal year. At birth, significant differences were found between group A and group B with regard to all the auxological parameters (W, mean 1846.6 versus 3170.8 g, p < 0.0001; HC, 30.1 versus 34.4 cm, p < 0.0001; L, mean 43.4 versus 49.4 cm, p < 0.0001). During the 1st year, 8 of 12 (70%) IUGR infants exhibited a significant catch-up growth in the 3 anthropometric parameters and a regular growth until the 3rd year of follow up. The majority but not all infants born with IUGR in our series showed significant postnatal catch-up growth essentially during the first 12 months of life. An improved knowledge of the causes of IUGR will help to develop measures for its prevention and individualized treatment. PMID- 28713833 TI - Association between Hemoglobin Levels and Diabetic Peripheral Neuropathy in Patients with Type 2 Diabetes: A Cross-Sectional Study Using Electronic Health Records. AB - OBJECTIVE: To investigate the relationship between hemoglobin levels and diabetic peripheral neuropathy (DPN) in type 2 diabetes mellitus (T2DM). METHODS: 1511 patients with T2DM were included in the study. DPN was diagnosed based on symptoms, signs, and laboratory tests. Hemoglobin was defined as both a continuous variable and a quartile category variable. We compared patient characteristics between the no diabetic peripheral neuropathy (NDPN) and DPN groups. Logistic regression was conducted to investigate the association of DPN with hemoglobin in all T2DM patients. Linear regression was also performed to investigate the impact of hemoglobin on the vibrating perception threshold (VPT). RESULTS: Compared with the NDPN group, hemoglobin level in the DPN group was significantly lower (118.54 +/- 16.91 versus 131.62 +/- 18.32 g/L, P < 0.01). The prevalence of DPN increased by 50.1% (95% CI: 42.2-57.0%; P < 0.001) per standard deviation decrease in hemoglobin. Compared to the highest quartile of hemoglobin, the lower quartiles were associated with a significantly increased risk of DPN in the entire T2DM population (all P < 0.01). A per unit decrease in hemoglobin leads to a 0.12 (95% CI: 0.07-0.168) unit increase in VPT after adjustment for possible confounders (P < 0.001). CONCLUSIONS: Lower hemoglobin levels were associated with increased prevalence of DPN and higher VPT. PMID- 28713834 TI - Renoprotective Effect of the Shen-Yan-Fang-Shuai Formula by Inhibiting TNF alpha/NF-kappaB Signaling Pathway in Diabetic Rats. AB - Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease, and satisfactory therapeutic strategies have not yet been established. The Shen Yan-Fang-Shuai Formula (SYFSF) is a traditional Chinese formula composed of Astragali radix, Radixangelicae sinensis, Rheum officinale Baill, and four other herbs. It has been widely used as an effective treatment for DKD patients in China. However, little is known about the molecular mechanisms underlying SYFSF's renoprotection. In this study, we compared the protective effect of SYFSF to irbesartan on the histology and renal cells in type 2 DKD rat model and high glucose (HG) cultured mesangial cells, respectively. We found that SYFSF could significantly decrease urinary albumin, cholesterol, and triglyceride. And a decrease in serum creatinine was also found in SYFSF-treated group compared with irbesartan-treated rats. In addition, SYFSF inhibited the interstitial expansion and glomerulosclerosis in diabetic rats. Notably, SYFSF markedly downregulated the expression of MCP-1, TGF-beta1, collagen IV, and fibronectin in diabetic rat models and HG-induced mesangial cell models. The renoprotection was closely associated with a reduced expression of TNF-alpha and phosphorylated NF kappaBp65. Our study suggests that SYFSF may ameliorate diabetic kidney injury. The observed renoprotection is probably attributable to an inhibition of inflammatory response and extracellular matrix (ECM) accumulation mediated by TNF alpha/NF-kappaBp65 signaling pathway. PMID- 28713835 TI - Rapid Detection of the mt3243A > G Mutation Using Urine Sediment in Elderly Chinese Type 2 Diabetic Patients. AB - OBJECTIVE: In this study, we aimed to identify mt3243A > G mutation carriers in a group of Chinese elderly type 2 diabetic patients by a rapid and noninvasive diagnostic system. METHODS: DNA was extracted from blood, saliva, and urine sediment samples. The mutation screening and quantitation of heteroplasmy were performed by high-resolution melting (HRM) curve and pyrosequencing, respectively. Patients with mt3243A > G mutation underwent a detailed audiometric, ophthalmologic, neurological, and cardiac examination. RESULTS: Two patients (2/1041) carrying the mt3243A > G mutation were detected among all type 2 diabetic patients. In patient 1, the heteroplasmy was 0.8%, 2.8%, and 14.7% in peripheral blood leukocytes, saliva, and urine sediment, respectively. In patient 2, the heteroplasmy was 5.3%, 8.4%, and 37.7% in peripheral blood leukocytes, saliva, and urine sediment, respectively. Both of the two patients showed hearing impairment. Abnormal ophthalmologic conditions and hyperintensity on T2-weighted magnetic resonance images were showed in patient 1. CONCLUSION: The occurrence of mt3243 A > G mutation was 0.2% in Chinese elderly type 2 diabetic patients. Moreover, detection of mt3243 A > G mutation in urine sediment with high resolution melting (HRM) curve and pyrosequencing is feasible in molecular genetic diagnosis. PMID- 28713837 TI - The Predictive Role of Tooth Extractions, Oral Infections, and hs-C-Reactive Protein for Mortality in Individuals with and without Diabetes: A Prospective Cohort Study of a 12 1/2-Year Follow-Up. AB - The predictive role of high-sensitivity C-reactive protein (hs-CRP), number of tooth extractions, and oral infections for mortality in people with and without diabetes is unclear. This prospective cohort study is a 12 1/2-year follow-up of the Oslo II study, a health survey in 2000. In all, 12,764 men were invited. Health information was retrieved from 6434 elderly men through questionnaire information, serum measurements, and anthropometric and blood pressure measurements. Diabetes was reported by 425 men. Distinct differences were observed in baseline characteristics in individuals with and without diabetes. In the diabetes group, age and hs-CRP were statistically significant whereas in the nondiabetes group, age, hs-CRP, number of tooth extractions, tooth extractions for infections and oral infections combined, nonfasting glucose, systolic blood pressure, total cholesterol, regular alcohol drinking, daily smoking, and level of education were independent risk factors. The number of tooth extractions <5 was inversely related whereas more extractions increased the risk. Multivariate analyses showed that hs-CRP was a significant predictor in persons with diabetes and tooth extractions and oral infections combined; the number of teeth extracted and hs-CRP were for persons without diabetes. Infection and inflammation were associated with mortality in individuals both with and without diabetes. PMID- 28713836 TI - Increased Serum Uric Acid Level Is a Risk Factor for Left Ventricular Hypertrophy but Not Independent of eGFR in Patients with Type 2 Diabetic Kidney Disease. AB - BACKGROUND: Although the relation between serum uric acid (SUA) and left ventricular hypertrophy (LVH) has been studied for decades, however, their association remains debatable. METHODS: This is a retrospective study in which a total of 435 hospitalized Chinese patients with type 2 DKD were enrolled. The subjects were stratified into quartiles according to SUA level. LVH was assessed by two-dimensional guided M-mode echocardiography. RESULTS: There was a significant increase in the prevalence of LVH in patients with type 2 DKD across SUA quartiles (28.9, 26.5, 36.1, and 49.5%; p < 0.001). The Spearman analysis indicated that SUA was positively correlated to LVMI and negatively correlated to eGFR. The logistic regression analysis revealed that the odd ratio for LVH in the highest SUA quartile was 2.439 (95% CI 1.265-4.699; p = 0.008; model 1) or 2.576 (95% CI 1.150-5.768; p = 0.021; model 2) compared with that in the lowest SUA quartile. However, there was no significant increased risk of LVH in the subjects with the highest SUA quartile after adjusting the eGFR (OR = 1.750; 95% CI 0.685 4.470; p = 0.242; model 3). CONCLUSIONS: In selected population, such as type 2 DKD, the elevated SUA level is positively linked with the increased risk of LVH, but this relationship is not independent of eGFR. PMID- 28713839 TI - Informal Convergence at Major Emergency Incidents in Kenya. AB - "Convergence behavior" is the informal, spontaneous movement of people, messages, and supplies toward a major emergency incident area. This form of movement brings needed aid to many victims, but at the same time the resultant congestion makes organization and control of the rescue and relief efforts more difficult. Whenever a major emergency incident occurs in Kenya, typically a huge crowd of sightseers and personnel converge at the scene. This report provides a review of informal convergence behavior in Kenya during major emergency incidents over the last 15 years (1998-2013) and some of the risks that have been associated with this phenomenon. It also provides some recommendations that have been successfully implemented in other countries, as well as in rare instances in Kenya, to control informal convergence behavior. PMID- 28713838 TI - Role of Interferons in the Development of Diagnostics, Vaccines, and Therapy for Tuberculosis. AB - Tuberculosis (TB) is an airborne infection caused by Mycobacterium tuberculosis (Mtb). About one-third of the world's population is latently infected with TB and 5-15% of them will develop active TB in their lifetime. It is estimated that each case of active TB may cause 10-20 new infections. Host immune response to Mtb is influenced by interferon- (IFN-) signaling pathways, particularly by type I and type II interferons (IFNs). The latter that consists of IFN-gamma has been associated with the promotion of Th1 immune response which is associated with protection against TB. Although this aspect remains controversial at present due to the lack of established correlates of protection, currently, there are different prophylactic, diagnostic, and immunotherapeutic approaches in which IFNs play an important role. This review summarizes the main aspects related with the biology of IFNs, mainly associated with TB, as well as presents the main applications of these cytokines related to prophylaxis, diagnosis, and immunotherapy of TB. PMID- 28713840 TI - Ultrafast kinetics of linkage isomerism in Na2[Fe(CN)5NO] aqueous solution revealed by time-resolved photoelectron spectroscopy. AB - The kinetics of ultrafast photoinduced structural changes in linkage isomers is investigated using Na2[Fe(CN)5NO] as a model complex. The buildup of the metastable side-on configuration of the NO ligand, as well as the electronic energy levels of ground, excited, and metastable states, has been revealed by means of time-resolved extreme UV (XUV) photoelectron spectroscopy in aqueous solution, aided by theoretical calculations. Evidence of a short-lived intermediate state in the isomerization process and its nature are discussed, finding that the complete isomerization process occurs in less than 240 fs after photoexcitation. PMID- 28713841 TI - Design and implementation of an optimal laser pulse front tilting scheme for ultrafast electron diffraction in reflection geometry with high temporal resolution. AB - Ultrafast electron diffraction is a powerful technique to investigate out-of equilibrium atomic dynamics in solids with high temporal resolution. When diffraction is performed in reflection geometry, the main limitation is the mismatch in group velocity between the overlapping pump light and the electron probe pulses, which affects the overall temporal resolution of the experiment. A solution already available in the literature involved pulse front tilt of the pump beam at the sample, providing a sub-picosecond time resolution. However, in the reported optical scheme, the tilted pulse is characterized by a temporal chirp of about 1 ps at 1 mm away from the centre of the beam, which limits the investigation of surface dynamics in large crystals. In this paper, we propose an optimal tilting scheme designed for a radio-frequency-compressed ultrafast electron diffraction setup working in reflection geometry with 30 keV electron pulses containing up to 105 electrons/pulse. To characterize our scheme, we performed optical cross-correlation measurements, obtaining an average temporal width of the tilted pulse lower than 250 fs. The calibration of the electron laser temporal overlap was obtained by monitoring the spatial profile of the electron beam when interacting with the plasma optically induced at the apex of a copper needle (plasma lensing effect). Finally, we report the first time-resolved results obtained on graphite, where the electron-phonon coupling dynamics is observed, showing an overall temporal resolution in the sub-500 fs regime. The successful implementation of this configuration opens the way to directly probe structural dynamics of low-dimensional systems in the sub-picosecond regime, with pulsed electrons. PMID- 28713843 TI - Probing ultrafast changes of spin and charge density profiles with resonant XUV magnetic reflectivity at the free-electron laser FERMI. AB - We report the results of resonant magnetic XUV reflectivity experiments performed at the XUV free-electron laser FERMI. Circularly polarized XUV light with the photon energy tuned to the Fe M2,3 edge is used to measure resonant magnetic reflectivities and the corresponding Q-resolved asymmetry of a Permalloy/Ta/Permalloy trilayer film. The asymmetry exhibits ultrafast changes on 240 fs time scales upon pumping with ultrashort IR laser pulses. Depending on the value of the wavevector transfer Qz , we observe both decreasing and increasing values of the asymmetry parameter, which is attributed to ultrafast changes in the vertical spin and charge density profiles of the trilayer film. PMID- 28713842 TI - Femtosecond time-resolved X-ray absorption spectroscopy of anatase TiO2 nanoparticles using XFEL. AB - The charge-carrier dynamics of anatase TiO2 nanoparticles in an aqueous solution were studied by femtosecond time-resolved X-ray absorption spectroscopy using an X-ray free electron laser in combination with a synchronized ultraviolet femtosecond laser (268 nm). Using an arrival time monitor for the X-ray pulses, we obtained a temporal resolution of 170 fs. The transient X-ray absorption spectra revealed an ultrafast Ti K-edge shift and a subsequent growth of a pre edge structure. The edge shift occurred in ca. 100 fs and is ascribed to reduction of Ti by localization of generated conduction band electrons into shallow traps of self-trapped polarons or deep traps at penta-coordinate Ti sites. Growth of the pre-edge feature and reduction of the above-edge peak intensity occur with similar time constants of 300-400 fs, which we assign to the structural distortion dynamics near the surface. PMID- 28713844 TI - Epidemiology, Diagnosis, and Management of Neurogenic Orthostatic Hypotension. AB - BACKGROUND: Orthostatic hypotension (OH) is a sustained fall in blood pressure on standing which can cause symptoms of organ hypoperfusion. OH is associated with increased morbidity and mortality and leads to a significant number of hospital admissions particularly in the elderly (233 per 100,000 patients over 75 years of age in the US). OH can be due to volume depletion, blood loss, large varicose veins, medications, or due to defective activation of sympathetic nerves and reduced norepinephrine release upon standing (i.e., neurogenic OH). METHODS AND FINDINGS: Literature review. Neurogenic OH is a frequent and disabling problem in patients with synucleinopathies such as Parkinson disease, multiple system atrophy, and pure autonomic failure, and is commonly associated with supine hypertension. Several pharmacological and non-pharmacological therapeutic options are available. CONCLUSIONS: Here we review the epidemiology, diagnosis, and management of neurogenic OH, and provide an algorithm for its treatment emphasizing the importance of removing aggravating factors, implementing non pharmacologic measures, and selecting appropriate pharmacological treatments. PMID- 28713845 TI - Impact of Phonons on Dephasing of Individual Excitons in Deterministic Quantum Dot Microlenses. AB - Optimized light-matter coupling in semiconductor nanostructures is a key to understand their optical properties and can be enabled by advanced fabrication techniques. Using in situ electron beam lithography combined with a low temperature cathodoluminescence imaging, we deterministically fabricate microlenses above selected InAs quantum dots (QDs), achieving their efficient coupling to the external light field. This enables performing four-wave mixing microspectroscopy of single QD excitons, revealing the exciton population and coherence dynamics. We infer the temperature dependence of the dephasing in order to address the impact of phonons on the decoherence of confined excitons. The loss of the coherence over the first picoseconds is associated with the emission of a phonon wave packet, also governing the phonon background in photoluminescence (PL) spectra. Using theory based on the independent boson model, we consistently explain the initial coherence decay, the zero-phonon line fraction, and the line shape of the phonon-assisted PL using realistic quantum dot geometries. PMID- 28713846 TI - Feasibility of implementing a community-based randomized trial of yoga for women undergoing chemotherapy for breast cancer. AB - BACKGROUND: Treatment-related symptoms and decreased health-related quality of life (HRQoL) frequently occur during chemotherapy for breast cancer. Although research findings suggest that yoga can reduce symptoms and Improve HRQoL after treatment, potential benefits of yoga during chemotherapy have received minimal attention. OBJECTIVE: To estimate accrual, adherence, study retention, and preliminary efficacy of a yoga intervention compared with an active control group for breast cancer patients during chemotherapy. METHODS: Women with stage I-III breast cancer were recruited from 3 community cancer clinics and randomized to 10 weeks of gentle yoga or wellness education. Depressive symptoms, fatigue, sleep, and HRQoL were assessed at baseline, mid-intervention (Week 5), and after intervention (Week 10). RESULTS: 40 women aged 29-83 years (median, 48 years; 88% white) were randomized to yoga (n = 22) or wellness education (n = 18). The groups did not differ significantly on baseline characteristics, adherence, or study retention. Participant feedback was positive and comparable between groups. Meaningful within-group differences were identified For sleep adequacy and quantity in yoga participants and for somnolence in wellness-education participants. LIMITATIONS: Small sample size and lack of a usual-care control group. CONCLUSIONS: This study established Feasibility of a community-based randomized trial of yoga and an active comparison group for women undergoing chemotherapy for breast cancer. Preliminary efficacy estimates suggest that yoga improves sleep adequacy Symptom severity and interference remained stable during chemotherapy for the yoga group and snowed a trend toward increasing in the control group. The study highlighted obstacles to multisite yoga research during cancer treatment. FUNDING/SPONSORSHIP: National Cancer Institute (3U10 CA081851, PI; Shaw; R25 CA122061, PI: Avis); Translational Science Institute, Wake Forest School of Medicine. PMID- 28713847 TI - Next-generation Sequencing of the DNA Virome from Fecal Samples. AB - Herein we describe a detailed protocol for DNA virome analysis of low input human stool samples (Monaco et al., 2016). This protocol is divided into four main steps: 1) stool samples are pulverized to evenly distribute microbial matter; 2) stool is enriched for virus-like particles and DNA is extracted by phenol chloroform; 3) purified DNA is multiple-strand displacement amplified (MDA) and fragmented; and 4) libraries are constructed and sequenced using Illumina Miseq. Subsequent sequence analysis for viral sequence identification should be sensitive but stringent. PMID- 28713848 TI - Evaluation of Muscle Performance in Mice by Treadmill Exhaustion Test and Whole limb Grip Strength Assay. AB - In vivo muscle function testing has become of great interest as primary phenotypic analysis of muscle performance. This protocol provides detailed procedures to perform the treadmill exhaustion test and the whole-limb grip strength assay, two methods commonly used in the neuromuscular research field. PMID- 28713849 TI - Glare suppression by coherence gated negation. AB - Imaging of a weak target hidden behind a scattering medium can be significantly confounded by glare. We report a method, termed coherence gated negation (CGN), that uses destructive optical interference to suppress glare and allow improved imaging of a weak target. As a demonstration, we show that by permuting through a set range of amplitude and phase values for a reference beam interfering with the optical field from the glare and target reflection, we can suppress glare by an order of magnitude, even when the optical wavefront is highly disordered. This strategy significantly departs from conventional coherence gating methods in that CGN actively "gates out" the unwanted optical contributions while conventional methods "gate in" the target optical signal. We further show that the CGN method can outperform conventional coherence gating image quality in certain scenarios by more effectively rejecting unwanted optical contributions. PMID- 28713850 TI - Collagen and heparan sulfate coatings differentially alter cell proliferation and attachment in vitro and in vivo. AB - Tissue engineering is an innovative field of research applied to treat intestinal diseases. Engineered smooth muscle requires dense smooth muscle tissue and robust vascularization to support contraction. The purpose of this study was to use heparan sulfate (HS) and collagen coatings to increase the attachment of smooth muscle cells (SMCs) to scaffolds and improve their survival after implantation. SMCs grown on biologically coated scaffolds were evaluated for maturity and cell numbers after 2, 4 and 6 weeks in vitro and both 2 and 6 weeks in vivo. Implants were also assessed for vascularization. Collagen-coated scaffolds increased attachment, growth and maturity of SMCs in culture. HS-coated implants increased angiogenesis after 2 weeks, contributing to an increase in SMC survival and growth compared to HS-coated scaffolds grown in vitro. The angiogenic effects of HS may be useful for engineering intestinal smooth muscle. PMID- 28713851 TI - Building an experimental model of the human body with non-physiological parameters. AB - New advances in engineering and biomedical technology have enabled recent efforts to capture essential aspects of human physiology in microscale, in-vitro systems. The application of these advances to experimentally model complex processes in an integrated platform - commonly called a 'human-on-a-chip (HOC)' - requires that relevant compartments and parameters be sized correctly relative to each other and to the system as a whole. Empirical observation, theoretical treatments of resource distribution systems and natural experiments can all be used to inform rational design of such a system, but technical and fundamental challenges (e.g. small system blood volumes and context-dependent cell metabolism, respectively) pose substantial, unaddressed obstacles. Here, we put forth two fundamental principles for HOC design: inducing in-vivo-like cellular metabolic rates is necessary and may be accomplished in-vitro by limiting O2 availability and that the effects of increased blood volumes on drug concentration can be mitigated through pharmacokinetics-based treatments of solute distribution. Combining these principles with natural observation and engineering workarounds, we derive a complete set of design criteria for a practically realizable, physiologically faithful, five-organ millionth-scale (* 10-6) microfluidic model of the human body. PMID- 28713852 TI - The Role of Context in the Implementation of Trauma-Focused Treatments: Effectiveness Research and Implementation in Higher and Lower Income Settings. AB - In recent years, the implementation of trauma-focused treatments has expanded across settings that vary widely in the availability of resources, infrastructure, and personnel. The present review aims to inform researchers, policy makers, trainers, and administrators about this diverse range of research. Taking a global health perspective, this review of effectiveness trials and implementation studies compares strategies used in high-income countries to those in low- and medium-income countries. A primary difference between studies in high income and low- and medium-income countries is the relative emphasis placed on fidelity or adaptation. Adaptations used in low- and medium-income countries might offer useful ideas for increasing the portability, impact, and accessibility of evidence-based interventions in high-income countries. PMID- 28713853 TI - Factors Associated with Acute Postoperative Pain Following Breast Reconstruction. AB - INTRODUCTION: Post-mastectomy breast reconstruction has become an increasingly important component of breast cancer treatment. Unfortunately, some patients experience severe postoperative pain, placing them at risk for increased clinical morbidity and the development of disabling chronic pain. In an attempt to identify at-risk patients, we prospectively evaluated patient characteristics and medical/surgical variables associated with more severe acute post-reconstruction pain. METHODS: Women (N = 2207; one-week 82.8% response rate) undergoing breast reconstruction were assessed for pain experience, anxiety, depression, and sociodemographic characteristics prior to surgery. Pain assessments were made preoperatively and postoperative at 1-week using validated survey instruments including the McGill Pain Questionnaire-Short Form (MPQ-SF), Numerical Pain Rating Scale (NPRS), and BREAST-Q Chest and Upper Body scale. Depressive symptoms and anxiety severity were assessed by the Patient Health Questionnaire and Generalized Anxiety Disorders Scale, respectively. Mixed-effects regression modeling was used to examine the relationships between patient characteristics and medical/surgical factors and 1-week postoperative pain. RESULTS: Younger age, bilateral reconstruction, and severity of preoperative pain, anxiety and depression were all associated with more severe acute postoperative pain on all the pain measures and BREAST-Q. Comparison of surgical procedure type indicated less severe postoperative pain for PTRAM, DIEP and SIEA reconstructive surgery compared to tissue expander/implant reconstruction. CONCLUSIONS: This study identified patients at risk for greater acute postoperative pain following breast reconstruction. These findings will allow plastic surgeons to better tailor postoperative care to improve patient comfort, reduce clinical morbidity, and further enhance patient satisfaction with their surgical outcome. PMID- 28713854 TI - Forced migration in childhood: are there long-term health effects? AB - Studies on the health of migrants have increased considerably in number in recent years, but little is still known about the long-term health effects associated with forced migration, and particularly for people who were forced to migrate as children. Data shortcomings together with the methodological challenges of studying migrant populations limit the ability to disentangle the roles of various factors that influence migrant health outcomes. Finland provides an unusual opportunity to study long-term health consequences associated with forced migration. During World War II, twelve per cent of the Finnish population was forced to leave the region nowadays referred to as Ceded Karelia. After the war, these Karelians could not return home because the area was relinquished to the Soviet Union. Using high quality, linked register-based data for the period 1988 2012, we investigate whether this forced migration had long-term health consequences for those who were forced to migrate as children. Comparison groups are non-displaced persons born on the adjacent side of the new border, and people born elsewhere in Finland. Health at ages 43-65 years is measured by receipt of sickness benefit, which is an indicator of short-term illness, and receipt of disability pension, which reflects long-term illness or permanent disability. All cause and cause-specific mortality is analysed at ages 43-84 years. We find no support for the hypothesis that the traumatic event of being forced to migrate during childhood has long-term negative health consequences. The forced child migrants have lower odds for receipt of sickness benefit, and women also have lower odds for receipt of disability pension. The mortality results are largely driven by patterns specific for eastern-born populations of Finland. A likely reason behind the absence of negative health consequences is that these migrants seem to have integrated well into post-war Finnish society. PMID- 28713855 TI - High Aspect Ratio Nanotubes Formed by Tobacco Mosaic Virus for Delivery of Photodynamic Agents Targeting Melanoma. AB - Melanoma is a highly aggressive cancer that is unresponsive to many traditional therapies. Recently, photodynamic therapy has shown promise in its treatment as an adjuvant therapy. However, conventional photosensitizers are limited by poor solubility and limited accumulation within target tissue. Here, we report the delivery of a porphyrin-based photosensitizer encapsulated within a plant viral nanoparticle. Specifically, we make use of the hollow, high aspect ratio nanotubes formed by the nucleoprotein components of tobacco mosaic virus (TMV) to encapsulate the drug for delivery and targeting of cancer cells. The cationic photosensitizer was successfully and stably loaded into the interior channel of TMV via electrostatic interactions. Cell uptake and efficacy were evaluated using a model of melanoma. The resulting TMV-photosensitizer exhibited improved cell uptake and efficacy when compared to free photosensitizer, making it a promising platform for improved therapy of melanoma. PMID- 28713856 TI - Differences in ME and CFS Symptomology in Patients with Normal and Abnormal Exercise Test Results. AB - Post-exertional malaise (PEM) is a cardinal symptom of myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS), which often distinguishes patients with this illness from healthy controls or individuals with exclusionary illnesses such as depression. However, occurrence rates for PEM fluctuate from subject to how the symptom is operationalized. One commonly utilized method is exercise testing, maximal or submaximal. Many patients with ME and CFS experience PEM after participating in these tests, and often show abnormal results. However, some patients still exhibit normal results after participating in the exercise testing. This study examined the differences between two patient groups with ME and CFS, those with normal results and those with abnormal results, on several PEM-related symptoms and illness characteristics. The results suggest those that displayed abnormal results following testing have more frequent and severe PEM, worse overall functioning, and are more likely to be bedbound than those that displayed normal results. PMID- 28713857 TI - A New Clade of Insect-Specific Flaviviruses from Australian Anopheles Mosquitoes Displays Species-Specific Host Restriction. AB - Flaviviruses are arthropod-borne viruses found worldwide and are responsible for significant human and veterinary diseases, including dengue, Zika, and West Nile fever. Some flaviviruses are insect specific and replicate only in mosquitoes. We report a genetically divergent group of insect-specific flaviviruses from Anopheles mosquitoes that do not replicate in arthropod cell lines or heterologous Anopheles species, exhibiting unprecedented specialization for their host species. Determination of the complete sequences of the RNA genomes of three of these viruses, Karumba virus (KRBV), Haslams Creek virus, and Mac Peak virus (McPV), that are found in high prevalence in some Anopheles mosquito populations and detection of virus-specific proteins, replicative double-stranded RNA, and small interfering RNA responses in the host mosquito species provided strong evidence of a functional replicating virus in the mosquito midgut. Analysis of nucleotide composition in the KRBV and McPV sequences also revealed a pattern consistent with the virus evolving to replicate only in insects. These findings represent a significant advance in our knowledge of mosquito-borne flavivirus ecology, host restriction, and evolution. IMPORTANCE Flaviviruses like dengue, Zika, or West Nile virus infect millions of people each year and are transmitted to humans via infected-mosquito bites. A subset of flaviviruses can only replicate in the mosquito host, and recent studies have shown that some can interfere with pathogenic flaviviruses in mosquitoes and limit the replication and transmission of the latter. The insect-specific flaviviruses (ISFs) reported here form a new Anopheles mosquito-associated clade separate from the Aedes- and Culex-associated ISF clades. The identification of distinct clades for each mosquito genus provides new insights into the evolution and ecology of flaviviruses. One of these viruses was shown to replicate in the midgut of the mosquito host and exhibit the most specialized host restriction reported to date for ISFs. Understanding this unprecedented host restriction in ISFs could help identify the mechanisms involved in the evolution of flaviviruses and their emergence as mosquito-borne pathogens. PMID- 28713859 TI - Fungus Causing White-Nose Syndrome in Bats Accumulates Genetic Variability in North America with No Sign of Recombination. AB - Emerging fungal diseases of wildlife are on the rise worldwide, and the white nose syndrome (WNS) epidemic in North American bats is a catastrophic example. The causal agent of WNS is a single clone of the fungus Pseudogymnoascus destructans. Early evolutionary change in this clonal population has major implications for disease ecology and conservation. Accumulation of variation in the fungus through mutation, and shuffling of variation through recombination, could affect the virulence and transmissibility of the fungus and the durability of what appears to be resistance arising in some bat populations. Our genome-wide analysis shows that the clonal population of P. destructans has expanded in size from a single genotype, has begun to accumulate variation through mutation, and presents no evidence as yet of genetic exchange among individuals. IMPORTANCE Since its discovery in 2006, the emerging infectious disease known as white-nose syndrome has killed millions of bats in North America, making it one of the most devastating wildlife epidemics in recorded history. We demonstrate that there has been as yet only spontaneous mutation across the North American population of P. destructans, and we find no indication of recombination. Thus, selective forces, which might otherwise impact pathogenic virulence, have so far had essentially no genetic variation on which to act. Our study confirmed the time of origin for the first and, thus far, only introduction of P. destructans to North America. This system provides an unprecedented opportunity to follow the evolution of a host pathogen interaction unfolding in real time. PMID- 28713858 TI - Life Stage-Specific Cargo Receptors Facilitate Glycosylphosphatidylinositol Anchored Surface Coat Protein Transport in Trypanosoma brucei. AB - The critical virulence factor of bloodstream-form Trypanosoma brucei is the glycosylphosphatidylinositol (GPI)-anchored variant surface glycoprotein (VSG). Endoplasmic reticulum (ER) exit of VSG is GPI dependent and relies on a discrete subset of COPII machinery (TbSec23.2/TbSec24.1). In other systems, p24 transmembrane adaptor proteins selectively recruit GPI-anchored cargo into nascent COPII vesicles. Trypanosomes have eight putative p24s (TbERP1 to TbERP8) that are constitutively expressed at the mRNA level. However, only four TbERP proteins (TbERP1, -2, -3, and -8) are detectable in bloodstream-form parasites. All four colocalize to ER exit sites, are required for efficient GPI-dependent ER exit, and are interdependent for steady-state stability. These results suggest shared function as an oligomeric ER GPI-cargo receptor. This cohort also mediates rapid forward trafficking of the soluble lysosomal hydrolase TbCatL. Procyclic insect-stage trypanosomes have a distinct surface protein, procyclin, bearing a different GPI anchor structure. A separate cohort of TbERP proteins (TbERP1, -2, 4, and -8) are expressed in procyclic parasites and also function in GPI dependent ER exit. Collectively, these results suggest developmentally regulated TbERP cohorts, likely in obligate assemblies, that may recognize stage-specific GPI anchors to facilitate GPI-cargo trafficking throughout the parasite life cycle. IMPORTANCE African trypanosomes are protozoan parasites that cause African sleeping sickness. Critical to the success of the parasite is the variant surface glycoprotein (VSG), which covers the parasite cell surface and which is essential for evasion of the host immune system. VSG is membrane bound by a glycolipid (GPI) anchor that is attached in the earliest compartment of the secretory pathway, the endoplasmic reticulum (ER). We have previously shown that the anchor acts as a positive forward trafficking signal for ER exit, implying a cognate receptor mechanism for GPI recognition and loading in coated cargo vesicles leaving the ER. Here, we characterize a family of small transmembrane proteins that act at adaptors for this process. This work adds to our understanding of general GPI function in eukaryotic cells and specifically in the synthesis and transport of the critical virulence factor of pathogenic African trypanosomes. PMID- 28713860 TI - ICAM-1-Targeted Nanocarriers Attenuate Endothelial Release of Soluble ICAM-1, an Inflammatory Regulator. AB - Targeting of drug nanocarriers (NCs) to intercellular adhesion molecule-1 (ICAM 1), an endothelial-surface protein overexpressed in many pathologies, has shown promise for therapeutic delivery into and across this lining. Yet, due to the role of ICAM-1 in inflammation, the effects of targeting this receptor need investigation. Since ICAM-1 binding by natural ligands (leukocyte integrins) results in release of the "soluble ICAM-1" ectodomain (sICAM-1), an inflammatory regulator, we investigated the influence of targeting ICAM-1 with NCs on this process. For this, sICAM-1 was measured by ELISA from cell-medium supernatants, after incubation of endothelial cell (EC) monolayers in the absence versus presence of anti-ICAM NCs. In the absence of NCs, ECs released sICAM-1 when treated with a pro-inflammatory cytokine (TNFalpha). This was reduced by inhibiting matrix metalloproteinases MMP-9 or MMP-2, yet inhibiting both did not render additive effects. Release of sICAM-1 mainly occurred at the basolateral versus apical side, and both MMP-9 and MMP-2 influenced apical release, while basolateral release depended on MMP-9. Interestingly, anti-ICAM NCs reduced sICAM 1 to a greater extent than MMP inhibition, both at the apical and basolateral sides. This effect was enhanced with time, although NCs had been removed after binding to cells, ruling out a "trapping" effect of NCs. Instead, inhibiting anti ICAM NC endocytosis counteracted their inhibition on sICAM-1 release. Hence, anti ICAM NCs inhibited sICAM-1 release by mobilizing ICAM-1 from the cell-surface into intracellular vesicles. Since elevated levels of sICAM-1 associate with numerous diseases, this effect represents a secondary benefit of using ICAM-1 targeted NCs for drug delivery. PMID- 28713861 TI - Behavioural clusters and predictors of performance during recovery from stroke. AB - We examined the patterns and variability of recovery post-stroke in multiple behavioral domains. A large cohort of first time stroke patients with heterogeneous lesions was studied prospectively and longitudinally at 1-2 weeks, 3 months and one year post-injury with structural MRI to measure lesion anatomy and in-depth neuropsychological assessment. Impairment was described at all timepoints by a few clusters of correlated deficits. The time course and magnitude of recovery was similar across domains, with change scores largely proportional to the initial deficit and most recovery occurring within the first three months. Damage to specific white matter tracts produced poorer recovery over several domains: attention and superior longitudinal fasciculus II/III, language and posterior arcuate fasciculus, motor and corticospinal tract. Finally, after accounting for the severity of the initial deficit, language and visual memory recovery/outcome was worse with lower education, while the occurrence of multiple deficits negatively impacted attention recovery. PMID- 28713862 TI - Metabolic surgery: gastric bypass for the treatment of type 2 diabetes mellitus. AB - Type 2 diabetes mellitus (T2DM) is one of the largest health emergencies of the 21st century given the worldwide increase of obesity during the last decades and its close association. T2DM is an inherited, polygenic and chronic disease caused by the interaction between several genetic variants in genes and the environment. The continuous search for new and more effective tools to achieve appropriate glycemic control became imperative in order to reduce long-term complications and mortality rates related to T2DM. Treatment options includes lifestyle modifications and several pharmacotherapies as first step in the therapeutical algorithm, but high corps of evidence have shown that gastrointestinal (GI) operations, especially those that involve food rerouting through the GI tract, are safe interventions and achieve superior outcomes for improvement in glucose metabolism when comparing with optimal medical and lifestyle changes. GI Surgery, specially Roux-en-Y gastric bypass (RYGB), is currently the most accepted surgical procedure to treat T2DM, and has also demonstrated to reduce significantly other cardiovascular risk factors (lipids and blood pressure control) when compared with optimal medical treatment, with good long-term effects on cardiovascular risks and mortality. Although the most effective technique in achieving diabetes remission is biliopancreatic diversion, the effectiveness-adverse effects balance is superior for RYGB. For these reasons, metabolic surgery (which was defined as "the operative manipulation of a normal organ or organ system to achieve a biological result for a potential health gain") has been considered and accepted as a new step in the therapeutic algorithm for T2DM when optimal lifestyle and medical interventions don't achieve optimal glycemic goals. PMID- 28713863 TI - Another brick in the large wall against colorectal cancer: a commentary on effectiveness of screening colonoscopy. PMID- 28713864 TI - MAPS - a Magic Angle Positioning System for Enhanced Imaging in High-Field Small Bore MRI. AB - The "magic angle" MRI effect can enhance signal intensity in aligned collagenous structures oriented at approximately 55 degrees with respect to the main magnetic field. The difficulty of positioning tissue inside closed-bore scanners has hampered magic angle use in research and clinics. An MRI-conditional mechatronic system has been developed to control sample orientation inside a 9.4T small bore MRI scanner. The system orients samples to within 0.5 degrees and enables a 600% increase in tendon signal intensity. PMID- 28713865 TI - A standardized and automated method of perineuronal net analysis using Wisteria floribunda agglutinin staining intensity. AB - Perineuronal nets (PNNs) are aggregations of extracellular matrix molecules that are critical for plasticity. Their altered development or changes during adulthood appear to contribute to a wide range of diseases/disorders of the brain. An increasing number of studies examining the contribution of PNN to various behaviors and types of plasticity have analyzed the fluorescence intensity of Wisteria floribunda agglutinin (WFA) as an indirect measure of the maturity of PNNs, with brighter WFA staining corresponding to a more mature PNN and dim WFA staining corresponding to an immature PNN. However, a clearly-defined and unified method for assessing the intensity of PNNs is critical to allow us to make comparisons across studies and to advance our understanding of how PNN plasticity contributes to normal brain function and brain disease states. Here we examined methods of PNN intensity quantification and demonstrate that creating a region of interest around each PNN and subtracting appropriate background is a viable method for PNN intensity quantification that can be automated. This method produces less variability and bias across experiments compared to other published analyses, and this method increases reproducibility and reliability of PNN intensity measures, which is critical for comparisons across studies in this emerging field. PMID- 28713866 TI - Implications of the Hierarchical Structure of Psychopathology for Psychiatric Neuroimaging. AB - Research into the neurobiological substrates of psychopathology has been impeded by heterogeneity within diagnostic categories, comorbidity among mental disorders, and the presence of symptoms that transcend diagnostic categories. Solutions to these issues increasingly focus neurobiological research on isolated or narrow groupings of symptoms or functional constructs rather than categorical diagnoses. Here we argue for a more integrative approach that also incorporates the broad hierarchical structure of psychopathological symptoms and their etiological mechanisms. This approach places clinical neuroscience research in the context of a hierarchy of empirically defined factors of symptoms such as internalizing disorders, externalizing disorders, and the general factor of psychopathology. Application of this hierarchical approach has the potential to reveal neural substrates that nonspecifically contribute to multiple forms of psychopathology and their comorbidity, and in doing so, facilitate the study of mechanisms that are specific to single dimensions and subsets of symptoms. Neurobiological research on the hierarchy of dimensions of psychopathology is only just beginning to emerge, but has the potential to radically alter our understanding of the neurobiology of abnormal behavior. PMID- 28713867 TI - Circadian Dysregulation in Parkinson's Disease. AB - Parkinson's disease (PD) is the second most common neurodegenerative disorder that affects over one million individuals in the US alone. PD is characterized by a plethora of motor and non-motor manifestations, resulting from a progressive degeneration of dopaminergic neurons and disbalance of several other neurotransmitters. A growing body of evidence points to significant alterations of the circadian system in PD. This is not surprising given the pivotal role that dopamine plays in circadian regulation as well as the role of circadian influences in dopamine metabolism. In this review we present basic and clinical investigations that examined the function of the circadian system in PD. PMID- 28713869 TI - Association of Anisocytosis with Markers of Immune Activation and Exhaustion in Treated HIV. AB - BACKGROUND: Treated HIV infection is associated with heightened inflammation which can contribute to increased risk of cardiovascular disease (CVD). We have previously shown that anisocytosis, as measured by red cell distribution width (RDW), is independently associated with prevalent CVD in people living with HIV (PLHIV). In this study, we sought to identify immune correlates of RDW in PLHIV receiving antiretroviral therapy. METHODS: We performed a cross-sectional and longitudinal analysis of 147 virally-suppressed PLHIV, who had LDL < 130 mg/dL and evidence of heightened inflammation, in a randomized trial of statin therapy. A complete blood count and biomarkers of inflammation and immune activation/exhaustion were measured in peripheral blood at entry and after 24 and 48 weeks. Associations with RDW were estimated using linear regression and linear mixed models. RESULTS: The median age (IQR) for the cohort at enrollment was 46 (40-53) years; 78% were male and 68% were African American. The median RDW for the cohort was 13.4% (12.9-14.0). Compared with the lowest RDW tertile, patients in the highest tertile were less likely to be male, and more likely to be African American, have lower hemoglobin, lower mean corpuscular volume, and higher platelet counts (all P < 0.05). At baseline, RDW weakly correlated with C reactive protein (r = 0.196), d-dimer (r = 0.214), fibrinogen (r = 0.192), IL-6 (r = 0.257), CD4+DR+38+ T cells (r = 0.195), and CD4+PD1+ T cells (r = 0.227), all P < 0.05. Only IL-6, CD4+38+DR+ T cells, and CD4+PD1+ T_cells remained associated after adjustment for clinical factors known to affect RDW in the general population. Over 48 weeks, RDW did not change and there was no significant effect of statin (P = 0.45). After adjustment for clinical parameters, RDW remained positively associated with CD4+38+DR+ and CD4+PD1+ T cells across all time points (P = 0.05). CONCLUSION: In this population of treated HIV+ subjects, anisocytosis was associated with biomarkers of inflammation and T-cell activation/exhaustion over time and independent of clinical confounders. Therefore, RDW may be a useful prognostic biomarker of cardiovascular risk that partially reflects chronic inflammation and immune exhaustion in PLHIV receiving antiretroviral therapy. PMID- 28713868 TI - 21st Century Cardio-Oncology: Identifying Cardiac Safety Signals in the Era of Personalized Medicine. AB - Cardiotoxicity is a well-established complication of oncology therapies. Cardiomyopathy resulting from anthracyclines is a classic example. In the past decade, an explosion of novel cancer therapies, often targeted and more specific than traditional therapies, has revolutionized oncology therapy and dramatically changed cancer prognosis. However, some of these therapies have introduced an assortment of cardiovascular (CV) complications. At times, these devastating outcomes have only become apparent after drug approval and have limited the use of potent therapies. There is a growing need for better testing platforms, both for CV toxicity screening, as well as for elucidating mechanisms of cardiotoxicities of approved cancer therapies. This review discusses the utility of nonclinical models (in vitro, in vivo, & in silico) available and highlights recent advancements in modalities like human stem cell-derived cardiomyocytes for developing more comprehensive cardiotoxicity testing and new means of cardioprotection with targeted anticancer therapies. PMID- 28713870 TI - IL-10 induces a STAT3-dependent autoregulatory loop in TH2 cells that promotes Blimp-1 restriction of cell expansion via antagonism of STAT5 target genes. AB - Blimp-1 expression in T cells extinguishes the fate of T follicular helper cells, drives terminal differentiation, and limits autoimmunity. Although various factors have been described to control Blimp-1 expression in T cells, little is known about what regulates Blimp-1 expression in T helper 2 (TH2) cells and the molecular basis of its actions. We report that signal transducer and activator of transcription 3 (STAT3) unexpectedly played a critical role in regulating Blimp-1 in TH2 cells. Furthermore, we found that the cytokine interleukin-10 (IL-10) acted directly on TH2 cells and was necessary and sufficient to induce optimal Blimp-1 expression through STAT3. Together, Blimp-1 and STAT3 amplified IL-10 production in TH2 cells, creating a strong autoregulatory loop that enhanced Blimp-1 expression. Increased Blimp-1 in T cells antagonized STAT5-regulated cell cycle and antiapoptotic genes to limit cell expansion. These data elucidate the signals required for Blimp-1 expression in TH2 cells and reveal an unexpected mechanism of action of IL-10 in T cells, providing insights into the molecular underpinning by which Blimp-1 constrains T cell expansion to limit autoimmunity. PMID- 28713871 TI - Immune dysfunctionality of replicative senescent mesenchymal stromal cells is corrected by IFNgamma priming. AB - Industrial-scale expansion of mesenchymal stromal cells (MSCs) is often used in clinical trials, and the effect of replicative senescence on MSC functionality is of mechanistic interest. Senescent MSCs exhibit cell-cycle arrest, cellular hypertrophy, and express the senescent marker beta-galactosidase. Although both fit and senescent MSCs display intact lung-homing properties in vivo, senescent MSCs acquire a significant defect in inhibiting T-cell proliferation and cytokine secretion in vitro. IFNgamma does not upregulate HLA-DR on senescent MSCs, whereas its silencing did not reverse fit MSCs' immunosuppressive properties. Secretome analysis of MSC and activated peripheral blood mononuclear cell coculture demonstrate that senescent MSCs are significantly defective in up (vascular endothelial growth factor [VEGF], granulocyte colony-stimulating factor [GCSF], CXCL10, CCL2) or down (IL-1ra, IFNgamma, IL-2r, CCL4, tumor necrosis factor-alpha, IL-5) regulating cytokines/chemokines. Unlike indoleamine 2,3 dioxygenase (IDO), silencing of CXCL9, CXCL10, CXCL11, GCSF, CCL2, and exogenous addition of VEGF, fibroblast growth factor-basic do not modulate MSCs' immunosuppressive properties. Kynurenine levels were downregulated in senescent MSC cocultures compared with fit MSC counterparts, and exogenous addition of kynurenine inhibits T-cell proliferation in the presence of senescent MSCs. IFNgamma prelicensing activated several immunomodulatory genes including IDO in fit and senescent MSCs at comparable levels and significantly enhanced senescent MSCs' immunosuppressive effect on T-cell proliferation. Our results define immune functional defects acquired by senescent MSCs, which are reversible by IFNgamma prelicensing. PMID- 28713873 TI - Wireless Strain Measurement with a Micromachined Magnetoelastic Resonator Using Ringdown Frequency Locking. AB - Resonant magnetoelastic devices are widely used as anti-theft tags and are also being investigated for a range of sensing applications. The vast majority of magnetoelastic devices are operated at resonance, and rely upon an external interface to wirelessly detect the resonant frequency, and other characteristics. For micromachined devices, this detection method must accommodate diminished signal strength and elevated resonant frequencies. Feedthrough of the interrogating stimulus to the detector also presents a significant challenge. This paper describes a method of interrogating wireless magnetoelastic strain sensors using a new frequency-lock approach. Following a brief excitation pulse, the sensor ring-down is analyzed and a feedback loop is used to match the excitation frequency and the resonant frequency. Data acquisition hardware is used in conjunction with custom software to implement the frequency-lock loop. Advantages of the method include temporal isolation of interrogating stimulus from the sensor response and near real-time tracking of resonant frequencies. The method was investigated using a family of wireless strain sensors with resonant frequencies ranging from 120 to 240 kHz. Strain levels extending to 3.5 mstrain and sensitivities up to 14300 ppm/mstrain were measured with response times faster than 0.5 s. The standard deviation of the locked frequency did not exceed 0.1%. PMID- 28713872 TI - Systems Medicine-Complexity Within, Simplicity Without. AB - This paper presents a brief history of Systems Theory, progresses to Systems Biology, and its relation to the more traditional investigative method of reductionism. The emergence of Systems Medicine represents the application of Systems Biology to disease and clinical issues. The challenges faced by this transition from Systems Biology to Systems Medicine are explained; the requirements of physicians at the bedside, caring for patients, as well as the place of human-human interaction and the needs of the patients are addressed. An organ-focused transition to Systems Medicine, rather than a genomic-, molecular-, or cell-based effort is emphasized. Organ focus represents a middle-out approach to ease this transition and to maximize the benefits of scientific discovery and clinical application. This method manages the perceptions of time and space, the massive amounts of human- and patient-related data, and the ensuing complexity of information. PMID- 28713875 TI - Live animals for preclinical medical student surgical training. AB - AIMS: The use of live animals for surgical training is a well-known, deliberated topic. However, medical students who use live animals rate the experience high not only in improving their surgical techniques, but also positively influencing their confidence levels in the operating room later in their careers. Therefore, we hypothesized that the use of live animal models is a unique and influential component of preclinical medical education. MATERIALS AND METHODS: Medical student performed the following surgical procedures using mice; surgical orthotopic implantation of cancer cells into fat pad and subsequently a radical mastectomy. The improvement of skill was then analyzed. RESULTS: All cancer cell inoculations were performed successfully. Improvement of surgical skills during the radical mastectomy procedure was documented in all parameters. All wounds healed without breakdown or dehiscence. The appropriate interval between interrupted sutures was ascertained after fifth wound closure. The speed of interrupted sutures was doubled by last wound closure. The time required to complete a radical mastectomy decreased by almost half. A single animal died immediately following the operation due to inappropriate anesthesia, which was attributed to the lack of understanding of the overall operative management. CONCLUSION: Surgical training using live animals for preclinical medical students provides a unique learning experience, not only in improving surgical skills but also and arguably most importantly, to introduce the student to the complexities of the perioperative environment in a way that most closely resembles the stress and responsibility that the operating room demands. PMID- 28713874 TI - Gender Differences in Non-Toxigenic Clostridium difficile Colonization and Risk of Subsequent C. difficile Infection. AB - OBJECTIVES: Previous studies suggest that colonization with non-toxigenic Clostridium difficile may protect against toxigenic C. difficile infection (CDI), yet most of the studies were conducted in men. Therefore, we conducted a study to examine this hypothesis in both genders. METHODS: Patients (n=1492) were classified by disease status at baseline and observed for 1 year. Cox proportional hazards regression was used to evaluate CDI rates within 8 weeks post-baseline (short-term) and from 8 weeks to 1 year (long-term follow-up). RESULTS: During short-term follow-up, CDI rates were 5 times greater in females with non-toxigenic Clostridium difficile compared to females without C. difficile (hazard ratio (HR) = 5.13; 95% CI: 1.47-17.83). The comparable HR in males was 0.44 (95% CI: 0.04-4.43). During long term follow-up, CDI rates were similar in those with non-toxigenic C. difficile and those without C. difficile at baseline, for both females and males. Mortality rates were significantly lower for patients colonized by non-toxigenic C. difficile than those with toxigenic C. difficile at baseline, for both genders combined (HR=0.51; 95% CI: 0.28-0.92) and were similar to those with no C. difficile at baseline (HR=0.78; 95% CI: 0.43-1.41). CONCLUSIONS: There were gender differences in the short-term risk of CDI. Mortality was similar for patients colonized with non-toxigenic C. difficile and patients without C. difficile. PMID- 28713876 TI - Detecting Changes in Suicide Content Manifested in Social Media Following Celebrity Suicides. AB - The Werther effect describes the increased rate of completed or attempted suicides following the depiction of an individual's suicide in the media, typically a celebrity. We present findings on the prevalence of this effect in an online platform: r/SuicideWatch on Reddit. We examine both the posting activity and post content after the death of ten high-profile suicides. Posting activity increases following reports of celebrity suicides, and post content exhibits considerable changes that indicate increased suicidal ideation. Specifically, we observe that post-celebrity suicide content is more likely to be inward focused, manifest decreased social concerns, and laden with greater anxiety, anger, and negative emotion. Topic model analysis further reveals content in this period to switch to a more derogatory tone that bears evidence of self-harm and suicidal tendencies. We discuss the implications of our findings in enabling better community support to psychologically vulnerable populations, and the potential of building suicide prevention interventions following high-profile suicides. PMID- 28713877 TI - The Impact of Limited Housing Opportunities on Formerly Incarcerated People in the Context of Addiction Recovery. AB - BACKGROUND: Formerly incarcerated individuals with substance use disorders encounter numerous obstacles following incarceration that threaten their sobriety. Obtaining safe and stable housing is a notoriously difficult task resulting in precarious housing that can increase the likelihood of relapse. The current study examined the relationship between substance use and 11 housing settings in a sample of 211 formerly incarcerated individuals with a history of substance abuse to identify the housing characteristics with the highest risk of use. METHODS: Participants retroactively reported their alcohol and illicit drug consumption as well as their dwelling for the past 180 days using the Timeline Follow-back method. Housing settings were collapsed into four conceptually distinct categories: Regulated, Independent, Precarious, and Homeless. FINDINGS: Results showed differences in alcohol and drug consumption across categories, with Regulated settings having less alcohol and substance use reported. The remaining settings with less oversight had a similar percentage of individuals endorse substance use; however, the Precarious setting was associated with the highest consumption of drug use. CONCLUSION: Formerly incarcerated individuals with a history of substance use problems would likely benefit from housing with some degree of oversight and financial obligation. More resources should be funnelled into programs to help formerly incarcerated individuals with substance use disorders find housing that will facilitate abstinence during community re entry. PMID- 28713878 TI - Access to Medical Care for Individuals with Myalgic Encephalomyelitis and Chronic Fatigue Syndrome: A Call for Centers of Excellence. AB - The current study sought to better understand the experience of individuals with myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS) in accessing care for their debilitating illness. Of 898 participants, less than half had ever seen an ME or CFS specialist, though 99% of participants were interested in specialist care. Participants cited geographic and financial barriers as most frequently precluding access to specialists. Furthermore, satisfaction with specialist care greatly exceeded satisfaction with non-specialist care. These findings suggested that individuals with ME and CFS represent a medically underserved population, due to lack of available care. The CFS Advisory Committee and NIH Pathways to Prevention Working Group recommended the creation of ME and CFS Centers of Excellence to improve the healthcare access of patients with ME and CFS. The current study documents the need for these centers, as they would ameliorate geographic and financial barriers to quality care. PMID- 28713879 TI - Examining those Meeting IOM Criteria Versus IOM Plus Fibromyalgia. AB - The Institute of Medicine (IOM) recently developed clinical criteria for chronic fatigue syndrome (CFS). There might be additional criteria that could select a more homogenous and impaired group of patients, particularly those with pain. The current study focused on criteria which involved meeting the four IOM criteria, excluding medical and psychiatric co-morbidities, along with having fibromyalgia (FM). Findings indicated that those meeting the IOM clinical criteria plus FM were more impaired on a wide variety of symptoms and functional areas than those meeting on the IOM criteria or those with just 6 months of fatigue. The implications of using such research criteria are discussed. PMID- 28713880 TI - Finding Street Gang Members on Twitter. AB - Most street gang members use Twitter to intimidate others, to present outrageous images and statements to the world, and to share recent illegal activities. Their tweets may thus be useful to law enforcement agencies to discover clues about recent crimes or to anticipate ones that may occur. Finding these posts, however, requires a method to discover gang member Twitter profiles. This is a challenging task since gang members represent a very small population of the 320 million Twitter users. This paper studies the problem of automatically finding gang members on Twitter. It outlines a process to curate one of the largest sets of verifiable gang member profiles that have ever been studied. A review of these profiles establishes differences in the language, images, YouTube links, and emojis gang members use compared to the rest of the Twitter population. Features from this review are used to train a series of supervised classifiers. Our classifier achieves a promising F1 score with a low false positive rate. PMID- 28713881 TI - Drug Delivery and Nanoformulations for the Cardiovascular System. AB - Therapeutic delivery to the cardiovascular system may play an important role in the successful treatment of a variety of disease state, including atherosclerosis, ischemic-reperfusion injury and other types of microvascular diseases including hypertension. In this review we evaluate the different options available for the development of suitable delivery systems that include the delivery of small organic compounds [adenosin A2A receptor agonist (CGS 21680), CYP-epoxygenases inhibitor (N-(methylsulfonyl)-2-(2-propynyloxy) benzenehexanamide, trans-4-[4-(3-adamantan-1-ylureido)cyclohexyloxy] benzoic acid), soluble epoxide hydrolase inhibitor (N-methylsulfonyl-12,12-dibromododec 11-enamide), PPARgamma agonist (rosiglitazone) and PPARgamma antagonist (T0070907)], nanoparticles, peptides, and siRNA to the cardiovascular system. Effective formulations of nanoproducts have significant potential to overcome physiological barriers and improve therapeutic outcomes in patients. As per the literature covering targeted delivery to the cardiovascular system, we found that this area is still at infancy stage, as compare to the more mature fields of tumor cancer or brain delivery (e.g. blood-brain barrier permeability) with fewer publications focused on the targeted drug delivery technologies. Additionally, we show how pharmacology needs to be well understood when considering the cardiovascular system. Therefore, we discussed in this review various receptors agonists, antagonists, activators and inhibitors which will have effects on cardiovascular system. PMID- 28713883 TI - Spectroscopic and reactivity differences in metal complexes derived from sulfur containing Triphos homologs. AB - Herein, we report a simplified method for the synthesis of Triphos homologs H3CC(CH2X)n(CH2Y)3-n (X = SPh, Y = PPh2, n = 0-3). The multidentate compounds were tested for their potential to coordinate metals such as Ni, Fe, and Mo under the same experimental conditions. Cyclic voltammetry, spectroelectrochemical IR investigations as well as DFT calculations were used to examine the electronic alterations in a series of [{H3CC(CH2X)n(CH2Y)3-n}Mo(CO)3] complexes and to evaluate their potential to open coordination sites or to release CO upon oxidation or in the presence of different solvents. In addition, we demonstrate that the catalytic hydrosilylation of N,N-dimethylbenzamide to N,N dimethylbenzylamine is influenced by the applied tripodal ligand. Our investigations show the high potential of such manipulations to selectively alter the dynamics of the binding properties of Triphos-metal complexes and their reactivity. PMID- 28713882 TI - Evaluating a De-Centralized Regional Delivery System for Breast Cancer Screening and Patient Navigation for the Rural Underserved. AB - : Providing breast cancer screening services in rural areas is challenging due to the fractured nature of healthcare delivery systems and complex reimbursement mechanisms that create barriers to access for the under- and uninsured. Interventions that reduce structural barriers to mammography, like patient navigation programs, are effective and recommended, especially for minority and underserved women. Although the literature on rural healthcare is significant, the field lacks studies of adaptive service delivery models and rigorous evaluation of evidence-based programs that facilitate routine screening and appropriate follow-up across large geographic areas. OBJECTIVES: To better understand how to implement a decentralized regional delivery "hub & spoke" model for rural breast cancer screening and patient navigation, we have designed a rigorous, structured, multi-level and mixed-methods evaluation based on Glasgow's RE-AIM model (Reach, Effectiveness, Adoption, Implementation, and Maintenance). METHODS AND DESIGN: The program is comprised of three core components: 1) Outreach to underserved women by partnering with county organizations; 2) Navigation to guide patients through screening and appropriate follow-up; and 3) Centralized Reimbursement to coordinate funding for screening services through a central contract with Medicaid Breast and Cervical Cancer Services (BCCS). Using Glasgow's RE-AIM model, we will: 1) assess which counties have the resources and capacity to implement outreach and/or navigation components, 2) train partners in each county on how to implement components, and 3) monitor process and outcome measures in each county at regular intervals, providing booster training when needed. DISCUSSION: This evaluation strategy will elucidate how the heterogeneity of rural county infrastructure impacts decentralized service delivery as a navigation program expands. In addition to increasing breast cancer screening access, our model improves and maintains time to diagnostic resolution and facilitates timely referral to local cancer treatment services. We offer this evaluation approach as an exemplar for scientific methods to evaluate the translation of evidence-based federal policy into sustainable health services delivery in a rural setting. PMID- 28713885 TI - Synergistic effect of Au-Ag nano-alloying: intense SEIRA and enhanced catalysis. AB - The well-known AuAg nanohybrid system was effectively synthesized, utilizing polyvinyl pyrrolidone (PVP) as a multiple metal precursor reducing agent (based solely on their reduction potentials), thereby drastically decreasing their activation energy of diffusion and readily facilitating the homogenous alloy nanoparticle formation, duly confirmed by Vegard's law. Furthermore, the crucial parameters in determining the local electric field enhancement in the vicinity of the alloy nanoparticles such as the quality factor Q, dephasing time, T2 and the homogenous line width Gamma were also evaluated in a systematic manner, in correlation with their unique visible optical absorption spectra. Optical band gap calculations of this robust AuAg/PVP nanocomposite system demonstrate the formation of trap levels between the HOMO and LUMO energy states with increasing Urbach's energy for decreasing Au content. The surface enhanced infrared (SEIRA) measurements with the analyte bromophenol, not only highlight the differential metal-PVP-analyte binding, but also corroborate the optical constants of the nanohybrids. Moreover, the catalytic conversion of 4-nitro-aniline (4-NA) to p phenylenediamine (p-PDA) in the presence of AuAg nanohybrids visibly distinguishes their excellent stability and reproducibility along with their moderate rate constant in direct contrast to the poor recycling ability of their individual metal counterparts. PMID- 28713884 TI - Antimicrobial activity of organometallic isonicotinyl and pyrazinyl ferrocenyl derived complexes. AB - Isonicotinyl and pyrazinyl ferrocenyl-derived complexes were prepared using various hydrazides and ferrocenyl aldehydes. Three heterobimetallic complexes were also synthesized from the Schiff base-derived isonicotinyl ferrocene complex using various platinum group metal dimers based on ruthenium, rhodium and iridium. All complexes were evaluated in vitro for antimycobacterial and antiparasitic activity. Against Mycobacterium tuberculosis H37Rv, the platinum group metal complexes showed glycerol-dependent antimycobacterial activity. The antiplasmodial activities against the NF54 chloroquine-sensitive strain of Plasmodium falciparum of some compounds were moderate, while some complexes also showed promising activity against Trichomonas vaginalis. Incorporation of the ferrocenyl-salicylaldimine moiety resulted in enhanced antimicrobial activity compared to the non-ferrocenyl compound in some cases. The bimetallic iridium ferrocene isonicotinyl complex exhibited superior antitrichomonal activity relative to its organic counterpart, isoniazid. Furthermore, all these compounds, when screened on several normal flora bacteria of humans, showed no effect on the microbiome, emphasizing the selection of these compounds for these pathogens. The promising antimicrobial activities of the complexes thus supports incorporation of ferrocene as part of existing antimicrobial therapies in order to alter their biological activities favorably. PMID- 28713886 TI - A new tetrapodal 3-hydroxy-4-pyridinone ligand for complexation of 89zirconium for positron emission tomography (PET) imaging. AB - Zirconium-89 (89Zr) is an ideal radiometal isotope for antibody-based positron emission tomography (immunoPET) as its physical half-life (3.27 days) is a good match with the biological half-life of larger molecular weight targeting molecules, such as antibodies (3-4 days), and its positron emission (BR = 100% EC/beta+, Ebeta+,avg = 395.5 keV) is suited for high resolution PET imaging. Concerns over the in vivo stability of the most commonly used 89Zr-chelator, desferrioxamine B (DFO), have spurred efforts into the development of alternative 89Zr-chelators that withstand the release of osteophilic 89Zr4+. Herein we report the new chelator 1,3-propanediamine-N,N,N',N'-tetrakis[(2-(aminomethyl)-3-hydroxy 1,6-dimethyl-4(1H)-pyridinone)acetamide] (THPN) based on four 3-hydroxy-4 pyridinone (3,4-HOPO) coordinating groups, as a potentially superior chelator over DFO. THPN has been demonstrated to quantitatively form a monometallic complex with Zr4+ within 10 min at ambient temperature at as low as 10-6 M concentrations of the chelator. The resulting complexes were studied in vitro and in vivo. The 89Zr-THPN complex was stable in serum and outperformed the 89Zr-DFO complex in a direct transchelation challenge. Healthy mice excreted 89Zr-THPN rapidly without signs of demetalation or residual organ uptake. This renders THPN as a promising alternative to DFO and introduces the first octadentate 3,4-HOPO chelator to the field. PMID- 28713887 TI - Morphology dependent catalysis and surface enhanced Raman scattering (SERS) studies using Pd nanostructures in DNA, CTAB and PVA scaffolds. AB - Palladium nanoparticles (Pd NPs) of three different morphologies viz., nanocubes with cetyltrimethylammonium bromide (CTAB), nanowires with polyvinyl alcohol (PVA) and Pd NPs with deoxyribonucleic acid (DNA) scaffolds were synthesized by UV-irradiation. Catalysis and surface enhanced Raman scattering (SERS) studies were done with the synthesized morphologically distinct Pd nanostructures for the very first time. The catalytic rate was extremely high with Pd nanowires templated with PVA and the order of the catalytic rate was Pd nanowires in PVA > Pd nanocubes in CTAB > DNA-Pd wire-like assemblies. The highest catalytic rate was observed for PVA capped Pd nanowires which is a few hundred fold higher than other metal NP catalysts. Methylene blue (MB) was used as a Raman analyte for the SERS study and the largest EF of 1.9 * 105 at a peak position of 1391 cm-1 was observed with Pd nanowires in the DNA scaffold as a SERS substrate. The order of the SERS EF values was DNA-Pd wire-like assemblies > Pd nanocubes in CTAB > Pd nanowires in PVA. Beyond everything, the present synthesis route is easy, faster, candid, highly reproducible and cost-effective. In the near future, the same protocol could be applied to synthesize other materials for various applications. PMID- 28713888 TI - A road map for multi-way calibration models. AB - A large number of experimental applications of multi-way calibration are known, and a variety of chemometric models are available for the processing of multi-way data. While the main focus has been directed towards three-way data, due to the availability of various instrumental matrix measurements, a growing number of reports are being produced on order signals of increasing complexity. The purpose of this review is to present a general scheme for selecting the appropriate data processing model, according to the properties exhibited by the multi-way data. In spite of the complexity of the multi-way instrumental measurements, simple criteria can be proposed for model selection, based on the presence and number of the so-called multi-linearity breaking modes (instrumental modes that break the low-rank multi-linearity of the multi-way arrays), and also on the existence of mutually dependent instrumental modes. Recent literature reports on multi-way calibration are reviewed, with emphasis on the models that were selected for data processing. PMID- 28713889 TI - TFE3 regulates renal adenocarcinoma cell proliferation via activation of the mTOR pathway. AB - The present study aimed to investigate the role of transcription factor E3 (TFE3) in the regulation of proliferation in renal adenocarcinoma cells. The LV-TFE3 overexpression (OE) lentivirus and negative control CON195 (NC) lentivirus were transfected into the ACHN cell line. Protein expression of FLAG-tag TFE3 was determined using western blot analysis. Differences in cell proliferation, plate clone formation and cell cycle distribution between OE and NC groups were compared using MTT, plate colony formation and flow cytometry assays, respectively. The levels of mammalian target of rapamycin (mTOR) and phosphorylated ribosomal protein S6 (p-rpS6) were analyzed by western blotting. Cell proliferation and colony formation increased significantly in the OE group compared with the NC group. The % of cells in the G1 and G2 phases of the cell cycle decreased, while the % of cells in the S phase of the cell cycle increased in the OE group compared with the NC group. In addition, mTOR and p-rpS6 levels were increased in the OE group compared with the NC group. The results of the present study demonstrated that TFE3 overexpression resulted in increased ACHN cell proliferation and plate clone formation. TFE3 may promote renal tumor growth by regulating cell cycle progression and activating the phosphatidylinositol 3 kinase/AKT serine/threonine kinase 1/mTOR signaling pathway. PMID- 28713890 TI - HO-1 alleviates cholesterol-induced oxidative stress through activation of Nrf2/ERK and inhibition of PI3K/AKT pathways in endothelial cells. AB - Heme oxygenase-1 (HO-1), as an inducible and cytoprotective enzyme, has a protective effect against cellular oxidative stress. In the present study, cholesterol was used to induce lipid overload and increase reactive oxygen species (ROS), leading to oxidative stress in EA.hy926 cells. In the present study, western blotting and immunofluorescence analysis were used to detect the expression level of important molecules in the metabolism process of cholesterol. It was confirmed that cholesterol stimulation upregulated the expression of HO-1 in a time-dependent manner via the activation and translocation of nuclear factor erythroid 2-related factor 2 (Nrf2), activation of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling pathway and increasing intercellular Ca2+ ([Ca2+]i) concentration. The results showed that increasing the expression of HO-1 decreased activation of the phosphoinositide 3 kinase (PI3K)/AKT signaling pathway and inhibited the expression of c-Myc. It was confirmed that cholesterol-mediated oxidative damage in vascular endothelial cells induced an increase in the expression of HO-1 via the activation of Nrf2 and the MAPK/ERK signaling pathway, and increasing the [Ca2+]i concentration. The overexpression of HO-1 alleviated oxidative damage through inhibition of the PI3K/AKT signaling pathway and downregulation of the expression of c-Myc. PMID- 28713891 TI - Hypothermia exerts early neuroprotective effects involving protein conjugation of SUMO-2/3 in a rat model of middle cerebral artery occlusion. AB - How hypothermia serves an early protective role against cerebral ischemia remains to be determined. The small ubiquitin-related modifier protein (SUMO) functions as a post-translational modification system and SUMO-2/3 subtypes are often activated in early stress. The present study investigated changes in the protein level of SUMO using western blotting and immunocytochemistry when neurons were exposed to oxygen-glucose deprivation (OGD) in vitro, as well as in a rat model of middle cerebral artery occlusion (MCAO) in vivo. The results demonstrated that a large number of proteins were conjugated to SUMO-2/3 in OGD-injured neurons (within 10 min, peaking at 12 h), and was markedly enhanced under conditions of hypothermia (33C). Concordantly, lactate dehydrogenase (LDH) release and the apoptosis rate, as determined by LDH and TUNEL assays, respectively, were lower in hypothermia-treated neurons. Similar results were obtained in a rat model of MCAO. Neurological deficit scores were lower in the hypothermia group than in the sham group in the early stage of cerebral ischemia (P<0.05). However, no significant differences in neurological deficit scores were detected between the hypothermia group and the sham group in the late stage of ischemia (21 days; P>0.05). This study implicates a role for SUMO-2/3 in early hypothermia-induced neuroprotection against stroke. The development of small molecule therapeutics based on SUMO-2/3 may benefit patients with cerebral ischemia. PMID- 28713892 TI - Trichostatin A induces bladder cancer cell death via intrinsic apoptosis at the early phase and Sp1-survivin downregulation at the late phase of treatment. AB - Histone deacetylase (HDAC) inhibitors have been widely shown to result in cancer cell death. The present study investigated the mechanisms underlying the antitumor effects of the phytochemical trichostatin A (TSA), a classic pan-HDAC inhibitor, in 5,637 urinary bladder cancer cells. It was found that TSA caused cell cycle arrest at the G2/M and G1 phase accompanied by reduced expression of cyclin D1 and upregulated induction of p21. In addition, TSA induced morphological changes, reduced cell viability and apoptotic cell death in 5,637 cells through caspase-3 activation followed by PARP cleavage. The loss of mitochondrial membrane potential (MMP) indicated that TSA induced apoptosis in 5,637 cells through the intrinsic mitochondrial pathway. TSA significantly suppressed Akt activity at 12 h after treatment, suggesting that the apoptosis in the early phase was mediated by Akt inhibition. In addition, the protein level of transcription factor Sp1 was decreased at 24 h after TSA treatment, which likely led to the downregulation of survivin gene expression, and then contributed to the antitumor activity of TSA. Taken together, the present study delineated that TSA-induced growth inhibition and apoptosis in 5,637 cells was associated with pAKT inhibition and MMP loss at the early phase, followed by downregulation of Sp1 and survivin at the late phase of treatment. PMID- 28713893 TI - Interleukin-6 RNA knockdown ameliorates acute lung injury induced by intestinal ischemia reperfusion in rats by upregulating interleukin-10 expression. AB - Acute lung injury (ALI) is a common complication following intestinal ischemia/reperfusion (II/R) injury and contributes to the associated high mortality rate. However, the underlying mechanism is poorly understood and treatments are limited. RNA interference (RNAi) has been demonstrated to provide a promising disease treatment strategy both in vitro and in vivo. Therefore, the present study aimed to test whether blocking the proinflammatory cytokine IL-6 by RNAi may protect the lungs from remote organ injury following II/R, and to investigate the potential underlying mechanisms. A total of 176 adult healthy male Sprague-Dawley rats were randomly divided into sham, II/R, negative-control and IL-6-short hairpin (sh)RNA groups. The rats underwent II/R injury with occlusion of the superior mesenteric artery and coeliac artery to induce ischemia for 40 min, and were subsequently reperfused for 0-48 h. The negative-control group received a control lentiviral vector containing scrambled or non-specific sequences, and the IL-6-shRNA groups were administered with a vector containing an IL-6 shRNA sequence to affect RNAi-mediated knockdown of IL-6. ALI severity was determined by lung edema (lung wet/dry ratio) and histological analysis (lung injury scores). IL-6 localization, and mRNA and protein expression levels, were detected by immunofluorescence, reverse transcription-quantitative polymerase chain reaction and western blot analysis, respectively. IL-10 expression induced by IL-6 knockdown in lung tissues was additionally detected. IL-6 RNAi was revealed to significantly reduce the expression of IL-6, which was associated with upregulated IL-10 expression in lung tissues. Consequently, the severities of ALI and edema induced by II/R were substantially improved. In conclusion, the present study demonstrated that IL-6 RNAi may protect the lung from ALI induced by II/R, and that this protective role may be associated with upregulation of IL 10. These findings may contribute to the development of an IL-6-RNAi-based therapeutic strategy for the treatment of II/R-induced ALI. PMID- 28713894 TI - Identification of a compound heterozygous mutation of ABCC2 in a patient with hyperbilirubinemia. AB - Bilirubin is the end product of heme catabolism, which is produced primarily from the breakdown of erythrocyte hemoglobin in the reticuloendothelial system. Hyperbilirubinemia is induced not only by increased bilirubin synthesis, but can also be caused by decreased bilirubin clearance. There are several disorders, which can contribute to hyperbilirubinemia, including Dubin-Johnson syndrome (DJS). DJS is a rare autosomal recessive disorder, which is characterized by predominantly conjugated hyperbilirubinemia without progression to end-stage liver disease. Previous studies have demonstrated that defects in multidrug resistance proteins ATP-binding cassette C2 (ABCC2)/multidrug resistance associated protein 2 (MRP2) contribute to DJS. In the present study, a case of a patient with hyperbilirubinemia was examined and identified a compound heterozygous mutation in the ABCC2 gene (p.T435P and W442X). These were predicted to be deleterious by three bioinformatics programs (Polymorphism Phenotyping-2, Sorting Intolerant From Tolerant and MutationTaster). These finding expand on the spectrum of ABCC2 mutations and provide additional evidence that ABCC2 is key in the development of DJS. PMID- 28713895 TI - Role of quercetin in protecting ARPE-19 cells against H2O2-induced injury via nuclear factor erythroid 2 like 2 pathway activation and endoplasmic reticulum stress inhibition. AB - Age-related macular degeneration (AMD) is a common cause of irreversible blindness in the elderly in the western world. Research has demonstrated that degenerative and progressive conditions of retinal pigmented epithelial (RPE) cells are the key pathogenic mechanisms in AMD. Previous research has indicated the anti-apoptosis, anti-oxidant, anti-inflammatory and anti-cancer properties of quercetin. Therefore, the present study aimed to investigate the protective effects of quercetin on the ARPE-19 human retinal pigment epithelial cell line. ARPE-19 cells were pretreated with various concentrations of quercetin (0-80 uM) before exposure to 300 uM H2O2. Cell viability was assessed and reactive oxygen species (ROS) were determined. The importance of the NF-E2-related factor 2 (Nrf2) signaling pathway was corroborated by western blotting and immunostaining. The protein expression levels of endoplasmic reticulum-associated stress responsive genes and apoptotic markers were assessed by western blotting. The results demonstrated that in the H2O2 group, cell viability was weakened, but preserved in quercetin group in a dose-dependent manner, particularly at 20 uM. The level of ROS decreased in the quercetin group compared with the control groups. In the quercetin group, the expression levels of Nrf2 and phase II enzymes (NQO1 and HO-1) were increased, whereas the levels of ER stress markers (binding of immunoglobulin protein, CCAAT/enhancer-binding protein homologous protein and phosphorylated eukaryotic translation initiation factor 2alpha) were reduced. Cell apoptosis-associated protein expression levels were altered, with the increase of B-cell lymphoma 2 and reduction of Bcl-2 X-associated protein. In conclusion, quercetin protected ARPE-19 cells from H2O2-induced cytotoxicity by activating the Nrf2 pathway, inhibiting ER stress and targeting anti-apoptotic proteins. PMID- 28713896 TI - An optimized gene transfection system in WERI-Rb1 cells. AB - The pathogenesis of Rb1 gene inactivation indicates that gene therapy could be a promising treatment for retinoblastoma. An appropriate gene transfer system is the basis for successful gene therapy; however, little attention has been given to an effective gene transfer system for retinoblastoma therapy in previous studies. This study was designed to provide an optimized transgene system for WERI-Rb1 cells (W-RBCs). Green fluorescent protein (GFP) was adopted as a reporter. Four classic viral vectors based on retroviruses, recombinant adeno associated viruses (rAAV2, rAAV2/1), lentiviruses (LVs) and a novel non-viral vector X-treme HP reagent were adopted for W-RBC gene transfection. The efficacy and cytotoxicity were comprehensively compared among the different vectors through GFP expression and the trypan blue exclusion test. Furthermore, the serum and cell culture status were also optimized for better transfection. Cells transfected by rAAV2/1 expressed more GFP protein and exhibited less staining with trypan blue, compared to the rAAV2 counterpart. However, in comparison to the retroviral group, both the rAAV2/1 and LV groups had considerably less GFP+ cells. Interestingly, the X-treme HP presented a similar GFP transfection capacity to the retroviral vector, but with a much lower cytotoxicity. Furthermore, there were more GFP+ cells in a suspended condition than that in an adherent culture. Moreover, cells in a serum-positive system expressed more GFP, while cells in a serum-free system showed lower GFP expression and higher cytotoxicity. In conclusion, the retroviral vector and the X-treme HP are effective for W-RBC gene transfection, while the X-treme HP is more preferable due to its lower cytotoxicity. Moreover, the suspended cell culture system is superior to the adherent system, and the serum protects cell viability and facilitates the gene transfection of W-RBCs. This study presents an effective, convenient, and low toxic transfection system for gene delivery in W-RBCs and provides a promising system for further gene therapy of retinoblastoma. PMID- 28713897 TI - Expression of IRAK-3 is associated with colitis-associated tumorigenesis in mice. AB - Interleukin-1 receptor-associated kinase-3 (IRAK-3) is a negative regulator in Toll-like receptor (TLR) pathways. The present study investigated the importance of IRAK-3 in a mouse model of chemically-induced colitis-associated tumorigenesis. The colitis-associated tumorigenesis was induced in ICR mice by the administration of 1,2-dimethyl hydrazine (DMH) and dextran sodium sulfate (DSS), termed the DMH + DSS group. In the DSS group, mice were administered with DSS; in the DMH group, mice were injected with DMH; in the control group, mice were injected with physiological saline. The clinical signs were examined for 20 weeks; tissue samples were analyzed at week 4, 9, 13 and 20. At week 20, the levels of IRAK-3 were analyzed using immunohistochemistry, western blot analysis, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis, and methylation-specific PCR. At week 20, the DMH + DSS group mice exhibited a decrease in total body weight and had developed canalicular adenoma or adenocarcinoma. The mice in the DSS group and DMH group presented with significant colitis at week 20. The mice with colitis-associated tumorigenesis were found to have decreased levels of IRAK-3, compared with the mice in the other groups, as evidenced by the results of the immunohistochemistry (P=0.002), RT-qPCR analysis (P<0.001) and western blot analysis (P<0.001). IRAK-3 methylation was observed in all experimental groups. Taken together, DMH + DSS induction in colitis led to increased inflammation and risk of tumorigenesis. IRAK-3 methylation may be a predictive factor in the transition from colitis to cancer. PMID- 28713898 TI - Identification of potential biomarkers and therapeutic targets for human IgA nephropathy and hypertensive nephropathy by bioinformatics analysis. AB - In order to further elucidate the potential correlations and treatments of IgA nephropathy (IgAN) and hypertensive nephropathy (HT), bioinformatics analysis of IgAN and HT was performed. The mRNA expression profiles of human renal biopsy samples from patients with IgAN, patients with HT and pre-transplant healthy living controls (LD) were downloaded from the Gene Expression Omnibus database. Then, the differentially expressed genes (DEGs) were identified and functions of DEGs were analyzed. Finally, the regulatory networks containing DEGs and related transcription factors (TFs) were constructed using Cytoscape software. When compared with the LD group, 134 and 188 DEGs were obtained in the IgAN and HT groups, respectively. A total of 39 genes were altered in the HT group when compared with the IgAN group. In addition, 66 genes were shared in the IgAN and HT groups when compared with the LD group, 6 of which [early growth response 1, activating transcription factor 3, nuclear receptor subfamily 4 group A member 2 (NR4A2), NR4A1, v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog F and Kruppel like factor 6] were identified as TFs. In addition, DEGs including interleukin (IL) 1 receptor antagonist, collagen type 4 alpha2 chain, IL8, FBJ murine osteosarcoma viral oncogene homolog and somatostatin were enriched in a number of inflammation-associated biological processes, and DEGs including structural maintenance of chromosomes protein 3, v-crk avian sarcoma virus CT10 oncogene homolog and myosin 6 were enriched in non-inflammation-associated biological processes. Therefore, the differentially expressed TF genes and the genes associated with inflammation may be effective as potential therapeutic targets for IgAN and HT. PMID- 28713899 TI - miR-320a serves as a negative regulator in the progression of gastric cancer by targeting RAB14. AB - Gastric cancer (GC) is one of the most common types of malignancy worldwide, with high morbidity and mortality rates. The dysregulation of microRNAs (miRs) has been found to be involved in the carcinogenesis of GC. The present study aimed to investigate the underlying association between GC and miR-320a. Analysis using reverse transcription quantitative polymerase chain reaction indicated that the expression of miR-320a was downregulated and the expression of RAB14 was upregulated in GC tissues and cells, compared with the corresponding controls. MTT, colony formation assays, and flow cytometric analyses were used to evaluate the effect of miR-320a on cell proliferation and the cell cycle. The ectopic expression of miR-320a using miR-320a mimics suppressed cell viability, inhibited G1/S transition, and induced apoptosis in AGS and MKN45 cells. In addition, RAB14 was identified as a direct target gene of miR-320a, according to the results of bioinformatics analysis and a luciferase reporter assay. Downregulation of RAB14 by RAB14-small interfering RNA inhibited the viability of GC cells, which was similar to the phenotype of miR-320a mimics. Furthermore, the reintroduction of RAB14 partially abrogated the miR-320a-mediated downregulation of RAB14 and rescued the miR-320a-induced effects on GC cell growth. These findings suggest a potential novel therapeutic target for the treatment of GC. PMID- 28713900 TI - NLRC5 silencing ameliorates cardiac fibrosis by inhibiting the TGF-beta1/Smad3 signaling pathway. AB - The proliferation of cardiac fibroblasts (CFs) and excessive deposition of extracellular matrix are the predominant pathological characteristics of cardiac fibrosis. As the largest member of the nucleotide-binding domain and leucine-rich repeat (NLR) family, NLRC5 has been shown to be pivotal in the development of hepatic fibrosis. However, whether NLRC5 is involved in the pathogenesis of cardiac fibrosis remains to be elucidated. The present study aimed to investigate the role of NLRC5 and its mechanisms in regulating cardiac fibrosis. CFs were stimulated with transforming growth factor (TGF)-beta1 for various times and the mRNA and protein expression of NLRC5 was assessed using reverse transcription quantitative polymerase chain reaction and western blot analysis, respectively. In addition, CFs were transfected with small interfering (si)RNA targeting NLRC5 or scramble siRNA for 24 h and then stimulated with TGF-beta1 for 24 h. Subsequently, cell proliferation was measured using an MTT assay, whereas cell migration was evaluated using a Transwell migration assay. The protein expression levels of alpha-smooth muscle actin, collagen I, connective tissue growth factor, phosphorylated-Smad3 and Smad3 were measured using western blot analysis. The results demonstrated that NLRC5 was upregulated in TGF-beta1-induced CFs. The knockdown of NLRC5 significantly inhibited cell proliferation and migration, and suppressed myofibroblast differentiation and the expression of pro-fibrotic molecules in TGF-beta1-treated CFs. Furthermore, the knockdown of NLRC5 attenuated TGF-beta1-induced phosphorylation of small mothers against decapentaplegic (Smad)3 in the CFs. The results of the present study indicated that NLRC5 acted as a key regulator of pathological cardiac fibrosis, and NLRC5 silencing ameliorated cardiac fibrosis by inhibiting the TGF-beta1/Smad3 signaling pathway. These results suggested that NLRC5 may be a novel target for attenuating cardiac fibrosis. PMID- 28713901 TI - Protective effects of marrubiin improve endometriosis through suppression of the expression of RANTES. AB - Marrubiin can improve blood and lymph microcirculation disturbance, and has pharmacological effects in myocardial protection, anti-inflammation and anti oxidation. The aim of the present study was to evaluate the protective effects of marrubiin on endometriosis through suppression of the expression of regulated on activation, normal T cell expressed and secreted (RANTES). Endometriotic cells were implanted into the peritoneal cavity of mice, and these mice were injected estradiol benzoate (30 ug/kg) once each day for 14 days. The mice with endometriosis were then treated with 12, 25 or 50 mg/kg marrubiin. Reverse transcription-quantitative polymerase chain reaction was used to assess the mRNA expression of RANTES, and western blot analysis was used to analyze the protein expression of RANTES, TNF-alpha and PGE2. Inflammation factors were measured by ELISA. Treatment with marrubiin effectively improved lesion regression and inhibited toxicity in the mouse model of endometriosis. Marrubiin significantly inhibited endometrial lesions and monocyte chemotaxis in the mice with endometriosis, and reduced U937 cell migration. Calcium mobilization, levels of tumor necrosis factor-alpha and the secretion of RANTES were effectively suppressed by marrubiin treatment. The calcium levels were effectively induced, whereas the protein expression of prostaglandin E2 (PGE2) and formation of thromboxane B2 (TXB2) were effectively inhibited by marrubiin treatment. These findings indicated that the protective effect of marrubiin improved endometriosis in the mice through the suppression of inflammation and downregulation of the expression of RANTES, followed by mediation of the levels of calcium, PGE2 and TXB2. PMID- 28713902 TI - Establishment and characterization of cell lines derived from complete hydatidiform mole. AB - Gestational trophoblastic diseases (GTDs) are a group of diseases characterized by abnormal cellular proliferation of atypical trophoblasts. A hydatidiform mole is an abnormal pregnancy caused by genetic fertilization disorders, and it can be classified as a complete hydatidiform mole (CHM) or a partial hydatidiform mole. The aim of this study was to establish cell lines from CHMs and to characterize the cells for future studies concerning GTD. HMol1-2C, HMol1-3B, HMol1-8 and HMol3-1B were established from primary cultures of CHM explants following the introduction of different combinations of genes including human telomerase reverse transcriptase (hTERT), a mutant form of CDK (CDK4R24C), cyclin D1, p53C234, MYC and HRAS. HMol1-2C, HMol1-3B, and HMol3-1B were confirmed to originate from trophoblasts of androgenic, homozygous CHMs. These three cell lines exhibited low human chorionic gonadotropin secretion, low migration and invasion abilities, and the potential to differentiate into syncytiotrophoblastic cells via forskolin treatment. These results suggest that these cells exhibit characteristics of trophoblastic cells, especially cytotrophoblastic cells. HMol1 8 was found to consist of diploid cells and originated from maternal cells, suggesting that they were derived from decidual cells. In conclusion, we successfully established three cell lines from CHMs by introduction of hTERT and other genes. Analysis revealed that the genetic origin of each cell line was identical with that of the original molar tissue, and the cell lines exhibited characteristics of trophoblastic cells, which are similar to undifferentiated cytotrophoblasts. PMID- 28713903 TI - Hsp90 inhibitor induces KG-1a cell differentiation and apoptosis via Akt/NF kappaB signaling. AB - Heat-shock protein 90 (Hsp 90) acts as a molecular chaperone that maintains protein stability and regulates cell proliferation, survival, differentiation and apoptosis. The present study investigated the effect of Hsp90 inhibition on human acute myeloid leukemia (AML) cells using the novel small-molecule inhibitor SNX 2112. We found that SNX-2112 more potently inhibited KG-1a cell growth than the classical Hsp90 inhibitor 17-(2-dimethylaminoethyl)amino-17-demethoxygeldanamycin as determined by CCK-8 assay. Flow cytometry was used to examine the cell cycle, differentiation, and apoptosis, and western blotting and qRT-PCR were used to analyze the underlying mechanism. The results revealed that low concentrations of SNX-2112 arrested the cells in the G2/M phase and induced their differentiation and apoptosis, possibly by suppressing Akt and inhibitor of kappaB kinase, a component of the nuclear factor (NF)-kappaB signaling pathway. We also found that SNX-2112 increased the expression of the differentiation transcription factors PU.1 and CCAAT-enhancer-binding protein-alpha. Thus, SNX-2112 induced KG-1a cell differentiation, cell cycle arrest and apoptosis via modulation of Akt and NF kappaB signaling, suggesting that it is a promising therapeutic agent for the treatment of AML. PMID- 28713904 TI - Bisphosphonate inhibits the expression of cyclin A2 at the transcriptional level in normal human oral keratinocytes. AB - Nitrogen-containing bisphosphonates (N-BPs) are the most widely used anti resorptive agents in the treatment of bone-related diseases. N-BPs inhibit bone resorption by specifically targeting osteoclasts, bone-resorbing cells. However, soft tissue toxicity, such as oral or gastrointestinal (GI) ulcerations has frequently been reported in N-BP users, suggesting that N-BPs may also directly target cells other than osteoclasts. Previously, we reported that BPs inhibit proliferation without inducing the apoptosis of normal human oral keratinocytes (NHOKs). However, the molecular mechanisms through which N-BPs inhibit the proliferation of NHOKs are not yet fully understood. In this study, we performed gene expression profiling in N-BP-treated NHOKs and identified cyclin A2 as one of the most commonly downregulated genes. When the NHOKs were treated with N-BPs, we found that the level of cyclin A2 was suppressed in a dose- and time-dependent manner. In addition, the protein level of cyclin A2 was also significantly lower in oral epithelial cells in N-BP-treated oral mucosal tissue constructs. Cyclin A2 promoter reporter assay revealed that N-BPs inhibited the luciferase activity, indicating that the inhibition of cyclin A2 expression occurs at the transcriptional level. Furthermore, N-BPs did not alter the expression of cyclin A2 in normal human oral fibroblasts (NHOFs), suggesting that the effect of N-BPs on cyclin A2 expression may be cell-type specific. Thus, the findings of our study demonstrate that the inhibition of NHOK proliferation by N-BPs is mediated, at least in part, by the suppression of cyclin A2 expression at the transcriptional level, which may explain the underlying mechanisms of soft tissue toxicity by N-BPs. PMID- 28713905 TI - Lactobacilli inhibit cervical cancer cell migration in vitro and reduce tumor burden in vivo through upregulation of E-cadherin. AB - The present study was designed to investigate the antitumor effects of Lactobacillus and the potential mechanisms. Cell Counting Kit-8 (CCK-8) assays were carried out to determine suitable doses for investigating the inhibitory effect of lactobacilli on cell migration ability of HeLa and U14 cells in vitro. In addition, western blot assays were performed to investigate the possible mechanisms corresponding to its antitumor effects. Furthermore, a xenograft mouse model was established for investigating the E-cadherin expression in tumor tissues after treatment with lactobacilli. Our results showed that live lactobacilli [multiplicity of infection (MOI) of 1,000:1] significantly possessed inhibitory effects on cell migration ability of cervical cancer cells. Lactobacilli (MOI: 1,000:1) significantly upregulated E-cadherin expressions in HeLa and U14 cells (p<0.05). On the contrary, our results showed that inactivated lactobacilli could not affect the E-cadherin expression levels in HeLa and U14 cells. Similar to the western blot assay, immunohistochemistry results also indicated that lactobacilli treatment significantly upregulated E-cadherin in tumor tissues (p<0.05). In conclusion, our results above suggest that lactobacilli have the potential for inhibiting the migratory ability of cervical cancer cell lines, and the possible pharmacological mechanism may be closely related to the upregulation of E-cadherin. PMID- 28713906 TI - Chronic administration of SUMO-1 has negative effects on novel object recognition memory as well as cell proliferation and neuroblast differentiation in the mouse dentate gyrus. AB - Post-translational modifications have been associated with developmental and aging processes, as well as in the pathogenesis of certain diseases. The present study aimed to investigate the effects of small ubiquitin-like modifier 1 (SUMO 1) on hippocampal dependent memory function, cell proliferation and neuroblast differentiation. To facilitate the delivery of SUMO-1 into hippocampal neurons, a transactivator of transcription (Tat)-SUMO-1 fusion protein was constructed and mice were divided into two groups: A vehicle (Tat peptide)-treated group and a Tat-SUMO-1-treated group. The vehicle or Tat-SUMO-1 was administered intraperitoneally to 7-week-old mice once daily for 3 weeks, and a novel object recognition test was conducted following the final treatment; the animals were sacrificed 2 h following the test for further analysis. Administration of Tat SUMO-1 significantly decreased exploration of a new object in a novel object recognition test compared with mice in the vehicle-treated group. In addition, cell proliferation and neuroblast differentiation analyses (based on Ki67 and doublecortin immunohistochemistry, respectively) revealed that the administration of Tat-SUMO-1 significantly reduced cell proliferation and neuroblast differentiation in the dentate gyrus. These results suggested that chronic supplementation of Tat-SUMO-1 affects hippocampal functions by decreasing cell proliferation and neuroblast differentiation in the mouse dentate gyrus. PMID- 28713907 TI - Roles of miR-4463 in H2O2-induced oxidative stress in human umbilical vein endothelial cells. AB - Oxidative stress is implicated in the pathophysiology of vascular diseases, including atherosclerosis, aneurysm and arteriovenous fistula. A previous study from our lab suggested that microRNA (miR)-4463 may be involved in the pathogenesis of vascular disease; however, the roles of oxidative stress in the molecular mechanisms underlying the actions of miR-4463 in vascular disease have yet to be elucidated. The aim of the present study was to investigate the role of miR-4463 in hydrogen peroxide (H2O2)-induced oxidative stress in human umbilical vein endothelial cells (HUVECs). Reverse transcription-quantitative polymerase chain reaction was used to assess the expression levels of miR-4463 in HUVECs treated with various concentrations of H2O2. Flow cytometry was used to evaluate the percentage of apoptotic cells, and the protein expression levels of the apoptotic markers cleaved (C)-caspase3, poly (adenosine diphosphate-ribose) polymerase 1 (PARP1), B cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (Bax) and X-linked inhibitor of apoptosis protein (XIAP) were determined using western blot analysis. The results demonstrated that the apoptotic rate of HUVECs was increased following treatment with H2O2 in a concentration-dependent manner, and the expression of miR-4463 was also upregulated in a dose-dependent manner. Following transfection with miR-4463 mimics, the levels of malondialdehyde and reactive oxygen species were increased in HUVECs, with a corresponding increase in the apoptotic rate. Furthermore, western blot analysis revealed that the protein expression levels of C-caspase3, PARP1 and Bax were upregulated, whereas the levels of Bcl-2 and XIAP were downregulated. In conclusion, the present findings suggested that the upregulation of miR-4463 may enhance H2O2-induced oxidative stress and promote apoptosis in HUVECs in vitro. PMID- 28713909 TI - Effects of lentiviral vector-mediated shRNA silencing of TGFbeta1 on the expression of Col1a1 in rat hepatic stellate cells. AB - The present study aimed to construct a lentiviral RNA interference (RNAi) vector targeting the transforming growth factor beta1 (TGFbeta1) gene of rats, in order to examine its effect on silencing of the TGFbeta1 gene and on the expression of collagen type 1 alpha1 (Col1a1) in HSC-T6 rat hepatic stellate cells. Three RNAi sites of the TGFbeta1 gene were selected according to its CDs sequence. Three pairs of small interfering RNA (siRNA) of these RNAi sites were synthesized and then transfected into HSC-T6 cells, respectively, to confirm the optimal siRNA sequence via reverse transcription-polymerase chain reaction analysis. Subsequently, shRNA targeting the sequence of the optimal siRNA was designed, synthesized and annealed to form a double-stranded structure. The annealed oligonucleotide fragment was cloned into pGreenPuro plasmids to establish the pGreenPuro/TGFbeta1 shRNA lentiviral vector, which was then transfected into 293T cells, following identification by restriction enzyme digestion and sequencing for the production of lentiviral particles exhibiting high reactivity. These particles were used to infect HSC-T6 cells, following which the expression of GFP in the transfected cells was observed under an inverted microscope. The effects on TGFbeta1 gene silencing and the expression levels of Colla1 were detected at the mRNA and protein levels. The results provided confirmation of the optimal siRNA sequence. Enzyme digestion and sequencing verified successful construction of the pGreenPuro/TGFbeta1 shRNA lentiviral vector. This lentiviral vector effectively silenced the TGFbeta1 gene in the HSC-T6 cells, and inhibited the expression of Col1a1 at the mRNA and protein levels. Taken together, the lentiviral RNAi vector targeting the TGFbeta1 gene of rats was successfully constructed, which effectively silenced the TGFbeta1 gene of the HSC-T6 cells and inhibited the expression of Col1a1. PMID- 28713908 TI - Comparison of gene expression profiles between dental pulp and periodontal ligament tissues in humans. AB - There are anatomical and functional differences between human dental pulp (DP) and periodontal ligament (PDL). However, the molecular biological differences and function of these tissues are poorly understood. In the present study, we employed a cDNA microarray array to screen for differentially expressed genes (DEGs) between human DP and PDL tissues, and used the online software WebGestalt to perform the functional analysis of the DEGs. In addition, the STRING database and KEGG pathway analysis were applied for interaction network and pathway analysis of the DEGs. DP and PDL samples were obtained from permanent premolars (n=16) extracted for orthodontic purposes. The results of the microarray assay were confirmed by RT-qPCR. The DEGs were found to be significantly associated with the extracellular matrix and focal adhesion. A total of 10 genes were selected to confirm the results. The mRNA levels of integrin alpha 4 (ITGA4), integrin alpha 8 (ITGA8), neurexin 1 (NRXN1) and contactin 1 (CNTN1) were significantly higher in the DP than in the PDL tissues. However, the levels of collagen type XI alpha 1 (COL11A1), aggrecan (ACAN), collagen type VI alpha 1 (COL6A1), chondroadherin (CHAD), laminin gamma 2 (LAMC2) and laminin alpha 3 (LAMA3) were higher in the PDL than in the DP samples. The gene expression profiles provide novel insight into the characterization of DP and PDL tissues, and contribute to our understanding of the potential molecular mechanisms of dental tissue mineralization and regeneration. PMID- 28713910 TI - Anti-obesity effects of yellow catfish protein hydrolysate on mice fed a 45% kcal high-fat diet. AB - Obesity contributes to the etiologies of a variety of comorbid conditions, such as type 2 diabetes, hypertension and cardiovascular disease. In the present study, the anti-obesity effects of yellow catfish protein hydrolysate (YPh) were observed in mice fed a 45% kcal high-fat diet (HFD) compared with those of mice treated with simvastatin. The HFD-fed control mice exhibited noticeable increase in body weight, and whole-body and abdominal fat densities, periovarian and abdominal wall-deposited fat pad weight, as well as in the levels of triglycerides (TG), blood total cholesterol (TC), low-density lipoprotein, alanine aminotransferase, aspartate aminotransferase, creatinine, blood urea nitrogen, and in the fecal TG and TC contents. However, they exhibited a decrease in serum high-density lipoprotein levels. In addition, an increase was detected in periovarian and dorsal abdominally deposited fat pad thickness, adipocyte hypertrophy, the number of steatohepatitis regions, hepatocyte hypertrophy and lipid droplet deposition-related renal tubular vacuolation degenerative lesions, along with increased hepatic lipid peroxidation and a deteriorated endogenous antioxidant defense system (glutathione, catalase and superoxide dismutase). However, all the above-mentioned obesity-related complications were dose dependently and significantly inhibited after 84 days of thye consecutive oral administration of 125, 250 and 500 mg/kg YPh. In addition, YPh dose-dependently depleted the liver endogenous antioxidant defense system and inhibited hepatic lipid peroxidation. Overall, the effects of 250 mg/kg YPh on HFD-induced obesity and related complications were similar or more potent than those of 10 mg/kg simvastatin. These results indicate that YPh is a promising new potent medicinal ingredient for possible use in the treatment of obesity and related complications. PMID- 28713911 TI - Glucagon-like peptide-1 analogue liraglutide ameliorates atherogenesis via inhibiting advanced glycation end product-induced receptor for advanced glycosylation end product expression in apolipoprotein-E deficient mice. AB - Glucagon-like peptide-1 (GLP-1) can protect arteriosclerotic lesions in apolipoprotein-E deficient (ApoE-/-) mice. Advanced glycation end products (AGEs)/receptor for advanced glycation end products (RAGE) interaction serves a key role in the development of diabetic vascular complications. The present study examined whether the GLP-1 analogue liraglutide can ameliorate atherogenesis via inhibiting AGEs-induced RAGE expression. Male ApoE-/- mice (age, 10 weeks) were divided into control, GLP-1, AGEs and AGEs+GLP-1 group. All mice were fed a high fat diet. The AGEs and AGEs+GLP-1 groups were treated with intraperitoneal injection of AGEs (30 mg/kg/day). The GLP-1 and AGEs+GLP-1 groups were treated with subcutaneous injections of liraglutide (0.4 mg/kg/day). After 9 weeks, blood was drawn and the aortas were rapidly procured. The serum levels of AGEs, soluble RAGE (sRAGE), stromal cell-derived factor-1alpha (SDF-1alpha), total cholesterol and triacylglycerol were measured. Atherosclerotic plaque area was determined by Sudan IV staining. The mRNA and protein expression levels of RAGE were determined using reverse transcription-quantitative polymerase chain reaction and western blotting, respectively. The results demonstrated that AGEs treatment increased serum AGEs levels, increased the expression of RAGE in the aorta, and aggravated atherosclerotic lesions compared with the control. Liraglutide treatment reduced serum AGEs levels, reduced the expression of RAGE in aorta, and relieved atherosclerotic lesions compared with the control. In conclusion, these data suggested that liraglutide serves an anti-atherosclerotic effect via inhibiting AGEs-induced RAGE expression in ApoE-/- mice. These findings provide novel evidence for the use of GLP-1-type agents for the treatment of diabetic vascular complications. PMID- 28713912 TI - Progesterone suppresses triple-negative breast cancer growth and metastasis to the brain via membrane progesterone receptor alpha. AB - Progesterone plays an important role in mammary epithelial cell proliferation and differentiation. Evidence from experimental and clinical studies indicates that progesterone is a risk factor for breast cancer under certain conditions through binding nuclear progesterone receptor (PR). These mechanisms, however, are not applicable to triple-negative breast cancer (TNBC) due to the lack of PR in these cancers. In this study, we demonstrate that membrane progesterone receptor alpha (mPRalpha) is expressed in TNBC tissues and the expression level of mPRalpha is negatively associated with the TNM stage. We found that progesterone suppressed the growth, migration and invasion of mPRalpha+ human TNBC cells in vitro, which was neither mediated by PR nor by PR membrane component 1 (PGRMCl). Notably, these effects exerted by progesterone were significantly blocked by shRNA specific to mPRalpha. Moreover, the knockdown of mPRalpha expression impaired the inhibitory effects of progesterone on mPRalpha+ tumor growth and metastasis in vivo. These data collectively indicate that progesterone suppresses TNCB growth and metastasis via mPRalpha, which provides evidence of the anti-neoplastic effects of progesterone-mPRalpha pathway in the treatment of human TNBC. PMID- 28713914 TI - Systematic identification of human housekeeping genes possibly useful as references in gene expression studies. AB - The ideal reference, or control, gene for the study of gene expression in a given organism should be expressed at a medium-high level for easy detection, should be expressed at a constant/stable level throughout different cell types and within the same cell type undergoing different treatments, and should maintain these features through as many different tissues of the organism. From a biological point of view, these theoretical requirements of an ideal reference gene appear to be best suited to housekeeping (HK) genes. Recent advancements in the quality and completeness of human expression microarray data and in their statistical analysis may provide new clues toward the quantitative standardization of human gene expression studies in biology and medicine, both cross- and within-tissue. The systematic approach used by the present study is based on the Transcriptome Mapper tool and exploits the automated reassignment of probes to corresponding genes, intra- and inter-sample normalization, elaboration and representation of gene expression values in linear form within an indexed and searchable database with a graphical interface recording quantitative levels of expression, expression variability and cross-tissue width of expression for more than 31,000 transcripts. The present study conducted a meta-analysis of a pool of 646 expression profile data sets from 54 different human tissues and identified actin gamma 1 as the HK gene that best fits the combination of all the traditional criteria to be used as a reference gene for general use; two ribosomal protein genes, RPS18 and RPS27, and one aquaporin gene, POM121 transmembrane nucleporin C, were also identified. The present study provided a list of tissue- and organ specific genes that may be most suited for the following individual tissues/organs: Adipose tissue, bone marrow, brain, heart, kidney, liver, lung, ovary, skeletal muscle and testis; and also provides in these cases a representative, quantitative portrait of the relative, typical gene-expression profile in the form of searchable database tables. PMID- 28713913 TI - Upregulation of long non-coding RNA MALAT-1 confers poor prognosis and influences cell proliferation and apoptosis in acute monocytic leukemia. AB - Metastasis-associated lung adenocarcinoma transcript 1 (MALAT-1), a long non coding RNA, has been documented to be a new prognostic marker and gene regulator in several types of cancer, but its potential involvement in acute myeloid leukemia (AML) remains unclear. This study investigated the expression and functional role of MALAT-1 in AML. MALAT-1 expression was assessed by real-time quantitative PCR. After lentiviral-mediated MALAT-1 knockdown, the proliferation of AML cells was determined by CCK-8 and colony formation assays. Cell cycle progression and apoptosis were evaluated by flow cytometry and the expression of caspase-3, -8 and -9 was assessed by western blot analysis. We found that MALAT-1 expression in patients with acute monocytic leukemia (M5) was significantly increased when compared with that of healthy controls, and the overall survival of M5 patients with high MALAT-1 expression was markedly reduced when compared with the overall survival of patients with low MALAT-1 expression. The analysis of cellular experiments showed that MALAT-1 silencing decreased the proliferation of M5 cells (U-937 and THP-1), inhibited cell cycle progression and increased apoptosis. Taken together, these findings suggest that high MALAT-1 expression is closely associated with poor prognosis in M5 patients and may play a role in leukemia cell proliferation and apoptosis, and may serve as a promising theranostic marker. PMID- 28713915 TI - Concurrent administration of thyroxine and donepezil induces plastic changes in the prefrontal cortex of adult hypothyroid rats. AB - The aim of the present study was to observe the effects of the concurrent administration of thyroxine (T4) and an acetylcholinesterase (AChE) inhibitor, donepezil (DON), on the hypothyroidism-induced ultrastructural changes of the prefrontal cortex (PFC) in adult rats. The acetylcholine (ACh) content and AChE activity was assessed, as well as the expressions of synaptotagmin-1 (syt-1) and SNAP-25 were analyzed in the rats. Adding 0.05% propylthiouracil to rats' drinking water induced a hypothyroid rat model. The animals were treated with T4 and DON administered separately or in combination from the fifth week. Transmission electron microscope analysis revealed that hypothyroidism induced marked ultrastructural changes, including the neurons, the synapses and the myelin sheath in the PFC. T4 or DON treatment improved the morphologic features of the PFC, and the performance of the T4 combined DON group was the closest to the control group. Moreover, hypothyroidism significantly decreased the content of ACh (29.8%) and activity of AChE (27.8%), which were restored to control values by T4 admi-nistration. In addition, DON treatment restored ACh content to normal. At the protein level, hypothyroidism increased the levels of syt-1 and SNAP-25 in the PFC, both of which were not restored to control values following T4 administration, while concurrent administration of T4 and DON was able to induce this effect. These results suggested that adult-onset hypothyroidism induce morphological, biochemical and molecular alterations in the PFC, combined administration of T4 and DON induce plastic changes in the PFC, different from that of the standard T4 therapy, and that the DON treatment may facilitate the recovery of synaptic protein impairments induced by hypothyroidism. PMID- 28713916 TI - Activation of the HMGB1-TLR4-NF-kappaB pathway may occur in patients with atopic eczema. AB - High mobility group protein B1 (HMGB1) has been reported to serve important roles in various pathological conditions. Toll-like receptor 4 (TLR4), as one of the HMGB1 receptors, has been reported to be involved in the development of certain inflammatory diseases by activating nuclear factor NF-kappa-B (NF-kappaB). However, there are few studies investigating the effects of HMGB1, TLR4 and NF kappaB on human inflammatory dermatoses. In the present study, the distribution and characteristics of HMGB1, TLR4 and NF-kappaB p65 expression in psoriasis and atopic eczema (AE) were investigated. In addition, immunohistochemical analysis was performed to evaluate their expression and distribution in normal skin, and in patients with AE or psoria-sis. Spearman's correlation analysis was used to predicate their relevancy. The present study identified that the p65 level in epithelial nuclei in AE skin was increased compared with normal and psoriasis skin (P<0.01). The level of extracellular HMGB1 in AE skin was also increased compared with normal and psoriasis skin (P<0.01). Meanwhile, TLR4 expression on the epithelial membranes of AE skin was increased compared with psoriasis skin (P<0.01). Furthermore, the level of extracellular HMGB1 was positively correlated with epithelial membrane TLR4 (r=0.3856; P<0.05) and epithelial nuclear p65 (r=0.5894; P<0.01) in AE skin. These results indicated that the HMGB1-TLR4-NF kappaB signaling pathway is activated in AE and may account for its pathogenesis, but not in psoriasis. Therefore, HMGB1, TLR4 and NF-kappaB p65 have the potential to be targets for the treatment of human inflammatory dermatoses, including AE. PMID- 28713917 TI - STIM1 silencing inhibits the migration and invasion of A549 cells. AB - The present study aimed to explore the effects of stromal interaction molecule 1 (STIM1) knockdown on the migration, invasion and metastasis of A549 cells in vitro and in vivo. Western blotting and immunohistochemistry were used to detect protein expression levels. Wound healing and Transwell invasion assays were used to assess the migratory and invasive abilities of A549 cells transfected with STIM1-specific short hairpin (sh)RNA (shSTIM1). In addition, a tail vein metastatic assay was performed. The results demonstrated that the frequency of STIM1 high-expression was significantly increased in metastatic lung cancer tissues (72.2%) compared with in non-metastatic lung cancer tissues (33.0%). STIM1 knockdown inhibited A549 cell migration and invasion in vitro and tumor metastasis in vivo. The protein expression levels of Snail1, Vimentin, matrix metalloproteinase (MMP) 2 and MMP9 were markedly decreased in A549-shSTIM1 compared with in A549 cells transfected with control shRNA (shcon). In addition, the protein expression levels of E-cadherin were markedly increased in A549 shSTIM1 cells compared with in A549-shcon cells. These results suggested that STIM1 knockdown may inhibit the migration and invasion of A549 cells in vitro, and metastasis in vivo. PMID- 28713918 TI - Endothelial growth medium suppresses apoptosis of mesenchymal stem cells in vitro via decrease of miR-29a. AB - The administration of mesenchymal stem cells (MSCs) in cases of cardiac ischemia/reperfusion injury (IRI) has been associated with a significant reduction of myocardial cell death and an effective improvement in cardiac function. However, one major limiting factor in MSCs transplantation therapy is the low survival rate of the transplanted cells. The present study aimed to demonstrate that human amnion-derived mesenchymal stem cells (hAMSCs) cultured with endothelial growth medium (EGM-2) exhibited reduced apoptosis when exposed to serum-free and hypoxic conditions; and that the expression of microRNA (miR) 29a decreased significantly. Furthermore, miR-29a knockdown resulted in decreased apoptosis of hAMSCs and increased myeloid cell leukemia (MCL)-1 at the mRNA and protein levels. These results suggested that EGM-2 promoted survival of hAMSCs partly through the regulation of miR-29a and MCL-1 expression levels. These findings may provide a novel understanding of a potential effective therapeutic strategy for cardiac IRI. PMID- 28713919 TI - Ganetespib induces G2/M cell cycle arrest and apoptosis in gastric cancer cells through targeting of receptor tyrosine kinase signaling. AB - Heat shock protein 90 (HSP90) regulates several important cellular processes via its repertoire of 'client proteins'. These client proteins have been found to play fundamental roles in signal transduction, cell proliferation, cell cycle progression and survival, as well as other features of malignant cells, such as invasion, tumor angiogenesis and metastasis. Thus, HSP90 is an emerging target for cancer therapy. To this end, we evaluated ganetespib (STA-9090), a novel and potent HSP90 inhibitor, for its activity in gastric cancer cell lines. Ganetespib significantly inhibited the proliferation of AGS and N87 human gastric cancer cell lines and potently induced G2/M cell cycle arrest and apoptosis. Upregulation of cleaved poly(ADP-ribose) polymerase (c-PARP), c-caspase-3, c caspase-8 and c-caspase-9 and suppression of gastric cancer-associated HSP90 client proteins, including ErbB2, Erk, Akt, mTOR, GSK3 and Src, were observed in ganetespib-treated cells. These findings demonstrate that the ganetespib-induced mechanism of cell growth inhibition involves the activation of death receptor and mitochondrial pathways and the inhibition of receptor tyrosine kinase signaling pathways. Our study implicates ganetespib as a potential strategy for gastric cancer treatment, which warrants further preclinical and clinical investigation. PMID- 28713920 TI - Low-dose halofuginone inhibits the synthesis of type I collagen without influencing type II collagen in the extracellular matrix of chondrocytes. AB - Full-thickness and large area defects of articular cartilage are unable to completely repair themselves and require surgical intervention, including microfracture, autologous or allogeneic osteochondral grafts, and autologous chondrocyte implantation. A large proportion of regenerative cartilage exists as fibrocartilage, which is unable to withstand impacts in the same way as native hyaline cartilage, owing to excess synthesis of type I collagen in the matrix. The present study demonstrated that low-dose halofuginone (HF), a plant alkaloid isolated from Dichroa febrifuga, may inhibit the synthesis of type I collagen without influencing type II collagen in the extracellular matrix of chondrocytes. In addition, HF was revealed to inhibit the phosphorylation of mothers against decapentaplegic homolog (Smad)2/3 and promoted Smad7 expression, as well as decrease the synthesis of type I collagen synthesis. Results from the present study indicated that HF treatment suppressed the synthesis of type I collagen by inhibiting the transforming growth factor-beta signaling pathway in chondrocytes. These results may provide an alternative solution to the problems associated with fibrocartilage, and convert fibrocartilage into hyaline cartilage at the mid early stages of cartilage regeneration. HF may additionally be used to improve monolayer expansion or 3D cultures of seed cells for the tissue engineering of cartilage. PMID- 28713921 TI - Anti-lung cancer effect of glucosamine by suppressing the phosphorylation of FOXO. AB - Lung cancer is the most common cause of cancer-associated mortality worldwide, and glucosamine has the potential to exhibit antitumor activity. To reveal its anti-lung cancer mechanism, the present study investigated the effect of glucosamine on the transcriptional activity of forkhead box O (FOXO)1 and FOXO3, and associated signal transduction pathways in A549 cells. An MTT assay was performed to investigate cell viability and immunoblotting was performed to detect protein levels of FOXO1/3, phosphorylated (p)-FOXO1/3, AKT, p-AKT, extracellular signal-regulated kinase (ERK) and p-ERK, and the levels of beta-O linked N-acetylglucosamine (O-GlcNAc)-modified FOXO1 protein. Immunoprecipitation was performed to purify O-GlcNAc-modified protein prior to immunoblotting. Glucosamine inhibited FOXO1- and FOXO3-specific amino acid phosphorylation, which was correlated with its translocation from the nucleus to cytoplasm, indicating a possible anti-lung cancer mechanism of glucosamine. The present study also examined the phosphoinositide 3-kinase (PI3K)/AKT and mitogen-activated protein kinase (MAPK)/ERK pathways, which induce FOXO1- and FOXO3-specific site phosphorylation. The data showed that glucosamine suppressed the translocation of FOXO from the cytoplasm to the nucleus via glucosamine-induced O-GlcNAc modification. These observations suggested that glucosamine modulated A549 cell proliferation, possibly via O-GlcNAc modification-induced downregulation of the PI3K/AKT and MAPK/ERK pathways and their downstream signaling molecules, FOXO1 and FOXO3. PMID- 28713922 TI - Selection of an optimal promoter for gene transfer in normal B cells. AB - Gene transfer into normal quiescent human B cells is a challenging procedure. The present study aimed to investigate whether it is possible to increase the levels of transgene expression by using various types of promoters to drive the expression of selected genes-of-interest. To produce lentiviral particles, the present study used the 2nd generation psPAX2 packaging vector and the vesicular stomatitis virus -expressing envelope vector pMD2.G. Subsequently, lentiviral vectors were generated containing various promoters, including cytomegalovirus (CMV), elongation factor-1 alpha (EF1alpha) and spleen focus-forming virus (SFFV). The present study was unable to induce satisfactory transduction efficiency in quiescent normal B cells; however, infection of normal B cells with Epstein-Barr virus resulted in increased susceptibility to lentiviral transduction. In addition, the SFFV promoter resulted in a higher level of transgene expression compared with CMV or EF1alpha promoters. As a proof-of concept that this approach allows for stable gene expression in normal B cells, the present study used bicistronic lentiviral vectors with genes encoding fluorescent reporter proteins, as well as X-box binding protein-1 and binding immunoglobulin protein. PMID- 28713923 TI - The differential regulation of microRNAs is associated with oral cancer. AB - Oral squamous cell carcinoma (OSCC), is the most frequently occurring malignant head and neck tumor, generally it exhibits a poor prognosis, and metastasis is the main cause of death in these cancer patients. The discovery of reliable prognostic indicators for tumors progression would greatly improve clinical treatments. MicroRNAs (miRNAs) play a critical role in the degradation of mRNA and the inhibition of protein synthesis. The miRNAs function either as tumor suppressors or as oncogenes in tumorigenesis, and little is known about the clinical significance of miRNA expression profiles in oral cancers. In the present study, we investigated the expression profiles of miR-375, miR-204 and miR-196a in 39 healthy and tumor tissue pairs of oral cancer patients using TaqMan real-time quantitative polymerase chain reaction (qPCR). The predicted target genes for miR-375, miR-204 and miR-196a were confirmed using luciferase reporter-based assays and western blot analyses. In oral cancer tissue, the expression of miR-375 and miR-204 decreased, whereas the expression of miR-196a was significantly elevated. In OSCC, HOXB8 and p27 (CDKN1B) were the direct target genes of miR-196a, whereas HMGA2 was the direct target gene of miR-204. HOXB8 and p27 (CDKN1B) protein expression levels were inhibited by miR-196a, whereas the protein expression level of HMGA2 was inhibited by miR-204. Furthermore, the miR-196a inhibitor blocked cell proliferation. Our results indicate that the combined expression signatures of miR-375, miR-204 and miR-196a are promising biomarkers for the diagnosis, prognosis and treatment of OSCC. PMID- 28713924 TI - A systematic study of Girdin on cell proliferation, migration and angiogenesis in different breast cancer subtypes. AB - Breast cancer has one of the highest incidences in females worldwide. Girdin is a novel actin-binding protein, that induces cell migration and angiogenesis. However, a systematic study of Girdin function in distinct subtypes of breast cancer has not been reported to date. Therefore, the present study aimed to investigate the role of Girdin on cell proliferation, migration and angiogenesis in different subtypes of breast cancer. For this purpose, the breast epithelial MCF-7, breast ductal T47D and breast metastatic MDA-MB-231 cancer cell lines were selected. Girdin small interfering RNA (siRNA) was transfected into MCF-7, T47D and MDA-MB-231 cells. Girdin knockdown suppressed cell viability and migration in the different cancer cells tested. Girdin knockdown also suppressed mRNA expression of vascular endothelial growth factor (VEGF), and activation of phosphatidyl inositol 3-kinase (PI3K) and RAC-alpha serine/threonine-protein kinase (Akt) in the subtypes tested. In conclusion, these data indicate that Girdin knockdown suppressed cell viability and migration and may suppress angiogenesis via the PI3K/Akt signaling pathway, in various breast cancers subtypes. The present study therefore suggests a role for Girdin as a novel therapeutic target for breast cancer, independent of subtype. PMID- 28713925 TI - The atrophy of white and gray matter volume in patients with comitant strabismus: Evidence from a voxel-based morphometry study. AB - To compare the difference in white matter volume (WMV) and gray matter volume (GMV) between the comitant strabismus (CS) patients and health controls by voxel based morphometry (VBM) and the relationship with behavioral performance. A total of 20 patients with comitant strabismus (10 males and 10 females), and 20 healthy subjects (10 males and 10 females) with matched age, sex status underwent magnetic resonance examination. The authors analyzed the original 3D T1 brain images using the VBM module. The comitant strabismus groups were compared with the control groups for the GMW and WMV of the entire brain. Correlation analysis was performed to investigate the relationship between the GMV and WMV altered areas and the behavioral performance in comitant strabismus. CS patients were distinguishable from the healthy controls (HCs) by receiver operating characteristic curves. Results of the VBM analysis demonstrated that the CS groups had decreased GMV in the brain regions of the left middle temporal pole, left cerebellum posterior lobe, right posterior cingulate cortex, left cuneus and right premotor cortex. Meanwhile, the WMV was significantly decreased in the brain regions of the left middle temporal gyrus, right middle temporal gyrus, left middle temporal gyrus, right precuneus and right premotor cortex in the comitant strabismus patients compared with HCs. Furthermore, the duration of CS was negatively correlated with the GMV values of the left middle temporal pole (r=-0.486, P=0.030). CS caused GMV and WMV atrophy in many brain regions, which may indicate the neural mechanisms of the ocular motility disorders in CS patients. PMID- 28713926 TI - Association between TNFSF4 and BLK gene polymorphisms and susceptibility to allergic rhinitis. AB - Allergic rhinitis (AR) is a common inflammatory disease of the upper airway. Recent evidence suggests that gene-gene interactions between tumor necrosis factor receptor superfamily 4 (TNFSF4) and B cell lymphocyte kinase (BLK) may have a synergistic effect on T and B cells in determining immunologic aberration, via the nuclear factor-kappaB pathway. The present study was performed to evaluate the potential association between specific single nucleotide polymorphisms (SNPs) in the TNFSF4 and BKL genes with susceptibility to AR in Chinese subjects. A population-based case-control study was performed in 600 Chinese AR patients and 700 controls. Blood was drawn for DNA extraction, and 9 SNPs (6 in TNFSF4 and 3 in BKL genes) were selected and genotyped. The TNFSF4 SNPs rs1234314 and rs1234315, and the BLK SNPs rs13277113 and rs1600249 were observed to occur in different frequencies between the AR patients and the controls. The CC (rs1234314, rs1234315) and AA (rs1600249, rs13277113) genotypes provided protective effects against AR, whereas the AG (rs13277113) genotype presented a risk factor for AR. The haplotypes ACC in the rs1234313-rs1234314 rs1234315 block and GA in the rs2254546-rs13277113 block significantly decreased the risk of AR, whereas the GGT and AG haplotypes served protective roles. SNP interaction analysis further indicated that there may be synergistic effects among the selected sets of polymorphisms. The present study suggests a novel association between specific TNFSF4 and BLK gene polymorphisms and AR risk, highlighting their potential utility as genetic biomarkers for AR susceptibility in a Chinese Han population. PMID- 28713927 TI - Classifier of cross talk genes predicts the prognosis of hepatocellular carcinoma. AB - The present study aimed to establish a prediction model for hepatocellular carcinoma (HCC) based on the cross talk genes from important biological pathways involved in HCC. Differentially expressed genes (DEGs) for HCC were identified from mRNA profiles of GSE36376, which were mapped to protein-protein interaction (PPI) networks from BioGrid and the human protein reference database. Then critical genes based on the deviation score and the degree of node were selected from the novel PPI network. Cross talk genes were screened from the network established based on the associations of gene-gene, gene-pathway and pathway pathway. A classifier based on specific cross talk genes was constructed for prediction of HCC using the random forest algorithm. Finally, the diagnostic performance of this prediction model was verified by predicting survival time of patients with HCC from the genome cancer atlas (TCGA) and other independent gene expression omnibus (GEO) databases. From the novel PPI network, a total of 200 critical genes were screened out and they were significantly enriched in 23 pathways, which have been reported to be significantly associated with the development of HCC. Based on these identified pathways, cross talk genes were identified including AKT1, SOS1, EGF, MYC, IGF1, ERBB2, CDKN1B, SHC2, VEGFA and INS. The prediction model has a relative average classification accuracy of 0.94 for HCC, which has a stable predicting efficacy for survival time of HCC patients validated in the TCGA database and two other independent GEO datasets. In conclusion, a total of 39 cross talk genes in HCC were identified and a classifier based on the cross talk genes was constructed, which indicates a high prognosis prediction efficacy in several independent datasets. The results provide a novel perspective to develop a multiple gene diagnostic tool for HCC prognosis, which also provided potential biomarkers or therapeutic targets for HCC. PMID- 28713928 TI - Upregulation of Wnt signaling under hypoxia promotes lung cancer progression. AB - The hypoxic tumor microenvironment induces epithelial-mesenchymal transition (EMT) in tumor cells and increases tumor cell malignancy. Previous studies indicated that malfunction of Wnt signaling is observed in some lung cancer patients. Athough crosstalk between hypoxia and Wnt signaling in tumor cells has recently been revealed, the detailed underlying mechanisms have not been well defined. In the present study, we demonstrated that hypoxia in lung adenocarcinoma cells can enhance Wnt signaling activity by stabilizing beta catenin and altering its localization into the nucleus. Overexpression of HIF 2alpha increased beta-catenin expression, promoted cell mobility, and induced morphological changes to a greater degree than HIF-1alpha overexpression. Knockdown of HIF-2alpha decreased beta-catenin expression and inhibited hypoxia induced cell mobility. Moreover, we identified that phosphorylational activation of AKT1 by hypoxia and HIF-2alpha was required for Wnt activation upon hypoxia treatment. Downregulation of HIF-2alpha and beta-catenin reduced colony formation when cells were exposed to long-term hypoxia treatment. Taken together, our data support that hypoxia activates PI3K/AKT as well as Wnt signaling in a HIF-2alpha dependent manner, thus elevating the resistance of lung cancer cells to chronic hypoxia-induced stress. PMID- 28713929 TI - MicroRNA-379 inhibits metastasis and epithelial-mesenchymal transition via targeting FAK/AKT signaling in gastric cancer. AB - Accumulating evidence demonstrates that aberrant miRNAs contribute to gastric cancer (GC) development and progression. However, the roles of various miRNAs in GC remain to be determined. In the present study, we confirmed that a reduced miR 379 expression was present in GC tissues and cell lines. Our clinical analysis revealed that the downregulated miR-379 expression was significantly correlated with poor prognostic features including lymph node metastasis and advanced TNM stage. Moreover, we confirmed that miR-379 was a novel independent prognostic marker for predicting 5-year survival of GC patients. The ectopic overexpression of miR-379 inhibited cell migration, invasion and EMT progress, while downregulated miR-379 reversed the effect. In addition, miR-379 regulated the focal adhesion kinase (FAK) by directly binding to its 3'-UTR, resulting in suppression of AKT signaling. In clinical samples of GC, miR-379 inversely correlated with FAK, which was upregulated in GC. Alteration of FAK expression or activating AKT signaling at least partially abolished the migration, invasion and EMT progress effects of miR-379 on GC cells. In conclusion, our results indicated that miR-379 functioned as a tumor suppressor gene in regulating the EMT and metastasis of GC via targeting FAK/AKT signaling, and may represent a novel potential therapeutic target and prognostic marker for GC. PMID- 28713930 TI - Overexpression of NAC1 confers drug resistance via HOXA9 in colorectal carcinoma cells. AB - Colorectal carcinoma (CRC) is one of the most common types of malignancy worldwide. Recently, neoadjuvant chemotherapy has become an important treatment strategy for CRC. However, treatment frequently fails due to the development of chemoresistance, which is a major obstacle for positive prognosis. However, the underlying mechanisms of chemoresistance remain unclear. The present study assessed the functions of nucleus accumbens-associated protein 1 (NAC1), an important transcriptional regulator, in CRC progression. Reverse transcription quantitative polymerase chain reaction, western blot analysis and immunohistochemistry were performed to detect the expression levels of NAC1. It was identified that NAC1 was significantly overexpressed in CRC compared with non tumorous tissues, indicating an oncogenic role. Following this, gain and loss of function analyses were performed in vitro to further investigate the function of NAC1. Cell viability and caspase-3/7 activity assays were used to assess chemotherapy-induced apoptosis. These results indicated that overexpression of NAC1 in CRC cells increased resistance to chemotherapy and inhibited apoptosis. Additionally, RNA interference-mediated knockdown of NAC1 restored the chemosensitivity of CRC cells. Furthermore, mechanistic investigation revealed that NAC1 increased drug resistance via inducing homeobox A9 (HOXA9) expression, and that knockdown of HOXA9 abrogated NAC1-induced drug resistance. In conclusion, the results of the present study demonstrated that NAC1 may be a critical factor in the develo-pment of chemoresistance, offering a potential novel target for the treatment of CRC. PMID- 28713931 TI - Downregulation of miRNA-26b inhibits cancer proliferation of laryngeal carcinoma through autophagy by targeting ULK2 and inactivation of the PTEN/AKT pathway. AB - Laryngeal carcinoma is one of the most common tumors of the head and neck cancers, the pathogenesis of which remains yet unclear. It has been discovered through research that microRNAs (miRNAs) play an important role during the genesis of laryngeal carcinoma. In the present study we investigated the effect of miRNA-26b on the proliferation of laryngeal carcinoma and elucidated the potential underlying mechanisms in order to provide new targets for laryngeal carcinoma. Firstly, we found that miRNA-26b expression was significantly increased in patients with laryngeal carcinoma, compared with normal volunteers. The downregulation of miRNA-26b inhibited cell proliferation and induced apoptosis of Hep-2 cells. Furthermore, downregulation of the expression of miRNA 26b promoted Bax, LC3 and p62 protein expression, decreased ULK2 mRNA and protein expression, as well as PTEN protein expression and increased phosphorylated-AKT protein expression in Hep-2 cells as determined using quantification by real-time PCR and western blotting. The concomitant downregulation of ULK2 and miRNA-26b futher enhanced the miRNA-26b-induced autophagy and apoptosis in addition to the miRNA-26b-inhibited cell proliferation of Hep-2 cells by targeting ULK2 and inactivating the PTEN/AKT pathway as determined by immunocytofluorescence. These findings revealed that miRNA-26b may play a key role in cell growth and death of laryngeal carcinoma through ULK2 and the PTEN/AKT pathway, and thus may be a new target for gene therapy in laryngeal carcinoma. PMID- 28713932 TI - Human trypsin inhibitor reduces the apoptosis of lipopolysaccharide-induced human kidney-2 cells by promoting mitochondrial fusion. AB - Imbalance in mitochondrial fusion/fission is one of the mechanisms leading to sepsis-induced mitochondrial dysfunction and cell apoptosis. The present study examined the effects of human trypsin inhibitor (UTI), a well-known antioxidant and anti-inflammatory substance, on mitochondrial dynamics and cell apoptosis in lipopolysaccharide (LPS)-induced human kidney-2 (HK-2) cells. The HK-2 cells were incubated for 24 h either with LPS (800 ng/ml) or LPS (800 ng/ml) mixed with UTI (250 U/ml). Cell viability was assessed using a3-(4,5-dimethyl-2-thiazolyl)-2, 5 diphenyl-2-H-tetrazolium bromide assay. Oxidative activities (estimated by maleic dialdehyde and superoxide dismutase), levels of inflammatory cytokines interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha, and levels of ATP were measured using an enzyme-linked immunosorbent assay. The expression levels of the mitochondrial fission protein, death-associated protein kinase 2 (DAPK-2), mitofusin (Mfn)1 and Mfn2 mitochondrial fusion proteins, and apoptotic and anti apoptotic biomarkers, including cytochrome c, caspase-3, caspase-9, B-cell lymphoma (Bcl)-2, Bcl-extra large and poly ADP-ribose polymerase (PARP), were assessed using western blot analyses. The changes in mitochondrial membrane potential were analyzed following JC-1 staining. Annexin V/propidium iodide assays were used to evaluate cell apoptosis. The results showed that the balance of mitochondrial dynamics was towards mitochondrial fusion in the UTI group, as a reduced expression of DAPK2, and increased expression levels of Mfn1 and Mfn2 were detected (P<0.05, vs. LPS group). In addition, adecline in the levels of the inflammatory cytokines, TNF-alpha and IL-6, and the oxidative activities, reflected by an increase in SOD and a decrease in MDA (P<0.05, vs. LPS group) were observed. Cell apoptosis was inhibited following co-treatment with UTI (P<0.05, vs. LPS group). It was concluded that UTI may protect mitochondrial functions by promoting mitochondrial fusion and limiting mitochondrial fission, thus reducing the apoptosis of LPS-induced HK-2 cells. PMID- 28713933 TI - miR-146b-5p promotes the neural conversion of pluripotent stem cells by targeting Smad4. AB - Pluripotent stem cells (PSCs) are regarded as potential sources that provide specific neural cells for cell therapy in some nervous system diseases. However, the mechanisms underlying the neural differentiation of PSCs remain largely unknown. MicroRNAs (miRNAs or miRs) are a class of small non-pro-tein-coding RNAs that act as critical regulatory molecules in many cellular processes. In this study, we found that miR-146b-5p expression was markedly increased following the neural induction of mouse embryonic stem cells (ESCs) or induced PSCs (iPSCs). In this study, to further identify the role of miR-146b-5p, we generated stable miR 146b-5p-overexpressing ESC and iPSC cell lines, and induced the differentiation of these cells by the adherent monolayer culture method. In the miR-146b-5p overexpressing ESC- or iPSC-derived cultures, RT-qPCR analysis revealed that the mRNA expression levels of neuroectoderm markers, such as Sox1, Nestin and Pax6, were markedly increased, and flow cytometric analysis verified that the number of Nestin-positive cells was higher in the miR-146b-5p-overexpressing compared with the control cells. Mechanistically, the miR-146b-5p-overexpressing ESCs or iPSCs exhibited a significant reduction in Oct4 expression, which may be an explanation for these cells having a tendency to differentiate towards the neural lineage. Moreover, we confirmed that miR-146b-5p directly targeted Smad4 and negatively regulated the transforming growth factor (TGF)-beta signaling pathway, which contributed to the neural commitment of PSCs. Collectively, our findings uncover the essential role of miR-146b-5p in the neural conversion of PSCs. PMID- 28713934 TI - Upregulation of connexin 43 and apoptosis-associated protein expression by high glucose in H9c2 cells was improved by resveratrol via the autophagy signaling pathway. AB - The expression of connexin43 (Cx43) protein and the apoptotic rate of cardiomyocytes may be regulated by autophagy and associated with diabetic cardiomyopathy. It is possible that the beneficial effect of resveratrol on diabetic cardiomyocytes occurs via the autophagy pathway. However, it remains to be elucidated whether resveratrol treatment may attenuate the hyperglycemia induced remodeling of Cx43 and apoptosis through the regulation of autophagy. H9c2 cardiac cells were incubated with 5.5 and 25 mM glucose, 25 mM glucose with chloroquine (50 uM), and 25 mM glucose with or without resveratrol (10, 25 uM) for 24 h. H9c2 cells were also incubated with 25 uM resveratrol in the presence of chloroquine (50 uM). Cell viability was determined using an MTT cell survival assay. Cytotoxicity was determined by quantification of the release of lactate dehydrogenase. The expression of Cx43, autophagic maker proteins [Beclin-1, p62 and microtubule-associated protein 1 light chain 3 (LC3)], apoptosis maker proteins (B-cell lymphoma-2 and Bcl-2 associated X protein), AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) were determined using western blotting. Resveratrol treatment led to reduced Cx43 expression levels compared with the 25 mM glucose treatment and significantly reduced the expression of apoptosis-associated proteins in H9c2 cells under hyperglycemic conditions. Autophagy was increased as indicated by the upregulation of Beclin-1 and p62 expression and the reduced LC3-II/LC3-I ratio. AMPK expression was increased, whereas mTOR expression was reduced in the resveratrol treatment groups. Treatment with chloroquine reversed effect of resveratrol. In conclusion, administration resveratrol may protect H9c2 cells against hyperglycemia-induced Cx43 upregulation and apoptosis, which may be mediated through the induction of the autophagy signaling pathway. PMID- 28713935 TI - Curcumin pretreatment protects against PM2.5-induced oxidized low-density lipoprotein-mediated oxidative stress and inflammation in human microvascular endothelial cells. AB - A previous study demonstrated that particulate matter (<=2.5 um in diameter; PM2.5) may promote atherosclerosis. However, the underlying mechanisms of PM2.5 in human microvascular endothelial cells (HMEC-1) remain to be elucidated. It has been reported that inflammation and oxidative stress can be reduced by curcumin, and in the present study, the aim was to investigate the protective effects of curcumin on PM2.5-induced oxidative stress and inflammatory response in HMEC-1. HMEC-1 were stimulated with curcumin and PM2.5. The HMEC-1 viability and apoptosis were detected by MTT and annexin V-fluorescein isothiocyanate/propidium iodide assays. The levels of oxidized low-density lipoprotein (oxLDL), tumor necrosis factor (TNF)-alpha and interleukin (IL)-8 were detected by ELISA. The intracellular reactive oxygen species formation in HMEC-1 was detected using flow cytometry and 2',7'-dichlorofluorescin diacetate. Nuclear factor (NF)-kappaB, caspase 3 activity and adhesion molecule expression were also investigated. The results suggested that curcumin reduced PM2.5 (300 ug/ml)-induced cell apoptosis and intracellular caspase 3 activity in HMEC-1. ELISA analysis demonstrated that curcumin reduced PM2.5-induced oxLDL, TNF-alpha and IL-8 levels. Curcumin induced NF-kappaB, cell adhesion molecule 1 and vascular cell adhesion protein 1 expression. Thus, curcumin treatment may reduce PM2.5-induced oxidative stress and inflammation in HMEC-1. In summary, it was indicated that the effects of PM2.5 are associated with oxLDL via the NF-kappaB signaling pathway, thereby inducing PM2.5 mediated oxidative and inflammatory responses. The results also suggested that curcumin may be able to reduce the oxidative and inflammatory effects of PM2.5 in HMEC-1. PMID- 28713936 TI - Epigallocatechin gallate attenuates overload-induced cardiac ECM remodeling via restoring T cell homeostasis. AB - It has previously been demonstrated that Epigallocatechin gallate (EGCG) has regulatory effects on cellular immunity. The present study explored whether EGCG inhibits the overload-induced cardiac extracellular matrix (ECM) remodeling through targeting the balance of T cell subpopulations. Sprague-Dawley rats were subjected to either transverse aortic constriction (TAC) or sham operation. TAC rats were treated with EGCG or valsartan (Val) for 6 weeks. The administration of EGCG or Val ameliorated the overproduction of cardiac collagen, inhibited matrix metalloproteinase (MMP) activity, decreased the expression of tissue inhibitor of MMP-2, atrial natriuretic peptide and brain natriuretic peptide. EGCG regulated the population of effector T cells and naive T cells, restored the balance of T helper (Th) cell 17/regulatory T cells, via modulating the downstream regulator signal transducer and activator of transcription (STAT3) and STAT5. Furthermore, the ratio of interferon-gamma/interleukin (IL)-10 which indicates the balance of Th1/Th2, was restored by the treatments at varying degrees. EGCG and Val administration rescued IL-7 production, and decreased the level of IL-15 in TAC rats. EGCG has positive therapeutic potential in inhibiting cardiac ECM remodeling. Regulation of the balance of T lymphocyte subsets may be one of the underlying mechanisms responsible for this effect. PMID- 28713937 TI - Correlation between secreted protein acidic and rich in cysteine protein expression and the prognosis of postoperative patients exhibiting esophageal squamous cell carcinoma. AB - The aim of the present study was to investigate the association between the expression level of secreted protein acidic and rich in cysteine (SPARC) and the prognosis of postoperative patients with esophageal squamous cell carcinoma (ESCC). The expression level of SPARC was detected in the 89 ESCC tissue cases and 100 healthy esophageal mucosa cases, which served as the controls. Immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR) were employed to evaluate the SPARC expression in cases with ESCC. RT-PCR demonstrated that the positive rates of SPARC mRNA expression in ESCC were 71.91% (64/89). The positive rates of normal esophageal mucosa mRNA expression were 15.00% (15/100), which were significantly lower than that in the ESCC tissue samples. The difference was statistically significant (P<0.001). Immunohistochemical staining indicated that the positive expression rate of SPARC protein in the ESCC tissue samples was significantly higher than that in the esophageal mucosa tissue samples (65.17 vs. 8.00%; P<0.001). The expression of SPARC protein was negatively correlated with lymph node metastasis (P<0.05), which was not associated with the pathologic gross morphology, tumor differentiation degree or other clinical features. The survival of patients with ESCC was not associated with the expression level of SPARC protein (P>0.05), but was associated with the tumor location (P<0.05), differentiation (P<0.001) and staging (P<0.05). Thus, SPARC mRNA and protein were highly expressed in ESCC, and negatively correlated with lymph node metastasis, which was not associated with postoperative survival of ESCC patients. Thus, detection of SPARC mRNA and protein expression levels may facilitate early diagnosis and prognosis assessment of ESCC. PMID- 28713938 TI - Effects of age on biological and functional characterization of adipose-derived stem cells from patients with end-stage liver disease. AB - Adipose-derived mesenchymal stromal cells (ADSCs) possess a multilineage potential and immunoregulatory properties, and may have great potential in autologous cell-based technologies. The aim of the present study was to investigate how the age of patients with benign end-stage liver disease affected the biological and functional characteristics of ADSCs, which is important for increasing the potential effectiveness of autologous cell therapy. ADSCs were obtained and cultured from three distinct age groups: Infant, adult and elderly. Cell immunophenotypic characteristics and antiapoptotic capacity were determined by flow cytometry, and cell proliferation and migration were monitored with a Real-Time Cell Analyzer. Multilineage differentiation potential was investigated by evaluating the induction response and by reverse transcription-quantitative polymerase chain reaction. Suppression of T cell proliferation was assessed in a co-culture system by MTT assay. The regulatory T cells (Tregs) were analyzed by flow cytometry, and ELISAs were performed to detect the cytokine profile in culture supernatants. All ADSC sample phenotypes were characterized as CD90+/CD73+/CD105+/CD45-/CD34-, and the apoptotic rate was not statistically different among all ages. However, the proliferation and migratory capacity were significantly increased in infant-derived ADSCs. In addition, ADSCs derived from infant patients demonstrated a relatively high proclivity for osteogenic differentiation compared with cells derived from either adult or elderly patients. Furthermore, ADSCs co-cultured with mitogen-activated T cells significantly suppressed T-cell proliferation, downregulated the secretion of interferon-gamma and increased the percentage of Tregs, with infant-derived ADSCs being most effective. Results from the present study indicated that ADSCs derived from infant patients may have biological advantages compared with older cell sources, and may provide an effective reference for the clinical application of ADSCs. PMID- 28713939 TI - Microarray analysis reveals key genes and pathways in Tetralogy of Fallot. AB - The aim of the present study was to identify key genes that may be involved in the pathogenesis of Tetralogy of Fallot (TOF) using bioinformatics methods. The GSE26125 microarray dataset, which includes cardiovascular tissue samples derived from 16 children with TOF and five healthy age-matched control infants, was downloaded from the Gene Expression Omnibus database. Differential expression analysis was performed between TOF and control samples to identify differentially expressed genes (DEGs) using Student's t-test, and the R/limma package, with a log2 fold-change of >2 and a false discovery rate of <0.01 set as thresholds. The biological functions of DEGs were analyzed using the ToppGene database. The ReactomeFIViz application was used to construct functional interaction (FI) networks, and the genes in each module were subjected to pathway enrichment analysis. The iRegulon plugin was used to identify transcription factors predicted to regulate the DEGs in the FI network, and the gene-transcription factor pairs were then visualized using Cytoscape software. A total of 878 DEGs were identified, including 848 upregulated genes and 30 downregulated genes. The gene FI network contained seven function modules, which were all comprised of upregulated genes. Genes enriched in Module 1 were enriched in the following three neurological disorder-associated signaling pathways: Parkinson's disease, Alzheimer's disease and Huntington's disease. Genes in Modules 0, 3 and 5 were dominantly enriched in pathways associated with ribosomes and protein translation. The Xbox binding protein 1 transcription factor was demonstrated to be involved in the regulation of genes encoding the subunits of cytoplasmic and mitochondrial ribosomes, as well as genes involved in neurodegenerative disorders. Therefore, dysfunction of genes involved in signaling pathways associated with neurodegenerative disorders, ribosome function and protein translation may contribute to the pathogenesis of TOF. PMID- 28713940 TI - A novel method to identify hub pathways of rheumatoid arthritis based on differential pathway networks. AB - The aim of the current study was to identify hub pathways of rheumatoid arthritis (RA) using a novel method based on differential pathway network (DPN) analysis. The present study proposed a DPN where protein-protein interaction (PPI) network was integrated with pathway-pathway interactions. Pathway data was obtained from background PPI network and the Reactome pathway database. Subsequently, pathway interactions were extracted from the pathway data by building randomized gene gene interactions and a weight value was assigned to each pathway interaction using Spearman correlation coefficient (SCC) to identify differential pathway interactions. Differential pathway interactions were visualized using Cytoscape to construct a DPN. Topological analysis was conducted to identify hub pathways that possessed the top 5% degree distribution of DPN. Modules of DPN were mined according to ClusterONE. A total of 855 pathways were selected to build pathway interactions. By filtrating pathway interactions of weight values >0.7, a DPN with 312 nodes and 791 edges was obtained. Topological degree analysis revealed 15 hub pathways, such as heparan sulfate/heparin-glycosaminoglycan (HS-GAG) degradation, HS-GAG metabolism and keratan sulfate degradation for RA based on DPN. Furthermore, hub pathways were also important in modules, which validated the significance of hub pathways. In conclusion, the proposed method is a computationally efficient way to identify hub pathways of RA, which identified 15 hub pathways that may be potential biomarkers and provide insight to future investigation and treatment of RA. PMID- 28713941 TI - Additive antitumor effects of celecoxib and simvastatin on head and neck squamous cell carcinoma in vitro. AB - Lipid-lowering statins as well as non-steroidal anti-inflammatory drugs (NSAIDs) have been reported to possess cancer-protective effects in many epidemiologic cohort studies. However, the underlying mechanisms of these findings are mostly unknown. To evaluate possible additive antitumor effects of statins and NSAIDs in vitro, PJ-41 and HLaC78 head and neck squamous cell carcinoma cells (HNSCC) were treated with 40 uM celecoxib, 50 uM simvastatin or a combination of both. Analysis of tumor viability, proliferation, apoptosis, cell cycle changes and secretion of interleukin-6 (IL-6) and interleukin-8 (IL-8) was conducted via MTT assay, Annexin V-propidium iodide test, cell cycle analysis, colony assay and enzyme-linked immunosorbent assay (ELISA). Celecoxib and simvastatin alone as well as a combined treatment showed a significant reduction in tumor cell viability, proliferation and secretion of IL-6 and IL-8 compared to the control group. The combined treatment even proved to have significantly greater effects. We postulate that simvastatin and celecoxib have additive antitumor effects on HNSCC in vitro, which warrants further investigation. PMID- 28713942 TI - Ginsenoside Rc protects against UVB-induced photooxidative damage in epidermal keratinocytes. AB - Ginsenoside Rc (Rc) is a major ginsenoside isolated from Panax ginseng, and has exhibited pharmacological effects on skin cells. The present study aimed to investigate the putative skin-protective properties of Rc, including its anti photoaging and barrier function-protective effects, in human HaCaT keratinocytes exposed to UVB radiation. The protective properties of Rc were evaluated through the assessment of keratinocyte viability, reactive oxygen species (ROS) production, total glutathione (GSH) and superoxide dismutase (SOD) activity, caspase-14, matrix metalloproteinase (MMP)-2 and -9 activity, and MMP-2, MMP-9 and filament aggregating protein (filaggrin) expression following UVB irradiation. Treatment with Rc was revealed to prevent the UVB-induced increase in ROS production and pro-MMP-2 and -9 levels in HaCaT keratinocytes. In addition, treatment with Rc resulted in enriched GSH contents and enhanced SOD activity following exposure to UVB radiation. Furthermore, Rc treatment enhanced caspase-14 activity and counteracted the UVB-induced downregulation in filaggrin expression. However, no significant difference was identified between Rc-treated and normal groups in terms of keratinocyte viability, regardless of exposure to radiation. The present findings suggested that Rc may exert anti-photoaging and barrier function-protective effects in keratinocytes, and thus protect the skin against photooxidative stress induced by exposure to UV radiation. PMID- 28713943 TI - Astragaloside IV downregulates the expression of MDR1 in Bel-7402/FU human hepatic cancer cells by inhibiting the JNK/c-Jun/AP-1 signaling pathway. AB - Previous studies demonstrated that astragaloside IV (ASIV) is a potential P glycoprotein (P-gp)-mediated multidrug resistance (MDR) reversal agent through mechanisms involving downregulation of the gene expression of mdr1. In order to investigate whether the c-Jun N-terminal kinase (JNK) signaling pathway is involved in the mechanism underlying ASIV-induced downregulated the expression of mdr1, the present study used 5-fluorouracil-resistant Bel-7402/FU human hepatic cancer cells as target cells. ASIV (0.1 mM) decreased the protein expression of phosphorylated (p)-JNK and p-c-Jun in the Bel-7402/FU cells, as determined using western blot analysis. Treatment with the JNK pathway inhibitor, SP600125, at a concentration of 11 uM, decreased the mRNA expression levels of mdr1 and P-gp, as determined using reverse transcription-quantitative polymerase chain reaction and western blot analyses, and similar effects were observed following exposure to ASIV. Furthermore, electrophoretic mobility shift assays demonstrated that the DNA-binding activity of activator protein-1 (AP-1) was decreased by 0.1 mM ASIV or 11 uM SP600125. Flow cytometric analysis revealed that 0.1 mM ASIV or 11 uM SP600125 increased the intracellular accumulation of fluorescent P-gp substrates, including rhodamine 123. Taken together, these results indicated that ASIV reversed the drug resistance of Bel-7402/FU cells by downregulating the expression of mdr1 via inhibition of the JNK/c-Jun/AP-1 signaling pathway. PMID- 28713944 TI - Truncated apolipoprotein C-I induces apoptosis in neuroblastoma by activating caspases in the extrinsic and intrinsic pathways. AB - Truncated apolipoprotein C-I is a post-translationally modified protein characterized by the loss of threonine and proline residues from the N-terminus of the mature peptide. The truncated peptide is involved in many physiological and pathological processes in vivo and is related to malignant diseases. The aim of the present study was to assess the effects of the truncated peptide on tumorigenesis in neuroblastoma. The truncated peptide was chemically synthesized, and a signal peptide was used as the negative control. The results of the CCK-8 assay showed that the truncated peptide selectively inhibited cell proliferation compared with the signal peptide, and inhibited migration and invasion as determined by wound healing and Transwell assays. Flow cytometry analysis demonstrated that the truncated peptide induced apoptosis and cell cycle arrest in the S phase. Bax, Bim, and tBid upregulation, and Bcl-2 and Bcl-xl downregulation were associated with permeabilization of the mitochondrial membrane, as detected by the JC-1 assay and the release of cytochrome c and apoptosis. Activation of caspase-8 was associated with activation of cell death receptors such as the tumor necrosis factor receptor. PARP cleavage indicated apoptosis, and DNA damage was observed in the TUNEL assay. The results showed that the truncated apoC-I induced apoptosis in neuroblastoma by the extrinsic and intrinsic pathways. The anticancer effects were confirmed in vivo in a xenograft mouse model. In conclusion, the endogenous protein apoC-I may be a new promising therapeutic target to suppress tumor growth. PMID- 28713945 TI - miR-433 protects pancreatic beta cell growth in high-glucose conditions. AB - Pancreatic beta cell dysfunction is a key characteristic in the pathogenesis of diabetes mellitus (DM). MicroRNAs (miRNAs) have been identified to serve a role in DM pathogenesis, but how specific miRNAs regulate glucose-stimulated beta cell functions remain unclear. The present study aimed to explore the effects of miR 433 on cell growth under high-glucose culture conditions and to determine the possible mechanisms involved. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis was performed to detect the expression levels of miRNAs in Min-6 pancreatic beta cells cultured in high-glucose medium, which revealed that miR-433 was significantly downregulated. Results from in vitro Cell Counting Kit-8, colony formation and flow cytometry analyses indicated that overexpression of miR-433 may enhance cell viability and proliferation by promoting cell cycle progression and suppressing apoptosis. Furthermore, bioinformatics prediction and luciferase analysis demonstrated that miR-433 was able to inhibit the expression of cyclooxygenase 2 (COX2) through targeting its 3'-UTR. Moreover, knockdown of COX2 expression alleviated the inhibition of cell growth induced by high glucose, similar to overexpression of miR-433. In conclusion, the present results suggested that miR-433 may protect pancreatic beta cells cultured in high glucose, which suggests that miR-433 may have beneficial effects in preventing and treating DM. PMID- 28713946 TI - Ginkgo biloba extract prevents acute myocardial infarction and suppresses the inflammation- and apoptosis-regulating p38 mitogen-activated protein kinases, nuclear factor-kappaB and B-cell lymphoma 2 signaling pathways. AB - Ginkgo biloba is a plant known from the Mesozoic and has been regarded as one of the first to be used in traditional Chinese medicine (TCM). The plant extract has attracted a great deal of attention in recent years. The Ginkgo biloba leaf contains flavones and diterpenes. In addition, Ginkgo biloba performs certain pharmacologic actions, including antioxidant and anti-aging activities. The aim of the present study was to examine whether Ginkgo biloba extract prevents acute myocardial infarction (AMI). The results demonstrated that Ginkgo biloba extract significantly inhibited infarct size, increased serum histamine levels and weakened creatine kinase (CK)-MB activity in AMI mice. Ginkgo biloba extract significantly inhibited serum interleukin (IL)-6 and IL-1beta levels, and caspase 3/9 activity. In addition, it suppressed matrix metallopeptidase-9, transforming growth factor-beta, p38 mitogen-activated protein kinases (MAPK) and nuclear factor (NF)-kappaB protein expression, and promoted B-cell lymphoma 2 (Bcl-2) protein expression in AMI mice. The results of in vivo assays demonstrated that Ginkgo biloba extract prevents AMI and suppresses inflammation- and apoptosis regulating p38 MAPK, NF-kappaB and Bcl-2 signaling pathways. PMID- 28713947 TI - MicroRNA-582 promotes tumorigenesis by targeting phosphatase and tensin homologue in colorectal cancer. AB - A number of studies have implicated that a class of non-coding RNAs named microRNAs (miRNAs or miRs) is associated with tumorigenesis and have identified miRNAs as promising targets for pharmaceutical intervention. Recently, the deregulated expression of miR-582 in tumor cells has been reported. However, the exact function of miR-582 in colorectal cancer (CRC) remains largely unknown. In thi study, we demonstrate that miR-582 is extensively upregulated in CRC tissues and cell lines. The overexpression of miR-582 significantly enhanced the proliferation and migration ability of the CRC cells. However, the use of a specific miR-582 inhibitor counteracted these effects. miR-582 may also play an oncogenic role by promoting tumor growth in vivo. Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) was identified as a putative target of miR-582; transfection of the cells with a lentivirus with miR-582 mimics substantially decreased both the mRNA and protein levels of PTEN. The restoration of PTEN expression in the CRC cells reversed the adverse effects of miR-582. Our findings therefore indicate that miR-582 promotes CRC progression by decreasing PTEN expression. These findings may also imply that miR-582 may be a target for therapeutic intervention in patients with CRC. PMID- 28713948 TI - MicroRNA-126 inhibits endothelial permeability and apoptosis in apolipoprotein E knockout mice fed a high-fat diet. AB - Endothelial dysfunction and apoptosis have key roles in the initiation and progression of atherosclerosis (AS). AS has been demonstrated to be associated with a high-fat diet, which may increase endothelial permeability and apoptosis; however, the exact mechanisms underlying the development of AS remain poorly understood. MicroRNAs (miRNAs) are vital for the regulation of cardiovascular disease, and dysregulated miRNAs have been implicated in AS. The present study investigated whether miRNA (miR)-126 regulates high-fat diet-induced endothelial permeability and apoptosis by targeting transforming growth factor beta (TGFbeta), a secreted protein that controls cellular proliferation and apoptosis. In the present study, apolipoprotein E (apoE)-/- mice were fed a high-fat diet in order to establish a model of AS. Mice were subcutaneously injected with a miR 126 mimic, a miR-126 antagomir or control miRNA. Reverse transcription quantitative polymerase chain reaction was used to assess miR-126 expression, and a fluorometric assay was used to evaluate caspase-3 activity. The effects of miR 126 on the endothelial permeability of the aortic intima were also explored. Western blotting and immunohistochemical analysis were used to investigate the effects of miR-126 on B-cell lymphoma-2 (Bcl-2) and transforming growth factor (TGF) beta protein expression levels. Furthermore, a luciferase assay was performed to verify whether TGFbeta may be a direct target gene of miR-126. In apolipoprotein E-knockout mice, a high-fat diet reduced miR-126 expression and induced apoptosis as determined by the upregulation of caspase-3 activity. A miR 126 antagomir increased endothelial permeability and apoptosis in mice fed a high fat diet. By contrast, an miR-126 mimic attenuated endothelial permeability and apoptosis. The reduction in miR-126 was associated with a reduction in protein expression levels of Bcl-2 and an increase of TGFbeta in mice fed a high-fat diet. In addition, the present study demonstrated that miR-126 reduced TGFbeta expression following binding to the 3'-untranslated region of TGFbeta mRNA. The current study demonstrated a role for miR-126 in AS and identified TGFbeta as a direct target of miR-126. Furthermore, the present study demonstrated that miR 126 contributed to endothelial permeability and apoptosis, and suggested that the downregulation of TGFbeta may be involved in the molecular mechanisms underlying the actions of miR-126. miR-126 may therefore have potential as a novel therapeutic target for the treatment of AS. PMID- 28713950 TI - MicroRNA-302a suppresses cell proliferation, migration and invasion in osteosarcoma by targeting ADAM9. AB - Osteosarcoma (OS) is the most frequent malignant primary bone tumor arising from primitive bone-forming mesenchymal cells in children and adolescents. The dysregulation of microRNAs (miRNAs) has been reported in OS, and these aberrantly expressed miRNAs are involved in the initiation and progression of OS. The aim of the present study was to investigate the expression and functions of miRNA-302a (miR-302a) in OS and its underlying mechanism. It was found that the expression of miR-302a was reduced in OS tissues and cell lines. The low expression of miR 302a was significantly correlated with tumor-node-metastasis stage and metastasis. The ectopic overexpression of miR-302a inhibited the proliferation, migration and invasion of OS cells. Bioinformatics analysis showed that a disintegrin and metalloproteinase 9 (ADAM9) was a potential target gene of miR 302a. Subsequently, reverse transcription-quantitative polymerase chain reaction and western blot analyses revealed that miR-302a regulated the expression of ADAM9 at the post-transcriptional level in OS cells. In addition, a luciferase reporter assay demonstrated that miR-302a directly targeted the 3'untranslated region of ADAM9. In clinical OS tissues, the mRNA expression of ADAM9 was upregulated and inversely correlated with the expression of miR-302a. In addition, the effects of ADAM9 knockdown on cell proliferation, migration and invasion were similar to those induced by the overexpression of miR-302a in OS cells. These findings suggested that miR-302a inhibited OS cell growth and metastasis by targeting ADAM9. miR-302a may serve as a potential therapeutic target for patients with OS. PMID- 28713949 TI - Shikonin suppresses proliferation and induces apoptosis in human leukemia NB4 cells through modulation of MAPKs and c-Myc. AB - Acute promyelocytic leukemia (APL) is a special subtype of acute myeloid leukemia that responds to treatment with all-trans retinoic acid and arsenic trioxide. However, severe side effects and drug resistance limit the effectiveness of these treatments. Hence, new drugs for APL are required urgently. Shikonin, an active naphthoquinone derived from the Chinese medical herb Zi Cao exerts antitumor activity in several cancers. In the present study, the effects of shikonin on proliferation and apoptosis in NB4 cells, as well as related mechanisms were assessed. Treatment of NB4 cells with shikonin inhibited proliferation in a concentration- and time-dependent manner. The cell cycle was arrested in the G1 phase. NB4 cells treated with shikonin exhibited more apoptosis and higher levels of cleaved caspase-3 and poly ADP-ribose polymerase than control cells. Western blotting results demonstrated that the expression of p-p38 mitogen-activated protein kinase (p-p38MAPK) and p-c-Jun N-terminal kinase (p-JNK) was increased significantly by shikonin treatment, while the expression of p-ERK and c-Myc was decreased. In summary, these findings indicated that shikonin inhibited cell proliferation and induced apoptosis partly through modulation of the MAPKs and downregulation of c-Myc. PMID- 28713951 TI - Cytisine induces apoptosis of HepG2 cells. AB - Cytisine is a quinolizidine alkaloid, which has been reported to be among the major bioactive components of Sophora alopecuraides L. Quinolizidine alkaloids have previously been demonstrated to inhibit the proliferation of several types of tumor cells. However, few studies have investigated the effects of cytisine on cancer cells. The present study was performed to further investigate the molecular mechanisms underlying cytisine-induced apoptosis of HepG2 human hepatocellular carcinoma cells. The results of an MTT assay demonstrated that cytisine inhibited the growth of HepG2 cells in a dose-dependent manner. In addition, the induction of apoptosis was detected, as determined by morphological observation and flow cytometry. As determined by fluorescence microscopy, apoptotic morphological alterations were detected following cytisine administration. Flow cytometric analyses demonstrated that cytisine induced cytotoxicity through apoptosis-like mechanisms in HepG2 cells. Furthermore, western blot analysis was performed to investigate the release of cytochrome c (Cyt-c) and activation of the caspase cascade, and the results indicated that treatment of HepG2 cells with cytisine induced caspase-dependent apoptosis via the release of Cyt-c from the mitochondria, upregulation of caspase-3 and downregulation of pro-caspase-3. These results indicated that cytisine may induce apoptosis of HepG2 cells through the mitochondrial pathway. PMID- 28713952 TI - Exploration of the sequential gene changes in epithelial ovarian cancer induced by carboplatin via microarray analysis. AB - The purpose of the current study was to explore the carboplatin-induced sequential changes in gene expression and screen out key genes, which were associated with effects of carboplatin on epithelial ovarian cancer (EOC). The microarray dataset GSE13525 was downloaded from the Gene Expression Omnibus database, including 6 EOC cell samples separately treated with carboplatin at 24, 30 and 36 h (case group), and 6 samples treated with phosphate-buffered saline at the same time points (control group). A total of 3 sets of differentially expressed genes (DEGs) were respectively identified in case samples at 24, 30 and 36 h compared with the control group via the Limma package, and separately recorded as DEG-24, DEG-30 and DEG-36. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of the overlapped DEGs were performed via the Database for Annotation, Visualization and Integrated Discovery. The protein-protein interaction (PPI) network was constructed and analyzed by Cytoscape software. In addition, the survival curves were drawn to illustrate the association between the expression levels of certain critical genes and the prognosis of EOC. A total of 170, 605 and 1043 DEGs were separately obtained in DEG-24 DEG-30 and DEG-36, and 110 overlaps were identified. The overlaps were enriched in 77 GO terms and 3 KEGG pathways. A total of 152 pairs were involved in the PPI network, and the abnormal expression levels (high or low) of c-Jun and cyclin B1 (CCNB1) would reduce the survival time of patients with EOC. The study indicated that c-Jun and CCNB1 may be the prognostic biomarkers of EOC treated with carboplatin, and certain pathways (such as p53 signaling pathway, cell cycle and mitogen-activation protein kinase signaling pathway) may be involved in carbo-platin-resistant EOC. PMID- 28713953 TI - MicroRNA-326 inhibits cell proliferation and invasion, activating apoptosis in hepatocellular carcinoma by directly targeting LIM and SH3 protein 1. AB - Hepatocellular carcinoma (HCC) is the fifth-most common cancer and third leading cause of cancer-related deaths worldwide. Increasing evidence indicates that dysregulation of microRNAs is often observed in HCC, and has been extensively investigated in terms of cancer formation, progression, diagnosis, therapy, and prognosis. Recently, microRNA-326 (miR-326) has been demonstrated to play important roles in multiple types of human cancer. However, the expression pattern, clinical significance, roles and regulatory mechanisms of miR-326 in HCC have yet to be elucidated. In this study, miR-326 was frequently downregulated in HCC tissues and cell lines. Low miR-326 expression was significantly associated with the TNM stage, differentiation and lymph node metastasis of HCC patients. Further functional assays demonstrated that the recovered miR-326 expression inhibited HCC cell proliferation and invasion and activated cell apoptosis in vitro. In addition, LIM and SH3 protein 1 (LASP1) was identified as a direct target gene of miR-326 in HCC. Furthermore, LASP1 was upregulated in HCC tissues and cell lines. The expression level of LASP1 mRNA was inversely correlated with that of miR-326 in HCC tissues. Moreover, LASP1 silencing elicited effects similar to miR-326 overexpression on HCC cells, and LASP1 upregulation markedly reversed the effects of miR-326 overexpression on HCC cells. These results revealed that miR-326 suppressed the progression of HCC by directly targeting LASP1. Therefore, miR-326 may be used as a potential therapeutic target for the treatment of patients with HCC. PMID- 28713954 TI - MicroRNA-139 suppressed tumor cell proliferation, migration and invasion by directly targeting HDGF in epithelial ovarian cancer. AB - The current study investigated the expression and functional roles of microRNA 139 (miR-139) on human epithelial ovarian cancer (EOC). Reverse transcription quantitative polymerase chain reaction (RT-qPCR) was performed to measure miR-139 expression in EOC tissues and cell lines. The effects of miR-139 on EOC cell proliferation, migration and invasion were assessed using MTT, cell migration and invasion assays, respectively. Subsequently, the molecular mechanism underlying the tumor suppressive roles of miR-139 on EOC was determined by bioinformatics analysis, RT-qPCR, western blotting and the luciferase reporter assay. According to the results, it was identified that miR-139 was significantly downregulated in EOC tissues and cell lines. In addition, restoration of miR-139 suppressed tumor cell proliferation, migration and invasion in EOC. Furthermore, hepatoma-derived growth factor (HDGF) was identified as a target of miR-139 in EOC. Upregulation of HDGF could rescue the inhibitory effects exerted by miR-139 overexpression on EOC cell proliferation, migration and invasion. Collectively, the results indicated that miR-139 was downregulated in EOC, and acted as a tumor suppressor by directly targeting HDGF. To the best of our knowledge, this was the first study to identify that miR-139 contributes to the growth and metastasis of EOC. PMID- 28713956 TI - MDG-1 inhibits H2O2-induced apoptosis and inflammation in human umbilical vein endothelial cells. AB - MDG-1, a water-soluble polysaccharide extracted from Ophiopogon japonicus, has been reported to serve a role in antimyocardial ischemia by protecting cardiomyocytes from hypoxia/reoxygenation-induced damage. However, it remains unknown whether MDG-1 protects human umbilical vein endothelial cells (HUVECs) against oxidative stress-induced damage. In the present study, HUVECs were treated with hydrogen peroxide (H2O2) to establish an oxidative stress-induced cell injury model. Treatment of HUVECs with different concentrations of H2O2 significantly attenuated cell viability and increased cell apoptosis in a time and dose-dependent manner. Pretreatment with MDG-1 markedly reduced H2O2-induced cell death, ROS generation and inflammatory factor secretion. In addition, pretreatment with MDG-1 decreased the expression levels of proapoptotic proteins BCL2 associated X (Bax) and caspase-3, while it increased the expression levels of the antiapoptotic protein BCL2 apoptosis regulator (Bcl-2), compared with H2O2 treatment alone. Taken together, the present data suggest that MDG-1 protected HUVECs against H2O2-induced apoptosis and inflammation through inhibition of Bax/Bcl-2 protein ratio, caspase-3 expression, and inflammatory factor secretion. This study provides a potential application for MDG-1 in the treatment of cardiovascular disease. PMID- 28713955 TI - Altered axon initial segment in hippocampal newborn neurons, associated with recurrence of temporal lobe epilepsy in rats. AB - Hippocampal neurogenesis in temporal lobe epilepsy (TLE) may result in alteration of the excitability of neurons, which contributes to spontaneous recurrent seizures. Axon initial segment (AIS) structural and functional plasticity is important in the control of neuronal excitability. It remains to be elucidated whether the plasticity of AIS occurs in hippocampal newly-generated neurons that are involved in recurrent seizures following pilocarpine-induced status epilepticus (SE). The present study first established a pilocarpine-induced TLE rat model to assess the features of newborn neurons and AIS plasticity alterations using double immunofluorescence staining of Ankyrin G and doublecortin (DCX). AIS plasticity alterations include length and distance from soma in the hippocampal newly-generated neurons post-SE. The results of the present study demonstrated that pilocarpine-induced epileptic rats exhibited aberrant hippocampal neurogenesis and longer DCX-labeled cell dendrites in the dentate gyrus. Pilocarpine-induced epileptic rats demonstrated shortened lengths of AIS and an increased distance from the soma in hippocampal newborn neurons. Mibefradil, a T/L-type calcium blocker, reversed the alterations in length and position of AIS in hippocampal newborn neurons post-SE, accompanied by decreased long-term seizure activity without increased aberrant neurogenesis. These findings indicate that the plasticity of AIS in hippocampal neurogenesis may have profound consequences in epilepsy, at least in animals. PMID- 28713957 TI - Soyasaponin Ag inhibits alpha-MSH-induced melanogenesis in B16F10 melanoma cells via the downregulation of TRP-2. AB - Saponins, which are glycosylated, represent a diverse group of biologically functional products in plants. In the present study, we investigated the effects of soyasaponin Ag, a secondary metabolite extracted from soybean, on alpha melanocyte-stimulating hormone (alpha-MSH)-induced melanin synthesis in B16F10 mouse melanoma cells and the underlying molecular mechanisms. To elucidate the mechanisms through which soyasaponin Ag inhibits melanin synthesis, we performed cellular tyrosinase activity assays and analyzed the expression of the melanogenesis-related genes, tyrosinase, tyrosinase-related protein (TRP)-1 and TRP-2. We demonstrated that soyasaponin Ag inhibited alpha-MSH-induced melanin synthesis in melanoma cells. Of note, soyasaponin Ag had no inhibitory effect on intracellular tyrosinase activity. However, soyasaponin Ag inhibited TRP-2 expression in a dose-dependent manner. Therefore, the depigmenting effect of soyasaponin Ag may be due to the inhibition of tyrosinase expression or the enhancement of tyrosinase degradation. Moreover, soyasaponin Ag did not exert any toxic on B16F10 mouse melanoma cells, suggesting that soyasaponin is a safe component for use in skin care cosmetic formulations that are used for skin whitening. PMID- 28713958 TI - Lipo-prostaglandin E1 modifies cognitive impairment in rats with vascular cognitive impairment by promoting angiogenesis via the VEGF/VEGFR pathway. AB - The pathological mechanism of vascular cognitive impairment (VCI) involves ischemic lesions in the hippocampus. Prostaglandin E1 (PGE1) serves roles in the promotion of vascular endothelial growth factor (VEGF) expression, angiogenesis and enhances blood flow to ischemic regions. However, the effect of PGE1 on cognitive function in VCI rats and the underlying mechanism are unknown. In the current study, learning and memory function in VCI rats treated by lipo-PGE1 injection was assessed through Morris Water Maze test. Furthermore, the histological alterations, blood vessel numbers in the hippocampal CA1 region and relative VEGF protein and mRNA expression were researched. The results confirmed that VCI rats treated with lipo-PGE1 presented improved cognitive function, less neuronal cell loss, a greater number of blood vessels in the hippocampal region and higher VEGF protein and mRNA expression. However, the role of lipo-PGE1 in VCI rats can be inhibited by SU5416 (a specific VEGFR2 antagonist). The results indicated that lipo-PGE1 may alleviate cognitive deficits in VCI rats. The underlying mechanism may be associated with angiogenesis promoted by lipo-PGE1, which may involve the VEGF/VEGFR pathway. These findings may have therapeutic implications for cognitive impairment induced by hypoperfusion or chronic ischemic lesions. PMID- 28713959 TI - Overexpression of Derlin 3 is associated with malignant phenotype of breast cancer cells. AB - Breast cancer (BC) is the most common malignant tumor among women worldwide. Development of novel molecular targets is important to improve prognosis of BC patients. Derlin 3 (DERL3) gene is a member of derlin family, and its coding protein is critical to the endoplasmic reticulum-associated degradation mechanism. However, its oncological role in breast cancer remains unclear. This study evaluated DERL3 expression and function in BC. We analyzed DERL3 mRNA in 13 BC and two non-cancerous cell lines, and explored effects of DERL3 knockdown on BC proliferation, invasion and migration. We also evaluated correlation of DERL3 mRNA expression levels with clinicopathological factors and prognosis in 167 BC patients. DERL3 mRNA expression was detected in five (38%) BC cell lines. Inhibiting DERL3 expression significantly decreased proliferation and invasion in BC cells. Specimens from patients with lymph node metastasis had higher DERL3 mRNA expression than those without (P=0.030). Patients in the highest quartile for DERL3 mRNA expression (n=42) were more likely to experience shorter overall survival than other patients (P=0.032). These findings indicate that DERL3 promotes malignant phenotype in BC cells. DERL3 may serve as a potential prognostic marker and therapeutic target for BC. PMID- 28713960 TI - Prediction and identification of B-cell epitopes for tumor necrosis factor-alpha. AB - The aim of the present study was to predict and identify B-cell epitopes for mouse tumor necrosis factor-alpha (mTNF-alpha). DNAStar and BcePred software were used to predict B-cell epitopes for mTNF-alpha. A predicted eight-branch multiple antigenic polypeptide (MAP) was synthesized and used to immunize BALB/c mice, combined with a promiscuous helper interleukin-1beta epitope (VQGEESNDK, amino acids 163-171). The serum titer was measured. The specificity and avidity were determined by western blotting and indirect enzyme-linked immunosorbent assay (ELISA). Amino acids 54-65 (MAP1) and 78-92 (MAP2) of mTNF-alpha were predicted as most likely to be B-cell epitopes. Dynamic monitoring of antibody concentration demonstrated that MAP1 and MAP2 may induce the production of specific antibodies with a higher antibody level for MAP2. Furthermore, MAP1 and MAP2 were confirmed to induce mTNF-alpha-specific antibodies by western blotting. Indirect ELISA was used to confirm that MAP2 had the highest affinity with commercial anti-mTNF-alpha antibody. Amino acids 54-65 and 78-94 of mTNF-alpha are B-cell epitopes, wherein amino acids 78-94 have the strongest immunogenicity. The present study provides a theoretical basis for further research into the mTNF alpha polypeptide antibody and a B-cell MAP vaccine. PMID- 28713961 TI - Adipose differentiation-related protein knockdown inhibits vascular smooth muscle cell proliferation and migration and attenuates neointima formation. AB - Vascular smooth muscle cells (VSMCs) have an important role in atherosclerosis development. Evidence has demonstrated that adipose differentiation-related protein (ADRP) is associated with foam cell formation and atherosclerosis progression. However, to the best of our knowledge, no previous studies have investigated the role of ADRP knockdown in platelet-derived growth factor (PDGF) stimulated proliferation and migration of VSMCs in vitro. Furthermore, the effect of ADRP knockdown on neointima formation in vivo remains unclear. In the present study, primary human aortic VSMCs were incubated with PDGF following ADRP small interfering (si)RNA transfection. Cell viability, migration and cell cycle distribution were analyzed by MTT, wound healing and Transwell assays and flow cytometry, respectively. Extracellular signal-regulated kinase (ERK), phosphorylated (p)-ERK, Akt, p-Akt, proliferating cell nuclear antigen (PCNA), matrix metalloproteinase (MMP)-2 and MMP-9 protein levels were determined by western blotting. Apolipoprotein E-/- mice fed an atherogenic diet were injected with siADRP or control siRNA twice a week. After 3 weeks of therapy, aortas were excised and ADRP mRNA and protein expression was determined. Neointima formation was assessed by hematoxylin and eosin staining. The results of the current study demonstrated that ADRP knockdown significantly inhibited PDGF-induced increases in VSMC viability, caused G1 phase cell cycle arrest and decreased PCNA expression. Knockdown of ADRP inhibited PDGF-induced migration of VSMCs by reducing MMP protein expression and activity. In addition, the present study also demonstrated that ADRP knockdown inhibited ERK and Akt signaling pathways in response to PDGF. Furthermore, siADRP administration suppressed neointima formation in the mouse model. The results of the present study indicate that ADRP may be a potential target for the treatment of atherosclerosis. PMID- 28713962 TI - Bioinformatics analysis of key genes and signaling pathways associated with myocardial infarction following telomerase activation. AB - The present study aimed to identify key genes and signaling pathways associated with myocardial infarction (MI) following telomerase activation, and investigate the possible underlying molecular mechanisms involved in this process. Array data of GSE62973 was downloaded, including 11 samples from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were analyzed in infarct vs. control, infarct + telomerase vs. control, and infarct + telomerase vs. infarct with the Linear Models for Microarray and RNA-Seq Data package. Gene Ontology annotation and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis were performed for upregulated and downregulated genes by the Database for Annotation, Visualization and Integrated Discovery. Sub network modules of 3 protein-protein interaction (PPI) networks were analyzed by Clustering with Overlapping Neighbourhood Expansion, and genes associated with telomerase were analyzed. Proto-oncogene tyrosine-protein kinase Src (Src) and proto-oncogene tyrosine-protein kinase Fyn (Fyn) were the hub nodes of the greatest degree in the PPI network for the infarct + telomerase vs. control comparison group and infarct + telomerase vs. infarct comparison group, respectively. Olfactory receptor gene family associated genes, including olfactory receptor 10 were significantly enriched in the sub network modules of the 3 comparison groups. In addition, olfactory transduction was a significantly enriched pathway by downregulation of DEGs in the infarct vs. control comparison group, and was additionally a significantly enriched pathway by upregulated DEGs in infarct + telomerase vs. infarct comparison group. Olfactory transduction was a significant pathway enriched by genes associated with telomerase. Telomerase activation may serve an important role in MI, in part, via the regulation of Src, Fyn and olfactory receptor family associated genes. PMID- 28713963 TI - Sexual dimorphism of frailty and cognitive impairment: Potential underlying mechanisms (Review). AB - The aim of the present study was to assess systematically gender differences in susceptibility to frailty and cognitive performance decline, and the underlying mechanisms. A systematic assessment was performed of the identified reviews of cohort, mechanistic and epidemiological studies. The selection criteria of the present study included: i) Sexual dimorphism of frailty, ii) sexual dimorphism of subjective memory decline (impairment) and atrophy of hippocampus during early life, iii) sexual dimorphism of late-onset Alzheimer's disease and iv) sexual dimorphism mechanisms underlying frailty and cognitive impairment. Males exhibit a susceptibility to poor memory performance and a severe atrophy of the hippocampus during early life and females demonstrate a higher prevalence for frailty and late-life dementia. The different alterations within the hypothalamic pituitary-gonadal/adrenal axis, particularly with regard to gonadal hormones, cortisol and dehydroepiandrosterone/sulfate-bound dehydroepiandrosterone prior to and following andropause in males and menopause in females, serve important roles in sexual dimorphism of frailty and cognitive impairment. These endocrine changes may accelerate immunosenescence, weaken neuroprotective and neurotrophic effects, and promote muscle catabolism. The present study suggested that these age associated endocrine alterations interact with gender-specific genetic and epigenetic factors, together with immunosenescence and iron accumulation. Environment factors, including psychological factors, are additional potential causes of the sexual dimorphism of frailty and cognitive impairment. PMID- 28713964 TI - Musashi1, a potential prognostic marker in esophageal squamous cell carcinoma. AB - Esophageal cancer ranks as the sixth leading cause of cancer-related deaths worldwide. Cancer stemness is mainly considered to be the key factor for cancer recurrence particularly in esophageal cancer. It is important to identify cancer stem cell markers as targets in future therapies. The present study aimed to investigate the expression of putative cancer stem cell-related marker musashi1 (Msi1) and assess the correlation with clinicopathologcal status of esophageal squamous cell carcinoma (ESCC) cases. We then clarified the role of Msi1 in esophageal cancer cells during proliferation, apoptosis, sphere formation and migration. Finally, we investigated the relationship of Msi1 with the prognosis of ESCC patients. ESCC tissue samples from 93 patients and 20 paired histologically normal tissues were procured for immunohistochemical analysis. We analyzed the characteristics of Msi1, using sphere formation and anchorage independent growth. Moreover, using flow cytometry and Cell Counting Kit-8 (CCK 8) assay, we investigated the role of Msi1 in cancer cell proliferation and apoptosis. Furthermore, we clarified the role of Msi1 in the process of sphere formation and migration of ESCC cells through knockdown of Msi1 expression by siRNA in ESCC cell lines. The results revealed that there was a higher expression of Msi1 in ESCC specimens compared with normal tissues. In addition, Msi1 expression was significantly associated with clinical stage and lymph node metastasis. Most importantly, the increased immunocytochemical staining of Msi1 in spheroid cells revealed the stemness characteristics of Msi1 in ESCC. In addition, we found that silencing of Msi1 decreased cell proliferation, migration and induced apoptosis in TE-7 and KYSE70 cells. Furthermore, downregulation of Msi1 attenuated the sphere formation ability of ESCC cells. Patients with higher expression of Msi1 had a shorter survival. In conclusion, Msi1 acts as a stemness associated gene in esophageal cancer cell lines and could serve as a prognostic marker in patients with ESCC. PMID- 28713965 TI - Dihydroartemisinin and gefitinib synergistically inhibit NSCLC cell growth and promote apoptosis via the Akt/mTOR/STAT3 pathway. AB - Non-small cell lung cancer (NSCLC) is among the leading causes of cancer associated mortality worldwide. In clinical practice, therapeutic strategies based on drug combinations are often used for the treatment of various types of cancer. The present study aimed to investigate the effects of the combination of dihydroartemisinin (DHA) and gefitinib on NSCLC. Cell Counting kit 8 assay was used to evaluate cell viability. Transwell assays were performed to investigate cellular migration and invasion, and cellular apoptosis was evaluated using the terminal deoxynucleotidyl transferase dUTP nick-end labeling assay. Flow cytometry was used to investigate cell cycle distribution and the expression levels of target proteins were determined using western blot analysis. The results of the present study demonstrated that DHA (5, 10, 20, 50 and 100 uM) reduced cancer cell viability in a dose-dependent manner in the NCI-H1975 human NSCLC cell line and significantly enhanced gefitinib-induced apoptosis. Furthermore, DHA and gefitinib co-administration induced cell cycle arrest in G2/M phase, which was associated with a marked decline in the protein expression levels of G2/M regulatory proteins, including cyclin B1 and cyclin-dependent kinase 1. The addition of DHA appeared to potentiate the inhibitory actions of gefitinib on the migratory and invasive capabilities of NCI-H1975 cells. DHA and gefitinib co-administration also downregulated the expression levels of phosphorylated (p)-Akt, p-mechanistic target of rapamycin, p-signal transducer and activator of transcription 3 and B-cell lymphoma 2 (Bcl-2), and upregulated the expression of Bcl-2-associated X protein. In conclusion, the present results suggested that the combination of DHA and gefitinib may have potential as a novel and more effective therapeutic strategy for the treatment of patients with NSCLC. PMID- 28713966 TI - Spica Prunellae extract suppresses the growth of human colon carcinoma cells by targeting multiple oncogenes via activating miR-34a. AB - Spica Prunellae is the spike of the herb Prunella vulgaris L. in traditional Chinese medicine which is often used for the treatment of various cancers including colorectal cancer. In the present study, we found that a key tumor suppressor, microRNA-34a (miR-34a) is involved in the antitumor activity for Spica Prunellae. Human colon carcinoma HCT-8 cells treated with an ethanol extract of Spica Prunellae (EESP) had significantly decreased cell proliferation and viability, in a dose-dependent manner. Flow cytometry analysis with Annexin V/PI staining analysis revealed that EESP treatment could induce apoptosis of HCT 8 cells. The level of miR-34a was upregulated in HCT-8 cells following EESP treatment, whereas expression levels of its target genes Notch1, Notch2 and Bcl-2 were downregulated. Inhibition of miR-34a rescued the expression of these target genes. These results revealed that Spica Prunellae can suppress the growth of HCT 8 cells by targeting Notch1, Notch2 and Bcl-2 via activation of miR-34a. PMID- 28713967 TI - Involvement of Notch2 in all-trans retinoic acid-induced inhibition of mouse embryonic palate mesenchymal cell proliferation. AB - Cleft palate is among the most common congenital disorders, and can be induced by exposure to all-trans retinoic acid (atRA) during mice and human embryogenesis. However, the mechanism underlying the implication of atRA in the development of cleft palate has yet to be elucidated. In the present study, atRA administered by gavage resulted in formation of a cleft palate in 99% of treated C57BL/6 mice. Notch2 was revealed to be upregulated in mouse embryonic palate mesenchymal (MEPM) cells in the atRA-treated group compared with untreated control mice between embryonic day (E)12.5 and E14.5. In addition, atRA was demonstrated to mediate Notch2 expression via the activation of RA receptors (RARs). Since Notch2 activation has previously been reported to inhibit the proliferation of MEPM cells, the expression levels of extracellular signal-regulated kinase (ERK), p21, cyclin D1 and Ki-67 were assessed in samples from atRA-treated and control mouse embryos between E12.5 and E14.5. It was demonstrated that Notch2 silencing partially reversed the atRA-induced inhibition of ERK phosphorylation in MEPM cells. In addition, the atRA-induced cyclin D1 downregulation and p21 upregulation were partially reversed following Notch2 silencing, whereas the atRA induced inhibition of cellular proliferation was also attenuated. Furthermore, it was revealed that Notch2 expression was upregulated, whereas Ki-67 expression was downregulated following atRA exposure, as assessed using resin bead-released atRA in MEPM cells. The present findings suggested that during embryonic development, atRA may enhance the expression of Notch2, which may inhibit cellular proliferation, possibly through ERK signaling. PMID- 28713968 TI - Inhibition of proliferation and invasion of hepatocellular carcinoma cells by lncRNA-ASLNC02525 silencing and the mechanism. AB - One of the most differentially expressed long non-coding RNAs (lncRNAs) that we identified by high throughput screening from liver cancer and para-carcinoma tissues, ASLNC02525, was highly expressed in the tissues and cell lines of liver cancer but not in adjacent tissues or normal hepatic cells. Knockdown of ASLNC02525 in hepatocellular carcinoma cells inhibited the proliferation and invasion. In the process, expression level of transcription factor twist1 (twist related protein 1) was reduced, but no change at transcription level was observed. According to bioinformatics analysis, ASLNC02525 may play a crucial role in inactivation of regulation of twist1 by hsa-miRNA-489-3p. The mechanism study revealed that ASLNC02525, as an RNA sponge, broke the negative regulation of twist1 by hsa-miRNA-489-3p, and once ASLNC02525 was silenced, the highly expressed hsa-miRNA-489-3p regained its regulation on twist1 and inhibited the proliferation and invasion. The importance of this study lies in shedding light on the potential for lncRNAs to become targets for gene therapy, by demonstrating that lncRNAs can suppress tumor inhibiting activity of miRNAs via breaking regulation of some miRNA target genes. PMID- 28713969 TI - Downregulation of PTPRH (Sap-1) in colorectal tumors. AB - Tyrosine phosphorylation is one of the basic mechanisms for signal transduction in the cell. Receptors exhibiting tyrosine kinase activity are widely involved in carcinogenesis and are negatively regulated by receptor protein tyrosine phosphatases (RPTP). Genes encoding different RPTPs are affected by aberrant epigenetic regulation in cancer. PTPRH (SAP-1) has been previously described to be overexpressed in colorectal cancer (CRC) and classified as an oncogenic factor. Previous microarray-based mRNA expression comparison of colorectal adenomas (AD), CRC and normal mucosa samples (NM) demonstrated that PTPRH tumor expression is the most reduced of all RPTP genes. qRT-PCR validation revealed gene downregulation for CRC (7.6-fold-change; P<0.0001) and AD (3.4-fold-change; P<0.0001) compared to NM. This was confirmed by immunohistochemical staining of tumor and NM sections as pronounced decrease of protein expression was observed in CRCs compared to the corresponding normal tissue. DNA methylation of two PTPRH promoter fragments was analyzed by pyrosequencing in a group of CRC, and AD patients as well as NM samples and CRC cell lines. The mean DNA methylation levels of these two regions were significantly higher in CRC than in NM. Both regions were highly methylated in SW480 and HCT116 cell lines contrary to unmethylated HT29 and COLO205. Cell lines with highly methylated promoters notably showed lower PTPRH expression levels, lower RNA II polymerase concentrations and higher levels of H3K27 trimethylation in the promoter and gene body, measured by chromatin immunoprecipitation. Cells were cultured with 5-aza deoxycitidine and an increase in PTPRH expression was observed in SW480 and HCT116, whereas this was unchanged in the unmethylated cell lines. The results indicate that PTPRH is downregulated in colorectal tumors and its expression is epigenetically regulated via DNA methylation and chromatin modifications. PMID- 28713970 TI - Human chorionic gonadotropin beta regulates epithelial-mesenchymal transition and metastasis in human ovarian cancer. AB - Human chorionic gonadotropin beta (beta-hCG) is a well-known and accurate marker for the diagnosis and monitoring of pregnancy, trophoblastic tumors and ovarian germ cell tumors. Recently, beta-hCG has been found to be closely related to poor prognosis and metastasis in various other malignant tumors, while its role and mechanism in ovarian cancer is still unclear. In the present study, lentiviral mediated transfection and small interfering RNA (siRNA) were used to alter beta hCG expression in the ovarian cancer cell lines ES-2 and SKOV3, respectively. Then, migration and invasion activity regulated by beta-hCG were evaluated by wound-healing and Transwell assays in vitro and in a peritoneal xenograft nude mouse model in vivo. EDTA and trypsin were utilized to investigate the attachment ability of these cells. Moreover, the expression of epithelial mesenchymal transition (EMT) markers (beta-catenin, Slug, vimentin, Snail, claudin, E cadherin and N-cadherin) was assessed by western blotting and immunofluorescence in ES-2 and SKOV3 cells. Furthermore, beta-hCG and EMT markers were evaluated in human ovarian cancer specimens by IHC. The results showed that overexpression of beta-hCG clearly promoted migration and invasion in ES-2 and SKOV3 cells (P<0.05) and facilitated metastasis in peritoneal xenografts, while silencing of beta-hCG led to the opposite effect. Moreover, beta-hCG was closely associated with cell morphology, attachment ability and EMT marker expression in ES-2 and SKOV3 cells and human ovarian cancer specimens. Upregulation of beta-hCG promoted cells from an epithelial-like morphology to a mesenchymal-like phenotype, decreased the adhesion ability (P<0.05), and reduced the expression of epithelial markers (E cadherin) while inducing the expression of mesenchymal markers (vimentin, N cadherin, beta-catenin and Slug). Furthermore, the converse effects were confirmed by knockdown of beta-hCG. These findings strongly suggest that beta-hCG may regulate metastasis of ovarian cancer through EMT, and it may become a new target for therapeutic intervention. PMID- 28713971 TI - Systematic analysis of lncRNAs, miRNAs and mRNAs for the identification of biomarkers for osteoporosis in the mandible of ovariectomized mice. AB - Osteoporosis is a complex and multifactorial disease caused by an imbalance between bone formation and resorption. Post-menopausal women with endogenous estrogen deficiency suffer from systemic bone loss and osteoporosis, and are at high risk of this affecting the jaw bones. MicroRNAs (miRNAs or miRs) have been implicated in the mechanisms of metabolic bone diseases and are expressed at differential levels in alveolar bone following ovariectomy. In the present study, we systematically analyzed the expression profiles of miRNAs, mRNAs and long non coding RNA (lncRNAs) in the mandible of ovariectomized (OVX) mice. A complex miRNA-mRNA-lncRNA regulatory network was constructed based on differentially expressed RNAs. Two core differentially expressed genes (DEGs), namely, LRP2 binding protein (Lrp2bp) and perilipin 4 (Plin4), significantly influenced the network targeted by differentially expressed miRNAs. Moreover, peroxisome proliferator-activated receptor (PPAR) and insulin signaling pathways were significantly dysregulated in the mandible of OVX mice. Several differentially expressed lncRNAs were also implicated in the two signaling pathways, which influenced mandible development by forming competing endogenous RNA. On the whole, our data indicate that the comprehensive analysis of miRNAs, mRNAs and lncRNAs provides insight into the pathogenesis of estrogen deficiency-induced osteoporosis in the mandible. This study proposes potential biomarkers for diagnosis or therapeutic targets for osteoporosis which may aid in the development of novel drugs for the treatment of osteoporosis. PMID- 28713972 TI - Expression and subcellular localization of AT motif binding factor 1 in colon tumours. AB - AT motif binding factor 1 (ATBF1) is a transcriptional regulator that functions as a tumour suppressor to negatively affect cancer cell growth. In the present study four specific polyclonal antibodies against ATBF1 were generated, and the expression and intracellular localization of ATBF1 in colonic mucosae, polyps, adenoma and adenocarcinoma tissue samples were investigated. The four polyclonal antibodies produced were as follows: MB34 and MB49, which recognize the N- and C terminal fragments of ATBF1, respectively; and D1-120 and MB44, which recognize the middle fragments of ATBF1 that contain three nuclear localization signals (NLS). In total, 191 colon samples were examined by immunohistochemical analysis. In addition, colon cancer cells were transfected with four ATBF1 expression vectors, and the subcellular localization of each fragment was examined. Normal colon mucosal cells were not observed to express ATBF1. However, a small number of hyperplastic polyps, serrated adenomas and tubular adenomas expressed ATBF1. Colon cancer cells were observed to express D1-120- and MB44-reactive middle fragments of ATBF1 in their cell nuclei. However, the N- and C-terminal fragments of ATBF1 did not translocate to the nucleus. Transfection of ATBF1 fragments revealed cleavage of the ATBF1 protein and nuclear translocation of the cleaved middle portion containing the NLS. A positive correlation between the cytoplasmic localization of the N- and C-termini of ATBF1, nuclear localization of the middle portion of ATBF1 and malignant cancer cell invasion was observed. In conclusion, the results of the present study suggest that alterations in the expression and subcellular localization of ATBF1, as a result of post-transcriptional modifications, are associated with malignant features of colon tumours. PMID- 28713973 TI - A dichloromethane fraction of Triticum aestivum sprouts reduces allergic immune response through inhibiting Th2 differentiation in ovalbumin-immunized mice. AB - Triticum aestivum sprouts are small shoots that germinate from seeds and are consumed as a dietary supplement. The present study aimed to determine whether a dichloromethane fraction isolated from Triticum aestivum sprouts (TDF) suppressed the allergic immune response in ovalbumin (OVA)-sensitized mice. In vivo experiments were performed by administering TDF or vehicle to mice during the sensitization and this was immediately followed by an intradermal injection of OVA into the ears. Splenocytes isolated from OVA-sensitized mice were pre-treated with TDF and re-challenged with OVA for ex vivo evaluation. Results demonstrated that TDF suppressed the inflammatory response in ear tissues and levels of total immunoglobulin (Ig)E and OVA-specific IgE in serum. TDF inhibited the production of interleukin (IL)-4 and expression of GATA-binding protein-3 (GATA-3) transcription factor which regulates the differentiation of naive T helper (Th) cells into Th2 cells in OVA-stimulated splenocytes. TDF inhibited Th1-associated cytokine interferon-gamma and IL-12 production and downregulated the expression of Th1 specific transcription factor T-box 21 in OVA-stimulated splenocytes. Overall, these results indicated that TDF attenuates OVA-induced allergic immune response by suppressing the production of Th2 specific cytokine IL-4, through inhibiting transcription factor GATA-3, and suggests that TDF may exhibit the potential to regulate the immune response in allergic diseases. PMID- 28713974 TI - miRNA-125b regulates apoptosis of human non-small cell lung cancer via the PI3K/Akt/GSK3beta signaling pathway. AB - The present investigation demonstrated that regulation of microRNA (miR)-125b affected the apoptosis of human non-small cell lung cancer (NSCLC) through targeting of the PI3K/Akt and Wnt/beta-catenin signaling pathways. The expression of miR-125b was assessed in patients with NSCLC, which demonstrated that miR-125b expression in NSCLC tissue was higher than that in para-carcinoma tissue. Furthermore, survival analysis of patients with NSCLC over 3 years indicated that the overall survival (OS) and disease-free survival (DFS) rates of patients with low miR-125b expression were higher than those of patients with high miR-125b expression. Proliferation and apoptosis assays were subsequently conducted in the human NSCLC cell line A549 using MTT assay and Annexin V-FITC/PI kits, respectively. Caspase-3 activity ELISA and western blot analysis were also used to assess caspase-3 activity and the protein expression of Bax, Akt, phosphorylated (p)-Akt, p-GSK3beta, Wnt and beta-catenin. It was observed that downregulation of miR-125b inhibited the proliferation and induced the apoptosis of A549 cells. Downregulation of miR-125b also suppressed the protein expression of p-Akt, Wnt and beta-catenin, and increased caspase-3 activity and Bax protein expression in A549 cells. In addition, downregulation of miR-125b combined with the PI3K inhibitor LY294002 enhanced cell growth inhibition, suppression of p GSK3beta, Wnt and beta-catenin protein expression and promotion of caspase-3 activity in A549 cells. These results revealed that the downregulation of miR 125b regulates apoptosis in human NSCLC through the suppression of the PI3K/Akt/GSK3beta and Wnt/beta-catenin signaling pathways. PMID- 28713976 TI - Melittin exerts an antitumor effect on non-small cell lung cancer cells. AB - Lung cancer accounts for a significant percentage of all cancer-associated mortalities in men and women, with non-small cell lung cancer being the most frequently occurring type of lung cancer. Melittin is the principal active component of apitoxin (bee venom) that has been reported to exert anti-chronic inflammatory and anti-cancer effects. In the present study, the antitumor effect of melittin was evaluated using in vivo and in vitro analyses. The results demonstrated that melittin significantly inhibited the epidermal growth factor induced invasion and migration of non-small cell lung cancer cells. Subcutaneous injection of melittin at doses of 1 and 10 mg/kg significantly suppressed non small cell lung cancer tumor growth by 27 and 61%, respectively. In addition, melittin significantly inhibited the secretion of vascular endothelial growth factor (VEGF) in non-small cell lung cancer cells. Furthermore, melittin decreased the protein expression of VEGF and hypoxia-inducible factor 1-alpha. Therefore, the antitumor activity of melittin may be associated with the anti angiogenic actions of inhibiting the VEGF and hypoxia-inducible factor signaling pathways. PMID- 28713975 TI - CCL28 promotes breast cancer growth and metastasis through MAPK-mediated cellular anti-apoptosis and pro-metastasis. AB - Breast cancer is one of the most commonly diagnosed cancers worldwide and the second leading cause of cancer-related deaths among females. CCL28 (mucosa associated epithelial chemokine, MEC), a CC subfamily chemokine, has been well studied in the process of inflammation, and recently increasing evidence indicates that CCL28 is related to tumor progression. However, little is known concerning its function in breast cancer. In the present study, we generated a CCL28-overexpressing breast cancer cell line MDA-MB-231HM/CCL28 from parental MDA MB-231HM cells. We found that overexpression of CCL28 promoted cell proliferation and tumor formation, and also enhanced migration, invasion and metastasis both in vitro and in vivo. Mechanistic studies revealed that CCL28 mediated intracellular activation of the mitogen-activated protein kinase (MAPK) signaling pathway to promote breast cancer cell proliferation and metastasis by upregulating anti apoptotic protein Bcl-2 and suppressing cell adhesion protein beta-catenin. However, overexpression of CCL28 did not influence the expression of metastasis related protein matrix metalloproteinase MMP2 and MMP9 and VEGF. Tissue sample analysis from animal models also indicated that overexpression of CCL28 was associated with enhanced pERK expression and reduced beta-catenin expression in breast carcinomas. Thus, our results show for the first time that CCL28 contributes to breast cancer progression through the ERK/MAPK-mediated anti apoptotic and metastatic signaling pathway. Antagonists of CCL28 and the MAPK signaling pathway may be used synergistically to treat breast cancer patients. PMID- 28713977 TI - Analysis of gene expression profile microarray data in complex regional pain syndrome. AB - The aim of the present study was to predict key genes and proteins associated with complex regional pain syndrome (CRPS) using bioinformatics analysis. The gene expression profiling microarray data, GSE47603, which included peripheral blood samples from 4 patients with CRPS and 5 healthy controls, was obtained from the Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) in CRPS patients compared with healthy controls were identified using the GEO2R online tool. Functional enrichment analysis was then performed using The Database for Annotation Visualization and Integrated Discovery online tool. Protein-protein interaction (PPI) network analysis was subsequently performed using Search Tool for the Retrieval of Interaction Genes database and analyzed with Cytoscape software. A total of 257 DEGs were identified, including 243 upregulated genes and 14 downregulated ones. Genes in the human leukocyte antigen (HLA) family were most significantly differentially expressed. Enrichment analysis demonstrated that signaling pathways, including immune response, cell motion, adhesion and angiogenesis were associated with CRPS. PPI network analysis revealed that key genes, including early region 1A binding protein p300 (EP300), CREB-binding protein (CREBBP), signal transducer and activator of transcription (STAT)3, STAT5A and integrin alpha M were associated with CRPS. The results suggest that the immune response may therefore serve an important role in CRPS development. In addition, genes in the HLA family, such as HLA-DQB1 and HLA-DRB1, may present potential biomarkers for the diagnosis of CRPS. Furthermore, EP300, its paralog CREBBP, and the STAT family genes, STAT3 and STAT5 may be important in the development of CRPS. PMID- 28713978 TI - Bone marrow mesenchymal stem cell-derived extracellular vesicles improve the survival of transplanted fat grafts. AB - Autologous fat grafting is a promising surgical technique for soft tissue augmentation, reconstruction and rejuvenation. However, it is limited by the low survival rate of the transplanted fat, due to the slow revascularization of such grafts. Previous studies have demonstrated that bone marrow mesenchymal stem cell derived extracellular vesicles (BMSC-EVs) are proangiogenic. The present study aimed to investigate whether BMSC-EVs could improve the survival of transplanted fat grafts. Extracellular vesicles were isolated from the supernatant of cultured rat bone marrow mesenchymal stem cells, and characterized by flow cytometry and scanning electron microscopy. Their proangiogenic potential was measured in vitro using tube formation and cell migration assays. Subsequently, human fat tissue grafts, alongside various concentrations of BMSC-EVs, were subcutaneously injected into nude mice. A total of 12 weeks following transplantation, the mice were sacrificed and the grafts were harvested. The grafts from the experimental group had a higher survival rate and an increased number of vessels compared with grafts from the control group, as demonstrated by tissue volume, weight and histological analyses. Reverse transcription-quantitative polymerase chain reaction analysis indicated that the expression levels of proangiogenic factors were increased in the experimental group compared with in the control group, thus suggesting that BMSC-EVs may promote neovascularization by stimulating the secretion of proangiogenic factors. The present study is the first, to the best of our knowledge, to demonstrate that supplementation of fat grafts with BMSC-EVs improves the long-term retention and quality of transplanted fat. PMID- 28713979 TI - Roles of electro-acupuncture in glucose metabolism as assessed by 18F-FDG/PET imaging and AMPKalpha phosphorylation in rats with ischemic stroke. AB - Targeted energy metabolism balance contributes to neural survival during ischemic stroke. Herein, we tested the hypothesis that electro-acupuncture (EA) can enhance cerebral glucose metabolism assessed by 18F-fluorodeoxyglucose/positron emission tomography (18F-FDG/PET) imaging to prevent propagation of tissue damage and improve neurological outcome in rats subjected to ischemia and reperfusion injury. Rats underwent middle cerebral artery occlusion (MCAO) and received EA treatment at the LI11 and ST36 acupoints or non-acupoint treatment once a day for 7 days. After EA treatment, a significant reduction in the infarct volume was determined by T2-weighted imaging, accompanied by the functional recovery in CatWalk and Rota-rod performance. Moreover, EA promoted higher glucose metabolism in the caudate putamen (CPu), motor cortex (MCTX), somatosensory cortex (SCTX) regions as assessed by animal 18F-FDG/PET imaging, suggesting that three-brain regional neural activity was enhanced by EA. In addition, the AMP-activated protein kinase alpha (AMPKalpha) in the CPu, MCTX and SCTX regions was phosphorylated at threonine 172 (Thr172) after ischemic injury; however, phosphorylation of AMPK was further increased by EA. These results indicate that EA could promote AMPKalpha phosphorylation of the CPu, MCTX and SCTX regions to enhance neural activity and motor functional recovery after ischemic stroke. PMID- 28713980 TI - miRNA-1284 inhibits cell growth and induces apoptosis of lung cancer cells. AB - Lung cancer is the most common cancer worldwide, and morbidity and mortality associated with lung cancer has been increasing annually in recent decades. MicroRNAs (miRNAs), which are short non-coding RNA sequences that are involved in the regulation of gene expression, have been previously demonstrated to be key regulators in cancer. The present study aimed to clarify the role of miRNA (miR) 1284 in lung cancer. A549 lung carcinoma cells were transfected with miR-1284 mimic or miR-1284 inhibitor using Lipofectamine 2000. Subsequently, cell viability, growth and apoptosis of A459 cells in the miR-1284 mimic, miR-1284 inhibitor and control groups were assayed by MTT assay, bromodeoxyuridine assay and flow cytometry, respectively. Furthermore, the protein expression levels of p27, p21, Bax, pro-caspase-3, activated caspase-3 and Myc were detected by western blot analysis to investigate the molecular mechanisms underlying the effect of miR-1284 on A549 cells. The cell viability and growth of A549 cells were significantly decreased in the miR-1284 mimic group compared with the control group, whereas the percentage of apoptotic cells was significantly increased. By contrast, miR-1284 inhibitor transfection significantly increased the cell viability and growth compared with control, and decreased apoptosis. Furthermore, expression of p27 was increased in miR-1284 mimic-transfected A549 cells compared with the control group, whereas p21 was unaffected by miR-1284 overexpression or inhibition. The expression of Myc was decreased by miR-1284 mimic transfection compared with the control group. For the other apoptosis associated proteins that were investigated (Bax, pro-caspase-3 and active caspase 3), the expression levels in the miR-1284 mimic transfected cells were higher than in the other two groups (control and miR-1284 inhibitor). In conclusion, the results suggest that miR-1284 affects cell proliferation and apoptosis of lung cancer cells, indicating that miR-1284 may have a key role in lung tumorigenesis. PMID- 28713982 TI - Protective effects of SOCS3 overexpression in high glucose-induced lung epithelial cell injury through the JAK2/STAT3 pathway. AB - Previous studies have suggested that the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway is involved in hyperglycemia induced lung injury. The present study aimed to investigate the roles of suppressor of cytokine signaling3 (SOCS3) in the regulation of JAK2/STAT3 activation following high glucose (HG) treatment in A549 human pulmonary epithelial cells. Cell viability was evaluated using Cell Counting Kit-8 and lactate dehydrogenase assays. HG-induced inflammatory injury in A549 cells was assessed through the evaluation of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) levels using ELISA. The protein expression levels of SOCS3, JAK2, STAT3, phosphorylated (p)-JAK2 and p-STAT3 were determined using western blot analysis. Cellular viability was significantly decreased, whereas IL-6 and TNF-alpha levels were significantly increased, following HG stimulation of A549 cells. In addition, the protein levels of SOCS3, p-JAK2 and p-STAT3 were significantly increased in HG-treated cells. Treatment with the JAK2/STAT3 inhibitor tyrphostin AG490, or SOCS3 overexpression, appeared to prevent the HG induced alterations in protein expression. Furthermore, cellular viability was enhanced, whereas the levels of proinflammatory cytokines were suppressed. These finding suggested the involvement of the SOCS3/JAK2/STAT3 signaling pathway in HG induced responses in lung cells. Therefore, it may be hypothesized that the inhibition of the JAK2/STAT3 pathway through SOCS3 overexpression may prevent hyperglycemia-induced lung injury, and may have therapeutic potential for the treatment of patients with diabetic lung injury. PMID- 28713983 TI - Malformin A1 treatment alters invasive and oncogenic phenotypes of human colorectal cancer cells through stimulation of the p38 signaling pathway. AB - Malformin A1 (MA1), a cyclic pentapeptide isolated from Aspergillus niger, has been found to possess a range of bioactive properties including antibacterial activity. However, it is unclear whether MA1 exerts an anticancer effect or not. In this study, we conducted in vitro experiments to investigate its anticancer properties in human colorectal cancer cells. The effect of MA1 on human colorectal cancer cells, SW480 and DKO1, was examined by the WST-1 cell viability assay, inverted microscopy, 5-bromo-2-deoxyuridine (BrdU) incorporation, flow cytometry, DNA fragmentation, wound healing, Transwell assays, and western blotting. MA1 treatment showed potent cytotoxic activities on human colorectal cancer cells. MA1 treatment induced apoptosis by activating the poly(ADP-ribose) polymerase (PARP), caspase-3, -7, and -9. MA1 treatment led to the increase in p53 upregulated modulator of apoptosis (PUMA) and the decrease in X-linked inhibitor of apoptosis protein (XIAP) and Survivin. In addition, MA1 treatment induced cell cycle arrest in the sub-G1 phase. The pan-caspase inhibitor, Z-VAD FMK, attenuated these MA1-induced apoptotic effects on human colorectal cancer cells. Moreover, MA1 treatment suppressed tumor cell migration and invasion. The phosphorylation level of p38 was upregulated by MA1 treatment, and the inhibitor of p38, SB203580, attenuated the MA1-induced p38 phosphorylation as well as caspase-3 and PARP activation. These results indicate that MA1 treatment alters invasive and oncogenic phenotypes of human colorectal cancer cells through the stimulation of the p38 signaling pathway. PMID- 28713984 TI - Downregulation of microRNA-199a-5p protects cardiomyocytes in cyanotic congenital heart disease by attenuating endoplasmic reticulum stress. AB - Chronic hypoxia is a key pathological change in patients with cyanotic congenital heart defect (CCHD). It has been demonstrated that enhanced myocardial unfolded protein response (UPR) increases the capacity to buffer endoplasmic reticulum (ER) stress and to avoid subsequent apoptosis caused by the hypoxia that underlies CCHD. The present study was performed to determine the regulatory role of microRNAs (miRNAs) in this cytoprotective UPR process. The results revealed that miR-199a-5p was markedly downregulated in the cardiac tissue of patients with CCHD and in human myocardial cells cultured in hypoxic conditions. The two major UPR modulators, 78 kDa glucose-regulated protein (GRP78) and activating transcription factor 6 (ATF6), were potential target genes of miR-199a-5p in CCHD myocardial specimens. In addition, the miR-199a-5p mimic and inhibitor were evidently able to change GRP78 and ATF6 gene expression and ER stress-associated apoptosis in hypoxia-treated cardiomyocytes. The interaction between miR-199a-5p and the ATF6 and GRP78 3'-UTR binding sites in myocardial cells was also confirmed by luciferase assay. Thus, it is concluded that myocardial downregulation of miR-199a-5p favors the UPR against hypoxia-induced ER stress in CCHD, which contributes to myocardial protection. PMID- 28713981 TI - Neuroendocrine factors: The missing link in non-melanoma skin cancer (Review). AB - Non-melanoma skin cancer (NMSC) is the most common form of cancer worldwide, comprising 95% of all cutaneous malignancies and approximately 40% of all cancers. In spite of intensive efforts aimed towards awareness campaigns and sun protective measures, epidemiological data indicate an increase in the incidence of NMSC. This category of skin cancers has many common environmental triggers. Arising primarily on sun-exposed skin, it has been shown that ultraviolet radiation is, in the majority of cases, the main trigger involved in the pathogenesis of NMSC. Aside from the well-known etiopathogenic factors, studies have indicated that several neuroactive factors are involved in the carcinogenesis of two of the most common types of NMSC, namely basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), with the exception of penile SCC, for which a paucity of specific data on their pathogenic role exists. The complex interaction between the peripheral nervous system and target cells in the skin appears to be mediated by locally released neuroendocrine factors, such as catecholamines, substance P, calcitonin gene-related peptide and somatostatin, as well as neurohormones, such as proopiomelanocortin and its derived peptides, alpha-melanocyte-stimulating hormone and adrenocorticotropin. All these factors have been, at least at some point, a subject of debate regarding their precise role in the pathogenesis of NMSC. There is also a significant body of evidence indicating that psychological stress is a crucial impact factor influencing the course of skin cancers, including SCC and BCC. Numerous studies have suggested that neuroendocrine factor dysregulation, as observed in stress reactions, may be involved in tumorigenesis, accelerating the development and progression, and suppressing the regression of NMSC. Further studies are required in order to elucidate the exact mechanisms through which neuroactive molecules promote or inhibit cutaneous carcinogenesis, as this could lead to the development of more sophisticated and tailored treatment protocols, as well as open new perspectives in skin cancer research. PMID- 28713985 TI - Microarray expression profiles of long non-coding RNAs in germinal center-like diffuse large B-cell lymphoma. AB - Long non-coding RNAs (lncRNAs) are continuously transcribed and are involved in various cellular activities. However, their contributions to the occurrence and development of germinal center B-cell (GCB)-like diffuse large B-cell lymphoma (DLBCL) remain largely unknown. We applied microarray technology to profile the expression of lncRNAs in two different GCB-DLBCL cell lines (OCI-ly1 and OCI ly19) and normal B lymphocytes. We demonstrated that 21,539 lncRNAs were expressed in all of the samples analyzed. This included 1,648 lncRNAs that showed a >=2-fold upregulation and 2,671 lncRNAs that displayed a >=2-fold downregulation in tumor cell lines (P<0.05). The expression levels of 8 lncRNAs were validated by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Bioinformatic analyses (Gene Ontology, pathway and network analysis) were performed to predict how the differentially expressed lncRNAs may function in GCB-DLBCL. Results from the pathway analysis suggested that totals of 64 and 62 biological pathways corresponded to upregulated and downregulated transcripts, respectively (P<0.05). Additionally, we constructed a lncRNA-mRNA network for the purpose of identifying specific coding genes which were co-expressed with 5 selected lncRNAs. Conclusively, our results may contribute to a better understanding of GCB-DLBCL pathogenesis. PMID- 28713986 TI - Hydrogen sulfide prevents homocysteine-induced endoplasmic reticulum stress in PC12 cells by upregulating SIRT-1. AB - It was previously confirmed that hydrogen sulfide (H2S) has a neuroprotective effect, preventing homocysteine-induced neurotoxicity. However, the exact molecular mechanisms underlying this protective effect remain to be fully elucidated. Endoplasmic reticulum (ER) stress contributes to homocysteine-induced neurotoxicity. Silent mating type information regulator 2 homolog 1 (SIRT-1) can attenuate ER stress, exerting its neuroprotective effect. Therefore, the present study aimed to investigate whether H2S protects PC12 cells against homocysteine induced ER stress and whether SIRT-1 mediates this protective effect of H2S. Western blotting was used to detect the expression of SIRT-1, glucose-regulated protein 78 (GRP78), and cleaved caspase-12 in PC12 cells. It was observed that sodium hydrosulfide (NaHS), an exogenous H2S donor, significantly attenuated the homocysteine-induced ER stress responses, including increases in the protein expression levels of GRP78 and cleaved caspase-12. Simultaneously, NaHS upregulated the expression of SIRT-1 and reversed the homocysteine-induced downregulation of SIRT-1 in PC12 cells. Sirtinol, a specific inhibitor of SIRT-1, eliminated the protective effects of H2S in homocysteine-induced ER stress. These data indicated that H2S prevented homocysteine-induced ER stress via enhancing the expression of SIRT-1. These findings offer novel insight into the protective mechanisms of H2S against homocysteine-induced neurotoxicity. PMID- 28713987 TI - Angiotensin-(1-7) attenuates caerulein-induced pancreatic acinar cell apoptosis. AB - Extensive apoptosis of pancreatic acinar cells frequently occurs in acute pancreatitis (AP), and has been identified to be closely associated with the decrease of pancreatic parenchymal cells and pancreatic damage. The present study aimed to investigate the possible effect of angiotensin (Ang)-(1-7) on caerulein (CAE)-induced pancreatic acinar cell apoptosis. Mouse pancreatic acinar cancer cells (MPC-83) were divided into 4 groups: Control group; CAE group; CAE + Ang-(1 7) group; and CAE + Ang-(1-7) antagonist (A779) group. The control group consisted of normal MPC-83 cells without special treatment. The CAE group was stimulated with 10 nmol/l CAE and harvested at 2, 6, 12, 24 and 48 h. For the CAE + Ang-(1-7) group and CAE + A779 group, the CAE-induced pancreatic acinar cells were mock pretreated or pretreated with different concentrations of Ang-(1-7) or A779 (10-7, 10-6 or 10-5 mol/l) for 30 min. Caspase-3 is a critical executioner of apoptosis, as it is either partly or completely responsible for the proteolytic cleavage of numerous key proteins including the nuclear enzyme poly (ADP-ribose) polymerase. Activation of caspase-3 requires proteolytic processing of its inactive zymogen into activated p17 and p12 fragments. Thus, the present study investigated the apoptotic markers, including cleaved caspase-3, B-cell lymphoma 2 (Bcl-2), Bcl-2-like protein 4 (Bax) and renin-angiotensin system (RAS) pathway related proteins (ACE2 and Mas receptor). The results demonstrated that the cleaved caspase-3 levels were increased in the CAE group (P<0.05), peaking at 24 h, and declined when incubated with Ang-(1-7). Following treatment with Ang-(1 7), levels of the anti-apoptotic protein Bcl-2 rose dramatically in a dose dependent manner. The ratio of the pro-apoptotic protein Bax to the anti apoptotic protein Bcl-2 dropped notably, which demonstrated a tendency towards curbing apoptosis. In addition, the cleaved caspase-3 levels, and the ratio of Bax to Bcl-2 in the CAE + A779 group presented a significant rise compared with the CAE group. It was concluded that Ang-(1-7) may possess an inhibitory effect on CAE-induced pancreatic acinar cell apoptosis and that appropriate interventions in RAS may attenuate pancreatic injury during AP. PMID- 28713988 TI - Coronin 3 negatively regulates G6PC3 in HepG2 cells, as identified by label-free mass-spectrometry. AB - Human coronin 3 is involved in many types of cancers, but the underlying molecular mechanisms require further elucidation. The present study demonstrated that coronin 3 is significantly upregulated in clinical primary hepatocellular carcinoma (HCC) samples by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and immunohistochemical staining. Subsequently, proteins that were regulated by coronin 3 in both coronin 3 overexpressing or knocked down HepG2 cells were analyzed by label free mass spectrometry; overall, 249 proteins were identified to be closely regulated by coronin 3, and those coronin 3 regulated proteins were enriched in cellular, physiological and metabolism processes. By further in-depth pathway analysis, it was demonstrated that those proteins were involved into 94 different pathways. Finally, the expression levels of glucose-6-phosphatase catalytic subunit 3 (G6PC3) were confirmed to be negatively regulated by coronin 3, as determined by RT-qPCR and western blotting. In conclusion, these results indicated that coronin3 is significantly dysregulated in HCC tumor tissues, and may exert its function via regulating G6PC3 expression. These results provide valuable information for further study of coronin 3-mediated signaling pathways, and implicate coronin 3 as a potential therapeutic target for HCC. PMID- 28713989 TI - Effects of proton beam irradiation on mitochondrial biogenesis in a human colorectal adenocarcinoma cell line. AB - Proton beam therapy has recently been used to improve local control of tumor growth and reduce side-effects by decreasing the global dose to normal tissue. However, the regulatory mechanisms underlying the physiological role of proton beam radiation are not well understood, and many studies are still being conducted regarding these mechanisms. To determine the effects of proton beams on mitochondrial biogenesis, we investigated: mitochondrial DNA (mtDNA) mass; the gene expression of mitochondrial transcription factors, functional regulators, and dynamic-related regulators; and the phosphorylation of the signaling molecules that participate in mitochondrial biogenesis. Both the mtDNA/nuclear DNA (nDNA) ratio and the mitochondria staining assays showed that proton beam irradiation increases mitochondrial biogenesis in 12-O-tetradecanoylphorbol-13 acetate (TPA)-induced aggressive HT-29 cells. Simultaneously, proton beam irradiation increases the gene expression of the mitochondrial transcription factors PGC-1alpha, NRF1, ERRalpha, and mtTFA, the dynamic regulators DRP1, OPA1, TIMM44, and TOM40, and the functional regulators CytC, ATP5B and CPT1-alpha. Furthermore, proton beam irradiation increases the phosphorylation of AMPK, an important molecule involved in mitochondrial biogenesis that is an energy sensor and is regulated by the AMP/ATP ratio. Based on these findings, we suggest that proton beam irradiation inhibits metastatic potential by increasing mitochondrial biogenesis and function in TPA-induced aggressive HT-29 cells. PMID- 28713990 TI - Inhibition of p38MAPK potentiates mesenchymal stem cell therapy against myocardial infarction injury in rats. AB - The present study aimed to investigate the protective effect of mesenchymal stem cell (MSC) therapy in combination with p38 mitogen-activated protein (MAPK) inhibition against myocardial infarction (MI) injury in rats, and to elucidate the underlying mechanisms. An MI model was established by ligation of the anterior descending branch of the left coronary artery. The rats were divided into four groups: MSC transplantation, p38MAPK inhibitor (SB203580), MSC + SB203580 and model control group. HE staining and a TUNEL assay were performed to evaluate pathological changes and apoptosis. The expression levels of p38MAPK and transforming growth factor beta-activated kinase 1 (TAK1) were determined using reverse transcription-polymerase chain reaction and western blot analyses. As shown by HE staining, classical morphological changes, including irregular cell arrangement and inflammatory infiltration were observed in the model rats, whereas MSC therapy or injection of the p38MAPK inhibitor ameliorated these pathological changes. Of note, the combined application of MSCs with the p38MAPK inhibitor exerted additive effects. The TUNEL assay showed that the combined application of MSCs with p38MAPK inhibitor also led to potentiation of effects, compared with either MSCs therapy or p38MAPK inhibitor injection alone. Mechanistically, the combined application of MSCs with p38MAPK inhibitor decreased the expression levels of TAK1 and p38MAPK at the mRNA and protein levels. In conclusion, p38MAPK inhibition potentiated the protective effects of MSCs therapy against MI in rats. PMID- 28713992 TI - miR-140-5p inhibits human glioma cell growth and invasion by targeting JAG1. AB - miR-140-5p has been reported to be a tumor suppressor in several types of human cancer, however, little is known about its expression and function in human gliomas. The present study aimed to detect the expression of miR-140-5p in human glioma tissues and cell lines, and to investigate the effect of miR-140-5p on glioma cell growth, invasion and adhesion using in vitro gain-of-function and loss-of-function experiments. Furthermore, the hypothesis that Jagged1 (JAG1) may be a target gene of miR-140-5p was tested. Reverse transcription-quantitative polymerase chain reaction analysis revealed that miR-140-5p was significantly downregulated in human glioma tissues and cell lines compared with normal tissues, and that its expression was correlated with the grade of gliomas. Transfection of a miR-140-5p mimic into SW1783 glioma cells promoted cell growth, invasion and adhesion, as determined by MTT, Transwell and cell adhesion assays respectively. By contrast, transfection of a miR-140-5p inhibitor had the opposite effect. A dual-luciferase reporter assay confirmed that JAG1 was a target gene of miR-140-5p, and miR-140-5p inhibited JAG1 expression both at the mRNA and protein level. In addition, JAG1 overexpression reversed the effect of miR-140-5p on glioma cell growth, invasion and adhesion. In conclusion, the present study is the first to reveal that miR-140-5p acts as a tumor suppressor in human gliomas. JAG1 was demonstrated to be a novel target of miR-140-5p, and miR-140-5p exerted its inhibitory effect on human glioma growth and invasion, partly by suppressing JAG1. The present study may provide useful information toward novel targets for the treatment of gliomas. PMID- 28713991 TI - Pien Tze Huang Gan Bao attenuates carbon tetrachloride-induced hepatocyte apoptosis in rats, associated with suppression of p53 activation and oxidative stress. AB - Pien Tze Huang Gan Bao (PZH-GB), a traditional Chinese medicine, has been used for thousands of years as a protective remedy effective against liver injury induced by excessive alcohol and smoking. The present study aimed to evaluate the protective effects and potential mechanisms of PZH-GB against carbon tetrachloride (CCl4)-induced hepatic injury. Rats were pre-treated with silymarin (50 mg/kg) or different doses of PZH-GB (150, 300 or 600 mg/kg) orally administered for 7 days. At the end of treatment, the rats were intraperitoneally injected with CCl4, or control rats received a corn oil injection. The lactate dehydrogenase (LDH) levels in serum were evaluated. Apoptosis was assessed via terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. p53, B-cell lymphoma 2 (Bcl-2), B cell-lymphoma 2-associated X protein (Bax), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS) and cytochrome P450 family 2 subfamily E member 1 (CYP2E1) were measured by reverse transcription-quantitative polymerase chain reaction and western blotting. The activity of caspase-9 and caspase-3 were measured by a colorimetric assay. The results indicated that silymarin and PZH-GB prevented CCl4-induced serum LDH elevations, and CCl4 induced high levels of LDH. Compared with the CCl4 group, silymarin and PZH-GB treatment significantly decreased LDH levels. Histopathological results revealed that silymarin and PZH-GB ameliorated the CCl4 induced liver histological alterations. The TUNEL results showed that compared with the control group, CCl4 induced liver cell apoptosis, while silymarin and PZH-GB treatment inhibited apoptosis and the TUNEL-positive cells. The elevated expression of Bax, p53, iNOS, COX-2 and CYP2E1 were reduced by silymarin or PZH GB pretreatment, whereas reduced Bcl-2 expression levels were increased. CCl4 increased the activity of caspase-9 and -3 by 6.86- and 7.42-fold, respectively; however, silymarin and PZH-GB ameliorated this effect. In conclusion, silymarin and PZH-GB treatment prevented the deleterious effects on liver functions by attenuation of oxidative stress, inflammation and mitochondrial apoptosis via the p53 signaling pathway. PMID- 28713993 TI - Gene microarray analysis of expression profiles in liver ischemia and reperfusion. AB - Liver ischemia and reperfusion (I/R) injury is of primary concern in cases of liver disease worldwide and is associated with hemorrhagic shock, resection and transplantation. Numerous studies have previously been conducted to investigate the underlying mechanisms of liver I/R injury, however these have not yet been fully elucidated. To determine the difference between ischemia and reperfusion in signaling pathways and the relative pathological mechanisms, the present study downloaded microarray data GSE10657 from the Gene Expression Omnibus database. A total of two data groups from 1-year-old mice were selected for further analysis: i) A total of 90 min ischemia; ii) 90 min ischemia followed by 1 h of reperfusion, n=3 for each group. The Limma package was first used to identify the differentially expressed genes (DEGs). DEGs were subsequently uploaded to the Database for Annotation Visualization and Integrated Discovery online tool for Functional enrichment analysis. A protein-protein interaction (PPI) network was then constructed via STRING version 10.0 and analyzed using Cytoscape software. A total of 114 DEGs were identified, including 21 down and 93 upregulated genes. These DEGs were primarily enriched in malaria and influenza A, in addition to the tumor necrosis factor and mitogen activated protein kinase signaling pathways. Hub genes identified in the PPI network were C-X-C motif chemokine ligand (CXCL) 1, C-C motif chemokine ligand (CCL) 2, interleukin 6, Jun proto-oncogene, activator protein (AP)-1 transcription factor subunit, FOS proto-oncogene, AP-1 transcription factor subunit and dual specificity phosphatase 1. CXCL1 and CCL2 may exhibit important roles in liver I/R injury, with involvement in the immune and inflammatory responses and the chemokine-mediated signaling pathway, particularly at the reperfusion stage. However, further experiments to elucidate the specific roles of these mediators are required in the future. PMID- 28713994 TI - Molecular-cytogenetic study of de novo mosaic karyotype 45,X/46,X,i(Yq)/46,X,idic(Yq) in an azoospermic male: Case report and literature review. AB - The present study describes a 36-year-old male with the 45,X/46,X,i(Yq)/46,X,idic(Yq) karyotype, who suffered from azoospermia attributed to maturation arrest of the primary spermatocyte. To the best of our knowledge, this rare karyotype has not yet been reported in the literature. The results of detailed molecular-cytogenetic studies of isodicentric (idic)Y chromosomes and isochromosome (iso)Y, which are identified in patient with complex mosaic karyotypes, are presented. The presence of mosaicism of the three cell lines 45,X, 46,X,i(Yq) and 46,X,idic(Yq) may be a contributing factor for spermatogenic failure, in addition to the instability of iso/idic Y chromosomes to pass the spermatogenesis process. Possible mechanisms of the formation of the mosaic karyotype and karyotype-phenotype correlations are discussed. The current study highlights that routine karyotype analysis and fluorescent in situ hybridization based technology are more useful in detecting mosaic chromosomal abnormality, predicting the clinical features of patients during genetic counseling and improving artificial reproductive technologies. PMID- 28713995 TI - Bioinformatic analysis of computational identified differentially expressed genes in tumor stoma of pregnancy-associated breast cancer. AB - The present study aimed to screen the differentially expressed genes (DEGs) in tumor-associated stroma of pregnancy-associated breast cancer (PABC). By analyzing Affymetrix microarray data (GSE31192) from the Gene Expression Omnibus database, DEGs between tumor asso-ciated stromal cells and normal stromal cells in PABC were identified. Gene Ontology (GO) function and pathway enrichment analyses for the DEGs were then performed, followed by construction of a protein protein interaction (PPI) network. A total of 94 upregulated and 386 downregulated DEGs were identified between tumor associated stromal cells and normal stromal cells in patients with PABC. The upregulated DEGs were primarily enriched in the cytokine-cytokine receptor interaction pathway and GO terms associated with the immune response, which included the DEGs of interleukin 18 (IL18) and cluster of differentiation 274 (CD274). The downregulated DEGs were primarily involved in GO terms associated with cell surface receptor linked signal transduction and pathways of focal adhesion and pathways in cancer. In the PPI network, nodes of jun proto-oncogene (JUN), FBJ murine osteosarcoma viral oncogene homolog (FOS), V-myc avian myelocytomatosis viral oncogene homolog (MYC), and alpha-smooth muscle actin (ACTA2) had higher degrees. The hub genes of JUN, FOS, MYC and ACTA2, as well as the DEGs IL18 and CD274 that were associated with the immune response in GO terms may exert important functions in the molecular mechanisms of PABC. These genes may be used as new molecular targets in the treatment of this disease. PMID- 28713996 TI - Downregulation of AQP2 in the anterior vaginal wall is associated with the pathogenesis of female stress urinary incontinence. AB - The pathogenesis of stress urinary incontinence (SUI) is unclear. Aquaporins (AQPs) are a family of transmembrane proteins that transport water and small solutes, including glycerol, across cell membranes. AQPs have been demonstrated to serve a role in skin hydration, cellular proliferation, migration, immunity, wound healing and vascular remodeling in multiple organs. Furthermore, studies have confirmed that abnormal synthesis and degradation of collagens in extracellular matrix (ECM) remodeling contributes to SUI, by altering normal tissue architecture and mechanical properties. The authors previously demonstrated that AQP2 expressed in the human endometrium varies during the menstrual cycle. However, it is unknown whether AQP2 serves a role in the pathogenesis of SUI in the urethral supporting tissue. In the present study, AQP2 location and expression was examined in the anterior vaginal wall, and investigated the association between AQP2 and collagen I/III in female SUI. Western blotting, immunohistochemistry and immunofluorescence were used to measure AQP2 expression levels, and to reveal the location of AQP2 in the anterior vaginal wall, as well as fibroblasts in SUI and non-SUI. The association between AQP2 and collagen I/III was subsequently investigated by AQP2-small interfering RNA knockdown and overexpression 2 in fibroblasts. AQP2 expression in the anterior vaginal wall was significantly increased in women without SUI compared with those with SUI (P<0.05). Downregulation of AQP2 significantly decreased the mRNA and protein expression of collagen I/III, while AQP2 overexpression significantly increased the mRNA and protein expression of collagen I/III in fibroblasts (P<0.05). AQP2 was demonstrated to be expressed in the anterior vaginal wall and fibroblasts, and to regulate the expression level of collagen I/III in the anterior vaginal wall and fibroblasts, suggesting that AQP2 is associated with the pathogenesis of female SUI through collagen metabolism during ECM remodeling. PMID- 28713998 TI - Identification of microRNAs in acute respiratory distress syndrome based on microRNA expression profile in rats. AB - Acute respiratory distress syndrome (ARDS) remains a severe disease associated with an ~40% mortality rate and as many as 200,000 new cases annually. MicroRNAs (miRNAs) have important roles in gene regulation and cancer development. The present study aimed to identify the potential roles of miRNAs in the pathogenesis and progression of ARDS. The miRNA expression profile of the GSE57223 dataset was downloaded from the Gene Expression Omnibus database. Following data normalization, differentially expressed miRNAs were identified using the t-test method. The miRWalk database was searched to predict target genes of the identified miRNAs and then a miRNA-miRNA network with co-regulated target genes was constructed. Additionally, Gene Ontology (GO) analysis was performed for the target genes and a miRNA-miRNA functional synergistic network (MFSN) was established. GO and pathway analyses were performed for the co-regulated target genes of significant miRNAs in MFSN. Additionally, a protein-protein-interaction network was constructed for these target genes. A total of 19 miRNAs were differentially expressed between ARDS and normal lung tissue were identified. The four downregulated rno-let-7 family members were detected to have numerous co regulated target genes and synergistic functions. Additionally, the target genes of the four miRNAs were significantly enriched the biological processes of wounding and inflammatory response. Additionally, interleukin (IL)-6 was identified as a hub protein with a high degree. The four downregulated rno-let-7 miRNAs may be involved in the inflammatory process in the pathogenesis and progression of ARDS, via the synergistic regulation of their target genes, such as IL-6. However, additional experimental validation is required. PMID- 28713997 TI - The biological functions and mechanism of miR-212 in prostate cancer proliferation, migration and invasion via targeting Engrailed-2. AB - Accumulating evidence indicates that Engrailed-2 (EN-2), which is a homeobox containing transcription factor, act as a candidate oncogene in prostate cancer (PCa). Even though there are some treatments targeting EN-2, however, it is limited because the mechanism of EN-2 upregulation in PCa cells is still unknown. In this study, we investigate the role of miR-212 on EN-2 expression and explored the mechanism of prostate cancer survival and metastasis. The relative expression levels of miR-212 and EN-2 in PCa samples and adjacent normal tissues as well as in PCa cell lines were detected by using quantitative real-time PCR. CCK-8, TUNEL and Transwell assays were used to analyze cell proliferation, apoptosis and invasion, respectively. EN-2 was identified as a direct target of miR-212 via luciferase reporter and western blot assays. Results showed that the expression level of miR-212 was downregulated in both PCa samples and PCa cell lines when compared with prostate epithelial cells and the adjacent no tumor tissues. Moreover, we found that overexpression of miR-212 suppressed PCa cell proliferation and invasion, promoted PCa cell apoptosis. EN-2 was identified as a direct target gene of miR-212 by using luciferase reporter and western blot assays. Also, the expression of EN-2 and miR-212 in the PCa cells had an opposite correlation. The critical role of miR-212 in inhibiting prostate tumor growth was verified in xenograft models of prostate cancer. These findings highlighted the role of miR-212 in PCa progression. More importantly, we speculate that EN-2 is a direct target gene of miR-212. PMID- 28713999 TI - Elevated fibrinogen-like protein 2 in TNBS-induced colitis mice: Association with Th17 and regulatory T cells. AB - The etiology and pathogenesis of inflammatory bowel disease (IBD) is complex and remains to be completely elucidated. Numerous cytokines are associated with the initiation and development of IBD. Fibrinogen-like protein 2 (FGL2), an immunosuppressive cytokine expressed by regulatory cluster of differentiation (CD)4+ T (Treg) cells, has been identified to be important for immunomodulatory activity in the inflammatory state. Therefore, the present study investigated the expression of FGL2 and interleukin (IL)-17 in trinitro-benzene-sulfonic acid (TNBS)-induced colitis mice to identify the function of FGL2, based on the effector CD4+ T helper (Th)17/Treg balance, in IBD. Compared with control mice, TNBS-induced mice exhibited marked alterations in clinical manifestation, including macroscopic and histopathological damage. Intestinal and peripheral expression of FGL2 was upregulated in TNBS-induced mice, while the level of FGL2 in the spleen was decreased. Expression of IL-17 in the plasma, colon and spleen was increased in TNBS-induced mice. The percentage of Treg cells was markedly decreased, although Th17 cells were increased following TNBS induction. The results of the present study indicated that, in the colitis model, FGL2 was associated with the immunopathogenesis of IBD. PMID- 28714000 TI - Circulating levels of angiogenesis-related growth factors in breast cancer: A study to profile proteins responsible for tubule formation. AB - The present study exploited a versatile in vitro endothelial cell/fibroblast co culture cell system to investigate the association between angiogenesis and breast cancer by comparing the capacity of plasma from women with breast cancer and age-matched controls, to influence tubule formation and modulate angiogenesis in vitro, and to identify plasma circulating factors which might be responsible. Plasma from women with breast cancer (n=8) (added on day 7 after co-culture establishment) significantly increased tubule formation by 57% (P<0.01) when compared to cultures grown in culture medium lacking in vascular endothelial growth factor (VEGF) and fetal bovine serum (FBS), whereas plasma from controls (n=8) did not. Higher levels of VEGF, tumour necrosis factor-alpha (TNFalpha) and interleukin (IL)-6, but not leptin, were observed in plasma samples of the breast cancer group compared to the control group (n=20 in each group). In independent experiments, the effects of VEGF, TNFalpha, IL-6 and leptin were assessed and it was found that tubule formation was differentially affected whether these inflammatory cytokines or adipokines were added individually or in combination to the co-culture system. Using Proteome Profiler human angiogenesis array kits, 12 out of 55 angiogenesis-related proteins were differentially expressed in plasma from the breast cancer group compared to the control group. Pro-angiogenic proteins included: amphiregulin, artemin, coagulation factor III, fibroblast growth factor (FGF) acidic, GDNF, IL-8, macrophage inflammatory protein (MIP) 1alpha, platelet derived growth factor-AB/platelet derived growth factor-BB (PDGF AB/PDGF-BB) and VEGF, whereas anti-angiogenic proteins were: angiopoietin-2, serpin F1 and serpin B5. In addition, FGF acidic was further identified as differentially expressed, with increased expression, when plasma samples from the normal and cancer groups, which induced an increase in tubule formation, were compared to one another. In conclusion, the present study identified angiogenesis related proteins circulating in the serum of women with breast cancer that are likely to facilitate the growth and metastasis of breast cancer, in part through their influence on tubule formation, and, therefore, may be potential targets for new cancer therapies. PMID- 28714001 TI - LPS enhances TLR4 expression and IFN-gamma production via the TLR4/IRAK/NF-kappaB signaling pathway in rat pulmonary arterial smooth muscle cells. AB - The aim of the present study was to investigate the role of the Toll-like receptor (TLR)4 signaling pathway in cellular response to lipopolysaccharide (LPS) in rat pulmonary artery smooth muscle cells (PASMCs). Chronic obstructive pulmonary disease (COPD) rats were established with passive inhaling cigarette smoke plus injection of LPS. The TLR4 protein in lung tissues was determined with immunohistochemical staining and protein levels of the components of the TLR4 pathway in PASMCs were analyzed with western blotting. The production of interferon (IFN)-gamma upon LPS stimulation in PASMCs was measured with ELISA. TLR4 expression in lung tissue from COPD rats was increased obviously compared with that in normal group. LPS enhances TLR4 expression in rat PASMCs and induced production of IFN-gamma dramatically. LPS treatment resulted in increased phosphor-interleukin-1 receptor-associated kinase (IRAK), IkappaB and IkappaB kinase, as well as the total protein of nuclear factor (NF)-kappaB p65. TLR4 inhibitor TAK-242, IRAK1/4 inhibitor and NF-kappaB inhibitor Bay 117082 were capable of suppressing the effects of LPS. TLR4 signaling pathway is functional in PASMCs, and may be involved in the inflammatory response during the pathogenesis of COPD. PMID- 28714002 TI - Identification of key genes in Gram-positive and Gram-negative sepsis using stochastic perturbation. AB - Sepsis is an inflammatory response to pathogens (such as Gram-positive and Gram negative bacteria), which has high morbidity and mortality in critically ill patients. The present study aimed to identify the key genes in Gram-positive and Gram-negative sepsis. GSE6535 was downloaded from Gene Expression Omnibus, containing 17 control samples, 18 Gram-positive samples and 25 Gram-negative samples. Subsequently, the limma package in R was used to screen the differentially expressed genes (DEGs). Hierarchical clustering was conducted for the specific DEGs in Gram-negative and Gram-negative samples using cluster software and the TreeView software. To analyze the correlation of samples at the gene level, a similarity network was constructed using Cytoscape software. Functional and pathway enrichment analyses were conducted for the DEGs using DAVID. Finally, stochastic perturbation was used to determine the significantly differential functions between Gram-positive and Gram-negative samples. A total of 340 and 485 DEGs were obtained in Gram-positive and Gram-negative samples, respectively. Hierarchical clustering revealed that there were significant differences between control and sepsis samples. In Gram-positive and Gram negative samples, myeloid cell leukemia sequence 1 was associated with apoptosis and programmed cell death. Additionally, NADH:ubiquinone oxidoreductase subunit S4 was associated with mitochondrial respiratory chain complex I assembly. Stochastic perturbation analysis revealed that NADH:ubiquinone oxidoreductase subunit B2 (NDUFB2), NDUFB8 and ubiquinol-cytochrome c reductase hinge protein (UQCRH) were associated with cellular respiration in Gram-negative samples, whereas large tumor suppressor kinase 2 (LATS2) was associated with G1/S transition of the mitotic cell cycle in Gram-positive samples. NDUFB2, NDUFB8 and UQCRH may be biomarkers for Gram-negative sepsis, whereas LATS2 may be a biomarker for Gram-positive sepsis. These findings may promote the therapies of sepsis caused by Gram-positive and Gram-negative bacteria. PMID- 28714003 TI - MicroRNA-130a inhibits growth and metastasis of osteosarcoma cells by directly targeting ZEB1. AB - Osteosarcoma (OS) is the most common malignant bone tumor in children and adolescents. microRNAs (miRNAs) have previously been reported to be involved in the carcinogenesis and progression of OS, and may be useful prognostic markers or therapeutic targets for patients with OS. miRNA-130a has been previously studied in multiple types of human cancer. However, its expression and function in OS has not been well documented. The aim of the present study was to investigate the expression, biological functions and molecular mechanisms underlying the effect of miR-130a in OS. miR-130a was significantly downregulated in OS tissues and cell lines compared with normal bone tissue and a normal osteoblast cell line. miR-130a expression levels was significantly negatively correlated with the clinical stage and metastasis of OS. Further studies indicated that overexpression of miR-130a inhibited OS cell proliferation, migration and invasion in vivo. In terms of the mechanisms underlying this effect, zinc finger E-box binding homeobox 1 (ZEB1) was demonstrated to act as a direct target of miR 130a in OS. Furthermore, downregulation of ZEB1 by interference with small interfering RNA mimicked the effects of transfection with an miR-130a mimic in OS. In conclusion, these results demonstrated that miR-130a functioned as a tumor suppressor in OS, partially via targeting ZEB1, suggesting that miR-130a may be considered as a target for the treatment of patients with OS. PMID- 28714004 TI - Expression and function of transforming growth factor-beta-activated protein kinase 1 in gastric cancer. AB - The present study aimed to investigate the expression and role of transforming growth factor (TGF) -beta-activated protein kinase 1 (TAK1) in human gastric cancer. Immunohistochemistry was performed to investigate the expression of TAK1 in surgical specimens of human gastric cancer tissue and adjacent normal tissue. The association between TAK1 and clinicopathologic factors was analyzed and the association between TAK1 expression and the overall survival rates was evaluated using Kaplan-Meier curves. In addition, the effect of the TAK1 selective inhibitor 5Z-7-oxozeaenol (OZ) on the biological characteristics of MGC803 human gastric cancer cells in vitro were investigated. The role of TAK1 in gastric cancer cell proliferation, apoptosis and invasion were determined by cell proliferation assays, flow cytometry analysis and transwell invasion assays, respectively. The findings of the present study demonstrated that the positive expression rate of TAK1 in gastric cancer and adjacent normal tissues was 70.5 and 25.9%, respectively. Furthermore, TAK1 expression was significantly associated with advanced N stage and pathological stage (P<0.05). Survival analysis of 139 patients with gastric cancer indicated a lower overall survival rate of patients in the TAK1-positive group compared with the TAK1-negative group (P<0.05). In addition, treatment with the TAK1 selective inhibitor OZ reduced the proliferation and invasion abilities of MGC803 cells and significantly reduced the expression levels of phosphorylated-TAK1 (Thr187), nuclear p65, cyclin D1, Bcl-2 apoptosis regulator and matrix metallopeptidase (MMP)9 (P<0.05). OZ treatment significantly increased the expression levels of cytosolic cytochrome c and cleaved caspase 3 and the apoptosis rate in MGC803 cells (P<0.05). In conclusion, these findings suggest that increased TAK1 expression may be involved in the progression of gastric cancer; therefore, TAK1 may be used as a future therapeutic target for gastric cancer treatment. PMID- 28714005 TI - MicroRNA-455 is downregulated in gastric cancer and inhibits cell proliferation, migration and invasion via targeting insulin-like growth factor 1 receptor. AB - Gastric cancer is the fourth most common and the second leading cause of cancer mortality worldwide. The dysregulation of microRNAs has been demonstrated to be significant in gastric cancer carcinogenesis and progression due to changes in expression of their target genes. In the current study, microRNA-455 (miR-455) was identified to be significantly downregulated in gastric cancer tissue samples and cell lines. A low expression level of miR-455 was correlated with the clinical stage, lymph node metastasis and tumor invasion in gastric cancer. Restoration of miR-455 expression inhibited cell proliferation, migration and invasion of gastric cancer cells in vitro. Bioinformatic analysis and luciferase reporter assay revealed that miR-455 directly targeted the 3'-untranslated region of insulin-like growth factor 1 receptor (IGF-1R). In addition, the IGF-1R mRNA expression level was increased in gastric cancer tissue samples and was inversely correlated with miR-455 expression levels. Restoration of miR-455 downregulated IGF-1R mRNA and protein expression levels in gastric cancer cells. Furthermore, silencing of IGF-1R significantly inhibited gastric cancer cell proliferation, migration and invasion, which was similar to the functions induced by miR-455 overexpression. Thus, these results indicate that miR-455 is involved in gastric cancer progression by directly targeting IGF-1R and may serve as a novel therapeutic target for the treatment of gastric cancer. PMID- 28714007 TI - Long non-coding RNA LINK-A promotes glioma cell growth and invasion via lactate dehydrogenase A. AB - Long non-coding RNAs (lncRNAs) have recently been identified in mammals as new modulators of cancer origin and progression participating in various cellular pro cesses. Long intergenic non-coding RNA for kinase activation (LINK-A), belonging to one of the intergenic lncRNAs, was reported to regulate signaling pathways correlated with triple-negative breast cancer. However, the expression and the functional role of LINK-A in glioma are still unclear. In the present study, we demonstrated that LINK-A was upregulated in human glioma cells compared with the expression noted in normal astrocytes. Knockdown of LINK-A inhibited cell proliferation, migration and invasion in U87 and U251 glioma cells. In addition, we found that lactate dehydrogenase A (LDH-A) was regulated by LINK-A, and enforced expression of LDH-A promoted glycolysis and proliferation in glioma cells. More importantly, we found that LDH-A was involved in the LINK-A-mediated proliferation and invasion of glioma cells. Collectively, these results provide new evidence of an important role for LINK-A in the development of glioma. PMID- 28714006 TI - ALDH1L1 variant rs2276724 and mRNA expression predict post-operative clinical outcomes and are associated with TP53 expression in HBV-related hepatocellular carcinoma. AB - Aldehyde dehydrogenase 1 family member L1 (ALDH1L1) is downregulated in hepatocellular carcinoma (HCC) tumors, and its decreased expression is associated with the poor prognosis of HCC patients. We, therefore, evaluated the effect of single nucleotide polymorphisms (SNPs) of ALDH1L1, and its mRNA expression on the survival of hepatitis B virus (HBV)-related HCC patients and the association with tumor protein p53 (TP53) expression. ALDH1L1 SNPs in 415 HBV-related HCC patients were genotyped via direct sequencing. Expression profile chip datasets and survival information were obtained from GSE14520. The C allele (CT/CC) carriers of rs2276724 were significantly associated with a favorable prognosis [adjusted P=0.040; adjusted hazard ratio (HR)=0.725; 95% confidence interval (CI)=0.533 0.986]. Joint-effect analyses suggested that the CT/CC genotype of rs2276724 in TP53-negative patients was significantly associated with a decreased risk of death, compared to the TT genotype of rs2276724 in TP53-positive patients (adjusted P=0.037; adjusted HR=0.621; 95% CI=0.396-0.973). Furthermore, low expression of ALDH1L1 predicted a poor prognosis for the HBV-related HCC patients (adjusted P=0.04 for disease-free survival; adjusted P=0.001 for overall survival). Patients with high ALDH1L1 expression and low TP53 expression were significantly associated with a decreased risk of recurrence and death, and patients with a high TP53 expression were also significantly associated with a decreased risk of death in HBV-related HCC, compared with low ALDH1L1 and low TP53 expression. Our results suggest that ALDH1L1 may be a biomarker for predicting postoperative clinical outcomes. Moreover, ALDH1L1-rs2276724 and mRNA expression were associated with TP53 expression in HBV-related HCC patients. PMID- 28714008 TI - Astragaloside IV protects against apoptosis in human degenerative chondrocytes through autophagy activation. AB - Increased cell apoptosis in chondrocytes is a feature of degenerative cartilage. Astragaloside IV (AST) has been proven to possess an antiarthritic effect by preventing interleukin (IL)-1beta-induced cartilage damage. However, the role of AST on chondrocyte apoptosis and its underlying mechanism remains unknown. In the present study, degenerative chondrocytes isolated from patients with osteoarthritis (OA) were subjected to AST and IL-1beta treatment. Results indicated that AST protected against chondrocyte apoptosis induced by IL-1beta. Western blotting indicated that AST increased the protein expression of LC3-II/I and decreased P62/SQSTM1 expression, which suggested that AST upregulated autophagy activity in chondrocytes. Fluorescent protein GFP-LC3 analysis and transmission electron microscopy observation confirmed that autophagy was promoted by AST. In contrast, after autophagy inhibited by 3-methyladenine, chondrocyte apoptosis was further increased under IL-1beta treatment. Ultimately, rapamycin was used as a positive control, whose results confirmed that rapamycin mediated autophagy also decreased chondrocyte apoptosis induced by IL-1beta. In conclusion, these results suggested that AST-mediated autophagy serves an anti apoptotic role in chondrocytes, which may aid the development of novel therapeutic approaches for OA treatment. PMID- 28714009 TI - MicroRNA-202 inhibits cell proliferation, migration and invasion of glioma by directly targeting metadherin. AB - Glioma is the most common and aggressive type of primary malignant brain tumour. Increasing evidence has revealed that microRNAs play important roles in multiple biological processes related to glioma occurrence, development, diagnosis, treatment and prognosis. MicroRNA-202 (miR-202) has been studied in several types of human cancer, whereas the biological roles of miR-202 in glioma remain unknown. The present study, aimed to investigate the expression, clinical significance and biological roles of miR-202 in glioma, as well as its underlying molecular mechanism. We found that miR-202 was significantly downregulated in glioma tissues and cell lines. Low miR-202 expression was associated with Karnofsky performance status (KPS) score and World Health Organization (WHO) grade of glioma patients. Functional assays revealed that ectopic expression of miR-202 inhibited cell proliferation, migration and invasion of glioma. In addition, metadherin (MTDH) was identified as a direct target gene of miR-202 in glioma through bioinformatic analysis, luciferase reporter assay, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting. Furthermore, MTDH expression was upregulated and negatively correlated with miR-202 expression in clinical glioma tissues. MTDH knockdown had similar roles to miR-202 overexpression in glioma cells. Rescue experiments revealed that upregulation of MTDH reversed the suppression of glioma cell growth and metastasis by miR-202. Moreover, miR-202 impaired the PI3K/Akt and Wnt/beta catenin pathways. These results highlight the tumour-suppressive effect of miR 202 in glioma, thereby suggesting that miR-202 may be a potential therapeutic target for the treatment of patients with this malignancy. PMID- 28714010 TI - PTPRQ as a potential biomarker for idiopathic normal pressure hydrocephalus. AB - Idiopathic normal pressure hydrocephalus (iNPH) is caused by the accumulation of cerebrospinal fluid (CSF) and is characterized by gait disturbance, urinary incontinence, and dementia. iNPH dementia is treatable by shunt operation; however, since the cognitive symptoms of iNPH are often similar to those of other dementias, including Alzheimer's disease (AD), accurate diagnosis of iNPH is difficult. To overcome this problem, the identification of novel diagnostic markers to distinguish iNPH and AD is warranted. Using comparative proteomic analysis of CSF from patients with iNPH and AD, protein tyrosine phosphatase receptor type Q (PTPRQ) was identified as a candidate biomarker protein for discriminating iNPH from AD. ELISA analysis indicated that the PTPRQ concentration in the CSF was significantly higher in patients with iNPH compared with those with AD. In addition, the PTPRQ concentration in the CSF of non responders to shunt operation (SNRs) tended to be relatively lower compared with that in the responders. PTPRQ may be a useful biomarker for discriminating between patients with iNPH and AD, and may be a potential companion biomarker to identify SNRs among patients with iNPH. Additional large-scale analysis may aid in understanding the novel aspects of iNPH. PMID- 28714011 TI - Mangiferin induces apoptosis in human ovarian adenocarcinoma OVCAR3 cells via the regulation of Notch3. AB - Ovarian cancer is the most lethal gynecological malignancy in the world. Our previous studies showed that mangiferin, purified from plant source, possessed anti-neoplasm effect on human lung adenocarcinoma A549 cells. This study aimed to determine the apoptosis-inducing effect of mangiferin on human ovarian carcinoma OVCAR3 cells. By in vitro studies, we found mangiferin significantly inhibited viability of OVCAR3 cells, and remarkably increased the sensitivity of OVCAR3 cells to cisplatin. In addition, the activation of caspase-dependent apoptosis was observed in mangiferin treated ovarian cancer cells. Importantly, we observed an obviously downregulated Notch expression after mangiferin treatment, indicating the crucial role of Notch in mangiferin mediated apoptosis. In contrast, overexpression of Notch3 abrogated the apoptosis-inducing efficacy of mangiferin, further demonstrating that mangiferin induced apoptosis via Notch pathway. Furthermore, OVCAR3 cell xenograft models revealed that mangiferin treatment inhibited tumor growth and expanded survival of tumor xenograft mice. Based on these results, we concluded that mangiferin could significantly inhibit the proliferation and induce apoptosis in OVCAR3 cells. Our study also suggested the anti-neoplasm effect of mangiferin might be via the regulation of Notch3. Taken together, by targeting cell apoptosis pathways and enhancing the response to cisplatin treatment, mangiferin may represent a potential new drug for the treatment of human ovarian cancer. PMID- 28714012 TI - Knockdown of JARID2 inhibits the viability and migration of placenta trophoblast cells in preeclampsia. AB - Protein Jumonji (JARID2) is a member of the Jumonji family of proteins and has been demonstrated to regulate cell proliferation and invasion. However, little is known about the role of JARID2 in the metastasis of placenta trophoblast cells. In the present study, the effect and the underlying molecular mechanism of JARID2 on trophoblast cell viability and invasion was investigated. The expression of JARID2 in placental tissues was analyzed by reverse transcription-quantitative polymerase chain reaction and western blotting. HTR8/SVneo cells were transfected with si-JARID2 or scramble for 24 h. Cell viability, migration and invasion in HTR8/SVneo cells were then evaluated. The expression levels of matrix metallopeptidase 2 (MMP2), MMP9, phosphorylated phosphatidylinositol 3-kinase (p PI3K), PI3K, phosphorylated AKT serine/threonine kinase 1 (p-Akt) and Akt in HTR8/SVneo cells were also detected using western blotting. The results of the present study demonstrated that JARID2 is underexpressed in human preeclamptic placentas. The knockdown of JARID2 significantly inhibited the viability, migration and invasion of HTR8/SVneo cells. In addition, the knockdown of JARID2 significantly decreased the levels of phosphorylated PI3K and Akt in HTR8/SVneo cells. The results of the present study demonstrated that JARID2 may serve a role in the progression of preeclampsia. The knockdown of JARID2 inhibited the viability and invasion of trophoblast cells in preeclampsia by suppressing the PI3K/Akt signaling pathway. Therefore, JARID2 may serve as a novel potential target for treating preeclampsia. PMID- 28714014 TI - MicroRNA-219 is downregulated in non-small cell lung cancer and inhibits cell growth and metastasis by targeting HMGA2. AB - Lung cancer is the most commonly diagnosed cancer and the leading cause of cancer associated mortality worldwide. Non-small cell lung cancer (NSCLC) is the predominant type of lung cancer, and accounts for ~85% of all lung cancer cases. An increasing number of studies suggest that microRNAs (miRs) may be involved in the regulation of NSCLC carcinogenesis and progression. However, the expression and function of miRNA-219 in NSCLC, and its underlying mechanisms of action, remain unknown. In the present study, miR-219 expression in NSCLC tissues and cell lines was determined using reverse transcription-quantitative polymerase chain reaction. Following transfection with miR-219 mimics, the effects of miR 219 overexpression on NSCLC cell proliferation, migration and invasion were examined. Furthermore, the miR-219 target in NSCLC was investigated. miR-219 was observed to be downregulated in NSCLC tissues and NSCLC cell lines. In addition, miR-219 was demonstrated to function as a tumor suppressor in NSCLC, through inhibiting cell proliferation, migration and invasion in vitro. Furthermore, high mobility group AT-hook 2 (HMGA2) was identified to be a direct target of miR-219 in NSCLC, and downregulation of HMGA2 suppressed NSCLC cell proliferation, migration and invasion in vitro. HMGA2 expression was upregulated in NSCLC tissues, and was inversely correlated with miR-219 expression. In conclusion, miR 219 functions as a tumor suppressor and may be important in inhibiting the growth and metastasis of NSCLC cells via directly targeting HMGA2. Therefore, miR-219 may present a potential novel therapeutic target for NSCLC. PMID- 28714013 TI - Glioblastoma entities express subtle differences in molecular composition and response to treatment. AB - Glioblastoma (GBM) is a grade IV astrocytoma. GBM patients show resistance to chemotherapy such as temozolomide (TMZ), the gold standard treatment. In order to simulate the molecular mechanisms behind the different chemotherapeutic responses in GBM patients we compared the cellular heterogeneity and chemotherapeutic resistance mechanisms in different GBM cell lines. We isolated and characterized a human GBM cell line obtained from a GBM patient, named GBM11. We studied the GBM11 behaviour when treated with Tamoxifen (TMX) that, among other functions, is a protein kinase C (PKC) inhibitor, alone and in combination with TMZ in comparison with the responses of U87 and U118 human GBM cell lines. We evaluated the cell death, cell cycle arrest and cell proliferation, mainly through PKC expression, by flow cytometry and western blot analysis and, ultimately, cell migration capability and f-actin filament disorganization by fluorescence microscopy. We demonstrated that the constitutive activation of p-PKC seems to be one of the main metabolic implicated on GBM malignancy. Despite of its higher resistance, possibly due to the overexpression of P-glycoprotein and stem-like cell markers, GBM11 cells presented a subtle different chemotherapeutic response compared to U87 and U118 cells. The GBM11, U87, U118 cell lines show subtle molecular differences, which clearly indicate the characterization of GBM heterogeneity, one of the main reasons for tumor resistance. The adding of cellular heterogeneity in molecular behaviour constitutes a step closer in the understanding of resistant molecular mechanisms in GBM, and can circumvents the eventual impaired therapy. PMID- 28714015 TI - miR-142 inhibits the migration and invasion of glioma by targeting Rac1. AB - Increasing evidence has shown that aberrant microRNAs (miRNAs) are implicated in tumorigenesis and tumor progression by regulating oncogenes or tumor suppressors. Dysregulation of miR-142 has been reported in multiple tumors. However, its clinical roles and underlying mechanism in glioma remain to be elucidated. In the present study, we found that the expression of miR-142 was significantly downregulated in both glioma tissues and cell lines by qRT-PCR. Clinical analysis revealed that decreased miR-142 was markedly associated with advanced World Health Organization (WHO) grade. Moreover, we disclosed that miR-142 was a novel independent prognostic marker in the prediction of the 5-year survival of glioma patients. The ectopic overexpression of miR-142 inhibited cell migration, invasion and invasion-related gene expression. Notably, miR-142 modulated Rac1 by directly binding to its 3'-untranslated (3'-UTR) region, leading to the suppression of the expression of matrix metalloproteinases (MMPs). In glioma clinical samples, miR-142 was inversely correlated with Rac1 expression, and played positive roles in glioma migration and invasion. Alteration of Rac1 expression at least partially abolished the migration, invasion and MMP expression of miR-142 in glioma cells. In the present study, we identified Rac1 as a functional target of miR-142 in glioma. In conclusion, our data indicated that miR-142 inhibited the migration, invasion and MMP expression of glioma by targeting Rac1, and may represent a novel potential therapeutic target and prognostic marker for glioma. PMID- 28714016 TI - Elastin-derived peptides are involved in the processes of human temporomandibular disorder by inducing inflammatory responses in synovial cells. AB - Temporomandibular joint dysfunction (TMD) is a collection of clinical symptoms that involve masticatory muscles and the temporomandibular joint (TMJ). Common symptoms include limited jaw motion and joint sound/pain, along with TMJ disc displacement. TMD is frequently associated with synovitis, a chronic inflammation of the synovium. Fibroblast-like synovial cells have been identified to produce several inflammatory mediators and may have an important role in the progression of TMJ inflammation. Degradation of the extracellular matrix molecule elastin may lead to the release of bioactive peptides. The present study aimed to explore the role of elastin-derived peptides (EDPs) in human temporomandibular disorders. Therefore, interleukin-6 (IL-6) expression in the synovial fluid obtained from patients with TMD correlated significantly with two clinical parameters, specifically TMJ locking and pain/jaw function on a visual analog scale (VAS). To the best of our knowledge, this is the first study to determine that the concentration of EDPs in synovial fluid from patients with TMD may also be significantly correlated with the duration of TMJ locking, the VAS score and IL-6 expression. In vitro, EDPs act on human TMJ synovial cells to promote upregulation of IL-6 and the elastin-degrading enzyme matrix metalloproteinase-12 (MMP-12). The upregulation of IL-6 and MMP-12 expression by EDPs may be mediated through elastin-binding proteins (EBP) and a protein kinase A signalling cascade. These findings suggest a model for inflammation in the TMJ where EDPs are generated by harmful mechanical stimuli, induce both a pro-inflammatory cascade and increase expression of MMP-12 through activation of the EBP signalling cascade. This may lead to further increases in EDP levels, establishing a positive feedback loop leading to chronic inflammation in the TMJ. Therefore, significantly elevated levels of EDPs and IL-6 in the synovial fluid of the TMJ may be indicators of the pathological conditions of the joint. PMID- 28714017 TI - Targeting VEGFR and FGFR in head and neck squamous cell carcinoma in vitro. AB - Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous disease characterized by a tumor microenvironment (TME) that overexpresses vascular endothelial growth factor receptor (VEGFR) and fibroblast growth factor receptor (FGFR), which can lead to neovascularization, tumor growth and metastasis. Therapeutic strategies inhibiting these signaling pathways might lead to innovative HNSCC treatments. Five HNSCC cell lines were characterized based on VEGFR1-3 and FGFR1-4 expression by sqRT-PCR and treated with three different tyrosine kinase inhibitors (TKIs) (nintedanib, dovitinib and pazopanib), all of which are effective against VEGFR and FGFR family members. Crystal violet assays were performed to analyze the effect of the treatments on cell growth (viability). Additionally, VEGFR1-3 and FGFR1-4 expression data were retrieved from The Cancer Genome Atlas (TCGA), and statistical analyses were performed to investigate the receptor expression level in the different cell lines and the efficacy of the single-agent treatments. A correlation analysis was performed to quantify the degree of relationship between receptor expression and drug efficacy. With the exception of VEGFR2, the targeted receptors were expressed at different levels in all of the cell lines. The cell lines exhibited concentration dependent responses with cell line-specific differences toward two of the three TKIs (nintedanib and dovitinib). Notably, all of the cell lines were resistant to pazopanib. TKIs have potential as therapeutic agents for HNSCC. Cell line specific differences were observed in our in vitro experiments. The observed pazopanib resistance could be explained by receptor expression. Further investigation is required to determine TKI efficacy in HNSCC. PMID- 28714018 TI - miR-125a-5p upregulation suppresses the proliferation and induces the cell apoptosis of lung adenocarcinoma by targeting NEDD9. AB - MicroRNAs (miRNAs) are critical translational regulators that act as oncogenes or tumor-suppressor genes. qRT-PCR assay results showed that the expression levels of miR-125a-5p are lower in lung adenocarcinoma (AD) tissues than expression levels in adjacent non-neoplastic tissues. This relative expression was found to be significantly associated with lymph node metastases. Cell growth, apoptosis, caspase activity and Transwell invasion assay results showed that in two lung adenocarcinoma cell lines transfected with a miR-125a-5p mimic, proliferation and invasion rates were found to be significantly reduced, whereas the apoptosis rate of the miR-125a-5p mimic group was enhanced. Subsequent western blotting and luciferase reporter assays showed that miR-125a-5p is able to bind to putative binding sites within the mRNA 3' untranslated region (UTR) of neural precursor cell expressed, developmentally downregulated 9 (NEDD9). Our findings suggest that miR-125a-5p may serve as a therapeutic agent for lung adenocarcinoma through its major target, NEDD9. PMID- 28714019 TI - Salidroside protects PC12 cells from Abeta1-40-induced cytotoxicity by regulating the nicotinamide phosphoribosyltransferase signaling pathway. AB - Alzheimer's disease (AD) is the most common type of senile dementia, which often develops in elderly or presenile individuals. As one of the pathological features of AD, amyloid beta-protein (Abeta) causes energy dysmetabolism, thereby inducing cellular damage and apoptosis. Salidroside is the main active component of the traditional Chinese medicine Rhodiola. Previous studies have demonstrated that salidroside exerts a regulatory role in energy metabolism. However, the role and the mechanism of action of salidroside in AD remain unclear. Therefore, the present study used Abeta1-40 to induce damage in PC12 cells, thereby establishing a cell model of AD. In addition, salidroside treatment was performed to investigate the protective effect of salidroside and the underlying mechanisms. Abeta1-40-induced neuronal toxicity reduced cell viability and caused cellular damage. As a result, the expression level of nicotinamide phosphoribosyltransferase (NAMPT) decreased, the synthesis of nicotinamide adenine dinucleotide (NAD+; an energy metabolism-associated coenzyme) became insufficient, and the NAD+/nicotinamide adenine dinucleotide hydride ratio was reduced. Administration of salidroside alleviated Abeta-induced cell damage and increased the expression level of the key protein NAMPT and the synthesis of NAD+. The results of the present study demonstrate that salidroside exerts a protective effect on Abeta1-40-damaged PC12 cells. The underlying mechanism may be associated with the regulation of energy metabolism that relies predominantly on the NAMPT signaling pathway. PMID- 28714020 TI - Potential role of upregulated microRNA-146b and -21 in renal fibrosis. AB - The aim of the present study was to identify candidate microRNAs (miRNAs) involved in the progression of renal fibrosis. Dataset GSE42716 of miRNAs extracted from kidneys from mice with unilateral ureteral obstruction (UUO), and mice without UUO was downloaded from the Gene Expression Omnibus database. The Limma package was used to identify differential expression between mice with and without UUO. Renal disease-related miRNAs were predicted based on the miRWalk database. Thereafter, candidate miRNAs were screened by taking the intersection of differentially expressed miRNAs and predicted miRNAs, followed by screening of target genes using miRWalk and transcription factors using the TransmiR database. An integrative regulatory network was constructed using Cytoscape software. Enrichment analysis of target genes was also performed. In total, 76 differentially expressed miRNAs were identified in kidneys with UUO compared with the normal samples based on dataset and 9 miRNAs were identified as related to renal disease from the miRWalk database. A Venn diagram revealed two overlapping upregulated miRNAs; miR-146b and miR-21. Transcription factor NFKB1 may activate miR-146b and AKT may activate miR-21. In addition, miR-21 had a regulatory effect on IFNG expression and miR-146b may regulate the expression of BCL2, PTEN and IFNG. Furthermore, target genes of miR-146b and miR-21 were significantly enriched in 14 Gene Ontology terms including regulation of cell proliferation (e.g., BCL2, PTEN and IFNG). Overexpression of miR-21 may be activated by AKT2 and contribute to renal fibrosis by negatively regulating IFNG expression. Furthermore, miR-146b may be activated by NFKB1 and subsequently reduce the expression of BCL2, PTEN and IFNG in the progression of renal fibrosis. PMID- 28714021 TI - Iodine-131 induces apoptosis in human cardiac muscle cells through the p53/Bax/caspase-3 and PIDD/caspase-2/ t-BID/cytochrome c/caspase-3 signaling pathway. AB - The aim of this study was to elucidate the effects of iodine-131 on the induction of apoptosis in human cardiac muscle cells and the underlying molecular mechanisms. We found that iodine-131 reduced cell proliferation, induced apoptosis, induced p53, PIDD, t-BID (mitochondria) protein expression, suppressed cytochrome c (mitochondria) protein expression, and increased Bax protein expression, and promoted caspase-2, -3 and -9 expression levels in human cardiac muscle cells. Meanwhile, si-p53 inhibited the effects of iodine-131 on the reduction in cell proliferation and induction of apoptosis in human cardiac muscle cells through regulation of Bax/cytochrome c/caspase-3 and PIDD/caspase 2/t-BID/cytochrome c/caspase-3 signaling pathway. After si-Bax reduced the effects of iodine-131, it reduced cell proliferation and induced apoptosis in human cardiac muscle cells through the cytochrome c/caspase-3 signaling pathway. However, si-caspase-2 also reduced the effects of iodine-131 on the reduction of cell proliferation and induction of apoptosis in human cardiac muscle cells through the t-BID/cytochrome c/caspase-3 signaling pathway. These findings demonstrated that iodine-131 induces apoptosis in human cardiac muscle cells through the p53/Bax/caspase-3 and PIDD/caspase-2/t-BID/cytochrome c/caspase-3 signaling pathway. PMID- 28714022 TI - Platelet poor plasma gel combined with amnion improves the therapeutic effects of human umbilical cord-derived mesenchymal stem cells on wound healing in rats. AB - The aim of the present study was to investigate the efficacy of human umbilical cord-derived mesenchymal stem cell (HUMSCs) embedded in platelet poor plasma (PPP) gel combined with amnion (PPPA) in improving wound healing on Sprague Dawley (SD) rats. HUMSCs were cultured and labeled with chloromethylbenzamido 1,1'-dioctadecyl-3,3,3'3'-tetramethylindocarbocyanine perchlorate (CM-DiI) on their third passage. The expression levels of growth factors of HUMSCs in PPPA were assessed by ELISA. Full-thickness excisional skin wounds were induced in 36 male SD rats, which were treated with PPPA grafted with HUMSCs (PPPAC), PPPA, or HUMSC or PBS injection. The degree of healing and the distribution of labeled HUMSCs in the wound were evaluated by hematoxylin and eosin (H&E) staining and immunofluorescence. On day 14 post-surgery, wound healing in PPPAC-treated rats was significantly higher than the PPPA group, compared with rats treated with HUMSCs alone and control rats (P<0.05 and P<0.01, respectively). H&E staining showed that morphology and thickness of the epidermis in the PPPAC group was similar to that of healthy skin. ELISA revealed that levels of growth factors of HUMSCs in PPPAC were higher than in monolayer cells. In conclusion, PPPA can modify growth factor expression levels of HUMSCs and improve the efficiency of HUMSCs in the healing of full thickness wounds in rats. PMID- 28714023 TI - Protective effects of Shexiang Tongxin Dropping Pill on pituitrin-induced acute myocardial ischemia in rats. AB - Shexiang Tongxin Dropping Pill (STP) is an established traditional Chinese medicine that is widely used for the treatment of ischemic heart disease (IHD), although its mechanisms remain unclear. The present study investigated the protective effects of STP following pituitrin (PTT)-induced myocardial ischemia in rats. ST-segment elevation, blood rheology, and the serum levels of creatine kinase-MB (CK-MB) and lactate dehydrogenase (LDH) were measured. Following heart excision, histological analysis using hematoxylin and eosin and terminal deoxynucleotidyl transferase dUTP nick end labeling were performed. The mRNA expression levels of B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X protein (Bax) were determined using reverse transcription-quantitative polymerase chain reaction, and their protein expression was detected using immunohistochemistry. The results demonstrated that STP treatment protected against ST elevation, lowered whole blood viscosity, and reduced the serum levels of CK-MB and LDH following acute myocardial ischemia. In addition, STP treatment restored the histopathological change following PTT-induced myocardial ischemia, and resulted in downregulated expression of Bax and upregulated expression of Bcl-2 in myocardial tissue. The present study demonstrates the cardioprotective ability of STP in a rat model of myocardial ischemic injury, which may be attributed to its anti-apoptotic properties. The cardioprotective properties of STP require further investigation to determine whether it may be used for the clinical treatment of IHDs. PMID- 28714025 TI - Effect of CCL2 siRNA on proliferation and apoptosis in the U251 human glioma cell line. AB - Glioma is one of the most common types of tumor of the central nervous system. Increased expression of C-C motif chemokine 2 (CCL2) has previously been observed in various types of cancer. The effect of CCL2 small interfering (si)RNA on the proliferation, angiogenesis and apoptosis of the glioma cell line U251 was investigated in the present study. Data on CCL2 expression in glioma and normal tissues were obtained from The Cancer Genome Atlas. A total of 30 patients with glioma were enrolled in the present study. Cell proliferation was measured using a Cell Counting kit-8 assay, while cellular apoptosis and cell cycle distribution were examined using flow cytometric analysis. The reverse transcription quantitative polymerase chain reaction and western blot analysis were used to measure the expression levels of biological pathway-associated proteins caspase 3, caspase-7, tumor necrosis factor receptor superfamily member 10C (TNFRSF10C), growth regulated alpha protein (CXCL1), C-X-C motif chemokine 2 (CXCL2), C-X-C chemokine receptor type 2 (CXCR2), vascular endothelial growth factor (VEGF)A, VEGFB and VEGF. In addition, the mechanism of cellular apoptosis was analyzed by examining the phosphorylation of extracellular signal-related kinase (ERK)1/2 and p38 mitogen-activated protein kinase (p38) in cells treated with the C-C chemokine receptor type 2 inhibitor RS-102895. CCL2 was observed to be expressed in the glioma cell line U251 and was inhibited by CCL2 siRNA. Cells transfected with CCL2 siRNA exhibited inhibited cell proliferation, cell cycle arrest and increased cellular apoptosis. The expression levels of the apoptosis-associated proteins caspase-3, caspase-7 and TNFRSF10C were observed to be downregulated, in addition to those of the angiogenesis-associated proteins CXCL1, CXCL2, CXCR2, VEGFA, VEGFB and VEGF. The decrease in the rate of phosphorylation of ERK1/2 and p38 demonstrated the involvement of the mitogen-activated protein kinase/ERK pathway in apoptosis. In conclusion, CCL2 siRNA exhibited effective inhibition of cell proliferation and angiogenesis in the glioma cell line U251, which may provide a theoretical basis for the use of CCL2 in in vivo research and clinical treatment as a novel anticancer agent. PMID- 28714024 TI - Magnesium isoglycyrrhizinate protects against renal-ischemia-reperfusion injury in a rat model via anti-inflammation, anti-oxidation and anti-apoptosis. AB - The present study aimed to investigate whether magnesium isoglycyrrhizinate protects against renal ischemia-reperfusion injury (RIRI), and to verify the underlying mechanisms. An RIRI rat model was induced by removing the right kidney, and exposing and clamping the left kidney. RIRI model rats were administered 30 mg/kg magnesium isoglycyrrhizinate for 3 days. Blood urea nitrogen (BUN) and serum creatinine levels in the blood of RIRI model rat were examined, compared with sham-operated controls. Magnesium isoglycyrrhizinate suppressed the activities of tumor necrosis factor-alpha, interleukin (IL)-1beta, IL-6, superoxide dismutase, glutathione peroxidase, inducible nitric oxide synthase (iNOS) and caspase-3 in RIRI model rats. Renal iNOS, matrix metalloproteinase (MMP)-2, phosphorylated-signal transducers and activators of transcription 3 (STAT3) and intercellular adhesion molecule-1 (ICAM-1) protein expression levels were suppressed by magnesium isoglycyrrhizinate treatment in RIRI model rats. These findings suggested that magnesium isoglycyrrhizinate protects RIRI via anti-inflammatory, -oxidative and -apoptotic mechanisms in an RIRI rat model. These results implicate magnesium isoglycyrrhizinate pretreatment as a potential approach to protect against RIRI via suppression of the iNOS, ICAM 1, MMP-2 and STAT3 signaling pathways. PMID- 28714026 TI - miR-206 inhibits cancer initiating cells by targeting EHF in gastric cancer. AB - Cancer initiating cells (CIC) are defined as the unique subpopulation in the tumors that possess the ability to initiate tumor growth and sustain self-renewal as well as metastatic potential. In this study, we found that EHF overexpression promoted formation of CIC traits and silencing it inhibited the traits in gastric cancer NCI-N87 cells. Overexpressing EHF downregulated the antitumor effect of 5 fluorouracil (5-FU) in NCI-N87 cells. We found that miR-206 downregulated EHF protein expression by targeting its 3'UTR in NCI-N87 cells and GES-1 cells. Overexpressing miR-206 inhibited formation of CIC in NCI-N87 cells. In gastric cancer tissues, EHF protein expression was upregulated and miR-206 was downregulated. We identified a negative correlation between EHF protein and miR 206 expression in gastric cancer tissues. Thus, we concluded that miR-206 inhibits formation of CICs by targeting EHF in gastric cancer. PMID- 28714028 TI - Identification of potential target genes associated with the pathogenesis of osteoarthritis using microarray based analysis. AB - The aim of the present study was to investigate the molecular circuitry of osteoarthritis (OA) and identify more potential target genes for OA treatment. Microarray data of GSE32317 was downloaded from the National Center for Biotechnology Information Gene Expression Omnibus database. Differentially expressed genes (DEGs) were identified in samples of synovial membrane from patients with early stage of knee OA (OA_Early) and late stage of knee OA (OA_End) that were compared with healthy specimens. Bioinformatics analysis was applied to analyze the significant functions and pathways that were enriched by the common DEGs identified in OA_Early and OA_End samples. Furthermore, a protein protein interaction (PPI) network was constructed and significant modules were extracted. Transcription factors (TFs) that could regulate genes in the significant modules were identified. A total of 1,207 and 1,575 DEGs were identified in OA_Early and OA_End samples compared with healthy samples, respectively. A total of 740 genes were upregulated and 308 genes were downregulated across the OA_Early and OA_End samples. These common DEGs were enriched in different gene ontology terms and pathways, such as immune response. Angiotensinogen (AGT) and C-X-C motif chemokine ligand 12 (CXCL12) were identified to be hub proteins in the PPI network or in the selected module 1. In addition, the DEG lysine demethylase 2B (KDM2B) was identified as a TF that can regulate genes in the significant modules 2 and 3. In conclusion, the present study has identified AGT, CXCL12 and KDM2B as potentially essential genes associated with the pathogenesis of knee OA. PMID- 28714027 TI - Enhanced anticancer effects of a mixture of low-dose mushrooms and Panax ginseng root extracts in human colorectal cancer cells. AB - Worldwide, colorectal cancer is the third most common cancer in men and the second most common in women. As conventional colorectal cancer therapies result in various side effects, there is a need for adjuvant therapy that can enhance the conventional therapies without complications. In this study, we investigated the anticancer effects of combined mixture of the several medicinal mushrooms and Panax ginseng root extracts (also called Amex7) as an adjuvant compound in the treatment of human colorectal cancer. We observed the in vivo inhibitory effect of Amex7 (1.25, 6.25, and 12.5 ml/kg, oral administration, twice daily) on tumor growth in a mouse model xenografted with HT-29 human colorectal cancer cells. In vitro, at 6, 12, and 24 h after 4% Amex7 treatment, we analyzed cell cycle by flow cytometry and the expression levels of cell cycle progression, apoptosis, and DNA damage repair-related proteins using immunoblotting and immunofluorescence staining in HT-29 cell line. As a result, Amex7 significantly suppressed tumor growth in HT-29 human colorectal cancer cells and xenografts. In vitro, Amex7 induced G2/M arrest through the regulation of cell cycle proteins and cell death by apoptosis and autophagy. Additionally, Amex7 consistently induced DNA damage and delayed the repair of Amex7-induced DNA damage by reducing the level of HR repair proteins. In conclusion, Amex7 enhanced anticancer effects through the induction of G2/M arrest and cell death, including apoptosis and autophagy. Furthermore, Amex7 impaired DNA damage repair. The present study provides a scientific rationale for the clinical use of a combined mixture of medicinal mushrooms and P. ginseng root extracts as an adjuvant treatment in human colorectal cancer. PMID- 28714029 TI - Involvement of gut microbiota in the association between gastrointestinal motility and 5-HT expression/M2 macrophage abundance in the gastrointestinal tract. AB - Serotonin (5-hydroxytryptamine; 5-HT) may be a key player in gastrointestinal (GI) motility and the GI immune system. In the present study, the effect of gut microbiota on the association between GI motility, and 5-HT expression and macrophage abundance in the GI tract was examined. Germ-free (GF) mice (6 weeks old) were orally administered a fecal bacterial suspension prepared from specific pathogen-free mice and their GI tissues were evaluated 4 weeks later. The expression of 5-HT and mannose receptor (MR) was examined by immunohistochemistry, and GI transit time (GITT) was measured by administration of carmine red solution. The numbers of 5-HT-positive endocrine cells and muscularis MR-positive macrophages were significantly increased in the upper GI and colon of GF mice subjected to fecal transplantation (FT) compared with control GF mice without FT. GITT was significantly decreased in GF mice subjected to FT compared with GF mice without FT, and negatively correlated with the numbers of 5-HT-positive cells in the upper GI and muscularis MR-positive macrophages throughout the GI tract. The numbers of 5-HT-positive endocrine cells and muscularis MR-positive macrophages were significantly correlated throughout the GI tract. The present results suggest that the gut microbiota is involved in the association between accelerated GI motility and induction of the 5 HT/muscularis MR-positive macrophage axis in the GI tract. PMID- 28714030 TI - KDM5A promotes proliferation and EMT in ovarian cancer and closely correlates with PTX resistance. AB - The authors initially performed reverse transcription-quantitative polymerase chain reaction to determine the expression profile of KDM5A in ovarian cancer tissues and adjacent normal tissue. Compared with adjacent normal tissue, it was identified that KDM5A was highly expressed in ovarian cancer tissues. Moreover, human ovarian cell lines also confirmed that KDM5A was highly expressed in ovarian cancer. KDM5A was especially highly expressed in SKOV3/paclitaxel (PTX) cells, which are resistant to PTX. Previous studies demonstrated that chemoresistance in cancer cells facilitates epithelial-to-mesenchymal transition (EMT). Following this, whether KDM5A influenced EMT and metastasis was investigated. The expression of KDM5A and N-cadherin were obviously higher in SKOV3/PTX cells than in SKOV3 cells. The expression of E-cadherin was decreased and the expression of N-cadherin was increased following ectopic expression of KDM5A, while the expression of E-cadherin was increased and the expression of N cadherin was decreased following KDM5A depletion. Transwell and wound healing assays were used to explore the function of KMD5A in metastasis. The present results indicated that KDM5A facilitated EMT and metastasis in ovarian cells. Moreover, it was identified that P-glycoprotein was increased while KDM5A was expressed ectopically in SKOV3 cells. Following fluorescence-activated cell sorting flow cytometry analysis and CCK-8 assay all revealed that KDM5A regulated the PTX sensitivity in SKOV3 and SKOV3/PTX cells. In brief, KDM5A is a crucial oncogene that is significantly upregulated in ovarian cancer. Its expression is closely correlated with cancer cell proliferation, EMT and metastasis. KDM5A suppresses ovarian cancer cell apoptosis under PTX treatment. PMID- 28714031 TI - Effects of neuritin on the differentiation of bone marrow-derived mesenchymal stem cells into neuron-like cells. AB - While the neurotrophic factor neuritin is known to be involved in neurodevelopment, the effects of this compound on cell differentiation remain unclear. The present study demonstrated that neuritin treatment induced the differentiation of rat bone marrow-derived mesenchymal stem cells (rBM-MSCs) into neuron-like (NL) cells. For these analyses, rBM-MSCs were incubated with 0.5 ug/ml neuritin for 24 h. Following induction, 27% of the rBM-MSCs exhibited typical NL cell morphologies. Subsequently, NL cells were characterized by examining the expression of neuronal markers and by analysis of cell functions. The findings demonstrated that the NL cells produced by neuritin treatment expressed the neuronal markers neuron-specific enolase and microtubule associate protein 2, and secreted the neurotransmitter 5-hydroxytryptamine. Furthermore, the NL cells exhibited certain partial neural-electrophysiological functions. In conclusion, neuritin treatment may be an effective method for inducing the differentiation of BM-MSCs towards NL cells. This may provide an alternative, potentially complementary tool for disease modeling and the development of cell based therapies. PMID- 28714032 TI - ATF3 promotes migration and M1/M2 polarization of macrophages by activating tenascin-C via Wnt/beta-catenin pathway. AB - There are different polarization states of macrophages, including the classically activated M1 phenotype and the alternatively activated M2 phenotype. These have different functions in the inflammation process. Activating transcription factor 3 (ATF3) is a key transcriptional regulator that inhibits the inflammatory response. However, the effects of ATF3 on migration and anti-inflammatory control mechanisms of macrophages have not been thoroughly investigated. The present study investigated the effect of ATF3 on macrophage migration and M1/M2 polarization. Results revealed that overexpression of ATF3 promoted macrophage migration and the expression of the M2 phenotype markers [cluster of differentiation (CD) 163, mannose receptor C type 1, arginase 1 and peroxisome proliferator-activated receptor gamma] and inhibited expression of the M1 phenotype markers (monocyte chemoattractant protein-1, inducible nitric oxide synthase, CD16 and tumor necrosis factor-alpha), whereas knockdown of ATF3 resulted in a contrary effect. In addition, the wingless-type MMTV integration site family member (Wnt)/beta-catenin signaling pathway was activated and the expression level of tenascin (TNC) was significantly upregulated by overexpression of ATF3. Additionally, inhibition of Wnt/beta-catenin signaling significantly attenuated the upregulatory effect of ATF3 on TNC. Finally, the effect of ATF3 on macrophage migration and markers of the M1 or M2 state was investigated using TNC-specific siRNA. In conclusion, the results of the present study suggested that ATF3 promotes macrophage migration and reverses M1-polarized macrophages to the M2 phenotype by upregulation of TNC via the Wnt/beta-catenin signaling pathway. PMID- 28714033 TI - Evaluation of velvet antler total protein effect on bone marrow-derived endothelial progenitor cells. AB - Lu Rong, velvet antler (VA), is a traditional Chinese medicine, which is used as a food supplement and therapeutic drug in China, Japan, Russia, New Zealand and Southeast Asia. The regenerative characteristics of VA have resulted in great research interest, particularly regarding the fields of organ grafting and stem cell differentiation. Various VA proteomic studies verified that proteins act as the primary bioactive components of VA. The present study aimed to investigate if VA proteins (VA-pro) influence endothelial progenitor cell (EPC) viability. Various methods have previously been used to investigate VA-pro, including freeze drying technology, ultrasonic wave methods, high performance liquid chromatography-mass spectrometry, EPCs extraction and culture. Results demonstrated that VA-pro promoted EPCs proliferation and migration, particularly at a concentration of 1 mg/ml. Furthermore, VA-pro increased the activation level of Notch1 intracellular domain and Hes1, and the level of phosphorylated-Akt and phosphorylated-mechanistic target of rapamycin. VA-pro may therefore affect EPC viability via regulation of the Notch and Akt signaling pathways. The present study revealed the effects and potential molecular mechanism of VA-pro on EPCs, and suggested an association between VA regeneration characteristics and the optimization of EPC viability. These findings may contribute to EPC transplantation research and aid in providing a novel treatment method for vascular diseases in the future. PMID- 28714034 TI - Inhibition of NAMPT decreases cell growth and enhances susceptibility to oxidative stress. AB - Nicotinamide adenine dinucleotide (NAD) is an essential molecule for living organisms and plays a vital role in aging and age-associated diseases. In eukaryotic cells, cellular NAD is mainly generated by the scavenge pathway in which nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the formation of nicotinamide mononucleotide. Inhibition of NAMPT is a therapeutic strategy for cancer treatment. To explore the effects of NAMPT inhibition on cellular processes, cells were treated with 10 nM FK866, an NAMPT inhibitor, resulting in a decrease in the cellular NAD level, a lower growth rate, and enhanced susceptivity to oxidative stress as compared to the untreated cells. Quantitative proteomics revealed that 325 proteins were downregulated in the FK866-treated cells, and were involved in diverse cellular processes including nucleobase containing compound metabolic process, protein metabolic process, antioxidant and DNA repair processes. Downregulation of 4 selected proteins was confirmed by western blotting and quantitative PCR. Downregulation of antioxidant proteins GRX1 and catalase, and DNA-repair proteins PCNA and PARP1 contributed to the enhanced susceptibility of FK866-treated cells to oxidative stress. FK866 treatment also caused mitochondrial dysfunction through downregulation of mitochondrial ribosomal proteins. Taken together, these results demonstrate that FK866 treatment efficiently decreases the cellular NAD level and induces autonomous changes in proteostasis, leading to cell growth inhibition and increased susceptibility to oxidative stress. PMID- 28714035 TI - Immunocytochemical stem cell markers can predict clinical stage of breast cancer. AB - We present a computational-statistical algorithm that, from data on the staining degree of immunocytochemical markers: i) evaluates the ability of the considered immuno-panel in predicting the breast cancer stage; ii) makes the accurate identification of breast cancer stage possible; iii) provides the best stage prognosis compatible with the considered sample; and iv) does so through the use of the minimum number of markers minimizing time and resource costs. After running the algorithm on two data sets [triple-negative breast cancer, (TNBC), and estrogen receptor-negative breast cancer, (ERNBC)], we conclude that EpCAM and beta1 integrin are enough to accurately predict TNBC stage, being ALDH1, CD24, CD61, and CK5 the necessary markers to exactly predict ERNBC stage. PMID- 28714036 TI - Pharmacokinetics of intravenous pan-class I phosphatidylinositol 3-kinase (PI3K) inhibitor [14C]copanlisib (BAY 80-6946) in a mass balance study in healthy male volunteers. AB - PURPOSE: To determine the pharmacokinetics of radiolabeled copanlisib (BAY 80 6946) in healthy male volunteers and to investigate the disposition and biotransformation of copanlisib. METHODS: A single dose of 12 mg copanlisib containing 2.76 MBq [14C]copanlisib was administered as a 1-h intravenous infusion to 6 volunteers with subsequent sampling up to 34 days. Blood, plasma, urine and feces were collected to monitor total radioactivity, parent compound and metabolites. RESULTS: Copanlisib treatment was well tolerated. Copanlisib was rapidly distributed throughout the body with a volume distribution of 1870 L and an elimination half-life of 52.1-h (range 40.4-67.5-h). Copanlisib was the predominant component in human plasma (84% of total radioactivity AUC) and the morpholinone metabolite M1 was the only circulating metabolite (about 5%). Excretion of drug-derived radioactivity based on all 6 subjects was 86% of the dose within a collection interval of 20-34 days with 64% excreted into feces as major route of elimination and 22% into urine. Unchanged copanlisib was the main component excreted into urine (15% of dose) and feces (30% of dose). Excreted metabolites (41% of dose) of copanlisib resulted from oxidative biotransformation. CONCLUSIONS: Copanlisib was eliminated predominantly in the feces compared to urine as well as by hepatic biotransformation, suggesting that the clearance of copanlisib would more likely be affected by hepatic impairment than by renal dysfunction. The dual mode of elimination via unchanged excretion of copanlisib and oxidative metabolism decreases the risk of clinically relevant PK-related drug-drug interactions. PMID- 28714037 TI - Preparing pathology for the molecular era. PMID- 28714038 TI - One and two-year persistence with different anti-osteoporosis medications: a retrospective cohort study. AB - : Adherence to anti-osteoporosis medications is poor. We carried out a cohort study using a real-world population database to estimate the persistence of anti osteoporosis drugs. Unadjusted 2-year persistence ranged from 10.3 to 45.4%. Denosumab users had a 40% lower risk of discontinuation at 2 years compared to alendronate users. PURPOSE: The purpose of this study was to estimate real-world persistence amongst incident users of anti-osteoporosis medications. METHODS: This is a retrospective cohort using data from anonymised records and dispensation data ( www.sidiap.org ). Eligibility comprised the following: women aged >=50, incident users of anti-osteoporosis medication (2012), with data available for at least 12 months prior to therapy initiation. Exclusions are other bone diseases/treatments and uncommon anti-osteoporosis drugs (N < 100). Follow-up was from first pharmacy dispensation until cessation, end of study, censoring or switching. Outcomes are 2- and 1-year persistence with a permissible gap of up to 90 days. Persistence with alendronate was compared to other bisphosphonates, strontium ranelate, selective oestrogen receptor modulators, teriparatide and denosumab. Cox models were used to estimate hazard ratios of therapy cessation according to drug used after adjustment for age, sex, BMI, smoking, alcohol drinking, Charlson co-morbidity index, previous fractures, use of anti-osteoporosis medication/s, oral corticosteroids and socio-economic status. RESULTS: A total of 19,253 women were included. Unadjusted 2-year persistence [95% CI] ranged from 10.3% [9.1-11.6%] (strontium ranelate) to 45.4% [43.1-47.8%] (denosumab). One-year persistence went from 35.8% [33.9%-37.7%] (strontium ranelate) to 65.8% [63.6%-68.0%] (denosumab). At the end of the first year and compared to alendronate users, both teriparatide and denosumab users had reduced cessation risk (adjusted HR 0.76, 95% CI 0.67-0.86 and 0.54, 95% CI 0.50 0.59 respectively) while at the end of the second year, only denosumab had a lower risk of discontinuation (adjusted HR 0.60, 95% CI 0.56-0.64). CONCLUSIONS: Unadjusted 2-year persistence is suboptimal. However, both teriparatide and denosumab users had better 1-year persistence and only denosumab had 2-year better persistence compared to alendronate users. Unmeasured confounding by indication might partially explain our findings. PMID- 28714041 TI - Was molar-incisor hypomineralisation (MIH) present in archeological case series? PMID- 28714040 TI - Perspectives of pharmacy staff on dispensing subtherapeutic doses of antibiotics: a theory informed qualitative study. AB - Background Injudicious dispensing of antibiotics in subtherapeutic doses is common in many developing countries. In Egypt, as in many developing countries, a few pills of common cold products are offered under the name cold group (CG). A cold group may contain one or more pills of antibiotics. A pharmacy client may obtain subtherapeutic doses of antibiotics upon direct request or as part of a CG. Objective To examine factors associated with the unwarranted dispensing of subtherapeutic doses of antibiotics in community pharmacies as part of a CG or upon direct request from patients among community pharmacy staff. Setting Community pharmacy staff in Alexandria, Egypt. Methods Semi-structured interviews were conducted with a purposeful sample of community pharmacy staff. An interview guide was developed based on the theory of planned behavior. Constructs related to attitudes, subjective norm, perceived behavioral control and perceived moral obligation were explored. Directed content analysis was conducted using interview data which were recorded and transcribed verbatim. Main outcome measures Community pharmacy staff's views on factors associated with the unwarranted dispensing of subtherapeutic doses of antibiotics. Results Nine Pharmacists and six pharmacy assistants were purposively sampled to assure variance in age, gender, time in practice and socioeconomic status of patients served by their corresponding pharmacies. Factors contributing to dispensing antibiotics injudiciously included incorrect beliefs about potential benefit of antibiotics, profit, client pressure, ease of obtaining antibiotics from other pharmacies, inadequate enforcement of the law, pharmacist absenteeism, and assuming that the 'nonmalfeasance' principle is not violated. Reasons for lying to clients about the actual content of CGs included protecting the patient from harm resulting from antibiotic resistance and avoiding a possible argument. Conclusions Examining constructs related to pharmacy staff's attitude, subjective norm, perceived behavioral control as well as perceived moral obligation provided insight into community pharmacy staff's behavior related to dispensing subtherapeutic doses of antibiotics. Multi-tiered interventions are urgently needed to tackle different factors contributing to this dangerous practice. PMID- 28714042 TI - Magnetic nanoparticles-carbon nanotubes hybrid composites for selective solid phase extraction of polycyclic aromatic hydrocarbons and determination by ultra high performance liquid chromatography. AB - A rapid and reliable method based on magnetic solid-phase extraction (MSPE) and ultra-high performance liquid chromatography (UHPLC-FLD) analysis was developed and validated for the quantitative determination of seven polycyclic aromatic hydrocarbons (PAHs) in water samples. Hybrid composites made up of magnetic nanoparticles (MNPs) and carbon nanotubes (CNTs) were tested as adsorbent materials. The main factors influencing the extraction yields were optimized, namely the amount and type of adsorbent in the adsorption, and the solvent, the type of energy and the time in the desorption step. The selected composite was made up of Fe3O4 and multiwalled (MW)-CNTs. The desorption was carried out with sonication probe and tetrahydrofuran (THF); this solvent makes the method directly compatible with the chromatographic mobile phase and it reduces the analysis time. Under the optimized conditions, the LODs and LOQs achieved were in the range of 0.025-0.73 and 0.04-2.4 ng mL-1, respectively. The calibration curves were linear (R 2 >= 0.9936) over the concentration ranges from 1 to 500 ng mL-1. The recoveries of PAHs were from 76.4 +/- 1.7 up to 106.5 +/- 3.5%. The method was applied to synthetic and real (tap, dam, river and mineral) water samples with different characteristics to evaluate the performance under real conditions. PMID- 28714043 TI - Effects of surgically assisted rapid maxillary expansion on mandibular position: a three-dimensional study. AB - BACKGROUND: This study aimed to evaluate three-dimensional changes in mandibular position after surgically assisted rapid maxillary expansion (SARME). METHODS: A retrospective study was carried out with tomographic records of 30 adult patients with maxillary transverse deficiency who underwent SARME. Cone beam computed tomography scans were obtained preoperatively (T1), after expansion (T2) and 6 months after expansion (T3). Mandibular landmarks were measured with respect to axial, sagittal, and coronal planes. Repeated measures ANOVA was used for statistical analysis. RESULTS: Clockwise rotation and lateral displacement of the mandible were observed immediately after SARME. However, mandibular displacements tended to return close to their initial values at T3. CONCLUSIONS: Clockwise rotation and lateral shift of the mandible are transient effects of SARME. PMID- 28714039 TI - Current role of echocardiography in cardiac resynchronization therapy. AB - Cardiac resynchronization therapy (CRT) is an established treatment for patients with heart failure and left ventricular systolic dysfunction. Patients are usually assessed by echocardiography, which provides a number of anatomical and functional information used for cardiac dyssynchrony assessment, prognostic stratification, identification of the optimal site of pacing in the left ventricle, optimization of the CRT device, and patient follow-up. Compared to other cardiac imaging techniques, echocardiography has the advantage to be non invasive, repeatable, and safe, without exposure to ionizing radiation or nefrotoxic contrast. In this article, we review current evidence about the role of echocardiography before, during, and after the implantation of a CRT device. PMID- 28714044 TI - Care burden and its predictive factors in parents of newly diagnosed children with acute lymphoblastic leukemia in academic hospitals in China. AB - PURPOSE: Caring for children with acute lymphoblastic leukemia (ALL) is a distressing experience for parents without medical training. The experience can lead to parents' care burden. This study explored care burden among parents of children with ALL and its related factors. METHODS: A total of 130 parents were surveyed with the Zarit Burden Inventory (ZBI), Perceived Social Support Scale (PSSS), Zung's Self-rating Anxiety Scale (SAS), Zung's Self-rating Depression Scale (SDS), Medical Outcome Study Short Form 36 (SF-36), and a study specific demographic information questionnaire. Independent-samples T test, one-way ANOVA, Pearson correlation analysis and multivariate linear regression analysis (stepwise method), and binomial logistic regression were used in data analysis. RESULTS: The mean score of parents' care burden overall was 37.74 +/- 16.57, 17 (13.08%) had little or no burden, 57 (43.85%) had mild-to-moderate burden, 44 (33.84%) had moderate-to-severe burden, and 12 (9.23%) had severe burden. Regression analyses indicated daily care time, anxiety, general health, average monthly family income, social support, and number of co-caregivers were factors associated with care burden. These variables accounted for 51% of the variance in care burden. Other demographic information of parents and children, depression, and other dimensions of SF-36 were not related to care burden. The severe burden level was associated the increase risk of emotional distress compared with little or no burden group (OR = 37.500, 95% CI = 4.515-311.348, P = 0.001). CONCLUSION: The results indicated that care burden in parents of children newly diagnosed with ALL is high. Parents with lower levels of care burden tend to have less daily care time, more co-caregivers, higher income, less anxiety, better general health, and social support. Strategies are needed to help reduce parents' care burden. PMID- 28714045 TI - Characterization, drug loading and antibacterial activity of nanohydroxyapatite/polycaprolactone (nHA/PCL) electrospun membrane. AB - Considering the important factor of bioactive nanohydoxyapatite (nHA) to enhance osteoconductivity or bone-bonding capacity, nHA was incorporated into an electrospun polycaprolactone (PCL) membrane using electrospinning techniques. The viscosity of the PCL and nHA/PCL with different concentrations of nHA was measured and the morphology of the electrospun membranes was compared using a field emission scanning electron microscopy. The water contact angle of the nanofiber determined the wettability of the membranes of different concentrations. The surface roughness of the electrospun nanofibers fabricated from pure PCL and nHA/PCL was determined and compared using atomic force microscopy. Attenuated total reflectance Fourier transform infrared spectroscopy was used to study the chemical bonding of the composite electrospun nanofibers. Beadless nanofibers were achieved after the incorporation of nHA with a diameter of 200-700 nm. Results showed that the fiber diameter and the surface roughness of electrospun nanofibers were significantly increased after the incorporation of nHA. In contrast, the water contact angle (132 degrees +/- 3.5 degrees ) was reduced for PCL membrane after addition of 10% (w/w) nHA (112 degrees +/- 3.0 degrees ). Ultimate tensile strengths of PCL membrane and 10% (w/w) nHA/PCL membrane were 25.02 +/- 2.3 and 18.5 +/- 4.4 MPa. A model drug tetracycline hydrochloride was successfully loaded in the membrane and the membrane demonstrated good antibacterial effects against the growth of bacteria by showing inhibition zone for E. coli (2.53 +/- 0.06 cm) and B. cereus (2.87 +/- 0.06 cm). PMID- 28714047 TI - Erratum to: Evaluation of the Safety, Tolerability, and Pharmacokinetics of Gammaplex(r) 10% Versus Gammaplex(r) 5% in Subjects with Primary Immunodeficiency. PMID- 28714046 TI - Effects of Cd and Zn on physiological and anatomical properties of hydroponically grown Brassica napus plants. AB - Clarifying the connection between metal exposure and anatomical changes represents an important challenge for a better understanding of plant phytoextraction potential. A hydroponic screening experiment was carried out to evaluate the effects of combined interactions of Cd and Zn on mineral uptake (Mg, K, Ca, Na) and on the physiological and anatomical characteristics of Brassica napus L cv. Cadeli, Viking, and Navajo. Plants were exposed to 5 MUM Cd (CdCl2), 10 MUM Zn (ZnSO4), or both Cd + Zn, for 14 days. Cadmium exposure led to a significant reduction in root growth, shoot biomass, and chlorophyll content. After Cd-only and Cd + Zn treatment, primary root tips became thicker and pericycle cells were enlarged compared to the control and Zn-only treatment. No differences between metals were observed under UV excitation, where all treatments showed more intensive autofluorescence connected with lignin/suberin accumulation compared to control conditions. The highest concentrations of Cd and Zn were found in the roots of all tested plants, and translocation factors did not exceed the threshold of 1.0. The root mineral composition was not affected by any treatment. In the shoots, the Mg concentration slightly increased after Cd only and Cd + Zn treatments, whereas Zn-only treatment caused a sharp decrease in Ca content. Slight increases in K were seen after the addition of Zn. Significantly higher concentrations of Na were induced by Cd- or Zn-only treatment. PMID- 28714048 TI - Avoidant/Restrictive Food Intake Disorder: a Three-Dimensional Model of Neurobiology with Implications for Etiology and Treatment. AB - PURPOSE OF REVIEW: DSM-5 defined avoidant/restrictive food intake disorder (ARFID) as a failure to meet nutritional needs leading to low weight, nutritional deficiency, dependence on supplemental feedings, and/or psychosocial impairment. We summarize what is known about ARFID and introduce a three-dimensional model to inform research. RECENT FINDINGS: Because ARFID prevalence, risk factors, and maintaining mechanisms are not known, prevailing treatment approaches are based on clinical experience rather than data. Furthermore, most ARFID research has focused on children, rather than adolescents or adults. We hypothesize a three dimensional model wherein neurobiological abnormalities in sensory perception, homeostatic appetite, and negative valence systems underlie the three primary ARFID presentations of sensory sensitivity, lack of interest in eating, and fear of aversive consequences, respectively. Now that ARFID has been defined, studies investigating risk factors, prevalence, and pathophysiology are needed. Our model suggests testable hypotheses about etiology and highlights cognitive-behavioral therapy as one possible treatment. PMID- 28714049 TI - Vision-based fluid-type tactile sensor for measurements on biological tissues. AB - Hardness, dimensions, and location of biological tissues are important parameters for electronic palpation protocols with standardized performance. This study presents a novel fluid-type tactile sensor able to measure size and depth of heterogeneous substances in elastic bodies. The new sensor is very simple and can be easily fabricated. It consists of an image sensor, LED lights, and a touchpad filled with translucent water. The intensity field of the light traveling in the touchpad is analyzed to estimate the touchpad shape which conforms to the shape of an object in contact. The use of the new sensor for measuring size and depth of heterogeneous substances inside elastic bodies as well as hardness of elastic bodies is illustrated. Results obtained for breast cancer dummies demonstrate the effectiveness of the proposed approach. PMID- 28714050 TI - Superiority of the sonication method against conventional periprosthetic tissue cultures for diagnosis of prosthetic joint infections. AB - INTRODUCTION: Diagnosis of periprosthetic infections is challenging. The aim of this study was to compare the diagnostic accuracy of conventional periprosthetic tissue culture and culture of sonication fluid of the explanted prostheses. METHODS: We prospectively enrolled 114 patients undergoing revision hip or knee arthroplasty because of loosening of the prostheses, at our institution, between July 2012 and July 2016. Patients' medical history and demographic characteristics were recorded. The explanted hardware was separated in sterile containers and sonicated under sterile conditions. At least five samples of periprosthetic tissue were sent for culture and histological examination. We compared the culture of samples obtained by sonication of explanted hip and knee prostheses with conventional culture of periprosthetic tissue for the microbiological diagnosis of prosthetic joint infection. RESULTS: Infectious Diseases Society of America guidelines were used for the definition of prosthetic joint infection. Sixty-one patients had periprosthetic infection and 53 aseptic loosening (73 hip prostheses and 41 knee prostheses). The sensitivity of sonication fluid culture was 77.04%, and the sensitivity of conventional tissue cultures was 55.73% (p value = 0.012). The specificities of the two methods were 98.11 and 94.34%, respectively. The sensitivity of the histopathological examination of the periprosthetic tissue was 72.10%. There were 17 patients with PJI where the isolated pathogen was detected in SFC but not in PTC, while in five cases the pathogen was detected only in PTC. There were nine patients where no bacteria were detected by any microbiological method and the diagnosis was based on clinical and histological findings, according to the guidelines. CONCLUSIONS: The sonication method represents a reliable test for the diagnosis of prosthetic joint infections with a greater sensitivity and specificity than the conventional periprosthetic tissue cultures. PMID- 28714051 TI - Contributions of Genes and Environment to Developmental Change in Alcohol Use. AB - The precise nature of how genetic and environmental risk factors influence changes in alcohol use (AU) over time has not yet been investigated. Therefore, the aim of the present study is to examine the nature of longitudinal changes in these risk factors to AU from mid-adolescence through young adulthood. Using a large sample of male twins, we compared five developmental models that each makes different predictions regarding the longitudinal changes in genetic and environmental risks for AU. The best-fitting model indicated that genetic influences were consistent with a gradual growth in the liability to AU, whereas unique environmental risk factors were consistent with an accumulation of risks across time. These results imply that two distinct processes influence adolescent AU between the ages of 15-25. Genetic effects influence baseline levels of AU and rates of change across time, while unique environmental effects are more cumulative. PMID- 28714052 TI - Conservation of Phenotypes in the Roman High- and Low-Avoidance Rat Strains After Embryo Transfer. AB - The Roman high- (RHA-I) and low-avoidance (RLA-I) rat strains are bi directionally bred for their good versus non-acquisition of two-way active avoidance, respectively. They have recently been re-derived through embryo transfer (ET) to Sprague-Dawley females to generate specific pathogen free (SPF) RHA-I/RLA-I rats. Offspring were phenotyped at generations 1 (G1, born from Sprague-Dawley females), 3 and 5 (G3 and G5, born from RHA-I and RLA-I from G2 G4, respectively), and compared with generation 60 from our non-SPF colony. Phenotyping included two-way avoidance acquisition, context-conditioned fear, open-field behaviour, novelty-seeking, baseline startle, pre-pulse inhibition (PPI) and stress-induced increase in plasma corticosterone concentration. Post-ET between-strain differences in avoidance acquisition, context-conditioned freezing and novelty-induced self-grooming are conserved. Other behavioural traits (i.e. hole-board head-dipping, novel object exploration, open-field activity, startle, PPI) differentiate the strains at G3-G5 but not at G1, suggesting that the pre /post-natal environment may have influenced these co-segregated traits at G1, though further selection pressure along the subsequent generations (G1-G5) rescues the typical strain-related differences. PMID- 28714053 TI - The influence of surface texture and wettability on initial bacterial adhesion on titanium and zirconium oxide dental implants. AB - BACKGROUND: This study aims to investigate bacterial adhesion on different titanium and ceramic implant surfaces, to correlate these findings with surface roughness and surface hydrophobicity, and to define the predominant factor for bacterial adhesion for each material. METHODS: Zirconia and titanium specimens with different surface textures and wettability (5.0 mm in diameter, 1.0 mm in height) were prepared. Surface roughness was measured by perthometer (R a ) and atomic force microscopy, and hydrophobicity according to contact angles by computerized image analysis. Bacterial suspensions of Streptococcus sanguinis and Staphylococcus epidermidis were incubated for 2 h at 37 degrees C with ten test specimens for each material group and quantified with fluorescence dye CytoX Violet and an automated multi-detection reader. RESULTS: Variations in surface roughness (R a ) did not lead to any differences in adhering S. epidermidis, but higher R a resulted in increased S. sanguinis adhesion. In contrast, higher bacterial adhesion was observed on hydrophobic surfaces than on hydrophilic surfaces for S. epidermidis but not for S. sanguinis. The potential to adhere S. sanguinis was significantly higher on ceramic surfaces than on titanium surfaces; no such preference could be found for S. epidermidis. CONCLUSIONS: Both surface roughness and wettability may influence the adhesion properties of bacteria on biomaterials; in this context, the predominant factor is dependent on the bacterial species. Wettability was the predominant factor for S. epidermidis and surface texture for S. sanguinis. Zirconia did not show any lower bacterial colonization potential than titanium. Arithmetical mean roughness values R a (measured by stylus profilometer) are inadequate for describing surface roughness with regard to its potential influence on microbial adhesion. PMID- 28714055 TI - Chronic stiff, aching left foot. PMID- 28714054 TI - The functional relevance of diffusion tensor imaging in comparison to conventional MRI in patients with cervical compressive myelopathy. AB - OBJECTIVE: To determine the functional relevance of diffusion tensor imaging (DTI) metrics and conventional MRI (signal intensity change in T2, compression ratio) by measuring the correlation of these parameters with clinical outcome measured by the modified Japanese Orthopedic Association (mJOA) score. MATERIALS AND METHODS: A total of 20 cervical myelopathy (CM) patients participated in this prospective cohort study. The severities of CM were assessed using the mJOA score. Conventional MRIs (T2-weighted images) measuring the signal changes of spinal cords and the degree of compression at the lesion level and DTI metrics [fractional anisotropy (FA), apparent diffusion coefficient (ADC)] at each lesion and below each lesion (C7/T1) level were acquired using a 3-T Achieva MRI. These parameters were correlated with the mJOA scores to determine the functional relevance. RESULTS: Ninety percent of CM patients showed signal changes and 30 % of patients noted a more than 40% canal compression ratio in conventional MRIs at the lesion level; however, these findings were not correlated with the mJOA score (p < 0.05). In contrast, FA values on DTI showed high sensitivity to CM (100%), which was well correlated with the mJOA score (p = 0.034, r = 0.475) below the lesion level (C7/T1). CONCLUSIONS: This study showed a meaningful symptomatic correlation between mJOA scores and FA values below the lesion levels in CM patients. It could give us more understanding of the pathological changes in spinal cords matched with various clinical findings in CM patients than the results from conventional MRI. PMID- 28714056 TI - Quality control in diagnostic immunohistochemistry: integrated on-slide positive controls. AB - Standardization in immunohistochemistry is a priority in modern pathology and requires strict quality control. Cost containment has also become fundamental and auditing of all procedures must take into account both these principles. Positive controls must be routinely performed so that their positivity guarantees the appropriateness of the immunohistochemical procedure. The aim of this study is to develop a low cost (utilizing a punch biopsy-PB-tool) procedure to construct positive controls which can be integrated in the patient's tissue slide. Sixteen frequently used control blocks were selected and multiple cylindrical samples were obtained using a 5-mm diameter punch biopsy tool, separately re-embedding them in single blocks. For each diagnostic immunoreaction requiring a positive control, an integrated PB-control section (cut from the appropriate PB-control block) was added to the top right corner of the diagnostic slide before immunostaining. This integrated control technique permitted a saving of 4.75% in total direct lab costs and proved to be technically feasible and reliable. Our proposal is easy to perform and within the reach of all pathology labs, requires easily available tools, its application costs is less than using external paired controls and ensures that a specific control for each slide is always available. PMID- 28714057 TI - Population-Specific Responses to Interspecific Competition in the Gut Microbiota of Two Atlantic Salmon (Salmo salar) Populations. AB - The gut microbial community in vertebrates plays a role in nutrient digestion and absorption, development of intestine and immune systems, resistance to infection, regulation of bone mass and even host behavior and can thus impact host fitness. Atlantic salmon (Salmo salar) reintroduction efforts into Lake Ontario, Canada, have been unsuccessful, likely due to competition with non-native salmonids. In this study, we explored interspecific competition effects on the gut microbiota of two Atlantic salmon populations (LaHave and Sebago) resulting from four non native salmonids. After 10 months of rearing in semi-natural stream tanks under six interspecific competition treatments, we characterized the gut microbiota of 178 Atlantic salmon by parallel sequencing the 16S rRNA gene. We found 3978 bacterial OTUs across all samples. Microbiota alpha diversity and abundance of 27 OTUs significantly differed between the two populations. Interspecific competition reduced relative abundance of potential beneficial bacteria (six genera of lactic acid bacteria) as well as 13 OTUs, but only in the LaHave population, indicating population-specific competition effects. The pattern of gut microbiota response to interspecific competition may reflect local adaptation of the host-microbiota interactions and can be used to select candidate populations for improved species reintroduction success. PMID- 28714058 TI - In vitro and in vivo effects of PDGF-BB delivery strategies on tendon healing: a review. AB - To promote and support tendon healing, one viable strategy is the use or administration of growth factors at the wound/rupture site. Platelet derived growth factor-BB (PDGF-BB), together with other growth factors, is secreted by platelets after injury. PDGF-BB promotes mitogenesis and angiogenesis, which could accelerate tendon healing. Therefore, in vitro studies with PDGF-BB have been performed to determine its effect on tenocytes and tenoblasts. Moreover, accurate and sophisticated drug delivery devices, aiming for a sustained release of PDGF-BB, have been developed, either by using heparin-binding and fibrin-based matrices or different electrospinning techniques. In this review, the structure and composition, as well as the healing process of tendons, are described. Part A deals with in vitro studies. They focus on the multiple effects evoked by PDGF-BB on the cellular level. Moreover, they address strategies for the sustained delivery of PDGF-BB. Part B focuses on animal models used to test different delivery strategies for PDGF-BB, in the context of tendon reconstruction. These studies showed that dosage and timing of PDGF-BB application are the most important factors for deciding which delivery device should be applied for a specific tendon laceration. PMID- 28714059 TI - Kaposiform haemangioendothelioma in a nine-year-old boy with Kasabach-Merritt phenomenon. PMID- 28714060 TI - Childhood experiences of female family-violence perpetrators. AB - PURPOSE: To explore the childhood experiences of women who have perpetrated family-violence and voluntarily sought help. DESIGN AND METHODS: The qualitative design includes in-depth, unstructured individual interviews with 19 women who have perpetrated family-violence. FINDINGS: The categories of maltreatment exposure, parental capability, and a role of the sensitive, good girl are identified and described in this article. PRACTICE IMPLICATIONS: The findings provide guidance for nurses who encounter families at risk of female family violence perpetration and for those developing preventive interventions for female family-violence perpetrators whose family-of-origin issues are essential in processing issues of self. PMID- 28714061 TI - Establishing and prioritizing research questions for the prevention, diagnosis and treatment of hair loss (excluding alopecia areata): the Hair Loss Priority Setting Partnership. AB - BACKGROUND: Hair and scalp problems are common. Unfortunately, many uncertainties exist around the most effective management and treatment strategies for these disorders. OBJECTIVES: To identify uncertainties in hair-loss management, prevention, diagnosis and treatment that are important to both people with hair loss and healthcare professionals. METHODS: A Hair Loss Priority Setting Partnership was established between patients, their carers and relatives, and healthcare professionals to identify the most important uncertainties in hair loss. The methodology of the James Lind Alliance was followed to ensure a balanced, inclusive and transparent process. RESULTS: In total, 2747 treatment uncertainties were submitted by 912 participants; following exclusions 884 uncertainties relating to hair loss (excluding alopecia areata) were analysed. Questions were combined into 'indicative uncertainties' following a structured format. A series of ranking exercises further reduced this list to a top 25 that was taken to a final prioritization workshop where the top 10 priorities were agreed. CONCLUSIONS: We present the top 10 research priorities for hair loss (excluding alopecia areata) to guide researchers and funding bodies to support studies important to both patients and clinicians. PMID- 28714062 TI - Splitting the difference: New insights into distinguishing features of human versus feline models of adaptive locomotor control. PMID- 28714063 TI - MicroRNA-206 prevents the pathogenesis of hepatocellular carcinoma by modulating expression of met proto-oncogene and cyclin-dependent kinase 6 in mice. AB - : Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide, and therapeutic agents for this malignancy are lacking. MicroRNAs play critical roles in carcinogenesis and present tremendous therapeutic potential. Here, we report that microRNA-206 is a robust tumor suppressor that plays important roles in the development of HCC by regulating cell-cycle progression and the cMet signaling pathway. MicroRNA-206 was underexpressed in livers of two HCC mouse models, human individuals bearing HCC, and human HCC cell lines. Combining bioinformatic prediction and molecular and cellular approaches, we identified cMET (Met proto oncogene), cyclin D1 (CCND1), and cyclin-dependent kinase 6 (CDK6) as functional targets of microRNA-206. By inhibiting expression of cMET, CCND1, and CDK6, microRNA-206 delayed cell-cycle progression, induced apoptosis, and impaired proliferation of three distinct human HCC cell lines. Systemic administration of microRNA-206 completely prevented HCC development in both cMyc and V-Akt murine thymoma viral oncogene homolog 1/neuroblastoma RAS viral oncogene homolog (AKT/Ras) HCC mice, whereas 100% of control mice died from lethal tumor burdens. Conversely, reintroduction of cMet or Cdk6 into livers of cMyc and AKT/Ras HCC mice recovered growth of HCC inhibited by microRNA-206. These results strongly suggested that cMet and Cdk6 were two functional targets that mediated the inhibitory effect of microRNA-206 on the development of HCC. MicroRNA-206 overexpression demonstrated a profound therapeutic effect on HCC in xenograft and cMyc HCC mice. CONCLUSION: In summary, this study defines a potentially critical role of microRNA-206 in preventing the growth of HCC and suggests its use as a potential therapeutic strategy for this malignancy. (Hepatology 2017;66:1952 1967). PMID- 28714065 TI - Genotyping by sequencing defines independent novel RHD variants for an antenatal patient and a blood donor. PMID- 28714064 TI - Assessing the validity of the approximation of diffusion-weighted-MRI signals from crossing fascicles by sums of signals from single fascicles. AB - PURPOSE: To assess the validity of the superposition approximation for crossing fascicles, i.e., the assumption that the total diffusion-weighted MRI signal is the sum of the signals arising from each fascicle independently, even when the fascicles intermingle in a voxel. METHODS: Monte Carlo simulations were used to study the impact of the approximation on the diffusion-weighted MRI signal and to assess whether this approximate model allows microstructural features of interwoven fascicles to be accurately estimated, despite signal differences. RESULTS: Small normalized signal differences were observed, typically 10-3-10-2. The use of the approximation had little impact on the estimation of the crossing angle, the axonal density index, and the radius index in clinically realistic scenarios wherein the acquisition noise was the predominant source of errors. In the absence of noise, large systematic errors due to the superposition approximation only persisted for the radius index, mainly driven by a low sensitivity of diffusion-weighted MRI signals to small radii in general. CONCLUSION: The use of the superposition approximation rather than a model of interwoven fascicles does not adversely impact the estimation of microstructural features of interwoven fascicles in most current clinical settings. Magn Reson Med 79:2332-2345, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28714066 TI - Diabetes education, education and education. PMID- 28714067 TI - Technical Note: Evaluation of plastic scintillator detector for small field stereotactic patient-specific quality assurance. AB - PURPOSE: To evaluate the performance of a commercial plastic scintillator detector (PSD) for small-field stereotactic patient-specific quality assurance (QA) measurements using flattening-filter-free beam. METHODS: A total of 10 spherical targets [volume range: (0.03 cc-2 cc)] were planned with two techniques: (a) dynamic conformal arc (DCA-10 plans) and (b) volumetric modulated arc therapy (VMAT-10 plans). All plans were generated using Varian Eclipse treatment planning system, and AcurosXB v.13 algorithm in 1.0 mm grid size. Additionally, 14 previously treated cranial and spine SRS plans were evaluated [6 DCA, 8 VMAT, volume range: (0.04 cc-119.02 cc)]. Plan modulation was quantified via two metrics: MU per prescription dose (MU/Rx) and Average Leaf Pair Opening (ALPO). QA was performed on the Varian Edge linear accelerator equipped with HDMLC. Three detectors were used: (a) PinPoint ion chamber (PTW; active volume 0.015 cc), (b) Exradin W1 PSD (Standard Imaging; active volume 0.002 cc), and (c) Gafchromic EBT3 film (Ashland). PinPoint chamber and PSD were positioned perpendicular to beam axis in a Lucy phantom (Standard Imaging); films were placed horizontally capturing the coronal plane. RESULTS: PSD, film, and PinPoint chamber measured average differences of 1.00 +/- 1.54%, 1.30 +/- 1.69%, and -0.66 +/- 2.36%, respectively, compared to AcurosXB dose calculation. As the target volume decreased, PinPoint chamber measured lower doses (maximum -5.07% at 0.07 cc target), while PSD and film measured higher doses (2.87% and 2.54% at 0.03 cc target) than AcurosXB. Film agreed with the benchmark detector PSD by an average difference of 0.31 +/- 1.20%, but suffered from larger uncertainty; PinPoint chamber underestimated dose by more than 4% for targets smaller than 0.2 cc. Taking PSD as the measurement standard, DCA plans achieved good QA results across all volumes studied, with an average of -0.07 +/- 0.89%; for VMAT plans, PSD measured consistently higher dose (1.95 +/- 1.36%) than AcurosXB. Correlation study revealed that plan modulation quantified by both MU/Rx and ALPO correlated significantly with QA results. CONCLUSION: Among all three detectors, PSD demonstrated superior performances in plans with small fields and heavy modulation. High consistency and low uncertainty made PSD a suitable detector for clinical routine SRS QA. PinPoint chamber should be avoided for targets smaller than 0.2 cc; film dosimetry can be utilized with careful evaluation of its uncertainty bracket. Compared to PSD measurements, AcurosXB calculation demonstrated high accuracy for nonmodulated small fields. The positive correlation between plan modulation and QA discrepancy calls for our attention for clinical SRS plans with high modulation. PMID- 28714068 TI - Efficacy and Safety of Mechanical Thrombectomy in Older Adults with Acute Ischemic Stroke: Methodological Concerns. PMID- 28714069 TI - Discriminant biomarkers of acute respiratory distress syndrome associated to H1N1 influenza identified by metabolomics HPLC-QTOF-MS/MS platform. AB - Acute respiratory distress syndrome (ARDS) is a serious complication of influenza A (H1N1) virus infection. Its pathogenesis is unknown and biomarkers are lacking. Untargeted metabolomics allows the analysis of the whole metabolome in a biological compartment, identifying patterns associated with specific conditions. We hypothesized that LC-MS could help identify discriminant metabolites able to define the metabolic alterations occurring in patients with influenza A (H1N1) virus infection that developed ARDS. Serum samples from patients diagnosed with 2009 influenza A (H1N1) virus infection with (n = 25) or without (n = 32) ARDS were obtained on the day of hospital admission and analyzed by LC-MS/MS. Metabolite identification was determined by MS/MS analysis and analysis of standards. The specificity of the patterns identified was confirmed in patients without 2009 influenza A(H1N1) virus pneumonia (15 without and 17 with ARDS). Twenty-three candidate biomarkers were found to be significantly different between the two groups, including lysophospholipids and sphingolipids related to inflammation; bile acids, tryptophan metabolites, and thyroxine, related to the metabolism of the gut microflora. Confirmation results demonstrated the specificity of major alterations occurring in ARDS patients with influenza A (H1N1) virus infection. PMID- 28714070 TI - A reduction in SK channels contributes to increased activity of hypothalamic magnocellular neurons during heart failure. AB - KEY POINTS: Small conductance Ca2+ -activated K+ (SK) channels play an important role in regulating the excitability of magnocellular neurosecretory cells (MNCs). Although an increased SK channel function contributes to adaptive physiological responses, it remains unknown whether changes in SK channel function/expression contribute to exacerbated MNC activity under disease conditions. We show that the input-output function of MNCs in heart failure (HF) rats is enhanced. Moreover, the SK channel blocker apamin enhanced the input-output function in sham, although not in HF rats. We found that both the after-hyperpolarizing potential magnitude and the underlying apamin-sensitive IAHP are blunted in MNCs from HF rats. The magnitude of spike-induced increases in intracellular Ca2+ levels was not affected in MNCs of HF rats. We found a diminished expression of SK2/SK3 channel subunit mRNA expression in the supraoptic nucleus of HF rats. Our studies suggest that a reduction in SK channel expression, but not changes in Ca2+ mediated activation of SK channels, contributes to exacerbated MNC activity in HF rats. ABSTRACT: Small conductance Ca2+ -activated K+ channels (SK) play an important role in regulating the activity of magnocellular neurosecretory cells (MNCs) and hormone release from the posterior pituitary. Moreover, enhanced SK activity contributes to the adaptive responses of MNCs to physiological challenge, such as lactation. Nevertheless, whether changes in SK function/expression contribute to exacerbated MNC activity during diseases such as heart failure (HF) remains unknown. In the present study, we used a combination of patch clamp electrophysiology, confocal Ca2+ imaging and molecular biology in a rat model of ischaemic HF. We found that the input-output function of MNCs was enhanced in HF compared to sham rats. Moreover, although the SK blocker apamin (200 nm) strengthened the input-output function in sham rats, it failed to have an effect in HF rats. The magnitude of the after-hyperpolarizing potential (AHP) following a train of spikes and the underlying apamin-sensitive IAHP were blunted in MNCs from HF rats. However, spike-induced increases in intracellular Ca2+ were not affected in the MNCs of HF rats. Real-time PCR measurements of SK channel subunits mRNA in supraoptic nucleus punches revealed a diminished expression of SK2/SK3 subunits in HF compared to sham rats. Together, our studies demonstrate that MNCs from HF rats exhibit increased membrane excitability and an enhanced input-output function, and also that a reduction in SK channel-mediated, apamin-sensitive AHP is a critical contributing mechanism. Moreover, our results suggest that the reduced AHP is related to a down regulation of SK2/SK3 channel subunit expression but not the result of a blunted activity-dependent intracellular Ca2+ increase following a burst of action potentials. PMID- 28714071 TI - Humidity-Responsive Single-Nanoparticle-Layer Plasmonic Films. AB - 2D materials possess many interesting properties, and have shown great application potentials. In this work, the development of humidity-responsive, 2D plasmonic nanostructures with switchable chromogenic properties upon wetting dewetting transitions is reported. By exploiting DNA hybridization-directed anchoring of gold nanoparticles (AuNPs) on substrates, a series of single nanoparticle-layer (SNL) plasmonic films is fabricated. Due to the collective plasmonic responses in SNL, these ultrathin 2D films display rapid and reversible red-blue color change upon the wetting-dewetting transition, suggesting that hydration-induced microscopic plasmonic coupling between AuNPs is replicated in the macroscopic, centimeter-scale films. It is also found that hydration finely tunes the electric field distribution between AuNPs in the SNL film, based on which responsive surface-enhanced Raman scattering substrates with spatially homogeneous hot spots are developed. Thus it is expected that DNA-mediated 2D SNL structures open new avenues for designing miniaturized plasmonic nanodevices with various applications. PMID- 28714072 TI - Survival of patients with cirrhosis and acute peptic ulcer bleeding compared with variceal bleeding using current first-line therapies. AB - : The presence of cirrhosis increases the mortality of patients with peptic ulcer bleeding (PUB). Both acute variceal bleeding (AVB) and PUB are associated with substantial mortality in cirrhosis. This multicenter cohort study was performed to assess whether the mortality of patients with cirrhosis with PUB is different from that of those with AVB. Patients with cirrhosis and acute gastrointestinal bleeding were consecutively included and treated with somatostatin and proton pump inhibitor infusion from admission and with antibiotic prophylaxis. Emergency endoscopy with endoscopic therapy was performed within the first 6 hours. 646 patients with AVB and 144 with PUB were included. There were baseline differences between groups, such as use of gastroerosive drugs or beta-blockers. Child-Pugh and Model for End-Stage Liver Disease MELD scores were similar. Further bleeding was more frequent in the AVB group than those in the PUB group (18% vs. 10%; odds ratio [OR] = 0.50; 95% confidence interval [CI] = 0.29-0.88). However, mortality risk at 45 days was similar in both groups (19% in the AVB group vs. 17% in the PUB group; OR = 0.85; 95% CI = 0.55-1.33; P = 0.48). Different parameters, such as Child-Pugh score, acute kidney injury, acute on chronic liver failure, or presence of shock or bacterial infection, but not the cause of bleeding, were related to the risk of death. Only 2% of the PUB group versus 3% of the AVB group died with uncontrolled bleeding (P = 0.39), whereas the majority of patients in either group died from liver failure or attributed to other comorbidities. CONCLUSION: Using current first-line therapy, patients with cirrhosis and acute peptic ulcer bleeding have a similar survival than those with variceal bleeding. The risk of further bleeding is higher in patients with variceal hemorrhage. However, few patients in both groups died from uncontrolled bleeding, rather the cause of death was usually related to liver failure or comorbidities. (Hepatology 2018;67:1458-1471). PMID- 28714073 TI - Sex differences in angiotensin II-stimulated fluid intake. AB - NEW FINDINGS: What is the topic of this review? This report describes sex differences in the responses to angiotensin II, with a focus on fluid intake. What advances does it highlight? There are conflicting reports on the direction of the sex difference in fluid intake in response to angiotensin II. This review highlights how accounting for differences in body weight contributes to the discrepancies in the literature. In certain conditions, body weight influences fluid intake in a sex-specific manner. This review also highlights the divergent effects of oestrogen receptor activation on fluid intake, which are likely to underlie the discussed sex differences. Sex has a clear effect on the renin angiotensin-aldosterone system. Although sex differences in the pressor response to angiotensin II (Ang II) are well established, understanding of the sex differences in the fluid intake response to Ang II is clouded by conflicting reports. Here, I suggest that accounting for differences in body weight contributes to the discrepancies in the literature. Our recent findings demonstrate that body weight influences Ang II-stimulated water intake in certain conditions in male, but not in female rats. When differences in body weight are corrected for in the appropriate circumstances, we found that males consume more water in response to Ang II compared with females. Males and females also show differences in drinking microstructure, i.e. bottle spout lick patterns, which provide clues into the mechanism(s) underlying this sex difference. Oestrogens, which inhibit Ang II-stimulated fluid intake and circulate at higher concentrations in females, are likely to contribute to this sex difference. This review also discusses the diversity in oestrogen signalling via multiple oestrogen receptor subtypes, which selectively inhibit Ang II-stimulated fluid intake. PMID- 28714074 TI - Altered metabolomic-genomic signature: A potential noninvasive biomarker of epilepsy. AB - OBJECTIVE: This study aimed to identify noninvasive biomarkers of human epilepsy that can reliably detect and localize epileptic brain regions. Having noninvasive biomarkers would greatly enhance patient diagnosis, patient monitoring, and novel therapy development. At the present time, only surgically invasive, direct brain recordings are capable of detecting these regions with precision, which severely limits the pace and scope of both clinical management and research progress in epilepsy. METHODS: We compared high versus low or nonspiking regions in nine medically intractable epilepsy surgery patients by performing integrated metabolomic-genomic-histological analyses of electrically mapped human cortical regions using high-resolution magic angle spinning proton magnetic resonance spectroscopy, cDNA microarrays, and histological analysis. RESULTS: We found a highly consistent and predictive metabolite logistic regression model with reduced lactate and increased creatine plus phosphocreatine and choline, suggestive of a chronically altered metabolic state in epileptic brain regions. Linking gene expression, cellular, and histological differences to these key metabolites using a hierarchical clustering approach predicted altered metabolic vascular coupling in the affected regions. Consistently, these predictions were validated histologically, showing both neovascularization and newly discovered, millimeter-sized microlesions. SIGNIFICANCE: Using a systems biology approach on electrically mapped human cortex provides new evidence for spatially segregated, metabolic derangements in both neurovascular and synaptic architecture in human epileptic brain regions that could be a noninvasively detectable biomarker of epilepsy. These findings both highlight the immense power of a systems biology approach and identify a potentially important role that magnetic resonance spectroscopy can play in the research and clinical management of epilepsy. PMID- 28714076 TI - Target value of oxygen saturation during the first 10 min after birth. AB - BACKGROUND: During neonatal resuscitation, careful oxygenation is needed. Pulse oximetry is recommended to evaluate the need for oxygenation, but it is not clear whether peripheral perfusion is adequate for the evaluation of arterial oxygen saturation (SpO2 ). Additionally, there has been no study on the changes in SpO2 immediately after birth in Japan, despite the indispensable need for definitive oxygenation criteria. METHODS: A prospective observational study was performed in neonates at gestational age 35-41 weeks. An SpO2 measurement probe was attached to the neonates immediately after birth at the right palm or wrist, and the perfusion index (PI), pulse rate, and SpO2 were measured until 10 min after birth. RESULTS: Sixty neonates were examined. Stable PI was obtained soon after birth, preceding SpO2 measurement. The median PI (%) was constant at approximately 1.3, and the median SpO2 at 2-10 min was 70%, 81%, 82%, 87%, 89%, 92%, 92%, 94%, and 95%, respectively. The current target value for SpO2 in the Neonatal Cardiopulmonary Resuscitation (NCPR) guideline in Japan is approximately the 25th percentile. CONCLUSION: PI is stable and sufficient in the early postnatal period, meaning that peripheral perfusion is adequate for the measurement of SpO2 . The current target SpO2 used in the NCPR guidelines is at approximately the 25th percentile and is thought to be sufficient for meeting oxygenation criteria. PMID- 28714075 TI - Working memory and organizational skills problems in ADHD. AB - BACKGROUND: This study tested model-driven predictions regarding working memory's role in the organizational problems associated with ADHD. METHOD: Children aged 8 13 (M = 10.33, SD = 1.42) with and without ADHD (N = 103; 39 girls; 73% Caucasian/Non-Hispanic) were assessed on multiple, counterbalanced working memory tasks. Parents and teachers completed norm-referenced measures of organizational problems (Children's Organizational Skills Scale; COSS). RESULTS: Results confirmed large magnitude working memory deficits (d = 1.24) and organizational problems in ADHD (d = 0.85). Bias-corrected, bootstrapped conditional effects models linked impaired working memory with greater parent- and teacher-reported inattention, hyperactivity/impulsivity, and organizational problems. Working memory predicted organization problems across all parent and teacher COSS subscales (R2 = .19-.23). Approximately 38%-57% of working memory's effect on organization problems was conveyed by working memory's association with inattentive behavior. Unique effects of working memory remained significant for both parent- and teacher-reported task planning, as well as for teacher-reported memory/materials management and overall organization problems. Attention problems uniquely predicted worse organizational skills. Hyperactivity was unrelated to parent-reported organizational skills, but predicted better teacher-reported task planning. CONCLUSIONS: Children with ADHD exhibit multisetting, broad-based organizational impairment. These impaired organizational skills are attributable in part to performance deficits secondary to working memory dysfunction, both directly and indirectly via working memory's role in regulating attention. Impaired working memory in ADHD renders it extraordinarily difficult for these children to consistently anticipate, plan, enact, and maintain goal-directed actions. PMID- 28714077 TI - The association of smartphone-based activity space measures with cognitive functioning and pain sickle cell disease. PMID- 28714078 TI - Ternary Porous Cobalt Phosphoselenide Nanosheets: An Efficient Electrocatalyst for Electrocatalytic and Photoelectrochemical Water Splitting. AB - Exploring efficient and earth-abundant electrocatalysts is of great importance for electrocatalytic and photoelectrochemical hydrogen production. This study demonstrates a novel ternary electrocatalyst of porous cobalt phosphoselenide nanosheets prepared by a combined hydrogenation and phosphation strategy. Benefiting from the enhanced electric conductivity and large surface area, the ternary nanosheets supported on electrochemically exfoliated graphene electrodes exhibit excellent catalytic activity and durability toward hydrogen evolution in alkali, achieving current densities of 10 and 20 mA cm-2 at overpotentials of 150 and 180 mV, respectively, outperforming those reported for transition metal dichalcogenides and first-row transition metal pyrites catalysts. Theoretical calculations reveal that the synergistic effects of Se vacancies and subsequent P displacements of Se atoms around the vacancies in the resulting cobalt phosphoselenide favorably change the electronic structure of cobalt selenide, assuring a rapid charge transfer and optimal energy barrier of hydrogen desorption, and thus promoting the proton kinetics. The overall-water-splitting with 10 mA cm-2 at a low voltage of 1.64 V is achieved using the ternary electrode as both the anode and cathode, and the performance surpasses that of the Ir/C-Pt/C couple for sufficiently high overpotentials. Moreover, the integration of ternary nanosheets with macroporous silicon enables highly efficient solar-driven photoelectrochemical hydrogen production. PMID- 28714080 TI - Studying entrepreneurial occupations in the Terman women. AB - To achieve a better understanding of entrepreneurship development in women, longitudinal data on 672 individuals collected from 1922 to 1959 were analysed in a secondary investigation of the Terman Longitudinal Study. Women's reports on their occupations during 10 different years were assigned to one of two categories: work for pay (0/1), and work allowing for self-employment (0/1) in the respective year. Structural equation modelling supported earlier results concerning male entrepreneurial activity. Personality and aspects of the parenting context the women had experienced by the average age of 12 predicted early entrepreneurial competencies (inventions, leadership) and occupational interests by age 13, which related to an entrepreneurship-related career goal in 1936, when the participants were about 27 years of age on average. Such a career goal in turn predicted a higher number of occasions of entrepreneurship-prone work. Surprisingly, we also found a relationship to divorce. Women who had experienced the failure of a marriage were in occupations with a potential for entrepreneurship more often. Reasons are discussed against a backdrop of historical timing and current findings to identify general aspects of entrepreneurship development. PMID- 28714079 TI - Increased endocan expression in lesional skin and decreased endocan expression in sera in atopic dermatitis. AB - Endocan is a novel human endothelial cell-specific molecule and is mainly expressed in endothelial cells in various tissues. Endocan has the capacity to inhibit leukocytes binding to the vascular endothelium. It also can promote the angiogenesis alongside vascular endothelial growth factor A. Through these functions, endocan has been implicated in the pathogenesis of various inflammatory diseases. To investigate the possible roles of endocan in atopic dermatitis (AD), we examined endocan expression in lesional skin and sera in patients with AD. Endocan mRNA and protein levels were increased in lesional skin of AD compared with healthy skin and endocan was expressed on epidermal keratinocytes and dermal endothelial cells. On the other hand, serum endocan levels in patients with AD were significantly lower than those in healthy controls. Our results suggest that elevated endocan expression in lesional skin may be associated with development of AD through angiogenesis and that decreased endocan expression in sera may be associated with increased leukocyte recruitment in AD. PMID- 28714081 TI - Combining two model systems of psychosis: The effects of schizotypy and sleep deprivation on oculomotor control and psychotomimetic states. AB - Model systems of psychosis, such as schizotypy or sleep deprivation, are valuable in informing our understanding of the etiology of the disorder and aiding the development of new treatments. Schizophrenia patients, high schizotypes, and sleep-deprived subjects are known to share deficits in oculomotor biomarkers. Here, we aimed to further validate the schizotypy and sleep deprivation models and investigated, for the first time, their interactive effects on smooth pursuit eye movements (SPEM), prosaccades, antisaccades, predictive saccades, and measures of psychotomimetic states, anxiety, depression, and stress. To do so, n = 19 controls and n = 17 high positive schizotypes were examined after both a normal sleep night and 24 h of sleep deprivation. Schizotypes displayed higher SPEM global position error, catch-up saccade amplitude, and increased psychotomimetic states. Sleep deprivation impaired SPEM, prosaccade, antisaccade, and predictive saccade performance and increased levels of psychotomimetic experiences. Additionally, sleep deprivation reduced SPEM gain in schizotypes but not controls. We conclude that oculomotor impairments are observed in relation to schizotypy and following sleep deprivation, supporting their utility as biomarkers in model systems of psychosis. The combination of these models with oculomotor biomarkers may be particularly fruitful in assisting the development of new antipsychotic or pro-cognitive drugs. PMID- 28714083 TI - Acute liver failure with amiodarone infusion: A case report and systematic review. AB - WHAT IS KNOWN AND OBJECTIVE: Amiodarone, a commonly used class III antiarrhythmic agent notable for a relatively long half-life of up to 6 months and its pronounced adverse effect profile, is used for both acute and chronic management of cardiac arrhythmias. Chronic use of amiodarone has been associated with asymptomatic hepatotoxicity; however, acute toxicity is thought to be uncommon. There are only six reported cases of acute liver failure (ALF) secondary to amiodarone. In all these cases the outcome of death during the same hospitalization resulted. We aimed to report the only case of acute liver failure secondary to amiodarone infusion in the existing literature where the patient survived. CASE SUMMARY: A 79-year-old woman admitted with atrial flutter was being treated with intravenous (IV) amiodarone when she abruptly developed coagulopathy, altered mental status and liver enzyme derangement. She was diagnosed with acute liver failure (ALF) secondary to an amiodarone adverse drug reaction, with a calculated score of seven on the Naranjo adverse drug reaction probability scale. Amiodarone was immediately withheld, and N-acetylcysteine (NAC) was initiated. Clinical improvement was seen within 48 hours of holding the drug and within 24 hours of initiating NAC. On post-hospital follow-up visit she was reported to have complete recovery. WHAT IS NEW AND CONCLUSION: This report emphasizes the importance of monitoring liver enzymes and mental status while a patient is being administered IV amiodarone. N-acetylcysteine administration may have possibly contributed to the early and successful recovery from ALF in our patient. To date, she is the only patient in the existing literature who has been reported to survive ALF secondary to amiodarone administration. PMID- 28714084 TI - Applying the erythrocyte Pig-a assay concept to rat epididymal sperm for germ cell mutagenicity evaluation. AB - The Pig-a assay, a recently developed in vivo somatic gene mutation assay, is based on the identification of mutant erythrocytes that have an altered repertoire of glycosylphosphatidylinositol (GPI)-anchored cell surface markers. We hypothesized that the erythrocyte Pig-a assay concept could be applied to rat cauda epididymal spermatozoa (sperm) for germ cell mutagenicity evaluation. We used GPI-anchored CD59 as the Pig-a mutation marker and examined the frequency of CD59-negative sperm using flow cytometry. A reconstruction experiment that spiked un-labeled sperm (mutant-mimic) into labeled sperm at specific ratios yielded good agreement between the detected and expected frequencies of mutant-mimic sperm, demonstrating the analytical ability for CD59-negative sperm detection. Furthermore, this methodology was assessed in F344/DuCrl rats administered N ethyl-N-nitrosourea (ENU), a prototypical mutagen, or clofibrate, a lipid lowering drug. Rats treated with 1, 10, or 20 mg/kg body weight/day (mkd) ENU via daily oral garage for five consecutive days showed a dose-dependent increase in the frequency of CD59-negative sperm on study day 63 (i.e., 58 days after the last ENU dose). This ENU dosing regimen also increased the frequency of CD59 negative erythrocytes. In rats treated with 300 mkd clofibrate via daily oral garage for consecutive 28 days, no treatment-related changes were detected in the frequency of CD59-negative sperm on study day 85 (i.e., 57 days after the last dose) or in the frequency of CD59-negative erythrocytes on study day 29. In conclusion, these data suggest that the epidiymal sperm Pig-a assay in rats is a promising method for evaluating germ cell mutagenicity. Environ. Mol. Mutagen. 58:485-493, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28714085 TI - Neural control of sweat secretion: a review. AB - BACKGROUND: Humans have 4 million exocrine sweat glands, which can be classified into two types: eccrine and apocrine glands. Sweat secretion, a constitutive feature, is directly involved in thermoregulation and metabolism, and is regulated by both the central nervous system (CNS) and autonomic nervous system (ANS). OBJECTIVES: To explore how sweat secretion is controlled by both the CNS and the ANS and the mechanisms behind the neural control of sweat secretion. METHODS: We conducted a literature search on PubMed for reports in English from 1 January 1950 to 31 December 2016. RESULTS AND CONCLUSIONS: Acetylcholine acts as a potent stimulator for sweat secretion, which is released by sympathetic nerves. beta-adrenoceptors are found in adipocytes as well as apocrine glands, and these receptors may mediate lipid secretion from apocrine glands for sweat secretion. The activation of beta-adrenoceptors could increase sweat secretion through opening of Ca2+ channels to elevate intracellular Ca2+ concentration. Ca2+ and cyclic adenosine monophosphate play a part in the secretion of lipids and proteins from apocrine glands for sweat secretion. The translocation of aquaporin 5 plays an important role in sweat secretion from eccrine glands. Dysfunction of the ANS, especially the sympathetic nervous system, may cause sweating disorders, such as hypohidrosis and hyperhidrosis. PMID- 28714082 TI - In situ macrophage phenotypic transition is affected by altered cellular composition prior to acute sterile muscle injury. AB - KEY POINTS: The in situ phenotypic switch of macrophages is delayed in acute injury following irradiation. The combination of bone marrow transplantation and local muscle radiation protection allows for the identification of a myeloid cell contribution to tissue repair. PET-MRI allows monitoring of myeloid cell invasion and metabolism. Altered cellular composition prior to acute sterile injury affects the in situ phenotypic transition of invading myeloid cells to repair macrophages. There is reciprocal intercellular communication between local muscle cell compartments, such as PAX7 positive cells, and recruited macrophages during skeletal muscle regeneration. ABSTRACT: Skeletal muscle regeneration is a complex interplay between various cell types including invading macrophages. Their recruitment to damaged tissues upon acute sterile injuries is necessary for clearance of necrotic debris and for coordination of tissue regeneration. This highly dynamic process is characterized by an in situ transition of infiltrating monocytes from an inflammatory (Ly6Chigh ) to a repair (Ly6Clow ) macrophage phenotype. The importance of the macrophage phenotypic shift and the cross-talk of the local muscle tissue with the infiltrating macrophages during tissue regeneration upon injury are not fully understood and their study lacks adequate methodology. Here, using an acute sterile skeletal muscle injury model combined with irradiation, bone marrow transplantation and in vivo imaging, we show that preserved muscle integrity and cell composition prior to the injury is necessary for the repair macrophage phenotypic transition and subsequently for proper and complete tissue regeneration. Importantly, by using a model of in vivo ablation of PAX7 positive cells, we show that this radiosensitive skeletal muscle progenitor pool contributes to macrophage phenotypic transition following acute sterile muscle injury. In addition, local muscle tissue radioprotection by lead shielding during irradiation preserves normal macrophage transition dynamics and subsequently muscle tissue regeneration. Taken together, our data suggest the existence of a more extensive and reciprocal cross-talk between muscle tissue compartments, including satellite cells, and infiltrating myeloid cells upon tissue damage. These interactions shape the macrophage in situ phenotypic shift, which is indispensable for normal muscle tissue repair dynamics. PMID- 28714087 TI - Clinical and pathological classification of canine intraocular lymphoma. AB - The objectives of this retrospective study of 100 dogs with intraocular lymphoma were to describe the histomorphologic and immunohistochemical features of canine intraocular lymphoma, determine the proportion of cases with presumed solitary ocular lymphoma (PSOL) compared to multicentric disease, and assess the clinical outcomes of these patients. Selected cases from Penn Vet Diagnostic Laboratory and Comparative Ocular Pathology Lab of Wisconsin (2004-2015) were evaluated and subtyped using the WHO classification system. Peripheral T-cell lymphoma and diffuse large B-cell lymphoma were the two most common subtypes. Questionnaires were distributed to the referring veterinarians and veterinary ophthalmologists inquiring about clinical signs at time of enucleation, staging, patient outcome, treatment, and disease progression. Cases were categorized as PSOL if only ocular involvement was noted at the time of diagnosis based on the clinical staging criteria. The majority of cases (61%) did not have systemic involvement at the time of diagnosis, and these cases did not progress postoperatively. Median survival time (MST) was significantly higher for the presumed solitary intraocular cases: 769 vs. 103 days, hazard ratio of 0.23 (95% CI: 0.077-0.68). The subtype of lymphoma did not affect survival time. The results of this study suggest two significant points of clinical interest: the majority of dogs (61%) presented without signs of systemic involvement of lymphoma at the time of enucleation, and dogs with only ocular involvement showed no disease progression postenucleation. PMID- 28714086 TI - N-glycan content modulates kainate receptor functional properties. AB - KEY POINTS: Ionotropic glutamate receptor (iGluR) subunits are N-glycosylated at 4-12 sites, and Golgi processing produces mature receptors that contain high mannose, hybrid and complex oligosaccharides. N-glycosylation is crucial for receptor biogenesis, influences receptor trafficking and provides a binding site for carbohydrate binding proteins. Glycan moieties are large, polar and occasionally charged, and they are attached at sites along iGluRs that position them for involvement in the structural changes underlying gating. Altering glycan content on kainate receptors (KARs), a subfamily of iGluRs, changes functional properties of the receptor, such as desensitization, recovery from desensitization and deactivation. We report the first observation that the charged trisaccharide HNK-1 is conjugated to native KARs, and we find that it substantially alters recombinant KAR functional properties. Our results show that the molecular composition of N-glycans can influence KAR biophysical properties, revealing a potential mechanism for fine-tuning the function of these receptors. ABSTRACT: Ionotropic glutamate receptors (iGluRs) are tetrameric proteins with between four and 12 consensus sites for N-glycosylation on each subunit, which potentially allows for a high degree of structural diversity conferred by this post-translational modification. N-glycosylation is required for proper folding of iGluRs in mammalian cells, although the impact of oligosaccharides on the function of successfully folded receptors is less clear. Glycan moieties are large, polar, occasionally charged and mediate many protein-protein interactions throughout the nervous system. Additionally, they are attached at sites along iGluR subunits that position them for involvement in the structural changes underlying gating. In the present study, we show that altering glycan content on kainate receptors (KARs) changes the functional properties of the receptors in a manner dependent on the identity of both the modified sugars and the subunit composition of the receptor to which they are attached. We also report that native KARs carry the complex capping oligosaccharide human natural killer-1. Glycosylation patterns probably differ between cell types, across development or with pathologies, and thus our findings reveal a potential mechanism for context specific fine-tuning of KAR function through diversity in glycan structure. PMID- 28714088 TI - Pressure-based alkaline lysis with immunocapture, a method for enhanced recovery in differential extraction. AB - A pressure-based protocol for differential extraction has been optimized to provide a rapid and selective alternative to conventional differential extraction techniques with the advantage of an increased recovery of genomic DNA. The protocol involves treating cotton swabs containing mixtures of sperm and vaginal epithelial cells with two sets of pressure treatment using a Barocycler(r) NEP 2320 in alkaline conditions. This first step quantitatively and selectively removes female epithelial cells. The cotton swab is removed and further treated with alkali at 95 degrees C for the removal of sperm cell DNA. The resultant solution provides a clean male profile at a 20:1 cell ratio. Furthermore, the inclusion of a pretreatment step involving immunomagnetic cell capture of the female cells, permits nearly complete isolation of male sperm cells at cell ratios of up to 200:1 female to male cells. PMID- 28714089 TI - Fecal microbiota transplant from a rational stool donor improves hepatic encephalopathy: A randomized clinical trial. PMID- 28714090 TI - Habitat availability drives the distribution-abundance relationship in phytophagous true bugs in managed grasslands. AB - The nearly universal positive relationship between the distribution and abundance of species has been explained by several hypotheses but hitherto no consensus has been reached. Here, we used monitoring data of 105 phytophagous true bug species (Heteroptera) from 150 grassland sites over six years to test how (1) range position, (2) resource use, (3) resource availability, (4) density-dependent habitat selection, (5) metapopulation dynamics, and (6) habitat dispersal affect the distribution-abundance relationship. For the use in a confirmatory path analysis, we constructed causal pathways representing the hypothesized relationships and tested them separately and in a combined analysis. Our results show that the distribution-abundance relationship in phytophagous true bugs is driven by habitat-availability. An increasing local density of the host-plants increases the distribution of the species in the landscape, which in turn increases their local abundance. Thereby habitat availability facilitates dispersal success. We conclude that local abundance of herbivores facing habitat destruction could decline owing to a decrease in population dynamics between sites at the landscape scale. Finally, our results underline the potential of confirmatory path analysis for testing competing hypotheses. PMID- 28714091 TI - Habitual diet and diet quality in Irritable Bowel Syndrome: A case-control study. AB - BACKGROUND: Diet is considered to be a key factor in symptom generation in Irritable Bowel Syndrome (IBS) and patients tend to exclude food products from their diet in pursue of symptom relief, which may impair diet quality. METHODS: We evaluated habitual dietary intake in IBS patients with regard to nutrients and food products using an extensive food frequency questionnaire. One hundred ninety four IBS patients were compared to 186 healthy controls using multiple logistic regression analysis. An overall diet quality score was calculated for each participant based on the criteria of the Dutch Healthy Diet (DHD) index. KEY RESULTS: A lower DHD-score was found for IBS (mean [SD]: 52.9 [9.6]) vs controls (55.1 [9.2], P=.02). The diet of patients was lower in fibers (21 g vs 25 g per day, P=.002) and fructose (14 g vs 16 g, P=.033), while higher in total fat (37% vs 36% of total energy intake, P=.010) and added sugars (46 g vs 44 g, P=.029). Differences in daily intake of food products included lower consumption of apples (40 g vs 69 g, P<.001), pasta (28 vs 37 g, P=.029) and alcoholic beverages (130 g vs 193 g, P=.024) and higher consumption of processed meat (38 g vs 29 g, P<.001). Some of these findings correlated with gastrointestinal symptoms, showing differences between IBS subtypes. CONCLUSIONS AND INFERENCES: Differences in habitual diet were described, showing lower diet quality in IBS patients compared to controls, with increased consumption of fat and lower intake of fibers and fructose. Our data support the importance of personalized and professional nutritional guidance of IBS patients. PMID- 28714092 TI - Serial block-face scanning electron microscopy of erythrocytes protruding through the human placental syncytiotrophoblast. AB - The syncytiotrophoblast forms a continuous barrier between the maternal and fetal circulations. Here we present a serial block-face scanning electron microscopy (SBFSEM) study, based on a single image stack, showing pooling of fetal blood underneath a region of stretched syncytiotrophoblast that has become detached from the basement membrane. Erythrocytes are protruding from discrete holes in the syncytiotrophoblast suggesting that, under specific circumstances, the syncytiotrophoblast may be permeable to fetal cells. This observation represents a pathological process but it poses questions about the physical properties and permeability of the syncytiotrophoblast and may represent an early stage in the formation of fibrin deposits in areas of syncytial denudation. This study also illustrates how the 3D images generated by SBFSEM allow the interpretation of structures that could not be understood from a single histological section. PMID- 28714093 TI - Sexual care for patients receiving dialysis: A cross-sectional study identifying the role of nurses working in the dialysis department. AB - AIMS: To explore the role of nurses in the dialysis department in providing sexual care to patients receiving dialysis. BACKGROUND: Sexual health is not self evident for patients undergoing dialysis; 70% experience sexual dysfunction. Nevertheless, sexual care is often not provided. DESIGN: A national cross sectional survey. METHODS: Questionnaires (n = 1211) were sent to employees of 34 dialysis centres from January-May 2016. Descriptive statistics and statistical tests were used to describe and interpret data. RESULTS: The response rate was 45.6%. Three-quarter of nurses discussed sexual dysfunction with less than half of their patients. Main barriers for discussing were based on language and ethnicity (57.3%), culture and religion (54.1%) and the older age of the patient (49.7%). Eighteen per cent of nurses had sufficient knowledge on sexual dysfunction, competence was present in 51.2% of nurses and 68.3% indicated a need for training. Forty-three per cent knew about guidelines on sexual care by renal care providers. Nurses who rated their knowledge or competence higher or who were aware of guidelines discussed sexuality more often. The accountability for discussing sexuality was appointed to nephrologists (82.8%) and their own group of professionals (66.3%). Nurses referred 1.16% of their patients to sexual care providers. CONCLUSION: Dialysis nurses do not consistently address patients' sexuality, although they feel accountable to do so. This seems due to self imposed insufficient knowledge, cultural barriers and organizational problems. Study findings imply that current situation could benefit from guidelines, additional training, a private moment to discuss sexual dysfunction and adequate referral systems to specialized care providers. PMID- 28714094 TI - Selective High-Frequency Mechanical Actuation Driven by the VO2 Electronic Instability. AB - Relaxation oscillators consist of periodic variations of a physical quantity triggered by a static excitation. They are a typical consequence of nonlinear dynamics and can be observed in a variety of systems. VO2 is a correlated oxide with a solid-state phase transition above room temperature, where both electrical resistance and lattice parameters undergo a drastic change in a narrow temperature range. This strong nonlinear response allows to realize spontaneous electrical oscillations in the megahertz range under a DC voltage bias. These electrical oscillations are employed to set into mechanical resonance a microstructure without the need of any active electronics, with small power consumption and with the possibility to selectively excite specific flexural modes by tuning the value of the DC electrical bias in a range of few hundreds of millivolts. This actuation method is robust and flexible and can be implemented in a variety of autonomous DC-powered devices. PMID- 28714096 TI - Enactors of horizontal violence: The pathological bully, the self-justified bully and the unprofessional co-worker. AB - AIM: To suggest an alternative approach to improving recognition of horizontal violence using enactor types identified in a study exploring nurses' perceptions of horizontal violence. BACKGROUND: Horizontal violence is an umbrella term used to describe a range of aggressive behaviours between nurse colleagues. It is suggested that nurses do not recognize the phenomenon when they witness or experience it, contributing to its perpetuation. DESIGN: This was a qualitative, descriptive study undertaken to inform theory development and the design of future interventions to address horizontal violence. METHOD: Observation, document review and semi-structured interviews took place in two inpatient hospital units in the Northeastern United States between June - November 2012. Ongoing analysis identified three distinct types of enactors of horizontal violence. FINDINGS: Nurse participants rarely used terms from hospital policies or nursing literature to describe behaviours associated with horizontal violence but identified behaviours by describing the attributes of the enactor and the situation. Three enactor types were disaggregated from the data: the pathological bully, the self-justified bully and the unprofessional co-worker. CONCLUSION: Findings support previous research suggesting nurses do not recognize aggressive behaviours when they witness or experience them and do not have a name for those who enact these behaviours. This disaggregation of enactors of horizontal violence into recognizable types introduces an alternative approach to addressing the phenomenon. Development of instruments to identify these enactors, as well as testing of these instruments, is required to establish the utility of this disaggregation in nursing practice and in designing future interventions. PMID- 28714098 TI - Rational Design of Three-Layered TiO2 @Carbon@MoS2 Hierarchical Nanotubes for Enhanced Lithium Storage. AB - Here we demonstrate the rational design and synthesis of three-layered TiO2 @carbon@MoS2 hierarchical nanotubes for anode applications in lithium-ion batteries (LIBs). Through an efficient step-by-step strategy, ultrathin MoS2 nanosheets are grown on nitrogen-doped carbon (NC) coated TiO2 nanotubes to achieve the TiO2 @NC@MoS2 tubular nanostructures. This smart design can effectively shorten the diffusion length of Li+ ions, increase electric conductivity of the electrode, relax volume variation of electrode materials upon cycling, and provide more active sites for electrochemical reactions. Owing to these structural and compositional features, the hierarchical TiO2 @NC@MoS2 nanotubes manifest remarkable lithium storage performance with good rate capability and long cycle life. PMID- 28714095 TI - Effect of dietary salt intake on epithelial Na+ channels (ENaC) in vasopressin magnocellular neurosecretory neurons in the rat supraoptic nucleus. AB - KEY POINTS: A growing body of evidence suggests that epithelial Na+ channels (ENaCs) in the brain play a significant role in the regulation of blood pressure; however, the brain structures that mediate the effect are not well understood. Because vasopressin (VP) neurons play a pivotal role in coordinating neuroendocrine and autonomic responses to maintain cardiovascular homeostasis, a basic understanding of the regulation and activity of ENaC in VP neurons is of great interest. We show that high dietary salt intake caused an increase in the expression and activity of ENaC which resulted in the steady state depolarization of VP neurons. The results help us understand one of the mechanisms underlying how dietary salt intake affects the activity of VP neurons via ENaC activity. ABSTRACT: All three epithelial Na+ channel (ENaC) subunits (alpha, beta and gamma) are located in vasopressin (VP) magnocellular neurons in the hypothalamic supraoptic (SON) and paraventricular nuclei. Our previous study demonstrated that ENaC mediates a Na+ leak current that affects the steady state membrane potential in VP neurons. In the present study, we evaluated the effect of dietary salt intake on ENaC regulation and activity in VP neurons. High dietary salt intake for 7 days caused an increase in expression of beta- and gammaENaC subunits in the SON and the translocation of alphaENaC immunoreactivity towards the plasma membrane. Patch clamp experiments on hypothalamic slices showed that the mean amplitude of the putative ENaC currents was significantly greater in VP neurons from animals that were fed a high salt diet compared with controls. The enhanced ENaC current contributed to the more depolarized basal membrane potential observed in VP neurons in the high salt diet group. These findings indicate that high dietary NaCl intake enhances the expression and activity of ENaCs, which augments synaptic drive by depolarizing the basal membrane potential close to the action potential threshold during hormonal demand. However, ENaCs appear to have only a minor role in the regulation of the firing activity of VP neurons in the absence of synaptic inputs as neither the mean intraburst frequency, burst duration, nor interspike interval variability of phasic bursting activity was affected. Moreover, ENaC activity did not affect the initiation, sustention, or termination of the phasic bursting generated in an intrinsic manner without synaptic inputs. PMID- 28714099 TI - Case of inflammatory tinea corporis affecting the dorsal surface of the thumb in a nail salon technician. PMID- 28714097 TI - A randomized, comparative pilot trial of family-based interpersonal psychotherapy for reducing psychosocial symptoms, disordered-eating, and excess weight gain in at-risk preadolescents with loss-of-control-eating. AB - OBJECTIVE: Preadolescent loss-of-control-eating (LOC-eating) is a risk factor for excess weight gain and binge-eating-disorder. We evaluated feasibility and acceptability of a preventive family-based interpersonal psychotherapy (FB-IPT) program. FB-IPT was compared to family-based health education (FB-HE) to evaluate changes in children's psychosocial functioning, LOC-eating, and body mass. METHOD: A randomized, controlled pilot trial was conducted with 29 children, 8 to 13 years who had overweight/obesity and LOC-eating. Youth-parent dyads were randomized to 12-week FB-IPT (n = 15) or FB-HE (n = 14) and evaluated at post treatment, six-months, and one-year. Changes in child psychosocial functioning, LOC-eating, BMI, and adiposity by dual-energy-X-ray-absorptiometry were assessed. Missing follow-up data were multiply imputed. RESULTS: FB-IPT feasibility and acceptability were indicated by good attendance (83%) and perceived benefits to social interactions and eating. Follow-up assessments were completed by 73% FB IPT and 86% FB-HE at post-treatment, 60% and 64% at six-months, and 47% and 57% at one-year. At post-treatment, children in FB-IPT reported greater decreases in depression (95% CI -7.23, -2.01, Cohen's d = 1.23) and anxiety (95% CI -6.08, 0.70, Cohen's d = .79) and less odds of LOC-eating (95% CI -3.93, -0.03, Cohen's d = .38) than FB-HE. At six-months, children in FB-IPT had greater reductions in disordered-eating attitudes (95% CI -0.72, -0.05, Cohen's d = .66) and at one year, tended to have greater decreases in depressive symptoms (95% CI -8.82, 0.44, Cohen's d = .69) than FB-HE. There was no difference in BMI gain between the groups. DISCUSSION: Family-based approaches that address interpersonal and emotional underpinnings of LOC-eating in preadolescents with overweight/obesity show preliminary promise, particularly for reducing internalizing symptoms. Whether observed psychological benefits translate into sustained prevention of disordered-eating or excess weight gain requires further study. PMID- 28714100 TI - Why is it so hard to reach agreement on terminology? The case of developmental language disorder (DLD). AB - A recent project entitled CATALISE used the Delphi method to reach a consensus on terminology for unexplained language problems in children. 'Developmental language disorder' (DLD) was the term agreed by a panel of 57 experts. Here I reflect on points of difficulty that arose when attempting to reach a consensus, using qualitative information from comments made by panel members to illustrate the kinds of argument used. One issue of debate was the use of labels, in particular the term 'disorder', which was seen as having both pros and cons. The potential for labels to stigmatize or create low expectations was a particular concern. However, labels could also ensure language problems were not trivialized and could help avoid stigma by providing an explanation for behaviours that might otherwise meet with disapproval. Further debate surrounded issues of how best to identify cases of disorder. Although it was agreed there should be a focus on cases with a poor prognosis, it was recognized that our knowledge of factors related to prognosis was still incomplete. Furthermore, there was a tension between use of standardized tests, which allow for a relatively objective and reliable assessment of language, and more qualitative observations, which can capture functional aspects of communication that are not always picked up on formal assessment. Debate also surrounded the issue of the relationship between DLD and other conditions. Some favoured drawing a distinction between DLD and language disorders associated with other conditions, and others regarded such distinctions as unnecessary. We concluded that it was misleading to assume co occurring conditions were causes of language disorder, but it was helpful to distinguish DLD from cases of language disorder associated with 'differentiating conditions' that had a known or likely biomedical origin, including brain injury, sensorineural hearing loss, genetic syndromes, intellectual disability and autism spectrum disorder. Furthermore, DLD could co-occur with milder neurodevelopmental disorders that did not have a clear biomedical aetiology. Normal-range non-verbal IQ has traditionally been incorporated in the diagnosis of DLD, but this was rejected as unsupported by evidence. DLD is a category that has utility in identifying children who would benefit from speech-language therapy services, but it should not be thought of as a well-defined condition. DLD has a multifactorial aetiology, is heterogeneous in terms of language features and overlaps with other neurodevelopmental disorders. Our notions of DLD are likely to be refined by further research into aetiology, associated characteristics and intervention effectiveness. PMID- 28714101 TI - Children born extremely preterm had different sleeping habits at 11 years of age and more childhood sleep problems than term-born children. AB - AIM: This study explored whether extremely preterm (EPT) children had different sleep characteristics in childhood than children born at term and how neurodevelopmental disabilities (NDD) affected sleep in children born EPT. METHODS: A Norwegian national cohort of 231 children born EPT from 1999 to 2000 and separate study data on 556 children born at term in 2001 were compared. Parental questionnaires mapped the children's current sleep habits at 11 years of age, namely the prevalence of sleep problems throughout childhood until this age and five categories of sleep problems. In addition, the EPT children were clinically assessed at five years of age. RESULTS: The EPT children had different sleep habits than the controls, for example they went to bed earlier. EPT children had a higher prevalence of sleep problems than the controls throughout childhood (26% versus 14%, p < 0.001) and this was also higher for the 93 EPT children with no NDD (20%) than for the controls (14%) and increased with increasing NDD to 67% (p = 0.015) for the six children with severe NDD. CONCLUSION: EPT children had different sleep habits to term-born controls at 11 years of age, including those with no NDD. The prevalence of sleep problems increased with increasing NDD. PMID- 28714102 TI - Reply. PMID- 28714103 TI - Hunger and microbiology: is a low gastric acid-induced bacterial overgrowth in the small intestine a contributor to malnutrition in developing countries? AB - Underproduction of hydrochloric acid into the stomach is frequently encountered in subjects from developing countries. We explore the hypothesis that hypochlorhydria compromises the gastric barrier and favours bacterial overgrowth in the proximal parts of the small intestine where nutrient absorption takes place. Food calories are thus deviated into bacterial metabolism. In addition to an adequate caloric supply, correcting hypochlorhydria might be needed to decrease childhood malnutrition. PMID- 28714105 TI - Spinal cord imaging using averaged magnetization inversion recovery acquisitions. AB - PURPOSE: To establish a novel approach for fast high-resolution spinal cord (SC) imaging using averaged magnetization inversion recovery acquisitions (AMIRA). METHODS: The AMIRA concept is based on an inversion recovery (IR) prepared, segmented, and time-limited cine balanced steady state free precession sequence. Typically, for the fastest SC imaging without any signal averaging, eight consecutive images in time with an in-plane resolution of 0.67 * 0.67 mm2 and 6 mm to 8 mm slice thickness are acquired in 51 s. AMIRA does not require parallel acquisition techniques. RESULTS: AMIRA measures eight images of remarkable tissue contrast variation between spinal cord gray (GM) and white matter (WM) and cerebrospinal fluid (CSF). Following the AMIRA concept, averaging the first IR contrast images not only improves the signal-to-noise ratio but also offers a surprising enhancement of the contrast-to-noise ratio between GM and WM, whereas averaging the last images considerably improves the contrast-to-noise ratio between WM and CSF. These observations are supported by quantitative data. CONCLUSION: The AMIRA concept provides 2D spinal cord imaging with multiple tissue contrasts and enhanced contrast-to-noise ratios with a typical 0.67 * 0.67 mm2 in-plane resolution and a slice thickness between 4 mm and 8 mm acquired in only 1 to 2 min per slice. Magn Reson Med 79:1870-1881, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28714104 TI - Chronic inflammation-elicited liver progenitor cell conversion to liver cancer stem cell with clinical significance. AB - : The substantial heterogeneity and hierarchical organization in liver cancer support the theory of liver cancer stem cells (LCSCs). However, the relationship between chronic hepatic inflammation and LCSC generation remains obscure. Here, we observed a close correlation between aggravated inflammation and liver progenitor cell (LPC) propagation in the cirrhotic liver of rats exposed to diethylnitrosamine. LPCs isolated from the rat cirrhotic liver initiated subcutaneous liver cancers in nonobese diabetic/severe combined immunodeficient mice, suggesting the malignant transformation of LPCs toward LCSCs. Interestingly, depletion of Kupffer cells in vivo attenuated the LCSC properties of transformed LPCs and suppressed cytokeratin 19/Oval cell 6-positive tumor occurrence. Conversely, LPCs cocultured with macrophages exhibited enhanced LCSC properties. We further demonstrated that macrophage-secreted tumor necrosis factor-alpha triggered chromosomal instability in LPCs through the deregulation of ubiquitin D and checkpoint kinase 2 and enhanced the self-renewal of LPCs through the tumor necrosis factor receptor 1/Src/signal transducer and activator of transcription 3 pathway, which synergistically contributed to the conversion of LPCs to LCSCs. Clinical investigation revealed that cytokeratin 19/Oval cell 6 positive liver cancer patients displayed a worse prognosis and exhibited superior response to sorafenib treatment. CONCLUSION: Our results not only clarify the cellular and molecular mechanisms underlying the inflammation-mediated LCSC generation but also provide a molecular classification for the individualized treatment of liver cancer. (Hepatology 2017;66:1934-1951). PMID- 28714106 TI - Prevalence and distribution of sesamoid bones and accessory ossicles of the foot as determined by digital tomosynthesis. AB - We previously reported that digital tomosynthesis (DTS) is a reliable tool for evaluating bony structures of the hand. The current study aimed to identify the prevalence and distribution of sesamoid bones and accessory ossicles of the foot using DTS and to compare the results to those of conventional radiography (CR). Foot images (DTS, 213; CR, 44) of 213 patients taken at a tertiary hospital were retrospectively reviewed. Sesamoid bones were identified in the metatarsaophalangeal (MTP), distal interphalangeal (DIP) and interphalangeal (IP) joints of the great (I), second (II), third (III), fourth (IV), and fifth (V) toes. Accessory ossicles were observed in the midfoot and hindfoot. The mean number of sesamoid bones and accessory ossicles was 3.9 +/- 1.3 for the left foot and 3.7 +/- 1.0 for the right foot on CR; and 3.9 +/- 1.4 for the left foot and 3.9 +/- 1.3 for the right foot on DTS. Sesamoid bones were observed in MTP I (100%), MTP II (5%), MTP III (2%), MTP IV (2%), MTP V (14%), and IP (68%) on CR. Sesamoid bones were observed in MTP I (100%), MTP II (8%), MTP III (1%), MTP IV (2%), MTP V (25%), and IP I(65%) on DTS. Among accessory ossicles, the most common bone identified was os tibiale externum (23% on CR and 33% on DTS) andos peroneum (14% on CR and 21% on DTS), and os trigonum (32% on CR and 0.5% on DTS). DTS was useful for finding sesamoid bones and accessory ossicles, although there were some limitations in observing the hindfoot. Clin. Anat. 30:1072-1076, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28714107 TI - The BRAF and NRAS mutation prevalence in dermoscopic subtypes of acquired naevi reveals constitutive mitogen-activated protein kinase pathway activation. AB - BACKGROUND: Acquired naevi can have unique dermoscopic patterns that correspond to distinct microanatomical growth patterns. Previous studies on acquired naevi stratified according to dermoscopic pattern focused on the frequency of somatic BRAF mutations, whereas NRAS mutations remained to be elucidated. OBJECTIVES: To investigate the BRAF and NRAS mutation prevalence and activation of the mitogen activated protein kinase (MAPK) pathway in distinct dermoscopic subtypes of acquired naevi. METHODS: Common mutations present in BRAF and NRAS were assessed in 40 globular, reticular and peripheral rim of globules (PG) subtypes of acquired naevi from 27 participants (19 male, 8 female; mean age 46.7 years) selected from 1261 eligible volunteers. Mutations were determined using the highly sensitive and quantitative QX200 droplet digitalTM polymerase chain reaction (ddPCR) system. RESULTS: The BRAF V600E (c.1799T>A or c.1799_1800delTGinsA) and BRAF V600K mutations were detected in 85% (n = 34/40) of naevi. All BRAF wild-type naevi (15%; n = 6/40) harboured an NRAS codon 12/13 or 61 mutation. BRAF mutations were present in 92% (n = 12/13) of globular and 100% (n = 12/12) of PG naevi, whereas reticular naevi were 67% (n = 10/15) BRAF- and 33% (n = 5/15) NRAS-mutant (P = 0.037). CONCLUSIONS: We discovered that 100% of the assessed acquired naevi had either a BRAF or NRAS mutation. Using sensitive techniques capable of single-cell mutation detection, it is likely that all acquired naevi will be mutated for BRAF or NRAS. Because both of these mutations are prevalent in distinct dermoscopic naevus subsets, our study supports the role of the MAPK pathway in the development of benign melanocytic proliferations, indicating that additional genomic events besides somatic mutations in BRAF or NRAS are required for melanoma development. PMID- 28714108 TI - Assessing the spatial distribution of Tuta absoluta (Lepidoptera: Gelechiidae) eggs in open-field tomato cultivation through geostatistical analysis. AB - BACKGROUND: The spatial distribution of insects is due to the interaction between individuals and the environment. Knowledge about the within-field pattern of spatial distribution of a pest is critical to planning control tactics, developing efficient sampling plans, and predicting pest damage. The leaf miner Tuta absoluta (Meyrick) (Lepidoptera: Gelechiidae) is the main pest of tomato crops in several regions of the world. Despite the importance of this pest, the pattern of spatial distribution of T. absoluta on open-field tomato cultivation remains unknown. Therefore, this study aimed to characterize the spatial distribution of T. absoluta in 22 commercial open-field tomato cultivations with plants at the three phenological development stages by using geostatistical analysis. RESULTS: Geostatistical analysis revealed that there was strong evidence for spatially dependent (aggregated) T. absoluta eggs in 19 of the 22 sample tomato cultivations. The maps that were obtained demonstrated the aggregated structure of egg densities at the edges of the crops. Further, T. absoluta was found to accomplish egg dispersal along the rows more frequently than it does between rows. CONCLUSION: Our results indicate that the greatest egg densities of T. absoluta occur at the edges of tomato crops. These results are discussed in relation to the behavior of T. absoluta distribution within fields and in terms of their implications for improved sampling guidelines and precision targeting control methods that are essential for effective pest monitoring and management. (c) 2017 Society of Chemical Industry. PMID- 28714109 TI - Opioids out of control. PMID- 28714110 TI - Poly(Vinylpyrollidone)- and Selenocysteine-Modified Bi2 Se3 Nanoparticles Enhance Radiotherapy Efficacy in Tumors and Promote Radioprotection in Normal Tissues. AB - The development of a new generation of nanoscaled radiosensitizers that can not only enhance radiosensitization of tumor tissues, but also increase radioresistance of healthy tissue is highly desirable, but remains a great challenge. Here, this paper reports a new versatile theranostics based on poly(vinylpyrollidone)- and selenocysteine-modified Bi2 Se3 nanoparicles (PVP-Bi2 Se3 @Sec NPs) for simultaneously enhancing radiotherapeutic effects and reducing the side-effects of radiation. The as-prepared nanoparticles exhibit significantly enhanced free-radical generation upon X-ray radiation, and remarkable photothermal effects under 808 nm NIR laser irradiation because of their strong X-ray attenuation ability and high NIR absorption capability. Moreover, these PVP-Bi2 Se3 @Sec NPs are biodegradable. In vivo, part of selenium can be released from NPs and enter the blood circulation system, which can enhance the immune function and reduce the side-effects of radiation in the whole body. As a consequence, improved superoxide dismutase and glutathione peroxidase activities, promoted secretion of cytokines, increased number of white blood cell, and reduced marrow DNA suppression are found after radiation treatment in vivo. Moreover, there is no significant in vitro and in vivo toxicity of PVP-Bi2 Se3 @Sec NPs during the treatment, which demonstrates that PVP-Bi2 Se3 @Sec NPs have good biocompatibility. PMID- 28714111 TI - Room for improvement in breast milk feeding after very preterm birth in Europe: Results from the EPICE cohort. AB - Breast milk feeding (BMF) is associated with lower neonatal morbidity in the very preterm infant (<32 weeks gestation) and breastfeeding is beneficial for maternal health. Previous studies show large variations in BMF after very preterm birth and recognize the need for targeted breastfeeding support in the neonatal intensive care units (NICU). In a European collaboration project about evidence based practices after very preterm birth, we examined the association between maternal, obstetric, and infant clinical factors; neonatal and maternal care unit policies; and BMF at discharge from the NICU. In multivariable analyses, covariates associated with feeding at discharge were first investigated as predictors of any BMF and in further analysis as predictors of exclusive or partial BMF. Overall, 58% (3,826/6,592) of the infants received any BMF at discharge, but there were large variations between regions (range 36-80%). Primiparity, administration of antenatal corticosteroids, first enteral feed <24 hr after birth, and mother's own milk at first enteral feed were predictors positively associated with any BMF at discharge. Vaginal delivery, singleton birth, and receiving mother's own milk at first enteral feed were associated with exclusive BMF at discharge. Units with a Baby Friendly Hospital accreditation improved any BMF at discharge; units with protocols for BMF and units using donor milk had higher rates of exclusive BMF at discharge. This study suggests that there is a high potential for improving BMF through policies and support in the NICU. PMID- 28714112 TI - Wearables in epilepsy and Parkinson's disease-A focus group study. AB - OBJECTIVES: Wearable sensors that measure movement and physiological variables are attractive for clinical evaluation of neurological diseases such as epilepsy and Parkinson's disease (PD). The aim of this study was to explore perceptions regarding the use of wearable technology in disease monitoring and management as reported by individuals with epilepsy and Parkinson's disease as well as health professionals working with these patient groups. MATERIALS AND METHODS: Six patient groups (n=25) and two groups with health professionals (n=15) participated in this qualitative, descriptive study with focus group interviews. A manifest qualitative content analysis was used. RESULTS: Four categories and nine subcategories emerged from the analysis. Participants saw possible benefits for improved treatment effect and valued this benefit more than possible inconvenience of wearing the sensors. Discrete design and simplicity were considered as facilitators for improved usability. They emphasized the importance of interactive information between patients and health professionals. However, they were concerned about unclear information and inconclusive recordings and some fears about personal integrity were at odds with the expectations on interactivity. CONCLUSIONS: Patients need to feel well informed and find an added value in using wearables. Wearables need to be user-friendly, have an attractive design, and show clinical efficacy in improving disease management. Variations in perceptions regarding integrity, benefits, and effectiveness of monitoring indicate possible conflicts of expectations among participants. The engagement of end users, patients, and health professionals, in the design and implementation process, is crucial for the development of wearable devices that enhance and facilitate neurological rehabilitation practice. PMID- 28714113 TI - Secondary syphilis primarily presenting with multiple nodules on the scalp: Case report and published work review. AB - Syphilis, a sexually transmitted disease caused by Treponema pallidum, manifests with a broad spectrum of clinical presentations that usually involves skin. Nodular secondary syphilis occurs rarely, and mostly manifests as disseminated papulonodules or plaques over the trunk and limbs. We report an extremely rare case of nodular secondary syphilis that primarily presented with multiple nodules on the scalp, resembling Rosai-Dorfman disease or cutaneous malignant metastasis. Immunohistochemistry confirmed T. pallidum spirochetes microscopically. PMID- 28714114 TI - Split liver transplantation for retroperitoneal immature teratoma masquerading as hepatoblastoma. AB - Extragonadal teratoma originating from the retroperitoneum represents less than 5% of all teratomas and accounts for less than 10% of all pediatric retroperitoneal neoplasms. To date, there has been no report of teratoma managed with LT. This study reports an infant aged 3 months with retroperitoneal immature teratoma involving the hepatic hilum, refractory to chemotherapy and treated with LT. The patient was referred to our hospital for management of a growing abdominal mass. Histopathology of a fine needle biopsy of the lesion suggested the possibility of a hepatoblastoma with teratoid features. Cisplatin-based chemotherapy was initiated, but rapid growth of the tumor encasing the hepatic artery proper was detected, even after two cycles of chemotherapy. A split LT was carried out, and pathological examination of the explanted liver revealed the involvement of numerous neuroepithelial components, confirming the diagnosis of a Norris grade 3 immature teratoma. The patient recovered well and was discharged on day 19 post-LT. As on date, on postoperative day 240, he has completed seven cycles of a 12-cycle vinblastine and doxorubicin-based adjuvant chemotherapy. PMID- 28714115 TI - Editorial: Let's talk about sex - the gender binary revisited. AB - Sex refers to biological differences and gender to socioculturally delineated masculine and feminine roles. Sex or gender are included as a covariate or effect modifier in the majority of child psychology and psychiatry studies, and differences found between boys and girls have inspired many researchers to postulate underlying mechanisms. Empirical tests of whether including these proposed explanatory variables actually reduces the variance explained by gender are lagging behind somewhat. That is a pity, because a lot can be gained from a greater focus on the active agents of specific gender differences. As opposed to biological sex as such, some of the processes explaining why a specific outcome shows gender differences may be changeable and so possible prevention targets. Moreover, while the sex binary may be reasonable adequate as a classification variable, the gender binary is far from perfect. Gender is a multidimensional, partly context-dependent factor, and the dichotomy generally used in research does not do justice to the diversity existing within boys and girls. PMID- 28714116 TI - Commentary: An exciting evolutionary framework for new bridges between social emotional and cognitive development - a reflection on Suor et al. (2017). AB - Suor et al. () present a compelling new evolutionary framework that offers an alternative interpretation of the well-established findings of cognitive deficits in children raised in harsh early environments. They argue that such findings do not convey a complete picture of those children's cognitive development, because children's cognition becomes specialized to solve problems in fitness-enhancing ways, and traditional abstract problem-solving tasks do not fully capture their abilities. The authors demonstrate that children exposed to early harshness, particularly children with Hawk temperaments, preferentially shift cognition to salient fitness-enhancing stimuli, and thus develop better skills for solving reward-oriented tasks. This intriguing and heuristically generative study inspires multiple new research avenues, of which we outline three: (a) Further examination of the concept of harsh environments, (b) addressing questions about the conceptualization and the role of child temperament, and (c) further advances in the measurement of children's distinct skills. PMID- 28714117 TI - A Swellable Microneedle Patch to Rapidly Extract Skin Interstitial Fluid for Timely Metabolic Analysis. AB - Skin interstitial fluid (ISF) is an emerging source of biomarkers for disease diagnosis and prognosis. Microneedle (MN) patch has been identified as an ideal platform to extract ISF from the skin due to its pain-free and easy-to administrated properties. However, long sampling time is still a serious problem which impedes timely metabolic analysis. In this study, a swellable MN patch that can rapidly extract ISF is developed. The MN patch is made of methacrylated hyaluronic acid (MeHA) and further crosslinked through UV irradiation. Owing to the supreme water affinity of MeHA, this MN patch can extract sufficient ISF in a short time without the assistance of extra devices, which remarkably facilitates timely metabolic analysis. Due to covalent crosslinked network, the MN patch maintains the structure integrity in the swelling hydrated state without leaving residues in skin after usage. More importantly, the extracted ISF metabolites can be efficiently recovered from MN patch by centrifugation for the subsequent offline analysis of metabolites such as glucose and cholesterol. Given the recent trend of easy-to-use point-of-care devices for personal healthcare monitoring, this study opens a new avenue for the development of MN-based microdevices for sampling ISF and minimally invasive metabolic detection. PMID- 28714118 TI - Body wall structure in the starfish Asterias rubens. AB - The body wall of starfish is composed of magnesium calcite ossicles connected by collagenous tissue and muscles and it exhibits remarkable variability in stiffness, which is attributed to the mechanical mutability of the collagenous component. Using the common European starfish Asterias rubens as an experimental animal, here we have employed a variety of techniques to gain new insights into the structure of the starfish body wall. The structure and organisation of muscular and collagenous components of the body wall were analysed using trichrome staining. The muscle system comprises interossicular muscles as well as muscle strands that connect ossicles with the circular muscle layer of the coelomic lining. The collagenous tissue surrounding the ossicle network contains collagen fibres that form loop-shaped straps that wrap around calcite struts near to the surface of ossicles. The 3D architecture of the calcareous endoskeleton was visualised for the first time using X-ray microtomography, revealing the shapes and interactions of different ossicle types. Furthermore, analysis of the anatomical organisation of the ossicles indicates how changes in body shape may be achieved by local contraction/relaxation of interossicular muscles. Scanning synchrotron small-angle X-ray diffraction (SAXD) scans of the starfish aboral body wall and ambulacrum were used to study the collagenous tissue component at the fibrillar level. Collagen fibrils in aboral body wall were found to exhibit variable degrees of alignment, with high levels of alignment probably corresponding to regions where collagenous tissue is under tension. Collagen fibrils in the ambulacrum had a uniformly low degree of orientation, attributed to macrocrimp of the fibrils and the presence of slanted as well as horizontal fibrils connecting antimeric ambulacral ossicles. Body wall collagen fibril D period lengths were similar to previously reported mammalian D-periods, but were significantly different between the aboral and ambulacral samples. The overlap/D period length ratio within fibrils was higher than reported for mammalian tissues. Collectively, the data reported here provide new insights into the anatomy of the body wall in A. rubens and a foundation for further studies investigating the structural basis of the mechanical properties of echinoderm body wall tissue composites. PMID- 28714119 TI - High-Performance Polymers Sandwiched with Chemical Vapor Deposited Hexagonal Boron Nitrides as Scalable High-Temperature Dielectric Materials. AB - Polymer dielectrics are the preferred materials of choice for power electronics and pulsed power applications. However, their relatively low operating temperatures significantly limit their uses in harsh-environment energy storage devices, e.g., automobile and aerospace power systems. Herein, hexagonal boron nitride (h-BN) films are prepared from chemical vapor deposition (CVD) and readily transferred onto polyetherimide (PEI) films. Greatly improved performance in terms of discharged energy density and charge-discharge efficiency is achieved in the PEI sandwiched with CVD-grown h-BN films at elevated temperatures when compared to neat PEI films and other high-temperature polymer and nanocomposite dielectrics. Notably, the h-BN-coated PEI films are capable of operating with >90% charge-discharge efficiencies and delivering high energy densities, i.e., 1.2 J cm-3 , even at a temperature close to the glass transition temperature of polymer (i.e., 217 degrees C) where pristine PEI almost fails. Outstanding cyclability and dielectric stability over a straight 55 000 charge-discharge cycles are demonstrated in the h-BN-coated PEI at high temperatures. The work demonstrates a general and scalable pathway to enable the high-temperature capacitive energy applications of a wide range of engineering polymers and also offers an efficient method for the synthesis and transfer of 2D nanomaterials at the scale demanded for applications. PMID- 28714120 TI - Partial Fourier techniques in single-shot cross-term spatiotemporal encoded MRI. AB - PURPOSE: Cross-term spatiotemporal encoding (xSPEN) is a single-shot approach with exceptional immunity to field heterogeneities, the images of which faithfully deliver 2D spatial distributions without requiring a priori information or using postacquisition corrections. xSPEN, however, suffers from signal-to-noise ratio penalties due to its non-Fourier nature and due to diffusion losses-especially when seeking high resolution. This study explores partial Fourier transform approaches that, acting along either the readout or the spatiotemporally encoded dimensions, reduce these penalties. METHODS: xSPEN uses an orthogonal (e.g., z) gradient to read, in direct space, the low-bandwidth (e.g., y) dimension. This substantially changes the nature of partial Fourier acquisitions vis-a-vis conventional imaging counterparts. A suitable theoretical analysis is derived to implement these procedures, along either the spatiotemporally or readout axes. RESULTS: Partial Fourier single-shot xSPEN images were recorded on preclinical and human scanners. Owing to their reduction in the experiments' acquisition times, this approach provided substantial sensitivity gains vis-a-vis previous implementations for a given targeted in plane resolution. The physical origins of these gains are explained. CONCLUSION: Partial Fourier approaches, particularly when implemented along the low-bandwidth spatiotemporal dimension, provide several-fold sensitivity advantages at minimal costs to the execution and processing of the single-shot experiments. Magn Reson Med 79:1506-1514, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28714122 TI - A fast and accurate method for the pharmacokinetic research of four coumarin analogs in Fructus cnidii using capillary electro-chromatography with a methacrylate ester-based monolithic column. AB - In the present study, a monolithic capillary column with higher permeability was developed for the in vivo discrimination of four coumarin analogs (bergapten, 2' acetylangelicin, imperatorin, and osthole) that typically require long separation times in HPLC. Instead of conventional methacrylate ester monolith (containing 19.5% porogen) with insufficient permeability (K = 1.52 - 1.66 * 10-14 M2 ) for plasma sample, the proposed column (20.5% porogen) had better permeability (around 3.80 * 10-14 M2 ) while properties such as pore distribution, stability, and resolution changed slightly. As a result, due to the negatively charged electro-dynamic flow of the methacrylate ester groups in the monolith, the migration of targeted analytes was achieved within 6 min (compared with 30 min in HPLC) with acceptable resolution and improved sensitivity (0.005-0.02 MUg/mL vs. 0.04 MUg/mL). The proposed method was also applied to pharmacokinetic research: accelerated solvent extraction (ASE) was used to improve the extraction efficiency, which prepared extract much faster and more pure than conventional methods. As the pharmacokinetic parameters indicated, the monolithic capillary electro-chromatography method was efficient, sensitive, specific, and durable, guaranteeing its utility for the determination of multiple structure-related compounds in rat plasma. PMID- 28714123 TI - Defect Engineering of Chalcogen-Tailored Oxygen Electrocatalysts for Rechargeable Quasi-Solid-State Zinc-Air Batteries. AB - A critical bottleneck limiting the performance of rechargeable zinc-air batteries lies in the inefficient bifunctional electrocatalysts for the oxygen reduction and evolution reactions at the air electrodes. Hybridizing transition-metal oxides with functional graphene materials has shown great advantages due to their catalytic synergism. However, both the mediocre catalytic activity of metal oxides and the restricted 2D mass/charge transfer of graphene render these hybrid catalysts inefficient. Here, an effective strategy combining anion substitution, defect engineering, and the dopant effect to address the above two critical issues is shown. This strategy is demonstrated on a hybrid catalyst consisting of sulfur-deficient cobalt oxysulfide single crystals and nitrogen-doped graphene nanomeshes (CoO0.87 S0.13 /GN). The defect chemistries of both oxygen-vacancy rich, nonstoichiometric cobalt oxysulfides and edge-nitrogen-rich graphene nanomeshes lead to a remarkable improvement in electrocatalytic performance, where CoO0.87 S0.13 /GN exhibits strongly comparable catalytic activity to and much better stability than the best-known benchmark noble-metal catalysts. In application to quasi-solid-state zinc-air batteries, CoO0.87 S0.13 /GN as a freestanding catalyst assembly benefits from both structural integrity and enhanced charge transfer to achieve efficient and very stable cycling operation over 300 cycles with a low discharge-charge voltage gap of 0.77 V at 20 mA cm-2 under ambient conditions. PMID- 28714121 TI - Acetylcholine-dependent upregulation of TASK-1 channels in thalamic interneurons by a smooth muscle-like signalling pathway. AB - KEY POINTS: The ascending brainstem transmitter acetylcholine depolarizes thalamocortical relay neurons while it induces hyperpolarization in local circuit inhibitory interneurons. Sustained K+ currents are modulated in thalamic neurons to control their activity modes; for the interneurons the molecular nature of the underlying ion channels is as yet unknown. Activation of TASK-1 K+ channels results in hyperpolarization of interneurons and suppression of their action potential firing. The modulation cascade involves a non-receptor tyrosine kinase, c-Src. The present study identifies a novel pathway for the activation of TASK-1 channels in CNS neurons that resembles cholinergic signalling and TASK-1 current modulation during hypoxia in smooth muscle cells. ABSTRACT: The dorsal part of the lateral geniculate nucleus (dLGN) is the main thalamic site for state dependent transmission of visual information. Non-retinal inputs from the ascending arousal system and inhibition provided by gamma-aminobutyric acid (GABA)ergic local circuit interneurons (INs) control neuronal activity within the dLGN. In particular, acetylcholine (ACh) depolarizes thalamocortical relay neurons by inhibiting two-pore domain potassium (K2P ) channels. Conversely, ACh also hyperpolarizes INs via an as-yet-unknown mechanism. By using whole cell patch-clamp recordings in brain slices and appropriate pharmacological tools we here report that stimulation of type 2 muscarinic ACh receptors induces IN hyperpolarization by recruiting the G-protein betagamma subunit (Gbetagamma), class-1A phosphatidylinositol-4,5-bisphosphate 3-kinase, and cellular and sarcoma (c-Src) tyrosine kinase, leading to activation of two-pore domain weakly inwardly rectifying K+ channel (TWIK)-related acid-sensitive K+ (TASK)-1 channels. The latter was confirmed by the use of TASK-1-deficient mice. Furthermore inhibition of phospholipase Cbeta as well as an increase in the intracellular level of phosphatidylinositol-3,4,5-trisphosphate facilitated the muscarinic effect. Our results have uncovered a previously unknown role of c-Src tyrosine kinase in regulating IN function in the brain and identified a novel mechanism by which TASK-1 channels are activated in neurons. PMID- 28714124 TI - Primary Central Nervous System Post-Transplant Lymphoproliferative Disorder Following Kidney Transplantation: A Multi-Institution Study in Japan Over 30 years. PMID- 28714125 TI - Weight and Body Mass Index in Old Age: Do They Still Matter? PMID- 28714127 TI - High hepatitis E virus antibody positive rates in dogs and humans exposed to dogs in the south-west of China. AB - Hepatitis E (HE) is a zoonotic viral disease caused by hepatitis E virus (HEV). The objective of this study was to investigate the prevalence of HEV infection among dogs and humans exposed to dogs in the south-west region of China. A total of 4,490 dog serum samples and 2,206 relative practitioner serum samples were collected from 18 pet hospitals and dog farms in Yunnan, Sichuan and Guizhou province, and the anti-HEV IgG antibodies were detected by ELISA. The results showed that the total positive rate of anti-HEV antibodies was 36.55% with the highest rate in city stray dogs, and the differences in distinct species and growth phases were significant. The positive rate of anti-HEV antibody in veterinarian and farm staff-related practitioners was significantly higher than the general population. The finding of the present survey suggested that high HEV seroprevalence in dogs and humans exposed to dogs in the south-west area of China poses a significant public health concern. It is urgent to improve integrated strategies to detect, prevent and control HEV infection in dogs and humans exposed to dogs in this area. PMID- 28714128 TI - European guideline for the management of pediculosis pubis. AB - Pediculosis pubis is caused by Phthirus pubis. The disease can be sexually transmitted. Patients main complain is of itch in the pubic area. The parasite can be spotted with the naked eye and blue macules can be observed in the pubic area. First line therapy consists of permethrin or pyrethrins with piperonyl butoxide. Second line therapy contains phenothrin, malathion and oral ivermectin. Partner management needs a look-back period of time of 3 months. Pubic lice incidence is increased in populations groups living in crowded spaces with scarce sanitary conditions as in time of war or disaster. PMID- 28714126 TI - Annual Research Review: Early adversity, the hypothalamic-pituitary adrenocortical axis, and child psychopathology. AB - BACKGROUND: Research on early adversity, stress biology, and child development has grown exponentially in recent years. FINDINGS: We review the current evidence for the hypothalamic-pituitary-adrenocortical (HPA) axis as a stress-mediating mechanism between various forms of childhood adversity and psychopathology. We begin with a review of the neurobiology of the axis and evidence for relations between early adversity-HPA axis activity and HPA axis activity-psychopathology, as well as discuss the role of regulatory mechanisms and sensitive periods in development. CONCLUSIONS: We call attention to critical gaps in the literature to highlight next steps in this research including focus on developmental timing, sex differences, stress buffering, and epigenetic regulation. A better understanding of individual differences in the adversity-HPA axis-psychopathology associations will require continued work addressing how multiple biological and behavioral systems work in concert to shape development. PMID- 28714129 TI - Coevolution between flight morphology, vertical stratification and sexual dimorphism: what can we learn from tropical butterflies? AB - Occurrence patterns are partly shaped by the affinity of species with habitat conditions. For winged organisms, flight-related attributes are vital for ecological performance. However, due to the different reproductive roles of each sex, we expect divergence in flight energy budget, and consequently different selection responses between sexes. We used tropical frugivorous butterflies as models to investigate coevolution between flight morphology, sex dimorphism and vertical stratification. We studied 94 species of Amazonian fruit-feeding butterflies sampled in seven sites across 3341 ha. We used wing-thorax ratio as a proxy for flight capacity and hierarchical Bayesian modelling to estimate stratum preference. We detected a strong phylogenetic signal in wing-thorax ratio in both sexes. Stouter fast-flying species preferred the canopy, whereas more slender slow-flying species preferred the understorey. However, this relationship was stronger in females than in males, suggesting that female phenotype associates more intimately with habitat conditions. Within species, males were stouter than females and sexual dimorphism was sharper in understorey species. Because trait habitat relationships were independent from phylogeny, the matching between flight morphology and stratum preference is more likely to reflect adaptive radiation than shared ancestry. This study sheds light on the impact of flight and sexual dimorphism on the evolution and ecological adaptation of flying organisms. PMID- 28714130 TI - Nocturnal seizures are associated with more severe hypoxemia and increased risk of postictal generalized EEG suppression. AB - Patients with epilepsy have 20-fold risk of sudden death when compared to the general population. Uncontrolled seizures is the most consistent risk factor, and death often occurs at night or in relation to sleep. We examined seizure-related respiratory disturbances in sleep versus wakefulness, focusing on periictal oxygen saturation. Respiratory measures were examined in 48 recorded seizures (sleep, n = 23, wake, n = 25) from 20 adult patients with epilepsy. Seizures from sleep were associated with lower saturation, as compared to seizures from wakefulness, both during ictal (sleep median = 90.8, wake median = 95.5; p < 0.01) and postictal periods (sleep median = 94.3, wake median = 96.9; p = 0.05). Compared to wake-related seizures, seizures from sleep were also associated with a larger desaturation drop (sleep median = -4.2, wake median = -1.2; p = 0.01). Postictal generalized electroencephalography (EEG) suppression (PGES) occurred more frequently after seizures from sleep (39%), as compared to wake-related seizures (8%, p = 0.01). Our findings suggest that nocturnal seizures may entail a higher sudden unexpected death in epilepsy (SUDEP) severity burden, as they are associated with more severe and longer hypoxemia events, and more frequently followed by PGES, both factors implicated in sudden death. PMID- 28714131 TI - Evaluating a push-pull strategy for management of Drosophila suzukii Matsumura in red raspberry. AB - BACKGROUND: Drosophila suzukii Matsumura is a serious pest of small fruits that lays its eggs in growing fruit. Current management strategies rely on an unsustainable schedule of foliar applications of chemical insecticides. Alternative approaches to suppressing oviposition are under investigation, such as attract-and-kill and the use of oviposition deterrents. Here, we evaluated two behavioral control approaches in combination as a push-pull strategy using laboratory and field assays. RESULTS: In laboratory caged assays, both an attractive mass trapping device (pull) and an oviposition deterrent (push: 1 octen-3-ol) reduced oviposition by D. suzukii, and the combination of the two (push-pull) resulted in significantly greater reduction than either treatment alone. In field experiments, oviposition reduction was observed in fruit from plots treated with oviposition deterrent (push) or a combination of mass trapping devices and deterrent (push-pull) compared with fruit from control plots. However, oviposition in plots with mass trapping devices (pull) was higher than observed in all other treatments. Additionally, the protection provided by the deterrent in push plots extended to the entire plot rather than just in fruit closest to deterrent dispensers. CONCLUSION: Push-pull treatments negatively affected D. suzukii infestation in both laboratory and field experiments. The reduction in oviposition observed in laboratory experiments was based on the additive effect of push and pull components acting on a finite population, while the reduction observed in field experiments appeared to be mainly based on the effect of pull components. We discuss potential underlying reasons for the discrepancy results and suggest potential improvements. (c) 2017 Society of Chemical Industry. PMID- 28714133 TI - Tilted pillar array fabrication by the combination of proton beam writing and soft lithography for microfluidic cell capture Part 2: Image sequence analysis based evaluation and biological application. AB - As a continuation of our previously published work, this paper presents a detailed evaluation of a microfabricated cell capture device utilizing a doubly tilted micropillar array. The device was fabricated using a novel hybrid technology based on the combination of proton beam writing and conventional lithography techniques. Tilted pillars offer unique flow characteristics and support enhanced fluidic interaction for improved immunoaffinity based cell capture. The performance of the microdevice was evaluated by an image sequence analysis based in-house developed single-cell tracking system. Individual cell tracking allowed in-depth analysis of the cell-chip surface interaction mechanism from hydrodynamic point of view. Simulation results were validated by using the hybrid device and the optimized surface functionalization procedure. Finally, the cell capture capability of this new generation microdevice was demonstrated by efficiently arresting cells from a HT29 cell-line suspension. PMID- 28714134 TI - Implementation of oral health initiatives by Australian rural communities: Factors for success. AB - In this paper, we consider factors significant in the success of community participation in the implementation of new oral health services. Our analysis draws on data from the Rural Engaging Communities in Oral Health (Rural ECOH) study (2014-2016). We aimed to assess the Australian relevance of a Scottish community participation framework for health service development; Remote Service Futures. Internationally, community participation in planning of health initiatives is common, but less common in new service implementation. Health managers query the legitimacy of "lay" community members, whether they will persist, and whether they can act as change agents. Our data provide evidence that helps answer these queries. Six communities, located within regions covered by two large rural primary healthcare organisations (Medicare Locals), were selected in two Australian states. Two university-based facilitators worked with a group of local residents (for each community) to monitor implementation of new oral health initiatives designed through participatory processes. Data about implementation were collected through interviews with 28 key stakeholders at the beginning of implementation and 12 months later. Data were coded, themed and analysed abductively. Five themes emerged; the inter-relationship between community motivation to participate with the fortunes of the oral health initiatives, having the "right" people involved, continuing involvement of sponsors and/or significant people, trusting working relationships between participants and perceiving benefits from participation. Findings provide evidence of a role for community participation in implementing new community services if solid partnerships with relevant providers can be negotiated and services are seen to be relevant and useful to the community. PMID- 28714136 TI - Vitamin D and bone health: interpreting observational studies. PMID- 28714135 TI - YAP suppresses gluconeogenic gene expression through PGC1alpha. AB - : Cell growth and proliferation are tightly coupled to metabolism, and dissecting the signaling molecules which link these processes is an important step toward understanding development, regeneration, and cancer. The transcriptional regulator Yes-associated protein 1 (YAP) is a key regulator of liver size, development, and function. We now show that YAP can also suppress gluconeogenic gene expression. Yap deletion in primary hepatocytes potentiates the gluconeogenic gene response to glucagon and dexamethasone, whereas constitutively active YAP suppresses it. The effects of YAP are mediated by the transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator 1. YAP inhibits its ability to bind to and activate transcription from the promoters of its gluconeogenic targets, and the effects of YAP are blunted upon its knockdown. In vivo, constitutively active YAP lowers plasma glucose levels and increases liver size. CONCLUSION: YAP appears to reprogram cellular metabolism, diverting substrates away from the energy-consuming process of gluconeogenesis and toward the anabolic process of growth. (Hepatology 2017;66:2029-2041). PMID- 28714137 TI - Austerity, new public management and missed nursing care in Australia and New Zealand. AB - AIMS: To outline the way the culture of austerity arising from the Global Financial Crisis has been used by Australian and New Zealand governments to maintain and extend healthcare budget cuts, through new public management strategies leading to missed nursing care. BACKGROUND: Ten years on the cost of the Global Financial Crisis continues to be borne by tax payers and those employed by the welfare state, yet analysis shows clearly that it was caused by a failure to adequately regulate markets, particularly the banks and multinational corporations. In health care, one of the impacts is increased workload for nurses leading to missed care. DESIGN/METHODS: Registered Nurses and midwives (n = 7,302) completed the MISSCARE surveys between 2012 - 2015, in four Australian states and New Zealand providing quantitative and qualitative responses. The qualitative comments were analysed using a template analysis approach based on key features of New Public Management. FINDINGS: Sixty-two qualitative responses identified measures in place directly linked to austerity and new public management strategies that impacted on the quality of patient care and nursing work, as well as contributing to missed care. CONCLUSION: Opportunities for resistance may lie outside public and private health organizations in civil society, in the nurse union movements and other health and nursing professional associations. PMID- 28714138 TI - Production of beta-Lactoglobulin hydrolysates by monolith based immobilized trypsin reactors. AB - Tryptic hydrolysis of beta-Lactoglobulin (beta-Lg) is attracting more and more attention due to the reduced allergenicity and the functionality of resulting hydrolysates. To produce hydrolysates in an economically viable way, immobilized trypsin reactors (IMTRs), based on polymethacrylate monolith with pore size 2.1 MUm (N1) and 6 MUm (N2), were developed and used in a flow-through system. IMTRs were characterized in terms of permeability and enzymatic activity during extensive usage. N1 showed twice the activity compared with N2, correlating well with its almost two times higher amount of immobilized trypsin. N2 showed high stability over 18 cycles, as well as over more than 30 weeks during storage. The efficiency of IMTRs on hydrolyzing beta-Lg was compared with free trypsin, and the resulting hydrolysates were analyzed by MALDI-TOF/MS. The final hydrolysis degree by N1 reached 9.68% (86.58% cleavage sites) within 4 h, while only around 6% (53.67% cleavage sites) by 1.5 mg of free trypsin. Peptides analysis showed the different preference between immobilized trypsin and free trypsin. Under the experimental conditions used in this study, the potential cleavage site Lys135 Phe136 was resistant against the immobilized trypsin in N1. PMID- 28714139 TI - Simple Radical Polymerization of Poly(Alginate-Graft-N-Isopropylacrylamide) Injectable Thermoresponsive Hydrogel with the Potential for Localized and Sustained Delivery of Stem Cells and Bioactive Molecules. AB - In this study, thermoresponsive copolymers that are fully injectable, biocompatible, and biodegradable and are synthesized via graft copolymerization of poly(N-isopropylacrylamide) onto alginate using a free-radical reaction are presented. This new synthesis method does not involve multisteps or associated toxicity issues, and has the potential to reduce scale-up difficulties. Chemical and physical analyses verify the resultant graft copolymer structure. The lower critical solution temperature, which is a characteristic of sol-gel transition, is observed at 32 degrees C. The degradation properties indicate suitable degradation kinetics for drug delivery and bone tissue engineering applications. The synthesized P(Alg-g-NIPAAm) hydrogel is noncytotoxic with both human osteosarcoma (MG63) cells and porcine bone marrow derived mesenchymal stem cells (pBMSCs). pBMSCs encapsulated in the P(Alg-g-NIPAAm) hydrogel remain viable, show uniform distribution within the injected hydrogel, and undergo osteogenic and chondrogenic differentiation under appropriate culture conditions. Furthermore, for the first time, this work will explore the influence of alginate viscosity on the viscoelastic properties of the resulting copolymer hydrogels, which influences the rate of medical device formation and subsequent drug release. Together the results of this study indicate that the newly synthesized P(Alg-g NIPAAm) hydrogel has potential to serve as a versatile and improved injectable platform for drug delivery and bone tissue engineering applications. PMID- 28714140 TI - Prevascularization of natural nanofibrous extracellular matrix for engineering completely biological three-dimensional prevascularized tissues for diverse applications. AB - Self-sustainability after implantation is one of the critical obstacles facing large engineered tissues. A preformed functional vascular network provides an effective solution for solving the mass transportation problem. With the support of mural cells, endothelial cells (ECs) can form microvessels within engineered tissues. As an important mural cell, human mesenchymal stem cells (hMSCs) not only stabilize the engineered microvessel network, but also preserve their multi potency when grown under optimal culture conditions. A prevascularized hMSC/extracellular matrix (ECM) sheet fabricated by the combination of hMSCs, ECs and a naturally derived nanofibrous ECM scaffold offers great opportunity for engineering mechanically strong and completely biological three-dimensional prevascularized tissues. The objective of this study was to create a prevascularized hMSC/ECM sheet by co-culturing ECs and hMSCs on a nanofibrous ECM scaffold. Physiologically low oxygen (2% O2 ) was introduced during the 7 day hMSC culture to preserve the stemness of hMSCs and thereby their capability to secrete angiogenic factors. The ECs were then included to form microvessels under normal oxygen (20% O2 ) for up to 7 days. The results showed that a branched and mature vascular network was formed in the co-culture condition. Angiogenic factors vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and angiopoietin-1 (Ang-1) were significantly increased by low-oxygen culture of hMSCs, which further stabilized and supported the maturation of microvessels. A differentiation assay of the prevascularized ECM scaffold demonstrated a retained hMSC multi-potency in the hypoxia cultured samples. The prevascularized hMSC/ECM sheet holds great promise for engineering three dimensional prevascularized tissues for diverse applications. PMID- 28714141 TI - Intrinsic 3D Prestressing: A New Route for Increasing Strength and Improving Toughness of Hybrid Inorganic Biocements. AB - Cement is the most consumed resource and is the most widely used material globally. The ability to extrinsically prestress cementitious materials with tendons usually made from steel allows the creation of high-strength bridges and floors from this otherwise brittle material. Here, a dual setting cement system based on the combination of hydraulic cement powder with an aqueous silk fibroin solution that intrinsically generates a 3D prestressing during setting, dramatically toughening the cement to the point it can be cut with scissors, is reported. Changes of both ionic concentration and pH during cement setting are shown to create an interpenetrating silk fibroin inorganic composite with the combined properties of the elastic polymer and the rigid cement. These hybrid cements are self-densifying and show typical ductile fracture behavior when dry and a high elasticity under wet conditions with mechanical properties (bending and compressive strength) nearly an order of magnitude higher than the fibroin free cement reference. PMID- 28714142 TI - Comments on cochrane review on direct-acting antivirals for hepatitis C. PMID- 28714143 TI - Efficacy and safety of new direct antiviral agents in hepatitis C virus-infected patients with diffuse large B-cell non-Hodgkin's lymphoma. AB - : The association of hepatitis C virus (HCV) with non-Hodgkin's lymphoma (NHL) has been demonstrated throughout the world. The new interferon-free direct antiviral agents (DAAs) showed high efficacy and safety, and preliminary data seem to confirm their activity on low-grade NHL. The question arises as whether or not-and how-to treat the HCV-positive patients suffering from diffuse large B cell lymphomas (DLBCLs). The aim of this observational study was to evaluate whether DAA antiviral treatment of DLBCL/HCV-infected patients in concomitance with chemotherapy is a safe and effective option. Twenty (13 males and 7 females) HCV genotype 1b-positive subjects, undergoing chemotherapy for DLBCL, were enrolled between June 2015 and December 2015. After informed consent, all patients underwent antiviral therapy (AVT) with sofosbuvir/ledipasvir and chemotherapy (14 rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone and 6 cyclophosphamide, doxorubicin, vincristine, and prednisone) for DLBCL. Complete hematological (Revised European-American Lymphoma classification, Ann Arbor, and International Prognostic Index [IPI] scores) and hepatological (viral markers, liver stiffness, and biochemical parameters) evaluations were made. A historical retrospective cohort of 101 DLBCL/HCV-positive patients not undergoing AVT was enrolled for comparison. DAA-treated and untreated patients were similar for sex distribution, IPI score, and NHL stage, and differed for age (older in treated), chemotherapy and use of AVT. Overall survival (OS) and disease-free survival (DFS) were evaluated among a 52-week of follow-up. No statistical difference was found in OS after 52 weeks (P = 0.122), whereas a statistically significant higher DFS was achieved in treated patients (P = 0.036). At the multivariate analysis, only IPI score and AVT were independently correlated with a better DFS. No differences in adverse events were reported. CONCLUSION: DAA treatment in concomitance with chemotherapy was shown to be safe and effective in influencing remission of aggressive lymphomas in HCV patients. (Hepatology 2018;67:48-55). PMID- 28714145 TI - Metallic MXene Saturable Absorber for Femtosecond Mode-Locked Lasers. AB - 2D transition metal carbides, nitrides, and carbonitides called MXenes have attracted much attention due to their outstanding properties. However, MXene's potential in laser technology is not explored. It is demonstrated here that Ti3 CN, one of MXene compounds, can serve as an excellent mode-locker that can produce femtosecond laser pulses from fiber cavities. Stable laser pulses with a duration as short as 660 fs are readily obtained at a repetition rate of 15.4 MHz and a wavelength of 1557 nm. Density functional theory calculations show that Ti3 CN is metallic, in contrast to other 2D saturable absorber materials reported so far to be operative for mode-locking. 2D structural and electronic characteristics are well conserved in their stacked form, possibly due to the unique interlayer coupling formed by MXene surface termination groups. Noticeably, the calculations suggest a promise of MXenes in broadband saturable absorber applications due to metallic characteristics, which agrees well with the experiments of passively Q-switched lasers using Ti3 CN at wavelengths of 1558 and 1875 nm. This study provides a valuable strategy and intuition for the development of nanomaterial-based saturable absorbers opening new avenues toward advanced photonic devices based on MXenes. PMID- 28714146 TI - The effect of gender on transformational leadership and job satisfaction among Saudi nurses. AB - AIM: To compare nurses' job satisfaction and perceptions of transformational leadership style of their manager among four different nurse/manager gender dyads in Saudi Arabia. BACKGROUND: Women and men differ on many behavioural characteristics and are influenced by the cultural environment. Understanding these differences may have an impact on leadership behaviours and job satisfaction. DESIGN: A descriptive analysis of one-time survey data collected in 2011 from Saudi nurses employed in six general public hospitals located in three cities. METHOD: Three hundred and eight (51.3%) of 600 Saudi nurses solicited to participate completed anonymous questionnaires that measured their job satisfaction and perceptions of transformational leadership style of their manager. FINDINGS: Factorial ANOVA tested the main effects of gender of the nurse, gender of the manager and the interaction term on the nurse's job satisfaction, and perceived transformational leadership style of their manager. These analyses indicated a main effect of gender of the manager on both job satisfaction and perceived transformational leadership style of the manager (p < .05) with no significant effect of the gender of the nurse or the interaction term on these variables. Post hoc analysis indicated that nurses regardless of their gender reported higher job satisfaction and perceived transformational leadership style of their manager when their manager was male. CONCLUSION: These findings contrast with what other researchers have reported that nurse job satisfaction and perceived leadership characteristics of their manager are independent of the gender of the manager. These perceptions of Saudi nurses may be a result of "sex-role spillover" in a male-dominated, gender-segregated society. PMID- 28714144 TI - Cerebellins are differentially expressed in selective subsets of neurons throughout the brain. AB - Cerebellins are secreted hexameric proteins that form tripartite complexes with the presynaptic cell-adhesion molecules neurexins or 'deleted-in-colorectal cancer', and the postsynaptic glutamate-receptor-related proteins GluD1 and GluD2. These tripartite complexes are thought to regulate synapses. However, cerebellins are expressed in multiple isoforms whose relative distributions and overall functions are not understood. Three of the four cerebellins, Cbln1, Cbln2, and Cbln4, autonomously assemble into homohexamers, whereas the Cbln3 requires Cbln1 for assembly and secretion. Here, we show that Cbln1, Cbln2, and Cbln4 are abundantly expressed in nearly all brain regions, but exhibit strikingly different expression patterns and developmental dynamics. Using newly generated knockin reporter mice for Cbln2 and Cbln4, we find that Cbln2 and Cbln4 are not universally expressed in all neurons, but only in specific subsets of neurons. For example, Cbln2 and Cbln4 are broadly expressed in largely non overlapping subpopulations of excitatory cortical neurons, but only sparse expression was observed in excitatory hippocampal neurons of the CA1- or CA3 region. Similarly, Cbln2 and Cbln4 are selectively expressed, respectively, in inhibitory interneurons and excitatory mitral projection neurons of the main olfactory bulb; here, these two classes of neurons form dendrodendritic reciprocal synapses with each other. A few brain regions, such as the nucleus of the lateral olfactory tract, exhibit astoundingly high Cbln2 expression levels. Viewed together, our data show that cerebellins are abundantly expressed in relatively small subsets of neurons, suggesting specific roles restricted to subsets of synapses. PMID- 28714147 TI - Communication of Information about Genetic Risks: Putting Families at the Center. AB - Genetic information is a family affair. With the expansion of genomic technologies, many new causal genes and variants have been established and the potential for molecular diagnoses increased, with implications not only for patients but also their relatives. The need for genetic counseling and intrafamilial circulation of information on genetic risks grew accordingly. Also, the amount and, particularly, the complexity of the information to convey multiplied. Sharing information about genetic risks with family members, however, has never been an easy matter and often becomes a source of personal and familial conflicts and distress. Ethical requisites generally prevent healthcare professionals from directly contacting their consultands' relatives (affected or still at risk), who often feel unsupported throughout that process. We discuss here the communication of genetic risks to family members. We first consider genomic testing as a basis for family-centered health care, as opposed to a predominant focus on the individual. We reviewed the literature on sharing genetic risk information with family members, and the associated ethical issues for professionals. Some clinical cases are presented and discussed, and key issues for meeting the needs of individuals and families are addressed. We argue that genetic information is inextricably linked to the family and that communicating about genetic risks is a process grounded within the broader milieu of family relationships and functioning. We conclude for the need for a more family-centered approach and interventions that can promote sensitive attitudes to the provision of genetic information to and within the family, as well as its inclusion in educational and training programmes for genetic healthcare professionals. PMID- 28714148 TI - Palladium(II)-Catalyzed Site-Selective C(sp3 )-H Alkynylation of Oligopeptides: A Linchpin Approach for Oligopeptide-Drug Conjugation. AB - The palladium(II)-catalyzed C(sp3 )-H alkynylation of oligopeptides was developed with tetrabutylammonium acetate as a key additive. Through molecular design, the acetylene motif served as a linchpin to introduce a broad range of carbonyl containing pharmacophores onto oligopeptides, thus providing a chemical tool for the synthesis and modification of novel oligopeptide-pharmacophore conjugates by C-H functionalization. Dipeptide conjugates with coprostanol and estradiol were synthesized by this method for potential application in targeted drug delivery to tumor cells with overexpressed nuclear hormone receptors. PMID- 28714149 TI - Elimination of Plasma Cytokines Markedly Improves Non-Septic Multiple Organ Dysfunction Syndrome in Human Immunodeficiency Virus-Associated Hodgkin Lymphoma. PMID- 28714150 TI - Development and psychometric testing of a new instrument to measure the caring behaviour of nurses in Italian acute care settings. AB - AIM: To develop and psychometrically test the Italian-language Nurse Caring Behaviours Scale, a short measure of nurse caring behaviour as perceived by inpatients. BACKGROUND: Patient perceptions of nurses' caring behaviours are a predictor of care quality. Caring behaviours are culture-specific, but no measure of patient perceptions has previously been developed in Italy. Moreover, existing tools show unclear psychometric properties, are burdensome for respondents, or are not widely applicable. DESIGN: Instrument development and psychometric testing. METHOD: Item generation included identifying and adapting items from existing measures of caring behaviours as perceived by patients. A pool of 28 items was evaluated for face validity. Content validity indexes were calculated for the resulting 15-item scale; acceptability and clarity were pilot tested with 50 patients. To assess construct validity, a sample of 2,001 consecutive adult patients admitted to a hospital in 2014 completed the scale and was split into two groups. Reliability was evaluated using nonlinear structural equation modelling coefficients. Measurement invariance was tested across subsamples. RESULTS: Item 15 loaded poorly in the exploratory factor analysis (n = 983) and was excluded from the final solution, positing a single latent variable with 14 indicators. This model fitted the data moderately. The confirmatory factor analysis (n = 1018) returned similar results. Internal consistency was excellent in both subsamples. Full scalar invariance was reached, and no significant latent mean differences were detected across subsamples. CONCLUSION: The new instrument shows reasonable psychometric properties and is a promising short and widely applicable measure of inpatient perceptions of nurse caring behaviours. PMID- 28714152 TI - Cognitive orientation to daily occupational performance (CO-OP): Sylvia Rodger's contributions to the understanding and implementation of this approach. PMID- 28714151 TI - Resilience as a moderator of the indirect effects of conflict and workload on job outcomes among nurses. AB - AIM: To examine the relative effects of interpersonal conflict and workload on job outcomes (turnover intentions, burnout, injuries) and examine if resilience moderates the indirect effects of conflict and workload on job outcomes via job related negative effect. BACKGROUND: There is interest in understanding resilience in the nursing profession. Placing resilience in the context of the Emotion-Centred Model of Occupational Stress (Spector, ) is a novel approach to understanding how resilience ameliorates the negative effects of workplace stressors. DESIGN: This study used a two-wave survey design to collect data from 97 nurses across medical units. METHODS: Nurses working in the US were recruited in June 2014 using Qualtrics Panels, an online survey platform service that secures participants for research. Nurses were contacted via email at two time points, two weeks apart and provided a link to an online survey. SPSS v. 23 and PROCESS v2.15 were used to analyse regressions and moderated mediation. RESULTS/FINDINGS: Interpersonal conflict predicted turnover intentions and burnout; workload predicted injuries. Job-related negative affect mediated the relationships between stressors and job outcomes except for the direct effect of workload on injuries. Low resilience increased the magnitude of the indirect effects of conflict on job outcomes. CONCLUSION: Job characteristics like workload predicted unique variability in self-reported physical injuries. Conflict at work, a social stressor, predicted well-being and job attitudes. Highly resilient nurses bounced back after experiencing conflict in the workplace. Resilience should be explored for its potential as a method to reduce the negative effects of social stressors. PMID- 28714153 TI - Ripples of influence: Professor Sylvia Rodger's contribution to the body of knowledge on developmental coordination disorder. PMID- 28714154 TI - Professor Sylvia Rodger's scholarship and contributions to the Autism Spectrum Disorder Body of Knowledge. PMID- 28714155 TI - Advancements in measurement and methodology in Occupational Therapy: The contribution of Professor Sylvia Rodger. PMID- 28714156 TI - Participation of children and youth with disability: New perspectives and scholarship of Sylvia Rodger. PMID- 28714157 TI - Illuminating a new perspective: A commemorative issue celebrating Prof Sylvia Rodger's work to improve lives. PMID- 28714158 TI - Leadership comes in many guises: Sylvia Docker Memorial Award Lecturer 2011, Professor Sylvia Rodger. PMID- 28714159 TI - Sylvia Rodger's contribution to a dynamic and diverse curriculum and education evidence base. PMID- 28714161 TI - Occupation-centred paediatric practice Sylvia Rodger's contribution. PMID- 28714160 TI - Occupational therapists working with children and families: two decades of progress. PMID- 28714162 TI - Occupational performance coaching: Client-centered and goal-directed practice; A commentary on collaborations with Sylvia Rodger. PMID- 28714163 TI - Occupational therapists' role in facilitating pain management in children with burn injuries. PMID- 28714164 TI - Commemorative issue: Vale Emeritus Professor Sylvia Rodger, AM. PMID- 28714165 TI - Professional issues, challenges and opportunities: Professor Sylvia Rodger's contribution. PMID- 28714166 TI - Emeritus Professor Sylvia Rodger, AM: Australian Occupational Therapy Champion and Visionary. PMID- 28714167 TI - Prioritising practice education through collaborations. PMID- 28714168 TI - Career Reflections of Sylvia Rodger AM, Occupational therapist and woman who taught by being. PMID- 28714169 TI - Reliable quantification of marrow fat content and unsaturation level using in vivo MR spectroscopy. AB - PURPOSE: To develop a novel technique for reliable quantification of bone marrow fat content and composition using in vivo MR spectroscopy (MRS). METHODS: An MRS quantification method combining both advantages of Voigt line shape model and time-domain analysis was developed. The proposed method was tested using computer simulated data and in vivo data acquired at lumbar vertebral bodies of 23 subjects (age, 83.8 +/- 3.7 y; male, n = 13; female, n = 10) from L1 to L4. Reliability and reproducibility were calculated for the quantification results. Comparisons between the proposed method and some conventional methods were conducted. RESULTS: Low mean absolute percentage errors and low mean coefficients of variation for computer simulations suggest that the proposed method is accurate and precise. By using this method, marrow fat content can be quantified reliably, even for data with low spectral resolution and low signal-to-noise ratio (SNR). Unsaturation level can be reliably quantified for data with moderate spectral resolution and moderate SNR. Results obtained from in vivo data using the proposed method demonstrated better model fit than conventional methods. CONCLUSION: The method proposed in this study has better performance than conventional methods in the quantification of bone marrow MRS data and has great potential for wide applications of studying marrow fat content and composition. Magn Reson Med 79:1722-1729, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28714170 TI - Safety and efficacy of low dose intramuscular magnesium sulphate (MgSO4) compared to intravenous regimen for treatment of eclampsia. AB - AIM: This study was performed to compare the safety and efficacy of low dose intramuscular magnesium sulphate (MgSO4) (Dhaka regimen) and intravenous (IV) MgSO4 (Zuspan regimen) for the prevention of eclampsia recurrence and to compare serum magnesium concentration. METHODS: Forty one eligible patients with eclampsia were randomly divided into two groups: group I patients received IV MgSO4 according to the Zuspan regime, while group II patients received intramuscular (IM) MgSO4 according to the Dhaka regimen (i.e. low dose MgSO4). The total dose MgSo4 requirements per patient were calculated and serum MgSo4 level was measured. Maternal and fetal outcomes were compared between the groups. RESULTS: The mean total dose of MgSO4 required for the treatment of eclampsia was higher in group I compared to group II (32 +/- 6.8 g vs 25.4 +/- 8.8 g, respectively; P < 0.5). The mean serum MgSO4 levels were significantly higher (P < 0.003) in group I compared to group II, although there were no significant differences in seizure recurrence. Statistically, more patients in group I experienced a loss of knee jerk reaction and required dose deferral compared to group II. There was a significantly higher number of babies with poor Apgar scores in group I. Overall the maternal and fetal outcomes were comparable between the groups. CONCLUSIONS: A low dose IM regimen (Dhaka regimen) of MgSo4 is equally efficacious and safe compared to an IV regimen (Zuspan regimen) for the control and prevention of seizures in patients with eclampsia. PMID- 28714171 TI - Controlled Gelation of Graphene Towards Unprecedented Superstructures. AB - Graphene exhibits a range of exceptional physical properties and holds great promise for development of novel bulk materials for widespread applications. Properly engineering of assembled structures of graphene at multiple length scales is essential to realize its full potential in bulk forms. In this Concept article, we highlight the unique colloidal and gelation behavior of a commonly used precursor for graphene, graphene oxide (GO), and discuss how the colloidal chemistry of GO and reduced GO can enable new scalable and cost-effective approaches to construct graphene-based soft superstructures with excellent properties. PMID- 28714172 TI - A study of DNA damage in buccal cells of consumers of well- and/or tap-water using the comet assay: Assessment of occupational exposure to genotoxicants. AB - Because of concerns that natural aquifers in the region of Todos Santos (Baja California Sur, Mexico) might be contaminated by organochlorine pesticides and heavy metals, a case-control study was conducted among consumers and non consumers of well- and/or tap-water to determine risks to human health. This study was based on a genotoxic evaluation of buccal cells using the Comet assay technique. Levels of DNA damage in the consumers group were significantly higher than those of the control group. However, occupational exposure to genotoxicants showed to be the critical factor rather than water consumption. Taking into account the professions of well- and/or tap-water consumers, agricultural workers exposed directly (those who fumigated) or indirectly (those not involved in fumigating) to agrochemicals showed greater genetic damage than controls. This difference persisted even when age, and whether the person smoked or consumed alcoholic drinks were considered. These factors were not associated with the level of genetic damage observed. Chemical analyses of organochlorine pesticides and heavy metals were carried out to evaluate the water quality of wells, faucets, and surface water of canals consumed by the population and/or used for irrigation. High concentrations of alpha and beta endosulfan were detected in water of surface canals. Although our inventory of agrochemicals employed in the region showed the use of products considered carcinogenic and/or mutagenic, they were not detected by the analytical techniques used. Heavy metals (arsenic, mercury, and lead) were detected in water of some wells used for irrigation and human consumption. Environ. Mol. Mutagen. 58:619-627, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28714173 TI - The use of advanced web-based survey design in Delphi research. AB - AIM: A discussion of the application of metadata, paradata and embedded data in web-based survey research, using two completed Delphi surveys as examples. BACKGROUND: Metadata, paradata and embedded data use in web-based Delphi surveys has not been described in the literature. The rapid evolution and widespread use of online survey methods imply that paper-based Delphi methods will likely become obsolete. Commercially available web-based survey tools offer a convenient and affordable means of conducting Delphi research. Researchers and ethics committees may be unaware of the benefits and risks of using metadata in web-based surveys. DESIGN: Discussion paper. DATA SOURCES: Two web-based, three-round Delphi surveys were conducted sequentially between August 2014 - January 2015 and April - May 2016. Their aims were to validate the Australian nurse practitioner metaspecialties and their respective clinical practice standards. Our discussion paper is supported by researcher experience and data obtained from conducting both web-based Delphi surveys. IMPLICATIONS FOR NURSING: Researchers and ethics committees should consider the benefits and risks of metadata use in web-based survey methods. Web-based Delphi research using paradata and embedded data may introduce efficiencies that improve individual participant survey experiences and reduce attrition across iterations. Use of embedded data allows the efficient conduct of multiple simultaneous Delphi surveys across a shorter timeframe than traditional survey methods. CONCLUSION: The use of metadata, paradata and embedded data appears to improve response rates, identify bias and give possible explanation for apparent outlier responses, providing an efficient method of conducting web-based Delphi surveys. PMID- 28714174 TI - Immunological properties and protective efficacy of a single mycobacterial antigen displayed on polyhydroxybutyrate beads. AB - In 2015, there were an estimated 10.4 million new tuberculosis (TB) cases and 1.4 million deaths worldwide. Bacille Calmette-Guerin (BCG), an attenuated strain of Mycobacterium bovis, is the vaccine available against TB, but it is insufficient for global TB control. This study evaluated the immunogenicity of the Mycobacterium tuberculosis antigen Rv1626 in mice while assessing the effect of co-delivering either Cpe30 (immunostimulatory peptide), CS.T3378-395 (promiscuous T helper epitope) or flagellin (TLR5 agonist) or a combination of all three immunostimulatory agents. Rv1626 and the respective immunostimulatory proteins/peptides were co-displayed on polyhydroxybutyrate beads assembled inside an engineered endotoxin-free mutant of Escherichia coli. Mice vaccinated with these beads produced immune responses biased towards Th1-/Th17-type responses, but inclusion of Cpe30, CS.T3378-395 and flagellin did not enhance immunogenicity of the Rv1626 protein. This was confirmed in a M. bovis challenge experiment in mice, where Rv1626 beads reduced bacterial cell counts in the lungs by 0.48 log10 compared with the adjuvant alone control group. Co-delivery of immunostimulatory peptides did not further enhance protective immunity. PMID- 28714175 TI - Schwann cells secrete extracellular vesicles to promote and maintain the proliferation and multipotency of hDPCs. AB - OBJECTIVES: Schwann cells (SCs) are the principal glial cells in peripheral nerve system, involved in neuropathies with great regenerative potential. Dental pulp cells have been reported to maintain neurogenic potential. In contrast, the regulatory role of SCs on human dental pulp cells (hDPCs) development remains undefined. MATERIALS AND METHODS: SC secretion and SC-derived extracellular vesicles (EVs) were collected and used to treat hDPCs; and proliferation and multiple differentiation of hDPCs were detected after EVs treatments. Finally, we analysed the proteomes of SC-EVs and SCs through mass spectrum. RESULTS: In this study, we found SC secretion showed a predominantly regulatory role on the development of hDPCs. Further, we identified EVs from SC secretion with similar function as SC secretion in regulating hDPCs proliferation and multipotency. And expression of transcription factor Oct4 was upregulated after treatment of both SC secretion and EVs, as well as Sox2 and Nanog. We detected abundant enrichment of Oct4 in EVs, which might be responsible for the upregulation of stem cell related genes in hDPCs. Through proteome and western blot analysis, we found enriched TGFbetas in EVs, indicating that accelerated hDPCs proliferation may be mediated by activated TGFbeta-Samd and TGFbeta-MAPK signalling. CONCLUSIONS: In summary, our study sheds light on critical regulatory ability of SC-derived EVs on hDPCs proliferation and multipotency, suggesting great implications for seeding cells used in tissue engineering. PMID- 28714176 TI - Osteogenic differentiation of 3D cultured mesenchymal stem cells induced by bioactive peptides. AB - OBJECTIVES: Bioactive peptides derived from receptor binding motifs of native proteins are a potent source of bioactive molecules that can induce signalling pathways. These peptides could substitute for osteogenesis promoting supplements. The work presented here compares three kinds of bioactive peptides derived from collagen III, bone morphogenetic protein 7 (BMP-7) and BMP-2 with their potential osteogenic activity on the model of porcine mesenchymal stem cells (pMSCs). MATERIALS AND METHODS: pMSCs were cultured on electrospun polycaprolactone nanofibrous scaffolds with different concentrations of the bioactive peptides without addition of any osteogenic supplement. Analysis of pMSCs cultures included measurement of the metabolic activity and proliferation, immunofluorescence staining and also qPCR. RESULTS: Results showed no detrimental effect of the bioactive peptides to cultured pMSCs. Based on qPCR analysis, the bioactive peptides are specific for osteogenic differentiation with no detectable expression of collagen II. Our results further indicate that peptide derived from BMP-2 protein promoted the expression of mRNA for osteocalcin (OCN) and collagen I significantly compared to control groups and also supported deposition of OCN as observed by immunostaining method. CONCLUSION: The data suggest that bioactive peptide with an amino acid sequence of KIPKASSVPTELSAISTLYL derived from BMP-2 protein was the most potent for triggering osteogenic differentiation of pMSCs. PMID- 28714177 TI - Curved microstructures promote osteogenesis of mesenchymal stem cells via the RhoA/ROCK pathway. AB - OBJECTIVES: Cells in the osteon reside in a curved space, accordingly, the curvature of the microenvironment is an important geometric feature in bone formation. However, it is not clear how curved microstructures affect cellular behaviour in bone tissue. MATERIALS AND METHODS: Rat primary bone marrow mesenchymal stem cells (BMSCs) on wavy microgrooves were exposed to PDMS substrates with various curvatures to investigate alterations in cellular morphology and osteogenic differentiation. Additionally, the expression levels of RhoA and its effectors were examined by immunofluorescence and quantitative PCR to determine the mechanisms of curvature-dependent osteogenic differentiation. RESULTS: Wavy microgrooves caused dramatic nuclear distortion and cytoskeletal remodelling. We detected a noticeable increase in the expression of osteogenic related genes in BMSCs in wavy microgroove groups, and the maximum expression was observed in the high curvature group. Moreover, immunofluorescent staining and quantitative RT-PCR results for RhoA and its effectors showed that the RhoA/ROCK signalling pathway is associated with curvature-dependent osteogenic differentiation. CONCLUSIONS: Our results illustrated that curved microstructures could promote BMSC differentiation to the osteogenic lineage, and the osteogenic effects of higher curvature are more obvious. Wavy microstructures could also influence the RhoA/ROCK pathway. Accordingly, curved microstructures may be useful in bone tissue engineering. PMID- 28714178 TI - Emergence and whole-genome sequence of Senecavirus A in Colombia. AB - In 2015 and 2016, Senecavirus A (SVA) emerged as an infectious disease in Brazil, China and the United States (US). In a Colombian commercial swine farm, vesicles on the snout and coronary bands were reported and tested negative for foot-and mouth disease virus (FMDv), but positive for SVA. The whole-genome phylogenetic analysis indicates the Colombian strain clusters with the strains from the United States, not with the recent SVA strains from Brazil. PMID- 28714179 TI - Platelet storage in 60% bicarbonated Ringer's solution/40% plasma. PMID- 28714181 TI - Involvement of adenosine triphosphate-binding cassette subfamily B member 1 in the augmentation of triacylglycerol excretion by Propionibacterium acnes in differentiated hamster sebocytes. AB - An onset of acne, a common inflammatory skin disease, is associated with excess sebum production and secretion in sebaceous glands. Because Propionibacterium acnes has been reported to augment intracellular sebum accumulation in sebaceous glands in hamsters, it remains unclear whether P. acnes influences sebum secretion from differentiated sebocytes. Both P. acnes culture media (Acnes73-CM) and formalin-killed P. acnes (F-Acnes73) dose-dependently increased the extracellular levels of triacylglycerol (TG), a major sebum component, and Rhodamine 123, a substrate of adenosine triphosphate-binding cassette (ABC) transporter, from differentiated hamster sebocytes (DHS). In addition, the gene expression of the ABC subfamily B member 1 (ABCB1) was dose-dependently augmented by adding Acnes73-CM and F-Acnes73 into DHS. Furthermore, the F-Acnes73-induced increase of TG excretion was suppressed by PSC833, a selective ABCB1 inhibitor. On the other hand, peptidoglycan (PGN), which is a Toll-like receptor 2 (TLR2) ligand in P. acnes, increased extracellular TG levels, transporter activity and ABCB1 mRNA expression in DHS. The PGN-augmented TG excretion was suppressed by PSC833. Thus, these results provide novel evidence that P. acnes facilitates sebum secretion due to the activation of ABCB1 concomitantly with the increased ABCB1 expression, which may result from the activation of the TLR2 pathway in DHS. Therefore, the ABCB1 inhibitor is likely to become a candidate as a possible therapeutic for the treatment of acne. PMID- 28714180 TI - Tofacitinib for the treatment of moderate to severe chronic plaque psoriasis in Japanese patients: Subgroup analyses from a randomized, placebo-controlled phase 3 trial. AB - Tofacitinib is an oral Janus kinase inhibitor. These post-hoc analyses assessed tofacitinib efficacy and safety in Japanese patients with psoriasis enrolled in a 52-week global phase 3 study. Patients received tofacitinib 5 mg, tofacitinib 10 mg or placebo twice daily (b.i.d.); placebo-treated patients advanced to tofacitinib at week 16. Primary efficacy end-points were the proportions of patients with 75% or more reduction from baseline Psoriasis Area and Severity Index (PASI-75) and Physician's Global Assessment (PGA) of "clear" or "almost clear" (PGA response) at week 16. Other end-points included: Itch Severity Item (ISI), Dermatology Life Quality Index (DLQI) score and Nail Psoriasis Severity Index (NAPSI). Adverse events (AEs) were recorded throughout the study. Overall, 58 Japanese patients were included in this analysis (tofacitinib 5 mg b.i.d., n = 22; 10 mg b.i.d., n = 24; placebo, n = 12); 29 completed the study. At week 16, significantly more patients receiving tofacitinib 5 and 10 mg b.i.d. versus placebo achieved PASI-75 (50% and 75% vs 0%, P < 0.01) and PGA response (59% and 75% vs 0%, P < 0.001). Substantial improvements in ISI, DLQI and NAPSI score were observed with both tofacitinib doses. Over 52 weeks, similar rates of AEs were reported across treatment groups; one serious AE occurred with tofacitinib 10 mg b.i.d. Herpes zoster occurred in three patients receiving tofacitinib 10 mg b.i.d. No deaths, serious infections, malignancies or gastrointestinal perforations were reported. Results were generally consistent with global analysis, suggesting sustained efficacy and a manageable safety profile, with increased herpes zoster incidence, of tofacitinib in Japanese patients with psoriasis. PMID- 28714182 TI - Rare coding variants in MAPK7 predispose to adolescent idiopathic scoliosis. AB - Adolescent idiopathic scoliosis (AIS) is a complex genetic disorder characterized by three-dimensional spinal curvatures, affecting 2%-3% of school age children, yet the causes underlying AIS are not well understood. Here, we first conducted a whole-exome sequencing and linkage analysis on a three-generation Chinese family with autosomal-dominant (AD) AIS, and then performed targeted sequencing in a discovery cohort comprising 20 AD AIS families and 86 simplex patients, and finally identified three disease-associated missense variants (c.886G> A, c.1943C> T, and c.1760C> T) in the MAPK7 gene (encoding mitogen-activated protein kinase 7). Genotyping of the three rare variants in a Chinese replication cohort comprising 1,038 simplex patients and 1,841 controls showed that their combined allele frequency was significantly over-represented in patients as compared with controls (2.0% [41/2,076] vs. 0.7% [27/3,682]; odds ratio = 2.7; P = 2.8 * 10-5 ). In vitro, we demonstrated that the three MAPK7 mutants disrupted nuclear translocation in cellular models, which is necessary for the normal function of MAPK7. In vivo, we also conducted CRISPR/Cas9-mediated deletion of mapk7 in zebrafish recapitulating the characteristic phenotype of idiopathic scoliosis. Taken together, our findings suggest that rare coding variants in MAPK7 predispose to AIS, providing clues to understanding the mechanisms of AIS. PMID- 28714183 TI - The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases. PMID- 28714185 TI - Empirical and narrative approaches to case study designs: A commentary on 'Nidotherapy in the successful management of comorbid depressive and personality disorder'. PMID- 28714184 TI - Research Review: What have we learned about adolescent substance use? AB - BACKGROUND: Adolescence is a critical biological, psychological, and social developmental stage involving heightened risk for substance use and associated adverse consequences. This review, synthesizing emerging findings on this complex topic, is intended to inform research and clinical care focused on adolescents. METHODS: Literature searches were conducted using PubMed, yielding a cross section of observational and interventional studies focused on adolescent substance use. Findings were organized and categorized to cover key areas of epidemiology, neurobiology, prevention, and treatment. FINDINGS: Adolescent substance-related attitudes and use patterns have evolved over time, informed by adult and peer behaviors, public policy, media messaging, substance availability, and other variables. A number of risk and resiliency factors contribute to individual differences in substance use and related consequences. Advances in observational techniques have provided enhanced understanding of adolescent brain development and its implications for substance use. Prevention efforts have yielded mixed results, and while a number of adolescent-targeted evidence-based treatments for substance use disorders have been developed, effect sizes are generally modest, indicating the need for further research to enhance prevention and treatment outcomes. CONCLUSIONS: Substance use in adolescence is heterogeneous, ranging from normative to pathological, and can lead to significant acute and long-term morbidity and mortality. Understanding risk and resiliency factors, underlying neurobiology, and optimal developmentally sensitive interventions is critical in addressing substance-associated problems in adolescence. PMID- 28714186 TI - The Pinocchio effect and the Cold Stress Test: Lies and thermography. AB - We applied the use of thermography to cognitive neuropsychology, particularly as an objective marker of subjective experiences, in the context of lying. We conducted three experiments: (a) An important lie was invented by the participants in 3 min, and it was recounted by phone to a significant person while they were recorded by the thermographic camera, obtaining a face and hands map of the lie. (b) A similar methodology was carried out, but adding the Cold Stress Test (CST) of the dominant hand during the phone call, obtaining a second physiologic marker (the percentage of thermal recovery) to detect the lie. Further, it established a control condition where it generated anxiety in the participants using IAPS images with negative valence and high arousal, which were described by phone to a loved one. We obtained results that showed significant correlations between changes in body temperature and mental set. Of particular interest was the temperature of the nose and hand, which tended to decrease during lying (Experiment 1). The participants also showed a lower recovery of the temperature after the CST when they were lying (Experiment 2). (c) Experiment 3 is a replication of Experiment 2 but with a different type of lie (a more ecological task) in a different scenario (following the ACID interview, with the use of the phone eliminated and participants motivated to lie well). The main pattern of results was replicated. We obtained an accuracy of 85% in detection of deception with 25% of false alarms. PMID- 28714187 TI - A critique of utilitarian and instrumentalist concepts for the teaching of gross anatomy to medical and dental students: Provoking debate. AB - Medical and dental curricula, together with anatomical sciences courses, are increasingly having to change, mainly because there is a drive to being what is termed, without adequate definition, "clinically relevant." The concept of "clinical anatomy" has accordingly been invented and it is expected that, at all times, the teaching of anatomy is directly focused on clinical scenarios, meaning almost invariably the disease-based model of medicine and dentistry. Furthermore, students are not expected to have a detailed knowledge of gross anatomy and the time devoted to teaching and learning the subject has decreased significantly. The notion being fostered is that knowledge is not required "just in case" but "just in time." However, the absence of agreed core syllabuses that are internationally accepted complicates a discussion about what is relevant practically and what does not need to be taught. In this article, we critique such an utilitarian and instrumentalist approach to the teaching of gross anatomy within medical and dental curricula. We draw attention to the need to embrace the functionality-based model of medicine and dentistry by returning to an understanding that the role of the medical or dental practitioner is to value health and to restore to functionality the ill person or the pathologically affected region/organ/system. A fuller knowledge of anatomy than is presently taught is regarded as a prerequisite for appreciating normality and health. A further problem with the instrumentalist approach to medical education is that, by concentrating on what is seen to be at the time "useful" or "clinically relevant," there is the danger of undermining, or discouraging, future developments that rely on what contemporaneously seems "useless" and "irrelevant" knowledge. Finally, the reliance instrumentalism has on just what is pragmatic and regardless of scientific validity is contrary to the ethos and practice of a university education that values deep learning and the development of learned professions. Clin. Anat. 30:912-921, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28714188 TI - Energy-Efficient Oil-Water Separation of Biomimetic Copper Membrane with Multiscale Hierarchical Dendritic Structures. AB - Membrane-based materials with special surface wettability have been applied widely for the treatment of increasing industrial oily waste water, as well as frequent oil spill accidents. However, traditional technologies are energy intensive and limited, either by fouling or by the inability of a single membrane to separate all types of oil-water mixtures. Herein, a biomimetic monolayer copper membrane (BMCM), composed of multiscale hierarchical dendritic structures, is cleverly designed and successfully fabricated on steel mesh substrate. It not only possesses the ability of energy-efficient oil-water separation but also excellent self-recovery anti-oil-fouling properties (<150 s). The BMCM even keeps high separation efficiency (>93%) after ten-time cycling tests. More importantly, it retains efficient oil-water separation capacity for five different oils. In fact, these advanced features are benefited by the synergistic effect of chemical compositions and physical structures, which is inspired by the typical nonwetting strategy of butterfly wing scales. The findings in this work may inspire a facile but effective strategy for repeatable and antipollution oil-water separation, which is more suitable for various applications under practical conditions, such as wastewater treatment, fuel purification, separation of commercially relevant oily water, and so forth. PMID- 28714189 TI - Esthesiometric evaluation of corneal analgesia after topical application of 1% morphine sulfate in normal horses. AB - OBJECTIVE: To evaluate whether topical ocular application of 1% morphine sulfate would change corneal sensitivity and to identify the duration of action. ANIMAL STUDIED: Eight healthy adult horses. PROCEDURE: Corneal touch threshold (CTT) was measured in the center of one randomly selected eye of each horse by Cochet Bonnet esthesiometer (Luneau Cochet-Bonnet Esthesiometer; Western Ophthalmics, Lynnwood, WA, USA). Immediately following baseline CTT measurement, 0.3 ml of 1.0% preservative-free morphine sulfate (Morphine Sulfate 25 mg/ml Preservative free; Hospira, Lake Forest, IL, USA) (3 mg) was applied to the tested eye. The same volume of artificial tear (LiquiTears; Major Pharmacauticals, Livonia, MI, USA) solution was then applied to the control eye following acquisition of baseline CTT. Corneal touch threshold was then subsequently measured at 1 min after medication application, followed by every 5 min until 60 min post administration. If the corneal touch threshold had not returned to baseline by 60 min, measurements were continued at 15-min intervals until corneal sensitivity returned to baseline CTT measurement up to 180 min post administration if needed. The control eye was treated identically and measurements on the control eye stopped when the corresponding treated eye returned to baseline. RESULTS: Mean baseline CTT of both eyes was 21.8 mm with an identical range of 15-30 mm. Mean corneal touch threshold was not statistically different between morphine-treated and control eyes (P = 0.22). There was a large degree of inter- and intrasubject variation in the CTT measurements obtained. All but three horses were considered to be at baseline values by 60 min. CONCLUSIONS: Topical ophthalmic 1% morphine sulfate did not have a clinically significant analgesic effect on the corneal touch threshold of intact healthy equine corneas. PMID- 28714190 TI - Polymorphisms of xenobiotic-metabolizing genes and colorectal cancer risk in patients with lynch syndrome: A retrospective cohort study in Taiwan. AB - Cytochrome P450 (CYP), glutathione-S-transferase (GST), and N-acetyltransferase (NAT) are crucial for metabolism and clearance of xenobiotics. This study investigated whether CYP, GST, and NAT single nucleotide polymorphisms (SNPs) are associated with colorectal cancer (CRC) in patients with Lynch syndrome. The interaction between these SNPs and cigarette smoking or meat consumption was also explored. We identified 270 patients with Lynch syndrome from the Taiwan Hereditary Nonpolyposis Colorectal Cancer Consortium. A weighted Cox proportional hazard model was used to calculate the hazard ratios (HRs) and 95% confidence interval (CIs). The GSTA1 rs3957356 TT (HR = 5.36, 95% CI = 2.39-12.0) and CYP1B1 rs1056836 CC (HR = 7.24, 95% CI = 3.51-14.9) were significantly associated with CRC risk when compared to wild-type CC and GG genotypes, respectively. However, the CYP1A1 rs4646903 CC genotype significantly reduced the risk of CRC (HR = 0.33, 95% CI = 0.12-0.89) when compared to TT genotype. Moreover, significant interactions were observed between NAT1 acetylation and CYP1B1 rs1056827 and meat consumption.Our results suggest that xenobiotic-metabolizing SNPs are not only associated with CRC risk in patients with Lynch syndrome in Taiwan but also interact with meat consumption to modify the disease risk. Environ. Mol. Mutagen. 59:69-78, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 28714191 TI - Disordered Conformation with Low Pii Helix in Phosphoproteins Orchestrates Biomimetic Apatite Formation. AB - The interplay between noncollagenous proteins and biomineralization is widely accepted, yet the contribution of their secondary structure in mineral formation remains to be clarified. This study demonstrates a role for phosvitin, an intrinsically disordered phosphoprotein, in chick embryo skeletal development, and using circular dichroism and matrix least-squares Henderson-Hasselbalch global fitting, unravels three distinct pH-dependent secondary structures in phosvitin. By sequestering phosvitin on a biomimetic 3D insoluble cationic framework at defined pHs, access is gained to phosvitin in various conformational states. Induction of biomimetic mineralization at near physiological conditions reveals that a disordered secondary structure with a low content of PII helix is remarkably efficient at promoting calcium adsorption, and results in the formation of biomimetic hydroxyapatite through an amorphous calcium phosphate precursor. By extending this finding to phosphorylated full-length human recombinant dentin matrix protein-1 (17-513 AA), this bioinspired approach provides compelling evidence for the role of a disordered secondary structure in phosphoproteins in bone-like apatite formation. PMID- 28714192 TI - Secreted Tumor Antigens - Immune Biomarkers for Diagnosis and Therapy. AB - With the advent of immunotherapies for cancer, there is growing interest in the identification of tumor antigens. Tumor antigens are self-molecules altered through e.g. genetic mutations (neoantigens), protein truncation, protein misfolding, or abnormal posttranslational modifications. To induce an immune response, tumor antigens need to be secreted into the tumor environment and presented to the immune system in the draining lymph nodes, resulting in the generation of tumor-specific effector cells and antibodies. Cytotoxic T cells are thought to be responsible for killing of tumor cells, and several recent studies have used MS, combined with exome/transcriptome sequencing and bioinformatics, to identify their cognate peptide ligands on tumor MHC class I molecules. Circulating (serum) antibodies have been more widely used to identify tumor antigens in a range of human cancers, using 2D Western blots, immunoaffinity, and microarray technologies. More specific antibody probes have been generated by harvesting antibodies directly from antibody-secreting cells through in vitro cultures of lymph node cells (antibody-secreting cells probes) or B-cell immortalization. Further identification and characterization of tumor antigens is likely to have important implications for cancer diagnostic and biomarker discovery, immune profiling, and the development of cancer vaccines and targeted immunotherapies. PMID- 28714194 TI - Erratum. PMID- 28714193 TI - Alteration of oxidative phosphorylation as a possible mechanism of the antifungal action of p-coumaric acid against Botrytis cinerea. AB - AIMS: The aim of this study was to analyse the mechanism of action of p-coumaric acid against isolate B05.10 of Botrytis cinerea. For this purpose, the effect of this compound on cell membrane, cell wall and oxidative phosphorylation was determined. Induction of oxidative stress triggered by this compound was also studied. METHODS AND RESULTS: p-coumaric acid showed antifungal effect on the mycelial growth. Additionally, the compound was able to retard the germination of Botrytis cinerea conidia. The mechanism of action of this compound was analysed using fluorescent probes. p-Coumaric acid did not affect the integrity of cell wall and plasmatic membrane and neither produced oxidative stress. Finally, it was shown that the compound produced an increase in oxygen consumption. CONCLUSIONS: p-coumaric acid performs as a mitochondrial uncoupler in B. cinerea. Its role as an uncoupler of oxidative phosphorylation could be explained to its acidic, nonpolar and planar characteristics. These structural and chemical characteristics would favour ability of p-coumaric acid to pass through cellular membranes. SIGNIFICANCE AND IMPACT OF THE STUDY: Plant secondary metabolites can be used as an alternative way to control phytopathogenic fungi. The knowledge of the action mechanism of these compounds can contribute to design modified molecules with higher antifungal activity. PMID- 28714195 TI - Research Review: The role of obstetric and neonatal complications in childhood attention deficit and hyperactivity disorder - a systematic review. AB - BACKGROUND: Attention deficit and hyperactivity disorder (ADHD) is a developmental disorder characterized by an inability to sustain attention, activity levels and impulse control, and, according to the latest studies, the prevalence is about 8% and in some countries less than 1%. Currently, it is well known that complications during the perinatal period have significant implications on child's physical and mental health. Purpose of the present paper is to review the literature about the association between perinatal complications and future risk of an ADHD diagnosis. METHODS: A research in the main database sources has been conducted to obtain a systematic review on the perinatal risk factors of ADHD. RESULTS: Among perinatal complications, available data indicate low birth weight (LBW) (Cohen's d effect size range: 0.31-1.64-small effect size) and preterm birth (PB) (range d: 0.41-0.68) as the most important factors associated with a future diagnosis of ADHD. CONCLUSIONS: PB and LBW children should be carefully monitored for an early diagnosis of ADHD limiting the impact of the disease in life span. A systematic review focusing on these risk factors have not been published until now, in the next future preventive strategies should be developed in order to minimize ADHD onset. PMID- 28714197 TI - Novel COL5A1 mutation in a Chinese family with classic type of Ehlers-Danlos syndrome. PMID- 28714196 TI - Impact of an electronic health record alert in primary care on increasing hepatitis c screening and curative treatment for baby boomers. AB - : Despite effective treatment for chronic hepatitis C, deficiencies in diagnosis and access to care preclude disease elimination. Screening of baby boomers remains low. The aims of this study were to assess the impact of an electronic health record-based prompt on hepatitis C virus (HCV) screening rates in baby boomers in primary care and access to specialty care and treatment among those newly diagnosed. We implemented an electronic health record-based "best practice advisory" (BPA) that prompted primary care providers to perform HCV screening for patients seen in primary care clinic (1) born between 1945 and 1965, (2) who lacked a prior diagnosis of HCV infection, and (3) who lacked prior documented anti-HCV testing. The BPA had associated educational materials, order set, and streamlined access to specialty care for newly diagnosed patients. Pre-BPA and post-BPA screening rates were compared, and care of newly diagnosed patients was analyzed. In the 3 years prior to BPA implementation, 52,660 baby boomers were seen in primary care clinics and 28% were screened. HCV screening increased from 7.6% for patients with a primary care provider visit in the 6 months prior to BPA to 72% over the 1 year post-BPA. Of 53 newly diagnosed patients, all were referred for specialty care, 11 had advanced fibrosis or cirrhosis, 20 started treatment, and 9 achieved sustained virologic response thus far. CONCLUSION: Implementation of an electronic health record-based prompt increased HCV screening rates among baby boomers in primary care by 5-fold due to efficiency in determining needs for HCV screening and workflow design. Streamlined access to specialty care enabled patients with previously undiagnosed advanced disease to be cured. This intervention can be easily integrated into electronic health record systems to increase HCV diagnosis and linkage to care. (Hepatology 2017;66:1805-1813). PMID- 28714198 TI - Enhancing Performance of Nonfullerene Acceptors via Side-Chain Conjugation Strategy. AB - A side-chain conjugation strategy in the design of nonfullerene electron acceptors is proposed, with the design and synthesis of a side-chain-conjugated acceptor (ITIC2) based on a 4,8-bis(5-(2-ethylhexyl)thiophen-2-yl)benzo[1,2-b:4,5 b']di(cyclopenta-dithiophene) electron-donating core and 1,1-dicyanomethylene-3 indanone electron-withdrawing end groups. ITIC2 with the conjugated side chains exhibits an absorption peak at 714 nm, which redshifts 12 nm relative to ITIC1. The absorption extinction coefficient of ITIC2 is 2.7 * 105 m-1 cm-1 , higher than that of ITIC1 (1.5 * 105 m-1 cm-1 ). ITIC2 exhibits slightly higher highest occupied molecular orbital (HOMO) (-5.43 eV) and lowest unoccupied molecular orbital (LUMO) (-3.80 eV) energy levels relative to ITIC1 (HOMO: -5.48 eV; LUMO: 3.84 eV), and higher electron mobility (1.3 * 10-3 cm2 V-1 s-1 ) than that of ITIC1 (9.6 * 10-4 cm2 V-1 s-1 ). The power conversion efficiency of ITIC2-based organic solar cells is 11.0%, much higher than that of ITIC1-based control devices (8.54%). Our results demonstrate that side-chain conjugation can tune energy levels, enhance absorption, and electron mobility, and finally enhance photovoltaic performance of nonfullerene acceptors. PMID- 28714199 TI - The effect of dopaminergic medication on conflict adaptation in Parkinson's disease. AB - Parkinson's disease (PD) is a neurological disorder associated primarily with motor symptoms such as tremor, slowness of movement, and difficulties with gait and balance. Most patients take dopaminergic medication to improve their motor functions. Previous studies reported indications that such medication can impair higher cognitive functions (cf. dopamine overdose hypothesis). In the present study, we examined the effect of medication status on conflict adaptation. PD patients performed a Stroop task in which we manipulated the proportion of congruent and incongruent items, thereby allowing us to explore conflict adaptation. The use of mouse movements allowed us to examine the action dynamics of conflict adaptation in PD, and their sensitivity to dopaminergic medication. Each patient performed the same task twice: once without making changes to their regular medication regime, and once after overnight withdrawal from their medication. Results showed that medication improved mouse movements and alleviated motor symptoms. Moreover, patients' mouse movements were modulated as a function of the proportion congruency manipulation, revealing conflict adaptation in PD, which was unaffected by medication status. The present study extends earlier work on conflict adaptation in PD where reduced transient (trial by-trial) conflict adaptation was observed ON compared to OFF medication (Duthoo et al., 2013, Neuropsychology, 27, 556). Our findings suggest that more sustained cognitive control processes may not be sensitive to dopamine overdose effects. PMID- 28714200 TI - Hierarchical VS2 Nanosheet Assemblies: A Universal Host Material for the Reversible Storage of Alkali Metal Ions. AB - Reversible electrochemical storage of alkali metal ions is the basis of many secondary batteries. Over years, various electrode materials are developed and optimized for a specific type of alkali metal ions (Li+ , Na+ , or K+ ), yet there are very few (if not none) candidates that can serve as a universal host material for all of them. Herein, a facile solvothermal method is developed to prepare VS2 nanosheet assemblies. Individual nanosheets are featured with a few atomic layer thickness, and they are hierarchically arranged with minimized stacking. Electrochemical measurements show that VS2 nanosheet assemblies enable the rapid and durable storage of Li+ , Na+ , or K+ ions. Most remarkably, the large reversible specific capacity and great cycling stability observed for both Na+ and K+ are extraordinary and superior to most existing electrode materials. The experimental results of this study are further supported by density functional theory calculations showing that the layered structure of VS2 has large adsorption energy and low diffusion barriers for the intercalation of alkali metal ions. PMID- 28714201 TI - Encoding Random Hot Spots of a Volume Gold Nanorod Assembly for Ultralow Energy Memory. AB - Data storage with ultrahigh density, ultralow energy, high security, and long lifetime is highly desirable in the 21st century and optical data storage is considered as the most promising way to meet the challenge of storing big data. Plasmonic coupling in regularly arranged metallic nanoparticles has demonstrated its superior properties in various applications due to the generation of hot spots. Here, the discovery of the polarization and spectrum sensitivity of random hot spots generated in a volume gold nanorod assembly is reported. It is demonstrated that the two-photon-induced absorption and two-photon-induced luminescence of the gold nanorods adjacent to such hot spots are enhanced significantly because of plasmonic coupling. The polarization, wavelength, and spatial multiplexing of the hot spots can be realized by using an ultralow energy of only a few picojoule per pulse, which is two orders of magnitude lower than the value in the state-of-the-art technology that utilizes isolated gold nanorods. The ultralow recording energy reduces the cross-talk between different recording channels and makes it possible to realize rewriting function, improving significantly both the quality and capacity of optical data storage. It is anticipated that the demonstrated technology can facilitate the development of multidimensional optical data storage for a greener future. PMID- 28714202 TI - An All-Solution-Based Hybrid CMOS-Like Quantum Dot/Carbon Nanotube Inverter. AB - The development of low-cost, flexible electronic devices is subordinated to the advancement in solution-based and low-temperature-processable semiconducting materials, such as colloidal quantum dots (QDs) and single-walled carbon nanotubes (SWCNTs). Here, excellent compatibility of QDs and SWCNTs as a complementary pair of semiconducting materials for fabrication of high performance complementary metal-oxide-semiconductor (CMOS)-like inverters is demonstrated. The n-type field effect transistors (FETs) based on I- capped PbS QDs (Vth = 0.2 V, on/off = 105 , SS-th = 114 mV dec-1 , ue = 0.22 cm2 V-1 s-1 ) and the p-type FETs with tailored parameters based on low-density random network of SWCNTs (Vth = -0.2 V, on/off > 105 , SS-th = 63 mV dec-1 , uh = 0.04 cm2 V-1 s 1 ) are integrated on the same substrate in order to obtain high-performance hybrid inverters. The inverters operate in the sub-1 V range (0.9 V) and have high gain (76 V/V), large maximum-equal-criteria noise margins (80%), and peak power consumption of 3 nW, in combination with low hysteresis (10 mV). PMID- 28714203 TI - Posterior cordotomy in bilateral vocal cord paralysis using monopolar microelectrodes and radiofrequency in 18 patient. PMID- 28714204 TI - Investigation on the pH-independent photoluminescence emission from carbon dots impregnated on polymer matrix. AB - Highly luminescent, polymer nanocomposite films based on poly(vinyl alcohol) (PVA), and monodispersed carbon dots (C-dots) derived from multiwalled carbon nanotubes (MWCNTs), as coatings on substrates as well as free standing ones are obtained via solution-based techniques. The synthesized films exhibit pH independent photoluminescence (PL) emission, which is an advantageous property compared with the pH-dependent photoluminescence intensity variations, generally observed for the C-dots dispersed in aqueous solution. The synthesized C-dots and the nanocomposite films are characterized by transmission electron microscopy (TEM), scanning electron microscopy (SEM), X-ray diffraction (XRD), Fourier transform infra-red spectroscopy (FTIR), ultraviolet (UV) - visible spectroscopy and photoluminescence spectroscopy (PL) techniques. The TEM image provides clear evidence for the formation of C-dots of almost uniform shape and average size of about 8 nm, homogeneously dispersed in aqueous medium. The strong anchoring of C dots within the polymer matrix can be confirmed from the XRD results. The FTIR spectral studies conclusively establish the presence of oxygen functional groups on the surfaces of the C-dots. The photoluminescence (PL) emission spectra of the nanocomposite films are broad, covering most part of the visible region. The PL spectra do not show any luminescence intensity variations, when the pH of the medium is changed from 1 to 11. The pH-independent luminescence, shown by these films offers ample scope for using them as coatings for designing diagnostic and imaging tools in bio medical applications. The non-toxic nature of these nanocomposite films has been established on the basis of cytotoxicity studies. PMID- 28714205 TI - Photothermal Ring Integrated Intraocular Lens for High-Efficient Eye Disease Treatment. AB - Posterior capsule opacification (PCO) is the most common complication after cataract surgery. So far, the only method for PCO treatment is the precisely focused laser surgery. However, it causes severe complications such as physical damages and neuron impairments. Here, a nanostructured photothermal ring integrated intraocular lens (Nano-IOLs) is reported, in which the rim of commercially available IOLs (C-IOLs) is decorated with silica coated Au nanorods (Au@SiO2 ), for high-efficient prevention of PCO after cataract surgery. The Nano IOLs is capable of eliminating the residual lens epithelial cells (LECs) around Nano-IOLs under mild laser treatment and block the formation of disordered LECs fibrosis, which eventually leads to the loss of vision. The Nano-IOLs shows good biocompatibility as well as extraordinary region-confined photothermal effect. In vivo studies reveal that PCO occurrence in rabbit models is about 30%-40% by using Nano-IOLs, which is significantly lower than the control group that treated with C-IOLs (100% PCO occurrence) 30 d postsurgery. To the best of our knowledge, it is the first example to integrate nanotechnology with intraocular implants aiming to clinically relevant PCO. Our findings indicate that spatial controllability of photothermal effect from nanomaterials may provide a unique way to intervene the PCO-induced loss of vision. PMID- 28714206 TI - Efficacy of ultrasound and nerve stimulation guidance in peripheral nerve block: A systematic review and meta-analysis. AB - Evidence was controversial about whether nerve stimulation (NS) can optimize ultrasound guidance (US)-guided nerve blockade for peripheral nerve block. This review aims to explore the effects of the two combined techniques. We searched EMBASE (from 1974 to March 2015), PubMed (from 1966 to Mar 2015), Medline (from 1966 to Mar 2015), the Cochrane Central Register of Controlled Trials and clinicaltrials.gov. Finally, 15 randomized trials were included into analysis involving 1,019 lower limb and 696 upper limb surgery cases. Meta-analysis indicated that, compared with US alone, USNS combination had favorable effects on overall block success rate (risk ratio [RR] 1.17; confidence interval [CI] 1.05 to 1.30, P = 0.004), sensory block success rate (RR 1.56; CI 1.29 to 1.89, P < 0.00001), and block onset time (mean difference [MD] -3.84; CI -5.59 to -2.08, P < 0.0001). USNS guidance had a longer procedure time in both upper and lower limb nerve block (MD 1.67; CI 1.32 to 2.02, P < 0.00001; MD 1.17; CI 0.95 to 1.39, P < 0.00001) and more patients with anesthesia supplementation (RR 2.5; CI 1.02 to 6.13, P = 0.05). USNS guidance trends to result in a shorter block onset time than US alone as well as higher block success rate, but no statistical difference was demonstrated, as more data are required. (c) 2017 IUBMB Life, 69(9):720-734, 2017. PMID- 28714207 TI - Synthetic multispecies microbial communities reveals shifts in secondary metabolism and facilitates cryptic natural product discovery. AB - Chemically mediated interactions have been hypothesized to be essential for ecosystem functioning as co-occurring organisms can influence the performance of each other by metabolic means. Here, we present a co-culture device that allows co-culturing of microorganisms that are physically separated but can exchange chemical signals and metabolites. This setup was adopted to perform investigations on the secondary metabolisms of both a fungal-bacterial community and an actinomycetic-actinomycetic community. This study employed a metabolomics approach integrating LC-MS profiling, multivariate data analysis and molecular networking techniques. LC-MS measurements revealed a pronounced influence of such chemical communication on the metabolic profiles of synthetic co-culture communities with a group of molecules being induced or upregulated in co cultures. A novel antibiotic exhibiting antibiotic properties against Klebsiella pneumoniae was unveiled in the fungal-bacterial community. Besides, a further survey of the fungal-bacterial cross-talk indicated that the production of co culture-induced diphenyl ethers by fungi might result from the fungal response against the secretion of surfactins by bacteria in the cross-talk. This study demonstrated that the presented co-culture device and the metabolomic routine would facilitate the investigation on chemically mediated interactions in nature as well as cryptic natural products discovery. PMID- 28714208 TI - Bifunctional Transition Metal Hydroxysulfides: Room-Temperature Sulfurization and Their Applications in Zn-Air Batteries. AB - Bifunctional electrocatalysis for oxygen evolution reaction (OER) and oxygen reduction reaction (ORR) constitutes the bottleneck of various sustainable energy devices and systems like rechargeable metal-air batteries. Emerging catalyst materials are strongly requested toward superior electrocatalytic activities and practical applications. In this study, transition metal hydroxysulfides are presented as bifunctional OER/ORR electrocatalysts for Zn-air batteries. By simply immersing Co-based hydroxide precursor into solution with high concentration S2- , transition metal hydroxides convert to hydroxysulfides with excellent morphology preservation at room temperature. The as-obtained Co-based metal hydroxysulfides are with high intrinsic reactivity and electrical conductivity. The electron structure of the active sites is adjusted by anion modulation. The potential for 10 mA cm-2 OER current density is 1.588 V versus reversible hydrogen electrode (RHE), and the ORR half-wave potential is 0.721 V versus RHE, with a potential gap of 0.867 V for bifunctional oxygen electrocatalysis. The Co3 FeS1.5 (OH)6 hydroxysulfides are employed in the air electrode for a rechargeable Zn-air battery with a small overpotential of 0.86 V at 20.0 mA cm-2 , a high specific capacity of 898 mAh g-1 , and a long cycling life, which is much better than Pt and Ir-based electrocatalyst in Zn-air batteries. PMID- 28714209 TI - Biotransporting Self-Assembled Nanofactories Using Polymer Vesicles with Molecular Permeability for Enzyme Prodrug Cancer Therapy. AB - As "biotransporting nanofactories", in vivo therapeutic biocatalyst nanoreactors would enable encapsulated enzymes to transform inert prodrugs or neutralize toxic compounds at target disease sites. This would offer outstanding potential for next-generation therapeutic platforms, such as enzyme prodrug therapy. Designing such advanced materials has, however, proven challenging. Here, it is shown that self-assembled nanofactories formulate with polymeric vesicles with an intrinsically permeable membrane. The vesicles, CAPsomes, are composed of carbohydrate-b-poly(propylene glycol) and show molecular-weight-depended permeability. This property enables CAPsomes to act as biocatalyst nanoreactors, protecting encapsulated enzymes from degradation while acting on low-molecular weight substrates. In tumor bearing mice, combined treatment with enzyme-loaded CAPsomes and doxorubicin prodrug inhibit tumor growth in these mice without any observable toxicity. The results demonstrate, for the first time, in vivo therapeutic efficacy of CAPsomes as nanofactories for enzyme prodrug cancer therapy. PMID- 28714210 TI - NAM 2017 report: A national plan to eliminate hepatitis B and C in the United States by 2030 and the AASLD's response. PMID- 28714211 TI - Modeling of bispecific antibody elution in mixed-mode cation-exchange chromatography. AB - The increasing demand for cost-efficient manufacturing of biopharmaceuticals has been the main driving force for the development of novel chromatography resins, which resulted in the development of multimodal or mixed-mode chromatographic resins. Most of them combine electrostatic and hydrophobic functionalities and are designed to deliver unique selectivity and increased binding capacities also at increased ionic strength. However, the mechanism of the protein-resin interaction in mixed-mode chromatography is still not fully understood. The performance of protein separations in mixed-mode chromatography is consequently difficult to predict. In this work, we present a model combining both salt and pH dependence to characterize and to predict protein retention in mixed-mode chromatography. The model parameters are determined based on simple linear pH gradient elution experiments at different ionic strengths and they are directly transferable for the prediction of salt-induced elution at fixed pH. Validity of the model is demonstrated for a bispecific antibody and its product-related impurities. PMID- 28714212 TI - Fragment-Based Drug Discovery in the Bromodomain and Extra-Terminal Domain Family. AB - Bromodomain and extra-terminal domain (BET) inhibition has emerged recently as a potential therapeutic target for the treatment of many human disorders such as atherosclerosis, inflammatory disorders, chronic obstructive pulmonary disease (COPD), some viral infections, and cancer. Since the discovery of the two potent inhibitors, I-BET762 and JQ1, different research groups have used different techniques to develop novel potent and selective inhibitors. In this review, we will be concerned with the trials that used fragment-based drug discovery (FBDD) approaches to discover or optimize BET inhibitors, also showing fragments that can be further optimized in future projects to reach novel potent BET inhibitors. PMID- 28714214 TI - Climate-related environmental variation in a visual signalling device: the male and female dewlap in Anolis sagrei lizards. AB - Animals communicate using a variety of signals that differ dramatically among and within species. The astonishing dewlap diversity in anoles has attracted considerable attention in this respect. Yet, the evolutionary processes behind it remain elusive and have mostly been explored for males only. Here, we considered Anolis sagrei males and females to study signal divergence among populations. First, we assessed the degree of variation in dewlap design (size, pattern and colour) and displays by comparing 17 populations distributed across the Caribbean. Second, we assessed whether the observed dewlap diversity is associated with variation in climate-related environmental conditions. Results showed that populations differed in all dewlap characteristics, with the exception of display rate in females. We further found that males and females occurring in 'xeric' environments had a higher proportion of solid dewlaps with higher UV reflectance. In addition, lizards inhabiting 'mesic' environments had primarily marginal dewlaps showing high reflectance in red. For dewlap display, a correlation with environment was only observed in males. Our study provides evidence for a strong relationship between signal design and prevailing environmental conditions, which may result from differential selection on signal efficacy. Moreover, our study highlights the importance of including females when studying dewlaps in an evolutionary context. PMID- 28714215 TI - Maurice KH Yap: academic, administrator, innovator in myopia research and public health. PMID- 28714213 TI - Smoking and alcohol and subsequent risk of myelodysplastic syndromes in Japan: the Japan Public Health Centre-based Prospective Study. AB - Smoking and alcohol are important modifiable risk factors for human cancers. However, few epidemiological studies have investigated their association with the risk of myelodysplastic syndromes (MDS). Here, we investigated the association of smoking and alcohol consumption and the risk of MDS in a large-scale population based cohort study in Japan. We included 95 510 Japanese subjects (45 451 men and 50 059 women; age 40-69 years at baseline) and identified 70 MDS cases (50 men and 20 women) during 18.3 years of follow-up. Hazard ratios (HRs) and 95% confidence intervals (95% CI) were estimated using a Cox regression model adjusted for potential confounders. Smoking was marginally associated with an increased risk of MDS among men, with a HR for current smokers relative to never smokers of 2.11 (95% CI: 0.91-4.89). In contrast, alcohol consumption was associated with a dose-dependent decrease in the risk of MDS among men (nondrinkers: reference, occasional drinkers: HR = 0.48, 0.16-1.41; 0-299 g/week: HR = 0.37, 0.19-0.73; >=300 g/week: HR = 0.49, 0.22-1.08, P for trend = 0.010). This study showed that alcohol has a significant protective effect on the risk of MDS. In addition, this study might indicate that smoking increases the risk of MDS among Japanese population, as it does in Western populations. PMID- 28714217 TI - Evolutionary relationships among pollinators and repeated pollinator sharing in sexually deceptive orchids. AB - The mechanism of pollinator attraction is predicted to strongly influence both plant diversification and the extent of pollinator sharing between species. Sexually deceptive orchids rely on mimicry of species-specific sex pheromones to attract their insect pollinators. Given that sex pheromones tend to be conserved among related species, we predicted that in sexually deceptive orchids, (i) pollinator sharing is rare, (ii) closely related orchids use closely related pollinators and (iii) there is strong bias in the wasp lineages exploited by orchids. We focused on species that are pollinated by sexual deception of thynnine wasps in the distantly related genera Caladenia and Drakaea, including new field observations for 45 species of Caladenia. Specialization was extreme with most orchids using a single pollinator species. Unexpectedly, seven cases of pollinator sharing were found, including two between Caladenia and Drakaea, which exhibit strikingly different floral morphology. Phylogenetic analysis of pollinators using four nuclear sequence loci demonstrated that although orchids within major clades primarily use closely related pollinator species, up to 17% of orchids within these clades are pollinated by a member of a phylogenetically distant wasp genus. Further, compared to the total diversity of thynnine wasps within the study region, orchids show a strong bias towards exploiting certain genera. Although these patterns may arise through conservatism in the chemical classes used in sex pheromones, apparent switches between wasp clades suggest unexpected flexibility in floral semiochemical production. Alternatively, wasp sex pheromones within lineages may exhibit greater chemical diversity than currently appreciated. PMID- 28714216 TI - Contributions of the oligopeptide permeases in multistep of Vibrio alginolyticus pathogenesis. AB - Vibrio alginolyticus has been associated with several diseases of cultivated marine animals, and has led to considerable economic losses. The oligopeptide permease (Opp) has been proven to play a variety of important roles in nutrition and virulence in several bacteria. In our previous research, the opp gene cluster was identified in Vibrio alginolyticus with transcriptome sequence, which also indicated that the Opp system might play roles in the regulation of adhesion. In this study, the relationship between V. alginolyticus virulence and the opp gene cluster was determined using gene silencing followed by RT-qPCR, in vitro adhesion assay, growth curves detection in the presence of glutathione (GSH) as a toxic substrate, hemolysis assay, biofilm assay, and artificial infection. Silencing these genes led to deficiencies in adhesion, peptide internalization, biofilm production, hemolytic activity, and virulence. The expression levels of hapr, hapa, tlh, and hlya, which are important genes closely related to the hemolytic activity of Vibrio, were significantly downregulated in all of the RNAi groups. Furthermore, the expression of oppA, oppB, oppC, oppD, and oppF was significantly influenced by temperature, starvation, and pH. These results indicate that (1) oppABCDF contributed in multistep of V. alginolyticus pathogenesis, including adhesion, biofilm production, and hemolytic activity; (2) oppABCDF was sensitive to different temperatures, changes in pH, and increased starvation time. PMID- 28714218 TI - Empowerment and performance of managers and subordinates in elderly care: A longitudinal and multilevel study. AB - AIM: To investigate relationships between first-line managers' ratings of structural and psychological empowerment, and the subordinates' ratings of structural empowerment, as well as their ratings of the managers' leadership management performance. BACKGROUND: Work situations in elderly care are complex. To date, few studies have used a longitudinal, correlational and multilevel design to study the working life of subordinates and managers. METHOD: In five Swedish municipalities, questionnaires were answered twice during 2010-12 by 56 first-line managers and 769 subordinates working in nursing homes or home-help services. RESULTS: First-line managers' empowerment at Time 1 partially predicted subordinate's structural empowerment and ratings of their managers' leadership management performance at Time 2. Changes over time partially revealed that the more access managers had to structural empowerment, i.e. increase over time, the higher the ratings were for structural empowerment and managerial leadership management performance among subordinates. CONCLUSIONS: Findings strengthen research and theoretical suggestions linking first-line managers' structural empowerment to their subordinates' structural empowerment and ratings of their manager's leadership-management performance. IMPLICATIONS FOR NURSING MANAGEMENT: Managers with high access to structural empowerment are more likely to provide subordinates access to structural empowerment. PMID- 28714219 TI - Visible-Light-Excited Ultralong Organic Phosphorescence by Manipulating Intermolecular Interactions. AB - Visible light is much more available and less harmful than ultraviolet light, but ultralong organic phosphorescence (UOP) with visible-light excitation remains a formidable challenge. Here, a concise chemical approach is provided to obtain bright UOP by tuning the molecular packing in the solid state under irradiation of available visible light, e.g., a cell phone flashlight under ambient conditions (room temperature and in air). The excitation spectra exhibit an obvious redshift via the incorporation of halogen atoms to tune intermolecular interactions. UOP is achieved through H-aggregation to stabilize the excited triplet state, with a high phosphorescence efficiency of 8.3% and a considerably long lifetime of 0.84 s. Within a brightness of 0.32 mcd m-2 that can be recognized by the naked eye, UOP can last for 104 s in total. Given these features, ultralong organic phosphorescent materials are used to successfully realize dual data encryption and decryption. Moreover, well-dispersed UOP nanoparticles are prepared by polymer-matrix encapsulation in an aqueous solution, and their applications in bioimaging are tentatively being studied. This result will pave the way toward expanding metal-free organic phosphorescent materials and their applications. PMID- 28714220 TI - Histochemical analysis of collagen reorganization at the invasive front of oral squamous cell carcinoma tumors. AB - AIM: The aim of the present study was to: (a) analyze the nature of collagen with respect to cohesive and discohesive invasive tumor front (ITF) of oral squamous cell carcinoma (OSCC); (b) analyze the clinicopathological correlation with the nature of collagen at the ITF of OSCC; and (c) correlate the nature of collagen with Broder's and Bryne's histological grading system of OSCC. METHODS: Tissue sections of 29 OSCC with ITF were stained with hematoxylin-eosin and picrosirius red staining for evaluation under a polarized microscope. RESULTS: Tumors with a cohesive front had a thick collagen fiber, are predominantly organized, red yellow in color, well packed, and show strong birefringence (P<.005). A gradual change in the nature of the collagen fiber was observed in the discohesive tumor front, where the collagen fibers were thin, disorganized, yellow-orange to green yellow in color, loosely packed, and with weak birefringence (P<.005). CONCLUSION: A cohesive tumor front with organized collagen fibers prevents tumor invasion and metastasis. As it is inhibits an increase in tumor size, it is associated with the initial stage of tumor (I & II), whereas in a discohesive tumor front, the fibers might enhance the movement of tumor cells, resulting in invasion and metastasis. PMID- 28714221 TI - Social participation among older adults (55+): Results of a survey in the region of South Limburg in the Netherlands. AB - Social participation may improve the health and well-being of older adults, and may increase the social and human capacity of their communities. This study investigates the level and forms of social participation among older adults (aged 55 years or older) in the region of South Limburg, the Netherlands, and their association with socio-demographic and health-related characteristics. The study provides evidence that can be used by policy makers to enhance social participation in the region. We use cross-sectional data collected in a survey in 2012 among a sample of older adults (aged 55 years or older) representative for the region of South Limburg. The results indicate that 56% (N = 16,291/weighted sample N = 213,332) of the older adults in the region participate in social activities. Specifically, 25.5% perform paid labour, 20% give informal care and 25% participate in volunteer work. Older adults with a higher education (OR = 2.49 for the highest education group) or higher income (OR = 1.70 for the highest income group) are significantly more likely to participate in social activities compared with the respective reference categories. Increased age (OR = 0.23 for the oldest age group), female gender (OR = 0.83), loneliness (OR = 0.75 for severe loneliness) and restrictions (OR = 0.78 for restrictions on the OECD scale, OR = 0.68 for restrictions on the HDL scale, OR = 0.52 for transportation restrictions) significantly hinder social participation. The lower social participation rate among older adults that we observe compared with the national statistics can be explained by the relatively higher proportion of people with low or average socioeconomic status in South Limburg. And as South Limburg is the unhealthiest region of the Netherlands, this also contributes to the low social participation. Prevention of poor physical and mental health, and provision of care services are important to encourage social participation among the older adults in South Limburg. PMID- 28714222 TI - Barriers to vaccination in renal transplant recipients. AB - Vaccine-preventable diseases remain at the forefront of challenges in the long term care of renal transplant recipients (RTR). Although global vaccination campaigns targeting patients with end-stage renal disease or RTR are standard, rates of vaccination among renal transplant candidates and RTRs remain suboptimal. We highlight the multifactorial barriers leading to low vaccination rates in this vulnerable population. PMID- 28714223 TI - Uric acid and dehydration in children with gastroenteritis. AB - BACKGROUND: Clinical assessment of dehydration in children with acute gastroenteritis (AGE) is crucial for treatment. The gold standard for assessment is acute weight loss. Dehydration severity, as determined by weight loss, significantly correlates with serum urea nitrogen (UN) in children with AGE. The disadvantage of using serum UN as a marker of dehydration severity, however, is that the level can be affected by nutrition. Serum uric acid (UA) theoretically could serve as an alternative in this regard, but there have been no reports on the direct relationship between serum UA and weight loss. The aim of this study was therefore to assess the relationship between serum UA and weight loss in patients with AGE. METHODS: This was a prospective observational study of children 1-71 months of age admitted to Tokyo Metropolitan Children's Medical Center with AGE between 1 December 2010 and 31 March 2015. Patients with symptoms of AGE >= 8 days, chronic disease, or incomplete data were excluded from the study. Pre-post-rehydration weight change was used as an alternative, gold standard marker for the assessment of dehydration severity. RESULTS: The study participants consisted of 97 children. Serum UA correlated significantly with weight change, and increased significantly along with dehydration severity. CONCLUSIONS: Serum UA can be considered as an adjunct to the clinical assessment of dehydration in children with AGE. PMID- 28714224 TI - Codelivery for Paclitaxel and Bcl-2 Conversion Gene by PHB-PDMAEMA Amphiphilic Cationic Copolymer for Effective Drug Resistant Cancer Therapy. AB - Antiapoptotic Bcl-2 protein's upregulated expression is a key reason for drug resistance leading to failure of chemotherapy. In this report, a series of biocompatible amphiphilic cationic poly[(R)-3-hydroxybutyrate] (PHB)-b-poly(2 (dimethylamino)ethyl methacrylate) (PDMAEMA) copolymer, comprising hydrophobic PHB block and cationic PDMAEMA block, is designed to codeliver hydrophobic chemotherapeutic paclitaxel and Bcl-2 converting gene Nur77/DeltaDBD with enhanced stability, due to the micelle formation by hydrophobic PHB segment. This copolymer shows less toxicity but similar gene transfection efficiency to polyethyenimine (25k). More importantly, this codelivery approach by PHB-PDMAEMA leads to increased drug resistant HepG2/Bcl-2 cancer cell death, by increased expression of Nur77 proteins in the Bcl-2 present intracellular mitochondria. This work signifies for the first time that cationic amphiphilic PHB-b-PDMAEMA copolymers can be utilized for the drug and gene codelivery to drug resistant cancer cells with high expression of antiapoptosis Bcl-2 protein and the positive results are encouraging for the further design of codelivery platforms for combating drug resistant cancer cells. PMID- 28714226 TI - Extranasopharyngeal angiofibroma revisited. AB - BACKGROUND: Angiofibromas in the head and neck region usually arise in the nasopharynx, but may also occur elsewhere. This study aims at evaluating the incidence and clinical features of extranasopharyngeal angiofibroma (ENA). MATERIAL AND METHODS: Systematic review of the literature (Medline(r) and GoogleTM ) up to 31 December 2015. RESULTS: 174 cases of ENA were retrieved from a total of 170 publications. In contrast to former publications and previous understanding, the nasal septum was by far the most common site of the disease. Four patients had a congenital lesion, the oldest patient was 87 years old (mean: 28.7 years; median: 23 years). Male gender was predominantly affected, but the sex ratio was more balanced (2.13:1) than in previous reports in the literature until 12/2015. The majority of patients presented with nasal obstruction, either in combination with epistaxis (25.8%) or other symptoms (12.6%). Symptoms had developed within 13.1 months on average (median: 4 months). Brisk bleeding resulted in 11 of 43 biopsy procedures. Surgical resection as first-line therapy was performed in 170 patients. A tumour regrowth within 12 months was registered in four patients. CONCLUSION: The increasing awareness of ENA and the willingness to publish case reports-not only in Medline-listed journals-resulted in a significant increase of published case reports lately. Although extremely rare, ENAs have to be taken into account in the differential diagnosis of unclear masses, particularly in adult patients presenting with a rapidly developing nasal obstruction resulting from a nasal septum tumour. Female gender or normal vascularity does not exclude the diagnosis. Transnasal resection is sufficient in most cases, and recurrences are rare. Pathologists as well as clinicians should consider ENA in their differential diagnosis of any mass of the upper airway. PMID- 28714227 TI - Transepithelial transport of milk-derived angiotensin I-converting enzyme inhibitory peptide with the RLSFNP sequence. AB - BACKGROUND: To exert an antihypertensive effect after oral administration, angiotensin I-converting enzyme (ACE)-inhibitory peptides must remain active after intestinal transport. The purpose of this article is to elucidate the transport permeability and route of ACE-inhibitory peptide Arg-Leu-Ser-Phe-Asn Pro (RLSFNP) across the intestinal epithelium using Caco-2 cell monolayers. RESULTS: Intact RLSFNP and RLSFNP breakdown fragments F, FNP, SFNP and RLSF were found in RLSFNP transport solution across Caco-2 cell monolayers using ultra performance liquid chromatography-tandem mass spectrometry. RLSFNP fragments FNP, SFNP and RLSF also contributed to ACE inhibitory effects. Protease inhibitors (bacitracin and leupeptin) and absorption enhancers (sodium glycocholate hydrate, sodium deoxycholate and Na2 EDTA) improved the transport flux of RLSFNP. A transport inhibitor experiment showed that intact RLSFNP may be transported via the paracellular route. CONCLUSION: Intact RLSFNP can be transported across the Caco-2 cell monolayers via the paracellular route. Extensive hydrolysis was the chief reason for the low permeability of RLSFNP. (c) 2017 Society of Chemical Industry. PMID- 28714225 TI - Leveraging splice-affecting variant predictors and a minigene validation system to identify Mendelian disease-causing variants among exon-captured variants of uncertain significance. AB - The genetic heterogeneity of Mendelian disorders results in a significant proportion of patients that are unable to be assigned a confident molecular diagnosis after conventional exon sequencing and variant interpretation. Here, we evaluated how many patients with an inherited retinal disease (IRD) have variants of uncertain significance (VUS) that are disrupting splicing in a known IRD gene by means other than affecting the canonical dinucleotide splice site. Three in silico splice-affecting variant predictors were leveraged to annotate and prioritize variants for splicing functional validation. An in vitro minigene system was used to assay each variant's effect on splicing. Starting with 745 IRD patients lacking a confident molecular diagnosis, we validated 23 VUS as splicing variants that likely explain disease in 26 patients. Using our results, we optimized in silico score cutoffs to guide future variant interpretation. Variants that alter base pairs other than the canonical GT-AG dinucleotide are often not considered for their potential effect on RNA splicing but in silico tools and a minigene system can be utilized for the prioritization and validation of such splice-disrupting variants. These variants can be overlooked causes of human disease but can be identified using conventional exon sequencing with proper interpretation guidelines. PMID- 28714228 TI - Polyladderane Constructed from a Gemini Monomer through Photoreaction. AB - Polyladderane, the first polymer to contain the ladderane functional group, was synthesized from a gemini monomer through photoreaction in the solid state. The modular design of the gemini monomers used to create polyladderane allowed specific structural modification, resulting in the formation of two distinct polymer products. Monomers were synthesized by connecting two photoreactive units, either sorbic acids (monomer I) or 2-furanacrylic acids (monomer II), with a 1,4-butanediol linker. Single-crystal X-ray diffraction analysis of the monomers confirmed that they packed in the desired head-to-tail orientation and within a viable distance for photoreaction by electronically complementary interaction. Pre-organized gemini monomers were irradiated with UV light and monitored by FT-IR. Two polyladderanes with cis,anti,cis-[3]-ladderane as a characteristic functional group were constructed stereospecifically in 24-36 hours. PMID- 28714229 TI - Implementing a protocol to optimize blood use in a cardiac surgery service: results of a pre-post analysis and the impact of high-volume blood users. AB - BACKGROUND: Blood transfusions are a common and costly intervention for cardiac surgery patients. Evidence suggests that a more restrictive transfusion strategy may reduce costs and transfusion-related complications without increasing perioperative morbidity and mortality. STUDY DESIGN AND METHODS: A transfusion limiting protocol was developed and implemented in a cardiovascular surgery unit. Over a 5-year period, data were collected on patient characteristics, procedures, utilization of blood products, morbidity, and mortality, and these were compared before and after the protocol was implemented. RESULTS: After the protocol was put in place, fewer patients required transfusions (38.2% vs. 45.5%, p = 0.004), with the greatest reduction observed in postoperative blood use (29.1% vs. 37.2%, p = 0.001). In-hospital morbidity and mortality did not increase. When patients who received transfusions were stratified by procedure, the protocol was most effective in reducing transfusions for patients undergoing isolated coronary artery bypass grafting (CABG; 4.09 units vs. 2.51 units, p = 0.009) and CABG plus valve surgery (10.32 units vs. 4.77 units, p = 0.014). A small group of patients were disproportionate recipients of transfusions, with approximately 6% of all patients receiving approximately half of the blood products. CONCLUSION: A protocol to limit transfusions decreased the proportion of cardiothoracic surgery patients who received blood products. A very small group of patients received a large number of transfusions, and within that group the observed mortality was significantly higher than in the general patient population. Current protocols cannot possibly account for these patients, and this should be considered when analyzing the performance of protocols designed to reduce unnecessary transfusions. PMID- 28714230 TI - Wet-Spun Superelastic Graphene Aerogel Millispheres with Group Effect. AB - Graphene aerogel has attracted great attention due to its unique properties, such as ultralow density, superelasticity, and high specific surface area. It shows huge potential in energy devices, high-performance pressure sensors, contaminates adsorbents, and electromagnetic wave absorbing materials. However, there still remain some challenges to further promote the development and real application of graphene aerogel including cost-effective scalable fabrication and miniaturization with group effect. This study shows millimeter-scale superelastic graphene aerogel spheres (GSs) with group effect and multifunctionality. The GSs are continuously fabricated on a large scale by wet spinning of graphene oxide liquid crystals followed by facile drying and thermal annealing. Such GS has an unusual core-shell structure with excellent elasticity and specific strength. Significantly, both horizontally and vertically grouped spheres exhibit superelasticity comparable to individual spheres, enabling it to fully recover at 95% strain, and even after 1000 compressive cycles at 70% strain, paving the way to wide applications such as pressure-elastic and adsorbing materials. The GS shows a press-fly behavior with an extremely high jump velocity up to 1.2 m s-1 . For the first time, both free and oil-adsorbed GSs are remotely manipulated on water by electrostatic charge due to their ultralow density and hydrophobic properties. PMID- 28714231 TI - A Highly Versatile and Adaptable Artificial Leaf with Floatability and Planar Compact Design Applicable in Various Natural Environments. AB - As a promising means of solar energy conversion, photovoltaic (PV) cell-based electrolysis has recently drawn considerable attention for its effective solar fuel generation; especially the generation of hydrogen by solar water splitting. Inspired by remarkable accomplishments in enhancing the solar-to-hydrogen conversion efficiency, various efforts have aimed at fostering convenient and practical uses of PV electrolysis to make this technology ubiquitous, manageable, and efficient. Here, the design and function of a monolithic photoelectrolysis system-a so-called artificial leaf-for use in various environments are highlighted. The uniquely designed artificial-leaf system facilitates an unbiased water-splitting reaction by combining superstrate PV cells in series with single face electrodes in a compact 2D catalytic configuration. Floatability is a new feature of the water-splitting artificial leaf; this feature maximizes solar light utilization and allows for easy retrieval for recycling. Additionally, its planar design enables operation of the device in water-scarce conditions. These characteristics endow the artificial leaf with versatility and a high adaptability to natural environments, widening the applicability of the device. PMID- 28714232 TI - Intermediate Product Regulation in Tandem Solid Catalysts with Multimodal Porosity for High-Yield Synthetic Fuel Production. AB - Tandem catalysis is an attractive strategy to intensify chemical technologies. However, simultaneous control over the individual and concerted catalyst performances poses a challenge. We demonstrate that enhanced pore transport within a Co/Al2 O3 Fischer-Tropsch (FT) catalyst with hierarchical porosity enables its tandem integration with a Pt/ZSM-5 zeolitic hydrotreating catalyst in a spatially distant fashion that allows for catalyst-specific temperature adjustment. Nevertheless, this system resembles the case of close active-site proximity by mitigating secondary reactions of primary FT alpha-olefin products. This approach enables the combination of in situ dewaxing with a minimum production of gaseous hydrocarbons (18 wt %) and an up to twofold higher (50 wt %) selectivity to middle distillates compared to tandem pairs based on benchmark mesoporous FT catalysts. An overall 80 % selectivity to liquid hydrocarbons from syngas is attained in one step, attesting to the potential of this strategy for increasing the carbon efficiency in intensified gas-to-liquid technologies. PMID- 28714233 TI - Bioinspired, Size-Tunable Self-Assembly of Polymer-Lipid Bilayer Nanodiscs. AB - Polymer-based nanodiscs are valuable tools in biomedical research that can offer a detergent-free solubilization of membrane proteins maintaining their native lipid environment. Herein, we introduce a novel ca. 1.6 kDa SMA-based polymer with styrene:maleic acid moieties that can form nanodiscs containing a planar lipid bilayer which are useful to reconstitute membrane proteins for structural and functional studies. The physicochemical properties and the mechanism of formation of polymer-based nanodiscs are characterized by light scattering, NMR, FT-IR, and TEM. A remarkable feature is that nanodiscs of different sizes, from nanometer to sub-micrometer diameter, can be produced by varying the lipid-to polymer ratio. The small-size nanodiscs (up to ca. 30 nm diameter) can be used for solution NMR spectroscopy studies whereas the magnetic-alignment of macro nanodiscs (diameter of > ca. 40 nm) can be exploited for solid-state NMR studies on membrane proteins. PMID- 28714234 TI - An improved correlation to predict molecular weight between crosslinks based on equilibrium degree of swelling of hydrogel networks. AB - Accurate characterization of hydrogel diffusional properties is of substantial importance for a range of biotechnological applications. The diffusional capacity of hydrogels has commonly been estimated using the average molecular weight between crosslinks (Mc ), which is calculated based on the equilibrium degree of swelling. However, the existing correlation linking Mc and equilibrium swelling fails to accurately reflect the diffusional properties of highly crosslinked hydrogel networks. Also, as demonstrated herein, the current model fails to accurately predict the diffusional properties of hydrogels when polymer concentration and molecular weight are varied simultaneously. To address these limitations, we evaluated the diffusional properties of 48 distinct hydrogel formulations using two different photoinitiator systems, employing molecular size exclusion as an alternative methodology to calculate average hydrogel mesh size. The resulting data were then utilized to develop a revised correlation between Mc and hydrogel equilibrium swelling that substantially reduces the limitations associated with the current correlation. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1339-1348, 2018. PMID- 28714235 TI - Tuberculosis after kidney transplantation is associated with significantly impaired allograft function. AB - BACKGROUND: This study aimed to evaluate renal function before, during, and after the course of tuberculosis (TB) disease in kidney transplant recipients, and assess the risk factors for non-recovery of baseline renal function. METHODS: We performed a retrospective, single-center cohort study, including all patients with confirmed or presumed TB diagnosis after kidney transplant (n=34, 2.1%). Renal function was assessed by serum creatinine (Cr) and glomerular filtration rate (GFR) adjusted for deaths and graft losses. RESULTS: A significant increase was seen in serum Cr during TB disease and treatment: 1.5 mg/dL at baseline (Crbase ), 1.7 mg/dL at diagnosis (P<.001 vs. Crbase ), and 2.4 mg/dL during the peak (P<.001 vs. Crbase ). According to acute kidney injury (AKI) Kidney Disease: Improving Global Outcomes (KDIGO) classification, 29 (85%) patients had AKI: 16 stage 1, 2 stage 2, and 11 stage 3. Three months after the end of the TB treatment, five patients (14.7%) had lost their graft and two others (5.9%) had died. The GFR was lower than the baseline (42.4 mL/min vs 51.6 mL/min, P=.007). In the univariate analysis, peak Cr (odds ratio [OR] 1.276, 95% confidence interval [CI] 0.955-1.705, P=.100), AKI KDIGO stages 2 or 3 (OR 4.958, 95% CI 1.062-23.157, P=.042), severe disease (OR 5.700, 95% CI 1.147-28.330, P=.033), and acute rejection (AR) episodes after TB diagnosis (OR 3.937, 95% CI 0.551 28.116, P=.172) were associated with non-recovery of baseline renal function. No variable was identified in the multivariable model. CONCLUSION: Post transplantation TB was associated with a high incidence of AKI, and complete recovery of baseline renal function was not achieved after treatment. The severity of TB disease, AKI, and AR episodes that occurred after TB diagnosis are potential causes for this outcome. PMID- 28714236 TI - Effectiveness of tissue engineered three-dimensional bioactive graft on bone healing and regeneration: an in vivo study with significant clinical value. AB - Several strategies have been used to promote bone repair, with many failing due to the lack of osteoinduction. This report describes an approach for promoting bone healing that attempts to overcome prior shortcomings. First, the role was compared of different concentrations of gelatine (Gel), nanostructured hydroxyapatite (nHA), simvastatin (Sim) and nHA-Sim particles on healing of small femoral bone defects in rabbits. The effective concentration of each was studied, and then a three-dimensional porous scaffold was designed using Gel, nHA and Sim, which was then cross-linked with genipin. Morphology, degradation profile and Sim delivery properties of the scaffolds were evaluated in vitro. Then, the scaffolds were subcutaneously tested in vivo to determine their biocompatibility, biodegradability and osteogenic properties. Finally, the scaffolds were implanted in a large radial bone defect model in rabbits and their effect on bone regeneration was investigated. The Gel, nHA and Sim with concentrations of 1, 1 and 5 mg/femoral hole were effective during bone healing respectively, and the Sim showed the most osteoinduction and osteoconduction when compared to controls. The Gel-Sim and Gel-nHA-Sim scaffolds continuously and homogenously released Sim into the simulated body fluid in vitro. Subcutaneously, the scaffolds were biocompatible, biodegradable and able to produce ectopic bone after 30 days. Thirty and 60 days after implantation of the scaffolds in radial bone defects, they were completely degraded and replaced with the new bone that had significantly superior morphology, mineral density, bioelectrical, biophysical and micromechanical properties compared with controls. Such bioactive grafts may be a suitable option for bone reconstruction, healing and repair. PMID- 28714237 TI - Effects of intracameral ascorbic acid on the corneal endothelium of dogs undergoing phacoemulsification. AB - OBJECTIVE: Cataracts are the most common ocular disorder in dogs. Phacoemulsification is the preferred treatment method among ophthalmologists, but the cellularity of the endothelium must be considered for its success, as endothelial lesions may produce permanent corneal decompensation. The objective of this study was to evaluate the effects of intracameral ascorbic acid, a known antioxidant, on the corneal endothelium of dogs undergoing phacoemulsification. ANIMAL STUDIED: In all, 40 eyes from 20 dogs, males and females from 7 to 12 years of age, were assessed for mature cataracts. PROCEDURES: Two groups were formed (n = 20): Group 1 (G1) received a balanced salt solution (BSS), whereas Group 2 (G2) received sterile ascorbic acid diluted in a BSS, at a final concentration of 0.001 m ascorbic acid. The corneal endothelium was assessed via non-contact specular microscopy at multiple time points before and after phacoemulsification. Cell density (cells/mm2 ) and area (mm2 ), corneal thickness (mm), hexagonality, and the coefficient of variation of cell size were all assessed. P values equal to or less than 0.05 were considered significant. RESULTS: With respect to the density of endothelial cells, both groups showed losses, but they were less severe in G2. There were no differences in corneal thickness. Hexagonality decreased significantly in the postoperative period in G1. Also in G1, the coefficient of variation of cell size increased significantly. CONCLUSION: According to the results obtained, ascorbic acid minimizes cellular losses in the corneal endothelium. PMID- 28714238 TI - Green biofuels and bioproducts: bases for sustainability analysis. PMID- 28714239 TI - Self-Powered Real-Time Arterial Pulse Monitoring Using Ultrathin Epidermal Piezoelectric Sensors. AB - Continuous monitoring of an arterial pulse using a pressure sensor attached on the epidermis is an important technology for detecting the early onset of cardiovascular disease and assessing personal health status. Conventional pulse sensors have the capability of detecting human biosignals, but have significant drawbacks of power consumption issues that limit sustainable operation of wearable medical devices. Here, a self-powered piezoelectric pulse sensor is demonstrated to enable in vivo measurement of radial/carotid pulse signals in near-surface arteries. The inorganic piezoelectric sensor on an ultrathin plastic achieves conformal contact with the complex texture of the rugged skin, which allows to respond to the tiny pulse changes arising on the surface of epidermis. Experimental studies provide characteristics of the sensor with a sensitivity (~0.018 kPa-1 ), response time (~60 ms), and good mechanical stability. Wireless transmission of detected arterial pressure signals to a smart phone demonstrates the possibility of self-powered and real-time pulse monitoring system. PMID- 28714240 TI - Tunable SnSe2 /WSe2 Heterostructure Tunneling Field Effect Transistor. AB - The burgeoning 2D semiconductors can maintain excellent device electrostatics with an ultranarrow channel length and can realize tunneling by electrostatic gating to avoid deprivation of band-edge sharpness resulting from chemical doping, which make them perfect candidates for tunneling field effect transistors. Here this study presents SnSe2 /WSe2 van der Waals heterostructures with SnSe2 as the p-layer and WSe2 as the n-layer. The energy band alignment changes from a staggered gap band offset (type-II) to a broken gap (type-III) when changing the negative back-gate voltage to positive, resulting in the device operating as a rectifier diode (rectification ratio ~104 ) or an n-type tunneling field effect transistor, respectively. A steep average subthreshold swing of 80 mV dec-1 for exceeding two decades of drain current with a minimum of 37 mV dec-1 at room temperature is observed, and an evident trend toward negative differential resistance is also accomplished for the tunneling field effect transistor due to the high gate efficiency of 0.36 for single gate devices. The ION /IOFF ratio of the transfer characteristics is >106 , accompanying a high ON current >10-5 A. This work presents original phenomena of multilayer 2D van der Waals heterostructures which can be applied to low-power consumption devices. PMID- 28714242 TI - Rechargeable Aluminum-Ion Batteries Based on an Open-Tunnel Framework. AB - Rechargeable batteries based on an abundant metal such as aluminum with a three electron transfer per atom are promising for large-scale electrochemical energy storage. Aluminum can be handled in air, thus offering superior safety, easy fabrication, and low cost. However, the development of Al-ion batteries has been challenging due to the difficulties in identifying suitable cathode materials. This study presents the use of a highly open framework Mo2.5 + y VO9 + z as a cathode for Al-ion batteries. The open-tunnel oxide allows a facile diffusion of the guest species and provides sufficient redox centers to help redistribute the charge within the local host lattice during the multivalent-ion insertion, thus leading to good rate capability with a specific capacity among the highest reported in the literature for Al-based batteries. This study also presents the use of Mo2.5 + y VO9 + z as a model host to develop a novel ultrafast technique for chemical insertion of Al ions into host structures. The microwave-assisted method employing diethylene glycol and aluminum diacetate (Al(OH)(C2 H3 O2 )2 ) can be performed in air in as little as 30 min, which is far superior to the traditional chemical insertion techniques involving moisture-sensitive organometallic reagents. The Al-inserted Al x Mo2.5 + y VO9 + z obtained by the microwave-assisted chemical insertion can be used in Al-based rechargeable batteries. PMID- 28714241 TI - Cytokine profiles in Tibetan macaques following alpha-1,3-galactosyltransferase knockout pig liver xenotransplantation. AB - BACKGROUND: Pig-to-nonhuman primate orthotopic liver xenotransplantation is often accompanied by thrombocytopenia and coagulation disorders. Furthermore, the release of cytokines can trigger cascade reactions of coagulation and immune attacks within transplant recipients. To better elucidate the process of inflammation in liver xenograft recipients, we utilized a modified heterotopic auxiliary liver xenotransplantation model for xeno-immunological research. We studied the cytokine profiles and the relationship between cytokine levels and xenograft function after liver xenotransplantation. METHODS: Appropriate donor and recipient matches were screened using complement-dependent cytotoxicity assays. Donor liver grafts from alpha1,3-galactosyltransferase gene-knockout (GTKO) pigs or GTKO pigs additionally transgenic for human CD47 (GTKO/CD47) were transplanted into Tibetan macaques via two different heterotrophic auxiliary liver xenotransplantation procedures. The cytokine profiles, hepatic function, and coagulation parameters were monitored during the clinical course of xenotransplantation. RESULTS: Xenograft blood flow was stable in recipients after heterotopic auxiliary transplantation. A Doppler examination indicated that the blood flow speed was faster in the hepatic artery (HA) and hepatic vein (HV) of xenografts subjected to the modified Sur II (HA-abdominal aorta+HV-inferior vena cava) procedure than in those subjected to our previously reported Sur I (HA splenic artery+HV-left renal vein) procedure. Tibetan macaques receiving liver xenografts did not exhibit severe coagulation disorders or immune rejection. Although the recipients did suffer from a rapid loss of platelets, this loss was mild. In blood samples dynamically collected after xenotransplantation (post-Tx), dramatic increases in the levels of monocyte chemoattractant protein 1, interleukin (IL)-8, granulocyte-macrophage colony-stimulating factor, IL-6, and interferon gamma-induced protein 10 were observed at 1 hour post-Tx, even under immunosuppression. We further confirmed that the elevation in individual cytokine levels was correlated with the onset of graft damage. Finally, the release of cytokines might contribute to leukocyte infiltration in the xenografts. CONCLUSION: Here, we established a modified auxiliary liver xenotransplantation model resulting in near-normal hepatic function. Inflammatory cytokines might contribute to early damage in liver xenografts. Controlling the systemic inflammatory response of recipients might prevent early post-Tx graft dysfunction. PMID- 28714243 TI - Regulation of the activity of the promoter of RNA-induced silencing, C3PO. AB - RNA-induced silencing is a process which allows cells to regulate the synthesis of specific proteins. RNA silencing is promoted by the protein C3PO (component 3 of RISC). We have previously found that phospholipase Cbeta, which increases intracellular calcium levels in response to specific G protein signals, inhibits C3PO activity towards certain genes. Understanding the parameters that control C3PO activity and which genes are impacted by G protein activation would help predict which genes are more vulnerable to downregulation. Here, using a library of 1018 oligonucleotides, we show that C3PO binds oligonucleotides with structural specificity but little sequence specificity. Alternately, C3PO hydrolyzes oligonucleotides with a rate that is sensitive to substrate stability. Importantly, we find that oligonucleotides with higher Tm values are inhibited by bound PLCbeta. This finding is supported by microarray analysis in cells over expressing PLCbeta1. Taken together, this study allows predictions of the genes whose post-transcriptional regulation is responsive to the G protein/phospholipase Cbeta/calcium signaling pathway. PMID- 28714245 TI - Drug-Loaded Multifunctional Nanoparticles Targeted to the Endocardial Layer of the Injured Heart Modulate Hypertrophic Signaling. AB - Ischemic heart disease is the leading cause of death globally. Severe myocardial ischemia results in a massive loss of myocytes and acute myocardial infarction, the endocardium being the most vulnerable region. At present, current therapeutic lines only ameliorate modestly the quality of life of these patients. Here, an engineered nanocarrier is reported for targeted drug delivery into the endocardial layer of the left ventricle for cardiac repair. Biodegradable porous silicon (PSi) nanoparticles are functionalized with atrial natriuretic peptide (ANP), which is known to be expressed predominantly in the endocardium of the failing heart. The ANP-PSi nanoparticles exhibit improved colloidal stability and enhanced cellular interactions with cardiomyocytes and non-myocytes with minimal toxicity. After confirmation of good retention of the radioisotope 111-Indium in relevant physiological buffers over 4 h, in vivo single-photon emission computed tomography (SPECT/CT) imaging and autoradiography demonstrate increased accumulation of ANP-PSi nanoparticles in the ischemic heart, particularly in the endocardial layer of the left ventricle. Moreover, ANP-PSi nanoparticles loaded with a novel cardioprotective small molecule attenuate hypertrophic signaling in the endocardium, demonstrating cardioprotective potential. These results provide unique insights into the development of nanotherapies targeted to the injured region of the myocardium. PMID- 28714244 TI - The role of de novo mutations in the development of amyotrophic lateral sclerosis. AB - The genetic basis combined with the sporadic occurrence of amyotrophic lateral sclerosis (ALS) suggests a role of de novo mutations in disease pathogenesis. Previous studies provided some evidence for this hypothesis; however, results were conflicting: no genes with recurrent occurring de novo mutations were identified and different pathways were postulated. In this study, we analyzed whole-exome data from 82 new patient-parents trios and combined it with the datasets of all previously published ALS trios (173 trios in total). The per patient de novo rate was not higher than expected based on the general population (P = 0.40). We showed that these mutations are not part of the previously postulated pathways, and gene-gene interaction analysis found no enrichment of interacting genes in this group (P = 0.57). Also, we were able to show that the de novo mutations in ALS patients are located in genes already prone for de novo mutations (P < 1 * 10-15 ). Although the individual effect of rare de novo mutations in specific genes could not be assessed, our results indicate that, in contrast to previous hypothesis, de novo mutations in general do not impose a major burden on ALS risk. PMID- 28714246 TI - Carbon Nanodot-Sensitized Modulation of Alzheimer's beta-Amyloid Self-Assembly, Disassembly, and Toxicity. AB - The self-assembly of amyloidogenic peptides into beta-sheet-rich aggregates is a general feature of many neurodegenerative diseases, including Alzheimer's disease, which signifies the need for the effective attenuation of amyloid aggregation toward alleviating amyloid-associated neurotoxicity. This study reports that photoluminescent carbon nanodots (CDs) can effectively suppress Alzheimer's beta-amyloid (Abeta) self-assembly and function as a beta-sheet breaker disintegrating preformed Abeta aggregates. This study synthesizes CDs using ammonium citrate through one-pot hydrothermal treatment and passivates their surface with branched polyethylenimine (bPEI). The bPEI-coated CDs (bPEI@CDs) exhibit hydrophilic and cationic surface characteristics, which interact with the negatively charged residues of Abeta peptides, suppressing the aggregation of Abeta peptides. Under light illumination, bPEI@CDs display a more pronounced effect on Abeta aggregation and on the dissociation of beta-sheet-rich assemblies through the generation of reactive oxygen species from photoactivated bPEI@CDs. The light-triggered attenuation effect of Abeta aggregation using a series of experiments, including photochemical and microscopic analysis, is verified. Furthermore, the cell viability test confirms the ability of photoactivated bPEI@CDs for the suppression of Abeta-mediated cytotoxicity, indicating bPEI@CDs' potency as an effective anti-Abeta neurotoxin agent. PMID- 28714247 TI - Molecular cytogenetics to characterize mechanisms of gene duplication in pesticide resistance. AB - Recent advances in molecular cytogenetics empower construction of physical maps to illustrate the precise position of genetic loci on the chromosomes. Such maps provide visible information about the position of DNA sequences, including the distribution of repetitive sequences on the chromosomes. This is an important step toward unraveling the genetic mechanisms implicated in chromosomal aberrations (e.g., gene duplication). In response to stress, such as pesticide selection, duplicated genes provide an immediate adaptive advantage to organisms that overcome unfavorable conditions. Although the significance of gene duplication as one of the important events driving genetic diversity has been reported, the precise mechanisms of gene duplication that contribute to pesticide resistance, especially to herbicides, are elusive. With particular reference to pesticide resistance, we discuss the prospects of application of molecular cytogenetic tools to uncover mechanism(s) of gene duplication, and illustrate hypothetical models that predict the evolutionary basis of gene duplication. The cytogenetic basis of duplicated genes, their stability, as well as the magnitude of selection pressure, can determine the dynamics of the genetic locus (loci) conferring pesticide resistance not only at the population level, but also at the individual level. (c) 2017 Society of Chemical Industry. PMID- 28714248 TI - Functionalized superparamagnetic nanoparticles with a polymer containing beta cyclodextrin for the extraction of sertraline hydrochloride in biological samples. AB - In this study, a novel magnetic nanoadsorbent was synthesized by grafting beta cyclodextrin onto the modified surface of Fe3 O4 nanoparticles for the sorption and extraction of sertraline hydrochloride from human biological fluids. The extracted sertraline hydrochloride was measured by high-performance liquid chromatography. The grafted nanosorbent was confirmed by Fourier transform infrared spectroscopy, transmission electron microscopy, thermogravimetric analysis, and elemental analysis. The kinetic sorption of sertraline hydrochloride by magnetic nanosorbent was 1 h. The best temperature for sorption of sertraline hydrochloride was at 25 degrees C at an optimum pH of 5. The adsorbed sertraline hydrochloride can be desorbed by using methanol solution containing acetic acid (5%) and trifluoroacetic acid (1%). PMID- 28714249 TI - Simultaneous magnetic resonance diffusion and pseudo-diffusion tensor imaging. AB - PURPOSE: An emerging topic in diffusion magnetic resonance is imaging blood microcirculation alongside water diffusion using the intravoxel incoherent motion (IVIM) model. Recently, a combined IVIM diffusion tensor imaging (IVIM-DTI) model was proposed, which accounts for both anisotropic pseudo-diffusion due to blood microcirculation and anisotropic diffusion due to tissue microstructures. In this article, we propose a robust IVIM-DTI approach for simultaneous diffusion and pseudo-diffusion tensor imaging. METHODS: Conventional IVIM estimation methods can be broadly divided into two-step (diffusion and pseudo-diffusion estimated separately) and one-step (diffusion and pseudo-diffusion estimated simultaneously) methods. Here, both methods were applied on the IVIM-DTI model. An improved one-step method based on damped Gauss-Newton algorithm and a Gaussian prior for the model parameters was also introduced. The sensitivities of these methods to different parameter initializations were tested with realistic in silico simulations and experimental in vivo data. RESULTS: The one-step damped Gauss-Newton method with a Gaussian prior was less sensitive to noise and the choice of initial parameters and delivered more accurate estimates of IVIM-DTI parameters compared to the other methods. CONCLUSION: One-step estimation using damped Gauss-Newton and a Gaussian prior is a robust method for simultaneous diffusion and pseudo-diffusion tensor imaging using IVIM-DTI model. Magn Reson Med 79:2367-2378, 2018. (c) 2017 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. PMID- 28714250 TI - Development of antimicrobial nanoemulsion-based delivery systems against selected pathogenic bacteria using a thymol-rich Thymus daenensis essential oil. AB - AIMS: Thymol-rich medicinal plants have been used in traditional medicine to relieve infectious diseases. However, the application of essential oils as medicine is limited by its low water solubility and high vapour pressure. The objective of this study was to produce stable nanoemulsions of Thymus daenensis oil in water by preventing Ostwald ripening and phase separation. METHODS AND RESULTS: The antibacterial activity of bulk and emulsified essential oil against selected pathogenic bacteria including Gram-negative (Haemophilus influenzae, Pseudomonas aeruginosa) and Gram-positive (Streptococcus pneumoniae) were investigated in the liquid and vapour phase. The optimum formulation (L2) contained 2% Tween 80 (surfactant) and 0.1% lecithin (cosurfactant) had a mean droplet diameter of 131 nm. In the liquid phase, the optimized nanoemulsion exhibited good antibacterial activity against S. pneumonia with MIC value of 0.0039 mg mL-1 . In the vapour phase, the MIC values against S. pneumonia were similar (<7.35 MUL L-1 ) for both bulk and emulsified essential oil. However, there was no antibacterial activity in the vapour phase against H. influenzae and P. aeruginosa. Analysis of thymol concentration in the head space indicated that the nanoemulsion retarded the release of thymol into the vapour phase. CONCLUSIONS: These findings highlight the potential applications of nanoemulsions containing essential oils as antibacterial products. SIGNIFICANCE AND IMPACT OF THE STUDY: The results of the current study highlight the advantages of nanoemulsification for improvement of the physicochemical properties and the antibacterial activity of T. daenensis EOs in the liquid and vapour phase for therapeutic purposes. PMID- 28714251 TI - Reply to: Efficacy and Safety of Mechanical Thrombectomy in Older Adults with Acute Ischemic Stroke: Methodological Concerns. PMID- 28714252 TI - Ultra-High Pyridinic N-Doped Porous Carbon Monolith Enabling High-Capacity K-Ion Battery Anodes for Both Half-Cell and Full-Cell Applications. AB - An ultrahigh pyridinic N-content-doped porous carbon monolith is reported, and the content of pyridinic N reaches up to 10.1% in overall material (53.4 +/- 0.9% out of 18.9 +/- 0.4% N content), being higher than most of previously reported N doping carbonaceous materials, which exhibit greatly improved electrochemical performance for potassium storage, especially in term of the high reversible capacity. Remarkably, the pyridinic N-doped porous carbon monolith (PNCM) electrode exhibits high initial charge capacity of 487 mAh g-1 at a current density of 20 mA g-1 , which is one of the highest reversible capacities among all carbonaceous anodes for K-ion batteries. Moreover, the K-ion full cell is successfully assembled, demonstrating a high practical energy density of 153.5 Wh kg-1 . These results make PNCM promising for practical application in energy storage devices and encourage more investigations on a similar potassium storage system. PMID- 28714253 TI - An OFF-ON-OFF type fluorescent probe based on a naphthalene derivative for Al3+ and F- ions and its biological application. AB - A novel fluorescent probe-based naphthalene Schiff, 1-(C2-glucosyl-ylimino methyl)-naphthalene-2-ol (L) was synthesized by coupling d-glucosamine hydrochloride with 2-hydroxy-1-naphthaldehyde. It exhibited excellent selectivity and highly sensitivity for Al3+ in ethanol with a strong fluorescence response, while other common metal ions such as Pb2+ , Mg2+ , Cu2+ , Co2+ , Ni2+ , Cd2+ , Fe2+ , Mn2+ , Hg2+ , Li+ , Na+ , K+ , Fe3+ , Cr3+ , Zn2+ , Ag+ , Ba2+ and Ca2+ did not cause the same fluorescence response. The probe selectively bound Al3+ with a binding constant (Ka ) of 5.748 * 103 M-1 and a lowest detection limit (LOD) of 4.08 nM. Moreover, the study found that the fluorescence of the L - Al3+ complex could be quenched after addition of F- in the same medium, while other anions, including Cl- , Br- , I- , NO2- , NO3- , ClO4- , CO32- , HCO3- , SO42- , HSO4- , CH3 COO- , PO43- , HPO42- , S2- and S2 O32- had nearly no influence on probe behaviour. Binding of the [L - Al3+ ] complex to a F- anion was established by different fluorescence titration studies, with a detection limit of 3.2 nM in ethanol. The fluorescent probe was also successfully applied in the imaging detection of Al3+ and F- in living cells. PMID- 28714254 TI - Microbial biotechnology addressing the plastic waste disaster. AB - Oceans are a major source of biodiversity, they provide livelihood, and regulate the global ecosystem by absorbing heat and CO2 . However, they are highly polluted with plastic waste. We are discussing here microbial biotechnology advances with the view to improve the start and the end of life of biodegradable polymers, which could contribute to the sustainable use of marine and coastal ecosystems (UN Sustainability development goal 14). PMID- 28714255 TI - Hypoglycemic Emergency in Patients With Diabetic Kidney Disease. PMID- 28714257 TI - Dissecting heterogeneous outcomes for paediatric Burkitt lymphoma in Malawi after anthracycline-based treatment. PMID- 28714256 TI - A1S_2811, a CheA/Y-like hybrid two-component regulator from Acinetobacter baumannii ATCC17978, is involved in surface motility and biofilm formation in this bacterium. AB - Two-component systems in Acinetobacter baumannii are associated with its virulence, drug resistance, motility, biofilm formation, and other characteristics. In this study, we used RecAb , a genetic engineering method, to investigate the function of A1S_2811 in A. baumannii strain ATCC17978. A1S_2811, a hypothetical hybrid sensor histidine kinase/response regulator, has four histidine-containing phosphotransfer domains, a CheA-like regulatory domain, and a CheY-like receiver domain at its C terminus. Compared with the ATCC17978 strain, both surface motility and biofilm formation at the gas-liquid interface decreased significantly in the A1S_2811 knock-out strain. The number of pilus like structures and the amount of extrapolymeric substances on the cell surface also decreased in the A1S_2811 null strain. Transcription of abaI, which encodes an N-acylhomoserine lactone synthase in A. baumannii , decreased significantly in the A1S_2811 null strain, and supplementation with synthetic N-(3-oxodecanoyl) homoserine-l-lactone rescued the surface motility and biofilm formation phenotype in the null mutant. We speculate that A1S_2811 regulates surface motility and biofilm formation, not by regulating type IV pili-associated genes expression, but by regulating the chaperone/usher pili-associated csuA/ABCDE operon and the AbaI-dependent quorum-sensing pathway-associated A1S_0112-0119 operon instead. PMID- 28714260 TI - Abandoning ASD? A response to Waterhouse, London, and Gillberg. PMID- 28714258 TI - Renal neuroendocrine control of desiccation and cold tolerance by Drosophila suzukii. AB - BACKGROUND: Neuropeptides are central to the regulation of physiological and behavioural processes in insects, directly impacting cold and desiccation survival. However, little is known about the control mechanisms governing these responses in Drosophila suzukii. The close phylogenetic relationship of D. suzukii with Drosophila melanogaster allows, through genomic and functional studies, an insight into the mechanisms directing stress tolerance in D. suzukii. RESULTS: Capability (Capa), leucokinin (LK), diuretic hormone 44 (DH44 ) and DH31 neuropeptides demonstrated a high level of conservation between D. suzukii and D. melanogaster with respect to peptide sequences, neuronal expression, receptor localisation, and diuretic function in the Malpighian tubules. Despite D. suzukii's ability to populate cold environments, it proved sensitive to both cold and desiccation. Furthermore, in D. suzukii, Capa acts as a desiccation- and cold stress-responsive gene, while DH44 gene expression is increased only after desiccation exposure, and the LK gene after nonlethal cold stress recovery. CONCLUSION: This study provides a comparative investigation into stress tolerance mediation by neuroendocrine signalling in two Drosophila species, providing evidence that similar signalling pathways control fluid secretion in the Malpighian tubules. Identifying processes governing specific environmental stresses affecting D. suzukii could lead to the development of targeted integrated management strategies to control insect pest populations. (c) 2017 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry. PMID- 28714259 TI - Dopant-Free Hole-Transporting Materials for Stable and Efficient Perovskite Solar Cells. AB - Molecularly engineered novel dopant-free hole-transporting materials for perovskite solar cells (PSCs) combined with mixed-perovskite (FAPbI3 )0.85 (MAPbBr3 )0.15 (MA: CH3 NH3+ , FA: NH=CHNH3+ ) that exhibit an excellent power conversion efficiency of 18.9% under AM 1.5 conditions are investigated. The mobilities of FA-CN, and TPA-CN are determined to be 1.2 * 10-4 cm2 V-1 s-1 and 1.1 * 10-4 cm2 V-1 s-1 , respectively. Exceptional stability up to 500 h is measured with the PSC based on FA-CN. Additionally, it is found that the maximum power output collected after 1300 h remained 65% of its initial value. This opens up new avenue for efficient and stable PSCs exploring new materials as alternatives to Spiro-OMeTAD. PMID- 28714261 TI - The ASD diagnosis has blocked the discovery of valid biological variation in neurodevelopmental social impairment. PMID- 28714262 TI - Baroreflex-mediated sympathetic overactivation induced by mental stress in post traumatic stress disorder depends on the type of stressor. PMID- 28714263 TI - Enhancing methyl parathion degradation by the immobilization of Burkholderia sp. isolated from agricultural soils. AB - Organophosphate pesticides are of great interest for research because they are currently the most commonly used pesticides. In this study, a bacterial strain capable of completely degrading methyl parathion (MP) was isolated from agricultural soils in central Mexico. This strain was designated strain S5-2 and was identified as Burkholderia cenocepacia. To increase degradation yields, cells were immobilized on three different supports: powdered zeolite and Opuntia sp. and Agave sp. fibers. The results indicated a significant increase in MP hydrolysis and p-nitrophenol (PNP) degradation with immobilized cells compared to free cell cultures. Furthermore, immobilized cells were capable of withstanding and degrading higher concentrations of PNP compared to cell suspension cultures. The cell viability in the free cell cultures, as well as PNP degradation, was affected at concentrations greater than 25 mg/L. In contrast, cells immobilized on Opuntia sp. and Agave sp. fibers completely degraded PNP at concentrations of 100 mg/L. To verify that MP solution toxicity was decreased by B. cenocepacia strain S5-2 via pesticide degradation, we measured the acetylcholinesterase activity, both before and after treatment with bacteria. The results demonstrate that the activity of acetylcholinesterase was unaffected after MP degradation by bacteria. PMID- 28714264 TI - Response surface methodology based on central composite design accompanied by multivariate curve resolution to model gradient hydrophilic interaction liquid chromatography: Prediction of separation for five major opium alkaloids. AB - Hydrophilic interaction liquid chromatography on bare silica presents some benefits for analysis and purification of ionizable basic alkaloids. This mode was used to separate five major opium alkaloids: morphine, codeine, thebaine, papaverine, and noscapine. Central composite design based on response surface methodology was applied for experimental design, modeling, and optimization in a single-step gradient method. The main effects and their interactions (initial percentage of modifier, changing range of modifier in run time, pH of buffer, and its concentration) were investigated in 30 experiments. Multivariate curve resolution-alternating least squares, by resolving overlapped curves, helped in the accurate calculation of baseline resolution factors to be modeled and optimized more accurately. Then three crucial resolution factors besides elution time were modeled in quadratic and cubic equations and optimized. In addition to the four factors, five extra logarithmic, and nonlogarithmic factors extracted from the four factors to give nine factors overall were inspected on mechanism of retention. It was shown that a linear combination consist of four independence variables successfully describes morphinans retentivity in a single-step gradient method. PMID- 28714265 TI - Can malignant and inflammatory pleural effusions in dogs be distinguished using computed tomography? AB - Computed tomography (CT) is the primary imaging modality used to investigate human patients with suspected malignant or inflammatory pleural effusion, but there is a lack of information about the clinical use of this test in dogs. To identify CT signs that could be used to distinguish pleural malignant neoplasia from pleuritis, a retrospective case-control study was done based on dogs that had pleural effusion, pre- and postcontrast thoracic CT images, and cytological or histopathological diagnosis of malignant or inflammatory pleural effusion. There were 20 dogs with malignant pleural effusion (13 mesothelioma, 6 carcinoma; 1 lymphoma), and 32 dogs with pleuritis (18 pyothorax; 14 chylothorax). Compared to dogs with pleuritis, dogs with malignant pleural effusions were significantly older (median 8.5 years vs. 4.9 years, P = 0.001), more frequently had CT signs of pleural thickening (75% vs.44%, P = 0.04), tended to have thickening of the parietal pleura only (65% vs. 13%, P = 0.01) and had more marked pleural thickening (median 3 mm vs. 0 mm, P = 0.01). Computed tomography signs of thoracic wall invasion were observed only in dogs with malignant pleural effusions (P = 0.05). There were no significant differences in pleural fluid volume, distribution or attenuation, degree of pleural contrast accumulation, amount of pannus, or prevalence of mediastinal adenopathy. Although there was considerable overlap in findings in dogs with malignant pleural effusion and pleuritis, marked thickening affecting the parietal pleural alone and signs of thoracic wall invasion on CT support diagnosis of pleural malignant neoplasia, and may help prioritize further diagnostic testing. PMID- 28714266 TI - Potential biotechnological capabilities of cultivable mycobiota from carwash effluents. AB - Urban life has created man-made extreme environments like carwashes. These environments have, however, not been sufficiently explored for mycobiota that can be sources of biotechnologically useful products, as has been the case with natural extreme environments. Using a combination of culture and molecular techniques, fungi from carwash effluents was characterized for production of lipase and cellulase enzymes, nonpolar and polar biotechnologically relevant secondary metabolites and hydrocarbon utilization. The isolated fungal strains belonged to the genera Alternaria, Cladosporium, Penicillium, Peyronellaea, Rhizopus, Spegazzinia, Trichoderma, Ulocladium and Yarrowia. Sixty-six percent (66%) of the fungal isolates were found to be able to metabolize naphthalene and benzanthracene, showing potential for application in bioremediation of hydrocarbon polluted sites. Lipase production by the isolates Penicillium sp. BPS3 (2.61 U/ml), Trichoderma sp. BPS9 (2.01 U/ml), Rhizopus sp. CAL1 (2.05 U/ml), Penicillium sp. PCW1 (2.99 U/ml) and Penicillium sp. SAS1 (2.16 U/ml) compared well with previously recorded lipase production levels by other fungi. The highest producers of cellulase were Penicillium sp. SAS1 (12.10 U/ml), Peyronella sp. CAW5 (4.49 U/ml) and Cladosporium sp. SAS3 (4.07 U/ml), although these activities were lower than previously reported levels. GC-MS analysis of the fungal secondary metabolites resulted in identification of 572 compounds, including azulene, methanamine, N-pentylidene, metoclopramide, and mepivacaine while compounds determined by UHPLC-MS included 10-undecen-1-ol, piquerol A, 10 undecyn-1-ol, cyclo(leucylprolyl) and rac-etomidate. These compounds were previously determined to have various activities including anticancer, antibacterial, antifungal, antihypertensive, antidiabetic and anti-inflammatory properties. The study demonstrated that fungi from carwash effluents are natural sources of some biotechnologically important products. PMID- 28714267 TI - Pulmonary hypoplasia resulting from prolonged rupture of membranes: A distinct clinical entity with instructive experimental models. PMID- 28714268 TI - Nidotherapy in the successful management of comorbid depressive and personality disorder. AB - Nidotherapy is a new form of psychological therapy that aims to improve mental health by a systematic and collaborative manipulation of the environment in all its forms without focusing on alleviation of symptoms. Following treatment with nidotherapy, we describe a dramatic, and continuing, improvement in a woman with comorbid severe depressive illness and borderline personality disorder. She had made repeated serious suicide attempts over the previous 25 years and had received many drug and psychological treatments without success. The nidotherapy solution enabled her to leave home and achieve greater autonomy. Prior to this, she had been demeaned and undermined in her role as a family carer, and no health professionals had appreciated previously the restrictions it had placed on her health and well-being. Nidotherapy effected a smooth and orderly transition with family approval; the reasons for this seem to lie in the emotional neutrality of nidotherapy as a purely environmental intervention. Without this approach, we judge that separation from the family would not have been possible. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28714269 TI - Impermeable Robust Hydrogels via Hybrid Lamination. AB - Hydrogels have been proposed for sensing, drug delivery, and soft robotics applications, yet most of these materials suffer from low mechanical robustness and high permeability to small molecules, limiting their widespread use. This study reports a general strategy and versatile method to fabricate robust, highly stretchable, and impermeable hydrogel laminates via hybrid lamination of an elastomer layer bonded between hydrogel layers. By controlling the layers' composition and thickness, it is possible to tune the stiffness of the impermeable hydrogels without sacrificing the stretchability. These hydrogel laminates exhibit ultralow surface coefficients of friction and, unlike common single-material hydrogels, do not allow diffusion of various molecules across the structure due to the presence of the elastomer layer. This feature is then used to release different model drugs and, in a subsequent experiment, to sense different pH conditions on the two sides of the hydrogel laminate. A potential healthcare application is shown using the presented method to coat medical devices (catheter, tubing, and condom) with hydrogel, to allow for drug release and sensing of environmental conditions for gastrointestinal or urinary tract. PMID- 28714270 TI - Resistive breathing and respiratory muscle fatigue: a load of concern just expired! PMID- 28714271 TI - Influence of Residual Renal Function in Carotid Modeling as a Marker of Early Atherosclerosis in Dialysis Patients. AB - Atherosclerosis is frequently present in patients with chronic kidney disease (CKD) treated with dialysis. We evaluated the association between residual renal function (RRF), phosphate level, inflammation and other risk factors in carotid modeling as a marker of early atherosclerosis in peritoneal dialysis (PD) compared with hemodialysis (HD) patients. We studied 39 stable PD and 53 HD patients on renal replacement therapy (RRT) for 3 to 36 months duration. B-mode ultrasonography was used to determine carotid artery intima media thickness (CIMT). We classified patients with atherosclerosis if they have CIMT >10 mm and or presence of plaque. Out of our total dialysis population studied of 92 patients, 16.3% were diabetics and 57.6% were on hemodialysis. Expectedly, PD patients had a higher RRF (P < 0.001), 24 h urine volume (P < 0.001); C-reactive protein (P = 0.047), and a lower serum phosphate (P = 0.01), PTH (P < 0.05), alkaline phosphatase (P < 0.05), and albumin levels (P < 0.001) compared to hemodialysis patients. Atherosclerosis was found in 66.3% of patients and in 100% of a diabetic population. There was no significant difference in the presence of atherosclerosis between PD and HD patients [56.4 vs 73.6% HD, respectively]. Multiple regression analysis showed age, diabetes, HD modality, RRF, phosphate, PTH and pulse pressure as independent parameters associated with atherosclerosis. Apart from the traditional risk factors like age and diabetes, our study showed a link of atherosclerosis with metabolic abnormalities secondary to renal failure. We demonstrated a novel, independent association between RRF and atherosclerosis, underlining the importance of preservation of the RRF in dialysis patients. PMID- 28714272 TI - Fluorescence spectroscopy coupled with independent components analysis to monitor molecular changes during heating and cooling of Cantal-type cheeses with different NaCl and KCl contents. AB - BACKGROUND: Reduction of NaCl content of cheeses has received considerable attention by research during the past decades because of its health effects. Nonetheless, NaCl reduction is a challenge since it plays an important role in cheese quality, such as structure, texture and functional properties. Several methods were used to evaluate the effect of NaCl on these attributes. In this study, Cantal-type cheeses with different salts (NaCl and KCl) were analyzed for their structure at a molecular level and rheological properties during heating (20-60 degrees C) and cooling (60-20 degrees C). The structure was investigated by synchronous fluorescence spectroscopy (SFS) and the rheological properties by small-amplitude oscillatory test. RESULTS: Independent components analysis (ICA) gave three independent components that were attributed to coenzyme/Maillard reaction products (IC1), tryptophan (IC2) and vitamin A (IC3). Signal proportions of each IC depicted information regarding the changes in those fluorophores with salts, heating and cooling. In addition, canonical correlation analysis (CCA) of the IC proportions and rheological measurements related modifications at a molecular level evaluated by fluorescence to cheese texture (0.34 < R2 < 0.99). CONCLUSION: This study demonstrated that SFS can monitor and characterize modification of Cantal-type cheeses at a molecular level, based on the analysis of the fluorescence spectra by ICA. The nature of correlation between signal proportions and the rheological parameters depicted that rheological attributes of cheeses observed at the macroscopic level can be derived from fluorescence spectra. (c) 2017 Society of Chemical Industry. PMID- 28714273 TI - beta-Catenin regulation of farnesoid X receptor signaling and bile acid metabolism during murine cholestasis. AB - : Cholestatic liver diseases result from impaired bile flow and are characterized by inflammation, atypical ductular proliferation, and fibrosis. The Wnt/beta catenin pathway plays a role in bile duct development, yet its role in cholestatic injury remains indeterminate. Liver-specific beta-catenin knockout mice and wild-type littermates were subjected to cholestatic injury through bile duct ligation or short-term exposure to 3,5-diethoxycarbonyl-1,4-dihydrocollidine diet. Intriguingly, knockout mice exhibit a dramatic protection from liver injury, fibrosis, and atypical ductular proliferation, which coincides with significantly decreased total hepatic bile acids (BAs). This led to the discovery of a role for beta-catenin in regulating BA synthesis and transport through regulation of farnesoid X receptor (FXR) activation. We show that beta-catenin functions as both an inhibitor of nuclear translocation and a nuclear corepressor through formation of a physical complex with FXR. Loss of beta-catenin expedited FXR nuclear localization and FXR/retinoic X receptor alpha association, culminating in small heterodimer protein promoter occupancy and activation in response to BA or FXR agonist. Conversely, accumulation of beta-catenin sequesters FXR, thus inhibiting its activation. Finally, exogenous suppression of beta-catenin expression during cholestatic injury reduces beta-catenin/FXR complex activation of FXR to decrease total BA and alleviate hepatic injury. CONCLUSION: We have identified an FXR/beta-catenin interaction whose modulation through beta-catenin suppression promotes FXR activation and decreases hepatic BAs, which may provide unique therapeutic opportunities in cholestatic liver diseases. (Hepatology 2018;67:955-971). PMID- 28714274 TI - The relevance of the lymph node ratio as predictor of prognosis is higher in HPV negative than in HPV-positive oropharyngeal squamous cell carcinoma. AB - OBJECTIVES: Lymph node ratio (LNR) is an established predictor in different entities of carcinoma, including head and neck malignancies. In oropharyngeal squamous cell carcinoma (OPSCC), lymph node involvement differs between human papilloma virus (HPV)-positive and HPV-negative tumours. Herein, we evaluate the impact of HPV association on the concept of LNR. METHODS: 88 surgically treated patients were included in this retrospective chart review. HPV-positive and HPV negative OPSCC were evaluated for prediction of outcome by LNR separately. The endpoints were 5-year overall survival (OS) and recurrence-free survival (RFS). RESULTS: The OS of all patients was 60.1%. In univariate analysis, LNR was a significant predictor of overall survival rate (P=.008) in OPSCC independently of the HPV status, as well as extracapsular spread (ECS). T-classification was only a significant predictor in the univariate analysis in HPV-positive OPSCC carcinoma. However, in the multivariate analysis LNR remained predictor of prognosis in all OPSCC and in HPV-negative OPSCC. In patients with HPV-positive OPSCC, only T-classification reached significance to predict OS. CONCLUSION: Prognosis of primarily operated HPV-positive patients might be more dependent on the extent of primary tumour site, whereas prognosis of HPV-negative patients is based more on cervical metastatic spread, represented by LNR. PMID- 28714275 TI - Fucoidan-induced osteogenic differentiation promotes angiogenesis by inducing vascular endothelial growth factor secretion and accelerates bone repair. AB - Osteogenesis and angiogenesis, including cell-cell communication between blood vessel cells and bone cells, are essential for bone repair. Fucoidan is a chemical compound that has a variety of biological activities. It stimulates osteoblast differentiation in human mesenchymal stem cells (MSCs), which in turn induces angiogenesis. However, the mechanism by which this communication between osteoblasts and endothelial cells is mediated remains unclear. Thus, the aim of this study was to clarify the relationship between fucoidan-induced osteoblastic differentiation in MSCs and angiogenesis in endothelial cells. First, the effect was confirmed of fucoidan on osteoblast differentiation in MSCs and obtained conditioned media from these cells (Fucoidan-MSC-CM). Next, the angiogenic activity of Fucoidan-MSC-CM was investigated and it was found that it stimulated angiogenesis, demonstrated by proliferation, tube formation, migration and sprout capillary formation in human umbilical vein endothelial cells. Messenger ribonucleic acid expression and protein secretion of vascular endothelial growth factor (VEGF) were dramatically increased during fucoidan-induced osteoblast differentiation and that its angiogenic activities were reduced by a VEGF/VEGF receptor-specific binding inhibitor. Furthermore, Fucoidan-MSC-CM increased the phosphorylation of mitogen-activated protein kinase and PI3K/AKT/eNOS signalling pathway, and that its angiogenic effects were markedly suppressed by SB203580 and AKT 1/2 inhibitor. Finally, an in vivo study was conducted and it was found that fucoidan accelerated new blood vessel formation and partially promoted bone formation in a rabbit model of a calvarial bone defect. This is the first study to investigate the angiogenic effect of fucoidan-induced osteoblastic differentiation through VEGF secretion, suggesting the therapeutic potential of fucoidan for enhancing bone repair. PMID- 28714276 TI - Human platelet lysate supports the formation of robust human periodontal ligament cell sheets. AB - The use of stem cell-derived sheets has become increasingly common in a wide variety of biomedical applications. Although substantial evidence has demonstrated that human platelet lysate (PL) can be used for therapeutic cell expansion, either as a substitute for or as a supplement to xenogeneic fetal bovine serum (FBS), its impact on cell sheet production remains largely unexplored. In this study, we manufactured periodontal ligament stem cell (PDLSC) sheets in vitro by incubating PDLSCs in sheet-induction media supplemented with various ratios of PL and FBS, i.e. 10% PL without FBS, 7.5% PL + 2.5% FBS, 5% PL + 5% FBS, 2.5% PL + 7.5% FBS or 10% FBS without PL. Cultures with the addition of all the designed supplements led to successful cell sheet production. In addition, all the resultant cellular materials exhibited similar expression profiles of matrix-related genes and proteins, such as collagen I, fibronectin and integrin beta1. Interestingly, the cell components within sheets generated by media containing both PL and FBS exhibited improved osteogenic potential. Following in vivo transplantation, all sheets supported significant new bone formation. Our data suggest that robust PDLSC sheets can be produced by applying PL as either an alternative or an adjuvant to FBS. Further examination of the relevant influences of human PL that benefit cell behaviour and matrix production will pave the way towards optimized and standardized conditions for cell sheet production. PMID- 28714277 TI - Free fatty acid receptor 3 activation suppresses neurogenic motility in rat proximal colon. AB - BACKGROUND: Short-chain fatty acids (SCFA) are microbial fermentation products absorbed by the colon. We recently reported that activation of the SCFA receptor termed free fatty acid receptor 3 (FFA3), expressed on cholinergic nerves, suppresses nicotinic acetylcholine receptor (nAChR)-mediated transepithelial anion secretion. This study aimed to clarify how activation of neurally expressed FFA3 affects colonic motor function. METHODS: FFA3-expressing myenteric neurons were identified by immunostaining; contractions of isolated circular muscle strips obtained from rat proximal colon were measured by isometric transducers. The effect of FFA3 agonists on defecation in vivo was examined in an exogenous serotonin-induced defecation model. KEY RESULTS: FFA3 immunoreactivity was located in nitrergic and cholinergic neurons in the myenteric plexus. In isolated circular muscle strips without mucosa and submucosa, the addition of nicotine (10 MUM) or serotonin transiently relaxed the muscle through nitrergic neurons, whereas high concentrations of nicotine (100 MUM) induced large-amplitude contractions that were mediated by cholinergic neurons. Pretreatment with FFA3 agonists inhibited nicotine- or serotonin-induced motility changes but had no effect on bethanechol-induced direct muscle contractions. The Gi/o inhibitor pertussis toxin reversed the inhibitory effect of an FFA3 agonist AR420626 on nicotine-evoked contractions, suggesting that FFA3 activation suppresses nAChR mediated neural activity in myenteric neurons, consistent with an FFA3-mediated antisecretory effect. In conscious rats, exogenous serotonin increased the volume of fecal output, compared with the vehicle- or AR420626-treated groups. Pretreatment with AR420626 significantly suppressed serotonin-induced fecal output. CONCLUSION AND INFERENCES: FFA3 is a promising target for the treatment of neurogenic diarrheal disorders by suppressing nAChR-mediated neural pathways. PMID- 28714278 TI - Extension of the association structure in joint models to include weighted cumulative effects. AB - Motivated by a study measuring diabetes-related risk factors and complications, we postulate an extension to the standard formulation of joint models for longitudinal and survival outcomes, wherein the longitudinal outcome has a cumulative effect on the hazard of the event, weighted by recency. We focus on the relationship between the biomarker HbA1c and the development of sight threatening retinopathy, since the impact of the HbA1c marker on the risk of sight threatening retinopathy is expected to be cumulative, with the evolution of the HbA1c marker over time contributing to progressively greater damage to the vascular structure of the retina. Opting for a parametric approach, we propose the use of the normal and skewed normal probability density functions as weight functions, estimating the relevant parameters directly from the data. The use of the recency-weighted cumulative effect specification allows us to incorporate differences in the development of the longitudinal profile over time in the calculation of hazard ratios between subjects. The proposed functions provide us with parameters with clinically relevant interpretations while retaining a degree of flexibility. In addition, they also allow answering of important clinical questions regarding the relative importance of various segments of the biomarkers history in the estimation of the risk of the event. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28714280 TI - pH-Responsive Nanoscale Coordination Polymer for Efficient Drug Delivery and Real Time Release Monitoring. AB - Both excess dosages of drug and unwanted drug carrier can lead to severe side effects as well as the failure of tumor therapy. Here, an Fe3+ -gallic acid based drug delivery system is designed for efficient monitoring of drug release in tumor. Fe3+ and polyphenol gallic acid can form polygonal nanoscale coordination polymer in aqueous solution, which exhibits certain antitumor effect. Importantly, this coordination polymer possesses extremely high doxorubicin (DOX) loading efficacy (up to 48.3%). In vitro studies demonstrate that the fluorescence of DOX can be quenched efficiently when DOX is loaded on the coordination polymer. The acidity in lysosome also triggers the release of DOX and fluorescence recovery simultaneously, which realizes real-time monitoring of drug release in tumor cells. In vivo studies further indicate that this polyphenol-rich drug delivery system can significantly inhibit tumor growth with negligible heart toxicity of DOX. This system with minimal side effects should be a promising nanoplatform for tumor treatment. PMID- 28714281 TI - The ethics and politics of patient-physician mistrust in contemporary China. AB - Focusing on the shared sense of victimization and disadvantage-ness by both patients and doctors/medical workers in cases of medical conflicts, this paper aims to examine the current patient-doctor tensions in the larger context of moral transformation in Chinese society since the 1980s. Although the decline of public trust in certain aspects is closely associated with the impact of commodification and commercialization of medical sector during the past two decades, other factors play important role as well. In the case of patient-doctor tension, mutual disrespect and mistrust also result from the ongoing process of individualization and the remaking of moral self, in which the individual demand for respect, dignity, and trust seem to have unexpectedly and ironically contributed to the rise of tensions and conflicts between patients and doctors as well as other medical workers. PMID- 28714279 TI - Predicting IDH mutation status in grade II gliomas using amide proton transfer weighted (APTw) MRI. AB - PURPOSE: To assess the amide proton transfer-weighted (APTw) MRI features of isocitrate dehydrogenase (IDH)-wildtype and IDH-mutant grade II gliomas and to test the hypothesis that the APTw signal is a surrogate imaging marker for identifying IDH mutation status preoperatively. METHODS: Twenty-seven patients with pathologically confirmed low-grade glioma, who were previously scanned at 3T, were retrospectively analyzed. The Mann-Whitney test was used to evaluate relationships between APTw intensities for IDH-mutant and IDH-wildtype groups, and receiver operator characteristic (ROC) analysis was used to assess the diagnostic performance of APTw. RESULTS: Based on histopathology and molecular analysis, seven cases were diagnosed as IDH-wildtype grade II gliomas and 20 cases as IDH-mutant grade II gliomas. The maximum and minimum APTw values, based on multiple regions of interest, as well as the whole-tumor histogram-based mean and 50th percentile APTw values, were significantly higher in the IDH-wildtype gliomas than in the IDH-mutant groups. This corresponded to the areas under the ROC curves of 0.89, 0.76, 0.75, and 0.75, respectively, for the prediction of the IDH mutation status. CONCLUSION: IDH-wildtype lesions typically were associated with relatively high APTw signal intensities as compared with IDH-mutant lesions. The APTw signal could be a valuable imaging biomarker by which to identify IDH1 mutation status in grade II gliomas. Magn Reson Med 78:1100-1109, 2017. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28714282 TI - Variability of 4D flow parameters when subjected to changes in MRI acquisition parameters using a realistic thoracic aortic phantom. AB - PURPOSE: To assess the variability of peak flow, mean velocity, stroke volume, and wall shear stress measurements derived from 3D cine phase contrast (4D flow) sequences under different conditions of spatial and temporal resolutions. METHODS: We performed controlled experiments using a thoracic aortic phantom. The phantom was connected to a pulsatile flow pump, which simulated nine physiological conditions. For each condition, 4D flow data were acquired with different spatial and temporal resolutions. The 2D cine phase contrast and 4D flow data with the highest available spatio-temporal resolution were considered as a reference for comparison purposes. RESULTS: When comparing 4D flow acquisitions (spatial and temporal resolution of 2.0 * 2.0 * 2.0 mm3 and 40 ms, respectively) with 2D phase-contrast flow acquisitions, the underestimation of peak flow, mean velocity, and stroke volume were 10.5, 10 and 5%, respectively. However, the calculated wall shear stress showed an underestimation larger than 70% for the former acquisition, with respect to 4D flow, with spatial and temporal resolution of 1.0 * 1.0 * 1.0 mm3 and 20 ms, respectively. CONCLUSIONS: Peak flow, mean velocity, and stroke volume from 4D flow data are more sensitive to changes of temporal than spatial resolution, as opposed to wall shear stress, which is more sensitive to changes in spatial resolution. Magn Reson Med 79:1882 1892, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28714283 TI - Association between maternal social capital and infant complementary feeding practices in rural Ethiopia. AB - Few studies have explored the potential of social capital in improving child nutritional status; however, most components of pathways between social capital and nutritional status have remained unexplained. Complementary feeding practice is a strong mediator of child nutritional status. This study examined the association between complementary feeding practice and maternal social capital in rural Ethiopia, using cross-sectional data of infant aged 6-12 months and their mother pairs (n = 870). The Short Social Capital Assessment Tool was used to assess maternal structural (i.e., community group membership, having emotional/economic support from individuals, and citizenship activities) and cognitive social capital (i.e., trust, social harmony, and sense of belonging) in the past 12 months. Infant's dietary diversity score (DDS, range: 0-7), minimum dietary diversity (MDD), and minimum meal frequency (MMF) were assessed using a 24-hr dietary recall. Multivariable ordinal/binary logistic regression analyses were conducted. Having support from two or more individuals was associated with higher DDS (OR = 1.84) and meeting a minimum level of dietary diversity (MDD: OR = 5.20) but not with MMF, compared to those having no support. Having two or more group memberships was associated with higher DDS (OR = 2.2) but not with MDD or MMF, compared to those without group membership. Citizenship activities showed mixed associations with MMF and no association with DDS or MDD. Cognitive social capital showed no association with DDS or MDD and lower odds of meeting MMF (OR = 0.56). These mixed results call for further studies to examine other potential pathways (e.g., hygiene and caring behaviours) in which social capital could improve child nutritional status. PMID- 28714285 TI - Dynamic Cooperation of Hydrogen Binding and pi Stacking in ssDNA Adsorption on Graphene Oxide. AB - Functional nanoscale structures consisting of a DNA molecule coupled to graphene or graphene oxide (GO) have great potential for applications in biosensors, biomedicine, nanotechnology, and materials science. Extensive studies using the most sophisticated experimental techniques and theoretical methods have still not clarified the dynamic process of single-stranded DNA (ssDNA) adsorbed on GO surfaces. Based on a molecular dynamics simulation, this work shows that an ssDNA segment could be stably adsorbed on a GO surface through hydrogen bonding and pi pi stacking interactions, with preferential binding to the oxidized rather than to the unoxidized region of the GO surface. The adsorption process shows a dynamic cooperation adsorption behavior; the ssDNA segment first captures the oxidized groups of the GO surface by hydrogen bonding interaction, and then the configuration relaxes to maximize the pi-pi stacking interactions between the aromatic rings of the nucleobases and those of the GO surface. We attributed this behavior to the faster forming hydrogen bonding interaction compared to pi-pi stacking; the pi-pi stacking interaction needs more relaxation time to regulate the configuration of the ssDNA segment to fit the aromatic rings on the GO surface. PMID- 28714284 TI - Egg Albumen as a Fast and Strong Medical Adhesive Glue. AB - Sutures penetrate tissues to close wounds. This process leads to inflammatory responses, prolongs healing time, and increases operation complexity. It becomes even worse when sutures are applied to stress-sensitive and fragile tissues. By bonding tissues via forming covalent bonds, some medical adhesives are not convenient to be used by surgeons and have side effects to the tissues. Here egg albumen adhesive (EAA) is reported with ultrahigh adhesive strength to bond various types of materials and can be easily used without any chemical and physical modifications. Compared with several commercial medical glues, EAA exhibits stronger adhesive property on porcine skin, glass, polydimethylsiloxane. The EAA also shows exceptional underwater adhesive strength. Finally, wound closure using EAA on poly(caprolactone) nanofibrous sheet and general sutures is investigated and compared in a rat wound model. EAA also does not show strong long-term inflammatory response, suggesting that EAA has potential as a medical glue, considering its abundant source, simple fabrication process, inherent nontoxicity, and low cost. PMID- 28714286 TI - Mosquitoes can harbour yeasts of clinical significance and contribute to their environmental dissemination. AB - There is still a lack of studies on fungal microbiota in mosquitoes, compared with the number available on bacterial microbiota. This study reports the identification of yeasts of clinical significance in laboratory mosquito species: Anopheles gambiae, Anopheles stephensi, Culex quinquefasciatus, Aedes albopictus and Aedes aegypti. Among the yeasts isolated, they focused on the opportunistic pathogen Candida parapsilosis, since there is a need to better understand breakthrough candidaemia with resistance to the usual antifungals, which requires careful consideration in the broad-spectrum therapy, as documented in many clinical reports. C. parapsilosis occurs widely and has been isolated from diverse sources, including insects, which may contribute to its dissemination. In this study, it was isolated from the gut of An. gambiae and its presence in developmental stages and organs of different mosquito species was studied. Our results indicated that there was a stable association between C. parapsilosis and reared mosquitoes during the entire life cycle, and in adult male and female gut and gonads. A wide occurrence of C. parapsilosis was also documented in several populations of wild mosquitoes. Based on these findings, it can be said that mosquitoes might participate in the spreading of this opportunistic pathogen, not only as a carrier. PMID- 28714287 TI - Bacteremia Prediction Model for Community-acquired Pneumonia: External Validation in a Multicenter Retrospective Cohort. AB - OBJECTIVE: Many studies have described constructing a prediction model for bacteremia in community-acquired pneumonia (CAP), but these studies were not validated in external heterogeneous groups. The objective of this study was to test the generalizability of a previous bacteremia prediction model for CAP by external validation. METHODS: This multicenter retrospective cohort analysis was performed in eight tertiary urban hospital emergency departments (EDs). We reviewed adult patients who were hospitalized after presentation to the ED with CAP. We categorized the enrolled patients into three groups according to the bacteremia prediction model score and calculated the number of patients with or without a blood culture-positive result. We performed a multivariable analysis to identify significant predictors for bacteremia. RESULTS: Among the enrolled 2,001 patients, 1,592 (79.6%), 371 (18.5%), and 38 (1.9%) were stratified to a low-, moderate-, and high-risk group, respectively, and this proportion was similar with previous study. Each group had a bacteremia-positive rate as follows: 1.2% for the low-risk group, 7.2% for the moderate-risk group, and 31.5% for the high risk group. The area under the receiver operating characteristic curve for the bacteremia model in the external validation cohort was 0.81, and there was no significant difference with that of the previous internal validation cohort (p = 0.246). Assuming that blood cultures were not performed in the low-risk patients, the sensitivity and specificity of this model were 0.68 and 0.81, respectively. Additionally, the positive predictive value and negative predictive value were 9.54 and 98.87%, respectively. A platelet count less than 130 * 109 cells/L, albumin less than 3.3 mg/dL, and C-reactive protein greater than 17 mg/dL were identified as significant predictors with a sensitivity and specificity of 0.70 and 0.83, respectively. CONCLUSION: The bacteremia prediction model was well validated in the general population and could help physicians make the decision to reduce the number of blood cultures in patients with CAP. PMID- 28714288 TI - Tolterodine treatment of women with overactive bladder syndrome: Comparison of night-time and daytime dosing for nocturia. AB - AIM: We aimed to clarify the impact of night-time dosing with tolterodine extended release (ER) on nocturia. METHODS: The bladder diaries, urodynamic studies, and medical records of female patients with overactive bladder syndrome who were diagnosed between January 2005 and December 2015, and treated with tolterodine ER 4 mg once per day (night-time or daytime dosing) for 12 weeks in the urogynecology outpatient clinics of two tertiary referral centers were reviewed retrospectively. RESULTS: A total of 72 female patients were reviewed. Thirty-six patients were in the daytime dosing group, and the other 36 patients were in the night-time dosing group. In the daytime dosing group, a decrease in the volume of fluid intake was found at 06.00-12.00, 12.00-18.00, and 18.00-24.00 hours, and a decrease in total voided volume was found at 12.00-18.00, 18.00 24.00, and 24.00-06.00 hours with a between-group difference at 18.00-24.00 hours (coefficient = 542 mL, P = 0.01). In the night-time dosing group, an increase in voided volume per micturition was found at 06.00-12.00 and 24.00-06.00 hours with a between-group difference at 24.00-6.00 hours (coefficient = 92 mL, P = 0.003) compared with the daytime dosing group. Nonetheless, pre-treatment proportions of nocturnal polyuria did not differ from post-treatment proportions (night-time: 20% vs 20%, P = 1.00; daytime: 48% vs 42%, P = 0.48). Decreases in the number of voiding and urgency episodes at nearly all time periods and increases in the volumes at strong desire to void were also found in both groups. CONCLUSION: Night-time dosing of tolterodine ER may benefit female patients suffering from nocturia due to a greater voided volume per micturition at midnight. PMID- 28714290 TI - In Vitro and In Vivo Characterization of Biodegradable Reactive Isocyanate Terminated Three-Armed- and Hyperbranched Block Copolymeric Tissue Adhesives. AB - Tissue adhesives are an attractive class of biomaterials, which can serve as a treatment for meniscus tears. In this study, physicochemical and adhesive properties of novel biodegradable three-armed- and hyperbranched block copolymeric adhesives are evaluated. Additionally, their degradation in vitro and in vivo, and the tissue reaction after subcutaneous injection in rats are assessed. The developed adhesives have sufficient adhesive strength to meniscus tissue after curing (66-88 kPa). Networks based on the three-armed adhesive have tensile properties that are in the same range as human meniscus. After 26 weeks, networks based on the hyperbranched adhesive show a faster mass loss (25.4%) compared to networks prepared from the three-armed ones (5.5%). Both adhesives induce an inflammatory reaction, however, no necrosis and only initial toxic effects on peripheral tissues are observed. The proposed materials are suitable candidates for the use as resorbable tissue adhesives for meniscus repair. PMID- 28714291 TI - Mechanism of midline defect-causing mutation P151L in MID1 revealed. AB - The P151L mutation in the B-box1 domain of MID1 causes midline defects in X linked Opitz G Syndrome. MID1 is known to be a key regulator of phosphatase PP2A through formation of a complex with its catalytic (PP2Ac) and regulatory (alpha4) subunits. Wright et al. show that this mutation retains B-box1 domain structure and E3 ligase activity (star) but blocks interaction with alpha4, indicating disruption of the MID1-alpha4-PP2Ac complex. PMID- 28714294 TI - Fungal nanoscale metal carbonates and production of electrochemical materials. AB - Fungal biomineralization of carbonates results in metal removal from solution or immobilization within a solid matrix. Such a system provides a promising method for removal of toxic or valuable metals from solution, such as Co, Ni, and La, with some carbonates being of nanoscale dimensions. A fungal Mn carbonate biomineralization process can be applied for the synthesis of novel electrochemical materials. PMID- 28714295 TI - One-Step Cationic Grafting of 4-Hydroxy-TEMPO and its Application in a Hybrid Redox Flow Battery with a Crosslinked PBI Membrane. AB - By using a one-step epoxide ring-opening reaction between 4-hydroxy-2,2,6,6 tetramethylpiperidine 1-oxyl (4-hydroxy-TEMPO) and glycidyltrimethylammonium cation (GTMA+ ), we synthesized a cation-grafted TEMPO (g+ -TEMPO) and studied its electrochemical performance against a Zn2+ /Zn anode in a hybrid redox flow battery. To conduct Cl- counter anions, a crosslinked methylated polybenzimidazole (PBI) membrane was prepared and placed between the catholyte and anolyte. Compared to 4-hydroxy-TEMPO, the positively charged g+ - TEMPO exhibits enhanced reaction kinetics. Moreover, flow battery tests with g+ -TEMPO show improved Coulombic, voltage, and energy efficiencies and cycling stability over 140 cycles. Crossover of active species through the membrane was not detected. PMID- 28714296 TI - 68 Ga-somatostatin analogue PET-CT: Analysis of costs and benefits in a public hospital setting. AB - INTRODUCTION: Between 2009 and 2012, 68 Ga-somatostatin analogue PET-CT progressively replaced 111 In-octreotide scintigraphy for imaging neuroendocrine tumours in WA public hospitals due to published literature demonstrating improved diagnostic accuracy and increased availability. Despite significantly improved sensitivity and specificity, 68 Ga-somatostatin analogue PET is currently unfunded in Australia. This study sought to undertake cost analysis of the two modalities in a public hospital setting and to compare them with regard to patient factors such as imaging time and radiation dose. METHODS: This analysis was based on retrospective clinical data from 95 111 In-octreotide scintigraphies performed in 2007 and 2008 at Sir Charles Gairdner (SCGH) and Royal Perth (RPH) hospitals and 219 68 Ga-somatostatin analogue PET-CT studies performed in 2013 at SCGH. Whole body effective radiation dose was derived from the radiopharmaceutical and low-dose CT scan. The cost analysis included radiopharmaceutical and imaging costs. RESULTS: The median imaging time for an 111 In-octreotide scintigraphy was 152 min at SCGH, 100 min at RPH and 20 min for a 68 Ga-somatostatin analogue PET-CT scan. The mean effective radiation dose for 111 In-octreotide scintigraphy was 18.1 mSv at SCGH and 13.8 mSv at RPH. The effective dose for 68 Ga-somatostatin analogue PET-CT was 8.7-10.8 mSv. The average cost of 68 Ga-somatostatin analogue PET-CT was four times less than 111 In-octreotide scintigraphy. CONCLUSION: 68 Ga-somatostatin analogue PET-CT is not only more accurate than 111 In-octreotide scintigraphy, this study has also shown that it is significantly less expensive, delivers a lower radiation dose to patients and requires less imaging time for patients and staff. 68 Ga somatostatin PET-CT provides an important combination of both reduced cost and improved clinical care for patients. PMID- 28714297 TI - Inter and intra-rater reliability and minimal detectable difference of Movement Disorder-Childhood Rating Scale. AB - BACKGROUND: Movement Disorder-Childhood Rating Scales (MD-CRS) have been designed in two forms (0-3 and 4-18 years) to accurately evaluate various movement disorders in children. AIM: The aim of this study is to evaluate the MD-CRS reliability when used by clinicians and professionals of rehabilitation after a one-day training on scoring it. DESIGN: This is a measurement-focused study of video-recorded sessions. SETTING: Video session carried out inpatient and outpatient. POPULATION: Children with different types of movement disorders. METHODS: After brief training in scoring MD-CRS, five health professionals (a resident doctor, a child neurologist and three physical therapists) independently scored 40 patient videotapes, of children with movement disorders for inter-rater reliability. In addition, the resident doctor scored 80 videos of 40 patients evaluated twice for intra-rater reliability. Reliability was assessed by Intraclass Correlation Coefficient (ICC) and was calculated separately for the two forms of the scale and for each score (Index I, Index II and Global Index). Standard Error of Measurement (SEM) and Minimal Detectable Difference (MDD) were also calculated. RESULTS: For both forms, inter-rater reliability of Global Index and Index I were good with an ICC ranged between 0.83 and 0.95. Instead, results of Index II were substantially moderate for both forms, with an ICC of 0.53 and 0.57, respectively. Intra-rater reliability for all Indexes in both forms was substantial or almost perfect, with values of ICCs ranging from 0.74 to 0.99. MDD values were between 0.05 and 0.17. CONCLUSIONS: MD-CRS 0-3 and MD-CRS 4-18 remain reliable clinical measurement tools for evaluation of movement disorders in developmental age when used by clinicians and professionals of rehabilitation after a specific short training. CLINICAL REHABILITATION IMPACT: MD-CRS 0-3 and MD-CRS 4-18 appear to be a promising outcome measurement tool in large scale studies with children and adolescents affected by various movement disorders either to verify natural history of the disorder or to plan pharmacological and/or surgical intervention programs. PMID- 28714298 TI - Effect of sugammadex on coagulation as detected by rotational thromboelastometry in morbidly obese patients. AB - BACKGROUND: Sugammadex, which is used to reverse rocuronium-induced neuromuscular blockade, has a limited and transient effect on activated partial thromboplastin time and prothrombin time. However, no data are available on the effects of sugammadex on coagulation in morbidly obese patients, as assessed by rotational thromboelastometry (ROTEM(r)). METHODS: Sixty patients received sugammadex 2 mg/kg or 4 mg/kg to reverse moderate or deep rocuronium-induced neuromuscular blockade (N.=30/group) at the end of surgery under desflurane anesthesia. Arterial blood samples were collected before and 3 min and 30 min after sugammadex administration for ROTEM(r) analysis, including measurements of clotting time (CT), clot formation time, alpha angle, and maximum clot firmness in INTEM, EXTEM, and FIBTEM assays. Major and minor bleeding events were also monitored during the postoperative period. RESULTS: Sugammadex 2 and 4 mg/kg has a limited and transient (<30 min) effect on INTEM CTs of 7.7% (P=0.04) and 10.7% (P<0.0001), respectively. There were no relevant effects on other ROTEM(r) parameters. A multivariate analysis indicated a significant effect of total sugammadex dose (<250, 250-500, >500 mg) on the INTEM CT (P=0.002). A regression analysis showed a positive relationship between sugammadex dose and INTEM CT value at 3 min after administration (coefficient = 0.052 s; 95% CI: 0.005-0.098 s; P=0.03). No major or minor bleeding events were observed in either group during the postoperative period. CONCLUSIONS: Sugammadex produces a slight effect on coagulation in morbidly obese patients, without increasing the risk for postoperative bleeding. PMID- 28714299 TI - New serum markers for detection of early hepatocellular carcinoma. PMID- 28714300 TI - Anchoring Ultrafine ZnFe2O4/C Nanoparticles on 3D ZnFe2O4 Nanoflakes for Boosting Cycle Stability and Energy Density of Flexible Asymmetric Supercapacitor. AB - Heterostructure-based metal oxide thin films are recognized as the leading material for new generation, high-performance, stable, and flexible supercapacitors. However, morphologies, like nanoflakes, nanotubes, nanorods, and so forth, have been found to suffer from issues related to poor cycle stability and energy density. Thus, to circumvent these problems, herein, we have developed a low-cost, high surface area, and environmentally benign self-assembled ZnFe2O4 nanoflake@ZnFe2O4/C nanoparticle heterostructure electrode via anchoring ZnFe2O4 and carbon nanoparticles using an in situ biomediated green rotational chemical bath deposition approach for the first time. The synthesized ZnFe2O4 nanoflake@ZnFe2O4/C nanoparticle heterostructure thin films demonstrate an excellent specific capacitance of 1884 F g-1 at a current density of 5 mA cm-2. Additionally, all solid-state flexible asymmetric supercapacitor devices were designed on the basis of ZnFe2O4 nanoflake@ZnFe2O4/C nanoparticle heterostructures as the negative electrode and reduced graphene oxide and energy density of 81 Wh kg-1 at a power density of 3.9 kW kg-1. Similarly, the asymmetric device exhibits ultralong cycle stability of 35 000 cycles by losing only 2% capacitance. The excellent performance of the device is attributed to the self-assembled organization of the heterostructures. Moreover, the in situ biomediated green strategy is also applicable for the synthesis of other metal oxide and carbon-based heterostructure electrodes. PMID- 28714301 TI - Assessing Fukushima-Derived Radiocesium in Migratory Pacific Predators. AB - The 2011 release of Fukushima-derived radionuclides into the Pacific Ocean made migratory sharks, teleosts, and marine mammals a source of speculation and anxiety regarding radiocesium (134+137Cs) contamination, despite a lack of actual radiocesium measurements for these taxa. We measured radiocesium in a diverse suite of large predators from the North Pacific Ocean and report no detectable (i.e., >= 0.1 Bq kg-1 dry wt) Fukushima-derived 134Cs in all samples, except in one olive ridley sea turtle (Lepidochelys olivacea) with trace levels (0.1 Bq kg 1). Levels of 137Cs varied within and across taxa, but were generally consistent with pre-Fukushima levels and were lower than naturally occurring 40K by one to one to two orders of magnitude. Predator size had a weaker effect on 137Cs and 40K levels than tissue lipid content. Predator stable isotope values (delta13C and delta15N) were used to infer recent migration patterns, and showed that predators in the central, eastern, and western Pacific should not be assumed to accumulate detectable levels of radiocesium a priori. Nondetection of 134Cs and low levels of 137Cs in diverse marine megafauna far from Fukushima confirms negligible increases in radiocesium, with levels comparable to those prior to the release from Fukushima. Reported levels can inform recently developed models of cesium transport and bioaccumulation in marine species. PMID- 28714302 TI - A Small Push-Pull Fluorophore for Turn-on Fluorescence. AB - A new class of push-pull dyes is reported based on the structures of benzoxa- and benzothiadiazole heterocycles. This new class of dyes displays red-shifted wavelengths of emission and greater sensitivity to polarity and hydrogen bonding solvents relative to previously known derivatives. PMID- 28714303 TI - Melittin-Containing Hybrid Peptide Hydrogels for Enhanced Photothermal Therapy of Glioblastoma. AB - The design of biocompatible and efficacious anticancer biomaterials to achieve relatively low tumor recurrence rates is the main pursuit of cancer photothermal therapy (PTT). RADA16-I is a synthetic amphiphilic peptide with the sequence RADARADARADARADA that can self-assemble into a peptide nanofiber hydrogel. In this study, we synthesized a novel melittin-RADA32-indocyanine green (ICG) hydrogel ("MRI hydrogel"), which contains melittin in the peptide hydrogel backbone and ICG in the hydrogel matrix, for enhanced PTT of glioblastomas. The MRI hydrogel exhibited physiologic characteristics similar to those of the RADA16 hydrogel, while displaying concentration-dependent cytotoxicity to C6 glioma cells and photothermal effects. The in vivo biodistribution of the MRI hydrogel was visualized by near-infrared fluorescence and photoacoustic imaging. More importantly, in vivo PTT provided by the MRI hydrogel significantly reduced the tumor size and the tumor recurrence rate compared with the RADR16-ICG hydrogel and other controls, suggesting a synergistic effect of MRI hydrogel-carried melittin and ICG-based PTT treatment. Thus, MRI provides an alternative tool for the safe and efficient PTT treatment of tumors. PMID- 28714304 TI - Enhanced Thermochemical Stability of CH3NH3PbI3 Perovskite Films on Zinc Oxides via New Precursors and Surface Engineering. AB - Hydroxyl groups on the surface of ZnO films lead to the chemical decomposition of CH3NH3PbI3 perovskite films during thermal annealing, which limits the application of ZnO as a facile electron-transporting layer (ETL) in perovskite solar cells. In this work, we report a new recipe that leads to substantially reduced hydroxyl groups on the surface of the resulting ZnO films by employing polyethylenimine (PEI) to replace generally used ethanolamine in the precursor solutions. Films derived from the PEI-containing precursors are denoted as P-ZnO and those from the ethanolamine-containing precursors as E-ZnO. Besides the fewer hydroxyl groups that alleviate the thermochemical decomposition of CH3NH3PbI3 perovskite films, P-ZnO also provides a template for the fixation of fullerene ([6,6]-phenyl-C61-butyric acid methyl ester, PCBM) owing to its nitrogen-rich surface that can interact with PCBM. The fullerene was used to block the direct contact between P-ZnO and CH3NH3PbI3 films and therefore further enhance the thermochemical stability of perovskite films. As a result, perovskite solar cells based on the P-ZnO/PCBM ETL yield an optimal power conversion efficiency (PCE) of 15.38%. We also adopt P-ZnO as the ETL for organic solar cells that yield a remarkable PCE of 10.5% based on the PBDB-T:ITIC photoactive layer. PMID- 28714305 TI - SPME-Based Ca-History Method for Measuring SVOC Diffusion Coefficients in Clothing Material. AB - Clothes play an important role in dermal exposure to indoor semivolatile organic compounds (SVOCs). The diffusion coefficient of SVOCs in clothing material (Dm) is essential for estimating SVOC sorption by clothing material and subsequent dermal exposure to SVOCs. However, few studies have reported the measured Dm for clothing materials. In this paper, we present the solid-phase microextraction (SPME) based Ca-history method. To the best of our knowledge, this is the first try to measure Dm with known relative standard deviation (RSD). A thin sealed chamber is formed by a circular ring and two pieces of flat SVOC source materials that are tightly covered by the targeted clothing materials. Dm is obtained by applying an SVOC mass transfer model in the chamber to the history of gas-phase SVOC concentrations (Ca) in the chamber measured by SPME. Dm's of three SVOCs, di iso-butyl phthalate (DiBP), di-n-butyl phthalate (DnBP), and tris(1-chloro-2 propyl) phosphate (TCPP), in a cotton T-shirt can be obtained within 16 days, with RSD less than 3%. This study should prove useful for measuring SVOC Dm in various sink materials. Further studies are expected to facilitate application of this method and investigate the effects of temperature, relative humidity, and clothing material on Dm. PMID- 28714306 TI - Meta-analysis and Harmonization of Life Cycle Assessment Studies for Algae Biofuels. AB - Algae biodiesel (BioD) and renewable diesel (RD) have been recognized as potential solutions to mitigating fossil-fuel consumption and the associated environmental issues. Life cycle assessment (LCA) has been used by many researchers to evaluate the potential environmental impacts of these algae derived fuels, yielding a wide range of results and, in some cases, even differing on indicating whether these fuels are preferred to petroleum-derived fuels or not. This meta-analysis reviews the methodological preferences and results for energy consumption, greenhouse gas emissions, and water consumption for 54 LCA studies that considered algae BioD and RD. The significant variation in reported results can be primarily attributed to the difference in scope, assumptions, and data sources. To minimize the variation in life cycle inventory calculations, a harmonized inventory data set including both nominal and uncertainty data is calculated for each stage of the algae-derived fuel life cycle. PMID- 28714307 TI - Biscysteine-Bearing Peptide Probes To Reveal Extracellular Thiol-Disulfide Exchange Reactions Promoting Cellular Uptake. AB - In recent years, delivery systems based on the incorporation of thiols/disulfides have been extensively explored to promote the intracellular delivery of biological cargoes. However, it remains unclear about the detailed processes of thiol-disulfide exchanges taking place on the cell surface and how the exchange reactions promote the cellular uptake of cargoes bearing thiols or disulfide bonds. In this work, we report the rational design of biscysteine motif containing peptide probes with substantially different ring-closing property and how these peptide probes were employed to explore the thiol-disulfide exchanges on the cell surface. Our results show that extensive thiol-disulfide exchanges between peptides and exofacial protein thiols/disulfides are involved in the cellular uptake of these peptide probes, and importantly glutathione (GSH) exported from the cytosols participates extensively in the exchange reactions. Cysteine-glycine-cysteine (CGC)-containing peptide probes can be more efficiently taken up by cells compared to other probes, and we suggested that the driving force for the superior cellular uptake arises from very likely the unique propensity of the CGC motif in forming doubly bridged disulfide bonds with exofacial proteins. Our probe-based strategy provides firsthand information on the detailed processes of the exchange reactions, which would be of great benefit to the development of delivery systems based on the extracellular thiol-disulfide exchanges for intracellular delivery of biologics. PMID- 28714308 TI - Supersensitive Oxidation-Responsive Biodegradable PEG Hydrogels for Glucose Triggered Insulin Delivery. AB - Reactive oxygen species (ROS)-responsive polymers and hydrogels represent an emerging family of intelligent materials owing to the key functions of ROS in physiological processes or pathological diseases. Nonetheless, the weaknesses such as low sensitivity, slow response, instability, and low mechanical strength are associated with the limited ROS-responsive polymeric or supramolecular hydrogels. In this study, a novel type of oxidation-responsive degradable hydrogels was fabricated by the redox-initiated radical polymerization of a 4-arm poly(ethylene glycol) (PEG) acrylic macromonomer that possesses a H2O2-cleavable phenylboronic acid linker in each of the arms. The macroscopic hydrogels have the features of good cytocompatibility, moderate mechanical strength, and fast response toward H2O2 of low concentration, owing to the covalently cross-linked hydrophilic PEG network and high sensitivity of the linker. They could encapsulate biomacromolecules, such as insulin and glucose oxidase (GOx), with high efficacy, affording a new glucose-responsive insulin-delivery platform on the basis of enzymatic transformation of a biochemical signal (glucose) into an oxidative stimulus (H2O2). Interestingly, in vitro results demonstrate that the same GOx-loaded hydrogel exhibited disparate degradation modes under different triggering molecules, that is, bulk degradation by H2O2 and surface erosion by glucose. Moreover, compared to the macroscopic hydrogel, the nanogel with a diameter of ~160 nm prepared by inverse emulsion polymerization showed a much higher degradation rate even under triggering of 20 MUM H2O2, a pathologically available concentration in vivo. PMID- 28714309 TI - Characterization of Blebbistatin Inhibition of Smooth Muscle Myosin and Nonmuscle Myosin-2. AB - Blebbistatin is a potent and specific inhibitor of the motor functions of class II myosins, including striated muscle myosin and nonmuscle myosin-2 (NM2). However, the blebbistatin inhibition of NM2c has not been assessed and remains controversial with respect to its efficacy with smooth muscle myosin (SmM), which is highly homologous to NM2. To clarify these issues, we analyzed the effects of blebbistatin on the motor activities of recombinant SmM and three NM2s (NM2a, 2b, and -2c). We found that blebbistatin potently inhibits the actin-activated ATPase activities of SmM and NM2s with following IC50 values: 6.47 MUM for SmM, 3.58 MUM for NM2a, 2.30 MUM for NM2b, and 1.57 MUM for NM2c. To identify the blebbistatin-resistant myosin-2 mutant, we performed mutagenesis analysis of the conserved residues in the blebbistatin-binding site of SmM and NM2s. We found that the A456F mutation renders SmM and NM2s resistant to blebbistatin without greatly altering their motor activities or phosphorylation-dependent regulation, making A456F a useful mutant for investigating the cellular function of NM2s. PMID- 28714310 TI - High-Yielding Syntheses of Crown Ether-Based Pyridyl Cryptands. AB - Pyridinium bis(trifluoromethylsulfonyl)imide (PyTFSI)-templated syntheses of 2,6 pyridyl cryptands of cis(4,4')-dibenzo-30-crown-10 (3a), the p-bromobenzyloxy derivative 3b, bis(m-phenylene)-32-crown-10 (5), cis(4,4')-dibenzo-27S-crown-9 (7), cis(4,4')-dibenzo-27L-crown-9 (9), and cis(4,4')-dibenzo-24-crown-8 (11) are reported. Here we provide a fast (12 h), high-yielding (89%, 74%, 80%, and 62% for 3a, 3b, 5, and 9, respectively) templation method without the use of a syringe pump. The yields for 7 (19%) and 11 (26%) were lower than with the previous pseudo-high-dilution method, indicating ineffective templation in these cases. Coupled with our previously developed templated syntheses of dibenzo crown ethers, this protocol makes powerful cryptand hosts readily available in gram quantities in good yields from methyl 4(or 3)-hydroxy-3(or 4)-benzyloxybenzoate. PMID- 28714311 TI - Localized Liquid-Phase Synthesis of Porous SnO2 Nanotubes on MEMS Platform for Low-Power, High Performance Gas Sensors. AB - We have developed highly sensitive, low-power gas sensors through the novel integration method of porous SnO2 nanotubes (NTs) on a micro-electro-mechanical systems (MEMS) platform. As a template material, ZnO nanowires (NWs) were directly synthesized on beam-shaped, suspended microheaters through an in situ localized hydrothermal reaction induced by local thermal energy around the Joule heated area. Also, the liquid-phase deposition process enabled the formation of a porous SnO2 thin film on the surface of ZnO NWs and simultaneous etching of the ZnO core, eventually to generate porous SnO2 NTs. Because of the localized synthesis of SnO2 NTs on the suspended microheater, very low power for the gas sensor operation (<6 mW) has been realized. Moreover, the sensing performance (e.g., sensitivity and response time) of synthesized SnO2 NTs was dramatically enhanced compared to that of ZnO NWs. In addition, the sensing performance was further improved by forming SnO2-ZnO hybrid nanostructures due to the heterojunction effect. PMID- 28714312 TI - Molecular Dynamics Simulations of the Rotational and Translational Diffusion of a Janus Rod-Shaped Nanoparticle. AB - The diffusion of a Janus rod-shaped nanoparticle in a dense Lennard-Jones fluid is studied using molecular dynamics (MD) simulations. The Janus particle is modeled as a rigid cylinder whose atoms at each end have different interaction energies with fluid molecules, thus comprising wetting and nonwetting surfaces. We found that both rotational and translational diffusion coefficients are larger for Janus particles with lower average wettability, and these values are bound between the two limiting cases of uniformly wetting and nonwetting particles. It was also shown that values of the diffusion coefficients for displacements parallel and perpendicular to the major axis of a uniformly wetting particle agree well with analytical predictions despite a finite slip at the particle surface present in MD simulations. It was further demonstrated that diffusion of Janus particles is markedly different from that of uniform particles; namely, Janus particles preferentially rotate and orient their nonwetting ends along the displacement vector to reduce drag. This correlation between translation and rotation is consistent with the previous results on diffusive dynamics of a spherical Janus particle with two hemispheres of different wettability. PMID- 28714313 TI - Artificial Metalloenzymes: Reaction Scope and Optimization Strategies. AB - The incorporation of a synthetic, catalytically competent metallocofactor into a protein scaffold to generate an artificial metalloenzyme (ArM) has been explored since the late 1970's. Progress in the ensuing years was limited by the tools available for both organometallic synthesis and protein engineering. Advances in both of these areas, combined with increased appreciation of the potential benefits of combining attractive features of both homogeneous catalysis and enzymatic catalysis, led to a resurgence of interest in ArMs starting in the early 2000's. Perhaps the most intriguing of potential ArM properties is their ability to endow homogeneous catalysts with a genetic memory. Indeed, incorporating a homogeneous catalyst into a genetically encoded scaffold offers the opportunity to improve ArM performance by directed evolution. This capability could, in turn, lead to improvements in ArM efficiency similar to those obtained for natural enzymes, providing systems suitable for practical applications and greater insight into the role of second coordination sphere interactions in organometallic catalysis. Since its renaissance in the early 2000's, different aspects of artificial metalloenzymes have been extensively reviewed and highlighted. Our intent is to provide a comprehensive overview of all work in the field up to December 2016, organized according to reaction class. Because of the wide range of non-natural reactions catalyzed by ArMs, this was done using a functional-group transformation classification. The review begins with a summary of the proteins and the anchoring strategies used to date for the creation of ArMs, followed by a historical perspective. Then follows a summary of the reactions catalyzed by ArMs and a concluding critical outlook. This analysis allows for comparison of similar reactions catalyzed by ArMs constructed using different metallocofactor anchoring strategies, cofactors, protein scaffolds, and mutagenesis strategies. These data will be used to construct a searchable Web site on ArMs that will be updated regularly by the authors. PMID- 28714314 TI - Management of myocardial infarction in the elderly. Insights from Spanish Minimum Basic Data Set. AB - BACKGROUND: We aimed to assess the impact of implementation of reperfusion networks, the type of hospital and specialty of the treating physician on the management and outcomes of ST segment elevation myocardial infarction in patients aged ?75 years. METHODS: We analysed data from the Minimum Basic Data Set of the Spanish public health system, assessing hospital discharges between 2004 and 2013. Discharges were distributed in three groups depending on the clinical management: percutaneous coronary intervention, thrombolysis or no reperfusion. Primary outcome measure was all cause in-hospital mortality. For risk adjustment, patient comorbidities were identified for each index hospitalization. RESULTS: We identified 299,929 discharges, of whom 107,890 (36%) were in-patients aged ?75 years. Older patients had higher prevalence of comorbidities, were less often treated in high complexity hospitals and were less frequently managed by cardiologists ( p<0.001). Both percutaneous coronary intervention and fibrinolysis were less often performed in elderly patients ( p<0.001). A progressive increase in the rate of percutaneous coronary intervention was observed in the elderly across the study period (from 17% in 2004 to 45% in 2013, p<0.001), with a progressive reduction of crude mortality (from 23% in 2004 to 19% in 2013, p<0.001). Adjusted analysis showed an association between being treated in high complexity hospitals, being treated by cardiologists and lower in hospital mortality ( p <0.001). CONCLUSIONS: Elderly patients with ST segment elevation myocardial infarction are less often managed in high complexity hospitals and less often treated by cardiologists. Both factors are associated with higher in-hospital mortality. PMID- 28714315 TI - Two new linear acetogenins from the fruits of Goniothalamus gracilipes. AB - Two new linear acetogenins, gracilipin A (1) and methylsaccopetrin A (2) along with seven known compounds, saccopetrin A (3), 7,3',4'-trimethylquercetin (4), rhamnazin (5), casticin (6), isokanugin (7), melisimplexin (8) and 5-hydroxy-3,7 dimethoxy-3',4'-methylenedioxyflavone (9) were isolated from the fruits of Goniothalamus gracilipes Ban. Their structures were established by spectral analysis, such as mass spectrometry, 1D-NMR, 2D-NMR and circular dichroism (CD). Compounds 1 and 3 showed cytotoxic activity against KB cell line with IC50 values of 14.6 and 15.3 MUM, respectively. PMID- 28714316 TI - Through a Window, Brightly: A Review of Selected Nanofabricated Thin-Film Platforms for Spectroscopy, Imaging, and Detection. AB - We present a review of the use of selected nanofabricated thin films to deliver a host of capabilities and insights spanning bioanalytical and biophysical chemistry, materials science, and fundamental molecular-level research. We discuss approaches where thin films have been vital, enabling experimental studies using a variety of optical spectroscopies across the visible and infrared spectral range, electron microscopies, and related techniques such as electron energy loss spectroscopy, X-ray photoelectron spectroscopy, and single molecule sensing. We anchor this broad discussion by highlighting two particularly exciting exemplars: a thin-walled nanofluidic sample cell concept that has advanced the discovery horizons of ultrafast spectroscopy and of electron microscopy investigations of in-liquid samples; and a unique class of thin-film based nanofluidic devices, designed around a nanopore, with expansive prospects for single molecule sensing. Free-standing, low-stress silicon nitride membranes are a canonical structural element for these applications, and we elucidate the fabrication and resulting features-including mechanical stability, optical properties, X-ray and electron scattering properties, and chemical nature-of this material in this format. We also outline design and performance principles and include a discussion of underlying material preparations and properties suitable for understanding the use of alternative thin-film materials such as graphene. PMID- 28714317 TI - Prospective observational study to determine the accuracy of first-trimester serum biomarkers and uterine artery Dopplers in combination with maternal characteristics and arteriography for the prediction of women at risk of preeclampsia and other adverse pregnancy outcomes. AB - OBJECTIVES: To assess the efficacy of biomarkers, arteriography and uterine artery Dopplers for predicting hypertensive disease of pregnancy, small for gestational age (SGA) and stillbirth. METHODS: This was a prospective first trimester study. Ultrasound was used to assess uterine artery Doppler. Maternal arteriography was performed and serum was taken for the measurement of placental growth factor (PlGF), alpha-fetoprotein (AFP), pregnancy-associated plasma protein (PAPP-A) and beta-human chorionic gonadotrophin levels. Logistic regression with stepwise selection was performed to determine multivariate models. RESULTS: One thousand and forty-five women were left for analysis after exclusions. Fourteen developed preeclampsia, 23 pregnancy induced hypertension, 64 SGA <5th centile, 118 SGA <10th centile and three stillbirth. Systolic blood pressure (SBP) in the aorta (SBPAO) (p = .002) was significantly associated with preeclampsia. Detection rate (DR) was 72% for a false-positive rate (FPR) of 15%, an area under the curve (AUC) of 0.81, 95% CI 0.69-0.93. MAP and maternal weight (p = .001) were significantly associated with PIH. DR 48%, AUC 0.76, 95% CI 0.65 0.86. Low PAPP-A and PlGF were significantly associated with SGA <10th centile (p = .007 and .004, respectively), DR 30%, AUC 0.608, 95% CI 0.54-0.68. SGA <5th centile was significantly associated with low PlGF (p = <.001), DR 57%, AUC 0.73, 95% CI 0.65-0.80. CONCLUSIONS: No association was found between first-trimester biomarkers and preeclampsia/PIH. There was a significant association between low PlGF and PAPP-A and SGA. PMID- 28714318 TI - GC-MS analysis of the bioactive phytoconstituents of various organic crude extracts from the seed kernels of Manilkara bidentata (balata) collected in Trinidad, W.I. AB - The present study reports the first phytochemical investigation of the seed kernels of Manilkara bidentata (Balata) harvested in Trinidad, W.I. Gas chromatography-mass spectrometry (GC-MS) analysis of the n-hexane, chloroform, ethyl acetate, ethanol and methanol extracts showed a total of 39 components. 2,6,10,14,18-pentamethyl-2,6,10,14,18-eicosapentaene (74.93%), 9-octadecenoic acid, (Z)- 2,3-dihydroxypropyl ester (79.98%), (Z)-ethyl oleate (92.75%), Z,E-2 methyl-3,13-octadecadien-1-ol (80.51%) and 5-(hydroxymethyl)-2 furancarboxyaldehyde (50.32%) were the major constituents identified in the n hexane, chloroform, ethyl acetate, ethanol and methanol extracts, respectively. The extracts showed the presence of several bioactive components and provides reference data for further research of its active constituents. PMID- 28714319 TI - Protective effect of Teucrium polium on carbon tetrachloride induced genotoxicity and oxidative stress in rats. AB - This study aimed to investigate the protective effects of Teucrium polium (TP) on carbon tetrachloride (CCl4) induced spleen, erythrocyte's oxidative stress, and genotoxicity in rats. TP was found to contain large amounts of polyphenols (150 mg GAE/G of dry plant) and flavonoids (60 mg QE/g of quercetin dry plant). The CCl4 (0.5 ml/kg) treated rats exhibited significant reductions in serum vitamin A (VA), vitamin E (VE) and total antioxidant status (TAS). Thiobarbituric acid reactive substances (TBARS) and conjugated dienes (CD) were significantly high in the CCl4 group compared to controls. Superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) were significantly decreased in CCl4 rats. Cytogenetic trials revealed remarkable increases in the frequency of chromosomal aberrations (CAs) and sister chromatid exchange (SCE) following CCl4 administration. Pretreatment with TP prevented damages caused by CCl4. Spleen characterised by necrosis was detected in CCl4 as compared to controls. Pretreatment with TP considerably decreased the perturbation. PMID- 28714321 TI - Zoophilia in an adolescent with high-functioning autism from Sri Lanka. AB - OBJECTIVE: Zoophilia is a rare paraphilic disorder with intense sexual urges involving animals. Autism is characterised by impairments in social communication and repetitive, restricted behaviours (RRB). Reported cases of zoophilia are limited worldwide, and zoophilia in autism is rarer. METHOD: This is a case report describing this unique and relatively unrecognised association in a male adolescent from Sri Lanka. RESULTS: A 17-year-old boy diagnosed with autism has average intelligence and academic capabilities. He had spent increasing time at his grandparents' cattle house. First, he was found masturbating near the cows and later having penetrative intercourse with a heifer. The shocked parents first sought traditional healing in the form of 'thovil', a demonic ritual of exorcist nature. Later, clinical evaluation found intense sexual urges towards cattle, which had led to marked distress and academic impairment. Sex hormone profile was normal. The adolescent was treated with a combination of cognitive-behaviour therapy and a selective serotonin reuptake inhibitor. CONCLUSION: We postulate that his persistent social difficulties contributed to the development of a paraphilic disorder. Unlike with his RRBs, he was markedly distressed about this sexual behaviour. Further research is required to explore this rarely reported, potential association. PMID- 28714320 TI - Anticancer effect of Polyphyllin Iota in colorectal cancer cells through ROS dependent autophagy and G2/M arrest mechanisms. AB - Polyphyllin Iota is a steroidal saponin isolated from the rhizoma of Paris polyphylla. In the present study, we aimed to investigate the anticancer effects of polyphyllin Iota in colorectal cancer and to elucidate the potential underlying molecular mechanisms. Using, CCK8 assay, flow cytometry, laser confocal microscope analysis and western blot, the anticancer effects of the polyphyllin Iota were analysed in colorectal cells. Our results indicate that polyphyllin Iota significantly decreased cell viability of HCT 116 cells and induced autophagy. Furthermore, we found that polyphyllin Iota induced autophagy in an ROS-dependent cell death and not related with PI3 K/AKT/mTOR pathway. We also provide evidence that excessive ROS triggered by polyphyllin Iota could induce G2/M phase arrest via regulating cycle proteins expression of cell cycle regulators, such as p21 and cyclinB1. In conclusion, polyphyllin Iota exhibit anticancer effect through ROS-dependent autophagy and induces G2/M arrest in colorectal cancer. PMID- 28714322 TI - Raman Spectroscopy Combined with Principal Component Analysis for Screening Nasopharyngeal Cancer in Human Blood Sera. AB - This study demonstrates the analysis of nasopharyngeal cancer (NPC) in human blood sera using Raman spectroscopy combined with the multivariate analysis technique. Blood samples of confirmed NPC patients and healthy individuals have been used in this study. The Raman spectra from all these samples were recorded using 785 nm laser for excitation. Important Raman bands at 760, 800, 815, 834, 855, 1003, 1220-1275, and 1524 cm-1, have been observed in both normal and NPC samples. A decrease in the lipids content, phenylalanine, and beta-carotene, whereas increases in amide III, tyrosine, and tryptophan have been observed in the NPC samples. The two data sets were well separated using principal component analysis (PCA) based on Raman spectral data. The spectral variations between the healthy and cancerous samples have been further highlighted by plotting loading vectors PC1 and PC2, which shows only those spectral regions where the differences are obvious. PMID- 28714323 TI - Goal satisfaction improves with individualized powered wheelchair skills training. AB - PURPOSE: To determine improvements in goal satisfaction following individualized mobility-related powered wheelchair skills training and whether changes in satisfaction are maintained 3 months post-training. MATERIALS AND METHODS: Seventeen powered wheelchair users, from two centres, who were randomized to the training intervention from a larger multicentre study, were included in this secondary analysis. The intervention consisted of five 30-min individualized Wheelchair Skills Training Program sessions. Participants rated their current satisfaction with each of their goals from 0 to 10 (10 being the highest) prior to training, immediately after the intervention, and approximately 3 months following the intervention. Themes relating to the participants' goals were also explored. RESULTS: Goal satisfaction scores improved statistically (p < .001) from baseline (4.7 +/- 1.9) to immediately following training (8.0 +/- 1.0) and were maintained 3 months (8.3 +/- 1.2) following the intervention. Participants' goal satisfaction scores were not significantly correlated with goal attainment scores recorded by the trainer (r = 0.387, n = 17, p = .125). The majority of goals set fell into the broader "manoeuvring" category. CONCLUSION: Goal satisfaction following the Wheelchair Skills Training Program improved years after initially learning how to operate a powered wheelchair. The five training sessions were effective in improving goal satisfaction. The quantification of goal satisfaction appears to be a sensitive outcome for powered wheelchair users undergoing mobility-related training. Implications for rehabilitation Goal satisfaction improved following the Wheelchair Skills Training Program. Even with years of powered wheelchair experience, the majority of goals set fell into the broader "manoeuvring" category. An individual's goal satisfaction may not correlate with whether they have attained their goal as determined by a trainer. PMID- 28714324 TI - Probing the Sulfur-Modified Capping Layer of Gold Nanoparticles Using Surface Enhanced Raman Spectroscopy (SERS) Effects. AB - Gold nanoparticles (AuNP) exhibit particular plasmonic properties when stimulated by visible light, which makes them a promising tool to many applications in sensor technology and biomedical applications, especially when associated to sulfur-based compounds. Sulfur species form a great variety of self-assembled structures that cap AuNP and this interaction rules the optical and plasmonic properties of the system. Here, we report the behavior of citrate-stabilized gold nanospheres in two distinct sulfur colloidal solutions, namely, thiocyanate and sulfide ionic solutions. Citrate-capped gold nanospheres were characterized using ultraviolet-visible (UV-Vis) absorption, transmission electron microscopy (TEM), energy dispersive spectroscopy (EDS), and atomic force microscopy (AFM). In the presence of sulfur species, we have observed the formation of NP clusters and chain-like structures, giving rise to surface-enhanced effects. Surface-enhanced Raman spectroscopy (SERS) pointed to a modification in citrate vibrational modes, which suggests substitution of citrate by either thiocyanate or sulfide ions with distinct dynamics, as showed by in situ fluorescence. Moreover, we report the emergence of surface-enhanced infrared absorption (SEIRA) effect, which corroborates SERS conclusions. Further, SEIRA shows a great potential as a tool for specification of sulfur compounds in colloidal solutions, which is particularly useful when dealing with sensor technology. PMID- 28714325 TI - Actor-Network-Theory and Micro-Learning Networks. PMID- 28714326 TI - Spinal cord ischemia-reperfusion causes damage of neurocyte by inhibiting RAP2C. AB - OBJECTIVE: To explore the mechanism of RAP2C participating in spinal cord ischemia-reperfusion injury (SCII). MATERIALS AND METHODS: mRNA expressions of miR-204 and RAP2C were measured by qRT-PCR. Protein level of RAP2C was detected by Western blot. Cell apoptosis in AGE1.HN and PC12 cells was detected by Annexin V/propidium iodide assay. The effect of miR-204 knockdown or overexpression on RAP2C expression was observed by luciferase assay. RESULTS: In this experimental research, RAP2C expression in SCII group was lower than control group, while miR 204 expression was higher. In addition, RAP2C expression in AGE1.HN and PC12 cells under hypoxic condition was lower than control group, while miR-204 expression was higher. Hypoxia increased cell apoptosis, and overexpression of RAP2C reversed this effect. In cells treated with hypoxia and miRNA-204 inhibitor, hypoxia upregulated the expression of miR-204, while miRNA-204 inhibitor reversed this effect. Hypoxia downregulated the expression of RAP2C, while miR-204 inhibitor reversed this effect. Moreover, miR-204 could bind to 3' UTR of RAP2C. And miR-204 inhibitor upregulated the activity and expression of RAP2C, while miR-204 mimic played the opposite role. Finally, hypoxia downregulated RAP2C expression, miR-204 inhibitor upregulated RAP2C expression, while Ad-sh-RAP2C inhibited RAP2C expression. What's more, hypoxia increased the apoptosis rate, miR-204 inhibitor decreased the apoptosis rate, while si-RAP2C increased the apoptosis rate. CONCLUSION: SCII causes increase of neurocyte apoptosis by inhibiting RAP2C via miR-204. PMID- 28714327 TI - Elevated levels of circulating cell-free DNA and neutrophil proteins are associated with neonatal sepsis and necrotizing enterocolitis in immature mice, pigs and infants. AB - Preterm infants are highly susceptible to late-onset sepsis (LOS) and necrotizing enterocolitis (NEC), but disease pathogenesis and specific diagnostic markers are lacking. Circulating cell-free DNA (cfDNA) and immune cell-derived proteins are involved in multiple immune diseases in adults but have not been investigated in preterm neonates. We explored the relation of circulating neutrophil-associated proteins and cfDNA to LOS and/or NEC. Using a clinically relevant preterm pig model of spontaneous LOS and NEC development, we investigated neutrophil associated proteins and cfDNA in plasma, together with cytokines in gut tissues. The changes in cfDNA levels were further studied in preterm pigs and neonatal mice with induced sepsis, and in preterm infants with or without LOS and/or NEC. Fifteen of 114 preterm pigs spontaneously developed both LOS and NEC, and they showed increased intestinal levels of IL-6 and IL-1beta and plasma levels of cfDNA, neutrophil-associated proteins, and proteins involved in platelet neutrophil interaction during systemic inflammation. The abundance of neutrophil associated proteins highly correlated with cfDNA levels. Further, Staphylococcus epidermidis challenge of neonatal mice and preterm pigs increased plasma cfDNA levels and bacterial accumulation in the spleen. In infants, plasma cfDNA levels were elevated at LOS diagnosis and 1-6 d before NEC. In conclusion, elevated levels of plasma cfDNA and neutrophil proteins are associated with LOS and NEC diagnosis. PMID- 28714329 TI - Synthetic sutures: Clinical evaluation and future developments. AB - Today's sutures are the result of a 4000-year innovation process with regard to their materials and manufacturing techniques, yet little has been done to enhance the therapeutic value of the suture itself. In this review, we explore the historical development, regulatory database and clinical literature of sutures to gain a fuller picture of suture advances to date. First, we examine historical shifts in suture manufacturing companies and review suture regulatory databases to understand the forces driving suture development. Second, we gather the existing clinical evidence of suture efficacy from reviewing the clinical literature and the Food and Drug Administration database in order to identify to what extent sutures have been clinically evaluated and the key clinical areas that would benefit from improved suture materials. Finally, we apply tissue engineering and regenerative medicine design hypotheses to suture materials to identify routes by which bioactive sutures can be designed and passed through regulatory hurdles, to improve surgical outcomes. Our review of the clinical literature revealed that many of the sutures currently in use have been available for decades, yet have never been clinically evaluated. Since suture design and development is industry driven, incremental modifications have allowed for a steady outflow of products while maintaining a safe regulatory position and limiting costs. Until recently, there has been little academic interest in suture development, however the rise of regenerative medicine strategies is shifting the suture paradigm from an inert material, which mechanically approximates tissue, to a bioactive material, which also actively promotes cell-directed repair and a positive healing response. These materials hold significant therapeutic potential, but could be associated with an increased regulatory burden, cost, and clinical evaluation compared with current devices. PMID- 28714330 TI - [The role of environmental factors in managing labour stress]. AB - INTRODUCTION: Emotional, cognitive and behavioural aspects of birth and labour stress are strongly associated with the underlying physiological processes. AIM: To study the factors of physical security and social support, the administration of synthetic oxytocin, and how they relate to perceived stress during childbirth. METHOD: Women's experienced physical security, social support and oxytocin administration was measured with targeted questions, and their perceived stress with the short and modified version of the Perceived Stress Scale. RESULTS: A strong negative association was found between perceived stress and physical and social security. The group of women experiencing low physical and social security perceived significantly higher stress, while those given synthetic oxytocin perceived higher stress, and lower physical and social security. CONCLUSIONS: Since physiological, psychological processes and behaviours are strongly intertwined, the support of natural physiological birth without interventions is recommended, which considers not only short-term but long-term health consequences for mother and child. The contribution of calming physical surroundings, minimal interventions and empowering support of caregivers to safe and satisfying birth is demonstrated in a model. Orv Hetil. 2017; 158(29): 1149 1156. PMID- 28714328 TI - Neuronal expression of the mitochondrial protein prohibitin confers profound neuroprotection in a mouse model of focal cerebral ischemia. AB - The mitochondrial protein prohibitin (PHB) has emerged as an important modulator of neuronal survival in different injury modalities . We previously showed that viral gene transfer of PHB protects CA1 neurons from delayed neurodegeneration following transient forebrain ischemia through mitochondrial mechanisms. However, since PHB is present in all cell types, it is not known if its selective expression in neurons is protective, and if the protection occurs also in acute focal ischemic brain injury, the most common stroke type in humans. Therefore, we generated transgenic mice overexpressing human PHB1 specifically in neurons (PHB1 Tg). PHB1 Tg mice and littermate controls were subjected to transient middle cerebral artery occlusion (MCAo). Infarct volume and sensory-motor impairment were assessed three days later. Under the control of a neuronal promoter (CaMKIIalpha), PHB1 expression was increased by 50% in the forebrain and hippocampus in PHB1 Tg mice. The brain injury produced by MCAo was reduced by 63 +/- 11% in PHB1 Tg mice compared to littermate controls. This reduction was associated with improved sensory-motor performance, suggesting that the salvaged brain remains functional. Approaches to enhance PHB expression may be useful to ameliorate the devastating impact of cerebral ischemia on the brain. PMID- 28714331 TI - [Hand hygiene technique assessment using electronic equipment in 26 Hungarian healthcare institutions]. AB - INTRODUCTION: Hand hygiene is probably the most effective tool of nosocomial infection prevention, however, proper feedback and control is needed to develop the individual hand hygiene practice. AIM: Assessing the efficiency of modern education tools, and digital demonstration and verification equipment during their wide-range deployment. METHOD: 1269 healthcare workers took part in a training organized by our team. The training included the assessment of the participants' hand hygiene technique to identify the most often missed areas. The hand hygiene technique was examined by a digital device. RESULTS: 33% of the participants disinfected their hands incorrectly. The most often missed sites are the fingertips (33% on the left hand, 37% on the right hand) and the thumbs (42% on the left hand, 32% on the right hand). CONCLUSION: The feedback has a fundamental role in the development of the hand hygiene technique. With the usage of electronic devices feedback can be provided efficiently and simply. Orv Hetil. 2017; 158(29): 1143-1148. PMID- 28714332 TI - [Miscellaneous]. PMID- 28714333 TI - [Borrelia miyamotoi: a recently identified human pathogenic tick-borne relapsing fever spirochete]. AB - Borrelia miyamotoi is a recently described relapsing fever spirochete transmitted by ticks of the Ixodes ricinus complex. This pathogen is different from Borrelia burgdorferi sensu lato (the Lyme borreliosis spirochetes) in its epidemiology, ecology and also genetics. Over 50 patients have been described worldwide with Borrelia miyamotoi disease, and three immunocompromised patients were reported with neurological symptoms. Our knowledge about Borrelia miyamotoi infection in ticks and its distribution in different habitats and also the mechanism of the infection is limited. The most common symptom is fever; thus it can be easily confused with other tick-borne diseases. Due to the intensive research in recent years, Borrelia miyamotoi infection in ticks and hosts has been reported from different regions and also the number of patients is increasing, thus this bacterium is considered as an emerging pathogen. In this literature review we would like to summarize the available knowledge about this spirochete. Orv Hetil. 2017, 158(29): 1124-1130. PMID- 28714334 TI - [Regional inequalities of health status of pregnant women in Hungary - Long-term series analysis]. AB - INTRODUCTION: Monitoring the health status of populations is essential for good health policy decisions. This is particularly true in maternal and child health where targeted and timely interventions may have long-term consequences. AIM: Our objective was to describe changes in the health status of pregnant women at the national and county level during the period of 1997-2012. METHOD: Data were extracted from the mandatory annual reports of district nurses responsible for primary maternal care. Information on the smoking status of expecting mothers, special care during pregnancy, pregnant women entering into maternity care after 28 weeks of pregnancy, borne woman without district nurse care were analysed using Microsoft Excel and STATA 13.0. RESULTS: The mean prevalence of smoking was 13.8% among pregnant women during the investigation period. The ratio of smoking pregnant women was higher (p<0.01) in Borsod-Abauj-Zemplen, Nograd, Heves, Szabolcs-Szatmar-Bereg, and Somogy counties. The ratio of pregnants requiring special care was higher (p<0.01) than the national average in Somogy, Szabolcs Szatmar-Bereg, Borsod-Abauj-Zemplen and Nograd counties. More, than 1% of the pregnant women entered into care only after the 28th week of the pregnancy. Women who were registered by district nurses and gave birth less than 1% did not participate in pregnant nursing. CONCLUSION: National data hide significant regional disparities within the country which should be amended by targeted interventions, taking into account the large regional inequalities in the country. Orv Hetil. 2017; 158(29): 1131-1142. PMID- 28714335 TI - [Prof. Attila Fonyo has turned 90]. PMID- 28714336 TI - Specific plasma oxylipins increase the odds of cardiovascular and cerebrovascular events in patients with peripheral artery disease. AB - Oxylipins and fatty acids may be novel therapeutic targets for cardiovascular disease. The objective was to determine if plasma oxylipins or fatty acids can influence the odds of cardiovascular/cerebrovascular events. In 98 patients (25 female, 73 male) with peripheral artery disease, the prevalence of transient ischemic attacks, cerebrovascular accidents, stable angina, and acute coronary syndrome was n = 16, 10, 16, and 24, respectively. Risk factors such as being male, diagnosed hypertension, diabetes mellitus, and hyperlipidemia were not associated with events. Plasma fatty acids and oxylipins were analyzed with gas chromatography and HPLC-MS/MS, respectively. None of 24 fatty acids quantified were associated with events. In contrast, 39 plasma oxylipins were quantified, and 8 were significantly associated with events. These 8 oxylipins are known regulators of vascular tone. For example, every 1 unit increase in Thromboxane B2/Prostaglandin F1alpha and every 1 nmol/L increase in plasma 16 hydroxyeicosatetraenoic acid, thromboxane B2, or 11,12-dihydroxyeicosatrienoic acid (DiHETrE) increased the odds of having had >=2 events versus no event (p < 0.05). The greatest predictor was plasma 8,9-DiHETrE, which increased the odds of acute coronary syndrome by 92-fold. In conclusion, specific oxylipins were highly associated with clinical events and may represent specific biomarkers and (or) therapeutic targets of cardiovascular disease. PMID- 28714337 TI - Correlation Between Natural Killer Cell Activity and Systemic Inflammatory Markers for Heterogeneous Cancer Patients Treated With Wheel Balance Cancer Therapy. AB - BACKGROUND AND OBJECTIVE: Natural killer (NK) cells are known to have an effect on the prevention of tumorigenesis for the initial cancer, as well as the metastatic cancer. For the past several years, the relationship between cancer and inflammation has been actively studied in preclinical and clinical settings, but there are no reports on alterations in and correlation for NK cell activity (NKA) and systemic inflammatory markers. Accordingly, this study aimed to measure correlation between NKA and the levels of other systemic inflammatory markers in patients with gastric, breast, and pancreatic cancer who received Wheel Balance Cancer Therapy (WBCT). METHODS: Forty-two electronic charts of patients with gastric, breast, and pancreatic cancer treated with WBCT from February 1, 2015 to September 30, 2015, were reviewed retrospectively. These charts were statistically analyzed, looking for alterations of and correlation for NKA and the expressions of systemic inflammatory markers. RESULTS: Patients with a NKA of under 300 pg/mL at admission showed significantly higher erythrocyte sedimentation rate (ESR) and neutrophil-to-lymphocyte ratio (NLR) values and decreasing NLR values due to WBCT than patients with an NKA greater than 300 pg/mL. As a result of the correlation analysis between NKA and the levels of the systemic inflammatory markers, NKA showed significant negative correlation with NLR, ESR, and fibrinogen values. CONCLUSIONS: Negative correlation was identified between NKA and NLR, NKA and ESR, and NKA and fibrinogen in patients with heterogeneous cancer patients. PMID- 28714338 TI - Antiplasmodial prenylated flavanonols from Tephrosia subtriflora. AB - The CH2Cl2/MeOH (1:1) extract of the aerial parts of Tephrosia subtriflora afforded a new flavanonol, named subtriflavanonol (1), along with the known flavanone spinoflavanone B, and the known flavanonols MS-II (2) and mundulinol. The structures were elucidated by the use of NMR spectroscopy and mass spectrometry. The absolute configuration of the flavanonols was determined based on quantum chemical ECD calculations. In the antiplasmodial assay, compound 2 showed the highest activity against chloroquine-sensitive Plasmodium falciparum reference clones (D6 and 3D7), artemisinin-sensitive isolate (F32-TEM) as well as field isolate (KSM 009) with IC50 values 1.4-4.6 MUM without significant cytotoxicity against Vero and HEp2 cell lines (IC50 > 100 MUM). The new compound (1) showed weak antiplasmodial activity, IC50 12.5-24.2 MUM, but also showed selective anticancer activity against HEp2 cell line (CC50 16.9 MUM). PMID- 28714339 TI - Inhaled and systemic steroid exposure and neurodevelopmental outcome of preterm neonates. AB - OBJECTIVES: To compare death and/or neurodevelopmental outcomes of preterm infants exposed to inhaled and/or systemic steroids with those without exposure, and examine the impact of timing of exposure. METHODS: Retrospective study of infants born <29 weeks gestation and assessed at 18-21 months corrected age (CA). Neurodevelopmental impairment (NDI) was defined as any Bayley Scales of Infant and Toddler Development-III (BSID-III) score <85, cerebral palsy >= grade one, and visual or hearing impairment. Significant NDI (sNDI) was defined as any Bayley Scales of Infant Development (BSID-III) score <70, cerebral palsy >= grade three, or severe vision or hearing impairment. RESULTS: Of 2570 neonates, 1811 had no exposure, 125 were exposed to inhaled steroids, 522 to systemic steroids and 112 to both. Infants exposed to inhaled steroids had lower odds of bronchopulmonary dysplasia [adjusted odds ratio (AOR) 0.51, (0.33, 0.79)], and displayed no difference in death/NDI or death/significant neurodevelopmental impairment (sNDI), regardless of timing of exposure. Infants only exposed to systemic steroids before 4 weeks of age were at increased odds of death/NDI [AOR 1.83 (1.43, 2.34)] and death/sNDI [AOR 2.28 (1.76, 2.96)]. CONCLUSIONS: Exposure to inhaled steroids was not associated with increased odds of death/NDI or death/sNDI. Systemic steroids use before 4 weeks of age was associated with significantly worse outcomes. PMID- 28714340 TI - Statement of Redundant Publication. AB - For 'Factors Associated With Specific Language Impairment and Later Language Development During Early Life: A Literature Review' by Benjamas Prathanee, MA, Bandit Thinkhamrop, PhD, Sumalee Dechongkit, PhD; Clinical Pediatrics; Volume 46 Number 1, January 2007; 22-29; (c) 2007; SAGE Publications; 10.1177/0009922806297153 This statement has been added based on determining significant overlap with the following article, published earlier, with an authorship including one of the co-authors, Bandit Thinkhamrop: 'Risk Factors Associated with Language Development Problems in Childhood - A Literature Review' by Bhunyabhadh Chaimay, MPH, Bandit Thinkhamrop PhD, and Jadsada Thinkhamrop; Journal of the Medical Association of Thailand; Volume 89, Number 7; 1080-86; 2006 The similarities between the two papers include referencing data from the same 15 studies, paper structure, and the overall conclusions. Additionally, the Clinical Pediatrics article did not include reference to the Journal of the Medical Association of Thailand paper. Author Bandit Thinkhamrop responded that the authors of the two papers worked collaboratively on the covered topic as part of their coursework. PMID- 28714341 TI - Identification of phenolic compounds from the leaf part of Teucrium pseudo Scorodonia Desf. collected from Algeria. AB - In the present paper,we reported for the first time, the identification of the phenolic compounds in butanolic fraction obtained from the leaf part of Teucrium pseudo-Scorodonia Desf. collected from Algeria using RP-HPLC-PDA (Reversed Phase High Performance Liquid Chromatography/Photo Diode Array) technique. Several standards were used for this purpose. The analysis led to the identification of six phenolic acids (ferulic, sinapic, rosmarinic, syringique, caffeic, p-coumaric acids) and one flavonoid (rutin), the last one, has interesting pharmacological properties. PMID- 28714342 TI - A multicentre study of how goal-setting is practised during inpatient stroke rehabilitation. AB - OBJECTIVE: To describe goal-setting during inpatient stroke rehabilitation. DESIGN: There were two stages: an electronic questionnaire for multidisciplinary teams and an analysis of goal-setting documentation for rehabilitation patients. SETTING: Five inpatient stroke units. PARTICIPANTS: Staff involved in goal setting and patients undergoing stroke rehabilitation. RESULTS: A total of 13 therapists and 49 patients were recruited, and 351 documented goals were examined. All units used therapist-led goal-setting (60% of goals were set by therapists). In total, 72% of goals were patient-focused but patients and families were rarely directly involved. Goals focussed on basic mobility and activities of daily living (~50% and ~25% of goals, respectively). Only 41% of documented goals met the SMART criteria. Review of progress was limited: 48% of goals were never reviewed and 24% of the remainder were merely marked as 'ongoing' without a date or plan for completion. New goals and actions were often documented without any connection to previous goals. Integration between goals and treatment/action plans was mixed. In two units, goals were unconnected to a treatment or action plan, but for the remainder it was 90%-100%. However, that connection was generally vague and amounted to suggestions of the type of treatment modality that staff might employ. CONCLUSION: Goal-setting during inpatient stroke rehabilitation is therapist-led but discussed with the multidisciplinary team. Therapists mainly identified patient-focussed mobility and activities of daily living goals. Monitoring progress and revising goals were often uncompleted. Links between goals and treatment, action plans and progress were patchy. PMID- 28714344 TI - Going to the Bank: Fecal Microbiota Transplantation in Pediatrics. PMID- 28714343 TI - A randomized controlled trial of a combined self-management and exercise intervention for elderly people with osteoarthritis of the knee: the PLE2NO program. AB - OBJECTIVE: To assess the effectiveness of a 12-week self-management and exercise intervention (the PLE2NO program) in elderly individuals with knee osteoarthritis. DESIGN: Randomized controlled trial. SETTING: Four different community settings. SUBJECTS: Eighty individuals aged 60 years or older with clinical and radiographic knee osteoarthritis enrolled in the study. INTERVENTION: A combined self-management and exercise intervention (treatment group) and an educational intervention (control group). MAIN MEASURES: The primary outcomes were pain and other knee osteoarthritis symptoms (swelling, crackling, limitation on movement, and stiffness), self-management behaviors (communication with physician and cognitive symptom management), and functional lower limb strength. Secondary outcomes were knee osteoarthritis-specific health related quality of life, self-perceived health, aerobic capacity, lower and upper limb flexibility, and handgrip strength. RESULTS: In all, 67 participants, mean age 69.1 +/- 5.8 years, completed the study: 32 in the Educational Group and 35 in the Self-Management and Exercise Group. A significant group effect favorable to the Self-Management and Exercise Group was observed in the following variables: communication with the physicians ( P = .048), aerobic capacity ( P = .035), and functional lower limb strength ( P = .015). Although no significant group effect was detected, clinical improvements in pain (31%) and knee osteoarthritis symptoms (29%) were observed in the experimental group. No improvements regarding cognitive symptom management, self-perceived health, lower limb flexibility, and handgrip strength were found. CONCLUSION: This study supports the importance of a combined self-management and exercise intervention to improve functional lower limb strength and aerobic capacity in a Portuguese sample. Additionally, pain and other symptoms have improved clinically. PMID- 28714345 TI - Chemical composition and antioxidant activity of aerial parts of Ferula longipes Coss. ex Bonnier and Maury. AB - This is the first study on the phytochemistry and antioxidant activity of Ferula longipes Coss. ex Bonnier and Maury (Apiaceae). A new flavonoid quercetin-3-O alpha-L-rhamnopyranoside-7-O-beta-D-[2-O-caffeoyl]-glucopyranoside (1), along with 10 known compounds kaempferol-3-O-alpha-L-rhamnopyranoside (2), quercetin-3 O-alpha-L-rhamnopyranoside (3), kaempferol-3-O-beta-D-glucopyranoside-7-O-alpha-L rhamnopyranoside (4), isorhamnetin-3-O-alpha-L-rhamnopyranoside-7-O-beta-D glucopyranoside (5), quercetin-3-O-alpha-L-rhamnopyranoside-7-O-beta-D glucopyranoside (6), isorhamnetin-3,7-di-O-beta-D-glucopyranoside (7), apigenin (8), apigenin-7-O-beta-D-glucopyranoside (9), 3,5-dicaffeoylquinic acid (10), deltoin (11) were isolated from the aerial parts of Ferula longipes Coss. Structures elucidation was performed by comprehensive 1D and 2D NMR analyses, mass spectrometry and by comparison with literature data. The compounds 1, 3, 4, 6, 7 and 10 were evaluated for their antioxidant activity, compound 1 exhibited the best antiradical activity potential and showed IC50 and A0.5 values 5.70, 7.25, 5.00, and 2.63 MUg/mL towards DPPH free radical-scavenging, ABTS, CUPRAC, and reducing power assays, respectively compared with BHA, BHT and ascorbic acid which were used as positive controls. PMID- 28714346 TI - Neuroprotective effects of Cassia tora against paraquat-induced neurodegeneration: relevance for Parkinson's disease. AB - The aim of the present study was to determine whether Cassia tora extracts could reverse the oxidative stress-induced neurodegeneration in a Parkinson's disease in vitro model. The leaves were treated with ethyl acetate (CtEA) or methanol (CtME). The extracts were first analysed by HPLC for their phenolic content and then tested for their neuroprotective effects in human SK-N-SH neuroblastoma cells. Cells were pre-treated with various concentrations of extracts followed by incubation with paraquat (14 MUM). Firstly, pre-treatment of SK-N-SH cells with 100 MUg/mL of CtEA or CtME significantly reduced the paraquat-induced production of reactive oxygen species. Furthermore, both CtEA and CtME reduced the paraquat induced apoptosis. Moreover, there was a significant reduction of paraquat induced DNA damage in SK-N-SH cells pre-treated with CtEA or CtME. Finally, both extracts significantly inhibited paraquat-dependent lipid peroxidation. Altogether, these in vitro data establish C. tora as a possible anti-Parkinson natural remedy. PMID- 28714347 TI - Antifungal activities and active ingredients of Melodinus suaveolens Champ. ex Benth. AB - Four Melodinus species with antifungal activity were found in survey of the floral resources, in Shiwan Mountain Natural Reserve, Guangxi Province, China. Crude methanolic extracts of the twigs and leaves of Melodinus suaveolens exhibited potent antifungal activities against the plant pathogenic fungi Colletotrichum musae, Colletotrichum graminicola, Colletotrichum gloeosporioides and Alternaria musae, and the ethyl acetate fraction inhibited these pathogens at rates of 85.37, 91.47, 72.77 and 89.87%, respectively (5 mg/mL). A new compound, (2R, 3S, 5S, 6R)-1-O-methyl- chiro-inositol was isolated from the ethyl acetate fraction, along with 15 known compounds. The antifungal activities of compounds (1-16) were evaluated for the first time. Compound (4) had potent antifungal activity against C. gloeosporioides, C. graminicola and A. musae. PMID- 28714348 TI - Two new 14, 15-secopregnane-type steroidal glycosides from the roots of Cynanchum limprichtii. AB - Two new steroidal glycosides 1 and 2, along with three known ones (3-5), were isolated from the 95% ethanol extract of the roots of Cynanchum limprichtii Schltr. The structure of the new compounds was elucidated as 3-O-alpha-L diginopyranosyl-(1->4)-beta-D-digitoxopyranosyl-(1->4)-beta-D-cymaropyranosyl-(1 >4)-beta-D-thevetopyranosyl-14, 16:15, 20:18, 20-triepoxy-14, 15-secopregn-4, 6, 8 (14)-triene (1) and 3-O-alpha-L-cymaropyranosyl-(1->4)-beta-D-digitoxopyranosyl (1->4)-beta-D-3-demethyl-2-deoxythevetopyranosyl-14, 16: 15, 20: 8, 20-triepoxy 14, 15-secopregn-5, 8 (14)-diene (2) on the basis of spectroscopic analysis together with acidic hydrolysis. All compounds showed cytotoxic activity against the human cancer cell line HL60, with IC50 values of 55.36, 65.41, 17.88, 17.68 and 33.5 MUM, respectively. While, only compound 3 showed cytotoxicity against the Caco-2 cell line, with an IC50 value of 67.47 MUM. PMID- 28714349 TI - Be an NIH Reviewer: Contribute to Multidisciplinary Research. AB - One of the best ways to contribute to multidisciplinary research and to improve your own knowledge of the review process at the National Institutes of Health (NIH) is to serve as a peer reviewer for research, traineeship, and small business innovation research proposals. Proactive targeted outreach to Scientific Review Officers (SROs) at NIH will increase your chances to become a reviewer. Reviewers with nursing expertise are especially welcome as multidisciplinary research is becoming more prevalent. Steps to identify a likely study section, contact the correct SRO, and review responsibly are described in this article, written by an experienced NIH review officer. PMID- 28714350 TI - Activation and expression of MU-calpain in dorsal root contributes to RTX-induced mechanical allodynia. AB - Background Calpain is a calcium-dependent cysteine protease, and inhibition of calpain by pre-treatment with MDL28170 attenuated the rat mechanical allodynia in a variety of pain models. Postherpetic neuralgia (Shingles) is a neuropathic pain conditioned with the presence of profound mechanical allodynia. Systemic injection of resiniferatoxin can reproduce the clinical symptoms of postherpetic neuralgia. In this study, we determined to study whether activation of calpain contributes to cleave the myelin basic protein of dorsal root and is involved in resiniferatoxin-induced mechanical allodynia of postherpetic neuralgia animal model. Results Resiniferatoxin up-regulated the expression and activation of u calpain in dorsal root. The expression of u-calpain was located in Schwann cell of dorsal root, and resiniferatoxin increased the expression of u-calpain in Schwann cell in L4-L6 dorsal root at six weeks after injection. Resiniferatoxin also induced myelin basic protein degradation in L4-L6 dorsal root at six weeks after injection. Moreover, intraperitoneal injection of calpain inhibitor MDL28170 prevented the degradation of myelin basic protein and then reduced the sprouting of myelinated afferent fibers into spinal lamina II, thus relieving resiniferatoxin-induced mechanical allodynia. Conclusions Up-regulation and activation of u-calpain located in Schwann cell may be the mechanism underlying resiniferatoxin-mediated proteolysis of myelin basic protein in dorsal root. Calpain inhibitor MDL28170 prevents resiniferatoxin-induced sprouting of myelinated afferent fibers and mechanical allodynia through inhibition of degradation of the myelin basic protein in dorsal root. Our results indicate that inhibition of pathological u-calpain activation may present an interesting novel drug target in the treatment of postherpetic neuralgia. PMID- 28714351 TI - Activation of NLRP3 inflammasome in peripheral nerve contributes to paclitaxel induced neuropathic pain. AB - Background Paclitaxel is commonly used as a cancer chemotherapy drug that frequently causes peripheral neuropathic pain. Inflammasome is a multiprotein complex consisting of Nod-like receptor proteins (NLRPs), apoptosis-associated speck-like protein, and caspase-1, which functions to switch on the inflammatory process and the release of interleukin-1beta. Growing evidences have supported that peripheral interleukin-1beta is critical in enhancing paclitaxel-induced neuropathic pain. However, whether activation of NLRP3 inflammasome in peripheral nerve contributes to paclitaxel-induced neuropathic pain is still unclear. Results Paclitaxel induced mechanical allodynia of rats from day 3 and worsened gradually till 3 weeks after injection. Paclitaxel resulted in expression of NLRP3 and activated fragments of caspase-1 and interleukin-1beta in L4-6 dorsal root ganglia and sciatic nerve three weeks after injection, indicating activation of NLRP3 inflammasome. The expression of NLRP3 was located in CD68-labeled macrophages infiltrating in L4-6 dorsal root ganglia and sciatic nerve, and paclitaxel increased the expression of NLRP3 in macrophage. Moreover, the paclitaxel elicited mitochondria damage, which became swollen and enlarged in macrophages and axons of sciatic nerve three weeks after injection. In vitro, paclitaxel increased the number of damaged mitochondria and mitochondrial reactive oxygen species production in the rat alveolar macrophage cell line NR8383. The administration of a non-specific reactive oxygen species scavenger, phenyl-N-tert-butylnitrone, markedly alleviated mechanical allodynia and inhibited the activation of NLRP3 inflammasome in L4-6 dorsal root ganglia and sciatic nerve of the paclitaxel-induced neuropathic pain model. Conclusions Paclitaxel induced mechanical allodynia and activation of NLRP3 inflammasome in infiltrated macrophages of L4-6 dorsal root ganglia and sciatic nerve. Paclitaxel elicited mitochondria damage and reactive oxygen species production may result in activation of NLRP3 inflammasome in peripheral nerve, which contributes to paclitaxel-induced neuropathic pain. PMID- 28714353 TI - Spatial Analysis of Temporal Changes in the Pandemic of Severe Cassava Mosaic Disease in Northwestern Tanzania. AB - To improve understanding of the dynamics of the cassava mosaic disease (CMD) pandemic front, geospatial approaches were applied to the analysis of 3 years' data obtained from a 2-by-2 degrees (approximately 222-by-222 km) area of northwestern Tanzania. In total, 80 farmers' fields were assessed in each of 2009, 2010, and 2011, with 20 evenly distributed fields per 1-by-1 degrees quadrant. CMD-associated variables (CMD incidence, CMD severity, vector-borne CMD infection, and vector abundance) increased in magnitude from 2009 to 2010 but showed little change from 2010 to 2011. Increases occurred primarily in the two westernmost quadrants of the study area. A pandemic "front" was defined by determining the values of CMD incidence and whitefly abundance where predicted disease gradients were greatest. The pandemic-associated virus (East African cassava mosaic virus-Uganda) and vector genotype (Bemisia tabaci sub-Saharan Africa 1-subgroup 1) were both present within the area bounded by the CMD incidence front but both also occurred ahead of the front. The average speed and direction of movement of the CMD incidence front (22.9 km/year; southeast) and whitefly abundance front (46.6 km/year; southeast) were calculated, and production losses due to CMD were estimated to range from US$4.3 million to 12.2 million. PMID- 28714352 TI - Enhancement of spinal dorsal horn neuron NMDA receptor phosphorylation as the mechanism of remifentanil induced hyperalgesia: Roles of PKC and CaMKII. AB - Background: Modulation of N-methyl-D-aspartate receptor subunits NR1 and NR2 through phosphorylation mediates opioid-induced hyperalgesia, and activations of protein kinase C and extracellular signal-regulated kinase 1/2 potentiate while activation of calcium/calmodulin-dependent protein kinase II inhibits opioid induced hyperalgesia. However, the mechanism of opioid-induced hyperalgesia development and in particular the potential interplay between N-methyl-D aspartate receptors and protein kinase C or calcium/calmodulin-dependent protein kinase II or extracellular signal-regulated kinase 1/2 in the development of remifentanil-induced hyperalgesia is unclear. Methods: Remifentanil (1 ug c kg-1 c min-1) was given intravenously over 60 min in rats, followed by the infusion of either vehicle solution or the respective inhibitors of protein kinase C (chelerythrine), extracellular signal-regulated kinase II (KN93), or extracellular signal-regulated kinase 1/2 (PD98059). Thereafter, the pain behaviors were evaluated by the paw withdrawal mechanical threshold and paw withdrawal thermal latency. In in vitro studies, fetal spinal cord dorsal horn neurons were primary cultured in the presence of 4 nM remifentanil for 60 min, and then the remifentanil was washed out and replaced immediately by culturing in the absence or presence of chelerythrine, KN93 or PD98059, respectively for up to 8 h. The expressions of N-methyl-D-aspartate receptors subunits and their phosphorylation (NR1, NR2B, p-NR1, p-NR2B) were analyzed by Western blotting after the completion of treatments. Functional changes of N-methyl-D-aspartate receptors were evaluated by electrophysiologic recordings of N-methyl-D-aspartate currents. Results: Remifentanil induced significant thermal and mechanical hyperalgesia, which were significantly attenuated by Chelerythrine or KN93 but not PD98059. The expressions of NR1, NR2B, p-NR1, and p-NR2B were increased significantly and progressively over time after remifentanil administration, and these increases were all significantly attenuated by either chelerythrine or KN93 but not PD98059. Intriguingly, N-methyl-D-aspartate receptor functional enhancement induced by remifentanil was attenuated by Chelerythrine, KN93, and PD98059. Conclusions: It is concluded that the enhancements in function and quantity of N-methyl-D-aspartate receptor via phosphorylation of its subunits through protein kinase C and calcium/calmodulin-dependent protein kinase II activation may represent the major mechanism whereby remifentanil induced hyperalgesia. PMID- 28714355 TI - Editorial. PMID- 28714354 TI - Is cerebral microbleed prevalence relevant as a biomarker in amnestic mild cognitive impairment and mild Alzheimer's disease? AB - Introduction The search for a reliable neuroimaging biomarker in Alzheimer's disease is a matter of intense research. The presence of cerebral microbleeds seems to be a potential biomarker. However, it is not clear if the presence of microbleeds has clinical usefulness to differentiate mild Alzheimer's disease and amnestic mild cognitive impairment from normal aging. We aimed to verify if microbleed prevalence differs among three groups: mild Alzheimer's disease, amnestic mild cognitive impairment due to Alzheimer's disease, and normal controls. Moreover, we studied whether microbleeds were associated with apolipoprotein E allele E4 status, cerebrospinal fluid amyloid-beta, total and phosphorylated tau protein levels, vascular factors, and cognition. Methods Twenty-eight mild Alzheimer's disease patients, 34 with amnestic mild cognitive impairment and 36 cognitively normal elderly subjects underwent: magnetic resonance imaging with a susceptibility-weighted imaging sequence on a 3T scanner, apolipoprotein E genotyping and a full neuropsychological evaluation. Only amnestic mild cognitive impairment and mild Alzheimer's disease underwent cerebrospinal fluid analysis. We compared the groups and verified if microbleeds were predicted by all other variables. Results Mild Alzheimer's disease presented a higher prevalence of apolipoprotein E allele E4 in relation to amnestic mild cognitive impairment and control group. No significant differences were found between groups when considering microbleed presence. Logistic regression tests failed to find any relationship between microbleeds and the variables. We performed three different regression models using different independent variables: Model 1 - amyloid-beta, phosphorylated tau protein, total tau, apolipoprotein E allele E4 status, age, and sex; Model 2 - vascular risk factors, age, and sex; Model 3 - cognitive scores sex, age, and education. Conclusion Although microbleeds might be related to the Alzheimer's disease process, their presence is not a good candidate for a neuroimaging biomarker of the disease, especially in its early phases. PMID- 28714356 TI - Complexity of macrophage migration inhibitory factor (MIF) and other angiogenic biomarkers profiling in pulmonary arterial hypertension. AB - Macrophage migration inhibitory factor (MIF) and 22 a priori selected biomarkers were measured from pulmonary arterial hypertension (PAH) patients. Significant positive correlations were found between MIF and several angiogenic factors suggesting a possible MIF regulation role in PAH angiogenesis and pathobiology, but simultaneously highlighting the biomarkers profiling complexity in PAH. PMID- 28714357 TI - Pharmaceutical assistance programs for cancer patients in the era of orally administered chemotherapeutics. AB - Introduction The rising cost of cancer drugs may make treatment unaffordable for some patients. Patients often rely on drug manufacturer-administered Pharmaceutical Assistance Programs (PAPs) to obtain drugs and reduced or no cost. The overall usage of PAPs within cancer care delivery is unknown. Methods We included all cancer patients across an academically affiliated, integrated health system in North Carolina during 2014 ( N = 8591). We identified the subset of patients receiving PAP assistance to afford one or more cancer drugs, in order to calculate the proportion of patients receiving PAP assistance, and the retail value of the assistance. Results Among 8591 cancer patients, 215 unique patients submitted a total of 478 successful PAP requests for cancer drugs. 40% of PAP utilizing patients were uninsured, 23% had Medicaid coverage, 20% had Medicare coverage, 2% were dual Medicare/Medicaid eligible, and 14% were commercially insured. Among all cancer patients who received medical treatment, 6.0% required PAP assistance, whereas 10.6% receiving an oral agent required PAP assistance. The proportion receiving PAP assistance varied substantially by drug, ranging from <1% of patients (e.g. carboplatin, methotrexate) to 50% of patients (e.g. ponatinib, temsirolimus). The majority of the retail value obtained was for oral agents, including $1,556,575 of imatinib and $1,449,633 of dasatinib, which were the two drugs with the highest aggregate retail value. Conclusions A substantial proportion of cancer patients receive private charitable assistance to obtain standard-of-care treatments. This includes patients with federal and private insurance, suggesting an inability of patients to meet cost-sharing requirements. PMID- 28714359 TI - Optimal sizing of iliac vein stents. AB - Background Iliac vein stenting has emerged as a therapeutic option in chronic venous disease. The optimal stent size is unknown but should match normal caliber at a minimum. Methods Teleology: The iliac-femoral outflow caliber was measured by Duplex in healthy volunteers to determine normal caliber. Patient IVUS data: The distribution curve of IVUS planimetry data in 345 chronic venous disease limbs was analyzed: values at the right tail end of the curve should approach normal values according to distribution theory. The optimal stent size was also projected using Poiseuille equation and Young's scaling rule. Results The optimal stent sizes in the common iliac, external iliac, and common femoral vein segments are: 16, 14, and 12 mm diameters, respectively. Conclusion Stent correction of iliac vein stenosis should aim to restore the lumen to the minimum recommended caliber during the initial procedure and later re-interventions. PMID- 28714360 TI - Knockdown of calponin 2 suppressed cell growth in gastric cancer cells. AB - Calponin family members are actin filament-associated regulatory proteins with distinct expression patterns. Previous studies on CNN2 (calponin 2) have demonstrated that CNN2 is expressed in a broad range of tissues and cell types, exhibiting potential regulatory roles in a number of cellular activities, including cell proliferation, cell migration, and platelet adhesion. In this work, we found that both messenger RNA and protein expression levels of CNN2 were remarkably upregulated in 60%-70% of gastric cancer tissues by comparison with those of neighboring non-tumorous mucosa. By utilizing specific shCNN2 (small hairpin RNA targeting CNN2), the potential role of CNN2 in regulating AGS gastric cancer cell growth was then further investigated. AGS cells infected with shCNN2 exhibited significantly decreased cell growth ability by comparison with control cells in vitro. Moreover, while there was no obvious difference in cell cycle distribution between two groups, enhanced cell apoptosis was detected in cells with reduced CNN2 expression. Consistently, caspase 3/7 activity was also remarkably activated upon shCNN2 lentivirus infection. Taken together, our results demonstrated that knockdown of endogenous CNN2 in AGS cells could significantly activate cell apoptosis pathway and therefore suppress cell growth in vitro. The deletion of CNN2 might be a potential therapeutic approach to inhibit aggressive growth of gastric cancer. PMID- 28714361 TI - RNA editing is induced by type I interferon in esophageal squamous cell carcinoma. AB - In recent years, abnormal RNA editing has been shown to play an important role in the development of esophageal squamous cell carcinoma, as such abnormal editing is catalyzed by ADAR (adenosine deaminases acting on RNA). However, the regulatory mechanism of ADAR1 in esophageal squamous cell carcinomas remains largely unknown. In this study, we investigated ADAR1 expression and its association with RNA editing in esophageal squamous cell carcinomas. RNA sequencing applied to esophageal squamous cell carcinoma clinical samples showed that ADAR1 expression was correlated with the expression of STAT1, STAT2, and IRF9. In vitro experiments showed that the abundance of ADAR1 protein was associated with the induced activation of the JAK/STAT pathway by type I interferon. RNA sequencing results showed that treatment with type I interferon caused an increase in the number and degree of RNA editing in esophageal squamous cell carcinoma cell lines. In conclusion, the activation of the JAK/STAT pathway is a regulatory mechanism of ADAR1 expression and causes abnormal RNA editing profile in esophageal squamous cell carcinoma. This mechanism may serve as a new target for esophageal squamous cell carcinoma therapy. PMID- 28714362 TI - Impact of tumor architecture on disease recurrence and cancer-specific mortality of upper tract urothelial carcinoma treated with radical nephroureterectomy. AB - Upper tract urinary carcinoma (UTUC) is a relatively uncommon but aggressive disease. Recent publications have assessed the prognostic significance of tumor architecture in UTUC, but there is still controversy regarding the significance and importance of tumor architecture on disease recurrence. We retrospectively reviewed the medical records of 101 patients with clinical UTUC who had undergone surgery. Univariate and multivariate analyses were conducted to identify factors associated with disease recurrence and cancer-specific mortality. As our single center study and the limited sample size may influence the clinical significance, we further quantitatively combined the results with those of existing published literature through a meta-analysis compiled from searching several databases. At a median follow-up of 41.3 months, 25 patients experienced disease recurrence. Spearman's correlation analysis showed that tumor architecture was found to be positively correlated with the tumor location and the histological grade. Kaplan Meier curves showed that patients with sessile tumor architecture had significantly poor recurrence free survival (RFS) and cancer specific survival (CSS). Furthermore, multivariate analysis suggested that tumor architecture was independent prognostic factors for RFS (Hazard ratio, HR = 2.648) and CSS (HR = 2.072) in UTUC patients. A meta-analysis of investigating tumor architecture and its effects on UTUC prognosis was conducted. After searching PubMed, Medline, Embase, Cochrane Library and Scopus databases, 17 articles met the eligibility criteria for this analysis. The eligible studies included a total of 14,368 patients and combined results showed that sessile tumor architecture was associated with both disease recurrence with a pooled HR estimate of 1.454 and cancer-specific mortality with a pooled HR estimate of 1.416. Tumor architecture is an independent predictor for disease recurrence after radical nephroureterectomy for UTUC. Therefore, closer surveillance is necessary, especially in patients with sessile tumor architecture. PMID- 28714363 TI - Portulaca oleracea extract can inhibit nodule formation of colon cancer stem cells by regulating gene expression of the Notch signal transduction pathway. AB - To investigate whether Portulaca oleracea extract affects tumor formation in colon cancer stem cells and its chemotherapy sensitivity. In addition, to analyze associated genetic changes within the Notch signal transduction pathway. Serum free cultures of colon cancer cells (HT-29) and HT-29 cancer stem cells were treated with the chemotherapeutic drug 5-fluorouracil to assess sensitivity. Injections of the stem cells were also given to BALB/c mice to confirm tumor growth and note its characteristics. In addition, the effect of different concentrations of P. oleracea extract was tested on the growth of HT-29 colon cancer cells and HT-29 cancer stem cells, as determined by the 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method. The effects of P. oleracea extract on the expression of beta-catenin, Notch1, and Notch2 in the HT 29 cells were studied using reverse transcription polymerase chain reaction and Western blotting. The tumor volume of the HT29 cells was two times larger than that of HT29 cancer stem cells. Treatment with P. oleracea extract inhibited the proliferation of both HT-29 cancer cells and HT-29 cancer stem cells at doses from 0.07 to 2.25 ug/mL. Apoptosis of HT-29 cancer cells and HT-29 cancer stem cells was assessed by flow cytometry; it was enhanced by the addition of P. oleracea extract. Finally, treatment with P. oleracea extract significantly downregulated the expression of the Notch1 and beta-catenin genes in both cell types. The results of this study show that P. oleracea extract inhibits the growth of colon cancer stem cells in a dose-dependent manner. Furthermore, it inhibits the expression of the Notch1 and beta-catenin genes. Taken together, this suggests that it may elicit its effects through regulatory and target genes that mediate the Notch signal transduction pathway. PMID- 28714364 TI - Influence of endoscopic sinus surgery on the quality of life of patients with early nasopharyngeal carcinoma and the analysis of prognosis-related factors. AB - The aim of this study is investigate the influence of endoscopic sinus surgery on the quality of life and prognosis of patients with early nasopharyngeal carcinoma. Patients initially diagnosed with early nasopharyngeal carcinoma and received surgical treatment were matched with nasopharyngeal carcinoma patients who received chemoradiotherapy at a ratio of 1:1, according to the following seven factors: gender, age, T staging, N staging, clinical staging, radiotherapy options, and chemotherapy options. Patients in the surgery group received endoscopic sinus surgery plus chemoradiotherapy, while subjects in the control group received chemoradiotherapy. The quality of life of patients before and after treatment was evaluated based on the FACT-H&N (Functional Assessment of Cancer Therapy-Head and Neck) and QLQ-H&N35 (Head and Neck Cancer Specific Module) questionnaires. In addition, overall survival and disease-free survival were compared between these two groups. The results showed overall survival was superior in the surgery group compared with the control group ( p = 0.007). However, the difference in disease-free survival between these two groups was not statistically significant ( p = 0.128). Furthermore, subgroup analysis revealed that for N0 patients, the effect of surgery combined with chemoradiotherapy on overall survival was superior to that of chemoradiotherapy ( p = 0.048); while for N1 patients, the difference in overall survival between these two groups was not statistically significant ( p = 0.065). For early nasopharyngeal carcinoma patients without lymph node metastasis, overall survival and disease-free survival in T1 patients were superior to those in T2 patients (chi2 = 4.403, p = 0.036; chi2 = 4.542, p = 0.033). At the end of treatment, the pain score was found to be significantly lower in the surgery group than in the chemoradiotherapy group ( p = 0.027). At 3 months and 1 year after treatment, dry mouth scores were significantly lower in the surgery group than in the chemoradiotherapy group ( p = 0.002, p = 0.026). These results demonstrated that the curative effect of surgery combined with chemoradiotherapy in the treatment of nasopharyngeal carcinoma was satisfactory and was particularly suitable for N0 patients. PMID- 28714365 TI - Conjugation of gold nanoparticles and recombinant human endostatin modulates vascular normalization via interruption of anterior gradient 2-mediated angiogenesis. AB - Several studies have revealed the potential of normalizing tumor vessels in anti angiogenic treatment. Recombinant human endostatin is an anti-angiogenic agent which has been applied in clinical tumor treatment. Our previous research indicated that gold nanoparticles could be a nanoparticle carrier for recombinant human endostatin delivery. The recombinant human endostatin-gold nanoparticle conjugates normalized vessels, which improved chemotherapy. However, the mechanism of recombinant human endostatin-gold nanoparticle-induced vascular normalization has not been explored. Anterior gradient 2 has been reported to be over-expressed in many malignant tumors and involved in tumor angiogenesis. To date, the precise efficacy of recombinant human endostatin-gold nanoparticles on anterior gradient 2-mediated angiogenesis or anterior gradient 2-related signaling cohort remained unknown. In this study, we aimed to explore whether recombinant human endostatin-gold nanoparticles could normalize vessels in metastatic colorectal cancer xenografts, and we further elucidated whether recombinant human endostatin-gold nanoparticles could interrupt anterior gradient 2-induced angiogenesis. In vivo, it was indicated that recombinant human endostatin-gold nanoparticles increased pericyte expression while inhibit vascular endothelial growth factor receptor 2 and anterior gradient 2 expression in metastatic colorectal cancer xenografts. In vitro, we uncovered that recombinant human endostatin-gold nanoparticles reduced cell migration and tube formation induced by anterior gradient 2 in human umbilical vein endothelial cells. Treatment with recombinant human endostatin-gold nanoparticles attenuated anterior gradient 2-mediated activation of MMP2, cMyc, VE-cadherin, phosphorylation of p38, and extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) in human umbilical vein endothelial cells. Our findings demonstrated recombinant human endostatin-gold nanoparticles might normalize vessels by interfering anterior gradient 2-mediated angiogenesis in metastatic colorectal cancer. PMID- 28714366 TI - High MRPS23 expression contributes to hepatocellular carcinoma proliferation and indicates poor survival outcomes. AB - Hepatocellular carcinoma is one of the most prevalent neoplasms and the leading cause of cancer-related mortality worldwide. Mitochondrial ribosomal protein S23 is encoded by a nuclear gene and participates in mitochondrial protein translation. Mitochondrial ribosomal protein S23 overexpression has been found in many types of cancer. In this study, we explored mitochondrial ribosomal protein S23 expression in primary hepatocellular carcinoma tissues compared with matched adjacent non-tumoral liver tissues using mitochondrial ribosomal protein S23 messenger RNA and protein levels collected from public databases and clinical samples. Immunohistochemistry was performed to analyze the relationship between mitochondrial ribosomal protein S23 and various clinicopathological features. The results indicated that mitochondrial ribosomal protein S23 was significantly overexpressed in hepatocellular carcinoma. High mitochondrial ribosomal protein S23 expression was correlated with the tumor size and tumor-metastasis-node stage. Moreover, patients with high mitochondrial ribosomal protein S23 expression levels presented poorer survival rates. Mitochondrial ribosomal protein S23 was an independent prognostic factor for survival, especially at the early stage of hepatocellular carcinoma. In addition, the downregulation of mitochondrial ribosomal protein S23 decreased the proliferation of hepatocellular carcinoma in vitro and in vivo. In conclusion, we verified for the first time that mitochondrial ribosomal protein S23 expression was upregulated in hepatocellular carcinoma. High mitochondrial ribosomal protein S23 levels can predict poor clinical outcomes in hepatocellular carcinoma, and this protein plays a key role in tumor proliferation. Therefore, mitochondrial ribosomal protein S23 may be a potential therapeutic target for hepatocellular carcinoma. PMID- 28714368 TI - Cordycepin induces apoptosis in human bladder cancer cells via activation of A3 adenosine receptors. AB - Bladder cancer is a neoplasm originated from bladder epithelial cells. The therapy for bladder cancer is so far not satisfactory. In this study, we examined the effects of Cordyceps militaris hot water extracts containing cordycepin on human bladder cells. Cordyceps militaris hot water extracts containing cordycepin was used to treat human T24 bladder carcinoma cells, and we found that Cordyceps militaris hot water extracts containing cordycepin decreased T24 cell survival in a dose-dependent manner, which was seemingly mediated by activation of A3 adenosine receptor and the subsequent inactivation of Akt pathways, resulting in increases in cleaved Caspase-3 and apoptosis. Overexpression of A3 adenosine receptor in T24 cells mimicked the effects of Cordyceps militaris hot water extracts, while A3 adenosine receptor depletion abolished the effects of Cordyceps militaris hot water extracts containing cordycepin. Together, these data suggest that Cordyceps militaris hot water extracts containing cordycepin may be a promising treatment for bladder cancer via A3 adenosine receptor activation. PMID- 28714367 TI - PARP-1 serves as a novel molecular marker for hepatocellular carcinoma in a Southern Chinese Zhuang population. AB - PARP-1 (poly(ADP-ribose) polymerase-1) plays an important role in tumorigenesis. Since its effects on different populations are varied, this study investigated the impact of PARP-1 on primary hepatocellular carcinoma in a Southern Chinese Zhuang population. We assessed the global PARP-1 messenger RNA expression in patients with hepatocellular carcinoma using The Cancer Genome Atlas dataset. Increased PARP-1 expression, related to alpha-fetoprotein level, was observed. The area under the receiver operating characteristic curve value was 0.833. Kaplan-Meier survival curves indicated that higher PARP-1 expression was not correlated with poorer overall survival and recurrence-free survival. In a Zhuang population, PARP-1 messenger RNA and protein levels were increased in the hepatocellular carcinoma tissue and its adjacent liver tissues as assessed by quantitative polymerase chain reaction, immunohistochemistry, and western blotting. Higher PARP-1 level was associated with a higher tumor stage (p < 0.05), without correlation with age, gender, smoking, drinking, tumor size, serum alpha-fetoprotein level, hepatitis B virus infection, metastasis, and invasion (p > 0.05). Further analysis suggested that H2AX, a PARP-1 protein interaction partner, was coordinated with PARP-1 in hepatocellular carcinoma tumorigenesis. Overall, some new characteristics of PARP-1 expression were noted in the Zhuang population. PARP-1 is a novel promising diagnostic marker for hepatocellular carcinoma in the Southern Chinese Zhuang population. PMID- 28714369 TI - Sporamin induces apoptosis and inhibits NF-kappaB activation in human pancreatic cancer cells. AB - Sporamin, a Kunitz-type trypsin inhibitor (TI) from sweet potato tuberous roots, has demonstrated anti-tumor activity through poorly defined mechanisms. Furthermore, the effects of sporamin on pancreatic cancer have not been explored. Herein, we studied the effects of sporamin on two human pancreatic cancer cell lines, PANC-1 and BxPC-3. Sporamin significantly inhibited the cell viability and proliferation activity and induced apoptosis in PANC-1 and BxPC-3 cells. Consistently, in sporamin-treated PANC-1 and BxPC-3 cells, the anti-apoptotic proteins Bcl-2 and Bcl-XL were downregulated and the pro-apoptotic protein Bax was upregulated. Moreover, nuclear factor kappa B activation and IkappaBalpha phosphorylation were inhibited, and total IkappaBalpha expression was increased in sporamin-treated PANC-1 and BxPC-3 cells. Thus, our results suggest that the anti-tumor effects of sporamin in pancreatic cancer cells might result partly from induction of apoptosis by downregulating nuclear factor kappa B pathway. PMID- 28714370 TI - Phosphatase and tensin homolog deleted on chromosome 10 degradation induced by NEDD4 promotes acquired erlotinib resistance in non-small-cell lung cancer. AB - Acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors, such as gefitinib and erlotinib, is a critical issue in the treatment of patients with epidermal growth factor receptor mutant-positive non-small-cell lung cancer. Recent evidence suggests that downregulation of gene of phosphatase and tensin homolog deleted on chromosome 10 plays an important role in acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors in various types of cancers, including lung cancer. It was reported that the E3 ubiquitin ligase neural precursor cell expressed developmentally downregulated gene (NEDD4) (also known as NEDD4-1) negatively regulated phosphatase and tensin homolog deleted on chromosome 10 protein levels through poly-ubiquitination and proteolysis in carcinomas of the prostate, lung, and bladder. Whether this process plays a role in epidermal growth factor receptor-tyrosine kinase inhibitors resistance in non-small-cell lung cancer has not been studied extensively. In view of this, we investigated the involvement of NEDD4 and phosphatase and tensin homolog deleted on chromosome 10 in acquired erlotinib resistance with tyrosine kinase inhibitor-sensitive (HCC827) or tyrosine kinase inhibitor-resistant (Erlotinib-resistant HCC827/ER cells which harbored exon 19 deletion. Overexpression of NEDD4 in HCC827/ER cells was detected, and the reverse correlation between NEDD4 and phosphatase and tensin homolog deleted on chromosome 10 expression in these cells was also revealed. In HCC827/ER cells with knockdown of NEDD4, phosphatase and tensin homolog deleted on chromosome 10 and p-Akt expressions were decreased; the sensitivity of HCC827/ER cells to erlotinib was partially restored. Similar results were also observed in vivo. In H1650/ER cells harboring both exon 19 and phosphatase and tensin homolog deleted on chromosome 10 deletion, expression of p-Akt and sensitivity to erlotinib were not affected by simple knockdown of NEDD4 but affected after transfection of phosphatase and tensin homolog deleted on chromosome 10 into H1650/ER cells. Our results demonstrate that NEDD4 may promote the acquired resistance of non-small cell lung cancer cells to erlotinib by decreasing phosphatase and tensin homolog deleted on chromosome 10 protein expression. Targeted decrease in NEDD4 expression may be a potential therapeutic strategy for tyrosine kinase inhibitor resistant non-small-cell lung cancer. PMID- 28714371 TI - High expression of nucleobindin 2 is associated with poor prognosis in gastric cancer. AB - Nucleobindin 2 has been reported that its high expression is associated with poor outcome and promotes cell migration and lymph node metastasis in breast cancer, colon cancer, and prostate cancer. However, we aimed to investigate the nucleobindin 2 expression in gastric cancer tissues and adjacent non-tumor tissues and its potential relevance to clinicopathological factors and prognosis using immunohistochemical analysis. In our study, nucleobindin 2 level in gastric cancer tissues was higher than in non-tumor tissues. A high expression of nucleobindin 2 is significantly associated with tumor depth, lymph node metastasis, lymphatic invasion, venous invasion, and clinical stage. Furthermore, the expression level of nucleobindin 2 protein was independent predictor of progression-free survival. In summary, nucleobindin 2 might play a crucial role in gastric cancer development and could serve as an independent predictor of prognosis of gastric cancer patients. PMID- 28714372 TI - Risk of severe pulmonary embolism in cancer patients receiving bevacizumab: Results from a meta-analysis of published and unpublished data. AB - To evaluate the association between severe pulmonary embolism events and bevacizumab, we conducted the first meta-analysis evaluating the incidence and risk of pulmonary embolism associated with bevacizumab-based therapy. We searched PubMed, EMBASE, Cochrane Library, and ClinicalTrials.gov up to September 2016 for randomized controlled trials comparing bevacizumab with no bevacizumab on cancer patients. Incidence rates, relative risks, and 95% confidence intervals were calculated using fixed- or random-effects models. The primary end point was the association of bevacizumab with pulmonary embolism. Subgroup analyses were performed according to tumor type, dose, and publication status. In total, 23 randomized controlled trials were included. For patients receiving bevacizumab, the overall incidence of severe pulmonary embolism events was 1.76% (95% confidence interval = 1.25%-2.27%). Cancer patients treated with bevacizumab did not increase the risk of pulmonary embolism events (relative risk = 1.00, 95% confidence interval = 0.80-1.25). No significant differences in pulmonary embolism incidence or risk among subgroup analyses were observed. No evidence of publication bias was observed. This study suggested that bevacizumab may not increase the risk of pulmonary embolism in cancer patients. PMID- 28714373 TI - Targeting miR-21 decreases expression of multi-drug resistant genes and promotes chemosensitivity of renal carcinoma. AB - Renal cell carcinoma, the most common neoplasm of adult kidney, accounts for about 3% of adult malignancies and is usually highly resistant to conventional therapy. MicroRNAs are a class of small non-coding RNAs, which have been previously shown to promote malignant initiation and progression. In this study, we focused our attention on miR-21, a well described oncomiR commonly upregulated in cancer. Using a cohort of 99 primary renal cell carcinoma samples, we showed that miR-21 expression in cancer tissues was higher than in adjacent non-tumor tissues whereas no significant difference was observed with stages, grades, and metastatic outcome. In vitro, miR-21 was also overexpressed in renal carcinoma cell lines compared to HK-2 human proximal tubule epithelial cell line. Moreover, using Boyden chambers and western blot techniques, we also showed that miR-21 overexpression increased migratory, invasive, proliferative, and anti-apoptotic signaling pathways whereas opposite results were observed using an anti-miR-21 based silencing strategy. Finally, we assessed the role of miR-21 in mediating renal cell carcinoma chemoresistance and further showed that miR-21 silencing significantly (1) increased chemosensitivity of paclitaxel, 5-fluorouracil, oxaliplatin, and dovitinib; (2) decreased expression of multi-drug resistance genes; and (4) increased SLC22A1/OCT1, SLC22A2/OCT2, and SLC31A1/CTR1 platinum influx transporter expression. In conclusion, our results showed that miR-21 is a key actor of renal cancer progression and plays an important role in the resistance to chemotherapeutic drugs. In renal cell carcinoma, targeting miR-21 is a potential new therapeutic strategy to improve chemotherapy efficacy and consequently patient outcome. PMID- 28714374 TI - Screening key genes and miRNAs in early-stage colon adenocarcinoma by RNA sequencing. AB - Colon adenocarcinoma is the third leading cause of cancer-related deaths across the world, developing novel and non-invasive diagnostic and prognostic biomarkers for the early-stage colon adenocarcinoma at molecular level is essential. In our study, RNA-sequencing was performed to identify the differentially expressed genes and miRNAs (DEmiRNAs) in early-stage colon adenocarcinoma compared to tissues of precancerous lesions, colonic intraepithelial neoplasia. The DEmiRNA target interaction network was constructed and functional annotation of targets of DEmiRNAs was performed. The Cancer Genome Atlas was used to verify the expression of selected differentially expressed genes. The receiver operating characteristic analyses of selected differentially expressed genes was performed. In total, 865 differentially expressed genes, 26 DEmiRNAs, and 329 DEmiRNA-target pairs were obtained. Based on the early-stage colon adenocarcinoma network, miR 548c-5p, miR-548i, and miR-548am-5p were the top three DEmiRNAs that covered most differentially expressed genes. NTRK2, DTNA, and BTG2 were the top three differentially expressed genes regulated by most DEmiRNAs. Cancer and colorectal cancer pathways were two significantly enriched pathways in early-stage colon adenocarcinoma. The common differentially expressed genes in both the pathways were AXIN2, Smad2, Smad4, PIK3R1, and BCL2. The expression levels of eight differentially expressed genes (NTRK2, DTNA, BTG2, COL11A1, Smad2, Smad4, PIK3R1, and BCL2) in The Cancer Genome Atlas database were compatible with our RNA sequencing. All these eight differentially expressed genes and AXIN2 had the potential diagnosis value for Colon adenocarcinoma. In conclusion, a total of ten differentially expressed genes (NTRK2, DTNA, BTG2, COLCA1, COL11A1, AXIN2, Smad2, Smad4, PIK3R1, and BCL2) and four DEmiRNAs (miR-548c-5p, miR-548i, mir-424-5p, and miR-548am-5p) may be involved in the pathogenesis of early-stage colon adenocarcinoma which may make a contribution for developing new diagnostic and therapeutic strategies for early-stage colon adenocarcinoma. PMID- 28714375 TI - The association of miR-126-3p, miR-126-5p and miR-664-3p expression profiles with outcomes of patients with metastatic colorectal cancer treated with bevacizumab. AB - MicroRNAs regulate the expression of genes involved in several important cancer related processes including cell adhesion, proliferation, and tumour angiogenesis. Bevacizumab is routinely used in the treatment of patients with metastatic colorectal cancer, but, so far, no reliable biomarker predicting response to bevacizumab has been established. The aim of our retrospective study was to evaluate the association of miR-126-3p, miR-126-5p and miR-664-3p tumour expression levels with outcomes of patients with metastatic colorectal cancer treated with bevacizumab. The study included 63 patients. For the assessment of microRNA expression, gene-specific TaqMan assays were used. The median progression-free survival and overall survival for patients with low tumour expression of miR-126-3p were 8.8 and 20.6 months versus 13.5 months and median overall survival was not reached for patients with high expression ( p = 0.0064 and p = 0.0027), respectively. The median progression-free survival and overall survival for patients with low tumour expression of miR-126-5p were 9.0 and 22.2 months versus 12.0 and 23.4 months for patients with high expression ( p = 0.2113 and 0.6858), respectively. The median progression-free survival and overall survival for patients with low tumour expression of miR-664-3p were 9.1 and 22.5 months versus 8.8 and 23.4 months for patients with high expression ( p = 0.2542 and p = 0.1922), respectively. The multivariable Cox proportional hazards model revealed that miR-126-3p expression was significantly associated with progression free survival (hazard ratio = 0.28, p = 0.0053) and also with overall survival (hazard ratio = 0.18, p = 0.0046). In conclusion, the results of this study suggest that the expression of miR-126-3p in the tumour tissue was associated with outcome of metastatic colorectal cancer patients treated with bevacizumab. PMID- 28714376 TI - Retrospective comparison of low molecular weight heparin vs. warfarin vs. oral Xa inhibitors for the prevention of recurrent venous thromboembolism in oncology patients: The Re-CLOT study. AB - Background There is increasing evidence indicating oral factor Xa inhibitors can be used for secondary prevention of venous thromboembolism. Studies are needed to compare oral factor Xa inhibitors, low molecular weight heparins, and warfarin in the oncology population. The purpose of this study is to evaluate the recurrent venous thromboembolism incidence in oncology patients utilizing oral Xa inhibitors, low molecular weight heparins, or warfarin. Methods Using retrospectively collected data, we compared the recurrent venous thromboembolism incidence in oncology patients taking rivaroxaban/apixaban, enoxaparin, or warfarin with at least three months of follow-up. Patients were included if they had an active cancer, venous thromboembolism, and taking warfarin, enoxaparin, or rivaroxaban/apixaban. The primary endpoint was the first episode of recurrent venous thromboembolism at three months. Secondary endpoints included recurrent venous thromboembolism after six months, major bleeding, and mortality. Results Of 127 venous thromboembolism patients, 48 received rivaroxaban or apixaban, 23 received enoxaparin, and 56 received warfarin. The three most common cancer diagnoses were lung (21%), colorectal (14%), and breast (14%). There was no difference in venous thromboembolism recurrence at three months between the rivaroxaban/apixaban (0%), warfarin (3.6%), and the enoxaparin cohorts (4.4%) (p = 0.8319). Major bleeding at three months was only seen in one patient in the enoxaparin arm (4.2%). Mortality at three months was 0%, 3.6%, and 17.4% in the rivaroxaban/apixaban, warfarin, and enoxaparin cohorts, respectively. Conclusion The results of this retrospective study suggest that oral factor Xa inhibitors are potential options for cancer patients with venous thromboembolism. However, randomized, controlled trials are needed to confirm these results. PMID- 28714377 TI - Ibrutinib-associated tumor lysis syndrome in chronic lymphocytic leukemia/small lymphocytic lymphoma and mantle cell lymphoma: A case series and review of the literature. AB - Background Tumor lysis syndrome results when intracellular contents are released during cell lysis. Ibrutinib, a Bruton tyrosine kinase inhibitor, is used for the treatment of chronic lymphocytic leukemia, small lymphocytic lymphoma, Waldenstrom's macroglobulinemia, mantle cell lymphoma, and marginal zone lymphoma. Tumor lysis syndrome caused by ibrutinib therapy is potentially life threatening, but is rare and not often reported in clinical trials. Objective The purpose of this case series is to describe the occurrence of tumor lysis syndrome in two patients initiated on ibrutinib, and to highlight the importance of close monitoring during therapy. Discussion One patient with chronic lymphocytic leukemia/small lymphocytic lymphoma and one patient with mantle cell lymphoma developed laboratory and clinical tumor lysis syndrome following initiation of ibrutinib therapy. Assessment with the Naranjo Adverse Drug Reaction Probability Scale indicated one probable relationship and one possible relationship between ibrutinib therapy and tumor lysis syndrome. There were additional factors that may have confounded the laboratory and clinical factors observed, including baseline laboratory values and concurrent medications. Both patients were managed with supportive therapies. A literature review identified five additional reported cases of tumor lysis syndrome following ibrutinib therapy. Conclusion This case series identifies one patient with a probable relationship and one patient with a possible relationship between the development of tumor lysis syndrome and treatment with ibrutinib. Although uncommon, proper attention should be given to monitoring for this adverse drug reaction and appropriate follow-up should occur despite ibrutinib's ease of administration. PMID- 28714378 TI - Utilization of capecitabine plus oxaliplatin and 5-fluorouracil/folinic acid plus oxaliplatin in the adjuvant treatment of stage IIB and stage III colon cancer: A multi-centre, retrospective, chart review study. AB - Purpose First, to assess drug utilization rates of capecitabine plus oxaliplatin (CAPOX) versus 5-fluorouracil plus oxaliplatin (mFOLFOX6) regimens in the treatment of stage IIB and stage III colon cancer. Second, to assess patient characteristics used to select CAPOX versus FOLFOX therapy, dose-limiting toxicities, dose intensities and treatment completion rates. Methods Patients with resected stage IIB or stage III colon cancer from five British Columbia Cancer Agency centres treated with CAPOX or mFOLFOX6 were selected for the analysis. Protocol utilization rates, patient characteristics and toxicities of the two regimens were collected and compared by descriptive statistics. Results A total of 306 patients were included over study period. mFOLFOX6 is the most commonly used regimen with 69% utilization rate. CAPOX patients were younger (57 years old vs. 62 years old, p < 0.01), but no other significant differences were found. CAPOX was associated with more dose-limiting toxicities compared to mFOLFOX6 (95% vs. 82%, p < 0.01). Fewer patients completed the intended 24-week course of CAPOX compared to mFOLFOX6 (67% vs. 82%, p < 0.01). Conclusion FOLFOX is the most commonly utilized adjuvant treatment option for stage IIB and stage III colon cancer in British Columbia, and is associated with better tolerability and higher treatment completion rates. PMID- 28714379 TI - Prevalence study on potential drug-drug interaction in cancer patients in Piacenza hospital's Onco-Haematology department. AB - Background Cancer patients can be a human model of potential drug interactions. Usually they receive a large number of different medications, including antineoplastic agents, drugs for comorbid illness and medication for supportive care, however information about these interactions are fragmented and poor. Objective We assessed a prospective study to evaluate the prevalence of drug interaction among patients hospitalized in the Onco-Haematology department, Hospital of Piacenza. Methods Data on drugs administered for cancer, comorbidities, or supportive care were collected from different computerized prescription software in use in the department; we compared them with a database to focus on the co-administration of drugs. A literature review was performed to identify major potential drug interaction and to classify them by level of severity and by strengths of scientific evidence. Results In this study 284 cancer patients were enrolled; patients had taken an average of seven drugs on each day of therapy plus chemotherapeutic agents, we identified 67 potential drug interactions. At least 53 patients had one potential drug interaction. Of all potential drug interactions 63 were classified as moderate severity and only four as major. In 55 cases chemotherapeutic agents were involved in possible interactions with supportive care drugs, meanwhile in 12 cases the potential drug interactions were between supportive care drugs. Conclusions In our centre, thanks to a computerized prescription software, integrated with caution alarm in case of possible interaction, we had a lower rate of potential drug interactions than the one from literature. It is possible to improve the software integrating the alarm with the potential drug interactions between chemotherapy agents and supportive care drugs. PMID- 28714380 TI - Loperamide and cardiac events: Is high-dose use still safe for chemotherapy induced diarrhea? AB - High-dose loperamide is often used for the acute management of chemotherapy induced diarrhea, with a maximum daily dosing of up to 24 mg. Recently, the US Food and Drug Administration has issued a warning that loperamide can cause rare serious cardiac events, including QT prolongation, torsades de pointes, cardiac arrest and death. Most events were reported in patients taking very high doses for an extended period of time. Daily intake ranged from 64 mg to 1600 mg, often continuously for weeks or months. In addition, the reported serum levels of loperamide ranged from 22 ng/mL to 210 ng/mL, which is likely significantly higher than that expected from patients taking the recommended doses for chemotherapy-induced diarrhea. Overall, the incidence of serious cardiac events associated with loperamide remains low. In balance, the risk of uncontrolled complications from chemotherapy-induced diarrhea is likely greater than the rare cardiac risk associated with the chronic misuse of much higher doses of loperamide. PMID- 28714381 TI - Gemcitabine associated pseudocellulitis: A missed diagnosis. AB - We report a case of a 51-year-old male with past medical history significant for cholangiocarcinoma presented with two weeks of worsening bilateral lower extremity swelling and erythema. Patient has been on active chemotherapy for his cholangiocarcinoma with Gemcitabine weekly infusions. Physical exam was significant for bilaterally petechial rash coalescing into ecchymoses over the dorsum of the feet, sparing soles and toes, which dissipated into thinning petechiae more proximally. On labs he did not have any leukocytosis, his platelet count was 50 * 103/uL and basic metabolic panel was benign. Patient was started on Vancomycin for presumed cellulitis. Lower extremity ultrasound Doppler ruled out deep venous thrombosis. Patient did have biopsies bilaterally on his legs, which showed hypersensitivity reaction consistent with the diagnosis of pseudocellulitis. His Vancomycin was discontinued and his symptoms improved. Our case further supports that pseudocellulitis is underrecognized and underreported, potentially leading to unnecessary antibiotic exposure and unnecessary diagnostic work-up as seen unfortunately in our patient. Unnecessary antibiotic exposure is increasing the risk for clostridium difficile and or antibiotic resistance, therefore awareness of this reaction is critical, as to avoid unnecessary antibiotics, and costly diagnostic workups. PMID- 28714382 TI - Low Prevalence of Insulin Resistance Among Iranian Patients with Chronic Hepatitis C Virus Infection: A Case-Control Study. AB - BACKGROUND: Association between Chronic Hepatitis C virus (CHC) infection and type 2 diabetes mellitus has been challenging in recent decades. Despite of extensive research in this area, there is no general agreement on the direct effect of HCV infection on insulin resistance. PATIENTS AND METHODS: The study was performed in 52 CHC patients (mean age = 39.48) and 52 sex-matched healthy Iranian controls, referred to the Hepatitis Clinic, Department of Gastroenterohepatology, Shiraz University of medical sciences, Shiraz, Iran, from 2012 to 2015. Fasting blood glucose level, fasting insulin level and insulin resistance defined as a Homeostasis Model Assessment of Insulin Resistance (HOMA IR) index were determined and compared between two groups. RESULTS: Insulin resistance was present in 26.9% of CHC patients and 34.62% of healthy controls. Mean HOMA index was 1.93 in patients and 2.18 in controls. There were no statistically significant differences between patient and control groups with regard to fasting insulin level, fasting blood glucose, HOMA index and insulin resistance. HOMA index and fasting insulin level were significantly higher in IR CHC patients relative to IR controls. Fasting blood glucose was also significantly higher in controls younger than 40 years. CONCLUSION: Results obtained in this study showed that chronic hepatitis C cannot be considered as a risk factor for insulin resistance and diabetes in Iranian population. However, regular screening for insulin resistance is recommended in CHC patients with age >= 40 years and fasting blood glucose >= 100 mg/dl. PMID- 28714383 TI - Novel Mannich-bases as Potential Anticonvulsants: Syntheses, Characterization and Biological Evaluation. AB - BACKGROUND: Mannich bases are known to be an important pharmacophore or bioactive leads in the synthesis of various potential agents that have a variety of therapeutic activities like anticancer, antipsychotic, anticonvulsant, antimalarial, anti-inflammatory, antibacterial and so forth. Thus, in the present research, conjugation of moieties like 1,5-benzoxazepines and 1,5 benzothiazepines with secondary amines like piperazine, methyl piperazine and morpholine was carried out in a Mannich base with an anticipation of good anticonvulsant activity. OBJECTIVE: Synthesis, characterization, structure activity relationship and anticonvulsant activity of the Mannich bases of 1,5 benzothiazepine and 1,5-benzoxazepine derivatives. METHODS: All the derivatives were synthesized in three steps. In the first step, substituted 4-hydroxy chalconylbenzene was synthesized by the reaction of 4-hydroxyacetophenone and substituted benzaldehyde, in the presence of potassium hydroxide. In the second step, 2,3-dihydro- 1,5- benzothiazepines and 2,3-dihydro-1,5-benzoxazepines were synthesized by the reaction of 2- thio/aminophenol with chalcones in the presence of glacial acetic acid. In the third step, these compounds finally underwent Mannich reaction with different secondary amines to the respective title compounds. All the synthesized derivatives were characterised and evaluated for anticonvulsant activity using MES (Maximal Electroshock Induced Seizure) and INH (Isoniazide Induced Convulsion) models. RESULTS: The synthesized derivatives were found to be more active in the MES model than INH model, with phenytoin and diazepam being the standards respectively. Accordingly, the mode of action of the synthesized compounds may be similar to phenytoin. The methyl piperazine containing compound, at a dose of 30 mg/kg., was found to be the most active and promising compound in the series. CONCLUSION: The benzothiazepine derivatives showed better anticonvulsant activity than the benzoxazepines derivatives. PMID- 28714384 TI - Chemistry in the Bioactivity of Chlorophylls: An Overview. AB - BACKGROUND: In addition to the considerable number of different chlorophyll structures originated naturally, prominent research is made to produce new specific semisynthetic structures. The final target is to obtain chlorophyll derivatives with even better bioactive properties than those of the natural parent compounds. METHOD: A detailed, extensive and critic literature search has been made in Web of ScienceTM. RESULTS: Great efforts are applying to optimize the function of chlorophyll-based photosensitizers, to understand the molecular mechanisms of the antioxidant and antigenotoxic properties of chlorophyll derivatives and, lastly, to investigate new biological actions of them. However, the fundamental physiological functions of the chlorophylls are their physicochemical properties. CONCLUSION: This review aims to reflect the chemical grounds of the healthy and/or medical features of chlorophylls, including the consequences, advantages or even new actions that modifications over the chlorophyll structure introduce. Finally, new perspectives in the functionality of chlorophylls at molecular level are discussed. PMID- 28714385 TI - Therapeutic Application of Natural Medicine Monomers in Cancer Treatment. AB - BACKGROUND: Natural medicine monomers (NMMs) isolated from plants have been recognized for their roles in treating different human diseases including cancers. Many NMMs exhibit effective anti-cancer activities and can be used as drugs or adjuvant agents to enhance the efficacy of chemotherapy and radiotherapy. Some NMMs, such as paclitaxel and camptothecin, have been extensively studied for decades and are now used as anti-cancer medicines due to their remarkable curative effects, such as inhibiting cancer cell proliferation and metastasis, and inducing cell death and differentiation. METHODS: After extensively reviewing papers related to NMM studies in cancers, we grouped NMMs into six categories based on their chemical structures. We summarized the anti cancer activities of these NMMs and current knowledge of molecular mechanisms for them to exert their functions. RESULTS AND CONCLUSION: Many NMMs from plants can effectively inhibit cancer cells with low or tolerable toxicity to patients. Some NMMs have been well-characterized for their anti-cancer activities and have already been used as clinical drugs or adjuvant agents; however, the mechanisms underlying the cancer suppressive activities of most NMMs remain poorly understood. Many NMMs can be used as initial structural scaffolds to design and develop novel therapeutics against cancers. This review summarizes reports related to signaling pathways mediated by different NMMs and can provide a theoretical basis for clinical application and new drug development of NMMs. PMID- 28714386 TI - Nitroisoxazolones Showing Diverse Chemical Behavior: A Use ful Building Block for Polyfunctionalized Systems. AB - BACKGROUND: 4-Functionalized isoxazolin-5-ones (isoxazolones) have attracted much attentions as precursors of functionalized building blocks because the multiple functionalities. These structural features facilitate the construction of large compound libraries that is important for development of new functional materials. However, the systematic review article dealing with nitroisoxazolone has not been published although they exhibit different reactivity from other functionalized isoxazolones. This review describes the interesting behavior of the nitroisoxazolone motif and its application to the synthesis of polyfunctionalized compounds. METHODS: Peer-reviewed research literatures describing the chemistry of nitroisoxazolones were collected, and each paper was appraised using standard criteria. inclusion/exclusion criteria. The papers were analyzed, and divided according to the reaction patterns. RESULTS: This review consists of two parts. In the former part, the chemistry of pyridinium salt of nitroisoxazolone is described, and in the latter part, chemistry of methylnitroisoxazolone is introduced. Sixty-eight papers were included in this review. Twelve papers deal with pyridinium salt or its ring-opened product, cyano-aci-nitroacetate. Nine papers mention the chemistry of methylnitroisoxazolones and derived nitroenamines and nitrile oxide. With regard to each chemistry, reaction mechanism and reactivity are discussed with citing related literatures. CONCLUSION: The findings of this review confirm the importance of nitroisoxazolones in synthetic chemistry for polyfunctionalized compounds, which are not readily available by alternative methods. This review will provide useful information and synthetic tools for many chemists studying synthetic chemistry and medicinal chemistry. PMID- 28714387 TI - Macrophage Migration Inhibitory Factor - A Favorable Marker in Inflammatory Diseases? AB - BACKGROUND: Macrophage migration inhibitory factor (MIF) was firstly described in the 1960s as a pleiotropic cytokine affecting a variety of immune cells. Different physiological functions mainly involving inflammatory reactions such as chemokine-like function and regulating systemic stress responses have been reported. OBJECTIVE: In several clinical studies the use of MIF as a biomarker has been investigated promising support for diseases with an inflammatory aspect such as sepsis, systemic infections and autoimmune diseases. This article in detail reviews clinical data and evaluates the function as biomarker focusing on inflammatory and autoimmune diseases. CONCLUSION: Recent studies suggest MIF to be a marker for different inflammatory diseases and might serve as therapeutic target in the future. PMID- 28714388 TI - Prospective Role of MicroRNAs in Depression. AB - BACKGROUND: Depression is a debilitating disease that is affecting a growing number of patients, both physically and mentally. In addition to mood changes, depression results in cognitive impairment. Although depression studies have been going on for decades, the underlying mechanism still remains unclear. MicroRNAs (miRNAs), a type of small non-coding RNAs, predominantly control the expression of their target mRNAs to exert their functions. Some evidences have revealed the importance of miRNAs in the mechanism of depression,however, these studies are still in their infancy. Alterations in brain regions, synaptic plasticity, hypothalamic-pituitary-adrenal (HPA) axis, changes in the levels of serotonin and glucocorticoids, together with stress response have been proven to be involved in depression. These alterations can influence cognition, learning and memory, with recent evidences demonstrating the involvement of miRNAs in several aspects of stress response, neural plasticity and neurogenesis as well as pathogenesis of depression. OBJECTIVE: In light of these theories of depression, this review was aimed at elucidating the role of miRNAs in the underlying mechanisms of depression resulting in cognitive, learning and memory impairments. METHOD/RESULTS: Both PubMed and Scopus databases were employed in scouring for research reports pertaining to this area of study. A total of 180 articles were obtained from these two databases. CONCLUSION: With the probing of classical theories of depression as well as the connection between miRNAs and depression, more studies,nevertheless, are needed to ascertain the full mechanism of depression along with its resultant cognitive, learning and memory impediments. PMID- 28714389 TI - A Peptide Based Pro-Drug Ameliorates Amyloid-beta Induced Neuronal Apoptosis in In Vitro SH-SY5Y Cells. AB - BACKGROUND: Alzheimer's disease (AD), a common protein misfolding progressive neurodegenerative disorder, is one of the most common forms of dementia. Amyloid precursor protein (APP) derived amyloid-beta (Abeta) protein accumulate into interneuronal spaces and plays a crucial role in the disease progression and its pathology. The aggregated Abeta exerts its neurotoxic effects by inducing apoptosis and oxidative damage in neuronal cells. OBJECTIVES: We have investigated the effects of a synthesized Pro-Drug peptide (PDp) on Abeta1-40 induced cytotoxicity in human neuroblastoma SH-SY5Y cells, represents one of the most effective strategies in combating human AD. METHODS: Cells were treated with Abeta1-40 to induce cytotoxicity in the experimental model of AD to screen the inhibitory effect of PDp. Assays for cell viability, reactive oxygen species (ROS) generation, levels of intracellular free Ca2+ and expression of key apoptotic proteins were assessed by Western Blotting. RESULTS: Our results showed that Abeta1-40 induces for 24h caused reduce cell viability, imbalance in Ca2+ homeostasis and increase in neuronal apoptosis in vitro. Treatment with PDp could effectively ameliorated Abeta1-40 induced neurotoxicity and attenuates ROS generation that mediates apoptotic signaling through Bcl-2, Bax, Caspase-3 activity and cytochrome c in the cells. CONCLUSION: These findings suggested that PDp has potential role as a neuroprotective and therapeutic agent for combating human AD. PMID- 28714390 TI - CDK5 and MAPT Gene Expression in Alzheimer's Disease Brain Samples. AB - BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by extracellular amyloid plaque and neurofibrillary tangles in the brain. Studies have shown that neurons are able to re-enter the cell cycle, but not enough to enable full replication. This leads to cell death and consequent neurodegeneration. OBJECTIVE: This study aimed to characterize the expression of the MAPT gene and CDK5 (the gene involved in cell cycle regulation) in brain samples from patients with AD and controls. METHOD: The real-time-PCR technique was used to characterize 150 samples from three areas of the brain (entorhinal cortex, auditory cortex, and hippocampus) of 26 AD patients and 24 healthy elderly subjects. RESULTS: When the brain samples were analyzed collectively, a decrease in CDK5 and MAPT gene expression was found in AD patients. When each groups' samples were separated by area of the brain and compared, significant differences were found in CDK5 expression in the hippocampus and the entorhinal cortex. In both cases, mRNA was lower in the AD group (p=0.0001); however, the same analysis using the MAPT gene revealed no significant statistical differences. No statistical differences were found when gene expression was compared between the different regions of the brain within each group. CONCLUSION: These results may contribute to a better understanding of the involvement of CDK5 and MAPT genes in AD in that they consider different areas of the brain that are affected differently based on disease progression. The main challenge is to establish an effective therapy for this debilitating disease in the future. PMID- 28714391 TI - Dancing as an Intervention Tool for People with Dementia: A Mini-Review Dancing and Dementia. AB - BACKGROUND: Research studies show a positive impact of physical activities such as dancing on the improvement of cognitive reserves of people with dementia. OBJECTIVE: The purpose of this study is to explore dancing efficacy on people with dementia and list the key benefits and limitations of dancing therapy for these people. METHODS: The methods used in this study include a method of literature review of available Englishwritten sources with respect to the dancing therapy and dementia in the acknowledged databases Pub- Med, Web of Science, Springer, and Scopus, and a method of comparison and evaluation of their findings. RESULTS: The findings of this mini review confirm positive efficacy of dancing therapy on cognitive, physical, emotional and social performance of people with dementia. CONCLUSION: More randomized controlled clinical trials should be conducted in this field, as well as other non-pharmacological therapies should be employed in order to holistically contribute to the prevention and treatment of dementia. PMID- 28714392 TI - Natural Steroids and Androgen Antagonists used as Neuroprotection in Common Neurological Disorders. AB - BACKGROUND & OBJECTIVE: Multiple classes of natural products, such as antiandrogens or steroids have been used as antioxidants and anti-inflammatory treatments in neurodegenerative diseases. This paper aims to review current knowledge on these substances and their possible relationship with free radicals as an alternative therapy and prevention of common neurological disorders. An exhaustive review of the neurochemical mechanisms of these substances in the central nervous system of humans and animal models is yet to be undertaken in the literature, particularly regarding their importance and increasing use. CONCLUSION: Androgen receptor antagonists act in a different way that may underlie the benefits of natural products, with the expectation that in adults, neurological disorders would respond to natural antiandrogens. We hope that this work would provide valuable insight into the protective and therapeutic roles for natural antiandrogens and steroids in common neurological disorders. PMID- 28714393 TI - Interrelationships Among Gut Microbiota and Host: Paradigms, Role in Neurodegenerative Diseases and Future Prospects. AB - BACKGROUND & OBJECTIVE: Advances in the knowledge of the microbiota and concepts related to it have triggered a wake-up call in biomedicine. The development in various scientific areas has enabled a better and broader approach to everything concerning the set of families of microorganisms that coexist with an individual and are able to function as one or more organs in its body. Among the aforementioned scientific areas, those worth mentioning are the advances/progress in biotechnological resources and, in particular, molecular biology and related areas. This has given rise to the era of "omics", marking a turning point in the understanding of numerous physiologic and pathophysiologic processes of the organism. The current theory is that the microbiota and the host maintain an intimate relationship that is of a markedly bilateral nature. This continuous feedback has different connotations between one individual and another, but also within the same individual throughout its life span, which is determined by its own conditioning factors (such as its genetic profile), and environmental ones (mainly diet and lifestyles). Both elements (microbiota and host) coexist harmoniously, maintaining a balance, which can be altered and give rise to different morbid entities. Among these is its relation to chronic processes, and especially those of an autoimmune origin. Such may be neurological diseases situations and, specifically, those of a neurodegenerative nature. In disorders such as multiple sclerosis, amyotrophic lateral sclerosis, Huntington's chorea and Alzheimer's disease, among others, it has been found that a disharmonic coexistence between microbiota and host may have implications in their etiology and pathogenesis. A better understanding of those implications has led to the development of actions on the gut microbiota as a target to slow down the advancement or establishment of neurodegeneration. CONCLUSION: In this scenario, several treatment strategies have emerged, such as probiotic food intake and stool transplantation. Their real potentialities remain to be elucidated, although current scientific evidence infers that the development of those therapeutic approaches could offer a ray of hope in the prospects of tackling neurodegenerative diseases. PMID- 28714395 TI - Five decades of cuprizone, an updated model to replicate demyelinating diseases. AB - Multiple sclerosis, Guillain-Barre syndrome, peripheral nerve polyneuropathy and others comprise a group of demyelinating diseases characterized by progressive (and eventually irreversible) loss of oligodendrocytes and myelin sheaths in the white matter of the brain. To date, the etiology of these disorders is not well known and no effective treatments are currently available. Therefore, further research is needed to gain a better understand and treat these patients. To accomplish this goal, it is necessary to have appropriate animal models that closely resemble the pathophysiology of these diseases. Herein, we describe the model of toxic demyelination induced by cuprizone, a copper chelator that reduces the cytochrome and monoamine oxidase activity into the brain, produces mitochondrial stress and triggers local immunological responses. These biochemical and cellular changes ultimately result in selective loss of oligodendrocytes, extensive areas of demyelination and reactive gliosis in the corpus callosum, superior cerebellar peduncles and cerebral cortex. Remarkably, some aspects of the histological pattern induced by cuprizone are similar to those found in multiple sclerosis. Cuprizone exposure also provokes behavioral changes, impairs motor skills and affects mood as that observed in several demyelinating diseases. Upon cuprizone removal, the pathological and histological changes gradually revert. Therefore, the cuprizone model allows to partially mimic the disease relapses of some demyelinating diseases. In summary, the model of cuprizone-induced demyelination is a good experimental approach to study demyelinating diseases that has maintained its validity, and is a suitable pharmacological model for reproducing some key features of demyelinating diseases, including multiple sclerosis. PMID- 28714394 TI - Nanoparticle-Mediated Delivery of Neuroprotective Substances for the Treatment of Diabetic Retinopathy. AB - BACKGROUND: Diabetic retinopathy (DR) is a major complication of diabetes, characterized by extensive vascular pathology leading to vision loss. Neuronal suffering and death are also present in the diabetic retina as a result of different molecular mechanisms that are compromised or modified in response to high glucose. The aim of this paper is to highlight recent data indicating that neurodegeneration is likely to play a primary role in the development of DR and that strategies based on nanomedicine may be exploited to deliver neuroprotection to the retina. METHODS: An extensive analysis of the publications dealing with the role of neuroprotection in DR and with nanoparticle-mediated drug delivery to the retina has been conducted using PubMed, with particular attention to the most recent papers. RESULTS: There are important limitations related to possible systemic side effects of neuroprotective substances and to drug bioavailability in the retina such as, for instance, the amount of drug reaching the retina, the need of keeping to a minimum the number of administrations (especially, for example, in the case of intraocular injections) and the need of assuring a long lasting, graded intraocular drug delivery. In recent years, a variety of investigations have been aimed at the exploitation of approaches of nanomedicine to enhance the pharmacokinetics and pharmacodynamic activity of intraocularly delivered drugs. In particular, we provide some preliminary results that we have obtained about the feasibility of delivering magnetic nanoparticles functionalized with a neuroprotectant to mouse eyes through intraocular injections. CONCLUSION: We propose that nanoparticles functionalized with neuroprotective substances may be used to protect the diabetic retina, thus causing an impact in the design of future pharmacologic treatments for DR. PMID- 28714397 TI - Prognostic Value of Copeptin in Chronic Kidney Disease: From General Population to End-Stage Renal Disease. AB - Arginine vasopressin (AVP), also known as antidiuretic hormone (ADH), is released in response to osmotic and non-osmotic stimuli and plays a key role in many physiologic and pathologic processes. The main function of AVP is the control of fluid homeostasis by inducing water conservation by the kidney, but it also stimulates arteriolar vasoconstriction and the release of adrenocorticotropic hormone (ACTH). These actions are mediated by different AVP receptors located on various target cells. Produced in hypothalamus from a larger precursor, pre proAVP, AVP is produced in equimolar amounts to copeptin, a glycopeptide with yet unknown biologic function. Copeptin remains stable in plasma and its circulating concentrations correlate directly with those of AVP. Because AVP is unstable in isolated plasma or serum and its half-life is short, copeptin has become an easily measured surrogate marker reflecting vasopressin concentration. Recently, associations between high circulating copeptin and decline in glomerular filtration rate as well as greater risk of new-onset chronic kidney disease (CKD) have been reported. In addition, copeptin has been shown to be associated with increased risk of complications such as myocardial infarction, heart failure, diabetes mellitus and metabolic syndrome. In this brief review, studies on the prognostic value of copeptin measurement in the general population and in CKD are presented and discussed. PMID- 28714396 TI - Differential Effects of Nicotine Exposure on the Hippocampus Across Lifespan. AB - BACKGROUND: Nicotine exposure affects the hippocampus through activation of hippocampal nicotinic acetylcholine receptors (nAChRs), which are present throughout excitatory and inhibitory hippocampal circuitry. The role of cholinergic functioning in the hippocampus varies across developmental stages so that nicotine exposure differentially affects this region depending upon timing of exposure, producing developmentally distinct changes in structure, function, and behavior. METHODS: We synthesize findings across literature in this area to comprehensively review current understanding of the unique effects of nicotine exposure on the hippocampus throughout the lifespan with a focus on hippocampal morphology, cholinergic functioning, and hippocampusdependent learning and memory. CONCLUSIONS: Chronic and acute nicotine exposure differentially affect hippocampus structure, functioning, and related learning and memory in the perinatal period, adolescence, and aging. Age-related differences in sensitivity to nicotine exposure should be considered in the research of nicotine addiction and the development of nicotine addiction treatments. PMID- 28714399 TI - Design, Synthesis and Antibacterial Evaluation of Compounds Based on New Benzoxepine-oxime-1,2,3-triazole Hybrid. AB - BACKGROUND: A library of compounds related to the new benzoxepine-oxime-1,2,3 triazole hybrid was created as probable antibacterial agents. Their synthesis involved a Cu-catalyzed azidealkyne cycloaddition (CuAAC) as a key step to construct the desired 1,2,3-triazole ring. Thus the click reaction between the appropriate alkyne containing the benzoxepine-oxime framework with aryl azides afforded the target compounds in good yields. METHOD: To assess their antibacterial properties all the synthesized compounds were tested using four bacterial strains consisting of one Gram-positive and three Gram-negative species. RESULTS & CONCLUSION: These compounds were generally found to be effective towards gram -ve species and one of them showed selective cytotoxicity against lung cancer cell line. PMID- 28714398 TI - Nutlin-3, A p53-Mdm2 Antagonist for Nasopharyngeal Carcinoma Treatment. AB - Nasopharyngeal carcinoma (NPC) is a form of head and neck cancer of multifactorial etiologies that is highly prevalent among men in the population of Southern China and Southeast Asia. NPC has claimed many thousands of lives worldwide; but the low awareness of NPC remains a hindrance in early diagnosis and prevention of the disease. NPC is highly responsive to radiotherapy and chemotherapy, but radiocurable NPC is still dependent on concurrent treatment of megavoltage radiotherapy with chemotherapy. Despite a significant reduction in loco-regional and distant metastases, radiotherapy alone has failed to provide a significant improvement in the overall survival rate of NPC, compared to chemotherapy. In addition, chemo-resistance persists as the major challenge in the management of metastatic NPC although the survival rate of advanced metastatic NPC has significantly improved with the administration of chemotherapy adjunctive to radiotherapy. In this regard, targeted molecular therapy could be explored for the discovery of alternative NPC therapies. Nutlin-3, a small molecule inhibitor that specifically targets p53-Mdm2 interaction offers new therapeutic opportunities by enhancing cancer cell growth arrest and apoptosis through the restoration of the p53-mediated tumor suppression pathway while producing minimal cytotoxicity and side effects. This review discusses the potential use of Nutlin-3 as a p53-activating drug and the future directions of its clinical research for NPC treatment. PMID- 28714400 TI - Cholinesterase Inhibitory Activity of Some semi-Rigid Spiro Heterocycles: POM Analyses and Crystalline Structure of Pharmacophore Site. AB - BACKGROUND: Cholinesterase family consists of two sister enzymes; acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) which hydrolyze acetylcholine. Since deficit of acetylcholine has been evidenced in patients of Alzheimer's disease (AD), cholinesterase inhibitors are currently the most prescribed drugs for the treatment of AD. OBJECTIVE: our aim in this article was to investigate the inhibitory potential of five known compounds (2-6) with spiro skeleton against AChE and BChE using ELISA microplate assays. In addition to their ChE inhibitory effect, their physico-chemical properties were also calculated. Moreover, the present work aims at investigating the charge/geometrical effect of a hypothetical pharmacophore or bidentate site in a bioactive group, on the inhibition efficiency of spiro compounds 2-6 by using Petra/Osiris/ molinspiration (POM) and X-ray analyses. METHOD: In the present study, five compounds (2-6) with spiro skeleton have been synthesized and tested in vitro for their inhibitory potential against AChE and BChE using ELISA microtiter plate assays at 25 ug/mL. RESULTS: Results revealed that three of the spiro compounds tested exert more than 50% inhibition against one of cholinesterases. Compound 5 displayed 68.73 +/- 4.73% of inhibition toward AChE, whereas compound 6 showed 56.17 +/- 0.83% of inhibition toward BChE; these two previously synthesized compounds have been the most active hits. CONCLUSIONS: Our data obtained from screening of compounds 2-6 against the two cholinesterases indicate that three of these show good potential to selectively inhibit AChE or BChE. Spiro compounds 2, 5, and 6 exhibited the most potent activity of the series against AChE or BChE with inhibition values in the range 55-70%. PMID- 28714402 TI - Editorial The Role of Mesenchymal Stem Cells in Bone Regeneration: Underlying Mechanisms and Systemic Regulatory Factors. PMID- 28714401 TI - Chemical Consequences of Radioactive Decay and their Biological Implications. AB - The chemical effects of radioactive decay arise from (1) transmutation, (2) formation of charged daughter nuclei, (3) recoil of the daughter nuclei, (4) electron "shakeoff" phenomenon and (5) vacancy cascade in decays via electron capture and internal conversion. This review aims to reiterate what has been known for a long time regarding the chemical consequences of radioactive decay and gives a historical perspective to the observations that led to their elucidation. The energetics of the recoil process in each decay mode is discussed in relation to the chemical bond between the decaying nucleus and the parent molecule. Special attention is given to the biological effects of the Auger process following decay by electron capture and internal conversion because of their possible utility in internal radiotherapy. PMID- 28714403 TI - GSK3 Inhibitors in the Therapeutic Development of Diabetes, Cancer and Neurodegeneration: Past, Present and Future. AB - GSK3 has gained a considerable attention of researchers in the late 1970s as an inevitable drug target to treat diabetes. Furthermore, it was found to have a key role in the development of diseases like cancer and neurodegeneration (ND). A broad spectrum of GSK3 inhibitors have been discovered from time to time in order to curb these diseases. Inhibition of GSK3 by insulin boosts the dephosphorylation of glycogen synthase, hence its activation to convert UDP glucose into glycogen. Lack of insulin and insulin-resistance is supposed to be the cause of type 2 diabetes (Diabetes mellitus). Additionally, GSK3 stabilizes the components of beta-catenin complex, hence promotes oncogenesis. Phosphorylation of GSK3 by Akt and some other kinases also favours the carcinogenesis. However, in some cases GSK3 has tumor supressing character. GSK3 has been found to have a prominent role in the formation of amyloid plaques and neurofibrillary tangles (abnormal protein accumulations) which are the main suspects of Alzheimer's disease (AD). GSK3 inhibitors have been reported to have amyloidbeta disaggregation property and have been found to promote the adult hippocampal neurogenesis in vivo as well as in vitro. This manuscript thoroughly reviews the involvement of GSK3 in diabetes, cancer and ND. Furthermore, development of GSK3 inhibitors as antidiabetes, anticancer and antineurodegenerative agents focusing mainly on lead optimization has been discussed. PMID- 28714404 TI - Current and Emerging Strategies in Osteoporosis Management. AB - The abnormal loss of bone tissue is defined as osteoporosis. Increased risk of fractures, low bone mineral density (BMD) and loss of the structural and biomechanical properties of the bone tissue characterize this pathological condition. Physiologically bone undergoes a continuous remodeling process involving balance between the activity of osteoblast and osteoclast. Disruption in this balanced condition increases the risk of osteoporosis. Both sexes are affected, but with higher prevalence in women after menopause. This review aims to enlighten the established and emerging trends in prevention and treatment of bone loss. Herbal supplementation and physical exercises are suggested as addition to the well-established therapy in prevention and management of osteoporosis. Treatment strategies of osteoporosis include non- pharmacological treatment - diet rich of calcium and vitamin D, healthy lifestyle, proper exercise plan, and pharmacological therapy. Preventive and treatment strategies have to consider combination of non-pharmacological and pharmacological approaches for minimization of the fracture risk in osteoporosis. PMID- 28714406 TI - Role of the Immune Component of Tumor Microenvironment in the Efficiency of Cancer Treatment: Perspectives for the Personalized Therapy. AB - Despite significant progress in cancer diagnostics and development of novel therapeutic regimens, successful treatment of advanced forms of cancer is still a challenge and may require personalized therapeutic approaches. In this review, we analyzed major mechanisms responsible for tumor cells chemoresistance and emphasized that intratumor heterogeneity is a critical factor that limits efficiency of cancer treatment. Intratumor heterogeneity is caused by genomic instability in cancer cells, resulting in the selection of resistant clones. Moreover, cancer cells in solid tumors are surrounded by cellular and molecular microenvironment that actively influences tumor cell behavior. Local tumor microenvironment (TME) consisting of immune cells with diverse phenotypes and functions strongly contributes to intratumor heterogeneity and modulates responses to treatment. Thus, targeting specific components of TME is a novel treatment strategy that can improve the outcome of conventional anti-cancer therapy. Here, we discuss modern immunotherapeutic approaches based on targeting tumorinfiltrating immune cells including neutrophils, dendritic cells, NK cells, T cells, B cells and macrophages. Among those, tumor-associated macrophages (TAM) that display a pronounced heterogeneity and phenotypic plasticity appear to be a major component in the TME of solid tumors, and emerge as perspective targets for cancer immunotherapy. TAM intratumor heterogeneity and the possible existence of patient-specific phenotype signature generate the basis for the development of individualized TAM-based therapeutic approaches. PMID- 28714405 TI - Emerging Targets to Relieve Fat Stress-Induced Liver Diseases: UDCA, Tocotrienol, omega-3 PUFAs, and IgY Targeted NPC1L1 Cholesterol Transporter. AB - Fat stress-induced liver disease is a hepatic manifestation of metabolic syndrome initiated by excess fat accumulation and encompasses a wide spectrum of diseases from non-alcoholic fatty liver disease to nonalcoholic steatohepatitis, a precursor lesion progressing to more aggressive liver cirrhosis and hepatocellular carcinoma. Although the incidence of these fat stress-induced liver diseases is rapidly increasing worldwide in parallel with the growing epidemics of obesity and metabolic diseases, its exact pathogenesis is not well defined. Although obesity, sedentary life-style, altered dietary pattern, insulin resistance, altered intestinal barrier function, inflammatory cytokines, and oxidative stress have been acknowledged as contributing factors because of the indefinite pathogenesis of metabolic diseases, the only reliable treatment is lifestyle intervention composed of restrictive diet and exercise. Additionally, some existing medications such as pioglitazone and antioxidants such as vitamin E were reported to be effective; in this review, several novel agents especifically targeting nonalcoholic fatty liver disease pathogenesis under clinical trial will be introduced. These include an NPC1L1 blocker (ezetimibe), which significantly improved histological and symptomatic scores associated with steatohepatitis and fibrosis; clofibrate, phentoxyfylline, ursodeoxycholic acid, and tocopherol, all of which are prescribed to relieve fat stress; and additional IgY targeted NPC1L1, tocotrienol, ursodeoxycholic acid, and omega-3 polyunsaturated fatty acids, which are actively under investigation to confirm the safety of long-term use. PMID- 28714407 TI - Update of Standard Practices for New Method Validation in Forensic Toxicology. AB - International agreement concerning validation guidelines is important to obtain quality forensic bioanalytical research and routine applications as it all starts with the reporting of reliable analytical data. Standards for fundamental validation parameters are provided in guidelines as those from the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), the German speaking Gesellschaft fur Toxikologie und Forensische Chemie (GTFCH) and the Scientific Working Group of Forensic Toxicology (SWGTOX). These validation parameters include selectivity, matrix effects, method limits, calibration, accuracy and stability, as well as other parameters such as carryover, dilution integrity and incurred sample reanalysis. It is, however, not easy for laboratories to implement these guidelines into practice as these international guidelines remain nonbinding protocols, that depend on the applied analytical technique, and that need to be updated according the analyst's method requirements and the application type. In this manuscript, a review of the current guidelines and literature concerning bioanalytical validation parameters in a forensic context is given and discussed. In addition, suggestions for the experimental set-up, the pros and cons of statistical approaches and adequate acceptance criteria for the validation of bioanalytical applications are given. PMID- 28714408 TI - Biomaterials and Supercritical Fluid Technologies: Which Perspectives to Fabricate Artificial Extracellular Matrix? AB - The foundation of tissue engineering for either therapeutic or diagnostic applications is the ability to exploit living cells. Tissue engineering utilizes living cells as engineering materials implanted, seeded or bioplotted into an artificial structure capable of supporting three-dimensional tissue formation. These structures, typically called scaffolds, are critical, both ex vivo and in vivo, to influence their own microenvironments. Scaffolds can serve the following purposes: allow cell attachment and migration, deliver and retain cells and biochemical factors, enable diffusion of vital cell nutrients or expressed products, exert certain mechanical and biological influences to modify the behaviour of the cell phase. Traditional tissue engineering strategies typically employ a "top-down" approach, in which cells are seeded on a biodegradable three dimensional monolithic polymeric scaffold. More recently they have been updated by a "bottom- up" approach, also known as modular tissue engineering; it is aimed to address the challenge of recreating bio-mimetic structures by designing structural micro-features to build modular tissues, used as building blocks to re create larger ones. These two different approaches will require scaffolds with given characteristics obtainable by choosing different fabrication technologies. Conventional and innovative supercritical technologies for monolithic scaffold production or biopolymer micro/nano devices will be discussed in this chapter. Some examples of bone and cartilage tissue engineering produced by using modular scaffold will be also discussed, as well as the fabrication of artificial extracellular matrix for spatio-temporally delivery of biological and mechanical signal to address cell fate. PMID- 28714409 TI - AMPK: Therapeutic Target for Diabetes and Cancer Prevention. AB - BACKGROUND: AMP-activated protein kinase (AMPK) is a protein kinase that maintains homeostasis in cells and organs. As a master regulator of metabolism, AMPK coordinates many metabolic reactions. AMPK is a key factor in diabetes and metabolic syndrome associated with dysregulation of the metabolic status. Recently, AMPK has also attracted attention as a tumor suppressor. The aim of this article is to discuss about the role of AMPK in diabetes as well as cancer and to evaluate its effectiveness in treatment and prevention of these diseases. METHOD: We reviewed studies of signaling mechanism involving AMPK and research on the role of AMPK in human disease including diabetes and cancer. In particular, we focused our attention on clinical trials about cancer treatment and prevention targeting AMPK. RESULTS: Many experimental studies reported the relation of AMPK and various metabolic reactions, mainly regulating energy homeostasis. Recent studies showed effect of AMPK on arrest of cell cycle as well as suppression of inflammation, which are important factors for carcinogenesis. Although some clinical studies investigated cancer treatment and prevention targeting AMPK, the effective yields in clinical trial have been limited. CONCLUSION: AMPK activation as represented by metformin showed to improve disorders associated with diabetes and metabolic syndrome and became a well-established treatment strategy for these diseases. The increasing evidence suggests that AMPK is a promising target in the treatment and prevention of cancer. Further investigation including long-term clinical trials with large sample size is needed. PMID- 28714410 TI - Management of Blood Pressure and Heart Rate in Patients with Acute Stroke. AB - BACKGROUND: Stroke represent one of the most devastating of all neurological diseases, affecting about 15 million people per year and is an important cause of morbidity and mortality worldwide and currently the leading cause of adult disability in developed countries. Blood pressure and heart rate may undergo several modifications in patients with both ischemic and hemorrhagic stroke in fact raised blood pressure levels may lead to cerebral edema, hematoma expansion or hemorrhagic transformation and in contrast low blood pressure can lead to increased cerebral infarction or perihematomal ischemia. In addition, ECG abnormalities and cardiac arrhythmias, especially atrial fibrillation, are relatively frequent after stroke, and other well known complications such as heart failure, miocardial infarction and sudden death have been reported. The acute phase of brain infarction requires a careful management of both blood pressure levels and heart rate but despite the large amount of information, blood pressure and heart rate management are still under debate. OBJECTIVE: Provide clear indications about the optimal blood pressure and heart rate management of both ischemic and hemorrhagic stroke, in view of the main available evidence. METHOD: In this review, we discuss the evidence for blood pressure and heart rate management in acute stroke, the challenges and issues raised, and look to on going and future trials that may provide some clarity in this controversial area. PMID- 28714411 TI - Pharmacology and Literature Review Based on Related Death and Non-Fatal Case Reports of the Benzofurans and Benzodifurans Designer Drugs. AB - BACKGROUND: Benzofurans and benzodifurans are two groups of psychoactive substances that had originally been synthesized for research purpose. Benzofurans' structure is quite similar to the known recreational drug 3,4 methylenedioxymethamphetamine together with its active metabolite 3,4 methylenedioxyamphetamine. Benzodifurans are closely related to phenethylamines, but have more hallucinogens effects and much longer duration of action. This study aims to review the accessible evidence-based literature on benzofurans and benzodifurans pharmacology and toxicology. METHODS: A literature search on benzofurans and benzodifurans has been conducted using PubMed. We reviewed articles up to February 2017 and also included data from various governmental websites and discussion groups. RESULTS: This review describes the emergent literature that illustrates the chemical composition of these drugs, patterns of use, pharmacology, toxicology, desired and clinical effects, and treatments of patients. It also provides a compilation of case reports. CONCLUSION: The knowledge regarding usage prevalence, pharmacokinetic and pharmacodynamic profiles, acute toxic effects, the effects desired on patients and drug related mortality attributed to these drugs is still limited. Nowadays, there are no specific guidelines available to treat benzofurans or dibenzofurans intoxications. For that reason, clinical effects should be the base of treatment. Backing exposures analytically confirmed in clinical and forensic cases and reported clinical effects need to be combined with these compounds while monitoring its prevalence. PMID- 28714412 TI - Regulation Mechanism of MicroRNAs in Non-Small Cell Lung Cancer. AB - MicroRNAs are small non-coding RNAs with regulatory biological activity, by modulating target genes on epigenetic, transcriptional, post-transciptional and translational levels. Hundreds of reports indicated that miRNAs play important roles in non-small cell lung cancer (NSCLC). Actually, microRNAs are both regulation targets and regulators targeting effector genes. This article reviewed multifaceted role of microRNAs associated to NSCLC, not only targeting to but also targeted by tumor related genes, to help us understand microRNAs related complex regulation networks. Aberrant expressed micoRNAs and their targets were summarized; the statistical results showed that several microRNAs may play key roles by targeting multiple tumor associated targets. On the other hand, Oncogenes and tumor repressors represented by PTEN were also shown to be the most popular targets of microRNAs. Additionally, ZEB1/2 may be a featured pathway in NSCLC, with significant frequency modulated by microRNAs. PMID- 28714413 TI - MiRNA-based Therapeutics for Lung Cancer. AB - BACKGROUND: miRNA, a small non-coding RNA molecule containing about 22 nucleotides, functions in RNA silencing and post-transcriptional regulation of gene expression. With these qualities, miRNAs modulate multiple signaling pathways involved in cancer development, such as cellular proliferation, apoptosis, and migration. METHODS: The goal of this review is to discuss possible miRNAs-based therapeutic strategies, through defining performance of miRNAs in carcinogenesis, in particular in lung cancer. RESULTS: miRNA, a non-coding RNA, is divided into two main types: tumor suppressor miRNAs and oncogenic miRNAs. In addition, special processed miRNAs can be an assistant therapeutic tool. CONCLUSION: In order to develope antitumor therapy, miRNAs-based therapeutic strategies are worth of deeper studies. In this process, the stability, effectiveness, and side effects should be considered. PMID- 28714414 TI - Role of miRNA in Lung Cancer-Potential Biomarkers and Therapies. AB - MicroRNAs (miRNAs) are small noncoding RNAs, which downregulate gene expression by repressing or degrading mRNA targets. Lung cancer (LC), together with liver and colorectal cancers are the three leading causes of cancer death worldwide, and 80% of LCs belong to non-small cell lung cancers (NSCLCs). Despite a great advancement in developing distinct and delicate tools for early diagnosis and targeted therapies over the last decade, only about 15% of the NSCLC patients eventually survived. MiRNAs are frequently dysregulated in carcinoma, including LC. Numerous lines of evidence have demonstrated various roles played by miRNAs in the development and progression of LC. In this review, we propose to summarize the current understanding of miRNAs in LC, with a particular focus on translational application of miRNAs as novel diagnostic and prognostic biomarkers and tools for treatment. PMID- 28714415 TI - Aquaporin 4 in Astrocytes is a Target for Therapy in Alzheimer's Disease. AB - Current experimental evidence points to the conclusion that aquaporin 4 (AQP4), which is an important water-channel membrane protein found in the brain, could play major roles in various brain conditions pathologically including pathogenesis of Alzheimer's disease (AD). In this paper, we review how AQP4 and altered astrocyte functions interact in AD, and provide experimental evidence highlighting the importance of this topic for the future investigations. The interactions of AQP4 are as follows: (i) AQP4 could influence astrocytic calcium signaling and potassium homeostasis. (ii) AQP4 is linked with the removal of interstitial beta-amyloid and glutamate transmission. (iii) Furthermore, AQP4 modulates the reactive astrogliosis and neuroinflammation mechanisms. (iv) To add to this, AQP4 could participate in the AD pathogenesis through affecting neurotrophic factor production. It is therefore possible to identify certain functional molecules that regulate astrocyte make-up and functions. However, making crucial efforts to develop specific agents or drugs that target AQP4 function and test their therapeutic efficiency will be a breakthrough for addressing AD in that AQP4 controls the various physiological as well as pathophysiological features of astrocytes. PMID- 28714416 TI - Application of Kinase Inhibitors for Anti-aging Intervention. AB - Protein phosphorylation, mediated by protein kinases, has important physiological and pathological implications in our lives. Targeting kinase is one of the most interesting of the emerging topics in the pharmaceutical industry, especially since there is a focus on cancer therapy. Given that kinases may be involved in the aging process the focus will be on using the kinase inhibitor for anti-aging intervention to enhance healthspan and increase longevity. In this review, we will summarize: (i) the impact of the phosphoproteomic approach to elucidate molecular mechanisms of diseases; (ii) importance of the drug discovery approach for targeting kinases; (iii) the dysregulation of Janus kinase (JAK) / signal transducing adapter molecules (STAT) and p70 ribosomal protein S6 kinase (S6Ks) pathway in aging and the age-related process; (iv) the epidemiological studies available in order to see whether a correlation between JAK/STAT and S6Ks mRNA expression levels exist in cancer and in patient outcome; (v) finally, we will show selected inhibitors of these kinases approved by the US Food and Drug Administration (FDA). PMID- 28714417 TI - Molecular Targeting of ERKs/RSK2 Signaling in Cancers. AB - Accumulating studies have provided concrete evidence that p90 ribosomal S6 kinase 2 (RSK2) is a key signaling molecule involved in cell proliferation, transformation, and cancer development. RSK2 is known to be an etiological gene of Coffin-Lowry Syndrome (CLS). Recently, signaling analysis and molecular biological approaches have provided concrete evidence that RSK2 plays an essential role in human cancers. Here, we will extensively discuss signaling pathways regulating RSK2 activity, the role of RSK2 in human cancer development, inhibitors suppressing RSK2 activity, and why RSK2 is an important target to develop drugs for human cancers. PMID- 28714418 TI - LC/MS/MS Profiling of Tissue Oxysterols and its Application in Dextran Sodium Sulphate Induced Mouse Colitis Models. AB - We have developed a workflow to extract, separate, and semi-quantify bioactive oxysterols from mouse colon tissues and fecal matters using solid- and liquid phase extractions, enzymatic and chemical modifications, and stable-isotope dilution LC/MS/MS. The method was applied to a dextran sodium sulphate (DSS) induced mouse colitis model, which revealed that one particular dihydroxycholesterol (diOHC), 7alpha,25-diOHC, was significantly elevated in both colon tissue and fecal matters of mice with colitis compared to that in naive mice. The extent of 7alpha,25-diOHC elevation was positively correlated with colitis severity. PMID- 28714419 TI - Therapeutic Agents in Alzheimer's Disease Through a Multi-targetdirected Ligands Strategy: Recent Progress Based on Tacrine Core. AB - Alzheimer's Disease (AD) is one of the most common forms of dementia in elderly people. To date, efficacious therapeutic agent for the treatment of AD is still very limited, so it has long been a challenging and attractive task to discover new anti-AD drugs. Considering the multifactorial nature of AD, recently, the concept of Multi-Target-Directed Ligands (MTDLs) has emerged as a new strategy for designing therapeutic agents on AD. MTDLs are believed to exert their effects through simultaneously affecting multiple targets which contribute to etiology of AD. Therefore, MTDLs are considered to be more efficacious than mono-target agents. Tacrine is the first drug approved by Food and Drug Administration (FDA). Although the clinical use of tacrine is restricted because of its hepatotoxicity, the high Ligand Efficiency (LE) of this compound makes it an ideal component for designing MTDLs. This article provides an update review of the advances on the development of MTDLs based on tacrine. Case studies are carefully selected to show the detailed strategy on medicinal modification of Tacrine-Based MTDLs. Finally, several concerns and opinions on designing new MTDLs are discussed as well. PMID- 28714420 TI - Evaluation of Temporal Changes in Urine-based Metabolomic and Kidney Injury Markers to Detect Compound Induced Acute Kidney Tubular Toxicity in Beagle Dogs. AB - Urinary protein biomarkers and metabolomic markers have been leveraged to detect acute Drug Induced Kidney Injury (DIKI) in rats; however, the utility of these indicators to enable early detection of DIKI in canine models has not been well documented. Therefore, we evaluated temporal changes in biomarkers and metabolites in urine from male and female beagle dogs. Gentamicin- induced kidney lesions in male dogs were characterized by moderate to severe tubular epithelial cell degeneration/necrosis, epithelial cell regeneration and dilation; and a unique urinebased metabolomic fingerprint. These metabolite changes included time and treatment-dependent increases in lactate, taurine, glucose, lactate, alanine, and citrate as well as 9 other known metabolites. As early as 3 days post dose, gentamicin induced increases in urinary albumin, clusterin, neutrophil gelatinase associated protein (NGAL) and total protein concentrations. Urinary albumin, clusterin, and NGAL showed earlier and more robust elevations than traditional kidney safety biomarkers, blood urea nitrogen and serum creatinine. Elevations in urinary kidney injury molecule 1 (KIM-1) were less reliable for detection of gentamicin nephrotoxicity in dogs based on values generated utilizing multiple first-generation, canine-specific KIM-1 immunoassays. The metabolic fingerprint was further evaluated in male and female dogs that received Compound A which induced slightly reversible renal tubular alterations characterized as degeneration/necrosis and concurrent significant increases in urinary taurine amongst other markers. These data support further investigations to demonstrate the value of urinary metabolites, albumin, clusterin, NGAL and taurine as promising markers to enable early detection of DIKI in dogs. PMID- 28714421 TI - The prevalence, age-of-onset and the correlates of DSM-IV psychiatric disorders in the Tianjin Mental Health Survey (TJMHS). AB - BACKGROUND: To effectively shape mental healthcare policy in modern-day China, up to-date epidemiological data on mental disorders is needed. The objective was to estimate the prevalence, age-of-onset (AOO) and sociodemographic correlates of mental disorders in a representative household sample of the general population (age ? 18) in the Tianjin Municipality in China. METHODS: Data came from the Tianjin Mental health Survey (TJMHS), which was conducted between July 2011 and March 2012 using a two-phase design. 11 748 individuals were screened with an expanded version of the General Health Questionnaire and 4438 subjects were selected for a diagnostic interview by a psychiatrist, using the Structured Clinical Interview for the Diagnostic and Statistical Manual - fourth edition (SCID). RESULTS: The lifetime and 1-month prevalence of any mental disorder were 23.6% and 12.8%, respectively. Mood disorders (lifetime: 9.3%; 1-month: 3.9%), anxiety disorders (lifetime: 4.5% 1-month: 3.1%) and substance-use disorders (lifetime: 8.8%; 1-month: 3.5%) were most prevalent. The median AOO ranged from 25 years [interquartile range (IQR): 23-32] for substance-use disorders to 36 years (IQR: 24-50) for mood disorders. Not being married, non-immigrant status (i.e. local 'Hukou'), being a farmer, having <6 years of education and male gender were associated with a higher lifetime prevalence of any mental disorder. CONCLUSION: Results from the current survey indicate that mental disorders are steadily reported more commonly in rapidly-developing urban China. Several interesting sociodemographic correlates were observed (e.g. male gender and non immigrant status) that warrant further investigation and could be used to profile persons in need of preventive intervention. PMID- 28714422 TI - Household availability of ultra-processed foods and obesity in nineteen European countries. AB - OBJECTIVE: To assess household availability of NOVA food groups in nineteen European countries and to analyse the association between availability of ultra processed foods and prevalence of obesity. DESIGN: Ecological, cross-sectional study. SETTING: Europe. SUBJECTS: Estimates of ultra-processed foods calculated from national household budget surveys conducted between 1991 and 2008. Estimates of obesity prevalence obtained from national surveys undertaken near the budget survey time. RESULTS: Across the nineteen countries, median average household availability amounted to 33.9 % of total purchased dietary energy for unprocessed or minimally processed foods, 20.3 % for processed culinary ingredients, 19.6 % for processed foods and 26.4 % for ultra-processed foods. The average household availability of ultra-processed foods ranged from 10.2 % in Portugal and 13.4 % in Italy to 46.2 % in Germany and 50.4 % in the UK. A significant positive association was found between national household availability of ultra-processed foods and national prevalence of obesity among adults. After adjustment for national income, prevalence of physical inactivity, prevalence of smoking, measured or self-reported prevalence of obesity, and time lag between estimates on household food availability and obesity, each percentage point increase in the household availability of ultra-processed foods resulted in an increase of 0.25 percentage points in obesity prevalence. CONCLUSIONS: The study contributes to a growing literature showing that the consumption of ultra-processed foods is associated with an increased risk of diet-related non-communicable diseases. Its findings reinforce the need for public policies and actions that promote consumption of unprocessed or minimally processed foods and make ultra-processed foods less available and affordable. PMID- 28714423 TI - Distinctive neuropsychological profiles differentiate patients with functional memory disorder from patients with amnestic-mild cognitive impairment. AB - OBJECTIVES: Patients with functional memory disorder (FMD) report significant memory failures in everyday life. Differentiating these patients from those with memory difficulties due to early stage neurodegenerative conditions is clinically challenging. The current study explored whether distinctive neuropsychological profiles could be established, suitable to differentiate patients with FMD from healthy individuals and those experiencing amnestic mild cognitive impairment (a MCI). METHODS: Patients with a clinical diagnosis of FMD were compared with patients with a-MCI, and healthy matched controls on several tests assessing different cognitive functions. Patients with clinically established mood disorders were excluded. Patients with FMD and a-MCI were broadly comparable on the level of their subjective memory complaints as assessed by clinical interview. RESULTS: The neuropsychological profile of the FMD patients, although they expressed subjective memory and attention concerns during their clinical interview was distinct from patients with a-MCI on tests of memory [semantic fluency, age of acquisition (AoA) analysis of semantic fluency, verbal and non verbal memory]. FMD patients did not differ significantly from healthy controls, but their scores on the letter fluency and digit cancellation tasks were not significantly different from those of the a-MCI patients indicating a possible sub-threshold deficit on these tasks. CONCLUSION: Whilst subjective complaints are common within the FMD population, no objective impairment could be detected, even on a sensitive battery of tasks designed to detect subtle deficits caused by an early neurodegenerative brain disease. This study indicates that FMD patients can be successfully differentiated from patients with neurodegenerative memory decline by characterising their neuropsychological profile. PMID- 28714424 TI - An unusual case of exertional dyspnea: Atrial myxoma on point-of-care ultrasound. PMID- 28714425 TI - The share of ultra-processed foods determines the overall nutritional quality of diets in Brazil. AB - OBJECTIVE: To estimate the dietary share of ultra-processed foods and to determine its association with the overall nutritional quality of diets in Brazil. DESIGN: Cross-sectional. SETTING: Brazil. SUBJECTS: A representative sample of 32 898 Brazilians aged >=10 years was studied. Food intake data were collected. We calculated the average dietary content of individual nutrients and compared them across quintiles of energy share of ultra-processed foods. Then we identified nutrient-based dietary patterns, and evaluated the association between quintiles of dietary share of ultra-processed foods and the patterns' scores. RESULTS: The mean per capita daily dietary energy intake was 7933 kJ (1896 kcal), with 58.1 % from unprocessed or minimally processed foods, 10.9 % from processed culinary ingredients, 10.6 % from processed foods and 20.4 % from ultra-processed foods. Consumption of ultra-processed foods was directly associated with high consumption of free sugars and total, saturated and trans fats, and with low consumption of protein, dietary fibre, and most of the assessed vitamins and minerals. Four nutrient-based dietary patterns were identified. 'Healthy pattern 1' carried more protein and micronutrients, and less free sugars. 'Healthy pattern 2' carried more vitamins. 'Healthy pattern 3' carried more dietary fibre and minerals and less free sugars. 'Unhealthy pattern' carried more total, saturated and trans fats, and less dietary fibre. The dietary share of ultra processed foods was inversely associated with 'healthy pattern 1' (-0.16; 95 % CI -0.17, -0.15) and 'healthy pattern 3' (-0.18; 95 % CI -0.19, -0.17), and directly associated with 'unhealthy pattern' (0.17; 95 % CI 0.15, 0.18). CONCLUSIONS: Dietary share of ultra-processed foods determines the overall nutritional quality of diets in Brazil. PMID- 28714427 TI - Discrepancy between information provided and information required by emergency physicians for long-term care patients. AB - OBJECTIVES: The primary objective of this study was to identify information included in long-term care (LTC) transfer documentation and to compare it to the information required by local emergency department (ED) physicians to provide optimal care and make decisions for LTC patients. METHODS: A retrospective chart review was conducted for a sample of LTC residents transferred by ambulance to the ED of an academic, tertiary care hospital over a 1-year period. All emergency physicians working at the institution were invited to complete an online questionnaire about information included in LTC transfer documentation and information required by emergency physicians to provide care for LTC patients. RESULTS: Of the 200 charts reviewed, the most common information transferred to the ED with the LTC patient was the patient's past medical history (n=184, 92.0%), name of family physician (n=182, 91.0%), a list of known allergies (n=179, 89.5%), the reason for transfer to the ED (n=155, 77.5%), the patient's emergency contact information (n=152, 76.0%), and medication administration record (n=150, 75.0%). From a physician's perspective, the most frequently requested pieces of information included reason for transfer, past medical history, cognitive status, advanced directives for level of care and resuscitation, and the patient's emergency contact information. This information was provided 77.5% (n=155), 92.0% (n=184), 24.0% (n=48), 62.0% (n=124), and 76.0% (n=152) of the time, respectively. CONCLUSIONS: Our study demonstrates a clear discrepancy between information provided and information required by emergency physicians for LTC patients. Quality improvement initiatives at the local level may help reduce this discrepancy. PMID- 28714426 TI - Suicide following acute admissions for physical illnesses across England and Wales. AB - BACKGROUND: The study aim was to establish and quantify suicide risk following acute admissions for all major physical illnesses, for confirmatory purposes, from two independent information sources from different countries. METHODS: Record linkage of inpatient and death certificate data for 11 004 389 acute admissions for physical illnesses in England and 713 496 in Wales. The main outcome measure was standardised mortality ratios (SMRs) for suicide at 1 year following discharge from hospital. RESULTS: There were 1781 suicides within 1 year of discharge in England (SMR = 1.7; 95% = 1.6-1.8) and 131 in Wales (SMR = 2.0; 1.7-2.3). Of 48 major physical illnesses that were associated with at least eight suicides in either country, there was high consistent suicide mortality (significant SMR >3) in both countries for constipation (SMR = 4.1 in England, 7.5 in Wales), gastritis (4.4 and 4.9) and upper gastrointestinal bleeding (3.4 and 4.5). There was high suicide mortality in one country for alcoholic liver disease, other liver disease and chronic pancreatitis; for epilepsy and Parkinson's disease; for diabetes, hypoglycaemia and hypo-osmolality & hyponatraemia; and for pneumonia, back pain and urinary tract infections. CONCLUSIONS: There is little or no increased suicide mortality following acute admissions for most physical illnesses. Much of the increased suicide mortality relates to gastrointestinal disorders that are often alcohol related or specific chronic conditions, which may be linked to side effects from certain therapeutic medications. Acute hospital admissions for physical illnesses may therefore provide an opportunity for targeted suicide prevention among people with certain conditions, particularly alcohol related disorders. PMID- 28714428 TI - Are newly added and lost confidants in later life related to subsequent mental health? AB - BACKGROUND: This study examined internal changes in the personal social networks of older people and the relationship between these changes and mental health over time. It focused on two key aspects: emotional closeness and contact frequency with lost and newly added confidants. METHODS: The study was based on data from the fourth (2011) and sixth (2015) waves of the Survey of Health, Ageing and Retirement in Europe (SHARE). The study sample consisted of respondents aged 65 years and older who participated in both waves (n = 14,101). We performed OLS regressions in which the scores on two mental health indicators over time - depressive symptoms (Euro-D) and perceived quality of life (CASP-12) - were regressed on the relationship with lost and newly added confidants, controlling for baseline social networks, socio-demographic, and health variables. RESULTS: The nature of the relationship with the lost and newly added confidants was associated with mental health, beyond the number of these confidants. Emotional closeness with newly added confidants was related to improved mental health in both indicators (B = -0.09, CI = -0.14 to -0.04 for depression; B =1.13, CI = 0.67-1.60 for quality of life). Losing frequently contacted confidants was associated with higher depressive symptoms (B = 0.09, CI = 0.02-0.15). CONCLUSIONS: The results show the positive mental health implications of adding emotionally close confidants to older adults' social milieus, and the negative effects of losing frequently contacted confidants. Practitioners are advised to pay attention to the quality of such changing relationships, due to their mental health consequences. PMID- 28714430 TI - Laparoscopic instrument use in laryngeal surgery: transoral resection of a supraglottic haemangioma. AB - BACKGROUND: Adult laryngeal haemangiomas are rare vascular tumours that have been managed by a variety of surgical techniques. METHODS: This paper describes a case of near-fatal acute airway obstruction secondary to such a lesion, followed by our approach to surgical resection using a laparoscopic bipolar tissue-sealing device. RESULTS: This technique resulted in successful excision of the lesion, with no evidence of recurrence at one year of follow up. CONCLUSION: Laparoscopic bipolar instruments can be used for the resection of moderate to large laryngeal haemangiomas as an alternative to laser excision. PMID- 28714429 TI - Structural Brain Correlations of Visuospatial and Visuoperceptual Tests in Parkinson's Disease. AB - BACKGROUND: Diagnosis of mild cognitive impairment in Parkinson's disease (PD) is relevant because it is a marker for evolution to dementia. However, the selection of suitable tests to evaluate separate cognitive domains in mild cognitive impairment related to PD remains an open question. The current work aims to investigate the neuroanatomical correlates of several visuospatial/visuoperceptual tests using the same sample and a multimodal MRI approach. METHODS: The study included 36 PD patients and 20 healthy subjects matched for age, sex, and education. The visuospatial/visuoperceptual tests selected were: Pentagon Copying Test (PCT), Judgment of Line Orientation Test (JLOT), Visual Form Discrimination Test (VFDT), Facial Recognition Test (FRT), Symbol Digit Modalities Test (SMDT), and clock copying task (CLOX2). FreeSurfer was used to assess cortical thickness, and tract-based spatial statistics was used for fractional anisotropy analysis. RESULTS: Lower performance in the PCT, JLOT, and SDMT was associated with extensive cortical thickness reductions in lateral parietal and temporal regions. VFDT and CLOX2 did not show this common pattern and correlated with more limited medial occipito-temporal and occipito parietal regions. Performance in all visuospatial/visuoperceptual tests correlated with fractional anisotropy in the corpus callosum. CONCLUSIONS: Our findings show that JLOT, SDMT, and PCT, in addition to differentiating patients from controls, are suitable visuospatial/visuoperceptual tests to reflect cortical thinning in lateral temporo-parietal regions in PD patients. We did not observe the dissociation between dorsal and ventral streams that was expected according to the neuropsychological classification of visuospatial and visuoperceptual tests. (JINS, 2018, 24, 33-44). PMID- 28714431 TI - Effectiveness of patching traumatic eardrum perforations with lens cleaning paper via an otoscope. AB - OBJECTIVE: To study the clinical effect of lens cleaning paper patching on traumatic eardrum perforations. METHODS: A total of 122 patients were divided into 2 groups, of which 56 patients were treated with lens cleaning paper patching and 66 acted as controls. The closure rate and healing time were compared between the two groups. RESULTS: The healing rate of small perforations was 96.4 per cent (27 out of 28) in the patching group and 90 per cent (27 out of 30) in the control group. The difference was not statistically significant (p > 0.05). The healing rate of large perforations was 89.3 per cent (25 out of 28) and 80.6 per cent (29 out of 36) in the two groups, respectively. The difference was statistically significant (p < 0.05). The healing time of large perforations was shorter in the patching group than in the control group (p < 0.01). CONCLUSION: Patching with lens cleaning paper under an endoscope can accelerate the closure of large traumatic eardrum perforations. PMID- 28714432 TI - Paths to improving care of Australian Aboriginal and Torres Strait Islander women following gestational diabetes. AB - : Aim To understand enablers and barriers influencing postpartum screening for type 2 diabetes following gestational diabetes in Australian Indigenous women and how screening might be improved. BACKGROUND: Australian Indigenous women with gestational diabetes mellitus (GDM) are less likely than other Australian women to receive postpartum diabetes screening. This is despite a fourfold higher risk of developing type 2 diabetes within eight years postpartum. METHODS: We conducted interviews with seven Indigenous women with previous GDM, focus groups with 20 Indigenous health workers and workshops with 24 other health professionals. Data collection included brainstorming, visualisation, sorting and prioritising activities. Data were analysed thematically using the Theoretical Domains Framework. Barriers are presented under the headings of 'capability', 'motivation' and 'opportunity'. Enabling strategies are presented under 'intervention' and 'policy' headings. Findings Participants generated 28 enabling environmental, educational and incentive interventions, and service provision, communication, guideline, persuasive and fiscal policies to address barriers to screening and improve postpartum support for women. The highest priorities included providing holistic social support, culturally appropriate resources, improving Indigenous workforce involvement and establishing structured follow-up systems. Understanding Indigenous women's perspectives, developing strategies with health workers and action planning with other health professionals can generate context-relevant feasible strategies to improve postpartum care after GDM. Importantly, we need evidence which can demonstrate whether the strategies are effective. PMID- 28714433 TI - Ultra-processed family foods in Australia: nutrition claims, health claims and marketing techniques. AB - OBJECTIVE: To objectively evaluate voluntary nutrition and health claims and marketing techniques present on packaging of high-market-share ultra-processed foods (UPF) in Australia for their potential impact on public health. DESIGN: Cross-sectional. SETTING: Packaging information from five high-market-share food manufacturers and one retailer were obtained from supermarket and manufacturers' websites. SUBJECTS: Ingredients lists for 215 UPF were examined for presence of added sugar. Packaging information was categorised using a taxonomy of nutrition and health information which included nutrition and health claims and five common food marketing techniques. Compliance of statements and claims with the Australia New Zealand Food Standards Code and with Health Star Ratings (HSR) were assessed for all products. RESULTS: Almost all UPF (95 %) contained added sugars described in thirty-four different ways; 55 % of UPF displayed a HSR; 56 % had nutrition claims (18 % were compliant with regulations); 25 % had health claims (79 % were compliant); and 97 % employed common food marketing techniques. Packaging of 47 % of UPF was designed to appeal to children. UPF carried a mean of 1.5 health and nutrition claims (range 0-10) and 2.6 marketing techniques (range 0-5), and 45 % had HSR<=3.0/5.0. CONCLUSIONS: Most UPF packaging featured nutrition and health statements or claims despite the high prevalence of added sugars and moderate HSR. The degree of inappropriate or inaccurate statements and claims present is concerning, particularly on packaging designed to appeal to children. Public policies to assist parents to select healthy family foods should address the quality and accuracy of information provided on UPF packaging. PMID- 28714434 TI - Altered interoceptive activation before, during, and after aversive breathing load in women remitted from anorexia nervosa. AB - BACKGROUND: The neural mechanisms of anorexia nervosa (AN), a severe and chronic psychiatric illness, are still poorly understood. Altered body state processing, or interoception, has been documented in AN, and disturbances in aversive interoception may contribute to distorted body perception, extreme dietary restriction, and anxiety. As prior data implicate a potential mismatch between interoceptive expectation and experience in AN, we examined whether AN is associated with altered brain activation before, during, and after an unpleasant interoceptive state change. METHODS: Adult women remitted from AN (RAN; n = 17) and healthy control women (CW; n = 25) underwent functional magnetic resonance imaging during an inspiratory breathing load paradigm. RESULTS: During stimulus anticipation, the RAN group, relative to CW, showed reduced activation in right mid-insula. In contrast, during the aversive breathing load, the RAN group showed increased activation compared with CW in striatum and cingulate and prefrontal cortices (PFC). The RAN group also showed increased activation in PFC, bilateral insula, striatum, and amygdala after stimulus offset. Time course analyses indicated that RAN responses in interoceptive processing regions during breathing load increased more steeply than those of CW. Exploratory analyses revealed that hyperactivation after breathing load was associated with markers of past AN severity. CONCLUSIONS: Anticipatory deactivation with a subsequent exaggerated brain response during and after an aversive body state may contribute to difficulty predicting and adapting to internal state fluctuation. Because eating changes our interoceptive state, restriction may be one method of avoiding aversive, unpredictable internal change in AN. PMID- 28714435 TI - A multicenter family practitioners' research on Chronic Obstructive Pulmonary Disease screening using the COPD Assessment Test. AB - OBJECTIVES: Spirometry is known to be a gold standard for the diagnosis of chronic obstructive pulmonary disease (COPD). COPD Assessment Test (CAT) is an eight-item questionnaire currently in use to evaluate patients with COPD. In the present study, we aimed to evaluate if CAT is an adequate tool for screening COPD. METHODS: In total, 600 persons aging ?40 years old were randomly selected from three different family practice units located in the city center. CAT was asked to the participants and a spirometry was used to assess pulmonary obstruction. Pulmonary obstruction was defined as forced expiratory volume in first second/forced vital capacity (FEV1/FVC)<70% and then COPD diagnosis was confirmed with the reversibility test. The relationship between CAT results and pulmonary function test values was evaluated. RESULTS: In this sampling, the prevalence of COPD was 4.2%. Reliability of the CAT in the study group was acceptable (Cronbach's alpha: 0.84). The CAT scores was significantly higher in patients with COPD (P<0.001). There was a significant negative correlation between CAT score and FEV1, FVC and FEV1/FVC ratio (r=-0.31, P<0.001; r=-0.26, P<0.001; r=0.18, P=0.001). Among smokers, phlegm was the predominating symptom (P=0.01). Sensitivity of CAT was 66.67% and its specificity was 75.15% to determine COPD. CONCLUSIONS: CAT is a reliable questionnaire and there is an apparent relationship between the total CAT scores and COPD. However, CAT's ability to screen COPD is limited since it may miss the symptom-free cases. PMID- 28714437 TI - The Pragmatic Utility of Watson-Based Caring Measures. AB - PURPOSE: This study aims to clarify the caring concept with emphasis on the pragmatic utility of caring measures. METHOD: The Morse et al. (Morse, Hupcey, Mitcham, & Lenz, 1996; Morse, Mitcham, Hupcey, & Tason, 1996) criteria for concept maturity were used as a framework. A literature review of Watson-based caring concept was undertaken to evaluate the logical, epistemological, linguistical, and pragmatic parameters. RESULTS: The concept of caring as conceptualized by Watson and operationalized through different measures appeared mature. Despite differences, shorter scales of caring measures were effective to capture caring behavior. CONCLUSIONS: Caring concept was further clarified and more confidence in using caring measures for assessment, evaluation, and modification of caring behavior become more feasible. PMID- 28714436 TI - Development and Validation of the Caring Loneliness Scale. AB - BACKGROUND AND PURPOSE: The Caring Loneliness Scale (CARLOS) includes 5 categories derived from earlier qualitative research. This article assesses the reliability and construct validity of a scale designed to measure patient experiences of loneliness in a professional caring relationship. METHODS: Statistical analysis with 4 different sample sizes included Cronbach's alpha and exploratory factor analysis with principal axis factoring extraction. RESULTS: The sample size of 250 gave the most useful and comprehensible structure, but all 4 samples yielded underlying content of loneliness experiences. The initial 5 categories were reduced to 4 factors with 24 items and Cronbach's alpha ranging from .77 to .90. CONCLUSION: The findings support the reliability and validity of CARLOS for the assessment of Finnish breast cancer and heart surgery patients' experiences but as all instruments, further validation is needed. PMID- 28714438 TI - Psychometrics of the Kansas City Cardiomyopathy Questionnaire Adapted for Family Caregiver/Significant Other. AB - BACKGROUND AND PURPOSE: The Kansas City Cardiomyopathy Questionnaire (KCCQ) was adapted to be administered to the family caregiver/significant other (FC/SO) of hospitalized patients with heart failure (HF). The objective was to examine the psychometrics of the adapted scale (KCCQ-SO). METHODS: Factor analysis, Cronbach's alpha, and correlations were used. RESULTS: A 5-factor solution was found that explained 67.9% of the variance. The internal consistency of the KCCQ SO factors were all greater than .70. Patient and FC/SO perceived health status scores were significantly related. CONCLUSIONS: Because the scores were found to have high internal consistency and correlated with patient scores on the KCCQ, there is evidence that the FC/SOs' reports may be used in circumstances when the patient is unable or unwilling to answer questions. PMID- 28714439 TI - Psychometric Properties of the Brief Symptom Inventory Hostility Subscale in Patients With Heart Failure. AB - BACKGROUND AND PURPOSE: Patients with heart failure (HF) often have increased hostility. The Brief Symptom Inventory (BSI) Hostility subscale has not been evaluated in this population. The purpose of this study was to explore dimensionality, internal consistency, and construct validity of BSI Hostility subscale in HF. METHOD: Measures examined were BSI Hostility, Depression, and Anxiety subscales; Patient Health Questionnaire-9 (PHQ-9); and Multidimensional Scale of Perceived Social Support (MSPSS). Cronbach's alpha, exploratory factor analysis, and correlational analysis were used. RESULTS: Cronbach's alpha for the BSI Hostility subscale was .77. Hostility was positively associated with the PHQ 9, BSI Depression, and Anxiety subscales and negatively related to the MSPSS. DISCUSSION: The BSI Hostility subscale provides a reliable and valid measure of hostility in patients with HF. PMID- 28714440 TI - Editorial. PMID- 28714441 TI - Nurses' Attitudes Regarding the Safe Handling of Patients Who Are Morbidly Obese: Instrument Development and Psychometric Analysis. AB - BACKGROUND AND PURPOSE: Nurses' attitudes play an important role in the consistent practice of safe patient handling behaviors. The purposes of this study were to develop and assess the psychometric properties of a newly developed instrument measuring attitudes of nurses related to the care and safe handling of patients who are obese. METHODS: Phases of instrument development included (a) item generation, (b) content validity assessment, (c) reliability assessment, (d) cognitive interviewing, and (e) construct validity assessment through factor analysis. RESULTS: The final data from the exploratory factor analysis produced a 26-item multidimensional instrument that contains 9 subscales. CONCLUSIONS: Based on the factor analysis, a 26-item instrument can be used to examine nurses' attitudes regarding patients who are morbidly obese and related safe handling practices. PMID- 28714442 TI - Content Validity of a Screening Instrument for Breast Cancer Early Detection Among Asian American Women: The Cultural Health and Screening Mammography Belief Scale. AB - BACKGROUND AND PURPOSE: Asian American women have the lowest mammography screening rate in the United States. There is no standardized instrument available to measure their cultural beliefs regarding screening mammography. The purpose of this study is to evaluate the content validity of the Cultural Health and Screening Mammography Belief Scale (CHSMBS) developed for this population. Procedures for Instrument Development: The content validity was examined using content validity index (CVI). Both item-level (I-CVI) and scale-level CVIs (S CVI) were evaluated. RESULTS: The instrument's I-CVIs ranged from 0.75 to 1.00, and the S-CVI was 1.00, reflecting excellent inter-rater agreement. CONCLUSIONS: The study has established the scale's content validity to evaluate Asian American women's use of screening mammography. Further examination of the reliability and construct validity will add further support of the scale's utility in health research and practice. PMID- 28714443 TI - A Spanish-Language Risk Perception Survey for Developing Diabetes: Translation Process and Assessment of Psychometric Properties. AB - BACKGROUND AND PURPOSE: Create a Spanish-language version of the Risk Perception Survey for Developing Diabetes (RPS-DD) and assess psychometric properties. RESEARCH DESIGN AND METHODS: The Spanish-language version was created through translation, harmonization, and presentation to the tool's original author. It was field tested in a foreignborn Latino sample and properties evaluated in principal components analysis. RESULTS: Personal Control, Optimistic Bias, and Worry multi-item Likert subscale responses did not cluster together. A clean solution was obtained after removing two Personal Control subscale items. Neither the Personal Disease Risk scale nor the Environmental Health Risk scale responses loaded onto single factors. Reliabilities ranged from .54 to .88. Test of knowledge performance varied by item. CONCLUSIONS: This study contributes to evidence of validation of a Spanish-language RPS-DD in foreign-born Latinos. PMID- 28714444 TI - Development of an Arabic Translation of the Cancer Behavior Inventory-Brief. AB - PURPOSE: The objective was to develop an Arabic version of the Cancer Behavior Inventory-Brief (CBI-B). METHODS: The CBI-B was translated into Arabic using two forward and back translations. A translation validity index (TVI) was computed from review by an expert panel. RESULTS: Both back translations had issues with word choice, grammar, and meaning, which were resolved by selecting items from each forward translation. Item TVI was 0.83-1.0, with an overall mean of 0.95. CONCLUSION: The Arabic version of the CBI-B (CBI-BA) has acceptable evidence of translation validity. Two rounds of forward and back translation of the CBI-BA were needed to ensure semantic equivalence of the CBI-BA with the original instrument. Further psychometric testing with cognitive interviewing is recommended. PMID- 28714446 TI - Development and Psychometric Evaluation of Health Protective Sexual Communication Content Discussed Scale for Young Women in Gaborone, Botswana. AB - Health protective sexual communication can reduce HIV transmission, but women in Botswana find it difficult because of cultural barriers, suggesting the need for relevant measures. A Health Protective Sexual Communication Content Discussed Scale was developed and tested among young women aged 21-35 years in Gaborone, Botswana, to guide HIV prevention interventions. The project was conducted from June 2006 to August 2007. Literature review, expert advice, and a qualitative pilot guided the process. The scale had 22 items. The content validity index was 97%. Cronbach's alpha was .69. Eight extracted factors included risky sexual behaviors and relationships, sexually transmitted infections, substance abuse, genital health concerns, and safer sex practices. The scale was valid and reliable and therefore useful in future research and interventions. PMID- 28714445 TI - Reliability Estimates for the Arabic Versions of the Cancer Behavior Inventory Brief and the Functional Assessment of Cancer Therapy-Breast. AB - PURPOSE: The study aims were to (a) test reliability of the Arabic versions of the Cancer Behavior Inventory-Brief Arabic (CBI-BA) among patients diagnosed with any type of cancer and the Functional Assessment of Cancer Therapy-Breast (FACT BA) in women with breast cancer and (b) assess participant understanding of CBI BA items. METHODS: A cross-sectional design was used to assess preliminary evidence for internal consistency reliability of the CBI-BA and the FACT-BA in a community-dwelling sample of Arabicspeaking persons diagnosed with cancer. Participants were randomly selected for cognitive interview. RESULTS: Cronbach's alphas were >=.76 for the CBI-BA, .91 for the FACT-BA, and .43-.89 for the FACT BA subscales. Cognitive interviews revealed several CBI-BA items required revision. CONCLUSION: The total CBI-BA and the FACT-BA scales have adequate internal consistency reliability estimates. PMID- 28714447 TI - Feasibility of Automating Patient Acuity Measurement Using a Machine Learning Algorithm. AB - BACKGROUND AND PURPOSE: One method of determining nurse staffing is to match patient demand for nursing care (patient acuity) with available nursing staff. This pilot study explored the feasibility of automating acuity measurement using a machine learning algorithm. METHODS: Natural language processing combined with a machine learning algorithm was used to predict acuity levels based on electronic health record data. RESULTS: The algorithm was able to predict acuity relatively well. A main challenge was discordance among nurse raters of acuity in generating a gold standard of acuity before applying the machine learning algorithm. CONCLUSIONS: This pilot study tested applying machine learning techniques to acuity measurement and yielded a moderate level of performance. Higher agreement among the gold standard may yield higher performance in future studies. PMID- 28714448 TI - Theoretical to Tangible: Creating a Measure of Self-Advocacy for Female Cancer Survivors. AB - BACKGROUND AND PURPOSE: Self-advocacy is well appreciated but poorly defined concept in oncology. METHODS: The development of the Female Self-Advocacy in Cancer Survivorship (FSACS) Scale's theoretical underpinnings and item development led to evaluations of the measure's content validity and reliability. RESULTS: The construct of self-advocacy contains 3 subdimensions with 57 Likert type self-report items. Content validity results (S-CVI = 0.81 and S-CVI/UA = 0.83) indicated strong relevancy of items. Reliability results for each of the 3 subdimensions supported the consistency of the FSACS Scale scores, with strong internal consistency (Cronbach's alphas = .88, .81, and .90) and test-retest reliability (PPMC r = .85, .97, and .88). CONCLUSIONS: The FSACS Scale captures the construct of self-advocacy, and its scores show strong reliability. PMID- 28714449 TI - Initial Evidence for the Reliability and Validity of the Educational Needs Assessment Questionnaire. AB - BACKGROUND AND PURPOSE: The purpose of this study was to evaluate the reliability and validity of the revised Educational Needs Assessment (ENA) questionnaire, a 32-item questionnaire designed to assess educational needs of nurses. METHODS: Data were obtained from 317 nursing home nurses in central Illinois and underwent testing for psychometric properties. RESULTS: The principal component analysis yielded a 6-factor solution that explained 65.9% of the variance and Cronbach's alpha for each factor was satisfactory. CONCLUSIONS: The revised ENA can be a useful tool to measure and identify in what areas of educational needs nursing home nurses need to develop their skills to help patients more effectively. PMID- 28714450 TI - Psychometric Properties of the Ambulatory Surgery Index of Nausea, Vomiting, and Retching. AB - BACKGROUND AND PURPOSE: At least one-third of ambulatory surgery patients will experience nausea or vomiting during the recovery period. The purpose of this study was to examine the psychometric properties of the Ambulatory Surgery Index of Nausea, Vomiting, and Retching (AS-INVR). METHODS: Secondary analysis of longitudinal data from a study of 203 adult ambulatory surgery patients was conducted. RESULTS: Based on the results of factor analysis, the retching item was eliminated and the 6-item, 2-dimensional AS-INV was formed. Cronbach's alphas for the AS-INV ranged from .83 to .87 across the 5 days postsurgery. Higher AS INV scores were associated with self-reported presence of nausea and lower quality of life. CONCLUSIONS: The shortened AS-INV provides a reliable and valid measure of the amount and distress because of nausea and vomiting in adult patients after ambulatory surgery and should be considered for use in future studies. PMID- 28714451 TI - Psychometric Evaluation of the Attitudes to Disability Scale for Use With Nurse Educators. AB - BACKGROUND AND PURPOSE: This article tests the construct validity of the Attitudes to Disability Scale (ADS) for use with nurse educators. The ADS was designed to assess the attitudes of people with disabilities and the general population. METHODS: The responses of 126 nurse educators were analyzed using multivariate statistics. RESULTS: Reliability analysis of the original ADS factors yielded Cronbach's alpha of .655, .689, .781, and .621 (Inclusion, Discrimination, Gains, and Prospects, respectively). Principal component analysis confirmed factors Discrimination and Gains and identified two new factors. Principal axis factor confirmed Discrimination and Gains and defined one new factor (Opportunity) with a Cronbach's alpha of .73. CONCLUSIONS: The original form ADS is not reliable for use with nurse educators although a modified version may prove suitable. PMID- 28714452 TI - Predict Moral Distress Using Workplace Stress, Stress of Conscience Mediated by Coping Using Roy Adaptation Model: A Path Analysis. AB - BACKGROUND: Moral distress can be predisposed when nurses are exposed to ambiguous moral situations. PURPOSE: Is to test a conceptual model based on Roy adaptation model (RAM) to examine the relationship among workplace stress, conscience stress, and moral distress mediated by coping. DESIGN: A correlational, cross sectional. RESULTS: Data were collected from 199 licensed nurses. The findings indicated that workplace stress was related negatively to coping processes (beta = -.12) and that stress of conscience was predictive of greater use of coping process (beta = -.21). CONCLUSION: The results indicated that the model suggested based on RAM is saturated and is the perfect fit. However, the alternative models indicated that workplace stress moderately predicted moral distress. PMID- 28714453 TI - Preparation of nitrogen and sulfur co-doped ordered mesoporous carbon for enhanced microwave absorption performance. AB - Ordered mesoporous carbon nanomaterials (OMCs) co-doped with homogeneous nitrogen and sulfur heteroatoms were prepared by nanocasting with the pyrrole oligomer catalyzed by sulfuric acid as a precursor and ordered mesoporous silica SBA-15 as a hard-template. By multi-technique approach utilization, it was demonstrated that the N and S co-doped OMCs possessed high ordered mesoporous structures, large surface areas and homogeneous distribution of heteroatoms. As a microwave absorber, the as-prepared materials exhibited a minimum reflection loss (RL) of 32.5 dB at the thickness of 2.5 mm and an absorption bandwidth of 3.2 GHz (RL < 10 dB) in X-band (8.2-12.4 GHz). The good microwave absorption performance was mainly originated from the high electrical conductivity induced by the high surface activity and special structures. And microwave energy can be effectively attenuated through multiple reflections and absorptions in complex conductive network. The design strategy in this work would contribute to the production of a lightweight absorber, presenting a strong absorbency and a wide bandwidth in microwave frequency. PMID- 28714454 TI - A back-projection algorithm in the presence of an extra attenuating medium: towards EPID dosimetry for the MR-Linac. AB - In external beam radiotherapy, electronic portal imaging devices (EPIDs) are frequently used for pre-treatment and for in vivo dose verification. Currently, various MR-guided radiotherapy systems are being developed and clinically implemented. Independent dosimetric verification is highly desirable. For this purpose we adapted our EPID-based dose verification system for use with the MR Linac combination developed by Elekta in cooperation with UMC Utrecht and Philips. In this study we extended our back-projection method to cope with the presence of an extra attenuating medium between the patient and the EPID. Experiments were performed at a conventional linac, using an aluminum mock-up of the MRI scanner housing between the phantom and the EPID. For a 10 cm square field, the attenuation by the mock-up was 72%, while 16% of the remaining EPID signal resulted from scattered radiation. 58 IMRT fields were delivered to a 20 cm slab phantom with and without the mock-up. EPID reconstructed dose distributions were compared to planned dose distributions using the [Formula: see text]-evaluation method (global, 3%, 3 mm). In our adapted back-projection algorithm the averaged [Formula: see text] was [Formula: see text], while in the conventional it was [Formula: see text]. Dose profiles of several square fields reconstructed with our adapted algorithm showed excellent agreement when compared to TPS. PMID- 28714455 TI - Non-contact lateral force microscopy. AB - The goal of atomic force microscopy (AFM) is to measure the short-range forces that act between the tip and the surface. The signal recorded, however, includes long-range forces that are often an unwanted background. Lateral force microscopy (LFM) is a branch of AFM in which a component of force perpendicular to the surface normal is measured. If we consider the interaction between tip and sample in terms of forces, which have both direction and magnitude, then we can make a very simple yet profound observation: over a flat surface, long-range forces that do not yield topographic contrast have no lateral component. Short-range interactions, on the other hand, do. Although contact-mode is the most common LFM technique, true non-contact AFM techniques can be applied to perform LFM without the tip depressing upon the sample. Non-contact lateral force microscopy (nc-LFM) is therefore ideal to study short-range forces of interest. One of the first applications of nc-LFM was the study of non-contact friction. A similar setup is used in magnetic resonance force microscopy to detect spin flipping. More recently, nc-LFM has been used as a true microscopy technique to systems unsuitable for normal force microscopy. PMID- 28714456 TI - On Moliere and Fermi-Eyges scattering theories in hadrontherapy. AB - We consider the evaluation of lateral spread distributions of charged particle beams at therapeutic energies, due to an absorber in the form of a homogeneous slab or of a stack. We show that the Moliere theory has the same degree of flexibility as the Fermi-Eyges, but is much more accurate and does not present particular computing difficulties with the energy loss formula we have employed. It is also shown that the non-Gaussian shape of the projected one dimensional (1D) distributions is not a complication for passing from the projected to the spatial two-dimensional (2D) distribution, if one assumes circular symmetry. All the calculations are compared with the results of the FLUKA code. The nuclear interaction is not considered here, because it is outside of the scope of this work. PMID- 28714457 TI - Summaries of articles in this issue. AB - Summaries of the articles in this issue are given in the PDF file. PMID- 28714458 TI - A graphical approach to optimizing variable-kernel smoothing parameters for improved deformable registration of CT and cone beam CT images. AB - A systematic method is presented for determining optimal parameters in variable kernel deformable image registration of cone beam CT and CT images, in order to improve accuracy and convergence for potential use in online adaptive radiotherapy. Assessed conditions included the noise constant (symmetric force demons), the kernel reduction rate, the kernel reduction percentage, and the kernel adjustment criteria. Four such parameters were tested in conjunction with reductions of 5, 10, 15, 20, 30, and 40%. Noise constants ranged from 1.0 to 1.9 for pelvic images in ten prostate cancer patients. A total of 516 tests were performed and assessed using the structural similarity index. Registration accuracy was plotted as a function of iteration number and a least-squares regression line was calculated, which implied an average improvement of 0.0236% per iteration. This baseline was used to determine if a given set of parameters under- or over-performed. The most accurate parameters within this range were applied to contoured images. The mean Dice similarity coefficient was calculated for bladder, prostate, and rectum with mean values of 98.26%, 97.58%, and 96.73%, respectively; corresponding to improvements of 2.3%, 9.8%, and 1.2% over previously reported values for the same organ contours. This graphical approach to registration analysis could aid in determining optimal parameters for Demons based algorithms. It also establishes expectation values for convergence rates and could serve as an indicator of non-physical warping, which often occurred in cases >0.6% from the regression line. PMID- 28714459 TI - A comprehensive model for sub-10 nm electron-beam patterning through the short time and cold development. AB - In this study, we propose a set of single-spot experiment to construct a comprehensive model of electron-beam lithography to describe the relation among the incident electrons, resist, and the development conditions such as durations and temperatures. Through the experiments, small feature can be achieved by performing a short-time development due to the high acceleration voltage and large depth of focus of electron-beam system. The singular point in the beginning of the development is also observed in our model and supported by the experimental data. In addition, we verify the characteristic region of each incident spot induced by the point spread function of the electron-beam system. We further fabricate the single line with narrow groove width by utilizing the results from single-spot experiment at low developing temperatures. The line is formed by arranging a series of incident points with a distance close to the characteristic radius. This method can eliminate the proximity effect effectively and thus the groove width is scaled down to 8 nm. By adopting the successful experience in the single line formation, dense array with narrow linewidth is also demonstrated under well suppression of the proximity effect. The minimum groove width of 9 nm with 30 nm pitch is achieved with 5 s development time at 10 degrees C. Finally, the exceptional capability of pattern transfer is presented due to the high aspect ratio of the resist. PMID- 28714460 TI - Magnetic behavior of metallic kagome lattices, Tb3Ru4Al12 and Er3Ru4Al12. AB - We report the magnetic behavior of two intermetallic-based kagome lattices, Tb3Ru4Al12 and Er3Ru4Al12, crystallizing in the Gd3Ru4Al2-type hexagonal crystal structure, by measurements in the range 1.8-300 K with bulk experimental techniques (ac and dc magnetization, heat capacity, and magnetoresistance). The main finding is that the Tb compound, known to order antiferromagnetically below (T N =) 22 K, shows glassy characteristics at lower temperatures ([Formula: see text]15 K), thus characterizing this compound as a re-entrant spin-glass. The data reveal that the glassy phase is quite complex and is of a cluster type. Since glassy behavior was not seen for the Gd analog in the past literature, this finding on the Tb compound emphasizes that this kagome family could provide an opportunity to explore the role of higher-order interactions (such as quadrupole) in bringing out magnetic frustration. Additional findings reported here for this compound are: (i) The plots of temperature dependence of magnetic susceptibility and electrical resistivity data in the range 12-20 K, just below T N , are found to be hysteretic leading to a magnetic phase in this intermediate temperature range, mimicking disorder-broadened first-order magnetic phase transitions; (ii) features attributable to an interesting magnetic phase co-existence phenomenon in the isothermal magnetoresistance in zero field, after travelling across metamagnetic transition fields, are observed. With respect to the Er compound, we do not find any evidence for long-range magnetic ordering down to 2 K, but this compound appears to be on the verge of magnetic order at 2 K. PMID- 28714461 TI - Predicting the dynamics of bacterial growth inhibition by ribosome-targeting antibiotics. AB - Understanding how antibiotics inhibit bacteria can help to reduce antibiotic use and hence avoid antimicrobial resistance-yet few theoretical models exist for bacterial growth inhibition by a clinically relevant antibiotic treatment regimen. In particular, in the clinic, antibiotic treatment is time-dependent. Here, we use a theoretical model, previously applied to steady-state bacterial growth, to predict the dynamical response of a bacterial cell to a time-dependent dose of ribosome-targeting antibiotic. Our results depend strongly on whether the antibiotic shows reversible transport and/or low-affinity ribosome binding ('low affinity antibiotic') or, in contrast, irreversible transport and/or high affinity ribosome binding ('high-affinity antibiotic'). For low-affinity antibiotics, our model predicts that growth inhibition depends on the duration of the antibiotic pulse, and can show a transient period of very fast growth following removal of the antibiotic. For high-affinity antibiotics, growth inhibition depends on peak dosage rather than dose duration, and the model predicts a pronounced post-antibiotic effect, due to hysteresis, in which growth can be suppressed for long times after the antibiotic dose has ended. These predictions are experimentally testable and may be of clinical significance. PMID- 28714463 TI - Summaries of articles in this issue. AB - Summaries of the articles in this issue are given in the PDF file. PMID- 28714462 TI - A hybrid phantom Monte Carlo-based method for historical reconstruction of organ doses in patients treated with cobalt-60 for Hodgkin's lymphoma. AB - Historical radiotherapy treatment plans lack 3D images sets required for estimating mean organ doses to patients. Alternatively, Monte Carlo-based models of radiotherapy devices coupled with whole-body computational phantoms can permit estimates of historical in-field and out-of-field organ doses as needed for studies associating radiation exposure and late tissue toxicities. In recreating historical patient treatments with 60Co based systems, the major components to be modeled include the source capsule, surrounding shielding layers, collimators (both fixed and adjustable), and trimmers as needed to vary field size. In this study, a computational model and experimental validation of the Theratron T-1000 are presented. Model validation is based upon in-field commissioning data collected at the University of Florida, published out-of-field data from the British Journal of Radiology (BJR) Supplement 25, and out-of-field measurements performed at the University of Wisconsin's Accredited Dosimetry Calibration Laboratory (UWADCL). The computational model of the Theratron T-1000 agrees with central axis percentage depth dose data to within 2% for 6 * 6 to 30 * 30 cm2 fields. Out-of-field doses were found to vary between 0.6% to 2.4% of central axis dose at 10 cm from field edge and 0.42% to 0.97% of central axis dose at 20 cm from the field edge, all at 5 cm depth. Absolute and relative differences between computed and measured out-of-field doses varied between +/-2.5% and +/ 100%, respectively, at distances up to 60 cm from the central axis. The source term model was subsequently combined with patient-morphometry matched computational hybrid phantoms as a method for estimating in-field and out-of field organ doses for patients treated for Hodgkin's Lymphoma. By changing field size and position, and adding patient-specific field shaping blocks, more complex historical treatment set-ups can be to recreated, particularly those for which 2D or 3D image sets are unavailable. PMID- 28714464 TI - Dynamic breaking of a single gold bond. AB - While one might assume that the force to break a chemical bond gives a measure of the bond strength, this intuition is misleading. If the force is loaded slowly, thermal fluctuations may break the bond before it is maximally stretched, and the breaking force will be less than the bond can sustain. Conversely, if the force is loaded rapidly it is more likely that the maximum breaking force is measured. Paradoxically, no clear differences in breaking force were observed in experiments on gold nanowires, despite being conducted under very different conditions. Here we explore the breaking behaviour of a single Au-Au bond and show that the breaking force is dependent on the loading rate. We probe the temperature and structural dependencies of breaking and suggest that the paradox can be explained by fast breaking of atomic wires and slow breaking of point contacts giving very similar breaking forces. PMID- 28714465 TI - Enhanced anti-tumour immunity requires the interplay between resident and circulating memory CD8+ T cells. AB - The goal of successful anti-tumoural immunity is the development of long-term protective immunity to prevent relapse. Infiltration of tumours with CD8+ T cells with a resident memory (Trm) phenotype correlates with improved survival. However, the interplay of circulating CD8+ T cells and Trm cells remains poorly explored in tumour immunity. Using different vaccination strategies that fine tune the generation of Trm cells or circulating memory T cells, here we show that, while both subsets are sufficient for anti-tumour immunity, the presence of Trm cells improves anti-tumour efficacy. Transferred central memory T cells (Tcm) generate Trm cells following viral infection or tumour challenge. Anti-PD-1 treatment promotes infiltration of transferred Tcm cells within tumours, improving anti-tumour immunity. Moreover, Batf3-dependent dendritic cells are essential for reactivation of circulating memory anti-tumour response. Our findings show the plasticity, collaboration and requirements for reactivation of memory CD8+ T cells subsets needed for optimal tumour vaccination and immunotherapy. PMID- 28714466 TI - Quantifying the critical thickness of electron hybridization in spintronics materials. AB - In the rapidly growing field of spintronics, simultaneous control of electronic and magnetic properties is essential, and the perspective of building novel phases is directly linked to the control of tuning parameters, for example, thickness and doping. Looking at the relevant effects in interface-driven spintronics, the reduced symmetry at a surface and interface corresponds to a severe modification of the overlap of electron orbitals, that is, to a change of electron hybridization. Here we report a chemically and magnetically sensitive depth-dependent analysis of two paradigmatic systems, namely La1-xSrxMnO3 and (Ga,Mn)As. Supported by cluster calculations, we find a crossover between surface and bulk in the electron hybridization/correlation and we identify a spectroscopic fingerprint of bulk metallic character and ferromagnetism versus depth. The critical thickness and the gradient of hybridization are measured, setting an intrinsic limit of 3 and 10 unit cells from the surface, respectively, for (Ga,Mn)As and La1-xSrxMnO3, for fully restoring bulk properties. PMID- 28714467 TI - Cryo-EM structures of the ATP-bound Vps4E233Q hexamer and its complex with Vta1 at near-atomic resolution. AB - The cellular ESCRT-III (endosomal sorting complex required for transport-III) and Vps4 (vacuolar protein sorting 4) comprise a common machinery that mediates a variety of membrane remodelling events. Vps4 is essential for the machinery function by using the energy from ATP hydrolysis to disassemble the ESCRT-III polymer into individual proteins. Here, we report the structures of the ATP-bound Vps4E233Q hexamer and its complex with the cofactor Vta1 (vps twenty associated 1) at resolutions of 3.9 and 4.2 A, respectively, determined by electron cryo microscopy. Six Vps4E233Q subunits in both assemblies exhibit a spiral-shaped ring-like arrangement. Locating at the periphery of the hexameric ring, Vta1 dimer bridges two adjacent Vps4 subunits by two different interaction modes to promote the formation of the active Vps4 hexamer during ESCRT-III filament disassembly. The structural findings, together with the structure-guided biochemical and single-molecule analyses, provide important insights into the process of the ESCRT-III polymer disassembly by Vps4. PMID- 28714468 TI - High-order harmonic generation from the dressed autoionizing states. AB - In high-order harmonic generation, resonant harmonics (RH) are sources of intense, coherent extreme-ultraviolet radiation. However, intensity enhancement of RH only occurs for a single harmonic order, making it challenging to generate short attosecond pulses. Moreover, the mechanism involved behind such RH was circumstantial, because of the lack of direct experimental proofs. Here, we demonstrate the exact quantum paths that electron follows for RH generation using tin, showing that it involves not only the autoionizing state, but also a harmonic generation from dressed-AIS that appears as two coherent satellite harmonics at frequencies +/-2Omega from the RH (Omega represents laser frequency). Our observations of harmonic emission from dressed states open the possibilities of generating intense and broadband attosecond pulses, thus contributing to future applications in attosecond science, as well as the perspective of studying the femtosecond and attosecond dynamics of autoionizing states. PMID- 28714470 TI - Essential role of FBXL5-mediated cellular iron homeostasis in maintenance of hematopoietic stem cells. AB - Hematopoietic stem cells (HSCs) are maintained in a hypoxic niche to limit oxidative stress. Although iron elicits oxidative stress, the importance of iron homeostasis in HSCs has been unknown. Here we show that iron regulation by the F box protein FBXL5 is required for HSC self-renewal. Conditional deletion of Fbxl5 in mouse HSCs results in cellular iron overload and a reduced cell number. Bone marrow transplantation reveals that FBXL5-deficient HSCs are unable to reconstitute the hematopoietic system of irradiated recipients as a result of stem cell exhaustion. Transcriptomic analysis shows abnormal activation of oxidative stress responses and the cell cycle in FBXL5-deficient mouse HSCs as well as downregulation of FBXL5 expression in HSCs of patients with myelodysplastic syndrome. Suppression of iron regulatory protein 2 (IRP2) accumulation in FBXL5-deficient mouse HSCs restores stem cell function, implicating IRP2 as a potential therapeutic target for human hematopoietic diseases associated with FBXL5 downregulation. PMID- 28714471 TI - Progression through mitosis promotes PARP inhibitor-induced cytotoxicity in homologous recombination-deficient cancer cells. AB - Mutations in homologous recombination (HR) genes BRCA1 and BRCA2 predispose to tumorigenesis. HR-deficient cancers are hypersensitive to Poly (ADP ribose) polymerase (PARP) inhibitors, but can acquire resistance and relapse. Mechanistic understanding how PARP inhibition induces cytotoxicity in HR-deficient cancer cells is incomplete. Here we find PARP inhibition to compromise replication fork stability in HR-deficient cancer cells, leading to mitotic DNA damage and consequent chromatin bridges and lagging chromosomes in anaphase, frequently leading to cytokinesis failure, multinucleation and cell death. PARP-inhibitor induced multinucleated cells fail clonogenic outgrowth, and high percentages of multinucleated cells are found in vivo in remnants of PARP inhibitor-treated Brca2-/-;p53-/- and Brca1-/-;p53-/- mammary mouse tumours, suggesting that mitotic progression promotes PARP-inhibitor-induced cell death. Indeed, enforced mitotic bypass through EMI1 depletion abrogates PARP-inhibitor-induced cytotoxicity. These findings provide insight into the cytotoxic effects of PARP inhibition, and point at combination therapies to potentiate PARP inhibitor treatment of HR-deficient tumours. PMID- 28714472 TI - Targeting the differential addiction to anti-apoptotic BCL-2 family for cancer therapy. AB - BCL-2 family proteins are central regulators of mitochondrial apoptosis and validated anti-cancer targets. Using small cell lung cancer (SCLC) as a model, we demonstrated the presence of differential addiction of cancer cells to anti apoptotic BCL-2, BCL-XL or MCL-1, which correlated with the respective protein expression ratio. ABT-263 (navitoclax), a BCL-2/BCL-XL inhibitor, prevented BCL XL from sequestering activator BH3-only molecules (BH3s) and BAX but not BAK. Consequently, ABT-263 failed to kill BCL-XL-addicted cells with low activator BH3s and BCL-XL overabundance conferred resistance to ABT-263. High-throughput screening identified anthracyclines including doxorubicin and CDK9 inhibitors including dinaciclib that synergized with ABT-263 through downregulation of MCL 1. As doxorubicin and dinaciclib also reduced BCL-XL, the combinations of BCL-2 inhibitor ABT-199 (venetoclax) with doxorubicin or dinaciclib provided effective therapeutic strategies for SCLC. Altogether, our study highlights the need for mechanism-guided targeting of anti-apoptotic BCL-2 proteins to effectively activate the mitochondrial cell death programme to kill cancer cells. PMID- 28714475 TI - Acylated heptapeptide binds albumin with high affinity and application as tag furnishes long-acting peptides. AB - The rapid renal clearance of peptides in vivo limits this attractive platform for the treatment of a broad range of diseases that require prolonged drug half lives. An intriguing approach for extending peptide circulation times works through a 'piggy-back' strategy in which peptides bind via a ligand to the long lived serum protein albumin. In accordance with this strategy, we developed an easily synthesized albumin-binding ligand based on a peptide-fatty acid chimera that has a high affinity for human albumin (Kd=39 nM). This ligand prolongs the elimination half-life of cyclic peptides in rats 25-fold to over seven hours. Conjugation to a peptide factor XII inhibitor developed for anti-thrombotic therapy extends the half-life from 13 minutes to over five hours, inhibiting coagulation for eight hours in rabbits. This high-affinity albumin ligand could potentially extend the half-life of peptides in human to several days, substantially broadening the application range of peptides as therapeutics. PMID- 28714473 TI - Prioritizing multiple therapeutic targets in parallel using automated DNA-encoded library screening. AB - The identification and prioritization of chemically tractable therapeutic targets is a significant challenge in the discovery of new medicines. We have developed a novel method that rapidly screens multiple proteins in parallel using DNA-encoded library technology (ELT). Initial efforts were focused on the efficient discovery of antibacterial leads against 119 targets from Acinetobacter baumannii and Staphylococcus aureus. The success of this effort led to the hypothesis that the relative number of ELT binders alone could be used to assess the ligandability of large sets of proteins. This concept was further explored by screening 42 targets from Mycobacterium tuberculosis. Active chemical series for six targets from our initial effort as well as three chemotypes for DHFR from M. tuberculosis are reported. The findings demonstrate that parallel ELT selections can be used to assess ligandability and highlight opportunities for successful lead and tool discovery. PMID- 28714474 TI - Facultative CTCF sites moderate mammary super-enhancer activity and regulate juxtaposed gene in non-mammary cells. AB - Precise spatiotemporal gene regulation is paramount for the establishment and maintenance of cell-specific programmes. Although there is evidence that chromatin neighbourhoods, formed by the zinc-finger protein CTCF, can sequester enhancers and their target genes, there is limited in vivo evidence for CTCF demarcating super-enhancers and preventing cross talk between distinct regulatory elements. Here, we address these questions in the Wap locus with its mammary specific super-enhancer separated by CTCF sites from widely expressed genes. Mutational analysis demonstrates that the Wap super-enhancer controls Ramp3, despite three separating CTCF sites. Their deletion in mice results in elevated expression of Ramp3 in mammary tissue through augmented promoter-enhancer interactions. Deletion of the distal CTCF-binding site results in loss of Ramp3 expression in non-mammary tissues. This suggests that CTCF sites are porous borders, allowing a super-enhancer to activate a secondary target. Likewise, CTCF sites shield a widely expressed gene from suppressive influences of a silent locus. PMID- 28714469 TI - Transancestral mapping and genetic load in systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is an autoimmune disease with marked gender and ethnic disparities. We report a large transancestral association study of SLE using Immunochip genotype data from 27,574 individuals of European (EA), African (AA) and Hispanic Amerindian (HA) ancestry. We identify 58 distinct non-HLA regions in EA, 9 in AA and 16 in HA (~50% of these regions have multiple independent associations); these include 24 novel SLE regions (P<5 * 10-8), refined association signals in established regions, extended associations to additional ancestries, and a disentangled complex HLA multigenic effect. The risk allele count (genetic load) exhibits an accelerating pattern of SLE risk, leading us to posit a cumulative hit hypothesis for autoimmune disease. Comparing results across the three ancestries identifies both ancestry-dependent and ancestry independent contributions to SLE risk. Our results are consistent with the unique and complex histories of the populations sampled, and collectively help clarify the genetic architecture and ethnic disparities in SLE. PMID- 28714476 TI - Modulation of nongenomic activation of PI3K signalling by tetramerization of N terminally-cleaved RXRalpha. AB - Retinoid X receptor-alpha (RXRalpha) binds to DNA either as homodimers or heterodimers, but it also forms homotetramers whose function is poorly defined. We previously discovered that an N-terminally-cleaved form of RXRalpha (tRXRalpha), produced in tumour cells, activates phosphoinositide 3-kinase (PI3K) signalling by binding to the p85alpha subunit of PI3K and that K-80003, an anti cancer agent, inhibits this process. Here, we report through crystallographic and biochemical studies that K-80003 binds to and stabilizes tRXRalpha tetramers via a 'three-pronged' combination of canonical and non-canonical mechanisms. K-80003 binding has no effect on tetramerization of RXRalpha, owing to the head-tail interaction that is absent in tRXRalpha. We also identify an LxxLL motif in p85alpha, which binds to the coactivator-binding groove on tRXRalpha and dissociates from tRXRalpha upon tRXRalpha tetramerization. These results identify conformational selection as the mechanism for inhibiting the nongenomic action of tRXRalpha and provide molecular insights into the development of RXRalpha cancer therapeutics. PMID- 28714477 TI - MUS81 nuclease activity is essential for replication stress tolerance and chromosome segregation in BRCA2-deficient cells. AB - Failure to restart replication forks stalled at genomic regions that are difficult to replicate or contain endogenous DNA lesions is a hallmark of BRCA2 deficiency. The nucleolytic activity of MUS81 endonuclease is required for replication fork restart under replication stress elicited by exogenous treatments. Here we investigate whether MUS81 could similarly facilitate DNA replication in the context of BRCA2 abrogation. Our results demonstrate that replication fork progression in BRCA2-deficient cells requires MUS81. Failure to complete genome replication and defective checkpoint surveillance enables BRCA2 deficient cells to progress through mitosis with under-replicated DNA, which elicits severe chromosome interlinking in anaphase. MUS81 nucleolytic activity is required to activate compensatory DNA synthesis during mitosis and to resolve mitotic interlinks, thus facilitating chromosome segregation. We propose that MUS81 provides a mechanism of replication stress tolerance, which sustains survival of BRCA2-deficient cells and can be exploited therapeutically through development of specific inhibitors of MUS81 nuclease activity. PMID- 28714478 TI - Immobilization of single argon atoms in nano-cages of two-dimensional zeolite model systems. AB - The confinement of noble gases on nanostructured surfaces, in contrast to bulk materials, at non-cryogenic temperatures represents a formidable challenge. In this work, individual Ar atoms are trapped at 300 K in nano-cages consisting of (alumino)silicate hexagonal prisms forming a two-dimensional array on a planar surface. The trapping of Ar atoms is detected in situ using synchrotron-based ambient pressure X-ray photoelectron spectroscopy. The atoms remain in the cages upon heating to 400 K. The trapping and release of Ar is studied combining surface science methods and density functional theory calculations. While the frameworks stay intact with the inclusion of Ar atoms, the permeability of gasses (for example, CO) through them is significantly affected, making these structures also interesting candidates for tunable atomic and molecular sieves. These findings enable the study of individually confined noble gas atoms using surface science methods, opening up new opportunities for fundamental research. PMID- 28714479 TI - Erratum: Growth of organic crystals via attachment and transformation of nanoscopic precursors. AB - This corrects the article DOI: 10.1038/ncomms15933. PMID- 28714482 TI - Type 2 immunity: Hero turns villain in fatty liver. PMID- 28714483 TI - Understanding Research and Scientific Publication. PMID- 28714484 TI - The Associations between Periodontitis and Respiratory Disease. AB - Researches have shown positive correlation between periodontitis and respiratory diseases such as chronic obstructive pulmonary disease. We reviewed the literature to assess the relationship between periodontitis and respiratory diseases. This study involved a review of relevant English literature published regarding periodontitis and respiratory diseases during the period of 1994-2015. The analysis of literature related to the topic showed there is association between periodontitis and respiratory diseases such as chronic obstructive pulmonary disease and pneumonia. It was found that periodontitis is associated with respiratory diseases due to poor oral hygiene and low immunity state. PMID- 28714480 TI - The impact of replication stress on replication dynamics and DNA damage in vertebrate cells. AB - The interplay between replication stress and the S phase checkpoint is a key determinant of genome maintenance, and has a major impact on human diseases, notably, tumour initiation and progression. Recent studies have yielded insights into sequence-dependent and sequence-independent sources of endogenous replication stress. These stresses result in nuclease-induced DNA damage, checkpoint activation and genome-wide replication fork slowing. Several hypotheses have been proposed to account for the mechanisms involved in this complex response. Recent results have shown that the slowing of the replication forks most commonly results from DNA precursor starvation. By concomitantly increasing the density of replication initiation, the cell elicits an efficient compensatory strategy to avoid mitotic anomalies and the inheritance of damage over cell generations. PMID- 28714485 TI - Health Care Waste Management Practice in Health Care Institutions of Nepal. AB - BACKGROUND: Medical waste is considered as a major public health hazard. In a developing country like Nepal, there is much concern about the management practice of medical waste. This study aimed to assess Health Care Waste Management practice among Health Care Institutions in Nepal. METHODS: A cross sectional study was carried out between July 2012 to June 2013 in 62 different Health Care Institutions, selected from stratified proportionate random sampling technique from all administrative regions of Nepal. A structured questionnaire and observation checklist were used for data collection. RESULTS: The waste generation rate is found significantly correlated with bed capacity, patient flow rate and annual budget spent in the hospital. It is found significantly higher in Teaching hospital than other Health Care Institutions of Nepal. An average of 3.3 kg/day/patient of medical waste (2.0 kg/day/patient non-hazardous and 1.0 kg/day/patient hazardous waste) was generated during the study period. Further, it was found that most of the Health care wastes were not disinfected before transportation to waste disposal sites. Very limited number of Health Care Institutions had conducted Environmental Assessment. Similarly, some of the Health Care Institutions had not followed Health care waste management guideline 2009 of Nepal Government. CONCLUSIONS: We found poor compliance of medical waste management practice as per existing legislation of Government of Nepal. Hence, additional effort is needed for improvement of Health care waste management practice at Health Care Institutions of Nepal. PMID- 28714481 TI - Evolutionary biology through the lens of budding yeast comparative genomics. AB - The budding yeast Saccharomyces cerevisiae is a highly advanced model system for studying genetics, cell biology and systems biology. Over the past decade, the application of high-throughput sequencing technologies to this species has contributed to this yeast also becoming an important model for evolutionary genomics. Indeed, comparative genomic analyses of laboratory, wild and domesticated yeast populations are providing unprecedented detail about many of the processes that govern evolution, including long-term processes, such as reproductive isolation and speciation, and short-term processes, such as adaptation to natural and domestication-related environments. PMID- 28714486 TI - Factors Associated with Smokeless Tobacco Use among Pregnant Women in Rural Areas of the Southern Terai, Nepal. AB - BACKGROUND: Tobacco use among women during pregnancy leading to poor maternal and child health outcomes has been well documented. However, factors influencing use of smokeless tobacco in Nepal has not yet been well established. This study aims at exploring the factors related to smokeless tobacco use among pregnant women in rural southern Terai of Nepal. METHODS: A community-based cross-sectional study was performed at 52 wards within 6 Village Development Committee in Dhanusha district of Nepal. A total of 426 expectant mothers in their second trimester were selected using a multistage cluster sampling method. Descriptive and regression analyses were done to explore the factors that influence smokeless tobacco use. RESULTS: In a total of 426 pregnant mothers, one in five used tobacco in any form. Among the users, 13.4% used smokeless tobacco. Pregnant mothers who were smoking tobacco (AOR 6.01; 95% CI (1.88-19.23), having alcohol consumption (AOR 3.86; 95% CI (1.23-12.08), stressed (AOR 5.04; 95% CI (1.81 14.03), non-vegetarian (AOR 3.31;(1.84-13.03), not attending regular mothers' group meetings (AOR 4.63; (1.41-15.19), and not-exposed to mass media (AOR 5.02; (1.89-13.33) were significantly associated with smokeless tobacco use. Similarly, mothers of age group 20-34 years, dalit, aadibasi and janajati, hill origin, no education and primary education were more likely to use smokeless tobacco than their counterparts. CONCLUSIONS: Factors such as smoking tobacco, alcohol consumption, stress, and poor education were found to be significantly associated with smokeless tobacco use among pregnant women in southern Terai of Nepal. This requires an immediate attention develop an effective strategy to prevent and control smokeless tobacco use among pregnant women in southern Terai of Nepal. PMID- 28714487 TI - Screening Mentally Retarded Children for Inborn Errors of Metabolism. AB - BACKGROUND: Most inborn errors of metabolism result in mental retardation and death due to accumulation of abnormal metabolites in the tissues. The presence of abnormal metabolites in the urine of mentally retarded individuals has been used worldwide for detection of inborn errors of metabolism. The purpose of the study is to determine the prevalence of inborn error of metabolism in mentally retarded children. METHODS: Random urine samples were collected from mentally retarded children at two institutes in Kathmandu, and also from 60 normal children from Duwakot, Nepal after obtaining consent from their parents. Urine was then tested for the presence of amino acids, keto-acids, mucopolysaccharides, fructose, glucose and protein using simple qualitative color reactions in the laboratory. RESULTS: The tests detected eight cases of Phenylketonuria, which turned out to be false positive on paper chromatography. Three cases of presence of ketone bodies (acetoacetate), ten cases of alpha-ketoaciduria, two cases of mucopolysaccharidosis and twelve cases of fructosuria amongst the sixty-two urine samples were also found. CONCLUSIONS: Certain aminoacidurias, ketoacidurias and mucopolysaccharidoses might be present in the Nepalese population. Within consideration of errors, the samples tested positive should be evaluated by a higher end method to confirm the utility of these simple and cheap chemical tests. PMID- 28714488 TI - Nasal Carriage Rate of Methicillin Resistant Staphylococcus aureus among Health Care Workers at a Tertiary Care Hospital in Kathmandu, Nepal. AB - BACKGROUND: Methicillin-resistant Staphylococcus aureus is one of the most common causes of nosocomial infections. Due to its multidrug resistant nature; infections due to Methicillin-resistant Staphylococcus aureus are often very difficult to treat. Colonized health care workers are the important sources of Methicillin-resistant Staphylococcus aureus. The objectives of this study were to determine the nasal carriage rate of Methicillin-resistant Staphylococcus aureus among health care workers at Kathmandu Medical College and Teaching Hospital, Nepal and to assess their antimicrobial susceptibility patterns. METHODS: A cross sectional study was conducted among 252 health care workers from July to November 2013. Mannitol salt agar was used to culture the nasal swabs. Antimicrobial susceptibility testing was performed by Kirby-Bauer disc diffusion technique following Clinical and Laboratory Standards Institute guidelines. Methicillin resistant Staphylococcus aureus strains were confirmed by using cefoxitin disc and by determining the minimum inhibitory concentration of oxacillin by agar dilution method. RESULTS: Of 252 healthcare workers, 46(18.3%) were positive for Staphylococcus aureus among which 19(41.3%) were Methicillin-resistant Staphylococcus aureus carriers. Overall rate of nasal carriage of Methicillin resistant Staphylococcus aureus was 7.5% (19/252).The higher percentages of lab personnel were nasal carriers of S. aureus (31.6%) and Methicillin-resistant Staphylococcus aureus (10.5%).The percentages of nasal carriage of S. aureus (35.7%) and Methicillin-resistant Staphylococcus aureus (14.3%) were highest in the health care workers from post operative department. Higher percentage of Methicillin-resistant Staphylococcus aureus were susceptible toward amikacin (100%) and vancomycin (100%) followed by cotrimoxazole (84.2%). CONCLUSIONS: High rates of nasal carriage of S. aureus and Methicillin-resistant Staphylococcus aureus were observed among the healthcare workers, which indicate the need of strict infection control measures to be followed to control the nosocomial infections. PMID- 28714489 TI - Knowledge, Attitude and Practice Regarding Pharmacovigilance and Consumer Pharmacovigilance among Consumers at Lalitpur District, Nepal. AB - BACKGROUND: Adverse drug reactions (ADRs) can be a big threat to the health of people in Nepal as a variety of medicines are consumed in the country. Involving consumers in pharmacovigilance can strengthen ADR reporting. The study aims to find out knowledge, attitude and practice regarding pharmacovigilance and consumer pharmacovigilance among consumers at Lalitpur district, Nepal Methods: It was carried out in outpatients visiting in KIST Medical College and Teaching Hospital, Lalitpur, Nepal. Participant's knowledge, attitude and practice were measured by noting their agreement with a set of 21 statements along with multiple choice and open ended questions. RESULTS: A total of 157 outpatients were surveyed. The knowledge scores for males (12) was better compared to the females (11), but the scores for attitude and practice were same for both groups. The maximum score for knowledge was 29, attitude was 6 and practice was 10. The overall KAP scores was 45. The total scores for knowledge, attitude and practice for males (24) were better compared to female (22) respondents. Seventy-one patients (68%) who participated in this study favoured establishing a consumer centre for obtaining information about ADRs. CONCLUSIONS: Knowledge scores among consumers regarding pharmacovigilance is low and require advocacy and improvement. PMID- 28714490 TI - Current Diagnostic Approach and Initial Treatment Patterns for Renal Colic in Emergency Department. AB - BACKGROUND: Renal colic is a common clinical presentation in emergency. The goal of this study was to describe the epidemiology, current diagnostic and treatment strategies of ureteric colic in our emergency department. METHODS: This is a retrospective study performed over a six months period of patients with clinically suspected renal colic. Data collected included age, sex, urine analysis, ultrasound studies regarding size, site of the stone and presence of hydronephrosis. Comparative statistical analysis was performed using SPSS 12.2 software. RESULTS: Among the total 201 cases, 134(67%) had ultrasound performed which yielded ureteric stone in 61/134 (45.5%) cases, out of which 52.5% (32/61), 32.8% (20/61) and 14.8% (9/61) had stones measuring 5-9.9mm, <= 4.9mm and >= 10mm respectively. The mean age was 31.6+/-11 with male: female of 3:1. Hydronephrosis was strongly correlated with the presence of ureteric stone (sensitivity -85.2%, specificity-94.5%, positive predictive value-92.9% and negative predictive value of 88.5%) and was significantly more common with larger stones (p=0.05). Hematuria and pyuria was present among 44.3% (27/61) and 31.1% (19/61) of the ultrasound confirmed ureteric stones respectively. Nonsteroidal anti-inflammatory drugs and smooth muscle relaxants were the most common drug offered. CONCLUSIONS: Ultrasound to detect hydronephrosis, which is the most significant finding, may help to establish the probability of obstruction due to clinically important stone. Absence of hydronephrosis probably suggests small or passed out calculus requiring no immediate urological intervention or may indicate alternate diagnosis. Presence or absence of hematuria cannot be reliable diagnosing and excluding ureteral stones. PMID- 28714491 TI - Molecular Epidemiology and Antigenic Characterization of Seasonal Influenza Viruses Circulating in Nepal. AB - BACKGROUND: Influenza is one of the public health burdens in Nepal and its epidemiology is not clearly understood. The objective of this study was to explore the molecular epidemiology and the antigenic characteristics of the circulating influenza viruses in Nepal. METHODS: A total of 1495 throat swab specimens were collected from January to December, 2014. Real time PCR assay was used for identification of influenza virus types and subtypes. Ten percent of the positive specimens were randomly selected and inoculated onto Madin-Darby Canine Kidney Epithelial cells (MDCK) for influenza virus isolation. All viruses were characterized by the hemagglutination inhibition (HI) assay. RESULTS: Influenza viruses were detected in 421/1495 (28.2%) specimens. Among positive cases, influenza A virus was detected in 301/421 (71.5%); of which 120 (39.9%) were influenza A/H1N1 pdm09 and 181 (60.1%) were influenza A/H3 subtype. Influenza B viruses were detected in 119/421 (28.3%) specimens. Influenza A/H1N1 pdm09, A/H3 and B viruses isolated in Nepal were antigenically similar to the vaccine strain influenza A/California/07/2009(H1N1pdm09), A/Texas/50/2012(H3N2), A/New York/39/2012(H3N2) and B/Massachusetts/2/2012, respectively. CONCLUSIONS: Influenza viruses were reported year-round in different geographical regions of Nepal which was similar to other tropical countries. The circulating influenza virus type and subtypes of Nepal were similar to vaccine candidate virus which could be prevented by currently used influenza vaccine. PMID- 28714492 TI - Estimated Fetal Weight: Comparison of Clinical Versus Ultrasound Estimate. AB - BACKGROUND: Accurate estimation of fetal weight is of paramount importance in the management of labour and delivery. METHODS: This was a cross sectional study conducted over a period of 6 months in a tertiary care teaching hospital. All singleton term mothers with cephalic presentation and intact membranes with ultrasound examination done within a week were included in the study. IUFD, multiple gestation, malpresentation, diagnosed oligohydramnios or polyhydramnios, pelvic and or abdominal masses, and current weight more than 80 Kgs were excluded from the study. Expected fetal weight was estimated by clinical method (Johnson's formula), which was compared with Ultrasound weight estimation (Hadlock method) and actual birth weight. RESULTS: The estimated mean birth weight by clinical method was 3492.75+/-393.16g, by Ultrasound was 3230.02+/-407.22g and actual mean birth weight was 3236.32+/-472.87g. The estimated birth weight by ultrasonographic method showed slightly stronger positive correlation (r=0.54; p<0.001) with actual birth weight as compared to the clinical method (r=0.44; p<0.001). The error of estimation of weight by clinical method showed significant negative correlation (r=-0.24; p=0.01) with gestational age, however ultrasonographic method did not show significant correlation (r= +0.045; p=0.64). The sensitivity and specificity of clinical method and ultrasonographic method for identifying fetal birth weight above 3500 gm was 69.23; 65.67% and 46.15; 80.60%, respectively. CONCLUSIONS: Ultrasound was more reliable method to establish fetal weight at term and more consistent in various period of gestations. Clinical method can be reliably used to screen large babies in centers where ultrasound has limited availability. PMID- 28714493 TI - Handwashing Practices in Neonatal Intensive Care Unit, Paediatric Intensive Care Unit and Neonatal Nurseries in Patan Hospital. AB - BACKGROUND: Hand hygiene has been identified as the single most important factor in minimising hospital acquired infections. However, compliance of handwashing guidelines has remained low. The aim of this study was to study the handwashing practices in the Paediatric and Neonatal intensive care units and Neonatal nurseries in Patan Hospital, and secondly to re-evaluate the improvement on compliance of handwashing guidelines after intervention. METHODS: Pre intervention study was conducted by covertly observing the handwashing practices by the healthcare workers. The healthcare workers were then shown the video demonstrating correct methods of handwashing as recommended by World health organization. The cycle was completed by discretely re-observing the handwashing practices following intervention. RESULTS: Sixty five samples were collected initially. Only 6 (9.2%) had completed all steps of handwashing correctly. Post- intervention, 51 samples were collected, out of which 35 (68.6%) had correctly completed all the steps. Following audio-visual demonstration, 100% correctly completed 8/10 steps of handwashing with soap and water. 8 (16%) failed to dry hands using a single use towel and 14 (28%) failed to turn off the tap using elbow. Post- intervention, 100% correctly completed 4/7 steps of handwashing using chlorhexidine. Four (15%) still failed to rub backs of fingers to opposite palm, eight (30%) failed to palm to palm with fingers interlaced, and rub thumb to opposite palm. CONCLUSIONS: Compliance in hand hygiene is low despite the known fact that it reduces nosocomial infections. However, a simple intervention like video demonstration can improve the compliance among healthcare workers. PMID- 28714494 TI - Computerized Axial Tomography Findings in Children with Afebrile Seizures: A Hospital Based Study at Eastern Nepal. AB - BACKGROUND: Computerized Tomography can be performed in resource limited areas where Magnetic Resonance Imaging is less practical. This study was conducted to find out the proportion of cases with abnormal CT scan and findings of CT scan in children with afebrile seizures in a resource limited area. METHODS: This prospective study was conducted from 1st July 2009 to 31st March 2014 in a university hospital of Nepal. Patients (1 month to 20 years of age) presenting with history of afebrile seizure were included. Neuroimaging was prescribed; children were treated and followed-up as per standard guideline. Data were analyzed using SPSS 16.0. RESULTS: There were 447 children with afebrile seizures included in the study. Male to female ratio was 1.6:1. Median age at presentation was 84 (interquartile range 36-144) months. CT scan was done in 321 (71.8%) cases. CT was abnormal in 143 cases, accounting for 32.0% out of total cases and 44.5% out of investigated cases. Among investigated cases, common CT findings were atrophy (13.4%), neurocysticercosis (12.1%), structural abnormalities (4.4%), stroke (3.7%), post-encephalitis changes (3.1%), nonspecific calcification (1.6%), tuberculoma (1.2%), tumor (0.9%), neurocutaneous syndromes (0.9%), hydrocephalus (0.9%) and other findings (2.2%). CONCLUSIONS: In a resource limited area CT scan is a valuable alternative tool in evaluating a child with afebrile seizure. Majority of these children have remote symptomatic seizures and the underlying brain pathologies can be well detected by CT scan. PMID- 28714495 TI - Laparoscopic Approach for Management of Hydatid Cyst of Liver. AB - BACKGROUND: Adequate health services for improving maternal and neonatal health is an important global health issues. Institutional delivery is most important component to address maternal and neonatal issue. Institutional delivery service utilization assures safe birth and minimizes the maternal morbidity and mortality. This study was aimed to assess the utilization of institutional delivery service among the mothers of Gorkha district. METHODS: A cross sectional study of 180 mothers having child below 2 years residing in Palungtar municipality was done between March to July 2015. Information was collected by using an interviewer administered semi-structured questionnaire. Chi-square test was used to for data analysis. RESULTS: Of total, 93.3% of the mother gave birth to their current child at health institution. The study variables like age at marriage, knowledge on delivery incentive, long waiting hours at health facility, Information on maternal health before current pregnancy, age at first pregnancy, gestational age at first ANC visit and women knowing differences between home and institutional delivery were independent factors influencing utilization of institutional delivery service. CONCLUSIONS: Promotion of information, education and communication on maternal health services and delivery incentives could result in utilization of institutional delivery services. PMID- 28714496 TI - Clinical Outcome of Autologous Serum Therapy in Chronic Idiopathic Urticaria. AB - BACKGROUND: Quality of life in chronic idiopathic urticaria is hampered as efficacy of H1-antihistamines is limited. Autologous serum containing tolerance generating anti-idiotype antibodies is a novel and cost-effective therapy. This study was conducted to evaluate the efficacy of autologous serum therapy (AST) among chronic urticaria patients with autologous skin prick test positive and negative status. METHODS: Untreated 102 patients of chronic urticaria were enrolled in a non-randomized interventional study. Patients were categorized into two groups based on autologous serum skin prick test as test positive (ASST +) and test negative (ASST -). Patients were then treated with intramuscular injection of 0.05ml per kg body weight of autologous serum weekly for 10 weeks. Urticaria activity scoring (UAS) tool was used for quantification of the symptoms. Weekly recording of UAS (range: 0-42) was made before the therapy (baseline) and during the therapy for 10 weeks. RESULTS: Significant improvement with AST in the mean UAS was noted from baseline to 10 weeks in both the group of patients (14.6 +/- 6.3 and 10.2 +/- 5.1 for ASST+ group ; 16.9 +/- 7.8 and 8.6 +/ 4.8 for ASST- group; at baseline and 10 weeks, respectively (p-value for both <0.05)). However no statistical significance was found while comparing the efficacy of the therapy against ASST + and ASST - Groups (p-value > 0.05). CONCLUSIONS: Irrespective of autologous skin prick test results, autologous serum therapy showed significant improvement in patients with chornic idiopathic urticaria. AST can, thus, be an effective treatment modality for it. PMID- 28714497 TI - Admitting Deserving Medical Students from Rural and Disadvantaged: Patan Academy of Health Sciences' Approach. AB - BACKGROUND: Patan Academy of Health Sciences (PAHS) aims to produce physicians who would be able and willing to serve in the rural areas. Recognizing the critical importance of student selection strategy, among others, in achieving the program goals, it has adopted an innovative scheme for selecting medical students. This paper describes PAHS medical student selection scheme that favors enrollment of deserving applicants from rural and disadvantaged groups so as to help improve distribution of physicians in rural Nepal. METHODS: A student admission committee comprising a group of medical educators finalized a three step student selection scheme linked with scholarships after reviewing relevant literatures and consultative meetings with experts within and outside Nepal. The committee did local validation of Personal Quality Assessment (PQA) that tested cognitive ability and personality traits, Admission OSPE (Objective Structured Performance Examination) that assessed non-cognitive attributes of applicants. It also provided preferential credits to applicants' socio-economic characteristics to favor the enrollment of deserving applicants from rural and disadvantaged groups through Social Inclusion Matrix (SIM). Three different categories of scholarship schemes namely Partial, Collaborative and Full were devised with Partial providing 50% and other two categories each providing 100% coverage of tuition fee. RESULTS: PAHS student selection scheme succeeded in enrolling more than half of its students from rural areas of Nepal, including about 10% of the students from that of the most backward region of the country. About one third of students were female and about the same were from public and community school. Sixty percent of students receive different categories of scholarships. CONCLUSIONS: Limited findings indicate the success of the selection scheme in enrolling high proportion of applicants from rural and disadvantageous groups and enable them to pursue study by providing scholarships. PMID- 28714498 TI - Chondrodysplasia Punctata: A Case Report of Fetal Warfarin Syndrome. AB - Chondrodysplasia punctata is abnormal calcification in the cartilage of developing bones and has been seen in association with deranged vitamin K metabolism. Warfarin, an oral anticoagulant acting on vitamin K dependent clotting factors is known to cause chondrodysplasia punctata. Despite the knowledge of the condition the management of patients with prosthetic heart valves might require use of the drug for anticoagulation. Here, we present a case of a fetal warfarin syndrome in a second born child of a 27 year lady under warfarin for prosthetic heart valve. The pregnancy was complicated by polyhydramnios in third trimester and terminated at term by normal vaginal delivery. The baby was well, except for facial dysmorphism in the form of depressed nasal bridge, narrow nares and suspected left choanal atresia. Radiograph revealed stippled ephiphysis of vertebra, femora and humera supporting diagnosis of fetal warfarin syndrome. The baby did not develop any perinatal complication and was discharged home. PMID- 28714499 TI - Governance and Purchasing Function under Social Health Insurance in Nepal: Looking Back and Moving Forward. AB - Nepal is pursuing Social Health Insurance as a way of mobilizing revenues to achieve Universal Health Coverage. The Social Health Insurance governance encourages service providers to maintain quality and efficiency in services provision by practicing strategic purchasing. Social Health Security Programme is a social protection program which aspires to achieve the goals of Social Health Insurance. Social Health Security Development Committee needs to consider following experiences to function as a strategic purchaser. The Social Health Security Development Committee need to be an independent body instead of falling under Ministry of Health. Similarly, purchasing of health services needs to be made strategic, i.e., Social Health Security Development Committee should use its financial power to guide the provider behavior that will eventually contribute to achieving the goals of quality and efficiency in service provision. The other social health security funds should be merged with Social Health Security Development Committee and develop a single national fund. Finally, the state has to regulate and monitor the performance of the SHI agency. PMID- 28714500 TI - Exploring the immunomodulatory and anticancer properties of zerumbone. AB - Plant-derived immunomodulators and anti-cancer agents have attracted a lot of interest from natural product scientists for their efficacy and safety and their significant contribution towards understanding targeted drug action and drug delivery mechanisms. Zerumbone, the main constituent of Zingiber zerumbet rhizomes, has been investigated for its wide-spectrum role in treating multitargeted diseases. The rhizomes have been used as food flavoring agents in various cuisines and in herbal medicine. Many in vivo and in vitro studies have provided evidence of zerumbone as a potent immunomodulator as well as a potential anti-cancer agent. This review is an interesting compilation of all those significant outcomes from investigations carried out to date to explore the immunomodulatory and anticancer properties of zerumbone. The ultimate objective of this comprehensive review is to provide updated information and a critical assessment on zerumbone including its chemistry and immunomodulating and anticancer properties, which may be of paramount importance to provide a new path for ensuing research to discover new agents to treat cancers and immune-related diseases. In addition, updated information on the toxicology of zerumbone has also been summarized to provide its safety profile. PMID- 28714501 TI - Understanding the role of tyrosine in glycogenin. AB - We explored the molecular basis of tyrosine as the docking amino acid for the first glucose molecule during the synthesis of glycogen. The IR spectra show that the aromatic ring acts as bait to keep the position where the next glucose unit has to bind clear, by luring non-desirable molecules towards the aromatic ring. Only, alpha-/beta-glucose shows particular affinity for the O3H and O4H moieties. PMID- 28714502 TI - Insights into the RNA binding mechanism of human L1-ORF1p: a molecular dynamics study. AB - The recognition and binding of nucleic acids by ORF1p, an L1 retrotransposon protein, have not yet been clearly understood due to the lack of structural knowledge. The present study attempts to identify the probable single-stranded RNA binding pathway of trimeric ORF1p using computational methods like ligand mapping methodology combined with molecular dynamics simulations. Using the ligand mapping methodology, the possible RNA interacting sites on the surface of the trimeric ORF1p were identified. The crystal structure of the ORF1p timer and an RNA molecule of 29 nucleotide bases in length were used to generate the structure of the ORF1p complex based on information on predicted binding sites as well as the functional states of the CTD. The various complexes of ORF1p-RNA were generated using polyU, polyA and L1RNA sequences and were simulated for a period of 75 ns. The observed stable interaction pattern was used to propose the possible binding pathway. Based on the binding free energy for complex formation, both polyU and L1RNA complexes were identified as stable complexes, while the complex formed with polyA was the least stable one. Furthermore, the importance of the residues in the CC domain (Lys137 and Arg141), the RRM loop (Arg206, Arg210 and Arg211) and the CTD (Arg 261 and Arg262) of all three chains in stabilizing the wrapped RNA has been highlighted in this study. The presence of several electrostatic interactions including H-bond interactions increases the affinity towards RNA and hence plays a vital role in retaining the wrapped position of RNA around ORF1p. Altogether, this study presents one of the possible RNA binding pathways of ORF1p and clearly highlights the functional state of ORF1p visited during RNA binding. PMID- 28714503 TI - Protective effects of fisetin and other berry flavonoids in Parkinson's disease. AB - Parkinson's disease (PD) is an age-associated degenerative disease of the midbrain that results from the loss of dopaminergic neurons in the substantia nigra. It initially presents as a movement disorder with cognitive and other behavioral problems appearing later in the progression of the disease. Current therapies for PD only delay the onset or reduce the motor symptoms. There are no treatments to stop the nerve cell death or to cure the disease. It is becoming increasingly clear that neurological diseases such as PD are multi-factorial involving disruptions in multiple cellular systems. Thus, it is unlikely that modulating only a single factor will be effective at either preventing disease development or slowing disease progression. A better approach is to identify small molecules that have multiple biological activities relevant to the maintenance of brain function. Flavonoids are polyphenolic compounds that are widely distributed in fruits and vegetables and therefore regularly consumed in the human diet. While flavonoids were historically characterized on the basis of their antioxidant and free radical scavenging effects, more recent studies have shown that flavonoids have a wide range of activities that could make them particularly effective as agents for the treatment of PD. In this article, the multiple physiological benefits of flavonoids in the context of PD are first reviewed. Then, the evidence for the beneficial effects of the flavonol fisetin in models of PD are discussed. These results, coupled with the known actions of fisetin, suggest that it could reduce the impact of PD on brain function. PMID- 28714504 TI - Tartary buckwheat flavonoids ameliorate high fructose-induced insulin resistance and oxidative stress associated with the insulin signaling and Nrf2/HO-1 pathways in mice. AB - The present study was conducted to explore the effects of a purified tartary buckwheat flavonoid fraction (TBF) on insulin resistance and hepatic oxidative stress in mice fed high fructose in drinking water (20%) for 8 weeks. The results indicated that continuous administration of TBF dose-dependently improved the insulin sensitivity and glucose intolerance in high fructose-fed mice. TBF treatment also reversed the reduced level of insulin action on the phosphorylation of insulin receptor substrate-1 (IRS-1), protein kinase B (Akt) and phosphatidylinositol 3-kinase (PI3K), as well as the translocation of glucose transporter type 4 (GLUT4) in the insulin-resistant liver. Furthermore, TBF was found to exert high antioxidant capacity as it acts as a shield against oxidative stress induced by high fructose by restoring the antioxidant status, and modulating nuclear factor E2 related factor 2 (Nrf2) translocation to the nucleus with subsequently up-regulated antioxidative enzyme protein expression. Histopathological examinations revealed that impaired pancreatic/hepatic tissues were effectively restored in high fructose-fed mice following TBF treatment. Our results show that TBF intake is effective in preventing the conversion of high fructose-induced insulin resistance and hepatic oxidative stress in mice by improving the insulin signaling molecules and the Nrf2 signal pathway in the liver. PMID- 28714505 TI - The antiproliferative activity of di-2-pyridylketone dithiocarbamate is partly attributed to catalase inhibition: detailing the interaction by spectroscopic methods. AB - The bioactivity of drugs is attributed to their interaction with biological molecules, embodied in either their direct or indirect influence on enzyme activity and conformation. Di-2-pyridylketone hydrazine dithiocarbamate (DpdtC) exhibits significant antitumor activity in our preliminary study. We speculated that its activity may partly stem from enzyme inhibition due to strong metal chelating ability. To this end, we assessed its effect on catalase from erythrocytes and found evidence of inhibition, which was further confirmed by ROS determination in vivo. Thus, detailing the interaction between the agent and catalase via spectroscopic methods and molecular docking was required to obtain information on both the dynamics and thermodynamic parameters. The Lineweaver Burk plot implied an uncompetitive pattern between DpdtC and catalase from beef liver, and IC50 = ~7 MUM. The thermodynamic parameters from fluorescence quenching measurements indicated that DpdtC could bind to catalase with moderate affinity (Ka = approximately 104 M-1). CD spectra revealed that DpdtC could significantly disrupt the secondary structure of catalase. Docking studies indicated that DpdtC bound to a flexible region of catalase, involving hydrogen bonds and salt bond; this was consistent with thermodynamic results from spectral investigations. Our data clearly showed that catalase inhibition of DpdtC was not due to direct chelation of iron from heme (killing), but through an allosteric effect. Thus, it can be concluded that the antiproliferative activity of DpdtC is partially attributed to its catalase inhibition. PMID- 28714506 TI - An integrated microwell array platform for cell lasing analysis. AB - Biological cell lasers are emerging as a novel technology in biological studies and biomedical engineering. The heterogeneity of cells, however, can result in various lasing behaviors from cell to cell. Thus, the capability to track individual cells during laser investigation is highly desired. In this work, a microwell array was integrated with high-quality Fabry-Perot cavities for addressable and automated cell laser studies. Cells were captured in the microwells and the corresponding cell lasing was achieved and analyzed using SYTO9-stained Sf9 cells as a model system. It is found that the presence of the microwells does not affect the lasing performance, but the cell lasers exhibit strong heterogeneity due to different cell sizes, cycle stages and polyploidy. Time series laser measurements were also performed automatically with the integrated microarray, which not only enables the tracking and multiplexed detection of individual cells, but also helps identify "abnormal" cells that deviate from a large normal cell population in their lasing performance. The microarrayed cell laser platform developed here could provide a powerful tool in single cell analysis using lasing emission that complements conventional fluorescence-based cell analysis. PMID- 28714507 TI - Postsynthetic modification of a zirconium metal-organic framework at the inorganic secondary building unit with diphenylphosphinic acid for increased photosensitizing properties and stability. AB - A zirconium metal-organic framework (MOF) PCN-222 was postsynthetically modified with diphenylphosphinic acid, resulting in an increased stability when activated from water and 4 times higher photosensitizing properties for singlet oxygen production. The phosphinic acid did not compromise the crystallinity of the MOF but made strong bonds with the zirconia secondary building units. PMID- 28714508 TI - Gold glyconanoparticles coupled to listeriolysin O 91-99 peptide serve as adjuvant therapy against melanoma. AB - Dendritic cell-based (DC-based) vaccines are promising immunotherapies for cancer. However, several factors, such as the lack of efficient targeted delivery and the sources and types of DCs, have limited the efficacy of DCs and their clinical potential. We propose an alternative nanotechnology-based vaccine platform with antibacterial prophylactic abilities that uses gold glyconanoparticles coupled to listeriolysin O 91-99 peptide (GNP-LLO91-99), which acts as a novel adjuvant for cancer therapy. GNP-LLO91-99, when used to vaccinate mice, exhibited dual antitumour activities, namely, the inhibition of tumour migration and growth and adjuvant activity for recruiting and activating DCs, including those from melanoma patients. GNP-LLO91-99 nanoparticles caused tumour apoptosis and induced antigen- and melanoma-specific cytotoxic Th1 responses (P <= 0.5). We propose this adjuvant nanotherapy for preventing the progression of the first stages of melanoma. PMID- 28714509 TI - A comparative review of computational methods for pathway perturbation analysis: dynamical and topological perspectives. AB - Stem cells offer great promise within the field of regenerative medicine but despite encouraging results, the large scale use of stem cells for therapeutic applications still faces challenges when it comes to controlling signaling pathway responses with respect to environmental perturbations. This step is critical for the elaboration of stable and reproducible differentiation protocols, and computational modeling can be helpful to overcome these difficulties. This article is a comparative review of the mechanism-based methods used for hypothesis-driven approaches and data-driven methods which are two types of computational approaches commonly used for analysing the dynamics of pathways involved in stem cell regulation. We firstly review works based on kinetic modelling. We emphasize the relationships between the dynamics of these pathways and their topological features, and illustrative examples are described to show how the analysis of these relationships can contribute to a more detailed and formal understanding of the signaling dynamics. This discussion is followed by a review of the recent data-driven pathway analysis methods. Based on a simplified description of the pathways, these methods are able to handle high dimensionality data, and topological features of the pathways taken into account in the latest methods improve both accuracy and predictive power. Nevertheless, progress is still needed to clarify the biological meaning of the topological decompositions used by these methods. PMID- 28714511 TI - Tailoring crack morphology in coffee-ring deposits via substrate heating. AB - The drying of a sessile drop consisting of colloidal particles and the formation of particulate deposits with spatially periodic cracks were ubiquitous. The drying induced stress, which is generated during the evaporation of a colloidal drop, is released by the formation of cracks. We find that the morphology of cracks formed in particulate films dried at substrate temperature, Tsub = 25 degrees C is markedly different from that of cracks formed at Tsub > 45 degrees C. The cracks are disordered in the former case, but ordered and periodic in the latter. The disorderedness of cracks observed at Tsub = 25 degrees C is mainly due to the formation of a coffee-ring like particle deposit that exhibits a larger height gradient. The ultimate deposit pattern after complete drying is observed to be different for colloidal dispersion drops evaporated at different substrate temperatures. This is attributed to temperature-dependent solvent flow mechanisms and capillary-driven flow, which occur inside the colloidal drop during the course of drying. In addition, for the coffee-ring-like particulate deposit obtained at Tsub <= 45 degrees C, the ratio between the width of the deposit w and the radius of the ring R scales with the volume fraction of the colloids phi, w/R ~ phi0.5, in the range of volume fractions studied in this work. The deposited patterns obtained at temperature Tsub > 45 degrees C are largely dominated by the capture of particles by the receding liquid-vapor interface. This is due to the faster rate of decrease of the liquid-vapor interface position with an increase in substrate temperature. PMID- 28714510 TI - Radical reactions of diamine bis(phenolate) vanadium(iii) complexes. Solid state binding of O2 to form a vanadium(v) peroxo complex. AB - [VCl3(THF)3] reacted with the sodium salt of a tripodal diamine bisphenolate ligand precursor Na2L2 to give a paramagnetic d2 complex [V(L2)Cl] (2). The reaction of 2 with oxygen is strongly dependent on the experimental conditions, affording [VO(L2)Cl] (6) or [V(eta2-O2)(L2)Cl] (7). The formation of 7 involves the direct addition of O2 to V(iii) in the solid state with oxidation to V(v) without significantly disturbing the structure of 2. DFT calculations showed that compound 7 is an intermediate in the formation of 6 from 2. The reaction involves the cleavage of the eta1-O-O bond in a proposed dimeric species. The overall reaction of 2 moles of vanadium(iii), complex 2, and one mole of O2 to yield two moles of product 6 is a favourable process with DeltaG298 = -38.3 kcal mol-1. 7 is the first non-oxido peroxidovanadium(v) complex obtained directly from the reaction of a crystal and the second example of a structurally characterized complex of that type. Reactions of V(L1)Cl (1) and V(L2)Cl (2) with one equivalent of the nitroxyl radical TEMPO in toluene also result in the formation of oxido V(v) complexes, VO(L1)Cl (5) and VO(L2)Cl (6). The reaction of VO(OiPr)3 with Na2L2 afforded [VO(L2)(OiPr)] (8) in high yield. A major isomer having the V[double bond, length as m-dash]O moiety in the equatorial plane was characterised by X-ray diffraction although solution NMR data showed the presence of a minor species with the oxido ligand trans to the tripodal nitrogen, as in 6. Complexes 6 and 8 are very active and selective sulfoxidation catalysts of thioanisole, but no enantiomeric excess was obtained. PMID- 28714512 TI - Inhibition of STAT3 signaling pathway by ursolic acid suppresses growth of hepatocellular carcinoma. AB - The signal transducer and activator of transcription 3 (STAT3) has been found to be constitutively active in liver cancer. There is no STAT3 inhibitors approved to be used clinically for the treatment or prevention of liver cancer. Some dietary compounds including ursolic acid (UA) have been reported to inhibit the growth of cancer cells. However, whether UA could inhibit STAT3 phosphorylation in hepatocellular carcinoma has not been reported. The inhibitory effects of UA on STAT3 phosphorylation, along with cell viability, migration, colony formation in vitro, as well as tumor growth in vivo were examined in human liver cancer cell lines. Our data showed that UA inhibited the P-STAT3 induced by interleukin 6 (IL-6) in Hep3B liver cancer cells which express very low basal level of P STAT3. The constitutive STAT3 phosphorylation was also inhibited by UA in HEPG2, 7721 and Huh7 human liver cancer cell lines. UA decreased the expression of downstream target genes of STAT3, such as Bcl-2, Bcl-xl and survivin in general, with difference in these cell lines. UA also suppressed cell viability, cell migration and colony formation in liver cancer cells. Furthermore, UA suppressed STAT3 phosphorylation and HEPG2 tumor growth by oral daily treatment in vivo. UA, which exists widely in fruits and herbs, could inhibit STAT3 activation and the growth of human liver cancer cells in vitro and in vivo. It might be a potential health care product that could be used daily for prevention, as well as a promising candidate for chemotherapy of liver cancer. PMID- 28714513 TI - In vivo evaluation of tumour acidosis for assessing the early metabolic response and onset of resistance to dichloroacetate by using magnetic resonance pH imaging. AB - Dichloroacetate (DCA) can reverse the glycolytic phenotype that is responsible of increased lactate production and extracellular pH acidification in cancer cells. Magnetic resonance imaging-chemical exchange saturation transfer (MRI-CEST) pH mapping is a novel non-invasive imaging approach that can measure in vivo extracellular tumour pH. We examined whether MRI-CEST pH mapping can monitor in vivo changes in tumour acidosis for assessing treatment response to DCA. Cell viability and extracellular pH were assessed in TS/A breast cancer cells treated with 1-10 mM DCA for 24 h in normoxia or hypoxia (1% O2) conditions. Extracellular tumour pH values were measured in vivo by MRI-CEST pH mapping of TS/A tumour-bearing mice before, three days and fifteen days after DCA or saline treatment. Reduced extracellular acidification and vitality were observed in DCA treated TS/A cells. Tumour-bearing mice showed a marked and significant increase of tumour extracellular pH at 3 days post-DCA treatment, reflecting DCA-induced glycolysis inhibition, as confirmed by reduced lactate production. After 15 days of DCA treatment, the onset of resistance to DCA was observed, with recover of tumour extracellular acidification and lactate levels that returned to baseline values. A significant correlation was observed between tumour extracellular pH values and lactate levels (r= -0.97, P<0.05). These results suggest that MRI-CEST pH imaging is a promising tool to monitor the early response and efficacy of cancer metabolic targeting drugs. PMID- 28714514 TI - Nuclear expression of Y box binding-1 is important for resistance to chemotherapy including gemcitabine in TP53-mutated bladder cancer. AB - The development and acquisition of multiple drug resistance in cancer cells remain a major obstacle in the treatment of bladder cancer. Nuclear translocation of Y box binding-1 (YB-1), which is a member of a family of DNA-binding proteins that contain a cold shock domain, plays a significant role in the acquisition of drug resistance by upregulating expression of the multidrug resistance-1 (MDR-1) gene product, p-glycoprotein. The tumor suppressor protein p53 is thought to be essential for nuclear translocation of YB-1. We hypothesized that nuclear translocation of YB-1 might be associated with drug resistance of bladder cancer with an abnormality of the TP53 gene that results in a mutated p53 protein. To test this hypothesis, we analyzed the association of YB-1 with drug resistance of TP53-mutated bladder cancer, including immunohistochemical analysis of YB-1, p glycoprotein and p53 in vivo as well as the function of YB-1 nuclear translocation and regulation of its translocation by p53 in vitro. Additionally, we examined the association between the nuclear translocation of YB-1 and gemcitabine, a major anticancer-drug for bladder cancer, in cancer cell lines. Nuclear expression of YB-1 was correlated with the expression of p-glycoprotein and p53 in bladder cancer cases (p<0.05). In vitro, both introduction of TP53 and gemcitabine induced nuclear translocation of YB-1. These data indicate that YB-1 translocates to the nucleus coordinately with p53 expression and is involved in gemcitabine resistance in bladder cancer. Nuclear expression of YB-1 is important for resistance to chemotherapy including gemcitabine in TP53-mutated bladder cancer. PMID- 28714515 TI - ElncRNA1, a long non-coding RNA that is transcriptionally induced by oestrogen, promotes epithelial ovarian cancer cell proliferation. AB - Previously, the novel oestrogen (E2)-upregulated lncRNA TC0101441, was identified by us, via microarray analysis. However, the detailed mechanism by which E2 upregulates TC0101441 and the role of TC0101441 in epithelial ovarian cancer (EOC) progression have not been elucidated. In the present study, we further analysed TC0101441, which we designated oestrogen-induced long non-coding RNA-1 (ElncRNA1). We showed that E2 transcriptionally upregulates ElncRNA1 through the oestrogen receptor alpha (ERalpha)-oestrogen response element (ERE) pathway using RNA stability assays, bioinformatics-based searches for ERE binding sites, chromatin immunoprecipitation (ChIP) assays and dual luciferase reporter assays. Clinically, ElncRNA1 levels are significantly higher in EOC tissues than in normal ovarian surface epithelium. In vitro and in vivo loss-of-function assays revealed that ElncRNA1 promotes EOC cell proliferation. This pro-proliferation effect of ElncRNA1 was partially mediated by the regulation of CDK4, CDK6 and cyclin D1. These findings provide the first evidence that E2 upregulates ElncRNA1 at the transcriptional level through the ERalpha-ERE pathway and that this novel E2-upregulated lncRNA has an oncogenic role in EOC growth. The placement of ElncRNA1 in the E2-ERalpha-ERE signalling pathway may provide greater insight into the effects of oestrogen on EOC progression from the perspective of lncRNA. PMID- 28714517 TI - Overexpression of the erythropoietin receptor in RAMA 37 breast cancer cells alters cell growth and sensitivity to tamoxifen. AB - Erythropoietin (EPO) is the main regulator of erythropoiesis, and its receptor (EPOR) is expressed in various tissues, including tumors. Expression of EPOR in breast cancer tissue has been shown to correlate with expression of the estrogen receptor (ER). However, EPOR promotes proliferation in an EPO-independent manner. In patients with breast cancer, EPOR is associated with impaired tamoxifen response in ER-positive tumors, but not in ER-negative tumors. Furthermore, a positive correlation between EPOR/ER status and increased local cancer recurrence has been demonstrated, and EPOR expression is associated with G-protein coupled ER (GPER). Herein, we assessed the effects of EPOR on cell physiology and tamoxifen response in the absence of EPO stimulation using two cell lines that differ only in their EPOR expression status: RAMA 37 cells (low EPOR expression) and RAMA 37-28 cells (high EPOR expression). Alterations in cell growth, morphology, response to tamoxifen cytotoxicity, and EPOR-activated signal transduction were observed. RAMA 37 cells showed higher proliferation capacity without tamoxifen treatment, while RAMA 37-28 cells were more resistant to tamoxifen and proliferated more rapidly in the presence of tamoxifen. EPOR overexpression induced cell-morphology changes upon tamoxifen treatment, which resulted in the production of cell protrusions and subsequent cell death. Short term treatment with tamoxifen (6 h) prompted RAMA 37 cells to acquired longer protrusions than RAMA 37-28 cells, which indicated a pre-apoptotic stage. Furthermore, prolonged treatment with tamoxifen (72 h) caused a greater reduction in RAMA 37 cell numbers, which indicated a higher rate of cell death. RAMA 37-28 cells showed prolonged activation of AKT signaling. We propose sustained AKT phosphorylation in EPOR-overexpressing cells as a mechanism that can lead to EPOR induced tamoxifen resistance. PMID- 28714516 TI - (-)-Epigallocatechin-3-gallate attenuates myocardial injury induced by ischemia/reperfusion in diabetic rats and in H9c2 cells under hyperglycemic conditions. AB - (-)-Epigallocatechin gallate (EGCG) exerts multiple beneficial effects on cardiovascular performance. In this study, we aimed to examine the effects of EGCG on diabetic cardiomyopathy during myocardial ischemia/reperfusion (I/R) injury. EGCG (100 mg/kg/day) was administered at week 6 for 2 weeks to diabetic rats following the induction of type 1 diabetes by streptozotocin (STZ). At the end of week 8, the animals were subjected to myocardial I/R injury. The EGCG elicited structural and functional effects were analyzed. Additionally, EGCG (20 uM) was administered for 24 h to cultured cardiac H9c2 cells under hyperglycemic conditions (30 mM glucose) prior to hypoxia/reoxygenation (H/R) challenge, and its effects on oxidative stress were compared to H9c2 cells transfecteed with silent information regulator 1 (SIRT1) small interfering RNA (siRNA). In rats with STZ-induced diabetes, EGCG treatment ameliorated post-ischemic cardiac dysfunction, decreased the myocardial infarct size, apoptosis and cardiac fibrosis, and reduced the elevated lactate dehydrogenase (LDH) and malonaldehyde (MDA) levels, and attenuated oxidative stress. Furthermore, EGCG significantly reduced H/R injury in cardiac H9c2 cells exposed to high glucose as evidenced by reduced apoptotic cell death and oxidative stress. The protein expression levels of SIRT1 and manganese superoxide dismutase (MnSOD) were reduced in the diabetic rats and the H9c2 cells under hyperglycemic conditions, compared with the control rats following I/R injury and H9c2 cells under normal glucose conditions. EGCG pre-treatment significantly upregulated the levels of htese proteins in vitro and in vivo. However, treatment with EX527 and SIRT1 siRNA blocked the EGCG-mediated cardioprotective effects. Taken together, our data indicate that SIRT1 plays a critical role in the EGCG-mediated amelioration of I/R injury in diabetic rats, which suggests that EGCG may be a promising dietary supplement for the prevention of diabetic cardiomyopathy. PMID- 28714518 TI - Regulation of tubular recycling endosome biogenesis by the p53-MICALL1 pathway. AB - p53, one of the most frequently mutated genes in colon cancer, suppresses cancer development through transactivation of its targets. Herein, we conducted a comprehensive analysis of the p53 downstream pathway in colorectal cancer by using multi-omics analysis. Mass spectrometric analysis of HCT116 p53+/+ and HCT116 p53-/- cells treated with adriamycin identified 124 proteins increased by DNA damage in a p53-dependent manner. Further screening using a cDNA microarray and the TCGA database revealed MICALL1 as a novel p53 target, and we identified functional p53 binding motifs located approximately 3000 base pairs upstream of the MICALL1 gene. MICALL1 expression was significantly decreased in colorectal cancer tissues with p53 mutation compared with those without p53 mutation. In response to DNA damage, MICALL1 co-localized with RAB8A and CD2AP at tubular recycling endosomes, whereas these proteins hardly localized at tubular recycling endosomes when p53 or MICALL1 expression was inhibited by siRNA. Our findings show that p53 regulates tubular recycling endosome biogenesis via transcriptional regulation of MICALL1, whose expression is frequently suppressed in colorectal cancer tissues. PMID- 28714519 TI - Circulating regulatory T cell subsets predict overall survival of patients with unresectable pancreatic cancer. AB - Most patients with pancreatic ductal adenocarcinoma (PDAC) have unresectable cancers with a dismal prognosis, in which cohort chemotherapy is the primary treatment. T cell immune adaption is critical for tumor immune escape and prognosis of this disease. The present study aimed to determine the correlation between peripheral T cell subset distribution in patients with unresectable PDAC and their response to chemotherapy. Two hundred and twelve patients with unresectable PDAC were included whose blood samples were collected for analysis of T cell subsets, including CD3+, CD4+, CD8+, CD8+CD28+ and CD4+CD25+CD127 T cells by flow cytometry before and after gemcitabine-based chemotherapy. Enzyme linked immunosorbent assay was used to detect the expression levels of tumor growth factor (TGF)-beta1, interleukin (IL)-6 and IL-17A in the patients before and after chemotherapy. Univariate and multivariate analyses found that an initial CD4/CD8 ratio or T regulatory (Treg) cell level before any treatment was associated with the prognosis of unresectable PDAC. After two cycles of chemotherapy, there was no significant change in percentages of T cell subsets, except elevation to a higher level of CD3+ T cells. Decreased Tregs or CD4/CD8 ratio after two cycles of chemotherapy predicts a longer overall survival (OS). Levels of Tregs in stable disease (SD) and partial remission (PR) cases significantly decreased after chemotherapy, but increased in progressive disease (PD) patients. There was no correlation between Tregs and the expression level of either TGF-beta1 or IL-6. IL-17A expression was elevated in Treg-decreased patients, whereas IL-17A was reduced in Treg-increased patients after chemotherapy. The circulating signature of T cell subsets can predict OS and chemotherapeutic response in patients with unresectable PDAC, and may be attributable to the plasticity of T cell subsets. PMID- 28714520 TI - Genomic profiling of long non-coding RNA and mRNA expression associated with acquired temozolomide resistance in glioblastoma cells. AB - Temozolomide (TMZ) is an alkylating chemotherapeutic agent widely used in anti glioma treatment. However, acquired TMZ resistance represents a major clinical challenge that leads to tumor relapse or progress. This study investigated the genomic profiles including long non-coding RNA (lncRNA) and mRNA expression associated with acquired TMZ resistance in glioblastoma (GBM) cells in vitro. The TMZ-resistant (TR) of GBM sub-cell lines were established through repetitive exposure to increasing TMZ concentrations in vitro. The differentially expressed lncRNAs and mRNAs between the parental U87 and U87TR cells were detected by human lncRNA microarray method. In this study, we identified 2,692 distinct lncRNAs demonstrating >2-fold differential expression with 1,383 lncRNAs upregulated and 1,309 lncRNAs downregulated. Moreover, 4,886 differential mRNAs displayed 2,933 mRNAs upregulated and 1,953 mRNAs downregulated. Further lncRNA classification and subgroup analysis revealed the potential functions of the lncRNA-mRNA relationship associated with the acquired TMZ resistance. Gene ontology and pathway analysis on mRNAs showed significant biological regulatory genes and pathways involved in acquired TMZ resistance. Moreover, we found the ECM-receptor interaction pathway was significantly downregulated and ECM related collagen Iota, fibronectin, laminin and CD44 were closely associated with the TR phenotype in vitro. Our findings indicate that the dysregulated lncRNAs and mRNAs identified in this work may provide novel targets for overcoming acquired TMZ resistance in GBM chemotherapy. PMID- 28714521 TI - Longitudinal relationships between cardiovascular events, risk factors, and time dependent sleep duration. AB - BACKGROUND: Although many studies have evaluated the relationships between sleep duration and cardiovascular (CV) events/risk factors, longitudinal associations with time-dependent sleep duration have not been adequately assessed. METHODS: A retrospective, longitudinal study was conducted involving individuals aged 20 years or older that received annual health check-ups at St. Luke's International Hospital from 2005 to 2010. Data collection included self-reported demographic, clinical and health habit information (including sleep duration; < 6, 6-7, 7-8, >= 8 h), baseline examinations, and laboratory measures for each year. We conducted mixed effects analyses to examine the associations between non-fatal CV events, risk factors, and time-dependent sleep duration longitudinally. RESULTS: Of the total of 31,830 participants enrolled, 70.1% of participants changed their sleep dura-tion, and 365 participants experienced CV events during follow-up periods. Compared to those reporting 7-8 h of sleep, those reporting less than 6 h of sleep were significantly more likely to experience non-fatal CV events (odds ratio [OR] 1.78; 95% confidence interval [CI] 1.03-3.07; p = 0.04), but other groups were not (OR 1.12; 95% CI 0.70-1.77; p = 0.64 for 6-7 h and OR 1.22; 95% CI 0.68-2.23; p = 0.50 for >= 8 h). The shortest sleep duration was associated with a higher likelihood of obesity/overweight status (OR 1.49; 95% CI 1.32-1.69; p < 0.01). CONCLUSIONS: Individuals reporting less than 6 h of sleep were significantly more likely to have non-fatal CV events than those reporting 7-8 h of sleep. For the risk factors, short sleep duration was associ-ated with obesity/overweight status. PMID- 28714522 TI - Factors associated with safe early discharge after transcatheter aortic valve implantation. AB - BACKGROUND: As transcatheter aortic valve implantation (TAVI) becomes more straightforward, a larger proportion of patients will be well enough to be discharged early. This study sought to charac-terise the clinical features that allowed patients to be discharged early after TAVI and to evaluate the safety of an early discharge policy. METHODS: All patients undergoing TAVI at the above cited center from August 2007 to March 2015 were included in this study. Baseline characteristics, in-hospital outcomes, re-admissions and mortality were compared. RESULTS: Three hundred thirty-seven TAVIs were performed during the study period, and 18 died in-hospital (18/337, 5.3%). Of the remaining patients, 56 were discharged within 3 days of the index procedure ('early discharge group' 56/319, 17.5%). There was no difference between the early discharge and late discharge group in terms of Valve Academic Research Consortium-2 (VARC-2) criteria out comes, all-cause re-admission rates and the need for permanent pacemaker implantation. Mortality at 1 year was better among the early discharge group (3.6% vs. 15.6%, p = 0.014); a reflection of baseline clinical differences. CONCLUSION: Early discharge of clinically selected TAVI patients is safe and appropriate. Lower logistic EuroSCORE, smaller delta creatinine and not developing any complications are factors associated with early discharge. (Cardiol J 2018; 25, 1: 14-23). PMID- 28714523 TI - Echocardiographic parameters versus CHA2DS2-VASc score in prediction of overall cardiac events, heart failure, and stroke in non-valvular atrial fibrillation. AB - BACKGROUND: Apart from stroke, atrial fibrillation (AF) is associated with higher mortality and heart failure (HF), in which risk stratification scheme is lacking. Therefore this investigation examined the prognostic value of echocardiographic predictors against CHA2DS2-VASc score in permanent non- -valvular AF (NVAF). METHODS: In 252 asymptomatic or mildly symptomatic consecutive patients with NVAF, comprehensive echocardiography was performed. Left atrial deformation parameters were also obtained by two-dimen-sional speckle tracking echocardiography. End-points pertaining to HF deterioration, ischemic stroke and cardiac death were recorded. RESULTS: There were 74 cardiovascular events, including 44 deterioration of HF, 22 ischemic strokes and 8 cardiovascular deaths during an average follow-up period of 20.8 +/- 13.5 months (interquartile range, 8-31 months). For prediction of overall prognosis and HF, left ventricular mass index, peak early filling velocity (E), and E to tissue Doppler mitral annular early diastolic velocity ratio (E/e') outper-formed CHA2DS2-VASc score in multivariate analysis, area under curve, and stepwise nested regression models. Left ventricular hypertrophy and E/e' > 8 showed worse overall and heart-failure free survival in Kaplan-Meier curves. For prediction of ischemic stroke, the addition of E or E/e' to CHA2DS2-VASc score provides extra prognostic value. CONCLUSIONS: Echocardiographic parameters offer incremental value over CHA2DS2 VASc score for prediction of future cardiac events in NVAF. (Cardiol J 2018; 25, 1: 60-71). PMID- 28714524 TI - Simple platelet markers: Mean platelet volume and congestive heart failure coexistent with periodontal disease. Pilot studies. AB - BACKGROUND: Conducted pilot study concerning mean platelet volume parameter among patients suffering from congestive heart failure and periodontal disease. METHODS: Examination of dynamic changes of platelet and periodontal markers in group of 50 patients before and an average of 6 months subsequent to professional periodontal treatment. RESULTS: Both platelet and periodontal parameters decreased after periodontal treatment, what is more, the decrease of mean platelet volume (MPV) value due to periodontal disease/mm improvement was shown to be statistically significant (p = 0.05). CONCLUSIONS: Improvement of periodontal status may influence decrease of MPV value andincrease of congestive heart failure treatment efficacy and effect patient comfort. It is a new, not frequently used pattern of chronic disease treatment optimalization. PMID- 28714525 TI - Dedicated bifurcation stents or regular drug eluting stents in distal left main stenosis: A retrospective study. AB - BACKGROUND: In the distal left main (LM) atherosclerosis mainly develops within bifurcation or trifur-cation. The aim of this study was to analyze the strategy of distal LM stenosis treatment and associated clinical outcomes in a large hospital in Northern Poland. METHODS: The study population consisted of consecutive patients with stable coronary artery disease or acute coronary syndrome (ACS) and distal LM stenosis who were hospitalized between June 2012 and June 2013. Patients were treated with regular drug-eluting stents (rDES), including bioresorbable vascular scaffolds, or dedicated bifurcation stents (BiOSS LIM(r)). Clinical outcomes were analyzed at 12, 24 and 36 months. Primary endpoint was cumulative major adverse cardiovascular events (MACE) inducing rate of cardiac death, myocardial infarction, and target lesion revascularization (TLR) after 36 months. RESULTS: One hundred and two patients were identified, 90 of whom were treated with percutaneous coronary intervention (56 rDES, including 9 Absorb, and 34 BiOSS) with no stent implantation fail-ure. In 15 (16.7%) patients rDES was required within side branch (SB). After 36 months MACE rate was 19.0% (BiOSS: 18.8% vs. rDES 19.2%), whereas TLR rate was 10.7% (BiOSS 12.5% vs. rDES 9.6%). In logistic regression for 36-month TLR rate proximal optimization technique (OR 0.311, 95% CI 0.211-0.644) was a prognostic factor of better clinical outcome, whereas non-ST-elevation ACS (OR 2.211, 95% CI 1.642-5.110), ST elevation myocardial infarction (OR 2.771, 95% CI 1.325-7.209) and SB stenting (OR 1.141, 95% CI 1.002-1.881) were risk factors of poor outcome. CONCLUSIONS: Regular drug-eluting stents as well as dedicated bifurcation BiOSS LIM(r) stents enabled a simple and fast distal LM treatment option with a single stent. Both resulted in comparable MACE and TLR rates. PMID- 28714526 TI - Different postconditioning cycles affect prognosis of aged patients undergoing primary percutaneous coronary intervention. AB - BACKGROUND: Postconditioning can affect the infarct size in acute myocardial infarction (AMI). However, few studies show an effect of different postconditioning cycles on AMI aged patients. This study sought to assess the effect of different postconditioning cycles on prognosis in aged patients with AMI who underwent primary percutaneous coronary intervention (PCI). METHODS: 74 aged patients were randomly assigned to three groups. Control group; PC-1 group accepted postconditioning 4 cycles of 30 s inflation and 30 s deflation; PC-2 group accepted postconditioning 4 cycles of 60 s. Creatine kinase MB (CK-MB), troponin I (cTnI), high-sensitive C-reactive protein (hs-CRP) and corrected Thrombolysis in Myocardial Infarction (TIMI) frame counts (CTFC) were analyzed before andafter treatment. All patients received an echocardiographic examination for whole heart function, wall motion score index (WMSI) and single-photon emission computed tomography (SPECT) examination at 7 days and 6 months after treatment. RESULT: S: The peak of CK-MB, postoperative 72 h cTnI and CTFC were significantly attenuated by postconditioning when compared with the control group. The hs-CRP of the postconditioning group was lower than the control group 24 h postoperative. No difference was observed between PC-1 and PC-2 group about the effect described above. At 7 days, heart function in the postconditioning group was improved when compared with the control group. At 6 months, the WMSI and SPECT score significantly reduced in the PC-2 group compared with the control and PC-1 groups, but there was no difference among the three groups about echo data except the left ventricular end-systolic diameter. CONCLUSIONS: Postconditioning is significantly beneficial to prognosis in aged patients with AMI. The cardiac protective effect of 4 cycles of 60 s procedure was observed in WMSI and SPECT. It is favorable to implement this procedure in aged patients with AMI in clinic. PMID- 28714527 TI - Multimodality imaging of intermediate lesions: Data from fractional flow reserve, optical coherence tomography, near-infrared spectroscopy-intravascular ultrasound. AB - BACKGROUND: Fractional flow reserve (FFR) assesses a functional impact of the atheroma on the myocardial ischemia, but it does not take into account the morphology of the lesion. Previous optical coherence tomography (OCT), intravascular ultrasound (IVUS) and near-infrared spectroscopy (NIRS) studies presented their potential to detect vulnerable plaques, which is not possible by FFR assessment. With the following study, the intermediate lesions were assessed by FFR, OCT and combined NIRS-IVUS imaging to identify plaque vulnerability. METHODS: Thirteen intermediate lesions were analyzed simultaneously by FFR, OCT and combined NIRS-IVUS imaging. RESULTS: Two lesions were found to have FFR <= 0.80 (0.65 and 0.76). The other 11 lesions had FFR > 0.80 with a mean FFR 0.88 +/ 0.049. Two lesions with FFR <= 0.80 had plaque burden (PB) > 70% and minimal lumen area (MLA) < 4 mm2, but neither of these 2 lesions were identified as OCT de-fined thin fibrous cap atheroma (TCFA), or NIRS-IVUS possible TCFA. Among the other 11 lesions with FFR > 0.80, 8 were identified as OCT-defined TCFA, 4 had PB > 70%, 6 had MLA < 4 mm2, 2 had both PB > 70% and MLA < 4 mm2, 3 lesions were identified as NIRS-IVUS possible TCFA, and 4 lesions had lipid core burden index > 400. CONCLUSIONS: The FFR-negative lesions pose traits of vulnerability as assessed simultaneously by IVUS, OCT and NIRS imaging. PMID- 28714528 TI - Salivary duct stenosis: Short-term symptom outcomes after sialendoscopy-assisted salivary duct surgery. AB - OBJECTIVES: To prospectively assess short-term symptom change after sialendoscopy assisted salivary duct surgery (SASDS) for salivary duct stenosis. STUDY DESIGN: Prospective cohort study. METHODS: Patients with obstructive sialadenitis from duct stenosis completed the 20-item Chronic Obstructive Sialadenitis Symptoms (COSS) Questionnaire (scored 0-100) prior to SASDS and 3 months postoperatively. RESULTS: Thirty glands in 19 patients with endoscopically confirmed salivary duct stenosis showed overall symptom improvement, with a mean COSS score reduction of 12.9 points (standard deviation [SD] 13.1) to a mean postoperative score of 25.1 (range 0-75.5) (P < 0.001) with six (20%) glands (5 patients) achieving complete symptom resolution. Symptoms improved significantly for parotid glands (n = 20) by 16.6 points (SD 15.9) (P < 0.0001). For distal duct stenoses (n = 25), significant symptom improvement was seen in cases treated with dilation only (n = 17; partial stenoses) with a mean 20.6 point COSS reduction (SD 19.0) (P < 0.0005) and in cases treated with sialodochoplasty (n = 5; 4 complete, 1 partial stenosis) with a mean 13.8 point reduction (SD 4.7) (P < 0.005). Symptom scores did not improve after SASDS in proximal stenoses (n = 3) and distal stenoses cases not amenable to treatment (n = 3). CONCLUSION: SASDS for salivary duct stenosis often can improve obstructive salivary symptoms; however, many patients report persistent symptoms after surgery. Partial duct stenoses or distal duct stenoses are associated with the greatest improvements in COSS scores after SASDS. LEVEL OF EVIDENCE: 4. Laryngoscope, 127:2770-2776, 2017. PMID- 28714530 TI - Acoustic changes in the speech of children with cerebral palsy following an intensive program of dysarthria therapy. AB - BACKGROUND: The speech intelligibility of children with dysarthria and cerebral palsy has been observed to increase following therapy focusing on respiration and phonation. AIMS: To determine if speech intelligibility change following intervention is associated with change in acoustic measures of voice. METHODS & PROCEDURES: We recorded 16 young people with cerebral palsy and dysarthria (nine girls; mean age 14 years, SD = 2; nine spastic type, two dyskinetic, four mixed; one Worster-Drought) producing speech in two conditions (single words, connected speech) twice before and twice after therapy focusing on respiration, phonation and rate. In both single-word and connected speech we measured vocal intensity (root mean square-RMS), period-to-period variability (Shimmer APQ, Jitter RAP and PPQ) and harmonics-to-noise ratio (HNR). In connected speech we also measured mean fundamental frequency, utterance duration in seconds and speech and articulation rate (syllables/s with and without pauses respectively). All acoustic measures were made using Praat. Intelligibility was calculated in previous research. OUTCOMES & RESULTS: In single words statistically significant but very small reductions were observed in period-to-period variability following therapy: Shimmer APQ -0.15 (95% CI = -0.21 to -0.09); Jitter RAP -0.08 (95% CI = 0.14 to -0.01); Jitter PPQ -0.08 (95% CI = -0.15 to -0.01). No changes in period to-period perturbation across phrases in connected speech were detected. However, changes in connected speech were observed in phrase length, rate and intensity. Following therapy, mean utterance duration increased by 1.11 s (95% CI = 0.37 1.86) when measured with pauses and by 1.13 s (95% CI = 0.40-1.85) when measured without pauses. Articulation rate increased by 0.07 syllables/s (95% CI = 0.02 0.13); speech rate increased by 0.06 syllables/s (95% CI = < 0.01-0.12); and intensity increased by 0.03 Pascals (95% CI = 0.02-0.04). There was a gradual reduction in mean fundamental frequency across all time points (-11.85 Hz, 95% CI = -19.84 to -3.86). Only increases in the intensity of single words (0.37 Pascals, 95% CI = 0.10-0.65) and reductions in fundamental frequency (-0.11 Hz, 95% CI = -0.21 to -0.02) in connected speech were associated with gains in intelligibility. CONCLUSIONS & IMPLICATIONS: Mean reductions in impairment in vocal function following therapy observed were small and most are unlikely to be clinically significant. Changes in vocal control did not explain improved intelligibility. PMID- 28714529 TI - Immunologic responses to a novel DNA vaccine targeting human papillomavirus-11 E6E7. AB - OBJECTIVES/HYPOTHESIS: Recurrent respiratory papillomatosis (RRP) is a benign disease caused by human papillomavirus (HPV) types 6 and 11. Although a prophylactic vaccine against RRP is available, a therapeutic vaccine is needed to treat those already infected. The objective of our study was to design and test a DNA vaccine targeting HPV11 proteins. STUDY DESIGN: Preclinical scientific investigation. METHODS: A DNA vaccine encoding the HPV11 E6 and E7 genes linked to calreticulin (CRT) was generated. Immunologic response to the HPV11 CRT/E6E7 vaccine was measured by vaccinating C57BL/6 mice via electroporation and measuring CD8 + T cell responses from harvested splenocytes. A tumor cell line containing HPV11-E6E7 was created, and the ability of novel DNA vaccine to control tumor growth was measured in vivo. RESULTS: Our vaccine generated a significant and specific CD8 + T-cell response against the HPV11-E6aa41-70 peptide. The CD8 + T-cell responses did not recognize E7 epitopes, indicating E6 immunodominance. CD8 + responses were augmented in the CRT-linked vaccine compared to a control non-CRT vaccine. The HPV11 CRT/E6E7 vaccine was used to treat mice inoculated with a HPV11 E6E7 expressing tumor cell line after temporary CD3 depletion to facilitate tumor growth. Vaccinated mice had a significantly lower tumor growth rate (P = .029) and smaller tumor volumes compared to control mice, indicating an augmented immunologic response in vaccinated mice. CONCLUSIONS: A DNA vaccine targeting HPV11 E6E7 generates a specific HPV11 CD-8 + T-cell response capable of reducing the growth of HPV11 expressing tumors. DNA vaccines are a promising immunologic strategy for treating RRP. LEVEL OF EVIDENCE: NA. Laryngoscope, 127:2713-2720, 2017. PMID- 28714531 TI - Using patients as educators for communication skills: Exploring dental students' and patients' views. AB - TITLE: A qualitative study to explore the issues for patients and students when giving feedback on the communication of dental students. OBJECTIVES: The Department of Health and National Institute for Health Research are committed to involving patients in improving clinical education, research and service delivery. Yet, there is a limited body of evidence on the perceptions of patients when asked to be involved in this way, and specifically when asked to provide feedback on the communication skills of dental students. This study seeks to address this gap and heighten the understanding of the issues faced by patients when asked to be involved in clinical education. METHODS: Data were collected using focus groups with dental students (n=10) and patients (n=8) being treated by these students. Both groups were asked about their thoughts, feelings and beliefs about patients being asked to provide feedback on the communication skills of dental students. Data analysis involved inductive thematic analysis of transcribed audio recordings. RESULTS: Four themes emerged from the data: "legitimacy," "co-educators," "maintaining the equilibrium of the patient-student relationship" and the "timing of patient feedback." Support for involving patients in giving feedback on students' communication skills was established, with patients considering they were best placed to comment on the communication skills of dental students. Patients and students do not want to provide feedback alone and want support to assist them, especially if feedback was negative. Issues of anonymity, confidentiality and ownership of the feedback process were worrisome, and the positioning of patient feedback in the programme was seen as critical. CONCLUSIONS: Patients and students are willing to engage in patient feedback on students' communication skills, and with support and training, the concerns around this are not insurmountable and the benefits could potentially profit both groups. These findings have resonance with other healthcare educators when using patients as educators in the development of communication skills. PMID- 28714532 TI - Thyroid nodules classified as atypia or follicular lesions of undetermined significance deserve further research: Analysis of 305 surgically confirmed nodules. AB - OBJECTIVE: The objective of the present study was to determine the malignancy risk for nodules categorised as atypia or follicular lesions of undetermined significance atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) and to investigate the predictors of malignancy. METHODS: All nodules diagnosed as AUS/FLUS on fine needle aspiration (FNAs) performed between January 2011 and December 2015 were retrospectively reviewed. Clinical data, ultrasonographic features, follow-up data and the final pathological results were recorded. After further exclusion, only nodules that underwent surgical excision were included in the final analysis. The malignancy rate and the range of malignancy rates were calculated. Clinical and ultrasound features were examined to determine the predictors of malignancy. RESULTS: During the study period, FNA was performed on 9938 nodules, and 1019 (10.2%) nodules were diagnosed as AUS/FLUS. After further exclusion, 976 nodules were evaluated. After the initial diagnosis of AUS/FLUS, 139 (14.2%) patients underwent surgery, 518 (53.1%) had repeated FNAs. A total of 305 (31%) had undergone surgical excision at different time points. For surgically confirmed nodules, the malignancy rate after the initial FNA was 34.5% (the lower and upper thresholds for the malignancy rate were 19.3% and 66.3%, respectively), and 37.9% after the repeated FNA. No ultrasound feature was determined as a predictor, whereas age (>55 years) was a predictor for malignancy. CONCLUSIONS: The overall malignancy rate for nodules diagnosed as AUS/FLUS and the malignancy rate for nodules that underwent repeated FNA after AUS/FLUS were higher than the expected malignancy rates of the National Cancer Institute. It is, therefore, suggested that the current recommendations should be reconsidered. PMID- 28714533 TI - Multicenter Retrospective Study of Neurostimulation With Exit of Therapy by Explant. AB - INTRODUCTION: Spinal cord stimulation (SCS) devices are cost effective and improve function as well as quality of life. Despite the demonstrated benefits of SCS, some patients have the device explanted. We are interested in exploring the patient characteristics of those explanted. METHODS: This is a retrospective chart review of neurostimulation patients who underwent explantation at 18 centers across the United States within the previous five years. RESULTS: Data from 352 patients were collected and compiled. Failed Back Surgery syndrome was the most common diagnosis (38.9%; n = 136/350) and over half of the patients reported numerical rating scale (NRS) scores >=8 prior to implant (64.3%; n = 207/322). All patients reported changes in NRS scores across time, with an initial decrease after implant followed by a pre-explant increase (F (2, 961) = 121.7, p < 0.001). The most common reason for device explant was lack or loss of efficacy (43.9%; 152/346) followed by complications (20.2%; 70/346). Eighteen percent (18%; 62/343) of patients were explanted by a different physician than the implanting one. Rechargeable devices were explanted at a median of 15 months, whereas primary cell device explants occurred at a median of 36 months (CI 01.434, 2.373; median endpoint time ratio = 2.40). DISCUSSION: Loss or lack of efficacy and complications with therapy represent the most frequent reasons for neurostimulation explantation. Of the devices that were explanted, therapy was terminated earlier when devices were rechargeable, when complications occurred, or when pain relief was not achieved or maintained. Furthermore, in nearly 20% of the cases, a different provider than the implanting physician performed device removal. CONCLUSIONS: SCS is largely a safe and efficacious strategy for treating select chronic refractory pain syndromes. Further prospective data and innovation are needed to improve patient selection, maintain SCS therapeutic efficacy and reduce the reasons that lead to device explant. PMID- 28714534 TI - Adjustable thermoplastic oral appliance versus positive airway pressure for obstructive sleep apnea. AB - OBJECTIVES/HYPOTHESIS: To compare outcomes of continuous positive airway pressure (CPAP) and the adjustable thermoplastic mandibular advancement splint (AT-MAS) for obstructive sleep apnea treatment. STUDY DESIGN: Randomized crossover, noninferiority, tertiary center setting. METHODS: Fifty patients with a mean age of 49.5 +/- 10.6 years were enrolled. Inclusion criteria were age >=18 years, apnea-hypopnea index (AHI) >=5 events/hour, and oxygen saturation >=70%. Exclusion criteria were temporomandibular joint disorders, severe periodontitis, inadequate teeth, and unstable medical diseases. Treatment intolerance was considered a failure. Two-week periods without treatment were followed by questionnaires and randomization into two groups: CPAP/AT-MAS (25) and AT MAS/CPAP (25). After 6 weeks of intervention, questionnaires and home WatchPAT monitoring were performed. Following each 2-week washout period, patients crossed over to the other treatment followed by similar procedures. Primary outcomes involved the scores from the Functional Outcomes of Sleep Questionnaire (FOSQ). Secondary outcomes were AHI, side effects, and treatment adherence. RESULTS: Seven patients withdrew from this study: five (AT-MAS intolerance) and two (lost follow-up). There was no significant difference among FOSQ scores, particularly on global scores, between both treatments (0.57, 95% confidential interval of difference: -0.15 to 1.29). Mean AHI decreased from pretreatment 39.2 +/- 2.53 to 2.56 +/- 0.49 and 12.92 +/- 2.05 events/hour while using CPAP and the AT-MAS, respectively (P < .05). Most common side effects of CPAP were dry throat and inconvenience to carry, whereas those of the AT-MAS were jaw pain and excessive salivation. CONCLUSIONS: Both devices improved short-term quality of life similarly; however, the AT-MAS was not as efficacious as CPAP on resolving sleep test parameters. The AT-MAS might be considered only a temporary treatment alternative. LEVEL OF EVIDENCE: 1b. Laryngoscope, 128:516-522, 2018. PMID- 28714535 TI - Neandertal talus bones from El Sidron site (Asturias, Spain): A 3D geometric morphometrics analysis. AB - OBJECTIVES: The El Sidron tali sample is assessed in an evolutionary framework. We aim to explore the relationship between Neandertal talus morphology and body size/shape. We test the hypothesis 1: talar Neandertal traits are influenced by body size, and the hypothesis 2: shape variables independent of body size correspond to inherited primitive features. MATERIALS AND METHODS: We quantify 35 landmarks through 3D geometric morphometrics techniques to describe H. neanderthalensis-H. sapiens shape variation, by Mean Shape Comparisons, Principal Component, Phenetic Clusters, Minimum spanning tree analyses and partial least square and regression of talus shape on body variables. Shape variation correlated to body size is compared to Neandertals-Modern Humans (MH) evolutionary shape variation. The Neandertal sample is compared to early hominins. RESULTS: Neandertal talus presents trochlear hypertrophy, a larger equality of trochlear rims, a shorter neck, a more expanded head, curvature and an anterior location of the medial malleolar facet, an expanded and projected lateral malleolar facet and laterally expanded posterior calcaneal facet compared to MH. DISCUSSION: The Neandertal talocrural joint morphology is influenced by body size. The other Neandertal talus traits do not co-vary with it or not follow the same co-variation pattern as MH. Besides, the trochlear hypertrophy, the trochlear rims equality and the short neck could be inherited primitive features; the medial malleolar facet morphology could be an inherited primitive feature or a secondarily primitive trait; and the calcaneal posterior facet would be an autapomorphic feature of the Neandertal lineage. PMID- 28714536 TI - The evaluation of acute toxicity, antimicrobial activity of 1-phenyl-5-p-tolyl-1H 1, 2, 3-triazole, and binding to human serum albumin. AB - 1-Phenyl-5-p-tolyl-1H-1, 2, 3-triazole (PPTA) was a synthesized compound. The result of acute toxicities to mice of PPTA by intragastric administration indicated that PPTA did not produce any significant acute toxic effect on Kunming strain mice. It exhibited the various potent inhibitory activities against two kinds of bananas pathogenic bacteria, black sigatoka and freckle, when compared with that of control drugs and the inhibitory rates were up to 64.14% and 43.46%, respectively, with the same concentration of 7.06 mM. The interaction of PPTA with human serum albumin (HSA) was studied using fluorescence polarization, absorption spectra, 3D fluorescence, and synchronous spectra in combination with quantum chemistry and molecular modeling. Multiple modes of interaction between PPTA and HSA were suggested to stabilize the PPTA-HSA complex, based on thermodynamic data and molecular modeling. Binding of PPTA to HSA induced perturbation in the microenvironment around HSA as well as secondary structural changes in the protein. PMID- 28714537 TI - Surgical outcome for empty nose syndrome: Impact of implantation site. AB - OBJECTIVE/HYPOTHESIS: Endonasal submucosal implantation has been confirmed to be beneficial for patients with empty nose syndrome (ENS). However, the optimal implantation site has not been defined. This study aimed to evaluate whether lateral nasal wall implantation is superior to inferior nasal wall implantation in terms of clinical benefits and improvements in quality of life. STUDY DESIGN: Retrospective study in a tertiary medical center. METHODS: Consecutive ENS patients between 2010 and 2015 with operative histories of inferior turbinectomies and indicated for surgical implantation were enrolled, with at least 1-year follow-up. Patients were divided into lateral and inferior nasal wall groups. SinoNasal Outcome Test (SNOT)-22, Beck Depression Inventory (BDI) II, and Beck Anxiety Inventory (BAI) were applied before and 1 year after implantation. RESULTS: Of the total 30 ENS patients analyzed, 14 were in the inferior nasal wall group and 16 were in the lateral nasal wall group. There were no significant intergroup differences in demographic data and preoperative SNOT 22, BDI-II, and BAI scores. Postoperative assessment revealed that the lateral nasal wall group had significantly better SNOT-22 score improvements than the inferior nasal wall group, particularly regarding rhinological symptoms and sleep function. CONCLUSION: Lateral nasal wall implantation may provide significantly better clinical outcomes than inferior nasal wall implantation, and thus may be the preferred, more optimal site for implant placement in ENS patients. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:554-559, 2018. PMID- 28714538 TI - The symphony of smell: a role for electrical synapses. PMID- 28714539 TI - Safety and efficacy of functional laryngectomy for end-stage dysphagia. AB - OBJECTIVES/HYPOTHESIS: To evaluate functional outcomes and complication rate after total laryngectomy (TL) for dysfunctional larynx with end-stage dysphagia. STUDY DESIGN: Retrospective chart review. METHODS: Chart review was performed on all patients who underwent TL from January 2008 to July 2016 at a single tertiary academic medical center. Patients who underwent TL for dysfunctional larynx without preoperative evidence of malignancy were included. Main outcome measures were post-TL functional swallowing and speech outcomes, and complication rate. RESULTS: The study included 19 patients from a cohort of 278 consecutive patients. All patients were previously treated with radiotherapy (RT), whereas 13/19 (68%) previously received chemoradiotherapy. The median time from RT to TL was 10.98 years (range, 0.67-23.94 years). Aspiration was evident preoperatively in 17/19 (89%) patients, with 11 experiencing recurrent aspiration pneumonia. Seventeen of 19 (89%) patients were nil per os (NPO) requiring enteral nutrition. Six of 19 (32%) patients had surgical complications, including three (16%) pharyngocutaneous fistulas. At 3-month and 1-year postoperative follow-up, there was significant improvement in mean Functional Oral Intake Scale (FOIS) score and aspiration, recurrent pneumonia, enteral nutrition, and NPO status rates (P < .05). At 1-year follow-up, no patients were NPO, and only one patient required gastrostomy tube supplementation. Mean FOIS score increased from 1.3 to 6.1 (P = .001). Eight of 13 patients (62%) were actively using a tracheoesophageal prosthesis at 1-year follow-up. CONCLUSIONS: Laryngectomy for dysfunctional larynx eliminates the morbidity of aspiration while improving diet and reducing gastrostomy tube dependence with an acceptable complication rate. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:597-602, 2018. PMID- 28714540 TI - Anti-feeding and insecticidal efficacy of a topical administration of dinotefuran pyriproxyfen-permethrin spot-on (Vectra(r) 3D) on mice against Stegomyia albopicta (= Aedes albopictus). AB - An ectoparasiticide combining three active ingredients [dinotefuran, permethrin and pyriproxyfen (DPP)] was used in mice in an experiment designed to evaluate its anti-feeding and insecticidal efficacy against Stegomyia albopicta (= Aedes albopictus) (Diptera: Culicidae) mosquitoes. Twenty-two adult mice were randomly allocated into two groups consisting of an untreated control group and a DPP treated group. Mice were exposed individually for 1 h to a mean +/- standard deviation of 27 +/- 2 starved female mosquitoes on days 1, 7, 14, 21 and 28 post treatment. At the end of the exposure (1 h), mosquitoes were assessed for immediate survival and engorgement status. Additionally, live mosquitoes in both groups were incubated separately and observed for mortality at 24 h after the end of the exposure. The anti-feeding efficacy of DPP after the 1-h exposure period was 99.2, 100, 98.0, 89.3 and 87.4% at 1, 7, 14, 21 and 28 days, respectively. Levels of insecticidal efficacy evaluated at 1 h and 24 h after exposure on days 1, 7, 14, 21 and 28 were 36.7, 28.9, 30.8, 23.1 and 11.9%, and 68.4, 45.0, 43.3, 37.9 and 19.9%, respectively. Based on the mouse model, the present study demonstrates that the DPP combination has significant anti-feeding and insecticidal efficacy against S. albopicta for at least 4 weeks. PMID- 28714541 TI - Full-night measurement of level of obstruction in sleep apnea utilizing continuous manometry. AB - OBJECTIVES/HYPOTHESIS: To determine the average proportion of retropalatal or retroglossal obstruction occurring during a whole night in single patients with obstructive sleep apnea. STUDY DESIGN: Retrospective analysis. METHODS: Patients who underwent full-night polysomnography and upper airway pressure manometry at the same time were retrospectively enrolled. Airway obstruction levels were categorized into retropalatal or retroglossal obstruction according to the pressure change shown during pressure manometry. The proportion of retropalatal/retroglossal obstruction was calculated for each patient. Independent factors associated with the proportion were assessed. RESULTS: A total of 218 patients (198 men) with obstructive sleep apnea were included in the study (mean age, 46.8 +/- 1.6 years; body mass index, 26.7 +/- 3.1 kg/m2 ). The average proportion of retroglossal and retropalatal obstruction in individuals was 36.2% and 63.8%, respectively. The apnea-hypopnea index was not significantly correlated with the proportion of retroglossal obstruction (P = .219) after adjustment for age, sex, and body mass index. Meanwhile, the proportion of retroglossal obstruction was significantly correlated with oxygen desaturation index (P = .036), average oxygen saturation (P = .006), lowest oxygen saturation (P = .028), and time below 90% oxygen saturation (P = .021). CONCLUSIONS: To our knowledge, this is the first study showing the average proportions of retropalatal/retroglossal obstruction occurring in single individuals with obstructive sleep apnea during a whole night. The proportion of upper airway obstruction site was significantly associated with oxygen desaturation. LEVEL OF EVIDENCE: 4. Laryngoscope, 127:2897-2902, 2017. PMID- 28714542 TI - Two Enabling Strategies for the Stereoselective Conversion of Internal Alkynes into Trisubstituted Alkenes. AB - An expedient method for the C-methylation of alkenylstannanes with formation of trisubstituted alkenes is described, which relies on the use of MeI in combination with copper thiophene-2-carboxylate (CuTC) as promotor and tetra-n butylammonium diphenylphosphinate as an effective tin scavenger; in some cases, it proved beneficial to further supplement the mixture with catalytic amounts of Pd(PPh3 )4 . Under these conditions, the reaction is robust, high yielding, and compatible with many functional groups that might not subsist under more traditional conditions used to C-alkylate organotin derivatives. A qualitative analysis of the reaction profile suggested that the in situ formation of a reactive organocopper intermediate and its interception by MeI is only barely faster than O-methylation of the phosphinate additive by the same alkylating agent. To guarantee high yields and prevent net protodestannation from occurring, the reaction protocol had to be optimized such that these competing processes are properly decoupled. The new method is particularly well suited for the stereoselective preparation of the (E)-2-methylbut-2-en-1-ol motif that is present in numerous natural products. Alternatively, this particular target structure can be accessed starting from alpha-hydroxy alkenylsiloxane precursors, which get C-methylated upon exposure to CuI/LiOtBu and MeI by what is thought to be a Brook rearrangement/ alkylation sequence. The required substrates are best prepared by ruthenium-catalyzed trans-hydrosilylation or trans-hydrostannation of propargyl alcohols. PMID- 28714543 TI - Effect of psychosocial distress on outcome for head and neck cancer patients undergoing radiation. AB - OBJECTIVES/HYPOTHESIS: To determine the impact of pretreatment psychosocial distress on compliance to radiation therapy (RT) and clinical outcomes for patients with head and neck cancer STUDY DESIGN: Self-reported responses to the mood and anxiety domains of the University of Washington Quality of Life instrument were reviewed among 133 patients with newly diagnosed head and neck cancer prior to initiating RT. METHODS: Varying definitions were used (total number of unexpectedly missed RT days, >5 days continuous interruption of RT outside of weekends, >10 days continuous interruption of RT, and failure to complete prescribed course of RT) to analyze the effect of psychosocial disruption on compliance. Survival was determined using the Kaplan-Meier method. RESULTS: The prevalence of pretreatment depression and anxiety was 23% and 47%, respectively. Continuous RT breaks >5 days occurred in 46%, 33%, 10%, 9%, and 0% of patients whose mood was rated as "extremely depressed," "somewhat depressed," "neither in a good mood or depressed," "generally good," and "excellent," respectively (P = .0016). The corresponding proportion of patients who did not complete their planned RT was 23%, 11%, 5%, and 3%, and 0%, respectively (P = .043). The 2-year overall survival of patients who were "extremely depressed" or "somewhat depressed" at baseline was 71% versus 86% for all others (P = .026). Depression was independently associated with decreased overall survival on logistical regression analysis. CONCLUSIONS: Pretreatment depression predicted for decreased RT compliance and inferior survival for head and neck cancer. Additional research to overcome potential barriers to treatment in this setting may be warranted. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:641-645, 2018. PMID- 28714544 TI - Otolaryngology externships and the match: Productive or futile? AB - OBJECTIVES/HYPOTHESIS: The objectives of this study were to summarize externship experiences among recent graduates and current residents in otolaryngology residency programs and determine whether externships affect the match process. STUDY DESIGN: Cross-sectional survey. METHODS: A survey was distributed to otolaryngology residents in allopathic US residency programs and otolaryngology graduates from the past 5 years (2011-2015). There were 2,141 surveys distributed. RESULTS: There were 654 subjects who responded, for a 30.5% response rate. Most respondents were residents (n = 438, 67%). Of the residents, 85.6% had completed at least one externship compared to 75.9% of graduates (P = .002). The most common reasons for selecting a particular externship were geographic location (74.2%) and program reputation (71.1%), whereas the most common reason for not completing an externship was being advised not to (59.1%). Furthermore, 82.6% of respondents received at least one interview from their externships, 90% went to those interviews, and 89.1% reported that externship experiences affected their rank list. Respondents had a 32.7% match rate to the externship residency program if it was ranked versus a 48.8% match rate if the program was ranked first. Respondents who matched at the externship residency program matched higher on their rank list (P < .001). Of the respondents, 90.7% found externships to be valuable, and 74.5% recommended completing one. CONCLUSIONS: Externships are beneficial because they influence the rank list of applicants and are viewed as valuable experiences. Completing an externship is advisable for the experience, but applicants should weigh the benefits versus the possible risk of being judged more harshly during a month-long rotation. LEVEL OF EVIDENCE: NA Laryngoscope, 127:2242-2246, 2017. PMID- 28714545 TI - Focal Hemodynamic Responses in the Stimulated Hemisphere During High-Definition Transcranial Direct Current Stimulation. AB - OBJECTIVE: High-definition transcranial direct current stimulation (HD-tDCS) using a 4 * 1 electrode montage has been previously shown using modeling and physiological studies to constrain the electric field within the spatial extent of the electrodes. The aim of this proof-of-concept study was to determine if functional near-infrared spectroscopy (fNIRS) neuroimaging can be used to determine a hemodynamic correlate of this 4 * 1 HD-tDCS electric field on the brain. MATERIALS AND METHODS: In a three session cross-over study design, 13 healthy males received one sham (2 mA, 30 sec) and two real (HD-tDCS-1 and HD tDCS-2, 2 mA, 10 min) anodal HD-tDCS targeting the left M1 via a 4 * 1 electrode montage (anode on C3 and 4 return electrodes 3.5 cm from anode). The two real HD tDCS sessions afforded a within-subject replication of the findings. fNIRS was used to measure changes in brain hemodynamics (oxygenated hemoglobin integral-O2 Hbint ) during each 10 min session from two regions of interest (ROIs) in the stimulated left hemisphere that corresponded to "within" (Lin ) and "outside" (Lout ) the spatial extent of the 4 * 1 electrode montage, and two corresponding ROIs (Rin and Rout ) in the right hemisphere. RESULTS: The ANOVA showed that both real anodal HD-tDCS compared to sham induced a significantly greater O2 Hbint in the Lin than Lout ROIs of the stimulated left hemisphere; while there were no significant differences between the real and sham sessions for the right hemisphere ROIs. Intra-class correlation coefficients showed "fair-to-good" reproducibility for the left stimulated hemisphere ROIs. CONCLUSIONS: The greater O2 Hbint "within" than "outside" the spatial extent of the 4 * 1 electrode montage represents a hemodynamic correlate of the electrical field distribution, and thus provides a prospective reliable method to determine the dose of stimulation that is necessary to optimize HD-tDCS parameters in various applications. PMID- 28714546 TI - Silver-Catalyzed Dehydrogenative Synthesis of Carboxylic Acids from Primary Alcohols. AB - A simple silver-catalyzed protocol has been developed for the acceptorless dehydrogenation of primary alcohols into carboxylic acids and hydrogen gas. The procedure uses 2.5 % Ag2 CO3 and 2.5-3 equiv of KOH in refluxing mesitylene to afford the potassium carboxylate which is then converted into the acid with HCl. The reaction can be applied to a variety of benzylic and aliphatic primary alcohols with alkyl and ether substituents, and in some cases halide, olefin, and ester functionalities are also compatible with the reaction conditions. The dehydrogenation is believed to be catalyzed by silver nanoparticles that are formed in situ under the reaction conditions. PMID- 28714547 TI - Beyond symptom counts to case-wise probabilities. PMID- 28714548 TI - Role of the protease corin in chondrogenic differentiation of human bone marrow derived mesenchymal stem cells. AB - Mesenchymal stem cells (MSCs) have the potency to differentiate into chondrocytes, osteocytes and adipocytes. Corin is a cardiac protease that activates the natriuretic peptides, thereby regulating blood volume and pressure. In addition to the heart, corin gene upregulation was reported in bone marrow- and adipose tissue-derived MSCs that underwent osteogenic differentiation. To date, the biological significance of corin expression in MSC differentiation remains unknown. In this study we isolated and cultured human bone marrow-derived MSCs that were capable of undergoing chondrogenic, osteogenic and adipogenic lineage differentiation. By reverse transcription polymerase chain reaction (RT PCR) and immunostaining, we found that corin expression was upregulated when these MSCs underwent chondrogenic, osteogenic and adipogenic differentiation. The upregulation of corin expression was most significant in the cells undergoing chondrogenic lineage differentiation. Silencing corin gene expression by small hairpin RNA in the MSCs inhibited chondrogenic, but not osteogenic and adipogenic, differentiation. These results suggest a novel function of corin in MSC differentiation and chondrocyte development. PMID- 28714549 TI - Increased level of DNA damage in some organs of obese Zucker rats by gamma-H2AX analysis. AB - In a recent study, we showed that lymphocytes of obese Italian children/adolescents displayed levels of double strand breaks (DSB), assayed as serine 139-phosphorylated histone H2AX (gamma-H2AX), about eightfold higher than normal weight controls, and that 30% of this damage-generated micronuclei. These findings suggested that obese children could be at increased risk of obesity mediated cancer later in life. We therefore aimed to assess the level of gamma H2AX in a genetic animal model of obesity (Zucker rat) to identify a genotoxic/carcinogenic risk in some organs. The DSB marker was studied in 3- to 4 week-old rats and in 9- to 13-week-old rats. Paraffin-embedded sections of heart, thyroid, liver, pancreas, lung, kidney, esophagus, and gut from the fa-/fa- (obese) and the fa+/fa- (lean) control animals were processed for immunohistochemistry detection of gamma-H2AX. Pancreas (0.0624 +/- 0.0195), lung (0.1197 +/- 0.0217), esophagus (0.1230 +/- 0.0351), kidney (0.1546 +/- 0.0149), and gut (0.1724 +/- 0.0352) of 9- to 13-week-old obese rats showed a higher proportion of gamma-H2AX-positive nuclei, than their lean counterparts (0.0092 +/ 0.0033, 0.0416 +/- 0.0185, 0.0368 +/- 0.0088, 0.0686 +/- 0.0318, and 0.0703 +/- 0.0239, respectively). No difference was seen in the 3- to 4-week-old age group with regard to obesity, indicating that the DNA damage increased with older age of the rats. We hypothesize that the organs of the obese animals showing high levels of DSB could represent target tissues for the development of obesity related cancers. Environ. Mol. Mutagen. 58:477-484, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28714550 TI - Optimal timing and frequency of bone marrow soup therapy for functional restoration of salivary glands injured by single-dose or fractionated irradiation. AB - Injections of bone marrow (BM) cell extract, known as 'BM soup', were previously reported to mitigate ionizing radiation (IR) injury to salivary glands (SGs). However, the optimal starting time and frequency to maintain BM soup therapeutic efficacy remains unknown. This study tested the optimal starting time and frequency of BM soup injections in mice radiated with either a single dose or a fractionated dose. First, BM soup treatment was started at 1, 3 or 7 weeks post IR; positive (non-IR) and negative (IR) control mice received injections of saline (vehicle control). Second, BM soup-treated mice received injections at different frequencies (1, 2, 3 and 5 weekly injections). Third, a 'fractionated dose radiation' model to injure mouse SGs was developed (5 Gy * 5 days) and compared with the single high dose radiation model. All mice (n = 65) were followed for 16 weeks post-IR. The results showed that starting injections of BM soup between 1 and 3 weeks mitigated the effect of IR-induced injury to SGs and improved the restoration of salivary function. Although the therapeutic effect of BM soup lessens after 8 weeks, it can be sustained by increasing the frequency of weekly injections. Moreover, both single-dose and fractionated-dose radiation models are efficient and comparable in inducing SG injury and BM soup treatments are effective in restoring salivary function in both radiation models. In conclusion, starting injections of BM soup within 3 weeks post-radiation, with 5 weekly injections, maintains 90-100% of saliva flow in radiated mice. PMID- 28714551 TI - Influence of the mode of administration on the results of medication adherence questionnaires. AB - INTRODUCTION AND OBJECTIVES: Adherence to medication regimen is commonly assessed through questionnaires, some of which are validated via self-administration. The inadequate health literacy of elderly people pushes researchers to the use of interviews as a method of administration. The aims of this study were to compare the results obtained with an interviewer-administered and a self-administered medication adherence questionnaire and to evaluate the consequences of the adherence status classification of individuals. METHODS: A cross-sectional study was performed in which the Medida de Adesao aos Tratamentos adherence questionnaire was administered to adult patients who were taking at least 1 antihypertensive drug. The data were collected in 7 community pharmacies in central Portugal between March 2014 and September 2015 in 2 different phases: in the first phase, the questionnaire was applied during a healthcare professional interview, and the second phase involved a self-report administration. A confirmatory factor analysis was conducted, and the measurement and structural invariances across the application methods were examined. RESULTS: A sample of 425 patients with a mean age of 68.21 +/- 10.56 years participated in the study. The confirmatory factor analysis revealed that both the interview and self-report had a good fit with the original model, although the self-report results exhibited a better fit. In the interview administration, we obtained lower values for skewness and higher levels of kurtosis. The patients subjected to the interview administration presented with a 9.7% higher tendency to answer "never" when compared with the self-administered application, which overestimated adherence. CONCLUSIONS: The interview administration method induced bias that led to a higher percentage of "never" answers and a subsequent overestimation of adherence levels. Self-report administration should be preferred in the application of medication adherence questionnaires. PMID- 28714552 TI - Annulated 1,3,4-Azadiphospholides: Heterocycles with Widely Tunable Optical Properties. AB - Phosphorus heterocycles find applications in the synthesis of pi-conjugated compounds and as precursors for optoelectronic materials such as organic light emitting diodes (OLEDs), electronic switches, and transistors. A high-yield, one pot synthesis of anionic annulated 1,3,4-azadiphospholides from Na(OCP) and 2 chloropyridines is presented. The synthesis proceeds without the use of transition metals and tolerates a wide range of substrates. Cyano-substituted compounds are especially deeply colored and have absorption maxima which range from lambdamax =525 to 596 nm. The optical properties are dominated by the spatial separation of an electron acceptor and donor unit within one molecule (push-pull chromophore). The anionic 1,3,4-azadiphospholides are silylated to neutral siloxy compounds with a strong blue-shifted absorption. This reaction can be reversed by addition of fluoride ions, which allows fluoride ions to be detected in optically low concentrations. PMID- 28714554 TI - Type IX secretion: the generation of bacterial cell surface coatings involved in virulence, gliding motility and the degradation of complex biopolymers. AB - The Type IX secretion system (T9SS) is present in over 1000 sequenced species/strains of the Fibrobacteres-Chlorobi-Bacteroidetes superphylum. Proteins secreted by the T9SS have an N-terminal signal peptide for translocation across the inner membrane via the SEC translocon and a C-terminal signal for secretion across the outer membrane via the T9SS. Nineteen protein components of the T9SS have been identified including three, SigP, PorX and PorY that are involved in regulation. The inner membrane proteins PorL and PorM and the outer membrane proteins PorK and PorN interact and a complex comprising PorK and PorN forms a large ring structure of 50 nm in diameter. PorU, PorV, PorQ and PorZ form an attachment complex on the cell surface of the oral pathogen, Porphyromonas gingivalis. P. gingivalis T9SS substrates bind to PorV suggesting that after translocation PorV functions as a shuttle protein to deliver T9SS substrates to the attachment complex. The PorU component of the attachment complex is a novel Gram negative sortase which catalyses the cleavage of the C-terminal signal and conjugation of the protein substrates to lipopolysaccharide, anchoring them to the cell surface. This review presents an overview of the T9SS focusing on the function of T9SS substrates and machinery components. PMID- 28714553 TI - Lithium in drinking water and the incidence of bipolar disorder: A nation-wide population-based study. AB - OBJECTIVE: Animal data suggest that subtherapeutic doses, including micro doses, of lithium may influence mood, and lithium levels in drinking water have been found to correlate with the rate of suicide. It has never been investigated whether consumption of lithium may prevent the development of bipolar disorder (primary prophylaxis). In a nation-wide population-based study, we investigated whether long-term exposure to micro levels of lithium in drinking water correlates with the incidence of bipolar disorder in the general population, hypothesizing an inverse association in which higher long-term lithium exposure is associated with lower incidences of bipolar disorder. METHODS: We included longitudinal individual geographical data on municipality of residence, data from drinking water lithium measurements and time-specific data from all cases with a hospital contact with a diagnosis of mania/bipolar disorder from 1995 to 2013 (N=14 820) and 10 age- and gender-matched controls from the Danish population (N= 140 311). Average drinking water lithium exposure was estimated for all study individuals. RESULTS: The median of the average lithium exposure did not differ between cases with a diagnosis of mania/bipolar disorder (12.7 MUg/L; interquartile range [IQR]: 7.9-15.5 MUg/L) and controls (12.5 MUg/L; IQR: 7.6 15.7 MUg/L; P=.2). Further, the incidence rate ratio of mania/bipolar disorder did not decrease with higher long-term lithium exposure, overall, or within age categories (0-40, 41-60 and 61-100 years of age). CONCLUSION: Higher long-term lithium exposure from drinking water was not associated with a lower incidence of bipolar disorder. The association should be investigated in areas with higher lithium levels than in Denmark. PMID- 28714555 TI - Evidence that eye-movement profiles do not explain slow binocular rivalry rate in bipolar disorder: support for a perceptual endophenotype. AB - OBJECTIVES: Presenting conflicting images simultaneously, one to each eye, produces perceptual alternations known as binocular rivalry (BR). Slow BR rate has been proposed as an endophenotype for bipolar disorder (BD) for use in large scale genome-wide association studies. However, the trait could conceivably reflect eye movement (EM) dysfunction in BD rather than anomalous perceptual processing per se. To address this question, we examined the relationship between EM profiles and BR rate for various stimulus types in BD and healthy subjects. We also examined differences in EM profiles between these groups. METHODS: Employing a repeated-measures within-subjects design, 20 BD outpatients and 20 age- and sex matched healthy controls completed EM tasks and separate BR tasks involving a range of stimuli with different drift speeds. The association between each EM measure and BR rate was examined with correlational analyses for all stimulus conditions in both groups. Between-group comparisons were performed to determine any differences in those EM measures. Corresponding Bayesian analyses were also conducted. RESULTS: There were no EM measures that showed a significant relationship with BR rate in either the BD group or the healthy group (P>=7.87*10 3 ), where those EM measures were also significantly different between the BD and healthy groups (P>=1.32 * 10-2 ). These findings were verified with Bayes factors. CONCLUSIONS: The results provide evidence that EM profiles do not explain the slow BR endophenotype for BD, thus indicating that the trait reflects anomalous perceptual processing per se. This perceptual trait can be employed in clinical, genetic, mechanistic and pathophysiological studies. PMID- 28714556 TI - Non-canonical activation of histidine kinase KdpD by phosphotransferase protein PtsN through interaction with the transmitter domain. AB - The two-component system KdpD/KdpE governs K+ homeostasis by controlling synthesis of the high affinity K+ transporter KdpFABC. When sensing low environmental K+ concentrations, the dimeric kinase KdpD autophosphorylates in trans and transfers the phosphoryl-group to the response regulator KdpE, which subsequently activates kdpFABC transcription. In Escherichia coli, KdpD can also be activated by interaction with the non-phosphorylated form of the accessory protein PtsN. PtsN stimulates KdpD kinase activity thereby increasing phospho KdpE levels. Here, we analyzed the interplay between KdpD/KdpE and PtsN. PtsN binds specifically to the catalytic DHp domain of KdpD, which is also contacted by KdpE. Accordingly, PtsN and KdpE compete for binding, providing a paradox. Low levels of non-phosphorylated PtsN stimulate, whereas high amounts reduce kdpFABC expression by blocking access of KdpE to KdpD. Ligand fishing experiments provided insight as they revealed ternary complex formation of PtsN/KdpD2 /KdpE in vivo demonstrating that PtsN and KdpE bind different protomers in the KdpD dimer. PtsN may bind one protomer to stimulate phosphorylation of the second KdpD protomer, which then phosphorylates bound KdpE. Phosphorylation of PtsN prevents its incorporation in ternary complexes. Interaction with the conserved DHp domain enables PtsN to regulate additional kinases such as PhoR. PMID- 28714558 TI - Everolimus and reduced calcineurin inhibitor therapy in pediatric liver transplant recipients: Results from a multicenter, prospective study. AB - In a 24-month, multicenter, single-arm, prospective study, 56 pediatric liver transplant patients with or without basiliximab induction were converted at 1-6 months post-transplant from standard calcineurin inhibitor (CN) therapy (+/- mycophenolic acid), to everolimus with reduced exposure to CNI (tacrolimus n=50, cyclosporine n=6). Steroid therapy was optional. Recruitment was stopped prematurely due to high rates of PTLD, treatment-related serious infections leading to hospitalization and premature study drug discontinuation. Subsequently, patients aged <7 years reverted to local standard-of-care immunosuppression. Mean tacrolimus concentration was above or near the upper end of the maintenance target range (2-5 ng/mL) until after month 6 post-enrollment. The primary variable, mean (SD) change in eGFR from baseline to month 12 (last observation carried forward), was +6.2 (19.5) mL/min/1.73 m2 . Two patients experienced treated biopsy-proven acute rejection. No graft losses or deaths occurred. PTLD occurred in five patients (8.9%) (3/25 [12.0%] patients <2 years, 2/31 aged 2-18 years [6.5%]). Adverse events, serious adverse events, and discontinuation due to adverse events were reported in 100.0%, 76.8%, and 44.6% of patients, respectively. In conclusion, everolimus with reduced CNI improved renal function while maintaining antirejection potency in pediatric liver transplant patients but safety outcomes suggest that patients were overimmunosuppressed. PMID- 28714557 TI - Concise Review: Developing Best-Practice Models for the Therapeutic Use of Extracellular Vesicles. AB - Growing interest in extracellular vesicles (EVs, including exosomes and microvesicles) as therapeutic entities, particularly in stem cell-related approaches, has underlined the need for standardization and coordination of development efforts. Members of the International Society for Extracellular Vesicles and the Society for Clinical Research and Translation of Extracellular Vesicles Singapore convened a Workshop on this topic to discuss the opportunities and challenges associated with development of EV-based therapeutics at the preclinical and clinical levels. This review outlines topic-specific action items that, if addressed, will enhance the development of best-practice models for EV therapies. Stem Cells Translational Medicine 2017;6:1730-1739. PMID- 28714559 TI - How We Make DNA Origami. AB - DNA origami has attracted substantial attention since its invention ten years ago, due to the seemingly infinite possibilities that it affords for creating customized nanoscale objects. Although the basic concept of DNA origami is easy to understand, using custom DNA origami in practical applications requires detailed know-how for designing and producing the particles with sufficient quality and for preparing them at appropriate concentrations with the necessary degree of purity in custom environments. Such know-how is not readily available for newcomers to the field, thus slowing down the rate at which new applications outside the field of DNA nanotechnology may emerge. To foster faster progress, we share in this article the experience in making and preparing DNA origami that we have accumulated over recent years. We discuss design solutions for creating advanced structural motifs including corners and various types of hinges that expand the design space for the more rigid multilayer DNA origami and provide guidelines for preventing undesired aggregation and on how to induce specific oligomerization of multiple DNA origami building blocks. In addition, we provide detailed protocols and discuss the expected results for five key methods that allow efficient and damage-free preparation of DNA origami. These methods are agarose-gel purification, filtration through molecular cut-off membranes, PEG precipitation, size-exclusion chromatography, and ultracentrifugation-based sedimentation. The guide for creating advanced design motifs and the detailed protocols with their experimental characterization that we describe here should lower the barrier for researchers to accomplish the full DNA origami production workflow. PMID- 28714560 TI - Validation and reliability of the sex estimation of the human os coxae using freely available DSP2 software for bioarchaeology and forensic anthropology. AB - OBJECTIVES: A new tool for skeletal sex estimation based on measurements of the human os coxae is presented using skeletons from a metapopulation of identified adult individuals from twelve independent population samples. For reliable sex estimation, a posterior probability greater than 0.95 was considered to be the classification threshold: below this value, estimates are considered indeterminate. By providing free software, we aim to develop an even more disseminated method for sex estimation. MATERIALS AND METHODS: Ten metric variables collected from 2,040 ossa coxa of adult subjects of known sex were recorded between 1986 and 2002 (reference sample). To test both the validity and reliability, a target sample consisting of two series of adult ossa coxa of known sex (n = 623) was used. The DSP2 software (Diagnose Sexuelle Probabiliste v2) is based on Linear Discriminant Analysis, and the posterior probabilities are calculated using an R script. RESULTS: For the reference sample, any combination of four dimensions provides a correct sex estimate in at least 99% of cases. The percentage of individuals for whom sex can be estimated depends on the number of dimensions; for all ten variables it is higher than 90%. Those results are confirmed in the target sample. DISCUSSION: Our posterior probability threshold of 0.95 for sex estimate corresponds to the traditional sectioning point used in osteological studies. DSP2 software is replacing the former version that should not be used anymore. DSP2 is a robust and reliable technique for sexing adult os coxae, and is also user friendly. PMID- 28714561 TI - Service quality and maturity of health care organizations through the lens of Complexity Leadership Theory. AB - RATIONALE, AIMS AND OBJECTIVES: This research focuses on Complexity Leadership Theory and the relationship between leadership-examined through the lens of Complexity Leadership Theory-and organizational maturity as an indicator of the performance of health organizations. METHODS: The research adopts a perspective that conceptualizes organizations as complex adaptive systems and draws upon a survey of opinion of 189 managers working in Serbian health organizations. RESULTS AND CONCLUSIONS: As the results indicate a dependency between functions of leadership and levels of the maturity of health organizations, we propose a model that connects the two. The study broadens our understanding of the implications of complexity thinking and its reflection on leadership functions and overall organizational performance. The correlations between leadership functions and maturity could have practical applications in policy processing, thus improving the quality of outcomes and the overall level of service quality. PMID- 28714562 TI - A Multiobjective Optimization Including Results of Life Cycle Assessment in Developing Biorenewables-Based Processes. AB - A decision support tool has been developed that uses global multiobjective optimization based on 1) the environmental impacts, evaluated within the framework of full life cycle assessment; and 2) process costs, evaluated by using rigorous process models. This approach is particularly useful in developing biorenewable-based energy solutions and chemicals manufacturing, for which multiple criteria must be evaluated and optimization-based decision-making processes are particularly attractive. The framework is demonstrated by using a case study of the conversion of terpenes derived from biowaste feedstocks into reactive intermediates. A two-step chemical conversion/separation sequence was implemented as a rigorous process model and combined with a life cycle model. A life cycle inventory for crude sulfate turpentine was developed, as well as a conceptual process of its separation into pure terpene feedstocks. The performed single- and multiobjective optimizations demonstrate the functionality of the optimization-based process development and illustrate the approach. The most significant advance is the ability to perform multiobjective global optimization, resulting in identification of a region of Pareto-optimal solutions. PMID- 28714563 TI - The Effect of Prefrontal Transcranial Direct Current Stimulation on Attention Network Function in Healthy Volunteers. AB - OBJECTIVES: The effect of acute transcranial direct current stimulation (tDCS) on cortical attention networks remains unclear. We examined the effect of 20 min of 2 mA dorsolateral prefrontal cortex tDCS (bipolar balanced montage) on the efficiency of alerting, orienting and executive attention networks measured by the attention network test. MATERIALS AND METHODS: A between-subjects stratified randomized design compared active tDCS vs. sham tDCS on attention network function in healthy young adults. RESULTS: Executive attention was greater following active vs. sham stimulation (d = 0.76) in the absence of effects on alerting, orienting, or global RT or error rates. Group differences were not moderated by state-mood. CONCLUSION(S): Twenty minutes of active 2 mA tDCS over left DLPFC is associated with greater executive attention in healthy humans. PMID- 28714564 TI - Laryngeal distribution of recurrent respiratory papillomatosis in a previously untreated cohort. AB - OBJECTIVES/HYPOTHESIS: To describe the distribution of recurrent respiratory papillomatosis (RRP) lesions across 21 laryngeal anatomic regions in previously untreated patients at initial presentation to provide insight regarding the natural history of RRP. STUDY DESIGN: Multi-institutional, retrospective case series. METHODS: Initial laryngoscopic examination videos of 83 previously untreated patients with adult-onset RRP were reviewed. Papilloma locations were recorded using a 21-region laryngeal schematic. Multivariate analyses by anatomic subsite were conducted for the entire population and for subgroups stratified by sex, age, and proton pump inhibitor (PPI) usage. Heat maps were generated, hierarchically color coding the anatomic distribution of disease. RESULTS: In this cohort, RRP was most likely to occur on the true vocal folds (TVFs) and anterior commissure (P < .0001, odds ratio [OR]: 7.02); within the TVFs, the membranous vocal folds (MVFs) were most likely to be affected (P < .0001, OR: 3.56). The cohort was predominantly male (80.7%); males had a higher average number of affected sites (P = .005) and were more likely to have lesions in any laryngeal subsite (P < .0001, OR: 2.88,) compared to females. PPI users were more likely than nonusers to have disease in any laryngeal subsite (P = .0037, OR: 1.62), particularly in the posterior and subglottic regions (P = .0061, OR: 2.53). Age was not correlated with lesion prevalence or distribution. CONCLUSIONS: In untreated patients presenting to three laryngology clinics, the MVFs were most likely to be affected by RRP. Males had more anatomic sites affected by papilloma than females. The influence of PPI use on RRP distribution warrants further investigation. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:138-143, 2018. PMID- 28714565 TI - MRI-compatible breast/rib phantom for evaluating ultrasonic thermal exposures. AB - INTRODUCTION: The target of this study was the development of a magnetic resonance imaging (MRI) compatible breast phantom for focused ultrasound which includes plastic (ABS) ribs. The objective of the current study was the evaluation of a focused ultrasound procedure using the proposed phantom that eliminates rib heating. MATERIAL AND METHODS: The proposed phantom was evaluated using two different focused ultrasound exposures. The surrounding breast tissue was mimicked using an agar-silica-evaporation milk gel (2% w/v - 2% w/v - 40% v/v). RESULTS: The attenuation of the ABS was similar to that of ribs. MR thermometry of focused ultrasound exposures were acquired using the breast/rib phantom. In one exposure focused ultrasound was applied with far-field targeting of the ribs. In the other exposure, the transducer was positioned laterally, thus avoiding exposure of the rib to focused ultrasound. CONCLUSIONS: Due to growing interest in using MRI guided focused ultrasound (MRgFUS) for patients with breast cancer, the proposed breast/rib phantom can be utilized as a very useful tool for evaluating ultrasonic protocols. PMID- 28714567 TI - Comparison of the effects of topical application of UMF20 and UMF5 manuka honey with a generic multifloral honey on wound healing variables in an uncontaminated surgical equine distal limb wound model. AB - OBJECTIVE: To compare the effect of application of manuka honey with unique manuka factor (UMF) 5 or 20 with a generic multifloral honey on equine wound healing variables. METHODS: Two full-thickness skin wounds (2.5 * 2.5 cm) were created on the metatarsus of both hindlimbs of eight Standardbred horses. The wounds on each horse were assigned to 1 of 4 treatments: UMF20 (UMF20) and UMF5 (UMF5) manuka honey; generic multifloral honey (GH); and a saline control. Bandages were changed daily for 12 days, after which treatment was stopped and the bandages were removed. Wound area was measured on day 1, then weekly until day 42. Overall wound healing rate (cm2 /day) and time to complete healing were recorded. RESULTS: There was no difference in wound area for any of the treatments on any measurement day except for day 21, where the mean wound area for wounds treated with UMF20 was smaller than the mean wound area for the UMF5 treated wounds (P = 0.031). There was no difference in mean (+/- SE) overall healing rate (cm2 /day) among the treatment groups. There were differences in mean (+/- SE) days to complete healing. Wounds treated with UMF20 healed faster than wounds treated with GH (P = 0.02) and control wounds (P = 0.01). CONCLUSIONS: Treatment of wounds with UMF20 reduced overall wound healing time compared with wounds treated with GH and control wounds. However, using this model the difference in the overall time to complete healing was small. PMID- 28714566 TI - GSK-3beta activation index is a potential indicator for recurrent inflammation of chronic rhinosinusitis without nasal polyps. AB - Chronic rhinosinusitis without nasal polyps (CRSsNP) is one of the most common otorhinolaryngologic diseases worldwide. However, the underlying mechanism remains unclear. In this study, the expression of glycogen synthase kinase 3 (GSK 3) was quantitatively evaluated in patients with CRSsNP (n = 20) and healthy controls (n = 20). The mRNA levels of GSK-3alpha and GSK-3beta were examined by qPCR, the immunoreactivities of GSK-3beta and nuclear factor-kappaB (NF-kappaB) were examined by immunohistochemistry (IHC) staining, and the protein levels of GSK-3beta, phospho-GSK-3beta (p-GSK-3beta, s9) and NF-kappaB were examined using Western blot analysis. We found that GSK-3 was highly expressed in both CRSsNP and control groups without significant difference in both GSK-3beta mRNA and protein levels. However, when compared with healthy control group, the GSK-3beta activation index, defined as the ratio of GSK-3beta over p-GSK-3beta, was significantly decreased, whereas the NF-kappaB protein abundance was significantly increased in CRSsNP group (P < 0.05). Strikingly, the GSK-3beta activation index, was highly correlated with NF-kappaB protein level, as well as CT scores in CRSsNP group (P < 0.05). It was also highly correlated with the mRNA expressions of inflammation-related genes, including T-bet, IFN-gamma and IL-4 in CRSsNP group (P < 0.05). Our findings suggest that GSK-3beta activation index, reflecting the inhibitory levels of GSK-3beta through phosphorylation, may be a potential indicator for recurrent inflammation of CRSsNP, and that the insufficient inhibitory phosphorylation of GSK-3beta may play a pivotal role in the pathogenesis of CRSsNP. PMID- 28714568 TI - Exposure to reversine affects the chondrocyte morphology and phenotype in vitro. AB - Articular chondrocytes derived from osteoarthritic tissues (OA HAC) show a severely reduced chondrogenic commitment. This impairment undermines their use for tissue-engineered cartilage repair, which relies on cell proliferation and growth to meet therapeutic needs, but also on efficient cell plasticity to recover the chondrogenic phenotype. Reversine (Rev), a 2,6-disubstituted purine inhibitor of spindle-assembly checkpoints, was described to convert differentiated mesenchymal cells to their undifferentiated precursors. We hypothesized that Rev exposure could divert OA HAC to more plastic cells, re boosting their subsequent commitment. HAC were enzymatically released from OA cartilage specimens, expanded for 2 weeks and treated with 5 MUm Rev in dimethylsulphoxide (DMSO) or with DMSO alone for 6 days. Cell growth was assessed using the AlamarBlueTM assay. Cytoskeletal structure, endoproliferation and caspase-3-immunopositivity were assayed by epifluorescence microscopy. The OA HAC chondrogenic performance was evaluated by quantitative reverse transcription polymerase chain reaction (RT-PCR) for glyceraldehyde-3-phosphate dehydrogenase, Sox9, Aggrecan (Agg), type II collagen (Col2), Ki67, cyclinD1, transforming growth factor-beta1 (TGF-beta1), -2 and -3, interleukin-1beta (IL-1beta) and -6 , SMAD3 and -7, and vascular endothelial growth factor. Rev-treated OA HAC recovered polygonal morphology and reduced Ki67 expression and proliferation. Cell-cycle impairment accounted for altered cytoskeletal organization, endoproliferation and apoptosis, whereas a compensatory mechanism sustained the increased cyclinD1 transcript levels. Sox9, Agg and TGFs were overexpressed, but not Col2. IL transcripts were massively downregulated. These events were dose related and transient. Overall, in spite of a higher Rev-induced transcriptional activity for extracellular matrix components and in spite of a Rev-treated cell phenotype closer to that of the three-dimensional native articular chondrocyte, Rev effects seem unleashed from a full regained chondrogenic potential. PMID- 28714569 TI - Seasonal dynamics of the tick Haemaphysalis tibetensis in the Tibetan Plateau, China. AB - The tick Haemaphysalis tibetensis (Acari: Ixodidae) Hoogstraal is an important arthropod vector widespread in the Qinghai-Tibet Plateau, and knowledge of its seasonal dynamics is still poor. The current study investigated the seasonal dynamics of the parasitic and non-parasitic H. tibetensis over a 2-year period from March 2014 to February 2016 in the Tibetan Plateau, China. During this timeframe, non-parasitic ticks were collected weekly by flag-dragging in grassland and shrubland areas, and parasitic ticks were removed weekly from selected sheep. Plateau pikas were captured using traps and examined for immature ticks between May to September 2014. Results suggest that non-parasitic H. tibetensis were mainly distributed in the grassland, and the parasitic adults and nymphs were found mostly on sheep. Larvae were usually found on Plateau pikas and the prevalence of infestation and mean parasitic intensity were 72.1 and 1.81%, respectively. Adults were observed from March to July with the major peak occurring in mid-April. Nymphs were found from March to August and reached a peak in late June. Larvae were collected from April to September, and their numbers peaked in late May. In the parasitic and non-parasitic period, the overall sex ratio of males to females was 1.62 and 1.30, respectively. Results show that H. tibetensis can complete one generation per year, with a population overlap between stages over the spring-summer months. These findings provide additional information on the biology and ecology of H. tibetensis as well as insights on its control in the environment and on sheep. PMID- 28714570 TI - Human osteoarthritic chondrons outnumber patient- and joint-matched chondrocytes in hydrogel culture-Future application in autologous cell-based OA cartilage repair? AB - Autologous chondrocyte implantation (ACI) is used in 34-60% for osteoarthritic (OA) cartilage defects, although ACI is neither recommended nor designed for OA. Envisioning a hydrogel-based ACI for OA that uses chondrons instead of classically used chondrocytes, we hypothesized that human OA chondrons may outperform OA chondrocytes. We compared patient- and joint surface-matched human OA chondrons with OA chondrocytes cultured for the first time in a hydrogel, using a self-assembling peptide system. We determined yield, viability, cell numbers, mRNA expression, GAPDH mRNA enzyme activity, Collagen II synthesis (CPII) and degradation (C2C), and sulfated glycosaminoglycan. Ex vivo, mRNA expression was comparable. Over time, significant differences in survival led to 3.4-fold higher OA chondron numbers in hydrogels after 2 weeks (p = .002). Significantly, more enzymatically active GAPDH protein indicated higher metabolic activity. The number of cultures that expressed mRNA for Collagen Types I and VI, COMP, aggrecan, VEGF, TGF-beta1, and FGF-2 (but not Collagen Types II and X) was different, resulting in a 3.5-fold higher number of expression-positive OA chondron cultures (p < .05). Measuring CPII and C2C per hydrogel, OA chondron hydrogels synthesized more than they degraded Collagen Type II, the opposite was true for OA chondrocytes. Per cell, OA chondrons but not OA chondrocytes displayed more synthesis than degradation. Thus, OA chondrons displayed superior biosynthesis and mRNA expression of tissue engineering and phenotype-relevant genes. Moreover, human OA chondrons displayed a significant survival advantage in hydrogel culture, whose presence, drastic extent, and timescale was novel and is clinically significant. Collectively, these data highlight the high potential of human OA chondrons for OA ACI, as they would outnumber and, thus, surpass OA chondrocytes. PMID- 28714571 TI - Domestication and fitness in the wild: A multivariate view. AB - Domesticated species continually escaping and interbreeding with wild relatives impose a migration load on wild populations. As domesticated stocks become increasingly different as a result of artificial and natural selection in captivity, fitness of escapees in the wild is expected to decline, reducing the effective rate of migration into wild populations. Recent theory suggest that this may alleviate and eventually eliminate the resulting migration load. I develop a multivariate model of trait and wild fitness evolution resulting from the joint effects of artificial and natural selection in the captive environment. Initially, the evolutionary trajectory is dominated by the effects of artificial selection causing a fast initial decline in fitness of escapees in the wild. In later phases, through the counteracting effects of correlational multivariate natural selection in captivity, the mean phenotype is pushed in directions of weak stabilizing selection, allowing a sustained response in the trait subject to artificial selection. Provided that there is some alignment between the adaptive landscapes in the wild and in captivity, these phases are associated with slower rates of decline in wild fitness of the domesticated stock, suggesting that detrimental effects on wild populations are likely to remain a concern in the foreseeable future. PMID- 28714572 TI - Surface-Modified Mesh Filter for Direct Nucleic Acid Extraction and its Application to Gene Expression Analysis. AB - Rapid and convenient isolation of nucleic acids (NAs) from cell lysate plays a key role for onsite gene expression analysis. Here, this study achieves one-step and efficient capture of NA directly from cell lysate by developing a cationic surface-modified mesh filter (SMF). By depositing cationic polymer via vapor phase deposition process, strong charge interaction is introduced on the surface of the SMF to capture the negatively charged NAs. The NA capturing capability of SMF is confirmed by X-ray photoelectron spectroscopy, fluorescent microscopy, and zeta potential measurement. In addition, the genomic DNAs of Escherichia Coli O157:H7 can be extracted by the SMF from artificially infected food, and fluorescent signal is observed on the surface of SMF after amplification of target gene. The proposed SMF is able to provide a more simplified, convenient, and fast extraction method and can be applied to the fields of food safety testing, clinical diagnosis, or environmental pollutant monitoring. PMID- 28714574 TI - A humanised tissue-engineered bone model allows species-specific breast cancer related bone metastasis in vivo. AB - Bone metastases frequently occur in the advanced stages of breast cancer. At this stage, the disease is deemed incurable. To date, the mechanisms of breast cancer related metastasis to bone are poorly understood. This may be attributed to the lack of appropriate animal models to investigate the complex cancer cell-bone interactions. In this study, two established tissue-engineered bone constructs (TEBCs) were applied to a breast cancer-related metastasis model. A cylindrical medical-grade polycaprolactone-tricalcium phosphate scaffold produced by fused deposition modelling (scaffold 1) was compared with a tubular calcium phosphate coated polycaprolactone scaffold fabricated by solution electrospinning (scaffold 2) for their potential to generate ectopic humanised bone in NOD/SCID mice. While scaffold 1 was found not suitable to generate a sufficient amount of ectopic bone tissue due to poor ectopic integration, scaffold 2 showed excellent integration into the host tissue, leading to bone formation. To mimic breast cancer cell colonisation to the bone, MDA-MB-231, SUM1315, and MDA-MB-231BO breast cancer cells were cultured in polyethylene glycol-based hydrogels and implanted adjacent to the TEBCs. Histological analysis indicated that the breast cancer cells induced an osteoclastic reaction in the TEBCs, demonstrating analogies to breast cancer-related bone metastasis seen in patients. PMID- 28714573 TI - Assessment of the DNA damaging potential of environmental chemicals using a quantitative high-throughput screening approach to measure p53 activation. AB - Genotoxicity potential is a critical component of any comprehensive toxicological profile. Compounds that induce DNA or chromosomal damage often activate p53, a transcription factor essential to cell cycle regulation. Thus, within the US Tox21 Program, we screened a library of ~10,000 (~8,300 unique) environmental compounds and drugs for activation of the p53-signaling pathway using a quantitative high-throughput screening assay employing HCT-116 cells (p53+/+ ) containing a stably integrated beta-lactamase reporter gene under control of the p53 response element (p53RE). Cells were exposed (-S9) for 16 hr at 15 concentrations (generally 1.2 nM to 92 MUM) three times, independently. Excluding compounds that failed analytical chemistry analysis or were suspected of inducing assay interference, 365 (4.7%) of 7,849 unique compounds were concluded to activate p53. As part of an in-depth characterization of our results, we first compared them with results from traditional in vitro genotoxicity assays (bacterial mutation, chromosomal aberration); ~15% of known, direct-acting genotoxicants in our library activated the p53RE. Mining the Comparative Toxicogenomics Database revealed that these p53 actives were significantly associated with increased expression of p53 downstream genes involved in DNA damage responses. Furthermore, 53 chemical substructures associated with genotoxicity were enriched in certain classes of p53 actives, for example, anthracyclines (antineoplastics) and vinca alkaloids (tubulin disruptors). Interestingly, the tubulin disruptors manifested unusual nonmonotonic concentration response curves suggesting activity through a unique p53 regulatory mechanism. Through the analysis of our results, we aim to define a role for this assay as one component of a comprehensive toxicological characterization of large compound libraries. Environ. Mol. Mutagen. 58:494-507, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28714575 TI - Rate and predictors of conversion from unipolar to bipolar disorder: A systematic review and meta-analysis. AB - OBJECTIVES: For the first time to present a systematic review and meta-analysis of the conversion rate and predictors of conversion from unipolar disorder to bipolar disorder. METHODS: A systematic literature search up to October 2016 was performed. For the meta-analysis, we only included studies that used survival analysis to estimate the conversion rate. RESULTS: A total of 31 studies were identified, among which 11 used survival analyses, including two register-based studies. The yearly rate of conversion to bipolar disorder decreased with time from 3.9% in the first year after study entry with a diagnosis of unipolar disorder to 3.1% in years 1-2, 1.0% in years 2-5 and 0.8% in years 5-10. A total of eight risk factors were evaluated comprising gender, age at onset of unipolar disorder, number of depressive episodes, treatment resistance to antidepressants, family history of bipolar disorder, the prevalence of psychotic depression, the prevalence of chronic depression, and severity of depression. It was not possible to identify risk factors that were consistently or mainly confirmed to predict conversion across studies. CONCLUSIONS: The conversion rate from unipolar to bipolar disorder decreases with time. It was not possible to identify predictors of conversion that were consistently or mainly confirmed across studies, which may be due to variations in methodology across studies. PMID- 28714576 TI - Metal-Organic Framework-Derived FeCo-N-Doped Hollow Porous Carbon Nanocubes for Electrocatalysis in Acidic and Alkaline Media. AB - Metal-organic frameworks (MOFs) are ideal precursors/ templates for porous carbons with homogeneous doping of active components for energy storage and conversion applications. Herein, metalloporphyrinic MOFs, PCN-224-FeCo, with adjustable molar ratio of FeII /CoII alternatively residing inside the porphyrin center, were employed as precursors to afford FeCo-N-doped porous carbon (denoted as FeCo-NPC) by pyrolysis. Thanks to the hollow porous structure, the synergetic effect between highly dispersed FeNx and CoNx active sites accompanied with a high degree of graphitization, the optimized FeCo2 -NPC-900 obtained by pyrolysis at 900 degrees C exhibits more positive half-wave potential, higher diffusion limited current density, and better stability than the state-of-the-art Pt/C, under both alkaline and acidic media. More importantly, the current synthetic approach based on MOFs offers a rational strategy to structure- and composition controlled porous carbons for efficient electrocatalysis. PMID- 28714577 TI - Direct Laser Interference Patterning of CoCr Alloy Surfaces to Control Endothelial Cell and Platelet Response for Cardiovascular Applications. AB - The main drawbacks of cardiovascular bare-metal stents (BMS) are in-stent restenosis and stent thrombosis as a result of an incomplete endothelialization after stent implantation. Nano- and microscale modification of implant surfaces is a strategy to recover the functionality of the artery by stimulating and guiding molecular and biological processes at the implant/tissue interface. In this study, cobalt-chromium (CoCr) alloy surfaces are modified via direct laser interference patterning (DLIP) in order to create linear patterning onto CoCr surfaces with different periodicities (~3, 10, 20, and 32 um) and depths (~20 and 800 nm). Changes in surface topography, chemistry, and wettability are thoroughly characterized before and after modification. Human umbilical vein endothelial cells' adhesion and spreading are similar for all patterned and plain CoCr surfaces. Moreover, high-depth series induce cell elongation, alignment, and migration along the patterned lines. Platelet adhesion and aggregation decrease in all patterned surfaces compared to CoCr control, which is associated with changes in wettability and oxide layer characteristics. Cellular studies provide evidence of the potential of DLIP topographies to foster endothelialization without enhancement of platelet adhesion, which will be of high importance when designing new BMS in the future. PMID- 28714578 TI - Efficacy and Initial Safety Profile of CXCL12 Treatment in a Rodent Model of Urinary Sphincter Deficiency. AB - Disappointing results of skeletal muscle precursor cell (skMPC) therapy for women with intrinsic urinary sphincter deficiency (ISD) associated urinary incontinence has increased interest in alternative sphincter regenerative approaches. This study was to measure the safety and efficacy of the cell homing chemokine CXCL12 versus skMPCs in a rat model of ISD. Thirty-six adult female Sprague Dawley rats were divided into 6 treatment (Tx) conditions: (a) no ISD/noTx [Control]; (b) ISD/noTx; (c) ISD + skMPCs; (d) ISD + 3.5 mg CXCL12; (e) ISD + 7mg CXCL12; and (f) ISD + 14 mg CXCL12. Tx's were injected directly into the sphincter complex 30 days post ISD and rats euthanized 30 days post Tx. Blood samples for measurements of kidney and liver function, white and red blood cell counts, were taken at baseline and at euthanasia. Leak point pressures (LPP) were measured prior to, and sphincter collagen/muscle content measured after, euthanasia. There were no effects of treatments on white or red/white blood cell counts, kidney/liver function tests or histopathology of the urinary sphincter complex or surrounding tissues. ISD lowered LPP 35% and sphincter muscle content by 17% versus control rats. CXCL12, but not skMPC injections, restored both LPP to control values in a dose-dependent fashion. Both skMPCs and CXCL12 restored sphincter muscle content to control values. This chemokine approach may represent a novel therapeutic option for ISD and appears, at least short-term, to produce little clinical or tissue pathology. Stem Cells Translational Medicine 2017;6:1740-1746. PMID- 28714579 TI - History of the Parkinson's foundation: Looking after patient needs and promoting research. PMID- 28714580 TI - Differential failure to deactivate the default mode network in unipolar and bipolar depression. AB - OBJECTIVES: Neuroimaging studies have revealed evidence of brain functional abnormalities in bipolar depressive disorder (BDD) and major depressive disorder (MDD). However, few studies to date have compared these two mood disorders directly. METHODS: Matched groups of 26 BDD type I patients, 26 MDD patients and 26 healthy controls underwent functional magnetic resonance imaging (fMRI) while performing the n-back working memory task. A whole-brain ANOVA was used to compare the three groups and clusters of significant difference were examined further using region-of-interest (ROI) analysis. RESULTS: The whole-brain ANOVA revealed a single cluster of significant difference in the medial frontal cortex. The BDD and MDD patients both showed failure to deactivate in this area compared to the controls. The BDD patients showed significantly greater failure of deactivation than the MDD patients, which was not accounted for by differences in severity or chronicity of illness between them. CONCLUSIONS: Failure of deactivation, considered to reflect default mode network dysfunction, is present to a greater extent in bipolar than unipolar depression. The study of this network may be useful in the search for brain markers that distinguish the two disorders. PMID- 28714581 TI - Psychometric Evaluation and Norms for the Multidimensional Assessment of Interoceptive Awareness (MAIA) in a Clinical Eating Disorders Sample. AB - Altered interoceptive awareness (IA) has been implicated in the pathophysiology of eating disorders; however, few comprehensive self-report measures of IA exist in eating disorders. The present study sought to validate the Multidimensional Assessment of Interoceptive Awareness (MAIA), originally developed to assess IA in individuals practicing mind-body therapies, in an eating disorder sample. Adult and adolescent patients (n = 376) completed assessments upon admission to a partial hospital programme. Analyses examined the factor structure of the MAIA, scale means, scale-scale correlations, internal consistency and construct validity. Analyses also examined associations between MAIA subscales and eating disorder symptoms. Results supported the original eight-factor structure of the MAIA. Internal consistency was acceptable, and the scales converged with associated measures. Importantly, Not Distracting, Self-regulation, Body Listening and Trusting were most strongly associated with eating disorder symptoms. Results support use of the MAIA among eating disorders and provide further support for the relevance of IA in eating disorders. Copyright (c) 2017 John Wiley & Sons, Ltd and Eating Disorders Association. PMID- 28714582 TI - Altered levels of soluble CD18 may associate immune mechanisms with outcome in sepsis. AB - The pathogenesis of sepsis involves a dual inflammatory response, with a hyperinflammatory phase followed by, or in combination with, a hypoinflammatory phase. The adhesion molecules lymphocyte function-associated antigen (LFA-1) (CD11a/CD18) and macrophage-1 (Mac-1) (CD11b/CD18) support leucocyte adhesion to intercellular adhesion molecules and phagocytosis through complement opsonization, both processes relevant to the immune response during sepsis. Here, we investigate the role of soluble (s)CD18 in sepsis with emphasis on sCD18 as a mechanistic biomarker of immune reactions and outcome of sepsis. sCD18 levels were measured in 15 septic and 15 critically ill non-septic patients. Fifteen healthy volunteers served as controls. CD18 shedding from human mononuclear cells was increased in vitro by several proinflammatory mediators relevant in sepsis. sCD18 inhibited cell adhesion to the complement fragment iC3b, which is a ligand for CD11b/CD18, also known as Mac-1 or complement receptor 3. Serum sCD18 levels in sepsis non-survivors displayed two distinct peaks permitting a partitioning into two groups, namely sCD18 'high' and sCD18 'low', with median levels of sCD18 at 2158 mU/ml [interquartile range (IQR) 2093-2811 mU/ml] and 488 mU/ml (IQR 360 617 mU/ml), respectively, at the day of intensive care unit admission. Serum sCD18 levels partitioned sepsis non-survivors into one group of 'high' sCD18 and low CRP and another group with 'low' sCD18 and high C-reactive protein. Together with the mechanistic data generated in vitro, we suggest the partitioning in sCD18 to reflect a compensatory anti-inflammatory response syndrome and hyperinflammation, respectively, manifested as part of sepsis. PMID- 28714583 TI - Mapping social-ecological vulnerability to inform local decision making. AB - An overarching challenge of natural resource management and biodiversity conservation is that relationships between people and nature are difficult to integrate into tools that can effectively guide decision making. Social ecological vulnerability offers a valuable framework for identifying and understanding important social-ecological linkages, and the implications of dependencies and other feedback loops in the system. Unfortunately, its implementation at local scales has hitherto been limited due at least in part to the lack of operational tools for spatial representation of social-ecological vulnerability. We developed a method to map social-ecological vulnerability based on information on human-nature dependencies and ecosystem services at local scales. We applied our method to the small-scale fishery of Moorea, French Polynesia, by combining spatially explicit indicators of exposure, sensitivity, and adaptive capacity of both the resource (i.e., vulnerability of reef fish assemblages to fishing) and resource users (i.e., vulnerability of fishing households to the loss of fishing opportunity). Our results revealed that both social and ecological vulnerabilities varied considerably through space and highlighted areas where sources of vulnerability were high for both social and ecological subsystems (i.e., social-ecological vulnerability hotspots) and thus of high priority for management intervention. Our approach can be used to inform decisions about where biodiversity conservation strategies are likely to be more effective and how social impacts from policy decisions can be minimized. It provides a new perspective on human-nature linkages that can help guide sustainability management at local scales; delivers insights distinct from those provided by emphasis on a single vulnerability component (e.g., exposure); and demonstrates the feasibility and value of operationalizing the social-ecological vulnerability framework for policy, planning, and participatory management decisions. PMID- 28714585 TI - Mathematical model of collective cell migrations based on cell polarity. AB - Individual cells migrate toward the direction of the cell polarity generated by interior or exterior factors. Under situations without guides such as chemoattractants, they migrate randomly. On the other hand, it has been observed that cell groups lead to systematic collective cell migrations. For example, Dictyostelium discoideum and Madin-Darby canine kidney (epithelial) cells exhibit typical collective cell migration patterns such as uniformly directional migration and rotational migration. In particular, it has been suggested from experimental investigations that rotational migrations are intimately related to morphogenesis of organs and tissues in several species. Thus, it is conjectured that collective cell migrations are controlled by universal mechanisms of cells. In this paper, we review actual experimental data related to collective cell migrations on dishes and show that our self-propelled particle model based on the cell polarity can accurately represent actual migration behaviors. Furthermore, we show that collective cell migration modes observed in our model are robust. PMID- 28714584 TI - Oscillations during observations: Dynamic oscillatory networks serving visuospatial attention. AB - The dynamic allocation of neural resources to discrete features within a visual scene enables us to react quickly and accurately to salient environmental circumstances. A network of bilateral cortical regions is known to subserve such visuospatial attention functions; however the oscillatory and functional connectivity dynamics of information coding within this network are not fully understood. Particularly, the coding of information within prototypical attention network hubs and the subsecond functional connections formed between these hubs have not been adequately characterized. Herein, we use the precise temporal resolution of magnetoencephalography (MEG) to define spectrally specific functional nodes and connections that underlie the deployment of attention in visual space. Twenty-three healthy young adults completed a visuospatial discrimination task designed to elicit multispectral activity in visual cortex during MEG, and the resulting data were preprocessed and reconstructed in the time-frequency domain. Oscillatory responses were projected to the cortical surface using a beamformer, and time series were extracted from peak voxels to examine their temporal evolution. Dynamic functional connectivity was then computed between nodes within each frequency band of interest. We find that visual attention network nodes are defined functionally by oscillatory frequency, that the allocation of attention to the visual space dynamically modulates functional connectivity between these regions on a millisecond timescale, and that these modulations significantly correlate with performance on a spatial discrimination task. We conclude that functional hubs underlying visuospatial attention are segregated not only anatomically but also by oscillatory frequency, and importantly that these oscillatory signatures promote dynamic communication between these hubs. Hum Brain Mapp 38:5128-5140, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28714587 TI - Stretchable Dry Electrodes with Concentric Ring Geometry for Enhancing Spatial Resolution in Electrophysiology. AB - The multichannel concentric-ring electrodes are stencil printed on stretchable elastomers modified to improve adhesion to skin and minimize motion artifacts for electrophysiological recordings of electroencephalography, electromyography, and electrocardiography. These dry electrodes with a poly(3,4-ethylenedioxythiophene) polystyrene sulfonate interface layer are optimized to show lower noise level than that of commercial gel disc electrodes. The concentric ring geometry enables Laplacian filtering to pinpoint the bioelectric potential source with spatial resolution determined by the ring distance. This work shows a new fabrication approach to integrate and create designs that enhance spatial resolution for high quality electrophysiology monitoring devices. PMID- 28714588 TI - Cellular force assay detects altered contractility caused by a nephritis associated mutation in nonmuscle myosin IIA. AB - Recent progress in understanding the essential roles of mechanical forces in regulating various cellular processes expands the field of biology to one where interdisciplinary approaches with engineering techniques become indispensable. Contractile forces or contractility-inherently present in proliferative cells due to the activity of ubiquitous nonmuscle myosin II (NMII)-are one of such mechano regulators, but because NMII works downstream of diverse signaling pathways, it is often difficult to predict how the inherent cellular forces change upon perturbations to particular molecules. Here, we determine whether the contractility of individual cells is upregulated or downregulated based on an assay analyzing specific deformations of silicone gel substrates. We focus on the effect of mutations in the human MYH9 gene that encodes NMIIA, which have been implicated in the pathogenesis of various diseases including nephritis. Our assay equipped with a high-throughput data analysis capability reveals that a point mutation of E1841K but not I1816V significantly reduces the magnitude of the endogenous forces of human embryonic kidney (HEK293) cells. Given the increasingly recognized roles of the endogenous forces as a critical mechano regulator as well as that no apparent morphological changes were induced to cells even by introducing the mutations, our findings suggest a possibility that the detected reduction in the force magnitude at the individual cellular level may underlie the pathogenesis of the kidney disease. PMID- 28714586 TI - Activation of autophagy is involved in the protective effect of 17beta-oestradiol on endotoxaemia-induced multiple organ dysfunction in ovariectomized rats. AB - Oestrogens have been reported to attenuate acute inflammation in sepsis. In this study, the effects of long-term oestrogen replacement with 17beta-oestradiol (E2 ) on endotoxaemia-induced circulatory dysfunction and multiple organ dysfunction syndrome were evaluated in ovariectomized (Ovx) rats. E2 (50 MUg/kg, s.c., 3 times/week) was administered for 8 weeks, followed by the induction of endotoxaemia by intravenous infusion of lipopolysaccharides (LPS; 30 mg/kg/4 hrs). Oestrogen deficiency induced by ovariectomy for 9 weeks augmented the LPS induced damage, including endotoxic shock, myocardial contractile dysfunction, renal dysfunction and rhabdomyolysis. Cardiac levels of NF-kappaB p65, iNOS and oxidized glutathione, free radical production in skeletal muscles, myoglobin deposition in renal tubules, and plasma levels of plasminogen activator inhibitor 1, TNF-alpha, and IL-6 were more pronounced in the Ovx + LPS group than in the Sham + LPS group. Long-term treatment of E2 prevented this amplified damage in Ovx rats. Six hours after LPS initiation, activation of the autophagic process, demonstrated by increases in Atg12 and LC3B-II/LC3B-I ratios, and induction of haem oxygenase (HO)-1 and heat-shock protein (HSP) 70 protein expression in myocardium were increased significantly in the Ovx + E2 + LPS group. These results suggest that activation of autophagy and induction of HO-1 and HSP70 contribute to the protective effect of long-term E2 replacement on multiple organ dysfunction syndrome in endotoxaemia. PMID- 28714590 TI - Adaptive testing for association between two random vectors in moderate to high dimensions. AB - Testing for association between two random vectors is a common and important task in many fields, however, existing tests, such as Escoufier's RV test, are suitable only for low-dimensional data, not for high-dimensional data. In moderate to high dimensions, it is necessary to consider sparse signals, which are often expected with only a few, but not many, variables associated with each other. We generalize the RV test to moderate-to-high dimensions. The key idea is to data adaptively weight each variable pair based on its empirical association. As the consequence, the proposed test is adaptive, alleviating the effects of noise accumulation in high-dimensional data, and thus maintaining the power for both dense and sparse alternative hypotheses. We show the connections between the proposed test with several existing tests, such as a generalized estimating equations-based adaptive test, multivariate kernel machine regression (KMR), and kernel distance methods. Furthermore, we modify the proposed adaptive test so that it can be powerful for nonlinear or nonmonotonic associations. We use both real data and simulated data to demonstrate the advantages and usefulness of the proposed new test. The new test is freely available in R package aSPC on CRAN at https://cran.r-project.org/web/packages/aSPC/index.html and https://github.com/jasonzyx/aSPC. PMID- 28714589 TI - MEG biomarker of Alzheimer's disease: Absence of a prefrontal generator during auditory sensory gating. AB - Magnetoencephalography (MEG), a direct measure of neuronal activity, is an underexplored tool in the search for biomarkers of Alzheimer's disease (AD). In this study, we used MEG source estimates of auditory gating generators, nonlinear correlations with neuropsychological results, and multivariate analyses to examine the sensitivity and specificity of gating topology modulation to detect AD. Our results demonstrated the use of MEG localization of a medial prefrontal (mPFC) gating generator as a discrete (binary) detector of AD at the individual level and resulted in recategorizing the participant categories in: (1) controls with mPFC generator localized in response to both the standard and deviant tones; (2) a possible preclinical stage of AD participants (a lower functioning group of controls) in which mPFC activation was localized to the deviant tone only; and (3) symptomatic AD in which mPFC activation was not localized to either the deviant or standard tones. This approach showed a large effect size (0.9) and high accuracy, sensitivity, and specificity (100%) in identifying symptomatic AD patients within a limited research sample. The present results demonstrate high potential of mPFC activation as a noninvasive biomarker of AD pathology during putative preclinical and clinical stages. Hum Brain Mapp 38:5180-5194, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28714591 TI - Experimental evolution with a multicellular host causes diversification within and between microbial parasite populations-Differences in emerging phenotypes of two different parasite strains. AB - Host-parasite coevolution is predicted to have complex evolutionary consequences, potentially leading to the emergence of genetic and phenotypic diversity for both antagonists. However, little is known about variation in phenotypic responses to coevolution between different parasite strains exposed to the same experimental conditions. We infected Caenorhabditis elegans with one of two strains of Bacillus thuringiensis and either allowed the host and the parasite to experimentally coevolve (coevolution treatment) or allowed only the parasite to adapt to the host (one-sided parasite adaptation). By isolating single parasite clones from evolved populations, we found phenotypic diversification of the ancestral strain into distinct clones, which varied in virulence toward ancestral hosts and competitive ability against other parasite genotypes. Parasite phenotypes differed remarkably not only between the two strains, but also between and within different replicate populations, indicating diversification of the clonal population caused by selection. This study highlights that the evolutionary selection pressure mediated by a multicellular host causes phenotypic diversification, but not necessarily with the same phenotypic outcome for different parasite strains. PMID- 28714592 TI - Optimized Solid-Phase-Assisted Synthesis of Oleic Acid Containing siRNA Nanocarriers. AB - Cationic lipo-oligomers containing unsaturated oleic acid are potent siRNA carriers based on electrostatic and hydrophobic lipo-polyplex formation and endosomal membrane destabilization. Lipo-oligomers can be produced by solid-phase supported synthesis in sequence-defined form. However, the trifluoroacetic acid (TFA)-mediated removal of acid-labile protecting groups and cleavage from the resin can be accompanied by side products caused by the addition of TFA to the double bonds of oleic acid. Under aqueous conditions, these TFA adducts of oleic acid are converted into hydroxystearic acid derivatives. The cleavage protocol was optimized to decrease TFA adducts. The pure oleic acid (C18:1) containing lipo-oligomer was compared with analogous structures containing saturated or modified hydrophobic moieties (stearic acid (C18:0), hydroxystearic acid, and 8 nonanamidooctanoic acid). The structure containing intact oleic acid shows favorable pH dependency of lytic activity, efficient gene silencing, and excellent cell tolerability relative to its counterparts. PMID- 28714594 TI - Neural correlates of heart rate variability in PTSD during sub- and supraliminal processing of trauma-related cues. AB - BACKGROUND: Posttraumatic stress disorder (PTSD) is characterized by dysregulated arousal and altered cardiac autonomic response as evidenced by decreased high frequency heart rate variability (HF-HRV), an indirect measure of parasympathetic modulation of the heart. Indeed, subtle threatening cues can cause autonomic dysregulation, even without explicit awareness of the triggering stimulus. Accordingly, examining the neural underpinnings associated with HF-HRV during both sub- and supraliminal exposure to trauma-related cues is critical to an enhanced understanding of autonomic nervous system dysfunction in PTSD. METHODS: We compared neural activity in brain regions associated with HF-HRV in PTSD (n = 18) and healthy controls (n = 18) during exposure to sub- and supraliminal processing of personalized trauma-related words. RESULTS: As compared to controls, PTSD exhibited decreased HF-HRV reactivity in response to sub- and supraliminal cues. Notably, during subliminal processing of trauma-related versus neutral words, as compared to controls, PTSD showed decreased neural response associated with HF-HRV within the left dorsal anterior insula. By contrast, during supraliminal processing of trauma-related versus neutral words, decreased neural activity associated with HF-HRV within the posterior insula/superior temporal cortex, and increased neural activity associated with HF-HRV within the left centromedial amygdala was observed in PTSD as compared to controls. CONCLUSIONS: Impaired parasympathetic modulation of autonomic arousal in PTSD appears related to altered activation of cortical and subcortical regions involved in the central autonomic network. Interestingly, both sub- and supraliminal trauma-related cues appear to elicit dysregulated arousal and may contribute to the maintenance of hyperarousal in PTSD. Hum Brain Mapp 38:4898 4907, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28714593 TI - Free water improves detection of changes in the substantia nigra in parkinsonism: A multisite study. AB - BACKGROUND: Imaging markers that are sensitive to parkinsonism across multiple sites are critically needed for clinical trials. The objective of this study was to evaluate changes in the substantia nigra using single- and bi-tensor models of diffusion magnetic resonance imaging in PD, MSA, and PSP. METHODS: The study cohort (n = 425) included 107 healthy controls and 184 PD, 63 MSA, and 71 PSP patients from 3 movement disorder centers. Bi-tensor free water, free-water corrected fractional anisotropy, free-water-corrected mean diffusivity, single tensor fractional anisotropy, and single-tensor mean diffusivity were computed for the anterior and posterior substantia nigra. Correlations were computed between diffusion MRI measures and clinical measures. RESULTS: In the posterior substantia nigra, free water was greater for PSP than MSA and PD patients and controls. PD and MSA both had greater free water than controls. Free-water corrected fractional anisotropy values were greater for PSP patents than for controls and PD patients. PSP and MSA patient single-tensor mean diffusivity values were greater than controls, and single-tensor fractional anisotropy values were lower for PSP patients than for healthy controls. The parkinsonism effect size for free water was 0.145 in the posterior substantia nigra and 0.072 for single-tensor mean diffusivity. The direction of correlations between single tensor mean diffusivity and free-water values and clinical scores was similar at each site. CONCLUSIONS: Free-water values in the posterior substantia nigra provide a consistent pattern of findings across patients with PD, MSA, and PSP in a large cohort across 3 sites. Free water in the posterior substantia nigra relates to clinical measures of motor and cognitive symptoms in a large cohort of parkinsonism. (c) 2017 International Parkinson and Movement Disorder Society. PMID- 28714596 TI - Multifunctional Nanotube-Mucoadhesive Poly(methyl vinyl ether-co-maleic acid)@Hydroxypropyl Methylcellulose Acetate Succinate Composite for Site-Specific Oral Drug Delivery. AB - An advanced oral drug delivery system that can effectively deliver drugs with poor oral bioavailability is strongly desirable. Herein, a multifunctional nano in-micro structured composite is developed by encapsulation of the mucoadhesive poly(methyl vinyl ether-co-maleic acid) modified halloysite nanotubes (HNTs) with the pH-responsive hydroxypropyl methylcellulose acetate succinate by the microfluidics to control the drug release, increase cell-particle interaction, and improve drug absorption. The microparticles show spherical shape, homogeneous particle size distribution (58 +/- 1 um), and pH-responsive dissolution behavior at pH > 6, and they prevent the premature release of curcumin in simulated pH conditions of the stomach and immediately release the curcumin in simulated pH conditions of the small intestine. The surface modification of HNT with mucoadhesive poly(methyl vinyl ether-co-maleic acid) significantly enhances its interactions with the intestinal Caco-2/HT29-MTX cells and the mouse small intestines, and increases the permeability of curcumin across the co-cultured Caco-2/HT29-MTX cell monolayers by about 13 times compared to the free curcumin. Therefore, the developed multifunctional nanotube-mucoadhesive poly(methyl vinyl ether-co-maleic acid)@hydroxypropyl methylcellulose acetate succinate composite is a promising oral drug delivery system for drugs with poor oral bioavailability. PMID- 28714595 TI - Telocytes in normal and keratoconic human cornea: an immunohistochemical and transmission electron microscopy study. AB - Telocytes (TC) are typically defined as cells with telopodes by their ultrastructural features. Their presence was reported in the interstitium of various organs in vertebrates, including humans. However, no study has yet described the presence of TC in the human eye and in particular, within the stromal compartment of the cornea. To address this issue, samples of normal and pathologic (keratoconic) human corneas were tested by immunohistochemistry for CD34, platelet-derived growth factor receptor alpha (PDGFRalpha) and c-kit/CD117 or examined by transmission electron microscopy. We found that TC coexpressing CD34 and PDGFRalpha were distributed throughout the whole normal corneal stroma with different TC subtypes being distinguishable on the basis of the expression of the stemness marker c-kit (i.e. c-kit-positive and c-kit-negative TC subpopulations). Transmission electron microscopy examination confirmed the existence of spindle-shaped and bipolar TC typically displaying two long and thin moniliform telopodes establishing intercellular contacts formed by gap junctions. Keratoconic corneas were characterized by ultrastructural damages and patchy loss of TC with an almost complete depletion of the c-kit-positive TC subpopulation. We propose that TC may contribute to the maintenance of corneal stromal homoeostasis and that, in particular, the c-kit-positive TC subtype might have stemness capacity participating in corneal regeneration and repair processes. Further studies are needed to clarify the differential roles of corneal TC subtypes as well as the possible therapeutic applications of TC in degenerative corneal disorders such as keratoconus. PMID- 28714600 TI - Phytic acid induced three-dimensional graphene for the enrichment of phthalate esters from bottled water and sports beverage samples. AB - A three-dimensional graphene was synthesized through a hydrothermal reaction of graphene oxide with phytic acid. The microstructure and morphology of the phytic acid induced three-dimensional graphene were investigated by nitrogen adsorption desorption isotherms, scanning electron microscopy, and transmission electron microscopy. With a large surface area and three-dimensional structure, the graphene was used as the solid-phase extraction adsorbent for the extraction of phthalate esters from bottled water and sports beverage samples before high performance liquid chromatographic analysis. The results indicated that the graphene was efficient for the solid-phase extraction of phthalate esters. The limits of detection (S/N = 3) of the method for the analytes were 0.02-0.03 ng/mL for the water samples and 0.03-0.15 ng/mL for the sports beverage sample. The limits of quantitation (S/N = 9) for the analytes were 0.06-0.09 ng/mL for water samples and 0.09-0.45 ng/mL for sports beverage sample. The calibration curves for the phthalate esters by the method had a good linearity from 0.1 to 80.0 ng/mL with correlation coefficients larger than 0.9997. The recoveries of the analytes for the method fell in the range of 86.7-116.2% with the relative standard deviations between 1.5 and 6.8%. PMID- 28714599 TI - The utility of empirically assigning ancestry groups in cross-population genetic studies of addiction. AB - BACKGROUND AND OBJECTIVES: Given moderate heritability and significant heterogeneity among addiction phenotypes, successful genome-wide association studies (GWAS) are expected to need very large samples. As sample sizes grow, so can genetic diversity leading to challenges in analyzing these data. Methods for empirically assigning individuals to genetically informed ancestry groups are needed. METHODS: We describe a strategy for empirically assigning ancestry groups in ethnically diverse GWAS data including extensions of principal component analysis (PCA) and population matching through minimum Mahalanobis distance. We apply these methods to data from Spit for Science (S4S): the University Student Survey, a study following college students longitudinally that includes genetic and environmental data on substance use and mental health (n = 7,603). RESULTS: The genetic-based population assignments for S4S were 48.7% European, 22.5% African, 10.4% Americas, 9.2% East Asian, and 9.2% South Asian descent. Self reported census categories "More than one race" and "Unknown"as well as "Hawaiian/Pacific Islander" and "American-Indian/Native Alaskan" were empirically assigned representing a +9% sample retention over conventional methods. Although there was high concordance between self-reported race and empirical population match (+.924), there was reduction in variance for most ancestry PCs for genetic based population assignments. CONCLUSIONS: We were able to create more genetically homogenous groups and reduce sample and marker loss through cross ancestry meta-analysis, potentially increasing power to detect etiologically relevant variation. Our approach provides a framework for empirically assigning genetic ancestry groups which can be applied to other ethnically diverse genetic studies. SCIENTIFIC SIGNIFICANCE: Given the important public health impact and demonstrable gains in statistical power from studying diverse populations, empirically sound practices for genetic studies are needed. (Am J Addict 2017;26:494-501). PMID- 28714601 TI - CF-related diabetes: Containing the metabolic miscreant of cystic fibrosis. AB - Cystic fibrosis-related diabetes (CFRD) is associated with both an increase in morbidity and mortality in people with cystic fibrosis (CF). With increased screening and improved life expectancy of people with CF, the prevalence of CFRD is expected to rise further. The underlying pathophysiological mechanisms causing glucose intolerance and diabetes in patients with CF are not well understood but both functional and structural abnormalities in islet cells are likely to have key roles. Insulin therapy improves health outcomes in patients with CF. Future research is needed to better understand the mechanisms underlying the development of CFRD and to develop new screening and treatment strategies to minimize the detrimental impact of CFRD on health outcomes in people with CF. PMID- 28714602 TI - Genome-wide identification and characterization of HSP gene superfamily in whitefly (Bemisia tabaci) and expression profiling analysis under temperature stress. AB - Heat shock proteins (HSP) are essential molecular chaperones that play important roles in the stress stimulation of insects. Bemisia tabaci, a phloem feeder and invasive species, can cause extensive crop damage through direct feeding and transmission of plant viruses. Here we employed comprehensive genomics approaches to identity HSP superfamily members in the Middle East Asia Minor 1 whitefly genome. In total, we identified 26 Hsp genes, including three Hsp90, 17 Hsp70, one Hsp60 and five sHSP (small heat shock protein) genes. The HSP gene superfamily of whitefly is expanded compared with the other five insects surveyed here. The gene structures among the same families are relatively conserved. Meanwhile, the motif compositions and secondary structures of BtHsp proteins were predicted. In addition, quantitative polymerase chain reaction analysis showed that the expression patterns of BtHsp gene superfamily were diverse across different tissues of whiteflies. Most Hsp genes were induced or repressed by thermal stress (40 degrees C) and cold treatment (4 degrees C) in whitefly. Silencing the expression of BtHsp70-6 significantly decreased the survival rate of whitefly under 45 degrees C. All the results showed the Hsps conferred thermo tolerance or cold-tolerance to whiteflies that protect them from being affected by detrimental temperature conditions. Our observations highlighted the molecular evolutionary properties and the response mechanism to temperature assaults of Hsp genes in whitefly. PMID- 28714603 TI - Variations in Neurodevelopmental Outcomes in Children with Prenatal SSRI Antidepressant Exposure. AB - Mood disorders and treatment with selective serotonin reuptake inhibitor (SSRI) antidepressants during pregnancy are common and both pose neurodevelopmental risks. This often makes the decision to treat prenatal depression with pharmacotherapy (i.e., antidepressants) challenging for clinicians and mothers. SSRIs block the reuptake of the neurotransmitter serotonin (5HT) and given its developmental role, it is not inconceivable that early changes in 5HT signaling could have an impact on early brain development. Identifying long-term neurodevelopmental effects of prenatal SSRI exposure is challenging in humans due to difficulties in distinguishing the effect of the drug from mother's mood during pregnancy and everyday environment in which the child lives, all of which contribute to shaping emotional, cognitive, and social development long after birth. In this review, we focus on the long-term neurobehavioral effects in childhood illustrating wide variations in outcomes revealing that some, but not all children appear to be affected by prenatal SSRI exposure. Emerging research reports findings that are beginning to distinguish the impact of genetic factors and the environment from prenatal medication exposure. Future research is needed to identify genetic, maternal, and environmental factors that put some children at developmental risk and others who may even benefit from maternal SSRI treatment. Birth Defects Research 109:909-923, 2017.(c) 2017 Wiley Periodicals, Inc. PMID- 28714604 TI - Antidepressants, Antipsychotics, and Mood Stabilizers in Pregnancy: What Do We Know and How Should We Treat Pregnant Women with Depression. AB - Depression is generally treated with antidepressants, but may often need antipsychotics and mood stabilizers. We discuss the updated data regarding the safety in pregnancy of antidepressants and antipsychotics, except selective serotonin reuptake inhibitors, and their possible impact on the long-term development of the offspring. Several earlier studies demonstrated a slight increase in the rate of major anomalies following maternal tricyclic antidepressant treatment, but most current literature shows their relative safety in pregnancy. Data on the development of the offspring are also reassuring. The antipsychotic drugs are also safe for the developing fetus and do not seem to induce developmental delay. Both groups of drugs may cause perinatal withdrawal symptoms and difficulties in neonatal adaptation. The mood stabilizers, lithium, and several anti-epileptic drugs, may adversely affect the developing embryo and fetus. While valproic acid, carbamazepine, and topiramate are teratogenic and may also affect postnatal development, the newer antiepileptic and mood stabilizers, lamotrigine and levetiracetam, seem to be safe in pregnancy and apparently have no long-term neurodevelopmental damage. Lithium may increase the rate of cardiac anomalies, especially of Ebstein's anomaly, and may warrant a mid-trimester fetal echocardiography. Although data on the development of the offspring are reassuring, we should remember that most studies were carried out during early childhood, at a time when inattention, learning difficulties, behavioral and psychiatric problems are not yet identifiable. When considering medical treatment for depression in women at child-bearing age, we have to weigh the severity of the symptoms and their impact on the developing fetus and child. Birth Defects Research 109:933-956, 2017.(c) 2017 Wiley Periodicals, Inc. PMID- 28714606 TI - Treating Depression during Pregnancy: Are We Asking the Right Questions? AB - BACKGROUND: Major depressive disorder (MDD) is a common complication of pregnancy. Once the diagnosis of MDD is made, the physician must assist the pregnant woman in developing a treatment plan. METHODS: In considering antidepressants, the benefit of medication treatment for maternal disease control must be balanced against the risk of the drug to the developing embryo-fetus. This is an individualized decision depending on the disease characteristics, likelihood of maternal depression response, probability of adverse fetal effects, and patient characteristics and values. RESULTS: There is no "zero risk" solution in caring for the pregnant woman with MDD; both the disorder and the medication present risks to the mother and the embryo-fetus. If the decision to use antidepressant medication during pregnancy is made, the justification is that the disease is associated with greater risk than the treatment. The goal should be remission of symptoms to maximally reduce disease risk to the mother and developing fetus. CONCLUSION: Optimization of selective serotonin reuptake inhibitor dosing during pregnancy dictates several treatment goals: (1) the drug must be at the optimal dose for the woman; that is, the dose that produces the best response with tolerable side effects; (2) a continuous measure of symptoms must be repeated and adjustments to maintain optimal antidepressant efficacy may be required, due to pharmacokinetic changes during pregnancy; and (3) the resolution of pregnancy at birth also requires dose adjustment in accord with the woman's transition to the nonpregnant, breastfeeding state. Birth Defects Research 109:879-887, 2017.(c) 2017 Wiley Periodicals, Inc. PMID- 28714605 TI - Epigenetic Alterations and Prenatal Maternal Depression. AB - Major depressive disorder of the mother affects 6 to 17% of pregnancies worldwide and can lead to negative outcomes, such as preterm delivery and later mental health problems of the child. It has been proposed that developmental programming has long-lasting effects in the offspring that might be mediated by epigenetic mechanisms, such as DNA methylation. Altered stress regulation or impaired immunological function of the mother can potentially affect DNA methylation processes of the fetus, changing gene expression levels in utero. These underlying biological processes can be tested in animal models, where pharmacological experiments using epigenetic drugs can prove causality. Recent human studies show that DNA methylation changes of hypothesis-driven candidate gene regions, such as the promoter of the glucocorticoid receptor and the serotonin transporter, were associated with maternal depression in peripheral tissue samples of newborns' cord blood, infants' saliva, or adults' peripheral blood. In addition, epigenome-wide association studies using blood cells show modest but significant changes in a subset of genes involved in immune functions. These DNA methylation changes were found mainly in enhancers, which point to regulatory effects in gene expression. Limited number of studies using brain tissue showed a significant overlap of differentially methylated genes in the different studies. In conclusion, prenatal maternal depression can induce covalent modifications in the offspring's DNA, which are detectable at birth in leukocytes and could be potentially present in other tissues, consistent with the hypothesis that system-wide epigenetic changes are involved in life-long responses to the psychosocial environment in utero. Birth Defects Research 109:888-897, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28714607 TI - New Insights into How Serotonin Selective Reuptake Inhibitors Shape the Developing Brain. AB - Development passes through sensitive periods, during which plasticity allows for genetic and environmental factors to exert indelible influence on the maturation of the organism. In the context of central nervous system (CNS) development, such sensitive periods shape the formation of neuro-circuits that mediate, regulate, and control behavior. This general mechanism allows for development to be guided by both the genetic blueprint, as well as the environmental context. While allowing for adaptation, such sensitive periods are also windows of vulnerability during which external and internal factors can confer risk to brain disorders by derailing adaptive developmental programs. Our group has been particularly interested in developmental periods that are sensitive to serotonin (5-HT) signaling, and impact behavior and cognition relevant to psychiatry. Specifically, we review a 5-HT-sensitive period that impacts fronto-limbic system development, resulting in cognitive, anxiety, and depression-related behaviors. We discuss preclinical data to establish biological plausibility and mechanistic insights. We also summarize epidemiological findings that underscore the potential public health implications resulting from the current practice of prescribing 5-HT reuptake inhibiting antidepressants during pregnancy. These medications enter the fetal circulation, likely perturb 5-HT signaling in the brain, and may be affecting circuit maturation in ways that parallel our findings in the developing rodent brain. More research is needed to better disambiguate the dual effects of maternal symptoms on fetal and child development from the effects of 5-HT reuptake inhibitors on clinical outcomes in the offspring. Birth Defects Research 109:924-932, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28714608 TI - Selective Serotonin Reuptake Inhibitors during Pregnancy: Do We Have Now More Definite Answers Related to Prenatal Exposure? AB - Despite extensive studies, there still seems to be uncertainty as to the possible reproductive risk of selective serotonin reuptake inhibitors (SSRIs) and selective serotonin norepinephrine reuptake inhibitors (SNRIs) in pregnancy. We, therefore, assess the current data on the risk/benefit of SSRI use in pregnancy. As the neurodevelopmental effects of SSRIs are discussed in another paper in this issue, we will not address the possible neurodevelopmental effects. Special emphasis is given to the newer, large population-based studies. Most studies have shown that the overall risk of major malformations is similar to that in unexposed children, except for some small increased risk for cardiac anomalies. Persistent pulmonary hypertension of the newborn has also been described with a low absolute risk of <1%, less than twice that observed in nonexposed newborns. Poor neonatal adaptation was described in up to 25% of exposed neonates. However, newer population-based studies have also shown similarly high rates among offspring of women with untreated depression. There is a higher risk for psychiatric problems possibly related to the maternal psychiatric disease for which SSRIs were prescribed. Judging from the new population registry-based studies with comparison to disease controls, there seems to be no demonstrable increase in the rate of major anomalies, prematurity, small for gestational age, or miscarriage. Therefore, the risk associated with treatment discontinuation (e.g., higher frequency of relapse, and postpartum depression) appears to outweigh the fetal and neonatal risks of maternal treatment. Thus, following appropriate explanation regarding possible risks, treatment should continue during pregnancy with minimal effective doses. Birth Defects Research 109:898 908, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28714609 TI - Depression and Its Treatment During Pregnancy: Overview and Highlights. PMID- 28714610 TI - Use of Psychotropic Medications in Breastfeeding Women. AB - BACKGROUND: Breastfeeding women who are prescribed with psychotropic medications on a regular basis are often concerned, regarding the possible implications of such treatment on the breastfed infant. A mother's well-being has a direct influence on the well-being of the baby. However, the notorious reputation of psychotropic medications may lead to suboptimal prescribing by the physician and poor adherence by the mother. METHODS: A PubMed search (from 1976 through February 2017) was conducted for commonly used psychotropic drug classes, as well as individual medications commonly prescribed in these classes, along with the MeSH terms "breastfeeding"/"lactation". In each case, we chose studies that describe the pharmacokinetics of passage into breast milk and/or adverse effects in breastfed infants. RESULTS: No large-scale controlled studies regarding the safety of psychotropic medications in breastfeeding mothers were reported. Based on case reports and small studies, most psychotropic medications produce low milk levels and low plasma levels in the infant, while serious adverse effects in the breastfed infant are rarely reported. Safety data for some psychotropic medications are still unavailable. CONCLUSION: According to the data available in the literature to date, most psychotropic medications are expected to produce low levels in breast milk with no clinical importance. Nevertheless, an individual risk-benefit assessment of a proposed treatment should always be performed, as inter-individual differences may have a substantial effect on the breastfeeding infant's response to the treatment. Further studies and additional objective data are needed to consolidate and improve our current knowledge of psychopharmacotherapy in breastfeeding women. Birth Defects Research 109:957-997, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28714613 TI - ? PMID- 28714612 TI - Weaning from long term continuous positive airway pressure or noninvasive ventilation in children. AB - OBJECTIVES: A significant number of children are able to discontinue long term continuous positive airway pressure (CPAP) or noninvasive ventilation (NIV) but the underlying disorders, weaning criteria, and outcome of these children have not been studied. STUDY DESIGN: Retrospective cohort follow up. SUBJECT SELECTION: Consecutive children who were weaned from long term CPAP/NIV between October 2013 and January 2016. METHODOLOGY: Underlying disorders, weaning criteria, and clinical outcome were analyzed. RESULTS: Fifty eight (27%) of the 213 patients on long term CPAP/NIV could be weaned from CPAP/NIV with 50 patients being weaned from CPAP and 8 from NIV. Most patients were young children with upper airway anomalies, Prader Willi syndrome or bronchopulmonary dysplasia. CPAP/NIV was discontinued following spontaneous improvement of sleep-disordered breathing in 33 (57%) patients, upper airway surgery (n = 14, 24%), maxillofacial surgery (n = 6, 11%), neurosurgery (n = 1, 2%), upper airway and neurosurgery (n = 2, 3%), or switch to oxygen therapy (n = 2, 3%). CPAP/NIV was discontinued due to normal nocturnal gas exchange during spontaneous breathing in all patients, with an obstructive apnea-hypopnea index <=6 events/h on a combined poly(somno)graphy in 27 patients. A relapse of obstructive sleep apnea was observed after a median delay of 2 years in six patients who resumed CPAP and in one patient who underwent midface distraction. CONCLUSIONS: Weaning from CPAP/NIV is possible in children treated with long term CPAP/NIV but is highly dependent on the underlying disorder. Spontaneous improvement is possible but most children need specific surgery. Long term follow-up is necessary in children with underlying disorders. PMID- 28714614 TI - [Wearable activity trackers are watching you]. AB - A growing number of people are using wearable activity trackers, collecting a wide array of parameters including vital signs. This data collection, and the occasional abnormal value, will inevitably raise questions in the doctor's office. In order to correctly answer and address potential concerns, physicians should get familiar with those devices' characteristics, prospects and limitations in a medical setting. This article is an introduction to this topic and offers some insights as to how best handle patients' expectations. PMID- 28714611 TI - Mapping targetable inflammation and outcomes with cystic fibrosis biomarkers. AB - Cystic fibrosis is characterized by an overly exuberant neutrophilic inflammatory response to pathogens and other stimuli that starts very early in disease. The overwhelming nature of this response is a primary cause of remodeling and destruction of the airways, suggesting that anti-inflammatory therapies could be beneficial in CF. However, finding therapies that can effectively reduce the inflammatory response without compromising host defenses remains elusive. New approaches towards mapping inflammatory targets promise to aid in developing novel therapeutic strategies and improve outcomes in individuals with CF. PMID- 28714615 TI - [ARNI, new abbreviation for a new class of treatment of heart failure]. AB - ARNI (Angiontensin Receptor Neprilysin Inhibitor) are a new class of drug : the angiotensin and neprilysin inhibitors. This combined effect allows an optimisation of the heart failure treatment by acting on both pathways of the renin-angiotensin-aldosterone and of the natriuretic peptides. LCZ696 is a combined molecule of valsartan and sacubitril and is currently the only one on the market. Its efficacy has been shown in a large randomised trial in 2014, and LCZ696 is now part of the last 2016 European Society of Cardiology guidelines for the management of heart failure. PMID- 28714616 TI - [LifeVest - a novel treatment option prior to implantable cardioverter defibrillator]. AB - Implantable cardioverter defibrillation has taken a predominant place in secondary and primary preventions of sudden rhythmic cardiac death in high-risk patients. However, in certain clinical situations, the implantation of definitive system should be postponed. The LifeVest, a portable external cardiac defibrillator system, has emerged as a novel therapeutic option before a final decision. PMID- 28714618 TI - [Robotic cardiac surgery]. AB - Cardiac surgery has evolved towards less traumatic procedures. Minimal invasive cardiac surgery is a well-established technic offering patients the same level of excellence accomplished with open surgery. Technological evolution has lead to robotic assistance for minimal invasive cardiac surgery, helping surgeons to perform even better in cardiac repairs or reconstructions. PMID- 28714617 TI - [Left atrial appendage occlusion for atrial fibrillation]. AB - Embolic stroke is the most dangerous complication of atrial fibrillation (AF). Oral anticoagulation represents the treatment of choice for thromboembolic (TE) prophylaxis in patients with a CHADS2VASc score >= 1 but is associated with a significant increase in haemorrhagic events. Almost 90 % of thrombi originate in the left atrial appendage. Registries have shown that percutaneous occlusion of this appendage reduces embolic risk and may be considered for TE prophylaxis in patients with a high TE (CHADS2VASc score >= 2) and haemorrhagic (HAS-BLED score >= 3) risk. However, available randomized trials of this technique did not include patients with contraindication to oral anticoagulants. PMID- 28714619 TI - [Intermittent claudication and critical limb ischemia : from diagnosis to management]. AB - In case of atheromatous disease, the practitioner should be part of a multidisciplinary decision due to the associated comorbities. The angiologic assessment is of paramount importance in the diagnosis of peripheral artery disease even when the diagnosis seems clear. Unfortunately the patient is very often straightforward sent to radiological investigations who are faster. In all stages of peripheral artery disease, the medical treatment should be tried first except in case of critical limb ischemia where an invasive approach must be performed for revascularisation. In case of lifestyle-limiting symptoms and only after failure of medical treatment a revascularisation strategy is then indicated. PMID- 28714620 TI - [Management of aortic aneurysms in the endovascular era]. AB - Abdominal aortic aneurysm is a disease seen in the elderly. Without intervention, an aneurysm can rupture which leads to death in most cases. Surgical resection was the gold standard treatment for many years but since two decades, endovascular repair has surged drastically. Less invasive and morbid than open repair, this technique has significantly evolved in the recent years. Nowadays the whole aorta can be treated with endovascular techniques in expert hands. This article presents an overview of different endovascular solutions and innovations in the management of aortic aneurysms. PMID- 28714621 TI - ? PMID- 28714622 TI - ? PMID- 28714624 TI - ? PMID- 28714623 TI - ? PMID- 28714625 TI - ? PMID- 28714627 TI - ? PMID- 28714626 TI - ? PMID- 28714628 TI - ? PMID- 28714629 TI - ? PMID- 28714630 TI - ? PMID- 28714631 TI - [Velopharyngeal insufficiency in children]. AB - Velopharyngeal insufficiency (VPI) represents an incomplete closure between the soft palate and the posterior pharyngeal wall. Its etiology can be anatomical (cleft palate), neurologic, or iatrogenic (after adenoidectomy). The evaluation of a VPI begins with a through speech and language assessment and can be complemented by instrumental investigations. VPI treatment relies on its early identification, followed by a specific speech therapy management. Surgery is performed in case of no improvement with speech therapy or in case of an anatomical defect not allowing the child to improve. IVP management requires a multidisciplinary team. PMID- 28714632 TI - [Diagnosis and management of testicular torsion in children]. AB - Testicular torsion is a true urologic emergency with a bimodal age presentation : the perinatal testicular torsion presenting with a hard, tender or non-tender scrotal mass usually with underlying dark discoloration of the skin and the peripubertal testicular torsion presenting with severe acute testicular pain, vomiting and frequently pain irradiation in the inguinal area, a high riding horizontally positioned testis and absence of the cremasteric reflex. Obtaining a US Doppler must not add unnecessary delay to the urgent surgical treatment which entails detorsion and bilateral orchidopexy. We do not recommend manual detorsion as around 30 % of testis rotate externally. Up to 50 % of patients presenting with a testicular torsion suffered beforehand from intermittent testicular pain episodes. PMID- 28714633 TI - [Ritual circumcision : a society challenge]. AB - Male circumcision is one of the most common surgical procedure in the world. At the world level, 30 % of the men are circumcised. The reasons of circumcisions are ritual for 97 %. The medical circumcisions represent less than 3 %. The non medical circumcision made in the childhood became, these last years, a highly polemical subject entailing deep passionate debates within our societies both on the political and medical point. Our society is in constant changes with the apparition of an undeniable multiculturalism because of the immigrations. The requests of ritual circumcisions are a reality. As specialists of the child or as family doctors, we have to answer it in a professional way by respecting the child and his family, the swiss legislation and the medical ethics. PMID- 28714634 TI - [Pectus excavatumn and carinatum in children and adolescents : what to say, what to do ?] AB - In children presenting with a pectus excavatum (PE) or pectus carinatum (PC) an underlying syndrome including Marfan's syndrome needs to be excluded. In adolescents, severe chest wall deformities may cause cardiac or respiratory problems but most commonly they have a psychological impact. The conservative treatment is a Vacuum Bell for PE, and a Dynamic Compression System for PC ; they play an increasing role in young patients. These devices need to be worn multiple hours per day for several months for an optimal result. Surgery is usually reserved for adolescents. The Nuss procedure for PE, also known as minimal invasive repair of PE offers excellent results. Sterno-chondro-plasty with stabilisation of the sternum with struts clipped to the ribs offers the same good results for PC. In our opinion, a multidisciplinary approach is preferable. PMID- 28714635 TI - [Adolescent idiopathic scoliosis : diagnostic criteria and management]. AB - The rapid growth of the spine during the pubertal spurt requires greater vigilance for the pediatrician at the annual check during this period to detect the occurrence of scoliosis. Before confirming the diagnosis of idiopathic scoliosis, it is imperative to exclude a secondary cause with appropriate history and clinical examination, and in selective cases with additional testing. Any scoliosis detected during growth should be considered potentially progressive and sent to a specialist if it is equal to or exceeds 20 degrees on the X-rays. Radiological changes of more than 5 degrees during a 6 months interval must also motivate an appointment with a specialist. Regular clinical and radiological surveillance, every 6 months, remains imperative to confirm or deny this risk of progression and decide on treatment. PMID- 28714636 TI - [Corrective surgery for lower limb length discrepancy and malalignment in paediatric orthopaedics]. AB - Lower limb length discrepancy and malalignment in paediatric orthopaedics constitute a set of acquired or malformative structural pathologies. These anomalies, which may alter statics of lower limbs, are susceptible to engender an asymmetry of mechanical constraints' distribution across joints, and thus to promote the onset of arthritic phenomenons. The purpose of this review's article is to define the limits of tolerance of the various malformations and describe the innovative techniques available in order to correct them. PMID- 28714637 TI - ? PMID- 28714638 TI - ? PMID- 28714639 TI - ? PMID- 28714640 TI - ? PMID- 28714641 TI - ? PMID- 28714642 TI - ? PMID- 28714643 TI - ? PMID- 28714644 TI - [Dialysis implementation in elderly patients : a difficult clinical choice ?] AB - Prevalence of elderly patients with end-stage kidney disease has increased. Implementation of dialysis does not offer a clear advantage in terms of life expectancy and quality of life compared to a conservative treatment in these patients, especially in emergency and in those with severe comorbidities. The choice between dialysis and supportive care should be based on a shared decision making process between the patient, his family and the caregivers. PMID- 28714645 TI - [Extra-renal manifestations of the autosomal dominant polycystic kidney disease]. AB - Extra-renal complications of autosomal dominant polycystic kidney disease (ADPKD) are often unrecognized. Liver cysts are usually benign, but may cause chronic pain, may interfere with nutrition and may necessitate partial liver resection or even liver transplant. Somatostatin analogs may be an alternative therapy. Cerebral aneurisms are rare, but devastating. They must be investigated in case of positive familial history. Cardiac valvulopathies will be searched for by echocardiography. Abdominal wall herniae are often identified during the physical exam in ADPKD patients. ADPKD patients may present with higher incidence of diverticulitis. Cysts of the seminal vesicle are frequent but are usually asymptomatic. Recognizing extra-renal complications helps improving the overall survival of ADPKD patients. PMID- 28714646 TI - [Biopsy transcriptome in kidney transplantation : ready for primetime ?] AB - Kidney graft biopsy is the main diagnostic tool used in kidney transplantation to classify disease processes. Graft biopsies are performed at a predetermined time (protocol) or by indication. However, they bear limitations including the interobserver variability. Intragraft transcriptomics has taken the center stage in the field of biomarkers research in kidney transplantation as it might improve disease stratification. Although already included in the international Banff classification, clinical transition has yet to be confirmed in external validation studies. Also transcriptomics performance could benefit from association with other omics data. PMID- 28714647 TI - [Therapeutic advances in monoclonal gammopathy-associated renal diseases]. AB - During the last ten years, significant advances have been made in the field of monoclonal gammopathy-associated renal diseases. These have consisted in a better recognition of their pathological and clinical significations and correlation. Furthermore, therapeutic advances have allowed improving the prognosis of B-cell monoclonal proliferations and of the related renal complications. In the peculiar case of the multiple myeloma with severe renal failure requiring dialysis, one can now expect better survival and chance of recovering renal function. PMID- 28714648 TI - [Phosphate binders : What are the recent evidences ?] AB - Hyperphosphatemia is a late complication of chronic kidney disease (CKD). It is a major non-traditional cardiovascular risk factor in CKD. The management of hyperphosphatemia is based on restriction of phosphate intake, phosphate binders and dialysis. Phosphate binders are divided into calcium-based and non-calcium based binders. Recent evidence suggest restricting the dose of calcium-based phosphate binders because of the associated increased mortality in compared to non-calcic ones. New treatments are under development such as inhibitors of kidney or intestinal phosphate absorption. These therapies could improve patients' compliance. PMID- 28714649 TI - [Gender differences in chronic kidney diseases : myth or reality ?] AB - Chronic kidney disease (CKD) concerns about 10 % of the population in Switzerland. Epidemiological studies suggest that women are less prone to the development of CKD than men, and progress less rapidly to end stage renal disease. This protection seems lost when entering menopause. The reasons for this finding may stem from hormonal, structural or hemodynamic differences, yet the precise underlying mechanisms are so far incompletely understood. Some animal studies suggest a potentially beneficial effect of estrogen therapy, mainly in diabetes, yet data in humans are lacking. This article provides an overview of epidemiological data and the different hypotheses concerning gender differences in CKD, and discusses the eventual benefits of estrogen therapy to retard CKD progression. PMID- 28714650 TI - [Stigmatisation : a widespread problem with multiple consequences]. AB - Stigmatisation is a well known social phenomenon based on the discrimination of an individual or a sub-group of individuals by a dominant or majority group. Often discussed in the frame of psychiatry, it is also observed in other domains of medicine. It impacts not only patients, but their relatives and their children, as well as the health professionals taking care of them. Moreover, it is detrimental to the implementation of preventive strategies and induces depressive reactions, loss of self esteem and reduction of patients' quality of life. Finally, it keeps researchers away from certain domains of medicine and has a negative impact on funding for research and treatment. It is therefore important to understand its underlying mechanisms in order to fight it more efficiently. PMID- 28714651 TI - ? PMID- 28714652 TI - ? PMID- 28714653 TI - ? PMID- 28714655 TI - ? PMID- 28714654 TI - ? PMID- 28714656 TI - ? PMID- 28714657 TI - Women with late whiplash syndrome have greatly reduced load-bearing of the cervical spine. In-vivo biomechanical, cross-sectional, lateral radiographic study. AB - BACKGROUND: No study has been conducted to ascertain whether the load-bearing capacity of the cervical spine is reduced in vivo in late whiplash syndrome (LWS). AIM: To compare the segmental cervical angular values across C0-C6, between two conditions: without versus with external axial load upon the head in three groups of women. DESIGN: A single-blind, age-Body Mass Index (BMI) matched, radiographic, cross-sectional study. SETTING: Radiographic Department at a University Hospital. POPULATION: One hundred eighty-two women, aged between 18-50 years were enrolled. METHODS: Participants were divided into 3 groups: a group with LWS (N.=62) and two control groups: a chronic insidious neck pain (IONP) group (N.=60) and an asymptomatic group (N.=60). Prior to and on the same day as the radiographic examination took place, BMI in kg/m2 was recorded and all participants answered the Neck Disability Index (NDI). The two symptomatic groups answered also three other pain and disability questionnaires. RESULTS: Analysis of variance (mixed-model ANOVA) for repeated measures was used for comparison. Significant differences between groups, and the two conditions tested was revealed, but only within the asymptomatic and the IONP groups (P<0.0001), but not within the LWS group (P=0.9433). Unexpectedly the women with LWS adopted a rigid horizontal translation strategy when external load was applied upon their head. The inter-rater and intra-rater segmental measurements were highly reliable. Women with LWS scored significantly higher on all questionnaires. CONCLUSIONS: The results of this study strongly indicate that the load-bearing capacity of the cervical spine is reduced in vivo in women with LWS. The study shows, for the first time, that the cervical spine in women with LWS predominately functions such as a rigid cylinder when loaded. CLINICAL REHABILITATION IMPACT: The study implies that the cervical column is extremely weak in the LWS and that the superficial neck muscles, which are designed to move the head-neck, must compensate and act as rigid stabilizers. This causes great joint reaction forces through the cervical spine and its injured inert structures maintaining the pain and disability, as the results of the questionnaires show. PMID- 28714658 TI - Progressive shoulder-neck exercise on cervical muscle functions in middle-aged and senior patients with chronic neck pain. AB - BACKGROUND: Although neck pain is a common musculoskeletal disorder, there is no consensus on suitable exercise methods for middle-aged and senior patients with chronic neck pain. Therefore, this study investigated the effectiveness of a 6 week shoulder-neck exercise intervention program on cervical muscle function improvement in patients aged 45 years or older with chronic neck pain. AIM: The aim of the present study was to evaluate the effects of progressive shoulder-neck exercise on cervical muscle functions of middle-aged and senior patients with chronic neck pain. DESIGN: A randomized controlled single-blind trial. SETTING: Rehabilitation department of a hospital. POPULATION: A total of 72 subjects aged >=45 years with chronic neck pain were randomly allocated to either an experimental group (N.=36; age 57.3+/-8.74 years) or a control group (N.=36; age 58.15+/-8.17 years). METHODS: The control group received only traditional physiotherapy, whereas the experimental group participated in a 6-week shoulder neck exercise program consisting of cranio-cervical flexion and progressive resistance exercises in addition to receiving traditional physiotherapy. The muscle functions of subjects in both groups were tested before the experiment and also after the intervention program. The pretest and posttest measured the cranio cervical flexion test (CCFT) and the superficial cervical muscle strength. RESULTS: After the intervention, the experimental group had a 56.48 point improvement in the performance index of the CCFT (P<0.001), a 1.71-kg improvement in superficial neck flexor strength (P<0.001), and a 2.52-kg improvement in superficial neck extensor strength (P<0.001), indicating that in 6-week intervention significantly influenced the improvement of cervical muscle functions. CONCLUSIONS: This study confirmed that the 6-week progressive shoulder neck exercise program can effectively improve cervical muscle function in middle aged and senior patients with chronic neck pain. CLINICAL REHABILITATION IMPACT: Progressive shoulder-neck exercise might provide positive effect on deep and superficial neck muscle strength in patients with chronic neck pain. Therefore, this study may serve as a reference for the clinical rehabilitation of patients with chronic neck pain. PMID- 28714659 TI - Are patients referred to rehabilitation diagnosed accurately? AB - BACKGROUND: An accurate diagnosis of the leading health condition and comorbidities is a prerequisite for safe and effective rehabilitation. The problem of diagnostic errors in physical and rehabilitation medicine (PRM) has not been addressed sufficiently. The responsibility of a referring physician is to determine indications and contraindications for rehabilitation. AIM: To assess the rate of and risk factors for inaccurate referral diagnoses (RD) in patients referred to a rehabilitation facility. We hypothesized that inaccurate RD would be more common in patients: 1) referred by non-PRM physicians; 2) waiting longer for the admission; 3) older patients. DESIGN: Retrospective observational study. POPULATION: One thousand randomly selected patients admitted between 2012 and 2016 to a day-rehabilitation center (DRC). SETTING: University DRC specialized in musculoskeletal diseases. METHODS: On admission all cases underwent clinical verification of RD. Inappropriateness regarding primary diagnoses and comorbidities were noted. Influence of several factors affecting probability of inaccurate RD was analyzed with multiple binary regression model applied to 6 categories of diseases. RESULTS: The rate of inaccurate RD was 25.2%. Higher frequency of inaccurate RD was noted among patients referred by non-PRM specialists (30.3% vs. 17.3% in cases referred by PRM specialists). Application of logit regression showed highly significant influence of the specialty of a referring physician on the odds of inaccurate RD (joint Wald Test chi2 (6)=38.98, P value =0.000), controlling for the influence of other variables. This may reflect a suboptimal knowledge of the rehabilitation process and a tendency to neglect of comorbidities by non-PRM specialists. The rate of inaccurate RD did not correlate with time between referral and admission (joint Wald Test of all odds ratios equal to 1, chi2 (6)=5.62, P value =0.467), however, mean and median waiting times were relatively short (35.7 and 25 days respectively). A high risk of overlooked multimorbidity was revealed in elderly patients (all odds ratios for variable age significantly higher than 1). Hypotheses 1 and 3 were confirmed. CONCLUSIONS: Over 25% of patients referred to DRC had inaccurate RD. Risk factors for inaccurate RD include referral by a non-PRM specialist and elderly age. CLINICAL REHABILITATION IMPACT: Verification of RD should be routinely introduced to PRM practice. PMID- 28714660 TI - Maternal mortality in the developed world: a review of surveillance methods, levels and causes of maternal deaths during 2006-2010. AB - This article provides an overview of surveillance methods, levels, and causes of maternal mortality in developed countries, in Europe and the United States, during 2006-2010. Accurate identification of maternal deaths is not always possible, and no two countries in the world use the same surveillance methods for maternal mortality. Despite limitations (e.g. underestimation, misclassification), routine vital registration systems are the backbone of maternal mortality surveillance systems in developed countries. Enhanced surveillance methods involve linkages between deaths of women of reproductive age and births within the preceding year, or the use of additional data sources for maternal deaths. Confidential enquiries into maternal deaths, in place in France, the Netherlands, and the UK are the gold standard in maternal mortality surveillance. Levels of maternal mortality in Europe were the lowest in the world during 2006-2010. While Europe has not seen major changes in maternal mortality in recent years, pregnancy-related mortality increased considerably in the USA, where improvements in the identification of deaths appear to play a part. The triad of infection, hemorrhage, and hypertensive disorders of pregnancy, which in the past accounted for >90% of all maternal deaths, now accounts for 60-70% of such deaths in developed countries. Maternal mortality surveillance provides learning opportunities to prevent future maternal deaths. There is need for integration of linked, multiple data sources into current maternal mortality surveillance systems to improve their utility. PMID- 28714661 TI - Generalizable, Electroless, Template-Assisted Synthesis and Electrocatalytic Mechanistic Understanding of Perovskite LaNiO3 Nanorods as Viable, Supportless Oxygen Evolution Reaction Catalysts in Alkaline Media. AB - The oxygen evolution reaction (OER) is a key reaction for water electrolysis cells and air-powered battery applications. However, conventional metal oxide catalysts, used for high-performing OER, tend to incorporate comparatively expensive and less abundant precious metals such as Ru and Ir, and, moreover, suffer from poor stability. To attempt to mitigate for all of these issues, we have prepared one-dimensional (1D) OER-active perovskite nanorods using a unique, simple, generalizable, and robust method. Significantly, our work demonstrates the feasibility of a novel electroless, seedless, surfactant-free, wet solution based protocol for fabricating "high aspect ratio" LaNiO3 and LaMnO3 nanostructures. As the main focus of our demonstration of principle, we prepared as-synthesized LaNiO3 rods and correlated the various temperatures at which these materials were annealed with their resulting OER performance. We observed generally better OER performance for samples prepared with lower annealing temperatures. Specifically, when annealed at 600 degrees C, in the absence of a conventional conductive carbon support, our as-synthesized LaNiO3 rods not only evinced (i) a reasonable level of activity toward OER but also displayed (ii) an improved stability, as demonstrated by chronoamperometric measurements, especially when compared with a control sample of commercially available (and more expensive) RuO2. PMID- 28714662 TI - Enhancing the Osteogenic Capability of Core-Shell Bilayered Bioceramic Microspheres with Adjustable Biodegradation. AB - This study describes the fabrication and biological evaluation of core-shell bilayered bioceramic microspheres with adjustable compositional distribution via a coaxial bilayer capillary system. Beyond the homogeneous hybrid composites, varying the diameter of capillary nozzles and the composition of the bioceramic slurries makes it easy to create bilayered beta-tricalcium phosphate (CaP)/beta calcium silicate (CaSi) microspheres with controllable compositional distribution in the core or shell layer. Primary investigations in vitro revealed that biodegradation could be adjusted by compositional distribution or shell thickness and that poorly soluble CaP located on the shell layer of CaP or CaSi@CaP microspheres was particularly beneficial for mesenchymal stem cell adhesion and growth in the early stage, but the ion release from the CaP@CaSi exhibited a potent stimulating effect on alkaline phosphatase expression of the cells at longer times. When the bilayered microspheres (CaSi@CaP, CaP@CaSi) and the monolayered microspheres (CaP, CaSi) were implanted into the critical-sized femoral bone defect in rabbit models, significant differences in osteogenic capacity over time were measured at 6-18 weeks post implantation. The CaP microspheres showed the lowest biodegradation rate and slow new bone regeneration, whereas the CaSi@CaP showed a fast degradation of the CaSi core through the porous CaP shell so that a significant osteogenic response was observed at 12-18 weeks. The CaP@CaSi microspheres possessed excellent surface bioactivity and osteogenic activity, whereas the CaSi microspheres group exhibited a poor bone augmentation in the later stage due to extreme biodegradation. These findings demonstrated that the bioactive response in such core-shell-structured bioceramic systems could be adjusted by compositional distribution, and this strategy can be used to fabricate a variety of bioceramic microspheres with adjustable biodegradation rates and enhanced biological response for bone regeneration applications in medicine. PMID- 28714663 TI - Harnessing Hot Electrons from Near IR Light for Hydrogen Production Using Pt-End Capped-AuNRs. AB - Gold nanorods show great potential in harvesting natural sunlight and generating hot charge carriers that can be employed to produce electrical or chemical energies. We show that photochemical reduction of Pt(IV) to Pt metal mainly takes place at the ends of gold nanorods (AuNRs), suggesting photon-induced hot electrons are localized in a time-averaged manner at AuNR ends. To use these hot electrons efficiently, a novel synthetic method to selectively overgrow Pt at the ends of AuNRs has been developed. These Pt-end-capped AuNRs show relatively high activity for the production of hydrogen gas using artificial white light, natural sunlight, and more importantly, near IR light at 976 nm. Tuning of the surface plasmon resonance (SPR) wavelength of AuNRs changes the hydrogen gas production rate, indicating that SPR is involved in hot electron generation and photoreduction of hydrogen ions. This study shows that gold nanorods are excellent for converting low-energy photons into high-energy hot electrons, which can be used to drive chemical reactions at their surfaces. PMID- 28714664 TI - Iron-Doped Nickel Phosphide Nanosheet Arrays: An Efficient Bifunctional Electrocatalyst for Water Splitting. AB - Exploring efficient and earth-abundant electrocatalysts for water splitting is crucial for various renewable energy technologies. In this work, iron (Fe)-doped nickel phosphide (Ni2P) nanosheet arrays supported on nickel foam (Ni1.85Fe0.15P NSAs/NF) are fabricated through a facile hydrothermal method, followed by phosphorization. The electrochemical analysis demonstrates that the Ni1.85Fe0.15P NSAs/NF electrode possesses high electrocatalytic activity for water splitting. In 1.0 M KOH, the Ni1.85Fe0.15P NSAs/NF electrode only needs overpotentials of 106 mV at 10 mA cm-2 and 270 mV at 20 mA cm-2 to drive the hydrogen evolution reaction (HER) and oxygen evolution reaction (OER), respectively. Furthermore, the assembled two-electrode (Ni1.85Fe0.15P NSAs/NF?Ni1.85Fe0.15P NSAs/NF) alkaline water electrolyzer can produce a current density of 10 mA cm-2 at 1.61 V. Remarkably, it can maintain stable electrolysis over 20 h. Thus, this work undoubtedly offers a promising electrocatalyst for water splitting. PMID- 28714665 TI - Correction to Red Emissive Sulfur, Nitrogen Codoped Carbon Dots and Their Application in Ion Detection and Theranostics. PMID- 28714666 TI - Highly Efficient Br-/NO3- Dual-Anion Electrolyte for Suppressing Charging Instabilities of Li-O2 Batteries. AB - The main issues with Li-O2 batteries are the high overpotential at the cathode and the dendrite formation at the anode during charging. Various types of redox mediators (RMs) have been proposed to reduce the charging voltage. However, the RMs tend to lose their activity during cycling owing to not only decomposition reactions but also undesirable discharge (shuttle effect) at the Li metal anode. Moreover, the dendrite growth of the Li metal anode is not resolved by merely adding RMs to the electrolytes. Here we report a simple yet highly effective method to reduce the charge overpotential while protecting the Li metal anode by incorporating LiBr and LiNO3 in a tetraglyme solvent as the electrolyte for Li-O2 cells. The Br-/Br3- couple acts as an RM to oxidize the discharge product Li2O2 at the cathode, whereas the NO3- anion oxidizes the Li metal surface to prevent the shuttle reaction. In this work, we found that both anions work synergistically in the mixed Br-/NO3- electrolyte to dramatically suppress both parasitic reactions and dendrite formation by generating a solid Li2O thin film on the Li metal anode. As a result, the charge voltage was reduced to below 3.6 V over 40 cycles. The O2 evolution during charging was more than 80% of the theoretical value, and CO2 emission during charging was negligible. After cycling, the Li metal anode showed smooth surfaces with no indication of dendrite formation. These observations clearly demonstrate that the Br-/NO3- dual-anion electrolyte can solve the problems associated with both the overpotential at the cathode and the dendrite formation at the anode. PMID- 28714667 TI - Highly Concentrated Seed-Mediated Synthesis of Monodispersed Gold Nanorods. AB - The extremely large optical extinction coefficient of gold nanorods (Au-NRs) enables their use in a diverse array of technologies, rnging from plasmonic imaging, therapeutics and sensors, to large area coatings, filters, and optical attenuators. Development of the latter technologies has been hindered by the lack of cost-effective, large volume production. This is due in part to the low reactant concentration required for symmetry breaking in conventional seed mediated synthesis. Direct scale up of laboratory procedures has limited viability because of excessive solvent volume, exhaustive postsynthesis purification processes, and the generation of large amounts of waste (e.g., hexadecyltrimethylammonium bromide(CTAB)). Following recent insights into the growth mechanism of Au-NRs and the role of seed development, we modify the classic seed-mediated synthesis via temporal control of seed and reactant concentration to demonstrate production of Au-NRs at more than 100-times the conventional concentration, while maintaining independent control and narrow distribution of nanoparticle dimensions, aspect ratio, and volume. Thus, gram scale synthesis of Au-NRs with prescribed aspect ratio and volume is feasible in a 100 mL reactor with 1/100th of organic waste relative to conventional approaches. Such scale-up techniques are crucial to cost-effectively meet the increased demand for large quantities of Au-NRs in emerging applications. PMID- 28714668 TI - Self-Registered Self-Assembly of Block Copolymers. AB - Directed self-assembly (DSA) of block copolymer (BCP) thin films, especially with density multiplication, is one of the most promising options for further improving resolution and throughput in nanolithography. However, controlling defect density has been one of the major hurdles for many DSA applications. Both thermodynamically and kinetically, defect-free patterns favor the use of low density multiplication factors and thinner films, which undermine the promise of enhanced resolution and the formation of robust masks for pattern transfer. Here, we demonstrate a self-registered self-assembly method to enable nearly perfect DSA on loosely defined chemical patterns with high density multiplication factor. Self-registered self-assembly involves two DSA steps. In the first step, an ultrathin BCP blend film is used to obtain vanishingly low defect densities. Concurrently as the film is annealed, preloaded chemical markers separate into the different polymer blocks and graft to the substrate locking in a new chemical contrast pattern with 1:1 feature registration. After thorough removal of the blend film, the remaining self-registered chemical pattern can establish defect free DSA of thick BCP films. PMID- 28714669 TI - Interconnected Hierarchical ZSM-5 with Tunable Acidity Prepared by a Dealumination-Realumination Process: A Superior MTP Catalyst. AB - ZSM-5 that uses TPAOH as a template has an Al-rich exterior and defective Si-rich interior; thus, a simple base leaching selectively removed the Si-rich interior while the Al-rich exterior was protected. This catalyst showed no change in stability comparing with parent ZSM-5 during the MTP reaction that was attributed to the enclosed hollow structure and richly acidic outer shell. A preliminary fluorination, however, both removed defective Si-sites and caused distortion in tetrahedral aluminum that made the outer shell susceptible to alkaline treatment. These distorted tetrahedral Al were mostly leached out by NaOH in 1 min. Furthermore, aluminum in the filtrate was slowly redeposited onto the zeolite, serving as external pore-directing agents to control silicon dissolution from the Si-rich interior. This dealumination-realumination alkaline treatment process led to a higher solid yield and a uniform opened-mesopore structure with mesopores around 13 nm in diameter. This material was characterized by SEM, TEM, N2 adsorption, and mercury porosimetry. In addition, NH3-TPD, OH-IR, 27Al MAS NMR, and 1H MAS NMR results demonstrated that the reinserted Al were unlike the framework Al, contributing less to acidity. The dealumination-realumination process, therefore, was also capable of tuning the acidity of the mesoporous ZSM 5. This mesoporous catalyst exhibited a longer lifetime and a higher propylene selectivity than other catalysts with an enclosed mesopore structure. PMID- 28714671 TI - Facile Method for the Preparation of Covalent Triazine Framework coated Monoliths as Catalyst Support: Applications in C1 Catalysis. AB - A quasi chemical vapor deposition method for the manufacture of well-defined covalent triazine framework (CTF) coatings on cordierite monoliths is reported. The resulting supported porous organic polymer is an excellent support for the immobilization of two different homogeneous catalysts: (1) an IrIIICp*-based catalyst for the hydrogen production from formic acid and (2) a PtII-based catalyst for the direct activation of methane via Periana chemistry. The immobilized catalysts display a much higher activity in comparison with the unsupported CTF operated in slurry because of improved mass transport. Our results demonstrate that CTF-based catalysts can be further optimized by engineering at different length scales. PMID- 28714670 TI - Cross-Linking Furan-Modified Kisspeptin-10 to the KISS Receptor. AB - Chemical cross-linking is well-established for investigating protein-protein interactions. Traditionally, photo cross-linking is used but is associated with problems of selectivity and UV toxicity in a biological context. We here describe, with live cells and under normal growth conditions, selective cross linking of a furan-modified peptide ligand to its membrane-presented receptor with zero toxicity, high efficiency, and spatio-specificity. Furan-modified kisspeptin-10 is covalently coupled to its glycosylated membrane receptor, GPR54(KISS1R). This newly expands the applicability of furan-mediated cross linking not only to protein-protein cross-linking but also to cross-linking in situ. Moreover, in our earlier reports on nucleic acid interstrand cross-linking, furan activation required external triggers of oxidation (via addition of N-bromo succinimide or singlet oxygen). In contrast, we here show, for multiple cell lines, the spontaneous endogenous oxidation of the furan moiety with concurrent selective cross-link formation. We propose that reactive oxygen species produced by NADPH oxidase (NOX) enzymes form the cellular source establishing furan oxidation. PMID- 28714672 TI - Chemical Denaturants Smoothen Ruggedness on the Free Energy Landscape of Protein Folding. AB - To characterize experimentally the ruggedness of the free energy landscape of protein folding is challenging, because the distributed small free energy barriers are usually dominated by one, or a few, large activation free energy barriers. This study delineates changes in the roughness of the free energy landscape by making use of the observation that a decrease in ruggedness is accompanied invariably by an increase in folding cooperativity. Hydrogen exchange (HX) coupled to mass spectrometry was used to detect transient sampling of local energy minima and the global unfolded state on the free energy landscape of the small protein single-chain monellin. Under native conditions, local noncooperative openings result in interconversions between Boltzmann-distributed intermediate states, populated on an extremely rugged "uphill" energy landscape. The cooperativity of these interconversions was increased by selectively destabilizing the native state via mutations, and further by the addition of a chemical denaturant. The perturbation of stability alone resulted in seven backbone amide sites exchanging cooperatively. The size of the cooperatively exchanging and/or unfolding unit did not depend on the extent of protein destabilization. Only upon the addition of a denaturant to a destabilized mutant variant did seven additional backbone amide sites exchange cooperatively. Segmentwise analysis of the HX kinetics of the mutant variants further confirmed that the observed increase in cooperativity was due to the smoothing of the ruggedness of the free energy landscape of folding of the protein by the chemical denaturant. PMID- 28714673 TI - Direct Monitoring of Exogenous gamma-Hydroxybutyric Acid in Body Fluids by NMR Spectroscopy. AB - gamma-Hydroxybutyric acid (GHB) is a popular drug increasingly associated with cases of drug-facilitated sexual assault (DFSA). Currently, expanding procedures of analysis and having forensic evidence of GHB intake in a long term are mandatory. Up to now, most studies have been performed using GC/MS and LC-MS as analytical platforms, which involve significant manipulation of the sample and, often, indirect measurements. In this work, procedures used in NMR-based metabolomics were applied to a GHB clinical trial on urine and serum. Detection, identification, and quantification of the drug by NMR methods were surveyed, as well as the use of NMR-based metabolomics for the search of potential surrogate biomarkers of GHB consumption. Results demonstrated the suitability of NMR spectroscopy, as a robust nondestructive technique, to fast and directly monitor (detect, identify, and quantify) exogenous GHB in almost intact body fluids and its high potential in the search for metabolites associated with GHB intake. PMID- 28714674 TI - Characterization of Chemical Exchange Using Relaxation Dispersion of Hyperpolarized Nuclear Spins. AB - Chemical exchange phenomena are ubiquitous in macromolecules, which undergo conformational change or ligand complexation. NMR relaxation dispersion (RD) spectroscopy based on a Carr-Purcell-Meiboom-Gill pulse sequence is widely applied to identify the exchange and measure the lifetime of intermediate states on the millisecond time scale. Advances in hyperpolarization methods improve the applicability of NMR spectroscopy when rapid acquisitions or low concentrations are required, through an increase in signal strength by several orders of magnitude. Here, we demonstrate the measurement of chemical exchange from a single aliquot of a ligand hyperpolarized by dissolution dynamic nuclear polarization (D-DNP). Transverse relaxation rates are measured simultaneously at different pulsing delays by dual-channel 19F NMR spectroscopy. This two-point measurement is shown to allow the determination of the exchange term in the relaxation rate expression. For the ligand 4-(trifluoromethyl)benzene-1 carboximidamide binding to the protein trypsin, the exchange term is found to be equal within error limits in neutral and acidic environments from D-DNP NMR spectroscopy, corresponding to a pre-equilibrium of trypsin deprotonation. This finding illustrates the capability for determination of binding mechanisms using D-DNP RD. Taking advantage of hyperpolarization, the ligand concentration in the exchange measurements can reach on the order of tens of MUM and protein concentration can be below 1 MUM, i.e., conditions typically accessible in drug discovery. PMID- 28714675 TI - Construction of Highly Porous Pillared Metal-Organic Frameworks: Rational Synthesis, Structure, and Gas Sorption Properties. AB - Different from the conventional method to construct pillared-layer metal-organic frameworks (MOFs) by using mixed bipyridyl and dicarboxylate ligands, herein, we present a new approach to build pillared-layer frameworks based on the pyridyldicarboxylate ligands which were predesigned with a certain shape. As exemplified, the ligands of 3-(2',5'-dicarboxyphenyl)benzoic acid (H3dbba) and 3 (2',5'-dicarboxylphenyl)pyridine acid (H2dcpy) were selected and employed to construct three pillared-layer MOFs, [Zn3(dbba)2(bipy)(DMF)].3DMF.4H2O (1) (bipy = 4,4'-bipyridine), and a pair of crystal polymorphs of [Zn(dcpy)].1.5DMF.1.5H2O (2 and 3), under solvothermal reactions, respectively. In the structures of 1-3, the [Zn2(COO)4] clusters are bridged by the terephthalate units of dbba3-/dcpy2- to form 2D layers; these layers are further pillared by bipy and the benzoate units of dbba3- or the pyridine units of dcpy2- to furnish the 3D frameworks. All of them possess high porosity characterized by N2 adsorption and exhibit high selective adsorption of C2H4 and CO2 over CH4. PMID- 28714676 TI - Tunable Magnetization Dynamics through Solid-State Ligand Substitution Reaction. AB - The dimeric molecule [Dy2(acac)6(MeOH)2(bpe)].bpe.2MeOH (1, acac = acetylacetonate, bpe = 1,2-bis(4-pyridyl)ethylene) undergoes a solid-state ligand substitution reaction upon heating, leading to the one-dimensional chain [Dy(acac)3(bpe)]n (2). This structural transformation takes advantage of the potential coordination of the guest bpe molecules present in 1. In both complexes the Dy(III) ions adopt similar octacoordinated D4d geometries. However, the different arrangement of the negatively charged and neutral ligands alters the direction of magnetic anisotropy axis and the energy states, thus resulting in largely distinct magnetization dynamics, as revealed by the CASSCF/RASSI calculations. PMID- 28714677 TI - Synthesis of Manganese ZIF-8 from [Mn(BH4)2.3THF].NaBH4. AB - Cubic and highly porous [Mn(2-methylimidazolate)2] (Mn-ZIF-8) was synthesized from [Mn(BH4)2.3THF].NaBH4 under an Ar atmosphere. The structure contains rare Mn2+-4N tetrahedral geometry and has larger cell parameters, resulting in 20% larger amounts of gas uptake compared with [Zn(2-methylimidazolate)2]. A kinetically favored reaction using a reactive metal borohydride precursor is key for the construction of new metal-organic framework systems. PMID- 28714678 TI - Review of the Fuel Saving, Life Cycle GHG Emission, and Ownership Cost Impacts of Lightweighting Vehicles with Different Powertrains. AB - The literature analyzing the fuel saving, life cycle greenhouse gas (GHG) emission, and ownership cost impacts of lightweighting vehicles with different powertrains is reviewed. Vehicles with lower powertrain efficiencies have higher fuel consumption. Thus, fuel savings from lightweighting internal combustion engine vehicles can be higher than those of hybrid electric and battery electric vehicles. However, the impact of fuel savings on life cycle costs and GHG emissions depends on fuel prices, fuel carbon intensities and fuel storage requirements. Battery electric vehicle fuel savings enable reduction of battery size without sacrificing driving range. This reduces the battery production cost and mass, the latter results in further fuel savings. The carbon intensity of electricity varies widely and is a major source of uncertainty when evaluating the benefits of fuel savings. Hybrid electric vehicles use gasoline more efficiently than internal combustion engine vehicles and do not require large plug-in batteries. Therefore, the benefits of lightweighting depend on the vehicle powertrain. We discuss the value proposition of the use of lightweight materials and alternative powertrains. Future assessments of the benefits of vehicle lightweighting should capture the unique characteristics of emerging vehicle powertrains. PMID- 28714679 TI - Spectroscopic Study of the Reversible Chemical Reduction and Reoxidation of Substitutional Cr Ions in Sr2TiO4. AB - The solid-state synthesis and controllable speciation of Cr dopants in the layered perovskite Sr2TiO4 is reported. We employed a chemical reduction procedure with NaBH4 at relatively mild temperatures (<450 degrees C) to impart sensitive control over the relative concentration of Cr3+ dopants, the charge state of oxygen-vacancy defects, and presence of Ti3+ defects in highly reduced Cr-doped Sr2TiO4. The electron paramagnetic resonance (EPR) spectra of the reduced powder samples reveal a 12-fold increase in the Cr3+ concentration within the axially compressed Ti4+-site of the Sr2TiO4 host. The increase in Cr3+ content is achieved through the reduction of higher-valence Cr ions that are either EPR silent or diamagnetic. The spin-Hamiltonian parameters for Cr3+ substituted at the B-site of Sr2TiO4 were refined to D = -201 * 10-4 cm-1, g? = 1.980, and g? = 1.978. In addition, the Cr3+ ion exhibits a temperature-dependent axial component to the zero-field splitting of the 4A2 ground term that is accounted for by ligand field theory and an isotropic contraction of the Sr2TiO4 lattice with decreasing temperature. The observed changes to the electronic structure upon reduction are quantitatively reversible upon reoxidation of the sample under aerobic annealing at the same temperature and duration as the reduction conditions. This temperature dependence of the Cr3+ content in the Cr doped Sr2TiO4 powders is discussed and contrasted to our recent study on Cr-doped SrTiO3. PMID- 28714680 TI - Correction to Discovery of Pyrazolo[1,5-a]pyrimidine B-Cell Lymphoma 6 (BCL6) Binders and Optimization to High Affinity Macrocyclic Inhibitors. PMID- 28714681 TI - "Visible" 5d Orbital States in a Pleochroic Oxychloride. AB - Transition metal compounds sometimes exhibit attractive colors. Here, we report a new oxychloride, Ca3ReO5Cl2, that shows unusually distinct pleochroism; that is, the material exhibits different colors depending on the viewing direction. This pleochroism is a consequence of the coincidental complex crystal field splitting of the 5d orbitals of the Re6+ ion in a square-pyramidal coordination of low symmetry in the energy range of the visible spectrum. Since the relevant d-d transitions show characteristic polarization dependence according to the optical selection rule, the orbital states are "visible" in Ca3ReO5Cl2. PMID- 28714682 TI - Efficient Calculation of Electronic Structure Using O(N) Density Functional Theory. AB - We propose an efficient way to calculate the electronic structure of large systems by combining a large-scale first-principles density functional theory code, Conquest, and an efficient interior eigenproblem solver, the Sakurai Sugiura method. The electronic Hamiltonian and charge density of large systems are obtained by Conquest, and the eigenstates of the Hamiltonians are then obtained by the Sakurai-Sugiura method. Applications to a hydrated DNA system and adsorbed P2 molecules and Ge hut clusters on large Si substrates demonstrate the applicability of this combination on systems with 10,000+ atoms with high accuracy and efficiency. PMID- 28714683 TI - Regioselective Diversification of 2,1-Borazaronaphthalenes: Unlocking Isosteric Space via C-H Activation. AB - Methods for the regioselective C-H borylation and subsequent cross-coupling of the 2,1-borazaronaphthalene core are reported. Azaborines are dependent on B N/C?C isosterism when employed in strategies for developing diverse heterocyclic scaffolds. Although 2,1-borazaronaphthalene is closely related to naphthalene in terms of structure, the argument is made that the former has electronic similarities to indole. Based on that premise, iridium-mediated C-H activation has enabled facile installation of a versatile, nucleophilic coupling handle at a previously inaccessible site of 2,1-borazaronaphthalenes. A variety of substituted 2,1-borazaronaphthalene cores can be successfully borylated and further cross-coupled in a facile manner to yield diverse C(8)-substituted 2,1 borazaronaphthalenes. PMID- 28714684 TI - The Surface of Protein lambda6-85 Can Act as a Template for Recurring Poly(ethylene glycol) Structure. AB - PEGylated proteins play an increasingly important role in pharmaceutical drug delivery. We recently showed that short poly(ethylene glycol) (PEG) chains can affect protein structure, even when they are not making extensive contact with the protein surface. In contrast, PEG is generally thought to form a relatively unstructured coil, and its compactness depends on solvent conditions. Here we test whether a host protein could allow PEG to form recurrent structural motifs while the PEG chain is in contact with the protein surface. We link a PEG oligomer (n = 45) to one of two nearly opposite locations on the small alpha helical protein lambda6-85 to investigate this question. We first demonstrate experimentally that in these particular positions, PEG does not significantly affect the thermodynamic stability or folding kinetics of lambda6-85. We then use several all-atom molecular dynamics (MD) simulations 1 MUs in duration to show how PEG equilibrates between states extending into the solvent and states packed onto the protein surface. The packing reveals recurring structures, including persistent hydrogen bond and hydrophobic contact patterns that appear multiple times. Some interactions of PEG with surface lysines are best described as an "intermittent slithering" motion of the PEG around the side chain, as seen in short MD movies. Thus, PEG achieves a variety of metastable organized structures on the protein surface, somewhere between a random globule and true folding. We also investigated the PEG-protein interaction in the unfolded state of the protein. We find that PEG has a propensity to stabilize certain helices of lambda6-85, no matter which of the two positions it was attached to. Thus, sufficiently long PEG chains are organized by the protein surface and in turn interact with certain elements of protein structure more than others, even when PEG is attached to very different sites. PMID- 28714685 TI - Adsorption-Coupled Diffusion of Gold Nanoclusters within a Large-Pore Protein Crystal Scaffold. AB - Large-pore protein crystals (LPCs) are ordered biologically derived nanoporous materials exhibiting pore diameters greater than 8 nm. These substantial pores distinguish LPCs from typical nanoporous scaffolds, enabling engineered LPC materials to readily uptake, immobilize, and release macromolecular guests. In this study, macromolecular transport within an LPC environment was experimentally and computationally investigated by studying adsorption-coupled diffusion of Au25(glutathione)18 nanoclusters within a cross-linked LPC scaffold via time lapse confocal microscopy, bulk equilibrium adsorption, and hindered diffusion simulation. Equilibrium adsorption data is congruent with a Langmuir adsorption model, exhibiting strong binding behavior between nanoclusters and the scaffold. The standard Gibbs free energy of binding is equivalent to -37.2 kJ/mol, and the maximum binding capacity of 1.25 * 103 mg/g corresponds to approximately 29 nanoclusters per LPC unit cell. The hindered diffusion model showed good agreement with experimental data, revealing a pore diffusion coefficient of 3.7 * 10-7 cm2/s under low nanocluster concentration. Furthermore, the model was sufficient to determine adsorption and desorption kinetic values for ka and kd equal to 13 cm3/mol.s and 1.7 * 10-7 s-1, respectively. At higher nanocluster concentrations, the simulated pore diffusion coefficient could be reduced by 3 orders of magnitude to 3.4 * 10-10 cm2/s due to the effects of pore occlusion. This study demonstrates a strategy to analyze adsorption-coupled diffusion data to better understand complex transport of fluorescent macromolecules into LPCs. This approach fits the observable fluorescence data to the key molecular details and will benefit downstream efforts to engineer LPC-based nanoporous materials. PMID- 28714686 TI - An Unconventional Redox Cross Claisen Condensation-Aromatization of 4 Hydroxyprolines with Ketones. AB - Reaction of alpha-amino acids, particularly prolines and their derivatives with carbonyl compounds via decarboxylative redox process, is a viable strategy for synthesis of structurally diverse nitrogen centered heterocyclics. In these processes, the decarboxylation is the essential driving force for the processes. The realization of the redox process without decarboxylation may offer an opportunity to explore new reactions. Herein, we report the discovery of an unprecedented redox Claisen-type condensation aromatization cascade reaction of 4 substituted 4-hydroxyproline and its esters with unreactive ketones. We found that the use of propionic acid as a catalyst and a co-solvent can change the reaction course. The commonly observed redox decarboxylation and aldol condensation reactions are significantly minimized. Moreover, unreactive ketones can effectively participate in the Claisen condensation reaction. The new reactivity enables a redox cyclization via an unconventional Claisen-type condensation reaction of in situ formed enamine intermediates from ketone precursors with 4-substituted 4-hydroxyproline and its esters as electrophilic acylation partners. Under the reaction conditions, the cascade process proceeds highly regio- and stereoselectively to afford highly synthetically and biologically valued cis-2,3-dihydro-1H-pyrrolizin-1-ones with a broad substrate scope in efficient 'one-pot' operation, whereas such structures generally require multiple steps. PMID- 28714687 TI - Total Synthesis of (-)-Chanoclavine I and an Oxygen-Substituted Ergoline Derivative. AB - An efficient and direct route to ergot alkaloid (-)-chanoclavine I (3) is described using the inexpensive compound (2R)-(+)-phenyloxirane (15) as a chiral pool in 13 steps with 17% overall yield. Key features of the synthesis include a palladium-catalyzed intramolecular aminoalkynylation of terminal olefin and a rhodium-catalyzed intramolecular [3 + 2] annulation. An oxygen-substituted ergoline derivative (-)-25 was also achieved by using the same strategy. PMID- 28714688 TI - Design of a Chemical Probe for the Bromodomain and Plant Homeodomain Finger Containing (BRPF) Family of Proteins. AB - The bromodomain and plant homeodomain finger-containing (BRPF) family are scaffolding proteins important for the recruitment of histone acetyltransferases of the MYST family to chromatin. Here, we describe NI-57 (16) as new pan-BRPF chemical probe of the bromodomain (BRD) of the BRPFs. Inhibitor 16 preferentially bound the BRD of BRPF1 and BRPF2 over BRPF3, whereas binding to BRD9 was weaker. Compound 16 has excellent selectivity over nonclass IV BRD proteins. Target engagement of BRPF1B and BRPF2 with 16 was demonstrated in nanoBRET and FRAP assays. The binding of 16 to BRPF1B was rationalized through an X-ray cocrystal structure determination, which showed a flipped binding orientation when compared to previous structures. We report studies that show 16 has functional activity in cellular assays by modulation of the phenotype at low micromolar concentrations in both cancer and inflammatory models. Pharmacokinetic data for 16 was generated in mouse with single dose administration showing favorable oral bioavailability. PMID- 28714689 TI - Design, Synthesis, and Evaluation of New Selective NM23-H2 Binders as c-MYC Transcription Inhibitors via Disruption of the NM23-H2/G-Quadruplex Interaction. AB - c-MYC is one of the important human proto-oncogenes, and transcriptional factor NM23-H2 can activate c-MYC transcription by recognizing the G-quadruplex in the promoter of the gene. Small molecules that inhibit c-MYC transcription by disrupting the NM23-H2/G-quadruplex interaction might be a promising strategy for developing selective anticancer agents. In recent studies, we developed a series of isaindigotone derivatives, which can bind to G-quadruplex and NM23-H2, thus down-regulating c-MYC ( J. Med. Chem. 2017 , 60 , 1292 - 1308 ). Herein, a series of novel isaindigotone derivatives were designed, synthesized, and screened for NM23-H2 selective binding ligands. Among them, compound 37 showed a high specific binding affinity to NM23-H2, effectively disrupting the interaction of NM23-H2 with G-quadruplex, and it strongly down-regulated c-MYC transcription. Furthermore, 37 induced cell cycle arrest and apoptosis, and it exhibited good tumor growth inhibition in a mouse xenograft model. This work provides a new strategy to modulate c-MYC transcription for the development of selective anticancer drugs. PMID- 28714691 TI - Catalyst-free Synthesis of 6-Hydroxy Indoles via the Condensation of Carboxymethyl Cyclohexadienones and Amines. AB - An efficient catalyst-free synthesis of 6-hydroxy indoles from carboxymethyl cyclohexadienones and primary amines has been developed. The aza-Michael addition of the in situ formed enamine, generated through the condensation of carboxymethyl unit of the substrates with an external amine, to cyclohexadienone moiety followed by rearomatization reaction to provide such indoles. Anilines, aliphatic amines, alpha-chiral aliphatic amines, or even ammonia were used as amine counterpart. Some of the cyclohexadienones gave 6-amino indoles instead of 6-hydroxy indoles using the Re2O7 catalyst. Various post methodological transformations were performed to explore the synthetic utility of the synthesized hydroxy indoles. PMID- 28714690 TI - Selective Affinity Enrichment of Nitrotyrosine-Containing Peptides for Quantitative Analysis in Complex Samples. AB - Protein tyrosine nitration by oxidative and nitrate stress is important in the pathogenesis of many inflammatory or aging-related diseases. Mass spectrometry analysis of protein nitrotyrosine is very challenging because the non-nitrated peptides suppress the signals of the low-abundance nitrotyrosine (NT) peptides. No validated methods for enrichment of NT-peptides are currently available. Here we report an immunoaffinity enrichment of NT-peptides for proteomics analysis. The effectiveness of this approach was evaluated using nitrated protein standards and whole-cell lysates in vitro. A total of 1881 NT sites were identified from a nitrated whole-cell extract, indicating that this immunoaffinity-MS method is a valid approach for the enrichment of NT-peptides, and provides a significant advance for characterizing the nitrotyrosine proteome. We noted that this method had higher affinity to peptides with N-terminal nitrotyrosine relative to peptides with other nitrotyrosine locations, which raises the need for future study to develop a pan-specific nitrotyrosine antibody for unbiased, proteome wide analysis of tyrosine nitration. We applied this method to quantify the changes in protein tyrosine nitration in mouse lungs after intranasal poly(I:C) treatment and quantified 237 NT sites. This result indicates that the immunoaffinity-MS method can be used for quantitative analysis of protein nitrotyrosines in complex samples. PMID- 28714692 TI - Design, Synthesis, and Pharmacological Evaluation of Novel Multisubstituted Pyridin-3-amine Derivatives as Multitargeted Protein Kinase Inhibitors for the Treatment of Non-Small Cell Lung Cancer. AB - A novel series of pyridin-3-amine derivatives were designed, synthesized, and evaluated as multitargeted protein kinase inhibitors for the treatment of non small cell lung cancer (NSCLC). Hit 1 was first disclosed by in silico screening against fibroblast growth factor receptors (FGFR), which was subsequently validated by in vitro experiments. The structure-activity relationship (SAR) of its analogues was then explored to afford novel FGFR inhibitors 2a-2p and 3a-3q. Among them, 3m showed potent inhibition against FGFR1, 2, and 3. Interestingly, compound 3m not only inhibited various phosphorylation and downstream signaling across different oncogenic forms in FGFR-overactivated cancer cells but also showed nanomolar level inhibition against several other NSCLC-related oncogene kinases, including RET, EGFR, EGFR/T790M/L858R, DDR2, and ALK. Finally, in vivo pharmacology evaluations of 3m showed significant antitumor activity (TGI = 66.1%) in NCI-H1581 NSCLC xenografts with a good pharmacokinetic profile. PMID- 28714693 TI - Stochastic Simulation of Dopamine Neuromodulation for Implementation of Fluorescent Neurochemical Probes in the Striatal Extracellular Space. AB - Imaging the dynamic behavior of neuromodulatory neurotransmitters in the extracelluar space that arise from individual quantal release events would constitute a major advance in neurochemical imaging. Spatial and temporal resolution of these highly stochastic neuromodulatory events requires concurrent advances in the chemical development of optical nanosensors selective for neuromodulators in concert with advances in imaging methodologies to capture millisecond neurotransmitter release. Herein, we develop and implement a stochastic model to describe dopamine dynamics in the extracellular space (ECS) of the brain dorsal striatum to guide the design and implementation of fluorescent neurochemical probes that record neurotransmitter dynamics in the ECS. Our model is developed from first-principles and simulates release, diffusion, and reuptake of dopamine in a 3D simulation volume of striatal tissue. We find that in vivo imaging of neuromodulation requires simultaneous optimization of dopamine nanosensor reversibility and sensitivity: dopamine imaging in the striatum or nucleus accumbens requires nanosensors with an optimal dopamine dissociation constant (Kd) of 1 MUM, whereas Kds above 10 MUM are required for dopamine imaging in the prefrontal cortex. Furthermore, as a result of the probabilistic nature of dopamine terminal activity in the striatum, our model reveals that imaging frame rates of 20 Hz are optimal for recording temporally resolved dopamine release events. Our work provides a modeling platform to probe how complex neuromodulatory processes can be studied with fluorescent nanosensors and enables direct evaluation of nanosensor chemistry and imaging hardware parameters. Our stochastic model is generic for evaluating fluorescent neurotransmission probes, and is broadly applicable to the design of other neurotransmitter fluorophores and their optimization for implementation in vivo. PMID- 28714694 TI - Rapid Thermal Annealing of Cathode-Garnet Interface toward High-Temperature Solid State Batteries. AB - High-temperature batteries require the battery components to be thermally stable and function properly at high temperatures. Conventional batteries have high temperature safety issues such as thermal runaway, which are mainly attributed to the properties of liquid organic electrolytes such as low boiling points and high flammability. In this work, we demonstrate a truly all-solid-state high temperature battery using a thermally stable garnet solid-state electrolyte, a lithium metal anode, and a V2O5 cathode, which can operate well at 100 degrees C. To address the high interfacial resistance between the solid electrolyte and cathode, a rapid thermal annealing method was developed to melt the cathode and form a continuous contact. The resulting interfacial resistance of the solid electrolyte and V2O5 cathode was significantly decreased from 2.5 * 104 to 71 Omega.cm2 at room temperature and from 170 to 31 Omega.cm2 at 100 degrees C. Additionally, the diffusion resistance in the V2O5 cathode significantly decreased as well. The demonstrated high-temperature solid-state full cell has an interfacial resistance of 45 Omega.cm2 and 97% Coulombic efficiency cycling at 100 degrees C. This work provides a strategy to develop high-temperature all solid-state batteries using garnet solid electrolytes and successfully addresses the high contact resistance between the V2O5 cathode and garnet solid electrolyte without compromising battery safety or performance. PMID- 28714695 TI - Double-Protected All-Inorganic Perovskite Nanocrystals by Crystalline Matrix and Silica for Triple-Modal Anti-Counterfeiting Codes. AB - Novel fluorescence with highly covert and reliable features is quite desirable to combat the sophisticated counterfeiters. Herein, we report a simultaneously triple-modal fluorescent characteristic of CsPbBr3@Cs4PbBr6/SiO2 by the excitation of thermal, ultraviolet (UV) and infrared (IR) light for the first time, which can be applied for the multiple modal anti-counterfeiting codes. The diphasic structure CsPbBr3@Cs4PbBr6 nanocrystals (NCs) was synthesized via the typical reprecipitation method followed by uniformly encapsulation into silica microspheres. Cubic CsPbBr3 is responsible for the functions of anti counterfeiting, while Cs4PbBr6 crystalline and SiO2 are mainly to protect unstable CsPbBr3 NCs from being destroyed by ambient conditions. The as-prepared CsPbBr3@Cs4PbBr6/SiO2 NCs possess improved stability and are capable of forming printable ink with organic binders for patterns. Interestingly, the fluorescence of diphasic CsPbBr3@Cs4PbBr6/SiO2 capsule patterns can be reversibly switched by the heating, UV, and IR light irradiation, which has been applied as triple-modal fluorescent anti-counterfeiting codes. The results demonstrate that the perovskite@silica capsules are highly promising for myriad applications in areas such as fluorescent anti-counterfeiting, optoelectronic devices, medical diagnosis, and biological imaging. PMID- 28714696 TI - Genetically Encoded Fluorescent RNA Sensor for Ratiometric Imaging of MicroRNA in Living Tumor Cells. AB - Light-up RNA aptamers are valuable tools for fluorescence imaging of RNA in living cells and thus for elucidating RNA functions and dynamics. However, no light-up RNA sensor has been reported for imaging of microRNAs (miRs) in mammalian cells. We report a novel genetically encoded RNA sensor for fluorescent imaging of miRs in living tumor cells using a light-up RNA aptamer that binds to sulforhodamine and separates it from a conjugated contact quencher. On the basis of the structural switching mechanism for molecular beacon, we show that the RNA sensor activates high-contrast fluorescence from the sulforhodamine-quencher conjugate when its stem-loop responsive motif hybridizes with target miR. The RNA sensor can be stably expressed within a designed tRNA scaffold in tumor cells and deliver light-up response to miR target. We also realize the RNA sensor for dual emission, ratiometric imaging by coexpression of RNA sensor with GFP, enabling quantitative studies of target miR in living cells. Our design may provide a new paradigm for developing robust, sensitive light-up RNA sensors for RNA imaging applications. PMID- 28714697 TI - Molybdenum Oxide Nitrides of the Mo2(O,N,?)5 Type: On the Way to Mo2O5. AB - Blue-colored molybdenum oxide nitrides of the Mo2(O,N,?)5 type were synthesized by direct nitridation of commercially available molybdenum trioxide with a mixture of gaseous ammonia and oxygen. Chemical composition, crystal structure, and stability of the obtained and hitherto unknown compounds are studied extensively. The average oxidation state of +5 for molybdenum is proven by Mo K near-edge X-ray absorption spectroscopy; the magnetic behavior is in agreement with compounds exhibiting MoVO6 units. The new materials are stable up to ~773 K in an inert gas atmosphere. At higher temperatures, decomposition is observed. X ray and neutron powder diffraction, electron diffraction, and high-resolution transmission electron microscopy reveal the structure to be related to VNb9O24.9 type phases, however, with severe disorder hampering full structure determination. Still, the results demonstrate the possibility of a future synthesis of the potential binary oxide Mo2O5. On the basis of these findings, a tentative suggestion on the crystal structure of the potential compound Mo2O5, backed by electronic-structure and phonon calculations from first principles, is given. PMID- 28714698 TI - MicroRNA Intercellular Transfer and Bioelectrical Regulation of Model Multicellular Ensembles by the Gap Junction Connectivity. AB - We have studied theoretically the microRNA (miRNA) intercellular transfer through voltage-gated gap junctions in terms of a biophysically grounded system of coupled differential equations. Instead of modeling a specific system, we use a general approach describing the interplay between the genetic mechanisms and the single-cell electric potentials. The dynamics of the multicellular ensemble are simulated under different conditions including spatially inhomogeneous transcription rates and local intercellular transfer of miRNAs. These processes result in spatiotemporal changes of miRNA, mRNA, and ion channel protein concentrations that eventually modify the bioelectrical states of small multicellular domains because of the ensemble average nature of the electrical potential. The simulations allow a qualitative understanding of the context dependent nature of the effects observed when specific signaling molecules are transferred through gap junctions. The results suggest that an efficient miRNA intercellular transfer could permit the spatiotemporal control of small cellular domains by the conversion of single-cell genetic and bioelectric states into multicellular states regulated by the gap junction interconnectivity. PMID- 28714699 TI - Putting "context" in context: The effects of body posture and emotion scene on adult categorizations of disgust facial expressions. AB - Affective face perception is influenced by nonfacial contextual elements. However, investigations often conflate body posture and emotion scene, making it unclear whether posture or the combination of posture and scene produces perception-altering effects. This study examined adults' categorizations of disgust facial expressions superimposed onto isolated emotion postures or postures embedded in emotion scenes. Results indicated that emotional postures exerted a significant contextual effect on adults' emotion categorizations of disgust faces. Of note, postures in emotion scenes exerted a stronger contextual effect than isolated postures for sadness and fear contexts. These findings suggest that contextual elements exert varying degrees of influence on emotion perception and produce combinatorial effects. (PsycINFO Database Record PMID- 28714700 TI - Children's prototypic facial expressions during emotion-eliciting conversations with their mothers. AB - Despite theoretical claims that emotions are primarily communicated through prototypic facial expressions, empirical evidence is surprisingly scarce. This study aimed to (a) test whether children produced more components of a prototypic emotional facial expression during situations judged or self-reported to involve the corresponding emotion than situations involving other emotions (termed "intersituational specificity"), (b) test whether children produced more components of the prototypic expression corresponding to a situation's judged or self-reported emotion than components of other emotional expressions (termed "intrasituational specificity"), and (c) examine coherence between children's self-reported emotional experience and observers' judgments of children's emotions. One hundred and 20 children (ages 7-9) were video-recorded during a discussion with their mothers. Emotion ratings were obtained for children in 441 episodes. Children's nonverbal behaviors were judged by observers and coded by FACS-trained researchers. Children's self-reported emotion corresponded significantly to observers' judgments of joy, anger, fear, and sadness but not surprise. Multilevel modeling results revealed that children produced joy facial expressions more in joy episodes than nonjoy episodes (supporting intersituational specificity for joy) and more joy and surprise expressions than other emotional expressions in joy and surprise episodes (supporting intrasituational specificity for joy and surprise). However, children produced anger, fear, and sadness expressions more in noncorresponding episodes and produced these expressions less than other expressions in corresponding episodes. Findings suggest that communication of negative emotion during social interactions-as indexed by agreement between self-report and observer judgments may rely less on prototypic facial expressions than is often theoretically assumed. (PsycINFO Database Record PMID- 28714701 TI - Does a culture of happiness increase rumination over failure? AB - Promoting happiness within society is good for health, but could the overpromotion of happiness have a downside? Across 2 studies, we investigate 2 emotion norms associated with an emphasis on happiness-the importance of (a) seeking positive emotion, and (b) avoiding negative emotion-and whether these norms have implications for how people respond to, and seek to regulate, their negative emotional experiences. In Study 1, we used an experimental design to show that emphasizing the importance of happiness increased rumination in response to failure. In Study 2, we drew on cross-sectional evidence to investigate the other side of this equation, finding that emphasizing the importance of not experiencing negative emotional states (e.g., depression and anxiety) was also associated with increased rumination, and that this had downstream consequences for well-being. Together, the findings suggest that the overpromotion of happiness, and, in turn, the felt social pressure not to experience negative emotional states, has implications for maladaptive responses to negative emotional experiences. (PsycINFO Database Record PMID- 28714702 TI - The effect of positive mood on flexible processing of affective information. AB - Recent efforts have been made to understand the cognitive mechanisms underlying psychological resilience. Cognitive flexibility in the context of affective information has been related to individual differences in resilience. However, it is unclear whether flexible affective processing is sensitive to mood fluctuations. Furthermore, it remains to be investigated how effects on flexible affective processing interact with the affective valence of information that is presented. To fill this gap, we tested the effects of positive mood and individual differences in self-reported resilience on affective flexibility, using a task switching paradigm (N = 80). The main findings showed that positive mood was related to lower task switching costs, reflecting increased flexibility, in line with previous findings. In line with this effect of positive mood, we showed that greater resilience levels, specifically levels of acceptance of self and life, also facilitated task set switching in the context of affective information. However, the effects of resilience on affective flexibility seem more complex. Resilience tended to relate to more efficient task switching when negative information was preceded by positive information, possibly because the presentation of positive information, as well as positive mood, can facilitate task set switching. Positive mood also influenced costs associated with switching affective valence of the presented information. This latter effect was indicative of a reduced impact of no longer relevant negative information and more impact of no longer relevant positive information. Future research should confirm these effects of individual differences in resilience on affective flexibility, considering the affective valence of the presented information. (PsycINFO Database Record PMID- 28714703 TI - Localizationism, antilocalizationism, and the emergence of the unitary construct of consciousness in Luigi Luciani (1840-1919). AB - This article aims to present the construct of unitary consciousness as it emerged in the work of the Italian physiologist Luigi Luciani (1840-1919). We highlight how Luciani's work, conducted during the late 19th and early 20th centuries, integrated experimental research with the clinical observation of patients, enabling him to develop elaborate theoretical conceptions. From our historical analysis of Luciani's main works, an innovative model of unitary consciousness emerges with respect to his contemporary context. We also propose Luciani's model as a contribution to the modern debate on consciousness. An analysis of his work, not considered up to now, leads us to reevaluate the assumption of an ancient opposition between localization and antilocalization in the history of cerebral localization. (PsycINFO Database Record PMID- 28714704 TI - Planes of phenomenological experience: The psychology of deafness as an early example of American Gestalt psychology, 1928-1940. AB - When, in 1928, the Clarke School for the Deaf in Northampton, Massachusetts, opened a psychological research division, it was nothing unusual in a time fascinated with the sciences of education. Yet with its longstanding ties to Northampton's Smith College, the school was able to secure the collaboration of eminent Gestalt psychologist Kurt Koffka, who, in turn, engaged 2 more German speaking emigrants, Margarete Eberhardt and social psychologist Fritz Heider, and Heider's American wife Grace Moore Heider. This collaboration has seen little attention from historians, who have treated Koffka's and Heider's time in Northampton as a transitory phase. I argue, however, that their research on deafness adds to the history of emigration and knowledge transfer between European and American Schools of psychology, and to historical understanding of the interrelation of Gestalt, child, and social psychology. Professionals in child studies and developmental psychology were keenly interested in the holistic and introspective approach Gestalt psychology offered. Deaf children were considered a particularly fascinating research population for exploring the relationship between thought and language, perception and development, Gestalt, and reality. At the Clarke School, Grace Moore Heider was among the first Americans to apply Gestalt principles to child psychology. In a time in which pejorative eugenic beliefs dominated professional perceptions of disability, the Heiders' groundbreaking work defined the deaf as a social and phenomenological minority. This was in opposition to dominant beliefs in deaf education, yet it points to early roots of a social model of deafness and disability, which historians usually locate in 1960s and '70s activism. (PsycINFO Database Record PMID- 28714705 TI - Professional psychology in Germany, National Socialism, and the Second World War. AB - Hundreds of positions for psychologists were established after the National Socialists seized power in 1933. It has accordingly been asserted that professional psychology in Germany experienced significant growth during the National Socialist period. An analysis of archival materials and of a recent collection of biographies indicates otherwise, however. German psychology, in fact, declined because of systematic persecution and a surge of emigration, a deficit that subsequent cohorts were barely able to make up until 1945. The new positions for psychologists were mainly in the military testing service, and could only be filled after manpower was shifted from the civilian to the military sector. In 1941, the Ministry of Science and Education released regulations for an innovative practice-oriented national curriculum for psychology. The move was in line with Nazi policy, but it was initiated by a group of protagonists from psychology under the aegis of the German Psychological Association, not the National Socialist German Workers Party, the government, or the military. The present article elaborates how the conception of practice-oriented, state approved studies was part of the traditional German dual system of academic and professional qualification, and thus actually predated 1933. The new curriculum was largely not implemented because of the exigencies of the war. However, as a regulatory framework it marked a turning point in the merging of academic and professional psychology in Germany. The relationship between academic and professional psychology is also discussed, along with the role of German psychology vis-a-vis National Socialism and the German military. (PsycINFO Database Record PMID- 28714706 TI - HIV risk and multiple sources of heterosexism among young Black men who have sex with men. AB - OBJECTIVE: This study examined whether the association between social support and condom self-efficacy would be moderated by (a) internalized heterosexism among and (b) enacted heterosexism experienced by young Black men who have sex with men (YBMSM), who contend with high HIV incidence, heterosexism, and low uptake of preexposure prophylaxis. METHOD: Participants were 1,210 YBMSM (ages 18-29) who completed measures of social support, internalized and enacted heterosexism, and condom self-efficacy in 2 large cities in the southern United States as part of a community-level HIV-prevention study. RESULTS: A significant 3-way interaction between social support and both hypothesized moderators, internalized and enacted heterosexism, showed that social support was positively associated with condom self-efficacy when both internalized and enacted heterosexism were high (1 SD above the mean; b = .177, 95% confidence interval [CI: .088, .266]). However, social support was not associated with condom self-efficacy when scores were low (1 SD below the mean) on both internalized and enacted heterosexism (b = .024, 95% CI [-.054, .101]), low on internalized and high on enacted heterosexism (b = .058, 95% CI [-.061, .117]), or high on internalized and low on enacted heterosexism (b = .039, 95% CI [-.083, .161]). CONCLUSIONS: YBMSM who are high in both internalized and enacted heterosexism may see greater benefits from social support on condom self-efficacy than would YBMSM who grapple with less heterosexism. In addition to promoting social support, interventions should aim to assess and reduce multiple forms of stigma. (PsycINFO Database Record PMID- 28714708 TI - Ethnic identity in context of ethnic discrimination: When does gender and other group orientation increase risk for depressive symptoms for immigrant-origin young adults? AB - OBJECTIVES: Ethnic discrimination increases risk for depressive symptoms, but less is known about factors that influence the impact of this cultural challenge on psychological adjustment for immigrant-origin college students. Sociocultural identity development is especially relevant during emerging adulthood. Studies examining exacerbating or buffering impacts of ethnic identity have yielded mixed results. The current study examines conditions under which one aspect of ethnic identity, affirmation/belonging, moderates the impact of perceived ethnic discrimination stress on depressive symptoms. This was expected to vary by other group orientation and gender, in accordance with rejection sensitivity theory. METHOD: A multicultural sample of 290 non-White immigrant-origin emerging adults (aged 18-25) from mixed cultural backgrounds and generational statuses attending a college in the Southeastern United States completed electronic self-report questionnaires. RESULTS: More robust support was provided for social identity theory rather than rejection sensitivity theory: stronger affirmation/belonging was inversely associated with depressive symptoms across the sample, with a notable buffering impact for women. Trend-level results indicated a protective effect for those endorsing stronger affirmation/belonging paired with greater other-group orientation. Additionally, women with weaker affirmation/belonging demonstrated greater increased depressive symptoms compared to men with weaker affirmation/belonging. CONCLUSIONS: For this sample, social identity theory was relevant to the impact of affirmation/belonging on the relation between ethnic discrimination and depressive symptoms contingent on other-group orientation and gender. This finding underscores the importance of examining ethnic identity in a nuanced manner. Implications for these results extend to college counseling centers, where inclusion of sociocultural identity in case conceptualization would be useful. (PsycINFO Database Record PMID- 28714707 TI - Prospective relations between parent-adolescent acculturation conflict and mental health symptoms among Vietnamese American adolescents. AB - OBJECTIVES: Intergenerational acculturation conflict in immigrant families has been implicated as a risk factor for adolescent maladjustment. However, the directionality and specific family related mediators of this association have not been identified. The present study prospectively examined relations between adolescent reports of perceived acculturation conflict and internalizing and externalizing mental health symptoms. Perceived parent-adolescent relationship strain and perceived parental psychological control were examined as potential mediators. METHOD: Survey measures were administered to 375 Vietnamese American adolescents (48.8% males; M = 15.55 years, SD = .59) at 3 time points over 6 months. RESULTS: Using cross-lagged path analysis, perceived acculturation conflict predicted externalizing symptoms, whereas internalizing symptoms predicted perceived acculturation conflict. Perceived maternal psychological control mediated the association between perceived acculturation conflict and later externalizing symptoms, whereas maternal psychological control, parental unresponsiveness, and unmet parent expectations mediated the association between internalizing symptoms and later acculturation conflict. CONCLUSION: Culturally competent enhancement of parental sensitivity and responsiveness might be targeted as a modifiable protective factor in family-based preventive interventions for at-risk immigrant families. (PsycINFO Database Record PMID- 28714709 TI - Asian Americans respond less favorably to excitement (vs. calm)-focused physicians compared to European Americans. AB - OBJECTIVES: Despite being considered a "model minority," Asian Americans report worse health care encounters than do European Americans. This may be due to affective mismatches between Asian American patients and their European American physicians. We predicted that because Asian Americans value excitement (vs. calm) less than European Americans, they will respond less favorably to excitement focused (vs. calm) physicians. METHOD: In Study 1, 198 European American, Chinese American, and Hong Kong Chinese community adults read a medical scenario and indicated their preference for an excitement-focused versus calm-focused physician. In Study 2, 81 European American and Asian American community college students listened to recommendations made by an excitement-focused or calm focused physician in a video, and later attempted to recall the recommendations. In Study 3, 101 European American and Asian American middle-aged and older adults had multiple online encounters with an excitement-focused or calm-focused physician and then evaluated their physicians' trustworthiness, competence, and knowledge. RESULTS: As predicted, Hong Kong Chinese preferred excitement-focused physicians less than European Americans, with Chinese Americans falling in the middle (Study 1). Similarly, Asian Americans remembered health information delivered by an excitement-focused physician less well than did European Americans (Study 2). Finally, Asian Americans evaluated an excitement-focused physician less positively than did European Americans (Study 3). CONCLUSIONS: These findings suggest that while physicians who promote and emphasize excitement states may be effective with European Americans, they may be less so with Asian Americans and other ethnic minorities who value different affective states. (PsycINFO Database Record PMID- 28714711 TI - Children understand that agents maximize expected utilities. AB - A growing set of studies suggests that our ability to infer, and reason about, mental states is supported by the assumption that agents maximize utilities-the rewards they attain minus the costs they incur. This assumption enables observers to work backward from agents' observed behavior to their underlying beliefs, preferences, and competencies. Intuitively, however, agents may have incomplete, uncertain, or wrong beliefs about what they want. More formally, agents try to maximize their expected utilities. This understanding is crucial when reasoning about others' behavior: It dictates when actions reveal preferences, and it makes predictions about the stability of behavior over time. In a set of 7 experiments we show that 4- and 5-year-olds understand that agents try to maximize expected utilities, and that these responses cannot be explained by simpler accounts. In particular, these results suggest a modification to the standard belief/desire model of intuitive psychology. Children do not treat beliefs and desires as independent; rather, they recognize that agents have beliefs about their own desires and that this has consequences for the interpretation of agents' actions. (PsycINFO Database Record PMID- 28714710 TI - A relative bilingual advantage in switching with preparation: Nuanced explorations of the proposed association between bilingualism and task switching. AB - Bilingual language switching may increase general switching efficiency, but the evidence on this question is mixed. We hypothesized that group differences in switching might be stronger at a long cue-target interval (CTI), which may better tap general switching abilities (Yehene & Meiran, 2007). Eighty Spanish-English bilinguals and 80 monolinguals completed a color-shape switching task, and an analogous language-switching task, varying CTI (short vs. long) in both tasks. With longer preparation time (long CTI), bilinguals exhibited significantly smaller task-switching costs than monolinguals, but only in the first half of trials. Group differences diminished with practice, though practice benefitted RTs on short CTI trials more than long, and bilinguals committed fewer errors with practice especially at short CTI. Groups did not differ in mixing costs; however, across CTIs and tasks, bilinguals and monolinguals alike, exhibited robust correlations between mixing costs, but not between switching costs. These results confirm an association between bilingualism and switching efficiency that may be magnified with manipulations that target general switching ability (or could reflect better ability to take advantage of preparation time). However, practice effects observed within experimental paradigms, and between task correlations in costs, may reflect cognitive mechanisms specific to laboratory tasks much more than associations with general switching ability and executive control mechanisms-for which more reliable and valid measures can hopefully be developed in future work. (PsycINFO Database Record PMID- 28714712 TI - Spatial cues influence the visual perception of gender. AB - Spatial localization is a basic process in vision, occurring reliably when people encounter an object or person. Yet the role of spatial-location in the visual perception of people is poorly understood. We explored the extent to which spatial-location distorts the perception of gender. Consistent with evidence that the perception of objects is constrained by their location in visual scenes, enhancing perception for objects in their typical location (e.g., Biederman et al., 1982), we hypothesized that people would see relatively greater femininity in faces that appeared lower in space. On each of many trials, participants briefly viewed a pair of faces that varied in gender-ambiguity. One face appeared higher than the other, and participants identified the 1 that looked more like a woman's face (Study 1) or indicated whether the 2 faces were the same (Study 2). Across 2 experiments, participants perceived greater femininity in faces seen lower (vs. higher) in space. These effects seem to be perceptual-changes to spatial location were sufficient for altering whether 2 faces looked identical or different. Thus, spatial-location modulates visual percepts of gender, providing a biased foundation for downstream processes involved in gender biases, sexual attraction, and sex-roles. (PsycINFO Database Record PMID- 28714713 TI - Promoting transparency and reproducibility in Behavioral Neuroscience: Publishing replications, registered reports, and null results. AB - The editors of Behavioral Neuroscience have been discussing several recent developments in the landscape of scientific publishing. The discussion was prompted, in part, by reported issues of reproducibility and concerns about the integrity of the scientific literature. Although enhanced rigor and transparency in science are certainly important, a related issue is that increased competition and focus on novel findings has impeded the extent to which the scientific process is cumulative. We have decided to join the growing number of journals that are adopting new reviewing and publishing practices to address these problems. In addition to our standard research articles, we are pleased to announce 3 new categories of articles: replications, registered reports, and null results. In joining other journals in psychology and related fields to offer these publication types, we hope to promote higher standards of methodological rigor in our science. This will ensure that our discoveries are based on sound evidence and that they provide a durable foundation for future progress. (PsycINFO Database Record PMID- 28714714 TI - No evidence for enhancements to visual working memory with transcranial direct current stimulation to prefrontal or posterior parietal cortices. AB - The present study examined the relative contributions of the prefrontal cortex (PFC) and posterior parietal cortex (PPC) to visual working memory. Evidence from a number of different techniques has led to the theory that the PFC controls access to working memory (i.e., filtering), determining which information is encoded and maintained for later use whereas the parietal cortex determines how much information is held at 1 given time, regardless of relevance (i.e., capacity; McNab & Klingberg, 2008; Vogel, McCollough, & Machizawa, 2005). To test this theory, we delivered transcranial DC stimulation (tDCS) to the right PFC and right PPC and measured visual working memory capacity and filtering abilities both during and immediately following stimulation. We observed no evidence that tDCS to either the PFC or PPC significantly improved visual working memory. Although the present results did not allow us to make firm theoretical conclusions about the roles of the PFC and PPC in working memory, the results add to the growing body of literature surrounding tDCS and its associated behavioral and neurophysiological effects. (PsycINFO Database Record PMID- 28714715 TI - The development of perineuronal nets around parvalbumin gabaergic neurons in the medial prefrontal cortex and basolateral amygdala of rats. AB - Perineuronal nets (PNNs) are extracellular matrix structures that preferentially surround mature GABAergic neurons that express the calcium-binding protein parvalbumin (PV). It has been suggested that aberrant PNN formation in humans may contribute to psychological disorders, many of which emerge during childhood and adolescence. The present experiment investigated the normative developmental trajectory of PNN formation in the medial prefrontal cortex (mPFC) and basolateral amygdala (BLA) in juvenile (P24), adolescent (P35-36), and adult (~P70) rats. Dual-immunofluorescence staining revealed that there was a marked increase in the number of PNNs in both the prelimbic and infralimbic regions of the mPFC across the transition from the juvenile to adolescent period. Although there were no differences in the number of PV neurons across age groups, adolescent and adult rats had more PNNs surrounding PV neurons than juveniles. In contrast to the mPFC, juvenile and adolescent rats had similar total numbers of PNNs in the BLA, and total numbers of PNNs were even higher in adults in this region. In the BLA, adults had more PNNs around non-PV cells whereas the number of PV cells with PNNs did not differ across ages. However, expression patterns differed within subregions of the BLA such that adults had the most PNNs around both PV and non-PV cells in the lateral nucleus, with no age differences observed in the basal nucleus. These findings demonstrate that the juvenile to adolescent developmental period is an important time for the formation of prefrontal PNNs and the maturation of PV inhibitory neurons. (PsycINFO Database Record PMID- 28714716 TI - CB1 receptor antagonism in the bed nucleus of the stria terminalis interferes with affective opioid withdrawal in rats. AB - The bed nucleus of the stria terminalis (BNST) is a region of the extended amygdala that is implicated in addiction, anxiety, and stress related behaviors. This region has been identified in mediating the aversive state of naloxone precipitated morphine withdrawal (MWD) and cannabinoid Type I (CB1) receptors have been found to modulate neurotransmission within this region. Previous findings suggest that the CB1 antagonist/inverse agonist, AM251, administered systemically or by infusion into the central nucleus of the amygdala (CeA) prevented the aversive affective properties of MWD as measured by conditioned place aversion learning. As well, when administered systemically or by infusion into the basolateral nucleus of the amygdala (BLA) or the interoceptive insular cortex, the monoaclyglycerol lipase (MAGL) inhibitor, MJN110 (which elevates 2 arachidonlyglycerol), also prevented a naloxone-precipitated MWD induced place aversion. Given the connectivity of these regions and the BNST, the present study sought to determine whether cannabinoid modulation of the BNST would also prevent the affective properties of naloxone precipitated MWD-induced place aversion learning. Prior to conditioning trials, rats received intra-BNST infusions of AM251, in Experiment 1, or MJN110 in Experiment 2. AM251, but not MJN110, prevented the establishment of the MWD-induced place aversion. The current findings emphasize an important role for the BNST in opioid withdrawal and suggest that the ameliorative effects of systemically administered CB1 antagonists are mediated, in part, by their actions within this region. (PsycINFO Database Record PMID- 28714718 TI - Multiple sclerosis reduces sensitivity to immediate reward during decision making. AB - Individuals with multiple sclerosis (MS) often face important health-related and financial decisions that involve trade-offs between short-term and long-term benefits, yet decision making is rarely studied in MS patients. The temporal discounting paradigm is a useful tool for investigating such time-dependent choices in humans. Here, we investigated whether patients with relapsing remitting MS differed from healthy controls when making choices between hypothetical monetary rewards available at different points in time. Participants were tested in two conditions: in one, the choice was between a smaller amount of money available immediately and a larger amount of money available at a later date; in the other, a fixed delay of 60 days was added to both options. We found that, compared with healthy controls, MS patients favored less the sooner reward in the condition involving an immediate reward, whereas no difference between MS patients and the control group emerged in the condition involving only delayed rewards. Moreover, the decreased immediacy bias was corroborated by lower scores at scale that assesses responsiveness to rewards in MS patients. Taken together, these findings indicate reduced sensitivity to immediate reward and a consequent stronger willingness to defer gratification in MS individuals. (PsycINFO Database Record PMID- 28714717 TI - Acetylcholine contributes to the integration of self-movement cues in head direction cells. AB - Acetylcholine contributes to accurate performance on some navigational tasks, but details of its contribution to the underlying brain signals are not fully understood. The medial septal area provides widespread cholinergic input to various brain regions, but selective damage to medial septal cholinergic neurons generally has little effect on landmark-based navigation, or the underlying neural representations of location and directional heading in visual environments. In contrast, the loss of medial septal cholinergic neurons disrupts navigation based on path integration, but no studies have tested whether these path integration deficits are associated with disrupted head direction (HD) cell activity. Therefore, we evaluated HD cell responses to visual cue rotations in a familiar arena, and during navigation between familiar and novel arenas, after muscarinic receptor blockade with systemic atropine. Atropine treatment reduced the peak firing rate of HD cells, but failed to significantly affect other HD cell firing properties. Atropine also failed to significantly disrupt the dominant landmark control of the HD signal, even though we used a procedure that challenged this landmark control. In contrast, atropine disrupted HD cell stability during navigation between familiar and novel arenas, where path integration normally maintains a consistent HD cell signal across arenas. These results suggest that acetylcholine contributes to path integration, in part, by facilitating the use of idiothetic cues to maintain a consistent representation of directional heading. (PsycINFO Database Record PMID- 28714719 TI - Temporal ventriloquism effect in European starlings: Evidence for two parallel processing pathways. AB - The brain constantly has to interpret stimuli from a range of modalities originating from the same or different objects to create unambiguous percepts. The mechanisms of such multisensory processing have been intensely studied with respect to the time window of integration or the effect of spatial separation. However, the neural mechanisms remain elusive with respect to the role of alerting effects and multisensory integration. We addressed this issue by choosing a test paradigm where we could manipulate potentially alerting stimuli and simultaneously activating stimuli independently: We measured the temporal ventriloquism effect in European starlings by using the temporal order judgment paradigm with subjects judging the temporal order of the lighting of 2 spatially separated lights. If spatially noninformative acoustic stimuli were added to the visual stimuli the performance improved when the 2 visual stimuli were flanked by acoustic cues with a small time-offset compared to synchronous presentation. Two acoustic cues presented with asymmetric offsets showed that this effect was mainly driven by the cue trailing the second visual stimulus, while an acoustic cue leading the first visual stimulus had less effect. In contrast, 1 singleton acoustic cue prior to the first visual stimulus, without a second acoustic cue, enhanced performance. Our results support the hypothesis that the first stimulus pair with the leading sound activates alerting mechanisms and enhances neural processing, while the second stimulus pair with the trailing sound drives multisensory integration by simultaneous activation within the temporal binding window. (PsycINFO Database Record PMID- 28714720 TI - The behavioral effects of chronic sugar and/or caffeine consumption in adult and adolescent rats. AB - Caffeine is a psychostimulant frequently consumed by adults and children, often in combination with high levels of sugar. Chronic pretreatment with either substance can amplify both amphetamine and cocaine-induced hyperactivity in rodents. The present study sought to elucidate whether age at the time of exposure to sugar and/or caffeine alters sensitivity to an acute illicit psychostimulant (methamphetamine, [METH]) challenge in adulthood. Adult and adolescent (Postnatal Day 35 on first day of treatment) male Sprague-Dawley rats were treated for 26 days with water, caffeine (0.6 g/L), 10% sucrose or their combination. Locomotor behavior was measured on the first and last day of treatment. Following 9-days treatment free, animals were challenged with saline (1 ml/kg, i.p.) or METH (1 mg/kg, i.p.) and locomotor activity was measured. During the treatment period, adolescent rats maintained a higher caffeine (mg/kg) dose than their adult counterparts. Adding sugar to caffeine increased adolescent consumption and the highest caffeine dose consumed was measured in these animals. Drinking sugar-sweetened caffeinated water or combination did not produce cross sensitization to METH administration in either age group. Nevertheless, the finding that regular exposure through adolescence to caffeinated sugar-sweetened beverages could increase consumption of caffeine and sugar later in life is important, as there is a large body of evidence that has linked excess consumption of sugar-sweetened beverages to a broad range of other negative physical and mental health outcomes. (PsycINFO Database Record PMID- 28714721 TI - Mental health productivity monitoring in the Veterans Health Administration: Challenges and lessons learned. AB - Achieving quality outcomes and cost efficiency within mental health are overarching objectives of the Veterans Health Administration (VHA). The mental health care workforce has long been oriented toward the goal of high quality outcomes; however, cost efficiency has only recently been elevated into this important value equation. With increased demand for access to mental health services within the VHA, leadership sought to advance methods of determining and improving mental health provider productivity. Monitoring of productivity data may also provide data signaling the potential need for additional staffing to keep up with demand for services. This article outlines VHA's development and specification of mental health productivity policy, implementation strategies, and a discussion of challenges and lessons learned for other systems to consider in implementing productivity monitoring. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 28714722 TI - Pilot testing the Daily Activities List for Inmates (DALI): Item evaluation and content validity. AB - Scheduling enjoyable daily activities is a Cognitive Behavioral Therapy intervention used in the treatment of depression and substance abuse disorders that are prevalent disorders among inmates. To effectively use this intervention with inmates, an activities list with items ecologically sensitive to the correctional setting needs to be created. The purpose of this study was to develop and evaluate items; thus, establishing a content valid Daily Activities List for Inmates (DALI). Fifteen corrections professionals representing a wide range of disciplines and managerial backgrounds served as subject matter experts (SMEs). Each SME evaluated 403 daily activity items that were aggregated from 4 separate lists. Each item was evaluated in relation to appropriateness for corrections, availability to inmates, need for editing, and where the activity could take place (in cell, out of cell, or both) then analyzed for removal following a criteria-driven, stage-based approach. The final daily activity list consisted of a total 227 items with the majority of the items developed by inmates in a correctional environment enduring through each stage. The majority of all 227 final DALI items were also considered to be used as both in and out of cell activities. An additional 22 items were created through SME suggestions or edits and were reserved for possible future use. With an ecologically sensitive daily activities list for inmates developed, implications for using the DALI to deliver psychological services to inmates are discussed. (PsycINFO Database Record PMID- 28714723 TI - The implementation and testing of a referral management system to address barriers to treatment seeking among primary care veterans with PTSD. AB - Primary care (PC) patients have low rates of engagement in evidence-based psychotherapy for PTSD due to a variety of patient- and system-level barriers. We conducted a hybrid effectiveness-implementation study of a referral management system, called coordinated and alternative pathway to engagement (CAPE), to address barriers to receiving evidence-based treatment for PTSD. CAPE included the delivery of 1 session of cognitive-behavioral therapy (CBT) within PC to identify and change treatment-seeking beliefs, phone contacts to assist veterans in attending appointments, and PC staff trainings on how to implement clinical practice guidelines for PTSD in PC. The study was conducted in 3 phases. In Phase 1, PC and mental health (MH) leaders were interviewed regarding potential barriers and facilitators to implementation. In Phase 2, CAPE was implemented for 6 months and study outcomes were analyzed using the reach, effectiveness, adoption, implementation, maintenence (RE-AIM) framework. In Phase 3, local and national stakeholders provided feedback on study results to guide future implementation research. Phase 1 feedback informed the implementation plan regarding the content of training and communication strategies for PC staff. Phase 2 results indicated CAPE clinic patients were significantly more likely to engage in psychotherapy for posttraumatic stress disorder (PTSD) than those from a similar clinic where CAPE was not implemented. Phase 3 stakeholder feedback focused on how to generate more CAPE referrals and improve rates of evidence based psychotherapy initiation in future implementation efforts. This study provides a description of how patient and system-level modifications can be implemented within PC to improve treatment engagement and patient health outcomes. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 28714724 TI - Gambling-Related Cognition Scale (GRCS): Are skills-based games at a disadvantage? AB - The Gambling-Related Cognition Scale (GRCS; Raylu & Oei, 2004) was developed to evaluate gambling-related cognitive distortions for all types of gamblers, regardless of their gambling activities (poker, slot machine, etc.). It is therefore imperative to ascertain the validity of its interpretation across different types of gamblers; however, some skills-related items endorsed by players could be interpreted as a cognitive distortion despite the fact that they play skills-related games. Using an intergroup (168 poker players and 73 video lottery terminal [VLT] players) differential item functioning (DIF) analysis, this study examined the possible manifestation of item biases associated with the GRCS. DIF was analyzed with ordinal logistic regressions (OLRs) and Ramsay's (1991) nonparametric kernel smoothing approach with TestGraf. Results show that half of the items display at least moderate DIF between groups and, depending on the type of analysis used, 3 to 7 items displayed large DIF. The 5 items with the most DIF were more significantly endorsed by poker players (uniform DIF) and were all related to skills, knowledge, learning, or probabilities. Poker players' interpretations of some skills-related items may lead to an overestimation of their cognitive distortions due to their total score increased by measurement artifact. Findings indicate that the current structure of the GRCS contains potential biases to be considered when poker players are surveyed. The present study conveys new and important information on bias issues to ponder carefully before using and interpreting the GRCS and other similar wide-range instruments with poker players. (PsycINFO Database Record PMID- 28714725 TI - Intervention effects on stage transitions for adolescent smoking and alcohol use acquisition. AB - The health impacts of smoking and alcohol abuse have been long established with smoking representing one of the most preventable causes of disease and alcohol use the most popular psychoactive substance among adolescents. The current study evaluated stage of change progression in a large (N = 4,158) school-based, computer-delivered, transtheoretical model (TTM)-tailored multiple behavior intervention focused on preventing acquisition of smoking and alcohol use in adolescents. Assessments began in sixth grade and continued yearly until eighth grade, with a follow-up in ninth grade. Markov modeling was used to (a) characterize the best pattern of stage movement (e.g., no stage change, stage sequential change, stages skipped), (b) test whether the identified pattern was stable over time (e.g., between assessments and after intervention completion), and (c) to determine whether the substance use prevention (SP) intervention effectively kept adolescents in acquisition stages (e.g., prevents stage movement toward substance use), relative to the comparison intervention. Major findings supported positive effects for both the intervention and comparison condition, which focused on energy balance (EB) behaviors and provided no direct intervention on substance use behaviors. Substantial differences in stage membership and transitions across intervention conditions highlighted the process of smoking and alcohol use acquisition in middle school students across each intervention condition. (PsycINFO Database Record PMID- 28714726 TI - Pilot investigation of a phosphatidylethanol-based contingency management intervention targeting alcohol use. AB - Phosphatidylethanol (PEth) can be detected in blood from 14 to as many as 28 days after alcohol consumption, depending on the amount and frequency of alcohol consumed. PEth may have utility for verifying abstinence in a contingency management (CM) intervention for alcohol use, particularly in settings where frequent verification of abstinence is impossible or impractical. Five nontreatment-seeking heavy drinkers (40% men) participated in an 11-week, ABA phased within-subject experiment for which they submitted blood spots for PEth measurement, urine samples for ethyl glucuronide (EtG) testing, and self-report drinking data weekly. Participants received reinforcers for submitting samples throughout the A phases. During the B phase (CM phase), they received additional reinforcers when their PEth level was reduced from the previous week and was verified by a negative EtG (<150 ng/ml) urine test and self-report. PEth, EtG, and self-report outcomes were compared between A phases (Weeks 1-3, 8-11) and B phases (Weeks 4-7). During the A phases, 23% of PEth results indicated alcohol abstinence, whereas 53% of PEth samples submitted during the CM (B phase) indicated alcohol abstinence. Participants were more likely to submit EtG negative urine samples and report lower levels of drinking and heavy drinking during the B phase, relative to the A phases. We also explored the ability of PEth to detect self-reported drinking. The combined PEth homologs (16:0/18:1 and 16:0/18:2) predicted self-reported drinking with area under the curve from 0.81 (1 week) to 0.80 (3 weeks). Results support the initial feasibility of a Peth based CM intervention. (PsycINFO Database Record PMID- 28714727 TI - The prospective relationship between distress tolerance and cigarette smoking expectancies in adolescence. AB - The current study examined the prospective relationship between distress tolerance (DT) and positive and negative cigarette smoking outcome expectancies, which are reliable predictors of the onset and maintenance of smoking behaviors. Data from a longitudinal study (N = 204) examining risk behaviors in adolescence were used to assess whether DT predicts individual differences in rate of change in smoking outcome expectancies over 4 annual assessment waves through adolescence. Adolescents (mean age at first wave: 13.03 years; SD = 0.88 years) completed a behavioral task assessing DT at baseline and a self-report measure of adolescent smoking expectancies annually across 4 years. Latent growth curve models were estimated to test our hypotheses. Results showed that DT at baseline did not significantly predict initial levels of negative affect reduction (NAR) expectancies, but NAR expectancies increased more quickly over time for adolescents with lower DT. Moreover, as hypothesized, DT did not prospectively predict significant changes in smoking expectancies outside of the domain of NAR, including negative physical feelings, negative social impression, and boredom reduction expectancies. These findings suggest that DT is a useful indicator of adolescent expectancies about the consequences of cigarette smoking, particularly those focused on reducing negative affect. Thus, DT may be an important target for preventing smoking initiation among adolescents via this putative mechanism. Theoretical and clinical implications are discussed within the context of observed effect sizes. (PsycINFO Database Record PMID- 28714729 TI - Benefits of open and high-powered research outweigh costs. AB - Several researchers recently outlined unacknowledged costs of open science practices, arguing these costs may outweigh benefits and stifle discovery of novel findings. We scrutinize these researchers' (a) statistical concern that heightened stringency with respect to false-positives will increase false negatives and (b) metascientific concern that larger samples and executing direct replications engender opportunity costs that will decrease the rate of making novel discoveries. We argue their statistical concern is unwarranted given open science proponents recommend such practices to reduce the inflated Type I error rate from .35 down to .05 and simultaneously call for high-powered research to reduce the inflated Type II error rate. Regarding their metaconcern, we demonstrate that incurring some costs is required to increase the rate (and frequency) of making true discoveries because distinguishing true from false hypotheses requires a low Type I error rate, high statistical power, and independent direct replications. We also examine pragmatic concerns raised regarding adopting open science practices for relationship science (preregistration, open materials, open data, direct replications, sample size); while acknowledging these concerns, we argue they are overstated given available solutions. We conclude benefits of open science practices outweigh costs for both individual researchers and the collective field in the long run, but that short term costs may exist for researchers because of the currently dysfunctional academic incentive structure. Our analysis implies our field's incentive structure needs to change whereby better alignment exists between researcher's career interests and the field's cumulative progress. We delineate recent proposals aimed at such incentive structure realignment. (PsycINFO Database Record PMID- 28714730 TI - Replicability and other features of a high-quality science: Toward a balanced and empirical approach. AB - Finkel, Eastwick, and Reis (2015; FER2015) argued that psychological science is better served by responding to apprehensions about replicability rates with contextualized solutions than with one-size-fits-all solutions. Here, we extend FER2015's analysis to suggest that much of the discussion of best research practices since 2011 has focused on a single feature of high-quality science replicability-with insufficient sensitivity to the implications of recommended practices for other features, like discovery, internal validity, external validity, construct validity, consequentiality, and cumulativeness. Thus, although recommendations for bolstering replicability have been innovative, compelling, and abundant, it is difficult to evaluate their impact on our science as a whole, especially because many research practices that are beneficial for some features of scientific quality are harmful for others. For example, FER2015 argued that bigger samples are generally better, but also noted that very large samples ("those larger than required for effect sizes to stabilize"; p. 291) could have the downside of commandeering resources that would have been better invested in other studies. In their critique of FER2015, LeBel, Campbell, and Loving (2016) concluded, based on simulated data, that ever-larger samples are better for the efficiency of scientific discovery (i.e., that there are no tradeoffs). As demonstrated here, however, this conclusion holds only when the replicator's resources are considered in isolation. If we widen the assumptions to include the original researcher's resources as well, which is necessary if the goal is to consider resource investment for the field as a whole, the conclusion changes radically-and strongly supports a tradeoff-based analysis. In general, as psychologists seek to strengthen our science, we must complement our much-needed work on increasing replicability with careful attention to the other features of a high-quality science. (PsycINFO Database Record PMID- 28714728 TI - Functional neural changes following behavioral therapies and disulfiram for cocaine dependence. AB - A growing literature exists on neural correlates of treatment outcome. However, different types-or components of-treatment have distinct theorized mechanisms of action. And it is not yet known how changes in neural activity across treatment relate to engagement in different treatment components. Participants with cocaine use disorders in a randomized clinical trial received cognitive-behavioral therapy (CBT) plus, in a 2 * 2 design, contingency management (CM) or no CM, and disulfiram or placebo. Participants performed a functional MRI Stroop task, a measure of cognitive control, at the beginning of and after the 12-week treatment. Analyses assessed changes in Stroop-related neural activity within the sample overall and assessed how changes in Stroop-related activity correlated with measures of treatment process specific to each form of treatment (i.e., participation in CBT sessions, receipt of CM prizes, administration of disulfiram pills). Within the sample overall, compared with beginning of treatment, posttreatment Stroop-related neural activity was diminished in the hippocampus, thalamus, cingulate, precentral, post- and precentral gyrus, and precuneus and culmen regions (pFWE < .05). In separate whole-brain correlation analyses, greater reductions in Stroop-related activity were associated with more treatment engagement-"CBT sessions" with the precentral gyrus, inferior parietal lobule, and middle and medial frontal gyrus; "CM prizes" with the postcentral frontal gyrus. Disulfiram "medication days" were not associated with changes in Stroop related activity. Findings suggest that key process indicators of CBT and CM may be associated with functional changes in cognitive-control-related neurocircuitry. (PsycINFO Database Record PMID- 28714731 TI - Falsifiability is not optional. AB - Finkel, Eastwick, and Reis (2016; FER2016) argued the post-2011 methodological reform movement has focused narrowly on replicability, neglecting other essential goals of research. We agree multiple scientific goals are essential, but argue, however, a more fine-grained language, conceptualization, and approach to replication is needed to accomplish these goals. Replication is the general empirical mechanism for testing and falsifying theory. Sufficiently methodologically similar replications, also known as direct replications, test the basic existence of phenomena and ensure cumulative progress is possible a priori. In contrast, increasingly methodologically dissimilar replications, also known as conceptual replications, test the relevance of auxiliary hypotheses (e.g., manipulation and measurement issues, contextual factors) required to productively investigate validity and generalizability. Without prioritizing replicability, a field is not empirically falsifiable. We also disagree with FER2016's position that "bigger samples are generally better, but . . . that very large samples could have the downside of commandeering resources that would have been better invested in other studies" (abstract). We identify problematic assumptions involved in FER2016's modifications of our original research-economic model, and present an improved model that quantifies when (and whether) it is reasonable to worry that increasing statistical power will engender potential trade-offs. Sufficiently powering studies (i.e., >80%) maximizes both research efficiency and confidence in the literature (research quality). Given that we are in agreement with FER2016 on all key open science points, we are eager to start seeing the accelerated rate of cumulative knowledge development of social psychological phenomena such a sufficiently transparent, powered, and falsifiable approach will generate. (PsycINFO Database Record PMID- 28714732 TI - Type and timing of maltreatment influence criminal persistence in sexually abusive adolescents. AB - The development of sexuality is a major goal in the normative course of puberty. However, some adolescents start and maintain sexually coercive behaviors. Maltreatment appears as a contributing factor in juvenile criminal persistence, although its role regarding reoffenses in juveniles convicted of sexual offenses (JSOs) is unclear. We examined time-dependent associations of maltreatment categories and subtypes with criminal persistence in JSOs. Files of 278 male JSOs (M = 14.64 years, SD = 1.58 years) were analyzed for experiences of emotional abuse, physical abuse, sexual victimization, emotional neglect, and physical neglect. We found 3 subtypes reflecting severe maltreatment, neglectful experiences, and low maltreatment. Severe maltreatment proved to be a consistent predictor of nonsexual criminal persistence, whereas overall neglectful experiences were related to sexual criminal persistence. More specifically, physical neglect (including lack of parental supervision) appeared of major importance for criminal persistence. Results indicate that maltreatment is a contributing factor in criminal persistence in JSOs and emphasize the potential gain of applying family oriented interventions to reduce criminal persistence in JSOs. (PsycINFO Database Record PMID- 28714733 TI - Keep your bias to yourself: How deliberating with differently biased others affects mock-jurors' guilt decisions, perceptions of the defendant, memories, and evidence interpretation. AB - This experiment explored how mock-jurors' (N = 648) guilt decisions, perceptions of the defendant, memories, and evidence interpretation varied as a function of jury type and pretrial publicity (PTP); utilizing a 2 (jury type: pure-PTP vs. mixed-PTP) * 3 (PTP: defendant, victim, and irrelevant) factorial design. Mock juries (N = 126) were composed of jurors exposed to the same type of PTP (pure PTP; e.g., defendant-PTP) or different types of PTP (mixed-PTP; e.g., half exposed to defendant-PTP and half to irrelevant-PTP). Before deliberations jurors exposed to defendant-PTP were most likely to vote guilty; while those exposed to victim-PTP were least likely. After deliberations, jury type and PTP affected jurors' guilt decisions. Specifically, jurors deliberating on pure-PTP juries had verdict distributions that closely resembled the predeliberation distributions. The verdict distributions of jurors on mixed-PTP juries suggested that jurors were influenced by those they deliberated with. Jurors not exposed to PTP appeared to incorporate bias from PTP-exposed jurors. Only PTP had significant effects on postdeliberation measures of memory and evidence interpretation. Mediation analyses revealed that evidence interpretation and defendant credibility assessments mediated the effect of PTP on guilt ratings. Taken together these findings suggest that during deliberations PTP bias can spread to jurors not previously exposed to PTP. In addition, juries composed of jurors exposed to different PTP slants, as opposed to a single PTP slant, can result in less biased decisions. Finally, deliberating with others who do not share similar biases may have little, if any, impact on biased evidence interpretation or memory errors. (PsycINFO Database Record PMID- 28714734 TI - Being disconnected from life: meanings of existential loneliness as narrated by frail older people. AB - OBJECTIVES: This study illuminated the meanings of existential loneliness (EL) as narrated by frail older people. METHOD: Data were collected through individual narrative interviews with 23 people 76-101 years old receiving long-term care and services. A phenomenological hermeneutical analysis was performed, including a naive reading and two structural analyses as a basis for a comprehensive understanding of EL. RESULT: Four themes were identified related to meanings of EL: (1) being trapped in a frail and deteriorating body; (2) being met with indifference; (3) having nobody to share life with; and (4) lacking purpose and meaning. These intertwined themes were synthesized into a comprehensive understanding of EL as 'being disconnected from life'. CONCLUSION: Illness and physical limitation affects access to the world. When being met with indifference and being unable to share one's thoughts and experiences of life with others, a sense of worthlessness is reinforced, triggering an experience of meaninglessness and EL, i.e. disconnection from life. It is urgent to develop support strategies that can be used by health care professionals to address older people in vulnerable situations, thereby facilitating connectedness. PMID- 28714736 TI - Does Music Therapy Improve Anxiety and Depression in Alzheimer's Patients? AB - OBJECTIVE: To evaluate the effectiveness of the implementation of a short protocol of music therapy as a tool to reduce stress and improve the emotional state in patients with mild Alzheimer's disease. METHODS: A sample of 25 patients with mild Alzheimer's received therapy based on the application of a music therapy session lasting 60 min. Before and after the therapy, patient saliva was collected to quantify the level of salivary cortisol using the Enzyme-Linked ImmunoSorbent Assay (ELISA) immunoassay technique and a questionnaire was completed to measure anxiety and depression (Hospital Anxiety and Depression Scale). RESULTS: The results show that the application of this therapy lowers the level of stress and decreases significantly depression and anxiety, establishing a linear correlation between the variation of these variables and the variation of cortisol. CONCLUSIONS: A short protocol of music therapy can be an alternative medicine to improve emotional variables in Alzheimer patients. PMID- 28714735 TI - Effect of Yoga Breathing (Pranayama) on Exercise Tolerance in Patients with Chronic Obstructive Pulmonary Disease: A Randomized, Controlled Trial. AB - OBJECTIVE: Pulmonary rehabilitation improves exercise tolerance in patients with chronic obstructive pulmonary disease (COPD). However, many patients do not have access to pulmonary rehabilitation programs. We hypothesized that an alternative to pulmonary rehabilitation to improve exercise tolerance is the practice of pranayama, or yoga breathing, which could be done independently at home. We also sought to determine whether yoga nonprofessionals could adequately teach pranayama to patients. DESIGN: Proof-of-concept, randomized, double-blind, controlled pilot trial. SETTINGS/LOCATION: Two academic pulmonary practices. SUBJECTS: Forty-three patients with symptomatic, moderate-to-severe COPD. INTERVENTIONS: Twelve weeks of pranayama plus education versus education alone. Two yoga professionals trained the research coordinators to conduct all pranayama teaching and monitored the quality of the teaching and the practice of pranayama by study participants. OUTCOME MEASURES: The primary outcome was a change in the 6-min walk distance (6MWD). Secondary outcomes included changes in lung function, markers of oxidative stress and systemic inflammation, and measures of dyspnea and quality of life. RESULTS: The 6MWD increased in the pranayama group (least square mean [95% confidence interval] = 28 m [-5 to 61]) and decreased in the control group (-15 m [-47 to 16]), with a nearly significant treatment effect (p = 0.06) in favor of pranayama. Pranayama also resulted in small improvements in inspiratory capacity and air trapping. Both groups had significant improvements in various measures of symptoms, but no overall differences in respiratory system impedance or markers of oxidative stress or systemic inflammation. CONCLUSION: This pilot study successfully demonstrated that pranayama was associated with improved exercise tolerance in patients with COPD. Lay personnel were able to adequately teach patients to practice pranayama. These results suggest that pranayama may have significant clinical benefits for symptomatic patients with COPD, a concept that needs to be confirmed in future, larger clinical trials. PMID- 28714737 TI - Breastfeeding: A Review of Its Physiology and Galactogogue Plants in View of Traditional Persian Medicine. AB - INTRODUCTION: The beneficial effects of breastfeeding for the infant and mother are well recognized. Many natural products are reputed to be galactogogue agents in major Traditional Persian Medicine (TPM) textbooks. The aim of this study is to review those medicinal plants that are reported to be effective in increasing breast milk in TPM and to compare the data from TPM texts with the findings of modern pharmacological and clinical research. MATERIALS AND METHODS: Data on the medicinal plants used to increase breast milk were obtained from major TPM textbooks. A detailed search in PubMed, Science Direct, Scopus, Google Scholar, and Web of Science databases was performed to confirm the effects of medicinal plants mentioned in TPM on lactation in view of the identified pharmacological actions. RESULTS: Foeniculum vulgare, Anethum graveolens, Pimpinella anisum, Nigella sativa, and Vitex agnus-castus are among the most effective galactogogue TPM plants. Many pharmacologically relevant activities have been reported for these herbs. CONCLUSION: The use of traditional knowledge can pave the way toward finding effective phytopharmaceuticals for increasing breast milk. PMID- 28714738 TI - Dealing with daily challenges in dementia (deal-id study): process evaluation of the experience sampling method intervention 'Partner in Sight' for spousal caregivers of people with dementia. AB - OBJECTIVES: This study describes the process evaluation of the experience sampling method (ESM) intervention 'Partner in Sight' for spousal caregivers of people with dementia. The aim was to determine internal and external validity of the intervention and provide information for future implementation in clinical practice. METHOD: Qualitative and quantitative data on sampling quality (recruitment and randomization, reach) and intervention quality (relevance and feasibility, adherence to protocol) were evaluated using descriptive statistics and conventional content analysis. RESULTS: The participation rate included 31.4%. Due to recruitment difficulties and time constraints the original goal to include 90 caregivers was not met. The intervention was largely performed according to protocol and well received by the participants. Overall, the ESM derived feedback was considered supportive and increased participants' awareness of their feelings and behavior. A large variance was found in the extent to which caregivers applied the feedback into their daily lives. The importance of the personal coach to provide face-to-face feedback and stimulate caregivers to implement new insights into their daily lives was emphasized. Suggestions for improvement were to reduce the time intensity of the program, to better tailor the program content to one's personal situation, and to improve the ESM device. CONCLUSION: Although recruitment barriers were encountered, results indicate that future implementation of the ESM intervention 'Partner in Sight' is likely to be feasible in regular health care. If the intervention turns out to be (cost-) effective, a fine-tuned version of the program could be a valuable addition to the current health care system. PMID- 28714739 TI - Relationships Between Model Estimates and Actual Match-Performance Indices in Professional Australian Footballers During an In-Season Macrocycle. AB - PURPOSE: To assess and compare the validity of internal and external Australian football (AF) training-load measures for predicting match exercise intensity (MEI/min) and player-rank score (PRScore) using a variable dose-response model. METHODS: A cohort of 25 professional AF players (23 +/- 3 y, 188.3 +/- 7.2 cm, 87.7 +/- 8.4 kg) completed a 24-wk in-season macrocycle. In-season internal training and match load were quantified using session rating of perceived exertion (sRPE) and external load from satellite and accelerometer data. Using a training-impulse (TRIMP) calculation, external load (au) was represented as distance (TRIMPDist), distance >=4.16 m/s (TRIMPHSDist), and PlayerLoad (TRIMPPL). In-season training load, MEI/min, and PRScore were applied to a variable dose-response model, which provided estimates of MEI/min and PRScore. Predicted MEI/min and PRScore were correlated with actual measures from each match. The magnitude of the difference between MEI/min and PRScore estimates for each model input and the difference between the precision of internal and external load measures to predict MEI/min and PRScore were calculated using the effect size +/- 90% confidence interval (CI). RESULTS: Estimates of MEI/min demonstrated very large associations with actual MEI/min (r, 90% CI) (eg, TRIMPDist .76 +/- .13, and sRPESkills .73 +/- .14). Estimates of PRScore demonstrated associations of large magnitude with actual PRScore using the same inputs. Precision of actual MEI/min was lowest using sRPE compared with (ES +/- 90% CI) TRIMPDist, -.67 +/- .34, and TRIMPPL, -.91 +/- .39. There were trivial and unclear differences in the precision of PRScore estimates between TRIMP and sRPE inputs. CONCLUSIONS: Dose-response models from multiple training-load inputs can predict within-individual variation of MEI/min and PRScore. Internal and external training-input methods exhibited comparable predictive power. PMID- 28714740 TI - Do STAT3 inhibitors have potential in the future for cancer therapy? PMID- 28714741 TI - The efficacy and safety of adding either vildagliptin or glimepiride to ongoing metformin therapy in patients with type 2 diabetes mellitus. AB - OBJECTIVE: To compare the effects of either vildagliptin or glimepiride on glycemic variability, oxidative stress, and endothelial parameters in patients with type 2 diabetes mellitus (T2DM) inadequately controlled with metformin alone. METHODS: In this randomized, open-label, parallel study, 34 patients with T2DM being treated with metformin having an HbA1c of 7.0-10.0% were allocated into either the vildagliptin or glimepiride group. A mixed-meal tolerance test and 72-hour continuous glucose monitoring were conducted, and urinary 8-iso prostaglandinF2alpha (PGF2alpha) and endothelial-dependent flow-mediated dilatation (FMD) were evaluated at baseline and after 12 weeks of treatment. RESULTS: Similar significant improvements in HbA1c level were shown in both vildagliptin (-0.8%) and glimepiride (-0.9%) groups after treatment (Ps<0.001). The mean amplitude of glycemic excursions (MAGE) and the mean of daily differences (MODD) were significantly decreased by vildagliptin (P = 0.044 and P = 0.031, respectively) but not by glimepiride. Glimepiride was significantly associated with a higher incidence of hypoglycemia than vildagliptin (P = 0.005). There were no significant differences in urinary 8-iso-PGF2alpha or FMD between the two groups. CONCLUSIONS: Vildagliptin effectively improved glucose level with a significantly greater reduction in glycemic variability and hypoglycemia than glimepiride in patients with T2DM ongoing metformin therapy. The two drugs showed no significant differences in urinary 8-iso-PGF2alpha and FMD. TRIAL REGISTRATION: NCT01404676. PMID- 28714742 TI - Application of the European quality indicators for psychosocial dementia care in long-term care facilities in the Asia-Pacific region: a pilot study. AB - OBJECTIVES: An Asia-Pacific regional collaboration group conducted its first multi-country research project to determine whether or not European quality indicators (QIs) for psychosocial care in dementia could be implemented as a valid tool in residential aged care across seven Asia-Pacific sites (Australia, Hong Kong Special Administrative Region, Mainland China, Malaysia, Singapore, South Korea, and Thailand). METHOD: Following the European QI protocol, auditing and data extraction of medical records of consenting residents with dementia were conducted by trained auditors with relevant health care backgrounds. Detailed field notes by the auditors were also obtained to describe the characteristics of the participating care facilities, as well as key issues and challenges encountered, for each of the 12 QIs. RESULTS: Sixteen residential care facilities in the seven Asia-Pacific sites participated in this study. Data from 275 residents' records revealed each of the 12 Qis' endorsement varied widely within and between the study sites (0%-100%). Quality of the medical records, family and cultural differences, definitions and scoring of certain indicators, and time consuming nature of the QI administration were main concerns for implementation. CONCLUSION: Several items in the European QIs in the current format were deemed problematic when used to measure the quality of psychosocial care in the residential aged care settings in participating Asia-Pacific countries. We propose refinements of the European QIs for the Asian-Pacific context, taking into account multiple factors identified in this study. Our findings provide crucial insights for future research and implementation of psychosocial dementia care QIs in this region. PMID- 28714743 TI - An Alternative Test of Tackling Ability in Rugby League Players. AB - This study investigated the relationship between 2 tests of tackling ability, muscle strength, and power in semiprofessional rugby league players. Thirty-one players, 19 first-grade and 12 second-grade, underwent tests of muscle strength (1-repetition-maximum bench press, chin-up, and squat) and power (plyometric push up and countermovement jump). Tackling ability was assessed via video analysis of under-and over-the-ball tackle drills. The first-grade players had significantly greater scores in both the under-the-ball (P = .03, effect size [ES] = 0.84, 95% CI 0.07-1.50) and over-the-ball tackling-ability tests (P < .001, ES =1.86, 95% CI 0.83-2.52) than the second-grade players. A large, significant relationship was found between under- and over-the-ball tackling ability (r = .55, 95% CI .24 .76, P = .001). Lower-body strength (r = .37, 95% CI .02-.64, P = .04) was moderately associated with under-the-ball tackling ability, whereas over-the-ball tackling ability was moderately associated with plyometric push-up performance (r = .39, 95% CI .04-.65, P = .03). This study found that over-the-ball tackling ability was significantly associated with under-the-ball tackling in semiprofessional rugby league players. Furthermore, it was found that, compared with the second-grade players, the first-grade players had superior tackle ability in both tackle drills. In this study it was observed that plyometric push up peak power was significantly related to over-the-ball tackling ability and absolute lower-body strength was associated with under-the-ball tackling ability. These findings provide skill coaches and strength and conditioning staff a greater understanding of elements that contribute to effective tackling ability. PMID- 28714744 TI - Marathon Pace Control in Masters Athletes. AB - PURPOSE: Pacing strategies are key to overall performance outcome in distance running events. Presently, no literature has examined pacing strategies used by masters athletes of all running levels during a competitive marathon. Therefore, this study aimed to examine masters athletes' pacing strategies, categorized by gender, age, and performance level. METHODS: Data were retrieved from the 2015 TSC New York City Marathon for 31,762 masters athletes (20,019 men and 11,743 women). Seven performance-classification (PC) groupings were identified via comparison of overall completion time compared with current world records, appropriate to age and gender. Data were categorized via, age, gender, and performance level. Mean 5-km speed for the initial 40 km was calculated, and the fastest and slowest 5-km-split speeds were identified and expressed as a percentage faster or slower than mean speed. Pace range, calculated as the absolute sum of the fastest and slowest split percentages, was then analyzed. RESULTS: Significant main effects were identified for age, gender, and performance level (P < .001), with performance level the most determining factor. Athletes in PC1 displayed the lowest pace range (14.19% +/- 6.66%), and as the performance levels of athletes decreased, pace range increased linearly (PC2-PC7, 17.52% +/- 9.14% to 36.42% +/- 18.32%). A significant interaction effect was found for gender * performance (P < .001), with women showing a smaller pace range (-3.81%). CONCLUSIONS: High-performing masters athletes use more-controlled pacing strategies than their lower-ranked counterparts during a competitive marathon, independent of age and gender. PMID- 28714745 TI - Long-term use of inhaled corticosteroids and risk of upper respiratory tract infection in chronic obstructive pulmonary disease: a meta-analysis. AB - Recent studies have suggested that inhaled corticosteroids (ICS) may be associated with higher risks of tuberculosis and pneumonia in patients with COPD. However, it is not known whether ICS increases the risk of upper respiratory tract infection (URTI). Aim of this study was to explore the relationship between ICS and URTI. Through a comprehensive literature search of PubMed, EMBASE, Cochrane Library, and Google Scholar from inception to March 2016, we identified randomized controlled trials of ICS therapy lasting at least 6 months. A meta analysis by the Peto approach was also conducted to generate summary estimates comparing ICS with non-ICS treatment on the risk of URTI. A total of 14 studies involving 19,777 subjects were considered in the meta-analysis. Compared with non ICS treatment, ICS were associated with a significantly increased risk of URTI (Peto OR: 1.16; 95% CI: 1.05-1.29; I2 = 9%; p = .004). Subgroup analyzes were performed for different dose, high-dose ICS was associated with a significantly increased risk of URTI (Peto OR: 1.19; 95% CI: 1.05-1.34; I2 = 0%; p = .005), whereas low-dose ICS showed a non-significant increased risk of URTI (Peto OR: 1.10; 95% CI: 0.91-1.33; I2 = 0%; p = .32). Moreover, fluticasone was observed with an increased risk of URTI but not mometasone; high-dose fluticasone treatment was associated with a significantly higher risk of URTI but not low dose. These results suggested to us that ICS use may increase the risk of URTI in patients with COPD, but it should be further investigated. PMID- 28714746 TI - Variation of Age-Related Changes in Endurance Performance Between Modes of Locomotion in Men: An Analysis of Master World Records. AB - BACKGROUND: Age-related declines in sport performance are characteristic of all endurance and sprinting disciplines. However, it is not known if the mode of locomotion (ie, swimming, cycling or running) influences the age-related decline in sport performance in sprinting and endurance events. METHODS: To examine the age-related decline in 3 different modes of locomotion (ie, swimming, cycling, and running) for endurance and sprint events, the world-best performances achieved for men in the age groups 18-39, 40-44, 45-49, 50-54, 55-59, 60-64, 65 69, 70-74, 75-79, and 80-84 y were compared in swimming (1500 and 50 m), cycling (1 h and 200 m), and running (10 and 100 m). Each performance was considered as an average speed (throughout the distance), and the age-related decline in performance was expressed as a percentage of the world record (regardless of age group) for that discipline. RESULTS: The age-related decline in 1-h track cycling is less pronounced than in 1500-m swimming and 10-km running after 60 y. In contrast, the age-related decline was similar among the 3 locomotion modes for the sprinting events. CONCLUSION: The data show that the maintenance of high performance in cycling persists longer into old age than in running and swimming. PMID- 28714747 TI - Onset of white striping and progression into wooden breast as defined by myopathic changes underlying Pectoralis major growth. Estimation of growth parameters as predictors for stage of myopathy progression. AB - The broiler industry has incurred significant economic losses due to two muscle myopathies, white striping (WS) and wooden breast (WB), affecting the Pectoralis major (P. major) of commercial broilers. The present study documented macroscopic changes occurring with age/growth in the P. major and P. minor muscles of commercial broilers from day 2 through day 46 (n = 27/day). Distinct myopathic aberrations observed in both breast muscles corresponded to the onset of WB. These distinct morphological changes were used as determinants in developing a ranking system, defining the ontogeny of WB as the following four stages: (1) WS, (2) petechial epimysium haemorrhages, (3) intramuscular haemorrhages and (4) ischaemia. A cumulative logit proportional odds model was used to relate the rank probabilities with the following growth parameters: body weight, P. major and P. minor weight/yield/length/width/depth. The best-fit model included P. major length/width/depth, P. minor width, P. major and P. minor yield as predictors for rank. Increasing P. major depth, P. minor width and P. major yield increased the odds of falling into higher ranks (more severe myopathy). Conversely, increasing P. major length, P. major width and P. minor yield increased the odds of falling into smaller ranks (less severe myopathy). This study describes the macroscopic changes associated with WB ontogeny in the development of a ranking system and the contribution of growth parameters in the determination of rank (WB severity). Results suggest that physical measurements inherent to selection for high yielding broiler genotypes are contributing to the occurrence and severity of WS and WB. PMID- 28714748 TI - No adverse lung effects of 7- and 28-day inhalation exposure of rats to emissions from petrodiesel fuel containing 20% rapeseed methyl esters (B20) with and without particulate filter - the FuelHealth project. AB - Increased use of biofuels raises concerns about health effects of new emissions. We analyzed relative lung health effects, on Fisher 344 rats, of diesel engine exhausts emissions (DEE) from a Euro 5-classified diesel engine running on petrodiesel fuel containing 20% rapeseed methyl esters (B20) with and without diesel particulate filter (DPF). One group of animals was exposed to DEE for 7 days (6 h/day), and another group for 28 days (6 h/day, 5 days/week), both with and without DPF. The animals (n = 7/treatment) were exposed in whole body exposure chambers. Animals breathing clean air were used as controls. Genotoxic effects of the lungs by the Comet assay, histological examination of lung tissue, bronchoalveolar lavage fluid (BALF) markers of pulmonary injury, and mRNA markers of inflammation and oxidative stress were analyzed. Our results showed that a minor number of genes related to inflammation were slightly differently expressed in the exposed animals compared to control. Histological analysis also revealed only minor effects on inflammatory tissue markers in the lungs, and this was supported by flow cytometry and ELISA analysis of cytokines in BALF. No exposure related indications of genotoxicity were observed. Overall, exposure to DEE with or without DPF technology produced no adverse effects in the endpoints analyzed in the rat lung tissue or the BALF. Overall, exposure to DEE from a modern Euro 5 light vehicle engine run on B20 fuel with or without DPF technology produced no adverse effects in the endpoints analyzed in the rat lung tissue or the BALF. PMID- 28714749 TI - The Influence of Verbal and Tactile Feedback on Electromyographic Amplitude of the Shoulder Musculature During Common Therapeutic Exercises. AB - CONTEXT: Verbal and tactile feedback (VTF) during rehabilitation exercises can increase muscle activation, thus improving the therapeutic benefits. However, it is unclear which feedback method elicits the greatest electromyographic (EMG) amplitude. OBJECTIVE: To determine if the addition of tactile to verbal feedback (VF) increases EMG amplitude of selected shoulder musculature during scapular plane elevation (Ys), shoulder horizontal abduction with external rotation (Ts), and scapular retraction with external rotation (Ws). DESIGN: Repeated-measures cross-over design. SETTING: Biomechanics laboratory. PARTICIPANTS: A total of 30 physically active adults volunteered for this study-age = 20.23 (1.25) years; height = 1.71 (0.073) m; and mass = 70.11 (15.14) kg. INTERVENTIONS: Electromyography of the serratus anterior; upper, middle, and lower trapezii; and anterior and posterior deltoids was recorded during Ys, Ts, and Ws with VTF and VF alone during separate testing sessions. Participants completed baseline trials without feedback, then received VTF and VF across 2 counterbalanced sessions. MAIN OUTCOME MEASURES: Difference scores were calculated between prefeedback and postfeedback interventions, and the difference score between baseline measurements was used as a control. One-way analysis of variance of the difference scores was used to evaluate the influence of VTF and VF on EMG amplitude during Ys, Ts, and Ws. RESULTS: There was a significant difference between conditions for EMG amplitude of the middle trapezius (F2,28 = 4.09, P = .02) and serratus anterior (F2,28 = 3.91, P = .03) during Ys, the middle trapezius (F2,28 = 7.82, P = .001) during Ws, and the upper (F2,28 = 3.61, P = .03) and middle trapezii (F2,28 = 5.81, P = .01) during Ts. Post hoc testing revealed that both feedback conditions elicited greater EMG amplitude compared with no feedback, but there were no significant differences between the feedback conditions. CONCLUSIONS: The addition of tactile feedback to VF does not increase EMG amplitude compared with VF alone. This study indicates that feedback, regardless of type, is more beneficial than providing no feedback, for increasing EMG amplitude. PMID- 28714750 TI - "Hand in Glove": Using Qualitative Methods to Connect Research and Practice. AB - Recent work has espoused the idea that in applied sporting environments, "fast" working practitioners should work together with "slow"-working researchers. However, due to economical and logistical constraints, such a coupling may not always be practical. Therefore, alternative means of combining research and applied practice are needed. A particular methodology that has been used in recent years is qualitative research. Examples of qualitative methods include online surveys, 1-on-1 interviews, and focus groups. This article discusses the merits of using qualitative methods to combine applied practice and research in sport science. This includes a discussion of recent examples of the use of such methods in published journal articles, a critique of the approaches employed, and future directions and recommendations. The authors encourage both practitioners and researchers to use and engage with qualitative research with the ultimate goal of benefiting athlete health and sporting performance. PMID- 28714751 TI - Antidepressant efficacy of electroconvulsive therapy is associated with a reduction of the innate cellular immune activity in the cerebrospinal fluid in patients with depression. AB - OBJECTIVES: A bidirectional link between the antidepressant effects of electroconvulsive therapy (ECT) and the modulation of the immune system has been proposed. To elucidate the interplay between antidepressant treatment and macrophage/microglia activation in humans, we performed a study on the effects of the antidepressant treatment by ECT on markers of macrophage/microglia activation in patients with depression. METHODS: We measured six different markers (IL-6, neopterin, sCD14, sCD163 MIF and MCP1) of macrophage/microglia activation in the cerebrospinal fluid (CSF) and blood of 12 patients with a severe, treatment resistant depressive episode before and after a course of ECT. RESULTS: Some markers in the CSF of remitters were reduced after the ECT course and differed from non-remitters, but no differences were found before and after ECT independently from the antidepressant efficacy. CSF baseline levels of some markers could predict the reduction of depressive psychopathology during ECT. Higher CSF levels indicating increased macrophage/microglia activation at baseline predicted a better treatment response to ECT. CONCLUSIONS: Although the sample size was small, our data suggest that macrophages/microglia are involved in the pathophysiology of major depression and that antidepressant efficacy by ECT might be partly explained by the modulation of the innate immune system within the brain. PMID- 28714752 TI - Differences in the Load-Velocity Profile Between 4 Bench-Press Variants. AB - PURPOSE: To compare the load-velocity relationship between 4 variants of the bench-press (BP) exercise. METHODS: The full load-velocity relationship of 30 men was evaluated by means of an incremental loading test starting at 17 kg and progressing to the individual 1-repetition maximum (1RM) in 4 BP variants: concentric-only BP, concentric-only BP throw (BPT), eccentric-concentric BP, and eccentric-concentric BPT. RESULTS: A strong and fairly linear relationship between mean velocity (MV) and %1RM was observed for the 4 BP variants (r2 > .96 for pooled data and r2 > .98 for individual data). The MV associated with each %1RM was significantly higher in the eccentric-concentric technique than in the concentric-only technique. The only significant difference between the BP and BPT variants was the higher MV with the light to moderate loads (20-70%1RM) in the BPT using the concentric-only technique. MV was significantly and positively correlated between the 4 BP variants (r = .44-.76), which suggests that the subjects with higher velocities for each %1RM in 1 BP variant also tend to have higher velocities for each %1RM in the 3 other BP variants. CONCLUSIONS: These results highlight the need for obtaining specific equations for each BP variant and the existence of individual load-velocity profiles. PMID- 28714754 TI - Clinical outcomes associated with carbapenem resistant Klebsiella pneumoniae (CRKP) in abdominal solid organ transplant (SOT) recipients. PMID- 28714753 TI - Pediatric Acute-Onset Neuropsychiatric Syndrome Response to Oral Corticosteroid Bursts: An Observational Study of Patients in an Academic Community-Based PANS Clinic. AB - BACKGROUND: Sudden-onset severe obsessive-compulsive symptoms and/or severely restrictive food intake with at least two coinciding, similarly debilitating neuropsychiatric symptoms define Pediatric Acute-onset Neuropsychiatric Syndrome (PANS). When associated with Group A Streptococcus, the syndrome is labeled Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal infections (PANDAS). An abnormal immune response to infection and subsequent neuroinflammation is postulated to play an etiologic role. Most patients have a relapsing-remitting course. Treatment outcome data for youth with PANS and PANDAS are limited. METHODS: One hundred seventy-eight consecutive patients were seen in the Stanford PANS clinic between September 1, 2012 and January 15, 2016, of whom 98 met PANS or PANDAS criteria, had a single episode of PANS or relapsing/remitting course, and collectively experienced 403 flares. Eighty-five flares were treated with 102 total courses of oral corticosteroids of either short (4-5 days) or long (5 days-8 weeks) duration. Response to treatment was assessed within 14 days of initiating a short burst of corticosteroids and at the end of a long burst based on clinician documentation and patient questionnaires. Data were analyzed by using multilevel random-effects models. RESULTS: Patients experienced shorter flares when treated with oral corticosteroids (6.4 +/- 5.0 weeks vs. 11.4 +/- 8.6 weeks) than when not treated (p < 0.001), even after controlling for presumed confounding variables, including age at flare, weeks since onset of PANS illness, sex, antibiotic treatment, prophylactic antibiotics, previous immunomodulatory treatment, maintenance anti-inflammatory therapy, psychiatric medications, and cognitive behavioral therapy (p < 0.01). When corticosteroids were given for the initial PANS episode, flares tended to be shorter (10.3 +/- 5.7 weeks) than when not treated (16.5 +/- 9.6 weeks) (p = 0.06). This difference was statistically significant after controlling for the relevant confounding variables listed earlier (p < 0.01). Earlier use of corticosteroids was associated with shorter flare durations (p < 0.001). Longer courses of corticosteroids were associated with a more enduring impact on the duration of neuropsychiatric symptom improvement (p = 0.014). CONCLUSION: Corticosteroids may be a helpful treatment intervention in patients with new onset and relapsing/remitting PANS and PANDAS, hastening symptom improvement or resolution. When corticosteroids are given earlier in a disease flare, symptoms improve more quickly and patients achieve clinical remission sooner. Longer courses of corticosteroids may result in more durable remissions. A double-blind placebo-controlled clinical trial of corticosteroids in PANS is warranted to formally assess treatment efficacy. PMID- 28714755 TI - Foot and Ankle Kinematics During Descent From Varying Step Heights. AB - In the general population, one-third of incidences during step negotiation occur during the transition to level walking. Furthermore, falls during curb negotiation are a common cause of injury in older adults. Distal foot kinematics may be an important factor in determining injury risk associated with transition step negotiation. The purpose of this study was to identify foot and ankle kinematics of uninjured individuals during descent from varying step heights. A 7 segment foot model was used to quantify kinematics as participants walked on a level walkway, stepped down a single step (heights: 5 cm, 15 cm, 25 cm), and continued walking. As step height increased, landing strategy transitioned from the rearfoot to the forefoot, and the rearfoot, lateral and medial midfoot, and medial forefoot became more plantar flexed. During weight acceptance, sagittal plane range of motion of the rearfoot, lateral midfoot, and medial and lateral forefoot increased as step height increased. The changes in landing strategy and distal foot function suggest a less stable ankle position at initial contact and increased demand on the distal foot at initial contact and through the weight acceptance phase of transition step negotiation as step height increases. PMID- 28714756 TI - Study of the influence of coating methods on lipid spheres manufactured on rotor fluidized bed process. AB - Different previous works have shown that various kinds of spheres can be manufactured by rotor granulation in a 'single-pot process' using a lipid base: hydrogenated castor oil. This single-pot technology is based on wet granulation where all components are placed in the powder form in the rotor bowl; then, they are continuously suspended in a fluidized air, with a tangentially sprayed liquid solution. This process allows the granulation and manufacturing of sphere during the same time. Previous experiments have studied the influence of the formulation and the manufacturing process parameters on spheres in terms of feasibility and dissolution properties. Both the spraying time and the weight of liquid sprayed were found to be the most relevant parameters that govern the final quality of the sphere. Now, in a second part of the work, a first comparison is made with two different fluid bed methods: the tangential rotor spray and the Wurster bottom spray for coating the lipid spheres previously manufactured with the rotor tangential spray. The external aspect of the coated spheres manufactured has been evaluated with an electronic microscopy analysis and a study of dissolution properties of the active ingredient has been done by USP in vitro dissolution tests. PMID- 28714757 TI - Comparative Effects of 4 Single-Leg Squat Exercises in Subjects With Gluteus Medius Weakness. AB - CONTEXT: Of the weight-bearing exercises, single-leg squats (SLSs) represent one of the most commonly used hip-strengthening exercises that require more gluteus medius (GMED) activity. To date, no studies have investigated how the 4 SLS exercises affect muscle imbalance of GMED, tensor fasciae latae (TFL), and adductor longus (AL), and kinematics of hip. OBJECTIVE: To investigate the hip muscle activities, onset time, and kinematics during 4 different SLS exercises (unilateral squat, unilateral wall-squat [UWS], lateral step-down, and front step down) in subjects with GMED weakness. DESIGN: Repeated-measures experimental design. SETTING: Research laboratory. PARTICIPANTS: Twenty-two subjects (11 males and 11 females) participated in this study and were compared using 1-way repeated measures analysis of variance. MAIN OUTCOME MEASURES: Surface electromyography was used to measure the muscle activities and onset time of the GMED, TFL, and AL, and 3-dimensional motion tracking system was used to measure the hip adduction and internal/external rotation angles during SLS exercises. One-way repeated-measures analysis of variance was used at a significance level of P < .05. RESULTS: The UWS produced higher GMED/TFL activity ratio and lower GMED/TFL onset time ratio than in the other 3 exercises (P < .05). No difference in GMED/AL activity ratio and GMED/AL onset time ratio was observed. The hip adduction angle was greater in UWS than in the other 3 exercises (P < .05). As for the hip internal/external rotation, lateral step-down exhibited higher hip internal rotation angle than front step-down (P < .05). CONCLUSION: The UWS may be recommended as an effective exercise for the subjects with GMED weakness, but they should take care to avoid excessive hip adduction during the exercise. PMID- 28714759 TI - Effects of Rigid and Kinesio Taping on Shoulder Rotation Motions, Posterior Shoulder Tightness, and Posture in Overhead Athletes: A Randomized Controlled Trial. AB - CONTEXT: Alterations in posture and motion patterns are thought to play a role in developing shoulder injuries in overhead athletes. Taping is widely used in the sporting population, but there are limited empirical data regarding its effectiveness. OBJECTIVES: To determine and compare the effects of rigid and kinesio taping on shoulder rotation motions, posterior shoulder tightness (PST), and posture in overhead athletes. DESIGN: Randomized controlled trial. SETTING: Athletic training rooms. PARTICIPANTS: Eighty-six asymptomatic elite overhead athletes. INTERVENTIONS: Participants were randomly divided into 4 groups: rigid taping group (RTG) that underwent therapeutic rigid taping, kinesio taping group (KTG) that underwent therapeutic kinesio taping, placebo group that underwent placebo kinesio taping (shoulder and scapular region taping for taping groups), and control group (no taping). MAIN OUTCOME MEASURES: Shoulder rotation motions, PST, and head and shoulder posture were evaluated at baseline, immediately after application and 60 to 72 hours after application for all groups. RESULTS: Glenohumeral internal rotation increased immediately (P < .001) and at 60 to 72 hours after application in the KTG (P = .01), whereas it decreased immediately after application in the RTG (P < .001). Immediately after application, total rotation range of motion increased in the KTG (P =.02) and decreased in the RTG (P < .001), and there was a difference between groups (P = .02). Immediately after application, PST increased in the RTG (P < .001); after 60 to 72 hours, it decreased in the KTG (P = .04) and increased in the RTG (P = .01). Posture outcomes did not change significantly (P > .05). CONCLUSIONS: Kinesio taping may improve and rigid taping may worsen glenohumeral internal rotation and PST in overhead athletes. For increasing total rotation range of motion, kinesio taping is superior to rigid taping. Taping did not affect posture. Short-term kinesio taping in overhead athletes may be useful to improve glenohumeral internal rotation, total rotation range of motion, and PST. PMID- 28714758 TI - Even if they are not aware of it, general practitioners improve well-being in their adolescent patients. AB - BACKGROUND: Most adolescents consult their general practitioner (GP) for common reasons, somatic or administrative but many of them have hidden feelings of distress. OBJECTIVES: To assess the immediate impact of 'ordinary' consultations on feelings of distress among adolescents and to compare adolescents experiencing difficulties (D) to those with no difficulties (N). To analyse how accurately GPs assess the impact of their consultation on adolescents' feelings. METHODS: GPs were randomly selected from two non-contiguous French administrative areas between April and June 2006. Fifty-three GPs gave two questionnaires to the first 10 to 15 adolescents aged 12 to 20 seen in consultation. One questionnaire was issued before the consultation and the other one afterwards. Adolescents had to position themselves about different aspects of well-being and say where they would seek help if they had problems. A GP questionnaire assessed how well they estimated their impact on the adolescent's feeling of well-being. RESULTS: Six hundred and sixty-five adolescents were assessed. They reported feeling better about their health, being able to talk, having someone to talk to or to confide in and on feeling understood. The D group (n = 147) felt significantly better compared to the N group (n = 518). GPs tended to underestimate this improvement, especially regarding adolescents in the D group feeling better about their health. CONCLUSIONS: Consulting a GP generates increased well-being among adolescents, especially for those experiencing difficulties. GPs tend to underestimate the positive impact they may have. Further studies are needed to explore if this benefit is permanent over time. PMID- 28714760 TI - Houston, We Still Have a Problem. AB - Apollo 13 was initially looking like it would be the smoothest flight ever. After the explosion of an oxygen tank, however, the astronauts were close to spending the rest of their lives in rotation around the planet. This well-known incident is used to further discuss the link, or lack thereof, between sport-science research and current field practices. There is a feeling that the academic culture and its publishing requirements have created a bit of an Apollo 13-like orbiting world (eg, journals and conferences) that is mostly disconnected from the reality of elite performance. The author discusses how poor research discredits our profession and provides some examples from the field where the research does not apply. In fact, the reality is that sport scientists often do not have the right answers. Some perspectives to improve translation are finally discussed, including a rethink of the overall publishing process: promotion of relevant submission types (eg, short-paper format, short reports, as provided by IJSPP), improvement of the review process (faster turnaround, reviewers identified to increase accountability, and, in turn, review quality), and media types (eg, free downloads, simplified versions published in coaching journals, book chapters, infographics, dissemination via social media). When it comes to guiding practitioners and athletes, instead of using an evidence-based approach, we should rather promote an "evidence-led" or "informed-practice" approach-one that appreciates context over simple scientific conclusions. PMID- 28714761 TI - Gamma irradiation of medicinally important plants and the enhancement of secondary metabolite production. AB - PURPOSE: The profitable production of some important plant-based secondary metabolites (ginsenosides, saponins, camptothecin, shikonins etc.) in vitro by gamma irradiation is a current area of interest. We reviewed different types of secondary metabolites, their mode of synthesis and effect of gamma-radiation on their yield for different plants, organs and in vitro cultures (callus, suspension, hairy root). Special effort has been made to review the biochemical mechanisms underlying the increase in secondary metabolites. A comparison of yield improvement with biotic and abiotic stresses was made. RESULTS: Phenolic compounds increase with gamma-irradiation in whole plants/plant parts; psoralen content in the common herb babchi (Psoralea corylifolia) was increased as high as 32-fold with gamma-irradiation of seeds at 20 kGy. The capsaicinoids, a phenolic compound increased about 10% with 10 kGy in paprika (Capsicum annum L.). The in vitro studies show all the three types of secondary metabolites are reported to increase with gamma-irradiation. Stevioside, total phenolic and flavonoids content were slightly increased in 15 Gy-treated callus cultures of stevia (Stevia rebaudiana Bert.). In terpenoids, total saponin and ginsenosides content were increased 1.4- and 1.8-fold, respectively, with 100 Gy for wild ginseng (Panax ginseng Meyer) hairy root cultures. In alkaloids, camptothecin yield increased as high as 20-fold with 20 Gy in callus cultures of ghanera (Nothapodytes foetida). Shikonins increased up to 4-fold with 16 Gy in suspension cultures of purple gromwell (Lithospermum erythrorhizon S.). The enzymes associated with secondary metabolite production were increased with gamma irradiation of 20 Gy; namely, phenylalanine ammonia-lyase (PAL) for phenolics, chalcone synthase (CHS) for flavonoids, squalene synthase (SS), squalene epoxidase (SE) and oxidosqualene cyclases (OSC) for ginsenosides and PHB (p hydroxylbenzoic acid) geranyl transferase for shikonins. CONCLUSIONS: An increase in secondary metabolites in response to various biotic and abiotic stresses is compared with ionizing radiation. A ~5- to 20-fold increase is noted with ~20 Gy irradiation dose. It increases the yield of secondary metabolites by enhancing the activity of certain key biosynthetic enzymes. Identification of the optimum dose is the important step in the large-scale production of secondary metabolites at industrial level. PMID- 28714762 TI - Effectiveness of PRP Injection in Reducing Recovery Time of Acute Hamstring Injury: A Critically Appraised Topic. AB - Clinical Scenario: Hamstring strains are common athletic injuries, with a high recurrence rate (34%). Recently, platelet-rich plasma (PRP) injections have gained popularity as a potential treatment option to accelerate healing of hamstring injury. Focused Clinical Question: Does the combination of PRP injection and rehabilitation decrease recovery time of acute hamstring injury as compared to rehabilitation alone in college athletes? Summary of Key Findings: A literature search resulted in 3 randomized controlled trials. One study showed benefits in various outcome measures with PRP, compared to rehabilitation alone, while 2 showed no benefits. One study reported improved pain, ultrasonography regenerative indications, and recovery time with PRP injection following acute hamstring injury; however, larger studies have shown no benefits. The literature demonstrates conflicting evidence regarding benefits of PRP injections in hamstring injuries. Clinical Bottom Line: At this time, PRP injections cannot be recommended as having value for hamstring injuries, compared to rehabilitation alone. Strength of Recommendation: Due to inconsistent or limited quality patient oriented evidence in existing literature, the strength of this recommendation is grade B, based on the strength of recommendation taxonomy. PMID- 28714763 TI - Effects of Trial Duration on Intrasession Reliability of Single Leg Balance Testing on Stable and Unstable Surfaces. AB - CONTEXT: Single leg balance testing is a commonly used tool in sports medicine; however, there has been no consensus on trial duration needed to obtain reliable measures. OBJECTIVE: This investigation sought to determine the minimum trial duration required to obtain the highest intrasession single and average trial reliability for single leg balance testing on stable and unstable surfaces using dominant and nondominant limbs. DESIGN: Intrasession reliability. SETTING: Biomechanics laboratory. PARTICIPANTS: 70 healthy (35 men, 35 women), physically active young adults aged 22.8 +/- 2.8 y divided into 3 subgroups (n = 10, 30, 30) across a 3-phase study. METHODS: 3 phases of single leg balance testing were performed. For phase 1, the duration of time each participant could maintain posture on each limb/surface were computed. Phase 2 considered performance for 6 cumulative time intervals (5s, 10s, 15s, 20s, 25s, 30s). Phase 3 served to solidify results of phase 2 by computing reliability of 15s trials. MAIN OUTCOME MEASURES: Overall stability index of the center of pressure and platform tilt. RESULTS: Intraclass correlation coefficients for phase 2 ranged from .74 (5s interval for nondominant limb on unstable surface) to .94 (20s interval for nondominant limb on stable surface). Phase 3 intraclass correlation coefficients ranged from .66 to .78 for single trial and .85 to .92 for 3 trial average with coefficients of variation ranging from 23.9% to 40.4% for single trial and 13.8% to 23.0% for 3 trial average. CONCLUSIONS: These results ultimately suggest 15s as the optimal trial duration to provide reliable measures while reducing compensatory event occurrence. PMID- 28714764 TI - The Effect of Abdominal Muscle Activation Techniques on Trunk and Lower Limb Mechanics During the Single-Leg Squat Task in Females. AB - CONTEXT: Females suffer 4 to 6 times more noncontact anterior cruciate ligament (ACL) injuries than males due to neuromuscular control deficits of the hip musculature leading to increases in hip adduction angle, knee abduction angle, and knee abduction moment during dynamic tasks such as single-leg squats. Lateral trunk displacement has been further related to ACL injury risk in females, leading to the incorporation of core strength/stability exercises in ACL preventative training programs. However, the direct mechanism relating lateral trunk displacement and lower limb ACL risk factors is not well established. OBJECTIVE: To assess the relationship between lateral trunk displacement and lower limb measures of ACL injury risk by altering trunk control through abdominal activation techniques during single-leg squats in healthy females. DESIGN: Interventional study setting: movement and posture laboratory. PARTICIPANTS: A total of 13 healthy females (21.3 [0.88] y, 1.68 [0.07] m, and 58.27 [5.46] kg). INTERVENTION: Trunk position and lower limb kinematics were recorded using an optoelectric motion capture system during single-leg squats under differing conditions of abdominal muscle activation (abdominal hollowing, abdominal bracing, and control), confirmed using surface electromyography. MAIN OUTCOME MEASURES: Lateral trunk displacement, peak hip adduction angle, peak knee abduction angle/moment, and average muscle activity from bilateral internal oblique, external oblique, and erector spinae muscles. RESULTS: No differences were observed for peak lateral trunk displacement, peak hip adduction angle, or peak knee abduction angle/moment. Abdominal hollowing and bracing elicited greater muscle activation than the control condition, and bracing was greater than hollowing in 4 of 6 muscles recorded. CONCLUSION: The lack of reduction in trunk, hip, and knee measures of ACL injury risk during abdominal hollowing and bracing suggests that these techniques alone may provide minimal benefit in ACL injury prevention training. PMID- 28714765 TI - Comparison of Estrogen and Progesterone Receptor Antibody Reagents Using Proficiency Testing Data. AB - CONTEXT: - Immunohistochemical analysis of estrogen receptor (ER) and progesterone receptor (PgR) expression in breast cancer is the current standard of care and directly determines therapy. In 2010 the American Society of Clinical Oncology and the College of American Pathologists (ASCO/CAP) published guidelines for ER and PgR predictive testing, encompassing preanalytic, analytic, postanalytic factors; antibody validation; and proficiency testing. OBJECTIVE: - To compare the performance of different antibody reagents for ER and PgR immunohistochemical analysis by using CAP proficiency testing data. DESIGN: - The CAP PM2 survey uses tissue microarrays of ten 2-mm cores per slide. We analyzed survey data from 80 ER and 80 PgR cores by antibody clone from more than 1200 laboratories. RESULTS: - Laboratories used the ER antibodies SP1 (72%), 6F11 (17%), 1D5 (3%), and the PgR antibodies 1E2 (61%), 16 (12%), PgR-636 (13%), PgR 1294 (8%) in 2015. While 63 of 80 ER cores (79%) were scored similarly using each of the 3 antibodies, there were significant differences for others, with SP1 yielding more positive interpretations. Four cores were scored as ER negative by more than half of the laboratories using 1D5 or 6F11, while SP1 produced positive results in more than 70% of laboratories using that antibody. Despite the greater variety of PgR antibody reagents and greater PgR tumor heterogeneity, 61 of 80 cores (76%) were scored similarly across the 4 PgR antibodies. CONCLUSIONS: - Accurate ER and PgR testing in breast cancer is crucial for appropriate treatment. The CAP proficiency testing data demonstrate differences in staining results by ER clone, with SP1 yielding more positive results. PMID- 28714767 TI - Comparison of Methods of Calculating Dynamic Strength Index. AB - PURPOSE: To determine the reliability and variability of the Dynamic Strength Index (DSI) calculated from squat-jump (SJ) vs countermovement-jump (CMJ) peak force (PF) and to compare DSI values between methods. METHODS: Male youth soccer and rugby league players (N = 27; age 17.2 +/- 0.7 y, height 173.9 +/- 5.7 cm, body mass 71.1 +/- 7.2 kg) performed 3 trials of the SJ, CMJ, and isometric midthigh pull (IMTP) on 2 separate days. DSI was calculated by dividing the PF during each jump by the IMTP PF. RESULTS: DSI-SJ exhibited moderate (intraclass correlation coefficient [ICC] = .419) within-session reliability and high variability (percentage coefficient of variation [%CV] = 15.91) during session 1; however, this improved noticeably during session 2 (ICC = .948, %CV = 4.03). In contrast, DSI-CMJ showed nearly perfect within-session reliability (ICC = .920 .952) and low variability (%CV = 3.80-4.57) for both sessions. Moreover, DSI-SJ values demonstrated a small yet significant increase between sessions (P = .01, d = 0.37), whereas only a trivial and nonsignificant increase was observed for DSI CMJ between sessions (P = .796, d = 0.07). Between-sessions reliability was very high for the DSI-SJ (ICC = .741) and nearly perfect for the DSI-CMJ (ICC = .924). There was no significant or meaningful difference (P = .261, d = 0.12) between DSI-SJ (0.82 +/- 0.18) and DSI-CMJ (0.84 +/- 0.15). CONCLUSIONS: Practitioners should use DSI-CMJ, as it is a more reliable measure than DSI-SJ, although it produces similar ratios. PMID- 28714766 TI - Cancer-Related Fatigue in Adolescents and Young Adults After Cancer Treatment: Persistent and Poorly Managed. AB - Cancer-related fatigue is the most prevalent and distressing symptom experienced by adolescents and young adults (AYAs). An electronic survey was undertaken to ascertain current fatigue management and perceptions of its effectiveness. Eighty five percent of responders (68/80) experienced fatigue, and it was worse more than 1 year after cancer treatment ended, compared to <1 year (p = 0.007). Forty one percent received no fatigue management. Although advice to exercise was the most frequent intervention, the greatest impact of fatigue was on the ability to exercise and most did not find exercise advice helpful. Early intervention is warranted, supporting AYAs to persevere with increasing activity. PMID- 28714769 TI - Effects of Meridian Acupressure Massage on Body Composition, Edema, Stress, and Fatigue in Postpartum Women. AB - OBJECTIVES: This study aims to investigate the effects of meridian acupressure massage on body composition, edema, stress, and fatigue in postpartum women. DESIGN: A quasi-experimental design with a nonequivalent control group was utilized. SETTINGS/LOCATION: The Postpartum Care Center of Women's Hospital in Gwangju City, Republic of Korea. SUBJECTS: The study group consisted of 39 postpartum women, 19 in the experimental group and 20 in the control group, recruited from the postpartum care center of Women's Hospital in Gwangju city, South Korea. INTERVENTIONS: The experimental group was provided with meridian acupressure massage for 90 min daily over 5 days as an experimental therapy. OUTCOME MEASURES: Body composition (body weight, BMI, total body water, ECW ratio, LBM, and body fat) Edema (subjective edema, average girth of the upper limbs, and average girth of the lower limbs), Stress (psychological stress and physical stress), and Fatigue. RESULTS: The experimental group demonstrated a significantly larger decrease compared with the control group in measures of body composition, edema, total subjective stress, psychological stress, and subjective fatigue. CONCLUSIONS: Meridian acupressure massage can hasten the return to original body composition after childbirth. PMID- 28714768 TI - Macronutrient composition of a morning meal and the maintenance of attention throughout the morning. AB - BACKGROUND: At present, the impact of macronutrient composition and nutrient intake on sustained attention in adults is unclear, although some prior work suggests that nutritive interventions that engender slow, steady glucose availability support sustained attention after consumption. A separate line of evidence suggests that nutrient consumption may alter electroencephalographic markers of neurophysiological activity, including neural oscillations in the alpha-band (8-14 Hz), which are known to be richly interconnected with the allocation of attention. It is here investigated whether morning ingestion of foodstuffs with differing macronutrient compositions might differentially impact the allocation of sustained attention throughout the day as indexed by both behavior and the deployment of attention-related alpha-band activity. METHODS: Twenty-four adult participants were recruited into a three-day study with a cross over design that employed a previously validated sustained attention task (the Spatial CTET). On each experimental day, subjects consumed one of three breakfasts with differing carbohydrate availabilities (oatmeal, cornflakes, and water) and completed blocks of the Spatial CTET throughout the morning while behavioral performance, subjective metrics of hunger/fullness, and electroencephalographic (EEG) measurements of alpha oscillatory activity were recorded. RESULTS: Although behavior and electrophysiological metrics changed over the course of the day, no differences in their trajectories were observed as a function of breakfast condition. However, subjective metrics of hunger/fullness revealed that caloric interventions (oatmeal and cornflakes) reduced hunger across the experimental day with respect to the non-caloric, volume-matched control (water). Yet, no differences in hunger/fullness were observed between the oatmeal and cornflakes interventions. CONCLUSION: Observation of a relationship between macronutrient intervention and sustained attention (if one exists) will require further standardization of empirical investigations to aid in the synthesis and replicability of results. In addition, continued implementation of neurophysiological markers in this domain is encouraged, as they often produce nuanced insight into cognition even in the absence of overt behavioral changes. ClinicalTrials.gov Identifier: NCT03169283. PMID- 28714770 TI - On the Nature of Clinical Evaluations With Low Sensitivity for Concussion-Related Balance Deficits. PMID- 28714771 TI - Effect of Acute Static Stretching on Lower Limb Movement Performance Using STABL Virtual Reality System. AB - CONTEXT: The effect of acute static stretching (ASS) on the lower limb reaction time (RT) has been recently questioned to decrease the risk of falling and injuries in situations requiring a rapid reaction, as in the cases of balance disturbance. OBJECTIVE: The main purpose of this study was to detect the effect of ASS on the lower limb RT using a virtual reality device. DESIGN: Two-group control group design. SETTING: Research laboratory. PARTICIPANTS: The control and experimental groups were formed randomly from 60 female university students. INTERVENTION: Each participant in the experimental group was tested before and after ASS for the quadriceps, hamstrings, and planter flexor muscles, and compared with the control group with warming-up exercise alone. The stretching program involved warming up in the form of circular running inside the lab for 5 minutes followed by stretching of each muscle group three times, to the limit of discomfort of 45 seconds, with resting period of 15 seconds between stretches. MAIN OUTCOME MEASURES: The measurements included the RT of the dominant lower extremity using the dynamic stability program STABL Virtual Reality System (model no. DIZ 2709; Motekforce Link). RESULTS: There was a statistically significant reduction (F = 162, P < .05) in posttest RT between the 2 groups and significant decrease in RT after stretching in the experimental group (7.5%; P < .05). CONCLUSION: ASS of the lower limb muscles tends to decrease the lower limb RT and improve movement performance. PMID- 28714772 TI - Can typical US home visits affect infant attachment? Preliminary findings from a randomized trial of Healthy Families Durham. AB - US government-funded early home visiting services are expanding significantly. The most widely implemented home visiting models target at-risk new mothers and their infants. Such home visiting programs typically aim to support infant-parent relationships; yet, such programs' effects on infant attachment quality per se are as yet untested. Given these programs' aims, and the crucial role of early attachments in human development, it is important to understand attachment processes in home visited families. The current, preliminary study examined 94 high-risk mother-infant dyads participating in a randomized evaluation of the Healthy Families Durham (HFD) home visiting program. We tested (a) infant attachment security and disorganization as predictors of toddler behavior problems and (b) program effects on attachment security and disorganization. We found that (a) infant attachment disorganization (but not security) predicted toddler behavior problems and (b) participation in HFD did not significantly affect infant attachment security or disorganization. Findings are discussed in terms of the potential for attachment-specific interventions to enhance the typical array of home visiting services. PMID- 28714773 TI - Impact of Martial Arts (Judo, Karate, and Kung Fu) on Bone Mineral Density Gains in Adolescents of Both Genders: 9-Month Follow-Up. AB - PURPOSE: To compare bone mineral density (BMD) gains in adolescents of both genders stratified according to different martial art styles in a 9-month follow up study. METHODS: The longitudinal study consisted of 29 adolescents of both genders and age between 11 and 17 years stratified into a control group (not engaged in any sport) and 50 fighters (kung fu/karate, n = 29; judo, n = 21). All 79 subjects underwent anthropometric measures (weight, height, leg length, and height set) and dual-energy X-ray absorptiometry (BMD, in g/cm2) at 2 moments, baseline and 9 months later. Maturity offset (age at peak height velocity), lean soft tissue, chronological age, and resistance training were treated as covariates. RESULTS: Male judoists presented higher gains in BMD-spine [0.098 g/cm2 (95% confidence interval, 0.068-0.128)] than control group [0.040 g/cm2 (95% confidence interval, 0.011-0.069)] (post hoc test with P = .030). There was no effect of martial art on BMD gains among girls. Independently of gender, in all multivariate models, lean soft tissue constituted the most relevant covariate. CONCLUSIONS: Judo practice in adolescents affected the bone accrual significantly after 9-month follow-up compared with controls, mainly in boys. PMID- 28714774 TI - Small-Sided Games in Elite Soccer: Does One Size Fit All? AB - PURPOSE: To compare the peak intensity of typical small-sided games (SSGs) with those of official matches in terms of running demands and mechanical work (MechW) over different rolling average durations and playing positions. METHODS: Data were collected in 21 players (25 [5] y, 181 [7] cm, and 77 [7] kg) belonging to an elite French football team. SSG data were collected over 2 seasons during typical training sessions (249 files, 12 [4] per player) and official matches (n = 12). Players' locomotor activity was recorded using 5-Hz Global Positioning System. Total distance (m), high-speed distance (HS, distance above 14.4 km.h-1, m), and MechW (a.u.) were analyzed during different rolling average periods (1-15 min). The SSGs examined were 4v4+goalkeepers (GKs), 6v6+GKs, 8v8+GKs, and 10v10+GKs. RESULTS: Peak total distance and HS during 4v4, 6v6, and 8v8 were likely-to-most likely lower than during matches (effect size: -0.59 [+/-0.38] to 7.36 [+/-1.20]). MechW during 4v4 was likely-to-most likely higher than during matches (1-4 min; 0.61 [+/-0.77] to 2.30 [+/-0.64]). Relative to their match demands, central defenders performed more HS than other positions (0.63 [+/-0.81] to 1.61 [+/-0.52]) during 6v6. Similarly, central midfielders performed less MechW than the other positions during 6v6 (0.68 [+/-0.72] to 1.34 [+/-0.99]) and 8v8 (0.73 [+/-0.50] to 1.39 [+/-0.32]). CONCLUSION: Peak locomotor intensity can be modulated during SSGs of various formats and durations to either overload or underload match demands, with 4v4 placing the greatest and the least emphasis on MechW and HS, respectively. Additionally, in relation to match demands central defenders and central midfielders tend to be the most and least overloaded during SSGs, respectively. PMID- 28714775 TI - The implementation of guided Internet-based cognitive behaviour therapy for panic disorder in a routine-care setting: effectiveness and implementation efforts. AB - Panic disorder is a common mental disorder. Guided Internet-based cognitive behavioural therapy (Guided Internet-based cognitive behaviour therapy (ICBT)) is a promising approach to reach more people in need of help. In the present effectiveness study, we investigated the outcome of guided ICBT for panic disorder after implementation in routine care. A total of 124 patients were included in the study, of which 114 started the treatment. Large within-group effect sizes were observed on the primary panic disorder symptoms (post treatment: d = 1.24; 6-month follow-up: d = 1.39) and moderate and large effects on secondary panic disorder symptoms and depressive symptoms at post-treatment and follow-up (d = .55-1.13). More than half (56.1%) of the patients who started treatment recovered or improved at post-treatment. Among treatment takers (completed at least five of the nine modules), 69.9% recovered or improved. The effectiveness reported in the present trial is in line with previous effectiveness and efficacy trials of guided ICBT for panic disorder. This provides additional support for guided ICBT as a treatment alternative in routine care. PMID- 28714776 TI - Tissue Localization of Glycosphingolipid Accumulation in a Gaucher Disease Mouse Brain by LC-ESI-MS/MS and High-Resolution MALDI Imaging Mass Spectrometry. AB - To better understand regional brain glycosphingolipid (GSL) accumulation in Gaucher disease (GD) and its relationship to neuropathology, a feasibility study using mass spectrometry and immunohistochemistry was conducted using brains derived from a GD mouse model (4L/PS/NA) homozygous for a mutant GCase (V394L [4L]) and expressing a prosaposin hypomorphic (PS-NA) transgene. Whole brains from GD and control animals were collected using one hemisphere for MALDI FTICR IMS analysis and the other for quantitation by LC-ESI-MS/MS. MALDI IMS detected several HexCers across the brains. Comparison with the brain hematoxylin and eosin (H&E) revealed differential signal distributions in the midbrain, brain stem, and CB of the GD brain versus the control. Quantitation of serial brain sections with LC-ESI-MS/MS supported the imaging results, finding the overall HexCer levels in the 4L/PS-NA brains to be four times higher than the control. LC ESI-MS/MS also confirmed that the elevated hexosyl isomers were glucosylceramides rather than galactosylceramides. MALDI imaging also detected differential analyte distributions of lactosylceramide species and gangliosides in the 4L/PS-NA brain, which was validated by LC-ESI-MS/MS. Immunohistochemistry revealed regional inflammation, altered autophagy, and defective protein degradation correlating with regions of GSL accumulation, suggesting that specific GSLs may have distinct neuropathological effects. PMID- 28714777 TI - Resisting Temptation: Tracking How Self-Control Conflicts Are Successfully Resolved in Real Time. AB - Across four studies, we used mouse tracking to identify the dynamic, on-line cognitive processes that underlie successful self-control decisions. First, we showed that individuals display real-time conflict when choosing options consistent with their long-term goal over short-term temptations. Second, we found that individuals who are more successful at self-control-whether measured or manipulated-show significantly less real-time conflict in only self-control relevant choices. Third, we demonstrated that successful individuals who choose a long-term goal over a short-term temptation display movements that are smooth rather than abrupt, which suggests dynamic rather than stage-based resolution of self-control conflicts. These findings have important implications for contemporary theories of self-control. PMID- 28714778 TI - How clients "change emotion with emotion": A programme of research on emotional processing. AB - This paper reviews a body of research that has examined Pascual-Leone and Greenberg's sequential model of emotional processing or used its accompanying measure (the Classification of Affective Meaning States). Research from 24 studies using a plurality of methods examined process-outcome relationships from micro to macro levels of observation and builds support for emotional transformation as a possible causal mechanism of change in psychotherapy. A pooled sample of 310 clinical and 130 sub-clinical cases have been studied, reflecting the process of 7 different treatment approaches in addressing over 5 different presenting clinical problems (including depression, anxiety, relational trauma, and personality disorders). The initial findings on this model support the hypothesis that emotional transformation occurs in specific canonical sequences and these show large effects in the prediction of positive treatment outcomes. This model is the first in the field of psychotherapy to show how non linear temporal patterns of moment-by-moment process relate to the unfolding of increasingly larger changes to create good psychotherapy treatment outcomes. Finally, clinical application of the model is also considered as a template for case formulations focused on emotion. Clinical or methodological significance of this article: This review article examines research on a specific model of emotional processing. (i) Experiencing certain key emotions during psychotherapy seems to predict good treatment outcomes, at both the session and treatment levels. (ii) There is also evidence to suggest that these productive emotional experiences unfold in an ordered pattern. Moreover, (iii) support for this way of understanding emotional processing comes from a number of very different treatment approaches and for several kinds of major disorders. PMID- 28714779 TI - Serum-free placental growth factor isoform 1 at 11-13-week gestation: effects of maternal factors, mean arterial pressure, placental volume, and uterine artery pulsatility index. AB - INTRODUCTION: To define the effects of maternal factors, mean arterial pressure (MAP), placental volume (PV), and uterine artery Doppler pulsatility index (UtAPI) to serum level of free form of placental growth factor isoform 1 (free PlGF-1) measured with a novel automated assay. METHODS: We enrolled 200 Thai women singleton pregnancy from 11+0 to 13+6 weeks gestation with low prior risk maternal factors (age, parity, tobacco use, assisted reproductive technology, and body mass index). MAP was measured. Serum-free PlGF-1, PV, and UtAPI were measured with a new assay, transabdominal three-dimensional, and color Doppler ultrasounds, respectively. Effects of these variables to serum-free PlGF-1 level were assessed. RESULTS: Data from 195 eligible subjects showed an elevation of serum-free PlGF-1 from 11, 12, and 13 weeks (mean +/- SD; 36.89 +/- 24.92, 38.71 +/- 17.44, and 49.68 +/- 22.30 pg/mL, respectively (p < .05)). Serum-free PlGF-1 level showed positive correlation with PV (r = 0.290, p < .01), and negative correlation with right and left UtAPI (r = -0.717, p = .05 and r = -0.221, p < .05, respectively). PV showed negative correlation with right and left UtAPI (r = -0.243, p < .05 and r = -0.372, p < .05, respectively). Serum-free PlGF-1 level had no significant correlation with maternal factors or MAP (p > .05). There was no preeclampsia at <34 weeks in 161 subjects (82.6%) with known pregnancy outcomes. CONCLUSIONS: There was modest correlation of serum-free PlGF-1, PV, and UtAPI, but not with maternal factors or MAP. Adjustment of serum-free PlGF-1 in early preeclampsia screening algorithm should be considered. PMID- 28714781 TI - Hatchery Vaccination Against Poultry Viral Diseases: Potential Mechanisms and Limitations. AB - Commercial broiler and layer chickens are heavily vaccinated against economically important viral diseases with a view of preventing morbidity, mortality, and production impacts encountered during short production cycles. Hatchery vaccination is performed through in ovo embryo vaccination prehatch or spray and subcutaneous vaccinations performed at the day of hatch before the day-old chickens are being placed in barns with potentially contaminated environments. Commercially, multiple vaccines (e.g., live, live attenuated, and viral vectored vaccines) are available to administer through these routes within a short period (embryo day 18 prehatch to day 1 posthatch). Although the ability to mount immune response, especially the adaptive immune response, is not optimal around the hatch, it is possible that the efficacy of these vaccines depends partly on innate host responses elicited in response to replicating vaccine viruses. This review focuses on the current knowledge of hatchery vaccination in poultry and potential mechanisms of hatchery vaccine-mediated protective responses and limitations. PMID- 28714782 TI - Delayed antibiotic prescription for upper respiratory tract infections in children under primary care: Physicians' views. AB - BACKGROUND: Overprescribing antibiotics for common or inaccurately diagnosed childhood infections is a frequent problem in primary healthcare in most countries. Delayed antibiotic prescriptions have been shown to reduce the use of antibiotics in primary healthcare. OBJECTIVE: The aim was to examine primary care physicians' views on delayed antibiotic prescriptions to preschool children with symptoms of upper respiratory tract infections (URTIs). METHODS: A questionnaire was sent to 1180 physicians working in general practice in the Capital Region of Denmark, between January and March 2015. The questions focused on physicians' attitude and use of delayed antibiotic prescriptions to children with URTIs. RESULTS: The response rate was 49% (n = 574). Seven per cent of the physicians often used delayed prescriptions to children with symptoms of URTI, but 46% believed that delayed prescription could reduce antibiotic use. The physicians' views on delayed antibiotic prescription were significantly associated with their number of years working in general practice. Parents' willingness to wait-and see, need for reassurance, and knowledge about antibiotics influenced the physicians' views. Also, clinical symptoms and signs, parents' willingness to shoulder the responsibility, the capability of observation without antibiotic treatment, and structural factors like out-of-hour services were relevant factors in the decision. CONCLUSIONS: Most physicians, especially those with fewer years of practice, had a positive attitude towards delayed antibiotic prescription. Several factors influence the views of the physicians-from perceptions of parents to larger structural elements and years of experience. PMID- 28714780 TI - Atezolizumab for the treatment of non-small cell lung cancer. AB - INTRODUCTION: The immune system can restrain or promote cancer development and growth. Antibodies targeting immune checkpoints have revolutionized cancer treatment. Among the best responses have been in non-small cell lung cancer (NSCLC) which is largely caused by chronic exposure to carcinogens; associated with high neoantigen creation and sensitization to immune recognition. Atezolizumab was the first approved antibody that targets the PD-1 ligand (PD L1). Areas covered: This drug profile article covers the basics of the cancer immunity cycle and reviews some aspects of innate and adaptive immunology. We discuss the discovery of PD-L1 and PD-L2 while highlight the potential differences in targeting PD-L1 versus PD-1. In addition, we briefly summarized the available pre-clinical and clinical data of atezolizumab use in NSCLC. A special section covers the challenges of PD-L1 immunohistochemistry assay. Expert commentary: PD-1:PD-L1 blockade has taken the lead in the immunotherapeutics field and represents the backbone of developing combination immunotherapies. Atezolizumab represents a step forward in the treatment of advanced NSCLC, nonetheless PD1:PD-L1 blockade in early-stage lung cancer is still a matter of debate. PMID- 28714783 TI - Performance Outcomes After Hook of Hamate Fractures in Major League Baseball Players. AB - CONTEXT: Major League Baseball (MLB) players are at risk of hook of hamate fractures. There is a paucity of data assessing the effect of a hook of hamate fracture on MLB players' future athletic performance. OBJECTIVE: To determine if MLB players who sustain hook of hamate fractures demonstrate decreased performance upon return to competition when compared with their performance before injury and that of their control-matched peers. DESIGN: Retrospective case control design. SETTING: Retrospective database study. PARTICIPANTS: 18 MLB players who sustained hook of hamate fractures. METHODS: Data for 18 MLB players with hook of hamate fractures incurred over 26 seasons (1989-2014) were obtained from injury reports, press releases, and player profiles ( www.mlb.com and www.baseballreference.com ). Player age, position, number of years in the league, mechanism of injury, and treatment were recorded. Individual season statistics for the 2 seasons immediately prior to injury and the 2 seasons after injury for the main performance variable-Wins Above Replacement-were obtained. Eighteen controls matched by player position, age, and performance statistics were identified. A performance comparison of the cohorts was performed. MAIN OUTCOME MEASURES: Postinjury performance compared with preinjury performance and matched controls. RESULTS: Mean age at the time of injury was 25.1 years with a mean of 4.4 seasons of MLB experience prior to injury. All injuries were sustained to their nondominant batting hand. All players underwent operative intervention. There was no significant change in Wins Above Replacement or isolated power when preinjury and postinjury performance were compared. When compared with matched controls, no significant decline in performance in Wins Above Replacement the first season and second season after injury was found. CONCLUSION: MLB players sustaining hook of hamate fractures can reasonably expect to return to their preinjury performance levels following operative treatment. PMID- 28714784 TI - The management of paediatric neurogenic bladder: an approach in a resource-poor setting. AB - BACKGROUND: If untreated, paediatric neurogenic bladder can cause renal failure and urinary incontinence. It is usually caused by neural tube defects such as myelomeningocele. Children with a neurogenic bladder should be monitored from birth and management should aim to preserve renal function and achieve social continence. This article outlines the management options appropriate for these children in resource-poor settings. ASSESSMENT: In most low- and middle-income countries, a general lack of awareness of the neurological effects on the urinary tract results in late presentation, usually with urological complications even when spina bifida is diagnosed early. Physical examination must include neurological examination for spinal deformities and intact sacral reflexes. About 90% of children with occult spinal dysraphisms will have cutaneous sacral lesions. The work-up includes urinalysis, serial ultrasound of the urinary tracts and urodynamics. Urodynamic assessment is essential for the diagnosis and prognosis of the paediatric neurogenic bladder. In poorly resourced settings, simple eyeball urodynamics can be performed in the absence of a conventional urodynamic set-up. TREATMENT: Clean intermittent catheterisation (CIC), the mainstay of treatment, is most suitable for resource-poor settings because it is effective and inexpensive. Antimuscarinic drugs such as oxybutynin complement CIC by reducing detrusor overactivity. Intravesical injection of Botox and bladder augmentation surgery is required by a small subset of patients who fail to respond to combined CIC and oxybutynin therapy. CONCLUSION: Children with neurogenic bladder in resource-poor settings should have early bladder management to preserve renal function and provide social continence. PMID- 28714785 TI - Effects of Alcohol on Inhibitory Avoidance Learning in Zebrafish (Danio rerio). AB - The zebrafish (Danio rerio) can be used in studies addressing the effects of drugs on learning, memory, and anxiety. In the present study, we investigated the effect of different alcohol treatments (chronic and acute) on the learning and anxiety response of zebrafish in an inhibitory avoidance paradigm. Zebrafish were initially exposed to different alcohol treatments and submitted to an inhibitory avoidance protocol, where an electroshock was applied to the fish as they swam from the white to the black side of a shuttle box tank (naturally preferred environment of zebrafish). Animals from the control and 0.5% acute alcohol groups exhibited high latency to enter the black side of the tank after the first exposure to electroshock, in addition to higher freezing and a shorter distance from the bottom of the tank, suggesting acute alcohol exposure did not affect aversive learning in zebrafish. However, chronic exposure and alcohol withdrawal impaired the fish's capacity to properly respond to the aversive stimulus. Overall, our results show the harmful effects of chronic alcohol exposure, both continued intake and its cessation, but avoidance behavior persisted and anxiety increased following acute alcohol exposure. PMID- 28714786 TI - Effects of a Prophylactic Knee Sleeve on Anterior Cruciate Ligament Loading During Sport-Specific Movements. AB - CONTEXT: Prophylactic knee bracing is extensively utilized in athletic populations to reduce the high risk from knee injuries, but its role in the attenuation of anterior cruciate ligament (ACL) pathologies is not well understood. OBJECTIVE: The aim of this investigation was to explore the effects of a prophylactic knee sleeve on ACL loading parameters linked to the etiology of injury in recreational athletes. SETTING: Laboratory. DESIGN: Repeated measures. PARTICIPANTS: Thirteen healthy male recreational athletes. INTERVENTION: Participants performed run, cut, and single-leg hop movements under 2 conditions; prophylactic knee sleeve and no sleeve. MAIN OUTCOME MEASURES: Biomechanical data were captured using an 8-camera 3D motion capture system and a force platform. Peak ACL force, average ACL load rate, and instantaneous ACL load rate were quantified using a musculoskeletal modeling approach. RESULTS: The results showed that both average and instantaneous ACL load rates were significantly reduced when wearing the knee sleeve in the hop (sleeve = 612.45/1286.39 N/kg/s and no sleeve = 743.91/1471.42 N/kg/s) and cut (sleeve = 222.55/1058.02 N/kg/s and no sleeve = 377.38/1183.01 N/kg/s) movements. CONCLUSIONS: Given the biomechanical association between ACL loading and the etiology of ACL injuries, it is proposed that athletes may be able to attenuate their risk from injury during cut and hop movements through utilization of a prophylactic knee sleeve. PMID- 28714787 TI - Corrigendum. PMID- 28714788 TI - Acute Effects and Perceptions of Deep Oscillation Therapy for Improving Hamstring Flexibility. AB - CONTEXT: Hamstring inflexibility is typically treated using therapeutic massage, stretching, and soft tissue mobilization. An alternative intervention is deep oscillation therapy (DOT). Currently, there is a lack of evidence to support DOT's effectiveness to improve flexibility. OBJECTIVE: To explore the effectiveness of DOT to improve hamstring flexibility. DESIGN: Randomized single cohort design. SETTING: Research laboratory. PARTICIPANTS: Twenty-nine healthy, physically active individuals (self-reported activity of a minimum 200 min/wk). INTERVENTIONS: All participants received a single session of DOT with randomization of the participant's leg for the intervention. The DOT intervention parameters included a 1?1 mode and 70% to 80% dosage at various frequencies for 28 minutes. Hamstring flexibility was assessed using passive straight leg raise for hip flexion using a digital inclinometer. Patient-reported outcomes were evaluated using the Copenhagen Hip and Groin Outcome Score and the Global Rating of Change (GRoC). MAIN OUTCOME MEASURE: The independent variable was time (pre and post). The dependent variables included passive straight leg raise, the GRoC, and the participant's perceptions of the intervention. Statistical analyses included a dependent t test and a Pearson correlation. RESULTS: Participants reported no issues with sport, activities of daily living, or quality of life prior to beginning the intervention study on the Copenhagen Hip and Groin Outcome Score. Passive straight leg raise significantly improved post-DOT (95% confidence interval, 4.48 degrees -7.85 degrees , P < .001) with a mean difference of 6.17 +/- 4.42 degrees (pre-DOT = 75.43 +/- 21.82 degrees and post-DOT = 81.60 +/- 23.17 degrees ). A significant moderate positive correlation was identified (r = .439, P = .02) among all participants between the GRoC and the mean change score of hamstring flexibility. Participants believed that the intervention improved their hamstring flexibility (5.41 +/- 1.02 points) and was relaxing (6.21 +/- 0.86). CONCLUSIONS: DOT is an effective intervention to increase hamstring flexibility. PMID- 28714789 TI - The Role of Physical Activity in the Association Between Resilience and Mental Health in Older Adults. AB - The aim of this study is to evaluate the relationship between resilience and mental health in older adults and how physical activity influences that relationship. A cross-sectional study was carried out with 312 older adults (179 active and 133 sedentary classified by IPAQ). Considering the whole sample, an inverse relationship was found for resilience (Wagnild-Young's Resilience Scale) with depression and stress (DASS-21). Among the sedentary, in spite of there not being an association between total resilience and mental health, there was an inverse relationship for the "meaning of life" component of the resilience and depression scale. For the active group, there was a relationship between total resilience and its components with depression and stress, but not for the "meaning of life" component of the resilience scale. Physical activity played an important role in the relationship between resilience and depression, showing that active and sedentary people use different components of resilience. PMID- 28714790 TI - The Relationship Between Hip Strength and the Y Balance Test. AB - CONTEXT: The Y Balance Test was developed as a test of dynamic postural control and has been shown to be predictive of lower-extremity injury. However, the relationship between hip strength and performance on the Y Balance Test has not been fully elucidated. OBJECTIVE: The goal of this study was to identify the relationship between components of isometric hip strength and the Y Balance Test, to provide clinicians better guidance as to specific areas of muscle performance to address in the event of poor performance on the Y Balance Test. DESIGN: Laboratory study. SETTING: Biomechanics laboratory. PARTICIPANTS: A total of 73 healthy participants (40 males and 33 females) volunteered for this study. INTERVENTION: None. MAIN OUTCOME MEASURES: Participants completed the Y Balance Test on the right leg. The authors then measured peak isometric torque in hip external rotation, abduction, and extension. Correlations were calculated between torque measurements, normalized for mass and Y Balance Test performance. Significant relationships were used in linear regression models to determine which variables were predictive of the Y Balance Test performance. RESULTS: The authors found significant positive correlations between Y Balance Test performance and hip abduction strength. They also found correlations between the Y Balance Test and hip extension and external rotation strengths. Linear regression analysis showed hip abduction to be the only significant predictor of Y Balance performance. CONCLUSIONS: The authors found the strongest association between the Y Balance Test and hip abduction strength. They also showed smaller but significant associations with hip extension and external rotation strength. When entered into a linear regression analysis, hip abduction strength was the only significant predictor of Y Balance performance. Using this information, practitioners should look to hip abduction strength when patients exhibit deficits in the Y Balance Test. PMID- 28714791 TI - Influence of Body Composition on Functional Movement ScreenTM Scores in College Football Players. AB - CONTEXT: The functional movement screen (FMSTM) is used to identify movement asymmetries and deficiencies. While obesity has been reported to impede movement, the correlation between body mass index (BMI), body fat percentage (BF%), and FMSTM in athletes is unknown. OBJECTIVE: To determine if there is a relationship between BMI, BF%, and FMSTM scores in a sample of National Collegiate Athletic Association Division I football athletes. DESIGN: Cross-sectional study. SETTING: Biodynamics laboratory. PARTICIPANTS: A total of 38 male freshman football players (18.0 [0.7] y, 185.3 [5.5] cm, and 103.9 [20.3] kg). INTERVENTIONS: Height, weight, and BF% were collected, and subjects underwent the FMSTM conducted by a certified athletic trainer. MAIN OUTCOME MEASURES: The dependent variables were BMI, BF%, composite FMSTM score, and 7 individual FMSTM test scores. Subjects were grouped as normal BMI (BMI < 30 kg/m2) or obese (BMI >= 30 kg/m2). A composite FMSTM score of <=14 and an individual FMSTM score of <=1 were classified as cutoffs for poor movement performance. RESULTS: A negative correlation between composite FMSTM score and BMI approached significance (P = .07, rho = .296). A negative correlation between composite FMSTM score and BF% was significant (P = .01, rho = -.449). There was a significant difference in the number of obese subjects scoring below the composite FMSTM cutoff (chi2 = 5.179, P = .02) and the individual FMSTM cutoff on the deep squat (chi2 = 6.341, P = .01), hurdle step (chi2 = 9.870, P = .002), and in-line lunge (chi2 = 5.584, P = .02) when compared with normal BMI subjects. CONCLUSIONS: Increased BF% and BMI relate to lower composite FMSTM and individual FMSTM test scores, indicating potentially poor movement patterns in larger National Collegiate Athletic Association football athletes. Future research should focus on examining lower extremity-specific FMSTM tasks individually from composite FMSTM scores. PMID- 28714792 TI - Height, Weight, and Age Predict Quadriceps Tendon Length and Thickness in Skeletally Immature Patients: Response. PMID- 28714794 TI - Height, Weight, and Age Predict Quadriceps Tendon Length and Thickness in Skeletally Immature Patients: Letter to the Editor. PMID- 28714793 TI - Equivalent Knee Injury and Osteoarthritis Outcome Scores 12 and 24 Months After Anterior Cruciate Ligament Reconstruction: Results From the Swedish National Knee Ligament Register. AB - BACKGROUND: It is not clear whether Knee injury and Osteoarthritis Outcome Score (KOOS) results will be different 1 or 2 years after anterior cruciate ligament (ACL) reconstruction. PURPOSE: To investigate within individual patients enrolled in the Swedish National Knee Ligament Register whether there is equivalence between KOOS at 1 and 2 years after primary ACL reconstruction. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: This cohort study was based on data from the Swedish National Knee Ligament Register during the period January 1, 2005, through December 31, 2013. The longitudinal KOOS values for each individual at the 1- and 2-year follow-up evaluations were assessed through the two one sided test (TOST) procedure with an acceptance criterion of 4. Subset analysis was performed with patients classified by sex, age, graft type, and type of injury (meniscal and/or cartilage injury). RESULTS: A total of 23,952 patients were eligible for analysis after exclusion criteria were applied (10,116 women, 42.2%; 13,836 men, 57.8%). The largest age group was between 16 and 20 years of age (n = 6599; 27.6%). The most common ACL graft was hamstring tendon (n = 22,504; 94.0%), of which the combination of semitendinosus and gracilis was the most common. A total of 7119 patients reported on the KOOS Pain domain at both 1- and 2-year follow-ups, with a mean difference of 0.21 (13.1 SD, 0.16 SE [90% CI, 0.05 to 0.46], P < .001). The same results were found for the other KOOS subscales: symptoms (mean difference -0.54, 14.1 SD, 0.17 SE [90% CI, -0.81 to 0.26], P < .001), activities of daily living (mean difference 0.45, 10.8 SD, 0.13 SE [90% CI, 0.24 to 0.66], P < .001), sports and recreation (mean difference 0.35, 22.7 SD, 0.27 SE [90% CI, -0.79 to 0.09], P < .001), quality of life (mean difference -0.92, 20.0 SD, 0.24 SE [90% CI, -1.31 to -0.53], P < .001), and the combined KOOS-4 score (mean difference -0.41, 14.5 SD, 0.17 SE [90% CI, -0.70 to 0.13], P < .001). Analyses within specific subsets of patients showed equivalent results between the 2 follow-up evaluations. CONCLUSION: Equivalent results within patients were found in KOOS values at 1- and 2-year follow-ups after ACL reconstruction. The finding was consistent across all KOOS subscales and for all evaluated subsets of patients. This result implies that there is no additional value in capturing both 1- and 2-year KOOS outcomes after ACL reconstruction. However, these findings of equivalence at 1- and 2-year endpoints do not alleviate the need for longer follow-up periods. PMID- 28714795 TI - Analysis of Physical Activity Among Free-Living Nonagenarians From a Sardinian Longevous Population. AB - Physical activity was identified as a major determinant of longevity. Using wearable accelerometers, we evaluated energy expenditure (EE), including resting- (REE) and total-energy expenditure (TEE), physical activity level (PAL), percentage of PAL >= 3 metabolic equivalent tasks (METs), number of steps, resting index (RI%) and sleep patterns in 44 free-living nonagenarians (27 men) residing in a Sardinian village famous for its longevous population. The average REE and TEE recorded were 1275 +/- 163 kcal/day and 2284 +/- 543 in the men and 952 +/- 108 kcal/day and 1810 +/- 302 in the women, respectively. The average PAL was 1.8, and the percentage of physical activity >3 METs was greater than 40%. A significant negative correlation (p < 0.05) between disability and PAL was found among the women. This study provides evidence that nonagenarians from the longevous population of Sardinia show excellent physical functionality indexes. Their longevity might result, at least in part, from their ability to stay physically fit during aging. PMID- 28714796 TI - Effect of bariatric surgery on heart failure. AB - INTRODUCTION: Obesity increases the risk of heart failure (HF), which continues to be a significant proportion of all cardiovascular diseases and affects increasingly younger populations. The cross-talk between adipose and the heart involves insulin resistance, adipokine signaling and inflammation, with the capacity of adipose tissue to mediate hemodynamic signals, promoting progressive cardiomyopathy. Areas covered: From a therapeutic perspective, there is not yet a single obesity-related pathway that when addressed, can ameliorate cardiomyopathy in obese patients and this is a matter of ongoing research. There is poor evidence of the beneficial long-term effect of small nonsurgical intentional weight loss on HF outcomes, in contrast to the field of HF accompanying severe obesity where observational studies have shown that bariatric surgery is associated with improved cardiac structure/function in severely obese patients with HF and preserved ejection fraction (HFpEF) as well as with improved cardiac structure/function in those with HF and reduced ejection fraction (HFrEF). Few studies report positive outcomes in subjects with obesity and HF, both severe, who underwent bariatric surgery as a rescue treatment, including bridge to heart transplantation. Expert commentary: The fast growing prevalence of obesity will continue to require the development of appropriate interventions directed at controlling or slowing pathways of cardiac damage in these patients, but at present, bariatric surgery should be considered an option to try to decrease morbidity associated with HF in severely obese adults. PMID- 28714797 TI - Editor's Presentation. PMID- 28714798 TI - Foot Rollover Temporal Parameters During Walking Straight Ahead and Stepping Over Obstacles: Obese and Non-Obese Postmenopausal Women. AB - The aim of this study was to compare the temporal foot rollover data between walking straight ahead and stepping over obstacles for obese and non-obese postmenopausal women. Plantar pressure data were collected from 67 women. The initial, final, and duration of contact of 10 foot areas were measured. Both limbs of both groups showed a longer foot contact duration on the obstacle task. Significant temporal differences were found for both groups between straight ahead and crossing obstacles on the initial, final, and duration of contact for several foot areas. The propulsion phase of the trailing limb during the obstacle task was anticipated. Regarding the leading limb, the first foot contact was not made with the heel areas; however, a backward foot rollover movement from the metatarsal to the heel areas occurred, possibly to provide support to better control the trailing limb swing phase. PMID- 28714799 TI - In silico approaches to identify novel myeloid cell leukemia-1 (Mcl-1) inhibitors for treatment of cancer. AB - Myeloid cell leukemia-1 (Mcl-1) has been a validated and attractive target for cancer therapy. Over-expression of Mcl-1 in many cancers allows cancer cells to evade apoptosis and contributes to the resistance to current chemotherapeutics. Here, we identified new Mcl-1 inhibitors using a multi-step virtual screening approach. First, based on two different ligand-receptor complexes, 20 pharmacophore models were established by simultaneously using 'Receptor-Ligand Pharmacophore Generation' method and manual build feature method, and then carefully validated by a test database. Then, pharmacophore-based virtual screening (PB-VS) could be performed by using the 20 pharmacophore models. In addition, docking study was used to predict the possible binding poses of compounds, and the docking parameters were optimized before performing docking based virtual screening (DB-VS). Moreover, a 3D QSAR model was established by applying the 55 aligned Mcl-1 inhibitors. The 55 inhibitors sharing the same scaffold were docked into the Mcl-1 active site before alignment, then the inhibitors with possible binding conformations were aligned. For the training set, the 3D QSAR model gave a correlation coefficient r2 of 0.996; for the test set, the correlation coefficient r2 was 0.812. Therefore, the developed 3D QSAR model was a good model, which could be applied for carrying out 3D QSAR-based virtual screening (QSARD-VS). After the above three virtual screening methods orderly filtering, 23 potential inhibitors with novel scaffolds were identified. Furthermore, we have discussed in detail the mapping results of two potent compounds onto pharmacophore models, 3D QSAR model, and the interactions between the compounds and active site residues. PMID- 28714800 TI - Differences in Psychoactive Substance Abuse Between Youths Residing in and Outside Conflict Zones as a Function of Level of Religiosity and Political Commitment. AB - The aim of the present study was to examine the effect of the unique characteristics of residing in security and political conflict zones on the willingness to use and on the actual abuse of psychoactive substances. The study focuses on the differences between youths residing in and outside conflict zones in Israel. The present study examines the link between the adolescents' level of psychoactive substance abuse and town size as well as the youths' level of ideological commitment and religiosity. 1032 adolescents aged 14-18 participated in the study. 595 (57%) lived in the nonconflict zones and 437 (43%) in conflict zones. The findings reveal that the level of psychoactive substance abuse among youths residing in conflict zones is significantly lower than that found among youths living outside conflict zones. Moreover, although town size and level of religiosity are linked to psychoactive substance abuse, no such link was found with the level of ideological commitment or place of residence (within or outside conflict zones). The study findings underscore the important effect of social supervision and perceived norms in the adolescents' environment with regard to their willingness to use psychoactive substances and to their actual abuse of such substances. PMID- 28714802 TI - Binocular Vision Disorders and Visual Attention: Associations With Balance and Mobility in Older Adults. AB - Understanding which aspects of vision are related to falls is important. We examine the associations between tests of balance, mobility, fear of falling (FES 1) and aspects of vision in 72 adults aged 70+. Balance and mobility were examined using the One Legged Stance test (OLST), the Sit to Stand test (STST) and the 5 Meter Walking test (5MWT). Visual measures included visual acuity (VA), contrast sensitivity, stereoacuity, binocular vision (BV) measurements, Useful field of View (UFV) and Attended Field of View (AFOV). Reduced performance on the OLST and the STST was significantly correlated with abnormal BV and poorer intermediate VA. Poorer function on the 5MWT and the FES-I was also predicted by poor intermediate VA and poorer performance on the OLST, STST and the 5MWT was associated with UFV errors. The results are of high importance as many BV disorders are treatable and visual attention is trainable. PMID- 28714801 TI - Muleshoe Virus and Other Hantaviruses Associated with Neotomine or Sigmodontine Rodents in Texas. AB - The broad objective of this study was to increase our knowledge of Muleshoe virus and other hantaviruses associated with cricetid rodents in Texas. Anti-hantavirus antibody was found in 38 (3.2%) of 1171 neotomine rodents and 6 (1.8%) of 332 sigmodontine rodents from 10 Texas counties; hantaviral RNA was detected in 23 (71.9%) of 32 antibody-positive rodents. Analyses of nucleocapsid protein gene sequences indicated Muleshoe virus infection in four hispid cotton rats (Sigmodon hispidus) from northern Texas; Bayou virus, three Texas marsh oryzomys (Oryzomys texensis) from the Gulf Coast; Limestone Canyon virus, five brush mice (Peromyscus boylii) from western Texas; and Sin Nombre virus-five Texas mice (P. attwateri), one Lacey's white-ankled deer mouse (P. laceianus), four white-footed mice (P. leucopus), and one fulvous harvest mouse (Reithrodontomys fulvescens) from northern, central, or southern Texas. The results of this study together with the results of a previous study revealed that Muleshoe virus, perhaps in association with S. hispidus, is distributed across northern Texas. Finally, the results of Bayesian analyses of glycoprotein precursor (GPC) gene sequences and pairwise comparisons of complete GPC (amino acid) sequences strengthened support for the notion that Muleshoe virus is distinct from Black Creek Canal virus, Bayou virus, and all other species included in the Bunyaviridae, genus Hantavirus. PMID- 28714803 TI - Comparing NMR and X-ray protein structure: Lindemann-like parameters and NMR disorder. AB - Disordered protein chains and segments are fast becoming a major pathway for our understanding of biological function, especially in more evolved species. However, the standard definition of disordered residues: the inability to constrain them in X-ray derived structures, is not easily applied to NMR derived structures. We carry out a statistical comparison between proteins whose structure was resolved using NMR and using X-ray protocols. We start by establishing a connection between these two protocols for obtaining protein structure. We find a close statistical correspondence between NMR and X-ray structures if fluctuations inherent to the NMR protocol are taken into account. Intuitively this tends to lend support to the validity of both NMR and X-ray protocols in deriving biomolecular models that correspond to in vivo conditions. We then establish Lindemann-like parameters for NMR derived structures and examine what order/disorder cutoffs for these parameters are most consistent with X-ray data and how consistent are they. Finally, we find critical value of [Formula: see text] for the best correspondence between X-ray and NMR derived order/disorder assignment, judged by maximizing the Matthews correlation, and a critical value [Formula: see text] if a balance between false positive and false negative prediction is sought. We examine a few non-conforming cases, and examine the origin of the structure derived in X-ray. This study could help in assigning meaningful disorder from NMR experiments. PMID- 28714804 TI - Cellular proliferation and differentiation induced by single-layer molybdenum disulfide and mediation mechanisms of proteins via the Akt-mTOR-p70S6K signaling pathway. AB - Single-layer molybdenum disulfide (SLMoS2) is a novel kind of 2D nanosheet that has attracted great attention regarding its use in biosensors, drug delivery, tissue engineering, and therapy. However, our results demonstrated that SLMoS2 accelerated proliferation and promoted myogenic differentiation and epithelial mesenchymal transition (EMT) in human embryonic lung fibroblasts (HELFs). The abnormal proliferation and differentiation of HELFs contribute to idiopathic pulmonary fibrosis. Specifically, SLMoS2 significantly stimulated the expression of myofibroblast- and mesenchymal-associated genes and proteins. The Akt-mTOR p70S6K signaling pathway plays a critical role in the acceleration of proliferation and promotion of myogenic differentiation and EMT in HELFs induced by SLMoS2. After cell uptake, SLMoS2 was primarily located in the cytoplasm and the perinuclear region and activated Akt-dependent signaling due to the generation of reactive oxygen species (ROS). Moreover, bovine serum albumin (BSA) binding markedly inhibited the cellular uptake of SLMoS2 and the production of intracellular ROS due to an increased thickness and reduced adhesion of HELFs. BSA binding also mitigated the SLMoS2-activated phosphorylation of Akt-dependent signaling pathways. This study is the first to illustrate the induction of cellular proliferation and differentiation by SLMoS2 and the related mediation by proteins through Akt-mTOR-p70S6K signaling pathway. PMID- 28714805 TI - Partnership duration, concurrency, and HIV in sub-Saharan Africa. AB - A widely accepted explanation for the exceptionally high HIV prevalence in sub Saharan Africa is the practice of long-term overlapping heterosexual partnering. This article shows that long-duration concurrent partnering can be protective against HIV transmission rather than promoting it. Monogamous partnering prevents sexual transmission to anyone outside the partnership and, in an initially concordant-seronegative partnership, prevents sexual acquisition of HIV by either partner. Those protections against transmission and acquisition last as long as the partnership persists without new outside partnerships. Correspondingly, these two protective effects characterise polygynous partnerships, whether or not the polygyny is formal or informal, until a partner initiates a new partnership. Stable and exclusive unions of any size protect against HIV transmission, and more durable unions provide a longer protective effect. Survey research provides little information on partnership duration in sub-Saharan Africa and sheds no light on the interaction of duration, concurrency, and HIV. This article shows how assumptions about partnership duration in individual-based sexual-network models affect the contours of simulated HIV epidemics. Longer mean partnership duration slows the pace at which simulated epidemics grow. With plausible assumptions about partnership duration and at levels of concurrency found in the region, simulated HIV epidemics grow slowly or not at all. Those results are consistent with the hypothesis that long-duration partnering is protective against HIV and inconsistent with the hypothesis that long-term concurrency drives the HIV epidemics in sub-Saharan Africa. PMID- 28714807 TI - Structural analysis, spectroscopic characterization and molecular docking studies of the cyclic heptapeptide. AB - The theoretically possible stable conformer of the cyclic heptapeptide, that has significant anti-metastatic activity, was examined by conformational analysis followed by DFT calculations. Experimental infrared and Raman spectroscopy, together with theoretical DFT (6-31G (d,p) basis set)-based quantum chemical calculations, have been used to understand the structural and spectral characteristics of cyclo(Gly-Arg-Gly-Asp-Ser-Pro-Ala) {cyclo(GRGDSPA)}. A complete analysis of the vibrational spectrum has been reported on the basis of potential energy distribution (PED%) data of the vibrational modes. Finally, the calculation results were applied to simulate infrared and Raman spectra of the title compound. The simulated spectra satisfactorily coincide with the experimental spectra. In addition, molecular electrostatic potential and frontier molecular orbital analysis were investigated using theoretical calculations. The stability of the molecule, arising from hyperconjugative interaction and charge delocalization, has been analyzed using natural bond orbital analysis and a high E(2) value reveals the presence of strong interaction between donors and acceptors. Molecular docking studies with fibronectin were performed on cyclo(GRGDSPA) in order to understand its inhibitory nature. The results indicate that the docked ligand {cyclo(GRGDSPA)} forms a stable complex with human fibronectin and gives a binding affinity value of -7.7 kcal/mol, which points out that cyclo(GRGDSPA) might exhibit inhibitory activity against the attachment of melanoma cells to human fibronectin. PMID- 28714806 TI - Loss of control over the ethanol consumption: differential transcriptional regulation in prefrontal cortex. AB - Alcohol use disorder (AUD) is a complex multifactorial disease with heritability of ~50% and corresponds to the state in which the body triggers a reinforcement or reward compulsive behavior due to ethanol consumption, even when faced with negative consequences. Although several studies have shown the impact of high ethanol intake on the prefrontal cortex (PFC) gene expression, few have addressed the relationship between the patterns of gene expression underlying the compulsive behaviour associated with relapsing. In this study, we used a chronic three-bottle free-choice mouse model to investigate the PFC transcriptome in three different groups of mice drinkers: 'Light drinkers' (preference for water throughout the experiment); 'Heavy drinkers' (preference for ethanol with a non compulsive intake), and 'Inflexible drinkers' (preference for ethanol with a compulsive drinking component). Our aim was to correlate the intake patterns observed in this model with gene expression changes in the PFC, a brain region critical for the development and maintenance of alcohol addiction. We found that the Camk2a gene showed a downregulated profile only in the Inflexible when compared to the Light drinkers group, the Camk2n1 and Pkp2 genes showed an upregulated profile only in the Inflexible drinkers when compared to the Control group, and the Gja1 gene showed an upregulated profile in the Light and Inflexible drinkers when compared to the Control group. These different transcription patterns have been associated to the presence of alcohol, in the Camk2n1 and Gja1 genes; to the amount of ethanol consumed, in the Camk2a gene; and to the loss of control in the alcohol consumption, in the Pkp2 gene. Here, we provide, for the first time, the potential involvement of the Pkp2 gene in the compulsivity and loss of control over the voluntary ethanol consumption. PMID- 28714808 TI - "It was hard work every session": Therapists' view of successful psychoanalytic treatments. AB - OBJECTIVE: To explore therapists' experiences of the therapeutic process in successful cases of psychoanalytic psychotherapy. METHOD: A two-stage, mixed method design was used. Sixteen successful cases were drawn from a sample of 92 young adults in psychoanalytic psychotherapy according to Jacobson's criteria for reliable and clinically significant improvement. Therapist interviews at baseline and termination were analyzed applying Inductive Thematic Analysis. RESULTS: Three core themes emerged: Being Particularly Motivated to be This Patient's Therapist, Maintaining a Safe and Attentive Therapeutic Position, and Assiduous Work Every Session. The therapists experienced positive feelings towards the patient from the outset of treatment and described active, relational work that included paying attention to incongruities in the patient's self-presentation and being mindful of patient's avoidant behavior. The therapist's motivation and attentive position made it possible to balance support and challenge in the therapeutic relationship. CONCLUSIONS: Successful therapeutic work presupposes positive expectations, an active therapeutic stance and assiduous work session-by session. Therapist expertise may involve the ability to mobilize and work effectively with patient-specific resources and obstacles from the beginning of treatment. In addition to identifying the characteristics and actions of effective therapists, research should also focus on processes emerging within effective therapeutic dyads. Clinical or methodological significance of this article: Our study indicates several factors that seem to characterize therapist expertise and can inform psychotherapy training. Successful therapeutic work presupposes positive expectations, an active therapeutic stance, courage to challenge the patient, and assiduous work session-by-session. Therapist expertise may involve the ability to mobilize and work effectively with patient-specific resources and obstacles from the beginning of treatment. In addition to identifying the characteristics and actions of effective therapists, research should also focus on processes emerging within effective therapeutic dyads. PMID- 28714809 TI - Reticence in disclosure of HIV infection and reasons for bereavement: impact on perinatally infected adolescents' mental health and understanding of HIV treatment and prevention in Johannesburg, South Africa. AB - Survival rates of perinatally infected HIV-positive adolescents (PIA) are increasing in sub-Saharan Africa. There is a gap in understanding how disclosure and bereavement have an impact on PIA beliefs and understanding of their HIV infection and its management. In-depth interviews were conducted with 25 purposively selected adolescents aged 13-19 years from 5 public health clinics in Johannesburg, South Africa. Data were analysed using NVivo 10 using a thematic approach. PIA experience incomplete disclosure both of their HIV status and reasons for their bereavements, which limits their understanding of how they became infected, vertical transmission and prevention options like prevention of mother-to-child transmission (PMTCT). Most participants were orphaned and were experiencing complicated grieving (i.e., engaged in unresolved tasks of grieving) which had a negative impact on their mental health, and ability to accept their HIV status and adhere to treatment. PIA need improved communication regarding vertical transmission and how they became HIV-positive, as well as reasons for death of their loved ones to properly understand their HIV status and engage effectively in management. Honest communication about how relatives died and truthful engagement in the process of disclosure of HIV status is necessary to reduce stigma and complicated grieving, and improve mental health in this population. PMID- 28714811 TI - PolicyMap: Mapping Social Determinants of Health. AB - PolicyMap is a mapping resource from The Reinvestment Fund that offers access to a range of demographic and health-related data, including chronic disease incidence, health care provider locations, food access, mass transit, and other social determinates of health. This column features a sample search and describes the types of outputs available with PolicyMap. PMID- 28714812 TI - Interprofessional Education and Medical Libraries: Partnering for Success, edited by Mary E. Edwards. PMID- 28714813 TI - Altmetrics: A Practical Guide for Librarians, Researchers, and Academics, edited by Andy Tattersall. PMID- 28714810 TI - Advances in Cardiovascular Health in Women over the Past Decade: Guideline Recommendations for Practice. AB - Cardiovascular disease (CVD) remains the number one cause of death in women. It is estimated that 44 million women in the United States are either living with or at risk for heart disease. This article highlights the recent significant progress made in improving care, clinical decision-making, and policy implications for women with CVD. We provide our perspective supported by evidence based advances in cardiovascular research and clinical care guidelines in seven areas: (1) primary CVD prevention and community heart care, (2) secondary prevention of CVD, (3) stroke, (4) heart failure and cardiomyopathies, (5) ischemia with nonobstructive coronary artery disease, (6) spontaneous coronary artery dissection, and (7) arrhythmias and device therapies. Advances in these fields have improved the lives of women living with and at risk for heart disease. With increase awareness, partnership with national organizations, sex specific research, and changes in policy, the morbidity and mortality of CVD in women can be further reduced. PMID- 28714814 TI - Using Time-Driven Activity-Based Costing to Implement Change. AB - Academic medical libraries have responded to changes in technology, evolving professional roles, reduced budgets, and declining traditional services. Libraries that have taken a proactive role to change have seen their librarians emerge as collaborators and partners with faculty and researchers, while para professional staff is increasingly overseeing traditional services. This article addresses shifting staff and schedules at a single-service-point information desk by using time-driven activity-based costing to determine the utilization of resources available to provide traditional library services. Opening hours and schedules were changed, allowing librarians to focus on patrons' information needs in their own environment. PMID- 28714815 TI - An Introduction to the Blockchain and Its Implications for Libraries and Medicine. AB - The blockchain is a relatively new technology used to verify and store transaction records for online cryptocurrencies like Bitcoin. The system is redundant and distributed, making it difficult for transactions to be rescinded, duplicated, or faked. Beyond online currencies, the blockchain has potential uses in health care, education, and many other fields. This column will briefly describe what the blockchain is and how it is being used, potential future uses that may be of interest to librarians and medical practitioners, and some of the problems with the system. PMID- 28714816 TI - Opportunities and Efficiencies in Building a New Service Desk Model. AB - In July 2015, the Health Sciences and Human Services Library (HS/HSL) at the University of Maryland, Baltimore (UMB), merged its reference and circulation services, creating the Information Services Department and Information Services Desk. Designing the Information Services Desk with a team approach allowed for the re-examination of the HS/HSL's service model from the ground up. With the creation of a single service point, the HS/HSL was able to create efficiencies, improve the user experience by eliminating handoffs, create a collaborative team environment, and engage information services staff in a variety of new projects. PMID- 28714818 TI - Adding a Feature: Can a Pop-Up Chat Box Enhance Virtual Reference Services? AB - Online users seek help from virtual reference services via email, phone, texting, and live chat. Technologies have enabled new features in library websites to help make this service more accessible and effective. This article is an evaluation of an experimental pop-up live chat box on the website of a health sciences library to see whether the feature would enhance virtual reference services. PMID- 28714819 TI - An Institutional Repository Experience at a Large Health Care System. AB - Institutional repositories (IRs) collect, preserve, and disseminate the scholarly output of an organization. Though common in academic settings, they are less so in hospitals or health care systems. The librarians for Aurora Health Care decided to create a primarily citation-level IR to organize and promote the scholarly output of Aurora faculty, residents, and fellows using the proprietary software Digital Commons, a product of the company bepress. The repository also hosts a newly published peer-reviewed journal and includes digitized historical images and institutional memorabilia. Suggested alternatives are given for hospitals or health care systems that may not currently be able to pursue a full fledged IR. PMID- 28714820 TI - Evaluating the Impact of Mediated Literature Searches at a Comprehensive Cancer Center. AB - Research informationists at a comprehensive cancer center sought to evaluate the impact and value of mediated literature searches in support of their users' work activities. An assessment tool was identified in the literature and modified by the investigators to solicit feedback from library users and identify the major reason(s) why scientists and health care professionals request literature searches, how they use the resulting information, and the impact that the results may or may not have on their research or patient care/decision-making activities. Survey results were qualitatively analyzed, and future avenues of outreach and promotion of mediated literature search services were identified. PMID- 28714821 TI - Leaving the Lecture Behind: Putting PubMed Instruction into the Hands of the Students. AB - This column describes the development of a one-shot PubMed instruction class for medical students at a health sciences library. Background information on the objective is presented and discussed in the context of educational practice literature. The new course design centers on a guided group method of instruction in order to integrate more active learning. Surveyed students reported that the method was an effective way to learn how to search PubMed and that they preferred it to a traditional lecture. Pros and cons of the method are offered for other health sciences libraries interested in presenting PubMed instruction in a similar manner. PMID- 28714822 TI - Developing Librarian Competencies for the Digital Age, edited by Jeffrey G. Coghill and Roger G. Russell. PMID- 28714823 TI - Seeing the Big Picture: Sustaining Success in Liaison Services. AB - While the liaison program at the Tompkins-McCaw Library for the Health Sciences has existed for more than 15 years, it has yet to be fully evaluated. This article seeks to evaluate the scope and impact of the program at a broad level using quantitative and qualitative data. Descriptive statistics to summarize liaison activity were collected for the fiscal years 2012-2016. In addition, liaisons and users were surveyed to gain insight into the effectiveness and the perception of the program. Program statistics show that users' engagement with liaisons is high and growing. Qualitative data reveals that while better methods are needed to assess the extent of the program's impact, users appreciate the value that liaisons bring by supporting the educational and research missions of various programs. PMID- 28714824 TI - Molecular dynamics studies on the domain swapped Salmonella typhimurium survival protein SurE: insights on the possible reasons for catalytic cooperativity. AB - Stationary phase survival protein SurE from Salmonella typhimurium is a dimeric protein formed by the swapping of a tetramerization loop involved in the formation of a loose tetramer and a C-terminal helix. It functions as a phosphatase. The two-fold symmetry of the dimeric protein was lost in the mutants H234A and D230A/H234A in which a crucial hydrogen bond in the hinge involved in C terminal helix swapping was eliminated. The catalytic activity of both mutants was drastically reduced. In contrast to the native protein, H234A exhibited positive cooperativity in its catalytic activity. In order to relate these observations to the dynamics of the native and distorted mutants, molecular dynamics (MD) simulations were carried out using GROMACS v4.0.7. In all the simulations, the swapped segments and a segment near the active site were found to be highly flexible. These segments exhibited distinct dynamic features in the two protomers (A and B) of the dimeric protein. The dimeric organization was more significantly affected in the mutants when compared to the native structure, suggesting that the mutations enhance the intrinsic flexibility of the protein. The larger flexibility of the mutants affects the relative movement between the loops near the two active sites. The positive cooperativity observed in H234A mutant is most likely due to this increased flexibility and loop movement. PMID- 28714825 TI - Quadriceps and Patient-Reported Function in ACL-Reconstructed Patients: A Principal Component Analysis. AB - CONTEXT: Assessment of physical function for individuals after anterior cruciate ligament reconstruction (ACL-R) is complex and warrants the use of diverse evaluation strategies. To maximize the efficiency of assessment, there is a need to identify tests that provide the most meaningful information about this population. OBJECTIVE: To investigate underlying constructs of quadriceps muscle function that uniquely describe aspects of performance in patients after ACL-R and establish clinical thresholds for measures able to classify patients with and without ACL-R. DESIGN: Cross-sectional. SETTING: Research laboratory. Patients (or Other Participants): Seventy-two patients with a primary, unilateral ACL-R (32 males and 40 females, age = 26.0 [9.3] y, time since surgery = 46.5 [58.0] mo) and 30 healthy controls (12 males and 18 females, age = 22.7 [4.6] y). INTERVENTION(S): Quadriceps function was assessed bilaterally during 1 study visit. MAIN OUTCOME MEASURES: Isokinetic strength (peak torque, total work, and average power) at 90 degrees and 180 degrees /s, maximal voluntary isometric contraction torque, fatigue index, central activation ratio, Hoffmann reflex, and active motor threshold. Principal component analyses were performed for the involved limb, contralateral limb, and limb symmetry. Receiver-operator characteristic curve analyses were conducted to determine the diagnostic utility of each variable. Binary logistic regression was used to predict group membership (ACL-R vs healthy). RESULTS: Three components of peripheral, central, and combined (peripheral and central) muscle function were identified, explaining 70.7% to 80.5% of variance among measures of quadriceps function. Total knee extensor work at 90 degrees /s (>=18.4 J/kg), active motor threshold (>=39.5%), and central activation ratio (>=94.7%) of the involved limb were strong predictors of patient status and correctly classified 83.5% of patients with ACL R (P < .001). CONCLUSIONS: Unique constructs of peripheral, central, and combined muscle function exist in patients with ACL-R. Total knee-extensor work at 90 degrees /s, active motor threshold, and central activation ratio consistently explained a significant portion of variance in measures of quadriceps function, demonstrated acceptable to excellent diagnostic utility, and predicted group membership with 72.8% to 83.5% accuracy. PMID- 28714827 TI - Corrigendum. PMID- 28714826 TI - Effects of Peroneal Muscles Fatigue on Dynamic Stability Following Lateral Hop Landing: Time to Stabilization Versus Dynamic Postural Stability Index. AB - CONTEXT: Dynamic stability is a necessary requirement in many sports competitions. Muscle fatigue, which can impair stability, may be occurred in many sports competitions in which lateral movements and landing repeated frequently. OBJECTIVE: To assess the effects of peroneal muscles fatigue on dynamic stability following lateral hop landing through measuring time to stabilization (TTS) and dynamic postural stability index (DPSI). DESIGN: Quasi-experimental. SETTING: Laboratory study. PARTICIPANTS: A total of 20 recreationally active, healthy males with no lower-extremity injury during the previous 6 months participated in this study. INTERVENTION: Participants performed a lateral hop on a force plate before and immediately after a fatigue intervention using a Biodex dynamometer. For inducing fatigue, the participant made a prolonged eversion effort with 40% of the maximal voluntary contraction. Fatigue was met when the eversion torque declined by 50% of the initial value. TTS and DPSI were calculated using sequential averaging method and relevant formulas, respectively. MAIN OUTCOME MEASURES: Premeasures and postmeasures of TTS in the anteroposterior, mediolateral and vertical directions, resultant vector of TTS, stability indices in the anteroposterior, mediolateral and vertical directions, and DPSI. RESULTS: Means of the DPSI or its components did not change significantly due to fatigue (P > .05). Means of the TTS in the anteroposterior and mediolateral directions, and the mean of the resultant vector of the TTS increased significantly after fatigue (P < .05). CONCLUSIONS: The question that the dynamic stability is affected or not affected by fatigue depends on which of the TTS or DPSI is used for analysis. The TTS may be a sensitive measure to detect subtle changes in postural stability due to fatigue. But, the DPSI which may be changed after a more strenuous fatigue may be related to actual fatiguing situations. PMID- 28714828 TI - Reducing wrong intraocular lens implants in cataract surgery. AB - Purpose Wrong lens implants have been associated with the highest frequency of medical errors in cataract surgery. The purpose of this paper is to explore the use of the Systems Engineering Initiative for Patient Safety (SEIPS) framework to sustainably reduce wrong intraocular lens (IOL) implants in cataract surgery. Design/methodology/approach In this mixed-methods study, the SEIPS framework was used to analyse a series of (near) misses of IOL implants in a national tertiary specialty hospital in Singapore. A series of interventions was developed and applied in the case hospital. Risk assessment audits were done before the interventions (2012; n=6,111 surgeries), during its implementation ( n=7,475) and in the two years post-interventions (2013-2015; n=39,390) to compare the wrong IOL-rates. Findings Although the absolute number of incidents was low, the incident rate decreased from 4.91 before to 2.54 per 10,000 cases after. Near miss IOL error decreased from 5.89 before to 3.55 per 1,000 cases after. The number of days between two IOL incidents increased from 35 to an initial peak of 385 before stabilizing on 56. The large variety of available IOL types and vendors was found as the main root cause of wrong implants that required reoperation. Practical implications The SEIPS framework seems to be helpful to assess components involved and develop sustainable quality and safety interventions that intervene at different levels of the system. Originality/value The SEIPS model is supportive to address differences between person and system root causes comprehensively and thereby foster quality and patient safety culture. PMID- 28714829 TI - Do you like jigsaws? PMID- 28714830 TI - Efficiency of inpatient orthopedic surgery in Japan: a medical claims database analysis. AB - Purpose The purpose of this paper is to determine the characteristics of healthcare facilities that produce the most efficient inpatient orthopedic surgery using a large-scale medical claims database in Japan. Design/methodology/approach Reimbursement claims data were obtained from April 1 through September 30, 2014. Input-oriented Banker-Charnes-Cooper model of data envelopment analysis (DEA) was employed. The decision-making unit was defined as a healthcare facility where orthopedic surgery was performed. Inputs were defined as the length of stay, the number of beds, and the total costs of expensive surgical devices. Output was defined as total surgical fees for each surgery. Efficiency scores of healthcare facilities were compared among different categories of healthcare facilities. Findings The efficiency scores of healthcare facilities with a diagnosis-procedure combination (DPC) reimbursement were significantly lower than those without DPC ( p=0.0000). All the efficiency scores of clinics with beds were 1. Their efficiency scores were significantly higher than those of university hospitals, public hospitals, and other hospitals ( p=0.0000). Originality/value This is the first research that applied DEA for orthopedic surgery in Japan. The healthcare facilities with DPC reimbursement were less efficient than those without DPC. The clinics with beds were the most efficient among all types of management bodies of healthcare facilities. PMID- 28714831 TI - Improving the quality of nutrition in pediatric trauma. AB - Purpose Nutrition plays a key role in the recovery of pediatric trauma patients. A catabolic state in trauma patients may hinder recovery and inadequate nutrition may increase morbidity, mortality and length of hospital stay. The purpose of this paper is to review the current nutrition support practices for pediatric trauma patients at McMaster Children's Hospital (MCH), describe patient demographics and identify areas to improve the quality of patient care. Design/methodology/approach A retrospective chart review was conducted on pediatric trauma patients (age<18 years) identified through the trauma registry of MCH. Pediatric trauma patients admitted from January 2010 to March 2014 with an Injury Severity Score (ISS)=12 and a hospitalization of =24 hours were included. Findings In total, 130 patients were included in this study, 61.1 percent male, median age ten years (range: 0-17 years) and median ISS of 17 (range: 12-50). Blunt trauma accounted for 97.7 percent of patients admitted and 73.3 percent had trauma team activation. In total, 93 patients (71.5 percent) had ICU stays. The median time to feed was 29 hours (interquartile range: 12.5-43 hours) from the time of admission. An increased hospital length of stay was associated with longer time to initiation of nutrition support, a higher ISS and greater number of surgeries ( p<0.05). Originality/value Local nutritional support practices for pediatric trauma patients correspond with recommended principles of early feeding and preferential enteral nutrition. Harmonization of paper-based and electronic data collection is recommended to ensure that prescribed nutritional support is being delivered and nutritional needs of pediatric trauma patients are being met. PMID- 28714832 TI - Satisfaction of tuberculosis patients with health services in Ghana. AB - Purpose Within human services, client satisfaction is highly prioritised and considered a mark of responsiveness in service delivery. A large body of research has examined the concept of satisfaction from the perspective of service users. However, not much is known about how service providers construct client satisfaction. The purpose of this paper is to throw light on healthcare professionals' perspectives on patient satisfaction, using tuberculosis (TB) clinics as a case study. Design/methodology/approach In-depth interviews were conducted with 35 TB clinic supervisors purposively sampled from six out of the ten regions of Ghana. An unstructured interview guide was employed. The recorded IDIs were transcribed, edited and entered into QSR NVivo 10.0 and analysed inductively. Findings Respondents defined service satisfaction as involving education/counselling (on drugs, nature of condition, sputum production, caregivers and contacts of patients), patient follow-up, assignment of reliable treatment supporters as well as being attentive and receptive to patients, service availability (e.g. punctuality at work, availability of commodities), positive assurances about disease prognosis and respect for patients. Practical implications Complementing opinions of health service users with those of providers can offer key performance improvement areas for health managers. Originality/value To the best of the authors' knowledge, this is a first study that has examined healthcare providers' views on what makes their clients satisfied with the services they provide. PMID- 28714833 TI - Patients' expectations and solutions for improving primary diabetes care. AB - Purpose The purpose of this paper is to document health care needs expressed by people living with diabetes, describe the solutions they envisaged for improving the quality of primary care (PC) services and empower them to make better use of PC services. Design/methodology/approach A participatory research approach was used. Six workshops were organised to provide diabetes patients with knowledge on available services and to engage them in sharing their experience. Group discussions were recorded. Data were analysed using the thematic analysis method. Findings In total, 79 persons living with diabetes for a mean of 13 years participated. Needs expressed were grouped under seven themes: assurance of satisfactory follow-up by a family physician, continuous access to services adapted to evolving needs, motivation to adopt and maintain healthy behaviours, maintenance of knowledge about diabetes, psychological support, financial constraints, and collaboration with secondary-level services. Patients proposed solutions for improving services that were grouped under five themes: facilitating access to services, disseminating information about available services, centralising diabetes information on the internet, offering personalised services and improving interprofessional collaboration. Practical implications Needs expressed by diabetic patients concern different aspects of care such as accessibility, organisation, coordination, and better dissemination and visibility of services. The solutions proposed by patients focussed on better access to information and interprofessional services. Originality/value The workshop format used in this study offers an original and interesting approach and tool for actively engaging patients in quality improvement of services. PMID- 28714834 TI - Adjusting patients streaming initiated by a wait time threshold in emergency department for minimizing opportunity cost. AB - Purpose Two different systems for streaming patients were considered to improve efficiency measures such as waiting times (WTs) and length of stay (LOS) for a current emergency department (ED). A typical fast track area (FTA) and a fast track with a wait time threshold (FTW) were designed and compared effectiveness measures from the perspective of total opportunity cost of all patients' WTs in the ED. The paper aims to discuss these issues. Design/methodology/approach This retrospective case study used computerized ED patient arrival to discharge time logs (between July 1, 2009 and June 30, 2010) to build computer simulation models for the FTA and fast track with wait time threshold systems. Various wait time thresholds were applied to stream different acuity-level patients. National average wait time for each acuity level was considered as a threshold to stream patients. Findings The fast track with a wait time threshold (FTW) showed a statistically significant shorter total wait time than the current system or a typical FTA system. The patient streaming management would improve the service quality of the ED as well as patients' opportunity costs by reducing the total LOS in the ED. Research limitations/implications The results of this study were based on computer simulation models with some assumptions such as no transfer times between processes, an arrival distribution of patients, and no deviation of flow pattern. Practical implications When the streaming of patient flow can be managed based on the wait time before being seen by a physician, it is possible for patients to see a physician within a tolerable wait time, which would result in less crowded in the ED. Originality/value A new streaming scheme of patients' flow may improve the performance of fast track system. PMID- 28714835 TI - Interventions to support and develop clinician-researcher leadership in one health district. AB - Purpose Clinical leadership, researcher capacity and a culture of clinical inquiry are needed in the clinical workforce. The purpose of this paper is to report on a program which was used to develop and support clinicians to explore practice, implement innovation, translate evidence and build researcher capacity. Design/methodology/approach This pragmatic paper presents a case study of a nursing and midwifery clinician-researcher development program. The multi-site, multi-modal program focused on education, mentoring and support, communication networks, and clinician-university partnerships strategies to build workforce capacity and leadership. Findings Over 2,000 staff have been involved in the program representing a range of health disciplines. The study day program has been delivered to 500 participants with master classes having over 1,500 attendees. The research mentor program has demonstrated that participants increased their confidence for research leadership roles and are pursuing research and quality assurance projects. Communication strategies improved the visibility of nursing and midwifery. Research limitations/implications This case study was conducted in one health district, which may not have relevance to other geographical areas. The small numbers involved in the research mentor program need to be considered when reviewing the findings. Practical implications The program has been a catalyst for developing a research culture, clinical leadership and research networks that strengthen workforce capacity. Building researcher skills in the workforce will better support quality healthcare and the examination of everyday practice. Social implications Building a culture of healthcare that is based on inquiry and evidence-based practice will lead to more appropriate and consistent healthcare delivery. Consumers have the right to expect health clinicians will challenge everyday practice and have the skills and capability to translate or generate best evidence to underpin professional and service delivery. Originality/value This paper provides strategies for building workforce researcher capacity and capability. The program provides opportunity for building research networks and role modeling the value and importance of research to practice and quality improvement. PMID- 28714836 TI - The importance of the evaluation of expectations and perceptions to improve the dental service quality. AB - Purpose The purpose of this paper is to evaluate the use of SERVQUAL to assess service quality in Dentistry, by evaluating patients' expectations and perceptions of dental care and their association to patients' sociodemographic data. Design/methodology/approach The sample constituted of 379 subjects in the first assessment and 155 in the second phase. All employees of the companies that were clients of the dental insurance participated, a total of four companies in two states (Sao Paulo and Minas Gerais) of Brazil. SERVQUAL questionnaires about expectations and sociodemographic data were dispatched in the first phase, and in a second phase SERVQUAL questionnaires about perceptions. Those who had not yet received dental treatment and had agreed to participate filled out their survey in the first phase. In the second phase, the respondents had to have completed their treatment. Findings When the value gap is considered, Reliability (as a dimension) had the smallest score (-3.71). This means that it was the worst result, i.e. there is a higher difference between expectations and perceptions, and problems can be identified here. t-test confirmed that all the dimensions had some statistically significant difference with p<0.05 in relation to expectations and perceptions. Women presented higher prevalence of dissatisfaction (Tangible and Reliability dimensions), as well as the oldest participants (Empathy dimension) and those with lower parental literacy (Assurance and Empathy dimensions). The only dimension that was not significantly associated was Responsiveness. Originality/value This research suggests that the patients evaluated the physical characteristics of the premises and the interaction with the staff as the priority issues that need special attention in this service. Moreover, the use of SERVQUAL was extremely relevant for the oral health service, because it assessed the users' subjective perceptions. PMID- 28714837 TI - Validating Center-of-Pressure Balance Measurements Using the MatScan(r) Pressure Mat. AB - CONTEXT: Measurements of center-of-pressure (COP) excursions during balance are common practice in clinical and research settings to evaluate adaptations in postural control due to pathological or environmental conditions. Traditionally measured using laboratory force plates, pressure-mat devices may be a suitable option for clinicians and scientist to measure COP excursions. OBJECTIVE: Compare COP measures and changes during balance between MatScan(r) pressure mat and force plate. DESIGN: Validation study. SETTING: Laboratory. PARTICIPANTS: 30 healthy, young adults (19 female, 11 male, 22.7 +/- 3.4 y, 70.3 +/- SD kg, 1.71 +/- 0.09 m). MAIN OUTCOMES: COP excursions were simultaneously measured using pressure-mat and force-plate devices. Participants completed 3 eyes-open and 3 eyes-closed single-leg balance trials (10 s). Mean of the 3 trials was used to calculate 4 COP variables: medial-lateral and anterior-posterior excursion, total distance, and area with eyes open and eyes closed. Percent change and effect sizes were calculated between eyes-open to eyes-closed conditions for each variable and for both devices. RESULTS: All COP variables were highly correlated between devices for eyes-open and eyes-closed conditions (all r > .92, P < .001). Bland-Altman plots suggest the pressure-mat COP measurements were smaller than those of the force-plate, and the differences between devices appeared to increase as the measurement magnitude increased. Percent change in COP variables was highly correlated between devices (r > .85, P < .001). Cohen d effect sizes between eyes open and eyes-closed were all large (d > 2.25) and similar in magnitude between devices. CONCLUSION: COP measures were correlated between devices, but values tended to be smaller using the pressure mat. The pressure mat and force plate detected comparable magnitude changes in COP measurements between eyes-open and eyes-closed. Pressure mats may provide a viable option for detecting large magnitude changes in postural control during short-duration testing. PMID- 28714838 TI - Lower-Extremity Muscle Activity, Kinematics, and Dynamic Postural Control in Individuals With Patellofemoral Pain. AB - CONTEXT: Altered lower-extremity muscle activity has been associated with lower extremity kinematics in individuals with patellofemoral pain (PFP). However, few studies have examined these relationships, and the results are inconsistent. OBJECTIVE: To compare the lower-extremity muscle activity, kinematics, pain level, and reach distance during the anterior reach of the star excursion balance test (SEBT) between participants with PFP and healthy individuals (control [CON] group). DESIGN: Case control. SETTING: Research laboratory. PARTICIPANTS: Twenty eight (PFP = 14 and CON = 14) participants volunteered. INTERVENTION: Each participant performed 3 maximal voluntary isometric contractions of the gluteus maximus, gluteus medius (GMED), adductor longus (AL), and vastus medialis, and 5 anterior reaches of the SEBT. MAIN OUTCOME MEASURES: Three-dimensional joint kinematics of the hip and knee at the time of touchdown of the SEBT and integrated electromyography of each muscle were recorded during the descent phase of the SEBT. Coactivation ratios between the GMED and AL were calculated (GMED/AL). Pain level was assessed at the baseline and during performance of the SEBT, using a visual analog scale. RESULTS: Participants with PFP demonstrated decreased GMED/AL coactivation ratio (P = .01) and shorter reach distance (P = .01) during anterior reach of the SEBT compared with the CON group. Participants with PFP demonstrated higher pain levels at baseline (P = .03) and during test performance (P < .001) compared with the CON group and increased pain level during the test performance compared with the baseline (P < .001). No other significant differences were observed. CONCLUSIONS: There were alterations in muscle activity during SEBT performance, suggesting that overactivity of AL relative to GMED is a unique neural recruitment pattern in those with PFP. However, hip and knee joint kinematics did not seem to contribute to deficits in the anterior reach distance, suggesting a need for continued assessment of these deficiencies. PMID- 28714839 TI - The Psychotherapy Outcome Problem: The Development of the Outcome Stability Index. AB - OBJECTIVE: Psychotherapy research commonly utilizes clients' last session score as an indicator of treatment outcome. We examined whether this last session score is consistent with what would be predicted based on clients' general trajectory in psychological functioning across sessions. We focused on the unstandardized residual variance at the last session, as this represents the degree to which the session score is divergent (or not) from what is predicted from the previous sessions (i.e., Outcome Stability Index; OSI). METHOD: The sample included 27,958 clients who attended on average 9.41 sessions. Each session, clients completed the Behavioral Health Measure-20 as a measure of psychological functioning. We converted the unstandardized residual variance for clients' last session score into a Cohen's d coefficient to aid in interpretation. RESULTS: The mean OSI was 0.07 (SD = 0.58), suggesting excellent stability in their last session therapy outcome scores. However, approximately 33% of clients demonstrated poor or extremely problematic stability in their last session therapy outcome scores. Clients who demonstrated poor stability were classified as demonstrating reliable deterioration. CONCLUSIONS: Researchers may want to consider reporting OSI to assist readers' understanding of the stability of therapy outcomes. Clinical or methodological significance of this article: Therapy outcome scores can vary from session to session, which can influence how we understand therapy outcomes that rely on last session scores. Studies examining therapy outcomes could report the Outcome Stability Index to better contextualize the results. PMID- 28714840 TI - Shoulder Strength Requirements for Upper Limb Functional Tasks: Do Age and Rotator Cuff Tear Status Matter? AB - Understanding upper limb strength requirements for daily tasks is imperative for early detection of strength loss that may progress to disability due to age or rotator cuff tear. We quantified shoulder strength requirements for 5 upper limb tasks performed by 3 groups: uninjured young adults and older adults, and older adults with a degenerative supraspinatus tear prior to repair. Musculoskeletal models were developed for each group representing age, sex, and tear-related strength losses. Percentage of available strength used was quantified for the subset of tasks requiring the largest amount of shoulder strength. Significant differences in strength requirements existed across tasks: upward reach 105 degrees required the largest average strength; axilla wash required the largest peak strength. However, there were limited differences across participant groups. Older adults with and without a tear used a larger percentage of their shoulder elevation (p < .001, p < .001) and external rotation (p < .001, p = .017) strength than the young adults, respectively. Presence of a tear significantly increased percentage of internal rotation strength compared to young (p < .001) and uninjured older adults (p = .008). Marked differences in strength demand across tasks indicate the need for evaluating a diversity of functional tasks to effectively detect early strength loss, which may lead to disability. PMID- 28714841 TI - Bifidobacterium apri sp. nov., a thermophilic actinobacterium isolated from the digestive tract of wild pigs (Sus scrofa). AB - Fresh samples of intestinal contents of three wild pigs originating from the Central Bohemia region were examined for the presence of bifidobacterial strains. During the study, we isolated many fructose-6-phosphate phosphoketolase-positive, strictly anaerobic, irregular rod-shaped bacterial isolates. Three of them were preliminarily identified as representing a novel species of the genus Bifidobacterium because their 16S rRNA gene sequence similarity with the closest relatives of thermophilic bifidobacteria (Bifidobacterium boum DSM 20432T, Bifidobacterium thermophilum DSM 20210T, Bifidobacterium thermacidophilumsubsp. porcinum LMG 21689T, Bifidobacterium thermacidophilumsubsp. thermacidophilum DSM 15837T) was in the range of 97.9 - 98.4 %. All three bacterial isolates had identical 16S rRNA, dnaJ1, fusA, gyrB and rplB gene sequences. Isolate RP115T was chosen as a representative of the bacterial group and DNA G+C content (mol%) determination, biochemical tests and analyses of physiological and morphological characteristics, habitat and chemotaxonomic traits (peptidoglycan structure, cellular fatty acids and polar lipids profile) were performed. The DNA-DNA hybridization analyses of RP115T and species representing the group of thermophilic bifidobacteria revealed values in the range from 33 to 53 %. This fact, together with relatively low sequence similarities of particular phylogenetic markers among examined bacterial strains and the phenotyping and chemotaxonomy results obtained, indicated that the evaluated bacterial isolate should be classified as representing a separate taxon within the specific group of thermophilic bifidobacteria. The name Bifidobacterium apri (of boar) sp. nov. has been proposed for the representative strain RP115T (=CCM 8605T=DSM 100238T=LMG 28779T). PMID- 28714842 TI - Molecular and biochemical characteristics of the inulosucrase HugO from Streptomyces viridochromogenes DSM40736 (Tu494). AB - Polyfructans are synthesized from sucrose by plants (mostly inulin) and by both Gram-negative and Gram-positive bacteria (mostly levan). In the phylum Actinobacteria only levan synthesis by Actinomyces species has been reported. We have identified a putative fructansucrase gene (hugO) in Streptomyces viridochromogenes DSM40736 (Tu494). HugO was heterologously expressed and biochemically characterized. HPSEC-MALLS and 2D-1H-13C nuclear magnetic resonance (NMR) spectroscopy analysis showed that the fructan polymer produced in vitro has an Molecular Weight of 2.5*107 Da and is an inulin that is mainly composed of (beta2-1)-linked fructose units. This is the first report of a fructansucrase from Streptomyces and an inulosucrase from Actinobacteria. Database searches showed that fructansucrases clearly occur more widely in streptomycetes. Analysis of the active site of HugO and other actinobacterial Gram-positive fructansucrases revealed that their +1 substrate-binding sites are conserved, but are most similar to those in Gram-negative fructansucrases. HugO also resembles Gram-negative fructansucrases in not requiring calcium ions for activity. The origin and properties of HugO and other actinobacterial fructansucrases thus clearly differ from those of previously characterized Gram-positive fructansucrases. PMID- 28714843 TI - Roseomonas suffusca sp. nov., isolated from lagoon sediments. AB - Three light-brown-coloured, Gram-stain-negative, small rod- to oval-shaped, motile bacteria were isolated from lagoon sediments collected from North Carolina, USA. The strains (S1T, AS3 and AS6) grew aerobically at 13-42 degrees C (optimum, 30-35 degrees C) and pH 6.5-9.1 (optimum, pH 7.0-7.5). All three strains were positive for catalase and oxidase activity, and no added NaCl was required for growth. C18 : 1omega6c/C18 : 1omega7c, C16 : 1omega6c/C16 : 1omega7c, C18 : 1omega7c 11-methyl and C16 : 0 were the predominant fatty acids (>5 %). Diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, phosphatidylcholine and an unidentified glycolipid were the major polar lipids. The genomic DNA G+C content of strains S1T, AS3 and AS6 was 70.5, 70.1 and 70.8 mol%, respectively. Strain S1T showed 16S rRNA gene sequence similarity of 99.1 % with Roseomonas rubra S5T, 98.7 % with Roseomonas rhizosphaerae YW11T, 98.5 % with Roseomonas cervicalis E7107T, 97.8 % with Roseomonas aestuarii JC17T, 97.2 % with Roseomonas oryzae JC288T, 97.2 % with Roseomonas ludipueritiae 170/96Tand <97 % with other members of the genus Roseomonas. Strains AS3 and AS6 shared 99.9 % 16S rRNA gene sequence similarity with strain S1T. DNA-DNA hybridization values among strains S1T, AS3 and AS6 were >89 %, while all the three strains showed <56 % relatedness with the most closely related type strains. Distinct phenotypic, genotypic and phylogenetic differences from the previously described taxa support the classification of strain S1T as a representative of a novel species in the genus Roseomonas, for which the name Roseomonas suffusca sp. nov. is proposed. The type strain is S1T (=KEMB 563-465T=JCM 31176T). Strains AS3 and AS6 serve as additional strains of the newly proposed species. PMID- 28714844 TI - Puzihella rosea gen. nov., sp. nov., a novel member of the family Microbacteriaceae isolated from freshwater. AB - Two Gram-stain-positive, aerobic, pink, curved, rod-shaped, non-motile bacterial strains, designated MI-28T and SKY-11, were isolated from freshwater samples taken from a river and fish pond, respectively. Based on characterization using a polyphasic approach, the two strains showed highly similar phenotypic, physiological and genetic profiles. They demonstrated 99.9 % 16S rRNA gene sequence similarity and a 93-95 % DNA-DNA relatedness value, suggesting that they represent a single genomic species. Phylogenetic analyses, based on 16S rRNA gene sequences, showed that strains MI-28T and SKY-11 form a distinct lineage with respect to closely related genera within the family Microbacteriaceae of the class Actinobacteria, which is most closely related to Rhodoluna and Pontimonas, and levels of 16S rRNA gene sequence similarity with the type species of related genera were less than 95 %. Cell-wall analysis showed that the peptidoglycan contained 2,4-diaminobutyric acid, alanine, glycine and glutamic acid. The predominant fatty acids were iso-C14 : 0, anteiso-C15 : 0 and iso-C16 : 0. The polar lipid profile consisted of a mixture of phosphatidylglycerol, diphosphatidylglycerol, an uncharacterized glycolipid and an uncharacterized aminophospholipid. The major polyamine was putrescine. The major isoprenoid quinone was MK-10. The G+C content of DNA was between 62.6 and 62.9 mol%. On the basis of the genotypic and phenotypic data, strains MI-28T and SKY-11 represent a novel genus and species of the family Microbacteriaceae, for which the name Puzihella rosea gen. nov., sp. nov. is proposed. The type strain of the type species is MI-28T (=BCRC 80688T=LMG 27848T=KCTC 29239T). PMID- 28714845 TI - Bacillus mangrovi sp. nov., isolated from a sediment sample from a mangrove forest. AB - A facultatively anaerobic, endospore forming, alkali-tolerant, Gram-stain positive, motile, rod-shaped bacterium, designated strain AK61T, was isolated from a sediment sample collected from Coringa mangrove forest, India. Colonies were circular, 1.5 mm in diameter, shiny, smooth, yellowish and convex with entire margins after 48 h growth at 30 degrees C. Growth occurred at 15-42 degrees C, with 0-3 % (w/v) NaCl and at pH 6-9. AK61T was positive for amylase activity and negative for oxidase, catalase, aesculinase, caseinase, cellulase, DNase, gelatinase, lipase and urease activities. The fatty acids were dominated by branched types with iso- and anteiso- saturated fatty acids with a high abundance of iso-C14 : 0, iso-C15 : 0, anteiso-C15 : 0 and iso-C16 : 0; the cell wall peptidoglycan contained meso-diaminopimelic acid as the diagnostic diamino acid; and MK-7 was the major menaquinone. DNA-DNA hybridization between AK61T and Bacillus indicus MTCC 4374T and between AK61T and Bacillus indicus KCTC 3880 showed relatedness of 37.99 and 33.32 % respectively. The DNA G+C content of AK61T was 44 mol%. The results of a blast sequence similarity search based on 16S rRNA gene sequences indicated that Bacillus cibi and Bacillus indicus were the nearest phylogenetic neighbours, with a pair-wise sequence similarity of 97.69 and 97.55 % respectively. The results of phylogenetic analysis indicated that AK61T was clustered with Bacillus idriensis and Bacillus indicus. On the basis of its phenotypic characteristics and phylogenetic inference, AK61T represents a novel species of the genus Bacillus, for which the name Bacillus mangrovi sp. nov. is proposed. The type strain is AK61T (=JCM 31087T=MTCC 12015T=KCTC 33872T). PMID- 28714846 TI - ICTV Virus Taxonomy Profile: Benyviridae. AB - The Benyviridae is a family of multipartite plant viruses with rod-shaped virions. Genomes are segmented and comprised of single-stranded, positive-sense RNAs, each with a 5' m7G cap. Unlike rod-shaped viruses classified in the Virgaviridae family, the genome segments have a 3' polyA tract and there is post translational cleavage of the viral replicase. The better-known members are transmitted by root-infecting vectors in the Plasmodiphorales family, once described as fungi but now classified as Cercozoa. The family has a single genus. This is a summary of the International Committee on Taxonomy of Viruses (ICTV) Report on the taxonomy of Benyviridae, which is available at www.ictv.global/report/benyviridae. PMID- 28714848 TI - Hepatitis B virus X protein activates E3 ubiquitin ligase Siah-1 to control virus propagation via a negative feedback loop. AB - The seven in absentia homologue 1 (Siah-1) protein is an E3 ubiquitin ligase that induces ubiquitin-dependent proteasomal degradation of HBx, the principal regulatory protein of hepatitis B virus (HBV); however, its role in HBV propagation remains unknown. Here, we found that HBx upregulates Siah-1 levels in HepG2 but not in Hep3B cells, in which p53 is absent. For this effect, HBx sequentially activated ataxia telangiectasia mutated kinase and checkpoint kinase 2 via phosphorylation at the Ser-1981 and Thr-68 residues, respectively, which led to the activation of p53 via phosphorylation at the Ser-15 and Ser-20 residues. As a result, HBx was heavily ubiquitinated by Siah-1 and degraded by the ubiquitin-proteasome system in HepG2 cells, whereas this effect was marginal or undetectable in Hep3B cells. Knock-down of p53 in HepG2 cells downregulated Siah-1 levels and subsequently upregulated HBx levels, whereas ectopic p53 expression in Hep3B cells upregulated Siah-1 levels and subsequently downregulated HBx levels. In addition, Siah-1 knock-down impaired the ubiquitination and proteasomal degradation of HBx in HepG2 cells, whereas ectopic Siah-1 expression induced ubiquitin-dependent proteasomal degradation of HBx in Hep3B cells. The effects of HBx on p53 and Siah-1 were exactly reproduced in a 1.2-mer HBV replicon system, mimicking the natural course of HBV infection. In particular, Siah-1 knock-down upregulated the levels of HBx derived from the HBV replicon, resulting in an increase in HBV production. In conclusion, HBx modulates its own protein level via a negative feedback loop involving p53 and Siah-1 to control HBV propagation. PMID- 28714847 TI - Modulation of the transcription factor NF-kappaB in antigen-presenting cells by bovine respiratory syncytial virus small hydrophobic protein. AB - Bovine respiratory syncytial virus (BRSV) is an important cause of respiratory disease in young cattle and is closely related to human RSV (HRSV), which causes severe respiratory disease in infants and the elderly. The RSV genome encodes a small hydrophobic (SH) protein with viroporin activity. Previous studies have shown that recombinant BRSV lacking the SH gene (rBRSVDeltaSH) is attenuated in the lungs, but not in the upper respiratory tract, of calves and mucosal vaccination with rBRSVDeltaSH induced long-lasting protective immunity. Attenuation of rBRSVDeltaSH may be due to the ability of this virus to induce an early innate response as rBRSVDeltaSH induces higher levels of pro-inflammatory cytokines than wild-type (wt) rBRSV. In this study, we investigated the effects of the BRSV SH protein on NF-kappaB p65 phosphorylation, a master step in the regulation of pro-inflammatory cytokines. Expression of SH resulted in the inhibition of NF-kappaB p65 phosphorylation in response to BRSV infection and extracellular lipopolysaccharide, and a reduction in the production of pro inflammatory cytokines. In contrast, rBRSVDeltaSH does not inhibit NF-kappaB p65 phosphorylation in bovine antigen-presenting cells, including monocytes, macrophages and dendritic cells, resulting in increased expression of pro inflammatory cytokines and increased activation of T cells compared to cells infected with wt BRSV. These findings highlight an important role for the BRSV SH protein in immune modulation. PMID- 28714849 TI - Proposal for a unified classification system and nomenclature of lagoviruses. AB - Lagoviruses belong to the Caliciviridae family. They were first recognized as highly pathogenic viruses of the European rabbit (Oryctolagus cuniculus) and European brown hare (Lepus europaeus) that emerged in the 1970-1980s, namely, rabbit haemorrhagic disease virus (RHDV) and European brown hare syndrome virus (EBHSV), according to the host species from which they had been first detected. However, the diversity of lagoviruses has recently expanded to include new related viruses with varying pathogenicity, geographic distribution and host ranges. Together with the frequent recombination observed amongst circulating viruses, there is a clear need to establish precise guidelines for classifying and naming lagovirus strains. Therefore, here we propose a new nomenclature based on phylogenetic relationships. In this new nomenclature, a single species of lagovirus would be recognized and called Lagovirus europaeus. The species would be divided into two genogroups that correspond to RHDV- and EBHSV-related viruses, respectively. Genogroups could be subdivided into genotypes, which could themselves be subdivided into phylogenetically well-supported variants. Based on available sequences, pairwise distance cutoffs have been defined, but with the accumulation of new sequences these cutoffs may need to be revised. We propose that an international working group could coordinate the nomenclature of lagoviruses and any proposals for revision. PMID- 28714850 TI - High-resolution mapping of heteroduplex DNA formed during UV-induced and spontaneous mitotic recombination events in yeast. AB - In yeast, DNA breaks are usually repaired by homologous recombination (HR). An early step for HR pathways is formation of a heteroduplex, in which a single strand from the broken DNA molecule pairs with a strand derived from an intact DNA molecule. If the two strands of DNA are not identical, there will be mismatches within the heteroduplex DNA (hetDNA). In wild-type strains, these mismatches are repaired by the mismatch repair (MMR) system, producing a gene conversion event. In strains lacking MMR, the mismatches persist. Most previous studies involving hetDNA formed during mitotic recombination were restricted to one locus. Below, we present a global mapping of hetDNA formed in the MMR defective mlh1 strain. We find that many recombination events are associated with repair of double-stranded DNA gaps and/or involve Mlh1-independent mismatch repair. Many of our events are not explicable by the simplest form of the double strand break repair model of recombination. PMID- 28714851 TI - Pdgfralpha functions in endothelial-derived cells to regulate neural crest cells and the development of the great arteries. AB - Originating as a single vessel emerging from the embryonic heart, the truncus arteriosus must septate and remodel into the aorta and pulmonary artery to support postnatal life. Defective remodeling or septation leads to abnormalities collectively known as conotruncal defects, which are associated with significant mortality and morbidity. Multiple populations of cells must interact to coordinate outflow tract remodeling, and the cardiac neural crest has emerged as particularly important during this process. Abnormalities in the cardiac neural crest have been implicated in the pathogenesis of multiple conotruncal defects, including persistent truncus arteriosus, double outlet right ventricle and tetralogy of Fallot. However, the role of the neural crest in the pathogenesis of another conotruncal abnormality, transposition of the great arteries, is less well understood. In this report, we demonstrate an unexpected role of Pdgfra in endothelial cells and their derivatives during outflow tract development. Loss of Pdgfra in endothelium and endothelial-derived cells results in double outlet right ventricle and transposition of the great arteries. Our data suggest that loss of Pdgfra in endothelial-derived mesenchyme in the outflow tract endocardial cushions leads to a secondary defect in neural crest migration during development. PMID- 28714854 TI - Evaluation of bone formation in calcium phosphate scaffolds with MUCT-method validation using SEM. AB - There is a plethora of calcium phosphate (CaP) scaffolds used as synthetic substitutes to bone grafts. The scaffold performance is often evaluated from the quantity of bone formed within or in direct contact with the scaffold. Micro computed tomography (MUCT) allows three-dimensional evaluation of bone formation inside scaffolds. However, the almost identical x-ray attenuation of CaP and bone obtrude the separation of these phases in MUCT images. Commonly, segmentation of bone in MUCT images is based on gray scale intensity, with manually determined global thresholds. However, image analysis methods, and methods for manual thresholding in particular, lack standardization and may consequently suffer from subjectivity. The aim of the present study was to provide a methodological framework for addressing these issues. Bone formation in two types of CaP scaffold architectures (foamed and robocast), obtained from a larger animal study (a 12 week canine animal model) was evaluated by MUCT. In addition, cross sectional scanning electron microscopy (SEM) images were acquired as references to determine thresholds and to validate the result. MUCT datasets were registered to the corresponding SEM reference. Global thresholds were then determined by quantitatively correlating the different area fractions in the MUCT image, towards the area fractions in the corresponding SEM image. For comparison, area fractions were also quantified using global thresholds determined manually by two different approaches. In the validation the manually determined thresholds resulted in large average errors in area fraction (up to 17%), whereas for the evaluation using SEM references, the errors were estimated to be less than 3%. Furthermore, it was found that basing the thresholds on one single SEM reference gave lower errors than determining them manually. This study provides an objective, robust and less error prone method to determine global thresholds for the evaluation of bone formation in CaP scaffolds. PMID- 28714853 TI - Unveiling the development of intracranial injury using dynamic brain EIT: an evaluation of current reconstruction algorithms. AB - OBJECTIVE: Dynamic brain electrical impedance tomography (EIT) is a promising technique for continuously monitoring the development of cerebral injury. While there are many reconstruction algorithms available for brain EIT, there is still a lack of study to compare their performance in the context of dynamic brain monitoring. APPROACH: To address this problem, we develop a framework for evaluating different current algorithms with their ability to correctly identify small intracranial conductivity changes. Firstly, a simulation 3D head phantom with realistic layered structure and impedance distribution is developed. Next several reconstructing algorithms, such as back projection (BP), damped least square (DLS), Bayesian, split Bregman (SB) and GREIT are introduced. We investigate their temporal response, noise performance, location and shape error with respect to different noise levels on the simulation phantom. The results show that the SB algorithm demonstrates superior performance in reducing image error. To further improve the location accuracy, we optimize SB by incorporating the brain structure-based conductivity distribution priors, in which differences of the conductivities between different brain tissues and the inhomogeneous conductivity distribution of the skull are considered. We compare this novel algorithm (called SB-IBCD) with SB and DLS using anatomically correct head shaped phantoms with spatial varying skull conductivity. Main results and Significance: The results showed that SB-IBCD is the most effective in unveiling small intracranial conductivity changes, where it can reduce the image error by an average of 30.0% compared to DLS. PMID- 28714852 TI - Trimebutine, a small molecule mimetic agonist of adhesion molecule L1, contributes to functional recovery after spinal cord injury in mice. AB - Curing spinal cord injury (SCI) in mammals is a daunting task because of the lack of permissive mechanisms and strong inhibitory responses at and around the lesion. The neural cell adhesion molecule L1CAM (L1) has been shown to favor axonal regrowth and enhance neuronal survival and synaptic plasticity but delivery of full-length L1 or its extracellular domain could encounter difficulties in translation to therapy in humans. We have, therefore, identified several small organic compounds that bind to L1 and stimulate neuronal survival, neuronal migration and neurite outgrowth in an L1-dependent manner. Here, we assessed the functions of two L1 mimetics, trimebutine and honokiol, in regeneration following SCI in young adult mice. Using the Basso Mouse Scale (BMS) score, we found that ground locomotion in trimebutine-treated mice recovered better than honokiol-treated or vehicle-receiving mice. Enhanced hindlimb locomotor functions in the trimebutine group were observed at 6 weeks after SCI. Immunohistology of the spinal cords rostral and caudal to the lesion site showed reduced areas and intensities of glial fibrillary acidic protein immunoreactivity in both trimebutine and honokiol groups, whereas increased regrowth of axons was observed only in the trimebutine-treated group. Both L1- and L1 mimetic-mediated intracellular signaling cascades in the spinal cord lesion sites were activated by trimebutine and honokiol, with trimebutine being more effective than honokiol. These observations suggest that trimebutine and, to a lesser extent under the present experimental conditions, honokiol have a potential for therapy in regeneration of mammalian spinal cord injuries. PMID- 28714855 TI - Fabrication of an ideal nanoring from a black phosphorus nanoribbon upon movable bundling carbon nanotubes. AB - As a low dimensional material, black phosphorus (BP) continues to attract much attention from researchers due to its excellent electric properties. In particular, the one-dimensional material, in the form of a ring or tube formed from BP, has been extensively studied and found to be a perfect semiconductor. But the BP ring has never been reported in laboratories. To form an ideal ring from a rectangular BP ribbon, we choose a carbon nanotube (CNT) bundle to attract the ribbon and move one or more CNTs in the bundle to induce the unsaturated ends of the BP ribbon to become covalently bonded. Numerical experiments are applied to BP ribbons with lengths either equal to, shorter, or longer than the perimeter of the CNT bundle, to investigate the formation of a BP ring. Experiments show that if one end of the BP ribbon is attracted by a CNT, moving the other CNTs away endows the ribbon with high probability of forming an ideal ring. The conclusions drawn from these results will benefit future in situ experiments involving forming a ring from a BP ribbon. PMID- 28714856 TI - Use of human aortic extracellular matrix as a scaffold for construction of a patient-specific tissue engineered vascular patch. AB - Synthetic or biologic materials are usually used to repair vascular malformation in congenital heart defects; however, non-autologous materials show both mismatch compliance and antigenicity, as well as a lack of recellularization on its surface. Here, we constructed a tissue-engineered vascular patch (TEVP) using decellularized extracellular matrix (ECM) scaffold obtained from excised human aorta during surgery, which was seeded with patient-derived bone marrow CD34 positive (CD34+) progenitor cells. While cellular components were removed, the decellularized ECM scaffold retained native ECM composition, similar mechanical performance to undecellularized aortic tissue, and supported the adhesion, survival and proliferation of CD34+ progenitor cells. Interestingly, after in vitro seeding of decellularized aortic ECM scaffold for 21 d, CD34+ progenitor cells differentiated into mature vascular endothelial cells without addition of any growth factors, as confirmed by the increased levels of endothelial surface markers (CD31, Von Willebrand factor (VWF), VE-cadherin and ICAM-2) and upregulated gene levels (CD31, VWF and eNOS) concurrently with decreased expression of stem cell markers (CD133 and CD34), thus, resulting in surface endothelialization of decellularized ECM scaffold. Consequently, the patient specific TEVP constructed in this study holds great potential for clinical use in pediatric patients with vascular malformation. PMID- 28714857 TI - Comparative analysis on resistance profiling along tapered semiconductor nanowires: multi-tip technique versus transmission line method. AB - The detection of doping dependent values like contact- and path resistances along nanowires (NWs) still proves to be rather challenging compared to planar structures. Unfortunately, the usually used and well established TLM (transmission line measurement) setup exhibits some drawbacks. Complex preliminary preparation steps and the necessity of ohmic contacts limit the investigation to certain semiconductor materials. The simultaneous determination of contact- and path resistances with an unknown distribution makes an analysis on complex structures like tapered nanowires very challenging. Our approach is the utilization of a multi-tip scanning tunneling microscope (MT-STM) as a four point prober, which allows the investigation of freestanding nanowires with an increased spatial resolution. Here, the used measurement setup allows a local separation of current injection and potential measurement and thus a highly precise determination of path resistances. Tapered p-doped GaAs-NWs were used to compare both techniques. Whereas the evaluation of the axial doping profile by MT STM was rather simple, correction factors had to be introduced for the TLM measurement to calculate the specific resistances and transfer length. By comparing the results of both methods for the very same NW-sample, the precision and accuracy of MT-STM measurements was demonstrated. We found an agreement, which allows the conclusion that both methods exhibit advantages; however the MT STM was determined as the more precise setup, which enables additional characterization capabilities, such as surface, temperature or light dependent measurements. PMID- 28714858 TI - Hybridization effects on wave packet dynamics in topological insulator thin films. AB - Theoretical study of electron wave packet dynamics in topological insulator (TI) thin films is presented. We have investigated real space trajectories and spin dynamics of electron wave packets in TI thin films. Our focus is on the role of hybridization between the electronic states of the two surfaces. This allows us to access the crossover regime of a thick film with no hybridization to a thin film with finite hybridization. We show that the electron wave packet undergoes side-jump motion in addition to zitterbewegung. The oscillation frequency of zitterbewegung can be tuned by the strength of hybridization, which in turn can be tuned by the thickness of the film. We find that the spin expectations also exhibit zitterbewegung tunable by hybridization. We also show that it is possible to obtain persistent zitterbewegung, oscillations which do not decay, in both the real space trajectories as well as spin dynamics. The zitterbewegung oscillation frequency in TI thin films falls in a parameter regime where it might be possible to observe these effects using present day experimental techniques. PMID- 28714859 TI - Regrowth mechanism for oxide isolation of GaAs nanowires. AB - Oxide-isolated GaAs nanowires (NWs) were obtained through a lithography-free method in which axial growth of NWs coated in aluminum oxide (Al2O3) is restarted using an annealing step. NWs are grown using the vapor-liquid-solid method and coated in nanometer thin oxide films using atomic layer deposition. Continued growth at the oxide-coated nanoparticle (NP) occurs after the thermally-induced fracture of the oxide during annealing. This oxide fracture is observed to depend on NP diameter, oxide thickness and annealing temperature. A thermal expansion mismatch model for stresses on the oxide shell is put forward to explain these results. PMID- 28714860 TI - Charge carrier relaxation in InGaAs-GaAs quantum wire modulation-doped heterostructures. AB - The time dependencies of the carrier relaxation in modulation-doped InGaAs-GaAs low-dimensional structures with quantum wires have been studied as functions of temperature and light excitation levels. The photoconductivity (PC) relaxation follows a stretched exponent with decay constant, which depends on the morphology of InGaAs epitaxial layers, presence of deep traps, and energy disorder due to inhomogeneous distribution of size and composition. A hopping model, where electron tunnels between bands of localized states, gives appropriate interpretation for temperature-independent PC decay across the temperature range 150-290 K. At low temperatures (T < 150 K), multiple trapping-retrapping via 1D states of InGaAs quantum wires (QWRs), sub-bands of two-dimensional electron gas of modulation-doped n-GaAs spacers, as well as defect states in the GaAs environment are the dominant relaxation mechanism. The PC and photoluminescence transients for samples with different morphologies of the InGaAs nanostructures are compared. The relaxation rates are found to be largely dependent on energy disorder due to inhomogeneous distribution of strain, nanostructure size and composition, and piezoelectric fields in and around nanostructures, which have a strong impact on efficiency of carrier exchange between bands of the InGaAs QWRs, GaAs spacers, or wetting layers; presence of local electric fields; and deep traps. PMID- 28714861 TI - Microglia in steady state. AB - Microglial cells are the resident tissue macrophages of the CNS and are widely recognized for their immune surveillance of the healthy CNS. In addition to this well-accepted function, recent findings point to major roles for microglia in instructing and regulating the proper function of the neuronal networks in the adult CNS, but these cells are also involved in creating neuronal networks by orchestrating construction of the whole network during development. In this Review, we highlight recent findings about the steady-state functions of microglial cells, the factors that are important for physiological microglial function, and how microglia help to maintain tissue homeostasis in the CNS. PMID- 28714862 TI - A leptin-regulated circuit controls glucose mobilization during noxious stimuli. AB - Adipocytes secrete the hormone leptin to signal the sufficiency of energy stores. Reductions in circulating leptin concentrations reflect a negative energy balance, which augments sympathetic nervous system (SNS) activation in response to metabolically demanding emergencies. This process ensures adequate glucose mobilization despite low energy stores. We report that leptin receptor-expressing neurons (LepRb neurons) in the periaqueductal gray (PAG), the largest population of LepRb neurons in the brain stem, mediate this process. Application of noxious stimuli, which often signal the need to mobilize glucose to support an appropriate response, activated PAG LepRb neurons, which project to and activate parabrachial nucleus (PBN) neurons that control SNS activation and glucose mobilization. Furthermore, activating PAG LepRb neurons increased SNS activity and blood glucose concentrations, while ablating LepRb in PAG neurons augmented glucose mobilization in response to noxious stimuli. Thus, decreased leptin action on PAG LepRb neurons augments the autonomic response to noxious stimuli, ensuring sufficient glucose mobilization during periods of acute demand in the face of diminished energy stores. PMID- 28714863 TI - DNA methylation-based immune response signature improves patient diagnosis in multiple cancers. AB - BACKGROUND: The tumor immune response is increasingly associated with better clinical outcomes in breast and other cancers. However, the evaluation of tumor infiltrating lymphocytes (TILs) relies on histopathological measurements with limited accuracy and reproducibility. Here, we profiled DNA methylation markers to identify a methylation of TIL (MeTIL) signature that recapitulates TIL evaluations and their prognostic value for long-term outcomes in breast cancer (BC). METHODS: MeTIL signature scores were correlated with clinical endpoints reflecting overall or disease-free survival and a pathologic complete response to preoperative anthracycline therapy in 3 BC cohorts from the Jules Bordet Institute in Brussels and in other cancer types from The Cancer Genome Atlas. RESULTS: The MeTIL signature measured TIL distributions in a sensitive manner and predicted survival and response to chemotherapy in BC better than did histopathological assessment of TILs or gene expression-based immune markers, respectively. The MeTIL signature also improved the prediction of survival in other malignancies, including melanoma and lung cancer. Furthermore, the MeTIL signature predicted differences in survival for malignancies in which TILs were not known to have a prognostic value. Finally, we showed that MeTIL markers can be determined by bisulfite pyrosequencing of small amounts of DNA from formalin fixed, paraffin-embedded tumor tissue, supporting clinical applications for this methodology. CONCLUSIONS: This study highlights the power of DNA methylation to evaluate tumor immune responses and the potential of this approach to improve the diagnosis and treatment of breast and other cancers. FUNDING: This work was funded by the Fonds National de la Recherche Scientifique (FNRS) and Televie, the INNOVIRIS Brussels Region BRUBREAST Project, the IUAP P7/03 program, the Belgian "Foundation against Cancer," the Breast Cancer Research Foundation (BCRF), and the Fonds Gaston Ithier. PMID- 28714864 TI - An erythroid-specific ATP2B4 enhancer mediates red blood cell hydration and malaria susceptibility. AB - The lack of mechanistic explanations for many genotype-phenotype associations identified by GWAS precludes thorough assessment of their impact on human health. Here, we conducted an expression quantitative trait locus (eQTL) mapping analysis in erythroblasts and found erythroid-specific eQTLs for ATP2B4, the main calcium ATPase of red blood cells (rbc). The same SNPs were previously associated with mean corpuscular hemoglobin concentration (MCHC) and susceptibility to severe malaria infection. We showed that Atp2b4-/- mice demonstrate increased MCHC, confirming ATP2B4 as the causal gene at this GWAS locus. Using CRISPR-Cas9, we fine mapped the genetic signal to an erythroid-specific enhancer of ATP2B4. Erythroid cells with a deletion of the ATP2B4 enhancer had abnormally high intracellular calcium levels. These results illustrate the power of combined transcriptomic, epigenomic, and genome-editing approaches in characterizing noncoding regulatory elements in phenotype-relevant cells. Our study supports ATP2B4 as a potential target for modulating rbc hydration in erythroid disorders and malaria infection. PMID- 28714865 TI - Microglia in prion diseases. AB - Prion diseases are a group of progressive and fatal neurodegenerative disorders characterized by deposition of scrapie prion protein (PrPSc) in the CNS. This deposition is accompanied by neuronal loss, spongiform change, astrogliosis, and conspicuous microglial activation. Here, we argue that microglia play an overall neuroprotective role in prion pathogenesis. Several microglia-related molecules, such as Toll-like receptors (TLRs), the complement system, cytokines, chemokines, inflammatory regulators, and phagocytosis mediators, are involved in prion pathogenesis. However, the molecular mechanisms underlying the microglial response to prion infection are largely unknown. Consequently, we lack a comprehensive understanding of the regulatory network of microglial activation. On the positive side, recent findings suggest that therapeutic strategies modulating microglial activation and function may have merit in prion disease. Moreover, studies on the role of microglia in prion disease could deepen our understanding of neuroinflammation in a broad range of neurodegenerative disorders. PMID- 28714867 TI - Enhanced astrocytic d-serine underlies synaptic damage after traumatic brain injury. AB - After traumatic brain injury (TBI), glial cells have both beneficial and deleterious roles in injury progression and recovery. However, few studies have examined the influence of reactive astrocytes in the tripartite synapse following TBI. Here, we have demonstrated that hippocampal synaptic damage caused by controlled cortical impact (CCI) injury in mice results in a switch from neuronal to astrocytic d-serine release. Under nonpathological conditions, d-serine functions as a neurotransmitter and coagonist for NMDA receptors and is involved in mediating synaptic plasticity. The phasic release of neuronal d-serine is important in maintaining synaptic function, and deficiencies lead to reductions in synaptic function and plasticity. Following CCI injury, hippocampal neurons downregulated d-serine levels, while astrocytes enhanced production and release of d-serine. We further determined that this switch in the cellular source of d serine, together with the release of basal levels of glutamate, contributes to synaptic damage and dysfunction. Astrocyte-specific elimination of the astrocytic d-serine-synthesizing enzyme serine racemase after CCI injury improved synaptic plasticity, brain oscillations, and learning behavior. We conclude that the enhanced tonic release of d-serine from astrocytes after TBI underlies much of the synaptic damage associated with brain injury. PMID- 28714866 TI - Ibrutinib treatment improves T cell number and function in CLL patients. AB - BACKGROUND: Ibrutinib has been shown to have immunomodulatory effects by inhibiting Bruton's tyrosine kinase (BTK) and IL-2-inducible T cell kinase (ITK). The relative importance of inhibiting these 2 kinases has not been examined despite its relevance to immune-based therapies. METHODS: Peripheral blood mononuclear cells from chronic lymphocytic leukemia (CLL) patients on clinical trials of ibrutinib (BTK/ITK inhibitor; n = 19) or acalabrutinib (selective BTK inhibitor; n = 13) were collected serially. T cell phenotype, immune function, and CLL cell immunosuppressive capacity were evaluated. RESULTS: Ibrutinib markedly increased CD4+ and CD8+ T cell numbers in CLL patients. This effect was more prominent in effector/effector memory subsets and was not observed with acalabrutinib. Ex vivo studies demonstrated that this may be due to diminished activation-induced cell death through ITK inhibition. PD-1 and CTLA-4 expression was significantly markedly reduced in T cells by both agents. While the number of Treg cells remained unchanged, the ratio of these to conventional CD4+ T cells was reduced with ibrutinib, but not acalabrutinib. Both agents reduced expression of the immunosuppressive molecules CD200 and BTLA as well as IL-10 production by CLL cells. CONCLUSIONS: Ibrutinib treatment increased the in vivo persistence of activated T cells, decreased the Treg/CD4+ T cell ratio, and diminished the immune-suppressive properties of CLL cells through BTK-dependent and -independent mechanisms. These features provide a strong rationale for combination immunotherapy approaches with ibrutinib in CLL and other cancers. TRIAL REGISTRATION: ClinicalTrials.gov NCT01589302 and NCT02029443. Samples described here were collected per OSU-0025. FUNDING: The National Cancer Institute. PMID- 28714868 TI - Interval dosing with the HDAC inhibitor vorinostat effectively reverses HIV latency. AB - BACKGROUND: The histone deacetylase (HDAC) inhibitor vorinostat (VOR) can increase HIV RNA expression in vivo within resting CD4+ T cells of aviremic HIV+ individuals. However, while studies of VOR or other HDAC inhibitors have reported reversal of latency, none has demonstrated clearance of latent infection. We sought to identify the optimal dosing of VOR for effective serial reversal of HIV latency. METHODS: In a study of 16 HIV-infected, aviremic individuals, we measured resting CD4+ T cell-associated HIV RNA ex vivo and in vivo following a single exposure to VOR, and then in vivo after a pair of doses separated by 48 or 72 hours, and finally following a series of 10 doses given at 72-hour intervals. RESULTS: Serial VOR exposures separated by 72 hours most often resulted in an increase in cell-associated HIV RNA within circulating resting CD4+ T cells. VOR was well tolerated by all participants. However, despite serial reversal of latency over 1 month of VOR dosing, we did not observe a measurable decrease (>0.3 log10) in the frequency of latent infection within resting CD4+ T cells. CONCLUSIONS: These findings outline parameters for the experimental use of VOR to clear latent infection. Latency reversal can be achieved by VOR safely and repeatedly, but effective depletion of persistent HIV infection will require additional advances. In addition to improvements in latency reversal, these advances may include the sustained induction of potent antiviral immune responses capable of recognizing and clearing the rare cells in which HIV latency has been reversed. TRIAL REGISTRATION: Clinicaltrials.gov NCT01319383. FUNDING: NIH grants U01 AI095052, AI50410, and P30 CA016086 and National Center for Advancing Translational Sciences grant KL2 TR001109. PMID- 28714869 TI - The Occurrence of Zearalenone in South Korean Feedstuffs between 2009 and 2016. AB - Mycotoxins produced by Fusarium plant pathogen species have harmful effects on humans and livestock by natural contamination in food and feed. Zearalenone, one of the well-known Fusarium mycotoxins, causes hyperestrogenism and toxicosis resulting in reproductive dysfunction in animals. This study investigated the occurrence of zearalenone in feedstuffs (compound feeds, feed ingredients) between 2009 and 2016 in South Korea to obtain information on zearalenone contamination in feeds for management. A total of 653 animal feed samples (494 compound feeds, 159 feed ingredients) produced domestically were sampled five times from 2009 to 2016 (2009, 2010, 2012, 2014, and 2016) from feed factories in South Korea. The levels of zearalenone were analyzed every year by high performance liquid chromatography (HPLC) after pretreatment with an immunoaffinity column showing limit of detection (LOD) and limit of quantification (LOQ) of 0.1-3 MUg/kg and 0.3-8 MUg/kg, respectively. Four feed samples out of 494 compound feeds exceeded the EU and South Korea commission regulations over the eight-year test period, and no feed ingredients exceeded the guidelines. PMID- 28714870 TI - Antiviral Lipopeptide-Cell Membrane Interaction Is Influenced by PEG Linker Length. AB - A set of lipopeptides was recently reported for their broad-spectrum antiviral activity against viruses belonging to the Paramyxoviridae family, including human parainfluenza virus type 3 and Nipah virus. Among them, the peptide with a 24 unit PEG linker connecting it to a cholesterol moiety (VG-PEG24-Chol) was found to be the best membrane fusion inhibitory peptide. Here, we evaluated the interaction of the same set of peptides with biomembrane model systems and isolated human peripheral blood mononuclear cells (PBMC). VG-PEG24-Chol showed the highest insertion rate and it was among the peptides that induced a larger change on the surface pressure of cholesterol rich membranes. This peptide also displayed a high affinity towards PBMC membranes. These data provide new information about the dynamics of peptide-membrane interactions of a specific group of antiviral peptides, known for their potential as multipotent paramyxovirus antivirals. PMID- 28714872 TI - Immunomodulatory Activity of Octenyl Succinic Anhydride Modified Porang (Amorphophallus oncophyllus) Glucomannan on Mouse Macrophage-Like J774.1 Cells and Mouse Primary Peritoneal Macrophages. AB - Porang is a local plant of Indonesia, which has a high content of glucomannan. In this study, porang glucomannan (PG) was esterified with octenyl succinic anhydride (OSA) to enhance emulsion properties to be widely used in food industry. OSA-modified PG (OSA-PG) enhanced the phagocytosis activity of macrophage-like J774.1 cells and mouse peritoneal macrophages. In addition, OSA PG increased the production of IL-6 and TNF-alpha by enhancing their gene expression. Immunoblot analysis displayed that OSA-PG tended to activate both nuclear factor-kappaB and mitogen-activated protein kinase cascades. Treatment of OSA-PG with polymyxin B revealed that cytokine production induced by OSA-PG was not caused by endotoxin contamination. Our findings also indicated that OSA-PG activates macrophages through not only Toll-like receptor (TLR) 4, but another receptor. Overall findings suggested that OSA-PG has a potential as an immunomodulatory food factor by stimulating macrophages. PMID- 28714871 TI - Signaling within Allosteric Machines: Signal Transmission Pathways Inside G Protein-Coupled Receptors. AB - In recent years, our understanding of function of G protein-coupled receptors (GPCRs) has changed from a picture of simple signal relays, transmitting only a particular signal to a particular G protein heterotrimer, to versatile machines, capable of various responses to different stimuli and being modulated by various factors. Some recent reports provide not only the data on ligands/modulators and resultant signals induced by them, but also deeper insights into exact pathways of signal migration and mechanisms of signal transmission through receptor structure. Combination of these computational and experimental data sheds more light on underlying mechanisms of signal transmission and signaling bias in GPCRs. In this review we focus on available clues on allosteric pathways responsible for complex signal processing within GPCRs structures, with particular emphasis on linking compatible in silico- and in vitro-derived data on the most probable allosteric connections. PMID- 28714873 TI - A Label-Free Fluorescent Array Sensor Utilizing Liposome Encapsulating Calcein for Discriminating Target Proteins by Principal Component Analysis. AB - A new fluorescent arrayed biosensor has been developed to discriminate species and concentrations of target proteins by using plural different phospholipid liposome species encapsulating fluorescent molecules, utilizing differences in permeation of the fluorescent molecules through the membrane to modulate liposome target protein interactions. This approach proposes a basically new label-free fluorescent sensor, compared with the common technique of developed fluorescent array sensors with labeling. We have confirmed a high output intensity of fluorescence emission related to characteristics of the fluorescent molecules dependent on their concentrations when they leak from inside the liposomes through the perturbed lipid membrane. After taking an array image of the fluorescence emission from the sensor using a CMOS imager, the output intensities of the fluorescence were analyzed by a principal component analysis (PCA) statistical method. It is found from PCA plots that different protein species with several concentrations were successfully discriminated by using the different lipid membranes with high cumulative contribution ratio. We also confirmed that the accuracy of the discrimination by the array sensor with a single shot is higher than that of a single sensor with multiple shots. PMID- 28714875 TI - Current Knowledge in Thyroid Cancer-From Bench to Bedside. PMID- 28714874 TI - Inhibitory Growth of Oral Squamous Cell Carcinoma Cancer via Bacterial Prodigiosin. AB - Chemotherapy drugs for oral cancers always cause side effects and adverse effects. Currently natural sources and herbs are being searched for treated human oral squamous carcinoma cells (OSCC) in an effort to alleviate the causations of agents in oral cancers chemotherapy. This study investigates the effect of prodigiosin (PG), an alkaloid and natural red pigment as a secondary metabolite of Serratia marcescens, to inhibit human oral squamous carcinoma cell growth; thereby, developing a new drug for the treatment of oral cancer. In vitro cultured human OSCC models (OECM1 and SAS cell lines) were used to test the inhibitory growth of PG via cell cytotoxic effects (MTT assay), cell cycle analysis, and Western blotting. PG under various concentrations and time courses were shown to effectively cause cell death and cell-cycle arrest in OECM1 and SAS cells. Additionally, PG induced autophagic cell death in OECM1 and SAS cells by LC3-mediated P62/LC3-I/LC3-II pathway at the in vitro level. These findings elucidate the role of PG, which may target the autophagic cell death pathways as a potential agent in cancer therapeutics. PMID- 28714876 TI - Sustained Low Serum Substance P Levels in Non-Surviving Septic Patients. AB - Previously, researchers found higher serum substance P (SP) concentrations in survivors of severe sepsis than in non-survivors at the time of severe sepsis diagnosis. The objectives of our current study were to determine whether there is an association between serum SP levels during the first week and sepsis mortality, sepsis severity, serum levels of tumor necrosis factor (TNF)-alpha and interleukin (IL)-10, and whether serum SP levels during the first week could be used as a biomarker of sepsis mortality. We determined serum concentration of SP, TNF-alpha, and IL-10 at days 1, 4, and 8. The end-point of the study was mortality at 30 days. We found that non-survivor (n = 104) compared to survivor patients (n = 206) showed lower serum SP levels at days 1, 4, and 8 (p < 0.001). Multiple logistic regression analyses showed an association between 30-day mortality and serum SP levels at days 1, 4, and 8 (p < 0.001) controlling for SOFA score, diabetes mellitus, age, and lactic acid levels. The most interesting findings of our study were that there is an association between serum SP levels during the first week and sepsis mortality, and that serum SP levels during the first week could be used as a biomarker of sepsis mortality. PMID- 28714878 TI - Integrated Metabolomics Assessment of Human Dried Blood Spots and Urine Strips. AB - (1) Background: Interest in the application of metabolomics toward clinical diagnostics development and population health monitoring has grown significantly in recent years. In spite of several advances in analytical and computational tools, obtaining a sufficient number of samples from patients remains an obstacle. The dried blood spot (DBS) and dried urine strip (DUS) methodologies are a minimally invasive sample collection method allowing for the relative simplicity of sample collection and minimal cost. (2) Methods: In the current report, we compared results of targeted metabolomics analyses of four types of human blood sample collection methods (with and without DBS) and two types of urine sample collection (DUS and urine) across several parameters including the metabolite coverage of each matrix and the sample stability for DBS/DUS using commercially available Whatman 903TM paper. The DBS/DUS metabolomics protocols were further applied to examine the temporal metabolite level fluctuations within hours and days of sample collection. (3) Results: Several hundred polar metabolites were monitored using DBS/DUS. Temporal analysis of the polar metabolites at various times of the day and across days identified several species that fluctuate as a function of day and time. In addition, a subset of metabolites were identified to be significantly altered across hours within a day and within successive days of the week. (4) Conclusion: A comprehensive DBS/DUS metabolomics protocol was developed for human blood and urine analyses. The described methodology demonstrates the potential for enabling patients to contribute to the expanding bioanalytical demands of precision medicine and population health studies. PMID- 28714879 TI - The Influence of Spatial Configuration of Residential Area and Vector Populations on Dengue Incidence Patterns in an Individual-Level Transmission Model. AB - Dengue is a mosquito-borne infectious disease that is endemic in tropical and subtropical countries. Many individual-level simulation models have been developed to test hypotheses about dengue virus transmission. Often these efforts assume that human host and mosquito vector populations are randomly or uniformly distributed in the environment. Although, the movement of mosquitoes is affected by spatial configuration of buildings and mosquito populations are highly clustered in key buildings, little research has focused on the influence of the local built environment in dengue transmission models. We developed an agent based model of dengue transmission in a village setting to test the importance of using realistic environments in individual-level models of dengue transmission. The results from one-way ANOVA analysis of simulations indicated that the differences between scenarios in terms of infection rates as well as serotype specific dominance are statistically significant. Specifically, the infection rates in scenarios of a realistic environment are more variable than those of a synthetic spatial configuration. With respect to dengue serotype-specific cases, we found that a single dengue serotype is more often dominant in realistic environments than in synthetic environments. An agent-based approach allows a fine-scaled analysis of simulated dengue incidence patterns. The results provide a better understanding of the influence of spatial heterogeneity on dengue transmission at a local scale. PMID- 28714877 TI - Alternative Pre-mRNA Splicing in Mammals and Teleost Fish: A Effective Strategy for the Regulation of Immune Responses Against Pathogen Infection. AB - Pre-mRNA splicing is the process by which introns are removed and the protein coding elements assembled into mature mRNAs. Alternative pre-mRNA splicing provides an important source of transcriptome and proteome complexity through selectively joining different coding elements to form mRNAs, which encode proteins with similar or distinct functions. In mammals, previous studies have shown the role of alternative splicing in regulating the function of the immune system, especially in the regulation of T-cell activation and function. As lower vertebrates, teleost fish mainly rely on a large family of pattern recognition receptors (PRRs) to recognize pathogen-associated molecular patterns (PAMPs) from various invading pathogens. In this review, we summarize recent advances in our understanding of alternative splicing of piscine PRRs including peptidoglycan recognition proteins (PGRPs), nucleotide binding and oligomerization domain (NOD) like receptors (NLRs), retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) and their downstream signaling molecules, compared to splicing in mammals. We also discuss what is known and unknown about the function of splicing isoforms in the innate immune responses against pathogens infection in mammals and teleost fish. Finally, we highlight the consequences of alternative splicing in the innate immune system and give our view of important directions for future studies. PMID- 28714880 TI - Upregulation of Phosphatidylinositol 3-Kinase (PI3K) Enhances Ethylene Biosynthesis and Accelerates Flower Senescence in Transgenic Nicotiana tabacum L. AB - Phosphatidylinositol 3-kinase (PI3K) is a key enzyme that phosphorylates phosphatidylinositol at 3'-hydroxyl position of the inositol head group initiating the generation of several phosphorylated phosphatidylinositols, collectively referred to as phosphoinositides. The function of PI3K in plant senescence and ethylene signal transduction process was studied by expression of Solanum lycopersicum PI3K in transgenic Nicotiana tabacum, and delineating its effect on flower senescence. Detached flowers of transgenic tobacco plants with overexpressed Sl-PI3K (OX) displayed accelerated senescence and reduced longevity, when compared to the flowers of wild type plants. Flowers from PI3K overexpressing plants showed enhanced ethylene production and upregulated expression of 1-aminocyclopropane-1-carboxylic acid oxidase 1 (ACO1). Real time polymerase chain reaction (PCR) analysis showed that PI3K was expressed at a higher level in OX flowers than in the control. Seedlings of OX-lines also demonstrated a triple response phenotype with characteristic exaggerated apical hook, shorter hypocotyls and increased sensitivity to 1-aminocyclopropane-1 carboxylate than the control wild type seedlings. In floral tissue from OX-lines, Solanum lycopersicum phosphatidylinositol 3-kinase green fluorescent protein (PI3K-GFP) chimera protein was localized primarily in stomata, potentially in cytoplasm and membrane adjacent to stomatal pores in the guard cells. Immunoblot analysis of PI3K expression in OX lines demonstrated increased protein level compared to the control. Results of the present study suggest that PI3K plays a crucial role in senescence by enhancing ethylene biosynthesis and signaling. PMID- 28714882 TI - Vitamin D Supplementation Enhances C18(dihydro)ceramide Levels in Type 2 Diabetes Patients. AB - Sphingolipids are characterized by a broad range of bioactive properties. Particularly, the development of insulin resistance, a major pathophysiological hallmark of Type 2 Diabetes mellitus (T2D), has been linked to ceramide signaling. Since vitamin D supplementation may slow down T2D progression by improving glucose concentrations and insulin sensitivity, we investigated whether vitamin D supplementation impacts on plasma sphingolipid levels in T2D patients. Thus, plasma samples of 59 patients with non-insulin-requiring T2D from a placebo controlled, randomized, and double-blind study were retrospectively analyzed. Once per week, patients received either 20 drops of Vigantol oil, corresponding to a daily dose of 1904 IU/d vitamin D (verum: n = 31), or a placebo oil consisting of medium chain triglycerides (placebo: n = 28). Blood samples were taken from all of the participants at three different time points: 1) at the beginning of the study (baseline), 2) after 6 months supplementation, and 3) after an additional 6 months of follow-up. Plasma sphingolipids were measured by high-performance liquid chromatography tandem mass spectrometry. At baseline and 6 months follow-up, no significant differences in plasma sphingolipid species were detected between the placebo and verum groups. After 6 months, vitamin D supplementation significantly enhanced plasma C18dihydroceramide (dhCer; N stearoyl-sphinganine (d18:0/18:0)) and C18ceramide (Cer; N-stearoyl-sphingosine (d18:1/18:0)) levels were observed in the verum group compared to the placebo group. This was accompanied by significantly higher 25-hydroxyvitamin D3 (25(OH)D3) blood levels in patients receiving vitamin D compared to the placebo group. Taken together, vitamin D supplementation induced changes of the C18 chain length-specific dhCer and Cer plasma levels in patients with T2D. The regulation of sphingolipid signaling by vitamin D may thus unravel a novel mechanism by which vitamin D can influence glucose utilization and insulin action. Whether this acts favorably or unfavorably for the progression of T2D needs to be clarified. PMID- 28714883 TI - NMR Insights into the Structure-Function Relationships in the Binding of Melanocortin Analogues to the MC1R Receptor. AB - Linear and cyclic analogues of the alpha-melanocyte stimulating hormone (alpha MSH) targeting the human melanocortin receptor 1 (MC1R) are of pharmacological interest for detecting and treating melanoma. The central sequence of alpha-MSH (His-Phe-Arg-Trp) has been identified as being essential for receptor binding. To deepen current knowledge on the molecular basis for alpha-MSH bioactivity, we aimed to understand the effect of cycle size on receptor binding. To that end, we synthesised two macrocyclic isomeric alpha-MSH analogues, c[NH-NO2-C6H3-CO-His DPhe-Arg-Trp-Lys]-Lys-NH2 (CycN-K6) and c[NH-NO2-C6H3-CO-His-DPhe-Arg-Trp-Lys Lys]-NH2 (CycN-K7). Their affinities to MC1R receptor were determined by competitive binding assays, and their structures were analysed by 1H and 13C NMR. These results were compared to those of the previously reported analogue c[S-NO2 C6H3-CO-His-DPhe-Arg-Trp-Cys]-Lys-NH2 (CycS-C6). The MC1R binding affinity of the 22-membered macrocyclic peptide CycN-K6 (IC50 = 155 +/- 16 nM) is higher than that found for the 25-membered macrocyclic analogue CycN-K7 (IC50 = 495 +/- 101 nM), which, in turn, is higher than that observed for the 19-membered cyclic analogue CycS-C6 (IC50 = 1770 +/- 480 nM). NMR structural study indicated that macrocycle size leads to changes in the relative dispositions of the side chains, particularly in the packing of the Arg side chain relative to the aromatic rings. In contrast to the other analogues, the 22-membered cycle's side chains are favorably positioned for receptor interaction. PMID- 28714884 TI - Design and Implementation of a Smart Home System Using Multisensor Data Fusion Technology. AB - This paper aims to develop a multisensor data fusion technology-based smart home system by integrating wearable intelligent technology, artificial intelligence, and sensor fusion technology. We have developed the following three systems to create an intelligent smart home environment: (1) a wearable motion sensing device to be placed on residents' wrists and its corresponding 3D gesture recognition algorithm to implement a convenient automated household appliance control system; (2) a wearable motion sensing device mounted on a resident's feet and its indoor positioning algorithm to realize an effective indoor pedestrian navigation system for smart energy management; (3) a multisensor circuit module and an intelligent fire detection and alarm algorithm to realize a home safety and fire detection system. In addition, an intelligent monitoring interface is developed to provide in real-time information about the smart home system, such as environmental temperatures, CO concentrations, communicative environmental alarms, household appliance status, human motion signals, and the results of gesture recognition and indoor positioning. Furthermore, an experimental testbed for validating the effectiveness and feasibility of the smart home system was built and verified experimentally. The results showed that the 3D gesture recognition algorithm could achieve recognition rates for automated household appliance control of 92.0%, 94.8%, 95.3%, and 87.7% by the 2-fold cross validation, 5-fold cross-validation, 10-fold cross-validation, and leave-one subject-out cross-validation strategies. For indoor positioning and smart energy management, the distance accuracy and positioning accuracy were around 0.22% and 3.36% of the total traveled distance in the indoor environment. For home safety and fire detection, the classification rate achieved 98.81% accuracy for determining the conditions of the indoor living environment. PMID- 28714881 TI - Assessment of Enzyme Inhibition: A Review with Examples from the Development of Monoamine Oxidase and Cholinesterase Inhibitory Drugs. AB - The actions of many drugs involve enzyme inhibition. This is exemplified by the inhibitors of monoamine oxidases (MAO) and the cholinsterases (ChE) that have been used for several pharmacological purposes. This review describes key principles and approaches for the reliable determination of enzyme activities and inhibition as well as some of the methods that are in current use for such studies with these two enzymes. Their applicability and potential pitfalls arising from their inappropriate use are discussed. Since inhibitor potency is frequently assessed in terms of the quantity necessary to give 50% inhibition (the IC50 value), the relationships between this and the mode of inhibition is also considered, in terms of the misleading information that it may provide. Incorporation of more than one functionality into the same molecule to give a multi-target-directed ligands (MTDLs) requires careful assessment to ensure that the specific target effects are not significantly altered and that the kinetic behavior remains as favourable with the MTDL as it does with the individual components. Such factors will be considered in terms of recently developed MTDLs that combine MAO and ChE inhibitory functions. PMID- 28714886 TI - Non-Convex Sparse and Low-Rank Based Robust Subspace Segmentation for Data Mining. AB - Parsimony, including sparsity and low-rank, has shown great importance for data mining in social networks, particularly in tasks such as segmentation and recognition. Traditionally, such modeling approaches rely on an iterative algorithm that minimizes an objective function with convex l1-norm or nuclear norm constraints. However, the obtained results by convex optimization are usually suboptimal to solutions of original sparse or low-rank problems. In this paper, a novel robust subspace segmentation algorithm has been proposed by integrating lp-norm and Schatten p-norm constraints. Our so-obtained affinity graph can better capture local geometrical structure and the global information of the data. As a consequence, our algorithm is more generative, discriminative and robust. An efficient linearized alternating direction method is derived to realize our model. Extensive segmentation experiments are conducted on public datasets. The proposed algorithm is revealed to be more effective and robust compared to five existing algorithms. PMID- 28714885 TI - Differences in Genetic Background Contribute to Pseudomonas Exotoxin A-Induced Hepatotoxicity in Rats. AB - Pseudomonas aeruginosa exotoxin A (PEA) causes severe hepatotoxicity in experimental animals and is useful in investigations of immune-mediated liver injury. However, strain differences in the sensitivity to PEA-induced hepatotoxicity in rats remains be elucidated. In this study, we determined the severity of PEA-induced hepatotoxicity in six genetically different rat strains. Male LE (Long Evans), Wistar, F344, WKY, BN/SsN and LEW rats were administered a single intravenous injection of PEA (20 MUg/kg). Significantly elevated serum ALT and AST levels, massive necrosis and hemorrhage, and numerous TUNEL-positive hepatocytes were observed in BN/SsN rats. In contrast, low levels of ALT and AST as well as mild changes in liver histopathology were observed in Wistar and F344 rats. Moderate levels of hepatic injuries were observed in LE, WKY, and LEW rats. Pro-inflammatory cytokines including TNF-alpha, IL-2 and IL-6 serum levels were markedly increased in BN/SsN rats compared to Wistar and F344 rats. However, the hepatic levels of low density lipoprotein receptor-related protein (LRP), which functions as the PEA receptor, were not significantly different in each strain. Taken together, we suggest that BN/SsN is the most sensitive rat strain, whereas Wistar and F344 were the most resistant rat strains to PEA-induced liver damage. The different genetic background of rat strains plays an important role in the susceptibility to PEA-induced epatotoxicity that may depend on immune-regulation but not LRP receptor levels. PMID- 28714888 TI - A Multiscale Approach to the Smart Deployment of Micro-Sensors over Lightweight Structures. AB - A topology optimization approach has been recently proposed to maximize the sensitivity to damage of measurements, collected through a network of sensors to be deployed over thin plates for structural health monitoring purposes. Within such a frame, damage is meant as a change in the structural health characterized by a reduction of relevant stiffness and load-carrying properties. The sensitivity to a damage of unknown amplitude and location is computed by comparing the response to the external actions of the healthy structure and of a set of auxiliary damaged structures, each one featuring reduced mechanical properties in a small region only. The topology optimization scheme has been devised to properly account for the information coming from all of the sensors to be placed on the structure and for damage depending on its location. In this work, we extend the approach within a multiscale frame to account for three different length scales: a macroscopic one, linked to the dimensions of the whole structure to be monitored; a mesoscopic one, linked to the characteristic size of the damaged region; a microscopic one, linked to the size of inertial microelectromechanical systems (MEMS) to be used within a marginally-invasive health monitoring system. Results are provided for a square plate and for a section of fuselage with stiffeners, to show how the micro-sensors have to be deployed to maximize the capability to detect a damage, to assess the sensitivity of the results to the measurement noise and to also discuss the speedup in designing the network topology against a standard single-scale approach. PMID- 28714887 TI - Characterization of Enterotoxigenic Bacillus cereus sensu lato and Staphylococcus aureus Isolates and Associated Enterotoxin Production Dynamics in Milk or Meat Based Broth. AB - Bacillus cereus sensu lato species, as well as Staphylococcus aureus, are important pathogenic bacteria which can cause foodborne illness through the production of enterotoxins. This study characterised enterotoxin genes of these species and examined growth and enterotoxin production dynamics of isolates when grown in milk or meat-based broth. All B. cereus s. l. isolates harboured nheA, hblA and entFM toxin genes, with lower prevalence of bceT and hlyII. When grown at 16 degrees C, toxin production by individual B. cereus s. l. isolates varied depending on the food matrix; toxin was detected at cell densities below 5 log10(CFU/mL). At 16 degrees C no staphylococcal enterotoxin C (SEC) production was detected by S. aureus isolates, although low levels of SED production was noted. At 30 degrees C all S. aureus isolates produced detectable enterotoxin in the simulated meat matrix, whereas SEC production was significantly reduced in milk. Relative to B. cereus s. l. toxin production, S. aureus typically required reaching higher cell numbers to produce detectable levels of enterotoxin. Phylogenetic analysis of the sec and sel genes suggested population evolution which correlated with animal host adaptation, with subgroups of bovine isolates or caprine/ovine isolates noted, which were distinct from human isolates. Taken together, this study highlights the marked differences in the production of enterotoxins both associated with different growth matrices themselves, but also in the behaviour of individual strains when exposed to different food matrices. PMID- 28714889 TI - Staphylococcus aureus Regulator Sigma B is Important to Develop Chronic Infections in Hematogenous Murine Osteomyelitis Model. AB - Staphylococcus aureus is a major pathogen causing bone infections that can become chronic and difficult to treat. Recently, we described the mechanism employed by S. aureus to switch to small colony variants (SCVs) and trigger intracellular bacterial persistence through the global stress regulator SigB. Here, we studied the role of SigB in the formation of chronic osteomyelitis. We used a murine hematogenous osteomyelitis model, where the mice were infected via the tail vein and subsequently developed chronic osteomyelitis. Mice were infected with S. aureus LS1, LS1DeltasigB and LS1DeltasigB complemented and kidney and bone tissues were analyzed six weeks after infection. S. aureus LS1DeltasigB formed a high rate of abscesses in kidneys, but the bacterial loads and the weight loss of the animals were lower in comparison with animals infected with the wild type and the complemented strain, indicating a more rapid and efficient bacterial clearing by the host immune system. Moreover, the sigB-mutant was not able to form SCV phenotypes either in kidney or in bone tissue. Our results demonstrate that staphylococcal SigB is important to avoid bacterial elimination by the host immune response, establish a bone infection and mediate bacterial adaptation (SCV formation) for persistent infections. PMID- 28714890 TI - Cardamom, Cumin, and Dill Weed Essential Oils: Chemical Compositions, Antimicrobial Activities, and Mechanisms of Action against Campylobacter spp. AB - Natural antimicrobials as well as essential oils (EOs) have gained interest to inhibit pathogenic microorganisms and to control food borne diseases. Campylobacter spp. are one of the most common causative agents of gastroenteritis. In this study, cardamom, cumin, and dill weed EOs were evaluated for their antibacterial activities against Campylobacter jejuni and Campylobacter coli by using agar-well diffusion and broth microdilution methods, along with the mechanisms of antimicrobial action. Chemical compositions of EOs were also tested by gas chromatography (GC) and gas chromatography-mass spectrometry (GC-MS). The results showed that cardamom and dill weed EOs possess greater antimicrobial activity than cumin with larger inhibition zones and lower minimum inhibitory concentrations. The permeability of cell membrane and cell membrane integrity were evaluated by determining relative electric conductivity and release of cell constituents into supernatant at 260 nm, respectively. Moreover, effect of EOs on the cell membrane of Campylobacter spp. was also investigated by measuring extracellular ATP concentration. Increase of relative electric conductivity, extracellular ATP concentration, and cell constituents' release after treatment with EOs demonstrated that tested EOs affected the membrane integrity of Campylobacter spp. The results supported high efficiency of cardamom, cumin, and dill weed EOs to inhibit Campylobacter spp. by impairing the bacterial cell membrane. PMID- 28714892 TI - Passive Downhole Pressure Sensor Based on Surface Acoustic Wave Technology. AB - A passive surface acoustic wave (SAW) pressure sensor was developed for real-time pressure monitoring in downhole application. The passive pressure sensor consists of a SAW resonator, which is attached to a circular metal diaphragm used as a pressure transducer. While the membrane deflects as a function of pressure applied, the frequency response changes due to the variation of the SAW propagation parameters. The sensitivity and linearity of the SAW pressure sensor were measured to be 8.3 kHz/bar and 0.999, respectively. The experimental results were validated with a hybrid analytical-numerical analysis. The good results combined with the robust design and packaging for harsh environment demonstrated it to be a promising sensor for industrial applications. PMID- 28714891 TI - Structural and Functional Neuroimaging of Visual Hallucinations in Lewy Body Disease: A Systematic Literature Review. AB - Patients with Lewy body disease (LBD) frequently experience visual hallucinations (VH), well-formed images perceived without the presence of real stimuli. The structural and functional brain mechanisms underlying VH in LBD are still unclear. The present review summarises the current literature on the neural correlates of VH in LBD, namely Parkinson's disease (PD), and dementia with Lewy bodies (DLB). Following a systematic literature search, 56 neuroimaging studies of VH in PD and DLB were critically reviewed and evaluated for quality assessment. The main structural neuroimaging results on VH in LBD revealed grey matter loss in frontal areas in patients with dementia, and parietal and occipito temporal regions in PD without dementia. Parietal and temporal hypometabolism was also reported in hallucinating PD patients. Disrupted functional connectivity was detected especially in the default mode network and fronto-parietal regions. However, evidence on structural and functional connectivity is still limited and requires further investigation. The current literature is in line with integrative models of VH suggesting a role of attention and perception deficits in the development of VH. However, despite the close relationship between VH and cognitive impairment, its associations with brain structure and function have been explored only by a limited number of studies. PMID- 28714893 TI - Loneliness, Insomnia and Suicidal Behavior among School-Going Adolescents in Western Pacific Island Countries: Role of Violence and Injury. AB - This study aimed to examine whether being bullied, fighting, and injury, regarded in terms of frequency and nature, were significantly associated with psychological distress and suicidal behavior, independent of substance abuse and parental support in adolescents. Secondary analysis of data from the Global School-based Student Health Survey from Kiribati, the Solomon Islands, and Vanuatu was conducted. Binomial logistic regression analysis was used to examine the association of being bullied, fighting and injury with psychological health outcomes (loneliness, insomnia, suicidal ideation and suicide attempt) at a 5% level of significance. A total of 4122 students were included; 45.5% were male, and 52.0% were 14 years of age or younger. Of the total, 9.3% felt lonely and 9.5% had insomnia most of the time over the last 12 months; 27.6% had suicidal ideation, and 30.9% reported at least one suicide attempt in the last 12 months. Multivariable logistic regression analysis showed that being bullied, fighting and injury were significantly associated with psychological health outcomes; adjusted odds ratios (AORs) of loneliness, insomnia, suicidal ideation and suicide attempt increased with increased exposure to bullying, fighting, and injury compared to non-exposed group. Among the types of bullying victimization, the highest AORs of insomnia and suicide attempt were among students who were left out of activities, compared to the non-bullied. Among the causes of injury, adolescents injured due to a physical attack were the most likely to report the highest AORs of loneliness, insomnia and suicidal ideation compared to those not injured. Preventing violence and injury among adolescents might contribute to better mental health and reduction of suicidal behavior. PMID- 28714895 TI - Flexible Boron-Doped Diamond (BDD) Electrodes for Plant Monitoring. AB - Detecting the bio-potential changes of plants would be useful for monitoring their growth and health in the field. A sensitive plant monitoring system with flexible boron-doped diamond (BDD) electrodes prepared from BDD powder and resin (Nafion or Vylon-KE1830) was investigated. The properties of the electrodes were compared with those of small BDD plate-type electrodes by monitoring the bioelectric potentials of potted Aloe and hybrid species in the genus Opuntia. While flexible BDD electrodes have wide potential windows, their cyclic voltammograms are different from those of the BDD plate. Further, the potential gap between a pair of electrodes attached to the plants changes as the plants are stimulated artificially with a finger touch, suggesting that the bioelectric potentials in the plant also changed, manifesting as changes in the potential gap between the electrodes. The BDD electrodes were assessed for their response reproducibility to a finger stimulus for 30 days. It was concluded that the plant monitoring system worked well with flexible BDD electrodes. Further, the electrodes were stable, and as reliable as the BDD plate electrodes in this study. Thus, a flexible and inexpensive BDD electrode system was successfully fabricated for monitoring the bioelectric potential changes in plants. PMID- 28714894 TI - Carbonic Anhydrase from Porphyromonas Gingivalis as a Drug Target. AB - Periodontitis originates from a microbial synergy causing the development of a mouth microbial imbalance (dysbiosis), consisting of a microbial community composed of anaerobic bacteria. Most studies concerning the treatment of periodontitis have primarily take into account the Gram-negative bacterium Porphyromonas gingivalis, because it is a prominent component of the oral microbiome and a successful colonizer of the oral epithelium. Here, we focus our attention on the study of the carbonic anhydrases (CAs, EC 4.2.1.1) encoded in the genome of this pathogen as a possible drug target. Carbonic anhydrases are a superfamily of metalloenzymes, which catalyze the simple but physiologically crucial reaction of carbon dioxide hydration to bicarbonate and protons. Bacterial CAs have attracted significant attention for affecting the survival, invasion, and pathogenicity of many microorganisms. The P. gingivalis genome encodes for two CAs belonging to beta-CA (PgiCAbeta) and gamma-CA (PgiCAgamma) families. These two enzymes were cloned, heterologously expressed in Escherichia coli, and purified to homogeneity. Moreover, they were subject to extensive inhibition studies using the classical CA inhibitors (sulfonamides and anions) with the aim of identifying selective inhibitors of PgiCAbeta and PgiCAgamma to be used as pharmacological tools for P. gingivalis eradication. PMID- 28714896 TI - Localization with Graph Diffusion Property. AB - Node localization is an essential issue in wireless sensor networks (WSNs). Many range-free localization methods have been proposed to satisfy the requirement of low-system cost. However, some range-free methods only depend on network connectivity, and others only utilize the proximity information attached in neighborhood ordering. To employ the strength of the above two aspects, this paper introduces a new metric system called Combined and Weighted Diffusion Distance (CWDD). CWDD is designed to obtain the relative distance among nodes based on both graph diffusion property and neighbor information. We implement our design by embedding CWDD into two well-known localization algorithms and evaluate it by extensive simulations. Results show that our design improves the localization performance in large scale and non-uniform sensor networks, which reduces positioning errors by as much as 26%. PMID- 28714897 TI - Development of Three-Dimensional Dental Scanning Apparatus Using Structured Illumination. AB - We demonstrated a three-dimensional (3D) dental scanning apparatus based on structured illumination. A liquid lens was used for tuning focus and a piezomotor stage was used for the shift of structured light. A simple algorithm, which detects intensity modulation, was used to perform optical sectioning with structured illumination. We reconstructed a 3D point cloud, which represents the 3D coordinates of the digitized surface of a dental gypsum cast by piling up sectioned images. We performed 3D registration of an individual 3D point cloud, which includes alignment and merging the 3D point clouds to exhibit a 3D model of the dental cast. PMID- 28714898 TI - Frame Transmission Efficiency-Based Cross-Layer Congestion Notification Scheme in Wireless Ad Hoc Networks. AB - Different from the traditional wired network, the fundamental cause of transmission congestion in wireless ad hoc networks is medium contention. How to utilize the congestion state from the MAC (Media Access Control) layer to adjust the transmission rate is core work for transport protocol design. However, recent works have shown that the existing cross-layer congestion detection solutions are too complex to be deployed or not able to characterize the congestion accurately. We first propose a new congestion metric called frame transmission efficiency (i.e., the ratio of successful transmission delay to the frame service delay), which describes the medium contention in a fast and accurate manner. We further present the design and implementation of RECN (ECN and the ratio of successful transmission delay to the frame service delay in the MAC layer, namely, the frame transmission efficiency), a general supporting scheme that adjusts the transport sending rate through a standard ECN (Explicit Congestion Notification) signaling method. Our method can be deployed on commodity switches with small firmware updates, while making no modification on end hosts. We integrate RECN transparently (i.e., without modification) with TCP on NS2 simulation. The experimental results show that RECN remarkably improves network goodput across multiple concurrent TCP flows. PMID- 28714899 TI - Electrochemical Flow-ELISA for Rapid and Sensitive Determination of Microcystin LR Using Automated Sequential Injection System. AB - An amperometric immunoanalysis system based on monoclonal antibodies immobilized on Sepharose beads and packed into a micro-immunocolumn was developed for the quantification of microcystin-LR. Microcystin-LR (MCLR) was used as a reference microcystin variant. Inside the immunocolumn, free microcystins and microcystin horseradish peroxidase (tracer) were sequentially captured by the immobilized antibodies, and the detection was performed electrochemically using Super AquaBlue ELISA substrate 2,2'-azinobis(3-ethylbenzothiazoline-sulfonic acid) (ABTS). The ABTS?+ generated by enzymatic oxidation of ABTS was electrochemically determined at a carbon working electrode by applying a reduction potential set at 0.4 V versus Ag/AgCl reference electrode. The peak current intensity was inversely proportional to the amount of analyte bound to the immunocolumn. The amperometric flow-ELISA system, which was automatically controlled through the CapSenzeTM (Lund, Sweden) computer software, enabled determination of MCLR as low as 0.01 ug/L. The assay time was very short (20 min for one assay cycle). In addition, the electrochemical signals were not significantly affected by possible interferences which could be present in the real samples. Along with the simplicity of automation, this makes the developed method a promising tool for use in water quality assessment. PMID- 28714900 TI - A Nutrigenomic Approach to Non-Alcoholic Fatty Liver Disease. AB - Following the epidemics of obesity due to the consumption of high-calorie diet and sedentary lifestyle, nonalcoholic fatty liver disease (NAFLD) is now the leading cause of liver disease in Western countries. NAFLD is epidemiologically associated with metabolic syndrome and insulin resistance, and in susceptible individuals it may progress to cirrhosis and hepatocellular carcinoma. Genetic factors play a key role in NAFLD predisposition by interacting with nutritional and other environmental factors. To date, there is no drug therapy for the treatment of NAFLD, and the main clinical recommendation is lifestyle modification. In the last years, nutrigenomics is promoting an increased understanding of how nutrition affects the switch from health to disease by altering the expression of an individual's genetic makeup. The present review tries to summarize the most recent data evidencing how the interactions between nutrients and genetic factors can influence NAFLD development. The final goal should be to develop tools to quantify these complex interactions. The definition of a "nutrigenomic risk score" for each individual may represent a novel therapeutic approach for the management of NAFLD patients. PMID- 28714901 TI - Selenium-Containing Polysaccharide-Protein Complex in Se-Enriched Ulva fasciata Induces Mitochondria-Mediated Apoptosis in A549 Human Lung Cancer Cells. AB - The role of selenium (Se) and Ulva fasciata as potent cancer chemopreventive and chemotherapeutic agents has been supported by epidemiological, preclinical, and clinical studies. In this study, Se-containing polysaccharide-protein complex (Se PPC), a novel organoselenium compound, a Se-containing polysaccharide-protein complex in Se-enriched Ulva fasciata, is a potent anti-proliferative agent against human lung cancer A549 cells. Se-PPC markedly inhibited the growth of cancer cells via induction of apoptosis which was accompanied by the formation of apoptotic bodies, an increase in the population of apoptotic sub-G1 phase cells, upregulation of p53, and activation of caspase-3 in A549 cells. Further investigation on intracellular mechanisms indicated that cytochrome C was released from mitochondria into cytosol in A549 cells after Se-PPC treatment. Se PPC induced depletion of mitochondrial membrane potential (DeltaPsim) in A549 cells through regulating the expression of anti-apoptotic (Bcl-2, Bcl-XL) and pro apoptotic (Bax, Bid) proteins, resulting in disruption of the activation of caspase-9. This is the first report to demonstrate the cytotoxic effect of Se-PPC on human cancer cells and to provide a possible mechanism for this activity. Thus, Se-PPC is a promising novel organoselenium compound with potential to treat human cancers. PMID- 28714902 TI - Fluorescence Modulation of Green Fluorescent Protein Using Fluorinated Unnatural Amino Acids. AB - The ability to modulate protein function through minimal perturbations to amino acid structure represents an ideal mechanism to engineer optimized proteins. Due to the novel spectroscopic properties of green fluorescent protein, it has found widespread application as a reporter protein throughout the fields of biology and chemistry. Using site-specific amino acid mutagenesis, we have incorporated various fluorotyrosine residues directly into the fluorophore of the protein, altering the fluorescence and shifting the pKa of the phenolic proton associated with the fluorophore. Relative to wild type GFP, the fluorescence spectrum of the protein is altered with each additional fluorine atom, and the mutant GFPs have the potential to be employed as pH sensors due to the altered electronic properties of the fluorine atoms. PMID- 28714903 TI - Sensing Responses Based on Transfer Characteristics of InAs Nanowire Field-Effect Transistors. AB - Nanowire-based field-effect transistors (FETs) have demonstrated considerable promise for a new generation of chemical and biological sensors. Indium arsenide (InAs), by virtue of its high electron mobility and intrinsic surface accumulation layer of electrons, holds properties beneficial for creating high performance sensors that can be used in applications such as point-of-care testing for patients diagnosed with chronic diseases. Here, we propose devices based on a parallel configuration of InAs nanowires and investigate sensor responses from measurements of conductance over time and FET characteristics. The devices were tested in controlled concentrations of vapour containing acetic acid, 2-butanone and methanol. After adsorption of analyte molecules, trends in the transient current and transfer curves are correlated with the nature of the surface interaction. Specifically, we observed proportionality between acetic acid concentration and relative conductance change, off current and surface charge density extracted from subthreshold behaviour. We suggest the origin of the sensing response to acetic acid as a two-part, reversible acid-base and redox reaction between acetic acid, InAs and its native oxide that forms slow, donor like states at the nanowire surface. We further describe a simple model that is able to distinguish the occurrence of physical versus chemical adsorption by comparing the values of the extracted surface charge density. These studies demonstrate that InAs nanowires can produce a multitude of sensor responses for the purpose of developing next generation, multi-dimensional sensor applications. PMID- 28714904 TI - BRD9 Inhibition, Alone or in Combination with Cytostatic Compounds as a Therapeutic Approach in Rhabdoid Tumors. AB - Rhabdoid tumors (RT) are malignant neoplasms of early childhood. Despite intensive therapy, survival is poor and new treatment approaches are required. The only recurrent mutations in these tumors affect SMARCB1 and less commonly SMARCA4, both subunits of the chromatin remodeling complex SWItch/Sucrose Non Fermentable (SWI/SNF). Loss of these two core subunits alters the function of the SWI/SNF complex, resulting in tumor development. We hypothesized that inhibition of aberrant SWI/SNF function by selective blockade of the BRD9 subunit of the SWI/SNF complex would reduce tumor cell proliferation. The cytotoxic and anti proliferative effects of two specific chemical probes (I-BRD9 and BI-9564) which target the bromodomain of SWI/SNF protein BRD9 were evaluated in 5 RT cell lines. Combinatorial effects of I-BRD9 and cytotoxic drugs on cell proliferation were evaluated by cytotoxicity assays. Single compound treatment of RT cells with I BRD9 and BI-9564 resulted in decreased cell proliferation, G1-arrest and apoptosis. Combined treatment of doxorubicin or carboplatin with I-BRD9 resulted in additive to synergistic inhibitory effects on cell proliferation. In contrast, the combination of I-BRD9 with vincristine demonstrated the antagonistic effects of these two compounds. We conclude that the BRD9 bromodomain is an attractive target for novel therapies in this cancer. PMID- 28714905 TI - Effects of Eicosapentaenoic Acid (EPA) and Docosahexaenoic Acid (DHA) on Fetal Pulmonary Circulation: An Experimental Study in Fetal Lambs. AB - Background: Persistent pulmonary hypertension of the newborn (PPHN) causes significant morbidity and mortality in neonates. n-3 Poly-unsaturated fatty acids have vasodilatory properties in the perinatal lung. We studied the circulatory effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in fetal sheep and in fetal pulmonary arterial rings. Methods: At 128 days of gestation, catheters were placed surgically in fetal systemic and pulmonary circulation, and a Doppler probe around the left pulmonary artery (LPA). Pulmonary arterial pressure and LPA flow were measured while infusing EPA or DHA for 120 min to the fetus, to compute pulmonary vascular resistance (PVR). The dose effects of EPA or DHA were studied in vascular rings pre-constricted with serotonin. Rings treated with EPA were separated into three groups: E+ (intact endothelium), E- (endothelium stripped) and LNA E+ (pretreatment of E+ rings with l-nitro arginine). Results: EPA, but not DHA, induced a significant and prolonged 25% drop in PVR (n = 8, p < 0.001). Incubation of vascular rings with EPA (100 uM) caused a maximum relaxation of 60% in the E+ (n = 6), whereas vessel tone did not change in the E- (n = 6, p < 0.001). The vascular effects of EPA were significantly decreased in LNA E+ (n = 6). Incubation with DHA resulted in only a mild relaxation at the highest concentration of DHA (300 uM) compared to E+. Conclusions: EPA induces a sustained pulmonary vasodilatation in fetal lambs. This effect is endothelium- and dose-dependent and involves nitric oxide (NO) production. We speculate that EPA supplementation may improve pulmonary circulation in clinical conditions with PPHN. PMID- 28714906 TI - Effect of Alkali Metal Atoms Doping on Structural and Nonlinear Optical Properties of the Gold-Germanium Bimetallic Clusters. AB - A new series of alkali-based complexes, AM@GenAu (AM = Li, Na, and K), have been theoretically designed and investigated by means of the density functional theory calculations. The geometric structures and electronic properties of the species are systematically analyzed. The adsorption of alkali metals maintains the structural framework of the gold-germanium bimetallic clusters, and the alkali metals prefer energetically to be attached on clusters' surfaces or edges. The high chemical stability of Li@Ge12Au is revealed by the spherical aromaticity, the hybridization between the Ge atoms and Au-4d states, and delocalized multi center bonds, as well as large binding energies. The static first hyperpolarizability (betatot) is related to the cluster size and geometric structure, and the AM@GenAu (AM = Na and K) clusters exhibit the much larger betatot values up to 13050 a.u., which are considerable to establish their strong nonlinear optical (NLO) behaviors. We hope that this study will promote further application of alkali metals-adsorbed germanium-based semiconductor materials, serving for the design of remarkable and tunable NLO materials. PMID- 28714908 TI - MUetal Uptake by Sunflower (Helianthus annuus) Irrigated with Water Polluted with Chromium and Nickel. AB - The water aquifers of the regions of Asopos River in Viotia and Messapia in Evia (Greece) have been contaminated with hexavalent chromium (Cr (VI)) and bivalent nickel (Ni (II)). Given that these areas are the two biggest tuber producing regions of Greece, in our previous work, the cross-contamination of the food chain with these two heavy metals was quantified. In the present study, the potential of sunflower (Helianthus annuus) cultivation in these regions is evaluated. The scope of our study was to investigate the uptake of chromium and nickel by sunflower, in a greenhouse experiment. The study included two cultivation periods of plants in six irrigation lines with different levels of Cr (VI) and Ni (II) ranging from 0 MUg/L (control) to 10,000 MUg/L. In all plant parts, statistically significant increased levels of Cr (VI) and Ni (II) were found when compared to control ones. Also, a positive correlation, both for Cr and Ni, between levels of heavy metals in irrigation water and plants was observed. Following European Food Safety Authority recommendations, the obtained oil was evaluated as safe for consumption, therefore, sunflower cultivation could be a valid bioremediation solution for the Asopos and Messapia regions. PMID- 28714907 TI - Genetic Contribution to Alcohol Dependence: Investigation of a Heterogeneous German Sample of Individuals with Alcohol Dependence, Chronic Alcoholic Pancreatitis, and Alcohol-Related Cirrhosis. AB - The present study investigated the genetic contribution to alcohol dependence (AD) using genome-wide association data from three German samples. These comprised patients with: (i) AD; (ii) chronic alcoholic pancreatitis (ACP); and (iii) alcohol-related liver cirrhosis (ALC). Single marker, gene-based, and pathway analyses were conducted. A significant association was detected for the ADH1B locus in a gene-based approach (puncorrected = 1.2 * 10-6; pcorrected = 0.020). This was driven by the AD subsample. No association with ADH1B was found in the combined ACP + ALC sample. On first inspection, this seems surprising, since ADH1B is a robustly replicated risk gene for AD and may therefore be expected to be associated also with subgroups of AD patients. The negative finding in the ACP + ALC sample, however, may reflect genetic stratification as well as random fluctuation of allele frequencies in the cases and controls, demonstrating the importance of large samples in which the phenotype is well assessed. PMID- 28714910 TI - Minding the Cyber-Physical Gap: Model-Based Analysis and Mitigation of Systemic Perception-Induced Failure. AB - The cyber-physical gap (CPG) is the difference between the 'real' state of the world and the way the system perceives it. This discrepancy often stems from the limitations of sensing and data collection technologies and capabilities, and is inevitable at some degree in any cyber-physical system (CPS). Ignoring or misrepresenting such limitations during system modeling, specification, design, and analysis can potentially result in systemic misconceptions, disrupted functionality and performance, system failure, severe damage, and potential detrimental impacts on the system and its environment. We propose CPG-Aware Modeling & Engineering (CPGAME), a conceptual model-based approach to capturing, explaining, and mitigating the CPG. CPGAME enhances the systems engineer's ability to cope with CPGs, mitigate them by design, and prevent erroneous decisions and actions. We demonstrate CPGAME by applying it for modeling and analysis of the 1979 Three Miles Island 2 nuclear accident, and show how its meltdown could be mitigated. We use ISO-19450:2015-Object Process Methodology as our conceptual modeling framework. PMID- 28714911 TI - Nutrition and Allergic Diseases. AB - The development of IgE-mediated allergic diseases is influenced by many factors, including genetic and environmental factors such as pollution and farming, but also by nutrition. In the last decade, substantial progress has been made in our understanding of the impact that nutrition can have on allergic diseases. Many studies have addressed the effect of breastfeeding, pre-, pro- and synbiotics, vitamins and minerals, fiber, fruit and vegetables, cow's milk, and n-3 fatty acids, on the development of allergies. In addition, nutrition can also have indirect effects on allergic sensitization. This includes the diet of pregnant and breastfeeding women, which influences intrauterine development, as well as breastmilk composition. These include the diet of pregnant and breastfeeding women that influences intrauterine development as well as breastmilk composition, effects of food processing that may enhance allergenicity of foods, and effects via modulation of the intestinal microbiota and their metabolites. This editorial review provides a brief overview of recent developments related to nutrition and the development and management of allergic diseases. PMID- 28714909 TI - The Interplay between the Host Receptor and Influenza Virus Hemagglutinin and Neuraminidase. AB - The hemagglutinin (HA) and neuraminidase (NA) glycoproteins of influenza A virus are responsible for the surface interactions of the virion with the host. Entry of the virus is mediated by functions of the HA: binding to cellular receptors and facilitating fusion of the virion membrane with the endosomal membrane. The HA structure contains receptor binding sites in the globular membrane distal head domains of the trimer, and the fusion machinery resides in the stem region. These sites have specific characteristics associated with subtype and host, and the differences often define species barriers. For example, avian viruses preferentially recognize alpha2,3-Sialic acid terminating glycans as receptors and mammalian viruses recognize alpha2,6-Sialic acid. The neuraminidase, or the receptor-destroying protein, cleaves the sialic acid from cellular membrane constituents and viral glycoproteins allowing for egress of nascent virions. A functional balance of activity has been demonstrated between the two glycoproteins, resulting in an optimum level of HA affinity and NA enzymatic cleavage to allow for productive infection. As more is understood about both HA and NA, the relevance for functional balance between HA and NA continues to expand, with potential implications for interspecies transmission, host adaptation, and pathogenicity. PMID- 28714912 TI - Urinary Excretion of Tetrodotoxin Modeled in a Porcine Renal Proximal Tubule Epithelial Cell Line, LLC-PK1. AB - This study examined the urinary excretion of tetrodotoxin (TTX) modeled in a porcine renal proximal tubule epithelial cell line, LLC-PK1. Time course profiles of TTX excretion and reabsorption across the cell monolayers at 37 degrees C showed that the amount of TTX transported increased linearly for 60 min. However, at 4 degrees C, the amount of TTX transported was approximately 20% of the value at 37 degrees C. These results indicate that TTX transport is both a transcellular and carrier-mediated process. Using a transport inhibition assay in which cell monolayers were incubated with 50 uM TTX and 5 mM of a transport inhibitor at 37 degrees C for 30 min, urinary excretion was significantly reduced by probenecid, tetraethylammonium (TEA), l-carnitine, and cimetidine, slightly reduced by p-aminohippuric acid (PAH), and unaffected by 1-methyl-4 phenylpyridinium (MPP+), oxaliplatin, and cefalexin. Renal reabsorption was significantly reduced by PAH, but was unaffected by probenecid, TEA and l carnitine. These findings indicate that TTX is primarily excreted by organic cation transporters (OCTs) and organic cation/carnitine transporters (OCTNs), partially transported by organic anion transporters (OATs) and multidrug resistance-associated proteins (MRPs), and negligibly transported by multidrug and toxic compound extrusion transporters (MATEs). PMID- 28714913 TI - Novel Fri1-like Viruses Infecting Acinetobacter baumannii-vB_AbaP_AS11 and vB_AbaP_AS12-Characterization, Comparative Genomic Analysis, and Host-Recognition Strategy. AB - Acinetobacter baumannii is a gram-negative, non-fermenting aerobic bacterium which is often associated with hospital-acquired infections and known for its ability to develop resistance to antibiotics, form biofilms, and survive for long periods in hospital environments. In this study, we present two novel viruses, vB_AbaP_AS11 and vB_AbaP_AS12, specifically infecting and lysing distinct multidrug-resistant clinical A. baumannii strains with K19 and K27 capsular polysaccharide structures, respectively. Both phages demonstrate rapid adsorption, short latent periods, and high burst sizes in one-step growth experiments. The AS11 and AS12 linear double-stranded DNA genomes of 41,642 base pairs (bp) and 41,402 bp share 86.3% nucleotide sequence identity with the most variable regions falling in host receptor-recognition genes. These genes encode tail spikes possessing depolymerizing activities towards corresponding capsular polysaccharides which are the primary bacterial receptors. We described AS11 and AS12 genome organization and discuss the possible regulation of transcription. The overall genomic architecture and gene homology analyses showed that the phages are new representatives of the recently designated Fri1virus genus of the Autographivirinae subfamily within the Podoviridae family. PMID- 28714914 TI - Online Vape Shop Customers Who Use E-Cigarettes Report Abstinence from Smoking and Improved Quality of Life, But a Substantial Minority Still Have Vaping Related Health Concerns. AB - (1) Background: Characteristics and usage patterns of vapers (e-cigarette users) have mainly been studied in web-based convenience samples or in visitors of brick and-mortar vape shops. We extended this by targeting customers of one particular online vape shop in the Netherlands; (2) Methods: Customers were questioned on their smoking history, current smoking and vaping status, reasons for vaping, perceived harmfulness, and potential health changes due to vaping; (3) Results: Almost everyone (99%, 95% CI 0.96, 1.00) smoked before they started vaping. A great majority agreed that unlike with other smoking-cessation aids, they could quit smoking (81%, 95% CI 0.79, 0.90) due to vaping. Almost all customers were regular vapers (93.6%, 95% CI 0.89, 0.96) who used state-of-the-art open system devices without modifications and e-liquid with 10 mg/mL nicotine on average. Vapers reported using e-cigs to quit smoking, because e-cigs are healthier, and for financial reasons. The majority (52.6%, 95% CI 0.46, 0.60) perceived vaping as not that harmful to not harmful at all, but one fifth (21.8%, 95% CI 0.16, 0.28) believed vaping to be harmful. More than half (57.8%, 95% CI 0.50, 0.65) reported gaining more pleasure from vaping than from smoking. A substantial majority (84.2%, 95% CI 0.78, 0.89) agreed that their health had improved since they started vaping; (4) Conclusions: Findings are similar to those obtained in other vape shop studies, but also to the results of convenience samples of less well-defined populations. PMID- 28714915 TI - Vibration Measurement Method of a String in Transversal Motion by Using a PSD. AB - A position sensitive detector (PSD) is frequently used for the measurement of a one-dimensional position along a line or a two-dimensional position on a plane, but is more often used for measuring static or quasi-static positions. Along with its quick response when measuring short time-spans in the micro-second realm, a PSD is also capable of detecting the dynamic positions of moving objects. In this paper, theoretical modeling and experiments are conducted to explore the frequency characteristics of a vibrating string while moving transversely across a one-dimensional PSD. The theoretical predictions are supported by the experiments. When the string vibrates at its natural frequency while moving transversely, the PSD will detect two frequencies near this natural frequency; one frequency is higher than the natural frequency and the other is lower. Deviations in these two frequencies, which differ from the string's natural frequency, increase while the speed of motion increases. PMID- 28714916 TI - Targeting of Tumor Neovasculature with GrB/VEGF121, a Novel Cytotoxic Fusion Protein. AB - Angiogenesis is a critical process in numerous diseases, and intervention in neovascularization has therapeutic value in several disease settings, including ocular diseases, arthritis, and in tumor progression and metastatic spread. Various vascular targeting agents have been developed, including those that inhibit growth factor receptor tyrosine kinases, blocking antibodies that interfere with receptor signal transduction, and strategies that trap growth factor ligands. Limited anti-tumor efficacy studies have suggested that the targeted delivery of the human pro-apoptotic molecule Granzyme B to tumor cells has significant potential for cancer treatment. Here, we review biological vascular targeting agents, and describe a unique vascular targeting agent composed of Granzyme B and the VEGF receptor ligand VEGF121. The fusion protein GrB/VEGF121 demonstrates cytotoxicity at nanomolar or sub-nanomolar levels, excellent pharmacokinetic and efficacy profiles, and has significant therapeutic potential targeting tumor vasculature. PMID- 28714917 TI - Larvicidal and Nematicidal Activities of 3-Acylbarbituric Acid Analogues against Asian Tiger Mosquito, Aedes albopictus, and Pine Wood Nematode, Bursaphelenchus xylophilus. AB - Widespread concern for the occurrence of resistant strains, along with the avoidance of the use of highly toxic insecticides and their wide environmental dispersal, highlights the need for the development of new and safer pest control agents. Natural products provide inspiration for new chemical entities with biological activities, and their analogues are good lead compounds for the development of new pest control agents. For this purpose, we evaluated the larvicidal and nematicidal activities of 48 3-acylbarbituric acid analogues against the Asian tiger mosquito, Aedes albopictus and the pine wood nematode, Bursaphelenchus xylophilus, organisms of increasing global concern. Among the 48 3-acylbarbituric acid analogues, four compounds-10, 14d, 14g and 19b-showed >90% larvicidal activity against Ae. albopictus at 10 MUg/mL concentration, and one (compound 10) showed the strongest larvicidal activity against Ae. albopictus, with a LC50 value of 0.22 MUg/mL. Only compound 18 showed strong nematicidal activity against pine wood nematode. Most active compounds possessed similar physicochemical properties; thus, actives typically had ClogP values of around 1.40-1.50 and rel-PSA values of 16-17% and these similar cheminformatic characteristics reflect their similar structure. This study indicates that active 3-acylbarbituric acids analogues have potential as lead compounds for developing novel mosquito control agents. PMID- 28714918 TI - Anti-Inflammatory Effects of Vitisinol A and Four Other Oligostilbenes from Ampelopsis brevipedunculata var. Hancei. AB - In this study, the cytotoxicities and anti-inflammatory activities of five resveratrol derivatives-vitisinol A, (+)-epsilon-viniferin, (+)-vitisin A, (-) vitisin B, and (+)-hopeaphenol-isolated from Ampelopsis brevipedunculata var. hancei were evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and lipopolysaccharide (LPS)-stimulated RAW264.7 cells, respectively. The result from MTT assay analysis indicated that vitisinol A has lower cytotoxicity than the other four well-known oligostilbenes. In the presence of vitisinol A (5 MUM), the significant reduction of inflammation product (nitric oxide, NO) in LPS-induced RAW264.7 cells was measured using Griess reaction assay. In addition, the under-expressed inflammation factors cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) in LPS-induced RAW264.7 cells monitored by Western blotting simultaneously suggested that vitisinol A has higher anti-inflammatory effect compared with other resveratrol derivatives. Finally, the anti-inflammatory effect of vitisinol A was further demonstrated on 12-O-tetradecanoylphorbol 13-acetate (TPA)-induced ear edema in mice. As a preliminary functional evaluation of natural product, the anti-inflammatory effect of vitisinol A is the first to be examined and reported by this study. PMID- 28714920 TI - The Role of Perceived Social Norms in Rural Sanitation: An Explorative Study from Infrastructure-Restricted Settings of South Ethiopia. AB - The perception of social sanitation norms (PSSNs) around unacceptability of open defecation has been a key aspect of recent sanitation interventions. However, underlying mechanisms through which "reconstructed" PSSNs affect sanitation outcomes have been a black box. This explorative cross-sectional study examines direct and indirect links between PSSNs and sanitation safety using data from structured interviews and observations in 368 households in rural South Ethiopia. In addition to a positive association between PSSNs and sanitation safety, we propose and examine the following two mechanisms: First, we confirm a potentially adverse feedback of PSSNs on future sanitation safety by enhancing the emotional satisfaction with current sanitation practice (satisfaction independent of the functionality of sanitation facilities). Second, inspired by the social amplification/attenuation of risk framework, we demonstrate that PSSNs work as a "social filter" that can amplify or attenuate the effects of other variables targeted in sanitation interventions such as perceived health-related and non health risks and benefits associated with open defecation and private latrine ownership, respectively, and factual hygiene and sanitation knowledge. These findings imply that PSSNs are not only important per se, but they are also important instrumentally because sanitation outcomes depend upon the capacity of social influences to shape the perception of sanitation risks and benefits and sanitation-related awareness in desirable ways. The mechanisms outlined in this paper as well as the sustainability of sanitation outcomes depend on whether and how social sanitation norms are internalized. PMID- 28714921 TI - Accumulation of Microcystin (LR, RR and YR) in Three Freshwater Bivalves in Microcystis aeruginosa Bloom Using Dual Isotope Tracer. AB - Abstract: Stable isotope tracers were first applied to evaluate the Microcystis cell assimilation efficiency of Sinanodonta bivalves, since the past identification method has been limited to tracking the changes of each chl-a, clearity, and nutrient. The toxicity profile and accumulation of MC-LR, -RR and YR in different organs (foot and digestive organs) from the three filter-feeders (Sinanodonta woodina, Sinanodonta arcaeformis, and Unio douglasiae) were assessed under the condition of toxigenic cyanobacteria (Microcystis aeruginosa) blooms through an in situ pond experiment using 13C and 15N dual isotope tracers. Chl-a concentration in the manipulated pond was dramatically decreased after the beginning of the second day, ranging from 217.5 to 15.6 MUg.L-1. The highest amount of MCs was incorporated into muscle and gland tissues in U. douglasiae during the study period, at nearly 2 or 3 times higher than in S.woodiana and S. arcaeformis. In addition, the incorporated 13C and 15N atom % in the U. douglasiae bivalve showed lower values than in other bivalves. The results demonstrate that U. douglasiae has less capacity to assimilate toxic cyanobacteria derived from diet. However, the incorporated 13C and 15N atom % of S. arcaeformis showed a larger feeding capacity than U. douglasiae and S. wodiana. Our results therefore also indicate that S. arcaeformis can eliminate the toxin more rapidly than U. douglasiae, having a larger detoxification capacity. PMID- 28714919 TI - Overcoming Oncogenic Mediated Tumor Immunity in Prostate Cancer. AB - Immunotherapy is being tested intensively in clinical trials for prostate cancer; it includes immune checkpoint inhibition, prostate specific antigen (PSA) vaccines and dendritic cell-based strategies. Despite increasing evidence for clinical responses, the consensus of multiple trials is that prostate cancers are poorly responsive to immunotherapy. Prostate cancer has a high degree of pathological and genetic heterogeneity compared to other cancer types, which may account for immunotherapeutic resistance. This hypothesis also implies that select types of prostate tumors may be differentially responsive to immune-based strategies and that the clinical stage, pathological grade and underlying genetic landscape may be important criteria in identifying tumors that respond to immune therapies. One strategy is to target oncogenic driver pathways in combination with immunotherapies with the goal of overcoming tumor immunity and broadening the number of patients achieving a clinical response. In this analysis, we address the hypothesis that driver oncogenic signaling pathways regulate cancer progression, tumor immunity and resistance to current immune therapeutics in prostate cancer. We propose that increased responsiveness may be achieved through the combined use of immunotherapies and inhibitors targeting tumor cell autonomous pathways that contribute towards anti-tumor immunity in patients with prostate cancer. PMID- 28714922 TI - Application of An Improved HPLC-FL Method to Screen Serine Palmitoyl Transferase Inhibitors. AB - In this work, we reported the application and validation of an improved high performance liquid chromatography method coupled with a fluorimetric detector (HPLC-FL) to screen the activity of two heterocyclic derivatives reported as serine palmitoyl transferase (SPT) inhibitors. The analytical conditions were optimized in terms of the derivatization procedure, chromatographic condition, extraction procedure, and method validation according to EMEA guidelines. Once fully optimized, the method was applied to assess the SPT-inhibitory activity of the above-mentioned derivatives and of the reference inhibitor myriocin. The obtained results, expressed as a percentage of residual SPT activity, were compared to those obtained with the reference radio immune assay (RIA). The good correlation between the two types of assay demonstrated that the improved HPLC-FL method is suitable for a preliminary and rapid screening of potential SPT inhibitors. PMID- 28714923 TI - Heterologous Humoral Response against H5N1, H7N3, and H9N2 Avian Influenza Viruses after Seasonal Vaccination in a European Elderly Population. AB - Avian influenza viruses are currently one of the main threats to human health in the world. Although there are some screening reports of antibodies against these viruses in humans from Western countries, most of these types of studies are conducted in poultry and market workers of Asian populations. The presence of antibodies against avian influenza viruses was evaluated in an elderly European population. An experimental study was conducted, including pre- and post-vaccine serum samples obtained from 174 elderly people vaccinated with seasonal influenza vaccines of 2006-2007, 2008-2009, 2009-2010, and 2010-2011 Northern Hemisphere vaccine campaigns. The presence of antibodies against A/H5N1, A/H7N3, and A/H9N2 avian influenza viruses were tested by using haemaglutination inhibition assays. Globally, heterotypic antibodies were found before vaccination in 2.9% of individuals against A/H5N1, 1.2% against A/H7N3, and 25.9% against A/H9N2. These pre-vaccination antibodies were present at titers >=1/40 in 1.1% of individuals against A/H5N1, in 1.1% against H7N3, and in 0.6% against the A/H9N2 subtype. One 76 year-old male showed pre-vaccine antibodies (Abs) against those three avian influenza viruses, and another three individuals presented Abs against two different viruses. Seasonal influenza vaccination induced a significant number of heterotypic seroconversions against A/H5N1 (14.4%) and A/H9N2 (10.9%) viruses, but only one seroconversion was observed against the A/H7N3 subtype. After vaccination, four individuals showed Abs titers >=1/40 against those three avian viruses, and 55 individuals against both A/H5N1 and A/H9N2. Seasonal vaccination is able to induce some weak heterotypic responses to viruses of avian origin in elderly individuals with no previous exposure to them. However, this response did not accomplish the European Medicament Agency criteria for influenza vaccine efficacy. The results of this study show that seasonal vaccines induce a broad response of heterotypic antibodies against avian influenza viruses, albeit at a low level. PMID- 28714924 TI - Cross-Sectional Study to Determine the Prevalence of Hepatitis B and C Virus Infection in High Risk Groups in the Northeast Region of Brazil. AB - Background: HBV (Hepatitis B Virus) and HCV (Hepatitis C Virus) infections are more prevalent in vulnerable populations than the general population. The objective of this study was to investigate the prevalence of HBV and HCV infection in HIV-positive patients (GI), chronic renal failure (CRF) patients (GII) and coagulation disorder individuals (GIII). Methods: A cross-sectional study was conducted from June 2014 to March 2015. Serum samples were tested for markers of hepatitis B and C by enzyme-linked immunosorbent assay (ELISA). Sociodemographic, epidemiological, clinical and laboratory data and accompanying statistical analyses were performed using Epi InfoTM 7. Results: A total of 348 individuals were recruited, i.e., 154 HIV-positive, 143 CRF and 51 coagulopathy patients. Among them, more than 66% were men, and the predominant age group was 26-35 years in GI and 56-65 years in GIII. Most patients had more than 8 years of education (66.2% in GI, 60.6% in GIII and 46.1% in GII), with a family income between 100-400 dollars in more than 48% of patients. The prevalence of the HBsAg marker was 3.9%, 7% and 3.9%, total anti-HBc was 28.6%, 55.9% and 31.4%, and anti HCV was 1.3%, 12.6% and 47% for GI, GII and GIII, respectively. However, the prevalence of anti-HBs was greater than 70% in all groups. Conclusions: This study shows a high prevalence of HBV and HCV among specific groups compared to the general population. Factors such as age, income, number of sexual partners, sexually transmitted disease burden, blood transfusion history or blood products and blood transfusions before 1994 were associated with a higher prevalence for these infections. PMID- 28714925 TI - Individual and Interactive Effects of Socio-Ecological Factors on Dengue Fever at Fine Spatial Scale: A Geographical Detector-Based Analysis. AB - Background: Large spatial heterogeneity was observed in the dengue fever outbreak in Guangzhou in 2014, however, the underlying reasons remain unknown. We examined whether socio-ecological factors affected the spatial distribution and their interactive effects. Methods: Moran's I was applied to first examine the spatial cluster of dengue fever in Guangzhou. Nine socio-ecological factors were chosen to represent the urbanization level, economy, accessibility, environment, and the weather of the 167 townships/streets in Guangzhou, and then the geographical detector was applied to analyze the individual and interactive effects of these factors on the dengue outbreak. Results: Four clusters of dengue fever were identified in Guangzhou in 2014, including one hot spot in the central area of Guangzhou and three cold spots in the suburban districts. For individual effects, the temperature (q = 0.33) was the dominant factor of dengue fever, followed by precipitation (q = 0.24), road density (q = 0.24), and water body area (q = 0.23). For the interactive effects, the combination of high precipitation, high temperature, and high road density might result in increased dengue fever incidence. Moreover, urban villages might be the dengue fever hot spots. Conclusions: Our study suggests that some socio-ecological factors might either separately or jointly influence the spatial distribution of dengue fever in Guangzhou. PMID- 28714927 TI - Development and Application of a Structural Health Monitoring System Based on Wireless Smart Aggregates. AB - Structural health monitoring (SHM) systems can improve the safety and reliability of structures, reduce maintenance costs, and extend service life. Research on concrete SHMs using piezoelectric-based smart aggregates have reached great achievements. However, the newly developed techniques have not been widely applied in practical engineering, largely due to the wiring problems associated with large-scale structural health monitoring. The cumbersome wiring requires much material and labor work, and more importantly, the associated maintenance work is also very heavy. Targeting a practical large scale concrete crack detection (CCD) application, a smart aggregates-based wireless sensor network system is proposed for the CCD application. The developed CCD system uses Zigbee 802.15.4 protocols, and is able to perform dynamic stress monitoring, structural impact capturing, and internal crack detection. The system has been experimentally validated, and the experimental results demonstrated the effectiveness of the proposed system. This work provides important support for practical CCD applications using wireless smart aggregates. PMID- 28714926 TI - A Protein Diet Score, Including Plant and Animal Protein, Investigating the Association with HbA1c and eGFR-The PREVIEW Project. AB - Higher-protein diets have been advocated for body-weight regulation for the past few decades. However, the potential health risks of these diets are still uncertain. We aimed to develop a protein score based on the quantity and source of protein, and to examine the association of the score with glycated haemoglobin (HbA1c) and estimated glomerular filtration rate (eGFR). Analyses were based on three population studies included in the PREVIEW project (PREVention of diabetes through lifestyle Intervention and population studies in Europe and around the World): NQplus, Lifelines, and the Young Finns Study. Cross-sectional data from food-frequency questionnaires (n = 76,777 subjects) were used to develop a protein score consisting of two components: 1) percentage of energy from total protein, and 2) plant to animal protein ratio. An inverse association between protein score and HbA1c (slope -0.02 +/- 0.01 mmol/mol, p < 0.001) was seen in Lifelines. We found a positive association between the protein score and eGFR in Lifelines (slope 0.17 +/- 0.02 mL/min/1.73 m2, p < 0.0001). Protein scoring might be a useful tool to assess both the effect of quantity and source of protein on health parameters. Further studies are needed to validate this newly developed protein score. PMID- 28714928 TI - Impact of Thermomechanical Fiber Pre-Treatment Using Twin-Screw Extrusion on the Production and Properties of Renewable Binderless Coriander Fiberboards. AB - The aim of this study consisted of manufacturing renewable binderless fiberboards from coriander straw and a deoiled coriander press cake, thus at the same time ensuring the valorization of crop residues and process by-products. The press cake acted as a natural binder inside the boards owing to the thermoplastic behavior of its protein fraction during thermopressing. The influence of different fiber-refining methods was evaluated and it was shown that a twin-screw extrusion treatment effectively improved fiber morphology and resulted in fiberboards with enhanced performance as compared to a conventional grinding process. The best fiberboard was produced with extrusion-refined straw using a 0.4 liquid/solid (L/S) ratio and with 40% press cake addition. The water sensitivity of the boards was effectively reduced by 63% through the addition of an extrusion raw material premixing operation and thermal treatment of the panels at 200 degrees C, resulting in materials with good performance showing a flexural strength of 29 MPa and a thickness swelling of 24%. Produced without the use of any chemical adhesives, these fiberboards could thus present viable, sustainable alternatives for current commercial wood-based materials such as oriented strand board, particleboard and medium-density fiberboard, with high cost-effectiveness. PMID- 28714929 TI - Synchronous Langat Virus Infection of Haemaphysalis longicornis Using Anal Pore Microinjection. AB - The tick-borne encephalitis virus (TBEV) serocomplex of flaviviruses consists of arboviruses that cause important diseases in animals and humans. The transmission of this group of viruses is commonly associated with tick species such as Ixodes spp., Dermacentor spp., and Hyalomma spp. In the case of Haemaphysalis longicornis, the detection and isolation of flaviviruses have been previously reported. However, studies showing survival dynamics of any tick-borne flavivirus in H. longicornis are still lacking. In this study, an anal pore microinjection method was used to infect adult H. longicornis with Langat virus (LGTV), a naturally attenuated member of the TBEV serocomplex. LGTV detection in ticks was done by real-time PCR, virus isolation, and indirect immunofluorescent antibody test. The maximum viral titer was recorded at 28 days post-inoculation, and midgut cells were shown to be the primary replication site. The tick can also harbor the virus for at least 120 days and can successfully transmit LGTV to susceptible mice as confirmed by detection of LGTV antibodies. However, no transovarial transmission was observed from the egg and larval samples. Taken together, our results highly suggest that anal pore microinjection can be an effective method in infecting adult H. longicornis, which can greatly assist in our efforts to study tick and virus interactions. PMID- 28714930 TI - Environmental Tobacco Smoke Exposure during Pregnancy and Child Neurodevelopment. AB - The developing fetus is especially vulnerable to environmental toxicants, including tobacco constituents. The aim of this study was to assess the impact of environmental tobacco smoke (ETS) exposure during pregnancy on child neurodevelopment within the first two years of life. The study population consisted of 461 non-smoking pregnant women (saliva cotinine level <10 ng/mL). Maternal passive smoking was assessed based on the cotinine level in saliva analyzed by the use of high-performance liquid chromatography coupled with tandem mass spectrometry (HPLC-ESI + MS/MS) and by questionnaire data. The cotinine cut off value for passive smoking was established at 1.5 ng/mL (sensitivity 63%, specificity 71%). Psychomotor development was assessed in children at the age of one- and two-years using the Bayley Scales of Infant and Toddler Development. Approximately 30% of the women were exposed to ETS during pregnancy. The multivariate linear regression model indicated that ETS exposure in the 1st and the 2nd trimesters of pregnancy were associated with decreasing child language functions at the age of one (beta = -3.0, p = 0.03, and beta = -4.1, p = 0.008, respectively), and two years (beta = -3.8, p = 0.05, and beta = -6.3, p = 0.005, respectively). A negative association was found for cotinine level >=1.5 ng/mL in the 2nd trimester of pregnancy and child cognition at the age of 2 (beta = -4.6, p = 0.05), as well as cotinine levels >=1.5 ng/mL in all trimesters of pregnancy and child motor abilities at two years of age (beta = -3.9, p = 0.06, beta = 5.3, p = 0.02, and beta = -4.2, p = 0.05, for the 1st, the 2nd, and the 3rd trimester of pregnancy, respectively; for the 1st trimester the effect was of borderline statistical significance). This study confirmed that ETS exposure during pregnancy can have a negative impact on child psychomotor development within the first two years of life and underscore the importance of public health interventions aiming at reducing this exposure. PMID- 28714933 TI - Macrophage Phenotypes Regulate Scar Formation and Chronic Wound Healing. AB - Macrophages and inflammation play a beneficial role during wound repair with macrophages regulating a wide range of processes, such as removal of dead cells, debris and pathogens, through to extracellular matrix deposition re vascularisation and wound re-epithelialisation. To perform this range of functions, these cells develop distinct phenotypes over the course of wound healing. They can present with a pro-inflammatory M1 phenotype, more often found in the early stages of repair, through to anti-inflammatory M2 phenotypes that are pro-repair in the latter stages of wound healing. There is a continuum of phenotypes between these ranges with some cells sharing phenotypes of both M1 and M2 macrophages. One of the less pleasant consequences of quick closure, namely the replacement with scar tissue, is also regulated by macrophages, through their promotion of fibroblast proliferation, myofibroblast differentiation and collagen deposition. Alterations in macrophage number and phenotype disrupt this process and can dictate the level of scar formation. It is also clear that dysregulated inflammation and altered macrophage phenotypes are responsible for hindering closure of chronic wounds. The review will discuss our current knowledge of macrophage phenotype on the repair process and how alterations in the phenotypes might alter wound closure and the final repair quality. PMID- 28714934 TI - Physical Outdoor Activity versus Indoor Activity: Their Influence on Environmental Behaviors. AB - There are strong evidences linking physical outdoor activity and health benefits; however, little is known about the impact on environmental behaviors. Thus, this study aims to close this gap by investigating the influence of physical outdoor activity on environmental behaviors. A total of 416 surveys were distributed to students in eight public primary schools located near the Hsinchu Science and Industrial Park in Taiwan. Findings from the analysis revealed that subjective norms had a more influential effect on environmental behaviors for participants who engaged in physical activity at outdoor parks. In contrast, descriptive norms had a direct predictive impact on environmental behaviors for participants whose main physical activity venue was at the indoor after-school centers. Research results also highlighted attitude as the strongest predictive variable influence on environmental behaviors for children who engaged in physical indoor and outdoor activities. PMID- 28714935 TI - Sensory and Physico-Psychological Metaphor Comprehension in Children with ASD: A Preliminary Study on the Outcomes of a Treatment. AB - Recent research into difficulties in figurative language in children with ASD highlighted that it is possible to devise training interventions to overcome these difficulties by teaching specific strategies. This study describes how children with ASD can improve their capability to explain metaphors with a treatment. Two types of metaphors, in the "X is Y" form, were addressed: sensory and physico-psychological. To face the difficulties posed by these metaphors, the adult taught two strategies: inserting the connective "is like" between "X" and "Y", which transforms the metaphor into a simile; comparing "X" and "Y" by means of thinking maps. Two tests of metaphor comprehension were used, one based on sensory and the other on physico-psychological metaphors. Sixteen 10 year-old children participated into the study, including an experimental group formed by 8 children with ASD (n = 4) which had received the treatment, and a control group (n = 4) which had not, and 8 typically-developing (TD) children. At the post test, the experimental group significantly outperformed the controls in explaining both types of metaphors, but only in the sensory metaphors did their performances reach TD children's levels. These results illuminate how clinical treatment can positively influence the developmental trajectories of metaphor comprehension. PMID- 28714931 TI - Correlation between Oxidative Stress, Nutrition, and Cancer Initiation. AB - Inadequate or excessive nutrient consumption leads to oxidative stress, which may disrupt oxidative homeostasis, activate a cascade of molecular pathways, and alter the metabolic status of various tissues. Several foods and consumption patterns have been associated with various cancers and approximately 30-35% of the cancer cases are correlated with overnutrition or malnutrition. However, several contradictory studies are available regarding the association between diet and cancer risk, which remains to be elucidated. Concurrently, oxidative stress is a crucial factor for cancer progression and therapy. Nutritional oxidative stress may be induced by an imbalance between antioxidant defense and pro-oxidant load due to inadequate or excess nutrient supply. Oxidative stress is a physiological state where high levels of reactive oxygen species (ROS) and free radicals are generated. Several signaling pathways associated with carcinogenesis can additionally control ROS generation and regulate ROS downstream mechanisms, which could have potential implications in anticancer research. Cancer initiation may be modulated by the nutrition-mediated elevation in ROS levels, which can stimulate cancer initiation by triggering DNA mutations, damage, and pro oncogenic signaling. Therefore, in this review, we have provided an overview of the relationship between nutrition, oxidative stress, and cancer initiation, and evaluated the impact of nutrient-mediated regulation of antioxidant capability against cancer therapy. PMID- 28714932 TI - Thrombospondins: A Role in Cardiovascular Disease. AB - Thrombospondins (TSPs) represent extracellular matrix (ECM) proteins belonging to the TSP family that comprises five members. All TSPs have a complex multidomain structure that permits the interaction with various partners including other ECM proteins, cytokines, receptors, growth factors, etc. Among TSPs, TSP1, TSP2, and TSP4 are the most studied and functionally tested. TSP1 possesses anti-angiogenic activity and is able to activate transforming growth factor (TGF)-beta, a potent profibrotic and anti-inflammatory factor. Both TSP2 and TSP4 are implicated in the control of ECM composition in hypertrophic hearts. TSP1, TSP2, and TSP4 also influence cardiac remodeling by affecting collagen production, activity of matrix metalloproteinases and TGF-beta signaling, myofibroblast differentiation, cardiomyocyte apoptosis, and stretch-mediated enhancement of myocardial contraction. The development and evaluation of TSP-deficient animal models provided an option to assess the contribution of TSPs to cardiovascular pathology such as (myocardial infarction) MI, cardiac hypertrophy, heart failure, atherosclerosis, and aortic valve stenosis. Targeting of TSPs has a significant therapeutic value for treatment of cardiovascular disease. The activation of cardiac TSP signaling in stress and pressure overload may be therefore beneficial. PMID- 28714936 TI - Extending Wireless Rechargeable Sensor Network Life without Full Knowledge. AB - When extending the life of Wireless Rechargeable Sensor Networks (WRSN), one challenge is charging networks as they grow larger. Overcoming this limitation will render a WRSN more practical and highly adaptable to growth in the real world. Most charging algorithms require a priori full knowledge of sensor nodes' power levels in order to determine the nodes that require charging. In this work, we present a probabilistic algorithm that extends the life of scalable WRSN without a priori power knowledge and without full network exploration. We develop a probability bound on the power level of the sensor nodes and utilize this bound to make decisions while exploring a WRSN. We verify the algorithm by simulating a wireless power transfer unmanned aerial vehicle, and charging a WRSN to extend its life. Our results show that, without knowledge, our proposed algorithm extends the life of a WRSN on average 90% of what an optimal full knowledge algorithm can achieve. This means that the charging robot does not need to explore the whole network, which enables the scaling of WRSN. We analyze the impact of network parameters on our algorithm and show that it is insensitive to a large range of parameter values. PMID- 28714937 TI - Photosynthesis-Inhibiting Activity of 1-[(2-Chlorophenyl)carbamoyl]- and 1-[(2 Nitrophenyl)carbamoyl]naphthalen-2-yl Alkylcarbamates. AB - Eight 1-[(2-chlorophenyl)carbamoyl]naphthalen-2-yl alkylcarbamates and eight 1 [(2-nitrophenyl)carbamoyl]naphthalen-2-yl alkylcarbamates were tested for their activity related to the inhibition of photosynthetic electron transport (PET) in spinach (Spinacia oleracea L.) chloroplasts. The PET-inhibiting activity of the compounds was relatively low; the corresponding IC50 values ranged from 0.05 to 0.664 mmol/L; and the highest activity within the series of compounds was observed for 1-[(2-chlorophenyl)-carbamoyl]naphthalen-2-yl propylcarbamate. It has been proven that the compounds are PET-inhibitors in photosystem II. Despite rather low PET-inhibiting activities, primary structure-activity trends can be discussed. PMID- 28714939 TI - Systematics of the Ceracis furcifer Species-Group (Coleoptera: Ciidae): The Specialized Consumers of the Blood-Red Bracket Fungus Pycnoporus sanguineus. AB - The Ceracis furcifer species-group (Coleoptera: Ciidae) originally comprised nine species names: Ceracis cornifer (Mellie, 1849); C. cylindricus (Brethes, 1922); C. furcifer Mellie, 1849; C. hastifer (Mellie, 1849); C. monocerus Lawrence, 1967; C. ruficornis Pic, 1916; C. simplicicornis (Pic, 1916); C. semipallidus Pic, 1922 and C. unicornis Gorham, 1898. Ceracis semipallidus was synonymised with C. furcifer and then no further changes were made to the composition of the group. Here, we provide a taxonomic revision of the Ceracis furcifer species group and new data on the geographic distribution and host fungi of the included species. Lectotypes are designated for C. cornifer, C. furcifer, C. hastifer, C. ruficornis, C. semipallidus and C. unicornis. As results we: (i) synonymise C. cylindricus, C. monocerus, C. simplicicornis, C. unicornis with C. cornifer; (ii) confirm the synonymy of C. semipallidus with C. furcifer; (iii) redescribe C. cornifer, C. hastifer, C. furcifer and C. ruficornis; and (iv) provide an identification key for species in the furcifer group. The frontoclypeal horn and body coloration showed great intraspecific variation. We show that species in the furcifer group have distributions wider than previously known and use mainly Pycnoporus sanguineus as host fungus. Species of the furcifer group are the only animals specialized in feeding on basidiomes of P. sanguineus. PMID- 28714938 TI - Taxifolin Activates the Nrf2 Anti-Oxidative Stress Pathway in Mouse Skin Epidermal JB6 P+ Cells through Epigenetic Modifications. AB - Nuclear factor erythroid-2 related factor 2 (Nrf2) is a vital transcription factor that regulates the anti-oxidative defense system. Previous reports suggested that the expression of the Nrf2 gene can be regulated by epigenetic modifications. The potential epigenetic effect of taxifolin (TAX), a potent cancer chemopreventive agent, in skin cancer chemoprotection is unknown. In this study, we investigated how Nrf2 is epigenetically regulated by TAX in JB6 P+ cells. TAX was found to inhibit the 12-O-tetradecanoylphorbol-13-acetate (TPA) induced colony formation of JB6 P+ cells. TAX induced antioxidant response element (ARE)-luciferase activity in HepG2-C8 cells and up-regulated mRNA and protein levels of Nrf2 and its downstream genes heme oxygenase-1 (HO-1) and NAD(P)H quinone oxidoreductase 1 (NQO1), in JB6 P+ cells. Furthermore, bisulfite genomic sequencing revealed that TAX treatment reduces the methylation level of the first 15 CpGs sites in the Nrf2 promoter. Western blotting showed that TAX inhibits the expression levels of DNA methyltransferase (DNMT) and histone deacetylase (HDAC) proteins. In summary, our results revealed that TAX can induce expression of Nrf2 and its downstream target genes in JB6 P+ cells by CpG demethylation. These finding suggest that TAX may exhibit a skin cancer preventive effect by activating Nrf2 via an epigenetic pathway. PMID- 28714940 TI - Non-Coding RNAs as Predictive Biomarkers to Current Treatment in Metastatic Colorectal Cancer. AB - The onset and selection of resistant clones during cancer treatment with chemotherapy or targeted therapy is a major issue in the clinical management of metastatic colorectal cancer patients. It is possible that a more personalized treatment selection, using reliable response-to-therapy predictive biomarkers, could lead to an improvement in the success rate of the proposed therapies. Although the process of biomarker selection and validation could be a long one, requiring solid statistics, large cohorts and multicentric validations, non coding RNAs (ncRNAs) and in particular microRNAs, proved to be extremely promising in this field. Here we summarize some of the main studies correlating specific ncRNAs with sensitivity/resistance to chemotherapy, anti-VEGF therapy, anti-EGFR therapy and immunotherapy in colorectal cancer (CRC). PMID- 28714942 TI - Palaeo leaf economics reveal a shift in ecosystem function associated with the end-Triassic mass extinction event. AB - Climate change is likely to have altered the ecological functioning of past ecosystems, and is likely to alter functioning in the future; however, the magnitude and direction of such changes are difficult to predict. Here we use a deep-time case study to evaluate the impact of a well-constrained CO2-induced global warming event on the ecological functioning of dominant plant communities. We use leaf mass per area (LMA), a widely used trait in modern plant ecology, to infer the palaeoecological strategy of fossil plant taxa. We show that palaeo-LMA can be inferred from fossil leaf cuticles based on a tight relationship between LMA and cuticle thickness observed among extant gymnosperms. Application of this new palaeo-LMA proxy to fossil gymnosperms from East Greenland reveals significant shifts in the dominant ecological strategies of vegetation found across the Triassic-Jurassic transition. Late Triassic forests, dominated by low LMA taxa with inferred high transpiration rates and short leaf lifespans, were replaced in the Early Jurassic by forests dominated by high-LMA taxa that were likely to have slower metabolic rates. We suggest that extreme CO2-induced global warming selected for taxa with high LMA associated with a stress-tolerant strategy and that adaptive plasticity in leaf functional traits such as LMA contributed to post-warming ecological success. PMID- 28714941 TI - Autophagy Induced FHL2 Upregulation Promotes IL-6 Production by Activating the NF kappaB Pathway in Mouse Aortic Endothelial Cells after Exposure to PM2.5. AB - Epidemiological and clinical studies have increasingly shown that fine particulate matter (PM2.5) is associated with cardiovascular morbidity and mortality, which share the common feature of PM2.5-induced vascular inflammation; however, the underlying mechanisms of how PM2.5 triggers increased inflammatory response in vascular endothelial cells are not well understood. After treating mouse aortic endothelial cells (MAECs) with different concentrations of PM2.5, we assessed interleukin (IL)-6 and four and a half LIM domains 2 (FHL2) expression in cell supernatant by enzyme-linked immunosorbent assay and Western blot, respectively, as well as activation of nuclear factor (NF)-kappaB and immune response signaling pathways. Additionally, changes in pathway activation, IL-6 expression, and autophagy were evaluated under PM2.5 exposure, following FHL2 knockdown with small interfering RNA. Our results indicated that PM2.5 exposure induced FHL2 expression and IL-6 secretion, as well as activation of pathways associated with immune response. Additionally, following FHL2 knockdown, the activation of NF-kappaB-related pathways and IL-6 secretion was inhibited under PM2.5 exposure, although the Akt- and p38-signaling pathways were not affected. Furthermore, PM2.5 exposure induced autophagy, whereas autophagy inhibition eventually inhibited PM2.5-induced FHL2 expression. These findings suggested a novel link between autophagy induced FHL2 upregulation and IL-6 production in MAECs under PM2.5 exposure. PMID- 28714943 TI - Dengue encephalitis in allogenic hematopoietic stem cell transplantation recipient. PMID- 28714944 TI - Impact of the presence of HLA 1-locus mismatch and the use of low-dose antithymocyte globulin in unrelated bone marrow transplantation. AB - HLA 1-locus-mismatched unrelated donors (1MMUD) have been used in allogeneic hematopoietic stem cell transplantation (allo-HCT) for patients who lack an HLA matched donor. We retrospectively analyzed 3313 patients with acute leukemia or myelodysplastic syndrome who underwent bone marrow transplantation from an HLA allele-matched unrelated donor (MUD) or 1MMUD between 2009 and 2014. We compared the outcomes of MUD (n=2089) and 1MMUD with antithymocyte globulin (ATG) (1MM ATG(+); n=109) with those of 1MMUD without ATG (1MM-ATG(-); n=1115). The median total dose of ATG (thymoglobulin) was 2.5 mg/kg (range 1.0-11.0 mg/kg) in the 1MM ATG(+) group. The rates of grade III-IV acute GvHD, non-relapse mortality (NRM) and overall mortality were significantly lower in the MUD group than in the 1MM ATG(-) group (hazard ratio (HR) 0.77, P=0.016; HR 0.74; P<0.001; and HR 0.87, P=0.020, respectively). Likewise, the rates of grade III-IV acute GVHD, NRM and overall mortality were significantly lower in the 1MM-ATG(+) group than in the 1MM-ATG(-) group (HR 0.42, P=0.035; HR 0.35, P<0.001; and HR 0.71, P=0.042, respectively). The outcome of allo-HCT from 1MM-ATG(-) was inferior to that of allo-HCT from MUD even in the recent cohort. However, the negative impact of 1MMUD disappeared with the use of low-dose ATG without increasing the risk of relapse. PMID- 28714945 TI - Impact of molecular residual disease post allografting in myelofibrosis patients. AB - We screened 136 patients with myelofibrosis and a median age of 58 years who underwent allogeneic stem cell transplantation (AHSCT) for molecular residual disease for JAKV617F (n=101), thrombopoietin receptor gene (MPL) (n=4) or calreticulin (CALR) (n=31) mutation in peripheral blood on day +100 and +180 after AHSCT. After a median follow-up of 78 months, the 5-year estimated overall survival was 60% (95% confidence interval (CI): 50-70%) and the cumulative incidence of relapse at 5 years was 26% (95% CI: 18-34%) for the entire study population. The percentage of molecular clearance on day 100 was higher in CALR mutated patients (92%) in comparison with MPL- (75%) and JAKV617F-mutated patients (67%). Patients with detectable mutation at day +100 or at day +180 had a significant higher risk of clinical relapse at 5 years than molecular-negative patients (62% vs 10%, P<0.001) and 70% vs 10%, P<0.001, respectively) irrespectively of the underlying mutation. In a multivariate analysis, high-risk diseases status (hazard ratio (HR) 2.5; 95% CI: 1.18-5.25, P=0.016) and detectable MRD at day 180 (HR 8.36, 95% CI: 2.76-25.30, P<0.001) were significant factors for a higher risk of relapse. PMID- 28714946 TI - Faecal microbiota transplant: a novel biological approach to extensively drug resistant organism-related non-relapse mortality. PMID- 28714948 TI - Early hepatitis E infection in an unrelated hematopoietic progenitor stem cell donor. PMID- 28714947 TI - Long-term systolic function in children and young adults after hematopoietic stem cell transplant. AB - Congestive heart failure and subclinical left ventricular systolic dysfunction (LVSD) affect long-term survivors of hematopoietic stem cell transplant (HSCT). Echocardiographic measurements of global longitudinal and circumferential strain have shown promise in identifying subclinical LVSD in cancer survivors. We analyzed echocardiograms in 95 children and young adults with malignancies or bone marrow failure syndromes performed before HSCT and 1-6 years after HSCT. We additionally measured the biomarkers soluble suppression of tumorigenicity-2 (sST 2) and cardiac troponin-I (cTn-I) in the same children through 49 days post HSCT. Ejection fraction (EF) after HSCT was unchanged from baseline (baseline: z-score 0.73 vs long-term follow up: -0.44, P=0.11). Global longitudinal strain was unchanged from baseline (-20.66 vs -20.74%, P=0.90) as was global circumferential strain (-24.3 vs -23.5%, P=0.32). Levels of sST-2 were elevated at all time points compared with baseline samples and cTn-I was elevated at days 14 and 28. Cardiac biomarkers at any time point did not correlate with long-term follow-up EF. In children and young adult survivors of HSCT, EF was unchanged in the first years after HSCT. Elevation in cardiac biomarkers occurring after HSCT suggest subclinical cardiac injury occurs in many patients and long-term monitoring for LVSD should continue. PMID- 28714949 TI - Aspartate beta-hydroxylase disrupts mitochondrial DNA stability and function in hepatocellular carcinoma. AB - The mechanism of aberrant mitochondrial genome and function in hepatocellular carcinoma (HCC) remains largely unknown. Our previous study demonstrated an increased expression of aspartate beta-hydroxylase (ASPH) in HCC tissues, which was associated with tumor invasiveness and a worse prognosis. Currently, we unexpectedly observed the presence of ASPH in purified mitochondrial protein fraction. In addition, immunostaining of both exogenously and endogenously expressed ASPH showed a colocalization with mitochondrial biomarkers. This study aimed to investigate whether the mitochondrial ASPH is involved in mitochondrial malfunction in HCC. Our results showed that ASPH overexpression in HCC tissues was correlated with decreased copy numbers of displacement loop (D-loop) and NADH dehydrogenase subunit 1 (ND-1) and enhanced D-loop mutation, suggesting the disrupted mitochondrial DNA (mtDNA) stability. The reduced mtDNA copy numbers were associated with aggressive clinicopathological features of HCC. The loss of mtDNA integrity induced by enforced expression of ASPH was accompanied with mitochondrial dysfunction, which was characterized by the aberrant mitochondrial membrane potential, decreased ATP generation and enhanced reactive oxygen species. In contrast, knocking down ASPH by siRNA in HCC cell lines showed the opposite impact on mtDNA integrity and function. Mass spectrometry and co immunoprecipitation further identified that ASPH interacted with histone H2A member X (H2AX). ASPH overexpression diminished the interaction between H2AX and mitochondrial transcription factor A (mtTFA), an important DNA-binding protein for mtDNA replication, which then reduced the binding of mtTFA to D-loop region. Collectively, our results demonstrate that ASPH overexpression disrupts the mtDNA integrity through H2AX-mtTFA signal, thereby affecting mitochondrial functions in HCC. PMID- 28714950 TI - Tid1-S regulates the mitochondrial localization of EGFR in non-small cell lung carcinoma. AB - The epidermal growth factor receptor (EGFR) is the major driver of non-small cell lung carcinoma (NSCLC). Mitochondrial accumulation of EGFR has been shown to promote metastasis in NSCLC, yet little is known about how the mitochondrial localization of EGFR is regulated. In this work, we show that Tid1 (also known as mitochondrial HSP40) is involved in the mitochondrial localization of EGFR, and that the DnaJ domain of Tid1-S is essential for the Tid1-S-mediated transportation of EGFR into mitochondria. Overexpression of Tid1-S increased the migration and invasion of NSCLC cells cultured in vitro. High levels of EGFR and Tid1-S were detected in the mitochondria of cancerous lesions from stage IV NSCLC patients, and high levels of mitochondrial Tid1-S/EGFR were correlated with lymph node metastasis and poor overall survival of NSCLC patients. We thus conclude that Tid1-S critically governs the mitochondrial localization of EGFR through the mtHSP70 transportation pathway, and that the mitochondrial accumulation of EGFR appears to promote metastasis in NSCLC. PMID- 28714952 TI - A circuit-based mechanism underlying familiarity signaling and the preference for novelty. AB - Novelty preference (NP) is an evolutionarily conserved, essential survival mechanism often dysregulated in neuropsychiatric disorders. NP is mediated by a motivational dopamine signal that increases in response to novel stimuli, thereby driving exploration. However, the mechanism by which once-novel stimuli transition to familiar stimuli is unknown. Here we describe a neuroanatomical substrate for familiarity signaling, the interpeduncular nucleus (IPN) of the midbrain, which is activated as novel stimuli become familiar with multiple exposures. In mice, optogenetic silencing of IPN neurons increases salience of and interaction with familiar stimuli without affecting novelty responses, whereas photoactivation of the same neurons reduces exploration of novel stimuli mimicking familiarity. Bidirectional control of NP by the IPN depends on familiarity signals and novelty signals arising from excitatory habenula and dopaminergic ventral tegmentum inputs, which activate and reduce IPN activity, respectively. These results demonstrate that familiarity signals through unique IPN circuitry that opposes novelty seeking to control NP. PMID- 28714953 TI - Gut microbiota is critical for the induction of chemotherapy-induced pain. AB - Chemotherapy-induced pain is a dose-limiting condition that affects 30% of patients undergoing chemotherapy. We found that gut microbiota promotes the development of chemotherapy-induced mechanical hyperalgesia. Oxaliplatin-induced mechanical hyperalgesia was reduced in germ-free mice and in mice pretreated with antibiotics. Restoring the microbiota of germ-free mice abrogated this protection. These effects appear to be mediated, in part, by TLR4 expressed on hematopoietic cells, including macrophages. PMID- 28714955 TI - Erratum: Acetate-mediated novel survival strategy against drought in plants. AB - This corrects the article DOI: 10.1038/nplants.2017.97. PMID- 28714951 TI - Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder. AB - We systematically analyzed postzygotic mutations (PZMs) in whole-exome sequences from the largest collection of trios (5,947) with autism spectrum disorder (ASD) available, including 282 unpublished trios, and performed resequencing using multiple independent technologies. We identified 7.5% of de novo mutations as PZMs, 83.3% of which were not described in previous studies. Damaging, nonsynonymous PZMs within critical exons of prenatally expressed genes were more common in ASD probands than controls (P < 1 * 10-6), and genes carrying these PZMs were enriched for expression in the amygdala (P = 5.4 * 10-3). Two genes (KLF16 and MSANTD2) were significantly enriched for PZMs genome-wide, and other PZMs involved genes (SCN2A, HNRNPU and SMARCA4) whose mutation is known to cause ASD or other neurodevelopmental disorders. PZMs constitute a significant proportion of de novo mutations and contribute importantly to ASD risk. PMID- 28714954 TI - C9orf72 expansion disrupts ATM-mediated chromosomal break repair. AB - Hexanucleotide repeat expansions represent the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, though the mechanisms by which such expansions cause neurodegeneration are poorly understood. We report elevated levels of DNA-RNA hybrids (R-loops) and double strand breaks in rat neurons, human cells and C9orf72 ALS patient spinal cord tissues. Accumulation of endogenous DNA damage is concomitant with defective ATM mediated DNA repair signaling and accumulation of protein-linked DNA breaks. We reveal that defective ATM-mediated DNA repair is a consequence of P62 accumulation, which impairs H2A ubiquitylation and perturbs ATM signaling. Virus mediated expression of C9orf72-related RNA and dipeptide repeats in the mouse central nervous system increases double strand breaks and ATM defects and triggers neurodegeneration. These findings identify R-loops, double strand breaks and defective ATM-mediated repair as pathological consequences of C9orf72 expansions and suggest that C9orf72-linked neurodegeneration is driven at least partly by genomic instability. PMID- 28714956 TI - The uncertainty of crop yield projections is reduced by improved temperature response functions. AB - Increasing the accuracy of crop productivity estimates is a key element in planning adaptation strategies to ensure global food security under climate change. Process-based crop models are effective means to project climate impact on crop yield, but have large uncertainty in yield simulations. Here, we show that variations in the mathematical functions currently used to simulate temperature responses of physiological processes in 29 wheat models account for >50% of uncertainty in simulated grain yields for mean growing season temperatures from 14 degrees C to 33 degrees C. We derived a set of new temperature response functions that when substituted in four wheat models reduced the error in grain yield simulations across seven global sites with different temperature regimes by 19% to 50% (42% average). We anticipate the improved temperature responses to be a key step to improve modelling of crops under rising temperature and climate change, leading to higher skill of crop yield projections. PMID- 28714957 TI - IL-11 contribution to tumorigenesis in an NRF2 addiction cancer model. AB - The interaction between cancer cells and their microenvironment is an important determinant of the pathological nature of cancers, particularly their tumorigenic abilities. The KEAP1-NRF2 system, originally identified as a critical defense mechanism against oxidative stress, is often dysregulated in various human cancers forming solid tumors, resulting in the aberrant activation of NRF2. Increased accumulation of NRF2 in cancers is strongly associated with the poor prognoses of cancer patients, including those with lung and breast cancers. Multiple lines of evidence suggest that aberrantly activated NRF2 in cancer cells drives their malignant progression and that the cancer cells consequently develop 'NRF2 addiction.' Although the downstream effectors of NRF2 that are responsible for cancer malignancy have been extensively studied, mechanisms of how NRF2 activation contributes to the aggressive tumorigenesis remains to be elucidated. In this study, we found a significant correlation between NRF2 and IL-11 status in breast cancer patients. Based on a recent report demonstrating that IL-11 is induced downstream of NRF2, we examined the significance of IL-11 in NRF2-driven tumorigenesis with a newly established NRF2 addiction cancer model. Expression of Il11 was elevated during the tumorigenesis of the NRF2 addiction cancer model, but intriguingly, it was hardly detected when the cancer model cells were cultured in vitro. These results imply that a signal originating from the microenvironment cooperates with NRF2 to activate Il11. To the best of our knowledge, this is the first report showing the influence of the microenvironment on the NRF2 pathway in cancer cells and the contribution of NRF2 to the secretory phenotypes of cancers. Disruption of Il11 in the NRF2 addiction cancer model remarkably inhibited the tumorigenesis, suggesting an essential role of IL-11 in NRF2-driven tumorigenesis. Thus, this study suggests that IL-11 is a potential therapeutic target for NRF2-addicted breast cancers. PMID- 28714959 TI - O-GlcNAcylation modulates Bmi-1 protein stability and potential oncogenic function in prostate cancer. AB - The Polycomb group transcriptional repressor Bmi-1 often overexpressed and participated in stem cells self-renewal and tumorigenesis initiating of prostate cancer. In this progression, Bmi-1 protein was regulated by transcription and post-translational modifications (PTMs). Nobly, the underlying PTMs regulation of Bmi-1 is poorly known. Here we use co-immunoprecipitation show that in C4-2 cell line, Bmi-1 directly interacted with OGT which is the only known enzyme catalyzed the O-GlcNAcylation in human. Furthermore, we identified that Ser255 is the site for Bmi-1 O-GlcNAcylation, and O-GlcNAcylation promoted Bmi-1 protein stability and its oncogenic activity. Finally, microarray analysis has characterized potential oncogenes associated pathway subject to repression via the OGT-Bmi-1 axis. Taken together, these results indicate that OGT-mediated O-GlcNAcylation at Ser255 stabilizes Bmi-1 and hence inhibits the TP53, PTEN and CDKN1A/CDKN2A pathway. The study not only uncovers a novel functional PTMs of Bmi-1 but also reveals a unique oncogenic role of O-GlcNAcylation in prostate cancer. PMID- 28714958 TI - Roles of Grainyhead-like transcription factors in cancer. AB - The mammalian homologs of the D. melanogaster Grainyhead gene, Grainyhead-like 1 3 (GRHL1, GRHL2 and GRHL3), are transcription factors implicated in wound healing, tubulogenesis and cancer. Their induced target genes encode diverse epithelial cell adhesion molecules, while mesenchymal genes involved in cell migration and invasion are repressed. Moreover, GRHL2 suppresses the oncogenic epithelial-mesencyhmal transition, thereby acting as a tumor suppressor. Mechanisms, some involving established cancer-related signaling/transcription factor pathways (for example, Wnt, TGF-beta, mir200, ZEB1, OVOL2, p63 and p300) and translational implications of the Grainyhead proteins in cancer are discussed in this review article. PMID- 28714960 TI - BIN1 reverses PD-L1-mediated immune escape by inactivating the c-MYC and EGFR/MAPK signaling pathways in non-small cell lung cancer. AB - Non-small cell lung cancer (NSCLC) is one of the most common and malignant carcinoma worldwide, and the incidence and mortality are increasing rapidly. Immunotherapy targeting programmed death 1/programmed death ligand 1 (PD-L1) signaling has shown prominent clinical effects in treating NSCLC; however, a poor understanding of the associated regulating molecular mechanisms of PD-L1 has become one of the biggest obstacles for further improving efficacy. Bridging integrator-1 (BIN1) can regulate numerous cancer-related molecules to exert multiple tumor-suppressing effects by either interacting or not interacting with c-MYC. In the present study, we observed that there exists a negative correlation between the expression of PD-L1 and BIN1 in NSCLC tissues. The expression levels of BIN1 and PD-L1 were significantly related to the tumor, lymph node and metastasis grade (TNM) stage, invasion range and lymph node metastasis. Simultaneously, for NSCLC patients, the expression statuses of BIN1 and PD-L1 might be independent prognostic factors. Furthermore, the expression of tumor infiltrating lymphocytes was positively associated with BIN1 expression and negatively related to PD-L1 expression in NSCLC tissues. Importantly, we showed that PD-L1 was under the control of BIN1. In addition, the overexpression of BIN1 could inhibit the c-MYC and epithelial growth factor receptor (EGFR)-dependent PD L1 expression and reverse the suppressive immuno-microenvironment in vivo. Taken together, our findings indicated that BIN1 restoration in NSCLC could reverse PD L1-mediated immune escape by inactivating the c-MYC and EGFR/mitogen-activated protein kinase pathways. PMID- 28714961 TI - B-cell lymphoma/leukemia 10 promotes oral cancer progression through STAT1/ATF4/S100P signaling pathway. AB - This corrects the article DOI: 10.1038/onc.2014.43. PMID- 28714962 TI - SHP-1 is a negative regulator of epithelial-mesenchymal transition in hepatocellular carcinoma. AB - This corrects the article DOI: 10.1038/onc.2014.445. PMID- 28714963 TI - FHIT loss confers cisplatin resistance in lung cancer via the AKT/NF-kappaB/Slug mediated PUMA reduction. AB - This corrects the article DOI: 10.1038/onc.2014.184. PMID- 28714965 TI - A wellness study of 108 individuals using personal, dense, dynamic data clouds. AB - Personal data for 108 individuals were collected during a 9-month period, including whole genome sequences; clinical tests, metabolomes, proteomes, and microbiomes at three time points; and daily activity tracking. Using all of these data, we generated a correlation network that revealed communities of related analytes associated with physiology and disease. Connectivity within analyte communities enabled the identification of known and candidate biomarkers (e.g., gamma-glutamyltyrosine was densely interconnected with clinical analytes for cardiometabolic disease). We calculated polygenic scores from genome-wide association studies (GWAS) for 127 traits and diseases, and used these to discover molecular correlates of polygenic risk (e.g., genetic risk for inflammatory bowel disease was negatively correlated with plasma cystine). Finally, behavioral coaching informed by personal data helped participants to improve clinical biomarkers. Our results show that measurement of personal data clouds over time can improve our understanding of health and disease, including early transitions to disease states. PMID- 28714964 TI - Inhibition of WNT signaling attenuates self-renewal of SHH-subgroup medulloblastoma. AB - The SMOOTHENED inhibitor vismodegib is FDA approved for advanced basal cell carcinoma (BCC), and shows promise in clinical trials for SONIC HEDGEHOG (SHH) subgroup medulloblastoma (MB) patients. Clinical experience with BCC patients shows that continuous exposure to vismodegib is necessary to prevent tumor recurrence, suggesting the existence of a vismodegib-resistant reservoir of tumor propagating cells. We isolated such tumor-propagating cells from a mouse model of SHH-subgroup MB and grew them as sphere cultures. These cultures were enriched for the MB progenitor marker SOX2 and formed tumors in vivo. Moreover, while their ability to self-renew was resistant to SHH inhibitors, as has been previously suggested, this self-renewal was instead WNT-dependent. We show here that loss of Trp53 activates canonical WNT signaling in these SOX2-enriched cultures. Importantly, a small molecule WNT inhibitor was able to reduce the propagation and growth of SHH-subgroup MB in vivo, in an on-target manner, leading to increased survival. Our results imply that the tumor-propagating cells driving the growth of bulk SHH-dependent MB are themselves WNT dependent. Further, our data suggest combination therapy with WNT and SHH inhibitors as a therapeutic strategy in patients with SHH-subgroup MB, in order to decrease the tumor recurrence commonly observed in patients treated with vismodegib. PMID- 28714966 TI - Nanoscale imaging of clinical specimens using pathology-optimized expansion microscopy. AB - Expansion microscopy (ExM), a method for improving the resolution of light microscopy by physically expanding a specimen, has not been applied to clinical tissue samples. Here we report a clinically optimized form of ExM that supports nanoscale imaging of human tissue specimens that have been fixed with formalin, embedded in paraffin, stained with hematoxylin and eosin, and/or fresh frozen. The method, which we call expansion pathology (ExPath), converts clinical samples into an ExM-compatible state, then applies an ExM protocol with protein anchoring and mechanical homogenization steps optimized for clinical samples. ExPath enables ~70-nm-resolution imaging of diverse biomolecules in intact tissues using conventional diffraction-limited microscopes and standard antibody and fluorescent DNA in situ hybridization reagents. We use ExPath for optical diagnosis of kidney minimal-change disease, a process that previously required electron microscopy, and we demonstrate high-fidelity computational discrimination between early breast neoplastic lesions for which pathologists often disagree in classification. ExPath may enable the routine use of nanoscale imaging in pathology and clinical research. PMID- 28714967 TI - Architecture of the type IV coupling protein complex of Legionella pneumophila. AB - Many bacteria, including Legionella pneumophila, rely on the type IV secretion system to translocate a repertoire of effector proteins into the hosts for their survival and growth. Type IV coupling protein (T4CP) is a hexameric ATPase that links translocating substrates to the transenvelope secretion conduit. Yet, how a large number of effector proteins are selectively recruited and processed by T4CPs remains enigmatic. DotL, the T4CP of L. pneumophila, contains an ATPase domain and a C-terminal extension whose function is unknown. Unlike T4CPs involved in plasmid DNA translocation, DotL appeared to function by forming a multiprotein complex with four other proteins. Here, we show that the C-terminal extension of DotL interacts with DotN, IcmS, IcmW and an additionally identified subunit LvgA, and that this pentameric assembly binds Legionella effector proteins. We determined the crystal structure of this assembly and built an architecture of the T4CP holocomplex by combining a homology model of the ATPase domain of DotL. The holocomplex is a hexamer of a bipartite structure composed of a membrane-proximal ATPase domain and a membrane-distal substrate-recognition assembly. The presented information demonstrates the architecture and functional dissection of the multiprotein T4CP complexes and provides important insights into their substrate recruitment and processing. PMID- 28714968 TI - Dll4 and Notch signalling couples sprouting angiogenesis and artery formation. AB - Endothelial sprouting and proliferation are tightly coordinated processes mediating the formation of new blood vessels during physiological and pathological angiogenesis. Endothelial tip cells lead sprouts and are thought to suppress tip-like behaviour in adjacent stalk endothelial cells by activating Notch. Here, we show with genetic experiments in postnatal mice that the level of active Notch signalling is more important than the direct Dll4-mediated cell-cell communication between endothelial cells. We identify endothelial expression of VEGF-A and of the chemokine receptor CXCR4 as key processes controlling Notch dependent vessel growth. Surprisingly, genetic experiments targeting endothelial tip cells in vivo reveal that they retain their function without Dll4 and are also not replaced by adjacent, Dll4-positive cells. Instead, activation of Notch directs tip-derived endothelial cells into developing arteries and thereby establishes that Dll4-Notch signalling couples sprouting angiogenesis and artery formation. PMID- 28714969 TI - Endothelial Notch signalling limits angiogenesis via control of artery formation. AB - Angiogenic sprouting needs to be tightly controlled. It has been suggested that the Notch ligand dll4 expressed in leading tip cells restricts angiogenesis by activating Notch signalling in trailing stalk cells. Here, we show using live imaging in zebrafish that activation of Notch signalling is rather required in tip cells. Notch activation initially triggers expression of the chemokine receptor cxcr4a. This allows for proper tip cell migration and connection to the pre-existing arterial circulation, ultimately establishing functional arterial venous blood flow patterns. Subsequently, Notch signalling reduces cxcr4a expression, thereby preventing excessive blood vessel growth. Finally, we find that Notch signalling is dispensable for limiting blood vessel growth during venous plexus formation that does not generate arteries. Together, these findings link the role of Notch signalling in limiting angiogenesis to its role during artery formation and provide a framework for our understanding of the mechanisms underlying blood vessel network expansion and maturation. PMID- 28714970 TI - Bone marrow adipocytes promote the regeneration of stem cells and haematopoiesis by secreting SCF. AB - Endothelial cells and leptin receptor+ (LepR+) stromal cells are critical sources of haematopoietic stem cell (HSC) niche factors, including stem cell factor (SCF), in bone marrow. After irradiation or chemotherapy, these cells are depleted while adipocytes become abundant. We discovered that bone marrow adipocytes synthesize SCF. They arise from Adipoq-Cre/ER+ progenitors, which represent ~5% of LepR+ cells, and proliferate after irradiation. Scf deletion using Adipoq-Cre/ER inhibited haematopoietic regeneration after irradiation or 5 fluorouracil treatment, depleting HSCs and reducing mouse survival. Scf from LepR+ cells, but not endothelial, haematopoietic or osteoblastic cells, also promoted regeneration. In non-irradiated mice, Scf deletion using Adipoq-Cre/ER did not affect HSC frequency in long bones, which have few adipocytes, but depleted HSCs in tail vertebrae, which have abundant adipocytes. A-ZIP/F1 'fatless' mice exhibited delayed haematopoietic regeneration in long bones but not in tail vertebrae, where adipocytes inhibited vascularization. Adipocytes are a niche component that promotes haematopoietic regeneration. PMID- 28714971 TI - Budding yeast Wee1 distinguishes spindle pole bodies to guide their pattern of age-dependent segregation. AB - Many asymmetrically dividing cells unequally partition cellular structures according to age. Yet, it is unclear how cells differentiate pre-existing from newly synthesized material. Yeast cells segregate the spindle pole body (SPB, centrosome equivalent) inherited from the previous mitosis to the bud, while keeping the new one in the mother cell. Here, we show that the SPB inheritance network (SPIN), comprising the kinases Swe1 (also known as Wee1) and Kin3 (also known as Nek2) and the acetyltransferase NuA4 (also known as Tip60), distinguishes pre-existing from new SPBs. Swe1 phosphorylated Nud1 (orthologous to Centriolin) on young SPBs as they turned into pre-existing ones. The subsequent inactivation of Swe1 protected newly assembling SPBs from being marked. Kin3 and NuA4 maintained age marks on SPBs through following divisions. Downstream of SPIN, the Hippo regulator Bfa1-Bub2 bound the marked SPB, directed the spindle-positioning protein Kar9 towards it and drove its partition to the bud. Thus, coordination of SPIN activity and SPB assembly encodes age onto SPBs to enable their age-dependent segregation. PMID- 28714973 TI - Light triggers PILS-dependent reduction in nuclear auxin signalling for growth transition. AB - The phytohormone auxin induces or represses growth depending on its concentration and the underlying tissue type. However, it remains unknown how auxin signalling is modulated to allow tissues transiting between repression and promotion of growth. Here, we used apical hook development as a model for growth transitions in plants. A PIN-FORMED (PIN)-dependent intercellular auxin transport module defines an auxin maximum that is causal for growth repression during the formation of the apical hook. Our data illustrate that growth transition for apical hook opening is largely independent of this PIN module, but requires the PIN-LIKES (PILS) putative auxin carriers at the endoplasmic reticulum. PILS proteins reduce nuclear auxin signalling in the apical hook, leading to the de repression of growth and the onset of hook opening. We also show that the phytochrome (phy) B-reliant light-signalling pathway directly regulates PILS gene activity, thereby enabling light perception to repress nuclear auxin signalling and to control growth. We propose a novel mechanism, in which PILS proteins allow external signals to alter tissue sensitivity to auxin, defining differential growth rates. PMID- 28714972 TI - Organelle biogenesis in the endoplasmic reticulum. AB - Understanding organelle biogenesis is a central focus of cell biology. Whereas some are generated from existing organelles, others can be generated de novo. Most de novo organelle biogenesis occurs in the endoplasmic reticulum (ER). Here, we review the role of the ER in the generation of peroxisomes, lipid droplets, and omegasomes, which are platforms for autophagosome production, and discuss how ER subdomains with specific protein and lipid composition form and promote organelle biogenesis. PMID- 28714974 TI - Genetic analysis in UK Biobank links insulin resistance and transendothelial migration pathways to coronary artery disease. AB - UK Biobank is among the world's largest repositories for phenotypic and genotypic information in individuals of European ancestry. We performed a genome-wide association study in UK Biobank testing ~9 million DNA sequence variants for association with coronary artery disease (4,831 cases and 115,455 controls) and carried out meta-analysis with previously published results. We identified 15 new loci, bringing the total number of loci associated with coronary artery disease to 95 at the time of analysis. Phenome-wide association scanning showed that CCDC92 likely affects coronary artery disease through insulin resistance pathways, whereas experimental analysis suggests that ARHGEF26 influences the transendothelial migration of leukocytes. PMID- 28714975 TI - Association analyses based on false discovery rate implicate new loci for coronary artery disease. AB - Genome-wide association studies (GWAS) in coronary artery disease (CAD) had identified 66 loci at 'genome-wide significance' (P < 5 * 10-8) at the time of this analysis, but a much larger number of putative loci at a false discovery rate (FDR) of 5% (refs. 1,2,3,4). Here we leverage an interim release of UK Biobank (UKBB) data to evaluate the validity of the FDR approach. We tested a CAD phenotype inclusive of angina (SOFT; ncases = 10,801) as well as a stricter definition without angina (HARD; ncases = 6,482) and selected cases with the former phenotype to conduct a meta-analysis using the two most recent CAD GWAS. This approach identified 13 new loci at genome-wide significance, 12 of which were on our previous list of loci meeting the 5% FDR threshold, thus providing strong support that the remaining loci identified by FDR represent genuine signals. The 304 independent variants associated at 5% FDR in this study explain 21.2% of CAD heritability and identify 243 loci that implicate pathways in blood vessel morphogenesis as well as lipid metabolism, nitric oxide signaling and inflammation. PMID- 28714977 TI - The promise of discovering population-specific disease-associated genes in South Asia. AB - The more than 1.5 billion people who live in South Asia are correctly viewed not as a single large population but as many small endogamous groups. We assembled genome-wide data from over 2,800 individuals from over 260 distinct South Asian groups. We identified 81 unique groups, 14 of which had estimated census sizes of more than 1 million, that descend from founder events more extreme than those in Ashkenazi Jews and Finns, both of which have high rates of recessive disease due to founder events. We identified multiple examples of recessive diseases in South Asia that are the result of such founder events. This study highlights an underappreciated opportunity for decreasing disease burden among South Asians through discovery of and testing for recessive disease-associated genes. PMID- 28714980 TI - Urban landscaping: Lawn legacy. PMID- 28714978 TI - alpha-ketoglutarate orchestrates macrophage activation through metabolic and epigenetic reprogramming. AB - Glutamine metabolism provides synergistic support for macrophage activation and elicitation of desirable immune responses; however, the underlying mechanisms regulated by glutamine metabolism to orchestrate macrophage activation remain unclear. Here we show that the production of alpha-ketoglutarate (alphaKG) via glutaminolysis is important for alternative (M2) activation of macrophages, including engagement of fatty acid oxidation (FAO) and Jmjd3-dependent epigenetic reprogramming of M2 genes. This M2-promoting mechanism is further modulated by a high alphaKG/succinate ratio, whereas a low ratio strengthens the proinflammatory phenotype in classically activated (M1) macrophages. As such, alphaKG contributes to endotoxin tolerance after M1 activation. This study reveals new mechanistic regulations by which glutamine metabolism tailors the immune responses of macrophages through metabolic and epigenetic reprogramming. PMID- 28714981 TI - Plant volatiles: Active emission. PMID- 28714979 TI - Translation is actively regulated during the differentiation of CD8+ effector T cells. AB - Translation is a critical process in protein synthesis, but translational regulation in antigen-specific T cells in vivo has not been well defined. Here we have characterized the translatome of virus-specific CD8+ effector T cells (Teff cells) during acute infection of mice with lymphocytic choriomeningitis virus (LCMV). Antigen-specific T cells exerted dynamic translational control of gene expression that correlated with cell proliferation and stimulation via the T cell antigen receptor (TCR). The translation of mRNAs that encode translation machinery, including ribosomal proteins, was upregulated during the T cell clonal expansion phase, followed by inhibition of the translation of those transcripts when the CD8+ Teff cells stopped dividing just before the contraction phase. That translational suppression was more pronounced in terminal effector cells than in memory precursor cells and was regulated by antigenic stimulation and signals from the kinase mTOR. Our studies show that translation of transcripts encoding ribosomal proteins is regulated during the differentiation of CD8+ Teff cells and might have a role in fate 'decisions' involved in the formation of memory cells. PMID- 28714982 TI - Dynamic surface self-reconstruction is the key of highly active perovskite nano electrocatalysts for water splitting. AB - The growing need to store increasing amounts of renewable energy has recently triggered substantial R&D efforts towards efficient and stable water electrolysis technologies. The oxygen evolution reaction (OER) occurring at the electrolyser anode is central to the development of a clean, reliable and emission-free hydrogen economy. The development of robust and highly active anode materials for OER is therefore a great challenge and has been the main focus of research. Among potential candidates, perovskites have emerged as promising OER electrocatalysts. In this study, by combining a scalable cutting-edge synthesis method with time resolved X-ray absorption spectroscopy measurements, we were able to capture the dynamic local electronic and geometric structure during realistic operando conditions for highly active OER perovskite nanocatalysts. Ba0.5Sr0.5Co0.8Fe0.2O3 delta as nano-powder displays unique features that allow a dynamic self reconstruction of the material's surface during OER, that is, the growth of a self-assembled metal oxy(hydroxide) active layer. Therefore, besides showing outstanding performance at both the laboratory and industrial scale, we provide a fundamental understanding of the operando OER mechanism for highly active perovskite catalysts. This understanding significantly differs from design principles based on ex situ characterization techniques. PMID- 28714983 TI - Tunable room-temperature magnetic skyrmions in Ir/Fe/Co/Pt multilayers. AB - Magnetic skyrmions are nanoscale topological spin structures offering great promise for next-generation information storage technologies. The recent discovery of sub-100-nm room-temperature (RT) skyrmions in several multilayer films has triggered vigorous efforts to modulate their physical properties for their use in devices. Here we present a tunable RT skyrmion platform based on multilayer stacks of Ir/Fe/Co/Pt, which we study using X-ray microscopy, magnetic force microscopy and Hall transport techniques. By varying the ferromagnetic layer composition, we can tailor the magnetic interactions governing skyrmion properties, thereby tuning their thermodynamic stability parameter by an order of magnitude. The skyrmions exhibit a smooth crossover between isolated (metastable) and disordered lattice configurations across samples, while their size and density can be tuned by factors of two and ten, respectively. We thus establish a platform for investigating functional sub-50-nm RT skyrmions, pointing towards the development of skyrmion-based memory devices. PMID- 28714984 TI - Carbon nanotubes: Wiry matter-light coupling. PMID- 28714985 TI - Electrical pumping and tuning of exciton-polaritons in carbon nanotube microcavities. AB - Exciton-polaritons are hybrid light-matter particles that form upon strong coupling of an excitonic transition to a cavity mode. As bosons, polaritons can form condensates with coherent laser-like emission. For organic materials, optically pumped condensation was achieved at room temperature but electrically pumped condensation remains elusive due to insufficient polariton densities. Here we combine the outstanding optical and electronic properties of purified, solution-processed semiconducting (6,5) single-walled carbon nanotubes (SWCNTs) in a microcavity-integrated light-emitting field-effect transistor to realize efficient electrical pumping of exciton-polaritons at room temperature with high current densities (>10 kA cm-2) and tunability in the near-infrared (1,060 nm to 1,530 nm). We demonstrate thermalization of SWCNT polaritons, exciton-polariton pumping rates ~104 times higher than in current organic polariton devices, direct control over the coupling strength (Rabi splitting) via the applied gate voltage, and a tenfold enhancement of polaritonic over excitonic emission. This powerful material-device combination paves the way to carbon-based polariton emitters and possibly lasers. PMID- 28714986 TI - Genome-wide reconstruction of complex structural variants using read clouds. AB - In read cloud approaches, microfluidic partitioning of long genomic DNA fragments and barcoding of shorter fragments derived from these fragments retains long range information in short sequencing reads. This combination of short reads with long-range information represents a powerful alternative to single-molecule long read sequencing. We develop Genome-wide Reconstruction of Complex Structural Variants (GROC-SVs) for SV detection and assembly from read cloud data and apply this method to Illumina-sequenced 10x Genomics sarcoma and breast cancer data sets. Compared with short-fragment sequencing, GROC-SVs substantially improves the specificity of breakpoint detection at comparable sensitivity. This approach also performs sequence assembly across multiple breakpoints simultaneously, enabling the reconstruction of events exhibiting remarkable complexity. We show that chromothriptic rearrangements occurred before copy number amplifications, and that rates of single-nucleotide variants and SVs are not correlated. Our results support the use of read cloud approaches to advance the characterization of large and complex structural variation. PMID- 28714987 TI - Comparison of algorithms for the detection of cancer drivers at subgene resolution. AB - Understanding genetic events that lead to cancer initiation and progression remains one of the biggest challenges in cancer biology. Traditionally, most algorithms for cancer-driver identification look for genes that have more mutations than expected from the average background mutation rate. However, there is now a wide variety of methods that look for nonrandom distribution of mutations within proteins as a signal for the driving role of mutations in cancer. Here we classify and review such subgene-resolution algorithms, compare their findings on four distinct cancer data sets from The Cancer Genome Atlas and discuss how predictions from these algorithms can be interpreted in the emerging paradigms that challenge the simple dichotomy between driver and passenger genes. PMID- 28714988 TI - SNP-mediated disruption of CTCF binding at the IFITM3 promoter is associated with risk of severe influenza in humans. AB - Previous studies have reported associations of IFITM3 SNP rs12252 with severe influenza, but evidence of association and the mechanism by which risk is conferred remain controversial. We prioritized SNPs in IFITM3 on the basis of putative biological function and identified rs34481144 in the 5' UTR. We found evidence of a new association of rs34481144 with severe influenza in three influenza-infected cohorts characterized by different levels of influenza illness severity. We determined a role for rs34481144 as an expression quantitative trait locus (eQTL) for IFITM3, with the risk allele associated with lower mRNA expression. The risk allele was found to have decreased IRF3 binding and increased CTCF binding in promoter-binding assays, and risk allele carriage diminished transcriptional correlations among IFITM3-neighboring genes, indicative of CTCF boundary activity. Furthermore, the risk allele disrupts a CpG site that undergoes differential methylation in CD8+ T cell subsets. Carriers of the risk allele had reduced numbers of CD8+ T cells in their airways during natural influenza infection, consistent with IFITM3 promoting accumulation of CD8+ T cells in airways and indicating that a critical function for IFITM3 may be to promote immune cell persistence at mucosal sites.Our study identifies a new regulator of IFITM3 expression that associates with CD8+ T cell levels in the airways and a spectrum of clinical outcomes. PMID- 28714989 TI - Correction of a splicing defect in a mouse model of congenital muscular dystrophy type 1A using a homology-directed-repair-independent mechanism. AB - Splice-site defects account for about 10% of pathogenic mutations that cause Mendelian diseases. Prevalence is higher in neuromuscular disorders (NMDs), owing to the unusually large size and multi-exonic nature of genes encoding muscle structural proteins. Therapeutic genome editing to correct disease-causing splice site mutations has been accomplished only through the homology-directed repair pathway, which is extremely inefficient in postmitotic tissues such as skeletal muscle. Here we describe a strategy using nonhomologous end-joining (NHEJ) to correct a pathogenic splice-site mutation. As a proof of principle, we focus on congenital muscular dystrophy type 1A (MDC1A), which is characterized by severe muscle wasting and paralysis. Specifically, we correct a splice-site mutation that causes the exclusion of exon 2 from Lama2 mRNA and the truncation of Lama2 protein in the dy2J/dy2J mouse model of MDC1A. Through systemic delivery of adeno associated virus (AAV) carrying clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 genome-editing components, we simultaneously excise an intronic region containing the mutation and create a functional donor splice site through NHEJ. This strategy leads to the inclusion of exon 2 in the Lama2 transcript and restoration of full-length Lama2 protein. Treated dy2J/dy2J mice display substantial improvement in muscle histopathology and function without signs of paralysis. PMID- 28714990 TI - An approach to suppress the evolution of resistance in BRAFV600E-mutant cancer. AB - The principles that govern the evolution of tumors exposed to targeted therapy are poorly understood. Here we modeled the selection and propagation of an amplification in the BRAF oncogene (BRAFamp) in patient-derived tumor xenografts (PDXs) that were treated with a direct inhibitor of the kinase ERK, either alone or in combination with other ERK signaling inhibitors. Single-cell sequencing and multiplex fluorescence in situ hybridization analyses mapped the emergence of extra-chromosomal amplification in parallel evolutionary trajectories that arose in the same tumor shortly after treatment. The evolutionary selection of BRAFamp was determined by the fitness threshold, the barrier that subclonal populations need to overcome to regain fitness in the presence of therapy. This differed for inhibitors of ERK signaling, suggesting that sequential monotherapy is ineffective and selects for a progressively higher BRAF copy number. Concurrent targeting of the RAF, MEK and ERK kinases, however, imposed a sufficiently high fitness threshold to prevent the propagation of subclones with high-level BRAFamp. When administered on an intermittent schedule, this treatment inhibited tumor growth in 11/11 PDXs of lung cancer or melanoma without apparent toxicity in mice. Thus, gene amplification can be acquired and expanded through parallel evolution, enabling tumors to adapt while maintaining their intratumoral heterogeneity. Treatments that impose the highest fitness threshold will likely prevent the evolution of resistance-causing alterations and, thus, merit testing in patients. PMID- 28714992 TI - Musashi 1 regulates the timing and extent of meiotic mRNA translational activation by promoting the use of specific CPEs. AB - The translational reactivation of maternal mRNAs encoding meiotic drivers in vertebrates is accomplished mainly by cytoplasmic polyadenylation. The cytoplasmic polyadenylation elements (CPEs) present in the 3' untranslated regions (3' UTRs) of these transcripts, together with their cognate CPE-binding proteins (CPEBs), define a combinatorial code that determines the timing and extent of translational activation upon meiosis resumption. In addition, the RNA binding protein Musashi1 (Msi1) regulates polyadenylation of CPE-containing mRNAs by a yet undefined CPEB-dependent or CPEB-independent mechanism. Here we show that Msi1 alone does not support cytoplasmic polyadenylation, but its binding triggers the remodeling of RNA structure, thereby exposing adjacent CPEs and stimulating polyadenylation. In this way, Msi1 directs the preferential use of specific CPEs, which in turn affects the timing and extent of polyadenylation during meiotic progression. Genome-wide analysis of CPEB1- and Msi1-associated mRNAs identified 491 common targets, thus revealing a new layer of CPE-mediated translational control. PMID- 28714991 TI - Resolution of inflammation by interleukin-9-producing type 2 innate lymphoid cells. AB - Inflammatory diseases such as arthritis are chronic conditions that fail to resolve spontaneously. While the cytokine and cellular pathways triggering arthritis are well defined, those responsible for the resolution of inflammation are incompletely characterized. Here we identified interleukin (IL)-9-producing type 2 innate lymphoid cells (ILC2s) as the mediators of a molecular and cellular pathway that orchestrates the resolution of chronic inflammation. In mice, the absence of IL-9 impaired ILC2 proliferation and activation of regulatory T (Treg) cells, and resulted in chronic arthritis with excessive cartilage destruction and bone loss. In contrast, treatment with IL-9 promoted ILC2-dependent Treg activation and effectively induced resolution of inflammation and protection of bone. Patients with rheumatoid arthritis in remission exhibited high numbers of IL-9+ ILC2s in joints and the circulation. Hence, fostering IL-9-mediated ILC2 activation may offer a novel therapeutic approach inducing resolution of inflammation rather than suppression of inflammatory responses. PMID- 28714994 TI - [Focus on Cardiovascular prevention]. PMID- 28714993 TI - A two-helix motif positions the lysophosphatidic acid acyltransferase active site for catalysis within the membrane bilayer. AB - Phosphatidic acid (PA), the central intermediate in membrane phospholipid synthesis, is generated by two acyltransferases in a pathway conserved in all life forms. The second step in this pathway is catalyzed by 1-acyl-sn-glycerol-3 phosphate acyltransferase, called PlsC in bacteria. Here we present the crystal structure of PlsC from Thermotoga maritima, revealing an unusual hydrophobic/aromatic N-terminal two-helix motif linked to an acyltransferase alphabeta-domain that contains the catalytic HX4D motif. PlsC dictates the acyl chain composition of the 2-position of phospholipids, and the acyl chain selectivity 'ruler' is an appropriately placed and closed hydrophobic tunnel. We confirmed this by site-directed mutagenesis and membrane composition analysis of Escherichia coli cells that expressed mutant PlsC. Molecular dynamics (MD) simulations showed that the two-helix motif represents a novel substructure that firmly anchors the protein to one leaflet of the membrane. This binding mode allows the PlsC active site to acylate lysophospholipids within the membrane bilayer by using soluble acyl donors. PMID- 28714995 TI - [The FOURIER study]. PMID- 28714996 TI - [Cardiovascular prevention in a change of era]. PMID- 28714998 TI - Diastereoselective synthesis of novel heterocyclic scaffolds through tandem Petasis 3-component/intramolecular Diels-Alder and ROM-RCM reactions. AB - A high-yielding, stereoselective and extraordinarily complexity-generating Petasis 3-component/intramolecular Diels-Alder reaction has been developed. In combination with ROM-RCM, rapid access to complex sp3-rich heterocyclic scaffolds amenable to subsequent functionalization and library synthesis is provided. PMID- 28714997 TI - [2016 European guidelines on cardiovascular disease prevention in clinical practice. The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts. Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation]. PMID- 28714999 TI - Enhanced durability of an iridium-bipyridine complex embedded into organosilica nanotubes for water oxidation. AB - Heterogeneous metal complex catalysts for the water oxidation reaction have ever been desired for the development of devices simulating photosynthesis. This paper describes the design of highly active and robust heterogeneous iridium complex catalysts for chemical water oxidation. The heterogeneous catalyst (Ir-BPy-NT) was prepared by the post-synthetic metalation of bipyridine-containing mesoporous organosilica nanotubes (BPy-NT) with an [IrCp*Cl(MU-Cl)]2 (Cp* = eta5 pentamethylcyclopentadienyl) complex. The as-prepared Ir-BPy-NT catalyst showed enhanced durability with high reaction activity compared to the analogous homogeneous and the conventional heterogeneous ones, due to the stable nanotube structures as well as the isolated active sites. The unique one-dimensional nanotubes with large pore diameters can also reduce the diffusion limitation and facilitate the transport of reactants and products during reactions. PMID- 28714976 TI - Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease. AB - We identified rare coding variants associated with Alzheimer's disease in a three stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 * 10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 * 10-8) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 * 10-10, odds ratio (OR) = 0.68, minor allele frequency (MAF)cases = 0.0059, MAFcontrols = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 * 10-10, OR = 1.43, MAFcases = 0.011, MAFcontrols = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 * 10-14, OR = 1.67, MAFcases = 0.0143, MAFcontrols = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease. PMID- 28715000 TI - Enhanced photoelectrochemical water splitting by oxides heterojunction photocathode coupled with Ag. AB - A novel one-dimensional Co3O4/CuO/Ag composite structure film was directly grown on indium tin oxide glass substrate by a simple hydrothermal method and electrodeposition method. The film was employed for the first time as a photocathode for photoelectrochemical (PEC) water splitting to generate hydrogen. The photocurrent density of the Co3O4/CuO/Ag composite structure achieved -5.13 mA cm-2 at -0.2 V vs. RHE, which is roughly 12.8 times that of 1D Co3O4 nanowires and 3.31 times Co3O4/CuO heterojunction photocathodes. The enhanced PEC performance of this Co3O4/CuO/Ag composite structure ascribes increased light harvesting and light-absorption, distensible photoresponse range, decreased interface charge transfer resistance, and improved photogenerated electron-hole pairs transfer and separation. PMID- 28715001 TI - Structural evidence for the covalent modification of FabH by 4,5-dichloro-1,2 dithiol-3-one (HR45). AB - We use mass spectrometry analysis and molecular modelling to show the established antimicrobial inhibitor 4,5-dichloro-1,2-dithiol-3-one (HR45) acts by forming a covalent adduct with the target beta-ketoacyl-ACP synthase III (FabH). The 5 chloro substituent directs attack of the essential active site thiol (C112) via a Michael-type addition elimination reaction mechanism. PMID- 28715002 TI - Cationic folate-mediated liposomal delivery of bis-arylidene oxindole induces efficient melanoma tumor regression. AB - The folate receptor (FR) is a well-validated and common target for cancer due to its high over-expression in many different cancer cells. Herein, we developed a new FR-targeting ligand (FA8) by conjugating folic acid and a cationic lipid. Owing to its favorable structural property FA8 as a ligand could be accommodated at an unusually higher molar ratio for a ligand-targeted liposome. We then encapsulated a drug-like molecule, bis-arylidene oxindole (NME2), in the targeted liposome. The resulting formulation induced potent caspase-8 up-regulation even in FR-moderately expressing melanoma cells. The NME2-associated non-targeted liposome (i.e., without FA8) or pristine NME2 could not up-regulate caspase-8. Caspase-8, an important apoptotic protein involved in the extrinsic pathway of apoptosis-signalling and inhibition of acquired drug resistance, was induced in cancer cells due to the combination treatment of liposomally associated FA8 and NME2 through the activation and subsequent cleavage of RIP-1. Consistently, in a melanoma tumor model too wherein FR is moderately expressed, significant tumour regression was obtained with this liposomal combination of FA8 and NME2. In conclusion, we demonstrate the development of a new FR-targeting ligand molecule whose higher level of inclusion (>10 mol%) in the liposomal formulation altered the mode of anticancer action of the encapsulated drug, thereby indicating a new therapeutic possibility involving FR targeted cancer treatment. PMID- 28715003 TI - Synthesis of seminaphtho-phospha-fluorescein dyes based on the consecutive arylation of aryldichlorophosphines. AB - Seminaphtho-phospha-fluorescein (SNAPF), a phosphine-oxide-containing unsymmetric fluorescein dye, was synthesized based on the consecutive arylation of PhPCl2, followed by Friedel-Crafts cyclization. The resulting SNAPF exhibited several attractive photophysical properties including an intense fluorescence in the NIR region and a large Stokes shift. PMID- 28715004 TI - An implantable multimodal sensor for oxygen, neurotransmitters, and electrophysiology during spreading depolarization in the deep brain. AB - Brain tissue injury is often accompanied by spreading depolarization (SD) events, marked by widespread cellular depolarization and cessation of neuronal firing. SD recruits viable tissue into the lesion, making it a focus for intervention. During SD, drastic fluctuations occur in ion gradients, extracellular neurotransmitter concentrations, cellular metabolism, and cerebral blood flow. Measuring SD requires a multimodal approach to capture the array of changes. However, the use of multiple sensors can inflict tissue damage. Here, we use carbon-fiber microelectrodes to characterize several aspects of SD with a single, minimally invasive sensor in the deep brain region of the nucleus accumbens. Fast scan cyclic voltammetry detects large changes in oxygen, which reflect the balance between cerebral blood flow and energy consumption, and also supraphysiological release of electroactive neurotransmitters (i.e., dopamine). We verify waves of SD with concurrent single-unit or DC potential electrophysiological recordings. The single-unit recordings reveal bursts of action potentials followed by inactivity. The DC potentials exhibit a slow negative voltage shift in the extracellular space indicative of wide-spread cellular depolarization. Here, we characterize the multiple modalities of our sensor and demonstrate its utility for improved SD recordings. PMID- 28715006 TI - Substitution reactions of iron(ii) carbamoyl-thioether complexes related to mono iron hydrogenase. AB - A C,N,S pincer complex has been synthesized for structural modeling of the organometallic active site of mono-[Fe] hydrogenase (HMD). The C,N,S chelate allows for systematic investigation of the substitution reactions of CO and other exogenous X/L-type ligands, as well as examination of the exact roles of the Fe carbamoyl and {Fe(CO)2}2+ units in stabilizing the low-spin Fe(ii) center. Reaction of the 'apo-ligand' 6-(2-(methylthio)phenyl)pyridin-2-amine (H2NNpySMe) with [Fe(CO)4(Br)2] affords the organometallic complex [(O[double bond, length as m-dash]CNHNpySMe)Fe(CO)2(Br)] (1). Facile substitutions of the halide with L-type ligands such as MeCN, PR3 (R = C6H5, OEt, Me), pyridine and tBuNC afford diamagnetic cations of the type [(O[double bond, length as m dash]CNHNpySMe)Fe(CO)2(L)]+ (2a-f). Treatment of 1 with Na[S(2,6-Me2C6H3)] affords the neutral complex [(O[double bond, length as m dash]CNHNpySMe)Fe(CO)2(S(2,6-Me2C6H3))] (2g). Substitution for CO ligand(s) was achieved with trimethylamine-N-oxide (TMAO), and in the presence of PPh3 or pyridine it afforded the six-coordinate monocarbonyl complexes [(O[double bond, length as m-dash]CNHNpySMe)Fe(CO)(Br)(PPh3)] (3a), [(O[double bond, length as m dash]CNHNpySMe)Fe(CO)(PPh3)2](BArF4) (3b), and [(O[double bond, length as m dash]CNHNpySMe)Fe(CO)(py)2](BArF4) (3c). Interestingly the stable low-spin Fe(ii), 5-coordinate complex of the formula [(O[double bond, length as m dash]CNHNpySMe)Fe(CO)2](BArF4) (4) was accessed by treating 1 with TlBArF4 in non coordinating solvents (DCE, FPh); notably, 4 does not react with H2 in the presence (or absence) of a base. To elucidate the electronic structure differences between the five-coordinate versus six-coordinate complexes, DFT calculations for 4 and 1 were performed. Geometry optimization indicates that 4+ maintains a square-pyramidal geometry, and the Hessian calculation accurately simulates the nu(C[triple bond, length as m-dash]O) in 4+. The electronic structure of 4+ predicts that the HOMO (comprised of Fe|Ncarb) and LUMO (Fe only) orbitals in 4+ are properly oriented to interact with an incoming ligand. However, we postulate that codirectional orientation of the HOMO and LUMO orbitals explains the lack of H2 reactivity with this equatorial CNS donor set, despite many other structural similarities to the endogenous active site. Based on a related work from our lab, we conclude that a facial C,N,S coordination mode is necessary to promote H2 activation and cleavage. PMID- 28715007 TI - The covalently bound diazo group as an infrared probe for hydrogen bonding environments. AB - Covalently bound diazo groups are frequently found in biomolecular substrates. The C[double bond, length as m-dash]N[double bond, length as m-dash]N asymmetric stretching vibration (nuas) of the diazo group has a large extinction coefficient and appears in an uncongested spectral region. To evaluate the solvatochromism of the C[double bond, length as m-dash]N[double bond, length as m-dash]N nuas band for studying biomolecules, we recorded the infrared (IR) spectra of a diazo model compound, 2-diazo-3-oxo-butyric acid ethyl ester, in different solvents. The width of the C[double bond, length as m-dash]N[double bond, length as m-dash]N nuas band was linearly dependent on the Kamlet-Taft solvent parameter, which reflects the polarizability and hydrogen bond accepting ability of the solvent. Therefore, the width of the C[double bond, length as m-dash]N[double bond, length as m-dash]N nuas band could be used to probe these properties for a solvent. We found that the position of the C[double bond, length as m-dash]N[double bond, length as m-dash]N nuas band was linearly correlated with the density of hydrogen bond donor groups in the solvent. We studied the relaxation dynamics and spectral diffusion of the C[double bond, length as m-dash]N[double bond, length as m dash]N nuas band of a natural amino acid, 6-diazo-5-oxo-l-norleucine, in water using nonlinear IR spectroscopy. The relaxation and spectral diffusion time constants of the C[double bond, length as m-dash]N[double bond, length as m dash]N nuas band were similar to those of the N[double bond, length as m dash]N[double bond, length as m-dash]N nuas band. We concluded that the position and width of the C[double bond, length as m-dash]N[double bond, length as m dash]N nuas band of the diazo group could be used to probe the hydrogen bond donating and accepting ability of a solvent, respectively. These results suggest that the diazo group could be used as a site-specific IR probe for the local hydration environments. PMID- 28715010 TI - Formation of ionic co-crystals of amphoteric azoles directed by the ionic liquid co-former 1-ethyl-3-methylimidazolium acetate. AB - The ionic liquid (IL) 1-ethyl-3-methylimidazolium acetate was utilized as a liquid-state crystallization agent to form ionic co-crystals using amphoteric azoles selected as model compounds for active pharmaceutical ingredients. Weakly acidic azoles crystallize the IL relatively quickly, while stronger acidic azoles undergo slower ion exchange with the IL to form salts. PMID- 28715012 TI - The properties of residual water molecules in ionic liquids: a comparison between direct and inverse Kirkwood-Buff approaches. AB - We study the properties of residual water molecules at different mole fractions in dialkylimidazolium based ionic liquids (ILs), namely 1-ethyl-3 methylimidazolium tetrafluoroborate (EMIM/BF4) and 1-butyl-3-methylimidazolium tetrafluoroborate (BMIM/BF4) by means of atomistic molecular dynamics (MD) simulations. The corresponding Kirkwood-Buff (KB) integrals for the water-ion and ion-ion correlation behavior are calculated by a direct evaluation of the radial distribution functions. The outcomes are compared to the corresponding KB integrals derived by an inverse approach based on experimental data. Our results reveal a quantitative agreement between both approaches, which paves a way towards a more reliable comparison between simulation and experimental results. The simulation outcomes further highlight that water even at intermediate mole fractions has a negligible influence on the ion distribution in the solution. More detailed analysis on the local/bulk partition coefficients and the partial structure factors reveal that water molecules at low mole fractions mainly remain in the monomeric state. A non-linear increase of higher order water clusters can be found at larger water concentrations. For both ILs, a more pronounced water coordination around the cations when compared to the anions can be observed, which points out that the IL cations are mainly responsible for water pairing mechanisms. Our simulations thus provide detailed insights in the properties of dialkylimidazolium based ILs and their effects on water binding. PMID- 28715013 TI - Self-assembling covalent organic framework functionalized magnetic graphene hydrophilic biocomposites as an ultrasensitive matrix for N-linked glycopeptide recognition. AB - The development of additional functions and applications of covalent organic framework (COF)-derived materials still remains highly desired. In our work, a novel COF-functionalized magnetic graphene biocomposite (MagG@COF-5) was first developed as an ultrasensitive hydrophilic matrix via a facile self-assembly method for efficiently recognizing N-linked glycopeptides. By integrating the characteristics of the magnetic graphene and COF-5 layer, the MagG@COF-5 owns features of an outstanding magnetic response, a high specific area, strong hydrophilic properties and a unique size-exclusion effect. Accordingly, the MagG@COF-5 biocomposite showed excellent performance in N-linked glycopeptide analysis with a low detection limit (0.5 fmol MUL-1), an excellent size-exclusion effect (HRP digests/BSA, 1 : 600), good recyclability and reusability. More excitingly, the practical applicability of the biocomposite was evaluated by treatment with human serum (1 MUL), in which 232 N-linked glycopeptides from 85 glycoproteins were detected. All the results demonstrate that the as-synthesized MagG@COF-5 biocomposite has huge potential for use in glycoproteome and clinical diagnosis fields. It will also open up new phases for application of COF-based materials. PMID- 28715015 TI - Ultralight, highly thermally insulating and fire resistant aerogel by encapsulating cellulose nanofibers with two-dimensional MoS2. AB - Thermally insulating materials, made from earth-abundant and sustainable resources, are highly desirable in the sustainable construction of energy efficient buildings. Cellulose from wood has long been recognized for these characteristics. However, cellulose can be a flammability hazard, and for construction this has been addressed via chemical treatment such as that with halogen and/or phosphorus, which leads to further environmental concerns. Fortunately, the structure of cellulose lends itself well to chemical modification, giving great potential to explore interaction with other compounds. Thus, in this study, cellulose nanofibers (CNFs) were nano-wrapped with ultrathin 1T phase molybdenum disulfide (MoS2) nanosheets via chemical crosslinking, to produce an aerogel. Thermal and combustion characterization revealed highly desirable properties (thermal conductivity k = 28.09 mW m-1 K-1, insulation R value = 5.2, limit oxygen index (LOI) = 34.7%, total heat release = 0.4 MJ m-2). Vertical burning tests also demonstrated excellent fire retardant and self extinguishing capabilities. Raman spectra further revealed that MoS2 remained unscathed after 30 seconds of burning in a 1300 degrees C butane flame. Considering the inherently low density of this material, there is significant opportunity for its usage in a number of insulating applications demanding specific fire resistance properties. PMID- 28715014 TI - Amyloid scaffolds as alternative chlorosomes. AB - Living systems contain remarkable functional capability built within sophisticated self-organizing frameworks. Defining the assembly codes that coordinate these systems could greatly extend nanobiotechnology. To that end, we have highlighted the self-assembling architecture of the chlorosome antenna arrays and report the emulation and extension of their features for the development of cell-compatible photoredox materials. We specifically review work on amyloid peptide scaffolds able to (1) organize light-harvesting chromophores, (2) break peptide bilayer symmetry for directional energy and electron transfer, and (3) incorporate redox active metal ions at high density for energy storage. PMID- 28715016 TI - Synthesis and properties of a series of beta-cyclodextrin/nitrone spin traps for improved superoxide detection. AB - Three new DEPMPO-based spin traps have been designed and synthesized for improved superoxide detection, each carrying a cyclodextrin (CD) moiety but with a different alkyl chain on the phosphorus atom or with a long spacer arm. EPR spectroscopy allowed us to estimate the half-life of the superoxide spin adducts which is close to the value previously reported for CD-DEPMPO (t1/2 ~ 50-55 min under the conditions investigated). The spectra are typical of superoxide adducts (almost no features of the HO adduct that usually forms with time for other nitrone spin traps such as DMPO) and we show that at 250 MUM, the new spin trap enables the reliable detection of superoxide by 1 scan at the position opposite to the corresponding spin trap without the CD moiety. The resistance of the spin adducts to a reduction process has been evaluated, and the superoxide spin adducts are sensitive to ascorbate and glutathione (GSH), but not to glutathione peroxidase/GSH, reflecting the exposed nature of the nitroxide moiety to the bulk solvent. To understand these results, 2D-ROESY NMR studies and molecular dynamics pointed to a shallow or surface self-inclusion of the nitrone spin traps and of nitroxide spin adducts presumably due to the high flexibility of the permethyl beta-CD rim. PMID- 28715017 TI - Multipodal dynamic coordination involving cation-pi interactions to control the structure of helical polymers. AB - A precise tuning of the four possible states of a helix (P/M helical sense and stretched/compressed helical backbone) is attained by controlling the complexation between Li+ and a poly(phenylacetylene) that bears amide, ester and phenyl ring functionalities at the pendant group. Depending on the MeOH ratio that is present as a cosolvent, different coordination sites are involved in interactions leading to complexes I-III, each one with a characteristic structure (tri-, bi-, and unipodal) and an associated helical state. This dynamic coordination allows the selective modification of the helical sense or the stretching/compression backbone of a helical polymer. PMID- 28715018 TI - First principles studies on the selectivity of dimethoxymethane and methyl formate in methanol oxidation over V2O5/TiO2-based catalysts. AB - First principles calculations using both molecular cluster and periodic slab models were performed to reveal the mechanism for the formation of dimethoxymethane (DMM) from methanol over V2O5/TiO2-based catalysts. Two different pathways were found, and the formation of DMM was predicted to be initiated by methanol chemisorption followed by a dehydration reaction with hemiacetal catalyzed by acidic sites. For unpromoted V2O5/TiO2 catalysts, we predicted the energy barrier for the rate determining step (RDS) to follow the order formaldehyde (FA) > methyl formate (MF) > DMM, consistent with the experimental observation for the preferential formation of DMM at a relatively low temperature and that of MF at a relatively high temperature. For sulfate promoted catalysts, the energy barriers were calculated to follow the order FA > DMM > MF, so the sulfate promoter was predicted to mainly enhance the selectivity of MF, consistent with our previous experiment in which very high yield of MF was obtained with the sulfate-promoted catalyst. Calculated rate constants for the RDS were further used for semi-quantitative predictions of the product selectivities, which were found to be in quite good agreement with some of the recent experimental data in the literature, showing the validity of our approach. We also investigated the effects of the titania support and the polymerization of the vanadia species on the reactivity of the V2O5/TiO2 catalyst. Finally, we benchmarked several popular exchange-correlation functionals for calculating the reaction energies for the formation of FA, MF, and DMM from methanol oxidation, and the M06 hybrid functional was found to be superior to other semi-local and hybrid functionals studied. PMID- 28715019 TI - Thermodynamic integration network study of electron transfer: from proteins to aggregates. AB - We describe electron transfer through the NrfHA nitrite reductase heterodimer using a thermodynamic integration scheme based upon molecular dynamics simulations. From the simulation data, we estimate two of the characteristic energies of electron transfer, the thermodynamic driving forces, DeltaG, and the reorganization energies, lambda. Using a thermodynamic network analysis, the statistical accuracy of the DeltaG values can be enhanced significantly. Although the reaction free energies and activation barriers are hardly affected by protein aggregation, the complete reaction mechanism only emerges from the simulations of the dimer rather than focussing on the individual protein chains: it involves an equienergetic transprotein element of electron storage and conductivity. PMID- 28715020 TI - 2-Nitroimidazole based fluorescent probes for nitroreductase; monitoring reductive stress in cellulo. AB - Two 2-nitroimidazole-1,8-naphthalimide conjugates, 1 and 2, have been synthesised as fluorescence probes for the detection of reductive stress in HeLa cells. The 4 substituted derivative 1 was shown to act as a highly sensitive and selective substrate for nitroreductase where it exhibited a clear blue to green ratiometric fluorescence response visible to the naked eye. Moreover, biological studies demonstrated 1 could be activated in cellulo where the impact of reductive stress was easily monitored using confocal microscopy and flow cytommetry. PMID- 28715021 TI - Graphitic nanocapsules: design, synthesis and bioanalytical applications. AB - Graphitic nanocapsules are emerging nanomaterials which are gaining popularity along with the development of carbon nanomaterials. Their unique physical and chemical properties, as well as good biocompatibility, make them desirable agents for biomedical and bioanalytical applications. Through rational design, integrating graphitic nanocapsules with other materials provides them with additional properties which make them versatile nanoplatforms for bioanalysis. In this feature article, we present the use and performance of graphitic nanocapsules in a variety of bioanalytical applications. Based on their chemical properties, the specific merits and limitations of magnetic, hollow, and noble metal encapsulated graphitic nanocapsules are discussed. Detection, multi-modal imaging, and therapeutic applications are included. Future directions and potential solutions for further biomedical applications are also suggested. PMID- 28715023 TI - Amorphous boron nanorod as an anode material for lithium-ion batteries at room temperature. AB - We report an amorphous boron nanorod anode material for lithium-ion batteries prepared through smelting non-toxic boron oxide in liquid lithium. Boron in theory can provide capacity as high as 3099 mA h g-1 by alloying with Li to form B4Li5. However, experimental studies of the boron anode have been rarely reported for room temperature lithium-ion batteries. Among the reported studies the electrochemical activity and cycling performance of the bulk crystalline boron anode material are poor at room temperature. In this work, we utilized an amorphous nanostructured one-dimensional (1D) boron material aiming at improving the electrochemical reactivity between boron and lithium ions at room temperature. The amorphous boron nanorod anode exhibited, at room temperature, a reversible capacity of 170 mA h g-1 at a current rate of 10 mA g-1 between 0.01 and 2 V. The anode also demonstrated good rate capability and cycling stability. The lithium storage mechanism was investigated by both sweep voltammetry measurements and galvanostatic intermittent titration techniques (GITTs). The sweep voltammetric analysis suggested that the contributions from lithium ion diffusion into boron and the capacitive process to the overall lithium charge storage are 57% and 43%, respectively. The results from GITT indicated that the discharge capacity at higher potentials (>~0.2 V vs. Li/Li+) could be ascribed to a capacitive process and at lower potentials (<~0.2 V vs. Li/Li+) to diffusion controlled alloying reactions. Solid state nuclear magnetic resonance (NMR) measurement further confirmed that the capacity is from electrochemical reactions between lithium ions and the amorphous boron nanorod. This work provides new insights into designing nanostructured boron materials for lithium-ion batteries. PMID- 28715025 TI - Compressed few-layer black phosphorus nanosheets from semiconducting to metallic transition with the highest symmetry. AB - The high-pressure response of few-layer black phosphorus (BP) nanosheets remains elusive, despite the special interest in it particularly after the achievement of an exotic few-layer BP based field effect transistor. Here, we identified a pressure-induced reversible phase transition on few-layer BP nanosheets by performing in situ ADXRD and Raman spectroscopy with the assistance of DAC apparatus. The few-layer BP nanosheets transformed from orthorhombic semiconductors to simple cubic metal with increasing pressure, which is well interpreted using the pressure-induced inverse Peierls distortion. The obtained simple cubic BP nanosheets exhibited an enhanced isothermal bulk modulus of 147.0(2) GPa, and negative Gruneisen parameters that were attributed to the pressure-driven softening of phonon energies. Note that the simple cubic BP nanosheets adopted the highest symmetry which is in stark contrast to the general phase transformation under high pressure. First-principles calculations indicated that the metallic BP was significantly related to the band overlapped metallization, resulting from the traversing of density of states across the Fermi level at high pressure. Such findings paved a potential pathway to design targeted BP nanostructures with functional properties at extremes, and opened up possibilities for conceptually new devices. PMID- 28715027 TI - Elongation of magnetic relaxation times in a single-molecule magnet through intermetallic interactions: a clamshell-type dinuclear terbium(iii) phthalocynaninato quadruple-decker complex. AB - A clamshell-type terbium(iii)-phthalocyaninato quadruple-decker complex was synthesized. Magnetic measurements revealed that Tb-Tb interactions caused an increase in the magnetic relaxation time and enhanced the SMM properties. PMID- 28715026 TI - Exchangeable proton ENDOR as a probe of the redox-active iron center in activated bleomycin and ferric bleomycin. AB - Activated bleomycin (ABLM) is a drug-Fe(iii)-hydroperoxide complex kinetically competent in DNA attack (via H4' abstraction). This intermediate is relatively stable, but its spontaneous conversion to ferric bleomycin (Fe(iii).BLM) is poorly characterized because no observable intermediate product accumulates. The Fe(iii).BLM formed cryophotolytically from ABLM and kept at 77 K was remarkably similar by EPR and ENDOR criteria to Fe(iii).BLM formed from Fe(iii) + BLM solution. The notable ENDOR criteria were the ENDOR frequencies and features of orientation-selected, strongly hyperfine-coupled, exchangeable protons associated with the environs of the iron within <3.5 A of paramagnetic Fe(iii) in Fe(iii).BLM and ABLM. Cryophotolytic conversion of activated bleomycin to its ferric bleomycin product in the frozen solid is a sign that the reaction requires only constrained local proton rearrangements. We have characterized the metal proton distances and orientations of the protons in that rearrangement, especially noting that these protons are of mechanistic importance in the ambient temperature conversion of ABLM to Fe(iii).BLM in concert with a directed radical forming attack on DNA. PMID- 28715030 TI - A chiral BINOL-based Gemini amphiphilic gelator and its specific discrimination of native arginine by gelation in water. AB - A novel axially chiral cationic Gemini amphiphile gelator (S1) derived from (S) BINOL has been synthesized and characterized by 1H NMR, 13C NMR, ESI-MS and FT-IR analyses. The critical micelle concentration (CMC) of S1 was determined to be 0.21 mM in water at room temperature. A transparent hydrogel with S1 at 43 mM was obtained at room temperature and characterized using various methods including SEM, CD, fluorescence, 1H NMR, FT-IR, and XRD. The results indicate that the hydrophobic effect of long alkyl chains, pi-pi stacking of naphthalene rings, and intermolecular hydrogen-bonding of the amide groups of S1 should be responsible for the hydrogel formation. Moreover, an 8.5 mM aqueous solution of S1 could gel by the addition of l-arginine, whereas it failed to gel in the presence of other 15 amino acids, respectively. It is suggested that S1 could discriminate native arginine by hydrogel formation, mainly due to the electrostatic interaction and hydrogen bonding effects between S1 and l-arginine molecules. PMID- 28715031 TI - Pd-Catalyzed double N-arylation of primary amines to synthesize phenoxazines and phenothiazines. AB - An efficient and versatile Pd-catalyzed tandem C-N bond formation between aryl halides and primary amines is developed. The transformation allows a one-pot synthesis of phenoxazine and phenothiazine derivatives with a broad range of substitution patterns from readily available precursors. PMID- 28715033 TI - Synthesis of metastable hard-magnetic epsilon-Fe2O3 nanoparticles from silica coated akaganeite nanorods. AB - We present a simple preparation route to obtain a nanoscale metastable hard magnetic epsilon-Fe2O3 phase, using silica coated beta-FeOOH nanorods as a precursor and an annealing process. The synthesized epsilon-Fe2O3 nanoparticles exhibit large coercivity (HC ~ 20 kOe at 300 K and HC ~ 1.6 kOe at 400 K), confirming their high potential for practical applications. PMID- 28715032 TI - The Langmuir-Hinshelwood approach for kinetic evaluation of cucurbit[7]uril capped gold nanoparticles in the reduction of the antimicrobial nitrofurantoin. AB - In this work, gold nanoparticles protected by the macrocycle cucurbit[7]uril were used as a catalyst in the reduction of the hazardous antimicrobial nitrofurantoin. 4-Nitrophenol was also employed as the substrate of the reduction for comparative purposes. The kinetic data were modeled to the Langmuir Hinshelwood equation to know the affinities of the reactants for the surface and the real kinetic constants, a comparison at the molecular level that is made for the first time. From the results, it was observed that the adsorption of nitrofurantoin was stronger than that of 4-nitrophenol whilst the kinetic constant on the surface was higher for 4-nitrophenol than for nitrofurantoin. Additionally, shifts in the nanoparticle surface plasmon band permitted insights to be obtained into the adsorption rate and strength. The reaction induction times were also investigated and were highly dependent on the borohydride concentration and, due to the higher surface affinity of nitrofurantoin compared with 4-nitrophenol, an increase in nitrofurantoin concentration increased the induction time, while a lag phase was not observed for 4-nitrophenol. PMID- 28715029 TI - Anisotropic microfibrous scaffolds enhance the organization and function of cardiomyocytes derived from induced pluripotent stem cells. AB - Engineering of myocardial tissue constructs is a promising approach for treatment of coronary heart disease. To engineer myocardial tissues that better mimic the highly ordered physiological arrangement and function of native cardiomyocytes, we generated electrospun microfibrous polycaprolactone scaffolds with either randomly oriented (14 MUm fiber diameter) or parallel-aligned (7 MUm fiber diameter) microfiber arrangement and co-seeded the scaffolds with human induced pluripotent stem cell-derived cardiomyocytes (iCMs) and endothelial cells (iECs) for up to 12 days after iCM seeding. Here we demonstrated that aligned microfibrous scaffolds induced iCM alignment along the direction of the aligned microfibers after 2 days of iCM seeding, as well as promoted greater iCM maturation by increasing the sarcomeric length and gene expression of myosin heavy chain adult isoform (MYH7), in comparison to randomly oriented scaffolds. Furthermore, the benefit of scaffold anisotropy was evident in the significantly higher maximum contraction velocity of iCMs on the aligned scaffolds, compared to randomly oriented scaffolds, at 12 days of culture. Co-seeding of iCMs with iECs led to reduced contractility, compared to when iCMs were seeded alone. These findings demonstrate a dominant role of scaffold anisotropy in engineering cardiovascular tissues that maintain iCM organization and contractile function. PMID- 28715034 TI - Surface chemistry and stability of metastable corundum-type In2O3. AB - To account for the explanation of an eventual sensing and catalytic behavior of rhombohedral In2O3 (rh-In2O3) and the dependence of the metastability of the latter on gas atmospheres, in situ electrochemical impedance spectroscopic (EIS), Fourier-transform infrared spectroscopic (FT-IR), in situ X-ray diffraction and in situ thermogravimetric analyses in inert (helium) and reactive gases (hydrogen, carbon monoxide and carbon dioxide) have been conducted to link the gas-dependent electrical conductivity features and the surface chemical properties to its metastability towards cubic In2O3. In particular, for highly reducible oxides such as In2O3, for which not only the formation of oxygen vacancies, but deep reduction to the metallic state (i.e. metallic indium) also has to be taken into account, this approach is imperative. Temperature-dependent impedance features are strongly dependent on the respective gas composition and are assigned to distinct changes in either surface adsorbates or free charge carrier absorbance, allowing for differentiating and distinguishing between bulk reduction-related features from those directly arising from surface chemical alterations. For the measurements in an inert gas atmosphere, this analysis specifically also included monitoring the fate of differently bonded, and hence, differently reactive, hydroxyl groups. Reduction of rh-In2O3 proceeds to a large extent indirectly via rh-In2O3 -> c-In2O3 -> In metal. As deduced from the CO and CO2 adsorption experiments, rhombohedral In2O3 exhibits predominantly Lewis acidic surface sites. The basic character is less pronounced, directly explaining the previously observed high (inverse) water-gas shift activity and the low CO2 selectivity in methanol steam reforming. PMID- 28715035 TI - Supersaturation dependence of glycine polymorphism using laser-induced nucleation, sonocrystallization and nucleation by mechanical shock. AB - The nucleation of glycine from aqueous supersaturated solution has been studied using non-photochemical laser-induced nucleation (NPLIN), ultrasound (sonocrystallization), and mechanical shock of sample vials. It was found that at higher supersaturation, samples were more susceptible to nucleation and produced more of the gamma-glycine polymorph. The results are described in terms of a mechanism common to all three nucleation methods, involving the induction of cavitation events and pressure shockwaves. The switch in preference from alpha- to gamma-glycine was observed to occur over a narrower range of supersaturation values for NPLIN. We attribute this to induction of cavitation events with higher energies, which result in higher localized pressures and supersaturations. Experiments on NPLIN using circularly versus linearly polarized light showed no evidence for binary polarization switching control of glycine polymorphism. PMID- 28715036 TI - Structure-induced variation of thermal conductivity in epoxy resin fibers. AB - The ability to control thermal conductivity is important in a wide variety of applications, especially in heat removal, heat insulation, and thermoelectric energy conversion. Herein, we reveal that the thermal conductivity of epoxy resin fibers increases on decreasing the fiber diameter and surpasses the bulk value (0.25 W m-1 K-1 at 300 K) for the fiber with a diameter of 211 nm. The variation of thermal conductivity in epoxy resin fibers can likely be attributed to their microstructure change-enhanced interface phonon scattering between amorphous and crystalline regions and the enhanced alignment of the molecular chain orientation. PMID- 28715037 TI - Enhanced current rectification and self-powered photoresponse in multilayer p MoTe2/n-MoS2 van der Waals heterojunctions. AB - Vertically stacked van der Waals (vdW) heterojunctions based on two-dimensional (2D) transition metal dichalcogenides (TMDs) have attracted a great deal of attention and have created a powerful new material platform for novel, high performance electronic and optoelectronic devices. Here, we report the construction of multilayer p-MoTe2/n-MoS2 vdW heterostructures with remarkable rectification behavior, self-powered photoresponse and distinct photosensitivity at different laser wavelengths and power densities. Field effect transistors (FETs) fabricated by MoTe2/MoS2 heterojunctions exhibit excellent gate-tunable rectification behavior and p-n junction transport characteristics, with the n type dominating. The MoTe2/MoS2 heterojunction devices generate a self-powered photocurrent at zero bias voltage with a considerable on-off ratio reaching ~780 and achieve a stable and fast photoresponse, due to the type-II band alignment facilitating efficient electron-hole separation. Utilizing the advantages of a p n junction with type-II band alignment, this MoTe2/MoS2 vdW heterostructure provides more opportunities for future electronic and optoelectronic applications. PMID- 28715039 TI - Erratum to: Computed tomographic evaluation of femoral and tibial conformation in English Staffordshire Bull Terriers with and without congenital medial patellar luxation. AB - OBJECTIVE: To compare hindlimb conformation of English Staffordshire Bull Terriers with and without medial patellar luxation using computed tomography. METHODS: Hindlimb computed tomography (CT) was performed on six English Staffordshire Bull Terriers with grade II or III medial patellar luxation, and six without medial patellar luxation. Inclination angle, femoral condyle trochanteric angle, anteversion angle (AA), distal anteversion angle (DAA), proximal anteversion angle (PAA), femoral varus angle (FVA), tibial valgus angle (TVA), and tibial torsion angle (TTA) were measured. Student's T-test was conducted to compare normal limbs to limbs with medial patellar luxation, all limbs of dogs with medial patellar luxation to limbs of the control group, and medial patellar luxation affected limbs (normal limbs of unilaterally affected dogs excluded) to the control group. P-values less than 0.05 were considered significant. RESULTS: Two dogs with medial patellar luxation were only affected unilaterally. Limbs of English Staffordshire Bull Terriers with medial patellar luxation had significantly diminished AA and DAA, in addition to decreased TVA. These differences were similar regardless of how the unaffected limbs from affected dogs were treated in our analysis. DISCUSSION AND CONCLUSION: Medial patellar luxation in this population of English Staffordshire Bull Terriers was characterized by a decrease in femoral anteversion, external rotation of the femoral diaphysis, and decreased tibial valgus. These findings may help inform clinical decision making when performing osteotomy for treatment of medial patellar luxation in this breed. PMID- 28715040 TI - [Taste dysfunction (dysgeusia) and radioiodine therapy of thyroid cancer - be aware of side effects by antidepressants and sedatives. Vorschadigung durch Antidepressiva und Sedativa beachten]. AB - In addition to xerostomia, taste dysfunction (hypo-, dysgeusia) is an independent side effect of radioiodine therapy of thyroid cancer. Hypogeusia results from damage of the small mucous salivary glands in the vicinity of the taste buds. Particularly in those patients, who are treated with drugs such as antidepressants or sedatives, taste dysfunction becomes frequently clinically symptomatic. If feasible, therapy regimens bearing a potential risk for taste dysfunction should be switched. Additional damage to taste function should be minimalized, including cessation of smoking, change of agents for dental hygiene, and change of toothpaste. If the medical indication for ablative radioiodine therapy is based on the patient's decision, the patient should be informed about alternative strategies. Potential clinical consequences of the sialadenitis (xerostomia, alteration in taste, risk of caries and tooth extraction, lacrimal gland dysfunction, tearing and need of dacryocystorhinostomy) should be revealed completely. Adapted to the initial risk of relapse, the 131I-activity for ablation should be reduced to the latest standard of care. Clinical data are currently too heterogeneous to decide whether rhTSH might reduce the rate of dysgeusia. The specialist in nuclear medicine should be aware of the multifactorial causes of taste dysfunction, in particular if the patient seeks medical advice after radioiodine therapy. PMID- 28715041 TI - Diagnostic single gene analyses beyond Sanger. Economic high-throughput sequencing of small genes involved in congenital coagulation and platelet disorders. AB - Molecular testing of congenital coagulation and platelet disorders offers confirmation of clinical diagnoses, supports genetic counselling, and enables predictive and prenatal diagnosis. In some cases, genotype-phenotype correlations are important for predicting the clinical course of the disease and adaptation of individualized therapy. Until recently, genotyping has been mainly performed by Sanger sequencing. While next generation sequencing (NGS) enables the parallel analysis of multiple genes, the cost-value ratio of custom-made panels can be unfavorable for analyses of specific small genes. The aim of this study was to transfer genotyping of small genes involved in congenital coagulation and platelet disorders from Sanger sequencing to an NGS-based method. A LR-PCR approach for target enrichment of the entire genomic regions of the genes F7, F10, F11, F12, GATA1, MYH9, TUBB1 and WAS was combined with high-throughput sequencing on a MiSeq platform. NGS detected all variants that had previously been identified by Sanger sequencing. Our results demonstrate that this approach is an accurate and flexible tool for molecular genetic diagnostics of single small genes. PMID- 28715042 TI - [Diagnostic significance of multiparametric MRI combined with US-fusion guided biopsy of the prostate in patients with increased PSA levels and negative standard biopsy results to detect significant prostate cancer - Correlation with the Gleason score. Korrelation mit dem Gleason Score]. AB - AIMS: To increase diagnostic precision and to reduce overtreatment of low-risk malignant disease, multiparametric MRI (mpMRI) combined with ultrasound (US) fusion guided biopsy of the prostate were performed. METHODS: In 99 male patients with increased PSA plasma levels and previous negative standard biopsy procedures, mpMRI was carried out followed by US fusion guided perineal biopsy. PI-RADS-Data (PS) of mpMRI and histopathological Gleason score (GS) were categorized and statistically compared. RESULTS: Lesions in 72/99 (73 %) of patients were determined to be suspect of malignancy, based on a PS 4 or 5. In 33/99 (33 %) of patients, malignancy could not be confirmed by histopathology. With regard to the remaining 66 patients with previous negative biopsy results, 42 (64 %) were diagnosed with a low-grade carcinoma (GS 6, 7a) and 24 (36 %) with a high-grade carcinoma (GS >= 7b). The proportion of corresponding results in mpMRI (PS 4-5) when a high-grade carcinoma had been detected, was 21/24 (88 %), which related to a sensitivity of 88 % and a negative predictive value (NPV) of 85 % (p = 0,002). In addition, 35 of 42 patients (83%), graded PS 4-5 in mpMRI, were diagnosed with low-grade carcinoma-positive (p < 0,001). Sensitivity to differentiation between low- and high-grade carcinomas (GS <= 7a vs. >= 7b) by means of PS was 88 % with a NPV of 70 % (p = 0,74). CONCLUSION: Our results suggest that mpMRI combined with US-fusion guided biopsy is able to detect considerably higher rates of clinically relevant prostate malignancies compared to conventional diagnostic procedures. However, no statistical significance could be shown regarding the differentiation between high- and low-grade carcinomas. It is hoped that the hybrid methods PSMA-PET/CT or PSMA-PET/MRI will lead to the next optimization step in the differentiation between high- and low-grade carcinomas which so far has been unsatisfactory. PMID- 28715043 TI - Presentation of the 5th and 6th issues of volume 29 of Annali di Igiene, dedicated to the memory of Prof Carmine Melino. PMID- 28715044 TI - Carmine Melino and the Institute of Hygiene. AB - Throughout his 94 years of life, Carmine Melino brilliantly pursued different professional paths, his life being a constant stimulus for students, colleagues, friends and the family. Following the early formative years of study, here, we briefly list his scientific achievements in Occupational Medicine and Hygiene as well as his broad literary interests. Carmine was an inspiration to his generation not only because of his professional achievements, but also for his warm personality, exemplary hard-playing life and unbounded enthusiasm. A polymath, post-enlightenment ethos flowed to all his friends and colleagues, creating an ambience where intellectual excellence was highly appreciated and avidly pursued. PMID- 28715045 TI - Carmine Melino. PMID- 28715046 TI - Carmine Melino. PMID- 28715047 TI - A tribute to Carmine Melino. PMID- 28715048 TI - A memory of Professor Carmine Melino. PMID- 28715049 TI - Carmine Melino: a Universe by his own. PMID- 28715050 TI - Carmine Melino and his love for the history of hygiene. PMID- 28715051 TI - Carmine Melino and the Occupational Medicine. AB - This short article, which describes the significant contribution Prof. Carmine Melino made to Occupational Medicine, underlines the Professor's great interest in this field and his outstanding ability in combining the lessons of the past with the most innovative aspects of this discipline. PMID- 28715052 TI - The Museum of the Department of Public Health and Infectious Diseases, Sapienza University of Rome. AB - This paper illustrates in detail the birth of the Museum of Public Health of the Sapienza University of Rome, which has been one of the most successful achievements of Prof Carmine Melino in the last few years of his academic career. Backed by a very thin group of enthousiastic coworkers and colleagues, he recuperated all the instruments which had been used by the research groups active since 1880 at the former Institute of Hygiene, to which he added samples of the different pieces of laboratory furniture, ancient reagents, etc. The goal was not to simply collect, restore and maintain the documents of the Institute's past, but to rebuild a vintage laboratory, as it was inhabited by the hygienists of the past and to describe the kinds of research being performed during a period more than a century long. Beginning from the days when Hygiene became a scientific discipline, he tried to demonstrate that only the transformation of Hygiene into an experimental discipline made it possible the numberless achievements, including the improvements of the environmental conditions, the reduction of infectious diseases and the successful fight against the chronic, degenerative diseases of the present times. PMID- 28715053 TI - Public Health and Hospitals: a Common Area for Clinical and Public Health Medicine. AB - Contrary to what has happened so far, hospitals should become a setting which jointly exercise Clinical and Public Health Medicine. The areas of activity that require the presence of multidisciplinary teams and can bring benefits both to the patients and to the community is briefly described. PMID- 28715054 TI - Sustainability of prevention practices at the workplace: safety, simplification, productivity and effectiveness. AB - Traditional full-time employment has evolved into various types of occupational situations, and, nowadays, new work organization strategies have been developed. Previously overlooked risk factors have emerged, such as traffic accidents while commuting or during work hours, poor work organization, and detrimental lifestyles (like alcohol and substance abuse, although recent statistics seem to show a declining trend for the latter). The global scenario shows greater attention to occupational risks, but also, to the reduced degree of protection. Moreover, the elevated costs, the unacceptably high fatal accident rates in some sectors, the complexity of the prevention systems, the lack of prevention training, the inadequate controls (despite the numerous independent supervisory bodies) and the obsolescence of certain precepts, call for a prompt review of the regulatory system. This is especially needed for general simplification, streamlining certification bodies and minimizing references to other provisions in the legislation that make it difficult for Italian and foreign workers to read and understand the rules "without legal interpreters". "New" occupational diseases and occupational risk factors have also been reported in addition to pollution. There are concerns for continued economic and social destabilization, unemployment, commuting, temporary and precarious contracts. All of these contribute to the lack of wellbeing in the working population. Thus, the timing, duration, and types of prevention training should be carefully assessed, making prevention more appealing by evaluating costs and benefits with a widespread use of indicators that make appropriate actions for health promotion "visible", thus encouraging awareness. Although reducing prevention is never justified, it should still be "sustainable" economically in order to avoid waste of resources. It is also essential to have laws which are easily and consistently interpreted and to work on the ethics of employers and employees to ensure that they conform to the standards of other European countries that currently operate with greater effectiveness and lower costs. PMID- 28715055 TI - Risk of surgical site infections following hip and knee arthroplasty: results of the ISChIA-GISIO study. AB - BACKGROUND: Surgical Site Infection (SSI) is one of the major complications following insertion of hip or knee prosthesis. The aim of the present study was to describe rates of SSIs and associated risk factors during hip and knee prosthesis procedures in Italian hospitals. METHODS: Italian hospitals were invited to join the ISChIA (Surgical Site Infections in Arthroplasty Surgery) project and participated in the study on a voluntary basis. SSI surveillance was performed according to the Hospitals in Europe Link for Infection Control through Surveillance (HELICS) -SSI protocol. The study population consisted of all patients who had a prosthetic knee or hip joint replacement between March 2010 and February 2011. Only elective operations were include. RESULTS: A total of 14 hospitals and 1285 surgical procedures were included. SSI cumulative incidence was 1.3 per 100 hip and 2.4 per 100 knee surgical procedures; a significant positive trend of SSI incidences was observed with increasing SSI risk index. In multivariate analysis, considering hip procedures, the single independent risk factor associated to SSI was operation length (RR: 4.54; 95%CI: 1.06-19.48). For knee procedures, no significant risk factor was identified. CONCLUSIONS: In the present study, SSI cumulative incidence was in the range of European data. However, a larger number of operations is needed to better estimate SSI rates. A second edition of the ISChIA project has been already conducted and results of the two surveys will provide new insight to further our knowledge for infection control. PMID- 28715056 TI - Evaluation of timing of re-appearance of VBNC Legionella for risk assessment in hospital water distribution systems. AB - BACKGROUND: In this study we estimated the presence of Legionella species, viable but non-culturable (VBNC), in hospital water networks. We also evaluated the time and load of Legionella appearance in samples found negative using the standard culture method. METHODS: A total of 42 samples was obtained from the tap water of five hospital buildings. The samples were tested for Legionella by the standard culture method and were monitored for up to 12 months for the appearance of VBNC Legionella. RESULTS: All the 42 samples were negative at the time of collection. Seven of the 42 samples (17.0%) became positive for Legionella at different times of monitoring. The time to the appearance of VBNC Legionella was extremely variable, from 15 days to 9 months from sampling. The most frequent Legionella species observed were Legionella spp and L. anisa and only in one sample L. pneumophila srg.1. CONCLUSIONS: Our study confirms the presence of VBNC Legionella in samples resulting negative using the standard culture method and highlights the different time to its appearance that can occur several months after sampling. The results are important for risk assessment and risk management of engineered water systems. PMID- 28715057 TI - The impact of bariatric surgery on health outcomes, wellbeing and employment rates: analysis from a prospective cohort study. AB - PURPOSE: Morbid obesity is associated with several comorbidities that often impair patients' ability to obtain and keep a job and that, eventually, could hinder their fitness to work. This study aimed at determining whether the employment status of morbidly obese patients may be positively affected by bariatric surgery. METHODS: A total of 30 morbidly obese patients who underwent Roux-en-Y gastric bypass (RYGB) from March 2014 to March 2015 were prospectively evaluated. All patients underwent a pre-operative assessment including the collection of personal and occupational data and the evaluation of musculoskeletal system. All evaluations were repeated at the end of a 24-month follow up. RESULTS: After RYGB, employment rates increased from 15/30 (50.0%) to 25/30 (83.3%, p = 0.012). Patients who were working at the end of follow-up referred lower rates of comorbidities, in particular of musculoskeletal complaints (4/25 vs. 4/5, p < 0.001), and presented significantly increased scores of energy/vitality at SF-36 assessment. CONCLUSIONS: Our study suggests that RYGB can increase employment rates, increasing tolerance to effort and reducing prevalence and severity of obesity-related symptoms and complaints. PMID- 28715058 TI - Public health and urban planning: a powerful alliance to be enhanced in Italy. AB - Urban planning has played and still plays a key role in improving urban health and indoor health. The authors sketch out the historical evolution of the relationships between Public Health and urban planning, in particular to what happened in Italy during the past 150 years. The authors suggest some lines for further research, but also describe some interventions that could obtain practical results in terms of health gains for the population. PMID- 28715059 TI - The Cost-effectiveness of Genetic Screening for Familial Hypercholesterolemia: a Systematic Review. AB - BACKGROUND: Familial hypercholesterolemia (FH) is a genetic disorder that leads to elevated plasma LDL-cholesterol levels and premature coronary heart disease (CHD). An understanding of the mutations responsible for FH and the effectiveness of statins in lowering the risk of CHD in FH patients has increased interest in genetic screening strategies to improve FH diagnosis. In this study, we aimed to evaluate the cost-effectiveness of such strategies. METHODS: We performed a systematic review of full economic evaluations that assessed the cost effectiveness of FH genetic screening strategies. We used relevant search terms to investigate Medline, Scopus, Web of Science, the Database of Abstracts of Reviews of Effects, the Health Technology Assessment Database, and the National Health Service Economic Evaluation Database. Data extraction and assessment of the quality of the studies were performed independently by two reviewers. The key features of the included studies are summarized in a narrative synthesis. RESULTS: We included seven economic evaluations that assessed the cost effectiveness of genetic screening for FH, published mainly in Europe between 2002 and 2015. Most studies had a no-screening strategy as a comparator, focused on relatives of index cases with genetic or clinical diagnosis of FH (cascade screening), considered a lifetime horizon and adopted a health care payer viewpoint. Cascade screening, based on genetic testing of relatives of an index case with confirmed clinical or genetic diagnosis of FH, was shown to be cost effective in most settings. CONCLUSIONS: Our review confirms the cost effectiveness of cascade genetic screening for the diagnosis of FH. Further research may be needed to assess the cost-effectiveness of cascade screening following the introduction of newly recommended therapeutic regimes and next generation sequencing. PMID- 28715060 TI - The Complex Interaction Between Polycystic Ovary Syndrome and Hereditary Angioedema: Case Reports and Review of the Literature. AB - Importance: Hereditary angioedema (HAE) is a rare but severe disease, with high risk of death, and attacks have been associated to high estrogen levels. Polycystic ovary syndrome (PCOS) is a common hyperandrogenic condition, which is frequently treated with combined oral contraceptives. Objective: The aim of this study was to describe 2 clinical cases of young women diagnosed as having PCOS who developed HAE attacks after the introduction of combined estrogen-progestin pills to treat PCOS symptoms. Evidence Acquisition: Literature review of sex hormones' role in genesis of HAE attacks and possible mechanisms involved. Results: In the cases reported, after initiation of combined contraceptives, patients presented with facial swelling with airway involvement (laryngeal edema) and abdominal pain. They had a familial history of angioedema and normal C1 inhibitor (C1-INH) levels, leading to the diagnosis of HAE with normal C1-INH (HAEnC1-INH) or HAE type III. After suspension of exogenous estrogen, patients remained asymptomatic from HAE. Conclusions and Relevance: HAEnC1-INH is an estrogen-dependent form of HAE. It is well established that exogenous estrogen triggers attacks of all types of HAE. However, this is the first description of the association between PCOS and HAE, in which PCOS could be masking HAE symptoms. We propose that PCOS might have a protective role regarding HAE attacks, because of its particular hormonal features, that is, hyperandrogenism and relative stable levels of estradiol. The use of combined estrogen-progestin compounds in women with PCOS and HAE must be avoided, and treatment must be individualized. PMID- 28715061 TI - Physical Activity Assessment During Gestation and Its Outcomes: A Review. AB - Background: Physical activity recommendations emphasize a positive influence of exercise on health. It is particularly recognized during pregnancy for both the mother and fetus. Aim: This review aims to identify the main trends of activity undertaken by women during gestation and to find out how it affects the expecting mother and her child. Methods: Review of the literature comprising the following databases: PubMed, Academic Search Complete, Health Source-Consumer Edition, Health Source: Nursing/Academic Edition, EMBASE (2000 to May 2013), used detailed search strategies. The review was restricted to experimental studies. Trials were excluded if they met any of the following criteria: reviews, letters, commentaries or editorials, only abstracts available, and any kind of pathology during pregnancy. Three assessors reviewed the titles, abstracts, and full articles using standardized data abstraction forms, and they assessed the study quality. A total of 474 potential articles remained for analyses. Findings: Twenty-eight articles were eligible for inclusion in the present review: randomized controlled trials and observational studies that evaluated maternal and offspring outcomes as a result of physical activity during pregnancy. Quasi randomized trials were excluded. The activities that were most frequently assessed included occupational activity, housework/caregiving, sport/exercise, and active living, as well as habits. The authors evaluated different types of physical activity in the loading conditions. The aerobic activities most frequently used for assessment included treadmill walking program; step aerobics or stair stepper; aerobics; bicycle ergometer; combination of rowing, stationary cycling, and walk jogging; rhythmic calisthenics class and step class; brisk walks; stretching; and relaxation. The benefits following being active during pregnancy are associated with improved maternal psychological well-being, a reduced risk of preterm birth and excessive gestational weight gain, and lower risk of birth-related complications. Conclusions: Patterns of activity change during pregnancy. Although exercise is safe for both the mother and fetus, most women reduce their activity level during the first weeks of gestation. Specifically, physical activity tends to be of lower duration, frequency, and intensity. Therefore, women should be encouraged by professionals to initiate or continue exercising during a healthy pregnancy. PMID- 28715062 TI - Gestational Weight Gain: Historical Evolution of a Contested Health Outcome. AB - : The history of research on gestational weight gain (GWG) in the United States and United Kingdom provides a context for current clinical practice. We trace the evolution of research on GWG in scientific literature from the 19th century to the present and examine its implications for contemporary clinical and public health practice. Obstetricians, beginning in the late 1800s, recommended dieting during pregnancy in order to limit GWG to 20 lb or less, driven by a belief that excessive weight gain was a cause of toxemia. Beginning in the 1930s, a burgeoning focus on nutrition and health allowed a better understanding of the effect of GWG on the health of the fetus and the newborn. Increased awareness of disparities in infant mortality in the 1960s, followed by systematic review of the literature, produced further refinements in GWG recommendations in the 1970s, which continue today. Current research focuses on epigenetic influences over the life course and has emphasized individualized recommendations. The complex historical perspective that this article provides serves as a reminder of both the interplay and the gaps between research and practice. These gaps result from the fact that clinical guidelines often reflect a specific point in a perpetually evolving state of knowledge that is influenced not only by advances in bench research, but also by refinements in statistical and epidemiologic methods, as well as by the political realities of the time in which they are drafted. Importance: Gestational weight gain and its relationship to maternal, fetal, and infant health are areas of active inquiry. Objective: We critically review evolution of scientific understanding of GWG from the 19th century to the present, and examine its implications for contemporary obstetric practice. Evidence Acquisition: We reviewed all English-language medical studies related to GWG published through 1930s as well as widely cited influential works from 1940s through present time. Results: During the past century, recommendations for GWG have reversed from emphasizing dieting during pregnancy to the importance of proper nutrition during pregnancy. Obstetricians' focus has also evolved from being exclusively on the newborn to include the health of mothers. Contemporary obstetric practice seeks to achieve a balance between mothers' and infants' risk of adverse outcomes. Conclusions: Historical and social contexts of the United States and the United Kingdom led to distinct GWG policies in the 2 countries. Changes in GWG recommendations over the past century reflect developments in the allied fields, such as epidemiology and nutrition, as much as progress in obstetrics and gynecology. Relevance: The complex historical perspective that this article provides serves as a reminder of both the interplay and the gaps between research and practice. These gaps result from the fact that clinical guidelines often reflect a specific point in a perpetually evolving state of knowledge that is influenced not only by advances in bench research, but also by refinements in statistical and epidemiologic methods, as well as by the political realities of the time in which they are drafted. PMID- 28715063 TI - Peripheral ARtery Atherosclerotic DIsease and SlEep disordered breathing (PARADISE) trial - protocol for an observational cohort study. AB - BACKGROUND: Peripheral arterial disease (PAD) is in fact a group of disease entities with different symptoms and course but a common underlying cause, i.e. atherosclerosis. Atherosclerosis is known to be aggravated by several cardiovascular risk factors, including obstructive sleep apnoea (OSA). AIM: Following paper is a protocol for the Peripheral ARtery Atherosclerotic DIsease and SlEep disordered breathing (PARADISE) trial, which aims to describe the prevalence of OSA in PAD patients scheduled for revascularisation, and to determine the effect of OSA on the procedure outcomes. METHODS: The PARADISE study is an observational cohort trial. It plans to include 200 consecutive patients hospitalised for revascularisation due to PAD. In every patient an overnight sleep study will be performed to diagnose sleep disorders. Accord!ing to the results of the test, patients will be divided into two groups: group A - patients with OSA, and group B - patients without OSA (control group). All patients will also be screened for classical and non-classical cardiovascular risk factors. In some of the patients, during surgery, a fragment of atherosclerotic plaque will be collected for further testing. Patients will be followed for one year for adverse events and end-points. Primary end-point of the study will be the failure of revascularisa!tion defined as recurrence or new onset of the symptoms of ischaemia from the treated region, a need for re operation or procedure revision, or recurrence of ischaemia signs on the imaging tests. DISCUSSION: The data obtained will help determine the incidence of OSA in the population of patients with PAD. The au!thors expect to show that, as with other cardiovascular diseases associated with atherosclerosis, also in patients with PAD the incidence of undiagnosed OSA is high and its presence is associated with elevated cholesterol, inflammatory markers, and higher prevalence of arterial hypertension and poor control of other cardiovascular risk factors. In addition, due to increased oxidative stress and vascular endothelial injury associated with OSA, patients afflicted with this condition will not only have more advanced atherosclerotic lesions, but also in their histopathological examination their atherosclerotic plaque will exhibit evidence of greater instability and adverse morphology. We also expect to show that in patients with OSA, achieving cor!rect control of cardiovascular risk factors will be more difficult. The study may improve PAD control through assuring better multispecialty care in PAD patients. PMID- 28715064 TI - New indexes of body fat distribution, visceral adiposity index, body adiposity index, waist-to-height ratio, and metabolic disturbances in the obese. AB - BACKGROUND AND AIM: The aim of this study was to examine the relationship between new obesity-related indexes, anthropometric and biochemical parameters, and body composition in individuals with obesity. METHODS: The study group consisted of 72 women and 34 men, aged 39.0 +/- 5.9 years, with a mean body mass index (BMI) of 32.6 +/- 2.4 kg/m2, admitted for body weight reduction. In all participants body weight (BW), height, waist circumference (WC), hip circumference (HC), BMI, waist to-hip-ratio (WHR), visceral adiposity index (VAI), body adiposity index (BAI), and waist-to-height ratio (WHtR) were assessed. Using bioelectrical impedance (BIA, TANITA MC 180M) the following parameters were obtained: the level of visceral adipose tissue (VAT) and body fat percentage (FM%). Serum concentrations of total cholesterol (TC), high-density lipoprotein cholesterol (HDL), low density lipoprotein cholesterol (LDL), triglycerides (TG), glucose, insulin, and insulin resistance (HOMA-IR) were determined. RESULTS: It was observed that almost all the studied indicators: WC, WHtR, BAI, VAI, and BMI, positively correlated with VAT estimated by bioimpedance, but only VAI, WC, and WHtR were strongly associated with glucose and lipid disturbances in the obese. BAI and BMI correlated with total FM%, while WC, WHtR, and VAI correlated with total body weight. CONCLUSIONS: The results indicate that VAI, WC, and WHtR can be useful in the assessment of increased VAT accumulation associated with disturbances in glucose and lipid metabolism. BAI should be calculated separately for each sex, then it could be also useful for the prediction of disturbances in glucose metabolism. However, further studies are needed to recognise cut-off values for BAI, as a marker of body fatness, associated with adverse health effects. PMID- 28715065 TI - Hypertension, dyslipidaemia, and cardiovascular risk in HIV-infected adults in Poland. AB - BACKGROUND: The prevalence of cardiovascular diseases (CVD) in HIV-infected patients increases with aging and duration of the disease. Hypertension, high cholesterol level obesity, diabetes, tobacco exposure, and use of alcohol are among the traditional risk factors that contribute to CVD. AIM: The aim of the study was to determinate the incidence of hypertension, lipid disturbances, and CVD risk in dependence on clinical, viral, and biochemical factors. METHODS: A total of 417 HIV-infected Caucasian adult patients from the four clinical centres in Poland were enrolled and analysed on the basis of available medical data from the years 2013-2015. RESULTS: Hypertension was diagnosed in 28% of all patients and in the age ranges: < 40 years, 41-60 years and > 60 years in 18%, 43%, and 53%, respectively. The percentage of optimal, normal, and high normal blood pressure was: 28%, 14%, and 30%, respectively. Hypertension grade 1, 2, and 3 was observed in 58%, 35%, and 7% of patients, respectively. Factors associated with hypertension were: increasing age, male sex, increased body mass index, hypercholesterolaemia, hypo-high density lipoprotein (HDL), hypertriglyceridaemia and duration of HIV infection more than 10 years. Hypercholesterolaemia, suboptimal level of HDL, elevated low-density lipoprotein, and hypertriglyceridaemia were observed in 37%, 20.5%, 31%, and 52%, respectively. Hypertriglyceridaemia was associated with protease inhibitor-based highly active antiretroviral therapy. HCV infection was negatively associated with hypercholesterolaemia. Cigarette smoking was reported in 55% of cases. CONCLUSIONS: Incidence of hypertension in particular age groups of HIV infected people is higher than in the general Polish population. Hypertension is influenced by traditional risk factors and duration of HIV infection but not antiretroviral treatment. HIV/HCV coinfection appears to be protective against hypercholesterolaemia. PMID- 28715066 TI - Comparison of phenoxybenzamine and doxazosin in perioperative management of patients with pheochromocytoma. AB - BACKGROUND: Adrenalectomy with preoperative pharmacological preparation is strongly recommended in patients diagnosed with pheochromocytoma, in order to prevent perioperative complications. AIM: To compare phenoxybenzamine (PhB) and doxazosin (DOX) in terms of perioperative haemodynamic status in patients with pheochromocytoma, who have been prepared for adrenalectomy. METHODS: Retrospective analysis of 44 patients with pheochromocytoma (aged 16-80 years, 29 females) who underwent adrenalectomy. Patients were divided into two groups: 35 patients on DOX and nine patients on PhB. RESULTS: Mean time of preparation for surgery was 38.8 days in the DOX group and 18.3 days in the PhB group (p = 0.04). No statistically significant differences between the DOX and PhB groups in intraoperative blood pressure (BP) fluctuations were found: < 170/100 mm Hg (34% vs. 44%, respectively, p = 0.42), >= 200/110 mm Hg (40% vs. 22%, respectively, p = 0.28). Mean greatest intraoperative systolic BP (195 +/- 53 vs. 166 +/- 42 mm Hg, p = 0.21) and diastolic BP (98 +/- 20 vs. 89 +/- 46 mm Hg, p = 0.21), and mean lowest intraoperative systolic BP (87 +/- 13 vs. 79 +/- 17 mm Hg, p = 0.25) and diastolic BP (49 +/- 8 vs. 46 +/- 12 mm Hg, p = 0.60) were not different between the DOX and PhB groups, respectively. Sodium nitroprusside was administrated in 30% DOX vs. 11% PhB patients (p = 0.25). Laparoscopic surgery was conducted in 97% DOX vs. 89% PhB patients (p = 0.64). Postoperative BP drop below 90/60 mm Hg was noted in 48% of the DOX vs. 43% of the PhB group (p = 0.56). Negative correlation was found between the length of DOX administration with maximal intraoperative systolic BP (r = -0.45, p = 0.006) and diastolic BP (r = -0.39, p = 0.019). CONCLUSIONS: There are no clinically relevant differences between patients with pheochromocytoma, who have been prepared for adrenalectomy with DOX or PhB. PMID- 28715067 TI - Viral heart disease - treatment. PMID- 28715068 TI - Severe mitral regurgitation is associated with increased copeptin levels in heart failure with reduced ejection fraction. AB - BACKGROUND AND AIM: The objective of this study was to assess the potential role of mitral regurgitation (MR) in the release of copeptin in heart failure patients with reduced ejection fraction (HFrEF). METHODS: The study included 63 patients of whom 33 had functional mild MR (Group 1) and 30 had functional severe MR (Group 2). The functional class of both groups was New York Heart Association (NYHA) Class III. Blood samples for the determination of plasma copeptin and B type natriuretic peptide (BNP) levels were obtained on the same day with the echo cardiographic examination. Standard echocardiographic studies were performed. RESULTS: Copeptin and BNP levels showed a substantial agreement in the whole study group (Kappa level: 0.607, p < 0.0001). Also, copeptin and BNP showed a strong correlation and were both increased and significantly higher in Group 2 than in Group 1 (p < 0.001 and p < 0.05, respectively). Left ventricular global longitudinal strain and left ventricular ejection fraction values were similar in both groups. The study population were divided into two subgroups on the basis of copeptin median level (6.4 ng/mL), and the prevalence of severe MR was significantly higher in the above-median-copeptin subgroup. A linear regression analysis showed that the presence of severe MR was the only independent predictor of high circulating plasma copeptin level (OR 7.5, 95% CI 2.8-12.1; p = 0.002). CONCLUSIONS: Severe MR is an independent predictor of elevated plasma copeptin level in HFREF irrespective of systolic function. PMID- 28715069 TI - The impact of diabetes on the association between epicardial fat thickness and extent and complexity of coronary artery disease in patients with non-ST elevation myocardial infarction. AB - BACKGROUND: Epicardial fat thickness (EFT) is associated with increased cardio metabolic risk. Recent studies have suggested that there is a strong relationship between diabetes and EFT. Although the relationship between EFT and coronary artery disease (CAD) is well known, the possible impact of diabetes on the relationship between EFT and extent and complexity of CAD was not fully investigated. AIM: We aimed to investigate the relationship between EFT and extent and complexity of CAD in patients with non-ST elevation myocardial infarction (NSTEMI) with and without diabetes. METHODS: We prospectively included 454 patients with NSTEMI (mean age: 61.8 +/- 10.4 years) in the present study. Patients were classified into two groups according to their diabetes status (diabetic group and non-diabetic group). EFT was measured by transthoracic echocardiography on the right ventricle in individuals having the left lateral decubitus position. SYNTAX score was used to define the extent and complexity of CAD. High-sensitivity C-reactive protein (hs-CRP) and other biochemical markers were measured in all participants. RESULTS: Diabetic patients had higher EFT values compared with non-diabetics (p < 0.05). EFT is independently associated with diabetes, SYNTAX score, and hs-CRP in all patients (p < 0.05, for all). When patients were divided into two groups, as diabetic and non-diabetic, the association between EFT and SYNTAX score was stronger in diabetic patients compared with non-diabetics (r = 0.635; p < 0.001 vs. r = 0.179; p = 0.003). CONCLUSIONS: Epicardial fat thickness is associated with SYNTAX score in both diabetic and non-diabetic patients. Furthermore, there is a stricter relationship between EFT and SYNTAX score in diabetic patients. PMID- 28715070 TI - Evaluation of the relationship between renal resistive index and extent and complexity of coronary artery disease in patients with acute coronary syndrome. AB - BACKGROUND: Despite advances in cardiovascular medicine, acute coronary syndrome (ACS) is still a major cause of morbidity and mortality worldwide. Synergy between percutaneous coronary intervention with TAXUSTM and Cardiac Surgery (SYNTAX) score is used to determine the extent and complexity of coronary artery disease (CAD). Renal resistive index (RRI), a renal Doppler ultrasound parameter, is used to detect renal haemodynamics. Although some risk factors for CAD, including hypertension and diabetes mellitus, were demonstrated to have an association with RRI; a direct relationship between the presence, extent, and complexity of CAD and RRI has not been investigated yet. AIM: In this study, we evaluated the relationship between RRI and SYNTAX score in patients with ACS. METHODS: This cross-sectional study enrolled 235 patients who were diagnosed with ACS and underwent coronary angiography at our tertiary clinic between February 2016 and August 2016. Regarding clinical presentation, 112 patients were diagnosed with non-ST-segment elevation ACS (NSTE-ACS) and 123 patients were diagnosed with ST-segment elevation ACS (STE-ACS). The patients' demographic, clinical, laboratory, echocardiographic data, SYNTAX scores and measurements of renal Doppler ultrasound parameters, including RRI, renal pulsatility index (RPI) and acceleration time (AT) were recorded. RESULTS: Among 235 patients, 112 (47.7%) were diagnosed with NSTE-ACS and 123 (52.3%) were diagnosed with STE-ACS. Mean SYNTAX score and RRI of patients with NSTE-ACS and STE-ACS were 15.4 and 0.69, 21.1 and 0.67, respectively. The SYNTAX score was associated with gender, height, plasma uric acid level, left atrial diameter, left ventricular (LV) end systolic and end-diastolic diameter, RPI, and RRI in patients with NSTE-ACS, as well as with low-density lipoprotein-cholesterol, total cholesterol, ejection fraction, and LV end-systolic diameter in patients with STE-ACS (p < 0.05 for each variable). RRI was significantly associated with age, haemoglobin level, left atrial diameter, SYNTAX score, AT, and RPI in patients with NSTE-ACS, as well as with weight, body mass index, interventricular septum thickness at diastole, LV posterior wall thickness at diastole, LV ejection fraction, and RRI in patients with STE-ACS. Multivariate logistic regression analysis demonstrated that LV end-systolic diameter (beta = 0.385, 95% CI 1.065-2.029, p = 0.019), RRI (beta = 32.230, 95% CI 5343.15-2.E+24, p = 0.008), and RPI (beta = -7.439, 95% CI 0.000-0.231, p = 0.015) were independent predictors of moderate to high SYNTAX score in patients with NSTE-ACS. CONCLUSIONS: Non-invasively detected RRI is closely associated with the extent and complexity of CAD in patients with NSTE ACS. However, there is a need for randomised, controlled studies involving wider populations. PMID- 28715071 TI - The influence of ablation power reduction associated with oesophagus location on pulmonary vein isolation results in patients with paroxysmal atrial fibrillation: six-month follow-up. AB - BACKGROUND: Catheter ablation of atrial fibrillation (AF) could be associated with a thermal oesophageal (EO) injury. To avoid this complication intraluminal EO temperature monitoring and ablation power reduction at the areas with excessive heating could be used. However, the reduced energy could limit the ablation lesion depth, without creation of lasting transmural scar and influence on long-term ablation results. AIM: The primary goal was to evaluate the homogeneity of forced ablation power reduction due to excessive EO heating in different parts of the left atrium. The secondary goal was to assess the influence of power reduction in different EO locations on long-term AF recurrence. METHODS: We examined retrospectively 109 consecutive patients with symptomatic, medically refractory paroxysmal AF, who underwent pulmonary vein isolation using radiofrequency ablation. In 40.4% of the patients the EO course was central (group B) left atrium posterior wall, in 31.2% it was left sided (group A), and in 28.4% it was right sided (group C). RESULTS: The maximal measured temperature (41.0 +/- 1.0 vs. 39.2 +/- 1.5 vs. 40.6 +/- 0.7 degrees C) and forced ablation power (15.9 +/- 5.6 vs. 23.5 +/- 6.1 vs. 17.4 +/- 5.7 W) differed significantly according to the EO course (A, B, C, respectively). In six month follow-up 76.15% of patients were free of arrhythmias. There was no statistically significant difference between groups (A-C) regarding the AF recurrence rate: 32.4% vs. 20.5% vs. 19.4% (p = 0.37). CONCLUSIONS: The maximal intraluminal EO temperatures and the necessary level of power reduction during AF ablation are inhomogeneous in different parts of the left atrium, but they are not associated with different six-month follow-up results. PMID- 28715072 TI - Association of mean platelet volume with presence of non-viable myocardium in ischaemic cardiomyopathy. AB - BACKGROUND: Parameters derived from complete blood count, such as mean platelet volume (MPV), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR), have recently been proposed as measures of inflammation in addition to C-reactive protein (CRP), a classical inflammatory marker. Significant association of these parameters with atherosclerosis and complications have increasingly been reported. AIM: The aim of the study is to evaluate the relationship between these parameters and the presence of myocardial viability assessed with positron emission tomography (PET) in patients with ischaemic cardiomyopathy (ICM). METHODS: A total of 122 ICM patients who had undergone PET were enrolled in this study. The patients were dichotomised depending on the presence of transmural scar. Group 1 consisted of 21 patients who had transmural scar tissue only, who were accepted as the group having non-viable myocardium. Group 2 consisted of 101 patients who had hibernation and/or non-transmural scar, who were accepted as the group having viable myocardium. Haematological parameters within 30 days of PET imaging were retrospectively analysed. RESULTS: There were no significant differences between the two groups regarding values of white blood cell, neutrophil, lymphocyte, platelet, haemoglobin, red cell distribution width, CRP, PLR, and NLR. Patients with non-viable myocardium have significantly higher levels of MPV (p = 0.002). In multiple logistic regression analysis, MPV (odds ratio [OR] = 0.373, 95% confidence interval [CI] 0.20-0.69, p = 0.002), was identified as an independent predictor of non-viable myocardium. In receiver-operator characteristic (ROC) analysis, a cut-point of 8.19 identified patients with non-viable myocardium (area under curve: 0.72, 95% CI 0.60-0.84). An MPV value greater than 8.19 demonstrated a sensitivity of 76% and a specificity of 55%. ? CONCLUSIONS: The present study showed that MPV is an inexpensive, clinical, and routinely measurable parameter that is associated with the presence of viable myocardium in ICM. PMID- 28715073 TI - Platelet distribution width and plateletcrit: novel biomarkers of ST elevation myocardial infarction in young patients. AB - BACKGROUND: Platelets play a central role in myocardial infarction, and platelet activity can be evaluated with platelet indices, including platelet distribution width (PDW) and plateletcrit (PCT). These indices have been demonstrated as markers of prothrombotic state in cardiovascular diseases. AIM: Therefore, we aimed to investigate, the usefulness of these biomarkers in ST-elevation myocardial infarction (STEMI) in young patients. METHODS: This cross-sectional study consisted of 565 subjects who were classified into three groups: group 1 (168 young patients with STEMI), group 2 (173 non-young patients with STEMI), and group 3 (224 age-matched controls with angiographically normal coronary arteries). Male patients aged under 45 years and female patients aged under 55 years were defined as young STEMI. RESULTS: In group 1, PDW and PCT (17.2 +/- 0.67, 0.249 +/- 0.05, respectively) were significantly higher than the other groups (group 2, 16.4 +/- 0.56, 0.231 +/- 0.04; group 3, 15.1 +/- 0.63, 0.227 +/- 0.04). PDW and PCT had moderate negative correlation (r = -0.305, r = -0.330, respectively) with age and moderate positive correlation with peak creatine kinase MB (r = 0.259, r = 0.320, respectively). At multivariate analysis, adjusted for other factors, 1 fL increase in PDW levels was 13.5% more likely to be associated with young STEMI, and similarly, a 1% increase in PCT levels was 18.9% more likely associated with young STEMI. CONCLUSIONS: Platelet distribution width and plateletcrit levels seem to be independent markers of STEMI in young patients and may reflect prothrombotic state in this specific population. PMID- 28715074 TI - Contemporary methods for the treatment of pulmonary embolism - is it prime-time for percutaneous interventions? PMID- 28715075 TI - Fifteen-year mortality trends due to cardiovascular diseases in Poland using standard expected years of life lost, 2000-2014. AB - BACKGROUND: Measures presenting the number of years of lost life point out social and economic aspects of premature mortality. AIM: The aim of the study was to determine trends and pace of changes in years of life lost, in inhabitants of Poland, in 2000-2014, due to cardiovascular diseases (CVD). METHODS: The study material was a database including 2,587,141 death certificates of Polish inhabitants who died of CVD in 2000-2014. We applied the standard expected years of life lost (SEYLL) indicators per living person (SEYLLp) and per death (SEYLLd) to calculate life years lost. We also estimated annual percentage changes (APC) and average annual percentage changes (AAPC) in the SEYLL indicators. RESULTS: In 2000 the SEYLLp index due to CVD was 860.3 years per 10,000 males and 586.9 years per 10,000 females. In 2000-2004 the indices were decreasing and the average annual rate was -0.8% in the male group and -1.2% in the female group. Eventually, in 2014 its values were 721.4 years per 10,000 males and 475.6 years per 10,000 females. The respondents were losing years of life due to ischaemic heart disease (IHD) most rapidly (AAPC = -3.3% in the male group and -3.2% in the female group) and due to cerebrovascular diseases (AAPC = -2.5% in the male group and AAPC = -3.3% in the female group). On the other hand, there was an increase in the number of years of life lost due to heart failure (HF) (AAPC = 5.7% in the male group and AAPC = 4.4% in the female group). In 2014 SEYLLp due to IHD were 207.3 per 10,000 males and 99.1 per 10,000 females, due to cerebrovascular diseases - 124.3 and 102.2, and due to HF - 155.3 and 104.9. Each male who died of CVD lost on average 19.1 years in the year 2000 and 17.0 years in the year 2014 (AAPC = -0.5%). Regarding women, SEYLLd values were 12.6 years in 2000 and 10.4 years in 2014 (AAPC = -1.4%). A decrease in the SEYLLd value was observed in all analysed causes of mortality, in both males and females. CONCLUSIONS: Among CVDs, IHD and cerebrovascular diseases contribute to the highest number of years of life lost in inhabitants of Poland. The constant decline in the average number of years of life lost by each person who died of CVD might result from implementation of more effective prophylaxis and more effective treatment, which extend lifespan. PMID- 28715076 TI - Increased plasma asymmetric dimethylarginine level is associated with ascending aorta dilatation: a case-control study. AB - BACKGROUND: Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase. AIM: We aimed to determine plasma ADMA levels in patients with ascending aorta dilatation in comparison to those without aorta dilatation, and to evaluate the diagnostic, predictive, and prognostic value of serum ADMA level for aorta dilatation. METHODS: This was a cross-sectional case-control study. A total of 104 consecutive patients (female/male, 35/69; mean age, 62.75 +/- 13.11 years) diagnosed with ascending aorta dilatation (>= 4.5 cm) on echocardiography (case group), and 52 age-and gender-matched patients (female/male, 17/35; mean age, 63.44 +/- 7.56 years) with normal aorta dimensions (<= 3.8 cm) (control group) were included. Routine biochemical and haematological analysis in addition to measurement of serum ADMA level were performed. RESULTS: The mean diameter of ascending aorta measured on echocardiography was 4.95 +/- 0.57 cm and 3.34 +/- 0.36 cm in patients with aorta dilatation and those without aorta dilatation, respectively (p < 0.001). Serum ADMA level was significantly higher in patients with aorta dilatation than in the control group (1.70 +/- 1.12 MUmol/L vs. 0.79 +/- 0.76 MUmol/L, respectively, p < 0.001). There was significant positive correlation between ADMA level and aortic diameter in Spearman correlation analysis (r = 0.317, p < 0.001). In linear regression analysis, ADMA was found to be a significant independent predictor of aorta diameter (Beta = 0.26, p < 0.001). Receiver-operator characteristic curve analysis also revealed that serum ADMA cut-off level over 0.29 MUmol/L predicts aorta dilatation (>= 4.5 cm) with 94% sensitivity and 92% specificity and with high ac-curacy (area under curve: 0.786; 95% confidence interval: 0.709-0.863, p < 0.001). CONCLUSIONS: Serum ADMA level is diagnostic for ascending aorta dilatation with high sensitivity and specificity, and should be considered for use in clinical diagnosis of aorta dilatation. PMID- 28715077 TI - Age- and gender-related peculiarities of patients with delirium in the cardiac intensive care unit. AB - BACKGROUND: The overall evidence base regarding delirium has been growing steadily over the past few decades. There has been considerable analysis of delirium concerning, for example, mechanically ventilated patients, patients in the general intensive care unit (ICU) setting, and patients with exclusively postoperative delirium. Nevertheless, there are few studies regarding delirium in a cardiovascular ICU (ICCU) setting and especially scarce literature about the particular features of delirium relating to patient age and gender. AIM: We aimed to determine particular features of delirium not induced by alcohol or other psychoactive substances, relating to patient age and gender in an ICCU setting. METHODS: An observational cross-sectional study was conducted to evaluate patients with delirium in a Lithuanian ICCU. From a sample of 19,007 ICCU admissions, 337 (1.8%) had documented delirium diagnosed through liaison and consultation with a psychiatrist and were included in the final analysis. The obtained data was then evaluated and analysed according to patients' gender and four categorised age groups: < 65 years, 65-74 years, 75-84 years, and >= 85 years. RESULTS: Female patients who experienced delirium demonstrated a higher prevalence of hypertension, hyponatraemia, heart failure, cardiac rhythm and conduction disorders, myocardial infarction (MI), and dementia. The men, who were on average seven years younger than the women, significantly more often had hypokalaemia, double- or triple-vessel coronary artery disease, and sepsis. Furthermore, MI, ST-segment elevated MI, and Killip class 4 were most frequent amongst patients less than 65 years of age. Moreover, the youngest patient group demonstrated the highest mortality. CONCLUSIONS: Our investigation presented a number of associated peculiarities related to gender and age. It was shown that delirium is a severe complication that more often affects men amongst patients < 65 years old and more frequently affects women in the age group of >= 85 years. Male patients < 65 years old, who develop delirium should be treated with more caution because they tend to have more serious forms of disorder and a poorer prognosis. PMID- 28715078 TI - Polish Stress Echocardiography Registry (Pol-STRESS registry) - a multicentre study. Stress echocardiography in Poland: numbers, settings, results, and complications. AB - BACKGROUND: Stress echocardiography (SE) is widely used in Europe. No collective data have been available on the use of SE in Poland until now. AIM: To evaluate the number of SE investigations performed in Poland, their settings, complications, and results. METHODS: In this retrospective survey, referral cardiology centres in Poland were asked to fill in a questionnaire regarding SE examinations performed from May 1, 2014 to May 1, 2015. RESULTS: The study included data from 17 university hospitals and large community hospitals, which performed 4611 SE exa-minations, including 4408 tests in patients investigated for coronary artery disease (CAD) and 203 tests to evaluate valvular heart disease (VHD). To evaluate CAD, all centres performed dobutamine SE (100%), 10 centres performed pacing SE (58.8%), while cycle ergometer SE and treadmill SE were performed by six (35.3%) and five (29.4%) centres, respectively. Dipyridamole SE was performed in one centre. All evaluated centres (100%) performed SE to evaluate low-flow/low-gradient aortic stenosis, eight (47%) performed SE to evaluate asymptomatic aortic stenosis, and also eight (47%) performed SE to evaluate mitral regurgitation. The mean number of examinations per year was 271 per centre. Most centres performed more than 100 examinations per year (11 centres, 64.7%). We did not identify any cardiac death during SE examination in any of the centres. Myocardial infarction occurred in three (0.07%) patients. Non-sustained ventricular tachycardia occurred in 52 (1.1%) SE examinations. The rates of minor complications were low. SE to evaluate CAD was more commonly performed in the hospital settings using cycle ergometer (72.6%), treadmill (87.6%), and low-dose dobutamine (68.0%), while a dipyridamole test was more frequently employed in ambulatory patients (77.6%). No significant differences between the rates of examina-tions performed in the ambulatory and hospital settings were found for high-dose dobutamine and pacing SE. Examinations to evaluate VHD were significantly more frequently performed in the hospital settings. SE examinations accounted for more than one third of all stress tests performed in the surveyed centres over the study period. CONCLUSIONS: Stress echocardiography is a safe diagnostic method, and major complications are very rare. Despite European recommendations, SE examinations to evaluate CAD are performed less frequently than electrocardiographic exercise tests, although they already comprise a significant proportion of all stress tests. It seems reasonable to promote SE further for the evaluation of both CAD and VHD. PMID- 28715079 TI - Recharge and Groundwater Flow Within an Intracratonic Basin, Midwestern United States. AB - The conservative nature of chloride (Cl- ) in groundwater and the abundance of geochemical data from various sources (both published and unpublished) provided a means of developing, for the first time, a representation of the hydrogeology of the Illinois Basin on a basin-wide scale. The creation of Cl- isocons superimposed on plan view maps of selected formations and on cross sections across the Illinois Basin yielded a conceptual model on a basin-wide scale of recharge into, groundwater flow within and through the Illinois Basin. The maps and cross sections reveal the infiltration and movement of freshwater into the basin and dilution of brines within various geologic strata occurring at basin margins and along geologic structures. Cross-formational movement of brines is also seen in the northern part of the basin. The maps and cross sections also show barriers to groundwater movement created by aquitards resulting in areas of apparent isolation/stagnation of concentrated brines within the basin. The distribution of Cl- within the Illinois Basin suggests that the current chemical composition of groundwater and distribution of brines within the basin is dependent on five parameters: (1) presence of bedrock exposures along basin margins; (2) permeability of geologic strata and their distribution relative to one another; (3) presence or absence of major geologic structures; (4) intersection of major waterways with geologic structures, basin margins, and permeable bedrock exposures; and (5) isolation of brines within the basin due to aquitards, inhomogeneous permeability, and, in the case of the deepest part of the basin, brine density effects. PMID- 28715080 TI - Asymmetric Alkynylation of beta-Ketoesters and Naphthols Promoted by New Chiral Biphenylic Iodanes. AB - The preparation of new chiral biphenylic lambda3 -iodane reagents bearing transferable alkynyl ligands is described. These reagents transfer their carbon based ligands onto beta-ketoesters with an enantiomeric excess (ee) up to 68 %, and most remarkably, enable the dearomative alkynylation of naphthols in good to high yields up to 84 % ee. PMID- 28715081 TI - Molecular constraints on resistance-tolerance trade-offs. AB - Plants have numerous mechanisms to cope with the negative effects of herbivory, including plant resistance, structural and chemical traits that reduce damage, and plant tolerance, the ability to compensate for tissues lost. It has been argued that resistance and tolerance represent alternate strategies and thus there should be a trade-off between resistance and tolerance. However, resistance and tolerance are controlled via the same molecular pathway, the oxidative pentose phosphate pathway and the process of endoreduplication. Endoreduplication is the replication of the genome without mitosis, which leads to an increase in cellular chromosome number. Increasing chromosome number and therefore gene copy number provides a means of increasing gene expression that has been shown to enhance compensation following herbivory. By measuring glucosinolate levels and seed production following the removal of apical dominance in genotypes of Arabidopsis thaliana we show that there is a positive association between tolerance and induced chemical defense. Similarly, the direct association between tolerance and resistance is demonstrated by genetically manipulating the endoreduplication pathway. By overexpressing ILP1, a positive regulator of endoreduplication, and thus compensation, we experimentally increased glucosinolate production and tolerance in the Col-0 genotype. We suggest that many herbaceous plants that endoreduplicate (~90%) would show a positive relationship between compensation and chemical defense, given that the molecular pathways are shared in common. We discuss these findings in light of contrasting results on measures of tolerance and resistance, given that the true relationship can be masked by ignoring genetic variation in endoreduplication and the timing of chemical measurement. PMID- 28715082 TI - Multimodel Groundwater Analysis in U.S. Courts: Potential Applications and Limitations. PMID- 28715083 TI - MacroEvoLution: A New Method for the Rapid Generation of Novel Scaffold-Diverse Macrocyclic Libraries. AB - Macrocycles are a structural class bearing great promise for future challenges in medicinal chemistry. Nevertheless, there are few flexible approaches for the rapid generation of structurally diverse macrocyclic compound collections. Here, an efficient method for the generation of novel macrocyclic peptide-based scaffolds is reported. The process, named here as "MacroEvoLution", is based on a cyclization screening approach that gives reliable access to novel macrocyclic architectures. Classification of building blocks into specific pools ensures that scaffolds with orthogonally addressable functionalities are generated, which can easily be used for the generation of structurally diverse compound libraries. The method grants rapid access to novel scaffolds with scalable synthesis (multi gram scale) and the introduction of further diversity at a late stage. Despite being developed for peptidic systems, the approach can easily be extended for the synthesis of systems with a decreased peptidic character. PMID- 28715084 TI - Synthesis of CuPF6 -(S)-BINAP loaded resin and its enantioselectivity toward phenylalanine enantiomers. AB - A type of resin-anchored CuPF6 -(S)-BINAP was synthesized and identified. The PS CuPF6 -(S)-BINAP resin was used to adsorb the phenylalanine enantiomers. The results showed that the adsorption capacity of PS-CuPF6 -(S)-BINAP resin toward L phenylalanine was higher than that of resin toward D-phenylalanine. PS-CuPF6 -(S) BINAP resin exhibited good enantioselectivity toward L-phenylalanine and D phenylalanine. The influence of phenylalanine concentration, pH, adsorption time, and temperature on the enantioselectivity of the resin were investigated. The results showed that the enantioselectivity of the resin increased with increasing the phenylalanine concentration, pH, and adsorption time, while it decreased with an increase in temperature. The causes for these influences are discussed. The highest enantioselectivity (alpha = 2.81) was obtained when the condition of phenylalanine concentration was 0.05 mmol/mL, pH was 8, adsorption time was 12 h, and temperature 5 degrees C. The desorption test for removing D/L-phenylalanine on PS-CuPF6 -(S)-BINAP resin was also investigated. The desorption ratios of D phenylalanine and L-phenylalanine at pH of 1 were 95.7% and 94.3%, respectively. This result indicated that the PS-CuPF6 -(S)-BINAP resin could be regenerated by shaking with an acidic solution. The reusability of the PS-CuPF6 -(S)-BINAP resin was also assessed and the resin exhibited considerable reusability. PMID- 28715085 TI - Nail histology processing techniques: What is happening around the world. PMID- 28715086 TI - Optimal Use of Transient Elastography and Acoustic Radiation Force Impulse to Stage Liver Fibrosis in HIV/HCV-Coinfected Patients in Clinical Practice. AB - OBJECTIVES: Liver fibrosis (LF) is crucial for the individualized management of patients with hepatitis C virus (HCV). We evaluated the concordance between two noninvasive methods for staging LF, transient elastography (TE) and acoustic radiation force impulse (ARFI), in patients coinfected with human immunodeficiency virus and HCV. We propose an algorithm for optimal use of both techniques in routine clinical practice. METHODS: A total of 89 human immunodeficiency virus/HCV-coinfected patients underwent TE and ARFI on the same day. The kappa index was used to assess concordance between the techniques. An algorithm combining ARFI and TE was proposed based on the independent factors associated with a kappa index greater than or equal to 0.70, obtained from a multiple regression analysis. We performed a cost-effectiveness analysis. The study was approved by our institutional review board and all patients signed the informed consent. RESULTS: Concordance between TE and ARFI for F2, F3, and F4 was 0.55, 0.59, and 0.69, respectively. Ultrasound normal spleen size (odds ratio [OR], 0.20; 95% confidence interval [CI], 0.05-0.91) and high viral load (OR, 0.36; 95% CI, 0.17-0.77) reduced the probability of agreement between TE and ARFI, whereas ultrasound normal left liver lobe size (OR, 3.32; 95% CI, 1.21 9.10) increased this probability. The algorithm revealed that LF was adequately assessed in 74.16%, with 25.84% of patients misclassified. The incremental cost effectiveness ratio of TE compared with ARFI to increase concordance by 1% was ?8.86. CONCLUSIONS: Concordance between TE and ARFI was moderate. In the algorithm we proposed, ARFI was cost-effective as a first technique for the staging of LF in the study population. PMID- 28715087 TI - Association Between Endometrial/Subendometrial Vasculature and Embryo Transfer Outcome: A Meta-analysis and Subgroup Analysis. AB - OBJECTIVES: To examine the association between endometrial/subendometrial vasculature and in vitro fertilization-embryo transfer (IVF-ET) and frozen embryo transfer (FET) outcomes. METHODS: A meta-analysis of studies using endometrial/subendometrial 3-dimensional ultrasound and power Doppler angiography was performed to examine the vascularization index (VI), flow index (FI), and vascularization-flow index (VFI) in pregnant and nonpregnant women. Ten articles were analyzed, including 895 pregnant women and 882 nonpregnant women. RESULTS: A subgroup analysis of the measuring time showed that the endometrial VI (standardized mean difference [SMD], 0.57; 95% confidence interval [CI], 0.40, 0.74; P < .00001), FI (SMD, 0.56; 95% CI, 0.33, 0.78; P < .00001), and VFI (SMD, 0.45; 95% CI, 0.28, 0.61; P < .00001) measured on the ET day, but not on the human chorionic gonadotropin (hCG) trigger day, were significantly higher in pregnant than nonpregnant women. Additionally, the subendometrial FI was significantly increased in pregnant women on the both hCG day (SMD, 0.68; 95% CI, 0.31, 1.06; P = .004) and ET day (SMD, 0.30; 95% CI, 0.08, 0.52; P = .007). A subgroup analysis of cycle type showed that the endometrial VI (SMD, 0.52; 95% CI, 0.30, 0.74; P < .00001), FI (SMD, 0.44; 95% CI, 0.22, 0.66; P = .0001), and VFI (SMD, 0.45; 95% CI, 0.23, 0.67; P = .03) on the ET day were significantly increased in pregnant women in the FET subgroup. CONCLUSIONS: The subendometrial FI on the hCG day and endometrial VI, FI, and VFI on the ET day are potentially associated with pregnancy occurrence during IVF-ET. The endometrial VI, FI, and VFI could help identify appropriate timing for FET. However, the accuracy of these indices in predicting pregnancy occurrence must be further evaluated in additional large-scale studies. PMID- 28715088 TI - Clinical limitations of the International Federation of Gynecology and Obstetrics (FIGO) classification of uterine fibroids. AB - OBJECTIVE: To determine the reproducibility of classifying uterine fibroids using the 2011 International Federation of Gynecology and Obstetrics (FIGO) staging system. METHODS: The present retrospective cohort study included patients presenting for the treatment of symptomatic uterine fibroids at the Gynecology Fibroid Clinic at Mayo Clinic, Rochester, USA, between April 1, 2013 and April 1, 2014. Magnetic resonance imaging of fibroid uteri was performed and the images were independently reviewed by two academic gynecologists and two radiologists specializing in fibroid care. Fibroid classifications assigned by each physician were compared and the significance of the variations was graded by whether they would affect surgical planning. RESULTS: There were 42 fibroids from 23 patients; only 6 (14%) fibroids had unanimous classification agreement. The majority (36 [86%]) had at least two unique answers and 4 (10%) fibroids had four unique classifications. Variations in classification were not associated with physician specialty. More than one-third of the classification discrepancies would have impacted surgical planning. CONCLUSION: FIGO fibroid classification was not consistent among four fibroid specialists. The variation was clinically significant for 36% of the fibroids. Additional validation of the FIGO fibroid classification system is needed. PMID- 28715089 TI - Drosophila mutants lacking octopamine exhibit impairment in aversive olfactory associative learning (Commentary on Iliadi et al. (2017)). PMID- 28715090 TI - Learning-based automated segmentation of the carotid artery vessel wall in dual sequence MRI using subdivision surface fitting. AB - PURPOSE: The quantification of vessel wall morphology and plaque burden requires vessel segmentation, which is generally performed by manual delineations. The purpose of our work is to develop and evaluate a new 3D model-based approach for carotid artery wall segmentation from dual-sequence MRI. METHODS: The proposed method segments the lumen and outer wall surfaces including the bifurcation region by fitting a subdivision surface constructed hierarchical-tree model to the image data. In particular, a hybrid segmentation which combines deformable model fitting with boundary classification was applied to extract the lumen surface. The 3D model ensures the correct shape and topology of the carotid artery, while the boundary classification uses combined image information of 3D TOF-MRA and 3D BB-MRI to promote accurate delineation of the lumen boundaries. The proposed algorithm was validated on 25 subjects (48 arteries) including both healthy volunteers and atherosclerotic patients with 30% to 70% carotid stenosis. RESULTS: For both lumen and outer wall border detection, our result shows good agreement between manually and automatically determined contours, with contour-to contour distance less than 1 pixel as well as Dice overlap greater than 0.87 at all different carotid artery sections. CONCLUSIONS: The presented 3D segmentation technique has demonstrated the capability of providing vessel wall delineation for 3D carotid MRI data with high accuracy and limited user interaction. This brings benefits to large-scale patient studies for assessing the effect of pharmacological treatment of atherosclerosis by reducing image analysis time and bias between human observers. PMID- 28715091 TI - Strongly Enhanced Photovoltaic Performance and Defect Physics of Air-Stable Bismuth Oxyiodide (BiOI). AB - Bismuth-based compounds have recently gained increasing attention as potentially nontoxic and defect-tolerant solar absorbers. However, many of the new materials recently investigated show limited photovoltaic performance. Herein, one such compound is explored in detail through theory and experiment: bismuth oxyiodide (BiOI). BiOI thin films are grown by chemical vapor transport and found to maintain the same tetragonal phase in ambient air for at least 197 d. The computations suggest BiOI to be tolerant to antisite and vacancy defects. All inorganic solar cells (ITO|NiOx |BiOI|ZnO|Al) with negligible hysteresis and up to 80% external quantum efficiency under select monochromatic excitation are demonstrated. The short-circuit current densities and power conversion efficiencies under AM 1.5G illumination are nearly double those of previously reported BiOI solar cells, as well as other bismuth halide and chalcohalide photovoltaics recently explored by many groups. Through a detailed loss analysis using optical characterization, photoemission spectroscopy, and device modeling, direction for future improvements in efficiency is provided. This work demonstrates that BiOI, previously considered to be a poor photocatalyst, is promising for photovoltaics. PMID- 28715092 TI - The origins of oral medicine in the Hippocratic collected works. AB - The collected works of Hippocrates describe for the first time in a systematic way a large number of oral diseases, such as ulcers, inflammations, abscesses and tumours from the epiglottis, mouth, tongue, palate, uvula and the sublingual area. Several of these case reports are remarkable for the accurate observation of clinical symptoms and signs, the aetiology, the pathogenesis and their therapeutic approach in relation to prognosis. The Hippocratic authors report cases of aphthae as part of a polysystemic disease, described many centuries later by Behcet and Adamantiades, while they associate features of splenomegaly from endemic malaria with gingivitis (ulitis). Benign lip ulcers, caused by sharp teeth bites, were distinguished from the difficult to treat herpes labialis (herpes) and from the necrotising nomae. Although staphylitis and angina (kynanche) were attributed to phlegm accumulation, they were recognised as true emergencies when they were associated with a swollen tongue and uvula. Several cases of kynanche with forward displacement of the first cervical vertebrae, atrophy of the uvula and oedema of the jaws are illustrated. A fatal outcome was anticipated in cases of phagedaenic ulcers of the teeth, causing necrosis and abscess formation. The therapeutic approach of oral diseases proceeded step by step, starting with simple regimens and progressing to invasive techniques, such as phlebotomy, surgical incisions for fluid drainage, and cauterisation. With the aim to avoid adverse events, special attention was paid to the correct timing of surgery and the maintenance of a patent airway with the insertion of small pharyngeal tubes. PMID- 28715093 TI - Photostriction of CH3 NH3 PbBr3 Perovskite Crystals. AB - Organic-inorganic hybrid perovskite materials exhibit a variety of physical properties. Pronounced coupling between phonon, organic cations, and the inorganic framework suggest that these materials exhibit strong light-matter interactions. The photoinduced strain of CH3 NH3 PbBr3 is investigated using high resolution and contactless in situ Raman spectroscopy. Under illumination, the material exhibits large blue shifts in its Raman spectra that indicate significant structural deformations (i.e., photostriction). From these shifts, the photostrictive coefficient of CH3 NH3 PbBr3 is calculated as 2.08 * 10-8 m2 W 1 at room temperature under visible light illumination. The significant photostriction of CH3 NH3 PbBr3 is attributed to a combination of the photovoltaic effect and translational symmetry loss of the molecular configuration via strong translation-rotation coupling. Unlike CH3 NH3 PbI3 , it is noted that the photostriction of CH3 NH3 PbBr3 is extremely stable, demonstrating no signs of optical decay for at least 30 d. These results suggest the potential of CH3 NH3 PbBr3 for applications in next-generation optical micro electromechanical devices. PMID- 28715094 TI - Drosophila mutants lacking octopamine exhibit impairment in aversive olfactory associative learning. AB - Octopamine is a biogenic amine in invertebrates that is considered a functional homolog of vertebrate norepinephrine, acting as a neurotransmitter, neuromodulator and neurohormone. Octopamine regulates many physiological processes such as metabolism, reproduction and different types of behaviour including learning and memory. Previous studies in insects led to the notion that acquisition of an olfactory memory depends on the octopaminergic system during appetitive (reward-based) learning, but not in the case of aversive (punishment based) learning. Here, we provide several lines of evidence demonstrating that aversive associative olfactory learning in Drosophila is also dependent on octopamine signalling. Specifically, we used Drosophila Tbetah (tyramine-beta hydroxylase) mutants, which lack octopamine and are female sterile, to determine whether octopamine plays a role in aversive learning. We show that Tbetah mutant flies exhibit a significant reduction in learning compared to control lines that is independent of either genetic background or the methods used to induce aversive olfactory memory. We also show that the learning deficits observed in Tbetah mutants are not due to defects in sensorimotor behaviours. Finally, to unambiguously demonstrate that octopamine synthesis plays a role in aversive olfactory learning, we performed rescue experiments using the Gal4/UAS system. We show that expression of UAS-Tbetah in octopamine/tyraminergic neurons using Tdc2 Gal4 in Tbetah null mutant flies fully rescued both the aversive learning defects and female sterility observed in Tbetah mutants. PMID- 28715095 TI - A Self-Sacrificing N-Methyltransferase Is the Precursor of the Fungal Natural Product Omphalotin. AB - Research on ribosomally synthesized and posttranslationally modified peptides (RiPPs) has led to an increasing understanding of biosynthetic mechanisms, mostly drawn from bacterial examples. In contrast, reports on RiPPs from fungal producers, apart from the amanitins and phalloidins, are still scarce. The fungal cyclopeptide omphalotin A carries multiple N-methylations on the peptide backbone, a modification previously known only from nonribosomal peptides. Mining the genome of the omphalotin-producing fungus for a precursor peptide led to the identification of two biosynthesis genes, one encoding a methyltransferase OphMA that catalyzes the automethylation of its C-terminus, which is then released and cyclized by the protease OphP. Our findings suggest a novel biosynthesis mechanism for a RiPP in which a modifying enzyme bears its own precursor peptide. PMID- 28715096 TI - Effect of avulsion storage media on periodontal ligament fibroblast differentiation. AB - BACKGROUND/AIM: An avulsed tooth must be stored in a solution which maintains periodontal ligament (PDL) cell viability. The aim of this study was to compare the effects of Hank's balanced salt solution (HBSS) and milk on the differentiation of PDL fibroblasts. MATERIALS AND METHODS: Eighteen extracted third molars, (n = 3 for each group), were immersed in HBSS, milk, and Dulbecco's modified Eagle medium-Ham's F12 (DMEM-F12) at 4 degrees C for 30- to 60 minutes or 12 hours. The growth dynamics of PDL fibroblasts were evaluated with cell proliferation graphics and population doubling time (PDT) values. Runt-related transcription factor 2 (RUNX2), receptor activator of nuclear factor kappa-B ligand (RANKL), and collagen type XII (COL12) expression were used to evaluate the differentiation of PDL fibroblasts. RESULTS: The percentage of cell numbers and PDT values of groups were statistically insignificant. In the HBSS groups, RUNX2 expression increased showing a direction to osteogenic differentiation of PDL fibroblasts. In the DMEM-F12 groups, RANKL expression increased, indicating there was a tendency for osteoclastogenic differentiation. In the milk groups, RUNX2 expression decreased while other markers were stable showing PDL fibroblasts could protect fibroblast identity. CONCLUSIONS: In terms of protecting fibroblast identity and resistance to differentiation, milk was more effective than HBSS. PMID- 28715097 TI - Human GABA, Receptor alphal and alpha3 Subunits Genes and Alcoholism. AB - gamma-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain. GABA effects are largely mediated by binding to the postsynaptic GABAA receptor, causing the opening of an integral chloride-ion channel. The GABAA antagonists picrotoxin and bicuculline reduce some ethanol-induced behaviors, such as motor impairment, sedation, and hypnosis. The role of this receptor in alcoholism is further supported by effective alleviation of alcohol withdrawal symptoms by GABAA agonists. To determine the role of the GABA, receptor (GABR) genes in the development of alcoholism, we have used alpha1 and alpha3 simple sequence repeat polymorphisms in a sample of unrelated alcoholics, alcoholic probands with both parents, and psychiatrically normal controls. For the GABRalpha1 gene, the differences between allele frequencies, when all alleles were compared together, were not significant between total alcoholics, subtypes of alcoholics, and normal controls. However, for GABRalpha3 , the differences between total alcoholics and normal controls were significant when all alleles were compared together. The differences between subtypes of alcoholics and normal controls were not significant. The results of haplotype relative risk analysis for both genes, GABRalpha1 and GABRalpha3 , were also negative. It is possible that the sample size in the haplotype relative risk is too small to have power to detect the differences in transmitted versus nontransmitted alleles. There is a need for a replication study in a large family sample, that will allow haplotype relative risk or affected sib-pair analysis. PMID- 28715098 TI - Association between Alcohol Use and Smoking in Adolescent and Young Adult Twins: A Bivariate Genetic Analysis. AB - The association between alcohol use and smoking was examined in a large population-based sample of Dutch twins consisting of three age groups; young adolescent twins aged 12-14 years (n= 650 twin pairs), 15-16-years-old adolescent twins (n= 705 twin pairs), and young adult twins aged 17-25 years (n= 1266 twin pairs). For all three age groups, alcohol use and smoking were correlated (r= 0.5 0.6). Adolescents and young adults who smoked were more likely to drink alcohol than nonsmokers. The relation between alcohol use and smoking was also found within a twin pair; alcohol use in one twin was correlated with smoking in the cotwin. This finding suggested that familial factors contribute to the association between alcohol and tobacco use. With a bivariate genetic model, it was examined to what extent the comorbidity was due to genetic and environmental factors that predispose to both alcohol use and smoking. The genetic analyses showed that the underlying factors that influence alcohol and tobacco use and cause their association were different for adolescent and young adult twins. Initiation of alcohol use and smoking in adolescents (aged 12-16 years) was substantially influenced by the same shared environmental features. Alcohol and tobacco use in young adults were associated due to the same genetic risk factors. PMID- 28715099 TI - Forskolin Delays the Ethanol-Induced Desensitization of Hypothalamic beta Endorphin Neurons in Primary Cultures. AB - Ethanol and its metabolite acetaldehyde have been shown to stimulate immunoreactive beta-endorphin (IR-beta-EP) secretion from hypothalamic neurons in primary cultures. Also, chronic ethanol and acetaldehyde have been shown to cause the development of tolerance and desensitization of these neurons. In this study, we determined some of the cellular events leading to desensitization of the function of beta-endorphin (p-EP) Secretory neurons. The fetal hypothalamic cells were treated with various doses of ethanol (W and 50 mM) or acetaldehyde (6.25,12.5, and 25 mM) for 6 hr or treated with these drugs at 12 hr intervals for 72 hr. Determination of IR-beta-EP concentrations in the media revealed that ethanol increased IR-beta-EP secretion from these cultures for 12 hr; after this period, the cultured cells did not respond to ethanol. Acetaldehyde stimulated IR beta-EP secretion from this culture for a period of 48 hr, but the IR-beta-EP secretory response to acetaldehyde reduced gradually with time during the first 48-hr period and reached the basal level at 72 hr. The desensitization of beta-EP neurons 12 hr after treatment with alcohol did not seem to be related to the loss of viable cells, because chronic ethanol exposures did not produce any effect on cell viability. However, reduced IR- beta-EP secretory response to acetaldehyde with time was associated with the time-dependent increase in cell death. Pretreatment of cultures with a cAMP analog, forskolin, increased the activity of functional beta-EP neurons and delayed the ethanol desensitization effects on these neurons. Pretreatment of forskolin did not delay the acetaldehyde desensitization of beta-EP neurons, but protected these cells from acetaldehyde toxicity. These results suggest that (i) chronic treatment with ethanol desensitizes beta-EP-secreting neurons due to reduced cellular functions and (ii) chronic acetaldehyde reduces beta-EP neurotransmission due to cell death. Furthermore, data suggest for the first time that cAMP pretreatments delay the ethanolinduced desensitization of opioid neurons and partly protect against the neurotoxic action of acetaldehyde on opioid neurons. PMID- 28715100 TI - Personality and Substance Use Disorders: I. Effects of Gender and Alcoholism Subtype. AB - The relationship between alcoholism and self-rated personality was explored in a community-ascertained sample of 303 male and 103 female alcoholics, and 304 male and 770 female nonalcoholics. Alcoholics met DSM-Ill-R lifetime criteria for alcohol dependence; personality was assessed using the Multidimensional Personality Questionnaire. Compared with controls, alcoholics scored significantly higher on all indicators of negative emotionality, and consistently lower on all indicators of constraint. Individual effect sizes were moderate in both the male and female samples. A subsample of severe male alcoholics, identified by cluster analysis, was characterized by relatively early onset of problem drinking and relatively high antisociality and familial loading of problem drinking; they were also more extreme than moderate male alcoholics on negative emotionality and constraint. When taken in aggregate, personality risk appears to be associated with a continuum of alcoholic risk such that individuals extreme in both negative emotionality and behavioral disinhibition have especially high rates of alcoholism. PMID- 28715101 TI - Alcohol Expectancies and Drinking Characteristics in Parents of Children with Attention Deficit Hyperactivity Disorder. AB - Alcohol expectancies, drinking characteristics, and their association were examined in 587 adults: 431 parents of children with attention deficit hyperactivity disorder (ADHD) and 156 parents of children without ADHD. In addition to examining both traditional and parenting-specific alcohol expectancies for these adults, risk variables cutting across the two groups were considered: single parenthood and male gender. Few differences in mean expectancy levels were found between parents of children with and without ADHD, between single and married mothers, and between men and women. Furthermore, expectancies did not predict drinking differently across groups. However, there was some support for the utility of assessing parental expectations of alcohol's effects on interactions with children, and there were robust and interesting effects of socioeconomic status on expectancies and drinking. Single mothers also reported consuming higher quantities of alcohol than married mothers. Findings are discussed in terms of the link between ADHD and alcoholism, the ability of alcohol expectancies to explain drinking differences between high risk groups, the effect of socioeconomic status on these variables, and single motherhood as a vulnerability factor for increased drinking. PMID- 28715102 TI - The Nitric Oxide Synthase Inhibitor l-NAME (Nomega-Nitro-L-Arginine Methyl Ester) Does Not Produce Discriminative Stimulus Effects Similar to Ethanol. AB - N-methyl-d-waspartate (NMDA) antagonists substitute for the discriminative stimulus effects of ethanol, indicating that a component of ethanol's behavioral activity is produced via blockade of NMDA receptor/channel function. Recently, it has been reported that ethanol inhibits NMDA-stimulated nitric oxide synthase (NOS) activity in cortical neurons, thereby decreasing the formation of nitric oxide (NO) in the brain. These findings suggest that some of the behavioral effects of ethanol may be mediated by inactivation of NOS. The present study examined the role of NO formation in mediating the discriminative stimulus effects of ethanol. To address this hypothesis, an NOS inhibitor, Nomega-nitro-L arginine methyl ester (l-NAME) and an NMDA competitive antagonist, (d)-4-(3 phosphonoprop-2-enyl)piperazine-2-carboxylic acid (CPPene), were administered to two groups of rats trained to discriminate 1.5 g/kg of ethanol (n= 6) or 2.0 gkg (n= 7) of ethanol from water. After training, dose ranges of CPPene (3 to 17 mg/kg, ip) and l-NAME (100 to 780 mg/kg, ip) were tested for ethanol-like effects. l-NAME was also tested under a range of pretreatment times (20,60,90, and 120 min). An additional group of rats trained to discriminate 2.0 g/kg (n = 7) of ethanol from water was also tested with CPPene (10 mg/kg, ip) and l-NAME (100 and 300 mg/kg, ip) to verify data gathered from the original 2.0 gkg of ethanol group tested with l-NAME after a 20-minute pretreatment. Although overall, 17 of 20 animals trained to discriminate ethanol from water exhibited complete substitution of CPPene for ethanol, l-NAME, without affecting response rates, did not consistently substitute for either 1.5 g/kg or 20 g/kg of ethanol. These results indicate that inhibition of NO formation is less effective than direct NMDA receptor antagonism in producing ethand-like discriminative stimulus effects. PMID- 28715103 TI - Subject-Collateral Reports of Drinking in Inpatient Alcoholics with Comorbid Mental Disorders. AB - Verbal self-report continues to be the primary method by which clinicians and researchers obtain measurements of a person's past drinking. In addition, collateral reports are an important second measure of an individual's drinking behavior. Although there is considerable confidence in the use of collateral reports as a measure of drinking in individuals with only a diagnosis of alcohol abuse or dependence, information about subject-collateral reports for alcoholics with a comorbid mental disorder is lacking. Given both that symptoms of mental illness can negatively impact cognitive processes relevant to the recall of information, and that such symptoms can be influenced by alcohol consumption, it is important to be confident in the reports of alcohol use in dually diagnosed individuals. This study examined subject-collateral reports of alcohol use in two groups of inpatient alcoholics: those meeting DSM-Ill-R criteria for an alcohol use disorder and a current mental disorder (n= 91) and those meeting criteria for an alcohol use disorder only (n= 93). Overall, the results show that the self reports of alcoholics with comorbid mental disorders are generally valid. In addition, subject-collateral agreement was found to be similar for both groups, with no consistent tendency to overreport or underreport alcohol or drug use in either group. Importantly, psychological symptom severity and cognitive functioning were not related to subject-collateral agreement. However, less frequent contact between subject and collateral had a more negative impact on subject-collateral agreement for the dual diagnosis group, compared with the alcohol-only group. Recommendations for enhancing the accuracy of self-reports of drinking in a dual diagnosis population are discussed. PMID- 28715104 TI - Introduction to the Symposium. AB - In June 1995, the National Institute on Alcohol Abuse and Alcoholism sponsored a symposium on "Alcohol and Osteoporosis" at the Research Society on Alcoholism in Steamboat Springs, Colorado. The goals of the symposium were to: (a) disseminate current information on the effects of alcohol on osteoporosis, both deleterious and beneficial; (b) discuss the mechanisms, direct and indirect, by which alcohol affects bone remodeling; and (c) encourage research in the area of alcohol and osteoporosis. This report provides an introduction to the problem, as well as to the three scientific presentations. Key Words: Alcohol, Osteoporosis, Bone. PMID- 28715105 TI - A Simulation-based Approach to Measuring Team Situational Awareness in Emergency Medicine: A Multicenter, Observational Study. AB - OBJECTIVES: Team situational awareness (TSA) is critical for effective teamwork and supports dynamic decision making in unpredictable, time-pressured situations. Simulation provides a platform for developing and assessing TSA, but these efforts are limited by suboptimal measurement approaches. The objective of this study was to develop and evaluate a novel approach to TSA measurement in interprofessional emergency medicine (EM) teams. METHODS: We performed a multicenter, prospective, simulation-based observational study to evaluate an approach to TSA measurement. Interprofessional emergency medical teams, consisting of EM resident physicians, nurses, and medical students, were recruited from the University of Washington (Seattle, WA) and Wayne State University (Detroit, MI). Each team completed a simulated emergency resuscitation scenario. Immediately following the simulation, team members completed a TSA measure, a team perception of shared understanding measure, and a team leader effectiveness measure. Subject matter expert reviews and pilot testing of the TSA measure provided evidence of content and response process validity. Simulations were recorded and independently coded for team performance using a previously validated measure. The relationships between the TSA measure and other variables (team clinical performance, team perception of shared understanding, team leader effectiveness, and team experience) were explored. The TSA agreement metric was indexed by averaging the pairwise agreement for each dyad on a team and then averaging across dyads to yield agreement at the team level. For the team perception of shared understanding and team leadership effectiveness measures, individual team member scores were aggregated within a team to create a single team score. We computed descriptive statistics for all outcomes. We calculated Pearson's product-moment correlations to determine bivariate correlations between outcome variables with two-tailed significance testing (p < 0.05). RESULTS: A total of 123 participants were recruited and formed three-person teams (n = 41 teams). All teams completed the assessment scenario and postsimulation measures. TSA agreement ranged from 0.19 to 0.9 and had a mean (+/-SD) of 0.61 (+/-0.17). TSA correlated with team clinical performance (p < 0.05) but did not correlate with team perception of shared understanding, team leader effectiveness, or team experience. CONCLUSIONS: Team situational awareness supports adaptive teams and is critical for high reliability organizations such as healthcare systems. Simulation can provide a platform for research aimed at understanding and measuring TSA. This study provides a feasible method for simulation-based assessment of TSA in interdisciplinary teams that addresses prior measure limitations and is appropriate for use in highly dynamic, uncertain situations commonly encountered in emergency department systems. Future research is needed to understand the development of and interactions between individual-, team-, and system (distributed)-level cognitive processes. PMID- 28715106 TI - Erythema multiforme as a complication of vaccination (occupational accident). PMID- 28715107 TI - Using Models to Identify the Best Data: An Example from Northern Wisconsin. PMID- 28715109 TI - Polymeric monolith column composited with multiwalled carbon nanotubes-beta cyclodextrin for the selective extraction of psoralen and isopsoralen. AB - A polymeric column that contains multiwalled carbon nanotubes-beta-cyclodextrin composite was developed. The composite was wrapped into the poly(butyl methacrylate-ethylene dimethacrylate) monolith column (0.76 mm id and 10 cm in length). The column was then applied for the online solid-phase microextraction of psoralen and isopsoralen from Fructus Psoraleae. Following microextraction, the coumarins were quantified by high-performance liquid chromatography with C18 separation column and UV detection. The effects of sample flow rate, sample volume, and pH value were optimized. The method showed low limits of detection (20 pg/mL, S/N = 3) for both psoralen and isopsoralen. Finally the method was successfully applied to the determination of psoralen and isopsoralen in spiked herb extracts and rat plasma where it gave recoveries that ranged between 93.2 and 102.1%. The empty hydrophobic cavities of beta-cyclodextrin and the hydrophobicity of multiwalled carbon nanotubes provided specific extraction capability for psoralen and isopsoralen. PMID- 28715108 TI - Ivermectin activates GIRK channels in a PIP2 -dependent, Gbetagamma -independent manner and an amino acid residue at the slide helix governs the activation. AB - KEY POINTS: Ivermectin (IVM) is a widely used antiparasitic drug in humans and pets which activates glutamate-gated Cl- channel in parasites. It is known that IVM binds to the transmembrane domains (TMs) of several ligand-gated channels, such as Cys-loop receptors and P2X receptors. We found that the G-protein-gated inwardly rectifying K+ (GIRK) channel, especially GIRK2, is activated by IVM directly in a Gbetagamma -independent manner, but the activation is dependent on phosphatidylinositol-4,5-biphosphate (PIP2 ). We identified a critical amino acid residue of GIRK2 for activation by IVM, Ile82, located in the slide helix between the TM1 and the N-terminal cytoplasmic tail domain (CTD). The results demonstrate that the TM-CTD interface in GIRK channel, rather than the TMs, governs IVM mediated activation and provide us with novel insights on the mode of action of IVM in ion channels. ABSTRACT: Ivermectin (IVM) is a widely used antiparasitic drug in humans and pets which activates glutamate-gated Cl- channel in parasites. It is also known that IVM binds to the transmembrane domains (TMs) of several ligand-gated channels, such as Cys-loop receptors and P2X receptors. In this study, we found that the G-protein-gated inwardly rectifying K+ (GIRK) channel is activated by IVM directly. Electrophysiological recordings in Xenopus oocytes revealed that IVM activates GIRK channel in a phosphatidylinositol-4,5 biphosphate (PIP2 )-dependent manner, and that the IVM-mediated GIRK activation is independent of Gbetagamma subunits. We found that IVM activates GIRK2 more efficiently than GIRK4. In cultured hippocampal neurons, we also observed that IVM activates native GIRK current. Chimeric and mutagenesis analyses identified an amino acid residue unique to GIRK2 among the GIRK family, Ile82, located in the slide helix between the TM1 and the N-terminal cytoplasmic tail domain (CTD), which is critical for the activation. The results demonstrate that the TM-CTD interface in GIRK channels, rather than the TMs, governs IVM-mediated activation. These findings provide us with novel insights on the mode of action of IVM in ion channels that could lead to identification of new pharmacophores which activate the GIRK channel. PMID- 28715110 TI - Irreversible Protein Labeling by Paal-Knorr Conjugation. AB - The application of new chemical reactions in a biological context has advanced bioconjugation methods for both fundamental research and commercial arenas. Recent adaptations of reactions such as Huisgen 1,3-dipolar or Diels-Alder cycloadditions have enabled the labeling of specific residues in biomolecules by the attachment of molecules carrying azides, alkynes, or strained alkenes. Although these are fundamental tools, there is a need for the discovery of reactions that can label native proteins. We report herein the adaptation of the Paal-Knorr reaction to label lysine residues in proteins via pyrrole linkages. PMID- 28715111 TI - Identification of a novel HLA-B allele, HLA-B*40:238, in a Taiwanese individual. AB - The HLA-B*40:238 allele has one non-synonymous transversion from HLA-B*40:01:01 at nucleotide position 484. PMID- 28715113 TI - Calcium deposition in photocrosslinked poly(Pro-Hyp-Gly) hydrogels encapsulated rat bone marrow stromal cells. AB - Reproducing the features of the extracellular matrix is important for fabricating three-dimensional (3D) scaffolds for tissue regeneration. A collagen-like polypeptide, poly(Pro-Hyp-Gly), is a promising material for 3D scaffolds because of its excellent physical properties, biocompatibility, and biodegradability. In this paper, we present a novel photocrosslinked poly(Pro-Hyp-Gly) hydrogel as a 3D scaffold for simultaneous rat bone marrow stromal cell (rBMSC) encapsulation. The hydrogels were fabricated using visible-light photocrosslinking at various concentrations of methacrylated poly(Pro-Hyp-Gly) (20-50 mg/ml) and irradiation times (3 or 5 min). The results show that the rBMSCs encapsulated in the hydrogels survived 7 days of incubation. Calcium deposition on the encapsulated rBMSCs was assessed with scanning electron microscope observation, Alizarin Red S, and von Kossa staining. The most strongly stained area was observed in the hydrogel formed with 30 mg/ml of methacrylated poly(Pro-Hyp-Gly) with 5-min irradiation. These findings demonstrate that poly(Pro-Hyp-Gly) hydrogels support rBMSC viability and differentiation, as well as demonstrating the feasibility of using poly(Pro-Hyp-Gly) hydrogels as a cytocompatible, biodegradable 3D scaffold for tissue regeneration. PMID- 28715112 TI - Effects of free air carbon dioxide enrichment (FACE) on nitrogen assimilation and growth of winter wheat under nitrate and ammonium fertilization. AB - A 2-year Free Air CO2 Enrichment (FACE) experiment was conducted with winter wheat. It was investigated whether elevated atmospheric CO2 concentration (e[CO2 ]) inhibit nitrate assimilation and whether better growth and nitrogen acquisition under e[CO2 ] can be achieved with an ammonium-based fertilization as it was observed in hydroponic culture with wheat. Under e[CO2 ] a decrease in nitrate assimilation has been discussed as the cause for observed declines in protein concentration in C3 cereals. Wheat was grown under ambient [CO2 ] and e[CO2 ] (600 ppm) with three levels (deficiency, optimal, and excessive) of nitrate-based fertilization (calcium ammonium nitrate; CAN) or with optimal ammonium-based fertilization. Ammonium fertilization was applied via injection of an ammonium solution into the soil in the 1st year and by surface application of urea combined with nitrification inhibitors (UNI) in the 2nd year. Results showed that ammonium-based fertilization was successfully achieved in the 2nd year with respect to nitrification control, as soil ammonium concentration was considerably higher over the growing season for UNI fertilized plots compared to optimal CAN plots. Also, stem nitrate concentration, flag leaf nitrate reductase activity, and transcript levels were lower in UNI fertilized plants compared to optimal CAN. Regarding the e[CO2 ] effect on nitrate reductase activity and transcript levels, no alteration could be observed for any nitrogen fertilizer treatment. Flag leaf growth was stimulated under e[CO2 ] leading to an enhanced nitrate reductase activity referred to m2 ground area at late flowering being in line with a higher nitrogen acquisition under e[CO2 ]. Moreover, nitrogen acquisition was considerably higher in nitrate fertilized plants compared to ammonium fertilized plants under e[CO2 ]. Our results obtained under field conditions show that a change from nitrate- to ammonium-based fertilization will not lead to a better growth and nitrogen acquisition of winter wheat under future e[CO2 ]. PMID- 28715114 TI - Rare case of obstructive duodenal phytobezoar caused by two lipomas. PMID- 28715115 TI - Membrane topology and identification of key residues of EaDAcT, a plant MBOAT with unusual substrate specificity. AB - Euonymus alatus diacylglycerol acetyltransferase (EaDAcT) catalyzes the transfer of an acetyl group from acetyl-CoA to the sn-3 position of diacylglycerol to form 3-acetyl-1,2-diacyl-sn-glycerol (acetyl-TAG). EaDAcT belongs to a small, plant specific subfamily of the membrane bound O-acyltransferases (MBOAT) that acylate different lipid substrates. Sucrose gradient density centrifugation revealed that EaDAcT colocalizes to the same fractions as an endoplasmic reticulum (ER) specific marker. By mapping the membrane topology of EaDAcT, we obtained an experimentally determined topology model for a plant MBOAT. The EaDAcT model contains four transmembrane domains (TMDs), with both the N- and C-termini orientated toward the lumen of the ER. In addition, there is a large cytoplasmic loop between the first and second TMDs, with the MBOAT signature region of the protein embedded in the third TMD close to the interface between the membrane and the cytoplasm. During topology mapping, we discovered two cysteine residues (C187 and C293) located on opposite sides of the membrane that are important for enzyme activity. In order to identify additional amino acid residues important for acetyltransferase activity, we isolated and characterized acetyltransferases from other acetyl-TAG-producing plants. Among them, the acetyltransferase from Euonymus fortunei possessed the highest activity in vivo and in vitro. Mutagenesis of conserved amino acids revealed that S253, H257, D258 and V263 are essential for EaDAcT activity. Alteration of residues unique to the acetyltransferases did not alter the unique acyl donor specificity of EaDAcT, suggesting that multiple amino acids are important for substrate recognition. PMID- 28715116 TI - Delayed transplantation may affect intellectual ability in children. AB - BACKGROUND: Decline in neurocognitive function is a reported complication in children with chronic illness. Concerns have been increasing that exposure to a major surgery or trauma may negatively affect cognitive performance in children. This study evaluated cognitive function in 43 Korean children who received organ transplantation (Tx), and sought to identify associated clinical factors. METHODS: Pediatric recipients of kidney (KT) or liver Tx (LT) from 1999 to 2011 were recruited for cognitive tests. Cognitive function was evaluated using intelligence quotient (IQ), social quotient (SQ), and Continuous Performance Test using Advanced Test for Attention scores, which reflect attention ability. Intellectual delay was graded as intellectual disability (ID; IQ <70) or low intelligence (LI; IQ<85). Diagnosis for attention-deficit-hyperactivity disorder (ADHD) was made by pediatric psychiatrists. RESULTS: The subjects consisted of 43 pediatric recipients of 28 LT and 15 KT. There were 20 boys (46.5%). Median age was 3.1 years (range, 0.5-15.3 years) at Tx. Median age at cognitive evaluation was 12.9 years (range, 3.4-18.4 years). Median pre-Tx duration of illness was 1.6 years (range, 0-13.5 years). The prevalence of ID, LI, and ADHD was 11.6%, 32.5%, and 32.5%, respectively. On multivariate analysis, longer pre-Tx duration of illness was a significant factor for LI (OR, 1.263; 95%CI: 1.033-1.544, P = 0.023). CONCLUSION: Longer pre-Tx duration may negatively affect intellectual ability in Korean children. Pre-Tx duration was more significant than the age at Tx or total disease duration per se. Early Tx may be beneficial for cognitive function in children. PMID- 28715117 TI - Differential activation of neuronal and glial STAT3 in the spinal cord of the SOD1G93A mouse model of amyotrophic lateral sclerosis. AB - Signal transducer and activator of transcription (STAT) proteins are activated by phosphorylation in the spinal cord of patients suffering from amyotrophic lateral sclerosis (ALS). The major scope of our study is a comprehensive histological characterization of the mechanisms underlying neuronal and glial STAT3 activation in the pathogenesis of ALS using SOD1G93A mice. We calculated the fold changes (FCs, ratios vs. appropriate controls) of the numerical densities of the following phosphorylated STAT3-positive (pSTAT3)+ cells - choline acetyltransferase (ChAT)+ alpha-motoneurons, ionized calcium-binding adapter molecule 1 (Iba1)+ microglia, and S100beta+ astrocytes in SOD1G93A mice. The FCs of pSTAT3+ microglia and pSTAT3+ astrocytes were increased from 9 to 15 weeks of age and then plateaued until 21 weeks. In contrast, the FCs of pSTAT3+ alpha motoneurons peaked at 9 weeks and then decreased until 21 weeks. The immunoreactivity for nonphosphorylated neurofilament protein (SMI-32), a marker of axonal impairment, was decreased in pSTAT3+ alpha-motoneurons compared with pSTAT3- alpha-motoneurons at 9 weeks of age. We then compared the following pharmacological models - the chronic administration of 3,3'-iminodipropionitrile (IDPN), which models axonal impairment, and the acute administration of lipopolysaccharide (LPS), which is a model of neuroinflammation. The FCs of pSTAT3+ alpha-motoneurons were increased in IDPN-treated mice, while those of pSTAT3+ microglia were increased in LPS-treated mice. The FCs of pSTAT3+ astrocytes were higher in SOD1G93A mice at 9 weeks compared with IDPN- and LPS treated mice. Our results indicate that axonopathy and neuroinflammation may trigger the respective activation of neuronal and glial STAT3, which is observed during ALS pathogenesis. PMID- 28715118 TI - microRNA159-targeted SlGAMYB transcription factors are required for fruit set in tomato. AB - The transition from flowering to fruit production, namely fruit set, is crucial to ensure successful sexual plant reproduction. Although studies have described the importance of hormones (i.e. auxin and gibberellins) in controlling fruit set after pollination and fertilization, the role of microRNA-based regulation during ovary development and fruit set is still poorly understood. Here we show that the microRNA159/GAMYB1 and -2 pathway (the miR159/GAMYB1/2 module) is crucial for tomato ovule development and fruit set. MiR159 and SlGAMYBs were expressed in preanthesis ovaries, mainly in meristematic tissues, including developing ovules. SlMIR159-overexpressing tomato cv. Micro-Tom plants exhibited precocious fruit initiation and obligatory parthenocarpy, without modifying fruit shape. Histological analysis showed abnormal ovule development in such plants, which led to the formation of seedless fruits. SlGAMYB1/2 silencing in SlMIR159 overexpressing plants resulted in misregulation of pathways associated with ovule and female gametophyte development and auxin signalling, including AINTEGUMENTA like genes and the miR167/SlARF8a module. Similarly to SlMIR159-overexpressing plants, SlGAMYB1 was downregulated in ovaries of parthenocarpic mutants with altered responses to gibberellins and auxin. SlGAMYBs likely contribute to fruit initiation by modulating auxin and gibberellin responses, rather than their levels, during ovule and ovary development. Altogether, our results unveil a novel function for the miR159-targeted SlGAMYBs in regulating an agronomically important trait, namely fruit set. PMID- 28715119 TI - Lateral prefrontal/orbitofrontal cortex has different roles in norm compliance in gain and loss domains: a transcranial direct current stimulation study. AB - Sanction is used by almost all known human societies to enforce fairness norm in resource distribution. Previous studies have consistently shown that the lateral prefrontal cortex (lPFC) and the adjacent orbitofrontal cortex (lOFC) play a causal role in mediating the effect of sanction threat on norm compliance. However, most of these studies were conducted in gain domain in which resources are distributed. Little is known about the mechanisms underlying norm compliance in loss domain in which individual sacrifices are needed. Here we employed a modified version of dictator game (DG) and high-definition transcranial direct current stimulation (HD-tDCS) to investigate to what extent lPFC/lOFC is involved in norm compliance (with and without sanction threat) in both gain- and loss sharing contexts. Participants allocated a fixed total amount of monetary gain or loss between themselves and an anonymous partner in multiple rounds of the game. A computer program randomly decided whether a given round involved sanction threat for the participants. Results showed that disruption of the right lPFC/lOFC by tDCS increased the voluntary norm compliance in the gain domain, but not in the loss domain; tDCS on lPFC/lOFC had no effect on compliance under sanction threat in either the gain or loss domain. Our findings reveal a context dependent nature of norm compliance and differential roles of lPFC/lOFC in norm compliance in gain and loss domains. PMID- 28715120 TI - Characterization of a multiple particle delivery complex and determination of cellular photodamage in skin fibroblast and breast cancer cell lines. AB - Zinc metallized Phthalocyanine (ZnPcSmix ), a potent photosensitizer, is conjugated to gold dendrimer encapsulated nanoparticles (AuDENPs) in order to improve the efficacy of photodynamic therapy (PDT) using MCF-7 breast cancer cells and WS1 fibroblast cells as a control. Both ZnPcSmix and AuDENPs are mixed in a nitrogen atmosphere for 48 hours and characterization analysis conducted using ultraviolet-visible (UV-vis) spectrometry for spectral properties, transmission electron microscopy (TEM) for morphological features and zeta potential measurement for surface stability and size distribution of the compound obtained or of the multiple particles delivery complex (MPDC). Cell viability, proliferation and membrane damage following PDT are assessed by the trypan blue exclusion test, adenosine triphosphate luminescence and lactate dehydrogenase cytotoxicity assays, respectively. Stable MPDCs are spherical shaped with a diameter lesser than 5 nm, and have a maximum absorption peak at 676 nm. The MPDC mediated PDT induces a decrease in cell viability and proliferation, and increased membrane damage or cytotoxicity. The conjugation enhances the therapeutic efficiency of PDT by improving drug delivery and targeting of MCF-7 cancer cells. PMID- 28715121 TI - Analytical Solutions of Three-Dimensional Contaminant Transport Models with Exponential Source Decay. AB - Despite the availability of numerical models, interest in analytical solutions of multidimensional advection-dispersion systems remains high. Such models are commonly used for performing Tier I risk analysis and are embedded in many regulatory frameworks dealing with groundwater contamination. In this work, we develop a closed-form solution of the three-dimensional advection-dispersion equation with exponential source decay, first-order reaction, and retardation, and present an approach based on some ease of use diagrams to compare it with the integral open form solution and with earlier versions of the closed-form solution. The comparison approach focuses on the relative differences associated with source decay and the effect of simulation time. The analysis of concentration contours, longitudinal sections, and transverse sections confirms that the closed-form solutions studied can be used with acceptable approximation in the central area of a plume bound transversely within the source width, both behind and beyond the advective front and for concentration values up to two orders of magnitude less than the initial source concentration. As the proposed closed-form model can be evaluated without nested numerical computations and with simple mathematical functions, it can be very useful in risk assessment procedures. PMID- 28715122 TI - Feasibility and acceptability of a telephone- and face-to-face-delivered counseling intervention for smoking cessation in Dutch patients with coronary heart disease. AB - Intensive behavioral counseling interventions combined with nicotine replacement therapy have increased smoking abstinence rates in cardiac patients, but little is known about their feasibility when initiated upon hospital admission and continued post-discharge. The current study was an evaluation of the use, appreciation, and fidelity of two post-discharge counseling interventions designed for cardiac patients to quit smoking that differed in their delivery mode. In a controlled trial with cross-over randomization at the cardiac unit level, hospitalized smokers in eight cardiac units of eight Dutch hospitals were assigned either telephone counseling (n = 223) or nurse-administered face-to-face counseling (n = 157) using the Ask-Advise-Refer strategy. Eligible patients also received nicotine replacement therapy. Data based on counselors' registration forms and patients' telephone surveys at 6-month follow-up were analyzed. Most patients (>90%) participated in at least one counseling session, and the majority participated in at least five out of a maximum of seven sessions. Higher levels of adherence to either the telephone or face-to-face counseling sessions were associated with higher smoking abstinence rates at the 6-month follow-up, whereas higher nicotine patch use was not associated with abstinence. Patients positively evaluated the content, duration, and number of sessions, and rated the face-to face counseling significantly better than the telephone counseling for quitting smoking. The counselors largely complied with the intervention protocols. The current intervention offers evidence of feasibility and may improve outpatient continuity of smoking care. Monitoring the use and delivery of such complex interventions is recommended to promote effective dissemination in cardiac practice. PMID- 28715123 TI - Recent Progress in the Preparation, Assembly, Transformation, and Applications of Layer-Structured Nanodisks beyond Graphene. AB - Layered nanodisks with confined thickness and lateral size have been emerging as a unique type of two-dimensional (2D) nanomaterials in recent years. Inheriting some properties of 2D nanosheets and meanwhile possessing the size-confinement effect, these layered nanodisks exhibit unique optical, electronic, and chemical properties, which endow them with great promise in a wide range of applications. Here, the recent progress of layered nanodisks is introduced. The synthetic strategies, assembly, structural/compositional transformation, and applications of layered nanodisks are systematically described and discussed, with emphasis on their new appealing structures and functions. Finally, some perspectives and future research directions of this promising field are given. PMID- 28715124 TI - Chemical imaging of fresh vascular smooth muscle cell response by epi-detected stimulated Raman scattering. AB - An understanding of deformation of cardiovascular tissue under hemodynamic load is crucial for understanding the health and disease of blood vessels. In the present work, an epi-detected stimulated Raman scattering (epi-SRS) imaging platform was designed for in situ functional imaging of vascular smooth muscle cells (VMSCs) in fresh coronary arteries. For the first time, the pressure induced morphological deformation of fresh VSMCs was imaged with no fixation and in a label-free manner. The relation between the loading pressure and the morphological parameters, including angle and length of the VSMCs, were apparent. The morphological responses of VMSCs to drug treatment were also explored, to demonstrate the capability of functional imaging for VSMCs by this method. The time-course imaging revealed the drug induced change in angle and length of VSMCs. The present study provides a better understanding of the biomechanical framework of blood vessels, as well as their responses to external stimulations, which are fundamental for developing new strategies for cardiovascular disease treatment. PMID- 28715125 TI - Acute Alcohol Binge Deteriorates Metabolic and Respiratory Compensation Capability After Blunt Chest Trauma Followed by Hemorrhagic Shock-A New Research Model. AB - BACKGROUND: The clinical relevance of blunt (thoracic) chest trauma (TxT) and hemorrhagic shock is indisputable due to the high prevalence of this injury type, as well as its close association with mortality and/or preventable deaths. Furthermore, there is an ongoing discussion about the influence of alcohol in trauma patients. Thus, we established a model of TxT followed by hemorrhagic shock with resuscitation (H/R) in alcohol-intoxicated rats. METHODS: Depending on group allocation, 12 (subacute) or 2 (acute) hours before experimentation, the animals received a single oral dose of alcohol (ethanol [EtOH]) or saline (NaCl) followed by TxT, hemorrhagic shock (35 +/- 3 mm Hg), and resuscitation (TxT + H/R). Arterial blood gas analyses and continuous monitoring of blood pressure were performed during the experimentation period. Survival during the experimentation procedure was determined. RESULTS: Subacute and acute EtOH group exhibited lower baseline mean arterial blood pressure values compared with the corresponding NaCl group, respectively. Both EtOH groups showed lower maximal bleed-out volume, which was necessary to induce hemorrhagic shock compared to NaCl groups, and the recovery during the resuscitation period was attenuated. During the experimentation in all groups, a trend to acidic pH was observed. Acute EtOH group showed lowest pH values compared to all other groups. Higher pCO2 values were observed in both EtOH groups. All groups developed negative base excess and decreasing HCO3- values until the end of hemorrhagic shock and showed increasing base excess and HCO3- values during resuscitation. Significantly higher mortality rate was found in the acute EtOH group. CONCLUSIONS: This study indicates that alcohol limits the metabolic and respiratory compensation capability, thereby promoting mortality. PMID- 28715129 TI - Defensible Model Complexity: A Call for Data-Based and Goal-Oriented Model Choice. PMID- 28715126 TI - An engineered photoswitchable mammalian pyruvate kinase. AB - Changes in allosteric regulation of glycolytic enzymes have been linked to metabolic reprogramming involved in cancer. Remarkably, allosteric mechanisms control enzyme function at significantly shorter time-scales compared to the long term effects of metabolic reprogramming on cell proliferation. It remains unclear if and how the speed and reversibility afforded by rapid allosteric control of metabolic enzymes is important for cell proliferation. Tools that allow specific, dynamic modulation of enzymatic activities in mammalian cells would help address this question. Towards this goal, we have used molecular dynamics simulations to guide the design of mPKM2 internal light/oxygen/voltage-sensitive domain 2 (LOV2) fusion at position D24 (PiL[D24]), an engineered pyruvate kinase M2 (PKM2) variant that harbours an insertion of the light-sensing LOV2 domain from Avena Sativa within a region implicated in allosteric regulation by fructose 1,6 bisphosphate (FBP). The LOV2 photoreaction is preserved in the PiL[D24] chimera and causes secondary structure changes that are associated with a 30% decrease in the Km of the enzyme for phosphoenolpyruvate resulting in increased pyruvate kinase activity after light exposure. Importantly, this change in activity is reversible upon light withdrawal. Expression of PiL[D24] in cells leads to light induced increase in labelling of pyruvate from glucose. PiL[D24] therefore could provide a means to modulate cellular glucose metabolism in a remote manner and paves the way for studying the importance of rapid allosteric phenomena in the regulation of metabolism and enzyme control. PMID- 28715127 TI - Increased aggression and lack of maternal behavior in Dio3-deficient mice are associated with abnormalities in oxytocin and vasopressin systems. AB - Thyroid hormones regulate many aspects of brain development and function, and alterations in the levels of thyroid hormone action lead to abnormal anxiety- and depression-like behaviors. A complement of factors in the brain function independently of circulating levels of hormone to strictly controlled local thyroid hormone signaling. A critical factor is the type 3 deiodinase (DIO3), which is located in neurons and protects the brain from excessive thyroid hormone. Here, we examined whether a local increase in brain thyroid hormone action secondary to DIO3 deficiency is of consequence for social behaviors. Although we did not observe alterations in sociability, Dio3-/- mice of both sexes exhibited a significant increase in aggression-related behaviors and mild deficits in olfactory function. In addition, 85% of Dio3-/- dams manifested no pup-retrieval behavior and increased aggression toward the newborns. The abnormal social behaviors of Dio3-/- mice were associated with sexually dimorphic alterations in the physiology of oxytocin (OXT) and arginine vasopressin (AVP), 2 neuropeptides with important roles in determining social interactions. These alterations included low adult serum levels of OXT and AVP, and an abnormal expression of Oxt, Avp and their receptors in the neonatal and adult hypothalamus. Our results demonstrate that DIO3 is essential for normal aggression and maternal behaviors, and indicate that abnormal local regulation of thyroid hormone action in the brain may contribute to the social deficits associated with neurodevelopmental disorders. PMID- 28715128 TI - Sibiriline, a new small chemical inhibitor of receptor-interacting protein kinase 1, prevents immune-dependent hepatitis. AB - Necroptosis is a regulated form of cell death involved in several disease models including in particular liver diseases. Receptor-interacting protein kinases, RIPK1 and RIPK3, are the main serine/threonine kinases driving this cell death pathway. We screened a noncommercial, kinase-focused chemical library which allowed us to identify Sibiriline as a new inhibitor of necroptosis induced by tumor necrosis factor (TNF) in Fas-associated protein with death domain (FADD) deficient Jurkat cells. Moreover, Sib inhibits necroptotic cell death induced by various death ligands in human or mouse cells while not protecting from caspase dependent apoptosis. By using competition binding assay and recombinant kinase assays, we demonstrated that Sib is a rather specific competitive RIPK1 inhibitor. Molecular docking analysis shows that Sib is trapped closed to human RIPK1 adenosine triphosphate-binding site in a relatively hydrophobic pocket locking RIPK1 in an inactive conformation. In agreement with its RIPK1 inhibitory property, Sib inhibits both TNF-induced RIPK1-dependent necroptosis and RIPK1 dependent apoptosis. Finally, Sib protects mice from concanavalin A-induced hepatitis. These results reveal the small-molecule Sib as a new RIPK1 inhibitor potentially of interest for the treatment of immune-dependent hepatitis. PMID- 28715130 TI - Average glandular dose coefficients for pendant-geometry breast CT using realistic breast phantoms. AB - PURPOSE: To design volume-specific breast phantoms from breast CT (bCT) data sets and estimate the associated normalized mean glandular dose coefficients for breast CT using Monte Carlo methods. METHODS: A large cohort of bCT data sets (N = 215) was used to evaluate breast volume into quintiles (plus the top 5%). The average radius profile was then determined for each of the six volume-specific groups and used to both fabricate physical phantoms and generate mathematical phantoms (V1-V6; "V" denotes classification by volume). The MCNP6 Monte Carlo code was used to model a prototype bCT system fabricated at our institution; and this model was validated against physical measurements in the fabricated phantoms. The mathematical phantoms were used to simulate normalized mean glandular dose coefficients for both monoenergetic source photons "DgNCT (E)" (8 70 keV in 1 keV intervals) and polyenergetic x-ray beams "pDgNCT " (35-70 kV in 1 kV intervals). The Monte Carlo code was used to study the influence of breast size (V1 vs. V5) and glandular fraction (6.4% vs. 45.8%) on glandular dose. The pDgNCT coefficients estimated for the V1, V3, and V5 phantoms were also compared to those generated using simple, cylindrical phantoms with equivalent volume and two geometrical constraints including; (a) cylinder radius determined at the breast phantom chest wall "Rcw "; and (b) cylinder radius determined at the breast phantom center-of-mass "RCOM ". RESULTS: Satisfactory agreement was observed for dose estimations using MCNP6 compared with both physical measurements in the V1, V3, and V5 phantoms (R2 = 0.995) and reference bCT dose coefficients using simple phantoms (R2 = 0.999). For a 49 kV spectrum with 1.5 mm Al filtration, differences in glandular fraction [6.5% (5th percentile) vs. 45.8% (95th percentile)] had a 13.2% influence on pDgNCT for the V3 phantom, and differences in breast size (V1 vs. V5) had a 16.6% influence on pDgNCT for a breast composed of 17% (median) fibroglandular tissue. For cylindrical phantoms with a radius of RCOM , the differences were 1.5%, 0.1%, and 2.1% compared with the V1, V3, and V5 phantoms, respectively. CONCLUSION: Breast phantoms were designed using a large cohort of bCT data sets across a range of six breast sizes. These phantoms were then fabricated and used for the estimation of glandular dose in breast CT. The mathematical phantoms and associated glandular dose coefficients for a range of breast sizes (V1-V6) and glandular fractions (5th to 95th percentiles) are available for interested users. PMID- 28715131 TI - Transcriptome analysis suggests a role for the differential expression of cerebral aquaporins and the MAPK signalling pathway in human temporal lobe epilepsy. AB - Epilepsies are common disorders of the central nervous system (CNS), affecting up to 2% of the global population. Pharmaco-resistance is a major clinical challenge affecting about 30% of temporal lobe epilepsy (TLE) patients. Water homeostasis has been shown crucial for regulation of neuronal excitability. The control of water movement is achieved through a family of small integral membrane channel proteins called aquaporins (AQPs). Despite the fact that changes in water homeostasis occur in sclerotic hippocampi of people with TLE, the expression of AQPs in the epileptic brain is not fully characterised. This study uses microarray and ELISA methods to analyse the mRNA and protein expression of the human cerebral AQPs in sclerotic hippocampi (TLE-HS) and adjacent neocortex tissue (TLE-NC) of TLE patients. The expression of AQP1 and AQP4 transcripts was significantly increased, while that of the AQP9 transcript was significantly reduced in TLE-HS compared to TLE-NC. AQP4 protein expression was also increased while expression of AQP1 protein remained unchanged, and AQP9 was undetected. Microarray data analysis identified 3333 differentially regulated genes and suggested the involvement of the MAPK signalling pathway in TLE pathogenesis. Proteome array data validated the translational profile for 26 genes and within the MAPK pathway (e.g. p38, JNK) that were identified as differentially expressed from microarray analysis. ELISA data showed that p38 and JNK inhibitors decrease AQP4 protein levels in cultured human primary cortical astrocytes. Elucidating the mechanism of selective regulation of different AQPs and associated regulatory proteins may provide a new therapeutic approach to epilepsy treatment. PMID- 28715132 TI - Return of neonatal CPAP resistance - the Medijet device family examined using in vitro flow simulations. AB - AIM: Medijet nasal continuous positive airway pressure (CPAP) generators are a family of devices developed from the Benveniste valve. Previous studies have shown that the in vitro performance of the Medijet disposable generator was similar to the Neopuff resistor system. We hypothesised that resistance would be the main mechanism of CPAP generation in the Medijet disposable generator. METHODS: The in vitro performance of the Medijet reusable and disposable systems, the Neopuff resistor system and the Benveniste and Infant Flow nonresistor systems were investigated using static and dynamic bench tests. RESULTS: Large differences in performance were found between the different systems. The disposable Medijet demonstrated high resistance, low pressure stability and high imposed work of breathing. The results also showed that encapsulating the Benveniste valve changed it into a resistor system. CONCLUSION: The main mechanism of CPAP generation for the disposable Medijet generator was resistance. The Medijet device family showed increasing resistance with each design generation. The high resistance of the Medijet disposable generator could be of great value when examining the clinical importance of pressure stability. Our results suggest that this device should be used cautiously in patients where pressure-stable CPAP is believed to be clinically important. PMID- 28715133 TI - Cyclodextrin Cavity-Induced Mechanistic Switch in Copper-Catalyzed Hydroboration. AB - N-heterocyclic carbene-capped cyclodextrin (ICyD) ligands, alpha-ICyD and beta ICyD derived from alpha- and beta-cyclodextrin, respectively give opposite regioselectivities in a copper-catalyzed hydroboration. The site-selectivity results from two different mechanisms: the conventional parallel one and a new orthogonal mechanism. The shape of the cavity was shown not only to induce a regioselectivity switch but also a mechanistic switch. The scope of interest of the encapsulation of a reactive center is therefore broadened by this study. PMID- 28715134 TI - Magnetic Shielding Studies of C2 and C2 H2 Support Higher than Triple Bond Multiplicity in C2. AB - The carbon-carbon bonds in the ground states of C2 and C2 H2 , at their equilibrium geometries, are compared by analysing the changes in the off-nucleus magnetic shielding tensor within the space surrounding each of these molecules. A wide range of quantum-chemical approaches, including full-valence CASSCF-GIAO, CCSD(T)-GIAO and CCSDT-GIAO, all with the cc-pVQZ basis set, as well as HF-GIAO and MP2-GIAO, with the cc-pVQZ, cc-pV5Z and cc-pV6Z basis sets, show that the surroundings of the carbon-carbon bond in C2 are more shielded than those of the carbon-carbon bond in C2 H2 . The additional shielding of the carbon-carbon bond in C2 is found to be due to a larger paramagnetic contribution to the component of the shielding tensor which is perpendicular to the molecular axis. The analysis of the off-nucleus shielding data indicates that the carbon-carbon bond in C2 is "bulkier" and, therefore, of a higher multiplicity, but weaker than the corresponding bond in C2 H2 . According to the results of the shielding calculations, the carbon nuclei in C2 should be much more shielded than those in C2 H2 , with 13 C isotropic magnetic shieldings in the ranges of around 224-227 ppm and around 123-125 ppm for C2 and C2 H2 , respectively. PMID- 28715135 TI - Chronic pharmacological blockade of the Na+ /Ca2+ exchanger modulates the growth and development of the Purkinje cell dendritic arbor in mouse cerebellar slice cultures. AB - The Na+ /Ca2+ exchanger (NCX) is a bidirectional plasma membrane antiporter involved in Ca2+ homeostasis in eukaryotes. NCX has three isoforms, NCX1-3, and all of them are expressed in the cerebellum. Immunostaining on cerebellar slice cultures indicates that NCX is widely expressed in the cerebellum, including expression in Purkinje cells. The pharmacological blockade of the forward mode of NCX (Ca2+ efflux mode) by bepridil moderately inhibited growth and development of Purkinje cell dendritic arbor in cerebellar slice cultures. However, the blockade of the reverse mode (Ca2+ influx mode) by KB-R7943 severely reduced the dendritic arbor and induced a morphological change with thickened distal dendrites. The effect of KB-R7943 on dendritic growth was unrelated to the activity of voltage gated calcium channels and was also apparent in the absence of bioelectrical activity indicating that it was mediated by NCX expressed in Purkinje cells. We have used additional NCX inhibitors including CB-DMB, ORM-10103, SEA0400, YM 244769, and SN-6 which have higher specificity for NCX isoforms and target either the forward, reverse, or both modes. These inhibitors caused a strong dendritic reduction similar to that seen with KB-R7943, but did not elicit thickening of distal dendrites. Our findings indicate that disturbance of the NCX-dependent calcium transport in Purkinje cells induces a reduction of dendritic arbor, which is presumably caused by changes in the calcium handling, and underline the importance of the calcium equilibrium for the dendritic development in cerebellar Purkinje cells. PMID- 28715137 TI - Evaluation of the umbilical sparing phenomenon of large congenital melanocytic nevi in a large case series. PMID- 28715136 TI - Underweight and hypoalbuminemia as risk indicators for mortality among psychiatric patients with medical comorbidities. AB - AIM: Medical comorbidities are a major cause of death among patients with mental illness. The purpose of this study was to clarify the risk factors for mortality among psychiatric patients with medical comorbidities. METHODS: We retrospectively reviewed the clinical files of patients transferred to Tokyo Metropolitan Matsuzawa Hospital from a psychiatric hospital to treat medical comorbidities during the 3-year period from January 2014 to December 2016. We analyzed the clinical differences between the expired and alive patients. RESULTS: Of the 287 patients included, 29 (10.1%) had expired at the time of hospital discharge, while 258 (89.9%) were living. A multivariable analysis to determine the prognostic factors related to mortality from medical comorbidities showed that body mass index <18.5 had the highest odds ratio among the predictive factors (5.1; 95% confidence interval, 1.5-17.1; P < 0.05), followed by a serum albumin level < 3.0 mg/dL (3.0; 95% confidence interval, 1.1-8.1; P < 0.05). CONCLUSION: We found that underweight and hypoalbuminemia were risk factors for mortality among psychiatric patients with medical comorbidities. Physicians at psychiatric hospitals should consider transferring patients with medical comorbidities to a general medical hospital in the presence of underweight and/or hypoalbuminemia. PMID- 28715138 TI - Microbial functional diversity covaries with permafrost thaw-induced environmental heterogeneity in tundra soil. AB - Permafrost soil in high latitude tundra is one of the largest terrestrial carbon (C) stocks and is highly sensitive to climate warming. Understanding microbial responses to warming-induced environmental changes is critical to evaluating their influences on soil biogeochemical cycles. In this study, a functional gene array (i.e., geochip 4.2) was used to analyze the functional capacities of soil microbial communities collected from a naturally degrading permafrost region in Central Alaska. Varied thaw history was reported to be the main driver of soil and plant differences across a gradient of minimally, moderately, and extensively thawed sites. Compared with the minimally thawed site, the number of detected functional gene probes across the 15-65 cm depth profile at the moderately and extensively thawed sites decreased by 25% and 5%, while the community functional gene beta-diversity increased by 34% and 45%, respectively, revealing decreased functional gene richness but increased community heterogeneity along the thaw progression. Particularly, the moderately thawed site contained microbial communities with the highest abundances of many genes involved in prokaryotic C degradation, ammonification, and nitrification processes, but lower abundances of fungal C decomposition and anaerobic-related genes. Significant correlations were observed between functional gene abundance and vascular plant primary productivity, suggesting that plant growth and species composition could be co evolving traits together with microbial community composition. Altogether, this study reveals the complex responses of microbial functional potentials to thaw related soil and plant changes and provides information on potential microbially mediated biogeochemical cycles in tundra ecosystems. PMID- 28715139 TI - UVB exposure of a humanized skin model reveals unexpected dynamic of keratinocyte proliferation and Wnt inhibitor balancing. AB - We developed human dermo-epidermal skin substitutes that are presently applied in phase I and II clinical trials. Here, we used these very same skin equivalents containing melanocytes, named MelSkin, as an experimental skin model. We investigated the effects of ultraviolet B (UVB) irradiation on the skin grafts transplanted on immune-compromised rats. The irradiation induces a strong wound healing response going along with massive proliferation of basal keratinocytes, basically quiescent under nonirradiated, homeostatic conditions. As a consequence of UVB irradiation, the initially clearly defined basal keratinocyte (mono)layer expands into about 3 layers of keratinocytes, all of which still express the basal keratinocyte marker keratin 15. In contrast, epidermal melanocytes remain quiescent under these circumstances. Moreover, the Wnt inhibitors Dickkopf 3 and Wif1 are downregulated upon UVB irradiation in basal keratinocytes, whereas melanocytes continue to express Wnt inhibitors. These findings suggest that there is (a) a suprabasal population, proliferating in the homeostatic state, hence maintaining the integrity of the epidermis, and (b) a basal, usually quiescent keratinocyte population that is induced to massively proliferate upon irradiation. Importantly, the finding that MelSkin responds in a physiological fashion to UVB is of paramount importance in light of the planned clinical application. PMID- 28715140 TI - The natural history of thin melanoma and the utility of sentinel lymph node biopsy. AB - BACKGROUND AND OBJECTIVES: Current literature may overestimate the risk of nodal metastasis from thin melanoma due to reporting of data only from lesions treated with SLNB. Our objective was to define the natural history of thin melanoma, assessing the likelihood of nodal disease, in order to guide selection for SLNB. METHODS: Retrospective review. The primary outcome was the rate of nodal disease. Clinicopathologic factors were evaluated to find associations with nodal disease. RESULTS: Five hundred and twelve lesions, follow up available for 488 (median: 48 months). Lesions treated with WLE/SLNB compared to WLE alone were more likely to have high-risk features. The rate of nodal disease was higher in the WLE/SLNB group (24 positive SLNB, five false-negative SLNB with nodal recurrence: 10.2%) compared to WLE alone (four nodal recurrences: 2.0%). Univariate analysis showed age <=45, Breslow depth >=0.85 mm, mitotic rate >1 mm2 , and ulceration were associated with nodal disease. Multivariate analysis confirmed the association of age <=45 and ulceration. CONCLUSIONS: SLNB for melanoma 0.75-0.99 mm should be considered in patients age <=45, Breslow depth >=0.85 mm, mitotic rate >1 mm2 , and/or with ulceration. Thin melanoma <0.85 mm without high-risk features may be treated with WLE alone. PMID- 28715141 TI - Walnut consumption increases activation of the insula to highly desirable food cues: A randomized, double-blind, placebo-controlled, cross-over fMRI study. AB - AIMS: The use of walnuts is recommended for obesity and type 2 diabetes, although the mechanisms through which walnuts may improve appetite control and/or glycaemic control remain largely unknown. MATERIALS AND METHODS: To determine whether short-term walnut consumption could alter the neural control of appetite using functional magnetic resonance imaging, we performed a randomized, placebo controlled, double-blind, cross-over trial of 10 patients who received, while living in the controlled environment of a clinical research center, either walnuts or placebo (using a validated smoothie delivery system) for 5 days each, separated by a wash-out period of 1 month. RESULTS: Walnut consumption decreased feelings of hunger and appetite, assessed using visual analog scales, and increased activation of the right insula to highly desirable food cues. CONCLUSIONS: These findings suggest that walnut consumption may increase salience and cognitive control processing of highly desirable food cues, leading to the beneficial metabolic effects observed. PMID- 28715142 TI - Cholinesterase inhibition reduces arrhythmias in asymptomatic Chagas disease. AB - INTRODUCTION: Parasympathetic dysfunction may play a role in the genesis of arrhythmias in Chagas disease. AIM: This study evaluates the acute effects of pyridostigmine (PYR), a reversible cholinesterase inhibitor, on the occurrence of arrhythmias in patients with Chagas cardiac disease. METHOD: Following a double blind, randomized, placebo-controlled, cross-over protocol, 17 patients (age 50+/ 2 years) with Chagas cardiac disease type B underwent 24-hour Holter recordings after oral administration of either pyridostigmine bromide (45 mg, 3 times/day) or placebo (PLA). RESULTS: Pyridostigmine reduced the 24-hours incidence (median [25%-75%]) of premature ventricular beats-PLA: 2998 (1920-4870), PYR: 2359 (940 3253), P=.044; ventricular couplets-PLA: 84 (15-159), PYR: 33 (6-94), P=.046. Although the total number of nonsustained ventricular tachycardia in the entire group was not different (P=.19) between PLA (1 [0-8]) and PYR (0 [0-4]), there were fewer episodes under PYR in 72% of the patients presenting this type of arrhythmia (P=.033). CONCLUSION: Acute administration of pyridostigmine reduced the incidence of nonsustained ventricular arrhythmias in patients with Chagas cardiac disease. Further studies that address the use of pyridostigmine by patients with Chagas cardiac disease under a more prolonged follow-up are warranted. PMID- 28715143 TI - Repetitive short-span application of extracellular calcium is osteopromotive to osteoprogenitor cells. AB - Extracellular calcium ([Ca2+ ]E ) concentration has been suggested to stimulate osteoblastic activity; thus, calcium can be used to enhance fracture healing. However, systemic administration of calcium at high dose levels may cause physiological problems such as hypercalcaemia. Short-span application of single or repetitive [Ca2+ ]E stimulus may be suggested as a novel regimen to reduce such side effects. However, osteopromotive effect of such short-term [Ca2+ ]E stimulus on osteoprogenitor cells has not yet been evaluated yet. This study investigated the effects of [Ca2+ ]E dose (6 and 18 mM) and regimen (single, repetitive, and continuous) on viability, proliferation, osteogenic gene expression, and mineral formation by osteoprogenitor cells. BMP-2 treatment was set as the positive control group. It was observed that repetitive and continuous calcium stimulation resulted in significant enhancement of osteoblastic activity. A 6 mM [Ca2+ ]E significantly increased cell viability and proliferation in all three regimens, and the expression of osteogenic transcription factors was significantly upregulated by continuous application of 6 mM [Ca2+ ]E . It was observed that application of [Ca2+ ]E repetitively at 18 mM had an osteopromotive effect to an extent that was as pronounced as BMP-2. Continuous application of 18 mM [Ca2+ ]E provided the greatest degree of osteogenic activity among all groups. This study demonstrated that repetitive [Ca2+ ]E exposure from the basal aspect of cells resulted in upregulation of osteogenic transcription factor and bone formation. The knowledge gained from the dose and treatment regimen of calcium therapy is important in setting the guidelines for developing approaches to treat fractures. PMID- 28715144 TI - International Endometrial Tumor Analysis (IETA) terminology in women with postmenopausal bleeding and sonographic endometrial thickness >= 4.5 mm: agreement and reliability study. AB - OBJECTIVE: To estimate intra- and interrater agreement and reliability with regard to describing ultrasound images of the endometrium using the International Endometrial Tumor Analysis (IETA) terminology. METHODS: Four expert and four non expert raters assessed videoclips of transvaginal ultrasound examinations of the endometrium obtained from 99 women with postmenopausal bleeding and sonographic endometrial thickness >= 4.5 mm but without fluid in the uterine cavity. The following features were rated: endometrial echogenicity, endometrial midline, bright edge, endometrial-myometrial junction, color score, vascular pattern, irregularly branching vessels and color splashes. The color content of the endometrial scan was estimated using a visual analog scale graded from 0 to 100. To estimate intrarater agreement and reliability, the same videoclips were assessed twice with a minimum of 2 months' interval. The raters were blinded to their own results and to those of the other raters. RESULTS: Interrater differences in the described prevalence of most IETA variables were substantial, and some variable categories were observed rarely. Specific agreement was poor for variables with many categories. For binary variables, specific agreement was better for absence than for presence of a category. For variables with more than two outcome categories, specific agreement for expert and non-expert raters was best for not-defined endometrial midline (93% and 96%), regular endometrial myometrial junction (72% and 70%) and three-layer endometrial pattern (67% and 56%). The grayscale ultrasound variable with the best reliability was uniform vs non-uniform echogenicity (multirater kappa (kappa), 0.55 for expert and 0.52 for non-expert raters), and the variables with the lowest reliability were appearance of the endometrial-myometrial junction (kappa, 0.25 and 0.16) and the nine category endometrial echogenicity variable (kappa, 0.29 and 0.28). The most reliable color Doppler variable was color score (mean weighted kappa, 0.77 and 0.69). Intra- and interrater agreement and reliability were similar for experts and non-experts. CONCLUSIONS: Inter- and intrarater agreement and reliability when using IETA terminology were limited. This may have implications when assessing the association between a particular ultrasound feature and a specific histological diagnosis, because lack of reproducibility reduces the reliability of the association between a feature and the outcome. Future studies should investigate whether using fewer categories of variable or offering practical training could improve agreement and reliability. Copyright (c) 2017 ISUOG. Published by John Wiley & Sons Ltd. PMID- 28715147 TI - Performance analysis of the T-DOC(r) air-charged catheters: An alternate technology for urodynamics. AB - AIMS: Urodynamics (UDS) is widely used for the diagnosis of lower urinary tract dysfunction. Air-Charged catheters (ACC), one of the newer technologies for UDS pressure recording, has been adopted in growing numbers around the world for the past 15 years. Currently, there is a lack of published studies characterizing specific performance of the ACC. Since linearity, hysteresis, pressure drift, and frequency response are important components in characterizing accuracy for catheter-manometer systems; this study aimed to assess these four aspects in ACC. METHODS: A total of 180 T-DOC(r) ACC were used in three different laboratory settings to assess pressure linearity and hysteresis (15 dual-sensor vesical and urethral and 30 single-sensor abdominal), pressure drift over 2 h (115 single sensor), and frequency response (20 single-sensor). Data are presented as mean +/ standard deviation. RESULTS: ACC showed linearity of 0.99 +/- 0.01, 0.99 +/- 0.01, and 1.01 +/- 0.01; and hysteresis of 0.57 +/- 0.3%, 0.76 +/- 0.48%, and 1 +/- 0.89% for the abdominal, vesical, and urethral sensors, respectively. A pressure drift of 2.2 +/- 1.4% at 1 h and 4.4 +/- 2.5% at 2 h were observed when compared to baseline pressures. The catheters did not show any amplification factor during the sweep from 1 to 30 Hz, and recorded signals up to 5 Hz attenuating higher frequency signals. CONCLUSIONS: In this study the T-DOC(r) ACC showed a linear performance with minimal hysteresis associated with acceptable pressure drift, and adequate frequency response to capture clinically relevant pressures. The accurate results observed in this study suggest that these catheters are technically suitable to be used as a measuring instrument for UDS. PMID- 28715145 TI - The Autophagy Receptor Adaptor p62 is Up-regulated by UVA Radiation in Melanocytes and in Melanoma Cells. AB - UVA (315-400 nm) is the most abundant form of UV radiation in sunlight and indoor tanning beds. However, much remains to be understood about the regulation of the UVA damage response in melanocytes and melanoma. Here, we show that UVA, but not the shorter waveband UVB (280-315 nm), up-regulates adaptor protein p62 in an Nrf2- and reactive oxygen species (ROS)-dependent manner, suggesting a UVA specific effect on p62 regulation. UVA-induced p62 up-regulation was inhibited by a mitochondria-targeted antioxidant or Nrf2 knockdown. In addition, p62 knockdown inhibited UVA-induced ROS production and Nrf2 up-regulation. We also report here a novel regulatory feedback loop between p62 and PTEN in melanoma cells. PTEN overexpression reduced p62 protein levels, and p62 knockdown increased PTEN protein levels. As compared with normal human skin, p62 was up-regulated in human nevus, malignant melanoma and metastatic melanoma. Furthermore, p62 was up regulated in melanoma cells relative to normal human epidermal melanocytes, independent of their BRAF or NRAS mutation status. Our results demonstrated that UVA up-regulates p62 and induces a p62-Nrf2 positive feedback loop to counteract oxidative stress. Additionally, p62 forms a feedback loop with PTEN in melanoma cells, suggesting p62 functions as an oncogene in UVA-associated melanoma development and progression. PMID- 28715146 TI - Identification of hypoglycin A binding adsorbents as potential preventive measures in co-grazers of atypical myopathy affected horses. AB - BACKGROUND: Intestinal absorption of hypoglycin A (HGA) and its metabolism are considered major prerequisites for atypical myopathy (AM). The increasing incidence and the high mortality rate of AM urgently necessitate new therapeutic and/or preventative approaches. OBJECTIVES: To identify a substance for oral administration capable of binding HGA in the intestinal lumen and effectively reducing the intestinal absorption of the toxin. STUDY DESIGN: Experimental in vitro study. METHODS: Substances commonly used in equine practice (activated charcoal composition, di-tri-octahedral smectite, mineral oil and activated charcoal) were tested for their binding capacity for HGA using an in vitro incubation method. The substance most effective in binding HGA was subsequently tested for its potential to reduce intestinal HGA absorption. Jejunal tissues of 6 horses were incubated in Ussing chambers to determine mucosal uptake, tissue accumulation, and serosal release of HGA in the presence and absence of the target substance. Potential intestinal metabolism in methylenecyclopropyl acetic acid (MCPA)-conjugates was investigated by analysing their concentrations in samples from the Ussing chambers. RESULTS: Activated charcoal composition and activated charcoal were identified as potent HGA binding substances with dose and pH dependent binding capacity. There was no evidence of intestinal HGA metabolism. MAIN LIMITATIONS: Binding capacity of adsorbents was tested in vitro using aqueous solutions, and in vivo factors such as transit time and composition of intestinal content, may affect adsorption capacity after oral administration. CONCLUSIONS: For the first time, this study identifies substances capable of reducing HGA intestinal absorption. This might have major implications as a preventive measure in cograzers of AM affected horses but also in horses at an early stage of intoxication. PMID- 28715149 TI - Welcome to the Real World: Do the Conditions of FDA Approval Devalue High sensitivity Troponin? PMID- 28715150 TI - Intraoperative radiotherapy: Patient selection, management, and follow-up. AB - Intraoperative partial breast radiotherapy is an alternative or an adjunct to fractionated whole breast irradiation for the administration of adjuvant radiotherapy in breast cancer following breast conserving surgery. Establishing intraoperative radiotherapy as a therapeutic modality requires a multidisciplinary approach to patient selection, workup, surgery, radiation protocols, chemotherapy, and patient follow up. In this article, we review the published evidence for best clinical practice, as a guide to the introduction of intraoperative radiotherapy for breast cancer treatment. PMID- 28715148 TI - Lineage-specific epitope profiles for HPAI H5 pre-pandemic vaccine selection and evaluation. AB - BACKGROUND: Multiple highly pathogenic avian influenza (HPAI) H5 viruses continue to co-circulate. This has complicated pandemic preparedness and confounded effective vaccine candidate selection and evaluation. OBJECTIVES: In this study, we aimed to predict and map the diversity of CD8+ T-cell epitopes among H5 hemagglutinin (HA) gene lineages to estimate CD8+ T-cell immunity in humans induced by vaccine candidates. METHODS: A dataset consisting of 1125 H5 HA sequences collected between 1996 and 2017 from avian and humans was assembled for phylogenetic and lineage-specific epitope analyses. Conserved epitopes were predicted from WHO-endorsed vaccine candidates and representative clade-defining strains by pairwise comparison with Immune Epitope Database (IEDB). The distribution of predicted epitopes was mapped to each HPAI H5 lineage. We assume that high similarity and conservancy of predicted epitopes from vaccine candidates among all circulating HPAI H5 lineages is correlated with high immunity. RESULTS: A total of 49 conserved CD8+ T-cell epitopes were predicted at 28 different amino acid positions of the HA protein. Mapping these epitopes to the phylogenetic tree allowed us to develop epitope profiles, or "fingerprints," for each HPAI H5 lineage. Vaccine epitope percentage analyses showed some epitope profiles were highly conserved for all H5 isolates and may be valuable for universal vaccine design. However, the positions with low coverage may explain why the vaccine candidates do not always function well. CONCLUSIONS: These findings demonstrate that our analytical approach to evaluate conserved CD8+ T cell epitope prediction in a phylogenetic framework may provide important insights for computational design of vaccine selection and future epitope-based design. PMID- 28715151 TI - Nickel-Catalyzed Intermolecular Carbosulfonylation of Alkynes via Sulfonyl Radicals. AB - beta,beta-Disubstituted vinyl sulfones were obtained with complete regio- and stereocontrol in a multicomponent reaction involving alkynes, organoboronic acids, and sulfonyl chlorides in the presence of a nickel catalyst. The reaction proceeds via sulfonyl radicals generated in situ under mild reaction conditions. PMID- 28715153 TI - Automated analysis of fetal cardiac function using color tissue Doppler imaging. AB - OBJECTIVE: To evaluate the feasibility of automated analysis of fetal myocardial velocity recordings obtained by color tissue Doppler imaging (cTDI). METHODS: This was a prospective cross-sectional observational study of 107 singleton pregnancies >= 41 weeks of gestation. Myocardial velocity recordings were obtained by cTDI in a long-axis four-chamber view of the fetal heart. Regions of interest were placed in the septum and the right (RV) and left (LV) ventricular walls at the level of the atrioventricular plane. Peak myocardial velocities and mechanical cardiac time intervals were measured both manually and by an automated algorithm and agreement between the two methods was evaluated. RESULTS: In total, 321 myocardial velocity traces were analyzed using each method. It was possible to analyze all velocity traces obtained from the LV, RV and septal walls with the automated algorithm, and myocardial velocities and cardiac mechanical time intervals could be measured in 96% of all traces. The same results were obtained when the algorithm was run repeatedly. The myocardial velocities measured using the automated method correlated significantly with those measured manually. The agreement between methods was not consistent and some cTDI parameters had considerable bias and poor precision. CONCLUSIONS: Automated analysis of myocardial velocity recordings obtained by cTDI was feasible, suggesting that this technique could simplify and facilitate the use of cTDI in the evaluation of fetal cardiac function, both in research and in clinical practice. Copyright (c) 2017 ISUOG. Published by John Wiley & Sons Ltd. PMID- 28715152 TI - Demographic and ecological risk factors for human influenza A virus infections in rural Indonesia. AB - BACKGROUND: Indonesia has the world's highest reported mortality for human infections with highly pathogenic avian influenza (HPAI) A(H5N1) virus. Indonesia is an agriculturally driven country where human-animal mixing is common and provides a unique environment for zoonotic influenza A virus transmission. OBJECTIVES: To identify potential demographic and ecological risk factors for human infection with seasonal influenza A viruses in rural Indonesia, a population-based study was conducted in Cileunyi and Soreang subdistricts near Bandung in western Java from 2008 to 2011. METHODS: Passive influenza surveillance with RT-PCR confirmation of influenza A viral RNA in respiratory specimens was utilized for case ascertainment. A population census and mapping were utilized for population data collection. The presence of influenza A(H3N2) and A(H1N1)pdm09 virus infections in a household was modeled using Generalized Estimating Equations. RESULTS: Each additional child aged <5 years in a household increased the odds of H3N2 approximately 5 times (OR=4.59, 95%CI: 3.30-6.24) and H1N1pdm09 by 3.5 times (OR=3.53, 95%CI: 2.51-4.96). In addition, the presence of 16-30 birds in the house was associated with an increased odds of H3N2 (OR=5.08, 95%CI: 2.00-12.92) and H1N1pdm09 (OR=12.51 95%CI: 6.23-25.13). CONCLUSION: Our findings suggest an increase in influenza A virus infections in rural Indonesian households with young children and poultry. PMID- 28715155 TI - Asteroid Hyalosis Masquerading as Vitreous Hemorrhage on Point-of-Care Sonography. AB - Point-of-care ocular sonography is frequently used in the emergency department to evaluate patients with vision disorders. We describe a case series of 3 patients who ultimately had a diagnosis of asteroid hyalosis, a lesser-known condition that on point-of-care sonography may be mistaken for vitreous hemorrhage. Asteroid hyalosis is considered a benign degenerative condition. In contrast, vitreous hemorrhage may be an ocular emergency that warrants an urgent ophthalmologic consultation if there is an underlying retinal tear or detachment. Although similar in appearance on sonography, recognition of the subtle pathognomonic sonographic features along with their clinical presentations can differentiate these diseases, with vastly different management strategies and dispositions. PMID- 28715154 TI - The role of oxidative stress in acute renal injury of newborn rats exposed to hypoxia and endotoxin. AB - Neonatal kidney injury is a frequent pathology, especially among premature infants. The search for effective nephroprotection requires the creation of adequate experimental models of nephropathy in newborns. In this study, we explored the development of acute kidney injury (AKI) in neonatal rats during hypoxia or administration of endotoxin. We found that 2-h hypoxia (8% O2 ) and the intraperitoneal injection of 4 mg.kg-1 lipopolysaccharide (LPS) causes the appearance of AKI markers, such as kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) in the rat urine after 24 and 72 h of exposure. On the other hand, the levels of blood urine nitrogen under the same conditions rise only slightly. The damaging effects of hypoxia and endotoxin were accompanied by histological changes in the renal tissue and a significant decrease in the proliferation marker, (proliferating cell nuclear antigen). It is revealed that 3 h after the introduction of LPS, levels of reactive oxygen species in the kidney were significantly increased, and the injection of the antioxidant N-acetylcysteine afforded protection from AKI, evaluated by urine KIM 1 and NGAL levels. Thus, the simulation of AKI in newborn rat pups can be employed in screening for potential nephroprotective drugs, particularly among antioxidative compounds to be used in neonatology. PMID- 28715156 TI - Neutrophil-mediated enhancement of angiogenesis and osteogenesis in a novel triple cell co-culture model with endothelial cells and osteoblasts. AB - Repair and regeneration of critical-sized bone defects remain a major challenge in orthopaedic and craniomaxillofacial surgery. Until now, attempts to bioengineer bone tissue have been hindered by the inability to establish proper angiogenesis and osteogenesis in the tissue construct. In the present study, we established a novel triple cell co-culture model consisting of osteoblasts, endothelial cells, and neutrophils and conducted a systematic investigation of the effects of neutrophils on angiogenesis and osteogenesis. Neutrophils significantly increased angiogenesis in the tissue construct, evidenced by the formation of microvessel-like structures with an extensive lattice-like, stable tubular network in the co-culture model. Moreover, neutrophils significantly induced the expression of pro-angiogenic markers, such as VEGF-A, CD34, EGF, and FGF-2 in a dose- and time-dependent manner. Subsequently, PCR arrays corroborated that neutrophils upregulate the important angiogenic markers and MMPs. Moreover, neutrophils also enhanced osteogenic markers, such as ALP, OCN, OPN, and COL-1 compared with the controls. As shown by the osteogenic gene arrays, neutrophils significantly regulated major osteogenic markers such as BMP2, BMP3, BMP4, BMP5, TGF-beta2, RUNX2, and ECM proteins. Significantly higher mineralization was observed in triple cell co-culture compared with controls. Foregoing data indicate that the triple cell co-culture model can be used to stimulate the growth of microvasculature within a bone bioengineering construct to improve cell viability. Neutrophil-mediated enhancement of angiogenesis and osteogenesis could be a viable, clinically relevant tissue engineering strategy to obtain optimal bone growth in defect sites, in the field of oral and maxillofacial surgery. PMID- 28715157 TI - Use of the ShangRing circumcision device in boys below 18 years old in Kenya: results from a pilot study. AB - INTRODUCTION: Male circumcision is a proven prevention strategy against the spread of HIV. The World Health Organization's new 2016-2021 strategic framework on voluntary medical male circumcision (VMMC) targets 90% of males aged 10-29 years to receive circumcision by 2021 in 14 priority sub-Saharan countries while anticipating an increase in the demand for infant circumcision. It also states that the use of circumcision devices is a safe and efficient innovation to accelerate attainment of these goals. The primary objective of this pilot study was to evaluate the safety and acceptability of the ShangRing, a novel circumcision device, in boys below 18 years of age. METHODS: A total of 80 boys, 3 months to 17 years old, were circumcised using the no-flip ShangRing technique. All rings were removed 5-7 days later. Participants were evaluated weekly until the wound was completely healed. Data on procedure times, adverse events (AEs), time to clinical wound healing and satisfaction were recorded and analysed. RESULTS: Nearly all (79/80, 98.8%) circumcisions were successfully completed using the no-flip ShangRing technique without complications. In one (1.2%) case, the outer ring slipped off after the foreskin was removed and the procedure was completed by stitching. The mean circumcision and ring removal times were 7.4 +/- 3.2 and 4.4 +/- 4.2 min, respectively. There were four (5%) moderate AEs, which were managed conservatively. No severe AEs occurred. The mean time to complete clinical healing was 29.8 +/- 7.3 days. Participants or their parents liked ShangRing circumcision because it improved hygiene, was quick and possessed an excellent cosmetic appearance. Most (72/80, 94.7%) were very satisfied with the appearance of the circumcised penis, and all (100%) said they would recommend circumcision to others. CONCLUSIONS: Our results suggest that no-flip ShangRing VMMC is safe and acceptable in boys below 18 years of age. Our results are to be compared those seen following ShangRing VMMC in African men. Further study with larger sample sizes are needed to explore the scalability of the ShangRing in larger paediatric cohorts in Africa. We believe that the ShangRing has great potential for use in all age groups from neonates to adults, which would simplify device implementation. PMID- 28715158 TI - Loss to follow-up among children and adolescents growing up with HIV infection: age really matters. AB - INTRODUCTION: Globally, increasing numbers of HIV-infected children are reaching adolescence due to antiretroviral therapy (ART). We investigated rates of loss-to follow-up (LTFU) from HIV care services among children as they transition from childhood through adolescence. METHODS: Individuals aged 5-19 years initiated on ART in a public-sector HIV clinic in Bulawayo, Zimbabwe, between 2005 and 2009 were included in a retrospective cohort study. Participants were categorized into narrow age-bands namely: 5-9 (children), 10-14 (young adolescents) and 15-19 (older adolescents). The effect of age at ART initiation, current age (using a time-updated Lexis expansion) and transitioning from one age group to the next on LTFU was estimated using Poisson regression. RESULTS: Of 2273 participants, 1013, 875 and 385 initiated ART aged 5-9, 10-14 and 15-19 years, respectively. Unlike those starting ART as children, individuals starting ART as young adolescents had higher LTFU rates after moving to the older adolescent age-band (Adjusted rate ratio (ARR) 1.54; 95% CI: 0.94-2.55) and similarly, older adolescents had higher LTFU rates after transitioning to being young adults (ARR 1.79; 95% CI: 1.05 3.07). In older adolescents, the LTFU rate among those who started ART in that age-band was higher compared to the rate among those starting ART at a younger age (ARR = 1.70; 95% CI: 1.05, 2.77). This however did not hold true for other age-groups. CONCLUSIONS: Adolescents had higher rates of LTFU compared to other age-groups, with older adolescents at particularly high risk in all analyses. Age updated analyses that examine movement across narrow age-bands are paramount in understanding how developmental heterogeneity in children affects HIV outcomes. PMID- 28715159 TI - Alcohol-antiretroviral interactive toxicity beliefs as a potential barrier to HIV pre-exposure prophylaxis among men who have sex with men. AB - INTRODUCTION: Pre-exposure prophylaxis (PrEP) offers as much as 90% protection against HIV transmission. However, the effectiveness of PrEP depends on uptake and adherence to even intermittent dosing. Along with intoxication leading to unintentional non-adherence, believing that alcohol mixed with pharmaceuticals is harmful (i.e., interactive toxicity beliefs) may lead to poor uptake and intentional non-adherence. METHODS: HIV-negative sexually active men who have sex with men (N = 272) at a large Gay Pride event in Atlanta, GA, completed anonymous surveys of demographic characteristics, sexual behaviour, alcohol use and PrEP related alcohol interactive toxicity beliefs. RESULTS: A total of 118 (43%) men surveyed had two or more male sex partners and condomless anal sex in the previous six months. Alcohol use was reported by over 90% of men and it was common for participants to believe that mixing alcohol and antiretrovirals is toxic; 75% endorsed at least one interactive toxicity belief. Among the 118 men who had engaged in condomless anal sex and had multiple sex partners, one in three stated that they were not interested in PrEP and men not interested in PrEP were significantly more likely to binge drink and hold interactive toxicity beliefs. CONCLUSIONS: These results mirror studies that find interactive toxicity beliefs are a potent predictor of intentional antiretroviral non-adherence among people living with HIV and suggest interactive toxicity beliefs may impede PrEP uptake and adherence. Messages to increase PrEP awareness and adherence may also take steps to counter erroneous beliefs about mixing alcohol with antiretrovirals in the context of PrEP. PMID- 28715161 TI - Schedules of Controlled Substances: Temporary Placement of Acryl Fentanyl Into Schedule I. Temporary scheduling order. AB - The Administrator of the Drug Enforcement Administration is issuing this temporary scheduling order to schedule the synthetic opioid, N-(1 phenethylpiperidin-4-yl)-N-phenylacrylamide (acryl fentanyl or acryloylfentanyl), and its isomers, esters, ethers, salts and salts of isomers, esters, and ethers, into Schedule I. This action is based on a finding by the Administrator that the placement of acryl fentanyl into Schedule I of the Controlled Substances Act is necessary to avoid an imminent hazard to the public safety. As a result of this order, the regulatory controls and administrative, civil, and criminal sanctions applicable to Schedule I controlled substances will be imposed on persons who handle (manufacture, distribute, reverse distribute, import, export, engage in research, conduct instructional activities or chemical analysis, or possess), or propose to handle, acryl fentanyl. PMID- 28715162 TI - Designation of Alpha-Phenylacetoacetonitrile (APAAN), a Precursor Chemical Used in the Illicit Manufacture of Phenylacetone, Methamphetamine, and Amphetamine, as a List I Chemical. Final rule. AB - The Drug Enforcement Administration (DEA) is finalizing the designation of the chemical alpha-phenylacetoacetonitrile (APAAN) and its salts, optical isomers, and salts of optical isomers, as a list I chemical under the Controlled Substances Act (CSA). The DEA proposed control of APAAN, due to its use in clandestine laboratories to illicitly manufacture the schedule II controlled substances phenylacetone (also known as phenyl-2-propanone or P2P), methamphetamine, and amphetamine. This rulemaking finalizes, without change, the control of APAAN as a list I chemical. This action does not establish a threshold for domestic and international transactions of APAAN. As such, all transactions involving APAAN, regardless of size, shall be regulated. In addition, chemical mixtures containing APAAN are not exempt from regulatory requirements at any concentration. Therefore, all transactions of chemical mixtures containing any quantity of APAAN shall be regulated pursuant to the CSA. However, manufacturers may submit an application for exemption for those mixtures that do not qualify for automatic exemption. PMID- 28715163 TI - Closing the Opportunity Gap in Early Childhood Education. AB - (1) Nineteen percent of low-income families enroll in high-quality early childhood education, while 29 percent of high income families do. (2) African American,Hispanic/Latino and low-income children enter kindergarten, on average, significantly behind in reading and math skills. (3) Gaps in math and reading achievement generally persist in fourth grade and are even larger by eighth grade. PMID- 28715164 TI - Sexual Harassment Policies and Training in State Legislatures. AB - (1) Sexual harassment is a violation of The Civil Rights Act of 1964. (2) Most states do not require employers to conduct sexual harassment training. (3) Most sexual harassment training for state legislators occurs at their orientation. PMID- 28715160 TI - Meeting the WHO 90% target: antiretroviral treatment efficacy in Poland is associated with baseline clinical patient characteristics. AB - INTRODUCTION: Modern combined antiretroviral therapies (cART) allow to effectively suppress HIV-1 viral load, with the 90% virologic success rate, meeting the WHO target in most clinical settings. The aim of this study was to analyse antiretroviral treatment efficacy in Poland and to identify variables associated with virologic suppression. M: ethods Cross-sectional data on 5152 (56.92% of the countrywide treated at the time-point of analysis) patients on cART for more than six months with at least one HIV-RNA measurement in 2016 were collected from 14 Polish centres. Patients' characteristics and treatment type based outcomes were analysed for the virologic suppression thresholds of <50 and <200 HIV-RNA copies/ml. CART was categorized into two nucleos(t)ide (2NRTI) plus non-nucleoside reverse transcriptase (NNRTI) inhibitors, 2NRTI plus protease (PI) inhibitor, 2NRTI plus integrase (InI) inhibitor, nucleos(t)ide sparing PI/r+InI and three drug class regimens. For statistics Chi-square and U-Mann Whitney tests and adjusted multivariate logistic regression models were used. RESULTS: Virologic suppression rates of <50 copies/mL were observed in 4672 (90.68%) and <200 copies/mL in 4934 (95.77%) individuals. In univariate analyses, for the suppression threshold <50 copies/mL higher efficacy was noted for 2NRTI+NNRTI based combinations (94.73%) compared to 2NRTI+PI (89.93%), 2NRTI+InI (90.61%), nucleos(t)ide sparing PI/r+InI (82.02%) and three drug class regimens (74.49%) (p < 0.0001), with less pronounced but significant differences for the threshold of 200 copies/mL [2NRTI+NNRTI-97.61%, 2NRTI+PI-95.27%, 2NRTI+InI-96.61%, PI/r+InI- 95.51% and 86.22% for three drug class cART) (p < 0.0001). However, in multivariate model, virologic efficacy for viral load <50 copies/mL was similar across treatment groups with significant influence by history of AIDS [OR:1.48 (95%CI:1.01-2.17) if AIDS diagnosed, p = 0.046], viral load < 5 log copies/mL at care entry [OR:1.47 (95%CI:1.08-2.01), p = 0.016], baseline lymphocyte CD4 count >=200 cells/uL [OR:1.72 (95%CI:1.04-2.78), p = 0.034] and negative HCV serology [OR:1.97 (95%CI:1.29-2.94), p = 0.002]. For viral load threshold <200 copies/mL higher likelihood of virologic success was only associated with baseline lymphocyte CD4 count >=200 cells/uL [OR:2.08 (95%CI:1.01-4.35), p = 0.049] and negative HCV status [OR:2.84 (95%CI:1.52-5.26), p = 0.001]. CONCLUSIONS: Proportion of virologically suppressed patients is in line with WHO treatment target confirming successful application of antiretroviral treatment strategy in Poland. Virological suppression rates depend on baseline patient characteristics, which should guide individualized antiretroviral tre0atment decisions. PMID- 28715165 TI - Relaxing School Suncreen Restrictions. AB - (1) Utah, Delaware, Vermont, Minnesota and Idaho have the highest skin cancer rates of all U.S. states, according to the Centers for Disease Control and Prevention. (2) Sunscreen is regulated by the U.S. Food and Drug Administration because it makes a "drug claim"--that it helps prevent sunburn and decreases the risks of skin cancer and early skin aging caused by the sun. (3) In Europe and some other countries, sunscreens are regulated as cosmetics, not as drugs. PMID- 28715167 TI - Computationally Driven Two-Dimensional Materials Design: What Is Next? AB - Two-dimensional (2D) materials offer many key advantages to innovative applications, such as spintronics and quantum information processing. Theoretical computations have accelerated 2D materials design. In this issue of ACS Nano, Kumar et al. report that ferromagnetism can be achieved in functionalized nitride MXene based on first-principles calculations. Their computational results shed light on a potentially vast group of materials for the realization of 2D magnets. In this Perspective, we briefly summarize the promising properties of 2D materials and the role theory has played in predicting these properties. In addition, we discuss challenges and opportunities to boost the power of computation for the prediction of the "structure-property-process (synthesizability)" relationship of 2D materials. PMID- 28715168 TI - Junctionless Diode Enabled by Self-Bias Effect of Ion Gel in Single-Layer MoS2 Device. AB - The self-biasing effects of ion gel from source and drain electrodes on electrical characteristics of single layer and few layer molybdenum disulfide (MoS2) field-effect transistor (FET) have been studied. The self-biasing effect of ion gel is tested for two different configurations, covered and open, where ion gel is in contact with either one or both, source and drain electrodes, respectively. In open configuration, the linear output characteristics of the pristine device becomes nonlinear and on-off ratio drops by 3 orders of magnitude due to the increase in "off" current for both single and few layer MoS2 FETs. However, the covered configuration results in a highly asymmetric output characteristics with a rectification of around 103 and an ideality factor of 1.9. This diode like behavior has been attributed to the reduction of Schottky barrier width by the electric field of self-biased ion gel, which enables an efficient injection of electrons by tunneling at metal-MoS2 interface. Finally, finite element method based simulations are carried out and the simulated results matches well in principle with the experimental analysis. These self-biased diodes can perform a crucial role in the development of high-frequency optoelectronic and valleytronic devices. PMID- 28715169 TI - Fabrication of Biocompatible, Functional, and Transparent Hybrid Films Based on Silk Fibroin and Epoxy Silane for Biophotonics. AB - In this work we explored the fabrication of flexible and transparent hybrids of silk fibroin (SF) and epoxy-modified siloxane for photonic applications. It is well-known that regenerated SF solutions can form free-standing films with high transparency. Although SF has a restricted number of chemically reactive side groups, the main issues of as-cast pristine SF films regard the high solubility into aqueous media, brittleness, and low thermal stability. The design of SF films with enhanced functionality but high transparency triggers new opportunities on a broader range of applications in biophotonics. Here we present a simple, functional, yet remarkably versatile hybrid material derived from silica sol-gel process based on SF protein and (3 glycidyloxypropyl)trimethoxysilane (GPTMS), an organically modified silicon alkoxide owning a reactive terminal epoxy group. Specifically, we investigated the effect of the addition of GPTMS into SF solutions on the processability, morphology, crystallinity, and mechanical and optical properties of the resulting hybrid films. Highly transparent (ca. 90%) and flexible free-standing hybrid films were achieved. Cell viability assays revealed that the hybrid films are noncytotoxic to rat osteoblast cells even at high GPTMS content (up to 70 wt %). The hybrid films showed enhanced thermal stability and were rich in organic (epoxy) and inorganic (silanol) functional groups according to the content of GPTMS. We also evaluated the successful preparation of high-quality optical red emissive SF hybrid films by loading YVO4:Eu3+ nanoparticles at low concentration (<5 wt %). A meaningful description of the hybrid film structure is reported from the combination of scanning electron and atomic force microscopies, vibrational spectroscopy, solid-state NMR, and X-ray diffraction analyses. PMID- 28715170 TI - Double Soft-Template Synthesis of Nitrogen/Sulfur-Codoped Hierarchically Porous Carbon Materials Derived from Protic Ionic Liquid for Supercapacitor. AB - Heteroatom-doped hierarchical porous carbon materials derived from the potential precursors and prepared by a facile, effective, and low-pollution strategy have recently been particularly concerned in different research fields. In this study, the interconnected nitrogen/sulfur-codoped hierarchically porous carbon materials have been successfully obtained via one-step carbonization of the self-assembly of [Phne][HSO4] (a protic ionic liquid originated from dilute sulfuric acid and phenothiazine by a straightforward acid-base neutralization) and the double soft template of OP-10 and F-127. During carbonization process, OP-10 as macroporous template and F-127 as mesoporous template were removed, while [Phne][HSO4] not only could be used as carbon, nitrogen, and sulfur source, but also as a pore forming agent to create micropores. The acquired carbon materials for supercapacitor not only hold a large specific capacitance of 302 F g-1 even at 1.0 A g-1, but also fine rate property with 169 F g-1 at 10 A g-1 and excellent capacitance retention of nearly 100% over 5000 circulations in 6 M KOH electrolyte. Furthermore, carbon materials also present eximious rate performance with 70% in 1 M Na2SO4 electrolyte. PMID- 28715171 TI - Limitations of Structural Superlubricity: Chemical Bonds versus Contact Size. AB - Structural superlubricity describes the state of virtually frictionless sliding if two atomically flat interfaces are incommensurate, that is, they share no common periodicity. Despite the exciting prospects of this low friction phenomenon, there are physical limitations to the existence of this state. Theory predicts that the contact size is one fundamental limit, where the critical size threshold mainly depends on the interplay between lateral contact compliance and interface interaction energies. Here we provide experimental evidence for this size threshold by measuring the sliding friction force of differently sized antimony particles on MoS2. We find that superlubric sliding with the characteristic linear decrease of shear stress with contact size prevails for small particles with contact areas below 15 000 nm2. Larger particles, however, show a transition toward constant shear stress behavior. In contrast, Sb particles on graphite show superlubricity over the whole size range. Ab initio simulations reveal that the chemical interaction energies for Sb/MoS2 are much stronger than for Sb/HOPG and can therefore explain the different friction properties as well as the critical size thresholds. These limitations must be considered when designing low friction contacts based on structural superlubricity concepts. PMID- 28715172 TI - Spatiotemporal Industrial Activity Model for Estimating the Intensity of Oil and Gas Operations in Colorado. AB - Oil and gas (O&G) production in the United States has increased in the last 15 years, and operations, which are trending toward large multiwell pads, release hazardous air pollutants. Health studies have relied on proximity to O&G wells as an exposure metric, typically using an inverse distance-weighting (IDW) approach. Because O&G emissions are dependent on multiple factors, a dynamic model is needed to describe the variability in air pollution emissions over space and time. We used information on Colorado O&G activities, production volumes, and air pollutant emission rates from two Colorado basins to create a spatiotemporal industrial activity model to develop an intensity-adjusted IDW well-count metric. The Spearman correlation coefficient between this metric and measured pollutant concentrations was 0.74. We applied our model to households in Greeley, Colorado, which is in the middle of the densely developed Denver-Julesburg basin. Our intensity-adjusted IDW increased the unadjusted IDW dynamic range by a factor of 19 and distinguishes high-intensity events, such as hydraulic fracturing and flowback, from lower-intensity events, such as production at single-well pads. As the frequency of multiwell pads increases, it will become increasingly important to characterize the range of intensities at O&G sites when conducting epidemiological studies. PMID- 28715173 TI - Influence of 18-Crown-6 Ether Coordination on the Catalytic Activity of Potassium and Calcium Diarylphosphinites in Hydrophosphorylation Reactions. AB - The addition of 18-crown-6 ether (1,4,7,10,13,16-hexaoxacyclooctadecane) to tetranuclear [(thf)K(OPAryl2)]4 and [(thf)4Ca(OPAryl2)2] yields the corresponding mononuclear complexes [(18C6)K(OPAryl2)] [Aryl = Ph (1a), Mes (1b)] and [(18C6)Ca(OPAryl2)2] [Aryl = Ph (2a), Mes (2b)]. The metathesis reaction of [(thf)K(OPAryl2)]4 with CaI2 yields the calciate [K2Ca(thf)x{OPMes2}4]. The addition of dimesitylphosphane oxide and crystallization from a hexane solution gives [K2Ca{OPMes2}4{Mes2P(O)H}] (3). The complexes [(thf)K(OPMes2)]4, [(thf)4Ca(OPMes2)2], 1b, 2b, and the calciate 3 are tested as catalysts in the hydrophosphorylation of isopropylisocyanate with dimesitylphosphane oxide, quantitatively yielding N-isopropyl(dimesitylphosphoryl)formamide. The potassium complexes are more efficient catalysts than the calcium congeners, and coordination of 18-crown-6 decelerates the catalytic conversion. PMID- 28715174 TI - Tunable Upper Critical Solution Temperatures for Acrylamide Copolymers with Bile Acid Pendants. AB - Acrylamide derivatives of bile acids are chosen as a hydrophobic comonomer to copolymerize with acrylamide via reversible addition and fragmentation chain transfer (RAFT) polymerization to afford a series of copolymers of P(AAm-co-CAA). These copolymers exhibit a sharp and reversible insoluble-soluble transition in water upon heating to a mixing temperature (Tmix) related to the upper critical solution temperature (UCST). Tmix of these copolymers can be conveniently tuned to a practical temperature range, around 37 degrees C for biomedical applications. Tmix rises with increasing molar fraction of the bile acid-based acrylamide and increasing concentration of the aqueous solution of the copolymers. The addition of a natural host molecule beta-cyclodextrin lowered the Tmix. The insoluble-soluble transition of the copolymers was also evidenced by dynamic light scattering and transmission electron microscopy. The biocompatible nature of the bile acids and beta-cyclodextrins may make these copolymers potentially useful for biomedical applications. PMID- 28715175 TI - Airborne Nanoparticle Release and Toxicological Risk from Metal-Oxide-Coated Textiles: Toward a Multiscale Safe-by-Design Approach. AB - Nano metal oxides have been proposed as alternatives to silver (Ag) nanoparticles (NPs) for antibacterial coatings. Here, cotton and polyester-cotton fabrics were sonochemically coated with zinc oxide (ZnO) and copper oxide (CuO) NPs. By varying the reaction solvent (water or ethanol), NPs with different sizes and shapes were synthesized. The cytotoxic and pro-inflammatory effects of studied NPs were investigated in vitro in human alveolar epithelial A549 and macrophage like THP1 cells. To understand the potential respiratory impact of the NPs, the coated textiles were subjected to the abrasion tests, and the released airborne particles were measured. A very small amount of the studied metal oxides NPs was released from abrasion of the textiles coated by the ethanol-based sonochemical process. The release from the water-based coating was comparably higher. Lung and immune cells viability decreased after 24 h of exposure only at the highest studied NPs concentration (100 MUg/mL). Different from the ZnO NPs, both formulations of CuO NPs induced IL-8 release in the lung epithelial cells already at subtoxic concentrations (1-10 MUg/mL) but not in immune cells. All of the studied NPs did not induce IL-6 release by the lung and immune cells. Calculations revealed that the exposures of the NPs to human lung due to the abrasion of the textiles were lower or comparable to the minimum doses in the cell viability tests (0.1 MUg/mL), at which acute cytotoxicity was not observed. The results alleviate the concerns regarding the potential risk of these metal oxide NPs in their applications for the textile coating and provide insight for the safe-by-design approach. PMID- 28715176 TI - A Fast and Scalable Approach for Synthesis of Hierarchical Porous Zeolitic Imidazolate Frameworks and One-Pot Encapsulation of Target Molecules. AB - A trimethylamine (TEA)-assisted synthesis approach that combines the preparation of hierarchical porous zeolitic imidazolate framework ZIF-8 nanoparticles and one pot encapsulation of target molecules is presented. Two dye molecules, rhodamine B (RhB) and methylene blue (MB), and one protein (bovine serum albumin, BSA) were tested as the target molecules. The addition of TEA into the solution of zinc nitrate promoted the formation of ZnO nanocrystals, which rapidly transformed to ZIF-8 nanoparticles after the addition of the linker 2-methylimidazole (Hmim). Hierarchical porous dye@ZIF-8 nanoparticles with high crystallinity, large BET surface areas (1300-2500 m2/g), and large pore volumes (0.5-1.0 cm3/g) could be synthesized. The synthesis procedure was fast (down to 2 min) and scalable. The Hmim/Zn ratio could be greatly reduced (down to 2:1) compared to previously reported ones. The surface areas, and the mesopore size, structure, and density could be modified by changing the TEA or dye concentrations, or by postsynthetic treatment using reflux in methanol. This synthesis and one-pot encapsulation approach is simple and can be readily scaled up. The photophysical properties such as lifetime and photostability of the dyes could be tuned via encapsulation. The lifetimes of the encapsulated dyes were increased by 3-27-fold for RhB@ZIF-8 and by 20-fold for MB@ZIF-8, compared to those of the corresponding free dyes. The synthesis approach is general, which was successfully applied for encapsulation of protein BSA. It could also be extended for the synthesis of hierarchical porous cobalt-based ZIF (dye@ZIF-67). PMID- 28715178 TI - Flexible and Robust Superomniphobic Surfaces Created by Localized Photofluidization of Azopolymer Pillars. AB - Springtails, insects which breathe through their skins, possess mushroom-shaped nanostructures. As doubly re-entrant geometry in the mushroom head enhances the resistance against liquid invasion, the springtails have robust, liquid-free omniphobic skins. Although omniphobic surfaces are promising for various applications, it remains an important challenge to mimic the structural feature of springtails. This paper presents a pragmatic method to create doubly re entrant nanostructures and robust superomniphobic surfaces by exploiting localized photofluidization of azopolymers. Irradiation of circularly polarized light reconfigures azopolymer micropillars to have a mushroom-like head with a doubly re-entrant nanogeometry through protrusion and inward bending of polymer film from the top edge. The light-driven reconfigured micropillars facilitate the pining of triple line as the springtails do. In particular, the unique geometry exhibits superomniphobicity even for liquids whose equilibrium contact angles are almost zero in the presence of a practical level of external pressure. In addition, the simple fabrication process is highly reproducible, scalable, and compatible with various substrate materials including flexible polymeric film. Our results suggest that our photofluidization technology will provide a practical route to develop robust superomniphobic surfaces. PMID- 28715177 TI - Ribosome Mediated Quinary Interactions Modulate In-Cell Protein Activities. AB - Ribosomes are present inside bacterial cells at micromolar concentrations and occupy up to 20% of the cell volume. Under these conditions, even weak quinary interactions between ribosomes and cytosolic proteins can affect protein activity. By using in-cell and in vitro NMR spectroscopy, and biophysical techniques, we show that the enzymes, adenylate kinase and dihydrofolate reductase, and the respective coenzymes, ATP and NADPH, bind to ribosomes with micromolar affinity, and that this interaction suppresses the enzymatic activities of both enzymes. Conversely, thymidylate synthase, which works together with dihydrofolate reductase in the thymidylate synthetic pathway, is activated by ribosomes. We also show that ribosomes impede diffusion of green fluorescent protein in vitro and contribute to the decrease in diffusion in vivo. These results strongly suggest that ribosome-mediated quinary interactions contribute to the differences between in vitro and in vivo protein activities and that ribosomes play a previously under-appreciated nontranslational role in regulating cellular biochemistry. PMID- 28715179 TI - Chemoselective Asymmetric Intramolecular Dearomatization of Phenols with alpha Diazoacetamides Catalyzed by Silver Phosphate. AB - We report asymmetric dearomatization of phenols using Ag carbenoids from alpha diazoacetamides. The Ag catalyst promoted intramolecular dearomatization of phenols, whereas a Rh or Cu catalyst caused C-H insertion and a Buchner reaction. Studies indicated Ag carbenoids have a carbocation-like character, making their behavior and properties unique. Highly enantioselective transformations using Ag carbenoids have not been reported. We achieved a Ag carbenoid-mediated chemo- and highly enantioselective phenol dearomatization with substrate generality for the first time. PMID- 28715180 TI - Inverting Conventional Chemoselectivity in Pd-Catalyzed Amine Arylations with Multiply Halogenated Pyridines. AB - A new catalyst system capable of selective chloride functionalization in the Pd catalyzed amination of 3,2- and 5,2- Br/Cl-pyridines is reported. A reaction optimization strategy employing ligand parametrization led to the identification of 1,1'-bis[bis(dimethylamino)phosphino]ferrocene "DMAPF", a readily available yet previously unutilized diphosphine, as a uniquely effective ligand for this transformation. PMID- 28715182 TI - Revisiting the Helical Cooperativity of Synthetic Polypeptides in Solution. AB - Using synthetic polypeptides as a model system, the theories of helix-coil transition were developed into one of the most beautiful and fruitful subjects in macromolecular science. The classic models proposed by Schellman and Zimm-Bragg more than 50 years ago, differ in the assumption on whether the configuration of multiple helical sequences separated by random coil sections is allowed in a longer polypeptide chain. Zimm also calculated the critical chain lengths that facilitate such interrupted helices in different solvent conditions. The experimental validation of Zimm's prediction, however, was not carefully examined at that time. Herein, we synthesize a series of homopolypeptide samples with different lengths, to systematically examine their helix-coil transition and folding cooperativity in solution. We find that for longer chains, polypeptides do exist as interrupted helices with scattered coil sections even in helicogenic solvent conditions, as predicted in the Zimm-Bragg model. The critical chain lengths that facilitate such interrupted helices, however, are substantially smaller than Zimm's original estimation. The inaccuracy is in part due to an approximation that Zimm made in simplifying the calculation. But more importantly, we find there exist intramolecular interactions between different structural segments in the longer polypeptides, which are not considered in the classic helix-coil theories. As such, even the Zimm-Bragg model in its exact form cannot fully describe the transition behavior and folding cooperativity of longer polypeptides. The results suggest that long "all-helix" chains may be much less prevalent in solution than previously imagined, and a revised theory is required to accurately account for the helix-coil transition of the longer chains with potential "non-local" intramolecular interactions. PMID- 28715183 TI - Dimethyl Sulfoxide Complexes Detected at Ambient Conditions. AB - Dimethyl sulfoxide (DMSO) is an important intermediate in the atmospheric oxidation of dimethyl sulfide (DMS). DMS, emitted from the ocean, is the main natural sulfur source, and its oxidation products are essential in the formation of sulfate aerosols. The high atmospheric concentration of water makes hydrogen bonding with DMS and its oxidation products likely. Through hydrogen bonding, water can potentially catalyze and affect the steps of the oxidation. We investigate binary hydrogen-bound complexes involving DMSO. Both water.DMSO and methanol.DMSO complexes are identified in an Ar matrix, and at room temperature, a Gibbs free energy of 0.7 kJ/mol for the formation of the methanol.DMSO complex is determined. Assuming a similar Gibbs free energy of the hydrate, it would suggest a relatively high abundance of the DMSO hydrate relative to the monomer in the atmosphere. The effect of changing the atom divalently bound to the hydrogen bond accepting oxygen, from S to C (DMSO to acetone), is found to significantly decrease the equilibrium constant of complex formation. PMID- 28715181 TI - Structural Insights into Selective Ligand-Receptor Interactions Leading to Receptor Inactivation Utilizing Selective Melanocortin 3 Receptor Antagonists. AB - Systematic N-methylated derivatives of the melanocortin receptor ligand, SHU9119, lead to multiple binding and functional selectivity toward melanocortin receptors. However, the relationship between N-methylation-induced conformational changes in the peptide backbone and side chains and melanocortin receptor selectivity is still unknown. We conducted comprehensive conformational studies in solution of two selective antagonists of the third isoform of the melanocortin receptor (hMC3R), namely, Ac-Nle-c[Asp-NMe-His6-d-Nal(2')7-NMe-Arg8-Trp9-Lys]-NH2 (15) and Ac-Nle-c[Asp-His6-d-Nal(2')7-NMe-Arg8-NMe-Trp9-NMe-Lys]-NH2 (17). It is known that the pharmacophore (His6-DNal7-Arg8-Trp9) of the SHU-9119 peptides occupies a beta II-turn-like region with the turn centered about DNal7-Arg8. The analogues with hMC3R selectivity showed distinct differences in the spatial arrangement of the Trp9 side chains. In addition to our NMR studies, we also carried out molecular-level interaction studies of these two peptides at the homology model of hMC3R. Earlier chimeric human melanocortin 3 receptor studies revealed insights regarding the binding and functional sites of hMC3R selectivity. Upon docking of peptides 15 and 17 to the binding pocket of hMC3R, it was revealed that Arg8 and Trp9 side chains are involved in a majority of the interactions with the receptor. While Arg8 forms polar contacts with D154 and D158 of hMC3R, Trp9 utilizes pi-pi stacking interactions with F295 and F298, located on the transmembrane domain of hMC3R. It is hypothesized that as the frequency of Trp9-hMC3R interactions decrease, antagonistic activity increases. The absence of any interactions of the N-methyl groups with hMC3R suggests that their primary function is to modulate backbone conformations of the ligands. PMID- 28715184 TI - Theoretical Investigation of C-H Vibrational Spectroscopy. 1. Modeling of Methyl and Methylene Groups of Ethanol with Different Conformers. AB - A flexible and polarizable molecular model of ethanol is developed to extend our investigation of thermodynamic, structural, and vibrational properties of the liquid and interface. A molecular dynamics (MD) simulation with the present model confirmed that this model well reproduces a number of properties of liquid ethanol, including density, heat of vaporization, surface tension, molecular dipole moment, and trans/gauche ratio. In particular, the present model can describe vibrational IR, Raman, and sum frequency generation (SFG) spectra of ethanol and partially deuterated analogues with reliable accuracy. The improved accuracy is largely attributed to proper modeling of the conformational dependence and the intramolecular couplings including Fermi resonance in C-H vibrations. Precise dependence of torsional motions is found to be critical in representing vibrational spectra of the C-H bending. This model allows for further vibrational analysis of complicated alkyl groups widely observed in various organic molecules with MD simulation. PMID- 28715186 TI - Improving the Efficiency of Configurational-Bias Monte Carlo: Extension of the Jacobian-Gaussian Scheme to Interior Sections of Cyclic and Polymeric Molecules. AB - The Jacobian-Gaussian method, which has recently been developed for generating bending angle trials, is extended to the conformational sampling of inner segments of a long chain or cyclic molecule where regular configurational-bias Monte Carlo was found to be very inefficient or simply incapable (i.e., for the cyclic case). For these molecules, a new conformational move would be required where one interior section is relocated while the rest of the molecule, before and after this section, is fixed. Techniques have been developed to extend the regular configurational-bias Monte Carlo to such a fixed-end points case by introducing a biasing probability function. Each trial is weighted by this function to ensure the closure of the molecule by selecting appropriate growth direction. However, the acceptance rate might be reduced significantly due to the incongruity of this weight and the energy weight. In addition, the last steps of closing the molecule include several bending and torsional energies that are coupled to each other. Thus, generating a trial that is acceptable for all energetic terms becomes a difficult problem. The Jacobian-Gaussian method can overcome these two problems with the following two principles: First, basic geometrical constraints must be fulfilled to guarantee molecular closure, which avoids the need of the biasing probability function. Second, the growth variables are transformed into those used explicitly in expressing the various intramolecular energies between fixed points to allow for the trials to be generated directly according to the Boltzmann distributions of these energetic terms, which improves the acceptance rates dramatically. This method has been examined on the growth of inner segments of linear and cyclic alkanes, which proves its higher efficiency over that of traditional methods. PMID- 28715185 TI - Substrate Binding Primes Human Tryptophan 2,3-Dioxygenase for Ligand Binding. AB - The human heme enzyme tryptophan 2,3-dioxygenase (hTDO) catalyzes the insertion of dioxygen into its cognate substrate, l-tryptophan (l-Trp). Its active site structure is highly dynamic, and the mechanism of enzyme-substrate-ligand complex formation and the ensuing enzymatic reaction is not yet understood. Here we have studied complex formation in hTDO by using time-resolved optical and infrared spectroscopy with carbon monoxide (CO) as a ligand. We have observed that both substrate-free and substrate-bound hTDO coexist in two discrete conformations with greatly different ligand binding rates. In the fast rebinding hTDO conformation, there is facile ligand access to the heme iron, but it is greatly hindered in the slowly rebinding conformation. Spectroscopic evidence implicates active site solvation as playing a crucial role for the observed kinetic differences. Substrate binding shifts the conformational equilibrium markedly toward the fast species and thus primes the active site for subsequent ligand binding, ensuring that formation of the ternary complex occurs predominantly by first binding l-Trp and then the ligand. Consequently, the efficiency of catalysis is enhanced because O2 binding prior to substrate binding, resulting in nonproductive oxidation of the heme iron, is greatly suppressed. PMID- 28715187 TI - Charge Density Wave and Narrow Energy Gap at Room Temperature in 2D Pb3 xSb1+xS4Te2-delta with Square Te Sheets. AB - We report a new two-dimensional compound, Pb3-xSb1+xS4Te2-delta, that has a charge density wave (CDW) at room temperature. The CDW is incommensurate with q vector of 0.248(6)a* + 0.246(8)b* + 0.387(9)c* for x = 0.29(2) and delta = 0.37(3) due to positional and occupational long-range ordering of Te atoms in the sheets. The modulated structure was refined from the single-crystal X-ray diffraction data with a superspace group P1(alphabetagamma)0 using (3 + 1) dimensional crystallography. The resistivity increases with decreasing temperature, suggesting semiconducting behavior. The transition temperature (TCDW) of the CDW is ~345 K, above which the Te square sheets become disordered with no q-vector. First-principles density functional theory calculations on the undistorted structure and an approximate commensurate supercell reveal that the gap is due to the structure modulation. PMID- 28715188 TI - Understanding the Microscopic Behavior of the Mixture of Ionic Liquid/Ethylene Glycol/Lithium Salt through Time-Resolved Fluorescence, Nuclear Magnetic Resonance (NMR), and Electron Paramagnetic Resonance (EPR) Studies. AB - The present study has been undertaken with an aim to find out the suitability of a binary solvent system, comprising an anionic liquid, 1-(2-hydroxyethyl)-3 methylimidazolium bis(trifluoromethylsulfonyl)imide ([OHEMIM][NTf2]) and ethylene glycol (EG), toward lithium ion battery applications. For this purpose, the behavior in terms of structure, intermolecular interaction, and dynamics of several solvent systems, [OHEMIM][NTf2], [OHEMIM][NTf2]-LiNTf2(lithium bis(trifluorimethylsulfonyl)imide), [OHEMIM][NTf2]-EG, and [OHEMIM][NTf2]-EG LiNTf2, is investigated by carrying out steady state and time-resolved fluorescence, nuclear magnetic resonance (NMR), and electron paramagnetic resonance (EPR) measurements. Both steady-state fluorescence and EPR studies have pointed out that the micropolarities of [OHEMIM][NTf2]-EG-LiNTf2 are close to those of neat RTIL. However, studies on rotational dynamics have revealed that the structural organization of [OHEMIM][NTf2]-LiNTf2 is significantly influenced upon addition of EG. Interestingly, the average solvation time is observed to be relatively faster in [OHEMIM][NTf2]-EG-LiNTf2 than those in other solvent systems. Since average solvation time and conductivity are inversely related to each other, the present observation indicates that the introduction of EG is helpful in increasing the electrical conductivity of [OHEMIM][NTf2]-EG-LiNTf2. Translational diffusion coefficient measurements in [OHEMIM][NTf2]-EG-LiNTf2 and [OHEMIM][NTf2]-LiNTf2 through NMR spectroscopy have also indicated the suitability of [OHEMIM][NTf2]-EG-LiNTf2 as a potential electrolytic medium for battery applications. PMID- 28715189 TI - Diamine-Tethered Bis(thiourea) Organocatalyst for Asymmetric Henry Reaction. AB - We have developed a novel multifunctional C2-symmetric biphenyl-based diamine tethered bis(thiourea) organocatalyst, which was tested in the asymmetric Henry reaction. Under thoroughly optimized conditions, the catalyst provided exceptionally high yields and excellent enantioselectivities especially for electron-deficient aromatic and heterocyclic substrates. Due to a high affinity of the catalyst to silica gel, a simple chromatography-free nitroaldol isolation procedure was feasible. Preliminary kinetic and spectroscopic experiments were performed in order to complete the mechanistic picture of the organocatalyzed nitroaldolization process. Finally, the developed synthetic strategy was successfully applied to the catalytic enantioselective syntheses of enantiopure (S)-econazole and (R)-mirabegron a late-stage intermediate. PMID- 28715190 TI - Chemical Topic Modeling: Exploring Molecular Data Sets Using a Common Text-Mining Approach. AB - Big data is one of the key transformative factors which increasingly influences all aspects of modern life. Although this transformation brings vast opportunities it also generates novel challenges, not the least of which is organizing and searching this data deluge. The field of medicinal chemistry is not different: more and more data are being generated, for instance, by technologies such as DNA encoded libraries, peptide libraries, text mining of large literature corpora, and new in silico enumeration methods. Handling those huge sets of molecules effectively is quite challenging and requires compromises that often come at the expense of the interpretability of the results. In order to find an intuitive and meaningful approach to organizing large molecular data sets, we adopted a probabilistic framework called "topic modeling" from the text mining field. Here we present the first chemistry-related implementation of this method, which allows large molecule sets to be assigned to "chemical topics" and investigating the relationships between those. In this first study, we thoroughly evaluate this novel method in different experiments and discuss both its disadvantages and advantages. We show very promising results in reproducing human assigned concepts using the approach to identify and retrieve chemical series from sets of molecules. We have also created an intuitive visualization of the chemical topics output by the algorithm. This is a huge benefit compared to other unsupervised machine-learning methods, like clustering, which are commonly used to group sets of molecules. Finally, we applied the new method to the 1.6 million molecules of the ChEMBL22 data set to test its robustness and efficiency. In about 1 h we built a 100-topic model of this large data set in which we could identify interesting topics like "proteins", "DNA", or "steroids". Along with this publication we provide our data sets and an open-source implementation of the new method (CheTo) which will be part of an upcoming version of the open source cheminformatics toolkit RDKit. PMID- 28715191 TI - Engineering the Self-Assembly Induced Emission of Cu Nanoclusters by Au(I) Doping. AB - Aggregation-induced emission (AIE) and self-assembly induced emission (SAIE) effects have been employed to tune the emission properties of metal nanoclusters (NCs). However, it is still not possible to further enhance the photoluminescence quantum yields (PLQYs) and control the emission colors of the NCs using AIE and SAIE. On the basis of our recent work studying the contribution of Cu(I) defects in the SAIE of Cu NCs, in this article, Au(I) was doped into Cu NC self-assembled nanosheets (NSASs) to construct a more stable Au(I)-centered state. As a result, the PLQYs, emission stability, and tunability of emission colors of the Cu NSASs were significantly improved. Detailed studies reveal that the doped Au(I) induces a Au(I)-Cu(I) metallophilic interaction, which leads to a ligand-to-Cu-Au charge transfer, which facilitates the relaxation of excited electrons via a radiative pathway, thereby enhancing the emission intensity. The charge transfer from Cu to Au lowers the energy, thus leading to the red-shift of PL emission. Au(I) is likely doped into the Cu NSASs rather than in individual NCs, because 0.3% Au doping is enough to alter the emission properties. By mixing Au(I)-doped Cu NSASs with different emission colors (due to different Au doping percentages) as color conversion materials on commercially available 365 nm GaN chips, a white light emitting diode prototype is fabricated. PMID- 28715192 TI - Flexible Semitransparent Energy Harvester with High Pressure Sensitivity and Power Density Based on Laterally Aligned PZT Single-Crystal Nanowires. AB - A flexible semitransparent energy harvester is assembled based on laterally aligned Pb(Zr0.52Ti0.48)O3 (PZT) single-crystal nanowires (NWs). Such a harvester presents the highest open-circuit voltage and a stable area power density of up to 10 V and 0.27 MUW/cm2, respectively. A high pressure sensitivity of 0.14 V/kPa is obtained in the dynamic pressure sensing, much larger than the values reported in other energy harvesters based on piezoelectric single-crystal NWs. Furthermore, theoretical and finite element analyses also confirm that the piezoelectric voltage constant g33 of PZT NWs is competitive to the lead-based bulk single crystals and ceramics, and the enhanced pressure sensitivity and power density are substantially linked to the flexible structure with laterally aligned PZT NWs. The energy harvester in this work holds great potential in flexible and transparent sensing and self-powered systems. PMID- 28715193 TI - Polymerization-Like Co-Assembly of Silver Nanoplates and Patchy Spheres. AB - Highly anisometric nanoparticles have distinctive mechanical, electrical, and thermal properties and are therefore appealing candidates for use as self assembly building blocks. Here, we demonstrate that ultra-anisometric nanoplates, which have a nanoscale thickness but a micrometer-scale edge length, offer many material design capabilities. In particular, we show that these nanoplates "copolymerize" in a predictable way with patchy spheres (Janus and triblock particles) into one- and two-dimensional structures with tunable architectural properties. We find that, on the pathway to these structures, nanoplates assemble into chains following the kinetics of molecular step-growth polymerization. In the same mechanistic framework, patchy spheres control the size distribution and morphology of assembled structures, by behaving as monofunctional chain stoppers or multifunctional branch points during nanoplate polymerization. In addition, both the lattice constant and the stiffness of the nanoplate assemblies can be manipulated after assembly. We see highly anisometric nanoplates as one representative of a broader class of dual length-scale nanoparticles, with the potential to enrich the library of structures and properties available to the nanoparticle self-assembly toolbox. PMID- 28715194 TI - Spin Hall Effect and Weak Antilocalization in Graphene/Transition Metal Dichalcogenide Heterostructures. AB - We report on a theoretical study of the spin Hall Effect (SHE) and weak antilocalization (WAL) in graphene/transition metal dichalcogenide (TMDC) heterostructures, computed through efficient real-space quantum transport methods, and using realistic tight-binding models parametrized from ab initio calculations. The graphene/WS2 system is found to maximize spin proximity effects compared to graphene on MoS2, WSe2, or MoSe2 with a crucial role played by disorder, given the disappearance of SHE signals in the presence of strong intervalley scattering. Notably, we found that stronger WAL effects are concomitant with weaker charge-to-spin conversion efficiency. For further experimental studies of graphene/TMDC heterostructures, our findings provide guidelines for reaching the upper limit of spin current formation and for fully harvesting the potential of two-dimensional materials for spintronic applications. PMID- 28715195 TI - Thermomechanical Response of Self-Assembled Nanoparticle Membranes. AB - Monolayers composed of colloidal nanoparticles, with a thickness of less than 10 nm, have remarkable mechanical moduli and can suspend over micrometer-sized holes to form free-standing membranes. In this paper, we discuss experiments and coarse grained molecular dynamics simulations characterizing the thermomechanical properties of these self-assembled nanoparticle membranes. These membranes remain strong and resilient up to temperatures much higher than previous simulation predictions and exhibit an unexpected hysteretic behavior during the first heating-cooling cycle. We show this hysteretic behavior can be explained by an asymmetric ligand configuration from the self-assembly process and can be controlled by changing the ligand coverage or cross-linking the ligand molecules. Finally, we show the screening effect of water molecules on the ligand interactions can strongly affect the moduli and thermomechanical behavior. PMID- 28715196 TI - Increasing the Room-Temperature Electric Double Layer Retention Time in Two Dimensional Crystal FETs. AB - Poly(vinyl alcohol) (PVA) and LiClO4, a solid polymer electrolyte with a glass transition temperature (Tg) of 80 degrees C, is used to electrostatically gate graphene field-effect transistors. The ions in PVA:LiClO4 are drifted into place by field-effect at T > Tg, providing n- or p-type doping, and when the device is cooled to room temperature, the polymer mobility and, hence ion mobility are arrested and the electric double layer (EDL) is "locked" into place in the absence of a gate bias. Unlike other electrolytes used to gate two-dimensional devices for which the Tg, and therefore the "locking" temperature, is well below room temperature, the electrolyte demonstrated in this work provides a route to achieve room-temperature EDL stability. Specifically, a 6 orders of magnitude increase in the room temperature EDL retention time is demonstrated over the commonly used electrolyte, poly(ethylene oxide) (PEO) and LiClO4. Hall measurements confirm that large sheet carrier densities can be achieved with PVA:LiClO4 at top gate programming voltages of +/-2 V (-6.3 +/- 0.03 * 1013 cm-2 for electrons and 1.6 +/- 0.3 * 1014 cm-2 for holes). Transient drain current measurements show that at least 75% of the EDL is retained after more than 4 h at room temperature. Unlike PEO-based electrolytes, PVA:LiClO4 is compatible with the chemicals used in standard photolithographic processes enabling the direct deposition of patterned, metal contacts on the surface of the electrolyte. A thermal instability in the electrolyte is detected by both I-V measurements and differential scanning calorimetry, and FTIR measurements suggest that thermally catalyzed cross-linking may be driving phase separation between the polymer and the salt. Nevertheless, this work highlights how the relationship between polymer and ion mobility can be exploited to tune the state retention time and the charge carrier density of a 2D crystal transistor. PMID- 28715197 TI - Spectroelectrochemical Characterization of the Dynamic Carbon-Fiber Surface in Response to Electrochemical Conditioning. AB - The effects of electrochemical preconditioning of P-55 pitch-based carbon-fiber microelectrodes were quantitatively examined in this study. Microstructural characterization of the electrode surface was done using Raman spectroscopy and scanning electron microscopy. Electrochemical performance was evaluated using cyclic voltammetry. The data show that application of positive potentials provides beneficial structural modifications to the electrode surface. Electrodes that were preconditioned using a static potential of +1.0 V exhibited enhanced sensitivity and electron transfer properties when compared to electrodes conditioned for the same amount of time with dynamic (triangular) waveforms reaching +1.0 V. Conditioning elicited microstructural changes to the electrode surface that were dependent on the amount of time spent at potentials greater than ~1.0 V. Importantly, the data demonstrate that the carbon-fiber microstructure is dynamic. It is able to quickly and continuously undergo rapid structural reorganization as potential is applied, repeatedly alternating between a relatively ordered state and one that exhibits greater disorder in response to applied electrochemical potentials that span the range commonly used in voltammetric experiments. PMID- 28715198 TI - Structural Variations in Hybrid All-Nanoparticle Gibbsite Nanoplatelet/Cellulose Nanocrystal Multilayered Films. AB - Cellulose nanocrystals (CNCs) are promising biosourced building blocks for the production of high performance materials. In the last ten years, CNCs have been used in conjunction with polymers for the design of multilayered thin films via the layer-by-layer assembly technique. Herein, polymer chains have been replaced with positively charged inorganic gibbsite nanoplatelets (GN) to form hybrid "nanoparticle-only" composite films. A combination of atomic force microscopy and neutron reflectivity experiments was exploited to investigate the growth and structure of the films. Data show that the growth and density of GN/CNC films can be tuned over a wide range during preparation by varying the ionic strength in the CNC suspension and the film drying protocol. Specifically, thin and dense multilayered films or very thick, more porous mixed slabs, as well as intermediate internal structures, could be obtained in a predictable manner. The influence of key physicochemical parameters on the multilayer film buildup was elucidated and the film architecture was linked to the dominating interaction forces between the components. The degree of structural control over these hybrid nanoparticle-only films is much higher than that reported for CNC/polymer films, which offers new properties and potential applications as separation membranes or flame retardant coatings. PMID- 28715199 TI - Jumping Hurdles: Peptides Able To Overcome Biological Barriers. AB - The cell membrane, the gastrointestinal tract, and the blood-brain barrier (BBB) are good examples of biological barriers that define and protect cells and organs. They impose different levels of restriction, but they also share common features. For instance, they all display a high lipophilic character. For this reason, hydrophilic compounds, like peptides, proteins, or nucleic acids have long been considered as unable to bypass them. However, the discovery of cell penetrating peptides (CPPs) opened a vast field of research. Nowadays, CPPs, homing peptides, and blood-brain barrier peptide shuttles (BBB-shuttles) are good examples of peptides able to target and to cross various biological barriers. CPPs are a group of peptides able to interact with the plasma membrane and enter the cell. They display some common characteristics like positively charged residues, mainly arginines, and amphipathicity. In this field, our group has been focused on the development of proline rich CPPs and in the analysis of the importance of secondary amphipathicity in the internalization process. Proline has a privileged structure being the only amino acid with a secondary amine and a cyclic side chain. These features constrain its structure and hamper the formation of H-bonds. Taking advantage of this privileged structure, three different families of proline-rich peptides have been developed, namely, a proline-rich dendrimer, the sweet arrow peptide (SAP), and a group of foldamers based on gamma-peptides. The structure and the mechanism of internalization of all of them has been evaluated and analyzed. BBB-shuttles are peptides able to cross the BBB and to carry with them compounds that cannot reach the brain parenchyma unaided. These peptides take advantage of the natural transport mechanisms present at the BBB, which are divided in active and passive transport mechanisms. On the one hand, we have developed BBB-shuttles that cross the BBB by a passive transport mechanism, like diketoperazines (DKPs), (N-MePhe)n, or (PhPro)n. On the other hand, we have investigated BBB-shuttles that utilize active transport mechanisms such as SGV, THRre, or MiniAp-4. For the development of both groups, we have explored several approaches, such as the use of peptide libraries, both chemical and phage display, or hit-to-lead optimization processes. In this Account, we describe, in chronologic order, our contribution to the development of peptides able to overcome various biological barriers and our efforts to understand the mechanisms that they display. In addition, the potential use of both CPPs and BBB-shuttles to improve the transport of promising therapeutic compounds is described. PMID- 28715200 TI - Unraveling the Single-Nanometer Thickness of Shells of Vesicle-Templated Polymer Nanocapsules. AB - Vesicle-templated nanocapsules have emerged as a viable platform for diverse applications. Shell thickness is a critical structural parameter of nanocapsules, where the shell plays a crucial role providing mechanical stability and control of permeability. Here we used small-angle neutron scattering (SANS) to determine the thickness of freestanding and surfactant-stabilized nanocapsules. Despite being at the edge of detectability, we were able to show the polymer shell thickness to be typically 1.0 +/- 0.1 nm, which places vesicle-templated nanocapsules among the thinnest materials ever created. The extreme thinness of the shells has implications for several areas: mass-transport through nanopores is relatively unimpeded; pore-forming molecules are not limited to those spanning the entire bilayer; the internal volume of the capsules is maximized; and insight has been gained on how polymerization occurs in the confined geometry of a bilayer scaffold, being predominantly located at the phase-separated layer of monomers and cross-linkers between the surfactant leaflets. PMID- 28715201 TI - Rational Design of S-UiO-66@GO Hybrid Nanosheets for Proton Exchange Membranes with Significantly Enhanced Transport Performance. AB - Metal-organic frameworks (MOFs) are being intensively explored as filler materials for polymeric proton exchange membranes (PEMs) due to their potentials for the systematic design and modification of proton-conducting properties. S-UiO 66, a stable MOF with functional groups of -SO3H in its ligands, was selected here to prepare S-UiO-66@graphene oxide (GO) hybrid nanosheets via a facile in situ growth procedure, and then a series of composite PEMs were prepared by hybridizing S-UiO-66@GO and sulfonated poly(ether ether ketone) (SPEEK). The resultant hybrid nanosheets not only possessed abundant -SO3H groups derived from the ligands of S-UiO-66 but also yielded a uniform dispersion of S-UiO-66 onto GO nanosheets, thus effectively eliminating the agglomeration of S-UiO-66 in the membrane matrix. Thanks to the well-tailored chemical composition and nanostructure of S-UiO-66@GO, the as-prepared SPEEK/S-UiO-66@GO composite PEMs present a significant increase in their proton conductivity under various conditions. In particular, the proton conductivity of the SPEEK/S-UiO-66@GO-10 membrane was up to 0.268 S.cm-1 and 16.57 mS.cm-1 at 70 degrees C-95% RH and 100 degrees C-40% RH (2.6 and 6.0 times that of recast SPEEK under the same condition), respectively. Moreover, the mechanical property of composite membranes was substantially strengthened and the methanol penetration was well suppressed. Our investigation indicates the great potential of S-UiO-66@GO in fabricating composite PEMs and also reveals that the high proton conductivity of MOFs can be fully utilized by means of MOF/polymer composite membranes. PMID- 28715202 TI - Antifouling Biomimetic Liquid-Infused Stainless Steel: Application to Dairy Industrial Processing. AB - Fouling is a widespread and costly issue, faced by all food-processing industries. Particularly, in the dairy sector, where thermal treatments are mandatory to ensure product safety, heat-induced fouling represents up to 80% of the total production costs. Significant environmental impacts, due the massive consumption of water and energy, are also to deplore. Fouling control solutions are thus desperately needed, as they would lead to substantial financial gains as well as tremendous progress toward eco-responsible processes. This work aims at presenting a novel and very promising dairy fouling-mitigation strategy, inspired by nature, and to test its antifouling performances in real industrial conditions. Slippery liquid-infused surfaces were successfully designed directly on food grade stainless steel, via femtosecond laser ablation, followed by fluorosilanization and impregnation with an inert perfluorinated oil. Resulting hydrophobic surfaces (water contact angle of 112 degrees ) exhibited an extremely slippery nature (contact angle hysteresis of 0.6 degrees ). Outstanding fouling release performances were obtained for these liquid-infused surfaces as absolutely no trace of dairy deposit was found after 90 min of pasteurization test in pilot-scale equipment followed by a short water rinse. PMID- 28715203 TI - A Bioinorganic Approach to Fragment-Based Drug Discovery Targeting Metalloenzymes. AB - Metal-dependent enzymes (i.e., metalloenzymes) make up a large fraction of all enzymes and are critically important in a wide range of biological processes, including DNA modification, protein homeostasis, antibiotic resistance, and many others. Consequently, metalloenzymes represent a vast and largely untapped space for drug development. The discovery of effective therapeutics that target metalloenzymes lies squarely at the interface of bioinorganic and medicinal chemistry and requires expertise, methods, and strategies from both fields to mount an effective campaign. In this Account, our research program that brings together the principles and methods of bioinorganic and medicinal chemistry are described, in an effort to bridge the gap between these fields and address an important class of medicinal targets. Fragment-based drug discovery (FBDD) is an important drug discovery approach that is particularly well suited for metalloenzyme inhibitor development. FBDD uses relatively small but diverse chemical structures that allow for the assembly of privileged molecular collections that focus on a specific feature of the target enzyme. For metalloenzyme inhibition, the specific feature is rather obvious, namely, a metal dependent active site. Surprisingly, prior to our work, the exploration of diverse molecular fragments for binding the metal active sites of metalloenzymes was largely unexplored. By assembling a modest library of metal-binding pharmacophores (MBPs), we have been able to find lead hits for many metalloenzymes and, from these hits, develop inhibitors that act via novel mechanisms of action. A specific case study on the use of this strategy to identify a first-in-class inhibitor of zinc-dependent Rpn11 (a component of the proteasome) is highlighted. The application of FBDD for the development of metalloenzyme inhibitors has raised several other compelling questions, such as how the metalloenzyme active site influences the coordination chemistry of bound fragments, how one can identify the best fragments for a given metalloenzyme, and many others. Among the most significant, and concerning, questions for metalloenzyme inhibition are those that reside around issues of specificity and whether metalloenzyme inhibitors can be as selective and specific as other small molecule inhibitors (i.e., compounds that inhibit enzymes that do not utilize a metal at their active site). This also leads to the question of whether metalloenzyme inhibitors might interfere more broadly with the metallome. Efforts to address these and related questions are discussed, with the expectation that our findings will illuminate some of these topics, alleviate some of these concerns, and encourage greater interest in this important, undervalued class of drug targets. PMID- 28715204 TI - A Prodomain Fragment from the Proteolytic Activation of Growth Differentiation Factor 11 Remains Associated with the Mature Growth Factor and Keeps It Soluble. AB - Growth differentiation factor 11 (GDF11), a member of the transforming growth factor beta (TGF-beta) family, plays diverse roles in mammalian development. It is synthesized as a large, inactive precursor protein containing a prodomain, pro GDF11, and exists as a homodimer. Activation requires two proteolytic processing steps that release the prodomains and transform latent pro-GDF11 into active mature GDF11. In studying proteolytic activation in vitro, we discovered that a 6 kDa prodomain peptide containing residues 60-114, PDP60-114, remained associated with the mature growth factor. Whereas the full-length prodomain of GDF11 is a functional antagonist, PDP60-114 had no impact on activity. The specific activity of the GDF11/PDP60-114 complex (EC50 = 1 nM) in a SMAD2/3 reporter assay was identical to that of mature GDF11 alone. PDP60-114 improved the solubility of mature GDF11 at neutral pH. As the growth factor normally aggregates/precipitates at neutral pH, PDP60-114 can be used as a solubility-enhancing formulation. Expression of two engineered constructs with PDP60-114 genetically fused to the mature domain of GDF11 through a 2x or 3x G4S linker produced soluble monomeric products that could be dimerized through redox reactions. The construct with a 3x G4S linker retained 10% activity (EC50 = 10 nM), whereas the construct connected with a 2x G4S linker could only be activated (EC50 = 2 nM) by protease treatment. Complex formation with PDP60-114 represents a new strategy for stabilizing GDF11 in an active state that may translate to other members of the TGF-beta family that form latent pro/mature domain complexes. PMID- 28715205 TI - Polymerase Chain Transcription: Exponential Synthesis of RNA and Modified RNA. AB - There is increasing demand for RNA and modified RNA oligonucleotides, but in contrast to DNA oligonucleotides, they are typically prohibitively expensive to chemically synthesize, and unlike longer RNAs, they are only inefficiently produced by in vitro transcription, especially when modified. To address these challenges, we previously reported the evolution of a thermostable DNA polymerase, SFM4-3, that more efficiently accepts substrates with 2' substituents. We now show that SFM4-3 efficiently transcribes RNA or 2'-F modified RNA and that it also efficiently PCR amplifies oligonucleotides of mixed RNA and DNA composition. In addition, with thermocycling and the use of a novel DNA template, we demonstrate a polymerase chain transcription (PCT) reaction that results in the exponential production of orders of magnitude more RNA or modified RNA than is available by conventional transcription. PCT is more efficient and general than conventional transcription and can produce large amounts of any RNA or modified RNA oligonucleotide at a fraction of the cost of chemical synthesis. PMID- 28715206 TI - High-Throughput Screening and Quantitation of Target Compounds in Biofluids by Coated Blade Spray-Mass Spectrometry. AB - Most contemporary methods of screening and quantitating controlled substances and therapeutic drugs in biofluids typically require laborious, time-consuming, and expensive analytical workflows. In recent years, our group has worked toward developing microextraction (MUe)-mass spectrometry (MS) technologies that merge all of the tedious steps of the classical methods into a simple, efficient, and low-cost methodology. Unquestionably, the automation of these technologies allows for faster sample throughput, greater reproducibility, and radically reduced analysis times. Coated blade spray (CBS) is a MUe technology engineered for extracting/enriching analytes of interest in complex matrices, and it can be directly coupled with MS instruments to achieve efficient screening and quantitative analysis. In this study, we introduced CBS as a technology that can be arranged to perform either rapid diagnostics (single vial) or the high throughput (96-well plate) analysis of biofluids. Furthermore, we demonstrate that performing 96-CBS extractions at the same time allows the total analysis time to be reduced to less than 55 s per sample. Aiming to validate the versatility of CBS, substances comprising a broad range of molecular weights, moieties, protein binding, and polarities were selected. Thus, the high throughput (HT)-CBS technology was used for the concomitant quantitation of 18 compounds (mixture of anabolics, beta-2 agonists, diuretics, stimulants, narcotics, and beta-blockers) spiked in human urine and plasma samples. Excellent precision (~2.5%), accuracy (>=90%), and linearity (R2 >= 0.99) were attained for all the studied compounds, and the limits of quantitation (LOQs) were within the range of 0.1 to 10 ng.mL-1 for plasma and 0.25 to 10 ng.mL-1 for urine. The results reported in this paper confirm CBS's great potential for achieving subsixty-second analyses of target compounds in a broad range of fields such as those related to clinical diagnosis, food, the environment, and forensics. PMID- 28715207 TI - Antifreeze Protein Mimetic Metallohelices with Potent Ice Recrystallization Inhibition Activity. AB - Antifreeze proteins are produced by extremophile species to control ice formation and growth, and they have potential applications in many fields. There are few examples of synthetic materials which can reproduce their potent ice recrystallization inhibition property. We report that self-assembled enantiomerically pure, amphipathic metallohelicies inhibited ice growth at just 20 MUM. Structure-property relationships and calculations support the hypothesis that amphipathicity is the key motif for activity. This opens up a new field of metallo-organic antifreeze protein mimetics and provides insight into the origins of ice-growth inhibition. PMID- 28715209 TI - Comparison of the Predictive Performance and Interpretability of Random Forest and Linear Models on Benchmark Data Sets. AB - The ability to interpret the predictions made by quantitative structure-activity relationships (QSARs) offers a number of advantages. While QSARs built using nonlinear modeling approaches, such as the popular Random Forest algorithm, might sometimes be more predictive than those built using linear modeling approaches, their predictions have been perceived as difficult to interpret. However, a growing number of approaches have been proposed for interpreting nonlinear QSAR models in general and Random Forest in particular. In the current work, we compare the performance of Random Forest to those of two widely used linear modeling approaches: linear Support Vector Machines (SVMs) (or Support Vector Regression (SVR)) and partial least-squares (PLS). We compare their performance in terms of their predictivity as well as the chemical interpretability of the predictions using novel scoring schemes for assessing heat map images of substructural contributions. We critically assess different approaches for interpreting Random Forest models as well as for obtaining predictions from the forest. We assess the models on a large number of widely employed public-domain benchmark data sets corresponding to regression and binary classification problems of relevance to hit identification and toxicology. We conclude that Random Forest typically yields comparable or possibly better predictive performance than the linear modeling approaches and that its predictions may also be interpreted in a chemically and biologically meaningful way. In contrast to earlier work looking at interpretation of nonlinear QSAR models, we directly compare two methodologically distinct approaches for interpreting Random Forest models. The approaches for interpreting Random Forest assessed in our article were implemented using open-source programs that we have made available to the community. These programs are the rfFC package ( https://r-forge.r project.org/R/?group_id=1725 ) for the R statistical programming language and the Python program HeatMapWrapper [ https://doi.org/10.5281/zenodo.495163 ] for heat map generation. PMID- 28715208 TI - Highly Stereoselective Synthesis of Tetrasubstituted Acyclic All-Carbon Olefins via Enol Tosylation and Suzuki-Miyaura Coupling. AB - A highly stereocontrolled synthesis of tetrasubstituted acyclic all-carbon olefins has been developed via a stereoselective enolization and tosylate formation, followed by a palladium-catalyzed Suzuki-Miyaura cross-coupling of the tosylates and pinacol boronic esters in the presence of a Pd(OAc)2/RuPhos catalytic system. Both the enol tosylation and Suzuki-Miyaura coupling reactions tolerate an array of electronically and sterically diverse substituents and generate high yield and stereoselectivity of the olefin products. Judicious choice of substrate and coupling partner provides access to either the E- or Z olefin with excellent yield and stereochemical fidelity. Olefin isomerization was observed during the Suzuki-Miyaura coupling. However, under the optimized cross coupling reaction conditions, the isomerization was suppressed to <5% in most cases. Mechanistic probes indicate that the olefin isomerization occurs via an intermediate, possibly a zwitterionic palladium carbenoid species. PMID- 28715210 TI - Intercalation of Primary Alcohols into Layered Titanoniobates. AB - Lamellar oxides form an important class of functional materials and are often susceptible to topotactic substitution of the ions between the layers. This opens up the structure to direct reactions with alkylammonium ions often substituting for group 1 ions forcing an increase in layer separation. Proton exchange with group 1 ions is also possible in mineral acids with the resulting protonated materials typically being acidic. These solid acids can further react with bases such as alkyl amines again causing an increase in interlayer separation. Alcohols do not readily form stable ROH2+X- (R alkyl chain, X halide) species and being less basic than RNH2 are less commonly investigated for intercalation into layered oxides. Here the intercalation of simple primary alcohols of the form ROH (R = CxH2x+1; x = 1-10) is investigated using the layered titanoniobate HTiNbO5 as the ceramic host. Direct reaction is found to be ineffective so instead butylamine is first intercalated followed by reaction with the primary alcohols. The butylamine remains in the final product, but intercalation of the alcohols causes a significant modification of the interlayer space of the ceramic. This shows how alcohols can be used to influence the interlayer space of oxide sheets in functional layered oxide ceramics. PMID- 28715211 TI - Alternating Sequence Controlled Copolymer Synthesis of alpha-Hydroxy Acids via Syndioselective Ring-Opening Polymerization of O-Carboxyanhydrides Using Zirconium/Hafnium Alkoxide Initiators. AB - The ring-opening polymerization (ROP) of O-carboxyanhydrides (OCAs) can give diverse poly(alpha-hydroxy acid)s (PAHAs) with different functional groups because of easy modification of the side group of OCAs, which can extend applications of PAHAs widely. The stereoselective polymerization of O carboxyanhydrides and further sequence controlled alternating copolymerization of OCAs were still big challenges until now for lack of suitable catalysts/initiators. In this work, a highly syndioselective ROP of OCAs system as the first stereoselective example in this area is reported using zirconium/hafnium alkoxides as initiators with the highest Pr value up to 0.95. Furthermore, these initiators were successfully applied in the precisely alternating sequence controlled copolymerization of PheOCA and Tyr(Bn)OCA, and alternating copolymerization of LacOCA and PheOCA was also achieved. PMID- 28715212 TI - Kinetics of Electrophilic Alkylations of Barbiturate and Thiobarbiturate Anions. AB - Second-order rate constants (k2) of the reactions of various barbiturate anions such as the parent barbiturate, 1,3-dimethylbarbiturate, 2-thiobarbiturate, and 1,3-diethyl-2-thiobarbiturate with diarylcarbenium ions and Michael acceptors have been determined in dimethyl sulfoxide solution at 20 degrees C. The reactivity parameters N and sN of the barbiturate anions were derived from the linear plots of log k2 versus the electrophilicity parameters E of these reference electrophiles, according to the linear-free-energy relationship log k2 (20 degrees C) = sN (E + N). Several reactions of these nucleophiles with benzylidenemalononitriles and quinone methides proceeded with reversible formation of the new C-C-bond followed by rate-determining proton shift. No evidence for initial attack of the electrophiles at the enolate oxygens of these nucleophiles was found by the kinetic measurements, in line with quantum chemical DFT calculations, which showed that in all cases C-attack is kinetically and thermodynamically preferred over O-attack. The nucleophilic reactivities of barbiturate anions were compared with those of structurally related carbanions, e.g., Meldrum's acid and dimedone anions. PMID- 28715213 TI - Probing the Hydrophobic Binding Pocket of G-Protein-Coupled Lysophosphatidylserine Receptor GPR34/LPS1 by Docking-Aided Structure-Activity Analysis. AB - The ligands of certain G-protein-coupled receptors (GPCRs) have been identified as endogenous lipids, such as lysophosphatidylserine (LysoPS). Here, we analyzed the molecular basis of the structure-activity relationship of ligands of GPR34, one of the LysoPS receptor subtypes, focusing on recognition of the long-chain fatty acid moiety by the hydrophobic pocket. By introducing benzene ring(s) into the fatty acid moiety of 2-deoxy-LysoPS, we explored the binding site's preference for the hydrophobic shape. A tribenzene-containing fatty acid surrogate with modifications of the terminal aromatic moiety showed potent agonistic activity toward GPR34. Computational docking of these derivatives with a homology modeling/molecular dynamics-based virtual binding site of GPR34 indicated that a kink in the benzene-based lipid surrogates matches the L-shaped hydrophobic pocket of GPR34. A tetrabenzene-based lipid analogue bearing a bulky tert-butyl group at the 4-position of the terminal benzene ring exhibited potent GPR34 agonistic activity, validating the present hydrophobic binding pocket model. PMID- 28715214 TI - Exploiting Carbonyl Groups to Control Intermolecular Rhodium-Catalyzed Alkene and Alkyne Hydroacylation. AB - Readily available beta-carbonyl-substituted aldehydes are shown to be exceptional substrates for Rh-catalyzed intermolecular alkene and alkyne hydroacylation reactions. By using cationic rhodium catalysts incorporating bisphosphine ligands, efficient and selective reactions are achieved for beta-amido, beta ester, and beta-keto aldehyde substrates, providing a range of synthetically useful 1,3-dicarbonyl products in excellent yields. A correspondingly broad selection of alkenes and alkynes can be employed. For alkyne substrates, the use of a catalyst incorporating the Ampaphos ligand triggers a regioselectivity switch, allowing both linear and branched isomers to be prepared with high selectivity in an efficient manner. Structural data, confirming aldehyde chelation, and a proposed mechanism are provided. PMID- 28715215 TI - Manipulating the Energetics and Rates of Electron Transfer in Rhodobacter capsulatus Reaction Centers with Asymmetric Pigment Content. AB - Seemingly redundant parallel pathways for electron transfer (ET), composed of identical sets of cofactors, are a cornerstone feature of photosynthetic reaction centers (RCs) involved in light-energy conversion. In native bacterial RCs, both A and B branches house one bacteriochlorophyll (BChl) and one bacteriopheophytin (BPh), but the A branch is used exclusively. Described herein are the results obtained for two Rhodobacter capsulatus RCs with an unnaturally high degree of cofactor asymmetry, two BPh on the RC's B side and two BChl on the A side. These pigment changes derive, respectively, from the His(M180)Leu mutation [a BPh (PhiB) replaces the B-side BChl (BB)], and the Leu(M212)His mutation [a BChl (betaA) replaces the A-side BPh (HA)]. Additionally, Tyr(M208)Phe was employed to disfavor ET to the A branch; in one mutant, Val(M131)Glu creates a hydrogen bond to HB to enhance ET to HB. In both PhiB mutants, the decay kinetics of the excited primary ET donor (P*) resolve three populations with lifetimes of ~9 ps (50-60%), ~40 ps (10-20%), and ~200 ps (20-30%), with P+PhiB- formed predominantly from the 9 ps fraction. The 50-60% yield of P+PhiB- is the highest yet observed for a PhiB-containing RC. The results provide insight into factors needed for efficient multistep ET. PMID- 28715216 TI - Long-Term Effect of a Leonardite Iron Humate Improving Fe Nutrition As Revealed in Silico, in Vivo, and in Field Experiments. AB - Novel, cheap and ecofriendly fertilizers that solve the usual iron deficiency problem in calcareous soil are needed. The aim of this work is to study the long term effect of an iron leonardite fertilizer on citrus nutrition taking into account a properly characterization, kinetic response with a ligand competition experiment, efficiency assessment using Saccharomyces cerevisiae strain and finally, in field conditions with citrus as test plants. Its efficiency was compared with the synthetic iron chelate FeEDDHA. Leonardite iron humate (LIH) is mainly humic acid with a high-condensed structure where iron is present as ferrihydrite and Fe3+ polynuclear compounds stabilized by organic matter. Iron and humic acids form aggregates that decrease the iron release from these kinds of fertilizers. Furthermore, LIH repressed almost 50% of the expression of FET3, FTR1, SIT1, and TIS11 genes in Saccharomyces cerevisiae cells, indicating increasing iron provided in cells and improved iron nutrition in citrus. PMID- 28715217 TI - Angular Dependence of Strong Field Ionization of CH3X (X = F, Cl, Br, or I) Using Time-Dependent Configuration Interaction with an Absorbing Potential. AB - Methyl halides have been used to test basis set effects on simulations of strong field ionization using time dependent configuration interaction with an absorbing potential. Standard atom centered basis sets need to be augmented by several sets of diffuse functions on each atom so that the wave function in the strong field can interact with the absorbing potential used to model ionization. An absorbing basis of 3 s functions, 2 p functions, 3 d functions, and 1 f function is sufficient for CH3F. Large absorbing basis sets with 4 s functions, 3 or 4 p functions, 4 or 5 d functions, and 2 f functions are recommended for the heavier halogens. The simulations used static fields in the 0.035-0.07 au range to explore the angular dependence of ionization of methyl halides. CH3F ionizes mainly from the methyl group; CH3Cl and CH3Br show ionization from both the methyl group and the halogen, and CH3I ionizes almost exclusively from the ppi orbitals of the iodine. PMID- 28715218 TI - A "Universal" Spectroscopic Map for the OH Stretching Mode in Alcohols. AB - Empirical maps are presented for the OH stretching vibrations in neat alcohols in which the relevant spectroscopic quantities are expressed in terms of the electric field exerted on the hydrogen atom by the surrounding liquid. It is found, by examination of the four lowest linear alcohols, methanol, ethanol, n propanol, and n-butanol, that a single map can be used for alcohols with different alkyl groups. This "universal" map is in very good agreement with maps optimized for the individual alcohols but differs from those previously developed for water. This suggests that one map can be used for all alcohols, perhaps even those not examined in the present study. The universal map gives IR lineshapes in good agreement with measured spectra for isotopically dilute methanol and ethanol, while the two-dimensional IR photon echo spectra give results that differ from experiments. The role of non-Condon effects, reorientation dynamics, hydrogen bonding, and spectral diffusion is discussed. PMID- 28715219 TI - Synthesis of Aromatic Thiolate-Protected Gold Nanomolecules by Core Conversion: The Case of Au36(SPh-tBu)24. AB - Ultrasmall nanomolecules (<2 nm) such as Au25(SCH2CH2Ph)18, Au38(SCH2CH2Ph)24, and Au144(SCH2CH2Ph)60 are well studied and can be prepared using established synthetic procedures. No such synthetic protocols that result in high yield products from commercially available starting materials exist for Au36(SPh-X)24. Here, we report a synthetic procedure for the large-scale synthesis of highly stable Au36(SPh-X)24 with a yield of ~42%. Au36(SPh-X)24 was conveniently synthesized by using tert-butylbenzenethiol (HSPh-tBu, TBBT) as the ligand, giving a more stable product with better shelf life and higher yield than previously reported for making Au36(SPh)24 from thiophenol (PhSH). The choice of thiol, solvent, and reaction conditions were modified for the optimization of the synthetic procedure. The purposes of this work are to (1) optimize the existing procedure to obtain stable product with better yield, (2) develop a scalable synthetic procedure, (3) demonstrate the superior stability of Au36(SPh-tBu)24 when compared to Au36(SPh)24, and (4) demonstrate the reproducibility and robustness of the optimized synthetic procedure. PMID- 28715220 TI - Dynamic-Mechanical and Dielectric Evidence of Long-Lived Mesoscale Organization in Ionic Liquids. AB - Experimental evidence of the dynamics of mesoscopic structure in room-temperature ionic liquids-a feature expected to correlate with many physicochemical properties of these materials-remains limited. Here, we report the observation of slow, sub-alpha relaxations corresponding to dynamics of nanoscale hydrophobic aggregates in a systematic series of 1-alkyl-3-methylimidazolium-based ionic liquids from detailed analysis of dynamic-mechanical and broad-band dielectric spectra. The emergence of the sub-alpha relaxations correlates with increases in the zero-shear viscosity and static dielectric permittivity, constituting direct evidence of the influence of mesoscale aggregation on the physicochemical properties of ionic liquids. PMID- 28715221 TI - Pressure-Dependent Light Emission of Charged and Neutral Excitons in Monolayer MoSe2. AB - Tailoring the excitonic properties in two-dimensional monolayer transition metal dichalcogenides (TMDs) through strain engineering is an effective means to explore their potential applications in optoelectronics and nanoelectronics. Here we report pressure-tuned photon emission of trions and excitons in monolayer MoSe2 via a diamond anvil cell (DAC) through photoluminescence measurements and theoretical calculations. Under quasi-hydrostatic compressive strain, our results show neutral (X0) and charged (X-) exciton emission of monolayer MoSe2 can be effectively tuned by alcohol mixture vs inert argon pressure transmitting media (PTM). During this process, X- emission undergoes a continuous blue shift until reaching saturation, while X0 emission turns up splitting. The pressure-dependent charging effect observed in alcohol mixture PTM results in the increase of the X- exciton component and facilitates the pressure-tuned emission of X- excitons. This substantial tunability of X- and X0 excitons in MoSe2 can be extended to other 2D TMDs, which holds potential for developing strained and optical sensing devices. PMID- 28715222 TI - Photoluminescence Enhancement through Symmetry Breaking Induced by Defects in Nanocrystals. AB - We present a theoretical model for the effect of symmetry breaking introduced by the doping of semiconductor nanocrystals with Coulomb impurities. The presence of a Coulomb center breaks the nanocrystal symmetry and affects its optical properties through the mixing of the hole spin and parity sublevels, breaking the selection rules responsible for the exciton dark state in undoped nanocrystals. After reviewing the effects on the exciton fine structure and optical selection rules using symmetry theory, we present a perturbative model to quantify the effects. We find that the symmetry breaking proceeds by two mechanisms: First, mixing by even parity terms in the Coulomb multipole expansion results in an exciton fine structure consisting of three optically active doublets which are polarized along x, y, and z axes with a ground optically passive dark exciton state, and second, odd parity terms which break inversion symmetry significantly activate optical transitions which are optically forbidden in the unperturbed nanocrystal due to both spin and parity selection rules. In the case of small sized "quasi-spherical" nanocrystals, the introduction of a single positively charged Coulomb center is shown here to result in significant enhancement of the radiative decay rate at room temperatures by up to a factor of 10. PMID- 28715223 TI - Plastic Deformation through Dislocation Saturation in Ultrasmall Pt Nanocrystals and Its in Situ Atomistic Mechanisms. AB - The atomic-scale deformation dynamic behaviors of Pt nanocrystals with size of ~18 nm were in situ investigated using our homemade device in a high-resolution transmission electron microscope. It was discovered that the plastic deformation of the nanosized single crystalline Pt commenced with dislocation "appreciation" first, then followed by a dislocation "saturation" phenomenon. The magnitude of strain plays a key role on dislocation behaviors. At the early to medium stage of deformation, the plastic deformation was controlled by the full dislocation activities accompanied by the formation of Lomer dislocation locks from reaction of full dislocations. When the strain increased to a significant level, stacking faults and extended dislocations as well as Lomer-Cottrell locks appeared. The Lomer-Cottrell locks can unlock through transferring into Lomer dislocation locks first, and then Lomer dislocation locks were destructed under high stresses. The very high density dislocations and the frequent dislocation reactions through Lomer dislocations and Lomer-Cottrell locks may lead to work hardening in nanosized Pt. PMID- 28715224 TI - Observation and Identification of a New OH Stretch Vibrational Band at the Surface of Ice. AB - We study the signatures of the OH stretch vibrations at the basal surface of ice using heterodyne-detected sum-frequency generation and molecular dynamics simulations. At 150 K, we observe seven distinct modes in the sum-frequency response, five of which have an analogue in the bulk, and two pure surface specific modes at higher frequencies (~3530 and ~3700 cm-1). The band at ~3530 cm 1 has not been reported previously. Using molecular dynamics simulations, we find that the ~3530 cm-1 band contains contributions from OH stretch vibrations of both fully coordinated interfacial water molecules and water molecules with two donor and one acceptor hydrogen bond. PMID- 28715225 TI - Structure, Ionic Conductivity, and Dielectric Properties of Li-Rich Garnet-type Li5+2xLa3Ta2-xSmxO12 (0 <= x <= 0.55) and Their Chemical Stability. AB - Lithium garnet oxides are considered as very promising solid electrolyte candidates for all-solid-state lithium ion batteries (SSLiBs). In this work, we present a cubic garnet-type Li5+2xLa3Ta2-xSmxO12 (0 <= x <= 0.55) system as a potential electrolyte for SSLiBs. Powder X-ray diffraction (PXRD) and scanning electron microscopy (SEM) were employed to investigate the structural stability of Li5+2xLa3Ta2-xSmxO12. The results from PXRD and SEM suggested structural and morphological transformation as a function of dopant concentration. In addition to Li-ion transport in Li5+2xLa3Ta2-xSmxO12, the dielectric properties were also investigated in the light of electron energy loss functions, which showed some surface energy loss and negligible volume energy loss for the studied garnets. Surface and volume energy loss functions of a mixed conducting LiCoO2 was studied for comparison. The long-term chemical stability of one of members, Li5.3La3Ta1.85Sm0.15O12, was performed on aged sample using PXRD, SEM, and thermogravimetric analysis. PMID- 28715226 TI - Photoelectron Spectroscopic and Computational Study of Pyridine-Ligated Gold Cluster Anions. AB - Pyridine-ligated gold cluster anions were studied through a combination of negative ion photoelectron spectroscopy and density functional theory calculations. Small gold cluster anions ligated by pyridine, Aun(py)- were generated with a ligation cell coupled to a laser vaporization source (LVS). We showed that pyridine is weakly bound (physisorbed) to the Au2- moiety of Au2(py)- by interactions between its gold atoms and either the hydrogen atoms or the pi ring of pyridine. We also found that pyridine's lone electron pair strongly binds (chemisorbs) to both Au3(py)- and Au4(py)- through single gold atoms on each of these clusters. Bonding analysis of two isomers of Au4(py)- supported the presence of two different ligand binding motifs, these differing in terms of the gold atom to which pyridine binds. PMID- 28715227 TI - Balancing Passive and Active Targeting to Different Tumor Compartments Using Riboflavin-Functionalized Polymeric Nanocarriers. AB - Riboflavin transporters (RFTs) and the riboflavin carrier protein (RCP) are highly upregulated in many tumor cells, tumor stem cells, and tumor neovasculature, which makes them attractive targets for nanomedicines. Addressing cells in different tumor compartments requires drug carriers, which are not only able to accumulate via the EPR effect but also to extravasate, target specific cell populations, and get internalized by cells. Reasoning that antibodies are among the most efficient targeting systems developed by nature, we consider their size (~10-15 nm) to be ideal for balancing passive and active tumor targeting. Therefore, small, short-circulating (10 kDa, ~7 nm, t1/2 ~ 1 h) and larger, longer-circulating (40 kDa, ~13 nm, t1/2 ~ 13 h) riboflavin-targeted branched PEG polymers were synthesized, and their biodistribution and target site accumulation were evaluated in mice bearing angiogenic squamous cell carcinoma (A431) and desmoplastic prostate cancer (PC3) xenografts. The tumor accumulation of the 10 kDa PEG was characterized by rapid intercompartmental exchange and significantly improved upon active targeting with riboflavin (RF). The 40 kDa PEG accumulated in tumors four times more efficiently than the small polymer, but its accumulation did not profit from active RF-targeting. However, RF-targeting enhanced the cellular internalization in both tumor models and for both polymer sizes. Interestingly, the nanocarriers' cell-uptake in tumors was not directly correlated with the extent of accumulation. For example, in both tumor models the small RF-PEG accumulated much less strongly than the large passively targeted PEG but showed significantly higher intracellular amounts 24 h after iv administration. Additionally, the size of the polymer determined its preferential uptake by different tumor cell compartments: the 10 kDa RF-PEGs most efficiently targeted cancer cells, whereas the highest uptake of the 40 kDa RF-PEGs was observed in tumor-associated macrophages. These findings imply that drug carriers with sizes in the range of therapeutic antibodies show balanced properties with respect to passive accumulation, tissue penetration, and active targeting. Besides highlighting the potential of RF-mediated (cancer) cell targeting, we show that strong tumor accumulation does not automatically mean high cellular uptake and that the nanocarriers' size plays a critical role in cell- and compartment-specific drug targeting. PMID- 28715228 TI - Mid-infrared Plasmonic Circular Dichroism Generated by Graphene Nanodisk Assemblies. AB - It is very interesting to bring plasmonic circular dichroism spectroscopy to the mid-infrared spectral interval, and there are two reasons for this. This spectral interval is very important for thermal bioimaging, and simultaneously, this spectral range includes vibrational lines of many chiral biomolecules. Here we demonstrate that graphene plasmons indeed offer such opportunity. In particular, we show that chiral graphene assemblies consisting of a few graphene nanodisks can generate strong circular dichroism (CD) in the mid-infrared interval. The CD signal is generated due to the plasmon-plasmon coupling between adjacent nanodisks in the specially designed chiral graphene assemblies. Because of the large dimension mismatch between the thickness of a graphene layer and the incoming light's wavelength, three-dimensional configurations with a total height of a few hundred nanometers are necessary to obtain a strong CD signal in the mid infrared range. The mid-infrared CD strength is mainly governed by the total dimensions (total height and helix scaffold radius) of the graphene nanodisk assembly and by the plasmon-plasmon interaction strength between its constitutive nanodisks. Both positive and negative CD bands can be observed in the graphene assembly array. The frequency interval of the plasmonic CD spectra overlaps with the vibrational modes of some important biomolecules, such as DNA and many different peptides, giving rise to the possibility of enhancing the vibrational optical activity of these molecular species by attaching them to the graphene assemblies. Simultaneously the spectral range of chiral mid-infrared plasmons in our structures appears near the typical wavelength of the human-body thermal radiation, and therefore, our chiral metastructures can be potentially utilized as optical components in thermal imaging devices. PMID- 28715230 TI - Nonparametric Calibration of Item-by-Attribute Matrix in Cognitive Diagnosis. AB - A nonparametric technique based on the Hamming distance is proposed in this research by recognizing that once the attribute vector is known, or correctly estimated with high probability, one can determine the item-by-attribute vectors for new items undergoing calibration. We consider the setting where Q is known for a large item bank, and the q-vectors of additional items are estimated. The method is studied in simulation under a wide variety of conditions, and is illustrated with the Tatsuoka fraction subtraction data. A consistency theorem is developed giving conditions under which nonparametric Q calibration can be expected to work. PMID- 28715229 TI - Reply: Benefit of the Shorter Multidrug-Resistant Tuberculosis Treatment Regimen in California and Modified Eligibility Criteria. PMID- 28715231 TI - Bayesian Estimation for Item Factor Analysis Models with Sparse Categorical Indicators. AB - Psychometric models for item-level data are broadly useful in psychology. A recurring issue for estimating item factor analysis (IFA) models is low-item endorsement (item sparseness), due to limited sample sizes or extreme items such as rare symptoms or behaviors. In this paper, I demonstrate that under conditions characterized by sparseness, currently available estimation methods, including maximum likelihood (ML), are likely to fail to converge or lead to extreme estimates and low empirical power. Bayesian estimation incorporating prior information is a promising alternative to ML estimation for IFA models with item sparseness. In this article, I use a simulation study to demonstrate that Bayesian estimation incorporating general prior information improves parameter estimate stability, overall variability in estimates, and power for IFA models with sparse, categorical indicators. Importantly, the priors proposed here can be generally applied to many research contexts in psychology, and they do not impact results compared to ML when indicators are not sparse. I then apply this method to examine the relationship between suicide ideation and insomnia in a sample of first-year college students. This provides an important alternative for researchers who may need to model items with sparse endorsement. PMID- 28715232 TI - Long-term Recording of Night-Time Respiratory Symptoms in Patients with Stable COPD II-IV. AB - INTRODUCTION: Night-time respiratory symptoms have a considerable impact on sleep and life quality in patients with chronic obstructive pulmonary disease (COPD). Lack of awareness of night-time symptoms can lead to worsened COPD control. Automated long-term monitoring of respiratory symptoms with LEOSound enables assessment of nocturnal wheezing and cough. METHODS: In this observational study we investigated the prevalence and severity of cough and wheezing in patients with stable COPD [Global Initiative for Chronic Obstructive Lung Disease (GOLD) II-IV] disease for two consecutive nights with the LEOSound system. 48 patients (30 males, 63%) were eligible for inclusion, median age was 67 years, and body mass index (BMI) was 25.3 kg/m2. RESULTS: In 15 out of 48 patients (31%), we found wheezing periods for at least 10-minute duration. Wheezing periods >30 minutes were monitored in seven patients and wheezing periods >60 minutes were monitored in three patients. The maximum duration of wheezing was 470 minutes in one patient with COPD II. The median wheezing rate differed between the COPD stages and between active and non-active smokers. Cough was found in 42 patients (87.5%) with a range of 1-326 events. The cough-period-index in night one was 0.83 n/hour (P25:0.33||P75: 2.04) and night two 0.97 n/hour (P25:0.25||P75: 1.9). Most of the cough events were non-productive with a median of 0.86. CONCLUSIONS: Night-time symptoms are common in COPD patients. LEOSound offers an opportunity to evaluate objectively night-time symptoms like wheezing and cough in patients with COPD which remain otherwise unnoticed. We found a high incidence of night time wheezing in these patients, which was related to persistant smoking. PMID- 28715233 TI - Betrayals in Emerging Adulthood: A Developmental Perspective of Infidelity. AB - Infidelity is associated with considerable distress and discord in dating relationships. The current mixed methods study examined both the written narratives and survey responses of 104 (59.6% women) emerging adults to investigate reasons for engaging in infidelity (i.e., sexual and emotional infidelity). Emerging adults' reasons for engaging in infidelity were attributed primarily to their primary relationships and/or their romantic partners not fulfilling their needs for interdependence and thus feeling motivated to fulfill these needs elsewhere. Although the majority of participants provided independence and/or interdependence reasons for their infidelity, a large proportion of responses (40%) referenced alternative reasons. These responses included (a) the opportunity to become intimate with an infidelity partner while under the influence of alcohol, (b) attraction to an infidelity partner, and (c) the excitement and novelty that the infidelity experience provided. Those who reported engaging in infidelity because of unmet interdependence needs, and intimacy needs in particular, were more avoidantly attached than those who did not reference unmet interdependence needs. Those who reported engaging in infidelity because of unmet independence needs were more anxiously attached than those who did not reference unmet independence needs. Implications for the developmental importance of infidelity in terms of research and applied work are discussed. PMID- 28715234 TI - Is cardiovascular disease in patients with diabetes associated with serum levels of MMP-2, LOX, and the elastin degradation products ELM and ELM-2? AB - BACKGROUND: Diabetes mellitus type 2 (T2DM) is a significant risk factor for the development of cardiovascular diseases (CVDs). In a previous microarray study of internal mammary arteries from patients with and without T2DM, we observed several elastin-related genes with altered mRNA-expression in diabetic patients, namely matrix metalloproteinase 2 (MMP-2), lysyl oxidase (LOX) and elastin itself. In this study we investigate whether the serum concentrations of elastin related proteins correlate to signs of CVD in patients with T2DM. METHODS: Blood samples from 302 type 2 diabetic patients were analysed for MMP-2, LOX, and the elastin degradation products ELM and ELM2. The results were investigated for correlations to signs of CVD in different vascular territories, as determined by myocardial perfusion scintigraphy, carotid artery thickness and ankle-brachial blood pressure index. RESULTS: T2DM patients with peripheral arterial disease (low ankle-brachial index) (PAD) display higher levels of MMP-2 and ELM compared to patients without PAD. However, none of the proteins or degradation products correlated with myocardial ischemia or a combined measure of CVD-signs, including myocardial ischemia, increased carotid thickness and decreased ankle-brachial blood pressure. CONCLUSIONS: Our results suggest that the diabetic environment affects the circulating amounts of MMP-2 and ELM in patients with PAD. However, the same connection could not be seen in diabetic patients with CVD broadly identified in three vascular territories. LOX and ELM-2 did not correlate to any type of CVD. Overall, serum levels of elastin-related molecules are only remotely related to CVD in type 2 diabetes. PMID- 28715235 TI - cutPrimers: A New Tool for Accurate Cutting of Primers from Reads of Targeted Next Generation Sequencing. AB - Cutting of primers from reads is an important step of processing targeted amplicon-based next generation sequencing data. Existing tools are adapted for cutting of one or several primer/adapter sequences from reads and removing all of their occurrences. Also most of the existing tools use kmers and may cut only part of primers or primers with studied sequence of gene. Because of this, use of such programs leads to incorrect trimming, reduction of coverage, and increase in the number of false-positive and/or false-negative results. We have developed a new tool named cutPrimers for accurate cutting of any number of primers from reads. Using sequencing reads that were obtained during study of BRCA1/2 genes, we compared it with cutadapt, AlienTrimmer, and BBDuk. All of them trimmed reads in such a way that coverage of at least two amplicons decreased to unacceptable level (<30 reads) comparing with reads trimmed with cutPrimers. At the same time, Trimmomatic and AlienTrimmer cut all occurrences of primer sequences, so the length of the remaining reads was less than prospective. PMID- 28715236 TI - Effects of different heel-raise-lower exercise interventions on the strength of plantarflexion, balance, and gait parameters in stroke survivors. AB - The objective of this study was to investigate the effects of Heel-Raise-Lower Exercise (HRLE) interventions on the strength of plantarflexion, balance, and gait parameters in people with stroke. Specifically, this study compared the two different HRLEs to identify whether heels raise-lower with forefoot on a block (HRB) is more effective or ineffective to enhance strength and functional capacities than heels raise-lower on a level floor (HRL) exercise in people with stroke. Repetitive heel raise-lower is a common exercise for improving the strength and power of ankle plantarflexors. It is a simple movement, requires no equipment, and can be performed at home. Each group of 10 people with stroke was given either HRB training or HRL training. The subjects performed the exercise 100 times per day, 5 days per week for 6 weeks. The strength of plantarflexors, static/dynamic balance, and gait parameters were measured using the manual muscle test (MMT), a Biodex Balance System (BBS) SD, and the GAITRite system. After 6 weeks of treatment, there were significant increases in the plantarflexors strength in both groups: by 34% in the HRB group and by 21% in the HRL group. Static and dynamic balance and gait speed also increased significantly in both groups. However, cadence, the paretic side single limb support period (SLSP), paretic side step length, and paretic side stride length significantly increased only in the HRB group. The HRB improved significantly the plantar flexor strength of the paretic side, gait speed, and cadence compared to the HRL. PMID- 28715237 TI - The Under- and Over-Identification of Autism: Factors Associated With Diagnostic Referral. AB - As reported prevalence and public awareness of Autism Spectrum Disorder (ASD) have grown in recent years, clinicians will likely see increased referrals for suspected ASD. The current study sought to elucidate factors associated with referral for possible ASD, as well as diagnostic outcome among youth referred for suspected ASD. Youth referred for psychological evaluations at an outpatient clinic (N = 69, 6-18 years, 48 male) were categorized into four groups: referred for suspected ASD and diagnosed as such, referred for ASD and not diagnosed as such, not referred for ASD but diagnosed as such, and neither referred for nor diagnosed with ASD. Approximately half of cases referred for suspected ASD did not meet diagnostic criteria. A significant effect of group was found for cognitive ability and anxiety. Youth receiving ASD diagnoses, regardless of whether they were referred for suspected ASD, demonstrated lower cognitive ability than children not receiving ASD diagnoses. Youth neither referred for nor diagnosed with ASD demonstrated lower anxiety than those who were referred and diagnosed. Maternal education significantly differed among the four groups. Although group differences are seen for youth cognitive ability, anxiety, and maternal education, we found no clear indicators differentiating referrals that were "accurate" (i.e., those diagnosed with ASD) and those that were not (i.e., those who did not receive ASD diagnosis). Comorbidity was high in all groups, including those referred primarily for ASD assessment, underscoring the importance of comprehensive assessment regardless of specificity of the referral. PMID- 28715239 TI - Parental Self-Efficacy to Support Teens During a Suicidal Crisis and Future Adolescent Emergency Department Visits and Suicide Attempts. AB - This study of adolescents seeking emergency department (ED) services and their parents examined parents' self-efficacy beliefs to engage in suicide prevention activities, whether these beliefs varied based on teens' characteristics, and the extent to which they were associated with adolescents' suicide-related outcomes. Participants included 162 adolescents (57% female, 81.5% Caucasian), ages 13-17, and their parents. At index visit, parents rated their self-efficacy to engage in suicide prevention activities and their expectations regarding their teen's future suicide risk. Adolescents' ED visits for suicide-related concerns and suicide attempts were assessed 4 months later. Parents endorsed high self efficacy to engage in most suicide prevention activities. At the same time, they endorsed considerable doubt in being able to keep their child safe if the teen has thoughts of suicide and in their child not attempting suicide in the future. Parents whose teens experienced follow-up suicide-related outcomes endorsed, at clinically meaningful effect sizes, lower self-efficacy for recognizing suicide warning signs, for obtaining the teen's commitment to refrain from suicide, and for encouraging their teen to cope, as well as lower confidence that their teen will not attempt suicide; self-efficacy to recognize warning signs was at trend level. Despite endorsing high self-efficacy for the majority of suicide prevention activities, parents of high-risk teens expressed less confidence in their capacity to influence their teen's suicidal behavior, which could undermine parents' effort to implement these strategies. The relationship between parental self-efficacy and youth suicide-related outcomes points to its potential value in guiding clinical decision making and interventions. PMID- 28715238 TI - The usage of fasting glucose and glycated hemoglobin for the identification of unknown type 2 diabetes in high risk patients with morbid obesity. AB - BACKGROUND: In spite of increased vigilance of undiagnosed type 2 diabetes (DM2), the prevalence of unknown DM2 in subjects with morbid obesity is not known. AIM: To assess the prevalence of undiagnosed DM2 and compare the performance of glycated A1c (HbA1c) and fasting glucose (FG) for the diagnosis of DM2 and prediabetes (preDM) in patients with morbid obesity. PATIENTS AND METHODS: We measured fasting glucose and HbA1c in 537 consecutive patients with morbid obesity without previously known DM2. RESULTS: A total of 49 (9%) patients with morbid obesity had unknown DM2 out of which 16 (33%) fulfilled both the criteria for HbA1c and FG. Out of 284 (53%) subjects with preDM, 133 (47%) fulfilled both the criteria for HbA1c and FG. Measurements of agreement for FG and HbA1c were moderate for DM2 (kappa = 0.461, p < .001) and fair for preDM (kappa = 0.317, p < .001). Areas under the curve for FG and HbA1c in predicting unknown DM2 were 0.970 (95% CI 0.942, 0.998) and 0.894 (95% CI 0.837, 0.951) respectively. The optimal thresholds to identify unknown DM2 were FG >=6.6 mmol/L and HbA1c >= 6.1% (43 mmol/mol). CONCLUSIONS: The prevalence of DM2 remains high and both FG and HbA1c identify patients with unknown DM2. FG was slightly superior to HbA1c in predicting and separating patients with unknown DM2 from patients without DM2. We suggest that an FG >=6.6 mmol/L or an HbA1c >=6.1% (43 mmol/mol) may be used as primary cut points for the identification of unknown DM2 among patients with morbid obesity. PMID- 28715240 TI - The effect of inspiratory muscle training on respiratory variables in a patient with ankylosing spondylitis: A case report. AB - : Ankylosing Spondylitis (AS) presents with both musculoskeletal and cardiorespiratory pathophysiological manifestations. Inspiratory muscle training (IMT) may be a useful intervention to address deficits in respiratory and functional status. CASE DESCRIPTION: A 25-year-old male with AS initially sought treatment for low back and right hip pain, but 7 weeks of IMT was also provided due to abnormal respiratory performance. OUTCOMES: At baseline, the patient presented with a resting respiratory rate (RR) of 14.5 breaths/minute, tidal volume (TV) of 0.76 L, minute ventilation (VE) of 10.87 L/min, and end tidal CO2 (PetCO2) of 30.56 mmHg. Baseline exercise test results revealed a VO2max of 44 ml/kg/min and VE to CO2 output (VE/VCO2) slope of 30. Baseline MIP, SMIP, and MEP were 54 cm H2O, 507 PTU, and 87 cm H2O, respectively, and increased to 176 cm H2O, 807 PTU, and 151 cm H2O, respectively, after IMT. The VO2max increased to 51 ml/kg/min with decreases in the VE/VCO2 slope (29), resting RR (12 breaths/minute), resting TV (0.52 L), and resting VE (6.83 L/min) after IMT. Improvements during postural challenges were also observed. DISCUSSION: This case demonstrates the clinical utility of respiratory gas analysis and respiratory performance measures to identify functional deficits and manage a patient with AS. The improvements in respiratory performance at rest, during postural challenges, and during maximal exercise after a relatively short period of IMT highlights the role IMT may have to improve functional status in patients with AS. Further investigation of IMT in patients with AS is warranted. PMID- 28715241 TI - Presentation and management of arthrofibrosis of the knee: A case report. AB - STUDY DESIGN: Case report. BACKGROUND: Arthrofibrosis is a debilitating condition that results in pain, decreased range of motion, and decreased function. Although surgical management of arthrofibrosis has been well described in the literature, rehabilitation of the arthrofibrotic knee is less well described. CASE DESCRIPTION: A 28-year-old female presented with swelling, pain, and decreased strength, range of motion, patellar mobility, and function following an exploratory arthroscopy of her left knee. After failed conservative management, the patient underwent two additional surgeries to remove scar tissue. Following each surgery, the emphasis was on decreasing inflammation and maintaining patellar mobility while increasing joint range of motion and strength. Therapy progression was determined by the presence or absence of inflammatory signs. The second scar tissue removal surgery resulted in a femoral neuropathy that further complicated the rehabilitation process. OUTCOMES: At 3-year follow-up, the patient continued to present with decreased range of motion and strength compared to the uninvolved limb, but had returned to a modified running program and reported pain no longer limited her ability to participate in activities of daily living. DISCUSSION: This case report highlights the importance of recognizing that arthrofibrosis may result following a minor knee surgery and with minimal range of motion loss. Additional complications also may result during arthrofibrosis treatment. Progressing rehabilitation based on the inflammatory response may decrease the likelihood of additional scar tissue formation and potentially improve the outcome for the patient. PMID- 28715242 TI - Not All Masks Are Created Equal: Masking Success in Clinical Trials of Children and Adolescents. AB - The current study assessed the success of masking omega-3 (Omega3) and psychotherapy in clinical trials of youth with depression or bipolar spectrum disorder. Participants were youth ages 7-14 with DSM-IV-TR diagnosed depressive (n = 72) or bipolar spectrum (n = 23) disorders. Inclusion diagnoses were depressive disorder, cyclothymic disorder, or bipolar disorder not otherwise specified. Exclusion diagnoses included bipolar I or II disorder, chronic medical condition or autism. Youth participated in 2 * 2 randomized controlled trials, in which they received Omega3 or placebo (PBO) and psychoeducational psychotherapy (PEP) or active monitoring (AM). Participants and study staff (including independent interviewers) were masked to Omega3/PBO allocation. Besides the masked independent interviewers, one coprincipal investigator (Co-PI) was fully masked to both conditions and completed all consensus conference ratings postrandomization. At the endpoint assessment or last completed interview, interviewers and the masked Co-PI guessed whether each child was assigned to Omega3 or PBO and to PEP or AM. Masking failure was calculated using the degree of correct guesses above chance level using binomial tests across all participants for Omega3 versus PBO and PEP versus AM. For all guessers, Omega3 allocation was guessed correctly approximately half the time (50%-52.5%). Rates of correct guessing were higher for PEP, but only the interviewer guesses were correct significantly more often (58.5%-68.7%) than chance. Reporting of masking success should be an essential element of RCTs. Psychotherapy is generally more difficult to mask, but with attentive masking procedures reasonable masking can be achieved. PMID- 28715244 TI - Small Sample Methods for Multilevel Modeling: A Colloquial Elucidation of REML and the Kenward-Roger Correction. AB - Studies on small sample properties of multilevel models have become increasingly prominent in the methodological literature in response to the frequency with which small sample data appear in empirical studies. Simulation results generally recommend that empirical researchers employ restricted maximum likelihood estimation (REML) with a Kenward-Roger correction with small samples in frequentist contexts to minimize small sample bias in estimation and to prevent inflation of Type-I error rates. However, simulation studies focus on recommendations for best practice, and there is little to no explanation of why traditional maximum likelihood (ML) breaks down with smaller samples, what differentiates REML from ML, or how the Kenward-Roger correction remedies lingering small sample issues. Due to the complexity of these methods, most extant descriptions are highly mathematical and are intended to prove that the methods improve small sample performance as intended. Thus, empirical researchers have documentation that these methods are advantageous but still lack resources to help understand what the methods actually do and why they are needed. This tutorial explains why ML falters with small samples, how REML circumvents some issues, and how Kenward-Roger works. We do so without equations or derivations to support more widespread understanding and use of these valuable methods. PMID- 28715243 TI - Deficits in young men's knowledge about accessing sexual and reproductive health services. AB - OBJECTIVE: The current study aimed to examine (1) gender differences in college students' knowledge of sexual and reproductive health care (K-SRHC) service access points, and (2) the relationship between demographic and psychosocial factors and college students' overall K-SRHC service access points. METHODS AND PARTICIPANTS: Self-report online surveys were administered to 18- and 19-year-old college students from a northern California public university (N = 183; 39.9% men; 32.2% Latino). RESULTS: Women reported higher overall K-SRHC service access point scores than men. Findings indicated that gender and family planning self efficacy were the strongest correlates of K-SRHC service access points. Men with a regular source of health care had higher K-SRHC service access points than men without. CONCLUSIONS: Results suggest that college men need additional education about how to access sexual and reproductive health services to support their own and their partner's health. PMID- 28715245 TI - Enhanced rutin accumulation in tobacco leaves by overexpressing the NtFLS2 gene. AB - Rutin, one of the metabolites of the flavonoid pathway, shows great potential in industrial applications as a key component in pharmaceutical medicines and biological pesticides. Although the genetic manipulation of transcription factors (TFs) could increase rutin levels in plants, the accompanying accumulation of structurally similar chemicals complicates industrial rutin extraction. In this study, we demonstrated remarkably elevated rutin content (3.5-4.4-fold relative to controls) in transgenic tobacco plants by overexpressing NtFLS2. The levels of other intermediates in the branch pathway did not change much except for a moderate increase of kaempferol-3-O-rutinoside. Furthermore, the transcript levels of pathway genes in transgenic lines were comparable with controls, indicating genetic engineering did not significantly alter the branch pathway. Additionally, the transgenic tobacco plants appeared normal except for a flower color change from light red to white suggesting that it could be a valuable material for industrial extraction of rutin. PMID- 28715246 TI - Changing the Natural History of Non-Small-Cell Lung Cancer Through Upfront Programmed Death Protein 1/Programmed Death-Ligand 1 Blockade. PMID- 28715247 TI - Comprehensive Reporting in Cost-Effectiveness Modeling. PMID- 28715248 TI - Reply to A. Benedict et al. PMID- 28715249 TI - Durable Molecular Remissions in Chronic Lymphocytic Leukemia Treated With CD19 Specific Chimeric Antigen Receptor-Modified T Cells After Failure of Ibrutinib. AB - Purpose We evaluated the safety and feasibility of anti-CD19 chimeric antigen receptor-modified T (CAR-T) cell therapy in patients with chronic lymphocytic leukemia (CLL) who had previously received ibrutinib. Methods Twenty-four patients with CLL received lymphodepleting chemotherapy and anti-CD19 CAR-T cells at one of three dose levels (2 * 105, 2 * 106, or 2 * 107 CAR-T cells/kg). Nineteen patients experienced disease progression while receiving ibrutinib, three were ibrutinib intolerant, and two did not experience progression while receiving ibrutinib. Six patients were venetoclax refractory, and 23 had a complex karyotype and/or 17p deletion. Results Four weeks after CAR-T cell infusion, the overall response rate (complete response [CR] and/or partial response [PR]) by International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria was 71% (17 of 24). Twenty patients (83%) developed cytokine release syndrome, and eight (33%) developed neurotoxicity, which was reversible in all but one patient with a fatal outcome. Twenty of 24 patients received cyclophosphamide and fludarabine lymphodepletion and CD19 CAR-T cells at or below the maximum tolerated dose (<= 2 * 106 CAR-T cells/kg). In 19 of these patients who were restaged, the overall response rate by IWCLL imaging criteria 4 weeks after infusion was 74% (CR, 4/19, 21%; PR, 10/19, 53%), and 15/17 patients (88%) with marrow disease before CAR-T cells had no disease by flow cytometry after CAR T cells. Twelve of these patients underwent deep IGH sequencing, and seven (58%) had no malignant IGH sequences detected in marrow. Absence of the malignant IGH clone in marrow of patients with CLL who responded by IWCLL criteria was associated with 100% progression-free survival and overall survival (median 6.6 months follow-up) after CAR-T cell immunotherapy. The progression-free survival was similar in patients with lymph node PR or CR by IWCLL criteria. Conclusion CD19 CAR-T cells are highly effective in high-risk patients with CLL after they experience treatment failure with ibrutinib therapy. PMID- 28715250 TI - The Development of Technology for Effective Respiratory-Gated Irradiation Using an Image-Guided Small Animal Irradiator. AB - The development of image-guided small animal irradiators represents a significant improvement over standard irradiators by enabling preclinical studies to mimic radiotherapy in humans. The ability to deliver tightly collimated targeted beams, in conjunction with gantry or animal couch rotation, has the potential to maximize tumor dose while sparing normal tissues. However, the current commercial platforms do not incorporate respiratory gating, which is required for accurate and precise targeting in organs subject to respiration related motions that may be up to the order of 5 mm in mice. Therefore, a new treatment head assembly for the Xstrahl Small Animal Radiation Research Platform (SARRP) has been designed. This includes a fast X-ray shutter subsystem, a motorized beam hardening filter assembly, an integrated transmission ionization chamber to monitor beam delivery, a kinematically positioned removable beam collimator and a targeting laser exiting the center of the beam collimator. The X-ray shutter not only minimizes timing errors but also allows beam gating during imaging and treatment, with irradiation only taking place during the breathing cycle when tissue movement is minimal. The breathing related movement is monitored by measuring, using a synchronous detector/lock-in amplifier that processes diffuse reflectance light from a modulated light source. After thresholding of the resulting signal, delays are added around the inhalation/exhalation phases, enabling the "no movement" period to be isolated and to open the X-ray shutter. Irradiation can either be performed for a predetermined time of X-ray exposure, or through integration of a current from the transmission monitor ionization chamber (corrected locally for air density variations). The ability to successfully deliver respiratory-gated X ray irradiations has been demonstrated by comparing movies obtained using planar X-ray imaging with and without respiratory gating, in addition to comparing dose profiles observed from a collimated beam on EBT3 radiochromic film mounted on the animal's chest. Altogether, the development of respiratory-gated irradiation facilitates improved dose delivery during animal movement and constitutes an important new tool for preclinical radiation studies. This approach is particularly well suited for irradiation of orthotopic tumors or other targets within the chest and abdomen where breathing related movement is significant. PMID- 28715251 TI - Body heat responsive gelation of methylcellulose formulation containing betaine. AB - We examined a methylcellulose (MC) formulation that gels at body temperature for enteral alimentation. Betaine was found to have a lowering effect on the gelation temperature of the MC solution. The thermal gelation temperature of a body heat responsive (BHR) gelling MC formulation, consisting of 2% MC, 15% glucose, 1.2% sodium citrate, and 3.5% betaine mixture, was approximately 32 degrees C, indicating that it could gel in response to body heat. Glucose release from the BHR gels was delayed at 37 degrees C in an in vitro study. In rats, oral administration of BHR gelling MC formulation delayed an increase in blood glucose and appearance of 13CO2 in expired air in a 13C-acetate breath test in comparison with the control. These results suggested that the BHR gelling MC formulation was gelled in the stomach and delayed gastric emptying after oral administration and glucose in the gels was absorbed slowly. PMID- 28715252 TI - Sorting Through the Spheres of Influence: Using Modified Pile Sorting to Describe Who Influences Dairy Farmers' Decision-Making About Safety. AB - OBJECTIVES: The primary goal of this study was to describe the mutually perceived influence of bankers and insurers on their agricultural clients' decision-making regarding health and safety. METHODS: Semistructured interviews were conducted with 10 dairy farmers, 11 agricultural bankers, and 10 agricultural insurers from central Wisconsin. Three of the interview questions involved pile sorting. Pile sorting included 5-point Likert-like scales to help participants sort through 32 index cards. Each card represented an individual or group that was thought to possibly affect farmers' decision-making, both generally and about health and safety. Results (photographs of piles of cards quantified into spread sheets, fieldnotes, and interview transcripts) were analyzed with SAS and NVivo. RESULTS: All three groups expressed moderate-to-strong positive opinions about involving agricultural bankers (x2(2) = 2.8155, p = 0.2695), although bankers qualitatively expressed apprehension due to regulations on the industry. Insurance agents received more positive support, particularly from bankers but also from dairy farmers themselves, and expressed more confidence in being involved in designing and implementing a farm safety program. CONCLUSION: Agricultural bankers and insurers can influence individual farmer's decision-making about health and safety. Both are believed to be good purveyors of safety programs and knowledge, especially when leveraging financial incentives. Insurance agents are thought to be more critical in the design of safety programs. Insurers and bankers being financially tied to safety programs may prove both positive and negative, as farmers may be skeptical about the intention of the incentives, making messaging critical. PMID- 28715253 TI - Drug helplines and adult marijuana users: An assessment in Washington, Colorado, Oregon, and Alaska. AB - Drug helplines are well-known and widely utilized resources for those seeking help with managing their substance use. Using "secret shoppers," a preliminary assessment of the drug helplines in 4 states was performed. Eleven calls were placed to the helpline staff, where the secret shopper posed as an adult users of marijuana interested in decreasing their marijuana use and asked questions about cannabinoids and methods of marijuana consumption. In 100% of the calls placed, helpline staff had no knowledge about the effects and interactions of marijuana's 2 main components (tetrahydrocannabinol [THC] and cannabidiol [CBD]), neither could they explain the risk differential of smoking, eating, or vaporizing marijuana. In all but one of the calls placed, helpline responders were respectful and empathic. The assessment suggests that drug helplines are equipped with a respectful, empathetic, and nonjudgmental staff who lack important knowledge to best serve those seeking help for marijuana use. PMID- 28715254 TI - Effects of ethyl-alpha-d-glucoside on human dermal fibroblasts. AB - Ethyl alpha-d-glucoside (alpha-EG) is a glycoside present in sake, Japanese rice wine. Previous studies have reported that alpha-EG suppresses skin roughness after ultraviolet B irradiation, transepidermal water loss, and hepatic function disorder, and has a skin moisturizing effect. In this study, 0.48 MUM of alpha-EG was found to increase the proliferation of normal human dermal fibroblasts (NHDF) by 121.0%, and the amount of collagen I produced by NHDF increased by 159.6% at an alpha-EG concentration of 0.048 MUM, compared to those in cells cultured without alpha-EG. In NHDF cultured in alpha-EG-supplemented medium, the expression of fibroblast growth factor I and VII mRNA increased by 148.8 and 153.1%, at an alpha-EG concentration of 4.8 and 0.048 MUM, respectively, as measured by a quantitative reverse transcription-polymerase chain reaction. Transcript levels of type I collagen genes, COL1A1 and COL1A2, increased by 152.4 and 129.7%, respectively, and that of a type III collagen gene, COL3A1, increased by 131.8% at an alpha-EG concentration of 0.48 MUM. These findings supported the possibility that alpha-EG was involved in the maintenance and improvement of skin homeostasis and moisturizing functions. PMID- 28715255 TI - Predicting personal self-care in informal caregivers. AB - Caregiver research often focuses on negative health outcomes, yet little is known about the self-care practices of caregivers. The present study investigates self care practices among family caregivers and the relationships between personal self-care, perceived stress, and other health variables. Data were collected from informal caregivers through self-administered Internet and paper surveys that included the Medical Outcomes Study Short Form 36-item Health Survey, Perceived Stress Scale, and Self-Care Practices Scale. Personal self-care was most strongly associated with emotional well-being, pain, perceived stress, and general health. The relevance of study findings to strengthening family caregiver programs and future research is discussed. PMID- 28715256 TI - Structural basis for activation of an archaeal ribonuclease P RNA by protein cofactors. AB - Ribonuclease P (RNase P) is an endoribonuclease that catalyzes the processing of the 5'-leader sequence of precursor tRNA (pre-tRNA) in all phylogenetic domains. We have found that RNase P in the hyperthermophilic archaeon Pyrococcus horikoshii OT3 consists of RNase P RNA (PhopRNA) and five protein cofactors designated PhoPop5, PhoRpp21, PhoRpp29, PhoRpp30, and PhoRpp38. Biochemical characterizations over the past 10 years have revealed that PhoPop5 and PhoRpp30 fold into a heterotetramer and cooperate to activate a catalytic domain (C domain) in PhopRNA, whereas PhoRpp21 and PhoRpp29 form a heterodimer and function together to activate a specificity domain (S-domain) in PhopRNA. PhoRpp38 plays a role in elevation of the optimum temperature of RNase P activity, binding to kink turn (K-turn) motifs in two stem-loops in PhopRNA. This review describes the structural and functional information on P. horikoshii RNase P, focusing on the structural basis for the PhopRNA activation by the five RNase P proteins. PMID- 28715257 TI - Association between Testicular Microlithiasis and Testicular Neoplasia: Large Multicenter Study in a Pediatric Population. AB - Purpose To retrospectively define the strength of association between testicular microlithiasis and testicular neoplasia in a large geographically diverse pediatric population. Materials and Methods Retrospective review of scrotal ultrasonographic (US) examination reports and pathology specimens obtained between January 2000 and May 2014 at six academic pediatric hospitals in North America was performed. Reported cases were reviewed to confirm microlithiasis. Radiology and pathology data bases were searched for pathology-proven testicular tumors (benign or malignant germ cell or stromal tumors). Association strength (risk) was expressed in terms of odds ratios (ORs) with and without adjustment for fixed study site effects based on logistic regression. Results A total of 37 863 individuals underwent scrotal US during the study period. Mean age was 11.1 years +/- 4.7 [standard deviation] in boys with microlithiasis and 9.1 years +/- 5.9 in boys without microlithiasis (P < .001). Microlithiasis was confirmed in 2.90% of patients (1097 of 37 863; range, 1.61%-5.25% across sites). It was unilateral in 21.97% (241 of 1097) of patients and bilateral in 78.0% (856 of 1097). Tumor was identified in 4.64% (51 of 1097) of boys with microlithiasis and 0.33% (122 of 36 766) of boys without (unadjusted OR, 14.65; 95% confidence interval [CI]: 10.29, 20.84; adjusted OR, 14.19). Malignant germ cell tumors were identified in 2.8% (31 of 1097) of boys with microlithiasis and 0.12% (45 of 36 766) of boys without microlithiasis (unadjusted OR, 17.26; 95% CI: 11.8, 25.25; adjusted OR, 22.37). Sex cord-stromal tumors were identified in 0.46% (five of 1097) of boys with microlithiasis and 0.079% (29 of 36 766) of boys without (unadjusted OR, 5.8; 95% CI: 2.1, 16; adjusted OR, 6.39). Conclusion There is a strong association between testicular microlithiasis and primary testicular neoplasia in this pediatric population. (c) RSNA, 2017. PMID- 28715258 TI - Reply: Benefit of the Shorter Multidrug-Resistant Tuberculosis Treatment Regimen in California and Modified Eligibility Criteria. PMID- 28715259 TI - Teaching Principal Components Using Correlations. AB - Introducing principal components (PCs) to students is difficult. First, the matrix algebra and mathematical maximization lemmas are daunting, especially for students in the social and behavioral sciences. Second, the standard motivation involving variance maximization subject to unit length constraint does not directly connect to the "variance explained" interpretation. Third, the unit length and uncorrelatedness constraints of the standard motivation do not allow re-scaling or oblique rotations, which are common in practice. Instead, we propose to motivate the subject in terms of optimizing (weighted) average proportions of variance explained in the original variables; this approach may be more intuitive, and hence easier to understand because it links directly to the familiar "R-squared" statistic. It also removes the need for unit length and uncorrelatedness constraints, provides a direct interpretation of "variance explained," and provides a direct answer to the question of whether to use covariance-based or correlation-based PCs. Furthermore, the presentation can be made without matrix algebra or optimization proofs. Modern tools from data science, including heat maps and text mining, provide further help in the interpretation and application of PCs; examples are given. Together, these techniques may be used to revise currently used methods for teaching and learning PCs in the behavioral sciences. PMID- 28715261 TI - Social Media Use and Conduct Problems in Emerging Adults. AB - Social media use has become pervasive in the lives of emerging adults. Although social media may provide individuals with positive opportunities for communication and learning, social media sites also may provide an outlet for youth conduct problems, such as bullying, harassment, and intentional hostility and aggression toward others. Yet, the relationship between social media use and conduct problems remains unclear. This study investigated the association between conduct disorder (CD) symptoms before age 15 and social media use during emerging adulthood in a large, nationally representative sample. Concurrent associations between antisocial personality disorder (ASPD) symptoms and social media use in emerging adults also were examined. Data for this study were based on 567 emerging adults (50.2 percent female; Mage = 20.0 years). Self-report questionnaires were completed online. Results suggested that more childhood CD symptoms were significantly associated with greater daily social media use during emerging adulthood, and that more daily social media use was significantly associated with current ASPD symptoms. Possible directional and cyclical explanations for these findings are explored. Given the pervasiveness of social media in the lives of emerging adults, these results underscore the importance of considering nuanced methods for using social media sites to encourage positive social interactions and to displace the promotion of conduct problems. PMID- 28715262 TI - Sexting Behaviors Exhibited by Men Who Have Sex with Men Between the Ages of 18 70 Who Live in a Socially Conservative State. AB - Sexting, defined as the sending and receiving of sexually suggestive or sexually explicit text or photos, has been growing in prevalence. Recent studies have demonstrated that over half of individuals sampled over 17 and regardless of gender participate in some type of sexting behavior. Most studies on sexting behaviors, including those looking at men who have sex with men (MSM) focus on emerging adult or university-based populations. The goal of the current study was to sample a nonuniversity-based MSM adult population to determine the prevalence of sexting behavior and the odds that a person engages in sexting behaviors based on certain sexual behaviors. The sample consisted of 213 MSM (mean age = 34.8 years, standard deviation [STD] = 12.1) who reside in Oklahoma. The majority of participants (133, 62.4 percent) participated in sexting behaviors. Logistic regression indicated that individuals had 10 times higher odds to engage in sexting if they had participated in a hookup (odds ratio [OR] = 10.44, 95% CI = [4.16-26.25]) and individuals who are married or in a committed relationship had 71 percent lower odds that they had sent a sext message (OR = 0.29, 95% CI = [0.12-0.71]). Sexting behaviors were not associated with condom use. Implications, including using third-party geolocation mobile application (such as Grindr) to deliver sexual health information, are discussed. PMID- 28715260 TI - Does Adding Information on Toxic Constituents to Cigarette Pack Warnings Increase Smokers' Perceptions About the Health Risks of Smoking? A Longitudinal Study in Australia, Canada, Mexico, and the United States. AB - BACKGROUND: Health warning labels (HWLs) on cigarette packs in Australia, Canada, Mexico, and the United States include varying information about toxic cigarette smoke constituents and smoking-related health risks. HWL information changed more recently in Australia, Canada, and Mexico than in the United States. AIMS: To investigate whether smokers' knowledge of toxic constituents and perceived smoking-related risks increased after adding this information to HWLs and how knowledge of toxic constituents is associated with perceptions of smoking-related risks. METHODS: Data come from a longitudinal, online cohort of 4,621 adult smokers surveyed every 4 months from September 2012 (Wave 1) to January 2014 (Wave 5) in Australia, Canada, and Mexico, with the United States being surveyed from Waves 2 to 5. Generalized estimating equation models estimated the association between perceived smoking-related risk at follow-up and prior wave knowledge of toxic constituents, adjusting for attention to HWLs, sociodemographics, and smoking-related characteristics. RESULTS: Between 2012 and 2014, knowledge of toxic constituents increased in Australia, Canada, and Mexico ( p < .001), but not in the United States. Higher levels of both attention to HWLs and knowledge of toxic constituents were associated with a higher perceived risk of smoking-related conditions at follow-up across all countries except for the United States. CONCLUSIONS: Our results suggest that information about toxic constituents on prominent HWLs not only increases smoker's knowledge of toxic constituents, but that it may also reinforce the effects of HWL messages about specific, smoking-related health outcomes. PMID- 28715263 TI - Acute Effect of Virtual Reality Exercise Bike Games on College Students' Physiological and Psychological Outcomes. AB - Commercially available virtual reality (VR) exercise systems are extensively used in many health domains among clinical populations. However, evidence regarding the efficacy of this technology on healthy adults' health-related outcomes is unknown. This pilot study compared physiological and psychological responses following exercise on a VR-based exercise bike (VirZoom) and traditional stationary exercise bike. Twelve healthy college students (9 females; Mage = 25.01, SD = +/- 4.74; MBMI = 22.84, SD = +/- 3.68) completed two separate 20 minute exercise sessions on the VR-based exercise bike and traditional stationary exercise bike. Blood pressure (BP), ratings of perceived exertion, self-efficacy, and enjoyment were assessed as primary outcomes. Dependent t-tests indicated no significant differences in mean systolic or diastolic BP changes from pre to postexercise between the VR-based exercise and traditional stationary biking sessions (all p > 0.05). Notably, participants reported significantly higher ratings of perceived exertion (p < 0.05, Cohen's d = 0.68) during the traditional exercise biking session compared with VR-based exercise biking session. However, participants had significantly higher self-efficacy (p < 0.05, Cohen's d = -0.83) and enjoyment (p < 0.05, Cohen's d = -0.89) during the VR-based exercise biking session compared with traditional stationary biking. The commercially available VR-based exercise bike (VirZoom) may be considered an effective, enjoyable, and motivating physical activity tool. Further interventions with larger and more diverse samples and examinations of more health-related outcomes are warranted to determine optimal application of VR-based exercise programming among various populations. PMID- 28715265 TI - Using Eye Tracking to Explore Consumers' Visual Behavior According to Their Shopping Motivation in Mobile Environments. AB - Despite a strong shift to mobile shopping trends, many in-depth questions about mobile shoppers' visual behaviors in mobile shopping environments remain unaddressed. This study aims to answer two challenging research questions (RQs): (a) how much does shopping motivation like goal orientation and recreation influence mobile shoppers' visual behavior toward displays of shopping information on a mobile shopping screen and (b) how much of mobile shoppers' visual behavior influences their purchase intention for the products displayed on a mobile shopping screen? An eye-tracking approach is adopted to answer the RQs empirically. The experimental results showed that goal-oriented shoppers paid closer attention to products' information areas to meet their shopping goals. Their purchase intention was positively influenced by their visual attention to the two areas of interest such as product information and consumer opinions. In contrast, recreational shoppers tended to visually fixate on the promotion area, which positively influences their purchase intention. The results contribute to understanding mobile shoppers' visual behaviors and shopping intentions from the perspective of mindset theory. PMID- 28715268 TI - Living in Fragments: The Necessity of Cloud Computing and Virtual Reality. PMID- 28715266 TI - Associations of Social Support, Friends Only Known Through the Internet, and Health-Related Quality of Life with Internet Gaming Disorder in Adolescence. AB - Internet Gaming Disorder (IGD) has been included in the current edition of the Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition (DSM-5). In the present study, the relationship among social support, friends only known through the Internet, health-related quality of life, and IGD in adolescence was explored for the first time. For this purpose, 1,095 adolescents aged from 12 to 14 years were surveyed with a standardized questionnaire concerning IGD, self perceived social support, proportion of friends only known through the Internet, and health-related quality of life. The authors conducted unpaired t-tests, a chi square test, as well as correlation and logistic regression analyses. According to the statistical analyses, adolescents with IGD reported lower self-perceived social support, more friends only known through the Internet, and a lower health related quality of life compared with the group without IGD. Both in bivariate and multivariate logistic regression models, statistically significant associations between IGD and male gender, a higher proportion of friends only known through the Internet, and a lower health-related quality of life (multivariate model: Nagelkerke's R2 = 0.37) were revealed. Lower self-perceived social support was related to IGD in the bivariate model only. In summary, quality of life and social aspects seem to be important factors for IGD in adolescence and therefore should be incorporated in further (longitudinal) studies. The findings of the present survey may provide starting points for the development of prevention and intervention programs for adolescents affected by IGD. PMID- 28715269 TI - FSG: Fast String Graph Construction for De Novo Assembly. AB - The string graph for a collection of next-generation reads is a lossless data representation that is fundamental for de novo assemblers based on the overlap layout-consensus paradigm. In this article, we explore a novel approach to compute the string graph, based on the FM-index and Burrows and Wheeler Transform. We describe a simple algorithm that uses only the FM-index representation of the collection of reads to construct the string graph, without accessing the input reads. Our algorithm has been integrated into the string graph assembler (SGA) as a standalone module to construct the string graph. The new integrated assembler has been assessed on a standard benchmark, showing that fast string graph (FSG) is significantly faster than SGA while maintaining a moderate use of main memory, and showing practical advantages in running FSG on multiple threads. Moreover, we have studied the effect of coverage rates on the running times. PMID- 28715270 TI - Reliability and validity of the Turkish version of ABILHAND-Kids' questionnaire in a group of patients with neuromuscular disorders. AB - This study was performed to examine the reliability and validity of the Turkish version of ABILHAND-Kids questionnaire which assesses manual functions of children with neuromuscular diseases (NMDs). A cross sectional survey study design and Rasch analysis were used to assess the reliability and validity of the Turkish version of scale. Ninety-three children with different neuromuscular disorders and their parents were included in the study. The scale was applied to the parents with face-to-face interview twice; on their first visit and after an interval of 15 days. The test-retest reliability was assessed with intraclass correlation coefficient (ICC), and internal consistency of the multi-item subscales by calculating Cronbach alpha values. Brooke Upper Extremity Functional Classification (BUEFC) and Wee-Functional Independency Measurement (Wee-FIM) were correlated to determine the construct validity. The ICC value for the test/retest reliability was 0.94. The internal consistency was 0.81. Floor (1.1%) and ceiling (11.8%) effects were not significant. There were moderate correlations between the Turkish version of ABILHAND-Kids and Wee-FIM (0.67) and BUEFC (-0.37). Rasch analysis indicated good item fit, unidimensionality, and model fit. The Turkish version of ABILHAND-Kids questionnaire was found to be a reliable and valid scale for the assessment of the manual ability of children with NMDs. PMID- 28715271 TI - Comparison of trunk impairment scale versions 1.0 and 2.0 in people with multiple sclerosis: A validation study. AB - BACKGROUND: Trunk control impairment often accompanies multiple sclerosis (MS). Trunk stability is necessary for movements of extremities, as are selective trunk movements for normal gait. Measuring trunk function is thus of interest. METHODS: We examined the relationships between the Trunk Impairment Scale (TIS1.0 and TIS2.0) and the Berg Balance Scale (BBS), 5 sit-to-stand test (5STS), Timed Up and Go test (TUG), 10-m timed walk test (10TW), 2-min walk test (2MWT), Falls Efficacy Scale - International, and 12-item MS Walking Scale (MSWS-12) in 47 outpatients. We determined construct validity by calculating the degree to which the TIS versions produced different scores between known groups: use or nonuse of walking aid, MS disability status, and whether participants experienced a fall or not during 14 weeks. RESULTS: TIS correlated moderately with BBS and 5STS; moderately (TIS1.0) or weakly (TIS2.0) with TUG, 10TW, and 2MWT; and weakly to moderately with MSWS-12 in subgroups with Expanded Disability Status Scale (EDSS) >6.0. No other clear correlation patterns were found. TIS did not discriminate between known groups. CONCLUSIONS: TIS1.0 is recommended for individuals with MS (EDSS score 4.0-7.5). Better trunk function correlates with better balance and walking ability. TIS has limited value in fall risk screening. PMID- 28715272 TI - Face-to-Face Versus Online Behavioral Parent Training for Young Children at Risk for ADHD: Treatment Engagement and Outcomes. AB - Attention deficit/hyperactivity disorder (ADHD) is associated with significant challenges in child functioning. Although behavioral parent training (BPT) can reduce ADHD symptoms, factors associated with traditional face-to-face (F2F) delivery results in only about half of families receiving BPT. The purpose of this pilot randomized controlled trial was to examine parent engagement and program acceptability of F2F and online BPT, as well as the efficacy of both formats relative to a waitlist control (WLC) group. Participants were 47 families with preschool children (30 boys, 17 girls) who were between the ages of 3 years 0 months (3;0) and 5 years 11 months (5;11) old who were identified at risk for ADHD. Children were randomly assigned to F2F or online BPT or to WLC; parents in the two treatment conditions received 10 sessions of BPT. Assessment data for all groups were collected at pre-, mid-, and posttreatment. Both intervention formats resulted in high attendance (M = 80%) and significantly improved parent knowledge of interventions, treatment implementation fidelity, and child behavior (reduced restlessness and impulsivity, improved self-control, affect, and mood) compared with WLC. However, parents in the F2F group reported significantly higher acceptability ratings than parents in the online group. Findings indicate a streamlined BPT delivered online or F2F results in high levels of engagement, acceptability, as well as parent treatment knowledge and fidelity. Online BPT is associated with similar efficacious outcomes with F2F BPT, suggesting the need for further research to determine variables that predict greater acceptability for and adoption of this format. PMID- 28715273 TI - Physiological effects of physical therapy interventions on lumbar intervertebral discs: A systematic review. AB - BACKGROUND CONTEXT: The use of physical therapy has been recommended in the treatment of low back pain based on primarily mechanical and neurophysiological effects. Recent studies have measured the physiological effects of physical therapy interventions, including manual therapy and traction, on the intervertebral discs (IVD), and these findings may have implications for the long term management or even prevention of low back pain. PURPOSE: The objective of this systematic review is to investigate the literature regarding possible physiological effects of physical therapy interventions on the intervertebral disc (IVD). STUDY DESIGN: Systematic Review. METHODS: A literature search of published articles through December 2014 resulted in the retrieval of 8 clinical studies assessing the influence of physical therapy interventions on the physiology of the IVD. RESULTS: Three studies, including two using animal models, investigated the effects of 30-minute intermittent traction on disc height. One in vivo animal study and two studies using human subjects assessed changes of disc height associated with static traction. Three studies investigated the effects of lumbar spine manipulation and mobilization on changes in water diffusion within the IVD. All studies confirmed, either directly or indirectly, that their respective intervention influenced disc physiology primarily through water flow. CONCLUSION: Physical therapy interventions may have an effect on the physiology of the IVD, primarily through water diffusion and molecular transport, which are important for the health of the IVD. PMID- 28715274 TI - A short synthetic chimeric sequence harboring matrix attachment region/PSAR2 increases transgene expression in Chinese hamster ovary cells. AB - A chimeric DNA fragment containing an interferon-beta matrix attachment region (MAR) and an immunoglobulin MAR (PSAR2) was synthesized. PSAR2 was cloned into the upstream or downstream region of an enhanced green fluorescent protein (eGFP) expression cassette in a eukaryotic vector, which was then transfected into CHO cells. The results showed that PSAR2 did not effectively increase transgene expression when it was cloned into the upstream region of the eGFP expression cassette. However, when inserted downstream of the eGFP expression cassette, PSAR2-enhanced transient transgene expression and significantly increased the numbers of stably transfected cells compared with the control vector. Additionally, PSAR2 significantly increased eGFP copy numbers as compared with the control vector. PSAR2 could significantly enhance transgene expression in CHO cells according to the position in the vector and increased transgene copy numbers. We found a short chimeric sequence harboring two MARs effectively increased transgene expression in CHO cells. PMID- 28715275 TI - Twice Silenced: The Underreporting of Child Sexual Abuse in Orthodox Jewish Communities. AB - Child sexual abuse remains an underreported crime throughout the world, despite extensive research and resources dedicated both to improving investigative techniques and helping children disclose their experiences. The discovery of rampant cover-ups within the Catholic Church has exposed some of the ways religious and cultural issues can impede reporting to authorities. This article examines specific factors that contribute to the underreporting of child sexual abuse within Orthodox Jewish communities. It also explores ways in which these communities have handled child sexual abuse reporting in the past and describes recent progress. Implications are offered for CSA prevention, detection, and recovery in Orthodox Jewish communities as well as other minority religious groups. PMID- 28715276 TI - Cancer Incidence after In Utero Exposure to Ionizing Radiation in Techa River Residents. AB - Health effects of in utero exposure to ionizing radiation, especially among adults, are still unclear. The aim of this study was to analyze cancer risk in a cohort of subjects exposed in utero due to releases of nuclear waste into the Techa River in the Southern Urals, taking into account additional postnatal exposure. Analysis for solid cancer was based on 242 cases among 10,482 cohort members, accumulating 381,948 person-years at risk, with follow-up from 1956 2009, while analysis for hematological malignancies was based on 26 cases among 11,070 persons, with 423,502 person-years at risk, with follow-up from 1953-2009. Mean doses accumulated in soft tissues and in red bone marrow during the prenatal period were 4 mGy and 30 mGy, respectively. Additional respective mean postnatal doses received by cohort members were 11 and 84 mGy. Poisson regression analysis was used to estimate the excess relative risk (ERR) of cancer incidence related to in utero and postnatal doses. No association was observed for in utero exposure with solid cancer risk [ERR per 10 mGy: -0.007; 95% confidence interval (CI): <-0.107; 0.148] or with hematological malignancy risk (ERR/10 mGy: -0.011; 95% CI: <-0.015; 0.099). However, ERR of solid cancer increased significantly with increasing postnatal dose (ERR/10 mGy: 0.11; 95% CI: 0.04; 0.22). The very wide confidence intervals in these ERR results are similar to those of studies performed on the LSS cohort and the offspring of the Mayak Female Worker Cohort, as well as case-control studies of effects after in utero medical exposure. There were limitations of this study, with decreased statistical power, due to the low prenatal doses received by most of the cohort members, the small number of cancer cases and the absence of cohort members over the age of 59 years (living cohort members had reached 49-59 years of age). Further aging of the cohort and extension of the follow-up period will enhance the statistical power of this study in the future. There is a shortage of cohort studies reporting on the effects of prenatal radiation exposure, as well as information on chronic exposure during the prenatal period. Therefore, further research of this unique cohort will be a useful addition to the published literature on this subject, and a valuable means of elucidating the long-term effects of low-dose radiation exposure in the fetus. PMID- 28715277 TI - Superantigen staphylococcal enterotoxin C1 inhibits the growth of bladder cancer. AB - Superantigens can induce cell-mediated cytotoxicity preferentially against MHC II positive target cells with large amounts of inflammatory cytokines releasing. In this study, superantigen staphylococcal enterotoxin C (SEC) 1 was investigated to evaluate its potential in bladder cancer immunotherapy in vitro and in vivo. Our results revealed that SEC1 could stimulate the proliferation of human peripheral blood mononuclear cells (PBMCs) in a dose-dependent manner, accompanied with the release of interleukin-2, interferon-gamma, and tumor necrosis factor-alpha, and increased the population of CD4+ T cells and CD8+ T cells. PBMCs stimulated by SEC1 could initiate significant cytotoxicity towards human bladder cancer cells in vitro. The results of in vivo antitumor experiment indicated that SEC1 could decrease the rate of tumor formation and prolong the survival time of tumor bearing mice. Our study demonstrated that SEC1 inhibited the growth of bladder cancer. And it is also suggested that SEC1 may become a candidate for bladder cancer immunotherapy. PMID- 28715278 TI - BI-RADS Category 3 Comparison: Probably Benign Category after Recall from Screening before and after Implementation of Digital Breast Tomosynthesis. AB - Purpose To evaluate Breast Imaging Reporting and Data System (BI-RADS) category 3 assessment at diagnostic examination after recall from screening in a large urban population after implementation of digital breast tomosynthesis (DBT) by focusing both on overall use and use stratified by recalled finding type and outcome at 2 years. Materials and Methods This was an intuitional review board-approved and HIPAA-compliant retrospective review of 10 728 digital mammography (DM) examinations from September 1, 2010, to August 30, 2011, and 15 571 screening DBT examinations from October 1, 2011, to February 28, 2013. The recall populations for DM and DBT were 1112 of 10 728 (10.4% of women screened) and 1366 of 15 571 (8.8% of women screened), respectively. Recall examinations were classified according to finding type: calcifications, asymmetry or focal asymmetry, mass, and architectural distortion. Differences between groups were compared by using the chi2 test. Results Although there was no significant change in the utilization rate of BI-RADS category 3 in those patients screened with DM compared with DBT (168 of 10 728, 1.6% for DM vs 206 of 15 571, 1.3% for DBT; P = .102), there was a mean overall reduction of 2.4 women per 1000 (95% confidence interval [CI]: -0.5, 5.4) recommended for short-term follow-up. Lesion types given a BI-RADS category 3 assessment after diagnostic work-up did not change. The distribution of recalled finding types significantly changed with DBT, with increased recall examinations for architectural distortion and mass (P < .001) and decreased recall examinations for asymmetries (P <= .001). There was no change in recall examinations for calcifications (P = .977). Conclusion Screening with DBT did not significantly change the utilization rate of BI-RADS category 3 classification; however, the overall number of patients recommended for short interval follow-up decreased by a mean of 2.4 women per 1000 (95% CI: -0.5, 5.4). (c) RSNA, 2017 Online supplemental material is available for this article. PMID- 28715279 TI - Crystal structure of a beta-fructofuranosidase with high transfructosylation activity from Aspergillus kawachii. AB - beta-Fructofuranosidases belonging to glycoside hydrolase family (GH) 32 are enzymes that hydrolyze sucrose. Some GH32 enzymes also catalyze transfructosylation to produce fructooligosaccharides. We found that Aspergillus kawachii IFO 4308 beta-fructofuranosidase (AkFFase) produces fructooligosaccharides, mainly 1-kestose, from sucrose. We determined the crystal structure of AkFFase. AkFFase is composed of an N-terminal small component, a beta-propeller catalytic domain, an alpha-helical linker, and a C-terminal beta sandwich, similar to other GH32 enzymes. AkFFase forms a dimer, and the dimerization pattern is different from those of other oligomeric GH32 enzymes. The complex structure of AkFFase with fructose unexpectedly showed that fructose binds both subsites -1 and +1, despite the fact that the catalytic residues were not mutated. Fructose at subsite +1 interacts with Ile146 and Glu296 of AkFFase via direct hydrogen bonds. PMID- 28715280 TI - Fatigue Moderates the Relationship Between Perceived Stress and Suicidal Ideation: Evidence From Two High-Resolution Studies. AB - Theoretical models of self-harm suggest that high perceived stress and high fatigue (which might affect the ability to cope with stress) may interact to predict the short-term occurrence of suicidal ideation and nonsuicidal self injury (NSSI). We tested 3 approaches to examining this interaction, each of which provided a different understanding of the specific nature of these associations: comparing each individual's daily stress/fatigue to the entire sample's overall average (i.e., grand-mean centering), comparing each individual's daily perceived stress/fatigue to his or her overall average (i.e., group- or participant-mean centering), and comparing each individual's average perceived stress/fatigue to the sample's overall average (i.e., centering participant means on overall grand mean). In 2 studies, adolescents (n = 30; 574 daily reports, M age = 17.3 years, range = 12-19; 87.6% female) and young adults (n = 60; 698 daily reports; M age = 23.25 years, range = 18-35; 85% female) completed daily measures of perceived stress, fatigue, suicidal ideation, and NSSI. In both samples, the interaction between high daily perceived stress and high daily fatigue predicted greater odds of daily suicidal ideation (but not NSSI). Only the model comparing each individual's daily stress/fatigue to the entire sample's overall average was consistently significant across the two studies. Participants were most likely to experience suicidal ideation on days when both perceived stress and fatigue were elevated relative to the average level experienced across people and time points. Studies should build upon these findings with more in-depth examination of the temporal nature of stability and change in these factors as they relate to sustained suicidal ideation. PMID- 28715281 TI - Admission for COPD Exacerbation Is Associated with the Clinical Diagnosis of Pulmonary Hypertension: Results from a Retrospective Longitudinal Study of a Veteran Population. AB - Patients with chronic obstructive pulmonary disease and pulmonary hypertension (PH-COPD) have an increased risk of hospitalizations and death compared to COPD alone. Identifying PH in COPD is challenging because performing right heart catheterization, the gold standard for PH diagnosis, is invasive and not routinely performed. Clinical characterization of COPD patients at risk who are progressing toward PH will aid therapeutic development at earlier stages of progressively fatal PH-COPD. We studied the records of 5,45,086 patients in a large Veterans Affairs healthcare network (2000-2012) with a primary discharge diagnosis of COPD based on encounters' ICD-9 codes and further stratified into those who received an additional ICD-9 code for a PH diagnosis. Patients with PH COPD were assigned to one of the four subgroups: those with (a) no history of exacerbation or hospital admissions, (b) history of exacerbations but no hospital admissions, (c) hospital admissions unrelated to COPD and (d) history of COPD exacerbation-related hospital admissions. We also examined the COPD and COPD-PH cohorts for associated comorbidities such as cardiac disease and the presence of obstructive sleep apnea (OSA). A regression analysis revealed that patients with COPD exacerbation-related hospital admissions had 7 * higher risk of having a concomitant clinical diagnosis of PH compared to non-hospitalized patients. COPD PH patients had higher rates of cardiac comorbidities (89% vs. 66%) and OSA (34% vs. 16%) compared to COPD alone. We conclude that COPD patients hospitalized for COPD exacerbations are at a higher risk for developing PH, and hospitalized COPD patients with cardiac comorbidities and/or OSA should be screened as at-risk population for developing PH. PMID- 28715282 TI - Player and Game Characteristics and Head Impacts in Female Youth Ice Hockey Players. AB - CONTEXT: Despite the growing popularity of ice hockey among female youth and interest in the biomechanics of head impacts in sport, the head impacts sustained by this population have yet to be characterized. OBJECTIVES: To describe the number of, biomechanical characteristics of, and exposure to head impacts of female youth ice hockey players during competition and to investigate the influences of player and game characteristics on head impacts. DESIGN: Cohort study. METHODS: Twenty-seven female youth ice hockey players (mean age = 12.5 +/- 0.52 years) wore instrumented ice hockey helmets during 66 ice hockey games over a 3-year period. Data specific to player, game, and biomechanical head impact characteristics were recorded. A multiple regression analysis identified factors most associated with head impacts of greater frequency and severity. RESULTS: A total of 436 total head impacts were sustained during 6924 minutes of active ice hockey participation (0.9 +/- 0.6 impacts per player per game; range, 0-2.1). A higher body mass index (BMI) significantly predicted a higher number of head impacts sustained per game (P = .008). Linear acceleration of head impacts was greater in older players and those who played the forward position, had a greater BMI, and spent more time on the ice (P = .008), whereas greater rotational acceleration was present in older players who had a greater BMI and played the forward position (P = .008). During tournament games, increased ice time predicted increased severity of head impacts (P = .03). CONCLUSIONS: This study reveals for the first time that head impacts are occurring in female youth ice hockey players, albeit at a lower rate and severity than in male youth ice hockey players, despite the lack of intentional body checking. PMID- 28715284 TI - Sexual violence screening practices of student health centers located on universities in Florida. AB - OBJECTIVE: The purpose of this study is to describe current sexual violence screening practices of student health centers located on universities in Florida. PARTICIPANTS: Institutional level data was collected from 33 student health centers from November 2015 through January 2016. The student health centers were located on public or private universities. METHODS: A cross-sectional descriptive study design was used. Data was collected from student health center representatives through use of a telephone administered survey. RESULTS: Findings reveal that the majority of student health centers screen for sexual violence. However, not all use effective screening strategies. Further, the majority of screening questions used are not specific to sexual violence. CONCLUSIONS: Findings can be used to assist universities with responding to campus sexual violence among the college population. Recommendations for strengthening sexual violence screening practices and future research are provided. PMID- 28715285 TI - Dietary daidzein, but not genistein, has a hypocholesterolemic effect in non ovariectomized and ovariectomized female Sprague-Dawley rats on a cholesterol free diet. AB - We compared the effects of two major isoflavones, daidzein and genistein, on lipid metabolism in rats. Daidzein (150 mg/kg diet), genistein (150 mg/kg diet), daidzein and genistein (1:1, 300 mg/kg diet), or control diets were fed to 4 groups of 6-week-old ovariectomized (Ovx) and non-Ovx Sprague Dawley rats for 4 weeks. Dietary daidzein, but not genistein, reduced serum and hepatic total cholesterol levels significantly relative to that by the control group, regardless of whether the rats had undergone ovariectomy. Genistein did not exhibit any physiological effects on lipid levels, but did affect genes involved in cholesterol metabolism. These results indicate that daidzein and genistein may influence lipid regulation via differing modes of action. PMID- 28715283 TI - Temperate-Water Immersion as a Treatment for Hyperthermic Humans Wearing American Football Uniforms. AB - CONTEXT: Cold-water immersion (CWI; 10 degrees C) can effectively reduce body core temperature even if a hyperthermic human is wearing a full American football uniform (PADS) during treatment. Temperate-water immersion (TWI; 21 degrees C) may be an effective alternative to CWI if resources for the latter (eg, ice) are unavailable. OBJECTIVE: To measure rectal temperature (Trec) cooling rates, thermal sensation, and Environmental Symptoms Questionnaire (ESQ) scores of participants wearing PADS or shorts, undergarments, and socks (NOpads) before, during, and after TWI. DESIGN: Crossover study. SETTING: Laboratory. PATIENTS OR OTHER PARTICIPANTS: Thirteen physically active, unacclimatized men (age = 22 +/- 2 years, height = 182.3 +/- 5.2 cm, mass = 82.5 +/- 13.4 kg, body fat = 10% +/- 4%, body surface area = 2.04 +/- 0.16 m2). INTERVENTION(S): Participants exercised in the heat (40 degrees C, 50% relative humidity) on 2 days while wearing PADS until Trec reached 39.5 degrees C. Participants then underwent TWI while wearing either NOpads or PADS until Trec reached 38 degrees C. Thermal sensation and ESQ responses were collected at various times before and after exercise. MAIN OUTCOME MEASURE(S): Temperate-water immersion duration (minutes), Trec cooling rates ( degrees C/min), thermal sensation, and ESQ scores. RESULTS: Participants had similar exercise times (NOpads = 38.1 +/- 8.1 minutes, PADS = 38.1 +/- 8.5 minutes), hypohydration levels (NOpads = 1.1% +/- 0.2%, PADS = 1.2% +/- 0.2%), and thermal sensation ratings (NOpads = 7.1 +/- 0.4, PADS = 7.3 +/- 0.4) before TWI. Rectal temperature cooling rates were similar between conditions (NOpads = 0.12 degrees C/min +/- 0.05 degrees C/min, PADS = 0.13 degrees C/min +/- 0.05 degrees C/min; t12 = 0.82, P = .79). Thermal sensation and ESQ scores were unremarkable between conditions over time. CONCLUSIONS: Temperate-water immersion produced acceptable (ie, >0.08 degrees C/min), though not ideal, cooling rates regardless of whether PADS or NOpads were worn. If a football uniform is difficult to remove or the patient is noncompliant, clinicians should begin water-immersion treatment with the athlete fully equipped. Clinicians should strive to use CWI to treat severe hyperthermia, but when CWI is not feasible, TWI should be the next treatment option because its cooling rate was higher than the rates of other common modalities (eg, ice packs, fanning). PMID- 28715286 TI - Effects of lifestyle intervention on soluble CD163, a macrophage activation marker, in patients with non-alcoholic fatty liver disease. AB - OBJECTIVE: Liver macrophages play an important role in the pathogenesis of non alcoholic fatty liver disease (NAFLD). Soluble CD163 (sCD163), a macrophage specific biomarker, reflects disease activity in the range of liver diseases. The impact of lifestyle intervention on sCD163 in adult NAFLD patients has not been investigated. MATERIAL AND METHODS: We assessed 126 NAFLD patients participating in a lifestyle intervention study for sCD163 concentrations at baseline, after the three-month intervention period, and at long-term follow-up after 12 and 24 months. RESULTS: The median sCD163 concentration at baseline was 2.59 mg/L (IQR = 1.78-3.63 mg/L). There was a significant decrease in sCD163 from baseline to three months follow-up (-0.64 mg/L, p < .001) with no difference between the four study groups (p = .6). At 12 and 24 months follow-up, the sCD163 concentrations had returned to baseline level (p = .3 and p = .1). Baseline sCD163 correlated with liver biomarkers and metabolic variables. There was a significantly greater decrease in sCD163 in patients who had a decrease in alanine aminotransferase (ALT) compared with patients with unchanged or increased ALT (-0.76 mg/L vs. 0.41 mg/L, p = .02), and in patients with a decrease in HOMA-IR compared with individuals with no decrease (-0.86 mg/L vs. -0.55 mg/L, p = .03). CONCLUSION: sCD163 is associated with markers of liver necro-inflammation and glucose homoeostasis in NAFLD. Participation in a lifestyle intervention programme resulted in a significant reduction in sCD163. Our data support the utility of sCD163 as a biomarker for monitoring the efficacy of therapeutic interventions in NAFLD. PMID- 28715287 TI - Outcome measures correlated with falls in nursing home residents-A pilot study. AB - Most fall risk and normal values are collected from the community-dwelling population, which is not representative of nursing home residents. The purpose of this study was twofold: 1) to determine the relationship of clinical impairment and activity limitation variables to the number of falls in nursing home residents; and 2) to determine the amount of variability that can be explained for the number of falls from these predictor variables. Seventeen active nursing home residents (83.7 +/- 11.7 years) consented to participate. Mini-Mental Status Examination (MMSE), lower extremity handheld dynamometry, ankle plantar flexion (PF)/dorsiflexion (DF) active range of motion (AROM), hand grip strength, gait speed (GS), Timed Up and Go (TUG), and 5 Times Sit-to-Stand (5TSTS) were recorded in a single visit. Regression analysis was performed to identify the better clinical outcome tool to determine falls. This was followed by a stepwise multiple regression model to predict the criterion variable-number of falls. Of the clinical impairment measures collected, significant correlations with past falls include the following: right DF AROM (-0.436; p = 0.040) and right DF strength (-0.504; p = 0.023). Of the activity limitation measures collected, significant correlations with past falls include the following: 5TSTS (0.585; p = 0.007); TUG time (0.475; p = 0.027); and GS (0.457; p = 0.032). The stepwise multiple regression model explained 59% of the variance using right DF AROM, right DF strength, 5TSTS, and TUG time. These measures are benchmarks for the community dwelling population. The present study indicates that these measures might also be useful in determining fall risk screening for ambulatory nursing home residents. PMID- 28715288 TI - An Evidence Framework for Genetic Testing. PMID- 28715289 TI - Survey of methods used to determine if a patient has a deep vein thrombosis: An exploratory research report. AB - BACKGROUND: The use of evidence-based practice (EBP) is encouraged in the physical therapy profession, but integrating evidence into practice can be difficult for clinicians because of lack of time and other constraints. OBJECTIVE: To survey physical therapy clinical instructors and determine the methods they use for screening for deep vein thrombosis (DVT), a type of venous thromboembolism (VTE) in the lower extremities. DESIGN: Exploratory survey. METHODS: Twelve survey questions written specifically for this study were sent to a convenience sample of clinical instructors associated with seven universities across 43 states. RESULTS: Eight hundred fifty clinical instructors (22.4% response rate) completed the survey. Of those who responded, 80.5% were taught to use Homans sign to screen for a possible DVT in their entry-level education and 67.9% continued to use Homans sign in clinical practice. Regardless of post graduate education, respondents were more likely to choose Homans sign than a clinical decision rule (CDR) to screen for a suspected DVT. Additionally, nearly two-thirds of respondents failed to correctly identify one or more of the major risk factors for developing a DVT/VTE. LIMITATIONS: The response rate was 22.4% and therefore may not fully represent the population of physical therapy clinical instructors in the United States. CONCLUSIONS: Results from this exploratory survey indicated that approximately two-thirds of physical therapy clinical instructors used outdated DVT/VTE screening methods that they were taught in their entry-level education and nearly two-thirds did not identify the major risk factors associated with DVT/VTE. These results suggest that change is necessary in physical therapy education, clinical practice, and continuing professional development to ensure a more evidenced-based identification of DVT and VTE. PMID- 28715290 TI - Trainees' knowledge, attitudes, and practices towards caring for the substance exposed mother-infant dyad. AB - BACKGROUND: As rates of substance use disorder during pregnancy rise, pediatric trainees are increasingly caring for infants with neonatal abstinence syndrome (NAS). This study evaluated the knowledge, attitudes, and practices of trainees caring for substance-exposed newborns and their families, comparing differences by level and type of training, and personal experience with addiction or trauma. METHODS: A cross-sectional survey of medical students and pediatric, medicine/pediatric, and family medicine residents in 2015-2106. Measures included knowledge about NAS, attitudes towards mothers who use drugs, and practices around discussing addiction and trauma with families. Descriptive and bivariate analyses were conducted. RESULTS: The overall response rate was 70%, with 229 trainees included in the final sample (99 students, 130 residents). Fifty percent of trainees endorsed personal experience with addiction, 50% with trauma, and 35% with both addiction and trauma. Increasing years of pediatric training was associated with greater comfort in managing symptoms of NAS but decreased comfort discussing addiction and trauma. Family medicine and medicine/pediatric residents were more comfortable discussing addiction and trauma than categorical pediatric residents (P < .01). Twenty-two percent of trainees felt confident that mothers would disclose illicit drug use, 39% felt that they would actively care for their infants with NAS, and 43% felt that mothers would not make unreasonable demands. Personal experience with addiction or trauma did not significantly impact trainees' attitudes towards women with substance use disorder. CONCLUSIONS: Trainees may benefit from educational interventions focused on developing a 2 generational model of trauma-informed care to improve attitudes and ultimately the care of substance-exposed infants and their families. PMID- 28715291 TI - Isolation of Brucella pinnipedialis from Grey Seals (Halichoerus grypus) in the Baltic Sea. AB - Brucella infection in seals was reported for the first time in 1994 around the coast of Scotland. Since then, marine mammal Brucella infections were found to be widely distributed in the northern hemisphere. Two Brucella species affect marine mammals: Brucella pinnipedialis in pinnipeds and Brucella ceti in cetaceans. We examined the livers of Baltic grey seals (Halichoerus grypus) from the Finnish coast (n=122) hunted, found dead, or killed as by-catch in fishing gear in 2013 15 as part of population health monitoring. We detected B. pinnipedialis in the livers of three grey seals. The bacterium was isolated from livers displaying parasitic cholangitis. We also detected Brucella DNA in liver flukes (Pseudamphistomum truncatum) obtained from a Brucella-infected grey seal, suggesting that flukes might be possible vectors of this pathogen in the marine environment. PMID- 28715292 TI - Brucella Infection in Asian Sea Otters (Enhydra lutris lutris) on Bering Island, Russia. AB - Infection with Brucella spp., long known as a cause of abortion, infertility, and reproductive loss in domestic livestock, has increasingly been documented in marine mammals over the past two decades. We report molecular evidence of Brucella infection in Asian sea otters (Enhydra lutris lutris). Brucella DNA was detected in 3 of 78 (4%) rectal swab samples collected between 2004 and 2006 on Bering Island, Russia. These 78 animals had previously been documented to have a Brucella seroprevalence of 28%, markedly higher than the prevalence documented in sea otters (Enhydra lutris) in North America. All of the DNA sequences amplified were identical to one or more previously isolated Brucella spp. including strains from both terrestrial and marine hosts. Phylogenetic analysis of this sequence suggested that one animal was shedding Brucella spp. DNA with a sequence matching a Brucella abortus strain, whereas two animals yielded a sequence matching a group of strains including isolates classified as Brucella pinnipedialis and Brucella melitensis. Our results highlight the diversity of Brucella spp. within a single sea otter population. PMID- 28715293 TI - SURVEILLANCE FOR ANTIBODIES AGAINST SIX CANINE VIRUSES IN WILD RACCOONS (PROCYON LOTOR) IN JAPAN. AB - Raccoons (Procyon lotor) are found worldwide. They are frequently seen in crowded inner cities as well as in forests or wooded areas, often living in proximity to humans and their pets. We examined sera from 100 wild raccoons in Japan for antibodies to six canine viruses with veterinary significance to assess their potential as reservoirs. We also aimed to understand the distribution of potentially infected wildlife. We found that 7% of samples were seropositive for canine distemper virus (CDV), 10% for canine parvovirus type 2, 2% for canine adenovirus type 1, 6% for canine adenovirus type 2, and 7% for canine coronavirus. No samples were found to be seropositive for canine parainfluenza virus. Seropositivity rates for canine distemper virus and canine parvovirus type 2 were significantly different between areas, and younger raccoons (<1 yr old) were more frequently seropositive than older raccoons. Because raccoons belong to the suborder Caniformia, similar to dogs (Canis lupus familiaris), our results suggest that they can act as reservoirs for some of these important canine viruses and might be involved in viral transmission. Further study should include isolation and analysis of canine viruses in wild raccoons from a wider area. PMID- 28715294 TI - Avian Pox Discovered in the Critically Endangered Waved Albatross (Phoebastria irrorata) from the Galapagos Islands, Ecuador. AB - The Waved Albatross (Phoebastria irrorata) is a critically endangered seabird in a rapidly shrinking population in the Galapagos Islands, Ecuador. The introduction of novel pathogens and parasites poses a threat to population persistence. Monitoring disease prevalence and guarding against the spread of such agents in endemic taxa are conservation priorities for the Galapagos, where recent increases in the prevalence of avian pox may have contributed to population declines and range contractions in other bird species. During November 2013-January 2014, we identified 14 Waved Albatross nestlings at our study site on Espanola Island with avian pox-like lesions and clinical signs. Other seabirds, landbirds, and adult Waved Albatrosses were apparently unaffected. Histopathology of tissue samples from five infected nestlings revealed inclusion bodies in all samples, consistent with avipoxvirus infection. We documented higher mortality (6 of 14 nestlings) in affected nestlings than in unaffected young in this small outbreak of avian pox, the first report of its kind in the world's only tropical albatross. PMID- 28715295 TI - Prevalence of Home Parenteral and Enteral Nutrition in the United States. AB - BACKGROUND: Malnutrition is highly prevalent and associated with increased morbidity and mortality. Studies continue to reveal significant clinical benefits with nutrition support, including improved wound healing, reduction in complications and length of stay, and mortality. Due to these benefits, the prevalence of home parenteral and enteral nutrition (HPEN) continues to increase worldwide. In the United States, given our healthcare insurance landscape, it has been very difficult to ascertain the true prevalence of HPEN. METHODS: Medicare beneficiary data for 2013 were obtained from Centers for Medicare and Medicaid Services. Commonly used Healthcare Common Procedure Coding System codes were used for home enteral nutrition (HEN) and home parenteral nutrition (HPN). Data regarding number of patients and insurance providers were also obtained from 3 of the largest home infusion providers in the United States (Coram CVS, Option Care Enterprises, and BioScrip Inc). Based on the ratio of Medicare to non-Medicare billing, an estimate of HPEN prevalence was obtained. RESULTS: For 2013, there were 6778 Medicare beneficiaries for HPN and 114,287 for HEN. The ratio of Medicare to non-Medicare was 0.271 for HPN and 0.261 for HEN, leading to an estimated prevalence of 25,011 patients receiving HPN (79 per million U.S. inhabitants) and 437,882 patients receiving HEN (1385 per million U.S. inhabitants). There are an estimated 4129 pediatric patients and 20,883 adult patients receiving HPN; for HEN, 189,036 pediatric patients and 248,846 adult patients. CONCLUSION: Compared with results from 1992, the prevalence of HEN has increased dramatically, while the prevalence of HPN has declined. PMID- 28715296 TI - A self-determination theory-based self-myofascial release program in older adults with myofascial trigger points in the neck and back: A pilot study. AB - PURPOSE: To examine the effectiveness and adherence to a self-determination theory (SDT)-based self-myofascial release (SMR) program in older adults with myofascial trigger points (MTrPs), and to investigate the factors that influence participant behavioral change while conducting the program in a home setting. METHODS: An explanatory mixed-method design was used to evaluate a 12-week SDT based SMR program, including a 4-week group-based education and practice (EP) phase and an 8-week home-based self-management (SM) phase. Pain intensity on palpation and sensitivity to pain were assessed at baseline and the post EP and post SM phase. Focus group interviews were conducted at the post SM phase. FINDINGS: Fifteen participants completed the study. Pain intensity and sensitivity to pain significantly improved at the post SM phase compared with the baseline. Adherence increased during the SM phase compared with that during the EP phase. Four main themes emerged as factors that influenced participant behavioral change: 1) "awareness of the effectiveness"; 2) "a sense of duty to perform the exercise"; 3) "obedience to expert instruction"; and 4) "lack of friendship." CONCLUSIONS: These results support the effectiveness of an SDT-based SMR program for the treatment of MTrPs and in motivating older adults to participate in the program. PMID- 28715297 TI - Cross Contamination: Are Hospital Gloves Reservoirs for Nosocomial Infections? AB - Use of disposable nonsterile gloves in the hospital setting is second only to proper hand washing in reducing contamination during patient contact. Because proper handwashing is not consistently practiced, added emphasis on glove use is warranted. There is a growing body of evidence that glove boxes and dispensers available to healthcare workers are contaminated by daily exposure to environmental organisms. This finding, in conjunction with new and emerging antibiotic-resistant bacteria, poses a threat to patients and healthcare workers alike. A newly designed glove dispenser may reduce contamination of disposable gloves. The authors investigated contamination of nonsterile examination gloves in an Emergency Department setting according to the type of dispenser used to access gloves. A statistically significant difference existed between the number of bacterial colonies and the type of dispenser: the downward-facing glove dispenser had a lower number of bacteria on the gloves. There was no statistically significant difference in the number of gloves contaminated between the two types of glove dispensers. The study demonstrated that contamination of disposable gloves existed. Additional research using a larger sample size would validate a difference in the contamination of disposable gloves using outward or downward glove dispensers. PMID- 28715298 TI - Assessment of in vivo 3D kinematics of cervical spine manipulation: Influence of practitioner experience and occurrence of cavitation noise. AB - BACKGROUND: Investigations on 3D kinematics during spinal manipulation are widely reported for assessing motion data, task reliability and clinical effects. However the link between cavitation occurrence and specific kinematics remains questionable. OBJECTIVES: This paper investigates the 3D head-trunk kinematics during high velocity low amplitude (HVLA) manipulation for different practitioners with respect to the occurrence of cavitation. METHODS: Head-trunk 3D motions were sampled during HVLA manipulation in twenty asymptomatic volunteers manipulated by four practitioners with different seniority (years of experience). Four target levels were selected, C3 and C5 on each side, and were randomly allocated to the different practitioners. The data was recorded before, during and after each set of trial in each anatomical plane. The number of trials with cavitation occurrence was collected for each practitioner. RESULTS: The manipulation task was performed using extension, ipsilateral side bending and contra-lateral axial rotation independent of side or target level. The displayed angular motion magnitudes did not exceed normal active ROM. Regardless cavitation occurrence, wide variations were observed between practitioners, especially in terms of velocity and acceleration. Cavitation occurrence was related to several kinematics features (i.e. frontal ROM and velocity, sagittal acceleration) and practitioner experience. In addition, multilevel cavitation was observed regularly. CONCLUSIONS: Kinematics of cervical manipulation is dependent on practitioner and years of experience. Cavitation occurrence could be related to particular kinematics features. These aspects should be further investigated in order to improve teaching and learning of cervical manipulation technique. PMID- 28715299 TI - Test-retest reliability of measurements of abdominal and multifidus muscles using ultrasound imaging in adults aged 50-79 years. AB - Test-retest reliability of the combined process of ultrasound imaging (USI) and image measurement of thickness of abdominal and upper lumbar multifidus (MF) muscles and MF cross sectional area (CSA) of older adults has not been established. Imaging muscles of older adults can be challenging due to age related changes in the spine and skeletal muscle so establishing test-retest reliability in this population is important. This study aimed to evaluate test retest reliability of USI of abdominal and MF muscle thickness and MF CSA for adults aged 50-79 years. One operator took single sets of ultrasound images of abdominal and MF muscles of 23 adults aged 50-79 years participating in a clinical trial of vitamin D supplementation for knee osteoarthritis, on two occasions, one week apart. Images were subsequently measured by a single examiner. Test-retest reliability for abdominal muscle thickness and MF CSA was substantial (intraclass correlation coefficients (ICC) > 0.81) and for MF thickness ranged from fair to substantial (ICC 0.55-0.86). The standard error of measurement (SEM) was low (0.02-0.21) in every case. ICCs were low and SEM values were high for percentage thickness change. The substantial test-retest reliability of abdominal and MF (L4-L5) muscle thickness and of MF CSA supports the use of USI as a clinical and research tool to assess abdominal and MF muscle thickness and MF CSA of older adults. PMID- 28715300 TI - Bridging the evidence-practice gaps in manual therapy: Getting the balance right. PMID- 28715301 TI - Editorial. PMID- 28715302 TI - Characterization of humeral head displacements during dynamic glenohumeral neuromuscular control exercises using quantitative ultrasound imaging: A feasibility study. AB - The objectives of the present study were to test the feasibility of measuring humeral head displacements using quantitative ultrasound imaging during the performance of two different dynamic glenohumeral neuromuscular control exercises and to investigate the influence of these exercises on the acromiohumeral distance (AHD) and anterior-posterior distance (APD). Ten individuals who have no history of shoulder injury at the non-dominant shoulder completed three repetitions of an active humeral head lowering exercise and three repetitions of a posteriorisation exercise in a random order in a seated position. The AHD and the APD of the humeral head relative to the glenoid cavity were measured continuously using an ultrasound imaging system during each exercise. Variations in AHD and APD, defined as the difference between the distance obtained before the exercise and the maximal distance reached during the exercise, were compared for each exercises. The active humeral head lowering exercise significantly increased the AHD by 0.94 +/- 0.28 mm (relative: + 11.4%), but had no significant effect on the APD. The active humeral head posteriorisation exercise significantly increased the AHD by 0.65 +/- 0.41 mm (relative: + 6.3%) and the APD by 1.51 +/- 0.51 mm (relative: + 13.8%). The use of quantitative ultrasound imaging allows physiotherapists to quantify inferior and posterior humeral head displacements during dynamic glenohumeral neuromuscular control exercises. These measures, confirming favourable inferior and posterior humeral head displacements at the shoulder, may become useful when studying the effectiveness of rehabilitation programs incorporating dynamic glenohumeral neuromuscular control exercises. PMID- 28715303 TI - Systematic review of comparative effectiveness and health economics research relating to osteopathic manipulative treatment. PMID- 28715304 TI - Influence of stretching velocity on musculotendinous stiffness of the hamstrings during passive straight-leg raise assessments. AB - BACKGROUND: Recently, passive musculotendinous stiffness (MTS) has been assessed manually in the field; however, when conducting these types of assessments, the stretching velocity must be controlled to avoid eliciting the stretch reflex, which can be observed by increased electromyographic (EMG) amplitude of the stretched muscles and greater resistive torque (indicating the assessment is no longer passive). OBJECTIVE: To examine the effects of slow, medium, and fast stretching velocities during manually-applied passive straight-leg raise (SLR) assessments on hamstrings MTS and EMG amplitude characteristics. STUDY DESIGN: Crossover study. METHODS: Twenty-three healthy, young adults underwent passive, manually-applied SLR assessments performed by the primary investigator at slow, medium, and fast stretching velocities. During each SLR, MTS and EMG amplitude were determined at 4 common joint angles (?) separated by 5 degrees during the final common 15 degrees of range of motion for each participant. RESULTS: The average stretching velocities were 7, 11, and 18 degrees .s?1 for the slow, medium, and fast SLRs. There were no velocity-related differences for MTS (P = 0.489) or EMG amplitude (P = 0.924). MTS increased (P < 0.001) with joint angle (?1 C=C. PMID- 28715344 TI - Community acquired pneumonia incidence before and after proton pump inhibitor prescription: population based study. AB - Objective To examine the risk of community acquired pneumonia before and after prescription of proton pump inhibitor (PPI) and assess whether unmeasured confounding explains this association.Design Cohort study and self controlled case series.Setting Clinical Practice Research Datalink (1990 to 2013) in UK.Participants Adult patients with a new prescription for a PPI individually matched with controls.Main outcome measures Association of community acquired pneumonia with PPI prescription estimated by three methods: a multivariable Cox model comparing risk in PPI exposed patients with controls, corrected for potential confounders; a self controlled case series; and a prior event rate ratio (PERR) analysis over the 12 month periods before and after the first PPI prescription.Results 160 000 new PPI users were examined. The adjusted Cox regression showed a risk of community acquired pneumonia 1.67 (95% confidence interval 1.55 to 1.79) times higher for patients exposed to PPI than for controls. In the self controlled case series, among 48 451 PPI exposed patients with a record of community acquired pneumonia, the incidence rate ratio was 1.19 (95% confidence interval 1.14 to 1.25) in the 30 days after PPI prescription but was higher in the 30 days before a PPI prescription (1.92, 1.84 to 2.00). The Cox regressions for prior event rate ratio similarly showed a greater increase in community acquired pneumonia in the year before than the year after PPI prescription, such that the analysis showed a reduced relative risk of pneumonia associated with PPI use (prior event rate ratio 0.91, 95% confidence interval 0.83 to 0.99).Conclusion The association between the use of PPIs and risk of community acquired pneumonia is likely to be due entirely to confounding factors. PMID- 28715346 TI - New prospective 4D-CT for mitigating the effects of irregular respiratory motion. AB - Artifact caused by irregular respiration is a major source of error in 4D-CT imaging. We propose a new prospective 4D-CT to mitigate this source of error without new hardware, software or off-line data-processing on the GE CT scanner. We utilize the cine CT scan in the design of the new prospective 4D-CT. The cine CT scan at each position can be stopped by the operator when an irregular respiration occurs, and resumed when the respiration becomes regular. This process can be repeated at one or multiple scan positions. After the scan, a retrospective reconstruction is initiated on the CT console to reconstruct only the images corresponding to the regular respiratory cycles. The end result is a 4D-CT free of irregular respiration. To prove feasibility, we conducted a phantom and six patient studies. The artifacts associated with the irregular respiratory cycles could be removed from both the phantom and patient studies. A new prospective 4D-CT scanning and processing technique to mitigate the impact of irregular respiration in 4D-CT has been demonstrated. This technique can save radiation dose because the repeat scans are only at the scan positions where an irregular respiration occurs. Current practice is to repeat the scans at all positions. There is no cost to apply this technique because it is applicable on the GE CT scanner without new hardware, software or off-line data-processing. PMID- 28715347 TI - Process Matters: Successes and Challenges of Recruiting and Retaining Participants for Nursing Education Research. AB - Researchers who study nursing education encounter difficulty when trying to recruit and retain nurse educator participants. Researchers would benefit from knowing more about effective and ineffective sampling strategies and methods to increase the efficiency of the research process. This article outlines the struggles and successes encountered with a mixed methods study that examined nurse educators' critical thinking. Specific examples are interwoven with current literature to uncover some important insights and future recommendations for researchers in nursing education. PMID- 28715348 TI - Effect of Increased Evaluation Objectivity on Grade Inflation: Precise Grading Rubrics and Rigorously Developed Tests. AB - This retrospective, comparative study examined the effect of increasing objectivity of evaluation methods on grade inflation in a graduate nursing research course. Multiple-choice testing and increased precision in grading rubrics were added to the course. Outcome measures of student grade distributions for the course were measured pre/post course revision. Statistically significant reductions in grade distributions were observed after course evaluation method revisions were implemented (U = 4575.0, P < .001). PMID- 28715349 TI - Altered neural responses to heat pain in drug-naive patients with Parkinson disease. AB - Pain is a frequent but still neglected nonmotor symptom of Parkinson disease (PD). However, neural mechanisms underlying pain in PD are poorly understood. Here, we explored whether the high prevalence of pain in PD might be related to dysfunctional descending pain control. Using functional magnetic resonance imaging we explored neural responses during the anticipation and processing of heat pain in 21 PD patients (Hoehn and Yahr I-III) and 23 healthy controls (HC). Parkinson disease patients were naive to dopaminergic medication to avoid confounding drug effects. Fifteen heat pain stimuli were applied to the participants' forearm. Intensity and unpleasantness ratings were provided for each stimulus. Subjective pain perception was comparable for PD patients and HC. Neural processing, however, differed between groups: PD patients showed lower activity in several descending pain modulation regions (dorsal anterior cingulate cortex [dACC], subgenual anterior cingulate cortex, and dorsolateral prefrontal cortex [DLPFC]) and lower functional connectivity between dACC and DLPFC during pain anticipation. Parkinson disease symptom severity was negatively correlated with dACC-DLPFC connectivity indicating impaired functional coupling of pain modulatory regions with disease progression. During pain perception PD patients showed higher midcingulate cortex activity compared with HC, which also scaled with PD severity. Interestingly, dACC-DLPFC connectivity during pain anticipation was negatively associated with midcingulate cortex activity during the receipt of pain in PD patients. This study indicates altered neural processing during the anticipation and receipt of experimental pain in drug-naive PD patients. It provides first evidence for a progressive decline in descending pain modulation in PD, which might be related to the high prevalence of pain in later stages of PD. PMID- 28715350 TI - A prospective, multisite, international validation of the Complex Regional Pain Syndrome Severity Score. AB - Clinical diagnosis of complex regional pain syndrome (CRPS) is a dichotomous (yes/no) categorization, a format necessary for clinical decision making. Such dichotomous diagnostic categories do not convey an individual's subtle gradations in the severity of the condition over time and have poor statistical power when used as an outcome measure in research. This prospective, international, multicenter study slightly modified and further evaluated the validity of the CRPS Severity Score (CSS), a continuous index of CRPS severity. Using a prospective design, medical evaluations were conducted in 156 patients with CRPS to compare changes over time in CSS scores between patients initiating a new treatment program and patients on stable treatment regimens. New vs stable categorizations were supported by greater changes in pain and function in the former. Results indicated that CSS values in the stable CRPS treatment group exhibited much less change over time relative to the new treatment group, with intraclass correlations nearly twice as large in the former. A calculated smallest real difference value revealed that a change in the CSS of >=4.9 scale points would indicate real differences in CRPS symptomatology (with 95% confidence). Across groups, larger changes in CRPS features on the CSS over time were associated in the expected direction with greater changes in pain intensity, fatigue, social functioning, ability to engage in physical roles, and general well-being. The overall pattern of findings further supports the validity of the CSS as a measure of CRPS severity and suggests it may prove useful in clinical monitoring and outcomes research. PMID- 28715351 TI - Interacting influences of gender and chronic pain status on parasympathetically mediated heart rate variability in adolescents and young adults. AB - Considerable research links chronic pain to autonomic nervous system (ANS) dysfunction, specifically low heart rate variability (HRV) mediated by reduced parasympathetic activity. However, little is known about factors that influence ANS function in chronic pain. The ANS is the primary pathway for brain-gut communication, making it of particular interest in gastrointestinal disorders, such as irritable bowel syndrome, characterized by functional abdominal pain (FAP). We evaluated the relation of sex, pain severity, and psychological stress to ANS function in adolescents/young adults from a database of pediatric FAP and control participants enrolled 8 years earlier in a prospective study of pain. At follow-up in adolescence/young adulthood (Mean age = 19.46, SD = 3.48), we classified participants as Pain-Remit (n = 130), Pain-Persist (n = 96), and pain free controls (n = 123). We recorded electrocardiogram data at rest and during laboratory stressors. Results demonstrated significantly lower HRV in Pain Persist females compared with Pain-Remit females, female controls, and all males regardless of pain category. Spectral analysis of electrocardiogram showed that Pain-Persist females had reduced power in the high frequency domain of cardiac activity, ie, reduced parasympathetic "braking" of sympathetic activity, both at rest and during stress. Pain-Remit females exhibited levels of autonomic imbalance intermediate between those of females with persistent FAP and all other participants. Parasympathetically mediated low HRV in young women with persistent FAP may reflect a peripheral mechanism (eg, gut dysfunction) or a central nervous system mechanism (eg, pain amplification or poor emotion self-regulation) involving prolonged sympathetic activation. PMID- 28715353 TI - Learned expectations and uncertainty facilitate pain during classical conditioning. AB - Pain spontaneously activates adaptive and dynamic learning processes affecting the anticipation of, and the responses to, future pain. Computational models of associative learning effectively capture the production and ongoing changes in conditioned anticipatory responses (eg, skin conductance response), but the impact of this dynamic process on unconditional pain responses remains poorly understood. Here, we investigated the dynamic modulation of pain and the nociceptive flexion reflex by fear learning in healthy human adult participants undergoing a classical conditioning procedure involving an acquisition, reversal and extinction phase. Conditioned visual stimuli (CS+) coterminated with a noxious transcutaneous stimulation applied to the sural nerve on 50% of trials (unconditioned stimuli). Expected pain probabilities and cue associability were estimated using computational modeling by fitting a hybrid learning model to skin conductance response elicited by the CS+. Multilevel linear regression analyses confirmed that trial-by-trial changes in expected pain and associability positively predict ongoing fluctuations in pain outcomes. Mediation analysis further demonstrated that both expected probability and associability affect pain perception through a direct effect and an indirect effect mediated by descending modulatory mechanisms affecting spinal nociceptive activity. Moderation analyses further showed that hyperalgesic effects of associability were larger in individuals reporting more harm vigilance and less emotional detachment. Higher harm vigilance was also associated with a stronger mediation of hyperalgesic effects by spinal processes. These results demonstrate how dynamic changes in pain can be explained by associative learning theory and that resilient attitudes towards fear/pain can attenuate the adverse impact of adaptive aversive learning processes on pain. PMID- 28715352 TI - Commensal bacterial modulation of the host immune response to ameliorate pain in a murine model of chronic prostatitis. AB - The human commensal microflora plays an essential role in modulating the immune response to control homeostasis. Staphylococcus epidermidis, a commensal bacterium most commonly associated with the skin exerts such effects locally, modulating local immune responses during inflammation and preventing superinfection by pathogens such as Staphylococcus aureus. Although the prostate is considered by many to be sterile, multiple investigations have shown that small numbers of gram-positive bacterial species such as S. epidermidis can be isolated from the expressed prostatic secretions of both healthy and diseased men. Chronic pelvic pain syndrome is a complex syndrome with symptoms including pain and lower urinary tract dysfunction. It has an unknown etiology and limited effective treatments but is associated with modulation of prostate immune responses. Chronic pelvic pain syndrome can be modeled using murine experimental prostatitis (EAP), where CD4+ve IL17A+ve T cells have been shown to play a critical role in disease orchestration and development of pelvic tactile allodynia. Here, we report that intraurethral instillation of a specific S. epidermidis strain (designated NPI [non-pain inducing]), isolated from the expressed prostatic secretion of a healthy human male, into EAP-treated mice reduced the pelvic tactile allodynia responses and increased CD4+ve IL17A+ve T cell numbers associated with EAP. Furthermore, a cell wall constituent of NPI, lipoteichoic acid, specifically recapitulates these effects and mediates increased expression of CTLA4-like ligands PDL1 and PDL2 on prostatic CD11b+ve antigen-presenting cells. These results identify a new potential therapeutic role for commensal S. epidermidis NPI lipoteichoic acid in the treatment of prostatitis-associated pain. PMID- 28715354 TI - Validation of EQ-5D and 15D in the assessment of health-related quality of life in chronic pain. AB - Chronic pain has a significant impact on quality of life. Measurement of health related quality of life (HRQoL) is essential in the assessment of pain management outcomes, but different instruments have produced varying results. We assessed the validity of 2 HRQoL instruments, EuroQol 5 dimensions questionnaire (EQ-5D) and 15-dimensional health-related quality of life measure (15D), in patients with challenging chronic pain. Three hundred ninety-one chronic noncancer pain patients referred to tertiary pain clinics completed EQ-5D, 15D, and a broad set of questionnaires mapping socioeconomic factors, self-rated health, pain intensity and interference, depression, pain acceptance, pain-related anxiety, and sleep. The 2 HRQoL instruments were compared with each other, and head-to head comparisons were made with self-rated health and the symptom-specific questionnaires. 15D and EQ-5D showed moderate agreement (rho = 0.66), but there were also considerable differences between the instruments. 15D correlated better with self-rated health than EQ-5D (rho = -0.62 vs -0.45, P < 0.001). The EQ-5D appeared less sensitive than 15D especially in those patients with chronic pain who had a better health status. The principal component constructed from measures of pain intensity and interference, anxiety, pain acceptance, depression, and sleep had higher standardized beta coefficients with 15D than with EQ-5D (P = 0.038). The principal component explained more variance in the 15D (R = 0.65) than in the EQ-5D (R = 0.43). The study identified differences in the pain related variables between the EQ-5D and the 15D. In patients with chronic pain, both instruments are valid, but 15D appears somewhat more sensitive than EQ-5D. PMID- 28715355 TI - Repeated exposure to sucrose for procedural pain in mouse pups leads to long-term widespread brain alterations. AB - Oral sucrose is administered routinely to reduce pain of minor procedures in premature infants and is recommended as standard care in international guidelines. No human or animal studies on effects of early repeated sucrose exposure on long-term brain development have been done in the context of pain. We evaluated the effects of repeated neonatal sucrose treatment before an intervention on long-term brain structure in mouse pups. Neonatal C57Bl/6J mice (n = 109) were randomly assigned to one of 2 treatments (vehicle vs sucrose) and one of 3 interventions (handling, touch, or needle-prick). Mice received 10 interventions daily from postnatal day 1 to 6 (P1-6). A dose of vehicle or 24% sucrose was given orally 2 minutes before each intervention. At P85-95, brains were scanned using a multichannel 7.0 T MRI. Volumes of 159 independent brain regions were obtained. Early repetitive sucrose exposure in mice (after correcting for whole brain volume and multiple comparisons) lead to smaller white matter volumes in the corpus callosum, stria terminalis, and fimbria (P < 0.0001). Cortical and subcortical gray matter was also affected by sucrose with smaller volumes of hippocampus and cerebellum (P < 0.0001). These significant changes in adult brain were found irrespective of the type of intervention in the neonatal period. This study provides the first evidence of long-term adverse effects of repetitive sucrose exposure and raises concerns for the use of this standard pain management practice during a period of rapid brain development in very preterm infants. PMID- 28715356 TI - A mouse model for pain and neuroplastic changes associated with pancreatic ductal adenocarcinoma. AB - Pancreatic ductal adenocarcinoma (PDAC) continues to be one of the deadliest human malignancies and is associated with excruciating pain, which is a serious complication and severely impacts the quality of life in patients. In human patients, poor survival prognosis is linked to remarkable remodeling of intrapancreatic nerves, which, in turn, is correlated to increased pain intensity. Understanding mechanisms underlying pain associated with PDAC has been hampered by the lack of animal models which replicate all germane aspects of the disease and importantly, enable analyses of pain associated with PDAC. In this study, we describe an immunocompetent orthotopic mouse model of PDAC involving intrapancreatic growth of K8484 mouse PDAC cells, which reliably exhibits a large number of key characteristics of human PDAC, including its unique histopathology and neuroplastic changes. We observed that tumor-bearing mice demonstrated significant abdominal mechanical hypersensitivity to von Frey stimuli as well as on-going pain in the conditioned place preference paradigm. Moreover, a myriad of other behavioral tests revealed that indicators of overall well-being were significantly reduced in tumor-bearing mice as compared to sham mice. Morphological and immunohistochemical analyses revealed structural remodeling in several different types of sensory and autonomic nerve fibers. Finally, perineural invasion of tumor cells, a cardinal manifestation in human PDAC, was also observed in our orthotopic mouse model. Thus, we describe a validated tumor model for quantitatively testing hypersensitivity and pain in PDAC, which lays a crucial basis for interrogating tumor-nerve interactions and the molecular and cellular mechanisms underlying pain in PDAC. PMID- 28715358 TI - Reply. PMID- 28715357 TI - Pain versus analgesia: TAOK3 as a pharmacogene. PMID- 28715359 TI - Attempting to validate the over/under triage matrix at a level I trauma center. AB - BACKGROUND: The Optimal Resources Document (ORD) mandates trauma activation based on injury mechanism, physiologic and anatomic criteria and recommends using the over/undertriage matrix (Matrix) to evaluate the appropriateness of trauma team activation. The purpose of this study was to assess the effectiveness of the Matrix method by comparing patients appropriately triaged with those undertriaged. We hypothesized that these two groups are different and Matrix does not discriminate the needs or outcomes of these different groups of patients. METHODS: Trauma registry data, from 1/2013-12/2015, at a Level I trauma center were reviewed. Over and undertriage rates were calculated by Matrix. Patients with ISS >=16 were classified by activation level (full, limited, consultation), and triage category by Matrix. Patients in the limited activation and consultation groups were compared to patients with full activation by demographics, injuries, initial vital signs, procedures, delays to procedure, ICU admission, length of stay, and mortality. RESULTS: 7031 patients met activation criteria. Compliance with ACS tiered activation criteria was 99%. The Matrix overtriage rate was 45% and undertriage was 24%. Of 2282 patients with an ISS >=16, 1026 were appropriately triaged (full activation), and 1256 were under triaged. Undertriaged patients had better GCS, blood pressure, and BD than patients with full activation. ICU admission, hospital stays, and mortality were lower in the undertriaged group. The under triaged group required fewer operative interventions with fewer delays to procedure. CONCLUSION: Despite having an ISS >= 16, patients with limited activations were dissimilar to patients with full activation. Level of activation and triage are not equivalent. The ACS-COT full and tiered activation criteria are a robust means to have the appropriate personnel present based on available pre-hospital information. Evaluation of the process of care, regardless of level of activation should be used to evaluate trauma center performance. LEVEL OF EVIDENCE: Level III Therapeutic and Care managementThis is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. PMID- 28715360 TI - Contemporary management of subclavian and axillary artery injuries-A Western Trauma Association multicenter review. AB - BACKGROUND: Subclavian and axillary artery injuries are uncommon. In addition to many open vascular repairs, endovascular techniques are used for definitive repair or vascular control of these anatomically challenging injuries. The aim of this study was to determine the relative roles of endovascular and open techniques in the management of subclavian and axillary artery injuries comparing hospital outcomes, and long-term limb viability. METHODS: A multicenter, retrospective review of patients with subclavian or axillary artery injuries from January 1, 2004, to December 31, 2014, was completed at 11 participating Western Trauma Association institutions. Statistical analysis included chi, t-tests, and Cochran-Armitage trend tests. A p value less than 0.05 was significant. RESULTS: Two hundred twenty-three patients were included; mean age was 36 years, 84% were men. An increase in computed tomography angiography and decrease in conventional angiography was observed over time (p = 0.018). There were 120 subclavian and 119 axillary artery injuries. Procedure type was associated with injury grade (p < 0.001). Open operations were performed in 135 (61%) patients, including 93% of greater than 50% circumference lacerations and 83% of vessel transections. Endovascular repairs were performed in 38 (17%) patients; most frequently for pseudoaneurysms. Fourteen (6%) patients underwent a hybrid procedure. Use of endovascular versus open procedures did not increase over the duration of the study (p = 0.248). In-hospital mortality rate was 10%. Graft or stent thrombosis occurred in 7% and graft or stent infection occurred in 3% of patients. Mean follow-up was 1.6 +/- 2.4 years (n = 150). Limb salvage was achieved in 216 (97%) patients. CONCLUSION: The management of subclavian and axillary artery injuries still requires a wide variety of open exposures and procedures, especially for the control of active hemorrhage from more than 50% vessel lacerations and transections. Endovascular repairs were used most often for pseudoaneurysms. Low early complication rates and limb salvage rates of 97% were observed after open and endovascular repairs. LEVEL OF EVIDENCE: Prognostic/epidemiologic, level IV. PMID- 28715361 TI - Trauma systems around the world: A systematic overview. AB - BACKGROUND: Implementation of trauma care systems has resulted in improved patient outcomes, but international differences obviously remain. Improvement of care can only be established if we recognize and clarify these differences. The aim of the current review is to provide an overview of the recent literature on the state of trauma systems globally. METHODS: The literature review over the period 2000 to 2016 was conducted following the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines. Prehospital care, acute hospital care and quality assurance were classified using the World Health Organization Trauma System Maturity Index in four levels from I (least mature) to IV (most mature). RESULTS: The search yielded 93 articles about trauma systems in 32 countries: 23 high-income (HI), 8 middle-income (MI) countries and 1 low-income (LI) country. Trauma-related mortality was highest in the MI and LI countries. Level IV prehospital care with Advanced Life Support was established in 19 HI countries, in contrast to the MI and LI countries where this was only reported in Brazil, China, and Turkey. In 18 HI countries, a Level III/IV hospital-based trauma system was implemented, whereas in nine LI- and MI countries Level I/II trauma systems were seen, mostly lacking dedicated trauma centers and teams. A national trauma registry was implemented in 10 HI countries. CONCLUSION: Despite the presence of seemingly sufficient resources and the evidence-based benefits of trauma systems, only nine of the 23 HI countries in our review have a well defined and documented national trauma system. Although 90% of all lethal traumatic injuries occur in middle and LI countries, according to literature which our study is limited to, only few of these countries a hold formal trauma system or trauma registry. Much can be gained concerning trauma systems in these countries, but unfortunately, the economic situation of many countries may render trauma systems not at their top priority list. LEVEL OF EVIDENCE: Systematic review, level III. PMID- 28715362 TI - Resuscitative endovascular balloon occlusion of the aorta for placenta percreta/previa. PMID- 28715363 TI - Decompressive craniectomy versus craniotomy only for intracranial hemorrhage evacuation: A propensity matched study. AB - BACKGROUND: Decompressive craniectomy (DC) is often performed in conjunction with evacuation of intracranial hemorrhage (ICH) to control intracranial pressure (ICP) in patients with a traumatic brain injury (TBI). The efficacy of DC in lowering ICP is well established; however, its effect on clinical outcomes remains controversial. The aim of our study is to assess outcomes in TBI patients undergoing DC versus craniotomy only (CO) for the evacuation of ICH. METHODS: We performed a 5-year retrospective analysis of TBI patients with ICH who underwent craniotomy or craniectomy for traumatic ICH. Patients were divided into two groups, those who underwent CO and those who underwent DC. Propensity scoring matched patients in a 1:2 ratio for demographics, admission Glasgow Coma Scale (GCS) score, severity of injury, type and size of ICH, and anticoagulant use. Outcome measures included mortality, adverse discharge disposition (skilled nursing facility), discharge GCS and Glasgow Outcome Scale scores, and complications. RESULTS: We reviewed 1,831 patients with TBI, of which 155 underwent craniotomy and/or craniectomy. After propensity score matching, we included 99 of those patients in our study (DC, 33; CO, 66). Matched groups were similar in age (p = 0.68), admission GCS score (p = 0.50), Injury Severity Score (p = 0.70), head Abbreviated Injury Scale score (p = 0.32), and intracranial bleeding characteristics. Overall, 26.3% (n = 26) of the patients died and 62.6% (n = 62) were discharged to Rehab/skilled nursing facility. There was no difference in the mortality rate (27.3% vs. 25.0%; p = 0.99), adverse discharge disposition (45% vs. 33%; p = 0.66), GCS score (p = 0.53), and Glasgow Outcome Scale (p = 0.80) at discharge between the DC and the CO groups. However, patients in DC group had higher complication rates and ventilator days. CONCLUSION: This study showed no significant difference in clinical outcomes for patients undergoing evacuation of ICH regardless of the procedure performed. DC did not appear to be superior to craniotomy alone for the treatment of acute ICH. LEVEL OF EVIDENCE: Therapeutic, level III. PMID- 28715364 TI - Accuracy of Multi-Slice Spiral Computed Tomography for Preoperative Tumor Node Metastasis (TNM) Staging of Colorectal Carcinoma. AB - BACKGROUND With the advances in imaging technologies, multi-slice spiral computed tomography (MSCT) has demonstrated superiority in the diagnosis and staging of colorectal carcinoma. In the current study, preoperative TNM staging of colorectal carcinoma by using MSCT was conducted and compared with the corresponding postoperative pathological examination findings, in order to evaluate the accuracy of preoperative MSCT for TNM staging. MATERIAL AND METHODS Combinations of biphasic or triphasic enhanced-phase MSCT scans were obtained for 76 patients with colorectal carcinoma, and the TNM stage was determined based on imaging reconstruction from various angles and perspectives to display the size, location, and affected range of tumors. The preoperative TNM stage was compared with the postoperative pathological stage, and the consistency between the 2 methods was tested by the k test using SPSS 17.0 software. RESULTS Among the different combinations of enhanced-phase MSCT scanning, triphasic MSCT imaging, comprising the arterial, portal venous, and delayed phases, showed the highest accuracy rates, at 81.6% (62/76), 82.89% (63/76), and 96.1% (73/76) for T, N, and M staging, respectively, with k values of 0.72, 0.65, and 0.56, respectively, indicating consistency with the postoperative pathological staging. CONCLUSIONS Combined MSCT scanning comprising the arterial phase, portal venous phase, and delayed phase showed satisfying consistency with the postoperative pathological analysis results for TNM staging of colorectal carcinoma. Thus, MSCT is an important clinical value for improving the accuracy of TNM staging and for planning the appropriate colorectal cancer treatment. PMID- 28715365 TI - Analysis of the c-KIT Ligand Promoter Using Chromatin Immunoprecipitation. AB - Multiple cellular processes, including DNA replication and repair, DNA recombination, and gene expression, require interactions between proteins and DNA. Therefore, DNA-protein interactions regulate multiple physiological, pathophysiological, and biological functions, such as cell differentiation, cell proliferation, cell cycle control, chromosome stability, epigenetic gene regulation, and cell transformation. In eukaryotic cells, the DNA interacts with histone and nonhistone proteins and is condensed into chromatin. Several technical tools can be used to analyze DNA-protein interactions, such as the Electrophoresis (gel) Mobility Shift Assay (EMSA) and DNase I footprinting. However, these techniques analyze the protein-DNA interaction in vitro, not within the cellular context. Chromatin immunoprecipitation (ChIP) is a technique that captures proteins at their specific DNA binding sites, thereby allowing for the identification of DNA-protein interactions within their chromatin context. It is done by fixation of the DNA-protein interaction, followed by immunoprecipitation of the protein of interest. Subsequently, the genomic site that the protein was bound to is characterized. Here, we describe and discuss ChIP and demonstrate its analytical value for the identification of the Transforming Growth Factor-beta (TGF-beta)-induced binding of the transcription factor SMAD2 to SMAD Binding Elements (SBE) within the promoter region of the tyrosine-protein kinase Kit (c-KIT) receptor ligand Stem Cell Factor (SCF). PMID- 28715366 TI - Continuous-wave Thulium Laser for Heating Cultured Cells to Investigate Cellular Thermal Effects. AB - An original method to heat cultured cells using a 1.94 um continuous-wave thulium laser for biological assessment is introduced here. Thulium laser radiation is strongly absorbed by water, and the cells at the bottom of the culture dish are heated through thermal diffusion. A laser fiber with a diameter of 365 um is set about 12 cm above the culture dish, without any optics, such that the laser beam diameter is almost equivalent to the inner diameter of the culture dish (30 mm). By keeping a consistent amount of culture medium in each experiment, it is possible to irradiate the cells with a highly reproducible temperature increase. To calibrate the temperature increase and its distribution in one cell culture dish for each power setting, the temperature was measured during 10 s of irradiation at different positions and at the cellular level. The temperature distribution was represented using a mathematical graphics software program, and its pattern across the culture dish was in Gaussian form. After laser irradiation, different biological experiments could be performed to assess temperature-dependent cell responses. In this manuscript, viability staining (i.e., distinguishing live, apoptotic, and dead cells) is introduced to help determine the threshold temperatures for cell apoptosis and death after different points in time. The advantages of this method are the preciseness of the temperature and the time of heating, as well as its high efficiency in heating cells in a whole cell culture dish. Furthermore, it allows for study with a wide variety of temperatures and time durations, which can be well-controlled by a computerized operating system. PMID- 28715367 TI - Microfluidic Imaging Flow Cytometry by Asymmetric-detection Time-stretch Optical Microscopy (ATOM). AB - Scaling the number of measurable parameters, which allows for multidimensional data analysis and thus higher-confidence statistical results, has been the main trend in the advanced development of flow cytometry. Notably, adding high resolution imaging capabilities allows for the complex morphological analysis of cellular/sub-cellular structures. This is not possible with standard flow cytometers. However, it is valuable for advancing our knowledge of cellular functions and can benefit life science research, clinical diagnostics, and environmental monitoring. Incorporating imaging capabilities into flow cytometry compromises the assay throughput, primarily due to the limitations on speed and sensitivity in the camera technologies. To overcome this speed or throughput challenge facing imaging flow cytometry while preserving the image quality, asymmetric-detection time-stretch optical microscopy (ATOM) has been demonstrated to enable high-contrast, single-cell imaging with sub-cellular resolution, at an imaging throughput as high as 100,000 cells/s. Based on the imaging concept of conventional time-stretch imaging, which relies on all-optical image encoding and retrieval through the use of ultrafast broadband laser pulses, ATOM further advances imaging performance by enhancing the image contrast of unlabeled/unstained cells. This is achieved by accessing the phase-gradient information of the cells, which is spectrally encoded into single-shot broadband pulses. Hence, ATOM is particularly advantageous in high-throughput measurements of single-cell morphology and texture - information indicative of cell types, states, and even functions. Ultimately, this could become a powerful imaging flow cytometry platform for the biophysical phenotyping of cells, complementing the current state-of-the-art biochemical-marker-based cellular assay. This work describes a protocol to establish the key modules of an ATOM system (from optical frontend to data processing and visualization backend), as well as the workflow of imaging flow cytometry based on ATOM, using human cells and micro-algae as the examples. PMID- 28715368 TI - Loading a Calcium Dye into Frog Nerve Endings Through the Nerve Stump: Calcium Transient Registration in the Frog Neuromuscular Junction. AB - One of the most feasible methods of measuring presynaptic calcium levels in presynaptic nerve terminals is optical recording. It is based on using calcium sensitive fluorescent dyes that change their emission intensity or wavelength depending on the concentration of free calcium in the cell. There are several methods used to stain cells with calcium dyes. Most common are the processes of loading the dyes through a micropipette or pre-incubating with the acetoxymethyl ester forms of the dyes. However, these methods are not quite applicable to neuromuscular junctions (NMJs) due to methodological issues that arise. In this article, we present a method for loading a calcium-sensitive dye through the frog nerve stump of the frog nerve into the nerve endings. Since entry of external calcium into nerve terminals and the subsequent binding to the calcium dye occur within the millisecond time-scale, it is necessary to use a fast imaging system to record these interactions. Here, we describe a protocol for recording the calcium transient with a fast CCD camera. PMID- 28715369 TI - Electrospinning of Photocatalytic Electrodes for Dye-sensitized Solar Cells. AB - This work demonstrates a protocol to fabricate a fiber-based photoanode for dye sensitized solar cells, consisting of a light-scattering layer made of electrospun titanium dioxide nanofibers (TiO2-NFs) on top of a blocking layer made of commercially available titanium dioxide nanoparticles (TiO2-NPs). This is achieved by first electrospinning a solution of titanium (IV) butoxide, polyvinylpyrrolidone (PVP), and glacial acetic acid in ethanol to obtain composite PVP/TiO2 nanofibers. These are then calcined at 500 degrees C to remove the PVP and to obtain pure anatase-phase titania nanofibers. This material is characterized using scanning electron microscopy (SEM) and powder X-ray diffraction (XRD). The photoanode is prepared by first creating a blocking layer through the deposition of a TiO2-NPs/terpineol slurry on a fluorine-doped tin oxide (FTO) glass slide using doctor blading techniques. A subsequent thermal treatment is performed at 500 degrees C. Then, the light-scattering layer is formed by depositing a TiO2-NFs/terpineol slurry on the same slide, using the same technique, and calcinating again at 500 degrees C. The performance of the photoanode is tested by fabricating a dye-sensitized solar cell and measuring its efficiency through J-V curves under a range of incident light densities, from 0.25-1 Sun. PMID- 28715370 TI - Inducible T7 RNA Polymerase-mediated Multigene Expression System, pMGX. AB - Co-expression of multiple proteins is increasingly essential for synthetic biology, studying protein-protein complexes, and characterizing and harnessing biosynthetic pathways. In this manuscript, the use of a highly effective system for the construction of multigene synthetic operons under the control of an inducible T7 RNA polymerase is described. This system allows many genes to be expressed simultaneously from one plasmid. Here, a set of four related vectors, pMGX-A, pMGX-hisA, pMGX-K, and pMGX-hisK, with either the ampicillin or kanamycin resistance selectable marker (A and K) and either possessing or lacking an N terminal hexahistidine tag (his) are disclosed. Detailed protocols for the construction of synthetic operons using this vector system are provided along with the corresponding data, showing that a pMGX-based system containing five genes can be readily constructed and used to produce all five encoded proteins in Escherichia coli. This system and protocol enables researchers to routinely express complex multi-component modules and pathways in E. coli. PMID- 28715371 TI - Determining Cell-surface Expression and Endocytic Rate of Proteins in Primary Astrocyte Cultures Using Biotinylation. AB - Cell-surface proteins mediate a wide array of functions. In many cases, their activity is regulated by endocytic processes that modulate their levels at the plasma membrane. Here, we present detailed protocols for 2 methods that facilitate the study of such processes, both of which are based on the principle of the biotinylation of cell-surface proteins. The first is designed to allow for the semi-quantitative determination of the relative levels of a particular protein at the cell-surface. In it, the lysine residues of the plasma membrane proteins of cells are first labeled with a biotin moiety. Once the cells are lysed, these proteins may then be specifically precipitated via the use of agarose-immobilized streptavidin by exploiting the natural affinity of the latter for biotin. The proteins isolated in such a manner may then be analyzed via a standard western blotting approach. The second method provides a means of determining the endocytic rate of a particular cell-surface target over a period of time. Cell-surface proteins are first modified with a biotin derivative containing a cleavable disulfide bond. The cells are then shifted back to normal culture conditions, which causes the endocytic uptake of a proportion of biotinylated proteins. Next, the disulfide bonds of non-internalized biotin groups are reduced using the membrane-impermeable reducing agent glutathione. Via this approach, endocytosed proteins may thus be isolated and quantified with a high degree of specificity. PMID- 28715372 TI - High-resolution Episcopic Microscopy (HREM) - Simple and Robust Protocols for Processing and Visualizing Organic Materials. AB - We provide simple protocols for generating digital volume data with the high resolution episcopic microscopy (HREM) method. HREM is capable of imaging organic materials with volumes up to 5 x 5 x 7 mm3 in typical numeric resolutions between 1 x 1 x 1 and 5 x 5 x 5 um3. Specimens are embedded in methacrylate resin and sectioned on a microtome. After each section an image of the block surface is captured with a digital video camera that sits on the phototube connected to the compound microscope head. The optical axis passes through a green fluorescent protein (GFP) filter cube and is aligned with a position, at which the bock holder arm comes to rest after each section. In this way, a series of inherently aligned digital images, displaying subsequent block surfaces are produced. Loading such an image series in three-dimensional (3D) visualization software facilitates the immediate conversion to digital volume data, which permit virtual sectioning in various orthogonal and oblique planes and the creation of volume and surface rendered computer models. We present three simple, tissue specific protocols for processing various groups of organic specimens, including mouse, chick, quail, frog and zebra fish embryos, human biopsy material, uncoated paper and skin replacement material. PMID- 28715373 TI - New Methods to Study Gustatory Coding. AB - The sense of taste allows animals to detect chemicals in the environment, giving rise to behaviors critical for survival. When Gustatory Receptor Neurons (GRNs) detect tastant molecules, they encode information about the identity and concentration of the tastant as patterns of electrical activity that then propagate to follower neurons in the brain. These patterns constitute internal representations of the tastant, which then allow the animal to select actions and form memories. The use of relatively simple animal models has been a powerful tool to study basic principles in sensory coding. Here, we propose three new methods to study gustatory coding using the moth Manduca sexta. First, we present a dissection procedure for exposing the maxillary nerves and the subesophageal zone (SEZ), allowing recording of the activity of GRNs from their axons. Second, we describe the use of extracellular electrodes to record the activity of multiple GRNs by placing tetrode wires directly into the maxillary nerve. Third, we present a new system for delivering and monitoring, with high temporal precision, pulses of different tastants. These methods allow the characterization of neuronal responses in vivo directly from GRNs before, during and after tastants are delivered. We provide examples of voltage traces recorded from multiple GRNs, and present an example of how a spike sorting technique can be applied to the data to identify the responses of individual neurons. Finally, to validate our recording approach, we compare extracellular recordings obtained from GRNs with tetrodes to intracellular recordings obtained with sharp glass electrodes. PMID- 28715374 TI - In Vivo Evaluation of the Mechanical and Viscoelastic Properties of the Rat Tongue. AB - The tongue is a highly innervated and vascularized muscle hydrostat on the floor of the mouth of most vertebrates. Its primary functions include supporting mastication and deglutition, as well as taste-sensing and phonetics. Accordingly, the strength and volume of the tongue can impact the ability of vertebrates to accomplish basic activities such as feeding, communicating, and breathing. Human patients with sleep apnea have enlarged tongues, characterized by reduced muscle tone and increased intramuscular fat that can be visualized and quantified by magnetic resonance imaging (MRI). The abilities to measure force generation and viscoelastic properties of the tongue constitute important tools for obtaining functional information to correlate with imaging data. Here, we present techniques for measuring tongue force production in anesthetized Zucker rats via electrical stimulation of the hypoglossal nerves and for determining the viscoelastic properties of the tongue by applying passive Lissajous force/deformation curves. PMID- 28715375 TI - Microfluidic-based Synthesis of Covalent Organic Frameworks (COFs): A Tool for Continuous Production of COF Fibers and Direct Printing on a Surface. AB - Covalent Organic Frameworks (COFs) are a class of porous covalent materials which are frequently synthesized as unprocessable crystalline powders. The first COF was reported in 2005 with much effort centered on the establishment of new synthetic routes for its preparation. To date, most available synthetic methods for COF synthesis are based on bulk mixing under solvothermal conditions. Therefore, there is increasing interest in developing systematic protocols for COF synthesis that provide for fine control over reaction conditions and improve COF processability on surfaces, which is essential for their use in practical applications. Herein, we present a novel microfluidic-based method for COF synthesis where the reaction between two constituent building blocks, 1,3,5 benzenetricarbaldehyde (BTCA) and 1,3,5-tris(4-aminophenyl)benzene (TAPB), takes place under controlled diffusion conditions and at room temperature. Using such an approach yields sponge-like, crystalline fibers of a COF material, hereafter called MF-COF. The mechanical properties of MF-COF and the dynamic nature of the approach allow the continuous production of MF-COF fibers and their direct printing onto surfaces. The general method opens new potential applications requiring advanced printing of 2D or 3D COF structures on flexible or rigid surfaces. PMID- 28715376 TI - A Rat Tibial Growth Plate Injury Model to Characterize Repair Mechanisms and Evaluate Growth Plate Regeneration Strategies. AB - A third of all pediatric fractures involve the growth plate and can result in impaired bone growth. The growth plate (or physis) is cartilage tissue found at the end of all long bones in children that is responsible for longitudinal bone growth. Once damaged, cartilage tissue within the growth plate can undergo premature ossification and lead to unwanted bony repair tissue, which forms a "bony bar." In some cases, this bony bar can result in bone growth deformities, such as angular deformities, or it can completely halt longitudinal bone growth. There is currently no clinical treatment that can fully repair an injured growth plate. Using an animal model of growth plate injury to better understand the mechanisms underlying bony bar formation and to identify ways to inhibit it is a great opportunity to develop better treatments for growth plate injuries. This protocol describes how to disrupt the rat proximal tibial growth plate using a drill-hole defect. This small animal model reliably produces a bony bar and can result in growth deformities similar to those seen in children. This model allows for investigation into the molecular mechanisms of bony bar formation and serves as a means to test potential treatment options for growth plate injuries. PMID- 28715377 TI - Creation of Cardiac Tissue Exhibiting Mechanical Integration of Spheroids Using 3D Bioprinting. AB - This protocol describes 3D bioprinting of cardiac tissue without the use of biomaterials, using only cells. Cardiomyocytes, endothelial cells and fibroblasts are first isolated, counted and mixed at desired cell ratios. They are co cultured in individual wells in ultra-low attachment 96-well plates. Within 3 days, beating spheroids form. These spheroids are then picked up by a nozzle using vacuum suction and assembled on a needle array using a 3D bioprinter. The spheroids are then allowed to fuse on the needle array. Three days after 3D bioprinting, the spheroids are removed as an intact patch, which is already spontaneously beating. 3D bioprinted cardiac patches exhibit mechanical integration of component spheroids and are highly promising in cardiac tissue regeneration and as 3D models of heart disease. PMID- 28715378 TI - The Optical Fractionator Technique to Estimate Cell Numbers in a Rat Model of Electroconvulsive Therapy. AB - Stereological methods are designed to describe quantitative parameters without making assumptions about size, shape, orientation and distribution of cells or structures. These methods have been revolutionary for quantitative analysis of the mammalian brain, in which volumetric cell populations are too high to count manually, and stereology is now the technique of choice whenever estimates of three-dimensional quantities need to be extracted from measurements on two dimensional sections. All stereological methods are in principle unbiased; however, they rely on proper knowledge about the structure of interest and the characteristics of the tissue. Stereology is based on Systematic Uniformly Random Sampling (SURS), with adjustment of sampling to the most efficient level in respect to precision, providing reliable, quantitative information about the whole structure of interest. Here we present the optical fractionator in conjunction with BrdU immunohistochemistry to estimate the production and survival of newly-formed neurons in the granule cell layer (including the sub granular zone) of the rat hippocampus following electroconvulsive stimulation, which is among the most potent stimulators of neurogenesis. The optical fractionator technique is designed to provide estimates of the total number of cells from thick sections sampled from the full structure. Thick sections provide the opportunity to observe cells in their full 3-D extent and thus, allow for easy and robust cell classification based on morphological criteria. When correctly implemented, the sensitivity and efficiency of the optical fractionator provides accurate estimates with a fixed and predetermined precision. PMID- 28715379 TI - Detection of microRNA Expression in Peritoneal Membrane of Rats Using Quantitative Real-time PCR. AB - MicroRNAs (miRNAs) are small noncoding RNAs that regulate messenger RNA expression post-transcriptionally. The miRNA expression profile has been investigated in various organs and tissues in rat. However, standard methods for the purification of miRNAs and detection of their expression in rat peritoneal membrane have not been well established. We have developed an effective and reliable method to purify and quantify miRNAs using quantitative real-time reverse-transcription polymerase chain reaction (qRT-PCR) in rat peritoneal membrane. This protocol consists of four steps: 1) purification of peritoneal membrane sample; 2) purification of total RNA including miRNA from peritoneal membrane sample; 3) reverse transcription of miRNA to produce cDNA; and 4) qRT PCR to detect miRNA expression. Using this protocol, we successfully determined that the expression of six miRNAs (miRNA-142-3p, miRNA-21-5p, miRNA-221-3p, miRNA 223-3p, miRNA-327, and miRNA-34a-5p) increased significantly in the peritoneal membrane of a rat peritoneal fibrosis model compared with those in control groups. This protocol can be used to study the profile of miRNA expression in the peritoneal membrane of rats in many pathological conditions. PMID- 28715380 TI - Production of Chemicals by Klebsiella pneumoniae Using Bamboo Hydrolysate as Feedstock. AB - Bamboo is an important biomass, and bamboo hydrolysate is used by Klebsiella pneumoniae as a feedstock for chemical production. Here, bamboo powder was pretreated with NaOH and washed to a neutral pH. Cellulase was added to the pretreated bamboo powder to generate the hydrolysate, which contained 30 g/L glucose and 15 g/L xylose and was used as the carbon source to prepare a medium for chemical production. When cultured in microaerobic conditions, 12.7 g/L 2,3 butanediol was produced by wildtype K. pneumoniae. In aerobic conditions, 13.0 g/L R-acetoin was produced by the budC mutant of K. pneumoniae. A mixture of 25.5 g/L 2-ketogluconic acid and 13.6 g/L xylonic acid was produced by the budA mutant of K. pneumoniae in a two-stage, pH-controlled fermentation with high air supplementation. In the first stage of fermentation, the culture was maintained at a neutral pH; after cell growth, the fermentation proceeded to the second stage, during which the culture was allowed to become acidic. PMID- 28715381 TI - Modified Terminal Restriction Fragment Analysis for Quantifying Telomere Length Using In-gel Hybridization. AB - There are several different techniques for measuring telomere length, each with their own advantages and disadvantages. The traditional approach, Telomere Restriction Fragment (TRF) analysis, utilizes a DNA hybridization technique whereby genomic DNA samples are digested with restriction enzymes, leaving behind telomere DNA repeats and some sub-telomeric DNA. These are separated by agarose gel electrophoresis, transferred to a filter membrane and hybridized to oligonucleotide probes tagged with either chemiluminescence or radioactivity to visualize telomere restriction fragments. This approach, while requiring a larger quantity of DNA than other techniques such as PCR, can measure the telomere length distribution of a population of cells and allows measurement expressed in absolute kilobases. This manuscript demonstrates a modified DNA hybridization procedure for determining telomere length. Genomic DNA is first digested with restriction enzymes (that do not cut telomeres) and separated by agarose gel electrophoresis. The gel is then dried and the DNA is denatured and hybridized in situ to a radiolabeled oligonucleotide probe. This in situ hybridization avoids loss of telomere DNA and improves signal intensity. Following hybridization, the gels are imaged utilizing phosphor screens and the telomere length is quantified using a graphing program. This procedure was developed by the laboratories of Drs. Woodring Wright and Jerry Shay at the University of Texas Southwestern1,2. Here, we present a detailed description of this procedure, with some modifications. PMID- 28715382 TI - ODELAY: A Large-scale Method for Multi-parameter Quantification of Yeast Growth. AB - Growth phenotypes of microorganisms are a strong indicator of their underlying genetic fitness and can be segregated into 3 growth regimes: lag-phase, log phase, and stationary-phase. Each growth phase can reveal different aspects of fitness that are related to various environmental and genetic conditions. High resolution and quantitative measurements of all 3 phases of growth are generally difficult to obtain. Here we present a detailed method to characterize all 3 growth phases on solid media using an assay called One-cell Doubling Evaluation of Living Arrays of Yeast (ODELAY). ODELAY quantifies growth phenotypes of individual cells growing into colonies on solid media using time-lapse microscopy. This method can directly observe population heterogeneity with each growth parameter in genetically identical cells growing into colonies. This population heterogeneity offers a unique perspective for understanding genetic and epigenetic regulation, and responses to genetic and environmental perturbations. While the ODELAY method is demonstrated using yeast, it can be utilized on any colony forming microorganism that is visible by bright field microscopy. PMID- 28715383 TI - Discrimination and Characterization of Heterocellular Populations Using Quantitative Imaging Techniques. AB - Cellular processes are complex and result from the interplay between multiple cell types and their environment. Existing cell biology techniques often do not allow for accurate interpretation of this interplay. Using a quantitative imaging based approach, we present a high-content protocol for characterizing the dynamic phenotypic responses (i.e. morphology changes, proliferation, apoptosis) of heterogeneous cell populations to changes in environmental stimuli. We highlight our ability to distinguish between cell types based upon either fluorescence intensity or inherent morphology features depending on the application. This platform allows for a more comprehensive characterization of subpopulation response to perturbation while utilizing shorter time, smaller amounts of reagents, and lower likelihood of error than traditional cell biology assays. However, in some cases, cell populations may be difficult to identify and quantitate based on complex cellular features and will require additional troubleshooting; we highlight some of these circumstances in the protocol. We demonstrate this application using response to drug in a cancer model; however, it can easily be applied more broadly to other physiological processes. This protocol allows one to identify subpopulations within a co-culture system and characterize the particular response of each to external stimuli. PMID- 28715384 TI - The Effect of Interfacial Chemical Bonding in TiO2-SiO2 Composites on Their Photocatalytic NOx Abatement Performance. AB - The chemical bonding of particulate photocatalysts to supporting material surfaces is of great importance in engineering more efficient and practical photocatalytic structures. However, the influence of such chemical bonding on the optical and surface properties of the photocatalyst and thus its photocatalytic activity/reaction selectivity behavior has not been systematically studied. In this investigation, TiO2 has been supported on the surface of SiO2 by means of two different methods: (i) by the in situ formation of TiO2 in the presence of sand quartz via a sol-gel method employing tetrabutyl orthotitanium (TBOT); and (ii) by binding the commercial TiO2 powder to quartz on a surface silica gel layer formed from the reaction of quartz with tetraethylorthosilicate (TEOS). For comparison, TiO2 nanoparticles were also deposited on the surfaces of a more reactive SiO2 prepared by a hydrolysis-controlled sol-gel technique as well as through a sol-gel route from TiO2 and SiO2 precursors. The combination of TiO2 and SiO2, through interfacial Ti-O-Si bonds, was confirmed by FTIR spectroscopy and the photocatalytic activities of the obtained composites were tested for photocatalytic degradation of NO according to the ISO standard method (ISO 22197 1). The electron microscope images of the obtained materials showed that variable photocatalyst coverage of the support surface can successfully be achieved but the photocatalytic activity towards NO removal was found to be affected by the preparation method and the nitrate selectivity is adversely affected by Ti-O-Si bonding. PMID- 28715385 TI - A Genetically Engineered Mouse Model of Sporadic Colorectal Cancer. AB - Despite the advantages of easy applicability and cost-effectiveness, colorectal cancer mouse models based on tumor cell injection have severe limitations and do not accurately simulate tumor biology and tumor cell dissemination. Genetically engineered mouse models have been introduced to overcome these limitations; however, such models are technically demanding, especially in large organs such as the colon in which only a single tumor is desired. As a result, an immunocompetent, genetically engineered mouse model of colorectal cancer was developed which develops highly uniform tumors and can be used for tumor biology studies as well as therapeutic trials. Tumor development is initiated by surgical, segmental infection of the distal colon with adeno-cre virus in compound conditionally mutant mice. The tumors can be easily detected and monitored via colonoscopy. We here describe the surgical technique of segmental adeno-cre infection of the colon, the surveillance of the tumor via high resolution colonoscopy and present the resulting colorectal tumors. PMID- 28715386 TI - Live-cell Imaging of Platelet Degranulation and Secretion Under Flow. AB - Blood platelets are essential players in hemostasis, the formation of thrombi to seal vascular breaches. They are also involved in thrombosis, the formation of thrombi that occlude the vasculature and injure organs, with life-threatening consequences. This motivates scientific research on platelet function and the development of methods to track cell-biological processes as they occur under flow conditions. A variety of flow models are available for the study of platelet adhesion and aggregation, two key phenomena in platelet biology. This work describes a method to study real-time platelet degranulation under flow during activation. The method makes use of a flow chamber coupled to a syringe-pump setup that is placed under a wide-field, inverted, LED-based fluorescence microscope. The setup described here allows for the simultaneous excitation of multiple fluorophores that are delivered by fluorescently labeled antibodies or fluorescent dyes. After live-cell imaging experiments, the cover glasses can be further processed and analyzed using static microscopy (i.e., confocal microscopy or scanning electron microscopy). PMID- 28715387 TI - A Modified Trier Social Stress Test for Vulnerable Mexican American Adolescents. AB - The Trier Social Stress Test (TSST) is a well validated and widely used social stressor that has been shown to induce a 2-4 fold increase in cortisol, the biological output produced by the Hypothalamic-Pituitary-Adrenal (HPA) axis in humans. While studies have explored how modifications to the TSST influence stress responsivity, few studies have created a modified TSST appropriate for vulnerable youth that elicits a significant cortisol stress response. Thus, the current study sought to modify or adjust the TSST in a culturally sensitive way for a vulnerable sample of 14 year-old adolescents. The present study took place within the context of a longitudinal birth cohort study of Mexican American families in California called the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS). The CHAMACOS sample was optimal to test the effectiveness of a modified culturally appropriate TSST, as it is comprised of Mexican American youth, who are often excluded from research. These youths also have experienced significant early life adversity. Example modifications included timed prompts, alternative math tasks, use of same-ethnicity peers as confederates, debriefing immediately after the conclusion of the TSST, and using an unknown youth examiner to administer the debrief. Saliva samples were collected at baseline (after a resting phase), and then again at 15, 30, and 45 min post-TSST onset to assess cortisol concentration. A pilot study of 50 participants (50% female) have been analyzed for cortisol reaction to the TSST. Results confirmed that this modified version of the TSST was successful at eliciting a significant cortisol reaction, with a wide range of variability likely due to individual differences. Goals for modifications and ethnicity considerations are discussed. This study provides the foundation for future research to utilize a modified TSST with vulnerable youth. PMID- 28715388 TI - Measuring the Densities of Aqueous Glasses at Cryogenic Temperatures. AB - We demonstrate a method for determining the vitreous phase cryogenic temperature densities of aqueous mixtures, and other samples that require rapid cooling, to prepare the desired cryogenic temperature phase. Microliter to picoliter size drops are cooled by projection into a liquid nitrogen-argon (N2-Ar) mixture. The cryogenic temperature phase of the drop is evaluated using a visual assay that correlates with X-ray diffraction measurements. The density of the liquid N2-Ar mixture is adjusted by adding N2 or Ar until the drop becomes neutrally buoyant. The density of this mixture and thus of the drop is determined using a test mass and Archimedes principle. With appropriate care in drop preparation, management of gas above the liquid cryogen mixture to minimize icing, and regular mixing of the cryogenic mixture to prevent density stratification and phase separation, densities accurate to <0.5% of drops as small as 50 pL can readily be determined. Measurements on aqueous cryoprotectant mixtures provide insight into cryoprotectant action, and provide quantitative data to facilitate thermal contraction matching in biological cryopreservation. PMID- 28715389 TI - Extraction and Purification of Polyphenols from Freeze-dried Berry Powder for the Treatment of Vascular Smooth Muscle Cells In Vitro. AB - Epidemiological studies indicate that increased flavonoid intake correlates with decreased mortality due to cardiovascular diseases (CVD) in the United States (US) and Europe. Berries are widely consumed in the US and have a high polyphenolic content. Polyphenols have been shown to interact with many molecular targets and to exert numerous positive biological functions, including antioxidant, anti-inflammatory, and cardioprotective effects. Polyphenols isolated from blackberry (BL), raspberry (RB), and black raspberry (BRB) reduce oxidative stress and cellular senescence in response to angiotensin II (Ang II). This work provides a detailed description of the protocol used to prepare the polyphenol extracts from freeze-dried berries. Polyphenol extractions from freeze dried berry powder were performed using 80% aqueous ethanol and an ultrasonic assisted extraction method. The crude extract was further purified and fractionated using chloroform and ethyl acetate, respectively. The effects of both crude and purified extracts were tested on Vascular Smooth Muscle Cells (VSMCs) in culture. PMID- 28715390 TI - Mammalian Cell Encapsulation in Alginate Beads Using a Simple Stirred Vessel. AB - Cell encapsulation in alginate beads has been used for immobilized cell culture in vitro as well as for immunoisolation in vivo. Pancreatic islet encapsulation has been studied extensively as a means to increase islet survival in allogeneic or xenogeneic transplants. Alginate encapsulation is commonly achieved by nozzle extrusion and external gelation. Using this method, cell-containing alginate droplets formed at the tip of nozzles fall into a solution containing divalent cations that cause ionotropic alginate gelation as they diffuse into the droplets. The requirement for droplet formation at the nozzle tip limits the volumetric throughput and alginate concentration that can be achieved. This video describes a scalable emulsification method to encapsulate mammalian cells in 0.5% to 10% alginate with 70% to 90% cell survival. By this alternative method, alginate droplets containing cells and calcium carbonate are emulsified in mineral oil, followed by a decrease in pH leading to internal calcium release and ionotropic alginate gelation. The current method allows the production of alginate beads within 20 min of emulsification. The equipment required for the encapsulation step consists in simple stirred vessels available to most laboratories. PMID- 28715391 TI - Isolation of Primary Murine Retinal Ganglion Cells (RGCs) by Flow Cytometry. AB - Neurodegenerative diseases often have a devastating impact on those affected. Retinal ganglion cell (RGC) loss is implicated in an array of diseases, including diabetic retinopathy and glaucoma, in addition to normal aging. Despite their importance, RGCs have been extremely difficult to study until now due in part to the fact that they comprise only a small percentage of the wide variety of cells in the retina. In addition, current isolation methods use intracellular markers to identify RGCs, which produce non-viable cells. These techniques also involve lengthy isolation protocols, so there is a lack of practical, standardized, and dependable methods to obtain and isolate RGCs. This work describes an efficient, comprehensive, and reliable method to isolate primary RGCs from mice retinae using a protocol based on both positive and negative selection criteria. The presented methods allow for the future study of RGCs, with the goal of better understanding the major decline in visual acuity that results from the loss of functional RGCs in neurodegenerative diseases. PMID- 28715392 TI - Immunofluorescence Analysis of Stress Granule Formation After Bacterial Challenge of Mammalian Cells. AB - Fluorescent imaging of cellular components is an effective tool to investigate host-pathogen interactions. Pathogens can affect many different features of infected cells, including organelle ultrastructure, cytoskeletal network organization, as well as cellular processes such as Stress Granule (SG) formation. The characterization of how pathogens subvert host processes is an important and integral part of the field of pathogenesis. While variable phenotypes may be readily visible, the precise analysis of the qualitative and quantitative differences in the cellular structures induced by pathogen challenge is essential for defining statistically significant differences between experimental and control samples. SG formation is an evolutionarily conserved stress response that leads to antiviral responses and has long been investigated using viral infections1. SG formation also affects signaling cascades and may have other still unknown consequences2. The characterization of this stress response to pathogens other than viruses, such as bacterial pathogens, is currently an emerging area of research3. For now, quantitative and qualitative analysis of SG formation is not yet routinely used, even in the viral systems. Here we describe a simple method for inducing and characterizing SG formation in uninfected cells and in cells infected with a cytosolic bacterial pathogen, which affects the formation of SGs in response to various exogenous stresses. Analysis of SG formation and composition is achieved by using a number of different SG markers and the spot detector plug-in of ICY, an open source image analysis tool. PMID- 28715393 TI - Generation and Long-term Maintenance of Nerve-free Hydra. AB - The interstitial cell lineage of Hydra includes multipotent stem cells, and their derivatives: gland cells, nematocytes, germ cells, and nerve cells. The interstitial cells can be eliminated through two consecutive treatments with colchicine, a plant-derived toxin that kills dividing cells, thus erasing the potential for renewal of the differentiated cells that are derived from the interstitial stem cells. This allows for the generation of Hydra that lack nerve cells. A nerve-free polyp cannot open its mouth to feed, egest, or regulate osmotic pressure. Such animals, however, can survive and be cultured indefinitely in the laboratory if regularly force-fed and burped. The lack of nerve cells allows for studies of the role of the nervous system in regulating animal behavior and regeneration. Previously published protocols for nerve-free Hydra maintenance involve outdated techniques such as mouth-pipetting with hand-pulled micropipette tips to feed and clean the Hydra. Here, an improved protocol for maintenance of nerve-free Hydra is introduced. Fine-tipped forceps are used to force open the mouth and insert freshly killed Artemia. Following force-feeding, the body cavity of the animal is flushed with fresh medium using a syringe and hypodermic needle to remove undigested material, referred to here as "burping". This new method of force-feeding and burping nerve-free Hydra through the use of forceps and syringes eliminates the need for mouth-pipetting using hand-pulled micropipette tips. It thus makes the process safer and significantly more time efficient. To ensure that the nerve cells in the hypostome have been eliminated, immunohistochemistry using anti-tyrosine-tubulin is conducted. PMID- 28715394 TI - A Filtration-based Method of Preparing High-quality Nuclei from Cross-linked Skeletal Muscle for Chromatin Immunoprecipitation. AB - Chromatin immunoprecipitation (ChIP) is a powerful method to determine protein binding to chromatin DNA. Fiber-rich skeletal muscle, however, has been a challenge for ChIP due to technical difficulty in isolation of high-quality nuclei with minimal contamination of myofibrils. Previous protocols have attempted to purify nuclei before cross-linking, which incurs the risk of altered DNA-protein interaction during the prolonged nuclei preparation process. In the current protocol, we first cross-linked the skeletal muscle tissue collected from mice, and the tissues were minced and sonicated. Since we found that ultracentrifugation was not able to separate nuclei from myofibrils using cross linked muscle tissue, we devised a sequential filtration procedure to obtain high quality nuclei devoid of significant myofibril contamination. We subsequently prepared chromatin by using an ultrasonicator, and ChIP assays with anti-BMAL1 antibody revealed robust circadian binding pattern of BMAL1 to target gene promoters. This filtration protocol constitutes an easily applicable method to isolate high-quality nuclei from cross-linked skeletal muscle tissue, allowing consistent sample processing for circadian and other time-sensitive studies. In combination with next-generation sequencing (NGS), our method can be deployed for various mechanistic and genomic studies focusing on skeletal muscle function. PMID- 28715395 TI - Expansion and Adipogenesis Induction of Adipocyte Progenitors from Perivascular Adipose Tissue Isolated by Magnetic Activated Cell Sorting. AB - Expansion of Perivascular Adipose Tissue (PVAT), a major regulator of vascular function through paracrine signaling, is directly related to the development of hypertension during obesity. The extent of hypertrophy and hyperplasia depends on depot location, sex, and the type of Adipocyte Progenitor Cell (APC) phenotypes present. Techniques used for APC and preadipocytes isolation in the last 10 years have drastically improved the accuracy at which individual cells can be identified based on specific cell surface markers. However, isolation of APC and adipocytes can be a challenge due to the fragility of the cell, especially if the intact cell must be retained for cell culture applications. Magnetic-activated Cell Sorting (MCS) provides a method of isolating greater number of viable APC per weight unit of adipose tissue. APC harvested by MCS can be used for in vitro protocols to expand preadipocytes and differentiate them into adipocytes through use of growth factor cocktails allowing for analysis of the prolific and adipogenic potential retained by the cells. This experiment focused on the aortic and mesenteric PVAT depots, which play key roles in the development of cardiovascular disease during expansion. These protocols describe methods to isolate, expand, and differentiate a defined population of APC. This MCS protocol allows isolation to be used in any experiment where cell sorting is needed with minimal equipment or training. These techniques can aid further experiments to determine the functionality of specific cell populations based on the presence of cell surface markers. PMID- 28715396 TI - Smartphone Fundus Photography. AB - Smartphone fundus photography is a simple technique to obtain ocular fundus pictures using a smartphone camera and a conventional handheld indirect ophthalmoscopy lens. This technique is indispensable when picture documentation of optic nerve, retina, and retinal vessels is necessary but a fundus camera is not available. The main advantage of this technique is the widespread availability of smartphones that allows documentation of macula and optic nerve changes in many settings that was not previously possible. Following the well defined steps detailed here, such as proper alignment of the phone camera, handheld lens, and the patient's pupil, is the key for obtaining a clear retina picture with no interfering light reflections and aberrations. In this paper, the optical principles of indirect ophthalmoscopy and fundus photography will be reviewed first. Then, the step-by-step method to record a good quality retinal image using a smartphone will be explained. PMID- 28715397 TI - Magnetic and Thermal-sensitive Poly(N-isopropylacrylamide)-based Microgels for Magnetically Triggered Controlled Release. AB - Magnetically and thermally sensitive poly(N-isopropylacrylamide) (PNIPAAm)/Fe3O4 NH2 microgels with the encapsulated anti-cancer drug curcumin (Cur) were designed and fabricated for magnetically triggered release. PNIPAAm-based magnetic microgels with a spherical structure were produced via a temperature-induced emulsion followed with physical-crosslinking by mixing PNIPAAm, polyethylenimine (PEI), and Fe3O4-NH2 magnetic nanoparticles. Because of their dispersity, the Fe3O4-NH2 nanoparticles were embedded inside the polymer matrix. The amine groups exposed on the Fe3O4-NH2 and PEI surface supported the spherical structure by physically crosslinking with the amide groups of the PNIPAAm. The hydrophobic anti-cancer drug curcumin can be dispersed in water after encapsulation into the microgels. The microgels were characterized by transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FT-IR), and UV-Vis spectral analysis. Furthermore, magnetically triggered release was studied under an external high frequency magnetic field (HFMF). A significant "burst release" of curcumin was observed after applying the HFMF to the microgels due to the magnetic inductive heating (hyperthermia) effect. This manuscript describes the magnetically triggered controlled release of Cur-PNIPAAm/Fe3O4-NH2 encapsulated curcumin, which can be potentially applied for tumor therapy. PMID- 28715398 TI - A Non-invasive Way to Isolate and Phenotype Cells from the Conjunctiva. AB - Traditionally, ocular surface cytology is studied with techniques such as spatula technology and brush technology. The problem with these techniques is that they may induce traumatic lesions on the surface of the eye, which can progress to scarring, eyelid deformity, limbal stem cell deficiency and in some cases, cause great discomfort to the subject. To avoid these clinical problems, impression cytology (IC) was developed to diagnose dry eye disease and later neoplasia, atopic disease, vernal keratoconjunctivitis and keratoconjunctivitis sicca. Typically, clinicians manually cut filter papers into required shapes and apply these to the ocular surface. Here, we describe how to perform IC using a commercially available medical device. This technique is explained here followed by immunophenotyping by flow cytometry. This technique requires less manual handling and causes less injury to the ocular surface. PMID- 28715399 TI - Integration Free Derivation of Human Induced Pluripotent Stem Cells Using Laminin 521 Matrix. AB - Xeno-free and fully defined conditions are key parameters for robust and reproducible generation of homogenous human induced pluripotent stem (hiPS) cells. Maintenance of hiPS cells on feeder cells or undefined matrices are susceptible to batch variances, pathogenic contamination and risk of immunogenicity. Utilizing the defined recombinant human laminin 521 (LN-521) matrix in combination with xeno-free and defined media formulations reduces variability and allows for the consistent generation of hiPS cells. The Sendai virus (SeV) vector is a non-integrating RNA-based system, thus circumventing concerns associated with the potential disruptive effect on genome integrity integrating vectors can have. Furthermore, these vectors have demonstrated relatively high efficiency in the reprogramming of dermal fibroblasts. In addition, enzymatic single cell passaging of cells facilitates homogeneous maintenance of hiPS cells without substantial prior experience of stem cell culture. Here we describe a protocol that has been extensively tested and developed with a focus on reproducibility and ease of use, providing a robust and practical way to generate defined and xeno-free human hiPS cells from fibroblasts. PMID- 28715400 TI - A Novel Method to Model Chronic Traumatic Encephalopathy in Drosophila. AB - Chronic Traumatic Encephalopathy (CTE) is an established neurodegenerative disease that is closely associated with exposure to repetitive mild Traumatic Brain Injury (mTBI). The mechanisms responsible for its complex pathological changes remain largely elusive, despite a recent consensus to define the neuropathological criteria. Here, we describe a novel method to develop a model of CTE in Drosophila melanogaster (Drosophila ) in an attempt to identify the key genes and pathways that lead to the characteristic hyperphosphorylated tau accumulation and neuronal death in the brain. Adjustable-strength impacts to inflict mild closed injury are delivered directly to the fly head, subjecting the head to rapid acceleration and deceleration. Our method eliminates the potential problems inherent with other Drosophila mTBI models (e.g.,animal death might be induced by damage to other parts of the body or to internal organs). The less labor- and cost-intensive animal care, short life span, and extensive genetic tools make the fruit fly ideal to study CTE pathogenesis and make it possible to perform large-scale, genome-wide forward genetic and pharmacological screens. We anticipate that the ongoing characterization of the model will generate important mechanistic insights on disease prevention and therapeutic approaches. PMID- 28715401 TI - Extraction of Organochlorine Pesticides from Plastic Pellets and Plastic Type Analysis. AB - Plastic resin pellets, categorized as microplastics (<=5 mm in diameter), are small granules that can be unintentionally released to the environment during manufacturing and transport. Because of their environmental persistence, they are widely distributed in the oceans and on beaches all over the world. They can act as a vector of potentially toxic organic compounds (e.g., polychlorinated biphenyls) and might consequently negatively affect marine organisms. Their possible impacts along the food chain are not yet well understood. In order to assess the hazards associated with the occurrence of plastic pellets in the marine environment, it is necessary to develop methodologies that allow for rapid determination of associated organic contaminant levels. The present protocol describes the different steps required for sampling resin pellets, analyzing adsorbed organochlorine pesticides (OCPs) and identifying the plastic type. The focus is on the extraction of OCPs from plastic pellets by means of a pressurized fluid extractor (PFE) and on the polymer chemical analysis applying Fourier Transform-InfraRed (FT-IR) spectroscopy. The developed methodology focuses on 11 OCPs and related compounds, including dichlorodiphenyltrichloroethane (DDT) and its two main metabolites, lindane and two production isomers, as well as the two biologically active isomers of technical endosulfan. This protocol constitutes a simple and rapid alternative to existing methodology for evaluating the concentration of organic contaminants adsorbed on plastic pieces. PMID- 28715402 TI - Fluorescent Dye Labeling of Erythrocytes and Leukocytes for Studying the Flow Dynamics in Mouse Retinal Circulation. AB - The retinal and choroidal blood flow dynamics may provide insight into the pathophysiology and sequelae of various ocular diseases, such as glaucoma, diabetic retinopathy, age-related macular degeneration (AMD) and other ocular inflammatory conditions. It may also help to monitor the therapeutic responses in the eye. The proper labeling of the blood cells, coupled with live-cell imaging of the labeled cells, allows for the investigation of the flow dynamics in the retinal and choroidal circulation. Here, we describe the standardized protocols of 1.5% indocyanine green (ICG) and 1% sodium fluorescein labeling of mice erythrocytes and leukocytes, respectively. Scanning laser ophthalmoscopy (SLO) was applied to visualize the labeled cells in the retinal circulation of C57BL/6J mice (wild type). Both methods demonstrated distinct fluorescently labeled cells in the mouse retinal circulation. These labeling methods can have wider applications in various ocular disease models. PMID- 28715403 TI - Improving Strength, Power, Muscle Aerobic Capacity, and Glucose Tolerance through Short-term Progressive Strength Training Among Elderly People. AB - This protocol describes the simultaneous use of a broad span of methods to examine muscle aerobic capacity, glucose tolerance, strength, and power in elderly people performing short-term resistance training (RET). Supervised progressive resistance training for 1 h three times a week over 8 weeks was performed by RET participants (71+/-1 years, range 65-80). Compared to a control group without training, the RET showed improvements on the measures used to indicate strength, power, glucose tolerance, and several parameters of muscle aerobic capacity. Strength training was performed in a gym with only robust fitness equipment. An isokinetic dynamometer for knee extensor strength permitted the measurement of concentric, eccentric, and static strength, which increased for the RET group (8-12% post- versus pre-test). The power (rate of force development, RFD) at the initial 0-30 ms also showed an increase for the RET group (52%). A glucose tolerance test with frequent blood glucose measurements showed improvements only for the RET group in terms of blood glucose values after 2 h (14%) and the area under the curve (21%). The blood lipid profile also improved (8%). From muscle biopsy samples prepared using histochemistry, the amount of fiber type IIa increased, and a trend towards a decrease in IIx in the RET group reflected a change to a more oxidative profile in terms of fiber composition. Western blot (to determine the protein content related to the signaling for muscle protein synthesis) showed a rise of 69% in both Akt and mTOR in the RET group; this also showed an increase in mitochondrial proteins for OXPHOS complex II and citrate synthase (both ~30%) and for complex IV (90%), in only the RET group. We demonstrate that this type of progressive resistance training offers various improvements (e.g., strength, power, aerobic capacity, glucose tolerance, and plasma lipid profile). PMID- 28715404 TI - An IL-8 Transiently Transgenized Mouse Model for the In Vivo Long-term Monitoring of Inflammatory Responses. AB - Airway inflammation is often associated with bacterial infections and represents a major determinant of lung disease. The in vivo determination of the pro inflammatory capabilities of various factors is challenging and requires terminal procedures, such as bronchoalveolar lavage and the removal of lungs for in situ analysis, precluding longitudinal visualization in the same mouse. Here, lung inflammation is induced through the intratracheal instillation of Pseudomonas aeruginosa culture supernatant (SN) in transiently transgenized mice expressing the luciferase reporter gene under the control of a heterologous IL-8 bovine promoter. Luciferase expression in the lung is monitored by in vivo bioluminescent image (BLI) analysis over a 2.5- to 48-h timeframe following the instillation. The procedure can be repeated multiple times within 2 - 3 months, thus permitting the evaluation of the inflammatory response in the same mice without the need to terminate the animals. This approach permits the monitoring of pro- and anti-inflammatory factors acting in the lung in real time and appears suitable for functional and pharmacological studies. PMID- 28715405 TI - Identification and pathological characterization of persistent asymptomatic Ebola virus infection in rhesus monkeys. AB - Ebola virus (EBOV) persistence in asymptomatic humans and Ebola virus disease (EVD) sequelae have emerged as significant public health concerns since the 2013 2016 EVD outbreak in Western Africa. Until now, studying how EBOV disseminates into and persists in immune-privileged sites was impossible due to the absence of a suitable animal model. Here, we detect persistent EBOV replication coinciding with systematic inflammatory responses in otherwise asymptomatic rhesus monkeys that had survived infection in the absence of or after treatment with candidate medical countermeasures. We document progressive EBOV dissemination into the eyes, brain and testes through vascular structures, similar to observations in humans. We identify CD68+ cells (macrophages/monocytes) as the cryptic EBOV reservoir cells in the vitreous humour and its immediately adjacent tissue, in the tubular lumina of the epididymides, and in foci of histiocytic inflammation in the brain, but not in organs typically affected during acute infection. In conclusion, our data suggest that persistent EBOV infection in rhesus monkeys could serve as a model for persistent EBOV infection in humans, and we demonstrate that promising candidate medical countermeasures may not completely clear EBOV infection. A rhesus monkey model may lay the foundation to study EVD sequelae and to develop therapies to abolish EBOV persistence. PMID- 28715407 TI - Building the biomedical data science workforce. AB - This article describes efforts at the National Institutes of Health (NIH) from 2013 to 2016 to train a national workforce in biomedical data science. We provide an analysis of the Big Data to Knowledge (BD2K) training program strengths and weaknesses with an eye toward future directions aimed at any funder and potential funding recipient worldwide. The focus is on extramurally funded programs that have a national or international impact rather than the training of NIH staff, which was addressed by the NIH's internal Data Science Workforce Development Center. From its inception, the major goal of BD2K was to narrow the gap between needed and existing biomedical data science skills. As biomedical research increasingly relies on computational, mathematical, and statistical thinking, supporting the training and education of the workforce of tomorrow requires new emphases on analytical skills. From 2013 to 2016, BD2K jump-started training in this area for all levels, from graduate students to senior researchers. PMID- 28715406 TI - Genetic polymorphisms of the IL6 and NOD2 genes are risk factors for inflammatory reactions in leprosy. AB - The pathways that trigger exacerbated immune reactions in leprosy could be determined by genetic variations. Here, in a prospective approach, both genetic and non-genetic variables influencing the amount of time before the development of reactional episodes were studied using Kaplan-Meier survival curves, and the genetic effect was estimated by the Cox proportional-hazards regression model. In a sample including 447 leprosy patients, we confirmed that gender (male), and high bacillary clinical forms are risk factors for leprosy reactions. From the 15 single nucleotide polymorphisms (SNPs) at the 8 candidate genes genotyped (TNF/LTA, IFNG, IL10, TLR1, NOD2, SOD2, and IL6) we observed statistically different survival curves for rs751271 at the NOD2 and rs2069845 at the IL6 genes (log-rank p-values = 0.002 and 0.023, respectively), suggesting an influence on the amount of time before developing leprosy reactions. Cox models showed associations between the SNPs rs751271 at NOD2 and rs2069845 at IL6 with leprosy reactions (HRGT = 0.45, p = 0.002; HRAG = 1.88, p = 0.0008, respectively). Finally, IL-6 and IFN-gamma levels were confirmed as high, while IL-10 titers were low in the sera of reactional patients. Rs751271-GT genotype-bearing individuals correlated (p = 0.05) with lower levels of IL-6 in sera samples, corroborating the genetic results. Although the experimental size may be considered a limitation of the study, the findings confirm the association of classical variables such as sex and clinical forms with leprosy, demonstrating the consistency of the results. From the results, we conclude that SNPs at the NOD2 and IL6 genes are associated with leprosy reactions as an outcome. NOD2 also has a clear functional pro-inflammatory link that is coherent with the exacerbated responses observed in these patients. PMID- 28715408 TI - Potential risk factors associated with human alveolar echinococcosis: Systematic review and meta-analysis. AB - BACKGROUND: Human alveolar echinococcosis (AE) is a severe zoonotic disease caused by the metacestode stage of Echinococcus multilocularis. AE is commonly associated with a long incubation period that may last for more than ten years. The objective of this systematic literature review was to identify and summarize the current knowledge on statistically relevant potential risk factors (PRFs) associated with AE in humans. METHODOLOGY/PRINCIPAL FINDINGS: Six bibliographic databases were searched, generating a total of 1,009 publications. Following the removal of duplicate records and the exclusion of papers that failed to meet the criteria of a previously agreed a priori protocol, 23 publications were retained; however, 6 of these did not contain data in a format that allowed their inclusion in the meta-analysis. The remaining 17 publications (6 case-control and 11 cross sectional studies) were meta-analysed to investigate associations between AE and PRFs. Pooled odds ratios (OR) were used as a measure of effect and separately analysed for case-control and cross-sectional studies. In the case-control studies, the following PRFs for human AE showed higher odds of outcome: "dog ownership", "cat ownership", "have a kitchen garden", "occupation: farmer", "haymaking in meadows not adjacent to water", "went to forests for vocational reasons", "chewed grass" and "hunting / handling foxes". In the cross-sectional studies, the following PRFs showed higher odds of outcome: "dog ownership", "play with dogs", "gender: female", "age over 20 years", "ethnic group: Tibetan", "low income", "source of drinking water other than well or tap", "occupation: herding" and "low education". Our meta-analysis confirmed that the chance of AE transmission through ingestion of food and water contaminated with E. multilocularis eggs exists, but showed also that food- and water-borne PRFs do not significantly increase the risk of infection. CONCLUSIONS/SIGNIFICANCE: This systematic review analysed international peer-reviewed articles that have over the years contributed to our current understanding of the epidemiology of human AE. The identification of potential risk factors may help researchers and decision makers improve surveillance and/or preventive measures that aim at decreasing human infection with E. multilocularis. More primary studies are needed to confirm potential risk factors and their role in the epidemiology of human AE. PMID- 28715409 TI - Zika virus inhibits eIF2alpha-dependent stress granule assembly. AB - Zika virus (ZIKV), a member of the Flaviviridae family, is the most recent emerging arbovirus with pandemic potential. During infection, viruses trigger the host cell stress response, leading to changes in RNA translation and the assembly of large aggregates of stalled translation preinitiation complexes, termed stress granules (SGs). Several reports demonstrate that flaviviruses modulate the assembly of stress granules (SG). As an emerging pathogen, little is known however about how ZIKV modulates the host cell stress response. In this work, we investigate how ZIKV modulates SG assembly. We demonstrate that ZIKV negatively impacts SG assembly under oxidative stress conditions induced by sodium arsenite (Ars), a treatment that leads to the phosphorylation of eIF2alpha. By contrast, no measurable difference in SG assembly was observed between mock and ZIKV infected cells treated with sodium selenite (Se) or Pateamine A (PatA), compounds that trigger eIF2alpha-independent SG assembly. Interestingly, ZIKV infection markedly impaired the phosphorylation of eIF2alpha triggered in Ars-treated infected cells, and the abrogation of SG assembly in ZIKV-infected cells is, at least in part, dependent on eIF2alpha dephosphorylation. These data demonstrate that ZIKV elicits mechanisms to counteract host anti-viral stress responses to promote a cellular environment propitious for viral replication. PMID- 28715410 TI - Cloning of HSP90, expression and localization of HSP70/90 in different tissues including lactating/non-lactating yak (Bos grunniens) breast tissue. AB - The aim of this study is to investigate the expression and localization of HSP70/90 in different tissues and explore the regulation effects of HSP70/90 at lactation period of female yaks. HSP90 mRNA was cloned from the heart samples of female yaks, Quantitative real-time (qRT-PCR), Western blotting (WB), immunohistochemistry and immunofluorescence assays were utilized to analyze the expressions of HSP70/90 mRNA and protein in different tissues. Sequence analysis showed that HSP90 is a conserved molecular chaperone of female yaks. The qRT-PCR, WB results showed that the expressions of HSP70/90 mRNA and protein were significantly different in different tissues, and 3-fold higher expression during the lactation period than the non-lactation period of breast tissue (P < 0.01). Immunohistochemistry and immunofluorescence assays results showed that HSP70/90 were located in the cardiac muscle cells, cerebellar medulla, theca cells lining at the reproductive system, and the mammary epithelia of the breasts. In addition, the expression level of HSP70 was higher than those of HSP90 in all examined tissues. Therefore, our results strongly suggest that the expression and localization of HSP70/90 could provide significant evidence to further research in tissue specific expression, and lactation function of female yaks. PMID- 28715411 TI - A curated genome-scale metabolic model of Bordetella pertussis metabolism. AB - The Gram-negative bacterium Bordetella pertussis is the causative agent of whooping cough, a serious respiratory infection causing hundreds of thousands of deaths annually worldwide. There are effective vaccines, but their production requires growing large quantities of B. pertussis. Unfortunately, B. pertussis has relatively slow growth in culture, with low biomass yields and variable growth characteristics. B. pertussis also requires a relatively expensive growth medium. We present a new, curated flux balance analysis-based model of B. pertussis metabolism. We enhance the model with an experimentally-determined biomass objective function, and we perform extensive manual curation. We test the model's predictions with a genome-wide screen for essential genes using a transposon-directed insertional sequencing (TraDIS) approach. We test its predictions of growth for different carbon sources in the medium. The model predicts essentiality with an accuracy of 83% and correctly predicts improvements in growth under increased glutamate:fumarate ratios. We provide the model in SBML format, along with gene essentiality predictions. PMID- 28715412 TI - Cell fate specification in the lingual epithelium is controlled by antagonistic activities of Sonic hedgehog and retinoic acid. AB - The interaction between signaling pathways is a central question in the study of organogenesis. Using the developing murine tongue as a model, we uncovered unknown relationships between Sonic hedgehog (SHH) and retinoic acid (RA) signaling. Genetic loss of SHH signaling leads to enhanced RA activity subsequent to loss of SHH-dependent expression of Cyp26a1 and Cyp26c1. This causes a cell identity switch, prompting the epithelium of the tongue to form heterotopic minor salivary glands and to overproduce oversized taste buds. At developmental stages during which Wnt10b expression normally ceases and Shh becomes confined to taste bud cells, loss of SHH inputs causes the lingual epithelium to undergo an ectopic and anachronic expression of Shh and Wnt10b in the basal layer, specifying de novo taste placode induction. Surprisingly, in the absence of SHH signaling, lingual epithelial cells adopted a Merkel cell fate, but this was not caused by enhanced RA signaling. We show that RA promotes, whereas SHH, acting strictly within the lingual epithelium, inhibits taste placode and lingual gland formation by thwarting RA activity. These findings reveal key functions for SHH and RA in cell fate specification in the lingual epithelium and aid in deciphering the molecular mechanisms that assign cell identity. PMID- 28715413 TI - Zika virus alters the microRNA expression profile and elicits an RNAi response in Aedes aegypti mosquitoes. AB - Zika virus (ZIKV), a flavivirus transmitted primarily by Aedes aegypti, has recently spread globally in an unprecedented fashion, yet we have a poor understanding of host-microbe interactions in this system. To gain insights into the interplay between ZIKV and the mosquito, we sequenced the small RNA profiles in ZIKV-infected and non-infected Ae. aegypti mosquitoes at 2, 7 and 14 days post infection. ZIKA induced an RNAi response in the mosquito with virus-derived short interfering RNAs and PIWI-interacting RNAs dramatically increased in abundance post-infection. Further, we found 17 host microRNAs (miRNAs) that were modulated by ZIKV infection at all time points. Strikingly, many of these regulated miRNAs have been reported to have their expression altered by dengue and West Nile viruses, while the response was divergent from that induced by the alphavirus Chikungunya virus in mosquitoes. This suggests that conserved miRNA responses occur within mosquitoes in response to flavivirus infection. This study expands our understanding of ZIKV-vector interactions and provides potential avenues to be further investigated to target ZIKV in the mosquito host. PMID- 28715414 TI - Kinesin-1 promotes chondrocyte maintenance during skeletal morphogenesis. AB - During skeletal morphogenesis diverse mechanisms are used to support bone formation. This can be seen in the bones that require a cartilage template for their development. In mammals the cartilage template is removed, but in zebrafish the cartilage template persists and the bone mineralizes around the cartilage scaffold. Remodeling of unmineralized cartilage occurs via planar cell polarity (PCP) mediated cell rearrangements that contribute to lengthening of elements; however, the mechanisms that maintain the chondrocyte template that supports perichondral ossification remain unclear. We report double mutants disrupting two zebrafish kinesin-I genes (hereafter kif5Blof) that we generated using CRISPR/Cas9 mutagenesis. We show that zygotic Kif5Bs have a conserved function in maintaining muscle integrity, and are required for cartilage remodeling and maintenance during craniofacial morphogenesis by a PCP-distinct mechanism. Further, kif5Blof does not activate ER stress response genes, but instead disrupts lysosomal function, matrix secretion, and causes deregulated autophagic markers and eventual chondrocyte apoptosis. Ultrastructural and transplantation analysis reveal neighboring cells engulfing extruded kif5Blof chondrocytes. Initial cartilage specification is intact; however, during remodeling, kif5Blof chondrocytes die and the cartilage matrix devoid of hypertrophic chondrocytes remains and impedes normal ossification. Chimeric and mosaic analyses indicate that Kif5B functions cell-autonomously in secretion, nuclear position, cell elongation and maintenance of hypertrophic chondrocytes. Interestingly, large groups of wild-type cells can support elongation of neighboring mutant cells. Finally, mosaic expression of kif5Ba, but not kif5Aa in cartilage rescues the chondrocyte phenotype, further supporting a specific requirement for Kif5B. Cumulatively, we show essential Kif5B functions in promoting cartilage remodeling and chondrocyte maintenance during zebrafish craniofacial morphogenesis. PMID- 28715415 TI - Characterizing the malaria rural-to-urban transmission interface: The importance of reactive case detection. AB - BACKGROUND: Reported urban malaria cases are increasing in Latin America, however, evidence of such trend remains insufficient. Here, we propose an integrated approach that allows characterizing malaria transmission at the rural to-urban interface by combining epidemiological, entomological, and parasite genotyping methods. METHODS/PRINCIPAL FINDINGS: A descriptive study that combines active (ACD), passive (PCD), and reactive (RCD) case detection was performed in urban and peri-urban neighborhoods of Quibdo, Colombia. Heads of households were interviewed and epidemiological surveys were conducted to assess malaria prevalence and identify potential risk factors. Sixteen primary cases, eight by ACD and eight by PCD were recruited for RCD. Using the RCD strategy, prevalence of 1% by microscopy (6/604) and 9% by quantitative polymerase chain reaction (qPCR) (52/604) were found. A total of 73 houses and 289 volunteers were screened leading to 41 secondary cases, all of them in peri-urban settings (14% prevalence). Most secondary cases were genetically distinct from primary cases indicating that there were independent occurrences. Plasmodium vivax was the predominant species (76.3%, 71/93), most of them being asymptomatic (46/71). Urban and peri-urban neighborhoods had significant sociodemographic differences. Twenty-four potential breeding sites were identified, all in peri-urban areas. The predominant vectors for 1,305 adults were Anopheles nuneztovari (56,2%) and An. Darlingi (42,5%). One An. nuneztovari specimen was confirmed naturally infected with P. falciparum by ELISA. CONCLUSIONS: This study found no evidence supporting the existence of urban malaria transmission in Quibdo. RCD strategy was more efficient for identifying malaria cases than ACD alone in areas where malaria transmission is variable and unstable. Incorporating parasite genotyping allows discovering hidden patterns of malaria transmission that cannot be detected otherwise. We propose to use the term "focal case" for those primary cases that lead to discovery of secondary but genetically unrelated malaria cases indicating undetected malaria transmission. PMID- 28715417 TI - A Hox complex activates and potentiates the Epidermal Growth Factor signaling pathway to specify Drosophila oenocytes. AB - Hox transcription factors specify distinct cell types along the anterior posterior axis of metazoans by regulating target genes that modulate signaling pathways. A well-established example is the induction of Epidermal Growth Factor (EGF) signaling by an Abdominal-A (Abd-A) Hox complex during the specification of Drosophila hepatocyte-like cells (oenocytes). Previous studies revealed that Abd A is non-cell autonomously required to promote oenocyte fate by directly activating a gene (rhomboid) that triggers EGF secretion from sensory organ precursor (SOP) cells. Neighboring cells that receive the EGF signal initiate a largely unknown pathway to promote oenocyte fate. Here, we show that Abd-A also plays a cell autonomous role in inducing oenocyte fate by activating the expression of the Pointed-P1 (PntP1) ETS transcription factor downstream of EGF signaling. Genetic studies demonstrate that both PntP1 and PntP2 are required for oenocyte specification. Moreover, we found that PntP1 contains a conserved enhancer (PntP1OE) that is activated in oenocyte precursor cells by EGF signaling via direct regulation by the Pnt transcription factors as well as a transcription factor complex consisting of Abd-A, Extradenticle, and Homothorax. Our findings demonstrate that the same Abd-A Hox complex required for sending the EGF signal from SOP cells, enhances the competency of receiving cells to select oenocyte cell fate by up-regulating PntP1. Since PntP1 is a downstream effector of EGF signaling, these findings provide insight into how a Hox factor can both trigger and potentiate the EGF signal to promote an essential cell fate along the body plan. PMID- 28715416 TI - Signatures of inflammation and impending multiple organ dysfunction in the hyperacute phase of trauma: A prospective cohort study. AB - BACKGROUND: Severe trauma induces a widespread response of the immune system. This "genomic storm" can lead to poor outcomes, including Multiple Organ Dysfunction Syndrome (MODS). MODS carries a high mortality and morbidity rate and adversely affects long-term health outcomes. Contemporary management of MODS is entirely supportive, and no specific therapeutics have been shown to be effective in reducing incidence or severity. The pathogenesis of MODS remains unclear, and several models are proposed, such as excessive inflammation, a second-hit insult, or an imbalance between pro- and anti-inflammatory pathways. We postulated that the hyperacute window after trauma may hold the key to understanding how the genomic storm is initiated and may lead to a new understanding of the pathogenesis of MODS. METHODS AND FINDINGS: We performed whole blood transcriptome and flow cytometry analyses on a total of 70 critically injured patients (Injury Severity Score [ISS] >= 25) at The Royal London Hospital in the hyperacute time period within 2 hours of injury. We compared transcriptome findings in 36 critically injured patients with those of 6 patients with minor injuries (ISS <= 4). We then performed flow cytometry analyses in 34 critically injured patients and compared findings with those of 9 healthy volunteers. Immediately after injury, only 1,239 gene transcripts (4%) were differentially expressed in critically injured patients. By 24 hours after injury, 6,294 transcripts (21%) were differentially expressed compared to the hyperacute window. Only 202 (16%) genes differentially expressed in the hyperacute window were still expressed in the same direction at 24 hours postinjury. Pathway analysis showed principally up-regulation of pattern recognition and innate inflammatory pathways, with down-regulation of adaptive responses. Immune deconvolution, flow cytometry, and modular analysis suggested a central role for neutrophils and Natural Killer (NK) cells, with underexpression of T- and B cell responses. In the transcriptome cohort, 20 critically injured patients later developed MODS. Compared with the 16 patients who did not develop MODS (NoMODS), maximal differential expression was seen within the hyperacute window. In MODS versus NoMODS, 363 genes were differentially expressed on admission, compared to only 33 at 24 hours postinjury. MODS transcripts differentially expressed in the hyperacute window showed enrichment among diseases and biological functions associated with cell survival and organismal death rather than inflammatory pathways. There was differential up-regulation of NK cell signalling pathways and markers in patients who would later develop MODS, with down-regulation of neutrophil deconvolution markers. This study is limited by its sample size, precluding more detailed analyses of drivers of the hyperacute response and different MODS phenotypes, and requires validation in other critically injured cohorts. CONCLUSIONS: In this study, we showed how the hyperacute postinjury time window contained a focused, specific signature of the response to critical injury that led to widespread genomic activation. A transcriptomic signature for later development of MODS was present in this hyperacute window; it showed a strong signal for cell death and survival pathways and implicated NK cells and neutrophil populations in this differential response. PMID- 28715418 TI - Early-life family income and subjective well-being in adolescents. AB - PURPOSE: Subjective well-being (SWB) in youths positively relates to family income, however its association with income during childhood is unclear. Using longitudinal data from the US Panel Study of Income Dynamics (n = 2234 adolescents, age 12-19 years), we examined whether the timing and duration of low family income in childhood was associated with adolescent SWB. METHODS: We categorized family income during childhood into state-specific quintiles. Adolescent SWB was assessed using a 12-item questionnaire (score range 3-18). We used marginal structural modelling to test for sensitive periods of exposure to low income and tested cumulative effects of income by modelling the number of years spent in the poorest income quintiles. RESULTS: A period in early childhood (age 0-2 years) was particularly sensitive to low family income. Adolescent SWB was 1.65 (95% CI 0.40, 2.91) points lower in those who grew up in the poorest income quintiles during early childhood compared with the top quintile. Further, each childhood year spent in the poorest income quintiles was associated with a 0.10 point (95% CI 0.04, 0.16) lower SWB score in adolescence. CONCLUSIONS: The timing and duration of low family income in childhood both predict individual differences in adolescent SWB. Further studies are needed to clarify the mechanisms of these models and inform public policies. PMID- 28715419 TI - The T-cell leukemia related rpl10-R98S mutant traps the 60S export adapter Nmd3 in the ribosomal P site in yeast. AB - Mutations in the ribosomal protein Rpl10 (uL16) can be drivers of T-cell acute lymphoblastic leukemia (T-ALL). We previously showed that these T-ALL mutations disrupt late cytoplasmic maturation of the 60S ribosomal subunit, blocking the release of the trans-acting factors Nmd3 and Tif6 in S. cerevisiae. Consequently, these mutant ribosomes do not efficiently pass the cytoplasmic quality control checkpoint and are blocked from engaging in translation. Here, we characterize suppressing mutations of the T-ALL-related rpl10-R98S mutant that bypass this block and show that the molecular defect of rpl10-R98S is a failure to release Nmd3 from the P site. Suppressing mutations were identified in Nmd3 and Tif6 that disrupted interactions between Nmd3 and the ribosome, or between Nmd3 and Tif6. Using an in vitro system with purified components, we found that Nmd3 inhibited Sdo1-stimulated Efl1 activity on mutant rpl10-R98S but not wild-type 60S subunits. Importantly, this inhibition was overcome in vitro by mutations in Nmd3 that suppressed rpl10-R98S in vivo. These results strongly support a model that Nmd3 must be dislodged from the P site to allow Sdo1 activation of Efl1, and define a failure in the removal of Nmd3 as the molecular defect of the T-ALL associated rpl10-R98S mutation. PMID- 28715420 TI - Blood vessel tortuosity selects against evolution of aggressive tumor cells in confined tissue environments: A modeling approach. AB - Cancer is a disease of cellular regulation, often initiated by genetic mutation within cells, and leading to a heterogeneous cell population within tissues. In the competition for nutrients and growth space within the tumors the phenotype of each cell determines its success. Selection in this process is imposed by both the microenvironment (neighboring cells, extracellular matrix, and diffusing substances), and the whole of the organism through for example the blood supply. In this view, the development of tumor cells is in close interaction with their increasingly changing environment: the more cells can change, the more their environment will change. Furthermore, instabilities are also introduced on the organism level: blood supply can be blocked by increased tissue pressure or the tortuosity of the tumor-neovascular vessels. This coupling between cell, microenvironment, and organism results in behavior that is hard to predict. Here we introduce a cell-based computational model to study the effect of blood flow obstruction on the micro-evolution of cells within a cancerous tissue. We demonstrate that stages of tumor development emerge naturally, without the need for sequential mutation of specific genes. Secondly, we show that instabilities in blood supply can impact the overall development of tumors and lead to the extinction of the dominant aggressive phenotype, showing a clear distinction between the fitness at the cell level and survival of the population. This provides new insights into potential side effects of recent tumor vasculature normalization approaches. PMID- 28715421 TI - Statistical correction of the Winner's Curse explains replication variability in quantitative trait genome-wide association studies. AB - Genome-wide association studies (GWAS) have identified hundreds of SNPs responsible for variation in human quantitative traits. However, genome-wide significant associations often fail to replicate across independent cohorts, in apparent inconsistency with their apparent strong effects in discovery cohorts. This limited success of replication raises pervasive questions about the utility of the GWAS field. We identify all 332 studies of quantitative traits from the NHGRI-EBI GWAS Database with attempted replication. We find that the majority of studies provide insufficient data to evaluate replication rates. The remaining papers replicate significantly worse than expected (p < 10-14), even when adjusting for regression-to-the-mean of effect size between discovery- and replication-cohorts termed the Winner's Curse (p < 10-16). We show this is due in part to misreporting replication cohort-size as a maximum number, rather than per locus one. In 39 studies accurately reporting per-locus cohort-size for attempted replication of 707 loci in samples with similar ancestry, replication rate matched expectation (predicted 458, observed 457, p = 0.94). In contrast, ancestry differences between replication and discovery (13 studies, 385 loci) cause the most highly-powered decile of loci to replicate worse than expected, due to difference in linkage disequilibrium. PMID- 28715422 TI - Unraveling the genetic diversity and phylogeny of Leishmania RNA virus 1 strains of infected Leishmania isolates circulating in French Guiana. AB - INTRODUCTION: Leishmania RNA virus type 1 (LRV1) is an endosymbiont of some Leishmania (Vianna) species in South America. Presence of LRV1 in parasites exacerbates disease severity in animal models and humans, related to a disproportioned innate immune response, and is correlated with drug treatment failures in humans. Although the virus was identified decades ago, its genomic diversity has been overlooked until now. METHODOLOGY/PRINCIPLES FINDINGS: We subjected LRV1 strains from 19 L. (V.) guyanensis and one L. (V.) braziliensis isolates obtained from cutaneous leishmaniasis samples identified throughout French Guiana with next-generation sequencing and de novo sequence assembly. We generated and analyzed 24 unique LRV1 sequences over their full-length coding regions. Multiple alignment of these new sequences revealed variability (0.5% 23.5%) across the entire sequence except for highly conserved motifs within the 5' untranslated region. Phylogenetic analyses showed that viral genomes of L. (V.) guyanensis grouped into five distinct clusters. They further showed a species-dependent clustering between viral genomes of L. (V.) guyanensis and L. (V.) braziliensis, confirming a long-term co-evolutionary history. Noteworthy, we identified cases of multiple LRV1 infections in three of the 20 Leishmania isolates. CONCLUSIONS/SIGNIFICANCE: Here, we present the first-ever estimate of LRV1 genomic diversity that exists in Leishmania (V.) guyanensis parasites. Genetic characterization and phylogenetic analyses of these viruses has shed light on their evolutionary relationships. To our knowledge, this study is also the first to report cases of multiple LRV1 infections in some parasites. Finally, this work has made it possible to develop molecular tools for adequate identification and genotyping of LRV1 strains for diagnostic purposes. Given the suspected worsening role of LRV1 infection in the pathogenesis of human leishmaniasis, these data have a major impact from a clinical viewpoint and for the management of Leishmania-infected patients. PMID- 28715423 TI - Antibody trapping: A novel mechanism of parasite immune evasion by the trematode Echinostoma caproni. AB - BACKGROUND: Helminth infections are among the most prevalent neglected tropical diseases, causing an enormous impact in global health and the socioeconomic growth of developing countries. In this context, the study of helminth biology, with emphasis on host-parasite interactions, appears as a promising approach for developing new tools to prevent and control these infections. METHODS/PRINCIPAL FINDINGS: The role that antibody responses have on helminth infections is still not well understood. To go in depth into this issue, work on the intestinal helminth Echinostoma caproni (Trematoda: Echinostomatidae) has been undertaken. Adult parasites were recovered from infected mice and cultured in vitro. Double indirect immunofluorescence at increasing culture times was done to show that in vivo-bound surface antibodies become trapped within a layer of excretory/secretory products that covers the parasite. Entrapped antibodies are then degraded by parasite-derived proteases, since protease inhibitors prevent for antibody loss in culture. Electron microscopy and immunogold-labelling of secreted proteins provide evidence that this mechanism is consistent with tegument dynamics and ultrastructure, hence it is feasible to occur in vivo. Secretory vesicles discharge their content to the outside and released products are deposited over the parasite surface enabling antibody trapping. CONCLUSION/SIGNIFICANCE: At the site of infection, both parasite secretion and antibody binding occur simultaneously and constantly. The continuous entrapment of bound antibodies with newly secreted products may serve to minimize the deleterious effects of the antibody-mediated attack. This mechanism of immune evasion may aid to understand the limited effect that antibody responses have in helminth infections, and may contribute to the basis for vaccine development against these highly prevalent diseases. PMID- 28715424 TI - Atrophy of gluteus maximus among women with a history of chronic low back pain. AB - BACKGROUND: Although the relationship between low back pain (LBP) and the size of certain trunk muscles has been extensively studied, the relationship between gluteus maximus (GM) size and LBP has been only minimally examined. Determining whether such a relationship exists would help improve our understanding of the etiology of LBP, and possibly provide a rationale for the use of therapeutic exercise interventions targeting GM with LBP patients. The objective of this study was to compare gluteus maximus cross-sectional area in individuals with chronic LBP, and in a group of individuals without LBP. Our hypothesis was that individuals with LBP would have greater atrophy in their gluteus maximus muscles than our control group. MATERIALS AND METHODS: For this case-control study, we analyzed medical history and pelvic computed tomography (CT) scans for 36 female patients with a history of chronic LBP, and 32 female patients without a history of LBP. Muscle cross-sectional area of gluteus maximus was measured from axial CT scans using OsiriX MD software, then was normalized to patient height, and used to compare the two groups. The number of back pain-related medical visits was also correlated with gluteus maximus cross-sectional area. RESULTS: Mean normalized cross-sectional area was significantly smaller in the LBP group than in the control group, with t = 2.439 and P<0.05. The number of back pain-related visits was found to be significantly correlated with normalized cross-sectional area, with r = -0.270 and P<0.05. The atrophy seen in the present research may reflect incidental disuse atrophy seen with LBP, which is present in many muscle groups after prolonged immobilization or with a sedentary lifestyle. CONCLUSIONS: This research demonstrated a previously only minimally explored relationship between gluteus maximus cross-sectional area and LBP in women. Further research is indicated in individuals with varying age, sex, and LBP diagnoses. PMID- 28715425 TI - Elimination of huntingtin in the adult mouse leads to progressive behavioral deficits, bilateral thalamic calcification, and altered brain iron homeostasis. AB - Huntington's Disease (HD) is an autosomal dominant progressive neurodegenerative disorder characterized by cognitive, behavioral and motor dysfunctions. HD is caused by a CAG repeat expansion in exon 1 of the HD gene that is translated into an expanded polyglutamine tract in the encoded protein, huntingtin (HTT). While the most significant neuropathology of HD occurs in the striatum, other brain regions are also affected and play an important role in HD pathology. To date there is no cure for HD, and recently strategies aiming at silencing HTT expression have been initiated as possible therapeutics for HD. However, the essential functions of HTT in the adult brain are currently unknown and hence the consequence of sustained suppression of HTT expression is unpredictable and can potentially be deleterious. Using the Cre-loxP system of recombination, we conditionally inactivated the mouse HD gene homologue at 3, 6 and 9 months of age. Here we show that elimination of Htt expression in the adult mouse results in behavioral deficits, progressive neuropathological changes including bilateral thalamic calcification, and altered brain iron homeostasis. PMID- 28715426 TI - Community effectiveness of pyriproxyfen as a dengue vector control method: A systematic review. AB - BACKGROUND: Vector control is the only widely utilised method for primary prevention and control of dengue. The use of pyriproxyfen may be promising, and autodissemination approach may reach hard to reach breeding places. It offers a unique mode of action (juvenile hormone mimic) and as an additional tool for the management of insecticide resistance among Aedes vectors. However, evidence of efficacy and community effectiveness (CE) remains limited. OBJECTIVE: The aim of this systematic review is to compile and analyse the existing literature for evidence on the CE of pyriproxyfen as a vector control method for reducing Ae. aegypti and Ae. albopictus populations and thereby human dengue transmission. METHODS: Systematic search of PubMed, Embase, Lilacs, Cochrane library, WHOLIS, Web of Science, Google Scholar as well as reference lists of all identified studies. Removal of duplicates, screening of abstracts and assessment for eligibility of the remaining studies followed. Relevant data were extracted, and a quality assessment conducted. Results were classified into four main categories of how pyriproxyfen was applied: - 1) container treatment, 2) fumigation, 3) auto dissemination or 4) combination treatments,-and analysed with a view to their public health implication. RESULTS: Out of 745 studies 17 studies were identified that fulfilled all eligibility criteria. The results show that pyriproxyfen can be effective in reducing the numbers of Aedes spp. immatures with different methods of application when targeting their main breeding sites. However, the combination of pyriproxyfen with a second product increases efficacy and/or persistence of the intervention and may also slow down the development of insecticide resistance. Open questions concern concentration and frequency of application in the various treatments. Area-wide ultra-low volume treatment with pyriproxyfen currently lacks evidence and cannot be recommended. Community participation and acceptance has not consistently been successful and needs to be further assessed. While all studies measured entomological endpoints, only two studies measured the reduction in human dengue cases, with inconclusive results. CONCLUSIONS: Although pyriproxyfen is highly effective in controlling the immature stages of dengue transmitting mosquitoes, and-to a smaller degree-adult mosquitoes, there is weak evidence for a reduction of human dengue cases. More well designed larger studies with appropriate standardised outcome measures are needed before pyriproxyfen is incorporated in routine vector control programmes. Additionally, resistance to pyriproxyfen has been reported and needs investigation. PMID- 28715427 TI - Global analysis of DNA methylation in young (J1) and senescent (J2) Gossypium hirsutum L. cotyledons by MeDIP-Seq. AB - DNA methylation is an important epigenetic modification regulating gene expression, genomic imprinting, transposon silencing and chromatin structure in plants and plays an important role in leaf senescence. However, the DNA methylation pattern during Gossypium hirsutum L. cotyledon senescence is poorly understood. In this study, global DNA methylation patterns were compared between two cotyledon development stages, young (J1) and senescence (J2), using methylated DNA immunoprecipitation (MeDIP-Seq). Methylated cytosine occurred mostly in repeat elements, especially LTR/Gypsy in both J1 and J2. When comparing J1 against J2, there were 1222 down-methylated genes and 623 up-methylated genes. Methylated genes were significantly enriched in carbohydrate metabolism, biosynthesis of other secondary metabolites and amino acid metabolism pathways. The global DNA methylation level decreased from J1 to J2, especially in gene promoters, transcriptional termination regions and regions around CpG islands. We further investigated the expression patterns of 9 DNA methyltransferase associated genes and 2 DNA demethyltransferase-associated genes from young to senescent cotyledons, which were down-regulated during cotyledon development. In this paper, we first reported that senescent cotton cotyledons exhibited lower DNA methylation levels, primarily due to decreased DNA methyltransferase activity and which also play important role in regulating secondary metabolite process. PMID- 28715429 TI - A microscopic simulation model for pedestrian-pedestrian and pedestrian-vehicle interactions at crosswalks. AB - This study aims to develop a microscopic pedestrian behavior model considering various interactions on pedestrian dynamics at crosswalks. Particularly, we take into account the evasion behavior with counter-flow pedestrians, the following behavior with leader pedestrians, and the collision avoidance behavior with vehicles. Aerial video data at one intersection in Beijing, China are extracted for model calibration. A microscopic calibration approach based on maximum likelihood estimation is applied to estimate the parameters of a modified social force model. Finally, we validate step-wise speed, step-wise acceleration, step wise direction change, crossing time and lane formation phenomenon by comparing the real data and simulation outputs. PMID- 28715428 TI - Cip29 is phosphorylated following activation of the DNA damage response in Xenopus egg extracts. AB - Acting through a complex signalling network, DNA lesions trigger a range of cellular responses including DNA repair, cell cycle arrest, altered gene expression and cell death, which help to limit the mutagenic effects of such DNA damage. RNA processing factors are increasingly being recognised as important targets of DNA damage signalling, with roles in the regulation of gene expression and also more directly in the promotion of DNA repair. In this study, we have used a Xenopus laevis egg extract system to analyse the DNA damage-dependent phosphorylation of a putative RNA export factor, Cip29. We have found that Cip29 is rapidly phosphorylated in response to DNA double-strand breaks in this experimental system. We show that the DNA damage-inducible modification of Cip29 is dependent on the activity of the key double-strand break response kinase, ATM, and we have identified a conserved serine residue as a damage-dependent phosphorylation site. Finally, we have determined that Cip29 is not required for efficient DNA end-joining in egg extracts. Taken together, these data identify Cip29 as a novel target of the DNA damage response and suggest that the damage dependent modification of Cip29 may relate to a role in the regulation of gene expression after DNA damage. PMID- 28715430 TI - Resequencing and variation identification of whole genome of the japonica rice variety "Longdao24" with high yield. AB - Japonica rice mainly distributes in north of China, which accounts for more than half of the total japonica rice cultivated area of China. High yield, good grain quality and early heading date were the main breeding traits and commercial property in this region. We performed re-sequencing and genome wide variation analysis of one typical northern japonica rice variety Longdao24 and its parents (Longdao5 and Jigeng83) using the Illumina sequencing technology. 53.17 G clean bases were generated and more than 96.8% of the reads were mapped to the genomic reference sequence. An overall average effective depth of 43.67 * coverage was achieved. We identified 420,475 SNPs, 95,624 InDels, and 14,112 SVs in Longdao24 genome with the genomic sequence of the japonica cultivar Nipponbare as reference. We identified 361,117 SNPs and 81,488 InDels between Longdao24 genome and Longdao5 genome. We also detected 428,908 SNPs and 97,209 InDels between Longdao24 genome and Jigeng83 genome. Twenty-two yield related genes, twenty-two grain quality related genes and thirty-nine heading date genes were analyzed in Longdao24. The alleles of Gn1a, EP3, SCM2, Wx, ALK, OsLF and Hd17 came from the female parent Longdao5. The other alleles of qGW8, SSIVa, SBE3, SSIIIb, SSIIc, DTH2, Ehd3 and OsMADS56 came from the male parent Jigeng83. These results will help us to research the genetics basis of yield, grain quality and early heading date in northern rice of China. PMID- 28715431 TI - Colony Collapse Disorder (CCD) and bee age impact honey bee pathophysiology. AB - Honey bee (Apis mellifera) colonies continue to experience high annual losses that remain poorly explained. Numerous interacting factors have been linked to colony declines. Understanding the pathways linking pathophysiology with symptoms is an important step in understanding the mechanisms of disease. In this study we examined the specific pathologies associated with honey bees collected from colonies suffering from Colony Collapse Disorder (CCD) and compared these with bees collected from apparently healthy colonies. We identified a set of pathological physical characteristics that occurred at different rates in CCD diagnosed colonies prior to their collapse: rectum distension, Malpighian tubule iridescence, fecal matter consistency, rectal enteroliths (hard concretions), and venom sac color. The multiple differences in rectum symptomology in bees from CCD apiaries and colonies suggest effected bees had trouble regulating water. To ensure that pathologies we found associated with CCD were indeed pathologies and not due to normal changes in physical appearances that occur as an adult bee ages (CCD colonies are assumed to be composed mostly of young bees), we documented the changes in bees of different ages taken from healthy colonies. We found that young bees had much greater incidences of white nodules than older cohorts. Prevalent in newly-emerged bees, these white nodules or cellular encapsulations indicate an active immune response. Comparing the two sets of characteristics, we determined a subset of pathologies that reliably predict CCD status rather than bee age (fecal matter consistency, rectal distension size, rectal enteroliths and Malpighian tubule iridescence) and that may serve as biomarkers for colony health. In addition, these pathologies suggest that CCD bees are experiencing disrupted excretory physiology. Our identification of these symptoms is an important first step in understanding the physiological pathways that underlie CCD and factors impacting bee health. PMID- 28715432 TI - An efficacy analysis of whole-body magnetic resonance imaging in the diagnosis and follow-up of polymyositis and dermatomyositis. AB - OBJECTIVES: To evaluate the value of whole-body magnetic resonance imaging (WBMRI) in diagnosing muscular and extra muscular lesions in patients with polymyositis (PM) and dermatomyositis (DM). METHODS: A retrospective analysis of WBMRI data from PM/DM patients who met the Bohan and Peter diagnostic criteria was performed. X2 test was used to compare the rate of positive diagnosis of newly diagnosed patients using WBMRI, serum creatine kinase test, and EMG. McNemar test was used to compare the performance of WBMRI and chest CT in detecting interstitial lung disease (ILD). RESULTS: The study included 129 patients (30 PM cases and 99 DM cases). Of them, 81.4% (105/129) showed a visible inflammatory muscular edema on their WBMRI; 29.5% (38/129) had varying degrees of fatty infiltration (9 cases with clear muscular atrophy). Of the 66 newly diagnosed patients, the positive rates of WBMRI, muscle biopsy, serum creatine kinase test and EMG were 86.4% (57/66), 92.4% (61/66), 71.2% (47/66) and 71.1% (32/45), respectively. There was no significant difference in the positive rates between WBMRI and muscle biopsy (X2 = 1.28, P = 0.258). The WBMRI had a higher positive rate than both serum creatine kinase test (X2 = 4.53, P = 0.033) and EMG (X2 = 3.92, P = 0.047). In addition to muscular changes, WBMRI also detected interstitial lung disease (ILD) in 38 cases (29.5%), osteonecrosis in 15 cases (11.6%), and neoplastic lesions (5 malignant; 7 benign) in 12 cases (9.3%). Of the 61 patients who underwent routine chest CT examinations, the WBMRI and CT revealed ILD in 29 cases and 35 cases respectively. There was no significant difference in the sensitivity between WBMRI and CT (p = 0.146). CONCLUSIONS: WBMRI is a sensitive, non-invasive and efficient imaging method. It comprehensively displays the extent of muscular involvement in PM/DM patients, and it has the ability to diagnose other associated extra muscular diseases, such as ILD and systemic malignancy. WBMRI can also help screen steroid-induced osteonecrosis. PMID- 28715433 TI - What determines the preference for future living arrangements of middle-aged and older people in urban China? AB - OBJECTIVE: Living arrangements are important to the elderly. However, it is common for elderly parents in urban China to not have a living situation that they consider ideal. An understanding of their preferences assists us in responding to the needs of the elderly as well as in anticipating future long term care demands. The aim of this study is to provide a clear understanding of preferences for future living arrangements and their associated factors among middle-aged and older people in urban China. METHODS: Data were extracted from the CHARLS 2011-2012 national baseline survey of middle-aged and elderly people. In the 2011 wave of the CHARLS, a total of 17,708 individual participants (10,069 main respondents and 7,638 spouses) were interviewed; 2509 of the main respondents lived in urban areas. In this group, 41 people who were younger than 45 years old and 162 who had missing data in the variable "living arrangement preference" were excluded. Additionally, 42 people were excluded because they chose "other" for the variable "living arrangement preference" (which was a choice with no specific answer). Finally, a total of 2264 participants were included in our study. RESULTS: The most popular preference for future living arrangements was living close to their children in the same community/neighborhoods, followed by living with adult children. The degree of community handicapped access, number of surviving children, age, marital status, access to community-based elderly care centers and number of years lived in the same community were significantly associated with the preferences for future living arrangements among the respondents. CONCLUSION: There is a trend towards preference for living near adult children in urban China. Additionally, age has a positive effect on preference for living close to their children. Considerations should be made in housing design and urban community development plans to fulfill older adults' expectations. In addition, increasing the accessibility of public facilities in the residential area was important to the elderly, especially for those who preferred living in proximity to their children rather than co-residing with their children. We found that more surviving children were associated with a lower likelihood of choosing "institutionalization", and it positively contributed to preference for intergenerational living arrangements in our study. As expected, compared with their married counterparts, people who were separated/divorced/widowed preferred living with adult children rather than living independently. A relatively shorter length of residence in the same community was an important indicator of preference for independent living; this finding might require further research. PMID- 28715434 TI - Engineered extracellular matrices with controlled mechanics modulate renal proximal tubular cell epithelialization. AB - Acute kidney injury (AKI) is common and associated with significant morbidity and mortality. Recovery from many forms of AKI involves the proliferation of renal proximal tubular epithelial cells (RPTECs), but the influence of the microenvironment in which this recovery occurs remains poorly understood. Here we report the development of a poly(ethylene glycol) (PEG) hydrogel platform to study the influence of substrate mechanical properties on the proliferation of human RPTECs as a model for recovery from AKI. PEG diacrylate based hydrogels were generated with orthogonal control of mechanics and cell-substrate interactions. Using this platform, we found that increased substrate stiffness promotes RPTEC spreading and proliferation. RPTECs showed similar degrees of apoptosis and Yes-associated protein (YAP) nuclear localization regardless of stiffness, suggesting these were not key mediators of the effect. However, focal adhesion formation, cytoskeletal organization, focal adhesion kinase (FAK) activation, and extracellular signal-regulated kinase (ERK) activation were all enhanced with increasing substrate stiffness. Inhibition of ERK activation substantially attenuated the effect of stiffness on proliferation. In long-term culture, hydrogel stiffness promoted the formation of more complete epithelial monolayers with tight junctions, cell polarity, and an organized basement membrane. These data suggest that increased stiffness potentially may have beneficial consequences for the renal tubular epithelium during recovery from AKI. PMID- 28715435 TI - Spatial patterns of dengue cases in Brazil. AB - Dengue infection plays a central role in our society, since it is the most prevalent vector-borne viral disease affecting humans. We statistically investigated patterns concerning the spatial spreading of dengue epidemics in Brazil, as well as their temporal evolution in all Brazilian municipalities for a period of 12 years. We showed that the distributions of cases in municipalities follow power laws persistent in time and that the infection scales linearly with the population of the municipalities. We also found that the average number of dengue cases does not have a clear dependence on the longitudinal position of municipalities. On the other hand, we found that the average distribution of cases varies with the latitudinal position of municipalities, displaying an almost constant growth from high latitudes until reaching the Tropic of Capricorn leveling to a plateau closer to the Equator. We also characterized the spatial correlation of the number of dengue cases between pairs of municipalities, where our results showed that the spatial correlation function decays with the increase of distance between municipalities, following a power-law with an exponential cut off. This regime leads to a typical dengue traveling distance. Finally, we considered modeling this last behaviour within the framework of a Edwards Wilkinson equation with a fractional derivative on space. PMID- 28715436 TI - Use of water turnover method to measure mother's milk flow in a rat model: Application to dams receiving a low protein diet during gestation and lactation. AB - Assessment of milk production is of utmost relevance for pediatricians and scientists interested in early life nutrition. The weight-suckle-weight (WSW) method, which consists of weighing babies before and after they suckle their mother, uses the difference in body weight as an estimate of milk intake. However, this is prone to many sources of error. In the current study, we used for the first time the water turnover method and compartmental analysis with deuterated water (D2O) as a non-toxic tracer to quantify in vivo milk production in a rat model. We assessed the effect of a nutritional intervention presumed to affect milk production, a maternal dietary protein restriction during gestation and lactation, which results in the birth of pups with intrauterine growth restriction. The specific aim of this study was to determine milk production with the body water turnover method in rat dams receiving during gestation and lactation, either a control diet (NP) or an iso-caloric low-protein diet (LP). In NP dams, mass of dam's total body water, output flow constant from dam to litter (K21) and median milk flow, calculated between days 11 to 14 after pup birth, were 282.1 g, 0.0122 h-1 and 3.30 g/h for NP dams, respectively. Maternal dietary protein restriction (-59%) during perinatal period led to a 34% reduction in milk flow (NP versus LP). With the WSW method, milk flow varied from 1.96 g/h to 2.37 g/h between days 11 to 14 for NP dams. The main advantage of the D20 method compared to the WSW method stems from its higher precision, as attested by the narrowest range of measured values of milk flow ([2.90; 3.75] and [0.98; 6.85] g/h, respectively) for NP group. This method could be suitable for testing the effectiveness of candidate galactologue molecules presumed to enhance milk production in the lactating rat model. PMID- 28715437 TI - High systemic IL-6 is associated with worse prognosis in patients with non-small cell lung cancer. AB - Characteristic cytokine patterns have been described in different cancer patients and they are related to their diagnosis, prognosis, prediction of treatment responses and survival. A panel of cytokines was evaluated in the plasma of non small cell lung cancer (NSCLC) patients and healthy controls to investigate their profile and relationship with clinical characteristics and overall survival. The case-controlled cross-sectional study design recruited 77 patients with confirmed diagnosis of NSCLC (cases) and 91 healthy subjects (controls) aimed to examine peripheral pro-inflammatory and anti-inflammatory cytokines (IL-2, IL-4, IL-6, IL 10, IL-17A, TNF and IFN-gamma) by Cytometry Beads Arrays (CBA Flex) in. The cytokine IL-6 showed a statistically significant difference among groups with increased expression in the case group (p < 0.001). The correlation between the cytokines expression with patient's clinical characteristics variables revealed the cytokine IL-6 was found to be associated with gender, showing higher levels in male (p = 0.036), whereas IL-17A levels were associated with TNM stage, being higher in III-IV stages (p = 0.044). We observed worse overall survival for individuals with high levels of IL-6 when compared to those with low levels of this cytokine in 6, 12 and 24 months. Further studies of IL-6 levels in independent cohort could clarify the real role of IL-6 as an independent marker of prognostic of NSCLC. PMID- 28715438 TI - A sequence level model of an intact locus predicts the location and function of nonadditive enhancers. AB - Metazoan gene expression is controlled through the action of long stretches of noncoding DNA that contain enhancers-shorter sequences responsible for controlling a single aspect of a gene's expression pattern. Models built on thermodynamics have shown how enhancers interpret protein concentration in order to determine specific levels of gene expression, but the emergent regulatory logic of a complete regulatory locus shows qualitative and quantitative differences from isolated enhancers. Such differences may arise from steric competition limiting the quantity of DNA that can simultaneously influence the transcription machinery. We incorporated this competition into a mechanistic model of gene regulation, generated efficient algorithms for this computation, and applied it to the regulation of Drosophila even-skipped (eve). This model finds the location of enhancers and identifies which factors control the boundaries of eve expression. This model predicts a new enhancer that, when assayed in vivo, drives expression in a non-eve pattern. Incorporation of chromatin accessibility eliminates this inconsistency. PMID- 28715439 TI - Knowledge, attitude and perceived stigma towards tuberculosis among pastoralists; Do they differ from sedentary communities? A comparative cross-sectional study. AB - BACKGROUND: Ethiopia is ninth among the world high tuberculosis (TB) burden countries, pastoralists being the most affected population. However, there is no published report whether the behavior related to TB are different between pastoralist and the sedentary communities. Therefore, the main aim of this study is to assess the pastoralist community knowledge, attitude and perceived stigma towards tuberculosis and their health care seeking behavior in comparison to the neighboring sedentary communities and this may help to plan TB control interventions specifically for the pastoralist communities. METHOD: A community based cross-sectional survey was carried out from September 2014 to January 2015, among 337 individuals from pastoralist and 247 from the sedentary community of Kereyu district. Data were collected using structured questionnaires. Three focus group discussions were used to collect qualitative data, one with men and the other with women in the pastoralist and one with men in the sedentary groups. Data were analyzed using Statistical Software for Social Science, SPSS V 22 and STATA. RESULTS: A Lower proportion of pastoralists mentioned bacilli (bacteria) as the cause of PTB compared to the sedentary group (63.9% vs. 81.0%, p<0.01), respectively. However, witchcraft was reported as the causes of TB by a higher proportion of pastoralists than the sedentary group (53.6% vs.23.5%, p<0.01), respectively. Similarly, a lower proportion of pastoralists indicated PTB is preventable compared to the sedentary group (95.8% vs. 99.6%, p<0.01), respectively. Moreover, majority of the pastoralists mentioned that most people would reject a TB patient in their community compared to the sedentary group (39.9% vs. 8.9%, p<0.001), respectively, and the pastoralists expressed that they would be ashamed/embarrassed if they had TB 68% vs.36.4%, p<0.001), respectively. CONCLUSION: The finding indicates that there is a lower awareness about TB, a negative attitude towards TB patients and a higher perceived stigma among pastoralists compared to their neighbor sedentary population. Strategic health communications pertinent to the pastoralists way of life should be planned and implemented to improve the awareness gap about tuberculosis. PMID- 28715440 TI - Transcriptional profiling of the rat nucleus accumbens after modest or high alcohol exposure. AB - Alcohol use disorder is a chronic relapsing brain disorder and a global health issue. Prolonged high alcohol consumption increases the risk for dependence development, a complex state that includes progressive alterations in brain function. The molecular mechanisms behind these changes remain to be fully disclosed, but several genes show altered expression in various regions of the rat brain even after modest alcohol exposure. The present study utilizes whole transcriptome sequencing (RNA-seq) to investigate expression changes in the brain nucleus accumbens (NAc), an area of particular interest in addictive disorders, of alcohol consuming rats. The impact on gene expression after eight weeks of moderate voluntary alcohol consumption or voluntary consumption combined with forced excessive exposure was explored in two separate experiments. The results point to a lack of strong and consistent expression alterations in the NAc after alcohol exposure, suggesting that transcriptional effects of alcohol are weak or transient, or occur primarily in brain regions other than NAc. PMID- 28715441 TI - MRI-based patient-specific human carotid atherosclerotic vessel material property variations in patients, vessel location and long-term follow up. AB - BACKGROUND: Image-based computational models are widely used to determine atherosclerotic plaque stress/strain conditions and investigate their association with plaque progression and rupture. However, patient-specific vessel material properties are in general lacking in those models, limiting the accuracy of their stress/strain measurements. A noninvasive approach of combining in vivo 3D multi contrast and Cine magnetic resonance imaging (MRI) and computational modeling was introduced to quantify patient-specific carotid plaque material properties for potential plaque model improvements. Vessel material property variation in patients, along vessel segment, and between baseline and follow up were investigated. METHODS: In vivo 3D multi-contrast and Cine MRI carotid plaque data were acquired from 8 patients with follow-up (18 months) with written informed consent obtained. 3D thin-layer models and an established iterative procedure were used to determine parameter values of the Mooney-Rivlin models for the 81slices from 16 plaque samples. Effective Young's Modulus (YM) values were calculated for comparison and analysis. RESULTS: Average Effective Young's Modulus (YM) and circumferential shrinkage rate (C-Shrink) value of the 81 slices was 411kPa and 5.62%, respectively. Slice YM value varied from 70 kPa (softest) to 1284 kPa (stiffest), a 1734% difference. Average slice YM values by vessel varied from 109 kPa (softest) to 922 kPa (stiffest), a 746% difference. Location wise, the maximum slice YM variation rate within a vessel was 311% (149 kPa vs. 613 kPa). The average slice YM variation rate for the 16 vessels was 134%. The average variation of YM values for all patients from baseline to follow up was 61.0%. The range of the variation of YM values was [-28.4%, 215%]. For plaque progression study, YM at follow-up showed negative correlation with plaque progression measured by wall thickness increase (WTI) (r = -0.7764, p = 0.0235). Wall thickness at baseline correlated with WTI negatively, with r = -0.5253 (p = 0.1813). Plaque burden at baseline correlated with YM change between baseline and follow-up, with r = 0.5939 (p = 0.1205). CONCLUSION: In vivo carotid vessel material properties have large variations from patient to patient, along the diseased segment within a patient, and with time. The use of patient-specific, location specific and time-specific material properties in plaque models could potentially improve the accuracy of model stress/strain calculations. PMID- 28715442 TI - Combining random forest with multi-block local binary pattern feature selection for multiclass head pose estimation. AB - A new head pose estimation technique based on Random Forest (RF) and texture features for facial image analysis using a monocular camera is proposed in this paper, especially about how to efficiently combine the random forest and the features. In the proposed technique a randomized tree with useful attributes is trained to improve estimation accuracy and tolerance of occlusions and illumination. Specifically, a number of features including Multi-scale Block Local Block Pattern (MB-LBP) are extracted from an image, and random features such as the MB-LBP scale parameters, a block coordinate, and a layer of an image pyramid in the feature pool are used for training the tree. The randomized tree aims to maximize the information gain at each node while random samples traverse the nodes in the tree. To this aim, a split function considering the uniform property of the LBP feature is developed to move sample blocks to the left or the right children nodes. The trees are independently trained with random inputs, yet they are grouped to form a random forest so that the results collected from the trees are used for make the final decision. Precisely, we use a Maximum-A Posteriori criterion in the decision. It is demonstrated with experimental results that the proposed technique provides significantly enhanced classification performance in the head pose estimation in various conditions of illumination, poses, expressions, and facial occlusions. PMID- 28715443 TI - Far infrared radiation promotes rabbit renal proximal tubule cell proliferation and functional characteristics, and protects against cisplatin-induced nephrotoxicity. AB - Far infrared radiation, a subdivision of the electromagnetic spectrum, is beneficial for long-term tissue healing, anti-inflammatory effects, growth promotion, sleep modulation, acceleration of microcirculation, and pain relief. We investigated if far infrared radiation is beneficial for renal proximal tubule cell cultivation and renal tissue engineering. We observed the effects of far infrared radiation on renal proximal tubules cells, including its effects on cell proliferation, gene and protein expression, and viability. We also examined the protective effects of far infrared radiation against cisplatin, a nephrotoxic agent, using the human proximal tubule cell line HK-2. We found that daily exposure to far infrared radiation for 30 min significantly increased rabbit renal proximal tubule cell proliferation in vitro, as assessed by MTT assay. Far infrared radiation was not only beneficial to renal proximal tubule cell proliferation, it also increased the expression of ATPase Na+/K+ subunit alpha 1 and glucose transporter 1, as determined by western blotting. Using quantitative polymerase chain reaction, we found that far infrared radiation enhanced CDK5R1, GNAS, NPPB, and TEK expression. In the proximal tubule cell line HK-2, far infrared radiation protected against cisplatin-mediated nephrotoxicity by reducing apoptosis. Renal proximal tubule cell cultivation with far infrared radiation exposure resulted in better cell proliferation, significantly higher ATPase Na+/K+ subunit alpha 1 and glucose transporter 1 expression, and significantly enhanced expression of CDK5R1, GNAS, NPPB, and TEK. These results suggest that far infrared radiation improves cell proliferation and differentiation. In HK-2 cells, far infrared radiation mediated protective effects against cisplatin-induced nephrotoxicity by reducing apoptosis, as indicated by flow cytometry and caspase-3 assay. PMID- 28715444 TI - Pyrrolidine dithiocarbamate ameliorates endothelial dysfunction in thoracic aorta of diabetic rats by preserving vascular DDAH activity. AB - OBJECTIVE: Endothelial dysfunction plays a pivotal role in the development of diabetic cardiovascular complications. Accumulation of endogenous nitric oxide synthase (NOS) inhibitor asymmetric dimethylarginine (ADMA) and inhibition of dimethylarginine dimethylaminohydrolase (DDAH) activity have been involved in diabetic endothelial dysfunction. This study was to investigate the effect of pyrrolidine dithiocarbamate (PDTC) on impairment of endothelium-dependent vasodilatation in diabetic rats and its potential mechanism. METHODS: Diabetic rats were induced by a single intraperitoneal injection of streptozotocin (60mg/kg), and PDTC (10mg/kg) was given in drinking water for 8 weeks. Blood glucose and serum ADMA concentrations were measured in experimental rats. Recombinant adenovirus encoding human DDAH2 gene were constructed and ex vivo transferred to isolated rat aortas. The maximal relaxation (Emax) and half maximal effective concentration (EC50) of aortic rings response to accumulative concentrations of acetylcholine and vascular DDAH activity were examined before and after gene transfection. RESULTS: Diabetic rats displayed significant elevations of blood glucose and serum ADMA levels compared to control group (P<0.01). Vascular DDAH activity and endothelium-dependent relaxation of aortas were inhibited, as expressed by the decreased Emax and increased EC50 in diabetic rats compared to control rats (P<0.01). Treatment with PDTC not only decreased blood glucose and serum ADMA concentration (P<0.01) but also restored vascular DDAH activity and endothelium-dependent relaxation, evidenced by the higher Emax and lower EC50 in PDTC-treated diabetic rats compared to untreated diabetic rats (P<0.01). Similar restoration of Emax, EC50 and DDAH activity were observed in diabetic aortas after DDAH2-gene transfection. CONCLUSIONS: These results indicate that PDTC could ameliorate impairment of endothelium-dependent relaxation in diabetic rats. The underlying mechanisms might be related to preservation of vascular DDAH activity and consequent reduction of endogenous ADMA in endothelium via its antioxidant action. This study highlights the therapeutic potential of PDTC in impaired vasodilation and provides a new strategy for treatment of diabetic cardiovascular complications. PMID- 28715445 TI - Cytological diagnostic features of late breast implant seromas: From reactive to anaplastic large cell lymphoma. AB - Late breast implant seroma may be the presentation of a breast implant-associated anaplastic large cell lymphoma (BI-ALCL), which claims for a prompt recognition. However, BI-ALCL diagnosis on fine-needle aspiration (FNA) might be challenging for pathologists lacking experience with peri-implant breast effusions. Sixty seven late breast implant seromas collected by FNA from 50 patients were evaluated by Papanicolaou smear stain and immunocytochemistry on cell blocks. A diagnostic algorithm based on the cellular composition, cell morphology and percentage of CD30+ cells was developed. Histological evaluation of the corresponding peri-prosthetic capsules was also performed. Most of the effusions (91% of the samples) were classified as reactive and 9% as BI-ALCL. In the BI ALCL cases, medium-to-large atypical cells expressing CD30 represented more than 70% of the cellularity, whereas in in the reactive effusions CD30+ elements were extremely rare (<5%) and consisted of non-atypical elements. The reactive effusions were categorized into three patterns: i) acute infiltrate with prominent neutrophilic component (33% of the samples); ii) mixed infiltrate characterized by a variable number of neutrophils, lymphocytes and macrophages (30% of the samples); iii) chronic infiltrate composed predominantly of T lymphocytes or macrophages with only sporadic granulocytes (37% of the samples). The inflammatory cytological patterns were consistent with the histology of the corresponding capsules. Our results indicate that cytological analysis of late breast implant effusions, supported by the knowledge of the heterogeneous cytomorphological spectrum of late seromas, is a valuable approach for the early recognition of BI-ALCL. PMID- 28715446 TI - Active subfractions of Abelmoschus esculentus substantially prevent free fatty acid-induced beta cell apoptosis via inhibiting dipeptidyl peptidase-4. AB - Lipotoxicity plays an important role in exacerbating type 2 diabetes mellitus (T2DM) and leads to apoptosis of beta cells. Recently dipeptidyl peptidase-4 (DPP 4) inhibitors have emerged as a useful tool in the treatment of T2DM. DPP-4 degrades type 1 glucagon-like peptide (GLP-1), and GLP-1 receptor (GLP-1R) signaling has been shown to protect beta cells by modulating AMPK/mTOR, PI3K, and Bax. The anti-hyperglycemic effect of Abelmoschus esculentus (AE) is well known, however its mucilage makes it difficult to further examine this effect. In our recent report, a sequence of extraction steps was used to obtain a series of subfractions from AE, each with its own composition and property. Among them F1 (rich in quercetin glucosides and pentacyclic triterpene ester) and F2 (containing large amounts of carbohydrates and polysaccharides) were found to be especially effective in attenuating DPP-4 signaling, and to have the potential to counter diabetic nephropathy. Hence, the aim of the present study was to investigate whether AE subfractions can prevent the palmitate-induced apoptosis of beta cells, and the putative signals involved. We demonstrated that AE, and especially 1 MUg/mL of F2, decreased palmitate-induced apoptosis analyzed by flow cytometry. The result of western blot revealed that palmitate-induced decrease in GLP-1R and increase in DPP-4 were restored by F1 and F2. The DPP-4 inhibitor linagliptin decreased the expression of caspase 3, suggesting that DPP-4 is critically involved in apoptotic signaling. Analysis of enzyme activity revealed that palmitate increased the activity of DPP4 nearly 2 folds, while F2 especially inhibited the activation. In addition, AMPK/mTOR, PI3K and mitochondrial pathways were regulated by AE, and this attenuated the palmitate-induced signaling cascades. In conclusion, AE is useful to prevent the exacerbation of beta cell apoptosis, and it could potentially be used as adjuvant or nutraceutical therapy for diabetes. PMID- 28715447 TI - Short-term alteration of biotic and abiotic components of the pelagic system in a shallow bay produced by a strong natural hypoxia event. AB - In January 2008 there was an intensive and extensive upwelling event in the southern Humboldt Current System. This event produced an intrusion of water with low dissolved oxygen into Coliumo Bay, which caused massive mortality and the beaching of pelagic and benthic organisms, including zooplankton. During this event, which lasted 3 to 5 days, we studied and evaluated the effect of the hypoxic water in the bay on the abundance of macrozooplankton, nanoplankton and microphytoplankton, the concentration of several nutrients and hydrographic conditions. At the beginning of the hypoxia event the water column had very low dissolved oxygen concentrations (<0.5 mL O2 L-1), low temperatures and high salinity which are characteristics of the oxygen minimum zone from the Humboldt Current System. Redox, pH, nitrate, phosphate, silicate and chlorophyll-a values were the lowest, while nitrate and the phaeopigment values were the highest. The N:P ratio was below 16, and the abundance of nano- and microphytoplankton were at their lowest, the latter also with the lowest proportion of live organisms. Macrozooplankton had the greatest abundance during hypoxia, dominated mainly by crustacean, fish eggs and amphipods. The hypoxia event generated a strong short term alteration of all biotic and abiotic components of the pelagic system in Coliumo Bay and the neighboring coastal zone. These negative effects associated with strong natural hypoxia events could have important consequences for the productivity and ecosystem functioning of the coastal zone of the Humboldt Current System if, as suggested by several models, winds favorable to upwelling should increase due to climate change. The effects of natural hypoxia in this coastal zone can be dramatic especially for pelagic and benthic species not adapted to endure conditions of low dissolved oxygen. PMID- 28715448 TI - Effect of synergistic interaction between abnormal adiposity-related metabolism and prediabetes on microalbuminuria in the general population. AB - Central obesity and related metabolic components are important risks for microalbuminuria. To describe the effects of interactions between central obesity and related metabolic components on microalbuminuria, we conducted a nation-wide, population-based interaction analysis using cardio-metabolic index (CMI) as a candidate indicator of central obesity and related abnormal lipid metabolism. We recruited native Koreans aged 20 years or older with no medical illness. A total of 5398 participants were divided into quintiles according to CMI with sex as a covariate factor. Participants in the highest CMI quintile had elevated blood pressure (BP), increased glycemic exposure, poor lipid profile, and increased urine albumin-to-creatinine ratio compared to other lower quintiles. Multiple logistic regression models adjusted for age, sex, systolic BP, and diastolic BP showed that CMI had an independent association with increased glycemic exposure and increased urine albumin-to-creatinine ratio. Our interaction analysis revealed a significant interaction between the highest CMI quintile and prediabetes with an increased risk of microalbuminuria (adjusted RERI = 0.473, 95% CI = 0.464-0.482; adjusted AP = 0.276, 95% CI = 0.156-0.395; adjusted SI = 2.952, 95% CI = 1.234-4.670). Our findings suggest a significant association between central obesity-related abnormal lipid metabolism and prediabetes, and their interaction may exert a synergistic effect on renal vascular endothelial dysfunction even before the appearance of full-blown diabetes mellitus. To confirm these findings, large population-based prospective studies are needed. PMID- 28715449 TI - A unique enhancer boundary complex on the mouse ribosomal RNA genes persists after loss of Rrn3 or UBF and the inactivation of RNA polymerase I transcription. AB - Transcription of the several hundred of mouse and human Ribosomal RNA (rRNA) genes accounts for the majority of RNA synthesis in the cell nucleus and is the determinant of cytoplasmic ribosome abundance, a key factor in regulating gene expression. The rRNA genes, referred to globally as the rDNA, are clustered as direct repeats at the Nucleolar Organiser Regions, NORs, of several chromosomes, and in many cells the active repeats are transcribed at near saturation levels. The rDNA is also a hotspot of recombination and chromosome breakage, and hence understanding its control has broad importance. Despite the need for a high level of rDNA transcription, typically only a fraction of the rDNA is transcriptionally active, and some NORs are permanently silenced by CpG methylation. Various chromatin-remodelling complexes have been implicated in counteracting silencing to maintain rDNA activity. However, the chromatin structure of the active rDNA fraction is still far from clear. Here we have combined a high-resolution ChIP Seq protocol with conditional inactivation of key basal factors to better understand what determines active rDNA chromatin. The data resolve questions concerning the interdependence of the basal transcription factors, show that preinitiation complex formation is driven by the architectural factor UBF (UBTF) independently of transcription, and that RPI termination and release corresponds with the site of TTF1 binding. They further reveal the existence of an asymmetric Enhancer Boundary Complex formed by CTCF and Cohesin and flanked upstream by phased nucleosomes and downstream by an arrested RNA Polymerase I complex. We find that the Enhancer Boundary Complex is the only site of active histone modification in the 45kbp rDNA repeat. Strikingly, it not only delimits each functional rRNA gene, but also is stably maintained after gene inactivation and the re-establishment of surrounding repressive chromatin. Our data define a poised state of rDNA chromatin and place the Enhancer Boundary Complex as the likely entry point for chromatin remodelling complexes. PMID- 28715450 TI - African genetic ancestry interacts with body mass index to modify risk for uterine fibroids. AB - Race, specifically African ancestry, and obesity are important risk factors for uterine fibroids, and likely interact to provide the right conditions for fibroid growth. However, existing studies largely focus on the main-effects rather than their interaction. Here, we firstly provide evidence for interaction between categories of body mass index (BMI) and reported-race in relation to uterine fibroids. We then investigate whether the association between inferred local European ancestry and fibroid risk is modified by BMI in African American (AA) women in the Vanderbilt University Medical Center bio-repository (BioVU) (539 cases and 794 controls) and the Coronary Artery Risk Development in Young Adults study (CARDIA, 264 cases and 173 controls). We used multiple logistic regression to evaluate interactions between local European ancestry and BMI in relation to fibroid risk, then performed fixed effects meta-analysis. Statistical significance threshold for local-ancestry and BMI interactions was empirically estimated with 10,000 permutations (p-value = 1.18x10-4). Admixture mapping detected an association between European ancestry and fibroid risk which was modified by BMI (continuous-interaction p-value = 3.75x10-5) around ADTRP (chromosome 6p24); the strongest association was found in the obese category (ancestry odds ratio (AOR) = 0.51, p-value = 2.23x10-5). Evaluation of interaction between genotyped/imputed variants and BMI in this targeted region suggested race-specific interaction, present in AAs only; strongest evidence was found for insertion/deletion variant (6:11946435), again in the obese category (OR = 1.66, p-value = 1.72x10-6). We found nominal evidence for interaction between local ancestry and BMI at a previously reported region in chromosome 2q31 32, which includes COL5A2, and TFPI, an immediate downstream target of ADTRP. Interactions between BMI and SNPs (single nucleotide polymorphisms) found in this region in AA women were also detected in an independent European American population of 1,195 cases and 1,164 controls. Findings from our study provide an example of how modifiable and non-modifiable factors may interact to influence fibroid risk and suggest a biological role for BMI in fibroid etiology. PMID- 28715451 TI - Transcriptome analysis of the sea cucumber (Apostichopus japonicus) with variation in individual growth. AB - The sea cucumber (Apostichopus japonicus) is an economically important aquaculture species in China. However, the serious individual growth variation often caused financial losses to farmers and the genetic mechanisms are poorly understood. In the present study, the extensively analysis at the transcriptome level for individual growth variation in sea cucumber was carried out. A total of 118946 unigenes were assembled from 255861 transcripts, with N50 of 1700. Of all unigenes, about 23% were identified with at least one significant match to known databases. In all four pair of comparison, 1840 genes were found to be expressed differently. Global hypometabolism was found to be occurred in the slow growing population, based on which the hypothesis was raised that growth retardation in individual growth variation of sea cucumber is one type of dormancy which is used to be against to adverse circumstances. Besides, the pathways such as ECM receptor interaction and focal adhesion were enriched in the maintenance of cell and tissue structure and communication. Further, 76645 SSRs, 765242 SNPs and 146886 ins-dels were detected in the current study providing an extensive set of data for future studies of genetic mapping and selective breeding. In summary, these results will provides deep insight into the molecular basis of individual growth variation in marine invertebrates, and be valuable for understanding the physiological differences of growth process. PMID- 28715452 TI - Including irrigation in niche modelling of the invasive wasp Vespula germanica (Fabricius) improves model fit to predict potential for further spread. AB - The European wasp, Vespula germanica (Fabricius) (Hymenoptera: Vespidae), is of Palaearctic origin, being native to Europe, northern Africa and Asia, and introduced into North America, Chile, Argentina, Iceland, Ascension Island, South Africa, Australia and New Zealand. Due to its polyphagous nature and scavenging behaviour, V. germanica threatens agriculture and silviculture, and negatively affects biodiversity, while its aggressive nature and venomous sting pose a health risk to humans. In areas with warmer winters and longer summers, queens and workers can survive the winter months, leading to the build-up of large nests during the following season; thereby increasing the risk posed by this species. To prevent or prepare for such unwanted impacts it is important to know where the wasp may be able to establish, either through natural spread or through introduction as a result of human transport. Distribution data from Argentina and Australia, and seasonal phenology data from Argentina were used to determine the potential distribution of V. germanica using CLIMEX modelling. In contrast to previous models, the influence of irrigation on its distribution was also investigated. Under a natural rainfall scenario, the model showed similarities to previous models. When irrigation is applied, dry stress is alleviated, leading to larger areas modelled climatically suitable compared with previous models, which provided a better fit with the actual distribution of the species. The main areas at risk of invasion by V. germanica include western USA, Mexico, small areas in Central America and in the north-western region of South America, eastern Brazil, western Russia, north-western China, Japan, the Mediterranean coastal regions of North Africa, and parts of southern and eastern Africa. PMID- 28715453 TI - Effects of glucose, insulin, and insulin resistance on cerebral 18F-FDG distribution in cognitively normal older subjects. AB - BACKGROUND: Increasing plasma glucose levels and insulin resistance can alter the distribution pattern of fluorine-18-labeled fluorodeoxyglucose (18F-FDG) in the brain and relatively reduce 18F-FDG uptake in Alzheimer's disease (AD)-related hypometabolic regions, leading to the appearance of an AD-like pattern. However, its relationship with plasma insulin levels is unclear. We aimed to compare the effects of plasma glucose levels, plasma insulin levels and insulin resistance on the appearance of the AD-like pattern in 18F-FDG images. METHODS: Fifty-nine cognitively normal older subjects (age = 75.7 +/- 6.4 years) underwent 18F-FDG positron emission tomography along with measurement of plasma glucose and insulin levels. As an index of insulin resistance, the Homeostasis model assessment of Insulin Resistance (HOMA-IR) was calculated. RESULTS: Plasma glucose levels, plasma insulin levels, and HOMA-IR were 102.2 +/- 8.1 mg/dL, 4.1 +/- 1.9 MUU/mL, and 1.0 +/- 0.5, respectively. Whole-brain voxelwise analysis showed a negative correlation of 18F-FDG uptake with plasma glucose levels in the precuneus and lateral parietotemporal regions (cluster-corrected p < 0.05), and no correlation with plasma insulin levels or HOMA-IR. In the significant cluster, 18F-FDG uptake decreased by approximately 4-5% when plasma glucose levels increased by 20 mg/dL. In the precuneus region, volume-of-interest analysis confirmed a negative correlation of 18F-FDG uptake with plasma glucose levels (r = -0.376, p = 0.002), and no correlation with plasma insulin levels (r = 0.156, p = 0.12) or HOMA-IR (r = 0.096, p = 0.24). CONCLUSION: This study suggests that, of the three parameters, plasma glucose levels have the greatest effect on the appearance of the AD-like pattern in 18F-FDG images. PMID- 28715454 TI - Reduction of Cav1.3 channels in dorsal hippocampus impairs the development of dentate gyrus newborn neurons and hippocampal-dependent memory tasks. AB - Cav1.3 has been suggested to mediate hippocampal neurogenesis of adult mice and contribute to hippocampal-dependent learning and memory processes. However, the mechanism of Cav1.3 contribution in these processes is unclear. Here, roles of Cav1.3 of mouse dorsal hippocampus during newborn cell development were examined. We find that knock-out (KO) of Cav1.3 resulted in the reduction of survival of newborn neurons at 28 days old after mitosis. The retroviral eGFP expression showed that both dendritic complexity and the number and length of mossy fiber bouton (MFB) filopodia of newborn neurons at >= 14 days old were significantly reduced in KO mice. Both contextual fear conditioning (CFC) and object-location recognition tasks were impaired in recent (1 day) memory test while passive avoidance task was impaired only in remote (>= 20 days) memory in KO mice. Results using adeno-associated virus (AAV)-mediated Cav1.3 knock-down (KD) or retrovirus-mediated KD in dorsal hippocampal DG area showed that the recent memory of CFC was impaired in both KD mice but the remote memory was impaired only in AAV KD mice, suggesting that Cav1.3 of mature neurons play important roles in both recent and remote CFC memory while Cav1.3 in newborn neurons is selectively involved in the recent CFC memory process. Meanwhile, AAV KD of Cav1.3 in ventral hippocampal area has no effect on the recent CFC memory. In conclusion, the results suggest that Cav1.3 in newborn neurons of dorsal hippocampus is involved in the survival of newborn neurons while mediating developments of dendritic and axonal processes of newborn cells and plays a role in the memory process differentially depending on the stage of maturation and the type of learning task. PMID- 28715455 TI - Synthetic melanin bound to subunit vaccine antigens significantly enhances CD8+ T cell responses. AB - Cytotoxic T-lymphocytes (CTLs) play a key role in immunity against cancer; however, the induction of CTL responses with currently available vaccines remains difficult. Because several reports have suggested that pigmentation and immunity might be functionally linked, we investigated whether melanin can act as an adjuvant in vaccines. Short synthetic peptides (8-35 amino acids long) containing T-cell epitopes were mixed with a solution of L-Dopa, a precursor of melanin. The mixture was then oxidized to generate nanoparticles of melanin-bound peptides. Immunization with melanin-bound peptides efficiently triggered CTL responses in mice, even against self-antigens and at a very low dose of peptides (microgram range). Immunization against a tumor antigen inhibited the growth of established tumors in mice, an effect that was abrogated by the depletion of CD8+ lymphocytes. These results demonstrate the efficacy of melanin as a vaccine adjuvant. PMID- 28715457 TI - An analogous wood barrel theory to explain the occurrence of hormesis: A case study of sulfonamides and erythromycin on Escherichia coli growth. AB - Hormesis has aroused much attention during the past two decades and may have great implications on many fields, including toxicology and risk assessment. However, the observation of hormesis remains challenged under laboratory conditions. To determine favorable conditions under which to observe hormesis, we investigated the hormetic responses of Escherichia coli (E. coli) upon exposure of different concentrations of sulfonamides and erythromycin at different time points and in different culture media: Luria-Bertani (LB) broth and Mueller Hinton (MH) broth. Our results reveal that the antibiotics, both individually and combined, produce hormetic effects on E. coli growth in MH broth at the stationary phase, with the maximum stimulatory response increasing with time. However, in LB broth, the hormetic response was not observed, which can be explained by an analogous "wood barrel theory". Our study suggests that the culture medium and time should be taken into consideration in hormetic studies, and compound mixtures should also receive more attention for their potential to induce hormesis. PMID- 28715456 TI - The Trypanosoma brucei dihydroxyacetonephosphate acyltransferase TbDAT is dispensable for normal growth but important for synthesis of ether glycerophospholipids. AB - Glycerophospholipids are the most abundant constituents of biological membranes in Trypanosoma brucei, which causes sleeping sickness in humans and nagana in cattle. They are essential cellular components that fulfill various important functions beyond their structural role in biological membranes such as in signal transduction, regulation of membrane trafficking or control of cell cycle progression. Our previous studies have established that the glycerol-3-phosphate acyltransferase TbGAT is dispensable for growth, viability, and ester lipid biosynthesis suggesting the existence of another initial acyltransferase(s). This work presents the characterization of the alternative, dihydroxyacetonephosphate acyltransferase TbDAT, which acylates primarily dihydroxyacetonephosphate and prefers palmitoyl-CoA as an acyl-CoA donor. TbDAT restores the viability of a yeast double null mutant that lacks glycerol-3-phosphate and dihydroxyacetonephosphate acyltransferase activities. A conditional null mutant of TbDAT in T. brucei procyclic form was created and characterized. TbDAT was important for survival during stationary phase and synthesis of ether lipids. In contrast, TbDAT was dispensable for normal growth. Our results show that in T. brucei procyclic forms i) TbDAT but not TbGAT is the physiologically relevant initial acyltransferase and ii) ether lipid precursors are primarily made by TbDAT. PMID- 28715458 TI - Evaluation of metagenetic community analysis of planktonic copepods using Illumina MiSeq: Comparisons with morphological classification and metagenetic analysis using Roche 454. AB - Metagenetics is a rapid and taxonomically comprehensive method for revealing community structures within environmental samples, based on large amounts of sequence data produced by high-throughput sequencers. Because community structures of planktonic copepods are important in the ocean owing to their high diversity and abundance, a metagenetic analysis of the 28S D2 region using Roche 454 was previously developed. However, the Illumina MiSeq platform with a high sequence output is being used more frequently in metagenetics, and non-calanoid copepods have not previously been fully evaluated. Here, we evaluated an Illumina MiSeq-based metagenetic analysis using a mock community and field-collected samples that were examined in a previous study using Roche 454, and the community structure, including non-calanoid copepods, was compared among morphological and metagenetic analyses. We removed a singleton read and applied an appropriate abundance threshold to remove erroneous Molecular Operational Taxonomic Units (MOTUs) with low-abundance sequences in the MiSeq-based analysis. Results showed that the copepod community was successfully characterized using Illumina MiSeq. Higher-quality sequences were obtained using MiSeq than by Roche 454, which reduced the overestimation of diversity, especially at a strict 99% similarity threshold for MOTU clustering. Taxonomic compositions in terms of both biomass and presence/absence of species, including non-calanoids, were more appropriately represented in the MiSeq- than in Roche 454-based analysis. Our data showed that metagenetic analysis using Illumina MiSeq is more useful for revealing copepod communities than Roche 454, owing to the lower cost and higher quality. PMID- 28715459 TI - Efficacy of abdominal acupuncture for neck pain: A randomized controlled trial. AB - OBJECTIVE: This study aims to provide evidence regarding the clinical efficacy of abdominal acupuncture for neck pain. METHODS: This randomized, patient and assessor-blind, sham-controlled trial was conducted at a Chinese medicine center in Hong Kong between November 2014 and March 2016. A total of 154 eligible participants (age range, 18-65 years) with neck pain were randomly assigned to receive abdominal (n = 77) or non-penetrating sham abdominal (sham group; n = 77) acupuncture. Each participant was administered treatment over six sessions by Registered Chinese Medicine Practitioners, in accordance with a standardized protocol. The primary outcome was mean improvement in neck pain disability scores evaluated by the Northwick Park Neck Pain Questionnaire (NPQ). Secondary outcomes included intensity of neck pain and health-related quality-of-life measures. The outcomes were assessed at baseline and at 2 and 6 weeks from baseline. Patients in the abdominal acupuncture group received additional follow-up evaluation at 14 weeks from baseline. Outcomes were evaluated by intention-to-treat analysis. RESULTS: All participants provided informed consent for treatment and follow-up evaluation. Patients who received abdominal acupuncture exhibited greater improvement in NPQ scores than those who received sham treatment at both 2 and 6 weeks from baseline (intergroup mean differences, -5.75; 95% confidence interval [CI], -9.48 to -2.03; P = 0.008 and -8.65; 95% CI, -12.13 to -5.16; P < 0.001, respectively). The improvement in NPQ scores in the abdominal acupuncture group was even more significant at 14 weeks from baseline. Patients in the abdominal acupuncture group also exhibited significantly greater improvements in intensity of neck pain and a few quality-of-life measures than those in the sham abdominal acupuncture group, without any serious adverse events. CONCLUSION: These findings suggest that abdominal acupuncture is an effective alternative treatment for neck pain. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR-TRC-14004932. PMID- 28715460 TI - Early infant diagnosis of HIV-1 infection in Luanda, Angola, using a new DNA PCR assay and dried blood spots. AB - BACKGROUND: Early diagnosis and treatment reduces HIV-1-related mortality, morbidity and size of viral reservoirs in infants infected perinatally. Commercial molecular tests enable the early diagnosis of infection in infants but the high cost and low sensitivity with dried blood spots (DBS) limit their use in sub-Saharan Africa. OBJECTIVES: To develop and validate a sensitive and cheap qualitative proviral DNA PCR-based assay for early infant diagnosis (EID) in HIV 1-exposed infants using DBS samples. STUDY DESIGN: Chelex-based method was used to extract DNA from DBS samples followed by a nested PCR assay using primers for the HIV-1 integrase gene. Limit of detection (LoD) was determined by Probit regression using limiting dilutions of newly produced recombinant plasmids with the integrase gene of all HIV-1 subtypes and ACH-2 cells. Clinical sensitivity and specificity were evaluated on 100 HIV-1 infected adults; 5 infected infants; 50 healthy volunteers; 139 HIV-1-exposed infants of the Angolan Pediatric HIV Cohort (APEHC) with serology at 18 months of life. RESULTS: All subtypes and CRF02_AG were amplified with a LoD of 14 copies. HIV-1 infection in infants was detected at month 1 of life. Sensitivity rate in adults varied with viral load, while diagnostic specificity was 100%. The percentage of HIV-1 MTCT cases between January 2012 and October 2014 was 2.2%. The cost per test was 8-10 USD which is 2 to 4-fold lower in comparison to commercial assays. CONCLUSIONS: The new PCR assay enables early and accurate EID. The simplicity and low-cost of the assay make it suitable for generalized implementation in Angola and other resource constrained countries. PMID- 28715461 TI - TLR1-10, NF-kappaB and p53 expression is increased in oral lichenoid disease. AB - Toll-like receptors (TLRs) and nuclear factor-kappaB (NF-kappaB) in keratinocytes play an important role in dermatological autoimmune diseases. Tumour suppressor protein p53 regulates TLR expression. The aim of this study was to compare the expression of TLR1-TLR10, p53 and NF-kappaB in patients with oral lichenoid disease (OLD) with healthy mucosa. Oral mucosal biopsies from 24 patients with OLD and 26 healthy controls (HC) were analysed for the expression of TLR1-TLR10, NF-kappaB and p53 by immunohistochemistry. The expression of all TLRs was increased in OLD epithelia compared to HC samples and the difference was significant in TLR1, TLR3, TLR4, TLR5, TLR6 and TLR7. In the basement membrane zone, the immunoreactivity of TLR5 was significantly more intense in OLD compared to HC. In the intermediate layer, the immunoreactivity of NF-kappaB was significantly stronger in OLD, whereas the staining for p53 was more intense in all layers of OLD compared to HC samples. In OLD, a positive correlation between TLR2 and NF-kappaB in the basal layer and between TLR5, p53 and NF-kappaB in the intermediate layers was discovered. The expression of TLRs, p53 and NF-kappaB is increased in OLD, which may play a role in the pathogenesis of this chronic immune-mediated mucosal disease. PMID- 28715462 TI - Cell specificity dictates similarities in gene expression in multiple sclerosis, Parkinson's disease, and Alzheimer's disease. AB - Drug repurposing is an efficient approach in new treatment development since it leverages previous work from one disease to another. While multiple sclerosis (MS), Parkinson's disease (PD), and Alzheimer's disease (AD) are all neurodegenerative diseases of the central nervous system (CNS) and differ in many clinical and pathological aspects, it is possible that they may share some mechanistic features. We hypothesized that focusing on gene expression in a CNS cell type specific manner might uncover similarities between diseases that could be missed using whole tissue gene expression analyses. We found similarities and differences in gene expression in these three distinct diseases, depending upon cell type. Microglia genes were increased in all three diseases, and gene expression levels were correlated strongly among these three neurodegenerative diseases. In astrocytes and endothelia, upregulation and correlations were observed only between MS and PD, but not AD. Neuronal genes were down-regulated in all three diseases, but correlations of changes of individual genes between diseases were not strong. Oligodendrocyte showed gene expression changes that were not shared among the three diseases. Together these data suggest that treatments targeting microglia are most amenable to drug repurposing in MS, PD, and AD, while treatments targeting other CNS cells must be tailored to each disease. PMID- 28715463 TI - Potassium citrate prevents increased osteoclastogenesis resulting from acidic conditions: Implication for the treatment of postmenopausal bone loss. AB - The extracellular acidic milieu in bones results in activation of osteoclasts (OC) and inhibition of osteoblasts (OB) causing a net loss of calcium from the skeleton and the deterioration of bone microarchitecture. Alkalinization through supplementation with potassium citrate (K citrate) has been proposed to limit the osteopenia progression, even though its pharmacological activity in bone microenvironment is not well defined. We evaluated if K citrate was able to prevent the adverse effects that acidic milieu induces on bone cells. OC and OB were maintained in neutral (pH 7.4) versus acidic (pH 6.9) culture medium, and treated with different K citrate concentrations. We evaluated the OC differentiation at seven days, by counting of multinucleated cells expressing tartrate-resistant acid phosphatase, and the activity of mature OC at 14 days, by quantifying of collagen degradation. To evaluate the effects on OB, we analyzed proliferation, mineralization, and expression of bone-related genes. We found that the low pH increased OC differentiation and activity and decreased OB function. The osteoclastogenesis was also promoted by RANKL concentrations ineffective at pH 7.4. Non-cytotoxic K citrate concentrations were not sufficient to steadily neutralize the acidic medium, but a) inhibited the osteoclastogenesis, the collagen degradation, and the expression of genes involved in RANKL-mediated OC differentiation, b) enhanced OB proliferation and alkaline phosphatase expression, whereas it did not affect the in vitro mineralization, and c) were effective also in OC cultures resistant to alendronate, i.e. the positive control of osteoclastogenesis inhibition. In conclusion, K citrate prevents the increase in OC activity induced by the acidic microenvironment, and the effect does not depend exclusively on its alkalizing capacity. These data provide the biological basis for the use of K citrate in preventing the osteopenia progression resulting from low-grade acidosis. PMID- 28715464 TI - Impact of an implicit social skills training group in children with autism spectrum disorder without intellectual disability: A before-and-after study. AB - INTRODUCTION: Children with Autism Spectrum Disorders (ASDs) have problems with social skills. Social skills training groups are among the proposed therapeutic strategies, but their efficacy still needs to be evaluated. OBJECTIVE: To evaluate the efficacy of an implicit social skills training group in children with ASDs without intellectual disability. METHODS: A before-and-after study of children with ASD without intellectual disability was conducted in a child psychiatry day hospital, where they participated in an implicit group with cooperative games. Their social skills were assessed using the Social-Emotional Profile (SEP), the Childhood Autism Rating Scale (CARS), and the empathy quotient (EQ) before and after 22 weeks. RESULTS: Six patients aged 9 to 10 years old were evaluated. A significant increase in overall adaptation and social skills (median 8 and 7.7 points) in the SEP was demonstrated in addition to a significant reduction in the CARS score (median: 4 points), including in the field of social relationships. The EQ increased two-fold. DISCUSSION-CONCLUSION: This implicit group improved the children's social skills. It would be interesting to evaluate the maintenance of these skills over time, examine more widespread results, and compare implicit and explicit groups. PMID- 28715465 TI - Multiplexing detection of IgG against Plasmodium falciparum pregnancy-specific antigens. AB - BACKGROUND: Pregnant women exposed to Plasmodium falciparum generate antibodies against VAR2CSA, the parasite protein that mediates adhesion of infected erythrocytes to the placenta. There is a need of high-throughput tools to determine the fine specificity of these antibodies that can be used to identify immune correlates of protection and exposure. Here we aimed at developing a multiplex-immunoassay to detect antibodies against VAR2CSA antigens. METHODS AND FINDINGS: We constructed two multiplex-bead arrays, one composed of 3 VAR2CSA recombinant-domains (DBL3X, DBL5E and DBL6E) and another composed of 46 new peptides covering VAR2CSA conserved and semi-conserved regions. IgG reactivity was similar in multiplexed and singleplexed determinations (Pearson correlation, protein array: R2 = 0.99 and peptide array: R2 = 0.87). IgG recognition of 25 out of 46 peptides and all recombinant-domains was higher in pregnant Mozambican women (n = 106) than in Mozambican men (n = 102) and Spanish individuals (n = 101; p<0.05). Agreement of IgG levels detected in cryopreserved plasma and in elutions from dried blood spots was good after exclusion of inappropriate filter papers. Under heterogeneous levels of exposure to malaria, similar seropositivity cutoffs were obtained using finite mixture models applied to antibodies measured on pregnant Mozambican women and average of antibodies measured on pregnant Spanish women never exposed to malaria. The application of the multiplex-bead array developed here, allowed the assessment of higher IgG levels and seroprevalences against VAR2CSA-derived antigens in women pregnant during 2003 2005 than during 2010-2012, in accordance with the levels of malaria transmission reported for these years in Mozambique. CONCLUSIONS: The multiplex bead-based immunoassay to detect antibodies against selected 25 VAR2CSA new-peptides and recombinant-domains was successfully implemented. Analysis of field samples showed that responses were specific among pregnant women and dependent on the level of exposure to malaria. This platform provides a high-throughput approach to investigating correlates of protection and identifying serological markers of exposure for malaria in pregnancy. PMID- 28715466 TI - The antenna transcriptome changes in mosquito Anopheles sinensis, pre- and post- blood meal. AB - Antenna is the main chemosensory organ in mosquitoes. Characterization of the transcriptional changes after blood meal, especially those related to chemoreception, may help to explain mosquito blood sucking behavior and to identify novel targets for mosquito control. Anopheles sinensis is an Asiatic mosquito species which transmits malaria and lymphatic filariasis. However, studies on chemosensory biology in female An. sinensis are quite lacking. Here we report a transcriptome analysis of An. sinensis female antennae pre- and post- blood meal. We created six An. sinensis antenna RNA-seq libraries, three from females without blood meal and three from females five hours after a blood meal. Illumina sequencing was conducted to analyze the transcriptome differences between the two groups. In total, the sequenced fragments created 21,643 genes, 1,828 of them were novel. 12,861 of these genes were considered to be expressed (FPKM >1.0) in at least one of the two groups, with 12,159 genes expressed in both groups. 548 genes were differentially expressed in the blood-fed group, with 331 genes up-regulated and 217 genes down-regulated. GO enrichment analysis of the differentially expressed genes suggested that there were no statistically over represented GO terms among down-regulated genes in blood-fed mosquitoes, while the enriched GO terms of the up-regulated genes occurred mainly in metabolic process. For the chemosensory gene families, a subtle distinction in the expression levels can be observed according to our statistical analysis. However, the firstly comprehensive identification of these chemosensory gene families in An. sinensis antennae will help to characterize the precise function of these proteins in odor recognition in mosquitoes. This study provides a first global view in the changes of transcript accumulation elicited by blood meal in An. sinensis female antennae. PMID- 28715467 TI - Dealing with foreign cultural paradigms: A systematic review on intercultural challenges of international medical graduates. AB - OBJECTIVES: An increasing number of International Medical Graduates (IMG), who are defined to be physicians working in a country other than their country of origin and training, immigrate to Western countries. In order to ensure safe and high-quality patient care, they have to take medical and language tests. This systematic review aims to (1) collect all empiric research on intercultural communication of IMGs in medical settings, (2) identify and categorize all text passages mentioning intercultural issues in the included studies, and (3) describe the most commonly reported intercultural areas of communication of IMGs. METHODS: This review was based on the PRISMA-Guidelines for systematic reviews. We conducted a broad and systematic electronic literature search for empiric research in the following databases: MEDLINE, BIOSIS Citation Index, BIOSIS Previews, KCI-Korean Journal Database and SciELO Citation Index. The search results were synthesized and analyzed with the aid of coding systems. These coding systems were based on textual analysis and derived from the themes and topics of the results and discussion sections from the included studies. A quality assessment was performed, comparing the studies with their corresponding checklist (COREQ or STROBE). Textual results of the studies were extracted and categorized. RESULTS: Among 10,630 search results, 47 studies were identified for analysis. 31 studies were qualitative, 12 quantitative and 4 studies used mixed methods. The quality assessment revealed a low level of quality of the studies in general. The following intercultural problems were identified: IMGs were not familiar with shared decision-making and lower hierarchies in the health care system in general. They had difficulties with patient-centered care, the subtleties of the foreign language and with the organizational structures of the new health care system. In addition, they described the medical education in their home countries as science-oriented, without focusing on psychosocial aspects. CONCLUSION: There is a need for a better training of IMGs on culture related and not culture-related topics in the new workplace country. The topics that emerged in this review constitute a basis for developing these courses. Further empiric research is needed to describe the findings of this review more precisely and should be in accordance with the existing reporting guidelines. PMID- 28715468 TI - Heterosubtypic cross-reactivity of HA1 antibodies to influenza A, with emphasis on nonhuman subtypes (H5N1, H7N7, H9N2). AB - Epidemics of influenza A vary greatly in size and age distribution of cases, and this variation is attributed to varying levels of pre-existing immunity. Recent studies have shown that antibody-mediated immune responses are more cross reactive than previously believed, and shape patterns of humoral immunity to influenza A viruses over long periods. Here we quantify antibody responses to the hemagglutinin subunit 1 (HA1) across a range of subtypes using protein microarray analysis of cross-sectional serological surveys carried out in the Netherlands before and after the A/2009 (H1N1) pandemic. We find significant associations of responses, both within and between subtypes. Interestingly, substantial overall reactivity is observed to HA1 of avian H7N7 and H9N2 viruses. Seroprevalence of H7N7 correlates with antibody titers to A/1968 (H3N2), and is highest in persons born between 1954 and 1969. Seroprevalence of H9N2 is high across all ages, and correlates strongly with A/1957 (H2N2). This correlation is most pronounced in A/2009 (H1N1) infected persons born after 1968 who have never encountered A/1957 (H2N2)-like viruses. We conclude that heterosubtypic antibody cross-reactivity, both between human subtypes and between human and nonhuman subtypes, is common in the human population. PMID- 28715469 TI - Cofactor engineering improved CALB production in Pichia pastoris through heterologous expression of NADH oxidase and adenylate kinase. AB - The cofactor engineering strategy can relieve the metabolic stress induced by expression of recombinant protein in cellular metabolism related to cofactor and energy reactions. To study the effect of cofactor regeneration on recombinant protein expression, NADH oxidase (noxE) was engineered in P. pastoris expressing lipase B (GSCALB). Expression of noxE in P. pastoris (GSCALBNOX) increased NAD+ levels by 85% with a concomitant reduction in NADH/NAD+ ratio of 67% compared to GSCALB. The change in the redox level positively influenced the methanol uptake rate and made 34% augment in CALB activity. The decline in NADH level (44%) by noxE expression had lowered the adenylate energy charge (AEC) and ATP level in GSCALBNOX. In order to regenerate ATP in GSCALBNOX, adenylate kinase (ADK1) gene from S. cerevisiae S288c was co-expressed. Expression of ADK1 showed a remarkable increase in AEC and co-expression of both the genes synergistically improved CALB activity. This study shows the importance of maintenance of cellular redox homeostasis and adenylate energy charge during recombinant CALB expression in P. pastoris. PMID- 28715470 TI - Impairment of cold injury-induced muscle regeneration in mice receiving a combination of bone fracture and alendronate treatment. AB - Alendronate, a nitrogen-containing bisphosphonate, is well established as a treatment for osteoporosis through regulation of osteoclast activity. Previously, the pharmacological effects of bisphosphonates on cells outside the bone environment have been considered irrelevant because bisphosphonates target bone. Here we show that administration of alendronate impairs muscle regeneration in mice after bone fracture. A series of injections of alendronate alone or bone fracture alone did not affect muscle regeneration induced by cold injury. In contrast, alendronate treatment plus bone fracture severely impaired the regeneration of muscle that closely contacts the bone fracture site after cold injury. After cold injury, M-cadherin-positive myogenic cells disappeared in the damaged muscle areas of mice receiving the combination of alendronate treatment and bone fracture. The present results suggest that the muscle regeneration capacity is impaired by bone fracture in mice receiving alendronate treatment. The present research on the pharmacological effects of alendronate on muscle regeneration will aid in understanding of the in vivo action of alendronate on skeletal muscles. PMID- 28715471 TI - Habitat and indigenous gut microbes contribute to the plasticity of gut microbiome in oriental river prawn during rapid environmental change. AB - Growing evidence points out that the capacity of organisms to acclimate or adapt to new habitat conditions basically depends on their phenomic plasticity attributes, of which their gut commensal microbiota might be an essential impact factor. Especially in aquatic organisms, which are in direct and continual contact with the aquatic environment, the complex and dynamic microbiota have significant effects on health and development. However, an understanding of the relative contribution of internal sorting (host genetic) and colonization (environmental) processes is still unclear. To understand how microbial communities differ in response to rapid environmental change, we surveyed and studied the environmental and gut microbiota of native and habitat-exchanged shrimp (Macrobrachium nipponense) using 16S rRNA amplicon sequencing on the Illumina MiSeq platform. Corresponding with microbial diversity of their living water areas, the divergence in gut microbes of lake-to-river shrimp (CK) increased, while that of river-to-lake shrimp (KC) decreased. Importantly, among the candidate environment specific gut microbes in habitat-exchanged shrimp, over half of reads were associated with the indigenous bacteria in native shrimp gut, yet more candidates presented in CK may reflect the complexity of new environment. Our results suggest that shrimp gut microbiota has high plasticity when its host faces environmental changes, even over short timescales. Further, the changes in external environment might influence the gut microbiome not just by providing environment-associated microbes directly, but also by interfering with the composition of indigenous gut bacteria indirectly. PMID- 28715473 TI - Population and colony structure and morphometrics in the queen dimorphic little black ant, Monomorium sp. AZ-02, with a review of queen phenotypes in the genus Monomorium. AB - The North American little black ant, Monomorium sp. AZ-02 (subfamily Myrmicinae), displays a dimorphism that consists of alate (winged) and ergatoid (wingless) queens. Surveys at our field site in southcentral Arizona, USA, demonstrated that only one queen phenotype (alate or ergatoid) occurred in each colony during the season in which reproductive sexuals were produced. A morphometric analysis demonstrated that ergatoid queens retained all specialized anatomical features of alate queens (except for wings), and that they were significantly smaller and had a lower mass than alate queens. Using eight morphological characters, a discriminant analysis correctly categorized all queens (40 of 40) of both phenotypes. A molecular phylogeny using 420 base pairs of the mitochondrial gene cytochrome oxidase I demonstrated that alate and ergatoid queens are two alternative phenotypes within the species; both phenotypes were intermixed on our phylogeny, and both phenotypes often displayed the same haplotype. A survey of the genus Monomorium (358 species) found that wingless queens (ergatoid queens, brachypterous queens) occur in 42 of 137 species (30.6%) in which the queen has been described. These wingless queen species are geographically and taxonomically widespread as they occur on several continents and in eight species groups, suggesting that winglessness probably arose independently on many occasions in the genus. PMID- 28715472 TI - A novel isoform of IL-33 revealed by screening for transposable element promoted genes in human colorectal cancer. AB - Remnants of ancient transposable elements (TEs) are abundant in mammalian genomes. These sequences contain multiple regulatory motifs and hence are capable of influencing expression of host genes. TEs are known to be released from epigenetic repression and can become transcriptionally active in cancer. Such activation could also lead to lineage-inappropriate activation of oncogenes, as previously described in lymphomas. However, there are few reports of this mechanism occurring in non-blood cancers. Here, we re-analyzed whole transcriptome data from a large cohort of patients with colon cancer, compared to matched normal colon control samples, to detect genes or transcripts ectopically expressed through activation of TE promoters. Among many such transcripts, we identified six where the affected gene has described role in cancer and where the TE-driven gene mRNA is expressed in primary colon cancer, but not normal matched tissue, and confirmed expression in colon cancer-derived cell lines. We further characterized a TE-gene chimeric transcript involving the Interleukin 33 (IL-33) gene (termed LTR-IL-33), that is ectopically expressed in a subset of colon cancer samples through the use of an endogenous retroviral long terminal repeat (LTR) promoter of the MSTD family. The LTR-IL-33 chimeric transcript encodes a novel shorter isoform of the protein, which is missing the initial N-terminus (including many conserved residues) of Native IL-33. In vitro studies showed that LTR-IL-33 expression is required for optimal CRC cell line growth as 3D colonospheres. Taken together, these data demonstrate the significance of TEs as regulators of aberrant gene expression in colon cancer. PMID- 28715475 TI - Free-ranging dogs show age related plasticity in their ability to follow human pointing. AB - Differences in pet dogs' and captive wolves' ability to follow human communicative intents have led to the proposition of several hypotheses regarding the possession and development of social cognitive skills in dogs. It is possible that the social cognitive abilities of pet dogs are induced by indirect conditioning through living with humans, and studying free-ranging dogs can provide deeper insights into differentiating between innate abilities and conditioning in dogs. Free-ranging dogs are mostly scavengers, indirectly depending on humans for their sustenance. Humans can act both as food providers and as threats to these dogs, and thus understanding human gestures can be a survival need for the free-ranging dogs. We tested the responsiveness of such dogs in urban areas toward simple human pointing cues using dynamic proximal points. Our experiment showed that pups readily follow proximal pointing and exhibit weaker avoidance to humans, but stop doing so at the later stages of development. While juveniles showed frequent and prolonged gaze alternations, only adults adjusted their behaviour based on the reliability of the human experimenter after being rewarded. Thus free-ranging dogs show a tendency to respond to human pointing gestures, with a certain level of behavioural plasticity that allows learning from ontogenic experience. PMID- 28715474 TI - Prognostic role of neutrophil-lymphocyte ratio in nasopharyngeal carcinoma: A meta-analysis. AB - BACKGROUND: Inflammatory markers are used to predict prognosis of nasopharyngeal carcinoma (NPC). Previous reports of neutrophil-to-lymphocyte ratio (NLR) and NPC mortality are inconsistent. This study aimed to quantify the prognostic impact of NLR on NPC. METHODS: The primary outcome was overall survival (OS), and the secondary outcomes were disease-specific survival (DSS), progression-free survival (PFS) and distant metastasis-free survival (DMFS). We systematically searched electronic databases, identified articles reporting an association between NLR and NPC prognosis. Hazard ratios (HRs) and 95% confidence intervals (CIs) were extracted, and pooled HRs for each outcome were estimated using random effect models. RESULTS: Nine studies enrolling 5397 patients were included in the analyses. NLR greater than the cutoff value was associated with poor overall survival (HR 1.51, 95% CI 1.27-1.78), disease-specific survival (HR 1.44, 95% CI 1.22-1.71), progression-free survival (HR 1.53, 95% CI 1.22-1.90), and distant metastasis-free survival (HR 1.83, 95% CI 1.14-2.95). CONCLUSIONS: Elevated NLR predicts worse OS, DSS, PFS and DMFS in patients with NPC. PMID- 28715476 TI - Spot on for liars! How public scrutiny influences ethical behavior. AB - We examine whether people are more honest in public than in private. In a laboratory experiment, we have subjects roll dice and report outcomes either in public or in private. Higher reports yield more money and lies cannot be detected. We also elicit subjects' ethical mindsets and their expectations about others' reports. We find that outcome-minded subjects lie less in public to conform with their expectations about others' reports. Ironically, these expectations are false. Rule-minded subjects, in turn, do not respond to public scrutiny. These findings challenge the common faith in public scrutiny to promote ethical behavior. While public scrutiny eventually increases honesty, this effect is contingent on people's mindsets and expectations. PMID- 28715477 TI - The RhlR quorum-sensing receptor controls Pseudomonas aeruginosa pathogenesis and biofilm development independently of its canonical homoserine lactone autoinducer. AB - Quorum sensing (QS) is a bacterial cell-to-cell communication process that relies on the production, release, and response to extracellular signaling molecules called autoinducers. QS controls virulence and biofilm formation in the human pathogen Pseudomonas aeruginosa. P. aeruginosa possesses two canonical LuxI/R type QS systems, LasI/R and RhlI/R, which produce and detect 3OC12-homoserine lactone and C4-homoserine lactone, respectively. Here, we use biofilm analyses, reporter assays, RNA-seq studies, and animal infection assays to show that RhlR directs both RhlI-dependent and RhlI-independent regulons. In the absence of RhlI, RhlR controls the expression of genes required for biofilm formation as well as genes encoding virulence factors. Consistent with these findings, DeltarhlR and DeltarhlI mutants have radically different biofilm phenotypes and the DeltarhlI mutant displays full virulence in animals whereas the DeltarhlR mutant is attenuated. The DeltarhlI mutant cell-free culture fluids contain an activity that stimulates RhlR-dependent gene expression. We propose a model in which RhlR responds to an alternative ligand, in addition to its canonical C4 homoserine lactone autoinducer. This alternate ligand promotes a RhlR-dependent transcriptional program in the absence of RhlI. PMID- 28715478 TI - Loneliness is adversely associated with physical and mental health and lifestyle factors: Results from a Swiss national survey. AB - INTRODUCTION: Loneliness is a common, emotionally distressing experience and is associated with adverse physical and mental health and an unhealthy lifestyle. Nevertheless, little is known about the prevalence of loneliness in different age groups in Switzerland. Furthermore, the existing evidence about age and gender as potential effect modifiers of the associations between loneliness, physical and mental health and lifestyle characteristics warrants further investigation. Thus, the aim of the study was to examine the prevalence of loneliness among adults in Switzerland and to assess the associations of loneliness with several physical and mental health and behavioral factors, as well as to assess the modifying effect of sex and age. METHODS: Data from 20,007 participants of the cross sectional population-based Swiss Health Survey 2012 (SHS) were analyzed. Logistic regression analyses were used to assess associations of loneliness with physical and mental health or lifestyle characteristics (e.g. diabetes, depression, physical activity). Wald tests were used to test for interactions. RESULTS: Loneliness was distributed in a slight U-shaped form from 15 to 75+ year olds, with 64.1% of participants who had never felt lonely. Lonely individuals were more often affected by physical and mental health problems, such as self-reported chronic diseases (Odds ratio [OR] 1.41, 95% confidence interval [CI] 1.30-1.54), high cholesterol levels (OR 1.31, 95% CI 1.18-1.45), diabetes (OR 1.40, 95% CI 1.16-1.67), moderate and high psychological distress (OR 3.74, 95% CI 3.37-4.16), depression (OR 2.78, 95% CI 2.22-3.48) and impaired self-perceived health (OR 1.94, 95% CI 1.74-2.16). Loneliness was significantly associated with most lifestyle factors (e.g. smoking; OR 1.13, 95% 1.05-1.23). Age, but not sex, moderated loneliness' association with several variables. CONCLUSION: Loneliness is associated with poorer physical and mental health and unhealthy lifestyle, modified by age, but not by sex. Our findings illustrate the importance of considering loneliness for physical and mental health and lifestyle factors, not only in older and younger, but also in middle-aged adults. Longitudinal studies are needed in Switzerland to elucidate the causal relationships of these associations. PMID- 28715479 TI - Retention and recruitment of general dentists in an adjunct teaching model-A pilot study. AB - PURPOSE/OBJECTIVES: Retention and recruitment of part time clinical adjunct faculty members in dental education is becoming increasingly difficult as dental schools come to rely on this workforce for their increased involvement in clinical education. Contributing factors include full time faculty shortage, aging workforce, practice and student debt, practice and family commitments, and financial compensation. This study attempts to ascertain barriers to teaching so appropriate strategies can be formulated to address this issue. METHODS: In the spring of 2016 an email survey was sent to current and former adjunct faculty members to ascertain demographics and retention and recruitment strategies. Descriptive analyses were completed for all variables in the sample. RESULTS: Twenty nine of forty six subjects responded to the survey with a response rate of 63%. Subjects over the age of sixty comprised 55% with only 17% being under the age of forty five. Overall family and practice commitments along with compensation were the primary barriers to teaching part time. For new dentists, student loan debt was the primary barrier to teaching. Travel to teach was also a barrier as 70% of respondents drove 200 miles or less to the dental school. CONCLUSION: The study demonstrated that the aging part time work force is a great concern and new part time clinical adjunct faculty members must be recruited. Barriers to recruitment and retention of faculty must be considered and addressed to sustain this teaching model. PMID- 28715481 TI - A preliminary evaluation of the training effects of a didactic and simulation based psychological first aid program in students and school counselors in South Korea. AB - The present study aimed to examine the training effects of a didactic and simulation-based psychological first aid (PFA) program. Based on the competency based model, the study sought to examine whether the PFA training would enhance knowledge, skills, and attitudes. Study 1 examined the training effects of the PFA program in a sample of undergraduate and graduate students in psychology. Study 2 was conducted with school counselors. In both studies, all participants completed a one-day PFA workshop with a 3-hour didactic lecture and a 3-hour simulation-based practice. Assessments were conducted prior to the didactic lecture and upon completion of the simulation-based practice. In study 1, an examination of pre- and posttest comparisons indicated that the training significantly improved students' PFA knowledge and perceived competence in PFA skill. In study 2, the same PFA training significantly improved school counselors' PFA knowledge, perceived competence in PFA skill, perceived preparedness and confidence to provide psychological assistance for future disasters, but their perceived willingness to participate in psychological assistance did not significantly change after the training. This study provides preliminary evidence supporting the effectiveness of the PFA training program using a combined method of didactic and simulation-based practice for disaster mental health providers in Korea. PMID- 28715482 TI - Impact of maternal body mass index and gestational weight gain on neonatal outcomes among healthy Middle-Eastern females. AB - BACKGROUND: Studies on the relative impact of body mass index in women in childbearing age and gestational weight gain on neonatal outcomes are scarce in the Middle East. OBJECTIVES: The primary objective of this research was to assess the impact of maternal body mass index (BMI) and gestational weight gain (GWG) on neonatal outcomes. The effect of maternal age and folic acid supplementation before and during pregnancy was also examined. SUBJECTS AND METHODS: This is a retrospective cross sectional observational study of 1000 full term deliveries of women enrolled thru the National Collaborative Perinatal Neonatal Network, in Lebanon. Maternal characteristics such as age, BMI and GWG and neonatal outcomes such as weight, height, head circumference and Apgar score were the primary studied variables in this study. Total maternal weight gain were compared to the guidelines depicted by the Institute of Medicine (IOM). RESULTS: The negative outcomes of newborns such as lean body weight and macrosomia were significantly present in women who gained respectively below or above the IOM's cut-off points. Pregestational body mass index influenced significantly the infants' birth weight, in both the underweight and obese categories. Birth height, head circumference and Apgar score were not influenced by pregestational body mass index or gestational weight gain. No significant associations were found between maternal age and pregestational body mass index and gestational weight gain. CONCLUSION: Studies evaluating the impact of weight before and during pregnancy on neonatal outcomes and anthropometrics measurements are lacking in the Middle East. Our results highlight the importance of nutritional counseling in order to shed the extra weights before conceiving and monitor weight gain to avoid the negative impact on feto-maternal health. PMID- 28715483 TI - Atomistic fingerprint of hyaluronan-CD44 binding. AB - Hyaluronan is a polyanionic, megadalton-scale polysaccharide, which initiates cell signaling by interacting with several receptor proteins including CD44 involved in cell-cell interactions and cell adhesion. Previous studies of the CD44 hyaluronan binding domain have identified multiple widespread residues to be responsible for its recognition capacity. In contrast, the X-ray structural characterization of CD44 has revealed a single binding mode associated with interactions that involve just a fraction of these residues. In this study, we show through atomistic molecular dynamics simulations that hyaluronan can bind CD44 with three topographically different binding modes that in unison define an interaction fingerprint, thus providing a plausible explanation for the disagreement between the earlier studies. Our results confirm that the known crystallographic mode is the strongest of the three binding modes. The other two modes represent metastable configurations that are readily available in the initial stages of the binding, and they are also the most frequently observed modes in our unbiased simulations. We further discuss how CD44, fostered by the weaker binding modes, diffuses along HA when attached. This 1D diffusion combined with the constrained relative orientation of the diffusing proteins is likely to influence the aggregation kinetics of CD44. Importantly, CD44 aggregation has been suggested to be a possible mechanism in CD44-mediated signaling. PMID- 28715480 TI - Tales of diversity: Genomic and morphological characteristics of forty-six Arthrobacter phages. AB - The vast bacteriophage population harbors an immense reservoir of genetic information. Almost 2000 phage genomes have been sequenced from phages infecting hosts in the phylum Actinobacteria, and analysis of these genomes reveals substantial diversity, pervasive mosaicism, and novel mechanisms for phage replication and lysogeny. Here, we describe the isolation and genomic characterization of 46 phages from environmental samples at various geographic locations in the U.S. infecting a single Arthrobacter sp. strain. These phages include representatives of all three virion morphologies, and Jasmine is the first sequenced podovirus of an actinobacterial host. The phages also span considerable sequence diversity, and can be grouped into 10 clusters according to their nucleotide diversity, and two singletons each with no close relatives. However, the clusters/singletons appear to be genomically well separated from each other, and relatively few genes are shared between clusters. Genome size varies from among the smallest of siphoviral phages (15,319 bp) to over 70 kbp, and G+C contents range from 45-68%, compared to 63.4% for the host genome. Although temperate phages are common among other actinobacterial hosts, these Arthrobacter phages are primarily lytic, and only the singleton Galaxy is likely temperate. PMID- 28715484 TI - Multiple renal cancer susceptibility polymorphisms modulate the HIF pathway. AB - Un-physiological activation of hypoxia inducible factor (HIF) is an early event in most renal cell cancers (RCC) following inactivation of the von Hippel-Lindau tumor suppressor. Despite intense study, how this impinges on cancer development is incompletely understood. To test for the impact of genetic signals on this pathway, we aligned human RCC-susceptibility polymorphisms with genome-wide assays of HIF-binding and observed highly significant overlap. Allele-specific assays of HIF binding, chromatin conformation and gene expression together with eQTL analyses in human tumors were applied to mechanistic analysis of one such overlapping site at chromosome 12p12.1. This defined a novel stage-specific mechanism in which the risk polymorphism, rs12814794, directly creates a new HIF binding site that mediates HIF-1alpha isoform specific upregulation of its target BHLHE41. The alignment of multiple sites in the HIF cis-acting apparatus with RCC susceptibility polymorphisms strongly supports a causal model in which minor variation in this pathway exerts significant effects on RCC development. PMID- 28715485 TI - Characterization of the maize lipoxygenase gene family in relation to aflatoxin accumulation resistance. AB - Maize (Zea mays L.) is a globally important staple food crop prone to contamination by aflatoxin, a carcinogenic secondary metabolite produced by the fungus Aspergillus flavus. An efficient approach to reduce accumulation of aflatoxin is the development of germplasm resistant to colonization and toxin production by A. flavus. Lipoxygenases (LOXs) are a group of non-heme iron containing dioxygenase enzymes that catalyze oxygenation of polyunsaturated fatty acids (PUFAs). LOX derived oxylipins play critical roles in plant defense against pathogens including A. flavus. The objectives of this study were to summarize sequence diversity and expression patterns for all LOX genes in the maize genome, and map their effect on aflatoxin accumulation via linkage and association mapping. In total, 13 LOX genes were identified, characterized, and mapped. The sequence of one gene, ZmLOX10, is reported from 5 inbred lines. Genes ZmLOX1/2, 5, 8, 9, 10 and 12 (GRMZM2G156861, or V4 numbers ZM00001D042541 and Zm00001D042540, GRMZM2G102760, GRMZM2G104843, GRMZM2G017616, GRMZM2G015419, and GRMZM2G106748, respectively) fell under previously published QTL in one or more mapping populations and are linked to a measurable reduction of aflatoxin in maize grains. Association mapping results found 28 of the 726 SNPs tested were associated with reduced aflatoxin levels at p <= 9.71 x 10-4 according to association statistics. These fell within or near nine of the ZmLOX genes. This work confirms the importance of some lipoxygenases for resistance to aflatoxin accumulation and may be used to direct future genetic selection in maize. PMID- 28715486 TI - Anti-Neu5Gc and anti-non-Neu5Gc antibodies in healthy humans. AB - Our group previously investigated the levels of anti-Gal and anti-nonGal IgM and IgG in a cohort of 75 healthy humans of various backgrounds, and found some significant differences related to factors such as age, gender, ABO blood group, diet, vaccination history, and geographic location during childhood. We have now expanded our cohort (n = 84) to investigate the levels of anti-Neu5Gc and anti nonGal/nonNeu5Gc antibodies in healthy humans. Anti-nonGal and anti nonGal/nonNeu5Gc human IgM and IgG binding to pRBCs and pAECs from GTKO/CD46 and GTKO/CD46/Neu5GcKO pigs were measured by flow cytometry. Anti-Gal and anti-Neu5Gc IgM and IgG levels were measured by ELISA. In summary, (i) the great majority (almost 100%) of humans had anti-Neu5Gc IgM and IgG antibodies that bound to pAECs and approximately 50% had anti-Neu5Gc antibodies that bound to pRBCs, (ii) there was significantly less human antibody binding to pig cells that did not express either Gal or Neu5Gc compared with those that did not express Gal alone, (iii) the levels of both IgM and IgG binding to GTKO/CD46/Neu5GcKO pRBCs and pAECs were low, (iv) the level of anti-Neu5Gc IgG was higher in men than women, (v) the level did not change with age or diet, and there was some variability associated with (vi) previous vaccination history and (vii) the geographic region in which the individual spent his or her childhood. Our study confirms that human antibody binding to RBCs and AECs from GTKO/CD46/Neu5GcKO pigs is greatly reduced compared to binding to GTKO/CD46 cells. However, all humans appear to have a low level of antibody that binds to pAECs that is not directed to either Gal or Neu5Gc. Our findings require consideration in planning clinical trials of xenotransplantation. PMID- 28715487 TI - Serum variations of anti-mullerian hormone and total testosterone with aging in healthy adult Iranian men: A population-based study. AB - BACKGROUND: Literature proves anti-mullerian hormone (AMH) and total testosterone (TT) as two important reproductive hormones in male development, however evidence regarding age variations of these hormones is lacking. AIMS: To estimate the normal serum AMH values and to assess the age-specific TT levels in men aged 30 70, we conducted the present population-based study. METHODS: A total of 831 healthy eligible men, aged 30-70 years, were recruited from Tehran Lipid and Glucose study cohort. Centiles for AMH were estimated according to the exponential normal 3-parameter model. The parametric method of Royston available in general software was applied for the first time to estimate the age-specific AMH and TT percentiles of 5th, 10th, 25th, 50th, 75th, 90th and 95th. RESULTS: Mean AMH level was 6.93, ranging from 0.1 to 40.1 ng/ml. Serum AMH concentrations followed a steady reduction with increasing age. Mean TT level was 4.8, ranging from 0.44 to 11.4 ng/ml. DISCUSSION: A measurable serum concentrations of AMH in healthy males throughout lifespan with variations, based on age, confirming a slight age-related AMH decline. Fractional polynomial (FP) regression models revealed that the mean and standard deviation (SD) of the TT were not associated with age, so the percentiles estimated were not age-specific. CONCLUSION: We presented a nomogram of age-specific AMH values in a healthy cohort of Iranian men. This finding might have clinical importance in dealing hormonal disorders in men. PMID- 28715488 TI - microRNA dependent and independent deregulation of long non-coding RNAs by an oncogenic herpesvirus. AB - Kaposi's sarcoma (KS) is a highly prevalent cancer in AIDS patients, especially in sub-Saharan Africa. Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent of KS and other cancers like Primary Effusion Lymphoma (PEL). In KS and PEL, all tumors harbor latent KSHV episomes and express latency associated viral proteins and microRNAs (miRNAs). The exact molecular mechanisms by which latent KSHV drives tumorigenesis are not completely understood. Recent developments have highlighted the importance of aberrant long non-coding RNA (lncRNA) expression in cancer. Deregulation of lncRNAs by miRNAs is a newly described phenomenon. We hypothesized that KSHV-encoded miRNAs deregulate human lncRNAs to drive tumorigenesis. We performed lncRNA expression profiling of endothelial cells infected with wt and miRNA-deleted KSHV and identified 126 lncRNAs as putative viral miRNA targets. Here we show that KSHV deregulates host lncRNAs in both a miRNA-dependent fashion by direct interaction and in a miRNA independent fashion through latency-associated proteins. Several lncRNAs that were previously implicated in cancer, including MEG3, ANRIL and UCA1, are deregulated by KSHV. Our results also demonstrate that KSHV-mediated UCA1 deregulation contributes to increased proliferation and migration of endothelial cells. PMID- 28715489 TI - Evaluation and comparison of statistical methods for early temporal detection of outbreaks: A simulation-based study. AB - The objective of this paper is to evaluate a panel of statistical algorithms for temporal outbreak detection. Based on a large dataset of simulated weekly surveillance time series, we performed a systematic assessment of 21 statistical algorithms, 19 implemented in the R package surveillance and two other methods. We estimated false positive rate (FPR), probability of detection (POD), probability of detection during the first week, sensitivity, specificity, negative and positive predictive values and F1-measure for each detection method. Then, to identify the factors associated with these performance measures, we ran multivariate Poisson regression models adjusted for the characteristics of the simulated time series (trend, seasonality, dispersion, outbreak sizes, etc.). The FPR ranged from 0.7% to 59.9% and the POD from 43.3% to 88.7%. Some methods had a very high specificity, up to 99.4%, but a low sensitivity. Methods with a high sensitivity (up to 79.5%) had a low specificity. All methods had a high negative predictive value, over 94%, while positive predictive values ranged from 6.5% to 68.4%. Multivariate Poisson regression models showed that performance measures were strongly influenced by the characteristics of time series. Past or current outbreak size and duration strongly influenced detection performances. PMID- 28715490 TI - Patterns of care of brain tumor-related epilepsy. A cohort study done in Italian Epilepsy Center. AB - : Epilepsy is the most common comorbidity in patients with brain tumors. STUDY AIMS: To define characteristics of brain tumor-related epilepsy (BTRE) patients and identify patterns of care. Nationwide, multicenter retrospective cohort study. Medical records of BTRE patients seen from 1/1/2010 to 12/31/2011, followed for at least one month were examined. Information included age, sex, tumor type/treatments, epilepsy characteristics, antiepileptic drugs (AEDs). Time to modify first AED due to inefficacy and/or toxicity was assessed with the Kaplan-Meier method and Cox proportional hazard models were used to identify predictors of treatment outcome. Enrolled were 808 patients (447 men, 361 women) from 26 epilepsy centers. Follow-up ranged 1 to 423 months (median 18 months). 732 patients underwent surgery, 483 chemotherapy (CT), 508 radiotherapy. All patients were treated with AEDs. Levetiracetam was the most common drug. 377 patients (46.7%) were still on first drug at end of follow-up, 338 (41.8%) needed treatment modifications (uncontrolled seizures, 229; side effects, 101; poor compliance, 22). Treatment discontinuation for lack of efficacy was associated with younger age, chemotherapy, and center with <20 cases. Treatment discontinuation for side effects was associated with female sex, enzyme-inducing drugs and center with > 20 cases. About one-half of patients with BTRE were on first AED at end of follow-up. Levetiracetam was the most common drug. A non enzyme-inducing AED was followed by a lower risk of drug discontinuation for SE. PMID- 28715491 TI - Towards the development of a comprehensive framework: Qualitative systematic survey of definitions of clinical research quality. AB - OBJECTIVE: To systematically survey existing definitions, concepts, and criteria of clinical research quality, both developed by stakeholder groups as well as in the medical literature. This study serves as a first step in the development of a comprehensive framework for the quality of clinical research. STUDY DESIGN AND SETTING: We systematically and in duplicate searched definitions, concepts and criteria of clinical research quality on websites of stakeholders in clinical research until no further insights emerged and in MEDLINE up to February 2015. Stakeholders included governmental bodies, regulatory agencies, the pharmaceutical industry, academic and commercial contract research organizations, initiatives, research ethics committees, patient organizations and funding agencies from 13 countries. Data synthesis involved descriptive and qualitative analyses following the Framework Method on definitions, concepts, and criteria of clinical research quality. Descriptive codes were applied and grouped into clusters to identify common and stakeholder-specific quality themes. RESULTS: Stakeholder concepts on how to assure quality throughout study conduct or articles on quality assessment tools were common, generally with no a priori definition of the term quality itself. We identified a total of 20 explicit definitions of clinical research quality including varying quality dimensions and focusing on different stages in the clinical research process. Encountered quality dimensions include ethical conduct, patient safety/rights/priorities, internal validity, precision of results, generalizability or external validity, scientific and societal relevance, transparency and accessibility of information, research infrastructure and sustainability. None of the definitions appeared to be comprehensive either in terms of quality dimensions, research stages, or stakeholder perspectives. CONCLUSION: Clinical research quality is often discussed but rarely defined. A framework defining clinical research quality across stakeholders' individual perspectives is desirable to facilitate discussion, assessment, and improvement of quality at all stages of clinical research. PMID- 28715492 TI - Small molecule perturbation of the CAND1-Cullin1-ubiquitin cycle stabilizes p53 and triggers Epstein-Barr virus reactivation. AB - The chemical probe C60 efficiently triggers Epstein-Barr Virus (EBV) reactivation from latency through an unknown mechanism. Here, we identify the Cullin exchange factor CAND1 as a biochemical target of C60. We also identified CAND1 in an shRNA library screen for EBV lytic reactivation. Gene expression profiling revealed that C60 activates the p53 pathway and protein analysis revealed a strong stabilization and S15 phosphorylation of p53. C60 reduced Cullin1 association with CAND1 and led to a global accumulation of ubiquitylated substrates. C60 also stabilized the EBV immediate early protein ZTA through a Cullin-CAND1-interaction motif in the ZTA transcription activation domain. We propose that C60 perturbs the normal interaction and function of CAND1 with Cullins to promote the stabilization of substrates like ZTA and p53, leading to EBV reactivation from latency. Understanding the mechanism of action of C60 may provide new approaches for treatment of EBV associated tumors, as well as new tools to stabilize p53. PMID- 28715493 TI - Host genetics play a critical role in controlling CD8 T cell function and lethal immunopathology during chronic viral infection. AB - Effective CD8 T cell responses are vital for the control of chronic viral infections. Many factors of the host immune response contribute to the maintenance of effector CD8 T cell responses versus CD8 T cell exhaustion during chronic infection. Specific MHC alleles and the degree of MHC heterogeneity are associated with enhanced CD8 T cell function and viral control during human chronic infection. However, it is currently unclear to what extent host genetics influences the establishment of chronic viral infection. In order to examine the impact of MHC heterogeneity versus non-MHC host genetics on the development of chronic viral infection, an F1 cross of B10.D2 x B6 (D2B6F1) and BALB.B x BALB/c (BCF1) mice were infected with the clone-13 (Cl-13) strain of lymphocytic choriomeningitis virus (LCMV). Following chronic Cl-13 infection both H-2bxd D2B6F1 and BCF1 mice demonstrated increased viral control compared to homozygous mice. Strikingly, H-2bxd D2B6F1 mice on a C57BL genetic background exhibited mortality following Cl-13 infection. CD8 T cell depletion prevented mortality in Cl-13-infected D2B6F1 mice indicating that mortality was CD8 T-cell-dependent. D2B6F1 mice maintained more CD8 T cell effector cytokine production and exhibited reduced expression of the T cell exhaustion marker PD-1. In addition, D2B6F1 mice also induced a larger Th1 response than BCF1 mice and Cl-13-induced mortality in D2B6F1 mice was also dependent on CD4 T-cell-mediated IFN-gamma production. Thus, following a chronic viral infection, increased functionality of the CD8 T cell response allowed for more rapid viral clearance at the cost of enhanced immunopathology dependent on both MHC diversity and the genetic background of the host. PMID- 28715494 TI - Development and validation of novel biomarker assays for osteoarthritis. AB - BACKGROUND: Osteoarthritis (OA) is the most common chronic joint disease usually diagnosed at relatively advanced stages when there is irreparable damage to the joint(s). Recently, we have identified two novel biomarkers C3f and V65 which appear to be OA-specific and therefore potential markers of early disease. We report the development of immunoassays for quantitative measure of these two novel biomarkers. METHOD: Monoclonal and polyclonal antibodies were generated by immunising mouse and rabbits respectively with peptide-carrier conjugates of C3f and V65. Affinity purified antibodies were used for immunoassays development and assays validated using serum from OA patients and controls. RESULTS: The ELISAs developed showed spiked recovery of up to 96% for C3f and V65 peptides depending on serum dilutions with a coefficient of variation (CV) <10%. The intra- and inter-assay CVs for C3f and V65 were 1.3-10.8% and 4.2-10.3% respectively. Both assays were insensitive for measurements of the peptides in patients and the use of different signal amplification systems did not increase assay sensitivity. CONCLUSION: We have developed two immunoassays for measurements of C3f and V65 peptides biomarkers discovered by our earlier proteomic study. These assays could detect the endogenous peptides in serum samples from patients and controls but lacked sensitivity for accurate measurements of the peptides in patients. Our study highlights the difficulties and challenges of validating biomarker from proteomic studies and demonstrates how to overcome some of the technical challenges associated with developing immunoassays for small peptides. PMID- 28715495 TI - Imagine the bright side of life: A randomized controlled trial of two types of interpretation bias modification procedure targeting adolescent anxiety and depression. AB - INTRODUCTION: Anxiety and depression are highly prevalent during adolescence and characterized by negative interpretation biases. Cognitive bias modification of interpretations (CBM-I) may reduce such biases and improve emotional functioning. However, as findings have been mixed and the traditional scenario training is experienced as relatively boring, a picture-based type of training might be more engaging and effective. METHODS: The current study investigated short- and long term effects (up to 6 months) and users' experience of two types of CBM-I procedure in adolescents with heightened symptoms of anxiety or depression (N = 119, aged 12-18 year). Participants were randomized to eight online sessions of text-based scenario training, picture-word imagery training, or neutral control training. RESULTS: No significant group differences were observed on primary or secondary emotional outcomes. A decrease in anxiety and depressive symptoms, and improvements in emotional resilience were observed, irrespective of condition. Scenario training marginally reduced negative interpretation bias on a closely matched assessment task, while no such effects were found on a different task, nor for the picture-word or control group. Subjective evaluations of all training paradigms were relatively negative and the imagery component appeared particularly difficult for adolescents with higher symptom levels. CONCLUSIONS: The current results question the preventive efficacy and feasibility of both CBM I procedures as implemented here in adolescents. PMID- 28715496 TI - Transition of phase response properties and singularity in the circadian limit cycle of cultured cells. AB - The circadian system has been regarded as a limit cycle oscillator constructed by the integrated interaction of clock genes and proteins. Here, we investigated a mammalian circadian oscillation geometrically before and after a perturbation. We detected the singular point and transition from a type 1 to type 0 phase response curve (PRC) and determined the embedding dimension to show how many variables are needed to describe the limit cycle oscillation and relaxation process after a perturbation. As a perturbation, forskolin (FK) was administered to Rat-1 cells expressing the Per2::luc gene. By broadly and finely changing the phase and strength of the perturbation, we detected the transition of the PRC from type 1 to type 0 and a possible singular transition point, the property of which agreed quite well with our numerical simulation of the noisy Goodwin model, a simple yet canonical model for the transcription-translation feedback loop of the core clock genes. Furthermore, we estimated the embedding dimension of the limit cycle before and after the perturbation. The trajectory of the limit cycle was embedded in two dimensions but with the perturbation of the state point moved out of the trajectory, the relaxation process was generally embedded in higher dimensions. The average number of embedding dimensions at each dose of FK increased as the FK dose increased but most of the relaxation process was generally embedded within four dimensions. These findings support the existence of a circadian limit cycle oscillator in mammalian cells and suggest that a small number of variables determine the relaxation process after a perturbation. PMID- 28715497 TI - Risk of gestational hypertension-preeclampsia in women with preceding endometriosis: A nationwide population-based study. AB - OBJECTIVE: To investigate the association between preceding endometriosis and gestational hypertension-preeclampsia (GH-PE). METHODS: In this nationwide population-based longitudinal study, data from 1998-2012 Taiwan National Health Insurance Research Database were used. We used ICD9-CM codes 617.X and 642.X respectively for the diagnoses of endometriosis and GH-PE, which were further confirmed by examining medical records of surgeries, blood pressure and urine protein to ensure the accuracy of the diagnoses. The study excluded women diagnosed with endometriosis at < 15 or > 45 years of age, chronic hypertension, and GH-PE prior to endometriosis. Each pregnant woman with a prior diagnosis of endometriosis was matched to 4 pregnant women without endometriosis by age. Logistic regression analysis was used to calculate odds ratios (ORs) for the risk of GH-PE with adjustment for age, occupation, urbanization, economic status and comorbidities. RESULTS: Among 6,300 women with a prior endometriosis diagnosis who were retrieved from a population of 1,000,000 residents, 2,578 (40.92%) had subsequent pregnancies that were eligible for further analysis and were compared with 10,312 pregnant women without previous endometriosis. GH-PE occurred more in women with prior endometriosis as compared to those without endometriosis (3.88% vs. 1.63%, p<0.0001). Further analysis revealed prior endometriosis was associated with GH-PE (adjusted OR = 2.27; 95% CI:1.76-2.93). For danazol-treated and non-danazol-treated subgroups, the incidences of GH-PE were 3.13% (15/480) and 4.05% (85/2,098), respectively. Although the risk for subsequent GH-PE was lower (adjusted OR = 1.49; 95% CI:0.86-2.56) after receiving danazol treatment than average (adjusted OR = 2.27; 95% CI:1.76-2.93) for women with preceding endometriosis, the reduction of risk was not statistically remarkable for danazol treated (adjusted OR = 1.49) vs. non-danazol-treated (adjusted OR = 2.48) subgroups (p heterogeneity = 0.12). CONCLUSIONS: Preceding endometriosis is an independent and significant risk factor for the occurrence of GH-PE. PMID- 28715498 TI - Growth hormone prescribing and initial BMI SDS: Increased biochemical adverse effects and costs in obese children without additional gain in height. AB - BACKGROUND: Recombinant human growth hormone (rhGH) treatment in children is usually prescribed using actual body weight. This may result in inappropriately high doses in obese children. METHODS: Retrospective audit of all paediatric patients treated with rhGH 2010-14 at a tertiary paediatric hospital in the UK. Change in height SDS and IGF-I SDS during the first year of treatment was stratified by initial BMI SDS in a mixed cohort, and a subgroup of GH deficient (GHD) patients. Alternative doses for those BMI SDS >=2.0 (Obese) were calculated using BSA, IBW and LBW. RESULTS: 354 patients (133 female) received rhGH, including 213 (60.2%) with GHD. Obesity was present in 40 patients (11.3%) of the unselected cohort, and 32 (15.0%) of the GHD cohort. For GHD patients, gain in height SDS was directly related to BMI SDS, except in obese patients (p<0.05). For both the entire cohort, and GHD patients only, IGF-1 SDS was significantly higher in obese patients (p<0.0001 for both groups). Cross sectional data identified 265 children receiving rhGH, 81 (30.5%) with a BMI-SDS >=1.75. Alternate prescribing strategies for rhGH prescribing in obese patients suggest a saving of 27% - 38% annually. CONCLUSIONS: Gain in IGF-I SDS is greater in obese children, and is likely to be related to relatively higher doses of rhGH. Additional gain in height was not achieved at the higher doses administered to obese children. Alternative dosing strategies in the obese patient population should be examined in rigorous clinical trials. PMID- 28715500 TI - Correction: Parameter estimation for multistage clonal expansion models from cancer incidence data: A practical identifiability analysis. AB - [This corrects the article DOI: 10.1371/journal.pcbi.1005431.]. PMID- 28715499 TI - Helicobacter pylori modulates host cell responses by CagT4SS-dependent translocation of an intermediate metabolite of LPS inner core heptose biosynthesis. AB - Highly virulent Helicobacter pylori cause proinflammatory signaling inducing the transcriptional activation and secretion of cytokines such as IL-8 in epithelial cells. Responsible in part for this signaling is the cag pathogenicity island (cagPAI) that codetermines the risk for pathological sequelae of an H. pylori infection such as gastric cancer. The Cag type IV secretion system (CagT4SS), encoded on the cagPAI, can translocate various molecules into cells, the effector protein CagA, peptidoglycan metabolites and DNA. Although these transported molecules are known to contribute to cellular responses to some extent, a major part of the cagPAI-induced signaling leading to IL-8 secretion remains unexplained. We report here that biosynthesis of heptose-1,7-bisphosphate (HBP), an important intermediate metabolite of LPS inner heptose core, contributes in a major way to the H. pylori cagPAI-dependent induction of proinflammatory signaling and IL-8 secretion in human epithelial cells. Mutants defective in the genes required for synthesis of HBP exhibited a more than 95% reduction of IL-8 induction and impaired CagT4SS-dependent cellular signaling. The loss of HBP biosynthesis did not abolish the ability to translocate CagA. The human cellular adaptor TIFA, which was described before to mediate HBP-dependent activity in other Gram-negative bacteria, was crucial in the cagPAI- and HBP pathway-induced responses by H. pylori in different cell types. The active metabolite was present in H. pylori lysates but not enriched in bacterial supernatants. These novel results advance our mechanistic understanding of H. pylori cagPAI-dependent signaling mediated by intracellular pattern recognition receptors. They will also allow to better dissect immunomodulatory activities by H. pylori and to improve the possibilities of intervention in cagPAI- and inflammation-driven cancerogenesis. PMID- 28715502 TI - Correction: Hard real-time closed-loop electrophysiology with the Real-Time eXperiment Interface (RTXI). AB - [This corrects the article DOI: 10.1371/journal.pcbi.1005430.]. PMID- 28715501 TI - Diversity and distribution of nuclease bacteriocins in bacterial genomes revealed using Hidden Markov Models. AB - Bacteria exploit an arsenal of antimicrobial peptides and proteins to compete with each other. Three main competition systems have been described: type six secretion systems (T6SS); contact dependent inhibition (CDI); and bacteriocins. Unlike T6SS and CDI systems, bacteriocins do not require contact between bacteria but are diffusible toxins released into the environment. Identified almost a century ago, our understanding of bacteriocin distribution and prevalence in bacterial populations remains poor. In the case of protein bacteriocins, this is because of high levels of sequence diversity and difficulties in distinguishing their killing domains from those of other competition systems. Here, we develop a robust bioinformatics pipeline exploiting Hidden Markov Models for the identification of nuclease bacteriocins (NBs) in bacteria of which, to-date, only a handful are known. NBs are large (>60 kDa) toxins that target nucleic acids (DNA, tRNA or rRNA) in the cytoplasm of susceptible bacteria, usually closely related to the producing organism. We identified >3000 NB genes located on plasmids or on the chromosome from 53 bacterial species distributed across different ecological niches, including human, animals, plants, and the environment. A newly identified NB predicted to be specific for Pseudomonas aeruginosa (pyocin Sn) was produced and shown to kill P. aeruginosa thereby validating our pipeline. Intriguingly, while the genes encoding the machinery needed for NB translocation across the cell envelope are widespread in Gram negative bacteria, NBs are found exclusively in gamma-proteobacteria. Similarity network analysis demonstrated that NBs fall into eight groups each with a distinct arrangement of protein domains involved in import. The only structural feature conserved across all groups was a sequence motif critical for cell killing that is generally not found in bacteriocins targeting the periplasm, implying a specific role in translocating the nuclease to the cytoplasm. Finally, we demonstrate a significant association between nuclease colicins, NBs specific for Escherichia coli, and virulence factors, suggesting NBs play a role in infection processes, most likely by enabling pathogens to outcompete commensal bacteria. PMID- 28715504 TI - Megalosauripus transjuranicus ichnosp. nov. A new Late Jurassic theropod ichnotaxon from NW Switzerland and implications for tridactyl dinosaur ichnology and ichnotaxomy. AB - A new ichnospecies of a large theropod dinosaur, Megalosauripus transjuranicus, is described from the Reuchenette Formation (Early-Late Kimmeridgian, Late Jurassic) of NW Switzerland. It is based on very well-preserved and morphologically-distinct tracks (impressions) and several trackways, including different preservational types from different tracksites and horizons. All trackways were excavated along federal Highway A16 near Courtedoux (Canton Jura) and systematically documented in the field including orthophotos and laserscans. The best-preserved tracks were recovered and additional tracks were casted. Megalosauripus transjuranicus is characterized by tridactyl tracks with clear claw and digital pad impressions, and notably an exceptionally large and round first phalangeal pad on the fourth digit (PIV1) that is connected to digit IV and forms the round heel area. Due to this combination of features, M. transjuranicus clearly is of theropod (and not ornithopod) origin. M. transjuranicus is compared to other Megalosauripus tracks and similar ichnotaxa and other unassigned tracks from the Early Jurassic to Early Cretaceous. It is clearly different from other ichnogenera assigned to large theropods such as Eubrontes-Grallator from the Late Triassic and Early Jurassic or Megalosauripus-Megalosauropus-Bueckeburgichnus and Therangospodus tracks from the Late Jurassic and Early Cretaceous. A second tridactyl morphotype (called Morphotype II) is different from Megalosauripus transjuranicus in being subsymmetric, longer than wide (sometimes almost as wide as long), with blunt toe impressions and no evidence for discrete phalangeal pad and claw marks. Some Morphotype II tracks are found in trackways that are assigned to M. transjuranicus, to M.? transjuranicus or M. cf. transjuranicus indicating that some Morphotype II tracks are intra-trackway preservational variants of a morphological continuum of Megalosauripus transjuranicus. On the other hand, several up to 40 steps long trackways very consistently present Morphotype II features (notably blunt digits) and do not exhibit any of the features that are typical for Megalosauripus (notably phalangeal pads). Therefore, it is not very likely that these tracks are preservational variants of Megalosauripus transjuranicus or Megalosauripus isp. These trackways are interpreted to have been left by an ornithopod dinosaur. The high frequency of large theropod tracks in tidal-flat deposits of the Jura carbonate platform, associated on single ichnoassemblages with minute to medium-sized tridactyl and tiny to large sauropod tracks has important implications for the dinosaur community and for paleoenvironmental and paleogeographical reconstructions. As with most other known occurrences of Megalosauripus tracks, M. transjuranicus is found in coastal settings, which may reflect the preference of their theropod trackmakers for expanded carbonate flats where food was abundant. PMID- 28715503 TI - Effects of preoperative aspirin on perioperative platelet activation and dysfunction in patients undergoing off-pump coronary artery bypass graft surgery: A prospective randomized study. AB - The benefit of aspirin use after coronary artery bypass graft surgery has been well proven. However, the effect of preoperative aspirin use in patients undergoing off-pump coronary artery bypass graft surgery (OPCAB) has not been evaluated sufficiently. To evaluate platelet function changes during OPCAB due to preoperative aspirin use, we conducted a randomized controlled trial using flow cytometry and the Multiplate(r) analyzer. Forty-eight patients scheduled for elective OPCAB were randomized to the aspirin continuation (100 mg/day until operative day) and discontinuation (4 days before the operative day) groups. Platelet function was measured using the platelet activation markers CD62P, CD63, and PAC-1 by flow cytometry, and platelet aggregation was measured using the Multiplate(r) analyzer, after the induction of anesthesia (baseline), at the end of the operation, and 24 and 48 h postoperatively. Findings of conventional coagulation assays, thromboelastography by ROTEM(r) assays, and postoperative bleeding-related clinical outcomes were compared between groups. No significant change in CD62P, CD63, or PAC-1 was observed at the end of the operation or 24 or 48 h postoperatively compared with baseline in either group. The area under the curve for arachidonic acid-stimulated platelet aggregation, measured by the Multiplate(r) analyzer, was significantly smaller in the aspirin continuation group (P < 0.01). However, chest tube drainage and intraoperative and postoperative transfusion requirements did not differ between groups. Our study showed that preoperative use of aspirin for OPCAB did not affect perioperative platelet activation, but it impaired platelet aggregation, which did not affect postoperative bleeding, by arachidonic acid. PMID- 28715505 TI - The clinical and immunological performance of 28 days survival model of cecal ligation and puncture in humanized mice. AB - Sepsis triggers a coordinated and thorough immune system response with long-term unfavorable sequelae after the initial insult. Long-term recovery from sepsis has garnered increasing attention recently, but a lack of suitable animal models impairs progress in this area. Our study, therefore, aimed to address the performance of the immune system in a survivable model of sepsis (cecal ligation and sepsis; CLP) for up to 28 d after the initial injury in humanized mice. Our model mimics human sepsis with weight loss and post-sepsis hypothermia. Within the first 7 d of sepsis, the M1 inflammatory cell subtype predominated, as evidenced by increased CD16 expression, but at 28 d, a mixed population of M1 and M2 inflammatory cells emerged, as evidenced by increased secretion of transforming growth factor TGFbeta and CD206 expression. This change was accompanied by normalized production of interleukin (IL)-6, tumor necrosis factor TNFalpha and IL-10 at 28 d. Furthermore, the ability of MO to become regulatory DC or the frequency of endogenous DC were severely affected at 28 days. Thus, sepsis results in profound and persistent changes in the function of myeloid cells up to 28 days after CLP demonstrating the persistence of the new acquired immunological features long after resolution of the sepsis. PMID- 28715507 TI - Independent Component Analysis (ICA) based-clustering of temporal RNA-seq data. AB - Gene expression time series (GETS) analysis aims to characterize sets of genes according to their longitudinal patterns of expression. Due to the large number of genes evaluated in GETS analysis, an useful strategy to summarize biological functional processes and regulatory mechanisms is through clustering of genes that present similar expression pattern over time. Traditional cluster methods usually ignore the challenges in GETS, such as the lack of data normality and small number of temporal observations. Independent Component Analysis (ICA) is a statistical procedure that uses a transformation to convert raw time series data into sets of values of independent variables, which can be used for cluster analysis to identify sets of genes with similar temporal expression patterns. ICA allows clustering small series of distribution-free data while accounting for the dependence between subsequent time-points. Using temporal simulated and real (four libraries of two pig breeds at 21, 40, 70 and 90 days of gestation) RNA-seq data set we present a methodology (ICAclust) that jointly considers independent components analysis (ICA) and a hierarchical method for clustering GETS. We compare ICAclust results with those obtained for K-means clustering. ICAclust presented, on average, an absolute gain of 5.15% over the best K-means scenario. Considering the worst scenario for K-means, the gain was of 84.85%, when compared with the best ICAclust result. For the real data set, genes were grouped into six distinct clusters with 89, 51, 153, 67, 40, and 58 genes each, respectively. In general, it can be observed that the 6 clusters presented very distinct expression patterns. Overall, the proposed two-step clustering method (ICAclust) performed well compared to K-means, a traditional method used for cluster analysis of temporal gene expression data. In ICAclust, genes with similar expression pattern over time were clustered together. PMID- 28715506 TI - Analysis of aquaporins from the euryhaline barnacle Balanus improvisus reveals differential expression in response to changes in salinity. AB - Barnacles are sessile macro-invertebrates, found along rocky shores in coastal areas worldwide. The euryhaline bay barnacle Balanus improvisus (Darwin, 1854) (= Amphibalanus improvisus) can tolerate a wide range of salinities, but the molecular mechanisms underlying the osmoregulatory capacity of this truly brackish species are not well understood. Aquaporins are pore-forming integral membrane proteins that facilitate transport of water, small solutes and ions through cellular membranes, and that have been shown to be important for osmoregulation in many organisms. The knowledge of the function of aquaporins in crustaceans is, however, limited and nothing is known about them in barnacles. We here present the repertoire of aquaporins from a thecostracan crustacean, the barnacle B. improvisus, based on genome and transcriptome sequencing. Our analyses reveal that B. improvisus contains eight genes for aquaporins. Phylogenetic analysis showed that they represented members of the classical water aquaporins (Aqp1, Aqp2), the aquaglyceroporins (Glp1, Glp2), the unorthodox aquaporin (Aqp12) and the arthropod-specific big brain aquaporin (Bib). Interestingly, we also found two big brain-like proteins (BibL1 and BibL2) constituting a new group of aquaporins not yet described in arthropods. In addition, we found that the two water-specific aquaporins were expressed as C terminal splice variants. Heterologous expression of some of the aquaporins followed by functional characterization showed that Aqp1 transported water and Glp2 water and glycerol, agreeing with the predictions of substrate specificity based on 3D modeling and phylogeny. To investigate a possible role for the B. improvisus aquaporins in osmoregulation, mRNA expression changes in adult barnacles were analysed after long-term acclimation to different salinities. The most pronounced expression difference was seen for AQP1 with a substantial (>100 fold) decrease in the mantle tissue in low salinity (3 PSU) compared to high salinity (33 PSU). Our study provides a base for future mechanistic studies on the role of aquaporins in osmoregulation. PMID- 28715508 TI - Biofilm extracellular polysaccharides degradation during starvation and enamel demineralization. AB - This study was conducted to evaluate if extracellular polysaccharides (EPS) are used by Streptococcus mutans (Sm) biofilm during night starvation, contributing to enamel demineralization increasing occurred during daily sugar exposure. Sm biofilms were formed during 5 days on bovine enamel slabs of known surface hardness (SH). The biofilms were exposed to sucrose 10% or glucose + fructose 10.5% (carbohydrates that differ on EPS formation), 8x/day but were maintained in starvation during the night. Biofilm samples were harvested during two moments, on the end of the 4th day and in the morning of the 5th day, conditions of sugar abundance and starvation, respectively. The slabs were also collected to evaluate the percentage of surface hardness loss (%SHL). The biofilms were analyzed for EPS soluble and insoluble and intracellular polysaccharides (IPS), viable bacteria (CFU), biofilm architecture and biomass. pH, calcium and acid concentration were determined in the culture medium. The data were analyzed by two-way ANOVA followed by Tukey's test or Student's t-test. The effect of the factor carbohydrate treatment for polysaccharide analysis was significant (p < 0.05) but not the harvest moment (p > 0.05). Larger amounts of soluble and insoluble EPS and IPS were formed in the sucrose group when compared to glucose + fructose group (p < 0.05), but they were not metabolized during starvation time (S-EPS, p = 0.93; I-EPS, p = 0.11; and IPS = 0.96). Greater enamel %SHL was also found for the sucrose group (p < 0.05) but the demineralization did not increase during starvation (p = 0.09). In conclusion, the findings suggest that EPS metabolization by S. mutans during night starvation do not contribute to increase enamel demineralization occurred during the daily abundance of sugar. PMID- 28715509 TI - Correction: A Naturally-Occurring Histone Acetyltransferase Inhibitor Derived from Garcinia indica Impairs Newly Acquired and Reactivated Fear Memories. AB - [This corrects the article DOI: 10.1371/journal.pone.0054463.]. PMID- 28715510 TI - Correction: Development and Validation of a Clinical Prediction Rule for Bacteremia among Maintenance Hemodialysis Patients in Outpatient Settings. AB - [This corrects the article DOI: 10.1371/journal.pone.0169975.]. PMID- 28715511 TI - Endovascular treatment of genetically linked aortic diseases. AB - BACKGROUND: The most important structural proteins of the vascular wall are collagen and elastin. Genetically linked connective tissue diseases lead to degeneration, aneurysm formation and spontaneous dissection or rupture of arteries. The most well-known are Marfan syndrome, vascular Ehlers-Danlos syndrome (type IV), Loeys-Dietz syndrome and familial aortic aneurysms and dissections. OBJECTIVE: This review article addresses the current status of endovascular treatment options for important connective tissue diseases. MATERIAL AND METHODS: Evaluation of currently available randomized studies and registry data. RESULTS: The treatment of choice for patients that are mostly affected at a young age is primarily conservative or open repair. There is only limited evidence for endovascular aortic repair (EVAR) of abdominal aneurysms or thoracic endovascular aortic repair (TEVAR). CONCLUSION: The progression of the disease with dilatation leads to secondary endoleaks and high reintervention rates with uncertain long-term results. For this reason, there is currently consensus that EVAR and TEVAR should be limited to justified exceptional cases and emergency situations in patients with genetically linked aortic diseases. PMID- 28715512 TI - Mouse models of deep vein thrombosis. AB - The pathogenesis of venous thromboembolism (VTE) is still not completely understood. Experimental animals in which human deep vein thrombosis can be modeled are useful tools to investigate the pathogenesis of VTE. Besides the availability of transgenic and genetically modified mice, the use of high frequency ultrasound and intravital microscopy plays an important role in identifying thrombotic processes in mouse models. In this article, an overview about the application of various new technologies and existing mouse models is provided, and the impact of venous side branches on deep vein thrombosis in the mouse model is discussed. PMID- 28715514 TI - I-SWOT as instrument to individually optimize therapy of thoracoabdominal aortic aneurysms: Effective, norm-compliant and meeting the needs. AB - BACKGROUND: Guidelines summarize medical evidence, they identify the most efficient therapy under study conditions and recommend this therapy for use. The physician now has the challenge to translate a therapy that is efficient under laboratory conditions to a patient who is an individual person. To accomplish this task the physician has to make sure that (I) the ideal typical therapy is applicable and effective in this individual patient taking the special features into consideration, that (II) therapy is compliant with the norm including guidelines, laws and ethical requirements (conformity) and that (III) the therapy meets the patient's needs. OBJECTIVE: How can physicians together with the patients translate the medical evidence into an individually optimized therapy? MATERIAL AND METHODS: At the German Aortic Center in Hamburg we use I-SWOT as an instrument to identify such individually optimized therapy. With I-SWOT, we present an instrument with which we have developed an (I) efficient, (II) conform and (III) needs-oriented therapeutic strategy for individual patients. RESULTS: I SWOT cross-tabulates strengths (S) and weaknesses (W) related to therapy with opportunities (O) and threats (T) related to individual patients. This I-SWOT matrix identifies four fundamental types of strategy, which comprise "SO" maximizing strengths and opportunities, "WT" minimizing weaknesses and threats, "WO" minimizing weaknesses and maximizing opportunities and "ST" maximizing strengths and minimizing threats. We discuss the case of a patient with asymptomatic thoracoabdominal aneurysm to show how I-SWOT is used to identify an individually optimized therapy strategy. PMID- 28715515 TI - Surgical suture releasing macrophage-targeted drug-loaded nanoparticles for an enhanced anti-inflammatory effect. AB - A surgical suture is a medical device to close the wound site of skin and organs but excessive inflammation surrounding the suture can disrupt the wound healing process. Although post-operative prescription of anti-inflammatory drugs is used to manage the inflammation, the need for local drug delivery systems has been rising because of low bioavailability and fast clearance of drugs. In this work, we proposed a new strategy for a local anti-inflammatory device by incorporating macrophage-targeted anti-inflammatory nanoparticles into the suture. For macrophage-targeted anti-inflammatory nanoparticles, poly(lactic-co-glycolic) nanoparticles were loaded with anti-inflammatory drug diclofenac and decorated with polyethylene glycol and macrophage-targeting ligand mannose. These anti inflammatory nanoparticles released diclofenac sustainably, and targeted activated macrophages efficiently. After nanoparticle optimization, a suture was coated with multiple layers of macrophage-targeted anti-inflammatory nanoparticles using a dip coating process. The suture releasing macrophage targeted anti-inflammatory nanoparticles showed an enhanced anti-inflammatory effect in both macrophage culture and excisional wound healing animal models compared to a free drug molecule-coated suture. These results suggest that anti inflammatory nanoparticle-coated sutures have great potential as an effective local delivery system to reduce inflammation and pain at the wound site. PMID- 28715516 TI - Data Sparsity in Study on Human Leukocyte Antigen Class I Genes Associated With Stevens-Johnson Syndrome and Severe Ocular Complications-Reply. PMID- 28715517 TI - Ethical Considerations for Nutrition Counseling About Processed Food-Reply. PMID- 28715513 TI - Percutaneous endovascular treatment of infrainguinal PAOD: Results of the PSI register study in 74 German vascular centers. AB - BACKGROUND: The percutaneous infrainguinal stent (PSI) register study aimed to collate all percutaneous endovascular procedures for infrainguinal peripheral arterial occlusive disease (PAOD) conducted in 74 German vascular centers between September and November 2015 (3 months). In order to obtain representative results all consecutive treatment procedures had to be submitted by the participating trial centers. MATERIAL AND METHODS: This was a prospective, nonrandomized multicenter study design. All patients suffering from intermittent claudication (IC, Fontaine stage II) or critical limb ischemia (CLI, Fontaine stages III and IV) were included. Trial centers with less than 5 cases reported within the 3 month trial period or centers that could not ensure the submission of all treated patients were excluded. RESULTS: In the final assessment 2798 treated cases from 74 trial centers were reported of which 65 (87.8 %) centers were under the leadership of a vascular surgeon. Approximately 33 % of the interventions in centers under the leadership of vascular surgeons were conducted by radiologists. Risk factors, especially chronic renal disease, diabetes and cardiac risk factors were significantly different between patients with IC and CLI. Of the patients with Fontaine stage II PAOD 41.3 % had 3 patent crural vessels compared to only 10.8 % of patients with Fontaine stage IV. With respect to peri-interventional complications, percutaneous endovascular treatment of IC was a safe procedure with severe complications in less than 1 % and no fatalities. Only 4.5 % of the procedures were conducted under ambulatory conditions. In the supragenual region self-expanding bare metal stents, standard percutaneous transluminal angioplasty (PTA) and drug-coated balloons were the most frequently used procedures. For interventions below the knee, standard PTA was the most commonly employed treatment. CONCLUSION: The main aim of the PSI study was to obtain a realistic picture of percutaneous endovascular techniques used to treat suprapopliteal and infrapopliteal PAOD lesions and to describe the treatment procedures used by vascular specialists in Germany. To investigate the change in trends for treatment over time, this study has to be repeated in the future in order to test how quickly the results of randomized studies can be implemented in practice. PMID- 28715519 TI - Nocturnal Dyspnea as a Result of a Hypopharyngeal Mass. PMID- 28715520 TI - Ethical Considerations for Nutrition Counseling About Processed Food. PMID- 28715518 TI - Early, Accurate Diagnosis and Early Intervention in Cerebral Palsy: Advances in Diagnosis and Treatment. AB - Importance: Cerebral palsy describes the most common physical disability in childhood and occurs in 1 in 500 live births. Historically, the diagnosis has been made between age 12 and 24 months but now can be made before 6 months' corrected age. Objectives: To systematically review best available evidence for early, accurate diagnosis of cerebral palsy and to summarize best available evidence about cerebral palsy-specific early intervention that should follow early diagnosis to optimize neuroplasticity and function. Evidence Review: This study systematically searched the literature about early diagnosis of cerebral palsy in MEDLINE (1956-2016), EMBASE (1980-2016), CINAHL (1983-2016), and the Cochrane Library (1988-2016) and by hand searching. Search terms included cerebral palsy, diagnosis, detection, prediction, identification, predictive validity, accuracy, sensitivity, and specificity. The study included systematic reviews with or without meta-analyses, criteria of diagnostic accuracy, and evidence-based clinical guidelines. Findings are reported according to the PRISMA statement, and recommendations are reported according to the Appraisal of Guidelines, Research and Evaluation (AGREE) II instrument. Findings: Six systematic reviews and 2 evidence-based clinical guidelines met inclusion criteria. All included articles had high methodological Quality Assessment of Diagnostic Accuracy Studies (QUADAS) ratings. In infants, clinical signs and symptoms of cerebral palsy emerge and evolve before age 2 years; therefore, a combination of standardized tools should be used to predict risk in conjunction with clinical history. Before 5 months' corrected age, the most predictive tools for detecting risk are term-age magnetic resonance imaging (86%-89% sensitivity), the Prechtl Qualitative Assessment of General Movements (98% sensitivity), and the Hammersmith Infant Neurological Examination (90% sensitivity). After 5 months' corrected age, the most predictive tools for detecting risk are magnetic resonance imaging (86%-89% sensitivity) (where safe and feasible), the Hammersmith Infant Neurological Examination (90% sensitivity), and the Developmental Assessment of Young Children (83% C index). Topography and severity of cerebral palsy are more difficult to ascertain in infancy, and magnetic resonance imaging and the Hammersmith Infant Neurological Examination may be helpful in assisting clinical decisions. In high-income countries, 2 in 3 individuals with cerebral palsy will walk, 3 in 4 will talk, and 1 in 2 will have normal intelligence. Conclusions and Relevance: Early diagnosis begins with a medical history and involves using neuroimaging, standardized neurological, and standardized motor assessments that indicate congruent abnormal findings indicative of cerebral palsy. Clinicians should understand the importance of prompt referral to diagnostic-specific early intervention to optimize infant motor and cognitive plasticity, prevent secondary complications, and enhance caregiver well-being. PMID- 28715521 TI - Association of Number of Dissected Lymph Nodes With Survival in Clinically Node Negative Oral Cavity Squamous Cell Carcinoma Patients Undergoing Primary Surgery: A Population-Based Analysis. PMID- 28715522 TI - Using Rho Kinase Inhibitors for Retinal Detachment. PMID- 28715523 TI - Pembrolizumab for Recurrent Conjunctival Melanoma. PMID- 28715524 TI - Data Sparsity in Study on Human Leukocyte Antigen Class I Genes Associated With Stevens-Johnson Syndrome and Severe Ocular Complications. PMID- 28715525 TI - Quality Metrics in Oral Cavity Cancer-Developing Standards for Optimal Lymph Node Yield. PMID- 28715526 TI - Using Rho Kinase Inhibitors for Retinal Detachment-Reply. PMID- 28715528 TI - Eyelid Mass in 6-Week-Old Girl. PMID- 28715527 TI - Screening Criteria for Ophthalmic Manifestations of Congenital Zika Virus Infection. AB - Importance: Current guidelines recommend screening eye examinations for infants with microcephaly or laboratory-confirmed Zika virus infection but not for all infants potentially exposed to Zika virus in utero. Objective: To evaluate eye findings in a cohort of infants whose mothers had polymerase chain reaction confirmed Zika virus infection during pregnancy. Design, Setting, and Participants: In this descriptive case series performed from January 2 through October 30, 2016, infants were examined from birth to 1 year of age by a multidisciplinary medical team, including a pediatric ophthalmologist, from Fernandes Figueira Institute, a Ministry of Health referral center for high-risk pregnancies and infectious diseases in children in Rio de Janeiro, Brazil. Participants: Mother-infant pairs from Rio de Janeiro, Brazil, who presented with suspected Zika virus infection during pregnancy were referred to our institution and had serum, urine, amniotic fluid, or placenta samples tested by real-time polymerase chain reaction for Zika virus. Main Outcomes and Measures: Description of eye findings, presence of microcephaly or other central nervous system abnormalities, and timing of infection in infants with confirmed Zika virus during pregnancy. Eye abnormalities were correlated with central nervous system findings, microcephaly, and the timing of maternal infection. Results: Of the 112 with polymerase chain reaction-confirmed Zika virus infection in maternal specimens, 24 infants (21.4%) examined had eye abnormalities (median age at first eye examination, 31 days; range, 0-305 days). Ten infants (41.7%) with eye abnormalities did not have microcephaly, and 8 (33.3%) did not have any central nervous system findings. Fourteen infants with eye abnormalities (58.3%) were born to women infected in the first trimester, 8 (33.3%) in the second trimester, and 2 (8.3%) in the third trimester. Optic nerve and retinal abnormalities were the most frequent findings. Eye abnormalities were statistically associated with microcephaly (odds ratio [OR], 19.1; 95% CI, 6.0-61.0), other central nervous system abnormalities (OR, 4.3; 95% CI, 1.6-11.2), arthrogryposis (OR, 29.0; 95% CI, 3.3-255.8), and maternal trimester of infection (first trimester OR, 5.1; 95% CI, 1.9-13.2; second trimester OR, 0.5; 95% CI, 0.2-1.2; and third trimester OR, 0.3; 95% CI, 0.1-1.2). Conclusions and Relevance: Eye abnormalities may be the only initial finding in congenital Zika virus infection. All infants with potential maternal Zika virus exposure at any time during pregnancy should undergo screening eye examinations regardless of the presence or absence of central nervous system abnormalities. PMID- 28715530 TI - Immunohistochemical Analysis of Capsular Contracture in Silicone Implant Rhinoplasty. PMID- 28715529 TI - Changes in Peak Airflow Measurement During Maximal Cough After Vocal Fold Augmentation in Patients With Glottic Insufficiency. AB - Importance: Compromised cough effectiveness is correlated with dysphagia and aspiration. Glottic insufficiency likely yields decreased cough strength and effectiveness. Although vocal fold augmentation favorably affects voice and likely improves cough strength, few data exist to support this hypothesis. Objective: To assess whether vocal fold augmentation improves peak airflow measurements during maximal-effort cough following augmentation. Design, Setting, and Participants: This case series study was conducted in a tertiary, academic laryngology clinic. Participants included 14 consecutive individuals with glottic insufficiency due to vocal fold paralysis, which was diagnosed via videostrobolaryngoscopy as a component of routine clinical examination. All participants who chose to proceed with augmentation were considered for the study whether office-based or operative augmentation was planned. Postaugmentation data were collected only at the first follow-up visit, which was targeted for 14 days after augmentation but varied on the basis of participant availability. Data were collected from June 5, 2014, to October 1, 2015. Data analysis took place between October 2, 2015, and March 3, 2017. Main Outcomes and Measures: Peak airflow during maximal volitional cough was quantified before and after vocal fold augmentation. Participants performed maximal coughs, and peak expiratory flow during the maximal cough was captured according to American Thoracic Society guidelines. Results: Among the 14 participants (7 men and 7 women), the mean (SD) age was 62 (18) years. Three types of injectable material were used for vocal fold augmentation: carboxymethylcellulose in 5 patients, hyaluronic acid in 5, and calcium hydroxylapatite in 4. Following augmentation, cough strength increased in 11 participants and decreased cough strength was observed in 3. Peak airflow measurements during maximal cough varied from a decrease of 40 L/min to an increase of 150 L/min following augmentation. When preaugmentation and postaugmentation peak airflow measurements were compared, the median improvement was 50 L/min (95% CI, 10-75 L/min; P = .01). Immediate peak airflow measurements during cough collected within 30 minutes of augmentation varied when compared with measurements collected at follow-up (103-380 vs 160-390 L/min). Conclusions and Relevance: Peak airflow during maximal cough may improve with vocal fold augmentation. Additional assessment and measurements are needed to further delineate which patients will benefit most regarding their cough from vocal fold augmentation. PMID- 28715531 TI - Preventing Human Immunodeficiency Virus Acquisition in Youth-Generations at Risk. PMID- 28715533 TI - Diagnosis and Treatment of Ankyloglossia in Newborns and Infants: A Review. AB - Importance: The influence of tongue tie, or ankyloglossia, on breastfeeding is the subject of growing debate. Restriction of tongue mobility from the frenulum varies greatly among newborns and infants (hereinafter referred to as infants). Controversies about whether an infant has ankyloglossia and which infants need treatment are evident with wide variations in medical practice and a lack of high quality clinical studies that provide guidance. Observations: Diagnosis and management of ankyloglossia in infants can be a source of confusion and frustration for clinicians and families. Frenotomy is a low-risk procedure that is likely to be beneficial with careful patient selection, but the natural history of untreated ankyloglossia is not well documented. The variability in presentation and treatment outcomes of ankyloglossia indicate that the complexity of infant feeding and tongue development is not fully encapsulated in a simplistic ankyloglossia etiologic framework. Conclusions and Relevance: Consistent terminology with emphasis on symptomatic ankyloglossia and a uniform grading system, such as the Hazelbaker Assessment Tool for Lingual Frenulum Function and Coryllos grading, are needed to improve the quality of research in the future. The ability to make definitive practice guidelines is limited with our current understanding of ankyloglossia. Additional research is needed to better understand the complexity of infant feeding and the role of ankyloglossia. PMID- 28715532 TI - Germline Mutation Status, Pathological Complete Response, and Disease-Free Survival in Triple-Negative Breast Cancer: Secondary Analysis of the GeparSixto Randomized Clinical Trial. AB - Importance: The GeparSixto trial provided evidence that the addition of neoadjuvant carboplatin to a regimen consisting of anthracycline, taxane, and bevacizumab increases pathological complete response (pCR) rates in patients with triple-negative breast cancer (TNBC). Whether BRCA1 and BRCA2 germline mutation status affects treatment outcome remains elusive. Objective: To determine whether BRCA1 and BRCA2 germline mutation status affects therapy response in patients with TNBC. Design, Setting, and Participants: This secondary analysis of a randomized clinical trial used archived DNA samples and cancer family history of 315 patients with TNBC enrolled between August 1, 2011, and December 31, 2012, in the GeparSixto trial. In all, 291 participants (92.4%) were included in this multicenter prospective investigation. DNA samples were analyzed for germline mutations in BRCA1, BRCA2, and 16 other cancer predisposition genes. The pCR rates between the carboplatin and noncarboplatin arms were compared. Genetic analyses were performed at the Center for Familial Breast and Ovarian Cancer in Cologne, Germany; data analysis, November 1 through December 31, 2015. Main Outcomes and Measures: Proportion of patients who achieved pCR and disease-free survival after neoadjuvant treatment according to BRCA1 and BRCA2 germline mutation status. For pCR rates, the ypT0/is ypN0 definition was used as a primary end point. Results: Of the 291 patients with TNBC, all were women; the mean (SD) age was 48 (11) years. The pCR rate in the carboplatin group was 56.8% (83 of 146) and 41.4% (60 of 145) in the noncarboplatin group (odds ratio [OR], 1.87; 95% CI, 1.17-2.97; P = .009). Pathogenic BRCA1 and BRCA2 germline mutations were present in 50 of the 291 patients (17.2%). In the noncarboplatin arm, the pCR rate was 66.7% (16 of 24) for patients with BRCA1 and BRCA2 mutations and 36.4% (44 of 121) for patients without (OR, 3.50; 95% CI, 1.39-8.84; P = .008). The high pCR rate observed in BRCA1 and BRCA2 mutation carriers (16 of 24 [66.7%]) was not increased further by adding carboplatin (17 of 26 [65.4%]). In contrast, carboplatin increased response rates in patients without BRCA1 and BRCA2 mutations: 66 of the 120 patients (55%) without BRCA1 and BRCA2 mutations achieved pCR in the carboplatin arm vs 44 of the 121 patients (36.4%) in the noncarboplatin arm (OR, 2.14; 95% CI, 1.28-3.58; P = .004). Patients without pathogenic BRCA1 and BRCA2 alterations showed elevated disease-free survival rates when carboplatin was added (without carboplatin, 73.5%; 95% CI, 64.1%-80.8% vs with carboplatin, 85.3%; 95% CI, 77.0%-90.8%; hazard ratio, 0.53; 95% CI, 0.29 0.96; P = .04). Conclusions and Relevance: Under the nonstandard GeparSixto polychemotherapy regimen, patients without BRCA1 and BRCA2 germline mutations benefited from the addition of carboplatin and those with BRCA1 and BRCA2 mutations showed superior response rates without additive effects observed for carboplatin. Trial Registration: clinicaltrials.gov Identifier: NCT01426880. PMID- 28715536 TI - Neutropenia in Patients With Multiple Sclerosis Treated With Alemtuzumab. PMID- 28715534 TI - The Association Between Vasectomy and Prostate Cancer: A Systematic Review and Meta-analysis. AB - Importance: Despite 3 decades of study, there remains ongoing debate regarding whether vasectomy is associated with prostate cancer. Objective: To determine if vasectomy is associated with prostate cancer. Data Sources: The MEDLINE, EMBASE, Web of Science, and Scopus databases were searched for studies indexed from database inception to March 21, 2017, without language restriction. Study Selection: Cohort, case-control, and cross-sectional studies reporting relative effect estimates for the association between vasectomy and prostate cancer were included. Data Extraction and Synthesis: Two investigators performed study selection independently. Data were pooled separately by study design type using random-effects models. The Newcastle-Ottawa Scale was used to assess risk of bias. Main Outcomes and Measures: The primary outcome was any diagnosis of prostate cancer. Secondary outcomes were high-grade, advanced, and fatal prostate cancer. Results: Fifty-three studies (16 cohort studies including 2 563 519 participants, 33 case-control studies including 44 536 participants, and 4 cross sectional studies including 12 098 221 participants) were included. Of these, 7 cohort studies (44%), 26 case-control studies (79%), and all 4 cross-sectional studies were deemed to have a moderate to high risk of bias. Among studies deemed to have a low risk of bias, a weak association was found among cohort studies (7 studies; adjusted rate ratio, 1.05; 95% CI, 1.02-1.09; P < .001; I2 = 9%) and a similar but nonsignificant association was found among case-control studies (6 studies; adjusted odds ratio, 1.06; 95% CI, 0.88-1.29; P = .54; I2 = 37%). Effect estimates were further from the null when studies with a moderate to high risk of bias were included. Associations between vasectomy and high-grade prostate cancer (6 studies; adjusted rate ratio, 1.03; 95% CI, 0.89-1.21; P = .67; I2 = 55%), advanced prostate cancer (6 studies; adjusted rate ratio, 1.08; 95% CI, 0.98 1.20; P = .11; I2 = 18%), and fatal prostate cancer (5 studies; adjusted rate ratio, 1.02; 95% CI, 0.92-1.14; P = .68; I2 = 26%) were not significant (all cohort studies). Based on these data, a 0.6% (95% CI, 0.3%-1.2%) absolute increase in lifetime risk of prostate cancer associated with vasectomy and a population-attributable fraction of 0.5% (95% CI, 0.2%-0.9%) were calculated. Conclusions and Relevance: This review found no association between vasectomy and high-grade, advanced-stage, or fatal prostate cancer. There was a weak association between vasectomy and any prostate cancer that was closer to the null with increasingly robust study design. This association is unlikely to be causal and should not preclude the use of vasectomy as a long-term contraceptive option. PMID- 28715535 TI - Improving Adherence to Long-term Opioid Therapy Guidelines to Reduce Opioid Misuse in Primary Care: A Cluster-Randomized Clinical Trial. AB - Importance: Prescription opioid misuse is a national crisis. Few interventions have improved adherence to opioid-prescribing guidelines. Objective: To determine whether a multicomponent intervention, Transforming Opioid Prescribing in Primary Care (TOPCARE; http://mytopcare.org/), improves guideline adherence while decreasing opioid misuse risk. Design, Setting, and Participants: Cluster randomized clinical trial among 53 primary care clinicians (PCCs) and their 985 patients receiving long-term opioid therapy for pain. The study was conducted from January 2014 to March 2016 in 4 safety-net primary care practices. Interventions: Intervention PCCs received nurse care management, an electronic registry, 1-on-1 academic detailing, and electronic decision tools for safe opioid prescribing. Control PCCs received electronic decision tools only. Main Outcomes and Measures: Primary outcomes included documentation of guideline concordant care (both a patient-PCC agreement in the electronic health record and at least 1 urine drug test [UDT]) over 12 months and 2 or more early opioid refills. Secondary outcomes included opioid dose reduction (ie, 10% decrease in morphine-equivalent daily dose [MEDD] at trial end) and opioid treatment discontinuation. Adjusted outcomes controlled for differing baseline patient characteristics: substance use diagnosis, mental health diagnoses, and language. Results: Of the 985 participating patients, 519 were men, and 466 were women (mean [SD] patient age, 54.7 [11.5] years). Patients received a mean (SD) MEDD of 57.8 (78.5) mg. At 1 year, intervention patients were more likely than controls to receive guideline-concordant care (65.9% vs 37.8%; P < .001; adjusted odds ratio [AOR], 6.0; 95% CI, 3.6-10.2), to have a patient-PCC agreement (of the 376 without an agreement at baseline, 53.8% vs 6.0%; P < .001; AOR, 11.9; 95% CI, 4.4 32.2), and to undergo at least 1 UDT (74.6% vs 57.9%; P < .001; AOR, 3.0; 95% CI, 1.8-5.0). There was no difference in odds of early refill receipt between groups (20.7% vs 20.1%; AOR, 1.1; 95% CI, 0.7-1.8). Intervention patients were more likely than controls to have either a 10% dose reduction or opioid treatment discontinuation (AOR, 1.6; 95% CI, 1.3-2.1; P < .001). In adjusted analyses, intervention patients had a mean (SE) MEDD 6.8 (1.6) mg lower than controls (P < .001). Conclusions and Relevance: A multicomponent intervention improved guideline-concordant care but did not decrease early opioid refills. Trial Registration: clinicaltrials.gov Identifier: NCT01909076. PMID- 28715537 TI - Antinuclear Antibody and Subserology Testing in the Evaluation of Fibromyalgia: A Teachable Moment. PMID- 28715538 TI - Sharing Clinical Research Data-Finding the Right Balance. PMID- 28715539 TI - Medical Assistance in Dying: Our Lessons Learned. PMID- 28715541 TI - Cerebrospinal Fluid Examination in Survivors of Ebola Virus Disease. PMID- 28715542 TI - Simultaneous Analysis of Elastic and Nonspecific Adhesive Properties of Thin Sample and Biological Cell Considering Bottom Substrate Effect. AB - A new asymptotically correct contact model has been developed for conical tip based atomic force microscopy (AFM) nanoindentation. This new model provides both elastic and nonspecific adhesion properties of cells and soft gels by taking sample thickness at the point of indentation and its depth of indentation into consideration. The bottom substrate effect (BSE) is the most common source of error in the study of "AFM force maps" of the cellular sample. The present model incorporates an asymptotically correct correction term as a function of depth of indentation to eliminate the substrate effect in the analysis. Later, the model is extended to analyze the unloading portion of the indentation curve to extract the stiffness and adhesive properties simultaneously. A comparative study of the estimated material properties using other established contact models shows that the provided corrections effectively curb the errors coming from infinite thickness assumption. Nonspecific adhesive nature of a cell is represented in terms of adhesion parameter (gammaa) based on the "work of adhesion," this is an alternative to the peak value of tip-sample attractive (negative) force commonly used as representative adhesion measurement. The simple analytical expression of the model can help in estimating more realistic and accurate biomechanical properties of cells from atomic force microscopy based indentation technique. PMID- 28715540 TI - Predictors of Hand-Foot Syndrome and Pyridoxine for Prevention of Capecitabine Induced Hand-Foot Syndrome: A Randomized Clinical Trial. AB - Importance: Hand-foot syndrome (HFS) is a common adverse effect of capecitabine treatment. Objective: To compare the incidence and time to onset of grade 2 or greater HFS in patients receiving pyridoxine vs placebo and to identify biomarkers predictive of HFS. Design, Setting, and Participants: This single center, randomized double-blind, placebo-controlled phase 3 trial conducted at National Cancer Centre Singapore assessed whether oral pyridoxine could prevent the onset of grade 2 or higher HFS in 210 patients scheduled to receive single agent capecitabine chemotherapy for breast, colorectal, and other cancers. Interventions: Patients were randomized to receive concurrent pyridoxine (200 mg) or placebo daily for a maximum of 8 cycles of capecitabine, with stratification by sex and use in adjuvant or neoadjuvant vs palliative setting. Patients were withdrawn from the study on development of grade 2 or higher HFS or cessation of capecitabine. Main Outcomes and Measures: Primary end point was the incidence of grade 2 or higher HFS in patients receiving pyridoxine. Secondary end points included the time to onset (days) of grade 2 or higher HFS and identification of biomarkers predictive of HFS, including baseline folate and vitamin B12 levels, as well as genetic polymorphisms with genome-wide arrays. Results: In this cohort of 210 patients (median [range] age, 58 [26-82] years; 162 women) grade 2 or higher HFS occurred in 33 patients (31.4%) in the pyridoxine arm vs 39 patients (37.1%) in the placebo arm (P = .38). The median time to onset of grade 2 or higher HFS was not reached in both arms. In univariate analysis, the starting dose of capecitabine (odds ratio [OR], 1.99; 95% CI, 1.32-3.00; P = .001), serum folate levels (OR, 1.27; 95% CI, 1.10-1.47; P = .001), and red blood cell folate levels (OR, 1.25; 95% CI, 1.08-1.44; P = .003) were associated with increased risk of grade 2 or higher HFS. In multivariate analyses, serum folate (OR, 1.30; 95% CI, 1.12-1.52; P < .001) and red blood cell folate (OR, 1.28; 95% CI, 1.10 1.49; P = .001) were the only significant predictors of grade 2 or higher HFS. Grade 2 or higher HFS was associated with 300 DNA variants at genome-wide significance (P < 5 * 10-8), including a novel DPYD variant (rs75267292; P = 1.57 * 10-10), and variants in the MACF1 (rs183324967, P = 4.80 * 10-11; rs148221738, P = 5.73 * 10-10) and SPRY2 (rs117876855, P < 1.01 * 10-8; rs139544515, P = 1.30 * 10-8) genes involved in wound healing. Conclusions and Relevance: Pyridoxine did not significantly prevent or delay the onset of grade 2 or higher HFS. Serum and red blood cell folate levels are independent predictors of HFS. Trial Registration: clinicaltrials.gov Identifier: NCT00486213. PMID- 28715543 TI - Determining the light scattering and absorption parameters from forward-directed flux measurements in cardiac tissue. AB - We describe a method to accurately measure the light scattering model parameters from forward-directed flux (FDF) measurements carried out with a fiber-optic probe (optrode). Improved determination of light scattering parameters will, in turn, permit better modeling and interpretation of optical mapping in the heart using voltage-sensitive dyes. Using our optrode-based system, we carried out high spatial resolution measurements of FDF in intact and homogenized cardiac tissue, as well as in intralipid-based tissue phantoms. The samples were illuminated with a broad collimated beam at 660 and 532 nm. Measurements were performed with a plunge fiber-optic probe (NA=0.22) at a spatial resolution of up to 10 MUm. In the vicinity of the illuminated surface, the FDF consistently manifested a fast decaying exponent with a space constant comparable with the decay rate of ballistic photons. Using a Monte Carlo model, we obtained a simple empirical formula linking the rate of the fast exponent to the scattering coefficient, the anisotropy parameter g, and the numerical aperture of the probe. The estimates of scattering coefficient based on this formula were validated in tissue phantoms. Potential applications of optical fiber-based FDF measurements for the evaluation of optical parameters in turbid media are discussed. PMID- 28715545 TI - "Bad at Faces"-A Prosopagnosic's Tale. PMID- 28715544 TI - Ultrafast optical recording reveals distinct capsaicin-induced ion dynamics along single nociceptive neurite terminals in vitro. AB - Pain signals are detected by terminals of nociceptive peripheral fibers situated among the keratinocytes and epithelial cells. Despite being key structures for pain-related stimuli detection and transmission, little is known about the functional organization of terminals. This is mainly due to their minute size, rendering them largely inaccessible by conventional experimental approaches. Here, we report the implementation of an ultrafast optical recording approach for studying cultured neurite terminals, which are readily accessible for assay manipulations. Using this approach, we were able to study capsaicin-induced calcium and sodium dynamics in the nociceptive processes, at a near-action potential time resolution. The approach was sensitive enough to detect differences in latency, time-to-peak, and amplitude of capsaicin-induced ion transients along the terminal neurites. Using this approach, we found that capsaicin evokes distinctive calcium signals along the neurite. At the terminal, the signal was insensitive to voltage-gated sodium channel blockers, and showed slower kinetics and smaller signal amplitudes, compared with signals that were measured further up the neurite. These latter signals were mainly abolished by sodium channel blockers. We propose this ultrafast optical recording approach as a model for studying peripheral terminal signaling, forming a basis for studying pain mechanisms in normal and pathological states. PMID- 28715547 TI - Identifying the Dimensionality of Oral Language Skills of Children With Typical Development in Preschool Through Fifth Grade. AB - Purpose: Language is a multidimensional construct from prior to the beginning of formal schooling to near the end of elementary school. The primary goals of this study were to identify the dimensionality of language and to determine whether this dimensionality was consistent in children with typical language development from preschool through 5th grade. Method: In a large sample of 1,895 children, confirmatory factor analysis was conducted with 19-20 measures of language intended to represent 6 factors, including domains of vocabulary and syntax/grammar across modalities of expressive and receptive language, listening comprehension, and vocabulary depth. Results: A 2-factor model with separate, highly correlated vocabulary and syntax factors provided the best fit to the data, and this model of language dimensionality was consistent from preschool through 5th grade. Conclusion: This study found that there are fewer dimensions than are often suggested or represented by the myriad subtests in commonly used standardized tests of language. The identified 2-dimensional (vocabulary and syntax) model of language has significant implications for the conceptualization and measurement of the language skills of children in the age range from preschool to 5th grade, including the study of typical and atypical language development, the study of the developmental and educational influences of language, and classification and intervention in clinical practice. Supplemental Materials: https://doi.org/10.23641/asha.5154220. PMID- 28715546 TI - Sensitivity to Audiovisual Temporal Asynchrony in Children With a History of Specific Language Impairment and Their Peers With Typical Development: A Replication and Follow-Up Study. AB - Purpose: Earlier, my colleagues and I showed that children with a history of specific language impairment (H-SLI) are significantly less able to detect audiovisual asynchrony compared with children with typical development (TD; Kaganovich & Schumaker, 2014). Here, I first replicate this finding in a new group of children with H-SLI and TD and then examine a relationship among audiovisual function, attention skills, and language in a combined pool of children. Method: The stimuli were a pure tone and an explosion-shaped figure. Stimulus onset asynchrony (SOA) varied from 0-500 ms. Children pressed 1 button for perceived synchrony and another for asynchrony. I measured the number of synchronous perceptions at each SOA and calculated children's temporal binding windows. I, then, conducted multiple regressions to determine if audiovisual processing and attention can predict language skills. Results: As in the earlier study, children with H-SLI perceived asynchrony significantly less frequently than children with TD at SOAs of 400-500 ms. Their temporal binding windows were also larger. Temporal precision and attention predicted 23%-37% of children's language ability. Conclusions: Audiovisual temporal processing is impaired in children with H-SLI. The degree of this impairment is a predictor of language skills. Once understood, the mechanisms underlying this deficit may become a new focus for language remediation. PMID- 28715548 TI - Interprofessional Peer-Assisted Learning as a Model of Instruction in Doctor of Audiology Programs. AB - Purpose: This study reports on interprofessional peer-assisted learning (PAL) as a model of instruction in the preparation of doctoral audiology students. Method: Ten Doctor of Audiology (AuD) students provided training in audiologic screening for 53 graduate speech-language pathology students in 9 individual PAL sessions. Pre- and post-surveys assessed the peer teaching experience for AuD students in 5 areas of their confidence in audiologic screening: knowledge, skill, making a referral based on outcomes, teaching, and supervising. Pre- and post-learning outcomes in audiologic screening for the speech-language pathology student trainees determined the effectiveness of training by their AuD student peers. Results: Survey outcomes revealed significant (p < .001) improvement in the overall confidence of AuD student peer instructors. Speech-language pathology students trained by their AuD peers exhibited significant (p = .003) improvements in their knowledge and skill and making outcome-based referrals in audiologic screening, supporting the effectiveness of the PAL paradigm. Conclusions: In addition to meeting required accreditation and professional certification competency standards, the PAL instructional model offers an innovative curricular approach in interprofessional education and in the teaching and supervisory preparation of students in doctoral audiology programs. PMID- 28715549 TI - Language Assessment With Children Who Speak Nonmainstream Dialects: Examining the Effects of Scoring Modifications in Norm-Referenced Assessment. AB - Purpose: We compared outcomes from 2 measures of language ability in children who displayed a range of dialect variation: 1 using features that do not contrast between mainstream American English (MAE) and nonmainstream dialects (NMAE), and 1 using contrastive features. We investigated how modified scoring procedures affected the diagnostic accuracy of the measure with contrastive features. Method: Second-grade students (N = 299; 167 White, 106 African American, 26 other) completed measures of language variation and ability (the Diagnostic Evaluation of Language Variation-Screening Test and the Clinical Evaluation of Language Fundamentals-Fourth Edition [CELF-4]). The CELF-4 was scored with and without the recommended scoring modifications for children who spoke African American English. Results: Partial correlations controlling for socioeconomic status revealed small to moderate correlations between measures of language ability and the use of NMAE features. Modified scoring yielded higher scores for children who spoke African American English and a reduced association between the use of NMAE features and CELF-4 scores. Modified scoring also affected the diagnostic accuracy of the CELF-4, resulting in a lower positive likelihood ratio and a higher negative likelihood ratio. Conclusions: The decision to apply scoring modifications affects both the false positive and false negative rates. Implications for language assessment for children who speak NMAE dialects are discussed, including the need for further investigation. PMID- 28715550 TI - Multidimensional Evidence Generation and FDA Regulatory Decision Making: Defining and Using "Real-World" Data. PMID- 28715551 TI - Both Urgency and Balance Needed in Addressing Opioid Epidemic: A Report From the National Academies of Sciences, Engineering, and Medicine. PMID- 28715552 TI - Large Perivascular Spaces Visible on Magnetic Resonance Imaging, Cerebral Small Vessel Disease Progression, and Risk of Dementia: The Age, Gene/Environment Susceptibility-Reykjavik Study. AB - Importance: With advancing age, an increased visibility of perivascular spaces (PVSs) on magnetic resonance imaging (MRI) is hypothesized to represent impaired drainage of interstitial fluid from the brain and may reflect underlying cerebral small vessel disease (SVD). However, whether large perivascular spaces (L-PVSs) (>3 mm in diameter) visible on MRI are associated with SVD and cognitive deterioration in older individuals is unknown. Objective: To examine whether L PVSs are associated with the progression of the established MRI markers of SVD, cognitive decline, and increased risk of dementia. Design, Setting, and Participants: The prospective, population-based Age, Gene/Environment Susceptibility-Reykjavik Study assessed L-PVSs at baseline (September 1, 2002, through February 28, 2006) on MRI studies of the brain in 2612 participants. Participants returned for additional MRI from April 1, 2007, through September 30, 2011, and underwent neuropsychological testing at the 2 time points a mean (SD) of 5.2 (0.2) years apart. Data analysis was conducted from August 1, 2016, to May 4, 2017. Exposures: The presence, number, and location of L-PVSs. Main Outcomes and Measures: Incident subcortical infarcts, cerebral microbleeds, and progression of white matter hyperintensities detected on MRI; cognitive decline defined as composite score changes between baseline and follow-up in the domains of memory, information processing speed, and executive function; and adjudicated incident dementia cases diagnosed according to international guidelines. Results: Of the 2612 study patients (mean [SD] age, 74.6 [4.8] years; 1542 [59.0%] female), 424 had L-PVSs and 2188 did not. The prevalence of L-PVSs was 16.2% (median number of L-PVSs, 1; range, 1-17). After adjusting for age, sex, and interval between baseline and follow-up scanning, the presence of L-PVSs was significantly associated with an increased risk of incident subcortical infarcts (adjusted risk ratio, 2.54; 95% CI, 1.76-3.68) and microbleeds (adjusted risk ratio, 1.43; 95% CI, 1.18-1.72) and a greater 5-year progression of white matter hyperintensity volume. The presence of L-PVSs was also associated with a steeper decline in information processing speed and more than quadrupled the risk of vascular dementia. All associations persisted when further adjusted for genetic and cerebrovascular risk factors. The associations with cognitive outcomes were independent of educational level, depression, and other SVD MRI markers. Conclusions and Relevance: Large PVSs are an MRI marker of SVD and associated with the pathogenesis of vascular-related cognitive impairment in older individuals. Large PVSs should be included in assessments of vascular cognitive impairment in the older population and as potential targets for interventions. PMID- 28715553 TI - Validation of the Children's Hospital of Philadelphia Retinopathy of Prematurity (CHOP ROP) Model. AB - Importance: The Children's Hospital of Philadelphia Retinopathy of Prematurity (CHOP ROP) model uses birth weight (BW), gestational age at birth (GA), and weight gain rate to predict the risk of severe retinopathy of prematurity (ROP). In a model development study, it predicted all infants requiring treatment, while greatly reducing the number of examinations compared with current screening guidelines. Objective: To validate the CHOP ROP model in a multicenter cohort that is large enough to obtain a precise estimate of the model's sensitivity for treatment-requiring ROP. Design, Setting, and Participants: This investigation was a secondary analysis of data from the Postnatal Growth and Retinopathy of Prematurity (G-ROP) Study. The setting was 30 hospitals in the United States and Canada between January 1, 2006, and June 30, 2012. The dates of analysis were September 28 to October 5, 2015. Participants were premature infants at risk for ROP with a known ROP outcome. Main Outcomes and Measures: Sensitivity for Early Treatment of Retinopathy of Prematurity type 1 ROP and potential reduction in the number of infants requiring examinations. In the primary analysis, the CHOP ROP model was applied weekly to predict the risk of ROP. If the risk was above a cut point level (high risk), examinations were indicated, while low-risk infants received no examinations. In a secondary analysis, low-risk infants received fewer examinations rather than no examinations. Results: Participants included 7483 premature infants at risk for ROP with a known ROP outcome. Their median BW was 1070 g (range, 310-3000 g), and their median GA was 28 weeks (range, 22-35 weeks). Among them, 3575 (47.8%) were female, and their race/ethnicity was 3615 white (48.3%), 2310 black (30.9%), 233 Asian (3.1%), 93 Pacific Islander (1.2%), and 40 American Indian/Alaskan native (0.5%). The original CHOP ROP model correctly predicted 452 of 459 infants who developed type 1 ROP (sensitivity, 98.5%; 95% CI, 96.9%-99.3%), reducing the number of infants requiring examinations by 34.3% if only high-risk infants received examinations. Lowering the cut point to capture all type 1 ROP cases (sensitivity, 100%; 95% CI, 99.2% 100%) resulted in only 6.8% of infants not requiring examinations. However, if low-risk infants were examined at 37 weeks' postmenstrual age and followed up only if ROP was present at that examination, all type 1 ROP cases would be captured, and the number of examinations performed among infants with GA exceeding 27 weeks would be reduced by 28.4%. Conclusion and Relevance: The CHOP ROP model demonstrated high but not 100% sensitivity and may be better used to reduce examination frequency. The model might be used reliably to guide a modified ROP screening schedule and decrease the number of examinations performed. PMID- 28715554 TI - Variable Practice to Enhance Speech Learning in Ultrasound Biofeedback Treatment for Childhood Apraxia of Speech: A Single Case Experimental Study. AB - Purpose: The purpose of this study was to evaluate the role of practice variability, through prosodic variation during speech sound training, in biofeedback treatment for children with childhood apraxia of speech. It was hypothesized that variable practice would facilitate speech sound learning. Method: Six children ages 8-16 years with persisting speech sound errors due to childhood apraxia of speech participated in a single-subject experimental design. For each participant, 2 speech sound targets were treated with ultrasound visual feedback training: one with prosodic variation (i.e., practicing sound targets in words and phrases spoken fast, slow, loud, as a question, command, and declarative), and one without prosodic variation. Each target was treated for half of the 1-hr session for 14 treatment sessions. Results: As measured by standardized effect sizes, all participants showed greater change on generalization probes for sound targets treated under the prosodic variation condition with mean effect sizes (d2) of 14.5 for targets treated with prosodic variation and 8.3 for targets treated without prosodic variation. The average increase in generalization scores was 38% in the prosodic variation condition compared to 31% without. Conclusions: Ultrasound visual feedback may facilitate speech sound learning and learning may be enhanced by treating speech sounds with explicit prosodic variation. Supplemental Materials: https://doi.org/10.23641/asha.5150119. PMID- 28715556 TI - Going Beyond Guideline-Concordant Opioid Therapy to Improve Patient Safety. PMID- 28715555 TI - Application of a Lifestyle-Based Tool to Estimate Premature Cardiovascular Disease Events in Young Adults: The Coronary Artery Risk Development in Young Adults (CARDIA) Study. AB - Importance: Few tools exist for assessing the risk for early atherosclerotic cardiovascular disease (ASCVD) events in young adults. Objective: To assess the performance of the Healthy Heart Score (HHS), a lifestyle-based tool that estimates ASCVD events in older adults, for ASCVD events occurring before 55 years of age. Design, Setting, and Participants: This prospective cohort study included 4893 US adults aged 18 to 30 years from the Coronary Artery Risk Development in Young Adults (CARDIA) study. Participants underwent measurement of lifestyle factors from March 25, 1985, through June 7, 1986, and were followed up for a median of 27.1 years (interquartile range, 26.9-27.2 years). Data for this study were analyzed from February 24 through December 12, 2016. Exposures: The HHS includes age, smoking status, body mass index, alcohol intake, exercise, and a diet score composed of self-reported daily intake of cereal fiber, fruits and/or vegetables, nuts, sugar-sweetened beverages, and red and/or processed meats. The HHS in the CARDIA study was calculated using sex-specific equations produced by its derivation cohorts. Main Outcomes and Measures: The ability of the HHS to assess the 25-year risk for ASCVD (death from coronary heart disease, nonfatal myocardial infarction, and fatal or nonfatal ischemic stroke) in the total sample, in race- and sex-specific subgroups, and in those with and without clinical ASCVD risk factors at baseline. Model discrimination was assessed with the Harrell C statistic; model calibration, with Greenwood-Nam-D'Agostino statistics. Results: The study population of 4893 participants included 2205 men (45.1%) and 2688 women (54.9%) with a mean (SD) age at baseline of 24.8 (3.6) years; 2483 (50.7%) were black; and 427 (8.7%) had at least 1 clinical ASCVD risk factor (hypertension, hyperlipidemia, or diabetes types 1 and 2). Among these participants, 64 premature ASCVD events occurred in women and 99 in men. The HHS showed moderate discrimination for ASCVD risk assessment in this diverse population of mostly healthy young adults (C statistic, 0.71; 95% CI, 0.66-0.76); it performed better in men (C statistic, 0.74; 95% CI, 0.68-0.79) than in women (C statistic, 0.69; 95% CI, 0.62-0.75); in white (C statistic, 0.77; 95% CI, 0.71 0.84) than in black (C statistic, 0.66; 95% CI, 0.60-0.72) participants; and in those without (C statistic, 0.71; 95% CI, 0.66-0.76) vs with (C statistic, 0.64; 95% CI, 0.55-0.73) clinical risk factors at baseline. The HHS was adequately calibrated overall and within each subgroup. Conclusions and Relevance: The HHS, when measured in younger persons without ASCVD risk factors, performs moderately well in assessing risk for ASCVD events by early middle age. Its reliance on self reported, modifiable lifestyle factors makes it an attractive tool for risk assessment and counseling for early ASCVD prevention. PMID- 28715557 TI - Overestimating the Benefit of Cancer Drugs-Reply. PMID- 28715558 TI - Prevalence of Intracranial Aneurysm in Women With Fibromuscular Dysplasia: A Report From the US Registry for Fibromuscular Dysplasia. AB - Importance: The prevalence of intracranial aneurysm in patients with fibromuscular dysplasia (FMD) is uncertain. Objective: To examine the prevalence of intracranial aneurysm in women diagnosed with FMD. Design, Setting, and Participants: This cross-sectional study included 669 women with intracranial imaging registered in the US Registry for Fibromuscular Dysplasia, an observational disease-based registry of patients with FMD confirmed by vascular imaging and currently enrolling at 14 participating US academic centers. Registry enrollment began in 2008, and data were abstracted in September 2015. Patients younger than 18 years at the time of FMD diagnosis were excluded. Imaging reports of all patients with reported internal carotid, vertebral, or suspected intracranial artery aneurysms were reviewed. Only saccular or broad-based aneurysms 2 mm or larger in greatest dimension were included. Extradural aneurysms in the internal carotid artery were included; fusiform aneurysms, infundibulae, and vascular segments with uncertainty were excluded. Main Outcomes and Measures: Percentage of women with FMD with intracranial imaging who had an intracranial aneurysm. Results: Of 1112 female patients in the registry, 669 (60.2%) had undergone intracranial imaging at the time of enrollment (mean [SD] age at enrollment, 55.6 [10.9] years). Of the 669 patients included in the analysis, 86 (12.9%; 95% CI, 10.3%-15.9%) had at least 1 intracranial aneurysm. Of these 86 patients, 25 (53.8%) had more than 1 intracranial aneurysm. Intracranial aneurysms 5 mm or larger occurred in 32 of 74 patients (43.2%), and 24 of 128 intracranial aneurysms (18.8%) were in the posterior communicating or posterior arteries. The presence of intracranial aneurysm did not vary with location of extracranial FMD involvement. A history of smoking was significantly associated with intracranial aneurysm: 42 of 78 patients with intracranial aneurysm (53.8%) had a smoking history vs 163 of 564 patients without intracranial aneurysm (28.9%; P < .001). Conclusions and Relevance: The prevalence of intracranial aneurysm in women diagnosed with FMD is significantly higher than reported in the general population. Although the clinical benefit of screening for intracranial aneurysm in patients with FMD has yet to be proven, these data lend support to the recommendation that all patients with FMD undergo intracranial imaging if not already performed. PMID- 28715560 TI - Peripheral Choroidal and Macular Retinal Vascular Nonperfusion. PMID- 28715561 TI - Giant Ocular Surface Squamous Cell Papilloma Treated With Topical Mitomycin C. PMID- 28715559 TI - Interferon-gamma Treatment of Human Laryngotracheal Stenosis-Derived Fibroblasts. AB - Importance: Laryngotracheal stenosis (LTS) is a fibroproliferative disorder of the glottis, subglottis, and trachea. In models of fibrosis from other organ systems, the CD4+ T-cell response has been shown to regulate extracellular matrix deposition. Specifically, helper T cell 2 (TH2) promotes fibrosis, whereas TH1 and associated cytokines have been shown to be antifibrotic. However, this antifibrotic effect of the TH1 response has not been demonstrated in LTS. Objective: To determine whether the TH1 cytokine interferon-gamma inhibits the function of LTS-derived fibroblasts in vitro. Design, Setting, and Participants: This in vitro controlled study included 6 patients with iatrogenic LTS undergoing routine surgical subglottic and tracheal dilation at a single institution. Fibroblasts were isolated from biopsy specimens of laryngotracheal scar and normal-appearing trachea. The presence of fibroblasts was confirmed by an immunohistochemical analysis. Laryngotracheal stenosis-derived fibroblasts were treated with interferon-gamma and compared with untreated controls (2 sets of untreated, LTS-derived fibroblasts [media did not contain interferon-gamma]) and normal airway fibroblasts (fibroblasts isolated from normal trachea). Data were collected from August 2015 through June 2016. Interventions: Treatment with interferon-gamma, 10 ng/mL. Main Outcomes and Measures: Cellular proliferation, fibrosis gene expression (using quantitative reverse transcription polymerase chain reaction analysis), soluble collagen, and cellular histologic features were assessed. Results: Among the 6 patients (6 women; mean [SD] age, 38.3 [17.2] years), LTS-derived fibroblast proliferation was reduced in patients who received interferon-gamma treatment compared with untreated controls on days 3 (mean difference, -6515 cells; 95% CI, -10 630 to -2600 cells) to 6 (mean difference, 47 521 cells; 95% CI, -81 285 to -13 757 cells). Interferon-gamma treatment reduced collagen types I and III gene expression by 86% and 68%, respectively, and resulted in lower total collagen production (10.94 vs 14.89 MUg/mL). In addition, interferon-gamma treatment resulted in a 32% reduction in expression of transforming growth factor beta in LTS-derived fibroblasts. Conclusions and Relevance: Interferon-gamma reduced proliferation, soluble collagen production, and collagen expression in LTS-derived fibroblasts while also reducing the expression of the profibrotic cytokine transforming growth factor beta. These findings suggest that therapeutics aimed at increasing interferon-gamma and the TH1 response could attenuate LTS. PMID- 28715562 TI - Ultra-Widefield Imaging of Retinal Hemorrhages Induced by Scleral Depression. PMID- 28715563 TI - Man With Femtosecond Laser Starfish Bubbles. PMID- 28715566 TI - Injurious Falls and Syncope in Older Community-Dwelling Adults Meeting Inclusion Criteria for SPRINT. PMID- 28715567 TI - Small Cell, Large Impact. PMID- 28715568 TI - Overestimating the Benefit of Cancer Drugs. PMID- 28715569 TI - What Is Medicaid? More Than Meets the Eye. PMID- 28715570 TI - Porcine and Bovine Surgical Products: Jewish, Muslim, and Hindu Perspectives Invited Critique. PMID- 28715571 TI - Liver Resection With a New Multiprobe Bipolar Radiofrequency Device-Invited Critique. PMID- 28715572 TI - Randomized Clinical Trial of Small-Incision and Laparoscopic Cholecystectomy in Patients With Symptomatic Cholecystolithiasis: Primary and Clinical Outcomes Invited Critique. PMID- 28715573 TI - Use of Vascular Clamping in Hepatic Surgery: Lessons Learned From 1260 Liver Resections-Invited Critique. PMID- 28715574 TI - The White Test: A New Dye Test for Intraoperative Detection of Bile Leakage During Major Liver Resection-Invited Critique. PMID- 28715575 TI - Saccadic suppression during voluntary versus reactive saccades. AB - Saccades are fast eye movements that reorient gaze. They can be performed voluntarily-for example, when viewing a scene-but they can also be triggered in reaction to suddenly appearing targets. The generation of these voluntary and reactive saccades have been shown to involve partially different cortical pathways. However, saccades of either type confront the visual system with a major challenge from massive image motion on the retina. Despite the fact that the whole scene is swept across the retina, a saccade usually does not elicit a percept of motion. This saccadic omission has been linked to a transient decrease of visual sensitivity during the eye movement, a phenomenon called saccadic suppression. A passive origin of saccadic suppression based on temporal masking has been proposed as well as an active central process that inhibits visual processing during the saccade. The latter one would need to include an extraretinal signal, which is generated already during saccade preparation. Since saccade generation differs for voluntary and reactive saccades, timing and nature of this extraretinal signal as well as its impact on visual sensitivity might also differ. We measured detection thresholds for luminance stimuli that were flashed during voluntary and reactive saccades and during fixation. Detection thresholds were higher during voluntary than during reactive saccades such that suppression appeared stronger during voluntary saccades. Stronger suppression in voluntary saccades could arise from a stronger extraretinal signal that activates suppression or could indicate that a suppression underlying process itself partially differs between voluntary and reactive saccades. PMID- 28715577 TI - Device Safety Implications of the Clinical Data Leading to US Food and Drug Administration Approval of Soft-Tissue Fillers: A Systematic Review. AB - Importance: The US Food and Drug Administration (FDA) recently issued a safety warning regarding soft-tissue fillers (STFs) based on the risk of blindness and facial necrosis. Objective: To examine the quality of evidence leading to FDA approval of STFs. Evidence Review: All original approvals for STFs were mined using the publicly available FDA database. The Cochrane Collaboration's risk of bias assessment tool was applied to all randomized clinical trials (RCTs). Findings: A total of 14 STF approvals were identified. Of those, 10 pivotal studies (71%) were RCTs and 9 (60%) were masked. The median number of patients per trial was 144 (range, 30-439). Eleven of 12 studies (92%) met their primary end point. Ten of 14 trials (71%) involved injections solely of the nasolabial folds or cheeks; only 4 trials involved treatment of other facial regions. All 10 RCTs had an unclear risk of selection bias. Only 2 RCTs reported exclusions and attrition. Conclusions and Relevance: Safety warnings relate more to the off label use of STFs, which has not been sufficiently studied prospectively. Although STFs remain a safe device, with approval based mostly on RCT outcomes, implementation of unique device identifiers and greater use of physician-led registries would ensure physician, consumer, and regulatory confidence in STF safety. PMID- 28715576 TI - Association of Ozone Exposure With Cardiorespiratory Pathophysiologic Mechanisms in Healthy Adults. AB - Importance: Exposure to ozone has been associated with cardiovascular mortality, but the underlying biological mechanisms are not yet understood. Objective: To examine the association between ozone exposure and cardiopulmonary pathophysiologic mechanisms. Design, Setting, and Participants: A longitudinal study involving 89 healthy adult participants living on a work campus in Changsha City, China, was conducted from December 1, 2014, to January 31, 2015. This unique quasiexperimental setting allowed for better characterization of air pollutant exposure effects because the participants spent most of their time in controlled indoor environments. Concentrations of indoor and outdoor ozone, along with the copollutants particulate matter, nitrogen dioxide, and sulfur dioxide, were monitored throughout the study period and then combined with time-activity information and filtration conditions of each residence and office to estimate 24 hour and 2-week combined indoor and outdoor mean exposure concentrations. Associations between each exposure measure and outcome measure were analyzed using single-pollutant and 2-pollutant linear mixed models controlling for ambient temperature, secondhand smoke exposure, and personal-level time-varying covariates. Main Outcomes and Measures: Biomarkers indicative of inflammation and oxidative stress, arterial stiffness, blood pressure, thrombotic factors, and spirometry were measured at 4 sessions. Results: Of the 89 participants, 25 (28%) were women and the mean (SD) age was 31.5 (7.6) years. The 24-hour ozone exposure concentrations ranged from 1.4 to 19.4 parts per billion (ppb), corresponding to outdoor concentrations ranging from 4.3 to 47.9 ppb. Within this range, in models controlling for a second copollutant and other potential confounders, a 10-ppb increase in 24-hour ozone was associated with mean increases of 36.3% (95% CI, 29.9%-43.0%) in the level of platelet activation marker soluble P-selectin, 2.8% (95% CI, 0.6%-5.1%) in diastolic blood pressure, 18.1% (95% CI, 4.5%-33.5%) in pulmonary inflammation markers fractional exhaled nitric oxide, and 31.0% (95% CI, 0.2%-71.1%) in exhaled breath condensate nitrite and nitrate as well as a 9.5% (95% CI, -17.7% to -1.4%) decrease in arterial stiffness marker augmentation index. A 10-ppb increase in 2-week ozone was associated with increases of 61.1% (95% CI, 37.8%-88.2%) in soluble P-selectin level and 126.2% (95% CI, 12.1% 356.2%) in exhaled breath condensate nitrite and nitrate level. Other measured biomarkers, including spirometry, showed no significant associations with either 24-hour ozone or 2-week ozone exposures. Conclusions and Relevance: Short-term ozone exposure at levels not associated with lung function changes was associated with platelet activation and blood pressure increases, suggesting a possible mechanism by which ozone may affect cardiovascular health. PMID- 28715578 TI - Adverse Pathologic Findings for Men Electing Immediate Radical Prostatectomy: Defining a Favorable Intermediate-Risk Group. AB - Importance: Active surveillance is recommended for patients with very low-risk (VLR) and low-risk (LR) prostate cancer. Despite controversy, recent clinical guidelines state surveillance may be considered for men with low-volume intermediate-risk (LVIR) disease. Objective: To compare rates of adverse pathologic findings among VLR, LR, and LVIR men electing immediate radical prostatectomy and evaluate criteria to define if a favorable intermediate-risk group minimizing risk exists. Design, Setting, and Participants: This was a cohort study of men (2005-July 2016) with clinically localized VLR (1264 patients), LR (4849 patients), and LVIR (608 patients) (1-2 cores, Gleason 3 + 4 = 7, prostate-specific antigen [PSA] level <20 ng/mL) prostate cancer undergoing radical prostatectomy evaluated retrospectively at Johns Hopkins Hospital. Interventions: Radical prostatectomy. Main Outcomes and Measures: The proportions of men found to have at least Gleason 4 + 3 = 7 disease and other adverse pathologic features were compared by risk group. Log-binomial regression calculated relative risk (RR) of adverse pathologic findings in the LVIR cohort compared with VLR and LR cohorts. Analyses were repeated in subgroups of the LVIR population who otherwise met criteria for VLR (T1c, PSA density [PSAD] <0.15 ng/mL/cm3, <=50% cancer in any core) and LR (<=T2a, PSA level <10 ng/mL) disease. Rates of adverse pathologic findings within the LVIR group were calculated based on various clinical thresholds, and univariable and multivariable logistic regression analyses were performed to identify predictors of adverse pathologic findings. Results: The rate of adverse pathologic findings was significantly higher for LVIR disease (150 of 608 patients [24.7%]; RR, 4.50; 95% CI, 3.73 5.43; P < .001) compared with LR disease (280 of 4849 [5.8%]), and LVIR disease (RR, 5.14; 95% CI, 3.84-6.89; P < .001) compared with men with VLR disease (60 of 1264 [4.7%]). Restriction of LVIR men to additional criteria did not significantly affect results. There were no preoperative clinical or pathologic criteria that could identify a subgroup of the LVIR population with rates of adverse pathologic findings comparable with those of the VLR and LR cohorts. PSAD was a significant predictor of adverse pathologic findings, but Gleason score had the largest effect (odds ratio, 4.30 (95% CI, 3.40-5.44; P < .001). Conclusions and Relevance: Nearly 25% of men (150 of 608) electing immediate radical prostatectomy with low-volume, Gleason 3 + 4 prostate cancer on biopsy are found to harbor adverse surgical pathologic findings. These data do not support the presence of a "favorable" subgroup among included patients and could have important implications for active surveillance in similar patients with Gleason 3 + 4 = 7 prostate cancer. PMID- 28715579 TI - Use of Neoadjuvant Platinum-The Ongoing Conundrum. PMID- 28715580 TI - Detection of Functional Change Using Cluster Trend Analysis in Glaucoma. AB - Purpose: Global analyses using mean deviation (MD) assess visual field progression, but can miss localized changes. Pointwise analyses are more sensitive to localized progression, but more variable so require confirmation. This study assessed whether cluster trend analysis, averaging information across subsets of locations, could improve progression detection. Methods: A total of 133 test-retest eyes were tested 7 to 10 times. Rates of change and P values were calculated for possible re-orderings of these series to generate global analysis ("MD worsening faster than x dB/y with P < y"), pointwise and cluster analyses ("n locations [or clusters] worsening faster than x dB/y with P < y") with specificity exactly 95%. These criteria were applied to 505 eyes tested over a mean of 10.5 years, to find how soon each detected "deterioration," and compared using survival models. This was repeated including two subsequent visual fields to determine whether "deterioration" was confirmed. Results: The best global criterion detected deterioration in 25% of eyes in 5.0 years (95% confidence interval [CI], 4.7-5.3 years), compared with 4.8 years (95% CI, 4.2-5.1) for the best cluster analysis criterion, and 4.1 years (95% CI, 4.0-4.5) for the best pointwise criterion. However, for pointwise analysis, only 38% of these changes were confirmed, compared with 61% for clusters and 76% for MD. The time until 25% of eyes showed subsequently confirmed deterioration was 6.3 years (95% CI, 6.0 7.2) for global, 6.3 years (95% CI, 6.0-7.0) for pointwise, and 6.0 years (95% CI, 5.3-6.6) for cluster analyses. Conclusions: Although the specificity is still suboptimal, cluster trend analysis detects subsequently confirmed deterioration sooner than either global or pointwise analyses. PMID- 28715581 TI - Incidence and Factors Influencing Retinal Displacement in Eyes Treated for Rhegmatogenous Retinal Detachment With Vitrectomy and Gas or Silicone Oil. AB - Purpose: The purpose of this study was to study the incidence and factors influencing retinal displacement in eyes treated for rhegmatogenous retinal detachment (RRD) with pars plana vitrectomy (PPV) and gas or silicone oil. Methods: This was a prospective observational case series. One hundred twenty five eyes with macula-off RRD from 125 patients underwent 25-gauge PPV at two vitreoretinal institutional practices. Eyes without proliferative vitreoretinopathy (PVR) or PVR grade A were tamponated with sulfur hexafluoride (SF6) gas, whereas eyes with PVR grade B received 1000 centistokes silicone oil (SO). The patients postured face-down immediately after surgery. Blue-fundus autofluorescence (B-FAF) pictures were obtained at each follow-up examination. Main outcome measures were incidence and direction of retinal displacement. Results: Ninety-seven eyes (77.6%) were tamponated with SF6 and 28 eyes (22.4%) with SO. After retinal reattachment, displacement was observed in 44 of 125 (35.2%) eyes (40 eyes in the SF6 group and 4 eyes in the SO group, respectively). The type of tamponade, specifically gas, was the only significant predictor of retinal displacement (P = 0.007). The displacement was downward in 39 (88.6%) eyes (36 tamponated with SF6 and 3 with SO) and upward in 5 (11.4%) eyes (4 tamponated with SF6 and 1 with SO). Conclusions: Displacement of the retina after repair of macula-off RRD with PPV is observed using either SF6 gas or SO. Downward and upward displacements may occur with both tamponades, but downward dislocation is more common. Of the factors potentially implicated in favoring displacement that were studied, only the type of tamponade, specifically the gas, was significant. PMID- 28715582 TI - Iris Freckles a Potential Biomarker for Chronic Sun Damage. AB - Purpose: To investigate the role of sunlight exposure in iris freckles formation. Methods: We prospectively examined volunteers attending a skin cancer screening program conducted by ophthalmologists and dermatologists. Frequency and topographical variability of iris freckles were noted and associated with behavioral and dermatologic characteristics indicating high sun exposure. Results: Six hundred thirty-two participants (n = 360; 57% female) were examined. Mean age of all participants was 38.4 +/- 18.4 years (range, 4-84 years). Of all individuals, 76.1% (n = 481) exhibited at least one iris freckle. Most freckles were observed in the inferior temporal quadrant. The presence of iris freckles was associated with higher age (participants with iris freckles: 41.8 +/- 16.8 years versus participants without iris freckles: 27.6 +/- 19.2 years), a high number of sunburns during lifetime (>10: 31% vs. 19%), sunlight-damaged skin (26% vs. 11%), presence of actinic lentigines (72% vs. 45%), and a high total nevus body count (>10; 78% vs. 67%). Conclusions: The association of iris freckles, behavioral factors, and dermatologic findings, as well as the topographical distribution, indicate that sunlight exposure may trigger the formation of iris freckles. The evaluation of iris freckles offers an easily accessible potential biomarker, which might be helpful in indicating sun damage on the skin associated with cutaneous malignancies. Furthermore, the evaluation of iris freckles could also be helpful in understanding the role of sunlight in several ophthalmologic diseases. PMID- 28715583 TI - TNFalpha-Induced Disruption of the Blood-Retinal Barrier In Vitro Is Regulated by Intracellular 3',5'-Cyclic Adenosine Monophosphate Levels. AB - Purpose: Proinflammatory cytokines such as tumor necrosis factor (TNFalpha) may have a causative role in blood-retinal barrier (BRB) disruption, which is an essential step in the development of diabetic macular edema. The purpose of our study was to determine whether TNFalpha increases permeability in an in vitro model of the BRB and to explore the mechanisms involved. Methods: Primary bovine retinal endothelial cells (BRECs) were grown on Transwell inserts and cells were stimulated with TNFalpha or a combination of TNFalpha, IL1beta, and VEGF. Molecular barrier integrity of the BRB was determined by gene and protein expression of BRB-specific components, and barrier function was assessed using permeability assays. Results: TNFalpha reduced the expression of tight and adherens junctions in BRECs. Permeability for a 376 Da molecular tracer was increased after TNFalpha stimulation, but not for larger tracers. We found that 3',5'-cyclic adenosine monophosphate (cAMP) stabilized the barrier properties of BRECs, and that TNFalpha significantly decreased intracellular cAMP levels. When BRECs were preincubated with a membrane-permeable cAMP analog, the effects of TNFalpha on claudin-5 expression and permeability were mitigated. The effects of TNFalpha on barrier function in BRECs were largely independent of the small Rho guanosine triphosphate (GTP)ases RhoA and Rac1, which is in contrast to TNFalpha effects on the nonbarrier endothelium. The combination of TNFalpha, IL1beta, and VEGF increased permeability for a 70 kDa-FITC tracer, also mediated by cAMP. Conclusions: TNFalpha alone, or in combination with IL1beta and VEGF, induces permeability of the BRB in vitro for differently sized molecular tracers mediated by cAMP, but independently of Rho/Rac signaling. PMID- 28715584 TI - Reduced Retinal Vessel Density in Obstructive Sleep Apnea Syndrome Patients: An Optical Coherence Tomography Angiography Study. AB - Purpose: To examine the retinal vasculature in patients with obstructive sleep apnea-hypopnea syndrome (OSAS) and to determine the correlation between retinal vascularity and the severity of OSAS. Design: Prospective, cross-sectional study. Methods: Sixty-nine consecutive subjects who underwent polysomnography were enrolled. Patients were divided into three groups according to the severity of OSAS, which was defined using the apnea-hypopnea index (AHI) as normal-to-mild (AHI <15), moderate (>=15 to <30), or severe (>=30). The vessel densities, and macular and retinal nerve fiber layer thicknesses were compared among the three groups. The correlations between clinical variables (age, heart rate, body mass index, ocular perfusion pressure, spherical equivalence, IOP, inner retinal thickness, and AHI) and vessel densities were also determined. Results: The full and inner parafoveal retinal thickness and the retinal nerve fiber layer thickness were similar in all three groups. The retinal vessel density decreased with greater severity of OSAS. The decrease in vessel density differed between the peripapillary and parafoveal areas. The moderate group had a significantly lower vessel density than the normal-to-mild group in the peripapillary area (P < 0.05), but similar vessel density as the normal-to-mild group in the parafoveal area (P > 0.05). The vessel densities in the parafoveal and peripapillary areas were significantly and negatively correlated with AHI (both P < 0.05); the relative reduction in vessel density was greater in the peripapillary area than in the parafoveal area. Conclusions: In OSAS patients, the vessel densities in the peripapillary and parafoveal areas decreased with greater disease severity, and the decrease was more prominent in the peripapillary area. PMID- 28715585 TI - Retinoic Acid Engineered Amniotic Membrane Used as Graft or Homogenate: Positive Effects on Corneal Alkali Burns. AB - Purpose: Alkali burns are the most common, severe chemical ocular injuries, their functional prognosis depending on corneal wound healing efficiency. The purpose of our study was to compare the benefits of amniotic membrane (AM) grafts and homogenates for wound healing in the presence or absence of previous all-trans retinoic acid (atRA) treatment. Methods: Fifty male CD1 mice with reproducible corneal chemical burn were divided into five groups, as follows: group 1 was treated with saline solution; groups 2 and 3 received untreated AM grafts or grafts treated with atRA, respectively; and groups 4 and 5 received untreated AM homogenates or homogenates treated with atRA, respectively. After 7 days of treatment, ulcer area and depth were measured, and vascular endothelial growth factor (VEGF) and matrix metalloproteinase 9 (MMP-9) were quantified. Results: AM induction by atRA was confirmed via quantification of retinoic acid receptor beta (RARbeta), a well-established retinoic acid-induced gene. Significant improvements of corneal wound healing in terms of ulcer area and depth were obtained with both strategies. No major differences were found between the efficiency of AM homogenates and grafts. This positive action was increased when AM was pretreated with atRA. Furthermore, AM induced a decrease in VEGF and MMP-9 levels during the wound healing process. The atRA treatment led to an even greater decrease in the expression of both proteins. Conclusions: Amnion homogenate is as effective as AM grafts in promoting corneal wound healing in a mouse model. A higher positive effect was obtained with atRA treatment. PMID- 28715586 TI - Iris-Claw Intraocular Lens and Scleral-Fixated Posterior Chamber Intraocular Lens Implantations in Correcting Aphakia: A Meta-Analysis. AB - Purpose: A meta-analysis to compare iris-claw intraocular lens (IC-IOL) and scleral-fixated posterior chamber intraocular lens (SF-PCIOL) implantations in correcting aphakia without sufficient capsular support. Methods: Eligible studies were collected through PubMed, Web of Science, Embase, and the Cochrane library. The pooled relative risks (RR), pooled standardized mean difference (SMD), and their 95% confidence interval of the eligible studies were then calculated. Seven studies met our inclusion criteria, involving 232 and 158 eyes in IC-IOL and SF PCIOL groups, respectively. Results: The pooled SMD of the mean postoperative corrected distance visual acuity (CDVA) (logMAR) was -0.25. The pooled RR of the eyes achieving 20/40 or better postoperatively was 1.16. The pooled SMD of the surgical time was -2.97. The pooled RR of the surgical complications was 0.86. The pooled RR of IOL dislocation, retinal detachment (RD), and cystoid macular edema (CME) between the two groups were 0.22, 0.63, and 0.64. Conclusions: Implantation of IC-IOL has a more simple procedure and shorter learning curve than SF-PCIOL implantation in correcting aphakia without sufficient capsular support. PMID- 28715587 TI - A Quantitative and Qualitative Exploration of Photoaversion in Achromatopsia. AB - Purpose: Photoaversion (PA) is a disabling and ubiquitous feature of achromatopsia (ACHM). We aimed to help define the characteristics of this important symptom, and present the first published assessment of its impact on patients' lives, as well as quantitative and qualitative PA assessments. Methods: Molecularly confirmed ACHM subjects were assessed for PA using four tasks: structured survey of patient experience, novel quantitative subjective measurement of PA, visual acuities in differing ambient lighting, and objective palpebral aperture-related PA testing. Results: Photoaversion in ACHM was found to be the most significant symptom for a substantial proportion (38%) of patients. A novel subjective PA measurement technique was developed and demonstrated fidelity with more invasive paradigms without exposing often very photosensitive patients to brighter light intensities used elsewhere. An objective PA measurement was also refined for use in trials, indicating that higher light intensities than previously published are likely to be needed. Monocular testing, as required for trials, was also validated for the first time. Conclusions: This study offers new insights into PA in ACHM. It provides the first structured evidence of the great significance of this symptom to patients, suggesting that PA should be considered as an additional outcome measure in therapeutic trials. It also offers new insights into the characteristics of PA in ACHM, and describes both subjective and objective measures of PA that could be employed in clinical trials. PMID- 28715588 TI - Caucasian Families Exhibit Significant Linkage of Myopia to Chromosome 11p. AB - Purpose: Myopia is a common visual disorder caused by eye overgrowth, resulting in blurry vision. It affects one in four Americans, and its prevalence is increasing. The genetic mechanisms that underpin myopia are not completely understood. Here, we use genotype data and linkage analyses to identify high-risk genetic loci that are significantly linked to myopia. Methods: Individuals from 56 Caucasian families with a history of myopia were genotyped on an exome-based array, and the single nucleotide polymorphism (SNP) data were merged with microsatellite genotype data. Refractive error measures on the samples were converted into binary phenotypes consisting of affected, unaffected, or unknown myopia status. Parametric linkage analyses assuming an autosomal dominant model with 90% penetrance and 10% phenocopy rate were performed. Results: Single variant two-point analyses yielded three significantly linked SNPs at 11p14.1 and 11p11.2; a further 45 SNPs at 11p were found to be suggestive. No other chromosome had any significant SNPs or more than seven suggestive linkages. Two of the significant SNPs were located in BBOX1-AS1 and one in the intergenic region between ORA47 and TRIM49B. Collapsed haplotype pattern two-point analysis and multipoint analyses also yielded multiple suggestively linked genes at 11p. Multipoint analysis also identified suggestive evidence of linkage on 20q13. Conclusions: We identified three genome-wide significant linked variants on 11p for myopia in Caucasians. Although the novel specific signals still need to be replicated, 11p is a promising region that has been identified by other linkage studies with a number of potentially interesting candidate genes. We hope that the identification of these regions on 11p as potential causal regions for myopia will lead to more focus on these regions and maybe possible replication of our specific linkage peaks in other studies. We further plan targeted sequencing on 11p for our most highly linked families to more clearly understand the source of the linkage in this region. PMID- 28715589 TI - Association Between Visual Function Response and Reduction of Inflammation in Noninfectious Uveitis of the Posterior Segment. AB - Purpose: To examine the association between visual function response (VFR) and inflammation reduction in active noninfectious uveitis of the posterior segment (NIU-PS). Methods: Phase 3 SAKURA Study 1 randomized 347 subjects in a double masked fashion to receive injections of intravitreal sirolimus 44 MUg (n = 117); 440 MUg (n = 114); or 880 MUg (n = 116) every other month. Vitreous haze (VH) response, a measure of inflammation reduction, was defined as a VH score of 0 or 0.5+ at month 5 based on the modified Standardized Uveitis Nomenclature Scale. Visual function was assessed with best-corrected visual acuity (BCVA) and the National Eye Institute (NEI) Visual Function Questionnaire-25 (VFQ-25). In this post-hoc analysis, principal component analysis was used to reduce the information in the multidimensional visual function outcome to a restricted number of independently relevant VFR measures. Minimal clinically important differences (MCID) for the VFQ-25-derived components were based on the standard error of measurements. Overall VFR was defined as either a BCVA improvement of >=2 lines, or an improvement exceeding the MCID in the VFQ-25 based visual function measures. Results: The VFQ-25 composite score (VFQCS) and mental health subscale score (VFQMHS) were retained as relevant VFRs, with MCIDs of 4.3 and 11.7 points, respectively. A vitreous haze response was significantly associated with each VFR measure: VFQCS (odds ratio [OR] = 2.23; P = 0.0004); VFQMHS (OR = 2.84; P < 0.0001); BCVA (OR = 2.60; P = 0.0009), and overall VFR (OR = 2.65; P < 0.0001). Conclusions: Inflammation reduction to a VH score of 0 or 0.5+ was significantly associated with improved visual function. Achieving a VH response of 0 or 0.5+ is a patient-relevant outcome. PMID- 28715591 TI - Choriocapillaris Flow in Myopia. PMID- 28715590 TI - Optical Coherence Tomography Features Preceding the Onset of Advanced Age-Related Macular Degeneration. AB - Purpose: Age-related macular degeneration (AMD) is a progressive disease with multifactorial etiology. There is a need to identify clinical features that are harbingers of advanced disease. We evaluated morphologic features of the retina and choroid on optical coherence tomography (OCT) to determine if they predict progression to advanced disease. Methods: Progressors transitioned from early or intermediate AMD to advanced disease (n = 40 eyes), and were matched on baseline AMD grade and follow-up interval to nonprogressors who did not develop advanced AMD (n = 40 eyes). Features of the neurosensory retina, photoreceptors, retinal pigment epithelium (RPE), and choroid were evaluated. Logistic regression was used to evaluate univariate associations between features and progression to overall advanced AMD, geographic atrophy (GA), and neovascular disease (NV). Multivariate associations based on stepwise regression models were also assessed. Results: Ellipsoid zone disruption was associated with progression to overall advanced AMD and NV (odds ratios [ORs]: 17.9 and 30.6; P < 0.001), with a similar trend observed for GA. Drusenoid RPE detachment, RPE thickening, and retinal pigmentary hyperreflective material were significantly associated with higher risk of progression to advanced AMD (ORs: 5.0-8.5) and NV (ORs: 10.8-17.2). Pigmentary hyperreflective material was associated with progression to GA (OR: 7.5, P = 0.009). Total retinal thickness, pigmentary hyperreflective material, nascent GA features, and choroidal vessel abnormalities were independently associated with progression to advanced AMD in a multivariate stepwise model. Conclusions: Abnormalities in the photoreceptors, retinal thickness, RPE, and choroid were associated with higher risk of developing advanced AMD. These findings provide insights into disease progression, and may be helpful to identify earlier endpoints for clinical studies. PMID- 28715592 TI - Inter-Relationship of Arterial Supply to Human Retina, Choroid, and Optic Nerve Head Using Micro Perfusion and Labeling. AB - Purpose: The prevailing view is that the human retina is supplied by the central retinal artery (CRA), the short posterior ciliary arteries (SPCAs) support the choroid, and both the CRA and the SPCAs are so-called "end artery" systems. In this study, we investigate whether vascular connections among the retina, choroid, and the optic nerve head (ONH) exist, using selective cannulation and microperfusion-labeling techniques. Methods: The CRA and/or one or more of the SPCAs were selected for cannulation in 18 human donor eyes. Fluorescent probes with different excitation wavelengths were perfused through different arteries on the same eye to distinguish the supply sources of different vascular beds. After labeling and fixation, the ONH region was dissected either longitudinally or transversely as thick sections for confocal microscopy. Retina, choroid, and ONH were imaged from whole-mount specimens. Results: Probes perfused through the CRA or the SPCA alone labeled the microvessels in the retina, choroid, and ONH regions, as well as the optic nerve trunk. The vessels of the lamina cribrosa and the optic nerve trunk were labeled when probes were perfused through the SPCA. Perfusion through both the CRA and SPCA produced double labeling of vessels in the retina, the choroid, and the ONH. Conclusions: The results indicate an inter relationship of arterial supply to the retina, choroid, and ONH in the human eye. This has important implications in understanding clinical observations and disease mechanisms such as that of glaucoma and ischemic optic nerve disease. PMID- 28715593 TI - Physical Exercise Improves Total Antioxidant Capacity and Gene Expression in Rat Hippocampal Tissue. AB - Exercise may exert beneficial effects on cognitive functions and play an important role in the prevention of neurodegenerative diseases. Such effects seem to be mediated by changes in anti-oxidative status, but limited information is available on the nature of molecular pathways supporting the antioxidant effects of exercise in the brain. In this study 3-5-month-old male Wistar albino rats were subjected to three times/week moderate intensity exercise on a rodent treadmill for a period of 6 weeks. The tissue antioxidant activity towards various reactive oxygen species (ROS) was determined in the hippocampus. In addition, to identify the molecular pathways that may be involved in ROS metabolism, the expression of nerve growth factor (NGF) and sirtuins (SIRT1 and SIRT3) were measured. Our results showed a higher antioxidant activity in the hippocampus of physically trained rats compared to sedentary controls. Furthermore, exercise induced an up-regulation of NGF, possibly related to an improved redox balance in the hippocampus. These results suggest that physical exercise might prevent age-induced oxidative damage in the hippocampus. PMID- 28715594 TI - Physical exercise and oxidative stress in muscular dystrophies: is there a good balance? AB - The effect of oxidative stress on muscle damage inducted by physical exercise is widely debated. It is generally agreed that endurance and intense exercise can increase oxidative stress and generate changes in antioxidant power inducing muscle damage; however, regular and moderate exercise can be beneficial for the health improving the antioxidant defense mechanisms in the majority of cases. Growing evidences suggest that an increased oxidative/nitrosative stress is involved in the pathogenesis of several muscular dystrophies (MDs). Notably, physical training has been considered useful for patients with these disorders. This review will focus on the involvement of oxidative stress in MDs and on the possible effects of physical activities to decrease oxidative damage and improve motor functions in MDs patients. PMID- 28715595 TI - Lifestyle, Physical Activity and Cognitive Functions: the impact on the scores of Montreal Cognitive Assessment (MoCa). AB - The Montreal Cognitive Assessment (MoCA) is a rapid screening tool, including subtests to assess several cognitive domains, developed to detect MCI from normal ageing cognitive changes. Several validation and normative studies have conducted around the world considering the influences of age and education on the MoCA score, but none takes into account the lifestyle and habits. However, lifestyles, and particularly physical activity (PA) have been positively associated with both physical and mental health in elderly. The aim of the present study is to investigate the influence of regularly practiced PA on the MoCA scores in a sample of Italian healthy elderly males. For this purpose sixty-five healthy adult males, aged 65-81 years were assigned to two groups, physically active group (PAG, N=33), and sedentary group (SG, N=32), according to recommended levels of physical activity by the World Health Organization. The Italian version of MoCA was administered to each participant. Raw data were analysed by a multiple regression model in which the independent variables were PA, age and education. Results showed a highly significant influence of PA on MoCA total score and on several cognitive domain sub-scores. Furthermore, multiple regression analysis indicated a larger impact on scores by PA than both age and education. In the light of these findings, it is advisable to pay attention to the life style of subject that undergoing a neuropsychological evaluation like the MoCa and in particular the level of PA practiced, as well as age and education. PMID- 28715596 TI - Influence of physical exercise on beta-amyloid, alpha-synuclein and tau accumulation: an in vitro model of oxidative stress in human red blood cells. AB - A common pathological feature of neurodegenerative disorders (NDs), such as Alzheimer's (AD) and Parkinson's (PD) diseases, is the abnormal accumulation and misfolding of specific proteins, primarily alpha-synuclein (alpha-syn), beta amyloid1-42 (Abeta) and tau, in brain and in peripheral tissues too. Oxidative stress has been proved to be involved in NDs at various levels and, in particular, in such protein alterations, on the contrary physical activity is emerging as a counteracting factor in NDs. In the present work, the content of Abeta, alpha-syn and tau in red blood cells (RBCs) derived from ten endurance athletes (ATHL) and ten sedentary volunteers (SED) were compared before and after in vitrooxidative stress treatment. Total Abeta, alpha-syn and tau were quantified in RBCs (isolated from the subjects) by immunoenzymatic assays. Oxidative stress was induced by in vitro H2O2 administration to RBCs. H2O2 treatment was confirmed to significantly enhance ROS accumulation in RBCs. Total Abeta content in RBCs was lower in the ATHL subgroup with respect to the SED one. In the SED subgroup, but not in the ATHL one, total Abeta levels were increased by oxidative stress. Total alpha-syn content was lower in the ATHL subgroup with respect to the SED one and alpha-syn levels were increased by oxidative stress in both subgroups, with the percentage of increase higher in SED. Total tau content was comparable in both ATHL and SED and it was not affected by oxidative stress. Our data confirm previous findings evidencing that both oxidative stress and sedentary style contribute to aberrant folding and accumulation of NDs-related proteins, pointing to the importance of both anti-oxidant therapies and exercising in the prevention and treating of such diseases. PMID- 28715597 TI - The proposal of a clinical protocol to assess central and peripheral fatigue in myotonic dystrophy type 1. AB - DM1 is an autosomal-dominant disorder characterized by muscle weakness, myotonia, and multisystemic involvement. According to current literature fatigue and daytime sleepiness are among the main symptoms of DM1. Oxidative stress has been proposed to be one of the pathogenic factors of fatigue consequent to DM1. In this study, we investigated the dimensions of experienced fatigue and physiological fatigue in a sample of 26 DM1 patients (17 males, 9 females, mean age 41.6 years, SD+/-12.7); experienced fatigue has been studied through Fatigue Severity Scale (FSS), and physiological fatigue was measured through an intermittent incremental exercise of the forearm muscles using a myometer; oxidative stress balance markers trend during aerobic exercise test have been collected. The occurrence of central fatigue in the sample means that central activation worsens during the motor contraction; interestingly FSS score was significantly correlated to MVC (before and after the effort, r-before=-0.583, p<0.01, r-after= -0.534, p<0.05), and to motor disability measured by MRC (r= 0.496, p<0.05); moreover we found a strong tendency towards significance in the association to lactate baseline (r=0.378, p=0.057).Results are discussed to define whether or not, based on clinical and laboratory grounds, such exercise training protocol may be suitable for proper management of DM1 patients; proper assessment of fatigue should be included in algorithms for data collection in DM1 patient registries. PMID- 28715598 TI - Aerobic exercise effects upon cognition in Mild Cognitive Impairment: A systematic review of randomized controlled trials. AB - Several studies have shown that physical activity has positive effects on cognition in healthy older adults without cognitive complains but lesser is known about the effectiveness of aerobic exercise in patients suffering from Mild Cognitive Impairment (MCI). The aim of the present study was to systematically review the evidence from randomized controlled trials (RCTs) about the effects of aerobic exercise upon cognition in MCI patients. To this end, PubMed, Cochrane and Web of Science databases were analytically searched for RCTs including aerobic exercise interventions for MCI patients. There is evidence that aerobic exercise improves cognition in MCI patients. Overall research reported moderate effects for global cognition, logical memory, inhibitory control and divided attention. Due to methodological limitations of the investigated studies, findings should be interpreted with caution. Standardized training protocols, larger scale interventions and follow-ups may also provide better insight into the preventive effects of aerobic exercise on cognitive deterioration in MCI and its conversion into dementia. PMID- 28715599 TI - Dreamlike events are correlated with the length of sleep mentation reports. AB - We investigated the relationship between length and dreamlike quality in sleep mentation reports. Reports were obtained by waking subjects at sleep onset (SO) and at 5 and 10 minutes into the second (REMP2) and fourth REM periods (REMP4). Reports were recorded, transcribed, and scored blindly for total word count (TWC) and dreamlike quality as measured by a composite dream scale score (CDS). Dreamlike quality was strongly correlated with TWC; both CDS and TWC scores increased across successively later awakenings. Significant differences were found in both TWC and CDS between SO and REMP4 and also between REMP2 and REMP4; however, differences were not significant between SO and REMP2 or between the 5 and 10 minute awakenings in REMPs 2 and 4. These findings provide further evidence that the amount of dreamlike mentation is related to the within-sleep arousal level rather than to REMP duration and that the dreamlike quality of reports increases as they become longer. PMID- 28715600 TI - Ultrastructural study of the neural microcircuits in the sensory epithelium of the paratympanic organ of the chicken. AB - The paratympanic organ (PTO) is a sensory organ located in the medial wall of the tympanic cavity of birds. The organ looks like a small tapering vesicle, and is equipped with a sensory epithelium formed by supporting cells (SCs) and Type II hair cells (Type II-HCs). The function of the PTO has not yet been precisely defined. The prevailing current hypothesis is that the PTO assesses the air pressure exerted on the external surface of the tympanic membrane. The PTO could may thus function as a barometer and, in flying birds, also as an altimeter. The afferent synapses of the PTO of chicken were described in detail in a previous paper. Reciprocal synapses between efferent nerve endings (ENEs) and the HCs were also observed, suggesting the existence of local microcircuits. The aim of this work was to provide a more detailed ultrastructural description of these microcircuits in the PTO of chicken. We observed for the first time: (1) reciprocal synapses between the HCs and the afferent nerve endings (ANEs); (2) presence of two distinct types of ENEs; (3) reciprocal synapses between the HCs and both types of ENEs. Overall, these results indicate that a complex processing of the incoming sensory signals may occur in the PTO. This thus suggests that the PTO may perform more complex functions than those supposed until now. We hypothesize that the PTO could have a role in the low-frequency sound perception. PMID- 28715601 TI - Methamphetamine increases Prion Protein and induces dopamine-dependent expression of protease resistant PrPsc. AB - The cellular prion protein (PrPc) is physiologically expressed within selective brain areas of mammals. Alterations in the secondary structure of this protein lead to scrapie-like prion protein (PrPsc), which precipitates in the cell. PrPsc has been detected in infectious, inherited or sporadic neurodegenerative disorders. Prion protein metabolism is dependent on autophagy and ubiquitin proteasome. Despite not being fully elucidated, the physiological role of prion protein relates to chaperones which rescue cells under stressful conditions.Methamphetamine (METH) is a widely abused drug which produces oxidative stress in various brain areas causing mitochondrial alterations and protein misfolding. These effects produce a compensatory increase of chaperones while clogging cell clearing pathways. In the present study, we explored whether METH administration modifies the amount of PrPc. Since high levels of PrPc when the clearing systems are clogged may lead to its misfolding into PrPsc, we further tested whether METH exposure triggers the appearance of PrPsc. We analysed the effects of METH and dopamine administration in PC12 and striatal cells by using SDS-PAGE Coomassie blue, immune- histochemistry and immune-gold electron microscopy. To analyze whether METH administration produces PrPsc aggregates we used antibodies directed against PrP following exposure to proteinase K or sarkosyl which digest folded PrPc but misfolded PrPsc. We fond that METH triggers PrPsc aggregates in DA-containing cells while METH is not effective in primary striatal neurons which do not produce DA. In the latter cells exogenous DA is needed to trigger PrPsc accumulation similarly to what happens in DA containing cells under the effects of METH. The present findings, while fostering novel molecular mechanisms involving prion proteins, indicate that, cell pathology similar to prion disorders can be mimicked via a DA dependent mechanism by a drug of abuse. PMID- 28715602 TI - Winter storm intensity, hazards, and property losses in the New York tristate area. AB - Winter storms pose numerous hazards to the Northeast United States, including rain, snow, strong wind, and flooding. These hazards can cause millions of dollars in damages from one storm alone. This study investigates meteorological intensity and impacts of winter storms from 2001 to 2014 on coastal counties in Connecticut, New Jersey, and New York and underscores the consequences of winter storms. The study selected 70 winter storms on the basis of station observations of surface wind strength, heavy precipitation, high storm tide, and snow extremes. Storm rankings differed between measures, suggesting that intensity is not easily defined with a single metric. Several storms fell into two or more categories (multiple-category storms). Following storm selection, property damages were examined to determine which types lead to high losses. The analysis of hazards (or events) and associated damages using the Storm Events Database of the National Centers for Environmental Information indicates that multiple category storms were responsible for a greater portion of the damage. Flooding was responsible for the highest losses, but no discernible connection exists between the number of storms that afflict a county and the damage it faces. These results imply that losses may rely more on the incidence of specific hazards, infrastructure types, and property values, which vary throughout the region. PMID- 28715603 TI - An Exploratory Study on Exemplary Practice of Nurse Consultants. AB - PURPOSE: To examine the exemplary practice of nurse consultants (NCs) and derive a model to illustrate the highest level of advanced nursing practice. DESIGN: A descriptive study was conducted to examine the practice and outcomes of seven NC roles in varied clinical specialties in Hong Kong. Exemplary practice was examined in relation to competencies for advanced practice nursing in Hong Kong and the United Kingdom. METHODS: Data about NC characteristics and their practices were collected using a structured questionnaire and analyzed using descriptive statistics. Health service documents and clinical notes were analyzed using the framework approach. FINDINGS: All NCs demonstrated the competence expected of an advanced practice nurse with impacts on patients, nursing profession, and the organization as identified in the advanced nursing practice framework in Hong Kong. NCs also performed at the highest level of practice delineated by Skills for Health in the United Kingdom. They were involved in diagnostic and therapeutic practice, and identified patient satisfaction and symptom management as key outcomes. CONCLUSIONS: This study provides new insight into levels of advanced practice and illustrates the exemplary work of NCs to demonstrate how they have developed and shaped services to bring about positive patient and organizational outcomes. Career laddering that places NCs at the highest level of advanced practice is important for making the best use of nursing expertise to achieve optimal patient and organizational outcomes. CLINICAL RELEVANCE: This study addresses a knowledge gap to enrich our current understanding of the impact of advanced practice nursing roles by linking NC role practices and competencies to key outcomes. PMID- 28715604 TI - Antioxidant Activities and Phenolic Compounds of Several Tissues of Pawpaw (Asimina triloba [L.] Dunal) Grown in Korea. AB - Pawpaw (Asimina triloba [L.] Dunal) possesses antioxidant compounds and strong inhibitors of cancer cells, and is widely cultivated in North America, Canada, and Korea. We analyzed the total phenolic and total flavonoid contents (TPC and TFC, respectively) of pawpaw plants grown in Korea and the antioxidant activities of their roots, twigs, leaves, and fruit with respect to 1,1-diphenyl-2-picryl hydrazyl (DPPH) radical scavenging activity, 2,2'-azino-bis diammonium salt (ABTS) radical scavenging activity, ferrous (Fe2+ ) chelating ability, and nitrite scavenging activity. Pearson's correlation analyses revealed a linear correlation between TPC and antioxidant activities (r2 >0.69). Root methanol extracts had higher TPC and antioxidant activities than other extracts, which was also consistent with those from the phenolic compounds found in those extracts. Therefore, antioxidant activities seem to depend on the TPC of each pawpaw tissue and pawpaw roots might be useful as a natural source of natural antioxidants. PMID- 28715605 TI - How to select a nanosimilar. AB - Nanomedicines in the class of nonbiological complex drugs (NBCDs) are becoming increasingly available. Up to 23 nanomedicines have been approved, and approximately 50 are in clinical development. Meanwhile, the first nanosimilars have entered the market through the generic approval pathway, but clinical differences have been observed. Many healthcare professionals may be unaware of this issue and must be informed of these clinically relevant variances. This article provides a tool for rational decision making for the inclusion of nanomedicines into the hospital formulary, including defined criteria for evaluation of substitutability or interchangeability. The tool was generated by conducting a roundtable with an international panel of experts and follows the same thought process that was developed and published earlier for the selection of biologicals/biosimilars. In addition to the existing criteria for biosimilars, a set of seven criteria was identified that specifically apply to nanosimilars. These include (1) particle size and size distribution, (2) particle surface characteristics, (3) fraction of uncaptured bioactive moiety, (4) stability on storage, (5) bioactive moiety uptake and (6) distribution, and (7) stability for ready-to-use preparation. Pharmacists should utilize their pharmaceutical expertise to use the appropriate criteria to evaluate the comparability of the drug to decide on interchangeability or substitutability. PMID- 28715606 TI - Enzymatic mechanisms of biological magnetic sensitivity. AB - Primary biological magnetoreceptors in living organisms is one of the main research problems in magnetobiology. Intracellular enzymatic reactions accompanied by electron transfer have been shown to be receptors of magnetic fields, and spin-dependent ion-radical processes can be a universal mechanism of biological magnetosensitivity. Magnetic interactions in intermediate ion-radical pairs, such as Zeeman and hyperfine (HFI) interactions, in accordance with proposed strict quantum mechanical theory, can determine magnetic-field dependencies of reactions that produce biologically important molecules needed for cell growth. Hyperfine interactions of electrons with nuclear magnetic moments of magnetic isotopes can explain the most important part of biomagnetic sensitivities in a weak magnetic field comparable to the Earth's magnetic field. The theoretical results mean that magnetic-field dependencies of enzymatic reaction rates in a weak magnetic field that can be independent of HFI constant a, if H << a, and are determined by the rate constant of chemical transformations in the enzyme active site. Both Zeeman and HFI interactions predict strong magnetic-field dependence in weak magnetic fields and magnetic-field independence of enzymatic reaction rate constants in strong magnetic fields. The theoretical results can explain the magnetic sensitivity of E. coli cell and demonstrate that intracellular enzymatic reactions are primary magnetoreceptors in living organisms. Bioelectromagnetics. 38:511-521, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28715607 TI - Variation in the dielectric properties of freshly excised colorectal cancerous tissues at different tumor stages. AB - The study was designed to identify differences in the dielectric properties of ex vivo colorectal cancerous tissues at different tumor stages. To date, 130 freshly excised colorectal cancerous specimens underwent measurement of both relative permittivity and conductivity on the serosal and mucosal surfaces of the carcinoma nidus, and the mucosa of the surgical resection margin ranging from 50 to 500 MHz at the Larmor frequencies. Tumor node metastasis staging was determined according to pathological reports for each patient. There were statistically significant differences in the relative permittivity of both colorectal cancerous serosa and mucosa among stages <=I, II, III, and IV and between stages <=II and >=III (P < 0.05) at most frequencies under 300 MHz; statistically significant differences in conductivity were also observed for most of the measured frequencies (P < 0.05). The significant differences in dielectric characteristics among tumor stages, especially between early and advanced stages, have value for selecting appropriate surgical strategies. The presented ex vivo data provide important information for magnetic resonance electrical properties tomography in vivo system because the frequencies of 64 MHz (1.5T) and 128 MHz (3T) are usually used in clinical settings. Bioelectromagnetics. 38:522-532, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28715609 TI - New Graduate Nurses' Professional Commitment: Antecedents and Outcomes. AB - PURPOSE: This study examines the factors that increase new graduate nurses' professional commitment and how this professional commitment in turn affects professional turnover intentions, anxiety, and physical health symptoms. DESIGN: The study was carried out in association with the nursing undergraduate's affiliation of Quebec, Canada. A three-wave longitudinal design was employed among nursing students. Nurses were surveyed before they entered the labor market, and then twice after they started working. METHODS: Participants were contacted by post at their home address. The hypotheses were tested using structural equation modeling. FINDINGS AND CONCLUSION: Professional commitment explains why good work characteristics and the provision of organizational resources related to patient care reduce nurses' anxiety and physical symptoms, and increase their professional turnover intentions. Pre-entry professional perceptions moderate the effects of work characteristics on professional commitment such that when participants hold positive pre-entry perceptions about the profession, the propensity to develop professional commitment is higher. CLINICAL RELEVANCE: There is a worldwide shortage of nurses. From a nurse training perspective, it is important to create realistic perceptions of the nursing role. In hospitals, providing a good work environment and resources conducive to their professional ethos is critical for ensuring nurses do not leave the profession early on in their careers. PMID- 28715608 TI - Ticagrelor mitigates ischaemia-reperfusion induced vascular endothelial dysfunction in healthy young males - a randomized, single-blinded study. AB - AIMS: Animal data suggest that ticagrelor but not clopidogrel protects against tissue injury. It is unclear if this effect of ticagrelor is also detectable in humans. We studied the effect of ticagrelor and clopidogrel at standard clinical doses on endothelial dysfunction in an experimental model of forearm vascular ischaemia-reperfusion (IR) injury. METHODS: In a randomized, single-blinded trial, 24 subjects underwent forearm blood flow (FBF) measurements in response to the endothelium-dependent vasodilator acetylcholine (ACh) and to glyceryltrinitrate (GTN; endothelium-independent) before and after a 20 min forearm ischaemia. FBF reactivity was assessed after an oral loading dose of ticagrelor or clopidogrel and after 14 days of regular intake of maintenance doses of the study medicines. In addition, the effect on platelet inhibition was evaluated using multiple electrode aggregometry. RESULTS: ACh-induced vasodilation was impaired during reperfusion and not completely normalized by acute or chronic treatment with ticagrelor or clopidogrel (post- vs. pre ischaemia). However, ticagrelor mitigated endothelial dysfunction compared to clopidogrel after loading (FBF AChAUC ratio post- vs. pre-ischaemia: 0.83 [0.70; 0.96] vs. 0.64 [0.56; 0.72]; P = 0.024) and after chronic administration (FBF AChAUC ratio: 0.86 [0.71; 1.00] vs. 0.66 [0.55; 0.77]; P = 0.027). As expected, GTN-induced vasodilation was not affected by ischaemia. Ticagrelor or clopidogrel treatment inhibited platelet activation to a similar degree. CONCLUSION: Our data indicate that ticagrelor treatment exerts a greater vascular salutary effect than clopidogrel during reperfusion after an acute vascular occlusion. IR-induced vascular injury cannot be prevented completely by administration of these antiplatelet agents at standard clinical doses. PMID- 28715611 TI - NGWA News. PMID- 28715610 TI - WITHDRAWN: Drugs for preventing postoperative nausea and vomiting. AB - BACKGROUND: Drugs can prevent postoperative nausea and vomiting, but their relative efficacies and side effects have not been compared within one systematic review. OBJECTIVES: The objective of this review was to assess the prevention of postoperative nausea and vomiting by drugs and the development of any side effects. SEARCH METHODS: We searched The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 2, 2004), MEDLINE (January 1966 to May 2004), EMBASE (January 1985 to May 2004), CINAHL (1982 to May 2004), AMED (1985 to May 2004), SIGLE (to May 2004), ISI WOS (to May 2004), LILAC (to May 2004) and INGENTA bibliographies. SELECTION CRITERIA: We included randomized controlled trials that compared a drug with placebo or another drug, or compared doses or timing of administration, that reported postoperative nausea or vomiting as an outcome. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted outcome data. MAIN RESULTS: We included 737 studies involving 103,237 people. Compared to placebo, eight drugs prevented postoperative nausea and vomiting: droperidol, metoclopramide, ondansetron, tropisetron, dolasetron, dexamethasone, cyclizine and granisetron. Publication bias makes evidence for differences among these drugs unreliable. The relative risks (RR) versus placebo varied between 0.60 and 0.80, depending upon the drug and outcome. Evidence for side effects was sparse: droperidol was sedative (RR 1.32) and headache was more common after ondansetron (RR 1.16). AUTHORS' CONCLUSIONS: Either nausea or vomiting is reported to affect, at most, 80 out of 100 people after surgery. If all 100 of these people are given one of the listed drugs, about 28 would benefit and 72 would not. Nausea and vomiting are usually less common and, therefore, drugs are less useful. For 100 people, of whom 30 would vomit or feel sick after surgery if given placebo, 10 people would benefit from a drug and 90 would not. Between one to five patients out of every 100 people may experience a mild side effect, such as sedation or headache, when given an antiemetic drug. Collaborative research should focus on determining whether antiemetic drugs cause more severe, probably rare, side effects. Further comparison of the antiemetic effect of one drug versus another is not a research priority. PMID- 28715612 TI - It's Complicated: Navigating Multiple Identities in Small Town America. AB - During the past few years, research focused on individuals who identify as gay, lesbian, bisexual, and transgender (LGBT) have increased. However, much of this literature focuses on White LGBT individuals, and less on individuals who have intersected identities, such as being both gay/lesbian and a person of color. Consequently, this population becomes obscured in scholarly discourses, thus being made "invisible" with regard to theory, research, and clinical interventions, with the result that clinicians are provided little or no knowledge of theories or best practices when working with individuals who are both sexual minority and people of color. This article discusses an integrated theoretical and treatment process when working with clients who are navigating multiple oppressed identities. PMID- 28715613 TI - Isolation and characterization of canine placenta-derived mesenchymal stromal cells for the treatment of neurological disorders in dogs. AB - Spinal cord injury (SCI) is a devastating disorder that affects humans and dogs. The prognosis of SCI depends on the severity of the injury and can include varying levels of motor and sensory deficits including devastating paraplegia and quadriplegia. Placental mesenchymal stromal cells (PMSCs) have been shown to improve wound healing and possess neuroprotective and immunomodulatory capabilities, but have not yet been clinically tested for the treatment of SCI. This study established a protocol to isolate fetal PMSCs from canine placentas and characterized their paracrine secretion profile and ability to stimulate neurons in vitro to assess their potential as a treatment option for neurological disorders in dogs. Canine PMSCs (cPMSCs) were plastic adherent and capable of trilineage differentiation. cPMSCs expressed typical MSC markers and did not express hematopoietic or endothelial cell markers. Genotyping of cPMSCs revealed fetal rather than maternal origin of the cells. cPMSCs were viable and mitotically expansive in a collagen hydrogel delivery vehicle, and they secreted the immunomodulatory and neurotrophic paracrine factors interleukin (IL)-6, IL-8, monocyte chemoattractant protein 1 (MCP-1), and vascular endothelial growth factor (VEGF). cPMSCs also stimulated the growth of complex neural networks when co-cultured with SH-SY5Y cells, a neuroblastoma cell line used to model neuron growth in vitro. cPMSCs are analogous to human PMSCs. They meet the criteria to be defined as MSCs and represent a potential regenerative therapy option for neurological disorders in dogs with their robust growth in collagen hydrogel, stimulation of neural network formation, and secretion of potent paracrine factors. (c) 2017 International Society for Advancement of Cytometry. PMID- 28715614 TI - Intraperitoneal administration of adipose tissue-derived stem cells for the rescue of retinal degeneration in a mouse model via indigenous CNTF up-regulation by IL-6. AB - As the world's population begins to age, retinal degeneration is an increasing problem, and various treatment modalities are being developed. However, there have been no therapies for degenerative retinal conditions that are not characterized by neovascularization. We investigated whether transplantation of mouse adipose tissue-derived stem cells (mADSC) into the intraperitoneal space has a rescue effect on NaIO3 -induced retinal degeneration in mice. In this study, mADSC transplantation recovered visual function and preserved the retinal outer layer structure compared to the control group without any integration of mADSC into the retina. Moreover, endogenous ciliary neurotrophic factor (CNTF) was elevated in the retinas of mADSC-treated mice. We found that lipopolysaccharide (LPS) or LPS-stimulated monocyte supernatant induced the secretion of granulocyte colony stimulating factor (GCSF), CD54, CXCL10, interleukin-6 (IL-6), and CCL5 from the mADSC by cytokine array. Network inference was conducted to investigate signaling networks related to CNTF regulation. Based on bioinformatics data, the expression of IL-6 was related to the expression of CNTF. Additionally, intravitreal injection of IL-6 in rats produced up-regulation of endogenous CNTF in the retina. mADSC had a rescue effect on retinal degeneration through the up-regulation of endogenous CNTF by IL 6. Thus, transplantation of mADSC could be a potential treatment option for retinal degeneration. PMID- 28715615 TI - Rational Design, Development, and Stability Assessment of a Macrocyclic Four Hydroxamate-Bearing Bifunctional Chelating Agent for 89 Zr. AB - Zirconium-89 is a positron-emitting radionuclide of high interest for medical imaging applications with positron emission tomography (PET). For the introduction of this radiometal into biologically active targeting vectors, the chelating agent desferrioxamine B (DFO) is commonly applied. However, DFO is known to form 89 Zr complexes of limited in vivo stability. Herein we describe the rational design and chemical development of a new macrocyclic four hydroxamate-bearing chelating agent-1,10,19,28-tetrahydroxy-1,5,10,14,19,23,28,32 octaazacyclohexatriacontan-2,6,11,15,20,24,29,33-octaone (CTH36)-for the stable complexation of Zr4+ . For this purpose, we first performed computational studies to determine the optimal chelator geometry before we developed different synthesis pathways toward the target structures. The best results were obtained using an efficient solution-phase-based synthesis strategy toward the target chelating agent. To enable efficient and chemoselective conjugation to biomolecules, a tetrazine-modified variant of CTH36 was also developed. The excellent conjugation characteristics of the so-functionalized chelator were demonstrated on the example of the model peptide TCO-c(RGDfK). We determined the optimal 89 Zr radiolabeling parameters for CTH36 as well as its bioconjugate, and found that 89 Zr radiolabeling proceeds efficiently under very mild reaction conditions. Finally, we performed comparative complex stability tests for 89 Zr CHT36-c(RGDfK) and 89 Zr-DFO-c(RGDfK), showing improved complex stability for the newly developed chelator CTH36. PMID- 28715616 TI - OMIP-039: Detection and analysis of human adaptive NKG2C+ natural killer cells. PMID- 28715617 TI - An Ionophore-Based Anion-Selective Optode Printed on Cellulose Paper. AB - A general anion-sensing platform is reported based on a portable and cost effective ion-selective optode and a smartphone detector equipped with a color analysis app. In contrast to traditional anion-selective optodes using a hydrophobic polymer and/or plasticizer to dissolve hydrophobic sensing elements, the new optode relies on hydrophilic cellulose paper. The anion ionophore and a lipophilic pH indicator are inkjet-printed and adsorbed on paper and form a "dry" hydrophobic sensing layer. Porous cellulose sheets also allow the sensing site to be modified with dried buffer that prevents any sample pH dependence of the observed color change. A highly selective fluoride optode using an AlIII porphyrin ionophore is examined as an initial example of this new anion sensing platform for measurements of fluoride levels in drinking water samples. Apart from Lewis acid-base recognition, hydrogen bonding recognition is also compatible with this sensing platform. PMID- 28715619 TI - Properties of Water Confined in Periodic Mesoporous Organosilicas: Nanoimprinting the Local Structure. AB - The properties of materials confined in porous media are important in scientific and technological aspects. Topology, size, and surface polarity of the pores play a critical role in the confinement effects, however, knowledge regarding the guest-pore interface structure is still lacking. Herein, we show that the molecular mobility of water confined in periodic mesoporous organosilicas (PMOs) is influenced by the polarity of the organic moiety. Multidimensional solid-state NMR spectroscopy directly probes the spatial arrangement of water inside the pores, showing that water interacts either with only the silicate layer or with both silicate and organic layers depending on the alternating surface polarity. A modulated and a uniform pore filling mode are proposed for different types of PMOs. PMID- 28715620 TI - Approaches towards optimizing individualized, high-quality, evidence-informed care. PMID- 28715618 TI - Measurement of NET formation in vitro and in vivo by flow cytometry. AB - Neutrophil extracellular traps (NETs) are extracellular chromatin fibers adorned with antimicrobial proteins, such as myeloperoxidase (MPO), which are extruded from activated neutrophils. NETosis is the metamorphosis of neutrophils with NET formation that follows decondensation of DNA and rupture of the plasma membrane. Although NETs play important roles in innate immunity, excessive formation of NETs can be harmful to the hosts. Until now, various methods for evaluation of NETs have been reported. Although each has a virtue, the gold standard has not been established. Here we demonstrate a simple, objective, and quantitative method to detect NETs using flow cytometry. This method uses a plasma membrane impermeable DNA-binding dye, SYTOX Green. SYTOX Green-positive cells were detected in human peripheral polymorphonuclear cells exposed to a NET inducer, phorbol 12-myristate 13-acetate (PMA). The number of SYTOX Green-positive cells was increased depending on the exposure duration and concentrations of PMA. Furthermore, co-localization of MPO and plasma membrane-appendant DNA of SYTOX Green-positive cells was demonstrated. Moreover, a NET inhibitor, diphenylene iodonium, could significantly reduce the number of SYTOX Green-positive cells induced by PMA. The collective evidence suggests that SYTOX Green-positive cells include neutrophils that formed NETs. The established method could detect neutrophils that underwent NETosis but not early apoptosis with equivalence in quantification to another well-used image analysis, which is based on fluorescent staining. Additionally, NETs that were formed in vivo were also detectable by this method. It is conceivable that the established method will bring us better understanding of the relation between NETosis and human diseases. (c) 2017 The Authors. Cytometry Part A published by Wiley Periodicals, Inc. on behalf of ISAC. PMID- 28715621 TI - Electroconvulsive Therapy During Pregnancy. AB - Women often experience worsening mood disorder symptoms during pregnancy. Women with mood disorders have an increased risk for suboptimal prenatal care, inadequate weight gain, and more substance abuse during pregnancy. It is often difficult to balance pharmacotherapy risks to a developing fetus versus not medicinally treating maternal mental health conditions. Electroconvulsive therapy (ECT) is a rapid and effective treatment option that can be an appropriate intervention in some women during pregnancy. This report presents an overview of ECT in pregnancy and the case of a 28-year-old pregnant woman with bipolar mania who responded well to ECT. PMID- 28715623 TI - [Opportunities and challenges in workplace gender violence: a context of opportunity for prevention]. PMID- 28715622 TI - Weight Gain in Psychiatric Inpatients: Are Interventions Making a Positive Impact? AB - Objective: The negative impact of weight gain is a common problem facing all patients, but it is especially concerning in the seriously mentally ill population. The literature is replete with interventions to mitigate weight gain in this population; however, most focus on outpatient settings. This study was undertaken to quantify weight gain in an inpatient setting and to assess whether instituted interventions to reduce weight gain were effective. Methods: This retrospective study analyzed weight changes in adult psychiatric inpatients with length of stay of 30 days or more. Data regarding weight changes were collected from records before (July 2005 to June 2006) a hospital-wide policy change to combat weight gain and after (July 2013 to June 2014) the changes were instituted. A total of 537 charts were reviewed. Results: Male inpatients gained a mean of 7.61 lb and females gained 6.02 lb. The mean weight change increased for the pre and post policy change periods: 6.08 lb and 7.85 lb, respectively, a 29% increase in mean weight. Conclusion: This study demonstrates that weight in psychiatric inpatients hospitalized for 30 days or longer increased despite widespread changes in the hospital setting implemented to limit weight gain. PMID- 28715624 TI - [Chickenpox seroprevalence among healthcare and social assistance workers in Catalonia (Spain)]. AB - AIMS: Chickenpox is a frequent and contagious disease in healthcare and social assistance settings, and there are limited data on seroprevalence among workers in this sector. We estimated susceptibility to chickenpox among workers, by demographic and occupational variables, and measured the rate of seroprotection after vaccination. METHODS: A retrospective seroprevalence study of chickenpox (varicella) and serological vaccine response. The earliest recorded varicella serology, analyzed by the ELISA method, was identified for each worker from a health surveillance database of a group of medical and healthcare companies in Catalonia, recorded between 2004 and 2013. The total study population consisted of 2958 workers, analyzed by gender, age, birth cohort preceding and following the introduction of the vaccine in the vaccination schedule of Catalonia (born after 1993), and occupational category, regardless of exposure risk. Vaccine effectiveness was determined in a group of 59 initi lly seronegative workers by measuring ELISA-based varicella titers, obtained at least 2 months after receiving a second dose of the VARIVAX(r) vaccine. RESULTS: 2820 workers (95.3%) had protective titers (PT) to chickenpox; 507 were men (97.1%) and 2313 were women (95%). The 1993 and earlier birth cohorts had a PT of 95.4% and those born after 1993 had a PT of 80.0%. Among at-risk categories, the PT was 95.2%, whereas among those not at risk it was was 96%. By birth decade, the lowest PT was among those age 60 years or older (93.3%). The postvaccination serological response was 89.8%. CONCLUSIONS: The prevalence of protective varicella serologies among healthcare and social assistance workers was similar to that found in recent seroprevalence studies in the general population in Catalonia. Men have significantly higher rates of protection than women. Those born after 1993 have significantly lower rates of protective titers than those born in 1993 or earlier. PMID- 28715625 TI - [Myelofibrosis in a benzene-exposed cleaning worker]. AB - Long-term exposure to benzene has been associated with several blood malignancies, including aplastic anemia, myeloproliferative neoplasms, and different leukemias. We present a case of primary myelofibrosis in a 59-year-old woman who worked as a cleaner at a car dealership and automobile mechanic shop. For 25 years, she used gasoline as a degreaser and solvent to clean engine parts, floors and work desks on a daily basis. She was referred by her primary care provider to the Occupational Health Unit of Barcelona to assess whether her illness was work-related. Review of her job history and working conditions revealed chronic exposure to benzene in the absence of adequate preventive measures. An association between benzene exposure and myeloproliferative disease was established, suspicious for an occupational disease. PMID- 28715626 TI - [Health surveillance and fitness for duty: deconstruct, reconceptualize and finding consensus on how to improve]. PMID- 28715627 TI - [Response: Health surveillance and fitness for duty: deconstruct, reconceptualize and finding consensus on how to improve]. PMID- 28715628 TI - Accurate DFT-D3 Calculations in a Small Basis Set. AB - Calculations of interaction energies of noncovalent interactions in small basis sets are affected by the basis set superposition error and dispersion-corrected DFT-D methods and are thus usually parametrized only for triple-zeta and larger basis sets. Nevertheless, some smaller basis sets could also perform well. Among many combinations tested, we obtained excellent results with the DZVP-DFT basis and newly parametrized D3 dispersion correction. The accuracy of interaction energies and geometries is close to significantly more expensive calculations. PMID- 28715629 TI - Structure and Dynamics of Electron Injection and Charge Recombination in i-Motif DNA Conjugates. AB - The dynamics of electron injection have been investigated in intramolecular i motif conjugates possessing stilbenediether (Sd) and perylenediimide (PDI) chromophores separated by either four or six hemiprotonated cytosine C-C base pairs assembled with synthetic loops. Circular dichroism spectra are consistent with the formation of i-motif structures in the absence or presence of Sd and PDI chromophores. The fluorescence of the Sd chromophore is essentially completely quenched by neighboring C-C base pairs, consistent with their function as an electron donor and electron acceptor, respectively. However, the fluorescence of the PDI chromophore is only partially quenched. The dynamics of electron injection from singlet Sd into the i-motif and subsequent charge recombination has been determined by femtosecond transient absorption (fsTA) spectroscopy and compared with the results for electron injection and charge recombination in Sd linked hairpins possessing cytosine-guanine (C-G) or 5-fluorouracil-adenine (F-A) base pairs. While charge injection is ultrafast (<0.8 ps) for the i-motifs, charge transport across the i-motif C-C base pairs to the PDI electron trap is not observed. The absence of electron transport is related to the structure of the stacked C-C base pairs in the i-motif. PMID- 28715630 TI - Misfolded SOD1 Accumulation and Mitochondrial Association Contribute to the Selective Vulnerability of Motor Neurons in Familial ALS: Correlation to Human Disease. AB - Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder, with a 10% genetic linkage, of which 20% of these cases may be attributed to mutations in superoxide dismutase (SOD1). Specific mutations in SOD1 have been associated with disease duration, which can be highly variable ranging from a life expectancy of 3 to beyond 10 years. SOD1 neurotoxicity has been attributed to aberrant accumulation of misfolded SOD1, which in its soluble form binds to intracellular organelles disrupting their function or forms insoluble toxic aggregates. To understand whether these biophysical properties of the mutant protein may influence disease onset and duration, we generated 19 point mutations in the SOD1 gene, based on available clinical data of disease onset and progression from patients. By overexpressing these mutants in motor-neuron-like NSC-34 cells, we demonstrate a variability in misfolding capacity between the different mutants with a correlation between the degree of protein misfolding and mutation severity. We also show a clear variation of the different SOD1 mutants to associate with mitochondrial-enriched fractions with a correlation between mutation severity and this association. In summary, these findings reveal a correlation between the accumulation of misfolded SOD1 species and their mitochondrial association with disease duration but not with disease onset, and they have implications for the potential therapeutic role of suppressing the accumulation of misfolded SOD1. PMID- 28715631 TI - Synergistic Bacteria Killing through Photodynamic and Physical Actions of Graphene Oxide/Ag/Collagen Coating. AB - Researchers have widely agreed that the broad spectrum antibacterial activity of silver nanoparticles (AgNPs) can be predominantly ascribed to the action of Ag+. This study marks the first report detailing the rapid and highly efficient synergistic bacteria killing of AgNPs, which is achieved by inspiring AgNPs' strong photocatalytic capability to rapidly produce radical oxygen species using 660 nm visible light together with the innate antimicrobial ability of Ag+. These AgNPs were uniformly distributed into well-defined graphene oxide (GO) nanosheets through an in situ reduction of Ag+ and subsequently wrapped with a thin layer of type I collagen. In vivo subcutaneous tests demonstrated that 20 min irradiation of 660 nm visible light could achieve a high antibacterial efficacy of 96.3% and 99.4% on the implant surface against Escherichia coli and Staphylococcus aureus, respectively. In addition, the collagen could reduce the coatings' possible cytotoxicity. The results of this work can provide a highly effective and universal GO-based bioplatform for combination with inorganic antimicrobial NPs (i.e., AgNPs) with excellent photocatalytic properties, which can be utilized for facile and rapid in situ disinfection, as well as long-term prevention of bacterial infection through the synergistic bacteria killing of both 660-nm light inspired photodynamic action and their innate physical antimicrobial ability. PMID- 28715632 TI - All-Graphene Oxide Flexible Solid-State Supercapacitors with Enhanced Electrochemical Performance. AB - The rapid development of flexible and wearable electronics has led to an increase in the demand for flexible supercapacitors with enhanced electrochemical performance. Graphene oxide (GO) and reduced GO (rGO) exhibit several key properties required for supercapacitor components. Although solid-state rGO/GO/rGO supercapacitors with unique structures are promising, their moderate capacitance is inadequate for practical applications. Herein, we report a flexible solid-state rGO/GO/rGO supercapacitor comprising H2SO4-intercalated GO electrolyte/separator and pseudocapacitive rGO electrodes, which demonstrate excellent electrochemical performance. The resulting supercapacitor delivered an areal capacitance of 14.5 mF cm-2, which is among the highest values achieved for any rGO/GO/rGO supercapacitor. High ionic concentration and fast ion conduction in the H2SO4-intercalated GO electrolyte/separator and abundant CH defects, which serve as pseudocapacitive sites on the rGO electrode, were responsible for the high capacitance of this device. The rGO electrode, well separated by the H2SO4 molecular spacer, supplied highly efficient ion transport channels, leading to excellent rate capability. The highly packed rGO electrode and high specific capacitance resulted in a high volumetric energy density (1.24 mWh cm-3) observed in this supercapacitor. The structure, without a clear interface between GO and rGO, provides extremely low resistance and flexibility for devices. Our device operated in air (25 degrees C 40%) without the use of external electrolytes, conductive additives, and binders. Furthermore, we demonstrate a simple and versatile technique for supercapacitor fabrication by combining photoreduction and electrochemical treatment. These advantages are attractive for developing novel carbon-based energy devices with high device performance and low fabrication costs. PMID- 28715633 TI - Diastereoselective Construction of the 6-Oxa-2-azabicyclo[3.2.1]octane Scaffold from Chiral alpha-Hydroxyaldehyde Derivatives by the Aza-Prins Reaction. AB - (R)-2,3-Di-O-benzylglyceraldehyde and N-tosyl homoallylamine undergo aza-Prins cyclization to afford (1R,5S,7S)-7-[(benzyloxy)methyl]-2-tosyl-6-oxa-2 azabicyclo[3.2.1]octane in a highly diastereoselective manner through an unexpected intramolecular nucleophilic attack. Our work has opened a new route toward the asymmetric synthesis of 7-(alkyl or aryl)-6-oxa-2 azabicyclo[3.2.1]octane derivatives from chiral alpha-hydroxyaldehyde derivatives in one step. PMID- 28715634 TI - Novel Strategy Utilizing Extracellular Cysteine-Rich Domain of Membrane Receptor for Constructing d-Peptide Mediated Targeted Drug Delivery Systems: A Case Study on Fn14. AB - The development of proteolysis-resistant d-peptide ligands for targeted drug/gene delivery has been greatly limited, due to the challenge that lies in the chemical synthesis of membrane receptors without altering their structures. In the present research, a novel strategy utilizing self-stabilized extracellular CRD of the membrane receptor was developed to construct d-peptide ligands and their mediated targeted drug delivery systems. Fn14, a cell surface receptor overexpressed in many cancers including pancreatic and triple-negative breast cancers, was selected as the model receptor. Fn14 CRD was synthesized and folded, and used to screen Fn14 binding peptides using phage display (l-peptide) and mirror-image phage display (d-peptide) techniques, respectively. The d-peptide ligand successfully mediated targeted drug delivery to Fn14 positive tumor cells. In addition, the d-peptide possessed better target-binding affinity, stromal barrier permeability, and tumor targeting ability in vivo when conjugated with liposomes. More importantly, d-peptide mediated liposomal paclitaxel delivery significantly inhibited pancreatic tumor growth in a subcutaneous xenograft model and drastically prolonged survival in a lung metastasis of breast cancer mouse model. This study demonstrated that mirror-image phage display based on the CRD of membrane receptor can be a promising strategy to advance active targeted drug delivery via biostable d-peptides. PMID- 28715635 TI - Redox Potentials from Ab Initio Molecular Dynamics and Explicit Entropy Calculations: Application to Transition Metals in Aqueous Solution. AB - We present a complete methodology to consistently estimate redox potentials strictly from first-principles, without any experimental input. The methodology is based on (i) ab initio molecular dynamics (MD) simulations, (ii) all-atom explicit solvation, (iii) the two-phase thermodynamic (2PT) model, and (iv) the use of electrostatic potentials as references for the absolute electrochemical scale. We apply the approach presented to compute reduction potentials of the following redox couples: Cr2+/3+, V2+/3+, Ru(NH3)62+/3+, Sn2+/4+, Cu1+/2+, FcMeOH0/1+, and Fe2+/3+ (in aqueous solution) and Fc0/1+ (in acetonitrile). We argue that fully quantum-mechanical simulations are required to correctly model the intricate dynamical effects of the charged complexes on the surrounding solvent molecules within the solvation shell. Using the proposed methodology allows for a computationally efficient and statistically stable approach to compute free energy differences, yielding excellent agreement between our computed redox potentials and the experimental references. The root-mean-square deviation with respect to experiment for the aqueous test set and the two exchange-correlation density functionals used, PBE and PBE with van der Waals corrections, are 0.659 and 0.457 V, respectively. At this level of theory, depending on the functional employed, its ability to correctly describe each particular molecular complex seems to be the factor limiting the accuracy of the calculations. PMID- 28715636 TI - Backbone Engineered gamma-Peptide Amphitropic Gels for Immobilization of Semiconductor Quantum Dots and 2D Cell Culture. AB - We are reporting a spontaneous supramolecular assembly of backbone engineered gamma-peptide scaffold and its utility in the immobilization of semiconductor quantum dots and in cell culture. The stimulating feature of this gamma-peptide scaffold is that it efficiently gelates both aqueous phosphate buffers and aromatic organic solvents. A comparative and systematic investigation reveals that the greater spontaneous self-aggregation property of gamma-peptide over the alpha- and beta-peptide analogues is mainly due to the backbone flexibility, increased hydrophobicity, and pi-pi stacking of gamma-phenylalanine residues. The hydrogels and organogels obtained from the gamma-peptide scaffold have been characterized through field emission scanning electron microscopy (FE-SEM), transmission electron microscopy (TEM), FT-IR, circular dichroism (CD), wide angle X-ray diffraction, and rheometric study. Additionally, the peptide hydrogel has displayed a stimuli-responsive and thixotropic signature, which leads to the injectable hydrogels. 2D cell culture studies using normal and cancer cell lines reveal the biocompatibility of gamma-peptide hydrogels. Further, the immobilization of semiconductor core-shell quantum dots in the transparent gamma peptide organogels showed ordered arrangement of quantum dots along the peptide fibrillar network with retaining photophysical property. Overall, gamma-peptide scaffolds may serve as potential templates for the design of new functional biomaterials. PMID- 28715637 TI - Unit Cell Level Thickness Control of Single-Crystalline Zinc Oxide Nanosheets Enabled by Electrical Double-Layer Confinement. AB - Ionic layer epitaxy (ILE) has recently been developed as an effective strategy to synthesize nanometer thick 2D materials with a nonlayered crystal structure, such as ZnO. The packing density of the amphiphilic monolayer is believed to be a key parameter that controls the nanosheet nucleation and growth. In this work, we systematically investigated the growth behavior of single-crystalline ZnO nanosheets templated at the water-air interface by an anionic oleylsulfate monolayer with different packing densities. The thicknesses of ZnO nanosheets were tuned from one unit cell to four unit cells and exhibited good correlation with the width of Zn2+ ion concentration zone (the Stern layer) underneath the ionized surfactant monolayer. Further analysis of the nanosheet sizes and density revealed that the nanosheet growth was dominated by the steric hindrance from the surfactant monolayer at lower surface pressure, while the nucleation density became the dominating factor at higher surface pressure. The ZnO nanosheets exhibited a decreasing work function as the thickness reduced to a few unit cells. This research validated a critical hypothesis that the nanosheet growth is self-limited by the formation of a double layer of ionic precursors. This work will open up a new way toward controlled synthesis of novel 2D nanosheets from nonlayered materials with a thickness down to one unit cell. PMID- 28715638 TI - Marcus Theory of Ion-Pairing. AB - We present a theory for ion pair dissociation and association, motivated by the concepts of Marcus theory of electron transfer. Despite the extensive research on ion-pairing in many chemical and biological processes, much can be learned from the exploration of collective reaction coordinates. To this end, we explore two reaction coordinates, ion pair distance and coordination number. The study of the correlation between these reaction coordinates provides a new insight into the mechanism and kinetics of ion pair dissociation and association in water. The potential of mean force on these 2D surfaces computed from molecular dynamics simulations of different monovalent ion pairs reveal a Marcus-like mechanism for ion-pairing: Water molecules rearrange forming an activated coordination state prior to ion pair dissociation or association, followed by relaxation of the coordination state due to further water rearrangement. Like Marcus theory, we find the existence of an inverted region where the transition rates are slower with increasing exergonicity. This study provides a new perspective for the future investigations of ion-pairing and transport. PMID- 28715639 TI - Probing Gelation and Rheological Behavior of a Self-Assembled Molecular Gel. AB - Molecular gels have been investigated over the last few decades; however, mechanical behavior of these self-assembled gels is not well understood, particularly how these materials fail at large strain. Here, we report the gelation and rheological behavior of a molecular gel formed by self-assembly of a low molecular weight gelator (LMWG), di-Fmoc-l-lysine, in 1-propanol/water mixture. Gels were prepared by solvent-triggered technique, and gelation was tracked using Fourier transform infrared (FTIR) spectroscopy and shear rheology. FTIR spectroscopy captures the formation of hydrogen bonding between the gelator molecules, and the change in IR spectra during the gelation process correlates with the gelation kinetics results captured by rheology. Self-assembly of gelator molecules leads to a fiber-like structure, and these long fibers topologically interact to form a gel-like material. Stretched-exponential function can capture the stress-relaxation data. Stress-relaxation time for these gels have been found to be long owing to long fiber dimensions, and the stretching exponent value of 1/3 indicates polydispersity in fiber dimensions. Cavitation rheology captures fracture-like behavior of these gels, and critical energy release rate has been estimated to be of the order 0.1 J/m2. Our results provide new understanding of the rheological behavior of molecular gels and their structural origin. PMID- 28715640 TI - Voluntary running of defined distances reduces body adiposity and its associated inflammation in C57BL/6 mice fed a high-fat diet. AB - This study investigated the effect of voluntary running of defined distances on body adiposity in male C57BL/6 mice fed a high-fat diet. Mice were assigned to 6 groups and fed a standard AIN93G diet (sedentary) or a modified high-fat AIN93G diet (sedentary; unrestricted running; or 75%, 50%, or 25% of unrestricted running) for 12 weeks. The average running distance was 8.3, 6.3, 4.2, and 2.1 km/day for the unrestricted, 75%, 50%, and 25% of unrestricted runners, respectively. Body adiposity was 46% higher in sedentary mice when fed the high fat diet instead of the standard diet. Running decreased adiposity in mice fed the high-fat diet in a dose-dependent manner but with no significant difference between sedentary mice and those running 2.1 km/day. In sedentary mice, the high fat instead of the standard diet increased insulin resistance, hepatic triacylglycerides, and adipose and plasma concentrations of leptin and monocyte chemotactic protein-1 (MCP-1). Running reduced these variables in a dose dependent manner. Adipose adiponectin was lowest in sedentary mice fed the high fat diet; running raised adiponectin in both adipose tissue and plasma. Running 8.3 and 6.3 km/day had the greatest, but similar, effects on the aforementioned variables. Running 2.1 km/day did not affect these variables except, when compared with sedentariness, it significantly decreased MCP-1. The findings showed that running 6.3 kg/day was optimal for reducing adiposity and associated inflammation that was increased in mice by feeding a high-fat diet. The findings suggest that voluntary running of defined distances may counteract the obesogenic effects of a high-fat diet. PMID- 28715641 TI - Genetic Influence on Intergenerational Educational Attainment. AB - Using twin (6,105 twin pairs) and genomic (5,825 unrelated individuals taken from the twin sample) analyses, we tested for genetic influences on the parent offspring correspondence in educational attainment. Genetics accounted for nearly half of the variance in intergenerational educational attainment. A genomewide polygenic score (GPS) for years of education was also associated with intergenerational educational attainment: The highest and lowest GPS means were found for offspring in stably educated families (i.e., who had taken A Levels and had a university-educated parent; M = 0.43, SD = 0.97) and stably uneducated families (i.e., who had not taken A Levels and had no university-educated parent; M = -0.19, SD = 0.97). The average GPSs fell in between for children who were upwardly mobile (i.e., who had taken A Levels but had no university-educated parent; M = 0.05, SD = 0.96) and children who were downwardly mobile (i.e., who had not taken A Levels but had a university-educated parent; M = 0.28, SD = 1.03). Genetic influences on intergenerational educational attainment can be viewed as an index of equality of educational opportunity. PMID- 28715642 TI - Reduced brain volume and impaired memory in betaine homocysteine S methyltransferase knockout mice. AB - Using a mouse model, this study examined the impact of lack of betaine homocysteine S-methyltransferase (BHMT) on neurological function. Bhmt-/- mice maintained on a control diet had elevated concentrations of homocysteine, reduced total brain magnetic resonance imaging (MRI) volume, as well as impaired reference and short-term memories. The results of this study indicate that the absence of BHMT may play a role in neurological function. PMID- 28715643 TI - New insights into the non-hemostatic role of von Willebrand factor in endothelial protection. AB - During exposure to ischemia-reperfusion (I/R) insult, angiotensin II (AngII) induced endothelin-1 (ET-1) upregulation in endothelial cells progressively impairs nitric oxide (NO) bioavailability while increasing levels of superoxide anion (O2-) and leading to the onset of endothelial dysfunction. Moreover, the overexpression of ET-1 increases the endothelial and circulating levels of von Willebrand factor (vWF), a glycoprotein with a crucial role in arterial thrombus formation. Nowadays, the non-hemostatic role of endothelial vWF is emerging, although we do not yet know whether its increased expression is cause or consequence of endothelial dysfunction. Notably, the vWF blockade or depletion leads to endothelial protection in cultured cells, animal models of vascular injury, and patients as well. Despite the recent efforts to develop an effective pharmacological strategy, the onset of endothelial dysfunction is still difficult to prevent and remains closely related to adverse clinical outcome. Unraveling the non-hemostatic role of endothelial vWF in the onset of endothelial dysfunction could provide new avenues for protection against vascular injury mediated by AngII. PMID- 28715644 TI - Detection and identification of serum protein peak at 6648 m/z as a novel indicator in breast cancer based on mass spectrometry. AB - Breast cancer (BC) is the second-leading cause of cancer mortality after lung cancer in women owing partly to a lack of specific and sensitive tests for early screening and monitoring. The detection of novel specific BC serum indicators for screening purposes is an essential clinical need. A total of 437 serum specimens from 310 BC patients that were divided into mining and testing sets were collected in this study. In contrast with the conventional BC indicators through receiver operating characteristic, survival and hazard function curves, and multivariate Cox regression analyses, we intended to hunt for stable protein indicators from serum specimens and identify their diagnostic and prognostic potential for BC. We identified a unique serum peptide located at 6648 Da originated from apoC-III with a validated correlation with BC tumorigenesis with confirmation in a substantive testing set and minimization of systematic bias by pre-analytical parameters. We found that the diagnostic efficacy of this peptide is better than the present conventional BC diagnostic indicators either alone or in combination with conventional indicators in distinguishing BC patients from control volunteers. Moreover, this peptide denotes a stronger prognostic factor for BC patients than conventional indicators. In light of these findings, we speculate that this peptide is a potential diagnostic and prognostic indicator and a supplement to conventional indicators in monitoring BC. The detection of this peptide located at 6648 Da in sera could enhance early screening and assessment of the postoperative survival opportunity for BC patients. PMID- 28715645 TI - Characteristics of regulatory B cells in patients with chronic hepatitis B virus infection in different immune phases. AB - Regulatory B cells (Bregs) are reported to play an important role in the immune responses to chronic hepatitis B virus (HBV) via Toll-like-receptors (TLRs) signaling. We aimed to investigate the characteristics of Bregs and the expressions of TLRs in Bregs in the peripheral blood of different immune phases of patients with chronic HBV infection. In this study, we determined the frequencies of Bregs and TLR9, TLR2, and TLR4 in peripheral blood using flow cytometry and determined the levels of IL-10 in serum with the Human Magnetic Cytokine/Chemokine Bead Panel. The results showed that the frequencies of CD19+ B cells and Bregs were elevated in patients with chronic HBV infection compared with healthy control (HC). The frequencies of Bregs were significantly increased in the immune active group compared with the immune tolerant group and HC group. Meanwhile, the frequencies of Bregs were higher in inactive carrier state group compared with HC group. The levels of serum IL-10 were elevated in the immune active group compared with immune tolerant, inactive carrier state and HC groups. Serum IL-10 levels were positively correlated with alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in the immune active group. Compared with HC group, the expression of TLR9 in Bregs reduced in chronic hepatitis B (CHB) patients. However, the expression of TLR2 in Bregs increased in CHB patients. There were no differences of the TLRs expressions in Bregs among various immune phases of chronic HBV infection. These data suggest that the frequencies of Bregs and levels of serum IL-10 were different in various immune phases in patients with chronic HBV infection. Bregs may play some important role in modulating the immune responses of chronic HBV infection. However, whether Bregs modulate immune responses via TLR signaling in chronic HBV infection remains ambiguous. PMID- 28715646 TI - L-form bacteria cohabitants in human blood: significance for health and diseases. AB - From a historical perspective, intriguing assumptions about unknown "live units" in human blood have attracted the attention of researchers, reflecting their desire to define a new class of microorganisms. Thus, the concept of "blood microbiota" brings about many questions about the nature, origin, and biological significance of the "unusual microbial cohabitants" in human blood. In contrast to current views that bloodstream in healthy humans is sterile, the hypothesis about the existence of microbes as L-forms (cell wall deficient bacteria) in human blood has evolved on the basis of known facts about their unique biology, as observed in our studies and those of other authors. Recently, we reported that bacterial L-forms persist in the human blood and that filterable, self replicating bodies with a virus-like size of 100 nm are able to cross the maternal-fetal barrier by vertically transmitted pathway, then enter fetus blood circulation and colonize newborns. Subjects discussed here include the following: Is the existence of L-form bacteria in human blood a natural phenomenon? Are L form bacteria commensal cohabitants in the human body? Since blood is an unfavorable compartment for the classical bacteria and their propagation, how do L-forms survive in blood circulation? How does L-form microbiota in blood influence the host immune system and contribute to systemic inflammatory, autoimmune, and tumor diseases? The current commentary presents the topic of "human microbiota and L-form bacteria" in its microcosm. It contains details of the hypothesis, supporting evidence and important implications. PMID- 28715647 TI - The role of netrin-1 in angiogenesis and diabetic retinopathy: a promising therapeutic strategy. AB - Netrin-1 is an axon guidance cue and is necessary for neural and vascular development. It is involved in regulating axon guidance for attraction or repulsion, and it has a dual function in endothelial tip cell migration during angiogenesis. Netrin-1 has been shown to play an important role in angiogenesis, cancer progression, and inflammatory disease. Here we review the role of netrin-1 in retinal and angiogenesis development and the associated signaling pathways in diabetic retinopathy. The currently available data suggest that netrin-1 is a promising target for the development of anti-angiogenesis drugs. PMID- 28715648 TI - Tumor suppressor candidate 2 (TUSC2, FUS-1) and human cancers. AB - Tumor suppressor candidate 2 (TUSC2, also known as FUS1) was identified in 2000 as a candidate tumor suppressor gene located in a region on chromosome 3p21.3 that is homozygously deleted in some lung and breast cancers. The deletion is rare in lung and breast cancers, but is frequent in malignant pleural mesothelioma. Evidence to date indicates that TUSC2 behaves as a tumor suppressor in lung cancer; however, its role as a tumor suppressor for other tumor types has not been fully established. Loss of TUSC2 expression at the mRNA and protein levels has been reported in various cancers. While the mechanisms underlying the loss are still not well understood, several microRNAs have been reported to downregulate TUSC2 expression. TUSC2 elicits its anti-tumor effects through regulating G1 cell cycle progression, apoptosis, calcium homeostasis, gene expression, and the activity of various protein tyrosine kinases and Ser/Thr kinases, albeit the precise mechanisms that TUSC2 utilizes to regulate these cellular processes and signaling molecules are still elusive. TUSC2 restoration has been exploited as an anti-cancer therapy in various cancers in preclinical models, and clinically in patients with lung cancer. The first-in-human phase I trial demonstrated desirable safety outcomes. Phase I/II trials are being conducted to evaluate the efficacy of combining TUSC2-nanoparticles with erlotinib, an FDA-approved EGFR inhibitor. This review summarizes recent findings that advanced our understanding of TUSC2 as a novel tumor suppressor and a therapeutic opportunity for treating TUSC2-deficient cancers. PMID- 28715650 TI - Erratum. PMID- 28715649 TI - Excellent response to Anti-PD-1 therapy in a patient with hepatocellular carcinoma: case report and review of literature. AB - Hepatocellular carcinoma (HCC) is an aggressive cancer associated with high mortality worldwide. HCC develops in the setting of underlying cirrhosis due to chronic liver disease. Surgery is usually considered the treatment of choice for early disease; however, most patients have locally advanced or metastatic HCC at diagnosis in which case treatments are limited. Immune checkpoint blockade of programmed death receptor-1 (PD-1) pathway offers a potential treatment strategy based on the encouraging results of the phase I/II trial of nivolumab (Checkmate 040 trial). This has led to the off-label use of nivolumab after failure of treatment with sorafenib either due to intolerance or progression of disease. Although rare (<5%), clinical response to anti-PD-1 antibody may be preceded by "pseudoprogression" -- increase in the size and number of tumor lesions before actual tumor shrinkage. We report a case of pseudoprogression followed by an excellent response in an HCC patient treated with nivolumab and review the literature for ongoing trials of immune checkpoint blockade in HCC. The pseudoprogression in our case is supported by increase in both tumor size and alpha-fetoprotein after four treatments with nivolumab; however, regression of tumor size and normalization of alpha-fetoprotein occurred after subsequent treatments. To our knowledge, there are no reports of pseudoprogression in HCC although pseudoprogression has been well described in melanoma. PMID- 28715651 TI - Erratum. PMID- 28715652 TI - Linkage between the leader sequence and leader RNA production in Borna disease virus-infected cells. AB - The 3'-untranslated region (UTR) of the non-segmented, negative-strand (NNS) RNA viral genome is called the leader sequence, and functions as the promoter for viral replication and transcription. NNS RNA viruses also use the sequence as a template to synthesize leader RNAs (leRNAs) with unknown functions. Borna disease virus (BDV) is unique because it establishes a persistent infection and replicates in the nucleus. No report has yet demonstrated the presence of leRNAs during BDV infection. Here, we report that BDV synthesizes leRNAs from the 3'-UTR of the genome. They started at position 5 in the 3'-UTR and ended by the transcription start signal of the nucleoprotein gene. The level of leRNA production is not correlated with the levels of viral replication and transcription. On the other hand, mutation of the 3'-UTR affects leRNA production. Our findings add a novel viral transcript to the BDV life cycle and shed light on BDV replication and/or transcription. PMID- 28715653 TI - Inhibition of NF-kappaB activity by the porcine epidemic diarrhea virus nonstructural protein 1 for innate immune evasion. AB - Porcine epidemic diarrhea virus emerged in the US is known to suppress the type I interferons response during infection. In the present study using porcine epithelial cells, we showed that PEDV inhibited both NF-kappaB and proinflammatory cytokines. PEDV blocked the p65 activation in infected cells and suppressed the PRD II-mediated NF-kappaB activity. Of the total of 22 viral proteins, nine proteins were identified as NF-kappaB antagonists, and nsp1 was the most potent suppressor of proinflammatory cytokines. Nsp1 interfered the phosphorylation and degradation of IkappaBalpha, and thus blocked the p65 activation. Mutational studies demonstrated the essential requirements of the conserved residues of nsp1 for NF-kappaB suppression. Our study showed that PEDV inhibited NF-kappaB activity and nsp1 was a potent NF-kappaB antagonist for suppression of both IFN and early production of pro-inflammatory cytokines. PMID- 28715654 TI - Generation of stable infectious clones of plant viruses by using Rhizobium radiobacter for both cloning and inoculation. AB - A novel Rhizobium radiobacter (synonym Agrobacterium tumefaciens)-mediated approach was developed to generate stable infectious clones of plant viruses. This method uses R. radiobacter for both cloning and inoculation of infectious clones, bypassing the requirement of cloning in E. coli to avoid the instability. Only three steps are included in this method: (i) construct viral genome-encoding plasmids in vitro by one-step Gibson assembly; (ii) transform the assembled DNA products into R. radiobacter; (iii) inoculate plants with the R. radiobacter clones containing the viral genome. Stable infectious clones were obtained from two potyviruses papaya ringspot virus (PRSV) and papaya leaf distortion mosaic virus (PLDMV) using this method, whereas attempts utilizing "classical" E. coli cloning system failed repeatedly. This method is simple and efficient, and is promising for a wide application in generation of infectious clones of plant virus, especially for those which are instable in E. coli. PMID- 28715656 TI - The prevalence of malnutrition and its associated risk factors among women of reproductive age in Ziway Dugda district, Arsi Zone, Oromia Regional State, Ethiopia. AB - OBJECTIVES: Adequate nutrition is an important factor to determine the health and well-being of women, children and society as a whole. Although various nutritional policies were formulated and aimed at reducing malnutrition at the global level, the magnitude of malnutrition (body mass index [BMI] <18.5 kg/m2) among women remained between 10% and 40% in most low- and middle-income countries. We aimed to determine the prevalence of malnutrition and to identify the associated risk factors among women of reproductive age. STUDY DESIGN: A cross-sectional study was conducted in Ziway Dugda district in Ethiopia among 430 women of reproductive age between September 20 and November 21, 2015. METHODS: A systematic sampling method was used to select the study participants. Descriptive statistics and logistic regression were used to determine the prevalence of malnutrition and to identify associated independent risk factors such as women's age, housing conditions, drinking water sources, habits of hand washing, dietary intake and food insecurity. RESULTS: The mean values of weight, height and BMI of the study participants were 51 kg, 157 cm and 18.1 kg/m2, respectively. Prevalence of malnutrition (BMI <18.5 kg/m2) among women of reproductive age was found to be 48.6%. Being in the age group of 26-35 years (adjusted odds ratio [AOR] = 0.50, 95% confidence interval [CI] = 0.26-0.84), thatched housing conditions (AOR = 1.83, 95% CI = 1.16-2.89), unprotected sources of drinking water (AOR = 1.65, 95% CI = 1.06-2.57), lack of habit of hand wash after using the toilet (AOR = 1.62, 95% CI = 1.06-2.47), consumption of fish (AOR = 2.12, 95% CI = 1.12-3.99), consumption of dairy products (AOR = 2.40, 95% CI = 1.42-4.03) and food insecurity (AOR = 2.44, 95% CI = 1.50-3.95) were considered as independent predictors of risk for having malnutrition among women of the same age group compared to women from food secured households. CONCLUSIONS: A high prevalence of malnutrition (48.6%) was observed among women of reproductive age. Although nutrient-rich foods were available, their consumption appears insufficient. Hence, it is strongly recommended to have behavioural change communication for enhancing adequate intake of a diversified diet and to promote environmental and hygienic conditions of women through improving their socio economic status. PMID- 28715655 TI - Macrophage exosomes as natural nanocarriers for protein delivery to inflamed brain. AB - Recent work has stimulated interest in the use of exosomes as nanocarriers for delivery of small drugs, RNAs, and proteins to the central nervous system (CNS). To overcome the blood-brain barrier (BBB), exosomes were modified with brain homing peptides that target brain endothelium but likely to increase immune response. Here for the first time we demonstrate that there is no need for such modification to penetrate the BBB in mammals. The naive macrophage (Mphi) exosomes can utilize, 1) on the one hand, the integrin lymphocyte function associated antigen 1 (LFA-1) and intercellular adhesion molecule 1 (ICAM-1), and, 2) on the other hand, the carbohydrate-binding C-type lectin receptors, to interact with brain microvessel endothelial cells comprising the BBB. Notably, upregulation of ICAM-1, a common process in inflammation, promotes Mphi exosomes uptake in the BBB cells. We further demonstrate in vivo that naive Mphi exosomes, after intravenous (IV) administration, cross the BBB and deliver a cargo protein, the brain derived neurotrophic factor (BDNF), to the brain. This delivery is enhanced in the presence of brain inflammation, a condition often present in CNS diseases. Taken together, the findings are of interest to basic science and possible use of Mphi-derived exosomes as nanocarriers for brain delivery of therapeutic proteins to treat CNS diseases. PMID- 28715657 TI - Age-specific patterns of health care expenditure in dying people. PMID- 28715658 TI - Perceptions of community, social capital, and how they affect self-reported health: a multilevel analysis. AB - OBJECTIVES: The link between social capital and self-reported health has been widely explored. On the other hand, we know less about the relationship between social capital, community socioeconomic characteristics, and non-social capital related individual differences, and about their impact on self-reported health in community settings. METHODS: Cross-sectional study design with a proportional sample of 7965 individuals from 20 US communities were analyzed using multilevel linear regression models, where individuals were nested within communities. The response rates ranged from 13.5% to 25.4%. RESULTS: Findings suggest that perceptions of the community and individual level socioeconomic characteristics were stronger predictors of self-reported health than were social capital or community socioeconomic characteristics. CONCLUSIONS: Policy initiatives aimed at increasing social capital should first assess community member's perceptions of their communities to uncover potential assets to help increase social capital. PMID- 28715659 TI - Fetal heart rate variation after corticosteroids for fetal maturation. AB - INTRODUCTION: Several studies report a decrease of fetal heart rate (FHR) short term variation (STV) after corticosteroids for improvement of fetal maturity and advice not to deliver a fetus for low STV within 2-3days after corticosteroids. However, literature is not unanimous in this respect. This study intends to asses STV longitudinally after corticosteroid administration. MATERIAL AND METHODS: A retrospective cohort study in a tertiary perinatal centre from 2009 to 2015 included all women who had been treated with corticosteroids at gestational age of 26-34 weeks, had a computerized cardiotocography (cCTG) before and after medication and did not deliver within 48h. FHR and STV were stratified over 12-h periods and compared before and after corticosteroids. Women with imminent preterm labour (including PPROM) and women with placental problems (fetal growth restriction (FGR) or preeclampsia) (PE) were analysed separately. The effect of co-medication and gestational age was assessed. RESULTS: The study included 406 women, 211 with imminent preterm labour, 195 with FGR-PE. After corticosteroids STV increased 1-2ms (median 1.4; IQR 0.1-3.1) during the first 36h after start of corticosteroids. Thereafter a small decrease of less than 1ms (median -0,6; IQR 1.6 to 0.3) compared to before CC was seen. CONCLUSIONS: The most conspicuous effect of corticosteroids is a short term increase of STV and decrease of FHR. A slight decrease after 48-71h is possible, but abnormally low values should be considered as a sign of fetal distress. The clinical guidance, given by some, not to intervene because of a low STV after corticosteroids appears invalid. PMID- 28715660 TI - Elevated basal progesterone levels are associated with increased preovulatory progesterone rise but not with higher pregnancy rates in ICSI cycles with GnRH antagonists. AB - OBJECTIVE: To ascertain the association between basal progesterone (P) levels and the occurrence of preovulatory progesterone rise (PPR) and clinical pregnancy rates (CPRs) in ICSI cycles with GnRH antagonists. STUDY DESIGN: Serum P levels of 464 patients were measured on day 2 and day of hCG of cycles. Cycles with basal P levels>1.6ng/mL were cancelled. All embryos were cryopreserved in cycles with P levels>=2ng/mL on the day of hCG. The primary outcome measures were the incidence of PPR (P>1.5ng/mL) and CPR with regard to basal P. RESULTS: Basal P levels were significantly higher in cycles with PPR than in those without PPR (0.63+/-0.31 vs. 0.48+/-0.28ng/mL). Area under the curve for basal P according to ROC analysis to discriminate between elevated and normal P levels on the day of hCG was 0.65 (0.58-0.71 95% CI, p<0.01). The cut-off value for basal P levels that best discriminates between cycles with and without PPR was 0.65ng/mL. Cycles with basal P levels above 0.65ng/mL had a significantly higher incidence of PPR (30.9% vs. 13.5%) but similar clinical and cumulative pregnancy rates (38.8% vs. 31.1% and 41.7% vs. 32.6%, respectively) in comparison to cycles with basal P levels below 0.65ng/mL. In multivariate regression analysis, basal P levels, LH level on the first day of antagonist administration, and estradiol levels on the day of hCG trigger were the variables that predicted PPR. CONCLUSION: Basal P levels were associated with increased incidence of PPR but not with CPR. PMID- 28715662 TI - Preaged remodeling of myofibrillar cytoarchitecture in skeletal muscle expressing R349P mutant desmin. AB - The majority of hereditary and acquired myopathies are clinically characterized by progressive muscle weakness. We hypothesized that ongoing derangement of skeletal muscle cytoarchitecture at the single fiber level may precede and be responsible for the progressive muscle weakness. Here, we analyzed the effects of aging in wild-type (wt) and heterozygous (het) and homozygous (hom) R349P desmin knock-in mice. The latter harbor the ortholog of the most frequently encountered human R350P desmin missense mutation. We quantitatively analyzed the subcellular cytoarchitecture of fast- and slow-twitch muscles from young, intermediate, and aged wt as well as desminopathy mice. We recorded multiphoton second harmonic generation and nuclear fluorescence signals in single muscle fibers to compare aging-related effects in all genotypes. The analysis of wt mice revealed that the myofibrillar cytoarchitecture remained stable with aging in fast-twitch muscles, whereas slow-twitch muscle fibers displayed structural derangements during aging. In contrast, the myofibrillar cytoarchitecture and nuclear density were severely compromised in fast- and slow-twitch muscle fibers of hom R349P desmin mice at all ages. Het mice only showed a clear degradation in their fiber structure in fast-twitch muscles from the adult to the presenescent age bin. Our study documents distinct signs of normal and R349P mutant desmin-related remodeling of the 3D myofibrillar architecture during aging, which provides a structural basis for the progressive muscle weakness. PMID- 28715661 TI - Cognitive decline and brain amyloid-beta accumulation across 3 years in adults with Down syndrome. AB - Adults with Down syndrome (DS) have a high incidence of Alzheimer's disease (AD), providing a unique opportunity to explore the early, preclinical stages of AD neuropathology. We examined change in brain amyloid-beta accumulation via the positron emission tomography tracer [11C] Pittsburgh compound B (PiB) across 2 data collection cycles, spaced 3 years apart, and decline in cognitive functioning in 58 adults with DS without clinical AD. PiB retention increased in the anterior cingulate gyrus, precuneus cortex, parietal cortex, and anterior ventral striatum. Across the 2 cycles, 14 (27.5%) participants were consistently PiB+, 31 (60.8%) were consistently PiB-, and 6 (11.7%) converted from PiB- at cycle 1 to PiB+ at cycle 2. Increased global amyloid-beta was related to decline in verbal episodic memory, visual episodic memory, executive functioning, and fine motor processing speed. Participants who were consistently PiB+ demonstrated worsening of episodic memory, whereas participants who were consistently PiB- evidenced stable or improved performance. Amyloid-beta accumulation may be a contributor to or biomarker of declining cognitive functioning in preclinical AD in DS. PMID- 28715663 TI - A laboratory model of impulsivity and alcohol use in late adolescence. AB - Impulsivity is a core characteristic of externalizing problems and a robust predictor of alcohol use in adolescence. There is little evidence on the causal mechanisms through which impulsivity influences drinking or how they are affected by key social factors (peer influence). This study reports the development of the first comprehensive laboratory model of adolescent impulsivity and alcohol use. One-hundred and twenty adolescents (50% female) of legal drinking age (M = 19.47 years, SD = 1.12) in Australia (18+ years) were subjected to 1 of 3 experimental manipulations to increase impulsive behavior (reward cue exposure, negative mood induction, ego depletion). Changes in disinhibition (stop-signal task) and reward seeking (BAS-Fun Seeking) were measured before completing a laboratory drinking task alone or with a heavy-drinking confederate. Reward cue exposure increased alcohol consumption, with the effect mediated by increased reward-seeking. Negative mood induction increased disinhibition, but not drinking. The presence of a heavy-drinking peer directly increased alcohol consumption in an additive fashion. Findings provide causal evidence that extends survey-based research by highlighting the role of reward-related impulsivity in adolescent alcohol use. The new laboratory model can provide novel insights into the psychological processes underlying adolescent impulsivity and impulsivity-related drinking. PMID- 28715664 TI - Electron transfer mediators accelerated the microbiologically influence corrosion against carbon steel by nitrate reducing Pseudomonas aeruginosa biofilm. AB - Electron transfer is a rate-limiting step in microbiologically influenced corrosion (MIC) caused by microbes that utilize extracellular electrons. Cross cell wall electron transfer is necessary to transport the electrons released from extracellular iron oxidation into the cytoplasm of cells. Electron transfer mediators were found to accelerate the MIC caused by sulfate reducing bacteria. However, there is no publication in the literature showing the effect of electron transfer mediators on MIC caused by nitrate reducing bacteria (NRB). This work demonstrated that the corrosion of anaerobic Pseudomonas aeruginosa (PAO1) grown as a nitrate reducing bacterium biofilm on C1018 carbon steel was enhanced by two electron transfer mediators, riboflavin and flavin adenine dinucleotide (FAD) separately during a 7-day incubation period. The addition of either 10ppm (w/w) (26.6MUM) riboflavin or 10ppm (12.7MUM) FAD did not increase planktonic cell counts, but they increased the maximum pit depth on carbon steel coupons considerably from 17.5MUm to 24.4MUm and 25.0MUm, respectively. Riboflavin and FAD also increased the specific weight loss of carbon steel from 2.06mg/cm2 to 2.34mg/cm2 and 2.61mg/cm2, respectively. Linear polarization resistance, electrochemical impedance spectroscopy and potentiodynamic polarization curves all corroborated the pitting and weight loss data. PMID- 28715665 TI - Electrochemical aptasensors for contaminants detection in food and environment: Recent advances. AB - The growing number of contaminants requires the development of new analytical tools to meet the increasing demand for legislative actions on food safety and environmental pollution control. In this context, electrochemical aptamer-based sensors appear promising among all biosensors because they permit multiplexed analysis and provide fast response, sensitivity, specificity and low cost. The aim of this review is to give the readers an overview of recent important achievements in the development of electrochemical aptamer-based biosensors for contaminant detection over the last two years. Special emphasis is placed on aptasensors based on screen-printed electrodes which show a substantial improvement of analytical performances. PMID- 28715666 TI - Cognitive, affective, and social factors maintaining paranoia in adolescents with mental health problems: A longitudinal study. AB - Paranoia may be a significant concern during adolescence, but there has been little research on excessive mistrust in young people. In this longitudinal study we set out to test the predictive ability of a number of cognitive, affective, and social factors in the early development of paranoia in a clinical adolescent population. Thirty four help-seeking adolescents, aged 11-16 years, reporting paranoid thoughts and attending mental health services were recruited. Self report and interview assessments of paranoia were conducted at baseline. Measures relating to a cognitive model of persecutory delusions were completed. Paranoia was reassessed after three months with thirty three participants. Significant predictors of paranoia persistence were anxiety, depression, worry, negative self beliefs, perceptual anomalies, insomnia, affective reactivity, bullying, and cyber victimization. No effect was found for reasoning bias or negative perceptions of academic ability, social competence, and physical appearance. In conclusion, many of the maintenance factors implicated in adult paranoia are likely to prove important in the early development of paranoia in young people. Further experimental and treatment studies are now needed to examine the causal role of these factors in the occurrence of paranoia in adolescents. PMID- 28715667 TI - Spectral and spatiotemporal variability ECG parameters linked to catheter ablation outcome in persistent atrial fibrillation. AB - With the increasing prevalence of atrial fibrillation (AF), there is a strong clinical interest in determining whether a patient suffering from persistent AF will benefit from catheter ablation (CA) therapy at long term. This work presents several regression models based on noninvasive measures automatically computed from the standard 12-lead electrocardiogram (ECG) such as AF dominant frequency (DF), spectral concentration and spatiotemporal variability (STV). Sixty-two AF patients referred to CA were enrolled in this study. Forty-seven of them had no recurrence after CA during an average follow-up of 14 +/- 8 months. The ECG features were extracted from an ECG recorded before the CA intervention and they were combined by means of logistic regression. The combination of DF and STV values from different precordial leads reached AUC = 0.939, outperforming the best results by using only one kind of features, such as DF (AUC = 0.801), and yielding a global accuracy of 93.5% for discriminating the best long-term responders to CA. These results point out the need to take into consideration the spatial variation of spectral ECG parameters to build predictive models dealing with AF. PMID- 28715668 TI - Spatial resolution and cathodoluminescence intensity dependence on acceleration voltage in electron beam excitation assisted optical microscopy using Y2O3:Eu3+ film. AB - This study presents relationship between acceleration voltage and spatial resolution of electron-beam assisted (EXA) optical microscope. The nanometric illumination light sources of the present EXA microscope was red-emitting cathodoluminescence (CL) in the Y2O3:Eu3+ thin film excited by focused electron beam. Our experimental results demonstrated that the spatial resolutions of the EXA microscope were higher as the acceleration voltage was higher. We managed to make images of the scattered gold particles with approximately 90 nm-resolutions at the voltages higher than 20 kV. The dependence of the spatial resolution on the acceleration voltage was explained by the distribution of simulated electron scattering trajectories in the luminescent thin film. PMID- 28715669 TI - The contributions of numerical acuity and non-numerical stimulus features to the development of the number sense and symbolic math achievement. AB - Numerical acuity, frequently measured by a Weber fraction derived from nonsymbolic numerical comparison judgments, has been shown to be predictive of mathematical ability. However, recent findings suggest that stimulus controls in these tasks are often insufficiently implemented, and the proposal has been made that alternative visual features or inhibitory control capacities may actually explain this relation. Here, we use a novel mathematical algorithm to parse the relative influence of numerosity from other visual features in nonsymbolic numerical discrimination and to examine the strength of the relations between each of these variables, including inhibitory control, and mathematical ability. We examined these questions developmentally by testing 4-year-old children, 6 year-old children, and adults with a nonsymbolic numerical comparison task, a symbolic math assessment, and a test of inhibitory control. We found that the influence of non-numerical features decreased significantly over development but that numerosity was a primary determinate of decision making at all ages. In addition, numerical acuity was a stronger predictor of math achievement than either non-numerical bias or inhibitory control in children. These results suggest that the ability to selectively attend to number contributes to the maturation of the number sense and that numerical acuity, independent of inhibitory control, contributes to math achievement in early childhood. PMID- 28715670 TI - Estimated lifetime effective dose to hunters and their families in the three most contaminated counties in Sweden after the Chernobyl nuclear power plant accident in 1986 - A pilot study. AB - Hunters and their families were one of the most exposed subpopulations in Sweden after the Chernobyl nuclear power plant accident in 1986. In this pilot study we used existing registries and whole-body measurements to develop algorithms to calculate lifetime effective doses and collective doses to some hunters in Sweden. Ten hunters and their family members were randomly selected from each of the three most contaminated counties in Sweden (Vasternorrland, Uppsala, Gavleborg) using the register for hunting weapons from the Police Authority in 1985. Hence, this design can be regarded as a closed cohort only including hunters and their family members living in these three counties at the time of the accident. Statistics Sweden matched these individuals (n = 85) with their dwelling coordinates onto the digital map produced by the Swedish Radiation Safety Authority after aerial measurements of 137Cs (kBq m-2). Internal effective doses were estimated using aggregated transfer factors from ground deposition to in-vivo body concentration for 134Cs and 137Cs in hunters (Bq kg-1). External effective doses were also calculated on the dwelling coordinate for 134Cs, 137Cs and short-lived nuclides in these three counties. Annual effective doses for external and internal doses were then cumulated up to a life expectancy of 80 years for men and 84 years for women, respectively. The total lifetime effective doses to the members of the hunter families in this cohort were on average 8.3 mSv in Vasternorrland, 4.7 mSv in Uppsala and 4.1 mSv in Gavleborg. The effective dose to men were about 40% higher than in women. In all counties the internal dose was about 75% of the total lifetime effective dose. The collective dose for all hunters with family members, in total about 44,000 individuals, in these three counties could be approximated at about 256 manSv. This study shows it is possible to use register data to develop algorithms for calculating lifetime effective dose commitments for hunters with relatively accuracy. PMID- 28715671 TI - Adipose triglyceride lipase protein abundance and translocation to the lipid droplet increase during leptin-induced lipolysis in bovine adipocytes. AB - Proper regulation of lipid metabolism is critical for preventing the development of metabolic diseases. It is clear that leptin plays a critical role in the regulation of energy homeostasis by regulating energy intake. However, leptin can also regulate energy homeostasis by inducing lipolysis in adipocytes, but it is unclear how the major lipases are involved in leptin-stimulated lipolysis. Therefore, the objectives of this study were to determine if (1) leptin acts directly to induce lipolysis in bovine adipocytes, (2) the potential lipases involved in leptin-induced lipolysis in bovine adipocytes, and (3) increases translocation of adipose triglyceride lipase (ATGL) and hormone sensitive lipase (HSL) during leptin-stimulated lipolysis in bovine stromal vascular cell-derived adipocytes. As hypothesized, leptin induced a lipolytic response (P = 0.02) in isolated adipocytes which was accompanied by an increase in phosphorylation of signal transducer and activator of transcription (STAT)3 (P = 0.03), a well documented secondary messenger of leptin, and ATGL protein abundance (P < 0.01). Protein abundance of STAT3, perilipin, HSL, and phosphorylation of HSL by PKA and AMPK were not altered during leptin-stimulated lipolysis (P > 0.05). Immunostaining techniques were employed to determine the location of HSL and ATGL. Both lipases translocated to the lipid droplet after 2 h of exposure to isoproterenol (P < 0.02). However, only ATGL was translocated to the lipid droplet during leptin-stimulated lipolysis (P = 0.04), indicating ATGL may be the active lipase in leptin-stimulated lipolysis. In summary, leptin stimulates lipolysis in bovine adipocytes. The lack of phosphorylated HSL and translocation of HSL to the lipid droplet during leptin-stimulated lipolysis suggest minimal activity by PKA. Interestingly, leptin-stimulated lipolysis is accompanied by an increase in ATGL protein abundance and translocation to the lipid droplet, indicating its involvement in leptin-stimulated lipolysis either due to an increase in protein abundance or through a novel lipolytic cascade. PMID- 28715672 TI - Genomic and pathogenic analysis of a Muscovy duck parvovirus strain causing short beak and dwarfism syndrome without tongue protrusion. AB - In 2008, clinical cases of short beak and dwarfism syndrome (SBDS) caused by Muscovy duck parvovirus (MDPV) infection were found in mule duck and Taiwan white duck farms in Fujian, China. A MDPV LH strain causing duck SBDS without tongue protrusion was isolated in this study. Phylogenetic analysis show that the MDPV LH strain was clustered together with other MDPV strains, but divergent from GPV isolates. Two major fragment deletions were found in the inverted terminal repeats (ITR) of MDPV LH similar to the ones in the ITR of MDPV GX5, YY and SAAS SHNH strains. To investigate the pathogenicity of the MDPV LH strain, virus infection of young mule ducks was performed. The infected ducks showed SBDS symptoms including retard growth and shorten beaks without tongue protrusion. Atrophy of thymus, spleen and bursa of Fabricius was identified in the infected ducks. The results show that MDPV LH strain is moderately pathogenic to mule duck, leading to occurrence of SBDS. As far as we know, it is the first study showing that SBDS without tongue protrusion, and atrophy of thymus, spleen and bursa of Fabricius possibly associated with immunosuppression were found in the MDPV-infected ducks. The established duck-MDPV-SBDS system will help us to further work on the virus pathogenesis and develop efficacious vaccine against MDPV infection. PMID- 28715673 TI - Activity level DNA evidence evaluation: On propositions addressing the actor or the activity. AB - More often than not, the source of DNA traces found at a crime scene is not disputed, but the activity or timing of events that resulted in their transfer is. As a consequence, practitioners are increasingly asked to assign a value to DNA evidence given propositions about activities provided by prosecution and defense counsel. Given that the dispute concerns the nature of the activity that took place or the identity of the actor that carried out the activity, several factors will determine how to formulate the propositions. Determining factors are (1) whether defense claims the crime never took place, (2) whether defense claims someone other than the accused (either an unknown individual or a known person) performed the criminal activity, and (3) whether it is claimed and disputed that the suspect performed an alternative, legitimate activity or has a relation to the victim, the object, or the scene of crime that implies a legitimate interaction. Addressing such propositions using Bayesian networks, we demonstrate the effects of the various proposition sets on the evaluation of the evidence. PMID- 28715674 TI - The presence of licit and illicit drugs in police stations and their implications for workplace drug testing. AB - The presence of licit and illicit drug residues on surfaces was studied in 10 police stations and a central drug evidence store in New South Wales, Australia, with the results compared to similar surfaces in four public buildings (to establish a community baseline). The results of almost 850 workplace surface swabs were also compared to the outcome of drug analysis in urine and hair samples volunteered by police officers. Surfaces were swabbed with alcohol and the swabs were extracted and analysed by LC-MS/MS. Low level concentrations of the more commonly used drugs were detected at four public sites and one restricted access police office facility. Surface swabs taken in 10 city and country police stations yielded positive results for a broader suite of drugs than at background sites however 75-93% of the positive drug results detected in police stations were below 40ng, which is only slightly greater than the largest background result measured in the current study. This study indicates that contamination issues are more likely to be focussed in higher risk areas in police stations, such as counters and balances in charge areas, and surfaces within drug safes although front reception counters also returned surface contamination. All 64 urine samples collected in this study were negative, while only 2 of the 11 hair samples collected from donors resulted in trace concentrations for cocaine, but not its metabolite benzoylecgonine. Positive hair samples were only obtained from police donors in very high risk jobs, indicating that the exposure risk is low. Minor changes to the materials used as work surfaces, and some procedural changes in police stations and large evidence stores are suggested to decrease the likelihood of drugs contaminating work surfaces, thereby reducing the potential exposure of police officers to drugs in the workplace. PMID- 28715675 TI - Resting-state brain networks in patients with Parkinson's disease and impulse control disorders. AB - INTRODUCTION: To investigate intrinsic neural networks connectivity changes in Parkinson's disease (PD) patients with and without impulse control disorders (ICD). METHODS: Fifteen patients with PD with ICD (ICD+), 15 patients with PD without ICD (ICD-) and 24 age and sex-matched healthy controls (HC) were enrolled in the study. To identify patients with and without ICD and/or punding, we used the Minnesota Impulsive Disorders Interview (MIDI) and a clinical interview based on diagnostic criteria for each symptom. All patients underwent a detailed neuropsychological evaluation. Whole brain structural and functional imaging was performed on a 3T GE MR scanner. Statistical analysis of functional data was completed using BrainVoyager QX software. Voxel-based morphometry (VBM) was used to test whether between-group differences in resting-state connectivity were related to structural abnormalities. RESULTS: The presence of ICD symptoms was associated with an increased connectivity within the salience and default-mode networks, as well as with a decreased connectivity within the central executive network (p < .05 corrected). ICD severity was correlated with both salience and default mode networks connectivity changes only in the ICD+ group. VBM analysis did not reveal any statistically significant differences in local grey matter volume between ICD+ and ICD- patients and between all patients and HC (p < .05. FWE). CONCLUSIONS: The presence of a disrupted connectivity within the three core neurocognitive networks may be considered as a potential neural correlate of ICD presence in patients with PD. Our findings provide additional insights into the mechanisms underlying ICD in PD, confirming the crucial role of an abnormal prefrontal-limbic-striatal homeostasis in their development. PMID- 28715676 TI - Modelling the impacts of altered management practices, land use and climate changes on the water quality of the Millbrook catchment-reservoir system in South Australia. AB - Sustainable management of drinking water reservoirs requires taking into account the potential effects of their catchments' development. This study is an attempt to estimate the daily patterns of nutrients transport in the catchment - reservoir systems through the application of the ensemble of complementary models SWAT-SALMO. SWAT quantifies flow, nitrate and phosphate loadings originating in catchments before entering downstream reservoirs meanwhile SALMO determines phosphate, nitrate, and chlorophyll-a concentrations within the reservoirs. The study applies to the semi-arid Millbrook catchment-reservoir system that supplies drinking water to north-eastern suburbs of Adelaide, South Australia. The catchment hosts viti- and horticultural land uses. The warm-monomictic, mesotrophic reservoir is artificially aerated in summer. After validating the simulation results for both Millbrook catchment and reservoir, a comprehensive scenario analysis has been conducted to reveal cascading effects of altered management practices, land uses and climate conditions on water quality in the reservoir. Results suggest that the effect on reservoir condition in summer would be severe, most likely resulting in chlorophyll-a concentrations of greater than 40 MUg/l if the artificial destratification was not applied from early summer. A 50% curbing of water diversion from an external pipeline to the catchment will slightly limit chlorophyll-a concentrations by 1.22% as an effect of reduced inflow phosphate loads. The simulation of prospective land use scenarios converting 50% of present pasture in the Millbrook catchment into residential and orchards areas indicates an increase of summer chlorophyll-a concentrations by 9.5-107.9%, respectively in the reservoir. Global warming scenarios based on the high emission simulated by SWAT-SALMO did result in earlier growth of chlorophyll a but overall the effects on water quality in the Millbrook reservoir was not significant. However scenarios combining global warming and land use changes resulted in significant eutrophication effects in the reservoir, especially in the unmanaged condition with stratification in summer. This study has demonstrated that complementary model ensembles like SWAT-SALMO allow to comprehend more realistically cascading effects of distinct catchment processes on internal reservoir's processes, and facilitate integrated management scenarios. PMID- 28715677 TI - Protected area coverage of threatened vertebrates and ecoregions in Peru: Comparison of communal, private and state reserves. AB - Protected areas (PAs) are a conservation mainstay and arguably the most effective conservation strategy for species protection. As a 'megadiverse' country, Peru is a priority for conservation actions. Peruvian legislation allows for the creation of state PAs and private/communal PAs. Using publicly available species distribution and protected area data sets we evaluated the coverage of Threatened terrestrial vertebrate species distributions and ecoregions provided by both kinds of PA in Peru. Peru's state PA system covers 217,879 km2 and private/communal PAs cover 16,588 km2. Of the 462 species of Threatened and Data Deficient species we evaluated, 75% had distributions that overlapped with at least one PA but only 53% had >=10% of their distributions within PAs, with inclusion much reduced at higher coverage targets. Of the species we evaluated, 118 species are only found in national PAs and 29 species only found in private/communal PAs. Of the 17 terrestrial ecoregions found in Peru all are represented in PAs; the national PA system included coverage of 16 and private/communal PAs protect 13. One ecoregion is only protected in private/communal PAs, whereas four are only covered in national PAs. Our results show the important role private/communal PAs can play in the protection of ecological diversity. PMID- 28715678 TI - Effects of the distribution density of a biomass combined heat and power plant network on heat utilisation efficiency in village-town systems. AB - The building of biomass combined heat and power (CHP) plants is an effective means of developing biomass energy because they can satisfy demands for winter heating and electricity consumption. The purpose of this study was to analyse the effect of the distribution density of a biomass CHP plant network on heat utilisation efficiency in a village-town system. The distribution density is determined based on the heat transmission threshold, and the heat utilisation efficiency is determined based on the heat demand distribution, heat output efficiency, and heat transmission loss. The objective of this study was to ascertain the optimal value for the heat transmission threshold using a multi scheme comparison based on an analysis of these factors. To this end, a model of a biomass CHP plant network was built using geographic information system tools to simulate and generate three planning schemes with different heat transmission thresholds (6, 8, and 10 km) according to the heat demand distribution. The heat utilisation efficiencies of these planning schemes were then compared by calculating the gross power, heat output efficiency, and heat transmission loss of the biomass CHP plant for each scenario. This multi-scheme comparison yielded the following results: when the heat transmission threshold was low, the distribution density of the biomass CHP plant network was high and the biomass CHP plants tended to be relatively small. In contrast, when the heat transmission threshold was high, the distribution density of the network was low and the biomass CHP plants tended to be relatively large. When the heat transmission threshold was 8 km, the distribution density of the biomass CHP plant network was optimised for efficient heat utilisation. To promote the development of renewable energy sources, a planning scheme for a biomass CHP plant network that maximises heat utilisation efficiency can be obtained using the optimal heat transmission threshold and the nonlinearity coefficient for local roads. PMID- 28715679 TI - A parametric study on hydraulic conductivity and self-healing properties of geotextile clay liners used in landfills. AB - Nowadays, the raise of excessive generation of solid wastes is considered as a major environmental concern due to the fast global population growth. The contamination of groundwater from landfill leachate compromises every living creature. Geotextile clay liner (GCL) that has a sandwich structure with two fibrous sheets and a clay core can be considered as an engineered solution to prevent hazardous pollutants from entering into groundwater. The main objective of the present study is therefore to enhance the performance of GCL structures. By changing some structural factors such as clay type (sodium vs. calcium bentonite), areal density of clay, density of geotextile, geotextile thickness, texture type (woven vs. nonwoven), and needle punching density a series of GCL samples were fabricated. Water pressure, type of cover soil and overburden pressure were the environmental variables, while the response variables were hydraulic conductivity and self-healing rate of GCL. Rigid wall constant head permeability test was conducted on all the samples. The outlet water flow was measured and evaluated at a defined time period and the hydraulic conductivity was determined for each sample. In the final stage, self-healing properties of samples were investigated and an analytical model was used to explain the results. It was found that higher Montmorillonite content of clay, overburden pressure, needle punching density and areal density of clay poses better self healing properties and less hydraulic conductivity, meanwhile, an increase in water pressure increases the hydraulic conductivity. Moreover, the observations were aligned with the analytical model and indicated that higher fiber inclusion as a result of higher needle-punching density produces closer contact between bentonite and fibers, reduces hydraulic conductivity and increases self-healing properties. PMID- 28715680 TI - Response surface methodology investigation into optimization of the removal condition and mechanism of Cr(VI) by Na2SO3/CaO. AB - The removal of Cr(VI) by chemical reduction-precipitation is widely applied in wastewater treatment plants. Nevertheless, the formation of Cr(OH)3 with gel properties has weak settlement performance, making it necessary to add a coagulant aid to reduce the settling time and improve the settling effect. In this investigation, a high concentration of Cr(VI) was removed using Na2SO3 as a reducing agent and CaO as a coagulant. An improved reduction and precipitation experiment was modeled by applying a three-factor central composite experimental design (CCD). To reveal as many mechanisms as possible for CrT removal, other verification experiments were performed. The CrT removal efficiency decreased, which can be explained by the following three reasons: dissolution of Cr(III), competition for adsorption between Ca2+ and Cr(III) at different coagulation times, and formation of a solubility complex with Cr(III) due to the surplus SO32 in solution. The increasing CrT removal efficiency can be explained by the following two reasons: dissolved Ca2+ from CaO can neutralize CrO2- that is produced by the dissolution of Cr(OH)3 in alkaline solution and can broaden the optimal final pH range of coagulation. Ca2+ could also strengthen the CrT removal through adsorption bridging and co-precipitation with CaO as the core of flocs. PMID- 28715681 TI - Adsorption of NH4+-N on Chinese loess: Non-equilibrium and equilibrium investigations. AB - NH4+-N is a crucial pollutant in landfill leachate and can be in high concentrations for a long period of time due to anaerobic condition of landfills. The adsorption properties of NH4+-N on the Chinese loess were investigated using Batch test. The influences of ammonium concentration, temperature, reaction time, slurry concentration, and pH on the adsorption process are evaluated. Adsorption kinetics and isotherm behaviors were studied by applying different models to the test data to determine the adsorption parameters. The equilibrating duration was shown to be less than 60 min. The data on adsorption kinetics can be well fitted by the pseudo-second-order kinetics model. According to the Langmuir isotherm model, the adsorption capacity of Chinese loess about NH4+-N was predicted to be 72.30 mg g-1. The uptake of NH4+-N by Chinese loess was considered to be the type of physical adsorption on the basis of D-R isotherm analysis. The optimal pH and slurry concentration are 4 and 2 g/50 ml, respectively. According to the calculated values of free energy, enthalpy and entropy change, the adsorption process is determined to be exothermic. The disorder of the system appeared lowest at temperature of 308.15 K. The predicted Gibb's free energies also indicate the adsorption process is endothermic and spontaneous. The FTIR spectrum and EDX analysis showed the adsorption process of NH4+ involves cation exchange and dissolution of calcite. PMID- 28715682 TI - CATH-2 and LL-37 increase mannose receptor expression, antigen presentation and the endocytic capacity of chicken mononuclear phagocytes. AB - Cathelicidins display in vitro and in vivo immunomodulatory activities and are part of the innate immune system. Previously, we found that in ovo treatment with chicken cathelicidin CATH-2 partially protects young broilers against respiratory E. coli infection. To determine the cellular aspects of this protection, we investigated immunomodulatory effects of CATH-2 and the human cathelicidin LL-37 on primary chicken peripheral blood mononuclear cells (PBMCs). Treatment of chicken PBMCs with L-CATH-2, D-CATH-2 or LL-37 increased the percentage of mononuclear phagocytes, but decreased that of B cells. L-CATH-2, D-CATH-2 and LL 37 treatment of chicken PBMCs also enhanced the expression levels of mannose receptor MRC1 and antigen presentation markers MHCII, CD40 and CD86 on mononuclear phagocytes, indicating increased antigen presentation capacity. Concomitantly, L-CATH-2, D-CATH-2 and LL-37 neutralized LPS-induced cytokine production, while increasing the endocytic capacity. We conclude that L-CATH-2, D CATH-2 and LL-37 can modulate the immune response of primary chicken immune cells by increasing mannose receptor expression, antigen presentation, endocytosis and neutralizing LPS-induced cytokine production and as a result augment activation of the adaptive immune system. PMID- 28715683 TI - IL-17RB enhances thyroid cancer cell invasion and metastasis via ERK1/2 pathway mediated MMP-9 expression. AB - IL-17RB, a member of the IL-17 receptor family that can be activated by IL-17B, has been proved to be involved in inflammatory diseases and cancers. However, the function of IL-17RB in thyroid cancer is still unknown. In this study, IL-17RB expression in thyroid cancer cell lines and tissues was examined by real-time PCR and western blot. The effects of IL-17RB on cell invasion and migration were determined by in vitro invasion and migration assays, while the effects of IL 17RB on cell metastasis were analyzed by in vivo experiments. The results showed that IL-17RB expression was upregulated in both thyroid cancer cells and tissues. IL-17B dose-dependently promoted the invasion, growth and migration of thyroid cancer cells, whereas knockdown of IL-17RB attenuated the effects of IL-17B in vitro. Moreover, IL-17RB was involved in the metastasis and growth of thyroid cancer cells in vivo. In addition, IL-17RB induced ERK1/2 activation and increased MMP-9 expression in vitro and in vivo. Inhibition of ERK1/2 pathway blocked the IL-17RB-mediated thyroid cancer cell invasion and MMP-9 expression. Together, our findings demonstrate that IL-17RB can enhance thyroid cancer cell invasion and metastasis via ERK1/2 pathway-mediated MMP-9 expression, suggesting that IL-17RB may act as a potential therapeutic target for thyroid cancer therapy. PMID- 28715684 TI - Enantiomeric separation and quantification of citalopram in serum by ultra-high performance supercritical fluid chromatography-tandem mass spectrometry. AB - A method for enantiomeric separation and quantification of R/S-citalopram in serum was developed and validated using ultra-high performance supercritical fluid chromatography-tandem mass spectrometry (UHPSFC-MS/MS). Sample preparation prior to UHPSFC-MS/MS analysis consisted of protein precipitation with acidic acetonitrile and filtration through a phospholipid removal plate. The UHPSFC MS/MS method used an UPC2 Trefoil CEL2 column with a mobile phase consisting of CO2 and methanol/acetonitrile (70:30, v/v) with 10mM ammonium acetate. The injection volume was 1MUL and run time was 4min. MS/MS detection was performed with positive electrospray ionization and two multiple reaction monitoring transitions (m/z 325.1>262.0 and m/z 325.1>109.0). The calibration range was 5 500nM for each analyte. The between-assay relative standard deviations were in the range of 3.4-4.5%. Recovery was 81-91% and matrix effects ranged from 96 to 101% (corrected with internal standard). After development and initial testing, the method has been successfully implemented in routine use in our laboratory for both separation and quantification of R/S-citalopram in more than 250 serum samples for therapeutic drug monitoring. PMID- 28715685 TI - Metabolic profile study of 7, 8-dihydroxyflavone in monkey plasma using high performance liquid chromatography-tandem mass spectrometry. AB - 7, 8-Dihydroxyflavone, as a high-affinity tropomyosin-receptor-kinase B agonist, can mimic the physiological actions of brain-derived neurotrophic factor and exert a variety of neurological actions in numerous models including Parkinsons disease, depression, learning and memory. Nonetheless, a limited number of studies have been focused on its metabolism in mammal and no methodology has been reported for the determination of 7, 8-DHF and its metabolites. Herein, we developed a rapid, sensitive and accurate method using high performance liquid chromatography-tandem mass spectroscopy for the determination of 7, 8-DHF and its metabolites in monkey plasma. The lower limits of quantification for analytes were 0.4-2.0ngmL-1. The intra-day and inter-day precisions (relative standard deviation, %) of analytes were within 11.83%, and the accuracy (relative error, %) ranged from -6.86 to 14.00%. The mean extraction recoveries for analytes were more than 89.14%. This validated method was successfully applied to the metabolic profile study of 7, 8-DHF in monkey plasma. The results indicated that 7, 8-DHF undergoes methylation, glucuronidation and/or sulfation, and the conjugated forms are the main metabolites in monkey plasma. We further demonstrated that methylated 7, 8-DHF can be also conjugated with glucuronidation/sulfation, and the methylation occurs mainly in the 8 position. PMID- 28715686 TI - A new aggregation-induced emission fluorescent probe for rapid detection of nitroreductase and its application in living cells. AB - The biological activity of nitroreductase (NTR) is closely related to biological hypoxia status in organisms. The development of effective methods for monitoring the activity of NTR is of great significance for medical diagnosis and tumor research. Toward this goal, we have developed a new aggregation-induced emission (AIE) fluorescence NTR probe TPE-HY used the tetraphenylethene as the fluorophore, and used the nitro group as the NTR recognition site. The probe TPE HY has many excellent properties, including rapid response, AIE characteristics, high sensitivity and selectivity, and low cytotoxicity. Importantly, the probe TPE-HY is successfully applied to monitor endogenous NTR in living HeLa cells. PMID- 28715687 TI - Highly selective and sensitive fluorogenic ferric probes based on aggregation enhanced emission with -SiMe3 substituted polybenzene. AB - In this study, thiophene was linked to polybenzene to generate novel fluorescent probes, namely 3,4-diphenyl-2,5-di(2-thienyl)phenyl-trimethylsilane (DPTB-TMS) with a -SiMe3 substituent and 3,4-diphenyl-2,5-di(2-thienyl)phenyl (DPTB) without the -SiMe3 substituent, respectively. Both of the two compounds exhibit aggregation-enhanced emission (AEE) properties in tetrahydrofuran/water mixtures due to restricted intramolecular rotation of the peripheral groups, which make the two compounds good candidates for the detection of Fe3+ ions in aqueous-based solutions. The fluorescence intensity of the two compounds decreases immediately and obviously upon addition of a trace amount of Fe3+, and decreases continuously as the amount of Fe3+ increases. The fluorescence was quenched to 92% of its initial intensity when the amount of Fe3+ ions reached 6MUmol for DPTB-TMS and to 80% for DPTB in the systems, indicating that the compound with the -SiMe3 group is a more effective probe. The detection limit was found to be 1.17MUM (65ppb). The detection mechanism is proposed to be static quenching. DPTB-TMS is highly efficient for the detection of ferric ions even in the presence of other metal ions. In addition, the method is also successfully applied to the detection of ferric ions in water, blood serum, or solid films. This indicates that these polybenzene compounds can be applied as low-cost, high selectivity, and high efficiency Fe3+ probes in water or in clinical applications. PMID- 28715688 TI - Colorimetric and fluorescent detection of hydrazine with high sensitivity and excellent selectivity. AB - It is critical to develop probes for rapid, selective, and sensitive detection of the highly toxic hydrazine in both environmental and biological science. In this work, under mild condition, a novel colorimetric and off-on fluorescent probe was synthesized for rapid recognition of hydrazine with excellent selectivity over other various species including some biological species, metal ions and anions. The limit of quantification (LOQ) value was 1.5*10-4M-3.2*10-3M (colorimetric method) and 1.5*10-4M-3.2*10-3M (fluorescent method) with as low as detection limit of 46.2MUM. PMID- 28715689 TI - Structure and absolute configuration of some 5-chloro-2-methoxy-N-phenylbenzamide derivatives. AB - The absolute configuration of 5-chloro-2-methoxy-N-phenylbenzamide single crystal [compound (1)] and the effect of introducing -[CH2]n-, n=1,2 group adjacent to the amide group [compounds (2) and (3)], were studied. Furthermore, the replacement of the methoxy group with a hydroxy group [compound (4)] was defined. Proton and carbon-13 NMR spectrometer were used to record the structural information of the prepared compounds. X-ray single crystal diffractometer were used to elucidate the 3D structural configurations. Intensity data for the studied compounds were collected at room temperature. The X-ray data prove that compound (1) is almost planar, with maximum r.m.s. deviations of 0.210(3)A corresponds to C13. This planarity starts to disturb by adding -[CH2]n-, n=1,2 groups between the NH group and the phenyl ring in compounds (2) and (3), respectively. By replacing the OCH3 group by an OH group in compound (4), the plane of the chlorophenyl moiety is nearly perpendicular to that of the phenyl ring. Such new structural configurations were further illustrated by the infrared, and ultraviolet-visible spectroscopy measurements in the frequency range 400-4000cm-1 and 190-1100nm, respectively. Spectroscopic analyses were verified with the help of molecular modeling using density functional theory. The estimated total dipole moment for the prepared compounds reflects its ability to interact with its surrounding molecules. The higher dipole moment for a given structures is combined with the higher reactivity for potential use in medicinal applications. PMID- 28715690 TI - A DFT study on surface-enhanced Raman spectroscopy of aromatic dithiol derivatives adsorbed on gold nanojunctions. AB - A computational study on aromatic dithiol derivatives (HS-Ar-X-Ar-SH, X=O, S, Se, NH, CH2, NN, CHCH, CC) interacting with gold cluster(s) was presented to investigate the chemical enhancement mechanism related to surface-enhanced Raman spectroscopy (SERS) for molecular junctions. Density functional theory (DFT) were performed on derivatives molecules as well as their single-end-linked (SEL) or double-end-linked (DEL) complexes for geometric, spectra, electronic and excitation properties, leading to discussions on dominant factor during SERS process. The resulted enhancement factors of SEL and DEL complexes exhibited specific dependency on linking atom or functional group between two phenyls, which was in accordance with the variation of polarizabilities and molecule cluster transition energy. PMID- 28715691 TI - A quinoline-based fluorometric and colorimetric dual-modal pH probe and its application in bioimaging. AB - The compound (E)-8-hydroxyl-2-[(E)-2-(2, 4-dihydroxyphenyl)vinyl]-quinoline (1) has been developed as a fluorometric and colorimetric dual-modal probe for pH detection in solution and in vivo. Remarkable changes in the fluorescence intensity with large Stokes shifts and colorimetric responses were observed as a function of pH. The sensing mechanisms involving protonation and deprotonation processes over the acidic and alkaline pH ranges were confirmed by 1H NMR and IR spectroscopic analysis. Furthermore, the application of probe 1 for the imaging of live PC3 cells was successfully achieved. Test strips based on probe 1 were fabricated, and were found to act as a convenient and efficient pH test kits. PMID- 28715692 TI - Propping the optical and electronic properties of potential photo-sensitizers with different pi-spacers: TD-DFT insights. AB - We report density functional theory (DFT) and time-dependent density functional theory (TD-DFT) calculations on the widely used N3 dye (cis-[Ru(2,2'-bipyridine 4,4'-dicarboxylic acid)2(NCS)2] and its trans isomer with different pi-spacers. The study compared the sensitization properties of the two isomers in terms of their electronic properties such as light harvesting efficiency (LHE), absorbed wavelength (lambdaMax) and molecular orbital distribution. Also, charge transfer descriptors, such as the charge transfer distance (DCT), dipole moment (MUCT), and the amount of charge transferred (qCT) were investigated. Upon replacing the two "2,2'-bipyridine-4,4'-dicarboxylic acid" ligands of the N3 dye with extended pi-spacers of "1,4-benzene and 2,5-thiophene" for both the cis and trans isomers, the LHE of the trans isomer was increased by 70% compared to the cis counterpart. The complexes with thiophene spacers showed the highest LHE. The trans isomers showed wider absorbance range of wavelengths and equal wide distribution of charge density in the excited state along the organic ligands. These findings highlight the importance of using pi-spacers between the organic ligands and the carboxylate groups to boost the LHE of DSSCs. Also, our study showed that the trans isomer is superior in its optical and electronic properties than the cis counterpart. However, the trans isomer is yet to be tested experimentally in DSSCs. PMID- 28715693 TI - Recommender system based on scarce information mining. AB - Guessing what user may like is now a typical interface for video recommendation. Nowadays, the highly popular user generated content sites provide various sources of information such as tags for recommendation tasks. Motivated by a real world online video recommendation problem, this work targets at the long tail phenomena of user behavior and the sparsity of item features. A personalized compound recommendation framework for online video recommendation called Dirichlet mixture probit model for information scarcity (DPIS) is hence proposed. Assuming that each clicking sample is generated from a representation of user preferences, DPIS models the sample level topic proportions as a multinomial item vector, and utilizes topical clustering on the user part for recommendation through a probit classifier. As demonstrated by the real-world application, the proposed DPIS achieves better performance in accuracy, perplexity as well as diversity in coverage than traditional methods. PMID- 28715694 TI - Associative cueing of attention through implicit feature-location binding. AB - In order to assess associative learning between two task-irrelevant features in cueing spatial attention, we devised a task in which participants have to make an identity comparison between two sequential visual stimuli. Unbeknownst to them, location of the second stimulus could be predicted by the colour of the first or a concurrent sound. Albeit unnecessary to perform the identity-matching judgment the predictive features thus provided an arbitrary association favouring the spatial anticipation of the second stimulus. A significant advantage was found with faster responses at predicted compared to non-predicted locations. Results clearly demonstrated an associative cueing of attention via a second-order arbitrary feature/location association but with a substantial discrepancy depending on the sensory modality of the predictive feature. With colour as predictive feature, significant advantages emerged only after the completion of three blocks of trials. On the contrary, sound affected responses from the first block of trials and significant advantages were manifest from the beginning of the second. The possible mechanisms underlying the associative cueing of attention in both conditions are discussed. PMID- 28715696 TI - Surfactants assist in lipid extraction from wet Nannochloropsis sp. AB - An efficient approach involving surfactant treatment, or the modification and utilization of surfactants that naturally occur in algae (algal-based surfactants), was developed to assist in the extraction of lipids from wet algae. Surfactants were found to be able to completely replace polar organic solvents in the extraction process. The highest yield of algal lipids extracted by hexane and algal-based surfactants was 78.8%, followed by 78.2% for hexane and oligomeric surfactant extraction, whereas the lipid yield extracted by hexane and ethanol was only 60.5%. In addition, the saponifiable lipids extracted by exploiting algal-based surfactants and hexane, or adding oligomeric surfactant and hexane, accounted for 78.6% and 75.4% of total algal lipids, respectively, which was more than 10% higher than the lipids extracted by hexane and ethanol. This work presents a method to extract lipids from algae using only nonpolar organic solvents, while obtaining high lipid yields and high selectivity to saponifiables. PMID- 28715695 TI - New liver cancer biomarkers: PI3K/AKT/mTOR pathway members and eukaryotic translation initiation factors. AB - Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. The initiation of protein translation is an important rate limiting step in eukaryotes and is crucial in many viral infections. Eukaryotic translation initiation factors (eIFs) are involved in the initiation step of protein translation and are linked to the phosphatidylinositol-3-kinases PI3K/AKT/mTOR pathway. Therefore we aimed to investigate a potential role of eIFs in HCC. We herein report on the immunohistochemical expression of the various eIF subunits in 235 cases of virus-related human HCC. Additionally, we used immunoblot analysis to investigate the expression of virus-related HCC and non virus-related HCC in comparison to controls. Mammalian target of rapamycin (or mechanistic target of rapamycin as it is known now (mTOR) and activated mTOR were significantly increased in chronic hepatitis C (HCV)-associated HCC, in HCC without a viral background, in alcoholic liver disease and Wilson disease. pPTEN, phosphatase and tensin homologue (PTEN) and pAKT showed a significant increase in HBV- and HCV-associated HCC, chronic hepatitis B, HCC without a viral background, alcoholic steatohepatitis (ASH) and Wilson disease. Phosphorylated (p)-eIF2alpha, eIF2alpha, eiF3B, eIF3D, eIF3J, p-eIF4B, eIF4G and eIF6 were upregulated in HCV associated HCC. eIF2alpha, p-eIF4B, eIF5 and various eIF3 subunits were significantly increased in chronic hepatitis B (HBV)-associated HCC. HCC without viral background displayed a significant increase for the eIF subunits p-2alpha, 3C, 3I, 4E and 4G. We noticed engraved differences in the expression pattern between chronic hepatitis B and C, HBV- and HCV-associated HCC and non-virus related HCC. PMID- 28715697 TI - Development of simultaneous nitrification-denitrification (SND) in biofilm reactors with partially coupled a novel biodegradable carrier for nitrogen-rich water purification. AB - Development of simultaneous nitrification-denitrification (SND) is a promising approach for nitrogen-rich water purification. Coupling biofilm reactors with novel biodegradable carrier of Pumelo Peel (PP) and various conventional plastic fillers (polyurethane filler, SPR-1 suspension filler, TA-II elastic filler and sphere filler) were examined to achieve SND in this study. Results represented that partially coupled with PP could achieve highly efficient SND. Optimal performance appealed in a bioreactor of coupling PP and SPR-1filler with ammonia and total nitrogen removal efficiencies of 96.8+/-4.0% and 78.9+/-9.5%, respectively, as well as low effluent CODMn of 1.85+/-0.86mgL-1. Notably, PP and conventional plastic filler played obviously different roles in combined bioreactor system. Microbial analysis suggested that dominant genera were Thiothrix, Gemmata, unclassified comanonadaceae, unclassified Rhizobiales, Salipiger, Chloronema and Klebsiella in optimal combined bioreactor, which indicated novel co-existence of heterotrophic nitrification, solid-phase, non solid-phase heterotrophic and sulfur-based autotrophic denitrification for achieving efficient SND. PMID- 28715698 TI - Acculturative stress as a moderator of the effect of drinking motives on alcohol use and problems among young adults. AB - BACKGROUND: Research has demonstrated a strong relationship between drinking motives and alcohol use among young adult populations. Further, there is substantial evidence of the association between psychosocial stressors and greater alcohol consumption. In the present study, we examined whether acculturative stress would moderate the relationship between major drinking motives and alcohol use behaviors and alcohol-related problems, and whether this relationship differs by racial/ethnic group. METHOD: Six hundred diverse undergraduate students (mean age=21.50, SD=2.46; 82.8% female; 40.2% White/Caucasian) completed a series of measures, including demographic information, alcohol use/alcohol problems, and acculturative stress. RESULTS: Findings showed varying patterns in the moderating effect of acculturative stress on the relationship between drinking motives and alcohol consumption and alcohol related problems, particularly for self-identified Hispanic, Black, and Asian students. Stronger drinking motives were associated with greater alcohol consumption and alcohol-related problems, and this relationship was stronger among Asian and Hispanic students who reported higher levels of acculturative stress. For Black students, greater acculturative stress was observed to weaken the relationship between coping, enhancement, and conformity motives and alcohol drinking frequency. CONCLUSIONS: Results are discussed in terms of incorporating acculturative stress in the development of tailored alcohol use interventions for vulnerable young adults, such as certain ethnic minority and immigrant groups. Clinical implications include screening for acculturative stress in primary care and counseling centers and early intervention programs to identify young adults who may be at-risk for or currently experiencing alcohol problems. PMID- 28715699 TI - Gambling and negative life events in a nationally representative sample of UK men. AB - INTRODUCTION: The links between gambling problems, trauma and life stressors are known to exist but understanding the extent of these relationships will allow for greater efficacy in early intervention and treatment. We investigated these relationships among men and sought to determine whether links were attenuated by alcohol and drug use problems. METHODS: A cross-sectional UK representative general population survey was conducted in 2009 with 3025 men aged 18-64years. Measurements included self-reported gambling behaviours, as measured by the South Oaks Gambling Scale (SOGS) and traumatic or stressful life events. Covariates included alcohol and drug dependence and socio-demographics. Binary logistic regression models were used to examine associations. RESULTS: Problem gambling (SOGS 3-4) and probable pathological gambling (SOGS 5+) were associated with increased odds of trauma in childhood (e.g. violence in the home (Adjusted Odd Ratios (AOR) 3.0 (CI=1.8-5.0) and 2.6 (CI=1.7-4.1) respectively), and life stressors in adulthood (e.g. intimate partner violence (AORs 4.5 (CI=2.0-10.3) and 4.7 (CI=2.3-9.7) and homelessness (AORs 2.2 (CI=1.1-4.6) and 3.2 (CI=1.9 5.5)). Results were attenuated when adjusted for probable alcohol and drug dependence with the latter having largest effects. CONCLUSIONS: Among men in the United Kingdom, disordered gambling remains uniquely associated with trauma and life stressors in childhood and adulthood after adjusting for alcohol and drug dependence. The results support a need for disordered gambling treatment services to undertake routine screening for alcohol, drugs, IPV and traumatic life events and to tailor treatment that specifically targets the effects of stress for clients who present with such a cluster of issues. PMID- 28715700 TI - A simultaneous multi-slice selective J-resolved experiment for fully resolved scalar coupling information. AB - Proton-proton scalar coupling plays an important role in molecular structure elucidation. Many methods have been proposed for revealing scalar coupling networks involving chosen protons. However, determining all JHH values within a fully coupled network remains as a tedious process. Here, we propose a method termed as simultaneous multi-slice selective J-resolved spectroscopy (SMS-SEJRES) for simultaneously measuring JHH values out of all coupling networks in a sample within one experiment. In this work, gradient-encoded selective refocusing, PSYCHE decoupling and echo planar spectroscopic imaging (EPSI) detection module are adopted, resulting in different selective J-edited spectra extracted from different spatial positions. The proposed pulse sequence can facilitate the analysis of molecular structures. Therefore, it will interest scientists who would like to efficiently address the structural analysis of molecules. PMID- 28715701 TI - Synthetic biological approaches to optogenetically control cell signaling. AB - Precise spatial and temporal control of cellular processes is in life sciences a highly sought-after capability. In the recent years, this goal has become progressively achievable through the field of optogenetics, which utilizes light as a non-invasive means to control genetically encoded light-responsive proteins. The latest optogenetic systems, such as those for control of subcellular localization or cellular decision-making and tissue morphogenesis provide us with insights to gain a deeper understanding of the cellular inner workings. Besides, they hold a potential for further development into biomedical applications, from in vitro optogenetics-assisted drug candidate screenings to light-controlled gene therapy and tissue engineering. PMID- 28715702 TI - Engineering carbon fixation in E. coli: from heterologous RuBisCO expression to the Calvin-Benson-Bassham cycle. AB - Carbon fixation is the gateway of inorganic carbon into the biosphere. Our ability to engineer carbon fixation pathways in living organisms is expected to play a crucial role in the quest towards agricultural and energetic sustainability. Recent successes to introduce non-native carbon fixation pathways into heterotrophic hosts offer novel platforms for manipulating these pathways in genetically malleable organisms. Here, we focus on past efforts and future directions for engineering the dominant carbon fixation pathway in the biosphere, the Calvin-Benson cycle, into the well-known model organism Escherichia coli. We describe how central carbon metabolism of this heterotrophic bacterium can be manipulated to allow directed evolution of carbon fixing enzymes. Finally, we highlight future directions towards synthetic autotrophy. PMID- 28715703 TI - Removal mechanisms in aerobic slurry bioreactors for remediation of soils and sediments polluted with hydrophobic organic compounds: An overview. AB - Hydrophobic organic compound (HOC)-contaminated soils are a great environmental and public health concern nowadays. Further research is necessary to develop environmental friendly biotechnologies that allows public and private sectors to implement efficient and adaptable treatment approaches. Aerobic soil-slurry bioreactor technology has emerged as an effective and feasible technique with a high remediation potential, especially for silt and clay soil fractions, which often contain the highest pollutant concentration levels and are usually difficult to remove by implementing conventional methods. However, the mechanisms involved in the HOC removal in bioslurry reactor are still not completely understood. Gas-liquid and solid-liquid mass transfer, mass transport and biodegradation phenomena are the main known processes taking place in slurry bioreactors. This review compiles the most up-to-date information available about these phenomena and tries to link them, enlightening the possible interactions between parameters. It gathers the basic information needed to understand the complex bioremediation technology and raises awareness of some considerations that should be made. PMID- 28715705 TI - Investigating the relationship between iron and depression. AB - Lower levels of circulating iron have been associated with depression. Our objective was to investigate the phenotypic and genetic relationship between measures of circulating levels of iron (serum iron, transferrin, transferrin saturation, and ferritin) and depressive symptoms. Data were available from ongoing studies at QIMR Berghofer Medical Research Institute (QIMRB), including twin adolescents (mean age 15.1 years, standard deviation (SD) 3.2 years), and twin adults (mean age 23.2 years, SD 2.2 years). In the adolescent cohort, there were 3416 participants from 1688 families. In the adult cohort there were 9035 participants from 4533 families. We estimated heritabilities of, and phenotypic and genetic correlations between, traits. We conducted analyses that linked results from published large-scale genome-wide association studies (including iron and Major Depressive Disorder) with our study samples using single SNP and multi-SNP genetic risk score analyses, and LD score regression analyses. In both cohorts, measures of iron, transferrin, transferrin saturation, and log 10 of ferritin (L10Fer) were all highly heritable, while depressive measures were moderately heritable. In adolescents, depression measures were higher in those in the middle 10th versus top 10th percentile of transferrin saturation measures (p = 0.002). Genetic profile risk scores of the iron measures were not significantly associated with depression in study participants. LD score analyses showed no significant genetic relationship between iron and depression. Genetic factors strongly influence iron measures in adolescents and adults. Using several different strategies we find no evidence for a genetic contribution to the relationship between blood measures of iron and measures of depression. PMID- 28715706 TI - Free-sodium salts mixture and AlgySalt(r) use as NaCl substitutes in fresh and cooked meat products intended for the hypertensive population. AB - This work aims at reducing the use of added NaCl in processed meat products because of its negative effects on hypertensive population by replacing it by sodium-free salts mixture (SM: KCl, MgCl2 and CaCl2) in fresh and cooked sausages. The technological, sensory, and microbiological effects of SM were compared with a commercial replacer based on seaweed extracts (AlgySalt(r)). A total substitution of NaCl with the latter and a partial one with SM (80% and 50%) were studied in cooked sausages and a total NaCl substitution with both substitutes was performed in fresh sausages. As a result, hardness increased in AlgySalt(r) reformulated samples, while it decreased when 80% SM were used. Whereas, AlgySalt(r) induced less cooking loses than SM. To some extent, microbiological counts showed a similarity between reformulated and control samples for both sausage types, whereas reformulated products containing SM revealed better sensory properties for both meat products. Therefore, using SM as NaCl replacer is adequate for processed meat products. PMID- 28715704 TI - Oxytocin receptor gene polymorphisms, attachment, and PTSD: Results from the National Health and Resilience in Veterans Study. AB - The human oxytocin system is implicated in social behavior and stress recovery. Polymorphisms in the oxytocin receptor gene (OXTR) may interact with attachment style to predict stress-related psychopathology like posttraumatic stress disorder (PTSD). The objective of this study was to examine independent and interactive effects of the OXTR single nucleotide polymorphism (SNP) rs53576, which has been associated with stress reactivity, support-seeking, and PTSD in prior studies, and attachment style on risk for PTSD in a nationally representative sample of 2163 European-American (EA) U.S. military veterans who participated in two independent waves of the National Health and Resilience in Veterans Study (NHRVS). Results revealed that insecure attachment style [adjusted odds ratio (OR) = 4.29; p < 0.001] and the interaction of rs53576 and attachment style (OR = 2.58, p = 0.02) were associated with probable lifetime PTSD. Among individuals with the minor A allele, the prevalence of probable PTSD was significantly higher among those with an insecure attachment style (23.9%) than those with a secure attachment style (2.0%), equivalent to an adjusted OR of 10.7. We attempted to replicate these findings by utilizing dense marker data from a genome-wide association study of 2215 high-risk civilians; one OXTR variant, though not rs53576, was associated with PTSD. Exploratory analyses in the veteran sample revealed that the interaction between this variant and attachment style predicting probable PTSD approached statistical significance. Results indicate that polymorphisms in the OXTR gene and attachment style may contribute to vulnerability to PTSD in U.S. military veterans. PMID- 28715707 TI - Design, synthesis and 2D QSAR study of novel pyridine and quinolone hydrazone derivatives as potential antimicrobial and antitubercular agents. AB - The increased development of highly resistant bacterial strains and tuberculosis, constitute a serious public health threat, highlighting the urgent need of novel antibacterial agents. In this work, two novel series of nicotinic acid hydrazone derivatives (6a-r) and quinolone hydrazide derivatives (12a-l) were synthesized and evaluated as antimicrobial and antitubercular agents. The synthesized compounds were evaluated in vitro for their antibacterial, antifungal and antimycobacterial activities. Compounds 6f and 6p bearing the 3,4,5- (OCH3)3 and 2,5-(OCH3)2 benzylidene motifs were the most potent and as antibacterial, antifungal (MIC: 0.49-1.95 MUg/mL) and (MIC: 0.49-0.98 MUg/mL) respectively and antimycobacterial activity (MIC = 0.76 and 0.39 MUg/mL) respectively. Besides, several derivatives, 6e, 6h, 6l-6o, 6q, 6r, 12a, 12b, 12e, 12h, 12k and 12l, exhibited significant antibacterial and antifungal activities with MIC values ranging from 1.95 to 7.81 MUg/mL, they also displayed excellent to good activity against Mycobacterium tuberculosis with MIC range from 0.39 to 3.12 MUg/mL. In addition, some of the most active compounds were tested for cytotoxic activities against human lung fibroblast normal cells (WI-38) and displayed low toxicity. Moreover, 2D-QSAR models to characterize the descriptors controlling the observed activities, were generated and validated. PMID- 28715708 TI - The evaluation of brain perfusion SPECT using an easy Z-score imaging system in the mild cognitive impairment subjects with brain amyloid-beta deposition. AB - OBJECTIVE: The analysis of 99mTc-ECD single-photon emission computed tomography (SPECT) images using the easy Z-score imaging system (eZIS) program is useful for the diagnosis of early AD in daily medical practice. However, it remains unclear whether eZIS analysis can identify the amnestic mild cognitive impairment (MCI) subjects with brain amyloid-beta deposition. The aim of this study was to evaluate the usefulness of an eZIS analysis for predicting amnestic MCI subjects with brain amyloid beta deposition. PATIENTS AND METHODS: Twenty-three subjects with MCI (10 men and 13 women, mean age; 74.2 years) underwent brain perfusion SPECT and 11C-Pittsburgh Compound B positron emission tomography (PiB-PET). MCI subjects were divided into PiB-positive and PiB-negative subgroups. SPECT data was analyzed using the Specific Volume of interest Analysis of the eZIS program. Three indicators (severity, extent, and ratio) were calculated automatically and compared between the two subgroups. RESULTS: Five of 12 (41.7%) subjects in the PiB-positive subgroup and three of 11 (27.3%) subjects in the PiB-negative subgroup showed the abnormal value for each indicator. The frequency of subjects with abnormal ratio values was significantly higher in the PiB-positive subgroup compared to the PiB-negative subgroup (p=0.02), whereas that of subjects with abnormal values in severity and extent did not differ among the two subgroups. In particular, all subjects in the PiB-negative subgroup showed normal ratio values. Moreover, the subjects with abnormal values on two indicators, including ratio, or on all three indicators, showed PiB-positive. CONCLUSION: The analysis of brain perfusion SPECT using an eZIS program cannot identify the amnestic MCI subjects with brain amyloid-beta deposition. However, abnormal three indicators or normal ratio values may be helpful SPECT findings for predicting the results of PiB-PET in the amnestic MCI subjects. PMID- 28715710 TI - Celiac disease and a novel association with a multifocal acquired motor axonopathy (MAMA). PMID- 28715709 TI - Parental age and childhood cancer risk: A Danish population-based registry study. AB - BACKGROUND: Though the association between parental age at child's birth and the risk of childhood cancer has been previously investigated, the evidence to date is inconclusive and scarce for rarer cancer types. METHODS: Cancer cases (N=5,856) were selected from all children born from 1968 to 2014 and diagnosed from 1968 to 2015 in Denmark at less than 16 years of age listed in the nationwide Danish Cancer Registry. Cases were individually matched to controls (1:100) on sex and year of birth with a total of 585,594 controls randomly sampled from all live births in Denmark from the Danish Central Population Registry. Parental age at child's birth was extracted from the Central Population Registry. Conditional logistic regression models were used to estimate odds ratios for the association between parental age at child's birth and childhood cancer risk. Parental age was modeled as both categorical (referent group, parents aged 25-29) and continuous per 5-year increase in age. RESULTS: Offspring of older mothers were at an increased risk of acute lymphoblastic leukemia [OR=1.10, 95% CI: (1.02, 1.19) per 5-year increase in age]. Older maternal age (40+) increased the risk of non-Hodgkin lymphoma [OR=1.96, 95%CI: (1.12, 3.43)]. The risk of Wilms' tumor also appeared elevated with older paternal age [OR=1.11, 95% CI: (0.97, 1.28) per 5-year increment in age]. CONCLUSION: Older parental age was a risk factor for various childhood cancers in Danish children. Further investigation of the biological and social factors that may be contributing to these associations is warranted. PMID- 28715711 TI - Sustained attention ability in schizophrenia: Investigation of conflict monitoring mechanisms. AB - OBJECTIVE: The main goal of the current study was to assess, with a time-on-task approach, sustained attention ability in schizophrenia, and to investigate conflict monitoring underlying this ability. METHODS: Behavioral and event related potentials data (N2 and P3a amplitudes) were recorded in a long-lasting sustained attention Go/NoGo task (sustained attention to response task, SART), over a period of 30min, in 29 patients with schizophrenia and 29 pair-matched healthy subjects. RESULTS: Our results revealed spared sustained attention ability in patients throughout the task. Impairment of conflict detection (N2) in patients was particularly significant at the end of the task. Furthermore, both schizophrenia and healthy subjects exhibited a decline in conflict detection from the beginning to the middle of the task. Whereas controls' conflict detection recovered in the last part of the task, patients' did not, suggesting a deficit in recovery processes reflecting a lack of additional resources sustained attention Go/NoGo task. Conflict resolution (P3a) was preserved throughout the task in both groups. CONCLUSIONS: Conflict monitoring processes are increasingly impaired in schizophrenia during a long-lasting sustained attention Go/NoGo task. SIGNIFICANCE: This impairment at the end of the task may rely on deficit in recovery processes, rather than a deficit in conflict detection per se in schizophrenia. PMID- 28715712 TI - Propriospinal cutaneous-induced EMG suppression is unaltered by anodal tDCS of healthy motor cortex. AB - OBJECTIVE: Cervical propriospinal premotoneurons (PN) relay descending motor commands and integrate peripheral afferent feedback. Effects of anodal transcranial direct current stimulation (a-tDCS) on propriospinal excitability in the upper limbs are unknown. METHODS: Healthy right-handed adults received a-tDCS or sham tDCS over primary motor cortex (M1) at 1mA (Experiment 1, n=18) or 2mA current intensity (Experiment 2, n=15). Propriospinal excitability was assessed by suppression of background electromyography (EMG) in extensor carpi radialis (ECR) from electrical stimulation of the superficial radial nerve during bilateral (Experiment 1 and 2) or unilateral (Experiment 2 only) activation of the left and/or right ECR. EMG suppression could be attributed to an early propriospinal component and late cortical component. Motor evoked potentials (MEP) were obtained as a manipulation check. RESULTS: Before tDCS, propriospinal mediated cutaneous-induced suppression was present in each arm for early and late components. ECR MEP amplitude increased after 1mA, but not 2mA, a-tDCS. Neither 1mA nor 2mA a-tDCS modulated either component of ipsilateral or contralateral propriospinal excitability during bilateral or unilateral tasks. CONCLUSIONS: Propriospinal-mediated cutaneous-induced suppression was not modulated by a-tDCS in healthy adults. SIGNIFICANCE: Reporting non-significant findings is paramount for the development of clinically-relevant tDCS protocols. PMID- 28715713 TI - Metastasis 'systems' biology: how are macro-environmental signals transmitted into microenvironmental cues for disseminated tumor cells? AB - Disseminated breast tumor cells reside on or near stable microvascular endothelium. Currently, the cues that disrupt DTC dormancy and facilitate outgrowth are largely unknown. This article explores the hypothesis that specific patient lifestyle exposures (e.g., alcohol abuse) may disrupt the microenvironments that maintain disseminated tumor cell (DTC) dormancy in a tissue-specific fashion. We suggest that such exposures are 'transmitted' to the dormant niche in the form of injury. Thus, we discuss the relationship between wound healing and metastasis using liver as an example to illustrate how injury steers the phenotype of liver endothelium and perivascular hepatic stellate cells to a potentially pro-metastatic one. We posit further that non-steroidal anti inflammatory drugs (NSAIDs) - recently shown to prevent metastatic relapse - may act by preserving the dormant niche. We conclude by suggesting that maintenance of the dormant niche - either through patient lifestyle or via development of therapeutics that mimic local molecular cues/responses that coincide with a healthy lifestyle - is a means to prevent metastatic relapse, and should be the subject of far greater research. PMID- 28715715 TI - Platinum(II) and palladium(II) complexes of tridentate hydrazone-based ligands as selective guanine quadruplex binders. AB - Several tridentate hydrazone-based ligands, synthesized by a condensation reaction of either 2-(1-methylhydrazinyl)pyridine or 2-(1 methylhydrazinyl)quinoline with an aldehyde (picolinaldehyde, 1H-pyrrole-2 carbaldehyde, 2-mercaptobenzaldehyde, 2-aminobenzaldehyde) have been reacted with palladium(II) and platinum(II) salts and precursor complexes to yield nine new metal complexes. These planar complexes were investigated with respect to their capability to interact with guanine quadruplex DNA. Two sequences (H-telo, derived from the human telomeric sequence, and c-myc, representing an excerpt of the promoter region of the c-Myc oncogene) were investigated. Circular dichroism (CD) spectroscopy, temperature-dependent CD spectroscopy, UV-Vis spectroscopy and a fluorescent intercalator displacement (FID) assay were applied in this respect. The spectroscopic data show that the complexes indeed interact with guanine quadruplex DNA. According to the FID assay, some of the complexes belong to the highest-affinity metal-containing quadruplex binders reported so far. Their affinity towards quadruplex DNA is up to 80-fold higher than to a reference double helix. These findings make the metal complexes good candidates as anticancer drugs, as guanine quadruplexes have been proposed as potential targets in anticancer drug design. PMID- 28715714 TI - Actomyosin contractility and collective migration: may the force be with you. AB - Collective cell migration is essential during physiological processes such as development or wound healing and in pathological conditions such as cancer dissemination. Cells migrating within multicellular tissues experiment different forces which play an intricate role during tissue formation, development and maintenance. How cells are able to respond to these forces depends largely on how they interact with the extracellular matrix. In this review, we focus on mechanics and mechanotransduction in collective migration. In particular, we discuss current knowledge on how cells integrate mechanical signals during collective migration and we highlight actomyosin contractility as a central hub coordinating mechanosensing and mechanotransduction responses. PMID- 28715717 TI - Reading network in dyslexia: Similar, yet different. AB - Dyslexia is a developmental disorder characterized by reading and phonological difficulties, yet important questions remain regarding its underlying neural correlates. In this study, we used partial least squares (PLS), a multivariate analytic technique, to investigate the neural networks used by dyslexics while performing a word-rhyming task. Although the overall reading network was largely similar in dyslexics and typical readers, it did not correlate with behavior in the same way in the two groups. In particular, there was a positive association between reading performance and both right superior temporal gyrus and bilateral insula activation in dyslexic readers but a negative correlation in typical readers. Together with differences in lateralization unique to dyslexics, this suggests that the combination of poor reading performance with high insula activity and atypical laterality is a consistent marker of dyslexia. These findings emphasize the importance of understanding right-hemisphere activation in dyslexia and provide promising directions for the remediation of reading disorders. PMID- 28715716 TI - Ronin influences the DNA damage response in pluripotent stem cells. AB - Early mammalian embryonic cells must maintain a particularly robust DNA repair system, as mutations at this developmental point have detrimental consequences for the organism. How the repair system can be tuned to fulfill such elevated requirements is largely unknown, but it may involve transcriptional regulation. Ronin (Thap11) is a transcriptional regulator responsible for vital programs in pluripotent cells. Here, we report that this protein also modulates the DNA damage response of such cells. We show that conditional Ronin knockout sensitizes embryonic stem cells (ESCs) to UV-C-induced DNA damage in association with Atr pathway activation and G2/M arrest. Ronin binds to and regulates the genes encoding several DNA repair factors, including Gtf2h4 and Rad18, providing a potential mechanism for this phenotype. Our results suggest that the unique DNA repair requirements of the early embryo are not met by a static system, but rather via highly regulated processes. PMID- 28715718 TI - When speaker identity is unavoidable: Neural processing of speaker identity cues in natural speech. AB - Speech sound acoustic properties vary largely across speakers and accents. When perceiving speech, adult listeners normally disregard non-linguistic variation caused by speaker or accent differences, in order to comprehend the linguistic message, e.g. to correctly identify a speech sound or a word. Here we tested whether the process of normalizing speaker and accent differences, facilitating the recognition of linguistic information, is found at the level of neural processing, and whether it is modulated by the listeners' native language. In a multi-deviant oddball paradigm, native and nonnative speakers of Dutch were exposed to naturally-produced Dutch vowels varying in speaker, sex, accent, and phoneme identity. Unexpectedly, the analysis of mismatch negativity (MMN) amplitudes elicited by each type of change shows a large degree of early perceptual sensitivity to non-linguistic cues. This finding on perception of naturally-produced stimuli contrasts with previous studies examining the perception of synthetic stimuli wherein adult listeners automatically disregard acoustic cues to speaker identity. The present finding bears relevance to speech normalization theories, suggesting that at an unattended level of processing, listeners are indeed sensitive to changes in fundamental frequency in natural speech tokens. PMID- 28715719 TI - Isolated caudate lobectomy: Left-sided approach. Case reports. AB - INTRODUCTION: The caudate lobe is a distinct liver lobe and surgical resection requires expertise and precise anatomic knowledge. Left-sided approach was described for resection of small tumors originated in the Spiegel lobe but now the procedure has been performed even for tumors more than five centimeters. The aim of this study is to present three cases of tumor of caudate lobe underwent isolated lobectomy by left-sided approach. PRESENTATION OF CASE: Three patients with metastasis of colorectal cancer, carcinoma hepatocellular and metastasis of neuroendocrine tumor underwent resection. After modified Makuuchi incision, early control of short hepatic e short portal veins before hepatectomy was performed. The operative time was 200, 270 and 230min respectively. No blood transfusion was used and no postoperative complications were observed. The length of stay was 7, 11 and 5days respectively. DISCUSSION: Some approaches have been described to access and resect tumors of the caudate lobe, including the left-sided approach, right-sided approach, combined left- and right-sided approach and the anterior transhepatic approach. For liver resection in patients with malignant disease, parenchymal preservation is important in order to avoid postoperative liver failure or due to the risk of second hepatectomy. In these patients isolated caudate lobectomy is a safe option. CONCLUSION: Isolated caudate lobectomy is a feasible procedure. Left-sided approach can be preformed even for tumors larger than 5cm. PMID- 28715720 TI - Extreme dilatation of the interposed jejunal pouch after proximal gastrectomy associated with portal venous gas: A case report. AB - INTRODUCTION: The jejunal pouch interposition (JPI) after proximal gastrectomy (PG) was proposed as a reconstructive procedure to provide a gastric reservoir substitute and prevent postgastrectomy syndrome. However, food residue remaining in some of the pouches resulted in the adverse effect of abdominal bloating, thereby body weight loss. Here, we report a rare case with an extreme dilation of the interposed jejunal pouch (JP) 8 years after PG, requiring pouch resection. PRESENTATION OF CASE: A 65-year-old-man who had undergone PG with an inverted U shaped JPI for early gastric cancer 8 years previously, suffered from shock after right hip joint implantation. Abdominal enhanced CT scan revealed an extremely dilated JP accompanied by portal venous gas. After 5 months of conservative therapy, he underwent resection of the JP and gastric remnant with Roux-en-Y esophagojejunostomy reconstruction. After the operation, the patient has remained in good health for over 3 years. DISCUSSION AND CONCLUSION: Long-term operative outcome following pouch operation for gastric cancer still remains controversial. Surgical intervention should be considered when we encounter patients who have refractory pouch dilatation after surgery for gastric cancer. PMID- 28715721 TI - Pushing the boundaries in liver graft utilisation in transplantation: Case report of a donor with previous bile duct injury repair. AB - INTRODUCTION: Liver transplantation is a recognised treatment for extensive bile duct injuries with secondary biliary cirrhosis or recurring sepsis. However, there have been no reports of successful liver transplantation from a donor who sustained a previous bile duct injury. PRESENTATION OF CASE: Here we discuss the case of a liver transplant from a 51-year-old brain dead donor who had suffered a Strasberg E1 bile duct injury and had undergone a Roux-en-Y hepaticojejunostomy 24 years prior to donation. The liver was successfully recovered and transplanted into a 56-year-old male recipient with end stage liver disease consequent to alpha 1 antitrypsin deficiency. The graft continues to function well 36 months post-transplant, with normal liver function tests and imaging revealing a patent hepaticojejunostomy. DISCUSSION: The potential associated vascular injuries should be identified during bench preparation whilst the management of biliary reconstruction at the time of transplant should follow the principles of biliary reconstruction in cases with biliary injuries, extending the hilar opening into the left duct. CONCLUSION: This case highlights the successful utilisation of a post bile duct injury repair liver, employing an experienced procurement team and careful bench assessment and reconstruction. PMID- 28715722 TI - Surgical management of scalp arteriovenous malformations using a novel surgical technique-Case series. AB - INTRODUCTION: Scalp AVM (SAVM) is a rare condition. Although surgical excision is considered as definitive treatment for these lesions, troublesome intraoperative bleeding may pose a challenge. Embolization as an alternative modality is gaining popularity. Proximal feeding artery temporary clipping has been utilized by the authors in this series to address troublesome intraoperative bleeding. PRESENTATION OF CASES: The authors present their experience in the surgical management of 3 cases with SAVMs using proximal feeding artery temporary occlusion followed by total surgical excision. The clinical presentations and radiological features of these cases are discussed in the article. Intraoperative blood loss was less than 150ml in all patients. Postoperative period was uneventful with no morbidity or mortality. DISCUSSION: Intraoperative bleeding during surgical excision of scalp AVMs can be troublesome and challenging. To combat this, the authors advocate proximal feeding artery temporary clipping prior to surgical excision of the lesion. The external carotid artery was temporarily clipped in one case and superficial temporal artery in two patients. CONCLUSION: Although most SAVMs can be operated by traditional method of excision, use of temporary clipping of feeding arteries (like Superficial temporal artery[STA], External carotid artery[ECA]) enables total excision of giant SAVMs with minimal blood loss for a definitive cure. This novel technique obviates the need for preoperative embolization. PMID- 28715723 TI - A comparison of ICD-11 and DSM criteria for posttraumatic stress disorder in two national samples of U.S. military veterans. AB - BACKGROUND: The proposed ICD-11 criteria for posttraumatic stress disorder (PTSD) differ substantially from the DSM-5. ICD-11 eliminated several PTSD symptoms thought to be nonspecific, with the goal of reducing psychiatric comorbidities. However, this change also results in a narrower PTSD definition that may fail to capture individuals with clinically significant PTSD. The purpose of the current study was to compare prevalence and psychiatric comorbidities of DSM (IV/5) and ICD-11 PTSD. METHODS: We evaluated concordance between DSM (IV/5) and ICD-11 PTSD diagnoses in a web survey of two nationally representative samples of U.S. military veterans (ns = 3517 and 1484). Lifetime and past-month PTSD symptoms were assessed with the DSM-IV-based PTSD Checklist-Specific Stressor version and the DSM-5-based PTSD Checklist-5. Psychiatric comorbidities were assessed using MINI Neuropsychiatric Interview modules. RESULTS: A significantly greater proportion of veterans met criteria for lifetime and past-month PTSD under DSM IV/5 than under ICD-11. 21.8-35.9% of those who met criteria under DSM IV/5 did not meet under ICD-11, whereas only 2.4-7.1% of those who met under ICD-11 did not meet under DSM-IV/5. Psychiatric comorbidities did not significantly differ between DSM-IV/5 and ICD-11. LIMITATIONS: This study relied upon self-report measures of PTSD, distress/impairment, and psychiatric comorbidities. CONCLUSIONS: The proposed ICD-11 criteria identify fewer PTSD cases than DSM-IV/5 without reducing psychiatric comorbidities. Veterans with clinically significant PTSD symptoms may not meet ICD-11 PTSD criteria, possibly affecting eligibility for healthcare, disability, and other services. The ICD-11 criteria could be revised to capture more PTSD cases before ICD-11 is published in 2018. PMID- 28715724 TI - Toxoplasma gondii infection and common mental disorders in the Finnish general population. AB - OBJECTIVE: We investigated whether T. gondii seropositivity is associated with 12 month depressive, anxiety and alcohol use disorders and current depressive symptoms and whether inflammation, measured by C-reactive protein (CRP) level, explains these associations. METHOD: Health 2000 study (BRIF8901), conducted in years 2000-2001, is based on a nationally representative sample of Finns aged 30 and above, with 7112 participants and 88.6% response rate. DSM-IV depressive, anxiety and alcohol use disorders were assessed with the Composite International Diagnostic Interview and depressive symptoms with the Beck Depressive Inventory (BDI-21). We used logistic regression to investigate the association of T. gondii seropositivity with mental disorders and linear regression with BDI-21 scores. RESULTS: T. gondii seroprevalence was significantly associated with 12-month generalized anxiety disorder but not with other anxiety, depressive or alcohol use disorders. T. gondii seropositivity was associated with higher BDI-21 scores (beta 0.56, 95% CI 0.12-1.00, P = 0.013) and with having a comorbid depressive and anxiety disorder (OR 1.86, 95% CI 1.16-2.97, P = 0.010). Higher CRP levels were associated with these outcomes and with T. gondii seropositivity, but adjusting for CRP did not change the effect of T. gondii seropositivity. LIMITATIONS: Cross-sectional study design with no information on the timing of T. gondii infection. CONCLUSION: T. gondii seropositivity is associated with generalized anxiety disorder, depressive symptoms and comorbid depressive and anxiety disorders, which is not mediated by inflammation. PMID- 28715725 TI - Antidepressant treatment postpartum and the risk of treatment-emergent mania. PMID- 28715726 TI - Internet- and mobile-based depression interventions for people with diagnosed depression: A systematic review and meta-analysis. AB - BACKGROUND: To summarize and critically evaluate the effectiveness of internet- and mobile-based interventions (IMIs) for depression in adults with a diagnosed depression. METHODS: Preregistered systematic review of RCTs investigating internet- and mobile-based interventions (IMIs) targeting adults with diagnosed depression. IMIs had to be compared with waitlist, attention placebo, other IMIs or other (face-to-face) therapies. A comprehensive search of primary studies was conducted. Study selection and data extraction was done by two independent researchers. Primary outcome was symptom severity of depression. Furthermore, treatment response, depression remission, treatment adherence, anxiety and quality of life were investigated. Random-effects meta-analyses were conducted where possible, as well as pre-planned subgroup and sensitivity analyses. RESULTS: Database search resulted in 4858 references, of which 19 studies were eligible for inclusion and provided data on 29 IMIs. IMIs showed beneficial effects on depression severity when compared to waitlist conditions at the end of treatment (pooled standardized mean difference (SMD) g = -0.90, 95% CI -1.07 to 0.73, n = 10). The comparison between different IMIs did not result in any superiority or inferiority. All IMIs reduced depression symptoms from pre- to post-treatment (within group SMD range -2.24; -0.64, n = 29) and from pre treatment to follow-up assessments (SMD range -3.07; -0.93, n = 27). CONCLUSION: IMIs significantly reduce depression symptoms in adults with diagnosed depression at the end of treatment and at follow-up assessments when compared to waitlist conditions. These findings argue for IMIs to be recommended in depression treatment guidelines. PMID- 28715727 TI - Efficacy and safety of long-term antidepressant treatment for bipolar disorders - A meta-analysis of randomized controlled trials. AB - OBJECTIVE: Efficacy and safety of long-term use of antidepressants (AD) in bipolar disorder (BD) patients remains highly controversial. Here we performed a meta-analysis of randomized controlled trials (RCTs) exploring the efficacy and safety of long-term AD use in BD patients. METHODS: English-written literature published in peer-reviewed journal was systematically searched from Pubmed, EMBASE, CENTRAL, PsycINFO and Clinicaltrials.gov. Each database was searched from its first available time to August 31, 2016. Additional papers were searched from recent guidelines, expert consensus and systematic reviews by hand. RCTs exploring the efficacy and safety of long-term (>=4m) antidepressant treatment for patients with bipolar disorder were eligible. Two authors (HF, JL) independently extracted the data. Risk ratio (RR), number needed to treat (NNT) and/or number needed to harm (NNH) for new depressive episodes and new manic/hypomanic episodes were calculated. Subgroup analyses were performed based on treatment regimen (AD monotherapy or combined with MS), types of antidepressants, funding source, bipolar subtypes and treatment duration. RESULTS: Eleven trials with 692 bipolar disorder patients were included in the meta-analysis. The risk of bias assessment demonstrated moderate bias risk. Antidepressants were superior to placebo in reducing new depressive episodes in bipolar disorders without increasing risk of new manic/hypomanic episodes either used as monotherapy or in combination with MS. Subgroup analyses revealed that greater benefit and lower risk may be achieved in BD II than in BD I. However, compared with MS monotherapy, AD monotherapy significantly increased the risk of affective switch with no improvement in prophylaxis of new depressive episodes. CONCLUSIONS: Reduced new depressive episodes may be achieved by long-term AD treatment with no significantly increased risk of new manic/hypomanic episodes in BD, particularly in BD II. The elevated risk of affective switch of AD monotherapy compared with MS monotherapy may be contributed to the protective effect of MS in diminishing manic/hypomanic episodes. Further studies are needed to verify our findings. PMID- 28715728 TI - Mobile phone use during driving: Effects on speed and effectiveness of driver compensatory behaviour. AB - This study analysed and modelled the effects of conversation and texting (each with two difficulty levels) on driving performance of Indian drivers in terms of their mean speed and accident avoiding abilities; and further explored the relationship between speed reduction strategy of the drivers and their corresponding accident frequency. 100 drivers of three different age groups (young, mid-age and old-age) participated in the simulator study. Two sudden events of Indian context: unexpected crossing of pedestrians and joining of parked vehicles from road side, were simulated for estimating the accident probabilities. Generalized linear mixed models approach was used for developing linear regression models for mean speed and binary logistic regression models for accident probability. The results of the models showed that the drivers significantly compensated the increased workload by reducing their mean speed by 2.62m/s and 5.29m/s in the presence of conversation and texting tasks respectively. The logistic models for accident probabilities showed that the accident probabilities increased by 3 and 4 times respectively when the drivers were conversing or texting on a phone during driving. Further, the relationship between the speed reduction patterns and their corresponding accident frequencies showed that all the drivers compensated differently; but, among all the drivers, only few drivers, who compensated by reducing the speed by 30% or more, were able to fully offset the increased accident risk associated with the phone use. PMID- 28715729 TI - Consistent association between hypnotics/sedatives and non-traffic injuries. Results from a national household survey. AB - AIM: To quantify the relationship between patterns of psychostimulants, hypnotics/sedatives and alcohol consumption and the frequency of unintentional non-traffic injuries (UNTIs) requiring medical assistant in Spain. METHODS: We carried out a cross sectional study using a randomized pooled sample from two household surveys on psychoactive drugs use (n=51,649 subjects aged 15-64 years). We estimated the magnitude of the association between the use of psychostimulants and hypnotics/sedatives in the last 12 months as well as alcohol consumption in the last 30days with the occurrence of UNTIs in the last 12 months (falls, knocks/bumps and cuts) by building several logistic regression models, which took into account the effect of sociodemographic characteristics and the use of other psychoactive drugs (including cannabis). The presence of interactions between age or gender with drug use was also assessed. RESULTS: Psychostimulants use was associated with a higher frequency of UNTIs (aOR=1.24; 95%CI:1.03-1.49). The strongest association was found with cuts (aOR=1.64; 95%CI:1.10-2.43). An association between hypnotics/sedatives and UNTIs was also found in each type of injury and was higher with regular use (>=30days) than with non-regular use (<30days). The age modified the association between hypnotic/sedatives and knocks/bumps, being higher in the 35-64 years group (aOR=2.34; 95%CI:1.78-3.06) than in the 15-34 years group (aOR=1.59; 95%CI:1.14-2.21). Regarding alcohol, an increased risk of UNTIs was also observed in all types of UNTIs, even with moderate use, being the association higher for cuts in heavy drinkers (aOR=2.41; 95%CI:1.63-3.57). CONCLUSIONS: Our results reveal a consistent relationship between hypnotics/sedatives and UNTIs, especially in regular users. Additional research should apply longitudinal designs to establish causal relationships and to gain an in-depth knowledge in this area in order to specific public health interventions. PMID- 28715730 TI - Redox regulation of proteasome function. AB - Reactive Oxygen Species (ROS) and Reactive Nitrogen Species (RNS) were initially regarded mainly as metabolic by-products with damaging properties. Over the last decade, our understanding of their role in metabolism was drastically changed and they were recognized as essential mediators in cellular signaling cascades, as well as modulators of biochemical pathways. Proteostasis is highly affected by the various levels of intracellular and extracellular free radicals with either mild or severe outcomes. As part of the proteostatic network, the proteasome system is equally affected by redox alterations. This short review summarizes the effects of oxidative stress on proteasome status while it also recapitulates conditions and processes where redox alterations signal changes to proteasome expression, assembly and function. PMID- 28715733 TI - Redescription of Keronopsis helluo Penard, 1922 from Antarctica and Paraholosticha pannonica Gellert and Tamas, 1959 from Alaska (Ciliophora, Hypotricha). AB - The morphology of Keronopsis helluo Penard, 1922, type species of Keronopsis, and Paraholosticha pannonica Gellert and Tamas, 1959, two little-known members of the Keronopsidae Jankowski, 1979, was described using standard methods. In addition, we sequenced the SSU rRNA of both species. Keronopsis helluo was isolated from a mossy soil from Robert Island (Antarctica) while P. pannonica was found in terrestrial moss from Alaska. Our data correspond very well with the original descriptions. The frontal ciliature of K. helluo is identical with that of Paraholosticha spp., indicating that some Keronopsis species (K. tasmaniensis, K. dieckmanni) are misclassified in the keronopsids. The type species has distinctly more transverse cirri (8-13) than K. wetzeli (1-3), type species of Parakeronopsis, which is thus perhaps a valid genus or subgenus. The phylogenetic analyses confirm the position of the keronopsids outside the Dorsomarginalia. The species sequenced so far (K. helluo, Paraholosticha muscicola, P. pannonica) emerge from a soft polytomy, which also comprises Bistichella-like species and a large cluster composed of amphisiellids, trachelostylids, and gonostomatids, that is, the method failed to resolve the relationships within the keronopsids. The Keronopsidae and the two species studied are characterized based on previous studies and our data. PMID- 28715734 TI - Simultaneous algae-polluted water treatment and electricity generation using a biocathode-coupled electrocoagulation cell (bio-ECC). AB - How to utilize electrocoagulation (EC) technology for algae-polluted water treatment in an energy-efficient manner remains a critical challenge for its widespread application. Herein, a novel biocathode-coupled electrocoagulation cell (bio-ECC) with sacrificial iron anode and nitrifying biocathode was developed. Under different solution conductivities (2.33+/-0.25mScm-1 and 4.94+/ 0.55mScm-1), the bio-ECC achieved almost complete removal of algae cells. The maximum power densities of 8.41 and 11.33Wm-3 at corresponding current densities of 48.03Am-3 and 66.26Am-3 were obtained, with the positive energy balance of 4.52 and 7.44Wm-3. In addition, the bio-ECC exhibited excellent NH4+-N removal performance with the nitrogen removal rates of 7.28mgL-1h-1 and 6.77mgL-1h-1 in cathode chamber, indicating the superiority of bio-ECC in NH4+-N removal. Pyrosequencing revealed that nitrifiers including Nitrospira, Nitrobacter, Nitrosococcus, and Nitrosomonas were enriched in biocathode. The removal mechanisms of algae in anode chamber were also explored by AFM and SEM-EDX tests. These results provide a proof-of-concept study of transferring energy-intensive EC process into an energy-neutral process with high-efficiency algae removal and electricity recovery. PMID- 28715731 TI - Metabolomics analysis reveals that benzo[a]pyrene, a component of PM2.5, promotes pulmonary injury by modifying lipid metabolism in a phospholipase A2-dependent manner in vivo and in vitro. AB - Particulate matter with an aerodynamic diameter less than 2.5MUM (PM2.5) is one of the major environmental pollutants in China. In this study, we carried out a metabolomics profile study on PM2.5-induced inflammation. PM2.5 from Beijing, China, was collected and given to rats through intra-tracheal instillation in vivo. Acute pulmonary injury were observed by pulmonary function assessment and H.E. staining. The lipid metabolic profile was also altered with increased phospholipid and sphingolipid metabolites in broncho-alveolar lavage fluid (BALF) after PM2.5 instillation. Organic component analysis revealed that benzo[a]pyrene (BaP) is one of the most abundant and toxic components in the PM2.5 collected on the fiber filter. In vitro, BaP was used to treat A549 cells, an alveolar type II cell line. BaP (4MUM, 24h) induced inflammation in the cells. Metabolomics analysis revealed that BaP (4MUM, 6h) treatment altered the cellular lipid metabolic profile with increased phospholipid metabolites and reduced sphingolipid metabolites and free fatty acids (FFAs). The proportion of omega-3 polyunsaturated fatty acid (PUFA) was also decreased. Mechanically, BaP (4MUM) increased the phospholipase A2 (PLA2) activity at 4h as well as the mRNA level of Pla2g2a at 12h. The pro-inflammatory effect of BaP was reversed by the cytosolic PLA2 (cPLA2) inhibitor and chelator of intracellular Ca2+. This study revealed that BaP, as a component of PM2.5, induces pulmonary injury by activating PLA2 and elevating lysophosphatidylcholine (LPC) in a Ca2+-dependent manner in the alveolar type II cells. PMID- 28715732 TI - Proteasome inhibitor-induced cleavage of HSP90 is mediated by ROS generation and caspase 10-activation in human leukemic cells. AB - Heat shock protein 90 (HSP90) is a molecular chaperone that supports the stability of client proteins. The proteasome is one of the targets for cancer therapy, and studies are underway to use proteasome inhibitors as anti-cancer drugs. In this study, we found that HSP90 was cleaved to a 55kDa protein after treatment with proteasome inhibitors including MG132 in leukemia cells but was not cleaved in other tissue-derived cells. HSP90 has two major isoforms (HSP90alpha and HSP90beta), and both were cleaved by MG132 treatment. MG132 treatment also induced a decrease in HSP90 client proteins. MG132 treatment generated ROS, and the cleavage of HSP90 was blocked by a ROS scavenger, N acetylcysteine (NAC). MG132 activated several caspases, and the activation was reduced by pretreatment with NAC. Based on an inhibitor study, the cleavage of HSP90 induced by MG132 was dependent on caspase 10 activation. Furthermore, active recombinant caspase 10 induced HSP90 cleavage in vitro. MG132 upregulated VDUP-1 expression and reduced the GSH levels implying that the regulation of redox-related proteins is involved. Taken all together, our results suggest that the cleavage of HSP90 by MG132 treatment is mediated by ROS generation and caspase 10 activation. HSP90 cleavage may provide an additional mechanism involved in the anti-cancer effects of proteasome inhibitors. PMID- 28715735 TI - Coupling electrochemical and biological methods for 17alpha-ethinylestradiol removal from water by different microorganisms. AB - 17alpha-ethynylestradiol (EE2) has become a growing concern due to its wide detection and high estrogenic potency. However, biodegradation of EE2 with individual microorganisms demonstrated poor degradation efficiency ranging from 10.3% to 45.8% in 120h. Now, a system combining electrochemical with biological degradation was tested for its ability to remove EE2 from aqueous solution. EE2 removal is promoted at high dissolved oxygen concentrations and low pH when electrochemical methods alone are employed. Coupling electrochemical methods with anaerobic bacteria can improve the EE2 removal after 90min to as much as 81.9% with a reaction rate constant of 0.0195min-1. An electric current of 100mA at pH5.5 inhibits the growth of most microbial species, but Shewanella and Aeromonas survive well. They can enhance the efficiency of direct electron transfer efficiency between the bacteria and the electrodes, promoting EE2 degradation. This study provided a theoretical basis for the future applicability of bioelectrochemical technology to remove steroids from waste water. PMID- 28715736 TI - Highly effective Cs+ removal by turbidity-free potassium copper hexacyanoferrate immobilized magnetic hydrogels. AB - Potassium copper hexacyanoferrate-immobilized magnetic hydrogel (MHPVA) has been synthesized via a facile freeze/thaw crosslinking method. The citric acid coated Fe3O4 is embedded into the hydrogel matrix to facilitate the dispersion of nano sized KCuHCF particles for Cs+ removal, followed by the rapid recovery of the composite in a magnetic field. The Cs+ adsorption behavior of the MHPVA is fitted well with the Langmuir isotherm and the pseudo-second-order kinetic model. The MHPVA exhibits both high Cs+ adsorption capacity (82.8mg/g) and distribution coefficient (Kd) of 1.18*106mL/g (8.3ppm Cs+, V/m=1000mL/g). Sorption of above 90% Cs+ to the MHPVA is achieved in less than 3h of contact time. Moreover, the MHPVA reveals stable and high Cs+ removal efficiency across a wide pH range from 4 to 10. In terms of Cs+ selectivity, the MHPVA shows above 96% removal efficiency in the presence of 0.01M competing cations such as Mg2+, Ca2+, Na+, and K+ with 1ppm of Cs+. From a practical perspective, the MHPVA still exhibits stable and promising selective properties even in groundwater and seawater conditions and after 5days of contact time the used adsorbent is rapidly recovered leaving a turbidity-free aqueous environment. PMID- 28715737 TI - Static and Continuous flow-through pulsed light technology for pesticide abatement in water. AB - Perspectives concerning pulsed light (PL) technology as a novel water decontamination treatment are overviewed in this work. Degradation of atrazine, malathion, chlorpyriphos-methyl and bromopropylate in aqueous solutions at different concentrations was performed employing static and continuous flow through PL units. Results for both PL systems were compared in terms of efficacy of pesticides degradation and derived photoproducts formed. The pesticides degradation increased with the applied total fluence for both PL systems. In general, PL induced rapid degradation of all studied compounds although some differences were observed in the rate of degradation among them. The most intense treatment in the static unit (11J/cm2) yielded degradations between 60 and 85% whereas degradations between 74 and 93% were observed after exposure to slightly lower fluences (10J/cm2) in the dynamic unit. For both PL systems bromopropylate was the most affected compound. Photodegradation products arose from chemical reactions involving structural changes like dehalogenation, desulfuration, dealkylaytion and oxidation of the alkyl chains. Although further research is needed before an efficient application in full-scale systems, PL appears as a promising technology in order to reduce the presence of pesticides residues in process or waste waters, allowing thereby recirculation of these waters with the subsequent economic and environmental advantages. PMID- 28715738 TI - Inhibition of ammonia on anaerobic digestion of synthetic coal gasification wastewater and recovery using struvite precipitation. AB - Coal gasification wastewater (CGW) contains very high concentrations of phenols and ammonia. However, the potential impact of ammonia on the anaerobic digestion of phenols remained unclear. Firstly, the methanogens and phenols degraders had a good tolerance up to 1gL-1 of total ammonia nitrogen (TAN), but the substrate utilization rate for phenol, and specific methanogenic activity of sludge were decreased by 89% and 67% at 5g TAN L-1, and 94% and 100% at 10g TAN L-1, respectively. Secondly, the optimum struvite crystallization conditions (pH=8.5, 10g TAN L-1, n(Mg2+):n(TAN):n(PO43-)=1:1:1) were obtained by the orthogonal tests. Thirdly, the removal efficiencies of chemical oxygen demand (COD) and phenols were recovered to around 82% and 66%, respectively in the upflow anaerobic sludge blanket reactor using the pretreatment of struvite precipitation at 10g TAN L-1 and 1g phenols L-1. Therefore, anaerobic digestion coupled with struvite precipitation was considered as an alternative way for CGW treatment. PMID- 28715739 TI - Antimicrobial and antibiofilm efficacy of self-cleaning surfaces functionalized by TiO2 photocatalytic nanoparticles against Staphylococcus aureus and Pseudomonas putida. AB - A photocatalytic sol of TiO2 nanoparticles has been used for creating self cleaning antimicrobial flat and porous glass surfaces. The substrates were irradiated to study their photocatalytic properties and behavior in the presence of biofilm-forming bacteria. Smooth glass surfaces and glass microfiber filters were covered with 1.98*10-3+/-1.5*10-4gcm-2 and 8.55*10-3+/-3.0*10-4gcm-2 densities, respectively. Self-cleaning properties were analyzed using the methylene blue 365nm UV-A photodegradation test. TiO2-coated filters achieved rapid and complete photodegradation of methylene blue because of the better TiO2 dispersion with respect to the glass slides. The effect of functionalized surfaces on the growth and viability of bacteria was studied using the strains Staphylococcus aureus and Pseudomonas putida. After irradiation (2h, 11.2Wm-2, 290-400nm), the initially hydrophobic surface turned hydrophilic. The antibacterial effect led to extensive membrane damage and significant production of intracellular reactive oxygen species in all TiO2-loaded irradiated specimens. The reduction of cell viability was over 99.9% (>3-log) for TiO2 on glass surfaces. However, the polymeric extracellular matrix formed before the irradiation treatment was not removed. This study highlights the importance of bacterial colonization during dark periods and the difficulty of removing the structure of biofilms. PMID- 28715740 TI - Rhamnolipid biosurfactant complexation of rare earth elements. AB - Rare earth elements (REE) are vital for modern technologies and considered critical materials. This study investigated monorhamnolipid biosurfactant interactions with REE as the basis for REE recovery technology. Conditional stability constants (log beta), measured using a resin-based ion exchange method, are reported for 16 REE and metals. These results were combined with existing data for 10 other metals to assess comparative strength and determinants of binding. The stability constants could be divided into three groups: weakly, moderately, and strongly bound. The REE were all in the strongly bound group (UO22+, Eu3+, Nd3+, Tb3+, Dy3+, La3+, Cu2+, Al3+, Pb2+, Y3+, Pr3+, and Lu3+) with log beta ranging from 9.82 to 8.20. The elements Cd2+, In3+, Zn2+, Fe3+, Hg2+, and Ca2+ were moderately bound with log beta=7.17-4.10. Finally, Sr2+, Co2+, Ni2+, UO22+, Ba2+, Mn2+, Mg2+, Rb+, and K+ were weakly bound with log beta=3.95 0.96. Two log beta values are reported for the uranyl ion due to two distinct binding regions. A mixed metals study and associated selectivity coefficients confirmed monorhamnolipids preferentially remove metals with large log beta values over those with smaller values. Preferential complexation by monorhamnolipids may constitute a green pathway for recovery of REE from alternative, non-traditional sources. PMID- 28715741 TI - A remarkable adsorbent for removal of contaminants of emerging concern from water: Porous carbon derived from metal azolate framework-6. AB - A series of metal-azolate frameworks or MAFs-MAF-4, -5, and -6-were synthesized and pyrolyzed to prepare porous carbons derived from MAFs (CDM-4, -5, -6, respectively). Not only the obtained carbons but also MAFs were characterized and applied for the adsorption of organic contaminants of emerging concern (CECs, including pharmaceuticals and personal care products) such as salicylic acid, clofibric acid, diclofenac sodium, bisphenol-A, and oxybenzone (OXB) from water. CDM-6 was found to be the most remarkable adsorbent among the tested ones (including activated carbon) for all the adsorbates. OXB was taken as a representative adsorbate for detailed adsorption studies as well as understanding the adsorption mechanism. H-bonding (H-acceptor: CDM; H-donor: CECs) was suggested as the principal mechanism for the adsorption of tested adsorbates. Finally, CDMs, especially CDM-6, were suggested as highly efficient and easily recyclable adsorbents for water purification. PMID- 28715742 TI - Development of high-performance supercapacitor electrode derived from sugar industry spent wash waste. AB - This study aims at developing supercapacitor materials from sugar and distillery industry wastes, thereby mediating waste disposal problem through reuse. In a two step process, biomethanated spent wash (BMSW) was acid treated to produce solid waste sludge and waste water with significantly reduced total organic carbon (TOC) and biological oxygen demand (BOD) content. Further, waste sludge was directly calcined in presence of activating agent ZnCl2 in inert atmosphere resulting in high surface area (730-900m2g-1) carbon of unique hexagonal morphology. Present technique resulted in achieving two-faceted target of liquid solid waste remediation and production of high-performance carbon material. The resulted high surface area carbon was tested in both three and two electrode systems. Electrochemical tests viz. cyclic voltammetry, galvanostatic charge discharge and impedance measurement were carried out in aqueous KOH electrolyte yielding specific capacitance as high as 120Fg-1, whereas all solid supercapacitor devised using PVA/H3PO4 polyelectrolyte showed stable capacitance of 105Fg-1 at 0.2Ag-1. The presence of transition metal particles and hetero atoms on carbon surface were confirmed by XPS, EDX and TEM analysis which enhanced the conductivity and imparted pseudocapacitance to some extent into the working electrode. The present study successfully demonstrated production of high performance electrode material from dirtiest wastewater making process green, sustainable and economically viable. PMID- 28715743 TI - Experimental study on the thermal decomposition and combustion characteristics of nitrocellulose with different alcohol humectants. AB - Although the thermal behaviors including thermal instability of nitrocellulose (NC) and its mixtures with some humectants have been comprehensively examined previously in the literature, their combustion characteristics have not been systematically studied. To address the issue, the combustion properties of NC with alcohol humectants are investigated by the means of the ISO 5660 cone calorimeter. Two kinds of NC-humectant mixtures with 30wt.% isopropanol and 30wt.% ethanol, respectively, were employed as samples. The tests were conducted under different external radiations, ranging from 0-15kW/m2. The experimental results indicate that the external radiation positively influences the peak heat release rate (HRR) intensity and the maximum mass loss rate (MLR), while the total heat release (THR) decreases with the elevated external radiation. Comparatively, the sample with isopropanol exhibits a higher fire risk, characterized by the higher peak HRR, THR and maximum MLR. Auxiliary investigating methods, including Scanning Electron Microscopy and Differential Scanning Calorimeter-Thermal Gravimetric Analysis, were applied to examine the micro structure and thermal behavior of NC-humectant mixtures. The results helped to explain the burning characteristics observed in the cone calorimeter tests. PMID- 28715744 TI - Short-term thermophilic treatment cannot remove tetracycline resistance genes in pig manures but exhibits controlling effects on their accumulation and spread in soil. AB - In this work, a microcosm experiment was conducted to merely mimic thermophilic phase in aerobic composting with pig manures in order to explore: (i) the effect of thermophilic phase in composting on the abundances of tetracycline resistance genes (TRGs); and (ii) the impacts of the treated manures on the abundances of TRGs in soil. It was found that 4days of thermophilic process reduced the abundance of TRGs in pig manures by ~1 lg unit compared to the samples without treatments, suggesting that other phases in composting may play significant roles in removal of TRGs. Once pig manures with thermophilic treatment were applied to soil, TRGs abundances decreased to the levels in unfertilized soil. With correlation analyses, it was concluded that pig manure derived tetracycline resistant bacteria (TRB) and nutrients exerted different effects on TRGs abundances in soil. In conclusion, short-term thermophilic treatment cannot remove tetracycline resistance genes in pig manures but exhibits controlling effects on their accumulation and spread in soil. Nutrients enrichment in soil following manuring of treated pig manures, together with a large proportion of gram-positive TRB left in treated pig manures with less risk to TRGs spread, contributed to the controlling effects. PMID- 28715745 TI - A practical protocol for comprehensive evaluation of sulfur-fumigation of Gastrodia Rhizoma using metabolome and health risk assessment analysis. AB - Gastrodia Rhizoma is one of the most heavily sulfur-fumigated edible and medical herbs in the marketplace. We developed a practical protocol using an ultra performance liquid chromatography coupled with quadrupole time-of-flight-MSE (UPLC/QTOF-MSE)-based metabolome and health risk assessment model to identify characteristic sulfur-fumigated markers, dissect chemical transformation mechanisms, and control the quality of sulfur-fumigated Gastrodia Rhizoma. Two sulfur-containing p-hydroxybenzyl products, one sulfur-containing disaccharide, one glycolipid, and two phospholipids were selected and identified as markers based on multivariate statistical analysis. In particular, the sulfur-containing markers p-hydroxybenzyl hydrogen sulfite and trace p-mercaptobenzyl hydrogen sulfate were positively correlated with the active major phenolics. Moreover, a practical index the time of the minimum content was useful for evaluating the extent of the sulfur-fumigation under different weight ratios of the sulfur to herbal materials (1:20, 1:40, and 1:80). Ultimately, the 1:40 ratio within 1h of sulfur-fumigation was considered as safe and efficient for herb quality preservation under the maximum residue limit of 750mg/kg. This study shows that the practical protocol-based discriminated markers and practical limits can be applied to quality assurance of sulfur-fumigation and non-fumigation Gastrodia Rhizoma and other edible or medical materials. PMID- 28715747 TI - Alumina/activated carbon nano-composites: Synthesis and application in sulphide ion removal from water. AB - An investigation of adsorption of sulphide ion (S2-) in water onto carbon/alumina nano-composites synthesized from aluminium carboxylate precursors, in presence of HCl, NaOH, NaCl and surfactant is reported in this paper. A controlled oxygen free pyrolytic technique has been adopted for the synthesis of nano-composites, using acetate, acetyl acetonate, lactate and distearate of aluminium and activated carbon. XRD, SEM and TEM studies of the composites show that they contain clusters made of nano carbon particles of size 50-130nm into which nano alumina particles of size around 10nm are dispersed. While applying the adsorption data in Langmuir, Freundlich, Temkin and Dubinin-Raduskevich isotherm models, the data fit well with Langmuir model. All composites have increased porosity and decreased surface area compared to bare carbon. The adsorption capacity of composites obtained from acetate and lactate are higher and are found to be in the range of 71-200mg/g. PMID- 28715746 TI - PFOA-induced metabolism disturbance and multi-generational reproductive toxicity in Oryzias latipes. AB - The aims of this study were to examine multi-generational reproductive toxicity and metabolism disturbances in Oryzias latipes exposed to 0.3, 3, and 30mg/L PFOA for 259-day. The highest concentration of PFOA suppressed fecundity over three generations from F0 to F2 and sac-fry survival rate in F2 generation, indicating that PFOA resulted in multi-generational reproductive toxicity (p<0.05). Histologically, in F1 and F2 generations, O. latipes exposed to 30mg/L PFOA revealed accelerated gonad development, and the atrophy and degeneration of thyroid follicular cell. Glucose content showed the highest increase in both genders in all metabolites. However, alanine, glutamine, threonine, and lactate content, which are converted into glucose showed decline tendency, suggesting that PFOA led to gluconeogenesis. Change of osmolyte content affecting osmosis such as a decrease of male myo-inositol (m-Ino), an increase of female trimethylamine N-oxide (TMAO) and an increase of male dimethylamine (DMA) suggest that PFOA might affect osmoregulation of O. latipes. Oxaloacetate of male fish and succinate of female fish showed significant alterations, indicating that PFOA may affect energy metabolism differently by sex. These findings will help elucidate the toxicity of PFOA in diverse biological responses including metabolism change. PMID- 28715748 TI - Fabrication uniform hollow Bi2S3 nanospheres via Kirkendall effect for photocatalytic reduction of Cr(VI) in electroplating industry wastewater. AB - Hazardous hexavalent chromium removal from wastewater is an urgent issue in industry environmental pollution. In this work, hollow Bi2S3 nanospheres have been successfully synthesized from unique Bi2O3 porous nanospheres via Kirkendall effect through hydrothermal process. It was found that the sulfur source and the initial Bi2O3 templates played key roles in the formation of the uniform morphologies and structures through an anion exchange process. Compared with other Bi2S3 samples, the synthesized hollow Bi2S3 nanospheres exhibited much enhanced photocatalytic ability for Cr(VI) photoreduction. XPS analysis demonstrated that Cr(VI) was reduced to less harmful Cr(III) species over hollow Bi2S3 nanospheres under visible-light irradiation. More importantly, the hollow Bi2S3 nanospheres remained high efficiency and good stability in the recycling Cr(VI) photoreduction, and exhibited remarkable Cr(VI) removal ability in actual electroplating industry wastewater treatment. PMID- 28715749 TI - Self-assembly of zinc hydroxystannate on amorphous hydrous TiO2 solid sphere for enhancing fire safety of epoxy resin. AB - Zinc hydroxystannate (ZHS) was fabricated on the surface of amorphous hydrous TiO2 solid spheres (AHTSS) via a layer-by-layer method for improving the fire safety of epoxy resin. AHTSS@PEI@ZHS was prepared by self-assembly of AHTSS, PEI and ZHS. The well-organized fabrication process was proved by TEM, XPS, XRD and SEM tests. TG results illustrated that the incorporation of AHTSS@PEI@ZHS show a higher residue compared with the addition of AHTSS or ZHS alone. In addition, AHTSS@PEI@ZHS filled EP composites exhibits improved flame retardancy and smoke suppression properties evaluated by cone calorimeter test. TG-IR results also indicated that the catalytic labyrinth structure of AHTSS@PEI@ZHS can effectively decrease the permeation of volatile organic compounds, thereby improving the fire safety of EP resin. PMID- 28715750 TI - Polyamines may influence phytochelatin synthesis during Cd stress in rice. AB - Although the metabolism of phytochelatins and higher polyamines are linked with each other, the direct relationship between them under heavy metal stress has not yet been clarified. Two approaches were used to reveal the influence of polyamine content on cadmium stress responses, particularly with regard to phytochelatin synthesis: putrescine pre-treatment of rice plants followed by cadmium stress, and treatment with the putrescine synthesis inhibitor, 2 (difluoromethyl)ornithine combined with cadmium treatment. The results indicated that putrescine pre-treatment enhanced the adverse effect of cadmium, while the application of 2-(difluoromethyl)ornithine reduced it to a certain extent. These differences were associated with increased polyamine content, more intensive polyamine metabolism, but decreased thiol and phytochelatin contents. The gene expression level and enzyme activity of phytochelatin synthase also decreased in rice treated with putrescine prior to cadmium stress, compared to cadmium treatment alone. In contrast, the inhibition of putrescine synthesis during cadmium treatment resulted in higher gene expression level of phytochelatin synthase. The results suggest that polyamines may have a substantial influence on phytochelatin synthesis at several levels under cadmium stress in rice. PMID- 28715751 TI - Sepiolite nanoplatform for the simultaneous assembly of magnetite and zinc oxide nanoparticles as photocatalyst for improving removal of organic pollutants. AB - Novel ternary ZnO/Fe3O4-sepiolite nanostructured materials were developed in a two-step procedure based on the incorporation of ZnO nanoparticles on a substrate composed by magnetite nanoparticles previously assembled to the sepiolite fibrous silicate (Fe3O4-sepiolite). The structural and morphological characterization shows that both, ZnO and Fe3O4 nanoparticles, were homogeneously dispersed on the surface of sepiolite. Therefore, the resulting material is characterized as a multifunctional nanoplatform simultaneously providing magnetic and photoactive properties. ZnO/Fe3O4-sepiolite materials exhibit superparamagnetic properties at room temperature, which is one of the sought properties in view to facilitate their recovery from the reaction medium after application as heterogeneous catalysts. ZnO/Fe3O4-sepiolite materials were tested as photocatalysts using methylene blue dye in water as model of a pollutant molecule, showing full decolorization after 2h of UV irradiation. Moreover, the photocatalytic activity of this nanoplataform may be maintained after reuse in several consecutive cycles of treatment. Remarkably, the ZnO/magnetite-sepiolite nanostructured material displays a similar activity as ZnO/sepiolite materials, but shows the additional advantage of easier recovery by means of a magnet which facilitates its reuse. PMID- 28715752 TI - Switching to sanitation: Understanding latrine adoption in a representative panel of rural Indian households. AB - Open defecation, which is still practiced by about a billion people worldwide, is one of the most compelling examples of how place influences health in developing countries. Efforts by governments and development organizations to address the world's remaining open defecation would be greatly supported by a better understanding of why some people adopt latrines and others do not. We analyze the 2005 and 2012 rounds of the India Human Development Survey (IHDS), a nationally representative panel of households in India, the country which is home to 60% of the people worldwide who defecate in the open. Among rural households that defecated in the open in 2005, we investigate what baseline properties and what changes over time are associated with switching to latrine use between 2005 and 2012. We find that households that are richer or better educated, that have certain demographic properties, or that improved their homes over this period were more likely to switch to using a latrine or toilet. However, each of these effect sizes is small; overall switching to latrine use from open defecation is low; and no ready household-level mechanisms are available for sanitation programs to widely influence these factors. Our research adds to a growing consensus in the literature that the social context should not be overlooked when trying to understand and bring about change in sanitation behavior. PMID- 28715753 TI - Wettability modification of Wender lignite by adsorption of dodecyl poly ethoxylated surfactants with different degree of ethoxylation: A molecular dynamics simulation study. AB - Lignite is an important and useful fossil fuel in the world and the strong hydrophilicity of it limits its applications. Surfactant adsorption on lignite is an effective way to make it hydrophobic. In this work, aiming to examine the effect of the degree of ethoxylation on the adsorption behavior of dodecyl poly ethoxylated surfactants on lignite and the wettability modification of modified lignite by surfactant adsorption, different combined systems formed by surfactants, water and a model surface of Wender lignite have been studied using molecular dynamics simulation. The adsorption configurations vary with the degree of ethoxylation. At the same adsorption amounts, increasing the degree of ethoxylation can make the adsorption layer more compactness and bring stronger adsorption strength. The results of binding energy and its components show that the adsorption of alkyl polyoxyethylene ethers surfactant on lignite is physically adsorbed rather than electrostatically or chemisorbed. Meanwhile, van der Waals interaction plays a dominant role in the adsorption. The addition of surfactant could reduce the possibility of the interaction between water and lignite. Compared to the original lignite, the interaction between them is weakened after surfactant adsorption in water/surfactant/lignite system, thus strengthening the hydrophobicity of lignite. Similar to the adsorption strength, hydrophobicity of modified lignite increases with the increase of the degree of ethoxylation. The lignite surface properties are changed due to surfactant adsorption by analyzing the compositions of interaction energy and the change of hydrogen bonds. PMID- 28715754 TI - Target identification, lead optimization and antitumor evaluation of some new 1,2,4-triazines as c-Met kinase inhibitors. AB - In silico target fishing approach using PharmMapper server identified c-Met kinase as the selective target for our previously synthesized compound NCI 748494/1. This approach was validated by in vitro kinase assay which showed that NCI 748494/1 possessed promising inhibitory activity against c-Met kinase (IC50=31.70MUM). Assessment of ADMET profiling, drug-likeness, drug score as well as docking simulation for the binding pose of that compound in the active site of c-Met kinase domain revealed that NCI 748494/1 could be considered as a promising drug lead. Based on target identification and validation, it was observed that there is structure similarity between NCI 748494/1 and the reported type II c-Met kinase inhibitor BMS-777607. Optimization of our lead NCI 748494/1 furnished newly synthesized 1,2,4-triazine derivatives based on well-established structure activity relationships, whereas three compounds namely; 4d, 7a and 8c displayed excellent in vitro cytotoxicity against three c-Met addicted cancer cell lines; A549 (lung adenocarcinoma), HT-29 (colon cancer) and MKN-45 (gastric carcinoma); with IC50 values in the range 0.01-1.86uM. In vitro c-Met kinase assay showed 8c to possess the highest c-Met kinase inhibition profile (IC50=4.31uM). Docking of the active compounds in c-Met kinase active site revealed strong binding interactions comparable to the lead NCI 748494/1 and BMS-777607, suggesting that c-Met inhibition is very likely to be the mechanism of the antitumor effect of these derivatives. PMID- 28715755 TI - Adsorption of mercury (II) from aqueous solutions using FeS and pyrite: A comparative study. AB - In this study, a comparative evaluation of synthetic FeS and natural pyrite was performed to investigate their adsorptive potentials toward Hg(II) in aqueous system. Characterization analyses such as BET, SEM and TEM suggested that FeS had porous structures with abundant active sites, while pyrite with a hard and smooth surface relied mainly on surface adsorption to immobilize Hg(II). Results of batch tests revealed that FeS offered much greater Hg(II) maximum adsorption capacity (769.2 mg/g) as compared to pyrite (9.9 mg/g). Both iron sulfides showed high removal efficiency (>96%) with the initial Hg(II) concentration (1 mg/L) at pH = 7.0 +/- 0.1, and the effluent could meet the permissible effluent concentration (<50 MUg/L). Condition experiments (such as pH, co-ions) proved that the adaptive capacity of FeS was significantly higher than that of pyrite. A pseudo-second-order kinetic model was better able to illustrate the sorption kinetics on both FeS and pyrite (R2 >= 0.9992). XRD and XPS analyses supported that precipitation, ion exchange and surface complexation were main reaction mechanisms involved in the adsorption process. In addition, it was also revealed that the structural changes of FeS before and after adsorption was much larger than pyrite. Findings from this study suggest FeS is a promising candidate for treatment of high-concentration Hg(II)-containing wastewater (<20 mg/L), while pyrite can be applied as a long-term adsorbing material in the immobilization of wastewater containing low Hg(II) concentration (<1 mg/L) due to its cost effective property and local availability. PMID- 28715756 TI - The occurrence and spatial-temporal distribution of tetrabromobisphenol A in the coastal intertidal zone of Qingdao in China, with a focus on toxicity assessment by biological monitoring. AB - Tetrabromobisphenol A (TBBPA) is a widely used flame retardant that has increasingly been found as contaminant in aquatic environments. The main goal of this study was to evaluate the pollution level of TBBPA at six locations around Qingdao and assess its biotoxicity through a two-generation toxicity study looking at a copepod species. In the chemical monitoring, the concentration of TBBPA in seawater samples ranged from nd to 1.8 MUg/L. Next, the biological indicator monitoring used 1.8 MUg/L as the middle exposure concentration to perform quantitative evaluations of the influence of TBBPA on the demographic traits of Pseudodiaptomus inopinus. The results showed that copepods became more sensitive to TBBPA exposure even in environmental concentration (1.8 MUg/L) as the generations developed. The detrimental effects of TBBPA further increased naupliar mortality and impaired copepodite development to adulthood. This study demonstrated that the water pollution condition of TBBPA was measured at all 6 sampling locations of Qingdao. Therefore, the present results call for a decreased discharge of TBBPA into the marine environment to avoid impairing copepod reproduction and development. PMID- 28715757 TI - Trace element concentrations in the groundwater of the Tamiraparani river basin, South India: Insights from human health risk and multivariate statistical techniques. AB - This study investigates the concentration of trace elements in the groundwater of Tamiraparani river basin, South India. 124 groundwater samples were collected representing diverse landuse condition over the study area. The results reveal that the mean concentrations of Fe, Mn, Cu, Cr, Pb, Zn and Ni were 0.269, 0.02, 0.007, 0.007, 0.003, 0.066, and 0.004 ppm respectively. The decreasing trend of trace element content shows the following order: Fe > Zn > Mn > Cu > Cr > Ni > Pb. Significant positive correlation (p < 0.05) is found between most of the variables such as water level and Fe, Pb; EC and Ni; Fe and Pb; Mn and Pb; Cu and Zn, Ni; Cr and Pb; Zn and Ni. The studied trace elements are found below the international drinking water guidelines except Fe, Mn, and Pb. The Empirical Bayesian Kriging (EBK) model is used to interpolate the studied metal concentrations in the groundwater of the study area. A health risk assessment was carried out using exposure dose index (CDI) and hazard quotient (HQ). The CDI values of trace elements for oral and dermal pathways shows the following order of Fe > Zn > Mn > Cu > Cr > Ni > Pb and Fe > Zn > Mn > Cr > Cu > Ni > Pb respectively. The Hazard quotients suggest that the risk of contamination through oral and dermal pathways is feeble as all the elements show values less than one. The multivariate statistical analysis reveals that the source of trace elements in the groundwater is through natural origin except copper, chromium and lead as these contaminants are derived from anthropogenic activities. PMID- 28715758 TI - Defence strategies and antibiotic resistance gene abundance in enterococci under stress by exposure to low doses of peracetic acid. AB - Peracetic acid (PAA) is an organic compound used efficiently as disinfectant in wastewater treatments. Yet, at low doses it may cause selection; thus, the effect of low doses of PAA on Enterococcus faecium as a proxy of human-related microbial waste was evaluated. Bacteria were treated with increasing doses of PAA (from 0 to 25 mg L-1 min) and incubated in regrowth experiments under non-growing, limiting conditions and under growing, favorable conditions. The changes in bacterial abundance, in bacterial phenotype (number and composition of small cell clusters), and in the abundance of an antibiotic resistance gene (ARG) was evaluated. The experiment demonstrated that the selected doses of PAA efficiently removed enterococci, and induced a long-lasting effect after PAA inactivation. The relative abundance of small clusters increased during the experiment when compared with that of the inoculum. Moreover, under growing favorable conditions the relative abundance of small clusters decreased and the number of cells per cluster increased with increasing PAA doses. A strong stability of the measured ARG was found, not showing any effect during the whole experiment. The results demonstrated the feasibility of low doses of PAA to inactivate bacteria. However, the stress induced by PAA disinfection promoted a bacterial adaptation, even if potentially without affecting the abundance of the ARG. PMID- 28715759 TI - Do PCDD/PCDF standard solutions used in dioxin analysis pose a risk as potentially acutely toxic to lab personnel? AB - Laboratory safety requires protecting personnel from chemical exposures. Working with stock solutions of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/PCDFs) in routine analysis of feed and food with bioanalytical or physicochemical methods raises some concerns. Since PCDD/PCDFs are considered as possibly acutely toxic, the potential risks were evaluated to determine whether supervision of their use is necessary. Based on LD50-data for oral or dermal intake, hazard classification of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) as a substance (category 1) and in commercially available TCDD standard solutions (category 4) is different. As worst case exposure scenario during routine laboratory work it was assumed that a dose of 100 ng TCDD gets onto the skin and is absorbed. This would result in the total body burden of a 70 kg person with 15 kg fat increasing from 10 (upper range of current background levels) to ~17 pg of toxic equivalents (TEQs) of PCDD/PCDFs per g lipid, a level commonly observed over past decades. Chloracne, the main acute effect occurring weeks after exposure, is observed at much higher blood concentrations than estimated from accidental laboratory exposure. Immunotoxicity, developmental effects and other toxic effects may occur at lower blood levels, but require longer periods to develop. Since acute toxic symptoms don't occur within an "8 h acute time window", no supervision is necessary when working with standard solutions in routine analysis. Nevertheless, precautionary measures are needed regarding long term adverse health effects and appropriate workplace conditions must exist to ensure that additional occupational exposure to PCDD/PCDFs by laboratory personnel is negligible. PMID- 28715760 TI - The Italian National Antarctic Research Programme (PNRA): Contribution to the study of environmental contamination in the Ross Sea and Victoria Land, Antarctica. PMID- 28715761 TI - Effects of lead mineralogy on soil washing enhanced by ferric salts as extracting and oxidizing agents. AB - In this study, we evaluated the feasibility of using ferric salts including FeCl3 and Fe(NO3)3 as extracting and oxidizing agents for a soil washing process to remediate Pb-contaminated soils. We treated various Pb minerals including PbO, PbCO3, Pb3(CO3)2(OH)2, PbSO4, PbS, and Pb5(PO4)3(OH) using ferric salts, and compared our results with those obtained using common washing agents of HCl, HNO3, disodium-ethylenediaminetetra-acetic acid (Na2-EDTA), and citric acid. The use of 50 mM Fe(NO3)3 extracted significantly more Pb (above 96% extraction) from Pb minerals except PbSO4 (below 55% extraction) compared to the other washing agents. In contrast, washing processes using FeCl3 and HCl were not effective for extraction from Pb minerals because of PbCl2 precipitation. Yet, the newly formed PbCl2 could be dissolved by subsequent wash with distilled water under acidic conditions. When applying our washing method to remediate field-contaminated soil from a shooting range that had high concentrations of Pb3(CO3)2(OH)2 and PbCO3, we extracted more Pb (approximately 99% extraction) from the soil using 100 mM Fe(NO3)3 than other washing agents at the same process conditions. Our results show that ferric salts can be alternative washing agents for Pb-contaminated soils in view of their extracting and oxidizing abilities. PMID- 28715762 TI - Adsorption behavior of 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin on pristine and doped black phosphorene: A DFT study. AB - Polychlorinated dibenzo-p-dioxins (PCDDs) are highly toxic to humans. The search for novel and effective methods and materials for detecting or removing these gas pollutants is becoming more important and urgent. With its high specific surface area, abundance, and variety of potential applications, phosphorene has attracted much research interest. In this study, density functional theory was used to study the interactions between a doped phosphorene sheet and a tetrachlorodibenzo p-dioxin (TCDD) molecule. The initial configurations of the TCDD and metallic (Ca or Ti) or nonmetallic (S and Se) dopants were investigated during the TCDD phosphorene interaction study. Adsorption energy, isosurface of electron density difference, and density of states analysis were utilized to explore the interactions between TCDD and phosphorene. The results indicated that Ca dopant effectively improved the interaction between TCDD and phosphorene. Se dopant reduced the interaction between TCDD and phosphorene. Combining interactions between TCDD and the pristine, Ca-doped, and Se-doped phosphorenes, phosphorene could be a promising candidate for TCDD sensing and removal. PMID- 28715763 TI - Quantification of the limitation of Langmuir model used in adsorption research on sediments via site energy heterogeneity. AB - The Langmuir model has been extensively introduced into the field of environmental adsorption, while some studies showed that it was difficult for the model to describe the adsorption of sediments. The purpose of this paper is to recognize the applicability of the Langmuir model used in the adsorption of contaminants onto sediments quantitatively through the relationship between the error of Langmuir (delta) and site energy heterogeneity (sigma). The formula for calculating delta in sediments was developed based on the heterogeneity parameters (m, n). The data was extracted from papers discussing about the adsorption of pollutants on natural sediments. It was further used to investigate the error of Langmuir and the effect on the error from the site energy heterogeneity. The results indicate that the Langmuir model can be applied in sediments when each one of the conditions below is satisfied, (1) m and n lie in the area which signifies that the relative error is less than 10%, (2) the site energy heterogeneity of sediment is under 5.668. These findings are vital for the proper choice of models fitting the adsorption process of sediments. PMID- 28715764 TI - DDT-related compounds as non-extractable residues in submarine sediments of the Palos Verdes Shelf, California, USA. AB - The Palos Verdes Shelf (PVS) and the continental slope off the Palos Verdes Peninsula are highly contaminated by degradation products of the pesticide DDT (1 chloro-4-[2,2,2-trichloro-1-(4-chlorophenyl)ethyl]benzene). Sediment samples from two box cores were analyzed to obtain further information about the fate of DDT and its degradation products within the environment. After solvent extraction, an alkaline hydrolysis procedure was applied. A comprehensive screening for 26 DDT compounds revealed that DDT and its degradates contaminate not only the extractable fraction but also the fraction released by alkaline hydrolysis. A comparison of the quantitative distribution of DDT degradation products in the extractable fraction and released by alkaline hydrolysis showed a distinct difference. DDE (1-chloro-4-[2,2-dichloro-1-(4-chlorophenyl)ethenyl]benzene), DDD (1-chloro-4-[2,2-dichloro-1-(4-chlorophenyl)ethyl]benzene), DDMS (1-chloro-4-[2 chloro-1-(4-chlorophenyl)ethyl]benzene), and DDMU (1-chloro-4-[2-chloro-1-(4 chlorophenyl)ethenyl]benzene) were predominant in the sediment extracts but minor components of the hydrolyzable fraction. The most abundant compounds released by the alkaline hydrolysis were DBP (bis(4-chlorophenyl)methanone), DDNU (1-chloro-4 [1-(4-chlorophenyl)ethenyl]benzene), DDM (1-chloro-4-[(4 chlorophenyl)methyl]benzene) and the water-soluble DDA (2,2-bis(4 chlorophenyl)acetic acid). The release of DDA may point to the presence of an important degradation pathway in marine environments. Concentration levels of DDT related compounds showed corresponding vertical profiles in both fractions, but were significantly lower in the fraction released by alkaline hydrolysis. In contrast to fluvial sediments contaminated by DDT and its degradates the alkaline hydrolysis products represented a minor portion of the total sedimentary burden in the analyzed marine sediments. These findings show the necessity of a comprehensive screening for all DDT isomers and breakdown products in the extractable and non-extractable fraction to assess the total contamination abundance and potential environmental risks. PMID- 28715765 TI - Impact of coated TiO2-nanoparticles used in sunscreens on two representative strains of the human microbiota: Effect of the particle surface nature and aging. AB - The impact of two differently coated TiO2-nanoparticles (NPs) was evaluated on two representative bacteria from the cutaneous microbiota (Staphylococcus aureus and Pseudomonas fluorescens) in conditions of use. Particles were coated in order to exhibit either hydrophilic or hydrophobic behavior. A first exposure scenario within some fresh/aged model emulsions was developed in order to measure both the impact of the NPs presence and their surface nature during the emulsions conservation. Thanks to this protocol, it was demonstrated that, during aging, the hydrophobic NPs modified the physicochemical characteristics of the emulsions, such as the pH or the colloids sizes, and favored the development of potential pathogenic bacteria. A second scenario was then envisaged, aiming to mimic the exposition of the skin, especially of the cutaneous bacteria, to NPs. Tested NPs were extracted from emulsions with different aging, and results highlighted the importance of both the NP coating nature and their history in emulsion. The different NPs impacts on the bacteria growth were discussed and linked to their surface properties modifications during aging, as polarity and charges. Finally, through two exposition scenarios, this work highlights the major impact of the NPs surface properties on bacteria. PMID- 28715766 TI - Different effects of matrix degrading enzymes towards biofilms formed by E. faecalis and E. faecium clinical isolates. AB - E. faecalis and E. faecium cause urinary tract infections highly resistant to therapies due to a protective extracellular matrix. To exploit a new strategy able to treat infections without increasing antibiotic doses, we used enzymes targeting specific biofilm matrix components in combination with Vancomycin. We investigated the activity of Vancomycin combined with two matrix-degrading enzymes, Alginate Lyase (AlgL) and Deoxyribonuclease I (DNase I) against in vitro biofilm of E. faecalis and E. faecium clinical isolates. The heterogeneity of matrix composition leads to defined physiological responses of biofilm communities to their environment: we demonstrated that the use of DNase I and AlgL enzymes affects biofilm structure, cell viability and reduces MBEC values of Vancomycin in E. faecalis and E. faecium, respectively. PMID- 28715767 TI - Non-human primates as a model for understanding the mechanism of action of toll like receptor-based vaccine adjuvants. AB - While transgenic mouse models are powerful for understanding how the immune system is manipulated by vaccines, they cannot fully recapitulate the characteristics of the innate immune responses leading to adaptive immunity after vaccination in humans. Outbred non-human primates are far more representative models of human vaccine responses as there is high degree of similarities in immune cell subset distributions, receptor expression (including toll-like receptors; TLRs), and immune cell functions, in addition to modeling doses and injection sites more accurately. Vaccine adjuvants targeting TLRs have shown great promise in their ability to enhance responses to non-live vaccines. As TLR ligands are molecularly defined, studies of the mechanisms by which they interact with the immune system are facilitated. In this brief review, we focus on the use of TLR3, 4, 7/8 and 9 stimulating adjuvants in NHPs by evaluating similarities between the specified TLRs in human and NHPs and highlighting recent work studying the mode of action or efficacy of TLR based adjuvants in NHPs. PMID- 28715768 TI - Dynamic complexity: plant receptor complexes at the plasma membrane. AB - Plant receptor complexes at the cell surface perceive many different external and internal signalling molecules and relay these signals into the cell to regulate development, growth and immunity. Recent progress in the analyses of receptor complexes using different live cell imaging approaches have shown that receptor complex formation and composition are dynamic and take place at specific microdomains at the plasma membrane. In this review we focus on three prominent examples of Arabidopsis thaliana receptor complexes and how their dynamic spatio temporal distribution at the PM has been studied recently. We will elaborate on the newly emerging concept of plasma membrane microdomains as potential hubs for specific receptor complex assembly and signalling outputs. PMID- 28715769 TI - High-throughput profiling and analysis of antibiotic resistance genes in East Tiaoxi River, China. AB - The rapid human activities and urbanization exacerbate the human health risks induced by antibiotic resistance genes (ARGs). In this study, the profiling of ARGs was investigated using high-throughput qPCR from water samples of 13 catchment areas in East Tiaoxi River, China. High prevalence of ARGs indicated significant antibiotic resistance pollution in the research area (absolute abundance: 6.1 * 108-2.1 * 1010 copies/L; relative abundance: 0.033-0.158 copies/cell). Conventional water qualities (COD, TN, TP, NH3-N), bacterial communities and mobile gene elements (MGEs) were detected and analyzed as factors of ARGs shift. Nutrient and MGEs showed positive correlation with most ARGs (P < 0.05) and bacteria community was identified as the key contributing factor driving ARGs alteration. With the land-use study and field investigation, country area, especially arable, was expected as a high spot for ARGs shift and pathogen breeding. Comparing to environmental background, promotion of ARGs and marked shift of bacterial community were observed in country and urban city areas, indicating that human activities may lead to the spread of ARGs. Analysis of factors affecting ARGs in this study may shed new light on the mechanism of the maintenance and propagation of ARGs in urban rivers. PMID- 28715770 TI - Influence of flue gas desulfurization (FGD) installations on emission characteristics of PM2.5 from coal-fired power plants equipped with selective catalytic reduction (SCR). AB - Flue gas desulfurization (FGD) and selective catalytic reduction (SCR) technologies have been widely used to control the emissions of sulphur dioxide (SO2) and nitrogen oxides (NOX) from coal-fired power plants (CFPPs). Field measurements of emission characteristics of four conventional CFPPs indicated a significant increase in particulate ionic species, increasing PM2.5 emission with FGD and SCR installations. The mean concentrations of PM2.5 from all CFPPs tested were 3.79 +/- 1.37 mg/m3 and 5.02 +/- 1.73 mg/m3 at the FGD inlet and outlet, respectively, and the corresponding contributions of ionic species were 19.1 +/- 7.7% and 38.2 +/- 7.8%, respectively. The FGD was found to enhance the conversion of NH3 slip from the SCR to NH4+ in the PM2.5, together with the conversion of SO2 to SO42-, and increased the primary NH4+ and SO42- aerosol emissions by approximately 18.9 and 4.2 times, respectively. This adverse effect should be considered when updating the emission inventory of CFPPs and should draw the attention of policy-makers for future air pollution control. PMID- 28715771 TI - A flow-through aqueous standard generation system for thin film microextraction investigations of UV filters and biocides partitioning to different environmental compartments. AB - In this paper problems associated with preparation of aqueous standard of highly hydrophobic compounds such as partial precipitation, being lost on the surfaces, low solubility in water and limited sample volume for accurate determination of their distribution coefficients are addressed. The following work presents two approaches that utilize blade thin film microextraction (TFME) to investigate partitioning of UV filters and biocides to humic acid (dissolved organic carbon) and sediment. A steady-state concentration of target analytes in water was generated using a flow-through aqueous standard generation (ASG) system. Dialysis membranes, a polytetrafluoroethylene permeation tube, and a frit porous (0.5 MUm) coated by epoxy glue were basic elements used for preparation of the ASG system. In the currently presented study, negligible depletion TFME using hydrophilic lipophilic balance (HLB) and octadecyl silica-based (C18) sorbents was employed towards the attainment of free concentration values of target analytes in the studied matrices. Thin film geometry provided a large volume of extraction phase, which improved the sensitivity of the method towards highly matrix-bound analytes. Extractions were performed in the equilibrium regime so as to prevent matrix effects and with aims to reach maximum method sensitivity for all analytes under study. Partitioning of analytes on dissolved organic carbon (DOC) was investigated in ASG to facilitate large sample volume conditions. Binding percentages and DOC distribution coefficients (Log KDOC) ranged from 20 to 98% and 3.71-6.72, respectively. Furthermore, sediment-water partition coefficients (Kd), organic-carbon normalized partition coefficients (Log KOC), and DOC distribution coefficients (Log KDOC) were investigated in slurry sediment, and ranged from 33 to 2860, 3.31-5.24 and 4.52-5.75 Lkg-1, respectively. The obtained results demonstrated that investigations utilizing ASG and TFME can yield reliable binding information for compounds with high log KOW values. This information is useful for study of fate, transport, and ecotoxicological effects of UV filters and biocides in aquatic environment. PMID- 28715772 TI - Stability of single dispersed silver nanoparticles in natural and synthetic freshwaters: Effects of dissolved oxygen. AB - Silver nanoparticles (AgNPs) are increasingly used in various commercial products. This increased use raises ecological concerns because of the large release of AgNPs into the environment. Once released, the local water chemistry has the potential to influence the environmental fates and behaviors of AgNPs. The impacts of dissolved oxygen and natural organic matter (NOM) on the dissolution and stability of AgNPs were investigated in synthetic and natural freshwaters for 7 days. In synthetic freshwater, the aggregation of AgNPs occurred due to the compression of the electric double layer, accompanied by the dissolution of AgNPs. However, once oxygen was removed, the highest dissolved Ag (Agdis) concentration decreased from 356.5 MUg/L to 272.1 MUg/L, the pH of the AgNP suspensions increased from less than 7.6 to more than 8.4, and AgNPs were regenerated by the reduction of released Ag+ by citrate. The addition of NOM mitigated aggregation, inhibited oxidative dissolution and induced the transformation of AgNPs into Ag2S due to the formation of NOM-adsorbed layers, the reduction of Ag+ by NOM, and the high affinity of sulfur-enriched species in NOM for Ag. Likewise, in oxygen-depleted natural freshwaters, the inhibition of oxidative dissolution was obtained in comparison with oxygenated freshwaters, showing a decrease in the maximum Agdis concentration from 137.6 and 57.0 MUg/L to 83.3 and 42.4 MUg/L from two natural freshwater sites. Our results suggested that aggregation and dissolution of AgNPs in aquatic environments depend on the chemical composition, where oxygen-depleted freshwaters more significantly increase the colloidal stability. In comparison with oxic conditions, anoxic conditions were more favorable to the regeneration of AgNPs by reducing species (e.g., citrate and NOM) and enhanced the stability of nanoparticles. This indicates that some AgNPs will be more stable for long periods in oxygen-deprived freshwaters, and pose more serious environmental risks than that in oxygenated freshwaters. PMID- 28715773 TI - Developmental toxicity of Fe3O4 nanoparticles on cysts and three larval stages of Artemia salina. AB - Using Artemia salina cysts (capsulated and decapsulated) and larvae (instar I, II and III) as experimental models, the potential effects of Fe3O4 nanoparticles (Fe3O4-NPs) on marine ecosystems were investigated. Hatchability, mortality and a number of ethological, morphological and biochemical parameters were selected as end-points to define the toxic responses. Data showed that the hatching rates of capsulated and decapsulated cysts were significantly decreased (p < 0.01) following exposure to 600 mg/L for 24 and 36 h. The LC50 values for instar II and III were 482 and 561 mg/L (could not be measured for instar I), and the EC50 values for swimming inhibition of instar I, II and III were 474, 365 and 421 mg/L, respectively. Effects on hatchability, mortality and swimming were accounted for Fe3O4-NPs rather than iron ion released from the NPs. Instar II larvae showed the greatest sensitivity to Fe3O4-NPs, and followed by instar III, instar I, decapsulated cysts and capsulated cysts. Body lengths of instar I, II and III larvae were decreased in dose-dependent manners. Fe3O4-NPs attached onto the gills and body surface, resulting in irreversible damages. Reactive oxygen species, malondialdehyde content, total antioxidant capacity and antioxidant enzymes (superoxide dismutase, catalase and glutathione peroxidase) activities were substantially increased following exposure, indicating that toxic effects were related to oxidative stress. Mitochondrial malformation, cristae rupturing and membranous structure disruption were clearly observed after Fe3O4-NPs exposure. Fe3O4-NPs were ingested and well distributed in the gut, yolk and primary body cavity. Uptake kinetics data showed that the maximum Fe3O4-NPs content (16.4 mg/g) was reached at 30 h. The combined results so far indicate that Fe3O4-NPs have the potential to affect aquatic organisms when released into the marine ecosystems. PMID- 28715774 TI - Model elucidating the sources and formation mechanisms of severe haze pollution over Northeast mega-city cluster in China. AB - Recent studies on regional haze pollution over China come up in general with strong variability of main causes of heavy polluted episodes, in linkage with local specificities, sources and pollution characteristics. This paper therefore aims at elucidating the main specific sources and formation mechanisms of observed strong haze pollution episodes over 1-15 November 2015 in Northeast region considered as one of biggest megacity clusters in China. The Northeast China mega-city cluster, including Heilong Jiang, Jilin and Liaoning provinces, is adjacent to Russia in the north, Mongolian at the west, North Korea at east, and representing key geographical location in the regional and transnational air pollution issues in China due to the presence of heavy industries and intense economic activities. The present study, based on air quality monitoring, remote sensing satellite data and sensitivity experiments carried on the Nested Air Quality Prediction Modeling System (NAQPMS), quantitatively assesses the impact of meteorological conditions and potential contributions from regional chemical transport, intensive energy combustion, illegal emission and biomass burning emissions to PM2.5 concentration variation. The results indicate strong inversion occurrence at lower atmosphere with weak near-surface wind speed and high relative humidity, leading to PM2.5 concentration increase of about 30-50%. Intensive energy combustion (plausibly for heating activities) and illegal emission also significantly enhance the overall PM2.5 accumulation by 100-200 MUg m-3 (60-70% increase), against 75-100 MUg m-3 from the biomass burning under the northeast-southwest transport pathway, corresponding to a contribution of 10-20% to PM2.5 concentration increase. Obviously, stagnant meteorological conditions, energy combustion, illegal emission and biomass burning are main drivers of strong haze formation and spatial distribution over Northeast China megacity cluster. In clear, much effort on emission abatement at both local and regional scales is still an urgent imperative to overcome current critical haze pollution. PMID- 28715775 TI - Evolution of anti-HER2 therapies for cancer treatment. AB - The development of HER2-directed monoclonal antibodies and tyrosine kinase inhibitors have provided benefits to cancer patients, as well as produced many insights into the biology of the ErbB receptor family. Current therapies based on ErbB family members have resulted in improved overall survival with associated improvements in quality of life for the cancer patients that respond to treatment. Compared to monotherapy using either two antibodies to block the HER2 receptor blockade or combinatorial approaches with HER2 antibodies and standard therapies has provided additional benefits. Despite the therapeutic success of existing HER2 therapies, personalising treatment and overcoming resistance to these therapies remains a significant challenge. The heterogeneous intra-tumoural HER2 expression and lack of fully predictive and prognostic biomarkers remain significant barriers to improving the use of HER2 antibodies. Imaging modalities using radiolabelled pertuzumab and trastuzumab allow quantitative assessment of intra-tumoural HER2 expression, HER2 antibody saturation and the success of different drug delivery systems to be assessed. Molecular imaging with HER2 antibodies has the potential to be a non-invasive, predictive and prognostic technique capable of influencing therapeutic decisions, predicting response and failure of treatments as well as providing insights into receptor recycling and signalling. Similarly, conjugating HER2 antibodies with novel toxic payloads or combining HER2 antibodies with cellular immunotherapy provide exciting new opportunities for the management of tumours overexpressing HER2. Future research will lead to higher therapeutic responses, lower toxicities and providing insight into the mechanisms of resistance to HER2-targeted treatments. PMID- 28715776 TI - Gender differences in the real-world effectiveness of smoking cessation medications: Findings from the 2010-2011 Tobacco Use Supplement to the Current Population Survey. AB - BACKGROUND: Meta-analyses of clinical trial data have identified clinically relevant gender differences in the efficacy of smoking cessation pharmacotherapy. It is unclear whether these findings are generalizable to smokers quitting in real-world contexts. METHODS: Using Tobacco Use Supplement to the Current Population Survey (TUS-CPS) 2010-2011 cross-sectional data, we generated propensity score matched samples of smokers who quit either unassisted by medication, using only varenicline, or using only transdermal nicotine patch (TNP). We used generalized estimating equations to estimate gender differences in the comparative effectiveness of these cessation options for achieving 30-days of abstinence, adjusting for potential confounders. RESULTS: When stratified by gender, TNP was significantly more effective than unassisted quit attempts for men (OR=1.37; 95%CI=1.02,1.83; p=0.03), but not for women (OR=0.96; 95%CI=0.71,1.31; p=0.82). Varenicline was significantly more effective than unassisted quit attempts for women (OR=1.63; 95%CI=1.16, 2.31; p=0.005), but not men (OR=1.35; 95%CI=0.94,1.96; p=0.11). Varenicline was also more effective than TNP for women (OR=1.51; 95%CI=0.12,2.05; p=0.007) but not men (OR=0.92; 95%CI=0.65,1.31; p=0.64). A significant gender by medication interaction was found only for the comparison of varenicline to TNP (OR=1.64; 95%CI=1.04,2.61; p=0.04). CONCLUSIONS: Findings for varenicline vs. TNP were consistent with clinical trial data, showing greater differences in effectiveness for women compared to men. Results lend support to the generalizability of clinical trial findings, highlighting the importance of considering gender when offering treatment for smoking cessation. PMID- 28715778 TI - Denitrifying sulfur conversion-associated EBPR: The effect of pH on anaerobic metabolism and performance. AB - The performance of the denitrifying sulfur conversion-associated enhanced biological phosphorus removal (DS-EBPR) process tends to be unstable and requires further study and development. This in turn requires extensive study of the anaerobic metabolism in terms of its stoichiometry and kinetics. This study evaluates the corresponding responses of DS-EBPR to pH, as it significantly influences both stoichiometry and biochemical kinetics. The impacts of five representative pH values ranging between 6.5 and 8.5 on the anaerobic metabolism were investigated, followed by identification of the optimal pH for performance optimization. A mature DS-EBPR sludge was used in the study, enriched with approximately 30% sulfate-reducing bacteria (SRB) and 33% sulfide-oxidizing bacteria (SOB). Through a series of batch tests, the optimal pH range was determined as 7.0-7.5. In this pH range, the anaerobic stoichiometry of phosphorus released/volatile fatty acid (VFA) uptake ratio, sulfate reduction, and internal polymer production (including poly-beta-hydroxyalkanoates and polysulfide and/or elemental sulfur) all increased along with the anaerobic kinetics of the VFA uptake ratio. Consequently, phosphorus removal was maximized at this pH range (>=95% vs. 84-93% at other pH values), as was sulfur conversion (16 mg S/L vs. 10-13 mg S/L). This pH range therefore favors the activity and synergy of the key functional bacteria (i.e. SRB and SOB). Anaerobic maintenance tests showed these bacteria required 38-61% less energy for maintenance than that reported for GAOs regardless of pH changes, improving their ability to cope with anaerobic starvation. Adversely, both bacteria showed much lower VFA uptake rates than that of GAOs at all tested pH values (0.03-0.06 vs. 0.2-0.24 mol-C/C-mol biomass/h), possibly revealing the primary cause of frequent instability in the DS-EBPR process. PMID- 28715777 TI - Regular cannabis and alcohol use is associated with resting-state time course power spectra in incarcerated adolescents. AB - Cannabis and alcohol are believed to have widespread effects on the brain. Although adolescents are at increased risk for substance use, the adolescent brain may also be particularly vulnerable to the effects of drug exposure due to its rapid maturation. Here, we examined the association between cannabis and alcohol use duration and resting-state functional connectivity in a large sample of male juvenile delinquents. The present sample was drawn from the Southwest Advanced Neuroimaging Cohort, Youth sample, and from a youth detention facility in Wisconsin. All participants were scanned at the maximum-security facilities using The Mind Research Network's 1.5T Avanto SQ Mobile MRI scanner. Information on cannabis and alcohol regular use duration was collected using self-report. Resting-state networks were computed using group independent component analysis in 201 participants. Associations with cannabis and alcohol use were assessed using Mancova analyses controlling for age, IQ, smoking and psychopathy scores in the complete case sample of 180 male juvenile delinquents. No associations between alcohol or cannabis use and network spatial maps were found. Longer cannabis use was associated with decreased low frequency power of the default mode network, the executive control networks (ECNs), and several sensory networks, and with decreased functional network connectivity. Duration of alcohol use was associated with decreased low frequency power of the right frontoparietal network, salience network, dorsal attention network, and several sensory networks. Our findings suggest that adolescent cannabis and alcohol use are associated with widespread differences in resting-state time course power spectra, which may persist even after abstinence. PMID- 28715779 TI - Mechanisms underlying the acute toxicity of fullerene to Daphnia magna: Energy acquisition restriction and oxidative stress. AB - The toxicity of fullerene (C60) to Daphnia magna has been a subject with increasing concerns. Nevertheless, the underlying mechanisms are still poorly understood. In the present study, we evaluated various aspects of the toxicological impacts of C60 on daphnia. After a 72-h exposure, the 50% effective concentration of C60 was 14.9 mg/L for immobilization, and 16.3 mg/L for mortality. Daphnia exhibited a quick uptake of C60 with a body burden value of 413 MUg/g in wet weight in the 1 mg/L C60 treatment group. Transmission electron microscopy observations revealed that C60 had mainly accumulated in the guts of organisms. The feeding rate, gut ultra-structural alterations, and digestive enzyme activities of daphnia in response to C60 treatment were evaluated. The results revealed a significant reduction in the digestion and filtration rates, as well as gut impairment and inhibition of digestive enzymes (cellulose, amylase, trypsin, and beta-galactosidase) activity of C60 exposed daphnia. In addition, the changes in superoxide dismutase (SOD) and malondialdehyde (MDA) levels in daphnia under C60 exposures were also discovered. These results, for the first time, provide systematic evidence that C60 caused a restriction in energy acquisition and increased oxidative damage in daphnia, which might be related to the bioaccumulation of C60 and finally led to the immobility and mortality. PMID- 28715780 TI - Use of perampanel in children and adolescents with Lennox-Gastaut Syndrome. AB - AIM: Report the use of perampanel treatment in children with Lennox-Gastaut syndrome (LGS). METHOD: We conducted a prospective study of 13 LGS patients (seven male; mean age, 12.8years) treated with adjunctive perampanel therapy. Perampanel was initiated at 2mg/day and titrated to a median maximum dose of 6mg/day. RESULTS: After a mean follow-up duration of 10.8months (range, 1 24months), nine patients (69.2%) were responders (>=50% reduction in total seizure frequency) and nine (69.2%) were rated by their physician as "much improved" or "very much improved". Four patients (30.8%) discontinued perampanel due to the lack of efficacy (n=2) and seizure aggravation (n=2). No patients discontinued due to other adverse events (AEs). AEs were reported for six patients (46.2%) and comprised decreased activity/social interaction (n=3), behavior disturbance with agitation (n=2), and/or fatigue (n=2). All AEs became manageable after perampanel dosing was decreased. Improvements in cognitive function and/or behavior were reported for seven patients (53.8%). Introduction of perampanel allowed the dose reduction and/or discontinuation of other treatments in seven patients (53.8%). INTERPRETATION: Perampanel was efficacious and generally well tolerated as an adjunctive treatment for seizures associated with LGS, supporting further research in this area. PMID- 28715781 TI - Effects of blue or violet light on the inactivation of Staphylococcus aureus by riboflavin-5'-phosphate photolysis. AB - The light sensitive compound riboflavin-5'-phosphate (or flavin mononucleotide, FMN) generates reactive oxygen species (ROS) upon photo-irradiation. FMN is required by all flavoproteins because it is a cofactor of biological blue-light receptors. The photochemical effects of FMN after irradiation by blue or violet light on the inactivation of Staphylococcus aureus strains, including a methicillin-resistant strain (MRSA), were investigated in this study. Upon blue- or violet-light photo-treatment, FMN was shown to inactivate S. aureus due to the generated ROS. Effective bacterial inactivation can be achieved by FMN photolysis without an exogenous electron provider. Inactivation rates of 94.9 and 95.2% in S. aureus and MRSA, respectively, can be reached by blue light irradiation (2.0mW/cm2) with 120MUM FMN for 120min. A lower FMN concentration and a shorter time are required to reach similar effects by violet light irradiation. Inactivation rates of 96.3 and 97.0% in S. aureus and MRSA, respectively, can be reached by violet light irradiation (1.0mW/cm2) with 30MUM FMN for 30min. The sensitivity of the inherent photosensitizers is lower under blue-light irradiation. A long exposure photolytic treatment of FMN by blue light is required to inactivate S. aureus. Violet light was found to be more efficient in S. aureus inactivation at the same radiant intensity. FMN photolysis with blue or violet light irradiation enhanced the inactivation rates of S. aureus and MRSA. FMN photochemical treatment could be a supplemental technique in hygienic decontamination processes. PMID- 28715782 TI - Approach and avoidance tendencies in depression and anxiety disorders. AB - Anxiety is linked to increased avoidance and inhibition, whereas depression is linked to decreased approach and diminished behavioral activation. Although these notions are widely recognized, systematic investigation of approach-avoidance tendencies is lacking across these diagnostic groups. Participants (mean age = 45.6; 65.8% female) were subdivided in healthy controls (405), remitted patients (877) and currently anxious (217), depressed (154) or comorbid (154) patients. Automatic approach-avoidance tendencies in reaction to facial expression were assessed using the Approach-Avoidance-Task (AAT). Self-reported trait approach and avoidance tendencies were assessed using the BIS/BAS scale. Severity of psychopathology was assessed to examine dose-response relationships. We did not find any consistent associations of automatic approach-avoidance tendencies with psychiatric variables. In contrast, medium to large differences in BIS scores showed increased trait avoidance tendencies in all patient groups relative to healthy controls. Overall, it seems that increased trait avoidance, rather than decreased approach, is a characteristic of affective disorders. This holds for both depressed and anxious patients and more strongly so in severe and chronic patients. It underlines the importance to address trait avoidance tendencies in the treatment of affective disorders. PMID- 28715783 TI - Development of land use regression models for PM2.5, SO2, NO2 and O3 in Nanjing, China. AB - Ambient air pollution has been a global problem, especially in China. Comparing with other methods, Land Use Regression (LUR) models can obtain air pollutant concentration distribution at finer scale without the air pollution source data based on a few monitoring sites and predictors. However, limited LUR studies have been conducted on the basis of regular monitoring networks. Thus, we explored the applicability of conducting LUR models for four key air pollutants: PM2.5, SO2, NO2 and O3, on the basis of national monitoring networks which have good representation of areas with different characteristics in Nanjing, China. Fifty nine potential predictor variables were considered, including land use type, population density, traffic emission, industrial emission, geographical coordinates, meteorology and topography. LUR models of these four air pollutants were with good explained variance for four key air pollutants. Adjusted explained variance of the LUR models was highest for NO2 (87%), followed by SO2 (83%), and was lower for PM2.5 (72%) and O3 (65%). Annual average distributions of pollutants in 2013 were obtained based on predicted values, which revealed that O3 in Nanjing was more heavily impacted by regional influences. This study would not only contribute to the wider use of LUR studies in China but also offer important reference for the application of regular monitoring network with high representativeness in LUR studies. These results would also support for air epidemiological studies in the future. PMID- 28715784 TI - Elemental content of the placenta: A comparison between two high-risk obstetrical populations, adult women carrying multiples and adolescents carrying singletons. AB - BACKGROUND: The placenta is responsible for the exchange of nutrients and for preventing harmful compounds from entering the fetal circulation. With increasing industrialization, exposures to commercial and toxic metals become a concern for both pregnant women and those planning a pregnancy. The understanding of transport mechanisms and pharmacokinetics for most inorganic elements is incomplete and limited to normal term deliveries. OBJECTIVES: To obtain novel data on 46 inorganic elements in placentae from two high-risk obstetric populations, women carrying multiples and adolescents carrying singletons, evaluating differences, if present, and identifying predictors of placental content. METHODS: Placental tissue was collected from adolescents carrying singletons and adults carrying multiples. Elemental content was analyzed using inductively coupled plasma-mass spectrometry (ICP-MS). Multivariate regression and factor analyses were used. RESULTS: With the exception of Au and Pt, almost all placentae contained quantifiable concentrations of each element analyzed. All placentae contained the essential elements Ca, Fe, Mg, Se and Zn, which clustered together onto the same factor. Most elements were higher in placentae from women carrying multiples. Differences in placental content disappeared after adjusting for maternal age. Rare earth elements (REEs) clustered together and remained higher in the multiples even after adjusting for maternal age. CONCLUSION: Human placentae contain a wide range of elements, including REEs. Ranges differed considerably between cohorts. Elements with similar chemical properties, like REEs or nutritionally essential elements, clustered together. Maternal age, and therefore longer environmental exposure, was significantly associated with elevated element concentrations in the placenta. Placental concentrations of several metals that are known to be nutritionally essential (e.g., Fe, Ca, Mg, and Zn) did not differ significantly between cohorts, suggesting tight regulation, whereas concentrations of environmental contaminants differed significantly between groups, even after adjusting for maternal age. PMID- 28715785 TI - Prenatal exposure estimation of BPA and DEHP using integrated external and internal dosimetry: A case study. AB - Prenatal exposure to Endocrine disruptors (EDs), such as Bisphenol A (BPA) and di (2-ethylhexyl) phthalate (DEHP), has been associated with obesity and diabetes diseases in childhood, as well as reproductive, behavioral and neurodevelopment problems. The aim of this study was to estimate the prenatal exposure to BPA and DEHP through food consumption for pregnant women living in Tarragona County (Spain). Probabilistic calculations of prenatal exposure were estimated by integrated external and internal dosimetry modelling, physiologically based pharmacokinetic (PBPK) model, using a Monte-Carlo simulation. Physical characteristic data from the cohort, along with food intake information from the questionnaires (concentrations of BPA and DEHP in different food categories and the range of the different food ratios), were used to estimate the value of the total dietary intake for the Tarragona pregnancy cohort. The major contributors to the total dietary intake of BPA were canned fruits and vegetables, followed by canned meat and meat products. In turn, milk and dairy products, followed by ready to eat food (including canned dinners), were the most important contributors to the total dietary intake of DEHP. Despite the dietary variations among the participants, the intakes of both chemicals were considerably lower than their respective current tolerable daily intake (TDI) values established by the European Food Safety Authority (EFSA). Internal dosimetry estimates suggest that the plasma concentrations of free BPA and the most important DEHP metabolite, mono (2-ethylhexyl) phthalate (MEHP), in pregnant women were characterized by transient peaks (associated with meals) and short half-lives (< 2h). In contrast, fetal exposure was characterized by a low and sustained basal BPA and MEHP concentration due to a lack of metabolic activity in the fetus. Therefore, EDs may have a greater effect on developing organs in young children or in the unborn child. PMID- 28715787 TI - Micronutrients during pregnancy and child psychomotor development: Opposite effects of Zinc and Selenium. AB - Studies on the impact of micronutrient levels during different pregnancy periods on child psychomotor functions are limited. The aim of this study was to evaluate the association between maternal plasma concentrations of selected micronutrients, such as: copper (Cu), zinc (Zn), selenium (Se), and child neuropsychological development. The study population consisted of 539 mother child pairs from Polish Mother and Child Cohort (REPRO_PL). The micronutrient levels were measured in each trimester of pregnancy, at delivery and in the cord blood. Psychomotor development was assessed in children at the age of 1 and 2 years using the Bayley Scales of Infant and Toddler Development. The mean plasma Zn, Cu and Se concentrations in the 1st trimester of pregnancy were 0.91+/ 0.27mg/l, 1.98+/-0.57mg/l and 48.35+/-10.54MUg/l, respectively. There were no statistically significant associations between Cu levels and any of the analyzed domains of child development. A positive association was observed between Se level in the 1st trimester of pregnancy and child language and motor skills (beta=0.18, p=0.03 and beta=0.25, p=0.005, respectively) at one year of age. Motor score among one-year-old children decreased along with increasing Zn levels in the 1st trimester of pregnancy and in the cord blood (beta=-12.07, p=0.003 and beta=-6.51, p=0.03, respectively). A similar pattern was observed for the association between Zn level in the 1st trimester of pregnancy and language abilities at one year of age (beta=-7.37, p=0.05). Prenatal Zn and Se status was associated with lower and higher child psychomotor abilities, respectively, within the first year of life. Further epidemiological and preclinical studies are necessary to confirm the associations between micronutrient levels and child development as well as to elucidate the underlying mechanisms of their effects. PMID- 28715786 TI - Background lead and mercury exposures: Psychological and behavioral problems in children. AB - BACKGROUND: The potential harm from exposure to nonessential metals, particularly mercury (Hg) and lead (Pb), has been the focus of research for years. Initial interest focused on relatively high exposures; however, recent evidence suggests that even background exposures might have adverse consequences for child development. Identifying the extent of these consequences is now a priority. METHODS: We assessed blood Pb and Hg levels in a biracial sample of 9-11 year-old children (N = 203). Neurodevelopment and psychological functioning assessments included hostility, disruptive behaviors, emotion regulation, and autism spectrum disorder behaviors. Parasympathetic (vagal) responses to acute stress were indexed by heart rate variability (HRV) at rest and during stress. RESULTS: With increasing Pb levels, children exhibit higher levels of hostile distrust and oppositional defiant behaviors, were more dissatisfied and uncertain about their emotions, and had difficulties with communication. These significant associations were found within a range of blood Pb levels from 0.19 to 3.25MUg/dL, well below the "reference value" for children of >5MUg/dL. Vagal reactivity interacted with Hg such that increasing Hg was associated with increasing autism spectrum behaviors for those children with sustained vagal tone during acute stress. CONCLUSIONS: This study is the first to demonstrate an association between very low-level Pb exposure and fundamental psychological mechanisms that might explain prior associations with more complex outcomes such as delinquency. Analyses of vagal reactivity yielded entirely novel associations suggesting that Hg may increase autism spectrum behaviors in children with sustained vagal tone during acute stress. The novelty of these later findings requires additional research for confirmation and the cross-sectional nature of the data caution against assumptions of causality without further research. PMID- 28715788 TI - Smoke-free homes and attitudes towards banning smoking in vehicles carrying children in Spain (2016). AB - OBJECTIVE: To describe the voluntary adoption of smoke-free homes and social attitudes in Spain towards banning smoking in vehicles in which children are present. METHODS: Cross-sectional study of a representative sample of the adult Spanish population age range, 18-75 years (n=1036). The field work was conducted via a computer-assisted telephone survey in March and April 2016. Survey respondents answered questions about smoking rules at home and attitudes towards a smoking ban in cars with or without children. Home smoking rules were defined as complete (smoking not allowed anywhere in the house), partial (smoking allowed in some areas inside the house) or absent (smoking allowed everywhere). RESULTS: Most (83.0%) of the surveyed population had some type of smoking restriction in place at home (45.6% complete and 37.5% partial). There were significant differences between groups according to age group (the highest prevalence was 86.1% from 66 to 75 years and the lowest prevalence was 77.8% from 46 to 65 years) and smoking status (the highest prevalence was 89.4% in people who had never been smokers and the lowest prevalence was 75.0% in current smokers) with regards to the prevalence of smoke-free homes (p<0.05), with partial bans more prevalent in smoking households (49.0%). Most (61.6%) of the population favored banning smoking in cars, and 90.1% supported a ban in cars carrying minors. Attitudes towards smoking regulation in cars (with or without children) varied significantly by age group (the highest prevalence was 81.9% from 66 to 75 years and the lowest prevalence was 54.5% from 18 to 45 years) and smoking status (the highest prevalence was 71.4% in people who had never been smokers and the lowest prevalence was 46.0% in current smokers). However, no significant differences were found with regard to attitudes towards smoking regulation in cars carrying children, regardless of sex, age, social class, or smoking status. CONCLUSION: Approximately half of the adult population in Spain have implemented a complete smoke-free rule at home. More than 9 out of 10 adults favor regulating smoking in cars in the presence of minors. These findings support the expansion of smoke free regulations to include private vehicles, particularly when minors are in the car. PMID- 28715789 TI - Quantification of IDP-73152, a novel antibiotic, in plasma from mice, rats and humans using an ultra-high performance liquid chromatography/tandem mass spectrometry method for use in pharmacokinetic studies. AB - IDP-73152, a novel inhibitor of a bacterial peptide deformylase, was recently approved as a new, investigational drug in Korea for the clinical management of infections caused by Gram positive bacteria. The objective of this study was to develop/validate a simple and robust analytical method for the determination of IDP-73152 in plasma samples from rodents and humans, and to assess the feasibility of the assay for use in pharmacokinetic studies using animal models. Plasma samples were processed using a standard method for protein precipitation and an aliquot of the extract then injected onto an UHPLC-MS/MS system. The drug and IDP-117293, an internal standard, were analyzed in the positive ion-mode by electrospray ionization and quantified by monitoring the transition at m/z 555.2 >245.2 for IDP-73152 and 563.3->253.1 for the internal standard, respectively. The lower and upper limit of the assay was determined to be 5 and 10000ng/ml, respectively, with an acceptable linearity (R>0.999) in the response concentration relationship. Validation parameters, including accuracy, precision, dilution, recovery, matrix effect and stability were found to be within the acceptable ranges recommended by the assay validation guidelines of the United States FDA. The method was successfully applied to the quantification of IDP 73152 in plasma from mice/rats that had received a single oral administration of 80mg/kg IDP-73152, in the form of the mesylate salt. These findings suggest that the validated assay can be used in preclinical and clinical pharmacokinetic studies of IDP-73152. PMID- 28715790 TI - Site- and species-specific hydrolysis rates of cocaine. AB - The hydroxide-catalyzed non-enzymatic hydrolysis of cocaine is quantified in terms of ten site- and species-specific rate constants in connection with also ten site- and species-specific acid-base equilibrium constants, comprising all the twelve coexisting species in solution. This characterization involves the major and minor decomposition pathways via benzoylecgonine and ecgonine methyl ester, respectively, leading to ecgonine, the final product. Hydrolysis has been found to be 10-330 times faster at site 2 than at site 3, depending on the ionization status of the amino moiety and the rest of the molecule. Nitrogen protonation accelerates the hydrolyses approximately ten times both at site 2 and site 3. PMID- 28715791 TI - New approach for the diagnosis of histamine intolerance based on the determination of histamine and methylhistamine in urine. AB - Histamine intolerance is a disorder in the homeostasis of histamine due to a reduced intestinal degradation of this amine, mainly caused by diamine oxidase (DAO) enzyme deficiency, which provokes its accumulation in plasma and the appearance of adverse health affects. A new approach for the diagnosis of this intolerance could be the determination of histamine and its metabolites in urine. The aim of this work was to develop and validate a rapid method to determine histamine and methylhistamine in human urine by Ultra High Performance Liquid Chromatography and Fluorimetric detection (UHPLC-FL). The proposed method is a consistent procedure to determine histamine and methylhistamine in less than 11min with adequate linearity and sensitivity. Relative standard deviation was always lower than 5.5%, ensuring method precision; and mean recovery was greater than 99% for both analytes. The structure of histamine and methylhistamine conjugated with OPA were confirmed by UHPLC-ITD-FTMS which enabled to unequivocally identify both analytes in standards and also in urine samples. The analysis of histamine and methylhistamine in urine samples could be a potential new approach for the routine diagnosis of histamine intolerance, more patient friendly and with clear advantages in terms of equipment and personnel demand for sample collection in comparison with current plasmatic DAO activity determination. PMID- 28715792 TI - Smartphone-based cyclic voltammetry system with graphene modified screen printed electrodes for glucose detection. AB - Smartphone-based electrochemical devices have such advantages as the low price, miniaturization, and obtaining the real-time data. As a popular electrochemical method, cyclic voltammetry (CV) has shown its great practicability for quantitative detection and electrodes modification. In this study, a smartphone based CV system with a simple method of electrode modification was constructed to perform electrochemical detections. The system was composed of these main portions: modified electrodes, portable electrochemical detector and smartphone. Among them, the detector was comprised of an energy transformation module applying the stimuli signals, and a low-cost potentiostat module for CV measurements with a Bluetooth module for transmitting data and commands. With an Application (App), the smartphone was used as the controller and displayer of the system. Through controlling of different scan rates, the smartphone-based system could perform CV detections for redox couples with test errors less than 3.8% compared to that of commercial electrochemical workstation. Also, the reduced graphene oxide (rGO) and sensitive substance could be modified by the system on the screen printed electrodes for detections. As a demonstration, 3-amino phenylboronic acid (APBA) was used as the sensitive substance to fabricate a glucose sensor. Finally, the experimental data of the system were shown the linear, sensitive, and specific responses to glucose at different doses, even in blood serum as low as about 0.026mM with 3delta/slope calculation. Thus, the system could show great potentials of detection and modification of electrodes in various fields, such as public health, water monitoring, and food quality. PMID- 28715793 TI - Monitoring in vivo metabolic flux with a designed whole-cell metabolite biosensor of shikimic acid. AB - Knowledge of intracellular metabolite levels is important for the understanding of metabolic flux distributions. Whole-cell biosensors of key metabolites are ideal for the monitoring of carbon flow in important metabolic pathways, thus guiding metabolic engineering for microbial improvement. However, lack of biosensors for metabolites of interests has limited their applications. In this study, a genetically encoded whole-cell biosensor specifically responding to shikimic acid has been developed by screening a site-saturation mutagenesis library of the binding pocket of a uric acid-responsive regulatory protein. This biosensor has been successfully applied in analyzing and engineering metabolic flux in the shikimic acid pathway, through genome-wide screening of gene targets critical for the pathway flux, and by improving the specific activity of pathway key enzyme, AroG. This work demonstrates the feasibility of monitoring metabolic flux with the aid of whole-cell biosensors designed for key metabolites. PMID- 28715794 TI - An introduction to the Emergency Department Adult Clinical Escalation protocol: ED-ACE. AB - PURPOSE OF THE STUDY: This study demonstrates how a participatory action research approach was used to address the challenge of the early and effective detection of the deteriorating patient in the ED setting. The approach enabled a systematic approach to patient monitoring and escalation of care to be developed to address the wide-ranging spectrum of undifferentiated presentations and the phases of ED care from triage to patient admission. This paper presents a longitudinal patient monitoring system, which aims to provide monitoring and escalation of care, where necessary, of adult patients from triage to admission to hospital in a manner that is feasible in the unique ED environment. METHODS: An action research approach was taken to designing a longitudinal patient monitoring system appropriate for the ED. While the first draft protocol for post-triage monitoring and escalation was designed by a core research group, six clinical sites were included in iterative cycles of planning, action, reviewing and further planning. Reasons for refining the system at each site were collated and the protocol was adjusted accordingly before commencing the process at the next site. RESULTS: The ED Adult Clinical Escalation longitudinal patient monitoring system (ED-ACE) evolved through iterative cycles of design and testing to include: (1) a monitoring chart for adult patients; (2) a standardised approach to the monitoring and reassessment of patients after triage until they are assessed by a clinician; (3) the ISBAR (I=Identify, S=Situation, B=Background, A=Assessment, R=Recommendation) tool for interprofessional communication relating to clinical escalation; (4) a template for prescribing a patient-specific monitoring plan to be used by treating clinicians to guide patient monitoring from the time the patient is assessed until when they leave the ED and (5) a protocol for clinical escalation prompted by single physiological triggers and clinical concern. CONCLUSIONS: This tool offers a link in the 'Chain of Prevention' between the Manchester Triage System and ward-based early warning scores taking account of the importance of standardisation, while being sufficiently adaptable for the unique working environment and patient population in the ED. PMID- 28715795 TI - Recycling and social technologies for sustainability: The Brazilian experience of wastepickers' inclusion in selective collection programs. AB - BACKGROUND: Alternatives are being developed for waste treatment all over the world. Solidary selective collection is a recognized social technology for taking millions of people out of absolute poverty. However, this technology raises crucial questions regarding its nature and development perspective. What can be said of the legitimacy of a social technology that is born from misery and maintains wastepickers in precarious work conditions? OBJECTIVE: This article approaches issues based on the analysis of the wastepickers' work process, highlighting the difficulties and interpersonal conflicts, the strong social bonds and creativity that reveal the potential of efficiency and solidarity of this social technology. METHODS: The analyses are founded on empirical descriptions of work situations and organizational arrangements that the wastepickers themselves have developed. The observations were made during the work, followed by interviews focused on significant events and behaviors. RESULTS: The contradiction between efficiency and solidarity, which excludes workers from the formal labor market, finds in the associations a solution for people with different capacities. This social technology offers much more than simple survival or exoticism. The wastepickers create a sustainable mode of production, putting together economic, social and environmental criteria in an innovative and fair production technology. PMID- 28715796 TI - Application of Long Noncoding RNAs in Osteosarcoma: Biomarkers and Therapeutic Targets. AB - Osteosarcoma is the most common primary bone malignancy in children and adolescents. Although improvements in therapeutic strategies were achieved, the outcome remains poor for most patients with metastatic or recurrent osteosarcoma. Therefore, it is imperative to identify novel and effective prognostic biomarker and therapeutic targets for the disease. Long noncoding RNAs (lncRNAs) are a novel class of RNA molecules defined as transcripts >200 nucleotides that lack protein coding potential. Many lncRNAs are deregulated in cancer and are important regulators for malignancies. Nine lncRNAs (91H, BCAR4, FGFR3-AS1, HIF2PUT, HOTTIP, HULC, MALAT-1, TUG1, UCA1) are upregulated and considered oncogenic for osteosarcoma. Loc285194 and MEG3 are two lncRNAs downregulated and as tumor suppressor for the disease. Moreover, the expressions of LINC00161 and ODRUL are associated with chemo-resistance of osteosarcoma. The mechanisms for these lncRNAs in regulating development of osteosarcoma are diverse, e.g. ceRNA, Wnt/beta-catenin pathway, etc. The lncRNAs identified may serve as potential biomarkers or therapeutic targets for osteosarcoma. PMID- 28715797 TI - Neurodevelopment at 3 Years in Neonates Born by Vaginal Delivery versus Cesarean Section at <26 Weeks of Gestation: Retrospective Analysis of a Nationwide Registry in Japan. AB - BACKGROUND: A high proportion of extremely preterm (EPT) infants are born by cesarean section (CS). However, whether the mode of delivery is related to long term neurodevelopment in these infants is unclear. OBJECTIVES: This study aimed to determine whether the mode of delivery is associated with mortality and long term outcomes in EPT infants. METHODS: We analyzed data of the Neonatal Research Network in Japan (NRNJ), a population-based, nationwide registry. Inclusion criteria were neonates who were born between 2003 and 2012 with a gestational age <26 weeks. The primary composite outcome was death before 3 years or neurodevelopmental impairment (NDI) at 3 years. Confounder-adjusted odds ratios (OR) were estimated by logistic generalized linear mixed models, which accounted for clustering within hospitals. RESULTS: 2,138 eligible infants (703 by vaginal delivery [VD] and 1,435 by CS) were identified for primary analysis. The composite outcome of death or NDI was not different between both groups (66.7% by VD and 62.7% by CS, p = 0.075). After multivariate analysis adjusting for confounders, we found that CS did not improve the composite outcome of death or NDI (OR = 0.839, 95% confidence interval = 0.816-1.328, p = 0.742). For secondary outcomes, mortality (OR = 0.824, p = 0.150), NDI (OR = 1.237, p = 0.165), and other neurodevelopmental outcomes were not different between the groups. CONCLUSIONS: Among neonates born at <26 weeks, CS does not improve mortality and neurodevelopmental outcomes at 3 years in the NRNJ cohort. However, because of several potential biases such as high rates of infants lost to follow-up, further evidence may be required. PMID- 28715798 TI - Bone Mineral Density in Women Living with Complete Androgen Insensitivity Syndrome and Intact Testes or Removed Gonads. AB - Complete androgen insensitivity syndrome (CAIS) is due to complete androgen resistance in androgen-dependent tissues. Since androgens are involved in growth, development, and mass maintenance of the skeleton, bone health may be a relevant clinical issue for improving quality of life of women living with CAIS. Bone mineral density (BMD) in women with CAIS and intact gonads has been reported in a normal range, although exceptions are known showing a low BMD mainly at the lumbar level. In women with CAIS and removed gonads, BMD is usually reduced at both the lumbar spine and femoral neck. However, the fracture risk remains largely unknown. In women with CAIS, hormonal replacement therapy may improve BMD, but it does not normalize it. Several factors may be operative (e.g., loss of AR signaling at the bone level, gonadal removal, and age at surgery [before or after attainment of the peak bone mass], inadequate sex steroid replacement therapy, poor compliance with hormonal treatment, high serum FSH levels, lack of testicular protein hormones after gonadal removal), but they are poorly evaluated. In conclusion, the maintenance of testes may represent a strategy to improve bone health in women with CAIS, but a strict follow-up to monitor the cancer risk is mandatory mainly from their 20s onwards. Optimal sex steroid substitutive therapy in adolescence and adulthood is a key factor to improve BMD status in women with CAIS and removed gonads, but conclusive data on optimal management are lacking. PMID- 28715799 TI - Resident Arterial Cells and Circulating Bone Marrow-Derived Cells both Contribute to Intimal Hyperplasia in a Rat Allograft Carotid Transplantation Model. AB - BACKGROUND/AIMS: Neointimal formation following vascular injury remains a major mechanism of restenosis, whereas the precise sources of neointimal cells are still uncertain. We tested the hypothesis that both injured arterial cells and non-arterial cells contribute to intimal hyperplasia. METHODS: Following allograft transplantation of the balloon-injured carotid common artery (n = 3-6), the cellular composition of the transplant grafts and the origins of neointimal cells were measured by immunohistochemistry and immunofluorescence staining. RESULTS: Smooth muscle actin (SMA)-positive and CD68-positive cells were clearly observed 14 days later in the neointima after allograft transplantation of the balloon-injured carotid common artery, where re-endothelialization was not yet complete. Green fluorescent protein (GFP) and wild-type (WT) allograft transplantation revealed that the majority of the neointima cells were apparently from the recipient (~85%) versus the donor (~15%). Both monocyte chemotactic protein-1 (MCP-1)/CCR2 and stromal cell-derived factor-1 (SDF-1)/CXCR4 signaling were involved in intimal hyperplasia, with bone marrow-derived cells also playing a role. CONCLUSION: These data support the hypothesis that intimal hyperplasia could develop in our novel rat allograft transplantation model of arterial injury, where neointima is attributable not only to local arterial cells but also non-arterial cells including the bone marrow. PMID- 28715800 TI - The Efficacy of Dienogest in the Treatment of Simple Endometrial Hyperplasia without Atypia. AB - AIM: The aim of the study was to compare the effectiveness of dienogest (DIE), depo medroxyprogesterone 17-acetate (MPA), and micronized progesteron (MP) regimens for treatment of simple endometrial hyperplasia (EH) without atypia. METHODS: One hundred and twenty premenopausal patients aged between 35 and 55, with simple EH without atypia, were offered 3 types of progestins (MPA, MP, and DIE) and were randomized to one of them. After 6 months of treatment, patients were reevaluated. The efficacy of different progestins in treatment of EH was compared with regard to resolution and regression rates. We classified the terms of resolution and regression as "complete response" and persistence as "no response". RESULTS: A total of 99 patients continued the study (31 in MP, 35 in MPA, and 33 in the DIE group). None of the results of endometrial pathology were progressed to atypia or complex hyperplasia. The complete response resolution rate was 93.5% in the MP, 88.5% in the MPA, and 96.9% in the DIE group. The highest complete response rate was in the DIE group, although there was no statistically significant difference between groups (p = 0.39). The efficacy of progestins was similar between the groups. CONCLUSION: DIE is an effective and convenient method for thinning the endometrium. PMID- 28715801 TI - Fetal Urine Production Rate in Preterm Premature Rupture of Membranes Is Associated with Adverse Neonatal Outcome: A Pilot Study. AB - AIM: In this study, we evaluate the associations between fetal urinary production rate (FUPR), measured by ultrasound, and adverse neonatal outcome in women with preterm premature rupture of membranes (PPROM). METHODS: We conducted a prospective pilot cohort of singleton pregnancies complicated by PPROM occurring at gestational week 24 or later managed until spontaneous labor (after 48 h of admission), chorioamnionitis, or induction by protocol at 35 + 0 weeks. FUPR was evaluated by 2D sonography at admission (corrected for gestational age). The main neonatal outcome measures were chorioamnionitis, placental inflammatory grading, first neonatal creatinine value, first neonatal dextrose value, length of neonatal intensive care unit (NICU) stay, necrotizing enterocolitis (NEC), intraventricular hemorrhage (IVH) (grades I-IV), blood transfusions, reduced neonatal urine production rate (<4 mL/kg/h), and early neonatal sepsis. Samples of maternal (at admission) and umbilical cord blood were analyzed for interleukin 6 (IL-6) level. RESULTS: The study included 38 women. Low FUPR was associated with clinical chorioamnionitis, longer NICU hospitalization (p = 0.01), higher rates of NEC or IVH (p = 0.008), and blood transfusion (p = 0.004). CONCLUSIONS: A finding of FUPR on in utero ultrasound examination in pregnancies complicated by PPROM may be indicative of adverse neonatal outcome. PMID- 28715802 TI - Nerve/Glial Antigen 2: A Novel Target for Anti-Tumor Therapy in Colorectal Cancer. AB - BACKGROUND/AIMS: To identify cell surface markers selectively expressed by tumor cells and tumor vasculature is the current goal for tumor therapy. One such marker is nerve/glial antigen 2 (NG2), which is a transmembrane glycoprotein. We aimed to investigate the expression of NG2 in colorectal cancer (CRC) and its association with clinicopathological parameters. METHODS: Immunohistochemical staining of NG2, vascular endothelial growth factor, and CD34 in 65 patients diagnosed with CRC over a 5-year period was performed. NG2 expression in both tumor cells and tumor vasculature was scored according to the German Reactive Scoring System. The association between NG2 and patient and tumor characteristics was analyzed. RESULTS: NG2 was expressed by tumor cells in 56.9%, tumor vasculature in 43%, and simultaneously by both in 27.6% of the cases. Tumor cell NG2 was more common in elderly patients (p = 0.023) and vascular NG2 was associated with better tumor differentiation (p = 0.035). Notably, vascular NG2 was expressed in half of the patients with left colon cancer, although it was not expressed in a majority of those with right colon cancer (50.9 vs. 17.7%, p = 0.041). CONCLUSION: Both tumor cell and vascular NG2 expression were shown to be present in a significant number of patients with CRC and this makes NG2 a double target for anti-tumor therapies. Such therapies might be more effective for elderly patients with well-differentiated left colon cancer. PMID- 28715803 TI - Antinociceptive Effects of Isosakuranetin in a Rat Model of Peripheral Neuropathy. AB - Chronic pain remains a challenging clinical reality, yet currently available analgesics are insufficient to meet clinical needs. Increasing attention has been paid to bioactive compounds from natural plants, which may be efficacious against pain. This study examined the antinociceptive effects of isosakuranetin, a plant derived transient receptor potential melastatin 3 blocker, in a rat model of peripheral neuropathy. Adult male Sprague-Dawley rats were first allowed to go through the chronic constriction injury surgery to develop neuropathic pain. They were then treated with isosakuranetin (1.5, 3, or 6 mg/kg) intraperitoneally and the effects on mechanical, thermal, and cold hyperalgesia were assessed using the von Frey filament test, Hargreaves' plantar test, and cold plate test, respectively. Isosakuranetin dose-dependently alleviated mechanical, thermal, and cold hyperalgesia and the antinociceptive potency was similar across the assays. In the rotarod test, isosakuranetin did not significantly affect motor performance within the doses tested, confirming the antinociceptive specificity. In summary, these findings suggest that isosakuranetin may be useful in treating neuropathic pain and deserves further investigation. PMID- 28715804 TI - Oligopeptide Transporters of the SLC15 Family Are Dispensable for Peptidoglycan Sensing and Transport in Drosophila. AB - Peptidoglycan (PGN) detection by PGN recognition proteins (PGRP) is the main trigger of the antibacterial immune response in Drosophila. Depending on the type of immune cell, PGN can be sensed either at the cell membrane by PGRP-LC or inside the cell by PGRP-LE, which plays a role similar to that of Nod2 in mammals. Previous work, mainly in cell cultures, has shown that oligopeptide transporters of the SLC15 family are essential for the delivery of PGN for Nod2 detection inside of the cells, and that this function might be conserved in flies. By generating and analyzing the immune phenotypes of loss-of-function mutations in 3 SLC15 Drosophila family members, we tested their role in mediating PGRP-LE-dependent PGN activation. Our results show that Yin, CG2930, and CG9444 are required neither for PGRP-LE activation by PGN nor for PGN transport from the gut lumen to the insect blood. These data show that, while intracellular PGN detection is an essential step of the antibacterial response in both insects and mammals, the types of PGN transporters and sensors are different in these animals. PMID- 28715805 TI - An Alternative Promoter in Intron1 of the Renin Gene is Regulated by Glucose Starvation via Serum Response Factor. AB - BACKGROUND/AIMS: Renin is known as a secretory glycoprotein that ultimately leads to angiotensin II generation. In this way renin exerts pro-inflammatory effects and promotes cardiac injury. Additional transcripts have been identified encoding for a cytosolic renin isoform that - in contrast to secretory renin - exhibits cardioprotective effects under ischemic conditions. The promoter of these transcripts is unknown. METHODS: Using qRT-PCR and dual-luciferase reporter assay we examined the expression and promotor activity of cytosolic renin as well as the regulation by glucose starvation in H9c2 cardiomyoblasts. RESULTS: We identified a promoter in intron1 of the rat renin gene with two glucose starvation-sensitive regions. One region contains a binding motif for serum response factor (SRF). Under glucose depletion expression of SRF increased prior to cytosolic renin. SRF knock down selectively decreased cytosolic renin expression and attenuated the increase of cytosolic renin expression under glucose depletion. CONCLUSIONS: Transcripts encoding for secretory and cytosolic renin are differentially expressed. The low basal expression of cytosolic renin as well as its induction under ischemia-related conditions represents an efficient system regulated in accordance with its previously identified unfavorable effects under control situations but protective effects seen after myocardial infarction or glucose depletion. PMID- 28715806 TI - Real-Time Volume Contrast Imaging in the A Plane with a Four-Dimensional Electronic Probe Facilitates the Evaluation of Fetal Extremities in Midtrimester Sonograms. AB - OBJECTIVE: To evaluate the efficiency of real-time volume contrast imaging in the A plane (VCI-A) of fetal extremities, compared with conventional two-dimensional ultrasound (2D). METHODS: This was a randomized controlled trial of 100 patients undergoing midtrimester sonography. The fetal limbs were imaged with either 2D or VCI-A with a four-dimensional (4D) electronic probe. Time required for the examination, number of images stored, and quality of the documentation were compared. During the study, 6 fetuses with abnormal extremities were scanned with both 2D and VCI-A, and the diagnostic accuracy and quality of the images were also compared. RESULTS: In the VCI-A group, the fetal extremities were imaged more rapidly (2.3 +/- 1.1 vs. 3.3 +/- 0.9 min, p < 0.0001), less images were required to document the examination (5.6 +/- 1.4 vs. 7.3 +/- 1.6), and an optimal documentation was more frequently obtained (84 vs. 54%, p < 0.0001) compared with the 2D group. In malformed fetuses, a precise diagnosis was achieved with both techniques, although images obtained with VCI-A were found to be of superior quality. CONCLUSIONS: Real-time VCI-A with a 4D electronic probe is an effective tool for imaging the fetal extremities in midtrimester examinations and carries some advantages over conventional 2D sonography. PMID- 28715807 TI - Amniotic Fluid Angiogenic and Inflammatory Factor Profiling in Foetal Down Syndrome. AB - OBJECTIVES: Angiogenic factors are proteins that can potentially be related to certain foetal chromosomal abnormalities. The goal of this study was to determine the concentrations of 60 angiogenic factors in the amniotic fluid of women carrying foetuses with Down syndrome (DS). METHODS: After analysis of the karyotyping results, for the purpose of this study, we chose 12 women with foetal DS. For the control group, we selected 12 healthy patients with uncomplicated pregnancies (15-18 weeks of gestation) who delivered healthy newborns at term. To assess the concentrations of proteins in the amniotic fluid, we used a protein macroarray, which enabled the simultaneous determination of 60 angiogenic factors per sample. RESULTS: In the amniotic fluid of women with foetal DS compared to patients with healthy foetuses, we reported significant decreases in the concentrations of 14 angiogenic factors, including leptin, angiopoietin 1 (ANG 1), angiostatin, epidermal growth factor (EGF), interleukin 1-beta (IL-1b), interleukin 4 (IL-4), interleukin 12p40 (IL-12p40), monocyte chemotactic protein 2 (MCP-2), matrix metalloproteinase-1 (MMP-1), matrix metalloproteinase-9 (MMP 9), platelet endothelial cell adhesion molecule 1 (PECAM-1), transforming growth factor alpha (TGF alpha), vascular endothelial growth factor 2 (VEGFR2), and vascular endothelial growth factor 3 (VEGFR3). CONCLUSIONS: Based on our findings, we hypothesise that angiogenic factors may play roles in the pathogenesis of DS. Defining the factors' potential as biochemical factors of DS requires further investigation in a larger group of patients. PMID- 28715808 TI - Retinoic Acid Facilitates Toll-Like Receptor 4 Expression to Improve Intestinal Barrier Function through Retinoic Acid Receptor Beta. AB - BACKGROUND/AIMS: Vitamin A (VA) protects the intestinal epithelial barrier by improving cell migration and proliferation. Our previous studies demonstrated that VA deficiency (VAD) during pregnancy suppresses the systemic and mucosal immune responses in the intestines of offspring and that VA supplementation (VAS) during early life can increase immune cell counts. However, little is known about the mechanisms by which VA regulates intestinal epithelial barrier function. METHODS: Caco-2 cells were treated with all-trans retinoic acid (ATRA) for 24 hours to determine the optimum ATRA concentration to which the cells in question respond. Caco-2 cells were infected with recombinant adenoviruses carrying retinoic acid receptor beta (Ad-RARbeta) and small interfering RARbeta(siRARbeta) to assess the effects of RARbeta signalling on the expression of specific proteins. A siTLR4 lentivirus was used to knockdown Toll-like receptor 4 (TLR4) in Caco-2 cells to determine its role in the protective effects of VA on the intestinal epithelial barrier, and experiments involving TLR4-knock-out mice were performed to verify the effect of TLR4. VA normal (VAN), VAD and VAS rat models were established to confirm that changes in RARbeta, TLR4 and ZO-2 expression levels that occurred following decreases or increases in retinol concentrations in vivo, and the permeability of the Caco-2 cell monolayer, as well as that of the epithelial barrier of the rat intestine was detected by measuring transepithelial resistance (TER) or performing enzyme-linked immunosorbent assay (ELISA). Retinoic acid receptor (RAR), toll like receptor (TLR) and tight junction (TJ) mRNA and protein expression levels in Caco-2 cells and the colon monolayers in the rat and mouse models were measured by PCR and western blotting, respectively. Co-immunoprecipitation (co-IP) and immunofluorescence staining were performed to assess the interactions among RARbeta, TLR4 and zonula occluden-2 (ZO-2) in Caco-2 cells, and chromatin immunoprecipitation (ChIP) assay was performed to assess the binding between RARbeta and the TLR4 promoter sequence in Caco-2 cells. RESULTS: In the present study, ATRA treatment not only increased the TER of the Caco-2 monolayer but also up-regulated the expression levels of RARbeta, TLR4 and ZO-2 in Caco-2 cells. The expression levels of these three proteins were significantly decreased in the colonic epithelial monolayers of VAD rats compared with those of VAN rats and were significantly increased following VAS in the corresponding group compared with the control group. Furthermore, the above changes in TLR4 and ZO-2 expression levels were augmented or attenuated by Ad-RARbeta or siRARbeta infection, respectively, in Caco-2 cells. Interestingly, siTLR4 down-regulated ZO-2 expression but did not affect RARbeta expression in Caco-2 cells, and in VAD mice the lack of TLR4 did not affect ZO-2 expression. We noted direct interactions between RARbeta and TLR4, TLR4 and ZO-2 in Caco-2 cells, and ChIP assay showed that RARbeta could bind to the TLR4 promoter but not the ZO-2 promoter in Caco-2 cells. CONCLUSION: Taken together, our results indicate that RARbeta enhanced ZO-2 expression by regulating TLR4 to improve intestinal epithelial barrier function in Caco-2 cells, as well as in rat and mouse models, but not in humans. PMID- 28715809 TI - Thyroid Surgery: To Drain or Not to Drain, That Is the Problem - A Randomized Clinical Trial. AB - PURPOSE: We conducted a prospective, randomized study to evaluate the necessity of drainage after thyroid surgery. METHODS: The patients (n = 215) were randomly assigned to be treated with suction drains (group 1; n = 108) or not (group 2; n = 107). RESULTS: The postoperative pain scores were significantly lower in the non-drained group than in the drained group of patients at postoperative days 0 and at 1. Hematomas, seromas, wound infections, transient biochemical hypoparathyroidism, and transient damage of the recurrent laryngeal nerve occurred more frequently in the drained group than in the non-drained group. The mean hospital stay was significantly shorter in the non-drained group than in the drained group. CONCLUSIONS: Routine drain emplacement after thyroidectomy is unnecessary. PMID- 28715810 TI - Population Pharmacokinetics of Diazoxide in Children with Hyperinsulinemic Hypoglycemia. AB - BACKGROUND: Diazoxide is the first-line treatment for pediatric hyperinsulinemic hypoglycemia (HI). This study aimed to elucidate the pharmacokinetics of diazoxide in children with HI. METHODS: We obtained 81 blood samples from 22 children with HI. Measured serum diazoxide concentrations were used for population pharmacokinetic analysis. Patient factors influencing pharmacokinetics were estimated using nonlinear mixed-effects model analysis. Relationships between drug exposure and adverse drug reactions were also investigated. RESULTS: Diazoxide disposition in the body was described by a 1-compartment model. Oral clearance (CL/F) and the volume of distribution were proportional to body weight (WT), as expressed by CL/F in males (liters/h) = 0.0358 + 0.00374 * WT (kg). CL/F in females was 39% greater than that in males. Steady-state concentrations of diazoxide were similar following twice- and 3 times-daily dosing when the total daily doses were comparable. A patient whose serum diazoxide concentration exceeded 100 MUg/mL over a 4-month period developed hyperglycemia. No significant correlation was observed between severity of hirsutism and diazoxide concentration. CONCLUSION: We have proposed for the first time a population pharmacokinetic model for diazoxide in children with HI. The potential risk of diabetes mellitus and/or hyperglycemia increases when serum concentrations of diazoxide exceed 100 MUg/mL. PMID- 28715811 TI - Early Response to Ranibizumab Is Associated with 12-Month Outcome in Diabetic Macular Edema after Prior Macular Laser Therapy. AB - PURPOSE: To evaluate the efficacy of ranibizumab in persistent or recurrent diabetic macular edema (DME) after previous laser therapy. METHODS: This prospective, interventional study consisted of a 3-month period of scheduled ranibizumab treatment followed by a 9-month period of pro re nata treatment. RESULTS: A total of 21 eyes (18 patients) were included. Both best corrected visual acuity and central retinal thickness had statistically significantly improved from baseline at month 12 (p < 0.001). The mean number of injections within these 12 months was 7.8 +/- 2.6 (range 3-11). The visual change at month 12 did not vary by more than 5 letters from the response observed at week 12. CONCLUSIONS: Our study showed a beneficial effect from ranibizumab in DME patients previously treated with macular laser therapy. The response at week 12 was sustained up to 1 year. A suboptimal early visual response may predict a long term suboptimal response and help identify patients who would benefit from an alternative regimen. PMID- 28715812 TI - Free Fatty Acid Is Associated with Thrombogenicity in Cardioembolic Stroke. AB - BACKGROUND: Recently, the role of free fatty acids (FFAs) in thromboembolism has re-emerged in the context of cardioembolic stroke. Therefore, we attempted to determine the role of FFAs in embolic risk in various potential sources of cardioembolism (PSCE). We hypothesized that if elevated FFA levels in stroke patients are associated with thrombogenesis, then patients with a well-known high risk of embolic sources would have high FFA levels. METHODS: Data collected from 2 hospital-based stroke registries were analyzed to investigate the association between FFA and PSCE. RESULTS: A total of 2,770 acute stroke patients, including 539 with cardioembolic stroke, were selected for analysis. FFA was an independent predictor for cardioembolism (OR 2.755, 95% CI 2.221-3.417, p < 0.001). Among the PSCE, FFA levels were significantly associated with high risk of atrial fibrillation (AF), valvular heart disease, congestive heart failure with low ejection fraction, left atrial thrombus, left ventricular thrombus, left atrial smoke, and ventricular wall motion abnormality. FFA levels increased with the number of PSCE per patient without interaction with the presence of AF. CONCLUSIONS: Among acute stroke patients, FFA levels increased in groups with higher risk of cardioembolic stroke irrespective of the presence of AF. These results suggest that enhanced thrombogenicity could be the main mechanism to explain the elevated FFA levels in patients with cardioembolic stroke. PMID- 28715813 TI - Efficacy of the Perfluoro-N-Octane-Assisted Single-Layered Inverted Internal Limiting Membrane Flap Technique for Large Macular Holes. AB - PURPOSE: The aim of this study was to evaluate the efficacy of the perfluoro-n octane-assisted single-layered inverted internal limiting membrane (ILM) flap for large macular holes (MHs). METHODS: We reviewed idiopathic MHs >400 MUm. The patients were divided into ILM peeling (group P, 51 eyes) and ILM flap (group F, 41 eyes). Closure of MHs, best-corrected visual acuity (BCVA), and postoperative optical coherence tomography findings were analyzed. RESULTS: MH closure was achieved in 88.2% in group P and in 100% in group F (p = 0.032). SF6 and air was used most frequently in groups P and F, respectively. Both had a significant improvement in BCVA, which was better in group F until 3 months, but not at 6 months. At 6 months, the ellipsoid zone and external limiting membrane were restored with no significant difference. CONCLUSION: The single-layered inverted ILM flap was better for the closure of large MHs than ILM peeling, without using long-acting gas that prevents early rehabilitation. PMID- 28715815 TI - Thiol Levels and Gastrointestinal Diseases. PMID- 28715814 TI - The Impact of Adolescent Obesity on Adult Height. AB - BACKGROUND: Childhood obesity is a major health concern. Excess adiposity during childhood affects growth and puberty. Our aim was to assess whether genetic adult height is compromised in adolescents with obesity. METHODS: In a retrospective study of 190 obese patients followed at our Pediatric Endocrinology Institute, adult height and delta height (the difference between adult height and mid parental height) were compared to those of 150 healthy age-matched normal-weight controls. Review of medical files yielded the relevant clinical and anthropometric data of patients, controls, and parents. RESULTS: Of the 190 obese adolescents, 150 were morbidly obese. The median adult height of morbidly obese males was 174.3 cm, of obese males 174 cm, and of normal-weight males 176 cm (p = 0.025). Delta height of morbidly obese males was -0.5 cm, of obese males -0.8 cm, and of normal-weight males, 3 cm (p < 0.0001). The median adult height of morbidly obese females was 161.3 cm, of obese females 162.8 cm, and of normal weight females 162 cm (p = 0.37). Delta height of morbidly obese females was 1.85 cm, of obese females -0.95 cm, and of normal-weight females 0.7 cm (p = 0.019). Impairment of potential genetic height was not associated with obesity related comorbidities. CONCLUSION: Adolescents with obesity showed impairment of potential genetic adult height as compared to that of normal-weight subjects. PMID- 28715816 TI - Distinct Dynamics of Mitotic Transition in B-Cell Lymphoma and Reactive B-Cell Lymphoproliferations Determined by H3S10 Phosphohistone Immunolabeling. AB - OBJECTIVES: Clonal selection in the follicular germinal centers in lymphatic tissues is accompanied by an intense proliferation of polyclonal B cells in a precisely regulated fashion. In contrast, B-cell neoplasias proliferate autonomously due to endogenous stimuli. The cell kinetic activity is obvious at many levels including progressive chromatin modification and elevated mitotic rates. We asked if there are differences in the kinetics of histone H3S10 phosphorylation required for mitotic entry between highly proliferating B cells of reactive germinal centers and in B-cell lymphomas with different proliferative capacity. MATERIAL AND METHODS: Phospho-H3 histone (pH3S10)-specific immunohistochemistry was applied to cultivated cell, reactive and selected indolent and aggressive lymphoma samples (diffuse large B-cell lymphoma, Burkitt lymphoma, lymphoblastic lymphoma, follicular lymphoma and small lymphocytic lymphoma). Microscopic quantification of the "dot-type" (representing late G2 phase) and "mitotic" immunolabeling patterns per field of view was performed and compared with classical cell proliferation markers. RESULTS: In addition to the dense homogeneous chromatin labeling highlighting mitotic figures, we stated a selective dot-type nuclear labeling representing ongoing chromatin condensation in premitotic G2 phase cells. While cell proliferation and mitotic counts correlated in general with histology, statistical analysis indicated an accumulation of G2 phase pH3S10 pattern in the reactive germinal centers in contrast to lymphomas. The dot-type G2 staining pattern was surprisingly overrepresented (1,321.7 +/- 356.5/10 HPF) in the reactive germinal centers compared to aggressive lymphomas (101.3 +/- 33.1) (p < 0.005). The relative G2/M value was significantly higher (4.6 +/- 0.6) in reactive germinal center B cells than in any lymphoma entity evaluated (0.7 +/- 0.2 in Burkitt lymphoma, 0.9 +/- 0.4 in grade 3b follicular lymphoma, 1.3 +/- 1.1 in diffuse large B-cell lymphoma, 1.5 +/- 0.6 in lymphoblastic lymphoma, and 0.9 +/- 0.2 in small lymphocytic lymphoma). CONCLUSIONS: pH3S10 immunohistochemistry enabled the presentation of significant differences in the cell cycle kinetics between reactive and neoplastic B-cell lymphoproliferations. Accumulation of G2 phase B cells in reactive folliculi directs to physiological G2/M checkpoint blockade. In contrast, accelerated G2/M transition in lymphomas is potentially associated with impaired genomic repair and cell death mechanisms. PMID- 28715817 TI - AMP010014A09 in Sus Scrofa Encodes an Analog of G Protein-Coupled Receptor 109A, Which Mediates the Anti-Inflammatory Effects of Beta-Hydroxybutyric Acid. AB - BACKGROUND: Hydroxy-carboxylic acid receptor 2 (HCA2, also called GPR109A) belongs to the G protein-coupled receptor (GPCR) family and is found in humans, rats, mice, hamsters and guinea pigs, but there are almost no reports of this protein in other species. In this investigation, we speculated that AMP010014A09 (AMP+) is a homologue of GPR109A in swine. METHODS: To test this hypothesis, the following experiments were designed: monocytes isolated from the peripheral blood of swine were treated with LPS after pretreating with or without beta hydroxybutyric acid (BHBA), and the levels of pro-inflammatory cytokines and inflammatory proteins were assessed. cAMP levels induced by Forskolin in swine testicular (ST) and IPEC-J2 cells were detected with or without BHBA treatment and following silencing or stable transfection of the AMP+ gene. RESULTS: AMP+ in swine exhibited a high level of homology with HM74A in humans and PUMA-G in mice. BHBA inhibited the LPS-induced secretion of the pro-inflammatory cytokines TNF alpha, IL-6 and IL-1beta and the inflammatory protein COX-2 in monocytes of swine. BHBA suppressed the Forskolin-induced cAMP level increase in ST cells, but failed to inhibit the accumulation of cAMP after the AMP+ gene was silenced with shRNA by transfecting cells with the pGPU6-GFP-Neo-AMP+-sus-392 plasmid. BHBA had no effect on cAMP levels in IPEC-J2 cells, but significantly inhibited the increase in cAMP induced by Forskolin treatment following transfection of the AMP+ gene into IPEC-J2 cells by a lentivirus vector. CONCLUSION: Our results indicated that AMP+ encodes a G protein-coupled receptor in Sus scrofa that inhibits cAMP levels and mediates anti-inflammatory effects in swine monocytes. PMID- 28715818 TI - First-Trimester Combined Multimarker Prospective Study for the Detection of Pregnancies at a High Risk of Developing Preeclampsia Using the Fetal Medicine Foundation-Algorithm. AB - OBJECTIVE: To evaluate the Fetal Medicine Foundation (FMF) algorithm prospectively at 11-13 weeks' gestation in the prediction of preeclampsia (PE). METHODS: Single-center prospective screening study for PE of singleton pregnancies at 11-13 weeks. The FMF algorithm takes into account maternal characteristics and biomarkers. Detection rate (DR) for a 10% false-positive rate (FPR) for delivery with preterm and term PE was estimated. RESULTS: Between January 2011 and December 2013, of 3,239 patients available for final analysis, 36 (1.1%) subsequently developed preterm and 44 (1.4%) term PE. In combined screening by maternal factors, mean arterial pressure, uterine artery pulsatility index, and serum placental growth factor, the DR was 80.6% (95% CI 64.0-91.8) for PE at <37 weeks and 31.8% (95% CI 18.6-47.6) for PE at >=37 weeks, at a 10% FPR. CONCLUSION: Our data suggest that the FMF algorithm provides effective first trimester screening for preterm PE. PMID- 28715819 TI - Effect of microRNA-135a on Cell Proliferation, Migration, Invasion, Apoptosis and Tumor Angiogenesis Through the IGF-1/PI3K/Akt Signaling Pathway in Non-Small Cell Lung Cancer. AB - OBJECTIVE: This study explored the ability of microRNA-135a (miR-135a) to influence cell proliferation, migration, invasion, apoptosis and tumor angiogenesis through the IGF-1/PI3K/Akt signaling pathway in non-small cell lung cancer (NSCLC). METHODS: NSCLC tissues and adjacent normal tissues were collected from 138 NSCLC patients. Quantitative real-time polymerase chain reaction (qRT PCR) was used to detect the expression levels of miR-135a and IGF-1, PI3K, Akt, VEGF, bFGF and IL-8 mRNA; western blotting was used to determine the expression levels of IGF-1, PI3K and Akt protein; and enzyme-linked immunosorbent assay (ELISA) was used to analyze the expression levels of VEGF, bFGF and IL-8 protein. Human NSCLC cell lines (A549, H460, and H1299) and the human bronchial epithelial cell line (HBE) were selected. A549 cells were assigned to blank, negative control (NC), miR-135a mimics, miR-135a inhibitors, IGF-1 siRNA and miR-135a inhibitors + IGF-1 siRNA groups. The following were performed: an MTT assay to assess cell proliferation, a scratch test to detect cell migration, a Transwell assay to measure cell invasion, and a flow cytometry to analyze cell apoptosis. RESULTS: The expression level of miR-135a was lower while those of IGF-1, PI3K and Akt mRNA were higher in NSCLC tissues than in the adjacent normal tissues. Dual-luciferase reporter assay indicated IGF-1 as a target of miR-135a. The in vitro results showed that compared with the blank group, cell proliferation, migration and invasion were suppressed, mRNA and protein levels of IGF-1, PI3K, Akt, VEGF, bFGF and IL-8 were reduced, and cell apoptosis was enhanced in the miR 135a mimics and IGF-1 siRNA groups. Compared with the IGF-1 siRNA group, cells in the miR-135a inhibitors + IGF-1 siRNA group demonstrated increased cell proliferation, migration and invasion, elevated mRNA and protein levels of IGF-1, PI3K, Akt, VEGF, bFGF and IL-8 and reduced cell apoptosis. CONCLUSION: These findings indicated that miR-135a promotes cell apoptosis and inhibits cell proliferation, migration, invasion and tumor angiogenesis by targeting IGF-1 gene through the IGF-1/PI3K/Akt signaling pathway in NSCLC. PMID- 28715820 TI - Therapeutic Plasma Exchange in Neonates and Infants: Successful Use of a Miniaturized Machine. AB - Therapeutic plasma exchange (TPE) in neonates and small infants is a treatment method at the forefront that may become a potentially life-saving procedure in a wide array of severe conditions. Indications for TPE in the pediatric population have been mainly derived from adult literature, with neonatal hyperbilirubinemia being the most notable exception. The only alternative to TPE in small pediatric patients is manual blood exchange transfusion, which, however, bears an unacceptably high risk of severe complications. Still, technical issues due to extracorporeal circulation in neonates have burdened TPE so far, since machines developed for adults require a relatively large blood volume to operate. We in this study, describe our preliminary experience of TPE for treating 2 potentially life-threatening conditions in neonatal age. To overcome the aforementioned limitations, plasmapheresis was performed in both cases using a machine specifically designed for patients weighing less than 10 kg. PMID- 28715821 TI - A History of Cow's Milk Allergy Is Associated with Lower Vitamin D Status in Schoolchildren. AB - BACKGROUND/AIMS: Vitamin D insufficiency is common in children. We aimed to evaluate the main determinants of vitamin D status in Finnish school-aged children, including the history of allergic diseases. METHODS: We conducted a cross-sectional study on 171 ten-year-olds where serum 25-hydroxyvitamin D (25[OH]D) levels were measured, and data on food consumption and use of vitamin D supplements were collected. The history of allergic diseases was evaluated with a validated questionnaire. RESULTS: Vitamin D insufficiency (<50 nmol/L) was observed in 16% of the children. In children with a history of cow's milk allergy, the mean 25(OH)D levels were lower than in children without allergy (60.5 +/- 12.6 nmol/L vs. 75.5 +/- 22.3 nmol/L, p = 0.004). Lack of vitamin D supplementation, female gender, non-Caucasian ethnicity, and a history of milk allergy were associated with lower vitamin D status. CONCLUSION: The vitamin D status in our study sample of Finnish schoolchildren was sufficient, which suggests that health policy strategies - such as the recommendation of vitamin D supplementation and the fortification of food products with vitamin D - have been successful in improving vitamin D status in children. Special concern should be given to children with a history of milk allergy to ensure their vitamin D sufficiency. PMID- 28715823 TI - Myeloperoxidase Activity and Oxidized Amino Acids as Biomarkers in Chronic Kidney Disease and Coronary Artery Disease. PMID- 28715822 TI - Long-Term Cortisol Concentration in Scalp Hair of Asthmatic Children Using Inhaled Corticosteroids: A Case-Control Study. AB - INTRODUCTION: Inhaled corticosteroids (ICS) can interfere with the hypothalamic pituitary-adrenal (HPA) axis and may lead to adrenal insufficiency, resulting in a decrease of cortisol production. Cortisol levels measured in scalp hair provide a marker for long-term cortisol exposure. Data regarding hair cortisol concentration (HCC) in asthmatic children with ICS therapy are scarce. The aim of this study is to compare HCC in asthmatic children under ICS treatment with a healthy control group. METHODS: We set up a case-control study measuring the cortisol concentration in scalp hair in asthmatic children (N = 80) treated with ICS and healthy controls (N = 252) aged 4-18 years. Anthropometric characteristics and hair samples from the posterior vertex were obtained. At least 5 mg of the most proximal 3 cm of hair was used for each hair sample. HCC was analyzed by liquid chromatography-tandem mass spectrometry. RESULTS: HCC did not significantly differ between asthmatic children using ICS and healthy controls (p = 0.950) after adjustment for age, gender, height, body mass index, and socioeconomic status. No correlation was found between budesonide dosage and HCC levels (r = -0.031, p = 0.78). CONCLUSION: There was no evidence of suppression of basal cortisol production, as measured in scalp hair, in asthmatic children using ICS, compared to healthy controls. No conclusions can be drawn on the HPA-axis stress response in these children. PMID- 28715824 TI - Preoperative geriatric assessment reduced hospital stay and complications in patients >= 65 y having vascular surgery. PMID- 28715825 TI - Review: In chronic hepatitis C virus infection, oral direct-acting antivirals have high sustained virologic response. PMID- 28715826 TI - In moderate-to-severe sciatica, pregabalin did not reduce leg pain intensity or improve quality of life. PMID- 28715827 TI - Review: Dapagliflozin increases, and empagliflozin reduces, adverse renal events in type 2 diabetes. PMID- 28715828 TI - Pooled RCTs: Early goal-directed therapy does not reduce mortality more than usual care in early septic shock. PMID- 28715829 TI - Evolocumab reduced CV events in patients with atherosclerotic CV disease taking high- or moderate-intensity statins. PMID- 28715830 TI - Patients with new-onset rheumatoid arthritis had increased risk for ischemic and nonischemic heart failure. PMID- 28715831 TI - In older men, 5alpha-reductase inhibitors were linked to increased risk for self harm and depression but not suicide. PMID- 28715832 TI - Aspirin plus clopidogrel was not linked to risk for cancer compared with aspirin alone or no antiplatelets. PMID- 28715833 TI - In patients receiving DAPT after coronary stents, the PRECISE-DAPT score predicted bleeding moderately well. PMID- 28715835 TI - Correction: Effect of Using the HEART Score in Patients With Chest Pain in the Emergency Department. PMID- 28715836 TI - Diary of a First-Year Doctoring Student. PMID- 28715837 TI - Are There Weapons in the Home? PMID- 28715838 TI - Annals for Hospitalists: Celebrating the One-Year Anniversary of an Easier Way for Hospitalists to Access Annals. PMID- 28715839 TI - Web Exclusives. Annals for Hospitalists Inpatient Notes - The Opioid Epidemic What's a Hospitalist to Do? PMID- 28715840 TI - Web Exclusives. Annals Consult Guys - Let Me Out of Here! How Long to Remain Hospitalized After an MI. PMID- 28715842 TI - Changing the Conversation About Opioid Tapering. PMID- 28715843 TI - The Pharmaceuticalization of the Tobacco Industry. PMID- 28715845 TI - Apatinib, an Inhibitor of Vascular Endothelial Growth Factor Receptor 2, Suppresses Pathologic Ocular Neovascularization in Mice. AB - Purpose: Vascular endothelial growth factor (VEGF) signaling via VEGF receptor 2 (VEGFR2) plays a crucial role in pathologic ocular neovascularization. In this study, we investigated the antiangiogenic effect of apatinib, a pharmacologic inhibitor of VEGFR2 tyrosine kinase, against oxygen-induced retinopathy (OIR) and laser-induced choroidal neovascularization (CNV) in mice. Methods: Western blotting and in vitro angiogenesis assays were performed using human retinal microvascular endothelial cells (HRMECs). OIR was induced in neonatal mice by exposure to 75% oxygen from postnatal day (P) 7 to P12 and to room air from P12 to P17. Experimental CNV was induced in mice using laser photocoagulation. Apatinib was intravitreally and orally administered to mice. Neovascularization and phosphorylation of VEGFR2 were evaluated by immunofluorescence staining. Results: Apatinib inhibited VEGF-mediated activation of VEGFR2 signaling and substantially reduced VEGF-induced proliferation, migration, and cord formation in HRMECs. A single intravitreal injection of apatinib significantly attenuated retinal or choroidal neovascularization in mice with OIR or laser injury-induced CNV, respectively. Retinal or choroidal tissues of the eyes treated with apatinib exhibited substantially lower phosphorylation of VEGFR2 than those of controls injected with vehicle. Intravitreal injection of apatinib did not cause noticeable ocular toxicity. Moreover, oral administration of apatinib significantly reduced laser-induced CNV in mice. Conclusions: Our study demonstrates that apatinib inhibits pathologic ocular neovascularization in mice with OIR or laser-induced CNV. Apatinib may, therefore, be a promising drug for the prevention and treatment of ischemia-induced proliferative retinopathy and neovascular age-related macular degeneration. PMID- 28715844 TI - Effects of Pathogenic Variations in the Human Rhodopsin Gene (hRHO) on the Predicted Accessibility for a Lead Candidate Ribozyme. AB - Purpose: The mutation-independent strategy for hammerhead ribozyme (hhRz) or RNA interference (RNAi)-based gene therapeutics to treat autosomal dominant diseases is predicated on the hypothesis that a single therapeutic would equivalently suppress all/most of the diverse mutant mRNAs in patients with the disease phenotype. However, the hypothesis has not been formally tested. We address this through a comprehensive bioinformatics study of how mutations affect target mRNA structure accessibility for a single lead hhRz therapeutic (725GUC?), designed against human rod rhodopsin mRNA (hRHO), for patients with hRHO mutations that cause autosomal dominant retinitis pigmentosa. Methods: A total of 199 in silico coding region mutations (missense, nonsense, insert, deletion, indel) were made in hRHO mRNA based on Human Gene Mutation Database and Database of Single Nucleotide Polymorphisms. Each mRNA was folded with MFold, SFold, and OligoWalk algorithms and subjected to a bioinformatics model called multiparameter prediction of RNA accessibility. Predicted accessibility of each mutant over both a broad local region and the explicit lead ribozyme annealing site were compared quantitatively to wild-type hRHO mRNA. Results: Accessibility of the 725GUC? site is sensitive to some mutations. For single nucleotide missense mutations, proximity of the mutation to the hhRz annealing site increases the impact on predicted accessibility, but some distant mutations also influence accessibility. Conclusions: A mutation-independent strategy appears viable in this specific context but certain mutations could significantly influence ribozyme or RNAi efficacy through impact on accessibility at the target annealing site/region. This possibility must be considered in applications of this gene therapy strategy. PMID- 28715847 TI - Language Sampling With Adolescents: Building a Normative Database With Fables. AB - Purpose: The goal of the study was to create a language sampling task appropriate for adolescents and to contribute normative data from speakers with typical language development. Method: Thirty adolescents (mean age = 14 years, 1 month) participated in an interview that involved the retelling and interpretation of 4 Greek fables. Each speaker's performance on the task was audio-recorded, transcribed verbatim, and entered into the Systematic Analysis of Language Transcripts computer program (Miller & Iglesias, 2015). Samples were analyzed statistically for language productivity and syntactic complexity. In addition, each participant's perspective on the moral messages of the fables was examined informally. Results: The Fables task was effective in prompting adolescents to use complex language and in encouraging them to express their opinions about the moral messages. Although boys and girls did not differ in their performance on the task, some fables were more effective than others at eliciting spoken language and complex syntax. Moreover, the adolescents tended to agree with the moral messages of the fables and appeared to find them relevant to their lives. Conclusion: The Fables task has potential for clinical use with adolescents. Research is necessary to expand the normative database to include larger and more diverse groups of adolescents. PMID- 28715846 TI - B Cell Anomalies in Autoimmune Retinopathy (AIR). AB - Purpose: Autoimmune retinopathy (AIR) is a retinopathy associated with unexplained vision loss presumably linked to circulating antiretinal antibodies; currently, however, there are no standardized criteria regarding the diagnosis, treatment strategy, or pathogenesis of this disease. The importance of B lymphocyte immunophenotyping in the classification of AIR is unknown. Methods: We utilized 15-color multiparametric flow cytometry to identify aberrations in B cell subsets that may contribute to the pathophysiology of AIR. Luminex cytokine analysis was also performed on plasma samples from AIR patients. Results: Significant differences in AIR patients compared to individuals with other inflammatory conditions or healthy donors were found in the B cell memory compartment, including an increase in naive B cells and a decrease in switched and unswitched memory B cells, which correlated with alterations in immunoglobulin secretion. Conclusions: These findings suggest that the maturation process of B cells may be impaired and that B cell immunophenotyping may help in understanding disease process in AIR. PMID- 28715849 TI - Erratum. PMID- 28715848 TI - Patient Outcomes in Dose Reduction or Discontinuation of Long-Term Opioid Therapy: A Systematic Review. AB - Background: Expert guidelines recommend reducing or discontinuing long-term opioid therapy (LTOT) when risks outweigh benefits, but evidence on the effect of dose reduction on patient outcomes has not been systematically reviewed. Purpose: To synthesize studies of the effectiveness of strategies to reduce or discontinue LTOT and patient outcomes after dose reduction among adults prescribed LTOT for chronic pain. Data Sources: MEDLINE, EMBASE, PsycINFO, CINAHL, and the Cochrane Library from inception through April 2017; reference lists; and expert contacts. Study Selection: Original research published in English that addressed dose reduction or discontinuation of LTOT for chronic pain. Data Extraction: Two independent reviewers extracted data and assessed study quality using the U.S. Preventive Services Task Force quality rating criteria. All authors assessed evidence quality using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system. Prespecified patient outcomes were pain severity, function, quality of life, opioid withdrawal symptoms, substance use, and adverse events. Data Synthesis: Sixty-seven studies (11 randomized trials and 56 observational studies) examining 8 intervention categories, including interdisciplinary pain programs, buprenorphine-assisted dose reduction, and behavioral interventions, were found. Study quality was good for 3 studies, fair for 13 studies, and poor for 51 studies. Many studies reported dose reduction, but rates of opioid discontinuation ranged widely across interventions and the overall quality of evidence was very low. Among 40 studies examining patient outcomes after dose reduction (very low overall quality of evidence), improvement was reported in pain severity (8 of 8 fair-quality studies), function (5 of 5 fair-quality studies), and quality of life (3 of 3 fair-quality studies). Limitation: Heterogeneous interventions and outcome measures; poor-quality studies with uncontrolled designs. Conclusion: Very low quality evidence suggests that several types of interventions may be effective to reduce or discontinue LTOT and that pain, function, and quality of life may improve with opioid dose reduction. Primary Funding Source: Veterans Health Administration. (PROSPERO: CRD42015020347). PMID- 28715850 TI - How willing are you? Willingness as a predictor of change during treatment of adults with obsessive-compulsive disorder. AB - OBJECTIVE: Exposure and response prevention (ERP) is an effective treatment for individuals with obsessive-compulsive disorder (OCD), yet a substantial number of individuals with OCD do not fully respond to this intervention. Based on emerging experimental and clinical research on acceptance, this study sought to explore whether willingness to experience unpleasant thoughts, emotions, and bodily sensations during ERP was associated with improved treatment response. METHODS: Two hundred eighty-eight adults with OCD receiving residential ERP provided self rated willingness and other exposure-related variables during each daily coached ERP session. Obsessive-compulsive and depressive symptom severity was assessed every week. Multilevel modeling was used to study the impact of willingness on treatment outcome during the first 6 weeks of residential care. RESULTS: Data indicated that individuals with higher willingness during ERP reported faster symptom reduction during residential treatment, even when controlling for length of stay, psychopharmacological intervention, depression, adherence, and rituals performed during ERP. These results appear to have both statistical and clinical significance. CONCLUSIONS: Willingness to fully experience unpleasant and unwanted thoughts, emotions, and bodily sensations during exposures appears to be a marker of successful exposure therapy in adults with OCD. Future research should examine how willingness may enhance extinction learning during ERP. PMID- 28715851 TI - Paradigm shifts, peregrinations and pixies in ophthalmology. AB - Human ingenuity is challenged by defending vision, our highest bandwidth sense. Special challenges are presented by the replacement or repair of highly specialized but scarce tissue within the constraints of transparency, tissue shape and alignment, tissue borders and pressure maintenance. Many, mostly destructive, surgical procedures were developed prior to an understanding of underlying pathophysiology. For a number of conditions, both reconstructive and destructive procedures co-exist, yet there are few guidelines as to the better approach. Because the consequences of these procedures may take many years to surface (consistent with a stem cell role in long-term tissue maintenance), guidance may be provided by the elucidation of underlying principles from these approaches. Illustrative examples from clinical, basic research and biotechnology, particularly relating to pterygium, ocular surface squamous neoplasia, dry-eye syndrome, corneal rehabilitation and replacement, cataract surgery, strabismus surgery and bionic eye research, are described. An unexpected consequence of bionic device development has been an appreciation of the sophistication of tissues being replaced, given the limitations of available biomaterials. Examples of how this has provided insights into ocular disease will be illustrated. Stem cell and biomaterial technologies are starting to impact at a time when cost-effectiveness is under scrutiny. Both efficacy and cost will need to be considered as these interventions are introduced. It appears that the paradigm shift rate is accelerating and there is evidence of this in ophthalmology. Lessons learned from the areas of destructive versus reconstructive surgery and the limitations of development of bionic replacements will be used to illustrate how new procedures and technologies can be developed. PMID- 28715852 TI - Treatment of premenstrual dysphoria with continuous versus intermittent dosing of oral contraceptives: Results of a three-arm randomized controlled trial. AB - BACKGROUND: Although traditionally dosed combined oral contraceptives (COCs) (21 days of active pills, 7 days of inactive pills) have not been demonstrated as superior to placebo for the treatment of premenstrual dysphoria (PMD), some randomized controlled trials (RCTs) indicate that oral contraceptives administered with a shortened or eliminated hormone-free interval are superior to placebo. However, results of such trials are mixed, and no existing studies have directly compared continuous and intermittent dosing schedules of the same oral contraceptive. The present study compared placebo, intermittent dosing of oral contraceptives, and continuous dosing of contraceptives for the treatment of PMD. METHODS: Fifty-five women with prospectively confirmed PMD completed a three-arm, RCT in which they were randomized to 3 months of placebo (n = 22), intermittent drospirenone/ethinyl estradiol dosed on a 21-7 schedule (n = 17), or continuous drospirenone/estradiol (n = 16) following a baseline assessment month. RESULTS: All three groups demonstrated similar, robust reductions in premenstrual symptoms over time. A marked placebo response was observed. CONCLUSIONS: The study fails to replicate a uniquely beneficial effect of continuous COC on PMD. Additional work is needed to understand the psychosocial context bolstering the placebo response in women with PMD. PMID- 28715854 TI - Metal-Metal Bonds: From Fundamentals to Applications. PMID- 28715855 TI - Assessing long-term impact of land-use change on hydrological ecosystem functions in a Mediterranean upland agro-forestry catchment. AB - During the second half of the 20th century farming systems in hilly and mountainous areas of Mediterranean Europe were progressively abandoned and the forest cover subsequently re-expanded. This paper investigates the environmental impacts of land-use/land-cover (LULC) changes on hydrological ecosystem functions (HEFs) in the Upper Alento River Catchment (UARC) in southern Italy. We document the human-driven post-war landscape in 1955 with its maximum expansion of pasture and crops. By 1998 forest cover had doubled and cropland had roughly halved due to decades of land abandonment and reduction in human pressure. In 2015 secondary forests occupied about 70% of the catchment and orchards about 20%. The 1998 land use scenario was implemented within the Automated Geospatial Watershed Assessment (AGWA) model which was calibrated and validated by direct water yield measurements recorded in the period 1995-2004 in the water reservoir delimited by an earth-dam located at the UARC outlet. Numerical simulations, assumed under "steady" climate conditions, offer "pseudo-realistic" scenarios that help interpret differences in water budget and sediment transport when the 1998 land use scenario is compared to those of 1955 and 2015. With reference to funding opportunities offered by the European Union in the recent decades, this study provides some practical guidance on the impact of cropland reconversion on HEFs and on measures to mitigate soil erosion in this Mediterranean area. Viewed from the demand-side perspective, natural re-expansion of forest and afforestation reduce water yield and increase actual evapotranspiration. However, our modeling results are framed also within a supply-side approach examining the sensitivity of water yield to precipitation characteristics. PMID- 28715853 TI - Effect of gemfibrozil and rifampicin on the pharmacokinetics of selexipag and its active metabolite in healthy subjects. AB - AIMS: Based on in vitro data, there is evidence to suggest that cytochrome P450 (CYP) 2C8 is involved in the metabolism of selexipag and its active metabolite, ACT-333679. The present study evaluated the possible pharmacokinetic interactions of selexipag with gemfibrozil, a strong CYP2C8 inhibitor, and rifampicin, an inducer of CYP2C8. METHODS: The study consisted of two independent parts, each conducted according to an open-label, randomized, crossover design. The pharmacokinetics and safety of selexipag and ACT-333679 were studied following single-dose administration either alone or in the presence of multiple-dose gemfibrozil (part I) or rifampicin (part II) in healthy male subjects. RESULTS: Gemfibrozil had comparatively small effects on selexipag (less than 2-fold difference in any pharmacokinetic variable) but, with respect to ACT-333679, increased the maximum plasma concentration (Cmax ) 3.6-fold [90% confidence interval (CI) 3.1, 4.3] and the area under the plasma concentration-time curve from zero to infinity (AUC0-infinity ) 11.1-fold (90% CI 9.2, 13.4). The marked increased exposure to ACT-333679, which mediates the majority of the pharmacological activity of selexipag, was accompanied by significantly more adverse events such as headache, nausea and vomiting. Coadministration of rifampicin increased the Cmax of selexipag 1.8-fold (90% CI 1.4, 2.2) and its AUC0-infinity 1.3-fold (90% CI 1.1, 1.4); its effects on ACT-333679 were to increase its Cmax 1.3-fold (90% CI 1.1, 1.6), shorten its half-life by 63% and reduce its AUC0-infinity by half (90% CI 0.45, 0.59). CONCLUSION: Concomitant administration of selexipag and strong inhibitors of CYP2C8 must be avoided, whereas when coadministered with inducers of CYP2C8, dose adjustments of selexipag should be envisaged. PMID- 28715856 TI - Nitrogen deposition changes ectomycorrhizal communities in Swiss beech forests. AB - Atmospheric pollution has implications for the health and diversity of temperate forests covering large parts of central Europe. Long-term elevated anthropogenic deposition of nitrogen (N) is driving forest ecosystems from the limitation by N to other nutrients and is found to affect tree health and ectomycorrhizal fungi (EMF), which most trees depend on for nutrient uptake. However, the consequence of EMF community changes for trees remains unclear. Therefore, we investigated changes in EMF communities on root tips and in soil of beech forests along a N deposition gradient ranging between 16 and 33kgNha-1a-1, where high N deposition was found to negatively affect tree growth and nutrient levels. The most important factors significantly explaining variation in root tip and mycelium EMF community composition in both root tips and mesh bags were increased N deposition, base saturation, growing season temperature and precipitation. With increasing N deposition, fine root length, EMF root colonization, EMF diversity on root tips and in soil, and production of extramatrical mycelium decreased significantly. Foliar P and potassium (K) were positively associated with increasing EMF diversity and we found EMF community composition to be associated with foliar P and N:P ratio. The decrease in root colonization, mesh bag ingrowth and abundance of the important species Cenococcum geophilum as well as high biomass species with increasing N availability clearly indicate repercussions for belowground carbon allocation, although some indicator species for high N deposition and low foliar P have long mycelia and may reflect a potential optimization of host P uptake. Our study supports the hypothesis that the decrease in nutrient uptake in beech forests across Europe is related to changes in EMF communities and suggests that continued high N deposition changes soil carbon and nutrient cycles, thereby affecting forest ecosystem health. PMID- 28715857 TI - Difference in growth and coalescing patterns of droplets on bi-philic surfaces with varying spatial distribution. AB - This paper reports the condensation and subsequent motion of water droplets on bi philic surfaces, surfaces that are patterned with regions of different wettability. Bi-philic surfaces can enhance the water collection efficiency: droplets condensing on hydrophobic regions wick into hydrophilic drain channels when droplets grow to a certain size, renewing the condensation on the dry hydrophobic region. The onset of drain phenomenon can be triggered by multiple events with distinct nature ranging from gravity, direct contact between a droplet and a drain channel, to a mutual coalescence between droplets. This paper focuses on the effect of the length scale of hydrophobic regions on the dynamics of mutual coalescence between droplets and subsequent drainage. The main hypothesis was that, when the drop size is sufficient, the kinetic energy associated with a coalescence of droplets may cause dynamic advancing of a newly formed drop, leading to further coalescence with nearby droplets and ultimately to a chain reaction. We fabricate bi-philic surfaces with hydrophilic and hydrophobic stripes, and the result confirms that coalescing droplets, when the length scale of droplets increases beyond 0.2mm, indeed display dynamic expansion and chain reaction. Multiple droplets can thus migrate to hydrophilic drain simultaneously even when the initial motion of the droplets was not triggered by the direct contact between the droplet and the hydrophilic drain. Efficiency of drain due to mutual coalescence of droplets varies depending on the length scale of bi-philic patterns, and the drain phenomenon reaches its peak when the width of hydrophobic stripes is between 800MUm and 1mm. The Ohnesorge number of droplets draining on noted surfaces is between 0.0042 and 0.0037 respectively. The observed length scale of bi-philic patterns matches that on the Stenocara beetle's fog harvesting back surface. This match between length scales suggests that the surface of the insect is optimized for the drain of harvested water. PMID- 28715858 TI - Biomimetic nitrogen doped titania nanoparticles as a colorimetric platform for hydrogen peroxide detection. AB - Nanoparticles proved a viable alternative to the already used sensing and diagnostics methods due to their low cost, good stability, easy availability and easy synthesis. In the present approach, nitrogen doped titania nanoparticles are prepared through freeze drying method, and subsequently stabilized through ionic liquid. These nanoparticles were characterized through various techniques such as X-ray diffraction (XRD), Fourier transformation infrared spectroscopy (FTIR), Scanning electron microscopy (SEM), BET pore size and surface area analyzer, X ray photoelectron spectroscopy (XPS) and UV-Visible diffuse reflectance spectroscopy (UV-Vis. DRS). The synthesized nitrogen doped titania nanoparticles were proved to be a novel peroxidase mimetic with great potential to catalyze oxidation of 3,3',5,5'-tetramethylbenzidine (TMB) in the presence of hydrogen peroxide (H2O2) to form a blue color product. As a proof of concept, this new enzyme mimic was used as a robust nanoprobe for the detection of hydrogen peroxide with improved analytical characteristics. A linear response for hydrogen peroxide detection was obtained in the range of 10-300MUmol/L, with a detection limit of 2.5MUmol/L. Taking into account the valuable intrinsic peroxidase activity, the present work may find widespread applications in the field of sensors and biosensors for diverse applications. PMID- 28715859 TI - Influence of newly synthesized geminal dicationic ionic liquid on electrochemical and pseudocapacitance performance of conductive polymer electroactive film. AB - In present work, for improving the electrochemical performance of conductive polymer, POAP/3-methyl-1-[2-(2-{2-[2-[(3-methyl-1-H-imidazol-3-ium-1 yl)ethoxy]ethoxy}-ethoxy)ethyl]-1-H-imidazol-3-ium dichloride (MIEID) composite films have been fabricated by poly ortho aminophenol (POAP) electropolymerization in the presence of MIEID as active electrodes for electrochemical supercapacitors. Different electrochemical methods including galvanostatic charge discharge experiments, cyclic voltammetry and electrochemical impedance spectroscopy have been applied to study the system performance. Analysis of density functional theory (DFT) results show that the atomic-scale electronic properties are generally depend on the bonding and electronic molecular structures (and thus their variation with the external bias in real nano electrochemical circuits). Composite film kept more than 90% percent of its capacitance after 1000 charging-discharging cycles, while the coulombic efficiency (eta) is as high as 95%. Results suggesting composite film can be used as supercapacitor electrode material with excellent specific capacitance (487Fg 1) which indicates this material is a promising electrode material used in high power applications. PMID- 28715860 TI - Hemoglobin bioconjugates with surface-protected gold nanoparticles in aqueous media: The stability depends on solution pH and protein properties. AB - The identification of the factors that dictate the formation and physicochemical properties of protein-nanomaterial bioconjugates are important to understand their behavior in biological systems. The present work deals with the formation and characterization of bioconjugates made of the protein hemoglobin (Hb) and gold nanoparticles (AuNP) capped with three different molecular layers (citrate anions (c), 6-mercaptopurine (MP) and omega-mercaptoundecanoic acid (MUA)). The main focus is on the behavior of the bioconjugates in aqueous buffered solutions in a wide pH range. The stability of the bioconjugates have been studied by UV visible spectroscopy by following the changes in the localized surface resonance plasmon band (LSRP), Dynamic light scattering (DLS) and zeta-potential pH titrations. It has been found that they are stable in neutral and alkaline solutions and, at pH lower than the protein isoelectric point, aggregation takes place. Although the surface chemical properties of the AuNPs confer different properties in respect to colloidal stability, once the bioconjugates are formed their properties are dictated by the Hb protein corona. The protein secondary structure, as analyzed by Attenuated total reflectance infrared (ATR-IR) spectroscopy, seems to be maintained under the conditions of colloidal stability but some small changes in protein conformation take place when the bioconjugates aggregate. These findings highlight the importance to keep the protein structure upon interaction with nanomaterials to drive the stability of the bioconjugates. PMID- 28715861 TI - Synthesis of less toxic gold nanorods by using dodecylethyldimethylammonium bromide as an alternative growth-directing surfactant. AB - Gold nanoparticles having a rod-like morphology are regularly investigated as potential nano-therapeutic materials owing to their interesting optical properties, facile surface modification, tunable aspect ratios, and low cytotoxicity. Gold nanorods are historically prepared starting from HAuCl4 in the presence of ascorbic acid, silver nitrate, and the growth directing surfactant, cetyltrimethylammonium bromide (CTAB). While CTAB drives a rod-like morphology, it is known to be cytotoxic. This inherent toxicity is often addressed by removing or masking the native CTAB surfactant present on the nanorod surface. In the current study we have investigated a less toxic alternative surfactant, dodecylethyldimethylammonium bromide (C12EDMAB), as a possible growth-directing agent. Monodisperse gold nanorods having various lengths have been grown in the presence of C12EDMAB. SEM data suggests that the quantity of C12EDMAB on the rod's surface is much higher than that of CTAB. Toxicity assays were performed on HEp-2 and A549 cells showing lower toxicity at select concentrations for C12EDMAB coated rods. PMID- 28715862 TI - Phenyl and ionic liquid based bifunctional periodic mesoporous organosilica supported copper: An efficient nanocatalyst for clean production of polyhydroquinolines. AB - A novel phenyl and ionic liquid based bifunctional periodic mesoporous organosilica supported copper (Cu@BPMO-Ph-IL) is prepared, characterized and its catalytic application is developed in the clean production of polyhydroquinolines. The Cu@BPMO-Ph-IL was prepared via chemical grafting of ionic liquid groups onto phenyl-based PMO followed by treatment with copper acetate. This nanocatalyst was characterized with transmission electron microscopy (TEM), scanning electron microscopy (SEM), diffuse reflectance infrared Fourier transform spectroscopy (DRIFTs), thermal gravimetric analysis (TGA), powder X-ray diffraction (PXRD), nitrogen-sorption and energy dispersive X ray (EDX) analyses. This was successfully applied in the one-pot Hantzsch condensation of aldehydes, ammonium acetate, alkylacetoacetates and dimedone to prepare a set of different derivatives of polyhydroquinolines in high yields and selectivity. The catalyst was effectively recovered and reused several times without important decrease in efficiency. The recovered catalyst was also characterized with TEM analysis to study its stability and durability under applied conditions. PMID- 28715863 TI - Structural elucidation of a pectin-type polysaccharide from Hovenia dulcis peduncles and its proliferative activity on RAW264.7 cells. AB - In this paper, an acidic polysaccharide HDP3A was isolated from Hovenia dulcis peduncles with 45.9% of uronic acid content. Structure of HDP3A was elucidated by chemical and spectroscopic analysis. HDP3A was mainly contained of galacturonic acid, galactose, rhamnose and arabinose with a small quantity of xylose, fucose, mannose, glucose. The structural analysis indicated that HDP3A was a pectin-type polysaccharide with HG and RG-I regions and hairy regions. HG was linear homopolymer with repeating units of (1->4)-alpha-d-galactopyranosyl uronic (GalA) residues. The GalpA residues in HG domain may be acetylated and/or methyl esterified. The backbone of RG-I contains repeating units of [->alpha-GalpA-1,2) alpha-Rhap-1,4->]n and the hairy regions attached in the Rha at position O-4. Hairy regions were mainly composed of galactans, arabinans, arabinogalactans, glucans, mannans and xylans. The immunomodulatory activities of HDP3A and its reduced (HDP3A-R) and hydrolyzed product (HDP3A-0.1) in vitro on macrophages were determined. The three polysaccharide fractions all stimulated the proliferation of RAW264.7 cells and the order of the proliferative effects was HDP3A>HDP3A R>HDP3A-0.1, indicating that the immune effects of pectin-type polysaccharides were related to branches and molecular weight. Consequently, HDP3A could be as a potential source for the proliferative activity. PMID- 28715864 TI - In vitro and in vivo anticancer activity of 2-acetyl-benzylamine isolated from Adhatoda vasica L. leaves. AB - One of the important aims of drug discovery for cancer is to find therapeutic agents from natural products that are effective and safe for cancer treatment. In the current study, an alkaloid, 2-acetyl-benzylamine, isolated from Adhatoda vasica, was screened for potent anticancer properties against leukemia cells. We used seven different types of leukemia cells such as CEM, NB-4, MOLM-14, Jurkat, IM-9, K562 and HL-60 for cytotoxic studies. 2-acetyl-benzylamine showed significant cytotoxic properties against MOLM-14 and NB-4 cells with IC50 values of 0.40 and 0.39mM at 24h when compared to other tested cells, respectively. Apoptosis was confirmed by annexin V-FITC/PI kit using flow cytometry and confocal microscope in MOLM-14 and NB-4 cells. In addition, 2-acetyl-benzylamine induced cell cycle arrest at G2/M phase in MOLM-14 cells and G0/G1 phase in NB-4 cells. Apoptosis mechanism was confirmed by RT-PCR and Western blot analysis. Treatment with 2-acetyl-benzylamine decreased the Bcl-2 activity and increased the Bax expression; cytochrome c was released and caspases-3 was activated in MOLM-14 and NB-4 cells. Besides, 2-acetyl-benzylamine inhibited the expression of JAK2/STAT3 in MOLM-14 and NB-4 cells. In vivo administration of 2-acetyl benzylamine inhibited the growth of MOLM-14 cells in xenograft mice model. Molecular docking study has been performed to investigate the binding mode and to estimate the binding energy of 2-acetyl-benzylamine with the active site of JAK 2, AKT1, FLT3 and Bcl-2. The above findings proved that 2-acetyl-benzylamine could be developed as a potential therapeutic agent against cancer. PMID- 28715865 TI - Chitosan oligosaccharides protect nucleus pulposus cells from hydrogen peroxide induced apoptosis in a rat experimental model. AB - Chitosan has been investigated for its protective effect on nucleus pulposus (NP) cells against intervertebral disc degeneration(IDD), but its high molecular weight prohibits its clinical application. The low molecular derivatives, chitosan oligosaccharides (COS) are easier to absorb; however, the protective effect of COS against IDD remains unclear. In this study, we investigated the effects of COS on NP degeneration. NP cells derived from rats were treated with H2O2 to induce an IDD-like transition. Then, COS was used to pre-treat cells before administering H2O2 and changes occurring in the cells were observed. As shown by the result of a cell counting kit-8(CCK-8) assay, COS protected the viability of the cells. The induced apoptosis rate fell when cells were pre treated with COS, revealed by annexin-V FITC/PI double staining analysis and Hoechst 33342 staining. COS administration also protected ECM synthesis and prevented its degradation, as shown by western blotting(WB) and polymerase chain reaction(PCR). We analyzed the activity of the PI3K/Akt pathway in H2O2 treated NP cells by WB and the result showed that COS could enhance activity of the pathway. To investigate the relationship between the PI3K/Akt pathway and the protective effects of COS on NP cells, the PI3K/Akt pathway was inhibited by wortmannin, and we subsequently found that this abolished the protective effects. These results support the hypothesis that COS exerts its protective effect on NP cells against H2O2-induced apoptosis via the PI3K/Akt pathway. PMID- 28715866 TI - Protective effects of isorhamnetin on N2a cell against endoplasmic reticulum stress-induced injury is mediated by PKCepsilon. AB - Endoplasmic reticulum stress (ERS)-induced intracellular calcium (Ca2+) overload and ROS burst plays a critical role in apoptosis. Protein kinase C epsilon (PKCepsilon) is involved in regulating the homeostasis of Ca2+ and ROS production. isorhamnetin (Iso), as an ROS scavenger, effectively inhibit apoptosis, but the mechanism is still unclear. This study was to investigate whether Iso can inhibit ERS-induced apoptosis in N2a cells, and the protective effects are involved in PKCepsilon-mediated Ca2+ homeostasis and inhibition of ROS. The effects of Iso against ERS injury in N2a cells were detected by cell viability, the levels of Ca2+, apoptosis and reactive oxygen species (ROS). The protein GRP78 expression levels were measured by western blot assay. The results showed that Iso can reduce ERS-induced injury by inhibiting Ca2+ overload, reducing the generation of ROS and decreasing apoptosis. In addition, Iso can promote PKCepsilon phosphorylation, and epsilonV1-2 (a PKCepsilon inhibitor) drastically attenuated the protective effects of Iso against ERS injury in N2a cells. In conclusion, we firstly demonstrated that Iso can elicit protective effects against ERS injury in N2a cells and these effects are mediated at least in part via PKCepsilon pathway. PMID- 28715867 TI - Therapeutic impact of grape leaves polyphenols on certain biochemical and neurological markers in AlCl3-induced Alzheimer's disease. AB - Alzheimer's disease (AD) is a grave and prevailing neurodegenerative disease, characterized by slow and progressive neurodegeneration in different brain regions. Aluminum (Al) is a potent and widely distributed neurotoxic metal, implicated in the neuropathogenesis of AD. This study aimed to evaluate the possible neurorestorative potential of Vitis vinifera Leaves Polyphenolic (VLP) extract in alleviating aluminum chloride (AlCl3)-induced neurotoxicity in male rats. AlCl3 neurotoxicity induced a significant decrease in brain/serum acetylcholine (ACh) contents and serum dopamine (DA) levels, along with a significant increment of brain/serum acetylcholinesterase (AChE) activities. In addition, Al treatment resulted in significantly decreased serum levels of both total antioxidant capacity (TAC) and brain-derived neurotrophic factor (BDNF), and significantly increased serum levels of both interleukin-6 (IL-6) and total homocysteine (tHcy), as compared to control. Behavioral alterations, assessed by the T-maze test, showed impaired cognitive function. Furthermore, AD-brains revealed an increase in DNA fragmentation as evidenced by comet assay. AlCl3 induction also caused histopathological alterations in AD-brain. Treatment of AD rats with VLP extract (100mg/kg body weight/day) improved neurobehavioral changes, as evidenced by the improvement in brain function, as well as, modulation of most biochemical markers, and confirmed by T-maze test, the histopathological study of the brain and comet assay. The current work indicates that the VLP extract has neuroprotective, antioxidative, anti-inflammatory, and anti-amnesic activities against AlCl3-induced cerebral damages and neurocognitive dysfunction. PMID- 28715868 TI - MicroRNA-150 attenuates hypoxia-induced excessive proliferation and migration of pulmonary arterial smooth muscle cells through reducing HIF-1alpha expression. AB - Pulmonary arterial hypertension (PAH) is a progressive, fatal disease for which currently there is no curative therapy available. Pathologic changes in this disease involve excessive proliferation and migration of pulmonary artery smooth muscle cells (PASMCs). However, the underlying role of miR-150 in PASMCs remains elusive. Here in this study, miR-150 down-regulation was observed in hypoxia treated PASMCs. Restoration of miR-150 attenuates hypoxia-treated PASMC proliferation and migration. Luciferase reporter assay showed that miR-150 directly regulated expression of HIF-1alpha. Moreover, overexpression of HIF 1alpha impaired the suppressive effect of miR-150 on the proliferative and migratory capacities of PASMCs. Altogether, our findings indicate that miR-150 may exert inhibitory effects on excessive proliferation and migration of PASMCs through down-regulation of HIF-1alpha, providing new insights into the potential mechanisms of human PAH. PMID- 28715869 TI - Rapamycin inhibits oxidative/nitrosative stress and enhances angiogenesis in high glucose-treated human umbilical vein endothelial cells: Role of autophagy. AB - Chronic hyperglycemia is a potent risk factor of abnormal angiogenesis with various tissue diseases. Autophagy, as an alternative cell response, is mostly generated by a vast array of insults. Applying autophagic response contributes to normal cell retrieval circumstance during various insults. We aimed to show whether stimulation/inhibition of autophagy could reduce or exacerbate oxidative status and angiogenic potential in endothelial cells after exposure to 30mM glucose. HUVECs were incubated with the combined regime of 100nM Rapamycin and 30mM glucose over a period of 72h. The effect of rapamycin on cell viability, malondialdehyde levels, and nitric oxide were monitored by convenient assays. Intracellular ROS level was measured by flow cytometric analysis and DCFDA. HUVECs migration and angiogenic properties were assessed using scratch test and tubulogenesis assay. The expression of autophagic modulators LC3, Becline-1 and P62 was measured by using western blotting. Data showed 30mM glucose reduced cell viability, migration and in vitro tubulogenesis and level of ROS and nitric oxide were found to increased (p<0.05). Rapamycin had potential to increase cell survival and significantly decreased the total levels of oxidative stress markers after cell exposure to 30mM glucose (p<0.05). Rapamycin potentially improved the detrimental effect of 30mM glucose on cell migration and tubulogenesis capacity (p<0.05). Effective autophagic response was stimulated by rapamycin by increasing beclin-1, and the LC3-II/I ratio and reducing intracellular P62 level (p<0.05), resulting in the improvement of cell health and function. Together, rapamycin protected HUVECs from damages caused by high glucose concentration. This effect was possibly mediated by autophagy-dependent pathway. PMID- 28715870 TI - Neuroprotective effect of trans-N-caffeoyltyramine from Lycium chinense against H2O2 induced cytotoxicity in PC12 cells by attenuating oxidative stress. AB - Natural products play a critical role in the promotion of good health as regards the prevention and management of oxidative stress related and neurodegenerative disorders. Oxidative stress has been implicated in several apoptotic pathways associated with cell damages in neuronal disorders. The aim of this study was to investigate the antioxidant effect of trans-N-caffeoyltyramine (TNC) isolated from Cortex lycii against hydrogen peroxide (H2O2) induced cell damages in PC12 cells as well as its mechanism of action. The results obtained indicated that pretreatment with TNC before the exposure of cells to H2O2 toxicity lead to a significant increase in the cell viability and the antioxidant enzyme activities catalase (CAT), superoxide dismutase (SOD), glutathione (GSH) and reduced the level of malondialdehyde (MDA). Furthermore, TNC attenuated the influx of Ca2+, ROS formation and restored the impaired mitochondria membrane potential (MMP). Thus TNC may be used as an alternative therapy for the prevention and treatment of neuronal disorders elicited by oxidative stress. PMID- 28715871 TI - Improvement of mitochondrial function by celastrol in palmitate-treated C2C12 myotubes via activation of PI3K-Akt signaling pathway. AB - Compelling evidences posited that high level of saturated fatty acid gives rise to mitochondrial dysfunction and inflammation in the development of insulin resistance in skeletal muscle. Celastrol is a pentacyclic triterpenoid derived from the root extracts of Tripterygium wilfordii that possesses potent anti inflammatory properties in a number of animal models with metabolic diseases. However, the cellular mechanistic action of celastrol in alleviating obesity induced insulin resistance in skeletal muscle remains largely unknown. Therefore, the present investigation evaluated the attributive properties of celastrol at different concentrations (10, 20, 30 and 40nM) on insulin resistance in C2C12 myotubes evoked by palmitate. We demonstrated that celastrol improved mitochondrial functions through significant enhancement of intracellular ATP content, mitochondrial membrane potential, citrate synthase activity and decrease of mitochondrial superoxide productions. Meanwhile, augmented mitochondrial DNA (mtDNA) content with suppressed DNA oxidative damage were observed following celastrol treatment. Celastrol significantly enhanced fatty acid oxidation rate and increased the level of tricarboxylic acid (TCA) cycle intermediates in palmitate-treated cells. Further analysis revealed that the improvement of glucose uptake activity in palmitate-loaded myotubes was partly mediated by celastrol via activation of PI3K-Akt insulin signaling pathway. Collectively, these findings provided evidence for the first time that the protection from palmitate-mediated insulin resistance in C2C12 myotubes by celastrol is likely associated with the improvement of mitochondrial functions-related metabolic activities. PMID- 28715872 TI - A novel compound LingH2-10 inhibits the growth of triple negative breast cancer cells in vitro and in vivo as a selective inverse agonist of estrogen-related receptor alpha. AB - Unlike other breast cancer subtypes, targeted therapies for triple negative breast cancer (TNBC) have yet to progress past clinical trial stage to approval. Accumulating evidences demonstrated that expression of estrogen-related receptor alpha (ERRalpha) indicated worse prognosis and correlated with poor outcome in breast cancers including TNBC. Therefore, ERRalpha modulators/regulators may be potential in the therapeutic treatment of breast cancers. In the current study, we presented a novel compound LingH2-10 that bound to ERRalpha, as identified using a time-resolved fluorescence resonance energy transfer assay (TR-FRET) with the IC50 value of 0.64+/-0.12MUM. Further, functional activity was determined by transient transfection luciferase reporter assay in order to validate the utility of the binding affinity in a cellular context. LingH2-10 showed selective inhibition on ERRalpha transcriptional activity with the IC50 value of 0.58+/ 0.09MUM in cell-based luciferase reporter assay. Moreover, representative in vitro results showed that LingH2-10 suppressed the proliferation of various human cancer cells, and inhibited the migration of triple negative breast cancer cell MDA-MB-231. In addition, our results demonstrated that well known ERRalpha target genes such as PDK4, Osteopontin and pS2, were all significantly down modulated by LingH2-10. In vivo experiments showed that LingH2-10 (30mg/kg, every other day) observably suppressed the growth of MDA-MB-231 xenograft tumors by 42.02% compared to untreated xenograft tumors. Taken together, all these data suggested that LingH2-10, as a selective inverse agonist of ERRalpha, was a lead compound of anti-cancer agents for treating TNBC patients. PMID- 28715873 TI - Subcritical water-hydrolyzed fish collagen ameliorates survival of endotoxemic mice by inhibiting HMGB1 release in a HO-1-dependent manner. AB - To investigate potential mechanisms underlying the bioactivity of hydrolyzed fish collagen, we examined the anti-inflammatory actions of subcritical water hydrolyzed fish collagen (SWFC) in lipopolysaccharide (LPS)-triggered inflammation and endotoxemia. SWFC markedly inhibited LPS-stimulated release of high mobility group box 1 (HMGB1) in murine RAW264.7 macrophages, along with decreased cytosolic translocation of HMGB1. Both the protein and mRNA levels of heme oxygenase-1 (HO-1) were significantly upregulated in SWFC-treated RAW 264.7 cells in an Nrf2-dependent manner. In line with these effects of SWFC, both HO-1 siRNA and ZnPPIX (zinc protoporphyrin IX) actually attenuated the effects of SWFC on HMGB1 release stimulated by LPS, indicating a possible mechanism by which SWFC modulates HMGB1 release through HO-1 signaling. Notably, administration of SWFC improved the survival rates of LPS-injected endotoxemic mice, in which the serum level of HMGB1 was significantly reduced. Taken together, these results indicate that the anti-inflammatory activities of SWFC are achieved by inhibiting HMGB1 release induced by LPS in a HO-1-sensitive manner. PMID- 28715874 TI - Detection of bacterial infection by a technetium-99m-labeled peptidoglycan aptamer. AB - Nuclear medicine clinicians are still waiting for the optimal scintigraphic imaging agents capable of distinguishing between infection and inflammation, and between fungal and bacterial infections. Aptamers have several properties that make them suitable for molecular imaging. In the present study, a peptidoglycan aptamer (Antibac1) was labeled with 99mTc and evaluated by biodistribution studies and scintigraphic imaging in infection-bearing mice. Labeling with 99mTc was performed by the direct method and the complex stability was evaluated in saline, plasma and in the molar excess of cysteine. The biodistribution and scintigraphic imaging studies with the 99mTc-Antibac1 were carried out in two different experimental infection models: Bacterial-infected mice (S. aureus) and fungal-infected mice (C. albicans). A 99mTc radiolabeled library, consisting of oligonucleotides with random sequences, was used as a control for both models. Radiolabeling yields were superior to 90% and 99mTc-Antibac1 was highly stable in presence of saline, plasma, and cysteine up to 6h. Scintigraphic images of S. aureus infected mice at 1.5 and 3.0h after 99mTc-Antibac1 injection showed target to non-target ratios of 4.7+/-0.9 and 4.6+/-0.1, respectively. These values were statistically higher than those achieved for the 99mTc-library at the same time frames (1.6+/-0.4 and 1.7+/-0.4, respectively). Noteworthy, 99mTc-Antibac1 and 99mTc-library showed similar low target to non-target ratios in the fungal infected model: 2.0+/-0.3 and 2.0+/-0.6for 99mTc-Antibac1 and 2.1+/-0.3 and 1.9 +/- 0.6 for 99mTc-library, at the same times. These findings suggest that the 99mTc-Antibac1 is a feasible imaging probe to identify a bacterial infection focus. In addition, this radiolabeled aptamer seems to be suitable in distinguishing between bacterial and fungal infection. PMID- 28715875 TI - Acute orexigenic effect of agmatine involves interaction between central alpha2 adrenergic and GABAergic receptors. AB - Agmatine and GABA have been abundantly expressed in brain nuclei involved in regulation of energy homeostasis and promoting stimulation of food intake in rodents. However, their mutual interaction, if any, in the elicitation of feeding behavior is largely remains unclear. The current study provides experimental evidence for the possible interaction of agmatine, adrenergic and GABAergic systems in stimulation of feeding in satiated rats. Satiated rats fitted with intracerebroventricular (i.c.v.) cannulae and were administered agmatine, alone or jointly with (a) GABAA receptor agonist, muscimol, diazepam or antagonist bicuculline and flumazenil, GABAA positive modulator, allopregnanolone or negative modulator of GABAA receptor, dehydroepiandrosterone (b) In view of the high affinity of agmatine for alpha2-adrenoceptors and the close association between alpha2-adrenoceptors and GABAergic system, the effect of their modulators on feeding elicited by agmatine/GABAergic agonists were also examined. I.c.v. administration of agmatine (40-80MUg/rat) induces the significant orexigenic effect in satiated rats. The orexigenic effect of agmatine was potentiated by muscimol (25ng/rat, i.c.v.); diazepam (0.5mg/kg, i.p.); allopregnanolone (0.5mg/kg, s.c.) and blocked by bicuculline (1mg/kg, i.p.) and dehydroepiandrosterone (4mg/kg,s.c.). However, it remained unaffected in presence of flumazenil (25ng/rat, i.c.v.). The orexigenic effect of agmatine and GABAergic agonists was potentiated by a alpha2-adrenoceptors agonist, clonidine (10ng/rat, i.c.v.) and blocked by its antagonist, yohimbine (5MUg/rat, i.c.v.). Yohimbine also blocked the hyperphagic effect elicited by ineffective dose combination of agmatine (5MUg/rat, i.c.v.) with muscimol (25ng/rat, i.c.v.) or diazepam (0.5mg/kg, i.p.) or allopregnanolone (0.5mg/kg,s.c.). The results of the present study suggest that agmatine induced alpha2-adrenoceptors activation might facilitate GABAergic activity to stimulate food intake in satiated rats. PMID- 28715876 TI - Combining TRAIL and liquiritin exerts synergistic effects against human gastric cancer cells and xenograft in nude mice through potentiating apoptosis and ROS generation. AB - Gastric cancer is one of the most factors, leading to cancer-related death worldwide. However, the therapies to prevent gastric cancer are still limited and the emergence of drug resistance leads to development of new anti-cancer drugs and combinational chemotherapy regimens. Our study was aimed to explore the anti gastric cancer effects of liquiritin (LIQ), a major constituent of Glycyrrhiza Radix, which possesses a variety of pharmacological activities. The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) preferentially inhibited tumor cells over other normal cells, when used in alone or in combination. The results indicated that LIQ, when applied in single, was moderately effective to suppress proliferation, and migration, as well as to induce apoptosis and reactive oxygen species (ROS) generation of human gastric cancer cell lines, AGS and SNU-216, which are TRAIL-resistant. Significantly, when used in combination, the two drugs functioned synergistically to impede the progression and growth of human gastric cancer cells in vitro and gastric cancer cell xenograft nude mice in vivo. Both intrinsic and extrinsic apoptosis were induced by the two in combination via activating Caspases. And c-Jun N-terminal kinase (JNK) activity was dramatically induced by TRAIL/LIQ. Importantly, TRAIL/LIQ-triggered apoptosis and JNK were dependent on ROS production. The data indicated that application of TRAIL/LIQ in combination had a potential value for clinical use to synergistically prevent human gastric cancer development. PMID- 28715877 TI - Prognostic value of Transglutaminase 2 in non-small cell lung cancer patients. AB - Transglutaminase 2 (TG2) plays important roles in cell survival and cancer progression. In this study, we examined TG2 expression in specimen of 194 patients diagnosed with non-small cell lung cancer (NSCLC), and found that the TG2 gene expression was significantly higher in lung cancer tissues as compared to paired incisal marginal tissues or normal tissues. Our data revealed that patients with lower level of TG2 expression detected in cancer tissues had longer disease free survival and overall survival as compared to the patients with higher TG2 expression. We also found that TG2 expression level correlated to NSCLC recurrence. These results suggest a potential prognosis impact of TG2 for NSCLC patients. PMID- 28715878 TI - Substitutional Doping for Aluminosilicate Mineral and Superior Water Splitting Performance. AB - Substitutional doping is a strategy in which atomic impurities are optionally added to a host material to promote its properties, while the geometric and electronic structure evolution of natural nanoclay mineral upon substitutional metal doping is still ambiguous. This paper first designed an efficient lanthanum (La) doping strategy for nanotubular clay (halloysite nanotube, HNT) through the dynamic equilibrium of a substitutional atom in the presence of saturated AlCl3 solution, and systematic characterization of the samples was performed. Further density functional theory (DFT) calculations were carried out to reveal the geometric and electronic structure evolution upon metal doping, as well as to verify the atom-level effect of the La doping. The CdS loading and its corresponding water splitting performance could demonstrate the effect of La doping. CdS nanoparticles (11 wt.%) were uniformly deposited on the surface of La doped halloysite nanotube (La-HNT) with the average size of 5 nm, and the notable photocatalytic hydrogen evolution rate of CdS/La-HNT reached up to 47.5 MUmol/h. The results could provide a new strategy for metal ion doping and constructive insight into the substitutional doping mechanism. PMID- 28715879 TI - High Photocatalytic Performance of Two Types of Graphene Modified TiO2 Composite Photocatalysts. AB - High quality and naturally continuous structure of three-dimensional graphene network (3DGN) endow it a promising candidate to modify TiO2. Although the resulting composite photocatalysts display outstanding performances, the lacking of active sites of the 3DGN not only goes against a close contact between the graphene basal plane and TiO2 nanoparticles (weaken electron transport ability) but also limits the efficient adsorption of pollutant molecules. Similar with surface functional groups of the reduced graphene oxide (RGO) nanosheets, surface defects of the 3DGN can act as the adsorption sites. However, the defect density of the 3DGN is difficult to control (a strict cool rate of substrate and a strict flow of precursor gas are necessary) because of its growth approach (chemical vapor deposition method). In this study, to give full play to the functions of graphene, the RGO nanosheets and 3DGN co-modified TiO2 composite photocatalysts are prepared. After optimizing the mass fraction of the RGO nanosheets in the composite photocatalyst, the resulting chemical adsorption ability and yields of strong oxidizing free radicals increase significantly, indicating the synergy of the RGO nanosheets and 3DGN. PMID- 28715881 TI - Comparison of bone metabolism based on the different ages and competition levels of junior and high school female rhythmic gymnasts. AB - PURPOSE: This study was to clarify the effect of age and competition level by measuring bone metabolism markers and bone mineral density measurements of junior high school and high school female rhythmic gymnasts, who restrict their diets to maintain a low body weight, while routinely undertaking long hours of high intensity exercise, comparing the gymnasts based on their elite/non-elite. METHODS: The study investigated 7 junior high school and 12 high school female rhythmic gymnasts. For comparison by competition level, the 7 junior high school gymnasts were separated into 3 gymnasts who competed at national level (junior high school elite), and 4 gymnasts who did not compete at that level (junior high school non-elite), and the 12 high school gymnasts were separated into 7 gymnasts who competed at national level (high school elite) and 5 gymnasts who did not compete at that level (high school non-elite). The measurement items were bone mineral density, bone metabolism markers (undercarboxylated osteocalcin (ucOC), osteocalcin (OC), bone-specific alkaline phosphatase (BAP), calcium (Ca), inorganic phosphorus (P), alkaline phosphatase (ALP), parathyroid hormone (PTH), type 1 collagen cross-linked N-telopeptide (NTx)). We also surveyed the gymnasts' height, weight and nutrition. RESULTS: In this study we found: 1) The high school gymnasts who competed at high-level rhythmic gymnastics had good results for bone metabolism markers and bone mineral density. 2) Elite high school gymnasts had restricted diets. 3) Nutritionally, their energy intake and carbohydrate intake was low, but their intake of protein, calcium, iron, vitamin D and vitamin K was good. CONCLUSION: The results found that the elite gymnastics showed a higher bone density than the non-elite group that suggests the possibility of inhibiting bone formation in the bone metabolism. PMID- 28715880 TI - Effects of acute high-Intensity resistance exercise on cognitive function and oxygenation in prefrontal cortex. AB - PURPOSE: Moderate-intensity exercise is known to be the best effective intensity to enhance cognitive function, including memory and learning. However, the effects of high-intensity exercise in comparison with moderate- intensity exercise on cognitive function remain controversial. The aim of this study was to investigate the effect of high-intensity resistance exercise on cognitive function. METHODS: Thirty-six healthy female college students volunteered to participate in this study. The participants were divided into four groups: (i) control group (CON); (ii) high-intensity resistance exercise group (HIR); (iii) high-intensity aerobic exercise group (HIA); and (iv) combined moderate-intensity exercise group (MIC). Immediately prior to and after exercise, the solved number (SN) and reaction times (RT) in the Stroop test (neutral task, NT and incongruent task, IT), as well as the tissue oxygen index (TOI) in the left and right prefrontal cortex (PFC) were measured in all groups. RESULTS: In the NT, both HIR and MIC groups showed significant improvements in SN and RT compared with the CON group. Meanwhile, performance in the HIA group was significantly attenuated compared with that in the MIC group. In the IT, only the MIC group showed a significant increase in SN and RT compared with the CON group. Furthermore, the TOI in the PFC (left PFC in the NT, and bilaterally in the IT) was significantly lower in the HIR group compared with that in the CON group. CONCLUSION: The results of this study show worse cognitive performance and decreased PFC oxygenation in high-intensity exercise compared with moderate-intensity exercise and controls. These results suggest that high-intensity exercise may not improve cognition as effectively as moderate-intensity exercise. PMID- 28715882 TI - Influences of body mass index and physical activity on hypertension and stroke in Korean adult males: 10-year longitudinal study. AB - PURPOSE: Hypertension and stroke have been major causes of increased mortality and social and economic burden in Korea. Although physical activity is one of the critical factors for managing adult diseases, studies on the long-term effects are rarely discussed. Therefore, the aim of this study was to elucidate the role of physical activity in hypertension and stroke via a 10-year longitudinal study. METHODS: Routinely performed health screening results of 5,624,503 Korean men between ages 20 to 70 obtained from the National Health Insurance Service (2002 2013) were assessed for this study. Data of subjects who met the initial criteria were divided into three groups based on their BMI: normal weight (18.5 to <25.0 kg/m2), overweight (25.0 to <30.0 kg/m2), and obese (>=30.0 kg/ m2) groups. The results were further sub-divided by physical activity frequencies (days/ week). The disease codes for hypertension and stroke were provided by the National Health Insurance Service for the adjusted relative risks (RR) assessment with the Cox proportional hazard model. RESULTS: Significant RRs of hypertension and stroke were shown in the overweight moderately active group (3 - 4 days/week). In addition, significant RR of hypertension was shown in the normal weight moderately active group. No significance was seen in the obese group in all physical activity frequencies. CONCLUSION: Regularly performed moderate amount of physical activity may be beneficial in reducing the risk for hypertension and stroke. However, the effects of excessive body weight may override the positive effects of physical activity on the occurrence of hypertension and stroke. PMID- 28715883 TI - Association between Meeting Physical Activity Guidelines and Mortality in Korean Adults: An 8-year Prospective Study. AB - PURPOSE: Although previous studies have investigated the association between physical activity and various health outcomes, limited information is available on the effect of meeting new governmental guidelines for physical activity on the risk of mortality in Korean adults. This study aimed to examine the prospective association between meeting these guidelines and all-cause mortality during an 8 year follow-up using a large nationwide sample of middle-aged and older adults in Korea. METHODS: This prospective study was conducted based on the Korean Longitudinal Study of Ageing. The study participants included 9,177 adults aged 45 years or older at baseline, and all participants were monitored in a 2-year cycle during an 8-year period (70,873 person-years). The risk of mortality was analyzed by determining physical activity levels using the Cox proportional hazard models, and the hazard ratio (HR) and 95% confidence interval (CI) were estimated using Cox models. RESULTS: A statistically significant effect of physical activity on the reduced risk of mortality was observed in cases in which the participants met the guidelines compared to the inactive group (HR: 0.68, 95% CI: 0.58-0.81 vs. the inactive group). A strong association between meeting the recommended physical activity levels and the reduced risk of mortality was also found for non-smokers (HR: 0.62; 95% CI: 0.51-0.76 vs. the inactive group), but not for current smokers (HR: 0.93; 95% CI: 0.67-1.29 vs. the inactive group). CONCLUSION: Meeting physical activity guidelines was associated with a decreased risk of all-cause mortality for Korean adults. Our results also suggest that smoking reduces the protective effect of physical activity on the risk of mortality. PMID- 28715884 TI - Association of daily physical activity level with health-related factors by gender and age-specific differences among Korean adults based on the sixth (2014 2015) Korea national health and nutrition examination survey AB - PURPOSE: This study examined the effects of daily physical activity level on health-related factors according to gender and identified age-specific differences among Korean adults. METHODS: Using data from the Korea National Health and Nutrition Examination Survey VI (2014-2015), we selected adults aged 19-64 years who participated in both a health examination and health interview survey. The study included 6,457 participants 19-64 years of age (2,611 men, 3,846 women). RESULTS: Assessment of the differences in health-related factors according to age and physical activity in men and women by repeated two-way analysis of variance (ANOVA) revealed significant interaction effects on total cholesterol (TC) and triglyceride (TG) levels and diastolic blood pressure (DBP) in male participants, but there were no significant interaction effects for any health-related factors in female participants. The group of female participants aged 40-64 years with daily physical activity levels over 200 kcal showed a significantly increased prevalence of 46% for dyslipidemia compared to that in female participants with daily physical activity levels below 200 kcal. Physical activity was positively correlated with weight and high-density lipoprotein cholesterol (HDL-C) levels in men 19-39 years of age, compared to weight, waist circumference (WC), body mass index (BMI), and DBP in men 40-64 years of age, and weight, WC, BMI, glycated hemoglobin (HbA1c) and triglyceride (TG) levels in women 19-39 years of age. In women 40- 64 years of age, physical activity was especially significantly positively correlated with weight, BMI, HDL-C and negatively correlated with fasting glucose and TG levels. CONCLUSION: In male and female participants, the 40-64-year age group showed negative results for health related factors compared to those in the 19-39-year age group. The higher the weight, WC, BMI, the higher is the physical activity level. Physical activity levels were significantly positively correlated with health-related variables. PMID- 28715885 TI - The effects of exercise and cold exposure on mitochondrial biogenesis in skeletal muscle and white adipose tissue. AB - PURPOSE: The purpose of this study was to determine whether exercise or/and cold exposure regulate mitochondria biogenesis-related gene expression in soleus and inguinal adipose tissue of mice. METHODS: Forty ICR 5-week old male mice were divided into four groups: thermoneutrality-untrained (23 +/- 1 degrees C in room temperature, n=10), cold-water immersion (24 +/- 1 degrees C, n=10), exercise in neutral temperature (34 +/- 1 degrees C, n=10), and exercise in cold temperature (24 +/- 1 degrees C, n=10). The mice performed swimming exercise (30 min to 60 min, 5 times) for 8 weeks. After 8 weeks, we confirmed mitochondrial biogenesis related gene expression changes for peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1alpha), nuclear respiratory factors 1 (NRF1), and mitochondrial transcription factor A (Tfam) in soleus muscle and inguinal adipose tissue, and the related protein expression in soleus muscle. RESULTS: In soleus muscle, PGC-1alpha expression significantly increased in response to cold exposure (p = 0.006) and exercise (p = 0.05). There was also significant interaction between exercise and cold exposure (p = 0.005). Only exercise had a significant effect on NRF1 relative expression (p=0.001). Neither cold exposure nor the interaction showed significant effects (p = 0.1222 and p = 0.875, respectively). Relative Tfam expression did not show any significant effect from exercise. In inguinal adipose tissue, relative PGC-1alpha expression did not significantly change in any group. NRF1 expression showed a significant change from exercise (p = 0.01) and cold exposure (p = 0.011). There was also a significant interaction between exercise and cold exposure (p = 0.000). Tfam mRNA expression showed a significant effect from exercise (p=0.000) and an interaction between exercise and cold exposure (p=0.001). Only temperature significantly affected PGC-1alpha protein levels (p=0.045). Neither exercise nor the interaction were significant (p = 0.397 and p = 0.292, respectively). NRF1 protein levels did not show a significant effect in any experimental treatments. Tfam protein levels showed a significant effect in the exercise group (p=0.012), but effects of neither cold exposure nor the interaction were significant (p = 0.085 and p=0.374, respectively). CONCLUSION: Exercise and cold exposure promoted increased expression of mitochondrial biogenesis- related genes in soleus muscle. Only cold exposure had a significant effect on PGC-1alpha protein expression and only exercise had a significant effect on Tfam protein expression. In inguinal adipose tissue, there was interaction between exercise and cold exposure in expression of mitochondrial biogenesis-related genes. PMID- 28715886 TI - Effects of swimming exercise on high-fat diet-induced low bone mineral density and trabecular bone microstructure in rats. AB - PURPOSE: This study aimed to investigate the effect of swimming exercise on high fat diet-induced low bone mineral density (BMD) and trabecular bone microstructure in rats. METHODS: Eight-week-old male Sprague- Dawley (SD) rats were divided into a normal diet group (n = 9) and a high-fat diet group (n = 15). Three rats in each group were sacrificed after 8 weeks of high-fat diet to evaluate the association between high-fat diet and bone health. The other 18 rats were reassigned to 3 groups (normal diet control, NC; high-fat diet control, HC; high-fat diet + Exercise, HEx) for up to another 8 weeks. Rats in the exercise group were trained for a swimming exercise program (1 h/day, 5 times/ week for 8 weeks). All rats were sacrificed 24 h after the last bout of exercise to analyze the BMD and trabecular bone microstructure in the femur and tibia, using micro computed tomography. RESULTS: First, the effect of high-fat diet on bone health was examined. It was observed that BMD, percent bone volume (BV/TV), and trabecular number (Tb.N) of the femur and tibia were lower in rats in the high fat diet group than in those in the normal diet group (p < .05). In addition, BMD, BV/TV, and Tb.N of the femur and tibia were significantly increased in rats that underwent the 8-week swimming exercise program, compared to the corresponding values in rats in the HC group (p < .05). CONCLUSION: These results indicate that high-fat diets negatively affect bone health; however, these negative effects can be improved by exercises such as swimming. PMID- 28715887 TI - Pectin lyase-modified red ginseng extract exhibits potent anti-glycation effects in vitro and in vivo. AB - PURPOSE: GS-E3D is a newly developed pectin lyase-modified red ginseng extract. The purpose of this study was to evaluate the inhibitory effects of GS-E3D against advanced glycation end products. METHODS: In this study, we evaluated the inhibitory effects of GS-E3D on the formation of advanced glycation end products (AGEs) and their cross-linking with collagen in vitro and in streptozotocin induced diabetic rats. RESULTS: An in vitro assay for the glycation of bovine serum albumin by methylglyoxal showed that GS-E3D inhibited AGE formation at an IC50 value of 19.65 +/- 4.35 MUg/mL. In addition, GS-E3D showed a potent inhibitory effect (IC50 = 0.42 +/- 0.08 mg/mL) on the cross-linking of AGEs with collagen. However, GS-E3D showed no effect on preformed AGEs cross-linked with collagen in the breakdown assay. To determine whether GS-E3D inhibits AGE formation and their cross-linking with proteins in vivo, streptozotocin induced diabetic rats were treated with GS-E3D (25, 50, and 100 mg/kg/day) for 6 weeks. The administration of GS-E3D decreased serum levels of AGEs and their cross linking with proteins in diabetic rats. CONCLUSION: The inhibitory effects of this agent on advanced glycation in vitro and in vivo suggested that it may have a potential therapeutic role in controlling diabetes-induced AGE burden in various tissues. PMID- 28715888 TI - H-pi Landscape of the Phenylacetylene-HCl System: Does This Provide the Gateway to the Markovnikov Addition? AB - Non covalently bonded complexes of phenylacetylene-HCl were studied using matrix isolation infrared spectroscopy and ab initio calculations. Phenylacetylene (PhAc) is an interesting hydrogen bond precursor as it has multiple sites for weak interactions, and it was therefore considered worthwhile to study PhAc-HCl landscape. The interactions in PhAc-HCl were identified using the shifts in the infrared frequencies of the precursor molecules, as a result of complex formation. Our experiments unambiguously revealed spectral signatures of two types of H-pi complexes, in both of which HCl was the proton donor. In one complex, the acetylenic pi cloud (H-piAc) was the proton acceptor, while in the second, the role of the proton acceptor was played by the phenyl pi cloud (H piPh). The H-piAc and H-piPh complexes were evidenced by a 124 and 80 cm-1 red shift respectively, in the fundamental HCl stretch, relative to that of the uncomplexed HCl monomer. Ab initio calculations performed at M06-2X and MP2 level of theory using 6-311++G(d,p) and aug-cc-pVDZ basis functions indicated the H piAc complex to be the global minimum and the H-piPh complex to be a local minimum; thus corroborating our experimental results. These conclusions were also confirmed by calculations at MP2/CBS and CCSD(T)/CBS limits. Interestingly, there were two isomers for the H-piAc complex, and it appears from an analysis of the charge densities, that one of the two isomers may serve as the gateway complex for the Markovnikov addition reaction. Computations identified a number of other minima, characterized by n-sigma* and possibly Cl-pi bonded structures, on the PhAc-HCl potential surface. AIM, NBO, and LMO-EDA analyses were also performed to characterize the non covalent interactions in the PhAc-HCl heterodimer. PMID- 28715889 TI - Robust and Elastic Polymer Membranes with Tunable Properties for Gas Separation. AB - Polymer membranes with the capability to process a massive volume of gas are especially attractive for practical applications of gas separation. Although much effort has been devoted to develop novel polymer membranes with increased selectivity, the overall gas-separation performance and lifetime of membrane are still negatively affected by the weak mechanical performance, low plasticization resistance and poor physical aging tolerance. Recently, elastic polymer membranes with tunable mechanical properties have been attracting significant attentions due to their tremendous potential applications. Herein, we report a series of urethane-rich PDMS-based polymer networks (U-PDMS-NW) with improved mechanical performance for gas separation. The cross-link density of U-PDMS-NWs is tailored by varying the molecular weight (Mn) of PDMS. The U-PDMS-NWs show up to 400% elongation and tunable Young's modulus (1.3-122.2 MPa), ultimate tensile strength (1.1-14.3 MPa), and toughness (0.7-24.9 MJ/m3). All of the U-PDMS-NWs exhibit salient gas-separation performance with excellent thermal resistance and aging tolerance, high gas permeability (>100 Barrer), and tunable gas selectivity (up to alpha[PCO2/PN2] ~ 41 and alpha[PCO2/PCH4] ~ 16). With well-controlled mechanical properties and gas-separation performance, these U-PDMS-NW can be used as a polymer-membrane platform not only for gas separation but also for other applications such as microfluidic channels and stretchable electronic devices. PMID- 28715890 TI - Spring Melt and the Redistribution of Organochlorine Pesticides in the Sea-Ice Environment: A Comparative Study between Arctic and Antarctic Regions. AB - Complementary sampling of air, snow, sea-ice, and seawater for a range of organochlorine pesticides (OCPs) was undertaken through the early stages of respective spring sea-ice melting at coastal sites in northeast Greenland and eastern Antarctica to investigate OCP concentrations and redistribution during this time. Mean concentrations in seawater, sea-ice and snow were generally greater at the Arctic site. For example, alpha-HCH was found to have the largest concentrations of all analytes in Arctic seawater and sea-ice meltwater samples (224-253 and 34.7-48.2 pg.L-1 respectively compared to 1.0-1.3 and <0.63 pg.L-1 respectively for Antarctic samples). Differences in atmospheric samples were generally not as pronounced however. Findings suggest that sea-ice OCP burdens originate from both snow and seawater. The distribution profile between seawater and sea-ice showed a compound-dependency for Arctic samples not evident with those from the Antarctic, possibly due to full submersion of sea-ice at the former. Seasonal sea-ice melt processes may alter the exchange rates of selected OCPs between air and seawater, but are not expected to reverse their direction, which fugacity modeling indicates is volatilisation in the Arctic and net deposition in the Antarctic. These predictions are consistent with the limited current observations. PMID- 28715892 TI - Ethanol Solvation in Water Studied on a Molecular Scale by Photoelectron Spectroscopy. AB - Because of the amphiphilic properties of alcohols, hydrophobic hydration is important in the alcohol-water system. In the present paper we employ X-ray photoelectron spectroscopy (XPS) to investigate the bulk and surface molecular structure of ethanol-water mixtures from 0.2 to 95 mol %. The observed XPS binding energy splitting between the methyl C 1s and hydroxymethyl C 1s groups (BES_[CH3-CH2OH]) as a function of the ethanol molar percentage can be divided into different regions: one below 35 mol % with higher values (about 1.53 eV) and one starting at 60 mol % up to 95 mol % with 1.49 eV as an average value. The chemical shifts agree with previous quantum mechanics/molecular mechanics (QM/MM) calculations [ Loytynoja , T. ; J. Phys. Chem. B 2014 , 118 , 13217 ]. According to these calculations, the BES_[CH3-CH2OH] is related to the number of hydrogen bonds between the ethanol and the surrounding molecules. As the ethanol concentration increases, the average number of hydrogen bonds decreases from 2.5 for water-rich mixtures to 2 for pure ethanol. We give an interpretation for this behavior based on how the hydrogen bonds are distributed according to the mixing ratio. Since our experimental data are surface sensitive, we propose that this effect may also be manifested at the interface. From the ratio between the XPS C 1s core lines intensities we infer that below 20 mol % the ethanol molecules have their hydroxyl groups more hydrated and possibly facing the solution's bulk. Between 0.1 and 14 mol %, we show the formation of an ethanol monolayer at approximately 2 mol %. Several parameters are derived for the surface region at monolayer coverage. PMID- 28715891 TI - Sulfur K-Edge XAS Studies of the Effect of DNA Binding on the [Fe4S4] Site in EndoIII and MutY. AB - S K-edge X-ray absorption spectroscopy (XAS) was used to study the [Fe4S4] clusters in the DNA repair glycosylases EndoIII and MutY to evaluate the effects of DNA binding and solvation on Fe-S bond covalencies (i.e., the amount of S 3p character mixed into the Fe 3d valence orbitals). Increased covalencies in both iron-thiolate and iron-sulfide bonds would stabilize the oxidized state of the [Fe4S4] clusters. The results are compared to those on previously studied [Fe4S4] model complexes, ferredoxin (Fd), and to new data on high-potential iron-sulfur protein (HiPIP). A limited decrease in covalency is observed upon removal of solvent water from EndoIII and MutY, opposite to the significant increase observed for Fd, where the [Fe4S4] cluster is solvent exposed. Importantly, in EndoIII and MutY, a large increase in covalency is observed upon DNA binding, which is due to the effect of its negative charge on the iron-sulfur bonds. In EndoIII, this change in covalency can be quantified and makes a significant contribution to the observed decrease in reduction potential found experimentally in DNA repair proteins, enabling their HiPIP-like redox behavior. PMID- 28715893 TI - 5-Formyl- and 5-Carboxydeoxycytidines Do Not Cause Accumulation of Harmful Repair Intermediates in Stem Cells. AB - 5-Formyl-dC (fdC) and 5-carboxy-dC (cadC) are newly discovered bases in the mammalian genome that are supposed to be substrates for base excision repair (BER) in the framework of active demethylation. The bases are recognized by the monofunctional thymine DNA glycosylase (Tdg), which cleaves the glycosidic bond of the bases to give potentially harmful abasic sites (AP-sites). Because of the turnover of fdC and cadC during cell state transitions, it is an open question to what extent such harmful AP-sites may accumulate during these processes. Here, we report the development of a new reagent that in combination with mass spectrometry (MS) allows us to quantify the levels of AP-sites. This combination also allowed the quantification of beta-elimination (betaE) products, which are repair intermediates of bifunctional DNA glycosylases. In combination with feeding of isotopically labeled nucleosides, we were able to trace the intermediates back to their original nucleobases. We show that, while the steady state levels of fdC and cadC are substantially increased in Tdg-deficient cells, those of both AP- and betaE-sites are unaltered. The levels of the detected BER intermediates are 1 and 2 orders of magnitude lower than those of cadC and fdC, respectively. Thus, neither the presence of fdC nor that of cadC in stem cells leads to the accumulation of harmful AP- and betaE-site intermediates. PMID- 28715894 TI - Nanosheets of Two-Dimensional Magnetic and Conducting Fe(II)/Fe(III) Mixed Valence Metal-Organic Frameworks. AB - We report the synthesis, magnetic properties, electrical conductivity, and delamination into thin nanosheets of two anilato-based Fe(II)/Fe(III) mixed valence two-dimensional metal-organic frameworks (MOFs). Compounds [(H3O)(H2O)(phenazine)3][FeIIFeIII(C6O4X2)3].12H2O [X = Cl (1) and Br (2)] present a honeycomb layered structure with an eclipsed packing that generates hexagonal channels containing the water molecules. Both compounds show ferrimagnetic ordering at ca. 2 K coexisting with electrical conductivity (with room temperature conductivities of 0.03 and 0.003 S/cm). Changing the X group from Cl to Br leads to a decrease in the ordering temperature and room temperature conductivity that is correlated with the decrease of the electronegativity of X. Despite the ionic charge of the anilato-based layers, these MOFs can be easily delaminated in thin nanosheets with the thickness of a few monolayers. PMID- 28715895 TI - Chronic diarrhea, weight loss and heart failure. Features of the same disease? AB - Carcinoid tumors are neoplasm that release hormone-like substances. They can produce liver metastasis and present with symptoms of the carcinoid syndrome. A 78 year old man presented with a history of chronic diarrhea, weight loss and shortness of breath. PMID- 28715896 TI - Use of abdominal ultrasound in the diagnosis of hepatic sinusoidal obstruction syndrome (SOS) in a patient receiving a hematopoietic-cell transplant. AB - The sinusoidal obstruction syndrome (SOS) is an uncommon form of portal hypertension that occurs in hematopoietic-cell transplant recipients who receive intense conditioning treatments. The diagnosis is clinical and it is usually delayed, because in these patients there are many causes that can damage the liver and can delay its detection. We present the case of a 47-year-old man, whose diagnosis was made with clinical and analytical data supported by ultrasound signs that showed hepatic congestion. After treatment with defibrotide the patient improved clinically and analytically. Hepatic vascularization and perfusion also improved. Therefore, abdominal doppler ultrasound is shown as a noninvasive exploration useful for the clinical management of SOS and as an early marker of good clinical evolution. PMID- 28715898 TI - Endoscopic full-thickness resection for a gastric angioleiomyoma. AB - Angioleiomyoma (ALM) is a rare benign tumor, which is generally occurs on extremity, particularly the lower legs. It is composed of varied smooth muscle bundles and vascular channels. In this letter to editor, we describe the first case report of gastric ALM. PMID- 28715897 TI - Hepatic abscesses secondary to a foreign body in the common bile duct. AB - Hepatic abscesses subsequent to a gastrointestinal perforation after the ingestion of a foreign body are rare, even more so if the perforation passes through the gastric antrum to the common bile duct. We present the case of a 75 year-old male who had been suffering from fever, discomfort and weakness for a week. PMID- 28715899 TI - The clinical challenge of chronic Q fever with isolated liver involvement. AB - Chronic Q fever is defined as an infection by Coxiella burnetii (C. burnetii) that lasts for six months or more. It occurs in 1-5% of individuals infected with this agent and develops over a period of months to years after the acute infection. Cases of hepatic involvement are rare. PMID- 28715900 TI - Gangliocytic paraganglioma: an unusual cause of upper gastrointestinal bleeding. AB - Gangliocytic paraganglioma is an uncommon tumor, which is usually located in the ampulla of Vater, and may get confused in the differential diagnosis with ampuloma or GIST. Here we present a case of a patient with upper gastrointestinal bleeding as a predominant symptom, objectified by endoscopy an ulcerative polypoid mass at the juxtapilar level, with histological result of gangliocitica paraganglioma after multiple biopsies, and finally surgical resection. The interest of this case is the difficulty for diagnosing, the different treatments and prognosis that this implies, especially for the tumor location, as surgery can lead to great complications. PMID- 28715901 TI - An intrahepatic cavoportal collateral pathway due to a liver hydatid cyst obstructing the inferior vena cava. AB - Congenital or acquired obstruction of the inferior vena cava may lead to the development of collateral pathways with tributary vein to portal system. We present a patient with intrahepatic cavoportal collateral pathway due to hepatic hydatid cyst. PMID- 28715902 TI - Two types of achalasia in the same patient. Is this really the case? An unusual finding in a single study. AB - Within the functional tests, the High Resolution Manometry has been a great improvement in the diagnosis of esophageal motor disorders, especially those that cause obstruction or difficulty for the normal progress of the alimentary content. We present the case of a patient with dysphagia to which a manometry is performed in the diagnostic process, where the presence of two types of Acalasia is present in the same tracing. PMID- 28715903 TI - Parkinson's disease and Parkinson's disease psychosis: a perspective on the challenges, treatments, and economic burden. AB - Parkinson's disease (PD) is a progressive neurodegenerative disease associated with a decrease in the neurotransmitter dopamine and characterized by the cardinal motor hallmarks of resting tremor, rigidity, bradykinesia/akinesia, and postural instability. Lesser-known features of PD revolve around nonmotor concerns including psychosis, dementia, sleep disturbances, autonomic dysfunction, and sensory abnormalities. Parkinson's disease psychosis (PDP) contributes significantly to morbidity, mortality, nursing home placement, and quality of life (QOL). PDP management suffers from a lack of safe, effective pharmacological agents and the opposing nature of atypical antipsychotics and dopaminergic therapies. Pimavanserin, the only atypical antipsychotic currently approved by the FDA for treating PDP-related hallucinations and delusions, has no appreciable affinity for dopaminergic receptors, and a controlled clinical study demonstrated its efficacy in treating PDP-associated hallucinations and delusions without affecting motor function. A recent analysis of all health resource utilization (HRU) and total costs attributable to PD and PDP found that mean 12 month HRU services per patient were 2.3 times higher and costs were 2.1 times higher in the PDP cases, while falls were 3.4 times higher and fractures 2.3 times higher, respectively. Products or services that prevent, delay, or lessen the severity of PDP may contribute to reduced healthcare system costs and improve the QOL of patients with PDP and of their caregivers. PMID- 28715904 TI - Considerations for optimal management of patients with pulmonary arterial hypertension: a multi-stakeholder roundtable discussion. AB - A roundtable panel of national and regional managed care decision makers and providers met to discuss pulmonary arterial hypertension (PAH) and strategies for management. As a rare, complex disease with high economic costs and potentially devastating outcomes, PAH necessitates that managed care providers balance optimal care with efficient use of healthcare resources. PAH specialists are recognized by health plans as knowledgeable experts and integral partners in managing patients and resources. The diagnosis of PAH must be confirmed by a right heart catheterization. Available therapies are indicated almost exclusively for patients with PAH (riociguat is also indicated in chronic thromboembolic pulmonary hypertension) and target 1 of 3 pathways: endothelin receptor antagonists for the endothelin pathway; phosphodiesterase type-5 inhibitors and soluble guanylate cyclase stimulators for the nitric oxide pathway; and prostanoids as well as a prostacyclin receptor agonist for the prostacyclin pathway, with combination therapy becoming more common. Even in the modern treatment era, as shown in the REVEAL and French registries, PAH is often diagnosed years after symptoms first appear, which leads to a poor prognosis and increased burden on the healthcare system. Facilitating treatment of patients with PAH through centers of excellence, and coordinating care management between health plans and providers with evidence-based approaches can lead to both better results for patients and lower healthcare costs. When PAH experts have access to the right treatments for the right patients at the right time, they can work with insurers to improve the health of patients with PAH while helping to reduce the impact on the healthcare system. PMID- 28715905 TI - Preventing Thromboembolism in Hospitalized Patients: Improving Quality Using a Peer-to-Peer Electronic Alerting System. PMID- 28715906 TI - T2* Mapping Provides Information That Is Statistically Comparable to an Arthroscopic Evaluation of Acetabular Cartilage. AB - Objectives The purpose of this study was to validate T2* mapping as an objective, noninvasive method for the prediction of acetabular cartilage damage. Methods This is the second step in the validation of T2*. In a previous study, we established a quantitative predictive model for identifying and grading acetabular cartilage damage. In this study, the model was applied to a second cohort of 27 consecutive hips to validate the model. A clinical 3.0-T imaging protocol with T2* mapping was used. Acetabular regions of interest (ROI) were identified on magnetic resonance and graded using the previously established model. Each ROI was then graded in a blinded fashion by arthroscopy. Accurate surgical location of ROIs was facilitated with a 2-dimensional map projection of the acetabulum. A total of 459 ROIs were studied. Results When T2* mapping and arthroscopic assessment were compared, 82% of ROIs were within 1 Beck group (of a total 6 possible) and 32% of ROIs were classified identically. Disease prediction based on receiver operating characteristic curve analysis demonstrated a sensitivity of 0.713 and a specificity of 0.804. Model stability evaluation required no significant changes to the predictive model produced in the initial study. Conclusions These results validate that T2* mapping provides statistically comparable information regarding acetabular cartilage when compared to arthroscopy. In contrast to arthroscopy, T2* mapping is quantitative, noninvasive, and can be used in follow-up. Unlike research quantitative magnetic resonance protocols, T2* takes little time and does not require a contrast agent. This may facilitate its use in the clinical sphere. PMID- 28715907 TI - Selective Effects of Psychotherapy on Frontopolar Cortical Function in PTSD. AB - OBJECTIVE: Exposure therapy is an effective treatment for posttraumatic stress disorder (PTSD), but a comprehensive, emotion-focused perspective on how psychotherapy affects brain function is lacking. The authors assessed changes in brain function after prolonged exposure therapy across three emotional reactivity and regulation paradigms. METHOD: Individuals with PTSD underwent functional MRI (fMRI) at rest and while completing three tasks assessing emotional reactivity and regulation. Individuals were then randomly assigned to immediate prolonged exposure treatment (N=36) or a waiting list condition (N=30) and underwent a second scan approximately 4 weeks after the last treatment session or a comparable waiting period, respectively. RESULTS: Treatment-specific changes were observed only during cognitive reappraisal of negative images. Psychotherapy increased lateral frontopolar cortex activity and connectivity with the ventromedial prefrontal cortex/ventral striatum. Greater increases in frontopolar activation were associated with improvement in hyperarousal symptoms and psychological well-being. The frontopolar cortex also displayed a greater variety of temporal resting-state signal pattern changes after treatment. Concurrent transcranial magnetic stimulation and fMRI in healthy participants demonstrated that the lateral frontopolar cortex exerts downstream influence on the ventromedial prefrontal cortex/ventral striatum. CONCLUSIONS: Changes in frontopolar function during deliberate regulation of negative affect is one key mechanism of adaptive psychotherapeutic change in PTSD. Given that frontopolar connectivity with ventromedial regions during emotion regulation is enhanced by psychotherapy and that the frontopolar cortex exerts downstream influence on ventromedial regions in healthy individuals, these findings inform a novel conceptualization of how psychotherapy works, and they identify a promising target for stimulation-based therapeutics. PMID- 28715909 TI - Ribosomal Stalling During Translation: Providing Substrates for Ribosome Associated Protein Quality Control. AB - Cells of all organisms survey problems during translation elongation, which may happen as a consequence of mRNA aberrations, inefficient decoding, or other sources. In eukaryotes, ribosome-associated quality control (RQC) senses elongation-stalled ribosomes and promotes dissociation of ribosomal subunits. This so-called ribosomal rescue releases the mRNA for degradation and allows 40S subunits to be recycled for new rounds of translation. However, the nascent polypeptide chains remain linked to tRNA and associated with the rescued 60S subunits. As a final critical step in this pathway, the Ltn1/Listerin E3 ligase subunit of the RQC complex (RQCc) ubiquitylates the nascent chain, which promotes clearance of the 60S subunit while simultaneously marking the nascent chain for elimination. Here we review the ribosomal stalling and rescue steps upstream of the RQCc, where one witnesses intersection with cellular machineries implicated in translation elongation, translation termination, ribosomal subunit recycling, and mRNA quality control. We emphasize both recent progress and future directions in this area, as well as examples linking ribosomal rescue with the production of Ltn1-RQCc substrates. PMID- 28715908 TI - PTSD Psychotherapy Outcome Predicted by Brain Activation During Emotional Reactivity and Regulation. AB - OBJECTIVE: Exposure therapy is an effective treatment for posttraumatic stress disorder (PTSD), but many patients do not respond. Brain functions governing treatment outcome are not well characterized. The authors examined brain systems relevant to emotional reactivity and regulation, constructs that are thought to be central to PTSD and exposure therapy effects, to identify the functional traits of individuals most likely to benefit from treatment. METHOD: Individuals with PTSD underwent functional MRI (fMRI) while completing three tasks assessing emotional reactivity and regulation. Participants were then randomly assigned to immediate prolonged exposure treatment (N=36) or a waiting list condition (N=30). A random subset of the prolonged exposure group (N=17) underwent single-pulse transcranial magnetic stimulation (TMS) concurrent with fMRI to examine whether predictive activation patterns reflect causal influence within circuits. Linear mixed-effects modeling in line with the intent-to-treat principle was used to examine how baseline brain function moderated the effect of treatment on PTSD symptoms. RESULTS: At baseline, individuals with larger treatment-related symptom reductions (compared with the waiting list condition) demonstrated 1) greater dorsal prefrontal activation and 2) less left amygdala activation, both during emotion reactivity; 3) better inhibition of the left amygdala induced by single TMS pulses to the right dorsolateral prefrontal cortex; and 4) greater ventromedial prefrontal/ventral striatal activation during emotional conflict regulation. Reappraisal-related activation was not a significant moderator of the treatment effect. CONCLUSIONS: Capacity to benefit from prolonged exposure in PTSD is gated by the degree to which prefrontal resources are spontaneously engaged when superficially processing threat and adaptively mitigating emotional interference, but not when deliberately reducing negative emotionality. PMID- 28715910 TI - Isotopic fingerprints of the Lake Zabinskie (NE Poland) hydrological system on contemporary carbonates precipitated in the lake. AB - An isotopic monitoring was undertaken in 2012-2014 at Lake Zabinskie (Mazurian Lakeland, NE Poland). The aim was to identify the factors and processes controlling an isotopic composition of the lake water and to explore the mechanism responsible for recording the climatic signal in stable isotope composition of deposited carbonates. delta18O and delta2H in the precipitation, lake water column, inflows and outflow, delta18O and delta13C in the carbonate fraction of sediments trapped in the water column were recorded with monthly resolution. A relationship between delta18O and delta2H in local precipitation was used to estimate the local meteoric water line. The dataset obtained for the water enabled to identify the modification of the water's isotopic composition due to evaporation, connected with seasonal lake water stratification and mixing patterns. Statistically significant correlation coefficients suggest that the delta18O of the carbonate fraction in the sediment traps depends on the delta18O of rainfall water and on air temperature. The fractionation coefficient alpha shows that in summer months the carbonate precipitation process is closest to equilibrium. As expected for an exorheic lake, no significant correlation was observed between delta18O and delta13C in precipitated carbonate. PMID- 28715911 TI - Hepatitis C Treatment Regimens Are Cost-Effective: But Compared With What? AB - BACKGROUND: Numerous economic models have been published evaluating treatment of chronic hepatitis C virus (HCV) infection, but none provide a comprehensive comparison among new antiviral agents. OBJECTIVE: Evaluate the cost-effectiveness of all recommended therapies for treatment of genotypes 1 and 4 chronic HCV. METHODS: Using data from clinical trials, observational analyses, and drug pricing databases, Markov decision models were developed for HCV genotypes 1 and 4 to compare all recommended drugs from the perspective of the third-party payer over a 5-, 10-, and 50-year time horizon. A probabilistic sensitivity analysis (PSA) was conducted by assigning distributions for clinical cure, age entering the model, costs for each health state, and quality-adjusted life years (QALYs) for each health state in a Monte Carlo simulation of 10 000 repetitions of the model. RESULTS: In the lifetime model for genotype 1, effects ranged from 18.08 to 18.40 QALYs and total costs ranged from $88 107 to $184 636. The lifetime model of genotype 4 treatments had a range of effects from 18.23 to 18.43 QALYs and total costs ranging from $87 063 to $127 637. Grazoprevir/elbasvir was the optimal strategy followed by velpatasvir/sofosbuvir as the second-best strategy in most simulations for both genotypes 1 and 4, with drug costs and efficacy of grazoprevir/elbasvir as the primary model drivers. CONCLUSIONS: Grazoprevir/elbasvir was cost-effective compared with all strategies for genotypes 1 and 4. Effects for all strategies were similar with cost of drug in the initial year driving the results. PMID- 28715912 TI - Acetyl- and O-alkyl- derivatives of beta-mangostin from Garcinia mangostana and their anti-inflammatory activities. AB - Pure beta-mangostin (1) was isolated from the stem bark of Garcinia mangostana L. One monoacetate (2) and five O-alkylated beta-mangostin derivatives (3-7) were synthesised from beta-mangostin. The structures of these compounds were elucidated and determined using spectroscopic techniques such as 1D NMR and MS. The cytotoxicities and anti-inflammatory activities of these five compounds against RAW cell 264.7 were tested. The structural-activity relationship studies indicated that beta-mangostin showed a significant activity against the LPS induced RAW cell 264.7, while the acetyl- as well as the O-alkyl- beta-mangostin derivatives did not give good activity. Naturally occurring beta-mangostin demonstrated comparatively better anti-inflammatory activity than its synthetic counterparts. PMID- 28715913 TI - Body parameters of Czech breastfed children compared to the Czech references and WHO growth standards. AB - BACKGROUND: The study concerns the comparison of percentile curves of Czech breastfed children with Czech national references from 1991 and 2001 and WHO growth standards. Growth charts of breastfed children demonstrate different curve shapes, especially in the first months of life. Incorrect interpretation of the growth curve could lead to premature introduction of complementary foods or infant formula. AIM: The comparison of four body parameters of Czech breastfed children with currently used Czech national references and WHO standards in order to recommend that Czech paediatricians use either Czech references or WHO standards in their practice. SUBJECTS AND METHODS: Nine hundred and sixty breastfed children were included in the study of length-for-age, head circumference-for-age, weight-for-age and weight-for-length parameters. All percentile curves were compared. Values of the 50th percentile expressed in z scores based on both Czech references and WHO standards were tested. RESULTS: The study confirmed results of previous surveys documenting that growth of breastfed children is specific. Nevertheless, percentile curves of growth parameters of Czech breastfed children are closer to Czech references than WHO standards. CONCLUSIONS: The Czech national references fulfil the needs of Czech paediatricians (with pointing to specifics of breastfed child growth) and WHO standards are suitable, especially for international comparison. PMID- 28715914 TI - Leprosy in a Lombard-Avar cemetery in central Italy (Campochiaro, Molise, 6th-8th century AD): ancient DNA evidence and demography. AB - BACKGROUND: The study of past infectious diseases increases knowledge of the presence, impact and spread of pathogens within ancient populations. AIM: Polymerase chain reaction (PCR) was used to examine bones for the presence of Mycobacterium leprae ancient DNA (aDNA) as, even when leprosy is present, bony changes are not always pathognomonic of the disease. This study also examined the demographic profile of this population and compared it with two other populations to investigate any changes in mortality trends between different infectious diseases and between the pre-antibiotic and antibiotic eras. SUBJECTS AND METHODS: The individuals were from a site in Central Italy (6th-8th CE) and were examined for the presence of Mycobacterium leprae aDNA. In addition, an abridged life mortality table was constructed. RESULTS: Two individuals had typical leprosy palaeopathology, and one was positive for Mycobacterium leprae aDNA. However, the demographic profile shows a mortality curve similar to that of the standard, in contrast to a population that had been subjected to bubonic plague. CONCLUSIONS: This study shows that, in the historical population with leprosy, the risk factors for health seem to be constant and distributed across all age classes, similar to what is found today in the antibiotic era. There were no peaks of mortality equivalent to those found in fatal diseases such as the plague, probably due to the long clinical course of leprosy. PMID- 28715915 TI - The uses of outcome measures within multidisciplinary early childhood intervention services: a systematic review. AB - : Purpose of the article: To review the use of outcome measures, across the domains of activity, participation, and environment, within multidisciplinary early childhood intervention services. MATERIALS AND METHODS: A systematic literature search was undertaken that included four electronic databases: Medline, CINAHL, EMBASE, and the Cochrane Library and Cochrane Database of Systematic Review. Inclusion criteria were age 0-24 months, having or at risk of a developmental disability, in receipt of multidisciplinary early childhood intervention services, and included outcome measures across all domains of the International Classification of Functioning-Child & Youth (ICF-CY). Only peer reviewed journal articles were considered. Eligible studies were coded using the Oxford Levels of Evidence. Methodological quality was assessed using the Physiotherapy Evidence Database (PEDro) Scale for randomised controlled trials and the QualSyst for non-randomised control trials. RESULTS: Of the total of 5764 records identified, 10 were considered to meet inclusion criteria. CONCLUSION: Fourteen outcome measures were identified, addressing the domains of activity, participation, and environment. Of these, eight have been recommended in the early intervention literature. While the methodological quality of the 10 studies varied, these papers make a contribution to the body of research that acknowledges the role of routine and enriched environments. Implications for Rehabilitation Core practice elements of multidisciplinary early childhood intervention services indicate it is necessary to select outcome measures framed within the International Classification of Functioning-Child & Youth to inform clinical decision-making for measuring intervention effectiveness across the domains of activity, participation and environment. Of the identified measures, three (Canadian Occupational Performance Measure, Pediatric Evaluation of Disability Inventory, and Goal Attainment Scaling) are well-established and identified in the literature as multidisciplinary outcome measures for children with developmental disability. The selection of an appropriate outcome measure depends on the age of the child, individual goals of the family, and the type of intervention. This requires the combination of measures as no one measure alone will capture all components of the International Classification of Functioning Child & Youth. PMID- 28715916 TI - Drug management of neutrophilic dermatoses. AB - INTRODUCTION: Neutrophilic dermatoses are a heterogenous group of chronic, cutaneous inflammatory conditions characterized by the accumulation of neutrophils in the skin and by systemic inflammation. Neutrophilic dermatoses can be idiopathic or associated with other inflammatory or systemic diseases, including the group of the hereditary, autoinflammatory syndromes. Clinical management is challenging, due to limited clinical evidence and lack of clinical practice guidelines. Areas covered: This review provides an overview of current therapeutic management of the three prototypical neutrophilic dermatoses, aseptic pustulosis of the folds, Sweet syndrome and pyoderma gangrenosum. In addition, we describe innovative, pathogenesis-oriented treatment approaches, which are based on recent advances in the pathophysiology of neutrophilic dermatoses and autoinflammatory syndromes. The increasing role of the IL-1 cytokine family in initiating neutrophilic inflammation in both idiopathic and syndromic disease opened the way for the use of targeted biological treatment. Another promising treatment strategy is aimed at blocking downstream effector cytokines, such as IL12/23 and IL-17, involved in the autoinflammatory immune cascade. Expert commentary: In chronic-recurrent and syndromic cases of neutrophilic dermatoses, there is an unmet clinical need for long-term, continuous disease control. Future controlled clinical studies will optimize the use of targeted-biological agents in sequential or combination treatment strategies. PMID- 28715917 TI - Self-reported discomfort associated with Daylight Saving Time in Brazilian tropical and subtropical zones. AB - BACKGROUND: Daylight Saving Time (DST) annually moves clocks 1 hour forward, when daytime is longer than night. Previous studies from medium and high latitude locations have pointed to a disruptive effect of DST on human circadian rhythms. Since Brazil is an equatorial country implementing DST, a different relationship between photic and social synchronisers may interfere with DST effects. AIM: To explore the prevalence and duration of self-reported discomfort related to DST among Brazilian residents (latitude 12-33 degrees S, longditude 39-57 degrees W). It was hypothesised that an elevated prevalence of self-reported discomfort would be found in Brazil, due to the pronounced uncoupling between social and geophysical synchronisers. SUBJECTS AND METHODS: In total, 12 467 volunteers completed a web-based, Brazilian version of Horne-Ostberg Morningness-Eveningness Questionnaire, provided demographic information, and answered questions related to DST complaints (discomfort, duration of discomfort). RESULTS: Of the total sample, 45.43% reported no discomfort related to DST, with meaningful proportions for all chronotypes. However, eveningness was most associated with discomfort. About one fourth of the total sample reported discomfort over the whole DST period. Gender interaction is largely supported by these results. CONCLUSIONS: DST at low latitude locations may be disruptive for circadian rhythms, since seasonality of sunrise near the equator is negligible or very mild. PMID- 28715918 TI - Anti-proliferation effects of ethanolic extracts from Sophora moorcroftiana seeds on human hepatocarcinoma HepG2 cell line. AB - Previous studies have shown that the ethanolic extracts from Sophora moorcroftiana seeds (ee-Sms) have in vitro anticancer properties. The anti proliferation effects of ee-Sms on HepG2 cells were assessed by MTT assay and cell cycle analysis. Total cell proteins were separated by two-dimensional electrophoresis (2-DE), and protein spots with more than two-fold difference were analysed by MALDI-TOF/TOF-MS. MTT assay showed that the anti-proliferation of ee Sms demonstrates dose- and time dependently. HepG2 cells were treated with ee-Sms at 1.30 mg/mL for 48 h induced cell cycle arrest in S phase. The differentially expressed proteins were involved in DNA repair, cell proliferation, cell metabolism and immunoreaction. This study sheds new insights into the molecular mechanisms underlying the anti-proliferation properties of ee-Sms in HepG2 cells. PMID- 28715919 TI - Lived experiences of Jordanian mothers caring for a child with disability. AB - PURPOSE: Caring for a child with a disability in the family is associated with a major increase in care-giving demands and burden. This qualitative study explores the perspectives, challenges and adaptations of Jordanian mothers living with a child with disability. METHODS: Phenomenological qualitative tradition was utilized. Seven Jordanian mothers of children with disability were purposefully selected as having rich experiences for caring for a child with a disability. In depth interviews were conducted using a semi-structured guide, audio-taped and transcribed verbatim. Interpretive phenomenological analysis was used to extract main themes and subthemes. RESULTS: Mothers' experiences were reflected into four main themes: (1) increased perceived stigma, (2) fear for the future, (3) increased perceived care-giving burden and (4) adaptations to the child's disability. CONCLUSIONS: This study highlights key gaps in the provision of family-centered services for this population as well as multiple sociocultural issues impacting participation and quality of life. Healthcare professionals must deal with the child's disability from a family-centered and cultural perspective. Implications for rehabilitation When therapists meet the whole family's needs through a family-centered approach, the child with disability is less likely to be ignored, maltreated or abused. Family-centered practice adopts a sociocultural model which looks at the child from a wider point of view rather than just the disability itself. It requires therapists to review the context in which the child lives and address the specific needs of parents, siblings and other involved family members. Culture plays a huge role in shaping the family's perspective on disability and has a huge impact and implications for service delivery and development, quality of life and participation for children with disability and their families. Rehabilitation professionals must accommodate their time schedules to provide families with the communication, education, advocacy and consultations needed. PMID- 28715920 TI - Genital tract GBS and rate of histologic chorioamnionitis in patients with preterm premature rupture of membrane. AB - INTRODUCTION: Histologic chorioamnionitis (HC) is a common finding in the placenta from patients with preterm premature rupture of membranes (PPROM). The purpose of this study is to determine if HC differs based on the Group B streptococcus (GBS) status in patients managed expectantly with PPROM <34 weeks gestation. METHODS: A retrospective study was performed of patients admitted with PPROM between 23 0/7 and 33 6/7 weeks from 2003 to 2014 at one institution. Patients were excluded if in labor, evidence of clinical chorioamnionitis, nonreassuring fetal status, multifetal gestation, HIV positive, or if GBS specimens or placental histology were not available. Placental pathology results were compared using Fisher's exact test. RESULTS: One hundred eighty-one patients met inclusion criteria and 55 (30.3%) were GBS positive. The prevalence of HC did not differ between the GBS positive and GBS negative groups (69 versus 64.2%, respectively; p = .62). Clinical chorioamnionitis, endomyometritis, wound infection, maternal and neonatal sepsis did not differ between the two groups. CONCLUSIONS: Vaginal-rectal colonization with GBS on admission does not appear to affect the rate of HC nor neonatal outcome in patients managed conservatively with PPROM <34 weeks gestation. PMID- 28715921 TI - The role of secreted heat shock protein-90 (Hsp90) in wound healing - how could it shape future therapeutics? AB - INTRODUCTION: Defects in tissue repair or wound healing pose a clinical, economic and social problem worldwide. Despite decades of studies, there have been few effective therapeutic treatments. Areas covered: We discuss the possible reasons for why growth factor therapy did not succeed. We point out the lack of human disorder-relevant animal models as another blockade for therapeutic development. We summarize the recent discovery of secreted heat shock protein-90 (Hsp90) as a novel wound healing agent. Expert commentary: Wound healing is a highly complex and multistep process that requires participations of many cell types, extracellular matrices and soluble molecules to work together in a spatial and temporal fashion within the wound microenvironment. The time that wounds remain open directly correlates with the clinical mortality associated with wounds. This time urgency makes the healing process impossible to regenerate back to the unwounded stage, rather forces it to take many shortcuts in order to protect life. Therefore, for therapeutic purpose, it is crucial to identify so-called 'driver genes' for the life-saving phase of wound closure. Keratinocyte-secreted Hsp90alpha was discovered in 2007 and has shown the promise by overcoming several key hurdles that have blocked the effectiveness of growth factors during wound healing. PMID- 28715923 TI - Correction to: Aryanpour and Farzaneh, On the die compaction of powders used in pharmaceutics. PMID- 28715922 TI - DLK1-DIO3 imprinted locus deregulation in development, respiratory disease, and cancer. AB - INTRODUCTION: The imprinted DLK1-DIO3 locus at 14q32.1-32.31 holds biological significance in fetal development, whereby imprinting errors are causal to developmental disorders. Emerging evidence has implicated this locus in other diseases including cancer, highlighting the biological parallels between fetal organ and tumour development. Areas covered: Controlled regulation of gene expression from the imprinted DLK1-DIO3 locus at 14q32.1-32.31 is crucial for proper fetal development. Deregulation of locus gene expression due to imprinting errors has been mechanistically linked to the developmental disorders Kagami Ogata Syndrome and Temple Syndrome. In adult tissues, deregulation of locus genes has been associated with multiple malignancies although the causal genetic mechanisms remain largely uncharacterised. Here, we summarize the genetic mechanisms underlying the developmental disorders that arise as a result of improper locus imprinting and the resulting developmental phenotypes, emphasizing both the coding and noncoding components of the locus. We further highlight biological parallels common to both fetal development and disease, with a specific focus on lung development, respiratory disease, and lung cancer. Expert commentary: Many commonalities between respiratory and developmental defects have emerged with respect to the 14q32 locus, emphasizing the importance of studying the effects of imprinting on gene regulation patterns at this locus in both biological settings. PMID- 28715924 TI - Moyamoya Disease in Children: Results From the International Pediatric Stroke Study. AB - This study aimed to describe children with moyamoya disease from an international multicenter stroke database, and explore risk factors for stroke recurrence. We reviewed data of children >28-days old with moyamoya disease enrolled in the International Pediatric Stroke Study from January 2003 to March 2013. A total of 174 children from 32 sites and 14 countries had moyamoya disease; median age 7.4 years, 49% male. Of these, 90% presented with ischemic stroke, 7.5% with transient ischemic attack, and 2.5% with hemorrhagic stroke. One-third of patients had moyamoya syndrome. Stroke recurrence was 20% over median follow-up of 13 months; 9% had multiple recurrences. Children treated with surgical revascularization were less likely to have stroke recurrence ( P = .046). Moyamoya disease accounted for 8% of arterial strokes in this international pediatric stroke registry. One-third of pediatric patients with moyamoya disease have an underlying syndromic condition. Surgical revascularization is effective at reducing the incidence of stroke recurrence. PMID- 28715925 TI - Factors Associated With Care Workers' Intention to Leave Employment in Nursing Homes: A Secondary Data Analysis of the Swiss Nursing Homes Human Resources Project. AB - The emerging care personnel shortage in Swiss nursing homes is aggravated by high turnover rates. As intention to leave is a predictor of turnover, awareness of its associated factors is essential. This study applied a secondary data analysis to evaluate the prevalence and variability of 3,984 nursing home care workers' intention to leave. Work environment factors and care worker outcomes were tested via multiple regression analysis. Although 56% of care workers reported intention to leave, prevalences varied widely between facilities. Overall, intention to leave showed strong inverse relationships with supportive leadership and affective organizational commitment and weaker positive relationships with stress due to workload, emotional exhaustion, and care worker health problems. The strong direct relationship of nursing home care workers' intention to leave with affective organizational commitment and perceptions of leadership quality suggest that multilevel interventions to improve these factors might reduce intention to leave. PMID- 28715926 TI - Microencapsulation of anthocyanin-rich black soybean coat extract by spray drying using maltodextrin, gum Arabic and skimmed milk powder. AB - Black soybean coat is insufficiently valorised food production waste rich in anthocyanins. The goal of the study was to examine physicochemical properties of spray dried extract of black soybean coat in regard to carrier materials: maltodextrin, gum Arabic, and skimmed milk powder. Maltodextrin and gum Arabic based microparticles were spherical and non-porous while skimmed milk powder based were irregularly shaped. Low water activity of microparticles (0.31-0.33), good powders characteristics, high solubility (80.3-94.3%) and encapsulation yields (63.7-77.0%) were determined. All microparticles exhibited significant antioxidant capacity (243-386 MUmolTE/g), good colour stability after three months of storage and antimicrobial activity. High content of total anthocyanins, with cyanidin-3-glucoside as predominant, were achieved. In vitro release of anthocyanins from microparticles was sustained, particularly from gum Arabic based. These findings suggest that proposed simple eco-friendly extraction and microencapsulation procedures could serve as valuable tools for valorisation and conversion of black soybean coat into highly functional and stable food colourant. PMID- 28715927 TI - MAWRID: A Model of Arabic Word Reading in Development. AB - This article offers a model of Arabic word reading according to which three conspicuous features of the Arabic language and orthography shape the development of word reading in this language: (a) vowelization/vocalization, or the use of diacritical marks to represent short vowels and other features of articulation; (b) morphological structure, namely, the predominance and transparency of derivational morphological structure in the linguistic and orthographic representation of the Arabic word; and (c) diglossia, specifically, the lexical and lexico-phonological distance between the spoken and the standard forms of Arabic words. It is argued that the triangulation of these features governs the acquisition and deployment of reading mechanisms across development. Moreover, the difficulties that readers encounter in their journey from beginning to skilled reading may be better understood if evaluated within these language specific features of Arabic language and orthography. PMID- 28715928 TI - Lack of evidence-the anti-stepwise introduction of metal-on-metal hip replacements. AB - Background and purpose - Orthopedics and especially joint replacement surgery have had more than their fair share of unsuccessful innovations that have violated widely endorsed principles for the introduction of new surgical innovations. We aimed to investigate (1) the trends in the use of the Birmingham Hip Resurfacing (BHR), the ASR hip resurfacing (ASR HRA) and the ASR XL total hip replacement (ASR XL THR) system with very different market approval processes and (2) whether their use was corroborated by clinical trials published in the peer reviewed literature. Methods - The literature was searched for any clinical studies that reported outcomes of the BHR, ASR HRA and ASR XL THRs. Data from 7 national hip arthroplasty registers were collected and the number of annually implanted devices was matched to those reported in the literature. Results - The cumulative number of implanted and published BHRs grew proportionally with a small lag. The growth of implanted BHRs started to decline at the same time as the ASR HR was introduced. With regard to ASR HRAs, the cumulative proportion of implanted hips and those included in the published studies grew disproportionately after the introduction of the ASR in 2003. For ASR XL THRs, the disproportionality is even higher. Interpretation - The adoption of ASR hip replacements did not follow the proposed stepwise introduction of orthopedic implants. The adoption and use of any new implant should follow a strict guideline and algorithm even if the theoretical basis or the results of preclinical studies are excellent. PMID- 28715929 TI - Molecular interactions of bisphenols and analogs with glucocorticoid biosynthetic pathway enzymes: an in silico approach. AB - Glucocorticoids are known to have vital effects on metabolism, behavior and immunity. Any sort of impairment in their synthesis may lead to the generation of numerous ill health effects. Different environmental toxicants, including bisphenols and their analogs pose deleterious effect on the biosynthesis of glucocorticoids, thereby leading to endocrine disruption. In order to assess the effect of these environmental toxicants on gluocorticoid biosynthetic pathway, an in silico study was performed. This involved molecular docking studies of 18 ligands with the selected participating enzymes of the pathway. These enzymes were CYP11A1, CYP11B2, CYP19A1, CYP17A1, 3alpha/20beta-HSD, 3beta/17beta-HSD and CYP21A2. Comparison of their binding affinity was made with the known inhibitors of these enzymes. In case of CYP11A1, Bisphenol M (BP M) had the lowest docking score (D score) of -8.699 kCal/mol, and was better than that of the standard, Metyrapone. Bisphenol PH (BP PH) was found to have significant affinity with CYP11B2. In case CYP19A1, results were found to be comparable with the standards, Exemestane and Letrozole. BP PH elicited better results than the standard Abiraterone acetate against CYP17A1. BP M had a D score of -7.759 against 3alpha/20beta-HSD, again better results than the standard, Trilostane. Upon molecular docking of BP PH against CYP21A2, it was seen that amongst all the analogs, it had maximum interactions along with the lowest D score. From all the above instances mentioned, it is quite evident that certain BPA analogs have more potential to modulate the enzymes involved in comparison to the known inhibitors. PMID- 28715930 TI - Transcription analysis of cochlear development in minipigs. AB - CONCLUSIONS: The critical stage for cochlear gene regulation in the embryo is E49 E56. These data provide a valuable resource to help elucidate gene regulation in cochlear development and will benefit ear-related studies, especially those that focus on gene and stem cell therapies in hearing loss. OBJECTIVES: To investigate gene regulation in cochlear development and provide reference information for ear related research. METHODS: Total RNA extraction from the Bama miniature pig cochlea was performed at five time points that covered most of the cochlea development process (E42, E49, E56, E91, P13). Transcriptome sequencing was performed by Illumina HiSeq 2500. Transcriptome data were mapped to the genome using TopHat2. Gene expression was quantified using the Cuffquant and Cuffnorm modules. GO and KEGG pathway-enrichment analysis were in progress about the differentially expressed genes (DEGs) by Perl programs. RESULTS: Sequencing of 1778643560000 paired reads revealed 35.9 G of data, and 19,432 expression genes were detected. The ratio of these pairs to the Ensembl genome database was approximately 71% in all samples. The stages E49-E91 and, especially, E49-E56 included the most rapid changes in gene regulation and differentiation for the cochlea. The stem cell characteristics of neural stem cells decreased most rapidly during this period. PMID- 28715932 TI - The Association of Socioeconomic Conditions and Readiness to Learn New Ways of Performing Daily Activities in Older Adults With Functional Difficulties. AB - Behavioral interventions for older adults can reduce difficulties in performing daily activities, hospitalizations, and mortality risk. The success of behavior change interventions, however, can be affected by a participant's readiness to adopt changes. This study evaluates whether socioeconomic conditions, particularly financial strain affording food, are associated with readiness to change. We conducted a cross-sectional, descriptive study of baseline data from disabled older adults ( N = 147) participating in an intervention to reduce physical disability. Readiness to change score was rated at the start of the intervention by interventionists as either pre-action (precontemplation = 1, contemplation = 2, preparation = 3) or action (=4). Participants reporting high financial strain affording food were more likely to have high readiness at the start of intervention; the association of this specific socioeconomic condition with readiness may be an important consideration in implementing interventions to reduce disability. PMID- 28715931 TI - Understanding and acting on the developmental origins of health and disease in Africa would improve health across generations. AB - Data from many high- and low- or middle-income countries have linked exposures during key developmental periods (in particular pregnancy and infancy) to later health and disease. Africa faces substantial challenges with persisting infectious disease and now burgeoning non-communicable disease.This paper opens the debate to the value of strengthening the developmental origins of health and disease (DOHaD) research focus in Africa to tackle critical public health challenges across the life-course. We argue that the application of DOHaD science in Africa to advance life-course prevention programmes can aid the achievement of the Sustainable Development Goals, and assist in improving health across generations. To increase DOHaD research and its application in Africa, we need to mobilise multisectoral partners, utilise existing data and expertise on the continent, and foster a new generation of young African scientists engrossed in DOHaD. PMID- 28715933 TI - Neuropsychological tools to predict conversion from amnestic mild cognitive impairment to dementia. The TREDEM Registry. AB - Most of the studies about conversion from Mild cognitive impairment (MCI) to dementia have focused on amnestic MCI (aMCI) which is considered a preclinical phase of Alzheimer's disease. The aim of the present study was to identify neuropsychological tools that would best predict conversion from aMCI to dementia. Fifty-five aMCI subjects on the Treviso Dementia Registry were investigated. They underwent a neuropsychological evaluation during their first assessment and again at follow-up. Cox proportional-hazard regression models were created to measure the association between the dependent variable (dementia diagnosis or MCI status maintenance) and the neuropsychological test scores at baseline. The sample (28 women and 27 men; mean age 76.82 +/- 5.88 years; education 7.62 +/- 3.99 years) was observed for an average time of 2.17 +/- 1.25 years. A Cox backward stepwise regression showed that the Rey Auditory Verbal Learning Test, Delayed Recall (p = .041) and Semantic Verbal Fluency tests (p = .031) appear to be useful in predicting conversion to dementia. PMID- 28715934 TI - 'First 1000 days' health interventions in low- and middle-income countries: alignment of South African policies with high-quality evidence. AB - BACKGROUND: In South Africa (SA), despite adoption of international strategies and approaches, maternal, neonatal and child (MNC) morbidity and mortality rates have not sufficiently declined. OBJECTIVES: To conduct an umbrella review (UR) that identifies interventions in low- and middle-income countries, with a high quality evidence base, that improve MNC morbidity and mortality outcomes within the first 1000 days of life; and to assess the incorporation of the evidence into local strategies, guidelines and documents. METHODS: We included publications about women and children in the first 1000 days of life; healthcare professionals and community members. Comparators were those who did not receive the intervention. Interventions were pharmacological and non-pharmacological. Outcomes were MNC morbidity and mortality. Authors conducted English language electronic and manual searches (2000-2013). The quality of systematic reviews and meta-analyses (SRs/MAs) were reviewed. Interventions were ranked according to level of evidence; and then aligned with SA strategies, policies and guidelines. A tool to extract data was developed and used by two authors who independently extracted data. Summary measures from MAs or summaries of SRs were reviewed and the specificities of the various interventions listed. A search of all local high level documents was done and these were assessed to determine the specificities of the recommendations and their alignment to the evidence. RESULTS: In total, 19 interventions presented in 32 SRs were identified. Overall, SA's policymakers have sufficiently included high-quality evidence-based interventions into local policies. However, optimal period of birth spacing (two to five years) is not explicitly promoted nor was ante- and postnatal depression adequately incorporated. Antenatal care visits should be increased from four to about eight according to the evidence. CONCLUSION: Incorporation of existing evidence into policies can be strengthened in SA. The UR methods are useful to inform policymaking and identify research gaps. RESPONSIBLE EDITOR Nawi Ng, Umea University, Sweden. PMID- 28715936 TI - Selection of gait parameters for differential diagnostics of patients with de novo Parkinson's disease. AB - BACKGROUND: Gait disturbances are an integral part of clinical manifestations of Parkinson's disease (PD), even in the initial stages of the disease. Our goal was to identify the set of spatio-temporal gait parameters that bear the highest relevance for characterizing de novo PD patients. METHODS: Forty patients with de novo PD and forty healthy controls were recorded while walking over an electronic walkway in three different conditions: (1) base walking, (2) walking with an additional motor task, (3) walking with an additional mental task. Both groups were well balanced concerning age and gender. To select a smaller number of relevant parameters, affinity propagation clustering was applied on parameter pairwise correlation. The exemplars were then sorted by importance using the random forest algorithm. Classification accuracy of a support vector machine was tested using the selected parameters and compared to the accuracy of the model using a set of parameters derived from literature. RESULTS: Final selection of parameters included: stride length and stride length coefficient of variation (CV), stride time and stride time CV, swing time and swing time CV, step time asymmetry, and heel-to-heel base support CV. Classification performed using these parameters showed higher overall accuracy (85%) than classification using the common parameter set containing: stride time, stride length, swing time and double support time, along with their CVs (78%). CONCLUSION: In early stages of PD, double support time and its CV appear to be weak indicators of the disease. We instead found step time asymmetry and support base CV to significantly contribute to classification accuracy. PMID- 28715937 TI - Offense Processes of Online Sexual Grooming and Abuse of Children Via Internet Communication Platforms. AB - The aim of the present study was to provide an inclusive and realistic account of the offense processes of naturally occurring, sexually exploitative interactions between offenders and victims that took place via Internet communication platforms, and develop an offense process diagram of online sexual grooming and abuse. Five case series, comprising 29 transcripts of 22 interactions, were analyzed using the qualitative approach of thematic analysis. Police reports were reviewed for descriptive and case-specific information. The five offenders were men aged between 27 and 52 years ( M = 33.6, SD = 5.6), and the number of children they communicated with ranged from one to 12 ( M = 4.6, SD = 4.5). Victims were aged between 11 and 15 ( M = 13.0, SD = 1.2), and were both female ( n = 17) and male ( n = 6). Findings revealed that offenders employed either an indirect or a direct approach to conversations with victims and initiating contact with them. The approach offenders employed was also reflected in the types of strategies they used. Only two offenders were found to engage in aspects of sexual grooming as part of an indirect approach; the majority of the interactions by the other three offenders, that lacked features of sexual grooming altogether, were found to be of a direct approach. These findings are discussed in relation to current issues surrounding terminology and definition of sexual grooming, as well as theoretical and practical implications, concluding with suggestions for future research. PMID- 28715935 TI - New findings of Toll-like receptors involved in Mycobacterium tuberculosis infection. AB - Tuberculosis (TB), an important issue in the present age, affects millions of people each year. The infectious agent of TB, Mycobacterium tuberculosis (Mtb), interacts with the immune system which prevents the development of this bacterium as much as possible. In fact, the receptors on the surface of immune cells identify the bacteria, one of which is Toll-like receptors (TLRs). Different TLRs including 2, 4, 9 and 8 play critical roles in tuberculosis infection. In this paper, we focused on the role of TLRs which interact with different components of Mtb and, consequently, prevent the entrance and influence of bacteria on the body. PMID- 28715938 TI - The design of civic technology: factors that influence public participation and impact. AB - Civic technology needs to be better understood in terms of the factors that promote representative public participation and impact. This paper reports on a mixed-methods study of a civic tech platform that enabled the public to provide feedback on public transport to the service providers. The overall aim of this research was to investigate the public's use of a leading civic tech platform, FixMyTransport. The key findings were that: an effective and easy-to-use civic technology platform enables broad participation; data and process complexity need to be removed; factual information can be captured in situ with impacts, consequences and opinions added later; emotions (if important) need to be explicitly elicited; feedback to, and a 'conversation' with, the users is important for engagement, as is a feeling of being part of a community. These findings can contribute to the future design of civic technology platforms. Practitioner Summary: There is a lack of understanding of how 'civic tech' platforms are used and how they may be designed for maximum effectiveness. Multiple data collection methods were used to investigate a well-developed example of civic tech. Effective civic tech can enable broad democratic participation to improve public services. PMID- 28715939 TI - Surgical versus non-operative treatment for lumbar disc herniation: a systematic review and meta-analysis. AB - OBJECTIVE: To investigate the effects of surgical versus non-operative treatment on the physical function and safety of patients with lumbar disc herniation. DATA SOURCES: PubMed, Cochrane Library, Embase, EBSCO, Web of Science, China National Knowledge Infrastructure and Chinese Biomedical Literature Database were searched from initiation to 15 May 2017. METHODS: Randomized controlled trials that evaluated surgical versus non-operative treatment for patients with lumbar disc herniation were selected. The primary outcomes were pain and side-effects. Secondary outcomes were function and health-related quality of life. A random effects model was used to calculate the pooled mean difference with 95% confidence interval. RESULTS: A total of 19 articles that involved 2272 participants met the inclusion criteria. Compared with non-operative treatment, surgical treatment was more effective in lowering pain (short term: mean difference = -0.94, 95% confidence interval = -1.87 to -0.00; midterm: mean difference = -1.59, 95% confidence interval = -2.24 to -9.94), improving function (midterm: mean difference = -7.84, 95% confidence interval = -14.00 to -1.68; long term: mean difference = -12.21, 95% confidence interval = -23.90 to -0.52) and quality of life. The 36-item Short-Form Health Survey for physical functions (short term: mean difference = 6.25, 95% confidence interval = 0.43 to 12.08) and bodily pain (short term: mean difference = 5.42, 95% confidence interval = 0.40 to 10.45) was also utilized. No significant difference was observed in adverse events (mean difference = 0.82, 95% confidence interval = 0.28 to 2.38). CONCLUSION: Low-quality evidence suggested that surgical treatment is more effective than non-operative treatment in improving physical functions; no significant difference was observed in adverse events. No firm recommendation can be made due to instability of the summarized data. PMID- 28715940 TI - Synthesis of lupeol derivatives and their antileishmanial and antitrypanosomal activities. AB - The natural product lupeol 1 was isolated from aerial parts of Vernonia scorpioides with satisfactory yield, which made it viable to be used as starting material in semisynthetic approach. Ten lupeol derivatives 2-11 were prepared by classical procedures. Including, five new esters derivatives 7-11, which were obtained by structural modifications in the isopropylidene fragment. All semisynthetic compounds and lupeol 1-11 were confirmed by 1H NMR, 13C NMR and HRMS. Their antiprotozoal activity was evaluated in vitro against L. amazonensis and T. cruzi. Derivative 6 showed the best antitrypanosomal activity (IC50 = 12.48 MUg/mL) and the lowest cytotoxic derivative (CC50 = 161.50 MUg/mL). The mechanism of action of the most active derivatives (4, 6 and 11) is not dependent from the enzyme trypanothione reductase. PMID- 28715941 TI - Moderate anemia at diagnosis is an independent prognostic marker of the EUTOS, Sokal, and Hasford scores for survival and treatment response in chronic-phase, chronic myeloid leukemia patients with frontline imatinib. AB - OBJECTIVES: This study aimed to examine the prognostic value of anemia for the diagnosis of chronic myeloid leukemia in the chronic phase (CML-CP) receiving imatinib. METHODS: One hundred and fifty-four CML-CP patients were enrolled. The influences of moderate anemia with hemoglobin (Hb) < 10 g/dl, four scoring systems, and the early molecular response at 3 months (BCR-ABL <=10%; 3M-EMR) on the achievement of a deep molecular response (DMR, MR4.5), progression-free survival (PFS), event-free survival (EFS), and overall survival (OS) were compared. RESULTS: Moderate anemia was identified in 44 (28.6%) patients. These patients had more aggressive baseline features and higher risks, as assessed by scoring systems, and less favorable treatment responses vs those without anemia, including 3M-EMR (50.0% vs 69.1%), a complete cytogenetic response at 6 months (20.5% vs 50.9%), and a major molecular response at 12 months (22.5% vs 45.2%), with a median follow-up of 54.0 months. Furthermore, an Hb of 10 g/dl better distinguished DMR, EFS, PFS, and OS than the EUTOS, Sokal, and Hasford scores, and better predicted the responses and survivals in combination with 3M-EMR than 3M-EMR alone. CONCLUSIONS: This finding highlights the significance of anemia in CML-CP, and suggests that patients with anemia at diagnosis should be carefully monitored and might benefit from more potent TKIs if not achieving 3M-EMR. PMID- 28715942 TI - Trends in conservative procedures and peripartum hysterectomy rates in severe postpartum haemorrhage. AB - OBJECTIVE: The objective of this study is to explore whether increase in use of second-line conservative surgical procedures will alter the rate of peripartum hysterectomies in management of severe postpartum haemorrhage (PPH). METHODS: This is a retrospective cohort. All pregnant patients with gestation > = 28 weeks with severe PPH (> = 1.5 L) within 72 h of delivery from year 2000 to 2015 (16 year period) in an obstetric training unit was recruited. Basic patient anthropometric characteristics and the main causes for PPH were calculated. The incidence of any second-line conservative surgical procedures and peripartum hysterectomies were evaluated. The total number of patients in each category was then stratified into four 4 years-intervals (4 quadrennium) to compare trends. RESULTS: The incidence of severe PPH gradually increased over the study period (lowest 0.21% in 2002 to 0.76% in 2015) (p < .001). There is an obvious increasing trend in the overall use of second-line surgical procedures from nil to 82% (p < .001), with balloon tamponade constituting up to 48%. The incidence of successful second-line procedures increased gradually from 72.2% in the second quadrennium to 89% in the fourth quadrennium. The total peripartum hysterectomy rate among cases of severe PPH could be seen to drop from 40.2% in the first to 10.9% in the fourth quadrennium (p = .04). CONCLUSIONS: Despite the increasing trends in PPH, the increasing utilisation of second-line conservative surgical procedures in severe PPH should be able to reduce the need for peripartum hysterectomy. PMID- 28715943 TI - Introducing treat-to-target strategies of autoimmune extrahepatic manifestations of chronic hepatitis C virus infection. AB - INTRODUCTION: The hepatitis C virus (HCV) is recognized as one of the hepatic viruses most often associated with extrahepatic manifestations (EHMs). It is currently accepted that cryoglobulinemic vasculitis (CV) is the key autoimmune extrahepatic disease associated with HCV infection. Therapeutic approaches have mainly been based on the use of old antiviral interferon (IFN)-based regimens and immunosuppressive therapies, often with an inadequate balance between therapeutic benefits and excess side effects. Areas covered: Therapeutic management of HCV patients with EHMs, including both non-autoimmune (cardiovascular, hematological, general features) and autoimmune complications (organ-specific and systemic autoimmune diseases). Therapies included antiviral (IFN, ribavirin, direct-acting antivirals - DAAs-) and non-antiviral (immunosuppressive agents, rituximab, plasma exchanges) options. The review analyses the current evidence for proposing a treat-to-target (T2T) approach for HCV-related autoimmune EHMs based on an organ-by-organ strategy. Expert commentary: Eradication of HCV must be considered the key T2T in the therapeutic approach to HCV-related EHMs, as there has been a disruptive change due to the appearance of direct-acting antivirals (DAAs) as game-changers in HCV therapy, with an efficacy reaching nearly 100%. In this scenario, the central role played until now by IFN and ribavirin is not currently supported and they will not be used in the future. PMID- 28715944 TI - Comparison of two different techniques used for the maintenance of peri-implant soft tissue health: a pilot randomized clinical trial. AB - OBJECTIVES: The aim of this pilot study was to compare the effectiveness of two different methods of debridement on maintaining and improving peri-implant soft tissue health over a period of 12 months. MATERIALS AND METHODS: Twenty adult patients (25 implants) were enrolled in a randomized, single-blinded, parallel group clinical trial. All implants included showed no signs of pathologic bone loss. Patients were scheduled to be reviewed every 3 months over a 12 months period. Nine patients (15 implants) were randomly allocated to a test group and treated with a low abrasive air polishing powder (Air-Flow(r) Perio, EMS) (AFP) and another nine (10 implants) to a control group and treated with titanium curettes (TC). Peri-implant crevicular fluid samples were analyzed to quantitatively measure the concentration of six interleukins (IL-6, IL-8, IL 1beta, TNF, IL-10 and IL-12). A multilevel analysis was used to test the comparison between the two treatments. The same analysis was used to study the relationship between clinical parameters and cytokines while controlling for confounding factors. RESULTS: There was no significant difference in bleeding on probing (BOP) between the two treatment methods (p = .35). Both debridement techniques resulted in a similar reduction of BOP (40.04% and 39.93%). IL-6 was the only cytokine of the six investigated that demonstrated a correlation with a clinical parameter (BOP) (p = .05). CONCLUSIONS: Both treatment methods were proven to be effective in reducing peri-implant inflammation and preventing further disease progression. Some cytokines may act as markers for peri-implant disease as the present study showed a significant relationship between IL-6 and BOP. PMID- 28715945 TI - Methodological issues associated with clinical trials in epilepsy. AB - INTRODUCTION: despite methodological advances in epilepsy clinical trials, the proportion of patients reaching seizure-freedom has not substantially changed over the years. We review the main methodological limitations of current trials, the possible strategies to overcome these limits, and the issues that need to be addressed in next future. Area covered: references were identified by PubMed search until March 2017 and unpublished literature was searched on ClinicalTrials.gov. Add-on trials mainly involve refractory epilepsy subjects, reducing overall response to the investigational drug. The inclusion of subjects with earlier disease from less developed countries has partially allowed overcoming this limitation, but has introduced more random variability of results. Monotherapy trials rise methodological, economical, and ethical concerns with different regulatory requirements in European Union and in the United States of America. Newer trial designs, such as futility trials or 'time-to-event' design, have been implemented. Moreover, both add-on and monotherapy trials results might be affected by patient's ability to recognize and record seizures, and by randomness of seizures occurrence over time. Possible strategies to achieve more reliable outcomes are detailed. Expert commentary: clinical trial methodology needs to be optimized to better address regulatory agencies requirements and to encounter both patients' and clinicians' needs. PMID- 28715946 TI - Sleep and psychiatric symptoms in young child psychiatric outpatients. AB - BACKGROUND: Sleep may underlie psychiatric symptoms in young children. However, not many studies have reported on sleep and its associations with symptoms in young child psychiatric patients. OBJECTIVES: To assess the amount and quality of sleep and how sleep associates with psychiatric symptoms in young child psychiatric patients. Furthermore, we evaluated how sleep and daytime somnolence differed in patients and their age- and gender-matched controls. METHOD: The sample consisted of 139 3- to 7-year-old child psychiatric outpatients and 139 age- and gender-matched controls from community. We evaluated sleep and daytime somnolence with the Sleep Disturbance Scale for Children in all children and psychiatric symptoms with Child Behaviour Checklist (CBCL) in the patient group. Family background information was collected from the patients. RESULTS: Of the patients, 31.6% had a significant sleep problem and 14.4% slept too little. The most typical sleep problems were restless sleep (31.7%), morning tiredness (21.6%) and difficulties getting to sleep at night (18.7%). All types of sleep problems were associated with CBCL total, internalising and externalising problems (all p-values < .01). We observed a strong association between all types of sleep problems and emotionally reactive subscale ( p-value < .001). Furthermore, parent-reported sleep problems increased significantly the risk of having high scores on total (odds ratio (OR) = 5.3, 95% confidence interval (CI) = [2.2, 12.6], p < .001), external (OR = 3.7, 95%, CI = [1.6, 8.5], p < .01) and internal (OR = 2.5, 95% CI = [1.1, 5.5], p < .05) scores after controlling for age, gender, family structure and parent's educational level. Even mild sleep disturbance increased the intensity of psychiatric symptoms. Compared to controls, patients slept less ( p < .001) and had significantly more frequent restless sleep, nightmares and morning and daytime somnolence. CONCLUSION: Sleep problems and too little sleep are prevalent in young child psychiatric patients, and they relate strongly to the intensity of psychiatric symptoms. Identification and treatment of sleep problems should be a routine part of the treatment plan for young child psychiatric patients. The results emphasise the need for assessing sleep in young child psychiatric patients, as treating the sleep problem may reduce psychiatric symptoms. PMID- 28715948 TI - The Motivation-Facilitation Model of Sexual Offending. AB - In this article, I describe the motivation-facilitation model of sexual offending, which identifies the traits of paraphilia, high sex drive, and intense mating effort as primary motivations for sexual offenses, as well as trait (e.g., antisocial personality) and state (e.g., intoxication) factors that can facilitate acting on these motivations when opportunities exist. Originally developed to explain contact sexual offending against children, the motivation facilitation model was subsequently extended as an explanation for child pornography offending and for online solicitations of young adolescents. Here, I argue it has the potential to be expanded to explain other forms of sexual offending, including sexual assaults of adults and noncontact offenses involving exhibitionism or voyeurism. In this review, I critically examine the evidence for and against the model, discuss its limitations, and identify critical gaps for future research. PMID- 28715949 TI - Contrast-Enhanced Ultrasound for Assessing Renal Perfusion Impairment and Predicting Acute Kidney Injury to Chronic Kidney Disease Progression. AB - AIMS: Acute kidney injury (AKI) is increasingly recognized as a major risk factor leading to progression to chronic kidney disease (CKD). However, the diagnostic tools for predicting AKI to CKD progression are particularly lacking. Here, we tested the utility of contrast-enhanced ultrasound (CEUS) for predicting progression to CKD after AKI by using both mild (20-min) and severe (45-min) bilateral renal ischemia-reperfusion injury mice. RESULTS: Renal perfusion measured by CEUS reduced to 25% +/- 7% and 14% +/- 6% of the pre-ischemic levels in mild and severe AKI 1 h after ischemia (p < 0.05). Renal perfusion returned to pre-ischemic levels 1 day after mild AKI followed by restoration of kidney function. However, severe AKI caused persistent renal perfusion impairment (60% +/- 9% of baseline levels) accompanied by progressive renal fibrosis and sustained decrease in renal function. Renal perfusion at days 1-21 significantly correlated with tubulointerstitial fibrosis 42 days after AKI. For predicting renal fibrosis at day 42, the area under the receiver operating characteristics curve of renal perfusion impairment at day 1 was 0.84. Similar changes in the renal image of CEUS were observed in patients with AKI-CKD progression. INNOVATION: This study demonstrates that CEUS enables dynamic and noninvasive detection of renal perfusion impairment after ischemic AKI and the perfusion abnormalities shown by CEUS can early predict the progression to CKD after AKI. CONCLUSIONS: These results indicate that CEUS enables the evaluation of renal perfusion impairment associated with CKD after ischemic AKI and may serve as a noninvasive technique for assessing AKI-CKD progression. Antioxid. Redox Signal. 27, 1397-1411. PMID- 28715952 TI - 41st Annual Southern Pediatric Neurology Society Meeting. PMID- 28715950 TI - Efficacy of the Novel Medical Adhesive, MAR-VIVO-107, in an Acute Porcine Liver Resection Model. AB - BACKGROUND: Despite modern surgical techniques, insufficient hemostasis after liver trauma is still a major cause of morbidity and mortality after injury. Therefore, efficient hemostatic agents are indicated. In this study, we evaluated the hemostatic efficacy of a novel synthetic wound adhesive (MAR-VIVO-107) based on polyurethane/polyurea, compared with a widely used fibrin adhesive (Tisseel). MATERIALS AND METHODS: Twelve German Landrace pigs were randomly assigned to 2 groups. The animals were operated under sterile conditions. A midline laparotomy was performed and the left liver lobe was isolated and resected, using a surgical scissor, in order to induce hepatic trauma. MAR-VIVO-107 or Tisseel was applied to the resected area. The animals were monitored for 60 minutes; thereafter, they were sacrificed under anesthesia. Blood and tissue samples were collected pre- and postresection for biochemical and hematological analyses. RESULTS: MAR-VIVO 107 versus Tisseel (mean +/- SD, P value)-postsurgical survival rate was 100% in both groups. Bleeding time was significantly higher in Tisseel compared with MAR VIVO-107 (10.3 +/- 5.0 vs 3.7 +/- 1.5 minutes, P = .0124). In trend, blood loss was less in the MAR-VIVO-107 group (54.3 +/- 34.9 vs 105.5 +/- 65.8 g, P = .222). Aspartate transaminase levels were significantly lower in the MAR-VIVO-107 group when compared with the Tisseel group (39.0 +/- 10.0 vs 72.4 +/- 23.4 U/L, P = .0459). CONCLUSION: The efficacy of MAR-VIVO-107 and comparable performance to the gold standard fibrin have been shown under pre-clinical conditions. MAR-VIVO 107 permits hemorrhage control within seconds, even in wet environment. PMID- 28715955 TI - The Functional Neuroanatomy of Human Face Perception. AB - Face perception is critical for normal social functioning and is mediated by a network of regions in the ventral visual stream. In this review, we describe recent neuroimaging findings regarding the macro- and microscopic anatomical features of the ventral face network, the characteristics of white matter connections, and basic computations performed by population receptive fields within face-selective regions composing this network. We emphasize the importance of the neural tissue properties and white matter connections of each region, as these anatomical properties may be tightly linked to the functional characteristics of the ventral face network. We end by considering how empirical investigations of the neural architecture of the face network may inform the development of computational models and shed light on how computations in the face network enable efficient face perception. PMID- 28715956 TI - Visual Decision-Making in an Uncertain and Dynamic World. AB - The right decision today may be the wrong decision tomorrow. We live in a world in which expectations, contingencies, and goals continually evolve and change. Thus, decisions do not occur in isolation but rather are tightly embedded in these streams of temporal dependencies. Accordingly, even relatively straightforward visual decisions must take into account not just the immediate sensory input but also past experiences and future goals and expectations. Here, we evaluate recent progress in understanding how the brain implements these dependencies. We show that visual decision-making relies on mechanisms of evidence accumulation and commitment that have been studied extensively under relatively static, isolated conditions but in general can operate much more flexibly. A deeper understanding of these mechanisms will require identifying the principles that govern this flexibility, which must operate across different timescales to produce effective decisions in uncertain and dynamic environments. PMID- 28715958 TI - Vision and Action. AB - Investigation of natural behavior has contributed a number of insights to our understanding of visual guidance of actions by highlighting the importance of behavioral goals and focusing attention on how vision and action play out in time. In this context, humans make continuous sequences of sensory-motor decisions to satisfy current behavioral goals, and the role of vision is to provide the relevant information for making good decisions in order to achieve those goals. This conceptualization of visually guided actions as a sequence of sensory-motor decisions has been formalized within the framework of statistical decision theory, which structures the problem and provides the context for much recent progress in vision and action. Components of a good decision include the task, which defines the behavioral goals, the rewards and costs associated with those goals, uncertainty about the state of the world, and prior knowledge. PMID- 28715959 TI - Preeclampsia and maternal risk of breast cancer: a meta-analysis of cohort studies. AB - BACKGROUND: Pregnancy-related hypertensive disorders, including preeclampsia (PE) and pregnancy-induced hypertension (PIH), may influence the maternal risk of breast cancer. However, results of the cohort studies were inconsistent. METHODS: An updated meta-analysis of cohort studies was performed to evaluate the association between PE, PIH and maternal breast cancer incidence. Relevant studies were identified via searching of PubMed and Embase databases. A random effect model was applied to synthesize the results. Stratified analyses were performed to evaluate the potential influence of parity, gender of offspring, and study design on the association between PE and maternal breast cancer incidence. RESULTS: Ten cohort studies with 2,417,899 pregnant women were included. Maternal risk of breast cancer was not significantly affected by PE (risk ration [RR] = 0.93, 95% confidence interval [CI]: 0.82-1.06, p = .27), or PIH (RR = 0.95, 95% CI: 0.81-1.12, p = .54). Interestingly, PE was associated with significantly lowered maternal incidence of breast cancer in women who give birth to male offspring (RR = 0.79, p < .01), and in those of prospective cohort studies (RR = 0.87, p < .01). However, no significant association between PE and maternal breast cancer was detected in primiparous women, those who gave birth to female offspring, or those of retrospective cohorts. CONCLUSIONS: Current evidence did not support a conclusive association between PE, PIH and the maternal risk of breast cancer. Gender of the offspring may influence the association between PE and maternal breast cancer incidence. PMID- 28715960 TI - Histone Methylation by SET Domain Proteins in Fungi. AB - Histone-modifying enzymes are responsible for regulating transcription, recombination, DNA repair, DNA replication, chromatid cohesion, and chromosome segregation. Fungi are ideally suited for comparative chromatin biology because sequencing of numerous genomes from many clades is coupled to existing rich methodology that allows truly holistic approaches, integrating evolutionary biology with mechanistic molecular biology and ecology, promising applications in medicine or plant pathology. While genome information is rich, mechanistic studies on histone modifications are largely restricted to two yeasts, Saccharomyces cerevisiae and Schizosaccharomyces pombe, and one filamentous fungus, Neurospora crassa-three species that arguably are not representative of this diverse kingdom. Here, histone methylation serves as a paradigm to illustrate the roles chromatin modifications may play in more complex fungal life cycles. This review summarizes recent advances in our understanding of histone H3 methylation at two sites associated with active transcription, lysine 4 and lysine 36 (H3K4, H3K36); a site associated with the formation of constitutive heterochromatin, lysine 9 (H3K9); and a site associated with the formation of facultative heterochromatin, lysine 27 (H3K27). Special attention is paid to differences in how methylation marks interact in different taxa. PMID- 28715957 TI - The Transduction Cascade in Retinal ON-Bipolar Cells: Signal Processing and Disease. AB - Our robust visual experience is based on the reliable transfer of information from our photoreceptor cells, the rods and cones, to higher brain centers. At the very first synapse of the visual system, information is split into two separate pathways, ON and OFF, which encode increments and decrements in light intensity, respectively. The importance of this segregation is borne out in the fact that receptive fields in higher visual centers maintain a separation between ON and OFF regions. In the past decade, the molecular mechanisms underlying the generation of ON signals have been identified, which are unique in their use of a G-protein signaling cascade. In this review, we consider advances in our understanding of G-protein signaling in ON-bipolar cell (BC) dendrites and how insights about signaling have emerged from visual deficits, mostly night blindness. Studies of G-protein signaling in ON-BCs reveal an intricate mechanism that permits the regulation of visual sensitivity over a wide dynamic range. PMID- 28715961 TI - Genetics and Epigenetics of Mating Type Determination in Paramecium and Tetrahymena. AB - While sex is an ancient and highly conserved eukaryotic invention, self incompatibility systems such as mating types or sexes appear to be derived limitations that show considerable evolutionary plasticity. Within a single class of ciliates, Paramecium and Tetrahymena species have long been known to present a wide variety of mating type numbers and modes of inheritance, but only recently have the genes involved been identified. Although similar transmembrane proteins mediate self/nonself recognition in both ciliates, the mechanisms of mating type determination differ widely, ranging from Mendelian systems to developmental nuclear differentiation, either stochastic or maternally inherited. The non Mendelian systems rely on programmed editing of the germline genome that occurs during differentiation of the somatic nucleus, and they have co-opted different DNA recombination mechanisms-some previously unknown. Here we review the recent molecular advances and some remaining unsolved questions and discuss the possible implications of these diverse mechanisms for inbreeding/outbreeding balance regulation. PMID- 28715962 TI - In Vitro Analysis of the Differentiation Capacity of Postmortally Isolated Human Chondrocytes Influenced by Different Growth Factors and Oxygen Levels. AB - Objective In the present in vitro study, we analyzed the chondrogenic differentiation capacity of human chondrocytes postmortally isolated from unaffected knee cartilage by the addition of transforming growth factor-beta1 (TGF-beta1) and/or insulin-like growth factor-1 (IGF-1) and different oxygen levels. Design After 14 and 35 days, DNA concentrations and protein contents of Col1, Col2, aggrecan as well as glycosaminoglycans (GAGs) of chondrocytes cultivated as pellet cultures were analyzed. Additionally, expression rates of mesenchymal stem cell (MSC)-associated differentiation markers were assessed in monolayer cultures. Results All cultivated chondrocytes were found to be CD29+/CD44+/CD105+/CD166+. Chondrocytic pellets stimulated with TGF-beta1 showed enhanced synthesis rates of hyaline cartilage markers and reduced expression of the non-hyaline cartilage marker Col1 under hypoxic culture conditions. Conclusions Our results underline the substantial chondrogenic potential of human chondrocytes postmortally isolated from unaffected articular knee cartilage especially in case of TGF-beta1 administration. PMID- 28715964 TI - Uterine and Abdominal Muscle Electromyographic Activities in Control and PCEA Treated Nulliparous Women During the Second Stage of Labor. AB - OBJECTIVE: Patient-controlled epidural analgesia (PCEA), used to relieve pain during delivery, delays labor but the mechanism is unknown. The aim was to investigate the effects of PCEA on uterine and abdominal muscles electromyographic (EMG) activity during the second stage of labor. METHODS: This study included 45 nulliparous pregnant women without PCEA, 42 women with standard PCEA treatment given during the first stage of labor and stopped near the end of the first stage, and 22 women with standard PCEA treatment with continued use throughout the first and second stages of labor. The EMG signals were recorded from the abdominal surface using PowerLab hardware and LabChart software (ADInstruments, New South Wales, Australia) and filtered to separate uterine and abdominal EMG. Various EMG burst parameters were obtained. RESULTS: There are no differences ( P > .05) in the age, body mass index, fetal weight, and Apgar scores between the patients from the various groups. PCEA (both stopped and continued) inhibits ( P < .05) duration, number of bursts, and root mean square of uterine EMG. PCEA also produces statistically significant ( P < .001) reductions in abdominal EMG. The decrease in EMG activity is accompanied by a significant ( P < .001) prolongation of the second stage duration (PCEA continued = 95.08 +/- 8.60 minutes, PCEA stopped = 79.39 +/- 6.25 minutes, no PCEA = 61.00 +/- 7.23 minutes). CONCLUSION: PCEA suppresses uterine and abdominal muscle EMG during the second stage of labor but inhibition depends upon the treatment schedule. PCEA prolongs the duration of labor by inhibition of uterine and abdominal muscle and neural activity. PMID- 28715965 TI - Dual Triggering With Gonadotropin-Releasing Hormone Agonist and Standard Dose Human Chorionic Gonadotropin in Patients With a High Immature Oocyte Rate. AB - In in vitro fertilization (IVF) cycles, some patients show a high rate of immature oocytes retrieved after controlled ovarian stimulation. In vitro oocyte maturation is an experimental technique, with poorer results than conventional IVF. For this reason, improving in vivo maturation could meliorate the reproductive outcome of these patients. We performed a retrospective, not interventional, study analyzing the difference in the number and percentage of mature oocytes retrieved in patients with more than 50% immature oocytes in a previous IVF cycle triggered with human chorionic gonadotropin (hCG) compared to the number and rate of mature oocytes retrieved in subsequent cycles, triggered with both gonadotropin-releasing hormone agonist (GnRH-a) and hCG. The number of mature oocytes retrieved with a dual trigger was significantly higher than that for hCG alone: 5.3 +/- 3.6 (4.4-6.1) versus 2.4 +/- 2.2 (2-2.9). The proportion of mature oocytes showed the same tendency (79.6% vs 43.6%). The implantation, clinical, and ongoing pregnancy rates were 17.3%, 26.9%, and 15.3%, respectively, for the hCG trigger and 30.8%, 43.6%, and 31.6%, respectively, for the dual trigger. In patients with a low percentage of retrieved mature oocytes, who were triggered with a combination of GnRH-a and hCG, the number and percentage of retrieved mature oocytes improved. The dual trigger also seemed to meliorate gestational outcomes after IVF. PMID- 28715966 TI - Protective Effects of Human Chorionic Gonadotropin Against Breast Cancer: How Can We Use This Information to Prevent/Treat the Disease? AB - Breast cancers (BCs) are the most common malignancies among women worldwide. Giving birth to a first child before 24 years of age decreases the BC risk by about half, when women reach menopausal years. The scientific evidence suggests that the actions of human chorionic gonadotropin (hCG) are responsible for this decrease. Human BC cells and tissues contain hCG/luteinizing hormone receptors. The activation of the receptors results in an increase in cell differentiation and apoptosis. Conversely, it decreases the cell proliferation, invasion, and survival. The hCG actions are primarily cyclic adenosine monophosphate/protein kinase A mediated, require the presence of receptors, and involve blocking the activation and nuclear translocation of the transcription factor, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB). The women with a higher hCG levels during pregnancy tend to have a lower BC incidence and those with the receptor-positive tumors have a longer metastasis-free survival. The long-term benefits of pregnancy/hCG seem to come from permanent signature genomic imprinting and expression changes, which are characterized by low cell proliferation, increased efficiency of DNA repair mechanisms, cell differentiation, and cells resistance to carcinogenesis. These findings could provide clinical opportunities to use hCG for the prevention of BC in this modern era of increasing number of young women in our societies waiting longer than ever to have their first child. In addition, hCG may be useful to reduce and/or eliminate cellular targets of carcinogenic changes during an active ongoing disease. PMID- 28715967 TI - Hyperthermia-enhanced targeted drug delivery using magnetic resonance-guided focussed ultrasound: a pre-clinical study in a genetic model of pancreatic cancer. AB - PURPOSE: The lack of effective treatment options for pancreatic cancer has led to a 5-year survival rate of just 8%. Here, we evaluate the ability to enhance targeted drug delivery using mild hyperthermia in combination with the systemic administration of a low-temperature sensitive liposomal formulation of doxorubicin (LTSL-Dox) using a relevant model for pancreas cancer. MATERIALS AND METHODS: Experiments were performed in a genetically engineered mouse model of pancreatic cancer (KPC mice: LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre). LTSL Dox or free doxorubicin (Dox) was administered via a tail vein catheter. A clinical magnetic resonance-guided high intensity focussed ultrasound (MR-HIFU) system was used to plan treatment, apply the HIFU-induce hyperthermia and monitor therapy. Post-therapy, total Dox concentration in tumour tissue was determined by HPLC and confirmed with fluorescence microscopy. RESULTS: Localized hyperthermia was successfully applied and monitored with a clinical MR-HIFU system. The mild hyperthermia heating algorithm administered by the MR-HIFU system resulted in homogenous heating within the region of interest. MR-HIFU, in combination with LTSL-Dox, resulted in a 23-fold increase in the localised drug concentration and nuclear uptake of doxorubicin within the tumour tissue of KPC mice compared to LTSL-Dox alone. Hyperthermia, in combination with free Dox, resulted in a 2-fold increase compared to Dox alone. CONCLUSION: This study demonstrates that HIFU induced hyperthermia in combination with LTSL-Dox can be a non-invasive and effective method in enhancing the localised delivery and penetration of doxorubicin into pancreatic tumours. PMID- 28715968 TI - Applications of hyperthermic intraperitoneal chemotherapy for metastatic colorectal cancer. AB - INTRODUCTION: Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) plays a pivotal role in the current treatment of peritoneal carcinomatosis (PC) from colorectal cancer (CRC). Since the first demonstration, benefits for patients and especially an increase in survival have been described. In recent years, feasibility, efficacy and safety of HIPEC have been improved and progress has been made in understanding its oncological mechanism. Areas covered: In this article, leading publications have been reviewed including clinical trials to describe the clinical presentation of PC due to CRC and present recent evidence of the CRS/HIPEC procedure. The surgical approach including evaluation of the extent of PC is described and, in addition, the article reports about different HIPEC techniques as well as several protocols. Furthermore, the development and prognostic benefit of the combination of intraperitoneal and intravenous chemotherapy are outlined. Consideration has been given in particular to patient selection and the use of HIPEC if complete cytoreduction is not feasible. Expert commentary: The CRS/HIPEC procedure represents a curative approach to treat patients with PC from CRC. However, surgical skills and the HIPEC technique still require specialized oncological centers. PMID- 28715969 TI - Hypoxia and Redox Signaling on Extracellular Matrix Remodeling: From Mechanisms to Pathological Implications. AB - SIGNIFICANCE: The extracellular matrix (ECM) is an essential modulator of cell behavior that influences tissue organization. It has a strong relevance in homeostasis and translational implications for human disease. In addition to ECM structural proteins, matricellular proteins are important regulators of the ECM that are involved in a myriad of different pathologies. Recent Advances: Biochemical studies, animal models, and study of human diseases have contributed to the knowledge of molecular mechanisms involved in remodeling of the ECM, both in homeostasis and disease. Some of them might help in the development of new therapeutic strategies. This review aims to review what is known about some of the most studied matricellular proteins and their regulation by hypoxia and redox signaling, as well as the pathological implications of such regulation. CRITICAL ISSUES: Matricellular proteins have complex regulatory functions and are modulated by hypoxia and redox signaling through diverse mechanisms, in some cases with controversial effects that can be cell or tissue specific and context dependent. Therefore, a better understanding of these regulatory processes would be of great benefit and will open new avenues of considerable therapeutic potential. FUTURE DIRECTIONS: Characterizing the specific molecular mechanisms that modulate matricellular proteins in pathological processes that involve hypoxia and redox signaling warrants additional consideration to harness the potential therapeutic value of these regulatory proteins. Antioxid. Redox Signal. 27, 802-822. PMID- 28715970 TI - Scaffold-in-Scaffold Potential to Induce Growth and Differentiation of Cardiac Progenitor Cells. AB - The design of reliable biocompatible and biodegradable scaffolds remains one of the most important challenges for tissue engineering. In fact, properly designed scaffolds must display an adequate and interconnected porosity to facilitate cell spreading and colonization of the inner layers, and must release physical signals concurring to modulate cell function to ultimately drive cell fate. In this study, a combination of optimal mechanical and biochemical properties has been considered to design a one-component three-dimensional (3D) multitextured hydrogel scaffold to favor cell-scaffold interactions. A polyethylene glycol diacrylate woodpile (PEGDa-Wp) structure of the order of 100 MUm has been manufactured using a microstereolithography process. Subsequently, the PEGDa-Wp has been embedded in a PEGDa hydrogel to obtain a 3D scaffold-in-scaffold (3D-SS) system. Finally, the 3D-SS capability to address cell fate has been assessed using human Lin- Sca-1+ cardiac progenitor cells (hCPCs). Results have shown that a multitextured 3D scaffold represents a favorable microenvironment to promote hCPC differentiation and orientation. In fact, while cultured on 3D-SS, hCPCs adopt an ordered 3D spatial orientation and activate the expression of structural proteins, such as the alpha-sarcomeric actinin, a specific marker of the cardiomyocyte phenotype, and connexin 43, the principal gap junction protein of the heart. Although preliminary, this study demonstrates that complex multitextured scaffolds closely mimicking the extracellular matrix structure and function are efficient in driving progenitor cell fate. A leap forward will be determined by the use of advanced 3D printing technologies that will improve multitextured scaffold manufacturing and their biological efficiency. PMID- 28715971 TI - A Consensus View of ESCRT-Mediated Human Immunodeficiency Virus Type 1 Abscission. AB - The strong dependence of retroviruses, such as human immunodeficiency virus type 1 (HIV-1), on host cell factors is no more apparent than when the endosomal sorting complex required for transport (ESCRT) machinery is purposely disengaged. The resulting potent inhibition of retrovirus release underscores the importance of understanding fundamental structure-function relationships at the ESCRT-HIV-1 interface. Recent studies utilizing advanced imaging technologies have helped clarify these relationships, overcoming hurdles to provide a range of potential models for ESCRT-mediated virus abscission. Here, we discuss these models in the context of prior work detailing ESCRT machinery and the HIV-1 release process. To provide a template for further refinement, we propose a new working model for ESCRT-mediated HIV-1 release that reconciles disparate and seemingly conflicting studies. PMID- 28715972 TI - Defensins in Viral Infection and Pathogenesis. AB - alpha, beta, and theta defensins are effectors of the innate immune system with potent antibacterial, antiviral, and antifungal activity. Defensins have direct antiviral activity in cell culture, with varied mechanisms for individual viruses, although some common themes have emerged. In addition, defensins have potent immunomodulatory activity that can alter innate and adaptive immune responses to viral infection. In some cases, there is evidence for paradoxical escape from defensin neutralization or enhancement of viral infection. The direct and indirect activities of defensins have led to their development as therapeutics and vaccine components. The major area of investigation that continues to lag is the connection between the effects of defensins in cell culture models and viral pathogenesis in vivo. Model systems to study defensin biology, including more physiologic models designed to bridge this gap, are also discussed. PMID- 28715973 TI - The Molecular Basis for Human Immunodeficiency Virus Latency. AB - Although potent combination antiretroviral therapy can effectively block viral replication in the host, human immunodeficiency virus (HIV) persists due to the existence of latent but replication-competent proviruses residing primarily in a very small population of resting memory CD4+ T cells. Viral latency is established when the expression of the autoregulatory viral trans-activating factor Tat is reduced to subthreshold levels. The absence of Tat reduces HIV transcription and protein production to levels that make the host cell invisible to the immune system and refractory to antiretroviral treatment. Key host cell mechanisms that drive HIV into latency are sequestration of transcription initiation factors, establishment of epigenetic barriers inactivating the proviral promoter, and blockage of the assembly of the host elongation factor P TEFb. This comprehensive understanding of the molecular control of HIV transcription is leading to the development of optimized combinatorial reactivation and immune surveillance strategies designed to purge the latent viral reservoir. PMID- 28715974 TI - Electron Cryomicroscopy of Viruses at Near-Atomic Resolutions. AB - Recently, dozens of virus structures have been solved to resolutions between 2.5 and 5.0 A by means of electron cryomicroscopy. With these structures we are now firmly within the "atomic age" of electron cryomicroscopy, as these studies can reveal atomic details of protein and nucleic acid topology and interactions between specific residues. This improvement in resolution has been the result of direct electron detectors and image processing advances. Although enforcing symmetry facilitates reaching near-atomic resolution with fewer particle images, it unfortunately obscures some biologically interesting components of a virus. New approaches on relaxing symmetry and exploring structure dynamics and heterogeneity of viral assemblies have revealed important insights into genome packaging, virion assembly, cell entry, and other stages of the viral life cycle. In the future, novel methods will be required to reveal yet-unknown structural conformations of viruses, relevant to their biological activities. Ultimately, these results hold the promise of answering many unresolved questions linking structural diversity of viruses to their biological functions. PMID- 28715975 TI - Viruses with Circular Single-Stranded DNA Genomes Are Everywhere! AB - Circular single-stranded DNA viruses infect archaea, bacteria, and eukaryotic organisms. The relatively recent emergence of single-stranded DNA viruses, such as chicken anemia virus (CAV) and porcine circovirus 2 (PCV2), as serious pathogens of eukaryotes is due more to growing awareness than to the appearance of new pathogens or alteration of existing pathogens. In the case of the ubiquitous human circular single-stranded DNA virus family Anelloviridae, there is still no convincing direct causal relation to any specific disease. However, infections may play a role in autoimmunity by changing the homeostatic balance of proinflammatory cytokines and the human immune system, indirectly affecting the severity of diseases caused by other pathogens. Infections with CAV (family Anelloviridae, genus Gyrovirus) and PCV2 (family Circoviridae, genus Circovirus) are presented here because they are immunosuppressive and affect health in domesticated animals. CAV shares genomic organization, genomic orientation, and common features of major proteins with human anelloviruses, and PCV2 DNA may be present in human food and vaccines. PMID- 28715978 TI - The Role of Efflux Pumps in Tuberculosis Treatment and Their Promise as a Target in Drug Development: Unraveling the Black Box. AB - Insight into drug transport mechanisms is highly relevant to the efficacious treatment of tuberculosis (TB). Major problems in TB treatment are related to the transport of antituberculosis (anti-TB) drugs across human and mycobacterial membranes, affecting the concentrations of these drugs systemically and locally. Firstly, transporters located in the intestines, liver, and kidneys all determine the pharmacokinetics and pharmacodynamics of anti-TB drugs, with a high risk of drug-drug interactions in the setting of concurrent use of antimycobacterial, antiretroviral, and antidiabetic agents. Secondly, human efflux transporters limit the penetration of anti-TB drugs into the brain and cerebrospinal fluid, which is especially important in the treatment of TB meningitis. Finally, efflux transporters located in the macrophage and Mycobacterium tuberculosis cell membranes play a pivotal role in the emergence of phenotypic tolerance and drug resistance, respectively. We review the role of efflux transporters in TB drug disposition and evaluate the promise of efflux pump inhibition from a novel holistic perspective. PMID- 28715977 TI - Iatrogenic tracheoarterial fistula: Case report and literature review. AB - Tracheo-innominate fistula is a rare but recognised life-threatening complication most commonly associated with prolonged endotracheal intubation. We report the case of a 16-year-old boy who developed a tracheo-innominate fistula secondary to the prolonged intubation after a pool accident. After 16 days of hospitalisation, the patient died as a consequence of a massive haemorrhage into the tracheobronchial tree and asphyxia. This is a rare complication, and to our knowledge, no case of tracheo-innominate fistula or any other case series concerning this rare complication has been reported in Serbia recently. This case report addresses the epidemiology of a trachea-innominate fistulisation as a complication of prolonged tracheal intubation, with a special overview of its forensic importance as an iatrogenic injury. PMID- 28715976 TI - Astrovirus Biology and Pathogenesis. AB - Astroviruses are nonenveloped, positive-sense single-stranded RNA viruses that cause gastrointestinal illness. Although a leading cause of pediatric diarrhea, human astroviruses are among the least characterized enteric RNA viruses. However, by using in vitro methods and animal models to characterize virus-host interactions, researchers have discovered several important properties of astroviruses, including the ability of the astrovirus capsid to act as an enterotoxin, disrupting the gut epithelial barrier. Improved animal models are needed to study this phenomenon, along with the pathogenesis of astroviruses, particularly in those strains that can cause extraintestinal disease. Much like for other enteric viruses, the current dogma states that astroviruses infect in a species-specific manner; however, this assumption is being challenged by growing evidence that these viruses have potential to cross species barriers. This review summarizes these remarkable facets of astrovirus biology, highlighting critical steps toward increasing our understanding of this unique enteric pathogen. PMID- 28715979 TI - A Serendipitous Scientist. AB - Growing up in a middle-class Jewish home in the Bronx, I had only one professional goal: to become a physician. However, as with most of my Vietnam-era MD colleagues, I found my residency training interrupted by the Doctor Draft in 1968. Some of us who were academically inclined fulfilled this obligation by serving in the US Public Health Service as commissioned officers stationed at the National Institutes of Health. This experience would eventually change the entire trajectory of my career. Here I describe how, over a period of years, I transitioned from the life of a physician to that of a physician-scientist; my 50 years of work on cellular receptors; and some miscellaneous thoughts on subjects as varied as Nobel prizes, scientific lineages, mentoring, publishing, and funding. PMID- 28715980 TI - Clinical aspects of infertile 47,XYY patients: a retrospective study. AB - 47,XYY syndrome is a sex chromosomal anomaly in men, which may be associated with infertility and has an incidence of 0.1% of male births. The clinical and paraclinical characteristics of men suffering from this anomaly have not been fully described. In this retrospective study, we present 37 cases of 47,XYY infertile men with sperm counts varying from normal to azoospermia, referred to the Genetics Laboratory at the Royan Institute, Iran. Thirteen individuals were mosaic and 24 non-mosaics. Non-mosaic patients were classified as azoospermic (nine cases) and normospermic/oligozoospermic men (15 cases). Two of the non mosaic and three mosaic patients had secondary infertility. In addition, 13 of them underwent IUI, IVF or ICSI, and in seven cases, there was a biochemical pregnancy. The remaining 14 patients did not have ART. The 47,XYY syndrome is relatively unusual and can be missed clinically because of the lack of symptoms and of diverse phenotypes. Diagnosis of this aneuploidy can provide valuable data for counselling and early management of the patients who undergo fertility evaluation. PMID- 28715982 TI - Journal of Correctional Health Care. PMID- 28715981 TI - Trajectory of Weight Patterns in Urban Youth Throughout Their Stay in a Juvenile Justice System. AB - Incarceration is associated with health risks including overweight and obesity. This study explored obesity rates and weight gain in incarcerated youth by tracking weight trajectory during continuous stays in juvenile justice facilities. Among 65 youth, mean weight gain was 17.8 pounds and significant, F(2, 12) = 25.44, p = .03. Youth gained an average of 15.6 pounds (standard deviation [ SD] = 3.6) during the initial incarceration period (mean = 71 days). From the assessment to treatment period (mean = 46 days), mean weight gain was 4.1 pounds ( SD = 4.3), which also was significant, F(2, 12) = 28.57, p = .03. Body mass index z-scores increased significantly for each monthly weight observation. Being incarcerated is associated with significant weight gain and should influence policy and planning in this setting. PMID- 28715983 TI - Addressing Social Anxiety Concurrently With Prison-Based Sex Offender Treatment: A Case of Individual Needs in an Era of Manualized Treatment. AB - Emotional regulation may be an underaddressed therapeutic target in sex offender treatment. This article presents a case report of "Adam," a Caucasian male referred to a prison-based sex offender treatment program. Adam's social anxiety was recognized as an antecendent to his sexual offending, and treatment of such, as a critical adjunct to sex offender treatment, is discussed herein. Adam's individualized treatment included aspects of rational emotive behavior therapy and time-limited dynamic psychotherapy. Adam showed an increased understanding of his anxiety and improvement in his social interactions, both in the context of treatment groups and with female staff, and was willing to continue follow-up care in the community. This case provides support for the individualized treatment of incarcerated offenders as opposed to exclusively utilizing manualized psychoeducational interventions. PMID- 28715984 TI - Cost of an Integrated Care Program to Reduce ED Visits During Diabetic Prisoner Court Hearings. AB - Diabetic events occurring during court hearings previously required emergency medical services (EMS) transport to the emergency department (ED). A new process was implemented whereby the provincial court (PC) was notified by the detention center of diabetes status of prisoners scheduled for court later that day, enabling a community nursing services provider to provide on-site diabetes assessment and treatment at the PC. During the 13-month pre-implementation phase, there were 10 incidents of diabetic distress resulting in an ED visit at a total cost of $797.58/prisoner, including police service personnel, EMS, and ED staff/physician. During the 12.5-month postimplementation phase, insulin was administered on-site during 72 court dates at a cost of $161.93/prisoner. The new process for managing diabetic needs of prisoners during court dates resulted in a substantial cost savings in terms of police services and health care personnel and improved the immediacy and quality of care for prisoners. PMID- 28715985 TI - Mental Disorders Among Criminal Offenders: A Review of the Literature. AB - This article examines mental illness among adult, juvenile, male, female, jail, and prison inmates. It also explores the way in which mental health diagnoses impact offending and violent behavior. A review of literature pertaining to differences between the genders and age of offenders suggests that psychiatric disorders are more common among criminal offenders than the population at large. Furthermore, it appears that many mentally ill offenders do not receive sufficient treatment during their incarcerations and that barriers inherent to incarceration prevent adequate treatment of mental illnesses. PMID- 28715986 TI - The HIV Care Cascade Among Individuals Under Community Supervision in Baltimore, Maryland. AB - An estimated one in seven HIV-infected individuals pass through U.S. correctional facilities each year. Transitioning from correctional to community settings may increase HIV treatment interruptions and increase the risk of continued HIV transmission in the community. This study assessed access to HIV providers in the community, antiretroviral treatment, and viral suppression to inform the development of interventions to improve HIV treatment outcomes among individuals involved in community corrections. The sample included 100 individuals under community supervision (probation or parole) in Baltimore, Maryland. While a large proportion of the study sample had undetectable HIV viral loads, 39% did not, and this represents a significant HIV transmission risk. Given the large proportion of individuals involved in the criminal justice system who are under community supervision, community corrections may be an important point of intervention to engage or reengage HIV-positive individuals who are currently out of care. PMID- 28715987 TI - Editor's Letter. PMID- 28715988 TI - A Metasynthesis of Phenomenographic Articles on Understandings of Work Among Healthcare Professionals. AB - Phenomenography is a qualitative research method based on the assumption that almost any phenomenon will be understood by a group of people in a limited number of ways. Our aim in this article was to identify the different ways work can be understood by healthcare professionals. In a world where the delivery of healthcare is continually changing, a metasynthesis of phenomenographic articles on healthcare professionals' understandings can provide knowledge about the focus and meaning of work for these individuals today. Our metaethnographic synthesis of 14 selected phenomenographic articles identified five different ways of understanding work, ranging from a limited to an all the more comprehensive view on patients and their needs. This range of understandings reveals problem areas and challenges facing healthcare professionals today. The possibility exists as well that limited understandings of work may be negative consequences of current demands for efficiency and all the more limited healthcare resources. PMID- 28715990 TI - Single-Subject Studies in Translational Nutrition Research. AB - There is a great deal of interest in personalized, individualized, or precision interventions for disease and health-risk mitigation. This is as true of nutrition-based intervention and prevention strategies as it is for pharmacotherapies and pharmaceutical-oriented prevention strategies. Essentially, technological breakthroughs have enabled researchers to probe an individual's unique genetic, biochemical, physiological, behavioral, and exposure profile, allowing them to identify very specific and often nuanced factors that an individual might possess, which may make it more or less likely that he or she responds favorably to a particular intervention (e.g., nutrient supplementation) or disease prevention strategy (e.g., specific diet). However, as compelling and intuitive as personalized nutrition might be in the current era in which data intensive biomedical characterization of individuals is possible, appropriately and objectively vetting personalized nutrition strategies is not trivial and requires novel study designs and data analytical methods. These designs and methods must consider a very integrated use of the multiple contemporary biomedical assays and technologies that motivate them, which adds to their complexity. Single-subject or N-of-1 trials can be used to assess the utility of personalized interventions and, in addition, can be crafted in such a way as to accommodate the necessarily integrated use of many emerging biomedical technologies and assays. In this review, we consider the motivation, design, and implementation of N-of-1 trials in translational nutrition research that are meant to assess the utility of personalized nutritional strategies. We provide a number of example studies, discuss appropriate analytical methods given the complex data they generate and require, and consider how such studies could leverage integration of various biomarker assays and clinical end points. Importantly, we also consider the development of strategies and algorithms for matching nutritional needs to individual biomedical profiles and the issues surrounding them. Finally, we discuss the limitations of personalized nutrition studies, possible extensions of N-of-1 nutritional intervention studies, and areas of future research. PMID- 28715991 TI - Trimethylamine N-Oxide, the Microbiome, and Heart and Kidney Disease. AB - Trimethylamine N-oxide (TMAO) is a biologically active molecule and is a putative promoter of chronic diseases including atherosclerosis in humans. Host intestinal bacteria produce its precursor trimethylamine (TMA) from carnitine, choline, or choline-containing compounds. Most of the TMA produced is passively absorbed into portal circulation, and hepatic flavin-dependent monooxygenases (FMOs) efficiently oxidize TMA to TMAO. Both observational and experimental studies suggest a strong positive correlation between increased plasma TMAO concentrations and adverse cardiovascular events, such as myocardial infarction, stroke, and death. However, a clear mechanistic link between TMAO and such diseases is not yet validated. Therefore, it is debated whether increased TMAO concentrations are the cause or result of these diseases. Here, we have tried to review the current understanding of the properties and physiological functions of TMAO, its dietary sources, and its effects on human metabolism. Studies that describe the potential role of TMAO in the etiology of cardiovascular and other diseases are also discussed. PMID- 28715989 TI - Use and effectiveness of behavioural economics in interventions for lifestyle risk factors of non-communicable diseases: a systematic review with policy implications. AB - AIM: There is limited evidence on what behavioural economics strategies are effective and can be used to inform non-communicable diseases (NCDs) public health policies designed to reduce overeating, excessive drinking, smoking, and physical inactivity. The aim of the review is to examine the evidence on the use and effectiveness of behavioural economics insights on reducing NCDs lifestyle risk factors. METHODS: Medline, Embase, PsycINFO, and EconLit were searched for studies published between January 2002 and July 2016 and reporting empirical, non pharmacological, interventional research focusing on reducing at least one NCDs lifestyle risk factor by employing a behavioural economics perspective. RESULTS: We included 117 studies in the review; 67 studies had a low risk of bias and were classified as strong or very strong, 37 were moderate, and 13 were weak. We grouped studies by NCDs risk factors and conducted a narrative synthesis. The most frequent behavioural economics precepts used were incentives, framing, and choice architecture. We found inconclusive evidence regarding the success of behavioural economics strategies to reduce alcohol consumption, but we identified several strategies with policy-level implications which could be used to reduce smoking, improve nutrition, and increase physical activity. CONCLUSION: Most studies targeting tobacco consumption, physical activity levels, and eating behaviours from a behavioural economics perspective had promising results with potential impact on NCDs health policies. We recommend future studies to be implemented in real-life settings and on large samples from diverse populations. PMID- 28715992 TI - The Hibernator Microbiome: Host-Bacterial Interactions in an Extreme Nutritional Symbiosis. AB - Animals that undergo seasonal cycles of feeding and fasting have adaptations that maintain integrity of organ systems when dietary nutrients are lacking. Food deprivation also challenges the gut microbiota, which relies heavily on host diet for metabolic substrates and the gastrointestinal tract, which is influenced by enteral nutrients and microbial activity. Winter fasting in hibernators shifts the microbiota to favor taxa with the capacity to degrade and utilize host derived substrates and disfavor taxa that prefer complex plant polysaccharides. Microbiome alterations may contribute to hibernation-induced changes in the intestinal immune system, epithelial barrier function, and other host features that are affected by microbial short-chain fatty acids and other metabolites. Understanding mechanisms by which the hibernator host and its gut symbionts adapt to the altered nutritional landscape during winter fasting may provide insights into protective mechanisms that are compromised when nonhibernating species, such as humans, undergo long periods of enteral nutrient deprivation. PMID- 28715993 TI - Metabolic Effects of Intermittent Fasting. AB - The objective of this review is to provide an overview of intermittent fasting regimens, summarize the evidence on the health benefits of intermittent fasting, and discuss physiological mechanisms by which intermittent fasting might lead to improved health outcomes. A MEDLINE search was performed using PubMed and the terms "intermittent fasting," "fasting," "time-restricted feeding," and "food timing." Modified fasting regimens appear to promote weight loss and may improve metabolic health. Several lines of evidence also support the hypothesis that eating patterns that reduce or eliminate nighttime eating and prolong nightly fasting intervals may result in sustained improvements in human health. Intermittent fasting regimens are hypothesized to influence metabolic regulation via effects on (a) circadian biology, (b) the gut microbiome, and (c) modifiable lifestyle behaviors, such as sleep. If proven to be efficacious, these eating regimens offer promising nonpharmacological approaches to improving health at the population level, with multiple public health benefits. PMID- 28715994 TI - FGF23 and Nutritional Metabolism. AB - The discovery of fibroblast growth factor 23 (FGF23) has provided a more complete understanding of the regulation of phosphate and mineral homeostasis in health and in chronic kidney disease. It has also offered new insights into stratification of risk of cardiovascular events and death among patients with chronic kidney disease and the general population. In this review, we provide an overview of FGF23 biology and physiology, summarize clinical outcomes that have been associated with FGF23, discuss potential mechanisms for these observations and their public health implications, and explore clinical and population health interventions that aim to reduce FGF23 levels and improve public health. PMID- 28715995 TI - Pacinian Signals Determine the Direction and Magnitude of the Effect of Vibration on Pain. AB - Although the ability of vibration to reduce pain has been extensively documented, an occasional participant reports that vibration increases pain. For pain patients, such reports may reflect pathophysiology, but this is unlikely in studies of experimental pain in healthy participants. In the present series of experiments on 27 pain-free individuals, we manipulated both the frequency (12, 50, and 80 Hz) and amplitude of vibration to more fully characterize vibratory pain modulation. The noxious stimulus was pressure applied to a finger, and vibration was delivered to the fleshy palmar pad at the base of the same finger. Subjects continuously reported pain on a Visual Analog Scale. Intermittent vibration was used to minimize peripheral vibratory adaptation. Pain records at 12 and 50 Hz were similar; pooling them revealed significant hypoalgesia at the highest amplitude. At 80 Hz, in contrast, the middle amplitude produced hypoalgesia, but a significant shift toward hyperalgesia occurred at the highest amplitude. The strong correlation ( r = .81) between the Pacinian-weighted power of a vibration and the absolute value of the pain modulation it produces indicates that the Pacinian system plays a key role in vibratory hypoalgesia or hyperalgesia. PMID- 28715996 TI - Social Categories Alone Are Insufficient to Elicit an In-Group Advantage in Perceptions of Within-Person Variability. AB - Within-person variability affects identity perception of other-race faces more than own-race faces; when participants sort images into piles representing different identities, they sort photographs of two other-race identities into more piles than two own-race identities. These results have been interpreted in terms of perceptual expertise, such that lack of experience with other-race faces leads to reduced ability to extract identity-relevant information across images. However, an alternative explanation is that sociocognitive factors (e.g., cognitive disregard for out-group faces) lead to differences in the number of perceived identities. Here, we examined whether social factors alone elicit an in group advantage in perceptions of within-person variability. Caucasian participants sorted 40 photographs of two unfamiliar Caucasian identities (20 photographs/model) into piles based on the number of identities they believed were present. Half of the participants were told that the images were of students attending their university (in-group), whereas half were told that the images were of students attending a rival university (out-group). Participants sorted the photographs into a comparable number of identities for in- and out-group faces. This lack of an in-group advantage suggests that sociocognitive factors alone cannot account for differences in the number of perceived identities across faces from two categories. PMID- 28715997 TI - An efficient algorithm for improving structure-based prediction of transcription factor binding sites. AB - BACKGROUND: Gene expression is regulated by transcription factors binding to specific target DNA sites. Understanding how and where transcription factors bind at genome scale represents an essential step toward our understanding of gene regulation networks. Previously we developed a structure-based method for prediction of transcription factor binding sites using an integrative energy function that combines a knowledge-based multibody potential and two atomic energy terms. While the method performs well, it is not computationally efficient due to the exponential increase in the number of binding sequences to be evaluated for longer binding sites. In this paper, we present an efficient pentamer algorithm by splitting DNA binding sequences into overlapping fragments along with a simplified integrative energy function for transcription factor binding site prediction. RESULTS: A DNA binding sequence is split into overlapping pentamers (5 base pairs) for calculating transcription factor pentamer interaction energy. To combine the results from overlapping pentamer scores, we developed two methods, Kmer-Sum and PWM (Position Weight Matrix) stacking, for full-length binding motif prediction. Our results show that both Kmer-Sum and PWM stacking in the new pentamer approach along with a simplified integrative energy function improved transcription factor binding site prediction accuracy and dramatically reduced computation time, especially for longer binding sites. CONCLUSION: Our new fragment-based pentamer algorithm and simplified energy function improve both efficiency and accuracy. To our knowledge, this is the first fragment-based method for structure-based transcription factor binding sites prediction. PMID- 28715998 TI - Detection of active transposable elements in Arabidopsis thaliana using Oxford Nanopore Sequencing technology. AB - BACKGROUND: Transposables elements (TEs) contribute to both structural and functional dynamics of most eukaryotic genomes. Because of their propensity to densely populate plant and animal genomes, the precise estimation of the impact of transposition on genomic diversity has been considered as one of the main challenges of today's genomics. The recent development of NGS (next generation sequencing) technologies has open new perspectives in population genomics by providing new methods for high throughput detection of Transposable Elements associated Structural Variants (TEASV). However, these have relied on Illumina platform that generates short reads (up to 350 nucleotides). This limitation in size of sequence reads can cause high false discovery rate (FDR) and therefore limit the power of detection of TEASVs, especially in the case of large, complex genomes. The newest sequencing technologies, such as Oxford Nanopore Technologies (ONT) can generate kilobases-long reads thus representing a promising tool for TEASV detection in plant and animals. RESULTS: We present the results of a pilot experiment for TEASV detection on the model plant species Arabidopsis thaliana using ONT sequencing and show that it can be used efficiently to detect TE movements. We generated a ~0.8X genome coverage of a met1-derived epigenetic recombinant inbred line (epiRIL) using a MinIon device with R7 chemistry. We were able to detect nine new copies of the LTR-retrotransposon Evade (EVD). We also evidenced the activity of the DNA transposon CACTA, CAC1. CONCLUSIONS: Even at a low sequence coverage (0.8X), ONT sequencing allowed us to reliably detect several TE insertions in Arabidopsis thaliana genome. The long read length allowed a precise and un-ambiguous mapping of the structural variations caused by the activity of TEs. This suggests that the trade-off between read length and genome coverage for TEASV detection may be in favor of the former. Should the technology be further improved both in terms of lower error rate and operation costs, it could be efficiently used in diversity studies at population level. PMID- 28715999 TI - Factors affecting interactome-based prediction of human genes associated with clinical signs. AB - BACKGROUND: Clinical signs are a fundamental aspect of human pathologies. While disease diagnosis is problematic or impossible in many cases, signs are easier to perceive and categorize. Clinical signs are increasingly used, together with molecular networks, to prioritize detected variants in clinical genomics pipelines, even if the patient is still undiagnosed. Here we analyze the ability of these network-based methods to predict genes that underlie clinical signs from the human interactome. RESULTS: Our analysis reveals that these approaches can locate genes associated with clinical signs with variable performance that depends on the sign and associated disease. We analyzed several clinical and biological factors that explain these variable results, including number of genes involved (mono- vs. oligogenic diseases), mode of inheritance, type of clinical sign and gene product function. CONCLUSIONS: Our results indicate that the characteristics of the clinical signs and their related diseases should be considered for interpreting the results of network-prediction methods, such as those aimed at discovering disease-related genes and variants. These results are important due the increasing use of clinical signs as an alternative to diseases for studying the molecular basis of human pathologies. PMID- 28716000 TI - Quantiprot - a Python package for quantitative analysis of protein sequences. AB - BACKGROUND: The field of protein sequence analysis is dominated by tools rooted in substitution matrices and alignments. A complementary approach is provided by methods of quantitative characterization. A major advantage of the approach is that quantitative properties defines a multidimensional solution space, where sequences can be related to each other and differences can be meaningfully interpreted. RESULTS: Quantiprot is a software package in Python, which provides a simple and consistent interface to multiple methods for quantitative characterization of protein sequences. The package can be used to calculate dozens of characteristics directly from sequences or using physico-chemical properties of amino acids. Besides basic measures, Quantiprot performs quantitative analysis of recurrence and determinism in the sequence, calculates distribution of n-grams and computes the Zipf's law coefficient. CONCLUSIONS: We propose three main fields of application of the Quantiprot package. First, quantitative characteristics can be used in alignment-free similarity searches, and in clustering of large and/or divergent sequence sets. Second, a feature space defined by quantitative properties can be used in comparative studies of protein families and organisms. Third, the feature space can be used for evaluating generative models, where large number of sequences generated by the model can be compared to actually observed sequences. PMID- 28716001 TI - Variant Ranker: a web-tool to rank genomic data according to functional significance. AB - BACKGROUND: The increasing volume and complexity of high-throughput genomic data make analysis and prioritization of variants difficult for researchers with limited bioinformatics skills. Variant Ranker allows researchers to rank identified variants and determine the most confident variants for experimental validation. RESULTS: We describe Variant Ranker, a user-friendly simple web-based tool for ranking, filtering and annotation of coding and non-coding variants. Variant Ranker facilitates the identification of causal variants based on novelty, effect and annotation information. The algorithm implements and aggregates multiple prediction algorithm scores, conservation scores, allelic frequencies, clinical information and additional open-source annotations using accessible databases via ANNOVAR. The available information for a variant is transformed into user-specified weights, which are in turn encoded into the ranking algorithm. Through its different modules, users can (i) rank a list of variants (ii) perform genotype filtering for case-control samples (iii) filter large amounts of high-throughput data based on user custom filter requirements and apply different models of inheritance (iv) perform downstream functional enrichment analysis through network visualization. Using networks, users can identify clusters of genes that belong to multiple ontology categories (like pathways, gene ontology, disease categories) and therefore expedite scientific discoveries. We demonstrate the utility of Variant Ranker to identify causal genes using real and synthetic datasets. Our results indicate that Variant Ranker exhibits excellent performance by correctly identifying and ranking the candidate genes CONCLUSIONS: Variant Ranker is a freely available web server on http://paschou-lab.mbg.duth.gr/Software.html . This tool will enable users to prioritise potentially causal variants and is applicable to a wide range of sequencing data. PMID- 28716002 TI - Epidemiological and clinical profile of paediatric malaria: a cross sectional study performed on febrile children in five epidemiological strata of malaria in Cameroon. AB - BACKGROUND: In the wake of a decline in global malaria, it is imperative to describe the epidemiology of malaria in a country to inform control policies. The purpose of this study was to describe the epidemiological and clinical profile of paediatric malaria in five epidemiological strata of malaria in Cameroon including: the Sudano-sahelian (SS) strata, the High inland plateau (HIP) strata, the South Cameroonian Equatorial forest (SCEF) strata, the High western plateau (HWP) strata, and the Coastal (C) strata. METHODS: This study involved 1609 febrile children (<=15 years) recruited using reference hospitals in the five epidemiological strata. Baseline characteristics were determined; blood glucose level was measured by a glucometer, malaria parasitaemia was assessed by Giemsa microscopy, and complete blood count was performed using an automated hematology analyser. Severe malaria was assessed and categorized based on WHO criteria. RESULTS: An overall prevalence of 15.0% (95% CI: 13.3-16.9) for malaria was observed in this study. Malaria prevalence was significantly higher in children between 60 and 119 months (p < 0.001) and in Limbe (C strata) (p < 0.001). The overall rate of severe malaria (SM) attack in this study was 29.3%; SM was significantly higher in children below 60 months (p < 0.046). Although not significant, the rate of SM was highest in Maroua (SS strata) and lowest in Limbe in the C strata. The main clinical phenotypes of SM were hyperparasitaemia, severe malaria anaemia and impaired consciousness. The majority (73.2%) of SM cases were in group 1 of the WHO classification of severe malaria (i.e. the most severe form). The malaria case-fatality rate was 5.8%; this was higher in Ngaoundere (HIP strata) (p = 0.034). CONCLUSION: In this study, malaria prevalence decreased steadily northward, from the C strata in the South to the SS strata in the North of Cameroon, meanwhile the mortality rate associated with malaria increased in the same direction. On the contrary, the rate of severe malaria attack was similar across the different epidemiological strata. Immunoepidemiological studies will be required to shed more light on the observed trends. PMID- 28716003 TI - Eccentric versus traditional resistance exercise for older adult fallers in the community: a randomized trial within a multi-component fall reduction program. AB - BACKGROUND: Addressing muscle deficits within a multi-component exercise fall reduction program is a priority, especially for the highest risk older adults, i.e., those who have fallen previously. Eccentric resistance exercise with its high-force producing potential, at a low energetic cost, may be ideally-suited to address muscle impairments in this population. The purpose of this study was to compare the effects of resistance exercise via negative, eccentrically-induced, work (RENEW) versus traditional (TRAD) resistance exercise on mobility, balance confidence, muscle power and cross sectional area, as well as the number of days high fall risk older adults survived without a fall event over a 1 year period. METHODS: Randomized, two group, four time point (over 1 year) clinical trial testing RENEW versus TRAD as part of a 3 month multi-component exercise fall reduction program (MCEFRP). Primary outcomes of mobility, balance confidence, muscle power output and cross sectional area were analyzed using mixed effects modeling. The secondary outcomes of days to fall and days to near-fall were analyzed using survival analysis. RESULTS: The MCEFRP did have an effect on fall risk factors considered reversible with exercise interventions though there was no differential effect of RENEW versus TRAD (p = 0.896) on mobility, balance confidence, muscle power and cross sectional area. There were also no group differences in the number of days survived without a fall (p = 0.565) or near fall (p = 0.678). Despite 100% of participants having at least one fall in the year prior to the MCEFRP, however, after 3 months of exercise and 9 months of follow-up <50% had experienced a fall or near fall. CONCLUSIONS: There were no differential effects of RENEW or TRAD as components of a MCEFRP on the primary or secondary outcomes. The two modes of resistance exercise had identical effects on fall risk and fall-free survival. TRIAL REGISTRATION: NCT01080196 ; March 2, 2010 (retrospectively registered). PMID- 28716004 TI - Concurrent use of alcohol interactive medications and alcohol in older adults: a systematic review of prevalence and associated adverse outcomes. AB - BACKGROUND: Older adults are susceptible to adverse effects from the concurrent use of medications and alcohol. The aim of this study was to systematically review the prevalence of concurrent use of alcohol and alcohol-interactive (AI) medicines in older adults and associated adverse outcomes. METHODS: A systematic search was performed using MEDLINE (PubMed), Embase, Scopus and Web of Science (January 1990 to June 2016), and hand searching references of retrieved articles. Observational studies reporting on the concurrent use of alcohol and AI medicines in the same or overlapping recall periods in older adults were included. Two independent reviewers verified that studies met the inclusion criteria, critically appraised included studies and extracted relevant data. A narrative synthesis is provided. RESULTS: Twenty studies, all cross-sectional, were included. Nine studies classified a wide range of medicines as AI using different medication compendia, thus resulting in heterogeneity across studies. Three studies investigated any medication use and eight focused on psychotropic medications. Based on the quality assessment of included studies, the most reliable estimate of concurrent use in older adults ranges between 21 and 35%. The most reliable estimate of concurrent use of psychotropic medications and alcohol ranges between 7.4 and 7.75%. No study examined longitudinal associations with adverse outcomes. Three cross-sectional studies reported on falls with mixed findings, while one study reported on the association between moderate alcohol consumption and adverse drug reactions at hospital admission. CONCLUSIONS: While there appears to be a high propensity for alcohol-medication interactions in older adults, there is a lack of consensus regarding what constitutes an AI medication. An explicit list of AI medications needs to be derived and validated prospectively to quantify the magnitude of risk posed by the concurrent use of alcohol for adverse outcomes in older adults. This will allow for risk stratification of older adults at the point of prescribing, and prioritise alcohol screening and brief alcohol interventions in high-risk groups. PMID- 28716005 TI - Clarifying the distinction between case series and cohort studies in systematic reviews of comparative studies: potential impact on body of evidence and workload. AB - Distinguishing cohort studies from case series is difficult.We propose a conceptualization of cohort studies in systematic reviews of comparative studies. The main aim of this conceptualization is to clarify the distinction between cohort studies and case series. We discuss the potential impact of the proposed conceptualization on the body of evidence and workload.All studies with exposure based sampling gather multiple exposures (with at least two different exposures or levels of exposure) and enable calculation of relative risks that should be considered cohort studies in systematic reviews, including non-randomized studies. The term "enables/can" means that a predefined analytic comparison is not a prerequisite (i.e., the absolute risks per group and/or a risk ratio are provided). Instead, all studies for which sufficient data are available for reanalysis to compare different exposures (e.g., sufficient data in the publication) are classified as cohort studies.There are possibly large numbers of studies without a comparison for the exposure of interest but that do provide the necessary data to calculate effect measures for a comparison. Consequently, more studies could be included in a systematic review. Therefore, on the one hand, the outlined approach can increase the confidence in effect estimates and the strengths of conclusions. On the other hand, the workload would increase (e.g., additional data extraction and risk of bias assessment, as well as reanalyses). PMID- 28716006 TI - Ethylene induces combinatorial effects of histone H3 acetylation in gene expression in Arabidopsis. AB - BACKGROUND: Histone acetylation and deacetylation are essential for gene regulation and have been implicated in the regulation of plant hormone responses. Many studies have indicated the role of histone acetylation in ethylene signaling; however, few studies have investigated how ethylene signaling regulates the genomic landscape of chromatin states. Recently, we found that ethylene can specifically elevate histone H3K14 acetylation and the non-canonical histone H3K23 acetylation in etiolated seedlings and the gene activation is positively associated with the elevation of H3K14Ac and H3K23Ac in response to ethylene. To assess the role of H3K9, H3K14, and H3K23 histone modifications in the ethylene response, we examined how ethylene regulates histone acetylation and the transcriptome at global level and in ethylene regulated genes both in wild type (Col-0) and ein2-5 seedlings. RESULTS: Our results revealed that H3K9Ac, H3K14Ac, and H3K23Ac are preferentially enriched around the transcription start sites and are positively correlated with gene expression levels in Col-0 and ein2 5 seedlings both with and without ethylene treatment. In the absence of ethylene, no combinatorial effect of H3K9Ac, H3K14Ac, and H3K23Ac on gene expression was detected. In the presence of ethylene, however, combined enrichment of the three histone acetylation marks was associated with high gene expression levels, and this ethylene-induced change was EIN2 dependent. In addition, we found that ethylene-regulated genes are expressed at medium or high levels, and a group of ethylene regulated genes are marked by either one of H3K9Ac, H3K14Ac or H3K23Ac. In this group of genes, the levels of H3K9Ac were altered by ethylene, but in the absence of ethylene the levels of H3K9Ac and peak breadths are distinguished in up- and down- regulated genes. In the presence of ethylene, the changes in the peak breadths and levels of H3K14Ac and H3K23Ac are required for the alteration of gene expressions. CONCLUSIONS: Our study reveals that the plant hormone ethylene induces combinatorial effects of H3K9Ac, K14Ac and K23Ac histone acetylation in gene expression genome widely. Further, for a group of ethylene regulated genes, in the absence of ethylene the levels and the covered breadths of H3K9Ac are the preexist markers for distinguishing up- and down- regulated genes, the change in the peak breadths and levels of H3K14Ac and H3K23Ac are required for the alteration of gene expression in the presence of ethylene. PMID- 28716007 TI - Silent myocarditis in systemic sclerosis detected by cardiovascular magnetic resonance using Lake Louise criteria. AB - BACKGROUND: Systemic sclerosis (SSc) is an autoimmune disease characterized by microvascular abnormalities, inflammation and fibrosis. We hypothesized that myocarditis may be diagnosed in asymptomatic SSc, undergoing routine cardio vascular magnetic resonance (CMR) for fibrosis assessment, using the Lake Louise criteria: T2 ratio, early (EGE) and late gadolinium enhanced (LGE) images. METHODS: Eighty-two asymptomatic SSc, diagnosed according to American College of Rheumatology criteria, aged 43 +/- 5 yrs., 62 with diffuse (dSSc) and 20 with localized (lSSc) systemic sclerosis were evaluated by CMR, performed at 1.5 T scanner, according to Lake Louise criteria. RESULTS: CMR documented normal biventricular function in all SSc. However, 7/62 (11.2%) with dSSc and 2/20 (10%) with lSSc, had CMR signs of myocarditis according to Lake Louise criteria, without any clinical cardiac symptom. In these 9 patients, T2 ratio, EGE ratio and LGE (positive in all 9 SSc) were 2.8 +/- 0.5%, 8 +/- 3% and 5 +/- 3% of LV mass, respectively. No correlation between CMR and blood inflammatory indices (C reactive protein and erythrocyte sedimentation rate), cardiac troponin T, disease characteristics or type of SSc was identified. A repeat CMR at 6 months, after treatment with prednisone and azathioprine, showed normalisation of the acute inflammation CMR indices. CONCLUSIONS: Silent myocarditis may be diagnosed using the Lake Louise paper criteria in SSc patients without cardiac symptoms, has no correlation with blood inflammatory indices, cardiac troponin or disease characteristics. CMR is a promising tool to diagnose silent myocarditis in SSc and monitor the response to immunosuppressive treatment. PMID- 28716008 TI - Does infection with human immunodeficiency virus have any impact on the cardiovascular outcomes following percutaneous coronary intervention?: a systematic review and meta-analysis. AB - BACKGROUND: A direct link between human immunodeficiency virus (HIV)-infected patients and the risk of cardiovascular diseases (CVD) has been shown in recent scientific research. However, this issue is controversial since other previous reports showed no apparent impact of HIV or its anti-retroviral drugs on the cardiovascular system. We aimed to systematically compare the postinterventional adverse cardiovascular outcomes which were observed in patients with and without HIV infection during a mean follow up period ranging from 1 year to 3 years. METHODS: Common electronic databases were searched for studies which compared postinterventional adverse cardiovascular outcomes [mortality, myocardial infarction (MI), cardiac death, target vessel revascularization (TVR), target lesion revascularization (TLR), stroke and major adverse cardiac events (MACEs)] in patients with and without HIV infection. Statistical analysis was carried out by the RevMan 5.3 software whereby Odds Ratios (OR) and 95% Confidence Intervals (CIs) were generated. RESULTS: Two thousand two hundred and sixty-eight (2268) patients (821 patients were HIV positive and 1147 patients were HIV negative) were analyzed. The current results showed that mortality was not significantly increased among patients who were HIV positive with OR: 1.13, 95% CI: 0.65-1.96; P = 0.66. Cardiac death was also similarly reported with OR: 1.16, 95% CI: 0.50 2.68; P = 0.74. However, even if recurrent MI, TVR, TLR, MACEs and stroke were higher in patients who were HIV positive, with OR: 1.32, 95% CI: 0.88-2.12; P = 0.18, OR: 1.36, 95% CI: 0.88-2.12; P = 0.17, OR: 1.22, 95% CI: 0.72-2.06; P = 0.46, OR: 1.29, 95% CI: 0.89-1.85; P = 0.17 and OR: 1.47, 95% CI: 0.44-4.89; P = 0.53 respectively, these results were not statistically significant. CONCLUSION: Patients who were infected with HIV had similar mortality post coronary intervention compared to patients who were not infected by the virus, during a mean follow-up period of 1-3 years. In addition, no significant increase in MI, TVR, TLR, MACEs and stroke were observed during this follow up period. Therefore, it might be concluded that no apparent impact of HIV on the cardiovascular outcomes was observed post coronary intervention. PMID- 28716009 TI - Prevalence and associated risk factors of malaria among adults in East Shewa Zone of Oromia Regional State, Ethiopia: a cross-sectional study. AB - BACKGROUND: Malaria is one of the most important causes of morbidity and mortality in sub-Saharan Africa. The disease is prevalent in over 75% of the country's area making it the leading public health problems in the country. Information on the prevalence of malaria and its associated factors is vital to focus and improve malaria interventions. METHODS: A cross-sectional study was carried out from October to November 2012 in East Shewa zone of Oromia Regional State, Ethiopia. Adults aged 16 or more years with suspected malaria attending five health centers were eligible for the study. Logistic regression models were used to examine the effect of each independent variable on risk of subsequent diagnosis of malaria. RESULTS: Of 810 suspected adult malaria patients who participated in the study, 204 (25%) had microscopically confirmed malaria parasites. The dominant Plasmodium species were P. vivax (54%) and P. falciparum (45%), with mixed infection of both species in one patient. A positive microscopic result was significantly associated with being in the age group of 16 to 24 years [Adjusted Odds Ratio aOR 6.7; 95% CI: 2.3 to 19.5], 25 to 34 years [aOR 4.2; 95% CI: 1.4 to 12.4], and 35 to 44 years [aOR 3.7; 95% CI: 1.2-11.4] compared to 45 years or older; being treated at Meki health center [aOR 4.1; 95% CI: 2.4 to 7.1], being in Shashemene health center [aOR = 2.3; 95% CI: 1.5 to 4.5], and living in a rural area compared to an urban area [aOR 1.7; 95% CI: 1.1 to 2.6)]. CONCLUSION: Malaria is an important public health problem among adults in the study area with a predominance of P. vivax and P. falciparum infection. Thus, appropriate health interventions should be implemented to prevent and control the disease. PMID- 28716010 TI - Risk scores to predict decreased glomerular filtration rate at 10 years in an Asian general population. AB - BACKGROUND: Asians have among the highest prevalence of chronic kidney disease (CKD) or end-stage renal disease in the world. A risk score capable of identifying high risk individuals at the primary care level could allow targeted therapy to prevent future development of CKD. Risk scores for new CKD have been developed in US general populations, but the impact of various risks factors for development of CKD may differ in Asian subjects. In this study, we aimed to develop risk models and simplified risk scores to predict the development of decreased glomerular filtration rate (GFR) at 10 years in an Asian general population using readily obtainable clinical and laboratory parameters. METHODS: Employees of EGAT (The Electric Generating Authority of Thailand) were studied prospectively. Multivariable logistic regression models were used to assess risk factors and used to derive risk models and risk scores for developing decreased GFR at 10 years: Model 1 (Clinical only), Model 2 (Clinical + Limited laboratory tests), and Model 3 (Clinical + Full laboratory tests). The performance of the risk models or risk scores to predict incident cases with decreased GFR were evaluated by tests of calibration and discrimination. RESULTS: Of 3186 subjects with preserved GFR (eGFR >=60) at baseline, 271 (8.5%) developed decreased GFR (eGFR < 60) at 10 years. Model 1 (Age, sex, systolic blood pressure, history of diabetes, and waist circumference) had good performance (chi2 = 9.02; AUC = 0.72). Model 2 (Age, Sex, systolic blood pressure, diabetes, glomerular filtration rate) had better discrimination (chi2 = 10.87, AUC = 0.79) than Model 1. Model 3 (Model 2+ Uric acid, Hemoglobin) did not provide significant improvement over Model 2. Based on these findings, simplified categorical risk scores were developed for Models 1 and 2. CONCLUSIONS: Clinical or combined clinical and laboratory risk models or risk scores using tests readily available in a resource-limited setting had good accuracy and discrimination power to estimate the 10-year probability of developing decreased GFR in a Thai general population. The benefits of the risk scores in identifying high risk individuals in the Thai or other Asian communities for special intervention requires further studies. PMID- 28716011 TI - Association study to evaluate TFPI gene in CAD in Han Chinese. AB - BACKGROUND: Tissue factor pathway inhibitor (TFPI) is the main physiological inhibitor of TF-induced blood coagulation process, and may play essential roles in the pathogenesis of major adverse cardiac events. This study was designed to determine whether the variation of TFPI was related with coronary artery disease (CAD) in the Han Chinese populations. METHODS: A total of 1271 patients with coronary atherosclerosis and 1287 normal individuals from northern China were enrolled in the present study. Four tagging single-nucleotide polymorphisms (SNPs) (rs7586970, rs6434222, rs10153820 and rs8176528) from TFPI were selected and genotyped by direct sequencing. And the genotypes of the above SNPs were determined in all these participants. RESULTS: In the populations from Beijing and Harbin, no significant case-control differences in the frequencies of TFPI polymorphism (rs10153820 and rs8176528) were observed between CAD patients and controls. Meanwhile, two SNPs of TFPI (rs7586970 and rs6434222) were found to be associated with CAD in both groups. In stratified analyses based on gender, smoking, hypertension, diabetes mellitus and hyperlipidemia, we further determined that the investigated genetic variations of the TFPI genes seemed to be related with diabetes mellitus in CAD patients. CONCLUSIONS: Genetic variations of the TFPI genes seem to be related with CAD, which likely cooperate with metabolic risk factor (diabetes mellitus) and play critical roles in the pathogenesis of coronary artery disease. PMID- 28716012 TI - Case reports of juvenile GM1 gangliosidosisis type II caused by mutation in GLB1 gene. AB - BACKGROUND: Type II or juvenile GM1-gangliosidosis is an autosomal recessive lysosomal storage disorder, which is clinically distinct from infantile form of the disease by the lack of characteristic cherry-red spot and hepatosplenomegaly. The disease is characterized by slowly progressive neurodegeneration and mild skeletal changes. Due to the later age of onset and uncharacteristic presentation, diagnosis is frequently puzzled with other ataxic and purely neurological disorders. Up to now, 3-4 types of GM1-gangliosidosis have been reported and among them type I is the most common phenotype with the age of onset around 6 months. Various forms of GM1-gangliosidosis are caused by GLB1 gene mutations but severity of the disease and age of onset are directly related to the position and the nature of deleterious mutations. However, due to its unique genetic cause and overlapping clinical features, some researchers believe that GM1 gangliosidosis represents an overlapped disease spectrum instead of four distinct types. CASE PRESENTATION: Here, we report a less frequent type of autosomal recessive GM1 gangliosidosis with perplexing clinical presentation in three families in the southwest part of Iran, who are unrelated but all from "Lurs" ethnic background. To identify disease-causing mutations, Whole Exome Sequencing (WES) utilizing next generation sequencing was performed. Four patients from three families were investigated with the age of onset around 3 years old. Clinical presentations were ataxia, gate disturbances and dystonia leading to wheelchair-dependent disability, regression of intellectual abilities, and general developmental regression. They all were born in consanguineous families with no previous documented similar disease in their parents. A homozygote missense mutation in GLB1 gene (c. 601 G > A, p.R201C) was found in all patients. Using Sanger sequencing this identified mutation was confirmed in the proband, their parents, grandparents, and extended family members, confirming its autosomal recessive pattern of inheritance. CONCLUSIONS: Our study identified a rare pathogenic missense mutation in GLB1 gene in patients with complex neurodevelopmental findings, which can extend the list of differential diagnoses for childhood ataxia in Iranian patients. PMID- 28716013 TI - Long-term renal survival of gamma3-heavy chain deposition disease: a case report. AB - BACKGROUND: Monoclonal immunoglobulin deposition disease (MIDD) is characterized by the non-amyloid deposition of monoclonal immunoglobulin fragments in the basement membranes. Heavy chain deposition disease (HCDD) is a type of MIDD. HCDD is an extremely rare disease, and only three cases have been reported in Japan up to the present. The prognosis of HCDD is very poor, and optimal treatment has not been established. Only a few cases of HCDD with favorable long-term renal prognosis have been reported to date. CASE PRESENTATION: The authors describe a 61-year-old woman who presented with massive proteinuria, progressive kidney impairment, and hypocomplementemia. Kidney biopsy was performed for a precise diagnosis. On light microscopy, glomerules were lobulated and presented with nodular sclerosing glomerulopathy with membranoproliferative glomerulonephritis like features. Immunofluorescence studies were positive for IgG, C3, and C1q within the mesangial nodules and in a linear distribution along the capillary walls without associated deposition of light chains. Staining for IgG showed the presence of linear deposits along tubular basement membranes. The analysis of the IgG subclass stain demonstrated intense positivity for IgG3 only. Electron microscopy revealed non-organized electron-dense deposits in the expanded mesangial area and inner aspect of the glomerular basement membranes. In accordance with the histological findings, we diagnosed gamma3-HCDD. There was no evidence of plasma cell dyscrasia as a result of bone marrow aspiration. Serum and urine monoclonal proteins were not detected by immunoelectrophoresis and immunofixation electrophoresis. The serum free light chain ratio was within normal range. At first, prednisolone was administrated at a dose of 40 mg/day. However, a therapeutic effect was not observed. Urinary protein was not decreased and renal function further deteriorated. Therefore, melphalan plus prednisolone (MP) therapy was initiated. After 4 courses of MP therapy, the clinical parameters, including proteinuria, serum creatinine, albumin, and complement level (C3 and C4) were ameliorated. To date, the patient has been followed for 28 months, and long-term renal survival has been observed. CONCLUSIONS: In this case, hematologic disease such as multiple myeloma was not detected; however, MP therapy was effective. Recently, the novel concept of monoclonal gammopathy of renal significance (MGRS) has been reported. MIDD, which includes HCDD, is one category of MGRS. In MGRS, aggressive chemotherapy may induce favorable renal outcomes. PMID- 28716014 TI - The Comprehensive Post-Acute Stroke Services (COMPASS) study: design and methods for a cluster-randomized pragmatic trial. AB - BACKGROUND: Patients discharged home after stroke face significant challenges managing residual neurological deficits, secondary prevention, and pre-existing chronic conditions. Post-discharge care is often fragmented leading to increased healthcare costs, readmissions, and sub-optimal utilization of rehabilitation and community services. The COMprehensive Post-Acute Stroke Services (COMPASS) Study is an ongoing cluster-randomized pragmatic trial to assess the effectiveness of a comprehensive, evidence-based, post-acute care model on patient-centered outcomes. METHODS: Forty-one hospitals in North Carolina were randomized (as 40 units) to either implement the COMPASS care model or continue their usual care. The recruitment goal is 6000 patients (3000 per arm). Hospital staff ascertain and enroll patients discharged home with a clinical diagnosis of stroke or transient ischemic attack. Patients discharged from intervention hospitals receive 2-day telephone follow-up; a comprehensive clinic visit within 2 weeks that includes a neurological evaluation, assessments of social and functional determinants of health, and an individualized COMPASS Care PlanTM integrated with a community-specific resource database; and additional follow-up calls at 30 and 60 days post-stroke discharge. This model is consistent with the Centers for Medicare and Medicaid Services transitional care management services provided by physicians or advanced practice providers with support from a nurse to conduct patient assessments and coordinate follow-up services. Patients discharged from usual care hospitals represent the control group and receive the standard of care in place at that hospital. Patient-centered outcomes are collected from telephone surveys administered at 90 days. The primary endpoint is patient-reported functional status as measured by the Stroke Impact Scale 16. Secondary outcomes are: caregiver strain, all-cause readmissions, mortality, healthcare utilization, and medication adherence. The study engages patients, caregivers, and other stakeholders (including policymakers, advocacy groups, payers, and local community coalitions) to advise and support the design, implementation, and sustainability of the COMPASS care model. DISCUSSION: Given the high societal and economic burden of stroke, identifying a care model to improve recovery, independence, and quality of life is critical for stroke survivors and their caregivers. The pragmatic trial design provides a real-world assessment of the COMPASS care model effectiveness and will facilitate rapid implementation into clinical practice if successful. TRIAL REGISTRATION: Clinicaltrials.gov: NCT02588664 ; October 23, 2015. PMID- 28716015 TI - Illegal gold miners in French Guiana: a neglected population with poor health. AB - BACKGROUND: In French Guiana, a French overseas territory in South America, 6 to 10 thousands undocumented persons work illegally in gold mining sites in the Amazonian forest. Precarious life conditions lead to poor health but few data exist on the health status of illegal gold miners in French Guiana. The objective of this article was to describe the sociodemographic and health status of this vulnerable population. METHOD: A prospective cross-sectional survey was conducted in 2015 on gold mine supply sites at the border between French Guiana and Suriname. Health status was assessed through medical examination, past medical history, haemoglobin concentration, and HIV and malaria testing. A questionnaire was used to collect data about the migration itinerary and life conditions on mining sites. RESULTS: Among the 421 adults included in the study, 93.8% (395/421) were Brazilian, mainly from Maranhao (55.7%, 220/395), the poorest Brazilian state. The sex ratio was 2.4. Overall, 48% of persons never went to school or beyond the primary level. The median time spent in gold mining was quite long (10 years), with a high turn-over. One third of the surveyed population (37.1%, 156/421) had high blood pressure, and only two had a medical follow-up. Most persons had experienced malaria (89.3%, 376/421). They declared frequent arboviroses and digestive disorders. Active leishmaniasis was observed in 8.3% of gold miners. Among women, 28.5% were anemic. Concerning HIV, 36.6% (154/421) of persons, mainly men, never got tested before and 6 were tested positive, which represented an HIV prevalence of 1.43% (95%CI =0.29-2.5). CONCLUSION: These findings support the hypothesis that mining in remote areas is linked to several specific illnesses. Theoretically, gold miners would be presumed to start their economical migration to French Guiana as a healthy group. However, their strenuous working and living conditions there lead to poor health caused by infectious and non infectious diseases. This description of their health status is precious for health policy planners in French Guiana given the importance of controlling communicable disease, and the severity and range of specific illnesses acquired by this neglected population. TRIAL REGISTRATION: Clinical trial registration PRS N degrees NCT02903706 . Retrospectively registered 09/13/2016. PMID- 28716016 TI - Identifying classes of persons with mild intellectual disability or borderline intellectual functioning: a latent class analysis. AB - BACKGROUND: Persons with mild intellectual disability or borderline intellectual functioning are often studied as a single group with similar characteristics. However, there are indications that differences exist within this population. Therefore, the aim of this study was to identify classes of persons with mild intellectual disability or borderline intellectual functioning and to examine whether these classes are related to individual and/or environmental characteristics. METHODS: Latent class analysis was performed using file data of 250 eligible participants with a mean age of 26.1 (SD 13.8, range 3-70) years. RESULTS: Five distinct classes of persons with mild intellectual disability or borderline intellectual functioning were found. These classes significantly differed in individual and environmental characteristics. For example, persons with a mild intellectual disability experienced fewer problems than those with borderline intellectual disability. CONCLUSIONS: The identification of five classes implies that a differentiated approach is required towards persons with mild intellectual disability or borderline intellectual functioning. PMID- 28716017 TI - Impact of injury-related mortality on life expectancy in Zhejiang, China based on death and population surveillance data. AB - BACKGROUND: Life expectancy is a statistical measure of the average time an organism is expected to live. The purpose of this study was to evaluate the impact of injury-related mortality on life expectancy in Zhejiang Province. METHODS: Our study used standard life tables to calculate life expectancy and cause-removed life expectancy based on mortality data from the Zhejiang Chronic Disease Surveillance System. RESULTS: Life expectancy of residents in Zhejiang was 77.83 years in 2013, with females having a higher life expectancy than males. The decrease in life expectancy caused by injury-related deaths was 1.19 years, the effect of which was reduced for females and urban residents compared with males and rural residents. The greatest impact on life expectancy was road traffic injuries (RTIs), (0.29 years lost overall, 0.36 for men vs. 0.21 for women and 0.26 for urban residents vs. 0.31 for rural residents). The main causes were falls (0.29 years lost overall, 0.30 for men vs. 0.28 for women and 0.28 for urban residents vs. 0.30 for rural residents), followed by drowning (0.15 years lost), suicide (0.11 years lost), and poisoning (0.04 years). For children less than 5 years old and elders aged over 65, drowning had a greater impact than falls. CONCLUSIONS: Our findings indicate that injury deaths had a major impact on life expectancy in Zhejiang. More attention should be paid to road traffic injury, and preventive action should be taken to reduce injury-related deaths to increase life expectancy, especially in children under five years of age and the elders over 65 years of age. PMID- 28716018 TI - Prediction of Extubation readiness in extremely preterm infants by the automated analysis of cardiorespiratory behavior: study protocol. AB - BACKGROUND: Extremely preterm infants (<= 28 weeks gestation) commonly require endotracheal intubation and mechanical ventilation (MV) to maintain adequate oxygenation and gas exchange. Given that MV is independently associated with important adverse outcomes, efforts should be made to limit its duration. However, current methods for determining extubation readiness are inaccurate and a significant number of infants fail extubation and require reintubation, an intervention that may be associated with increased morbidities. A variety of objective measures have been proposed to better define the optimal time for extubation, but none have proven clinically useful. In a pilot study, investigators from this group have shown promising results from sophisticated, automated analyses of cardiorespiratory signals as a predictor of extubation readiness. The aim of this study is to develop an automated predictor of extubation readiness using a combination of clinical tools along with novel and automated measures of cardiorespiratory behavior, to assist clinicians in determining when extremely preterm infants are ready for extubation. METHODS: In this prospective, multicenter observational study, cardiorespiratory signals will be recorded from 250 eligible extremely preterm infants with birth weights <=1250 g immediately prior to their first planned extubation. Automated signal analysis algorithms will compute a variety of metrics for each infant, and machine learning methods will then be used to find the optimal combination of these metrics together with clinical variables that provide the best overall prediction of extubation readiness. Using these results, investigators will develop an Automated system for Prediction of EXtubation (APEX) readiness that will integrate the software for data acquisition, signal analysis, and outcome prediction into a single application suitable for use by medical personnel in the neonatal intensive care unit. The performance of APEX will later be prospectively validated in 50 additional infants. DISCUSSION: The results of this research will provide the quantitative evidence needed to assist clinicians in determining when to extubate a preterm infant with the highest probability of success, and could produce significant improvements in extubation outcomes in this population. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT01909947 . Registered on July 17 2013. Trial sponsor: Canadian Institutes of Health Research (CIHR). PMID- 28716019 TI - Glenohumeral and scapulothoracic strength impairments exists in patients with subacromial impingement, but these are not reflected in the shoulder pain and disability index. AB - BACKGROUND: Pain and loss of function are cardinal symptoms associated with Subacromial impingement syndrome (SIS), while the presence and magnitude of deficits in strength and range of motion (ROM) are largely undescribed in non athletic patients with SIS. Moreover, the relevance of impairments in strength and ROM to patient-reported shoulder function is not well described, even though testing of strength is recommended in clinical guidelines. The purpose of this study was, first, to investigate impairments in glenohumeral and scapulothoracic strength and in abduction and internal rotation ROM in patients with SIS. Secondly, to investigate the influence of these impairments on patient-reported shoulder function. METHODS: Cross-sectional study based on a consecutive cohort of 157 patients referred to specialist examination and diagnosed with shoulder impingement (SIS) using predefined validated diagnostic criteria. Prior to specialist examination, questionnaires regarding shoulder function (Shoulder Pain And Disability Index, SPADI) demographics and kinesiophobia (TSK-11) were collected, and shoulder strength and ROM was measured by trained testers, with the patient reporting pain levels during testing and for the last week. Impairments in strength (abduction, external-rotation, (protraction and horizontal-extension) and ROM (abduction and internal rotation) were investigated in patients with unilateral shoulder pain, using one-sample t-tests. SPADI total score (SPADI) and SPADI function score (SPADI-F), were chosen as dependent variables in multiple regressions to investigate the influence of impairments on patient-reported shoulder function. Independent variables of interest were; strength in abduction and external rotation, abduction ROM, pain-during-tests, pain-last-week and kinesiophobia. RESULTS: Significant impairments were found for all impairment tests, but most pronounced for glenohumeral strength and abduction ROM (29-33% deficits), and less for scapulothoracic strength and internal rotation ROM (8-18% deficits). Pain variables influenced SPADI and SPADI-F score to a high degree (R2 = 23.4-31.6%, p < 0.001), while strength and ROM did not. CONCLUSION: Substantial strength and ROM impairments were found in patients with SIS. Only pain significantly influenced patient-reported function, while impairments did not. As SPADI score does not reflect the substantial strength and ROM impairments in external rotation and abduction observed in patients with SIS, supplemental assessment of these impairments seems important. PMID- 28716020 TI - Long non-coding RNA CASC2 suppresses epithelial-mesenchymal transition of hepatocellular carcinoma cells through CASC2/miR-367/FBXW7 axis. AB - BACKGROUND: Recently, it has been reported that long non-coding RNA (lncRNA) cancer susceptibility candidate 2 (CASC2), a novel tumor suppressor, participates in regulating the carcinogenesis and suppresses tumor progression by sponging microRNAs (miRNAs). However, the expression and function of CASC2 in hepatocellular carcinoma (HCC) remain unclear. METHODS: The expression of CASC2 and miR-367 in HCC specimens and cell lines were detected by real-time PCR. Western blotting and immunohistochemistry were carried out for detection of epithelial-to-mesenchymal transition (EMT) markers in HCC. Transwell assays were used to determine migration and invasion of HCC cells. A mouse model for lung metastasis was established to evaluated HCC metastasis in vivo. The correlation among CASC2, miR-367 and F-box and WD repeat domain containing 7 (FBXW7) were disclosed by a dual-luciferase reporter assay, RIP assay and biotin pull-down assay. RESULTS: Here, CASC2 expression was significantly downregulated in HCC tissues, especially in aggressive and recurrent cases. In accordance, CASC2 underexpression was observed in HCC cell lines compared to LO2. In vitro and in vivo experiments revealed that CASC2 inhibited migration and invasion of HCC cells. Additionally, CASC2 repressed EMT process of HCC cells. Further studies demonstrated that CASC2 could function as a competing endogenous RNA (ceRNA) by sponging miR-367 in HCC cells. Functionally, gain- and loss-of-function studies showed that miR-367 promoted migration, invasion and EMT progression of HCC cells. Moreover, further investigations disclosed that FBXW7 was a downstream target of miR-367 and CASC2 prohibited EMT progression and subsequently exerted its anti-metastatic effects via CASC2/miR-367/FBXW7 axis in HCC cells. Clinically, CASC2 underexpression and miR-367 overexpression were closely correlated with the metastasis-associated clinicopathologic features. Notably, CASC2 low-expressing and miR-367 high-expressing HCC patients showed the poorest clinical outcome. CONCLUSIONS: Overall, we conclude that the CASC2/miR-367/FBXW7 axis may be a ponderable and promising therapeutic target for HCC. PMID- 28716021 TI - Missed diagnoses in African Americans with obsessive-compulsive disorder: the structured clinical interview for DSM-IV Axis I disorders (SCID-I). AB - BACKGROUND: Research on the utility of structured interviews in assessing OCD is scarce, and even more so, in its use for OCD in African Americans. The purpose of this study was to examine the utility of the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I) in detecting OCD in African Americans when used by well-trained, culturally competent clinicians. METHODS: Seventy-four African American adults with OCD were assessed with the SCID-I and additional measures of OCD. RESULTS: Results revealed the poor diagnostic utility of the SCID OCD section (SCID-OCD), with 66.2% (N = 49) correctly identified and 33.8% (N = 25) incorrectly diagnosed. Participants receiving the correct diagnosis were more likely to endorse compulsive behaviors, specifically ordering compulsions, and experience greater symptom severity. CONCLUSION: The lack of sensitivity for identification of OCD is discussed as the SCID-OCD seems to often miss a true diagnosis of OCD in African Americans. PMID- 28716023 TI - Retraction Note to: Extranuclear ERalpha is associated with regression of T47D PKCalpha-overexpressing, tamoxifen-resistant breast cancer. PMID- 28716022 TI - Crisis resolution and home treatment: stakeholders' views on critical ingredients and implementation in England. AB - BACKGROUND: Crisis resolution teams (CRTs) can provide effective home-based treatment for acute mental health crises, although critical ingredients of the model have not been clearly identified, and implementation has been inconsistent. In order to inform development of a more highly specified CRT model that meets service users' needs, this study used qualitative methods to investigate stakeholders' experiences and views of CRTs, and what is important in good quality home-based crisis care. METHOD: Semi-structured interviews and focus groups were conducted with service users (n = 41), carers (n = 20) and practitioners (CRT staff, managers and referrers; n = 147, 26 focus groups, 9 interviews) in 10 mental health catchment areas in England, and with international CRT developers (n = 11). Data were analysed using thematic analysis. RESULTS: Three domains salient to views about optimal care were identified. 1. The organisation of CRT care: Providing a rapid initial responses, and frequent home visits from the same staff were seen as central to good care, particularly by service users and carers. Being accessible, reliable, and having some flexibility were also valued. Negative experiences of some referral pathways, and particularly lack of staff continuity were identified as problematic. 2. The content of CRT work: Emotional support was at the centre of service users' experiences. All stakeholder groups thought CRTs should involve the whole family, and offer a range of interventions. However, carers often feel excluded, and medication is often prioritised over other forms of support. 3. The role of CRTs within the care system: Gate-keeping admissions is seen as a key role for CRTs within the acute care system. Service users and carers report that recovery is quicker compared to in-patient care. Lack of knowledge and misunderstandings about CRTs among referrers are common. Overall, levels of stakeholder agreement about the critical ingredients of good crisis care were high, although aspects of this were not always seen as achievable. CONCLUSIONS: Stakeholders' views about optimal CRT care suggest that staff continuity, carer involvement, and emotional and practical support should be prioritised in service improvements and more clearly specified CRT models. PMID- 28716024 TI - MiR-661 promotes tumor invasion and metastasis by directly inhibiting RB1 in non small cell lung cancer. AB - BACKGROUND: Aberrant microRNA expression has been implicated in metastasis of cancers. MiR-661 accelerates proliferation and invasion of breast cancer and ovarian cancer, while impedes that of glioma. Its role in non small cell lung cancer (NSCLC) and underlying mechanism are worthy elucidation. METHODS: Expression of miR-661 was measured with real-time PCR in both NSCLC tissues and cell lines. The effects of miR-661 on migration, invasion and metastasis capacity of NSCLC were evaluated using wound healing, transwell assay and animal models. Dual reporter luciferase assay and complementary experiments were performed to validate RB1 as a direct target of miR-661 for participation in the progression of NSCLC. RESULTS: MiR-661 was upregulated in NSCLC tissues as compared to paired adjacent tissues and associated with shorter overall survival. Furthermore, miR 661 promoted proliferation, migration and metastasis of NSCLC. Then, we identified RB1 as a direct target of miR-661 through which miR-661 affected EMT process and metastasis of NSCLC. RB1 interacted with E2F1 and both could mediate EMT process in NSCLC. CONCLUSION: MiR-661 promotes metastasis of NSCLC through RB/E2F1 signaling and EMT events, thus may serves as a negative prognostic factor and possible target for treatment of NSCLC patient. PMID- 28716025 TI - Beta-mangostin demonstrates apoptogenesis in murine leukaemia (WEHI-3) cells in vitro and in vivo. AB - BACKGROUND: Beta-mangostin (BM) is a xanthone-type of natural compound isolated from Cratoxylum arborescens. This study aimed to examine the apoptosis mechanisms induced by BM in a murine monomyelocytic cell line (WEHI-3) in vitro and in vivo. METHODS: A WEHI-3 cell line was used to evaluate the cytotoxicity of BM by MTT. AO/PI and Hoechst 33342 dyes, Annexin V, multiparametric cytotoxicity 3 by high content screening (HCS); cell cycle tests were used to estimate the features of apoptosis and BM effects. Caspase 3 and 9 activities, ROS, western blot for Bcl2, and Bax were detected to study the mechanism of apoptosis. BALB/c mice injected with WEHI-3 cells were used to assess the apoptotic effect of BM in vivo. RESULTS: BM suppressed the growth of WEHI-3 cells at an IC50value of 14 +/- 3 MUg/mL in 24 h. The ROS production was increased inside the cells in the treated doses. Both caspases (9 and 3) were activated in treating WEHI-3 cells at 24, 48 and 72 h. Different signs of apoptosis were detected, such as cell membrane blebbing, DNA segmentation and changes in the asymmetry of the cell membrane. Another action by which BM could inhibit WEHI-3 cells is to restrain the cell cycle at the G1/G0 phase. In the in vivo study, BM reduced the destructive effects of leukaemia on the spleen and liver by inducing apoptosis in leukaemic cells. CONCLUSION: BM exerts anti-leukaemic properties in vitro and in vivo. PMID- 28716026 TI - Short stem total hip arthroplasty for osteonecrosis of the femoral head in patients 60 years or younger: a 3- to 10-year follow-up study. AB - BACKGROUND: In young patients with osteonecrosis of the femoral head (ONFH), short-stem total hip arthroplasty (THA) could allow a potential advantage in preserving metaphyseal bone-stock, when revision surgery might become necessary. However, only a few studies have evaluated the outcome of short-stem THAs in ONFH. We reviewed the prospectively collected data of a cementless partial neck retaining short-stem with ceramic-on-ceramic bearings in ONFH patients. METHODS: Thirty patients (37 hips) younger than 60 years (mean age at surgery, 51.5 years) underwent THA with the NANOS(r) stem (Smith and Nephew, Marl, Germany) from January 2006 to December 2012. All patients received a 32-mm or 36 mm ceramic femoral head. Harris hip score, WOMAC and UCLA activity score were recorded. Postoperative radiographs were evaluated for bone-implant fixation and osteolysis. Further analysis correlated clinical findings with implants characteristics and patient demographics at mean 5.6 years' follow-up (range, 3 10 years). RESULTS: The clinical and functional results improved significantly (p < 0.001). At latest follow-up, mean HHS, WOMAC, and UCLA activity scores were 90 (range, 71-100), 94 (range, 76-100), and 6.3 (range, 4-10) points, respectively. The diameter of the femoral head did not influence the clinical outcome (p = 0.661). All hips showed bone ingrowth fixation of the acetabular and femoral components. No patients showed osteolysis. No revision for any reason was performed during the study period. CONCLUSIONS: The excellent clinical results and fixation pattern at mean 5.6 years' follow-up reveal this implant as a reliable option in advanced stage of ONFH either. Further investigations are crucial to determine the long-term durability and to assess whether the association of ceramic-on-ceramic bearings, can be useful to achieve longer survivorship and lower complications rates. TRIAL REGISTRATION: Registry number: ISRCTN 91336248 ; date of registration: 04/07/2017. PMID- 28716027 TI - Cytomegalovirus viraemia and mortality in renal transplant recipients in the era of antiviral prophylaxis. Lessons from the western Australian experience. AB - BACKGROUND: Cytomegalovirus (CMV) establishes a lifelong infection that is efficiently controlled by the immune system; this infection can be reactivated in case of immunosuppression such as following solid organ transplantation. CMV viraemia has been associated with CMV disease, as well as increased mortality and allograft failure. Prophylactic antiviral medication is routinely given to renal transplant recipients, but reactivation during and following cessation of antiviral prophylaxis is known to occur. The aims of this study were to assess the incidence, timing and impact of CMV viraemia in renal transplant recipients and to determine the level of viraemia associated with adverse clinical outcomes. METHODS: Data from all adult (18 years and over) Western Australian renal transplant recipients transplanted between 1 January 2007 and 31 December 2012 were obtained from the Australia and New Zealand Dialysis and Transplant registry and were supplemented with data obtained from clinical records. Potential risk factors for detectable CMV viraemia (>=600 copies/ml) and all-cause mortality were assessed using univariable analysis and Cox Proportional Hazards Regression. RESULTS: There were 438 transplants performed on 435 recipients. The following factors increased the risk of CMV viraemia with viral loads >=600 copies/ml: Donor positive/Recipient negative status; receiving a graft from a deceased donor; and receiving a graft from a donor aged 60 years and over. CMV viraemia with viral loads >=656 copies/ml was a risk factor for death following renal transplantation, as was being aged 65 years and above at transplant, being Aboriginal and having vascular disease. Importantly 37% of the episodes of CMV viraemia with viral loads >=656 copies/ml occurred while the patients were expected to be on CMV prophylaxis. CONCLUSIONS: CMV viraemia (>=656 copies/ml) was associated with all-cause mortality in multivariable analysis, and CMV viraemia at >=656 copies/ml commonly occurred during the period when renal transplant recipients were expected to be on antiviral prophylaxis. A greater vigilance in monitoring CMV levels if antiviral prophylaxis is stopped prematurely or poor patient compliance is suspected could protect some renal transplant recipients from adverse outcomes such as premature mortality. PMID- 28716028 TI - Antiplasmodial potential and quantification of aloin and aloe-emodin in Aloe vera collected from different climatic regions of India. AB - BACKGROUND: In this study, Aloe vera samples were collected from different climatic regions of India. Quantitative HPTLC (high performance thin layer chromatography) analysis of important anthraquinones aloin and aloe-emodin and antiplasmodial activity of crude aqueous extracts was done to estimate the effects of these constituents on antiplasmodial potential of the plant. METHODS: HPTLC system equipped with a sample applicator Linomat V with CAMAG sample syringe, twin rough plate development chamber (20 x 10 cm), TLC Scanner 3 and integration software WINCATS 1.4.8 was used for analysis of aloin and aloe-emodin amount. The antiplasmodial activity of plant extracts was assessed against a chloroquine (CQ) sensitive strain of P. falciparum (MRC-2). Minimum Inhibitory Concentration (MIC) of aqueous extracts of selected samples was determined according to the World Health Organization (WHO) recommended method that was based on assessing the inhibition of schizont maturation in a 96-well microtitre plate. EC (effective concentration) values of different samples were observed to predict antiplasmodial potential of the plant in terms of their climatic zones. RESULTS: A maximum quantity of aloin and aloe-emodin i.e. 0.45 and 0.27 mg/g respectively was observed from the 12 samples of Aloe vera. The inhibited parasite growth with EC50 values ranging from 0.289 to 1056 MUg/ml. The antiplasmodial EC50 value of positive control Chloroquine was observed 0.034 MUg/ml and EC50 values showed by aloin and aloe-emodin was 67 MUg/ml and 22 MUg/ml respectively. A positive correlation was reported between aloin and aloe emodin. Antiplasmodial activity was increased with increase in the concentration of aloin and aloe-emodin. The quantity of aloin and aloe-emodin was decreased with rise in temperature hence it was negatively correlated with temperature. CONCLUSIONS: The extracts of Aloe vera collected from colder climatic regions showed good antiplasmodial activity and also showed the presence of higher amount of aloin and aloe-emodin in comparison to collected from warmer climatic sites. Study showed significant correlation between quantities of both the anthraquinones used as marker compounds and EC50 values of the different Aloe vera extracts. Although, both the anthraquinones showed less antiplasmodial potential in comparison to crude extracts of different Aloe vera samples. Diverse climatic factors affect the quantity of tested compounds and antiplasmodial potential of the plant in different Aloe vera samples. PMID- 28716030 TI - Modeling de novo granulation of anaerobic sludge. AB - BACKGROUND: A unique combination of mechanical, physiochemical and biological forces influences granulation during processes of anaerobic digestion. Understanding this process requires a systems biology approach due to the need to consider not just single-cell metabolic processes, but also the multicellular organization and development of the granule. RESULTS: In this computational experiment, we address the role that physiochemical and biological processes play in granulation and provide a literature-validated working model of anaerobic granule de novo formation. The agent-based model developed in a cDynoMiCs simulation environment successfully demonstrated a de novo granulation in a glucose fed system, with the average specific methanogenic activity of 1.11 ml C H 4/g biomass and formation of a 0.5 mm mature granule in 33 days. The simulated granules exhibit experimental observations of radial stratification: a central dead core surrounded by methanogens then encased in acidogens. Practical application of the granulation model was assessed on the anaerobic digestion of low-strength wastewater by measuring the changes in methane yield as experimental configuration parameters were systematically searched. CONCLUSIONS: In the model, the emergence of multicellular organization of anaerobic granules from randomly mixed population of methanogens and acidogens was observed and validated. The model of anaerobic de novo granulation can be used to predict the morphology of the anaerobic granules in a alternative substrates of interest and to estimate methane potential of the resulting microbial consortia. The study demonstrates a successful integration of a systems biology approach to model multicellular systems with the engineering of an efficient anaerobic digestion system. PMID- 28716029 TI - FOXP3 promotes tumor growth and metastasis by activating Wnt/beta-catenin signaling pathway and EMT in non-small cell lung cancer. AB - BACKGROUND: The role of cancer cell FOXP3 in tumorigenesis is conflicting. We aimed to study FOXP3 expression and regulation, function and clinical implication in human non-small cell lung cancer (NSCLC). METHODS: One hundred and six patients with histologically-confirmed NSCLC who underwent surgery were recruited for the study. Tumor samples and NSCLC cell lines were used to examine FOXP3 and its related molecules. Various cell functions related to tumorigenesis were performed. In vivo mouse tumor xenograft was used to confirm the in vitro results. RESULTS: NSCLC patients with the high level of FOXP3 had a significant decrease in overall survival and recurrence-free survival. FOXP3 overexpression significantly induced cell proliferation, migration, and invasion, whereas its inhibition impaired its oncogenic function. In vivo studies confirmed that FOXP3 promoted tumor growth and metastasis. The ectopic expression of FOXP3 induced epithelial-mesenchymal transition (EMT) with downregulation of E-cadherin and upregulation of N-cadherin, vimentin, snail, slug, and MMP9. The oncogenic effects by FOXP3 could be attributed to FOX3-mediated activation of Wnt/beta catenin signaling, as FOXP3 increased luciferase activity of Topflash reporter and upregulated Wnt signaling target genes including c-Myc and Cyclin D1 in NSCLC cells. Co-immunoprecipitation results further indicated that FOXP3 could physically interacted with beta-catenin and TCF4 to enhance the functions of beta catenin and TCF4, inducing transcription of Wnt target genes to promote cell proliferation, invasion and EMT induction. CONCLUSIONS: FOXP3 can act as a co activator to facilitate the Wnt-b-catenin signaling pathway, inducing EMT and tumor growth and metastasis in NSCLC. PMID- 28716031 TI - A rare case of intradural and extramedullary epidermoid cyst after repetitive epidural anesthesia: case report and review of the literature. AB - BACKGROUND: Spinal epidermoid cysts are benign tumors, which are rarely seen as an intradural extramedullary spinal cord tumor in the conus medullaris region. Acquired spinal epidermoid cysts are mostly caused by iatrogenic procedures, such as lumbar puncture, and the majority of acquired spinal epidermoid cysts have been reported below the L1 level, because lumbar puncture is usually performed around the iliac crest. Here, we report an extremely rare case of an epidermoid cyst that occurred as an intradural and extramedullary spinal cord tumor attached to the conus medullaris after repetitive epidural anesthesia. CASE PRESENTATION: A 67-year-old female presented with a low back pain and left sciatica. Although the patient had experienced occasional mild low back pain for several years, her low back pain markedly worsened 2 months before her visit, as well as newly developed left sciatica resulting in intermittent claudication. She had a history of several abdominal surgeries. All abdominal procedures were performed under general anesthesia with epidural anesthesia in her thoracolumbar spine. Magnetic resonance imaging of her lumbar spine demonstrated an intradural extramedullary spinal cord tumor at the T12-L1 level. Because her symptoms deteriorated, the tumor excision was performed using microscopy. Histological examination of the specimens demonstrated that the cyst walls lined with stratified squamous keratinizing epithelium surrounded by the outer layer of collagenous tissue with the absence of skin adnexa. A diagnosis of epidermoid cysts was confirmed. Her MRI showed complete resection of the tumor, and there was no recurrence at 2-year follow-up. CONCLUSIONS: In this case report, epidermoid cells might be contaminated into the spinal canal during repetitive epidural anesthesia. The patient was successfully treated by complete resection, and there was no recurrence at 2-year follow-up with a good clinical outcome. However, long-term follow-up is required for a potential risk of tumor recurrence. PMID- 28716032 TI - Association of financial status and the quality of life in Chinese women with recurrent ovarian cancer. AB - BACKGROUND: Very few studies have examined the association between financial status and the quality of life (QOL) of patients with specific cancers. Ovarian cancer survivors frequently suffer repeat recurrence and subsequent treatment and, as a result, a significant added financial burden. Financial burdens disproportionally affect patients of low income. This study examines the association between financial status, based upon family income and expenses, and QOL in Chinese women with recurrent ovarian cancer. METHODS: We assessed baseline and follow-up (3-month) QOL of Chinese women with recurrent ovarian cancer using the European Organization for Research and Treatment of Cancer 30-Item Core Quality of Life Questionnaire (EORTC QLQ-C30), and the Quality of Life Ovarian Cancer 28 Questionnaire (QLQ-OV28). Financial status was stratified based upon self-reported disposable income. Linear or logistic regression models were applied to determine the relationship between QOL in each financial status category, and key demographic and clinical factors. RESULTS: Among all 473 ovarian cancer patients, 123 of them met enrollment criteria were recruited to this study and completed baseline questionnaires; 95 of these patients completed the 3-month follow-up questionnaires. Our results showed that low financial status was significantly associated with worse QOL on all functioning domains and several symptom domains. QOL deteriorated during the follow-up. A significantly greater number of patients with low financial status experienced deteriorating QOL in several domains. Occupation and insurance type, two factors related to financial status, were significantly associated with QOL as well, but to a lesser extent. Education, recurrence interval, age and BMI were also significantly related to certain domains of QOL. CONCLUSIONS: Financial status is associated with QOL of Chinese women with recurrent ovarian cancer. These patients showed worsening QOL during active chemotherapy. Lower financial status is associated with a higher risk of deteriorating QOL in several domains. PMID- 28716033 TI - Current status of tertiary debulking surgery and prognosis after secondary debulking surgery for recurrent Mullerian epithelial cancer in Japan: a retrospective analysis of 164 patients (KCOG-G1402). AB - BACKGROUND: This study aimed to evaluate the current status of secondary debulking surgery (SDS) and tertiary debulking surgery (TDS; performed for recurrence after SDS) and to assess the overall survival after recurrence of Mullerian epithelial cancer in Japan. We also evaluated the data of patients who underwent a fourth debulking surgery (i.e., quaternary debulking surgery (QDS)). METHODS: We conducted a retrospective study of 164 patients with recurrent Mullerian epithelial cancers (i.e., ovarian, tubal, and peritoneal cancers). The SDS was performed between January 2000 and September 2014 in 20 Japanese hospitals. Clinicopathological data were collected and analyzed. RESULTS: Of the 164 patients, 66 patients did not have a recurrence or died after SDS. Ninety eight patients had a recurrence after SDS. Forty-three of the 98 patients underwent TDS; 55 of the 98 patients did not undergo TDS and were classified into the non-TDS group. The overall survival (OS) after SDS was significantly better in the TDS group than in the non-TDS group. The median OS after SDS was 123 and 42 months in the TDS group and non-TDS group, respectively. Of the 43 patients who received TDS, 11 patients were further treated with QDS. The median OS after SDS was 123 months for patients who underwent QDS. CONCLUSIONS: This multicenter study on the prognosis of post-SDS is apparently the first report on QDS in Japan. Patients undergoing TDS have a good prognosis, compared to patients in the non-TDS group. Novel drugs are being evaluated; however, debulking surgery remains a necessary treatment for recurrence. PMID- 28716034 TI - Growth arrest specific gene 2 in tilapia (Oreochromis niloticus): molecular characterization and functional analysis under low-temperature stress. AB - BACKGROUND: Growth arrest specific 2 (gas2) gene is a component of the microfilament system that plays a major role in the cell cycle, regulation of microfilaments, and cell morphology during apoptotic processes. However, little information is available on fish gas2. In this study, the tilapia (Oreochromis niloticus) gas2 gene was cloned and characterized for the first time. RESULTS: The open reading frame was 1020 bp, encoding 340 amino acids; the 5'-untranslated region (UTR) was 140 bp and the 3'-UTR was 70 bp, with a poly (A) tail. The highest promoter activity occurred in the regulatory region (-3000 to -2400 bp). The Gas2-GFP fusion protein was distributed within the cytoplasm. Quantitative reverse transcription-polymerase chain reaction and western blot analyses revealed that gas2 gene expression levels in the liver, muscle, and brain were clearly affected by low temperature stress. The results of gas2 RNAi showed decreased expression of the gas2 and P53 genes. CONCLUSION: These results suggest that the tilapia gas2 gene may be involved in low temperature stress-induced apoptosis. PMID- 28716035 TI - Systematic evaluation of characteristics of the membrane-based fed-batch shake flask. AB - BACKGROUND: The initial part of process development involves extensive screening programs to identify optimal biological systems and cultivation conditions. For a successful scale-up, the operation mode on screening and production scale must be as close as possible. To enable screening under fed-batch conditions, the membrane-based fed-batch shake flask was developed. It is a shake flask mounted with a central feed reservoir with an integrated rotating membrane tip for a controlled substrate release. Building on the previously provided proof of principle for this tool, this work extends its application by constructive modifications and improved methodology to ensure reproducible performance. RESULTS: The previously limited operation window was expanded by a systematic analysis of reservoir set-up variations for cultivations with the fast-growing organism Escherichia coli. Modifying the initial glucose concentration in the reservoir as well as interchanging the built-in membrane, resulted in glucose release rates and oxygen transfer rate levels during the fed-batch phase varying up to a factor of five. The range of utilizable membranes was extended from dialysis membranes to porous microfiltration membranes with the design of an appropriate membrane tip. The alteration of the membrane area, molecular weight cut-off and liquid volume in the reservoir offered additional parameters to fine tune the duration of the initial batch phase, the oxygen transfer rate level of the fed-batch phase and the duration of feeding. It was shown that a homogeneous composition of the reservoir without a concentration gradient is ensured up to an initial glucose concentration of 750 g/L. Finally, the experimental validity of fed-batch shake flask cultivations was verified with comparable results obtained in a parallel fed-batch cultivation in a laboratory-scale stirred tank reactor. CONCLUSIONS: The membrane-based fed-batch shake flask is a reliable tool for small-scale screening under fed-batch conditions filling the gap between microtiter plates and scaled-down stirred tank reactors. The implemented reservoir system offers various set-up possibilities, which provide a wide range of process settings for diverse biological systems. As a screening tool, it accurately reflects the cultivation conditions in a fed-batch stirred tank reactor and enables a more efficient bioprocess development. PMID- 28716036 TI - Short DNA sequence patterns accurately identify broadly active human enhancers. AB - BACKGROUND: Enhancers are DNA regulatory elements that influence gene expression. There is substantial diversity in enhancers' activity patterns: some enhancers drive expression in a single cellular context, while others are active across many. Sequence characteristics, such as transcription factor (TF) binding motifs, influence the activity patterns of regulatory sequences; however, the regulatory logic through which specific sequences drive enhancer activity patterns is poorly understood. Recent analysis of Drosophila enhancers suggested that short dinucleotide repeat motifs (DRMs) are general enhancer sequence features that drive broad regulatory activity. However, it is not known whether the regulatory role of DRMs is conserved across species. RESULTS: We performed a comprehensive analysis of the relationship between short DNA sequence patterns, including DRMs, and human enhancer activity in 38,538 enhancers across 411 different contexts. In a machine-learning framework, the occurrence patterns of short sequence motifs accurately predicted broadly active human enhancers. However, DRMs alone were weakly predictive of broad enhancer activity in humans and showed different enrichment patterns than in Drosophila. In general, GC-rich sequence motifs were significantly associated with broad enhancer activity, and consistent with this enrichment, broadly active human TFs recognize GC-rich motifs. CONCLUSIONS: Our results reveal the importance of specific sequence motifs in broadly active human enhancers, demonstrate the lack of evolutionary conservation of the role of DRMs, and provide a computational framework for investigating the logic of enhancer sequences. PMID- 28716037 TI - Phylogeny, expression patterns and regulation of DNA Methyltransferases in early development of the flatfish, Solea senegalensis. AB - BACKGROUND: The identification of DNA methyltransferases (Dnmt) expression patterns during development and their regulation is important to understand the epigenetic mechanisms that modulate larval plasticity in marine fish. In this study, dnmt1 and dnmt3 paralogs were identified in the flatfish Solea senegalensis and expression patterns in early developmental stages and juveniles were determined. Additionally, the regulation of Dnmt transcription by a specific inhibitor (5-aza-2'-deoxycytidine) and temperature was evaluated. RESULTS: Five paralog genes of dnmt3, namely dnmt3aa, dnmt3ab, dnmt3ba, dnmt3bb.1 and dnmt3bb.2 and one gene for dnmt1 were identified. Phylogenetic analysis revealed that the dnmt gene family was highly conserved in teleosts and three fish-specific genes, dnmt3aa, dnmt3ba and dnmt3bb.2 have evolved. The spatio-temporal expression patterns of four dnmts (dnmt1, dnmt3aa, dnmt3ab and dnmt3bb.1) were different in early larval stages although all of them reduced expression with the age and were detected in neural organs and dnmt3aa appeared specific to somites. In juveniles, the four dnmt genes were expressed in brain and hematopoietic tissues such as kidney, spleen and gills. Treatment of sole embryos with 5-aza-2'-deoxycytidine down-regulated dntm1 and up-regulated dntm3aa. Moreover, in lecithotrophic larval stages, dnmt3aa and dnmt3ab were temperature sensitive and their expression was higher in larvae incubated at 16 degrees C relative to 20 degrees C. CONCLUSION: Five dnmt3 and one dnmt1 paralog were identified in sole and their distinct developmental and tissue-specific expression patterns indicate that they may have different roles during development. The inhibitor 5-aza-2'-deoxycytidine modified the transcript abundance of dntm1 and dntm3aa in embryos, which suggests that a regulatory feedback mechanism exists for these genes. The impact of thermal regime on expression levels of dnmt3aa and dnmt3ab in lecithotrophic larval stages suggests that these paralogs might be involved in thermal programing. PMID- 28716039 TI - Extra-corporeal membrane oxygenation for refractory cardiogenic shock after adult cardiac surgery: a systematic review and meta-analysis. AB - BACKGROUND: Postcardiotomy cardiogenic shock (PCCS) refractory to inotropic support and intra-aortic balloon pump (IABP) occurs rarely but is almost universally fatal without mechanical circulatory support. In this systematic review and meta-analysis we looked at the evidence behind the use of veno arterial extra-corporeal membrane oxygenation (VA ECMO) in refractory PCCS from a patient survival rate and determinants of outcome viewpoint. METHODS: A systematic review was performed in January 2017 using PubMed (with no defined time period) using the keywords "postcardiotomy", "cardiogenic shock", "extracorporeal membrane oxygenation" and "cardiac surgery". We excluded papers pertaining to ECMO following paediatric cardiac surgery, medical causes of cardiogenic shock, as well as case reports, review articles, expert opinions, and letters to the editor. Once the studies were collated, a meta-analysis was performed on the proportion of survivors in those papers that met the inclusion criteria. Meta-regression was performed for the most commonly reported adverse prognostic indicators (API). RESULTS: We identified 24 studies and a cumulative pool of 1926 patients from 1992 to 2016. We tabulated the demographic data, including the strengths and weaknesses for each of the studies, outcomes of VA ECMO for refractory PCCS, complications, and APIs. All the studies were retrospective cohort studies. Meta-analysis of the moderately heterogeneous data (95% CI 0.29 to 0.34, p < 0.01, I 2 = 60%) revealed overall survival rate to hospital discharge of 30.8%. Some of the commonly reported APIs were advanced age (>70 years, 95% CI -0.057 to 0.001, P = 0.058), and long ECMO support (95% CI 0.068 to 0.166, P = 0.412). Postoperative renal failure, high EuroSCORE (>20%), diabetes mellitus, obesity, rising lactate whilst on ECMO, gastrointestinal complications had also been reported. CONCLUSION: Haemodynamic support with VA ECMO provides a survival benefit with reasonable intermediate and long-term outcomes. Many studies had reported advanced age, renal failure and prolonged VA ECMO support as the most likely APIs for VA ECMO in PCCS. EuroSCORE can be utilized to anticipate the need for prophylactic perioperative VA ECMO in the high-risk category. APIs can be used to aid decision-making regarding both the institution and weaning of ECMO for refractory PCCS. PMID- 28716038 TI - An update on the use of biologic therapies in the management of uveitis in Behcet's disease: a comprehensive review. AB - ?: Behcet's disease (BD) is a systemic vasculitis characterised by a relapsing remitting course, affecting multiple organ systems. In the eye, it is a cause of potentially blinding inflammation in the form of uveitis. Management of uveitis in BD often requires the use of systemic immunosuppression, in order to reduce disease activity and prevent accumulation of irreversible damage. Whilst corticosteroids remain the mainstay of treatment, long-term use is limited by the development of adrenocorticotrophic side effects. There has therefore been significant interest in the use of corticosteroid-sparing immunosuppressive agents, and more recently, biologic therapies. Recent publications have demonstrated biologic therapy to have beneficial effects both on overall disease control, and quality of life for patients with BD. Widespread use of such agents is however limited, partly by the lack of high quality research evidence, and partly by the prohibitive cost of biologic treatments. In this review, we discuss the most recent research investigating the use of biologic therapy in uveitis due to BD, with consideration of health economics and quality of life outcomes. PMID- 28716040 TI - The communication between patient relatives and physicians in intensive care units. AB - BACKGROUND: Patients in intensive care units (ICUs) are often physically unable to communicate with their physicians. Thus, the sharing of information about the on-going treatment of the patients in ICUs is directly related to the communication attitudes governing a patient's relatives and the physician. This study aims to analyze the attitudes displayed by the relatives of patients and the physician with the purpose of determining the communication between the two parties. METHODS: For data collection, two similar survey forms were created in context of the study; one for the relatives of the patients and one for the ICU physicians. The questionnaire included three sub-dimensions: informing, empathy and trust. The study included 181 patient relatives and 103 ICU physicians from three different cities and six hospitals. RESULTS: Based on the results of the questionnaire, identification of the mutual expectations and substance of the messages involved in the communication process between the ICU patients' relatives and physicians was made. The gender and various disciplines of the physicians and the time of the conversation with the patients' relatives were found to affect the communication attitude towards the patient. Moreover, the age of the patient's relatives, the level of education, the physician's perception, and the contact frequency with the patient when he/she was healthy were also proven to have an impact on the communication attitude of the physician. CONCLUSION: This study demonstrates the mutual expectations and substance of messages in the informing, empathy and trust sub-dimensions of the communication process between patient relatives and physicians in the ICU. The communication between patient relatives and physicians can be strengthened through a variety of training programs to improve communication skills. PMID- 28716041 TI - Potentially inappropriate home medications among older patients with cardiovascular disease admitted to a cardiology service in USA. AB - BACKGROUND: The use of potentially inappropriate medications (PIMs) may pose more risks than benefits to patients and is a major factor contributing to the likelihood of serious adverse drug reactions and negative health outcomes among older patients. METHODS: A retrospective chart review was conducted in a tertiary care center in USA where home medications of the older patients were reviewed and analyzed upon hospital admission over three months, from March till May 2016. Inclusion criteria were age of 65 years and above, history of cardiovascular disease, and admission to the cardiology service. The aim of our study was to determine the frequency and factors associated with PIMs, by applying the updated Beers 2015 criteria. RESULTS: A total of 404 patients were included in the study and were taking a total of 4669 medications at home, an average of 11.6 +/- 4.5 medications per patient. The proportion of PIMS was 20% of all medications reported, with an average of 2.4 PIM per patient, and 87.4% of patients were receiving at least one PIM. Significant association was found between use of PIMs and number of home medications, female gender, and number and types of comorbidities. Comorbidities associated with more PIMs were heart failure, atrial fibrillation/flutter, history of falls/fractures, cerebrovascular accident, and depression. The most commonly prescribed PIMs were: drugs that may exacerbate or cause syndrome of inappropriate antidiuretic hormone secretion or hyponatremia (29.7%), scheduled use of proton pump inhibitors (PPIs) > 8 weeks in non-high risk patients (11.3%), and benzodiazepines (8.1%). CONCLUSIONS: A high prevalence of PIMs in older patients with cardiovascular disease was observed. Provider education and detailed assessment of medication lists upon hospital admission by multidisciplinary teams can help in preventing the use of PIMs. PMID- 28716042 TI - Tuberculosis and HIV are the leading causes of adult death in northwest Ethiopia: evidence from verbal autopsy data of Dabat health and demographic surveillance system, 2007-2013. AB - BACKGROUND: Reliable data on causes of death form the basis for building evidence on health policy, planning, monitoring, and evaluation. In Ethiopia, the majority of deaths occur at home and civil registration systems are not yet functional. The main objective of verbal autopsy (VA) is to describe the causes of death at the community or population level where civil registration and death certification systems are weak and where most people die at home without having had contact with the health system. METHODS: Causes of death were classified and prepared based on the International Classification of Diseases (ICD-10). The cause of a death was ascertained based on an interview with next of kin or other caregivers using a standardized questionnaire that draws information on signs, symptoms, medical history, and circumstances preceding death. The cause of death, or the sequence of causes that led to death, is assigned based on the data collected by the questionnaire. The complete VA questionnaires were given to two blinded physicians and reviewed independently. A third physician was assigned to review the case when disagreements in diagnosis arose. RESULTS: Communicable diseases (519 deaths [48.0%]), non-communicable diseases (377 deaths [34.8%]), and external causes (113 deaths [10.4%]) were the main causes of death between 2007 and 2013. Of communicable diseases, tuberculosis (207 deaths [19.7%]), HIV/AIDS (96 deaths [8.9%]) and meningitis (76 deaths [7.0%]) were the most common causes of death. CONCLUSION: Tuberculosis, HIV/AIDS, and meningitis were the most common causes of deaths among adults. Death due to non-communicable diseases showed an increasing trend. Increasing community awareness of infections and their interrelationships, tuberculosis case finding, effective local TB programs, successful treatment, and interventions for HIV are supremely important. PMID- 28716043 TI - Evolution in the surgical management of gastric cancer: is extended lymph node dissection back in vogue in the USA? AB - BACKGROUND: Gastric cancer remains a formidable treatment challenge. For decades, treatment consisted mostly of surgical intervention for this deadly disease. With improvements in the multi-disciplinary management of solid organ malignancies, the approach to this disease is being stepwise refined. MAIN BODY: One of the prevalent controversies in the surgical management of gastric cancer rests on the need for adequate harvesting of lymph nodes. For decades, lymph node dissection is regarded as a staging technique useful in only upstaging the disease. The adoption of D2 lymphadenectomy has been particularly slow to mature. But with prevailing data from Asia consistently demonstrating a survival benefit from lymphadenectomy, it calls into question the notion of lymphadenectomy as being solely a staging procedure. CONCLUSIONS: As gastric resection techniques are being better defined in western countries and surgical morbidities lowered on its execution, D2 lymphadenectomy is becoming more accepted as the new standard in the management of gastric cancer. PMID- 28716044 TI - Type 2 diabetes is associated with an increased prevalence of respiratory symptoms as compared to the general population. AB - BACKGROUND: To estimate the prevalence of respiratory symptoms in individuals with type 2 diabetes, as compared to the general population. METHODS: Between 2007 and 2010 the screening questionnaire of GEIRD (Gene Environment Interactions in Respiratory Diseases) study was administered to two samples of Verona general population, aged respectively 45-64 years and 65-84 years, and to a convenience sample of individuals with type 2 diabetes, consequently recruited at the local Diabetes Centre. Ninety-four and 165 people with type 2 diabetes, aged respectively 45-64 and 65-84 years, were compared with 676 and 591 subjects in the same age range from the general population. The influence of type 2 diabetes on respiratory symptoms was evaluated by logistic regression models, controlling for sex, age (45-54, 55-64, 65-74, 75-84 years), education level, smoking habits and heavy vehicle traffic exposure and adjusting standard errors of ORs for intra-sample correlation. RESULTS: Compared to the general population, dyspnoea limiting walking pace on level ground (grade 2 dyspnoea) was more frequently reported by people with type 2 diabetes, irrespective of age (p < 0.001), while self-reported chronic cough/phlegm was more common in those aged 45 64 years (p = 0.02). These results were confirmed by multivariable analysis: compared to their counterparts from the general population, people with type 2 diabetes aged 45-54 years showed an increased risk of reporting grade 2 dyspnoea (OR = 3.92, 95% CI 3.28-4.68) or chronic cough/phlegm (OR = 1.69, 1.60-1.78). Similar figures held significant at older ages (75-84 years), although partially blunted (dyspnoea: OR = 1.79, 1.68-1.91; chough/phlegm: OR = 1.09, 1.03-1.16). As such, the interaction between age class and type 2 diabetes was significant for both respiratory disorders. The proportion of self-reported dyspnoea among individuals with type 2 diabetes significantly increased across incremental body mass index (BMI), from 15.4 to 25.4% and further to 41.3% respectively in normoweight, overweight and obese patients (p = 0.048). CONCLUSIONS: People with type 2 diabetes more frequently reported grade 2 dyspnoea and chronic cough/phlegm than the general population of the same age, although presenting similar smoking habits. Diabetes appears to anticipate the lung ageing process, recorded in the general population. The increased occurrence of dyspnoea at incremental BMI among individuals with type 2 diabetes may reflect both cardiovascular and respiratory impairment in this high-risk patient population. PMID- 28716045 TI - Barriers to accessing and using health insurance cards among methadone maintenance treatment patients in northern Vietnam. AB - BACKGROUND: Methadone maintenance treatment (MMT) patients face unique costs associated with their healthcare expenditures. As such, it is important that these patients have access to health insurance (HI) to help them pay for both routine and unforeseen health services. In this study, we explored factors related to health insurance enrollment and utilization among MMT patients, to move Vietnam closer to universal coverage among this patient population. METHODS: A cross-sectional study was conducted with 1003 patients enrolled in MMT in five clinics in Hanoi and Nam Dinh provinces. Patients were asked a range of questions about their health, health expenditures, and health insurance access and utilization. We used multivariate logistic regressions to determine factors associated with health insurance access among participants. RESULTS: The majority of participants (nearly 80%) were not currently enrolled in health insurance at the time of the study. Participants from rural regions were significantly more likely than urban participants to report difficulty using HI. Family members of participants from rural regions were more likely to have overall poor service quality through health insurance compared with family members of participants from urban regions. Overall, 37% of participants endorsed a lack of information about HI, nearly 22% of participants reported difficulty accessing HI, 22% reported difficulty using HI, and more than 20% stated they had trouble paying for HI. Older, more highly educated, and employed participants were more likely to have an easier time accessing HI than their younger, less well educated, and unemployed counterparts. HIV-positive participants were more likely to have sufficient information about health insurance options. CONCLUSIONS: Our study highlights the dearth of health insurance utilization among MMT patients in northern Vietnam. It also sheds light on factors associated with increased access to and utilization of health insurance among this underserved population. These results can help improve health insurance enrollment among MMT patients, a population that is at increased need of financial assistance in accessing health services. PMID- 28716046 TI - Blood volume-monitored regulation of ultrafiltration to decrease the dry weight in fluid-overloaded hemodialysis patients: a randomized controlled trial. AB - BACKGROUND: Because chronic fluid volume overload is associated with higher mortality, we tested whether blood-volume monitored regulation of ultrafiltration and dialysate conductivity (UCR) and/or regulation of ultrafiltration and temperature (UTR) would facilitate dry weight reduction, in comparison to conventional dialysis (CONV). METHODS: We carried out a multicenter, 4-week, randomized controlled trial in hemodialysis patients >=15% above normal extracellular fluid volume (ECV), per bioimpedance spectroscopy, who were randomized 1:1:1. Applying UCR (Nikkiso), UTR (Fresenius) and CONV, initial dry weight was reduced rapidly to target. Dry weight reduction was attenuated and eventually stopped at the occurrence of dialysis complications. The primary outcome was defined as intra- and postdialytic complications. Secondary outcomes were magnitudes of dry weight and blood pressure reduction. RESULTS: Of 244 patients assessed, N = 95 had volume overload >=15% above normal ECV. Fifty patients received the allocated interventions (N = 16 UCR, N = 18 UTR, N = 16 CONV) and completed the trial. The rate of complications was significantly lower in UTR compared to CONV (21 +/- 21% vs 34 +/- 20%, p = 0.022), and also compared to UCR (vs 39 +/- 27%, p = 0.028), but not statistically different between UCR and CONV (p = 0.93). Dry weight reduction was significantly higher in UTR compared to UCR (5.0 +/- 3.4% vs 2.0 +/- 2.7% body weight, p = 0.013), but not compared to CONV (vs 3.9 +/- 2.1% body weight, p = 0.31). Systolic blood pressure reduction throughout the intervention phase was 17 +/- 22 mmHg overall, but not significantly different between the three groups. Average maximum ultrafiltration rates were significantly higher in UTR than in UCR and CONV, at statistically similar dialysis times. Retrospective examination of randomly selected hemodialysis sessions in the UCR group identified technical mistakes in 36% of the dialysis sessions, despite considerable training efforts. CONCLUSIONS: Even in patients with volume overload, fluid removal was challenging. Despite the relative advantage of UTR, which must be interpreted with caution in view of the poor technical execution of UCR, this study renders clear that fluid removal must not be reinforced rapidly. Apprehension of this obstacle is imperative for future clinical and academic endeavors aimed at improving dialysis outcomes by correcting volume status. TRIAL REGISTRATION: ClinicalTrials.gov ( NCT01416753 ), trial registration date: August 12, 2011. PMID- 28716047 TI - Protocol adherence for continuously titrated interventions in randomized trials: an overview of the current methodology and case study. AB - BACKGROUND: The standard definition for protocol adherence is the proportion of all scheduled doses that are delivered. In clinical research, this definition has several limitations when evaluating protocol adherence in trials that study interventions requiring continuous titration. DISCUSSION: Building upon a specific case study, we analyzed a recent trial of a continuously titrated intervention to assess the impact of different definitions of protocol deviations on the interpretation of protocol adherence. The OVATION pilot trial was an open label randomized controlled trial of higher (75-80 mmHg) versus lower (60-65 mmHg) mean arterial pressure (MAP) targets for vasopressor therapy in shock. In this trial, potential protocol deviations were defined as MAP values outside the targeted range for >4 consecutive hours during vasopressor therapy without synchronous and consistent adjustments of vasopressor doses. An adjudication committee reviewed each potential deviation to determine if it was clinically justified or not. There are four reasons for this contextual measurement and reporting of protocol adherence. First, between-arm separation is a robust measure of adherence to complex protocols. Second, adherence assessed by protocol deviations varies in function of the definition of deviations and the frequency of measurements. Third, distinguishing clinically-justified vs. not clinically justified protocol deviations acknowledges clinically sensible bedside decision making and offers a clear terminology before the trial begins. Finally, multiple metrics exist to report protocol deviations, which provides different information but complementary information on protocol adherence. CONCLUSIONS: In trials of interventions requiring continuous titration, metrics used for defining protocol deviations have a considerable impact on the interpretation of protocol adherence. Definitions for protocol deviations should be prespecified and correlated with between-arm separation, if it can be measured. PMID- 28716048 TI - Transcriptome analysis uncovers Arabidopsis F-BOX STRESS INDUCED 1 as a regulator of jasmonic acid and abscisic acid stress gene expression. AB - BACKGROUND: The ubiquitin 26S proteasome system (UPS) selectively degrades cellular proteins, which results in physiological changes to eukaryotic cells. F box proteins are substrate adaptors within the UPS and are responsible for the diversity of potential protein targets. Plant genomes are enriched in F-box genes, but the vast majority of these have unknown roles. This work investigated the Arabidopsis F-box gene F-BOX STRESS INDUCED 1 (FBS1) for its effects on gene expression in order elucidate its previously unknown biological function. RESULTS: Using publically available Affymetrix ATH1 microarray data, we show that FBS1 is significantly co-expressed in abiotic stresses with other well characterized stress response genes, including important stress-related transcriptional regulators. This gene suite is most highly expressed in roots under cold and salt stresses. Transcriptome analysis of fbs1-1 knock-out plants grown at a chilling temperature shows that hundreds of genes require FBS1 for appropriate expression, and that these genes are enriched in those having roles in both abiotic and biotic stress responses. Based on both this genome-wide expression data set and quantitative real-time PCR (qPCR) analysis, it is apparent that FBS1 is required for elevated expression of many jasmonic acid (JA) genes that have established roles in combatting environmental stresses, and that it also controls a subset of JA biosynthesis genes. FBS1 also significantly impacts abscisic acid (ABA) regulated genes, but this interaction is more complex, as FBS1 has both positive and negative effects on ABA-inducible and ABA repressible gene modules. One noteworthy effect of FBS1 on ABA-related stress processes, however, is the restraint it imposes on the expression of multiple class I LIPID TRANSFER PROTEIN (LTP) gene family members that have demonstrated protective effects in water deficit-related stresses. CONCLUSION: FBS1 impacts plant stress responses by regulating hundreds of genes that respond to the plant stress hormones JA and ABA. The positive effect that FBS1 has on JA processes and the negative effect it has on at least some ABA processes indicates that it in part regulates cellular responses balanced between these two important stress hormones. More broadly then, FBS1 may aid plant cells in switching between certain biotic (JA) and abiotic (ABA) stress responses. Finally, because FBS1 regulates a subset of JA biosynthesis and response genes, we conclude that it might have a role in tuning hormone responses to particular circumstances at the transcriptional level. PMID- 28716049 TI - Comparison of DSM-IV and DSM-5 criteria for alcohol use disorders in VA primary care patients with frequent heavy drinking enrolled in a trial. AB - BACKGROUND: Criteria for alcohol use disorders (AUD) in the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) were intended to result in a similar prevalence of AUD as DSM-IV. We evaluated the prevalence of AUD using DSM-5 and DSM-IV criteria, and compared characteristics of patients who met criteria for: neither DSM-5 nor DSM-IV AUD, DSM-5 alone, DSM-IV alone, or both, among Veterans Administration (VA) outpatients in the Considering Healthier drinking Options In primary CarE (CHOICE) trial. METHODS: VA primary care patients who reported frequent heavy drinking and enrolled in the CHOICE trial were interviewed at baseline using the DSM-IV Mini International Neuropsychiatric Interview for AUD, as well as questions about socio-demographics, mental health, alcohol craving, and substance use. We compared characteristics across 4 mutually exclusive groups based on DSM-5 and DSM-IV criteria. RESULTS: Of 304 participants, 13.8% met criteria for neither DSM-5 nor DSM-IV AUD; 12.8% met criteria for DSM-5 alone, and 73.0% met criteria for both DSM-IV and DSM-5. Only 1 patient (0.3%) met criteria for DSM-IV AUD alone. Patients meeting both DSM-5 and DSM-IV criteria had more negative drinking consequences, mental health symptoms and self-reported readiness to change compared with those meeting DSM-5 criteria alone or neither DSM-5 nor DSM-IV criteria. CONCLUSIONS: In this sample of primary care patients with frequent heavy drinking, DSM-5 identified 13% more patients with AUD than DSM-IV. This group had a lower mental health symptom burden and less self-reported readiness to change compared to those meeting criteria for both DSM-IV and DSM-5 AUD. Trial Registration ClinicalTrials.gov NCT01400581. 2011 February 17. PMID- 28716050 TI - Working for patient safety: a qualitative study of women's help-seeking during acute perinatal events. AB - BACKGROUND: Women and their relatives can play an important role in early detection and help seeking for acute perinatal events. Recent UK reports indicate that patient-professional partnership in 'working for safety' can be difficult to achieve in practice, sometimes with catastrophic consequences. This research explored the experiences of women and relatives who had experienced early warning signs about their condition and sought help in escalating care. METHODS: Secondary analysis of case study data which included qualitative interviews with 22 women purposively sampled on account of experiencing a step up in care and 4 of their relatives from two NHS Trusts in England during 2010. Analysis focused on the type of safety work participants engaged in, and the opportunities and challenges reported by women and family members when negotiating safety at home and in hospital. RESULTS: Women and relatives took on a dual responsibility for self-diagnosis, self-care and seeking triage, whilst trying to avoid overburdening stretched services. Being informed, however, did not necessarily enable engagement from staff and services. The women's narratives highlighted the work that they engaged in to build a case for clinical attention, the negotiations that took place with health care professionals and the strategies women and partners drew on (such as objective signs and symptoms, use of verbal insistence and repetition) to secure clinical help. For some women, the events left them with a lasting feeling that their concerns had been disregarded. Some described a sense of betrayal and loss of trust in an institution they believed had failed to care for them. CONCLUSION: The notion of 'safety partnerships' which suggests a sense of equality and reciprocity was not borne out by our data, especially with regards to the experiences of teenage women. To enable women and families to secure a rapid response in clinical emergencies, strategies need to move beyond the provision of patient information about warning signs. Effective partnerships for safety may be supported by system level change such as improved triage, continuity of care, self-referral pathways and staff training to address asymmetries of power that persist within the health system. PMID- 28716051 TI - miR-380-5p-mediated repression of TEP1 and TSPYL5 interferes with telomerase activity and favours the emergence of an "ALT-like" phenotype in diffuse malignant peritoneal mesothelioma cells. AB - BACKGROUND: Understanding the molecular/cellular underpinnings of diffuse malignant peritoneal mesothelioma (DMPM), a fatal malignancy with limited therapeutic options, is of utmost importance for the fruitful management of the disease. In this context, we previously found that telomerase activity (TA), which accounts for the limitless proliferative potential of cancer cells, is prognostic for disease relapse and cancer-related death in DMPM patients. Consequently, the identification of factors involved in telomerase activation/regulation may pave the way towards the development of novel therapeutic interventions for the disease. Here, the capability of miR-380-5p, a microRNA negligibly expressed in telomerase-positive DMPM clinical specimens, to interfere with telomerase-mediated telomere maintenance and, hence, with cancer cell growth was assessed on preclinical models of DMPM. METHODS: DMPM cells were transfected with a miR-380-5p synthetic precursor, and the effects of miRNA replacement were evaluated in terms of growing capability, induction of apoptosis and interference with TA. Reiterated weekly transfections were also performed in order to analyse the phenotype arising upon prolonged miR-380-5p reconstitution in DMPM cells. RESULTS: The ectopic expression of miR-380-5p elicited a remarkable inhibition of TA and resulted in DMPM cell growth impairment and apoptosis induction. In particular, we demonstrated for the first time that these effects were the result of a molecular circuitry converging on telomerase associated protein 1 (TEP1), where the miRNA was able to target the gene both directly in unconventional targeting modality and indirectly via p53 accumulation consequent to miRNA-mediated downregulation of testis-specific protein, Y-encoded like 5 gene. Moreover, miR-380-5p did not cause telomere attrition and cell growth arrest in long-term DMPM transfectants, which in turn showed slightly elongated telomeres and molecular features (e.g. c-circle DNA and reduced expression levels of chromatin remodeler ATRX) resembling an alternative lengthening of telomeres (ALT) phenotype. CONCLUSIONS: miR-380-5p interferes with TA in DMPM cells by targeting TEP1. Notably, in the long-term setting, miR-380-5p mediated impairment of TA did not result in telomere attrition. Instead, a phenotype reminiscent of ALT emerged in DMPM cells as possible compensatory pathway that safeguards DMPM cell growth, an event that may be regarded as a potential resistance mechanism to anticancer therapies based on telomerase inhibitors. PMID- 28716052 TI - beta-arrestin1-mediated acetylation of Gli1 regulates Hedgehog/Gli signaling and modulates self-renewal of SHH medulloblastoma cancer stem cells. AB - BACKGROUND: Aberrant Sonic Hedgehog/Gli (Hh/Gli) signaling pathway is a critical regulator of Sonic hedgehog medulloblastoma (SHH-MB). Cancer stem cells (CSCs), thought to be largely responsible for tumor initiation, maintenance, dissemination and relapse, have been identified in SHH-MB. Since we previously demonstrated that Hh/Gli signaling controls CSCs features in SHH-MB and that in these tumors miR-326 is down regulated, here we investigated whether there is a functional link between Hh/Gli signaling and miR-326. METHODS: We evaluated beta arrestin1 (Arrb1) and its intragenic miR-326 levels in CSCs derived from SHH-MB. Subsequently, we modulated the expression of Arrb1 and miR-326 in CSCs in order to gain insight into their biological role. We also analyzed the mechanism by which Arrb1 and miR-326 control Hh/Gli signaling and self-renewal, using luciferase and protein immunoprecipitation assays. RESULTS: Low levels of Arrb1 and miR-326 represent a feature of CSCs derived from SHH-MB. We observed that re expression of Arrb1 and miR-326 inhibits Hh/Gli signaling pathway at multiple levels, which cause impaired proliferation and self-renewal, accompanied by down regulation of Nanog levels. In detail, miR-326 negatively regulates two components of the Hh/Gli pathway the receptor Smoothened (Smo) and the transcription factor Gli2, whereas Arrb1 suppresses the transcriptional activity of Gli1, by potentiating its p300-mediated acetylation. CONCLUSIONS: Our results identify a new molecular mechanism involving miR-326 and Arrb1 as regulators of SHH-MB CSCs. Specifically, low levels of Arrb1 and miR-326 trigger and maintain Hh/Gli signaling and self-renewal. PMID- 28716053 TI - Ibrutinib, a Bruton's tyrosine kinase inhibitor, exhibits antitumoral activity and induces autophagy in glioblastoma. AB - BACKGROUND: Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults. Ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, is a novel anticancer drug used for treating several types of cancers. In this study, we aimed to determine the role of ibrutinib on GBM. METHODS: Cell proliferation was determined by using cell viability, colony formation, and 5-ethynyl-2' deoxyuridine (EdU) assays. Cell cycle and cell apoptosis were analyzed by flow cytometry. Cell migratory ability was evaluated by wound healing assays and trans well migration assays. ATG7 expression was knocked-down by transfection with Atg7 specific small interfering RNA. Overexpression of active Akt protein was achieved by transfecting the cells with a plasmid expressing constitutively active Akt (CA Akt). Transmission electron microscopy was performed to examine the formation of autophagosomes in cells. Immunofluorescence and western blot analyses were used to analyze protein expression. Tumor xenografts in nude mice and immunohistochemistry were performed to evaluate the effect of ibrutinib on tumor growth in vivo. RESULTS: Ibrutinib inhibited cellular proliferation and migration, and induced apoptosis and autophagy in LN229 and U87 cells. Overexpression of the active Akt protein decreased ibrutinib-induced autophagy, while inhibiting Akt by LY294002 treatment enhanced ibrutinib-induced autophagy. Specific inhibition of autophagy by 3-methyladenine (3MA) or Atg7 targeting with small interfering RNA (si-Atg7) enhanced the anti-GBM effect of ibrutinib in vitro and in vivo. CONCLUSIONS: Our results indicate that ibrutinib exerts a profound antitumor effect and induces autophagy through Akt/mTOR signaling pathway in GBM cells. Autophagy inhibition promotes the antitumor activity of ibrutinib in GBM. Our findings provide important insights into the action of an anticancer agent combining with autophagy inhibitor for malignant glioma. PMID- 28716055 TI - Temporal and geographical external validation study and extension of the Mayo Clinic prediction model to predict eGFR in the younger population of Swiss ADPKD patients. AB - BACKGROUND: Prediction models in autosomal dominant polycystic kidney disease (ADPKD) are useful in clinical settings to identify patients with greater risk of a rapid disease progression in whom a treatment may have more benefits than harms. Mayo Clinic investigators developed a risk prediction tool for ADPKD patients using a single kidney value. Our aim was to perform an independent geographical and temporal external validation as well as evaluate the potential for improving the predictive performance by including additional information on total kidney volume. METHODS: We used data from the on-going Swiss ADPKD study from 2006 to 2016. The main analysis included a sample size of 214 patients with Typical ADPKD (Class 1). We evaluated the Mayo Clinic model performance calibration and discrimination in our external sample and assessed whether predictive performance could be improved through the addition of subsequent kidney volume measurements beyond the baseline assessment. RESULTS: The calibration of both versions of the Mayo Clinic prediction model using continuous Height adjusted total kidney volume (HtTKV) and using risk subclasses was good, with R2 of 78% and 70%, respectively. Accuracy was also good with 91.5% and 88.7% of the predicted within 30% of the observed, respectively. Additional information regarding kidney volume did not substantially improve the model performance. CONCLUSION: The Mayo Clinic prediction models are generalizable to other clinical settings and provide an accurate tool based on available predictors to identify patients at high risk for rapid disease progression. PMID- 28716054 TI - Combined biotic stresses trigger similar transcriptomic responses but contrasting resistance against a chewing herbivore in Brassica nigra. AB - BACKGROUND: In nature, plants are frequently exposed to simultaneous biotic stresses that activate distinct and often antagonistic defense signaling pathways. How plants integrate this information and whether they prioritize one stress over the other is not well understood. RESULTS: We investigated the transcriptome signature of the wild annual crucifer, Brassica nigra, in response to eggs and caterpillars of Pieris brassicae butterflies, Brevicoryne brassicae aphids and the bacterial phytopathogen Xanthomonas campestris pv. raphani (Xcr). Pretreatment with egg extract, aphids, or Xcr had a weak impact on the subsequent transcriptome profile of plants challenged with caterpillars, suggesting that the second stress dominates the transcriptional response. Nevertheless, P. brassicae larval performance was strongly affected by egg extract or Xcr pretreatment and depended on the site where the initial stress was applied. Although egg extract and Xcr pretreatments inhibited insect-induced defense gene expression, suggesting salicylic acid (SA)/jasmonic acid (JA) pathway cross talk, this was not strictly correlated with larval performance. CONCLUSION: These results emphasize the need to better integrate plant responses at different levels of biological organization and to consider localized effects in order to predict the consequence of multiple stresses on plant resistance. PMID- 28716056 TI - The inhibitory effect of Isoliquiritigenin on the proliferation of human arterial smooth muscle cell. AB - BACKGROUND: Isoliquiritigenin (ISL) has various biological activities including as antioxidant and an inhibitor of PI3K/AKT signaling pathway. However, both oxidative stress and activated PI3K/AKT signaling contribute to the aberrant proliferation of vascular smooth muscle cells (VSMCs). This study is aimed to explore the effect of ISL on the proliferation of human arterial smooth muscle cells (HASMCs) and to investigate the underlying mechanisms. METHODS: BrdU incorporation, cell cycle and reactive oxygen species (ROS) in normal or ISL treated HASMCs were analyzed by flow cytometry. Cell viablity was measured by CCK 8. Protein expression levels were examined by Western blot, and superoxide dismutase (SOD) activity was detected by using commercial kit. RESULTS: We observed that ISL could inhibit the proliferation of HASMCs in a dose and time dependent manner. Cell cycle of ISL treated HASMCs arrested mainly in G1/S phase and accompanied with elevated expression of p27 and decreased expression of CyclinD1 and CyclinE. In addition, ISL could down-regulated the expression of p PI3K and p-AKT, alleviated oxidative stress and enhanced the SOD activity in HASMCs. Furthermore, H2O2 treatment partly improved cell viability and up regulated p-PI3K and p-AKT in HASMCs. CONCLUSIONS: Therefore, we concluded that ISL inhibited the proliferation of HASMCs via attenuating oxidative stress and suppressing PI3K/AKT signaling pathway. The inhibitory effect of ISL on PI3K/AKT signaling pathway, at least partly, was mediated by ROS. PMID- 28716057 TI - The peripheral and Central Humphrey visual field - morphological changes during aging. AB - BACKGROUND: To define age-related changes in the visual field by comparing 'standard' central and unique peripheral visual field measurements in healthy volunteers. METHODS: In a single center, retrospective, Cross-sectional, observational study, 20 volunteers with no retinal diseases or risk factors, ranging in age between 30 and 94 years (four age groups: 30's, 50's, 70's, 90's) were measured in one eye (preferentially the right one) using a Humphrey visual field 24-2 and 60-4. RESULTS: While the central visual field remained relatively well preserved during aging showing only a mild reduction in sensitivity, a profound loss of the peripheral visual field was observed beginning in the fifth decade of life and decreasing continuously up to the 90ies. CONCLUSIONS: The peripheral visual field declined substantially from the 4th decade onward while the central visual field remained quite stable. PMID- 28716058 TI - SRF modulates seizure occurrence, activity induced gene transcription and hippocampal circuit reorganization in the mouse pilocarpine epilepsy model. AB - A hallmark of temporal lobe epilepsy (TLE) is hippocampal neuronal demise and aberrant mossy fiber sprouting. In addition, unrestrained neuronal activity in TLE patients induces gene expression including immediate early genes (IEGs) such as Fos and Egr1.We employed the mouse pilocarpine model to analyze the transcription factor (TF) serum response factor (SRF) in epileptogenesis, seizure induced histopathology and IEG induction. SRF is a neuronal activity regulated TF stimulating IEG expression as well as nerve fiber growth and guidance. Adult conditional SRF deficient mice (Srf CaMKCreERT2 ) were more refractory to initial status epilepticus (SE) acquisition. Further, SRF deficient mice developed more spontaneous recurrent seizures (SRS). Genome-wide transcriptomic analysis uncovered a requirement of SRF for SE and SRS induced IEG induction (e.g. Fos, Egr1, Arc, Npas4, Btg2, Atf3). SRF was required for epilepsy associated neurodegeneration, mossy fiber sprouting and inflammation. We uncovered MAP kinase signaling as SRF target during epilepsy. Upon SRF ablation, seizure evoked induction of dual specific phosphatases (Dusp5 and Dusp6) was reduced. Lower expression of these negative ERK kinase regulators correlated with altered P-ERK levels in epileptic Srf mutant animals.Overall, this study uncovered an SRF contribution to several processes of epileptogenesis in the pilocarpine model. PMID- 28716059 TI - Major adverse cardiac events and mortality in chronic obstructive pulmonary disease following percutaneous coronary intervention: a systematic review and meta-analysis. AB - BACKGROUND: We aimed to systematically compare Major Adverse Cardiac Events (MACEs) and mortality following Percutaneous Coronary Intervention (PCI) in patients with and without Chronic Obstructive Pulmonary Diseases (COPD) through a meta-analysis. METHODS: Electronic databases (Cochrane library, EMBASE and Medline/PubMed) were searched for English publications comparing in-hospital and long-term MACEs and mortality following PCI in patients with a past medical history of COPD. Statistical analysis was carried out by Revman 5.3 whereby Odds Ratio (OR) and 95% Confidence Intervals (CI) were considered the relevant parameters. RESULTS: A total number of 72,969 patients were included (7518 patients with COPD and 65,451 patients without COPD). Results of this analysis showed that in-hospital MACEs were significantly higher in the COPD group with OR: 1.40, 95% CI: 1.19-1.65; P = 0.0001, I2 = 0%. Long-term MACEs were still significantly higher in the COPD group with OR: 1.58, 95% CI: 1.38-1.81; P = 0.00001, I2 = 29%. Similarly, in-hospital and long-term mortality were significantly higher in patients with COPD, with OR: 2.25, 95% CI: 1.78-2.85; P = 0.00001, I2 = 0% and OR: 2.22, 95% CI: 1.33-3.71; P = 0.002, I2 = 97% respectively. However, the result for the long-term death was highly heterogeneous. CONCLUSION: Since in-hospital and long-term MACEs and mortality were significantly higher following PCI in patients with versus without COPD, COPD should be considered a risk factor for the development of adverse clinical outcomes following PCI. However, the result for the long-term mortality was highly heterogeneous warranting further analysis. PMID- 28716060 TI - Nonlinear joint models for individual dynamic prediction of risk of death using Hamiltonian Monte Carlo: application to metastatic prostate cancer. AB - BACKGROUND: Joint models of longitudinal and time-to-event data are increasingly used to perform individual dynamic prediction of a risk of event. However the difficulty to perform inference in nonlinear models and to calculate the distribution of individual parameters has long limited this approach to linear mixed-effect models for the longitudinal part. Here we use a Bayesian algorithm and a nonlinear joint model to calculate individual dynamic predictions. We apply this approach to predict the risk of death in metastatic castration-resistant prostate cancer (mCRPC) patients with frequent Prostate-Specific Antigen (PSA) measurements. METHODS: A joint model is built using a large population of 400 mCRPC patients where PSA kinetics is described by a biexponential function and the hazard function is a PSA-dependent function. Using Hamiltonian Monte Carlo algorithm implemented in Stan software and the estimated population parameters in this population as priors, the a posteriori distribution of the hazard function is computed for a new patient knowing his PSA measurements until a given landmark time. Time-dependent area under the ROC curve (AUC) and Brier score are derived to assess discrimination and calibration of the model predictions, first on 200 simulated patients and then on 196 real patients that are not included to build the model. RESULTS: Satisfying coverage probabilities of Monte Carlo prediction intervals are obtained for longitudinal and hazard functions. Individual dynamic predictions provide good predictive performances for landmark times larger than 12 months and horizon time of up to 18 months for both simulated and real data. CONCLUSIONS: As nonlinear joint models can characterize the kinetics of biomarkers and their link with a time-to-event, this approach could be useful to improve patient's follow-up and the early detection of most at risk patients. PMID- 28716061 TI - Colony-stimulating factor 1 receptor (CSF1R) inhibitors in cancer therapy. AB - The tumor-permissive and immunosuppressive characteristics of tumor-associated macrophages (TAM) have fueled interest in therapeutically targeting these cells. In this context, the colony-stimulating factor 1 (CSF1)/colony-stimulating factor 1 receptor (CSF1R) axis has gained the most attention, and various approaches targeting either the ligands or the receptor are currently in clinical development. Emerging data on the tolerability of CSF1/CSF1R-targeting agents suggest a favorable safety profile, making them attractive combination partners for both standard treatment modalities and immunotherapeutic agents. The specificity of these agents and their potent blocking activity has been substantiated by impressive response rates in diffuse-type tenosynovial giant cell tumors, a benign connective tissue disorder driven by CSF1 in an autocrine fashion. In the malignant disease setting, data on the clinical activity of immunotherapy combinations with CSF1/CSF1R-targeting agents are pending. As our knowledge of macrophage biology expands, it becomes apparent that the complex phenotypic and functional properties of macrophages are heavily influenced by a continuum of survival, differentiation, recruitment, and polarization signals within their specific tissue environment. Thus, the role of macrophages in regulating tumorigenesis and the impact of depleting and/or reprogramming TAM as therapeutic approaches for cancer patients may vary greatly depending on organ specific characteristics of these cells. We review the currently available clinical safety and efficacy data with CSF1/CSF1R-targeting agents and provide a comprehensive overview of ongoing clinical studies. Furthermore, we discuss the local tissue macrophage and tumor-type specificities and their potential impact on CSF1/CSF1R-targeting treatment strategies for the future. PMID- 28716062 TI - The effects of acute and elective cardiac surgery on the anxiety traits of patients with Marfan syndrome. AB - BACKGROUND: Marfan syndrome is a genetic disease, presenting with dysfunction of connective tissues leading to lesions in the cardiovascular and skeletal muscle system. Within these symptoms, the most typical is weakness of the connective tissue in the aorta, manifesting as aortic dilatation (aneurysm). This could, in turn, become annuloaortic ectasia, or life-threatening dissection. As a result, life-saving and preventative cardiac surgical interventions are frequent among Marfan syndrome patients. Aortic aneurysm could turn into annuloaortic ectasia or life-threatening dissection, thus life-saving and preventive cardiac surgical interventions are frequent among patients with Marfan syndrome. We hypothesized that patients with Marfan syndrome have different level of anxiety, depression and satisfaction with life compared to that of the non-clinical patient population. METHODS: Patients diagnosed with Marfan syndrome were divided into 3 groups: those scheduled for prophylactic surgery, those needing acute surgery, and those without need for surgery (n = 9, 19, 17, respectively). To examine the psychological features of the patients, Spielberger's anxiety (STAI) test, Beck's Depression questionnaire (BDI), the Berne Questionnaire of Subjective Well-being, and the Satisfaction with Life scale were applied. RESULTS: A significant difference was found in trait anxiety between healthy individuals and patients with Marfan syndrome after acute life-saving surgery (p < 0.01). The mean score of Marfan syndrome patients was 48.56 (standard deviation (SD): 5.8) as compared to the STAI population mean score of 43.72 (SD: 8.53). No difference was found between groups on the BDI (p > 0.1). Finally, a significant, medium size effect was found between patient groups on the Joy in Living scale (F (2.39) = 3.51, p = 0.040, eta2 = 0.15). CONCLUSIONS: Involving psychiatric and mental-health care, in addition to existing surgical treatment interventions, is essential for more successful recovery of patients with Marfan syndrome. PMID- 28716063 TI - The use of non-uniform drowning terminology: a follow-up study. AB - BACKGROUND: In 2002, the World Congress on Drowning developed a uniform definition for drowning. The aim of this study is to determine the prevalence of "non-uniform drowning terminology" (NUDT) and "non-uniform drowning definitions" (NUDD) in peer-reviewed scientific literature from 2010 to 2016, and compare these findings with those from our unpublished study performing a similar analysis on literature from 2003 to 2010. METHODS: A systematic review was performed using drowning-specific search terms in Pubmed and Web of Science. Titles and abstracts published between July 2010 and January 2016 were screened for relevance to the study focus. Articles meeting screening criteria were reviewed for exclusion criteria to produce the final group of studies. These articles were reviewed by four reviewers for NUDT and NUDD. The Fisher exact test was used to determine any statistically significant changes. RESULTS: The final group of studies included 167 articles. A total of 53 articles (32%) utilized NUDT, with 100% of these including the term "near drowning". The proportion of articles utilizing NUDT was significantly less than reported by our previous study (p < 0.05). In addition, 32% of the articles included a definition for drowning (uniform or non-uniform), with 15% of these utilizing NUDD. DISCUSSION: Our study reveals a statistically significant improvement over the past thirteen years in the use of uniform drowning terminology in peer-reviewed scientific literature, although year-to-year variability over the current study period does not yield an obvious trend. CONCLUSIONS: Of the articles reviewed during the 2010 2016 study period, 32% included outdated and non-uniform drowning terminology and definitions. While this reveals an absolute decrease of 11% as compared with the previous study period (2003-2010), there is still significant room for improvement. PMID- 28716064 TI - Informed consent in randomised controlled trials: development and preliminary evaluation of a measure of Participatory and Informed Consent (PIC). AB - BACKGROUND: Informed consent (IC) is an ethical and legal prerequisite for trial participation, yet current approaches evaluating participant understanding for IC during recruitment lack consistency. No validated measure has been identified that evaluates participant understanding for IC based on their contributions during consent interactions. This paper outlines the development and formative evaluation of the Participatory and Informed Consent (PIC) measure for application to recorded recruitment appointments. The PIC allows the evaluation of recruiter information provision and evidence of participant understanding. METHODS: Published guidelines for IC were reviewed to identify potential items for inclusion. Seventeen purposively sampled trial recruitment appointments from three diverse trials were reviewed to identify the presence of items relevant to IC. A developmental version of the measure (DevPICv1) was drafted and applied to six further recruitment appointments from three further diverse trials to evaluate feasibility, validity, stability and inter-rater reliability. Findings guided revision of the measure (DevPICv2) which was applied to six further recruitment appointments as above. RESULTS: DevPICv1 assessed recruiter information provision (detail and clarity assessed separately) and participant talk (detail and understanding assessed separately) over 20 parameters (or 23 parameters for three-arm trials). Initial application of the measure to six diverse recruitment appointments demonstrated promising stability and inter-rater reliability but a need to simplify the measure to shorten time for completion. The revised measure (DevPICv2) combined assessment of detail and clarity of recruiter information and detail and evidence of participant understanding into two single scales for application to 22 parameters or 25 parameters for three-arm trials. Application of DevPICv2 to six further diverse recruitment appointments showed considerable improvements in feasibility (e.g. time to complete) with good levels of stability (i.e. test-retest reliability) and inter-rater reliability maintained. CONCLUSIONS: The DevPICv2 provides a measure for application to trial recruitment appointments to evaluate quality of recruiter information provision and evidence of patient understanding and participation during IC discussions. Initial evaluation shows promising feasibility, validity, reliability and ability to discriminate across a range of recruiter practice and evidence of participant understanding. More validation work is needed in new clinical trials to evaluate and refine the measure further. PMID- 28716065 TI - The validity of the SF-12 and SF-6D instruments in people living with HIV/AIDS in Kenya. AB - BACKGROUND: Health-related quality of life (HRQoL) and health state utility value (HSUV) measurements are vital components of healthcare clinical and economic evaluations. Accurate measurement of HSUV and HRQoL require validated instruments. The 12-item Short-Form Health Survey (SF-12) is one of few instruments that can evaluate both HRQoL and HSUV, but its validity has not been assessed in people living with HIV/AIDS (PLWHA) in east Africa, where the burden of HIV is high. METHODS: This cross-sectional study used baseline data from a randomized trial involving PLWHA in Kenya. Data included responses from a translated and adapted SF-12 survey as well as key demographic and clinical data. Construct validity of the survey was examined by testing the SF-12's ability to distinguish between groups known in advance to have differences in their health based on their disease severity. We classified disease severity based on established definitions from the US Center for Disease Control (CDC) and WHO, as well as a previously studied viral load threshold. T-tests and ANOVA were used to test for differences in HRQoL and HSUV scores. Area under the receive operator curve (AUC) was used to test the discriminative ability of the HRQoL and HSUV instruments. RESULTS: Differences in physical component scores met the minimum clinically important difference among participants with more advanced HIV when defined by CD4 count (4.3 units) and WHO criteria (compared to stage 1, stages 2, 3 and 4 were 2.0, 7.2 and 9.8 units lower respectively). Mental score differences met the minimum clinically important difference between WHO stage 1 and stage 4 patients (4.4). Differences in the HSUV were statistically lower in more advanced HIV by all three definitions of severity. The AUC showed poor to weak discriminatory ability in most analyses, but had fair discriminatory ability between WHO clinical stage 1 and clinical stage 4 individuals (AUC = 0.71). CONCLUSION: Our findings suggest that the Kiswahili translated and adapted version of the SF-12 could be used as an assessment tool for physical health, mental health and HSUV for Kiswahili-speaking PLHWA. TRIAL REGISTRATION: Clinical trials.gov identifier: NCT00830622 . Registered 26 January 2009. PMID- 28716066 TI - Erratum to: more complications in uncemented compared to cemented hemiarthroplasty for displaced femoral neck fractures: a randomized controlled trial of 201 patients, with one year follow-up. PMID- 28716067 TI - Molecular characterization of group A rotaviruses in Mukuru slums Kenya: detection of novel strains circulating in children below 5 years of age. AB - BACKGROUND: Gastroenteritis is a public health concern due to high morbidity and mortality among children. Rotaviruses are the leading etiological agents of severe gastroenteritis in children and accounts for more than half a million deaths per year in Africa. The study aimed at investigating the rotavirus genotypes that were circulating in children aged 5 years and below in and around Mukuru slums in Nairobi County Kenya. METHODS: A purposive cross sectional sampling method was applied where 166 samples were collected from children below 5 years of age and taken to Kenya Medical Research Institute virology laboratory. Presence of rotaviruses was determined using reverse transcription polymerase chain reaction, while extraction was done using ZR Soil/Fecal RNA MicroPrepTM extraction kit. This was followed by reverse transcription and genotyping using various group A rotavirus primers. RESULTS: The G type was successfully determined in 37 (92.5%), while the P type was successfully determined in 35 (87.5%) of the 40 (24%) page positive samples. Type G1 was the most predominant of the G types (40.5%), and the incidences of G3 and G9 were 21.6 and 32.4% respectively. Mixed types G3/G9 were detected at 5.4%. Three P types existed in Mukuru slums, P[8] (60%), P[6] (22.9%), P[4] (11.4) and their relative incidence varied over the 15 months of this study. CONCLUSIONS: The G types and P types detected in this study are important causes of acute gastroenteritis in Mukuru slums Nairobi Kenya. An indication that the prevalence of certain genotypes may change over a rotavirus season is significant and mirrors observations from studies in other tropical climates. Thus monitoring of the genotypic changes among circulating viruses should be encouraged over the coming years. PMID- 28716068 TI - Highlights of the 31st annual meeting of the Society for Immunotherapy of Cancer (SITC), 2016. AB - Therapeutic efforts to engage the immune system against cancer have yielded exciting breakthroughs and a growing list of approved immune-based agents across a variety of disease states. Despite the early successes and durable responses associated with treatments such as immune checkpoint inhibition, there is still progress to be made in the field of cancer immunotherapy. The 31st annual meeting of the Society for Immunotherapy of Cancer (SITC 2016), which took place November 11-13, 2016 in National Harbor, Maryland, showcased the latest advancements in basic, translational, and clinical research focused on cancer immunology and immunotherapy. Novel therapeutic targets, insights into the dynamic tumor microenvironment, potential biomarkers, and novel combination approaches were some of the main themes covered at SITC 2016. This report summarizes key data and highlights from each session. PMID- 28716069 TI - Angiosarcoma treated successfully with anti-PD-1 therapy - a case report. AB - BACKGROUND: Angiosarcomas are tumors of malignant endothelial origin that have a poor prognosis with a five-year survival of less than 40%. These tumors can be found in all age groups, but are more common in older patients; with the cutaneous form most common in older white men. Combined modality therapy including surgery and radiation appears to have a better outcome than each modality alone. When metastatic, agents such as liposomal doxorubicin, paclitaxel and ifosfamide have activity but it is short-lived and not curative. Immunotherapy targeting either the PD-1 receptor or PD-L1 ligand has recently been shown to have activity in multiple cancers including melanoma, renal, and non-small lung cancer. Although these agents have been used in sarcoma therapy, their ability to treat angiosarcoma has not been reported. CASE PRESENTATION: Here we describe the case of a 63-year-old man who presented initially with angiosarcoma of the nose and received surgery for the primary. Over 4 years he had recurrent disease in the face and liver and was treated with nab-paclitaxel, surgery, and radioembolization, but continued to have progressive disease. His tumor was found to express PD-L1 and he received off-label pembrolizumab 2 mg/kg every 21 days for 13 cycles with marked shrinkage of his liver disease and no new facial lesions. Secondary to this therapy he developed hepatitis and has been treated with decreasing doses of prednisone. During the 8 months off therapy he has developed no new or progressive lesions. CONCLUSIONS: Although occasional responses to immunotherapy have been reported for sarcomas, this case report demonstrates that angiosarcoma can express PD-L1 and have a sustained response to PD-1 directed therapy. PMID- 28716070 TI - Comorbidity and metabolic syndrome in patients with multiple sclerosis from Asturias and Catalonia, Spain. AB - BACKGROUND: The impact of comorbidity on multiple sclerosis (MS) is a new area of interest. Limited data on the risk factors of metabolic syndrome (MetS) is currently available. The aim of this study was to estimate the presence of comorbid conditions and MetS in a sample of adult patients with MS. METHODS: A retrospective, cohort study was conducted using electronic medical records from 19 primary care centres in Catalonia and Asturias, Spain. The number of chronic diseases (diagnoses), the Charlson Comorbidity Index and the individual Case-mix Index were used to assess general comorbidity variables. MetS was defined using the National Cholesterol Education Program Adult Treatment Panel III. Patients were distributed into two groups according to the Expanded Disability Status Scale (EDSS) score: 0-3.5 and 4-10. RESULTS: A total of 222 patients were studied (mean age = 45.5 (SD 12.5) years, 64.4% were female and 62.2% presented a diagnosis of relapsing-remitting MS). Mean EDSS score was 3.2 (SD 2.0). Depression (32.4%), dyslipidaemia (31.1%), hypertension (23.0%) and obesity (22.5%) were the most common comorbidities. Overall MetS prevalence was 31.1% (95% CI: 25.0-37.2%). Patients with an EDSS >= 4.0 showed a significantly higher number of comorbidities (OR=2.2; 95% CI: 1.7-3.0; p<0.001). CONCLUSION: MS patients had a high prevalence of MetS. Screening for comorbidity should be part of standard MS care. Further studies are necessary to confirm this association and the underlying mechanisms of MS and its comorbidities. PMID- 28716071 TI - Primary solitary plasmacytoma of the liver - successful treatment with fractionated stereotactic radiotherapy (Cyberknife(r)): a case report. AB - BACKGROUND: Solitary plasmacytoma of the liver is a very rare and aggressive form of plasma cell dyscrasia. To the best of our knowledge, very few cases have been reported without systemic disease. We reported a rare case of hepatic solitary plasmacytoma that successfully responded to fractionated stereotactic radiotherapy. CASE PRESENTATION: A 64-year-old white French man had monoclonal gammopathy of the immune globulin G lambda type; he developed a cholestasis and cytolysis with the discovery of a subscapular nodule. A biopsy showed plasma cells and, for several reasons, the decision was made to use the fractionated stereotactic radiotherapy strategy. After 20 months, he is asymptomatic and the immune globulin G component has completely disappeared. CONCLUSION: We suggest considering Cyberknife(r) radiosurgery as an option for the treatment of hepatic solitary plasmacytoma. PMID- 28716072 TI - Effect of prenatal exposure to maternal cortisol and psychological distress on infant development in Bengaluru, southern India: a prospective cohort study. AB - BACKGROUND: The mental health status of a pregnant woman and its consequent impact on foetal well being is not given much importance compared to the risk imposed by obstetric complications and medical conditions. Maternal psychological distress is a major public health problem and needs timely detection and intervention to prevent any adverse pregnancy outcome. There is ample evidence from literature that justifies the association of prenatal maternal mental stress and elevated cortisol with delayed infant motor and cognitive development; evidence from India being rather limited. The study aim is to prospectively assess the association of maternal psychological distress and cortisol level with motor and cognitive development of the infant. METHODS: A sample of 2612 eligible pregnant women who have been registered for antenatal care at selected public sector hospitals in Bengaluru will be recruited after obtaining written informed consent. They will be assessed for the presence of maternal psychological distress in the form of depression and anxiety using appropriate scales and saliva samples will be collected for cortisol estimation during early, mid and late pregnancy. Follow up visits after delivery will be done on day 10, 3 months, 8 months and 12 months. The Bayley Scales of Infant and Toddler Development [BSID] (Third edition) will be used to measure both motor and mental milestones in terms of Psychomotor Development Index (PDI) and Mental Development Index (MDI). Logistic regression model will be used to determine the association between the exposure variables and outcomes which will be reported as Odd's Ratio (OR) and 95% confidence intervals (CI). DISCUSSION: Our study findings could add to the growing evidence that maternal psychological distress during pregnancy adversely influences growth and development in the offspring and subsequent development of the child. While maternal anxiety and depression can be measured by using self reporting instruments, estimation of maternal endogenous cortisol levels could serve as a biomarker of prenatal psychological stress. Findings from this study could be used to focus upon the burden of mental health problems during pregnancy and to consider steps to scale up prenatal mental health services in health care settings. PMID- 28716073 TI - Surgical correction of hyperlordosis in facioscapulohumeral muscular dystrophy: A case report. AB - BACKGROUND: Hyperlordosis is common in facioscapulohumeral muscular dystrophy (FSHD), which cannot be controlled by bracing. While the surgical treatment is neither reported nor recommended in previous studies, we report the first corrective surgery for hyperlordosis in one wheelchair-dependent FSHD patient. CASE PRESENTATION: A 15-year-old, wheelchair-dependent girl complaining of hyperlordosis and lower extremity weakness was diagnosed as FSHD. Preoperative examination showed hyperlordosis of 116 degrees with scoliosis of 44 degrees . Posterior correction and bone graft fusion was performed. Postoperatively, the hyperlordosis was corrected to 72 degrees and better sitting posture was gotten. 12 months' follow-up showed favorable correction with improvement in SF-36 and ODI score. CONCLUSIONS: The correction for hyperlordosis in FSHD is controversial. We report the first successful case of operative treatment by corrective spine surgery in these rare and demanding patient collective. Corrective surgery for spinal deformity, such as hyperlordosis and scoliosis, could do some help in posture and improve the quality of life especially in wheelchair-dependent patients. PMID- 28716074 TI - Evaluation of record linkage of two large administrative databases in a middle income country: stillbirths and notifications of dengue during pregnancy in Brazil. AB - BACKGROUND: Due to the increasing availability of individual-level information across different electronic datasets, record linkage has become an efficient and important research tool. High quality linkage is essential for producing robust results. The objective of this study was to describe the process of preparing and linking national Brazilian datasets, and to compare the accuracy of different linkage methods for assessing the risk of stillbirth due to dengue in pregnancy. METHODS: We linked mothers and stillbirths in two routinely collected datasets from Brazil for 2009-2010: for dengue in pregnancy, notifications of infectious diseases (SINAN); for stillbirths, mortality (SIM). Since there was no unique identifier, we used probabilistic linkage based on maternal name, age and municipality. We compared two probabilistic approaches, each with two thresholds: 1) a bespoke linkage algorithm; 2) a standard linkage software widely used in Brazil (ReclinkIII), and used manual review to identify further links. Sensitivity and positive predictive value (PPV) were estimated using a subset of gold-standard data created through manual review. We examined the characteristics of false-matches and missed-matches to identify any sources of bias. RESULTS: From records of 678,999 dengue cases and 62,373 stillbirths, the gold-standard linkage identified 191 cases. The bespoke linkage algorithm with a conservative threshold produced 131 links, with sensitivity = 64.4% (68 missed-matches) and PPV = 92.5% (8 false-matches). Manual review of uncertain links identified an additional 37 links, increasing sensitivity to 83.7%. The bespoke algorithm with a relaxed threshold identified 132 true matches (sensitivity = 69.1%), but introduced 61 false-matches (PPV = 68.4%). ReclinkIII produced lower sensitivity and PPV than the bespoke linkage algorithm. Linkage error was not associated with any recorded study variables. CONCLUSION: Despite a lack of unique identifiers for linking mothers and stillbirths, we demonstrate a high standard of linkage of large routine databases from a middle income country. Probabilistic linkage and manual review were essential for accurately identifying cases for a case-control study, but this approach may not be feasible for larger databases or for linkage of more common outcomes. PMID- 28716076 TI - Klf8 regulates left-right asymmetric patterning through modulation of Kupffer's vesicle morphogenesis and spaw expression. AB - BACKGROUND: Although vertebrates are bilaterally symmetric organisms, their internal organs are distributed asymmetrically along a left-right axis. Disruption of left-right axis asymmetric patterning often occurs in human genetic disorders. In zebrafish embryos, Kupffer's vesicle, like the mouse node, breaks symmetry by inducing asymmetric expression of the Nodal-related gene, spaw, in the left lateral plate mesoderm (LPM). Spaw then stimulates transcription of itself and downstream genes, including lft1, lft2, and pitx2, specifically in the left side of the diencephalon, heart and LPM. This developmental step is essential to establish subsequent asymmetric organ positioning. In this study, we evaluated the role of kruppel-like factor 8 (klf8) in regulating left-right asymmetric patterning in zebrafish embryos. METHODS: Zebrafish klf8 expression was disrupted by both morpholino antisense oligomer-mediated knockdown and a CRISPR-Cas9 system. Whole-mount in situ hybridization was conducted to evaluate gene expression patterns of Nodal signalling components and the positions of heart and visceral organs. Dorsal forerunner cell number was evaluated in Tg(sox17:gfp) embryos and the length and number of cilia in Kupffer's vesicle were analyzed by immunocytochemistry using an acetylated tubulin antibody. RESULTS: Heart jogging, looping and visceral organ positioning were all defective in zebrafish klf8 morphants. At the 18-22 s stages, klf8 morphants showed reduced expression of genes encoding Nodal signalling components (spaw, lft1, lft2, and pitx2) in the left LPM, diencephalon, and heart. Co-injection of klf8 mRNA with klf8 morpholino partially rescued spaw expression. Furthermore, klf8 but not klf8?zf overexpressing embryos showed dysregulated bilateral expression of Nodal signalling components at late somite stages. At the 10s stage, klf8 morphants exhibited reductions in length and number of cilia in Kupffer's vesicle, while at 75% epiboly, fewer dorsal forerunner cells were observed. Interestingly, klf8 mutant embryos, generated by a CRISPR-Cas9 system, showed bilateral spaw expression in the LPM at late somite stages. This observation may be partly attributed to compensatory upregulation of klf12b, because klf12b knockdown reduced the percentage of klf8 mutants exhibiting bilateral spaw expression. CONCLUSIONS: Our results demonstrate that zebrafish Klf8 regulates left-right asymmetric patterning by modulating both Kupffer's vesicle morphogenesis and spaw expression in the left LPM. PMID- 28716077 TI - Periorbital changes associated with prostaglandin analogs in Korean patients. AB - BACKGROUND: Prostaglandin analogs (PGAs) are commonly used to treat glaucoma because of their powerful intraocular pressure lowering effect. However, various periorbital changes associated with the use of PGAs have been reported. We investigated the incidence of periorbital changes in Korean patients who were treated with PGAs, and analyzed clinical factors associated with superior sulcus deepening. METHODS: This study included 58 glaucoma patients who were treated with latanoprost, travoprost, or bimatoprost unilaterally. Face photographs were collected, and periorbital changes such as superior sulcus deepening, eyelid pigmentation, ptosis, lid retraction, dermatochalasis, and redness were evaluated by two oculoplastic specialists. For each patient, the contralateral eye served as a control. The frequency of ptosis, dermatochalasis, pigmentation, erythema, and superior sulcus deepening were analyzed. Demographic and ocular factors were compared between patients who showed superior sulcus deepening and those who did not. RESULTS: Thirty-one patients (53.4%) showed one or more periorbital changes associated with PGAs. The most common change was superior sulcus deepening (24.1%), followed by eyelid pigmentation (19.0%), eyelid erythema (19.0%), dermatochalasis (10.3%), eyelid retraction (5.2%), and ptosis (3.4%). The age of the patient and the duration of PGA administration was significantly correlated with superior sulcus deepening (p = 0.007, p = 0.002, respectively). CONCLUSIONS: Periorbital changes are frequently seen in patients who use PGAs, and superior sulcus deepening is the most common change in Korean patients. Long-term use of PGAs and old age were associated with superior sulcus deepening. PMID- 28716075 TI - The role of tumour heterogeneity and clonal cooperativity in metastasis, immune evasion and clinical outcome. AB - BACKGROUND: The advent of rapid and inexpensive sequencing technology allows scientists to decipher heterogeneity within primary tumours, between primary and metastatic sites, and between metastases. Charting the evolutionary history of individual tumours has revealed drivers of tumour heterogeneity and highlighted its impact on therapeutic outcomes. DISCUSSION: Scientists are using improved sequencing technologies to characterise and address the challenge of tumour heterogeneity, which is a major cause of resistance to therapy and relapse. Heterogeneity may fuel metastasis through the selection of rare, aggressive, somatically altered cells. However, extreme levels of chromosomal instability, which contribute to intratumour heterogeneity, are associated with improved patient outcomes, suggesting a delicate balance between high and low levels of genome instability. CONCLUSIONS: We review evidence that intratumour heterogeneity influences tumour evolution, including metastasis, drug resistance, and the immune response. We discuss the prevalence of tumour heterogeneity, and how it can be initiated and sustained by external and internal forces. Understanding tumour evolution and metastasis could yield novel therapies that leverage the immune system to control emerging tumour neo-antigens. PMID- 28716078 TI - COGNATE: comparative gene annotation characterizer. AB - BACKGROUND: The comparison of gene and genome structures across species has the potential to reveal major trends of genome evolution. However, such a comparative approach is currently hampered by a lack of standardization (e.g., Elliott TA, Gregory TR, Philos Trans Royal Soc B: Biol Sci 370:20140331, 2015). For example, testing the hypothesis that the total amount of coding sequences is a reliable measure of potential proteome diversity (Wang M, Kurland CG, Caetano-Anolles G, PNAS 108:11954, 2011) requires the application of standardized definitions of coding sequence and genes to create both comparable and comprehensive data sets and corresponding summary statistics. However, such standard definitions either do not exist or are not consistently applied. These circumstances call for a standard at the descriptive level using a minimum of parameters as well as an undeviating use of standardized terms, and for software that infers the required data under these strict definitions. The acquisition of a comprehensive, descriptive, and standardized set of parameters and summary statistics for genome publications and further analyses can thus greatly benefit from the availability of an easy to use standard tool. RESULTS: We developed a new open-source command line tool, COGNATE (Comparative Gene Annotation Characterizer), which uses a given genome assembly and its annotation of protein-coding genes for a detailed description of the respective gene and genome structure parameters. Additionally, we revised the standard definitions of gene and genome structures and provide the definitions used by COGNATE as a working draft suggestion for further reference. Complete parameter lists and summary statistics are inferred using this set of definitions to allow down-stream analyses and to provide an overview of the genome and gene repertoire characteristics. COGNATE is written in Perl and freely available at the ZFMK homepage ( https://www.zfmk.de/en/COGNATE ) and on github ( https://github.com/ZFMK/COGNATE ). CONCLUSION: The tool COGNATE allows comparing genome assemblies and structural elements on multiples levels (e.g., scaffold or contig sequence, gene). It clearly enhances comparability between analyses. Thus, COGNATE can provide the important standardization of both genome and gene structure parameter disclosure as well as data acquisition for future comparative analyses. With the establishment of comprehensive descriptive standards and the extensive availability of genomes, an encompassing database will become possible. PMID- 28716079 TI - The human jejunum has an endogenous microbiota that differs from those in the oral cavity and colon. AB - BACKGROUND: The upper half of the human small intestine, known as the jejunum, is the primary site for absorption of nutrient-derived carbohydrates, amino acids, small peptides, and vitamins. In contrast to the colon, which contains 1011-1012 colony forming units of bacteria per ml (CFU/ml), the normal jejunum generally ranges from 103 to 105 CFU per ml. Because invasive procedures are required to access the jejunum, much less is known about its bacterial microbiota. Bacteria inhabiting the jejunal lumen have been investigated by classical culture techniques, but not by culture-independent metagenomics. RESULTS: The lumen of the upper jejunum was sampled during enteroscopy of 20 research subjects. Culture on aerobic and anaerobic media gave live bacterial counts ranging from 5.8 * 103 CFU/ml to 8.0 * 106 CFU/ml. DNA from the same samples was analyzed by 16S rRNA gene-specific quantitative PCR, yielding values from 1.5 * 105 to 3.1 * 107 bacterial genomes per ml. When calculated for each sample, estimated bacterial viability ranged from effectively 100% to a low of 0.3%. 16S rRNA metagenomic analysis of uncultured bacteria by Illumina MiSeq sequencing gave detailed microbial composition by phylum, genus and species. The genera Streptococcus, Prevotella, Veillonella and Fusobacterium, were especially abundant, as well as non-oral genera including Escherichia, Klebsiella, and Citrobacter. The jejunum was devoid of the genera Alistipes, Ruminococcus, Faecalibacterium, and other extreme anaerobes abundant in the colon. In patients with higher bacterial loads, there was no significant change in microbial species composition. CONCLUSIONS: The jejunal lumen contains a distinctive bacterial population consisting primarily of facultative anaerobes and oxygen-tolerant obligate anaerobes similar to those found in the oral cavity. However, the frequent abundance of Enterobacteriaceae represents a major difference from oral microbiota. Although a few genera are shared with the colon, we found no evidence for retrograde movement of the most abundant colonic microbes to the jejunum. Some individuals had much higher bacterial loads, but this was not correlated with decreases in bacterial species diversity or other evidence of dysbiosis. PMID- 28716080 TI - Pretreatment antigen-specific immunity and regulation - association with subsequent immune response to anti-tumor DNA vaccination. AB - BACKGROUND: Immunotherapies have demonstrated clinical benefit for many types of cancers, however many patients do not respond, and treatment-related adverse effects can be severe. Hence many efforts are underway to identify treatment predictive biomarkers. We have reported the results of two phase I trials using a DNA vaccine encoding prostatic acid phosphatase (PAP) in patients with biochemically recurrent prostate cancer. In both trials, persistent PAP-specific Th1 immunity developed in some patients, and this was associated with favorable changes in serum PSA kinetics. In the current study, we sought to determine if measures of antigen-specific or antigen non-specific immunity were present prior to treatment, and associated with subsequent immune response, to identify possible predictive immune biomarkers. METHODS: Patients who developed persistent PAP-specific, IFNgamma-secreting immune responses were defined as immune "responders." The frequency of peripheral T cell and B cell lymphocytes, natural killer cells, monocytes, dendritic cells, myeloid derived suppressor cells, and regulatory T cells were assessed by flow cytometry and clinical laboratory values. PAP-specific immune responses were evaluated by cytokine secretion in vitro, and by antigen-specific suppression of delayed-type hypersensitivity to a recall antigen in an in vivo SCID mouse model. RESULTS: The frequency of peripheral blood cell types did not differ between the immune responder and non responder groups. Non-responder patients tended to have higher PAP-specific IL-10 production pre-vaccination (p = 0.09). Responder patients had greater preexisting PAP-specific bystander regulatory responses that suppressed DTH to a recall antigen (p = 0.016). CONCLUSIONS: While our study population was small (n = 38), these results suggest that different measures of antigen-specific tolerance or regulation might help predict immunological outcome from DNA vaccination. These will be prospectively evaluated in an ongoing randomized, phase II trial. PMID- 28716081 TI - Impact of a nurse led telephone intervention on satisfaction and health outcomes of children with inflammatory rheumatic diseases and their families: a crossover randomized clinical trial. AB - BACKGROUND: Children suffering from rheumatic disease are faced with multidimensional challenges that affect their quality of life and family dynamics. Symptom management and monitoring of the course of the disease over time are important to minimize disability and pain. Poor disease control and anticipation of the need for treatment changes may be prompted by specialist medical follow-up and regular nurse-led consultations with the patient and families, in which information and support is provided. The purpose of this study was to evaluate the impact of a nurse-led telephone intervention or Telenursing (TN) compared to standard care (SC) on satisfaction and health outcomes of children with inflammatory rheumatic diseases and their parents. METHODS: A multicentered, randomized, longitudinal, crossover trial was conducted with pediatrics outpatients newly diagnosed with inflammatory rheumatic diseases. Participants were randomly assigned to two groups TN and SC for 12 months and crossed-over for the following 12 months. TN consisted of providing individualized affective support, health information and aid to decision making. Satisfaction (primary outcome) and health outcomes were assessed with the Client Satisfaction Questionnaire-8 and the Juvenile Arthritis Multidimensional Assessment Report, respectively. A mixed effect model, including a group x time interaction, was performed for each outcome. RESULTS: Satisfaction was significantly higher when receiving TN (OR = 7.7, 95% CI: 1.8-33.6). Morning stiffness (OR = 3.2, 95% CI: 0.97-7.15) and pain (OR = 2.64, 95% CI: 0.97-7.15) were lower in the TN group. For both outcomes a carry-over effect was observed with a higher impact of TN during the 12 first months of the study. The other outcomes did not show any significant improvements between groups. CONCLUSION: TN had a positive impact on satisfaction and on morning stiffness and pain of children with inflammatory rheumatic diseases and their families. This highlights the importance of support by specialist nurses in improving satisfaction and symptom management for children with inflammatory rheumatisms and their families. TRIAL REGISTRATION: ClinicalTrial.gov identifier: NCT01511341 (December 1st, 2012). PMID- 28716082 TI - Efficacy of hormonal and mental treatments with MMPI in FtM individuals: cross sectional and longitudinal studies. AB - BACKGROUND: Cross-sex hormone treatment (CSHT) is an important option for gender dysphoria (GD) individuals to improve the quality of life. However, in Japan, sex reassignment surgery (SRS) and CSHT for GD had been discontinued until 1998 (over 30 years). After resumption, the number of GD individuals wishing treatment rapidly increased. On the other hand, the number of medical institutions available for evaluation was limited. For this reason, hormonal treatment has been administered to GD individuals requiring the prompt start of CSHT in the absence of mental health assessment by specialists. In this study, we examined the efficacy of CSHT and psychotherapy. METHODS: The participants were 155 female to-male (FtM) individuals who consulted our gender identity clinic, and were definitively diagnosed. A cross-sectional study was conducted by dividing them into two groups: groups with and without CSHT on the initial consultation (Group CSHT: n = 53, Group no-CSHT: n = 102). In all participants, Minnesota Multiphasic Personality Inventory (MMPI) and blood hormone tests were performed on the initial consultation. In addition, CSHT was combined with psychotherapy for a specific period in Group no-CSHT, and FtM individuals in whom an additional MMPI test could be conducted (Group combined treatment (CT), n = 14) were enrolled in a longitudinal study. RESULTS: In the cross-sectional study, there was no significant difference on the MMPI test. In the longitudinal study, there were improvements in the clinical scales other than the Mf scale on the MMPI test. In Group CT, the D, Sc, and Si scale scores on the initial consultation were significantly higher than in Group CSHT. However, there was no clinical scale with a significantly higher value after the start of treatment. The Pd scale score was significantly lower. CONCLUSIONS: CSHT improved mental health. Psychotherapy-combined CSHT may further improve it. TRIAL REGISTRATION: The study was reviewed and approved by the Ethics Committee of Kansai Medical University (A comprehensive treatment for gender dysphoria: No. 0314 registered date 10th December 2003), and was approved at UMIN000028102 on 6th July 2017 as retrospectively registered. PMID- 28716083 TI - Influence of simethicone and fasting on the quality of abdominal ultrasonography in New Zealand White rabbits. AB - Presence of significant quantities of gas in the intestines may hinder a proper conduction of abdominal ultrasonography. In humans, preparatory techniques are used to solve this, but measures to avoid ultrasonographic complications due to intestinal gas in rabbits have not been reported. The objective of this study was to evaluate the influence of fasting and simethicone administered orally on the quality of ultrasonographic images of the gallbladder, kidneys, and jejunum in adult New Zealand White (NZW) rabbits. A total of 28 adult NZW rabbits were included in a crossover design study, involving four groups: F: fasting for 4-6 h before the examination; FS: fasting and application of simethicone (20 mg/kg, orally) 20 to 30 min before the examination; S: application of simethicone 20-30 min before the examination without fasting; and C: controls without fasting and no application of simethicone. Evaluation of the ultrasonographic images was done in terms of percentage of visualization of each organ and image quality using a 3 point scoring system (unacceptable, acceptable, or excellent). The kidneys and the gallbladder were visualized at an equal frequency in all groups, while the jejunum was visualized more frequently in the FS group. The image quality scores for gallbladder, right kidney, and left kidney was similar for all groups, but for the jejunum, a higher number of images with acceptable scores was found within the FS group. PMID- 28716084 TI - Development and validation of the Chinese version of dry eye related quality of life scale. AB - BACKGROUND: To develop the Chinese version of quality of life scale for dry eye patients based on the Impact of Dry Eye on Everyday Life (IDEEL) questionnaire and to assess the reliability and validity of the developed scale. METHODS: The original IDEEL was adapted cross-culturally to Chinese language and further developed following standard procedures. A total of 100 Chinese patients diagnosed with dry eye syndrome were included to investigate the psychometric properties of the Chinese version of scale. Psychometric tests included internal consistency (Cronbach's alpha coefficients), construct validity (exploratory factor analysis), and known-groups validity (the analysis of variance). RESULTS: The Chinese version of Dry Eye Related Quality of Life (CDERQOL) Scale contains 45 items classified into 5 domains. Good to excellent internal consistency reliability was demonstrated for all 5 domains (Cronbach's alpha coefficients range from 0.716 to 0.913). Construct validity assessment indicated a consistent factorial structure of the CDERQOL scale with hypothesized construct, with the exception of "Dry Eye Symptom-Bother" domain. All domain scores were detected with significant difference across three severity groups of dry eye patients (P < 0.05) except for "Satisfaction with Treatment" domain, indicating good known groups validity. CONCLUSIONS: The results indicated that the CDERQOL scale is a reliable and valid instrument for patients with dry eye syndrome among Chinese population, and could be used as a supplementary diagnostic and treatment effectiveness measure. PMID- 28716085 TI - The protective effect of fermented Curcuma longa L. on memory dysfunction in oxidative stress-induced C6 gliomal cells, proinflammatory-activated BV2 microglial cells, and scopolamine-induced amnesia model in mice. AB - BACKGROUND: Curcuma longa L. is a well-known medicinal plant that has been used for its anti-cancer, neuroprotective, and hepatoprotective effects. However, the neuroprotective effect of fermented C. longa (FCL) has not been reported. Therefore, in this study, the effectiveness of FCL for the regulation of memory dysfunction was investigated in two brain cell lines (rat glioma C6 and murine microglia BV2) and scopolamine-treated mice. METHODS: C. longa powder was fermented by 5% Lactobacillus plantarum K154 containing 2% (w/v) yeast extract at 30 degrees C for 72 h followed by sterilization at 121 degrees C for 15 min. The protective effects of fermented C. longa (FCL) on oxidative stress induced cell death were analyzed by MTT assay in C6 cells. The anti-inflammatory effects of FCL were investigated by measuring the production of nitric oxide (NO) and prostaglandin E2 (PGE2) as well as the expression levels of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) in LPS-stimulated BV2 cells. The step-through passive avoidance test, Morris water maze test, acetylcholinesterase (AChE) activity, and expression of cAMP response element-binding protein (CREB) and brain-derived neurotropic factor (BDNF) were employed to determine the effects of FCL on scopolamine-induced memory deficit in mice. The contents of curcuminoids were analyzed through LC/MS. RESULTS: Pretreatment with FCL effectively prevented the cell death induced by oxidative stress in C6 cells. Moreover, FCL inhibited the production NO and PGE2 via the inhibition of iNOS and COX-2 expression in BV2 cells. FCL significantly attenuated scopolamine-induced memory impairment in mice and prevented scopolamine-induced AChE activity in the hippocampus. Additionally, FCL reversed the reduction of CREB and BDNF expression. The curcuminoids content in FCL was 1.44%. CONCLUSION: FCL pretreatment could alleviate scopolamine induced memory impairment in mice, as well as oxidative stress and inflammation in C6 and BV2 cells, respectively. Thus, FCL might be a useful material for preventing impairment of learning and memory. PMID- 28716086 TI - Dynamics in multiplicity of Plasmodium falciparum infection among children with asymptomatic malaria in central Ghana. AB - BACKGROUND: The determinants of malaria parasite virulence is not entirely known, but the outcome of malaria infection (asymptomatic or symptomatic) has been associated with carriage of distinct parasite genotypes. Alleles considered important for erythrocyte invasion and selected as candidate targets for malaria vaccine development are increasingly being shown to have distinct characteristics in infection outcomes. Any unique/distinct patterns or alleles linked to infection outcome should be reproducible for a given malaria-cohort regardless of location, time or intervention. This study compared merozoite surface protein 2 (MSP2) genotypes from children with asymptomatic malaria at same geographical location, from two time periods. RESULTS: As the prevalence and incidence of malaria (measured for other studies) significantly reduced between 2004 (time point one) and 2009 (time point two), MSP2 multiplicity of infections (MOI) also reduced significantly from 2.3 at time point (TP) one to 1.9 at TP two. IC/3D7 genotypes out-numbered FC27 genotypes at both time points. At TP2 however, FC27 allele diversity was more than the IC/3D7 allele diversity. A decrease in the IC/3D7:FC27 genotype proportions from 2:1 at TP1 to 1:1 at TP2, seemed to be driven mainly by a decrease in carriage of IC/3D7 alleles. MOI was higher in the dry season than in the subsequent wet season, but the decrease was not significant at TP2. CONCLUSION: MSP2 MOI was higher in the dry season than in the subsequent wet season, while the carriage of IC/3D7 alleles decreased over this time period. It may be that decreases in transmission are related specifically to the IC/3D7 allelic family. The influence of transmission on MSP2 allele diversity needs to be clearly deciphered in studies which should include the use of sensitive methods for the detection of polymorphic parasite markers for both symptomatic and asymptomatic malaria. Such studies will enable better understanding of associations between allelic variants, MOI, transmission, malaria infection and disease. PMID- 28716087 TI - Explaining variation in adult Anopheles indoor resting abundance: the relative effects of larval habitat proximity and insecticide-treated bed net use. AB - BACKGROUND: Spatial determinants of malaria risk within communities are associated with heterogeneity of exposure to vector mosquitoes. The abundance of adult malaria vectors inside people's houses, where most transmission takes place, should be associated with several factors: proximity of houses to larval habitats, structural characteristics of houses, indoor use of vector control tools containing insecticides, and human behavioural and environmental factors in and near houses. While most previous studies have assessed the association of larval habitat proximity in landscapes with relatively low densities of larval habitats, in this study these relationships were analysed in a region of rural, lowland western Kenya with high larval habitat density. METHODS: 525 houses were sampled for indoor-resting mosquitoes across an 8 by 8 km study area using the pyrethrum spray catch method. A predictive model of larval habitat location in this landscape, previously verified, provided derivations of indices of larval habitat proximity to houses. Using geostatistical regression models, the association of larval habitat proximity, long-lasting insecticidal nets (LLIN) use, house structural characteristics (wall type, roof type), and peridomestic variables (cooking in the house, cattle near the house, number of people sleeping in the house) with mosquito abundance in houses was quantified. RESULTS: Vector abundance was low (mean, 1.1 adult Anopheles per house). Proximity of larval habitats was a strong predictor of Anopheles abundance. Houses without an LLIN had more female Anopheles gambiae s.s., Anopheles arabiensis and Anopheles funestus than houses where some people used an LLIN (rate ratios, 95% CI 0.87, 0.85-0.89; 0.84, 0.82-0.86; 0.38, 0.37-0.40) and houses where everyone used an LLIN (RR, 95% CI 0.49, 0.48-0.50; 0.39, 0.39-0.40; 0.60, 0.58-0.61). Cooking in the house also reduced Anopheles abundance across all species. The number of people sleeping in the house, presence of cattle near the house, and house structure modulated Anopheles abundance, but the effect varied with Anopheles species and sex. CONCLUSIONS: Variation in the abundance of indoor-resting Anopheles in rural houses of western Kenya varies with clearly identifiable factors. Results suggest that LLIN use continues to function in reducing vector abundance, and that larval source management in this region could lead to further reductions in malaria risk by reducing the amount of an obligatory resource for mosquitoes near people's homes. PMID- 28716088 TI - Loss of DIP2C in RKO cells stimulates changes in DNA methylation and epithelial mesenchymal transition. AB - BACKGROUND: The disco-interacting protein 2 homolog C (DIP2C) gene is an uncharacterized gene found mutated in a subset of breast and lung cancers. To understand the role of DIP2C in tumour development we studied the gene in human cancer cells. METHODS: We engineered human DIP2C knockout cells by genome editing in cancer cells. The growth properties of the engineered cells were characterised and transcriptome and methylation analyses were carried out to identify pathways deregulated by inactivation of DIP2C. Effects on cell death pathways and epithelial-mesenchymal transition traits were studied based on the results from expression profiling. RESULTS: Knockout of DIP2C in RKO cells resulted in cell enlargement and growth retardation. Expression profiling revealed 780 genes for which the expression level was affected by the loss of DIP2C, including the tumour-suppressor encoding CDKN2A gene, the epithelial-mesenchymal transition (EMT) regulator-encoding ZEB1, and CD44 and CD24 that encode breast cancer stem cell markers. Analysis of DNA methylation showed more than 30,000 sites affected by differential methylation, the majority of which were hypomethylated following loss of DIP2C. Changes in DNA methylation at promoter regions were strongly correlated to changes in gene expression, and genes involved with EMT and cell death were enriched among the differentially regulated genes. The DIP2C knockout cells had higher wound closing capacity and showed an increase in the proportion of cells positive for cellular senescence markers. CONCLUSIONS: Loss of DIP2C triggers substantial DNA methylation and gene expression changes, cellular senescence and epithelial-mesenchymal transition in cancer cells. PMID- 28716089 TI - Greater periventricular white matter hyperintensity severity in basilar artery branch atheromatous disease. AB - BACKGROUND: Basilar artery branch atheromatous disease (BABAD), in which basilar artery atheroma occludes penetrating arteries at their origin, is a common etiology of posterior circulation stroke (PCS). It is currently unknown whether white matter hyperintensity(WMH), a marker of small vessel disease(SVD), is associated with BABAD. METHODS: The present study analyzed data from patients with PCS who were enrolled in the Taipei Veterans General Hospital Stroke Registry between January 1, 2010 and February 28, 2014. WMH severity was rated using the Scheltens scale. We used multivariate analyses to: (1) compare the severity of WMH between patients with BABAD, patients with large-artery > 50% atherosclerotic stenosis-related PCS(LAA), and non-stroke subjects(NS); and (2) evaluate the relationship between WMH severity and the 3-month prognosis of patients with BABAD. RESULTS: The study pool included 151 BABAD, 97 LAA, and 78 non-stroke patients. Multivariate analyses adjusting for age, sex, and vascular risk factors showed that compared to patients with LAA [Odds ratio(OR) = 0.51, p = 0.037] and NS (OR = 0.40, p = 0.004), patients with BABAD (OR = 1) had greater WMH severity (score >= 50th percentile) in periventricular, but not subcortical, regions. Moreover, greater periventricular WMH severity predicted poor 3-month functional outcomes (modified Rankin Scale > 3) with an OR of 3.21 (p = 0.028) in BABAD patients. CONCLUSIONS: We are the first to show a significant association between WMH and BABAD that is independent of vascular risk factors and atherosclerotic large-artery disease. Our results suggest that small vessel abnormalities other than lipohyalinosis may be involved in BABAD pathophysiology. A future management strategy should include both large and small vessel protection. PMID- 28716090 TI - Clinical workflow for MR-only simulation and planning in prostate. AB - PURPOSE: To describe the details and experience of implementing a MR-only workflow in the clinic for simulation and planning of prostate cancer patients. METHODS: Forty-eight prostate cancer patients from June 2016 - Dec 2016 receiving external beam radiotherapy were scheduled to undergo MR-only simulation. MR images were acquired for contouring (T2w axial, coronal, sagittal), synthetic-CT generation (3D FFE-based) and fiducial identification (3D bFFE-based). The total acquisition time was 25 min. Syn-CT was generated at the console using commercial software called MRCAT. As part of acceptance testing of the MRCAT package, external laser positioning system QA (< 2 mm) and geometric fidelity QA (< 2 mm within 50 cm LR and 30 cm AP) were performed and baseline values were set. Our current combined CT + MR simulation process was modified to accommodate a MRCAT based MR-only simulation workflow. An automated step-by-step process using a MIMTM workflow was created for contouring on the MR images. Patient setup for treatment was achieved by matching the MRCAT DRRs with the orthogonal KV radiographs based on either fiducial ROIs or bones. 3-D CBCTs were acquired and compared with the MR/syn-CT to assess the rectum and bladder filling compared to simulation conditions. RESULTS: Forty-two patients successfully underwent MR-only simulation and met all of our institutional dosimetric objectives that were developed based on a CT + MR-based workflow. The remaining six patients either had a hip prosthesis or their large body size fell outside of the geometric fidelity QA criteria and thus they were not candidates for MR-only simulation. A total time saving of ~15 min was achieved with MR-based simulation as compared to CT + MR-based simulation. An automated and organized MIM workflow made contouring on MR much easier, quicker and more accurate compared with combined CT + MR images because the temporal variations in normal structure was minimal. 2D and 3D treatment setup localization based on bones/fiducials using a MRCAT reference image was successfully achieved for all cases. CONCLUSIONS: MR-only simulation and planning with equivalent or superior target delineation, planning and treatment setup localization accuracy is feasible in a clinical setting. Future work will focus on implementing a robust 3D isotropic acquisition for contouring. PMID- 28716091 TI - Suppression of the phytoene synthase gene (EgcrtB) alters carotenoid content and intracellular structure of Euglena gracilis. AB - BACKGROUND: Photosynthetic organisms utilize carotenoids for photoprotection as well as light harvesting. Our previous study revealed that high-intensity light increases the expression of the gene for phytoene synthase (EgcrtB) in Euglena gracilis (a unicellular phytoflagellate), the encoded enzyme catalyzes the first committed step of the carotenoid biosynthesis pathway. To examine carotenoid synthesis of E. gracilis in response to light stress, we analyzed carotenoid species and content in cells grown under various light intensities. In addition, we investigated the effect of suppressing EgcrtB with RNA interference (RNAi) on growth and carotenoid content. RESULTS: After cultivation for 7 days under continuous light at 920 MUmol m-2 s-1, beta-carotene, diadinoxanthin (Ddx), and diatoxanthin (Dtx) content in cells was significantly increased compared with standard light intensity (55 MUmol m-2 s-1). The high-intensity light (920 MUmol m-2 s-1) increased the pool size of diadinoxanthin cycle pigments (i.e., Ddx + Dtx) by 1.2-fold and the Dtx/Ddx ratio from 0.05 (control) to 0.09. In contrast, the higher-intensity light treatment caused a 58% decrease in chlorophyll (a + b) content and diminished the number of thylakoid membranes in chloroplasts by approximately half compared with control cells, suggesting that the high intensity light-induced accumulation of carotenoids is associated with an increase in both the number and size of lipid globules in chloroplasts and the cytoplasm. Transient suppression of EgcrtB in this alga by RNAi resulted in significant decreases in cell number, chlorophyll, and total major carotenoid content by 82, 82 and 86%, respectively, relative to non-electroporated cells. Furthermore, suppression of EgcrtB decreased the number of chloroplasts and thylakoid membranes and increased the Dtx/Ddx ratio by 1.6-fold under continuous illumination even at the standard light intensity, indicating that blocking carotenoid synthesis increased the susceptibility of cells to light stress. CONCLUSIONS: Our results indicate that suppression of EgcrtB causes a significant decrease in carotenoid and chlorophyll content in E. gracilis accompanied by changes in intracellular structures, suggesting that Dtx (de-epoxidized form of diadinoxanthin cycle pigments) contributes to photoprotection of this alga during the long-term acclimation to light-induced stress. PMID- 28716092 TI - The role of microglial P2X7: modulation of cell death and cytokine release. AB - BACKGROUND: ATP-gated P2X7 is a non-selective cation channel, which participates in a wide range of cellular functions as well as pathophysiological processes including neuropathic pain, immune response, and neuroinflammation. Despite its abundant expression in microglia, the role of P2X7 in neuroinflammation still remains unclear. METHODS: Primary microglia were isolated from cortices of P0-2 C57BL/6 wild-type or P2X7 knockout (P2X7-/-) mouse pups. Lipopolysaccharide, lipopolysaccharide plus IFNgamma, or IL4 plus IL13 were used to polarize microglia to pro-inflammatory or anti-inflammatory states. P2rx7 expression level in resting or activated mouse and human microglia was measured by RNA-sequencing and quantitative real-time PCR. Microglial cell death was measured by cell counting kit-8 and immunocytochemistry, and microglial secretion in wild-type or P2X7-/- microglia was examined by Luminex multiplex assay or ELISA using P2X7 agonist BzATP or P2X7 antagonist A-804598. P2X7 signaling was analyzed by Western blot. RESULTS: First, we confirmed that P2rx7 is constitutively expressed in mouse and human primary microglia. Moreover, P2rx7 mRNA level was downregulated in mouse microglia under both pro- and anti-inflammatory conditions. Second, P2X7 agonist BzATP caused cell death of mouse microglia, while this effect was suppressed either by P2X7 knockout or by A-804598 under both basal and pro inflammatory conditions, which suggests the mediating role of P2X7 in BzATP induced microglial cell death. Third, BzATP-induced release of IL1 family cytokines including IL1alpha, IL1beta, and IL18 was blocked in P2X7-/- microglia or by A-804598 in pro-inflammatory microglia, while the release of other cytokines/chemokines was independent of P2X7 activation. These findings support the specific role of P2X7 in IL1 family cytokine release. Finally, P2X7 activation was discovered to be linked to AKT and ERK pathways, which may be the underlying mechanism of P2X7 functions in microglia. CONCLUSIONS: These results reveal that P2X7 mediates BzATP-induced microglial cell death and specific release of IL1 family cytokines, indicating the important role of P2X7 in neuroinflammation and implying the potential of targeting P2X7 for the treatment of neuroinflammatory disorders. PMID- 28716094 TI - An analytical approach to reduce between-plate variation in multiplex assays that measure antibodies to Plasmodium falciparum antigens. AB - BACKGROUND: Antibodies play an important role in immunity to malaria. Recent studies show that antibodies to multiple antigens, as well as, the overall breadth of the response are associated with protection from malaria. Yet, the variability and reliability of antibody measurements against a combination of malarial antigens using multiplex assays have not been well characterized. METHODS: A normalization procedure for reducing between-plate variation using replicates of pooled positive and negative controls was investigated. Sixty test samples (30 from malaria-positive and 30 malaria-negative individuals), together with five pooled positive-controls and two pooled negative-controls, were screened for antibody levels to 9 malarial antigens, including merozoite antigens (AMA1, EBA175, MSP1, MSP2, MSP3, MSP11, Pf41), sporozoite CSP, and pregnancy associated VAR2CSA. The antibody levels were measured in triplicate on each of 3 plates, and the experiments were replicated on two different days by the same technician. The performance of the proposed normalization procedure was evaluated with the pooled controls for the test samples on both the linear and natural-log scales. RESULTS: Compared with data on the linear scale, the natural-log transformed data were less skewed and reduced the mean-variance relationship. The proposed normalization procedure using pooled controls on the natural-log scale significantly reduced between-plate variation. CONCLUSIONS: For malaria-related research that measure antibodies to multiple antigens with multiplex assays, the natural-log transformation is recommended for data analysis and use of the normalization procedure with multiple pooled controls can improve the precision of antibody measurements. PMID- 28716093 TI - C. elegans SUP-46, an HNRNPM family RNA-binding protein that prevents paternally mediated epigenetic sterility. AB - BACKGROUND: In addition to DNA, gametes contribute epigenetic information in the form of histones and non-coding RNA. Epigenetic programs often respond to stressful environmental conditions and provide a heritable history of ancestral stress that allows for adaptation and propagation of the species. In the nematode C. elegans, defective epigenetic transmission often manifests as progressive germline mortality. We previously isolated sup-46 in a screen for suppressors of the hexosamine pathway gene mutant, gna-2(qa705). In this study, we examine the role of SUP-46 in stress resistance and progressive germline mortality. RESULTS: We identified SUP-46 as an HNRNPM family RNA-binding protein, and uncovered a highly novel role for SUP-46 in preventing paternally-mediated progressive germline mortality following mating. Proximity biotinylation profiling of human homologs (HNRNPM, MYEF2) identified proteins of ribonucleoprotein complexes previously shown to contain non-coding RNA. Like HNRNPM and MYEF2, SUP-46 was associated with multiple RNA granules, including stress granules, and also formed granules on active chromatin. SUP-46 depletion disrupted germ RNA granules and caused ectopic sperm, increased sperm transcripts, and chronic heat stress sensitivity. SUP-46 was also required for resistance to acute heat stress, and a conserved "MYEF2" motif was identified that was needed for stress resistance. CONCLUSIONS: In mammals, non-coding RNA from the sperm of stressed males has been shown to recapitulate paternal stress phenotypes in the offspring. Our results suggest that HNRNPM family proteins enable stress resistance and paternally mediated epigenetic transmission that may be conserved across species. PMID- 28716095 TI - Development of real-time and lateral flow dipstick recombinase polymerase amplification assays for rapid detection of goatpox virus and sheeppox virus. AB - BACKGROUND: Goatpox virus (GTPV) and sheeppox virus (SPPV), which belong to the Capripoxvirus (CaPV), are economically important pathogens of small ruminants. Therefore, a sensitive, specific and rapid diagnostic assay for detection of GTPV and SPPV is necessary to accurately and promptly control these diseases. METHODS: Recombinase polymerase amplification (RPA) assays combined with a real-time fluorescent detection (real-time RPA assay) and lateral flow dipstick (RPA LFD assay) were developed targeting the CaPV G-protein-coupled chemokine receptor (GPCR) gene, respectively. RESULTS: The sensitivity of both CaPV real-time RPA assay and CaPV RPA LFD assay were 3 * 102 copies per reaction within 20 min at 38 degrees C. Both assays were highly specific for CaPV, with no cross-reactions with peste des petits ruminants virus, foot-and-mouth disease virus and Orf virus. The evaluation of the performance of these two assays with clinical sample (n = 107) showed that the CaPV real-time RPA assay and CaPV RPA LFD assay were able to specially detect SPPV or GTPV present in samples of ovine in liver, lung, kidney, spleen, skin and blood. CONCLUSIONS: This study provided a highly time efficient and simple alternative for rapid detection of GTPV and SPPV. PMID- 28716096 TI - Optimizing reproducibility of operant testing through reinforcer standardization: identification of key nutritional constituents determining reward strength in touchscreens. AB - Reliable and reproducible assessment of animal learning and behavior is a central aim of basic and translational neuroscience research. Recent developments in automated operant chamber technology have led to the possibility of universal standard protocols, in addition to increased translational potential, reliability and accuracy. However, the impact of regional and national differences in the supplies of available reinforcers in this system on behavioural performance and inter-laboratory variability is an unknown and at present uncontrolled variable. Therefore, we aimed to identify which constituent(s) of the reward determines reinforcer strength to enable improved standardization of this parameter across laboratories. Male C57BL/6 mice were examined in the touchscreen-based fixed ratio (FR) and progressive ratio (PR) schedules, reinforced with different kinds of milk-based reinforcers to directly compare the incentive values of plain milk (PM, high-calorie: high-fat/low-sugar), strawberry-flavored milk (SM, high calorie: low-fat/high-sugar), and semi-skimmed low-fat milk (LM, low-calorie: low fat/low-sugar) on the basis of differences in caloric content, sugar/fat content, and flavor. Use of a higher caloric content reward was effective in increasing operant training acquisition rate. Total trial number completed in FR and breakpoint in PR were higher using the two isocaloric milk products (PM and SM) than the lower caloric LM, with comparable outcomes between PM and SM conditions, suggesting that total caloric content determines reward strength. Analysis of within-session changes in response rate revealed that overall outputs in FR and PR primarily depend on the response rate at the initial phase of a session, which itself was dependent on reinforcer caloric content. Interestingly, the rate of satiation, indicated by decay in response rate within a FR session, was highest when reinforced with SM, suggesting a rapid satiating effect of sugar. The key contribution of reward caloric content to operant performance was confirmed in a multi-laboratory study using the touchscreen 5-choice serial reaction time task (5-CSRTT) reinforced by two isocaloric milk-based liquid rewards with different countries of origin, which yielded consistent performance parameters across sites. Our results indicate that milk-based liquid reinforcer standardization can be facilitated by matching caloric content across laboratories despite regional or national differences in other non-caloric aspects of the reinforcers. PMID- 28716097 TI - Regression of multifocoal in transit melanoma metastases after palliative resection of dominant masses and 2 years after treatment with ipilimumab. AB - BACKGROUND: Spontaneous regression of metastatic melanoma and delayed responses more than one year after treatment with ipilimumab are rarely seen. CASE PRESENTATION: Here, we present the case of a patient with in transit metastases from cutaneous melanoma on his right lower extremity who achieved complete regression of all metastatic lesions 13 months after the first of two consecutive palliative resections of dominant masses and more than two years after treatment with ipilimumab. CONCLUSION: The exact cause of our patient's sudden onset of tumor regression remains speculative. We hypothesize that the operative trauma followed by the postoperative infections augmented an innate immune response. PMID- 28716098 TI - Awakening sleeping beauty: production of propionic acid in Escherichia coli through the sbm operon requires the activity of a methylmalonyl-CoA epimerase. AB - BACKGROUND: Propionic acid is used primarily as a food preservative with smaller applications as a chemical building block for the production of many products including fabrics, cosmetics, drugs, and plastics. Biological production using propionibacteria would be competitive against chemical production through hydrocarboxylation of ethylene if native producers could be engineered to reach near-theoretical yield and good productivity. Unfortunately, engineering propionibacteria has proven very challenging. It has been suggested that activation of the sleeping beauty operon in Escherichia coli is sufficient to achieve propionic acid production. Optimising E. coli production should be much easier than engineering propionibacteria if tolerance issues can be addressed. RESULTS: Propionic acid is produced in E. coli via the sleeping beauty mutase operon under anaerobic conditions in rich medium via amino acid degradation. We observed that the sbm operon enhances amino acids degradation to propionic acid and allows E. coli to degrade isoleucine. However, we show here that the operon lacks an epimerase reaction that enables propionic acid production in minimal medium containing glucose as the sole carbon source. Production from glucose can be restored by engineering the system with a methylmalonyl-CoA epimerase from Propionibacterium acidipropionici (0.23 +/- 0.02 mM). 1-Propanol production was also detected from the promiscuous activity of the native alcohol dehydrogenase (AdhE). We also show that aerobic conditions are favourable for propionic acid production. Finally, we increase titre 65 times using a combination of promoter engineering and process optimisation. CONCLUSIONS: The native sbm operon encodes an incomplete pathway. Production of propionic acid from glucose as sole carbon source is possible when the pathway is complemented with a methylmalonyl-CoA epimerase. Although propionic acid via the restored succinate dissimilation pathway is considered a fermentative process, the engineered pathway was shown to be functional under anaerobic and aerobic conditions. PMID- 28716099 TI - Xenoantigenicity of porcine decellularized valves. AB - BACKGROUND: The xenoantigenicity of porcine bioprosthetic valves is implicated as an etiology leading to calcification and subsequent valve failure. Decellularization of porcine valves theoretically could erase the antigenicity of the tissue leading to more durable prosthetic valves, but the effectiveness of decellularization protocols in regard to completely removing antigens has yet to be verified. Our hypothesis was that decellularization would remove the more abundant alpha-gal antigens but not remove all the non alpha-gal antigens, which could mount a response. METHODS: Porcine aortic valves were decellularized with 1% sodium dodecyl sulfate for 4 days. Decellularized cusps were evaluated for alpha-gal epitopes by ELISA. To test for non alpha-gal antigens, valves were implanted into sheep. Serum was obtained from the sheep preoperatively and 1 week, 1 month, and 2 months postoperatively. This serum was utilized for anti porcine antibody staining and for quantification of anti-pig IgM and IgG antibodies and complement. RESULTS: Decellularized porcine cusps had 2.8 +/- 2.0% relative alpha-gal epitope as compared to fresh porcine aortic valve cusps and was not statistically significantly different (p = 0.4) from the human aortic valve cusp which had a 2.0 +/- 0.4% relative concentration. Anti-pig IgM and IgG increased postoperatively from baseline levels. Preoperatively anti-pig IgM was 27.7 +/- 1.7 MUg/mL and it increased to 71.9 +/- 12.1 MUg/mL average of all time points postoperatively (p = 0.04). Preoperatively anti-pig IgG in sheep serum was 44.9 +/- 1.5 MUg/mL and it increased to 72.6 +/- 6.0 MUg/mL average of all time points postoperatively (p = 0.01). There was a statistically significant difference (p = 0.00007) in the serum C1q concentration before valve implantation (2.5 +/- 0.2 IU/mL) and at averaged time points after valve implantation (5.3 +/- 0.3 IU/mL). CONCLUSIONS: Decellularization with 1% sodium dodecyl sulfate does not fully eliminate non alpha-gal antigens; however, significant reduction in alpha-gal presence on decellularized cusps was observed. Clinical implications of the non alpha-gal antigenic response are yet to be determined. As such, evaluation of any novel decellularized xenografts must include rigorous antigen testing prior to human trials. PMID- 28716100 TI - Quality of life and clinical-radiological long-term results after implant associated infections in patients with ankle fracture: a retrospective matched pair study. AB - BACKGROUND: Ankle fractures are frequently occurring injuries. Despite the relatively simple operative technique, patients often suffer from postoperative complications. Little is known about postoperative treatment of implant associated infections of the ankle. Therefore, this study shows and evaluates a treatment algorithm in long- and short-term outcomes compared to infection-free patients. METHODS: Data from patients of over 20 years of a level 1 trauma center and university hospital was retrospectively analyzed including age, gender, comorbidities, smoking status, fracture classification, number of revisions, length of in-patient stay due to fracture and infection, and results of microbiological specimen with the length of antibiotic treatment. Moreover, present long-term outcome was evaluated by the American Orthopaedic Foot and Ankle Society (AOFAS) hindfoot score, the Ankle Osteoarthritis Score, and the Short Form 36 score and compared to a matched-pair infection-free patient cohort. RESULTS: Forty-four patients could be retrospectively evaluated (51% male, 49% women, mean age 46 +/- 17 years). Most of the cases were Weber B fractures (38%) following an in-patient stay from 51 +/- 4.3 days after primary treatment and 77 +/- 10.0 days after secondary treatment in our hospital. Microbiological specimen showed in 77% Staphylococcus aureus with following intravenous antibiotic treatment for 13.9 +/- 3.1 days in mean. Common comorbidities/risk factors were cardiovascular disease (28%), smoking (15%), and diabetes (18%). Cure of infection and clinical and radiographic osseous consolidation could be documented for all cases. Patients with implant-associated infections had significantly more risk factors than infection-free patients (1.1/0.33; p = .02 per patient). The matched-pair group showed significantly better long-term outcome in mean regarding the Ankle Osteoarthritis Score (2.0 +/- 1.2/13.9 +/- 4.7) and AOFAS hindfoot score (96.7 +/- 1.9/87.3 +/- 3.4). CONCLUSION: Immediate revision surgery with aggressive debridement, microbiological diagnostics, antibiotic therapy, and use of a drain until osseous consolidation is reached with following removal of the implant in patients with implant-associated infections after ankle fracture and open reduction internal fixation lead to cure of infection and fair long-term outcome in all cases. Special care must be taken of risk factors like diabetes and smoking. TRIAL REGISTRATION: 24/2008BO2. PMID- 28716101 TI - Short-term impact of celebrating the international clinical trial day: experience from Ethiopia. AB - Just over 2 years ago on 20 May 2014, we celebrated the first International Clinical Trial Day (ICTD) in Ethiopia at the College of Health Sciences, Addis Ababa University. The main aim of the celebration was to express solidarity with clinical researchers, particularly clinical trialists, across the world. Since this first celebration, several major steps have been taken with potential for improving the conduct of clinical trials in our institution and more broadly within the country. These have included policy impact, particularly commitment from the government and the institution for supporting clinical trials and for the broader improvement of access to medicines. A Clinical Trial Unit, led by a multi-disciplinary team of researchers, has been established. A regional centre of excellence is being established to build regional capacity for translational research and clinical trials. These are important outputs attributable to the celebration of the ICTD. We encourage ICTD celebration at institutions conducting clinical research. This is likely to have unanticipated positive institutional, national and even regional consequences. PMID- 28716102 TI - Erratum to Analysis of factors that affect the precision of the radiographic lateral femoral bowing angle using a three-dimensional computed tomography-based modelling technique. PMID- 28716103 TI - Cytotoxic activity of extracts and crude saponins from Zanthoxylum armatum DC. against human breast (MCF-7, MDA-MB-468) and colorectal (Caco-2) cancer cell lines. AB - BACKGROUND: Zanthoxylum armatum DC has been an important traditional plant known for its medicinal properties. It is well known for its antimicrobial, larvicidal and cytotoxic activities. METHODS: The potential anticancer effects of the methanol extract and the crude saponins from fruit, bark and leaves of Z. armatum on breast (MDA-MB-468 and MCF-7) and colorectal (Caco-2) cancer cell lines using MTT, neutral red uptake(NRU) and DAPI stain assays were evaluated. RESULTS: In MTT assay the methanol extract of fruit (Zf), bark (Zb) and leaves (Zl) of Zanthoxylum armatum, showed significant and dose dependent growth inhibition of MCF-7, MDA MB-468 and Caco-2 cancer cell lines in a dose of 200 MUg/ml and above. The saponins (Zf.Sa, Zb.Sa and Zl.Sa) showed significant activity against MDA MB 468 (95, 94.5 and 85.3%) as compared to MCF-7 (79.8, 9.43, 49.08%) and Caco-2 (75.8, 61.8, 68.62%) respectively. The extracts were further tested in more sensitive NRU assay and its was found that Zf extract showed higher cytotoxic activity as compared to Zb and Zl extracts with 100 MUg/ml concentration. The breast cancer cell lines showed more sensitivity toward the crude saponins from fruit and bark with maximum inhibition of up to 93.81(+/-2.32) % with respect to 71.19(+/- 2.76) of Actinomycin-D. DAPI staining experiment showed that saponins from fruit induced apoptosis mode of cell death in all three types of cell lines while saponins form leaves and bark showed similar results against MDA MB-468 indicated by nuclear fragmentation and chromatin condensation. The effect of saponins from fruit, bark and leaves (Zf.Sa, Zb.Sa and Zl.Sa) against Caco-2 cell lines inhibited the growth of Caco-2 by 53.16 (+/-3.31) %, 66.43 (+/- 3.24) and 45.96 (+/- 10.67) respectively with respect to Actinomycin-D (4 MUM) which showed the growth inhibition of 65.40(+/-4.29) %. CONCLUSION: The current study clearly demonstrates that the extract and crude saponins from fruit, bark and leaves of traditional medicinal plant Zanthoxyllum armatum DC., has the potential to exert its cytotoxic effect on cancer cell lines isolated form human by a mechanism involving apoptosis. The overall finding demonstrate that this plant specially fruits, could be potential source of new anticancer compounds for possible drug development against cancer. PMID- 28716104 TI - Evaluating the potential of gold, silver, and silica nanoparticles to saturate mononuclear phagocytic system tissues under repeat dosing conditions. AB - BACKGROUND: As nanoparticles (NPs) become more prevalent in the pharmaceutical industry, questions have arisen from both industry and regulatory stakeholders about the long term effects of these materials. This study was designed to evaluate whether gold (10 nm), silver (50 nm), or silica (10 nm) nanoparticles administered intravenously to mice for up to 8 weeks at doses known to be sub toxic (non-toxic at single acute or repeat dosing levels) and clinically relevant could produce significant bioaccumulation in liver and spleen macrophages. RESULTS: Repeated dosing with gold, silver, and silica nanoparticles did not saturate bioaccumulation in liver or spleen macrophages. While no toxicity was observed with gold and silver nanoparticles throughout the 8 week experiment, some effects including histopathological and serum chemistry changes were observed with silica nanoparticles starting at week 3. No major changes in the splenocyte population were observed during the study for any of the nanoparticles tested. CONCLUSIONS: The clinical impact of these changes is unclear but suggests that the mononuclear phagocytic system is able to handle repeated doses of nanoparticles. PMID- 28716105 TI - Characterization of four rice UEV1 genes required for Lys63-linked polyubiquitination and distinct functions. AB - BACKGROUND: The error-free branch of the DNA-damage tolerance (DDT) pathway is orchestrated by Lys63-linked polyubiquitination of proliferating cell nuclear antigen (PCNA), and this polyubiquitination is mediated by a Ubc13-Uev complex in yeast. We have previously cloned OsUBC13 from rice, whose product functions as an E2 to promote Lys63-linked ubiquitin chain assembly in the presence of yeast or human Uev. RESULTS: Here we identify four highly conserved UEV1 genes in rice whose products are able to form stable heterodimers with OsUbc13 and mediate Lys63-linked ubiquitin chain assembly. Expression of OsUEV1s is able to rescue the yeast mms2 mutant from death caused by DNA-damaging agents. Interestingly, OsUev1A contains a unique C-terminal tail with a conserved prenylation site not found in the other three OsUev1s, and this post-translational modification appears to be required for its unique subcellular distribution and association with the membrane. The analysis of OsUEV1 expression profiles obtained from the Genevestigator database indicates that these genes are differentially regulated. CONCLUSIONS: We speculate that different OsUev1s play distinct roles by serving as a regulatory subunit of the Ubc13-Uev1 complex to respond to diverse cellular, developmental and environmental signals. PMID- 28716106 TI - Acute interstitial nephritis after sequential ipilumumab - nivolumab therapy of metastatic melanoma. AB - BACKGROUND: The anti-Programmed Death receptor 1 (anti-PD-1) antibodies nivolumab and pembrolizumab are new treatments in metastatic melanoma. Immunotherapies are best known to be responsible for thrombotic microangiopathy. However, immune interstitial nephritis has been described in a patient treated by nivolumab and ipilimumab concomitantly, and three cases of granulomatous interstitial nephritis have been reported with ipilimumab monotherapy. We report herein a case of acute interstitial immune nephritis in a patient treated with nivolumab after ipilimumab for pulmonary metastatic melanoma. CASE PRESENTATION: Interstitial nephritis was diagnosed after acute kidney injury following three cycles and was confirmed by kidney biopsy. Kidney injury responded rapidly to prednisolone, which was then gradually reduced. As a follow-up computed tomography scan indicated mixed response, with minimal size progression of a pulmonary nodule, but a significant reduction in the size of the other nodules, nivolumab was reintroduced after renal function improvement. Low-dose corticosteroids were first maintained during nivolumab treatment and subsequently discontinued. Only one month after prednisolone discontinuation, creatinine levels increased. A second kidney biopsy confirmed relapse of acute interstitial nephritis. CONCLUSIONS: To our knowledge, this is the first case of nivolumab-induced acute interstitial immune nephritis. This case highlights that anti-PD-1 immunotherapy may be continued when renal function is adequate, and this requires close interaction between dermatologists and nephrologists. This adverse effect should be made known to prescribers as nivolumab is associated with significant improvement of survival in metastatic melanoma and may be used in many different types of cancer. PMID- 28716107 TI - Biomarkers of resistance to radiation therapy: a prospective study in cervical carcinoma. AB - BACKGROUND: Clinical parameters and proteins have recently been suggested as possible causes of radiotherapy (RT) resistance in cervical carcinoma (CC). The objective of the present study was to validate prognostic biomarkers of radiation resistance. METHODS: The present prospective study included patients undergoing RT with curative intent for histologically proven locally advanced squamous cell CC. Tissues and blood samples were systematically collected before RT initiation. Immuno-histochemistry was performed (IGF-IR alpha and beta, GAPDH, HIF-1 alpha, Survivin, GLUT1, CAIX, hTERT and HKII). Response to radiation was assessed through tumour response 3 months after RT completion, through overall survival (OS) and through progression-free survival (PFS). RESULTS: One hundred forty nine patients with a mean age of 46 years were included, with FIGO IIB (n = 53) and FIGO IIIB (n = 96) CCs. 61 patients were treated with exclusive RT + brachytherapy and 88 underwent chemo-radiotherapy + brachytherapy. Our findings suggest an association between hemoglobin level (Hb) (>11 g/dL) and 3 months complete response (p = 0.02). Hb level < 11 g/dL was associated with decreased PFS (p = 0.05) and OS (p = 0.08). Overexpression of IGF-1R beta was correlated with a decreased OS (p = 0.007). Overexpression of GLUT1 was marginally correlated with reduced OS (p = 0.05). PFS and OS were significantly improved in patients undergoing chemoradiation versus exclusive radiotherapy (PFS: p = 0.04; OS: p = 0.01). CONCLUSIONS: IGF-1R beta overexpression and Hb level (<=11 g/dl) were associated with poor prognosis, and thus appear to be possible interesting biomarkers of radiation resistance. Our results corroborate previous pre-clinical studies suggesting IGF-1R and hypoxia to be part of the biological pathways leading to radio-resistance. PMID- 28716108 TI - Esoteric Connective Tissue Therapy for chronic low back pain to reduce pain, and improve functionality and general well-being compared with physiotherapy: study protocol for a randomised controlled trial. AB - BACKGROUND: Low back pain causes more global disability than any other condition. Once the acute pain becomes chronic, about two-thirds of sufferers will not fully recover after 1-2 years. There is a paucity of effective treatments for non specific, chronic low back pain. It has been noted that low back pain is associated with changes in the connective tissue in the affected area, and a very low-impact treatment, Esoteric Connective Tissue Therapy (ECTT), has been developed to restore flexibility in connective tissue. ECTT uses patterns of very small, circular movements, to the legs, arms, spine, sacrum and head, which anecdotally are effective in pain relief. In an unpublished single-arm phase I/II trial with chronic pain patients, ECTT showed a 56% reduction in pain after five treatments and 45% and 54% improvements at 6 months and 7-9 years of follow-up respectively. METHODS: The aim of this randomised controlled trial is to compare ECTT with physiotherapy for reducing pain and improving physical function and physical and mental well-being in patients with chronic low back pain. The trial will be held at two hospitals in Vietnam. One hundred participants with chronic low back pain greater than or equal to 40/100 on the visual analogue scale will be recruited and randomised to either ECTT or physiotherapy. Four weekly treatments will be provided by two experienced ECTT practitioners (Treatment Group, 40 minutes each) and hospital-employed physiotherapy nurses (Control Group, 50 minutes). The primary outcomes will be changes in pain, physical function per the Quebec Pain Functionality Questionnaire and physical and mental well-being recorded by the Short Form Health Survey (SF-36), with mixed modelling used as the primary statistical tool because the data are longitudinal. Initial follow-up will be at either 4 or 8 months, with a second follow-up after 12 months. DISCUSSION: The trial design has important strengths, because it is to be conducted in hospitals under medical supervision, because ECTT is to be compared with a standard therapy and because the assessor and analyst are to be blinded. The findings from this trial will provide evidence of the efficacy of ECTT for chronic low back pain compared with standard physiotherapy treatment. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12616001196437 . Registered on 30 August 2016. PMID- 28716109 TI - Clinical characteristics and outcomes of Pseudomonas aeruginosa bacteremia in febrile neutropenic children and adolescents with the impact of antibiotic resistance: a retrospective study. AB - BACKGROUND: Although the proportion of Pseudomonas aeruginosa infections has reduced after the introduction of antibiotics with anti-pseudomonal effects, P. aeruginosa bacteremia still causes high mortality in immunocompromised patients. This study determined the clinical characteristics and outcomes of P. aeruginosa bacteremia and the antibiotic susceptibilities of strains isolated from febrile neutropenic patients. METHODS: Thirty-one febrile neutropenic children and adolescents with underlying hematologic/oncologic disorders diagnosed with P. aeruginosa bacteremia between 2011 and 2016 were enrolled in the study. Their medical records were retrospectively reviewed to evaluate the demographic and clinical characteristics. Antibiotic susceptibility rates of the isolated P. aeruginosa to eight antibiotic categories (anti-pseudomonal penicillin, anti pseudomonal penicillin and beta-lactamase inhibitor combination, anti-pseudomonal cephalosporin, monobactam, carbapenem, aminoglycoside, fluoroquinolone, and colistin) were also determined. Among the investigated factors, risk factors for mortality and infections by a multidrug-resistance (MDR) strain were determined. RESULTS: Thirty-six episodes of P. aeruginosa bacteremia were identified. The mean age of the enrolled patients was 9.5 +/- 5.4 years, and 26 (72.2%) episodes occurred in boys. Acute myeloid leukemia (41.7%) and acute lymphoblastic leukemia (33.3%) were the most common underlying disorders. The 30-day mortality was 38.9%, and 36.1% of the episodes were caused by MDR strains. The deceased patients were more likely to experience breakthrough infection (P = 0.036) and bacteremia (P = 0.005) due to MDR strains when compared with the patients who survived. The survived patients more likely received appropriate empirical antibiotic therapy (P = 0.024) and anti-pseudomonal beta-lactam and aminoglycoside combination therapy (P = 0.039) compared with the deceased patients. The antibiotic susceptibility rates of the isolated P. aeruginosa strains were as follows: piperacillin/tazobactam, 67.6%; meropenem, 72.2%; and amikacin, 100%. CONCLUSIONS: Mortality due to P. aeruginosa bacteremia remained at 38.9% in this study, and more than one-third of the isolated strains were MDR. In this context, empirical antibiotic combination therapy to expand the antibiotic spectrum may be a strategy to reduce mortality due to P. aeruginosa bacteremia in febrile neutropenic patients. PMID- 28716110 TI - Phylogenic analysis of human bocavirus detected in children with acute respiratory infection in Yaounde, Cameroon. AB - OBJECTIVE: Human Bocavirus (HBoV) was first identified in 2005 and has been shown to be a common cause of respiratory infections and gastroenteritis in children. In a recent study, we found that 10.7% of children with acute respiratory infections (ARI) were infected by HBoV. Genetic characterization of this virus remains unknown in Central Africa, particularly in Cameroon Leeding us to evaluate the molecular characteristics of HBoV strains in Cameroonian children with ARI. RESULTS: Phylogenetic analysis of partial HBoV VP1/2 sequences showed a low level of nucleotide variation and the circulation of HBoV genotype 1 (HBoV-1) only. Three clades were obtained, two clustering with each of the reference strains ST1 and ST2, and a third group consisting of only Cameroon strains. By comparing with the Swedish reference sequences, ST1 and ST2, Cameroon sequences showed nucleotide and amino acid similarities of respectively 97.36-100% and 98.35-100%. These results could help improve strategies for monitoring and control of respiratory infections in Cameroon. PMID- 28716111 TI - Quantitation of DNA methylation in Epstein-Barr virus-associated nasopharyngeal carcinoma by bisulfite amplicon sequencing. AB - BACKGROUND: Epigenetic changes, including DNA methylation, disrupt normal cell function, thus contributing to multiple steps of carcinogenesis. Nasopharyngeal carcinoma (NPC) is endemic in southern China and is highly associated with Epstein-Barr virus (EBV) infection. Significant changes of the host cell methylome are observed in EBV-associated NPC with cancer development. Epigenetic marks for NPC diagnosis are urgently needed. In order to explore DNA methylation marks, we investigated DNA methylation of candidate genes in EBV-associated nasopharyngeal carcinoma. METHODS: We first employed methyl-capture sequencing and cDNA microarrays to compare the genome-wide methylation profiles of seven NPC tissues and five non-cancer nasopharyngeal epithelium (NNE) tissues. We found 150 hypermethylated CpG islands spanning promoter regions and down-regulated genes. Furthermore, we quantified the methylation rates of seven candidate genes using bisulfite amplicon sequencing for nine NPC and nine NNE tissues. RESULTS: All seven candidate genes showed significantly higher methylation rates in NPC than in NNE tissues, and the ratios (NPC/NNE) were in descending order as follows: ITGA4 > RERG > ZNF671 > SHISA3 > ZNF549 > CR2 > RRAD. In particular, methylation levels of ITGA4, RERG, and ZNF671 could distinguish NPC patients from NNE subjects. CONCLUSIONS: We identified the DNA methylation rates of previously unidentified NPC candidate genes. The combination of genome-wide and targeted methylation profiling by next-generation sequencers should provide useful information regarding cancer-specific aberrant methylation. PMID- 28716112 TI - Psychosocial interventions for managing occupational stress and burnout among medical doctors: a systematic review. AB - BACKGROUND: Occupational stress and burnout are highly prevalent among medical doctors and can have adverse effects on patient, doctor, and organisational outcomes. The purpose of the current study was to review and evaluate evidence on psychosocial interventions aimed at reducing occupational stress and burnout among medical doctors. METHOD: A systematic review was conducted for original research articles reporting on psychosocial interventions targeting occupational stress or burnout among medical doctors, published in the English language, and with data collected at a minimum of two time points. Searches were conducted across five electronic databases, as well as by manual search of Google Scholar. Data was extracted relating to study characteristics and outcomes, quality and rigour, as well as modes of delivery and engagement. Studies were appraised using the Strength of Recommendation Taxonomy (SORT) and Critical Appraisal Skills Programme (CASP). RESULTS: Twenty-three articles were reviewed, which reported on interventions utilising cognitive-behavioural, relaxation, and supportive discussion strategies. Only 12 studies allowed estimation of pre- to post intervention effects. Cognitive behavioural interventions demonstrated the strongest evidence, particularly for reducing stress. Some evidence was identified to support the efficacy of relaxation-based approaches, but no such evidence was found for the efficacy of discussion-based interventions, such as Balint groups. There was a lack of quality among reviewed studies, with no studies receiving a quality rating of 1, and the overall body of evidence being rated as level B, according to the SORT. Effect sizes were not pooled due to a lack of quality among the study sample. CONCLUSION: This review found that despite increased scientific attention, the quality of research examining the benefits of psychosocial/behavioural interventions for occupational stress and burnout in medical doctors remains low. Despite this, interventions focused on cognitive and behavioural principles appear to show promise in reducing doctor stress and burnout. Limitations of the current review include a lack of risk of bias assessment or pooling of analyses. Recommendations for improving the quality of research in this area, as well as implications of the current body of evidence are discussed. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42016032595. PMID- 28716113 TI - Whole metagenome profiles of particulates collected from the International Space Station. AB - BACKGROUND: The built environment of the International Space Station (ISS) is a highly specialized space in terms of both physical characteristics and habitation requirements. It is unique with respect to conditions of microgravity, exposure to space radiation, and increased carbon dioxide concentrations. Additionally, astronauts inhabit a large proportion of this environment. The microbial composition of ISS particulates has been reported; however, its functional genomics, which are pertinent due to potential impact of its constituents on human health and operational mission success, are not yet characterized. METHODS: This study examined the whole metagenome of ISS microbes at both species- and gene-level resolution. Air filter and dust samples from the ISS were analyzed and compared to samples collected in a terrestrial cleanroom environment. Furthermore, metagenome mining was carried out to characterize dominant, virulent, and novel microorganisms. The whole genome sequences of select cultivable strains isolated from these samples were extracted from the metagenome and compared. RESULTS: Species-level composition in the ISS was found to be largely dominated by Corynebacterium ihumii GD7, with overall microbial diversity being lower in the ISS relative to the cleanroom samples. When examining detection of microbial genes relevant to human health such as antimicrobial resistance and virulence genes, it was found that a larger number of relevant gene categories were observed in the ISS relative to the cleanroom. Strain-level cross-sample comparisons were made for Corynebacterium, Bacillus, and Aspergillus showing possible distinctions in the dominant strain between samples. CONCLUSION: Species-level analyses demonstrated distinct differences between the ISS and cleanroom samples, indicating that the cleanroom population is not necessarily reflective of space habitation environments. The overall population of viable microorganisms and the functional diversity inherent to this unique closed environment are of critical interest with respect to future space habitation. Observations and studies such as these will be important to evaluating the conditions required for long-term health of human occupants in such environments. PMID- 28716114 TI - Visumax femtolasik versus Moria M2 microkeratome in mild to moderate myopia: efficacy, safety, predictability, aberrometric changes and flap thickness predictability. AB - INTRODUCTION: This is an interventional prospective clinical study which was conducted to evaluate the efficacy, safety, predictability, ocular aberrations, and flap thickness predictability of Visumax femtosecond laser (FSL) compared to Moria M2 microkeratome (MK) in mild to moderate myopia. METHODS: This study included 60 eyes who were divided into two groups. Thirty eyes in group (I) in which the flap was created with Visumax FSL, while in group II (30 eyes) the Moria M2 MK was used. Keratometric, refractive, and aberrometric measurements were compared preoperatively and 3 months postoperatively. The intraoperative subtraction pachymetry (the SP 100 Handy pachymeter (Tomey, Nagoya, Japan) was used for preoperative pachymetry and flap thickness measurement. RESULTS: No significant difference was found between the two groups in regards to postoperative manifest sphere, spherical equivalent, astigmatism, safety indices nor ocular aberrations. Twenty six eyes (86.6%) in group I and 23 eyes in group II (76.6%) were within +/-0.5D of the intended correction and 23 eyes (76.6%) in group I and 15 eyes in group II (50%) were within +/-0.25D of the intended correction. In group I, the mean postoperative actual flap thickness was 100.12 +/- 16.1 MUm (81 to 122 MUm), while in group II, it was 104.6 +/- 20.1 MUm (62 to 155 MUm). The difference was statistically significant (p = 0.001). CONCLUSIONS: Both Visumax and Moria M2 MK are safe and effective in treating myopia with no statistically significant difference in induction of ocular aberrations but with potential advantage for Visumax regarding predictability. More accurate flap thickness is achieved with Visumax femtolasik. TRIAL REGISTRATION: This study was retrospectively registered on 19/6/2017. Trial registration number NCT03193411 , clinicalTrials.gov . PMID- 28716115 TI - Resectable adenocarcinoma developing in the remnant pancreas 7 years after partial pancreatoduodenectomy for invasive ductal adenocarcinoma of the pancreas: a case report. AB - BACKGROUND: Pancreatic adenocarcinoma still has an excessively high mortality rate and resection is the only potentially curative treatment. The postoperative 5-year survival rate is approximately 20% and recurrence develops generally within 2 years. We report a case of a localized recurrent pancreatic adenocarcinoma in the remnant pancreas, 7 years after initial resection. CASE PRESENTATION: In 2008 an abdominal computed tomography scan showed a mass in the pancreas of a 70-year-old white woman, who presented with occlusive jaundice and abdominal pain in her right upper quadrant. A pancreatoduodenectomy was performed for a clinically suspected pancreatic adenocarcinoma. Histology confirmed a ductal adenocarcinoma. Afterwards, she received adjuvant chemotherapy with gemcitabine. In 2015 a follow-up positron emission tomography-computed tomography scan showed a single lesion in her remnant pancreas. Subsequently, a partial re resection was performed. Histology confirmed once again a ductal adenocarcinoma. She received adjuvant chemotherapy with gemcitabine again and is still alive almost 9 years after she had first been diagnosed as having pancreatic cancer. CONCLUSIONS: In selected cases re-resection for pancreatic recurrence is feasible and provides a survival benefit. In cases involving late recurrence, it is difficult to distinguish between true recurrence and the development of a new tumor. In order to detect recurrences at an early stage in long-term survivors, follow-up needs to occur on a regular and long-term basis. PMID- 28716116 TI - Catching and monitoring clinical innovation through performance indicators. The case of the breast-conserving surgery indicator. AB - BACKGROUND: The evolution in the surgical and diagnostic procedures, the attention to women's preferences, the case mix, and differences in professional practices may lead to a variability in the quality of breast cancer clinical pathway. To catch and manage this variability it is important to use valid measures. The aim of this paper is to examine the concurrent validity of the breast-conserving surgery (BCS) indicator and to provide evidence to guide the quality improvement process. METHODS: The BCS indicator was calculated using hospital discharge records (HDRs) and was validated against surgical registry (SR) data in a random sample of 336 women undergoing breast cancer surgery in 2012 in two Tuscan teaching hospitals. The concurrent validity of BCS was examined by cross-tabulating patients using the ICD-9 CM codes for breast surgery obtained from the two data sources. RESULTS: The analysis, carried out involving breast cancer professionals, highlighted that the large majority of interventions coded as "mastectomies" in HDRs are in fact reconstructing procedures, including nipple-sparing, skin-sparing and skin-reducing mastectomies in SR. These results led us to refine the old algorithm, that calculates the proportion of breast conserving surgery over the total number of breast interventions, and reclassify breast cancer surgical procedures into three categories: conservative, reconstructive and traditional mastectomy. Based on this new classification algorithm, the percentages of (I) reconstructive interventions were 16% at Florence TH and 38.3% at Pisa TH; (II) breast-conserving interventions were respectively 72.8 and 52.1%; and (III) mastectomies 11.2 and 9.6%. After adjusting for age in a logistic regression model, the percentages of reconstructive interventions at Florence and Pisa were respectively 22 and 34% and those of breast-conserving interventions 63 and 53%. CONCLUSIONS: Our results indicate that breast cancer care indicators should be refined by distinguishing reconstructive procedures (nipple/skin-sparing surgery with implant or breast tissue expander insertion) from traditional mastectomy. The involvement of breast care professionals in the choice of indicators proved to be crucial to capture the up-to-date breast cancer surgical practice and inform the quality improvement process. PMID- 28716117 TI - Stress Prevention@Work: a study protocol for the evaluation of a multifaceted integral stress prevention strategy to prevent employee stress in a healthcare organization: a cluster controlled trial. AB - BACKGROUND: Adequate implementation of work-related stress management interventions can reduce or prevent work-related stress and sick leave in organizations. We developed a multifaceted integral stress-prevention strategy for organizations from several sectors that includes a digital platform and collaborative learning network. The digital platform contains a stepwise protocol to implement work-related stress-management interventions. It includes stress screeners, interventions and intervention providers to facilitate access to and the selection of matching work-related stress-management interventions. The collaborative learning network, including stakeholders from various organizations, plans meetings focussing on an exchange of experiences and good practices among organizations for the implementation of stress prevention measures. This paper describes the design of an integral stress-prevention strategy, Stress Prevention@Work, and the protocol for the evaluation of: 1) the effects of the strategy on perceived stress and work-related outcomes, and 2) the barriers and facilitators for implementation of the strategy. METHODS: The effectiveness of Stress Prevention@Work will be evaluated in a cluster controlled trial, in a large healthcare organization in the Netherlands, at six and 12 months. An independent researcher will match teams on working conditions and size and allocate the teams to the intervention or control group. Teams in the intervention group will be offered Stress Prevention@Work. For each intervention team, one employee is responsible for applying the strategy within his/her team using the digital platform and visiting the collaborative learning network. Using a waiting list design, the control group will be given access to the strategy after 12 months. The primary outcome is the employees' perceived stress measured by the stress subscale of the Depression, Anxiety, and Stress Scale (DASS-21). Secondary outcome measures are job demands, job resources and the number of preventive stress measures implemented at the team level. Alongside the trial, a process evaluation, including barriers and facilitators of the implementation of Stress Prevention@Work, will be conducted in one healthcare organisation. DISCUSSION: If Stress Prevention@Work is found to be effective in one healthcare organisation, further implementation on a broader scale might lead to increased productivity and decreased stress and sick leave in other organizations. Results are expected in 2018. TRIAL REGISTRATION: NTR5527 . Registered 7 Dec 2015. PMID- 28716118 TI - Evolutionary and genetic analysis of the VP2 gene of canine parvovirus. AB - BACKGROUND: Canine parvovirus (CPV) type 2 emerged in 1978 in the USA and quickly spread among dog populations all over the world with high morbidity. Although CPV is a DNA virus, its genomic substitution rate is similar to some RNA viruses. Therefore, it is important to trace the evolution of CPV to monitor the appearance of mutations that might affect vaccine effectiveness. RESULTS: Our analysis shows that the VP2 genes of CPV isolated from 1979 to 2016 are divided into six groups: GI, GII, GIII, GIV, GV, and GVI. Amino acid mutation analysis revealed several undiscovered important mutation sites: F267Y, Y324I, and T440A. Of note, the evolutionary rate of the CPV VP2 gene from Asia and Europe decreased. Codon usage analysis showed that the VP2 gene of CPV exhibits high bias with an ENC ranging from 34.93 to 36.7. Furthermore, we demonstrate that natural selection plays a major role compared to mutation pressure driving CPV evolution. CONCLUSIONS: There are few studies on the codon usage of CPV. Here, we comprehensively studied the genetic evolution, codon usage pattern, and evolutionary characterization of the VP2 gene of CPV. The novel findings revealing the evolutionary process of CPV will greatly serve future CPV research. PMID- 28716120 TI - Advancing team-based primary health care: a comparative analysis of policies in western Canada. AB - BACKGROUND: We analyzed and compared primary health care (PHC) policies in British Columbia, Alberta and Saskatchewan to understand how they inform the design and implementation of team-based primary health care service delivery. The goal was to develop policy imperatives that can advance team-based PHC in Canada. METHODS: We conducted comparative case studies (n = 3). The policy analysis included: Context review: We reviewed relevant information (2007 to 2014) from databases and websites. Policy review and comparative analysis: We compared and contrasted publically available PHC policies. Key informant interviews: Key informants (n = 30) validated narratives prepared from the comparative analysis by offering contextual information on potential policy imperatives. Advisory group and roundtable: An expert advisory group guided this work and a key stakeholder roundtable event guided prioritization of policy imperatives. RESULTS: The concept of team-based PHC varies widely across and within the three provinces. We noted policy gaps related to team configuration, leadership, scope of practice, role clarity and financing of team-based care; few policies speak explicitly to monitoring and evaluation of team-based PHC. We prioritized four policy imperatives: (1) alignment of goals and policies at different system levels; (2) investment of resources for system change; (3) compensation models for all members of the team; and (4) accountability through collaborative practice metrics. CONCLUSIONS: Policies supporting team-based PHC have been slow to emerge, lacking a systematic and coordinated approach. Greater alignment with specific consideration of financing, reimbursement, implementation mechanisms and performance monitoring could accelerate systemic transformation by removing some well-known barriers to team-based care. PMID- 28716119 TI - STAT1-dependent and -independent pulmonary allergic and fibrogenic responses in mice after exposure to tangled versus rod-like multi-walled carbon nanotubes. AB - BACKGROUND: Pulmonary toxicity of multi-walled carbon nanotubes (MWCNTs) is influenced by physicochemical characteristics and genetic susceptibility. We hypothesized that contrasting rigidities of tangled (t) versus rod-like (r) MWCNTs would result in differing immunologic or fibrogenic responses in mice and that these responses would be exaggerated in transgenic mice lacking the signal transducer and activator of transcription-1 (STAT1), a susceptible mouse model of pulmonary fibrosis. METHODS: Male wild type (Stat1 +/+ ) and STAT1-deficient (Stat1 -/- ) mice were exposed to 4 mg/kg tMWCNTs, rMWCNTs, or vehicle alone via oropharyngeal aspiration and evaluated for inflammation at one and 21 days post exposure via histopathology, differential cell counts, and cytokine levels in bronchoalveolar lavage fluid (BALF). Granuloma formation, mucous cell metaplasia, and airway fibrosis were evaluated by quantitative morphometry. Airway epithelial cell proliferation was assessed by bromodeoxyuridine (BrdU) incorporation. Cytokine protein levels in BALF and serum IgE levels were measured by ELISA. Lung protein Smad2/3 levels and activation were measured by Western blot. Lung mRNAs were measured by PCR. RESULTS: There was a 7-fold difference in rigidity between tMWCNTs and rMWCNTs as determined by static bending ratio. Both MWCNT types resulted in acute inflammation (neutrophils in BALF) after one-day post-exposure, yet only rMWCNTs resulted in chronic inflammation at 21 days as indicated by neutrophil influx and larger granulomas. Both MWCNTs induced BrdU uptake in airway epithelial cells, with the greatest proliferative response observed in rMWCNT-exposed mice after one-day. Only rMWCNTs induced mucous cell metaplasia, but this index was not different between genotypes. Stat1 -/- mice had higher levels of baseline serum IgE than Stat1 +/+ mice. Greater airway fibrosis was observed with rMWCNTs compared to tMWCNTs, and exaggerated airway fibrosis was seen in the Stat1 -/- mouse lungs with rMWCNTs but not tMWCNTs. Increased fibrosis correlated with elevated levels of TGF-beta1 protein levels in the BALF of Stat1 -/- mice exposed to rMWCNTs and increased lung Smad2/3 phosphorylation. CONCLUSIONS: Rigidity plays a key role in the toxicity of MWCNTs and results in increased inflammatory, immunologic, and fibrogenic effects in the lung. STAT1 is an important protective factor in the fibroproliferative response to rMWCNTs, regulating both induced TGF-beta1 production and Smad2/3 phosphorylation status. Therefore, both rigidity and genetic susceptibility should be major considerations for risk assessment of MWCNTs. PMID- 28716121 TI - Identification of trunk mutations in gastric carcinoma: a case study. AB - BACKGROUND: Intratumor heterogeneity (ITH) poses an urgent challenge for cancer precision medicine because it can cause drug resistance against cancer target therapy and immunotherapy. The search for trunk mutations that are present in all cancer cells is therefore critical for each patient. CASE PRESENTATION: In this study, we aimed to evaluate the efficiency of multiregional sequencing for the identification of trunk mutations present in all regions of a tumor as a case study. We applied multiregional whole-exome sequencing (WES) to investigate the genetic heterogeneity and homogeneity of a case of gastric carcinoma. Approximately 83% of common missense mutations present in two samples and approximately 89% of common missense mutations present in three samples were trunk mutations. Notably, trunk mutations appeared to have higher variant allele frequencies (VAFs) than non-trunk mutations. CONCLUSIONS: Our results indicate that small-scale multiregional sampling and subsequent screening of low VAF somatic mutations might be a cost-effective strategy for identifying the majority of trunk mutations in gastric carcinoma. PMID- 28716122 TI - Systematic evaluation of oligodeoxynucleotide binding and hybridization to modified multi-walled carbon nanotubes. AB - BACKGROUND: In addition to conventional chemotherapeutics, nucleic acid-based therapeutics like antisense oligodeoxynucleotides (AS-ODN) represent a novel approach for the treatment of bladder cancer (BCa). An efficient delivery of AS ODN to the urothelium and then into cancer cells might be achieved by the local application of multi-walled carbon nanotubes (MWCNT). In the present study, pristine MWCNT and MWCNT functionalized with hydrophilic moieties were synthesized and then investigated regarding their physicochemical characteristics, dispersibility, biocompatibility, cellular uptake and mucoadhesive properties. Finally, their binding capacity for AS-ODN via hybridization to carrier strand oligodeoxynucleotides (CS-ODN), which were either non-covalently adsorbed or covalently bound to the different MWCNT types, was evaluated. RESULTS: Pristine MWCNT were successfully functionalized with hydrophilic moieties (MWCNT-OH, -COOH, -NH2, -SH), which led to an improved dispersibility and an enhanced dispersion stability. A viability assay revealed that MWCNT-OH, MWCNT-NH2 and MWCNT-SH were most biocompatible. All MWCNT were internalized by BCa cells, whereupon the highest uptake was observed for MWCNT-OH with 40% of the cells showing an engulfment. Furthermore, all types of MWCNT could adhere to the urothelium of explanted mouse bladders, but the amount of the covered urothelial area was with 2-7% rather low. As indicated by fluorescence measurements, it was possible to attach CS-ODN by adsorption and covalent binding to functionalized MWCNT. Adsorption of CS-ODN to pristine MWCNT, MWCNT-COOH and MWCNT-NH2 as well as covalent coupling to MWCNT-NH2 and MWCNT-SH resulted in the best binding capacity and stability. Subsequently, therapeutic AS-ODN could be hybridized to and reversibly released from the CS-ODN coupled via both strategies to the functionalized MWCNT. The release of AS-ODN at experimental conditions (80 degrees C, buffer) was most effective from CS-ODN adsorbed to MWCNT-OH and MWCNT NH2 as well as from CS-ODN covalently attached to MWCNT-COOH, MWCNT-NH2 and MWCNT SH. Furthermore, we could exemplarily demonstrate that AS-ODN could be released following hybridization to CS-ODN adsorbed to MWCNT-OH at physiological settings (37 degrees C, urine). CONCLUSIONS: In conclusion, functionalized MWCNT might be used as nanotransporters in antisense therapy for the local treatment of BCa. PMID- 28716123 TI - Differentiating mouse embryonic stem cells express markers of human endometrium. AB - BACKGROUND: Modeling early endometrial differentiation is a crucial step towards understanding the divergent pathways between normal and ectopic endometrial development as seen in endometriosis. METHODS: To investigate these pathways, mouse embryonic stem cells (mESCs) and embryoid bodies (EBs) were differentiated in standard EB medium (EBM). Immunofluorescence (IF) staining and reverse transcription polymerase chain reaction (RT-PCR) were used to detect expression of human endometrial cell markers on differentiating cells, which were sorted into distinct populations using fluorescence-activated cell sorting (FACS). RESULTS: A subpopulation (50%) of early differentiating mESCs expressed both glandular (CD9) and stromal (CD13) markers of human endometrium, suggestive of a novel endometrial precursor cell population. We further isolated a small population of endometrial mesenchymal stem cells, CD45-/CD146+/PDGFR-beta+, from differentiating EBs, representing 0.7% of total cells. Finally, quantitative PCR demonstrated significantly amplified expression of transcription factors Hoxa10 and Foxa2 in CD13+ EBs isolated by FACS (p = 0.03). CONCLUSIONS: These findings demonstrate that mESCs have the capacity to express human endometrial cell markers and demonstrate potential differentiation pathways of endometrial precursor and mesenchymal stem cells, providing an in vitro system to model early endometrial tissue development. This model represents a key step in elucidating the mechanisms of ectopic endometrial tissue growth. Such a system could enable the development of strategies to prevent endometriosis and identify approaches for non-invasive monitoring of disease progression. PMID- 28716124 TI - Implementing maternal death surveillance and response: a review of lessons from country case studies. AB - BACKGROUND: Maternal Death Surveillance and Response (MDSR) implementation is monitored globally, but not much is known about what works well, where and why in scaling up. We reviewed a series of country case studies in order to determine whether and to what extent these countries have implemented the four essential components of MDSR and identify lessons for improving implementation. METHODS: A secondary analysis of ten case studies from countries at different stages of MDSR implementation, using a policy analysis framework to draw out lessons learnt and opportunities for improvement. We identify the consistent drivers of success in countries with well-established systems for MDSR, and common barriers in countries were Maternal Death Review (MDR) systems have been less successful. RESULTS: MDR is accepted and ongoing at subnational level in many countries, but it is not adequately institutionalised and the shift from facility based MDR to continuous MDSR that informs the wider health system still needs to be made. Our secondary analysis of country experiences highlights the need for a) social and team processes at facility level, for example the existence of a 'no shame, no blame' culture, and the ability to reflect on practice and manage change as a team for recommendations to be acted upon, b) health system inputs including adequate funding and reliable health information systems to enable identification and analysis of cases c) national level coordination of dissemination, and monitoring implementation of recommendations at all levels and d) mandatory notification of maternal deaths (and enforcement of this) and a professional requirement to participate in MDRs. CONCLUSIONS: Case studies from countries with established MDSR systems can provide valuable guidance on ways to set up the processes and overcome some of the barriers; but the challenge, as with many health system interventions, is to find a way to provide catalytic assistance and strengthen capacity for MDSR such that this becomes embedded in the health system. PMID- 28716125 TI - Mercury alters endogenous phosphorylation profiles of SYK in murine B cells. AB - BACKGROUND: Epidemiological evidence and animal models suggest that exposure to low and non-neurotoxic concentrations of mercury may contribute to idiosyncratic autoimmune disease. Since defects in function and signaling in B cells are often associated with autoimmunity, we investigated whether mercury exposure might alter B cell responsiveness to self-antigens by interfering with B cell receptor (BCR) signal transduction. In this study we determined the effects of mercury on the protein tyrosine kinase SYK, a critical protein involved in regulation of the BCR signaling pathway. METHODS: Phosphorylation sites of murine SYK were mapped before and after treatment of WEHI cell cultures with mercury, or with anti-IgM antibody (positive control) or pervanadate (a potent phosphatase inhibitor). Phosphopeptides were enriched by either titanium dioxide chromatography or anti phosphotyrosine immunoaffinity, and analyzed by liquid chromatography-mass spectrometry. Select SYK phosphosite cluster regions were profiled for responsiveness to treatments using multiple reaction monitoring (MRM) methodology. RESULTS: A total of 23 phosphosites were identified with high probability in endogenous SYK, including 19 tyrosine and 4 serine residues. For 10 of these sites phosphorylation levels were increased following BCR activation. Using MRM to profile changes in phosphorylation status we found that 4 cluster regions, encompassing 8 phosphosites, were activated by mercury and differentially responsive to all 3 treatments. Phosphorylation of tyrosine-342 and -346 residues were most sensitive to mercury exposure. This cluster is known to propagate normal BCR signal transduction by recruiting adaptor proteins such as PLC-gamma and Vav-1 to SYK during formation of the BCR signalosome. CONCLUSIONS: Our data shows that mercury alters the phosphorylation status of SYK on tyrosine sites known to have a role in promoting BCR signals. Considering the importance of SYK in the BCR signaling pathway, these data suggest that mercury can alter BCR signaling in B cells, which might affect B cell responsiveness to self-antigen and have implications with respect to autoimmunity and autoimmune disease. PMID- 28716127 TI - Influence of tumor extent on central lymph node metastasis in solitary papillary thyroid microcarcinomas: a retrospective study of 1092 patients. AB - BACKGROUND: The morbidity of papillary thyroid microcarcinomas is increasing worldwide. Surgery is the main treatment for papillary thyroid microcarcinomas, and the choice of surgical method partly depends on the T stage of the tumor. However, according to the American Joint Commission on Cancer staging system (7th edition), the T stage of papillary thyroid microcarcinomas with different tumor extent is unclear. We aimed to study the effect of tumor extent and other factors on central lymph node metastasis to explore the relationship between tumor extent and T stage and to identify the risk factors predicting central lymph node metastasis in papillary thyroid microcarcinomas. METHODS: We included 1092 patients diagnosed with solitary papillary thyroid microcarcinomas between July 2011 and April 2016. The tumor extent and other central lymph node metastasis risk factors were retrospectively analyzed. RESULTS: Univariate analysis revealed that capsule invasion and extracapsular extension (P = 0.013, <0.001; respectively) were significantly correlated with central lymph node metastasis. On multivariate analysis, extracapsular extension was independent central lymph node metastasis predictors (odds ratio 3.092, 95% CI 1.744-5.484), while capsule invasion was not (odds ratio 1.212, 95% CI 0.890-1.651). In addition, multivariate analysis revealed that male sex, tumor size >5 mm, and age <45 years were independent central lymph node metastasis predictors (odds ratio 2.072, 2.356, 2.302; 95% CI 1.483-2.894, 1.792-3.099, 1.748-3.031; respectively). CONCLUSIONS: This study supported that capsule invasion and tumor limited to the thyroid in papillary thyroid microcarcinomas were suitable for the lower T1, that is, capsule invasion in papillary thyroid microcarcinomas might not belong to the minimal extrathyroid extension included in T3 of TNM staging. In addition, patients with risk factors of extrathyroid extension, male sex, age <45 years, or tumor size >5 mm in papillary thyroid microcarcinomas should consider a more aggressive surgical treatment. PMID- 28716126 TI - The effects of potato virus Y-derived virus small interfering RNAs of three biologically distinct strains on potato (Solanum tuberosum) transcriptome. AB - BACKGROUND: Potato virus Y (PVY) is one of the most economically important pathogen of potato that is present as biologically distinct strains. The virus derived small interfering RNAs (vsiRNAs) from potato cv. Russet Burbank individually infected with PVY-N, PVY-NTN and PVY-O strains were recently characterized. Plant defense RNA-silencing mechanisms deployed against viruses produce vsiRNAs to degrade homologous viral transcripts. Based on sequence complementarity, the vsiRNAs can potentially degrade host RNA transcripts raising the prospect of vsiRNAs as pathogenicity determinants in virus-host interactions. This study investigated the global effects of PVY vsiRNAs on the host potato transcriptome. METHODS: The strain-specific vsiRNAs of PVY, expressed in high copy number, were analyzed in silico for their proclivity to target potato coding and non-coding RNAs using psRobot and psRNATarget algorithms. Functional annotation of target coding transcripts was carried out to predict physiological effects of the vsiRNAs on the potato cv. Russet Burbank. The downregulation of selected target coding transcripts was further validated using qRT-PCR. RESULTS: The vsiRNAs derived from biologically distinct strains of PVY displayed diversity in terms of absolute number, copy number and hotspots for siRNAs on their respective genomes. The vsiRNAs populations were derived with a high frequency from 6 K1, P1 and Hc-Pro for PVY-N, P1, Hc-Pro and P3 for PVY-NTN, and P1, 3' UTR and NIa for PVY-O genomic regions. The number of vsiRNAs that displayed interaction with potato coding transcripts and number of putative coding target transcripts were comparable between PVY-N and PVY-O, and were relatively higher for PVY-NTN. The most abundant target non-coding RNA transcripts for the strain specific PVY-derived vsiRNAs were found to be MIR821, 28S rRNA,18S rRNA, snoR71, tRNA-Met and U5. Functional annotation and qRT-PCR validation suggested that the vsiRNAs target genes involved in plant hormone signaling, genetic information processing, plant-pathogen interactions, plant defense and stress response processes in potato. CONCLUSIONS: The findings suggested that the PVY-derived vsiRNAs could act as a pathogenicity determinant and as a counter-defense strategy to host RNA silencing in PVY-potato interactions. The broad range of host genes targeted by PVY vsiRNAs in infected potato suggests a diverse role for vsiRNAs that includes suppression of host stress responses and developmental processes. The interactome scenario is the first report on the interaction between one of the most important Potyvirus genome-derived siRNAs and the potato transcripts. PMID- 28716128 TI - Tobacco dependence among people with mental illness: a facility-based cross sectional study from Southwest Ethiopia. AB - BACKGROUND: Tobacco smoking is a health care issue in developed as well as in developing countries. Tobacco smoking among people with mental illness is significantly higher than in the general population. Tobacco smoking has negative effects on physical, mental and financial well-being of people with mental illness but little is known about tobacco dependence among mental health service users in sub-Saharan African countries, including Ethiopia. Therefore, this study attempted to assess the prevalence of tobacco dependence and associated factors among mental health service users at Jimma University teaching hospital. METHODS: A cross-sectional study was conducted among 305 male and 117 female mental health service users at Jimma University teaching Hospital in 2014. The Fagerstrom Test for Nicotine Dependence (FTND) was used to assess tobacco dependence. Logistic regression analysis was used for bivariate and multivariate analysis. Variables with a P value of <0.05 were considered to be associated with tobacco dependence in the final model. RESULTS: The prevalence of current tobacco dependence among the study participants was 18.5%. Amongst people with tobacco dependence, 57.7, 29.5 and 12.8% had moderate, high and very high level of tobacco dependence respectively. All mental health service users with tobacco dependence were males. There was a significant association between tobacco dependence and high school education (AOR 3.02, 95% CI 1.07, 8. 48), alcohol use disorder (AOR 4.14, 95% CI = 1.54, 11.11), daily khat chewing (AOR 13.51, 95% CI = 4.27, 42.74), chewing khat 2-3 times per week (AOR 5.09, 95% CI = 1.37,18.95), chewing khat once a week (AOR 4.31, 95%CI = 1.04,17.78), having friends who smoke tobacco (AOR 4.88, 95% CI = 2.12, 11.25) and being diagnosed with schizophrenia compared to a diagnosis of major depression (AOR 5.26, 95% CI = 2.07, 13.37). However, daily attendance at a place of worship (AOR 0.46, 95% CI = 0.22, 0.95) was associated negatively with tobacco dependence. CONCLUSION: In this study, there was a high prevalence of tobacco dependence among mental health services users. There is a pressing need to increase availability of psychological and pharmacological interventions to reduce tobacco dependence and tobacco-related medical illness in this vulnerable group. PMID- 28716129 TI - Current knowledge on feline injection-site sarcoma treatment. AB - Feline injection-site sarcomas (FISS) are malignant skin tumours of mesenchymal origin, the treatment of which is a challenge for veterinary surgeons. The role of surgery, radiotherapy and chemotherapy in FISS treatment has been studied, and a correlation between "clean" surgical margins and disease-free survival has been shown. In addition, clean surgical margins are one of the most important factors for achieving a low recurrence rate. The most effective method of FISS treatment includes combining radical surgery with pre- or postoperative radiotherapy. Chemotherapy may be used as a palliative method of treatment or may be considered an adjunctive therapy for surgery and radiotherapy. In cats with FISS without metastasis, the use of immunostimulant treatment with Oncept IL-2, intended as a complementary immunotherapy in association with surgery and brachytherapy, may also be considered to reduce the risk of relapse and increase the time to relapse. Additionally, this review focuses on recent advances in FISS treatment, including the use of novel compounds, such as doxorubicin conjugated to glutathione-stabilized gold nanoparticles, liposomal doxorubicin or tyrosine kinase inhibitors. PMID- 28716130 TI - Psychometric properties and relations with coping and family strain of the Health Services and Caregiver Experience questionnaire (HSCE): an outcome measure of informal caregivers' experience for inpatient care in Italy. AB - BACKGROUND: In the last decade, the number of patients supported by informal caregivers has substantially increased. In the Italian healthcare context, informal caregivers' experience of care is a new under-recognized construct, and no assessment tool is available. Measuring caregivers' experience is important since in Italy the relationship between doctors and patients/relatives is still considered asymmetrical. The current study presented development and initial psychometric properties of the Health Services and Caregiver Experience questionnaire (HSCE), a self-report tool of caregivers' global experience for inpatient clinical care, including factor structure, reliability and its relations with measures of coping strategies and family strain. METHODS: The HSCE was administered to a total of 503 informal caregivers of inpatients admitted at an Italian University Hospital (mean age = 48.08 years, SD = 14.82, females = 61.40%). Family Strain Questionnaire-Short Form (FSQ-SF) and Coping Orientations to Problems Experience-New Italian Version (COPE-NVI) were administered to a subgroup of participants. First-grade relatives were 73.10%, whereas 13.20% were second-grade relatives and 13.70% were home-watch caregivers. RESULTS: Exploratory and confirmatory factor analyses showed a structure with a single factor, which explained 64.80% of the total variance. All the items had salient loadings. In the two subsamples, HSCE had excellent internal consistency (Cronbach's alpha = 0.95-0.97). Positive moderate correlations were found between HSCE and FSQ-SF scores (r = 0.45, p < .05), between HSCE and COPE-NVI scale scores, including COPE-NVI positive attitude and COPE-NVI problem solving scores (rs' range = 0.51-0.57, p < .05). Moreover, a positive large correlation between HSCE and COPE-NVI social support scores emerged (r = 0.72, p < .05). Correlations were not significant between HSCE scores and COPE-NVI turning to religion and avoidance strategies. CONCLUSIONS: The HSCE resulted to have good psychometric properties. Better caregivers' experience correlated with stronger family strain but also with better problem solving and social support. The study expanded knowledge on caregiver's experience in Italy and indicated that HSCE is a valid and reliable tool to measure this under-recognized construct in Italy. PMID- 28716131 TI - Rhabdomyolysis in an HIV cohort: epidemiology, causes and outcomes. AB - BACKGROUND: The Literature on rhabdomyolysis in the HIV-positive population is sparse and limited. We aimed to explore the incidence, patient characteristics, etiologies and outcomes of rhabdomyolysis in a cohort of HIV-positive patients identified through the Johns Hopkins HIV clinical registry between June 1992 and April 2014. METHODS: A retrospective analysis of 362 HIV-positive patients with non-cardiac CK elevation >=1000 IU/L was performed. Both inpatients and outpatients were included. Incidence rate and potential etiologies for rhabdomyolysis were ascertained. The development of acute kidney injury (AKI, defined as doubling of serum creatinine), need for dialysis, and death in the setting of rhabdomyolysis were determined. Logistic regression was used to evaluate the association of peak CK level with the development of AKI. RESULTS: Three hundred sixty two cases of rhabdomyolysis were identified in a cohort of 7079 patients with a 38,382 person years follow-up time. The incidence rate was nine cases per 1000 person-years (95% CI: 8.5-10.5). Infection was the most common etiology followed by compression injury and drug/alcohol use. One-third of cases had multiple potential etiologies. AKI developed in 46% of cases; 20% of which required dialysis. Thirteen percent died during follow-up. After adjustment, AKI was associated with higher CK (OR 2.05 for each 1-log increase in CK [95% CI: 1.40-2.99]), infection (OR 5.48 [95% CI 2.65-11.31]) and higher HIV viral load (OR 1.22 per 1-log increase [95% CI: 1.03-1.45]). CONCLUSION: Rhabdomyolysis in the HIV-positive population has many possible causes and is frequently multifactorial. HIV-positive individuals with rhabdomyolysis have a high risk of AKI and mortality. PMID- 28716132 TI - A patient-safety and professional perspective on non-conveyance in ambulance care: a systematic review. AB - BACKGROUND: This systematic review aimed to describe non-conveyance in ambulance care from patient-safety and ambulance professional perspectives. The review specifically focussed at describing (1) ambulance non-conveyance rates, (2) characteristics of non-conveyed patients, (3) follow-up care after non conveyance, (4) existing guidelines or protocols, and (5) influencing factors during the non-conveyance decision making process. METHODS: We systematically searched MEDLINE, PubMed, CINAHL, EMBASE, and reference lists of included articles, in June 2016. We included all types of peer-reviewed designs on the five topics. Couples of two independent reviewers performed the selection process, the quality assessment, and data extraction. RESULTS: We included 67 studies with low to moderate quality. Non-conveyance rates for general patient populations ranged from 3.7%-93.7%. Non-conveyed patients have a variety of initial complaints, common initial complaints are related to trauma and neurology. Furthermore, vulnerable patients groups as children and elderly are more represented in the non-conveyance population. Within 24 h-48 h after non conveyance, 2.5%-6.1% of the patients have EMS representations, and 4.6-19.0% present themselves at the ED. Mortality rates vary from 0.2%-3.5% after 24 h, up to 0.3%-6.1% after 72 h. Criteria to guide non-conveyance decisions are vital signs, ingestion of drugs/alcohol, and level of consciousness. A limited amount of non-conveyance guidelines or protocols is available for general and specific patient populations. Factors influencing the non-conveyance decision are related to the professional (competencies, experience, intuition), the patient (health status, refusal, wishes and best interest), the healthcare system (access to general practitioner/other healthcare facilities/patient information), and supportive tools (online medical control, high risk card). CONCLUSIONS: Non conveyance rates for general and specific patient populations vary. Patients in the non-conveyance population present themselves with a variety of initial complaints and conditions, common initial complaints or conditions are related to trauma and neurology. After non-conveyance, a proportion of patients re-enters the emergency healthcare system within 2 days. For ambulance professionals the non-conveyance decision-making process is complex and multifactorial. Competencies needed to perform non-conveyance are marginally described, and there is a limited amount of supportive tools is available for general and specific non conveyance populations. This may compromise patient-safety. PMID- 28716133 TI - 'To be able to support her, I must feel calm and safe': pregnant women's partners perceptions of professional support during pregnancy. AB - BACKGROUND: Professional support does not always meet the needs of expectant fathers or co-mothers. The way in which professional support is offered during pregnancy varies internationally, depending on the country. In order to attain a greater understanding of partners' experiences of professional support, it is necessary to further illuminate their perceptions of it. The aim of this study was therefore to explore pregnant women's partners' perceptions of professional support during pregnancy. METHODS: Qualitative research design. Partners of pregnant women were interviewed during gestational week 36-38. Individual semi structured interviews were used to explore the partners' perceptions. The data was analysed using a phenomenographic approach. The study was performed in a county in south-western Sweden; the data collection was conducted from November 2014 to February 2015. Fourteen partners (expectant fathers and co-mothers) of women who were expectant first-time mothers with singleton pregnancies, were interviewed. RESULTS: The findings of the study are presented through four descriptive categories: Ability to absorb adequate information; Possibility to meet and share with other expectant parents; Confirmation of the partner's importance; and Influence on the couple relationship. Using a theoretical assumption of the relationship between the categories showed that the fourth category was influenced by the other three categories. CONCLUSIONS: The partners perceived that professional support during pregnancy could influence the couple relationship. The partners' ability to communicate and to experience togetherness with the women increased when the expectant couple received professional support together. The support created also possibilities to meet and share experiences with other expectant parents. In contrast, a lack of support was found to contribute to partners' feelings of unimportance. It was essential that the midwives included the partners by confirming that they were individuals who had different needs for various types of professional support. The partners perceived it easier to absorb information when it was adequate and given with a pedagogic that made the partners become interested and emotionally engaged. PMID- 28716134 TI - Detecting protein variants by mass spectrometry: a comprehensive study in cancer cell-lines. AB - BACKGROUND: Onco-proteogenomics aims to understand how changes in a cancer's genome influences its proteome. One challenge in integrating these molecular data is the identification of aberrant protein products from mass-spectrometry (MS) datasets, as traditional proteomic analyses only identify proteins from a reference sequence database. METHODS: We established proteomic workflows to detect peptide variants within MS datasets. We used a combination of publicly available population variants (dbSNP and UniProt) and somatic variations in cancer (COSMIC) along with sample-specific genomic and transcriptomic data to examine proteome variation within and across 59 cancer cell-lines. RESULTS: We developed a set of recommendations for the detection of variants using three search algorithms, a split target-decoy approach for FDR estimation, and multiple post-search filters. We examined 7.3 million unique variant tryptic peptides not found within any reference proteome and identified 4771 mutations corresponding to somatic and germline deviations from reference proteomes in 2200 genes among the NCI60 cell-line proteomes. CONCLUSIONS: We discuss in detail the technical and computational challenges in identifying variant peptides by MS and show that uncovering these variants allows the identification of druggable mutations within important cancer genes. PMID- 28716135 TI - Assessing the link between implementation fidelity and health outcomes for a trial of intensive case management by community health workers: a mixed methods study protocol. AB - BACKGROUND: Better systems of care are required to address chronic disease in Indigenous people to ensure they can access all their care needs. Health research has produced evidence about effective models of care and chronic disease strategies to address Indigenous health, however the transfer of research findings into routine clinical practice has proven challenging. Complex interventions, such as those related to chronic disease, have many components that are often poorly implemented and hence rarely achieve implementation fidelity. Implementation fidelity is "the degree to which programs are implemented as intended by the program developer". Knowing if an intervention was implemented as planned is fundamental to knowing what has contributed to the success of an intervention. METHODS: The aim of this study is to adapt the implementation fidelity framework developed by Keith et al. and apply it to the intervention implemented in phase 1 of the Getting Better at Chronic Care in North Queensland study. The objectives are to quantify the level of implementation fidelity achieved during phase 1 of the study, measure the association between implementation fidelity and health outcomes and to explore the features of the primary health care system that contributed to improved health outcomes. A convergent parallel mixed methods study design will be used to develop a process for assessing implementation fidelity. Information collected via a questionnaire and routine data generated during phase 1 of the study will be used to explain the context for the intervention in each site and develop an implementation fidelity score for each component of the intervention. A weighting will be applied to each component of the intervention to calculate the overall implementation score for each participating community. Statistical analysis will assess the level of association between implementation fidelity scores and health outcomes. DISCUSSION: Health services research seeks to find solutions to social and technical problems to improve health outcomes. The development of a tool and methodology for assessing implementation fidelity in the Indigenous primary health care context will help address some of the barriers to the translation of research into practice. TRIAL REGISTRATION: ACTRN12610000812099 : 29.9.2010. PMID- 28716136 TI - Up-regulation of CDK16 by multiple mechanisms in hepatocellular carcinoma promotes tumor progression. AB - BACKGROUND: Hepatocellular carcinoma (HCC) remains difficult to cure due to lack of effective treatment and the molecular mechanisms are complex and not completely understood. In this study, We investigated the role of CDK16 in tumor progression of HCC. METHODS: We interrogated the expression level of CDK16 by polymerase chain reaction and immunohistochemistry(IHC) and studied its clinical significance. The functional role of CDK16 on HCC was studied via gain and loss of function in vitro and in vivo. Luciferase reporter assay and Chromatin immunoprecipitation(ChIP) assay were performed to investigate the transcriptional and post-transcriptional mechanisms involved in the regulation of CDK16. RESULTS: CDK16 expression was significantly up-regulated in HCC and higher expression of CDK16 was positively correlated with aggressive clinicopathological phenotype and poorer survival rates. Functionally, knockdown of CDK16 suppressed proliferation in vitro and in vivo. Inactivation of CDK16 also induced apoptosis and cell cycle arrest. Most importantly, CDK16 promoted epithelial mesenchymal transition and tumor invasion by activating beta-catenin signaling. In addition, We identified E2F1 as a positive transcriptional regulator of CDK16. Moreover, down regulation of miR-125b-5p enhanced CDK16 expression at post-transcriptional level. CONCLUSION: We provided the first evidence that CDK16 is an bona fide oncogene in HCC, and multiple activating mechanisms at transcriptional and posttranscriptional levels together contributes to CDK16 up-regulation in HCC. PMID- 28716137 TI - Progressive hypoventilation due to mixed CD8+ and CD4+ lymphocytic polymyositis following tremelimumab - durvalumab treatment. AB - BACKGROUND: The combination of CTLA-4 and PD-L1 inhibitors has a manageable adverse effect profile, although rare immune-related adverse events (irAE) can occur. CASE PRESENTATION: We describe an autoimmune polymyositis following a partial response to combination tremelimumab and durvalumab for the treatment of recurrent lung adenocarcinoma. Radiography revealed significant reduction in all metastases; however, the patient developed progressive neuromuscular hypoventilation due to lymphocytic destruction of the diaphragmatic musculature. Serologic testing revealed a low level of de novo circulating antibodies against striated muscle fiber. Immunohistochemistry revealed type II muscle fiber atrophy with a mixed CD8+ and CD4+ lymphocyte infiltrate, indicative of inflammatory myopathy. CONCLUSIONS: This case supports the hypothesis that muscle tissue is a target for lymphocytic infiltration in immune checkpoint inhibitor-associated polymyositis. Further insights into the autoimmune mechanism of PM will hopefully contribute to the prevention and treatment of this phenomenon. PMID- 28716138 TI - Prevalence of enteric infections among hospitalized patients in two referral hospitals in Ghana. AB - BACKGROUND: Diarrhea is an important cause of morbidity and mortality worldwide. In Africa and Ghana in particular, it is estimated to contribute directly to 19 and 25% of pediatric mortality among children under 5 years, respectively. METHODS: Surveillance for hospitalized acute diarrheal illness was initiated in November 2010 through October 2012 in a referral hospital in southern Ghana, and a teaching hospital in northern Ghana. Consenting hospitalized patients who met a standardized case definition for acute diarrheal illness provided demographic and epidemiologic data. Stool samples were collected and tested by culture for bacteria and by enzyme immunoassays for a panel of viruses and parasites. RESULTS: A total of 429 patients were enrolled; 216 (50.3%) were under 5 years, and 221 (51.5%) were females. Stool samples were received from 153 patients. Culture isolates included Shigella sp., Salmonella spp., Plesiomonas sp. and Vibrio cholerae. Of 147 samples tested for viruses, 41 (27.9%) were positive for rotaviruses, 11 (7.5%) for astroviruses, 10 (6.8%) for noroviruses, and 8 (5.4%) for adenoviruses. Of 116 samples tested for parasitic infections; 4 (3.4%) were positive for Cryptosporidium sp. and 3 (2.6%) for Giardia lamblia. Of the enrolled patients, 78.8% had taken antibiotics prior to sample collection. CONCLUSIONS: Diarrheal pathogens were identified across all ages, however, predominantly (81%) in the children under 5 years of age. This study also detected high antibiotic use which has the potential of increasing antibiotic resistance. The most common enteric pathogen detected (49.4%) was rotavirus. PMID- 28716139 TI - Elevated C-reactive protein, interleukin 6, tumor necrosis factor alpha and glycemic load associated with type 2 diabetes mellitus in rural Thais: a cross sectional study. AB - BACKGROUND: The elevated levels of inflammatory markers, including C-reactive protein (CRP), tumor necrosis factor alpha (TNF-alpha), and interleukin 6 (IL6) are supposed to be associated with type 2 diabetes mellitus (T2DM). Frequent high glycemic load (GL) consumption, central obesity, and a lack of physical activity are considered to be T2DM risk factors. This study aimed to determine the difference of these inflammatory markers as well as GL in individuals with versus those without T2DM in rural Thais. METHODS: A total of 296 participants aged 35 66 living in Sung Noen District, Nakhon Ratchasima Province, Thailand, were recruited. Blood was collected to evaluate blood glucose levels, lipid profiles, and inflammatory markers. A Semi-food frequency questionnaire was utilized to assess GL followed by socioeconomic and anthropometric assessment. Statistical analysis was subsequently performed. RESULTS: Elevated CRP and IL6 levels were associated with increased risk of developing T2DM [OR (95% CI): 7.51 (2.11, 26.74) and 4.95 (1.28, 19.11)], respectively. There was a trend towards increased risk of T2DM with elevated TNF-alpha levels [OR (95% CI): 1.56 (0.39, 6.14)]. GL correlated significantly with fasting blood glucose (r = 0.289, P = 0.016), suggesting that it is involved in T2DM in this study group. CONCLUSION: In this study, CRP, IL6, and TNF-alpha associated with T2DM. Our findings suggested that these inflammatory markers, especially CRP, may initiate T2DM. PMID- 28716140 TI - Modelling infectious diseases with relapse: a case study of HSV-2. AB - BACKGROUND: Herpes Simplex Virus Type 2 (HSV-2) is one of the most common sexually transmitted diseases. Although there is still no licensed vaccine for HSV-2, a theoretical investigation of the potential effects of a vaccine is considered important and has recently been conducted by several researchers. Although compartmental mathematical models were considered for each special case in the previous studies, as yet there are few global stability results. RESULTS: In this paper, we formulate a multi-group SVIRI epidemic model for HSV-2, which enables us to consider the effects of vaccination, of waning vaccine immunity, and of infection relapse. Since the number of groups is arbitrary, our model can be applied to various structures such as risk, sex, and age group structures. For our model, we define the basic reproduction number R0 and prove that if R0<=1, then the disease-free equilibrium is globally asymptotically stable, whereas if R0>1, then the endemic equilibrium is so. Based on this global stability result, we estimate R0 for HSV-2 by applying our model to the risk group structure and using US data from 2001 to 2014. Through sensitivity analysis, we find that R0 is approximately in the range of 2-3. Moreover, using the estimated parameters, we discuss the optimal vaccination strategy for the eradication of HSV-2. CONCLUSIONS: Through discussion of the optimal vaccination strategy, we come to the following conclusions. (1) Improving vaccine efficacy is more effective than increasing the number of vaccines. (2) Although the transmission risk in female individuals is higher than that in male individuals, distributing the available vaccines almost equally between female and male individuals is more effective than concentrating them within the female population. PMID- 28716141 TI - The German day-care study: multicomponent non-drug therapy for people with cognitive impairment in day-care centres supplemented with caregiver counselling (DeTaMAKS) - study protocol of a cluster-randomised controlled trial. AB - BACKGROUND: It is the wish of both people with cognitive impairment and their informal caregivers for the impaired person to live at home for as long as possible. This is also in line with economic arguments about health. The existing structure of day-care services for the elderly can be used to achieve this. Due to the current lack of empirical evidence in this field, most day-care centres do not offer a scientifically evaluated, structured intervention, but instead offer a mixture of individual activities whose efficacy has not yet been established. Informal caregivers of people with dementia use day-care centres primarily to relieve themselves of their care tasks and as a support service. METHODS/DESIGN: The present study therefore investigates the effectiveness of a combination of a multicomponent activation therapy for people with mild cognitive impairment (MCI) or mild to moderate dementia at day-care centres and a brief telephone intervention for their informal caregivers. The study is conducted as a cluster randomised intervention trial at 34 day-care centres in Germany with a 6-month treatment phase. The centres in the waitlist control group provide "care as usual". A power analysis indicated that 346 people should initially be included in the study. The primary endpoints of the study include the ability to perform activities of daily living (ADL) and cognitive capacities on the side of the day care centre users and the subjectively perceived burden and well-being of the informal caregivers. The total duration of the study is 3 years, during which data are collected both by the psychometric testing of the people with cognitive impairment and by telephone interviews with informal caregivers. DISCUSSION: The project has three distinctive quality features. First, it is embedded in real care situations since the day-care services have already been established for this target group. Second, due to the large number of cases and the fact that the participating day-care centres are spread across the entire country, the results can be expected to be generalisable. Third, the interventions can be assumed to be implementable as they required only a one-day training event for the staff already working at the centres. TRIAL REGISTRATION: ISRCTN16412551 (Registration date: 30 July 2014, registered retrospectively). PMID- 28716142 TI - Prevalence of and factors associated with burnout among health care professionals in Arab countries: a systematic review. AB - BACKGROUND: Burnout among healthcare professionals is one of the key challenges affecting health care practice and quality of care. This systematic review aims to (1) estimate the prevalence of burnout among health care professionals (HCP) in Arab countries; and (2) explore individual and work-related factors associated with burnout in this population. METHODS: Multiple electronic databases were searched for studies published in English or Arabic from January 1980 to November 2014 assessing burnout (using the Maslach Burnout Inventory; MBI) amongst health care professionals (HCP) in Arab countries. RESULTS: Nineteen studies (N = 4108; 49.3% females) conducted on HCP in Bahrain, Egypt, Jordan, Lebanon, Palestine, Saudi Arabia and Yemen were included in this review. There was a wide range of prevalence estimates for the three MBI subscales, high Emotional Exhaustion (20.0 81.0%), high Depersonalization (9.2-80.0%), and low Personal Accomplishment (13.3 85.8%). Gender, nationality, service duration, working hours, and shift patterns were all significantly associated with burnout. CONCLUSIONS: Within the constraints of the study and the range of quality papers available, our review revealed moderate-to-high estimates of self-reported burnout among HCP in Arab countries that are similar to prevalence estimates in non-Arabic speaking westernized developed countries. In order to develop culturally appropriate interventions, further research using longitudinal designs is needed to confirm the risk factors for burnout in specific HCP settings and specialties in Arab countries. PMID- 28716143 TI - The factors affecting the institutionalisation of two policy units in Burkina Faso's health system: a case study. AB - BACKGROUND: This paper is one of three linked studies that attempts to understand the process of institutionalisation of policy units within Burkina Faso's health system. It examines the relationships between the existence of an institutional framework, data production capacity and other resource availability in the institutionalisation of policy units in health systems. It therefore contributes to our understanding of the dynamics linking the key drivers and indicators of institutionalisation. Additionally, it examines how factors within the managerial setting, including workplace environment, and budgetary and human resource availability, may influence the institutionalisation process. METHODS: The study used an explanatory qualitative case study approach, examining two policy units in Burkina Faso's Ministry of Health, the first of which had been institutionalised successfully and the other less so. Data were collected from key policymakers, including 13 connected with the first policy unit and 10 with the second, plus two funders. We also conducted a documentary analysis of the National Program for Health Development, two mid-term strategic plans, 230 action plans, eight Ministry of Health state budgets, eight Ministry of Health annual statistics reports, 16 policy unit budgets and published literature. RESULTS: The framework within which the government gave the policy unit its mandate and policy focus had the strongest effect on the institutionalisation process. Institutionalisation depended on political will, in both the host government and any donors, and the priority given to the policy unit's focus. It was also affected by the leadership of the policy unit managers. These factors were influenced by human resource capacity, and our findings suggest that, for successful institutionalisation in Burkina Faso's health system, policy units need to be given sufficient human resources to achieve their objectives. CONCLUSION: Policy units' institutionalisation in Burkina Faso's health system depend on the leadership of the unit managers to implement relevant activities, mobilise funding, and recruit and maintain enough human resources, as well as the mandate given by the government. PMID- 28716144 TI - Macrophage type 2 differentiation in a patient with laryngeal squamous cell carcinoma and metastatic prostate adenocarcinoma to the cervical lymph nodes. AB - BACKGROUND: The tumor microenvironment often polarizes infiltrating macrophages towards a type 2, or M2 phenotype, that is characterized by expression of various cysteine-rich, scavenger receptors, including CD163. The primary function of M2 macrophages is to facilitate wound healing. As such, they are capable of providing metabolic support to a growing tumor, neovascularization, as well as protection from cytotoxic T cells. The tumor microenvironment contains a milieu of secreted factors and vesicles, which in certain circumstances can gain access to lymphatic vessels that drain to local lymph nodes. CASE PRESENTATION: We report a 59-year-old male with recurrent T4 squamous cell carcinoma (SCC) of the larynx with synchronous prostate adenocarcinoma confined to the prostate and regional pelvic lymph nodes, without metastatic disease. The patient underwent salvage total laryngectomy and bilateral neck dissection with final pathology revealing a recurrent moderately differentiated SCC involving the larynx as well as prostate cancer in draining level 4 cervical lymph nodes bilaterally. CD163 staining was performed on the primary tumor, a negative draining lymph node, and a level four lymph node with a focus of metastatic prostate cancer and compared to benign controls. The negative draining lymph node demonstrated a large CD163 population of cells as did the interface of the focus of prostate cancer and surrounding lymph node. CD163 levels were markedly increased in this patient compared to benign lymph node controls. The macrophage differentiation at the primary tumor in the larynx was strongly CD163 positive supporting an immune permissive environment for tumor growth and metastasis. CONCLUSION: We describe a unique case of solitary metastatic prostate cancer to cervical lymph nodes in the setting of a laryngeal cancer. These observations suggest that SCC-derived factors drive a tumor-supportive environment in draining lymph nodes dominated by an overwhelming number of CD163+, M2 macrophages. Lymph nodes that are 'primed' by SCC differentiation to M2 phenotype may be at higher risk of harboring metastases. PMID- 28716145 TI - Mortality differences by surgical volume among patients with stomach cancer: a threshold for a favorable volume-outcome relationship. AB - BACKGROUND: Many studies have assessed the volume-outcome relationship in cancer patients, but most focused on better outcomes in higher volume groups rather than identifying a specific threshold that could assist in clinical decision-making for achieving the best outcomes. The current study suggests an optimal volume for achieving good outcome, as an extension of previous studies on the volume-outcome relationship in stomach cancer patients. METHODS: We used National Health Insurance Service (NHIS) Sampling Cohort data during 2004-2013, comprising healthcare claims for 2550 patients with newly diagnosed stomach cancer. We conducted survival analyses adopting the Cox proportional hazard model to investigate the association of three threshold values for surgical volume of stomach cancer patients for cancer-specific mortality using the Youden index. RESULTS: Overall, 17.10% of patients died due to cancer during the study period. The risk of mortality among patients who received surgical treatment gradually decreased with increasing surgical volume at the hospital, while the risk of mortality increased again in "high" surgical volume hospitals, resulting in a j shaped curve (mid-low = hazard ratio (HR) 0.773, 95% confidence interval (CI) 0.608-0.983; mid-high = HR 0.541, 95% CI 0.372-0.788; high = HR 0.659, 95% CI 0.473-0.917; ref = low). These associations were especially significant in regions with unsubstantial surgical volumes and less severe cases. CONCLUSION: The optimal surgical volume threshold was about 727.3 surgical cases for stomach cancer per hospital over the 1-year study period in South Korea. However, such positive effects decreased after exceeding a certain volume of surgeries. PMID- 28716146 TI - Interactive weekly mobile phone text messaging plus motivational interviewing in promotion of breastfeeding among women living with HIV in South Africa: study protocol for a randomized controlled trial. AB - BACKGROUND: South Africa recently phased out access to free formula milk in the public sector in support of breastfeeding for women living with HIV. Few women living with HIV in South Africa choose breastfeeding and among those who do, many stop breastfeeding early. We sought to explore the feasibility of using mobile phone text messaging coupled with motivational interviewing to enhance adherence to breastfeeding practices. METHODS AND DESIGN: A randomized, parallel group, single-center pilot trial. Electronic sequence generation and random allocation will be done centrally. Women of low socioeconomic status, from Cape Town, South Africa will be randomly assigned within 24 h of giving birth at a primary healthcare clinic to a structured weekly text message plus motivational interviewing and usual standard of care, using a permutation of different block sizes. Criteria for feasibility success will include: five participants recruited per week (over 12 weeks), about 75% of all eligible participants consent for study participation, complete evaluation of outcomes in at least 70% of all recruited participants, breastfeeding adherence rates of at least 70% in the intervention group, six months after delivery. Participants will be evaluated soon after giving birth and post-delivery at weeks 2, 6, 10, and 24. Primary analysis will follow the "intention-to-treat" principle. Sub-group analysis will be used to assess sub-group effects. DISCUSSION: This pilot trial will evaluate the feasibility of conducting a larger trial on communication and support approaches to improve adherence to breastfeeding by HIV-infected women. Text messaging and motivational interviewing are simple interventions which may allow participants to access personalized adherence advice and support. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02949713 . Registered on 26 October 2016; Pan African Clinical Trial Registry PACTR201611001855404 . Registered on 8 November 2016. PMID- 28716147 TI - STOP smoking and alcohol drinking before OPeration for bladder cancer (the STOP OP study), perioperative smoking and alcohol cessation intervention in relation to radical cystectomy: study protocol for a randomised controlled trial. AB - BACKGROUND: To evaluate the effect of a smoking-, alcohol- or combined-cessation intervention starting shortly before surgery and lasting 6 weeks on overall complications after radical cystectomy. Secondary objectives are to examine the effect on types and grades of complications, smoking cessation and alcohol cessation, length of hospital stay, health-related quality of life and return to work or habitual level of activity up to 12 months postoperatively. METHODS/DESIGN: The study is a multi-institutional randomised clinical trial involving 110 patients with a risky alcohol intake and daily smoking who are scheduled for radical cystectomy. Patients will be randomised to the 6-week Gold Standard Programme (GSP) or treatment as usual (control). The GSP combines patient education and pharmacologic strategies. Smoking and alcohol intake is biochemically validated (blood, urine and breath tests) at the weekly meetings and at follow-up. DISCUSSION: Herein, we report the design of the STOP-OP study, objectives and accrual up-date. This study will provide new knowledge about how to prevent smoking and alcohol-related postoperative complications at the time of bladder cancer surgery. Till now 77 patients have been enrolled. Patient accrual is expected to be finalised before the end of 2017 and data will be published in 2018. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT02188446 . Registered on 28 May 2014. PMID- 28716148 TI - Prevalence of plasma autoantibody against cancer testis antigen NY-ESO-1 in HTLV 1 infected individuals with different clinical status. AB - BACKGROUND: Detection of specific immune responses against cancer/testis antigen NY-ESO-1 was recently reported in patients with adult T-cell leukemia/lymphoma (ATL) and human T-cell leukemia virus type 1 (HTLV-1)-infected asymptomatic carriers (ACs). However, the relationship of the responses with the HTLV-1 proviral load (PVL) and the levels of viral gene expression remain unclear. FINDINGS: We measured plasma levels of autoantibodies to NY-ESO-1 immunogenic tumor antigen in HTLV-1-infected individuals with different clinical status, and in healthy controls. Data were compared to tax and HBZ mRNA levels, and PVL. Plasma anti-NY-ESO-1 antibody was detectable in 13.7% (7/51) of ACs, 29.2% (38/130) of patients with HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP), and 18.9% (10/53) of patients with ATL. Anti-NY-ESO-1 plasma levels were significantly higher in patients with HAM/TSP than in patients with ATL or ACs. Anti-NY-ESO-1 levels were not associated with PVL or the expression levels of tax and HBZ mRNA among HTLV-1-infected individuals, regardless of clinical status. CONCLUSIONS: The present results indicate the strong humoral immune response against NY-ESO-1 in natural HTLV-1 infection, irrespective of the clinical status. The higher immunoreactivity against NY-ESO-1 is not simply associated with the levels of both HTLV-1 gene expression and the number of infected cells in vivo. Rather, it might reflect chronic and generalized immune activation in infected individuals. PMID- 28716150 TI - Swedish-Norwegian co-operation in the treatment of three hypothermia victims: a case report. AB - BACKGROUND: Accidental hypothermia with cardiac arrest represents a challenge for pre-hospital rescuers as well as in-hospital staff. For pre-hospital personnel, the main focus is to get the patient to the correct destination without unnecessary delay. For in-hospital personnel early information is vital to assess the possibility for resuscitation with extracorporeal re-warming. The challenge is augmented when rescuers must cross national borders to reach and/or deliver the patients. We present a case where three adolescent boys suffered severe hypothermia after a canoeing accident in Sweden. CASE PRESENTATION: Three 14-year old boys were canoeing a mountain lake close to the Norwegian border when their boat capsized and they all fell into the cold water. The rescue operation was hampered by rough weather conditions, and immersion times spanned from 63 to 125 min. Flight times from the scene of accident to the nearest ECMO center in Norway (Trondheim) and Sweden (Umea) were about 30 and 90 min respectively. Two of the victims showed no vital signs after retrieval from the water and had extremely low body temperatures. They were brought to Trondheim University Hospital where they were resuscitated successfully with extracorporeal re-warming. Unable to be weaned from ECMO in the initial phase, both patients were retrieved by mobile ECMO teams to Karolinska University Hospital, from where they were discharged to their homes with good outcomes, although with some sequelae. A third victim with moderate to severe hypothermia without cardiac arrest was treated at a local hospital, from where he after a short stay was discharged without physical sequelae. CONCLUSION: These cases are a reminder of the traditional mantra that "no one is dead until warm and dead". Good communication between pre- and in hospital staff can be vital for optimizing patient treatment when handling victims of severe hypothermia, and especially when there is multiple victims. Communication between neighboring countries, but even neighboring regions within the same country, can be challenging. We encourage regions similar to ours to review protocols regarding hypothermia management, making them more robust before incidents like this take place. PMID- 28716149 TI - Transition into adult care: factors associated with level of preparedness among adolescents living with HIV in Cambodia. AB - BACKGROUND: Preparing adolescents for transition into adult care and supporting their acquisition of self-health care management skills is a critical determinant of their post-transition HIV care outcomes. However, there is a scarcity of research on effective transition strategies. This study explores factors associated with adolescent preparedness for transition into adult care in Cambodia. METHODS: In August 2016, a cross-sectional study was conducted among 223 adolescents living with HIV aged 15-17, randomly selected from 11 antiretroviral therapy clinics, utilizing a structured questionnaire. The level of preparedness was determined using a pre-existing scale, and adolescents were categorized as having a high- or low level of preparedness for transition. Bivariate and multivariate analyses were conducted. RESULTS: Of 223 adolescents, 55.2% were male, and their mean age was 15.8 years. Overall, 53.3% had a high level of preparedness for transition. As part of the transition protocol, 2.7% had completed a transfer form, 24.7% had a transition case manager, 29.6% had been counselled about the transition, and 19.7% had visited an adult ART clinic. In multivariate analysis, a higher level of preparedness for transition was independently associated with older age (AOR 2.44, 95% CI 1.34-4.46; p = 0.004), family having received social support for their health (AOR 5.32, 95% CI 1.97 14.36; p = 0.001), knowing the kind of treatment they received (ART) (AOR 12.67, 95% CI 2.91-15.19; p = 0.001), trust in friends or family for HIV treatment (AOR 7.82, 95% CI 1.13-8.89; p = 0.008), receiving counseling on transition (AOR 3.17, 95% CI 1.15-8.76; p = 0.03), having a 'Case Manager' identified to support them during the preparation process for transition (AOR 3.89, 95% CI 1.08-13.96; p = 0.04), and satisfaction with preparation process for transition in general (AOR 0.35, 95% CI 0.03-0.87; p = 0.01). CONCLUSIONS: A range of individual, social and health system and services factors may determine successful transition preparedness among adolescents in Cambodia. Strengthening implementation of age appropriate and individualized case management transition at all sites, while creating supportive family, peer, and healthcare environments for adolescent transition is required. PMID- 28716151 TI - Predictive factors of ovarian carcinoma for women with ovarian endometrioma aged 45 years and older in China. AB - BACKGROUND: To explore the risk factors of endometriosis-associated ovarian cancer (EAOC) in women with ovarian endometriosis (OEM) aged 45 years and above in China. METHODS: This study reviewed the medical records of 1038 women in total who were aged 45 years and above, surgical-pathologically diagnosed with ovarian endometriosis, and were treated at Peking Union Medical College Hospital between December 1996 and December 2016. Histology evaluation was used to determine whether the ovarian endometriosis specimen was with (n = 30) or without (n = 1008) ovarian cancer. RESULTS: 2.9% (30/1038) of women with the surgical pathological diagnosis of ovarian endometriosis were found to have EAOC. Those patients with EAOC were prone to be in the postmenopausal status at the time of the diagnosis (OR 5.50, 95%CI 2.54-11.90, P < .001) and larger size of tumor (>=8 cm, OR 7.19, 95% CI 3.34-15.50, P < .001), and higher prevalence of coexisting with endometrial disorders (OR 4.11, 95%CI 1.73-9.73, P = .003). This study showed that patients of an older age when diagnosed with OEM, were at a higher risk of developing EAOC, respectively measuring of 1.7% (13/751) at 45-49 years, 5.6% (12/215) at 50-54 years, and 10.0%(5/50) at 55-59 years (P < 0.001). CONCLUSIONS: This study showed that for women aged 45 years and above who were diagnosed with OEM, the independent risk factors of EAOC were menopausal status, tumor size of 8 cm or greater in diameter, and coexisting endometrial disorders. Therefore, intensive follow-ups or active interventions should be considered for them. PMID- 28716152 TI - Development of a theory-informed implementation intervention to improve the triage, treatment and transfer of stroke patients in emergency departments using the Theoretical Domains Framework (TDF): the T3 Trial. AB - BACKGROUND: Theoretical frameworks and models based on behaviour change theories are increasingly used in the development of implementation interventions. Development of an implementation intervention is often based on the available evidence base and practical issues, i.e. feasibility and acceptability. The aim of this study was to describe the development of an implementation intervention for the T3 Trial (Triage, Treatment and Transfer of patients with stroke in emergency departments (EDs)) using theory to recommend behaviour change techniques (BCTs) and drawing on the research evidence base and practical issues of feasibility and acceptability. METHODS: A stepped method for developing complex interventions based on theory, evidence and practical issues was adapted using the following steps: (1) Who needs to do what, differently? (2) Using a theoretical framework, which barriers and enablers need to be addressed? (3) Which intervention components (behaviour change techniques and mode(s) of delivery) could overcome the modifiable barriers and enhance the enablers? A researcher panel was convened to review the list of BCTs recommended for use and to identify the most feasible and acceptable techniques to adopt. RESULTS: Seventy-six barriers were reported by hospital staff who attended the workshops (step 1: thirteen TDF domains likely to influence the implementation of the T3 Trial clinical intervention were identified by the researchers; step 2: the researcher panellists then selected one third of the BCTs recommended for use as appropriate for the clinical context of the ED and, using the enabler workshop data, devised enabling strategies for each of the selected BCTs; and step 3: the final implementation intervention consisted of 27 BCTs). CONCLUSIONS: The TDF was successfully applied in all steps of developing an implementation intervention for the T3 Trial clinical intervention. The use of researcher panel opinion was an essential part of the BCT selection process to incorporate both research evidence and expert judgment. It is recommended that this stepped approach (theory, evidence and practical issues of feasibility and acceptability) is used to develop highly reportable implementation interventions. The classifying of BCTs using recognised implementation intervention components will facilitate generalisability and sharing across different conditions and clinical settings. PMID- 28716153 TI - A nested mechanistic sub-study into the effect of tranexamic acid versus placebo on intracranial haemorrhage and cerebral ischaemia in isolated traumatic brain injury: study protocol for a randomised controlled trial (CRASH-3 Trial Intracranial Bleeding Mechanistic Sub-Study [CRASH-3 IBMS]). AB - BACKGROUND: Tranexamic acid prevents blood clots from breaking down and reduces bleeding. However, it is uncertain whether tranexamic acid is effective in traumatic brain injury. The CRASH-3 trial is a randomised controlled trial that will examine the effect of tranexamic acid (versus placebo) on death and disability in 13,000 patients with traumatic brain injury. The CRASH-3 trial hypothesizes that tranexamic acid will reduce intracranial haemorrhage, which will reduce the risk of death. Although it is possible that tranexamic acid will reduce intracranial bleeding, there is also a potential for harm. In particular, tranexamic acid may increase the risk of cerebral thrombosis and ischaemia. The protocol detailed here is for a mechanistic sub-study nested within the CRASH-3 trial. This mechanistic sub-study aims to examine the effect of tranexamic acid (versus placebo) on intracranial bleeding and cerebral ischaemia. METHODS: The CRASH-3 Intracranial Bleeding Mechanistic Sub-Study (CRASH-3 IBMS) is nested within a prospective, double-blind, multi-centre, parallel-arm randomised trial called the CRASH-3 trial. The CRASH-3 IBMS will be conducted in a cohort of approximately 1000 isolated traumatic brain injury patients enrolled in the CRASH 3 trial. In the CRASH-3 IBMS, brain scans acquired before and after randomisation are examined, using validated methods, for evidence of intracranial bleeding and cerebral ischaemia. The primary outcome is the total volume of intracranial bleeding measured on computed tomography after randomisation, adjusting for baseline bleeding volume. Secondary outcomes include progression of intracranial haemorrhage (from pre- to post-randomisation scans), new intracranial haemorrhage (seen on post- but not pre-randomisation scans), intracranial haemorrhage following neurosurgery, and new focal ischaemic lesions (seen on post-but not pre randomisation scans). A linear regression model will examine whether receipt of the trial treatment can predict haemorrhage volume. Bleeding volumes and new ischaemic lesions will be compared across treatment groups using relative risks and 95% confidence intervals. DISCUSSION: The CRASH-3 IBMS will provide an insight into the mechanism of action of tranexamic acid in traumatic brain injury, as well as information about the risks and benefits. Evidence from this trial could inform the management of patients with traumatic brain injury. TRIAL REGISTRATION: The CRASH-3 trial was prospectively registered and the CRASH-3 IBMS is an addition to the original protocol registered at the International Standard Randomised Controlled Trials registry ( ISRCTN15088122 ) 19 July 2011, and ClinicalTrials.gov on 25 July 2011 (NCT01402882). PMID- 28716154 TI - New insights from Gorongosa National Park and Niassa National Reserve of Mozambique increasing the genetic diversity of Trypanosoma vivax and Trypanosoma vivax-like in tsetse flies, wild ungulates and livestock from East Africa. AB - BACKGROUND: Trypanosoma (Duttonella) vivax is a major pathogen of livestock in Africa and South America (SA), and genetic studies limited to small sampling suggest greater diversity in East Africa (EA) compared to both West Africa (WA) and SA. METHODS: Multidimensional scaling and phylogenetic analyses of 112 sequences of the glycosomal glyceraldehyde phosphate dehydrogenase (gGAPDH) gene and 263 sequences of the internal transcribed spacer of rDNA (ITS rDNA) were performed to compare trypanosomes from tsetse flies from Gorongosa National Park and Niassa National Reserve of Mozambique (MZ), wild ungulates and livestock from EA, and livestock isolates from WA and SA. RESULTS: Multidimensional scaling (MDS) supported Tvv (T. vivax) and TvL (T. vivax-like) evolutionary lineages: 1) Tvv comprises two main groups, TvvA/B (all SA and WA isolates plus some isolates from EA) and TvvC/D (exclusively from EA). The network revealed five ITS genotypes within Tvv: Tvv1 (WA/EA isolates), Tvv2 (SA) and Tvv3-5 (EA). EA genotypes of Tvv ranged from highly related to largely different from WA/SA genotypes. 2) TvL comprises two gGAPDH-groups formed exclusively by EA sequences, TvLA (Tanzania/Kenya) and TvLB-D (MZ). This lineage contains more than 11 ITS genotypes, seven forming the lineage TvL-Gorongosa that diverged from T. vivax Y486 enough to be identified as another species of the subgenus Duttonella. While gGAPDH sequences were fundamental for classification at the subgenus, major evolutionary lineages and species levels, ITS rDNA sequences permitted identification of known and novel genotypes. CONCLUSIONS: Our results corroborate a remarkable diversity of Duttonella trypanosomes in EA, especially in wildlife conservation areas, compared to the moderate diversity in WA. Surveys in wilderness areas in WA may reveal greater diversity. Biogeographical and phylogenetic data point to EA as the place of origin, diversification and spread of Duttonella trypanosomes across Africa, providing relevant insights towards the understanding of T. vivax evolutionary history. PMID- 28716155 TI - Transplanters drive CARs to the clinic by brewing ICE-T: the Moffitt roadmap. AB - Recent single institution clinical trial successes with anti-CD19 Chimeric Antigen Receptor (CAR) T cell therapy for B cell malignancies attracted significant attention from industry. Our center sought to rapidly and safely bring industry sponsored pivotal trials to our patients and to prepare for additional cell therapy trials in solid and liquid tumors from both industry and our own investigators. We implemented a collaborative cross departmental program to provide clinical care and trial coordination for immune cell therapies. The Moffitt Immune Cell Therapy (ICE-T) program oversees and administers not only CAR T cell therapy for hematologic malignancies, but TIL and TCR therapy for solid tumor patients. Disease specific experts maintain oversight as principal investigators of these key trials yet the coordination and clinical care is centralized to leverage the expertise and infrastructure of our already robust Blood and Marrow Transplantation program. PMID- 28716156 TI - Generic atorvastatin is as effective as the brand-name drug (LIPITOR(r)) in lowering cholesterol levels: a cross-sectional retrospective cohort study. AB - BACKGROUND: In a world of ever increasing health care costs, generic drugs represent a major opportunity to ensure access to essential medicines for people who otherwise would be unable to afford them. However, some clinicians and patients are still questioning the safety and effectiveness of generic formulations compared to the proprietary drugs necessitating further systematic research analyzing the generic drugs' efficacy. Our objective was to compare the lipid lowering effects of generic and branded atorvastatin. METHODS: This cross sectional, retrospective cohort study was conducted at the University of Malaya Medical Centre from 1 May 2013 until 30 May 2013. We analyzed the lipid profiles (total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides) of 629 patients before and at least 3 months after switching them from proprietary atorvastatin (Lipitor(r)) to generic atorvastatin (atorvastatin calcium from Ranbaxy Laboratories, Inc.). We also investigated if there was any difference in the effectiveness of both atorvastatin formulations in various ethnic groups. RESULTS: 266 patients were included in this study. When comparing the median values we found no statistically significant differences (Wilcoxon signed-rank test; p < 0.05) between proprietary and generic atorvastatin in lowering total cholesterol (4.60 mmol/l pre-transition vs. 4.50 mmol/l post-transition; p = 0.583), LDL-cholesterol (2.42 mmol/l vs. 2.41 mmol/l; p = 0.923) and triglycerides (1.50 mmol/l vs. 1.50 mmol/l; p = 0.513). While there was a statistically significant (p = 0.009) difference in HDL-cholesterol levels favouring proprietary atorvastatin, the extent of this change (1.26 mmol/l vs. 1.25 mmol/l) was deemed not to be clinically relevant. There was no statistically significant difference when analyzing the effects on various ethnic groups. CONCLUSIONS: Substituting proprietary atorvastatin for its generic formulation atorvastatin calcium does not result in a less effective management of hyperlipidemia. Our findings lend support to the approach of lowering health care costs by switching patients from branded drugs to their less expensive generic analogues. PMID- 28716158 TI - Efficacy of single-dose 500 mg mebendazole in soil-transmitted helminth infections: a review. AB - Soil-transmitted helminthiasis (STH) is caused by Ascaris lumbricoides (roundworm), Trichuris trichiura (whipworm), and Ancylostoma duodenale and Necator americanus (hookworms). Mebendazole is one of the recommended preventive chemotherapy agents for STH. This review summarizes the efficacy data from 29 studies with single-dose 500 mg mebendazole in STH treatment and compares the results with those of a recently conducted phase 3 study of a 500 mg mebendazole chewable tablet against A. lumbricoides and T. trichiura infections. Studies that reported efficacy results against at least one STH infection were selected from the literature and efficacy data by each STH type were abstracted and pooled. Single-dose 500 mg mebendazole treatment resulted in a cure rate of 92.6% (range: 72.5-100%) for A. lumbricoides, 27.6% (range: 8.4-100%) for T. trichiura and 25.5% (range: 2.9-91.1%) for hookworms. Egg reduction rate for A. lumbricoides was 97.9% (range: 89.8-100%), for T. trichiura it was 72.9% (range: 31.6-93.0%) and for hookworms it was 72.0% (range: -6.5% (denoting an increase in egg count) to 98.3%). Similar results were observed in the studies that were placebo controlled. In the phase 3 study, the cure rate and egg reduction rate reported was 83.7% and 97.9%, respectively, for A. lumbricoides and 33.9% and 59.7%, respectively, for T. trichiura. In conclusion, single-dose 500 mg mebendazole showed a high cure rate against A. lumbricoides and a substantial reduction in faecal egg count for all STH types. These results are consistent with the recently conducted phase 3 study of a new 500 mg chewable mebendazole tablet. PMID- 28716157 TI - Advances and challenges in barcoding pathogenic and environmental Leptospira. AB - Leptospirosis is a zoonotic bacterial disease of global importance. A large spectrum of asymptomatic animal hosts can carry the infection and contribute to the burden of human disease. Environmental sources of human contamination also point to the importance of a hydrotelluric reservoir. Leptospirosis can be caused by as many as 15 different pathogenic or intermediate Leptospira species. However, classification of these bacteria remains complicated through the use of both serological and genetic classification systems that show poor correlation. With the advent of molecular techniques, DNA-based barcoding offers a conceptual framework that can be used for leptospirosis surveillance as well as source tracking. In this review, we summarize some of the current techniques, highlight significant successes and weaknesses and point to the future opportunities and challenges to successfully establish a widely applicable barcoding scheme for Leptospira. PMID- 28716160 TI - To the editor: how statistics killed the cat: conclusion. PMID- 28716159 TI - Bilateral Wilms tumour: a review of clinical and molecular features. AB - Wilms tumour (WT) is the most common paediatric kidney cancer and affects approximately one in 10 000 children. The tumour is associated with undifferentiated embryonic lesions called nephrogenic rests (NRs) or, when diffuse, nephroblastomatosis. WT or NRs can occur in both kidneys, termed bilateral disease, found in only 5-8% of cases. Management of bilateral WT presents a major clinical challenge in terms of maximising survival, preserving renal function and understanding underlying genetic risk. In this review, we compile clinical data from 545 published cases of bilateral WT and discuss recent progress in understanding the molecular basis of bilateral WT and its associated precursor NRs in the context of the latest radiological, surgical and epidemiological features. PMID- 28716161 TI - Post-adenoidectomy quality of life in children with refractory chronic rhinosinusitis. AB - OBJECTIVE: This study aimed to evaluate post-adenoidectomy quality of life in children with refractory chronic rhinosinusitis. METHODS: A prospective interventional study of children aged 4-12 years with chronic refractory rhinosinusitis was conducted. A total of 60 children completed follow up. Nasal endoscopy and non-contrast computed tomography of the paranasal sinuses were performed, and both symptoms and their effects on patient quality of life pre- and post-adenoidectomy were evaluated. RESULTS: The most frequent symptoms were nasal obstruction, cough, fever and fatigue, which were experienced by 100 per cent, 90 per cent, 85 per cent and 81.7 per cent of children, respectively. Nasal endoscopy showed oedema and discharge were present in all children. A statistically significant post-operative improvement in sinus and nasal quality of life was seen in 53 children (88.3 per cent). CONCLUSION: Adenoidectomy is a simple, first-line surgical procedure for managing paediatric chronic rhinosinusitis refractory to maximal medical therapy and leads to an improved quality of life. PMID- 28716162 TI - Changing our thinking about changing their thinking in older adulthood. AB - It is well-established that as people age, deterioration in cognitive abilities including processing speed, memory, and cognitive flexibility occurs, although vast individual differences occur in the rate and consequences of this decline (Christensen, 2001). Anxiety and depression in late life are also associated with specific cognitive deficits in memory and executive functioning that may impact on new learning (Yochim et al., 2013). Therefore, it is possible that cognitive changes make it more difficult for older adults to learn how to change their thinking particularly in the context of psychological therapy. PMID- 28716163 TI - Can nutritional information modify purchase of ultra-processed products? Results from a simulated online shopping experiment. AB - OBJECTIVE: The aim of the present work was to evaluate the influence of two front of-pack nutrition information schemes (traffic-light system and Chilean warning system) on consumer purchase of ultra-processed foods in a simulated online grocery store. DESIGN: Following a between-subjects design, participants completed a simulated weekly food purchase in an online grocery store under one of three experimental conditions: (i) a control condition with no nutrition information, (ii) a traffic-light system and (iii) the Chilean warning system. Information about energy (calories), sugar, saturated fats and salt content was included in the nutrition information schemes. SETTING: Participants were recruited from a consumer database and a Facebook advertisement. SUBJECTS: People from Montevideo (Uruguay), aged 18-77 years (n 437; 75 % female), participated in the study. All participants were in charge of food purchase in the household, at least occasionally. RESULTS: No significant differences between experimental conditions were found in the mean share of ultra-processed foods purchased by participants, both in terms of number of products and expenditure, or in the mean energy, sugar, saturated fat and salt content of the purchased items. However, the Chilean warning system decreased intended purchase of sweets and desserts. CONCLUSIONS: Results from this online simulation provided little evidence to suggest that the traffic-light system or the Chilean warning system in isolation could be effective in reducing purchase of ultra-processed foods or improving the nutritional composition of the purchased products. PMID- 28716164 TI - Collagen matrix as an inlay in endoscopic skull base reconstruction. AB - BACKGROUND: Multi-layer reconstruction has become standard in endoscopic skull base surgery. The inlay component used can vary among autografts, allografts, xenografts and synthetics, primarily based on surgeon preference. The short- and long-term outcomes of collagen matrix in skull base reconstruction are described. METHODS: A case series of patients who underwent endoscopic skull base reconstruction with collagen matrix inlay were assessed. Immediate peri-operative outcomes (cerebrospinal fluid leak, meningitis, ventriculitis, intracranial bleeding, epistaxis, seizures) and delayed complications (delayed healing, meningoencephalocele, prolapse of reconstruction, delayed cerebrospinal fluid leak, ascending meningitis) were examined. RESULTS: Of 120 patients (51.0 +/- 17.5 years, 41.7 per cent female), peri-operative complications totalled 12.7 per cent (cerebrospinal fluid leak, 3.3 per cent; meningitis, 3.3 per cent; other intracranial infections, 2.5 per cent; intracranial bleeding, 1.7 per cent; epistaxis, 1.7 per cent; and seizures, 0 per cent). Delayed complications did not occur in any patients. CONCLUSION: Collagen matrix is an effective inlay material. It provides robust long-term separation between sinus and cranial cavities, and avoids donor site morbidity, but carries additional cost. PMID- 28716165 TI - Frontal Assessment Battery in Parkinson's Disease: Validity and Morphological Correlates. AB - OBJECTIVES: Executive dysfunction is a common feature in Parkinson's disease (PD). However, there is a lack of brief validated instruments for executive dysfunction in PD. METHODS: The aim of the present study was to assess the relation of Frontal Assessment Battery (FAB) scores to age and education, to verify the utility of FAB in the evaluation of executive dysfunction in PD and to differentiate between controls (n=41), PD patients with normal cognition (PD-NC; n=41; Hoehn and Yahr stages 2-3) and PD with mild cognitive impairment (PD-MCI; n=32; Hoehn and Yahr stages 2-3). In addition, we studied the relation between voxel-based morphometric (VBM) data and FAB results in PD. RESULTS: We found that FAB scores are significantly related to age and education. The FAB has shown discriminative validity for the differentiation of PD-MCI from PD-NC and controls (area under the curve >.80). Also, the VBM analysis revealed lower FAB scores are specifically related to lower gray matter density in the right ventromedial prefrontal areas and precuneus. CONCLUSIONS: The FAB can be recommended as a valid instrument for PD-MCI Level I screening. FAB is sensitive to frontal lobe involvement in PD as reflected by lower gray matter density in prefrontal areas. (JINS, 2017, 23, 675-684). PMID- 28716166 TI - Invited review: Helping dairy farmers to improve economic performance utilizing data-driving decision support tools. AB - The objective of this review paper is to describe the development and application of a suite of more than 40 computerized dairy farm decision support tools contained at the University of Wisconsin-Madison (UW) Dairy Management website http://DairyMGT.info. These data-driven decision support tools are aimed to help dairy farmers improve their decision-making, environmental stewardship and economic performance. Dairy farm systems are highly dynamic in which changing market conditions and prices, evolving policies and environmental restrictions together with every time more variable climate conditions determine performance. Dairy farm systems are also highly integrated with heavily interrelated components such as the dairy herd, soils, crops, weather and management. Under these premises, it is critical to evaluate a dairy farm following a dynamic integrated system approach. For this approach, it is crucial to use meaningful data records, which are every time more available. These data records should be used within decision support tools for optimal decision-making and economic performance. Decision support tools in the UW-Dairy Management website (http://DairyMGT.info) had been developed using combination and adaptation of multiple methods together with empirical techniques always with the primary goal for these tools to be: (1) highly user-friendly, (2) using the latest software and computer technologies, (3) farm and user specific, (4) grounded on the best scientific information available, (5) remaining relevant throughout time and (6) providing fast, concrete and simple answers to complex farmers' questions. DairyMGT.info is a translational innovative research website in various areas of dairy farm management that include nutrition, reproduction, calf and heifer management, replacement, price risk and environment. This paper discusses the development and application of 20 selected (http://DairyMGT.info) decision support tools. PMID- 28716167 TI - Osteopontin induced vascular endothelial growth factor production in dispersed nasal polyp cells through the phosphatidylinositol 3-kinase-protein kinase B and the extracellular signal-regulated kinase 1/2 pathways. AB - BACKGROUND: Osteopontin (OPN) is involved in cell survival, migration, and angiogenesis. The role of OPN in inducing angiogenesis in tumor has been confirmed. In this study, we investigated the expression of OPN in patients with chronic rhinosinusitis (CRS) with nasal polyp (NP) and the relationship of OPN with vascular endothelial growth factor (VEGF) production. METHODS: We enrolled 45 subjects with CRS (25 with CRS with NPs [CRSwNP] and 20 subjects with CRS without NPs [CRSsNP]), and with 14 normal controls to determine the expression of OPN and VEGF. The distribution, messenger RNA (mRNA), and protein levels of OPN and VEGF were examined by immunohistochemistry, quantitative polymerase chain reaction, and enzyme-linked immunosorbent assay, respectively. The effect of OPN on the VEGF production was tested in dispersed NP cells (DNPC) and the involved signaling pathways were examined by Western blot. RESULTS: In NP tissue of the subjects with CRSwNP, the epithelial cells, interstitial cells, glandular cells, and endothelial cells were positive for OPN and VEGF staining, whereas OPN and VEGF immunoactivity in specimens of subjects with CRSsNP and in normal controls was significantly reduced. We found that the immunostainings, the mRNA expression, and the protein levels of OPN and VEGF were significantly increased in NPs compared with normal controls. OPN induced VEGF production by DNPCs in a time- and dose-dependent manner through phosphatidylinositol 3-kinase- protein kinase B and the extracellular signal-regulated kinase 1/2 pathway. Moreover, VEGF also induced OPN production, which formed a positive feedback between OPN and VEGF. CONCLUSION: Our findings demonstrated that OPN and VEGF were overproduced in NPs and that OPN induced VEGF production, which indicated that OPN-VEGF axis might contribute to angiogenesis in NPs. PMID- 28716168 TI - A randomized, double-blind, placebo controlled trial of sublingual immunotherapy with house-dust mite extract for allergic rhinitis. AB - OBJECTIVE: This study was designed to evaluate the efficacy and safety of sublingual immunotherapy (SLIT) with house-dust mite (HDM) extract in Chinese patients with HDM-induced allergic rhinitis (AR). METHODS: A randomized, double blind, placebo controlled trial was conducted with the outpatients of the Eye, Ear, Nose, and Throat Hospital, Fudan University. Forty-eight patients were eligible for randomization to SLIT with a mixture of Dermatophagoides pteronyssinus and Dermatophagoides farinae extract or placebo for 1 year. The primary outcome measures for efficacy were the total nasal symptom score (TNSS) and the individual nasal symptom score. Secondary end points were allergic conjunctivitis scores (ACS) and medication scores (MS). Adverse events (AE) also were monitored. RESULTS: Intragroup analysis demonstrated a significant improvement in the active treatment group for individual nasal symptom score and TNSS (p < 0.05), although no improvement was observed in the placebo group of congestion, sneezing, and itching (p > 0.05). Furthermore, the ACS and MS in the active treatment group also statistically decreased (p < 0.05). In addition, the active treatment had significant effects on relieving nasal symptoms both in adults and children (p < 0.05), and no statistical difference was observed between these two subgroups (p > 0.05). AEs that occurred ranged from mild to moderate, and no severe systematic reactions were observed. CONCLUSION: SLIT with a mixture of HDM extract significantly relieved allergy symptoms and reduced the need for antiallergic drugs, which indicated the superiority of active treatment over placebo for patients with HDM-induced AR. However, due to the limited sample size, the findings need to be further confirmed. PMID- 28716170 TI - Sinonasal T2R-mediated nitric oxide production in response to Bacillus cereus. AB - BACKGROUND: Upper airway epithelial cells produce bactericidal nitric oxide (NO) in response to both gram-positive and gram-negative bacteria. Our previous work demonstrated that T2R38, a bitter taste receptor (T2R) expressed in airway epithelium, produces NO in response to quorum-sensing molecules secreted by Pseudomonas aeruginosa. We also demonstrated that Staphylococci products elicit an NO response when using a T2R-independent pathway. When screening additional human pathogens for epithelial T2R activation, we found that the gram-positive aerobe Bacillus cereus secretes a T2R agonist that yields NO production. OBJECTIVE: The objective of this study was to characterize the activating B. cereus product(s) and to describe the epithelial cell signaling pathway involved. METHODS: Sinonasal air-liquid interface cultures were treated with B. cereus conditioned medium (CM), and NO production was measured by using 4-amino-5 methylamino-2',7'-difluorofluorescein fluorescence imaging. Ciliary beat frequency (CBF) was assessed in response to B. cereus CM. Pharmacologic studies that use inhibitors of the T2R-signaling pathway were used to determine if the production of NO was mediated by a T2R. Purification studies were performed to analyze the physical properties of the activating product(s) contained in the CM. RESULTS: A product(s) secreted by B. cereus induced NO production and increased CBF. The response varied markedly between individual patients and involved two important components of bitter taste signaling, phospholipase C isoform beta-2 and the transient receptor potential melastatin isoform 5 ion channel. CONCLUSIONS: This study demonstrated that a B. cereus product(s) elicited an NO mediated innate defense response in upper airway epithelium that seemed to be partially mediated by a T2R signaling pathway. The active product that elicited the NO response was likely a small nonpeptide compound, but further purification is required for identification. Patient variation in the NO response to B. cereus products could potentially be due to genetic differences in T2Rs. PMID- 28716171 TI - The personal financial burden of chronic rhinosinusitis: A Canadian perspective. AB - BACKGROUND: Previous studies describe the financial burden of chronic rhinosinusitis (CRS) from the perspective of third-party payers, but, to our knowledge, none analyze the costs borne by patients (i.e., out-of-pocket expenses [OOPE]). Furthermore, this burden has not been previously investigated in the context of a publicly funded health care system. OBJECTIVE: The purpose of this study was to characterize the financial impact of CRS on patients, specifically by evaluating its associated OOPEs and the perceived financial burden. The secondary aim was to determine the factors predictive of OOPEs and perceived burden. METHODS: Patients with CRS at a tertiary care sinus center completed a self-administered questionnaire that assessed their socioeconomic characteristics, disease-specific quality of life (22-item Sino-Nasal Outcome Test [SNOT-22]), workdays missed due to CRS, perceived financial burden, and direct medical and nonmedical OOPEs over a 12-month period. Total OOPEs were calculated from the sum of direct medical and nonmedical OOPEs. Regression analyses determined factors predictive of OOPEs and the perceived burden. RESULTS: A total of 84 patients completed the questionnaires. After accounting for health insurance coverage and the median direct medical, direct nonmedical, and total OOPEs per patient over a 12-month period were Canadian dollars (CAD) $336.00 (2011) [U.S. $339.85], CAD $129.87 [U.S. $131.86], and CAD $607.10 [U.S. $614.06], respectively. CRS resulted in an average of 20.6 workdays missed over a 12-month period. Factors predictive of a higher financial burden included younger age, a greater number of previous sinus surgeries, <80% health insurance coverage, residing out of town, and higher SNOT-22 scores. CONCLUSION: Total OOPEs incurred from the treatment of CRS may amount to CAD $607.10 [U.S. $614.06] per patient per year, within the context of a single-payer health care system. Managing clinicians should be aware of patient groups with a greater perceived financial burden and consider counseling them on strategies to offset expenses, including obtaining travel grants, using telemedicine for follow-up assessments, providing drug samples, and streamlining diagnostic testing with medical visits. PMID- 28716172 TI - The relationship between chronic rhinosinusitis and metabolic syndrome. AB - BACKGROUND: This study aimed to investigate the correlation between metabolic syndrome and chronic rhinosinusitis (CRS), with related risk factors for CRS according to data from the Korean National Health and Nutrition Examination Survey (KNHANES). METHODS: The KNHANES surveyed individuals >19 years of age from January 2010 to December 2011. CRS encompassed "symptom-based CRS" as defined by the European Position Paper on Rhinosinusitis and Nasal Polyps 2012. Metabolic syndrome was diagnosed according to the American Heart Association/National Heart Lung and Blood Institute criteria. A chi2 analysis, univariate analysis, and multivariate analysis were conducted. RESULTS: A total of 12,015 individuals were analyzed in this study. The prevalence of CRS in the patients with metabolic syndrome (high triglyceride level, reduced high-density lipoprotein level, and elevated blood pressure) was significantly higher than that in patients without metabolic syndrome (14.15 versus 10.16%) (p < 0.05). Allergic rhinitis was the only significant risk factor for CRS found to be associated with metabolic syndrome (p < 0.05). CONCLUSION: CRS was more prevalent in patients with metabolic syndrome, especially those with allergic rhinitis, than in patients without metabolic syndrome. Accordingly, CRS should be considered in patients with metabolic syndrome and allergic rhinitis. PMID- 28716173 TI - Central compartment atopic disease. AB - BACKGROUND: Isolated polypoid changes of the middle turbinate were recently reported as having a high association with inhalant allergy. A more advanced manifestation of this association may present as polypoid changes of the entire central sinonasal compartment (i.e., the middle and superior turbinates, and the posterosuperior nasal septum), while the lateral sinus mucosa remains relatively normal. OBJECTIVE: To introduce and describe this newly recognized variant of chronic rhinosinusitis (CRS), termed central compartment atopic disease (CCAD). METHODS: A case series of 15 patients from two institutions who presented with sinonasal symptoms and demonstrated central compartment polypoid mucosal changes on computed tomography (CT). The endoscopic appearance of central compartment edema was assessed. Allergy status was determined by skin or serum in vitro testing. RESULTS: The mean +/- standard deviation patient age was 42.4 +/- 14.8 years, and 47% of the patients were women. All 15 patients had a diagnosis of allergic rhinitis symptomatically, and those who underwent allergy assessment (14/15) tested positive. All the patients had central compartment polypoid edema on endoscopy and central nasal soft-tissue thickening with peripheral clearing on CT. Even with more severe sinus disease, a central focus of inflammatory change existed. CONCLUSION: CCAD may represent a local inhalant allergy process that affects the central nasal structures of ethmoid origin. Although inhalant allergy changes mainly appear within the nasal cavity, medial-to-lateral progression to involve the sinuses can occur as a simple obstructive phenomenon. This is a pattern of CRS distinct from the more diffuse sinonasal inflammatory disease and likely requires allergy management as a core component. PMID- 28716174 TI - Association between symptoms of allergic rhinitis with decreased general health related quality of life. AB - BACKGROUND: The impact of specific allergic rhinitis symptoms on patient quality of life (QOL) is currently unknown. OBJECTIVE: In this study, we sought to determine the association between nasal and extranasal symptoms of allergic rhinitis with general health-related QOL. METHODS: A total of 150 participants with ages > 18 years and persistent allergic rhinitis were prospectively recruited for this cross-sectional study. General health-related QOL was measured by using the visual analog scale (VAS) from the five-dimension EuroQol QOL survey (EQ-5D). The severity of nasal and extranasal symptoms was measured by using the 22-item Sino-Nasal Outcome Test (SNOT-22). The severity of nasal obstruction was measured by using the Nasal Obstruction Severity Evaluation (NOSE) scale. Each participant also completed a Rhinitis Control Assessment Test (RCAT). RESULTS: The total SNOT-22 score was significantly correlated with RCAT (r = -0.68 [95% confidence interval {CI}, -0.75 to -0.58]; p < 0.001) and EQ-5D VAS (r = -0.44 [95% CI, -0.56 to -0.30]; p < 0.001). Of the 22 symptoms assessed on the SNOT-22, sleep-related symptoms, and otologic symptoms were associated with the greatest decrease in general health-related QOL. Nasal symptoms were least associated with general health-related QOL. The symptom of nasal obstruction was not at all associated with general health-related QOL (p = 0.267). We confirmed this finding by showing no significant correlation between the NOSE score and EQ-5D VAS (r = 0.05 [95% CI, -0.21 to 0.12]; p = 0.582). CONCLUSION: Sleep and otologic symptoms were associated with the greatest negative impact on QOL in adults with persistent allergic rhinitis and should be routinely assessed in their clinical evaluation. PMID- 28716175 TI - Are prophylactic systemic antibiotics necessary with nasal packing? A systematic review. AB - BACKGROUND: The use of prophylactic systemic antibiotics with nasal packing has been a controversial topic. There are few evidence-based studies to determine the need for prophylactic systemic antibiotics. We performed a systematic literature review to determine the role of prophylactic systemic antibiotics with nasal packing in the prevention of toxic shock syndrome and local nasal infections. OBJECTIVE: The purpose of this study was to perform a systematic literature review to determine the role of prophylactic systemic antibiotics with nasal packing in the prevention of toxic shock syndrome and local nasal infections. METHODS: A search for studies that reviewed the efficacy of prophylactic systemic antibiotics in the prevention of toxic shock or nasal infections and/or sinusitis for patients with nasal packing for epistaxis and postoperative septoplasties was performed. This was conducted in a number of medical literature data bases by following the methods of the 2009 Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Only English publications and human studies that were randomized control trials, quasi-randomized control trials, controlled clinical trials, retrospective studies, and case series were included. RESULTS: Six studies, with a total of 990 patients, met the inclusion criteria for the review and were included. Primary outcomes were signs and symptoms of nasal or sinus infections in patients who underwent nasal packing for epistaxis or septoplasty. There were no reports of toxic shock syndrome in any patients, and there was no statistical difference in purulent drainage in patients who had septoplasty (9.9 versus 11.2%) treated with or without antibiotics. CONCLUSION: There is a paucity of literature that reviewed the need for prophylactic systemic antibiotics with nasal packing. The available literature does not show a significant benefit to the use of antibiotics with nasal packing, but the studies were underpowered to detect such a difference. One must consider the associated risks of prophylactic antibiotics to the patient as well when deciding to prescribe prophylactic antibiotics. PMID- 28716176 TI - Systematic review of patient-reported outcomes after revision endoscopic sinus surgery. AB - BACKGROUND: Revision endoscopic sinus surgery (RESS) may be required for partially controlled or uncontrolled chronic rhinosinusitis. Studies that reported technical success, e.g., sinus ostia patency after RESS, do not address whether the patient's symptoms and quality of life (QOL) improve after surgery. However, patient-reported outcome measures (PROM) are useful to assess the impact of sinus surgery on a patient's symptoms and QOL. OBJECTIVE: This systematic review was undertaken to evaluate the impact of RESS on PROMs. METHODS: Medical literature databases were searched for studies in English. References from retrieved articles and relevant reviews were examined for additional studies. Those studies that reported QOL outcome tools in patients who underwent RESS and with a minimum follow-up of 6 months were included. RESULTS: A search of the sources yielded 1856 citations. There were 72 articles after abstract review and exclusion, identified for full-text review, with 12 studies (which contained data from 1308 patients) that met the inclusion criteria for this systematic review. There were four "good" and eight "fair" studies. Three studies used the Rhinosinusitis Disability Index and Chronic Sinusitis Survey in tandem; two each used the 20-item Sino-Nasal Outcome Test and the 22-item Sino-Nasal Outcome Test; the remaining studies used either the Adelaide Disease Severity Score, Patient Response Score (PRS), Rhinosinusitis Symptom Inventory, Rhinosinusitis Outcome Measure 31, or the Chinese version of the University of Pennsylvania Smell Identification Test. All studies used validated PROMs apart from the study that used PRS. Studies consistently reported improvement in the five key symptoms of nasal obstruction, rhinorrhea, postnasal drip, facial pain, and anosmia, although improvement in halitosis, fever, dental pain, and cough were modest. CONCLUSION: Several PROMs demonstrated that RESS improves patient's QOL symptoms. Future studies that examine QOL should use a consistent PROM to allow a meta-analysis. PMID- 28716177 TI - Septal extension graft in "closed" revision rhinoplasty: A simplified technique. AB - BACKGROUND: The septal extension graft (SEG) is widely used in secondary rhinoplasty for correction of a short nose with loss of tip support and projection, columellar retraction, and hyper-rotated tip secondary to an overresection of the caudal septum. Although SEG precise fixation can be relatively easy in the external approach, the difficulties of SEG placement in "closed" rhinoplasty can be discouraging. OBJECTIVE: To describe an easy surgical technique for SEG placement in endonasal revision rhinoplasty and to analyze the aesthetic results of the procedure. METHODS: Thirty-eight patients were submitted to an endonasal approach revision rhinoplasty with endonasal placement of SEG for the correction of a short nose with a hypoprojected and hyper-rotated nasal tip. Pre- and postoperative nasal length, tip projection, and tip rotation (nasolabial and lobulocolumellar angles) were measured for each patient. RESULTS: An increase (mean +/- standard deviation) of nasal length by 15.02 +/- 3.91% and an augmentation of tip projection by 11.34 +/- 2.26% were noticed after surgery with respect to preoperative conditions. A significant (p < 0.001) decrease in the columellar-labial angle was recorded on postoperative (91.23 +/- 3.85 degrees ) examination with respect to preoperative (99.81 +/- 6.49 degrees ) conditions. A decrease (p < 0.001) in the columellar-lobular angle was noted on postoperative assessment (34.02 +/- 5.28 degrees ) with respect to preoperative examination (50.02 +/- 0.36 degrees ). No relevant postoperative complication was recorded. CONCLUSION: The "endonasal" approach described for SEG placement was an easy and reliable procedure to treat a short nose with loss of tip support and projection, columellar retraction, and hyper-rotated tip, especially in revision surgery. The advantages of our technique over previously described approaches were reported. PMID- 28716178 TI - Short-term morbidity after the endoscopic modified Lothrop (Draf-III) procedure compared with Draf-IIa. AB - BACKGROUND: The endoscopic modified Lothrop (Draf-III) surgery has improved treatment of recalcitrant frontal sinus disease, with favorable safety and long term results. However, the short-term clinical and quality-of-life morbidity after Draf-III relative to less-extensive procedures has yet to be investigated. OBJECTIVE: To evaluate the surgical and quality-of-life outcomes, including the burden of follow-up care, in patients who underwent endoscopic modified Lothrop (Draf-III), and compared these results with a less-extensive intervention, the endoscopic frontal sinusotomy (Draf-IIa). METHODS: A retrospective review of early (<8 weeks) postoperative recovery of patients who underwent Draf-III (2014 to 2016) for chronic rhinosinusitis was conducted and compared with age and radiographically matched Draf-IIa controls. Primary outcomes included perioperative complications, the number of postoperative clinic visits, debridements, and steroid and antibiotic therapy days. Secondary outcomes included the change in the 22-item Sino-Nasal Outcome Test (SNOT-22) scores and/or subscores (domains). RESULTS: Thirty-eight patients (19 Draf-III, 19 Draf IIa) were included. Patients who underwent Draf-III versus Draf-IIa required more postoperative clinic visits (4.9 +/- 1.7 versus 3.3 +/- 0.8; p < 0.05), debridements (4.2 +/- 2.0 versus 2.3 +/- 0.8; p < 0.05), and antibiotic therapy days (24.4 +/- 11.8 versus 15.6 +/- 6.3; p < 0.05). The mean (SD) SNOT-22 scores improved for both groups (-12.7 +/- 34.5 versus -9.5 +/- 20.4; p = 0.74) over the follow-up period, and subscore (domain) analysis demonstrated worsening extranasal symptoms (2.5 +/- 3.0 versus -1.5 +/- 4.7; p < 0.05) at the first postoperative visit, and less improvement in ear/facial symptoms at the second ( 0.5 +/- 2.6 versus -3.9 +/- 4.7; p = 0.03) and third postoperative visits (-1.1 +/- 1.6 versus 3.5 +/- 3.3; p = 0.01). CONCLUSION: Draf-III is associated with more postoperative clinic visits, debridements, and antibiotic therapy days. The patients who underwent Draf-III demonstrated worsening of extranasal symptoms at the first postoperative visit and less improvement in the ear/facial score at the second and third visits. Informed consent and counseling patients who may require Draf-III should include a detailed discussion of the burden of postoperative care and recovery. PMID- 28716179 TI - Surgical treatment of chronic rhinosinusitis after sinus lift. AB - BACKGROUND: The sinus lift (or sinus augmentation) is a common procedure to improve maxillary bone stock before dental implantation. Chronic rhinosinusitis (CRS) is a potential complication of this procedure and may be refractory to medical treatment. Functional endoscopic sinus surgery has previously been used to address CRS, however, results of previous studies indicated that implant removal is required. There are limited follow-up data available. OBJECTIVE: The purpose of this study was to characterize the long-term outcomes and efficacy of endoscopic sinus surgery for refractory CRS after sinus lift, including the ability to salvage dental implants. METHODS: This was a retrospective case series that described nine patients who, between June 2011 and September 2016, underwent endoscopic sinus surgery for CRS after a sinus lift procedure. The presenting symptoms of the patients, medical management, imaging results, operative procedures, and outcomes were reviewed. RESULTS: The majority of patients developed symptoms (mucopurulent nasal drainage, facial pain and/or pressure, nasal congestion, and foul smell) within 3 months of implant placement and were treated with at least three courses of antibiotics before referral to an otolaryngologist. All the patients underwent wide endoscopic maxillary antrostomy, with no surgical complications or postoperative reports of infection. There was a statistically significant improvement in 22-item Sino-Nasal Outcome Test scores (t(8) = -2.908; p = 0.02) and discharge, inflammation, and polyps/edema endoscopic scores ([z = -2.539; p = 0.011) between pre- and postsurgical treatment. Four patients had their dental implants removed before presentation. Among the five patients who presented with intact dental implants, none required removal before or after functional endoscopic sinus surgery. CONCLUSION: Functional endoscopic sinus surgery was a reasonable and efficacious treatment option for patients who presented with paranasal sinus disease after a sinus lift. Dental implant removal may not be a requirement for successful treatment of CRS associated with sinus lift procedures. PMID- 28716180 TI - Endoscopic septoplasty: "How I do it". AB - BACKGROUND: Multiple methods exist for nasal septoplasty. Proliferation of endoscopic technology has broadened these options. METHODS: Technical description of two techniques for endoscopic septoplasty. RESULTS: The endoscope can be utilized for visualization under the flaps after, a Killian or hemitransfixion incision, to address broad-based convexities.Endoscopic visualization is also useful when resecting focal spurs, with the incision placed directly over the spur apex. CONCLUSION: With careful patient selection and technique application, use of the endoscope has augmented the practice of septoplasty. PMID- 28716181 TI - Prevalence of polyp recurrence after endoscopic sinus surgery for chronic rhinosinusitis with nasal polyposis. PMID- 28716183 TI - The c-Jun N-terminal kinase pathway of a vector insect is activated by virus capsid protein and promotes viral replication. AB - No evidence has shown whether insect-borne viruses manipulate the c-Jun N terminal kinase (JNK) signaling pathway of vector insects. Using a system comprising the plant virus Rice stripe virus (RSV) and its vector insect, the small brown planthopper, we have studied the response of the vector insect's JNK pathway to plant virus infection. We found that RSV increased the level of Tumor Necrosis Factor-alpha and decreased the level of G protein Pathway Suppressor 2 (GPS2) in the insect vector. The virus capsid protein competitively bound GPS2 to release it from inhibiting the JNK activation machinery. We confirmed that JNK activation promoted RSV replication in the vector, whereas JNK inhibition caused a significant reduction in virus production and thus delayed the disease incidence of plants. These findings suggest that inhibition of insect vector JNK may be a useful strategy for controling the transmission of plant viruses. PMID- 28716182 TI - ATP sensing in living plant cells reveals tissue gradients and stress dynamics of energy physiology. AB - Growth and development of plants is ultimately driven by light energy captured through photosynthesis. ATP acts as universal cellular energy cofactor fuelling all life processes, including gene expression, metabolism, and transport. Despite a mechanistic understanding of ATP biochemistry, ATP dynamics in the living plant have been largely elusive. Here, we establish MgATP2- measurement in living plants using the fluorescent protein biosensor ATeam1.03-nD/nA. We generate Arabidopsis sensor lines and investigate the sensor in vitro under conditions appropriate for the plant cytosol. We establish an assay for ATP fluxes in isolated mitochondria, and demonstrate that the sensor responds rapidly and reliably to MgATP2- changes in planta. A MgATP2- map of the Arabidopsis seedling highlights different MgATP2- concentrations between tissues and within individual cell types, such as root hairs. Progression of hypoxia reveals substantial plasticity of ATP homeostasis in seedlings, demonstrating that ATP dynamics can be monitored in the living plant. PMID- 28716184 TI - Oxygen isotopes suggest elevated thermometabolism within multiple Permo-Triassic therapsid clades. AB - The only true living endothermic vertebrates are birds and mammals, which produce and regulate their internal temperature quite independently from their surroundings. For mammal ancestors, anatomical clues suggest that endothermy originated during the Permian or Triassic. Here we investigate the origin of mammalian thermoregulation by analysing apatite stable oxygen isotope compositions (delta18Op) of some of their Permo-Triassic therapsid relatives. Comparing of the delta18Op values of therapsid bone and tooth apatites to those of co-existing non-therapsid tetrapods, demonstrates different body temperatures and thermoregulatory strategies. It is proposed that cynodonts and dicynodonts independently acquired constant elevated thermometabolism, respectively within the Eucynodontia and Lystrosauridae + Kannemeyeriiformes clades. We conclude that mammalian endothermy originated in the Epicynodontia during the middle-late Permian. Major global climatic and environmental fluctuations were the most likely selective pressures on the success of such elevated thermometabolism. PMID- 28716185 TI - Pitavastatin and HDL: Effects on plasma levels and function(s). AB - Low high density lipoprotein cholesterol (HDL-C) levels represent an independent risk factor for cardiovascular disease; in addition to the reduced HDL-C levels commonly observed in patients at cardiovascular risk, the presence of dysfunctional HDL, i.e. HDL with reduced atheroprotective properties, has been reported. Despite the established inverse correlation between HDL-C levels and cardiovascular risk, several clinical trials with HDL-C-increasing drugs (such as niacin, CETP inhibitors or fibrate) failed to demonstrate that a significant rise in HDL-C levels translate into a cardiovascular benefit. Statins, that are the most used lipid-lowering drugs, can also increase HDL-C levels, although this effect is highly variable among studies and statins; the most recent developed statin, pitavastatin, beside its role as LDL-C-lowering agent, increases HDL-C levels at a significantly higher extent and progressively upon treatment; such increase was observed also when patients where shifted from another statin to pitavastatin. The stratification by baseline HDL-C levels revealed that only pitavastatin significantly increased HDL-C levels in patients with baseline HDL-C <=45 mg/dl, while no changes were observed in patients with higher baseline HDL-C levels. In the last years the hypothesis that functional properties of HDL may be more relevant than HDL-C levels has risen from several observations. The treatment with pitavastatin not only increased HDL-C levels, but also increased the phospholipid content of HDL, increased the HDL efflux capacity and their anti oxidant properties. These observations suggest that, besides its high LDL-C lowering effect, pitavastatin also exhibits a significantly higher ability to increase HDL-C levels and may also positively affect the quality and functionality of HDL particles. PMID- 28716186 TI - Formation of protein/surfactant adsorption layer as studied by dilational surface rheology. AB - The review discusses the mechanism of formation of protein/surfactant adsorption layers at the liquid - gas interface. The complexes of globular proteins usually preserve their compact structure a low surfactant concentrations. Therefore a simple kinetic model of the adsorption of charged compact nanoparticles is discussed first and compared with experimental data. The increase of surfactant concentrations results in various conformational transitions in the surface layer. One can obtain information on the changes of the adsorption layer structure using the dilational surface rheology. The kinetic dependencies of the dynamic surface elasticity are strongly different for the adsorption of unfolded macromolecules and compact globules, and have local maxima in the former case corresponding to different steps of the adsorption. These distinctions allow tracing the changes of the tertiary structure of protein/surfactant complexes in the surface layer. The adsorption from mixed solutions of ionic surfactants with beta-casein, beta-lactoglobulin, bovine serum albumin and myoglobin is discussed with some details. PMID- 28716187 TI - Impact of albumin based approaches in nanomedicine: Imaging, targeting and drug delivery. AB - A major challenge in the field of nanomedicine is to transform laboratory innovations into commercially successful clinical products. In this campaign, a variety of nanoenabled approaches have been designed and investigated for their role in biomedical applications. The advantages associated with the unique structure of albumin imparts it with the ability to interact with variety of molecules, while the functional groups present on their surface provide base for large number of modifications making it as an ideal nanocarrier system. So far, a variety of albumin based nanoenabled approaches have been intensively exploited for effective diagnosis and personalized medicine, among them some have successfully completed their journey from lab bench to marketed products. This review focuses on the recent most promising advancement in the field of albumin based nanoenabled approaches for various biomedical applications and their potential use in cancer diagnosis and therapy. PMID- 28716188 TI - Is toll-like receptor-2 really inhibiting FoxP3+ TLR2+ cells and enhancing the anti-tumour response in oral squamous cell carcinoma? PMID- 28716189 TI - Prediction of Streptococcus uberis clinical mastitis risk using Matrix-assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF MS) in dairy herds. AB - The purpose of this study was to evaluate whether the risk of Streptococcus uberis clinical mastitis at cow level could be predicted from the historical presence of specific strains of S. uberis on dairy farms. Matrix-assisted laser desorption ionization time of flight mass spectrometry was used to identify S. uberis isolates potentially capable of contagious transmission. Data were available from 10,652 cows from 52 English and Welsh dairy farms over a 14 month period, and 521 isolates of S. uberis from clinical mastitis cases were available for analysis. As well as the temporal herd history of clinical mastitis associated with particular S. uberis strains, other exposure variables included cow parity, stage of lactation, milk yield, and somatic cell count. Observations were structured longitudinally as repeated weekly measures through the study period for each cow. Data were analyzed in a Bayesian framework using multilevel logistic regression models. Similarity of mass spectral profiles between isolates of S. uberis from consecutive clinical cases of mastitis in herds was used to indicate potential for contagious phenotypic characteristics. Cross validation showed that new isolates with these characteristics could be identified with an accuracy of 90% based on bacterial protein mass spectral characteristics alone. The cow-level risk in any week of these S. uberis clinical mastitis cases increased with the presence of the same specific strains of S. uberis in other cows in the herd during the previous 2 weeks. The final statistical model indicated there would be a 2-3 fold increase in the risk of S. uberis clinical mastitis associated with particular strains if these occurred in the herd 1 and 2 weeks previously. The results suggest that specific strains of S. uberis may be involved with contagious transmission, and predictions based on their occurrence could be used as an early warning surveillance system to enhance the control of S. uberis mastitis. PMID- 28716190 TI - Risk factors for underweight and overweight in cats in metropolitan Sydney, Australia. AB - Obesity is regarded as one of the most significant welfare issues in companion animals. Some risk factors affecting body condition in cats have been determined, but many remain controversial. The current study aimed to investigate the risk factors for overweight and underweight in cats in metropolitan Sydney. Electronic patient records for 11 years (2005-2015) were acquired from a feline primary practice in metropolitan Sydney. The 9-point body condition score (BCS) evaluation in each visit was classified into three groups: underweight (1-3), ideal-weight (4-6) and overweight (7-9). Multinomial logistic regression was used to identify the risk factors for underweight and overweight. The risk factors tested included: breed, hair length, sex, neuter status, age at neutering, age at visit, microchip status, lifestyle, reason for the clinic visit and the number of visits by a cat in a calendar year. The BCS examiner was included as a confounder. Over the 11-year period, 4,020 cats had made 18,349 visits to the clinic, from which BCS records were available for 15,659 visits (85.3%), with 834 cats (5.3%) being underweight, 12,362 (79.0%) being ideal-weight and 2,463 (15.7%) being overweight. Although various cat breeds showed a different tendency for body condition, British Shorthair and mixed-breed cats were more likely to be overweight. Non-illness related visits and middle age (7-11 years old) were also risk factors for overweight. The risk factors for underweight included purebred cats (apart from British Shorthair and Burmese), medium-or-long hair, being intact, increase in age, not having a microchip and illness-related visits. Sex was not a significant risk factor for either overweight or underweight. The study demonstrated that the risk factors for overweight and the protective factors for underweight were not necessarily the same, highlighting the importance of investigating the risk factors for underweight and overweight separately in future research. PMID- 28716191 TI - Effect of immunologic solutions on sows and gilts on time to stability, and production losses in breeding herds infected with 1-7-4 PRRSv. AB - Porcine reproductive and respiratory syndrome virus (PRRSv) is an economically significant swine pathogen causing production losses in the global swine industry. Clinical impact depends on many factors including the virus itself. One method to sub-type PRRSv is using restriction fragment length polymorphism (RFLP). The RFLP pattern 1-7-4 emerged within the United States swine industry in 2014 and has become prevalent since then. This was a field study that prospectively followed 1-7-4-infected breeding herds (n=107) and compared time to stability (TTS), time to baseline production (TTBP) and total loss per 1000 sows between herds using modified-live virus vaccine (MLV) on sows and gilts (MLV MLV), MLV on sows and MLV in addition to field virus exposure on gilts (MLV MLV/FVE) or not deliberately exposing sows or gilts to PRRSv (Natural-Natural). Analyses were done in SAS 9.4 and results were adjusted by selected co-variates (duration of herd closure, number of previous PRRSv outbreaks of last 3 years, weaning frequency/week, gilt development unit location, herd size and production system). Survival analysis was conducted on TTS and TTBP and regression analysis on total loss. Herds in the Natural-Natural group achieved TTS and TTBP before other herds. Herds in the MLV-MLV/FVE had the longest TTS and TTBP. The total loss was numerically least in MLV-MLV herds (1194 pigs/1000 sows) compared to MLV/MLV-FVE (1810/1000 sows) and Natural-Natural (2671/1000 sows). This study provided additional information to assist veterinarians deciding between methods of exposure to manage PRRSv infection from breeding herds. PMID- 28716192 TI - Impact of FMD outbreak on milk production and heifers' growth on a dairy herd in southern Iran. AB - Foot and mouth disease is endemic in Middle Eastern countries including Iran but its impact is poorly characterized. The present study was conducted to evaluate the impact of FMD outbreak on milk production and heifers' growth in an industrial dairy herd located in Fars province, southern Iran. Data about individual milk production, heifers' growth and total daily milk (sold for manufacturing), its fat and protein content and somatic cell counts were collected from the herd database. Based on the results of the linear mixed models, a significant decline in individual milk production after the outbreak was observed compared with before the outbreak. There was a total reduction of 8.0 and 4.7% in mean daily milk production per cow after the outbreak when compared with before (over a 42days outbreak period) in lactation one (P<0.001) and lactation >=2 cows (P=0.024), respectively. The total daily milk (P=0.027) and protein (P=0.002) showed significant decline during the outbreak period. The fat content decreased after the outbreak (P=0.014). Somatic cell counts did not show significant changes. The recorded heifers' weights (4-17 months of age) showed 7.1kg decrease after the outbreak in comparison with the period before that (P<0.001). In conclusion, we observed a negative impact of FMD outbreak on milk production and heifers' growth in study herd. The impact on daily milk production was less than the values reported previously. This difference could be attributed at least partly to differences in livestock genetics and management practices. Lower growth rate of heifers after the outbreak period could potentially extend the age at first calving. It is suggested that farmers are educated on awareness and preparation for infectious disease outbreaks and to practice good management routines that could potentially reduce the economic impact of these diseases. PMID- 28716193 TI - Epidemiological features and financial loss due to clinically diagnosed Haemorrhagic Septicemia in bovines in Karnataka, India. AB - The epidemiological features and financial losses due to Haemorrhagic Septicemia (HS) in bovines were studied in Karnataka state using the primary data collected from 133 clinically diagnosed HS affected farms. The various losses due to HS and the Benefit- Cost of the vaccination programme in cattle and water buffaloes were studied using mathematical models. The number of HS outbreaks were higher during the year 2002 and peaked during 2005 and thereafter declined due to targeted vaccination against HS. The morbidity and mortality risks were lower in large farms than medium and small farms, and lower in indigenous cattle compared to high yielding crossbred cattle and water buffaloes. The disease occurrence was more in in-milk animals causing serious economic loss to the farmers. Most outbreaks were observed during monsoon season, though the disease was prevalent throughout the year. The mean milk loss per animal was $2, $11 and $50 in indigenous cattle, water buffaloes and crossbred cattle, respectively. In the case of draught animals, the average effective draught power was unavailable for 1.2days/outbreak resulting in a loss of $5 per affected oxen. The treatment and extra labor expenses incurred per animal were $24 and $7, respectively. The average loss per animal due to mortality loss was $275, $284 and $415 in case of indigenous cattle, water buffaloes and crossbred cattle, respectively. The projected loss for the state of Karnataka were $23.89, $17.92 and $11.95 million under high, medium and low HS incidence scenarios, respectively. The Benefit Cost Analysis (BCA) of the vaccination against HS has been estimated at 5.97:1, 4.48:1 and 2.98:1 under high, medium and low incidence scenarios, respectively. The results highlight the important epidemiological features and financial losses to the affected households and the state of Karnataka. PMID- 28716194 TI - VacciCost - A tool to estimate the resource requirements for implementing livestock vaccination campaigns. Application to peste des petits ruminants (PPR) vaccination in Senegal. AB - Vaccination is one of the main tools currently available to control animal diseases. In eradication campaigns, vaccination plays a crucial role by reducing the number of susceptible hosts with the ultimate goal of interrupting disease transmission. Nevertheless, mass vaccination campaigns may be very expensive and in some cases unprofitable. VacciCost is a tool designed to help decision-makers in the estimation of the resources required to implement mass livestock vaccination campaigns against regulated diseases. The tool focuses on the operational or running costs of the campaign, so acquisition of new equipment or vehicles is not considered. It takes into account different types of production systems to differentiate the vaccination productivity (number of animals vaccinated per day) in systems where animals are concentrated and easy to reach, from those characterized by small herds that are scattered and less accessible. The resource requirements are classified in eight categories: vaccines, injection supplies, personnel, transport, maintenance and overhead, training, social mobilization, and surveillance and monitoring. This categorization allows identifying the most expensive components of a vaccination campaign, which is crucial to design cost-reduction strategies. The use of the tool is illustrated using data collected in collaboration with Senegalese Veterinary Services regarding vaccination against peste des petits ruminants. The average daily number of animals vaccinated per vaccination team was found to be crucial for the costs of the campaign so significant savings can be obtained by implementing training to improve the performance of vaccination teams. PMID- 28716195 TI - Quantitative assessment of social and economic impact of African swine fever outbreaks in northern Uganda. AB - African swine fever (ASF) is one of the most important pig diseases, causing high case fatality rate and trade restrictions upon reported outbreaks. In Uganda, a low-income country with the largest pig population in East Africa, ASF is endemic. Animal disease impact is multidimensional and include social and economic impact along the value chain. In low-income settings, this impact keep people poor and push those that have managed to escape poverty back again. If the diseases can be controlled, their negative consequences can be mitigated. However, to successfully argue for investment in disease control, its cost benefits need to be demonstrated. One part in the cost-benefit equations is disease impact quantification. The objective of this study was therefore to investigate the socio-economic impact of ASF outbreaks at household level in northern Uganda. In a longitudinal study, structured interviews with two hundred, randomly selected, pig-keeping households were undertaken three times with a six month interval. Questions related to family and pig herd demographics, pig trade and pig business. Associations between ASF outbreaks and economic and social impact variables were evaluated using linear regression models. The study showed that pigs were kept in extreme low-input-low-output farming systems involving only small monetary investments. Yearly incidence of ASF on household level was 19%. Increasing herd size was positively associated with higher economic output. The interaction between ASF outbreaks and the herd size showed that ASF outbreaks were negatively associated with economic output at the second interview occasion and with one out of two economic impact variables at the third interview occasion. No significant associations between the social impact variables included in the study and ASF outbreaks could be established. Trade and consumption of sick and dead pigs were coping strategies used to minimize losses of capital and animal protein. The results indicate that causality of social and economic impact of ASF outbreaks in smallholder systems is complex. Pigs are mostly kept as passive investments rather than active working capital, complicating economic analyses and further disqualifying disease control arguments based only on standard economic models. PMID- 28716196 TI - Maximum entropy modeling risk of anthrax in the Republic of Kazakhstan. AB - The objective of this study was to zone the territory of the Republic of Kazakhstan (RK) into risk categories according to the probability of anthrax emergence in farm animals as stipulated by the re-activation of preserved natural foci. We used historical data on anthrax morbidity in farm animals during the period 1933 - 2014, collected by the veterinary service of the RK. The database covers the entire territory of the RK and contains 4058 anthrax outbreaks tied to 1798 unique locations. Considering the strongly pronounced natural focality of anthrax, we employed environmental niche modeling (Maxent) to reveal patterns in the outbreaks' linkages to specific combinations of environmental factors. The set of bioclimatic factors BIOCLIM, derived from remote sensing data, the altitude above sea level, the land cover type, the maximum green vegetation fraction (MGVF) and the soil type were examined as explanatory variables. The model demonstrated good predictive ability, while the MGVF, the bioclimatic variables reflecting precipitation level and humidity, and the soil type were found to contribute most significantly to the model. A continuous probability surface was obtained that reflects the suitability of the study area for the emergence of anthrax outbreaks. The surface was turned into a categorical risk map by averaging the probabilities within the administrative divisions at the 2nd level and putting them into four categories of risk, namely: low, medium, high and very high risk zones, where very high risk refers to more than 50% suitability to the disease re-emergence and low risk refers to less than 10% suitability. The map indicated increased risk of anthrax re-emergence in the districts along the northern, eastern and south-eastern borders of the country. It was recommended that the national veterinary service uses the risk map for the development of contra-epizootic measures aimed at the prevention of anthrax re emergence in historically affected regions of the RK. The map can also be considered when developing large-scale construction projects in the areas comprising preserved soil foci of anthrax. PMID- 28716197 TI - Quantitative and qualitative analysis of antimicrobial usage in white veal calves in France. AB - The development of antimicrobial resistance has made it necessary to measure antimicrobial usage in animal production sectors. France is a major European producer of white veal calves, but few data were previously available for that sector, even though these young animals are particularly susceptible to infection and considered as a reservoir of antimicrobial resistance. A cross-sectional study was conducted on 186 batches of French calves to estimate the exposure of white veal calves to antimicrobials and identify the potential risk factors related to antimicrobial usage. An indicator of calf exposure was calculated as a count of the number of antimicrobial treatments per calf. The indicator was based on veterinary prescriptions (products, quantity dispensed and dosage prescribed) and the estimated weight of calves at treatment, using the dates of treatment collected from farm registers. The study showed that calves were exposed to an average of 8.55 antimicrobial treatments (SD: 2.21, range: 2.75-15.86) over the five to six months of the fattening process. Group treatments were predominant (95.8%) and administered by the oral route. The "starting treatments", given during the first two weeks of the fattening period, were administered systematically (to all the calves in all the farms) and accounted for a third of all treatments. Tetracyclines, polypeptides and macrolides were the most widely used antimicrobials, with respectively 4.32, 1.59 and 1.01 treatments per calf. Only rare uses of 3rd and 4th generation cephalosporins and fluoroquinolones, considered as critically important in human medicine, were reported. Despite low variability of exposure between farms, a linear mixed-effects model highlighted a higher variability between farmers (ICC=0.14) or veterinarians (ICC=0.12), than between integrators (ICC=0.06). The number of calves per pen, introduced as a fixed effect in the model, was also significant: calves housed in pens of 6-10 and fed in buckets had on average 2.55 more antimicrobial treatments per calf than calves housed in pairs with the same feeding system. The model also highlighted an increase of 1.48 treatments per calf for farms with more than five percent of mortality, versus those with two percent or less. The present study showed that antimicrobial treatments are numerous in veal calf fattening farms, particularly at the arrival of the animals. Taking into account the development of resistance to antimicrobials, the necessity and the effectiveness of some of these treatments should be re-evaluated. PMID- 28716198 TI - Herd-specific interventions to reduce antimicrobial usage in pig production without jeopardising technical and economic performance. AB - Pig farmers are strongly encouraged to reduce their antimicrobial usage in order to reduce the risk of antimicrobial resistance. Herd-level intervention is needed to achieve national and European reduction targets. Alternative, especially preventive measures, have to be implemented to reduce the need for antimicrobial treatments. However, little is known about the feasibility, effectiveness and return on investment of such measures. The objective of this study was to assess, across four countries, the technical and economic impact of herd-specific interventions aiming at reducing antimicrobial usage in pig production while implementing alternative measures. An intervention study was conducted between February 2014 and August 2015 in 70 farrow-to-finish pig farms located in Belgium, France, Germany and Sweden. Herd-specific interventions were defined together with the farmer and the herd veterinarian. Farms were followed over one year and their antimicrobial usage and technical performance were compared with values from the year before intervention. Compliance with the intervention plan was also monitored. Changes in margin over feed cost and net farm profit were estimated in a subset of 33 Belgian and French farms with sufficient data, using deterministic and stochastic modeling. Following interventions, a substantial reduction in antimicrobial use was achieved without negative impact the overall farm technical performance. A median reduction of 47.0% of antimicrobial usage was achieved across four countries when expressed in terms of treatment incidence from birth to slaughter, corresponding to a 30.5% median reduction of antimicrobial expenditures. Farm compliance with intervention plans was high (median: 93%; min-max: 20; 100) and farms with higher compliance tended to achieve bigger reduction (rho=-0.18, p=0.162). No association was found between achieved reduction and type or number of alternative measures implemented. Mortality in suckling piglets, weaners and fatteners, daily weight gain and feed conversion ratio did not significantly change over the course of the study, while the number of weaned piglets per sow per year slightly increased. The median change in net farm profit among Belgian and French farms was estimated to be ?4.46 (Q25-Q75:-32.54; 80.50) and ?1.23 (Q25-Q75:-32.55; 74.45) per sow per year using the detererministic and stochastic models, respectively. It was more influenced by a change in feed conversion ratio and daily weight gain than by a change in antimicrobial expenditures or intervention direct net cost. Therefore, costs of alternative measures should not be perceived as a barrier, but rather as an opportunity to optimise production practices for sustained productivity and improved animal health. PMID- 28716199 TI - Strategic control of Rhipicephalus (Boophilus) microplus infestation on beef cattle grazed in Panicum maximum grasses in a subtropical semi-arid region of Argentina. AB - The aim of this work was to test the efficacy of strategic control methods of Rhipicephalus microplus infestation on beef cattle grazed in Panicum maximum grasses in northwestern Argentina. Also, an analysis to discern how the R. microplus population was distributed amongst cattle was also performed to determine if partial selective treatment or cull the small proportion of more heavily infested animals are feasible options to control this tick. The strategic scheme of treatments was designed to act on the small 1st generation of R. microplus in early spring and prevent in that way the appearance of the annual peak of abundance of R. microplus in summer and autumn. Animals of the group 1 were treated with ivermectin 3.15% on day 0 (25th September 2015), with fluazuron on day 32 (27th October 2015) and with fipronil on day 75 (9th December 2015). Animals of group 2 formed the control group. The overall effect of the treatments was positively significant. The number of ticks observed on the control group was significantly higher than the number of ticks observed on the treated group in all post-treatment counts (P<0.01), with the only exception of the count of March. The distribution of parasites among cattle in all counts was adjusted to the negative binomial distribution, but a temporal variation in the tick aggregation levels associated to changes in tick abundance was found. The higher the abundance of R. microplus, the lower the aggregation. It was found that the steers (15.8% of the total number of animals evaluated) belonging to the high infestation group accounted for 23.0% of the total ticks. The strategic control method evaluated during this study provides a remarkable overall effect against R. microplus because it significantly reduces the tick infestation on cattle with only three applications of acaricides in one-year period. The analyses of tick distribution amongst cattle suggest that partial selective treatment and culling do not represent feasible methods to control R. microplus infestation on cattle. PMID- 28716200 TI - Benchmarking of pluck lesions at slaughter as a health monitoring tool for pigs slaughtered at 170kg (heavy pigs). AB - Abattoir post-mortem inspections offer a useful tool for the development and monitoring of animal health plans and a source of data for epidemiological investigation. The aim of the present work was to develop an abattoir benchmarking system which provides feedback on the prevalence and severity of lesions of the pluck (lung, pleura and liver) in batches of pigs to inform individual producers and their veterinarians of the occurrence of pathological conditions affecting their herds. The weekly collection of data throughout a year (from September 2014 to September 2015) supported the further aim of providing benchmark values for the prevalence of lesions and their seasonality in Italian heavy pig production. Finally, correlations and redundancies among different lesions were evaluated. In total, 727 batches of heavy pigs (around 165kg live weight and 9 months of age) derived from 272 intensive commercial farms located in Northern Italy were monitored. Within each batch, an average number of 100 plucks was individually scored, assigning a value for lesions of lungs (0-24), pleura (0-4) and liver (1-3). Presence of lung scars, abscesses, consolidations, lobular/chessboard pattern lesions and pleural sequestra was also recorded. Statistical analysis showed a strong farm effect (36-68% of variation depending of the lesion) and a seasonal effect on all lesions. Winter showed the lowest percentage of severe lung and pleural lesions (P<0.001 and P=0.005), whereas lung scars from older lesions (P=0.003), as well as severe hepatic lesions (P<0.001), were reduced in autumn. In order to allow effective benchmarking of each farm in a determined health class, scores for each quartile of the population are reported. Whilst such a benchmarking scheme provides useful data for herd health management, challenges of repeatability of scoring and cost of implementation need to be overcome. PMID- 28716201 TI - A matched case-control study comparing udder health, production and fertility parameters in dairy farms before and after the eradication of Bovine Virus Diarrhoea in Switzerland. AB - An obligatory eradication programme for Bovine Virus Diarrhoea (BVD) was implemented in Switzerland in 2008. Between 2008 and 2012, all bovines were tested for antigen or antibodies against BVDV. By the year 2012, eradication was completed in the majority of farms. A decrease of the prevalence of persistently infected (PI) newborn calves was observed from 1.4% in 2008 to <0.02% in 2012. The objective of the present study was to assess the effects of BVD eradication on different parameters of animal health, production and fertility in Swiss dairy herds which had completed the eradication programme. A matched case-control study was carried out using data from two periods, before (Period 1) and after (Period 2) the active phase of eradication. Case farms had at least two PI animals detected before or during the eradication; controls were BVD-free and matched for region, herd size and use of alpine pasture. A total of 110 farmers (55 pairs) were recruited. During a phone interview, a questionnaire about farm characteristics, animal health and appreciation of the BVD eradication programme was filled in. Breeding data and milk test day records were also analyzed. Parameters were first compared between (i) case and control herds before eradication, and (ii) Period 1 and Period 2 for case herds only. Milk yield (MY), bulk milk somatic cell count (BMSCC), prevalence of subclinical mastitis (SCM), and non-return rate (NRR) showed a p-value<0.25 in at least one of the univariable comparisons and were thus further analyzed with a multilevel mixed effects model to account for repeated measures over time. In order to assess whether changes in health status over time were due to BVD eradication, an interaction variable between period and group (case-control) was created (IA). Except for MY, the IA was significant for all parameters modelled. Despite an overall p-value of 0.27, case herds tended to have a higher MY after eradication (beta=0.53, p=0.050). For BMSCC and SCM, case herds had higher values than controls in both periods; udder health was significantly improved in control herds and it remained stable in case herds, with a slight decrease of BMSCC (beta=-0.19, p=0.010). Finally, among fertility parameters, NRR showed a general improvement but it was significant only in control herds (beta=0.29, p=0.019). Even though the effects of the eradication programme measured in this study were less pronounced than expected, 73% of the participants of this study had a positive attitude towards the campaign. PMID- 28716202 TI - A scoping review of published research on the population dynamics and control practices of companion animals. AB - Companion animal population dynamics is a global, diverse issue that can affect society in multiple ways, including impacts on public health, environmental destruction and shelter management. The purpose of this scoping review was to use structured and transparent methods to identify all published research investigating companion animal population dynamics and/or control practices. A comprehensive search strategy was implemented using five online databases (i.e., PubMed, CAB Direct, Agricola, PsycINFO, and Scopus) and resulted in the identification of 7810 unique citations. These citations were screened for relevance by two independent reviewers. Of these, 1410 were initially deemed relevant. Full articles were procured and 931 articles (456 primary research and 475 reviews) were confirmed relevant and important data extracted. Most of the included articles were published in the United States (395, 42.4%) and 218 articles (23.4%) were published between 2012 and 2015. The majority of the articles investigated or discussed control practices (758, 81.4%), more specifically different reproduction control practices (597, 64.1%), or euthanasia (345, 37.1%) methods The quantity of research in these areas offers future opportunities for systematic review and meta-analysis. PMID- 28716203 TI - Testing of milk replacers for Mycobacterium avium subsp. paratuberculosis by PCR and bacterial culture as a possible source for Johne's disease (paratuberculosis) in calves. AB - Johne's disease (paratuberculosis) is caused by Mycobacterium avium subsp. paratuberculosis (MAP) and can lead to severe economic losses in the affected cattle herds. The transmission of the disease occurs mainly orally, by the ingestion of MAP, which is shed in the feces and milk of infected animals. Calves show a high susceptibility for the infection compared to adult animals. The use of milk replacers can, therefore, contribute to the prevention of the transmission of the disease to calves in MAP-positive herds by preventing the ingestion of the bacterium with milk from infected animals. The objective of this study was to test milk replacers for calves for the presence of MAP by bacteriological culture and PCR. Therefore, commercially available milk replacers for calves were purchased from 15 different companies. All of the products were tested for MAP by solid culture and real time quantitative PCR (qPCR) targeting IS900 and F57. During the present study, MAP could not be detected by qPCR or solid culture in commercially available milk replacers for calf rearing. The results of the present study underpins that the use of milk replacers for calf rearing might contribute to the reduction of MAP intake by calves in JD positive herds. Additional studies, including more products with a higher diversity, are needed to further elucidate the presence or absence of MAP in milk replacers for calves. PMID- 28716204 TI - A protocol to identify and minimise selection and information bias in abattoir surveys estimating prevalence, using Fasciola hepatica as an example. AB - Abattoir surveys and findings from post-mortem meat inspection are commonly used to estimate infection or disease prevalence in farm animal populations. However, the function of an abattoir is to slaughter animals for human consumption, and the collection of information on animal health for research purposes is a secondary objective. This can result in methodological shortcomings leading to biased prevalence estimates. Selection bias can occur when the study population as obtained from the abattoir is not an accurate representation of the target population. Virtually all of the tests used in abattoir surveys to detect infections or diseases that impact animal health are imperfect, leading to errors in identifying the outcome of interest and consequently, information bias. Examination of abattoir surveys estimating prevalence in the literature reveals shortcomings in the methods used in these studies. While the STROBE-Vet statement provides clear guidance on the reporting of observational research, we have not found any guidelines in the literature advising researchers on how to conduct abattoir surveys. This paper presents a protocol in two flowcharts to help researchers (regardless of their background in epidemiology) to first identify, and, where possible, minimise biases in abattoir surveys estimating prevalence. Flowchart 1 examines the identification of the target population and the appropriate study population while Flowchart 2 guides the researcher in identifying, and, where possible, correcting potential sources of outcome misclassification. Examples of simple sensitivity analyses are also presented which approximate the likely uncertainty in prevalence estimates due to systematic errors. Finally, the researcher is directed to outline any limitations of the study in the discussion section of the paper. This protocol makes it easier to conduct an abattoir survey using sound methods, identifying and, where possible, minimizing biases. PMID- 28716205 TI - Attitudes towards worm egg counts and targeted selective treatment against equine cyathostomins. AB - Gastrointestinal nematodes present a major threat to the health and welfare of equids worldwide. Anthelmintic resistance (AR) is increasingly reported and challenges effective control in horses and ponies in many regions. The use of faecal worm egg counts (FECs) to support targeted treatment (FEC-TT) and targeted selective treatment (FEC-TST) has been promoted as an effective deworming strategy that may prolong the useful life of anthelmintics and reduce the costs associated with parasite control. However, treatment applied at set intervals or on pre-determined dates remains common. A structural equation model was developed to identify factors influencing the uptake of FEC-directed treatment strategies, based on well-established socio-psychological theories of intentional health related behaviours: the Theory of Planned Behaviour and the Health Belief Model. More than 850 valid responses were received from horse owners in the UK via an online survey. The intention to use FECs prior to deworming was not influenced by the perceived risk of anthelmintic resistance or that of gastrointestinal nematode infection but was positively influenced by a negative attitude towards anthelmintics, a positive attitude towards FECs, an increase in social pressure (e.g. significant others think the respondent should use FECs) and an increase in perceived control over their deworming programme. The results were consistent with a similar study conducted on FEC-TT in cattle in Belgium. An increase in respondents' self-perceived level of knowledge significantly increased the intention to use FECs via mediating factors. These results suggest that knowledge transfer activities aimed at increasing awareness and understanding of sustainable nematode control practices may be more effective at encouraging behaviour change than emphasising the dangers of nematodes and AR, which had limited influence on behaviour intention in this study population. PMID- 28716206 TI - Contextual herd factors associated with cow culling risk in Quebec dairy herds: A multilevel analysis. AB - Several health disorders, such as milk fever, displaced abomasum, and mastitis, as well as impaired reproductive performance, are known risk factors for the removal of affected cows from a dairy herd. While cow-level risk factors are well documented in the literature, herd-level associations have been less frequently investigated. The objective of this study was to investigate the effect of cow- and herd-level determinants on variations in culling risk in Quebec dairy herds: whether herd influences a cow's culling risk. For this, we assessed the influence of herd membership on cow culling risk according to displaced abomasum, milk fever, and retained placenta. A retrospective longitudinal study was conducted on data from dairy herds in the Province of Quebec, Canada, by extracting health information events from the dairy herd health management software used by most Quebec dairy producers and their veterinarians. Data were extracted for all lactations starting between January 1st and December 31st, 2010. Using multilevel logistic regression, we analysed a total of 10,529 cows from 201 herds that met the inclusion criteria. Milk fever and displaced abomasum were demonstrated to increase the cow culling risk. A minor general herd effect was found for the culling risk (i.e. an intra-class correlation of 1.0% and median odds ratio [MOR] of 1.20). The proportion of first lactation cows was responsible for this significant, but weak herd effect on individual cow culling risk, after taking into account the cow-level factors. On the other hand, the herd's average milk production was a protective factor. The planning and management of forthcoming replacement animals has to be taken into consideration when assessing cow culling risks and herd culling rates. PMID- 28716207 TI - Influence of true within-herd prevalence of small ruminant lentivirus infection in goats on agreement between serological immunoenzymatic tests. AB - The study was conducted to evaluate influence of the true within-herd prevalence of small ruminant lentivirus (SRLV) infection on agreement beyond chance between three different types of commercial serological ELISAs. Blood samples were collected from 865 goats from 12 dairy goat herds. Serum samples were tested using three commercial ELISA kits: whole-virus indirect ELISA (wELISA), indirect ELISA based on recombined TM and CA antigens (TM/CA-ELISA), and competitive inhibition ELISA based on SU antigen (SU-ELISA). Herds were classed into three prevalence strata of high (>50%), moderate (10-50%) and low (<10%) true within herd prevalence of SRLV infection. The latter was estimated on the basis of results of wELISA adjusted by its sensitivity and specificity. Agreement beyond chance between the three ELISAs was assessed at two levels. First, the general agreement was determined using two coefficients corrected for chance-agreement: Cohen's kappa and Gwet's AC1. Then, agreement between tests was evaluated using Gwet's AC1 separately in the three prevalence strata and compared between them by computing 95% confidence intervals for differences with a Bonferroni correction for multiple comparisons. The general agreement between the three tests was very good: wELISA and TM/CA-ELISA - Cohen's kappa of 81.8% (CI 95%: 77.9% to 85.7%), Gwet's AC1 of 82.7% (CI 95%: 79.0% to 86.4%); wELISA and SU-ELISA - Cohen's kappa of 83.2% (CI 95%: 79.4% to 86.9%), Gwet's AC1 of 83.9% (CI 95%: 80.4% to 87.5%); TM/CA-ELISA and SU-ELISA - Cohen's kappa of 86.0% (CI 95%: 82.6% to 89.5%), Gwet's AC1 of 86.9% (CI 95%: 83.6% to 90.1%). However, agreement between ELISAs was significantly related to the within-herd true prevalence - it was significantly lower (although still high) when within-herd true prevalence was moderate (Gwet's AC1 between 67.2% and 78.7%), whereas remained very high, when true within-herd prevalence was either >50% (Gwet's AC1 between 91.9% and 98.8%) or <10% (Gwet's AC1 between 94.7% and 98.4%). Concluding, the three different commercial ELISAs for SRLV infection in goats available on the market yield highly consistent results. However, their agreement is affected by the true within-herd prevalence in a tested population, and the worse (although still high) agreement should be expected, when the percentage of infected goats is moderate. PMID- 28716208 TI - Spatial dynamics of porcine epidemic diarrhea (PED) spread in the southern Kyushu, Japan. AB - Porcine epidemic diarrhea (PED) was detected for the first time in seven years in Japan in October 2013 in Okinawa Prefecture. By December 2013, PED had spread into Miyazaki and Kagoshima Prefectures in the southern part of Kyushu, one of the regions with the highest farm density in the country. The objective of the study here was to assess the spatial dynamics of PED spread during the 8 months of the epidemic in the southern part of Kyushu between December 2013, the month observed first case in the studied region, and July 2014. Information on location and capacity of all farms in the prefectures (n=1269) was obtained from a government database containing demographic information for livestock producers. Additionally, data on PED detection (positive or negative) was obtained from the regional Livestock Hygiene Service Center. The Cuzick-Edwards (CE) test, the Knox test, the directional test, and the permutation model of the scan statistic were used to assess the spatio-temporal distribution of the epidemic. PED cumulative farm level incidence was 19.5% (248/1269) through the study period. The highest density of positive farms was observed in the most farm-populated areas of the prefecture. The CE test revealed an extensive degree of spatial clustering, with clustering of positive sites being significant (P<0.01) up to the 35th level of neighborhood (approximately 5km in the studied data). The observed-to-expected ratio of cases was maximized at short spatio-temporal distances, with values of the observed-to-expected ratio of cases maximized when the thresholds were set at 2km and 10days, respectively. A significant (P<0.01) direction of spread was detected towards the northeastern direction. The permutation model detected five significant (P<0.01) clusters occurring at different stages of the epidemic wave. The strong spatio-temporal clustering of PED-infected farms during the first 6 months of the epidemic in the southern part of Kyushu is consistent with results obtained elsewhere and demonstrates the rapid spread of the virus in naive populations. PMID- 28716209 TI - Understanding animal health communication networks among smallholder livestock producers in Australia using stakeholder analysis. AB - Smallholder livestock producers are a diverse population with wide ranging motivations for keeping livestock. The biosecurity risk posed by smallholders has been the subject of much conjecture, with comparisons often made between the level of animal health and biosecurity knowledge of smallholders, versus that of commercial livestock producers. This research aimed to gain a better understanding of current knowledge of smallholder production in Australia, particularly in relation to biosecurity and emergency animal disease, and to investigate the relationships that exist between smallholders and the organisations and individuals from which they seek information, assistance and support. Engagement with stakeholders is an important component of an effective biosecurity communication strategy as the dissemination of biosecurity related information from a single source cannot be expected to satisfy the needs of such a broad ranging population. A qualitative study involving a review of literature, semi-structured interviews with government and non-government stakeholders and the development of smallholder and stakeholder influence and interest grids was undertaken. This paper forms part of a broader mixed methods research project among smallholders. Results from the stakeholder analysis showed variation in the parameters used to define smallholders and in the level of stakeholder involvement. Smallholders identified breeding consultants, other producers, private veterinarians and family, friends and colleagues as having a significant to high level of interest and potential to influence their practices. Government agencies were perceived to only have some level of interest but significant influence. Industry stakeholders and rural suppliers were positioned in the quadrant reflecting perceived low levels of interest and influence. The interest and influence grid developed from stakeholder's perspectives demonstrate a clustering around the mid points for both interest and influence, with the exception of those from industry who described low levels of interest and influence. Commonwealth and State government stakeholders reported a higher level of interest than influence. Veterinarians, both government and private, reported some to significant levels of interest and influence. In contrast to the results from the smallholder grid, rural suppliers reported relatively high levels of both interest and influence. The current study demonstrates that to maximise the effectiveness of biosecurity communication, there is a need for government and industry organisations to further engage with all stakeholders involved with smallholders. PMID- 28716210 TI - Exploring injury severity measures and in-hospital mortality: A multi-hospital study in Kenya. AB - INTRODUCTION: Low- and middle-income countries (LMICs) have a disproportionately high burden of injuries. Most injury severity measures were developed in high income settings and there have been limited studies on their application and validity in low-resource settings. In this study, we compared the performance of seven injury severity measures: estimated Injury Severity Score (eISS), Glasgow Coma Score (GCS), Mechanism, GCS, Age, Pressure score (MGAP), GCS, Age, Pressure score (GAP), Revised Trauma Score (RTS), Trauma and Injury Severity Score (TRISS) and Kampala Trauma Score (KTS), in predicting in-hospital mortality in a multi hospital cohort of adult patients in Kenya. METHODS: This study was performed using data from trauma registries implemented in four public hospitals in Kenya. Estimated ISS, MGAP, GAP, RTS, TRISS and KTS were computed according to algorithms described in the literature. All seven measures were compared for discrimination by computing area under curve (AUC) for the receiver operating characteristics (ROC), model fit information using Akaike information criterion (AIC), and model calibration curves. Sensitivity analysis was conducted to include all trauma patients during the study period who had missing information on any of the injury severity measure(s) through multiple imputations. RESULTS: A total of 16,548 patients were included in the study. Complete data analysis included 14,762 (90.2%) patients for the seven injury severity measures. TRISS (complete case AUC: 0.889, 95% CI: 0.866-0.907) and KTS (complete case AUC: 0.873, 95% CI: 0.852-0.892) demonstrated similarly better discrimination measured by AUC on in-hospital deaths overall in both complete case analysis and multiple imputations. Estimated ISS had lower AUC (0.764, 95% CI: 0.736-0.787) than some injury severity measures. Calibration plots showed eISS and RTS had lower calibration than models from other injury severity measures. CONCLUSIONS: This multi-hospital study in Kenya found statistical significant higher performance of KTS and TRISS than other injury severity measures. The KTS, is however, an easier score to compute as compared to the TRISS and has stable good performance across several hospital settings and robust to missing values. It is therefore a practical and robust option for use in low-resource settings, and is applicable to settings similar to Kenya. PMID- 28716211 TI - To serve and protect: The modulatory role of von Willebrand factor on factor VIII immunogenicity. AB - Hemophilia A is a bleeding disorder characterized by the absence or dysfunction of blood coagulation factor VIII (FVIII). Patients are treated with regular infusions of FVIII concentrate. In response to treatment, approximately 30% of patients with severe hemophilia A develop inhibitory antibodies targeting FVIII. Both patient and treatment related risk factors for inhibitor development have been described. Multiple studies comparing the immunogenicity of recombinant and plasma-derived FVIII have yielded conflicting results. The randomized controlled SIPPET (Survey of Inhibitors in Plasma-Product Exposed Toddlers) trial demonstrated an increased risk of inhibitor development of recombinant FVIII when compared to von Willebrand factor (VWF)-containing plasma-derived FVIII. Presently, it is unclear which mechanism underlies the reduced immunogenicity of plasma-derived FVIII. In this review we address the potential role of VWF on FVIII immunogenicity and we discuss how VWF affects the immune recognition, processing and presentation of FVIII. We also briefly discuss the potential impact of glycan-composition on FVIII immunogenicity. It is well established that VWF shields the uptake of FVIII by antigen presenting cells. We have recently shown that VWF binds to the surface of dendritic cells. Here, we present a novel model in which surface bound FVIII-VWF complexes regulate the internalization of FVIII. Binding of FVIII to VWF is critically dependent on sulfation of Tyr1699 (HVGS numbering) in the light chain of FVIII. Incomplete sulfation of Tyr1699 has been suggested to occur in several recombinant FVIII products resulting in a loss of VWF binding. We hypothesize that this results in alternative pathways of FVIII internalization by antigen presenting cells which are not regulated by VWF. This hypothetical mechanism may explain the reduced immunogenicity of VWF containing plasma-derived FVIII concentrates as found in the SIPPET study. PMID- 28716212 TI - Virtual special issue: renal masses. PMID- 28716213 TI - Imaging of endoscopic approaches to the anterior and central skull base. AB - Sinonasal endoscopy for treatment of benign sinonasal diseases is a well established procedure. Recent advances in endoscope technology have substantially expanded its application with many institutions now offering resection of skull base lesions and sinonasal malignancies via the endoscopic approach. Its minimally invasive nature leads to faster recovery time, better cosmetic results, and fewer complications. Unfortunately, not all lesions involving the sinonasal region and skull base are accessible to sinonasal endoscopy. In addition, many of these disease processes are not directly visible on clinical examination. Therefore, the surgeon relies upon imaging to (1) determine the extent and possible nature of the disease; (2) provide guidance for surgical planning purposes, in particular, if a lesion is accessible to endoscopic surgery or if an open surgical approach is indicated. The radiologist, on the other hand, needs to be familiar with the technical limitations and contraindications of sinonasal endoscopy to provide a meaningful radiology report to the surgeon. The relative and absolute contraindications to endoscopic surgery can be categorised into technical factors, extent of a lesion, tumour vascularity, and anatomical variations and are discussed in this review article. PMID- 28716214 TI - Early 68GA-PSMA PET/MRI acquisition: assessment of lesion detectability and PET metrics in patients with prostate cancer undergoing same-day late PET/CT. AB - AIM: To compare lesion detectability and positron-emission tomography (PET) metric measurements between early-PET/magnetic resonance imaging (MRI) acquisition and same-day PET/computed tomography (CT). MATERIALS AND METHODS: The study was approved by the institutional review board and written informed consent was obtained from all patients. Twenty-one patients underwent non-time-of-flight (TOF) PET/MRI immediately following 68GA-prostate-specific membrane antigen (PSMA) tracer injection in two steps: firstly, early prostate PET/MRI (pPET/MRI) and early whole-body (WB) PET/MRI (wbPET/MR) followed by WB TOF PET/CT (wbPET/CT). Lesion detectability was compared between wbPET/MRI and wbPET/CT while PET metric measurements were compared between pPET/MR, wbPET/MRI, and wbPET/CT. RESULTS: Sixty-one and 63 lesions were found on wbPET/MRI and wbPET/CT, respectively (K=0.95, 95% confidence interval (CI)=0.89-1.0) with very good correlation between PET metric measurements (r=0.91; p=0.001). Bland-Altman plots demonstrated a mean percentage difference between wbPET/CT with wbPET/MRI of 34.4% with 95% limits of agreement (LOA) between -39% to 107.9% for metabolic tumour volume (MTV) and a mean difference of 30% with LOA between -13.4% to 73.4% for peak standardised uptake value (SUVpeak). CONCLUSION: Early PET/MRI demonstrates very good lesion detectability agreement and correlation with PET metrics compared to same-day PET/CT. Nevertheless, LOA are far beyond the clinically acceptable range, and therefore, PET/CT and early PET/MRI metrics cannot be used interchangeably. PMID- 28716215 TI - Clinical and Radiographic Assessment of the Efficacy of a Collagen Membrane in Regenerative Endodontics: A Randomized, Controlled Clinical Trial. AB - INTRODUCTION: Recent reviews confirm a general lack of randomized, controlled clinical studies on the efficacy of regenerative endodontics in immature teeth affected by pulp and periapical diseases. Moreover, we have no evidence of the curative efficacy of collagen membranes used as scaffolds in regenerative endodontics. Here, we evaluated whether a Bio-Gide collagen membrane (Geistlich Pharma AG, Wolhusen, Switzerland) has efficacy in promoting dentin formation in regenerative endodontics. METHODS: Forty-three patients yielding a total of 46 nonvital immature teeth were divided randomly into 2 groups. Subsequent to chemomechanical preparation, regenerative endodontics with (the experimental group) and without (the control group) Bio-Gide were performed. All cases were followed up clinically and radiographically every 3 months for at least 6 months. Quantitative analyses using an imaging program yielded percentage changes in root dimensions based on a comparison between preoperative and recall radiographs. RESULTS: The results of 40 patients (43 teeth) were included in the final analyses. All patients from both groups showed clinical success with complete resolution of signs and symptoms. Radiographically, the thickness of the dentin wall at the middle third of the root was higher for the experimental group than the control group. However, other indicators were comparable between both groups. CONCLUSIONS: The use of the Bio-Gide collagen membrane promoted the development of the dentin wall in the middle third of the root in patients undergoing regenerative endodontic procedures. The convenience of operation and the assured positioning of the sealing material make the Bio-Gide collagen membrane especially suitable for handling wide root canals. PMID- 28716216 TI - 1.4 times increase in atrial fibrillation-related ischemic stroke and TIA over 12years in a stroke center. AB - BACKGROUND AND PURPOSE: Prevalence of atrial fibrillation (AF) has quadrupled in the past 50years in the general population. However, there is uncertainty regarding prevalence of AF over time in ischemic stroke patients given the aging population and enhanced surveillance of AF. We aimed to explore the changing prevalence of AF as well as other risk factors, stroke subtypes, investigations and pre-stroke medications among ischemic stroke and transient ischemic attack (TIA) patients. METHODS: We performed a retrospective analysis of data from a prospective database of consecutive patients with acute ischemic stroke and TIA from 2004 to 2015. Trends in risk factors and other variables year by year were analyzed using logistic regression or median regression. RESULTS: Among 6275 patients (median age [interquartile range] 74 [62-82] years, 56% males), the prevalence of AF increased 1.4 times over 12years (from 23.3% to 32.7%, P<0.001). The increase in the prevalence of AF remained significant after adjustment for age and the use of Holter monitoring. There was also a significant increase in prevalence of hypertension (67.4% to 77.3%), structural heart disease (9.8% to 10.5%), and previous TIA (10.9% to 13.7%) and a significant decrease in prevalence of dyslipidemia (71.8% to 49.4%). CONCLUSIONS: There was a 1.4 times increase in the prevalence of AF among consecutive ischemic stroke and TIA patients in the past 12years in a hospital-based registry. More active screening of the general population for AF may be warranted in order to decrease the overall stroke burden. PMID- 28716217 TI - Comparison of all 19 published prognostic scores for intracerebral hemorrhage. AB - BACKGROUND AND AIMS: We evaluated the accuracy of 19 published prognostic scores to find the best tool for predicting mortality after intracerebral hemorrhage (ICH). METHODS: A retrospective single-center analysis of consecutive patients with ICH (n=1013). After excluding patients with missing data (n=131), we analyzed 882 patients for 3-month (primary outcome), in-hospital, and 12-month mortality. We analyzed the strength of the individual score components and calculated the c-statistics, Youden index, sensitivity, specificity, negative and positive predictive value (NPV and PPV) for the scores. Finally, we included every score component in a multivariable model to analyze the maximum predictive value of the data elements combined. RESULTS: Observed in-hospital mortality was 23.6%, 3-month mortality was 31.0%, and 12-month mortality was 35.3%. For in hospital mortality, the National Institutes of Health Stroke Scale (NIHSS) performed equally good as the best score for the other outcomes, the ICH Functional Outcome Score (ICH-FOS). The c-statistics of the scores varied from 0.6293 (95% CI 0.587-0.672) to 0.8802 (0.855-0.906). With all variables from all the scores in a multivariable regression model, the c-statistics did not improve, being 0.89 (0.867-0.913). Using the Youden index cutoff for the ICH-FOS score, the sensitivity (73%), specificity (90%), PPV (76%), and NPV (88%) for the primary outcome were good. CONCLUSIONS: A plethora of scores exists to help clinicians estimate the prognosis of an acute ICH patient. The NIHSS can be used to quantify the risk of in-hospital death while the ICH-FOS performed best for the other outcomes. PMID- 28716218 TI - The risk of dementia with the use of 5 alpha reductase inhibitors. AB - INTRODUCTION: There has been considerable interest in the interplay between testosterone and cognition. Dihydrotestosterone (DHT), which has been correlated with cognitive function, is significantly reduced with the use of 5 alpha reductase inhibitors (5ARI) for prostatic enlargement. Our objective was to assess whether the use of 5ARIs was associated with an increased risk of incident dementia. METHODS: We used a matched cohort design and linked administrative data from the province of Ontario, Canada. A total of 99 covariates were measured, and a propensity score was used for matching; 81,162 men who used a 5ARIs were matched to an equal number of men who did not. RESULTS: New initiation of 5ARI medication was associated with an increased risk of dementia during the first (HR 2.18, 95% CI 2.01-2.35) and second (HR 1.52, 95% CI 1.39-1.67) year, however this risk was nonsignificant among the men with the longest exposure to 5ARIs (HR 1.06, 95% CI 0.98-1.14). There was no difference in the results between types of 5ARIs. CONCLUSION: As the strength of the association decreased with increased exposure, the higher risk seen in the initial two years likely represents the presentation and treatment of urinary symptoms which coexist with mild cognitive impairment and eventually progresses to a diagnosis of dementia. PMID- 28716220 TI - More than meets the eye: Searching for additional findings in primary brain calcification. PMID- 28716219 TI - Sex differences in intracerebral hemorrhage expansion and mortality. AB - BACKGROUND AND OBJECTIVE: Due to conflicting results in multiple studies, uncertainty remains regarding sex differences in severity and mortality after intracerebral hemorrhage (ICH). We investigated the impact of sex on ICH severity, expansion, and mortality. METHODS: We analyzed prospectively collected ICH patients and assessed clinical variables and mortality rate. Mediation analyses were used to examine associations between sex and mortality and sex and hematoma expansion. RESULTS: 2212 patients were investigated, 53.5% male. Men with ICH were younger (72 vs. 77years), had greater smoking and alcohol use, and were more likely to have hypertension, diabetes, hypercholesterolemia and coronary artery disease (all p<0.05). Lobar hemorrhages were more frequent in women (47.6% vs 38.4%, p<0.001). Male sex was a risk factor for hematoma expansion (Odd Ratio (OR) 1.7, 95% confidence interval (CI) 1.15-2.50, p=0.007). Multivariable analysis found that male sex was independently associated with 90 day mortality (OR 2.15 (95% CI 1.46-3.19), p<0.001), and one-year mortality (Hazard Ratio 1.28 (95% CI: 1.09-1.50), p=0.003). Early hematoma expansion mediated a portion of the association between sex and mortality (mediation p=0.02). CONCLUSIONS: Men with ICH experience a higher risk of both expansion and early and late mortality, even after controlling for known risk factors. Further research is needed to explore the biological mechanisms underlying these observed differences. PMID- 28716221 TI - Parkin mutation may be associated with serious akinesia in a patient with Parkinson's disease. AB - Acute akinesia (AA) is an unusual motor complication in Parkinson's disease (PD). Reported risk factors for AA include infection, trauma, surgical intervention, and the withdrawal of antiparkinsonian medication. Recently, patients with genetic PD were reported to have a three-fold risk of AA than patients with non genetic PD. We describe a patient with PD associated with a Parkin mutation in whom serious akinesia developed. A 42-year-old man with exon 2 heterozygous deletion and exon 4 heterozygous deletion in the PARK2 gene showed five unexpected AA for several 12h. At fifth AA, he could not move any part of the body while lying in front of a stove in his house all night. He was admitted to our hospital because a third-degree burn had developed on 16% of the body surface area. Parkin mutation in addition to POLG1 or PINK1 mutation may be associated with serious AA. PMID- 28716222 TI - Lack of benefit of acetyl-dl-leucine in patients with multiple system atrophy of the cerebellar type. PMID- 28716223 TI - Temporal lobe epilepsy and anorexia nervosa in St. Catherine of Siena (1347 1380). PMID- 28716224 TI - B vitamins and cognition in subjects with small vessel disease: A Substudy of VITATOPS, a randomized, placebo-controlled trial. PMID- 28716225 TI - Regional cerebral glucose metabolism in systemic lupus erythematosus patients with major depressive disorder. AB - OBJECTIVES: Depression is frequently observed in patients with systemic lupus erythematosus (SLE). Neuropsychiatric SLE (NPSLE) patients often exhibit cerebral hypometabolism, but the association between cerebral metabolism and depression remains unclear. To elucidate the features of cerebral metabolism in SLE patients with depression, we performed brain 18F-fluoro-d-glucose positron emission tomography (FDG-PET) on SLE patients with and without major depressive disorder. METHODS: We performed brain FDG-PET on 20 SLE subjects (5 male, 15 female). The subjects were divided into two groups: subjects with major depressive disorder (DSLE) and subjects without major depressive disorder (non-DSLE). Cerebral glucose metabolism was analyzed using the three-dimensional stereotactic surface projection (3D-SSP) program. Regional metabolism was evaluated by stereotactic extraction estimation (SEE), in which the whole brain was divided into segments. RESULTS: Every SLE subject exhibited cerebral hypometabolism, in contrast to the normal healthy subjects. Regional analysis revealed a significantly lower ER in the left medial frontal gyrus (p=0.0055) and the right medial frontal gyrus (p=0.0022) in the DSLE group than in the non-DSLE group. CONCLUSION: Hypometabolism in the medial frontal gyrus may be related to major depressive disorder in SLE. Larger studies are needed to clarify this relationship. PMID- 28716226 TI - Cytokines do play a role in pathogenesis of tuberculous meningitis: A prospective study from a tertiary care center in India. AB - BACKGROUND: Though animal studies have suggested a role for proinflammatory cytokines in pathogenesis their exact role in pathogenesis of human meningeal tuberculosis continues to be controversial with different studies yielding contradictory results. AIM AND OBJECTIVES: To study the levels of proinflammatory cytokines in serum and cerebrospinal fluid (CSF) of patients with tubercular meningitis (TBM) and to determine whether these correlate with disease severity. PATIENTS AND METHODS: Present study included 146 patients with TBM (90- Definite TBM; 56- Probable TBM), diagnosed according to criteria laid by Ahuja et al. which were modified to include CSF nucleic acid based tests. Serum (n=146) and CSF (n=140) levels of various proinflammatory cytokines (IL-1beta, IL-2, IL-6, TNF-alpha and IFNgamma) were compared between TBM patients and healthy volunteers (n=99). These levels were correlated with various clinical, radiological and CSF parameters of TBM patients. RESULTS: Proinflammatory cytokines include cytokines which promote systemic inflammation. In current study, the serum and CSF levels of various cytokines (IL-2, IL-4, IL-6, IL-1beta, IFN-gamma and TNF-alpha) were significantly elevated in TBM patients compared to controls. A significant correlation was found between a) Higher stage of TBM and various cytokines (except for serum IL-6 and CSF IFN-gamma); b) High CSF TNF-alpha, IL-4 and IL 1beta with severity of hydrocephalus; c) High CSF IL1beta and IFN-gamma with presence of exudates on MRI; d) Serum and CSF levels of all cytokines with poor outcome as determined by death or as defined by S and E ADL (Schwab and England activities of daily living) score or by GOS (Glasgow outcome scale) (except for interferon gamma); and e) Serum and CSF IL-4 and IL1beta with presence of infarcts on MRI brain. CONCLUSION: Proinflammatory cytokines play an important role in the pathogenesis of TBM and contribute significantly towards severity of disease. PMID- 28716227 TI - Mitochondrial tRNA genes are hotspots for mutations in a cohort of patients with exercise intolerance and mitochondrial myopathy. AB - OBJECTIVE: Mitochondrial myopathy (MM) is a relatively rare type of mitochondrial disorder characterized by predominant skeletal muscle involvement. Both mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) mutations have been reported as the genetic causes of this disease. Here, we described the clinical and genetic features of a cohort of patients with MM. METHODS: We conducted a retrospective, single center study enrolling 22 patients with clinically and myopathologically diagnosed MM. The clinical records and results of laboratory examinations were collected and analyzed. The follow-up was conducted by telephone interview in 12 patients. Muscle biopsy and gene analysis was performed in all patients. MtDNA mutation load was quantified in all available tissues. RESULTS: Muscle biopsy revealed ragged red fibers and/or cytochrome c oxidase deficient fibers in all patients. Mitochondrial DNA analysis identified pathogenic mutations in 11 patients, including four previously reported mutations (mt-tRNALeu(UUR) m.3243A>G in five patients, mt-tRNALys m.8344A>G in four patients, mt-tRNALeu(UUR) m.3302A>G in one patient, and mt-tRNALeu(UUR) m.3250T>C in one patient) and a novel possible pathogenic variant (MTND1 m.3437G>A) in one patient. The mtDNA mutation load was consistently higher in muscles than in blood. In the remaining 10 patients, there was no pathogenic mutation found either by the Sanger sequencing of entire mitochondrial genome or by the targeted next-generation sequencing which included 238 nuclear genes related to mitochondrial diseases. Clinically, the onset age of these 22 MM patients ranged from 1 to 51years (mean=21.1+/-14.3years), and the disease duration was between 3 and 44years (mean=14.1+/-9.4years). Proximal limb weakness with or without exercise intolerance was present in 21 patients, and one patient showed only exercise intolerance. Out of these 22 patients, dysphagia/dysarthria, neck flexor muscle weakness, dyspnea, cardiomyopathy and exercise induced myalgia were observed in five, two, four, one and four patients, respectively. Neither central nervous system manifestation nor brain MRI abnormality was present in these patients. Notably, three of the four patients carrying the m.8344A>G mutation presented with dysarthria. The follow-up of 12 patients revealed symptom improvements in four cases, stable conditions in two cases, and worsened conditions in five cases. The case with the m.3302A>G mutation died of respiratory failure. CONCLUSIONS: Mitochondrial tRNA genes, as hotspots for mutations, accounted for 50% of MM in this cohort of patients. Patients associated with the m.8344A>G mutation were prone to laryngopharyngeal muscle involvement. The prognosis in our patients is relatively benign except one patient with the m.3302A>G mutation. PMID- 28716228 TI - Forced normalization and antiepileptic drugs interacting with glutamatergic neurotransmission: Caution is needed. PMID- 28716229 TI - Association between interleukin-32 polymorphism and multiple sclerosis. AB - BACKGROUND AND AIM: Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). Environmental and genetic factors play a key role in the development of the disease. Interleukin-32 (IL-32) is a cytokine inducing crucial inflammatory cytokines such as TNF-alpha, IL-6, IL-1beta, and MIP-2. The present study was an attempt to reveal any association between IL-32 levels and C/T promoter SNP with susceptibility to MS. METHODS: This case control study recruited a total of 304 subjects including 132 MS patients and 172 sex- and age-matched healthy controls. Clinical and epidemiological characteristics of the RRMS, PPMS, and PPMS populations were assessed. Serum levels and C/T polymorphism of IL-32 were determined by ELISA and RFLP-PCR methods, respectively. RESULTS: Serum levels of IL-32 were significantly different between MS patients and controls. IL-32 was dramatically higher in the patients than that healthy controls (2297.4+/-280.2 ver. 712.9+/-90.2, p=0.001). C allele was prominent in MS patients than the controls and might increase the risk of MS up to 1.6 fold (95% CI; 1.02-2.4, p=0.038). In addition, the presence of C allele enhanced IL-32 production drastically. CONCLUSION: This is the first study in which IL-32 gene promoter C/T polymorphism and its serum levels were investigated. The increase in serum levels of IL-32 in accordance with additive effect of the presence of C allele in MS patients might introduce IL-32 as a key player in MS pathogenesis or immunedysregulation. PMID- 28716230 TI - Early MRI results and odds of attaining 'no evidence of disease activity' status in MS patients treated with interferon beta-1a in the EVIDENCE study. AB - INTRODUCTION: 'No evidence of disease activity' (NEDA) is increasingly used as a treatment target with disease-modifying drugs for relapsing multiple sclerosis. METHODS: This post-hoc analysis of the randomised EVIDENCE trial compared interferon beta-1a injected subcutaneously three times weekly (IFN beta-1a SC tiw) with interferon beta-1a injected intramuscularly once weekly (IFN beta-1a IM qw) on NEDA and clinical activity-free (CAF) status. The influence of the frequency of magnetic resonance imaging (MRI) scanning on NEDA and the effect of baseline T1 gadolinium-enhancing (Gd+) lesions on NEDA and CAF were also investigated. RESULTS: More patients in the IFN beta-1a SC tiw group achieved NEDA compared with the IFN beta-1a IM qw group, although rates were lower when monthly MRI scans through 24weeks were included (35.0% vs. 21.6%, respectively; p<0.001) versus the 24-week scan alone (59.5% vs. 41.2%; p<0.001). Absence of baseline Gd+ lesions predicted NEDA through Week 72 in the IFN beta-1a IM qw group (p=0.022), and CAF through Week 48 in patients receiving IFN beta-1a SC tiw (p=0.024). CONCLUSIONS: IFN beta-1a SC tiw was associated with significantly higher rate of NEDA status compared with IFN beta-1a IM qw. Baseline Gd+ lesions augured less frequent CAF or NEDA status. Inclusion of more MRI scans in the analysis reduced rates of NEDA status. PMID- 28716231 TI - Measuring standing balance in multiple sclerosis: Further progress towards an automatic and reliable method in clinical practice. AB - BACKGROUND: Balance deficits in multiple sclerosis (MS) are often monitored by means of observer-rated tests. These may provide reliable data, but may also be time-consuming, subject to inter-rater variability, and potentially insensitive to mild fluctuations throughout the clinical course. On the other hand, laboratory assessments are often not available. The Nintendo Wii Balance Board (WBB) may represent a low-cost solution. The purpose of the current study was to examine the methodological quality of WBB data in MS (internal consistency, test retest reliability), convergent validity with observer-rated tests (Berg Balance Scale, BBS; Timed-Up and Go Test, TUG), and discriminative validity concerning clinical status (Expanded Disability Status Scale, EDSS). METHODS: Standing balance was assessed with the WBB for 4min in 63 MS patients at two assessment points, four months apart. Additionally, patients were examined with the BBS, TUG and the EDSS. RESULTS: A period of 4min on the WBB provided data characterized by excellent internal consistency and test-retest reliability. Significant correlations between WBB data and results of the BBS and TUG were obtained after merely 2min on the board. An EDSS median-split revealed that higher EDSS values (>3) were associated with significantly increased postural sway on the WBB. CONCLUSIONS: WBB measures reflecting postural sway are methodologically robust in MS, involving excellent internal consistency and test-retest reliability. They are also characterized by convergent validity with other considerably lengthier observer-rated balance measures (BBS) and sensitive to broader clinical characteristics (EDSS). The WBB may hence represent an effective, easy-to-use monitoring tool for MS patients in clinical practice. PMID- 28716232 TI - Serial neuroimaging findings in a novel case of sporadic progressive ataxia and palatal tremor (PAPT). PMID- 28716233 TI - 23Na MRI reveals persistent sodium accumulation in tumefactive MS lesions. AB - BACKGROUND: Chronic inflammatory demyelinating diseases of the CNS typically show a limited lesion size. However, extended lesions may appear with an atypical configuration. Large lesions with a diameter>2cm accompanied by tumor-like edema are entitled "tumefactive" and may occur in multiple sclerosis (MS) and other demyelinating diseases. Historically, differential diagnosis often requires histological analysis. Therefore, advanced imaging techniques are warranted to allow for a precise non-invasive diagnosis. Cerebral sodium (23Na) MRI was recently described as a new method to investigate in vivo sodium accumulation. Indicating extended sodium levels in MS lesions, 23Na MRI is a promising differential diagnostic tool further elucidating the role of sodium in demyelinating lesions. METHODS: Repetitive 23Na MRI measurements in a MS patient with a tumefactive demyelinating lesion providing insight into the medium-term course of cerebral sodium levels. RESULTS AND CONCLUSION: 23Na MRI depicts persistent lesional sodium accumulation after anti-inflammatory treatment and provides the opportunity of a non-invasive, in vivo analysis of sodium levels in inflammatory CNS lesions without need for contrast enhancing media. As a result of the extended dimension, tumefactive lesions may have an appropriate size for the analysis of inflammatory demyelination by 23Na MRI with sufficient resolution. PMID- 28716234 TI - Re-emergence of a tumefactive demyelinating lesion after initiation of fingolimod therapy. PMID- 28716235 TI - Psychosis in Parkinson's disease: From the soft signs to the hard science. AB - Patients with Parkinson's disease (PD) may develop a wide spectrum of non-motor symptoms during the course of illness. Psychosis is one such commonly observed non-motor symptoms of PD. Although several studies based on neuroimaging, genetics, retinal imaging, and neuropsychological evaluations have explored the pathogenesis of psychosis in PD; exact neural correlates are yet to be understood. Identification of factors related to psychosis in PD is important, as psychosis has been reported to be associated with higher rates of mortality, caregiver distress, and nursing home placements. This review highlights the potential of the previous studies to gain further insights into the soft signs and hard science related to psychosis in PD. Studies based on neuropsychological evaluations have revealed significant dysfunction in attention, executive and visuospatial functions in patients with PD and psychosis. Neuroimaging studies reveal grey matter atrophy in regions of the brain corresponding to both dorsal and ventral visual pathways, hippocampus, and cholinergic structures. Meanwhile, functional imaging studies suggest existence of an aberrant top-to-bottom visual processing system, which dominates the normal bottom-to-top system in patients with PD and visual hallucinations. Although nucleotide polymorphisms of several genes have been studied in PD patients with psychosis, those on -45C>T polymorphisms of cholecystokinin gene (CCK) have shown the greatest promise because of its association with psychosis in PD. All these taken together, cohesively unfold the current status of research in patients with PD and psychosis. This paper also highlights the missing links and discusses the approach to future research in this field. PMID- 28716236 TI - Abnormal glucose regulation, hypoglycemic treatment during hospitalization and prognosis of acute ischemic stroke. AB - BACKGROUND: To examine the effect of abnormal glucose regulation on prognosis and whether hypoglycemic treatment during hospitalization improves prognosis in acute ischemic stroke patients. METHODS: A total of 3882 acute ischemic stroke patients with an elevated systolic blood pressure between 140mmHg and 220mmHg were included in the China Antihypertensive Trial in Acute Ischemic Stroke (CATIS). The primary outcome was a combination of death and major disability (modified Rankin Scale score>=3) at 3months after stroke. Secondary outcomes included death, major disability, and vascular events. RESULTS: Compared with normal fasting plasma glucose, odds ratios (95% confidence interval) associated with impaired fasting glucose (IFG) and diabetes mellitus (DM) were 1.25 (0.92-1.68) and 1.38 (1.13-1.67) for composite outcome of death or major disability, respectively, and there was a significant trend for death or major disability (Ptrend=0.001). A linear association between fasting plasma glucose and the risk of combined outcome of death and major disability was observed among the patients without hypoglycemic treatment during hospitalization (P for linearity=0.005). We found protective effect of hypoglycemic treatment for risk of death (odds ratio, 0.47; 95% confidence interval, 0.24-0.92) among ischemic stroke patients with DM. CONCLUSIONS: Abnormal glucose regulation, especially DM, increased risks of 3 month poor outcomes after an acute ischemic stroke and hypoglycemic treatment during hospitalization might improve prognosis in ischemic stroke patients with DM. PMID- 28716238 TI - Posttraumatic dystonia. AB - In most cases the cause for dystonia is unknown. In a small number of patients, trauma precedes the onset of the dystonia. Significant head trauma is a well recognized precipitating factor in dystonia. However, it has become increasingly recognized that peripheral trauma can also result in dystonia. Secondary dystonia resulting from both central and peripheral trauma, its possible pathogenesis and treatment is discussed in this review. PMID- 28716237 TI - Long term follow-up on quality of life and its relationship to motor and cognitive functions in Parkinson's disease after deep brain stimulation. AB - INTRODUCTION: We aimed to examine temporal changes in health-related quality of life (HRQOL) and its relationship with motor and cognitive functions in patients with Parkinson's disease (PD) after subthalamic nucleus deep brain stimulation (STN-DBS). METHODS: In total, 31 patients with PD were enrolled in this study (mean age: 66.7+/-0.9years; mean disease duration: 11.6+/-3.7years). Participants completed the Unified Parkinson's Disease Rating Scale and the Parkinson's Disease Questionnaire-39. Cognitive function was assessed using the Mini Mental State Examination, the Frontal Assessment Battery, and the Montreal Cognitive Assessment. Postoperative evaluation was performed at three months, one year, three years, and five years after surgery; temporal changes in the correlation between HRQOL and motor and cognitive functions were evaluated at all follow-up periods. RESULTS: All patients completed postoperative clinical evaluations after three months, after one year. Of the 31 participants, twelve completed postoperative clinical evaluations after three years and seven after five years. Motor functions showed significant improvement over the five-year follow-up period. The mobility subdomain of the HRQOL worsened whereas the total score did not change significantly over years. Cognitive functions were not significantly impaired during follow-up periods. HRQOL was basically not significantly correlated with motor and cognitive functions during the follow-up period. CONCLUSIONS: The mobility subdomain of the HRQOL worsened after surgery, and the improvement in motor functions was basically not correlated with HRQOL after STN DBS in patients with PD. Cognitive functions were not significantly impaired during follow-up periods. PMID- 28716239 TI - Acquired transthyretin amyloidosis after domino liver transplant: Phenotypic correlation, implication of liver retransplantation. AB - Reports of acquired ATTRm in domino liver transplant (DLT) recipients are infrequent and the approach to management is unknown. We describe two patients, an inherited ATTRm patient who underwent liver transplant and his liver recipient who developed acquired ATTRm 8years following transplantation. The clinical manifestations of amyloidosis were similar between patients and consisted of peripheral neuropathy, diarrhea and weight loss. Following liver transplantation, the DLT donor went into remission for 4years, but eventually progressed and died. The DLT recipient was re-transplanted with a healthy liver, but amyloidosis progressed after 5years, with symptoms resembling the progression of the ATTRm liver donor. Proteomic analysis was utilized to type the amyloid deposits present in the DLT recipient fat aspirate specimen obtained prior to the second transplantation and stomach biopsy obtained at disease progression. The fat amyloid deposits contained almost equal amounts of mutant TTR and wild-type TTR peptides, but the stomach biopsy showed only wild-type TTR. There is a high concordance of disease phenotype between inherited and acquired ATTRm, which may help in early recognition of acquired ATTRm in DLT recipients. Liver re transplantation for acquired ATTRm may not interrupt the cycle of amyloid deposition since normal hepatically produced TTR may co-deposit with trace amount of pre-existing TTRm amyloid. PMID- 28716240 TI - A study of neuroendocrine dysfunction in patients of tuberculous meningitis. AB - BACKGROUND: Endocrine dysfunction is known to occur in various infectious diseases of the brain. The neuroendocrine dysfunction is not well studied in patients of Tuberculous meningitis (TBM). In this study, we aimed at knowing pattern of endocrine dysfunction in newly diagnosed patients of tuberculous meningitis, structural changes occurring in hypothalamic-pituitary region, assessing its predictors and correlative factors related to outcome. MATERIALS AND METHODS: This was a prospective observational study. All newly diagnosed patients of tuberculous meningitis were subjected to clinical, laboratory, and hormonal evaluation along with neuroimaging of hypothalamic-pituitary region. All the patients were treated with antituberculous drugs along with corticosteroids as per WHO guidelines. The clinical outcomes of the patients were assessed at the end of 3months. RESULTS: Out of 115 patients enrolled in the study, endocrine dysfunction was seen in 62 (53.9%) patients. Out of these 62 patients, single axis involvement was seen in 35 (30.4%) patients, while multiple axis dysfunction was observed in 27 (23.5%) patients. Most common hormonal axis involved was gonadotropic axis (33.9%) followed by hyperprolactinemia (22.6%), thyrotropic axis (17.4%), corticotropic axis (13%), SIADH (Syndrome of Inappropriate Antidiuretic Hormone secretion) (9.6%) and somatotropic axis (7.8%). None had diabetes insipidus. The presence of multiple cranial nerve palsies, hypotension, stage II and III of TBM, baseline MBI <=12 and basal exudates were significantly higher in endocrine dysfunction group, while the presence of basal exudates independently predicted the occurrence of endocrine dysfunction on multivariate analysis. Though the poor outcome was significantly higher in endocrine dysfunction group at the end of 3months, on multivariate analysis factors independently associated with poor outcome were the presence of altered sensorium and stage III of TBM. CONCLUSION: Endocrine dysfunction occurs in a significant proportion of patients with tuberculous meningitis. The presence of basal exudates is significantly associated with the occurrence of endocrine dysfunction. Patients with endocrine dysfunction had a poorer outcome although it was not an independent predictor of the same nor associated with increased mortality. PMID- 28716241 TI - Low risk of ICH after reperfusion therapy in acute stroke patients treated with direct oral anti-coagulant. AB - BACKGROUND: The safety of intravenous thrombolysis (IVT) and endovascular therapy (EVT) in patients treated with DOAC is unclear. We investigated whether recanalization therapy in patients treated with DOAC is safe. METHODS: A nationwide, multicenter, retrospective cohort questionnaire survey was conducted to investigate the: (1) frequency of intracerebral hemorrhage (ICH) after recanalization therapy in patients treated with DOAC; (2) independent factors related to ICH; (3) relationship between last intake time of DOAC and ICH; and (4) comparison of ICH frequency between patients treated with DOAC, vitamin K antagonist (VKA), and no-anticoagulation (no-ACT) (control). RESULTS: One hundred eighteen stroke centers returned the questionnaire and 100 patients (56 IVT alone, 29 EVT alone, and 15 both IVT and EVT) on DOAC were registered. The frequency of asymptomatic and symptomatic (>=4-point NIHSS score increase) ICH within 24h in DOAC patients were 18% and 2%, and were not different compared with the VKA and no-ACT groups (p=0.728; and p=0.626). On multivariate analysis, systolic blood pressure (OR, 1.04; p<0.001) and blood glucose (OR, 1.02; p=0.019) were independent factors for ICH. Among the 52 patients with a known last intake time of DOAC, the rate of ICH was higher in patients <=4h from last intake than those >4h (38% vs. 10%, p=0.033). CONCLUSIONS: Risk of ICH after reperfusion therapy in patients treated with DOAC should be low. Systolic blood pressure, glucose level, and DOAC intake time appear to be factors for ICH. PMID- 28716242 TI - A novel pathogenic variant in an Iranian Ataxia telangiectasia family revealed by next-generation sequencing followed by in silico analysis. AB - Ataxia telangiectasia (A-T) is a neurodegenerative autosomal recessive disorder with the main characteristics of progressive cerebellar degeneration, sensitivity to ionizing radiation, immunodeficiency, telangiectasia, premature aging, recurrent sinopulmonary infections, and increased risk of malignancy, especially of lymphoid origin. Ataxia Telangiectasia Mutated gene, ATM, as a causative gene for the A-T disorder, encodes the ATM protein, which plays an important role in the activation of cell-cycle checkpoints and initiation of DNA repair in response to DNA damage. Targeted next-generation sequencing (NGS) was performed on an Iranian 5-year-old boy presented with truncal and limb ataxia, telangiectasia of the eye, Hodgkin lymphoma, hyper pigmentation, total alopecia, hepatomegaly, and dysarthria. Sanger sequencing was used to confirm the candidate pathogenic variants. Computational docking was done using the HEX software to examine how this change affects the interactions of ATM with the upstream and downstream proteins. Three different variants were identified comprising two homozygous SNPs and one novel homozygous frameshift variant (c.80468047delTA, p.Thr2682ThrfsX5), which creates a stop codon in exon 57 leaving the protein truncated at its C terminal portion. Therefore, the activation and phosphorylation of target proteins are lost. Moreover, the HEX software confirmed that the mutated protein lost its interaction with upstream and downstream proteins. The variant was classified as pathogenic based on the American College of Medical Genetics and Genomics guideline. This study expands the spectrum of ATM pathogenic variants in Iran and demonstrates the utility of targeted NGS in genetic diagnostics. PMID- 28716243 TI - DOK7 congenital myasthenia may be associated with severe mitral valve insufficiency. PMID- 28716244 TI - Methotrexate-associated lymphoproliferative disorder in a patient with neuromyelitis optica spectrum disorder: An implication for pathogenesis mediated by Epstein-Barr virus. PMID- 28716245 TI - Neurosarcoidosis and multiple intracerebral hematomas: An unusual clinical presentation. PMID- 28716246 TI - Cognitive impairment predicts worse short-term response to spinal tap test in normal pressure hydrocephalus. AB - INTRODUCTION: In patients with idiopathic normal pressure hydrocephalus (iNPH), the spinal tap test (STT) is commonly used to predict ventriculoperitoneal shunt responsiveness. Clinical improvement following STT usually is measured by testing gait function. In our study, we investigated the impact of cognitive impairment on gait improvement after STT. METHODS: 22 patients with the clinical and radiological diagnosis of iNPH underwent gait analyses (mobile measuring system Medilogic) before and 2-4h after STT in self-paced gait velocity over 7m. Prior to STT, cognition was evaluated by the Mini Mental State Examination (MMSE). MMSE<24/30 points was used to define the subgroup of patients with cognitive impairment (iNPH-CI). Spatio-temporal parameters of gait before STT vs. after STT were analyzed with ANOVA with repeated measures. RESULTS: 1. Baseline gait parameters did not differ between the two groups: patients with iNPH and normal cognition (n=11) and patients with iNPH-CI (n=11). 2. Following STT, there was significant improvement of gait parameters in patients without cognitive impairment, while patients with iNPH-CI did not benefit from STT. CONCLUSION: Subjects with iNPH have a higher probability of lack of gait improvement 2-4h following STT, if cognitive impairment is present. Further studies are needed to elucidate the associations of cognitive impairment and quantitative gait parameters measured early and at later time points after STT. PMID- 28716247 TI - A newly homozygous variant in ZNF808: A possible candidate gene for Satoyoshi Syndrome? PMID- 28716249 TI - High risk of early conversion to multiple sclerosis in clinically isolated syndromes with dissemination in space at baseline. AB - INTRODUCTION: Multiple sclerosis (MS) usually presents at onset with a clinically isolated syndrome (CIS). According to 2010 McDonald criteria, a diagnosis of MS can be made if CIS patients satisfy clinical/MRI criteria of both dissemination in time (DIT) and space (DIS). OBJECTIVE: The aim of this study was to analyze the follow-up data and possible prognostic factors of CIS patients satisfying DIS MRI criteria. PATIENTS AND METHODS: We performed a retrospective, multicenter study across 2 Italian centers. Clinical, MRI, and laboratory assessments were performed according to real-life clinical workup. RESULTS: Out of the 137 enrolled patients, during a median follow-up time of 3.1years, 116 (84.7%) converted to MS with the large majority (78.4%) of the converters developing MS within 1year. In multivariate analysis, baseline predictors of an earlier conversion were a cerebellar/brainstem CIS (HR 2.00, 95% CI: 1.3-3.0, p=0.001) and the presence of all the Barkhof-Tintore MRI criteria (HR 1.67, 95% CI: 1.1 2.6, p=0.028). CONCLUSIONS: Patients with CIS and DIS are at very high risk of an early conversion to MS. The onset with cerebellar/brainstem symptoms and the evidence of a higher MRI lesion load at baseline are the strongest independent predictors of an early conversion to MS. PMID- 28716248 TI - Interleukin-6 (IL-6) rs1800796 and cyclin dependent kinase inhibitor (CDKN2A/CDKN2B) rs2383207 are associated with ischemic stroke in indigenous West African Men. AB - BACKGROUND: Inherited genetic variations offer a possible explanation for the observed peculiarities of stroke in sub - Saharan African populations. Interleukin-6 polymorphisms have been previously associated with ischemic stroke in some non-African populations. AIM: Herein we investigated, for the first time, the association of genetic polymorphisms of IL-6, CDKN2A- CDKN2B and other genes with ischemic stroke among indigenous West African participants in the Stroke Investigative Research and Education Network (SIREN) Study. METHODS: Twenty-three previously identified single nucleotide polymorphisms (SNPs) in 14 genes of relevance to the neurobiology of ischemic stroke were investigated. Logistic regression models adjusting for known cardiovascular disease risk factors were constructed to assess the associations of the 23 SNPs in rigorously phenotyped cases (N=429) of ischemic stroke (Men=198; Women=231) and stroke- free (N=483) controls (Men=236; Women=247). RESULTS: Interleukin-6 (IL6) rs1800796 (C minor allele; frequency: West Africans=8.6%) was significantly associated with ischemic stroke in men (OR=2.006, 95% CI=[1.065, 3.777], p=0.031) with hypertension in the model but not in women. In addition, rs2383207 in CDKN2A/CDKN2B (minor allele A with frequency: West Africans=1.7%) was also associated with ischemic stroke in men (OR=2.550, 95% CI=[1.027, 6.331], p=0.044) with primary covariates in the model, but not in women. Polymorphisms in other genes did not show significant association with ischemic stroke. CONCLUSION: Polymorphisms rs1800796 in IL6 gene and rs2383207 in CDKN2A/CDKN2B gene have significant associations with ischemic stroke in indigenous West African men. CDKN2A/CDKN2B SNP rs2383207 is independently associated with ischemic stroke in indigenous West African men. Further research should focus on the contributions of inflammatory genes and other genetic polymorphisms, as well as the influence of sex on the neurobiology of stroke in people of African ancestry. PMID- 28716250 TI - White matter lesions and cognitive impairment may be related to recovery from unilateral spatial neglect after stroke. AB - BACKGROUND: Unilateral spatial neglect (USN) is frequently found in ischemic stroke patients. Because USN is related to poor functional outcomes, evaluating recovery from USN after stroke is critical. METHODS: Patients with acute ischemic stroke with lesions in the right cerebral hemisphere on MRI and exhibiting left USN were administered the Behavior Inattention Test (BIT) at 1 and 3weeks after admission. BIT improvement was defined as a >=1-point increase in >=4 of the 6 BIT subtests from 1 to 3weeks, or a total BIT score >=131 at 3weeks. Factors associated with improvement of left USN were analyzed. RESULTS: Eighteen patients (8 men; mean age, 70+/-12years) were enrolled in this study. BIT was performed at 5.3+/-0.7 and 18.2+/-0.7days after admission. Twelve patients were classified to the improvement (I) group, and 6 to the non-improvement (NI) group. BIT scores increased substantially from 76.6+/-40.5 in the acute phase to 109.2+/-43.3 in the subacute phase. The I group displayed higher BIT scores than the NI group in both acute and subacute phases (P<0.01 each). The degree of white matter lesions on the Fazekas scale was lower in the I group (0.6+/-0.7) than in the NI group (1.7+/-1.2, P=0.028). Increased BIT scores correlated significantly with increased Mini Mental State Examination scores (r=0.487, P=0.040). CONCLUSIONS: Amelioration of left USN might be related to white matter lesions and cognitive impairment. Sample size in the current study was small, limiting the generalizability of results, and larger studies are warranted in the future. PMID- 28716251 TI - Unilateral right prosopometamorphopsia with positive "half-face-covering-test" after small occipitotemporal stroke. PMID- 28716252 TI - LMNB1 mutation causes cerebellar involvement and a genome instability defect. PMID- 28716253 TI - Teaching centers of the World Federation of Neurology - A concept to provide training resources from within. PMID- 28716254 TI - A predictive score followed by nucleic acid amplification for adult tuberculous meningitis diagnosis in Southern Brazil. AB - From 2012 to 2013, 300 adults under investigation of tuberculous meningitis (TBM) were tested with polymerase chain reaction (PCR) in central spinal fluid (CSF), followed by TBM score calculation. There were 33(11%) confirmed TBM cases based on clinical findings, CSF-culture; biopsy/necropsy exams and clinical improvement after tuberculosis specific treatment. Other 267 adults were classified as non TBM. Based on the original score there were 143 possible cases (6<=score<=11) and 20(60.6%) out of 33 TBM; among 27 probable TBM (score>=12) there were 13/33 (39.4%) confirmed cases. The CSF-PCR detected 48% (16/33) of TBM. Based on these findings, a new cut-off point was proposed to differentiate probable (score>=10) from possible (6<=score<=9) TBM. After score adjustment, there were 61 probable TBM with 26/33 (78.8%) TBM, and among the 109 possible TBM there were 7/33(21.2%) confirmed cases. In both systems, there were 130 non-TBM (score<=5) and no confirmed TBM. The association of adjusted score (>=10) and CSF-PCR showed high sensitivity (90.9%) and specificity (86.9%), positive and negative predictive value of 46.2% and 98.9%, respectively. The combination of CSF-PCR and TBM score is a useful tool for the management of adults under investigation of TBM, but the best cut-off point may need local/regional adjustments. PMID- 28716255 TI - Worldwide trends in the prevalence of dementia. PMID- 28716256 TI - Post-stroke depression in Ghana: Characteristics and correlates. AB - BACKGROUND: Poststroke depression (PSD) is prevalent and is an important determinant of functional recovery, quality of life and mortality after stroke. Scanty data on the nature of PSD among stroke survivors in sub-Saharan Africa prompted this study. OBJECTIVE: To assess the prevalence and predictors of depression in a convenience sample of Ghanaian stroke survivors. METHODS: We evaluated consecutive stroke survivors encountered at a comprehensive neurology clinic in a tertiary medical center in Ghana. The Center for Epidemiologic Studies Depression Scale (CES-D) and Geriatric Depression Scale (GDS) were both used to screen for depressive symptoms and subjects were considered as depressed if they scored >=16 on the CES-D scale and >5 on the GDS. Demographic and clinical data on stroke type and severity as well as health-related quality of life indicators were collected. Predictors of stroke-related depression were assessed using a logistic regression model. RESULTS: Of 200 stroke survivors, mean+/-SD age was 62.0+/-14.4years, and 105 (52.5%) patients were men. Among the cohort 78.5% were classified as being depressed by CES-D, 42.5% by GDS, and 36.5% on both CES-D and GDS. In multivariable analyses, for each unit increase on the Modified Rankin scale (i.e. worsening disability), there were higher odds of depression (adjusted OR 1.85; 1.28-2.69, p=0.001), and being divorced (vs. being married) was linked to depression (adjusted 2.82; 1.18-6.71, p=0.02). Stroke survivors with depression demonstrated profound diminutions in the physical, psycho-social, cognitive and eco-social domains of quality of life compared with those without depression (p<0.05). CONCLUSION: Almost 4 out of 10 stroke survivors in this Ghanaian cohort displayed clinically significant depression. Prospective interventional studies are urgently needed to provide solid evidence based and culturally tailored interventions to address post-stroke depression particularly in LMICs. PMID- 28716257 TI - Associations between white matter hyperintensities and cognitive decline over three years in non-dementia older adults with memory complaints. AB - We investigated whether the baseline level and overtime changes of white matter hyperintensities (WMH) would be associated with cognitive decline over three years in non-demented older adults with memory complaints. 109 participants with baseline magnetic resonance imaging (MRI) and follow-up cognitive assessments up to 3-year were included; among them, 82 also had a follow-up MRI assessment over three years. WMH volume was obtained by an automated segmentation algorithm. Baseline WMH volumes and change between baseline and follow-up WMH were related to cognitive scores over time using mixed-effect linear regressions. Secondary stratified analyses according to Clinical Dementia Rating (CDR) status, APOE4 status, and presence of amyloid in the brain were conducted using similar regression models. Change in WMH volume overtime was associated with declines in COWAT (beta=-0.239; 95% CI=-0.381, -0.096, p=0.001). Baseline WMH was not associated to any of the cognitive tests. Secondary analysis found that baseline WMH was associated to declines in TMT-A in APOE4 non-carriers (beta=0.343; 95% CI=0.121, 0.564, p=0.003) and CDR 0 groups (beta=0.307; 95% CI=0.095, 0.519, p=0.005); in CDR 0 group, overtime changes in WMH was associated to declines on both TMT-A (beta=0.698; 95% CI=0.270, 1.126, p=0.002) and TMT-B (beta=2.573; 95% CI=1.200, 3.947, p<0.001). Changes in WMH volume are associated with declines in information processing speed and executive function in non-demented older adults with memory complaints. Overtime changes in WMH volume is probably a better determinant of cognitive function in the elderly than baseline WMH volume. PMID- 28716258 TI - A multicenter prospective observational study on the safety and efficacy of tacrolimus in patients with myasthenia gravis. AB - INTRODUCTION: Several clinical studies using tacrolimus revealed reasonable therapeutic mechanisms and efficacy in patients with myasthenia gravis (MG). However, long-period studies in a large number of patients with MG are limited; therefore, the aim of this study was to investigate the therapeutic efficacies and safety of tacrolimus in patients with MG during a 12-month follow-up period. METHODS: Tacrolimus was administered to 150 patients with MG who were recruited based on the inclusion criteria. Fifteen medical centers in Korea participated in this study. The efficacy of tacrolimus was assessed using MG composite scales (MGCS) and the prednisolone-sparing effect. And the adverse drug reactions (ADRs) of tacrolimus were monitored in each patient from the beginning of tacrolimus treatment to the end of the follow-up period. RESULTS: After starting tacrolimus, the 32 patients were affected by ADRs, and consequentially 134 patients of the enrolled patients were followed up for 12months. They showed that the mean prednisolone dosage significantly decreased (6.1+/-7.6mg/day), compared to that in the baseline (11.3+/-9.5mg/day), and MGCS significantly improved after 12months of tacrolimus treatment, compared to that at the baseline. CONCLUSIONS: Our study showed that tacrolimus would be an effective immunosuppressant as an initial therapeutic agent in patients with MG; in addition, it showed tolerable safety profiles during the 12-month follow-up evaluation. PMID- 28716259 TI - Roald Dahl and the complete locked-in syndrome: "Cold dead body, living brain". AB - The classical locked-in syndrome in which partially preserved eye movements allow for communication is well-recognized by most neurologists. Yet, it is much less well-known that patients exist who are clearly conscious but have lost all means of communicating it to the outside world because they no longer have any motor output at all. Of note, Roald Dahl, the internationally acclaimed children book author, described this complete locked-in syndrome in one of his short stories, William and Mary (1959), almost half a century before the medical community became aware of this devastating condition. The present clinical commentary highlights an under-recognized and clinically highly relevant topic, exemplified by a lesser-known but stunning piece of literature from one of the most beloved contemporary novelist. PMID- 28716260 TI - Persistent geotropic positional nystagmus after meningitis: Evidence for light cupula. PMID- 28716261 TI - Stroke is a brain disease. PMID- 28716262 TI - New genetic causes for complex hereditary spastic paraplegia. AB - INTRODUCTION: Hereditary Spastic Paraplegia (HSP) represents a complex and heterogeneous group of rare neurodegenerative disorders that share a common clinical feature of weakness and lower limb spasticity that can occur alone or in combination with a constellation of other neurological or systemic signs and symptoms. Although the core clinical feature of weakness and lower limb spasticity is virtually universal, the genetic heterogeneity is almost uncountable with more than 70 genetic forms described so far. We performed review of medical records from twenty-one patients from seventeen Brazilian families with complex phenotype of HSP. All cases have previously negative mutations in SPG11/KIAA1840 and SPG7 gene and were evaluated by whole-exome sequencing. An extensive description of systemic and neurological signs has been described. RESULTS: Whole-exome sequencing was unremarkable in eight patients and established a definite genetic diagnosis in thirteen patients of twelve non related families. Mutations were found in genes previously implicated in other neurodegenerative disorders such as Amyotrophic Lateral Sclerosis, Hereditary Neuropathy, Spastic Ataxias, Neurodegeneration with Brain Iron Accumulation, Glycogen Metabolism, Congenital Lipodystrophy and aminoacyl-tRNA synthetases disorders. CONCLUSIONS: We report thirteen new genetically-proven cases of complex HSP, expanding the clinical spectrum of presentations of HSP, providing new pathophysiological mechanisms and disclosing new potential therapeutic targets. PMID- 28716263 TI - Exogenous Acrolein intensifies sensory hypersensitivity after spinal cord injury in rat. AB - Acrolein, an alpha,beta-unsaturated aldehyde associated with oxidative stress, is also a major toxic component of tobacco cigarette smoke, which has been reported in the clinic to coincide with the exacerbation of neuropathic pain after SCI. Previous reports have shown that acrolein involvement in spinal cord injury (SCI) is crucial to the development and persistence of neuropathic pain. Through the activation and upregulation of the transient receptor protein ankyrin-1 (TRPA1) cation channel, acrolein is capable of sensitizing the central nervous system in the acute and chronic stages of SCI. Here, we report that the acute or delayed nasal exposure of acrolein, apart from cigarette smoke but at concentrations similar to that found in cigarette smoke, resulted in increased neuropathic pain behaviors in a rat model of contusion SCI. We also found that this hyperalgesia occurred concurrently with an augmentation in systemic acrolein, detected by an acrolein-glutathione metabolite in the urine. The application of an acrolein scavenger, phenelzine, was shown to reduce the hyperalgesic effect of acrolein inhalation. The previously determined ability of acrolein to bind to and activate the TRPA1 channel and elicit algesic responses may be a mechanism of the phenomenon seen in this study. Upon the exposure to actual cigarette smoke after SCI, intensified neuropathic pain behaviors were also observed and persisted for at least 1week after the cessation of the exposure period. Taken together, these results indicate that cigarette smoke, through mechanisms involving acrolein, poses a threat to the vulnerable CNS after SCI and can contribute to neuropathic pain. This investigation also provides further evidence for the potential utility of acrolein scavengers as a therapeutic strategy in SCI-resultant neuropathic pain. PMID- 28716264 TI - Diagnosis of neurobrucellosis in resource-limited real-world settings: A case series of 8 patients. PMID- 28716265 TI - Exome sequencing results in identification and treatment of brain dopamine serotonin vesicular transport disease. PMID- 28716267 TI - The preparations of patients with amyotrophic lateral sclerosis for disaster after the Great East Japan earthquake. PMID- 28716268 TI - A novel indicator, the "Jinx sign," is associated with an altered frontal-basal ganglionic connection. PMID- 28716266 TI - Sativex(r) effects on promoter methylation and on CNR1/CNR2 expression in peripheral blood mononuclear cells of progressive multiple sclerosis patients. AB - Multiple sclerosis (MS) is a chronic demyelinating central nervous system (CNS) disease that involve oligodendrocyte loss and failure to remyelinate damaged brain areas causing a progressive neurological disability. Studies in MS mouse model suggest that cannabinoids ameliorate symptoms as spasticity, tremor and pain reducing inflammation via cannabinoid-mediated system. The aim of our study is to investigate the changes in cannabinoid type 1 (CNR1) and 2 (CNR2) receptors mRNA expression levels and promoter methylation in peripheral blood mononuclear cells (PBMCs) of MS secondary progressive (MSS-SP) patients treated with Sativex(r). Our cohort included MSS-SP patients, that at the time of Sativex(r) treatment, are treated (n=7), not treated (n=11) or that had terminated interferon-beta-1b (IFN-beta-1b) therapy (n=12). By Methylation Sensitive High Resolution Melting (MS-HRM), we characterized the methylation profile of CNR1 and CNR2 promoter region, while the relative mRNA transcript levels of these two genes were evaluated in the same samples by Quantitative Real-Time PCR (qRT-PCR) analysis. We did not find different pattern of cytosine-phosphate-guanine (CpG) methylation in the CNR1/CNR2 promoter region of all MSS-SP patients treated with Sativex(r). In addition, CNR1 and CNR2 expression did not significantly differ in MSS-SP patients not treated with IFN-beta-1b vs. them that have suspended, while in MSS-SP patients treated with IFN-beta-1b during Sativex(r) therapy we found a specific decrease of the CNR2 expression levels. These results suggest that the different expression of cannabinoid receptors by Sativex(r) treatment in leukocytes might be regulated through a molecular mechanism that involve interferon modulation. PMID- 28716269 TI - Dopamine agonist withdrawal syndrome (DAWS) in a tertiary Parkinson disease treatment center. AB - INTRODUCTION: Dopamine agonists are a mainstay of treatment for patients with Parkinson disease (PD). However, side effects limit their use, often necessitating dose change. Upon withdrawal, patients may experience dopamine agonist withdrawal syndrome (DAWS). To date, there is no established protocol for the prevention or treatment of DAWS. METHODS: We performed a retrospective chart review of PD patients who were taking a dopamine agonist. RESULTS: In our large cohort of 313 PD patients who were on a dopamine agonist, we found that 39.5% (n=124) had a change in their dose of medication for various reasons, including 102 patients who experienced a side effect on a dopamine agonist. Twenty out of 102 patients (19.6%) developed symptoms consistent with DAWS, whereas 1 out of 22 patients (4.5%) who had medication dose changed due to any other reason (e.g. dyskinesias, DBS surgery, decreased by another provider, etc.) developed symptoms consistent with DAWS. Our DAWS population had a shorter duration of PD, less exposure to a dopamine agonist, and was on a lower dose compared to those patients who did not develop DAWS. Agitation was the most common DAWS symptom reported in our cohort. Interestingly, in terms of developing DAWS, the prevalence of DAWS (19.0% vs 16.5%; p=0.76) between partial versus total discontinuation was not significantly different whether the dopamine agonist dose was decreased (21 patients) or completely stopped (103 patients). CONCLUSION: Contrary to previous reports, we have found that other side effects besides impulse control behavioral disorders also increase risk for developing DAWS. Furthermore, the prevalence of DAWS did not differ between partial versus total discontinuation of the dopamine agonist. PMID- 28716270 TI - Rapid sideline performance meets outpatient clinic: Results from a multidisciplinary concussion center registry. AB - OBJECTIVE: This study investigated the utility of sideline concussion tests, including components of the Sports Concussion Assessment Tool, 3rd Edition (SCAT3) and the King-Devick (K-D), a vision-based test of rapid number naming, in an outpatient, multidisciplinary concussion center treating patients with both sports-related and non-sports related concussions. The ability of these tests to predict clinical outcomes based on the scores at the initial visit was evaluated. METHODS: Scores for components of the SCAT3 and the K-D were fit into regression models accounting for age, gender, and sport/non-sport etiology in order to predict clinical outcome measures including total number of visits to the concussion center, whether the patient reached a SCAT3 symptom severity score<=7, and the total types of referrals each patient received over their course. Patient characteristics, differences between those with sport and non-sport etiologies, and correlations between the tests were also analyzed. RESULTS: Among 426 patients with concussion, SCAT3 total symptom score and symptom severity score at the initial visit predicted each of the clinical outcome variables. K-D score at the initial visit predicted the total number of visits and the total number of referrals. Those with sports-related concussions were younger, had less severely affected test scores, had fewer visits and types of referrals, and were more likely to have clinical resolution of their concussion and to reach a symptom severity score<=7. CONCLUSIONS: This large-scale study of concussion patients supports the use of sideline concussion tests as part of outpatient concussion assessment, especially the total symptom and symptom severity score portions of the SCAT3 and the K-D. Women in this cohort had higher total symptom and symptom severity scores compared to men. Our data also suggest that those with non-sports related concussions have longer lasting symptoms than those with sports-related concussions, and that these two groups should perhaps be regarded separately when assessing outcomes and needs in a multidisciplinary setting. PMID- 28716271 TI - Gastrointestinal compromise in Susac Syndrome. PMID- 28716272 TI - The need for a Global Neurology Alliance. AB - BACKGROUND: With increasing rapidity of advances in neuroscience and widening gaps in the accessibility to quality neurological care the risks of unpreparedness are growing. METHOD: To summarise the potential risks to the equal provision of neurological care and the resources available to improve the ability to plan and respond to the unexpected. RESULTS: To describe three examples of cooperative effort involving the World Federation of Neurology acting in concert with other neurological organisations. CONCLUSION: A global alliance of neurological organisations meeting and communicating regularly and willing to act rapidly and in concert is an essential prerequisite to managing emergent crises. PMID- 28716273 TI - Thiamine deficiency in metronidazole-induced encephalopathy: A metabolic correlation? PMID- 28716274 TI - Head CT findings at a public hospital in rural Haiti. AB - BACKGROUND: Neuroimaging is often unavailable in low-income countries, creating challenges for precise diagnosis of neurologic disease in individual patients, and impeding acquisition of precise neuroepidemiologic data for program and policy development. METHODS: We analyzed reports from 3614 head CTs performed between July 2013 and January 2016 at Hopital Universitaire de Mirebalais, a public academic hospital in rural Haiti, extracting patients' age, study indication, and radiologic findings. RESULTS: The most common indications for head CT were headache (27%), trauma (19.9%), abnormal neurological exam (12.2%), and stroke (11.3%). The most common categories of neurologic abnormalities were traumatic (31%), vascular (25.8%), and infectious (12%). Of 291 strokes, 64% were ischemic (median age at diagnosis 60.8years, SD 17.4) and 36% were hemorrhagic (median age 52.0, SD 15.5). In patients undergoing head CT for seizures or epilepsy, 17.5% had evidence of neurocysticercosis. In patients with head trauma, 42.6% had intracranial hemorrhage or fracture. Atrophy was noted on 10% of CTs (median age 57.1; SD 23.8), and was characterized as out of proportion to age in 2% (median age 34.1, SD 15.3). CONCLUSIONS: Median age of stroke patients in this rural low-income population is lower than in high-income countries and proportion of stroke due to intracerebral hemorrhage is higher. Neurocysticercosis is present in nearly one fifth of patients with seizures/epilepsy. These findings can inform policies and programs for prevention and treatment of neurologic disease in low-income settings. PMID- 28716275 TI - ATP1A3 mutant patient with alternating hemiplegia of childhood and brain spectroscopic abnormalities. PMID- 28716276 TI - Adult posthaemorrhagic hydrocephalus animal models. AB - Posthaemorrhagic hydrocephalus (PHH) is often associated with high morbidity and mortality and serves as an important clinical predictor of poor outcomes after intracranial haemorrhage (ICH). We are lack of effective medical intervention methods to improve functional outcomes in patients with PHH because little is still known about the mechanisms of PHH pathogenesis. Animal models play a key role in the study of PHH. Developed a suitable animal model that will help us to be better to find preventative strategies and improve the prognosis of patients with PHH. The purpose of this review is to summarize the body of knowledge gained from animal studies. PMID- 28716277 TI - Comparison of hematoma density heterogeneity and ultraearly hematoma growth in predicting hematoma expansion in patients with spontaneous intracerebral hemorrhage. AB - BACKGROUND: Hematoma density heterogeneity (HDH) and ultraearly hematoma growth (uHG) are novel imaging predictors for hematoma expansion (HE) based on computed tomography (CT). This study was aimed to compare the accuracy of HDH and uHG in HE prediction within a cohort of spontaneous intracerebral hemorrhage (sICH) patients. METHODS: This study included sICH patients with initial CT within 6h after onset. uHG was defined as baseline hematoma volume/onset-to-CT time (ml/h) and the cutoff was 4.7ml/h. HDH was evaluated following a 5-point categorical scale and HDH grade was dichotomized into homogeneous (1-2) and heterogeneous (3 5). The predictive accuracy of HDH and uHG was analyzed by receiver-operator analysis. RESULTS: A total of 137 patients were included in this study. The mean uHG and median HDH grade were significantly higher in patients with HE. In multivariable analysis, uHG>=4.7 and HDH grade>=3 were associated with HE independently. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of uHG>=4.7 were 76.5%, 57.3%, 37.1%, and 88.1%, respectively. The sensitivity, specificity, PPV and NPV of HDH grade>=3 were 55.9%, 70.9%, 39.8% and 83.0%, respectively. CONCLUSIONS: Both HDH and uHG are promising predictors for HE. HDH has higher specificity while uHG is more sensitive. PMID- 28716278 TI - Single-step blood direct PCR: A robust and rapid method to diagnose triplet repeat disorders. AB - OBJECTIVE: DNA extraction prior to polymerase chain reaction (PCR) amplification in genetic diagnoses of triplet repeat disorders (TRDs) is tedious and labour intensive and has the limitations of sample contamination with foreign DNA, including that from preceding samples. Therefore, we aimed to develop a rapid, robust, and cost-effective method for expeditious genetic investigation of TRDs from whole blood as a DNA template. METHODS: Peripheral blood samples were collected from 70 clinically suspected patients of progressive ataxia. The conventional method using genomic DNA and single-step Blood-Direct PCR (BD-PCR) method with just 2MUl of whole blood sample were tested to amplify triplet repeat expansion in genes related to spinocerebellar ataxia (SCA) types 1, 2, 3, 12 and Friedreich's ataxia (FRDA). Post-PCR, the allele sizes were mapped and repeat numbers were calculated using GeneMapper and macros run in Microsoft Excel programmes. RESULTS: Successful amplification of target regions was achieved in all samples by both methods. The frequency of the normal and mutated allele was concordant between both methods, diagnosing 37% positive for a mutation in either of the candidate genes. The BD-PCR resulted in higher intensities of product peaks of normal and pathogenic alleles. CONCLUSIONS: The nearly-accurate sizing of the normal and expanded allele was achieved in a shorter time (4-5h), without DNA extraction and any risk of cross contamination, which suggests the BD-PCR to be a reliable, inexpensive, and rapid method to confirm TRDs. This technique can be introduced in routine diagnostic procedures of other tandem repeat disorders. PMID- 28716279 TI - The initial time-course of headache in patients with spontaneous subarachnoid hemorrhage. AB - BACKGROUND: If acute severe headache disappears early after its onset, the question arises whether subarachnoid hemorrhage (SAH) should still be ruled out. We studied the initial time-course and minimal duration of headache in a consecutive series of neurologically intact patients with spontaneous SAH. METHODS: We included patients admitted between 2012 and 2015 within 48h after spontaneous SAH with a normal level of consciousness and no focal deficits. We retrieved data on headache severity, measured with a Numeric Rating Scale (NRS), <48h after ictus. We analyzed the proportion of patients with a first NRS 0 and NRS <3 within 48h after ictus and minimal headache duration. Patients were censored in case of a decrease in level of consciousness, aneurysm treatment, or early discharge. RESULTS: We included 106 patients (62 aneurysmal SAH, 33 perimesencephalic hemorrhage, 11 other spontaneous SAH). All patients were treated with analgesics. Within 48h after ictus, a first NRS 0 was reported by 9 patients (8%;95%CI:3%-14%) and a first NRS <3 by 22 patients (21%;95%CI:13%-28%). Shortest time lapse until NRS 0 was 10h in a patient with aneurysmal SAH who had been on acetaminophen and tramadol since 2:35h after ictus. CONCLUSIONS: In a cohort of SAH patients with a normal level of consciousness and no focal deficits who all used analgetics, headache disappeared in around 10% within 48h after ictus. Our data indicate that a diagnostic work-up for SAH is also needed in patients using analgesics in whom headache has disappeared after 10h. PMID- 28716280 TI - Association of polymorphisms and reduced expression levels of the NR4A2 gene with Parkinson's disease in a Mexican population. AB - INTRODUCTION: The NR4A2 transcription factor is important in the development, survival and phenotype of dopaminergic neurons and it is postulated as a possible biomarker for Parkinson's disease (PD). Therefore, our aim was to analyze in a sample of a Mexican population with idiopathic PD, mutations (in two hotspot mutation regions) and two polymorphisms (rs34884856 in promotor and rs35479735 intronic regions) of the NR4A2 gene. We also evaluate the levels of NR4A2 gene expression in peripheral blood for a Mexican population, and identify whether they are associated with NR4A2 gene polymorphisms. METHODS: We conducted a case control study, which included 227 idiopathic PD cases and 454 unrelated controls. Genetic variants of the NR4A2 gene were genotyped by high-resolution melting (HRM) and validated by an automated sequencing method. The gene expression was performed in peripheral blood using a real-time polymerase chain reaction. RESULTS: The rs35479735 polymorphism was associated with a higher risk of developing PD. In addition, NR4A2 gene expression was significantly decreased in patients with PD. Linkage disequilibrium analysis showed a haplotype H4 (3C-3G) that showed lower levels of expression, and contained the risk alleles for both polymorphisms. CONCLUSIONS: In summary, this is the first study in a Mexican population that considers the analysis of NR4A2 in patients with PD. An association was identified between genotype and mRNA expression levels of NR4A2 in patients with PD. These results suggest that polymorphisms and expression of the NR4A2 gene could play an important role in the risk of developing PD in Mexican populations. PMID- 28716281 TI - "Black butterfly" sign on T2*-weighted and susceptibility-weighted imaging: A novel finding of chronic venous congestion of the brain stem and spinal cord associated with dural arteriovenous fistulas. AB - A dural arteriovenous fistula (DAVF) with spinal perimedullary venous drainage can cause progressive myelopathy, and it is sometimes incorrectly diagnosed as another spinal cord disease. Here we report the cases of three individuals with a DAVF (one craniocervical junction DAVF and two tentorial DAVFs) with progressive myelopathy showing unique magnetic resonance (MR) imaging findings. MR T2*WI or susceptibility-weighted imaging (SWI) demonstrated symmetrical dark signal intensity lesions predominantly in the dorsal aspect of medulla and the central gray matter of cervical spinal cord that showed the "black butterfly" silhouette. Cerebral angiography revealed DAVFs draining into anterior and posterior spinal veins. Dark signals on T2*WI and SWI were presumed to be hemorrhages, which were probably caused by prolonged venous congestion. Identifying this "black butterfly" sign can facilitate the diagnosis of DAVF, differentiating DAVF from other spinal cord diseases such as demyelinating lesions and neoplasms. PMID- 28716282 TI - Serum amyloid P component: A novel potential player in vessel degeneration in CADASIL. AB - In cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), granular osmiophilic material (GOM) may play some roles in inducing cerebrovascular events. To elucidate the pathogenesis of CADASIL, we used laser microdissection and liquid chromatography-tandem mass spectrometry to analyze cerebrovascular lesions of patients with CADASIL for GOM. The analyses detected serum amyloid P component (SAP), annexin A2, and periostin as the proteins with the largest increase in the samples, which also demonstrated NOTCH3. For the three proteins, anti-human SAP antibody had the strongest reaction in the lesions where the anti-human NOTCH3 antibody showed positive staining. Moreover, immunofluorescence staining with the two antibodies clearly showed co-localization of SAP and NOTCH3. mRNA analyses indicated no positive SAP expression in the brain materials, which suggested that the source of SAP found in the GOM was only the liver. A solid phase enzyme-linked immunosorbent assay confirmed the binding of SAP with NOTCH3. Serum SAP concentrations were neither up-regulated nor down-regulated in CADASIL patients, when compared with those in control subjects. SAP may play an important role in GOM formation although precise mechanisms remain to be elucidated. PMID- 28716283 TI - Dalfampridine in Parkinson's disease related gait dysfunction: A randomized double blind trial. AB - BACKGROUND: Disease-related gait dysfunction causes extensive disability for persons with Parkinson's disease (PD), with no effective therapies currently available. The potassium channel blocker dalfampridine has been used in multiple neurological conditions and improves walking in persons with multiple sclerosis. OBJECTIVES: We aimed to evaluate the effect of dalfampridine extended release (D ER) 10mg tablets twice daily on different domains of walking in participants with PD. METHODS: Twenty-two participants with PD and gait dysfunction were randomized to receive D-ER 10mg twice daily or placebo for 4weeks in a crossover design with a 2-week washout period. The primary outcomes were change in the gait velocity and stride length. RESULTS: At 4weeks, gait velocity was not significantly different between D-ER (0.89m/s+/-0.33) and placebo (0.93m/s+/-0.27) conditions. The stride length was also similar between conditions: 0.96m+/-0.38 for D-ER versus 1.06m+/-0.33 for placebo. D-ER was generally well tolerated with the most frequent side effects being dizziness, nausea and balance problems. CONCLUSIONS: D-ER is well tolerated in PD patients, however it did not show significant benefit for gait impairment. PMID- 28716284 TI - Self-reported maximum walking distance in persons with MS may affect the EDSS. AB - BACKGROUND: In persons with MS (PwMS), the Expanded Disability Status Scale (EDSS) is used to monitor disability progression. Scores between 4.0 and 7.0 are determined by maximum walking distance. Self-estimation of this value is often employed in clinic settings. OBJECTIVE: To examine the accuracy with which PwMS estimate their walking distance, and observe subsequent changes to the EDSS. METHODS: This prospective cohort study recruited PwMS with previously recorded EDSS of 3.5-7.0. Participants estimated their maximum walking distance and then walked as far as they could along a pre-specified course. Each distance was converted to an EDSS score, the "estimated EDSS" and the "actual EDSS". Chi Square analysis was used to compare EDSS scores. Logistic regression was used to determine predictors of inaccurate estimations. RESULTS: Of the 66 PwMS in this study, 43.9% had a difference in the actual EDSS compared to the estimated EDSS. Median estimated EDSS was 4.75 (range 3.0-7.0); after walking assessment, median actual EDSS was 5.0 (range 3.0-7.0), which represented a significant difference [X2 (df 64, N=66)=206.9; p<0.001]. Actual EDSS decreased in 9 PwMS (13.6%) and increased in 20 PwMS (30.3%). Logistic regression did not find any demographic/disease characteristic to be predictive of this discrepancy. CONCLUSION: Some PwMS do not accurately estimate maximum walking distance; only 56.1% of PwMS accurately estimated their actual EDSS. PMID- 28716285 TI - Delayed leukoencephalopathy after recanalized cardioembolic stroke: Two case reports. PMID- 28716286 TI - Neurosarcoidosis according to Zajicek and Scolding criteria: 15 probable and definite cases, their treatment and outcomes. AB - INTRODUCTION: Neurosarcoidosis occurs in about 5% to 15% of patients with sarcoidosis. The purpose of this study was to identify and characterize a cohort of neurosarcoidosis patients and to review the largest previously reported neurosarcoidosis case series. METHODS: This retrospective study enrolled all patients with the diagnosis of probable or definitive neurosarcoidosis according to Zajicek and Scolding criteria, followed at the neurology department of a tertiary center in Portugal from January 1989 to December 2015. RESULTS: A total of 15 patients presented a diagnosis of probable or definitive neurosarcoidosis, with a mean age at time of diagnosis of 38.5years. The presenting neurologic syndrome was isolated cranial neuropathy, aseptic meningitis, myelitis, brain parenchymal lesion, myelorradiculitis and meningomyelorradiculitis. MRI study most often presented different enhancing lesions and the CSF analysis commonly revealed a lymphocytic pleocytosis and raised proteins. Thirteen patients had histopathology confirmation of systemic sarcoidosis and one preformed a spinal cord biopsy. Corticosteroids was the most often used treatment alone or in combination with immunosuppressive drugs. After a mean follow-up of 86.1months, the majority of patients fully recovered to a mRankin 0. DISCUSSION: Fully comprehension of neurosarcoidosis is still a challenge due to its rarity and limited number of large published series, which renders the epidemiological study of this disease very difficult. In this study, the thoroughly medical records review and the summarize of previous published cohorts allow to add some information in the epidemiological and clinical knowledge of this entity. PMID- 28716287 TI - Kidney dysfunction and silent brain infarction in generally healthy adults. AB - BACKGROUND: The association between silent brain infarction (SBI) and estimated glomerular filtration rate (eGFR)-based kidney dysfunction has not yet been definitively confirmed. This study aimed to investigate the association in generally healthy adults without a previous history of stroke or overt kidney disease. METHODS: The data from the screening health check-up program in the Seoul National University Hospital Health Promotion Center from January 1, 2009 to December 31, 2013 were used. A total of 2594 subjects who underwent brain MRI as part of health screening were included. SBIs were identified using T2-weighted and FLAIR images. Kidney dysfunction was defined as eGFR<60ml/min/1.73m2. To assess the effect of kidney dysfunction on the small perforating branches of cerebral vessels, subgroup analysis was performed using the presence of SLI as a dependent variable. RESULTS: The mean age was 56.8+/-9.3years, and 1422 subjects (54.8%) were male. The mean eGFR level was 81.9+/-15.4ml/min/1.73m2. The prevalence rates of kidney dysfunction and SBI were 5.1% and 7.1%, respectively. A higher proportion of subjects with SBI had kidney dysfunction than subjects without SBI (14.6% vs. 4.4%). The number of SBI lesions tended to increase with the progression of kidney dysfunction (p for trend<0.001). In multivariate logistic regression analyses, kidney dysfunction was significantly associated with the presence of SBI (adjusted odd ratio=1.99 to 2.21 in all four models). The same significant association was consistently identified in subgroup analyses using silent lacunar infarction (adjusted odd ratio=1.71 to 1.87 in all four models). CONCLUSION: Kidney dysfunction was found to be an independent risk factor for the presence and number of SBI in generally healthy adults. Physicians treating patients with a decreased creatinine-based eGFR level should try to identify and modify the coexisting risk factors of stroke followed by SBI. PMID- 28716288 TI - Uric acid levels correlate with the severity of diabetic sensorimotor polyneuropathy. AB - INTRODUCTION: Diabetic sensorimotor polyneuropathy (DSP) is the most frequent complication in patients with diabetes mellitus (DM), and is associated with age, DM duration, and HbA1c levels. In addition, higher uric acid (UA) levels are reported in patients with DSP. OBJECTIVES: To explore whether UA levels correlate with DSP severity. METHODS: We extracted the demographic data, clinical history, neurological and electrophysiological examinations and laboratory findings of 115 patients diagnosed with DSP from January 2012 to December 2015. RESULTS: The mean age of the total cohort was 62+/-13years, with 61% men. A positive correlation was demonstrated between uric acid levels and increasing sensory symptoms, and more abnormal electrophysiological findings and vibration perception thresholds. In addition, correlations with gait abnormality, the presence of paraproteinemia and creatine kinase levels were found. DISCUSSION: Our study results show that uric acid levels correlate with clinical and electrophysiological severity of DSP, providing additional evidence for the relationship between the two, and a potential therapeutic target for DSP. PMID- 28716289 TI - Devic's disease before Devic: On the contribution of Friedrich Albin Schanz (1863 1923). AB - Neuromyelitis optica (NMO, Devic's disease) is an autoimmune disorder of the CNS that mainly affects the optic nerves and spinal cord and, if not treated, can leave patients blind and wheelchair-bound. NMO was long considered a clinical variant of multiple sclerosis (MS). While the history of MS has been studied extensively, relatively little is known about the early history of NMO. A dissertation written by Fernand Gault (1873-1936), a doctoral student to Eugene Devic (1858-1930), a Lyon-based neurologist after whom the disease would later be named, is considered by many the first review of NMO. We would like to draw attention to a forgotten earlier review by the German oculist Friedrich Albin Schanz (1863-1923)-still known to ophthalmologists as one of the inventors of the corneal microscope ("slit lamp")-on which Devic and Gault's work was based and which points to most of the clinical and pathological features nowadays considered characteristic for NMO. The discovery of aquaporin-4 antibodies (NMO IgG) has revived the interest in NMO, which is now extensively studied as a prototypic autoimmune condition. We believe it is now time to do justice to those who were seminal in describing this rare yet intriguing disease. PMID- 28716290 TI - Yarsagumba Fungus: Health Problems in the Himalayan Gold Rush. AB - INTRODUCTION: Seasonal migration of people in search of Yarsagumba fungus creates a population of collectors that faces hardship and health risks in austere high altitude settings. METHODS: In 2016, our 4-person team performed a 2-day health needs survey of people collecting Yarsagumba fungus near the village of Yak Kharka (4020 m) in the Manang District of Nepal. RESULTS: There were approximately 800 people, both male and female, from age 10 to over 60, collecting Yarsagumba fungus. They had paid high prices for permits, hoping to recoup the cost and make a profit by selling specimens of Yarsagumba, but the fungus seemed scarce in 2016, resulting in a bleak economic forecast. Most collectors were living in austere conditions, walking long hours to the collection areas early in the morning and returning in the late afternoon. Most were subsisting on 1 daily meal. Health problems, including acute mountain sickness as well as respiratory and gastrointestinal illnesses, were common. Yarsagumba has become harder to find in recent years, increasing hardships and risk of injury. Medical care was almost nonexistent. CONCLUSION: As abundance decreases and demand increases, there is increasing pressure on collectors to find Yarsagumba. The collectors are an economically disadvantaged population who live in austere conditions at high altitude with poor shelter and sanitation, strenuous work, and limited availability of food. Health care resources are very limited. There are significant risks of illness, injury, and death. Targeted efforts by government entities and nongovernmental organizations might be beneficial in meeting the health needs. PMID- 28716291 TI - Similarities Between Large Animal-Related and Motor Vehicle Crash-Related Injuries. AB - OBJECTIVE: Many Americans sustain large animal-related injuries (LARIs) from blunt trauma. We compare the injuries and management of LARI in our region of the United States with those of motor vehicle crashes (MVCs). METHODS: A 15-year retrospective study of trauma patients with LARI matched to MVC controls by Injury Severity Score (ISS), age, and sex was conducted. Values were statistically compared, and differences were considered statistically significant at P < .05. RESULTS: There were 156 LARI cases, of which 87% were related to horses, 8% to bulls, and the remainder to deer, mules, bison, cows, and rams. In the LARI group, the age was 42+/-18 years (mean+/-SD), ISS was 7+/-4, and 61% were females. The MVC group had a significantly longer length of hospital stay (5+/-5 vs 4+/-3 days) and blood alcohol concentration (35+/-84 vs 3+/-20 g/L). There were no significant differences in injury patterns between LARI and MVC; however, additional radiological studies (RS) were performed on MVC (9+/-6 vs 7+/ 5). LARI patients were more often transferred from rural locations (39% vs 25%) and traveled further to our trauma center (40+/-32 vs 24+/-29 km) than did MVC patients. CONCLUSIONS: LARI has a similar pattern of injury to MVC, but fewer RS. LARI typically occurred further away, requiring transfer from rural areas to our institution. We recommend a similar approach for the evaluation of LARI and MVC. PMID- 28716292 TI - Production of sodium gluconate from delignified corn cob residue by on-site produced cellulase and co-immobilized glucose oxidase and catalase. AB - The production of sodium gluconate by enzymatic catalysis of delignified corn cob residue (DCCR) hydrolysate was studied. Penicillium oxalicum I1-13 was used for the production of cellulase with high beta-glucosidase activity. A fed-batch saccharification process was developed to obtain high yields of glucose. At the end of hydrolysis, the concentration of glucose reached 145.80g/L. Glucose oxidase and catalase were co-immobilized to catalyze DCCR hydrolysate to produce sodium gluconate. Under the optimum conditions, 166.87g/L sodium gluconate was obtained after 56h of reaction, with a yield of 98.24%. The immobilized enzymes could still maintain more than 60% of the activity after repeated use for 6 times. This study provides a potential route for the production of valuable chemicals by enzymatic conversion of lignocellulosic materials. PMID- 28716293 TI - Costs of Providing Infusion Therapy for Rheumatoid Arthritis in a Hospital-based Infusion Center Setting. AB - PURPOSE: Many hospital-based infusion centers treat patients with rheumatoid arthritis (RA) with intravenous biologic agents, yet may have a limited understanding of the overall costs of infusion in this setting. The purposes of this study were to conduct a microcosting analysis from a hospital perspective and to develop a model using an activity-based costing approach for estimating costs associated with the provision of hospital-based infusion services (preparation, administration, and follow-up) in the United States for maintenance treatment of moderate to severe RA. METHODS: A spreadsheet-based model was developed. Inputs included hourly wages, time spent providing care, supply/overhead costs, laboratory testing, infusion center size, and practice pattern information. Base-case values were derived from data from surveys, published studies, standard cost sources, and expert opinion. Costs are presented in year-2017 US dollars. The base case modeled a hospital infusion center serving patients with RA treated with abatacept, tocilizumab, infliximab, or rituximab. FINDINGS: Estimated overall costs of infusions per patient per year were $36,663 (rituximab), $36,821 (tocilizumab), $44,973 (infliximab), and $46,532 (abatacept). Of all therapies, the biologic agents represented the greatest share of overall costs, ranging from 87% to $91% of overall costs per year. Excluding infusion drug costs, labor accounted for 53% to 57% of infusion costs. IMPLICATIONS: Biologic agents represented the highest single cost associated with RA infusion care; however, personnel, supplies, and overhead costs also contributed substantially to overall costs (8%-16%). This model may provide a helpful and adaptable framework for use by hospitals in informing decision making about services offered and their associated financial implications. PMID- 28716294 TI - Life cycle assessment of the use of alternative fuels in cement kilns: A case study. AB - The benefits of using alternative fuels (AFs) in the cement industry include reduction of the use of non-renewable fossil fuels and lower emissions of greenhouse gases, since fossil fuels are replaced with materials that would otherwise be degraded or incinerated with corresponding emissions and final residues. Furthermore, the use of alternative fuels maximizes the recovery of energy. Seven different scenaria were developed for the production of 1 ton of clinker in a rotary cement kiln. Each of these scenaria includes the use of alternative fuels such as RDF (Refuse derived fuel), TDF (Tire derived fuel) and BS (Biological sludge) or a mixture of them, in partial replacement of conventional fuels such as coal and pet coke. The purpose of this study is to evaluate the environmental impacts of the use of alternative fuels in relation to conventional fuels in the kiln operation. The Life Cycle Assessment (LCA) methodology is used to quantify the potential environmental impacts in each scenario. The interpretation of the results provides the conclusion that the most environmentally friendly prospect is the scenario based on RDF while the less preferable scenario is the scenario based on BS. PMID- 28716295 TI - How preschoolers react to norm violations is associated with culture. AB - Children from the age of 3years understand social norms as such and enforce these norms in interactions with others. Differences in parental and institutional education across cultures make it likely that children receive divergent information about how to act in cases of norm violations. In the current study, we investigated whether cultural values are associated with the ways in which children react to norm violations. We tested 80 bicultural 3-year-olds with a norm enforcement paradigm and analyzed their reactions to norm violations. The reactions were correlated to the children's parental cultural values using the Global Leadership and Organizational Behavior Effectiveness (GLOBE) scales, and these results show that parental culture was associated with children's reactions to norm violations. The three strongest correlations were found for institutional collectivism, performance orientation, and assertiveness. PMID- 28716296 TI - Clinical and Radiologic Predictive Factors of Rib Fractures in Outpatients With Chest Pain. AB - PURPOSE: To identify the clinical and radiologic predictive factors of rib fractures in stable adult outpatients presenting with chest pain and to determine the utility of dedicated rib radiographs in this population of patients. METHOD AND MATERIALS: Following Institutional Review Board approval, we performed a retrospective review of 339 consecutive cases in which a frontal chest radiograph and dedicated rib series had been obtained for chest pain in the outpatient setting. The frontal chest radiograph and dedicated rib series were sequentially reviewed in consensus by two fellowship-trained musculoskeletal radiologists blinded to the initial report. The consensus interpretation of the dedicated rib series was used as the gold standard. Multiple variable logistic regression analysis assessed clinical and radiological factors associated with rib fractures. Fisher exact test was used to assess differences in medical treatment between the 2 groups. RESULTS: Of the 339 patients, 53 (15.6%) had at least 1 rib fracture. Only 20 of the 53 (37.7%) patients' fractures could be identified on the frontal chest radiograph. The frontal chest radiograph had a sensitivity of 38% and specificity of 100% when using the rib series as the reference standard. No pneumothorax, new mediastinal widening or pulmonary contusion was identified. Multiple variable logistic regression analysis of clinical factors associated with the presence of rib fractures revealed a significant association of trauma history (odds ratio 5.7 [p < 0.05]) and age >=40 (odds radio 3.1 [p < 0.05]). Multiple variable logistic regression analysis of radiographic factors associated with rib fractures in this population demonstrated a significant association of pleural effusion with rib fractures (odds ratio 18.9 [p < 0.05]). Patients with rib fractures received narcotic analgesia in 47.2% of the cases, significantly more than those without rib fractures (21.3%, p < 0.05). None of the patients required hospitalization. CONCLUSION: In the stable outpatient setting, rib fractures have a higher association with a history of minor trauma and age >=40 in the adult population. Radiographic findings associated with rib fractures include pleural effusion. The frontal chest radiograph alone has low sensitivity in detecting rib fractures. The dedicated rib series detected a greater number of rib fractures. Although no patients required hospitalization, those with rib fractures were more likely to receive narcotic analgesia. PMID- 28716297 TI - On the relative merits of invasive and non-invasive pre-surgical brain mapping: New tools in ablative epilepsy surgery. AB - Cortical Stimulation Mapping (CSM) and the Wada procedure have long been considered the gold standard for localizing motor and language-related cortical areas and for determining the language and memory-dominant hemisphere, respectively. In recent years, however, non-invasive methods such as magnetoencephalography (MEG), functional magnetic resonance imaging (fMRI), and transcranial magnetic stimulation (TMS) have emerged as promising alternatives to the aforementioned procedures, particularly in cases where the invasive localization of eloquent cortex has proven to be challenging. To illustrate this point, we will first introduce the evidence of the compatibility of invasive and non-invasive methods and subsequently outline the rationale and the conditions where the latter methods are applicable. PMID- 28716298 TI - The male-female earnings gap for nurses in Germany: A pooled cross-sectional study of the years 2006 and 2012. AB - BACKGROUND: Nursing is one of the largest occupations for women in every country. Evidence suggests a substantial male-female pay gap for registered nurses in the U.S., possibly contributing to disparities between genders more broadly. Differences in motivation and skills between men and women have long been considered important factors in the gender earnings gap, but these factors are difficult to measure. Because of country specific educational pathways and limited upward job mobility in Germany, nurses tend to be more homogenous in their motivation to work and their work skills compared to the U.S. OBJECTIVE: To study male-female earnings in the nursing labor market in Germany. DESIGN: This is a pooled cross-sectional study of survey data collected for the years 2006 and 2012. METHODS: We used a representative survey of nurses (n=828) who are active labor force participants. In a multivariate ordinary least squares regression, the analysis estimated the log of monthly earnings for male and female nurses. The full model accounted for demographic, human capital, and geographic characteristics, in addition to employment characteristics, such as hours worked, additional education obtained, years of nursing experience, years of labor market experience, career inactivity, years with the employer, and responsibilities at work, among other factors. We conducted follow-up analyses to test alternative explanations for the pay gap, examining earnings for nurses who no longer worked in nursing and testing potential differences in motivation with the likelihood of working nightshifts and length of time with current employer. RESULTS: Unadjusted monthly earnings for full-time male nurses were 30% higher, or 700 Euros more, than monthly earnings for full-time female nurses. In the fully adjusted analysis, male nurses out-earned female nurses by approximately 9.3%, or 260 Euros per month. Follow-up analyses suggested that better outside options exist for male than female nurses in the German labor market, while we found no support for gender differences in motivation. PMID- 28716299 TI - The adverse effects of virgin microplastics on the fertilization and larval development of sea urchins. PMID- 28716300 TI - The effect of training level on complications after free flap surgery of the head and neck. AB - OBJECTIVES: Analyze postoperative complications after free flap surgery based on PGY training level. METHODS: Data on free flap surgeries of the head and neck performed from 2005 to 2013 was collected from the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) database. Cases identifying the status of resident participation in the surgery and the PGY level were included. RESULTS: There were 582 cases with primary surgeon data available. 63 cases were performed with a junior resident, 211 were performed with the assistance of a senior resident, 279 cases were performed with a fellow, and 29 cases were performed by an attending alone without resident involvement. The overall complication rate was 55.2%. There was no statistically significant difference in the rate of complications between groups (47.6%, 59.7%, 53.0%, 58.6%, p=0.277). After controlling for all confounding variables using multivariate analysis there was no significant difference in morbidity, mortality, readmissions, and reoperation amongst the groups. Furthermore, when comparing resident versus fellow involvement using multivariate analysis there were no significant differences in morbidity (OR=0.768[0.522-1.129]), mortality (OR=1.489[0.341-6.499]), readmissions (OR=1.018[0.458-2.262]), and reoperation (OR=0.863[0.446-1.670]). CONCLUSION: Resident and fellow participation in microvascular reconstructive cases does not appear to increase 30-day rates of medical, surgical, or overall complications. PMID- 28716302 TI - Acute chest pain in an anxious woman. PMID- 28716303 TI - Early results of endovascular treatment of patients with bilateral stenoses of the internal carotid arteries using proximal protection systems at 30-day follow up. AB - BACKGROUND: Although surgical endarterectomy remains the treatment of choice for carotid artery stenosis, carotid artery stenting (CAS) with use of proximal protection systems (PPS) plays an very important role as alternative treatment modality, especially in patients with critical, symptomatic lesions. This study was single-centre study to evaluate the technical and clinical success of proximal protection devices as the first choice for embolic protection in symptomatic and asymptomatic carotid stenosis in patients with bilateral, advanced lesions of carotid arteries (bilateral stenoses or stenosis and occlusion). METHODS: This was a post hoc analysis, with 30-day follow up. We analyzed results of treatment of 38 patients who underwent 38 CAS with PPS, 17 such procedures in asymptomatic (group A), and 21 in symptomatic individuals (group B). The GORE(r) Flow Reversal System (W.L. Gore, Flagstaff, AZ, USA) was used in 2 patients, and the Mo.Ma Ultra device (Medtronic, Minneapolis, MN, USA) in 36 patients. Mean age was 68+/-7 years, 65% percent of patient were male. RESULTS: There were no procedural and during 30-day follow-up neurologic events. Intolerance of occlusion system occurred in 4 patients (11%) in both groups with any later symptoms. Risk factors of this adverse event comprised: lesions of the left internal carotid lesion and coexisiting diabetes mellitus. CONCLUSIONS: CAS in high risk patients with bilateral lesions of carotid arteries with the use of PPS seems to be a relatively very safe procedure. PMID- 28716301 TI - Discrete beta-adrenergic mechanisms regulate early and late erythropoiesis in erythropoietin-resistant anemia. AB - BACKGROUND: Anemia of critical illness is resistant to exogenous erythropoietin. Packed red blood cells transfusions is the only treatment option, and despite related cost and morbidity, there is a need for alternate strategies. Erythrocyte development can be divided into erythropoietin-dependent and erythropoietin independent stages. We have shown previously that erythropoietin-dependent development is intact in burn patients and the erythropoietin-independent early commitment stage, which is regulated by beta1/beta2-adrenergic mechanisms, is compromised. Utilizing the scald burn injury model, we studied erythropoietin independent late maturation stages and the effect of beta1/beta2, beta-2, or beta 3 blockade in burn mediated erythropoietin-resistant anemia. METHODS: Burn mice were randomized to receive daily injections of propranolol (nonselective beta1/beta2 antagonist), nadolol (long-acting beta1/beta2 antagonist), butoxamine (selective beta2 antagonist), or SR59230A (selective beta3 antagonist) for 6 days after burn. Total bone marrow cells were characterized as nonerythroid cells, early and late erythroblasts, nucleated orthochromatic erythroblasts and enucleated reticulocyte subsets using CD71, Ter119, and Syto-16 by flow cytometry. Multipotential progenitors were probed for MafB expressing cells. RESULTS: Although propranolol improved early and late erythroblasts, only butoxamine and selective beta3-antagonist administrations were positively reflected in the peripheral blood hemoglobin and red blood cells count. While burn impeded early commitment and late maturation stages, beta1/beta2 antagonism increased the early erythroblasts through commitment stages via beta2 specific MafB regulation. beta3 antagonism was more effective in improving overall red blood cells through late maturation stages. CONCLUSION: The study unfolds novel beta2 and beta3 adrenergic mechanisms orchestrating erythropoietin resistant anemia after burn, which impedes both the early commitment stage and the late maturation stages, respectively. PMID- 28716305 TI - Real-time monitoring of antibody microdistribution during photoimmunotherapy. PMID- 28716304 TI - Three-dimensional computational model of a blood oxygenator reconstructed from micro-CT scans. AB - Cardiopulmonary bypass procedures are one of the most common operations and blood oxygenators are the centre piece for the heart-lung machines. Blood oxygenators have been tested as entire devices but intricate details on the flow field inside the oxygenators remain unknown. In this study, a novel method is presented to analyse the flow field inside oxygenators based on micro Computed Tomography (MUCT) scans. Two Hollow Fibre Membrane (HFM) oxygenator prototypes were scanned and three-dimensional full scale models that capture the device-specific fibre distributions are set up for computational fluid dynamics analysis. The blood flow through the oxygenator is modelled as a non-Newtonian fluid. The results were compared against the flow solution through an ideal fibre distribution and show the importance of a uniform distribution of fibres and that the oxygenators analysed are not susceptible to flow directionality as mass flow versus area remain the same. However the pressure drop across the oxygenator is dependent on flow rate and direction. By comparing residence time of blood against the time frame to fully saturate blood with oxygen we highlight the potential of this method as design optimisation tool. In conclusion, image-based reconstruction is found to be a feasible route to assess oxygenator performance through flow modelling. It offers the possibility to review a product as manufactured rather than as designed, which is a valuable insight as a precursor to the approval processes. Finally, the flow analysis presented may be extended, at computational cost, to include species transport in further studies. PMID- 28716306 TI - Tertiary cytoreductive surgery in recurrent epithelial ovarian cancer: A multicentre MITO retrospective study. AB - OBJECTIVES: To evaluate the impact of tertiary cytoreductive surgery (TCS) on survival in recurrent epithelial ovarian cancer (EOC), and to determine predictors of complete cytoreduction. METHODS: A multi-institutional retrospective study was conducted within the MITO Group on a 5-year observation period. RESULTS: A total of 103 EOC patients with a >=6month treatment-free interval (TFI) undergoing TCS were included. Complete cytoreduction was achieved in 71 patients (68.9%), with severe post-operative complications in 9.7%, and no cases of mortality within 60days from surgery. Multivariate analysis identified the complete tertiary cytoreduction as the most potent predictor of survival followed by FIGO stage I-II at initial diagnosis, exclusive retroperitoneal recurrence, and TCS performed >=3years after primary diagnosis. Patients with complete tertiary cytoreduction had a significantly longer overall survival (median OS: 43months, 95% CI 31-58) compared to those with residual tumor (median OS: 33months, 95% CI 28-46; p<0.001). After multivariate adjustment the presence of a single lesion and good (ECOG 0) performance status were the only significant predictors of complete surgical cytoreduction. CONCLUSIONS: This is the only large multicentre study published so far on TCS in EOC with >=6month TFI. The achievement of postoperative no residual disease is confirmed as the primary objective also in a TCS setting, with significant survival benefit and acceptable morbidity. Accurate patient selection is of utmost importance to have the best chance of complete cytoreduction. PMID- 28716307 TI - Should epithelial ovarian carcinoma metastatic to the inguinal lymph nodes be assigned stage IVB? AB - OBJECTIVE: According to the revised FIGO staging system women with ovarian carcinoma and inguinal lymph node (LN) metastases, formerly stage III, are now considered stage IVB. In this study we compare their survival to that of women with stage III and stage IV disease. METHODS: Women diagnosed with epithelial ovarian carcinoma were drawn from the Surveillance, Epidemiology, and End Results database (2004-2013). Four groups were formed: group 1 (stage IV due to positive inguinal nodes), group 2 (stage III with positive para-aortic/pelvic nodes), group 3 (stage IV with positive distant nodes) and group 4 (stage IV with distant metastases). Overall (OS) and cancer-specific survival (CSS) rates were evaluated with the Kaplan-Meier method. The log-rank test and Cox-hazard models were employed for univariate and multivariate survival analysis. RESULTS: A total of 11,152 women were identified. Five-year OS for women in group 1 (n=151) was 46.3% compared to 44.9% for those in group 2 (n=4,403) (p=0.4), 32.9% in group 3 (n=642) (p<0.001) and 25.3% in group 4 (n=5,956) (p<0.001). After controlling for age, race and histology, group 1 had improved overall and cancer-specific mortality compared to groups 3 and 4 but not group 2. CONCLUSIONS: Ovarian cancer patients with stage IV ovarian cancer due solely to inguinal nodal metastases have similar survival as those with pelvic/para-aortic nodal involvement and improved survival compared to those harboring distant metastases. Our findings do not support the reclassification of these patients as stage IVB. PMID- 28716308 TI - Unexpected locations of sentinel lymph nodes in endometrial cancer. AB - INTRODUCTION: To evaluate the anatomical location of sentinel lymph nodes (SLN) following intra-operative cervical injection in endometrial cancer. METHODS: All consecutive patients with endometrial cancer undergoing sentinel lymph node mapping were included in this prospective study following intra-operative cervical injection of tracers. Areas of SLN detection distribution were mapped. RESULTS: Among 436 patients undergoing SLN mapping, there were 1095 SLNs removed, and 7.9% of these SLNs found in 13.1% of patients, were detected in areas not routinely harvested during a standard lymph node dissection. These included the internal iliac vein, parametrial, and pre-sacral areas. The SLN was the only positive node in 46.1% (15/36) of cases with successful mapping and completion lymphadenectomy, including 3 cases where the sentinel node in the atypical location was the only node with metastatic disease. CONCLUSION: SLN mapping using intra-operative cervical injection is capable to map out areas not typically included in a standard lymphadenectomy. The sentinel node is the most relevant lymph node to analyze and may enable to discover metastatic disease in unusual areas. PMID- 28716309 TI - Arginine vasopressin, copeptin, and the development of relative AVP deficiency in hemorrhagic shock. AB - BACKGROUND: Arginine vasopressin (AVP) is critical for maintaining vasomotor tone and low levels have been associated with the development of irreversible shock. We investigated the clinical relationship between AVP, copeptin (the C-terminal fragment of the AVP precursor), and the development of relative AVP deficiency following hemorrhagic shock. METHODS: A prospective, observational study of 21 hypotensive (SBP<90 mmHg X 2) or presumptively bleeding trauma patients was conducted. Demographics, mechanism of injury, vital signs, laboratory values, transfusions, crystalloid volume, and blood samples were collected on arrival and serially for 48 h. AVP and copeptin were measured post hoc. RESULTS: AVP and copeptin levels were markedly elevated on admission, but decreased rapidly over time (p < 0.001). AVP and copeptin levels were positively correlated on admission (r = 0.769, p < 0.001), in the ICU (r = 0.768, p < 0.001), and at 48 h (r = 0.537, p = 0.02). Initial AVP and copeptin levels predicted the need for >=10 unit blood product transfusion (AUC = 81% and 87%, respectively). The development of a relative AVP deficiency occurred frequently and was associated with an increased need for blood product transfusion. CONCLUSION: Copeptin correlates well with AVP and initial values predict the need for massive transfusion in trauma patients. Copeptin demonstrates promise as a clinical biomarker in hemorrhagic shock. PMID- 28716310 TI - The role of same-sex mentorship and organizational support in encouraging women to pursue surgery. AB - INTRODUCTION: While women represent approximately half of all medical students, only 38% of general surgery residents are women. The objective of this study is to explore how access to mentors and organizational support affects career choices. METHODS: In June of 2016, a survey was sent to medical students at a single institution (n = 472). Questions utilized a 5-point Likert scale. A two sample t-test was used to evaluate data. RESULTS: A total of 160 students participated in the survey. Among MS1/MS2 students, women were more likely to rank same-sex role models as a positive influence (mean 3.1 vs. 2.4; p < 0.05). Similar results were seen among MS3/MS4 students (mean 3.6 vs. 2.5; p < 0.05). More women ranked the presence of organizations that support women in surgery as being important (mean 4.6 vs. 4.1; p < 0.05). CONCLUSION: Exposure to same-sex mentors was highly rated among female participants. These findings encourage the creation of national mentorship programs. Early involvement in organizations can positively influence career choice. Addressing gaps in mentorship opportunities and widening accessibility to national organizations are important in reducing barriers. PMID- 28716311 TI - Building evidence for care beyond the medical centre. PMID- 28716312 TI - Ethical considerations in noise-induced hearing loss research. PMID- 28716313 TI - Telemedicine for management of inflammatory bowel disease (myIBDcoach): a pragmatic, multicentre, randomised controlled trial. AB - BACKGROUND: Tight and personalised control of inflammatory bowel disease in a traditional setting is challenging because of the disease complexity, high pressure on outpatient clinics, and rising incidence. We compared the effects of self-management with a telemedicine system, which was developed for all subtypes of inflammatory bowel disease, on health-care utilisation and patient-reported quality of care versus standard care. METHODS: We did this pragmatic, randomised trial in two academic and two non-academic hospitals in the Netherlands. Outpatients aged 18-75 years with inflammatory bowel disease and without an ileoanal or ileorectal pouch anastomosis, who had internet access and Dutch proficiency, were randomly assigned (1:1) to care via a telemedicine system (myIBDcoach) that monitors and registers disease activity or standard care and followed up for 12 months. Randomisation was done with a computer-generated sequence and used the minimisation method. Participants, health-care providers, and staff who assessed outcome measures were not masked to treatment allocation. Primary outcomes were the number of outpatient visits and patient-reported quality of care (assessed by visual analogue scale score 0-10). Safety endpoints were the numbers of flares, corticosteroid courses, hospital admissions, emergency visits, and surgeries. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT02173002. FINDINGS: Between Sept 9, 2014, and May 18, 2015, 909 patients were randomly assigned to telemedicine (n=465) or standard care (n=444). At 12 months, the mean number of outpatient visits to the gastroenterologist or nurse was significantly lower in the telemedicine group (1.55 [SD 1.50]) than in the standard care group (2.34 [1.64]; difference -0.79 [95% CI -0.98 to -0.59]; p<0.0001), as was the mean number of hospital admissions (0.05 [0.28] vs 0.10 [0.43]; difference -0.05 [-0.10 to 0.00]; p=0.046). At 12 months, both groups reported high mean patient-reported quality of care scores (8.16 [1.37] in the telemedicine group vs 8.27 [1.28] in the standard care group; difference 0.10 [-0.13 to 0.32]; p=0.411). The mean numbers of flares, corticosteroid courses, emergency visits, and surgeries did not differ between groups. INTERPRETATION: Telemedicine was safe and reduced outpatient visits and hospital admissions compared with standard care. This self management tool might be useful for reorganising care of inflammatory bowel disease towards personalised and value-based health care. FUNDING: Maastricht University Medical Centre and Ferring. PMID- 28716315 TI - Understanding the Economic Impact of Neurogenic Lower Urinary Tract Dysfunction. AB - Neurogenic bladder is a chronic and disabling condition associated with multiple comorbidities and a widespread economic impact. Literature on cost of care and resource utilization is sparse and heterogeneous. Nonstandardized approaches, impact perspectives, and types of costs are used to describe the economic implications of neurogenic bladder. The financial toll is difficult to ascertain due to indirect and intangible costs exacerbated by the underlying disability. Health resource utilization based on clinical manifestations of neurogenic bladder may serve as an alternative measure. Understanding the multifold economic implications and health resource utilization patterns of neurogenic bladder may guide improvement of treatment strategies. PMID- 28716314 TI - Safety and efficacy of ebselen for the prevention of noise-induced hearing loss: a randomised, double-blind, placebo-controlled, phase 2 trial. AB - BACKGROUND: Noise-induced hearing loss is a leading cause of occupational and recreational injury and disease, and a major determinant of age-related hearing loss. No therapeutic agent has been approved for the prevention or treatment of this disorder. In animal models, glutathione peroxidase 1 (GPx1) activity is reduced after acute noise exposure. Ebselen, a novel GPx1 mimic, has been shown to reduce both temporary and permanent noise-induced hearing loss in preclinical studies. We assessed the safety and efficacy of ebselen for the prevention of noise-induced hearing loss in young adults in a phase 2 clinical trial. METHODS: In this single-centre, randomised, double-blind, placebo-controlled phase 2 trial, healthy adults aged 18-31 years were randomly assigned (1:1:1:1) at the University of Florida (Gainsville, FL, USA) to receive ebselen 200 mg, 400 mg, or 600 mg, or placebo orally twice daily for 4 days, beginning 2 days before a calibrated sound challenge (4 h of pre-recorded music delivered by insert earphones). Randomisation was done with an allocation sequence generated by an independent third party. The primary outcome was mean temporary threshold shift (TTS) at 4 kHz measured 15 min after the calibrated sound challenge by pure tone audiometry; a reduction of 50% in an ebselen dose group compared with the placebo group was judged to be clinically relevant. All participants who received the calibrated sound challenge and at least one dose of study drug were included in the efficacy analysis. All randomly assigned patients were included in the safety analysis. This trial is registered with ClinicalTrials.gov, number NCT01444846. FINDINGS: Between Jan 11, 2013, and March 24, 2014, 83 participants were enrolled and randomly assigned to receive ebselen 200 mg (n=22), 400 mg (n=20), or 600 mg (n=21), or placebo (n=20). Two participants in the 200 mg ebselen group were discontinued from the study before the calibrated sound challenge because they no longer met the inclusion criteria; these participants were excluded from the efficacy analysis. Mean TTS at 4 kHz was 1.32 dB (SE 0.91) in the 400 mg ebselen group compared with 4.07 dB (0.90) in the placebo group, representing a significant reduction of 68% (difference -2.75 dB, 95% CI -4.54 to -0.97; p=0.0025). Compared with placebo, TTS at 4 kHz was non-significantly reduced by 21% in the 200 mg ebselen group (3.23 dB [SE 0.91] vs 4.07 dB [0.90] in the placebo group; difference -0.84 dB, 95% CI -2.63 to 0.94; p=0.3542) and by 7% in the 600 mg ebselen group (3.81 dB [0.90] vs 4.07 dB [0.90] in the placebo group; difference -0.27, 95% CI -2.03 to 1.50; p=0.7659). Ebselen treatment was well tolerated across all doses and no significant differences were seen in any haematological, serum chemistry, or radiological assessments between the ebselen groups and the placebo group. INTERPRETATION: Treatment with ebselen was safe and effective at a dose of 400 mg twice daily in preventing a noise-induced TTS. These data lend support to a role of GPx1 activity in acute noise-induced hearing loss. FUNDING: Sound Pharmaceuticals. PMID- 28716316 TI - How to Measure Quality-of-Life Concerns in Patients with Neurogenic Lower Urinary Tract Dysfunction. AB - There is an evolving role for quality-of-life measures and patient-reported outcomes in the evaluation of neurogenic lower urinary tract dysfunction. We review available health-related quality-of-life instruments and patient-reported outcomes measures used in the assessment of patients with neurogenic bladder. We also discuss considerations for incorporation of these measures into clinical and patient-reported research. Emphasizing patient-reported outcomes in neurogenic bladder research will guide clinicians and other stakeholders to improve quality of life in this patient population. PMID- 28716317 TI - Long-Term Complications of the Neurogenic Bladder. AB - It is widely accepted that neurogenic lower urinary tract dysfunction, when left untreated, has a natural history that has a potential for causing deterioration of renal function over time. However, certain patient profiles are at risk for this and other complications. This can be linked to their underlying neurologic disease process. Identifying risk profiles allows the provider to determine what surveillance strategies might be adopted. Risk factors for upper urinary tract deterioration include loss of bladder compliance, repeated bouts of pyelonephritis, and chronic indwelling catheterization. Other long-term complications include nephrolithiasis, refractory urinary incontinence, and malignancy. PMID- 28716318 TI - Surveillance Strategies for Neurogenic Lower Urinary Tract Dysfunction. AB - Patients with neurogenic lower urinary tract dysfunction (NLUTD) experience significant morbidity and mortality due to urological complications including upper tract damage and bladder malignancy. This has led to increased surveillance in patients NLUTD. This article discusses the methods available for surveillance of patients with NLUTD and pulls information from the largest and most established organizations that have produced evidence-based surveillance guidelines for NLUTD. These organizations include the Paralyzed Veterans of America (PVA), US Department of Veterans Affairs, European Association of Urology (EAU), The NICE organization from the UK, and cites additional literature not been included in these documents. PMID- 28716319 TI - Establishing a Multidisciplinary Approach to the Management of Neurologic Disease Affecting the Urinary Tract. AB - Neurologic diseases often affect the urinary tract and may be congential or acquired. The progressive nature of many neurologic diseases necessitates routine surveillance and treatment with a multidisciplinary approach. Urologic treatments may interact with pharmacologic or procedural interventions planned by other specialists, mandating close coordination of care and communication among providers. Primary care and nursing often can serve as the quarterbacks of the multidisciplinary team by identifying when a slowly progressive condition warrants further investigation and management by specialists. PMID- 28716320 TI - Evaluation and Lifetime Management of the Urinary Tract in Patients with Myelomeningocele. AB - In the United States, there are an estimated 25,000 children ages 0 to 19 years and about 166,000 of all ages currently affected by spina bifida. Management is multimodal and can be complex. Management techniques vary throughout a child's lifetime, but the goals remain the same: prevention of urinary tract infections and establishing acceptable continence. Continence is addressed as the child reaches school age. Additional considerations such as development of urolithiasis and the associated burden are highlighted in adolescence and into adulthood. These complex medical needs become more challenging as patients age and need to transition to adult providers. PMID- 28716321 TI - Contemporary Evaluation and Treatment of Poststroke Lower Urinary Tract Dysfunction. AB - Stroke is an extremely common clinical entity, and poststroke incontinence is a major cause of morbidity for stroke survivors. Although patients can experience a wide variety of lower urinary tract symptoms, detrusor overactivity is among the most common clinical findings following stroke. All forms of lower urinary tract symptoms can negatively impact physical and psychosocial function for affected patients and their caregivers and loved ones. Careful evaluation is critical for successful management. Treatment is tailored to the goals and needs of each individual patient. Improvements in continence status can help to enhance overall and health-related quality of life. PMID- 28716322 TI - Parkinson's Disease and Its Effect on the Lower Urinary Tract: Evaluation of Complications and Treatment Strategies. AB - Parkinson's disease (PD) and atypical Parkinsonism are the second most common neurodegenerative movement disorders. Lower urinary tract dysfunction is among the most common types of associated autonomic dysfunctions. Differentiating the subtypes of PD is important for symptom management and understanding prognosis, because Lower urinary tract symptoms (LUTS) can evolve differently depending on the primary disease. LUTS are caused by storage and/or voiding dysfunctions. Urodynamics is a key investigative tool. The complex pathophysiology of this bladder dysfunction is not responsive to levodopa, and add-on therapy is necessary. Newer interventions hold promise as therapy to improve bladder dysfunction. PMID- 28716323 TI - Chronic Urinary Retention in Multiple Sclerosis Patients: Physiology, Systematic Review of Urodynamic Data, and Recommendations for Care. AB - Many multiple sclerosis (MS) patients are affected by urinary retention. Common causes include neurogenic underactive bladder and/or bladder outlet obstruction from detrusor sphincter dyssynergia. Systemic review of contemporary MS urodynamic studies demonstrates that 53% of MS patients have detrusor overactivity, 43% have detrusor sphincter dyssynergia, and 12% have atonic bladder (12 studies, 1524 patients). There is no standard definition of MS related urinary retention, but greater than 300 mL is a proposed threshold value for the condition based on literature review. Treatment should be based on stratifying patients by risk from morbidity from retention and by symptoms caused by retention. PMID- 28716324 TI - Identifying Patients with High-Risk Neurogenic Bladder: Beyond Detrusor Leak Point Pressure. AB - More than 12,000 spinal cord injuries occur annually in the United States; more than 80% of these individuals will experience urinary tract dysfunction. Despite the clinical demand, there is a paucity of guidelines for the care of these patients. Although most urologists are familiar with dangerous urodynamic parameters and the benefits of clean intermittent catheterization, these patients face a myriad of risks that may go unrecognized. In this article, the authors discuss the impact of specific neurologic diseases on the urinary tract, examine the risks inherent to each, and determine strategies for screening, prevention, and treatment of these complications. PMID- 28716325 TI - Peripheral and Sacral Neuromodulation in the Treatment of Neurogenic Lower Urinary Tract Dysfunction. AB - Sacral and peripheral neuromodulation are minimally invasive surgical procedures that are third-line therapy options for the treatment of patients with idiopathic overactive bladder syndrome. There has been interest in their efficacy in the management of neurogenic lower urinary tract dysfunction (NLUTD). Contemporary data suggest promising outcomes for urinary and bowel symptoms in carefully selected patients with spinal cord injury and/or multiple sclerosis. This article reviews the current literature regarding urinary and bowel outcomes in patients with NLUTD and also discusses contemporary studies that suggest that treatment during particular stages of neurologic injury may prevent long-term urinary sequelae. PMID- 28716327 TI - Surgical Management of Neurogenic Lower Urinary Tract Dysfunction. AB - Surgery for patients with neurogenic urinary tract dysfunction (nLUTD) is indicated when medical therapy fails, to correct conditions affecting patient safety, or when surgery can enhance the quality of life better than nonoperative management. Examples include failure of maximal medical therapy, inability to perform or aversion to clean intermittent catheterization, refractory incontinence, and complications from chronic, indwelling catheters. Adults with nLUTD have competing risk factors, including previous operations, obesity, poor nutritional status, complex living arrangements, impaired dexterity/paralysis, and impaired executive and cognitive function. Complications are common in this subgroup of patients requiring enduring commitments from surgeons, patients, and their caretakers. PMID- 28716326 TI - Disease-Specific Outcomes of Botulinum Toxin Injections for Neurogenic Detrusor Overactivity. AB - Intradetrusor injection of botulinum toxin A (BTX-A) is an effective option for managing patients with neurogenic detrusor overactivity (NDO) who do not respond to or tolerate oral pharmacologic agents. There is level I evidence that intradetrusor injection of onabotulinumtoxinA for refractory NDO in patients with multiple sclerosis and spinal cord injury is associated with a significantly greater achievement of goals and improved performance in urodynamic studies than placebo. Pilot studies or small case series support BTX-A for NDO in patients with Parkinson's disease and cerebrovascular accident. BTX-A seems to be effective in children with myelomeningocele. However, no adult data exists. PMID- 28716329 TI - Mending Gaps in Knowledge: Collaborations in Neurogenic Bladder Research. AB - Patient-reported outcomes and quality of life assessments are essential to studying conditions such as neurogenic bladder in which multiple management strategies are approximately equally efficacious. Innovations for the treatment of neurogenic bladder need to be guided by both clinical and patient-reported outcomes that are rigorously tested via high-quality prospective cohort or randomized studies. Collaborative research groups in reconstructive urology are critical to the study of uncommon disease processes because they allow studies to be powered adequately, foster innovative treatment strategies through collaboration, and help moderate the risk of investigator and or institutional biases. PMID- 28716330 TI - The Impact of Neurologic Disease on the Urinary Tract. PMID- 28716331 TI - Introducing "The Impact of Neurologic Disease on the Urinary Tract". PMID- 28716328 TI - New Frontiers of Basic Science Research in Neurogenic Lower Urinary Tract Dysfunction. AB - The lower urinary tract's main functions are storage and elimination. The micturition reflex pathway is modulated by the spinobulbospinal reflex pathway as well as higher brain centers involved in the voluntary micturition control. Micturition is sensitive to numerous injuries, resulting in various types of dysfunction. Animal studies indicate that lower urinary tract dysfunction partly depends on plasticity of the neural pathways. Reflex plasticity is associated with changes in ion channels, receptors, and numerous mediators. Animal models may aid in understanding the mechanisms leading to pathologic conditions and the plasticity in reflex pathways to the lower urinary tract after neurogenic lesions. PMID- 28716332 TI - Shaping and Reshaping Transcriptome Plasticity during Evolution. AB - Transcriptome plasticity, usually associated with alternative isoform generation, is recognised as a key mechanism driving proteomic diversity and biological complexity. Recent findings of Liscovitch-Brauer et al. and Ma et al. suggest that RNA base modifications are an additional central mode of transcriptome malleability that have the potential to determine evolutionary outcomes. PMID- 28716333 TI - Congenital Anomalies of the Superior Vena Cava: Embryological Correlation, Imaging Perspectives, and Clinical Relevance. AB - There is a wide spectrum of congenital anomalies of the superior vena cava, which are more increasingly recognized in cross-sectional imaging. Although some of these anomalies are asymptomatic, others have important clinical and interventional implications. Imaging modalities such as computed tomography and magnetic resonance imaging play an important role in the accurate characterization of these anomalies, which is essential for mapping prior to surgeries or interventions. In this article, we review a wide range of anomalies of the superior vena cava, including the embryological basis, cross-sectional imaging findings, and clinical implications, particularly from an interventional radiology perspective. We also discuss the treatments and complications of these anomalies. PMID- 28716334 TI - A common password improves validation rates for elogbook: A brief overview of how a shared password is a secure and effective method of improving rates of validation of trainees' procedures in elogbook. PMID- 28716335 TI - Management of Chronic Total Coronary Occlusion in Stable Ischemic Heart Disease by Percutaneous Coronary Intervention Versus Coronary Artery Bypass Grafting Versus Medical Therapy. AB - Coronary chronic total occlusions (CTOs) are found in approximately 20% of angiograms. We sought to assess the variation in the management of patients with CTOs and to compare the clinical outcomes of CTO lesions with those of non-CTO lesions. We conducted a population-based cohort study and included all patients with stable angina who underwent cardiac catheterization from October 1, 2012, to June 30, 2013, in Ontario, Canada. The primary outcome was a composite of mortality and hospitalization for myocardial infarction. A total of 7,864 patients were included, of whom 2,279 (29%) had a CTO. There were substantial differences in revascularization rates for patients with CTOs across hospitals in Ontario (44.9% to 94.1%). Revascularization was associated with improved outcomes in the overall cohort. Although the advantage of coronary artery bypass grafting over medical therapy was consistent in both patients with CTOs and patients without CTOs, the benefit of percutaneous coronary intervention (PCI) was limited to patients without CTOs (hazard ratio 0.56, 95% confidence interval 0.40- to 0.78), with no difference in patients with CTOs. The CTO lesion, however, was revascularized in few of the PCI cases (41.1%), with PCI limited to the non-CTO lesion in most patients. PMID- 28716337 TI - Physical Models and Virtual Reality Simulators in Otolaryngology. AB - The increasing role of simulation in the medical education of future otolaryngologists has followed suit with other surgical disciplines. Simulators make it possible for the resident to explore and learn in a safe and less stressful environment. The various subspecialties in otolaryngology use physical simulators and virtual-reality simulators. Although physical simulators allow the operator to make direct contact with its components, virtual-reality simulators allow the operator to interact with an environment that is computer generated. This article gives an overview of the various types of physical simulators and virtual-reality simulators used in otolaryngology that have been reported in the literature. PMID- 28716336 TI - Relation of Exercise Capacity to Risk of Development of Diabetes in Patients on Statin Therapy (the Henry Ford Exercise Testing Project). AB - High exercise capacity (EC) has been associated with a lower risk of incident diabetes, whereas statin therapy has been associated with a higher risk. We sought to investigate whether the association between EC and diabetes risk is modified by statin therapy. This retrospective cohort study included 47,337 patients without diabetes or coronary artery disease at baseline (age 53 +/- 13 years, 48% women, 66% white) who underwent clinical treadmill stress testing within the Henry Ford Health System from January 1, 1991, to May 31, 2009. The patients were stratified by baseline statin use and estimated peak METs achieved during exercise testing. Hazard ratios for incident diabetes were calculated using Cox proportional hazards models adjusted for demographic characteristics, co-morbidities, pertinent medications, and stress test indication. We observed 6,921 new diabetes cases (14.6%) over a median follow-up period of 5.1 years (interquartile interval of 2.6 to 8.2 years). Compared with the statin group, the no-statin group achieved higher mean METs (8.9 +/- 2.7 vs 9.6 +/- 3.0, respectively; p <0.001). After adjustment for covariates, a higher EC was associated with a lower risk of incident diabetes, irrespective of statin use (p interaction = 0.15). Each 1-MET increment was associated with an 8%, 8%, and 6% relative risk reduction in the total cohort, the no-statin, and the statin groups, respectively (95% confidence interval, 0.91 to 0.93, 0.91 to 0.93, and 0.91 to 0.96, respectively; p <0.001 for all). We conclude that a higher EC is associated with a lower risk of incident diabetes regardless of statin use. PMID- 28716338 TI - Changing innovation into a registered product: From concept to regulatory approval. AB - Innovation in animal health pharmaceuticals is important to address unmet and underserved medical needs, and often comes from products initially developed for human medicine. The purpose of the review is to help readers understand how breakthroughs from human biotechnology may be developed for use in veterinary medicine, while understanding the key drivers to success, the difficulties of regulatory approval, and the realistic risks and rewards of developing applications for animals. The types of human drugs which may be useful for veterinary applications are reviewed, including examples. The regulatory path is discussed, with a review of the various oversight agencies, and the categories of data required to be submitted, including safety, efficacy, manufacturing, environmental impact and human food safety. In conclusion, the cost, development time, and barriers to innovation in veterinary medical pharmaceuticals are discussed. PMID- 28716339 TI - Collaborating to ease Africa's data drought. PMID- 28716340 TI - Achieving progress for mothers, babies, and children in Kenya. PMID- 28716341 TI - Does task shifting among parts of a weak health system help? PMID- 28716342 TI - A SoLiD base from which to prevent injuries in Bangladesh. PMID- 28716343 TI - Questioning progress towards universal health coverage for the most vulnerable. PMID- 28716344 TI - What global maternal and child nutrition can learn from animal science. PMID- 28716345 TI - China's Belt and Road Initiative from a global health perspective. PMID- 28716346 TI - Use of the GeneXpert tuberculosis system for HIV viral load testing in India. PMID- 28716347 TI - Role of the European Union in global health. PMID- 28716349 TI - Correction to Lancet Glob Health 2017; 5: e760-71. PMID- 28716348 TI - Role of the European Union in global health - Author's reply. PMID- 28716350 TI - Progress and priorities for reproductive, maternal, newborn, and child health in Kenya: a Countdown to 2015 country case study. AB - BACKGROUND: Progress in reproductive, maternal, newborn, and child health (RMNCH) in Kenya has been inconsistent over the past two decades, despite the global push to foster accountability, reduce child mortality, and improve maternal health in an equitable manner. Although several cross-sectional assessments have been done, a systematic analysis of RMNCH in Kenya was needed to better understand the push and pull factors that govern intervention coverage and influence mortality trends. As such, we aimed to determine coverage and impact of key RMNCH interventions between 1990 and 2015. METHODS: We did a comprehensive, systematic assessment of RMNCH in Kenya from 1990 to 2015, using data from nationally representative Demographic Health Surveys done between 1989 and 2014. For comparison, we used modelled mortality estimates from the UN Inter-Agency Groups for Child and Maternal Mortality Estimation. We estimated time trends for key RMNCH indicators, as defined by Countdown to 2015, at both the national and the subnational level, and used linear regression methods to understand the determinants of change in intervention coverage during the past decade. Finally, we used the Lives Saved Tool (LiST) to model the effect of intervention scale-up by 2030. FINDINGS: After an increase in mortality between 1990 and 2003, there was a reversal in all mortality trends from 2003 onwards, although progress was not substantial enough for Kenya to achieve Millennium Development Goal targets 4 or 5. Between 1990 and 2015, maternal mortality declined at half the rate of under-5 mortality, and changes in neonatal mortality were even slower. National level trends in intervention coverage have improved, although some geographical inequities remain, especially for counties comprising the northeastern, eastern, and northern Rift Valley regions. Disaggregation of intervention coverage by wealth quintile also revealed wide inequities for several health-systems-based interventions, such as skilled birth assistance. Multivariable analyses of predictors of change in family planning, skilled birth assistance, and full vaccination suggested that maternal literacy and family size are important drivers of positive change in key interventions across the continuum of care. LiST analyses clearly showed the importance of quality of care around birth for maternal and newborn survival. INTERPRETATION: Intensified and focused efforts are needed for Kenya to achieve the RMNCH targets for 2030. Kenya must build on its previous progress to further reduce mortality through the widespread implementation of key preventive and curative interventions, especially those pertaining to labour, delivery, and the first day of life. Deliberate targeting of the poor, least educated, and rural women, through the scale-up of community level interventions, is needed to improve equity and accelerate progress. FUNDING: US Fund for UNICEF, Bill & Melinda Gates Foundation. PMID- 28716351 TI - Effect of provision of home-based curative health services by public sector health-care providers on neonatal survival: a community-based cluster-randomised trial in rural Pakistan. AB - BACKGROUND: Although the effectiveness of community mobilisation and promotive care delivered by community health workers in reducing perinatal and neonatal mortality is well established, evidence in support of home-based neonatal resuscitation and infection management is mixed. We assessed the effectiveness of adding training in neonatal bag and mask resuscitation and oral antibiotic therapy for suspected neonatal infections to a basic preventive and promotive interventions package delivered by public sector community-based lady health workers (LHWs) in rural Pakistan. METHODS: We did a cluster-randomised controlled trial in two subdistricts of Naushahro Feroze in rural Sindh, Pakistan, between April 15, 2009, and Dec 10, 2012. LHWs, trained in basic newborn resuscitation and in recognition and treatment (with oral amoxicillin) of suspected neonatal respiratory infections, were linked with traditional birth attendants and encouraged to attend home births. Control clusters received routine care through the existing national programme. The primary outcome was all-cause neonatal mortality. Independent data collection teams recorded data for all pregnancies and their outcomes, morbidity, mortality, and household practices related to maternal and newborn care. FINDINGS: Of the 27 randomised clusters with functional LHW programmes, 13 were allocated to the intervention group (n=242 749) and 14 to the control group (n=256 985). In the intervention group, LHWs did 80% of the planned community mobilisation sessions, but were able to attend only 1184 (14%) of 8425 deliveries and 4318 (25%) of 17 288 neonatal visits within 72 h of birth (p<0.0001 for both variables compared with the control group). The neonatal mortality rate was 42 deaths per 1000 livebirths in intervention clusters compared with 55 per 1000 in the control group (risk ratio 0.80, 95% CI 0.68-0.93; p=0.005). INTERPRETATION: The reduction in neonatal mortality in intervention clusters occurred against a background of improvements in domiciliary practices for maternal and newborn care. However, the poor reach of LHWs in accessing newborn infants at birth and in the early postnatal period underscores the limitations of tasking community health workers in public sector programmes working in similar circumstances with such complex interventions. Such community-based interventions in health systems should be accompanied by concerted efforts to improve quality of care in facilities and referral systems. FUNDING: Saving Newborn Lives, Save the Children USA. PMID- 28716352 TI - Fatal and non-fatal injury outcomes: results from a purposively sampled census of seven rural subdistricts in Bangladesh. AB - BACKGROUND: 90% of the global burden of injuries is borne by low-income and middle-income countries (LMICs). However, details of the injury burden in LMICs are less clear because of the scarcity of data and population-based studies. The Saving of Lives from Drowning project, implemented in rural Bangladesh, did a census on 1.2 million people to fill this gap. This Article describes the epidemiology of fatal and non-fatal injuries from the study. METHODS: In this study, we used data from the baseline census conducted as part of the Saving of Lives from Drowning (SoLiD) project. The census was implemented in 51 unions from seven purposively sampled rural subdistricts of Bangladesh between June and November, 2013. Sociodemographic, injury mortality, and morbidity information were collected for the whole population in the study area. We analysed the data for descriptive measures of fatal and non-fatal injury outcomes. Age and gender distribution, socioeconomic characteristics, and injury characteristics such as external cause, intent, location, and body part affected were reported for all injury outcomes. FINDINGS: The census covered a population of 1 169 593 from 270 387 households and 451 villages. The overall injury mortality rate was 38 deaths per 100 000 population per year, and 104 703 people sustained major non-fatal injuries over a 6-month recall period. Drowning was the leading external cause of injury death for all ages, and falls caused the most number of non-fatal injuries. Fatal injury rates were highest in children aged 1-4 years. Non-fatal injury rates were also highest in children aged 1-4 years and those aged 65 years and older. Males had more fatal and non-fatal injuries than females across all external causes except for burns. Suicide was the leading cause of injury deaths in individuals aged 15-24 years, and more than 50% of the suicides occurred in females. The home environment was the most common location for most injuries. INTERPRETATION: The burden of fatal and non-fatal injuries in rural Bangladesh is substantial, accounting for 44 050 deaths and 21 million people suffering major events annually. Targeted approaches addressing drowning in children (especially those aged 1-4 years), falls among the elderly, and suicide among young female adults are urgently needed to reduce injury deaths and morbidity in Bangladesh. FUNDING: Bloomberg Philanthropies. PMID- 28716353 TI - Assessment of progress towards universal health coverage for people with disabilities in Afghanistan: a multilevel analysis of repeated cross-sectional surveys. AB - BACKGROUND: Since 2002, Afghanistan has made much effort to achieve universal health coverage. According to the UN Sustainable Development Goal 3, target eight, the provision of quality care to all must include usually underserved groups, including people with disabilities. We investigated whether a decade of international investment in the Afghan health system has brought quality health care to this group. METHODS: We used data from two representative household surveys, one done in 2005 and one in 2013, in 13 provinces of Afghanistan, that included questions about activity limitations and functioning difficulties, socioeconomic factors, perceived availability of health care, and experience with coverage of health-care needs. We used multilevel modelling and tests for interaction to investigate factors associated with differences in perception between timepoints and whether village remoteness affected changes in perception. FINDINGS: The 2005 survey included 334 people, and the 2013 survey included 961 people. Mean age, employment, and asset levels of participants with disabilities increased slightly between 2005 and 2013, but the level of education decreased. Formal education and higher asset level were associated with improved availability of health care and positive experience with coverage of health-care needs, whereas being employed was only associated with the latter. Perceived availability of health care and positive experience with coverage of health-care needs significantly worsened in 2013 compared with in 2005 (227 [69%] perceived that services were available in 2005 vs 405 [44%] in 2013, p<0.0001; 255 [78%] perceived a positive experience in 2005 vs 410 [45%] in 2013, p<0.0001). Village remoteness increased in 2013 (no connectivity by paved road 186 [57%] in 2005 vs 797 [87%] in 2013, p<0.0001; mean time to reach health-care facility 64.3 min [SD 167.7] vs 84.4 min [107.7], p<0.0001) and negatively affected perception of health-care availability. INTERPRETATION: Perceived availability of health care and experience with health-care coverage have not greatly improved for people with disabilities in Afghanistan, particularly in remote areas. Health policy in Afghanistan will need to address attitudinal, social, and accessibility barriers to health care. FUNDING: Swedish International Development Agency. PMID- 28716354 TI - Survey of Neospora caninum in eared doves (Zenaida auriculata) in Southern Brazil. AB - Neosporosis is an infectious disease caused by Neospora caninum, a protozoan parasite that has worldwide distribution and is responsible for enormous economic losses in cattle. Birds are considered a good bioindicator of environmental contamination, since they feed on the ground, being exposed to N. caninum oocysts. The aim of this study was to determine the occurrence of antibodies against N. caninum and to verify the presence of parasite DNA in brain from free ranging eared doves (Zenaida auriculata) from Southern Brazil. For this purpose, blood and brain samples were collected from 249 doves for ELISA and PCR analysis respectively. The prevalence of N. caninum antibodies in doves was 31.72% (79/249) and detection of parasite DNA was not observed in none of birds. This is the first report of antibodies against N. caninum in doves Z. auriculata, what show us that these birds had previously contact with the parasite but since no N. caninum DNA was detected, more studies should be performed to elucidate the real importance of doves in the epidemiologic cycle of the N. caninum. PMID- 28716355 TI - Study of relative response factors and mass balance in forced degradation studies with liquid chromatography/photo-diode array detector/evaporative light scattering detector/mass spectrometry system. AB - A case study was performed using photodiode array detection (PDA) in combination with evaporative light scattering (ELS) detection and mass spectrometry (MS) to assess both mass balance and the relative response factors (RRFs) in the forced degradation studies of the drug substance, glimepiride. The RRF value, which is the ratio of the response factor of the impurity to that of the API, was first determined using calibration curves of standards. This conventional technique was compared to a second, multi-detection technique, which used the PDA and ELS detectors to determine both the ultraviolet (UV) peak area and the concentration (based on measurement by ELS) in a single analysis. The resulting RRF values were then applied to forced degradation studies (acidic hydrolysis and oxidation) of glimepiride drug substance. This analysis was used to assess mass balance as well as impurity quantification. The impact of applying impurity RRF values was evaluated and found to have a significant impact on the percent of impurity quantified and on mass balance calculations at higher degradation levels. In addition, MS was used to quantify a non-chromophoric by-product and assess its impact on mass balance. Analysis of the forced degradation studies by MS detection also provided confirmation of the degradation pathway with new insights. Specifically, MS revealed differences in the stereoselectivity of the degradation processes: the acidic hydrolysis degradation was found to be stereoselective with the formation of the trans by-product while the oxidation degradation produced both the cis/trans isomers in a non-stereoselective reaction. PMID- 28716356 TI - Fractionation of poly(methacrylic acid) and poly(vinyl pyridine) in aqueous and organic mobile phases by multidetector thermal field-flow fractionation. AB - Multidetector thermal field-flow fractionation (ThFFF) is shown to be a versatile characterisation platform that can be used to characterise hydrophilic polymers in a variety of organic and aqueous solutions with various ionic strengths. It is demonstrated that ThFFF fractionates isotactic and syndiotactic poly(methacrylic acid) (PMAA) as well as poly(2-vinyl pyridine) (P2VP) and poly(4-vinyl pyridine) (P4VP) according to microstructure in organic solvents and that the ionic strength of the mobile phase has no influence on the retention behaviour of the polymers. With regard to aqueous solutions, it is shown that, despite the weak retention, isotactic and syndiotactic PMAA show different retention behaviours which can qualitatively be attributed to microstructure. Additionally, it is shown that the ionic strength of the mobile phase has a significant influence on the thermal diffusion of polyelectrolytes in aqueous solutions and that the addition of an electrolyte is essential to achieve a microstructure-based separation of P2VP and P4VP in aqueous solutions. PMID- 28716357 TI - Clinical and metabolic response to flaxseed oil omega-3 fatty acids supplementation in patients with diabetic foot ulcer: A randomized, double-blind, placebo-controlled trial. AB - BACKGROUND: Data on the effects of flaxseed oil omega-3 fatty acids supplementation on wound healing and metabolic status in subjects with diabetic foot ulcer (DFU) are scarce. OBJECTIVE: This study was conducted to evaluate the effects of flaxseed oil omega-3 fatty acids supplementation on wound healing and metabolic status in subjects with DFU. METHODS: The current randomized, double blind, placebo-controlled trial was conducted among 60 subjects (aged 40-85years old) with grade 3 DFU. Subjects were randomly allocated into two groups (30 subjects each group) to receive either 1000mg omega-3 fatty acids from flaxseed oil supplements or placebo twice a day for 12weeks. RESULTS: After the 12-week intervention, compared with the placebo, omega-3 fatty acids supplementation resulted in significant decreases in ulcer length (-2.0+/-2.3 vs. -1.0+/-1.1cm, P=0.03), width (-1.8+/-1.7 vs. -1.0+/-1.0cm, P=0.02) and depth (-0.8+/-0.6 vs. 0.5+/-0.5cm, P=0.01). Additionally, significant reductions in serum insulin concentrations (-4.4+/-5.5 vs. +1.4+/-8.3 MUIU/mL, P=0.002), homeostasis model of assessment-estimated insulin resistance (-2.1+/-3.0 vs. +1.0+/-5.0, P=0.005) and HbA1c (-0.9+/-1.5 vs. -0.1+/-0.4%, P=0.01), and a significant rise in the quantitative insulin sensitivity check index (+0.01+/-0.01 vs. -0.005+/-0.02, P=0.002) were seen following supplementation with omega-3 fatty acids compared with the placebo. In addition, omega-3 fatty acids supplementation significantly decreased serum high sensitivity C-reactive protein (hs-CRP) (-25.5+/-31.5 vs. 8.2+/-18.9MUg/mL, P=0.01), and significantly increased plasma total antioxidant capacity (TAC) (+83.5+/-111.7 vs. -73.4+/-195.5mmol/L, P<0.001) and glutathione (GSH) concentrations (+60.7+/-140.2 vs. -15.5+/-129.7MUmol/L, P=0.03) compared with the placebo. CONCLUSIONS: Overall, omega-3 fatty acids supplementation for 12weeks among subjects with DFU had beneficial effects on parameters of ulcer size, markers of insulin metabolism, serum hs-CRP, plasma TAC and GSH levels. In addition, flaxseed oil omega-3 fatty acids may have played an indirect role in wound healing due to its effects on improved metabolic profiles. PMID- 28716358 TI - The ability of lizards to identify an artificial Batesian mimic. AB - Birds are usually considered the main predators shaping the evolution of aposematic signals and mimicry. Nevertheless, some lizards also represent predominately visually oriented predators, so they may also play an important role in the evolution of aposematism. Despite this fact, experimental evidence regarding the responses of lizards to aposematic prey is very poor compared to such evidence in birds. Lizards possess very similar sensory and cognitive abilities to those of birds and their response to aposematic prey may thus be affected by very similar processes. We investigated the reactions of a lizard, the Gran Canaria skink (Chalcides sexlineatus), to an aposematic prey and its artificial Batesian mimic. Further, we attempted to ascertain whether the lizard's food experience has any effect on its ability to recognise an artificial Batesian mimic, by using two groups of predators differing in their prior experience with the prey from which the mimic was fabricated. The red firebug (Pyrrhocoris apterus) was used as an aposematic model, and the Guyana spotted roach (Blaptica dubia) as the palatable prey from which the mimic was fabricated. The appearance of the roach was modified by a paper sticker placed on its back. The skinks showed a strong aversion towards the model firebug. They also avoided attacking the cockroaches with the firebug pattern sticker. This suggests that a visual rather than a chemical signal is responsible for this aversion. The protection provided by the firebug sticker was even effective when the skinks were familiar with unmodified cockroaches (previous food experience). PMID- 28716359 TI - Predictors of polymyxin B treatment failure in Gram-negative healthcare associated infections among critically ill patients. AB - BACKGROUND: With increasing prevalence and spread of multidrug resistant Gram negative infections, parenteral polymyxins resurged in clinical practice. The primary aim of the study was to determine the predictors of treatment failure and in-hospital mortality among critically ill patients treated with polymyxin B. METHODS: Demographic data, underlying diseases, procedures and details on polymyxin B therapy were retrospectively analyzed in a cohort of 84 patients who received intravenous polymyxin B in an intensive care unit from 2010 to 2014. RESULTS: Polymyxin B was used to treat bacteremia (46.4% of cases) and pneumonia (53.6%). Majority of the pathogens isolated were Acinetobacter spp. (96.4%). The mortality rate was 48.8%, of which 82.9% was attributed to polymyxin B treatment failure. The independent predictors of treatment failure were low doses of polymyxin B (p = 0.002), shorter duration of therapy (p = 0.009), not combining with cefoperazone/sulbactam (p = 0.030), female gender (p = 0.004), administered for treatment of bacteremia (p = 0.023) and renal impairment (p = 0.021). Low polymyxin B doses (p = 0.007), not combining with cefoperazone/sulbactam (p = 0.024), female gender (p = 0.048) and renal impairment (p = 0.022) were also significant predictors for in-hospital mortality. CONCLUSIONS: To the best of our knowledge, this is the first report on the association of inadequate dose of polymyxin B (<15,000 units/kg/day) with poor outcome in critically ill patients. Besides that, further clinical studies are warranted to evaluate the use of cefoperazone/sulbactam as second antibiotic in the combination therapy. PMID- 28716361 TI - Aggregatibacter aphrophilus culture-negative endocarditis diagnosed by 16S rRNA gene sequencing in excised mitral valve - A case report. PMID- 28716360 TI - Comparison of synergism between colistin, fosfomycin and tigecycline against extended-spectrum beta-lactamase-producing Klebsiella pneumoniae isolates or with carbapenem resistance. AB - PURPOSE: To investigate the synergistic and bactericidal effects of antimicrobial combinations of any two of colistin, fosfomycin and tigecycline against the nine extended-spectrum beta-lactamase (ESBL)-producing Klebsiella pneumoniae (KP) clinical isolates, including 4 carbapenem-susceptible strains and five imipenem and/or meropenem-resistant strains. METHODS: In vitro synergism and bactericidal activity of combination of colistin, fosfomycin and tigecycline were evaluated by time-kill studies in standard inoculum of bacterial densities of a suspension containing 5 * 105 CFU/mL by using 1/2* MIC for each alone, and both 1/2* and 1/4* MIC for any two drugs. The settings of low MIC dosing were allowed to rapidly survey the most active drug combination. RESULTS: The most active combination group was colistin plus tigecycline, showing synergy in 8 isolates and bactericidal activities in 6 isolates by using concentrations of 1/2* MIC and 1/4* MIC, respectively. The least active combination was tigecycline plus fosfomycin, which showed synergy in only 4 isolates and no bactericidal activities by using concentrations of 1/2* MIC and 1/4* MIC, respectively. CONCLUSIONS: The combination of tigecycline and colistin may be considered as a last-resort approach to the ESBL-producing KP infections, especially those isolates with carbapenem resistance. PMID- 28716362 TI - Phosphoenolpyruvate phosphotransferase system components positively regulate Klebsiella biofilm formation. AB - BACKGROUND/PURPOSE: Klebsiella pneumoniae is one of the leading causes of device related infections (DRIs), which are associated with attachment of bacteria to these devices to form a biofilm. The latter is composed of not only bacteria but also extracellular polymeric substances (EPSes) consisting of extracellular DNAs, polysaccharides, and other macromolecules. The phosphoenolpyruvate (PEP):carbohydrate phosphotransferase system (PTS) regulates diverse processes of bacterial physiology. In the genome of K. pneumoniae MGH 78578, we found an uncharacterized enzyme II complex homolog of PTS: KPN00353 (EIIA homolog), KPN00352 (EIIB homolog), and KPN00351 (EIIC homolog). The aim of this study was to characterize the potential physiological role of KPN00353, KPN00352, and KPN00351 in biofilm formation by K. pneumoniae. METHODS/RESULTS: We constructed the PTS mutants and recombinant strains carrying the gene(s) of PTS. The recombinant K. pneumoniae strain overexpressing KPN00353-KPN00352-KPN00351 produced more extracellular matrix than did the vector control according to transmission and scanning electron microscopy. Judging by quantification of biofilm formation, of extracellular DNA (eDNA), and of capsular polysaccharide, the recombinant strain overexpressing KPN00353-KPN00352-KPN00351 produced more biofilm and capsular polysaccharide after overnight culture and more eDNA in the log phase as compared to the vector control. CONCLUSION: The genes, KPN00353 KPN00352-KPN00351, encode a putative enzyme II complex in PTS and positively regulate biofilm formation by enhancing production of eDNA and capsular polysaccharide in K. pneumoniae. Five proteins related to chaperones, to the citric acid cycle, and to quorum sensing are upregulated by the KPN00353-KPN00352 KPN00351 system. PMID- 28716363 TI - Clinical outcomes and prognostic factors of patients with severe influenza receiving intravenous peramivir salvage therapy in intensive care units. AB - BACKGROUND: Few studies have investigated patients with severe influenza who receive intravenous peramivir for salvage therapy. METHODS: We retrospectively analyzed data from 71 patients with severe influenza who received intravenous peramivir therapy in the intensive care units of three medical centers between 2012 and 2016. All patients received oseltamivir or zanamivir before the administration of peramivir. RESULTS: A total of 44 men and 27 women with a median age of 55 years were enrolled. Fifty-five (78%) had underlying comorbidities and 57 (80%) patients were infected with influenza type A. Forty four (62%) patients survived and 27 (38%) died. Five patients (7%) had attributable adverse events, including elevated hepatic aminotransferase levels (n = 2), hyperbilirubinemia (n = 2), leukopenia (n = 1), and skin rash (n = 1). Multivariable logistic regression analysis revealed that initial bacteremia (odds ratio [OR], 27.59; 95% confidence interval [95% CI], 2.36-322.07; P = 0.008) and septic shock (OR, 8.00; 95% CI, 1.69-37.90; P = 0.009) were the independent predictors of mortality. However, there was also a trend towards a positive correlation between mortality and steroid use (OR, 11.29; 95% CI, 0.67-188.86; P = 0.092). CONCLUSION: As a salvage therapy, intravenous peramivir provided a survival rate of 62% and was well tolerated in patients with severe influenza. The initiation of effective antiviral treatment as early as possible within 48 h is recommended for hospitalized patients. PMID- 28716364 TI - The influence of breastfeeding in breast-fed infants with atopic dermatitis. AB - BACKGROUND: The aim of this study was to evaluate whether breastfeeding should be discontinued for exclusively breast-fed infants with atopic dermatitis (AD). METHODS: Eighty-seven exclusively breast-fed infants with AD were enrolled in a prospective observational study. The infants were divided into 3 groups: breastfeeding only (BM group), partial breastfeeding and partial partially hydrolyzed whey formula (pHF-W) (Partial group) and pHF-W only (DC group). The extent and severity of AD were evaluated with the Patient-Oriented SCORing Atopic Dermatitis (PO-SCORAD) index at enrollment and 3 and 6 months later. RESULTS: There were no significant differences in parental atopy history, PO-SCORAD scores, and medication scores at baseline. At month 3 and 6, the PO-SCORAD scores were significantly decreased in all groups. PO-SCORAD scores at month 3 and 6 and at the last time point when topical corticosteroids were given were significantly different among the groups. Stepwise multiple linear regression analysis showed that baseline PO-SCORAD scores and stopping breastfeeding were significantly associated with month 3 PO-SCORAD scores (p < 0.001), after adjusting for sex, age, baseline medication scores, partial breastfeeding and parental atopy history. In addition to baseline PO-SCORAD scores and stopping breastfeeding, partial breastfeeding was significantly associated with month 6 PO-SCORAD scores. Long-term follow-up showed that only stopping breastfeeding was significantly associated with the last time point when topical corticosteroids were given (p = 0.014). CONCLUSION: For exclusively breast-fed infants with AD, discontinuing breastfeeding and shifting to pHF-W might help to improve symptoms and shorten the duration of AD regardless of sex, age and parental atopy history. PMID- 28716365 TI - Functional disability in patients with low back pain: the mediator role of suffering and beliefs about pain control in patients receiving physical and chiropractic treatment. AB - BACKGROUND: Low back pain is the leading cause of disability worldwide. There is evidence that depression, anxiety, and external locus of control are negative predictors of functional disability in low back patients. METHODS: This study focused on the mediator role of suffering and beliefs about pain control in the relationship between psychological morbidity and functional disability in patients receiving physical therapy and chiropractic treatment for chronic low back pain. The sample included 213 patients receiving chiropractic treatment and 125 receiving physical therapy, who answered the following instruments: Beliefs about Pain Control Questionnaire; Inventory of Subjective Experiences of Suffering in Illness; Oswestry Low Back Pain Disability Questionnaire; and the Hospital Anxiety and Depression Scales. RESULTS: Suffering was a mediator in the relationship between depression and functional disability in both treatment groups. Only beliefs related to external chance events mediated the relationship between depression and functional disability in the physical therapy group, but not in the chiropratic teratment group. CONCLUSION: Intervention should focus on suffering regardless of the type of treatment and target beliefs about pain control, in patients receiving physical therapy treatment since they seem to play a key role in functional disability in patients with low back pain. PMID- 28716366 TI - Cross-cultural adaptation and measurement properties of the Brazilian version of the Exercise Preference Questionnaire(stroke). AB - BACKGROUND: The Exercise Preference Questionnaire (EPQ(stroke)) captures exercise preferences and measures personal factors, that influence motivation and adherence to exercise in stroke subjects. OBJECTIVES: To perform the cross cultural adaptation of the EPQ(stroke) into the Brazilian-Portuguese language and to evaluate its measurement properties. METHODS: The EPQ(stroke) was cross culturally adapted and primarily tested in 30 chronic stroke subjects. After the final version of the EPQ(stroke)-Brazil was created, its test-retest reliability was verified, using Kappa indices and intra-class correlation coefficients (ICCs) (n=50), and internal consistency was verified using Cronbach's alpha coefficients (n=101). Construct validity was assessed using exploratory factor analysis (n=101), content validity using the content validity index (CVI) (n=8), and face validity using the rate of agreement regarding the clarity, wording, ability to answer the questions, and lay-out and style of the questionnaire with two groups, including individuals with stroke (n=81) and multidisciplinary health professionals (n=32). RESULTS: The pre-final version required revisions (items 9, 29, and 30) and, after another pre-test, it was shown to be appropriate. The Kappa indices ranged from 0.58 to 0.95; the ICCs from 0.35 to 0.93, and the Cronbach's alpha coefficient was 0.82 (0.768-0.869 CI), showing adequate internal consistency. The exploratory factor analysis and CVI confirmed the validity of the EPQ(stroke)-Brazil. The rate of agreement was greater than 80% for both groups. CONCLUSION: The EPQ(stroke)-Brazil was found to be a valid and reliable measure for verifying exercise preferences of Brazilian individuals with stroke. PMID- 28716368 TI - Surgeons' and surgical trainees' acute stress in real operations or simulation: A systematic review. AB - BACKGROUND AND PURPOSE: Acute stress in surgery is ubiquitous and has an immediate impact on surgical performance and patient safety. Surgeons react with several coping strategies; however, they recognise the necessity of formal stress management training. Thus, stress assessment is a direct need. Surgical simulation is a validated standardised training milieu designed to replicate real life situations. It replicates stress, prevents biases, and provides objective metrics. The complexity of stress mechanisms makes stress measurement difficult to quantify and interpret. This systematic review aims to identify studies that have used acute stress estimation measurements in surgeons or surgical trainees during real operations or surgical simulation, and to collectively present the rationale of these tools, with special emphasis in salivary markers. METHODS: A search strategy was implemented to retrieve relevant articles from MEDLINE and SCOPUS databases. The 738 articles retrieved were reviewed for further evaluation according to the predetermined inclusion/exclusion criteria. RESULTS: Thirty three studies were included in this systematic review. The methods for acute stress assessment varied greatly among studies with the non-invasive techniques being the most commonly used. Subjective and objective tests for surgeons' acute stress assessment are being presented. CONCLUSION: There is a broad spectrum of acute mental stress assessment tools in the surgical field and simulation and salivary biomarkers have recently gained popularity. There is a need to maintain a consistent methodology in future research, towards a deeper understanding of acute stress in the surgical field. PMID- 28716367 TI - Redefining essential fatty acids in the era of novel intravenous lipid emulsions. AB - The essentiality of fatty acids was determined by the Burrs in the 1920s. It is commonly accepted that provision of linoleic (LA) and alpha-linolenic acids (ALA) prevents and reverses essential fatty acid deficiency (EFAD). Development of alternative injectable lipid emulsions (ILE) low in LA and ALA has raised concern about their ability to prevent EFAD. This review provides biochemical evidence coupled with observations from animal and human studies that aim to characterize which fatty acids are truly essential to prevent EFAD. Retroconversion pathways and mobilization from body stores suggest that arachidonic and docosahexaenoic acids (ARA and DHA - the main derivatives of LA and ALA, respectively) also prevent EFAD. Our group first proposed the essentiality of ARA and DHA by feeding mice exclusively these fatty acids and proving that they prevent EFAD. Survival for 5 generations on this diet provides additional evidence that growth and reproductive capabilities are maintained. Moreover, the use of fish oil-based ILE, with minimal LA and ALA and abundant DHA and ARA, for treatment of intestinal failure-associated liver disease, does not result in EFAD. These findings challenge the essentiality of LA and ALA in the presence of ARA and DHA. Evidence discussed in this review supports the idea that ARA and DHA can independently fulfill dietary essential fatty acid requirements. The imminent introduction of new ILE rich in ARA and DHA in the United States highlights the importance of understanding their essentiality, especially when provision of ALA and LA is below the established daily minimum requirement. PMID- 28716369 TI - Re: Philipp Mandel, Felix Preisser, Markus Graefen, et al. High Chance of Late Recovery of Urinary and Erectile Function Beyond 12 Months After Radical Prostatectomy. Eur Urol 2017;71:848-50: Late Recovery of Erectile Function After Radical Prostatectomy: Should We Modify the Way of Assessment? PMID- 28716370 TI - A Systematic Review and Framework for the Use of Hormone Therapy with Salvage Radiation Therapy for Recurrent Prostate Cancer. AB - CONTEXT: Salvage radiotherapy (SRT) is a standard of care for men who recur postprostatectomy, and recent randomized trials have assessed the benefit and toxicity of adding hormone therapy (HT) to SRT with differing results. OBJECTIVE: To perform a systematic review of randomized phase III trials of the use of SRT +/- HT and generate a framework for the use of HT with SRT. EVIDENCE ACQUISITION: Systematic literature searches were conducted on February 15, 2017 in three databases (MEDLINE [via PubMed], EMBASE, and ClinicalTrials.gov) for human-only randomized clinical trials from January 30, 1990, through January 30, 2017. Only two randomized trials met all inclusion criteria. EVIDENCE SYNTHESIS: Overall survival benefits from HT were found in one trial, which was limited to when follow-up extended to >=10 yr, pre-SRT prostate-specific antigen (PSA) >=0.7 ng/ml, or when higher Gleason grade or positive margins were present. Both trials demonstrated a benefit from HT in men with higher pre-SRT PSAs. Three prognostic factors appeared to discriminate improvements in meaningful clinical endpoints (eg, distant metastasis or survival): pre-SRT PSA, Gleason score, and margin status. Two years of bicalutamide monotherapy resulted in higher rates of gynecomastia with a trend for worse survival when given in favorable risk patients, and 6 mo of luteinizing hormone-releasing hormone agonist therapy resulted in higher rates of hot flashes and long-term hypertension. CONCLUSIONS: Similar to the selective use of HT with radiotherapy in localized prostate cancer, not all patients appear to derive a meaningful benefit from HT with SRT. Patient, tumor, and treatment factors must be considered when recommending the use of HT with SRT. Knowledge gaps exist in the level 1 data regarding the optimal duration and type of HT, as well as the ability to use predictive biomarkers to personalize the use of HT with SRT. Important clinical trials (RADICALS and NRG GU-006) are aimed to answer these questions. PATIENT SUMMARY: In this report, we performed a systematic review of the literature to determine the benefit and harm of adding hormone therapy to salvage radiotherapy (SRT) for recurrent prostate cancer. We found that the benefit of hormone therapy varied by important prognostic factors, including pre-SRT prostate-specific antigen, Gleason grade, and surgical margin status. Our group then developed a framework on how best to utilize hormone therapy with SRT. PMID- 28716372 TI - Corrections. PMID- 28716371 TI - Detection, risk factors, and functional consequences of cerebral microinfarcts. AB - Cerebral microinfarcts are small lesions that are presumed to be ischaemic. Despite the small size of these lesions, affected individuals can have hundreds to thousands of cerebral microinfarcts, which cause measurable disruption to structural brain connections, and are associated with dementia that is independent of Alzheimer's disease pathology or larger infarcts (ie, lacunar infarcts, and large cortical and non-lacunar subcortical infarcts). Substantial progress has been made with regard to understanding risk factors and functional consequences of cerebral microinfarcts, partly driven by new in-vivo detection methods and the development of animal models that closely mimic multiple aspects of cerebral microinfarcts in human beings. Evidence from these advances suggests that cerebral microinfarcts can be manifestations of both small vessel and large vessel disease, that cerebral microinfarcts are independently associated with cognitive impairment, and that these lesions are likely to cause damage to brain structure and function that extends beyond their actual lesion boundaries. Criteria for the identification of cerebral microinfarcts with in-vivo MRI are provided to support further studies of the association between these lesions and cerebrovascular disease and dementia. PMID- 28716373 TI - Loop-mediated isothermal amplification in disposable polyester-toner microdevices. AB - In recent years, isothermal DNA amplification methods have emerged as an alternative in molecular diagnostics due to its ease of operation. The purpose of using isothermal amplification is to simplify the diagnostics work by i) eliminating heating cycles, ii) reducing equipment costs, and iii) providing rapid and accurate results in laboratories with limited resources. Here we show a simple and fast method for E. coli detection in disposable polyester-toner (PeT) microdevice. The amplification by LAMP of the malB gene from E. coli was carried out in a microchamber with 5-MUL capacity and the reaction was thermally controlled with a thermoblock at 66 degrees C for 60 min. The passivation of the surface of PeT channels with BSA improved the efficiency of the LAMP reaction. The detection of amplified LAMP fragments was performed directly on-chip by visual detection and validated with off-chip detection to compare results. Visualization of amplicons directly in the microchip yielded positive reactions as low as 10 double-stranded DNA copies. Separation by gel electrophoresis was able to detect amplicons in reactions that initiated only with one copy of double stranded DNA. We demonstrate that LAMP in PeT microchip is an important tool for molecular diagnostics at the point-of-care. PMID- 28716374 TI - High-throughput quantitation of Fc-containing recombinant proteins in cell culture supernatant by fluorescence polarization spectroscopy. AB - Measurement of recombinant protein product titer critically underpins all biopharmaceutical manufacturing process development, as well as diverse research and discovery activity. Here, we describe a simple rapid (<2 min per 96 samples) 96-well microplate-based assay that enables high-throughput quantitation of recombinant immunoglobulin G and Fc-containing IgG derivatives in mammalian cell culture supernatant over a wide dynamic range of 2.5-80 mg/L, using microplate fluorescence polarization (FP) spectroscopy. The solution-phase FP assay is based on the detection of immunoglobulin Fc domain containing analyte binding to FITC conjugated recombinant Protein G ligand to measure analyte concentration dependent changes in emitted FP. For ease of use and maximal shelf life, we showed that air-dried assay microplates containing pre-formulated ligand that is re-solubilized on addition of analyte containing solution did not affect assay performance, typically yielding an across plate coefficient of variation of <1%, and a between-plate standard deviation below 1%. Comparative assays of the same samples by FP and other commonly used IgG assay formats operating over a similar dynamic range (Protein A HPLC and bio-interferometry) yielded a coefficient of determination >0.99 in each case. PMID- 28716376 TI - Improving the safety of health information technology requires shared responsibility: It is time we all step up. AB - In 2011, an Institute of Medicine report on health information technology (IT) and patient safety highlighted that building health-IT for safer use is a shared responsibility between key stakeholders including: "vendors, care providers, healthcare organizations, health-IT departments, and public and private agencies". Use of electronic health records (EHRs) involves all these stakeholders, but they often have conflicting priorities and requirements. Since 2011, the concept of shared responsibility has gained little traction and EHR developers and users continue to attribute the substantial, long list of problems to each other. In this article, we discuss how these key stakeholders have complementary roles in improving EHR safety and must share responsibility to improve the current state of EHR use. We use real-world safety examples and outline a comprehensive shared responsibility approach to help guide development of future rules, regulations, and standards for EHR usability, interoperability and security as outlined in the 21st Century Cures Act. This approach clearly defines the responsibilities of each party and helps create appropriate measures for success. National and international policymakers must facilitate the local organizational and socio-political climate to stimulate the adoption of shared responsibility principles. When all major stakeholders are sharing responsibility, we will be more likely to usher in a new age of progress and innovation related to health IT. PMID- 28716375 TI - Aging and Post-Intensive Care Syndrome: A Critical Need for Geriatric Psychiatry. AB - Because of the aging of the intensive care unit (ICU) population and an improvement in survival rates after ICU hospitalization, an increasing number of older adults are suffering from long-term impairments because of critical illness, known as post-intensive care syndrome (PICS). This article focuses on PICS-related cognitive, psychological, and physical impairments and the impact of ICU hospitalization on families and caregivers. The authors also describe innovative models of care for PICS and what roles geriatric psychiatrists could play in the future of this rapidly growing population. PMID- 28716377 TI - Comparison of the 7th and proposed 8th editions of the AJCC/UICC TNM staging system for esophageal squamous cell carcinoma underwent radical surgery. AB - BACKGROUND: Recently, the 8th edition of the TNM classification of esophageal cancer has come up. The present study aims to compare the 7th and the proposed 8th edition of the AJCC/UICC TNM staging system for esophageal squamous cell carcinoma (ESCC). METHODS: A total of 1872 ESCC patients who underwent radical surgery with curative intent were analyzed retrospectively. Survival was analyzed using the Kaplan-Meier method, and values were compared using the log-rank test. Multivariate analysis was performed using the Cox proportional hazard model. The Akaike information criterion (AIC) and the concordance index (c-index) were applied to compare the two prognostic systems. RESULTS: On univariate analysis, the 7th staging system, the proposed 8th staging system, gender, age as well as adjuvant treatment were found to have significant association with overall survival (OS). In both the current staging system and the modified version, age and gender were independent prognostic factors in a multivariate analysis. The AIC value for the proposed 8th version was smaller than that for the 7th staging system; the c-index value for the proposed 8th version was larger than that for the 7th staging system. Subgroup analysis in patients with/without nodal metastasis obtained consistent results. CONCLUSION: Based on the data from our single center, the proposed 8th AJCC staging system seems to be superior to the 7th AJCC staging system in terms of OS for patients with thoracic ESCC who underwent radical surgery. PMID- 28716378 TI - Reducing infection rates through perioperative glycemic control - how sweet it is. PMID- 28716379 TI - From the Editor's desk...: August 2017. PMID- 28716380 TI - Erratum to "Human liver regeneration in advanced cirrhosis is organized by the portal tree" [J Hepatol 66 (2017) 778-786]. PMID- 28716382 TI - Combined Elbow Release and Humeral Rotational Osteotomy in Arthrogryposis. AB - PURPOSE: The purpose of this study was to determine if a simultaneous posterior elbow release and humeral osteotomy to correct both the elbow extension contracture and the humeral internal rotation contracture in children with arthrogryposis can produce similar results as a posterior elbow release alone. METHODS: This study was a retrospective chart review of consecutive patients with arthrogryposis treated surgically for elbow extension contracture between 2007 and 2014. A total of 43 procedures in 36 patients had adequate available follow up data and were included in the study. The postoperative range of motion reported was measured at the early follow-up (3-6 months), midterm follow-up (between 1 and 2 years), and the most recent long-term follow-up (after 2 years) from the date of surgery. Patients were grouped into 2 groups (simultaneous and release) based on the necessity of performing an ipsilateral humeral rotation osteotomy at the time of the release. RESULTS: At early follow-up, patients in both groups increased their total arc of motion. There was a significant difference in extension and arc of motion at midterm follow-up (between 1 and 2 years) between the simultaneous and the release groups with the simultaneous group significantly losing both terminal extension and total arc of motion. At more than 2 years follow-up, there remained a statistically significant difference in arc of motion, with the release group having a significantly larger arc of motion. Patients who underwent dual plating had a much larger arc of motion at early follow-up than the K-wire or single-plate fixation group, despite having similar preoperative extension, flexion, and arc of motion. This difference was also significant at late follow-up. CONCLUSIONS: Patients with posterior release alone had significantly greater improvement in total arc of motion and significantly better elbow extension than patients who underwent a simultaneous humeral osteotomy. However, rigid fixation with early mobilization may yield results comparable with the release alone group. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 28716381 TI - Smoking and the risk of type 2 diabetes in Japan: A systematic review and meta analysis. AB - Cigarette smoking is the leading avoidable cause of disease burden. Observational studies have suggested an association between smoking and risk of type 2 diabetes mellitus (T2DM). We conducted a meta-analysis of prospective observational studies to investigate the association of smoking status, smoking intensity, and smoking cessation with the risk of T2DM in Japan, where the prevalence of smoking has been decreasing but remains high. We systematically searched MEDLINE and the Ichushi database to December 2015 and identified 22 eligible articles, representing 343,573 subjects and 16,383 patients with T2DM. We estimated pooled relative risks (RRs) using a random-effects model and conducted subgroup analyses by participant and study characteristics. Compared with nonsmoking, the pooled RR of T2DM was 1.38 (95% confidence interval [CI], 1.28-1.49) for current smoking (19 studies) and 1.19 (95% CI, 1.09-1.31) for former smoking (15 studies). These associations persisted in all subgroup and sensitivity analyses. We found a linear dose-response relationship between cigarette consumption and T2DM risk; the risk of T2DM increased by 16% for each increment of 10 cigarettes smoked per day. The risk of T2DM remained high among those who quit during the preceding 5 years but decreased steadily with increasing duration of cessation, reaching a risk level comparable to that of never smokers after 10 years of smoking cessation. We estimated that 18.8% of T2DM cases in men and 5.4% of T2DM cases in women were attributable to smoking. The present findings suggest that cigarette smoking is associated with an increased risk of T2DM, so tobacco control programs to reduce smoking could have a substantial effect to decrease the burden of T2DM in Japan. PMID- 28716383 TI - Nonspecialist Raters Can Provide Reliable Assessments of Procedural Skills. AB - BACKGROUND: Competency-based learning has become a crucial component in medical education. Despite the advantages of competency-based learning, there are still challenges that need to be addressed. Currently, the common perception is that specialist assessment is needed for evaluating procedural skills which is difficult owing to the limited availability of faculty time. The aim of this study was to explore the validity of assessments of video recorded procedures performed by nonspecialist raters. METHODS: This study was a blinded observational trial. Twenty-three novices (senior medical students) and 9 experienced doctors were video recorded while each performing 2 flexible cystoscopies on patients. The recordings were anonymized and placed in random order and then rated by 2 experienced cystoscopists (specialist raters) and 2 medical students (nonspecialist raters). Flexible cystoscopy was chosen as it is a simple procedural skill that is crucial to master in a resident urology program. RESULTS: The internal consistency of assessments was high, Cronbach's alpha = 0.93 and 0.95 for nonspecialist and specialist raters, respectively (p < 0.001 for both correlations). The interrater reliability was significant (p < 0.001) with a Pearson's correlation of 0.77 for the nonspecialists and 0.75 for the specialists. The test-retest reliability showed the biggest difference between the 2 groups, 0.59 and 0.38 for the nonspecialist raters and the specialist raters, respectively (p < 0.001). CONCLUSION: Our study suggests that nonspecialist raters can provide reliable and valid assessments of video recorded cystoscopies. This could make mastery learning and competency-based education more feasible. PMID- 28716384 TI - A Review of Empathy, Its Importance, and Its Teaching in Surgical Training. AB - BACKGROUND: There has been much discussion in the medical literature about the importance of empathy and physician communication style in medical practice. Empathy has been shown to have a very real positive effect on patient outcomes. Most of the existing literature speaks to its role in medical education, with relatively little empiric study about empathy in the surgical setting. OBJECTIVE: Review of empathy and its importance as it pertains to the surgeon-patient relationship and improving patient outcomes, and the need for increased education in empathy during surgical training. METHODS: The published, peer-reviewed literature on patient-physician and patient-surgeon communication, medical student and resident education in empathy, and empathy research was reviewed. PubMed was queried for MESH terms including "empathy," "training," "education," "surgery," "resident," and "communication." RESULTS: There is evidence of a decline in empathy that begins during the clinical years of medical school, which continues throughout residency training. Surgeons are particularly susceptible to this decline as by-product of the nature of their work, and the current lack of formalised training in empathic patient communication poses a unique problem to surgical residents. CONCLUSIONS: The literature suggests that empathy training is warranted and should be incorporated into surgical residencies through didactics, role-playing and simulations, and apprenticeship to empathic attending role models. PMID- 28716385 TI - Protein lipograms. AB - Linguistic analysis of protein sequences is an underexploited technique. Here, we capitalize on the concept of the lipogram to characterize sequences at the proteome levels. A lipogram is a literary composition which omits one or more letters. A protein lipogram likewise omits one or more types of amino acid. In this article, we establish a usable terminology for the decomposition of a sequence collection in terms of the lipogram. Next, we characterize Uniref50 using a lipogram decomposition. At the global level, protein lipograms exhibit power-law properties. A clear correlation with metabolic cost is seen. Finally, we use the lipogram construction to assign proteomes to the four branches of the tree-of-life: archaea, bacteria, eukaryotes and viruses. We conclude from this pilot study that the lipogram demonstrates considerable potential as an additional tool for sequence analysis and proteome classification. PMID- 28716386 TI - Comparing the rankings obtained from two biodiversity indices: the Fair Proportion Index and the Shapley Value. AB - The Shapley Value and the Fair Proportion Index of phylogenetic trees have been frequently discussed as prioritization tools in conservation biology. Both indices rank species according to their contribution to total phylogenetic diversity, allowing for a simple conservation criterion. While both indices have their specific advantages and drawbacks, it has recently been shown that both values are closely related. However, as different authors use different definitions of the Shapley Value, the specific degree of relatedness depends on the specific version of the Shapley Value - it ranges from a high correlation index to equality of the indices. In this note, we first give an overview of the different indices. Then we turn our attention to the mere ranking order provided by either of the indices. We compare the rankings obtained from different versions of the Shapley Value for a phylogenetic tree of European amphibians and illustrate their differences. We then undertake further analyses on simulated data and show that even though the chance of two rankings being exactly identical (when obtained from different versions of the Shapley Value) decreases with an increasing number of taxa, the distance between the two rankings converges to zero, i.e., the rankings are becoming more and more alike. Moreover, we introduce our freely available software package FairShapley, which was implemented in Perl and with which all calculations have been performed. PMID- 28716387 TI - Infection with a respiratory virus before hematopoietic cell transplantation is associated with alloimmune-mediated lung syndromes. AB - BACKGROUND: Alloimmune-mediated lung syndromes (allo-LSs) are life-threatening complications after hematopoietic cell transplantation (HCT). Respiratory virus (RV) has been suggested to play a role in the pathogenesis. OBJECTIVE: We studied the relation between RV DNA/RNA detection in the upper/lower airways before HCT and the occurrence of allo-LSs. METHODS: We retrospectively analyzed all HCT recipients between 2004 and 2014, in whom real-time PCR for RV was performed in nasopharyngeal aspirates (NPAs) and bronchoalveolar lavage (BAL) fluid before HCT. The main outcome of interest was the presence of an allo-LS, which was defined as idiopathic pneumonia syndrome or bronchiolitis obliterans syndrome. Other outcomes were overall survival and treatment-related mortality. We used Cox proportional hazard models, logistic regression models, and Fine-Gray competing risk regression for analyses. RESULTS: One hundred seventy-nine children (median age, 6.8 years) were included. RVs were found in 61% (41% in BAL fluid/NPAs and 20% in NPAs only). Rhinovirus was the most frequently detected RV (42%). Allo-LSs occurred in 13%. RV positivity in BAL fluid was a predictor for allo-LSs (hazard ratio, 3.8; 95% CI, 1.4-10.7; P = .01), whereas RV positivity in NPAs only was not. No other predictors were found. Grade II to IV acute graft-versus-host disease related to steroid treatment shows a trend toward a protective effect (odds ratio, 0.16; 95% CI, 0.0-1.3; P = .08). Allo-LSs significantly increased treatment-related mortality (52% +/- 10% in allo-LSs and 20% +/- 4% in non-allo LSs, P = .007). CONCLUSIONS: These results show that pre-HCT BAL fluid RV positivity was a predictor for allo-LSs. Screening for RVs before HCT might identify patients at risk for allo-LSs. This could have implications for prevention and treatment and might subsequently influence the outcomes of HCT. PMID- 28716388 TI - Identification of co-infection by rotavirus and parvovirus in dogs with gastroenteritis in Mexico. AB - This is the first report on circulating canine rotavirus in Mexico. Fifty samples from dogs with gastroenteritis were analyzed used polymerase chain reaction and reverse transcription polymerase chain reaction in order to identify parvovirus and rotavirus, respectively; 7% of dogs were infected with rotavirus exclusively, while 14% were co-infected with both rotavirus and parvovirus; clinical signs in co-infected dogs were more severe. PMID- 28716390 TI - Impact of cytokine genetic polymorphisms on the risk of renal parenchymal infection in children. AB - BACKGROUND: Acute pyelonephritis is associated with renal scarring in up to 30% of patients. Renal scarring may cause significant long-term morbidity. The pathogenesis of acute pyelonephritis remains unclear, although it involves interaction among uroepithelium, the immune system cells, and the locally produced cytokines. That some UTI-prone children develop acute pyelonephritis, and eventually renal parenchymal scarring, suggests a genetic role. Interleukin 6, interleukin-8, chemokine receptor-1 (CXCR1), and tumor necrosis factor-alpha (TNFalpha), the key regulators of the host immune responses, are proteins whose secretion is controlled by genes. We postulated that functional polymorphic variants of their genes might have a role in APN susceptibility. OBJECTIVES: We sought to investigate a possible association of the common functional polymorphisms in genes encoding IL-6, IL-8, CXCR1, and TNFalpha with the risk of APN in children. METHODS: Urine culture was used to diagnose 300 children with UTI, of mean age of 51.31 +/- 37.4 months (2-180 months). 99Tc-DMSA scans diagnosed 86 children with APN. Follow-up scans identified new renal scars in 18 children. Six functional single-nucleotide polymorphisms (SNPs) in genes encoding IL-6, IL-8, CXCR1, and TNFalpha were genotyped in all subjects (IL-6 rs1800795 ( 174G/C), IL-6 rs1800796 (-572G/C), IL-8 rs2227306 (781C/T), IL8 rs4073 (-251A/T), CXCR1 rs2234671 (2607G/C), and TNFalpha rs1800629 (-308G/A)). RESULTS: TT genotype of IL-8 -251A/T polymorphism was significantly higher in APN patients (26.7%) than those with lower UTI (11.7%, p = 0.01) and control individuals (12.2%, p = 0.002). T allele was significantly more common in APN than in lower UTI (p = 0.025) and was significantly more common in APN (46%) than in the controls (p = 0.001). Similarly, TT genotype of IL-8 781C/T polymorphism was significantly more common in APN patients (31.4%) than those with lower UTI (17.3%, p = 0.003) and the controls (14.3%, p = 0.001). T allele was significantly more common in APN (55%) than lower UTI (40%, p = 0.005) and controls (37%, p = 0.001). However, IL-8 -251A/T and +781C/T SNPs did not qualify as an independent risk for parenchymal infection (OR 1.9, 95% CI 0.68-2.6, p = 0.13 and OR 2.3, 95% CI 0.89-3.7, p = 0.091, respectively). Lower UTI did not differ from the controls. The frequency of the genotypes and alleles of IL-6, CXCR1, and TNFalpha SNPs did not differ significantly among the different groups of the study. CONCLUSION: IL-8 -251A/T and +781C/T SNPs are associated with susceptibility to renal parenchymal infection in children and could be implicated in APN risk. However, none of these variants could clearly and independently predict this risk. PMID- 28716391 TI - Electroencephalographic markers of conscious and unconscious perception. PMID- 28716389 TI - Biomedical ethics and clinical oversight in multisite observational neuroimaging studies with children and adolescents: The ABCD experience. AB - Observational neuroimaging studies with children and adolescents may identify neurological anomalies and other clinically relevant findings. Planning for the management of this information involves ethical considerations that may influence informed consent, confidentiality, and communication with participants about assessment results. Biomedical ethics principles include respect for autonomy, beneficence, non-maleficence, and justice. Each project presents unique challenges. The Adolescent Brain and Cognitive Development study (ABCD) collaborators have systematically developed recommendations with written guidelines for identifying and responding to potential risks that adhere to biomedical ethics principles. To illustrate, we will review the ABCD approach to three areas: (1) hazardous substance use; (2) neurological anomalies; and (3) imminent potential for self-harm or harm to others. Each ABCD site is responsible for implementing procedures consistent with these guidelines in accordance with their Institutional Review Board approved protocols, state regulations, and local resources. To assure that each site has related plans and resources in place, site emergency procedures manuals have been developed, documented and reviewed for adherence to ABCD guidelines. This article will describe the principles and process used to develop these ABCD bioethics and medical oversight guidelines, the concerns and options considered, and the resulting approaches advised to sites. PMID- 28716392 TI - The amount of recent action-outcome coupling modulates the mechanisms of the intentional binding effect: A behavioral and ERP study. AB - Our everyday interactions depend on the ability to maintain a feeling of control over our bodily actions, that is, the sense of agency. The intentional binding effect - a perceived temporal shortening between voluntary actions and sensory outcomes - has been shown to implicitly measure agency. We investigated the effect's underlying mechanisms: prediction and retrospective inference. First, long-term and recent action-outcome coupling were compared. Second, brain activity was recorded to uncover the neural correlates of the two mechanisms. Our results show that the recent accumulation of action-outcome coupling, but not that of a long-term accumulation, is correlated with the binding effect of actions and accounts for both mechanisms. Temporal action binding was reflected in both the readiness potential and the auditory evoked potential. The results shed new light on our understanding of the influence that immediate context of an action has on its temporal binding and the neural substrate of human agency. PMID- 28716393 TI - Combine effect of Chondroitinase ABC and low level laser (660nm) on spinal cord injury model in adult male rats. AB - After spinal cord injury (SCI) there are many recoveries inhibiting factors such as chondroitin sulfate proteoglycan (CSPG) and inflammation. The present study investigated the combinational effect of low level laser therapy (LLLT) as anti inflammatory agent and Chondroitinase ABC (ChABC) enzyme as CSPG digesting factor on spinal cord after injury. This study performed on 44 male Wistar rats, spinal cord injury induced by a clip compression injury. Animals received two-weeks treatment of 660nm low level laser (LLL) and intraspinal injection of 1MUg ChABC. Functional recovery, cavity size, myelination, axonal projections around the cavity, fibroblast invasion and expression of glycogen synthase kinase-3beta (GSk 3beta), CSPG and aquaporin 4 (AQP4) expression were evaluated. In statistical evaluation p<0.05 considered significant. Result showed the combination of LLLT and ChABC have more effect on reduction of cavity size, improvement of myelination and number of axons around the cavity and decreasing the expression of GSK3beta, CSPG and AQP4 expression compared to LLLT and ChABC alone. In the laser and laser+enzyme groups AQP4 expression decreased significantly after SCI. Functional recovery, improved in LLLT and ChABC treated animals, but higher recovery belonged to the combination therapy group. The current study showed combination therapy by LLLT and ChABC is more efficient than a single therapy with each of them. PMID- 28716394 TI - Validation of a Spanish-language version of the ADHD Rating Scale IV in a Spanish sample. AB - OBJECTIVES: The purpose of this study is to validate a Spanish-language version of the 18-item ADHD Rating Scale-IV (ADHD-RS-IV.es) in a Spanish sample. METHODS: From a total sample of 652 children and adolescents aged 6 to 17 years (mean age was 11.14+/-3.27), we included 518 who met the DSM-IV-TR criteria for ADHD and 134 healthy controls. To evaluate the factorial structure, validity, and reliability of the scale, we performed a confirmatory factor analysis (CFA) using structural equation modelling on a polychoric correlation matrix and maximum likelihood estimation. The scale's discriminant validity and predictive value were estimated using ROC (receiver operating characteristics) curve analysis. RESULTS: Both the full scale and the subscales of the Spanish-language version of the ADHD-RS-IV showed good internal consistency. Cronbach's alpha was 0.94 for the full scale and >= 0.90 for the subscales, and ordinal alpha was 0.95 and >= 0.90, respectively. CFA showed that a two-factor model (inattention and hyperactivity/impulsivity) provided the best fit for the data. ADHD-RS-IV.es offered good discriminant ability to distinguish between patients with ADHD and controls (AUC=0.97). CONCLUSIONS: The two-factor structure of the Spanish language version of the ADHD-RS-IV (ADHD-RS-IV.es) is consistent with those of the DSM-IV-TR and DSM-5 as well as with the model proposed by the author of the original scale. Furthermore, it has good discriminant ability. ADHD-RS-IV.es is therefore a valid and reliable tool for determining presence and severity of ADHD symptoms in the Spanish population. PMID- 28716396 TI - The role of pilin protein of Xenorhabdus nematophila against immune defense reactions of insects. AB - Xenorhabdus nematophila is a symbiotic bacterium of the entomopathogenic nematode Steinernema carpocapsae (Weiser). It produces several toxic proteins which interfere with the immune system of insects. The current study shows that purified pilin protein could be a virulence trait of X. nematophila. The fifth instar larvae of Spodoptera exigua (Hubner) was injected with purified pilin. Changes in the cellular defenses in terms of total haemocyte counts and granulocyte percentage and humoral factors including total protease, phospholipase A2, and phenoloxidase activities (humoral defense) as well as the expression of the three main antimicrobial peptides attacin, cecropin, and spodoptericin were measured at specific times. The level of THC and granulocytes in larvae with different concentrations of pilin protein were less than the negative control. Also agglutination of haemocytes was observed 8-16h post injection. The pilin protein activated phenoloxidase in the initial hour post injection, by 2hpi, activity was stable. The activities of phospholipase A2 and protease activities reached maximum levels at 12 and 4hpi, respectively, and then decreased. The expressions of attacin, cecropin, and spodoptericin in larvae treated with pilin protein were up-regulated above that of the normal sample. The overexpression of cecropin was greater than the other antimicrobial protein mRNA transcripts. The spodoptericin expression had an irregular trend while expressions of attacin and cecropin reached maximum levels at 4hpi and then decreased. Generally, after the injection of pilin protein, the cellular and humoral immune system of S. exigua is activated but this toxin was able to inhibit them. This is the first report of the role of pilin protein when the bacterial symbiont of S. carpocapsae encounters the humoral defense of an insect. PMID- 28716397 TI - Polymicrobial infections and biofilms in women's health: Gahro Expert Group Meeting Report. PMID- 28716395 TI - "It Ruined My Life": The effects of the War on Drugs on people who inject drugs (PWID) in rural Puerto Rico. AB - BACKGROUND: The War on Drugs has raised the incarceration rates of racial minorities for non-violent drug-related crimes, profoundly stigmatized drug users, and redirected resources from drug prevention and treatment to militarizing federal and local law enforcement. Yet, while some states consider shifting their punitive approach to drug use, to one based on drug treatment and rehabilitation, nothing suggests that these policy shifts are being replicated in Puerto Rico. METHODS: This paper utilizes data from 360 PWID residing in four rural towns in the mountainous area of central Puerto Rico. We initially recruited 315 PWID using respondent-driven sampling (RDS) and collected data about risk practices and conducted HIV and HCV testing. During a second phase, we conducted 34 micro-ethnographic assays, in which we randomly recruited 34 participants from the first phase and included their ego networks in this phase. Our ethnographic inquiry produced significant data regarding the effects of the war on drugs on the local drug trade, drug availability, and injectors' social networks. RESULTS: Findings suggest that repressive policing has been ineffective in preventing drug distribution and use among those in our study. This type of law enforcement approach has resulted in the disproportionate incarceration of poor drug users in rural Puerto Rico, and mainly for nonviolent drug-related crimes. In addition, incarceration exposes PWID to a form of a cruel and unusual punishment: having to quit heroin "cold turkey" while the prison environment also represents a HIV/HCV risk. In turn, the war on drugs not only diverts resources from treatment but also shapes treatment ideologies, punishing non-compliant patients. CONCLUSION: Shifting the emphasis from repression to treatment and rehabilitation is likely to have a positive impact on the health and overall quality of life of PWID and their communities. PMID- 28716398 TI - Serotonin depletion increases seizure susceptibility and worsens neuropathological outcomes in kainate model of epilepsy. AB - Serotonin is implicated in the regulation of seizures, but whether or not it can potentiate the effects of epileptogenic factors is not fully established. Using the kainic acid model of epilepsy in rats, we tested the effects of serotonin depletion on (1) susceptibility to acute seizures, (2) development of spontaneous recurrent seizures and (3) behavioral and neuroanatomical sequelae of kainic acid treatment. Serotonin was depleted by pretreating rats with p-chlorophenylalanine. In different groups, kainic acid was injected at 3 different doses: 6.5mg/kg, 9.0mg/kg or 12.5mg/kg. A single dose of 6.5mg/kg of kainic acid reliably induced status epilepticus in p-chlorophenylalanine-pretreated rats, but not in saline pretreated rats. The neuroexcitatory effects of kainic acid in the p chlorophenylalanine-pretreated rats, but not in saline-pretreated rats, were associated with the presence of tonic-clonic convulsions and high lethality. Compared to controls, a greater portion of serotonin-depleted rats showed spontaneous recurrent seizures after kainic acid injections. Loss of hippocampal neurons and spatial memory deficits associated with kainic acid treatment were exacerbated by prior depletion of serotonin. The present findings are of particular importance because they suggest that low serotonin activity may represent one of the major risk factors for epilepsy and, thus, offer potentially relevant targets for prevention of epileptogenesis. PMID- 28716399 TI - Prelimbic alpha1-adrenoceptors are involved in the regulation of depressive-like behaviors in the hemiparkinsonian rats. AB - At present, it is not clear whether alpha1-adrenoceptors in the prelimbic cortex (PrL) are involved in Parkinson's disease-related depression. Here we examined effects of PrL alpha1-adrenoceptors on depressive-like behaviors in rats with unilateral 6-hydroxydopamine lesions of the medial forebrain bundle. The lesion induced depressive-like responses as measured by the sucrose preference and forced swim tests compared to sham-operated rats. Intra-PrL injection of alpha1 adrenoceptor agonist phenylephrine induced or increased the expression of depressive-like behaviors in sham-operated and the lesioned rats. Further, intra PrL injection of alpha1-adrenoceptor antagonist benoxathian produced antidepressant effects in two groups of rats. Intra-PrL injection of phenylephrine increased the mean firing rate of PrL pyramidal neurons in both sham-operated and the lesioned rats, while benoxathian decreased the mean firing rate of the neurons. Compared to sham-operated rats, the duration of phenylephrine and benoxathian action on the firing rate of the pyramidal neurons was shortened in the lesioned rats. Neurochemical results showed that intra-PrL injection of phenylephrine or benoxathian increased or decreased dopamine and noradrenaline and serotonin levels in the medial prefrontal cortex, ventral hippocampus and habenula in sham-operated and the lesioned rats, respectively. Altogether, these results suggest that activation and blockade of alpha1 adrenoceptors in the PrL change the firing activity of the pyramidal neurons, and then increase or decrease levels of three monoamines in the limbic and limbic related brain regions, which are involved in the regulation of depressive-like behaviors. Additionally, the results also suggest that the dopaminergic lesion leads to hypofunctionality of alpha1-adrenoceptors on pyramidal neurons of the PrL. PMID- 28716400 TI - Direct identification of generalized Prandtl-Ishlinskii model inversion for asymmetric hysteresis compensation. AB - In this study, we present an identification-based direct construction of the inverse generalized Prandtl-Ishlinskii (P-I) model to facilitate inverse model based feedforward compensation of asymmetric hysteresis nonlinearities. Compared with the derivation of the inverse model analytically from a generalized P-I model, this direct modeling approach has the following advantages. First, direct inverse model identification is formulated as a nonlinear optimization problem, which is not subject to the constraint condition on the generalized P-I model's threshold and density functions, where this is indispensable for the analytical model inversion procedure. Second, this approach may be a simple and attractive alternative when the identification precision of a generalized P-I model is limited by the constraint condition, which necessarily results in insufficient hysteresis compensation functionality for the analytically derived inverse model. Finally, direct inverse model identification can overcome the drawbacks of the analytical inversion method, including the accumulation of parameter estimation errors in an analytical inverse model because these parameters are computed from the generalized P-I model's parameters in a recursive manner. Our experimental results demonstrated that the implementation of open-loop control with the directly identified inverse generalized P-I model as a feedforward compensator achieved precise compensation for the asymmetric hysteresis nonlinearities of a piezoelectric stack actuator. PMID- 28716401 TI - Research on the parallel load sharing principle of a novel self-decoupled piezoelectric six-dimensional force sensor. AB - This paper presents a novel integrated piezoelectric six-dimensional force sensor which can realize dynamic measurement of multi-dimensional space load. Firstly, the composition of the sensor, the spatial layout of force-sensitive components, and measurement principle are analyzed and designed. There is no interference of piezoelectric six-dimensional force sensor in theoretical analysis. Based on the principle of actual work and deformation compatibility coherence, this paper deduces the parallel load sharing principle of the piezoelectric six-dimensional force sensor. The main effect factors which affect the load sharing ratio are obtained. The finite element model of the piezoelectric six-dimensional force sensor is established. In order to verify the load sharing principle of the sensor, a load sharing test device of piezoelectric force sensor is designed and fabricated. The load sharing experimental platform is set up. The experimental results are in accordance with the theoretical analysis and simulation results. The experiments show that the multi-dimensional and heavy force measurement can be realized by the parallel arrangement of the load sharing ring and the force sensitive element in the novel integrated piezoelectric six-dimensional force sensor. The ideal load sharing effect of the sensor can be achieved by appropriate size parameters. This paper has an important guide for the design of the force measuring device according to the load sharing mode. PMID- 28716403 TI - Unleashing the Potential of Public Genomic Resources to Find Parasite Genetic Data. AB - Genetic data generated by high-throughput sequencing and deposited in public databases are increasing exponentially. A substantial amount of these data is generated from wild animals, and can contain information from nontarget organisms, such as parasites. Methodologies that leverage this available information are warranted and can help to answer questions of general interest in parasitology. PMID- 28716402 TI - The Role of Low-dose Anti-thymocyte Globulin as Standard Prophylaxis in Mismatched and Matched Unrelated Hematopoietic Peripheral Stem Cell Transplantation for Hematologic Malignancies. AB - INTRODUCTION: Anti-thymocyte globulin (ATG)-based immunosuppressive therapy is often used in allogeneic hematopoietic cell transplantation to reduce incidence and severity of graft-versus-host disease (GVHD). PATIENTS AND METHODS: In our observational study, ATG (rabbit, Thymoglobulin; Sanofi, 5 mg/kg) was administered as a standardized part of the conditioning in 97 patients with a median age of 34 years (range, 14-58 years), allotransplanted for hematologic malignancies from matched (8/8; n = 52) and allele or antigen mismatched (7/8; n = 43 and 6/8; n = 2) unrelated donors. RESULTS: Five-year overall survival (OS) was 46.9%, disease-free survival was 46.5%, and treatment-related mortality was 20.6%, with a median follow-up of 29 months (range, 1-145 months). Acute GVHD (grade >= II) cumulative incidence was 26.9% in matched versus 50.5% in mismatched patients (P = .060), whereas extensive chronic GVHD was 45.6% versus 50%, respectively (P = .310). Five-year OS was 62.2% for the matched patients and 27.9% for the mismatched patients (P = .003) owing to a higher treatment-related mortality rate in mismatched patients (P = .032). In multivariate analysis including age, gender, time until transplantation, disease phase, mismatched donor, ABO mismatch, number of CD34+ infused, acute and chronic GVHD, the significant unfavorable factors for OS were HLA mismatch and advanced disease phase. CONCLUSION: A relatively low-dose ATG is effective in acute GVHD prophylaxis, leading to promising survival rates in matched transplants. Further comparative studies with adjusted ATG dose depending on Human leukocyte antigen disparity or alternative donors are warranted. PMID- 28716404 TI - Partial jejunal diversion using an incisionless magnetic anastomosis system: 1 year interim results in patients with obesity and diabetes. AB - BACKGROUND AND AIMS: Most patients with type 2 diabetes mellitus have obesity. Studies show that bariatric surgery is superior to medical treatment for remission of type 2 diabetes mellitus. Nevertheless, very few patients undergo surgery, and a less-invasive endoscopic alternative is desirable. METHODS: This was a single-arm first-in-human pilot study designed to evaluate the technical feasibility, safety, and clinical performance of the incisionless magnetic anastomosis system (IMAS) to create a partial jejunal diversion (PJD). Ten patients with obesity and type 2 diabetes mellitus, prediabetes, or no diabetes were enrolled. A PJD to the ileum was attempted in all patients under general anesthesia. The IMAS was delivered through the working channel of a colonoscope, with laparoscopic supervision. The patients were not required to participate in an intensive lifestyle/diet management program. Endoscopic visualization of the anastomosis was obtained at 2, 6, and 12 months. Patient weight, glycemic profile, and metabolic panels were acquired at 0.5, 1, 2, 3, 6, 9, and 12 months. RESULTS: A PJD was created in all patients with no device-related serious adverse events. The anastomosis remained widely patent in all patients at 1 year. Average total weight loss was 14.6% (40.2% excess weight loss at 12 months). A significant reduction in glycated hemoglobin level was observed in all diabetic (1.9%) and prediabetic (1.0%) patients, while reducing or eliminating the use of diabetes medications. CONCLUSIONS: Permanent anastomosis for PJD was created in all patients with the IMAS. This resulted in improvement in measures of hyperglycemia and progressive weight loss. (Clinical trial registration number: NCT02839512.). PMID- 28716405 TI - Critical and speculative review of the roles of multi-protein complexes in starch biosynthesis in cereals. AB - Starch accounts for the majority of edible carbohydrate resources generated through photosynthesis. Amylopectin is the major component of starch and is one of highest-molecular-weight biopolymers. Rapid and systematic synthesis of frequently branched hydro-insoluble amylopectin and efficient accumulation into amyloplasts of cereal endosperm is crucial. The functions of multiple starch biosynthetic enzymes, including elongation, branching, and debranching enzymes, must be temporally and spatially coordinated. Accordingly, direct evidence of protein-protein interactions of starch biosynthetic enzymes were first discovered in developing wheat endosperm in 2004, and they have since been shown in the developing seeds of other cereals. This review article describes structural characteristics of starches as well as similarities and differences in protein complex formation among different plant species and among mutant plants that are deficient in specific starch biosynthetic enzymes. In addition, evidence for protein complexes that are involved in the initiation stages of starch biosynthesis is summarized. Finally, we discuss the significance of protein complexes and describe new methods that may elucidate the mechanisms and roles of starch biosynthetic enzyme complexes. PMID- 28716406 TI - The tomato B-type cyclin gene, SlCycB2, plays key roles in reproductive organ development, trichome initiation, terpenoids biosynthesis and Prodenia litura defense. AB - Cyclins exist extensively in various plant species. Among them, B-type cyclins play important roles in the transition of G2-to-M. However, few B-type cyclins have been reported to participate in reproductive organ development and trichome formation. In this study, transgene analysis showed that SlCycB2 overexpression caused abnormal flower with the unclosed stamen, shortened style and aberrant pollen. In addition, nearly all non-glandular trichomes, as well as the glandular ones were disappeared. On the contrary, suppression of SlCycB2 could promote type III and type V trichomes formation. Detection of secondary metabolites indicated that the production of monoterpene and sesquiterpene were significantly decreased in SlCycB2-OE plants, which thus resulted in the reduction of the defense against Prodenia litura. Transcriptome profile demonstrated that the differentially expressed genes mainly participate in the biosynthesis of terpenes, cutin, suberine and wax. Furthermore, we identified several homologs of SlCycB2, SlCycB3, NtCycB2, AtCycB2, which have similar regulatory functions in trichome formation. These results indicate that SlCycB2 plays a critical role in reproductive organ development, multicellular trichome initiation, secondary metabolite biosynthesis and Prodenia litura defense in tomato. The similar roles of its homologs in multicellular trichome formation suggest that Solanaceous species may share common regulatory pathway. PMID- 28716407 TI - Overexpression of Lsi1 in cold-sensitive rice mediates transcriptional regulatory networks and enhances resistance to chilling stress. AB - Frequent cold spells in late spring can damage early rice seedlings. However, overexpression of the silicon-uptake gene Lsi1 (Lsi1-OX) in cold-sensitive rice (Oryza sativa L., accession: Dular) notably enhances its chilling resistance. In this study, we found that continual chilling led to chlorophyll and RNA degradation in wild-type Dular leaves, whereas leaves from a Lsi1-OX line exhibited no obvious changes. A comparison of the global mRNA expression between the two rice lines showed that genes encoding photosynthesis-antenna proteins were downregulated and those encoding the proteasome were upregulated in the wild type organism. Moreover, the differential responses of the two rice lines to chilling stress were found to correlate with the transcription factor OsWRKY53, which was predicted target of the respective microRNA (miRNA) novel-m0586-5p. In addition, miRNAs that targeted genes involved in the process of reactive oxygen species (ROS) metabolism were differentially expressed in the two rice lines after chilling stress, when comparative analysis of the outcomes of RNA sequencing on the two rice lines. Our results suggest that when overexpressed Lsi1 in cold-sensitive rice, it possibility regulates the transcription factor OsWRKY53 in addition to the genes involved in the ROS metabolism, thus mediating resistance to chilling stress. PMID- 28716408 TI - Molecular and biochemical characterization of a Vigna mungo MAP kinase associated with Mungbean Yellow Mosaic India Virus infection and deciphering its role in restricting the virus multiplication. AB - Yellow Mosaic Disease caused by the begomovirus Mungbean Yellow Mosaic India Virus (MYMIV) severely affects many economically important legumes. Recent investigations in Vigna mungo - MYMIV incompatible interaction identified a MAPK homolog in the defense signaling pathway. An important branch of immunity involves phosphorylation by evolutionary conserved Mitogen-activated protein kinases (MAPK) that transduce signals of pathogen invasion to downstream molecules leading to diverse immune responses. However, most of the knowledge of MAPKs is derived from model crops, and functions of these versatile kinases are little explored in legumes. Here we report characterization of a MAP kinase (VmMAPK1), which was induced upon MYMIV-inoculation in resistant V. mungo. Phylogenetic analysis revealed that VmMAPK1 is closely related to other plant stress-responsive MAPKs. Both mRNA and protein of VmMAPK1 were accumulated upon MYMIV infection. The VmMAPK1 protein localized in the nucleus as well as cytoplasm and possessed phosphorylation activity in vitro. A detailed biochemical characterization of purified recombinant VmMAPK1 demonstrated an intramolecular mechanism of autophosphorylation and self-catalyzed phosphate incorporation on both threonine and tyrosine residues. The Vmax and Km values of recombinant VmMAPK1 for ATP were 6.292nmol/mg/min and 0.7978MUM, respectively. Furthermore, the ability of VmMAPK1 to restrict MYMIV multiplication was validated by its ectopic expression in transgenic tobacco. Importantly, overexpression of VmMAPK1 resulted in the considerable upregulation of defense-responsive marker PR genes. Thus, the present data suggests the critical role of VmMAPK1 in suppressing MYMIV multiplication presumably through SA-mediated signaling pathway and inducing PR genes establishing the significant implications in understanding MAP kinase gene function during Vigna-MYMIV interaction; and hence paves the way for introgression of resistance in leguminous crops susceptible to MYMIV. PMID- 28716409 TI - From experiment-driven database analyses to database-driven experiments in Arabidopsis thaliana transcription factor research. AB - Experiment-driven database analysis is employed in forward genetics to predict the function of genes associated with a mutant phenotype. These analyses subsequently lead to database-driven experiments involving reverse genetics to verify functional predictions based on bioinformatic analyses. Genomic transcription factors (TFs) are key regulators of gene expression by binding to short regulatory sequences and by interacting with other TFs. Currently more than 2400 TFs are predicted for A. thaliana. As DNA-binding proteins they are particularly amenable to database-driven experiments, especially when their binding site specificities are known. Databases are available for predicting binding sites for specific TFs in regulatory sequences. Since most of these bioinformatically identified binding sites may not be functional, additional experiments for identifying the actual in vivo binding sites for TFs are required. Recently, large scale approaches were employed to determine binding sites for many A. thaliana TFs. With these approaches binding sites for 984 unique TFs were determined experimentally. An area deserving further research is proposed for interacting TFs. Most of the A. thaliana genes are under combinatorial control, and in vivo interacting TFs, similar to mammalian TFs, may bind to combinatorial elements in which the binding sites vary from those detected with the single TFs. PMID- 28716410 TI - Review: Nectar biology: From molecules to ecosystems. AB - Plants attract mutualistic animals by offering a reward of nectar. Specifically, floral nectar (FN) is produced to attract pollinators, whereas extrafloral nectar (EFN) mediates indirect defenses through the attraction of mutualist predatory insects to limit herbivory. Nearly 90% of all plant species, including 75% of domesticated crops, benefit from animal-mediated pollination, which is largely facilitated by FN. Moreover, EFN represents one of the few defense mechanisms for which stable effects on plant health and fitness have been demonstrated in multiple systems, and thus plays a crucial role in the resistance phenotype of plants producing it. In spite of its central role in plant-animal interactions, the molecular events involved in the development of both floral and extrafloral nectaries (the glands that produce nectar), as well as the synthesis and secretion of the nectar itself, have been poorly understood until recently. This review will cover major recent developments in the understanding of (1) nectar chemistry and its role in plant-mutualist interactions, (2) the structure and development of nectaries, (3) nectar production, and (4) its regulation by phytohormones. PMID- 28716411 TI - Genetic mitigation strategies to tackle agricultural GHG emissions: The case for biological nitrification inhibition technology. AB - Accelerated soil-nitrifier activity and rapid nitrification are the cause of declining nitrogen-use efficiency (NUE) and enhanced nitrous oxide (N2O) emissions from farming. Biological nitrification inhibition (BNI) is the ability of certain plant roots to suppress soil-nitrifier activity, through production and release of nitrification inhibitors. The power of phytochemicals with BNI function needs to be harnessed to control soil-nitrifier activity and improve nitrogen-cycling in agricultural systems. Transformative biological technologies designed for genetic mitigation are needed, so that BNI-enabled crop-livestock and cropping systems can rein in soil-nitrifier activity, to help reduce greenhouse gas (GHG) emissions and globally make farming nitrogen efficient and less harmful to environment. This will reinforce the adaptation or mitigation impact of other climate-smart agriculture technologies. PMID- 28716412 TI - Degradation of cytosolic ribosomes by autophagy-related pathways. AB - Ribosomes are essential molecular machines that require a large cellular investment, yet the mechanisms of their turnover are not well understood in any eukaryotic organism. Recent advances in Arabidopsis suggest that plants utilize selective mechanisms to transport rRNA or ribosomes to the vacuole, where rRNA is degraded and the breakdown products recycled to maintain cellular homeostasis. This review focuses on known mechanisms of rRNA turnover and explores unanswered questions on the specificity and pathways of ribosome turnover and the role of this process in maintenance of cellular homeostasis. PMID- 28716413 TI - Belowground microbes mitigate plant-plant competition. AB - Dimorphandra wilsonii, a Cerrado endemic Fabaceae tree, is threatened by land-use changes. The few remaining individuals occur in areas dominated by alien grasses like Urochloa decumbens. We tested the impact of nitrogen (N) availability and symbionts' presence on mitigating the effects of competition from U. decumbens. Dimorphandra wilsonii seedlings were 50-week pot-cultivated under limiting (3mM) or non-limiting (10mM) N, with or without U. decumbens, and inoculated or not with a N-fixer (Bradyrhizobium sp.) and an arbuscular mycorrhizal fungus (AMF - Glomus etunicatum), both forming symbioses in the field. Since D. wilsonii seedlings grew more and 'lost' fewer nutrients under the symbionts' presence, symbionts mitigated plant-plant competition. Under limiting N, inoculated D. wilsonii seedlings grew more (despite no nodulation), but N fixation was only suggested when inoculated D. wilsonii seedlings competed with U. decumbens. D. wilsonii13C, and substrate's carbon and respiration suggest that only the microbes performing key functions received plant carbon. Under non-limiting N, inoculated D. wilsonii seedlings became enriched in 13C, substrate accumulated carbon and microbial respiration increased, suggesting a more generalist microbial community. Data suggest inoculating D. wilsonii seeds/seedlings with AMF and N-fixers as a conservation measure. However, long-term field-studies need to confirm these conclusions. PMID- 28716414 TI - Functional characterization of the SbNrat1 gene in sorghum. AB - The Natural Resistance Associated Macrophage Protein (Nramp) members play diverse roles in metal transport in plants. Recent studies have showed that OsNrat1 (OsNramp4) encodes an Al transporter, which is required for rice Al tolerance. In this study, we functionally characterized a Nramp member in sorghum, SbNrat1, which is homologous to OsNrat1 with 88% identity. SbNrat1 was expressed in both roots and shoots, and its expression was not induced by Al treatment. When expressed in yeast, SbNrat1 transports trivalent Al ion, but not Mn and Cd. Furthermore, introduction of SbNrat1 into the rice mutant osnrat1 can rescue its sensitivity to Al. However, no correlation between Al tolerance and the expression level of SbNrat1 was found in thirteen sorghum cultivars tested. These results indicate that SbNrat1 functions as an Al transporter that is possibly involved in basic Al tolerance in sorghum. PMID- 28716415 TI - Primary root growth in Arabidopsis thaliana is inhibited by the miR159 mediated repression of MYB33, MYB65 and MYB101. AB - Organ growth is a fundamental developmental process basing on cell proliferation and differentiation. The growth of the plant root is sustained by the activity of the root meristem, a process controlled in part by various transcription factors. Here, the miR159 has been identified as a post transcriptional repressor of root growth, on the basis that the mir159ab double mutant developed a larger meristem than did the wild type, and that it formed longer roots. In the mutant, the abundance of MYB33, MYB65 and MYB101 transcript was substantially increased. When MYB33, MYB65 and MYB101 were replaced by the miR159-resistant forms mMYB33, mMYB65 and mMYB101 respectively, the root meristem was similarly enlarged and the growth of the primary root enhanced. MYB65 activity promoted cell division in the root meristem by accelerating the cell cycle. The data suggest that miR159 acts as a key repressor of the primary root's growth, acting through its repression of MYB65 and consequent blocking of the cell cycle. PMID- 28716416 TI - Role and interrelationship of MEK1-MPK6 cascade, hydrogen peroxide and nitric oxide in darkness-induced stomatal closure. AB - Pharmacological data have suggested the involvement of mitogen-activated protein kinase (MPK) cascades in dark-induced stomatal closure, but which specific MPK cascade participates in the darkness guard cell signaling and its relationship with hydrogen peroxide (H2O2) and nitric oxide (NO) remain unclear. In this paper, we observed that darkness induced activation of MPK6 in leaves of wild type Arabidopsis (Arabidopsis thaliana) and mutants for nitrate reductase 1 (NIA1), but this effect was inhibited in mutants for MPK Kinase 1 (MEK1) and ATRBOHD/F. Mutants for MEK1, MPK6 and NIA1 showed defect of dark-induced NO production in guard cells and stomatal closure, but were normal in the dark induced H2O2 generation, while stomata of mutant AtrbohD/F showed defect of dark induced H2O2 and NO production and subsequent closure. Moreover, exogenous NO rescued the defect of dark-induced stomatal closure in mutants of AtrbohD/F, mek1 and mpk6, while exogenous H2O2 could not rescue the defect of dark-induced stomatal closure in mutants of mek1, mpk6 and nia1. These genetic and biochemical evidences not only show that MEK1-MPK6 cascade, AtRBOHD/F-dependent H2O2 and NIA1 dependent NO are all involved in dark-induced stomatal closure in Arabidopsis, also indicate that MEK1-MPK6 cascade functions via working downstream of H2O2 and upstream of NO. PMID- 28716417 TI - Alcohol dehydrogenase 1 (ADH1) confers both abiotic and biotic stress resistance in Arabidopsis. AB - Although the transcriptional regulation and upstream transcription factors of AtADH1 in response to abiotic stress are widely revealed, the in vivo roles of AtADH1 remain unknown. In this study, we found that the expression of AtADH1 was largely induced after salt, drought, cold and pathogen infection. Further studies found that AtADH1 overexpressing plants were more sensitive to abscisic acid (ABA) in comparison to wide type (WT), while AtADH1 knockout mutants showed no significant difference compared with WT in ABA sensitivity. Consistently, AtADH1 overexpressing plants showed improved stress resistance to salt, drought, cold and pathogen infection than WT, but the AtADH1 knockout mutants had no significant difference in abiotic and biotic stress resistance. Moreover, overexpression of AtADH1 expression increased the transcript levels of multiple stress-related genes, accumulation of soluble sugars and callose depositions. All these results indicate that AtADH1 confers enhanced resistance to both abiotic and biotic stresses. PMID- 28716418 TI - Wheat ROP proteins modulate defense response through lignin metabolism. AB - ROP is a subfamily of small GTP-binding proteins that uniquely exist in plants. It acts as versatile molecular switches that regulate various developmental processes. Some ROP proteins are also reported to affect defense responses, although their exact mechanism is not fully understood. Herein, ROP members in wheat were mined; the functions of three wheat ROP proteins were studied. RT-PCR results showed that the expression of TaRac1 was rapidly and strongly induced after leaf rust infection. TaRac1 interacted with TaCCR in yeast-hybridization assay. The overexpression of TaRac1 in tobacco promoted CCR and CAD gene expression, increased the total lignin content and sinapyl lignin proportion, and then enhanced resistance to tobacco black shank and bacterial wilt diseases. In contrast, TaRac3 and TaRac4 did not show to interact with TaCCR. Furthermore, the overexpression of TaRac3 and TaRac4 did not increase lignin gene expression and lignin accumulation either. Unlike TaRac1, the overexpression of TaRac3 increased susceptibility to both black shank and bacterial wilt pathogens, while overexpression of TaRac4 showed no effect on disease resistance but promoted the root growth in tobacco seedling. These data collectively suggest that TaRac1 in Group II is mainly involved in regulating lignin metabolism which, in turn, responsible for the observed roles in pathogen resistance. TaRac3 and TaRac4 have the minor roles in defense response but may act on regulation in plant developmental processes. These results shed light on the complexity and diverse function of ROP in plant defense pathway. PMID- 28716419 TI - A zeta-carotene desaturase gene, IbZDS, increases beta-carotene and lutein contents and enhances salt tolerance in transgenic sweetpotato. AB - zeta-Carotene desaturase (ZDS) is one of the key enzymes in carotenoid biosynthesis pathway. However, the ZDS gene has not been applied to carotenoid improvement of plants. Its roles in tolerance to abiotic stresses have not been reported. In this study, the IbZDS gene was isolated from storage roots of sweetpotato (Ipomoea batatas (L.) Lam.) cv. Nongdafu 14. Its overexpression significantly increased beta-carotene and lutein contents and enhanced salt tolerance in transgenic sweetpotato (cv. Kokei No. 14) plants. Significant up regulation of lycopene beta-cyclase (beta-LCY) and beta-carotene hydroxylase (beta-CHY) genes and significant down-regulation of lycopene epsilon-cyclase (epsilon-LCY) and epsilon-carotene hydroxylase (epsilon-CHY) genes were found in the transgenic plants. Abscisic acid (ABA) and proline contents and superoxide dismutase (SOD), catalase (CAT) and peroxidase (POD) activities were significantly increased, whereas malonaldehyde (MDA) content was significantly decreased in the transgenic plants under salt stress. The salt stress-responsive genes encoding pyrroline-5-carboxylate reductase (P5CR), SOD, CAT, ascorbate peroxidase (APX) and POD were found to be significantly up-regulated in the transgenic plants under salt stress. This study indicates that the IbZDS gene has the potential to be applied for improving beta-carotene and lutein contents and salt tolerance in sweetpotato and other plants. PMID- 28716420 TI - Characterization of BdCBF genes and genome-wide transcriptome profiling of BdCBF3 dependent and -independent cold stress responses in Brachypodium distachyon. AB - Freezing stress substantially reduces crop yields and limits plant distribution. The identification of genes critical for cold acclimation is thus of great importance. C-repeat binding factors (CBFs) are transcription factors that play key regulatory roles in the cold acclimation process, which dramatically increases freezing tolerance in plants. We report here that B. distachyon can successfully cold acclimate and we identified a CBF gene family consisting of eight genes in a tandem array and are designated as BdCBF1-8. Expression analysis indicated that all the eight BdCBF genes are induced by cold. Freezing tolerance experiments showed that the knockdown of BdCBF3 gene in RNAi cbf3 mutant plants results in a significant reduction in survival after an exposure to freezing temperatures. RNA-seq transcriptomic analysis was conducted using the wild type and cbf3 mutant plants under both normal and cold conditions. We identified 460, 3213, 2839 and 1871 differentially expressed genes exhibiting different expression levels by pairwise comparisons of cbf3 (23 degrees C) vs. WT (23 degrees C), WT (23 degrees C) vs. WT (4 degrees C), cbf3 (23 degrees C) vs. cbf3 (4 degrees C), and cbf3 (4 degrees C) vs. WT (4 degrees C), respectively. These differentially expressed genes were enriched in several biological pathways. Combined analyses of differentially expressed genes in some of the enriched pathways provide insights into mechanisms of plant response to cold in the BdCBF3 dependent, -independent or -compensatory categories. PMID- 28716421 TI - Dual functioning of plant arginases provides a third route for putrescine synthesis. AB - Two biosynthetic routes are known for putrescine, an essential plant metabolite. Ornithine decarboxylase (ODC) converts ornithine directly to putrescine, while a second route for putrescine biosynthesis utilizes arginine decarboxylase (ADC) to convert arginine to agmatine, and two additional enzymes, agmatine iminohydrolase (AIH) and N-carbamoyl putrescine aminohydrolase (NLP1) to complete this pathway. Here we show that plants can use ADC and arginase/agmatinase (ARGAH) as a third route for putrescine synthesis. Transformation of Arabidopsis thaliana ADC2, and any of the arginases from A. thaliana (ARGAH1, or ARGHA2) or the soybean gene Glyma.03g028000 (GmARGAH) into a yeast strain deficient in ODC, fully complemented the mutant phenotype. In vitro assays using purified recombinant enzymes of AtADC1 and AtARGAH2 were used to show that these enzymes can function in concert to convert arginine to agmatine and putrescine. Transient expression analysis of the soybean genes (Glyma.06g007500, ADC; Glyma.03g028000 GmARGAH) and the A. thaliana ADC2 and ARGAH genes in leaves of Nicotiana benthamiana, showed that these proteins are localized to the chloroplast. Experimental support for this pathway also comes from the fact that expression of AtARGAH, but not AtAIH or AtNLP1, is co-regulated with AtADC2 in response to drought, oxidative stress, wounding, and methyl jasmonate treatments. Based on the high affinity of ARGAH2 for agmatine, its co-localization with ADC2, and typically low arginine levels in many plant tissues, we propose that these two enzymes can be major contributors to putrescine synthesis in many A. thaliana stress responses. PMID- 28716422 TI - Development of imidazolinone herbicide tolerant borage (Borago officinalis L.). AB - Borage (Borago officinalis) is an annual herb that produces a high level of gamma linolenic acid (GLA) in its seed oil. Due to the recognized health benefits of GLA, borage is now commercially cultivated worldwide. However, an herbicide tolerant variety for effective weed management has not yet been developed. Here we report the generation and characterization of ethyl methanesulfonate (EMS) induced borage mutant lines tolerant to the herbicide imidazolinone. An EMS mutagenized borage population was generated by using a series of concentrations of EMS to treat mature borage seeds. Screening of the M2 and M3 borage plants using an herbicide treatment resulted in the identification of two imidazolinone tolerant lines. Sequence analysis of two acetohydroxyacid synthase (AHAS) genes, AHAS1 and AHAS2, from the mutant (tolerant) and wild type (susceptible) borage plants showed that single nucleotide substitutions which resulted in amino acid changes occurred in AHAS1 and AHAS2, respectively in the two tolerant lines. A KASP marker was then developed to differentiate the homozygous susceptible, homozygous tolerant and heterozygous borage plants. An in vitro assay showed that homozygous tolerant borage carrying the AHAS1 mutation retained significantly higher AHAS activity than susceptible borage across different imazamox concentrations. A herbicide dose response test indicated that the line with the AHAS1 mutation could tolerate four times the normally used field concentration of "Solo" herbicide. PMID- 28716423 TI - NADK2 positively modulates abscisic acid-induced stomatal closure by affecting accumulation of H2O2, Ca2+ and nitric oxide in Arabidopsis guard cells. AB - NAD kinase2 (NADK2) plays key roles in chloroplastic NADP biosynthesis, stress adaptation and modulation of cellular metabolisms in Arabidopsis. However, it is unknown whether and how NADK2 affects abscisic acid (ABA)-mediated stomatal movement. Here, we detected that null mutant nadk2 was more sensitive to drought stress than WT, and NADK2 gene was active in guard cells. Furthermore, NADK2 mutation impaired ABA-induced stomatal closure and ABA inhibition of light promoted stomatal opening. NADK2 disruption also impaired ABA-stimulated accumulation of H2O2, Ca2+ and nitric oxide (NO) in guard cells, but did not affect the stomatal closure evoked by exogenous H2O2, Ca2+ or NO. Expression analysis revealed that ABA-promoted increases in transcripts of AtrbohD, AtrbohF and NIA1 were markedly arrested in guard cells of nadk2 compared with those of WT. Besides, genetic evidence indicated that NADK2 acted synergistically with OST1 and ABI1 during ABA-induced stomatal closure. Together, these results suggest that NADK2 is an essential positive regulator, and functions upstream of H2O2 in guard cell ABA signaling. It stimulates stomatal closure mainly through increasing the generation of H2O2, Ca2+ and NO in guard cells in Arabidopsis. PMID- 28716424 TI - Molecular cloning of an ester-forming triterpenoid: UDP-glucose 28-O glucosyltransferase involved in saponin biosynthesis from the medicinal plant Centella asiatica. AB - Triterpene saponins include bioactive compounds with structures consisting of triterpene aglycones (sapogenins) and one or more sugar moieties linked through acetal or ester glycosidic linkages at one or more sites. Centella asiatica (L.) Urban is a medicinal plant that contains bioactive ursane-type saponins, such as madecassoside and asiaticoside. In this work, glucosylation of triterpenoids in C. asiatica was investigated starting with plant extracts. An enzyme capable of glucosylating asiatic and madecassic acids was partially purified. Proteomics methods and cDNA sequence data were employed as tools to obtain a full-length cDNA clone encoding a glucosyltransferase. The recombinant gene product, UGT73AD1, was functionally expressed in Escherichia coli and purified by immobilized metal-affinity chromatography. Purified recombinant UGT73AD1 was found to have a narrow specificity, glucosylating asiatic and madecassic acids at the C28 carboxyl. mRNA accumulated in all tissues tested (leaves, stems, roots and flowers), with highest expression in leaves. Thus, UGT73AD1 was identified as a triterpenoid carboxylic acid: UDP-glucose 28-O-glucosyltransferase that appears to be involved in saponin biosynthesis in C. asiatica. PMID- 28716425 TI - Characterization and quantification of flavonoids and organic acids over fruit development in American cranberry (Vaccinium macrocarpon) cultivars using HPLC and APCI-MS/MS. AB - Cranberry flavonoids, including anthocyanins, flavonol glycosides and proanthocyanidins, and organic acids were characterized and quantified by HPLC and LC-MS/MS during fruit development and ripening in eight cranberry cultivars. Anthocyanin biosynthesis initiated at early fruit development and reached highest level in mature fruit, with significant differences between cultivars. Major flavonol glycosides, including the most abundant quercetin-3-galactoside and myricetin-3-galactoside, showed consistent concentrations during the season with moderate fluctuation, and were at similar levels in mature fruits of the eight cultivars. Proanthocyanidins declined during fruit development and then increased slightly in later maturation stages. Levels of various proanthocyanidin oligomers/polymers with different degree-of-polymerization were highly correlated within a cultivar during fruit development. Cultivars with coancestry exhibited similar levels (high/low) of anthocyanins or proanthocyanidins, indicating genetic effects on biosynthesis of such flavonoids. All cultivars showed similar levels of malic and citric acids, and declining levels of quinic acid during fruit development. Benzoic acid was extremely low early in the season and increased sharply during fruit ripening. Levels of quinic and citric acids were significantly different among cultivars in the mature fruit. Concentrations of proanthocyanidins, anthocyanins, quinic acid and benzoic acid have a strong developmental association in developing ovaries. PMID- 28716429 TI - Aging and Metabolism: Two Sides of the Same Coin. PMID- 28716427 TI - Influence of L-dopa on subtle motor signs in heterozygous Parkin- and PINK1 mutation carriers. AB - INTRODUCTION: A latent nigrostriatal deficit and its possible clinical consequences in asymptomatic heterozygous Parkin and PINK1 mutation carriers (AMC) have been a matter of investigation in recent years. Notably, mild Parkinsonian signs in heterozygous mutation carriers can be so subtle that they may be missed if not specifically investigated. METHODS: We studied 15 heterozygous Parkin and PINK1 AMC and 18 age- and sex-matched mutation-negative controls using a standardized video, instructing the probands to perform relevant parts of the UPDRS III to investigate fine motor movements at baseline and after first-time L-Dopa administration. Additionally, available UPDRS III scores of mutation carriers from the past ten years were reviewed. RESULTS: AMC showed a reduced number of fine motor movements per second compared to controls at baseline (p = 0.04). L-Dopa improved motor performance numerically but non significantly in AMC (p = 0.2301), but significantly in healthy controls (p = 6.1.10-5). Although none of the AMC reported symptoms, nine showed rigidity, bradykinesia, tremor, and postural instability when the UPDRS III was applied. Mean UPDRSIII scores significantly decreased after L-Dopa administration (p = 0.005), but did not increase over the past ten years. CONCLUSIONS: (i) Heterozygous AMC show subtle motor abnormalities when a detailed, specialized motor examination is applied and compared to mutation-negative matched control subjects. (ii) The mild motor deficit present in a subgroup of heterozygous Parkin and PINK1 AMC appears to be non-progressive and responsive to L-dopa administration. (iii) Evaluating motor changes, their progression, and treatment response in AMC can provide valuable insights into possible early disease stages and compensatory mechanisms. PMID- 28716426 TI - Hormone dependent uterine epithelial-stromal communication for pregnancy support. AB - Human fertility is a relatively inefficient process. Despite the presence of visibly healthy embryos, 30% of pregnancies generated by assisted reproductive technology (ART) fail before the second trimester. The uterine microenvironment plays a critical role in establishing and maintaining a successful pregnancy that requires coordinated communication between the epithelial and stromal cells of the endometrium. The epithelial cells must cease proliferation and become permissive for the conceptus (embryo and associated extraembryonic membranes), while the stromal cells undergoes mesenchymal-to-epithelioid transformation to form the decidua in support of subsequent embryo development. The ovarian steroids Estrogen (E2) and Progesterone (P4) are the major hormones governing these processes. These hormones act via their nuclear receptors, the estrogen receptor, ESR1, and progesterone receptor, PGR, to direct the transcription of genes that orchestrate epithelial and stromal cell communication. This review will discuss the molecular mechanisms utilized by steroid hormones that regulate uterine receptivity, as well, establish and maintain pregnancy. PMID- 28716428 TI - High-intensity Statin Treatments in Clinically Stable Patients on Aspirin Monotherapy 12 Months After Drug-eluting Stent Implantation: A Randomized Study. AB - INTRODUCTION AND OBJECTIVES: Current guidelines on the treatment of blood cholesterol recommend continuous maintenance of high-intensity statin treatment in drug-eluting stent (DES)-treated patients. However, high-intensity statin treatment is frequently underused in clinical practice after stabilization of DES treated patients. Currently, the impact of continuous high-intensity statin treatment on the incidence of late adverse events in these patients is unknown. We investigated whether high-intensity statin treatment reduces late adverse events in clinically stable patients on aspirin monotherapy 12 months after DES implantation. METHODS: Clinically stable patients who underwent DES implantation 12 months previously and received aspirin monotherapy were randomly assigned to receive either high-intensity (40mg atorvastatin, n = 1000) or low-intensity (20mg pravastatin, n = 1000) statin treatment. The primary endpoint was adverse clinical events at 12-month follow-up (a composite of all death, myocardial infarction, revascularization, stent thrombosis, stroke, renal deterioration, intervention for peripheral artery disease, and admission for cardiac events). RESULTS: The primary endpoint at 12-month follow-up occurred in 25 patients (2.5%) receiving high-intensity statin treatment and in 40 patients (4.1%) receiving low-intensity statin treatment (HR, 0.58; 95%CI, 0.36-0.92; P = .018). This difference was mainly driven by a lower rate of cardiac death (0 vs 0.4%, P = .025) and nontarget vessel myocardial infarction (0.1 vs 0.7%, P = .033) in the high-intensity statin treatment group. CONCLUSIONS: Among clinically stable DES treated patients on aspirin monotherapy, high-intensity statin treatment significantly reduced late adverse events compared with low-intensity statin treatment. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01557075. PMID- 28716430 TI - Non-invasive Evaluation of Right Ventricular Function with Real-Time 3-D Echocardiography. AB - The aim of this study was to evaluate the accuracy and feasibility of real-time 3 D echocardiography (3-DE) in assessing right ventricular (RV) systolic function. A latex balloon was inserted into the right ventricle of 20 freshly harvested pig hearts which were then passively driven by a pulsatile pump apparatus. The RV global longitudinal strain (GLS), global circumferential strain (GCS), global area strain (GAS) and RV ejection fraction (RVEF), derived from 3-DE, as well as the RVEF obtained from 2-D echocardiography (2-DE) were quantified at different stroke volumes (30-70 mL) and compared with sonomicrometry data. In all comparisons, 3-D GLS, GCS, GAS, 2-D RVEF and 3-D RVEF exhibited strong correlations with sonomicrometry data (r = 0.89, 0.79, 0.74, 0.80, and 0.93, respectively; all p values < 0.001). Bland-Altman analyses revealed slight overestimations of echo-derived GLS, GCS, 2-DE RVEF and 3-DE RVEF compared with sonomicrometry values (bias = 1.55, 2.72, 3.59 and 2.21, respectively). Furthermore, there is better agreement among GLS, 3-D RVEF and the sonomicrometry values than between GCS and 2-D RVEF. Real-time 3-DE is more feasible and accurate for assessing RV function than 2-DE. GLS is a potential alternative parameter for quantifying RV systolic function. PMID- 28716431 TI - Freehand 3-D Ultrasound Imaging: A Systematic Review. AB - Two-dimensional ultrasound (US) imaging has been successfully used in clinical applications as a low-cost, portable and non-invasive image modality for more than three decades. Recent advances in computer science and technology illustrate the promise of the 3-D US modality as a medical imaging technique that is comparable to other prevalent modalities and that overcomes certain drawbacks of 2-D US. This systematic review covers freehand 3-D US imaging between 1970 and 2017, highlighting the current trends in research fields, the research methods, the main limitations, the leading researchers, standard assessment criteria and clinical applications. Freehand 3-D US systems are more prevalent in the academic environment, whereas in clinical applications and industrial research, most studies have focused on 3-D US transducers and improvement of hardware performance. This topic is still an interesting active area for researchers, and there remain many unsolved problems to be addressed. PMID- 28716433 TI - Unmyelinated Peripheral Nerves Can Be Stimulated in Vitro Using Pulsed Ultrasound. AB - Appreciation for the medical and research potential of ultrasound neuromodulation is growing rapidly, with potential applications in non-invasive treatment of neurodegenerative disease and functional brain mapping spurring recent progress. However, little progress has been made in our understanding of the ultrasound tissue interaction. The current study tackles this issue by measuring compound action potentials (CAPs) from an ex vivo crab walking leg nerve bundle and analysing the acoustic nature of successful stimuli using a passive cavitation detector (PCD). An unimpeded ultrasound path, new acoustic analysis techniques and simple biological targets are used to detect different modes of cavitation and narrow down the candidate biological effectors with high sensitivity. In the present case, the constituents of unmyelinated axonal tissue alone are found to be sufficient to generate de novo action potentials under ultrasound, the stimulation of which is significantly correlated to the presence of inertial cavitation and is never observed in its absence. PMID- 28716432 TI - Effect of Frequency and Focal Spacing on Transcranial Histotripsy Clot Liquefaction, Using Electronic Focal Steering. AB - This in vitro study investigated the effects of ultrasound frequency and focal spacing on blood clot liquefaction via transcranial histotripsy. Histotripsy pulses were delivered using two 256-element hemispherical transducers of different frequency (250 and 500 kHz) with 30-cm aperture diameters. A 4-cm diameter spherical volume of in vitro blood clot was treated through 3 excised human skullcaps by electronically steering the focus with frequency proportional focal spacing: lambda/2, 2 lambda/3 and lambda with 50 pulses per location. The pulse repetition frequency across the volume was 200 Hz, corresponding to a duty cycle of 0.08% (250 kHz) and 0.04% (500 kHz) for each focal location. Skull heating during treatment was monitored. Liquefied clot was drained via catheter and syringe in the range of 6-59 mL in 0.9-42.4 min. The fastest rate was 16.6 mL/min. The best parameter combination was lambda spacing at 500 kHz, which produced large liquefaction through 3 skullcaps (23.1 +/- 4.0, 37.1 +/- 16.9 and 25.4 +/- 16.9 mL) with the fast rates (3.2 +/- 0.6, 5.1 +/- 2.3 and 3.5 +/- 0.4 mL/min). The temperature rise through the 3 skullcaps remained below 4 degrees C. PMID- 28716434 TI - Training Midwives to Perform Basic Obstetric Point-of-Care Ultrasound in Rural Areas Using a Tablet Platform and Mobile Phone Transmission Technology-A WFUMB COE Project. AB - Point-of-care ultrasound (POCUS) has become a topical subject and can be applied in a variety of ways with differing outcomes. The cost of all diagnostic procedures including obstetric ultrasound examinations is a major factor in the developing world and POCUS is only useful if it can be equated to good outcomes at a lower cost than a routine obstetric examination. The aim of this study was to assess a number of processes including accuracy of images and reports generated by midwives, performance of a tablet-sized ultrasound scanner, training of midwives to complete ultrasounds, teleradiology solution transmissions of images via internet, review of images by a radiologist, communication between midwife and radiologist, use of this technique to identify high-risk patients and improvement of the education and teleradiology model components. The midwives had no previous experience in ultrasound. They were stationed in rural locations where POCUS was available for the first time. After scanning the patients, an interim report was generated by the midwives and sent electronically together with all images to the main hospital for validation. Unique software was used to send lossless images by mobile phone using a modem. Transmission times were short and quality of images transmitted was excellent. All reports were validated by two experienced radiologists in our department and returned to the centers using the same transmission software. The transmission times, quality of scans, quality of reports and other parameters were recorded and monitored. Analysis showed excellent correlation between provisional and validated reports. Reporting accuracy of scans performed by the midwives was 99.63%. Overall flow turnaround time (from patient presentation to validated report) was initially 35 min but reduced to 25 min. The unique mobile phone transmission was faultless and there was no degradation of image quality. We found excellent correlation between final outcomes of the pregnancies and diagnoses on the basis of reports generated by the midwives. Only 1 discrepancy was found in the midwives' reports. Scan results versus actual outcomes revealed 2 discrepancies in the 20 patients identified as high risk. In conclusion, we found that it is valuable to train midwives in POCUS to use an ultrasound tablet device and transmit images and reports via the internet to radiologists for review of accuracy. This focus on the identification of high-risk patients can be valuable in a remote healthcare facility. PMID- 28716435 TI - Reference values for skin microanatomy: A systematic review and meta-analysis of ex vivo studies. AB - BACKGROUND: Few studies have characterized reference values of normal human skin microanatomy parameters. OBJECTIVE: To quantify histologic measurements of epidermal thickness, melanocyte density, hair follicle density, and eccrine gland density as a function of age and anatomic site. METHOD: We searched the PubMed, Embase, Web of Science, and Cochrane databases for articles published through May 25, 2017. Two reviewers independently screened 2016 articles; 327 relevant articles and 151 additional articles found via forward or reference citations underwent full-text review by 1 of 4 reviewers for relevance, data extraction, and critical appraisal. Weighted averages, meta-analysis, and meta-regression were used in statistical analysis. RESULTS: A total of 56 articles were included; when all anatomic locations were used, the overall estimates for epidermal thickness, melanocyte density, hair follicle density, and eccrine gland density were 99.75 MUm (95% confidence interval [CI], 83.25-116.25), 955.05 cells/mm2 (95% CI. 880.89-1029.21), 1.40 hairs/mm2 (95% CI. 0.91-1.89), and 1.28 glands/mm2 (95% CI. 0.91-1.64), respectively. LIMITATIONS: There was significant data heterogeneity across studies, possibly because of differences in histological techniques and absence of standardized microanatomy definitions. CONCLUSIONS: We established summary estimates for normal human skin microanatomy parameters. PMID- 28716436 TI - Frontal fibrosing alopecia among men: A clinicopathologic study of 7 cases. AB - BACKGROUND: Frontal fibrosing alopecia (FFA) is a lichen planopilaris-variant scarring alopecia that has rarely been described in men. OBJECTIVE: To characterize the clinicopathologic findings of FFA in men by studying a series of 7 male patients. METHODS: We conducted a retrospective review of all cases of male patients with FFA at the Mayo Clinic from 1992 to 2016. RESULTS: Seven male patients with FFA were identified. The frontal scalp (in 6 of 7 patients), sideburns (in 4 of 7), and temporal scalp (in 4 of 7) were most frequently involved. Three patients had involvement of the eyebrows. One patient had hair loss of the upper cutaneous lip. All patients had biopsy evidence of lichen planopilaris. None of the patients had associated autoimmune or thyroid disease. Two patients had hypogonadism upon testosterone studies. LIMITATIONS: Limitations include small sample size and varied follow-up. CONCLUSIONS: Although most often reported among postmenopausal women, FFA also occurs among men. The clinical and histopathologic characteristics of FFA in men parallel those described in women with FFA. Unique areas of involvement in men include sideburns and facial hair. Concomitant mucocutaneous lichen planus, autoimmune disease, and thyroid disease are infrequent among men with FFA. Distribution of hair loss and associated hormonal abnormalities aid in the recognition of FFA in men. PMID- 28716437 TI - Tumor programmed cell death ligand 1 expression correlates with nodal metastasis in patients with cutaneous squamous cell carcinoma of the head and neck. AB - BACKGROUND: Binding of tumor-expressed programmed cell death ligand 1 (PD-L1) to the programmed cell death 1 (PD-1) surface receptor blocks T-cell activation thereby leading to immune evasion. Tumor PD-L1 expression has been associated with poor outcome in a wide variety of cancers; however, data in cutaneous squamous cell carcinoma (cSCC) are scarce and conflicting. OBJECTIVE: To investigate the relationship of tumor PD-L1 expression with the clinicopathologic features and prognosis of cSCC. METHODS: PD-L1 expression was analyzed by immunohistochemistry on paraffin-embedded tissue samples from 100 patients with cSCC. Cumulative/dynamic receiver operating characteristic curve was used to determine the optimal PD-L1 threshold. Kaplan-Meier estimators and Cox proportional hazards regression models were also used. RESULTS: On the basis of cumulative/dynamic receiver operating characteristic curves, we defined the cut off score for PD-L1 expression as >=25% of tumor cells positively stained. PD-L1 expression was a significant risk factor for nodal metastasis with crude and adjusted hazard ratios of 3.39 (1.71-6.65) and 6.54 (2.28-18.78), respectively. LIMITATIONS: This is a retrospective study limited to cSCC of the head and neck. CONCLUSION: These findings indicate that tumor PD-L1 expression predicts increased risk for nodal metastasis in patients with cSCC. PMID- 28716438 TI - The impact of knowledge transfer on the detection of venous invasion in colorectal cancer. AB - Venous invasion (VI) is an independent predictor of hematogenous metastasis and mortality in colorectal cancer (CRC) yet remains widely underreported. Its detection may require recognition of subtle morphologic clues, which at times are only unmasked with an elastin stain. This study evaluates the impact of a knowledge transfer initiative (KTI) on VI detection in a "real-world" pathology practice setting. Following participation in an interobserver variability study of VI detection (Kirsch et al, 2013), 12 participants received educational materials highlighting key issues in VI detection. Eighteen months later, participants were invited to submit pathology reports from all CRC resections signed out 18 months prior to and 18 months following the KTI (n = 266 and n = 244, respectively). Nine pathologists participated. Reports were reviewed for VI and other established prognostic factors. Numbers of elastin stains and tumor containing blocks were also recorded. Comparative analyses were adjusted for baseline differences in tumor, lymph node, and metastasis stage; tumor location; use of neoadjuvant therapy; and number of tumor-containing blocks. VI detection increased significantly post-KTI versus pre-KTI (39.3% versus 18.4%, adjusted odds ratio [OR] 2.86 [1.91-4.28], P < .001). Increased VI detection post-KTI was observed in both stage II (31.8% versus 12.5%, adjusted OR 3.27 [1.45-7.42], P = .004) and stage III CRC (62.4% versus 28.2%, adjusted OR 4.23 [2.37-7.55], P < .001). All pathologists demonstrated increased VI detection post-KTI. Use of elastin stains was significantly higher post-KTI versus pre-KTI (61.5% versus 5.3% of cases respectively, P < .001). This study demonstrates the effectiveness of knowledge transfer in increasing VI detection in routine pathology practice. PMID- 28716439 TI - Renal cell carcinoma, unclassified with medullary phenotype: poorly differentiated adenocarcinomas overlapping with renal medullary carcinoma. AB - Renal medullary carcinoma (RMC) is a highly aggressive renal cell carcinoma arising in the collecting system and requiring careful correlation with status of sickle cell trait. A panel of international experts has recently proposed provisional diagnostic terminology, renal cell carcinoma, unclassified, with medullary phenotype, based on encountering an extraordinarily rare tumor with RMC morphology and immunophenotype in an individual proven not to have a hemoglobinopathy. Herein, we extend this observation to a cohort of 5 such tumors, morphologically similar to RMC, lacking SMARCB1 expression by immunohistochemistry, but each without evidence of a hemoglobinopathy. The tumors arose in 4 men and 1 woman with a mean age of 44 years, occurring in 3 left and 2 right kidneys. Clinically, aggression was apparent with involvement of perinephric adipose tissue in all 5 cases, nodal metastasis in 4 of 5 cases, and death of disease in 4 of 5 cases within 3-27 months. Histologic sections showed poorly differentiated adenocarcinoma, often with solid and nested growth patterns, as well as infiltrative glandular, tubulopapillary, cribriform, or reticular growth. Rhabdoid and sarcomatoid cytomorphology was seen in a subset. All tumors showed PAX8 nuclear positivity and SMARCB1 loss, with OCT3/4 expression in 4 of 5 cases. In summary, this first series of renal cell carcinoma, unclassified, with medullary phenotype documents tumors with morphologic, immunophenotypic, and prognostic features of RMC occurring in individuals without sickle cell trait. Although greater biologic and molecular understanding is needed, the available evidence points to these cases representing a sporadic counterpart to sickle cell trait-associated RMC. PMID- 28716440 TI - Removal notice to (617) - Candida Colonization Is Associated with Improved Survival After Lung Transplant J Heart Lung Transplant 36 (2017) S238. PMID- 28716441 TI - Unraveling the meaning of chemical shifts in protein NMR. AB - Chemical shifts are among the most informative parameters in protein NMR. They provide wealth of information about protein secondary and tertiary structure, protein flexibility, and protein-ligand binding. In this report, we review the progress in interpreting and utilizing protein chemical shifts that has occurred over the past 25years, with a particular focus on the large body of work arising from our group and other Canadian NMR laboratories. More specifically, this review focuses on describing, assessing, and providing some historical context for various chemical shift-based methods to: (1) determine protein secondary and super-secondary structure; (2) derive protein torsion angles; (3) assess protein flexibility; (4) predict residue accessible surface area; (5) refine 3D protein structures; (6) determine 3D protein structures and (7) characterize intrinsically disordered proteins. This review also briefly covers some of the methods that we previously developed to predict chemical shifts from 3D protein structures and/or protein sequence data. It is hoped that this review will help to increase awareness of the considerable utility of NMR chemical shifts in structural biology and facilitate more widespread adoption of chemical-shift based methods by the NMR spectroscopists, structural biologists, protein biophysicists, and biochemists worldwide. This article is part of a Special Issue entitled: Biophysics in Canada, edited by Lewis Kay, John Baenziger, Albert Berghuis and Peter Tieleman. PMID- 28716442 TI - Aphanomyces astaci isolate from latently infected stone crayfish (Austropotamobius torrentium) population is virulent. AB - Aphanomyces astaci infection is the cause of crayfish plague in European crayfish. Here the virulence of an A. astaci As strain isolated from apparently healthy stone crayfish (Austropotamobius torrentium) from Slovenia was compared to that of the Psl-Puujarvi A. astaci isolate in 3 crayfish species: noble crayfish (Astacus astacus), signal crayfish (Pacifastacus leniusculus) from Finland and stone crayfish from Slovenia. All 3 crayfish species were challenged with PsI-Puujarvi A. astaci and succumbed to crayfish plague, with both noble crayfish and stone crayfish showing 100% mortality, while 25% of the signal crayfish died during the challenge. In comparison, the As-Slovenia A. astaci isolate was pathogenic for noble crayfish but not for signal crayfish or stone crayfish. This finding suggests that A. astaci virulence could be species specific and a strain from latent A. astaci infection in one native European crayfish species could be detrimental to other native European crayfish species. PMID- 28716443 TI - Editorial Overview: Antigen Processing and Presentation; many fingers in many pies. PMID- 28716444 TI - Thiosemicarbazone derivatives, thiazolyl hydrazones, effectively inhibit leukemic tumor cell growth: Down-regulation of ribonucleotide reductase activity and synergism with arabinofuranosylcytosine. AB - Cellular growth inhibition exerted by thiosemicarbazones is mainly attributed to down-regulation of ribonucleotide reductase (RNR) activity, with RNR being responsible for the rate-limiting step of de novo DNA synthesis. In this study, we investigated the antineoplastic effects of three newly synthesized thiosemicarbazone derivatives, thiazolyl hydrazones, in human HL-60 promyelocytic leukemia cells. The cytotoxicity of compounds alone and in combination with arabinofuranosylcytosine (AraC) was determined by growth inhibition assays. Effects on deoxyribonucleoside triphosphate (dNTP) concentrations were quantified by HPLC, and the incorporation of radio-labeled 14C-cytidine into nascent DNA was measured using a beta counter. Cell cycle distribution was analyzed by FACS, and protein levels of RNR subunits and checkpoint kinases were evaluated by Western blotting. VG12, VG19, and VG22 dose-dependently decreased intracellular dNTP concentrations, impaired cell cycle progression and, consequently, inhibited the growth of HL-60 cells. VG19 also lowered the protein levels of RNR subunits R1 and R2 and significantly diminished the incorporation of radio-labeled 14C cytidine, being equivalent to an inhibition of DNA synthesis. Combination of thiazolyl hydrazones with AraC synergistically potentiated the antiproliferative effects seen with each drug alone and might therefore improve conventional chemotherapeutic regimens for the treatment of human malignancies such as acute promyelocytic or chronic myelogenous leukemia. PMID- 28716445 TI - Feeding Systems and the Gut Microbiome: Gut-Brain Interactions With Relevance to Psychiatric Conditions. AB - BACKGROUND: Physical and mental health is dependent on the environment, and feeding is a prime example of this environmental exchange. While the hypothalamus controls both feeding behavior and the stress response, the integration of the neural control centers and the peripheral gut allows for disruption in the gastrointestinal systems and dysfunctional communication to the brain. OBJECTIVE: The purpose of this review is to familiarize clinicians with the physiology controlling feeding behavior and its implications for psychiatric conditions, such as anorexia nervosa and depression. Growing understanding of how integrated bacterial life is in the body has shown that gut bacteria regulate basic physiologic processes and are implicated in various disease states and contribute to regulation of mood. Responses to stress have effects on feeding behavior and mood and the regulation of the stress response by the gut microbiota could contribute to the dysfunction seen in patients with psychiatric illnesses. CONCLUSIONS: Gut microbiota may contribute to dysfunction in psychiatric illnesses. New opportunities to modulate existing gut microbiota using probiotics could be novel targets for clinical interventions. PMID- 28716446 TI - Dose dependent effect of resveratrol in preventing cisplatin-induced ovarian damage in rats: An experimental study. AB - This study aimed to evaluate the effect of resveratrol in preventing cisplatin (CP) induced ovarian damage in rats. Twenty-eight female Wistar albino rats were separated into four groups. No medication was given to group 1. Over the 21-day study period, low-dose resveratrol was given to group 2, high-dose resveratrol was given to group 3, and saline was administered to group 4. On the 15th day of medication, all groups except for group 1 were treated with a single dose of CP. Serum levels of anti-Mullerian hormone (AMH) were tested at baseline and on the 15th and 21st days. All rats underwent oophorectomy one week after CP application. Primordial, primary, secondary, and tertiary follicles were counted microscopically. No significant difference was observed among the groups in mean AMH levels according to follow-up time. The numbers of primary and primordial follicles were statistically significantly higher in group 2 than in group 4 (p<0.05). The number of tertiary follicles was statistically significantly higher in group 1 than in groups 3 and 4 (p<0.05), but it was not statistically significantly different than in group 2. Resveratrol, particularly at low-doses, can prevent CP induced ovarian damage by maintaining the numbers of primordial and primary follicles. Further studies are needed to study the effect of resveratrol on human ovaries. PMID- 28716447 TI - Elevated Wall Shear Stress in Aortic Type B Dissection May Relate to Retrograde Aortic Type A Dissection: A Computational Fluid Dynamics Pilot Study. AB - OBJECTIVE: Retrograde aortic type A dissection (RTAD) is a known complication in patients with aortic type B dissection. The purpose of this computational fluid dynamics (CFD) study was to identify haemodynamic risk factors for the occurrence of RTAD. METHODS: Computed tomographic angiography (CTA) images of 10 patients with type B dissections, who subsequently developed a RTAD, were retrospectively analysed together with patients constituting a control group (n = 10) where no further vascular events after the initial type B dissection occurred. CFD simulations were conducted based on 3D surface models of the aortic lumen derived from CTA datasets. For both groups, pressures, velocity magnitudes and wall shear stress (WSS) were compared at the site of the future RTAD entry tear and the surrounding aortic wall. RESULTS: WSS at the site of the future entry tear was significantly elevated compared with the surrounding wall (15.10 Pa vs. 5.15 Pa, p < .001) and was significantly higher in the RTAD group than in the control group (6.05 Pa, p < .002). Pressures and velocity magnitudes were not significantly elevated at the entry tear (3825.8 Pa, 0.63 m/s) compared with the aortic arch (3549.8 Pa, 0.50 m/s) or control group (3501.7 Pa, 0.62 m/s). CONCLUSIONS: Increased WSS accompanies the occurrence of RTAD. The results merit the design for a prospective study to confirm whether WSS is a risk factor for the occurrence of RTAD. PMID- 28716449 TI - Venom-derived peptides inhibiting Kir channels: Past, present, and future. AB - Inwardly rectifying K+ (Kir) channels play a significant role in vertebrate and invertebrate biology by regulating the movement of K+ ions involved in membrane transport and excitability. Yet unlike other ion channels including their ancestral K+-selective homologs, there are very few venom toxins known to target and inhibit Kir channels with the potency and selectivity found for the Ca2+ activated and voltage-gated K+ channel families. It is unclear whether this is simply due to a lack of discovery, or instead a consequence of the evolutionary processes that drive the development of venom components towards their targets based on a collective efficacy to 1) elicit pain for defensive purposes, 2) promote paralysis for prey capture, or 3) facilitate delivery of venom components into the circulation. The past two decades of venom screening has yielded three venom peptides with inhibitory activity towards mammalian Kir channels, including the discovery of tertiapin, a high-affinity pore blocker from the venom of the European honey bee Apis mellifera. Venomics and structure-based computational approaches represent exciting new frontiers for venom peptide development, where re-engineering peptide 'scaffolds' such as tertiapin may aid in the quest to expand the palette of potent and selective Kir channel blockers for future research and potentially new therapeutics. This article is part of the Special Issue entitled 'Venom-derived Peptides as Pharmacological Tools.' PMID- 28716448 TI - Textile Aging Characterization on New Generations of Explanted Commercial Endoprostheses: A Preliminary Study. AB - OBJECTIVE/BACKGROUND: The goal of the present study was to assess the aging phenomena on second-generation textile endoprostheses (EPs) through explant analysis and to establish a preliminary classification of observed defects and material damages. METHODS: From January 2011 to June 2016 110 second- and recent generation EPs were collected as a part of a European collaborative retrieval program. The analysis focused on the first 41 consecutive commercial EPs collected between 2011 and 2014 and made from polyethylene terephthalate. Explants were submitted to a standardized evaluation protocol, which included data recording, eye-naked evaluation, cleaning of organic remnants, and structural analysis under numerical optical microscopy. Observations were reported using a classification based on 15 features evaluating the fabric, the stitches between the fabric and the stents, and the stents. The total surface area of the holes within the fabric was measured. RESULTS: EPs were implanted for thoracic and abdominal procedures in 12 and 29 cases, respectively. The mean +/- SD duration of implantation was 34 +/- 26 months (range 2 days-8 years). Sixty four percent of the samples demonstrated at least one defect caused by compression damage potentially related to the insertion of the EP within the delivery system, which promoted holes and tears. Ninety-five percent of all EPs demonstrated at least one type of abrasion on the stitches. The degradation of the stitches and the number of ruptures increased with duration of implantation. Stent degradation was rare and consisted of corrosion and rupture. Cumulated holed surface area increased with time and was measured up to 13.5 mm2. CONCLUSION: Various aging-related phenomena on commercial textile EPs were identified and classified. Main damaging mechanisms were related to compression and abrasion leading to tears and holes in the fabric and rupture of stitches. PMID- 28716450 TI - Moral cognition and homicide amongst forensic patients with schizophrenia and schizoaffective disorder: A cross-sectional cohort study. AB - Forensic patients with schizophrenia who had carried out a homicide scored higher on a measure of moral cognition (MFQ-30) than other violent patients. Neurocognitive impairment was associated with homicide by mediation via higher scores for in-group loyalty. PMID- 28716451 TI - Multidrug-resistant Pseudomonas aeruginosa lower respiratory tract infections in the intensive care unit: Prevalence and risk factors. AB - Intensive care unit (ICU) admission is a risk for multidrug-resistant (MDR) Pseudomonas aeruginosa, but factors specific to critically ill pneumonia patients are not fully characterized. Objective was to determine risk factors associated with MDR P. aeruginosa pneumonia among ICU patients. This was a retrospective case-control study of P. aeruginosa pneumonia in the ICU; cystic fibrosis and colonizers were excluded. Risk factors included comorbid conditions and prior healthcare exposure (anti-pseudomonal antibiotics, hospitalizations, nursing home, P. aeruginosa colonization/infection, mechanical ventilation). Of 200 patients, 47 (23.5%) had MDR P. aeruginosa pneumonia. Independent predictors for MDR were >=24h antibiotics in the preceding 90days (carbapenems, fluoroquinolones, and piperacillin-tazobactam) (odds ratio, 3.6 [95% CI, 1.6 8.1]) and nursing home residence (2.3 [1.1-4.9]). MDR P. aeruginosa remains prevalent among ICU patients with pneumonia. Given poor outcomes with delayed therapy, patients should be thoroughly assessed for prior anti-pseudomonal antibiotic exposure and nursing home residency. PMID- 28716452 TI - The proliferation of sexual health: Diverse social problems and the legitimation of sexuality. AB - Especially since the 1990s, the term sexual health has flourished in professional, commercial, and lay domains. Yet the more the phrase has become visible, the greater the mutability in its meanings. These developments matter for an understanding of healthism-the idea that modern individuals are enjoined to recognize a moral obligation to maximize their health. Theorists of healthism have paid relatively little attention to sexuality and its frequent rendering as controversial, illegitimate, or stigmatizing. We argue that because pairing "sexual" with "health" serves to legitimize and sanitize sexuality, the framing of sexual issues as matters of sexual health is widely appealing across multiple social arenas, and this appeal helps to explain both the proliferation of the term and the diversification of its uses. Secondly, we argue that while the polysemy of sexual health might suggest that the phrase lacks a clear meaning, in another sense the term is quite meaningful: content analysis of journal articles, newspaper articles, and websites shows that the semantics of sexual health can be categorized into six social problem niches, within which sexuality and health are construed in distinctive ways. For each social problem framing, we identify the implied meanings of both sexuality and health, the "opposite" of sexual health, the institutional action plans, the individual injunctions, and the presumed ontologies of bodies and selves. By focusing on how the conjoining of "sexual" and "health" changes the meanings of both terms, our analysis adds nuance to discussions of healthism: it challenges a singular conception of healthism and points to the need for clearer consideration of its different forms. At the same time, we call attention to the significance of "sexual healthism" as a particular example of the "will to health" while also highlighting implications of characterizing sexual issues as matters of health. PMID- 28716453 TI - The effects of whiteness on the health of whites in the USA. AB - Whites in the USA are the dominant racial group, with greater than average access to most material and social rewards. Yet, while whites have better outcomes than other racial groups on some health indicators, whites paradoxically compare poorly on other measures. Further, whites in the USA also rank poorly in international health comparisons. In this paper, we present a framework that combines the concept of whiteness-a system that socially, economically, and ideologically benefits European descendants and disadvantages people in other groups-with research from a variety of fields in order to comprehensively model the social factors that influence whites' health. The framework we present describes how whiteness and capitalism in the USA shape societal conditions, individual social characteristics and experiences, and psychosocial responses to circumstances to influence health outcomes. We detail specific examples of how social policies supported by whiteness, the narratives of whiteness, and the privileges of whiteness may positively and negatively affect whites' health. In doing so, we suggest several areas for future research that can expand our understanding of how social factors affect health and can contribute to the patterns and paradoxes of whites' health. By expanding research to include theoretically-grounded analyses of the dominant group's health, we can achieve a more complete picture of how systems of racial inequity affect health. PMID- 28716454 TI - A randomised trial of screening with digital breast tomosynthesis plus conventional digital 2D mammography versus 2D mammography alone in younger higher risk women. AB - INTRODUCTION: Digital breast tomosynthesis (DBT) has been shown to increase invasive cancer detection rates at screening compared to full field digital (2D) mammography alone, and some studies have reported a reduction in the screening recall rate. No prospective randomised studies of DBT have previously been published. This study compares recall rates with 2D mammography with and without concurrent DBT in women in their forties with a family history of breast cancer undergoing incident screening. MATERIALS AND METHODS: Asymptomatic women aged 40 49 who had previously undergone mammography for an increased risk of breast cancer were recruited in two screening centres. Participants were randomised to screening with 2D mammography only at the first study screen followed a year later by screening with 2D plus DBT, or vice versa. Recall rates were compared using an intention to treat analysis. Reading performance was analysed for the larger centre. RESULTS: 1227 women were recruited. 1221 first screens (604 2D, 617 2D+DBT) and 1124second screens (558 2D+DBT, 566 2D) were analysed. Eleven women had screen-detected cancers: 5 after 2D, 6 after 2D+DBT. The false positive recall rates were 2.4% for 2D and 2.2% for 2D+DBT (p=0.89). There was a significantly greater reduction between rounds in the number of women with abnormal reads who were not recalled after consensus/arbitration with 2D+DBT than 2D (p=0.023). CONCLUSION: The addition of DBT to 2D mammography in incident screening did not lead to a significant reduction in recall rate. DBT may increase reader uncertainty until DBT screening experience is acquired. PMID- 28716455 TI - The vitamin B6 paradox: Supplementation with high concentrations of pyridoxine leads to decreased vitamin B6 function. AB - Vitamin B6 is a water-soluble vitamin that functions as a coenzyme in many reactions involved in amino acid, carbohydrates and lipid metabolism. Since 2014, >50 cases of sensory neuronal pain due to vitamin B6 supplementation were reported. Up to now, the mechanism of this toxicity is enigmatic and the contribution of the various B6 vitamers to this toxicity is largely unknown. In the present study, the neurotoxicity of the different forms of vitamin B6 is tested on SHSY5Y and CaCo-2 cells. Cells were exposed to pyridoxine, pyridoxamine, pyridoxal, pyridoxal-5-phosphate or pyridoxamine-5-phosphate for 24h, after which cell viability was measured using the MTT assay. The expression of Bax and caspase-8 was tested after the 24h exposure. The effect of the vitamers on two pyridoxal-5-phosphate dependent enzymes was also tested. Pyridoxine induced cell death in a concentration-dependent way in SHSY5Y cells. The other vitamers did not affect cell viability. Pyridoxine significantly increased the expression of Bax and caspase-8. Moreover, both pyridoxal-5 phosphate dependent enzymes were inhibited by pyridoxine. In conclusion, the present study indicates that the neuropathy observed after taking a relatively high dose of vitamin B6 supplements is due to pyridoxine. The inactive form pyridoxine competitively inhibits the active pyridoxal-5'-phosphate. Consequently, symptoms of vitamin B6 supplementation are similar to those of vitamin B6 deficiency. PMID- 28716456 TI - Resveratrol inhibits IgE binding and down-regulates intracellular phosphorylation of Syk following IgE aggregation on human basophils. PMID- 28716458 TI - Talking about mediation in health and physical activity sciences. PMID- 28716457 TI - Interleukin-32 in chronic inflammatory conditions is associated with a higher risk of cardiovascular diseases. AB - Cardiovascular diseases (CVD) are the most frequent cause of death in developed countries. Their prevalence is higher in several chronic inflammatory conditions. This is likely due to the substantial contribution of the inflammatory status of the patients to the development and stability of atherosclerotic plaques. Recent evidence suggests that interleukin (IL)-32 may be involved in the conditions that contribute to CVD. IL-32 not only modulates important inflammatory pathways known to contribute to the pathogenesis of both inflammatory diseases and atherosclerosis, including tumor necrosis factor (TNF)alpha, IL-6 or IL-1beta, but it has been also suggested to modulate endothelial cell function and the serum concentration of high-density lipoprotein (HDL). In this review, we highlight the recent advances in the field of IL-32 in relation to chronic inflammatory disorders and argue for a role of IL-32 in the increased prevalence of CVD in these patients. PMID- 28716459 TI - Geographic Tongue. PMID- 28716460 TI - Ten Most Important Things to Know About Caring for Transgender Patients. AB - Transgender people have a gender that is not in agreement with their birth sex. Previous barriers, including lack of provider knowledge, have created significant healthcare disparities for this population. Recent societal changes are increasing the numbers of transgender people seen by primary care practitioners. Ten key principles are provided to help primary care practitioners create more welcoming environments and provide quality care to transgender patients. Overall, all members of the healthcare team (primary and specialty) need to become aware of the transition process and maintain communication regarding risks, benefits, and goals. Transwomen (aka male to female) can be treated with estrogens, antiandrogens, or a combination. Benefits include change in fat distribution, skin softening, and breast development. Significant risks for thrombosis from estrogens have been linked to genetic mutations, smoking, prolonged inactivity, and hormone formulation. Oral administration may provide increased risk over peripheral administration. Transmen (aka female to male) can be treated with peripheral testosterone preparations. Benefits include deepening of voice and development of facial and body hair with variable changes in muscle mass. Risks from testosterone appear to be less common than from estrogen. Laboratory monitoring can guide treatment decisions and provide early detection of some complications. Monitoring of "existing" anatomy (either hormonally or surgically created or removed) is an important component of healthcare for transgender patients. Primary care providers also should be aware of resources in their community and online, which can help patients optimize their transition. PMID- 28716461 TI - Chronic Diarrhea in a Traveler: Cyclosporiasis. PMID- 28716462 TI - Rapid identification of a Mycobacterium tuberculosis full genetic drug resistance profile through whole genome sequencing directly from sputum. AB - INTRODUCTION: Resistance to second-line tuberculosis drugs is common, but slow to diagnose with phenotypic drug sensitivity testing. Rapid molecular tests speed up diagnosis, but can only detect limited mutations. Whole genome sequencing (WGS) of culture isolates can generate a complete genetic drug resistance profile, but is delayed by the initial culture step. In the case presented here, successful WGS directly from sputum was achieved using targeted enrichment. CASE REPORT: A 29-year-old Nigerian woman was diagnosed with tuberculosis. Xpert MTB/RIF and Hain line probe assays identified rpoB and inhA mutations consistent with rifampicin and intermediate isoniazid resistance, and a further possible mutation conferring fluoroquinolone resistance. WGS directly from sputum identified a further inhA mutation consistent with high-level isoniazid resistance and confirmed the absence of fluoroquinolone resistance. Isoniazid was stopped, and the patient has completed 18 months of a fluoroquinolone-based regimen without relapse. DISCUSSION: Compared to rapid molecular tests (which can only examine a limited number of mutations) and WGS of culture isolates (which requires a culture step), WGS directly from sputum can quickly generate a complete genetic drug resistance profile. In this case, WGS altered the clinical management of drug-resistant tuberculosis and demonstrated potential for guiding individualized drug treatment where second-line drug resistance is common. PMID- 28716463 TI - Combination Strategies on the Basis of Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer: Where Do We Stand? AB - The era of immune checkpoint inhibitors, especially programmed death-1 (PD 1)/programmed death ligand-1 (PD-L1) antibodies in the treatment of advanced non small-cell lung cancer (NSCLC) is coming. Because of the lack of the definite biomarkers to select the optimal responders, only approximately 20% of patients with advanced NSCLC would respond to single checkpoint inhibitors-based immunotherapy. Moreover, primary or acquired resistance to conventional therapies is inevitable in most cases. Thus, combinations are pushed to move forward to be an alternative strategy and surely, it would be a future direction. Combination approaches on the basis of PD-1/PD-L1 inhibitors are currently designed to re energize the immune system with complementary/synergetic mechanisms and could achieve durable antineoplastic effects in NSCLC. Herein, we highlight the potential combinations on the basis of PD-1/PD-L1 inhibitors in NSCLC, with other immunotherapies, chemotherapy, radiotherapy, and targeted therapy in this current review. PMID- 28716464 TI - Modulating effects of omega-3 fatty acids and pioglitazone combination on insulin resistance through toll-like receptor 4 in type 2 diabetes mellitus. AB - Toll-like receptor 4 (TLR-4) plays important roles in innate immunity. Changes in the reduction-oxidation balance of tissues can lead to a pro-inflammatory state and insulin resistance. An action thought to be mediated by TLRs. Omega-3 fatty acids and Peroxisome Proliferator Activated Receptor gamma (PPAR-gamma) agonists as pioglitazone are used for decreasing inflammation. The aim of this study is to investigate the anti-diabetic effects of combining omega -3 fatty acid with pioglitazone on type 2 diabetes, and the modifying effects on TLR-4. Type 2 diabetes was induced in male Sprague-Dawley rats by combination of high fat diet and low dose streptozotocin (35mg/kg). Diabetic rats were treated with omega-3 fatty acids (10% W/W diet), pioglitazone (20mg/kg), and their combination for 4 weeks. Omega-3 fatty acids and the combination treatment significantly decreased TLR-4 activation. Omega-3 fatty acids, pioglitazone, and their combination significantly decreased TLR-4 mRNA expression, hepatic malondialdehyde, total cholesterol and triglycerides levels, compared to diabetic group. Pioglitazone and the combination significantly decreased blood glucose levels and improved insulin resistance. In conclusion, combining omega-3 fatty acids with pioglitazone showed potential effects in lowering blood glucose levels and improving lipid profile and insulin resistance. Such effects are mediated through modulation of TLR-4. PMID- 28716466 TI - Chronic low back pain patients walk with locally altered spinal kinematics. AB - Various studies have reported alterations of spinal kinematics in patients with chronic low back pain (CLBP) during gait. However, while recent findings stressed the importance of multi-segment analysis, most of prior gait studies modelled the lumbar spine as one segment, when it was not the entire trunk that was considered as a single segment. Therefore, there is a need for comprehensive multi-segment research that could improve our understanding of CLBP pathomechanism and thus possibly contribute to better care for CLBP. This study aimed at characterizing the angle patterns at the lower lumbar (LLS), upper lumbar (ULS), lower thoracic (LTS) and upper thoracic (UTS) joints in the three anatomical planes and at comparing CLBP patients and asymptomatic subjects. Spinal kinematics of 11 CLBP patients and 11 controls was measured using a marker-based motion capture system and described according to a previously proposed multi-segment biomechanical model. Characteristic patterns were observed at the UTS, LTS and ULS joints in the transverse plane and at the UTS, ULS and LLS joints in the frontal plane. CLBP patients walked with smaller frontal-plane LLS range of motion than controls. The results also suggested that patients had more asymmetrical LTS motion in the transverse plane. In conclusion, this work extended prior literature by showing specific CLBP-related alterations in multi-segment spinal kinematics during gait. Further research is necessary to understand the factors influencing kinematics alterations and how treatment strategies might improve motor behaviour in CLBP patients. PMID- 28716465 TI - Fibroblast-like synoviocyte mechanosensitivity to fluid shear is modulated by interleukin-1alpha. AB - Fibroblast-like synoviocytes (FLS) reside in the synovial membrane of diarthrodial joints and are exposed to a dynamic fluid environment that presents both physical and chemical stimuli. The ability of FLS to sense and respond to these stimuli plays a key role in their normal function, and is implicated in the alterations to function that occur in osteoarthritis (OA). The present work characterizes the response of FLS to fluid flow-induced shear stress via real time calcium imaging, and tests the hypothesis that this response is modulated by interleukin-1alpha (IL-1alpha), a cytokine elevated in OA. FLS demonstrated a robust calcium signaling response to fluid shear that was dose dependent upon stress level and required both external and internal calcium sources. Preconditioning with 10ng/mL IL-1alpha for 24h heightened this shear stress response by significantly increasing the percent of responding cells and peak magnitude, while significantly decreasing the time for a peak to occur. Intercellular communication via gap junctions was found to account for a portion of the FLS population response in normal conditions, and was significantly increased by IL-1alpha preconditioning. IL-1alpha was also found to significantly increase average length and incidence of the primary cilium, an organelle commonly implicated in shear mechanosensing. These findings suggest that the elevated levels of IL-1alpha found in the OA environment heighten FLS sensitivity to fluid shear by altering both intercellular communication and individual cell sensitivity, which could affect downstream functions and contribute to progression of the disease state. PMID- 28716467 TI - Clinically relevant potential drug-drug interactions among outpatients: A nationwide database study. AB - BACKGROUND: Adverse drug events due to drug-drug interactions (DDIs) represent a considerable public health burden, also in Slovenia. A better understanding of the most frequently occurring potential DDIs may enable safer pharmacotherapy and minimize drug-related problems. OBJECTIVES: The aim of this study was to evaluate the prevalence and predictors of potential DDIs among outpatients in Slovenia. METHODS: An analysis of potential DDIs was performed using health claims data on prescription drugs from a nationwide database. The Lexi-Interact Module was used as the reference source of interactions. The influence of patient-specific predictors on the risk of potential clinically relevant DDIs was evaluated using logistic regression model. RESULTS: The study population included 1,179,803 outpatients who received 15,811,979 prescriptions. The total number of potential DDI cases identified was 3,974,994, of which 15.6% were potentially clinically relevant. Altogether, 9.3% (N = 191,213) of the total population in Slovenia is exposed to clinically relevant potential DDIs, and the proportion is higher among women and the elderly. After adjustment for cofactors, higher number of medications and older age are associated with higher odds of clinically relevant potential DDIs. The burden of DDIs is highest with drug combinations that increase risk of bleeding, enhance CNS depression or anticholinergic effects or cause cardiovascular complications. CONCLUSION: The current study revealed that 1 in 10 individuals in the total Slovenian population is exposed to clinically relevant potential DDIs yearly. Taking into account the literature based conservative estimate that approximately 1% of potential DDIs result in negative health outcomes, roughly 1800 individuals in Slovenia experience an adverse health outcome each year as a result of clinically relevant potential interactions alone. PMID- 28716468 TI - Letter to the editor. PMID- 28716469 TI - Validated contraceptive knowledge assessment. PMID- 28716470 TI - Early or delayed reconstruction in multi-ligament knee injuries: A systematic review and meta-analysis. AB - BACKGROUND: Whether early or delayed surgical intervention in patients with multi ligament injuries results in better outcomes, is of current and controversial debate. PURPOSE: The purpose of this study was to perform a meta-analysis comparing early versus late surgical treatment of multi-ligament knee injuries. METHODS: We performed a systematic review of Medline, Embase, Scopus, and Google Scholar to identify relevant studies in the English and German literature. Eligibility criteria included studies comparing early or delayed surgical interventions for multi-ligament knee injuries, with a minimum follow-up of two years, reporting the primary clinical outcome using a validated functional scoring system and range of motion. Exclusion criteria were patients treated with multi-trauma, head injury, non-union, lower extremity fractures, or a documented history of previous knee injuries. Publication bias was assessed by funnel plot, and the risk of bias was established using the Cochrane Collaboration's risk of bias tool. Heterogeneity was assessed using chi2 and I2 statistic. RESULTS: Eight studies (n=260 patients) were included in the analysis. 149 patients were treated early with a mean of 10.6days; 111 patients were treated late with a mean of 294days. The pooled estimate for clinical outcome demonstrated that early surgery resulted in significantly higher Lysholm scores (SMD 0.669, 95% CI: 0.379 to 0.959, p=0.0001, I2=0%). Thirty-one per cent of all patients with early surgery had a normal or near normal knee, whereas only 15% of patients with late reconstruction reported the knee to be normal or near normal. The pooled estimates for total ROM did not demonstrate a significant difference between the groups (SMD 0.113, 95% CI: -0.271 to 0.498, p=0.564, I2=35.57%). CONCLUSIONS: The results of this meta-analysis suggest that early surgical intervention in multi ligament injuries of the knee produces a significantly superior clinical outcome, compared to late reconstruction. Although an overall trend of improved total range of knee motion was also demonstrated, this was very small and unlikely to be clinically relevant. LEVEL OF EVIDENCE: Level 4; Systematic review and meta analysis. PMID- 28716471 TI - Clinical significance of preoperative serum C-reactive protein in oral squamous cell carcinoma. AB - C-reactive protein (CRP) is an index of systemic inflammation. However, CRP is not usually assessed preoperatively. Hence the study intended to evaluate the preoperative serum CRP levels in oral squamous cell carcinoma (OSCC) patients and to analyse its relationship with the clinicopathologic characteristics. CRP values for 60 OSCCs and 30 healthy controls were evaluated using a CRP assessment kit and spectrophotometer. The Mann-Whitney U test, chi2 test, receiver operating characteristic (ROC) curve analysis, and logistic regression were applied. The CRP ranged from 0.3 to 86mg/L in OSCCs. CRP was significantly higher in OSCCs than in controls. A raised CRP was seen in 70% of OSCCs. CRP in OSCCs was associated with clinical nodal status and lymph node metastasis (LNM) (P<0.05). CRP was significantly higher in the metastatic than in the non-metastatic group. The area under the ROC was 0.819. The best cut-off value for predicting LNM was 8.65mg/L for the CRP with 0.767 sensitivity and 0.767 specificity (P<0.05). The cut-off revealed a significant association with LNM. Raised CRP may predict LNM. The CRP levels regressed significantly in relation to LNM. CRP could offer prognostic information beyond staging and histology. Hence, CRP can be added as an extension to known clinicopathologic parameters to predict the prognosis in OSCCs. PMID- 28716472 TI - The bone lid technique in oral surgery: a case series study. AB - The aim of this case series study was to illustrate the bone lid technique implemented using piezoelectric surgery to access mandibular alveolar bone diseases and to assess the clinical and radiographic outcomes. The technique was used to treat 21 consecutive patients with various conditions: cysts in six cases, impacted teeth with associated cysts in nine, keratocystic odontogenic tumours in three, impacted teeth in two, and an endodontic lesion in one. The bone lid was fashioned using piezoelectric surgery and a thin osteotomy insert. After the surgical procedure, the bone lid was replaced and fixed with miniplates. On clinical and radiological follow-up at 12 months, the outcome measures were bone lid integration and alveolar bone volume recovery. Any complications were also documented. The lesion and bone lid healed completely in 19 cases; one patient experienced permanent mild paresthesia and one experienced trauma-induced bone lid necrosis. Computed tomography volumetric analyses conducted on 11 cases indicated a mean recovery of 93.8% of the volume of bone lost. Based on healthy biological reasoning, the bone lid technique with piezoelectric surgery and rigid fixation may be considered a valid alternative to ostectomy for the purposes of bone tissue healing. PMID- 28716473 TI - Characteristics of mandibular injuries caused by bullets and improvised explosive devices: a comparative study. AB - The purpose of this study was to investigate the difference in mandibular trauma caused by two mechanisms for the delivery of missile injuries: firearms and improvised explosive devices (IEDs). The data investigated included sex, age, mechanism of injury, and other clinical and radiographic manifestations. Seventy consecutive patients, predominantly male, with a mean age of 28.6+/-14 years (range 2-60 years) were enrolled: 38 patients (54.3%) sustained mandibular fractures caused by bullet injuries and 32 patients (45.7%) had mandibular fractures caused by IED explosion injuries. The study revealed that the differences in most of the investigated variables were not statistically significant; the only significant differences were the incidence of trauma to other body regions and the presence of retained foreign bodies. The effect on the mandible of IED explosion resembles that of bullets. Bullet injuries are associated with a relatively higher number of mandibular sites involved and more bilateral fractures, in addition to more extensive bone loss. IEDs, on the other hand, cause more multisystem injuries and result in more retained foreign bodies. PMID- 28716474 TI - Cone beam computed tomography evaluation of midpalatal suture maturation in adults. AB - The aim of this study was to evaluate midpalatal suture maturation in adults, as observed in cone beam computed tomography (CBCT) images. CBCT scans from 78 subjects (64 female and 14 male, age range from 18 to 66 years) were evaluated. Midpalatal suture maturation was verified on the central cross-sectional axial slice in the superior-inferior dimension of the palate, using methods validated previously. Intra-examiner agreement was analyzed by weighted kappa test. Multinomial logistic regression was used to test whether sex and chronological age (adults <30 years or >=30 years) could be used as a predictor for the maturational stages of the midpalatal suture. The majority of the adults presented a fused midpalatal suture in the palatine (stage D) and/or maxillary bones (stage E). However, the midpalatal suture was not fused in 12% of the subjects. Sex and chronological age were not significant predictors of the maturational stages of the midpalatal suture. The individual assessment of midpalatal suture maturation by way of CBCT images may provide reliable information critical to making the clinical decision between rapid maxillary expansion and surgically assisted rapid maxillary expansion for the treatment of maxillary atresia in adults. PMID- 28716475 TI - Fouling assemblage of benthic plastic debris collected from Mersin Bay, NE Levantine coast of Turkey. AB - The Mediterranean is an ecosystem that faces more and more microplastic pollution every day. This causes the whole of the Mediterranean to face the negative effects of plastic pollution. This study examines the state of plastic debris and fouling organisms found on it in one of the areas most affected by plastic pollution, Mersin Bay. As a result, a total of 3.88kg plastic (mean=0,97kg; n=120; 2670item/km2; 86,3kg/km2) was collected and based on the ATR-FTIR analysis, it was determined that this total contained 9 types of plastics. 17 different fouling species belonging to 6 phylum (Annelida, Arthropoda, Bryozoa, Chordata, Cnidaria, Mollusca) 7 class and 11 order were discovered on plastics. Spirobranchus triqueter, Hydroides sp. and Neopycnodonte cochlear were the most abundant species. In the end, the example of Mersin Bay shows that plastic debris as a substrate can contain a very high diversity of life just like natural substrates. PMID- 28716476 TI - Influence of polycyclic aromatic hydrocarbons on nitrate reduction capability in mangrove sediments. AB - In the present study, we investigated the influence of phenanthrene (PHE), a three-ring polycyclic aromatic hydrocarbon (PAH) compound, on nitrate (NO3-) reduction processes in mangrove sediments using microcosms. After 10days, nitrate/nitrite reductase activity and abundance of narG and nirS significantly decreased in the bulk sediment at both 10/50mgPHEkg-1 contamination groups. In the rhizosphere, abundance of narG, nirS and nirK markedly declined at PHE treated sediments, while the drop in reductase activity at 10mgkg-1 PHE treatment was insignificant. After 50days, apart from 10mgPhekg-1 treated bulk sediment, abundance of denitrifiers and reductase activity in all PHE spiked sediment samples significantly dropped. Therefore, the influence of PAHs on NO3- reduction capability in mangrove sediments is dependent on spiked concentration, temporal scale of exposure and interaction with roots. Generally, PAHs play an inhibitor role, slowing NO3- turnover rates, which warrant attention from coastal managers. PMID- 28716477 TI - 2017 AHA/ACC Key Data Elements and Definitions for Ambulatory Electronic Health Records in Pediatric and Congenital Cardiology: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Data Standards. PMID- 28716478 TI - [Evaluation of practices and costs of vasectomy. French monocentric experience]. AB - INTRODUCTION: Since the law of 4 July 2001, vasectomy has been recognized as a method of male contraception. We report the experience of vasectomy practice in a hospital-university center. METHODS: A monocentric retrospective cohort study of 45 patients who benefited from a contraceptive vasectomy between July 2001 and May 2016. For each patient were studied: modalities of implementation, compliance with the recommendations of the 2001 law, costs and benefits generated by the intervention, the effectiveness of the gesture on the control spermograms, the satisfaction of the patients by a telephone questionnaire. RESULTS: The mean age was 41.3 years. The second consultation was carried out in 91 % of the cases but the reflection period was not respected in 24 % of the cases. Written consent was signed in 89 % of cases. Vasectomy was performed on an outpatient basis in 73 % of cases, under local anaesthesia in 6.7 % of cases. The average cost per patient was 660.63 euros for an average gain of 524.50 euros, a loss of 136.13 euros. On the control spermogram, 54.3 % were azoosperms but the 3-month delay was not observed in 23 % of them. No patients expressed regret after surgery. CONCLUSION: The recommendations of the 2001 law were not systematically followed. This lack of standardization of practices, potential reflection of a lack of interest, is to be highlighted with the extra cost generated. The revaluation of the act should be integrated into the reflection of improvement of male sterilization practices. LEVEL OF PROOF: 4. PMID- 28716479 TI - Lower exhaled nitric oxide in infants with Cystic Fibrosis compared to healthy controls. AB - Exhaled nitric oxide (FENO) is a well-known, non-invasive airway biomarker. In patients with Cystic Fibrosis (CF) FENO is decreased. To understand if reduced FENO is primary related to Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) dysfunction or an epiphenomenon of chronic inflammation, we measured FENO in 34 infants with CF prior to clinical symptoms and in 68 healthy controls. FENO was lower in CF compared to controls (p=0.0006) and the effect was more pronounced in CF infants without residual CFTR function (p<0.0001). This suggests that FENO is reduced in CF early in life, possibly associated with underlying CFTR dysfunction. PMID- 28716480 TI - Max Lab at heart. PMID- 28716481 TI - [Disseminated nocardiosis caused by Nocardia nova with brain abscesses and osteomyelitis in an immunocompetent patient]. AB - INTRODUCTION: Nocardia is an opportunist bacteria involved in patients with cellular immunodepression or chronic lung disease. The most frequent portals of entry are the respiratory tract by inhalation or direct inoculation through a cutaneous effraction. Nocardiosis may be localised or disseminated. CASE REPORT: We report a rare case of disseminated nocardiosis to Nocardia nova with pulmonary, cutaneous, cerebral attacks and femoral osteomyelitis. The diagnosis was confirmed by prolonged cultures of the bronchoalveolar fluid and the pus extracted from a cutaneous lesion. The outcome was favorable under adapted and prolonged antibiotherapy with imipenem and amikacine and then cotrimoxazole. CONCLUSION: This observation is original because it involves a immunocompetent patient with an association of two exceptional locations for N. nova: brain abscesses and femoral osteomyelitis. Screening for cerebral involvement should be systematic, even in the lack of neurological signs. An adapted and prolonged antibiotherapy must be conducted. PMID- 28716482 TI - [Respiratory distress of unusual cause]. PMID- 28716483 TI - Clinically relevant fungi in water and on surfaces in an indoor swimming pool facility. AB - The density of fungal contamination and the fungal diversity in an indoor swimming pool facility were assessed. A total of 16 surface samples and 6 water samples were analysed by using a combination of different (semi-) selective culture media. Isolated fungal colonies were identified to the genus or species level by sequencing of the internal transcribed spacer (ITS). The highest fungal counts in water and on surfaces were in the recreational pool (17CFU/100mL) and on a flexibeam (5.8CFU/cm2), respectively as compared with low counts (<0.1CFU/cm2) on the diving platform, bench tops and walls. The 357 obtained isolates belonged to 79 species and species complexes, 42 of which known as clinically relevant. Phialophora oxyspora (13.7%) and Phoma spp. (12.3%) were the most frequently identified groups. We demonstrated that despite chlorine treatment and regular cleaning of surfaces both water and surfaces were commonly infested with fungi, including many clinically relevant species. PMID- 28716484 TI - The anti-tumor activity of the STAT3 inhibitor STX-0119 occurs via promotion of tumor-infiltrating lymphocyte accumulation in temozolomide-resistant glioblastoma cell line. AB - STAT3 is considered to be a key molecule to mediating tumor-induced immunosuppression in various manners at tumor sites, by acting through immune regulatory cytokines derived from the tumor cells. Specific anti-STAT3 inhibitors have been developed using nude mouse models transplanted with human tumor cells. However, mouse systems cannot accurately represent the human immune response induced by STAT3 inhibitors, and more humanized therapeutic model based on human immune cells and tumors are needed. In the present study, an immune-deficient NOG mouse with the deletion of both MHC-class I and class II genes, an MHC-double knockout mouse (dKO-NOG), was developed and used to establish humanized immunotherapeutic model. We investigated the immunological effect of the STAT3 inhibitor STX-0119 against TMZ-resistant (TMZ-R) U87 glioma tumors by using humanized dKO-NOG mice. We compared the anti-tumor effects of STX-0119 between the nude and humanized dKO-NOG mouse models. An in vivo study using the nude mouse model showed that STX-0119 inhibited the growth of TMZR U87 tumors, but accumulation of tumor-infiltrating lymphocytes (TILs) were not promoted compared with the control levels. In contrast, STX-0119 inhibited tumor growth more rapidly and strongly in humanized dKO-NOG mice than in nude mice, and a large amount of TILs, mainly consisting of CD8+ T cells and macrophages, were found in the tumors. These results suggest that STX-0119 has anti-tumor activity occurring through the promotion of TIL accumulation at the tumor site and that humanized dKO-NOG mouse system may be a powerful tool to evaluate the effects of STAT3 inhibitors on human systems. PMID- 28716485 TI - Fatalism and educational disparities in beliefs about the curability of advanced cancer. AB - OBJECTIVE: Understanding socioeconomic disparities in the care of patients with incurable cancer is a high priority. We hypothesized that patients without a high school education are more likely to believe that they could be cured and we explored the role of fatalism. METHODS: We studied 977 patients with advanced, incurable cancer. Two logistic regression analyses were conducted. Model One examined the effect of education on beliefs about curability. Model Two added fatalism. RESULTS: The significant association between having less than a high school education and the belief that advanced cancer can be cured (OR=2.55; 95% CI: 1.09-5.96) in Model One was attenuated by 39% and rendered nonsignificant in Model Two. Fatalism was associated with the belief that advanced cancer can be cured. Whites were less likely to believe they could be cured than Blacks and Asians/Pacific Islanders. Beliefs about curability were not associated with income or insurance status. CONCLUSIONS: People who do not complete high school are more likely to believe that their advanced cancer is curable, in part because they are more likely to hold fatalistic worldviews. PRACTICE IMPLICATIONS: Interventions to help oncologists care for patients with fatalistic beliefs could mitigate socioeconomic disparities in end-of-life care. PMID- 28716487 TI - Student Acceptance of Plain Milk Increases Significantly 2 Years after Flavored Milk Is Removed from School Cafeterias: An Observational Study. AB - BACKGROUND: Previous studies document decreases in lunchtime milk consumption immediately after flavored milk is removed. Less is known about longer-term effects. OBJECTIVE: Plain milk selection and consumption were measured the first year flavored milk was removed in a school district (2010 to 2011 [Time 1]) and 2 years later (2012 to 2013 [Time 2]). Four behavioral economic interventions to promote milk were tested in one school at Time 2. DESIGN: This was a longitudinal, observational study. PARTICIPANTS/SETTING: Participants were kindergarten through grade 8 students in two schools in an urban district. Primary data were collected 10 times per school year at Time 1 and Time 2, yielding 40 days of data and 13,883 student observations. The milk promotion interventions were tested on 6 additional days. MAIN OUTCOME MEASURES: Outcomes were the percentage of students selecting milk at lunch, the ounces of milk consumed per carton, and the ounces of milk consumed school-wide per student. STATISTICAL ANALYSES: Logistic regressions were used to assess how sex, grade, time, availability of 100% juice, and behavioral interventions affected milk selection and consumption. RESULTS: At Time One, 51.5% of students selected milk and drank 4 oz (standard deviation=3.2 oz) per carton, indicating school-wide per student consumption of 2.1 oz (standard deviation=3.0 oz). At Time Two, 72% of students selected milk and consumed 3.4 oz per carton (standard deviation=3.2 oz), significantly increasing the school-wide per-student consumption to 2.5 oz (standard deviation=3.1 oz). Older students and boys consumed significantly more milk. Availability of 100% fruit juice was associated with a 16-percentage point decrease in milk selection. None of the behavioral economic interventions significantly influenced selection. CONCLUSIONS: These data suggest that after flavored milk is removed from school cafeterias, school-wide per-student consumption of plain milk increases over time. In addition, the presence of 100% juice is associated with lower milk selection. PMID- 28716486 TI - The impact of a peer support group for children with rheumatic heart disease in Uganda. AB - OBJECTIVE: To assess the impact of a peer-support group on knowledge, quality of life, and social support for children with rheumatic heart disease (RHD). METHODS: Children diagnosed with RHD and receiving 4-weekly injectable penicillin were invited to participate in a monthly support group for 6 months. Pre- and post-intervention assessments included a baseline RHD knowledge assessment, a measure of health related quality of life (HRQOL) (PedsQLTM4.0), and a measure of social support (Hawthorne Friendship Scale). Groups incorporated elements of cooperative play and team building, RHD education, and emotional support. RESULTS: 42 participants attended >=3 groups and were included in the analyses. Attending support groups resulted in increased total HRQOL scores (60.3v 70.2, p<0.001), as well as the following HRQOL sub-scores (physical functioning 55.3v 68.6 (p<0.001), social functioning 64.2v 75.8 (p<0.001) and school functioning 59.2v 69.1 (p=0.001)). Significant increases in Friendship Scale scores (15.4v 19.7, p<0.001) and RHD Knowledge scores were observed (3.6v 6.4, p<0.001). CONCLUSIONS: Peer-support groups may be effective at normalizing decreased HRQOL scores and increasing RHD disease knowledge and social support. PRACTICAL IMPLICATIONS: Peer-support groups implemented in conjunction with RHD screening can minimize the negative psychosocial effects associated with early RHD detection. PMID- 28716488 TI - Simultaneous anaerobic transformation of carbon tetrachloride to carbon dioxide and tetrachloroethene to ethene in a continuous flow column. AB - The simultaneous anaerobic transformation of tetrachloroethene (PCE) and carbon tetrachloride (CT) was evaluated in a continuous flow column. The column was packed with quartz sand and bioaugmented with the Evanite culture (EV) that is capable of transforming PCE to ethene. Azizian and Semprini (2016) reported that PCE and CT could be simultaneously transformed in the column, with PCE (0.1mM) transformed mainly to ethene and CT (0.015mM) to chloroform (CF) (20%) and an unknown transformation product, likely carbon dioxide (CO2). The fermentation of propionate, formed from lactate fermentation, was inhibited after the transformation of CT, likely from the exposure to CF. Reported here is the second phase of that study where a second bioaugmentation of the EV culture was made to reintroduce a lactate and propionate fermenting population to the column. Effective lactate and propionate fermentation were restored with a H2 concentration of ~25nM maintained in the column effluent. PCE (0.1mM) was effectively transformed to ethene (~98%) and vinyl chloride (VC) (~2%). Unlabeled CT (0.015 to 0.03mM) was completely transformed with a transient build-up of CF and chloromethane (CM), which were subsequently removed below their detection limits. A series of transient tests were initiated through the addition of carbon 13 labeled CT (13CT), with concentrations gradually increased from 0.03 to 0.10mM. GC-MS analysis of the column effluent showed that 13C labeled CO2 (13CO2) was formed, ranging from 82 to 93% of the 13CT transformed, with the transient increases in 13CO2 associated with the increased concentration of 13CT. A modified COD analysis indicated a lesser amount of 13CT (18%) was transformed to soluble products, while 13CO2 represented 82% the 13CT transformed. In a final transient test, the influent lactate concentration was decreased from 1.1 to 0.67mM. The transformation of both CT and PCE changed dramatically. Only 59% of the 13CT was transformed, primarily to CF. 13CO2 concentrations gradually decreased to background levels, indicating CO2 was no longer a transformation product. PCE transformation resulted in the following percentage of products formed: cDCE (60%), VC (36%), and ethene (4%). Incomplete propionate fermentation was also observed, consistent with the build-up of CF and the decrease in H2 concentrations to approximately 2nM. The results clearly demonstrate that high concentrations of CT were transformed to CO2, and effective PCE dehalogenation to ethene was maintained when excess lactate was fed and propionate was effectively fermented. However, when the lactate concentration was reduced, both PCE and CT transformation and propionate fermentation were negatively impacted. PMID- 28716489 TI - [J. Boujenah and B. Carbonne in answer to the article by H. Madar et al.: For a targeted use of aspirin. Gynecol Obstet Fertil Senol 2017;45:224-30]. PMID- 28716490 TI - [Self-evaluation of conization indications since the introduction of the French colposcopy and cervico-vaginal pathology quality charter in 2 colposcopy centers]. AB - OBJECTIVES: Analyze the efficiency of the implementation of the colposcopy and cervico-vaginal pathology quality charter. The question was to determine whether the criteria of more than 70% of excisional conizations containing CIN2+ lesions (cervical intraepithelial neoplasia 2 or 3 or carcinoma in situ) had been reached and demonstrate a reduction of the conization rate is possible. METHODS: An epidemiological descriptive, retrospective and multicenter study was performed in "Nord Franche-Comte Hospitals" (Belfort and Montbeliard, France) during the period from November 2013 to January 2015. Inclusion criteria were patients over 25 years undergoing cervical excisions for diagnostic and/or therapeutic purposes after Pap smear screening followed by colposcopically directed biopsies. The files were selected from a data collection and studied using the computerized patient record. RESULTS: In total, 116 conizations were performed: 103 by four French Society of Colposcopy and Cervico-Vaginal Pathology (SFCPCV) members and 13 by four SFCPCV non-members. The overall result of the primary outcome showed 53% of CIN2+ lesions found in cervical conization specimens, which can be broken down to 55% for the group of SFCPCV members and to 38% for the group of SFCPCV non-members. The statistical analysis indicates a significant difference (P=0.02) in the percentage of CIN2+ lesions discovered on the surgical specimen for the group of SFCPCV members. CONCLUSIONS: This self-evaluation shows that it is essential to be a SFCPCV member and to adhere to the charter. By complying with the charter and associating the new National Cancer Institute recommendations (December 2016), it is possible to reduce the conization rate and even to surpass the target of more than 70% of excisional conizations containing CIN2+ lesions. PMID- 28716491 TI - [Regression of vaccine coverage HPV: A French exception]. PMID- 28716492 TI - Unusual presenting manifestation of a rare polyposis, Cowden syndrome. PMID- 28716493 TI - Chemical screening and development of novel gibberellin mimics. AB - Gibberellin (GA) plays versatile roles in the regulation of plant growth and development and therefore is widely used as a regulator in agriculture. We performed a chemical library screening and identified a chemical, named 67D, as a stimulator of seed germination that was suppressed by paclobutrazol (PAC), a GA biosynthesis inhibitor. In vitro binding assays indicated that 67D binds to the GID1 receptor. Further studies on the structure-activity relationship identified a chemical, named chemical 6, that strongly promoted seed germination suppressed by PAC. Chemical 6 was further confirmed to promote the degradation of RGA (for repressor of ga1-3), a DELLA protein, and suppress the expression levels of GA3ox1 in the same manner as GA does. 67D and its analogs are supposed to be agonists of GID1 and are expected to be utilized in agriculture and basic research as an alternative to GA. PMID- 28716494 TI - Synthesis and in vitro antiproliferative activities of (5-aryl-1,2,4-oxadiazole-3 yl) methyl d-ribofuranosides. AB - The emergence of multidrug resistance cell lines is one of the major obstacles in the success of cancer chemotherapeutic treatment. Therefore, it remains a big challenge the development of new and effective drugs to defeat cancer. The presence of nitrogen heterocycles in the architectural design of drugs has led to the discovery of new leading compounds. Herein, we report the synthesis, characterization and in vitro antiproliferative activity against six cancer cell lines of d-ribofuranoside derivatives bearing a 1,2,4-oxadiazolic ring, with the aim of developing new active compounds. Most of these derivatives exhibit significant antiproliferative activities in the micromolar range. Noteworthy, the most potent compound of the series showed better selectivity towards the more resistant colon cancer cell line WiDr. PMID- 28716495 TI - 3,5-Bis(3-dimethylaminomethyl-4-hydroxybenzylidene)-4-piperidone and related compounds induce glutathione oxidation and mitochondria-mediated cell death in HCT-116 colon cancer cells. AB - This study aims at investigating the cytotoxicity and some of the modes of action of 3,5-bis(3-dimethylamino-4-hydroxybenzylidene)-4-piperidone trihydrochloride 3 and two related compounds 2 (which lacks the dimethylaminomethyl groups) and 4 (which has an additional dimethylaminoethyl substituent in both aryl rings) in order to ascertain the contribution of dimethylaminoethyl substituent to bioactivity. The bioactivities of 2-4 were compared with curcumin 5. Both 2 and 3 displayed submicromolar GI50 values towards HCT-116 cells and were significantly more potent than 4, 5 and 5-fluorouracil (5-FU). All of the compounds displayed greater toxicity towards HCT-116 cells than human CRL-1790 non-malignant colon cells. In HCT-116 cells, the compounds 2, 3 and 5 increased the ratio of oxidised to reduced glutathione and destabilized the mitochondrial membrane potential. Both 2 and 5 produced an increase in mitochondrial superoxide and a burst in intracellular reactive oxygen species in HCT 116 cells. In addition, 2 and 4 stimulated respiration in rat liver mitochondria while 2 and 5 induced mitochondrial swelling. The results suggest that 2 and 5 cause oxidation or cross linking of the thiols which control the mitochondrial permeability transition. PMID- 28716496 TI - Corrigendum to "Surrogacy of progression free survival for overall survival in metastatic breast cancer studies: Meta-analyses of published studies" [Contemp. Clin. Trials 53 (2017) 20-28]. PMID- 28716497 TI - Dual-energy X-ray Absorptiometry. AB - Bone mineral density (BMD) measurement by dual-energy X-ray absorptiometry (DXA) is the most commonly used method to assess fracture risk. DXA utilizes two different energy X-rays to calculate BMD and, by comparison to a young normative database, the T-score. In 1994, the World Health Organization defined osteoporosis based on T-score, changing the paradigm of the field and forever placing DXA measurements in the center of osteoporosis diagnosis. Since then, many large studies have demonstrated the predictive value of BMD by DXA-for every standard deviation decline in BMD, there is a relative risk of 1.5-2.5 for fracture. This predictive ability is similar to how blood pressure can predict myocardial infarction. Limitations of DXA are also important to consider. While BMD by DXA can identify those at risk, there is a significant overlap in the BMD of patients who will and will not fracture. Special considerations are also needed in men and ethnic minority groups. These groups may have different bone size, thus affecting the normative range of BMD, and/or distinct bone structure that affect the association between BMD and fractures. Finally, BMD can be affected by positioning errors or artifacts, including osteoarthritis, fracture, and jewelry. Of course, DXA has tremendous strengths as well-namely its wide availability, its low radiation exposure, and a large body of evidence that relate DXA measurements to fracture risk. For these reasons, DXA remains the cornerstone of fracture assessment now and for the foreseeable future. PMID- 28716498 TI - Bone Turnover Markers: Use in Fracture Prediction. AB - Bone turnover markers (BTMs) provide us with a noninvasive approach to studying bone turnover and they can be measured easily and with good precision, especially using automated analyzers. BTMs increase at menopause, and these higher levels are associated with more rapid bone loss. In some but not all studies, they are also associated with greater risk of fracture. However, the evidence base for use as predictors of fracture is not robust, and so BTMs have not been included in fracture prediction models. Further research is needed, and this might include (1) use of reference analytes such as C-telopeptide of type I collagen and procollagen I N-propeptide, measured using automated analyzers in subjects in the fasting state on more than 1 occasion; (2) careful collection of vertebral fractures, which would be the primary endpoint; and (3) common approach to statistical analyses with results expressed as hazard ratio per standard deviation of increase in BTM. We believe that by improving our approach to studying the relationship between BTMs and fracture risk, any association will become clearer and that in the future we might then be able to include BTMs in our fracture prediction models. PMID- 28716499 TI - Fracture Risk Assessment in Patients With Diabetes Mellitus. AB - Diabetes mellitus, both type 1 and type 2 (T2DM), is associated with decreased bone strength as well as increased fracture risk. Bone mineral density is decreased in type 1 diabetes but increased in T2DM, compared with controls. This suggests alterations in bone quality are a major player in the pathogenesis of fragility fractures in patients with diabetes. The link between diabetes and bone appears to be mediated by complex pathways, including the insulin-insulin growth factors system, accumulation of advanced glycation end-products in bone collagen, microangiopathy, and increased bone marrow fat content. Bone fragility in T2DM, which is not reflected by bone mineral density and bone mass reduction, depends on deterioration of bone quality. Also, at least in T2DM, the classical diagnosis of osteoporosis by dual-energy X-ray absorptiometry and the fracture risk estimation by FRAX (fracture risk assessment tool) are only partially useful in assessing fracture risk. Trabecular bone score and trabecular bone score-adjusted FRAX offer an enhanced estimation of fracture risk in these patients. Specific risk stratification criteria are needed in the future. The development of improved methods to assess the material properties of bone to better characterize fracture risk is also a priority. Adequate glycemic control is generally associated with decreased fracture risk, with the exception of specific antidiabetics (thiazolidinediones, canagliflozin) that have been shown to have a detrimental effect. Most currently used antiosteoporotic treatments seem equally effective in diabetic patients as compared with patients without diabetes, but clinical data regarding the reduction in fracture risk specifically in patients with diabetes mellitus are lacking. PMID- 28716501 TI - High incidence of recess formation at myopectineal orifice during laparoscopic surgery. AB - BACKGROUND: Groin hernias are frequently seen in clinical practice. The purpose of this study was to determine the rate of patients who might have latent groin hernia. METHODS: During laparoscopic abdominal surgery, we observed the area around the groin lesion and attempted to evaluate the degree of recess at myopectineal orifice. The classification defining the recess was as follows: Grade 0: no recess, Grade I: slight recess with a visible bottom, Grade II: deep recess with an invisible bottom, Grade III: other organ invaginated into the recess, and Grade IV: confirmed bulging on the body surface. RESULTS: From 2009 to 2011, 46 patients were enrolled. A recess around myopectineal orifice were detected in 20 patients. The lesions were as follows: 11 on the lateral side of the inferior epigastric artery (IEA), five on the internal side of the IEA, three at both sites and one found at the femoral ring. According to the grade classification of these groin hernias, 26 (57%) were Grade 0, 14 (30%) Grade I, 4 (9%) Grade II, 1 (2%) Grade III, and 1 (2%) Grade IV. CONCLUSIONS: This study showed that rate of patients with asymptomatic latent groin hernias is relatively high in Japanese. PMID- 28716500 TI - Overview of Fracture Prediction Tools. AB - The characterization of risk factors for fracture that contribute significantly to fracture risk, over and above that provided by the bone mineral density, has stimulated the development of risk assessment tools. The more adequately evaluated tools, all available online, include the FRAX(r) tool, the Garvan fracture risk calculator and, in the United Kingdom only, QFracture(r). Differences in the input variables, output, and model construct give rise to marked differences in the computed risks from each calculator. Reasons for the differences include the derivation of fracture probability (FRAX) rather than incidence (Garvan and QFracture), limited calibration (Garvan), and inappropriate source information (QFracture). These differences need to be taken into account in the evaluation of assessment guidelines. PMID- 28716502 TI - Crystalline Polymorphism Emerging From a Milling-Induced Amorphous Form: The Case of Chlorhexidine Dihydrochloride. AB - In this paper, solid-state amorphization induced by mechanical milling is shown to be a useful tool to explore the polymorphism of drugs and their mechanism of devitrification. We show in particular how the recrystallization of amorphous chlorhexidine dihydrochloride obtained by milling reveals a complex polymorphism that involves several polymorphic forms. Two new crystalline forms are identified, one of them appearing as a highly disordered precursor state which however clearly differs from the amorphous one. Several interpretations are here proposed to describe the puzzling nature of this phase. In addition, the possibility to amorphize chlorhexidine dihydrochloride by milling allowed to determine the main physical characters of the amorphous state which cannot be obtained through the usual thermal quench of the liquid because of a strong chemical degradation occurring on melting. PMID- 28716503 TI - Effectiveness of Otolith Repositioning Maneuvers and Vestibular Rehabilitation exercises in elderly people with Benign Paroxysmal Positional Vertigo: a systematic review. AB - INTRODUCTION: Benign Paroxysmal Positional Vertigo is highly prevalent in elderly people. This condition is related to vertigo, hearing loss, tinnitus, poor balance, gait disturbance, and an increase in risk of falls, leading to postural changes and quality of life decreasing. OBJECTIVE: To evaluate the outcomes obtained by clinical trials on the effectiveness of Otolith Repositioning Maneuver and Vestibular Rehabilitation exercises in the treatment of Benign Paroxysmal Positional Vertigo in elderly. METHODS: The literature research was performed using PubMed, Scopus, Web of Science and PEDro databases, and included randomized controlled clinical trials in English, Spanish and Portuguese, published during January 2000 to August 2016. The methodological quality of the studies was assessed by PEDro score and the outcomes analysis was done by critical revision of content. RESULTS: Six studies were fully reviewed. The average age of participants ranged between 67.2 and 74.5 years. The articles were classified from 2 to 7/10 through the PEDro score. The main outcome measures analyzed were vertigo, positional nystagmus and postural balance. Additionally, the number of maneuvers necessary for remission of the symptoms, the quality of life, and the functionality were also assessed. The majority of the clinical trials used Otolith Repositioning Maneuver (n=5) and 3 articles performed Vestibular Rehabilitation exercises in addition to Otolith Repositioning Maneuver or pharmacotherapy. One study showed that the addition of movement restrictions after maneuver did not influence the outcomes. CONCLUSION: There was a trend of improvement in Benign Paroxysmal Positional Vertigo symptomatology in elderly patients who underwent Otolith Repositioning Maneuver. There is sparse evidence from methodologically robust clinical trials that examined the effects of Otolith Repositioning Maneuver and Vestibular Rehabilitation exercises for treating Benign Paroxysmal Positional Vertigo in the elderly. Randomized controlled clinical trials with comprehensive assessment of symptoms, quality of life, function and long-term follow up are warranted. PMID- 28716504 TI - Series: Pragmatic trials and real world evidence: Paper 8. Data collection and management. AB - Pragmatic trials can improve our understanding of how treatments will perform in routine practice. In a series of eight papers, the GetReal Consortium has evaluated the challenges in designing and conducting pragmatic trials and their specific methodological, operational, regulatory, and ethical implications. The present final paper of the series discusses the operational and methodological challenges of data collection in pragmatic trials. A more pragmatic data collection needs to balance the delivery of highly accurate and complete data with minimizing the level of interference that data entry and verification induce with clinical practice. Furthermore, it should allow for the involvement of a representative sample of practices, physicians, and patients who prescribe/receive treatment in routine care. This paper discusses challenges that are related to the different methods of data collection and presents potential solutions where possible. No one-size-fits-all recommendation can be given for the collection of data in pragmatic trials, although in general the application of existing routinely used data-collection systems and processes seems to best suit the pragmatic approach. However, data access and privacy, the time points of data collection, the level of detail in the data, and the lack of a clear understanding of the data-collection process were identified as main challenges for the usage of routinely collected data in pragmatic trials. A first step should be to determine to what extent existing health care databases provide the necessary study data and can accommodate data collection and management. When more elaborate or detailed data collection or more structured follow-up is required, data collection in a pragmatic trial will have to be tailor-made, often using a hybrid approach using a dedicated electronic case report form (eCRF). In this case, the eCRF should be kept as simple as possible to reduce the burden for practitioners and minimize influence on routine clinical practice. PMID- 28716505 TI - alpha-Methyltyrosine, a tyrosine hydroxylase inhibitor, decreases stress response in zebrafish (Danio rerio). AB - In this article, we show that the tyrosine hydroxylase inhibitor alpha-Methyl-l tyrosine (AMPT) decreased the responsiveness of the zebrafish stress axis to an acute stressful challenge. These effects were specific for responses to stimulation, since unstimulated (basal) cortisol levels were not altered by AMPT. Moreover, AMPT decreased the stress response 15min after stimulation, but not after that time period. To our knowledge, this is the first report about the effects of AMPT on the neuroendocrine axis of adult zebrafish in acute stress responses. Overall, these results suggest a mechanism of catecholamine glucocorticoid interplay in neuroendocrine responses of fish, pointing an interesting avenue for physiological research, as well as an important endpoint that can be disrupted by environmental contamination. Further experiments will unravel the mechanisms by which AMPT blocked the cortisol response. PMID- 28716506 TI - How to prevent burnout in cardiologists? A review of the current evidence, gaps, and future directions. AB - Burnout is rising in all physicians, and cardiologists are not an exemption. Cardiology is a very popular specialty among medical students as it is associated with outstanding training standards and high prestige and income. In this review, we critically summarize the evidence on consequences, causes, and evidence-based interventions for burnout with a view toward recommending the best strategies for promoting wellness in cardiologists. Only a handful of studies have examined burnout specifically in cardiologists. Evidence therefore was mainly extrapolated by larger studies in all physicians and other physician specialties. Burnout in cardiologists has serious negative personal and professional consequences and is associated with suboptimal healthcare outcomes for patients. Burnout in cardiologists is primarily driven by professional and healthcare system demands and inefficiencies such as excessive workload and role complexity, training and certification demands, inefficient compensation models and lack of resources, computerization, and loss of autonomy. Moreover, loss of connectedness with patients, difficulties in balancing work and personal life and overvaluing compulsiveness and perfectionism in medical practice further increase the risk for burnout. Burnout among cardiologists may be best mitigated by organizational strategies complemented by individual stress reduction and reflection techniques under the resilience-based approach. Large-scale strategies are needed to mitigate burnout and promote physician wellness as a shared responsibility of healthcare systems and individuals and be committed in creating a new culture in medicine. PMID- 28716507 TI - A novel topoisomerase 2a inhibitor, cryptotanshinone, suppresses the growth of PC3 cells without apparent cytotoxicity. AB - DNA topoisomerase 2, which is ubiquitously expressed in eukaryotic cells, is an essential nuclear enzyme that promotes cell survival by regulating DNA topology and chromatid separation. This enzyme has been validated as a target for anticancer agent screening. It can be poisoned by common chemotherapeutics, such as etoposide and doxorubicin, which leads to the accumulation of cytotoxic enzyme linked DNA double-stranded breaks. However, recent studies have suggested that the topoisomerase 2a isozyme is predominantly responsible for the carcinogenic side effects associated with etoposide and doxorubicin chemotherapy. Thus, we need to find a promising topoisomerase 2-targeting anticancer agent that avoids these carcinogenic side effects. Recent studies have found that cryptotanshinone has obvious anticancer activities against diverse cancer cells. Here, we demonstrate that cryptotanshinone markedly decreases the steady-state mRNA level of topoisomerase 2a, thereby decreasing the protein and activity levels of this enzyme. Moreover, cryptotanshinone exhibited dramatic in vitro and in vivo antitumor activity with low toxicity to normal tissues. Collectively, our findings support the development of cryptotanshinone as a promising candidate for treating cancer by targeting topoisomerase 2a. PMID- 28716508 TI - Routine intraoperative cholangiography during cholecystectomy is a cost-effective approach when analysing the cost of iatrogenic bile duct injuries. AB - BACKGROUND: The total cost of bile duct injuries (BDIs) in an unselected national cohort of patients undergoing cholecystectomy are unknown. The aim was to evaluate costs associated with treatment of cholecystectomy-related BDIs and to calculate cost effectiveness of routine vs. on-demand intraoperative cholangiography (IOC). METHODS: Data from Swedish patients suffering a BDI during a 5 year period were analysed. Questionnaires to investigate loss-of-production and health status (EQ-5D) were distributed to patients who suffered a BDI during cholecystectomy and who underwent uneventful cholecystectomy (matched control group). Costs per quality-adjusted-life-year (QALY) gained by intraoperative diagnosis were estimated for two strategies: routine versus on-demand IOC during cholecystectomy. RESULTS: Intraoperative diagnosis, immediate intraoperative repair, and minor BDI were all associated with reduced direct treatment costs compared to postoperative diagnosis, delayed repair, and major BDI (all p < 0.001). No difference was noted in loss-of-production for minor versus major BDIs or between different treatment strategies. The cost per QALY gained with routine intraoperative cholangiography (ICER-incremental cost-effectiveness ratio) to achieve intraoperative diagnosis was ?50,000. CONCLUSIONS: Intraoperative detection and immediate intraoperative repair is the superior strategy with less than half the cost and superior functional patient outcomes than postoperative diagnosis and delayed repair. The cost per QALY gained (ICER) using routine IOC was considered reasonable. PMID- 28716509 TI - Assessing the value of endoscopic ultrasound in predicting symptom severity and long-term clinical course in chronic pancreatitis. AB - BACKGROUND: To date, no studies have evaluated the correlation between number of endoscopic ultrasound (EUS) criteria met for chronic pancreatitis (CP) and symptom severity over the course of the disease. This study assessed the relationship between number of EUS-based diagnostic criteria for CP and CP severity over time. METHODS: A University of Louisville database was queried for patients undergoing EUS due to concern for chronic pancreatitis between 2005 and 2016. Patients were grouped based on EUS criteria met for CP and groups were compared along outcome and procedural variables. RESULTS: Of a total of 243 patients, 24, 129, and 90 patients met 1-3, 4-5, and >=6 EUS diagnostic criteria, respectively. Median follow-up time was 33 months. Along all follow-up parameters, number of diagnostic criteria was positively correlated with an increased percentage of patients requiring operative intervention for chronic pancreatitis on univariate and multivariate analysis. CONCLUSIONS: In addition to the role of EUS criteria in establishing the diagnostic severity of patients with symptomatic chronic pancreatitis, the number of EUS-based criteria may help predict patients who will eventually require operative intervention and thus prompt referral to a pancreatobiliary surgeon earlier in the course of a patient's disease. PMID- 28716510 TI - Evaluation of in vivo and in vitro models of toxicity by comparison of toxicogenomics data with the literature. AB - Toxicity affecting humans is studied by observing the effects of chemical substances in animal organisms (in vivo) or in animal and human cultivated cell lines (in vitro). Toxicogenomics studies collect gene expression profiles and histopathology assessment data for hundreds of drugs and pollutants in standardized experimental designs using different model systems. These data are an invaluable source for analyzing genome-wide drug response in biological systems. However, a problem remains that is how to evaluate the suitability of heterogeneous in vitro and in vivo systems to model the many different aspects of human toxicity. We propose here that a given model system (cell type or animal organ) is supported to appropriately describe a particular aspect of human toxicity if the set of compounds associated in the literature with that aspect of toxicity causes a change in expression of genes with a particular function in the tested model system. This approach provides candidate genes to explain the toxicity effect (the differentially expressed genes) and the compounds whose effect could be modeled (the ones producing both the change of expression in the model system and that are associated with the human phenotype in the literature). Here we present an application of this approach using a computational pipeline that integrates compound-induced gene expression profiles (from the Open TG-GATEs database) and biomedical literature annotations (from the PubMed database) to evaluate the suitability of (human and rat) in vitro systems as well as rat in vivo systems to model human toxicity. PMID- 28716511 TI - An ensemble predictive modeling framework for breast cancer classification. AB - Molecular changes often precede clinical presentation of diseases and can be useful surrogates with potential to assist in informed clinical decision making. Recent studies have demonstrated the usefulness of modeling approaches such as classification that can predict the clinical outcomes from molecular expression profiles. While useful, a majority of these approaches implicitly use all molecular markers as features in the classification process often resulting in sparse high-dimensional projection of the samples often comparable to that of the sample size. In this study, a variant of the recently proposed ensemble classification approach is used for predicting good and poor-prognosis breast cancer samples from their molecular expression profiles. In contrast to traditional single and ensemble classifiers, the proposed approach uses multiple base classifiers with varying feature sets obtained from two-dimensional projection of the samples in conjunction with a majority voting strategy for predicting the class labels. In contrast to our earlier implementation, base classifiers in the ensembles are chosen based on maximal sensitivity and minimal redundancy by choosing only those with low average cosine distance. The resulting ensemble sets are subsequently modeled as undirected graphs. Performance of four different classification algorithms is shown to be better within the proposed ensemble framework in contrast to using them as traditional single classifier systems. Significance of a subset of genes with high-degree centrality in the network abstractions across the poor-prognosis samples is also discussed. PMID- 28716512 TI - Results of the Dubert procedure for chronic painful fracture-dislocations of the fifth carpometacarpal joint. A report of 6 cases. AB - Carpometacarpal (CMC) fracture-dislocations of the fifth ray are common. For chronic injuries, Dubert proposed combining resection arthroplasty of the base of the fifth metacarpal (M5) with synostosis with the fourth metacarpal (M4). Our aim was to evaluate the results of this procedure. Between 1994 and 2014, 7 men and 1 woman with an average age of 36 years (range, 27 to 45) were operated on. The right hand was involved in 6 of the 8 cases. All patients had symptomatic osteoarthritis secondary to isolated articular malunion and subluxation of the 5th CMC joint. Fusion was obtained right away in all 8 cases. Six patients were evaluated with a mean follow-up of 93 months (range, 7 to 249). At the final assessment, all patients reported a significant decrease in pain. The mean pain assessed by a visual analog scale (VAS) was 0.6/10 (range, 0 to 5). Range of motion in flexion-extension of the M4-M5 block ranged from 10 degrees to 20 degrees . Grip strength remained reduced by 15% to 70%. All patients except one were satisfied with the outcome. The technique described by Dubert is an effective method to relieve pain. By fusing together M5 and M4, it preserves the length of the fifth ray and a certain adaptability of the palm when gripping. However, it can be used only when the CMC joint of the 4th ray is healthy. This stabilized arthroplasty is an effective and reliable technique for the treatment of symptomatic osteoarthritis secondary to CMC fracture-dislocation of M5. PMID- 28716513 TI - Update in the Treatment of Chronic Pain within Pediatric Patients. AB - Pediatric chronic pain is a challenging entity to evaluate and treat as it encompasses a wide variety of presentations often with overlapping psychosocial implications. Chronic pain may have significant effects upon a child's involvement in academic, athletic, and social participation. If unrecognized, it may have deleterious effects upon family interactions and stability. The treatment of pediatric chronic pain is focused on not only providing analgesia, but also on assisting the child and family with reintegrating into a more functional lifestyle. Given the complex multifactorial causes of pain, a comprehensive multidisciplinary treatment plan is often the most effective way to achieve remission. This paper will discuss two examples of pediatric pain that have shown the good response to treatment with a multidisciplinary team approach: complex regional pain syndrome (CRPS) and amplified pain due to Ehlers-Danlos syndrome-hypermobility type (EDS-HT). Treatment of these patients often encompasses a multimodal approach that incorporates physical therapy (PT), occupational therapy (OT), medication(s), pain psychology, procedure(s), sleep hygiene, education, and encouragement of overall physiologic wellness. Management principles are to reduce pain and help prevent future occurrences. PMID- 28716514 TI - Toe Walking: When Do We Need to Worry? AB - Toe walking refers to the lack of heel strike during the stance phase of the gait cycle. It is a common variation of normal gait development in children. Persistent toe walking past 2-3 years of age warrants further evaluation as toe walking can be associated with cerebral palsy, muscular dystrophy, and autism spectrum disorders. The diagnosis of idiopathic toe walking is a diagnosis of exclusion used for children with persistent toe walking and no associated medical condition. Despite variable pathophysiology, the treatment of toe walking has similarities across diagnoses as it is focused on the maintenance of range of motion through the ankle. PMID- 28716515 TI - Calming the Storm: Dysautonomia for the Pediatrician. AB - Dysautonomia is a potentially life-threatening syndrome seen in many different types of brain injuries. It involves paroxysmal sympathetic hyperactivity and typically includes a constellation of symptoms, including: tachycardia, tachypnea, hyperthermia, hypertension, diaphoresis, hypertonia, and/or decerebrate or decorticate posturing. It is a clinical diagnosis of exclusion. A multimodal treatment approach is necessary including environmental modifications along with pharmacotherapy. Early management can help prevent comorbidities including secondary brain injury while also improving patient outcomes. This discussion serves as an overview of dysautonomia with a focus on management in the pediatric population including an example of a clinical algorithm and a review of the commonly used medications. PMID- 28716516 TI - Hypertonia. AB - Hypertonia is the abnormal increase in muscle tone as a result of upper motor neuron lesions. There are three following clinical types: spasticity, dystonia, and rigidity. Management of hypertonia is individualized and should be directed by the patient and/or family's goals of care as well as the underlying cause of the hypertonia. Treatment options include stretching, strengthening, positioning, oral medications, botulinum toxin injections, phenol injections, as well as surgical procedures. Without effective management, hypertonia can result in muscle imbalance, abnormal movement patterns, pain, joint contracture, joint deformity, and ultimately negatively impact a patient's function. This discussion serves as an overview of hypertonia, focusing on spasticity and dystonia, in the pediatric population by examining the causes and epidemiology, elucidating its symptoms, discussing available treatment and management options, and clarifying why this all matters. PMID- 28716517 TI - Lethal suicide attempt with a mixed-drug intoxication of metoprolol and propafenone - A first pediatric case report. AB - INTRODUCTION: The beta1 adrenergic receptor blocker metoprolol is often prescribed together with the antiarrhythmic drug propafenone. Both are metabolized by cytochrome P450 2D6 and propafenone is also an inhibitor of this enzyme. We present a pediatric case showing metoprolol and propafenone intoxication in combination. CASE: A 14-year-old girl was admitted to a local emergency department after ingestion of metoprolol (probably 1g) and propafenone (probably 1.5-3g) in a suicide attempt. She developed cardiogenic shock with cardiac arrest and was fully resuscitated. Veno-arterial femorofemoral extracorporeal membrane oxygenation was started immediately. High serum levels of both drugs were detected approximately 10h after ingestion (2630ng/mL metoprolol and 2500ng/mL propafenone). Other serial samples for the monitoring of the levels of metoprolol and its metabolite alfa-hydroxymetoprolol were obtained between days 2 and 4 after admission. The metoprolol/alfa-hydroxymetoprolol ratio on the 2nd day was 36.1, indicative of a poor metabolizer phenotype. The elimination half-life of metoprolol was prolonged to 13.2h and the clearance decreased by about 70%. The patient condition gradually worsened, brain edema and intracerebral hemorrhage occurred, and on the 6th day, the patient died. CONCLUSION: We document a pediatric case report of death due to a mixed drug overdose of metoprolol and propafenone, along with data regarding serum metoprolol, alfa-hydroxymetoprolol, and propafenone levels. PMID- 28716518 TI - Virtual animation of victim-specific 3D models obtained from CT scans for forensic reconstructions: Living and dead subjects. AB - Post-mortem CT scanning (PMCT) has been introduced at several forensic medical institutions many years ago and has proved to be a useful tool. 3D models of bones, skin, internal organs and bullet paths can rapidly be generated using post processing software. These 3D models reflect the individual physiognomics and can be used to create whole-body 3D virtual animations. In such way, virtual reconstructions of the probable ante-mortem postures of victims can be constructed and contribute to understand the sequence of events. This procedure is demonstrated in two victims of gunshot injuries. Case #1 was a man showing three perforating gunshot wounds, who died due to the injuries of the incident. Whole-body PMCT was performed and 3D reconstructions of bones, relevant internal organs and bullet paths were generated. Using 3ds Max software and a human anatomy 3D model, a virtual animated body was built and probable ante-mortem postures visualized. Case #2 was a man presenting three perforating gunshot wounds, who survived the incident: one in the left arm and two in the thorax. Only CT scans of the thorax, abdomen and the injured arm were provided by the hospital. Therefore, a whole-body 3D model reflecting the anatomical proportions of the patient was made combining the actual bones of the victim with those obtained from the human anatomy 3D model. The resulted 3D model was used for the animation process. Several probable postures were also visualized in this case. It has be shown that in Case #1 the lesions and the bullet path were not consistent with an upright standing position; instead, the victim was slightly bent forward, i.e. he was sitting or running when he was shot. In Case #2, one of the bullets could have passed through the arm and continued into the thorax. In conclusion, specialized 3D modelling and animation techniques allow for the reconstruction of ante-mortem postures based on both PMCT and clinical CT. PMID- 28716519 TI - Cost-Effectiveness of Simvastatin Plus Ezetimibe for Cardiovascular Prevention in Patients With a History of Acute Coronary Syndrome: Analysis of Results of the IMPROVE-IT Trial. AB - BACKGROUND: Simvastatin plus ezetimibe reduced the risk of cardiovascular events in the IMProved Reduction of Outcomes: Vytorin Efficacy International (IMPROVE IT) study. The aim of this study is to investigate the cost-effectiveness of adding ezetimibe to simvastatin treatment for patients with ACS based on the recently completed IMPROVE-IT trial. METHODS: We constructed a Markov state transition model to evaluate the costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness (ICER) associated with co-therapy compared with simvastatin alone from a health care perspective. We ran separate base-case analyses assuming a trial-length and longer term follow-up. One-way sensitivity analyses were used to explore uncertainty in model parameters. RESULTS: In the trial-length model, the ICERs compared with simvastatin alone were $114,400 per QALY for the combination therapy. In 5- and 10-year time horizons, the ICERs remained above the cost-effectiveness threshold of $50,000 per QALY. In the lifetime horizon model, The ICER was $45,046 per QALY for combination treatment compared with simvastatin alone. The combination therapy is cost-effective at an 80% decrease in the current branded simvastatin and ezetimibe cost. Probabilistic sensitivity analysis suggested simvastatin and ezetimibe co-therapy would be a cost-effective alternative to simvastatin monotherapy 60.7% of the time. CONCLUSIONS: In our trial-length, 5-year, and 10-year models, the co-therapy was not a cost-effective alternative; however, as follow-up was extended to lifetime, the co-therapy became a cost-effective treatment compared with the simvastatin monotherapy in patients with histories of ACS. PMID- 28716520 TI - Modeling color preference using color space metrics. AB - Studying color preferences provides a means to discover how perceptual experiences map onto cognitive and affective judgments. A challenge is finding a parsimonious way to describe and predict patterns of color preferences, which are complex with rich individual differences. One approach has been to model color preferences using factors from metric color spaces to establish direct correspondences between dimensions of color and preference. Prior work established that substantial, but not all, variance in color preferences could be captured by weights on color space dimensions using multiple linear regression. The question we address here is whether model fits may be improved by using different color metric specifications. We therefore conducted a large-scale analysis of color space models, and focused in-depth analysis on models that differed in color space (cone-contrast vs. CIELAB), coordinate system within the color space (Cartesian vs. cylindrical), and factor degrees (1st degree only, or 1st and 2nd degree). We used k-fold cross validation to avoid over-fitting the data and to ensure fair comparisons across models. The best model was the 2nd harmonic Lch model ("LabC Cyl2"). Specified in CIELAB space, it included 1st and 2nd harmonics of hue (capturing opponency in hue preferences and simultaneous liking/disliking of both hues on an opponent axis, respectively), lightness, and chroma. These modeling approaches can be used to characterize and compare patterns for group averages and individuals in future datasets on color preference, or other measures in which correspondences between color appearance and cognitive or affective judgments may exist. PMID- 28716521 TI - Update on quality of care in Hispanics and other racial-ethnic groups in the United States discharged with the diagnosis of Acute Myocardial Infarction in 2013. AB - BACKGROUND: Disparities in Acute Myocardial Infarction (AMI) care and outcomes have been frequently reported in racial-ethnic minorities in the U.S. Some studies have attributed disparities in Hispanics and other minorities to lower quality of services at hospitals where they seek care. Current information from hospitals with large Hispanic representations and updated quality resources is needed. METHODS: Retrospective observational study of 839 AMI patients discharged in 2013 from three Southern California Hospitals (A, B, C) with tertiary cardiac care level. Non-Hispanic Whites (NHW) and Hispanics (H) were the larger racial ethnic groups (68.3%), and the comparison of these two groups constitutes the focus of the study. Mortality, 30day readmissions, medication/performance measures (PRx); aspirin, statins/anti-lipids, beta-blockers, ACEI/ARB for LV systolic dysfunction, <90min door-balloon time, and revascularization procedures were compared between hospitals, NHW and H, using Chi-squared tests (chi2), Odds Ratios (OR) with 95% confidence intervals (CI), and Z tests for proportions - independent groups. RESULTS: No significant differences in hospital, 30day mortality, PRx or procedures were observed between NHW, H and other racial-ethnic minority groups, or hospitals. Hospital C had 47.3% H and Hospitals A+B 14.6% (p<0.001, effect size=0.430). AMI performance measures exceeded 2013 national rates across all facilities. NHW had more private/commercial insurance (52.5% vs. 25.4%, OR 3.24, 95% CI 2.19-4.80, p<0.001) than H. CONCLUSIONS: Equitable access to quality hospital services in three Southern California hospitals offset previously reported disparities in AMI management in Hispanics. These results may not necessarily reflect the reality of AMI care for Hispanics in other U.S. regions. PMID- 28716522 TI - Exercise individualized by TRIMPi method reduces arterial stiffness in early onset type 2 diabetic patients: A randomized controlled trial with aerobic interval training. AB - BACKGROUND: Arterial stiffness (AS) and baroreflex sensitivity (BRS) are subclinical markers of vascular diseases in type 2 diabetes (T2D). We evaluated the effects of aerobic interval training (AIT), with loads prescribed according to individual heart rate and lactate profiling obtained during a baseline treadmill test (TRIMPi method), on AS and BRS in patients with early-onset T2D without cardiovascular complications. POPULATION STUDY AND METHODS: Twenty-two sedentary overweight T2D patients (aged 57+/-7years) were randomized to 12-weeks open-label of supervised AIT by TRIMPi (n=8) or unsupervised physical activity as per usual care (SOC) (n=11). Following parameters were evaluated (pre- and post ): anthropometrics; six-minute walking test (6MWT); fasting glucose, insulin, HbA1c; Pulse Wave Velocity (PWV) and Augmentation Index (AIxHR75) using radial approach (SphigmoCor System); BRS using Finapress method. RESULTS: Both interventions significantly improved distance walked during 6MWT (AIT 52+/-21m; SOC 39+/-24m, p<0.001 for both). PWV significantly improved with AIT (p<0.001) whereas did not vary with SOC (p=0.47). Similar trend was observed for AIxHR75. Resulting percent changes from baseline were significantly better for AIT vs SOC, in both PWV (-15.8+/-2.1 vs +1.50+/-3.4%, p<0.001) and AIxHR75 (-28.9+/-3.2% vs +12.7+/-2.4%, p<0.001). BRS similarly improved in both groups (p<0.001 for both), as well as body weight, HbA1c and blood pressure. CONCLUSION: In sedentary T2D patients, 12-weeks AIT individualized by TRIMPi method improved AS to a greater extent than usual recommendation on physical activity, whilst exerting comparable effects on exercise capacity, glycemic control and body weight. Further researches are needed to ascertain durability of these effects. PMID- 28716523 TI - Sensitivity towards the GRP78 inhibitor KP1339/IT-139 is characterized by apoptosis induction via caspase 8 upon disruption of ER homeostasis. AB - The ruthenium drug and GRP78 inhibitor KP1339/IT-139 has already demonstrated promising anticancer activity in a phase I clinical trial. This study aimed to identify mechanisms underlying increased sensitivity to KP1339 treatment. Based on a screen utilizing 23 cell lines, a small panel was selected to compare KP1339 sensitive and low-responsive models. KP1339 sensitivity was neither based on differences in ruthenium accumulation, nor sensitivity to oxidative stress or constituents of KP1339 (ruthenium chloride and indazole). Subsequently, the biochemical response to KP1339 was analyzed using whole genome expression arrays indicating that, while sensitive cell lines were characterized by "response to chemical stimuli" and "regulation of cell death", low-responsive cells preferentially activated pathways controlling cell cycle, DNA repair, and metabolism. Cell culture experiments confirmed that, while low-responsive cells executed cell cycle arrest in G2 phase, pronounced apoptosis induction via activation of caspase 8 was found in sensitive cells. Cell death induction is based on a unique disruption of the ER homeostasis by depletion of key cellular chaperones including GRP78 in combination with enhanced KP1339-mediated protein damage. PMID- 28716524 TI - The E3 ligase HECTD3 promotes esophageal squamous cell carcinoma (ESCC) growth and cell survival through targeting and inhibiting caspase-9 activation. AB - Apoptosis resistance is an acquired hallmark of cancer cells and many factors can contribute to the tumor cell apoptosis resistance. In this study, we demonstrated that HECTD3, overexpressed in human esophageal squamous cell carcinoma (ESCC), confers cells resistance to cisplatin-induced apoptosis and promotes cancer cell survival. HECTD3 can bind and ubiquitinate caspase-9, which leads to inhibiting caspase-9 oligomerization and association with Apaf-1, and results in suppressing caspase-9 activation and inhibiting apoptosis. Furthermore, this antiapoptotic function of HECTD3 is dependent on its Thr-157 phosphorylation by ERK. HECTD3, but not T157A mutant, facilitates cell survival in ESCC cells in survival assay in vitro and promotes tumor growth in a xenograft mouse model in vivo. These findings establish a new mechanism of cancer cell resistance to apoptosis and provide a new potential strategy for ESCC treatment. PMID- 28716525 TI - Peri-tumor associated fibroblasts promote intrahepatic metastasis of hepatocellular carcinoma by recruiting cancer stem cells. AB - Fibroblasts have been reported to play an important role in hepatocellular carcinoma (HCC). However, the role of fibroblasts have not been fully understood. Conditioned medium collected from human peri-tumor tissue-derived fibroblasts (CM pTAFs) showed high metastasis ability than human HCC tissues-derived fibroblasts (CM-TAFs). To determine what component was secreted from fibroblasts, we used Bio Plex analysis system and compared the factors secreted from CM-pTAFs and CM-TAFs, found a series of up-regulated cytokines in the CM-pTAFs, including IL-6, CCL2, CXCL1, CXCL8, SCGF-beta, HGF and VEGF. Pretreatment of IL-6 inhibitor Tocilizumab could inhibit metastasis the HCC cell treated with CM-pTAFs in vitro and in vivo. The expression of CCR2 and CXCR1 were up-regulated after CM-pTAFs treatment in HCC cell line SMMC-7721. Flow cytometric analysis experiment showed that most CCR2 or CXCR1 positive cells were also EpCAM positive. In vitro studies also showed that CM-pTAFs could increase stemness of SMMC-7721. In addition, neutralization of SCGF-beta and HGF could significantly reduce metastasis and viability of cancer stem cells treated with CM-pTAFs. Taken together, these results indicated that the peri-tumor tissues derived fibroblasts may promote development of HCC by recruiting cancer stem cells and maintaining their stemness characteristic. PMID- 28716526 TI - SLC45A3-ELK4 functions as a long non-coding chimeric RNA. AB - Gene fusions in cancer typically lead to the expression of a fusion protein or disrupt the expression of one of the parental genes. Here we report a new phenomenon whereby a fusion transcript functions as a long non-coding chimeric RNA (lnccRNA). This fusion RNA, SLC45A3-ELK4, generated by cis-splicing between neighboring genes, was found in prostate cancer. The fusion RNA encodes the same protein as ELK4. Intriguingly, we found that the fusion RNA level is less than 1% of wild type ELK4, unlikely to perturb the general pool of ELK4 protein. Nonetheless, when the fusion RNA, but not ELK4 is silenced, cell proliferation is inhibited in both androgen-dependent and castration-resistant prostate cancer cells. This growth arrest can be rescued by exogenous expression of the fusion and a mutant designed to prevent translation of the ELK4 protein. In the same setting, the mutant could also suppress CDKN1A and several other targets of SLC45A3-ELK4. In addition, similar to many long non-coding RNAs, the fusion RNA is enriched in the nuclear fraction. Altogether, these results indicate that SLC45A3-ELK4 regulates cancer cell proliferation by its transcript, not translated protein. PMID- 28716527 TI - Identification of a synergistic combination of Smac mimetic and Bortezomib to trigger cell death in B-cell non-Hodgkin lymphoma cells. AB - Recently, copy number gains and increased expression levels of cIAP1 and cIAP2 have been reported in B-cell non-Hodgkin lymphomas (NHL). Therefore, we investigated the therapeutic potential of the Smac mimetic BV6 that antagonizes cIAP1/2 and XIAP. Here, we discover that subtoxic concentrations of BV6 prime B cell NHL cells to proteasome inhibitor Bortezomib-induced cell death. Synergistic induction of cell death by BV6 and Bortezomib is confirmed by calculation of combination index in different cell lines, emphasizing the broader relevance of this combination. Interestingly, addition of the caspase inhibitor zVAD.fmk provides no or only partial protection from BV6/Bortezomib-stimulated cell death. Consistently, BV6/Bortezomib co-treatment alone or in combination with zVAD.fmk increases phosphorylation of MLKL, a typical marker of necroptosis. Importantly, genetic silencing of key components of necroptosis signaling such as MLKL or RIP3 significantly protects DG-75 cells from BV6/Bortezomib-induced cell death in the presence and even the absence of zVAD.fmk. Similarly, pharmacological inhibitors of MLKL (i.e. NSA), RIP3 (i.e. GSK'872, Dabrafenib) or RIP1 (i.e. Necrostatin-1s) significantly rescue DG-75 cells from BV6/Bortezomib-induced cell death irrespective of the presence of zVAD.fmk. In addition, NSA or Nec-1s act in concert with zVAD.fmk to reduce BV6/Bortezomib-induced cell death in U-2932 cells. Together, these findings demonstrate that BV6 and Bortezomib synergize to induce cell death in B-cell NHL cells. BV6/Bortezomib co-treatment primarily triggers necroptosis or, alternatively, engages both apoptotic and necroptotic cell death. The discovery of this synergistic combination that is effective even when apoptosis is blocked has important implications for the development of new treatment strategies for B-cell NHL. PMID- 28716528 TI - Treatment with TREK1 and TRPC3/6 ion channel inhibitors upregulates microRNA expression in a mouse model of chronic mild stress. AB - Depression is a common mental disorder characterized by the mood of deep sadness. Recent studies have demonstrated that microRNAs and ion channels have significant roles in the etiopathogenesis of depression. Therefore, we investigated the effects of the TREK1 ion channel inhibitor anandamide and the TRPC3/6 inhibitor norgestimate on microRNA expression and antidepressant effect in the mouse chronic mild stress (CMS) model of depression. Male BALB/c mice were divided into groups as control, CMS, CMS+sertraline, CMS+anandamide, CMS+sertraline+anandamide, CMS+norgestimate and CMS+sertraline+norgestimate. Forced swim test (FST) and Sucrose Preference Test (SPT) were utilized to assess depression levels. Anandamide and norgestimate were administered subcutaneously (5mg/kg/day), and sertraline was applied intraperitoneally (10mg/kg/day) for two days during FST. miRNA and ion channel gene expression levels in the prefrontal cortex were assessed with qRT-PCR. qRT-PCR results demonstrated that there was a significant increase in miR-9-5p, miR-128-1-5p, and miR-382-5p, and a significant decrease in miR-16-5p, miR-129-5p, and miR-219a-5p in the CMS group compared with the control group. Generally, anandamide and norgestimate significantly increased all miRNA expression. It was also determined that anandamide and norgestimate had an antidepressant action in FST when used alone and especially when used in conjunction with sertraline. Based on the study results, it could be argued that an increase in miR-9-5p and miR-128-1-5p, consistent with the literature, could play significant roles in the etiopathogenesis of depression. The antidepressant action of anandamide and norgesimate in FST showed for the first time that these inhibitors could be used as in conjuction with sertraline in depression treatment. PMID- 28716529 TI - The pro-inflammatory cytokines, salivary cortisol and alpha-amylase are associated with generalized anxiety disorder (GAD) in patients with asthma. AB - Generalized anxiety disorder (GAD) is common in patients with asthma. High levels of GAD may lead both to exacerbation of the condition and poor management. However, the physiological mechanisms of GAD in asthma patient is unclear. This study investigated the associations between the diurnal rhythm of sputum cytokines, salivary cortisol, alpha-amylase and GAD in asthma patients. Patients with co-morbid GAD and asthma showed higher sputum IL-1 AUC, sputum IL-6 AUC and sAA AUC. And there were positive correlations between Hamilton anxiety scale (HAMA) scores and sputum IL-1 AUC concentrations (r=0.37, P=0.002), HAMA scores and sputum IL-6 AUC (r=0.56, P<0.001), HAMA scores and sAA AUC (r=0.75, P<0.001). Also, there were positive correlations between Sputum IL-1 AUC and sAA AUC (r=0.40, P<0.001), between Sputum IL-6 AUC and sAA AUC. Stepwise multiple regression analyses showed the combination of sputum sAA AUC, IL-1 AUC, IL-6 AUC and cortisol AUC was the best predictor of HAMA scores (DeltaR2=0.439, F(4,63)=14.086, p<0.001). Therefore, pro-inflammatory cytokines, salivary cortisol and alpha-amylase may all be involved in the occurrence of GAD in asthma patients. PMID- 28716530 TI - Genetic association analysis of serotonin and signal transduction pathways in suicide attempters from an Italian sample of psychiatric patients. AB - Genetic factors have been reported to contribute to the liability of suicide. We aimed to investigate functional polymorphisms in eight genes (serotonin transporter, SLC6A4; receptors, 5HTR1A, 1B, 5HTR2A; Tryptophan Hydroxylase, TPH1, TPH2; Monoamine Oxidase, MAOA and G Protein Subunit Beta 3, GNB3) to investigate their predictive value for suicide. The possible confounding effects of gender and phenotypic patients dissection were also valued. A sample of 111 consecutive psychiatric inpatients was recruited and assessed using specific psychometric instruments. Genomic DNA was isolated from peripheral white blood cell samples and polymorphisms were genotyped by pyrosequencing technology. Although no differences were observed between allele and genotype frequencies for all polymorphisms and suicide attempt (SA), a polygenic risk score was detected for three genes HTR2A (A-1438G), TPH1 and TPH2 increasing the prediction of SA risk (Thresh=0.43, p=0.038, R2=0.053). Moreover some nominal associations were obtained after gender and phenotypic dissection stratification (TEMPS-A, TEMPs-H, GSMD, SHSS, GAF, CGI) for SLC6A4 (5-HTTLPR), HTR1A (C-1019G), HTR2A (A-1438G), TPH1 (A799C) and GNB3 (C825T) genes, that were lost after Bonferroni correction. This is a first evidence that specific additive combinations of genes could increase the prediction of SA risk and that gender and phenotypic dissection could influence the association of the genes with SA. This could represent a further study also for future meta-analyses on larger samples. PMID- 28716531 TI - Continuous theta burst stimulation inhibits the bilateral hemispheres. AB - Transcranial magnetic stimulation induces changes in the cerebral cortex functions, either unilaterally or bilaterally. Here, we combined evoked potential recording and functional brain imaging to analyze the modulating effects of continuous theta burst stimulation in bilateral motor regions of the adult human cortex. We detected concurrent inhibition of the bilateral motor regions following stimulation, as evidenced by both the electrophysiological and imaging results. Our findings supported the notion that magnetic stimulation is able to modulate the contralateral hemisphere through the callosal connectivity. PMID- 28716532 TI - Multivariate analyses of peripheral blood leukocyte transcripts distinguish Alzheimer's, Parkinson's, control, and those at risk for developing Alzheimer's. AB - The need for a reliable, simple, and inexpensive blood test for Alzheimer's disease (AD) suitable for use in a primary care setting is widely recognized. This has led to a large number of publications describing blood tests for AD, which have, for the most part, not been replicable. We have chosen to examine transcripts expressed by the cellular, leukocyte compartment of blood. We have used hypothesis-based cDNA arrays and quantitative PCR to quantify the expression of selected sets of genes followed by multivariate analyses in multiple independent samples. Rather than a single study with no replicates, we chose an experimental design in which there were multiple replicates using different platforms and different sample populations. We have divided 177 blood samples and 27 brain samples into multiple replicates to demonstrate the ability to distinguish early clinical AD (Clinical Dementia Rating scale 0.5), Parkinson's disease (PD), and cognitively unimpaired APOE4 homozygotes, as well as to determine persons at risk for future cognitive impairment with significant accuracy. We assess our methods in a training/test set and also show that the variables we use distinguish AD, PD, and control brain. Importantly, we describe the variability of the weights assigned to individual transcripts in multivariate analyses in repeated studies and suggest that the variability we describe may be the cause of inability to repeat many earlier studies. Our data constitute a proof of principle that multivariate analysis of the transcriptome related to cell stress and inflammation of peripheral blood leukocytes has significant potential as a minimally invasive and inexpensive diagnostic tool for diagnosis and early detection of risk for AD. PMID- 28716533 TI - Novel UBQLN2 mutations linked to amyotrophic lateral sclerosis and atypical hereditary spastic paraplegia phenotype through defective HSP70-mediated proteolysis. AB - Mutations in UBQLN2 have been associated with rare cases of X-linked juvenile and adult forms of amyotrophic lateral sclerosis (ALS) and ALS linked to frontotemporal dementia (FTD). Here, we report 1 known (c.1489C>T, p.Pro497Ser, P497S) and 3 novel (c.1481C>T, p.Pro494Leu, P494L; c.1498C>T, p.Pro500Ser, P500S; and c.1516C>G, p.Pro506Ala, P506A) missense mutations in the PXX domain of UBQLN2 in familial motor neuron diseases including ALS and spastic paraplegia (SP). A novel missense mutation (c.1462G>A, p.Ala488Thr, A488T) adjacent to this hotspot UBQLN2 domain was identified in a sporadic case of ALS. These mutations are conserved in mammals, are absent from ExAC and gnomAD browsers, and are predicted to be deleterious by SIFT in silico analysis. Patient lymphoblasts carrying a UBQLN2 mutation showed absence of ubiquilin-2 accumulation, disrupted binding with HSP70, and impaired autophagic pathway. Our results confirm the role of PXX repeat in ALS pathogenesis, show that UBQLN2-linked disease can manifest like a SP phenotype, evidence a highly reduced disease penetrance in females carrying UBQLN2 mutations, which is important information for genetic counseling, and underline the pivotal role of ubiquilin-2 in proteolysis regulation pathways. PMID- 28716534 TI - Mutations in TYROBP are not a common cause of dementia in a Turkish cohort. AB - Mutations in TYROBP and TREM2 have been shown to cause polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy. Recently, variants in TREM2 were also associated with frontotemporal dementia and Alzheimer's disease. Given the functional proximity between these 2 genes, we investigated the genetic variation of TYROBP in a Turkish cohort of 103 dementia patients. No mutations or copy number variants predicted to be pathogenic were identified. These results indicate that mutations in TYROBP are not a common cause of dementia in this Turkish cohort. PMID- 28716535 TI - Variable compensation during the sit-to-stand task among individuals with severe knee osteoarthritis. AB - BACKGROUND: Individuals with knee osteoarthritis (OA) show variability during the sit-to-stand (STS) task, so they may not perform the STS in the same way. This study aimed to determine whether individuals with knee OA have different strategies in performing the STS. METHODS: Participants with knee OA and able bodied individuals underwent STS evaluation at a self-selected pace with use of a motion measurement system consisting of 12 cameras and 2 force plates. RESULTS: In total, 101 participants (57 women) with knee OA showed 3 main STS strategies. As compared with the 27 controls (14 women), 24 OA participants, compensated STS, showed greater trunk flexion (47.1 degrees vs. 38.3 degrees ; P<0.01) and trunk obliquity (4.6 degrees vs. -0.8 degrees ; P<0.001) when completing the STS task in the same amount of time as controls (2.4 vs. 2.7s; P=0.999). The second group (n=59), inadequately compensated STS, also compensated with trunk flexion (47.7 degrees vs. 38.3 degrees ; P<0.01) and trunk obliquity (1.6 degrees vs. -0.8 degrees ; P<0.001) but took longer than controls (3.4 vs. 2.7s; P=0.001). The third group (n=18), severe impaired STS, took an extended amount of time to execute the STS (6s), with marked trunk flexion (59.2 degrees ) and obliquity (4.1 degrees ), so participants in this group were perhaps severely impaired in completing the STS. CONCLUSION: This study identified 3 groups STS trunk strategies among participants with STS. Moreover, the data reveal a concise representation of the relations among strategy variables. The findings could be used to simplify the characterization of the STS among patients with knee OA and aid with follow-up. PMID- 28716536 TI - Looking at hospitalized persons throughout the prism of the handicap. AB - OBJECTIVE: To describe the disability status of non-selected hospitalized persons. METHODS AND FINDINGS: We conducted a cross-sectional survey to assess activity limitations of every person older than 18 years hospitalized in a regional university hospital covering all medical fields. Evaluators rated, on a scale from 0 to 4, 22 selected items of the International Classification of Functioning (ICF), covering the 6 following domains: learning and applying knowledge, general tasks and demands, communication, mobility, self-care, and interpersonal interactions and relationships. Univariate and multivariate analyses were performed to analyze the prevalence, severity and profile of the handicap in terms of sociodemographic characteristics and care pathways. RESULTS: Among 1572 eligible persons, 1267 (81%) were surveyed (mean age 62.7+/-20.4years; 655 males [51.7%]). Overall, 82% showed at least one activity limitation. For 52%, disability was severe or total for at least one ICF item. Prevalence of disabilities was higher for mobility (75%) and self-care domains (63%). Disability was strongly related to age: age older than 80years versus 18 to 44years (OR=12.8 95% CI 6.4-27.9]; P<0.01). Disability was associated with hospitalization in rehabilitation units (96%; OR=4.3 [95% CI 2.2-5.3]; P<0.01). Severe disability was associated with hospitalization in critical care units (OR=6.7 [CI 3.2-15.1]; P<0.001) and psychiatry units (OR=5.3 [CI 2.7-11.4]; P<0.001). CONCLUSION: Handicap was common in hospitalized persons, involving all 6 tested ICF activity domains, particularly mobility and self-care. This study alerts care givers, hospital administrators, and in general, people influencing health policies about the need to plan actions to reduce activity limitations of hospitalized persons, whatever the cause of the hospitalization. PMID- 28716537 TI - Participant and service provider perceptions of an outpatient rehabilitation program for people with acquired brain injury. AB - BACKGROUND: A holistic, intensive and interdisciplinary rehabilitation program for people with acquired brain injury (ABI) was developed at the Pitie Salpetriere Hospital, France (5 days/week for 7 weeks). This program, recently demonstrated effective, aimed to optimize the ability of people with ABI to perform activities and improve their participation by using individual and group interventions involving ecologically valid activities inside (e.g., in the gym and kitchen) and outside the hospital. However, the perception of the quality of the program by participants and service providers has not yet been reported. OBJECTIVES: This study had 3 objectives: (1) report the perception of participants (adults with ABI) in terms of service quality of the program, (2) report the strengths, weaknesses, opportunities, and threats (SWOT analysis) of the program as perceived by service providers, and (3) triangulate findings to draw conclusions about the program's quality and provide recommendations for quality improvement. METHODS: We used a mixed-methods design with a validated questionnaire (Perception of Quality of Rehabilitation Services [PQRS-Montreal]) and interviews (structured around a SWOT analysis) involving program participants and service providers. RESULTS: We included 33 program participants (mean age 43.6 years) and 12 service providers (mean years with program 7.6 years). In general, study participants showed a convergence of opinion about the high quality of the program, particularly regarding the team and its participant focused approach. Specific aspects of the program were viewed more negatively by both participants and service providers (i.e., addressing sexuality, family involvement and return to work/volunteer work/school). CONCLUSION: Participant and service provider perceptions of the rehabilitation program under study were generally positive. A reliable and valid questionnaire and interviews helped identify aspects of the program that worked well and those that could be targeted for future quality improvement. PMID- 28716538 TI - Reliability of pelvic floor muscle electromyography tested on healthy women and women with pelvic floor muscle dysfunction. AB - OBJECTIVES: Electromyography (EMG) is a well-established method to quantify the relative pelvic floor muscle (PFM) activity. PFM EMG has shown good reliability in healthy women. However, its reliability has not been tested in women with PFM dysfunction. The reliability of EMG analysis methods concerning EMG normalization needs to be determined to assess specific therapeutic interventions. Therefore, the aim of this study was to investigate the intra-session reliability of PFM EMG variables by using 3 different analysis methods in women with PFM dysfunction. METHODS: EMG data analysis involved women who were healthy, had weak PFM and had stress urinary incontinence (SUI). We evaluated the reliability of EMG during rest and maximum voluntary contraction and compared muscle activity onset by visual determination and by calculation. All variables were checked for normality (Shapiro-Wilk). Descriptive statistics (mean, SD), systematic error within repeated measures (Wilcoxon) and reliability indexes were tested and presented descriptively (intraclass correlation coefficient [ICC], standard error of measurement [SEM], SEM%, minimal difference [MD], MD%). RESULTS: For 20 women who were healthy, 17 with weak PFM and 50 with SUI, ICC values were high for all variables (0.780-0.994), and SEM and MD values were relatively high (SEM%: 7.5 15.7; MD%: 21.0-43.8). CONCLUSION: We need reliable methods to analyse clinical intervention studies. PFM EMG variables had high ICCs, but relatively high SEM and MD values modified the reliability. All EMG analysis methods were comparable in healthy women, but only the visual-onset determination was dependable in women with PFM dysfunction. PMID- 28716540 TI - Developmental vitamin D deficiency alters multiple neurotransmitter systems in the neonatal rat brain. AB - BACKGROUND: Epidemiological evidence suggests that developmental vitamin D (DVD) deficiency is a risk factor for neuropsychiatric disorders, such as schizophrenia. DVD deficiency in rats is associated with altered brain structure and adult behaviours indicating alterations in dopamine and glutamate signalling. Developmental alterations in dopamine neurotransmission have also been observed in DVD-deficient rats but a comprehensive assessment of brain neurochemistry has not been undertaken. Thus, the current study determined the regional concentrations of dopamine, noradrenaline, serotonin, glutamine, glutamate and gamma-aminobutyric acid (GABA), and associated metabolites, in DVD-deficient neonates. METHODS: Sprague-Dawley rats were fed a vitamin D deficient diet or control diet six weeks prior to mating until birth and housed under UVB-free lighting conditions. Neurotransmitter concentration was assessed by high performance liquid chromatography on post-mortem neonatal brain tissue. RESULTS: Ubiquitous reductions in the levels of glutamine (12-24%) were observed in DVD deficient neonates compared with control neonates. Similarly, in multiple brain regions DVD-deficient neonates had increased levels of noradrenaline and serine compared with control neonates. In contrast, increased levels of dopamine and decreased levels of serotonin in DVD-deficient neonates were limited to striatal subregions compared with controls. CONCLUSIONS: Our results confirm that DVD deficiency leads to changes in multiple neurotransmitter systems in the neonate brain. Importantly, this regionally-based assessment in DVD-deficient neonates identified both widespread neurotransmitter changes (glutamine/noradrenaline) and regionally selective neurotransmitter changes (dopamine/serotonin). Thus, vitamin D may have both general and local actions depending on the neurotransmitter system being investigated. Taken together, these data suggest that DVD deficiency alters neurotransmitter systems relevant to schizophrenia in the developing rat brain. PMID- 28716539 TI - Association of bystander interventions and hospital length of stay and admission to intensive care unit in out-of-hospital cardiac arrest survivors. AB - BACKGROUND: The impact of bystander interventions on post-arrest hospital course is sparsely studied. We examined the association between bystander interventions and length of hospital stay and admission to intensive care unit (ICU) in one-day survivors after OHCA. METHODS: This cohort study linked data of 4641 one-day OHCA survivors from 2001 to 2014 to data on hospital length of stay and ICU admission. We examined associations between bystander efforts and outcomes using regression, adjusted for age, sex, comorbidities, calendar year and witnessed status. We divided bystander efforts into three categories: 1. No bystander interventions; 2.Bystander CPR only; 3. Bystander defibrillation with or without bystander CPR. RESULTS: For patients surviving to hospital discharge, hospital length of stay was 20days for patients without bystander interventions, compared to 16 for bystander CPR, and 13 for bystander defibrillation. 82% of patients without bystander interventions were admitted to ICU compared to 77.2% for bystander CPR, and 61.2% for bystander defibrillation. In-hospital mortality was 60% in the first category compared to 40.5% and 21.7% in the two latter categories. In regression models, bystander CPR and bystander defibrillation were associated with a reduction of length of hospital stay of 21% (Estimate: 0.79 [95% CI: 0.72 0.86]) and 32% (Estimate: 0.68 [95% CI: 0.59-0.78]), respectively. Both bystander CPR (OR: 0.94 [95% CI: 0.91-0.97]) and bystander defibrillation (OR: 0.81 [0.76 0.85]), were associated with lower risk of ICU admission. CONCLUSIONS: Bystander interventions were associated with reduced hospital length of stay and ICU admission, suggesting that these efforts improve recovery in OHCA survivors. PMID- 28716541 TI - Development and validation of an accurate GATE model for NeuroPET scanner. AB - NeuroPET is a cylindrical full ring mobile PET/CT scanner for brain imaging that was developed by Photo Diagnostic Systems, Inc. The scanner has 7 modules, each with 3*4 detector blocks. The detectors have two layers of scintillator arrays with a half pixel pitch offset to realize two levels of depth of interaction. In this study, we evaluated the NeuroPET scanner modeled in the GATE simulation tool and analyzed the acquired data to better understand the contribution of inter detector scattering (IDS). The results show that the average difference between simulated and measured data for a point-like source is 2.5%. The differences are 4.7% and 2.7% for NEMA line source in two data acquisition modes and 5.5% for peak NECR measurement. IDS evaluation indicated that the total fractions of the cross-layer crystal scatter (CLCS) and inter-layer crystal scatter (ILCS) events in singles detection mode are 1.98% and 7.98%, respectively. Approximately 90% of these CLCS events deposit most of their energy in the crystal layer other than the layer of first interaction. Additionally, no significant difference in ILCS fractions between the two layers (8.05% vs 7.35%) was observed. The simulation results demonstrate that ILCS events account for ~79% of the total mis-positioned events. PMID- 28716542 TI - On the lateral dose profile of 4He beams in water. AB - PURPOSE: We investigate the possibility to improve the accuracy of the lateral dose profile for 4He beams with a novel approach, by extending an already validated model for proton beams to heavier ions. METHODS: The full Moliere theory for the Coulomb multiple scattering is applied to the case of 4He beams, with a complete separation of the electromagnetic and of the nuclear contributions in the calculation of the total dose. The latter is described with only three free parameters. RESULTS: The accuracy of the results compared with Monte Carlo predictions already validated with experimental data is comparable with other studies at low energy, but improves by a factor 2 at high energy. In addition the found solution is more stable with respect to (multi-) Gaussian and other parameterizations. This result makes this method of interest for applications to Treatment Planning Systems (TPS) in ion beam therapy. CONCLUSIONS: We propose a model, named MONETalpha (MOdel of ioN dosE for Therapy for alpha), for the calculation of the lateral dose of 4He beams in water that allows fast and accurate dose calculations by requiring a small data base of parameters as input. PMID- 28716543 TI - A novel method for CT dosimetry with a suspended phantom setup. AB - PURPOSE: This work presents a method for estimating CT dosimetric indices with a prototype designed for suspending the phantom/ion chamber system fixed at the CT isocenter. The purpose of this study was to validate the proposed methodology, which can be used to provide a direct assessment of dosimetric indices in helical scans. METHODS: The method is based on a reference setup in which the measuring system for CT dosimetry is in a stationary configuration, i.e. not bound to the CT table, and on a mathematical formalism developed for the proposed reference system. The reliability of the method was demonstrated through a set of experimental measurements. Firstly, dosimetric indices were measured with the new method and compared with the indices obtained with the procedure currently used for CT dosimetry (measuring system bound to the CT table). Secondly, dosimetric indices measured with the new method were compared with those displayed on the CT console. RESULTS: There is good agreement between the dosimetric indices obtained with the standard setup and those obtained with the suspended phantom setup, within the expected range of errors. The difference between dosimetric indices estimated with the proposed method and those displayed on the CT console is below 2%. CONCLUSIONS: The method enables CT dosimetry to be performed with the dose detector in a stationary longitudinal position thanks to the newly introduced suspended phantom setup. Using this approach, CT dose can be assessed for high pitch helical scans, acquisitions without complete tube rotation and for cases where dynamic collimation is used. PMID- 28716544 TI - Does HIV prematurely age the brain? PMID- 28716545 TI - Effect of ageing on neurocognitive function by stage of HIV infection: evidence from the Multicenter AIDS Cohort Study. AB - BACKGROUND: The demographics of the HIV epidemic in the USA have shifted towards older age. We aimed to establish the relationship between the processes of ageing and HIV infection in neurocognitive impairment. METHODS: With longitudinal data from the Multicenter AIDS Cohort Study, a long-term prospective cohort study of the natural and treated history of HIV infection among men who have sex with men in the USA, we examined the effect of ageing, HIV infection (by disease stage), and their interaction on five neurocognitive domains: information processing speed, executive function, episodic memory, working memory, and motor function. We controlled for duration of serostatus in a subanalysis, as well as comorbidities and other factors that affect cognition. Analyses were by linear mixed models for longitudinal data. FINDINGS: 5086 participants (47 886 visits) were included in the analytic sample (2278 HIV-seropositive participants contributed 20 477 visits and 2808 HIV-seronegative control participants contributed 27 409 visits). In an a-priori multivariate analysis with control variables including comorbidities and time since seroconversion, significant, direct negative effects of ageing were noted on all neurocognitive domains (p<0.0001 for all). Similar effects were noted for late-stage HIV disease progression on information processing speed (p=0.002), executive function (p<0.0001), motor function (p<0.0001), and working memory (p=0.001). Deleterious interaction effects were also noted in the domains of episodic memory (p=0.03) and motor function (p=0.02). INTERPRETATION: A greater than expected effect of ageing on episodic memory and motor function with advanced stages of HIV infection suggests that these two domains are most susceptible to the progression of neurocognitive impairment caused by ageing in individuals with HIV. This deficit pattern suggests differential damage to the hippocampus and basal ganglia (specifically nigrostriatal pathways). Older individuals with HIV infection should be targeted for regular screening for HIV-associate neurocognitive disorder, particularly with tests referable to the episodic memory and motor domains. FUNDING: National Institute of Mental Health. PMID- 28716546 TI - Delineating biological and technical variance in single cell expression data. AB - Single cell transcriptomics is becoming a common technique to unravel new biological phenomena whose functional significance can only be understood in the light of differences in gene expression between single cells. The technology is still in its early days and therefore suffers from many technical challenges. This review discusses the continuous effort to identify and systematically characterise various sources of technical variability in single cell expression data and the need to further develop experimental and computational tools and resources to help deal with it. PMID- 28716547 TI - Cellular senescence regulated by SWI/SNF complex subunits through p53/p21 and p16/pRB pathway. AB - SWI/SNF complex is an evolutionarily well-conserved chromatin-remodeling complex, which is implicated in the nucleosomes removing or sliding, impacting on the DNA repair, replication and genes expression regulation. The SWI/SNF complex consists up to 12 protein subunits. The catalytic subunits are BRG1 or BRM, which are exclusive ATPase subunits. BRG1 has been reported to play an important role in cellular senescence. However, The function of non-catalytic subunits involved in cellular senescence is rarely investigated. Therefore, we focused on the senescence regulation roles of SWI/SNF non-catalytic subunits in cellular senescent model induced by H2O2. H2O2 treatment was used to induce cellular senescence models in vitro. Screening the candidate subunits involved in this process by comparing the expression levels of SWI/SNF subunits with/without H2O2 treatment. Over-expression and knockdown the candidate subunits were utilized to investigate the functions and mechanism of the subunits involved in senescence regulation. The expressions of BAF57, BAF60a and SNF5 were changed significantly after H2O2 treatment. Overexpression of the three subunits separately induced cell growth arrest in both HaCaT and GLL19 cells, while knockdown of the subunits separately eased the senescence induced by H2O2 treatment. Results further showed that BAF57, BAF60a and SNF5 regulated cellular senescence via both p53/p21 and p16/pRB pathways, and the three subunits all had a directly interaction with p53. These results indicated that BAF57, BAF60a and SNF5 might act as novel pro senescence factors in both normal and tumor human skin cells. Therefore, inhibiting expression of the three factors might delay the cellular senescence process. PMID- 28716548 TI - Maternal pre-pregnancy body mass index, gestational weight gain influence birth weight. AB - BACKGROUND: Evidence suggests that pre-pregnancy body mass index and gestational weight gain have impact on pregnancy and birth weight, yet whether maternal gestational weight gain has a differential effect on the rates of adverse birth weight among women with different pre-pregnancy body mass index categories are unknown. METHODS: We selected 1617 children matched with their mothers as study subjects. The subjects were divided into three categories: weight gain below the American Institute of Medicine guidelines, weight gain within the American Institute of Medicine guidelines and weight gain above the American Institute of Medicine guidelines. RESULTS: The prevalence of pre-pregnancy underweight and overweight/obese women was 16.3% and 12.3%. And nearly 15.2% of the women had gestational weight gain below American Institute of Medicine guideline, 52.1% of the women had gestational weight gain above American Institute of Medicine guideline. Maternal overweight and obese was associated with increased risk for macrosomia and large-for-gestational age. Women had gestational weight gain below American Institute of Medicine guideline were more likely to have low birth weight and small-for-gestational age than women who had gestational weight gain within American Institute of Medicine guideline. Furthermore, the risks for macrosomia and large-for-gestational age were increased in women with above American Institute of Medicine guideline. And for women with a normal weight before pregnancy, gestational weight gain above the American Institute of Medicine guidelines were associated with higher rates of macrosomia and large-for gestational age, compared with the women of similar pre-pregnancy weight category but with gestational weight gain within the American Institute of Medicine guidelines. CONCLUSIONS: Women with abnormal pre-pregnancy body mass index and gestational weight gain are at risk for adverse birth weight outcomes. Moreover, gestational weight gain has a differential effect on the rates of adverse birth weight outcomes between women of different pre-pregnancy body mass index categories. PMID- 28716549 TI - Emotional labour and aboriginal maternal infant care workers: The invisible load. AB - BACKGROUND: The term 'emotional labour' has been used to describe the competing demands on midwives to empathize with clients whilst maintaining a level of professional detachment. Previous research indicates that when individuals experience difficulty managing these emotions, burnout may result. Aboriginal health care workers often have roles with large emotional demands, as they are relied upon heavily to engage clients in care. However, the concept of emotional labour has received little attention in relation to this group. AIM: To explore potential sources of emotional labour for Aboriginal Maternal Infant Care workers in a maternity care program for Aboriginal women in South Australia. The program involves these workers providing care for women in partnership with midwives. METHODS: We employed a phenomenological approach. Thirty in-depth interviews were conducted with staff and clients of the program. Recorded interviews were transcribed and coded and emerging themes identified. FINDINGS: This workforce undertakes extensive emotional labour. Key sources include the cultural and family obligations they have to clients, complex social needs of many clients, and potential for community backlash when poor perinatal outcomes occur. A lack of respect for the role within the workplace further contributes to these experiences. CONCLUSION: This study found that the responsibilities inherent to the role as both cultural broker and carer create significant emotional labour for workers. Recommendations to address this and enhance the sustainability of this workforce include: recognition and valuing of emotional work by management and other staff, enhancing cultural awareness training, and building stress relieving activities into the workplace. PMID- 28716550 TI - Co-deteriorations of anisotropic extracellular matrix arrangement and intrinsic mechanical property in c-src deficient osteopetrotic mouse femur. AB - Osteopetrotic bone shows dissociation between bone mineral density (BMD) and bone strength. In this study, volumetric BMD; preferential orientation of the extracellular matrix (ECM), which is composed of collagen fibers and apatite crystals as bone material quality; and mechanical properties of the src-/- osteopetrotic and normal mouse femoral cortical bone were analyzed and compared with each other at a bone tissue level. The degree of preferential orientation of ECM along the femoral long axis was significantly decreased in the src-/- mice femur, suggesting deteriorated bone quality. Young's modulus, as a tissue-level mechanical property analyzed by nano-indentation technique along the long bone direction, also was decreased in the src-/- mice cortical femur, in spite of the similar volumetric cortical BMD. To the best of our knowledge, this is the first report to demonstrate the synchronous deterioration of Young's modulus and anisotropic ECM organization in the src-/- osteopetrotic mouse bone. These results indicate that the deterioration of the preferential ECM orientation is one major cause of the impaired mechanical property in the src-/- mouse bone. PMID- 28716551 TI - Application of human induced pluripotent stem cells to model fibrodysplasia ossificans progressiva. AB - Fibrodysplasia ossificans progressiva (FOP) is a genetic condition characterized by massive heterotopic ossification. FOP patients have mutations in the Activin A type I receptor (ACVR1), a bone morphogenetic protein (BMP) receptor. FOP is a progressive and debilitating disease characterized by bone formation flares that often occur after trauma. Since it is often difficult or impossible to obtain large amounts of tissue from human donors due to the risks of inciting more heterotopic bone formation, human induced pluripotent stem cells (hiPSCs) provide an attractive source for establishing in vitro disease models and for applications in drug screening. hiPSCs have the ability to self-renew, allowing researchers to obtain large amounts of starting material. hiPSCs also have the potential to differentiate into any cell type in the body. In this review, we discuss how the application of hiPSC technology to studying FOP has changed our perspectives on FOP disease pathogenesis. We also consider ongoing challenges and emerging opportunities for the use of human iPSCs in drug discovery and regenerative medicine. PMID- 28716553 TI - Regional analysis of age-related local bone loss in the spine of a healthy population using 3D voxel-based modeling. AB - Local variations in bone loss may be of great importance to individually predict osteoporotic fractures but are neglected by current densitometry techniques. The purpose of this study was to evaluate regional variations of normal bone loss at the spine among different age groups using voxel-based morphometry. Non-contrast MDCT scans of 16 patients under the age of 40 (mean age 26years) without spinal pathology were identified as a reference cohort, where each thoracolumbar vertebra was assessed individually. For comparison, 38 patients >40years were grouped by decades in 4 cohorts of 10 patients each, except the youngest, including 8 patients only. All spines were automatically detected, segmented and non-rigidly registered for spatially normalized vertebral bodies. Afterwards, statistical and T-score mapping was performed to highlight local density differences in comparison to the reference cohort. The calculated statistical maps of significantly affected density regions (ADR) started to highlight small local changes of volumetric bone mineral density (vBMD) distribution within the vertebra of L5 (ADR: 7.9%) in the fifties cohort. Regions near the endplates were most affected. The effect dramatically increased in the sixties cohort, where bone loss was most prominent from T12 to L2. In the seventies cohort, around 50% of voxels in T10 to L5 showed significantly decreased vBMD. In conclusion, ADR and local T-score maps of the spine showed age-related local variations in a healthy population, corresponding to known areas of fracture origination and increased fracture incidence. It thus might provide a powerful tool in diagnosis of osteoporosis. PMID- 28716552 TI - Is heterotopic ossification getting nervous?: The role of the peripheral nervous system in heterotopic ossification. AB - Heterotopic ossification (HO), or de novo bone formation in soft tissue, is often observed following traumatic injury. Recent studies suggest that peripheral nerves may play a key functional role in this process. The results supporting a neurological basis for HO are examined in this article. Evidence supports the fact that BMPs released from bone matrix possess the capacity to induce HO. However, the process cannot be recapitulated using recombinant proteins without extremely high doses suggesting other components are required for this process. Study of injuries that increase risk for HO, i.e. amputation, hip replacement, elbow fracture, burn, and CNS injury suggests that a likely candidate is traumatic injury of adjacent peripheral nerves. Recent studies suggest neuroinflammation may play a key functional role, by its ability to open the blood-nerve barrier (BNB). Barrier opening is characterized by a change in permeability and is experimentally assessed by the ability of Evans blue dye to enter the endoneurium of peripheral nerves. A combination of BMP and barrier opening is required to activate bone progenitors in the endoneurial compartment. This process is referred to as "neurogenic HO". PMID- 28716555 TI - Attitudes about vaccines to prevent Ebola virus disease in Guinea at the end of a large Ebola epidemic: Results of a national household survey. AB - INTRODUCTION: In 2014-2016, an Ebola epidemic devastated Guinea; more than 3800 cases and 2500 deaths were reported to the World Health Organization. In August 2015, as the epidemic waned and clinical trials of an experimental, Ebola vaccine continued in Guinea and neighboring Sierra Leone, we conducted a national household survey about Ebola-related knowledge, attitudes, and practices (KAP) and opinions about "hypothetical" Ebola vaccines. METHODS: Using cluster randomized sampling, we selected participants aged 15+ years old in Guinea's 8 administrative regions, which had varied cumulative case counts. The questionnaire assessed socio-demographic characteristics, experiences during the epidemic, Ebola-related KAP, and Ebola vaccine attitudes. To assess the potential for Ebola vaccine introduction in Guinea, we examined the association between vaccine attitudes and participants' characteristics using categorical and multivariable analyses. RESULTS: Of 6699 persons invited to participate, 94% responded to at least 1 Ebola vaccine question. Most agreed that vaccines were needed to fight the epidemic (85.8%) and that their family would accept safe, effective Ebola vaccines if they became available in Guinea (84.2%). These measures of interest and acceptability were significantly more common among participants who were male, wealthier, more educated, and lived with young children who had received routine vaccines. Interest and acceptability were also significantly higher among participants who understood Ebola transmission modes, had witnessed Ebola response teams, knew Ebola-affected persons, believed Ebola was not always fatal, and would access Ebola treatment centers. In multivariable analyses of the majority of participants living with young children, interest and acceptability were significantly higher among those living with vaccinated children than among those living with unvaccinated children. DISCUSSION: The high acceptability of hypothetical vaccines indicates strong potential for introducing Ebola vaccines across Guinea. Strategies to build public confidence in use of Ebola vaccines should highlight any similarities with safe, effective vaccines routinely used in Guinea. PMID- 28716554 TI - Calcium phosphate nanoparticle (CaPNP) for dose-sparing of inactivated whole virus pandemic influenza A (H1N1) 2009 vaccine in mice. AB - The emergence of pandemic influenza strains, particularly the reemergence of the swine-derived influenza A (H1N1) in 2009, is reaffirmation that influenza viruses are very adaptable and influenza remains as a significant global public health treat. As recommended by the World Health Organization (WHO), the use of adjuvants is an attractive approach to improve vaccine efficacy and allow dose sparing during an influenza emergency. In this study, we utilized CaPtivate Pharmaceutical's proprietary calcium phosphate nanoparticles (CaPNP) vaccine adjuvant and delivery platform to formulate an inactivated whole virus influenza A/CA/04/2009 (H1N1pdm) vaccine as a potential dose-sparing strategy. We evaluated the relative immunogenicity and the efficacy of the formulation in BALB/c mice following single intramuscularly administration of three different doses (0.3, 1, or 3ug based on HA content) of the vaccine in comparison to non-adjuvanted or alum-adjuvant vaccines. We showed that, addition of CaPNP in vaccine elicited significantly higher hemagglutination inhibition (HAI), virus neutralization (VN), and IgG antibody titers, at all dose levels, relative to the non-adjuvanted vaccine. In addition, the vaccine containing CaPNP provided equal protection with 1/3rd of the antigen dose as compared to the non-adjuvanted or alum-adjuvanted vaccines. Our data provided support to earlier studies indicating that CaPNP is an attractive vaccine adjuvant and delivery system and should play an important role in the development of safe and efficacious dose-sparing vaccines. Our findings also warrant further investigation to validate CaPNP's capacity as an alternative adjuvant to the ones currently licensed for influenza/pandemic influenza vaccination. PMID- 28716557 TI - Is the SCORE chart underestimating the real cardiovascular (CV) risk of patients with psoriatic arthritis? Prevalence of subclinical CV disease detected by carotid ultrasound. AB - OBJECTIVES: To analyse the cardiovascular risk according to the SCORE chart in a series of patients with psoriatic arthritis, and to study the presence of subclinical cardiovascular disease by carotid ultrasound. METHODS: Cross sectional descriptive study of patients with psoriatic arthritis attended in a tertiary hospital. The presence of classical cardiovascular risk factors and the clinical characteristics of the patients were recorded. The cardiovascular risk was calculated with SCORE, calibrated for Spain. Common carotid ultrasound was conducted to assess intima-media thickness and the presence of atheroma plaques. Patients were reclassified upon ultrasound results. Statistical analyses were made for sample description, and multivariate analyses were performed to investigate the associations with the presence of atheroma plaques. RESULTS: A total of 102 patients were included. According to SCORE charts, 70.6% of the patients had intermediate cardiovascular risk, 25.5% high risk and 3.9% very high risk. After the ultrasound study, 26.5% of the patients were upgraded, and reclassified as very high risk due to the presence of plaques. The presence of subclinical vascular disease was associated with higher uric acid levels (P=0.036) and the presence of 2 or more cardiovascular risk factors (P=0.021). CONCLUSIONS: A considerable number of psoriatic arthritis patients have a priori moderate or high risk of a fatal cardiovascular event. Carotid ultrasound detects subclinical vascular disease and increases the real risk in a substantial proportion of patients. Cardiovascular risk prediction clinical tools such as the SCORE underestimate the presence of subclinical cardiovascular disease in patients with psoriatic arthritis. PMID- 28716556 TI - Impact of pneumococcal conjugate vaccine (PCV7 and PCV13) on pneumococcal invasive diseases in Italian children and insight into evolution of pneumococcal population structure. AB - BACKGROUND: The use of PCV7 for children immunization was gradually implemented in the Italian regions starting from 2006 and was replaced by PCV13 in 2010-2011. In this study we aimed to assess the PCV impact on invasive pneumococcal diseases (IPD) incidence, serotype distribution and antibiotic resistance in Italian children under 5years old. METHODS: All IPD cases in children from 5 Italian regions (Emilia-Romagna, Lombardia, A. P. Bolzano, A. P. Trento, and Piemonte) reported through the nationwide surveillance system during 2008-2014 were included in this study. Pneumococcal isolates were subjected to serotyping, antibiotic susceptibility testing, and clonal analysis according to standard methods. RESULTS: During the study period overall IPD incidence decreased from 7.8 cases/100,000 inhabitants in 2008 to 3.0 cases/100,000 in 2014 (61% decrease, P<0.001). In particular, from 2008 to 2014, PCV7-type IPD decreased from 2.92 to 0.13 cases/100,000 inhabitants (95% decrease, P<0.001) while PCV13-non-PCV7 type IPD decreased from 3.2 to 0.89 cases/100,000 inhabitants (72% decrease, P=0.008). Conversely, non-vaccine serotype (NVS) IPD increased overtime, becoming more common than PCV13 serotype IPD in 2013-2014. Emergent NVS 24F and 12F were the most prevalent in 2014. Antibiotic resistance testing revealed an overall increasing trend in penicillin resistance, from 14% in 2008 to 23% in 2014. Erythromycin resistance showed a downward trend, from 38% in 2008 to 27% in 2014. While in 2008 PCV13 serotypes were the major responsible for antibiotic resistance, during the following years antimicrobial resistance due to NVS increased, mainly as a result of expansion of pre-existing clones. CONCLUSIONS: Both PCVs led to a substantial decrease in vaccine-related IPD incidence in the children population. However NVS-related IPD increased, becoming the most prevalent in the last two-years period. Continuous surveillance is an essential tool to monitor evolution of pneumococcal population causing IPD in children. PMID- 28716558 TI - EMMPRIN overexpression in SVZ neural progenitor cells increases their migration towards ischemic cortex. AB - Stimulation of endogenous neurogenesis and recruitment of neural progenitors from the subventricular zone (SVZ) neurogenic site may represent a useful strategy to improve regeneration in the ischemic cortex. Here, we tested whether transgenic overexpression of extracellular matrix metalloproteinase inducer (EMMPRIN), the regulator of matrix metalloproteinases (MMPs) expression, in endogenous neural progenitor cells (NPCs) in the subventricular zone (SVZ) could increase migration towards ischemic injury. For this purpose, we applied a lentivector-mediated gene transfer system. We found that EMMPRIN-transduced progenitors exhibited enhanced MMP-2 activity in vitro and showed improved motility in 3D collagen gel as well as in cortical slices. Using a rat model of neonatal ischemia, we showed that EMMPRIN overexpressing SVZ cells invade the injured cortical tissue more efficiently than controls. Our results suggest that EMMPRIN overexpression could be suitable approach to improve capacities of endogenous or transplanted progenitors to invade the injured cortex. PMID- 28716560 TI - Integrated Mental Health Training for Pediatric and Psychology Trainees Using Standardized Patient Encounters. AB - Primary care pediatricians and psychology practitioners who comanage mental health problems can develop interdisciplinary communication and collaborative skills from joint standardized patient encounters and debriefings, combined with brief didactics. Learners showed increased confidence in shared management of behavior health problems. PMID- 28716559 TI - Optic nerve regeneration in mammals: Regenerated or spared axons? AB - Intraorbital optic nerve crush in rodents is widely used as a model to study axon regeneration in the adult mammalian central nervous system. Recent studies using appropriate genetic manipulations have revealed remarkable abilities of mature retinal ganglion cell (RGC) axons to regenerate after optic nerve injury, with some studies demonstrating that axons can then go on to re-innervate a number of central visual targets with partial functional restoration. However, one confounding factor inherent to optic nerve crush injury is the potential incompleteness of the initial lesion, leaving spared axons that later on could erroneously be interpreted as regenerating distal to the injury site. Careful examination of axonal projection pattern and morphology may facilitate separating spared from regenerating RGC axons. Here we discuss morphological criteria and strategies that may be used to differentiate spared versus regenerated axons in the injured mammalian optic nerve. PMID- 28716561 TI - Influence of renal biopsy results on the management of small kidney cancers in older patients: Results from a population-based cohort. AB - BACKGROUND AND OBJECTIVE: Small kidney cancers are a heterogeneous group with varying malignant potential. Pathologic information obtained from a renal biopsy may guide decision-making for small kidney cancers. We sought to assess the effect of pathologic information from renal biopsy on the nonsurgical management of small kidney cancers in a population-based cohort of patients over 65 years of age. METHODS: In the Surveillance, Epidemiology and End Results-Medicare dataset, we identified patients >=66 years diagnosed with a kidney cancer<4cm between 2002 and 2011. Diagnostic biopsy was defined by a Medicare claim within 1 month prior through 6 months following cancer diagnosis or before surgery. Nonsurgical management was defined by the absence of a claim for partial or radical nephrectomy or tumor ablation in the first 6 months following diagnosis. The relationship between patient and tumor characteristics and the likelihood of nonsurgical management by receipt of diagnostic biopsy was assessed by multivariable logistic regression models. RESULTS: From 8,933 patients, 2,782 (31%) had a diagnostic renal biopsy of whom 616 (22%) were managed nonsurgically. Controlling for patient, disease, and provider specialty, biopsy was associated with nonsurgical management (adjusted odds ratio = 1.61, 95% Cl: 1.43-1.82) in patients with low-grade tumors but also with more aggressive histology (clear cell renal cell carcinoma). Older age (85+) and geographic region were significantly associated with greater odds of diagnostic biopsy. Patients whose initial renal tumor diagnosis was made by a urologist (vs. other type of provider) were less likely to receive a biopsy (adjust odds ratio = 0.73, 95% Cl: 0.60-0.89). CONCLUSIONS: Although the use of renal biopsy has increased over time and is associated with the use of nonsurgical management of small kidney cancers, the use of the pathologic findings remains limited. Further advances, particularly with prognostic markers, are necessary before renal biopsy can be routinely implemented for treatment decision-making for small kidney cancers. PMID- 28716562 TI - Predictive factors for final pathologic ureteral sections on 700 radical cystectomy specimens: Implications for intraoperative frozen section decision making. AB - PURPOSE: To identify preoperative predictive factors for final ureteral section invasion after radical cystectomy (RC) and to validate significant factors on an external independent cohort. MATERIAL AND METHODS: We retrospectively reviewed data of all consecutive RC performed for bladder cancer in 2 high-volume institutions. Clinical, pathological, and follow-up data were collected prospectively and reviewed retrospectively. Pathological evaluation was performed by 2 well-trained uropathologists in each center. Logistic regression analyses were performed to identify predictive factors for final ureteral sections involvement. Significant factors in cohort A were validated in cohort B. Receiver operating curve and area under curve were modeled to evaluate predictive accuracy of the markers. RESULTS: A total of 441 RC were performed in center A and 307 RC were performed in center B. Mean follow-ups were 36.2 and 38.1 months, respectively. Invasion of the final ureteral section was observed on 5.5% of patients in cohort A and 4.8% of patients in cohort B. In cohort A, multivariable logistic regression identified preoperative hydronephrosis on computed tomography scan (odds ratio [OR] = 4.9, P = 0.004) and presence of Carcinoma in situ (CIS, OR = 3.9, P = 0.01) as the only factors associated with ureteral sections positivity. In cohort B, hydronephrosis and CIS were both associated with ureteral sections positivity in univariable analysis. In multivariable analysis, only hydronephrosis remained significant (OR = 5.9, P = 0.01). Predictive accuracy of hydronephrosis and CIS combined in 1 variable was 0.72. CONCLUSION: Hydronephrosis and bladder CIS have good accuracy in predicting ureteral sections positivity after RC. In the presence of those factors, ureteral frozen sections should be performed. PMID- 28716563 TI - Laparoscopic revision of transoral endoscopic vertical gastroplasty to Roux-en-Y gastric bypass. PMID- 28716564 TI - Endothelial to mesenchymal transition in the cardiovascular system. AB - Endothelial to mesenchymal transition (EndMT) is a special type of epithelial to mesenchymal transition. It is a process that is characterized by the loss of features of endothelial cells and acquisition of specific markers of mesenchymal cells. A variety of stimuli, such as inflammation, growth factors, and hypoxia, regulate EndMT through various signaling pathways and intracellular transcription factors. It has been demonstrated that epigenetic modifications are also involved in this process. Recent studies have identified the essential role of EndMT in the cardiovascular system. EndMT contributes to steps in cardiovascular development, such as cardiac valve formation and septation, as well as the pathogenesis of various cardiovascular disorders, such as congenital heart disease, myocardial fibrosis, myocardial infarction and pulmonary arterial hypertension. Thus, comprehensive understanding of the underlying mechanisms of EndMT will provide novel therapeutic strategies to overcome congenital heart disease due to abnormal development and other cardiovascular diseases. This review will focus on summarizing the currently understood signaling pathways and epigenetic modifications involved in the regulation of EndMT and the role of EndMT in pathophysiological conditions of the cardiovascular system. PMID- 28716565 TI - Mangiferin: A phytochemical with panacea potential. PMID- 28716566 TI - Combatting Bacterial Persister cell infections by auranofin? PMID- 28716567 TI - Moving the goalposts: A comparison of different definitions for primary external ventricular drain infection and its risk factors: A multi-center study of 2575 patients. AB - External ventricular drainage is the most common procedure performed in daily neurosurgical practice. One devastating complication is ventriculostomy associated infection, but the establishment of evidence-based management guidelines has been hindered by the lack of an universal definition. There is also limited data with regard to the utility of comorbidity health indices and surgery-related factors in predicting infection. This study aims to compare the incidence of infection according to five commonly used definitions and to identify risk factors for this complication. 2575 patients from seven neurosurgical centers in Hong Kong underwent primary external ventricular drainage. The frequency of infection according to Gozal was 2.2% (n=57), 4.7% (Chi), 0.6% (Lozier), 0.8% (Lyke) and 2.8% (Scheithauer). The commonest pathogen was coagulase negative staphylococcus (39%) and 49% of all microbial isolates were multiple-drug resistant. The mean Charlson comorbidity index was 0.5+/-1.1. Using Gozal's definition as the primary endpoint, the index was not predictive of infection and no surgical risk factors were identified. The only significant risk factor was the performance of two or more additional neurosurgical procedures within 30days of catheterization (OR: 2.1, 95% CI 1.1-4.5). The rate of infection is relatively low, but considerable disparity exists depending on the definition used. Our data implies that patient factors, in particular the Charlson comorbidity index, and variations in surgical practice are less influential than the strict observance of infection control measures. The high incidence of antibiotic-resistant bacteria is concerning and the routine of exchange of catheters within 30days should be discouraged. PMID- 28716568 TI - Factors associated with rerupture of intracranial aneurysms after endovascular treatment: A retrospective review of 11years experience at a single institution and review of the literature. AB - Aneurysm rebleeding following initial endovascular management is uncommon, and the factors associated with its occurrence are poorly defined. We retrospectively analyzed a consecutive series of patients presenting with aneurysmal subarachnoid hemorrhage who underwent endovascular management to determine factors associated with rebleeding. Rebleeding occurred in 7/183 (3.8%) patients, 6 of which had an adjacent hematoma on initial neuroimaging. Aneurysms were located on the ACoA (n=5), PCoA (n=1), and MCA (n=1). Sizes ranged from 3.5 to 13.0mm (mean 8.0), with neck sizes ranging from 1.8 to 4.6mm (mean 3.2). Time-to-rerupture ranged from hours to years, with 3/7 cases rebleeding within 30days and 4/7 cases rebleeding later than 30days. Initial incomplete angiographic occlusion occurred in 2/3 cases of early rebleeding. The presence of adjacent intracerebral hematoma (phi=0.354, p<0.005), increasing Fisher Grade (t(9.4)=7.72, p<0.005), and aneurysmal outpouching (phi=0.265, p<0.005) were found to be the only factors associated with rerupture status. Recurrent hemorrhage following endovascular management of ruptured intracranial aneurysms is an uncommon but important source of morbidity, particularly in the early post-embolization period. The presence of high-risk features, such as an adjacent intracerebral hematoma or aneurysm outpouching, warrant early and frequent angiographic follow up to document stability and mitigate rupture risk. PMID- 28716569 TI - Recombinant human bone morphogenetic protein-2 versus iliac crest bone graft in anterior cervical discectomy and fusion: Dysphagia and dysphonia rates in the early postoperative period with review of the literature. AB - Recombinant human bone morphogenetic protein-2 (rhBMP-2) is a growth factor utilized to stimulate bone development in several clinical scenarios. Although the U.S. Food and Drug Administration approved this therapeutic modality for only two applications, it is frequently used off-label in anterior cervical discectomy and fusion (ACDF) procedures as an alternative to iliac crest bone graft (ICBG), the prior standard of care. This usage has been a source of controversy in the medical community due to evidence of increased rates of postoperative edema and dysphagia. This retrospective cohort study investigates two groups of 200 patients having undergone ACDF, one using rhBMP-2 and the other using ICBG, to evaluate the incidence of complications in the early postoperative period. A significant reduction in average length of stay was found in the rhBMP-2 cohort (1.40days) compared to the ICBG cohort (1.85days) as well as a significantly increased rate of dysphagia (25.5% in rhBMP-2 vs. 15% in ICBG; p=0.01). An increased rate of dysphonia was observed among patients undergoing revision surgery (25.0%) compared to primary surgery (1.6%), but stratification by number of levels, gender, and smoking status yielded no differences in complication rates. Our evaluation of two large cohorts along with review of the literature on the topic sheds light on potential benefits and risks of rhBMP-2 in ACDF procedures. Further investigation is warranted to determine if clinical gains outweigh the potential harms of rhBMP-2 use in this setting. PMID- 28716570 TI - Protective Effects of Pistacia lentiscus L. fruit extract against calcium oxalate monohydrate induced proximal tubular injury. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The world prevalence of kidney stones is increasing and plants are frequently used to treat urolithiasis. Pistacia lentiscus L, a plant which freely grows around the Mediterranean basin areas, is widely used for various pathologies. P. lentiscus has an important impact as it has economical value on top of its pharmacological interest. Decoctions of its aerial parts and/or resin are used to treat kidney stones. AIM OF THE STUDY: To in vitro assess the potential nephroprotective effect of Pistacia lentiscus ethanolic fruit extract (PLEF) on proximal tubular cells in response to the adhesion of calcium oxalate monohydrate (COM) crystals. MATERIALS AND METHODS: Human Kidney [HK]-2 cells were incubated with and without COM in the presence or absence of PLEF. Cell viability was measured by the resazurin assay. The expression of E-cadherin was analyzed by PCR. The extracellular production of H2O2 was measured by Amplex(r) Red H2O2 Assay. The numbers of detached or non adherent COM crystals in the presence of PLEF were microscopically captured and counted using ImageJ software. The interaction of PLEF with COM and the effect of PLEF on crystal size were analyzed by flow cytometry. The spectrophotometric measurement of turbidity was performed for assessing the COM concentration. RESULTS: PLEF incubated with COM was able to increase the cell viability. The decrease of E-cadherin expression after incubation with COM was counteracted by PLEF. Overproduction of H2O2 induced by COM was also inhibited by PLEF. Observations using flow cytometry showed that interactions between PLEF and the COM crystals occurred. PLEF was also effective in reducing the particles size and in lowering COM concentration. CONCLUSION: Our data show that COM tubulotoxicity can be significantly reversed by PLEF -at least in part- via an inhibition of COM crystals adhesion onto the apical membrane. This early beneficial effect of PLEF needs to be further investigated as a useful strategy in nephrolithiasis prevention. PMID- 28716571 TI - Antiviral effect of forsythoside A from Forsythia suspensa (Thunb.) Vahl fruit against influenza A virus through reduction of viral M1 protein. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Yinqiaosan is a classical traditional Chinese medicine formula, which has been used to treat respiratory diseases since ancient China. It consists of nine herbs and among them, Forsythia suspensa (Thunb.) Vahl fruit is one of the major herbal components. Despite the long history of Yinqiaosan, the active compounds and the mechanisms of action of this formula remain elusive. AIM OF THE STUDY: The present study aimed to examine the suppressive effect of Yinqiaosan on influenza virus and to identify the active components in the formula targeting influenza. MATERIALS AND METHODS: Anti influenza virus effect of Yinqiaosan was assessed by tissue culture infective dose assay, and was also tested in an in vivo mouse model. Active compound from the formula was identified with a bioactivity-guided fractionation scheme. The potential mode of action of the compound was further investigated by identifying the host cell signaling pathways and viral protein production using in vitro cell culture models. RESULTS: Our results showed that forsythoside A from Forsythia suspensa (Thunb.) Vahl fruit, a major herbal component in Yinqiaosan, reduced the viral titers of different influenza virus subtypes in cell cultures and increased the survival rate of the mice in an in vivo influenza virus infection model. Further experiments on the mode of action of forsythoside A showed that it reduced the influenza M1 protein, which in turn intervened the budding process of the newly formed virions and eventually limited the virus spread. CONCLUSION: Results of our present study provides scientific evidence to support to the application of a traditional herbal formula. We also identify novel candidate compound for future drug development against influenza virus. PMID- 28716572 TI - DPPH-HPLC-MS assisted rapid identification of endothelial protective substances from Xiao-Ke-An. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Xiao-Ke-An formula (XKA) is a Chinese medicine widely used for treating diabetes and associated complications. Endothelial protection is thought to be one of its therapeutic mechanisms. However, the protective effect of XKA on endothelial cells remains unclear, especially in oxidative injury induced endothelial dysfunction. MATERIALS AND METHODS: A novel strategy to rapidly screen and identify potential endothelial protective substances from XKA was established by combining the 2,2'-diphenyl-1 picrylhydrazyl high performance liquid chromatography coupled with mass spectrometry (DPPH-HPLC-MS) approach with cell-based verification. Firstly, the DPPH-HPLC-MS approach was employed to identify the antioxidants in XKA. Then, the potent endothelial protective effect of XKA, and the potential active substances and mechanism of action were revealed in EA.hy926 cells injured by tert-butyl hydroperoxide (t-BHP). RESULTS: XKA exhibited potent antioxidant activity and endothelial protective effect. Phenolic acids derived from Salvia miltiorrhiza Bunge, root and rhizome, xanthones from Anemarrhena asphodeloides Bunge, rhizome, and acteoside from Rehmannia glutinosa (Gaertn.) DC., root, were identified as the major endothelial protective components in XKA. CONCLUSIONS: An efficient method for rapid identifying endothelial protective substances from complex mixtures was developed and used to identify the major endothelial protective components in XKA. This method would help reveal the material base of herbal medicine with endothelial protective effect, and could also be applied to discover novel natural-origin endothelial protective substances. PMID- 28716573 TI - HtrA3 stromal expression is correlated with tumor budding in stage II colorectal cancer. AB - Tumor budding is a well-established adverse prognostic factor in colorectal carcinoma (CRC). It may represent a form of epithelial-to-mesenchymal transition (EMT), although the underlying mechanisms remain unclear. High-temperature requirement A3 (HtrA3) is an inhibitor of the bone morphogenetic protein pathway, the suppression of which has been linked to EMT. Since HtrA3 is highly expressed in the desmoplastic stroma at the CRC invasive front, we sought to evaluate the relationship between tumor budding and HtrA3 expression in 172 stage II CRC resection specimens. All tumors were evaluated for tumor budding, with the highest budding slide selected for pan-keratin (CK) and HtrA3 immunohistochemistry. Representative areas of tumor core and invasive front, including budding and non-budding areas, were marked on CK stained slides, and then evaluated on HtrA3 stained slides. HtrA3 expression in tumor cells (tHtrA3) and peritumoral stroma (sHtrA3) was assessed for staining percentage and intensity (the product yielding a final score). Tumors with high-grade tumor budding (HGTB) showed increased expression of sHtrA3 in budding areas compared to non-budding areas at the invasive front (P<0.001). In addition, sHtrA3 expression at the invasive front was significantly higher in HGTB tumors compared to minimally budding tumors (P<0.05). tHtrA3 expression at the invasive front was significantly associated with high histological grade (P<0.05). Higher sHtrA3 expression in the tumor core (but not invasive front) was significantly associated with decreased 5-year overall survival on univariate analysis (P<0.05), but not multivariate analysis. HtrA3 expression in the peritumoral stroma of patients with stage II CRC is associated with HGTB and may be a novel marker of poor outcome. PMID- 28716574 TI - Foregut duplication cyst with pseudostratified columnar ciliated epithelium: A case report and review of the literature. AB - Foregut duplication cysts are extremely rare congenital malformations. Herein we report a case of 73 year old male with a left upper quadrant abdominal lesion identified on CT scan. PMID- 28716576 TI - TLR9-Mediated Conditioning of Liver Environment Is Essential for Successful Intrahepatic Immunotherapy and Effective Memory Recall. AB - Immune defense against hepatotropic viruses such as hepatitis B (HBV) and hepatitis C (HCV) poses a major challenge for therapeutic approaches. Intrahepatic cytotoxic CD8 T cells that are crucial for an immune response against these viruses often become exhausted resulting in chronic infection. We elucidated the T cell response upon therapeutic vaccination in inducible transgenic mouse models in which variable percentages of antigen-expressing hepatocytes can be adjusted, providing mosaic antigen distribution and reflecting the varying viral antigen loads observed in patients. Vaccination-induced endogenous CD8 T cells could eliminate low antigen loads in liver but were functionally impaired if confronted with elevated antigen loads. Strikingly, only by conditioning the liver environment with TLR9 ligand prior and early after peripheral vaccination, successful immunization against high intrahepatic antigen density with its elimination was achieved. Moreover, TLR9 immunomodulation was also indispensable for functional memory recall after high frequency antigen challenge. Together, the results indicate that TLR9-mediated conditioning of liver environment during therapeutic vaccination or antigen reoccurrence is crucial for an efficacious intrahepatic T cell response. PMID- 28716577 TI - Apoptosis-related genes induced in response to ketamine during early life stages of zebrafish. AB - Increasing evidence supports that ketamine, a widely used anaesthetic, potentiates apoptosis during development through the mitochondrial pathway of apoptosis. Defects in the apoptotic machinery can cause or contribute to the developmental abnormalities previously described in ketamine-exposed zebrafish. The involvement of the apoptotic machinery in ketamine-induced teratogenicity was addressed by assessing the apoptotic signals at 8 and 24 hpf following 20min exposure to ketamine at three stages of early zebrafish embryo development (256 cell, 50% epiboly and 1-4 somites stages). Exposure at the 256-cell stage to ketamine induced an up-regulation of casp8 and pcna at 8 hpf while changes in pcna at the mRNA level were observed at 24 hpf. After the 50% epiboly stage exposure, the mRNA levels of casp9 were increased at 8 and 24 hpf while aifm1 was affected at 24 hpf. Both tp53 and pcna expressions were increased at 8 hpf. After exposure during the 1-4 somites stage, no meaningful changes on transcript levels were observed. The distribution of apoptotic cells and the caspase-like enzymatic activities of caspase-3 and -9 were not affected by ketamine exposure. It is proposed that ketamine exposure at the 256-cell stage induced a cooperative mechanism between proliferation and cellular death while following exposure at the 50% epiboly, a p53-dependent and -independent caspase activation may occur. Finally, at the 1-4 somites stage, the defence mechanisms are already fully in place to protect against ketamine-insult. Thus, ketamine teratogenicity seems to be dependent on the functional mechanisms present in each developmental stage. PMID- 28716578 TI - Simulation to aid in interpreting biological relevance and setting of population level protection goals for risk assessment of pesticides. AB - Specific protection goals (SPGs) comprise an explicit expression of the environmental components that need protection and the maximum impacts that can be tolerated. SPGs are set by risk managers and are typically based on protecting populations or functions. However, the measurable endpoints available to risk managers, at least for vertebrates, are typically laboratory tests. We demonstrate, using the example of eggshell thinning in skylarks, how simulation can be used to place laboratory endpoints in context of population-level effects as an aid to setting the SPGs. We develop explanatory scenarios investigating the impact of different assumptions of eggshell thinning on skylark population size, density and distribution in 10 Danish landscapes, chosen to represent the range of typical Danish agricultural conditions. Landscape and timing of application of the pesticide were found to be the most critical factors to consider in the impact assessment. Consequently, a regulatory scenario of monoculture spring barley with an early spray treatment eliciting the eggshell thinning effect was applied using concentrations eliciting effects of zero to 100% in steps of 5%. Setting the SPGs requires balancing scientific, social and political realities. However, the provision of clear and detailed options such as those from comprehensive simulation results can inform the decision process by improving transparency and by putting the more abstract testing data into the context of real-world impacts. PMID- 28716575 TI - Strategic Targeting of Multiple BMP Receptors Prevents Trauma-Induced Heterotopic Ossification. AB - Trauma-induced heterotopic ossification (tHO) is a condition of pathologic wound healing, defined by the progressive formation of ectopic bone in soft tissue following severe burns or trauma. Because previous studies have shown that genetic variants of HO, such as fibrodysplasia ossificans progressiva (FOP), are caused by hyperactivating mutations of the type I bone morphogenetic protein receptor (T1-BMPR) ACVR1/ALK2, studies evaluating therapies for HO have been directed primarily toward drugs for this specific receptor. However, patients with tHO do not carry known T1-BMPR mutations. Here we show that, although BMP signaling is required for tHO, no single T1-BMPR (ACVR1/ALK2, BMPR1a/ALK3, or BMPR1b/ALK6) alone is necessary for this disease, suggesting that these receptors have functional redundancy in the setting of tHO. By utilizing two different classes of BMP signaling inhibitors, we developed a translational approach to treatment, integrating treatment choice with existing diagnostic options. Our treatment paradigm balances either immediate therapy with reduced risk for adverse effects (Alk3-Fc) or delayed therapy with improved patient selection but greater risk for adverse effects (LDN-212854). PMID- 28716579 TI - Urinary NNAL in hookah smokers and non-smokers after attending a hookah social event in a hookah lounge or a private home. AB - Tobacco smoking and exposure to tobacco secondhand smoke (SHS) can cause lung cancer. We determined uptake of NNK (4-(Methylnitrosamino)-1-(3-pyridyl)-1 butanone), a tobacco specific potent pulmonary carcinogen, in hookah smokers and non-smokers exposed to hookah tobacco SHS. We analyzed data from a community based convenience sample of 201 of adult (aged >=18 years) exclusive hookah smokers (n = 99) and non-smokers (n = 102) residing in San Diego County, California. Participants spent an average of three consecutive hours indoors, in hookah lounges or private homes, where hookah tobacco was smoked exclusively. Total NNAL [the sum of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and its glucuronides], the major metabolites of NNK, were quantified in spot urine samples provided the morning of and the morning after attending a hookah event. Among hookah smokers urinary NNAL increased significantly (p<0.001) following a hookah social event; the geometric mean doubled, from 1.97 to 4.16 pg/mg. Among non-smokers the increase was not significant (p = 0.059). Post hookah event urinary NNAL levels were highest in daily hookah smokers, and significantly higher than in non-daily smokers or non-smokers (GM: 14.96 pg/mg vs. 3.13 pg/mg and 0.67 pg/mg, respectively). For both hookah smokers and non-smokers, pre-to post event change in urinary NNAL was not significantly different between hookah lounges and homes. We suggest posting health warning signs inside hookah lounges, and encouraging voluntary bans of smoking hookah tobacco in private homes. PMID- 28716580 TI - [Determination of prognostic value of the OESIL risk score at 6 months in a Colombian cohort with syncope evaluated in the emergency department; first Latin American experience]. AB - OBJECTIVES: To establish the prognostic value, with sensitivity, specificity, positive predictive value, and negative predictive value for the OESIL syncope risk score to predict the presentation of severe outcomes (death, invasive interventions, and readmission) after 6 months of observation in adults who consulted the emergency department due to syncope. METHODS: Observational, prospective, and multicentre study with enrolment of subjects older than 18 years, who consulted in the emergency department due to syncope. A record was mad of the demographic and clinical information of all patients. The OESIL risk score was calculated, and severe patient outcomes were followed up during a 6 month period using telephone contact. RESULTS: A total of 161 patients met the inclusion criteria and were followed up for 6 months. A score above or equal to 2 in the risk score, classified as high risk, was present in 72% of the patients. The characteristics of the risk score to predict the combined outcome of mortality, invasive interventions, and readmission for a score above or equal to 2 were 75.7, 30.5, 43.1, and 64.4% for sensitivity, specificity, positive predictive value, and negative predictive value, respectively. CONCLUSIONS: A score above or equal to 2 in the OESIL risk score applied in Colombian population was of limited use to predict the studied severe outcomes. This score will be unable to discriminate between patients that benefit of early admission and further clinical studies. PMID- 28716581 TI - Diversifying Food Systems in the Pursuit of Sustainable Food Production and Healthy Diets. AB - Increasing demand for nutritious, safe, and healthy food because of a growing population, and the pledge to maintain biodiversity and other resources, pose a major challenge to agriculture that is already threatened by a changing climate. Diverse and healthy diets, largely based on plant-derived food, may reduce diet related illnesses. Investments in plant sciences will be necessary to design diverse cropping systems balancing productivity, sustainability, and nutritional quality. Cultivar diversity and nutritional quality are crucial. We call for better cooperation between food and medical scientists, food sector industries, breeders, and farmers to develop diversified and nutritious cultivars that reduce soil degradation and dependence on external inputs, such as fertilizers and pesticides, and to increase adaptation to climate change and resistance to emerging pests. PMID- 28716582 TI - A probabilistic Poisson-based model accounts for an extensive set of absolute auditory threshold measurements. AB - Thresholds for detecting sounds in quiet decrease with increasing sound duration in every species studied. The neural mechanisms underlying this trade-off, often referred to as temporal integration, are not fully understood. Here, we probe the human auditory system with a large set of tone stimuli differing in duration, shape of the temporal amplitude envelope, duration of silent gaps between bursts, and frequency. Duration was varied by varying the plateau duration of plateau burst (PB) stimuli, the duration of the onsets and offsets of onset-offset (OO) stimuli, and the number of identical bursts of multiple-burst (MB) stimuli. Absolute thresholds for a large number of ears (>230) were measured using a 3 interval-3-alternative forced choice (3I-3AFC) procedure. Thresholds decreased with increasing sound duration in a manner that depended on the temporal envelope. Most commonly, thresholds for MB stimuli were highest followed by thresholds for OO and PB stimuli of corresponding durations. Differences in the thresholds for MB and OO stimuli and in the thresholds for MB and PB stimuli, however, varied widely across ears, were negative in some ears, and were tightly correlated. We show that the variation and correlation of MB-OO and MB-PB threshold differences are linked to threshold microstructure, which affects the relative detectability of the sidebands of the MB stimuli and affects estimates of the bandwidth of auditory filters. We also found that thresholds for MB stimuli increased with increasing duration of the silent gaps between bursts. We propose a new model and show that it accurately accounts for our results and does so considerably better than a leaky-integrator-of-intensity model and a probabilistic model proposed by others. Our model is based on the assumption that sensory events are generated by a Poisson point process with a low rate in the absence of stimulation and higher, time-varying rates in the presence of stimulation. A subject in a 3I-3AFC task is assumed to choose the interval in which the greatest number of events occurred or randomly chooses among intervals which are tied for the greatest number of events. The subject is further assumed to count events over the duration of an evaluation interval that has the same timing and duration as the expected stimulus. The increase in the rate of the events caused by stimulation is proportional to the time-varying amplitude envelope of the bandpass-filtered signal raised to an exponent. We find the exponent to be about 3, consistent with our previous studies. This challenges models that are based on the assumption of the integration of a neural response that is directly proportional to the stimulus amplitude or proportional to its square (i.e., proportional to the stimulus intensity or power). PMID- 28716583 TI - Quantitative Analysis of Geometry and Lateral Symmetry of Proximal Middle Cerebral Artery. AB - BACKGROUND: The purpose of our work is to quantitatively assess clinically relevant geometric properties of proximal middle cerebral arteries (pMCA), to investigate the degree of their lateral symmetry, and to evaluate whether the pMCA can be modeled by using state-of-the-art deformable image registration of the ipsi- and contralateral hemispheres. METHODS: Individual pMCA segments were identified, quantified, and statistically evaluated on a set of 55 publicly available magnetic resonance angiography time-of-flight images. Rigid and deformable image registrations were used for geometric alignment of the ipsi- and contralateral hemispheres. Lateral symmetry of relevant geometric properties was evaluated before and after the image registration. RESULTS: No significant lateral differences regarding tortuosity and diameters of contralateral M1 segments of pMCA were identified. Regarding the length of M1 segment, 44% of all subjects could be considered laterally symmetrical. Dominant M2 segment was identified in 30% of men and 9% of women in both brain hemispheres. Deformable image registration performed significantly better (P < .01) than rigid registration with regard to distances between the ipsi- and the contralateral centerlines of M1 segments (1.5 +/- 1.1 mm versus 2.8 +/- 1.2 mm respectively) and between the M1 and the anterior cerebral artery (ACA) branching points (1.6 +/- 1.4 mm after deformable registration). CONCLUSIONS: Although natural lateral variation of the length of M1 may not allow for sufficient modeling of the complete pMCA, deformable image registration of the contralateral brain hemisphere to the ipsilateral hemisphere is feasible for localization of ACA-M1 branching point and for modeling 71 +/- 23% of M1 segment. PMID- 28716584 TI - P-Wave Terminal Force in Lead V1 Predicts Paroxysmal Atrial Fibrillation in Acute Ischemic Stroke. AB - BACKGROUND: Detection of paroxysmal atrial fibrillation (PAF) in cryptogenic stroke is critical to selecting an antithrombotic therapy for preventing recurrent stroke. However, the predictor of PAF in patients with acute ischemic stroke is not well elucidated. P-wave terminal force in lead V1 (PTFV1) is a standard electrocardiogram marker of left atrial abnormality. In this study, we aimed to investigate the utility of PTFV1 for the prediction of PAF in patients with acute ischemic stroke. METHODS: The study included 295 consecutive patients who had acute ischemic stroke and were admitted to the hospital between September 2014 and August 2016. Patients with a known history of PAF, persistent atrial fibrillation, or cardiac pacemaker were excluded from the study. The clinical characteristics of patients with or without PAF were compared, and multiple logistic regression analysis was performed to assess the independent contribution of each variable. RESULTS: Among 226 patients eligible for our analysis, 16 (7.1%) were diagnosed with PAF after admission. PTFV1 was significantly higher in patients with PAF than those without PAF (.051 versus .027 mm?s; P < .001). Multivariate analysis showed that PTFV1 per .01 mm?s increase was strongly associated with PAF (odds ratio, 1.61; 95% confidence interval, 1.24-2.09; P < .001). The optimal cutoff value of PTFV1 for the prediction of PAF was .04 mm?s. CONCLUSIONS: PTFV1 is a strong predictor of PAF detection in acute ischemic stroke. PMID- 28716585 TI - Ascertainment of Alaska Native Stroke Incidence, 2005-2009: Lessons for Assessing the Global Burden of Stroke. AB - BACKGROUND: Stroke is a critical public health issue in the United States and globally. System models to optimally capture stroke incidence in rural and culturally diverse communities are needed. The epidemiological transition to a western lifestyle has been associated with an increased burden of vascular risk factors among Alaska Native (AN) people. The burden of stroke in AN communities remains understudied. METHODS: The Alaska Native Stroke Registry (ANSR) was designed to screen and capture all stroke cases between 2005 and 2009 through its integration into the existing single-payer Alaska Tribal Health System infrastructure. Registry staff received notification each time stroke International Classification of Diseases, Ninth Revision codes (430-436) were initiated anywhere in the system. Trained chart abstractors reviewed medical records to document incident strokes among AN patients, which were adjudicated. RESULTS: Between October 2005 and October 2009, over 2100 alerts were screened identifying 514 unique stroke cases, of which 372 were incident strokes. The average annual incidence of stroke (per 100,000) among AN adults was 190.6: 219.2 in men and 164.7 in women. Overall, the ischemic stroke incidence rate was 148.5 per 100,000 with men (184.6) having higher ischemic rates per 100,000 than women (118.3). Men have higher rates of ischemic stroke at all ages, whereas older women experienced higher rates of hemorrhagic strokes over the age of 75 years. CONCLUSIONS: We report a high rate of overall stroke, 190.6 per 100,000. The ANSR methods and findings have implications for other indigenous populations and for global health populations currently undergoing similar epidemiological transitions. PMID- 28716586 TI - Comparison of Three-Dimensional T1-Weighted Magnetic Resonance and Contrast Enhanced Ultrasound Plaque Images for Severe Stenosis of the Cervical Carotid Artery. AB - BACKGROUND AND PURPOSE: Magnetic resonance (MR) and contrast-enhanced ultrasound assess characteristics and neovascularization, respectively, of the carotid plaque. The purpose of the present study was to clarify how findings of contrast enhanced ultrasound plaque imaging are related to those of 3-dimensional (3D) fast spin echo (FSE) T1-weighted MR plaque imaging (WI) in severe stenosis (>=70%) of the cervical carotid artery. METHODS: Fifty-three patients underwent 3D FSE T1-WI and contrast-enhanced ultrasound. For each patient, the averaged contrast ratio on MR (CRMR) was calculated by dividing the averaged internal carotid artery plaque signal intensity by the sternocleidomastoid muscle signal intensity; maximally enhanced intensities on the intraplaque and lumen time intensity curves were obtained from contrast-enhanced ultrasound data, and the ratio of the maximal intensity of the intraplaque curve to that of the lumen curve was calculated and defined as contrast effect (CEUS). RESULTS: A linear correlation (r = .702; P <.0001) was observed between CRMR and CEUS. Receiver operating characteristic curve analyses to evaluate the ability of the CEUS to differentiate each category of CRMR from the other 2 categories showed that the sensitivity was significantly lower for category II (1.30 <= CRMR <= 1.60) than for category I (CRMR < 1.30) or III (1.60 < CRMR). The CEUS was lower in plaques with higher CRMR than in those with lower CRMR in a subgroup of category III (P = .0196). CONCLUSION: Findings of contrast-enhanced ultrasound plaque imaging are related to those of 3D FSE T1-WI MR plaque imaging according to the life history of arterial plaque and its neovascularization. PMID- 28716587 TI - Botulinum neurotoxin A promotes functional recovery after peripheral nerve injury by increasing regeneration of myelinated fibers. AB - The injection of safe doses of botulinum neurotoxin A (BoNT/A) have been reported to be useful for the treatment of neuropathic pain, but it is still unknown how functional recovery is induced after peripheral nerve injury. We evaluated the effects of intranerve application of BoNT/A, on regeneration and sensorimotor functional recovery in partial and complete peripheral nerve injuries in the mouse. After sciatic nerve crush (SNC) and intranerve delivery of BoNT/A (15pg), axonal regeneration was measured by nerve pinch test at different days. Regeneration of myelinated and unmyelinated fibers was assessed by immunohistochemical double labeling for NF200/GAP43 and CGRP/GAP43. S100 was used as Schwann cells marker. Medial footpad skin reinnervation was assessed by PGP staining. Motor functions were assessed by means of nerve conduction tests. In other mice groups, nerve conduction tests were performed also after chronic constriction injury (CCI) of the sciatic nerve and intraplantar injection of BoNT/A (15pg). In SNC mice, BoNT/A increased the rate of axonal regeneration. The advantage of regrowing myelinated axons after BoNT/A injection was evidenced by longer NF200+ nerve profiles and confirmed by nerve histology. We observed also a higher expression of S100 in the distal portion of BoNT/A-injected regenerated nerves. In CCI mice, BoNT/A induced an increase in reinnervation of gastrocnemius and plantar muscles. These results show that a low dose of BoNT/A, insufficient to produce muscular dysfunction, conversely speeds up sensorimotor recovery by stimulating myelinated axonal regeneration, and points out its application as a multipotent treatment for peripheral neuropathies. PMID- 28716588 TI - Cathodal transcranial direct current stimulation of the extrastriate visual cortex modulates implicit anti-fat bias in male, but not female, participants. AB - Explicit negative attitudes toward obese individuals are well documented and seem to modulate the activity of perceptual areas, such as the Extrastriate Body Area (EBA) in the lateral occipito-temporal cortex, which is critical for body-shape perception. Nevertheless, it is still unclear whether EBA serves a role in implicit weight-stereotypical bias, thus reflecting stereotypical trait attribution on the basis of perceptual cues. Here, we used an Implicit Association Test (IAT) to investigate whether applying transcranial direct current stimulation (tDCS) over bilateral extrastriate visual cortex reduces pre existing implicit weight stereotypical associations (i.e. "Bad" with Fat and "Good" with Slim, valence-IAT). Furthermore, an esthetic-IAT, which focused on body-concepts related to esthetic dimensions (i.e. "Ugly" and "Beauty"), was developed as a control condition. Anodal, cathodal, or sham tDCS (2mA, 10min) over the right and left lateral occipito-temporal (extrastriate visual) cortex was administered to 13 female and 12male participants, before performing the IATs. Results showed that cathodal stimulation over the left extrastriate visual cortex reduced weight-bias for the evaluative dimensions (Bad vs. Good) as compared to sham stimulation over the same hemisphere. Furthermore, the effect was specific for the polarity and hemisphere of stimulation. Importantly, tDCS affected the responses only in male participants, who presented a reliable weight bias during sham condition, but not in female participants, who did not show reliable weight-bias at sham condition. The present results suggest that negative attitudes toward obese individuals may reflect neural signals from the extrastriate visual cortex. PMID- 28716589 TI - The role of dopamine D2 receptors in the nucleus accumbens during taste-aversive learning and memory extinction after long-term sugar consumption. AB - The nucleus accumbens (NAcc) is a forebrain region that may significantly contribute to the integration of taste and visceral signals during food consumption. Changes in dopamine release in the NAcc have been observed during consumption of a sweet taste and during compulsive consumption of dietary sugars, suggesting that NAcc dopaminergic transmission is strongly correlated with taste familiarity and the hedonic value content. NAcc core and shell nuclei are differentially involved during and after sugar exposure and, particularly, previous evidence suggests that dopamine D2 receptors could be related with the strength of the latent inhibition (LI) of conditioned taste aversion (CTA), which depends on the length of the taste stimulus pre-exposure. Thus, the objective of this work was to evaluate, after long-term exposure to sugar, the function of dopaminergic D2 receptors in the NAcc core during taste memory retrieval preference test, and during CTA. Adult rats were exposed during 14days to 10% sugar solution as a single liquid ad libitum. NAcc core bilateral injections of D2 dopamine receptor antagonist, haloperidol (1MUg/MUL), were made before third preference test and CTA acquisition. We found that sugar was similarly preferred after 3 acute presentations or 14days of continued sugar consumption and that haloperidol did not disrupt this appetitive memory retrieval. Nevertheless, D2 receptors antagonism differentially affects aversive memory formation after acute or long-term sugar consumption. These results demonstrate that NAcc dopamine D2 receptors have a differential function during CTA depending on the degree of sugar familiarity. PMID- 28716590 TI - Lumbar muscle inflammation alters spinally mediated locomotor recovery induced by training in a mouse model of complete spinal cord injury. AB - Locomotor networks after spinal cord injury (SCI) are shaped by training activated proprioceptive and cutaneous inputs. Nociception from injured tissues may alter these changes but has largely been overlooked. The objective of the present study was to ascertain whether lumbar muscle inflammation hinders locomotion recovery in a mouse model of complete SCI. Lower limb kinematics during treadmill training was assessed before and after complete SCI at T8 (2, 7, 14, 21 and 28days post-injury). Locomotor recovery was compared in 4 groups of CD1 mice: control spinal mice; spinal mice with daily locomotor training; spinal mice with lumbar muscle inflammation (Complete Freund's Adjuvant (CFA) injection); and spinal mice with locomotor training and CFA. On day 28, H-reflex excitability and its inhibition at high-frequency stimulation (frequency dependent depression: FDD) were compared between groups, all of which showed locomotor recovery. Recovery was enhanced by training, whereas lumbar muscle inflammation hindered these effects (knee angular excursion and paw drag: p's<0.05). In addition, lumbar muscle inflammation impaired hind limb coupling during locomotion (p<0.05) throughout recovery. Also, H-reflex disinhibition was prevented by training, with or without CFA injection (p's<0.05). Altogether, these results indicate that back muscle inflammation modulates spinally mediated locomotor recovery in mice with complete SCI, in part, by reducing adaptive changes induced by training. PMID- 28716591 TI - Clustering-making model for diagnosis of acute coronary syndrome using PCA based on K-MICA algorithms. PMID- 28716592 TI - The new face of heroin. PMID- 28716593 TI - The critical care literature 2016. AB - An emergency physician (EP) is often the first health care provider to evaluate, resuscitate, and manage a critically ill patient. Between 2001 and 2009, the annual hours of critical care delivered in emergency departments (EDs) across the United States increased >200%! (Herring et al., 2013). This trend has persisted since then. In addition to seeing more critically ill patients, EPs are often tasked with providing critical care long beyond the initial resuscitation period. In fact, >33% of critically ill patients who are brought to an ED remain there for >6h (Herring et al., 2013). During these crucial early hours of illness, detrimental pathophysiologic processes begin to take hold. During this time, lives can be saved or lost. Therefore, it is important for the EP to be knowledgeable about recent developments in critical care medicine. This review summarizes important articles published in 2016 pertaining to the care of select critically ill patients in the ED. The following topics are covered: intracerebral hemorrhage, traumatic brain injury, anti-arrhythmic therapy in cardiac arrest, therapeutic hypothermia, mechanical ventilation, sepsis, and septic shock. PMID- 28716594 TI - Adverse events from physostigmine: An observational study. PMID- 28716595 TI - The risk stratification and prognostic evaluation of soluble programmed death-1 on patients with sepsis in emergency department. AB - OBJECTIVE: To evaluate the efficacy of soluble programmed death-1 (sPD-1) for risk stratification and prediction of 28-day mortality in patients with sepsis, we compared serum sPD-1 with procalcitonin (PCT), C-reactive protein (CRP), and the Mortality in Emergency Department Sepsis (MEDS) score. METHODS: A total of 60 healthy volunteers and 595 emergency department (ED) patients were recruited for this prospective cohort study. According to the severity of their condition on ED arrival, the patients were allocated to the systemic inflammatory response syndrome group (130 cases), sepsis group (276 cases), severe sepsis group (121 cases), and septic shock group (68 cases). In addition, all patients with sepsis were also divided into the survivor group (349 cases) and nonsurvivor group (116 cases) according to the 28-day outcomes. RESULTS: When the severity of sepsis increased, the levels of sPD-1 gradually increased. The levels of sPD-1, PCT, CRP and the MEDS score were also higher in the nonsurvivor group compared to the survivor group. Logistic regression suggested that sPD-1, PCT, and the MEDS score were independent risk factors for 28-day mortality of patients with sepsis. Area under the curve (AUC) of sPD-1, PCT and the MEDS score for 28-day mortality was 0.725, 0.693, and 0.767, respectively, and the AUC was improved when all 3 factors were combined (0.843). CONCLUSION: Serum sPD-1 is positively correlated with the severity of sepsis, and it is valuable for risk stratification of patients and prediction of 28-day mortality. Combining sPD-1 with PCT and the MEDS score improves the prognostic evaluation. PMID- 28716596 TI - Quality comparison of umbilical cord blood cryopreserved with conventional versus automated systems. AB - Umbilical cord blood (CB) banks usually freeze and store CB for clinical transplantation using conventional controlled-rate freezer or the automated BioArchive system. The aim of this study is to compare the quality of CB cryopreserved with conventional and automated methods and to make clear the cause of the quality difference between the two methods. The experiment used 80 CB units: 40 were conventionally cryopreserved and the remainder were cryopreserved with a BioArchive. After thawing, the following measures of CB quality were compared: recovery rates of cell count, cell viability of total nucleated cells (TNCs), mononuclear cells (MNCs), and CD34+ cells, as well as colony-forming unit granulocyte/macrophage (CFU-GM) content. Additionally, processing and storage records were reviewed to quantify the number of exposures of CB units at room temperature (transient warming event, TWE), which was analyzed in relation to CB quality. MNC and CD34+ cell viability were as follows: MNC, 78.2% +/- 6.8% (conventional), 81.7% +/- 7.2% (automated); CD34+ cell, 90.6% +/- 6.9% (conventional), 94.7% +/- 3.5% (automated). The absolute CFU-GM content per CB unit was 7.1 * 105 +/- 5.9 * 105 with conventional cryopreservation and 12.3 * 105 +/- 12.0 * 105 with automated cryopreservation. CBs cryopreserved with BioArchive showed significantly higher MNC and CD34+ cell viability, and CFU-GM content than those conventionally cryopreserved. The CB quality comparison depending on the amount of TWEs showed no significant quality difference between groups that were more exposed to TWEs and groups that were less exposed. CBs cryopreserved with BioArchive were of higher quality than conventionally cryopreserved CBs, and the cause of quality difference might be due to the difference of freezing conditions rather than the TWE effect. PMID- 28716597 TI - Cells isolated from cryopreserved dental follicle display similar characteristics to cryopreserved dental follicle cells. AB - Dental follicle tissue is a promising resource of mesenchymal stem cells for cytotherapeutic approaches and tissue engineering applications. There are two procedures for banking of human dental follicle stem cells have been reported. Conventional method requires cell isolation, expansion and immediate cryopreservation. Whereas dental follicle stem cells can be isolated from cryopreserved dental follicle fragments. The aim of this study was to compare the characteristics of dental follicle cells isolated from cryopreserved fragments (DFCs-CF) with dental follicle cells recovered from cryopreserved cells (DFCs CC). Dental follicle fragments obtained after mechanical disaggregation were divided into two parts, with one part maintained in culture, while another part underwent cryopreservation. Dental follicle fragments and dental follicle cells from fresh tissue were stored in liquid nitrogen for 3 months. After thawing, the isolation, morphology, proliferation, cell cycle, colony-forming-unit ability, stemness-related marker expression, apoptosis, and multi-lineage differentiation potential of DFCs-CF were tested compared with DFCs-CC. DFCs-CF expressed mesenchymal stem cells marker, proliferated well, showed similar levels of mRNA for stemness- and apoptosis-related genes and exhibited the capacity of multi lineage differentiation similar to those of DFCs-CC. These results imply that cryopreservation of dental follicle fragments is an effective banking method for isolation of dental follicle cells. PMID- 28716598 TI - Effect of lecithin nanoliposome or soybean lecithin supplemented by pomegranate extract on post-thaw flow cytometric, microscopic and oxidative parameters in ram semen. AB - This investigation was carried out to study the effect of soybean lecithin 1.5% (wt/vol) (0, 2.5, 5 and 7.5 mg l-1 pomegranate extract (PE)) or PE-loaded lecithin nanoliposome (0, 2.5, 5 and 7.5 mg l-1) to Tris-based extender. Sperm motility (CASA), viability, membrane integrity (HOS test), abnormalities, mitochondrial activity, apoptosis status, lipid peroxidation, total antioxidant capacity (TAC)) and antioxidant activities (GPX, SOD) were investigated following freeze-thawing. No significant differences were detected in motility parameters, viability, membrane integrity, and mitochondria activity after thawing sperm between soybean lecithin and lecithin nanoliposomes. It was shown that PE5 significantly improved sperm total and progressive motility, membrane integrity, viability, mitochondria activity, TAC and reduced lipid peroxidation (malondialdehyde concentration). Moreover, the percentage of apoptotic sperm in PE5 extenders was significantly the lowest among other treatments. Sperm abnormalities, SOD and GPX were not affected by the antioxidant supplements. For apoptotic status, no differences were observed between soybean lecithin and lecithin nanoliposome. We showed that lecithin nanoliposome extender can be a beneficial alternative extender to protect ram sperm during cryopreservation without any adverse effects. It was also observed that regarding pomegranate concentration, PE5 can improve the quality of ram semen after thawing. PMID- 28716599 TI - Maintaining viability and characteristics of cholangiocarcinoma tissue by vitrification-based cryopreservation. AB - Tumor tissue has great clinical and scientific value which relies highly on the proper preservation of primary materials. Conventional tumor tissue cryopreservation using slow-freezing method has yielded limited success, leading to significant cell loss and morphological damage. Here we report a standardized vitrification-based cryopreservation method, by which we have successfully vitrified and warmed 35 intrahepatic cholangiocarcinoma (ICC) tissues with up to 80% viability of the fresh tumor tissues. Cryopreserved ICC tissue could generate patient-derived xenografts (PDXs) with take rates of 68.2% compared to 72.7% using fresh tumor tissues. Histological and genetic analyses showed that no significant alterations in morphology and gene expression were introduced by this cryopreservation method. Our procedure may facilitate collection, long-time storage and propagation of cholangiocarcinoma or other tumor specimens for (pre)clinical studies of novel therapies or for basic research. PMID- 28716600 TI - The utility of NAFLD fibrosis score for prediction of mortality among patients with nonalcoholic fatty liver disease: A systematic review and meta-analysis of cohort study. AB - BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a common liver disorder worldwide. Several noninvasive diagnostic scoring systems have been developed to determine the severity of liver fibrosis and to predict long-term outcome of patients with NAFLD in lieu of liver biopsy. We conducted this systematic review and meta-analysis to investigate the role of NAFLD fibrosis score (NFS) for prediction of mortality from NAFLD. METHODS: MEDLINE and EMBASE databases were searched through October 2016 for studies that investigated the association between high NFS and mortality. Pooled risk ratio (RR) and 95% confidence interval (CI) were calculated using a random-effects model, generic inverse variance method. The between-study heterogeneity of effect-size was quantified using the Q statistic and I2. RESULTS: A total of five cohort studies with 5033 NAFLD patients were identified. High NFS (score of greater than 0.675) was significantly associated with increased mortality with the pooled RR of 4.54 (95%CI: 1.85-11.17). The statistical heterogeneity was high with I2 of 88% (Pheterogeneity<0.01). CONCLUSIONS: High NFS is associated with increased risk of mortality among patients with NAFLD. This scoring system may be considered as an alternative to liver biopsy for prediction of mortality outcome. PMID- 28716601 TI - Changes in refractive status in an elderly Chinese population in a 7-year follow up: The Shihpai Eye Study. AB - BACKGROUND: Refractive error is the major cause of moderate and severe visual impairment. Visual impairment limits people's ability to perform daily tasks and affects their quality of life. Longitudinal data on the refractive status of the elderly was available only for whites and Africans. The purpose of this study was to report the 7-year incidence of myopia, hyperopia and refractive error change as well as their associated risk factors in a metropolitan elderly Chinese population. METHODS: The Shihpai Eye Study 2006 included 460/824 (55.8%) subjects (age range 72-94 years old) of 1361 participants in the 1999 baseline survey for a follow-up eye examination. Incidences were calculated for those who had emmetropia (-0.50D < spherical equivalent (SE) <+0.50D) at baseline. Refractive error change at 7 year was defined as (SE at the 7-year visit - SE at baseline). RESULTS: 90 (26.4%) subjects were emmetropic, 61 (17.9%) were myopic and 190 (55.7%) hyperopic. The mean refractive error was 0.49 +/- 2.19 D and the average change in refractive error was -0.13 +/- 1.03 D. The incidence of myopia at seven year was 26.8 % [95% Confidence interval (C.I.): 22.8%-30.9%] and the incidence of hyperopia was 19.7% (95% C.I.: 16.1%-23.3%). Nuclear sclerosis (>Grade 2 vs. <=Grade 2) [p < 0.0001; relative risk (RR): 8.94; 95% C.I.: 4.40-18.2], anterior chamber depth (mm) [p = 0.05; RR: 0.43; 95% C.I.: 0.18-1.01] and lens thickness (mm) [p < 0.01; RR: 2.35; 95% C.I.: 1.17-2.73] were significantly associated with myopic shift. On the other hand, hyperopic shift was significantly associated with cortical opacity (>Grade 2 vs. <=Grade 2) (p = 0.02; RR: 1.21; 95% C.I.: 1.02-3.54). CONCLUSION: In this elderly Asian population, there was on average a slight myopic shift. The incidence of myopia was comparable to population-based studies of other ethnic groups, whereas the incidence of hyperopia was substantially higher. PMID- 28716603 TI - The role of complete staging surgery for pure endometrioid-type endometrial cancer. PMID- 28716602 TI - Neoadjuvant chemotherapy may not benefit esophageal squamous cell carcinoma patients treated with definitive chemoradiotherapy. AB - BACKGROUND: To assess the efficacy of neoadjuvant chemotherapy (NAC) in esophageal squamous cell carcinoma (ESCC) patients treated with definitive chemoradiotherapy (CRT). METHODS: The clinical data of patients with ESCC treated with chemoradiotherapy with or without NAC were collected and retrospectively reviewed. The overall survival, locoregional failure-free survival, and distant failure-free survival were analyzed statistically. RESULTS: A total of 60 patients fulfilled the inclusion criteria, of which 41 were treated with NAC-CRT and 19 were treated with CRT-alone. Patient characteristics were well balanced between the NAC-CRT and CRT-alone groups, except for the ECOG scores. The tumor response to NAC included 11 patients (26.8%) with partial response (PR), 25 patients (61.0%) with stable disease (SD), 5 patients (12.2%) with progression disease (PD), and no patients with complete response (CR). After CRT, 21 patients achieved CR (14 after NAC-CRT and 7 after CRT-alone), 30 had PR (19 and 11, respectively), 6 maintained SD (5 and 1, respectively), and 3 patients (all in the NAC-CRT group) developed PD. Twenty-nine patients (18 in NAC-CRT and 11 in CRT-alone) succumbed to the disease from locoregional or distant failure, one patient in the NAC-CRT group died of radiation pneumonitis, one patient in the CRT-alone group died from unknown reasons, and 29 patients remained alive. The overall survival, locoregional failure-free survival, and distant failure-free survival at 1 and 2 years in all the patients were 64.9% and 40.5%, 58.6% and 52.0%, and 85.7% and 79.3%, respectively. The overall survival, locoregional failure-free survival, and distant failure-free survival between the NAC-CRT group and the CRT-alone group were not significantly different. CONCLUSION: In patients with ESCC treated with definitive CRT, NAC treatment using the current regimen does not prolong overall survival, locoregional failure-free survival or distant failure-free survival. Further development of NAC treatment is urgently needed. PMID- 28716604 TI - Endothelial progenitor cell subsets and preeclampsia: Findings and controversies. AB - Vascular remodeling is an essential component of gestation. Endothelial progenitor cells (EPCs) play an important role in the regulation of vascular homeostasis. The results of studies measuring the number of EPCs in normal pregnancies and in preeclampsia have been highly controversial or even contradictory because of some variations in technical issues and different methodologies enumerating three distinct subsets of EPCs: circulating angiogenic cells (CAC), colony forming unit endothelial cells (CFU-ECs), and endothelial colony-forming cells (ECFCs). In general, most studies have shown an increase in the number of CACs in the maternal circulation with a progression in the gestational age in normal pregnancies, while functional capacities measured by CFU-ECs and ECFCs remain intact. In the case of preeclampsia, mobilization of CACs and ECFCs occurs in the peripheral blood of pregnant women, but the functional capacities shown by culture of the derived colony-forming assays (CFU EC and ECFC assays) are altered. Furthermore, the number of all EPC subsets will be reduced in umbilical cord blood in the case of preeclampsia. As EPCs play an important role in the homeostasis of vascular networks, the difference in their frequency and functionality in normal pregnancies and those with preeclampsia can be expected. In this review, there was an attempt to provide a justification for these controversies. PMID- 28716605 TI - Mesenchymal stem cell in wound healing and regeneration. PMID- 28716606 TI - DNA-protein interactions explored by atomic force microscopy. AB - DNA-protein interactions play an important role in all living organisms on Earth. The advent of atomic force microscopy permitted for the first time to follow and to characterize interaction forces between these two molecular species. After a short description of the AFM and its imaging modes we review, in a chronological order some of the studies that we think importantly contributed to the field. PMID- 28716607 TI - Seven pass Cadherins CELSR1-3. AB - Cadherin EGF LAG seven-pass G-type receptors 1, 2 and 3 (CELSR1-3) form a family of three atypical cadherins with multiple functions in epithelia and in the nervous system. During the past decade, evidence has accumulated for a key role of CELSR1 in epithelial planar cell polarity (PCP), and for CELSR2 and CELSR3 in ciliogenesis and neural development, especially neuron migration and axon guidance in the central, peripheral and enteric nervous systems. Phenotypes in mutant mice indicate that CELSR proteins work in concert with FZD3 and FZD6, but several questions remain. Apart from PCP signaling pathways implicating CELSR1 that begin to be unraveled, little is known about other signals generated by CELSR2 and CELSR3. A crucial question concerns the putative ligands that trigger signaling, in particular what is the role of WNT factors. Another critical issue is the identification of novel intracellular pathways and effectors that relay and transmit signals in receptive cells? Answers to those questions should further our understanding of the role of those important molecules not only in development but also in regeneration and disease. PMID- 28716608 TI - Opioidergic and dopaminergic modulation of cost/benefit decision-making in Long Evans Rats. AB - Eating disorders are associated with impaired decision-making and dysfunctional reward-related neurochemistry. The present study examined the potential contributions of dopamine and opioid signaling to these processes using two different decision-making tasks. In one task, Long Evans Rats chose between working for a preferred food (high-carbohydrate banana-flavored sucrose pellets) by lever pressing on a progressive-ratio schedule of reinforcement vs. obtaining less preferred laboratory chow that was concurrently available. In a second (effort-free) task, rats chose between the same two reinforcers when they were both available freely. Rats were trained in these tasks before receiving haloperidol (0.00, 0.05, 0.10mg/kg, intraperitoneally (i.p.)) or naloxone (0.0, 1.5, 3.0mg/kg, i.p.). In the first task, haloperidol decreased breakpoint, lever presses, number of reinforcers earned, and increased chow intake, whereas naloxone decreased breakpoint and number of reinforcers earned but had no effect on chow consumption. In the effort-free task, haloperidol reduced intakes of both foods without affecting preference, whereas naloxone selectively reduced the consumption of banana-pellets. The present findings support converging evidence suggesting that DA signaling affects processes more closely related to appetitive motivation, leaving other components of motivation unchanged. By contrast, opioid signaling appears to mediate aspects of hedonic feeding by selectively altering intakes of highly palatable foods. For preferred foods, both appetitive and consummatory aspects of food intake were altered by opioid receptor antagonism. Our findings argue against a general suppression of appetite by either compound, as appetite manipulations have been shown to unselectively alter intakes of both types of food regardless of the task employed. PMID- 28716609 TI - Oxytocin reduces alcohol consumption in prairie voles. AB - Alcohol use disorder (AUD) negatively affects millions of people every year in the United States, and effective treatments for AUD are still needed. The neuropeptide oxytocin has shown promise for reducing alcohol drinking in mice and rats. Because oxytocin also plays a key role in complex prosocial behaviors like bonding and attachment, we tested the effect of oxytocin on alcohol drinking in prairie voles, a species that both consumes high amounts of alcohol and forms oxytocin dependent social bonds in a manner similar to humans. Oxytocin treatment (1.0, 3.0, and 10.0mg/kg, i.p.) reduced alcohol consumption in male and female prairie voles in animals that had access to 15% ethanol vs water every other day for 12 alcohol drinking sessions. In animals with continuous access to 15% alcohol and water, oxytocin (3.0mg/kg) reduced alcohol consumption only in the first hour of access after treatment, with no significant effects on consumption over the 24-hr period. In an open field locomotor test, oxytocin (1.0, 3.0, and 10.0mg/kg, i.p.) did not affect overall locomotor activity; however, ethanol (2g/kg, i.p.) increased locomotor activity in males and females, and produced anxiolytic effects (increased time in the center of an open field) in females only. Because prairie voles have been shown to match the alcohol consumption of their cage mate, we evaluated the relationship between cage mates' alcohol drinking. There was an overall pattern of social facilitation (consumption by one cage mate predicted consumption by the other cage mate); however, we found significant individual differences across cages in which many cages did not show significant matching, and, in some cases one cage mate's consumption negatively predicted the other cage mate's consumption. Overall, our data provide support for the potential of oxytocin as a treatment to reduce alcohol consumption. PMID- 28716610 TI - Current status and future direction of biodegradable metallic and polymeric vascular scaffolds for next-generation stents. AB - Because of the increasing incidence of coronary artery disease, the importance of cardiovascular stents has continuously increased as a treatment of this disease. Biodegradable scaffolds fabricated from polymers and metals have emerged as promising materials for vascular stents because of their biodegradability. Although such stent framework materials have shown good clinical efficacy, it is difficult to decide whether polymers or metals are better vascular scaffolds because their properties are different. Therefore, there are still obstacles in the development of biodegradable vascular scaffolds in terms of improving clinical efficacy. This review analyzes the pros and cons of current stent materials with respect to five key factors for next-generation stent and discusses methods of improvement. Furthermore, we discuss biodegradable electronic stents with electrical conductivity, which has been considered unimportant until now, and highlight electrical conductivity as a key factor in the development of next-generation stents. PMID- 28716611 TI - Predictability of action sub-steps modulates motor system activation during the observation of goal-directed actions. AB - Action perception and execution are linked in the human motor system, and researchers have proposed that this action-observation matching system underlies our ability to predict observed behavior. If the motor system is indeed involved in the generation of action predictions, activation should be modulated by the degree of predictability of an observed action. This study used EEG and eye tracking to investigate whether and how predictability of an observed action modulates motor system activation as well as behavioral predictions in the form of anticipatory eye-movements. Participants were presented with object-directed actions (e.g., making a cup of tea) consisting of three action steps which increased in their predictability. While the goal of the first step was ambiguous (e.g., when making tea, one can first grab the teabag or the cup), the goals of the following steps became predictable over the course of the action. Motor system activation was assessed by measuring attenuation of sensorimotor mu- and beta-oscillations. We found that mu- and beta-power were attenuated during observation, indicating general activation of the motor system. Importantly, predictive motor system activation, indexed by beta-band attenuation, increased for each action step, showing strongest activation prior to the final (i.e. most predictable) step. Sensorimotor activity was related to participants' predictive eye-movements which also showed a modulation by action step. Our results demonstrate that motor system activity and behavioral predictions become stronger for more predictable action steps. The functional roles of sensorimotor oscillations in predicting other's actions are discussed. PMID- 28716613 TI - A Novel Use of Peer Coaching to Teach Primary Palliative Care Skills: Coaching Consultation. AB - BACKGROUND: We aim to address palliative care workforce shortages by teaching clinicians how to provide primary palliative care through peer coaching. INTERVENTION: We offered peer coaching to internal medicine residents and hospitalists (attendings, nurse practioners, and physician assistants). MEASURES: An audit of peer coaching encounters and coachee feedback to better understand the applicability of peer coaching in the inpatient setting to teach primary palliative care. OUTCOMES: Residents and hospitalist attendings participated in peer coaching for a broad range of palliative care-related questions about pain and symptom management (44%), communication (34%), and hospice (22%). Clinicians billed for 68% of encounters using a time-based billing model. Content analysis of coachee feedback identified that the most useful elements of coaching are easy access to expertise, tailored teaching, and being in partnership. CONCLUSION/LESSONS LEARNED: Peer coaching can be provided in the inpatient setting to teach primary palliative care and potentially extend the palliative care work force. PMID- 28716612 TI - Impulsive personality dimensions are associated with altered behavioral performance and neural responses in the monetary incentive delay task. AB - Individual differences in dimensions of impulsivity personality including disinhibition and sensation seeking modulate approach responses to reinforcing stimuli, such as drugs and money. The current study examined the effects of monetary incentive on both behavioral performance and electrophysiological activity among individuals varying in disinhibition and sensation seeking. The monetary incentive delay (MID) task was completed under electroencephalogram (EEG) recording. Behavioral data showed that higher disinhibition and sensation seeking were associated with lower performance accuracy. Event-related potential (ERP) data showed that high reinforcement cues elicited a larger late positive component (LPC) than other conditions among high disinhibition participants, indicating its strong emotional influence. Additionally, in the neutral incentive condition, the feedback-related negativity (FRN) elicited by correct outcomes was larger than that elicited by incorrect outcomes in the high disinhibition group only. This novel finding indicates that high disinhibition participants were less likely to expect correct outcomes compared to incorrect outcomes in the neutral incentive condition. Finally, the P3 component elicited by outcome presentation showed an interaction between two impulsivity dimensions; when disinhibition level was low, the P3 was larger among high than low sensation seeking participants. PMID- 28716614 TI - Evaluation of a Pain Assessment Procedure in Long-Term Care Residents With Pain and Dementia. AB - BACKGROUND: The management of pain in long-term care (LTC) residents with dementia is complex. A prospective exploratory study was conducted to describe the course of pain and pain management strategies following a guideline-based pain assessment procedure in LTC residents with pain and dementia. MEASURES: Pain observations with the Mobilization Observation Behaviour Intensity Dementia (MOBID-2) Pain Scale, a review of the electronic patient file and pharmacy files and physical examination of LTC residents with pain and dementia. INTERVENTION: Communication of the assessment results to the attending physician including guideline-based treatment recommendations. OUTCOMES: After three months, complete follow-up data were obtained for 64 residents. Pain intensity was significantly reduced (P < 0.001). The proportion of residents with persistent pain was 58% and the total number of analgesic prescriptions did not change significantly. CONCLUSIONS: There is room for improvement regarding pain management in LTC residents with pain and dementia, and performance feedback seems a promising strategy to explore further. PMID- 28716615 TI - Development of a Protocol for Successful Palliative Care Consultation in Population of Patients Receiving Mechanical Circulatory Support. AB - BACKGROUND: In 2014, Joint Commission recommended palliative care (PC) engagement in ventricular assist device (VAD) implantation as destination therapy. Limited information is available on established PC protocols in the mechanical circulatory support (MCS) population. MEASURES: The goals of our PC consultation were to document advance care planning (ACP) discussions and designate a surrogate decision maker (SDM) before MCS implantation. A retrospective analysis compared the frequency of PC consults, ACP discussion, and SDM before and after protocol implementation. INTERVENTION: A protocol was developed to conduct interdisciplinary PC consultations for the MCS population. OUTCOMES: The percentage of PC consults placed before MCS implantation increased from 11 (17.2%) before protocol to 56 (96.6%) after protocol (P < 0.0001) and documented SDM increased from 26 (40.6%) before protocol to 57 (98.3%) after protocol (P < 0.0001). CONCLUSIONS: Close PC/cardiology collaboration can substantially improve ACP discussions and SDM documentation in the MCS population. This multidisciplinary protocol facilitates successful PC consultations. PMID- 28716616 TI - Relationship Between Spirituality, Meaning in Life, Psychological Distress, Wish for Hastened Death, and Their Influence on Quality of Life in Palliative Care Patients. AB - CONTEXT: Spiritual, existential, and psychological issues represent central components of quality of life (QOL) in palliative care. A better understanding of the dynamic nature underlying these components is essential for the development of interventions tailored to the palliative context. OBJECTIVES: The aims were to explore 1) the relationship between spirituality, meaning in life, wishes for hastened death and psychological distress in palliative patients and 2) the extent to which these nonphysical determinants influence QOL. METHODS: A cross sectional study involving face-to-face interviews with Swiss palliative patients was performed, including the Schedule for Meaning in Life Evaluation (SMILE), the Functional Assessment of Chronic Illness Therapy-Spiritual Well-Being Scale (FACIT-Sp), the Idler Index of Religiosity (IIR), the Hospital Anxiety and Depression Scale (HADS), and the Schedule of Attitudes toward Hastened Death (SAHD). QOL was measured with a single-item visual analogue scale (0-10). RESULTS: Two hundred and six patients completed the protocol (51.5% female; mean age = 67.5 years). The results indicated a significant negative relationship between FACIT-Sp/SMILE and HADS total scores (P = 0.000). The best model for QOL explained 32.8% of the variance (P = 0.000) and included the FACIT-Sp, SMILE, and SAHD total scores, the IIR "private religiosity" score, as well as the HADS "depression" score. CONCLUSION: Both spiritual well-being and meaning in life appear to be potential protective factors against psychological distress at the end of life. Since nonphysical determinants play a major role in shaping QOL at the end of life, there is a need for the development of meaning-oriented and spiritual care interventions tailored to the fragility of palliative patients. PMID- 28716617 TI - Dignity Therapy and Life Review for Palliative Care Patients: A Qualitative Study. AB - CONTEXT: Dignity therapy (DT) is a psychotherapeutic intervention whose aim was to bolster the sense of purpose, meaning, and sense of dignity in patients with terminal disease. OBJECTIVES: The aim of this study was to explore, compare, and better understand the content of standard DT, waitlist DT (WDT), and Life Review (LR) that used the DT interview protocol but omitted the creation of legacy documents. METHODS: Efficacy of these interventions was previously documented in a sample of 56 participants. In this study, DT and WDT legacy documents and LR session transcripts were qualitatively analyzed using the Framework approach, both deductively and inductively. RESULTS: All participants expressed a diverse set of beliefs, values, memories, and important relationships with the majority also indicating at least some sense of meaning and acceptance despite disappointments, regrets, and the impacts of illness. Sense of legacy, fighting spirit, and hope were particularly prevalent in legacy documents (DT and WDT groups), whereas relationship regrets, self-blame, unfinished business, and aftermath concerns were more likely to be expressed during the LR process. Themes of spirituality, illness impacts, and unfinished business were relatively less common in WDT participants. CONCLUSION: This study provides further insight into what palliative care patients consider to be most important and meaningful to them when taking part in DT and LR. Creating legacy documents is likely to result in session content that is different in several key areas compared with LR, even when controlling for interview questions, therapist influences, and session length. Consideration of the above is essential in optimizing psychotherapeutic outcomes near end of life. PMID- 28716618 TI - Evaluation of a Video-Based Seminar to Raise Health Care Professionals' Awareness of Culturally Sensitive End-of-Life Care. AB - CONTEXT: Health care workers serve diverse communities and face challenges in delivering culturally responsive EOL care, especially when caring for Latino elders. OBJECTIVE: The objective of this study was to investigate the effect of a newly developed telenovela, or video soap opera, on health care professionals (HCPs)' awareness of caregivers' stress and patients' cultural approaches to end of-life (EOL) care decisions. METHODS: A multicenter cross-sectional study among three communities in New York, Miami, and Missouri. Participants from a convenience sample of multidisciplinary HCPs were randomly assigned to view power point presentation with either a control video or an intervention-telenovela about caregiving as part of a one-hour audiovisual seminar and completed a pre- and post-test questionnaire to evaluate reaction and learning. RESULTS: Participants (N = 142) were mostly female (80%) nurses (54%) with a mean age of 44.5 +/- 12.4 years and from non-Hispanic white (41%) or Hispanics (37%) ethnicity. In both control and intervention groups, post-test responses demonstrated a high level (87%) of satisfaction with seminar and an increase in openness to discuss EOL issues with culturally diverse patients (P < 0.001). Although both groups reported post-test improvement in awareness of health literacy, cultural competency skills, cultural differences about EOL attitudes, family caregiver stress, and possible interventions, this improvement was significantly higher in the intervention group (P < 0.05) compared with the control group. CONCLUSION: The telenovela was effective in increasing health care workers' awareness of caregivers stress and cultural approach to EOL decisions. There is need for ongoing efforts to educate HCPs on cultural sensitivity to help ethnically diverse caregivers and their patients benefit from EOL care. PMID- 28716619 TI - Attachment Insecurity in Advanced Cancer Patients: Psychometric Properties of the German Version of the Brief Experiences in Close Relationships Scale (ECR-M16-G). AB - CONTEXT: Attachment insecurity refers to difficulty in trusting and relying on others in times of need. Its underlying factors attachment anxiety and attachment avoidance have been empirically associated with impaired coping in advanced cancer and, therefore, should be considered in individually tailored medical and psychosocial treatment. OBJECTIVES: The objective of this study was to evaluate the psychometric properties of the German translation of the Brief Experiences in Close Relationships Scale (ECR-M16-G). METHODS: We recruited 182 advanced cancer patients from outpatient psycho-oncology clinics of the University Medical Center Hamburg-Eppendorf and the University Medical Center Leipzig, local and external cancer care facilities. We performed confirmatory factor analysis to replicate the higher order factor structure reported in previous research. We conducted item and reliability analysis, also correlation analysis, to examine concurrent validity. RESULTS: One hundred fifty-eight patients completed the ECR-M16-G (women 61%, mean age 57.9, SD = 11.1). We replicated the factor structure with the subscales Attachment Anxiety and Attachment Avoidance as second-order factors and Worrying about relationships, Frustration about unavailability, Discomfort with close others, and Turning away from others as first-order factors. An adjusted model that interchanged factor loadings of items 4 and 10 showed good fit (Comparative Fit Index = 0.94, Non-Normed Fit Index = 0.93, root mean square error of approximation = 0.05). Subscales showed acceptable to good internal consistency (anxiety alpha = .81 and avoidance alpha = .78). Attachment insecurity (mean = 3.1, SD = 1.0) was positively associated with depression, anxiety, demoralization (P < 0.001), and symptom burden (P = 0.02) and negatively associated with spiritual well-being (P < 0.001). CONCLUSION: The ECR-M16-G is a valid and reliable measure of attachment insecurity in patients with advanced cancer and can be recommended as a tool for clinical care and further research. PMID- 28716622 TI - The art of systematic reviews. PMID- 28716620 TI - Distinct Physical Function Profiles in Older Adults Receiving Cancer Chemotherapy. AB - CONTEXT: Although physical function is an important patient outcome, little is known about changes in physical function in older adults receiving chemotherapy (CTX). OBJECTIVES: Identify subgroups of older patients based on changes in their level of physical function; determine which demographic and clinical characteristics were associated with subgroup membership; and determine if these subgroups differed on quality-of-life (QOL) outcomes. METHODS: Latent profile analysis was used to identify groups of older oncology patients (n = 363) with distinct physical function profiles. Patients were assessed six times over two cycles of CTX using the Physical Component Summary score from the Short Form 12. Differences, among the groups, in demographic and clinical characteristics and QOL outcomes were evaluated using parametric and nonparametric tests. RESULTS: Three groups of older oncology patients with distinct functional profiles were identified: Well Below (20.4%), Below (43.8%), and Above (35.8%) normative Physical Component Summary scores. Characteristics associated with membership in the Well Below class included the following: lower annual income, a higher level of comorbidity, being diagnosed with depression and back pain, and lack of regular exercise. Compared with the Above class, patients in the other two classes had significantly poorer QOL outcomes. CONCLUSION: Almost 65% of older oncology patients reported significant decrements in physical function that persisted over two cycles of CTX. Clinicians can assess for those characteristics associated with poorer functional status to identify high-risk patients and initiate appropriate interventions. PMID- 28716621 TI - Health Care Professionals' Attitudes About Physician-Assisted Death: An Analysis of Their Justifications and the Roles of Terminology and Patient Competency. AB - CONTEXT: Health care professionals (HCPs) are crucial to physician-assisted death (PAD) provision. OBJECTIVES: To quantitatively assess the favorability of justifications for or against PAD legalization among HCPs, the effect of the terms "suicide" and "euthanasia" on their views and their support for three forms of PAD. METHODS: Our questionnaire presented three cases: physician-assisted suicide, euthanasia for a competent patient, and euthanasia for an incompetent patient with an advance directive for euthanasia. Respondents judged whether each case was ethical and should be legal and selected their justifications from commonly cited reasons. The sample included physician clinicians, researchers, nonphysician clinicians, and other nonclinical staff at a major academic medical center. RESULTS: Of 221 HCPs, the majority thought that each case was ethical and should be legal. In order of declining favorability, justifications supporting PAD legalization were relief of suffering, right to die, mercy, acceptance of death, nonabandonment, and saving money for the health care system; opposing justifications were the slippery slope argument, unnecessary due to palliative care, killing patients is wrong, religious views, and suicide is wrong. The use of suicide and euthanasia terminology did not affect responses. Participants preferred physician-assisted suicide to euthanasia for a competent patient (P < 0.0001) and euthanasia for an incompetent patient to euthanasia for a competent patient (P < 0.005). CONCLUSIONS: HCPs endorsed patient-centered justifications over other reasons, including role-specific duties. Suicide and euthanasia language did not bias HCPs against PAD, challenging claims that such value-laden terms hinder dialogue. More research is required to understand the significance of competency in shaping attitudes toward PAD. PMID- 28716623 TI - A 'second truncation' in TTN causes early onset recessive muscular dystrophy. AB - Mutations in the gene encoding the giant skeletal muscle protein titin are associated with a variety of muscle disorders, including recessive congenital myopathies +/-cardiomyopathy, limb girdle muscular dystrophy (LGMD) and late onset dominant distal myopathy. Heterozygous truncating mutations have also been linked to dilated cardiomyopathy. The phenotypic spectrum of titinopathies is emerging and expanding, as next generation sequencing techniques make this large gene amenable to sequencing. We undertook whole exome sequencing in four individuals with LGMD. An essential splice site mutation, previously reported in dilated cardiomyopathy, was identified in all families in combination with a second truncating mutation. Affected individuals presented with childhood onset proximal weakness associated with joint contractures and elevated CK. Cardiac dysfunction was present in two individuals. Muscle biopsy showed increased internal nuclei and immunoblotting identified reduction or absence of calpain-3 and demonstrated a marked reduction of C-terminal titin fragments. We confirm the co-occurrence of cardiac and skeletal myopathies associated with recessive truncating titin mutations. Compound heterozygosity of a truncating mutation previously associated with dilated cardiomyopathy and a 'second truncation' in TTN was identified as causative in our skeletal myopathy patients. These findings add to the complexity of interpretation and genetic counselling for titin mutations. PMID- 28716624 TI - Recent Advances in Mitochondrial Aminoacyl-tRNA Synthetases and Disease. AB - Dysfunctions in mitochondria - the powerhouses of the cell - lead to several human pathologies. Because mitochondria integrate nuclear and mitochondrial genetic systems, they are richly intertwined with cellular activities. The nucleus-encoded mitochondrial aminoacyl-tRNA synthetases (mt-aaRSs) are key components of the mitochondrial translation apparatus. Mutations in these enzymes predominantly affect the central nervous system (CNS) but also target other organs. Comparable mutations in mt-aaRSs can lead to vastly diverse diseases, occurring at different stages in life, and within different tissues; this represents a confounding issue. With newer information available, we propose that the pleiotropy and tissue-specificity of mt-aaRS-associated diseases result from the molecular integration of mitochondrial translation events within the cell; namely, through specific crosstalk between the cellular program and the energy demands of the cell. We place particular focus on neuronal cells. PMID- 28716626 TI - Transcription Factor-Mediator Interfaces: Multiple and Multi-Valent. PMID- 28716625 TI - A comparative study of phenotypic and genotypic first- and second-line drug resistance testing of Mycobacterium tuberculosis. AB - This study aimed to evaluate the frequency of resistance to first- and second line drugs using phenotypic and genotypic methods and its correlation with resistance-linked mutations in Mycobacterium tuberculosis (M. tb) isolated in Iran. Three different methods, including the indirect proportion method(PM), direct and indirect nitrate reductase assay(NRA), and direct sequencing were used to assess drug resistance. In this study, sensitivity, specificity, agreement, costs, and turnaround time of these methods were compared in 395 smear positive isolates. Compared to the PM, the NRA and the direct sequencing methods demonstrated higher specificity, sensitivity, and agreement for detection of all anti-tuberculosis drugs. The NRA had a short turnaround time and was more cost effective than the other methods. Mutations in codon 531 in rpoB, 315 in katG, 18 in rpsL, and 306 in embB were associated with high-level resistance to the first line drugs, and mutations in codon 94 in gyrA, and A1401G in rrs were correlated with resistance to the second-line drugs. We found that the NRA is a highly sensitive, specific, inexpensive, and rapid test with strong potential to be a useful and interesting alternative tool, particularly in low-income countries. In addition, these molecular data will be helpful for developing new molecular methods for detecting first- and second-line drug-resistant M. tb. PMID- 28716627 TI - Membrane proteins structures: A review on computational modeling tools. AB - BACKGROUND: Membrane proteins (MPs) play diverse and important functions in living organisms. They constitute 20% to 30% of the known bacterial, archaean and eukaryotic organisms' genomes. In humans, their importance is emphasized as they represent 50% of all known drug targets. Nevertheless, experimental determination of their three-dimensional (3D) structure has proven to be both time consuming and rather expensive, which has led to the development of computational algorithms to complement the available experimental methods and provide valuable insights. SCOPE OF REVIEW: This review highlights the importance of membrane proteins and how computational methods are capable of overcoming challenges associated with their experimental characterization. It covers various MP structural aspects, such as lipid interactions, allostery, and structure prediction, based on methods such as Molecular Dynamics (MD) and Machine-Learning (ML). MAJOR CONCLUSIONS: Recent developments in algorithms, tools and hybrid approaches, together with the increase in both computational resources and the amount of available data have resulted in increasingly powerful and trustworthy approaches to model MPs. GENERAL SIGNIFICANCE: Even though MPs are elementary and important in nature, the determination of their 3D structure has proven to be a challenging endeavor. Computational methods provide a reliable alternative to experimental methods. In this review, we focus on computational techniques to determine the 3D structure of MP and characterize their binding interfaces. We also summarize the most relevant databases and software programs available for the study of MPs. PMID- 28716628 TI - Transduction of a Neospora caninum antigen gene into mammalian cells using a modified Bombyx mori nucleopolyhedrovirus for antibody production. AB - Autographa californica multiple nucleopolyhedrovirus (AcMNPV) can easily enter and transduce foreign genes into mammalian cells, but these functions are difficult for Bombyx mori nucleopolyhedrovirus (BmNPV). In this study, we investigated the induction of antibody production in mice immunized with an engineered BmNPV. The GP64 of BmNPV (BmGP64) was replaced with the GP64 of AcMNPV (AcGP64); this construct, designated BmNPVDeltabgp/AcGP64, displays AcGP64 on the surface of BmNPV. The Neospora caninum antigen (NcSRS2) expression cassette, consisting of the cytomegalovirus immediate-early promoter and NcSRS2 from N. caninum, was inserted into BmNPVDeltabgp/AcGP64; this construct was designated BmNPVDeltabgp/AcGP64/SRS2. For comparison, AcMNPV/SRS2, which contains the same NcSRS2 expression cassette as for BmNPVDeltabgp/AcGP64, was also constructed. NcSRS2 was expressed in HEK293T cells when the engineered BmNPVs were transduced at a multiplicity of infection of 150. BmNPVDeltabgp/AcGP64/SRS2 induced the production of NcSRS2-specific antibodies in mice, whereas AcMNPV/SRS2 and the control BmNPV did not. These results suggest that BmNPV prepared from silkworm hemolymph induces the production of antigen-specific antibodies in immunized mice and can be used for antibody production and vaccine development. PMID- 28716629 TI - Characterization of novel Bacillus strain N31 from mariculture water capable of halophilic heterotrophic nitrification-aerobic denitrification. AB - The development of an intensive aquaculture industry has been accompanied by increasing environmental impacts, especially nitrogen pollution. In this study, a novel halophilic bacterium capable of heterotrophic nitrification and aerobic denitrification was isolated from mariculture water and identified as Bacillus litoralis N31. The efficiency of ammonium, nitrite and nitrate removal by N31 were 86.3%, 89.3% and 89.4%, respectively, after a 48-h cultivation in sole N source medium with initial nitrogen approximately 20 mg/L. However, ammonium was removed preferentially, and no obvious nitrite accumulated during the simultaneous nitrification and denitrification process in mixed N-source media. The existence of hao, napA and nirS genes further proved the heterotrophic nitrification-aerobic denitrification capability of N31. The optimal conditions for ammonium removal were 30 degrees C, initial pH 7.5-8.5, C/N ratio 5-20 and salinity 30-400/00, and the nitrification rate of N31 increased with increasing initial [Formula: see text] from 10 to 250 mg/L. Biosecurity assessment with shrimp indicated that strain N31 could be applied in the marine aquaculture industry safely for culture water remediation and effluent treatment. PMID- 28716630 TI - Common measures of chronic kidney disease improve vascular risk prediction. PMID- 28716632 TI - Mitochondrial estrogen receptors as a vulnerability factor of chronic stress and mediator of fluoxetine treatment in female and male rat hippocampus. AB - Depression is a disease of an abnormal brain energy metabolism also marked with increased apoptosis in specific brain regions. Mounting evidence indicates that the mitochondrial oxidative phosphorylation and apoptosis are novel targets for the actions of estrogen receptors (ERs). In this study, we examined the effects of antidepressant (AD) fluoxetine (FLU) treatment on the mitochondrial ER alpha (ERalpha), ER beta (total and phospho-pERbeta) and their association with cytochrome c (cyt c) oxidase activity and apoptotic Bcl2/Bax-molecules in the hippocampal mitochondria of chronically isolated (CPSI) female and male rats depicting depression. Impaired behaviour induced by CPSI was followed by decreased corticosterone (CORT) in both sexes and downregulation of cyt c oxidase in males. CPSI did not affect the ERalpha in either of sexes, but it decreased mitochondrial ERbeta and increased pERbeta in both sexes. Stress-reduced ERbeta is associated with a decrease in mitochondrial energetic processes in males and with apoptotic mechanisms in females. FLU normalized behaviour in both sexes and increased cyt c oxidase in females. FLU elevated ERalpha in males, increased ERbeta and decreased pERbeta in both sexes. The AD-induced alterations of ERbeta paralleled with bioenergetics and pro-survival pathways in females. In conclusion, sex-unspecific regulation of ERbeta by the stress and by AD and its differential convergence with bioenergetics and apoptotic pathways in females and males implies its role as a vulnerability factor in the stress response and emphasizes mitochondrial ERbeta-dependent pathways as an important gateway of ADs action, at least in females. PMID- 28716633 TI - The synthetic cannabinoid WIN55212-2 ameliorates traumatic spinal cord injury via inhibition of GAPDH/Siah1 in a CB2-receptor dependent manner. AB - The essential role of GAPDH/Siah1 signaling pathway in the pathogenesis of various injurious conditions such as traumatic spinal cord injury (SCI) has been gradually recognized. However, the drugs targeting this signaling pathway are still lacking. The endocannabinoid system, including its receptors (CB1 and CB2), act as neuroprotective and immunomodulatory modulators in SCI. WIN55212-2, an agonist for CB1 and CB2 receptors, has been demonstrated with anti-inflammatory and anti-apoptotic effects in multiple neurological diseases. Therefore, the present study aimed to investigate whether WIN55212-2 could promote functional recovery after traumatic SCI via inhibition of the GAPDH/Siah1 signaling. The traumatic SCI was induced by dropping a 10-g impactor from 25mm on the dorsal surface of T9 and T10. Our results showed that WIN55212-2 alleviated the activation of GAPDH/Siah1 signaling pathway after SCI, as indicated by the reduction in GAPDH nuclear expression, GAPDH-Siah1 complex formation and iNOS protein expression. Furthermore, WIN55212-2 reduced apoptosis, production of IL 1beta and TNF-alpha and activation of NF-kappaB signaling in the spinal cord after SCI. The behavioral tests showed that WIN55212-2 improved the functional recovery after traumatic SCI as indicated by sustained increase in the locomotor scores. However, these neuroprotective effects of WIN55212-2 were blocked in the presence of the combined treatment of AM630 (an antagonist of CB2) rather than AM251 (an antagonist of CB1). In conclusion, our study indicates that, WIN55212-2 improves the functional recovery after SCI via inhibition of GAPDH/Siah1 cascades in a CB2 receptor dependent manner, indicative of its therapeutic potential for traumatic SCI or other traumatic conditions. PMID- 28716634 TI - Utilization of apical vaginal support procedures at time of inpatient hysterectomy performed for benign conditions: a national estimate. AB - BACKGROUND: Apical vaginal support is considered the keystone of pelvic organ support. Level I evidence supports reestablishment of apical support at time of hysterectomy, regardless of whether the hysterectomy is performed for prolapse. National rates of apical support procedure performance at time of inpatient hysterectomy have not been well described. OBJECTIVE: We sought to estimate trends and factors associated with use of apical support procedures at time of inpatient hysterectomy for benign indications in a large national database. STUDY DESIGN: The National (Nationwide) Inpatient Sample was used to identify hysterectomies performed from 2004 through 2013 for benign indications. International Classification of Diseases, Ninth Revision, Clinical Modification codes were used to select both procedures and diagnoses. The primary outcome was performance of an apical support procedure at time of hysterectomy. Descriptive and multivariable analyses were performed. RESULTS: There were 3,509,230 inpatient hysterectomies performed for benign disease from 2004 through 2013. In both nonprolapse and prolapse groups, there was a significant decrease in total number of annual hysterectomies performed over the study period (P < .0001). There were 2,790,652 (79.5%) hysterectomies performed without a diagnosis of prolapse, and an apical support procedure was performed in only 85,879 (3.1%). There was a significant decrease in the proportion of hysterectomies with concurrent apical support procedure (high of 4.0% in 2004 to 2.5% in 2013, P < .0001). In the multivariable logistic regression model, increasing age, hospital type (urban teaching), hospital bed size (large and medium), and hysterectomy type (vaginal and laparoscopically assisted vaginal) were associated with performance of an apical support procedure. During the study period, 718,578 (20.5%) inpatient hysterectomies were performed for prolapse diagnoses and 266,743 (37.1%) included an apical support procedure. There was a significant increase in the proportion of hysterectomies with concurrent apical support procedure (low of 31.3% in 2005 to 49.3% in 2013, P < .0001). In the multivariable logistic regression model, increasing age, hospital type (urban teaching), hospital bed size (medium and large), and hysterectomy type (total laparoscopic and laparoscopic supracervical) were associated with performance of an apical support procedure. CONCLUSION: This national database study demonstrates that apical support procedures are not routinely performed at time of inpatient hysterectomy regardless of presence of prolapse diagnosis. Educational efforts are needed to increase awareness of the importance of reestablishing apical vaginal support at time of hysterectomy regardless of indication. PMID- 28716635 TI - The effects of strength exercise on hippocampus volume and functional fitness of older women. AB - BACKGROUND: Various positive effects of exercise on older women have been identified in many studies. Despite the importance of preserving the health of brain as well as body, few studies have investigated the effects of strength exercise on the brain health of older women to date. This study aimed to identify the effects of 24weeks of the Growing Stronger program on hippocampus volume and functional fitness of older women. METHODS: Twenty one older women aged 67 to 81 participated in this study. Growing Stronger, which is a strength exercise program that is safe and effective for women and men of all ages, was conducted. The 11 strength exercise group (n=11) participated for 50-80min a day three times per week for a total of 24weeks. The control group maintained their lifestyles without any special intervention. Participants were given a pre-test (before applying for the program) and post-test (after 24weeks) to identify effects of the program. The data were analyzed with repeated measures ANOVA. RESULTS: Hippocampus volume was significantly increased in the strength exercise group, but decreased in the control group. Moreover, there was an interaction effect (p<0.001) between time and group. Strength exercise has improved upper and lower body strength, lower body flexibility, agility, and dynamic balance. Upper body flexibility significantly decreased in the strength exercise group, but there was no interaction between the strength exercise group and the control group. CONCLUSION: The results of this study suggest that strength exercise has beneficial effects on hippocampus volume and functional fitness. Therefore, strength exercise can be an effective exercise for older women. PMID- 28716631 TI - Measures of chronic kidney disease and risk of incident peripheral artery disease: a collaborative meta-analysis of individual participant data. AB - BACKGROUND: Some evidence suggests that chronic kidney disease is a risk factor for lower-extremity peripheral artery disease. We aimed to quantify the independent and joint associations of two measures of chronic kidney disease (estimated glomerular filtration rate [eGFR] and albuminuria) with the incidence of peripheral artery disease. METHODS: In this collaborative meta-analysis of international cohorts included in the Chronic Kidney Disease Prognosis Consortium (baseline measurements obtained between 1972 and 2014) with baseline measurements of eGFR and albuminuria, at least 1000 participants (this criterion not applied to cohorts exclusively enrolling patients with chronic kidney disease), and at least 50 peripheral artery disease events, we analysed adult participants without peripheral artery disease at baseline at the individual patient level with Cox proportional hazards models to quantify associations of creatinine-based eGFR, urine albumin-to-creatinine ratio (ACR), and dipstick proteinuria with the incidence of peripheral artery disease (including hospitalisation with a diagnosis of peripheral artery disease, intermittent claudication, leg revascularisation, and leg amputation). We assessed discrimination improvement through c-statistics. FINDINGS: We analysed 817 084 individuals without a history of peripheral artery disease at baseline from 21 cohorts. 18 261 cases of peripheral artery disease were recorded during follow-up across cohorts (median follow-up was 7.4 years [IQR 5.7-8.9], range 2.0-15.8 years across cohorts). Both chronic kidney disease measures were independently associated with the incidence of peripheral artery disease. Compared with an eGFR of 95 mL/min per 1.73 m2, adjusted hazard ratios (HRs) for incident study-specific peripheral artery disease was 1.22 (95% CI 1.14-1.30) at an eGFR of 45 mL/min per 1.73 m2 and 2.06 (1.70-2.48) at an eGFR of 15 mL/min per 1.73 m2. Compared with an ACR of 5 mg/g, the adjusted HR for incident study-specific peripheral artery disease was 1.50 (1.41-1.59) at an ACR of 30 mg/g and 2.28 (2.12-2.44) at an ACR of 300 mg/g. The adjusted HR at an ACR of 300 mg/g versus 5 mg/g was 3.68 (95% CI 3.00-4.52) for leg amputation. eGFR and albuminuria contributed multiplicatively (eg, adjusted HR 5.76 [4.90-6.77] for incident peripheral artery disease and 10.61 [5.70-19.77] for amputation in eGFR <30 mL/min per 1.73 m2 plus ACR >=300 mg/g or dipstick proteinuria 2+ or higher vs eGFR >=90 mL/min per 1.73 m2 plus ACR <10 mg/g or dipstick proteinuria negative). Both eGFR and ACR significantly improved peripheral artery disease risk discrimination beyond traditional predictors, with a substantial improvement prediction of amputation with ACR (difference in c statistic 0.058, 95% CI 0.045-0.070). Patterns were consistent across clinical subgroups. INTERPRETATION: Even mild-to-moderate chronic kidney disease conferred increased risk of incident peripheral artery disease, with a strong association between albuminuria and amputation. Clinical attention should be paid to the development of peripheral artery disease symptoms and signs in people with any stage of chronic kidney disease. FUNDING: American Heart Association, US National Kidney Foundation, and US National Institute of Diabetes and Digestive and Kidney Diseases. PMID- 28716636 TI - A simplified clinical prediction rule for prognosticating independent walking after spinal cord injury: a prospective study from a Canadian multicenter spinal cord injury registry. AB - BACKGROUND CONTEXT: Traumatic spinal cord injury (SCI) is a debilitating condition with limited treatment options for neurologic or functional recovery. The ability to predict the prognosis of walking post injury with emerging prediction models could aid in rehabilitation strategies and reintegration into the community. PURPOSE: To revalidate an existing clinical prediction model for independent ambulation (van Middendorp et al., 2011) using acute and long-term post-injury follow-up data, and to investigatethe accuracy of a simplified model using prospectively collected data from a Canadian multicenter SCI database, the Rick Hansen Spinal Cord Injury Registry (RHSCIR). STUDY DESIGN: Prospective cohort study. PARTICIPANT SAMPLE: The analysis cohort consisted of 278 adult individuals with traumatic SCI enrolled in the RHSCIR for whom complete neurologic examination data and Functional Independence Measure (FIM) outcome data were available. OUTCOME MEASURES: The FIM locomotor score was used to assess independent walking ability (defined as modified or complete independence in walk or combined walk and wheelchair modality) at 1-year follow-up for each participant. METHODS: A logistic regression (LR) model based on age and four neurologic variables was applied to our cohort of 278 RHSCIR participants. Additionally, a simplified LR model was created. The Hosmer-Lemeshow goodness of fit test was used to check if the predictive model is applicable to our data set. The performance of the model was verified by calculating the area under the receiver operating characteristic curve (AUC). The accuracy of the model was tested using a cross-validation technique. This study was supported by a grant from The Ottawa Hospital Academic Medical Organization ($50,000 over 2 years). The RHSCIR is sponsored by the Rick Hansen Institute and is supported by funding from Health Canada, Western Economic Diversification Canada, and the provincial governments of Alberta, British Columbia, Manitoba, and Ontario. ET and JP report receiving grants from the Rick Hansen Institute (approximately $60,000 and $30,000 per year, respectively). DMR reports receiving remuneration for consulting services provided to Palladian Health, LLC and Pacira Pharmaceuticals, Inc ($20,000-$30,000 annually), although neither relationship presents a potential conflict of interest with the submitted work. KEH received a grant for involvement in the present study from the Government of Canada as part of the Canada Summer Jobs Program ($3,000). JP reports receiving an educational grant from Medtronic Canada outside of the submitted work ($75,000 annually). TM reports receiving educational fellowship support from AO Spine, AO Trauma, and Medtronic; however, none of these relationships are financial in nature. All remaining authors have no conflicts of interest to disclose. RESULTS: The fitted prediction model generated 85% overall classification accuracy, 79% sensitivity, and 90% specificity. The prediction model was able to accurately classify independent walking ability (AUC 0.889, 95% confidence interval [CI] 0.846-0.933, p<.001) compared with the existing prediction model, despite the use of a different outcome measure (FIM vs. Spinal Cord Independence Measure) to qualify walking ability. A simplified, three-variable LR model based on age and two neurologic variables had an overall classification accuracy of 84%, with 76% sensitivity and 90% specificity, demonstrating comparable accuracy with its five variable prediction model counterpart. The AUC was 0.866 (95% CI 0.816-0.916, p<.01), only marginally less than that of the existing prediction model. CONCLUSIONS: A simplified predictive model with similar accuracy to a more complex model for predicting independent walking was created, which improves utility in a clinical setting. Such models will allow clinicians to better predict the prognosis of ambulation in individuals who have sustained a traumatic SCI. PMID- 28716637 TI - Update on the management of abnormal uterine bleeding. AB - Abnormal uterine bleeding (AUB) is a common complaint that affects large numbers of women from puberty to menopause. It negatively affects health by causing anemia, and impacts the quality of life of women affected. AUB also has an economic impact for both women and society. Therefore, it should not be under- or overestimate and diagnosis, investigations and treatment should be proposed, taking into account the scientific data available in the current state of medical knowledge. Using the new terminology and etiologic classification of AUB is essential to communicate properly around the subject. The evaluation of the bleeding includes self-report and more objective methods. Work out should focus on diagnosing anemia and researching for causal factors. It is important to differentiate AUB caused by anatomical changes and functional causes, and the PALM-COIEN classification has been developed on that dichotomy. Investigations may include blood test, ultrasound, hysteroscopy and endometrial sampling is required in a certain number of situations. Treatment for AUB can be medical and/or surgical depending on the cause. Medical treatment is based on iron supplementation, hormonal and non-hormonal therapies. Surgical treatments include removal of a focal lesion, endometrial resection or destruction and hysterectomy. Age, desire for future pregnancy and etiology for AUB are key factors to consider before initiating a treatment. Treatment efficiency can be assessed using the same tools as pretherapeutic evaluation, and improvement of quality of life has now become the main goal for most international guidelines addressing the subject. PMID- 28716638 TI - The temporal dynamics of miniscleral contact lenses: Central corneal clearance and centration. AB - PURPOSE: To examine the time course of the reduction in central corneal clearance and horizontal and vertical lens translation (decentration) during miniscleral contact lens wear and the theoretical influence upon the optics of the post-lens tear layer. METHODS: Repeated high-resolution OCT images were captured over an 8h period of miniscleral contact lens wear (using a rotationally symmetric 16.5mm diameter lens) in 15 young, healthy participants with normal corneae. Central corneal clearance and lens decentration were derived from OCT images using semi automated image processing techniques. RESULTS: Central corneal clearance decreased exponentially over time, reducing by 76+/-8MUm over 8h. Fifty percent of this reduction occurred within 45min of lens wear and seventy-five percent within 2h, with thinning of the post-lens tear layer plateauing 4h after lens insertion. Lens translation exhibited a similar pattern of change (0.18+/-0.04mm temporal and 0.20+/-0.09mm inferior decentration) stabilising 1.5-2h after insertion. The change in the lens fit over time resulted in a small reduction in the power of the post-lens tear layer (-0.12+/-0.01 D) and induced a prismatic effect of 0.01+/-0.16 Delta base out and 0.50+/-0.19 Delta base down relative to the pupil centre. CONCLUSIONS: For the miniscleral contact lens studied, horizontal and vertical lens decentration followed an exponential decay over 8h that plateaued approximately 2h after lens insertion, while central post-lens tear layer thinning plateaued after 4h of lens wear. PMID- 28716639 TI - Design, synthesis and biological evaluation of novel 4-phenoxyquinoline derivatives containing 3-oxo-3,4-dihydroquinoxaline moiety as c-Met kinase inhibitors. AB - A series of novel 4-phenoxyquinoline derivatives containing 3-oxo-3,4 dihydroquinoxaline moiety were synthesized and evaluated for their c-Met kinase inhibitory activity and antiproliferative activity against five cancer cell lines (HT-29, H460, A549, MKN-45 and U87MG) in vitro. Most of the compounds exhibited moderate-to-significant cytotoxicity as compared with foretinib. The most promising compound 41 (with c-Met IC50 value of 0.90nM) showed remarkable cytotoxicity against HT-29, H460, A549, MKN-45 and U87MG cell lines with IC50 values of 0.06MUM, 0.05MUM, 0.18MUM, 0.023MUM and 0.66MUM, respectively, and thus it was 1.22- to 3.50-fold more potent than foretinib. Their preliminary structure activity relationships (SARs) studies indicate that electron-withdrawing groups on the terminal phenyl rings are beneficial for improving the antitumor activity. PMID- 28716640 TI - Complex molecules, clever solutions - Enzymatic approaches towards natural product and active agent syntheses. AB - Natural compounds are often structurally complex and their synthesis is still highly challenging. The review intends to give an overview on developments in biotechnology and their role for the production of natural products and active agents. In vitro and in vivo methods are presented side by side beginning with rather simple but smart single step conversions, followed by cascade reactions, and finishing with complex bio-, semi- and mutasynthesis endeavours. All the enzymatic approaches do obviously complement traditional synthetic methods; with their particular strengths, the combined repertoire will lead to an increased efficiency in natural product synthesis as well as in providing analogues. PMID- 28716641 TI - Synthesis and evaluation of osimertinib derivatives as potent EGFR inhibitors. AB - Osimertinib has been identified as a promising therapeutic drug targeting for EGFR T790M mutant non-small cell lung cancer (NSCLC). A new series of N-oxidized and fluorinated osimertinib derivatives were designed and synthesized. The cellular anti-proliferative activity, kinase inhibitory activity and the activation of EGFR signaling pathways of 1-6 in vitro were determined against L858R/T790M and wild-type EGFR, the antitumor efficacy in NCI-H1975 xenografts in vivo were further studied. Compound 2, the newly synthesized N-oxide metabolite in N,N,N'-trimethylethylenediamine side chain of osimertinib, showed a comparable kinase selectivity in vitro and a slightly better antitumor efficacy in vivo to osimertinib, making it valuable and suitable for the potential lung cancer therapy. PMID- 28716642 TI - Long-term Use of Inhaled Corticosteroids in COPD and the Risk of Fracture. AB - BACKGROUND: It is uncertain whether long-term use of inhaled corticosteroids (ICSs), widely used to treat COPD, increases the risk of fracture, particularly in women, in view of the postmenopausal risks. We assessed whether long-term ICS use in patients with COPD increases the risk of hip or upper extremity fractures, and examined sex-related differences. METHODS: The Quebec health-care databases were used to form a cohort of patients with COPD over 1990 to 2005, followed until 2007 for the first hip or upper extremity fracture. In a nested case control analysis, each case of fracture was matched with 20 control subjects on age, sex, and follow-up time. The adjusted rate ratio (RR) of fracture with ICS use, by duration and dose, was estimated using conditional logistic regression, with an interaction term to compare the risk in men and women. RESULTS: In the cohort of 240,110 subjects, 19,396 sustained a fracture during a mean 5.3 years (rate, 15.2 per 1,000 per year). Any use of ICSs was not associated with an increased rate of fracture (RR, 1.00; 95% CI, 0.97-1.03). The fracture rate was increased with > 4 years of ICS use at daily doses >= 1,000 MUg in fluticasone equivalents (RR, 1.10; 95% CI, 1.02-1.19). This risk increase did not differ between men and women. CONCLUSIONS: Long-term ICS use at high doses is associated with a modest increase in the risk of hip and upper extremity fractures in patients with COPD. This dose-duration risk increase does not appear to be higher for women. PMID- 28716643 TI - Reduced Risk of Acute Exacerbation of COPD After Bariatric Surgery: A Self Controlled Case Series Study. AB - BACKGROUND: Obesity is common among individuals with COPD and associated with increased COPD morbidities. However, little is known about the impact of weight reduction on COPD-related outcomes in patients who are obese. METHODS: Using the population-based ED and inpatient sample in three US states (California, Florida, and Nebraska), we performed a self-controlled case series study of 481 adults who were obese (40-65 years of age) with COPD who underwent bariatric surgery. The primary outcome was an ED visit or hospitalization for acute exacerbation of COPD (AECOPD) from 2005 through 2011. We compared each patient's risk of the outcome during sequential 12-month periods using presurgery months 13 through 24 as the reference period. RESULTS: During the 13 to 24 months before bariatric surgery (ie, reference period), 28% (95% CI, 24%-32%) of patients had an ED visit or hospitalization for AECOPD. In the subsequent 12-month presurgery period, the risk did not change materially (31%; 95% CI, 27%-35%), with an adjusted OR (aOR) of 1.16 (95% CI, 0.88-1.53; P = .29). By contrast, during the first 12 months after bariatric surgery, the risk declined significantly (12%; 95% CI, 9%-15%; aOR, 0.35; 95% CI, 0.25-0.49; P < .001). Likewise, in the subsequent period of 13 to 24 months after bariatric surgery, the risk remained significantly low (13%; 95% CI, 11%-17%; aOR, 0.39; 95% CI, 0.28-0.55; P < .001). CONCLUSIONS: The risk of an ED visit or hospitalization for AECOPD substantially decreased after bariatric surgery in patients who are obese. This observation suggests the effectiveness of substantial weight reduction on COPD morbidity. PMID- 28716644 TI - MUC5AC and a Glycosylated Variant of MUC5B Alter Mucin Composition in Children With Acute Asthma. AB - BACKGROUND: Diffuse airway mucus obstruction is an important feature of severe and fatal asthma. MUC5AC and MUC5B are the principal gel-forming mucins found in airway mucus. The mucin composition of airway mucus likely affects its functional properties. METHODS: We quantified the principal airway mucins MUC5AC and MUC5B in the sputum of age-matched children with acute and stable asthma and healthy control subjects by using Western blotting. RESULTS: Sputum samples from 38 children (13 with acute asthma, 15 with stable asthma, 10 control subjects) were obtained. Sputum MUC5AC concentrations were 7.6 MUg/mL in control subjects, 22.4 MUg/mL in those with stable asthma (P = .17), and 44.7 MUg/mL in those with acute asthma (P < .05). MUC5B concentrations showed less variation, with 238.5, 208.4 and 165.9 MUg/mL in control subjects, those with stable asthma, and those with acute asthma, respectively. The greater MUC5AC concentration in those with acute asthma resulted in a significantly altered MUC5B:MUC5AC ratio between control subjects and those with acute asthma (P < .05). Significant differences in MUC5B glycoforms were present between the groups, with the low-charge-only glycoform being found uniquely in those with acute asthma. CONCLUSIONS: Increased MUC5AC and the presence of a low-charge-only MUC5B glycoform significantly altered mucin composition in children with acute asthma. These changes may be important contributory factors to the airway mucus obstruction observed during acute asthma. PMID- 28716645 TI - Update in Management of Severe Hypoxemic Respiratory Failure. AB - Mortality related to severe-moderate and severe ARDS remains high. We searched the literature to update this topic. We defined severe hypoxemic respiratory failure as Pao2/Fio2 < 150 mm Hg (ie, severe-moderate and severe ARDS). For these patients, we support setting the ventilator to a tidal volume of 4 to 8 mL/kg predicted body weight (PBW), with plateau pressure (Pplat) <= 30 cm H2O, and initial positive end-expiratory pressure (PEEP) of 10 to 12 cm H2O. To promote alveolar recruitment, we propose increasing PEEP in increments of 2 to 3 cm provided that Pplat remains <= 30 cm H2O and driving pressure does not increase. A fluid-restricted strategy is recommended, and nonrespiratory causes of hypoxemia should be considered. For patients who remain hypoxemic after PEEP optimization, neuromuscular blockade and prone positioning should be considered. Profound refractory hypoxemia (Pao2/Fio2 < 80 mm Hg) after PEEP titration is an indication to consider extracorporeal life support. This may necessitate early transfer to a center with expertise in these techniques. Inhaled vasodilators and nontraditional ventilator modes may improve oxygenation, but evidence for improved outcomes is weak. PMID- 28716646 TI - Pulmonary Infarction: In the Beginning: The Natural History of Pulmonary Infarction. AB - BACKGROUND: Massive pulmonary emboli can cause an abrupt onset of symptoms simultaneous with large pulmonary artery occlusions. In contrast, the temporal relationship between pulmonary vascular occlusion by smaller emboli and the development of symptoms of pulmonary infarction is unknown. We describe the time interval between embolization and the onset of clinical symptoms and signs compatible with pulmonary infarction. METHODS: We examined the records of 56 patients with hereditary hemorrhagic telangiectasia (HHT) who underwent therapeutic balloon embolization of pulmonary arteriovenous malformation (PAVM) in a single center after noting that some of them experienced symptoms and signs compatible with pulmonary infarction. Because both the times of embolization and the onset of clinical symptoms were documented in medical records, we were able to calculate the time interval between embolic occlusion of vessels and the onset of symptoms. RESULTS: The records of 56 patients who underwent therapeutic embolization for HHT were examined. Five patients experienced a single episode of pleuritic pain postembolization, and one patient experienced episodes of pleuritic pain after each of two separate embolization procedures. Four of these pleuritic pain events evolved into a complex compatible with pulmonary infarction. The time intervals between embolization and the onset of pleuritic pain in those experiencing the infarction symptoms and signs were 24 hours, 48 +/ 4 hours, 65 hours, and 67 hours, respectively. CONCLUSIONS: The clinically silent time interval between embolization of a pulmonary artery and the onset of symptoms and signs compatible with lung infarction is 24 hours or greater. PMID- 28716647 TI - Earwax: A clue to discover fluoroacetate intoxication in cattle. AB - An innovative method was developed to detect fluoroacetate poisoning in cattle by headspace/gas chromatographic analysis of earwax samples of intoxicated cattle. Samples were collected from 2 groups of cattle subjected to induced fluoroacetate intoxication, each group receiving a different dose of acetamide (antidote). Monofluoroacetic acid was detected in samples of intoxicated cattle in concentrations inversely proportional to the dose of acetamide. Thus, earwax analysis represents a successful approach for detection and monitoring of fluoroacetate poisoning. PMID- 28716648 TI - Applications of high-speed atomic force microscopy to real-time visualization of dynamic biomolecular processes. AB - BACKGROUND: Many biological processes in a living cell are consequences of sequential and hierarchical dynamic events of biological macromolecules such as molecular interactions and conformational changes. Hence, knowledge of structures, assembly and dynamics of proteins is the foundation for understanding how biological molecules work. Among several techniques to analyze dynamics of proteins, high-speed atomic force microscopy (HS-AFM) is unique to provide direct information about both structure and dynamics of single proteins at work. SCOPE OF REVIEW: The scope of this review is overviewing recent progresses of HS-AFM for studying dynamic processes of biomolecular systems. In the technical descriptions, key developments enabling fast and non-invasive imaging of biological samples are briefly mentioned. Then recent successful applications of HS-AFM are overviewed to showcase the power of HS-AFM in biological research. MAJOR CONCLUSIONS: We discuss examples where HS-AFM movies captured important dynamic biological processes, including conformational dynamics of membrane proteins, processive movements of enzymes, assembly and disassembly processes of protein supramolecular structures, and dynamics in a two-dimensional protein crystal. These examples demonstrate the usability of HS-AFM to reveal biomolecular processes at high spatiotemporal (nanometer and subsecond) resolution. GENERAL SIGNIFICANCE: Real-time movies of unlabeled proteins at work captured by HS-AFM allowed us to directly gain insights into mechanisms of molecular actions. Together with further functional extensions, HS-AFM will enable researchers to investigate more complex biological systems involving multiple proteins and will become an indispensable technique for life science. This article is part of a Special Issue entitled "Biophysical Exploration of Dynamical Ordering of Biomolecular Systems" Guest Editor: Dr., Professor Koichi Kato. PMID- 28716649 TI - Blood Platelet Volume Represents a Novel Prognostic Factor in Patients with Nonmetastatic Renal Cell Carcinoma and Improves the Predictive Ability of Established Prognostic Scores. AB - PURPOSE: The average size of blood platelets determined by mean platelet volume might represent a biologically meaningful parameter in carcinogenesis and potentially serve as a novel prognostic biomarker in renal cell carcinoma. MATERIALS AND METHODS: In this retrospective analysis of the records of 652 patients we evaluated the potential prognostic value of mean platelet volume and its ability to improve existing risk assessment tools used in adjuvant clinical trials in nonmetastatic renal cell carcinoma cases. Associations of mean platelet volume with baseline covariates and clinical outcomes (recurrence, and death from renal cell carcinoma and other causes) were assessed with the competing risk estimators of Kaplan-Meier, and Marubini and Valsecchi, respectively. Univariable and multivariable Cox proportional hazard models were constructed. The Harrell c index was applied to test improvements in the predictive accuracy of the established Leibovich prognosis score. RESULTS: Small platelet volume was associated with large tumors (p = 0.043), high Fuhrman grade (p = 0.001), sarcomatoid components (p <0.0001), histological tumor necrosis (p = 0.044) and vascular invasion (p = 0.022). On univariable and multivariable analyses small platelet volume accurately predicted recurrent renal cell carcinoma (continuously and binary coded) and cancer specific survival. Adding mean platelet volume to the Leibovich prognosis score improved its discriminative performance (c-index = 0.83, p = 0.004). CONCLUSIONS: Mean platelet volume represented a highly significant predictor of recurrence and cancer specific death in patients with renal cell carcinoma. This parameter improved the accuracy of the Leibovich prognosis score to better predict long-term outcomes in localized renal cell carcinoma cases after curative surgical resection. PMID- 28716650 TI - The Use of Prostate Specific Antigen Screening in Purchased versus Direct Care Settings: Data from the TRICARE(r) Military Database. AB - PURPOSE: Fee for service reimbursement incentives may affect care. We compared the odds of prostate specific antigen screening among former and active duty United States military service members based on receipt of primary care from integrated military health facilities vs community providers reimbursed via fee for service. MATERIALS AND METHODS: We retrospectively studied the records of all active duty and retired male service members 40 to 64 years old who were covered by the TRICARE(r) military health benefit in 2010. Beneficiaries may receive primary care at military run facilities via the direct care system or with private physicians via the purchased care system. We compared rates of prostate specific antigen screening between propensity score weighted cohorts of 219,290 men who received primary care in the direct care system and 177,748 who received it in the purchased care system. RESULTS: The screening rate was 35% in the direct care system vs 26% in the purchased care system. After propensity score weighting the former men were significantly more likely to undergo prostate specific antigen screening than men who received primary care in the purchased care system (adjusted OR 1.76, 95% CI 1.729-1.781). Age older than 52 years, rank and black race were associated with increased odds of prostate specific antigen screening in each cohort. CONCLUSIONS: These results suggest that salaried primary care providers employed at integrated military facilities are more likely to order prostate specific antigen screening compared to those reimbursed in a fee for service fashion by military insurance. Growing understanding of how fee for service incentives impact prostate specific antigen screening by primary care providers may enable advocates and policy makers to leverage reimbursement systems as a tool to change prostate cancer screening. PMID- 28716651 TI - Significance of A-to-I RNA editing of transcripts modulating pharmacokinetics and pharmacodynamics. AB - RNA editing is a post-transcriptional process that alters the nucleotide sequence of RNA transcripts to generate transcriptome diversity. Among the various types of RNA editing, adenosine-to-inosine (A-to-I) RNA editing is the most frequent type of RNA editing in mammals. Adenosine deaminases acting on RNA (ADAR) enzymes, ADAR1 and ADAR2, convert adenosines in double-stranded RNA structures into inosines by hydrolytic deamination. Inosine forms a base pair with cytidine as if it were guanosine; therefore, the conversion may affect the amino acid sequence, splicing, microRNA targeting, and miRNA maturation. It became apparent that disrupted RNA editing or abnormal ADAR expression is associated with several diseases including cancer, neurological disorders, metabolic diseases, viral infections, and autoimmune disorders. The biological significance of RNA editing in pharmacokinetics/pharmacodynamics (PK/PD)-related genes is starting to be demonstrated. The authors conducted pioneering studies to reveal that RNA editing modulates drug metabolism potencies in the human liver, as well as the response of cancer cells to chemotherapy agents. Awareness of the importance of RNA editing in drug therapy is growing. This review summarizes the current knowledge on the RNA editing that affects the expression and function of drug response related genes. Continuing studies on the RNA editing that regulates pharmacokinetics/pharmacodynamics would provide new beneficial information for personalized medicine. PMID- 28716652 TI - Toxicity profiles of immunotherapy. AB - Immunotherapies are changing the landscape of advanced solid tumor treatment. These therapies have different mechanisms of action and include oncolytic viruses, checkpoint inhibitors, such as CTLA-4 or PD1/PD-L1 monoclonal antibodies, and CSF-1R antibodies. Given the growing therapeutic impact of these agents in oncology, it is important to better understand their properties. Immunotherapies generate new toxicity profiles that are called immune-related adverse events and require specific management. This review focuses on the mechanisms of action of such side effects, as well as their description and their general management. PMID- 28716653 TI - Bioeconomy in Latin America. AB - This article provides the authors' view on how Latin America has embraced bioeconomy principles in the last two decades with different levels of socio economic impact. Examples of biodiversity resource valorization in medicine, eco intensification of agriculture, biotechnology applications in mature sectors such as mining, food and beverage production, bio-refineries and ecosystem services are provided. The importance of participatory and social innovation initiatives is highlighted. PMID- 28716654 TI - Exercise interventions for individuals with advanced cancer: A systematic review. AB - Despite improvements in therapy a large proportion of individuals with cancer will have a shortened life expectancy because of advanced or metastatic disease. Advances in therapy have however, extended life in those with advanced cancer thus heightening the importance of living well and preventing decline. The burdens of disease and cancer therapy impair aerobic fitness, strength, physical function and quality of life (QOL). Fatigue, the most common side effect of cancer and cancer therapy can further deteriorate QOL. Exercise has the potential to improve aerobic fitness, physical function, control fatigue and enhance QOL. However, exercise interventions are not routinely provided to those with advanced cancer. We present a systematic literature review of outcomes from interventions that include exercise for patients with advanced cancer. Studies were reviewed if they included an advanced cancer population and an intervention with a component of exercise. Overall, exercise containing interventions resulted in improvements in measures of aerobic capacity (14 of 19 studies) strength (11 of 12 studies), and components of physical function (9 of 9 studies). Fatigue and QOL were identified to improve in slightly over half of all evaluated studies (11 of 19 studies and 10 of 19 studies for fatigue and QOL respectively). The numbers of total participants reporting improvements in QOL (60%) were greater than fatigue (45%). Exercise provided to individuals with advanced cancer maintains or improves fitness and physical function and may diminish fatigue and enhance QOL and should be considered as an intervention to prevent further health complications. PMID- 28716655 TI - Trends in beverage prices following the introduction of a tax on sugar-sweetened beverages in Barbados. AB - A 10% excise tax on sugar sweetened beverages (SSBs) was implemented in Barbados in September 2015. A national evaluation has been established to assess the impact of the tax. We present a descriptive analysis of initial price changes following implementation of the SSB tax using price data provided by a major supermarket chain in Barbados over the period 2014-2016. We summarize trends in price changes for SSBs and non-SSBs before and after the tax using year-on-year mean price per liter. We find that prior to the tax, the year-on-year growth of SSB and non-SSB prices was very similar (approximately 1%). During the quarter in which the tax was implemented, the trends diverged, with SSB price growth increasing to 3% and that of non-SSBs decreasing slightly. The growth of SSB prices outpaced non-SSBs prices in each quarter thereafter, reaching 5.9% compared to <1% for non-SSBs. Future analyses will assess the trends in prices of SSBs and non-SSBs over a longer period and will integrate price data from additional sources to assess heterogeneity of post-tax price changes. A continued examination of the impact of the SSB tax in Barbados will expand the evidence base available to policymakers worldwide in considering SSB taxes as a lever for reducing the consumption of added sugar at the population level. PMID- 28716657 TI - Evaluation of Sofia Fluorescent immunoassay analyzer for pneumococcal urinary antigen detection in hospitalized patients with community-acquired pneumonia. AB - The Sofia Streptococcus pneumoniae FIA(r) test was prospectively evaluated in non concentrated urine samples of 106 hospitalized patients with community-acquired pneumonia. The test detected pneumococcal urinary antigen in 24/31 (77.4%) confirmed pneumococcal community-acquired pneumonia episodes. The specificity of the test was 86.7% (92% after urine heating). PMID- 28716656 TI - Atomoxetine in abstinent cocaine users: Cognitive, subjective and cardiovascular effects. AB - No pharmacotherapies are approved for the treatment of cocaine use disorders (CUD). Behavioral treatments for CUD are efficacious for some individuals, but recovery rates from CUD remain low. Cognitive impairments in CUD have been linked with poorer clinical outcomes. Cognitive enhancing pharmacotherapies have been proposed as promising treatments for CUD. Atomoxetine, a norepinephrine transporter inhibitor, shows potential as a treatment for CUD based on its efficacy as a cognitive enhancer in other clinical populations and impact on addictive processes in preclinical and human laboratory studies. In this randomized, double-blind, crossover study, abstinent individuals with CUD (N=39) received placebo, 40 and 80mg atomoxetine, over three sessions. Measures of attention, response inhibition and working memory; subjective medication effects and mood; and cardiovascular effects were collected. Analyses assessed acute, dose-dependent effects of atomoxetine. In addition, preliminary analyses investigating the modulation of atomoxetine dose effects by sex were performed. Atomoxetine increased heart rate and blood pressure, was rated as having positive and negative subjective drug effects, and had only modest effects on mood and cognitive enhancement. PMID- 28716659 TI - Articulating antibiotic impregnated spacers in prosthetic joint infections: Where do we stand? AB - Peri-prosthetic joint infection remains one of the most difficult and challenging complications following hip and knee arthroplasty for both patients and surgeons. Two-stage revision arthroplasty for infection remains the most popular option for the majority of patients and arguably the only option for some. The use antibiotic spacers and in particular articulating spacers has improved the quality of life for patients between stages. The spacers provides local delivery of high concentration antibiotics and provides many benefits to the soft tissues including maintaining soft tissue tension and range of movement. This benefit to the soft tissues also translates into reducing the difficulty and time spent doing the exposure during the second stage procedure. It is generally accepted that peri-prosthetic joint infection should be dealt with my specialist centers who deal with high volumes of patients with this diagnosis in a multidisciplinary approach. PMID- 28716658 TI - Stool antigen immunodetection for diagnosis of Giardia duodenalis infection in human subjects with HIV and cancer. AB - Human infection with the protozoan parasite Giardia duodenalis is one the most common parasitic diseases worldwide. Higher incidence rates of giardiasis have been reported from human subjects with multiple debilitating chronic conditions, including hypogammaglobulinemia and common variable immunodeficiency (CVID). In the current study, stool specimens were collected from 199 individuals diagnosed with HIV or cancer and immunocompetent subjects. The sensitivity of microscopy based detection on fresh stool preparations, trichrome staining and stool antigen immunodetection for the diagnosis of G. duodenalis were 36%, 45.5% and 100%, respectively when compared with a highly sensitive stool-based PCR method as the gold standard. Further multilocus molecular analyses using glutamate dehydrogenase (gdh) and triose phosphate isomerase (tpi) loci demonstrated that the AI genotype of G. duodenalis was the most prevalent, followed by the AII genotype and mixed (AI+B) infections. We concluded that stool antigen immunodetection-based immunoassays and stool-based PCR amplification had comparable sensitivity and specificity for the diagnosis of G. duodenalis infections in these populations. Stool antigen detection-based diagnostic modalities are rapid and accurate and may offer alternatives to conventional microscopy and PCR-based diagnostic methods for the diagnosis of G. duodenalis in human subjects living with HIV or cancer. PMID- 28716660 TI - Differentiation between gallbladder cancer with acute cholecystitis: Considerations for surgeons during emergency cholecystectomy, a cohort study. AB - PURPOSE: Gallbladder cancer (GBCA) is an uncommon malignancy with vague and non specific symptoms. GBCA is sometimes diagnosed after emergency cholecystectomy for acute cholecystitis. We investigated the differential diagnosis between GBCA with acute cholecystitis. MATERIALS AND METHODS: Thirteen patients were diagnosed with GBCA after emergency cholecystectomy carried out for acute cholecystitis. A radiologist who was blinded to the final diagnoses retrospectively reviewed the computed tomography (CT) scans of the patients with GBCA and 25 patients with acute cholecystitis. We retrospectively reviewed the medical records of these patients and compared the clinical characteristics and CT findings between patients with GBCA and those with acute cholecystitis. We also investigated the prognostic factors in patients with GBCA who underwent emergency cholecystectomy. RESULTS: Gallbladder (GB) stones were found more often in patients with acute cholecystitis (n = 17, 68%) than in patients with GBCA (n = 7, 53.8%) (p = 0.486). Patients with GBCA showed typical GB masses or focal enhanced wall thickening when compared to diffuse wall thickening in patients with acute cholecystitis. Some GBCA patients showed irregular mural thickening and GB enhancement. Differentiating carcinoma from acute cholecystitis might sometimes not possible, but the latter group of patients had significantly lower C-reactive protein (CRP) levels (p = 0.033) and less regional fat stranding (p = 0.047). Survival was significantly affected by aggressive tumor characteristics (lymphatic invasion [p = 0.025], depth of tumor invasion [p = 0.004]) or R0 resection (p = 0.013) rather than bile spillage (p = 0.112). CONCLUSIONS: Surgeons deciding on emergency cholecystectomy for elderly patients with acute cholecystitis must suspect GBCA in patients with a low CRP level, irregular mural thickening or enhancement of GB without regional fat stranding. PMID- 28716661 TI - The prevalence and morphometry of an accessory spleen: A meta-analysis and systematic review of 22,487 patients. AB - BACKGROUND: An accessory spleen (AS) is a lobule of splenic tissue found in ectopic locations. Identification of AS is particularly important in patients with immune thrombocytopenia (ITP) requiring splenectomy as unrecognized AS can later cause refractory symptoms. The AS can also be a source of significant intraabdominal hemorrhage. The aim of this meta-analysis was to systematically analyze the data on the prevalence, number, location, and morphometry of AS. MATERIALS AND METHODS: An extensive search of the major electronic databases was conducted to identify all studies that reported relevant data on the AS. No date or language restrictions were applied. Data on the study type, the prevalence of AS, location, morphometry and number of AS per patient were extracted from the eligible studies and pooled into a meta-analysis. RESULTS: A total of 81 studies (n = 22,487 subjects) were included into the quantitative analysis. The overall pooled prevalence of AS was 14.5% (95%CI: 12.4-16.7), while the pooled prevalence of AS in ITP patients was 16.7% (95%CI: 12.1-21.7). The majority of accessory spleens were located in the splenic hilum (62.1% [95%CI:51.5-76.3]). Moreover, 26% of ITP patients with an AS have more than one. CONCLUSIONS: The findings of this study provide an evidence-based foundation of anatomical knowledge about the AS. Surgeons should take particular caution in identifying an AS, as unnoticed AS during splenectomy can lead to recurrence of hematological diseases or can be a potential source of bleeding in the future. PMID- 28716662 TI - lgtF effects of Haemophilus parasuis LOS induced inflammation through regulation of NF-kappaB and MAPKs signaling pathways. AB - The lgtF gene encodes a glucosyltransferase responsible for adding a glucose to the first sugar of heptose I in the synthesis of lipooligosaccharides (LOS). To study the function of lgtF, we constructed an lgtF mutant (DeltalgtF) from Haemophilus parasuis SC096 using a natural transformation system. A highly purified preparation of LOS from DeltalgtF (DeltalgtF-LOS) exhibited an obvious truncation in structure compared to the LOS of the wild-type SC096 strain (WT LOS). The DeltalgtF-LOS also displayed a significantly reduced ability to induce inflammatory cytokine mRNA expression of tumor necrosis factor alpha (TNF-alpha), interleukin-1alpha (IL-1alpha), IL-1beta, IL-6 and IL-8 in porcine alveolar macrophages (PAMs) in comparison with the WT-LOS. Furthermore, we also found that DeltalgtF-LOS-treated cells had significantly decreased phospho-p65 and phospho p38, and inhibited IkappaBalpha degradation. These findings suggested that the lgtF gene mediated LOS induction of pro-inflammatory cytokines in PAMs by regulating the NF-kappaB and MAPKs signaling pathways during H. parasuis infection. PMID- 28716663 TI - Time-course of plasma inflammatory mediators in a rat model of brain death. AB - BACKGROUND: Brain death (BD) is a donor-associated risk factor that negatively affects transplantation outcome. The inflammation associated with BD appears to have a negative effect on organ quality. Complement activation, apoptosis, and pro-inflammatory cytokine and chemokine expression are significantly increased after BD. To better understand this process, we investigated plasma chemokine and cytokine levels for 8h after BD in a rodent model. METHODS: Thirteen healthy adult male Sprague Dawley rats were intubated and mechanically ventilated. After induction of BD, animals were kept hemodynamically stable for 8h. A panel of immune response factors, including cytokines and chemokines, were measured immediately prior to the induction of BD and at 1, 4, and 8h after BD by multiplex analyses in 10 rats. RESULTS: In the early phase of BD, we observed an increase in heart rate and a decrease in mean arterial pressure. Only limited fluctuations were noted in the partial pressure of O2, O2 saturation, and HCO3. Monocyte-/macrophage- and lymphocyte-derived mediators (IL-2, IL-4, and IFN gamma) increased steadily during the 8-hour monitoring period. CONCLUSIONS: The increase in immune responses, particularly pro-inflammatory responses, after BD is time-dependent. Cytokines and chemokines from donors and recipients require further investigation to determine the optimal time frames for organ transplantation in rodent models and humans. PMID- 28716665 TI - Applying label-free dynamic mass redistribution assay for studying endogenous FPR1 receptor signalling in human neutrophils. AB - INTRODUCTION: The label-free dynamic mass redistribution-based assay (DMR) is a powerful method for studying signalling pathways of G protein-coupled receptors (GPCRs). Herein we present the label-free DMR assay as a robust readout for pharmacological characterization of formyl peptide receptors (FPRs) in human neutrophils. METHODS: Neutrophils were isolated from fresh human blood and their responses to FPR1 and FPR2 agonists, i.e. compound 43, fMLF and WKYMVm were measured in a label-free DMR assay using Epic Benchtop System from Corning(r). Obtained DMR traces were used to calculate agonist potencies. RESULTS: The potencies (pEC50) of fMLF, WKYMVm and compound 43, determined on human neutrophils using the label-free DMR assay were 8.63, 7.76 and 5.92, respectively. The DMR response to fMLF, but not WKYMVm and compound 43 could be blocked by the FPR1-specific antagonist cyclosporin H. DISCUSSION: We conclude that the DMR assay can be used, and complements more traditional methods, to study the signalling and pharmacology of endogenous FPR receptors in human neutrophils. PMID- 28716664 TI - Advances and challenges in the search for D2 and D3 dopamine receptor-selective compounds. AB - Compounds that target D2-like dopamine receptors (DRs) are currently used as therapeutics for several neuropsychiatric disorders including schizophrenia (antagonists) and Parkinson's disease (agonists). However, as the D2R and D3R subtypes are highly homologous, creating compounds with sufficient subtype selectivity as well as drug-like properties for therapeutic use has proved challenging. This review summarizes the progress that has been made in developing D2R- or D3R-selective antagonists and agonists, and also describes the experimental conditions that need to be considered when determining the selectivity of a given compound, as apparent selectivity can vary widely depending on assay conditions. Future advances in this field may take advantage of currently available structural data to target alternative secondary binding sites through creating bivalent or bitopic chemical structures. Alternatively, the use of high-throughput screening techniques to identify novel scaffolds that might bind to the D2R or D3R in areas other than the highly conserved orthosteric site, such as allosteric sites, followed by iterative medicinal chemistry will likely lead to exceptionally selective compounds in the future. More selective compounds will provide a better understanding of the normal and pathological functioning of each receptor subtype, as well as offer the potential for improved therapeutics. PMID- 28716666 TI - Mouse cardiac mitochondria do not separate in subsarcolemmal and interfibrillar subpopulations. AB - Cardiomyocytes consist of longitudinally oriented myofibril bundles with a misaligned composition caused by the uneven contours of the intercalated discs. The cytoplasmic space harbors the organelles, including mitochondria. This study investigated whether cardiomyocytes contain spatially and ultrastructurally discrete pools of mitochondria that can be separated for structurally and functionally appraisal in (patho)physiology. Transmission electron microscopy disclosed continuous transitions of mitochondria without attributable characteristics from beneath the sarcolemma directly into the barrier-free cytoplasmic space between myofibrils. The various shapes and sizes of mitochondria are formed by myofibril positioning and the space available independent of their localization within the cardiomyocytes. Furthermore, the established enzymatic isolation procedure including proteinase treatment resulted in loss of mitochondrial proteins, as evidenced by immunogold labeling of Connexin43 in situ, a postulated marker for distinguishing mitochondrial subpopulations. Moreover, mitochondrial ATP produced in those mitochondria was not different. These findings preclude a spatial and ultrastructural grading of cardiac mitochondria and their distinct separation and classification in subsarcolemmal and interfibrillar subpopulations. PMID- 28716667 TI - Pupillometric evaluation of the melanopsin containing retinal ganglion cells in mitochondrial and non-mitochondrial optic neuropathies. AB - In recent years, chromatic pupillometry is used in humans to evaluate the activity of melanopsin expressing intrinsic photosensitive retinal ganglion cells (ipRGCs). Blue light is used to stimulate the ipRGCs and red light activates the rod/cone photoreceptors. The late re-dilation phase of pupillary light reflex is primarily driven by the ipRGCs. Optic neuropathies i.e. Leber hereditary optic neuropathy (LHON), autosomal dominant optic atrophy (ADOA), nonarteritic anterior ischemic optic neuropathy (NAION), glaucoma, optic neuritis and idiopathic intracranial hypertension (IIH) are among the diseases, which have been subject to pupillometric studies. The ipRGCs are differentially affected in these various optic neuropathies. In mitochondrial optic neuropathies, the ipRGCs are protected against degeneration, whereas in glaucoma, NAION, optic neuritis and IIH the ipRGCs are damaged. Here, we will review the results of pupillometric, histopathological and animal studies evaluating the ipRGCs in mitochondrial and non-mitochondrial optic neuropathies. PMID- 28716668 TI - Incomplete penetrance in mitochondrial optic neuropathies. AB - Incomplete penetrance characterizes the two most frequent inherited optic neuropathies, Leber's Hereditary Optic Neuropathy (LHON) and dominant optic atrophy (DOA), due to genetic errors in the mitochondrial DNA (mtDNA) and the nuclear DNA (nDNA), respectively. For LHON, compelling evidence has accumulated on the complex interplay of mtDNA haplogroups and environmental interacting factors, whereas the nDNA remains essentially non informative. However, a compensatory mechanism of activated mitochondrial biogenesis and increased mtDNA copy number, possibly driven by a permissive nDNA background, is documented in LHON; when successful it maintains unaffected the mutation carriers, but in some individuals it might be hampered by tobacco smoking or other environmental factors, resulting in disease onset. In females, mitochondrial biogenesis is promoted and maintained within the compensatory range by estrogens, partially explaining the gender bias in LHON. Concerning DOA, none of the above mechanisms has been fully explored, thus mtDNA haplogroups, environmental factors such as tobacco and alcohol, and further nDNA variants may all participate as protective factors or, on the contrary, favor disease expression and severity. Next generation sequencing, complemented by transcriptomics and proteomics, may provide some answers in the next future, even if the multifactorial model that seems to apply to incomplete penetrance in mitochondrial optic neuropathies remains problematic, and careful stratification of patients will play a key role for data interpretation. The deep understanding of which factors impinge on incomplete penetrance may shed light on the pathogenic mechanisms leading to optic nerve atrophy, on their possible compensation and, thus, on development of therapeutic strategies. PMID- 28716669 TI - Steam sterilization does not require saturated steam. PMID- 28716671 TI - Universal decontamination of hospital surfaces in an occupied inpatient room with a continuous 405 nm light source. AB - BACKGROUND: Previous work has shown that a ceiling-mounted, 405 nm high-intensity narrow-spectrum light environmental decontamination system (HINS-light EDS) reduces bacterial contamination of environmental surfaces in a burns unit by between 27% and 75%. Examination of the efficacy of the light over extended exposure times and its probable mode of action was performed. AIM: To ascertain the correlation between bacterial kill achieved on sampled surface sites around the burns unit and both irradiance levels of the 405 nm light, and exposure time. METHODS: Seventy samples were taken using contact agar plates from surfaces within an occupied side-room in the burns unit before, during, and after a seven day use of the HINS-light EDS. This was repeated in three separate studies. Statistical analysis determined whether there was significant decrease in environmental contamination during prolonged periods of HINS-light treatment, and whether there was an association between irradiance and bacterial kill. FINDINGS: A decrease of between 22% and 86% in the mean number of surface bacteria was shown during the use of the HINS-light EDS. When the light ceased to be used, increases of between 78% and 309% occurred. There was no correlation between bacterial kill and irradiance levels at each sampling site but strong correlation between bacterial kill and exposure time. CONCLUSION: Prolonged exposure to the HINS-light EDS causes a cumulative decontamination of the surfaces within a burns unit. The importance of exposure time and possible airborne effect over irradiance levels is emphasized. PMID- 28716672 TI - Influence of methylation on the bacterial efflux pump-inducing property of triclosan. PMID- 28716670 TI - Nationwide study on peripheral-venous-catheter-associated-bloodstream infections in internal medicine departments. AB - BACKGROUND: The use of peripheral venous catheters (PVCs) has increased outside intensive care units, as has the rate of PVC-associated-bloodstream infection (PVC-BSI). PVCs are widely used in internal medicine departments (IMDs), but data on the incidence of PVC-BSI and its characteristics in IMDs are scarce. AIM: To assess the incidence of PVC-BSI episodes detected in IMDs in Spain. METHODS: A one-year multi-centre prospective observational cohort study in 14 Spanish IMDs was undertaken. Adult patients admitted with at least one PVC and bacteraemia were included in the study. Demographic and clinical data were provided by local coordinators. FINDINGS: Seventy episodes of PVC-BSI were recorded, representing an overall rate of 1.64 PVC-BSI episodes/1000 IMD admissions. The mean age of patients was 67.44 (standard deviation 16.72) years. It was estimated that 25.7% of PVCs were no longer necessary. Staphylococcus aureus was the most frequently isolated micro-organism (41.7%). Phlebitis was clinically evident in 44 (62.9%) episodes, and proved to be an independent predictor of catheter insertion in emergency departments (odds ratio 5.44). The crude and attributable mortality rates were 12.9% and 5.7%, respectively. CONCLUSIONS: PVCs carry a significant risk for bacteraemia in Spanish IMDs. Phlebitis is not always clinically evident in patients with bacteraemia in this population. The study findings support the need for educational and interventional preventive measures in both IMDs and emergency departments to reduce the rate of PVC-BSI and associated comorbidities, and costs. PMID- 28716673 TI - Application of 3-Dimensional Computerized Tomography Angiography for Defining Cavernous Sinus Aneurysms and Intradural Aneurysms Involving the Internal Carotid Artery Around the Anterior Clinoid Process. AB - OBJECTIVE: This study aimed to investigate the application of 3-dimensional computed tomography angiography (3D-CTA) for defining cavernous sinus aneurysms and intradural aneurysms involving the internal carotid artery around the anterior clinoid process. METHODS: Results from 42 patients with an aneurysm of the internal carotid artery around the anterior clinoid process who underwent 3D CTA were reviewed and compared with those of observed clinical operations. RESULTS: Among the 42 patients, there was a total of 45 aneurysms of the internal carotid artery around the anterior clinoid process. After surgery, 33 of the 45 aneurysms were confirmed as intradural aneurysms, and the other 12 were confirmed as aneurysms in the cavernous sinus. 3D-CTA imaging of the medial sagittal plane showed that 31 out of 31 (100%) intradural aneurysms of the internal carotid artery were above the virtual line between the inferior border of the anterior clinoid process and the tuberculum sellae, and 12 out of 14 (86%) cavernous sinus aneurysms were below the virtual line (P < 0.0001). CONCLUSIONS: The virtual line between the inferior border of the anterior clinoid process and the tuberculum sellae on 3D-CTA indicates the proximal dural ring of the internal carotid artery. This line helps differentiate cavernous sinus aneurysms from intradural aneurysms involving the internal carotid artery around the anterior clinoid process. PMID- 28716674 TI - Pleasant and unpleasant odour-face combinations influence face and odour perception: An event-related potential study. AB - Odours alter evaluations of concurrent visual stimuli. However, neural mechanisms underlying the effects of congruent and incongruent odours on facial expression perception are not clear. Moreover, the influence of emotional faces on odour perception is not established. We investigated the effects of one pleasant and one unpleasant odour paired with happy and disgusted faces, on subjective ratings and ERP responses to faces. Participants rated the pleasantness of happy and disgusted faces that appeared during 3s pleasant or unpleasant odour pulses, or without odour. Odour pleasantness and intensity ratings were recorded in each trial. EEG was recorded continuously using a 128-channel system. Happy and disgusted faces paired with pleasant and unpleasant odour were rated as more or less pleasant, respectively, compared to the same faces presented in the other odour conditions. Odours were rated as more pleasant when paired with happy faces, and unpleasant odour was rated more intense when paired with disgusted faces. Unpleasant odour paired with disgusted faces also decreased inspiration. Odour-face interactions were evident in the N200 and N400 components. Our results reveal bi-directional effects of odours and faces, and suggest that odour-face interactions may be represented in ERP components. Pairings of unpleasant odour and disgusted faces resulted in stronger hedonic ratings, ERP changes, increased odour intensity ratings and respiratory adjustment. This finding likely represents heightened adaptive responses to multimodal unpleasant stimuli, prompting appropriate behaviour in the presence of danger. PMID- 28716675 TI - What we imagine is what we do? A critical overview about mental imagery as a strategy to study human defensive responses. AB - There is not a single and perfect instinctive behavior to react to threatening situations. However, the study of particular features of these situations suggests the existence of prototypical emotional reactions and associated defensive behaviors. Since all living beings are subjected to common evolutionary pressures, such as predation and conspecific competition, it is plausible that there is conservation of some basic defensive responses in their behavioral repertoire. The choice for approaching or withdrawing from a given situation depends, among others things, on environmental features, including the threat intensity and the distance from the source of the threat. If these basic responses were conserved in humans, they should be expressed in ways similar to those observed in non-human animals. Due to ethical reasons and easy application, mental imagery has been used to test this hypothesis. The studies included in this review point to the validity of this method, with both self-report and neurophysiological findings corroborating the hypothesis under scrutiny. Despite the need for additional investigation to deal with some limitations, the information obtained with this method can help to a better understanding of the conditions that provoke specific defensive behaviors and related emotions. This knowledge may also contribute to identify vulnerability factors for fear/anxiety related disorders. PMID- 28716676 TI - Latent tuberculosis infection in rural China: who will develop tuberculosis? PMID- 28716678 TI - Cancer recurrence monitoring using hyperpolarized [1-13C]pyruvate metabolic imaging in murine breast cancer model. AB - The purpose of this work was to study the anatomic and metabolic changes that occur with tumor progression, regression and recurrence in a switchable MYC driven murine breast cancer model. Serial 1H MRI and hyperpolarized [1 13C]pyruvate metabolic imaging were used to investigate the changes in tumor volume and glycolytic metabolism over time during the multistage tumorigenesis. We show that acute de-induction of MYC expression in established tumors results in rapid tumor regression and significantly reduced glycolytic metabolism as measured by pyruvate-to-lactate conversion. Moreover, cancer recurrences occurring at the tumor sites independently of MYC expression were observed to accompany markedly increased lactate production. PMID- 28716679 TI - Modified-BRISQUE as no reference image quality assessment for structural MR images. AB - An effective and practical Image Quality Assessment (IQA) model is needed to assess the image quality produced from any new hardware or software in MRI. A highly competitive No Reference - IQA (NR - IQA) model called Blind/Referenceless Image Spatial Quality Evaluator (BRISQUE) initially designed for natural images were modified to evaluate structural MR images. The BRISQUE model measures the image quality by using the locally normalized luminance coefficients, which were used to calculate the image features. The modified-BRISQUE model trained a new regression model using MR image features and Difference Mean Opinion Score (DMOS) from 775 MR images. Two types of benchmarks: objective and subjective assessments were used as performance evaluators for both original and modified-BRISQUE models. There was a high correlation between the modified-BRISQUE with both benchmarks, and they were higher than those for the original BRISQUE. There was a significant percentage improvement in their correlation values. The modified BRISQUE was statistically better than the original BRISQUE. The modified-BRISQUE model can accurately measure the image quality of MR images. It is a practical NR IQA model for MR images without using reference images. PMID- 28716680 TI - Three-dimensional adiabatic inversion recovery prepared ultrashort echo time cones (3D IR-UTE-Cones) imaging of cortical bone in the hip. AB - PURPOSE: We present three-dimensional adiabatic inversion recovery prepared ultrashort echo time Cones (3D IR-UTE-Cones) imaging of cortical bone in the hip of healthy volunteers using a clinical 3T scanner. METHODS: A 3D IR-UTE-Cones sequence, based on a short pulse excitation followed by a 3D Cones trajectory, with a nominal TE of 32MUs, was employed for high contrast morphological imaging of cortical bone in the hip of heathy volunteers. Signals from soft tissues such as muscle and marrow fat were suppressed via adiabatic inversion and signal nulling. T2* value of the cortical bone was also calculated based on 3D IR-UTE Cones acquisitions with a series of TEs ranging from 0.032 to 0.8ms. A total of four healthy volunteers were recruited for this study. Average T2* values and the standard deviation for four regions of interests (ROIs) at the greater trochanter, the femoral neck, the femoral head and the lesser trochanter were calculated. RESULTS: The 3D IR-UTE-Cones sequence provided efficient suppression of soft tissues with excellent image contrast for cortical bone visualization in all volunteer hips. Exponential single component decay was observed for all ROIs, with averaged T2* values ranging from 0.33 to 0.45ms, largely consistent with previously reported T2* values of cortical bone in the tibial midshaft. CONCLUSIONS: The 3D IR-UTE-Cones sequence allows in vivo volumetric imaging and quantitative T2* measurement of cortical bone in the hip using a clinical 3T scanner. PMID- 28716681 TI - MRI magic-angle effect in femorotibial cartilages of the red kangaroo. AB - OBJECTIVE: Kangaroo knee cartilages are robust tissues that can support knee flexion and endure high levels of compressive stress. This study aimed to develop a detailed understanding of the collagen architecture in kangaroo knee cartilages and thus obtain insights into the biophysical basis of their function. DESIGN: Cylindrical/square plugs from femoral and tibial hyaline cartilage and tibial fibrocartilage were excised from the knees of three adult red kangaroos. Multi slice, multi-echo MR images were acquired at the sample orientations 0 degrees and 55 degrees ("magic angle") with respect to the static magnetic field. Maps of the transverse relaxation rate constant (R2) and depth profiles of R2 and its anisotropic component (R2A) were constructed from the data. RESULTS: The R2A profiles confirmed the classic three-zone organisation of all cartilage samples. Femoral hyaline cartilage possessed a well-developed, thick superficial zone. Tibial hyaline cartilage possessed a very thick radial zone (80% relative thickness) that exhibited large R2A values consistent with highly ordered collagen. The R2A profile of tibial fibrocartilage exhibited a unique region near the bone (bottom 5-10%) consistent with elevated proteoglycan content ("attachment sub-zone"). CONCLUSIONS: Our observations suggest that the well developed superficial zone of femoral hyaline cartilage is suitable for supporting knee flexion; the thick and well-aligned radial zone of tibial hyaline cartilage is adapted to endure high compressive stress; while the innermost part of the radial zone of tibial fibrocartilage may facilitate anchoring of the collagen fibres to withstand high shear deformation. These findings may inspire new designs for cartilage tissue engineering. PMID- 28716682 TI - AIR-MRF: Accelerated iterative reconstruction for magnetic resonance fingerprinting. AB - Existing approaches for reconstruction of multiparametric maps with magnetic resonance fingerprinting (MRF) are currently limited by their estimation accuracy and reconstruction time. We aimed to address these issues with a novel combination of iterative reconstruction, fingerprint compression, additional regularization, and accelerated dictionary search methods. The pipeline described here, accelerated iterative reconstruction for magnetic resonance fingerprinting (AIR-MRF), was evaluated with simulations as well as phantom and in vivo scans. We found that the AIR-MRF pipeline provided reduced parameter estimation errors compared to non-iterative and other iterative methods, particularly at shorter sequence lengths. Accelerated dictionary search methods incorporated into the iterative pipeline reduced the reconstruction time at little cost of quality. PMID- 28716683 TI - Trimmed autocalibrating k-space estimation based on structured matrix completion. AB - PURPOSE: Parallel imaging allows the reconstruction of undersampled data from multiple coils. This provides a means to reject and regenerate corrupt data (e.g. from motion artefact). The purpose of this work is to approach this problem using the SAKE parallel imaging method. THEORY AND METHODS: Parallel imaging methods typically require calibration by fully sampling the center of k-space. This is a challenge in the presence of corrupted data, since the calibration data may be corrupted which leads to an errors-in-variables problem that cannot be solved by least squares or even iteratively reweighted least squares. The SAKE method, based on matrix completion and structured low rank approximation, was modified to detect and trim these errors from the data. RESULTS: Simulated and actual corrupted datasets were reconstructed with SAKE, the proposed approach and a more standard reconstruction method (based on solving a linear equation) with a data rejection criterion. The proposed approach was found to reduce artefacts considerably in comparison to the other two methods. CONCLUSION: SAKE with data trimming improves on previous methods for reconstructing images from grossly corrupted data. PMID- 28716684 TI - A comparison of retrobulbar and two peribulbar regional anesthetic techniques in dog cadavers. AB - OBJECTIVE: To compare injectate distribution and likelihood of regional anesthesia to the orbit following retrobulbar (RB) or peribulbar (PB) injections in dog cadavers. STUDY DESIGN: Randomized, masked study. ANIMALS: Twenty-four dog cadavers (aged 5.5-17 years, 2.0-36.3 kg). METHODS: Orbits underwent one of three injection techniques with bupivacaine 0.5% and iohexol (1:1): ventrolateral RB injection (1-2 mL; 15 orbits), medial canthal PB injection (2-8 mL; PB-1; 16 orbits), or dorsomedial and ventrolateral PB injections (each 1-4 mL; PB-2; 16 orbits). The likelihood of successful regional anesthesia was estimated based on computed tomographic images scored for injectate volume of distribution at the base and within the extraocular muscle cone (EOMC), and injectate distribution around the optic nerve. Intraocular pressure (IOP) was measured before and after injections. Mixed-effects linear regression with post hoc Bonferroni contrast adjustments was performed. Significance was set at 0.05. RESULTS: A difference in injectate volume of distribution within or at the base of the EOMC was not detected among groups. The median optic nerve circumference of injectate distribution was significantly higher in the RB injected group than in the PB-2 group. Injectate distribution following RB, PB-1 and PB-2 injections was graded as likely to provide regional anesthesia within the EOMC in 40%, 19% and 31% of eyes, and at the EOMC base in 60%, 63% and 50% of eyes, respectively. The probability of likelihood to provide regional anesthesia was lower in dogs of higher body weights. The IOP was significantly higher than baseline following PB 1 (18 +/- 14 mmHg) and in comparison with RB (2 +/- 3 mmHg), but not different from PB-2 injection (10 +/- 11 mmHg). CONCLUSIONS AND CLINICAL RELEVANCE: None of the techniques reliably produced 'successful' injectate distribution based on this study's definitions; however, clinical assessment of anesthetic success is required. PMID- 28716677 TI - Incidence of active tuberculosis in individuals with latent tuberculosis infection in rural China: follow-up results of a population-based, multicentre, prospective cohort study. AB - BACKGROUND: The management of latent Mycobacterium tuberculosis infection is a new priority action for the WHO End Tuberculosis (TB) Strategy. However, national guidelines on latent tuberculosis infection testing and treatment have not yet been developed in China. Here, we present the results from the 2-year follow-up of a study that aimed to track the development of active disease in individuals with latent tuberculosis infection, identify priority populations for latent infection management, and explore the most suitable latent infection diagnostic approach. METHODS: A population-based multicentre prospective study was done in four sites in rural China, between 2013 and 2015. The baseline survey in 2013 measured the prevalence of latent tuberculosis infection using QuantiFERON-TB Gold In-Tube (QFT) and tuberculin skin test (TST) in eligible participants. During the follow-up phase between 2014-15, we assessed individuals who had tuberculosis infection at baseline (QFT-positivity or TST tuberculin reaction size [induration] of >=10 mm) for the development of active disease through active case finding. Eligible participants included in follow-up survey had a birth date before June 1, 2008 (5 years or older in 2013), and continuous residence at the study site for 6 months or longer in the past year. Participants with current active tuberculosis at baseline survey were excluded. FINDINGS: Between Sept 1, 2013, and Aug 31, 2015, 7505 eligible participants (aged 5 years or older) were included in tuberculosis infection test positive cohorts (4455 were QFT positive, 6404 had TST induration >=10 mm, and 3354 were positive for both tests) after baseline examination. During the 2-year follow-up period, 84 incident cases of active tuberculosis were diagnosed. Of participants who developed active tuberculosis, 75 were diagnosed with latent infection by QFT, 62 were diagnosed by TST, and 53 were diagnosed by both tests. An incidence rate of 0.87 (95% CI 0.68-1.07) per 100 person-years was observed for individuals who tested positive with QFT, 0.50 (0.38-0.63) per 100 person-years for those who tested positive with TST (p<0.0001), and 0.82 (0.60-1.04) per 100 person-years for those who tested positive with both tests. Male sex and a history of tuberculosis were significantly associated with increased risk of disease development with adjusted hazard ratios of 2.36 (95% CI 1.30-4.30) for male sex and 5.40 (3.34-8.71) for a history of tuberculosis. INTERPRETATION: Our results suggest that high-risk populations in communities in rural China, such as individuals at a high risk of disease reactivation from previous tuberculosis, should be targeted for latent infection screening and treatment with an interferon-gamma releasing assay rather than a TST. FUNDING: National Science and Technology Major Project of China, Program for Changjiang Scholars and Innovative Research Team in University of China, CAMS Innovation Fund for Medical Sciences, and Sanming Project of Medicine in Shenzhen. PMID- 28716685 TI - The use of alfaxalone for premedication, induction and maintenance of anaesthesia in pigs: a pilot study. AB - OBJECTIVE: The evaluation of alfaxalone as a premedication agent and intravenous anaesthetic in pigs. STUDY DESIGN: Prospective, clinical trial. ANIMALS: Nine healthy, 6-8-week-old female Landrace pigs weighing 22.2 +/- 1.0 kg, undergoing epidural catheter placement. METHODS: All pigs were premedicated with 4 mg kg-1 alfaxalone, 40 MUg kg-1 medetomidine and 0.4 mg kg-1 butorphanol administered in the cervical musculature. Sedation was subjectively scored by the same observer from 1 (no sedation) to 10 (profound sedation) prior to induction of anaesthesia with alfaxalone intravenously to effect. All pigs were maintained on alfaxalone infusions with the rate of administration adjusted to maintain appropriate anaesthetic depth. Quality of induction was scored from 1 (poor) to 3 (smooth) and basic cardiorespiratory variables were recorded every 5 minutes during anaesthesia. Results are reported as mean +/- standard deviation or median (range) as appropriate. RESULTS: Sedation scores were 9 (7-10). Inductions were smooth in all pigs and cardiovascular variables remained within normal limits for the duration of anaesthesia. The induction dose of alfaxalone was 0.9 (0.0-2.3) mg kg-1. Three pigs did not require additional alfaxalone after premedication to facilitate intubation. CONCLUSIONS AND CLINICAL RELEVANCE: Intramuscular alfaxalone in combination with medetomidine and butorphanol produced moderate to deep sedation in pigs. Alfaxalone produced satisfactory induction and maintenance of anaesthesia with minimal cardiovascular side effects. Appropriate monitoring of pigs premedicated with this protocol is required as some pigs may become anaesthetized after intramuscular administration of this combination of drugs. PMID- 28716686 TI - Sedative and cardiovascular effects of intranasal or intramuscular dexmedetomidine in healthy dogs. AB - OBJECTIVE: To compare the clinical effects and sedation scores following either intranasal (IN) or intramuscular (IM) administration of dexmedetomidine in dogs. STUDY DESIGN: Prospective, blinded, randomized, clinical study. ANIMALS: A total of 20 client-owned dogs scheduled for noninvasive diagnostic procedures. METHODS: Dogs were allocated to be administered dexmedetomidine 0.02 mg kg-1 IN (IN group) or IM (IM group). Sedation was scored before and at 5 minute intervals (for 45 minutes) after drug administration using a composite simple descriptive sedation scale giving a score of 0 (not sedated) to 13 (well sedated). Respiratory frequency (fR), heart rate, haemoglobin oxygen saturation (SpO2) and noninvasive arterial blood pressure were recorded every 5 minutes for 45 minutes. Normally distributed data were analyzed using two-way ANOVA and post hoc Sidak's multiple comparison test. Non-normally distributed data were compared using the Scheier Ray Hare test and post hoc Mann-Whitney U test. Statistical significance was set at p<0.05. RESULTS: Weight, age and sex were not different between groups. Dexmedetomidine onset of action after IN administration was not shorter compared to IM administration (6.3+/-3.3 versus 9.4+/-4.6 minutes, p=0.120). Sedation score in the IN group was higher [10 (0-11)] compared to the IM group [6 (0-8)] (p<0.001). At time of peak sedation, heart rate decreased 56% from baseline values in the IM group, and 18% in the IN group. No significant differences in SpO2 and fR were found between the two groups at any time point. No undesirable effects were observed. CONCLUSIONS AND CLINICAL RELEVANCE: Intranasal dexmedetomidine 0.02 mg kg-1 produced effective sedation with less bradycardia and more profound sedation compared to IM administration in healthy dogs and may be considered as an alternative route for dexmedetomidine administration in dogs. PMID- 28716687 TI - Measures of Ventricular-Arterial Coupling and Incident Heart Failure With Preserved Ejection Fraction: A Matched Case-Control Analysis. AB - BACKGROUND: Evidence continues to demonstrate increasing prevalence, cost, and mortality implications of heart failure with preserved ejection fraction (HFpEF), but clearly defined parameters that distinguish between control subjects and HFpEF have not been established. OBJECTIVES: This study was designed to detect differences in markers associated with Ventricular-arterial coupling and HFpEF when comparing matched case and control groups. METHODS: A study cohort of case (incident patients with HFpEF; n = 155) and matched control (patients with no prior heart failure; n = 155) groups was retrospectively identified. Matching criteria included race, sex, age, and date of echocardiography (within 1 year). Physiologic and echocardiographic markers were collected from previously acquired transthoracic echocardiograms. These echocardiographic images were reanalyzed, and measures of ventricular-arterial coupling were calculated. Using conditional logistic regression and controlling for covariates, models were fitted to detect differences in HFpEF markers between case and control subjects. RESULTS: Statistically significant differences in markers that reflect ventricular elastance (Ees; P = .007) and left atrial diameter (LAdiam; P = .04) were detected when comparing the case and control groups. Conditional logistic regression analyses suggested a 40% higher odds of being in the case group with every 1-unit increase in Ees (odds ratio [OR] 1.40, 95% confidence interval [CI] 1.10-1.79) and a 2.92 times higher odds of being in the case group for every 1 cm increase in LAdiam (OR 2.92, 95% CI 1.064-7.994). CONCLUSIONS: Ees and LAdiam are easily measurable echocardiographic markers that may have a role in identifying and tracking the progression toward incident HFpEF without increasing cost or risk to the patient. Prospective studies are indicated to explore the use of Ees and LAdiam as predictors of impending HFpEF. PMID- 28716688 TI - Influence of Thoracic Fluid Compartments on Pulmonary Congestion in Chronic Heart Failure. AB - INTRODUCTION: Pulmonary congestion is a common finding of heart failure (HF), but it remains unclear how pulmonary and heart blood volumes (Vp and Vh, respectively) and extravascular lung water (EVLW) change in stable HF and affect lung function. METHODS: Fourteen patients with HF (age 68 +/- 11 y, LVEF 33 +/- 8%) and 12 control subjects (age 65 +/- 9 y) were recruited. A pulmonary function test, thoracic computerized tomographic (CT) scan, and contrast perfusion scan were performed. From the thoracic scan, a histogram of CT attenuation of lung tissue was generated and skew, kurtosis, and full-width half-max (FWHM) calculated as surrogates of EVLW. Blood volumes were calculated from the transit time of the contrast through the great vessels of the heart. RESULTS: Patients with HF had greater Vp and Vh (Vp 0.55 +/- 0.21 L vs 0.41 +/- 0.13 L; Vh 0.53 +/- 0.33 L vs 0.40 +/- 0.15 L) and EVLW (skew 3.2 +/- 0.5 vs 3.7 +/- 0.7; kurtosis 19.4 +/- 6.6 vs 25.9 +/- 9.4; FWHM 73 +/- 13 HU vs 59 +/- 9 HU). Spirometric measures were decreased in HF (percentage of predicted: forced vital capacity 86 +/- 17% vs 104 +/- 9%; forced expiratory volume in 1 second 83 +/- 20% vs 105 +/- 11%; maximal mid-expiratory flow 82 +/- 42% vs 115 +/- 43%). Vp was associated with decreased expiratory flows, and EVLW was associated with decreased lung volumes. CONCLUSIONS: Congestion in stable patients with HF includes expanded Vp and Vh and increased EVLW associated with reductions in lung volumes and expiratory flows. PMID- 28716690 TI - Does player time-in-game affect tackle technique in elite level rugby union? AB - OBJECTIVES: It has been hypothesised that fatigue may be a major factor in tackle related injury risk in rugby union and hence more injuries occur in the later stages of a game. The aim of this study is to identify changes in ball carrier or tackler proficiency characteristics, using elite level match video data, as player time-in-game increases. DESIGN: Qualitative observational cohort study. METHODS: Three 2014/15 European Rugby Champions Cup games were selected for ball carrier and tackler proficiency analysis. Analysis was only conducted on players who started and remained on the field for the entire game. A separate analysis was conducted on 10 randomly selected 2014/15 European Rugby Champions Cup/Pro 12 games to assess the time distribution of tackles throughout a game. A Chi-square test and one-way way ANOVA with post-hoc testing was conducted to identify significant differences (p<0.05) for proficiency characteristics and tackle counts between quarters in the game, respectively. RESULTS: Player time-in-game did not affect tackle proficiency for both the ball carrier and tackler. Any results that showed statistical significance did not indicate a trend of deterioration in proficiency with increased player time-in-game. The time distribution of tackles analysis indicated that more tackles occurring in the final quarter of the game than the first (p=0.04) and second (p=<0.01). CONCLUSIONS: It appears that player time-in-game does not affect tackler or ball carrier tackle technique proficiency at the elite level. More tackles occurring in the final quarter of a game provides an alternative explanation to more tackle related injuries occurring at this stage. PMID- 28716689 TI - BRG1 and SMARCAL1 transcriptionally co-regulate DROSHA, DGCR8 and DICER in response to doxorubicin-induced DNA damage. AB - Recent investigations have emphasized the role of miRNA biogenesis proteins in the synthesis of non-coding RNA when double-strand DNA breaks are induced by ionizing radiations. However, the role of these non-coding RNA and their regulation in response to doxorubicin-induced DNA damage is not known. In this paper, BRG1 and SMARCAL1, members of the ATP-dependent chromatin remodelling family, are shown to co-regulate the transcription of DROSHA, DGCR8, and DICER in response to double-strand DNA breaks induced by doxorubicin. Both BRG1 and SMARCAL1 are needed for the upregulation of the three miRNA biogenesis genes as absence of BRG1 results in downregulation of DGCR8 and DICER while absence of SMARCAL1 results in downregulation of DROSHA. These two proteins act in coordination to upregulate expression of DROSHA, DGCR8, and DICER when cells are treated with doxorubicin. This transcriptional regulation of the miRNA biogenesis proteins is needed for the formation of 53BP1 foci as downregulation of either BRG1 or SMARCAL1 reduced the number of 53BP1 foci in DNA damaged cells. The foci formation was restored when the downregulated cells were treated with ncRNA purified from doxorubicin treated HeLa cells. From the results obtained, we conclude that the regulation of miRNA biogenesis proteins by SMARCAL1 and BRG1 is needed for the formation of non-coding RNA and thus, 53BP1 foci in response to doxorubicin-induced DNA damage. PMID- 28716692 TI - The fatigue of a full body resistance exercise session in trained men. AB - OBJECTIVES: We examined the fatigue and recovery for 48h following a full-body resistance exercise session in trained men. DESIGN: Experimental cross-sectional study. METHODS: Eight resistance trained men volunteered to participate (mean+/ SD; age 27.0+/-6.0 years, height 1.79+/-0.05m, weight 81.8+/-6.8kg, training experience 7.8+/-5.0 years). Fatigue and pain was measured before, after, 1h post, 24h and 48h post the full-body resistance exercise session, which was based on in-season models used in contact team sports (e.g. AFL, NRL). Other measures included maximal torque and rate of torque development, central motor output (quadriceps muscle activation, voluntary activation, H-reflexes), and muscle contractility (evoked twitch responses). Linear mixed-model ANOVA procedures were used for data analysis. RESULTS: Fatigue, soreness, and muscle pain did not return to pre-exercise levels until after 48h rest. Quadriceps maximal torque and muscle contractility were reduced from pre-exercise (p<0.01), and did not return to pre-exercise levels until 24h. Early rates of torque development and muscle activation were unchanged. The amplitude and slope of the normalized quadriceps H reflex was higher immediately after exercise (p<0.05). CONCLUSIONS: Full-body resistance exercise including multiple lower limb movements immediately reduced maximal torque, muscle contractility, and increased pain. While recovery of voluntary and evoked torque was complete within a day, 48h rest was required for fatigue and pain to return to baseline. Maximal voluntary effort may be compromised for lower-limb training (i.e. sprinting, jumping) prescribed in the 48h after the session. PMID- 28716691 TI - Acute injuries in Finnish junior floorball league players. AB - OBJECTIVES: To investigate the incidence and characteristics of acute time-loss injuries in Finnish junior floorball league players. DESIGN: Prospective cohort study with 3-year follow-up. METHODS: One hundred and eighty-six female and male players (mean age 16.6+/-1.4) took part in the follow-up study (2011-2014). The training hours and games were recorded on a team diary. Floorball related acute injuries were registered and verified by a research physician. The injury incidence was expressed as the number of injuries per 1000h of exposure. Incidence rate was calculated separately for games and practices, and for males and females. RESULTS: One hundred and forty-four acute time-loss injuries occurred. Injury incidence was 26.87 (95% CI 20.10-33.63) in junior league games, and 1.25 (95% CI 0.99-1.52) in team practices. Female players had significantly higher game injury rate (IRR 1.88, 1.12-3.19) and joint/ligament injury rate (IRR 1.70, 1.07-2.73) compared to males. Eighty-one percent of the injuries affected the lower limbs. The ankle (37%), knee (18%), and thigh (14%) were the most commonly injured body sites. More than half of injuries involved joint or ligaments (54%). Twenty-six percent of the injuries were severe causing more than 28days absence from sports. Eight anterior cruciate ligament ruptures of the knee occurred among seven female players. CONCLUSION: The study revealed that risk of ankle and knee ligament injuries is high in adolescent floorball, specifically among female players. PMID- 28716693 TI - The effects of reflexology on constipation and motor functions in children with cerebral palsy. AB - BACKGROUND: There is no evidence regarding the effects of reflexology on constipation and motor functions in children with cerebral palsy. This study was planned to investigate the effects of reflexology combined with neurodevelopmental therapy on constipation and motor functions in children with cerebral palsy. METHODS: Forty children between the ages of 3 and 15 years with cerebral palsy within levels 3/4/5 according to the Gross Motor Function Classification System (GMFCS) were included in the study. The participants were divided into two groups. While children in Group 1 received neurodevelopmental therapy, children in Group 2 also received reflexology. The therapy continued for two sessions per week for 8 weeks. Each session of neurodevelopmental therapy lasted for 45-60 min and reflexology took around 20 min. Motor performance of the children was evaluated with the Gross Motor Function Measure (GMFM) while constipation was assessed with the Modified Constipation Assessment Scale (MCAS). RESULTS: Both groups showed significant improvements in the GMFM scores after therapy (<0.001). In the group where neurodevelopmental therapy was applied together with reflexology, there was a decrease in MCAS scores (<0.001). CONCLUSION: NGT improved motor performance in both groups and adding reflexology to therapy had a positive effect on constipation. We suggest applying reflexology to children with cerebral palsy who experience constipation problems. PMID- 28716694 TI - "Isolated long thoracic nerve palsy": More than meets the eye. AB - INTRODUCTION: Two main hypotheses have been proposed for the pathophysiology of long thoracic nerve (LTN) palsy: nerve compression and nerve inflammation. We hypothesized that critical reinterpretation of electrodiagnostic (EDX) studies and MRIs of patients with a diagnosis of non-traumatic isolated LTN palsy could provide insight into the pathophysiology and, potentially, the treatment. MATERIAL AND METHODS: A retrospective review was performed of all patients with a diagnosis of non-traumatic isolated LTN palsy and an EDX and brachial plexus or shoulder MRI studies performed at our institution. The original EDX studies and MR examinations were reinterpreted by a neuromuscular neurologist and musculoskeletal radiologist, respectively, both blinded to our hypothesis. RESULTS: Seven patients met the inclusion criteria as having a non-traumatic isolated LTN palsy. Upon reinterpretation, all of them were found to have findings not consistent with an isolated LTN. On physical examination, three of them (43%) presented with weakness in muscles not innervated by the LTN. Four of them (57%) had additional EDX abnormalities beyond the distribution of the LTN. Five of them (71%) had MRI evidence of enlargement of nerves or denervation atrophy of muscles outside the innervation of the LNT, without evidence of compression of the LTN in the middle scalene muscle. CONCLUSION: In our series, all 7 patients, originally diagnosed as having an isolated LTN, on reinterpretation, were found to have a more diffuse muscle/nerve involvement pattern, without MR findings to suggest nerve compression. These data strongly support an inflammatory pathophysiology. PMID- 28716695 TI - The "nugget design": A modified segmental gracilis free flap for small-sized defect reconstruction on the lower extremity. AB - BACKGROUND: Little attention has been given to the segmental free gracilis muscle flap supplied by secondary proximal pedicles. We introduce a technical refinement for small-sized three-dimensional defect reconstruction on the foot. METHODS: Between November 2013 and August 2016, three patients with a mean age of 66 years (range 47-70 years) were included. A segmental gracilis free flap supplied by the most proximal secondary pedicle was harvested according to a modified "nugget design" to treat small-sized defects on the lower extremity requiring dead space reconstruction. Minor and major complications, sensitivity with Semmes-Weinstein monofilament test, soft tissue stability and patient satisfaction at final follow up were recorded. RESULTS: In one case, a segmental gracilis muscle was used for dorsal foot reconstruction after debridement of metatarsal phalanx I with osteomyelitis. In two cases, the segmental gracilis free muscle was harvested for defect reconstruction on the right plantar foot after excision of a melanoma. The first patient required revision after partial failure of the initial segmental gracilis free muscle flap. Overall, good results in foot function and a high degree of patient satisfaction was achieved (Likert scale 9.7, range 9-10) after a mean follow-up of 13 months (range 3-24 months). CONCLUSIONS: Taken from the very proximal dorsal part of the gracilis muscle supplied by the most proximal secondary pedicle and leaving the vast majority of the muscle intact preserves the option to harvest a normal gracilis flap. This technique is especially suitable for small, three-dimensional defects on the lower extremity. PMID- 28716696 TI - Unusual presentation of primary cutaneous follicle centre B-cell Lymphoma (PC FCL) of the nose. PMID- 28716697 TI - Copy number variations of the IL-22 gene are associated with ankylosing spondylitis: A case-control study in Chinese Han population. AB - IL-22 provides a new insight into the mechanisms of autoimmunity, and copy number variations (CNVs) are associated with autoimmune diseases. This study aims to explore the association of IL-22 gene CNVs with ankylosing spondylitis (AS) susceptibility. The copy numbers of IL-22 gene (2 fragments: IL-22_1, IL-22_2) were examined by AccuCopyTM methods in a cohort of 649 AS patients and 628 controls. Association of IL-22 CNVs and AS susceptibility was analyzed, and AS risk was estimated by Odds Ratio (ORs) and 95% confidence intervals (CIs), and the Benjamini-Hochberg method was applied to regulate the false discovery rate (FDR). We found one copy of IL-22 gene was significantly associated with AS [OR=0.345, 95%CI (0.144, 0.827), P=0.013, PFDR=0.026] in the IL-22_2 fragment, and this association still exist after adjustment of age and sex [OR=0.344, 95%CI (0.143, 0.825), P=0.017, PFDR=0.034]. In the stratification analysis by gender, the statistical difference was detected in males in the IL-22_2 fragment [OR=0.306, 95%CI (0.121, 0.778), P=0.009, PFDR=0.018; adjusted OR=0.306, 95%CI (0.120, 0.777), P=0.013, PFDR=0.026]. We suggest that IL-22 CNVs are associated with AS and that lower copy number might be a protective factor for AS, especially in male patients. PMID- 28716699 TI - Bridge to success: A better method of cryoablation for atrioventricular nodal reentrant tachycardia in children. AB - BACKGROUND: Cryoablation for atrioventricular nodal reentrant tachycardia (AVNRT) is associated with higher recurrence rates than radiofrequency ablation (RFA). Junctional tachycardia marks procedural success with RFA, but no such indicator exists for cryoablation. OBJECTIVE: The purpose of this study as to determine the impact of voltage mapping plus longer ablation lesions on midterm success of cryoablation for children with AVNRT. METHODS: We performed a single-center retrospective analysis of pediatric patients with AVNRT who underwent cryoablation from 2011 to 2015. Patients ablated using a standard electroanatomic approach (control) were compared with patients ablated using voltage mapping (voltage group). In the voltage group, EnSite NavX navigation and visualization technology (St Jude Medical, St Paul, MN) was used to develop a "bridge" of lower voltage gradients (0.3-0.8 mV) of the posteroseptal right atrium to guide cryoablation. Kaplan-Meier analysis was used to determine freedom from recurrence of supraventricular tachycardia. RESULTS: In all, 122 patients were included (71 voltage, 51 control). There was no difference between groups regarding age, sex, or catheter-tip size. Short-term success was similar in both groups (98.5% voltage vs 92% control; P = .159), but recurrence rates were lower in the voltage group (0% vs 11%, P = .006). Follow-up time was shorter in the voltage group (15 +/- 7 months vs 22 +/- 17 months, P < .05). The 1-year freedom from recurrence was lower in the voltage group (100% vs 91.5%, P <.05). Ablation times were longer in the voltage group (43.7 +/- 20.9 minutes vs 34.3 +/- 20.5 minutes, P = .01), but overall procedure times were shorter in the voltage group (157 +/- 40 minutes vs 198 +/- 133 minutes; P = .018). No significant complication was seen in either group. CONCLUSION: Voltage gradient mapping and longer lesion time can decrease recurrence rates in pediatric patients with AVNRT. PMID- 28716698 TI - Cytokine balance and behavioral intervention; findings from the Peer Approaches to Lupus Self-Management (PALS) project. AB - The Peer Approaches to Lupus Self-Management program sought to address the disparate impact of systemic lupus erythematosus (SLE) on African American women through a peer mentoring intervention with aims of reducing stress, anxiety, and depression. Given the association between psychological health and immune function this study examines the relationship between patient reported outcomes (PROs) in these domains and immunologic indicators of disease activity. Twenty three African American women with SLE served as mentees in the intervention from whom PRO measures were collected at the outset, midpoint, and end of the 12week pilot study. Blood samples were collected pre- and post-intervention. Plasma was collected from the samples and cryopreserved for subsequent analyses. The strongest correlations were between the Generalized Anxiety Disorder measure and Th1/Th2 cytokine balance. Weaker correlations existed between depression and the Th1/Th2 cytokine balance. Assessment of fresh versus cryopreserved samples revealed that changes in Th1/Th2 cytokine balance within the intervention were generally equivalent, regardless of sample type. The PALS intervention resulted in significant improvements to anxiety and depression levels which were significantly associated with positive changes in Th1/Th2 cytokine balance indicating a possible underlying mechanism of action. The nature of this relationship warrants further study. PMID- 28716700 TI - Role of entrainment in the era of high-density activation mapping for characterizing the reentrant circuit. PMID- 28716701 TI - Reply to the Editor- Esophageal thermal probes and esophageal lesions during cryoablation. PMID- 28716702 TI - How to perform transconduit and transbaffle puncture in patients who have previously undergone the Fontan or Mustard operation. PMID- 28716703 TI - Bridge to surgery: Best practice protocol derived from early clinical experience with the Bridge Occlusion Balloon. Federated Agreement from the Eleventh Annual Lead Management Symposium. PMID- 28716704 TI - [Psychosocial working conditions of physician assistants: results from a qualitative study on occupational stress, resources, possible approaches to prevention and intervention needs]. AB - BACKGROUND: Numerous studies have documented adverse psychosocial working conditions among health care staff. Working conditions may not only impair the health outcomes of this professional group, but can also affect the quality of care they deliver to patients. Previous work stress research has mainly focused on physicians and nurses. Comparable evidence remains limited, however, for physician assistants (Medizinische Fachangestellte, MFAs), who represent the largest professional group in German primary care. This study aimed to gain insights into work stressors and resources experienced by MFAs and to explore both possible approaches to prevention and intervention needs. METHODS: Participants were recruited from a criterion-based sample of medical practices in and around the city of Dusseldorf (Germany) and with assistance provided by the Medical Staff Association (VMF e. V.). In total, 26 qualitative in-depth interviews were conducted (11/2015-02/2016), transcribed and content analyzed using MaxQDA. RESULTS: MFAs reported a high workload and unforeseeable incidents as salient occupational stressors. Additional stressors included interpersonal relationship problems with superiors and a lack of social support from colleagues. At the same time though, support from superiors and colleagues can provide a key resource for coping with work stressors. Furthermore, social interactions with patients and diversified tasks were perceived as supportive professional resources. Possible approaches to prevention were exclusively seen to operate at the organizational level. The perceived need for intervention primarily concerned adequate wages and appreciation from superiors and society. CONCLUSIONS: Physician assistants described their working conditions as being characterized by high demands, low job control and low rewards. We suggest basic approaches for employers to improve the working experience of MFAs, which may represent the starting point for further research efforts to develop preventive measures. PMID- 28716706 TI - Characterization of a presymptomatic stage in a Drosophila Parkinson's disease model: Unveiling dopaminergic compensatory mechanisms. AB - Parkinson's disease (PD) is a degenerative disorder characterized by several motor symptoms including shaking, rigidity, slow movement and difficult walking, which has been associated to the death of nigro-striatal dopaminergic neurons. >90% of PD patients also present olfactory dysfunction. Although the molecular mechanisms responsible for this disease are not clear, hereditary PD is linked to mutations in specific genes, including the PTEN-induced putative kinase 1 (PINK1). In this work we provide for the first time a thorough temporal description of the behavioral effects induced by a mutation in the PINK1 gene in adult Drosophila, a previously described animal model for PD. Our data suggests that the motor deficits associated to PD are fully revealed only by the third week of age. However, olfactory dysfunction is detected as early as the first week of age. We also provide immunofluorescence and neurochemical data that let us propose for the first time the idea that compensatory changes occur in this Drosophila model for PD. These compensatory changes are associated to specific components of the dopaminergic system: the biosynthetic enzymes, Tyrosine hydroxylase and Dopa decarboxylase, and the Dopamine transporter, a plasma membrane protein involved in maintaining dopamine extracellular levels at physiologically relevant levels. Thus, our behavioral, immunofluorescence and neurochemical data help define for the first time presymptomatic and symptomatic phases in this PD animal model, and that compensatory changes occur in the dopaminergic neurons in the presymptomatic stage. PMID- 28716707 TI - Non-oxidizable HMGB1 induces cardiac fibroblasts migration via CXCR4 in a CXCL12 independent manner and worsens tissue remodeling after myocardial infarction. AB - Myocardial infarction (MI) is a major health burden worldwide. Extracellular High mobility group box 1 (HMGB1) regulates tissue healing after injuries. The reduced form of HMGB1 (fr-HMGB1) exerts chemotactic activity by binding CXCL12 through CXCR4, while the disulfide form, (ds-HMGB1), induces cytokines expression by TLR4. Here, we assessed the role of HMGB1 redox forms and the non-oxidizable mutant (3S) on human cardiac fibroblast (hcFbs) functions and cardiac remodeling after infarction. Among HMGB1 receptors, hcFbs express CXCR4. Fr-HMGB1 and 3S, but not ds-HMGB1, promote hcFbs migration through Src activation, while none of HMGB1 redox forms induces proliferation or inflammatory mediators. 3S is more effective than fr-HMGB1 in stimulating hcFbs migration and Src phosphorylation being active at lower concentrations and in oxidizing conditions. Notably, chemotaxis toward both proteins is CXCR4-dependent but, in contrast to fr-HMGB1, 3S does not require CXCL12 since hcFbs migration persists in the presence of the CXCL12/CXCR4 inhibitor AMD3100 or an anti-CXCL12 antibody. Interestingly, 3S interacts with CXCR4 and induces a different receptor conformation than CXCL12. Mice undergoing MI and receiving 3S exhibit adverse LV remodeling owing to an excessive collagen deposition promoted by a higher number of myofibroblasts. On the contrary, fr-HMGB1 ameliorates cardiac performance enhancing neoangiogenesis and reducing the infarcted area and fibrosis. Altogether, our results demonstrate that non-oxidizable HMGB1 induce a sustained cardiac fibroblasts migration despite the redox state of the environment and by altering CXCL12/CXCR4 axis. This affects proper cardiac remodeling after an infarction. PMID- 28716705 TI - Pathobiology of biliary epithelia. AB - Cholangiocytes are epithelial cells that line the intra- and extrahepatic biliary tree. They serve predominantly to mediate the content of luminal biliary fluid, which is controlled via numerous signaling pathways influenced by endogenous (e.g., bile acids, nucleotides, hormones, neurotransmitters) and exogenous (e.g., microbes/microbial products, drugs etc.) molecules. When injured, cholangiocytes undergo apoptosis/lysis, repair and proliferation. They also become senescent, a form of cell cycle arrest, which may prevent propagation of injury and/or malignant transformation. Senescent cholangiocytes can undergo further transformation to a senescence-associated secretory phenotype (SASP), where they begin secreting pro-inflammatory and pro-fibrotic signals that may contribute to disease initiation and progression. These and other concepts related to cholangiocyte pathobiology will be reviewed herein. This article is part of a Special Issue entitled: Cholangiocytes in Health and Disease edited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen. PMID- 28716708 TI - Functional characteristics of a novel SMAD4 mutation from thoracic aortic aneurysms (TAA). AB - SMAD4 is as an essential mediator of the transforming growth factor beta (TGF beta) signaling pathway, and dysregulated TGF-beta signaling is linked with thoracic aortic aneurysms (TAAs). In this study, we functionally characterized the Smad4 S271N mutation (the mutation c. 812G>A in Smad4 results in the amino acid substitution Ser271Asn) that was isolated from TAA individuals. We first constructed wild-type human Smad4 and Smad4 S271N plasmids. These constructs were then transiently transfected into HEK293T cells, and subsequent real-time PCR and western blotting demonstrated that wild-type Smad4 and Smad4 S271N were successfully expressed in 293T cells. We found that HEK293T cells overexpressing Smad4 S271N showed a strong increase in both cytoplasmic and nuclear Smad4 protein levels in response to TGF-beta1. Although TGF-beta signaling was the same in wild-type Smad4- and Smad4 S271N-transfected cells following TGF-beta1 exposure, interestingly, we observed that transient Smad4 S271N expression in HEK293T cells caused a significant basal activation of TGF-beta signaling. These results indicated that Smad4 may not directly induce TAA; rather it may contribute to TAA in combination with other risk factors. PMID- 28716709 TI - Isolation and characterization of the 5'-flanking region of the human PDXK gene. AB - Pyridoxal kinase is a key enzyme for the biosynthesis of pyridoxal 5'-phosphate. Pyridoxal 5'-phosphate is the catalytically active form of vitamin B6, and acts as a cofactor in >140 different enzyme reactions. It is still unknown how the kinase synthesis is regulated in the cells, and nothing has been reported about the gene promoter. In the present study, based on the bioinformatics analysis of the 5'-flanking region of the human PDXK gene, we cloned the promoter region by PCR. Through the construction of a series of luciferase expression vectors containing the human PDXK promoter region, we characterized the promoter in terms of its structure and function. The transcription start site is at 198bp upstream of the ATG translation initiation site. An important regulatory region is located at -665/-433bp upstream of the transcription start site. The promoter lacks the canonical TATA box, but contains three GC-boxes and one E-box. A deletion and mutation experiment revealed that the transcription factor Sp1 binding site C ( 553/-543) is critical in maintaining the robust promoter activity. Knockdown of Sp1 by RNA interference and chromatin immunoprecipitation analysis further proved that the Sp1 is involved in the regulation of the PDXK gene expression. PMID- 28716710 TI - microRNA-143 acts as a suppressor of hemangioma growth by targeting Bcl-2. AB - Infantile hemangioma is the most common vascular tumor affecting infants, which is associated with clonal expansion of endothelial cells. The aim of this study is to determine the role of microRNA (miR)-143 in the growth and survival of hemangioma-derived endothelial cells (HemECs). We examined the expression of miR 143 in patients with proliferating-phase (n=10) and involuting-phase (n=8) hemangiomas. The effects of ectopic expression of miR-143 on the viability, proliferation, cell cycle distribution, and apoptosis of HemECs were explored. We also identified the target gene(s) that was involved in the activity of miR-143. It was found that proliferating hemangiomas had significantly (P<0.05) lower levels of miR-143 than involuting counterparts. Reexpression of miR-143 significantly reduced the viability and proliferation of HemECs, while knockdown of miR-143 led to an increase in the proliferation of HemECs. Moreover, overexpression of miR-143 arrested HemECs at the G0/G1 phase and promoted caspase 3-dependent apoptosis. At the molecular level, miR-143 overexpression significantly promoted the expression of p21 and p53 and reduced the expression of cyclin D1, CDK2, CDK4, and Bcl-2. Silencing of Bcl-2 phenocopied the effect of miR-143 overexpression on the proliferation and apoptosis of HemECs. Furthermore, co-expression of Bcl-2 reversed the growth-suppressive effect of miR-143 on HemECs. Taken together, miR-143 acts as a suppressor in the growth of HemECs, at least partially, through downregulation of Bcl-2. Reexpression of miR-143 may represent a potential therapeutic strategy for the treatment of proliferating hemangiomas. PMID- 28716711 TI - Epigenetic silencing of miRNA-143 regulates apoptosis by targeting BCL2 in human intervertebral disc degeneration. AB - Accumulating evidence indicates that microRNAs can regulate the apoptosis of various cells. Apoptosis of nucleus pulposus cells plays an important role in the progression of intervertebral disc degeneration. The aim of this study is to investigate whether microRNA-143 (miRNA-143) is involved in the progression of intervertebral disc degeneration. In this study, the expression of miRNA-143 and its biological modulatory effects were examined. Messenger RNA and protein expression of miRNA-143 and B-cell lymphoma-2 (BCL2) in both normal and degenerative disc tissues was determined by using RT-PCR and western-blot assays. After miRNA-143 transfection, BCL2 expression and NP cell apoptosis were assessed by using RT-PCR, western-blot, and flow cytometry. The relationship between miRNA 143 and BCL2 was assessed by bioinformatics and dual luciferase assays. Epigenetic regulation of miRNA-143 was determined by methylation-specific PCR and the effect of hypomethylation using 5-AZA. In this study, miRNA-143 expression significantly increased, while that of BCL2 decreased in degenerative disc specimens. In addition, CpG islands in the promoter region of miRNA-143 were hypomethylated in degenerative disc tissues. Furthermore, bioinformatics analysis and luciferase reporter assay indicated that BCL2 was a target gene of miRNA-143, and miRNA-143 suppressed BCL2 messenger RNA (mRNA) and protein expression. MiRNAmiRNA-143 overexpression enhances apoptosis of nucleus pulposus cells, while miRNA-143 inhibitor had the opposite effect. BCL2 knockdown reversed the effects of the miRNA-143 inhibitor on nucleus pulposus apoptosis. Our results suggest that miRNA-143 promotes the progression of nucleus pulposus apoptosis by directly targeting BCL2, providing a potential therapeutic target for the treatment of intervertebral disc degeneration disease. PMID- 28716712 TI - Effects of chemogenetic excitation or inhibition of the ventrolateral periaqueductal gray on the acquisition and extinction of Pavlovian fear conditioning. AB - The midbrain periaqueductal gray (PAG) has been implicated in the generation and transmission of a prediction error signal that instructs amygdala-based fear and extinction learning. However, the PAG also plays a key role in the expression of conditioned fear responses. The evidence for a role of the PAG in fear learning and extinction learning has been obtained almost exclusively using PAG-dependent fear responses. It is less clear whether the PAG regulates fear learning when other measures of learned fear are used. Here we combined a chemogenetic approach, permitting excitation or inhibition of neurons in the ventrolateral PAG (VLPAG), with conditioned suppression as the measure of learned fear to assess the role of VLPAG in the acquisition and extinction of fear learning. We show that chemogenetic excitation of VLPAG (with some encroachment on lateral PAG [LPAG]) impairs acquisition of fear and, conversely, chemogenetic inhibition impairs extinction of fear. These effects on fear and extinction learning were specific to the combination of DREADD expression and injection of CNO because they were observed relative to both eYFP controls injected with CNO as well as DREADD expressing controls injected with vehicle. Taken together, these results show that activity of L/VLPAG neurons regulates both the acquisition and extinction of Pavlovian fear learning. PMID- 28716714 TI - Functional density and edge maps: Characterizing functional architecture in individuals and improving cross-subject registration. AB - Population-level inferences and individual-level analyses are two important aspects in functional magnetic resonance imaging (fMRI) studies. Extracting reliable and informative features from fMRI data that capture biologically meaningful inter-subject variation is critical for aligning and comparing functional networks across subjects, and connecting the properties of functional brain organization with variations in behavior, cognition and genetics. In this study, we derive two new measures, which we term functional density map and edge map, and demonstrate their usefulness in characterizing the function of individual brains. Specifically, using data from the Human Connectome Project (HCP), we show that (1) both functional maps capture intrinsic properties of the functional connectivity pattern in individuals while exhibiting large variation across subjects; (2) functional maps derived from either resting-state or task evoked fMRI can be used to accurately identify subjects from a population; and (3) cross-subject alignment using these functional maps considerably reduces functional variation and improves functional correspondence across subjects over state-of-the-art multimodal registration algorithms. Our results suggest that the proposed functional density and edge maps are promising features in characterizing the functional architecture in individuals and provide an alternative way to explore the functional variation across subjects. PMID- 28716713 TI - N-myc regulates growth and fiber cell differentiation in lens development. AB - Myc proto-oncogenes regulate diverse cellular processes during development, but their roles during morphogenesis of specific tissues are not fully understood. We found that c-myc regulates cell proliferation in mouse lens development and previous genome-wide studies suggested functional roles for N-myc in developing lens. Here, we examined the role of N-myc in mouse lens development. Genetic inactivation of N-myc in the surface ectoderm or lens vesicle impaired eye and lens growth, while "late" inactivation in lens fibers had no effect. Unexpectedly, defective growth of N-myc-deficient lenses was not associated with alterations in lens progenitor cell proliferation or survival. Notably, N-myc deficient lens exhibited a delay in degradation of DNA in terminally differentiating lens fiber cells. RNA-sequencing analysis of N-myc-deficient lenses identified a cohort of down-regulated genes associated with fiber cell differentiation that included DNaseIIbeta. Further, an integrated analysis of differentially expressed genes in N-myc-deficient lens using normal lens expression patterns of iSyTE, N-myc-binding motif analysis and molecular interaction data from the String database led to the derivation of an N-myc-based gene regulatory network in the lens. Finally, analysis of N-myc and c-myc double deficient lens demonstrated that these Myc genes cooperate to drive lens growth prior to lens vesicle stage. Together, these findings provide evidence for exclusive and cooperative functions of Myc transcription factors in mouse lens development and identify novel mechanisms by which N-myc regulates cell differentiation during eye morphogenesis. PMID- 28716715 TI - Functional parcellation using time courses of instantaneous connectivity. AB - Functional neuroimaging studies have led to understanding the brain as a collection of spatially segregated functional networks. It is thought that each of these networks is in turn composed of a set of distinct sub-regions that together support each network's function. Considering the sub-regions to be an essential part of the brain's functional architecture, several strategies have been put forward that aim at identifying the functional sub-units of the brain by means of functional parcellations. Current parcellation strategies typically employ a bottom-up strategy, creating a parcellation by clustering smaller units. We propose a novel top-down parcellation strategy, using time courses of instantaneous connectivity to subdivide an initial region of interest into sub regions. We use split-half reproducibility to choose the optimal number of sub regions. We apply our Instantaneous Connectivity Parcellation (ICP) strategy on high-quality resting-state FMRI data, and demonstrate the ability to generate parcellations for thalamus, entorhinal cortex, motor cortex, and subcortex including brainstem and striatum. We evaluate the subdivisions against available cytoarchitecture maps to show that our parcellation strategy recovers biologically valid subdivisions that adhere to known cytoarchitectural features. PMID- 28716716 TI - Fiber tractography using machine learning. AB - We present a fiber tractography approach based on a random forest classification and voting process, guiding each step of the streamline progression by directly processing raw diffusion-weighted signal intensities. For comparison to the state of-the-art, i.e. tractography pipelines that rely on mathematical modeling, we performed a quantitative and qualitative evaluation with multiple phantom and in vivo experiments, including a comparison to the 96 submissions of the ISMRM tractography challenge 2015. The results demonstrate the vast potential of machine learning for fiber tractography. PMID- 28716718 TI - Multivariate pattern analysis of MEG and EEG: A comparison of representational structure in time and space. AB - Multivariate pattern analysis of magnetoencephalography (MEG) and electroencephalography (EEG) data can reveal the rapid neural dynamics underlying cognition. However, MEG and EEG have systematic differences in sampling neural activity. This poses the question to which degree such measurement differences consistently bias the results of multivariate analysis applied to MEG and EEG activation patterns. To investigate, we conducted a concurrent MEG/EEG study while participants viewed images of everyday objects. We applied multivariate classification analyses to MEG and EEG data, and compared the resulting time courses to each other, and to fMRI data for an independent evaluation in space. We found that both MEG and EEG revealed the millisecond spatio-temporal dynamics of visual processing with largely equivalent results. Beyond yielding convergent results, we found that MEG and EEG also captured partly unique aspects of visual representations. Those unique components emerged earlier in time for MEG than for EEG. Identifying the sources of those unique components with fMRI, we found the locus for both MEG and EEG in high-level visual cortex, and in addition for MEG in low-level visual cortex. Together, our results show that multivariate analyses of MEG and EEG data offer a convergent and complimentary view on neural processing, and motivate the wider adoption of these methods in both MEG and EEG research. PMID- 28716719 TI - Metacyclic VSG expression site promoters are recognized by the same general transcription factor that is required for RNA polymerase I transcription of bloodstream expression sites. AB - Infectious metacyclic Trypanosoma brucei cells develop in the salivary glands of tsetse flies. A critical aspect of the developmental program leading to acquisition of infectivity is the synthesis of a variant surface glycoprotein (VSG) coat. Metacyclic VSG genes are transcribed from a set of specialized VSG expression sites (ESs) that differ from bloodstream VSG ESs by being monocistronic, being significantly shorter, lacking long stretches of 70-bp repeats, and having distinct promoter sequences. Both metacyclic and bloodstream VSG ESs are transcribed by the multifunctional T. brucei RNA polymerase I (Pol I), however the factor that recognizes the divergent metacyclic VSG ES promoters and recruits Pol I during the development to infectious cells remains unknown. We used an in vitro assay to show that the promoters for both metacyclic and bloodstream VSG ESs are recognized by the same class I transcription factor A (CITFA). This general Pol I transcription initiation factor was previously shown to be essential for the transcription of bloodstream VSG genes, procyclin genes and rRNA genes, and was demonstrated to have distinct binding affinities for these three types of promoters. We now show that differences in the sequence of individual metacyclic VSG ESs promoters determine different affinities for CITFA. PMID- 28716717 TI - Big GABA: Edited MR spectroscopy at 24 research sites. AB - Magnetic resonance spectroscopy (MRS) is the only biomedical imaging method that can noninvasively detect endogenous signals from the neurotransmitter gamma aminobutyric acid (GABA) in the human brain. Its increasing popularity has been aided by improvements in scanner hardware and acquisition methodology, as well as by broader access to pulse sequences that can selectively detect GABA, in particular J-difference spectral editing sequences. Nevertheless, implementations of GABA-edited MRS remain diverse across research sites, making comparisons between studies challenging. This large-scale multi-vendor, multi-site study seeks to better understand the factors that impact measurement outcomes of GABA edited MRS. An international consortium of 24 research sites was formed. Data from 272 healthy adults were acquired on scanners from the three major MRI vendors and analyzed using the Gannet processing pipeline. MRS data were acquired in the medial parietal lobe with standard GABA+ and macromolecule- (MM-) suppressed GABA editing. The coefficient of variation across the entire cohort was 12% for GABA+ measurements and 28% for MM-suppressed GABA measurements. A multilevel analysis revealed that most of the variance (72%) in the GABA+ data was accounted for by differences between participants within-site, while site level differences accounted for comparatively more variance (20%) than vendor level differences (8%). For MM-suppressed GABA data, the variance was distributed equally between site- (50%) and participant-level (50%) differences. The findings show that GABA+ measurements exhibit strong agreement when implemented with a standard protocol. There is, however, increased variability for MM-suppressed GABA measurements that is attributed in part to differences in site-to-site data acquisition. This study's protocol establishes a framework for future methodological standardization of GABA-edited MRS, while the results provide valuable benchmarks for the MRS community. PMID- 28716720 TI - MET Signaling Mediates Intestinal Crypt-Villus Development, Regeneration, and Adenoma Formation and Is Promoted by Stem Cell CD44 Isoforms. AB - BACKGROUND & AIMS: Resistance of metastatic human colorectal cancer cells to drugs that block epidermal growth factor (EGF) receptor signaling could be caused by aberrant activity of other receptor tyrosine kinases, activating overlapping signaling pathways. One of these receptor tyrosine kinases could be MET, the receptor for hepatocyte growth factor (HGF). We investigated how MET signaling, and its interaction with CD44 (a putative MET coreceptor regulated by Wnt signaling and highly expressed by intestinal stem cells [ISCs] and adenomas) affects intestinal homeostasis, regeneration, and adenoma formation in mini-gut organoids and mice. METHODS: We established organoid cultures from ISCs stimulated with HGF or EGF and assessed intestinal differentiation by immunohistochemistry. Mice with total epithelial disruption of MET (AhCre/Metfl/fl/LacZ) or ISC-specific disruption of MET (Lgr5Creert2/Metfl/fl/LacZ) and control mice (AhCre/Met+/+/LacZ, Lgr5Creert2/Met+/+/LacZ) were exposed to 10 Gy total body irradiation; intestinal tissues were collected, and homeostasis and regeneration were assessed by immunohistochemistry. We investigated adenoma organoid expansion stimulated by HGF or EGF using adenomas derived from Lgr5Creert2/Metfl/fl/Apcfl/fl and Lgr5Creert2/Met+/+/Apcfl/fl mice. The same mice were evaluated for adenoma prevalence and size. We also quantified adenomas in AhCre/Metfl/fl/Apcfl/+ mice compared with AhCre/Met+/+/Apcfl/+ control mice. We studied expansion of organoids generated from crypts and adenomas, stimulated by HGF or EGF, that were derived from mice expressing different CD44 splice variants (Cd44+/+, Cd44-/-, Cd44s/s, or Cd44v4-10/v4-10 mice). RESULTS: Crypts incubated with EGF or HGF expanded into self-organizing mini-guts with similar levels of efficacy and contained all differentiated cell lineages. MET-deficient mice did not have defects in intestinal homeostasis. Total body irradiation reduced numbers of proliferating crypts in AhCre/Metfl/fl/LacZ mice. Lgr5Creert2/Metfl/fl/LacZ mice had impaired regeneration of MET-deficient ISCs. Adenoma organoids stimulated with EGF or HGF expanded to almost twice the size of nonstimulated organoids. MET deficient adenoma organoids did not respond to HGF stimulation, but did respond to EGF. ISC-specific disruption of Met (Lgr5Creert2/Metfl/fl/Apcfl/fl mice) caused a twofold increase in apoptosis in microadenomas, resulting in an approximately 50% reduction of microadenoma numbers and significantly reduced average adenoma size. Total epithelial disruption of Met (AhCre/Metfl/fl/Apcfl/+ mice) resulted in an approximate 50% reduction in (micro)adenoma numbers. Intestinal crypts from Cd44-/- mice did not expand to the same extent as crypts from Cd44+/+ mice on stimulation with HGF, but had the same response to EGF. The negative effect on HGF-mediated growth was overcome by expression of CD44v4-10, but not by CD44s. Similarly, HGF-mediated expansion of adenoma organoids required CD44v4-10. CONCLUSIONS: In studies of intestinal organoid cultures and mice with inducible deletion of MET, we found HGF receptor signaling to regulate intestinal homeostasis and regeneration, as well as adenoma formation. These activities of MET are promoted by the stem cell CD44 isoform CD44v4-10. Our findings provide rationale for targeting signaling via MET and CD44 during anti-EGF receptor therapy of patients with colorectal cancer or in patients resistant to EGF receptor inhibitors. PMID- 28716722 TI - Dynamics of Proliferative and Quiescent Stem Cells in Liver Homeostasis and Injury. AB - BACKGROUND & AIMS: Adult liver stem cells are usually maintained in a quiescent/slow-cycling state. However, a proliferative population, marked by leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5), was recently identified as an important liver stem cell population. We aimed to investigate the dynamics and functions of proliferative and quiescent stem cells in healthy and injured livers. METHODS: We studied LGR5-positive stem cells using diphtheria toxin receptor and green fluorescent protein (GFP) knock-in mice. In these mice, LGR5-positive cells specifically coexpress diphtheria toxin receptor and the GFP reporter. Lineage-tracing experiments were performed in mice in which LGR5 positive stem cells and their daughter cells expressed a yellow fluorescent protein/mTmG reporter. Slow-cycling stem cells were investigated using GFP-based, Tet-on controlled transgenic mice. We studied the dynamics of both stem cell populations during liver homeostasis and injury induced by carbon tetrachloride. Stem cells were isolated from mouse liver and organoid formation assays were performed. We analyzed hepatocyte and cholangiocyte lineage differentiation in cultured organoids. RESULTS: We did not detect LGR5-expressing stem cells in livers of mice at any stage of a lifespan, but only following liver injury induced by carbon tetrachloride. In the liver stem cell niche, where the proliferating LGR5+ cells are located, we identified a quiescent/slow-cycling cell population, called label-retaining cells (LRCs). These cells were present in the homeostatic liver, capable of retaining the GFP label over 1 year, and expressed a panel of progenitor/stem cell markers. Isolated single LRCs were capable of forming organoids that could be carried in culture, expanded for months, and differentiated into hepatocyte and cholangiocyte lineages in vitro, demonstrating their bona fide stem cell properties. More interestingly, LRCs responded to liver injury and gave rise to LGR5-expressing stem cells, as well as other potential progenitor/stem cell populations, including SOX9- and CD44 positive cells. CONCLUSIONS: Proliferative LGR5 cells are an intermediate stem cell population in the liver that emerge only during tissue injury. In contrast, LRCs are quiescent stem cells that are present in homeostatic liver, respond to tissue injury, and can give rise to LGR5 stem cells, as well as SOX9- and CD44 positive cells. PMID- 28716723 TI - Pharmacological characterization of the interaction between umeclidinium and vilanterol in human bronchi. AB - The long-acting beta2-agonist (LABA) / long-acting muscarinic antagonist (LAMA) fixed dose combination (FDC) therapy represents the cornerstone for the treatment of chronic obstructive pulmonary disease (COPD). Nevertheless, conflicting clinical findings still exist on the real benefit of the LABA/LAMA FDCs. Therefore, we investigated whether combining the LABA vilanterol with the LAMA umeclidinium may induce synergistic bronchorelaxant effect in isolated airways. The effect of umeclidinium and vilanterol, administered alone, in combination at the ratio of concentrations reproducing the doses delivered by Anoro(r) Ellipta(r) (55:22), or at isoeffective low concentrations, was investigated on the cholinergic contractile tone induced by the parasympathetic activation of human isolated airways. The interaction was analyzed by using the Bliss Independence and Unified Theory models. Umeclidinium and vilanterol induced a concentration-dependent relaxation of isolated bronchi, with umeclidinium significantly (P < 0.05) more potent than vilanterol (Emax at 10Hz: umeclidium 102.6 +/- 6.8%, vilanterol 75.1 +/- 13.8%; pEC50 at 10Hz: umeclidinium 8.6 +/- 0.4, vilanterol 6.9 +/- 0.6). When administered at 55:22 concentration-ratio, umeclidinium plus vilanterol completely relaxed the isolated airways (Emax at 10Hz: 99.6 +/- 8.0%; pEC50 at 10Hz: 8.2 +/- 0.4). No synergistic interaction was detected for umeclidinium/vilanterol combined at 55:22 ratio, whereas strong synergism was elicited when the drugs were administered at low isoeffective concentrations (+ 41.4 +/- 5.8% vs. monocomponents), leading to submaximal relaxant effect (81.4 +/- 5.8%). Umeclidinium and vilanterol are imbalanced when combined at 55:22 ratio, with umeclidinium over-dosed, or vice versa vilanterol under-dosed. Specific studies are needed to identify the dose ratio of umeclidinium/vilanterol combination to guarantee equipotency concentrations of each component into the lung, and induce synergistic bronchodilation. PMID- 28716721 TI - The Evolving Genomic Landscape of Barrett's Esophagus and Esophageal Adenocarcinoma. AB - We have recently gained unprecedented insight into genetic factors that determine risk for Barrett's esophagus (BE) and progression to esophageal adenocarcinoma (EA). Next-generation sequencing technologies have allowed us to identify somatic mutations that initiate BE and track genetic changes during development of tumors and invasive cancer. These technologies led to identification of mechanisms of tumorigenesis that challenge the current multistep model of progression to EA. Newer, cost-effective technologies create opportunities to rapidly translate the analysis of DNA into tools that can identify patients with BE at high risk for cancer, detect dysplastic lesions more reliably, and uncover mechanisms of carcinogenesis. PMID- 28716725 TI - WITHDRAWN: Cardamonin attenuates lung carcinoma and promotes autophagy via targeting p53 and regulating Mtor. PMID- 28716724 TI - The PPARalpha activator fenofibrate inhibits voltage-dependent K+ channels in rabbit coronary arterial smooth muscle cells. AB - We examined the effects of the PPARalpha activator fenofibrate on voltage dependent K+ (Kv) channels using a patch clamp technique in native rabbit coronary arterial smooth muscle cells. Kv current was inhibited by application of fenofibrate in a concentration-dependent manner, with an apparent IC50 value of 6.39 +/- 0.53MUM and a slope value (Hill coefficient) of 1.63 +/- 0.10. Fenofibrate accelerated the decay rate of Kv channel inactivation. The rate constants of association and dissociation for fenofibrate were 0.81+/- 0.05MUM-1s 1 and 4.70 +/- 0.47s-1, respectively. Although fenofibrate did not affect the steady-state activation curves, fenofibrate shifted the inactivation curves toward a more negative potential. Application of train pulses (1 or 2Hz) progressively increased the fenofibrate-induced inhibition of the Kv channel, and the recovery time constant from inactivation was increased in the presence of fenofibrate, which suggested that the inhibitory effect of fenofibrate is use dependent. Another PPARalpha activator, bezafibrate and PPARalpha inhibitor, GW 6471, did not affect the Kv current and also did not change the inhibitory effect of fenofibrate on the Kv current. From these results, we suggest that fenofibrate inhibited Kv current in a state-, time-, and use-dependent manner, completely independent of PPARalpha activation. PMID- 28716727 TI - Systematic review and meta-analysis links autism and toxic metals and highlights the impact of country development status: Higher blood and erythrocyte levels for mercury and lead, and higher hair antimony, cadmium, lead, and mercury. AB - BACKGROUND: Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder that affects cognitive and higher cognitive functions. Increasing prevalence of ASD and high rates of related comorbidities has caused serious health loss and placed an onerous burden on the supporting families, caregivers, and health care services. Heavy metals are among environmental factors that may contribute to ASD. However, due to inconsistencies across studies, it is still hard to explain the association between ASD and toxic metals. Therefore the objective of this study was to investigate the difference in heavy metal measures between patients with ASD and control subjects. METHODS: We included observational studies that measured levels of toxic metals (antimony, arsenic, cadmium, lead, manganese, mercury, nickel, silver, and thallium) in different specimens (whole blood, plasma, serum, red cells, hair and urine) for patients with ASD and for controls. The main electronic medical database (PubMed and Scopus) were searched from inception through October 2016. RESULTS: 52 studies were eligible to be included in the present systematic review, of which 48 studies were included in the meta-analyses. The hair concentrations of antimony (standardized mean difference (SMD)=0.24; 95% confidence interval (CI): 0.03 to 0.45) and lead (SMD=0.60; 95% confidence interval (CI): 0.17 to 1.03) in ASD patients were significantly higher than those of control subjects. ASD patients had higher erythrocyte levels of lead (SMD=1.55, CI: 0.2 to 2.89) and mercury (SMD=1.56, CI: 0.42 to 2.70). There were significantly higher blood lead levels in ASD patients (SMD=0.43, CI: 0.02 to 0.85). Sensitivity analyses showed that ASD patients in developed but not in developing countries have lower hair concentrations of cadmium (SMD=-0.29, CI: -0.46 to -0.12). Also, such analyses indicated that ASD patients in developing but not in developed lands have higher hair concentrations of lead (SMD=1.58, CI: 0.80 to 2.36) and mercury (SMD=0.77, CI: 0.31 to 1.23). These findings were confirmed by meta-regression analyses indicating that development status of countries significantly influences the overall effect size of mean difference for hair arsenic, cadmium, lead, and mercury between patients with ASD and controls. CONCLUSION: The findings help highlighting the role of toxic metals as environmental factors in the etiology of ASD, especially in developing lands. While there are environmental factors other than toxic metals that greatly contribute to the etiology of ASD in developed lands. It would be, thus, expected that classification of ASD includes etiological entities of ASD on the basis of implication of industrial pollutants (developed vs. developing ASD). PMID- 28716726 TI - Early-life risperidone enhances locomotor responses to amphetamine during adulthood. AB - Antipsychotic drug prescriptions for pediatric populations have increased over the past 20 years, particularly the use of atypical antipsychotic drugs such as risperidone. Most antipsychotic drugs target forebrain dopamine systems, and early-life antipsychotic drug exposure could conceivably reset forebrain neurotransmitter function in a permanent manner that persists into adulthood. This study determined whether chronic risperidone administration during development modified locomotor responses to the dopamine/norepinephrine agonist, D-amphetamine, in adult rats. Thirty-five male Long-Evans rats received an injection of one of four doses of risperidone (vehicle, .3, 1.0, 3.0mg/kg) each day from postnatal day 14 through 42. Locomotor activity was measured for 1h on postnatal days 46 and 47, and then for 24h once a week over the next two weeks. Beginning on postnatal day 75, rats received one of four doses of amphetamine (saline, .3, 1.0, 3.0mg/kg) once a week for four weeks. Locomotor activity was measured for 27h after amphetamine injection. Rats administered risperidone early in life demonstrated increased activity during the 1 and 24h test sessions conducted prior to postnatal day 75. Taking into account baseline group differences, these same rats exhibited significantly more locomotor activity in response to the moderate dose of amphetamine relative to controls. These results suggest that early-life treatment with atypical antipsychotic drugs, like risperidone, permanently alters forebrain catecholamine function and increases sensitivity to drugs that target such function. PMID- 28716728 TI - Cytochrome P450 3A selectively affects the pharmacokinetic interaction between erlotinib and docetaxel in rats. AB - Erlotinib as a first-line drug is used in non-small cell lung cancer (NSCLC) patients with sensitive EGFR mutations, while resistance to this drug will occur after several years of treatment. Therefore, the microtubule disturber docetaxel is introduced as combined regimen in clinical trials. This report investigated the potentials and mechanisms of drug-drug interaction (DDI) between erlotinib and docetaxel using wild type (WT) and Cyp3a1/2 knockout (KO) rats. The erlotinib O-demethylation and docetaxel hydroxylation reactions in the absence or the presence of another drug were analyzed in vitro via the assay of rat liver microsomes. In whole animal studies, erlotinib and docetaxel were given to WT and KO rats individually or jointly, and the pharmacokinetic profiles of these two drugs were analyzed and compared among different groups. The results showed that docetaxel not only inhibited the CYP3A-mediated biotransformation of erlotinib in vitro, but also significantly increased the maximum concentration and systemic exposure of erlotinib in vivo in WT rats. In contrast, the DDI was significantly attenuated in KO rats. On the other hand, erlotinib did not influence docetaxel either in vitro biotransformation or in vivo pharmacokinetic behaviors. These results exhibited the potentials of erlotinib-docetaxel interaction and indicated that the CYP3A played the perpetrating role of docetaxel on erlotinib in rats. A better understanding of this DDI with CYP3A may help the regulation of the use of these two drugs, avoid potential problems, and adjust dose carefully and early in clinic. PMID- 28716729 TI - Study of new interactions of glitazone's stereoisomers and the endogenous ligand 15d-PGJ2 on six different PPAR gamma proteins. AB - Diabetes mellitus is a chronic disease characterized by hyperglycemia, insulin resistance and hyperlipidemia. Glitazones or thiazolidinediones (TZD) are drugs that act as insulin-sensitizing agents whose molecular target is the peroxisome proliferator-activated receptor gamma (PPARgamma). The euglycemic action of TZD has been linked with the induction of type 4 glucose transporter. However, it has been shown that the effect of TZD depends on the specific stereoisomer that interacts with PPARgamma. Therefore, this work is focused on exploring the interactions and geometry adopted by glitazone's stereoisomers and one endogenous ligand on different conformations of the six crystals of the PPARgamma protein using molecular docking and molecular dynamics (MD) simulations accompanied by the MMGBSA approach. Specifically, the 2,4-thiazolidinedione ring, pioglitazone (PIO), rosiglitazone (ROSI) and troglitazone (TRO) stereoisomers (exogenous ligands), as well as the endogenous ligand 15d-PGJ2, were evaluated. The six crystallographic structures of PPARgamma are available at Protein Data Bank as the PDB entries 2PRG, 4PRG, 3T03, 1I7I, 1FM6, and 4EMA. According to the results, a boomerang shape and a particular location of ligands were found with low variations according to the protein conformations. The 15d-PGJ2, TZD, PIO, ROSI and (S,S)-TRO enantiomers were mostly stabilized by twenty hydrophobic residues: Phe226, Pro227, Leu228, Ile281, Phe282, Cys285, Ala292, Ile296, Ile326, Tyr327, Met329, Leu330, Leu333, Met334, Val339, Ile341, Met348, Leu353, Phe363 and Met364. Most hydrogen bond interactions were found between the polar groups of ligands with Arg288, Ser289, Lys367, Gln286, His323, Glu343 and His449 residues. An energetic analysis revealed binding free energy trends that supported known experimental findings of other authors describing better binding properties for PIO, ROSI and (S,S)-TRO than for 15d-PGJ2 and the TZD ring. PMID- 28716730 TI - Interaction of small G protein signaling modulator 3 with connexin 43 contributes to myocardial infarction in rat hearts. AB - Connexin 43 (Cx43), a ubiquitous connexin expressed in the heart and skin, is associated with a variety of hereditary conditions. Therefore, the characterization of Cx43-interacting proteins and their dynamics is important to understand not only the molecular mechanisms underlying pathological malfunction of gap junction-mediated intercellular communication but also to identify novel and unanticipated biological functions of Cx43. In the present study, we observed potential targets of Cx43 to determine new molecular functions in cardio protection. MALDI-TOF mass spectrometry analysis of Cx43 co-immunoprecipitated proteins showed that Cx43 interacts with several proteins related to metabolism. In GeneMANIA network analysis, SGSM3, which has not been previously associated with Cx43, was highly correlated with Cx43 in heart functions, and high levels of SGSM3 appeared to induce the turnover of Cx43 through lysosomal degradation in myocardial infarcted rat hearts. Moreover, we confirmed that lysosomal degradation of Cx43 is dependent upon the interaction between SGSM3 and Cx43 in H9c2 cardiomyocytes. The functional importance of the interaction between SGSM3 and Cx43 was confirmed by results showing that Cx43 expression was enhanced by SGSM3 siRNA knockdown in H9c2 cells. In summary, the results of this study elucidate the molecular mechanisms in which Cx43 with SGSM3 is degraded in myocardial infarcted rat hearts, which may contribute to the establishment of new therapeutic targets to modulate cardiac function in physiological and pathological conditions. PMID- 28716731 TI - ARID1A represses hepatocellular carcinoma cell proliferation and migration through lncRNA MVIH. AB - ARID1A, encoding the BAF250a subunit of SWI/SNF complex, has a high mutation frequency in numerous types of cancer. LncRNAs, a type of non-coding RNAs longer than 200 nucleotides, have been reported to interplay with SWI/SNF complex during cancer progression. However, whether the interaction between ARID1A and lncRNA affects hepatocellular carcinoma (HCC) still needs to be investigated. Here, we reveal that ARID1A interacts with lncRNA MVIH through some region(s) or domain(s) including ARID domain and C-terminal ARID1A protein binding domain. ARID1A upregulates its downstream target CDKN1A and suppresses HCC cell proliferation and migration through inhibiting MVIH. Our data suggests that deficiency or loss of functional mutations of ARID1A in HCC cells might contribute to the increased activity of certain cancer-promoting lncRNAs. PMID- 28716732 TI - Lysophosphatidic acid signaling regulates the KLF9-PPARgamma axis in human induced pluripotent stem cell-derived neurons. AB - Lysophosphatidic acid (LPA) is a lipid signaling molecule that plays several significant roles in the nervous system during development and injury. In this study, we differentiated human induced pluripotent stem cells (iPSCs) into neurons as an in vitro model to examine the specific effects of LPA. We demonstrated that LPA activates peroxisome proliferator-activated receptor gamma (PPARgamma), a ligand-activated nuclear receptor, as well as its cognate receptor LPA1 on human iPSC-derived neurons to enhance proliferation and neurite outgrowth. Furthermore, we found that the gene expression of Kruppel-like factor 9 (KLF9), a member of the large KLF transcription factor family, was induced by LPA treatment. Knockdown of KLF9 decreased proliferation and neurite outgrowth in vehicle- and LPA-treated IPSC-derived neurons compared to cells expressing KLF9. In conclusion, LPA plays dual roles as a ligand mediator through the activation of cell surface G-coupled protein receptors and as an intracellular second messenger through the activation of PPARgamma. We discuss the contribution of the LPA1-PPARgamma-KLF9 axis to neurite outgrowth and proliferation in human iPSC derived neurons. PMID- 28716734 TI - Crystal structure analysis of 3,6-anhydro-l-galactonate cycloisomerase suggests emergence of novel substrate specificity in the enolase superfamily. AB - 3,6-Anydro-l-galatonate cycloisomerase (ACI) catalyzes the cycloisomerization of a 3,6-anhydro-l-galactonic acid known as a novel metabolite in agarolytic bacteria. Here, we present 3-D structures of ACI from Vibrio sp. strain EJY3 (VejACI) in native and mutant forms at 2.2 A and 2.6 A resolutions, respectively. The enzyme belongs to the mandelate racemase subgroup of the enolase superfamily catalyzing common beta-elimination reactions by alpha-carbon deprotonation of substrates. The structure of VejACI revealed a notable 20s loop region in the capping domain, which can be a highly conserved structural motif in ACI homologs of agar metabolism. By comparing mutant (mVejAC/H300 N) and native VejACI structures, we identified a conformational change of Ile142 in VejACI that causes spatial expansion in the binding pocket. These observations imply that Ile142 and the 20s loop play important roles in enzymatic reactivity and substrate specificity. The structural phylogenetic analysis of the enolase superfamily including ACIs revealed sequential, structural, and functional relationships related to the emergence of novel substrate specificity. PMID- 28716733 TI - ML327 induces apoptosis and sensitizes Ewing sarcoma cells to TNF-related apoptosis-inducing ligand. AB - Ewing sarcomas are rare mesenchymal-derived bone and soft tissue tumors in children. Afflicted children with distant metastases have poor survival despite aggressive therapeutics. Epithelial-to-mesenchymal transition in epithelial carcinomas is associated with loss of E-cadherin and resistance to apoptosis. ML327 is a novel small molecule that we have previously shown to reverse epithelial-to-mesenchymal transition features in both epithelial and neural crest derived cancers. Herein, we sought to evaluate the effects of ML327 on mesenchymal-derived Ewing sarcoma cells, hypothesizing that ML327 initiates growth arrest and sensitizes to TNF-related apoptosis-inducing ligand. ML327 induced protein expression changes, increased E-cadherin and decreased vimentin, consistent with partial induction of mesenchymal-to-epithelial transition in multiple Ewing Sarcoma cell lines (SK-N-MC, TC71, and ES-5838). Induction of epithelial features was associated with apoptosis, as demonstrated by PARP and Caspase 3 cleavage by immunoblotting. Cell cycle analysis validated these findings by marked induction of the subG0 cell population. In vitro combination treatment with TRAIL demonstrated additive induction of apoptotic markers. Taken together, these findings establish a rationale for further in vivo trials of ML327 in cells of mesenchymal origin both alone and in combination with TRAIL. PMID- 28716736 TI - Reply. PMID- 28716735 TI - Pupillary measurements and anisocoria in Chinese preschoolers 3-4 years of age screened using the plusoptiX A12C. AB - PURPOSE: To evaluate the distribution of the pupil diameter and distance and the incidence of anisocoria in a screening setting for Chinese preschoolers 3-4 years of age. METHODS: This was a cross-sectional, population-based study conducted in children aged 3-4 years in Nanjing, China. Plusoptix photoscreening was conducted without cycloplegia. Additional assessments were conducted, including light reaction test, reevaluation for anisocoria (in dim and bright light), swinging flashlight test, and cocaine test, if necessary. RESULTS: A total of 1,818 children were screened. Pupillary measurements were conducted successfully in nearly all children (99.3% for the pupil diameter; 98.4% for the interpupillary distance). The pupil diameters of both eyes of each individual were highly correlated (5.9 +/- 0.7 mm in both eyes; P < 0.0001; r = 0.93). The mean interpupillary distance was 50.1 +/- 3.1 mm. The pupil diameters (6.0 mm in boys; 5.8 mm in girls) and interpupillary distance (50.6 mm in boys; 49.5 mm in girls) were correlated with sex (all P < 0.0001) but not age (P = 0.22; P = 0.68). General anisocoria of 0.5-0.9 mm in 7.8% of children and 1.0-1.2 mm in 0.4% of children was found. No child was diagnosed with pathological anisocoria, craniofacial trauma, or congenital malformation syndrome. CONCLUSIONS: The Plusoptix photoscreener is a useful tool for obtaining pupillary measurements and detecting anisocoria in a screening setting. For Chinese preschoolers 3-4 years of age the mean pupil diameter and distance were 5.9 and 50.1 mm, respectively, with sex-related difference; anisocoria of 0.5-0.9 mm is present in 7.8% of children. PMID- 28716737 TI - Reply. PMID- 28716738 TI - Photodynamic therapy and pain: A systematic review. AB - Photodynamic therapy (PDT) is an effective treatment for actinic keratoses and early skin cancers, and the only office procedure to control field cancerization. Procedure-associated pain limits widespread PDT use and by early termination of treatment can decrease overall therapeutic efficacy. Here we review and assess reported interventions on PDT-associated pain, in order to identify the most promising methods to manage treatment-associated pain and identify focus for future studies. Literature search was performed using MEDLINE, EMBASE, and the Cochrane Library by two independent reviewers to select publications that assessed and compared pain quantitatively during PDT treatment for actinic keratoses, basal cell carcinomas, and/or in situ squamous cell carcinomas. A total of 48 studies reporting on pain during PDT were identified and were comprised of two main categories of interventions: pain-controlling therapies and PDT parameter (photosensitizer or photo-irradiation) adjustments. Of these interventions: nerve block, subcutaneous infiltration anesthesia, cold analgesia, and transcutaneous electrical nerve stimulation, but not topical anesthetic gels, were associated with less PDT-related pain; 5-aminolevulinic acid (ALA) tended to be more painful than methyl-5-aminolevulinate (MAL); daylight PDT was less painful than conventional PDT; and lower irradiance delivery produced lower pain scores in general. There is no single crystalized protocol for management of PDT related pain. Evidence suggests that continuous activation of low levels of PpIX with methods using lower irradiance and possibly shorter incubation times are associated with decreased pain without loss of PDT efficacy. Protocols to reduce pain should be standardized and large controlled trials are needed. PMID- 28716739 TI - Phototoxicity in a laryngeal cancer cell line enhanced by a targeting amphiphilic chlorin photosensitizer. AB - BACKGROUND: Photodynamic therapy (PDT) has been established in several countries as an alternative therapy for the treatment of various malignancies. This therapy involves the incorporation of a photosensitizer (PS) that is activated by visible light and form reactive oxygen species leading to target cell death by apoptosis or necrosis. Previously, our group has demonstrated that CHL-T (semi-synthesized from chlorophyll a and containing a linked solubilizing group TRISMA(r)) presented a pronounced potential to induce death in HeLa cell line after PDT. In the present study, besides confirm the high cytotoxicity in another cell line, we have further investigated the cell death mechanisms caused by CHL-T as a photosensitizer in laryngeal carcinoma cells. METHODS: Cells were exposed to different concentrations of three photosensitizers, namely, hypericin (HY), unmodified chlorin (CHL) and a synthesized amphiphilic chlorin derivative (CHL T). PSs accumulation and localization were accessed by fluorescence assays. Photosensitization was induced at 6Jcm-2 using red LEDs (630+/-10nm). Viability was assessed by mitochondrial function (MTT); whereas apoptosis/necrosis was evaluated by fluorescence microscopy and flow cytometry. Expression of pro apoptotic p53 protein was studied by Western blot. RESULTS AND CONCLUSIONS: All PS showed similar localization profile in the HEp-2 cells. The use of CHL-T increased the percentage of apoptotic cells and also p53 expression in comparison with the use of HY and CHL as photosensitizers. This study shows a significant effect of CHLT associated with red light (630+/-10nm and 18mWcm-2) irradiation on a cancer cell line, indicating the potential of this amphiphilic chlorin in enhancing the therapeutic effectiveness of Photodynamic Therapy (PDT). PMID- 28716740 TI - Multilocus analysis of the catfish family Trichomycteridae (Teleostei: Ostariophysi: Siluriformes) supporting a monophyletic Trichomycterinae. AB - Trichomycteridae is the second most diverse family of the order Siluriformes, its members are widely distributed through the freshwaters of Central and South America, exhibiting an exceptional ecological and phenotypic disparity. The most diverse subfamily, Trichomycterinae, represented mainly by the genus Trichomycterus, historically has been recognized as non-monophyletic and various characters used to unite or divide its constituents are repeatedly called into question. No comprehensive molecular phylogenetic hypothesis regarding relationships of trichomycterids has been produced, and the present study is the first extensive phylogeny for the family Trichomycteridae, based on a multilocus dataset of three mitochondrial loci and two nuclear markers (3284bp total). Our analysis has the most comprehensive taxon-sampling of the Trichomycteridae published so far, including members of all subfamilies and a vast representation of Trichomycterus diversity. Analysis of these data showed a phylogenetic hypothesis with broad agreement between the Bayesian (BI) and maximum-likelihood (ML) trees. The results provided overwhelming support for the monophyletic status of Copionodontinae, Stegophilinae, Trichomycterinae, and Vandelliinae, but not Sarcoglanidinae and Glanapteryginae. A major feature of our results is the support to the current conceptualization of Trichomycterinae, which includes Ituglanis and Scleronema and excludes the "Trichomycterus" hasemani group. Divergence time analysis based on DNA substitution rates suggested a Lower Cretaceous origin of the family and the divergence events at subfamilial level shaped by Paleogene events in the geohistory of South America. This hypothesis lays a foundation for an array of future studies of evolution and biogeography of the family. PMID- 28716741 TI - Inferring the shallow phylogeny of true salamanders (Salamandra) by multiple phylogenomic approaches. AB - The rise of high-throughput sequencing techniques provides the unprecedented opportunity to analyse controversial phylogenetic relationships in great depth, but also introduces a risk of being misinterpreted by high node support values influenced by unevenly distributed missing data or unrealistic model assumptions. Here, we use three largely independent phylogenomic data sets to reconstruct the controversial phylogeny of true salamanders of the genus Salamandra, a group of amphibians providing an intriguing model to study the evolution of aposematism and viviparity. For all six species of the genus Salamandra, and two outgroup species from its sister genus Lyciasalamandra, we used RNA sequencing (RNAseq) and restriction site associated DNA sequencing (RADseq) to obtain data for: (1) 3070 nuclear protein-coding genes from RNAseq; (2) 7440 loci obtained by RADseq; and (3) full mitochondrial genomes. The RNAseq and RADseq data sets retrieved fully congruent topologies when each of them was analyzed in a concatenation approach, with high support for: (1) S. infraimmaculata being sister group to all other Salamandra species; (2) S. algira being sister to S. salamandra; (3) these two species being the sister group to a clade containing S. atra, S. corsica and S. lanzai; and (4) the alpine species S. atra and S. lanzai being sister taxa. The phylogeny inferred from the mitochondrial genome sequences differed from these results, most notably by strongly supporting a clade containing S. atra and S. corsica as sister taxa. A different placement of S. corsica was also retrieved when analysing the RNAseq and RADseq data under species tree approaches. Closer examination of gene trees derived from RNAseq revealed that only a low number of them supported each of the alternative placements of S. atra. Furthermore, gene jackknife support for the S. atra - S. lanzai node stabilized only with very large concatenated data sets. The phylogeny of true salamanders thus provides a compelling example of how classical node support metrics such as bootstrap and Bayesian posterior probability can provide high confidence values in a phylogenomic topology even if the phylogenetic signal for some nodes is spurious, highlighting the importance of complementary approaches such as gene jackknifing. Yet, the general congruence among the topologies recovered from the RNAseq and RADseq data sets increases our confidence in the results, and validates the use of phylotranscriptomic approaches for reconstructing shallow relationships among closely related taxa. We hypothesize that the evolution of Salamandra has been characterized by episodes of introgressive hybridization, which would explain the difficulties of fully reconstructing their evolutionary relationships. PMID- 28716742 TI - Never judge an iguana by its spines: Systematics of the Yucatan spiny tailed iguana, Ctenosaura defensor (Cope, 1866). AB - Spiny tailed iguanas are highly diverse clade of lizards in Mesoamerica, ranging from northern Mexico through Panama. Utilizing 2 regions of mitochondrial DNA (1948bp) and 4 nuclear loci (2232bp) we explored the relationships between these species and the phylogeographic history of the major clades. We discovered that the lineage endemic to the Yucatan Peninsula renders the genus Ctenosaura paraphyletic. To resolve this non-monophyly, we resurrect the taxon Cachryx Cope, 1866, and provide a new diagnosis for the genus. We also find that small body size and highly spinose tails in the species previously referred to the subgenus Enyaliosaurus, have evolved independently 3 times. Cachryx were recovered as sister to the lineage of iguanines endemic to the Galapagos Islands, and we discuss biogeographic scenarios to explain this relationship as well as those among the primary clades of Ctenosaura in Mesoamerica. PMID- 28716743 TI - Low level exposure to manganese from drinking water and cognition in school-age children. AB - BACKGROUND: Manganese (Mn) is an element found in the environment and certain geographic areas have elevated concentrations in soil and water du to natural conditions or anthropic activities. A growing body of data suggests that exposure to manganese in drinking water could be neurotoxic. OBJECTIVE: Firstly, we aimed to examine the association between exposure to manganese from drinking water and cognition in children consuming well water. Secondly, we also aimed to examine the relation between cognition and manganese concentrations in children's hair, nail, and saliva. METHODS: A total 259 children from 189 households consuming well water were included in the present study (ages 5.9 to 13.7 years). We assessed children's cognition with the WISC-IV, and we used five indicators of manganese exposure: concentration in tap water, intake from the consumption of water divided by child's weight, manganese concentration in children's hair, toe nail, and saliva. We used General Estimating Equation analysis to assess the relation between manganese exposure indicators and IQ scores, adjusting for potential confounders, and taking into account family clusters. RESULTS: Drinking water manganese concentrations were generally low, with 48% of children consuming water <5MUg/L, 25% >50MUg/L, and 4% >400MUg/L. Results differed by sex. In girls, higher manganese concentration in water, hair, and toe nail were associated with poorer Performance IQ scores but this was significant only for toe nail (for a 10 fold increase in manganese, beta: -5.65, 95% CIs: -10.97, -0.32). Opposite associations were observed in boys, i.e., better Performance IQ scores with higher manganese concentration hair, toe nail, and water, the latter being significant (beta: 2.66, 95% CIs: 0.44, 4.89). Verbal IQ scores did not seem to be associated with manganese exposure indicators. CONCLUSIONS: Drinking water manganese levels were considerably lower than in previous studies reporting neurotoxic effects. There was no clear indication of an association between exposure to manganese and cognitive development in this sample of school-age children although the data suggest there might be sex-specific associations. Given the low levels of exposure and sex-specific associations, a larger sample size would have been required to increase the statistical power and better characterize the relations. PMID- 28716745 TI - Gut-derived endotoxin stimulates factor VIII secretion from endothelial cells. Implications for hypercoagulability in cirrhosis. AB - BACKGROUND & AIMS: Patients with cirrhosis display enhanced blood levels of factor VIII, which may result in harmful activation of the clotting system; however, the underlying mechanism is unknown. METHODS: We performed a cross sectional study in patients with cirrhosis (n=61) and matched controls (n=61) comparing blood levels of factor VIII, von Willebrand factor (vWf), lipopolysaccharide (LPS) and positivity for Escherichia coli DNA. Furthermore, we performed an in vitro study to investigate if LPS, in a concentration range similar to that found in the peripheral circulation of cirrhotic patients, was able to elicit factor VIII secretion from human umbilical vein endothelial cells (HUVEC). RESULTS: Patients with cirrhosis displayed higher serum levels of LPS (55.8 [42.2-79.9] vs. 23.0 [7.0-34.0]pg/ml, p<0.001), factor VIII (172.0 [130.0 278.0] vs. 39.0 [26.0-47.0]U/dl, p<0.0001), vWf (265.0 [185.0-366.0] vs. 57.0 [48.0-65.0]U/dl, p<0.001) and positivity for Escherichia coli DNA (88% vs. 3%, p<0.001, n=34) compared to controls. Serum LPS correlated significantly with factor VIII (r=0.80, p<0.001) and vWf (r=0.63, p<0.001). Only LPS (beta coefficient=0.70, p<0.0001) independently predicted factor VIII levels. The in vitro study showed that LPS provoked factor VIII and vWf release from HUVEC via formation and secretion of Weibel-Palade bodies, a phenomenon blunted by pre treating HUVEC with an inhibitor of Toll-like receptor 4. CONCLUSIONS: The study provides the first evidence that LPS derived from gut microbiota increases the systemic levels of factor VIII via stimulating its release by endothelial cells. Lay summary: Cirrhosis is associated with thrombosis in portal and systemic circulation. Enhanced levels of factor VIII have been suggested to play a role but the underlying mechanism is still unclear. Here we show that patients with cirrhosis display a concomitant increase of factor VIII and lipopolysaccharide (LPS) from Escherichia coli and suggest that LPS contributes to the release of factor VIII from endothelial cells. PMID- 28716744 TI - A heterozygous mutation in GOT1 is associated with familial macro-aspartate aminotransferase. AB - BACKGROUND & AIMS: Macro-aspartate aminotransferase (macro-AST) manifests as a persistent elevation of AST levels, because of association of the protein with immunoglobulins in the circulation. Macro-AST is a rare, benign condition without a previously confirmed genetic basis. METHODS: Whole exome sequencing (WES)-based screening was performed on 32 participants with suspected familial macro-AST, while validation of variants was performed on an extended cohort of 92 probands and 1,644 healthy controls using Taqman genotyping. RESULTS: A missense variant (p.Gln208Glu, rs374966349) in glutamate oxaloacetate transaminase 1 (GOT1) was found, as a putative causal variant predisposing to familial macro-AST. The GOT1 p.Gln208Glu mutation was detected in 50 (54.3%) of 92 probands from 20 of 29 (69%) families, while its prevalence in healthy controls was only 0.18%. In silico analysis demonstrated that the amino acid at this position is not conserved among different species and that, functionally, a negatively charged glutamate on the GOT1 surface could strongly anchor serum immunoglobulins. CONCLUSIONS: Our data highlight that testing for the p.Gln208Glu genetic variant may be useful in diagnosis of macro-AST. LAY SUMMARY: Higher than normal levels of aspartate aminotransferase (AST) in the bloodstream may be a sign of a health problem. Individuals with macro-AST have elevated blood AST levels, without ongoing disease and often undergo unnecessary medical tests before the diagnosis of macro-AST is established. We found a genetic variant in the GOT1 gene associated with macro-AST. Genetic testing for this variant may aid diagnosis of macro-AST. PMID- 28716746 TI - Controlled release and anti-proliferative effect of imatinib mesylate loaded sporopollenin microcapsules extracted from pollens of Betula pendula. AB - Sporopollenin is a promising material for drug encapsulation due to its excellent properties; uniformity in size, non-toxicity, chemically and thermally resilient nature. Herein, morphologically intact sporopollenin microcapsules were extracted from Betula pendula pollens. Cancer therapeutic agent (imatinib mesylate) was loaded into the microcapsules. The encapsulation efficiency by passive loading technique was found to be 21.46%. Release behaviour of the drug from microcapsules was found to be biphasic, with an initial fast release followed by a slower rate of release. Imatinib mesylate release from the drug itself (control) was faster than from imatinib mesylate-loaded sporopollenin microcapsules. The release profiles for both free and entrapped drug samples were significantly slower and more controlled in PBS buffer (pH 7.4) than in HCl (pH 1.2) buffer. Cumulative drug release from IM-MES-loaded sporopollenin microcapsules was found to be 65% within 24h for PBS, whereas release from the control was completed within 1h. Also, a complete dissolution of control in HCl buffer was observed within first 30min. MTT assay revealed that drug-loaded microcapsules were effective on WiDr human colon carcinoma cell line. B. pendula sporopollenin can be suggested as an effective carrier for oral delivery of imatinib mesylate. PMID- 28716747 TI - Cysteine as a potential anti-amyloidogenic agent with protective ability against amyloid induced cytotoxicity. AB - Protein aggregation and misfolding have been allied with numerous human disorders and thus inhibition of such occurrence has been center for intense research efforts against these diseases. Here, we investigated anti-fibrillation activity of cysteine and its effect on kinetics of stem bromelain amyloid fibril formation. We established the anti-fibrillation and anti aggregation activities of cysteine by using multiple approaches like turbidity measurements, dye binding assays (ThT and ANS) and structural changes were monitored by circular dichroism (CD) followed by electron microscopy. Our experimental study inferred that cysteine inhibits temperature induced fibrillation of protein in a concentration dependent way. In addition, MDA-MB-231 cell viability of pre-formed amyloid was increased in presence of cysteine as compared to the fibrils alone. Furthermore, dynamic light scattering studies of native, aggregated as well as incubated (amyloids in presence of cysteine) samples indicates that cysteine restores native like structures of stem bromelain. Isothermal titration calorimetric results revealed that hydrogen bonding between cysteine and stem bromelain plays a significant role during inhibition of stem bromelain aggregation. However, thiophilic interaction between thiol group of cysteine and aromatic amino acid residue of stem bromelain may also have noteworthy role in inhibition of amyloid formation. PMID- 28716748 TI - A transparent wound dressing based on bacterial cellulose whisker and poly(2 hydroxyethyl methacrylate). AB - The current study was aimed to develop a transparent wound dressing comprised of bacterial cellulose (BC) and poly (2-hydroxyethyl methacrylate) (PHEMA) hydrogel coated with silver (Ag) nanoparticles. Briefly, different concentrations of BC whiskers (BCWs) were added into the HEMA solution to form PHEMA/BCWs hydrogel with volume ratio of monomer HEMA and BCWs as 7:3 and 1:1. The addition of BCWs into PHEMA matrix improved its equilibrium water content and light transmittance about 20%-40% and 10%, respectively. The Young's modulus for PHEMA was found to be 0.72MPa, which was improved to 0.57MPa and 0.50MPa for PHEMA/BCWs 7:3 and PHEMA/BCWs 1:1, respectively. Further, immersion of PHEMA/BCWs hydrogel in the AgNO3 and NaBH4 solutions bestowed it with antibacterial property and produced inhibition zones of 0.5+/-0.15cm and 0.25+/-0.15cm against Escherichia coli and Staphylococcus aureus, respectively. Similarly, PHEMA/BCWs prepared with 0.001M AgNO3 and 0.001M NaBH4 solutions showed 99% and 90% reduction in colony forming unit (CFU) for E. coli and S. aureus, respectively, after 24h. The PHEMA/BCWs/Ag hydrogel facilitated the growth of NIH3T3 fibroblast, showing their low toxicity. These results demonstrate the suitability of PHEMA/BCWs/Ag hydrogel for its application as potential transparent wound dressing material for skin repair. PMID- 28716749 TI - The targeting properties of folate-conjugated Pluronic F127/poly (lactic-co glycolic) nanoparticles. AB - Novel Folated Pluronic F127/poly (lactic-co-glycolic) (FA-F127-PLGA) and PLGA F127-PLGA block copolymer were synthesized and nanoparticles self-assembled from these two copolymers were prepared by dialysis method. Paclitaxel (PTX) was successfully encapsulated in these two nanoparticles. According to in vitro release studies of PTX-loaded nanoparticles, after an initial burst release during the first 11h, the entrapped PTX released slowly in the following 82h. The cytotoxicity studies demonstrated that the in vitro antitumor effect of PTX could be improved by encapsulating PTX into PLGA-F127-PLGA nanoparticles. Moreover, folate-targeted FA-F127-PLGA nanoparticles were more effective than PLGA-F127 PLGA when delivering PTX in folate receptor overexpressing OVCAR-3 cells, which mainly due to the FA-receptor-meditated endocytosis. As the treatment time became longer, the targeting effects were more obvious. The targeting effect of FA-F127 PLGA nanoparticles was also investigated in vitro by measuring the cellular uptake of the nanoparticles. The results showed that FA-F127-PLGA nanoparticles were more easily to be uptaken by OVCAR-3 cells in comparison with PLGA-F127-PLGA nanoparticles. In vivo pharmacokinetic studies indicated that FA-F127-PLGA nanoparticles prolong the circulation time of PTX in plasma, and delay the blood clearance of PTX. These results indicated that Folated FA-F127-PLGA could be a potential carrier in long-term PTX delivery. PMID- 28716750 TI - Hexadecylphosphocholine (Miltefosine) stabilized chitosan modified Ampholipospheres as prototype co-delivery vehicle for enhanced killing of L. donovani. AB - Lipid nanoparticles are stable, biodegradable and biocompatible carriers offering excellent therapeutic efficacy. Here, a novel effort has been made to develop Miltefosine (HePC- hexadecylphosphocholine) stabilized chitosan anchored nanostructured lipid carriers (NLC) of Amphotericin B (AmB) as co-delivery vehicle to enhance killing of L. donovani. The entrapment efficiency of AmB was achieved upto 85.3% for HePC-AmB-CNLCs with mean particle size of 150.8+/-8.4nm, and zeta potential value of +28.2+/-1.1mV, respectively. The cumulative amount of AmB released at even after the 24h was less than 65% from HePC-AmB-CNLCs and Tween-80-AmB-CNLCs. Intravenous administration of HePC-AmB-CNLCs revealed the significantly increased localization of AmB in both liver and spleen when estimated. FACS study represented enhanced uptake of FITC-HePC-CNLCs over FITC HePC-NLCs in J774A.1 cell lines. Highly significant in vitro and in vivo anti leishmanial activity (p<0.05 compared with Tween 80-AmB-CNLCs) was observed with HePC-AmB-CNLCs when tested against VL in Leishmania donovani-infected hamsters. The haemolysis and cytotoxicity studies showed the safety of HePC-AmB-CNLCs and Tween 80-AmB-CNLCs. The findings suggested that it would be preferable to deliver AmB through HePC stabilized chitosan anchored nanostructured lipid carriers for rapid and effective treatment with decreased adverse effects. PMID- 28716751 TI - Rehmannia glutinosa polysaccharide induced an anti-cancer effect by activating natural killer cells. AB - Rehmannia glutinosa polysaccharide (RGP) has exhibited an immune stimulatory effect, such as dendritic cell activation, but it has not been studied in terms of the activation capacity of natural killer (NK) cells in mice in vivo. In this study, we examined the effect of RGP on the proliferation and activation of NK cells in the spleen, mesenteric lymph node (mLN), and blood in vivo and compared that function with that of Escherichia coli lipopolysaccharide. The administration of RGP to C57BL/6 mice induced the increase in circulating blood NK cell numbers and in the proliferation of NK cells in the spleen, mLN, and blood. Moreover, RGP treatment promoted the toll-like receptor-4-dependent production of interferon-gamma and the up-regulation of CD69 expression in spleen NK cells. RGP-treated NK cells enhanced the cytotoxic activity with type I IFN production against target Yac-1 cells. Finally, RGP treatment inhibited the CT26 tumor growth in the lung. These findings demonstrated that RGP promoted the activation of NK cells and inhibited tumor growth in mice in vivo. PMID- 28716752 TI - Anticancer activity of silver and copper embedded chitin nanocomposites against human breast cancer (MCF-7) cells. AB - Chitin is a natural biopolymer widely used in biomedical and environmental applications due to its distinctive physical, chemical and mechanical properties. Although the anticancer property of chitin nanoforms and chitin derivatives against various cancers were studied earlier, there is no report in the chitin nanostructure incorporated metal nanocomposite. The present study was aimed to investigate the cytotoxicity of chitin incorporated silver and copper nanocomposite against human breast cancer (MCF-7) cells. Cytotoxicity of chitin nanoparticles (CNP), silver nanoparticles (AgNP), copper nanoparticles (CuNP), chitin/silver nanocomposite (CNP/AgNP) and chitin/copper nanocomposite (CNP/CuNP) was evaluated. Among all the above, CNP/AgNP has shown a lower of 31 mg as inhibitory concentration (IC50) value. Our study further showed the increased generation of reactive oxygen species with decreased activity of antioxidant enzymes and damage in the membrane integrity, thus confirms the cellular cytotoxic action of CNP/AgNP. In conclusion, the present study validates that, incorporating chitin nanoparticles with metallic nanostructure could be an effective and promising therapeutic agent against breast cancer. PMID- 28716753 TI - The structure-activity relationship between polysaccharides from Sargassum thunbergii and anti-tumor activity. AB - Polysaccharides derived from Sargassum thunbergii were prepared to investigate the structure-activity relationship between polysaccharides and anti-tumor activity in vitro. Many factors were examined. Overall, STW (polysaccharide extracted by hot water) had the best activity, followed by STJ (polysaccharide extracted by dilute alkali), and then STA (polysaccharide extracted by dilute acid). Location of algae had no effect at 500MUg/mL and 1000MUg/mL, while STW-QD (algae collected from Qingdao, China) had the best activity, followed by STW-WZ (algae collected from Wenzhou, China) and STW-LJ (algae collected from Lianjiang, China) and then STW-DL (algae collected from Dalian, China) and STW-RC (algae collected from Rongcheng, China) at 250MUg/mL. Moreover, molecular weight had no effect at 1000MUg/mL, while higher molecular weights were associated with better activities at 250MUg/mL and 500MUg/mL. Sulfate content had no effect at 1000MUg/mL, while anti-tumor activities decreased accompanying with the changes of sulfate content. Uronic acid content was an important factor influencing activity. The fractions of STW showed little anti-tumor activity; however, the mixture of the fractions of STW showed approximately 60% inhibition. Overall, these findings suggested that the anti-tumor activity of polysaccharides required multilateral cooperation and that some of the effective components were lost. PMID- 28716754 TI - Protective effect of Sargussum vulgare sulfated polysaccharide against molecular, biochemical and histopathological damage caused by alloxan in experimental diabetic rats. AB - Diabetes is a serious condition that is linked to the development of oxidative stress. In the context of enhancing the biodiversity of Tunisia's flora, this study aimed to evaluate the effect of Sargussum vulgare sulfated polysaccharide (SVSP) on hyperglycemia and diabetes complications in the alloxan-induced diabetic rats. Our results showed a disturbance of carbohydrate, lipid, hematological and histopathological parameters, an increase in the alpha-amylase enzyme activity and damage to the pancreatic, hepatic and renal tissues in rats rendered diabetic by alloxan. In contrast, treatment with SVSP resulted in a correction of fasting and postprandial blood glucose and HbA1c through inhibition of pancreatic alpha-amylase. We also noticed an improvement in hemogram parameters and an attenuation of the pancreatic oxidative stress markers as well as histological protections. On the other hand, the administration of SVSP to diabetic rats caused, besides the correction of glycemic and lipid parameters, a good defense against hepatotoxicity and nephrotoxicity of diabetes as well as good antioxidant status and histological protections. PMID- 28716755 TI - Construction of an amperometric glycated hemoglobin biosensor based on Au-Pt bimetallic nanoparticles and poly (indole-5-carboxylic acid) modified Au electrode. AB - The glucose level measurement in the diabetic patient plays a vital role in identification of the treatments going on and it also provides the control over the diabetics. A new electrochemical sensing device was constructed for determination of glycated hemoglobin (HbA1c) in whole blood samples. Fructosyl amine oxidase (FAO) was bioconjugated onto hybrid nanocomposite i.e., gold nanoparticles-platinum nanoparticles (AuNPs-PtNPs) and poly indole-5-carboxylic acid (PIN5COOH), deposited electrochemically on gold electrode. Bimetallic nanoparticles not only show their individual properties but also provides the synergistic effect between the two noble metal nanoparticles. AuNPs-PtNPs shown as an amplified sensing interface at lower voltage which makes the sensor more sensitive and specific. The FAO/AuNPs-PtNPs onto PIN5COOH/Au electrode shows a promising future in diagnosis of HbA1c and diabetes management. The novel sensor formed has good accuracy, selectivity, sensitivity, precision and reliability. In addition to these, it showed good storage stability and retained 50% of its initial activity within 12 weeks at 4 degrees C. PMID- 28716757 TI - Saturated phosphatidylcholine as matrix former for oral extended release dosage forms. AB - The aim of this study was to evaluate the suitability of saturated phosphatidylcholine (Phospholipon(r) 90H) as extended release excipient in matrix tablets for three model drugs with different aqueous solubility (theophylline, caffeine and diprophylline). The tablets could be prepared by direct compression because of the favorable phospholipid powder flow properties (Carr's index: 12.64 and angle of repose: 28.85) and good compactibility. Tablets of low porosity were formed already at low pressure of 40MPa and with drug loadings up to 70% due to high plasticity of the phospholipid. Extended drug release was achieved with the drugs of different solubility and at various drug loadings. For example, the caffeine release time (t80%) from 8mm tablets ranged from 1.5h to 18h at 70% and 10% drug loading, respectively. The drug release was governed by diffusion and could therefore be modelled by Fick's law of diffusion. Drug release profiles were thus a function of drug solubility, drug loading and tablet dimension. Matrix tablets of caffeine (20% drug loading) showed robust dissolution with regard to agitation (50-100rpm) and ionic strength of the release media (100-600 mOsmol/kg). Caffeine release was pH-dependent with a faster drug release at acidic pH, which was attributed to a protonization of the phosphatidyl group of the matrix-former and thus a higher hydrophilicity. PMID- 28716758 TI - Oral delivery of vancomycin by tetraether lipid liposomes. AB - Despite the outstanding progress in modern medicine, the oral delivery of peptide drugs is limited until today due to their instability in the gastrointestinal tract and low mucosa penetration. To overcome these hurdles, liposomes containing the specific tetraether lipid GCTE (glycerylcaldityltetraether lipid) were examined. For this purpose, the glycopeptide antibiotic vancomycin was used as model substance and liposomes were prepared by DAC (dual assymetric centrifugation). These liposomes showed a size and polydispersity index comparable to standard liposomes. A high encapsulation efficiency of 58.53+/ 1.76% of the peptide drug vancomycin could be obtained as detected by HPLC. FCS analysis showed that in average each liposome contains 30 molecules of vancomycin. TEM and Cryo-EM micrographs verified the size and lamellarity of the liposomal formulations. Cytotoxicity tests in Caco-2 cells showed no significant cytotoxicity for all liposomal concentrations tested, indicating the good tolerability of these formulations. Furthermore, the use of sucrose as lyoprotector enabled the long term storage of the liposomal formulation for at least three months. The potency of this drug delivery system could be proven in an animal model using Wistar rats. One hour after oral application, 4.82+/-0.56% of the administered dose of vancomycin could be found in the blood as detected by immunoassay measurements. This transport did also not affect the integrity of the peptide as verified by immunoassay measurements. In combination with long term storage stability, this formulation appears to be a promising delivery system for oral application of peptide drugs. PMID- 28716756 TI - Cartilage-specific deletion of Alk5 gene results in a progressive osteoarthritis like phenotype in mice. AB - OBJECTIVE: Previous studies have shown that Transforming growth factor-beta (TGF beta)/TGFbetaRII-Smad3 signaling is involved in articular cartilage homeostasis. However, the role of TGF-beta/ALK5 signaling in articular cartilage homeostasis has not been fully defined. In this study, a combination of in vitro and in vivo approaches was used to elucidate the role of ALK5 signaling in articular cartilage homeostasis and the development of osteoarthritis (OA). DESIGN: Mice with inducible cartilage-specific deletion of Alk5 were generated to assess the role of ALK5 in OA development. Alterations in cartilage structure were evaluated histologically. The expressions of genes associated with articular cartilage homeostasis and TGF-beta signaling were analyzed by qRT-PCR, western blotting and immunohistochemistry. The chondrocyte apoptosis was detected by TUNEL staining and immunohistochemistry. In addition, the molecular mechanism underlying the effects of TGF-beta/ALK5 signaling on articular cartilage homeostasis was explored by analyzing the TGF-beta/ALK5 signaling-induced expression of proteoglycan 4 (PRG4) using specific inhibitors. RESULTS: Postnatal cartilage specific deletion of Alk5 induced an OA-like phenotype with degradation of articular cartilage, synovial hyperplasia, osteophyte formation, subchondral sclerosis, as well as enhanced chondrocyte apoptosis, overproduction of catabolic factors, and decreased expressions of anabolic factors in chondrocytes. In addition, the expressions of PRG4 mRNA and protein were decreased in Alk5 conditional knockout mice. Furthermore, our results showed, for the first time, that TGF-beta/ALK5 signaling regulated PRG4 expression partially through the protein kinase A (PKA)-CREB signaling pathway. CONCLUSIONS: TGF-beta/ALK5 signaling maintains articular cartilage homeostasis, in part, by upregulating PRG4 expression through the PKA-CREB signaling pathway in articular chondrocytes. PMID- 28716759 TI - Vitamin D levels in childhood and adolescence and cardiovascular risk factors in a cohort of healthy Australian children. AB - As the prevalence of obesity appears to be increasing in Australia's youth the overall objective of this study was to examine serum 25-hydroxyvitamin D (25OHD) concentrations in a cohort of 8-year-olds (n=249) followed up at age 15 (n=162) and explore associations between 25OHD with cardiovascular disease (CVD) risk factors in these populations. This was done in two stages: the first, two cross sectional analyses (at ages 8 and 15); and the second, a prospective analysis from age 8 to 15. At both ages data on 25OHD, blood lipids, and anthropometry were measured. Date of blood draw was used as a surrogate of sunlight exposure. Results were then analysed by multivariate linear analyses taking into account interaction and confounding. Mean 25OHD concentrations decreased from 94+/ 25nmol/L to 63+/-16nmol/L between age 8 and 15 years (p<0.001). On cross sectional analysis of 8year olds, no CVD risk factor was found to be significantly associated with 25OHD concentrations. On cross-sectional analysis of 15year olds lower 25OHD levels were significantly associated with higher body fat (adjusted beta=-0.24, p=0.003). Prospectively, lower 25OHD levels in 8-year old boys, but not girls, were significantly associated with higher blood total cholesterol (adjusted beta=-0.28, p=0.040) and triglyceride levels (adjusted beta=-0.33, p=0.030) at age 15. The limitation of these data is the relatively small sample sizes, however these results suggest that low 25OHD in childhood needs to be further investigated in larger cohort studies as there may be later cardiovascular consequences in adolescence. PMID- 28716761 TI - Recent developments for introducing a hexafluoroisopropanol unit into the Vitamin D side chain. AB - Among numerous studies on synthetic approaches to and the biological activities of vitamin D analogues, we herein focused on falecalcitriol, an analogue of calcitriol (1alpha,25-dihydroxyvitamin D3), in which a 26,26,26,27,27,27 hexafluoroisopropanol unit has been introduced into the side chain. Falecalcitriol was designed to escape from the metabolism of CYP24A1 and has been used as a drug to treat secondary hyperparathyroidism since 2001. Its metabolite, the 23-hydroxy form, retains biological activity and resistants to further metabolism. Recent developments in synthetic methodologies for introducing the hexafluoroisopropanol unit into the vitamin D CD-ring side chain were described herein. PMID- 28716760 TI - Properties of purified CYP2R1 in a reconstituted membrane environment and its 25 hydroxylation of 20-hydroxyvitamin D3. AB - Recent studies indicate that CYP2R1 is the major 25-hydroxylase catalyzing the first step in vitamin D activation. Since the catalytic properties of CYP2R1 have been poorly studied to date and it is a membrane protein, we examined the purified enzyme in a membrane environment. CYP2R1 was expressed in E. coli and purified by nickel affinity- and hydrophobic interaction-chromatography and assayed in a reconstituted membrane system comprising phospholipid vesicles plus purified human NADPH-P450 oxidoreductase. CYP2R1 converted vitamin D3 in the vesicle membrane to 25-hydroxyvitamin D3 [25(OH)D3] with good adherence to Michaelis-Menten kinetics. The kinetic parameters for 25-hydroxylation of vitamin D3 by the two major vitamin D 25-hydroxylases, CYP2R1 and CYP27A1, were examined in vesicles under identical conditions. CYP2R1 displayed a slightly lower kcat than CYP27A1 but a much lower Km for vitamin D3, and thus an overall 17-fold higher catalytic efficiency (kcat/Km), consistent with CYP2R1 being the major vitamin D 25-hydroxylase. 20-Hydroxyvitamin D3 [20(OH)D3], the main product of vitamin D3 activation by an alternative pathway catalyzed by CYP11A1, was metabolized by CYP2R1 to 20,25-dihydroxyvitamin D3 [20,25(OH)2D3], with catalytic efficiency similar to that for the 25-hydroxylation of vitamin D3. 20,25(OH)2D3 retained full, or somewhat enhanced activity compared to the parent 20(OH)D3 for the inhibition of the proliferation of melanocytes and dermal fibroblasts, with a potency comparable to 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]. The 20,25(OH)2D3 was also able to act as an inverse agonist on retinoic acid-related orphan receptor alpha, like its parent 20(OH)D3. Thus, the major findings of this study are that CYP2R1 can metabolize substrates in a membrane environment, the enzyme displays higher catalytic efficiency than CYP27A1 for the 25-hydroxylation of vitamin D, it efficiently hydroxylates 20(OH)D3 at C25 and this product retains the biological activity of the parent compound. PMID- 28716762 TI - Selective Window Application of Gentamicin+ Dexamethasone in Meniere's Disease. AB - OBJECTIVE: The purpose of the study is to prevent hearing loss when using intratympanic (IT) gentamicin for intractable Meniere's disease. MATERIALS AND METHODS: It is a retrospective case review study. Twenty five patients who had definite Meniere's disease and had either selective window application or weekly IT gentamicin were included into the study. First group (selective) had dexamethasone on the round window and gentamicin on oval window during exploratory tympanotomy procedure. The second group had IT gentamicin at weekly intervals. The degree of caloric weakness (CW), average hearing level in low pitch (HLP) (250, 500, 1000, 2000 Hz) and high pitch (HHP) (4000, 6000, 8000 Hz) were compared before and after treatment. The need for further treatment was noted. RESULTS: In the first group, the average HLP was increased from 51.6+/-7dB to 52.2+/-5.6 dB. The average HHP was increased 41.96+/-20.2 dB to 47.2+/-18.3 dB after treatment. The CW changed from 37.6+/-23.9 % to 54.6+/-30.6 %. In the second group, the average HLP was increased from 56.3+/-10.5 dB to 61.65+/-18.3 dB. The average HHP was increased 59.05+/-17.4 dB to 69.4+/-21.98 dB after treatment. The CW changed from 45.8+/-22.3% to 71.53+/-29.63 %. Both methods had statisticaly significant increase in caloric weakness. But only IT gentamicin led a significant hearing loss in HHP. CONCLUSION: The use of dexamethasone and gentamycin via different windows in the middle ear is safe and effective method for Meniere's disease in the short term. Application of dexamethasone protects not only the hearing cells but vestibular cells also. PMID- 28716763 TI - Clinical Characteristics of Chronic Perforated Otitis Media in Different Age Groups. AB - OBJECTIVE: We aimed to analyze preoperative and intraoperative clinical characteristics of chronic perforated otitis media by patient age. MATERIALS AND METHODS: We analyzed 137 tympanoplasties for chronic perforated otitis media in 133 patients. Exclusion criteria were ear adhesions, cholesteatoma, and a history of tympanoplasty. Patients were divided into a younger group (aged 15-39 years), a middle group (40-64 years), and an elderly group (>=65 years). We compared tympanoplasty technique (using Wullstein classification), mastoid air-cell area measured by temporal bone computed tomography, preoperative aeration of the temporal bone, mean preoperative hearing (at 500 Hz, 1000 Hz, and 2000 Hz), and patch effect calculated by the pre- and post-patch air-bone gap at frequencies of 250 Hz and 500 Hz among the three age groups. RESULTS: Although type I tympanoplasty was performed most frequently in all age groups, it was performed significantly less often in the elderly group (p<0.05). The mean mastoid pneumatization index was significantly lower in the elderly group (p<0.05). Preoperative air-conduction hearing and bone-conduction hearing differed significantly among age groups (p<0.05 for both). There were no significant differences in the air-bone gap among the three groups. The mean patch effect was significantly better in the younger group than in middle or elderly groups (p<0.05). CONCLUSION: The less pneumatized mastoid and ossicular diseases in elderly patients with chronic perforated otitis media suggest that they had longer lasting and more severe childhood middle ear pathologies than did younger patients. PMID- 28716764 TI - Influence of Time and Direction Information on Video Head Impulse Gains. AB - OBJECTIVE: The objective of this study was to establish which factor leads to a higher vestibulo-ocular reflex (VOR) gain: the timing of the movement or the direction of the movement. For this purpose, healthy volunteers were examined under three conditions: (1) when they were informed about the timing of the head movement; (2) when they were informed about the direction of the head movement; and (3) when they knew both the timing and the direction of the head movement. MATERIALS AND METHODS: This study included data from 19 participants between the ages of 20 and 23 years with no neurological or vestibular ailments. The gains of the video head impulse test (vHIT) were measured under four different conditions and the final control tests. Five subgroups were defined, and the differences in the subgroups were assessed with using several statistical procedures. RESULTS: We found that there were significant differences between all subgroups gains on the right and left head rotations. Nevertheless, nonsignificant differences were found by performing independent samples t-tests and Mann-Whitney U tests between left and right head rotations for the pairwise comparisons of subgroups. Also, analysis of variance (ANOVA) results indicated that vHIT gains for the right and left , respectively). Thus, knowing the timing or direction or both does not affect vHIT gains. CONCLUSION: The results of these experiments revealed that there is no association whatsoever between VOR gain and awareness of the timing or direction of the movement or both. PMID- 28716765 TI - Sporadic Endolymphatic Sac Tumor-A Very Rare Cause of Hearing Loss, Tinnitus, and Dizziness. AB - Sporadic endolymphatic sac tumor is a very rare neoplasm. It is low malignant, locally destructive and expansive, but non-metastasizing. The tumor is very rare in the sporadic form, but more often associated with Von Hippel-Lindau disease. A 65-year old man with left sided tinnitus and hearing loss for several months. Audiometry showed an asymmetrical sensory neural hearing loss on the left side up to 60 dB. The speech discrimination score was 46% and stapedial reflexes were absent. Several years earlier, he had suffered from periods of dizziness. Magnetic resonance imaging (MRI) showed a destructive and locally invasive tumor in the peripheral vestibular system expanding into the cerebellopontine angle. Paraganglioma and von Hippel-Lindau's disease were excluded. Vestibular examination showed no function of vestibular organ left side. The tumor was resected radically by translabyrintine approach. Per-operative freeze-microscopy showed inflammation tissue, whereas subsequent microscopy showed papillary-cystic endolymphatic sac tumor. Endolymphatic sac tumor is a rare neoplasm. The tumor may present with asymmetrically sensory neural hearing loss with or without tinnitus, dizziness and facial nerve paresis. An MRI scan is the appropriate diagnostic tool final dianosis is made by the post-operative histo-pathology. Dizziness can be the first sign of a tumor in this area. PMID- 28716766 TI - Simultaneous Coexistence of Complications of Chronic Otitis Media in the Same Case. AB - Chronic otitis media (COM) is a common clinical entity, but the incidence of COM complications has declined recently due to broad use of antibiotics. Independent of this, these complications are still a significant challenge in otorhinolaryngology practice because of high morbidity and mortality rates. The most common etiologic diagnosis was cholesteatomatous COM. Simultaneous coexistence of complications of COM in the same case is a rare situation, and the present report describes a case with mastoiditis, Bezold abscess, lateral sinus thrombophlebitis, meningitis, and paraspinal abscess. PMID- 28716767 TI - Implementation of the "EAONO/JOS Definitions and Classification of Middle Ear Cholesteatoma" - from STAM to STAMCO. PMID- 28716768 TI - Effect of Viewing Smoking Scenes in Motion Pictures on Subsequent Smoking Desire in Audiences in South Korea. AB - BACKGROUND: In the modern era of heightened awareness of public health, smoking scenes in movies remain relatively free from public monitoring. The effect of smoking scenes in movies on the promotion of viewers' smoking desire remains unknown. OBJECTIVE: The study aimed to explore whether exposure of adolescent smokers to images of smoking in films could stimulate smoking behavior. METHODS: Data were derived from a national Web-based sample survey of 748 Korean high school students. Participants aged 16-18 years were randomly assigned to watch three short video clips with or without smoking scenes. After adjusting covariates using propensity score matching, paired sample t test and logistic regression analyses compared the difference in smoking desire before and after exposure of participants to smoking scenes. RESULTS: For male adolescents, cigarette craving was significantly higher in those who watched movies with smoking scenes than in the control group who did not view smoking scenes (t307.96=2.066, P<.05). In the experimental group, too, cigarette cravings of adolescents after viewing smoking scenes were significantly higher than they were before watching smoking scenes (t161.00=2.867, P<.01). After adjusting for covariates, more impulsive adolescents, particularly males, had significantly higher cigarette cravings: adjusted odds ratio (aOR) 3.40 (95% CI 1.40-8.23). However, those who actively sought health information had considerably lower cigarette cravings than those who did not engage in information-seeking: aOR 0.08 (95% CI 0.01-0.88). CONCLUSIONS: Smoking scenes in motion pictures may increase male adolescent smoking desire. Establishing a standard that restricts the frequency of smoking scenes in films and assigning a smoking-related screening grade to films is warranted. PMID- 28716769 TI - Web-Based Therapist Training in Interpersonal Psychotherapy for Depression: Pilot Study. AB - BACKGROUND: Training mental health professionals to deliver evidence-based therapy (EBT) is now required by most academic accreditation bodies, and evaluating the effectiveness of such training is imperative. However, shortages of time, money, and trained EBT clinician teachers make these challenges daunting. New technologies may help. The authors have developed the first empirically evaluated comprehensive Internet therapist training program for interpersonal psychotherapy (IPT). OBJECTIVE: The aim of this study was to examine whether (1) the training protocol would increase clinicians' knowledge of IPT concepts and skills and (2) clinicians would deem the training feasible as measured by satisfaction and utility ratings. METHODS: A total of 26 clinicians enrolled in the training, consisting of (1) a Web-based tutorial on IPT concepts and techniques; (2) live remote training via videoconference, with trainees practicing IPT techniques in a role-play using a case vignette; and (3) a Web based portal for therapists posttraining use to help facilitate implementation of IPT and maintain adherence over time. RESULTS: Trainees' knowledge of IPT concepts and skills improved significantly (P<.001). The standardized effect size for the change was large: d=2.53, 95% CI 2.23-2.92. Users found the technical features easy to use, the content useful for helping them treat depressed clients, and felt the applied training component enhanced their professional expertise. Mean rating of applied learning was 3.9 (scale range from 1=very little to 5=a great deal). Overall satisfaction rating was 3.5 (range from 1=very dissatisfied to 4=very satisfied). CONCLUSIONS: Results support the efficacy and feasibility of this technology in training clinicians in EBTs and warrant further empirical evaluation. PMID- 28716770 TI - Data Preparation for West Nile Virus Agent-Based Modelling: Protocol for Processing Bird Population Estimates and Incorporating ArcMap in AnyLogic. AB - BACKGROUND: West Nile Virus (WNV) was first isolated in 1937. Since the 1950s, many outbreaks have occurred in various countries. The first appearance of infected birds in Manitoba, Canada was in 2002. OBJECTIVE: This paper describes the data preparation phase of setting up a geographic information system (GIS) simulation environment for WNV Agent-Based Modelling in Manitoba. METHODS: The main technology used in this protocol is based on AnyLogic and ArcGIS software. A diverse variety of topics and techniques regarding the data collection phase are presented, as modelling WNV has many disparate attributes, including landscape and weather impacts on mosquito population dynamics and birds' roosting locations, population count, and movement patterns. RESULTS: Different maps were combined to create a grid land cover map of Manitoba, Canada in a shapefile format compatible with AnyLogic, in order to modulate mosquito parameters. A significant amount of data regarding 152 bird species, along with their population estimates and locations in Manitoba, were gathered and assembled. Municipality shapefile maps were converted to built-in AnyLogic GIS regions for better compatibility with census data and initial placement of human agents. Accessing shapefiles and their databases in AnyLogic are also discussed. CONCLUSIONS: AnyLogic simulation software in combination with Esri ArcGIS provides a powerful toolbox for developers and modellers to simulate almost any GIS-based environment or process. This research should be useful to others working on a variety of mosquito-borne diseases (eg, Zika, dengue, and chikungunya) by demonstrating the importance of data relating to Manitoba and/or introducing procedures to compile such data. PMID- 28716771 TI - An Intervention Using Gamification to Increase Human Immunodeficiency Virus and Sexually Transmitted Infection Screening Among Young Men Who Have Sex With Men in California: Rationale and Design of Stick To It. AB - BACKGROUND: In the United States, young men who have sex with men (YMSM) remain disproportionately affected by human immunodeficiency virus (HIV) and other sexually transmitted infections (STIs). Although routine HIV/STI screening is pivotal to the timely diagnosis of HIV and STIs, initiation of appropriate treatment, and reduced onward disease transmission, repeat screening is underused. Novel interventions that incorporate elements of games, an approach known as gamification, have the potential to increase routinization of HIV/STI screening among YMSM. OBJECTIVE: The study aims to test the hypothesis that an incentive-based intervention that incorporates elements of gamification can increase routine HIV/STI screening among YMSM in California. METHODS: The study consists of a formative research phase to develop the intervention and an implementation phase where the intervention is piloted in a controlled research setting. In the formative research phase, we use an iterative development process to design the intervention, including gathering information about the feasibility, acceptability, and expected effectiveness of potential game elements (eg, points, leaderboards, rewards). These activities include staff interviews, focus group discussions with members of the target population, and team meetings to strategize and develop the intervention. The final intervention is called Stick To It and consists of 3 components: (1) online enrollment, (2) Web-based activities consisting primarily of quizzes and a countdown "timer" to facilitate screening reminders, and (3) in-person activities that occur at 2 sexual health clinics. Participants earn points through the Web-based activities that are then redeemed for chances to win various prizes during clinic visits. The pilot study is a quasi-experimental study with a minimum of 60 intervention group participants recruited at the clinics, at community-based events, and online. We will compare outcomes in the intervention group with a historical control group consisting of individuals meeting the inclusion criteria who attended study clinics in the 12 months prior to intervention implementation. Eligible participants in the pilot study (1) are 18 to 26 years old, (2) were born or identify as male, 3) report male sexual partners, and 4) have a zip code of residence within defined areas in the vicinity of 1 of the 2 implementation sites. The primary outcome is repeat HIV/STI screening within 6 months. RESULTS: This is an ongoing research study with initial results expected in the fourth quarter of 2017. CONCLUSIONS: We will develop and pilot test a gamification intervention to encourage YMSM to be regularly screened for HIV/STIs. The results from this research will provide preliminary evidence about the potential effectiveness of using gamification to amplify health-related behavioral change interventions. Further, the research aims to determine the processes that are essential to developing and implementing future health-related gamification interventions. TRIAL REGISTRATION: Clinicaltrials.gov NCT02946164; https://clinicaltrials.gov/ct2/show/NCT02946164 (Archived by WebCite at http://www.webcitation.org/6ri3G4HwD). PMID- 28716772 TI - Chewing-induced facial dystonia: a rare presentation of task-specific dystonia. AB - This case is an addition to scarce literature available for a rare condition, chewing-induced task-specific dystonia. The patient was a 63-year-old woman who presented with a 4-year history of progressive difficulty in eating food only during chewing associated with abnormal facial grimaces without any difficulty in drinking, swallowing, speaking or singing. Examination revealed dystonia of facial muscles every time she chewed but absent during drinking and speaking. As movements were consistent and reproducible with the specific task, other differential diagnosis like motor tics, psychogenic disorder, tardive dystonia and parkinsonism syndrome were excluded leading to a diagnosis of task-specific facial dystonia triggered by chewing. Treatment was started with trihexyphenidyl and later on tetrabenazine was also added but she got only mild relief of symptoms. As she did not agreed for botulinum toxin therapy, so we continued with the same treatment without much improvement. PMID- 28716773 TI - Uncommon cause of cervicobrachial neuralgia: epidural abscess complicating tuberculous arthritis. PMID- 28716774 TI - Social considerations of inflammatory bowel disease in Southern Israel. AB - Chronic diseases pose unique social challenges beyond traditional health considerations that require specific attention. In this report, we examine the case of a middle-aged woman with ulcerative colitis, living in Southern Israel. Trust between the patient and physician is shown to positively influence a variety of therapeutic outcomes and should be considered a fundamental component of successful care. In context of the military conflict between Israel and Gaza, the needs of patients with chronic diseases cannot be forgotten. The work environment is also identified as an area of particular concern, as a supportive work environment is essential in order to maintain satisfaction in the workplace and sustain a high quality of life. Out-of-pocket costs for medications are confirmed to be a significant barrier to adherence. Better understanding of patientsa?TM financial capabilities, along with affordable therapeutic interventions, will alleviate healthcare-related financial burdens and improve health outcomes. PMID- 28716775 TI - Acute rehabilitation after resuscitative endovascular balloon occlusion of the aorta (REBOA) in major trauma. AB - We report a 23-year-old woman admitted post cyclist versus heavy goods vehicle accident in December 2014. This was the second case the life-saving procedure, that is, resuscitative endovascular balloon occlusion of the aorta (REBOA) was performed on at the roadside. This advanced procedure was performed due to the extensive haemorrhage from this patient's complex pelvic fracture . As a result of REBOA, the patient consequently lost her left lower limb and underwent a variety of complex pelvic and lower limb surgeries.The patient was admitted to the acute critical care unit and underwent repeated operations and was not ready to start active rehabilitation until 12 days into her admission. Prior to this she was on movement restrictions and received physiotherapy for limb care and dietetics in order to meet her nutritional requirements. The patient was stepped down to a ward setting and started on an extensive physiotherapy programme and was then transferred to the rehabilitation unit for amputees at Roehampton. PMID- 28716776 TI - Increased risk for thionamide-induced agranulocytosis in elderly patients: a case presentation and literature review. AB - Thionamides, such as methimazole and propylthiouracil, are used for the management of hyperthyroidism. Agranulocytosis is a rare adverse effect of thionamides and elderly patients are especially vulnerable. Here we discuss a case of an 80-year-old woman who developed agranulocytosis and pneumonia approximately 4 weeks after starting low dose methimazole therapy. Despite aggressive treatment with broad-spectrum antibiotics and granulocyte colony stimulating factor, she developed multiorgan failure and died. Our goals are to identify risk factors common to elderly patients and hopefully improve outcomes in this population when prescribed thionamides. PMID- 28716777 TI - Customised crescentic corneal transplant with conjunctival resection in an atypical case of malignant Mooren's ulcer. PMID- 28716779 TI - Localised pneumoperitoneum following liver mass biopsy in the setting of post ERCP pneumobilia. PMID- 28716778 TI - Thrombotic microangiopathy associated with intravenous injection of extended release oxycodone. AB - We describe the case of a 35-year-old man presenting with thrombotic microangiopathy (TMA) and renal impairment following, as he later disclosed, intravenous injection of oral formulation tamper-resistant extended-release oxycodone hydrochloride (Oxycontin). Recurrent misuse of this agent was associated with relapsing TMA despite treatment with terminal complement inhibitor eculizumab. Cases of TMA have been reported in the USA in association with intravenous misuse of extended-release oxymorphone (Opana ER) after the introduction of a new non-crushable formulation in 2012. There are two reported accounts of TMA associated with tamper-resistant Oxycontin, which became available in Australia in 2014. This is the first documented case in which eculizumab was used. This case illustrates the practical diagnostic challenges in identifying TMA disorders, and the importance of a detailed drug history. It also highlights the need to clarify what role, if any, eculizumab therapy has in cases of drug-associated TMA. PMID- 28716780 TI - A rare consequence of very common osteoporotic pubic rami fracture in a patient with myeloproliferative disease. PMID- 28716782 TI - The reticular activating system in the wake of temporal lobe epilepsy: dazed and confused. PMID- 28716781 TI - Incidence and Trends in Hypoglycemia Hospitalization in Adults With Type 1 and Type 2 Diabetes in England, 1998-2013: A Retrospective Cohort Study. AB - OBJECTIVE: To determine trends in hospitalization for hypoglycemia in adults with type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) in England. RESEARCH DESIGN AND METHODS: Adults with T1DM or T2DM were identified from 398 of the 684 practices within the Clinical Practice Research Datalink, for which linkage to the Hospital Episode Statistics was possible. Hypoglycemia as the primary reason for hospitalization between 1998 and 2013 was extracted. Trends were estimated using joinpoint regression models for adults with T1DM, young and middle-aged adults with T2DM (18-64 years), and elderly adults with T2DM (>=65 years), respectively. RESULTS: Among 23,246 adults with T1DM, 1,591 hypoglycemia hospitalizations occurred during 121,262 person-years. Among 241,441 adults with T2DM, 3,738 hypoglycemia hospitalizations occurred during 1,344,818 person-years. In adults with T1DM, the incidence increased 3.74% (95% CI 1.70-5.83) annually from 1998 to 2013. In young and middle-aged adults with T2DM, the annual incidence increase was 4.12% (0.61-7.75) from 1998 to 2013. In elderly adults with T2DM, the incidence increased 8.59% (5.76-11.50) annually from 1998 to 2009, and decreased 8.05% (-14.48 to -1.13) annually from 2009 to 2013, but the incidence was still higher in 2013 than 1998 (adjusted rate ratio 3.01 [1.76 5.14]). Trends in HbA1c level did not parallel trends of hypoglycemia hospitalization for both diabetes types. A possible reason for declined hypoglycemia trend in 2009-2013 in elderly adults with T2DM may be continuously decreased sulfonylurea use after 2009, which was not seen in young and middle aged adults with T2DM. CONCLUSIONS: Hypoglycemia requiring hospitalization has been an increasing burden in adults with T1DM and T2DM in England in the previous two decades, with the exception of the decline in elderly adults with T2DM starting in 2009. PMID- 28716783 TI - Adverse pregnancy outcomes in women exposed to gabapentin and pregabalin: data from a population-based study. PMID- 28716785 TI - Imbuing medical professionalism in relation to safety: a study protocol for a mixed-methods intervention focused on trialling an embedded learning approach that centres on the use of a custom designed board game. AB - INTRODUCTION: Healthcare organisations have a responsibility for ensuring that the governance of workplace settings creates a culture that supports good professional practice. Encouraging such a culture needs to start from an understanding of the factors that make it difficult for health professionals to raise issues of concern in relation to patient safety. The focus of this study is to determine whether a customised education intervention, developed as part of the study, with interns and senior house officers (SHOs) can imbue a culture of medical professionalism in relation to patient safety and support junior doctors to raise issues of concern, while shaping a culture of responsiveness and learning. METHODS AND ANALYSIS: We will use quantitative and qualitative methods to collect data. The sample size will be approximately 200 interns and SHOs across the two hospital sites. Two surveys will be included with one measuring leadership inclusiveness and psychological safety and a second capturing information on safety concerns that participants may have witnessed in their places of work. The PlayDecide embedded learning intervention will be developed with key stakeholders. This will be trialled in the middle stage of data collection for both interns and SHOs. A detailed content analysis will be conducted on the surveys to assess any changes in reporting following the PlayDecide intervention. This will be compared with the incident reporting levels and the results of the preintervention and postintervention leadership inclusiveness and psychological safety survey. Statistical analysis will be conducted using SPSS. Differences will be considered statistically significant at p<0.05. Semistructured interviews using a critical incident technique will be used for the ongoing analysis and evaluation of the project. These will be transcribed, de-identified and coded into themes. ETHICS AND DISSEMINATION: The study has been granted ethics approval from University College Dublin (Ref. LS-15 19-Ward-McAuliffe: Imbuing Medical Professionalism in Relation to Safety). The study results will be disseminated through peer-reviewed publications. PMID- 28716784 TI - Protocol for a prospective observational study to improve prehospital notification of injured patients presenting to trauma centres in India. AB - INTRODUCTION: Prehospital notification of injured patients enables prompt and timely care in hospital through adequate preparation of trauma teams, space, equipment and consumables necessary for resuscitation, and may improve outcomes. In India, anecdotal reports suggest that prehospital notification, in those few places where it occurs, is unstructured and not linked to a well-defined hospital response. The aim of this manuscript is to describe, in detail, a study protocol for the evaluation of a formalised approach to prehospital notification. METHODS AND ANALYSIS: This is a longitudinal prospective cohort study of injured patients being transported by ambulance to major trauma centres in India. In the preintervention phase, prospective data on patients will be collected on prehospital assessment, notification, inhospital assessment, management and outcomes and recorded in a new tailored multihospital trauma registry. All injured patients arriving by ambulance and allocated to a red or yellow priority category will be eligible for inclusion. The intervention will be a prehospital notification application to be used by ambulance clinicians to notify emergency departments of the impending arrival of a patient. The proportion of eligible patients arriving to hospital after notification will be the primary outcome measure. Secondary outcomes evaluated will be availability of a trauma cubicle, presence of a trauma team on patient arrival, time to first chest X-ray and inhospital mortality. PROGRESS: Ethical approval has been obtained from the All India Institute of Medical Sciences, New Delhi and site-specific approval granted by relevant trauma services. The trial has also been registered with the Monash University Human Research and Ethics Committee; Project number: CF16/1814 - 2016000929. Results will be fed back to prehospital and hospital clinicians via a series of reports and presentations. These will be used to facilitate discussions about service redesign and implementation. It is expected that evidence for improved outcomes will enable widespread adoption of this intervention among centres in all settings with less established tools for prehospital assessment and notification. TRIAL REGISTRATION NUMBER: NCT02877342; Pre-results. PMID- 28716786 TI - Online versus face-to-face pulmonary rehabilitation for patients with chronic obstructive pulmonary disease: randomised controlled trial. AB - OBJECTIVE: To obtain evidence whether the online pulmonary rehabilitation(PR) programme 'my-PR' is non-inferior to a conventional face-to-face PR in improving physical performance and symptom scores in patients with COPD. DESIGN: A two-arm parallel single-blind, randomised controlled trial. SETTING: The online arm carried out pulmonary rehabilitation in their own homes and the face to face arm in a local rehabilitation facility. PARTICIPANTS: 90 patients with a diagnosis of chronic obstructive pulmonary disease (COPD), modified Medical Research Council score of 2 or greater referred for pulmonary rehabilitation (PR), randomised in a 2:1 ratio to online (n=64) or face-to-face PR (n=26). Participants unable to use an internet-enabled device at home were excluded. MAIN OUTCOME MEASURES: Coprimary outcomes were 6 min walk distance test and the COPD assessment test (CAT) score at completion of the programme. INTERVENTIONS: A 6-week PR programme organised either as group sessions in a local rehabilitation facility, or online PR via log in and access to 'myPR'. RESULTS: The adjusted mean difference for the 6 min walk test (6MWT) between groups for the intention-to-treat (ITT) population was 23.8 m with the lower 95% CI well above the non-inferiority threshold of 40.5 m at -4.5 m with an upper 95% CI of +52.2 m. This result was consistent in the per-protocol (PP) population with a mean adjusted difference of 15 m (-13.7 to 43.8). The CAT score difference in the ITT was -1.0 in favour of the online intervention with the upper 95% CI well below the non-inferiority threshold of 1.8 at 0.86 and the lower 95% CI of -2.9. The PP analysis was consistent with the ITT. CONCLUSION: PR is an evidenced-based and guideline-mandated intervention for patients with COPD with functional limitation. A 6-week programme of online supported PR was non-inferior to a conventional model delivered in face-to-face sessions in terms of effects on 6MWT distance, and symptom scores and was safe and well tolerated. PMID- 28716787 TI - Can nurse teachers manage student incivility by guided democracy? A grounded theory study. AB - INTRODUCTION: Managing incivility in academic settings is among the basic concerns and challenges of most educational systems, including nursing education. Incivility management cannot be considered devoid of disruptive behaviors. However, incivility management is a complexphenomenon upon which few studies are conducted. OBJECTIVES: The present study aims at discovering teachers and students' experiences regarding incivility and developing an approach to manage nursing students' incivility. DESIGN: The present study was conducted based on the qualitative research design of the grounded theory methodology. SETTINGS: This study was conducted at schools of nursing in academic settings in Iran. PARTICIPANTS: Study participants in the present study include nurse teachers (N=20) and nursing students (N=9). METHOD: In-depth semi-structured interviews were conducted using theoretical and purposive sampling. Constant comparative analysis was used for data analysis. RESULTS: The results include four main categories; (1) deterioration of learning; (2) dominant individual and organisational culture; (3) guided democracy; and (4) movement toward professionalism. Guided democracy is recognised as the main basic psychosocial process for incivility management. CONCLUSIONS: Incivility management is pursued to help learners develop professional performance. As indicated by the results of the present study, guided democracy is an effective strategy for incivility management in nursing education. PMID- 28716788 TI - Long-term time trends in incidence, survival and mortality of lymphomas by subtype among adults in Manitoba, Canada: a population-based study using cancer registry data. AB - OBJECTIVE: To examine 30-year time trends in incidence, survival and mortality of lymphomas by subtype in Manitoba, Canada. METHODS: Lymphoma cases diagnosed between 1984 and 2013 were classified according to the 2008 WHO classification system for lymphoid neoplasms. Death data (1984-2014) were obtained from the Manitoba Vital Statistics Agency. To examine time trends in incidence and mortality, we used joinpoint regression to estimate annual percentage change and average annual percentage change. Age-period-cohort modelling was conducted to measure the effects of age, period and cohort on incidence and mortality time trends. We estimated age-specific and standardised 5-year relative survival and used Poisson regression model to test time trends in relative survival. RESULTS: Total Hodgkin lymphoma (HL) incidence in men and women was stable during the study period. Age-standardised total non-Hodgkin lymphoma (NHL) incidence increased by 4% annually until around 2000, and the trend varied by sex and NHL subtype. Total HL mortality continuously declined (by 2.5% annually in men and by 2.7% annually in women), while total NHL mortality increased (by 4.4% annually in men until 1998 and by 3.2% annually in women until 2001) and then declined (by 3.6% annually in men and by 2.5% annually in women). Age-standardised 5-year relative survival for HL improved from 72.6% in 1984-1993 to 85.8% in 2004-2013, and for NHL from 57.0% in 1984-1993 to 67.5% in 2004-2013. Survival improvement was also noted for NHL subtypes, although the extent varied, with the greatest improvement for follicular lymphoma (from 65.3% in 1984-1993 to 87.6% in 2004 2013). CONCLUSIONS: Time trends were generally consistent with those reported in other jurisdictions in total HL and NHL incidence, but were unique in incidence for HL and for NHL subtypes chronic/small lymphocytic leukaemia/lymphoma, diffuse large B cell lymphoma and follicular lymphoma. Survival improvements and mortality reductions were seen for HL and NHL in both sexes. PMID- 28716789 TI - Identification of the delivery of cognitive behavioural therapy for psychosis (CBTp) using a cross-sectional sample from electronic health records and open text information in a large UK-based mental health case register. AB - OBJECTIVE: Our primary objective was to identify cognitive behavioural therapy (CBT) delivery for people with psychosis (CBTp) using an automated method in a large electronic health record database. We also examined what proportion of service users with a diagnosis of psychosis were recorded as having received CBTp within their episode of care during defined time periods provided by early intervention or promoting recovery community services for people with psychosis, compared with published audits and whether demographic characteristics differentially predicted the receipt of CBTp. METHODS: Both free text using natural language processing (NLP) techniques and structured methods of identifying CBTp were combined and evaluated for positive predictive value (PPV) and sensitivity. Using inclusion criteria from two published audits, we identified anonymised cross-sectional samples of 2579 and 2308 service users respectively with a case note diagnosis of schizophrenia or psychosis for further analysis. RESULTS: The method achieved PPV of 95% and sensitivity of 96%. Using the National Audit of Schizophrenia 2 criteria, 34.6% service users were identified as ever having received at least one session and 26.4% at least two sessions of CBTp; these are higher percentages than previously reported by manual audit of a sample from the same trust that returned 20.0%. In the fully adjusted analysis, CBTp receipt was significantly (p<0.05) more likely in younger patients, in white and other when compared with black ethnic groups and patients with a diagnosis of other schizophrenia spectrum and schizoaffective disorder when compared with schizophrenia. CONCLUSIONS: The methods presented here provided a potential method for evaluating delivery of CBTp on a large scale, providing more scope for routine monitoring, cross-site comparisons and the promotion of equitable access. PMID- 28716790 TI - Human papillomavirus prevalence and genotype distribution among young women and men in Maputo city, Mozambique. AB - OBJECTIVES: Human papillomavirus (HPV) is a well-known cause of cervical cancer, the second most frequent cancer in female African populations. This study aimed at determining the prevalence of HPV infections and the genotype distribution in young adults aged 18-24, in Maputo city, Mozambique, and to assess the suitability of commercially available HPV vaccines. METHODS: This cross-sectional study was conducted between 2009 and 2011 at a youth clinic in Maputo Central Hospital. Cervical and urethral samples were obtained from 236 women and 176 men, respectively. Demographic and behavioural data were collected using structured questionnaires. HPV genotyping was performed for 35 different high, probably or possibly high-risk and low-risk HPV types using the CLART Human Papillomavirus 2. RESULTS: HPV prevalence was 168/412 (40.8%; 95% CI 36.0 to 45.5) and was significantly higher in women than in men (63.6%vs10.2%). HPV52 was the most frequent type found in women, followed by HPV35, -16,-53, -58,-6 and -51. In men, HPV51 ranked the highest, followed by HPV6, -11,-52, -59 and -70. HIV infection and sexual debut before 18 years of age were associated with multiple HPV infections (OR 3.03; 95% CI 1.49 to 6.25 and OR 6.03; 95% CI 1.73 to 21.02, respectively). Women had a significantly higher HPV infection prevalence than men (p<0.001). The 9-valent HPV vaccine would cover 36.8% of the high-risk genotypes circulating in women in this study, compared with 26.3% and 15.8% coverage by the bivalent and quadrivalent vaccines, respectively. CONCLUSION: This study confirmed the high burden of HPV infections in young women in Maputo city, Mozambique. The HPV prevalence was associated with high-risk sexual behaviour. Sex education and sexually transmitted infection prevention interventions should be intensified in Mozambique. Only a proportion of the high-risk HPV genotypes (37%) were covered by currently available vaccines. PMID- 28716792 TI - Influence of family history on the willingness of outpatients to undergo genetic testing for salt-sensitive hypertension: a cross-sectional study. AB - OBJECTIVES: It is unclear whether family medical history influences the willingness to undergo genetic testing. This study aimed to determine how family history affected the willingness to undergo genetic testing for salt-sensitive hypertension in patients with and without hypertension. DESIGN: Cross-sectional study using a self-administered questionnaire. SETTING: Six primary care clinics and hospitals in Japan. PARTICIPANTS: Consecutive 1705 outpatients aged >20 years, 578 of whom had hypertension. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome variable was the willingness to undergo genetic testing to determine the risk of salt-sensitive hypertension, and the secondary variables were age, sex, education level, family history and concerns about hypertension. Factors associated with a willingness to undergo genetic testing were evaluated in patients with and without hypertension using a logistic regression model. RESULTS: In the hypertension and non-hypertension groups, 323 (55.9%) and 509 patients (45.2%), respectively, were willing to undergo genetic testing. This willingness was related with a high level of education (adjusted OR (ad-OR): 1.81, 95% CI 1.12 to 2.93), family history of stroke (1.55, 1.04 to 2.31) and concerns about hypertension (2.04, 1.27 to 3.28) in the hypertension group, whereas in the non-hypertension group, it was influenced by education level (ad OR: 1.45, 95% CI 1.13 to 1.86), family history of hypertension (1.52, 1.17 to 1.98) and concerns about hypertension (2.03, 1.53 to 2.68). CONCLUSIONS: The influence of family history on the willingness to undergo genetic testing for risk of salt-sensitivity hypertension differed between participants with and without hypertension. In particular, participants without hypertension wished to know their likelihood of developing hypertension, whereas those with hypertension were interested to know the risk of stroke (a complication of hypertension). Family history could help better counsel patients about genetic testing on the basis of their medical history. PMID- 28716791 TI - Factors associated with nicotine dependence during methadone maintenance treatment: findings from a multisite survey in Vietnam. AB - OBJECTIVES: Smoking is associated with adverse health outcomes among drug users, including those in treatment. To date, however, there has been little evidence about smoking patterns among people receiving opioid-dependence treatment in developing countries. We examined self-reported nicotine dependence and associated factors in a large sample of opioid-dependent patients receiving methadone maintenance treatment (MMT) in northern Vietnam. SETTING: Five clinics in Hanoi (urban area) and Nam Dinh (rural area). PARTICIPANTS: Patients receiving MMT in the settings during the study period. PRIMARY AND SECONDARY OUTCOME MEASURES: We collected data about smoking patterns, levels of nicotine dependence and other covariates such as socioeconomic status, health status, alcohol use and drug use. The Fagerstrom test was used to measure nicotine dependence (FTND). Logistic regression and Tobit regression were employed to examine relationships between the smoking rate, nicotine dependence and potentially associated variables. RESULTS: Among 1016 drug users undergoing MMT (98.7% male), 87.2% were current smokers. The mean FTND score was 4.5 (SD 2.4). Longer duration of MMT (OR 0.98, 95% CI 0.96 to 0.99) and being HIV-positive (OR 0.46, 95% CI 0.24 to 0.88) were associated with lower likelihood of smoking. Being employed, older age at first drug injection and having long duration of MMT were inversely related with FTND scores. Higher age and continuing drug and alcohol use were significantly associated with higher FTND scores. CONCLUSION: Smoking prevalence is high among methadone maintenance drug users. Enhanced smoking cessation support should be integrated into MMT programmes in order to reduce risk factors for cigarette smoking and improve the health and well-being of people recovering from opiate dependence. PMID- 28716793 TI - The realities of partnership in person-centred care: a qualitative interview study with patients and professionals. AB - OBJECTIVE: Although conceptual definitions of person-centred care (PCC) vary, most models value the involvement of patients through patient-professional partnerships. While this may increase patients' sense of responsibility and control, research is needed to further understand how this partnership is created and perceived. This study aims to explore the realities of partnership as perceived by patients and health professionals in everyday PCC practice. DESIGN: Qualitative study employing a thematic analysis of semistructured interviews with professionals and patients. SETTING: Four internal medicine wards and two primary care centres in western Sweden. PARTICIPANTS: 16 health professionals based at hospital wards or primary care centres delivering person-centred care, and 20 patients admitted to one of the hospital wards. RESULTS: Our findings identified both informal and formal aspects of partnership. Informal aspects, emerging during the interaction between healthcare professionals and patients, without any prior guidelines or regulations, incorporated proximity and receptiveness of professionals and building a close connection and confidence. This epitomised a caring, respectful relationship congruent across accounts. Formal aspects, including structured ways of sustaining partnership were experienced differently. Professionals described collaborating with patients to encourage participation, capture personal goals, plan and document care. However, although patients felt listened to and informed, they were content to ask questions and felt less involved in care planning, documentation or exploring lifeworld goals. They commonly perceived participation as informed discussion and agreement, deferring to professional knowledge and expertise in the presence of an empathetic and trusting relationship. CONCLUSIONS: In our study, patients appear to value a process of human connectedness above and beyond formalised aspects of documenting agreed goals and care planning. PCC increases patients' confidence in professionals who are competent and able to make them feel safe and secure. Informal elements of partnership provide the conditions for communication and cooperation on which formal relations of partnership can be constructed. PMID- 28716794 TI - Incidence of live-attenuated influenza vaccine administration beyond expiry date in children and adolescents aged 2-17 years in the UK: a population-based cohort study. AB - OBJECTIVES: To estimate the proportion of live-attenuated influenza vaccine (LAIV) doses administered beyond expiry date in children and adolescents during influenza seasons 2013-2014 and 2014-2015 in the UK. DESIGN: This was a retrospective cohort study. Two cohorts of children and adolescents who received LAIV from 1 September 2013 to 31 March 2014 and from 1 September 2014 to 31 March 2015 and aged 2-17 years at time of LAIV administration were identified from the Clinical Practice Research Datalink (CPRD). SETTING: More than 500 primary care practices in the UK. POPULATION: Proportions of vaccine doses administered beyond expiry date were assessed among 47 396 and 67 099 LAIV recipients with a documented vaccine lot identifier in influenza seasons 2013-2014 and 2014-2015, respectively. INTERVENTION: None. MAIN OUTCOME MEASURE: Administrations of expired LAIV were ascertained by comparison of vaccination dates in CPRD records with expiration dates in AstraZeneca/MedImmune lot distribution data. RESULTS: Overall, 245 LAIV recipients, 80 in 2013-2014 and 165 in 2014-2015, received a dose after its expiration date, yielding proportion estimates of 1.7 per 1000 doses (95% CI 1.3 to 2.1) in season 2013-2014 and 2.5 per 1000 (95% CI 2.1 to 2.8) in season 2014-2015. This proportion increased above 1.0% after December during each season. Most (84% in influenza season 2013-2014 and 59% in influenza season 2014-2015) received an expired dose <30 days after its expiration date. The proportion was higher in London (relative risk 1.93 (95% CI 1.25 to 2.99)) and when the number of LAIV recipients registered in the practice was lower than the median number per practice (relative risk 2.69 (95% CI 1.99 to 3.62)). CONCLUSIONS: Administration of expired LAIV doses occurs infrequently. PMID- 28716795 TI - The magnitude of, and factors associated with, loss to follow-up among patients treated for sexually transmitted infections: a multilevel analysis. AB - OBJECTIVES: The loss to follow-up (LTFU) among patients attending care for sexually transmitted infections (STIs) in Sub-Saharan Africa is a major barrier to achieving the goals of the STI prevention and control programme. The objective of this study was to investigate individual- and facility-level factors associated with LTFU among patients treated for STIs in Ethiopia. METHODS: A prospective cohort study was conducted among patients attending care for STIs in selected facilities from January to June 2015 in the Tigray region of Ethiopia. LTFU was ascertained if a patient did not present in person to the same facility within 7 days of the initial contact. Multilevel logistic regression was used to identify factors associated with LTFU. RESULTS: Out of 1082 patients, 59.80% (647) were LTFU. The individual-level factors associated with LTFU included having multiple partners (adjusted OR (AOR) 2.89, 95% CI 1.74 to 4.80), being male (AOR 2.23, 95% CI 1.63 to 3.04), having poor knowledge about the means of STI transmission (AOR 2.08, 95% CI 1.53 to 2.82), having college level education (AOR 0.38, 95% CI 0.22 to 0.65), and low perceived stigma (AOR 0.60, 95% CI 0.43 to 0.82). High patient flow (AOR 3.06, 95% CI 1.30 to 7.18) and medium health index score (AOR 2.80, 95% CI 1.28 to 6.13) were facility-level factors associated with LTFU. CONCLUSIONS: Improving patient retention in STI follow-up care requires focused interventions targeting those who are more likely to be LTFU, particularly patients with multiple partners, male index cases and patients attending facilities with high patient flow. PMID- 28716796 TI - Clinical and cost-effectiveness of progressive exercise compared with best practice advice, with or without corticosteroid injection, for the treatment of rotator cuff disorders: protocol for a 2x2 factorial randomised controlled trial (the GRASP trial). AB - INTRODUCTION: Shoulder pain is very common, with around 70% of cases due to disorders of the rotator cuff. Despite widespread provision of physiotherapy, there is uncertainty about which type of exercise and delivery mechanisms are associated with best outcomes. There is also uncertainty around the long-term benefits and harms of corticosteroid injection therapy, which is often used in addition to physiotherapy. The Getting it Right: Addressing Shoulder Pain trial will assess the clinical and cost-effectiveness of individually tailored, progressive exercise compared with best practice advice, with or without corticosteroid injection, in adults with a rotator cuff disorder. METHODS AND ANALYSIS: We are conducting a large multicentre randomised controlled trial (2*2 factorial design). We will recruit adults >=18 years with a new episode of shoulder pain attributable to a rotator cuff disorder as per British Elbow and Shoulder Society guidelines, not currently receiving physiotherapy or being considered for surgery, from at least eight UK National Health Service primary care-based musculoskeletal and related physiotherapy services. Participants (n=704) will be randomised (centralised computer-generated 1:1:1:1 allocation ratio) to one of four interventions: (1) progressive exercise (<=6 physiotherapy sessions); (2) best practice advice (one physiotherapy session); (3) corticosteroid injection then progressive exercise (<=6 sessions) or (4) corticosteroid injection then best practice advice (one session). The primary outcome is the mean difference in Shoulder Pain and Disability Index (SPADI) total score at 12 months. Secondary outcomes are: pain and function SPADI subdomains; health-related quality of life (Five-Level version of the EuroQol EQ 5D-5L); sleep disturbance; return to activity; global impression of change; health resource use; out-of-pocket expenses; work disability. A parallel within trial economic evaluation will be conducted. The primary analysis will be intention to treat. ETHICS AND DISSEMINATION: Research Ethics Committee approval (REC: 16/SC/0508) has been obtained. Results of the main trial and secondary outcomes will be submitted for publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: ISRCTN16539266; EudraCT number: 2016-002991-28. PMID- 28716798 TI - Corrections: Systematic review of systematic reviews of non-pharmacological interventions to treat behavioural disturbances in older patients with dementia. The SENATOR-OnTop series. PMID- 28716799 TI - An assessment of the public healthcare infrastructure deficiency in a district of Bihar state of India. PMID- 28716797 TI - A pragmatic, phase III, multisite, double-blind, placebo-controlled, parallel arm, dose increment randomised trial of regular, low-dose extended-release morphine for chronic breathlessness: Breathlessness, Exertion And Morphine Sulfate (BEAMS) study protocol. AB - INTRODUCTION: Chronic breathlessness is highly prevalent and distressing to patients and families. No medication is registered for its symptomatic reduction. The strongest evidence is for regular, low-dose, extended- release (ER) oral morphine. A recent large phase III study suggests the subgroup most likely to benefit have chronic obstructive pulmonary disease (COPD) and modified Medical Research Council breathlessness scores of 3 or 4. This protocol is for an adequately powered, parallel-arm, placebo-controlled, multisite, factorial, block randomised study evaluating regular ER morphine for chronic breathlessness in people with COPD. METHODS AND ANALYSIS: The primary question is what effect regular ER morphine has on worst breathlessness, measured daily on a 0-10 numerical rating scale. Uniquely, the coprimary outcome will use a FitBit to measure habitual physical activity. Secondary questions include safety and, whether upward titration after initial benefit delivers greater net symptom reduction. Substudies include longitudinal driving simulation, sleep, caregiver, health economic and pharmacogenetic studies. Seventeen centres will recruit 171 participants from respiratory and palliative care. The study has five phases including three randomisation phases to increasing doses of ER morphine. All participants will receive placebo or active laxatives as appropriate. Appropriate statistical analysis of primary and secondary outcomes will be used. ETHICS AND DISSEMINATION: Ethics approval has been obtained. Results of the study will be submitted for publication in peer-reviewed journals, findings presented at relevant conferences and potentially used to inform registration of ER morphine for chronic breathlessness. TRIAL REGISTRATION NUMBER: NCT02720822; Pre-results. PMID- 28716800 TI - Relationship between Vascular Resistance and Sympathetic Nerve Fiber Density in Arterial Vessels in Children With Sleep Disordered Breathing. AB - BACKGROUND: Sleep disordered breathing in children is associated with increased blood flow velocity and sympathetic overactivity. Sympathetic overactivity results in peripheral vasoconstriction and reduced systemic vascular compliance, which increases blood flow velocity during systole. Augmented blood flow velocity is recognized to promote vascular remodeling. Importantly, increased vascular sympathetic nerve fiber density and innervation in early life plays a key role in the development of early-onset hypertension in animal models. Examination of sympathetic nerve fiber density of the tonsillar arteries in children undergoing adenotonsillectomy for Sleep disordered breathing will address this question in humans. METHODS AND RESULTS: Thirteen children scheduled for adenotonsillectomy to treat sleep disordered breathing underwent pupillometry, polysomnography, flow mediated dilation, resting brachial artery blood flow velocity (velocity time integral), and platelet aggregation. The dorsal lingual artery (tonsil) was stained and immunofluorescence techniques used to determine sympathetic nerve fiber density. Sympathetic nerve fiber density was correlated with increased resting velocity time integral (r=0.63; P<0.05) and a lower Neuronal Pupillary Index (r=-0.71, P<0.01), as well as a slower mean pupillary constriction velocity (mean, r=-0.64; P<0.05). A faster resting velocity time integral was associated with a slower peak pupillary constriction velocity (r=-0.77; P<0.01) and higher platelet aggregation to collagen antigen (r=0.64; P<0.05). Slower mean and peak pupillary constriction velocity were associated with higher platelet aggregation scores (P<0.05; P<0.01, respectively). CONCLUSIONS: These results indicate that sympathetic activity is associated with change in both the function and structure of systemic vasculature in children with sleep disordered breathing. PMID- 28716802 TI - Drug policy isn't working, medical leaders and lawmakers agree. PMID- 28716801 TI - Diabetes Mellitus, Microalbuminuria, and Subclinical Cardiac Disease: Identification and Monitoring of Individuals at Risk of Heart Failure. AB - BACKGROUND: Patients with type 2 diabetes mellitus and elevated urinary albumin:creatinine ratio (ACR) have increased risk of heart failure. We hypothesized this was because of cardiac tissue changes rather than silent coronary artery disease. METHODS AND RESULTS: In a case-controlled observational study 130 subjects including 50 ACR+ve diabetes mellitus patients with persistent microalbuminuria (ACR >2.5 mg/mol in males and >3.5 mg/mol in females, >=2 measurements, no previous renin-angiotensin-aldosterone therapy, 50 ACR-ve diabetes mellitus patients and 30 controls underwent cardiovascular magnetic resonance for investigation of myocardial fibrosis, ischemia and infarction, and echocardiography. Thirty ACR+ve patients underwent further testing after 1-year treatment with renin-angiotensin-aldosterone blockade. Cardiac extracellular volume fraction, a measure of diffuse fibrosis, was higher in diabetes mellitus patients than controls (26.1+/-3.4% and 23.3+/-3.0% P=0.0002) and in ACR+ve than ACR-ve diabetes mellitus patients (27.2+/-4.1% versus 25.1+/-2.9%, P=0.004). ACR+ve patients also had lower E' measured by echocardiography (8.2+/-1.9 cm/s versus 8.9+/-1.9 cm/s, P=0.04) and elevated high-sensitivity cardiac troponin T 18% versus 4% >=14 ng/L (P=0.05). Rate of silent myocardial ischemia or infarction were not influenced by ACR status. Renin-angiotensin-aldosterone blockade was associated with increased left ventricular ejection fraction (59.3+/ 7.8 to 61.5+/-8.7%, P=0.03) and decreased extracellular volume fraction (26.5+/ 3.6 to 25.2+/-3.1, P=0.01) but no changes in diastolic function or high sensitivity cardiac troponin T levels. CONCLUSIONS: Asymptomatic diabetes mellitus patients with persistent microalbuminuria have markers of diffuse cardiac fibrosis including elevated extracellular volume fraction, high sensitivity cardiac troponin T, and diastolic dysfunction, which may in part be reversible by renin-angiotensin-aldosterone blockade. Increased risk in these patients may be mediated by subclinical changes in tissue structure and function. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01970319. PMID- 28716803 TI - Psychiatric Boarding in the Pediatric Inpatient Medical Setting: A Retrospective Analysis. AB - BACKGROUND AND OBJECTIVES: Psychiatric concerns are a common presenting problem for pediatric providers across many settings, particularly on inpatient medical services. The volume of youth requiring intensive psychiatric treatment outnumbers the availability of psychiatric placements, and as a result many youth must board on pediatric medical units while awaiting placement. As the phenomenon of boarding in the inpatient pediatric setting increases, it is important to understand trends in boarding volume and characteristics of pediatric psychiatric boarders (PBs) and understand the supports they receive while boarding. METHODS: A retrospective chart review of patients admitted as PBs to a medical inpatient unit at a large northeastern US pediatric hospital during 2013. RESULTS: Four hundred thirty-seven PBs were admitted to the medical service from January to December 2013, representing a more than 50% increase from PB admissions in 2011 and 2012. Most PBs were admitted for suicidal attempt and/or ideation. Average length of boarding was 3.11 +/- 3.34 days. PBs received a wide range of mental health supports throughout their admissions. PBs demonstrated modest but statistically significant clinical improvements over the course of their stay, with only a small proportion demonstrating clinical deterioration. CONCLUSIONS: Psychiatric boarding presents many challenges for families, providers, and the health care system, and PBs have complex psychiatric histories and needs. However, boarding may offer a valuable opportunity for psychiatric intervention and stabilization among psychiatrically vulnerable youth. PMID- 28716806 TI - Different strokes for different synaptotagmins. AB - JGP study shows how synaptotagmins 1 and 7 affect chromaffin cell granule fusion. PMID- 28716807 TI - Antenatal corticosteroid administration between 24 hours and 7 days before extremely preterm delivery is associated with the lowest rate of mortality. PMID- 28716808 TI - Second trimester levothyroxine treatment for subclinical hypothyroidism or hypothyroxinaemia of pregnancy does not improve cognitive outcomes of children. PMID- 28716805 TI - Sensing of viral and endogenous RNA by ZBP1/DAI induces necroptosis. AB - Nucleic acids are potent triggers for innate immunity. Double-stranded DNA and RNA adopt different helical conformations, including the unusual Z-conformation. Z-DNA/RNA is recognised by Z-binding domains (ZBDs), which are present in proteins implicated in antiviral immunity. These include ZBP1 (also known as DAI or DLM-1), which induces necroptosis, an inflammatory form of cell death. Using reconstitution and knock-in models, we report that mutation of key amino acids involved in Z-DNA/RNA binding in ZBP1's ZBDs prevented necroptosis upon infection with mouse cytomegalovirus. Induction of cell death was cell autonomous and required RNA synthesis but not viral DNA replication. Accordingly, ZBP1 directly bound to RNA via its ZBDs. Intact ZBP1-ZBDs were also required for necroptosis triggered by ectopic expression of ZBP1 and caspase blockade, and ZBP1 cross linked to endogenous RNA These observations show that Z-RNA may constitute a molecular pattern that induces inflammatory cell death upon sensing by ZBP1. PMID- 28716804 TI - Type I interferon is required for T helper (Th) 2 induction by dendritic cells. AB - Type 2 inflammation is a defining feature of infection with parasitic worms (helminths), as well as being responsible for widespread suffering in allergies. However, the precise mechanisms involved in T helper (Th) 2 polarization by dendritic cells (DCs) are currently unclear. We have identified a previously unrecognized role for type I IFN (IFN-I) in enabling this process. An IFN-I signature was evident in DCs responding to the helminth Schistosoma mansoni or the allergen house dust mite (HDM). Further, IFN-I signaling was required for optimal DC phenotypic activation in response to helminth antigen (Ag), and efficient migration to, and localization with, T cells in the draining lymph node (dLN). Importantly, DCs generated from Ifnar1-/- mice were incapable of initiating Th2 responses in vivo These data demonstrate for the first time that the influence of IFN-I is not limited to antiviral or bacterial settings but also has a central role to play in DC initiation of Th2 responses. PMID- 28716809 TI - Determining clinical decision thresholds for HIV-positive patients suspected of having tuberculosis. AB - Clinical decision thresholds may aid the evaluation of diagnostic tests but have rarely been determined for tuberculosis (TB). We presented clinicians with six web-based clinical scenarios, describing patients with HIV and possible TB at various sites and with a range of clinical stability. The probability of disease was varied randomly and clinicians asked to make treatment decisions; threshold curves and therapeutic thresholds were calculated. Test and treatment thresholds were calculated using Bayes theorem and the diagnostic accuracy of Xpert MTB/RIF. We received 165 replies to our survey. Therapeutic thresholds vary depending on the clinical stability and site of suspected disease. For inpatients, it ranges from 3.4% in unstable to 79.6% in stable patients. For TB meningitis, it ranges from 0% in unstable to 51.4% in stable patients and for pulmonary TB in outpatients it ranges from 29.1% in unstable to 74.5% in the stable patients. Test and treatment thresholds vary in a similar way with test thresholds ranging from 0 in unstable patients with suspected meningitis to 8.2% for stable inpatients. Treatment thresholds vary from 0 for unstable patients with suspected meningitis to 97% for stable inpatients. Therapeutic thresholds for TB can be determined by presenting clinicians with patient scenarios with random probabilities of disease and can be used to calculate test and treatment thresholds using Bayes theorem. Thresholds are lower when patients are more clinically unstable and when the implications of inappropriately withholding therapy are more serious. These results can be used to improve use and evaluation of diagnostic tests. PMID- 28716810 TI - Clinicians should assess the benefits and risks of using bezlotoxumab for reducing the risk of recurrent Clostridium difficile infection. PMID- 28716811 TI - The Who, What, and Where of Plant Polyprenol Biosynthesis Point to Thylakoid Membranes and Photosynthetic Performance. PMID- 28716812 TI - Crossover Guard: MEICA1 Prevents Meiotic Mishaps. PMID- 28716813 TI - Inhibition of Heparanase in Pediatric Brain Tumor Cells Attenuates their Proliferation, Invasive Capacity, and In Vivo Tumor Growth. AB - Curative therapy for medulloblastoma and other pediatric embryonal brain tumors has improved, but the outcome still remains poor and current treatment causes long-term complications. Malignant brain tumors infiltrate the healthy brain tissue and, thus despite resection, cells that have already migrated cause rapid tumor regrowth. Heparan sulfate proteoglycans (HSPG), major components of the extracellular matrix (ECM), modulate the activities of a variety of proteins. The major enzyme that degrades HS, heparanase (HPSE), is an important regulator of the ECM. Here, we report that the levels of HPSE in pediatric brain tumors are higher than in healthy brain tissue and that treatment of pediatric brain tumor cells with HPSE stimulated their growth. In addition, the latent, 65 kDa form of HPSE (that requires intracellular enzymatic processing for activation) enhanced cell viability and rapidly activated the ERK and AKT signaling pathways, before enzymatically active HPSE was detected. The HPSE inhibitor PG545 efficiently killed pediatric brain tumor cells, but not normal human astrocytes, and this compound also reduced tumor cell invasion in vitro and potently reduced the size of flank tumors in vivo Our findings indicate that HPSE in malignant brain tumors affects both the tumor cells themselves and their ECM. In conclusion, HPSE plays a substantial role in childhood brain tumors, by contributing to tumor aggressiveness and thereby represents a potential therapeutic target. Mol Cancer Ther; 16(8); 1705-16. (c)2017 AACR. PMID- 28716814 TI - Potency-matched Dual Cytokine-Antibody Fusion Proteins for Cancer Therapy. AB - A novel biopharmaceutical, consisting of the F8 mAb (specific to a splice isoform of fibronectin) simultaneously fused to both TNF and IL2, was found to react with the majority of solid tumors and hematologic malignancies in mouse and man, but not with healthy adult tissues. The product selectively localized to neoplastic lesions in vivo, as evidenced by quantitative biodistribution studies using radioiodinated protein preparations. When the potency of the cytokine payloads was matched by a single-point mutation, the resulting fusion protein (IL2-F8 TNFmut) eradicated soft-tissue sarcomas in immunocompetent mice, which did not respond to individual antibody-cytokine fusion proteins or by standard doxorubicin treatment. Durable complete responses were also observed in mice bearing CT26, C1498, and F9 tumors. The simultaneous delivery of multiple proinflammatory payloads to the cancer site conferred protective immunity against subsequent tumor challenges. A fully human homolog of IL2-F8-TNFmut, which retained selectivity similar to its murine counterpart when tested on human material, may open new clinical applications for the immunotherapy of cancer. Mol Cancer Ther; 16(11); 2442-51. (c)2017 AACR. PMID- 28716815 TI - Exposure-Response Analyses of Ramucirumab from Two Randomized, Phase III Trials of Second-line Treatment for Advanced Gastric or Gastroesophageal Junction Cancer. AB - Ramucirumab is an IgG1 monoclonal antibody specific for the vascular endothelial growth factor receptor-2. Ramucirumab, 8 mg/kg every 2 weeks, administered as monotherapy (REGARD) or in combination with paclitaxel (RAINBOW), was safe and effective in patients with previously treated advanced gastric or gastroesophageal junction (GEJ) cancer. We evaluated exposure-efficacy and exposure-safety relationships of ramucirumab from two randomized, placebo controlled phase III trials. Sparse pharmacokinetic samples were collected, and a population pharmacokinetic analysis was conducted to predict ramucirumab minimum trough concentration at steady state (Cmin,ss). Kaplan-Meier methods and Cox proportional hazards models were used to evaluate the ramucirumab exposure (Cmin,ss)-efficacy relationship to overall survival (OS) and progression-free survival (PFS). Logistic regression analyses were used to evaluate exposure safety relationships. Analyses included 321 ramucirumab + paclitaxel and 335 placebo + paclitaxel patients from RAINBOW and 72 ramucirumab and 35 placebo patients from REGARD. Exposure-efficacy analysis showed ramucirumab Cmin,ss was a significant predictor of OS and PFS in both trials. Higher ramucirumab exposure was associated with longer OS and PFS. In RAINBOW, grade >=3 hypertension, leukopenia, and neutropenia, but not febrile neutropenia, significantly correlated with Cmin,ss, with increased exposure leading to increased incidence. Exploratory exposure-response analyses suggest a positive relationship between efficacy and ramucirumab exposure with manageable toxicities at exposures generated from a dose of 8 mg/kg ramucirumab given every 2 weeks for patients with advanced gastric/GEJ cancer. These findings suggest an opportunity to further optimize benefit versus risk profiles of ramucirumab treatment in patients with gastric/GEJ cancer. Mol Cancer Ther; 16(10); 2215-22. (c)2017 AACR. PMID- 28716816 TI - Sphingosine-1-Phosphate Receptor-1 Promotes Environment-Mediated and Acquired Chemoresistance. AB - Drug resistance is a major barrier for the development of effective and durable cancer therapies. Overcoming this challenge requires further defining the cellular and molecular mechanisms underlying drug resistance, both acquired and environment-mediated drug resistance (EMDR). Here, using neuroblastoma (NB), a childhood cancer with high incidence of recurrence due to resistance to chemotherapy, as a model we show that human bone marrow-mesenchymal stromal cells induce tumor expression of sphingosine-1-phosphate receptor-1 (S1PR1), leading to their resistance to chemotherapy. Targeting S1PR1 by shRNA markedly enhances etoposide-induced apoptosis in NB cells and abrogates EMDR, while overexpression of S1PR1 significantly protects NB cells from multidrug-induced apoptosis via activating JAK-STAT3 signaling. Elevated S1PR1 expression and STAT3 activation are also observed in human NB cells with acquired resistance to etoposide. We show in vitro and in human NB xenograft models that treatment with FTY720, an FDA approved drug and antagonist of S1PR1, dramatically sensitizes drug-resistant cells to etoposide. In summary, we identify S1PR1 as a critical target for reducing both EMDR and acquired chemoresistance in NB. Mol Cancer Ther; 16(11); 2516-27. (c)2017 AACR. PMID- 28716818 TI - Intimal hyperplasia induced by vascular intervention causes lipoprotein retention and accelerated atherosclerosis. AB - Accelerated atherosclerosis diminishes the long term patency of vascular interventions, such as percutaneous coronary intervention and implantation of saphenous vein grafts. However, the cause of this accelerated atherosclerosis is unclear. In this study, we tested the hypothesis that intimal hyperplasia formed following vascular intervention promotes retention of atherogenic lipoproteins. Intimal hyperplasia was surgically induced in the mouse common carotid artery. The surgery was combined with different mouse models of hypercholesterolemia to obtain different cholesterol levels and to control the onsets of hypercholesterolemia. Three weeks after surgery, samples were immunostained for apoB lipoproteins, smooth muscle cells and leukocytes. Already at mild hypercholesterolemia (193 mg/dL), pronounced apoB lipoprotein retention was found in the extracellular matrix in both intimal hyperplasia and the injured underlying media. In contrast, minimal retention was detected in the uninjured proximal region of the same vessel, or in vessels from mice with normal cholesterol levels (81 mg/dL). Induction of aggravated hypercholesterolemia 3 weeks after surgery, when a mature intimal hyperplasia had been formed, caused a very rapid development of atherosclerotic lesions. Mechanistically, we show that lipoprotein retention was almost exclusively dependent on electrostatic interactions to proteoglycan glycosaminoglycans, and the lipoprotein retention to intimal hyperplasia could be inhibited in vivo using glycosaminoglycan-binding antibodies. Thus, formation of intimal hyperplasia following vascular intervention makes the vessel wall highly susceptible for lipoprotein retention and accelerated atherosclerosis. The increased lipoprotein retention in intimal hyperplasia can be targeted by blocking the interaction between apoB lipoproteins and glycosaminoglycans in the extracellular matrix. PMID- 28716817 TI - PI3Kgamma/delta and NOTCH1 Cross-Regulate Pathways That Define the T-cell Acute Lymphoblastic Leukemia Disease Signature. AB - PI3K/AKT and NOTCH1 signaling pathways are frequently dysregulated in T-cell acute lymphoblastic leukemias (T-ALL). Although we have shown that the combined activities of the class I PI3K isoforms p110gamma and p110delta play a major role in the development and progression of PTEN-null T-ALL, it has yet to be determined whether their contribution to leukemogenic programing is unique from that associated with NOTCH1 activation. Using an Lmo2-driven mouse model of T-ALL in which both the PI3K/AKT and NOTCH1 pathways are aberrantly upregulated, we now demonstrate that the combined activities of PI3Kgamma/delta have both overlapping and distinct roles from NOTCH1 in generating T-ALL disease signature and in promoting tumor cell growth. Treatment of diseased animals with either a dual PI3Kgamma/delta or a gamma-secretase inhibitor reduced tumor burden, prolonged survival, and induced proapoptotic pathways. Consistent with their similar biological effects, both inhibitors downregulated genes involved in cMYC dependent metabolism in gene set enrichment analyses. Furthermore, overexpression of cMYC in mice or T-ALL cell lines conferred resistance to both inhibitors, suggesting a point of pathway convergence. Of note, interrogation of transcriptional regulators and analysis of mitochondrial function showed that PI3Kgamma/delta activity played a greater role in supporting the disease signature and critical bioenergetic pathways. Results provide insight into the interrelationship between T-ALL oncogenic networks and the therapeutic efficacy of dual PI3Kgamma/delta inhibition in the context of NOTCH1 and cMYC signaling. Mol Cancer Ther; 16(10); 2069-82. (c)2017 AACR. PMID- 28716819 TI - Effect of type 2 diabetes, surgical incision, and volatile anesthesia on hemodynamics in the rat. AB - Diabetic patients have increased cardiac complications during surgery, possibly due to impaired autonomic regulation. Anesthesia lowers blood pressure and heart rate (HR), whereas surgical intervention has opposing effects. The interaction of anesthesia and surgical intervention on hemodynamics in diabetes is unknown, despite being a potential perioperative risk factor. We aimed to determine the effect of diabetes on the integrative interaction between hemodynamics, anesthesia, and surgical incision. Zucker type 2 diabetic rats (DM) and their nondiabetic littermates (ND) were implanted with an intravenous port for drug delivery, and a radiotelemeter to measure mean arterial blood pressure (MAP) and derive HR (total n = 50). Hemodynamic pharmacological responses were assessed under conscious, isoflurane anesthesia (~2-2.5%), and anesthesia-surgical conditions; the latter performed as a laparotomy. MAP was not different between groups under conscious conditions (ND 120 +/- 6 vs. DM 131 +/- 4 mmHg, P > 0.05). Anesthesia reduced MAP, but not differently in DM (ND -30 +/- 6 vs. DM -38 +/- 4 DeltammHg, P > 0.05). Despite adequate anesthesia, surgical incision increased MAP, which tended to be less in DM (ND +21 +/- 4 vs. DM +13 +/- 2 DeltammHg, P = 0.052). Anesthesia disrupted central baroreflex HR responses to sympathetic activation (sodium nitroprusside 10 MUg.kg-1, ND conscious 83 +/- 13 vs. anesthetized 16 +/- 5 Deltabpm; P < 0.05) or to sympathetic withdrawal (phenylephrine 10 MUg.kg-1, ND conscious -168 +/- 37 vs. anesthetized -20 +/- 6 Deltabpm; P < 0.05) with no additional changes observed after surgical incision or during diabetes. During perioperative conditions, type 2 diabetes did not impact on short-term hemodynamic regulation. Anesthesia had the largest hemodynamic impact, whereas surgical effects were limited to modulation of baseline blood pressure. PMID- 28716820 TI - Complex object motion represented by context-dependent correlated activity of visual interneurones. AB - Accurate and adaptive encoding of complex, dynamic visual information is critical for the survival of many animals. Studies across a range of taxa have investigated behavioral and neuronal responses to objects that represent a threat, such as a looming object approaching along a direct collision course. By investigating neural mechanisms of avoidance behaviors through recording multineuronal activity, it is possible to better understand how complex visual information is represented in circuits that ultimately drive behaviors. We used multichannel electrodes to record from the well-studied locust nervous system to explore how object motion is reflected in activity of correlated neural activity. We presented locusts (Locusta migratoria) with objects that moved along one of 11 unique trajectories and recorded from descending interneurons within the ventral nerve cord. Spike sorting resulted in 405 discriminated units across 20 locusts and we found that 75% of the units responded to some form of object motion. Dimensionality reduction through principal component (PCA) and dynamic factor (DFA) analyses revealed population vector responses within individuals and common firing trends across the pool of discriminated units, respectively. Population vector composition (PCA) varied with the stimulus and common trends (DFA) showed unique tuning related to changes in the visual size and trajectory of the object through time. These findings demonstrate that this well-described collision detection system is more complex than previously envisioned and will drive future experiments to explore fundamental principles of how visual information is processed through context-dependent dynamic ensembles of neurons to initiate and control complex behavior. PMID- 28716821 TI - Abnormalities in alternative splicing in diabetes: therapeutic targets. AB - Diabetes mellitus (DM) is a non-communicable, metabolic disorder that affects 416 million individuals worldwide. Type 2 diabetes contributes to a vast 85-90% of the diabetes incidences while 10-15% of patients suffer from type 1 diabetes. These two predominant forms of DM cause a significant loss of functional pancreatic beta-cell mass causing different degrees of insulin deficiency, most likely, due to increased beta-cell apoptosis. Treatment options involve the use of insulin sensitisers, alpha-glucosidase inhibitors, and beta-cell secretagogues which are often expensive, limited in efficacy and carry detrimental adverse effects. Cost-effective options for treatment exists in the form of herbal drugs, however, scientific validations of these widely used medicinal plants are still underway. Alternative splicing (AS) is a co-ordinated post-transcriptional process in which a single gene generates multiple mRNA transcripts which results in increased amounts of functionally different protein isoforms and in some cases aberrant splicing leads to metabolic disease. In this review, we explore the association of AS with metabolic alterations in DM and the biological significance of the abnormal splicing of some pathogenic diabetes-related genes. An understanding of the molecular mechanism behind abnormally spliced transcripts will aid in the development of new diagnostic, prognostic and therapeutic tools. PMID- 28716822 TI - DOCK2 deficiency mitigates HFD-induced obesity by reducing adipose tissue inflammation and increasing energy expenditure. AB - Obesity is the major risk factor for type 2 diabetes, cardiovascular disorders, and many other diseases. Adipose tissue inflammation is frequently associated with obesity and contributes to the morbidity and mortality. Dedicator of cytokinesis 2 (DOCK2) is involved in several inflammatory diseases, but its role in obesity remains unknown. To explore the function of DOCK2 in obesity and insulin resistance, WT and DOCK2-deficient (DOCK2-/-) mice were given chow or high-fat diet (HFD) for 12 weeks followed by metabolic, biochemical, and histologic analyses. DOCK2 was robustly induced in adipose tissues of WT mice given HFD. DOCK2-/- mice with HFD showed decreased body weight gain and improved metabolic homeostasis and insulin resistance compared with WT mice. DOCK2 deficiency also attenuated adipose tissue and systemic inflammation accompanied by reduced macrophage infiltration. Moreover, DOCK2-/- mice exhibited increased expression of metabolic genes in adipose tissues with greater energy expenditure. Mechanistically, DOCK2 appeared to regulate brown adipocyte differentiation because increased preadipocyte differentiation to brown adipocytes in interscapular and inguinal fat was observed in DOCK2-/- mice, as compared with WT. These data indicated that DOCK2 deficiency protects mice from HFD-induced obesity, at least in part, by stimulating brown adipocyte differentiation. Therefore, targeting DOCK2 may be a potential therapeutic strategy for treating obesity-associated diseases. PMID- 28716823 TI - Father Loss and Child Telomere Length. AB - BACKGROUND AND OBJECTIVES: Father loss during childhood has negative health and behavioral consequences, but the biological consequences are unknown. Our goal was to examine how father loss (because of separation and/or divorce, death, or incarceration) is associated with cellular function as estimated by telomere length. METHODS: Data come from the 9-year follow-up of the Fragile Families and Child Wellbeing Study, a birth cohort study of children in 20 large American cities (N = 2420). Principal measures are as follows: salivary telomere length (sTL), mother reports of father loss, and polymorphisms in genes related to serotonergic and dopaminergic signaling. RESULTS: At 9 years of age, children with father loss have significantly shorter telomeres (14% reduction). Paternal death has the largest association (16%), followed by incarceration (10%), and separation and/or divorce (6%). Changes in income partially mediate these associations (95% mediation for separation and/or divorce, 30% for incarceration, and 25% for death). Effects are 40% greater for boys and 90% greater for children with the most reactive alleles of the serotonin transporter genes when compared with those with the least reactive alleles. No differences were found by age at father loss or a child's race/ethnicity. CONCLUSIONS: Father loss has a significant association with children's sTL, with the death of a father showing the largest effect. Income loss explains most of the association between child sTL and separation and/or divorce but much less of the association with incarceration or death. This underscores the important role of fathers in the care and development of children and supplements evidence of the strong negative effects of parental incarceration. PMID- 28716824 TI - Secular Trend of Age at Menarche in Chinese Adolescents Born From 1973 to 2004. AB - OBJECTIVES: To estimate secular trend and factors influencing the age at menarche for Chinese girls born from 1973 to 2004. METHODS: Data were collected from the China Health and Nutrition Survey, a prospective open cohort and an ongoing nationwide health and nutrition survey, consisting of 3199 apparently healthy Chinese girls aged 6 to 18 years at entry from 1991 to 2011. Average age at menarche and its 95% confidence interval were estimated by weighted means of Kaplan-Meier survival analysis. Cox proportional hazard models were applied to identify the independent predictive factors of age at menarche. RESULTS: The age at menarche declined from 14.25 in Chinese girls born before 1976 to 12.60 in girls born after 2000, with an estimated decline of 0.51 years per decade (P < .001). The downward trend of age at menarche for rural girls was greater than for urban girls (0.62 vs 0.35 years per decade; P < .001). Girls living in urban areas, living in central areas, with high BMI, and with high-energy diets had a high risk of early menarche, whereas girls living on the east coast who had high carbohydrate diets had a low risk of early menarche. CONCLUSIONS: The authors of this study found a continuous downward secular trend of age at menarche for Chinese girls in both urban and rural areas born from 1973 to 2004. Among all variables, urban residency, BMI, and energy intake are negatively associated with age at menarche, whereas carbohydrate intake is positively associated with age at menarche. PMID- 28716825 TI - Efficiency and Safety of CRAC Inhibitors in Human Rheumatoid Arthritis Xenograft Models. AB - Store-operated Ca2+ release-activated Ca2+ (CRAC) channels are involved in the pathogenesis of rheumatoid arthritis (RA) and have been studied as therapeutic targets in the management of RA. We investigated the efficacy and safety of CRAC inhibitors, including a neutralizing Ab (hCRACM1-IgG) and YM-58483, in the treatment of RA. Patient-derived T cell and B cell activity was suppressed by hCRACM1-IgG as well as YM-58483. Systemically constant, s.c. infused CRAC inhibitors showed anti-inflammatory activity in a human-NOD/SCID xenograft RA model as well as protective effects against the destruction of cartilage and bone. hCRACM1-IgG appeared to be safe for systemic application, whereas YM-58483 showed hepatic and renal toxicity in xenograft mice. Treatment with both CRAC inhibitors also caused hyperglycemia in xenograft mice. These results indicate the potential of hCRACM1-IgG and YM-58483 as anti-immunological agents for the treatment of RA. However, some safety issues should be addressed and application methods should be optimized prior to their clinical use. PMID- 28716826 TI - IL-10-Producing Infliximab-Specific T Cells Regulate the Antidrug T Cell Response in Exposed Patients. AB - Infliximab (IFX) is a chimeric mAb that can lead to the appearance of anti-drug Abs. Recent research has identified the presence of circulating IFX-specific T cells in treated patients. The aim of the study was to analyze the functional characteristics of IFX-specific T cells, in particular their capability to produce biologically active regulatory cytokines. Drug-stimulated PBMCs or coculture systems were used to detect memory T cells in treated patients. The cytokines produced by IFX-specific T cells, T cell lines, and T cell clones were evaluated at the mRNA and protein levels. Drug infusion induced an increase in IL 10 serum levels in vivo, whereas other cytokines were unchanged. IL-10 mRNA was higher in IFX-stimulated PBMCs from treated patients compared with untreated patients. When analyzed longitudinally, an early IL-10 mRNA expression was observed. HLA class II-restricted IL-10 production by drug-specific T cells from exposed patients was observed in different experimental settings, such as a coculture system, sorted CD154+ T cells, IFX peptide-stimulated PBMCs, and IFX specific T cell clones. Finally, IL-10-producing drug-specific T cell clones downregulated the response of autologous effector T cells to IFX. Overall, these findings identify IFX-specific T cells as a source of biologically active IL-10 and suggest interference by IL-10-producing cells in the detection of drug specific T cells. PMID- 28716827 TI - Galectin-1-Driven Tolerogenic Programs Aggravate Yersinia enterocolitica Infection by Repressing Antibacterial Immunity. AB - Yersinia enterocolitica is an enteropathogenic bacterium that causes gastrointestinal disorders, as well as extraintestinal manifestations. To subvert the host's immune response, Y. enterocolitica uses a type III secretion system consisting of an injectisome and effector proteins, called Yersinia outer proteins (Yops), that modulate activation, signaling, and survival of immune cells. In this article, we show that galectin-1 (Gal-1), an immunoregulatory lectin widely expressed in mucosal tissues, contributes to Y. enterocolitica pathogenicity by undermining protective antibacterial responses. We found higher expression of Gal-1 in the spleen and Peyer's patches of mice infected orogastrically with Y. enterocolitica serotype O:8 compared with noninfected hosts. This effect was prevented when mice were infected with Y. enterocolitica lacking YopP or YopH, two critical effectors involved in bacterial immune evasion. Consistent with a regulatory role for this lectin during Y. enterocolitica pathogenesis, mice lacking Gal-1 showed increased weight and survival, lower bacterial load, and attenuated intestinal pathology compared with wild-type mice. These protective effects involved modulation of NF-kappaB activation, TNF production, and NO synthesis in mucosal tissue and macrophages, as well as systemic dysregulation of IL-17 and IFN-gamma responses. In vivo neutralization of these proinflammatory cytokines impaired bacterial clearance and eliminated host protection conferred by Gal-1 deficiency. Finally, supplementation of recombinant Gal-1 in mice lacking Gal-1 or treatment of wild type mice with a neutralizing anti-Gal-1 mAb confirmed the immune inhibitory role of this endogenous lectin during Y. enterocolitica infection. Thus, targeting Gal 1-glycan interactions may contribute to reinforce antibacterial responses by reprogramming innate and adaptive immune mechanisms. PMID- 28716829 TI - The Best We Can Be. PMID- 28716830 TI - Reality and Truth: Balancing the Hope and the Hype of Real-World Evidence. PMID- 28716828 TI - Creation and Preliminary Characterization of Pregnane X Receptor and Constitutive Androstane Receptor Knockout Rats. AB - The nuclear receptors pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are closely related transcription factors that regulate the expression of phase I (cytochrome P450s) and phase II metabolizing enzymes and transporter genes in response to stimulation from xenobiotics, including prescription drugs. PXR and CAR knockout and humanized mouse models have proven useful. However, the rat being bigger in size is a preferred model system for studying drug metabolism and pharmacokinetics. Here, we report the creation and preliminary characterization of PXR and CAR knockout rats and PXR/CAR double knockout rats. Whereas the expression of phase I and II enzymes and transporter genes were not upregulated by nuclear receptor-specific agonists pregnenlone 16alpha-carbonitrile and 1,4-bis-[2-(3,5-dichloropyridyloxy)] benzene in the knockout rats, confirming the disruption of respective nuclear receptor(s), our data demonstrate that PXR appears to suppress the basal expression levels of Cyp2b2, Cyp3a23/3a1, Cyp3a2, Cyp3a18, and Ugt2b1 genes, while CAR maintains Cyp2b2 and Ugt2b1 and suppresses Cyp3a9 basal expression levels. In wild-type rats, agonist binding of the nuclear receptors relieves the suppression, and target genes are expressed at levels comparable to knockout rats, with or without drug treatment. Overall, our findings are in good agreement with data obtained from human primary hepatocytes, nuclear receptor knockout cell lines, and mouse knockout models. We believe these models are a useful complement to their mouse counterparts for drug development and as importantly, for functional studies on metabolic pathways involving nuclear receptors. PMID- 28716831 TI - Coronary Plaque Characterization in Psoriasis. PMID- 28716832 TI - Mechanical Circulatory Support Devices for Acute Right Ventricular Failure. AB - Right ventricular (RV) failure remains a major cause of global morbidity and mortality for patients with advanced heart failure, pulmonary hypertension, or acute myocardial infarction and after major cardiac surgery. Over the past 2 decades, percutaneously delivered acute mechanical circulatory support pumps specifically designed to support RV failure have been introduced into clinical practice. RV acute mechanical circulatory support now represents an important step in the management of RV failure and provides an opportunity to rapidly stabilize patients with cardiogenic shock involving the RV. As experience with RV devices grows, their role as mechanical therapies for RV failure will depend less on the technical ability to place the device and more on improved algorithms for identifying RV failure, patient monitoring, and weaning protocols for both isolated RV failure and biventricular failure. In this review, we discuss the pathophysiology of acute RV failure and both the mechanism of action and clinical data exploring the utility of existing RV acute mechanical circulatory support devices. PMID- 28716834 TI - Prosthetic Valve Endocarditis After Surgical Aortic Valve Replacement. PMID- 28716835 TI - Long-Term Efficacy and Safety of the Microsomal Triglyceride Transfer Protein Inhibitor Lomitapide in Patients With Homozygous Familial Hypercholesterolemia. PMID- 28716836 TI - Letter by Ceylan Regarding Article, "Risk Factors for Coarctation of the Aorta on Prenatal Ultrasound: A Systematic Review and Meta-Analysis". PMID- 28716837 TI - Response to Letter Regarding Article, "Risk Factors for Coarctation of the Aorta on Prenatal Ultrasound: A Systematic Review and Meta-Analysis". PMID- 28716838 TI - Letter by Leggio et al Regarding Article, "Mediterranean Diet Improves High Density Lipoprotein Function in High-Cardiovascular-Risk Individuals: A Randomized Controlled Trial". PMID- 28716840 TI - Correction. PMID- 28716839 TI - Response to Letter Regarding Article, "Mediterranean Diet Improves High-Density Lipoprotein Function in High-Cardiovascular-Risk Individuals: A Randomized Controlled Trial". PMID- 28716841 TI - International recruitment scheme brings 38 GPs to NHS. PMID- 28716843 TI - Strength in numbers: Phosphofructokinase polymerization prevails in the liver. AB - Numerous metabolic enzymes assemble into filamentous structures, which are thought to serve additional regulatory functions. In this issue, Webb et al. (2017. J. Cell Biol. https://doi.org/10.1083/jcb.201701084) show that the liver specific isoform of phosphofructokinase-1 forms filaments in vitro and localizes as puncta in cells along the plasma membrane. This suggests spatial organization of glycolysis in higher organisms. PMID- 28716842 TI - Outer nuclear membrane protein Kuduk modulates the LINC complex and nuclear envelope architecture. AB - Linker of nucleoskeleton and cytoskeleton (LINC) complexes spanning the nuclear envelope (NE) contribute to nucleocytoskeletal force transduction. A few NE proteins have been found to regulate the LINC complex. In this study, we identify one, Kuduk (Kud), which can reside at the outer nuclear membrane and is required for the development of Drosophila melanogaster ovarian follicles and NE morphology of myonuclei. Kud associates with LINC complex components in an evolutionarily conserved manner. Loss of Kud increases the level but impairs functioning of the LINC complex. Overexpression of Kud suppresses NE targeting of cytoskeleton-free LINC complexes. Thus, Kud acts as a quality control mechanism for LINC-mediated nucleocytoskeletal connections. Genetic data indicate that Kud also functions independently of the LINC complex. Overexpression of the human orthologue TMEM258 in Drosophila proved functional conservation. These findings expand our understanding of the regulation of LINC complexes and NE architecture. PMID- 28716845 TI - Caring for young carers in Canada. PMID- 28716844 TI - Microglia control the glycinergic but not the GABAergic synapses via prostaglandin E2 in the spinal cord. AB - Microglia control excitatory synapses, but their role in inhibitory neurotransmission has been less well characterized. Herein, we show that microglia control the strength of glycinergic but not GABAergic synapses via modulation of the diffusion dynamics and synaptic trapping of glycine (GlyR) but not GABAA receptors. We further demonstrate that microglia regulate the activity dependent plasticity of glycinergic synapses by tuning the GlyR diffusion trap. This microglia-synapse cross talk requires production of prostaglandin E2 by microglia, leading to the activation of neuronal EP2 receptors and cyclic adenosine monophosphate-dependent protein kinase. Thus, we now provide a link between microglial activation and synaptic dysfunctions, which are common early features of many brain diseases. PMID- 28716846 TI - Why support a separate medical access framework for cannabis? PMID- 28716848 TI - Managing thyroid disease in women planning pregnancy. PMID- 28716849 TI - Subclinical hypothyroidism in pregnancy. PMID- 28716847 TI - Nonnutritive sweeteners and cardiometabolic health: a systematic review and meta analysis of randomized controlled trials and prospective cohort studies. AB - BACKGROUND: Nonnutritive sweeteners, such as aspartame, sucralose and stevioside, are widely consumed, yet their long-term health impact is uncertain. We synthesized evidence from prospective studies to determine whether routine consumption of non-nutritive sweeteners was associated with long-term adverse cardiometabolic effects. METHODS: We searched MEDLINE, Embase and Cochrane Library (inception to January 2016) for randomized controlled trials (RCTs) that evaluated interventions for nonnutritive sweeteners and prospective cohort studies that reported on consumption of non-nutritive sweeteners among adults and adolescents. The primary outcome was body mass index (BMI). Secondary outcomes included weight, obesity and other cardiometabolic end points. RESULTS: From 11 774 citations, we included 7 trials (1003 participants; median follow-up 6 mo) and 30 cohort studies (405 907 participants; median follow-up 10 yr). In the included RCTs, nonnutritive sweeteners had no significant effect on BMI (mean difference -0.37 kg/m2; 95% confidence interval [CI] -1.10 to 0.36; I2 9%; 242 participants). In the included cohort studies, consumption of nonnutritive sweeteners was associated with a modest increase in BMI (mean correlation 0.05, 95% CI 0.03 to 0.06; I2 0%; 21 256 participants). Data from RCTs showed no consistent effects of nonnutritive sweeteners on other measures of body composition and reported no further secondary outcomes. In the cohort studies, consumption of nonnutritive sweeteners was associated with increases in weight and waist circumference, and higher incidence of obesity, hypertension, metabolic syndrome, type 2 diabetes and cardiovascular events. Publication bias was indicated for studies with diabetes as an outcome. INTERPRETATION: Evidence from RCTs does not clearly support the intended benefits of nonnutritive sweeteners for weight management, and observational data suggest that routine intake of nonnutritive sweeteners may be associated with increased BMI and cardiometabolic risk. Further research is needed to fully characterize the long-term risks and benefits of nonnutritive sweeteners. Protocol registration: PROSPERO CRD42015019749. PMID- 28716850 TI - Fluid-filled striae in a patient with hypoalbuminemia. PMID- 28716851 TI - Chronic obstructive pulmonary disease and Occam's razor. PMID- 28716852 TI - US Senate health care bill draws widespread criticism. PMID- 28716853 TI - No immediate plans to build new CMA HQ. PMID- 28716854 TI - India introducing routine pneumococcal vaccine. PMID- 28716855 TI - Frailty Screening Tools for Elderly Patients Incident to Dialysis. AB - BACKGROUND AND OBJECTIVES: A geriatric assessment is an appropriate method for identifying frail elderly patients. In CKD, it may contribute to optimize personalized care. However, a geriatric assessment is time consuming. The purpose of our study was to compare easy to apply frailty screening tools with the geriatric assessment in patients eligible for dialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A total of 123 patients on incident dialysis >=65 years old were included <3 weeks before to <=2 weeks after dialysis initiation, and all underwent a geriatric assessment. Patients with impairment in two or more geriatric domains on the geriatric assessment were considered frail. The diagnostic abilities of six frailty screening tools were compared with the geriatric assessment: the Fried Frailty Index, the Groningen Frailty Indicator, Geriatric8, the Identification of Seniors at Risk, the Hospital Safety Program, and the clinical judgment of the nephrologist. Outcome measures were sensitivity, specificity, positive predictive value, and negative predictive value. RESULTS: In total, 75% of patients were frail according to the geriatric assessment. Sensitivity of frailty screening tools ranged from 48% (Fried Frailty Index) to 88% (Geriatric8). The discriminating features of the clinical judgment were comparable with the other screening tools. The Identification of Seniors at Risk screening tool had the best discriminating abilities, with a sensitivity of 74%, a specificity of 80%, a positive predictive value of 91%, and a negative predictive value of 52%. The negative predictive value was poor for all tools, which means that almost one half of the patients screened as fit (nonfrail) had two or more geriatric impairments on the geriatric assessment. CONCLUSIONS: All frailty screening tools are able to detect geriatric impairment in elderly patients eligible for dialysis. However, all applied screening tools, including the judgment of the nephrologist, lack the discriminating abilities to adequately rule out frailty compared with a geriatric assessment. PMID- 28716856 TI - Statistical Methods for Recurrent Event Analysis in Cohort Studies of CKD. AB - Cardiovascular events, such as hospitalizations because of congestive heart failure, often occur repeatedly in patients with CKD. Many studies focus on analyses of the first occurrence of these events, and discard subsequent information. In this article, we review a number of statistical methods for analyzing ordered recurrent events of the same type, including Poisson regression and three commonly used survival models that are extensions of Cox proportional hazards regression. We illustrate the models by analyzing data from the Chronic Renal Insufficiency Cohort Study to identify risk factors for congestive heart failure hospitalizations in patients with CKD. We show that recurrent event analyses provide additional insights about the data compared with a standard survival analysis of time to the first event. PMID- 28716857 TI - Perspectives on Funding Initiatives in Clinical Research in Kidney Disease in the United States. PMID- 28716858 TI - Sparking Innovation To Improve the Lives of People with Kidney Disease. PMID- 28716859 TI - Complementary Initiatives from the NIDDK to Advance Kidney Health. PMID- 28716861 TI - Allogeneic hematopoietic cell transplantation for high-risk CLL: 10-year follow up of the GCLLSG CLL3X trial. PMID- 28716860 TI - Novel mechanisms of PIEZO1 dysfunction in hereditary xerocytosis. AB - Mutations in PIEZO1 are the primary cause of hereditary xerocytosis, a clinically heterogeneous, dominantly inherited disorder of erythrocyte dehydration. We used next-generation sequencing-based techniques to identify PIEZO1 mutations in individuals from 9 kindreds referred with suspected hereditary xerocytosis (HX) and/or undiagnosed congenital hemolytic anemia. Mutations were primarily found in the highly conserved, COOH-terminal pore-region domain. Several mutations were novel and demonstrated ethnic specificity. We characterized these mutations using genomic-, bioinformatic-, cell biology-, and physiology-based functional assays. For these studies, we created a novel, cell-based in vivo system for study of wild-type and variant PIEZO1 membrane protein expression, trafficking, and electrophysiology in a rigorous manner. Previous reports have indicated HX associated PIEZO1 variants exhibit a partial gain-of-function phenotype with generation of mechanically activated currents that inactivate more slowly than wild type, indicating that increased cation permeability may lead to dehydration of PIEZO1-mutant HX erythrocytes. In addition to delayed channel inactivation, we found additional alterations in mutant PIEZO1 channel kinetics, differences in response to osmotic stress, and altered membrane protein trafficking, predicting variant alleles that worsen or ameliorate erythrocyte hydration. These results extend the genetic heterogeneity observed in HX and indicate that various pathophysiologic mechanisms contribute to the HX phenotype. PMID- 28716863 TI - Opposing regulation and roles for PHD3 in lung dendritic cells and alveolar macrophages. AB - The prolyl hydroxylase domain-containing enzymes (PHDs) are important metabolic sensors of the cell and its environment, which might be employed to alert cells of the immune system. These enzymes regulate the expression of the hypoxia inducible factor (HIF) isoforms and NF-kappaB, crucial transcription factors controlling cellular metabolism and inflammation. PHD/HIF signaling is activated in the allergic lung and is proposed as a potential druggable pathway. Here, we investigated the regulation and role of the PHD isoforms in CD11c-expressing dendritic cells (DCs) and macrophages (Mphi), sensors of the environment and crucial antigen-presenting cells in the pathogenesis of asthma. Although PHD2 and PHD3 were expressed in baseline, stimulation with house dust mite (HDM) allergen, hypoxia, and TLR4 ligands induced the expression of PHD3 in DCs. Conditional deletion or overexpression of PHD3 in CD11chi cells had minor effects on DCs and alveolar Mphi biology in steady state. However, when put into competition with wild-type counterparts in mixed chimeric mice, alveolar Mphi uniquely required PHD3 for optimal reconstitution of the alveolar space. Using genetic and chemical approaches, we were unable to find a clear role for PHD3 or the other PHD isoforms in DCs in asthma development. These data show cell-specific competitive advantage of PHD3 expression in antigen-presenting cells, but question whether therapeutic manipulation of PHDs in DCs would offer therapeutic benefit in asthma. PMID- 28716862 TI - Gene therapy for Wiskott-Aldrich syndrome in a severely affected adult. AB - Until recently, hematopoietic stem cell transplantation was the only curative option for Wiskott-Aldrich syndrome (WAS). The first attempts at gene therapy for WAS using a Upsilon-retroviral vector improved immunological parameters substantially but were complicated by acute leukemia as a result of insertional mutagenesis in a high proportion of patients. More recently, treatment of children with a state-of-the-art self-inactivating lentiviral vector (LV-w1.6 WASp) has resulted in significant clinical benefit without inducing selection of clones harboring integrations near oncogenes. Here, we describe a case of a presplenectomized 30-year-old patient with severe WAS manifesting as cutaneous vasculitis, inflammatory arthropathy, intermittent polyclonal lymphoproliferation, and significant chronic kidney disease and requiring long term immunosuppressive treatment. Following reduced-intensity conditioning, there was rapid engraftment and expansion of a polyclonal pool of transgene-positive functional T cells and sustained gene marking in myeloid and B-cell lineages up to 20 months of observation. The patient was able to discontinue immunosuppression and exogenous immunoglobulin support, with improvement in vasculitic disease and proinflammatory markers. Autologous gene therapy using a lentiviral vector is a viable strategy for adult WAS patients with severe chronic disease complications and for whom an allogeneic procedure could present an unacceptable risk. This trial was registered at www.clinicaltrials.gov as #NCT01347242. PMID- 28716865 TI - Correction for Brigham et al., "Whole-Genome Microarray and Gene Deletion Studies Reveal Regulation of the Polyhydroxyalkanoate Production Cycle by the Stringent Response in Ralstonia eutropha H16". PMID- 28716864 TI - Alpha1-antitrypsin binds hemin and prevents oxidative activation of human neutrophils: putative pathophysiological significance. AB - Heme is a ubiquitous compound of human tissues, and it is involved in cellular physiology and metabolism. Once released from the cell, free heme oxidizes to the ferric state (hemin). High levels of hemin can cause oxidative stress and inflammation if not neutralized immediately by specialized scavenger proteins. Human alpha1-antitrypsin (A1AT), an acute-phase glycoprotein and important inhibitor of neutrophil proteases, is also a hemin-binding protein. A short-term exposure of freshly isolated human blood neutrophils to 4 uM hemin results in cell spreading, surface expression of filament protein, vimentin, free radical production, expression of heme oxygenase-1 (HO-1), release of IL-8, and enhanced neutrophil adhesion to human endothelial cells. Consequently, the phosphorylation of protein kinase C (PKC) occurs after 25 min. Under the same experimental conditions, addition of 1 mg/ml A1AT markedly reduces or abolishes neutrophil activating effects of hemin and prevents PKC phosphorylation. In a mouse model of acute kidney injury (AKI) plus injection of hemin, monotherapy with 4 mg/mouse A1AT significantly lowered serum levels of free hemin at 2 h after surgery. Moreover, a tendency toward lower AKI scores, reduced infiltration of neutrophils, and lower levels of serum chemokine [CXCL1/keratinocyte-derived chemokine (KC)] was observed. Our findings highlight A1AT as a potential serum scavenger of hemin and suggest that the commercial preparations of human plasma A1AT might prove to be useful therapeutics in conditions associated with hemolysis. PMID- 28716866 TI - Drug strategy will fail without new money, say critics. PMID- 28716867 TI - Syndromic congenital diarrhoea: new SPINT2 mutation identified in the UAE. AB - We are reporting a new mutation in the SPINT2 gene (c.443G>A (p. Arg148His)) that explains the association of choanal atresia with congenital sodium diarrhoea (CSD) in an Emirati family in the Middle East. To our knowledge, this mutation is neither listed in a mutation database nor described in the literature. Similar to other patients with CSD associated with SPINT2, this child remains dependent on parenteral nutrition for fluids and nutritional support resulting in failure to thrive. The determination of the molecular basis of syndromic CSD will facilitate prenatal and postnatal diagnosis of patients and will contribute to counselling of affected families, especially in areas like the UAE where consanguineous marriages are not uncommon. PMID- 28716868 TI - Solitary fibrous tumour: a rare tumour of the pleural cavity. AB - Solitary fibrous tumours are a rare group of tumours that originate from connective tissues such as the pleura and mediastinum. When growing within the thoracic cavity these tumours exert pressure on vital organs and large vessels. We have successfully operated on two patients with large solitary fibrous tumours and managed the pathophysiological changes manifested as superior vena cava syndrome resulting from these tumours. PMID- 28716869 TI - An uncommon cause of warm foot. PMID- 28716870 TI - Necrotising enterocolitis after supraventricular tachycardia: an unusual precursor to a common problem. AB - Supraventricular tachycardia (SVT) is the most common neonatal arrhythmia. Necrotising enterocolitis (NEC) is a disease with multifactorial aetiology, most common in preterm infants. There are three previous case reports in the literature of NEC following neonatal SVT. We present two cases of late preterm infants with NEC, characterised by pneumatosis on abdominal X-ray and ultrasound, following recurrent SVT without haemodynamic instability. The infants were successfully treated with antibiotic therapy and bowel rest. PMID- 28716871 TI - IgG4-related disease: long-term natural history and management of a relapsing multisystem disease entity. AB - Although awareness of IgG4-related disease has grown over the past decade, with earlier diagnosis and treatment, understanding of its natural history over the long term and the optimal management remains unclear. We report the case of a 48 year-old man who presented with a pancreatic pseudotumour causing bile duct obstruction with coexisting autoimmune hepatitis and multisystem involvement. His symptoms settled on steroids and maintenance with azathioprine was commenced, however periodic relapses occurred involving multiple organs. A timeline-relating IgG4 levels, clinical features and immunosuppressive therapy are presented. The protean and relapsing-remitting nature of this condition is emphasised, and a brief review of long-term therapeutic options is provided. PMID- 28716872 TI - The Duari hernia and recognition of the femoral vein compression sign. AB - Femoral hernias can be difficult to diagnose and are at high risk of strangulation. This report is of a rare case of an irreducible femoral hernia containing caecum and appendix presenting as an emergency. To the authors' knowledge, there have only been three cases reported, the first described by Duari. This case was incorrectly diagnosed preoperatively as an inguinal hernia, so the CT diagnosis of femoral hernias is reviewed, in particular demonstrating the radiological use of the femoral vein compression sign. PMID- 28716874 TI - Editors' Note. PMID- 28716873 TI - Multinodular vacuolating and neuronal tumor of the cerebrum. PMID- 28716875 TI - Letter re: Transient smartphone blindness: Relevance to misdiagnosis in neurologic practice. PMID- 28716876 TI - Author response: Transient smartphone blindness: Relevance to misdiagnosis in neurologic practice. PMID- 28716877 TI - Letter re: Munchausen syndrome by genetics: Next-generation challenges for clinicians. PMID- 28716878 TI - Author response: Munchausen syndrome by genetics: Next-generation challenges for clinicians. PMID- 28716879 TI - International Issues: Teleneurology in humanitarian crises: Lessons from the Medecins Sans Frontieres experience. AB - Humanitarian emergencies defined by armed conflict, political strife, famine, or natural disaster can devastate populations rapidly. Neurologic disorders accompany these complex humanitarian emergencies but often go unheeded, exacerbated by a scarcity of neurologists. Teleneurology offers the promise of neurologic care remotely in the face of this inadequate local clinician supply. We describe our experiences as voluntary neurology teleconsultants with Medecins Sans Frontieres in order to highlight both the promises and challenges of teleneurology in humanitarian contexts. We identified the major advantages of this service as (1) minimal resources and incurred costs while (2) changing a patient's clinical course favorably, and (3) creating a community for the field referrer and neurology specialist. Current challenges include (1) limited diagnostic resources and difficult diagnostic and therapeutic decision-making, (2) need for greater continuity and familiarity between the field site and neurologist, (3) gaps in the US neurology curriculum to provide expertise for all sites, (4) lack of follow-up and feedback from the field to advise future cases, and (5) low frequency of consultations. Growth opportunities include eventual expansion to the development of a community of neurologists who can provide context-specific care and maximize use of multimedia at low Internet bandwidth. Lessons from our experience may help optimize teleneurology's effect and reduce disparities in neurologic care, particularly in humanitarian crises. PMID- 28716880 TI - Teaching NeuroImages: Amlodipine-responsive trigeminal neuralgia: An alibi for vascular compression theory. PMID- 28716881 TI - Teaching Video NeuroImages: Bent spine syndrome as an early presentation of late onset Pompe disease. PMID- 28716884 TI - Which Dengue Vaccine Approach Is the Most Promising, and Should We Be Concerned about Enhanced Disease after Vaccination? The Challenges of a Dengue Vaccine. AB - A dengue vaccine has been pursued for more than 50 years and, unlike other flaviviral vaccines such as that against yellow fever, progress has been slow. In this review, we describe progress toward the first licensed dengue vaccine Dengvaxia, which does not give complete protection against disease. The antibody response to the dengue virion is reviewed, highlighting immunodominant yet poorly neutralizing responses in the context of a highly dynamic structurally flexible dengue virus particle. Finally, we review recent evidence for cross-reactivity between antibody responses to Zika and dengue viruses, which may further complicate the development of broadly protective dengue virus vaccines. PMID- 28716883 TI - Role of the beta Common (betac) Family of Cytokines in Health and Disease. AB - The beta common ([betac]/CD131) family of cytokines comprises granulocyte macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-3, and IL-5, all of which use betac as their key signaling receptor subunit. This is a prototypic signaling subunit-sharing cytokine family that has unveiled many biological paradigms and structural principles applicable to the IL-2, IL-4, and IL-6 receptor families, all of which also share one or more signaling subunits. Originally identified for their functions in the hematopoietic system, the betac cytokines are now known to be truly pleiotropic, impacting on multiple cell types, organs, and biological systems, and thereby controlling the balance between health and disease. This review will focus on the emerging biological roles for the betac cytokines, our progress toward understanding the mechanisms of receptor assembly and signaling, and the application of this knowledge to develop exciting new therapeutic approaches against human disease. PMID- 28716885 TI - Cytokines and Long Noncoding RNAs. AB - Cytokines and long noncoding RNAs (lncRNAs) are intertwined in the regulatory circuit controlling immunity. lncRNA expression levels are altered following cytokine stimulation in a cell-type-specific fashion. lncRNAs, in turn, regulate the inducible expression of cytokines following immune activation. These studies position lncRNAs as important regulators of gene expression within the complex pathways of the immune system. Our understanding of the functions of lncRNAs is just beginning. Current methodologies for functionally understanding how these transcripts mediate their effects are unable to keep up with the speed of genomic outputs cataloging thousands of these novel genes. In this review, we highlight the interplay between cytokines and lncRNAs and speculate on the future utility of these genes as potential biomarkers and therapeutic targets for the treatment of inflammatory disorders. PMID- 28716886 TI - Clinical Neurology and Epidemiology of the Major Neurodegenerative Diseases. AB - Neurodegenerative diseases are a common cause of morbidity and cognitive impairment in older adults. Most clinicians who care for the elderly are not trained to diagnose these conditions, perhaps other than typical Alzheimer's disease (AD). Each of these disorders has varied epidemiology, clinical symptomatology, laboratory and neuroimaging features, neuropathology, and management. Thus, it is important that clinicians be able to differentiate and diagnose these conditions accurately. This review summarizes and highlights clinical aspects of several of the most commonly encountered neurodegenerative diseases, including AD, frontotemporal dementia (FTD) and its variants, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Parkinson's disease (PD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), and Huntington's disease (HD). For each condition, we provide a brief overview of the epidemiology, defining clinical symptoms and diagnostic criteria, relevant imaging and laboratory features, genetics, pathology, treatments, and differential diagnosis. PMID- 28716882 TI - Protein kinase D at the Golgi controls NLRP3 inflammasome activation. AB - The inflammasomes are multiprotein complexes sensing tissue damage and infectious agents to initiate innate immune responses. Different inflammasomes containing distinct sensor molecules exist. The NLRP3 inflammasome is unique as it detects a variety of danger signals. It has been reported that NLRP3 is recruited to mitochondria-associated endoplasmic reticulum membranes (MAMs) and is activated by MAM-derived effectors. Here, we show that in response to inflammasome activators, MAMs localize adjacent to Golgi membranes. Diacylglycerol (DAG) at the Golgi rapidly increases, recruiting protein kinase D (PKD), a key effector of DAG. Upon PKD inactivation, self-oligomerized NLRP3 is retained at MAMs adjacent to Golgi, blocking assembly of the active inflammasome. Importantly, phosphorylation of NLRP3 by PKD at the Golgi is sufficient to release NLRP3 from MAMs, resulting in assembly of the active inflammasome. Moreover, PKD inhibition prevents inflammasome autoactivation in peripheral blood mononuclear cells from patients carrying NLRP3 mutations. Hence, Golgi-mediated PKD signaling is required and sufficient for NLRP3 inflammasome activation. PMID- 28716887 TI - Cell-Cell Contact and Receptor Tyrosine Kinase Signaling. AB - The behavior of cells within tissues is governed by the activities of adhesion receptors that provide spatial cues and transmit forces through intercellular junctions, and by growth-factor receptors, particularly receptor tyrosine kinases (RTKs), that respond to biochemical signals from the environment. Coordination of these two activities is essential for the patterning and polarized migration of cells during morphogenesis and for homeostasis in mature tissues; loss of this coordination is a hallmark of developing cancer and driver of metastatic progression. Although much is known about the individual functions of adhesion and growth factor receptors, we have a surprisingly superficial understanding of the mechanisms by which their activities are coordinated. PMID- 28716888 TI - Interleukin (IL)-12 and IL-23 and Their Conflicting Roles in Cancer. AB - The balance of proinflammatory cytokines interleukin (IL)-12 and IL-23 plays a key role in shaping the development of antitumor or protumor immunity. In this review, we discuss the role IL-12 and IL-23 plays in tumor biology from preclinical and clinical data. In particular, we discuss the mechanism by which IL-23 promotes tumor growth and metastases and how the IL-12/IL-23 axis of inflammation can be targeted for cancer therapy. PMID- 28716890 TI - Negative Regulation of Cytokine Signaling in Immunity. AB - Cytokines are key modulators of immunity. Most cytokines use the Janus kinase and signal transducers and activators of transcription (JAK-STAT) pathway to promote gene transcriptional regulation, but their signals must be attenuated by multiple mechanisms. These include the suppressors of cytokine signaling (SOCS) family of proteins, which represent a main negative regulation mechanism for the JAK-STAT pathway. Cytokine-inducible Src homology 2 (SH2)-containing protein (CIS), SOCS1, and SOCS3 proteins regulate cytokine signals that control the polarization of CD4+ T cells and the maturation of CD8+ T cells. SOCS proteins also regulate innate immune cells and are involved in tumorigenesis. This review summarizes recent progress on CIS, SOCS1, and SOCS3 in T cells and tumor immunity. PMID- 28716889 TI - Cytokines, Transcription Factors, and the Initiation of T-Cell Development. AB - Multipotent blood progenitor cells migrate into the thymus and initiate the T cell differentiation program. T-cell progenitor cells gradually acquire T-cell characteristics while shedding their multipotentiality for alternative fates. This process is supported by extracellular signaling molecules, including Notch ligands and cytokines, provided by the thymic microenvironment. T-cell development is associated with dynamic change of gene regulatory networks of transcription factors, which interact with these environmental signals. Together with Notch or pre-T-cell-receptor (TCR) signaling, cytokines always control proliferation, survival, and differentiation of early T cells, but little is known regarding their cross talk with transcription factors. However, recent results suggest ways that cytokines expressed in distinct intrathymic niches can specifically modulate key transcription factors. This review discusses how stage specific roles of cytokines and transcription factors can jointly guide development of early T cells. PMID- 28716891 TI - Which Dengue Vaccine Approach Is the Most Promising, and Should We Be Concerned about Enhanced Disease after Vaccination? The Path to a Dengue Vaccine: Learning from Human Natural Dengue Infection Studies and Vaccine Trials. AB - Dengue virus (DENV) is the most common arthropod-borne viral disease of humans. Although effective vaccines exist against other flaviviral diseases like yellow fever and Japanese encephalitis, dengue vaccine development is complicated by the presence of four virus serotypes and the possibility of partial immunity enhancing dengue disease severity. Several live attenuated dengue vaccines are being tested in human clinical trials. Initial results are mixed, with variable efficacy depending on DENV serotype and previous DENV exposure. Here, we highlight recent discoveries about the human antibody response to DENV and propose guidelines for advancing development of safe and effective dengue vaccines. PMID- 28716892 TI - Which Dengue Vaccine Approach Is the Most Promising, and Should We Be Concerned about Enhanced Disease after Vaccination? Questions Raised by the Development and Implementation of Dengue Vaccines: Example of the Sanofi Pasteur Tetravalent Dengue Vaccine. AB - Dengue is a still-growing public health concern in many tropical and subtropical regions of the world. The development and implementation of an effective dengue vaccine in these regions is a high priority. This insight focuses on the expected characteristics of a safe and efficacious vaccine, referring to the clinical experience obtained during the development of the first tetravalent dengue vaccine from Sanofi Pasteur, now licensed in several endemic countries. Safety and efficacy data from both short- and long-term follow-up of large-scale efficacy studies will be discussed, as well as the next steps following vaccine introduction. PMID- 28716893 TI - Which Dengue Vaccine Approach Is the Most Promising, and Should We Be Concerned about Enhanced Disease after Vaccination? There Is Only One True Winner. AB - The scientific community now possesses information obtained directly from human beings that makes it possible to understand why breakthrough-enhanced dengue virus (DENV) infections occurred in children receiving Sanofi Pasteur's Dengvaxia tetravalent live attenuated vaccine and to predict the possibility of breakthrough-enhanced DENV infections following immunization with two other tetravalent live attenuated vaccines now in phase III testing. Based upon recent research, Dengvaxia, lacking DENV nonstructural protein antigens, did not protect seronegatives because it failed to raise a competent T-cell response and/or antibodies to NS1. It is also possible that chimeric structure does not present the correct virion conformation permitting the development of protective neutralizing antibodies. A premonitory signal shared by the Sanofi Pasteur and the Takeda vaccines was the failure of fully immunized subhuman primates to prevent low-level viremia and/or anamnestic antibody responses to live DENV challenge. The vaccine developed by the National Institute of Allergy and Infectious Diseases (National Institutes of Health [NIH]) has met virtually all of the goals needed to demonstrate preclinical efficacy and safety for humans. Each monovalent vaccine was comprehensively studied for reactogenicity and immunogenicity in human volunteers. Protective immunity in subjects receiving tetravalent candidate vaccines was evidenced by the fact that when vaccinated subjects were given further doses of vaccine or different strains of DENV the result was "solid immunity," a nonviremic and nonanamnestic immune response. PMID- 28716894 TI - Which Dengue Vaccine Approach Is the Most Promising, and Should We Be Concerned about Enhanced Disease after Vaccination? The Risks of Incomplete Immunity to Dengue Virus Revealed by Vaccination. AB - Immune enhancement of dengue disease continues to be a concern for those with incomplete immunity in endemic areas. Advanced testing and follow-up of a newly available live attenuated dengue vaccine has recently shown the ability of vaccination to predispose some recipients for a severe outcome on subsequent infection. To improve safety, recommendations have been made to restrict use of the vaccine to those who are likely to have had prior exposure to dengue virus (DENV). Researchers continue to investigate dengue immunity and seek evidence that dengue vaccines can be safely administered to all populations needing protection. PMID- 28716895 TI - CTLA4 Promotes Tyk2-STAT3-Dependent B-cell Oncogenicity. AB - CTL-associated antigen 4 (CTLA4) is a well-established immune checkpoint for antitumor immune responses. The protumorigenic function of CTLA4 is believed to be limited to T-cell inhibition by countering the activity of the T-cell costimulating receptor CD28. However, as we demonstrate here, there are two additional roles for CTLA4 in cancer, including via CTLA4 overexpression in diverse B-cell lymphomas and in melanoma-associated B cells. CTLA4-CD86 ligation recruited and activated the JAK family member Tyk2, resulting in STAT3 activation and expression of genes critical for cancer immunosuppression and tumor growth and survival. CTLA4 activation resulted in lymphoma cell proliferation and tumor growth, whereas silencing or antibody-blockade of CTLA4 in B-cell lymphoma tumor cells in the absence of T cells inhibits tumor growth. This inhibition was accompanied by reduction of Tyk2/STAT3 activity, tumor cell proliferation, and induction of tumor cell apoptosis. The CTLA4-Tyk2-STAT3 signal pathway was also active in tumor-associated nonmalignant B cells in mouse models of melanoma and lymphoma. Overall, our results show how CTLA4-induced immune suppression occurs primarily via an intrinsic STAT3 pathway and that CTLA4 is critical for B-cell lymphoma proliferation and survival. Cancer Res; 77(18); 5118-28. (c)2017 AACR. PMID- 28716897 TI - MCPIP1 Downregulation in Clear Cell Renal Cell Carcinoma Promotes Vascularization and Metastatic Progression. AB - Clear cell renal cell carcinoma (ccRCC) is the most common type of kidney cancer and it forms highly vascularized tumors. The monocyte endoribonuclease MCPIP1 negatively regulates inflammation by degrading mRNA encoding proinflammatory cytokines, such as IL6, IL1, and IL12. MCPIP1 is also a negative regulator of NFkappaB and AP1 activity and it influences a broad range of miRNA activities. Here we report that MCPIP1 protein levels are decreased during renal cancer progression. In patient-derived tumors and xenografts established in NOD-SCID or nude mice, low MCPIP1 levels correlated strongly with increased proliferation, tumor outgrowth, and vascularity. MCPIP1 activity regulated secretion of VEGF, IL8, and CXCL12 leading to chemotaxis of microvascular endothelial cells, phosphorylation of VE-cadherin, and increased vascular permeability. Mechanistic investigations showed that MCPIP1 regulated ccRCC cell motility, lung metastasis, and mesenchymal phenotype by regulating key elements in the EMT signaling axis. Overall, our results illuminate how MCPIP1 serves as a key nodal point in coordinating tumor growth, angiogenesis, and metastatic spread in ccRCC. Cancer Res; 77(18); 4905-20. (c)2017 AACR. PMID- 28716896 TI - Poor Prognosis Indicated by Venous Circulating Tumor Cell Clusters in Early-Stage Lung Cancers. AB - Early detection of metastasis can be aided by circulating tumor cells (CTC), which also show potential to predict early relapse. Because of the limited CTC numbers in peripheral blood in early stages, we investigated CTCs in pulmonary vein blood accessed during surgical resection of tumors. Pulmonary vein (PV) and peripheral vein (Pe) blood specimens from patients with lung cancer were drawn during the perioperative period and assessed for CTC burden using a microfluidic device. From 108 blood samples analyzed from 36 patients, PV had significantly higher number of CTCs compared with preoperative Pe (P < 0.0001) and intraoperative Pe (P < 0.001) blood. CTC clusters with large number of CTCs were observed in 50% of patients, with PV often revealing larger clusters. Long-term surveillance indicated that presence of clusters in preoperative Pe blood predicted a trend toward poor prognosis. Gene expression analysis by RT-qPCR revealed enrichment of p53 signaling and extracellular matrix involvement in PV and Pe samples. Ki67 expression was detected in 62.5% of PV samples and 59.2% of Pe samples, with the majority (72.7%) of patients positive for Ki67 expression in PV having single CTCs as opposed to clusters. Gene ontology analysis revealed enrichment of cell migration and immune-related pathways in CTC clusters, suggesting survival advantage of clusters in circulation. Clusters display characteristics of therapeutic resistance, indicating the aggressive nature of these cells. Thus, CTCs isolated from early stages of lung cancer are predictive of poor prognosis and can be interrogated to determine biomarkers predictive of recurrence. Cancer Res; 77(18); 5194-206. (c)2017 AACR. PMID- 28716898 TI - TBK1 Provides Context-Selective Support of the Activated AKT/mTOR Pathway in Lung Cancer. AB - Emerging observations link dysregulation of TANK-binding kinase 1 (TBK1) to developmental disorders, inflammatory disease, and cancer. Biochemical mechanisms accounting for direct participation of TBK1 in host defense signaling have been well described. However, the molecular underpinnings of the selective participation of TBK1 in a myriad of additional cell biological systems in normal and pathophysiologic contexts remain poorly understood. To elucidate the context selective role of TBK1 in cancer cell survival, we employed a combination of broad-scale chemogenomic and interactome discovery strategies to generate data driven mechanism-of-action hypotheses. This approach uncovered evidence that TBK1 supports AKT/mTORC1 pathway activation and function through direct modulation of multiple pathway components acting both upstream and downstream of the mTOR kinase itself. Furthermore, we identified distinct molecular features in which mesenchymal, Ras-mutant lung cancer is acutely dependent on TBK1-mediated support of AKT/mTORC1 pathway activation for survival. Cancer Res; 77(18); 5077-94. (c)2017 AACR. PMID- 28716899 TI - HDAC1 Upregulation by NANOG Promotes Multidrug Resistance and a Stem-like Phenotype in Immune Edited Tumor Cells. AB - Cancer immunoediting drives the adaptation of tumor cells to host immune surveillance. Immunoediting driven by antigen (Ag)-specific T cells enriches NANOG expression in tumor cells, resulting in a stem-like phenotype and immune resistance. Here, we identify HDAC1 as a key mediator of the NANOG-associated phenotype. NANOG upregulated HDAC1 through promoter occupancy, thereby decreasing histone H3 acetylation on K14 and K27. NANOG-dependent, HDAC1-driven epigenetic silencing of cell-cycle inhibitors CDKN2D and CDKN1B induced stem-like features. Silencing of TRIM17 and NOXA induced immune and drug resistance in tumor cells by increasing antiapoptotic MCL1. Importantly, HDAC inhibition synergized with Ag specific adoptive T-cell therapy to control immune refractory cancers. Our results reveal that NANOG influences the epigenetic state of tumor cells via HDAC1, and they encourage a rational application of epigenetic modulators and immunotherapy in treatment of NANOG+ refractory cancer types. Cancer Res; 77(18); 5039-53. (c)2017 AACR. PMID- 28716900 TI - Structural insights into the extracellular recognition of the human serotonin 2B receptor by an antibody. AB - Monoclonal antibodies provide an attractive alternative to small-molecule therapies for a wide range of diseases. Given the importance of G protein-coupled receptors (GPCRs) as pharmaceutical targets, there has been an immense interest in developing therapeutic monoclonal antibodies that act on GPCRs. Here we present the 3.0-A resolution structure of a complex between the human 5 hydroxytryptamine 2B (5-HT2B) receptor and an antibody Fab fragment bound to the extracellular side of the receptor, determined by serial femtosecond crystallography with an X-ray free-electron laser. The antibody binds to a 3D epitope of the receptor that includes all three extracellular loops. The 5-HT2B receptor is captured in a well-defined active-like state, most likely stabilized by the crystal lattice. The structure of the complex sheds light on the mechanism of selectivity in extracellular recognition of GPCRs by monoclonal antibodies. PMID- 28716901 TI - Structural determination of lipid antigens captured at the CD1d-T-cell receptor interface. AB - Glycolipid antigens recognized by alphabeta T-cell receptors (TCRs) drive the activation of invariant natural killer T (iNKT) cells, a specialized subset of innate T lymphocytes. Glycolipids with alpha-linked anomeric carbohydrates have been identified as potent microbial lipid antigens for iNKT cells, and their unusual alpha-anomeric linkage has been thought to define a "foreign" lipid antigen motif. However, mammals use endogenous lipids to select iNKT cells, and there is compelling evidence for iNKT cell responses in various types of sterile inflammation. The nature of endogenous or environmental lipid antigens encountered by iNKT cells is not well defined. Here, we sought to identify lipid antigens in cow's milk, a prominent part of the human diet. We developed a method to directly capture lipid antigens within CD1d-lipid-TCR complexes, while excluding CD1d bound to nonantigenic lipids, followed by direct biochemical analysis of the lipid antigens trapped at the TCR-CD1d interface. The specific antigens captured by this "TCR trap" method were identified as alpha-linked monohexosylceramides by mass spectrometry fragmentation patterns that distinguished alpha- from beta-anomeric monohexosylceramides. These data provide direct biochemical evidence for alpha-linked lipid antigens from a common dietary source. PMID- 28716902 TI - Infants possess an abstract expectation of ingroup support. AB - One pervasive facet of human interactions is the tendency to favor ingroups over outgroups. Remarkably, this tendency has been observed even when individuals are assigned to minimal groups based on arbitrary markers. Why is mere categorization into a minimal group sufficient to elicit some degree of ingroup favoritism? We consider several accounts that have been proposed in answer to this question and then test one particular account, which holds that ingroup favoritism reflects in part an abstract and early-emerging sociomoral expectation of ingroup support. In violation-of-expectation experiments with 17-mo-old infants, unfamiliar women were first identified (using novel labels) as belonging to the same group, to different groups, or to unspecified groups. Next, one woman needed instrumental assistance to achieve her goal, and another woman either provided the necessary assistance (help event) or chose not to do so (ignore event). When the two women belonged to the same group, infants looked significantly longer if shown the ignore as opposed to the help event; when the two women belonged to different groups or to unspecified groups, however, infants looked equally at the two events. Together, these results indicate that infants view helping as expected among individuals from the same group, but as optional otherwise. As such, the results demonstrate that from an early age, an abstract expectation of ingroup support contributes to ingroup favoritism in human interactions. PMID- 28716903 TI - Autophagy-related protein Vps34 controls the homeostasis and function of antigen cross-presenting CD8alpha+ dendritic cells. AB - The class III PI3K Vacuolar protein sorting 34 (Vps34) plays a role in both canonical and noncanonical autophagy, key processes that control the presentation of antigens by dendritic cells (DCs) to naive T lymphocytes. We generated DC specific Vps34-deficient mice to assess the contribution of Vps34 to DC functions. We found that DCs from these animals have a partially activated phenotype, spontaneously produce cytokines, and exhibit enhanced activity of the classic MHC class I and class II antigen-presentation pathways. Surprisingly, these animals displayed a defect in the homeostatic maintenance of splenic CD8alpha+ DCs and in the capacity of these cells to cross-present cell corpse associated antigens to MHC class I-restricted T cells, a property that was associated with defective expression of the T-cell Ig mucin (TIM)-4 receptor. Importantly, mice deficient in the Vps34-associated protein Rubicon, which is critical for a noncanonical form of autophagy called "Light-chain 3 (LC3) associated phagocytosis" (LAP), lacked such defects. Finally, consistent with their defect in the cross-presentation of apoptotic cells, DC-specific Vps34 deficient animals developed increased metastases in response to challenge with B16 melanoma cells. Collectively, our studies have revealed a critical role of Vps34 in the regulation of CD8alpha+ DC homeostasis and in the capacity of these cells to process and present antigens associated with apoptotic cells to MHC class I-restricted T cells. Our findings also have important implications for the development of small-molecule inhibitors of Vps34 for therapeutic purposes. PMID- 28716904 TI - Intracellular zinc activates KCNQ channels by reducing their dependence on phosphatidylinositol 4,5-bisphosphate. AB - M-type (Kv7, KCNQ) potassium channels are proteins that control the excitability of neurons and muscle cells. Many physiological and pathological mechanisms of excitation operate via the suppression of M channel activity or expression. Conversely, pharmacological augmentation of M channel activity is a recognized strategy for the treatment of hyperexcitability disorders such as pain and epilepsy. However, physiological mechanisms resulting in M channel potentiation are rare. Here we report that intracellular free zinc directly and reversibly augments the activity of recombinant and native M channels. This effect is mechanistically distinct from the known redox-dependent KCNQ channel potentiation. Interestingly, the effect of zinc cannot be attributed to a single histidine- or cysteine-containing zinc-binding site within KCNQ channels. Instead, zinc dramatically reduces KCNQ channel dependence on its obligatory physiological activator, phosphatidylinositol 4,5-bisphosphate (PIP2). We hypothesize that zinc facilitates interactions of the lipid-facing interface of a KCNQ protein with the inner leaflet of the plasma membrane in a way similar to that promoted by PIP2 Because zinc is increasingly recognized as a ubiquitous intracellular second messenger, this discovery might represent a hitherto unknown native pathway of M channel modulation and provide a fresh strategy for the design of M channel activators for therapeutic purposes. PMID- 28716905 TI - MitoNEET-dependent formation of intermitochondrial junctions. AB - MitoNEET (mNEET) is a dimeric mitochondrial outer membrane protein implicated in many facets of human pathophysiology, notably diabetes and cancer, but its molecular function remains poorly characterized. In this study, we generated and analyzed mNEET KO cells and found that in these cells the mitochondrial network was disturbed. Analysis of 3D-EM reconstructions and of thin sections revealed that genetic inactivation of mNEET did not affect the size of mitochondria but that the frequency of intermitochondrial junctions was reduced. Loss of mNEET decreased cellular respiration, because of a reduction in the total cellular mitochondrial volume, suggesting that intermitochondrial contacts stabilize individual mitochondria. Reexpression of mNEET in mNEET KO cells restored the WT morphology of the mitochondrial network, and reexpression of a mutant mNEET resistant to oxidative stress increased in addition the resistance of the mitochondrial network to H2O2-induced fragmentation. Finally, overexpression of mNEET increased strongly intermitochondrial contacts and resulted in the clustering of mitochondria. Our results suggest that mNEET plays a specific role in the formation of intermitochondrial junctions and thus participates in the adaptation of cells to physiological changes and to the control of mitochondrial homeostasis. PMID- 28716907 TI - Correction for Li et al., Targeting reactive nitrogen species suppresses hereditary pancreatic cancer. PMID- 28716906 TI - Virus found in a boreal lake links ssDNA and dsDNA viruses. AB - Viruses have impacted the biosphere in numerous ways since the dawn of life. However, the evolution, genetic, structural, and taxonomic diversity of viruses remain poorly understood, in part because sparse sampling of the virosphere has concentrated mostly on exploring the abundance and diversity of dsDNA viruses. Furthermore, viral genomes are highly diverse, and using only the current sequence-based methods for classifying viruses and studying their phylogeny is complicated. Here we describe a virus, FLiP (Flavobacterium-infecting, lipid containing phage), with a circular ssDNA genome and an internal lipid membrane enclosed in the icosahedral capsid. The 9,174-nt-long genome showed limited sequence similarity to other known viruses. The genetic data imply that this virus might use replication mechanisms similar to those found in other ssDNA replicons. However, the structure of the viral major capsid protein, elucidated at near-atomic resolution using cryo-electron microscopy, is strikingly similar to that observed in dsDNA viruses of the PRD1-adenovirus lineage, characterized by a major capsid protein bearing two beta-barrels. The strong similarity between FLiP and another member of the structural lineage, bacteriophage PM2, extends to the capsid organization (pseudo T = 21 dextro) despite the difference in the genetic material packaged and the lack of significant sequence similarity. PMID- 28716908 TI - Sequential eviction of crowded nucleoprotein complexes by the exonuclease RecBCD molecular motor. AB - In physiological settings, all nucleic acids motor proteins must travel along substrates that are crowded with other proteins. However, the physical basis for how motor proteins behave in these highly crowded environments remains unknown. Here, we use real-time single-molecule imaging to determine how the ATP-dependent translocase RecBCD travels along DNA occupied by tandem arrays of high-affinity DNA binding proteins. We show that RecBCD forces each protein into its nearest adjacent neighbor, causing rapid disruption of the protein-nucleic acid interaction. This mechanism is not the same way that RecBCD disrupts isolated nucleoprotein complexes on otherwise naked DNA. Instead, molecular crowding itself completely alters the mechanism by which RecBCD removes tightly bound protein obstacles from DNA. PMID- 28716909 TI - Internalized CD44s splice isoform attenuates EGFR degradation by targeting Rab7A. AB - CD44 has been postulated as a cell surface coreceptor for augmenting receptor tyrosine kinase (RTK) signaling. However, how exactly CD44 triggers RTK-dependent signaling remained largely unclear. Here we report an unexpected mechanism by which the CD44s splice isoform is internalized into endosomes to attenuate EGFR degradation. We identify a CD44s-interacting small GTPase, Rab7A, and show that CD44s inhibits Rab7A-mediated EGFR trafficking to lysosomes and subsequent degradation. Importantly, CD44s levels correlate with EGFR signature and predict poor prognosis in glioblastomas. Because Rab7A facilitates trafficking of many RTKs to lysosomes, our findings identify CD44s as a Rab7A regulator to attenuate RTK degradation. PMID- 28716910 TI - Methylcytosine dioxygenase TET3 interacts with thyroid hormone nuclear receptors and stabilizes their association to chromatin. AB - Thyroid hormone receptors (TRs) are members of the nuclear hormone receptor superfamily that act as ligand-dependent transcription factors. Here we identified the ten-eleven translocation protein 3 (TET3) as a TR interacting protein increasing cell sensitivity to T3. The interaction between TET3 and TRs is independent of TET3 catalytic activity and specifically allows the stabilization of TRs on chromatin. We provide evidence that TET3 is required for TR stability, efficient binding of target genes, and transcriptional activation. Interestingly, the differential ability of different TRalpha1 mutants to interact with TET3 might explain their differential dominant activity in patients carrying TR germline mutations. So this study evidences a mode of action for TET3 as a nonclassical coregulator of TRs, modulating its stability and access to chromatin, rather than its intrinsic transcriptional activity. This regulatory function might be more general toward nuclear receptors. Indeed, TET3 interacts with different members of the superfamily and also enhances their association to chromatin. PMID- 28716911 TI - Activation and synchronization of the oscillatory morphodynamics in multicellular monolayer. AB - Oscillatory morphodynamics provides necessary mechanical cues for many multicellular processes. Owing to their collective nature, these processes require robustly coordinated dynamics of individual cells, which are often separated too distantly to communicate with each other through biomaterial transportation. Although it is known that the mechanical balance generally plays a significant role in the systems' morphologies, it remains elusive whether and how the mechanical components may contribute to the systems' collective morphodynamics. Here, we study the collective oscillations in the Drosophila amnioserosa tissue to elucidate the regulatory roles of the mechanical components. We identify that the tensile stress is the key activator that switches the collective oscillations on and off. This regulatory role is shown analytically using the Hopf bifurcation theory. We find that the physical properties of the tissue boundary are directly responsible for synchronizing the oscillatory intensity and polarity of all inner cells and for orchestrating the spatial oscillation patterns inthe tissue. PMID- 28716912 TI - Sialylation on O-glycans protects platelets from clearance by liver Kupffer cells. AB - Most platelet membrane proteins are modified by mucin-type core 1-derived glycans (O-glycans). However, the biological importance of O-glycans in platelet clearance is unclear. Here, we generated mice with a hematopoietic cell-specific loss of O-glycans (HC C1galt1-/- ). These mice lack O-glycans on platelets and exhibit reduced peripheral platelet numbers. Platelets from HC C1galt1-/- mice show reduced levels of alpha-2,3-linked sialic acids and increased accumulation in the liver relative to wild-type platelets. The preferential accumulation of HC C1galt1-/- platelets in the liver was reduced in mice lacking the hepatic asialoglycoprotein receptor [Ashwell-Morell receptor (AMR)]. However, we found that Kupffer cells are the primary cells phagocytosing HC C1galt1-/- platelets in the liver. Our results demonstrate that hepatic AMR promotes preferential adherence to and phagocytosis of desialylated and/or HC C1galt1-/- platelets by the Kupffer cell through its C-type lectin receptor CLEC4F. These findings provide insights into an essential role for core 1 O-glycosylation of platelets in their clearance in the liver. PMID- 28716913 TI - Antibody-based assay discriminates Zika virus infection from other flaviviruses. AB - Zika virus (ZIKV) is a mosquito-borne flavivirus that emerged recently as a global health threat, causing a pandemic in the Americas. ZIKV infection mostly causes mild disease, but is linked to devastating congenital birth defects and Guillain-Barre syndrome in adults. The high level of cross-reactivity among flaviviruses and their cocirculation has complicated serological approaches to differentially detect ZIKV and dengue virus (DENV) infections, accentuating the urgent need for a specific and sensitive serological test. We previously generated a ZIKV nonstructural protein 1 (NS1)-specific human monoclonal antibody, which we used to develop an NS1-based competition ELISA. Well characterized samples from RT-PCR-confirmed patients with Zika and individuals exposed to other flavivirus infections or vaccination were used in a comprehensive analysis to determine the sensitivity and specificity of the NS1 blockade-of-binding (BOB) assay, which was established in laboratories in five countries (Nicaragua, Brazil, Italy, United Kingdom, and Switzerland). Of 158 sera/plasma from RT-PCR-confirmed ZIKV infections, 145 (91.8%) yielded greater than 50% inhibition. Of 171 patients with primary or secondary DENV infections, 152 (88.9%) scored negative. When the control group was extended to patients infected by other flaviviruses, other viruses, or healthy donors (n = 540), the specificity was 95.9%. We also analyzed longitudinal samples from DENV-immune and DENV-naive ZIKV infections and found inhibition was achieved within 10 d postonset of illness and maintained over time. Thus, the Zika NS1 BOB assay is sensitive, specific, robust, simple, low-cost, and accessible, and can detect recent and past ZIKV infections for surveillance, seroprevalence studies, and intervention trials. PMID- 28716914 TI - Metabolic profiles of exercise in patients with McArdle disease or mitochondrial myopathy. AB - McArdle disease and mitochondrial myopathy impair muscle oxidative phosphorylation (OXPHOS) by distinct mechanisms: the former by restricting oxidative substrate availability caused by blocked glycogen breakdown, the latter because of intrinsic respiratory chain defects. We applied metabolic profiling to systematically interrogate these disorders at rest, when muscle symptoms are typically minimal, and with exercise, when symptoms of premature fatigue and potential muscle injury are unmasked. At rest, patients with mitochondrial disease exhibit elevated lactate and reduced uridine; in McArdle disease purine nucleotide metabolites, including xanthine, hypoxanthine, and inosine are elevated. During exercise, glycolytic intermediates, TCA cycle intermediates, and pantothenate expand dramatically in both mitochondrial disease and control subjects. In contrast, in McArdle disease, these metabolites remain unchanged from rest; but urea cycle intermediates are increased, likely attributable to increased ammonia production as a result of exaggerated purine degradation. Our results establish skeletal muscle glycogen as the source of TCA cycle expansion that normally accompanies exercise and imply that impaired TCA cycle flux is a central mechanism of restricted oxidative capacity in this disorder. Finally, we report that resting levels of long-chain triacylglycerols in mitochondrial myopathy correlate with the severity of OXPHOS dysfunction, as indicated by the level of impaired O2 extraction from arterial blood during peak exercise. Our integrated analysis of exercise and metabolism provides unique insights into the biochemical basis of these muscle oxidative defects, with potential implications for their clinical management. PMID- 28716915 TI - Prostaglandin dehydrogenase is a target for successful induction of cervical ripening. AB - The cervix represents a formidable structural barrier for successful induction of labor. Approximately 10% of pregnancies undergo induction of cervical ripening and labor with prostaglandin (PG) E2 or PGE analogs, often requiring many hours of hospitalization and monitoring. On the other hand, preterm cervical ripening in the second trimester predicts preterm birth. The regulatory mechanisms of this paradoxical function of the cervix are unknown. Here, we show that PGE2 uses cell specific EP2 receptor-mediated increases in Ca2+ to dephosphorylate and translocate histone deacetylase 4 (HDAC4) to the nucleus for repression of 15 hydroxy prostaglandin dehydrogenase (15-PGDH). The crucial role of 15-PGDH in cervical ripening was confirmed in vivo. Although PGE2 or 15-PGDH inhibitor alone did not alter gestational length, treatment with 15-PGDH inhibitor + PGE2 or metabolism-resistant dimethyl-PGE2 resulted in preterm cervical ripening and delivery in mice. The ability of PGE2 to selectively autoamplify its own synthesis in stromal cells by signaling transcriptional repression of 15-PGDH elucidates long sought-after molecular mechanisms that govern PG action in the cervix. This report details unique mechanisms of action in the cervix and serves as a catalyst for (i) the use of 15-PGDH inhibitors to initiate or amplify low dose PGE2-mediated cervical ripening or (ii) EP2 receptor antagonists, HDAC4 inhibitors, and 15-PGDH activators to prevent preterm cervical ripening and preterm birth. PMID- 28716916 TI - Genomic landscape of human diversity across Madagascar. AB - Although situated ~400 km from the east coast of Africa, Madagascar exhibits cultural, linguistic, and genetic traits from both Southeast Asia and Eastern Africa. The settlement history remains contentious; we therefore used a grid based approach to sample at high resolution the genomic diversity (including maternal lineages, paternal lineages, and genome-wide data) across 257 villages and 2,704 Malagasy individuals. We find a common Bantu and Austronesian descent for all Malagasy individuals with a limited paternal contribution from Europe and the Middle East. Admixture and demographic growth happened recently, suggesting a rapid settlement of Madagascar during the last millennium. However, the distribution of African and Asian ancestry across the island reveals that the admixture was sex biased and happened heterogeneously across Madagascar, suggesting independent colonization of Madagascar from Africa and Asia rather than settlement by an already admixed population. In addition, there are geographic influences on the present genomic diversity, independent of the admixture, showing that a few centuries is sufficient to produce detectable genetic structure in human populations. PMID- 28716917 TI - Diverse continuum of CD4+ T-cell states is determined by hierarchical additive integration of cytokine signals. AB - During cell differentiation, progenitor cells integrate signals from their environment that guide their development into specialized phenotypes. The ways by which cells respond to complex signal combinations remain difficult to analyze and model. To gain additional insight into signal integration, we systematically mapped the response of CD4+ T cells to a large number of input cytokine combinations that drive their differentiation. We find that, in response to varied input combinations, cells differentiate into a continuum of cell fates as opposed to a limited number of discrete phenotypes. Input cytokines hierarchically influence the cell population, with TGFbeta being most dominant followed by IL-6 and IL-4. Mathematical modeling explains these results using additive signal integration within hierarchical groups of input cytokine combinations and correctly predicts cell population response to new input conditions. These findings suggest that complex cellular responses can be effectively described using a segmented linear approach, providing a framework for prediction of cellular responses to new cytokine combinations and doses, with implications to fine-tuned immunotherapies. PMID- 28716918 TI - An invasive foundation species enhances multifunctionality in a coastal ecosystem. AB - While invasive species often threaten biodiversity and human well-being, their potential to enhance functioning by offsetting the loss of native habitat has rarely been considered. We manipulated the abundance of the nonnative, habitat forming seaweed Gracilaria vermiculophylla in large plots (25 m2) on southeastern US intertidal landscapes to assess impacts on multiple ecosystem functions underlying coastal ecosystem services. We document that in the absence of native habitat formers, this invasion has an overall positive, density-dependent impact across a diverse set of ecosystem processes (e.g., abundance and richness of nursery taxa, flow attenuation). Manipulation of invader abundance revealed both thresholds and saturations in the provisioning of ecosystem functions. Taken together, these findings call into question the focus of traditional invasion research and management that assumes negative effects of nonnatives, and emphasize the need to consider context-dependence and integrative measurements when assessing the impact of an invader, including density dependence, multifunctionality, and the status of native habitat formers. This work supports discussion of the idea that where native foundation species have been lost, invasive habitat formers may be considered as sources of valuable ecosystem functions. PMID- 28716919 TI - Decoupling of size and shape fluctuations in heteropolymeric sequences reconciles discrepancies in SAXS vs. FRET measurements. AB - Unfolded states of proteins and native states of intrinsically disordered proteins (IDPs) populate heterogeneous conformational ensembles in solution. The average sizes of these heterogeneous systems, quantified by the radius of gyration (RG ), can be measured by small-angle X-ray scattering (SAXS). Another parameter, the mean dye-to-dye distance (RE ) for proteins with fluorescently labeled termini, can be estimated using single-molecule Forster resonance energy transfer (smFRET). A number of studies have reported inconsistencies in inferences drawn from the two sets of measurements for the dimensions of unfolded proteins and IDPs in the absence of chemical denaturants. These differences are typically attributed to the influence of fluorescent labels used in smFRET and to the impact of high concentrations and averaging features of SAXS. By measuring the dimensions of a collection of labeled and unlabeled polypeptides using smFRET and SAXS, we directly assessed the contributions of dyes to the experimental values RG and RE For chemically denatured proteins we obtain mutual consistency in our inferences based on RG and RE , whereas for IDPs under native conditions, we find substantial deviations. Using computations, we show that discrepant inferences are neither due to methodological shortcomings of specific measurements nor due to artifacts of dyes. Instead, our analysis suggests that chemical heterogeneity in heteropolymeric systems leads to a decoupling between RE and RG that is amplified in the absence of denaturants. Therefore, joint assessments of RG and RE combined with measurements of polymer shapes should provide a consistent and complete picture of the underlying ensembles. PMID- 28716920 TI - VAMP3 and SNAP23 mediate the disturbed flow-induced endothelial microRNA secretion and smooth muscle hyperplasia. AB - Vascular endothelial cells (ECs) at arterial branches and curvatures experience disturbed blood flow and induce a quiescent-to-activated phenotypic transition of the adjacent smooth muscle cells (SMCs) and a subsequent smooth muscle hyperplasia. However, the mechanism underlying the flow pattern-specific initiation of EC-to-SMC signaling remains elusive. Our previous study demonstrated that endothelial microRNA-126-3p (miR-126-3p) acts as a key intercellular molecule to increase turnover of the recipient SMCs, and that its release is reduced by atheroprotective laminar shear (12 dynes/cm2) to ECs. Here we provide evidence that atherogenic oscillatory shear (0.5 +/- 4 dynes/cm2), but not atheroprotective pulsatile shear (12 +/- 4 dynes/cm2), increases the endothelial secretion of nonmembrane-bound miR-126-3p and other microRNAs (miRNAs) via the activation of SNAREs, vesicle-associated membrane protein 3 (VAMP3) and synaptosomal-associated protein 23 (SNAP23). Knockdown of VAMP3 and SNAP23 reduces endothelial secretion of miR-126-3p and miR-200a-3p, as well as the proliferation, migration, and suppression of contractile markers in SMCs caused by EC-coculture. Pharmacological intervention of mammalian target of rapamycin complex 1 in ECs blocks endothelial secretion and EC-to-SMC transfer of miR-126-3p through transcriptional inhibition of VAMP3 and SNAP23. Systemic inhibition of VAMP3 and SNAP23 by rapamycin or periadventitial application of the endocytosis inhibitor dynasore ameliorates the disturbed flow-induced neointimal formation, whereas intraluminal overexpression of SNAP23 aggravates it. Our findings demonstrate the flow-pattern-specificity of SNARE activation and its contribution to the miRNA-mediated EC-SMC communication. PMID- 28716921 TI - Toll ligand Spatzle3 controls melanization in the stripe pattern formation in caterpillars. AB - A stripe pattern is an aposematic or camouflage coloration often observed among various caterpillars. However, how this ecologically important pattern is formed is largely unknown. The silkworm dominant mutant Zebra (Ze) has a black stripe in the anterior margin of each dorsal segment. Here, fine linkage mapping of 3,135 larvae revealed a 63-kbp region responsible for the Ze locus, which contained three candidate genes, including the Toll ligand gene spatzle3 (spz-3). Both electroporation-mediated ectopic expression and RNAi analyses showed that, among candidate genes, only processed spz-3 induced melanin pigmentation and that Toll 8 was the candidate receptor gene of spz-3 This Toll ligand/receptor set is also involved in melanization of other mutant Striped (pS ), which has broader stripes. Additional knockdown of 5 other spz family and 10 Toll-related genes caused no drastic change in the pigmentation of either mutant, suggesting that only spz-3/Toll-8 is mainly involved in the melanization process rather than pattern formation. The downstream pigmentation gene yellow was specifically up regulated in the striped region of the Ze mutant, but spz-3 showed no such region specific expression. Toll signaling pathways are known to be involved in innate immunity, dorsoventral axis formation, and neurotrophic functions. This study provides direct evidence that a Toll signaling pathway is co-opted to control the melanization process and adaptive striped pattern formation in caterpillars. PMID- 28716922 TI - Local destabilization, rigid body, and fuzzy docking facilitate the phosphorylation of the transcription factor Ets-1 by the mitogen-activated protein kinase ERK2. AB - Mitogen-activated protein (MAP) kinase substrates are believed to require consensus docking motifs (D-site, F-site) to engage and facilitate efficient site specific phosphorylation at specific serine/threonine-proline sequences by their cognate kinases. In contrast to other MAP kinase substrates, the transcription factor Ets-1 has no canonical docking motifs, yet it is efficiently phosphorylated by the MAP kinase ERK2 at a consensus threonine site (T38). Using NMR methodology, we demonstrate that this phosphorylation is enabled by a unique bipartite mode of ERK2 engagement by Ets-1 and involves two suboptimal noncanonical docking interactions instead of a single canonical docking motif. The N terminus of Ets-1 interacts with a part of the ERK2 D-recruitment site that normally accommodates the hydrophobic sidechains of a canonical D-site, retaining a significant degree of disorder in its ERK2-bound state. In contrast, the C terminal region of Ets-1, including its Pointed (PNT) domain, engages in a largely rigid body interaction with a section of the ERK2 F-recruitment site through a binding mode that deviates significantly from that of a canonical F site. This latter interaction is notable for the destabilization of a flexible helix that bridges the phospho-acceptor site to the rigid PNT domain. These two spatially distinct, individually weak docking interactions facilitate the highly specific recognition of ERK2 by Ets-1, and enable the optimal localization of its dynamic phospho-acceptor T38 at the kinase active site to enable efficient phosphorylation. PMID- 28716923 TI - Molecular mechanism of environmental d-xylose perception by a XylFII-LytS complex in bacteria. AB - d-xylose, the main building block of plant biomass, is a pentose sugar that can be used by bacteria as a carbon source for bio-based fuel and chemical production through fermentation. In bacteria, the first step for d-xylose metabolism is signal perception at the membrane. We previously identified a three-component system in Firmicutes bacteria comprising a membrane-associated sensor protein (XylFII), a transmembrane histidine kinase (LytS) for periplasmic d-xylose sensing, and a cytoplasmic response regulator (YesN) that activates the transcription of the target ABC transporter xylFGH genes to promote the uptake of d-xylose. The molecular mechanism underlying signal perception and integration of these processes remains elusive, however. Here we purified the N-terminal periplasmic domain of LytS (LytSN) in a complex with XylFII and determined the conformational structures of the complex in its d-xylose-free and d-xylose-bound forms. LytSN contains a four-helix bundle, and XylFII contains two Rossmann fold like globular domains with a xylose-binding cleft between them. In the absence of d-xylose, LytSN and XylFII formed a heterodimer. Specific binding of d-xylose to the cleft of XylFII induced a large conformational change that closed the cleft and brought the globular domains closer together. This conformational change led to the formation of an active XylFII-LytSN heterotetramer. Mutations at the d xylose binding site and the heterotetramer interface diminished heterotetramer formation and impaired the d-xylose-sensing function of XylFII-LytS. Based on these data, we propose a working model of XylFII-LytS that provides a molecular basis for d-xylose utilization and metabolic modification in bacteria. PMID- 28716925 TI - Symmetry-related proton transfer pathways in respiratory complex I. AB - Complex I functions as the initial electron acceptor in aerobic respiratory chains of most organisms. This gigantic redox-driven enzyme employs the energy from quinone reduction to pump protons across its complete approximately 200-A membrane domain, thermodynamically driving synthesis of ATP. Despite recently resolved structures from several species, the molecular mechanism by which complex I catalyzes this long-range proton-coupled electron transfer process, however, still remains unclear. We perform here large-scale classical and quantum molecular simulations to study the function of the proton pump in complex I from Thermus thermophilus The simulations suggest that proton channels are established at symmetry-related locations in four subunits of the membrane domain. The channels open up by formation of quasi one-dimensional water chains that are sensitive to the protonation states of buried residues at structurally conserved broken helix elements. Our combined data provide mechanistic insight into long range coupling effects and predictions for site-directed mutagenesis experiments. PMID- 28716926 TI - Global analysis of depletion and recovery of seabed biota after bottom trawling disturbance. AB - Bottom trawling is the most widespread human activity affecting seabed habitats. Here, we collate all available data for experimental and comparative studies of trawling impacts on whole communities of seabed macroinvertebrates on sedimentary habitats and develop widely applicable methods to estimate depletion and recovery rates of biota after trawling. Depletion of biota and trawl penetration into the seabed are highly correlated. Otter trawls caused the least depletion, removing 6% of biota per pass and penetrating the seabed on average down to 2.4 cm, whereas hydraulic dredges caused the most depletion, removing 41% of biota and penetrating the seabed on average 16.1 cm. Median recovery times posttrawling (from 50 to 95% of unimpacted biomass) ranged between 1.9 and 6.4 y. By accounting for the effects of penetration depth, environmental variation, and uncertainty, the models explained much of the variability of depletion and recovery estimates from single studies. Coupled with large-scale, high-resolution maps of trawling frequency and habitat, our estimates of depletion and recovery rates enable the assessment of trawling impacts on unprecedented spatial scales. PMID- 28716924 TI - Insights into the red algae and eukaryotic evolution from the genome of Porphyra umbilicalis (Bangiophyceae, Rhodophyta). AB - Porphyra umbilicalis (laver) belongs to an ancient group of red algae (Bangiophyceae), is harvested for human food, and thrives in the harsh conditions of the upper intertidal zone. Here we present the 87.7-Mbp haploid Porphyra genome (65.8% G + C content, 13,125 gene loci) and elucidate traits that inform our understanding of the biology of red algae as one of the few multicellular eukaryotic lineages. Novel features of the Porphyra genome shared by other red algae relate to the cytoskeleton, calcium signaling, the cell cycle, and stress tolerance mechanisms including photoprotection. Cytoskeletal motor proteins in Porphyra are restricted to a small set of kinesins that appear to be the only universal cytoskeletal motors within the red algae. Dynein motors are absent, and most red algae, including Porphyra, lack myosin. This surprisingly minimal cytoskeleton offers a potential explanation for why red algal cells and multicellular structures are more limited in size than in most multicellular lineages. Additional discoveries further relating to the stress tolerance of bangiophytes include ancestral enzymes for sulfation of the hydrophilic galactan rich cell wall, evidence for mannan synthesis that originated before the divergence of green and red algae, and a high capacity for nutrient uptake. Our analyses provide a comprehensive understanding of the red algae, which are both commercially important and have played a major role in the evolution of other algal groups through secondary endosymbioses. PMID- 28716927 TI - Nuclear genomes distinguish cryptic species suggested by their DNA barcodes and ecology. AB - DNA sequencing brings another dimension to exploration of biodiversity, and large scale mitochondrial DNA cytochrome oxidase I barcoding has exposed many potential new cryptic species. Here, we add complete nuclear genome sequencing to DNA barcoding, ecological distribution, natural history, and subtleties of adult color pattern and size to show that a widespread neotropical skipper butterfly known as Udranomia kikkawai (Weeks) comprises three different species in Costa Rica. Full-length barcodes obtained from all three century-old Venezuelan syntypes of U. kikkawai show that it is a rainforest species occurring from Costa Rica to Brazil. The two new species are Udranomia sallydaleyae Burns, a dry forest denizen occurring from Costa Rica to Mexico, and Udranomia tomdaleyi Burns, which occupies the junction between the rainforest and dry forest and currently is known only from Costa Rica. Whereas the three species are cryptic, differing but slightly in appearance, their complete nuclear genomes totaling 15 million aligned positions reveal significant differences consistent with their 0.00065-Mbp (million base pair) mitochondrial barcodes and their ecological diversification. DNA barcoding of tropical insects reared by a massive inventory suggests that the presence of cryptic species is a widespread phenomenon and that further studies will substantially increase current estimates of insect species richness. PMID- 28716928 TI - Support for redistribution is shaped by compassion, envy, and self-interest, but not a taste for fairness. AB - Why do people support economic redistribution? Hypotheses include inequity aversion, a moral sense that inequality is intrinsically unfair, and cultural explanations such as exposure to and assimilation of culturally transmitted ideologies. However, humans have been interacting with worse-off and better-off individuals over evolutionary time, and our motivational systems may have been naturally selected to navigate the opportunities and challenges posed by such recurrent interactions. We hypothesize that modern redistribution is perceived as an ancestral scene involving three notional players: the needy other, the better off other, and the actor herself. We explore how three motivational systems compassion, self-interest, and envy-guide responses to the needy other and the better-off other, and how they pattern responses to redistribution. Data from the United States, the United Kingdom, India, and Israel support this model. Endorsement of redistribution is independently predicted by dispositional compassion, dispositional envy, and the expectation of personal gain from redistribution. By contrast, a taste for fairness, in the sense of (i) universality in the application of laws and standards, or (ii) low variance in group-level payoffs, fails to predict attitudes about redistribution. PMID- 28716929 TI - Nitric oxide is an obligate bacterial nitrification intermediate produced by hydroxylamine oxidoreductase. AB - Ammonia (NH3)-oxidizing bacteria (AOB) emit substantial amounts of nitric oxide (NO) and nitrous oxide (N2O), both of which contribute to the harmful environmental side effects of large-scale agriculture. The currently accepted model for AOB metabolism involves NH3 oxidation to nitrite (NO2-) via a single obligate intermediate, hydroxylamine (NH2OH). Within this model, the multiheme enzyme hydroxylamine oxidoreductase (HAO) catalyzes the four-electron oxidation of NH2OH to NO2- We provide evidence that HAO oxidizes NH2OH by only three electrons to NO under both anaerobic and aerobic conditions. NO2- observed in HAO activity assays is a nonenzymatic product resulting from the oxidation of NO by O2 under aerobic conditions. Our present study implies that aerobic NH3 oxidation by AOB occurs via two obligate intermediates, NH2OH and NO, necessitating a mediator of the third enzymatic step. PMID- 28716930 TI - Conserved gene regulatory module specifies lateral neural borders across bilaterians. AB - The lateral neural plate border (NPB), the neural part of the vertebrate neural border, is composed of central nervous system (CNS) progenitors and peripheral nervous system (PNS) progenitors. In invertebrates, PNS progenitors are also juxtaposed to the lateral boundary of the CNS. Whether there are conserved molecular mechanisms determining vertebrate and invertebrate lateral neural borders remains unclear. Using single-cell-resolution gene-expression profiling and genetic analysis, we present evidence that orthologs of the NPB specification module specify the invertebrate lateral neural border, which is composed of CNS and PNS progenitors. First, like in vertebrates, the conserved neuroectoderm lateral border specifier Msx/vab-15 specifies lateral neuroblasts in Caenorhabditis elegans Second, orthologs of the vertebrate NPB specification module (Msx/vab-15, Pax3/7/pax-3, and Zic/ref-2) are significantly enriched in worm lateral neuroblasts. In addition, like in other bilaterians, the expression domain of Msx/vab-15 is more lateral than those of Pax3/7/pax-3 and Zic/ref-2 in C. elegans Third, we show that Msx/vab-15 regulates the development of mechanosensory neurons derived from lateral neural progenitors in multiple invertebrate species, including C. elegans, Drosophila melanogaster, and Ciona intestinalis We also identify a novel lateral neural border specifier, ZNF703/tlp 1, which functions synergistically with Msx/vab-15 in both C. elegans and Xenopus laevis These data suggest a common origin of the molecular mechanism specifying lateral neural borders across bilaterians. PMID- 28716931 TI - Combining experimental and simulation data of molecular processes via augmented Markov models. AB - Accurate mechanistic description of structural changes in biomolecules is an increasingly important topic in structural and chemical biology. Markov models have emerged as a powerful way to approximate the molecular kinetics of large biomolecules while keeping full structural resolution in a divide-and-conquer fashion. However, the accuracy of these models is limited by that of the force fields used to generate the underlying molecular dynamics (MD) simulation data. Whereas the quality of classical MD force fields has improved significantly in recent years, remaining errors in the Boltzmann weights are still on the order of a few [Formula: see text], which may lead to significant discrepancies when comparing to experimentally measured rates or state populations. Here we take the view that simulations using a sufficiently good force-field sample conformations that are valid but have inaccurate weights, yet these weights may be made accurate by incorporating experimental data a posteriori. To do so, we propose augmented Markov models (AMMs), an approach that combines concepts from probability theory and information theory to consistently treat systematic force field error and statistical errors in simulation and experiment. Our results demonstrate that AMMs can reconcile conflicting results for protein mechanisms obtained by different force fields and correct for a wide range of stationary and dynamical observables even when only equilibrium measurements are incorporated into the estimation process. This approach constitutes a unique avenue to combine experiment and computation into integrative models of biomolecular structure and dynamics. PMID- 28716932 TI - Body ownership determines the attenuation of self-generated tactile sensations. AB - Self-perception depends on the brain's abilities to differentiate our body from the environment and to distinguish between the sensations generated as a consequence of voluntary movement and those arising from events in the external world. The first process refers to the sense of ownership of our body and relies on the dynamic integration of multisensory (afferent) signals. The second process depends on internal forward models that use (efferent) information from our motor commands to predict and attenuate the sensory consequences of our movements. However, the relationship between body ownership and sensory attenuation driven by the forward models remains unknown. To address this issue, we combined the rubber hand illusion, which allows experimental manipulation of body ownership, and the force-matching paradigm, which allows psychophysical quantification of somatosensory attenuation. We found that a rubber right hand pressing on the left index finger produced somatosensory attenuation but only when the model hand felt like one's own (illusory self-touch); reversely, the attenuation that was expected to occur during actual self-touch with the real hands was reduced when the participants simultaneously experienced ownership of a rubber right hand that was placed at a distance from their left hand. These results demonstrate that the sense of body ownership determines somatosensory attenuation. From a theoretical perspective, our results are important because they suggest that body ownership updates the internal representation of body state that provides the input to the forward model generating sensory predictions during voluntary action. PMID- 28716934 TI - Sigma-1 receptors control immune-driven peripheral opioid analgesia during inflammation in mice. AB - Sigma-1 antagonism potentiates the antinociceptive effects of opioid drugs, so sigma-1 receptors constitute a biological brake to opioid drug-induced analgesia. The pathophysiological role of this process is unknown. We aimed to investigate whether sigma-1 antagonism reduces inflammatory pain through the disinhibition of the endogenous opioidergic system in mice. The selective sigma-1 antagonists BD 1063 and S1RA abolished mechanical and thermal hyperalgesia in mice with carrageenan-induced acute (3 h) inflammation. Sigma-1-mediated antihyperalgesia was reversed by the opioid antagonists naloxone and naloxone methiodide (a peripherally restricted naloxone analog) and by local administration at the inflamed site of monoclonal antibody 3-E7, which recognizes the pan-opioid sequence Tyr-Gly-Gly-Phe at the N terminus of most endogenous opioid peptides (EOPs). Neutrophils expressed pro-opiomelanocortin, the precursor of beta endorphin (a known EOP), and constituted the majority of the acute immune infiltrate. beta-endorphin levels increased in the inflamed paw, and this increase and the antihyperalgesic effects of sigma-1 antagonism were abolished by reducing the neutrophil load with in vivo administration of an anti-Ly6G antibody. The opioid-dependent sigma-1 antihyperalgesic effects were preserved 5 d after carrageenan administration, where macrophages/monocytes were found to express pro-opiomelanocortin and to now constitute the majority of the immune infiltrate. These results suggest that immune cells harboring EOPs are needed for the antihyperalgesic effects of sigma-1 antagonism during inflammation. In conclusion, sigma-1 receptors curtail immune-driven peripheral opioid analgesia, and sigma-1 antagonism produces local opioid analgesia by enhancing the action of EOPs of immune origin, maximizing the analgesic potential of immune cells that naturally accumulate in painful inflamed areas. PMID- 28716933 TI - Cortical actin recovery at the immunological synapse leads to termination of lytic granule secretion in cytotoxic T lymphocytes. AB - CD8+ cytotoxic T lymphocytes (CTLs) eliminate virally infected cells through directed secretion of specialized lytic granules. Because a single CTL can kill multiple targets, degranulation must be tightly regulated. However, how CTLs regulate the termination of granule secretion remains unclear. Previous work demonstrated that centralized actin reduction at the immune synapse precedes degranulation. Using a combination of live confocal, total internal reflection fluorescence, and superresolution microscopy, we now show that, after granule fusion, actin recovers at the synapse and no further secretion is observed. Depolymerization of actin led to resumed granule secretion, suggesting that recovered actin acts as a barrier preventing sustained degranulation. Furthermore, RAB27a-deficient CTLs, which do not secrete cytotoxic granules, failed to recover actin at the synapse, suggesting that RAB27a-mediated granule secretion is required for actin recovery. Finally, we show that both actin clearance and recovery correlated with synaptic phosphatidylinositol 4,5 bisphosphate (PIP2) and that alterations in PIP2 at the immunological synapse regulate cortical actin in CTLs, providing a potential mechanism through which CTLs control cortical actin density. Our work provides insight into actin-related mechanisms regulating CTL secretion that may facilitate serial killing during immune responses. PMID- 28716935 TI - Severe viral respiratory infections in children with IFIH1 loss-of-function mutations. AB - Viral respiratory infections are usually mild and self-limiting; still they exceptionally result in life-threatening infections in previously healthy children. To investigate a potential genetic cause, we recruited 120 previously healthy children requiring support in intensive care because of a severe illness caused by a respiratory virus. Using exome and transcriptome sequencing, we identified and characterized three rare loss-of-function variants in IFIH1, which encodes an RIG-I-like receptor involved in the sensing of viral RNA. Functional testing of the variants IFIH1 alleles demonstrated that the resulting proteins are unable to induce IFN-beta, are intrinsically less stable than wild-type IFIH1, and lack ATPase activity. In vitro assays showed that IFIH1 effectively restricts replication of human respiratory syncytial virus and rhinoviruses. We conclude that IFIH1 deficiency causes a primary immunodeficiency manifested in extreme susceptibility to common respiratory RNA viruses. PMID- 28716936 TI - Bacterial infection imaging with [18F]fluoropropyl-trimethoprim. AB - There is often overlap in the diagnostic features of common pathologic processes such as infection, sterile inflammation, and cancer both clinically and using conventional imaging techniques. Here, we report the development of a positron emission tomography probe for live bacterial infection based on the small molecule antibiotic trimethoprim (TMP). [18F]fluoropropyl-trimethoprim, or [18F]FPTMP, shows a greater than 100-fold increased uptake in vitro in live bacteria (Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa) relative to controls. In a rodent myositis model, [18F]FPTMP identified live bacterial infection without demonstrating confounding increased signal in the same animal from other etiologies including chemical inflammation (turpentine) and cancer (breast carcinoma). Additionally, the biodistribution of [18F]FPTMP in a nonhuman primate shows low background in many important tissues that may be sites of infection such as the lungs and soft tissues. These results suggest that [18F]FPTMP could be a broadly useful agent for the sensitive and specific imaging of bacterial infection with strong translational potential. PMID- 28716937 TI - Altered metabotropic glutamate receptor 5 markers in PTSD: In vivo and postmortem evidence. AB - Posttraumatic stress disorder (PTSD) is a prevalent and highly disabling disorder, but there is currently no targeted pharmacological treatment for it. Dysfunction of the glutamate system has been implicated in trauma and stress psychopathology, resulting in a growing interest in modulation of the glutamate system for the treatment of PTSD. Specifically, the metabotropic glutamate receptor 5 (mGluR5) represents a promising treatment target. We used [18F]FPEB, a radioligand that binds to the mGluR5, and positron emission tomography (PET) to quantify in vivo mGluR5 availability in human PTSD vs. healthy control (HCs) subjects. In an independent sample of human postmortem tissue, we investigated expression of proteins that have a functional relationship with mGluR5 and glucocorticoids in PTSD. We observed significantly higher cortical mGluR5 availability in PTSD in vivo and positive correlations between mGluR5 availability and avoidance symptoms. In the postmortem sample, we observed up regulation of SHANK1, a protein that anchors mGluR5 to the cell surface, as well as decreased expression of FKBP5, implicating aberrant glucocorticoid functioning in PTSD. Results of this study provide insight into molecular mechanisms underlying PTSD and suggest that mGluR5 may be a promising target for mechanism based treatments aimed at mitigating this disorder. PMID- 28716938 TI - Dynamic responses of the adrenal steroidogenic regulatory network. AB - The hypothalamic-pituitary-adrenal axis is a dynamic system regulating glucocorticoid hormone synthesis in the adrenal glands. Many key factors within the adrenal steroidogenic pathway have been identified and studied, but little is known about how these factors function collectively as a dynamic network of interacting components. To investigate this, we developed a mathematical model of the adrenal steroidogenic regulatory network that accounts for key regulatory processes occurring at different timescales. We used our model to predict the time evolution of steroidogenesis in response to physiological adrenocorticotropic hormone (ACTH) perturbations, ranging from basal pulses to larger stress-like stimulations (e.g., inflammatory stress). Testing these predictions experimentally in the rat, our results show that the steroidogenic regulatory network architecture is sufficient to respond to both small and large ACTH perturbations, but coupling this regulatory network with the immune pathway is necessary to explain the dissociated dynamics between ACTH and glucocorticoids observed under conditions of inflammatory stress. PMID- 28716939 TI - Distinct requirements for energy metabolism in mouse primordial germ cells and their reprogramming to embryonic germ cells. AB - Primordial germ cells (PGCs), undifferentiated embryonic germ cells, are the only cells that have the ability to become gametes and to reacquire totipotency upon fertilization. It is generally understood that the development of PGCs proceeds through the expression of germ cell-specific transcription factors and characteristic epigenomic changes. However, little is known about the properties of PGCs at the metabolite and protein levels, which are directly responsible for the control of cell function. Here, we report the distinct energy metabolism of PGCs compared with that of embryonic stem cells. Specifically, we observed remarkably enhanced oxidative phosphorylation (OXPHOS) and decreased glycolysis in embryonic day 13.5 (E13.5) PGCs, a pattern that was gradually established during PGC differentiation. We also demonstrate that glycolysis and OXPHOS are important for the control of PGC reprogramming and specification of pluripotent stem cells (PSCs) into PGCs in culture. Our findings about the unique metabolic property of PGCs provide insights into our understanding of the importance of distinct facets of energy metabolism for switching PGC and PSC status. PMID- 28716940 TI - Reassessing the atmospheric oxidation mechanism of toluene. AB - Photochemical oxidation of aromatic hydrocarbons leads to tropospheric ozone and secondary organic aerosol (SOA) formation, with profound implications for air quality, human health, and climate. Toluene is the most abundant aromatic compound under urban environments, but its detailed chemical oxidation mechanism remains uncertain. From combined laboratory experiments and quantum chemical calculations, we show a toluene oxidation mechanism that is different from the one adopted in current atmospheric models. Our experimental work indicates a larger-than-expected branching ratio for cresols, but a negligible formation of ring-opening products (e.g., methylglyoxal). Quantum chemical calculations also demonstrate that cresols are much more stable than their corresponding peroxy radicals, and, for the most favorable OH (ortho) addition, the pathway of H extraction by O2 to form the cresol proceeds with a smaller barrier than O2 addition to form the peroxy radical. Our results reveal that phenolic (rather than peroxy radical) formation represents the dominant pathway for toluene oxidation, highlighting the necessity to reassess its role in ozone and SOA formation in the atmosphere. PMID- 28716941 TI - Cryptic oxygen cycling in anoxic marine zones. AB - Oxygen availability drives changes in microbial diversity and biogeochemical cycling between the aerobic surface layer and the anaerobic core in nitrite-rich anoxic marine zones (AMZs), which constitute huge oxygen-depleted regions in the tropical oceans. The current paradigm is that primary production and nitrification within the oxic surface layer fuel anaerobic processes in the anoxic core of AMZs, where 30-50% of global marine nitrogen loss takes place. Here we demonstrate that oxygenic photosynthesis in the secondary chlorophyll maximum (SCM) releases significant amounts of O2 to the otherwise anoxic environment. The SCM, commonly found within AMZs, was dominated by the picocyanobacteria Prochlorococcus spp. Free O2 levels in this layer were, however, undetectable by conventional techniques, reflecting a tight coupling between O2 production and consumption by aerobic processes under apparent anoxic conditions. Transcriptomic analysis of the microbial community in the seemingly anoxic SCM revealed the enhanced expression of genes for aerobic processes, such as nitrite oxidation. The rates of gross O2 production and carbon fixation in the SCM were found to be similar to those reported for nitrite oxidation, as well as for anaerobic dissimilatory nitrate reduction and sulfate reduction, suggesting a significant effect of local oxygenic photosynthesis on Pacific AMZ biogeochemical cycling. PMID- 28716942 TI - Maternal photoperiod programs hypothalamic thyroid status via the fetal pituitary gland. AB - In wild mammals, offspring development must anticipate forthcoming metabolic demands and opportunities. Within species, different developmental strategies may be used, dependent on when in the year conception takes place. This phenotypic flexibility is initiated before birth and is linked to the pattern of day length (photoperiod) exposure experienced by the mother during pregnancy. This programming depends on transplacental communication via the pineal hormone melatonin. Here, we show that, in the Siberian hamster (Phodopus sungorus), the programming effect of melatonin is mediated by the pars tuberalis (PT) of the fetal pituitary gland, before the fetal circadian system and autonomous melatonin production is established. Maternal melatonin acts on the fetal PT to control expression of thyroid hormone deiodinases in ependymal cells (tanycytes) of the fetal hypothalamus, and hence neuroendocrine output. This mechanism sets the trajectory of reproductive and metabolic development in pups and has a persistent effect on their subsequent sensitivity to the photoperiod. This programming effect depends on tanycyte sensitivity to thyroid stimulating hormone (TSH), which is dramatically and persistently increased by short photoperiod exposure in utero. Our results define the role of the fetal PT in developmental programming of brain function by maternal melatonin and establish TSH signal transduction as a key substrate for the encoding of internal calendar time from birth to puberty. PMID- 28716943 TI - Visualizing context-dependent calcium signaling in encephalitogenic T cells in vivo by two-photon microscopy. AB - In experimental autoimmune encephalitis (EAE), autoimmune T cells are activated in the periphery before they home to the CNS. On their way, the T cells pass through a series of different cellular milieus where they receive signals that instruct them to invade their target tissues. These signals involve interaction with the surrounding stroma cells, in the presence or absence of autoantigens. To portray the serial signaling events, we studied a T-cell-mediated model of EAE combining in vivo two-photon microscopy with two different activation reporters, the FRET-based calcium biosensor Twitch1 and fluorescent NFAT. In vitro activated T cells first settle in secondary (2 degrees ) lymphatic tissues (e.g., the spleen) where, in the absence of autoantigen, they establish transient contacts with stroma cells as indicated by sporadic short-lived calcium spikes. The T cells then exit the spleen for the CNS where they first roll and crawl along the luminal surface of leptomeningeal vessels without showing calcium activity. Having crossed the blood-brain barrier, the T cells scan the leptomeningeal space for autoantigen-presenting cells (APCs). Sustained contacts result in long lasting calcium activity and NFAT translocation, a measure of full T-cell activation. This process is sensitive to anti-MHC class II antibodies. Importantly, the capacity to activate T cells is not a general property of all leptomeningeal phagocytes, but varies between individual APCs. Our results identify distinct checkpoints of T-cell activation, controlling the capacity of myelin-specific T cells to invade and attack the CNS. These processes may be valuable therapeutic targets. PMID- 28716944 TI - Potent competitive inhibition of human ribonucleotide reductase by a nonnucleoside small molecule. AB - Human ribonucleotide reductase (hRR) is crucial for DNA replication and maintenance of a balanced dNTP pool, and is an established cancer target. Nucleoside analogs such as gemcitabine diphosphate and clofarabine nucleotides target the large subunit (hRRM1) of hRR. These drugs have a poor therapeutic index due to toxicity caused by additional effects, including DNA chain termination. The discovery of nonnucleoside, reversible, small-molecule inhibitors with greater specificity against hRRM1 is a key step in the development of more effective treatments for cancer. Here, we report the identification and characterization of a unique nonnucleoside small-molecule hRR inhibitor, naphthyl salicylic acyl hydrazone (NSAH), using virtual screening, binding affinity, inhibition, and cell toxicity assays. NSAH binds to hRRM1 with an apparent dissociation constant of 37 uM, and steady-state kinetics reveal a competitive mode of inhibition. A 2.66-A resolution crystal structure of NSAH in complex with hRRM1 demonstrates that NSAH functions by binding at the catalytic site (C-site) where it makes both common and unique contacts with the enzyme compared with NDP substrates. Importantly, the IC50 for NSAH is within twofold of gemcitabine for growth inhibition of multiple cancer cell lines, while demonstrating little cytotoxicity against normal mobilized peripheral blood progenitor cells. NSAH depresses dGTP and dATP levels in the dNTP pool causing S phase arrest, providing evidence for RR inhibition in cells. This report of a nonnucleoside reversible inhibitor binding at the catalytic site of hRRM1 provides a starting point for the design of a unique class of hRR inhibitors. PMID- 28716946 TI - Dynamic fluid connectivity during steady-state multiphase flow in a sandstone. AB - The current conceptual picture of steady-state multiphase Darcy flow in porous media is that the fluid phases organize into separate flow pathways with stable interfaces. Here we demonstrate a previously unobserved type of steady-state flow behavior, which we term "dynamic connectivity," using fast pore-scale X-ray imaging. We image the flow of N2 and brine through a permeable sandstone at subsurface reservoir conditions, and low capillary numbers, and at constant fluid saturation. At any instant, the network of pores filled with the nonwetting phase is not necessarily connected. Flow occurs along pathways that periodically reconnect, like cars controlled by traffic lights. This behavior is consistent with an energy balance, where some of the energy of the injected fluids is sporadically converted to create new interfaces. PMID- 28716945 TI - Evaluating optimal therapy robustness by virtual expansion of a sample population, with a case study in cancer immunotherapy. AB - Cancer is a highly heterogeneous disease, exhibiting spatial and temporal variations that pose challenges for designing robust therapies. Here, we propose the VEPART (Virtual Expansion of Populations for Analyzing Robustness of Therapies) technique as a platform that integrates experimental data, mathematical modeling, and statistical analyses for identifying robust optimal treatment protocols. VEPART begins with time course experimental data for a sample population, and a mathematical model fit to aggregate data from that sample population. Using nonparametric statistics, the sample population is amplified and used to create a large number of virtual populations. At the final step of VEPART, robustness is assessed by identifying and analyzing the optimal therapy (perhaps restricted to a set of clinically realizable protocols) across each virtual population. As proof of concept, we have applied the VEPART method to study the robustness of treatment response in a mouse model of melanoma subject to treatment with immunostimulatory oncolytic viruses and dendritic cell vaccines. Our analysis (i) showed that every scheduling variant of the experimentally used treatment protocol is fragile (nonrobust) and (ii) discovered an alternative region of dosing space (lower oncolytic virus dose, higher dendritic cell dose) for which a robust optimal protocol exists. PMID- 28716947 TI - Thermodynamic constraint on the depth of the global tropospheric circulation. AB - The troposphere is the region of the atmosphere characterized by low static stability, vigorous diabatic mixing, and widespread condensational heating in clouds. Previous research has argued that in the tropics, the upper bound on tropospheric mixing and clouds is constrained by the rapid decrease with height of the saturation water vapor pressure and hence radiative cooling by water vapor in clear-sky regions. Here the authors contend that the same basic physics play a key role in constraining the vertical structure of tropospheric mixing, tropopause temperature, and cloud-top temperature throughout the globe. It is argued that radiative cooling by water vapor plays an important role in governing the depth and amplitude of large-scale dynamics at extratropical latitudes. PMID- 28716948 TI - Cooperative Repression of Insulin-Like Growth Factor Type 2 Receptor Translation by MicroRNA 195 and RNA-Binding Protein CUGBP1. AB - Insulin-like growth factor type 2 (IGF2) receptor (IGF2R) recognizes mannose 6 phosphate-containing molecules and IGF2 and plays an important role in many pathophysiological processes, including gut mucosal adaptation. However, the mechanisms that control cellular IGF2R abundance are poorly known. MicroRNAs (miRNAs) and RNA-binding proteins (RBPs) critically regulate gene expression programs in mammalian cells by modulating the stability and translation of target mRNAs. Here we report that miRNA 195 (miR-195) and RBP CUG-binding protein 1 (CUGBP1) jointly regulate IGF2R expression at the posttranscriptional level in intestinal epithelial cells. Both miR-195 and CUGBP1 interacted with the 3' untranslated region (3'-UTR) of Igf2r mRNA, and the association of CUGBP1 with Igf2r mRNA enhanced miR-195 binding to Igf2r mRNA. Ectopically expressed CUGBP1 and miR-195 repressed IGF2R translation cooperatively without altering the stability of Igf2r mRNA. Importantly, the miR-195- and CUGBP1-repressed levels of cellular IGF2R led to a disruption in the structure of the trans-Golgi network. These findings indicate that IGF2R expression is controlled posttranscriptionally by two factors that associate with Igf2r mRNA and suggest that miR-195 and CUGBP1 dampen IGF signaling by inhibiting IGF2R translation. PMID- 28716949 TI - Biochemical Regulatory Features of Activation-Induced Cytidine Deaminase Remain Conserved from Lampreys to Humans. AB - Activation-induced cytidine deaminase (AID) is a genome-mutating enzyme that initiates class switch recombination and somatic hypermutation of antibodies in jawed vertebrates. We previously described the biochemical properties of human AID and found that it is an unusual enzyme in that it exhibits binding affinities for its substrate DNA and catalytic rates several orders of magnitude higher and lower, respectively, than a typical enzyme. Recently, we solved the functional structure of AID and demonstrated that these properties are due to nonspecific DNA binding on its surface, along with a catalytic pocket that predominantly assumes a closed conformation. Here we investigated the biochemical properties of AID from a sea lamprey, nurse shark, tetraodon, and coelacanth: representative species chosen because their lineages diverged at the earliest critical junctures in evolution of adaptive immunity. We found that these earliest-diverged AID orthologs are active cytidine deaminases that exhibit unique substrate specificities and thermosensitivities. Significant amino acid sequence divergence among these AID orthologs is predicted to manifest as notable structural differences. However, despite major differences in sequence specificities, thermosensitivities, and structural features, all orthologs share the unusually high DNA binding affinities and low catalytic rates. This absolute conservation is evidence for biological significance of these unique biochemical properties. PMID- 28716950 TI - Analysis of Small Critical Regions of Swi1 Conferring Prion Formation, Maintenance, and Transmission. AB - Saccharomyces cerevisiae contains several prion elements, which are epigenetically transmitted as self-perpetuating protein conformations. One such prion is [SWI+ ], whose protein determinant is Swi1, a subunit of the SWI/SNF chromatin-remodeling complex. We previously reported that [SWI+ ] formation results in a partial loss-of-function phenotype of poor growth in nonglucose medium and abolishment of multicellular features. We also showed that the first 38 amino acids of Swi1 propagated [SWI+]. We show here that a region as small as the first 32 amino acids of Swi1 (Swi11-32) can decorate [SWI+] aggregation and stably maintain and transmit [SWI+] independently of full-length Swi1. Regions smaller than Swi11-32 are either incapable of aggregation or unstably propagate [SWI+]. When fused to Sup35MC, the [PSI+ ] determinant lacking its PrD, Swi11-31 and Swi11-32 can act as transferable prion domains (PrDs). The resulting fusions give rise to a novel chimeric prion, [SPS+], exhibiting [PSI+]-like nonsense suppression. Thus, an NH2-terminal region of ~30 amino acids of Swi1 contains all the necessary information for in vivo prion formation, maintenance, and transmission. This PrD is unique in size and composition: glutamine free, asparagine rich, and the smallest defined to date. Our findings broaden our understanding of what features allow a protein region to serve as a PrD. PMID- 28716951 TI - A Calcium- and Diacylglycerol-Stimulated Protein Kinase C (PKC), Caenorhabditis elegans PKC-2, Links Thermal Signals to Learned Behavior by Acting in Sensory Neurons and Intestinal Cells. AB - Ca2+- and diacylglycerol (DAG)-activated protein kinase C (cPKC) promotes learning and behavioral plasticity. However, knowledge of in vivo regulation and exact functions of cPKCs that affect behavior is limited. We show that PKC-2, a Caenorhabditis elegans cPKC, is essential for a complex behavior, thermotaxis. C. elegans memorizes a nutrient-associated cultivation temperature (Tc ) and migrates along the Tc within a 17 to 25 degrees C gradient. pkc-2 gene disruption abrogated thermotaxis; a PKC-2 transgene, driven by endogenous pkc-2 promoters, restored thermotaxis behavior in pkc-2-/- animals. Cell-specific manipulation of PKC-2 activity revealed that thermotaxis is controlled by cooperative PKC-2 mediated signaling in both AFD sensory neurons and intestinal cells. Cold directed migration (cryophilic drive) precedes Tc tracking during thermotaxis. Analysis of temperature-directed behaviors elicited by persistent PKC-2 activation or inhibition in AFD (or intestine) disclosed that PKC-2 regulates initiation and duration of cryophilic drive. In AFD neurons, PKC-2 is a Ca2+ sensor and signal amplifier that operates downstream from cyclic GMP-gated cation channels and distal guanylate cyclases. UNC-18, which regulates neurotransmitter and neuropeptide release from synaptic vesicles, is a critical PKC-2 effector in AFD. UNC-18 variants, created by mutating Ser311 or Ser322, disrupt thermotaxis and suppress PKC-2-dependent cryophilic migration. PMID- 28716952 TI - Differential involvement of the medial prefrontal cortex across variants of contextual fear conditioning. AB - The context preexposure facilitation effect (CPFE) is a contextual fear conditioning paradigm in which learning about the context, acquiring the context shock association, and retrieving/expressing contextual fear are temporally dissociated into three distinct phases. In contrast, learning about the context and the context-shock association happens concurrently in standard contextual fear conditioning (sCFC). By infusing the GABAA receptor agonist muscimol into medial prefrontal cortex (mPFC) in adolescent Long-Evans rats, the current set of experiments examined the functional role of the mPFC in each phase of the CPFE and sCFC. In the CPFE, the mPFC is necessary for the following: acquisition and/or consolidation of context memory (Experiment 1), reconsolidation of a context memory to include shock (Experiment 2), and expression of contextual fear memory during a retention test (Experiment 3). In contrast to the CPFE, inactivation of the mPFC prior to conditioning in sCFC has no effect on acquisition, consolidation, or retention of a contextual fear memory (Experiment 4). Interestingly, the mPFC is not required for acquiring a context-shock association (measured by post-shock freezing) in the CPFE or sCFC (Experiment 2b and 4). Taken together, these results indicate that the mPFC is differentially recruited across stages of learning and variants of contextual fear conditioning (CPFE versus sCFC). More specifically, separating out learning about the context and the context-shock association necessitates activation of the medial prefrontal cortex during early learning and/or consolidation. PMID- 28716953 TI - A novel in vitro analog expressing learning-induced cellular correlates in distinct neural circuits. AB - When presented with noxious stimuli, Aplysia exhibits concurrent sensitization of defensive responses, such as the tail-induced siphon withdrawal reflex (TSWR) and suppression of feeding. At the cellular level, sensitization of the TSWR is accompanied by an increase in the excitability of the tail sensory neurons (TSNs) that elicit the reflex, whereas feeding suppression is accompanied by decreased excitability of B51, a decision-making neuron in the feeding neural circuit. The goal of this study was to develop an in vitro analog coexpressing the above cellular correlates. We used a reduced preparation consisting of buccal, cerebral, and pleural-pedal ganglia, which contain the neural circuits controlling feeding and the TSWR, respectively. Sensitizing stimuli were delivered in vitro by electrical stimulation of afferent nerves. When trained with sensitizing stimuli, the in vitro analog expressed concomitant increased excitability in TSNs and decreased excitability in B51, which are consistent with the occurrence of sensitization and feeding suppression induced by in vivo training. This in vitro analog expressed both short-term (15 min) and long-term (24 h) excitability changes in TSNs and B51, depending on the amount of training administered. Finally, in vitro application of serotonin increased TSN excitability without altering B51 excitability, mirroring the in vivo application of the monoamine that induces sensitization, but not feeding suppression. PMID- 28716954 TI - Synaptically driven phosphorylation of ribosomal protein S6 is differentially regulated at active synapses versus dendrites and cell bodies by MAPK and PI3K/mTOR signaling pathways. AB - High-frequency stimulation of the medial perforant path triggers robust phosphorylation of ribosomal protein S6 (rpS6) in activated dendritic domains and granule cell bodies. Here we dissect the signaling pathways responsible for synaptically driven rpS6 phosphorylation in the dentate gyrus using pharmacological agents to inhibit PI3-kinase/mTOR and MAPK/ERK-dependent kinases. Using phospho-specific antibodies for rpS6 at different sites (ser235/236 versus ser240/244), we show that delivery of the PI3-kinase inhibitor, wortmannin, decreased rpS6 phosphorylation throughout the somatodendritic compartment (granule cell layer, inner molecular layer, outer molecular layer), especially in granule cell bodies while sparing phosphorylation at activated synapses (middle molecular layer). In contrast, delivery of U0126, an MEK inhibitor, attenuated rpS6 phosphorylation specifically in the dendritic laminae leaving phosphorylation in the granule cell bodies intact. Delivery of the mTOR inhibitor, rapamycin, abolished activation of rpS6 phosphorylation in granule cell bodies and dendrites, whereas delivery of a selective S6K1 inhibitor, PF4708671, or RSK inhibitor, SL0101-1, attenuated rpS6 phosphorylation throughout the postsynaptic cell. These results reveal that MAPK/ERK-dependent signaling is predominately responsible for the selective induction of rpS6 phosphorylation at active synapses. In contrast, PI3-kinase/mTOR-dependent signaling induces rpS6 phosphorylation throughout the somatodendritic compartment but plays a minimal role at active synapses. Collectively, these results suggest a potential mechanism by which PI3-kinase/mTOR and MAPK/ERK pathways regulate translation at specific subcellular compartments in response to synaptic activity. PMID- 28716955 TI - Acute exercise enhances the consolidation of fear extinction memory and reduces conditioned fear relapse in a sex-dependent manner. AB - Fear extinction-based exposure therapy is the most common behavioral therapy for anxiety and trauma-related disorders, but fear extinction memories are labile and fear tends to return even after successful extinction. The relapse of fear contributes to the poor long-term efficacy of exposure therapy. A single session of voluntary exercise can enhance the acquisition and consolidation of fear extinction in male rats, but the effects of exercise on relapse of fear after extinction are not well understood. Here, we characterized the effects of 2 h of voluntary exercise during the consolidation phase of contextual or auditory fear extinction learning on long-term fear extinction memory and renewal in adult, male and female, Long-Evans rats. Results indicate that exercise enhances consolidation of fear extinction memory and reduces fear relapse after extinction in a sex-dependent manner. These data suggest that brief bouts of exercise could be used as an augmentation strategy for exposure therapy, even in previously sedentary subjects. Fear memories of discrete cues, rather than of contextual ones, may be most susceptible to exercise-augmented extinction, especially in males. Additionally, exercise seems to have the biggest impact on fear relapse phenomena, even if fear extinction memories themselves are only minimally enhanced. PMID- 28716956 TI - A comparison of behavioral and pharmacological interventions to attenuate reactivated fear memories. AB - Two experiments using rats in a contextual fear memory preparation compared two approaches to reduce conditioned fear: (1) pharmacological reconsolidation blockade and (2) reactivation-plus-extinction training. In Experiment 1, we explored different combinations of reactivation-plus-extinction parameters to reduce conditioned fear and attenuate reacquisition. In Experiment 2, memory reactivation was followed by extinction training or administration of midazolam (MDZ) (vs. vehicle) to reduce conditioned fear and attenuate spontaneous recovery. We found both treatments to be equally effective in both experiments. This study suggests that parameters leading to memory destabilization during reactivation are critical to observe long-lasting effects of MDZ or reactivation plus extinction. PMID- 28716957 TI - AMPA receptors control fear extinction through an Arc-dependent mechanism. AB - Activity-regulated cytoskeleton-associated protein (Arc) supports fear memory through synaptic plasticity events requiring actin cytoskeleton rearrangements. We have previously shown that reducing hippocampal Arc levels through antisense knockdown leads to the premature extinction of contextual fear. Here we show that the AMPA receptor antagonist CNQX elevates hippocampal Arc levels during extinction and blocks extinction that can be rescued by reducing Arc. Increasing Arc levels with CNQX also overcomes the actin-destabilizing properties of cytochalasin D and promotes extinction. Therefore, extinction is dependent on AMPA-mediated reductions of Arc via a mechanism consistent with a role for Arc in stabilizing the actin cytoskeleton to constrain extinction. PMID- 28716959 TI - Podocyte Growing Pains in Adaptive FSGS. PMID- 28716958 TI - delta Subunit-containing GABAA receptor prevents overgeneralization of fear in adult mice. AB - The role of delta subunit-containing GABAA receptor (GABAA(delta)R) in fear generalization is uncertain. Here, by using mice with or without genetic deletion of GABAA(delta)R and using protocols in which the conditioned tone stimuli were cross presented with different nonconditioned stimuli, we observed that when the two tone stimuli were largely similar, both genotypes froze similarly to either of them. However, when they differed markedly, the knockout mice froze much more than their wild-type littermates to the nonconditioned but not conditioned stimuli. Thus, GABAA(delta)R may prevent inappropriate fear generalization when the incoming stimuli differ clearly from the learned threat. PMID- 28716961 TI - Structural Basis of Large-Scale Functional Connectivity in the Mouse. AB - Translational neuroimaging requires approaches and techniques that can bridge between multiple different species and disease states. One candidate method that offers insights into the brain's functional connectivity (FC) is resting-state fMRI (rs-fMRI). In both humans and nonhuman primates, patterns of FC (often referred to as the functional connectome) have been related to the underlying structural connectivity (SC; also called the structural connectome). Given the recent rise in preclinical neuroimaging of mouse models, it is an important question whether the mouse functional connectome conforms to the underlying SC. Here, we compared FC derived from rs-fMRI in female mice with the underlying monosynaptic structural connectome as provided by the Allen Brain Connectivity Atlas. We show that FC between interhemispheric homotopic cortical and hippocampal areas, as well as in cortico-striatal pathways, emerges primarily via monosynaptic structural connections. In particular, we demonstrate that the striatum (STR) can be segregated according to differential rs-fMRI connectivity patterns that mirror monosynaptic connectivity with isocortex. In contrast, for certain subcortical networks, FC emerges along polysynaptic pathways as shown for left and right STR, which do not share direct anatomical connections, but high FC is putatively driven by a top-down cortical control. Finally, we show that FC involving cortico-thalamic pathways is limited, possibly confounded by the effect of anesthesia, small regional size, and tracer injection volume. These findings provide a critical foundation for using rs-fMRI connectivity as a translational tool to study complex brain circuitry interactions and their pathology due to neurological or psychiatric diseases across species.SIGNIFICANCE STATEMENT A comprehensive understanding of how the anatomical architecture of the brain, often referred to as the "connectome," corresponds to its function is arguably one of the biggest challenges for understanding the brain and its pathologies. Here, we use the mouse as a model for comparing functional connectivity (FC) derived from resting-state fMRI with gold standard structural connectivity measures based on tracer injections. In particular, we demonstrate high correspondence between FC measurements of cortico-cortical and cortico-striatal regions and their anatomical underpinnings. This work provides a critical foundation for studying the pathology of these circuits across mouse models and human patients. PMID- 28716962 TI - Gamma Oscillations in the Rat Ventral Striatum Originate in the Piriform Cortex. AB - Local field potentials (LFPs) recorded from the human and rodent ventral striatum (vStr) exhibit prominent, behaviorally relevant gamma-band oscillations. These oscillations are related to local spiking activity and transiently synchronize with anatomically related areas, suggesting a possible role in organizing vStr activity. However, the origin of vStr gamma is unknown. We recorded vStr gamma oscillations across a 1.4 mm2 grid spanned by 64 recording electrodes as male rats rested and foraged for rewards, revealing a highly consistent power gradient originating in the adjacent piriform cortex. Phase differences across the vStr were consistently small (<15 degrees ) and current source density analysis further confirmed the absence of local sink-source pairs in the vStr. Reversible occlusions of the ipsilateral (but not contralateral) nostril, known to abolish gamma oscillations in the piriform cortex, strongly reduced vStr gamma power and the occurrence of transient gamma-band events. These results imply that local circuitry is not a major contributor to gamma oscillations in the vStr LFP and that piriform cortex is an important driver of gamma-band oscillations in the vStr and associated limbic areas.SIGNIFICANCE STATEMENT The ventral striatum (vStr) is an area of anatomical convergence in circuits underlying motivated behavior, but it remains unclear how its inputs from different sources interact. A major proposal about how neural circuits may switch dynamically between convergent inputs is through temporal organization reflected in local field potential (LFP) oscillations. Our results show that, in the rat, the mechanisms controlling gamma-band oscillations in the vStr LFP are primarily located in the in the adjacent piriform cortex rather than in the vStr itself, providing a novel interpretation of previous rodent work on gamma oscillations in the vStr and related circuits and an important consideration for future work seeking to use oscillations in these areas as biomarkers for behavioral and neurological disorders. PMID- 28716960 TI - Bacterial Tubulins A and B Exhibit Polarized Growth, Mixed-Polarity Bundling, and Destabilization by GTP Hydrolysis. AB - Bacteria of the genus Prosthecobacter express homologs of eukaryotic alpha- and beta-tubulin, called BtubA and BtubB (BtubA/B), that have been observed to assemble into filaments in the presence of GTP. BtubA/B polymers are proposed to be composed in vitro by two to six protofilaments in contrast to that in vivo, where they have been reported to form 5-protofilament tubes named bacterial microtubules (bMTs). The btubAB genes likely entered the Prosthecobacter lineage via horizontal gene transfer and may be derived from an early ancestor of the modern eukaryotic microtubule (MT). Previous biochemical studies revealed that BtubA/B polymerization is reversible and that BtubA/B folding does not require chaperones. To better understand BtubA/B filament behavior and gain insight into the evolution of microtubule dynamics, we characterized in vitro BtubA/B assembly using a combination of polymerization kinetics assays and microscopy. Like eukaryotic microtubules, BtubA/B filaments exhibit polarized growth with different assembly rates at each end. GTP hydrolysis stimulated by BtubA/B polymerization drives a stochastic mechanism of filament disassembly that occurs via polymer breakage and/or fast continuous depolymerization. We also observed treadmilling (continuous addition and loss of subunits at opposite ends) of BtubA/B filament fragments. Unlike MTs, polymerization of BtubA/B requires KCl, which reduces the critical concentration for BtubA/B assembly and induces it to form stable mixed-orientation bundles in the absence of any additional BtubA/B binding proteins. The complex dynamics that we observe in stabilized and unstabilized BtubA/B filaments may reflect common properties of an ancestral eukaryotic tubulin polymer.IMPORTANCE Microtubules are polymers within all eukaryotic cells that perform critical functions; they segregate chromosomes, organize intracellular transport, and support the flagella. These functions rely on the remarkable range of tunable dynamic behaviors of microtubules. Bacterial tubulin A and B (BtubA/B) are evolutionarily related proteins that form polymers. They are proposed to be evolved from the ancestral eukaryotic tubulin, a missing link in microtubule evolution. Using microscopy and biochemical approaches to characterize BtubA/B assembly in vitro, we observed that they exhibit complex and structurally polarized dynamic behavior like eukaryotic microtubules but differ in how they self-associate into bundles and how this bundling affects their stability. Our results demonstrate the diversity of mechanisms through which tubulin homologs promote filament dynamics and monomer turnover. PMID- 28716965 TI - Neural Tuning to Low-Level Features of Speech throughout the Perisylvian Cortex. AB - Despite a large body of research, we continue to lack a detailed account of how auditory processing of continuous speech unfolds in the human brain. Previous research showed the propagation of low-level acoustic features of speech from posterior superior temporal gyrus toward anterior superior temporal gyrus in the human brain (Hullett et al., 2016). In this study, we investigate what happens to these neural representations past the superior temporal gyrus and how they engage higher-level language processing areas such as inferior frontal gyrus. We used low-level sound features to model neural responses to speech outside of the primary auditory cortex. Two complementary imaging techniques were used with human participants (both males and females): electrocorticography (ECoG) and fMRI. Both imaging techniques showed tuning of the perisylvian cortex to low level speech features. With ECoG, we found evidence of propagation of the temporal features of speech sounds along the ventral pathway of language processing in the brain toward inferior frontal gyrus. Increasingly coarse temporal features of speech spreading from posterior superior temporal cortex toward inferior frontal gyrus were associated with linguistic features such as voice onset time, duration of the formant transitions, and phoneme, syllable, and word boundaries. The present findings provide the groundwork for a comprehensive bottom-up account of speech comprehension in the human brain.SIGNIFICANCE STATEMENT We know that, during natural speech comprehension, a broad network of perisylvian cortical regions is involved in sound and language processing. Here, we investigated the tuning to low-level sound features within these regions using neural responses to a short feature film. We also looked at whether the tuning organization along these brain regions showed any parallel to the hierarchy of language structures in continuous speech. Our results show that low-level speech features propagate throughout the perisylvian cortex and potentially contribute to the emergence of "coarse" speech representations in inferior frontal gyrus typically associated with high-level language processing. These findings add to the previous work on auditory processing and underline a distinctive role of inferior frontal gyrus in natural speech comprehension. PMID- 28716964 TI - A GluN2B-Selective NMDAR Antagonist Reverses Synapse Loss and Cognitive Impairment Produced by the HIV-1 Protein Tat. AB - HIV-associated neurocognitive disorder (HAND) affects approximately half of HIV infected patients. Loss of synaptic connections is a hallmark of many neurocognitive disorders, including HAND. The HIV-1 protein transactivator of transcription (Tat) disrupts synaptic connections both in vitro and in vivo and has been linked to impaired neurocognitive function in humans. In vitro studies have shown that ifenprodil, an antagonist selective for GluN2B-containing NMDARs, reverses synapse loss when applied after Tat. Here, we tested the hypothesis that Tat-induced loss and ifenprodil-mediated rescue of synaptic spines in vivo would predict impairment and rescue of cognitive function. Using intracranial multiphoton imaging, we found that infusion of 100 ng of HIV-1 Tat into the lateral ventricle of yellow fluorescent protein-expressing transgenic mice produced a 17 +/- 1% loss of dendritic spines in layer 1 of retrosplenial cortex. Repeated imaging of the same dendrites over 3 weeks enabled longitudinal experiments that demonstrated sustained spine loss after Tat infusion and transient rescue after ifenprodil administration (10 mg/kg, i.p.). Parallel trace fear conditioning experiments showed that spine loss predicted learning deficits and that the time course of ifenprodil-induced rescue of spine density correlated with restoration of cognitive function. These results show for the first time that, during exposure to an HIV-1 neurotoxin in vivo, alteration of GluN2B containing NMDAR signaling suppresses spine density and impairs learning. Pharmacological inhibition of these NMDARs rescued spines and restored cognitive function. Drugs that rescue synapses may improve neurocognitive function in HAND.SIGNIFICANCE STATEMENT Synaptodendritic damage correlates with cognitive decline in HIV-associated neurocognitive disorder (HAND) patients. We developed an in vivo imaging approach for longitudinal tracking of spine density that enabled correlation of synaptic changes with behavioral outcomes in a model of HAND. We show for the first time that spine loss after exposure to an HIV-1 protein can be reversed pharmacologically and that loss and recovery of dendritic spines predict impairment and restoration of cognitive function, respectively. Therefore, synapse loss, the hallmark of cognitive decline in HAND, is reversible. Drugs that restore spine density may have broad application for improving cognitive function during the early phases of neurodegenerative diseases. PMID- 28716963 TI - Chemokine CCL2-CCR2 Signaling Induces Neuronal Cell Death via STAT3 Activation and IL-1beta Production after Status Epilepticus. AB - Elevated levels of chemokine C-C motif ligand 2 (CCL2) and its receptor CCR2 have been reported in patients with temporal lobe epilepsy and in experimental seizures. However, the functional significance and molecular mechanism underlying CCL2-CCR2 signaling in epileptic brain remains largely unknown. In this study, we found that the upregulated CCL2 was mainly expressed in hippocampal neurons and activated microglia from mice 1 d after kainic acid (KA)-induced seizures. Taking advantage of CX3CR1GFP/+:CCR2RFP/+ double-transgenic mice, we demonstrated that CCL2-CCR2 signaling has a role in resident microglial activation and blood derived monocyte infiltration. Moreover, seizure-induced degeneration of neurons in the hippocampal CA3 region was attenuated in mice lacking CCL2 or CCR2. We further showed that CCR2 activation induced STAT3 (signal transducer and activator of transcription 3) phosphorylation and IL-1beta production, which are critical for promoting neuronal cell death after status epilepticus. Consistently, pharmacological inhibition of STAT3 by WP1066 reduced seizure induced IL-1beta production and subsequent neuronal death. Two weeks after KA induced seizures, CCR2 deficiency not only reduced neuronal loss, but also attenuated seizure-induced behavioral impairments, including anxiety, memory decline, and recurrent seizure severity. Together, we demonstrated that CCL2-CCR2 signaling contributes to neurodegeneration via STAT3 activation and IL-1beta production after status epilepticus, providing potential therapeutic targets for the treatment of epilepsy.SIGNIFICANCE STATEMENT Epilepsy is a global concern and epileptic seizures occur in many neurological conditions. Neuroinflammation associated with microglial activation and monocyte infiltration are characteristic of epileptic brains. However, molecular mechanisms underlying neuroinflammation in neuronal death following epilepsy remain to be elucidated. Here we demonstrate that CCL2-CCR2 signaling is required for monocyte infiltration, which in turn contributes to kainic acid (KA)-induced neuronal cell death. The downstream of CCR2 activation involves STAT3 (signal transducer and activator of transcription 3) phosphorylation and IL-1beta production. Two weeks after KA-induced seizures, CCR2 deficiency not only reduced neuronal loss, but also attenuated seizure-induced behavioral impairments, including anxiety, memory decline, and recurrent seizure severity. The current study provides a novel insight on the function and mechanisms of CCL2-CCR2 signaling in KA-induced neurodegeneration and behavioral deficits. PMID- 28716966 TI - Hierarchically Organized Medial Frontal Cortex-Basal Ganglia Loops Selectively Control Task- and Response-Selection. AB - Adaptive behavior requires context-sensitive configuration of task-sets that specify time-varying stimulus-response mappings. Intriguingly, response time costs associated with changing task-sets and motor responses are known to be strongly interactive: switch costs at the task level are small in the presence of a response-switch but large when accompanied by a response-repetition, and vice versa for response-switch costs. The reasons behind this well known interdependence between task- and response-level control processes are currently not well understood. Here, we formalized and tested a model assuming a hierarchical organization of superordinate task-set and subordinate response-set selection processes to account for this effect. The model was found to successfully explain the full range of behavioral task- and response-switch costs across first and second order trial transitions. Using functional magnetic resonance imaging (fMRI) in healthy humans, we then characterized the neural circuitry mediating these effects. We found that presupplementary motor area (preSMA) activity tracked task-set control costs, SMA activity tracked response set control costs, and basal ganglia (BG) activity mirrored the interaction between task- and response-set regulation processes that characterized participants' response times. A subsequent fMRI-guided transcranial magnetic stimulation experiment confirmed dissociable roles of the preSMA and SMA in determining response costs. Together, these data provide evidence for a hierarchical organization of posterior medial frontal cortex and its interaction with the BG, where a superordinate preSMA-BG loop establishes task-set selection, which imposes a (unidirectional) constraint on a subordinate SMA-BG loop that determines response-selection, resulting in the characteristic interdependence in task- and response-switch costs in behavior.SIGNIFICANCE STATEMENT The ability to use context-sensitive task-sets to guide our responses is central to human adaptive behavior. Task and response selection are strongly interactive: it is more difficult to repeat a response in the context of a changing task-set, and vice versa. However, the neurocognitive architecture giving rise to this interdependence is currently not understood. Here we use modeling, neuroimaging, and noninvasive neurostimulation to show that this phenomenon derives from a hierarchical organization of posterior medial frontal cortex and its interaction with the basal ganglia, where a more anterior corticostriatal loop establishes task-set selection, which constrains a more posterior loop responsible for response-selection. These data provide a neural explanation for a key behavioral signature of human cognitive control. PMID- 28716967 TI - Contextual and Developmental Differences in the Neural Architecture of Cognitive Control. AB - Because both development and context impact functional brain architecture, the neural connectivity signature of a cognitive or affective predisposition may similarly vary across different ages and circumstances. To test this hypothesis, we investigated the effects of age and cognitive versus social-affective context on the stable and time-varying neural architecture of inhibition, the putative core cognitive control component, in a subsample (N = 359, 22-36 years, 174 men) of the Human Connectome Project. Among younger individuals, a neural signature of superior inhibition emerged in both stable and dynamic connectivity analyses. Dynamically, a context-free signature emerged as stronger segregation of internal cognition (default mode) and environmentally driven control (salience, cingulo opercular) systems. A dynamic social-affective context-specific signature was observed most clearly in the visual system. Stable connectivity analyses revealed both context-free (greater default mode segregation) and context-specific (greater frontoparietal segregation for higher cognitive load; greater attentional and environmentally driven control system segregation for greater reward value) signatures of inhibition. Superior inhibition in more mature adulthood was typified by reduced segregation in the default network with increasing reward value and increased ventral attention but reduced cingulo opercular and subcortical system segregation with increasing cognitive load. Failure to evidence this neural profile after the age of 30 predicted poorer life functioning. Our results suggest that distinguishable neural mechanisms underlie individual differences in cognitive control during different young adult stages and across tasks, thereby underscoring the importance of better understanding the interplay among dispositional, developmental, and contextual factors in shaping adaptive versus maladaptive patterns of thought and behavior.SIGNIFICANCE STATEMENT The brain's functional architecture changes across different contexts and life stages. To test whether the neural signature of a trait similarly varies, we investigated cognitive versus social-affective context effects on the stable and time-varying neural architecture of inhibition during a period of neurobehavioral fine-tuning (age 22-36 years). Younger individuals with superior inhibition showed distinguishable context-free and context-specific neural profiles, evidenced in both static and dynamic connectivity analyses. More mature individuals with superior inhibition evidenced only context-specific profiles, revealed in the static connectivity patterns linked to increased reward or cognitive load. Delayed expression of this profile predicted poorer life functioning. Our results underscore the importance of understanding the interplay among dispositional, developmental, and contextual factors in shaping behavior. PMID- 28716968 TI - Tackling submission and publication bias. PMID- 28716970 TI - Prolonged force depression after mechanically demanding contractions is largely independent of Ca2+ and reactive oxygen species. AB - Increased production of reactive oxygen/nitrogen species (ROS) and impaired cellular Ca2+ handling are implicated in the prolonged low-frequency force depression (PLFFD) observed in skeletal muscle after both metabolically and mechanically demanding exercise. Metabolically demanding high-intensity exercise can induce PLFFD accompanied by ROS-dependent fragmentation of the sarcoplasmic reticulum Ca2+ release channels, the ryanodine receptor 1s (RyR1s). We tested whether similar changes occur after mechanically demanding eccentric contractions. Human subjects performed 100 repeated drop jumps, which require eccentric knee extensor contractions upon landing. This exercise caused a major PLFFD, such that maximum voluntary and electrically evoked forces did not recover within 24 h. Drop jumps induced only minor signs of increased ROS, and RyR1 fragmentation was observed in only 3 of 7 elderly subjects. Also, isolated mouse muscle preparations exposed to drop-jump-mimicking eccentric contractions showed neither signs of increased ROS nor RyR1 fragmentation. Still, the free cytosolic [Ca2+] during tetanic contractions was decreased by ~15% 1 h after contractions, which can explain the exaggerated force decrease at low-stimulation frequencies but not the major frequency-independent force depression. In conclusion, PLFFD caused by mechanically demanding eccentric contractions does not involve any major increase in ROS or RyR1 fragmentation.-Kamandulis, S., de Souza Leite, F., Hernandez, A., Katz, A., Brazaitis, M., Bruton, J. D., Venckunas, T., Masiulis, N., Mickeviciene, D., Eimantas, N., Subocius, A., Rassier, D. E., Skurvydas, A., Ivarsson, N., Westerblad, H. Prolonged force depression after mechanically demanding contractions is largely independent of Ca2+ and reactive oxygen species. PMID- 28716969 TI - Genetic determinants of susceptibility to silver nanoparticle-induced acute lung inflammation in mice. AB - Silver nanoparticles (AgNPs) are employed in a variety of consumer products; however, in vivo rodent studies indicate that AgNPs can cause lung inflammation and toxicity in a strain- and particle type-dependent manner, but mechanisms of susceptibility remain unclear. The aim of this study was to assess the variation in AgNP-induced lung inflammation and toxicity across multiple inbred mouse strains and to use genome-wide association (GWA) mapping to identify potential candidate susceptibility genes. Mice received doses of 0.25 mg/kg of either 20-nm citrate-coated AgNPs or citrate buffer using oropharyngeal aspiration. Neutrophils in bronchoalveolar lavage fluid (BALF) served as markers of inflammation. We found significant strain- and treatment-dependent variation in neutrophils in BALF. GWA mapping identified 10 significant single-nucleotide polymorphisms (false discovery rate, 15%) in 4 quantitative trait loci on mouse chromosomes 1, 4, 15, and 18, and Nedd4l (neural precursor cell expressed developmentally downregulated gene 4-like; chromosome 18), Ano6 (anocatmin 6; chromosome 15), and Rnf220 (Ring finger protein 220; chromosome 4) were considered candidate genes. Quantitative RT-PCR revealed significant inverse associations between mRNA levels of these genes and neutrophil influx. Nedd4l, Ano6, and Rnf220 are candidate susceptibility genes for AgNP-induced lung inflammation that warrant additional exploration in future studies.-Scoville, D. K., Botta, D., Galdanes, K., Schmuck, S. C., White, C. C., Stapleton, P. L., Bammler, T. K., MacDonald, J. W., Altemeier, W. A., Hernandez, M., Kleeberger, S. R., Chen, L.-C., Gordon, T., Kavanagh, T. J. Genetic determinants of susceptibility to silver nanoparticle-induced acute lung inflammation in mice. PMID- 28716972 TI - Interaction between body mass index and physical fitness in primary heart failure prevention. PMID- 28716971 TI - 2015 Revised Utstein-Style Recommended Guidelines for Uniform Reporting of Data From Drowning-Related Resuscitation: An ILCOR Advisory Statement. AB - BACKGROUND: Utstein-style guidelines use an established consensus process, endorsed by the international resuscitation community, to facilitate and structure resuscitation research and publication. The first "Guidelines for Uniform Reporting of Data From Drowning" were published over a decade ago. During the intervening years, resuscitation science has advanced considerably, thus making revision of the guidelines timely. In particular, measurement of cardiopulmonary resuscitation elements and neurological outcomes reporting have advanced substantially. The purpose of this report is to provide updated guidelines for reporting data from studies of resuscitation from drowning. METHODS: An international group with scientific expertise in the fields of drowning research, resuscitation research, emergency medical services, public health, and development of guidelines met in Potsdam, Germany, to determine the data that should be reported in scientific articles on the subject of resuscitation from drowning. At the Utstein-style meeting, participants discussed data elements in detail, defined the data, determined data priority, and decided how data should be reported, including scoring methods and category details. RESULTS: The template for reporting data from drowning research was revised extensively, with new emphasis on measurement of quality of resuscitation, neurological outcomes, and deletion of data that have proved to be less relevant or difficult to capture. CONCLUSIONS: The report describes the consensus process, rationale for selecting data elements to be reported, definitions and priority of data, and scoring methods. These guidelines are intended to improve the clarity of scientific communication and the comparability of scientific investigations. PMID- 28716973 TI - Incremental benefit of cardiac resynchronisation therapy with versus without a defibrillator. AB - OBJECTIVE: To determine the incremental value of implantable cardioverter defibrillators (ICD) in contemporary optimally treated patients with heart failure (HF) undergoing cardiac resynchronisation therapy (CRT). METHODS: Consecutive patients with HF undergoing CRT-pacemaker (CRT-P) or CRT defibrillator (CRT-D) implantation in a single tertiary care centre between October 2008 and August 2015 were retrospectively evaluated. For patients with a primary prevention indication of the CRT-D, no benefit of the ICD was defined as absence of appropriate therapy (device analysis) or lethal ventricular tachyarrhythmias (mode of death analysis) during follow-up. RESULTS: 687 patients (CRT-P/CRT-D; n=361/326) were followed for 38+/-22 months. CRT-P recipients were older (75.7+/-9.1 vs 71.8+/-9.3 years; p<0.001) and had a higher comorbidity burden. Five patients with CRT-P (1%) experienced episodes of sustained ventricular-tachycardia vs 64 (20%) patients with CRT-D (p<0.001). Remote tele monitoring detected the episodes of sustained ventricular tachycardia in four patients with CRT-P, allowing for elective upgrade to CRT-D. All-cause mortality was higher in patients with CRT-P versus CRT-D (21% vs 12%, p=0.003), even after adjusting for baseline characteristics (HR 2.5; 95% CI 1.36 to 4.60; p=0.003). However, mode of death analysis revealed a predominant non-cardiac mode of death in CRT-P recipients (n=47 (71%) vs n=13 (38%) in CRT-D, p=0.002). Multivariate analysis revealed that age >80 years, New York Heart Association class IV, intolerance to beta-blockers and underlying non-ischaemic cardiomyopathy were independently associated with little incremental value of a primary prevention ICD on top of CRT. CONCLUSIONS: The majority of patients with contemporary HF as currently selected for CRT-P exhibit mainly non-cardiac-driven mortality. Weighing risk of ventricular-tachyarrhythmic death versus risk of all-cause mortality helps to address the incremental value of an ICD to CRT-P. PMID- 28716974 TI - Heart failure in patients with kidney disease. AB - Heart failure (HF) is a leading cause of morbidity and mortality in patients with chronic kidney disease (CKD), and the population of CKD patients with concurrent HF continues to grow. The accurate diagnosis of HF is challenging in patients with CKD in part due to a lack of validated imaging and biomarkers specifically in this population. The pathophysiology between the heart and the kidneys is complex and bidirectional. Patients with CKD have greater prevalence of traditional HF risk factors as well as unique kidney-specific risk factors including malnutrition, acid-base alterations, uraemic toxins, bone mineral changes, anemia and myocardial stunning. These risk factors also contribute to the decline of kidney function seen in patients with subclinical and clinical HF. More targeted HF therapies may improve outcomes in patients with kidney disease as current HF therapies are underutilised in this population. Further work is also needed to develop novel HF therapies for the CKD population. PMID- 28716975 TI - Metabolic phenotype in the mouse model of osteogenesis imperfecta. AB - Osteogenesis imperfecta (OI) is the most common heritable bone fragility disorder, usually caused by dominant mutations in genes coding for collagen type I alpha chains, COL1A1 or COL1A2 Osteocalcin (OCN) is now recognized as a bone derived regulator of insulin secretion and sensitivity and glucose homeostasis. Since OI is associated with increased rates of bone formation and resorption, we hypothesized that the levels of undercarboxylated OCN are increased in OI. The objective of this study was to determine changes in OCN and to elucidate the metabolic phenotype in the Col1a1Jrt/+ mouse, a model of dominant OI caused by a Col1a1 mutation. Circulating levels of undercarboxylated OCN were higher in 4 week-old OI mice and normal by 8 weeks of age. Young OI animals exhibited a sex dependent metabolic phenotype, including increased insulin levels in males, improved glucose tolerance in females, lower levels of random glucose and low adiposity in both sexes. The rates of O2 consumption and CO2 production, as well as energy expenditure assessed using indirect calorimetry were significantly increased in OI animals of both sexes, whereas respiratory exchange ratio was significantly higher in OI males only. Although OI mice have significant physical impairment that may contribute to metabolic differences, we specifically accounted for movement and compared OI and WT animals during the periods of similar activity levels. Taken together, our data strongly suggest that OI animals have alterations in whole body energy metabolism that are consistent with the action of undercarboxylated osteocalcin. PMID- 28716976 TI - Pregnant women should not be categorised as a 'vulnerable population' in biomedical research studies: ending a vicious cycle of 'vulnerability'. PMID- 28716977 TI - Vulnerability of pregnant women in clinical research. AB - BACKGROUND: Notwithstanding the need to produce evidence-based knowledge on medications for pregnant women, they remain underrepresented in clinical research. Sometimes they are excluded because of their supposed vulnerability, but there are no universally accepted criteria for considering pregnant women as vulnerable. Our aim was to explore whether and if so to what extent pregnant women are vulnerable as research subjects. METHOD: We performed a conceptual and empirical analysis of vulnerability applied to pregnant women. ANALYSIS: A conceptual analysis supports Hurst's definition of vulnerability. Consequently, we argue that pregnant women are vulnerable if they encounter an identifiably increased likelihood of incurring additional or greater wrong. According to the literature, this increased likelihood could exist of four alleged features for pregnant women's vulnerability: (i) informed consent, (ii) susceptibility to coercion, (iii) higher exposure to risk due to lack of knowledge, (iv) vulnerability of the fetus. DISCUSSION: Testing the features against Hurst's definition demonstrates that they all concern the same issue: pregnant women are only vulnerable because a higher exposure to risk due to lack of scientific knowledge comprises an increased wrong. Research Ethics Committees have a responsibility to protect the vulnerable, but a higher exposure to risk due to lack of scientific knowledge is a much broader issue and also needs to be addressed by other stakeholders. CONCLUSIONS: The only reason why pregnant women are potentially vulnerable is to the extent that they are increasingly exposed to higher risks due to a lack of scientific knowledge. Accordingly, the discussion can advance to the development of practical strategies to promote fair inclusion of pregnant women in clinical research. PMID- 28716978 TI - How do clinicians prepare family members for the role of surrogate decision maker? AB - PURPOSE: Although surrogate decision-making (SDM) is prevalent in intensive care units (ICUs) and concerns with decision quality are well documented, little is known about how clinicians help family members understand the surrogate role. We investigated whether and how clinicians provide normative guidance to families regarding how to function as a surrogate. SUBJECTS AND METHODS: We audiorecorded and transcribed 73 ICU family conferences in which clinicians anticipated discussing goals of care for incapacitated patients at high risk of death. We developed and applied a coding framework to identify normative statements by clinicians regarding what considerations should guide surrogates' decisions, including whether clinicians explained one or more of Buchanan and Brock's three standard principles of SDM to family members. RESULTS: Clinicians made at least one statement about how to perform the surrogate role in 24 (34%) conferences (mean of 0.83 statements per conference (1.77; range 0-9)). We observed three general types of normative guidance provided to surrogates, with some conferences containing more than one type of guidance: counselling about one or more standard principles of SDM (24% of conferences); counselling surrogates to make decisions centred on the patient as a person, without specifying how to accomplish that (14% of conferences); and counselling surrogates to make decisions based on the family's values (8% of conferences). CONCLUSIONS: Clinicians did not provide normative guidance about the surrogate role in two-thirds of family conferences for incapacitated patients at high risk for death. When they did, clinicians' guidance was often incomplete and sometimes conflicted with standard principles of SDM. Future work is needed to understand whether providing explicit guidance on how to perform the surrogate role improves decision-making or mitigates surrogates' psychological distress. PMID- 28716980 TI - Early Dysphagia Screening by Trained Nurses Reduces Pneumonia Rate in Stroke Patients: A Clinical Intervention Study. AB - BACKGROUND AND PURPOSE: Dysphagia is a common stroke symptom and leads to serious complications such as aspiration and pneumonia. Early dysphagia screening can reduce these complications. In many hospitals, dysphagia screening is performed by speech-language therapists who are often not available on weekends/holidays, which results in delayed dysphagia assessment. METHODS: We trained the nurses of our neurological department to perform formal dysphagia screening in every acute stroke patient by using the Gugging Swallowing Screen. The impact of a 24/7 dysphagia screening (intervention) over swallowing assessment by speech-language therapists during regular working hours only was compared in two 5-month periods with time to dysphagia screening, pneumonia rate, and length of hospitalization as outcome variables. RESULTS: Overall, 384 patients (mean age, 72.3+/-13.7 years; median National Institutes of Health Stroke Scale score of 3) were included in the study. Both groups (pre-intervention, n=198 versus post intervention, n=186) were comparable regarding age, sex, and stroke severity. Time to dysphagia screening was significantly reduced in the intervention group (median, 7 hours; range, 1-69 hours) compared with the control group (median, 20 hours; range, 1-183; P=0.001). Patients in the intervention group had a lower rate of pneumonia (3.8% versus 11.6%; P=0.004) and also a reduced length of hospital stay (median, 8 days; range, 2-40 versus median, 9 days; range, 1-61 days; P=0.033). CONCLUSIONS: 24/7 dysphagia screening can be effectively performed by nurses and leads to reduced pneumonia rates. Therefore, empowering nurses to do a formal bedside screening for swallowing dysfunction in stroke patients timely after admission is warranted whenever speech-language therapists are not available. PMID- 28716981 TI - Prediction of Clinical Outcome After Acute Ischemic Stroke: The Value of Repeated Noncontrast Computed Tomography, Computed Tomographic Angiography, and Computed Tomographic Perfusion. AB - BACKGROUND AND PURPOSE: Early prediction of outcome in acute ischemic stroke is important for clinical management. This study aimed to compare the relationship between early follow-up multimodality computed tomographic (CT) imaging and clinical outcome at 90 days in a large multicenter stroke study. METHODS: From the DUST study (Dutch Acute Stroke Study), patients were selected with (1) anterior circulation occlusion on CT angiography (CTA) and ischemic deficit on CT perfusion (CTP) on admission, and (2) day 3 follow-up noncontrast CT, CTP, and CTA. Follow-up infarct volume on noncontrast CT, poor recanalization on CTA, and poor reperfusion on CTP (mean transit time index <=75%) were related to unfavorable outcome after 90 days defined as modified Rankin Scale 3 to 6. Four multivariable models were constructed: (1) only baseline variables (model 1), (2) model 1 with addition of infarct volume, (3) model 1 with addition of recanalization, and (4) model 1 with addition of reperfusion. Area under the curves of the receiver operating characteristic curves of the models were compared using the DeLong test. RESULTS: A total of 242 patients were included. Poor recanalization was found in 21%, poor reperfusion in 37%, and unfavorable outcome in 44%. The area under the curve of the receiver operating characteristic curve without follow-up imaging was 0.81, with follow-up noncontrast CT 0.85 (P=0.02), CTA 0.86 (P=0.01), and CTP 0.86 (P=0.01). All 3 follow-up imaging modalities improved outcome prediction compared with no imaging. There was no difference between the imaging models. CONCLUSIONS: Follow-up imaging after 3 days improves outcome prediction compared with prediction based on baseline variables alone. CTA recanalization and CTP reperfusion do not outperform noncontrast CT at this time point. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00880113. PMID- 28716979 TI - Blood Biomarkers for the Early Diagnosis of Stroke: The Stroke-Chip Study. AB - BACKGROUND AND PURPOSE: Stroke diagnosis could be challenging in the acute phase. We aimed to develop a blood-based diagnostic tool to differentiate between real strokes and stroke mimics and between ischemic and hemorrhagic strokes in the hyperacute phase. METHODS: The Stroke-Chip was a prospective, observational, multicenter study, conducted at 6 Stroke Centers in Catalonia. Consecutive patients with suspected stroke were enrolled within the first 6 hours after symptom onset, and blood samples were drawn immediately after admission. A 21 biomarker panel selected among previous results and from the literature was measured by immunoassays. Outcomes were differentiation between real strokes and stroke mimics and between ischemic and hemorrhagic strokes. Predictive models were developed by combining biomarkers and clinical variables in logistic regression models. Accuracy was evaluated with receiver operating characteristic curves. RESULTS: From August 2012 to December 2013, 1308 patients were included (71.9% ischemic, 14.8% stroke mimics, and 13.3% hemorrhagic). For stroke versus stroke mimics comparison, no biomarker resulted included in the logistic regression model, but it was only integrated by clinical variables, with a predictive accuracy of 80.8%. For ischemic versus hemorrhagic strokes comparison, NT-proBNP (N-Terminal Pro-B-Type Natriuretic Peptide) >4.9 (odds ratio, 2.40; 95% confidence interval, 1.55-3.71; P<0.0001) and endostatin >4.7 (odds ratio, 2.02; 95% confidence interval, 1.19-3.45; P=0.010), together with age, sex, blood pressure, stroke severity, atrial fibrillation, and hypertension, were included in the model. Predictive accuracy was 80.6%. CONCLUSIONS: The studied biomarkers were not sufficient for an accurate differential diagnosis of stroke in the hyperacute setting. Additional discovery of new biomarkers and improvement on laboratory techniques seem necessary for achieving a molecular diagnosis of stroke. PMID- 28716982 TI - Real-World Setting Comparison of Nonvitamin-K Antagonist Oral Anticoagulants Versus Vitamin-K Antagonists for Stroke Prevention in Atrial Fibrillation: A Systematic Review and Meta-Analysis. AB - BACKGROUND AND PURPOSE: Evidence from the real-world setting complements evidence coming from randomized controlled trials. We aimed to summarize all available evidence from high-quality real-world observational studies about efficacy and safety of nonvitamin-K oral anticoagulants compared with vitamin-K antagonists in patients with atrial fibrillation. METHODS: We searched PubMed and Web of Science until January 7, 2017 for observational nationwide or health insurance databases reporting matched or adjusted results comparing nonvitamin-K oral anticoagulants versus vitamin-K antagonists in patients with atrial fibrillation. Outcomes assessed included ischemic stroke, ischemic stroke or systemic embolism, any stroke or systemic embolism, myocardial infarction, intracranial hemorrhage, major hemorrhage, gastrointestinal hemorrhage, and death. RESULTS: In 28 included studies of dabigatran, rivaroxaban, and apixaban compared with vitamin-K antagonists, all 3 nonvitamin-K oral anticoagulants were associated with a large reduction of intracranial hemorrhage (apixaban hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.31-0.63; dabigatran HR, 0.42; 95% CI, 0.37-0.49; rivaroxaban HR, 0.64; 95% CI, 0.47-0.86); similar rates of ischemic stroke and ischemic stroke or systemic embolism (apixaban HR, 1.05; 95% CI, 0.75-1.19 and HR, 1.08; 95% CI, 0.95-1.22 / dabigatran HR, 0.96; 95% CI, 0.80-1.16 and HR, 1.17; 95% CI, 0.92-1.50 / rivaroxaban HR, 0.89; 95% CI, 0.76-1.04 and HR, 0.73; 95% CI, 0.52-1.04, respectively); apixaban and dabigatran with lower mortality (HR, 0.65; 95% CI, 0.56-0.75 and HR, 0.63; 95% CI, 0.53-0.75, respectively); apixaban with fewer gastrointestinal (HR, 0.63; 95% CI, 0.42-0.95) and major hemorrhages (HR, 0.55; 95% CI, 0.48-0.63); dabigatran and rivaroxaban with more gastrointestinal hemorrhages (HR, 1.20; 95% CI, 1.06-1.36 and HR, 1.24; 95% CI, 1.08-1.41, respectively); dabigatran and rivaroxaban with similar rate of myocardial infarction (HR, 0.96; 95% CI, 0.77-1.21 and HR, 1.02; 95% CI, 0.54 1.89, respectively). CONCLUSIONS: This meta-analysis confirms the main findings of the randomized controlled trials of dabigatran, rivaroxaban, and apixaban in the real-world setting and, hence, strengthens their validity. PMID- 28716983 TI - Systematic Review of the Cost and Cost-Effectiveness of Rapid Endovascular Therapy for Acute Ischemic Stroke. AB - BACKGROUND AND PURPOSE: Rapid endovascular therapy (EVT) is an emerging treatment option for acute ischemic stroke. Several economic evaluations have been published examining the cost-effectiveness of EVT, and many international bodies are currently making adoption decisions. The objective of this study was to establish the cost-effectiveness of EVT for ischemic stroke patients and to synthesize all the publicly available economic literature. METHODS: A systematic review of the published literature was conducted to identify economic evaluations and cost analyses of EVT for acute ischemic stroke patients. Systematic review best practices were followed, and study quality was assessed. RESULTS: Four hundred sixty-three articles were identified from electronic databases. After deduplication, abstract review, and full-text review, 17 studies were included. Seven of the studies were cost analyses, and 10 were cost-effectiveness studies. Generally, the cost analyses reported on the cost of the approach/procedure or the hospitalization costs associated with EVT. All of the cost-effectiveness studies reported a cost per quality-adjusted life year as the primary outcomes. Studies varied in regards to the costs considered, the perspective adopted, and the time horizon used. All the studies reported a cost per quality-adjusted life year of <$50 000 as the primary outcome. CONCLUSIONS: There is a robust body of evidence for the cost and cost-effectiveness of EVT. The cost analyses suggested that although EVT was associated with higher costs, it also resulted in improved patient outcomes. From the cost-effectiveness studies, EVT seems to be good value for money when a threshold of $50 000 per quality-adjusted life year gained is adopted. PMID- 28716984 TI - The risk of ischemic events increased in patients with asymptomatic carotid stenosis with decreased cerebrovascular reserve. AB - Identifying high-risk patients with asymptomatic carotid stenosis (ACS) is necessary regardless of whether intensive medical therapy or aggressive treatment is applied. In order to assess the relationship between cerebrovascular reserve (CVR) measured by perfusion CT with inhalation of CO2 and the risk of ischemic events in ACS, this long-term follow-up study was conducted. Forty-five patients with ACS who underwent the examination of CVR measured by perfusion CT with inhalation of CO2 were collected and followed-up for at least 5 years. The primary end point was the occurrence of ipsilateral cerebral ischemic events. HRs and their 95% CI were calculated by Kaplan-Meier survival analysis and Cox regression models. The mean follow-up time was 68.7+/-10.7 months (40.0-84.0 months). 13 (28.9%) ipsilateral ischemic events were observed. The annual risk of ipsilateral ischemic events was 4.8%. Kaplan-Meier survival analysis and univariate Cox regression analysis indicated that patients with less CVR experienced more ischemic events (p=0.006 and p=0.013, respectively), which was confirmed by multiple Cox regression analysis (p=0.012). CVR measured by perfusion CT may potentially be the factor which can predict the risk of ipsilateral ischemic events in patients with ACS. Multidisciplinary management is necessary for these high-risk patients. PMID- 28716986 TI - Development of PKG Ialpha (Protein Kinase G Ialpha)-Dimerizing Antihypertensive Drugs: Are We Standing at the Shore of the Rubicon? PMID- 28716985 TI - Two microRNA signatures for malignancy and immune infiltration predict overall survival in advanced epithelial ovarian cancer. AB - MicroRNAs have been established as key regulators of tumor gene expression and as prime biomarker candidates for clinical phenotypes in epithelial ovarian cancer (EOC). We analyzed the coexpression and regulatory structure of microRNAs and their co-localized gene targets in primary tumor tissue of 20 patients with advanced EOC in order to construct a regulatory signature for clinical prognosis. We performed an integrative analysis to identify two prognostic microRNA/mRNA coexpression modules, each enriched for consistent biological functions. One module, enriched for malignancy-related functions, was found to be upregulated in malignant versus benign samples. The second module, enriched for immune-related functions, was strongly correlated with imputed intratumoral immune infiltrates of T cells, natural killer cells, cytotoxic lymphocytes, and macrophages. We validated the prognostic relevance of the immunological module microRNAs in the publicly available The Cancer Genome Atlas data set. These findings provide novel functional roles for microRNAs in the progression of advanced EOC and possible prognostic signatures for survival. PMID- 28716987 TI - Control of Pathological Cardiac Hypertrophy by Transcriptional Corepressor IRF2BP2 (Interferon Regulatory Factor-2 Binding Protein 2). AB - The transcription factor NFAT1 (nuclear factor of activated T-cells 1), with the aid of transcriptional coactivators, has been recognized for its necessity and sufficiency to drive pathological cardiac hypertrophy. However, how the transcriptional activity of NFAT1 in terms of cardiac hypertrophy is controlled at the transcriptional level has not been well defined. Herein, we showed that a cardiac-enriched protein IRF2BP2 (interferon regulatory factor-2 binding protein 2) was further upregulated in both human and mouse hypertrophied myocardium and negatively regulated cardiomyocyte hypertrophic response in vitro. By generating cardiomyocyte-specific Irf2bp2 knockout and Irf2bp2-transgenic mouse strains, our in vivo experiments showed that, whereas IRF2BP2 loss-of-function exacerbated both aortic banding- and angiotensin II infusion-induced cardiac hypertrophic response, IRF2BP2 overexpression exerted a strong protective effect against these maladaptive processes. Particularly, IRF2BP2 directly interacted with the C terminal transactivation domain of NFAT1 by competing with myocyte enhancer factor-2C and disturbing their transcriptional synergism, thereby impeding NFAT1 transactivated hypertrophic transcriptome. As a result, the devastating effect of Irf2bp2 deficiency on cardiac hypertrophy was largely rescued by NFAT1 blockage. Our study, thus, defined IRF2BP2 as a novel negative regulator in controlling pathological cardiac hypertrophy at the transcriptional level. PMID- 28716988 TI - Blood Pressure Lowering and Safety Improvements With Liver Angiotensinogen Inhibition in Models of Hypertension and Kidney Injury. AB - Uncontrolled hypertension is an important contributor to cardiovascular disease. Despite the armamentarium of antihypertensive treatments, there remains a need for novel agents effective in individuals who cannot reach acceptable blood pressure levels. Inhibitors targeting the renin-angiotensin-aldosterone system (RAAS) are widely used but may not optimally inhibit RAAS and demonstrate an acceptable safety profile. Experiments were conducted to characterize a series of AGT (angiotensinogen) antisense oligonucleotides (ASOs) and compare their efficacy and tolerability to traditional RAAS blockade. AGT ASOs which target multiple systemic sites of AGT versus an N-acetylgalactosamine-conjugated AGT ASO that targets the liver were compared with captopril and losartan. Spontaneously hypertensive rats fed an 8% NaCl diet, a model of malignant hypertension resistant to standard RAAS inhibitors, demonstrated robust and durable blood pressure reductions with AGT ASO treatments, which was not observed with standard RAAS blockade. Studies in rat models of acute kidney injury produced by salt deprivation revealed kidney injury with ASO treatment that reduced kidney expressed AGT, but not in animals treated with the N-acetylgalactosamine AGT ASO despite comparable plasma AGT reductions. Administration of either captopril or losartan also produced acute kidney injury during salt deprivation. Thus, intrarenal RAAS derived from kidney AGT, and inhibited by the standard of care, contributes to the maintenance of renal function during severe RAAS challenge. Such improvements in efficacy and tolerability by a liver-selective AGT inhibitor could be desirable in individuals not at their blood pressure goal with existing RAAS blockade. PMID- 28716989 TI - High Prevalence of Multiple Arterial Bed Lesions in Patients With Fibromuscular Dysplasia: The ARCADIA Registry (Assessment of Renal and Cervical Artery Dysplasia). AB - : Fibromuscular dysplasia (FMD) commonly affects the renal and cervical arteries but has been described to affect other vascular beds as well. The prevalence of and clinical characteristics associated with multisite FMD (string-of-beds or focal stenoses affecting at least 2 vascular beds) are not known. In the prospective ARCADIA registry (Assessment of Renal and Cervical Artery Dysplasia), symptomatic patients with renal artery (RA) FMD underwent tomographic- or magnetic resonance-angiography from the aortic arch to the intracranial arteries and those with cervical FMD from the diaphragm to the pelvis. Of 469 patients (84.0% women), 225 (48.0%) had multisite FMD. In addition, 86 of 244 patients with single-site disease had dissections or aneurisms affecting other vascular beds, totaling 311 patients (66.3%) with lesions in >1 vascular bed. Among patients with a cerebrovascular presentation, the prevalence of RA lesions was higher in patients with than in those without hypertension (odds ratio, 3.4; 95% confidence interval, 1.99-6.15). Among patients with a renal presentation, the prevalence of cervical lesions was higher in patients with bilateral than in those with unilateral RA lesions (odds ratio, 1.9; 95% confidence interval, 0.99 3.57). In conclusion, FMD is a systemic arterial disease. At least 2 vascular beds were affected by dysplastic stenoses in 48.0% of cases and by dysplastic stenoses, aneurysms, and dissections in 66.1% of cases. RA imaging should be proposed to hypertensive patients with a cerebrovascular presentation. Cervical artery imaging should be considered in patients with a renal presentation and bilateral RA lesions. CLINICAL TRIAL REGISTRATION: URL: www.Clinicaltrials.gov. Unique identifier: NCT02884141. PMID- 28716991 TI - Expanding Clinical Phenotype of Fibromuscular Dysplasia. PMID- 28716990 TI - Proof of Principle for a Novel Class of Antihypertensives That Target the Oxidative Activation of PKG Ialpha (Protein Kinase G Ialpha). AB - Arterial hypertension continues to be a major health burden. Development of new antihypertensive drugs that engage vasodilatory mechanisms not harnessed by available therapies offer therapeutic potential. Oxidants induce an interprotein disulfide in PKG Ialpha (protein kinase G Ialpha) at C42, which is associated with its targeting and activation, resulting in vasodilation and blood pressure lowering. Consequently, we developed an assay and screened for electrophilic drugs that activate PKG Ialpha by selectively targeting C42, as such compounds have potential as novel antihypertensives with a mechanism of action that differs from current therapies. In this way, a drug that we termed G1 was identified, which targets C42 of PKG Ialpha to induce vasodilation of isolated resistance blood vessels and blood pressure lowering in a mouse model of angiotensin II induced hypertension. In contrast, these antihypertensive effects were deficient in angiotensin II-induced hypertensive C42S PKG Ialpha knockin mice. These transgenic mice were engineered to have the reactive cysteinyl thiol replaced with a hydroxyl so that it cannot react with endogenous vasodilatory oxidants or electrophiles such as drug G1. These studies, therefore, provide validation of PKG Ialpha C42 as the target of G1, as well as proof-of-principle for a new class of antihypertensive drugs that have potential for further development for clinical use in humans. PMID- 28716992 TI - Blood Pressure Trajectories and the Risk of Intracerebral Hemorrhage and Cerebral Infarction: A Prospective Study. AB - The association between long-term blood pressure (BP) patterns in community dwelling adults and risk of intracerebral hemorrhage and cerebral infarction is not well characterized. This prospective study included 79 385 participants, free of stroke, myocardial infarction, and cancer in or before 2010 (baseline). Systolic BP trajectories were identified using latent mixture modeling with data from 2006, 2008, and 2010. Incident cases of intracerebral hemorrhage and cerebral infarction occurred during 2010 to 2014, confirmed by review of medical records, by 3 physicians. We identified 5 distinct systolic BP trajectories during 2006 to 2010. Each of the trajectories was labeled according to their BP range and pattern over time: normotensive-stable (n=26 740), prehypertension stable (n=35 674), stage 1 hypertension-increasing (n=8215), stage 1 hypertension decreasing (n=6422), and stage 2 hypertension-stable (n=2334). We documented 1034 incident cases of cerebral infarction and 187 cases of intracerebral hemorrhage. Although the prehypertension-stable trajectory exhibited systolic BP range within the normal range (120-140 mm Hg) during 2006 to 2010, this group had higher stroke risk relative to the normotensive-stable group (<120 mm Hg) (adjusted hazard ratio was 3.11 for intracerebral hemorrhage and 1.99 for cerebral infarction; P<0.001 for both), after adjusting for possible confounders. Individuals in the stage 2 hypertension-stable systolic BP trajectory (175-179 mm Hg) had the highest risk of intracerebral hemorrhage (adjusted hazard ratio was 12.4) and cerebral infarction (adjusted hazard ratio was 5.07), relative to the normotensive-stable group (P<0.001 for both). BP trajectories were associated with the risk of stroke and increasing BP trajectories within the currently designated normal range may still increase the risk for stroke. PMID- 28716993 TI - Low Soluble Fms-Like Tyrosine Kinase-1, Endoglin, and Endothelin-1 Levels in Women With Confirmed or Suspected Preeclampsia Using Proton Pump Inhibitors. AB - Patients with preeclampsia display elevated placenta-derived sFlt-1 (soluble Fms like tyrosine kinase-1) and endoglin levels and decreased placental growth factor levels. Proton pump inhibitors (PPIs) decrease trophoblast sFlt-1 and endoglin secretion in vitro. PPIs are used during pregnancy to combat reflux disease. Here, we investigated whether PPIs affect sFlt-1 in women with confirmed/suspected preeclampsia, making use of a prospective cohort study involving 430 women. Of these women, 40 took PPIs (6 esomeprazole, 32 omeprazole, and 2 pantoprazole) for 8 to 45 (median 29) days before sFlt-1 measurement. Measurements were only made once, at study entry between weeks 20 and 41 (median 33 weeks). PPI use was associated with lower sFlt-1 levels, with no change in placental growth factor levels, both when compared with all non-PPI users and with 80 gestational age-matched controls selected from the non-PPI users. No sFlt 1/placental growth factor alterations were observed in women using ferrous fumarate or macrogol while, as expected, women using antihypertensive medication displayed higher sFlt-1 levels and lower placental growth factor levels. The PPI use-associated decrease in sFlt-1 was independent of the application of antihypertensive drugs and also occurred when restricting our analysis to patients with hypertensive disease of pregnancy at study entry. PPI users displayed more cases with preexisting proteinuria, less gestational hypertension, and a lower number of neonatal sepsis cases. Finally, their plasma endoglin and endothelin-1 levels were lower while sFlt-1 levels correlated positively with both. In conclusion, PPI use associates with low sFlt-1, endoglin, and endothelin 1 levels, warranting prospective trials to investigate the therapeutic potential of PPIs in preeclampsia. PMID- 28716994 TI - Diagnosis and management of perinatal depression and anxiety in general practice: a meta-synthesis of qualitative studies. AB - BACKGROUND: Up to 20% of women experience anxiety and depression during the perinatal period. In the UK, management of perinatal mental health falls under the remit of GPs. AIM: This review aimed at synthesising the available information from qualitative studies on GPs' attitudes, recognition, and management of perinatal anxiety and depression. DESIGN AND SETTING: Meta synthesis of the available published qualitative evidence on GPs' recognition and management of perinatal anxiety and depression. METHOD: A systematic search was conducted on Embase, Medline, PsycInfo, Pubmed, Scopus, and Web of Science, and grey literature was searched using Google, Google Scholar, and British Library EThOS. Papers and reports were eligible for inclusion if they reported qualitatively on GPs' diagnosis or treatment of perinatal anxiety or depression. The synthesis was constructed using meta-ethnography. RESULTS: Five themes were established from five eligible papers: labels: diagnosing depression; clinical judgement versus guidelines; care and management; use of medication; and isolation: the role of other professionals. GPs considered perinatal depression to be a psychosocial phenomenon, and were reluctant to label disorders and medicalise distress. GPs relied on their own clinical judgement more than guidelines. They reported helping patients make informed choices about treatment, and inviting them back regularly for GP visits. GPs sometimes felt isolated when dealing with perinatal mental health issues. CONCLUSION: GPs often do not have timely access to appropriate psychological therapies and use several strategies to mitigate this shortfall. Training must focus on these issues and must be evaluated to consider whether this makes a difference to outcomes for patients. PMID- 28716995 TI - Impact of GP reminders on follow-up of abnormal cervical cytology: a before-after study in Danish general practice. AB - BACKGROUND: Dysplasia may progress because of a loss to follow-up after an abnormal cervical cytology. Approximately 18% of Danish women postpone the recommended follow-up, which depends on the cytology results. AIM: To investigate if a reminder to the GP about missed follow-up could reduce the proportion of women who fail to act on a recommended follow-up, and to analyse the effect on sociodemographic and general practice variations. DESIGN AND SETTING: A national electronic GP reminder system was launched in Denmark in 2012 to target missed follow-up after screening, opportunistic testing, or surveillance indication. The authors compared follow-up proportions in a national observational before-after study. METHOD: From national registries, 1.5 million cervical cytologies (from 2009 to 2013) were eligible for inclusion. Approximately 10% had a recommendation for follow-up. The proportion of cervical cytologies without follow-up was calculated at different time points. Results were stratified by follow-up recommendations and sociodemographic characteristics, and changes in practice variation for follow-up were analysed. RESULTS: Fewer women with a recommendation for follow-up missed follow-up 6 months after a GP reminder. Follow-up improved in all investigated sociodemographic groups (age, ethnicity, education, and cohabitation status). Interaction was found for age and cohabitation status. Variation between practices in loss to follow-up was significantly reduced. CONCLUSION: An electronic GP reminder system showed potential to improve the quality of cervical cancer screening through reduced loss to follow-up. PMID- 28716996 TI - Long-term benzodiazepine and Z-drugs use in England: a survey of general practice AB - BACKGROUND: Current British National Formulary (BNF) guidelines state that benzodiazepines and zolpidem, zopiclone, and zaleplon, commonly known as Z-drugs (BZD), be prescribed for no more than 4 weeks, although anecdotal data suggest that many patients are prescribed BZDs for much longer. As there are no recent, evidence-based estimates of long-term (>12 months) BZD use in the UK, the scale of this potential problem is unknown. AIM: To produce the first reliable, evidence-based estimate of long-term BZD use in the UK. DESIGN AND SETTING: Estimates of UK long-term BZD use were projected from data obtained from a survey conducted in 2014-2015 by the Bridge Project, a prescribed-drug withdrawal support charity in the North of England (Bradford). METHOD: Percentages of long term users of BZD were derived from the survey, by sampling primary care GP surgeries with around 100 000 registered patients, and these were applied to UK wide NHS patient numbers. The data were filtered to exclude the very young and old, and those with other health issues. RESULTS: The mean percentage of registered patients prescribed BZDs for more than a year in the survey sample is 0.69% (95% confidence interval [CI] = 0.54 to 0.84). Applying this value to national patient numbers yields a mean projection of 296 929 (95% CI = 232 553 to 361 305) long-term users of BZD in the UK. The data also suggest that as many as 119 165 of these patients may be willing to accept prescribed drug dependency withdrawal services. CONCLUSION: More than a quarter of a million people in the UK are likely to be taking highly dependency-forming hypnotic medication far beyond the recommended time scales. As there is evidence that long-term use of BZDs causes adverse physiological and neurological effects, and protracted withdrawal (with associated complications), this represents a serious public health problem. PMID- 28716997 TI - GPs' mental wellbeing and psychological resources: a cross-sectional survey. AB - BACKGROUND: The negative impact of work has been the traditional focus of GP surveys. We know little about GP positive mental health and psychological resources. AIM: To profile and contextualise GP positive mental health and personal psychological resources. DESIGN AND SETTING: Cross-sectional survey of GPs working in Northern Ireland (NI). METHOD: A questionnaire comprising the Warwick Edinburgh Mental Wellbeing Scale (WEMWBS) and measures of resilience, optimism, self-efficacy, and hope, and sociodemographic information was posted to 400 GPs randomly selected from a publicly available GP register. RESULTS: The response rate was 55% (n = 221 out of 400). Mean value for GP wellbeing (WEMWBS) was 50.2 (standard deviation [SD] 8) compared to UK vets 48.8 (SD 9), UK teachers 47.2 (SD 9), and the population of NI 50.8 (SD 9). After adjustment for confounding, mean WEMWBS was 2.4 units (95% CI = 0.02 to 4.7) higher in female GPs than males (P = 0.05), and 4.0 units (95% CI = 0.8 to 7.3) higher in GPs >=55 years than GPs <=44 years (P = 0.02). Optimism was 1.1 units higher in female GPs than male GPs (95% CI = 0.1 to 2.0), and 1.56 units higher in GPs >=55 years (95% CI = 0.2 to 2.9) than in those <=44 years. Hope was 3 units higher in GPs >=55 years (95% CI = 0.4 to 5.7) than in those aged 45-54 years. Correlation between WEMWBS and psychological resources was highest with hope (r = 0.65, P < 0.001). CONCLUSION: GPs have levels of positive mental health that are comparable to the local population and better than other occupational groups, such as vets and teachers. Male and younger GPs may have most to gain from wellbeing interventions. PMID- 28716998 TI - Extended training to prepare GPs for future workforce needs: a qualitative investigation of a 1-year fellowship in urgent care. AB - BACKGROUND: It has been argued that UK general practice specialist training should be extended to better prepare GPs for the challenges facing 21st-century health care. Evidence is needed to inform how this should occur. AIM: To investigate the experience of recently trained GPs undertaking a 1-year full-time fellowship programme designed to provide advanced skills training in urgent care, integrated care, leadership, and academic practice; and its impact on subsequent career development. DESIGN AND SETTING: Semi-structured interviews conducted longitudinally over 2 years augmented by observational data in the West Midlands, England. METHOD: Participants were interviewed on at least three occasions: twice while undertaking the fellowship, and at least once post-completion. Participants' clinical and academic activities were observed. Data were analysed using a framework approach. RESULTS: Seven GPs participated in the pilot scheme. The fellowship was highly rated and felt to be balanced in terms of the opportunities for skill development, academic advancement, and confidence building. GPs experienced enhanced employability on completing the scheme, and at follow-up were working in a variety of primary care/urgent care interface clinical and leadership roles. Participants believed it was making general practice a more attractive career option for newly qualified doctors. CONCLUSION: The 1-year fellowship provides a defined framework for training GPs to work in an enhanced manner across organisational interfaces with the skills to support service improvement and integration. It appears to be well suited to preparing GPs for portfolio roles, but its wider applicability and impact on NHS service delivery needs further investigation. PMID- 28717000 TI - Empathy, burnout, and antibiotic prescribing for acute respiratory infections: a cross-sectional primary care study in the US. AB - BACKGROUND: The impact of physician-patient relationship factors, such as physician empathy and burnout, on antibiotic prescribing has not been characterised. AIM: To assess associations between physician empathy and burnout and antibiotic prescribing for acute respiratory infections (ARIs) in primary care. DESIGN AND SETTING: Cross-sectional study of primary care practices in the Cleveland Clinic Health System in the US. METHOD: Patient and prescribing data were obtained from the medical record. All patients with primary diagnoses of ARIs from 1 January 2012 to 31 December 2013, except those with chronic obstructive pulmonary disease (COPD) or who were immunocompromised, were included. Physician empathy was measured using the Jefferson Scale of Empathy while physician burnout was measured using the Maslach Burnout Inventory. The relationship between empathy and burnout and antibiotic prescribing, adjusted for patient and provider characteristics, was analysed using multiple linear regression. RESULTS: In 5937 ARI visits to 102 primary care physicians, the median proportion resulting in antibiotic prescribing was 48.6% (interquartile range [IQR] 24.1% to 70.0%). Neither physician empathy (correlation coefficient [beta] 0.005, 95% confidence interval [CI] = -0.001 to 0.010, P = 0.07) nor any burnout measures were significantly associated with antibiotic prescribing: emotional exhaustion (beta 0.001, 95% CI = -0.005 to 0.006, P = 0.79), tendency to depersonalise patients (beta -0.009, 95% CI = -0.021 to 0.003, P = 0.13), and sense of personal accomplishment (beta -0.004, 95% CI = -0.014 to 0.006, P = 0.44). CONCLUSION: The authors found no significant association between empathy or burnout measures and antibiotic prescribing for ARIs in primary care. Other physician characteristics should be investigated to explain individual variation in antibiotic prescribing. PMID- 28716999 TI - Improving recognition of anxiety and depression in rheumatoid arthritis: a qualitative study in a community clinic. AB - BACKGROUND: Comorbid anxiety and depression are common in patients with rheumatoid arthritis (RA) but are often under-recognised and treated, contributing to worse outcomes. National Institute for Health and Care Excellence (NICE) recommends that patients with RA should be offered a holistic annual review, including an assessment of mood. AIM: To explore patients' perspectives of anxiety and depression in RA and preferences for disclosure and management of mood problems. DESIGN AND SETTING: Qualitative interview study with patients recruited from a nurse-led RA annual review clinic in the Midlands, England. METHOD: Patients attending the clinic who scored >=3 on the case-finding questions (PHQ-2 and GAD-2) were invited for interview. Data were analysed thematically using principles of constant comparison. RESULTS: Participants recognised a connection between their RA and mood, though this was perceived variably. Some lacked candidacy for care, normalising their mood problems. Fear of stigmatisation, a lack of time, and the perception that clinicians prioritise physical over mental health problems recursively affected help-seeking. Good communication and continuity of care were perceived to be integral to disclosure of mood problems. Participants expressed a preference for psychological therapies, though they reported problems accessing care. Some perceived medication to be offered as a 'quick fix' and feared potential drug interactions. CONCLUSION: Prior experiences can lead patients with RA and comorbid anxiety and depression to feel they lack candidacy for care. Provision of equal priority to mental and physical health problems by GPs and improved continuity of care could help disclosure of mood concerns. Facilitation of access to psychological therapies could improve outcomes for both mental and physical health problems. PMID- 28717001 TI - Over 100 US healthcare providers are charged in $1.3bn fraud case. PMID- 28717002 TI - Human ribonuclease H1 resolves R-loops and thereby enables progression of the DNA replication fork. AB - Faithful DNA replication is essential for genome stability. To ensure accurate replication, numerous complex and redundant replication and repair mechanisms function in tandem with the core replication proteins to ensure DNA replication continues even when replication challenges are present that could impede progression of the replication fork. A unique topological challenge to the replication machinery is posed by RNA-DNA hybrids, commonly referred to as R loops. Although R-loops play important roles in gene expression and recombination at immunoglobulin sites, their persistence is thought to interfere with DNA replication by slowing or impeding replication fork progression. Therefore, it is of interest to identify DNA-associated enzymes that help resolve replication impeding R-loops. Here, using DNA fiber analysis, we demonstrate that human ribonuclease H1 (RNH1) plays an important role in replication fork movement in the mammalian nucleus by resolving R-loops. We found that RNH1 depletion results in accumulation of RNA-DNA hybrids, slowing of replication forks, and increased DNA damage. Our data uncovered a role for RNH1 in global DNA replication in the mammalian nucleus. Because accumulation of RNA-DNA hybrids is linked to various human cancers and neurodegenerative disorders, our study raises the possibility that replication fork progression might be impeded, adding to increased genomic instability and contributing to disease. PMID- 28717003 TI - Surface Toll-like receptor 3 expression in metastatic intestinal epithelial cells induces inflammatory cytokine production and promotes invasiveness. AB - Toll-like receptors (TLRs) are innate immune receptors for sensing microbial molecules and damage-associated molecular patterns released from host cells. Double-stranded RNA and the synthetic analog polyinosinic:polycytidylic acid (poly(I:C)) bind and activate TLR3. This stimulation leads to recruitment of the adaptor molecule TRIF (Toll/IL-1 resistance (TIR) domain-containing adapter inducing interferon beta) and activation of the transcription factors nuclear factor kappaB (NF-kappaB) and interferon regulatory factor 3 (IRF-3), classically inducing IFNbeta production. Here we report that, unlike non-metastatic intestinal epithelial cells (IECs), metastatic IECs express TLR3 and that TLR3 promotes invasiveness of these cells. In response to poly(I:C) addition, the metastatic IECs also induced the chemokine CXCL10 in a TLR3-, TRIF-, and IRF3 dependent manner but failed to produce IFNbeta. This was in contrast to healthy and non-metastatic IECs, which did not respond to poly(I:C) stimulation. Endolysosomal acidification and the endosomal transporter protein UNC93B1 was required for poly(I:C)-induced CXCL10 production. However, TLR3-induced CXCL10 was triggered by immobilized poly(I:C), was only modestly affected by inhibition of endocytosis, and could be blocked with an anti-TLR3 antibody, indicating that TLR3 can still signal from the cell surface of these cells. Furthermore, plasma membrane fractions from metastatic IECs contained both full-length and cleaved TLR3, demonstrating surface expression of both forms of TLR3. Our results imply that metastatic IECs express surface TLR3, allowing it to sense extracellular stimuli that trigger chemokine responses and promote invasiveness in these cells. We conclude that altered TLR3 expression and localization may have implications for cancer progression. PMID- 28717004 TI - Two tyrosine residues, Tyr-108 and Tyr-503, are responsible for the deprotonation of phenolic substrates in vanillyl-alcohol oxidase. AB - A number of oxidoreductases from the VAO/para-cresol methylhydroxylase flavoprotein family catalyze the oxidation of para-substituted phenols. One of the best-studied is vanillyl-alcohol oxidase (VAO) from the fungus Penicillium simplicissimum For oxidation of phenols by VAO to occur, they must first be bound in the active site of the enzyme in their phenolate anion form. The crystal structure of VAO reveals that two tyrosine residues, Tyr-108 and Tyr-503, are positioned to facilitate this deprotonation. To investigate their role in catalysis, we created three VAO variants, Y108F, Y503F, and Y108F/Y503F, and studied their biochemical properties. Steady-state kinetics indicated that the presence of at least one of the tyrosine residues is essential for efficient catalysis by VAO. Stopped-flow kinetics revealed that the reduction of VAO by chavicol or vanillyl alcohol occurs at two different rates: kobs1, which corresponds to its reaction with the deprotonated form of the substrate, and kobs2, which corresponds to its reaction with the protonated form of the substrate. In Y108F, Y503F, and Y108F/Y503F, the relative contribution of kobs2 to the reduction is larger than in wild-type VAO, suggesting deprotonation is impaired in these variants. Binding studies disclosed that the competitive inhibitor isoeugenol is predominantly in its deprotonated form when bound to wild type VAO, but predominantly in its protonated form when bound to the variants. These results indicate that Tyr-108 and Tyr-503 are responsible for the activation of substrates in VAO, providing new insights into the catalytic mechanism of VAO and related enzymes that oxidize para-substituted phenols. PMID- 28717005 TI - Lipid oxidation inactivates the anticoagulant function of protein Z-dependent protease inhibitor (ZPI). AB - Lipid oxidation due to oxidative stress plays an important role in the pathogenesis of inflammatory and thrombotic cardiovascular diseases. Several findings suggest that lipid peroxidation can alter the function of coagulation proteins and contribute to a hypercoagulable state, but the molecular mechanisms are unclear. Here, we report that oxidized phospholipids suppress the anticoagulant function of the serpin, protein Z-dependent protease inhibitor (ZPI), a specific inhibitor of membrane-associated factor Xa (FXa) that requires protein Z (PZ), phospholipid, and calcium as cofactors. We found that this suppression arises from a diminished ability of the oxidized membrane to function as a cofactor to promote ZPI inhibition of membrane-bound FXa, due fully or in part to the susceptibility of the bound ZPI-PZ complex to oxidative inactivation. Surprisingly, free ZPI was also susceptible to inactivation by oxidized membrane vesicles in the absence of calcium. Oxidized vesicles containing both phosphatidylserine and polyunsaturated fatty acids were required to promote inactivation of the ZPI-PZ complex or free ZPI, indicating that binding of the PZ complexed or free ZPI to peroxide-modified phospholipid vesicles mediates the inactivation. Heparin protected the ZPI-PZ complex and free ZPI from inactivation, suggesting that blocking the heparin-binding site on ZPI interferes with ZPI binding to lipid or to PZ. This was confirmed by direct lipid-binding experiments. Native PAGE indicated that oxidization induced dissociation of the ZPI-PZ complex and increased the negative charge of ZPI. We conclude that compromised ZPI anticoagulant function could contribute to thrombus initiation and growth in oxidative stress-induced cardiovascular diseases. PMID- 28717006 TI - Extrinsic sialylation is dynamically regulated by systemic triggers in vivo. AB - Recent reports have documented that extracellular sialyltransferases can remodel both cell-surface and secreted glycans by a process other than the canonical cell autonomous glycosylation that occurs within the intracellular secretory apparatus. Despite association of the abundance of these extracellular sialyltransferases, particularly ST6Gal-1, with disease states such as cancer and a variety of inflammatory conditions, the prevalence of this extrinsic glycosylation pathway in vivo remains unknown. Here we observed no significant extrinsic sialylation in resting mice, suggesting that extrinsic sialylation is not a constitutive process. However, extrinsic sialylation in the periphery could be triggered by inflammatory challenges, such as exposure to ionizing radiation or to bacterial lipopolysaccharides. Sialic acids from circulating platelets were used in vivo to remodel target cell surfaces. Platelet activation was minimally sufficient to elicit extrinsic sialylation, as demonstrated with the FeCl3 model of mesenteric artery thrombosis. Although extracellular ST6Gal-1 supports extrinsic sialylation, other sialyltransferases are present in systemic circulation. We also observed in vivo extrinsic sialylation in animals deficient in ST6Gal-1, demonstrating that extrinsic sialylation is not mediated exclusively by ST6Gal-1. Together, these observations form an emerging picture of glycans biosynthesized by the canonical cell-autonomous glycosylation pathway, but subjected to remodeling by extracellular glycan-modifying enzymes. PMID- 28717007 TI - Epigenetic suppression of human telomerase (hTERT) is mediated by the metastasis suppressor NME2 in a G-quadruplex-dependent fashion. AB - Transcriptional activation of the human telomerase reverse transcriptase (hTERT) gene, which remains repressed in adult somatic cells, is critical during tumorigenesis. Several transcription factors and the epigenetic state of the hTERT promoter are known to be important for tight control of hTERT in normal tissues, but the molecular mechanisms leading to hTERT reactivation in cancer are not well-understood. Surprisingly, here we found occupancy of the metastasis suppressor non-metastatic 2 (NME2) within the hTERT core promoter in HT1080 fibrosarcoma cells and HCT116 colon cancer cells and NME2-mediated transcriptional repression of hTERT in these cells. We also report that loss of NME2 results in up-regulated hTERT expression. Mechanistically, additional results indicated that the RE1-silencing transcription factor (REST)-lysine specific histone demethylase 1 (LSD1) co-repressor complex associates with the hTERT promoter in an NME2-dependent way and that this assembly is required for maintaining repressive chromatin at the hTERT promoter. Interestingly, a G quadruplex motif at the hTERT promoter was essential for occupancy of NME2 and the REST repressor complex on the hTERT promoter. In light of this mechanistic insight, we studied the effects of G-quadruplex-binding ligands on hTERT expression and observed that several of these ligands repressed hTERT expression. Together, our results support a mechanism of hTERT epigenetic control involving a G-quadruplex promoter motif, which potentially can be targeted by tailored small molecules. PMID- 28717008 TI - The novel cardiac z-disc protein CEFIP regulates cardiomyocyte hypertrophy by modulating calcineurin signaling. AB - The z-disc is a structural component at the lateral borders of the sarcomere and is important for mechanical stability and contractility of both cardiac and skeletal muscles. Of note, the sarcomeric z-disc also represents a nodal point in cardiomyocyte function and signaling. Mutations of numerous z-disc proteins are associated with cardiomyopathies and muscle diseases. To identify additional z disc proteins that might contribute to cardiac disease, we employed an in silico screen for cardiac-enriched cDNAs. This screen yielded a previously uncharacterized protein named cardiac-enriched FHL2-interacting protein (CEFIP), which exhibited a heart- and skeletal muscle-specific expression profile. Importantly, CEFIP was located at the z-disc and was up-regulated in several models of cardiomyopathy. We also found that CEFIP overexpression induced the fetal gene program and cardiomyocyte hypertrophy. Yeast two-hybrid screens revealed that CEFIP interacts with the calcineurin-binding protein four and a half LIM domains 2 (FHL2). Because FHL2 binds calcineurin, a phosphatase controlling hypertrophic signaling, we examined the effects of CEFIP on the calcineurin/nuclear factor of activated T-cell (NFAT) pathway. These experiments revealed that CEFIP overexpression further enhances calcineurin-dependent hypertrophic signal transduction, and its knockdown repressed hypertrophy and calcineurin/NFAT activity. In summary, we report on a previously uncharacterized protein CEFIP that modulates calcineurin/NFAT signaling in cardiomyocytes, a finding with possible implications for the pathogenesis of cardiomyopathy. PMID- 28717009 TI - Acetylation on histone H3 lysine 9 mediates a switch from transcription initiation to elongation. AB - The transition from transcription initiation to elongation is a key regulatory step in gene expression, which requires RNA polymerase II (pol II) to escape promoter proximal pausing on chromatin. Although elongation factors promote pause release leading to transcription elongation, the role of epigenetic modifications during this critical transition step is poorly understood. Two histone marks on histone H3, lysine 4 trimethylation (H3K4me3) and lysine 9 acetylation (H3K9ac), co-localize on active gene promoters and are associated with active transcription. H3K4me3 can promote transcription initiation, yet the functional role of H3K9ac is much less understood. We hypothesized that H3K9ac may function downstream of transcription initiation by recruiting proteins important for the next step of transcription. Here, we describe a functional role for H3K9ac in promoting pol II pause release by directly recruiting the super elongation complex (SEC) to chromatin. H3K9ac serves as a substrate for direct binding of the SEC, as does acetylation of histone H4 lysine 5 to a lesser extent. Furthermore, lysine 9 on histone H3 is necessary for maximal pol II pause release through SEC action, and loss of H3K9ac increases the pol II pausing index on a subset of genes in HeLa cells. At select gene promoters, H3K9ac loss or SEC depletion reduces gene expression and increases paused pol II occupancy. We therefore propose that an ordered histone code can promote progression through the transcription cycle, providing new mechanistic insight indicating that SEC recruitment to certain acetylated histones on a subset of genes stimulates the subsequent release of paused pol II needed for transcription elongation. PMID- 28717010 TI - Phosphorylation of the kainate receptor (KAR) auxiliary subunit Neto2 at serine 409 regulates synaptic targeting of the KAR subunit GluK1. AB - Synaptic strength at excitatory synapses is determined by the presence of glutamate receptors (i.e. AMPA, NMDA, and kainate receptors) at the synapse. Synaptic strength is modulated by multiple factors including assembly of different receptor subunits, interaction with auxiliary subunits, and post translational modifications of either the receptors or their auxiliary subunits. Using mass spectrometry, we found that the intracellular region of neuropilin and tolloid-like proteins (Neto) 1 and Neto2, the auxiliary subunits of kainate receptor (KARs), are phosphorylated by multiple kinases in vitro Specifically, Neto2 was phosphorylated at serine 409 (Ser-409) by Ca2+/calmodulin-dependent protein kinase II (CaMKII) and protein kinase A (PKA) both in vitro and in heterologous cells. Interestingly, we observed a substantial increase in Neto2 Ser-409 phosphorylation in the presence of CaMKII, and this phosphorylation was reduced in the presence of the KAR subunit GluK1 or GluK2. We also found endogenous phosphorylation of Neto2 at Ser-409 in the brain. Moreover, Neto2 Ser 409 phosphorylation inhibited synaptic targeting of GluK1 because, unlike WT Neto2 and the phosphodeficient mutant Neto2 S409A, the Neto2 S409D phosphomimetic mutant impeded GluK1 trafficking to synapses. These results support a molecular mechanism by which Neto2 phosphorylation at Ser-409 helps restrict GluK1 targeting to the synapse. PMID- 28717011 TI - Dysregulation of BCL-2 family proteins by leukemia fusion genes. AB - The genomic lesions that characterize acute lymphoblastic leukemia in childhood include recurrent translocations that result in the expression of fusion proteins that typically involve genes encoding tyrosine kinases, cytokine receptors, and transcription factors. These genetic rearrangements confer phenotypic hallmarks of malignant transformation, including unrestricted proliferation and a relative resistance to apoptosis. In this Minireview, we discuss the molecular mechanisms that link these fusions to the control of cell death. We examine how these fusion genes dysregulate the BCL-2 family of proteins, preventing activation of the apoptotic effectors, BAX and BAK, and promoting cell survival. PMID- 28717012 TI - Intracellular metabolic pathway distribution in diatoms and tools for genome enabled experimental diatom research. AB - Diatoms are important primary producers in the oceans and can also dominate other aquatic habitats. One reason for the success of this phylogenetically relatively young group of unicellular organisms could be the impressive redundancy and diversity of metabolic isoenzymes in diatoms. This redundancy is a result of the evolutionary origin of diatom plastids by a eukaryote-eukaryote endosymbiosis, a process that implies temporary redundancy of functionally complete eukaryotic genomes. During the establishment of the plastids, this redundancy was partially reduced via gene losses, and was partially retained via gene transfer to the nucleus of the respective host cell. These gene transfers required re-assignment of intracellular targeting signals, a process that simultaneously altered the intracellular distribution of metabolic enzymes compared with the ancestral cells. Genome annotation, the correct assignment of the gene products and the prediction of putative function, strongly depends on the correct prediction of the intracellular targeting of a gene product. Here again diatoms are very peculiar, because the targeting systems for organelle import are partially different to those in land plants. In this review, we describe methods of predicting intracellular enzyme locations, highlight findings of metabolic peculiarities in diatoms and present genome-enabled approaches to study their metabolism.This article is part of the themed issue 'The peculiar carbon metabolism in diatoms'. PMID- 28717013 TI - Mechanisms of carbon dioxide acquisition and CO2 sensing in marine diatoms: a gateway to carbon metabolism. AB - Diatoms are one of the most successful marine eukaryotic algal groups, responsible for up to 20% of the annual global CO2 fixation. The evolution of a CO2-concentrating mechanism (CCM) allowed diatoms to overcome a number of serious constraints on photosynthesis in the marine environment, particularly low [CO2]aq in seawater relative to concentrations required by the CO2 fixing enzyme, ribulose-1,5-bisphosphate carboxylase/oxygenase (RubisCO), which is partly due to the slow diffusion rate of CO2 in water and a limited CO2 formation rate from [Formula: see text] in seawater. Diatoms use two alternative strategies to take up dissolved inorganic carbon (DIC) from the environment: one primarily relies on the direct uptake of [Formula: see text] through plasma-membrane type solute carrier (SLC) 4 family [Formula: see text] transporters and the other is more reliant on passive diffusion of CO2 formed by an external carbonic anhydrase (CA). Bicarbonate taken up into the cytoplasm is most likely then actively transported into the chloroplast stroma by SLC4-type transporters on the chloroplast membrane system. Bicarbonate in the stroma is converted into CO2 only in close proximity to RubisCO preventing unnecessary CO2 leakage. CAs play significant roles in mobilizing DIC as it is progressively moved towards the site of fixation. However, the evolutionary types and subcellular locations of CAs are not conserved between different diatoms, strongly suggesting that this DIC mobilization strategy likely evolved multiple times with different origins. By contrast, the recent discovery of the thylakoid luminal theta-CA indicates that the strategy to supply CO2 to RubisCO in the pyrenoid may be very similar to that of green algae, and strongly suggests convergent coevolution in CCM function of the thylakoid lumen not only among diatoms but among eukaryotic algae in general. In this review, both experimental and corresponding theoretical models of the diatom CCMs are discussed.This article is part of the themed issue 'The peculiar carbon metabolism in diatoms'. PMID- 28717014 TI - Investigating mixotrophic metabolism in the model diatom Phaeodactylum tricornutum. AB - Diatoms are prominent marine microalgae, interesting not only from an ecological point of view, but also for their possible use in biotechnology applications. They can be cultivated in phototrophic conditions, using sunlight as the sole energy source. Some diatoms, however, can also grow in a mixotrophic mode, wherein both light and external reduced carbon contribute to biomass accumulation. In this study, we investigated the consequences of mixotrophy on the growth and metabolism of the pennate diatom Phaeodactylum tricornutum, using glycerol as the source of reduced carbon. Transcriptomics, metabolomics, metabolic modelling and physiological data combine to indicate that glycerol affects the central-carbon, carbon-storage and lipid metabolism of the diatom. In particular, provision of glycerol mimics typical responses of nitrogen limitation on lipid metabolism at the level of triacylglycerol accumulation and fatty acid composition. The presence of glycerol, despite provoking features reminiscent of nutrient limitation, neither diminishes photosynthetic activity nor cell growth, revealing essential aspects of the metabolic flexibility of these microalgae and suggesting possible biotechnological applications of mixotrophy.This article is part of the themed issue 'The peculiar carbon metabolism in diatoms'. PMID- 28717015 TI - The peculiar carbon metabolism in diatoms. PMID- 28717016 TI - The effects of phosphorus limitation on carbon metabolism in diatoms. AB - Phosphorus is an essential element for life, serving as an integral component of nucleic acids, lipids and a diverse range of other metabolites. Concentrations of bioavailable phosphorus are low in many aquatic environments. Microalgae, including diatoms, apply physiological and molecular strategies such as phosphorus scavenging or recycling as well as adjusting cell growth in order to adapt to limiting phosphorus concentrations. Such strategies also involve adjustments of the carbon metabolism. Here, we review the effect of phosphorus limitation on carbon metabolism in diatoms. Two transcriptome studies are analysed in detail, supplemented by other transcriptome, proteome and metabolite data, to gain an overview of different pathways and their responses. Phosphorus, nitrogen and silicon limitation responses are compared, and similarities and differences discussed. We use the current knowledge to propose a suggestive model for the carbon flow in phosphorus-replete and phosphorus-limited diatom cells.This article is part of the themed issue 'The peculiar carbon metabolism in diatoms'. PMID- 28717017 TI - Modulation of lipid biosynthesis by stress in diatoms. AB - Diatoms are responsible for up to 40% of the carbon fixation in our oceans. The fixed carbon is moved through carbon metabolism towards the synthesis of organic molecules that are consumed through interlocking foodwebs, and this process is strongly impacted by the abiotic environment. However, it has become evident that diatoms can be used as 'platform' organisms for the production of high valuable bio-products such as lipids, pigments and carbohydrates where stress conditions can be used to direct carbon metabolism towards the commercial production of these compounds. In the first section of this review, some aspects of carbon metabolism in diatoms and how it is impacted by environmental factors are briefly described. The second section is focused on the biosynthesis of lipids and in particular omega-3 long-chain polyunsaturated fatty acids and how low temperature stress impacts on the production of these compounds. In a third section, we review the recent advances in bioengineering for lipid production. Finally, we discuss new perspectives for designing strains for the sustainable production of high-value lipids.This article is part of the themed issue 'The peculiar carbon metabolism in diatoms'. PMID- 28717018 TI - Structure and properties of oil bodies in diatoms. AB - Diatoms accumulate triacylglycerols in spherical organelles called oil bodies when exposed to nutrient deprivation conditions. Oil body biology in diatoms has attracted significant attention due to the complexity of the intracellular organelles and the unique combination of genes generated by the evolutionary history of secondary endosymbiosis. The demand for biofuel production has further increased the interest in and importance of a better understanding of oil body biology in diatoms, because it could provide targets for genetic engineering to further enhance their promising lipid accumulation. This review describes recent progress in studies of the structure and properties of diatom oil bodies. Firstly, the general features of diatom oil bodies are described, in particular, their number, size and morphology, as well as the quantity and quality of lipids they contain. Subsequently, the diatom oil body-associated proteins, which were recently discovered through oil body proteomics, are introduced. Then, the metabolic pathways responsible for the biogenesis and degradation of diatom oil bodies are summarized. During biogenesis and degradation, oil bodies interact with other organelles, including chloroplasts, the endoplasmic reticulum and mitochondria, suggesting their dynamic nature in response to environmental changes. Finally, the functions of oil bodies in diatoms are discussed.This article is part of the themed issue 'The peculiar carbon metabolism in diatoms'. PMID- 28717019 TI - 3-Hydroxyisobutyryl-CoA hydrolase involved in isoleucine catabolism regulates triacylglycerol accumulation in Phaeodactylum tricornutum. AB - Since methylmalonyl-CoA epimerase appears to be absent in the majority of photosynthetic organisms, including diatoms, (S)-methylmalonyl-CoA, the intermediate of isoleucine (Ile) catabolism, cannot be metabolized to (R) methylmalonyl-CoA then to succinyl-CoA. In this study, propionyl-CoA carboxylase (PCC) RNAi silenced strains and 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) overexpression strains were constructed to elucidate the Ile degradation pathway and its influence on lipid accumulation in Phaeodactylum tricornutum based on growth, neutral lipid content and metabolite profile analysis. Knockdown of PCC disturbed the metabolism of Ile through propionyl-CoA to methylmalonyl-CoA, as illustrated by much higher Ile content at day 6. However, Ile decreased to comparable levels to the wild-type at day 10. PCC silencing redirected propionyl CoA to acetyl-CoA via a modified beta-oxidation pathway, and transcript levels for some branched-chain amino acid (BCAA) degradation-related genes, especially HIBCH, significantly upregulated in the PCC mutant, which enhanced the BCAA degradations and thus resulted in higher triacylglycerol (TAG) content. Overexpression of HIBCH accelerates Ile degradation and results in a lowered Ile content in the overexpression strains, thus enhancing carbon skeletons to the tricarboxylic acid cycle and giving rise to increasing TAG accumulation. Our study provides a good strategy to obtain high-lipid-yield transgenic diatoms by modifying the propionyl-CoA metabolism.This article is part of the themed issue 'The peculiar carbon metabolism in diatoms'. PMID- 28717020 TI - Towards an understanding of the molecular regulation of carbon allocation in diatoms: the interaction of energy and carbon allocation. AB - In microalgae, the photosynthesis-driven CO2 assimilation delivers cell building blocks that are used in different biosynthetic pathways. Little is known about how the cell regulates the subsequent carbon allocation to, for example, cell growth or for storage. However, knowledge about these regulatory mechanisms is of high biotechnological and ecological importance. In diatoms, the situation becomes even more complex because, as a consequence of their secondary endosymbiotic origin, the compartmentation of the pathways for the primary metabolic routes is different from green algae. Therefore, the mechanisms to manipulate the carbon allocation pattern cannot be adopted from the green lineage. This review describes the general pathways of cellular energy distribution from light absorption towards the final allocation of carbon into macromolecules and summarizes the current knowledge of diatom-specific allocation patterns. We further describe the (limited) knowledge of regulatory mechanisms of carbon partitioning between lipids, carbohydrates and proteins in diatoms. We present solutions to overcome the problems that hinder the identification of regulatory elements of carbon metabolism.This article is part of the themed issue 'The peculiar carbon metabolism in diatoms'. PMID- 28717021 TI - Genetic and metabolic engineering in diatoms. AB - Diatoms have attracted considerable attention due to their success in diverse environmental conditions, which probably is a consequence of their complex origins. Studies of their metabolism will provide insight into their adaptation capacity and are a prerequisite for metabolic engineering. Several years of investigation have led to the development of the genome engineering tools required for such studies, and a profusion of appropriate tools is now available for exploring and exploiting the metabolism of these organisms. Diatoms are highly prized in industrial biotechnology, due to both their richness in natural lipids and carotenoids and their ability to produce recombinant proteins, of considerable value in diverse markets. This review provides an overview of recent advances in genetic engineering methods for diatoms, from the development of gene expression cassettes and gene delivery methods, to cutting-edge genome-editing technologies. It also highlights the contributions of these rapid developments to both basic and applied research: they have improved our understanding of key physiological processes; and they have made it possible to modify the natural metabolism to favour the production of specific compounds or to produce new compounds for green chemistry and pharmaceutical applications.This article is part of the themed issue 'The peculiar carbon metabolism in diatoms'. PMID- 28717022 TI - Response of CO2-starved diatom Phaeodactylum tricornutum to light intensity transition. AB - In this study, we investigated the responses of Phaeodactylum tricornutum cells acclimated to 300 umol m-2 s-1 photon flux density to an increase (1000 umol m-2 s-1) or decrease (30 umol m-2 s-1) in photon flux densities. The light shift occurred abruptly after 5 days of growth and the acclimation to new conditions was followed during the next 6 days at the physiological and molecular levels. The molecular data reflect a rearrangement of carbon metabolism towards the production of phosphoenolpyruvic acid (PEP) and/or pyruvate. These intermediates were used differently by the cell as a function of the photon flux density: under low light, photosynthesis was depressed while respiration was increased. Under high light, lipids and proteins accumulated. Of great interest, under high light, the genes coding for the synthesis of aromatic amino acids and phenolic compounds were upregulated suggesting that the shikimate pathway was activated.This article is part of the themed issue 'The peculiar carbon metabolism in diatoms'. PMID- 28717023 TI - The evolution of diatoms and their biogeochemical functions. AB - In contemporary oceans diatoms are an important group of eukaryotic phytoplankton that typically dominate in upwelling regions and at high latitudes. They also make significant contributions to sporadic blooms that often occur in springtime. Recent surveys have revealed global information about their abundance and diversity, as well as their contributions to biogeochemical cycles, both as primary producers of organic material and as conduits facilitating the export of carbon and silicon to the ocean interior. Sequencing of diatom genomes is revealing the evolutionary underpinnings of their ecological success by examination of their gene repertoires and the mechanisms they use to adapt to environmental changes. The rise of the diatoms over the last hundred million years is similarly being explored through analysis of microfossils and biomarkers that can be traced through geological time, as well as their contributions to seafloor sediments and fossil fuel reserves. The current review aims to synthesize current information about the evolution and biogeochemical functions of diatoms as they rose to prominence in the global ocean.This article is part of the themed issue 'The peculiar carbon metabolism in diatoms'. PMID- 28717024 TI - Inorganic carbon availability in benthic diatom communities: photosynthesis and migration. AB - Diatom-dominated microphytobenthos (MPB) is the main primary producer of many intertidal and shallow subtidal environments, being therefore of critical importance to estuarine and coastal food webs. Owing to tidal cycles, intertidal MPB diatoms are subjected to environmental conditions far more variable than the ones experienced by pelagic diatoms (e.g. light, temperature, salinity, desiccation and nutrient availability). Nevertheless, benthic diatoms evolved adaptation mechanisms to these harsh conditions, including the capacity to move within steep physical and chemical gradients, allowing them to perform photosynthesis efficiently. In this contribution, we will review present knowledge on the effects of dissolved inorganic carbon (DIC) availability on photosynthesis and productivity of diatom-dominated MPB. We present evidence of carbon limitation of photosynthesis in benthic diatom mats and highly productive MPB natural communities. Furthermore, we hypothesize that active vertical migration of epipelic motile diatoms could overcome local depletion of DIC in the photic layer, providing the cells alternately with light and inorganic carbon supply. The few available longer-term experiments on the effects of inorganic carbon enrichment on the productivity of diatom-dominated MPB have yielded inconsistent results. Therefore, further studies are needed to properly assess the response of MPB communities to increased CO2 and ocean acidification related to climate change.This article is part of the themed issue 'The peculiar carbon metabolism in diatoms'. PMID- 28717025 TI - The role of intraspecific variation in the ecological and evolutionary success of diatoms in changing environments. AB - Intraspecific variation in diatoms has been shown to play a key role in species' responses to several important environmental factors such as light, salinity, temperature and nutrients. Furthermore, modelling efforts indicate that this variation within species extends bloom periods, and likely provides sufficient variability in competitive interactions between species under hydrographically variable conditions. The intraspecific variation most likely corresponds to optimal fitness in temporary microhabitats and may help to explain the paradox of the plankton. Here, we examine the implications of intraspecific variation for the ecology and success of diatoms in general and emphasize the potential implications for our understanding of carbon metabolism in these important organisms. Additionally, data from palaeoecological studies have the potential for evaluating genetic variation through past climate changes, going thousands of years back in time. We suggest pathways for future research including the adoption of multiple strains of individual species into studies of diatom carbon metabolism, to refine our understanding of the variation within and between species, and the inclusion of experimental evolution as a tool for understanding potential evolutionary responses of diatom carbon metabolism to climate change.This article is part of the themed issue 'The peculiar carbon metabolism in diatoms'. PMID- 28717026 TI - Acquisition and metabolism of carbon in the Ochrophyta other than diatoms. AB - The acquisition and assimilation of inorganic C have been investigated in several of the 15 clades of the Ochrophyta other than diatoms, with biochemical, physiological and genomic data indicating significant mechanistic variation. Form ID Rubiscos in the Ochrophyta are characterized by a broad range of kinetics values. In spite of relatively high K0.5CO2 and low CO2 : O2 selectivity, diffusive entry of CO2 occurs in the Chrysophyceae and Synurophyceae. Eustigmatophyceae and Phaeophyceae, on the contrary, have CO2 concentrating mechanisms, usually involving the direct or indirect use of [Formula: see text] This variability is possibly due to the ecological contexts of the organism. In brown algae, C fixation generally takes place through a classical C3 metabolism, but there are some hints of the occurrence of C4 metabolism and low amplitude CAM in a few members of the Fucales. Genomic data show the presence of a number of potential C4 and CAM genes in Ochrophyta other than diatoms, but the other core functions of many of these genes give a very limited diagnostic value to their presence and are insufficient to conclude that C4 photosynthesis is present in these algae.This article is part of the themed issue 'The peculiar carbon metabolism in diatoms'. PMID- 28717027 TI - Regulation of the Calvin-Benson-Bassham cycle in the enigmatic diatoms: biochemical and evolutionary variations on an original theme. AB - In Plantae, the Calvin-Benson-Bassham (CBB) cycle is highly regulated and most of its enzymes have been thoroughly studied. Since diatoms arose as a result of secondary endosymbiosis with one or more Plantae ancestors, their precise evolutionary history is enigmatic and complex resulting in biochemical variations on the original CBB cycle theme. The Rubisco Michaelis constant for CO2 is higher in diatoms than land plants and the nuclear-encoded Rubisco activase in Plantae is replaced by an analogous chloroplast-encoded CbbX (Calvin-Benson-Bassham protein X) in diatoms. In the CBB cycle reduction phase, phosphoglycerate kinase in diatoms is redox-regulated and similar to that in red algae; however, glyceraldehyde phosphate dehydrogenase (GAPDH) is not redox-regulated, unlike in Plantae. The phosphoribulokinase (PRK)-GAPDH-CP12 complex found in many photosynthetic organisms has not yet been found in diatoms, but a ferredoxin-NADP reductase (FNR)-GAPDH-CP12 complex has been found in one species. In the CBB cycle regeneration phase, sedoheptulose 1,7-bisphosphatase and PRK are not redox regulated in diatoms, unlike in Plantae. Regulation at the transcriptional level seems to be important in diatoms. CBB cycle enzyme properties appear to be variable among diatoms, but this view relies on results from a few model species: a greater range of diatoms need to be studied to test this.This article is part of the themed issue 'The peculiar carbon metabolism in diatoms'. PMID- 28717028 TI - The Norepinephrine Metabolite 3,4-Dihydroxymandelic Acid Is Produced by the Commensal Microbiota and Promotes Chemotaxis and Virulence Gene Expression in Enterohemorrhagic Escherichia coli. AB - Enterohemorrhagic Escherichia coli (EHEC) is a commonly occurring foodborne pathogen responsible for numerous multistate outbreaks in the United States. It is known to infect the host gastrointestinal tract, specifically, in locations associated with lymphoid tissue. These niches serve as sources of enteric neurotransmitters, such as epinephrine and norepinephrine, that are known to increase virulence in several pathogens, including enterohemorrhagic E. coli The mechanisms that allow pathogens to target these niches are poorly understood. We previously reported that 3,4-dihydroxymandelic acid (DHMA), a metabolite of norepinephrine produced by E. coli, is a chemoattractant for the nonpathogenic E. coli RP437 strain. Here we report that DHMA is also a chemoattractant for EHEC. In addition, DHMA induces the expression of EHEC virulence genes and increases attachment to intestinal epithelial cells in vitro in a QseC-dependent manner. We also show that DHMA is present in murine gut fecal contents and that its production requires the presence of the commensal microbiota. On the basis of its ability to both attract and induce virulence gene expression in EHEC, we propose that DHMA acts as a molecular beacon to target pathogens to their preferred sites of infection in vivo. PMID- 28717030 TI - Intestinal Epithelial Ecto-5'-Nucleotidase (CD73) Regulates Intestinal Colonization and Infection by Nontyphoidal Salmonella. AB - Ecto-5'-nucleotidase (CD73) is expressed abundantly on the apical surface of intestinal epithelial cells (IECs) and functions as the terminal enzyme in the generation of extracellular adenosine. Previous work demonstrated that adenosine signaling in IECs results in a number of tissue-protective effects during inflammation; however, a rationale for its apical expression has been lacking. We hypothesized that the highly polarized expression of CD73 is indicative of an important role for extracellular adenosine as a mediator of host-microbe interactions. We show that adenosine harbors bacteriostatic activity against Salmonella enterica serovar Typhimurium that is not shared by the related purine metabolite 5'-AMP, inosine, or hypoxanthine. Analysis of Salmonella colonization in IEC-specific CD73 knockout mice (CD73f/fVillinCre ) revealed a nearly 10-fold increase in colonization compared to that in controls. Despite the increased luminal colonization by Salmonella, CD73f/fVillinCre mice were protected against Salmonella colitis and showed reduced Salmonella burdens in viscera, suggesting that adenosine promotes dissemination. The knockdown of CD73 expression in cultured IECs resulted in dramatic defects in intraepithelial localization and replication as well as defective transepithelial translocation by Salmonella In conclusion, we define a novel antimicrobial activity of adenosine in the gastrointestinal tract and unveil an important role for adenosine as a regulator of host-microbe interactions. These findings have broad implications for the development of new therapeutic agents for infectious disease. PMID- 28717029 TI - Metabolite Transporter PEG344 Is Required for Full Virulence of Hypervirulent Klebsiella pneumoniae Strain hvKP1 after Pulmonary but Not Subcutaneous Challenge. AB - Hypervirulent Klebsiella pneumoniae (hvKP) is an emerging pathotype that is capable of causing tissue-invasive and organ- and life-threatening infections in healthy individuals from the community. Knowledge on the virulence factors specific to hvKP is limited. In this report, we describe a new factor (PEG344) that increases the virulence of hvKP strain hvKP1. peg-344 is present on the hvKP1 virulence plasmid, is broadly prevalent among hvKP strains, and has increased RNA abundance when grown in human ascites. An isogenic derivative of hvKP1 (hvKP1Deltapeg-344) was constructed and compared with its wild-type parent strain in in vitro, ex vivo, and infection model studies. Both survival and competition experiments with outbred CD1 mice demonstrated that PEG344 was required for full virulence after pulmonary challenge but, interestingly, not after subcutaneous challenge. In silico analysis suggested that PEG344 serves as an inner membrane transporter. Compared to hvKP1, a small but significant decrease in the growth/survival of hvKP1Deltapeg-344 was observed in human ascites, but resistance to the bactericidal activity of complement was similar. These data suggested that PEG344 may transport an unidentified growth factor present in ascites. The data presented are important since they expand our limited knowledge base on virulence factors unique to hvKP, which is needed to lay the groundwork for translational approaches to prevent or treat these devastating infections. PMID- 28717031 TI - Phagocytic Receptors Activate Syk and Src Signaling during Borrelia burgdorferi Phagocytosis. AB - Phagocytosis of the Lyme disease-causing pathogen Borrelia burgdorferi has been shown to be important for generating an inflammatory response to the pathogen. As a result, understanding the mechanisms of phagocytosis has been an area of great interest in the field of Lyme disease. Several cell surface receptors that participate in B. burgdorferi phagocytosis have been reported, including the scavenger receptor MARCO and integrin alpha3beta1. We sought to define the mechanisms by which these receptors mediate phagocytosis and to identify signaling pathways activated downstream of these receptors upon contact with B. burgdorferi We identified both Syk and Src signaling pathways as ones that participate in B. burgdorferi phagocytosis and the resulting cytokine activation. In our studies, we found that both MARCO and integrin beta1 play a role in the activation of the Src kinase pathway. However, only integrin beta1 participates in the activation of Syk. Interestingly, the integrin activates Syk without the help of the signaling adaptor Dap12 or FcRgamma. Thus, we report that multiple pathways participate in B. burgdorferi internalization and that different cell surface receptors act simultaneously in cooperation and independently to mediate phagocytosis. PMID- 28717033 TI - Vocal fold paralysis on positron emission tomography-CT. PMID- 28717034 TI - Divide and conquer: identifying acute respiratory distress syndrome subphenotypes. PMID- 28717032 TI - Th17-Mediated Cross Protection against Pneumococcal Carriage by Vaccination with a Variable Antigen. AB - Serotype-specific protection against Streptococcus pneumoniae is an important limitation of the current polysaccharide-based vaccines. To prevent serotype replacement, reduce transmission, and limit the emergence of new variants, it is essential to induce broad protection and restrict pneumococcal colonization. In this study, we used a prototype vaccine formulation consisting of lipopolysaccharide (LPS)-detoxified outer membrane vesicles (OMVs) from Salmonella enterica serovar Typhimurium displaying the variable N terminus of PspA (alpha1alpha2) for intranasal vaccination, which induced strong Th17 immunity associated with a substantial reduction of pneumococcal colonization. Despite the variable nature of this protein, a common major histocompatibility complex class (MHC-II) epitope was identified, based on in silico prediction combined with ex vivo screening, and was essential for interleukin-17 A (IL-17A) mediated cross-reactivity and associated with cross protection. Based on 1,352 PspA sequences derived from a pneumococcal carriage cohort, this OMV-based vaccine formulation containing a single alpha1alpha2 type was estimated to cover 19.1% of strains, illustrating the potential of Th17-mediated cross protection. PMID- 28717035 TI - Neurotoxic Concentration of Piperacillin during Continuous Infusion in Critically Ill Patients. AB - This retrospective cohort study included 53 patients admitted to the intensive care unit (ICU), with an average age of 69 years, without neurologic disorder before initiation of a continuous piperacillin infusion at the standard dose and who underwent piperacillin serum concentration monitoring. Among them, 23 developed a neurologic disorder for which the piperacillin causality was chronologically and semiologically suggestive. A concentration threshold of 157.2 mg/liter independently predicted neurotoxicity with 96.7% specificity and 52.2% sensitivity and may constitute a limitation when targeting less susceptible pathogens. PMID- 28717036 TI - Transmission of Resistant Gram-Negative Bacteria to Health Care Worker Gowns and Gloves during Care of Nursing Home Residents in Veterans Affairs Community Living Centers. AB - The objectives of the study were to estimate the risk of transmission of antibiotic-resistant Gram-negative bacteria (RGNB) to gowns and gloves (G&G) worn by health care workers (HCWs) when providing care to nursing home residents and to identify the types of care and resident characteristics associated with transmission. A multicenter, prospective observational study was conducted with residents and HCWs from Veterans Affairs (VA) nursing homes. Perianal swabs to detect RGNB were collected from residents. HCWs wore G&G during usual care activities, and the G&G were swabbed at the end of the interaction in a standardized manner. Transmission of RGNB from a colonized resident to G&G by type of care was measured. Odds ratios (ORs) associated with type of care or resident characteristics were estimated. Fifty-seven (31%) of 185 enrolled residents were colonized with >=1 RGNB. RGNB transmission to HCW gloves or gowns occurred during 9% of the interactions (n = 905): 7% to only gloves and 2% to only gowns. Bathing the resident and providing hygiene and toilet assistance were associated with a high risk of transmission. Glucose monitoring and assistance with feeding or medication were associated with a low risk of transmission. In addition, antibiotic use by the resident was strongly associated with greater transmission (OR, 2.51; P < 0.01). RGNB were transferred to HCWs during ~9% of visits. High-risk types of care were identified for which use of G&G may be prioritized. Antibiotic use was associated with 2.5 times greater risk of transmission, emphasizing the importance of antibiotic stewardship. (This study has been registered at ClinicalTrials.gov under registration no. NCT01350479.). PMID- 28717037 TI - Impact of a Carbapenem Antimicrobial Stewardship Program on Patient Outcomes. AB - Antimicrobial stewardship programs (ASPs) aim to improve appropriate antimicrobial use. However, concerns of the negative consequences from accepting ASP interventions exist, particularly when deescalation or discontinuation of broad-spectrum antibiotics is recommended. Hence, we sought to evaluate the impact on clinical outcomes when ASP interventions for inappropriate carbapenem use were accepted or rejected by primary providers. We retrospectively reviewed all carbapenem prescriptions deemed inappropriate according to institutional guidelines with ASP interventions between July 2011 and December 2014. Intervention acceptance and outcomes, including carbapenem utilization, length of stay, hospitalization charges, 30-day readmission, and mortality rates were reviewed. Data were analyzed in two groups, one in which physicians accepted all interventions ("accepted") and one in which interventions were rejected ("rejected"). A total of 158 ASP interventions were made. These included carbapenem discontinuation (35%), change to narrower-spectrum antibiotic (32%), dose optimization (17%), further investigations (including imaging and procalcitonin) (11%), infectious diseases referral (3%), antibiotic discontinuation (other than carbapenem) (1%), and source control (1%). Of 220 unique patients, carbapenem use was inappropriate in 101 (45.9%) patients. A significant reduction in carbapenem utilization was observed in the accepted group versus rejected group (median defined daily doses, 0.224 versus 0.668 per 1,000 patient-days, respectively; P < 0.001). There was a significant reduction in 30-day mortality in the accepted (none) versus rejected group (10 deaths, P = 0.015), but there were no differences in length of stay, hospitalization charge, or 30-day readmission rates. Hypotension was independently associated with mortality in multivariate analysis (odds ratio, 5.25; 95% confidence interval, 1.34 to 20.6). In our institution, acceptance of carbapenem ASP interventions did not compromise patient safety in terms of clinical outcomes while reducing consumption. PMID- 28717038 TI - A Human Biofilm-Disrupting Monoclonal Antibody Potentiates Antibiotic Efficacy in Rodent Models of both Staphylococcus aureus and Acinetobacter baumannii Infections. AB - Many serious bacterial infections are antibiotic refractory due to biofilm formation. A key structural component of biofilm is extracellular DNA, which is stabilized by bacterial proteins, including those from the DNABII family. TRL1068 is a high-affinity human monoclonal antibody against a DNABII epitope conserved across both Gram-positive and Gram-negative bacterial species. In the present study, the efficacy of TRL1068 for the disruption of biofilm was demonstrated in vitro in the absence of antibiotics by scanning electron microscopy. The in vivo efficacy of this antibody was investigated in a well-characterized catheter induced aortic valve infective endocarditis model in rats infected with a methicillin-resistant Staphylococcus aureus (MRSA) strain with the ability to form thick biofilms, obtained from the blood of a patient with persistent clinical infection. Animals were treated with vancomycin alone or in combination with TRL1068. MRSA burdens in cardiac vegetations and within intracardiac catheters, kidneys, spleen, and liver showed significant reductions in the combination arm versus vancomycin alone (P < 0.001). A trend toward mortality reduction was also observed (P = 0.09). In parallel, the in vivo efficacy of TRL1068 against a multidrug-resistant clinical Acinetobacter baumannii isolate was explored by using an established mouse model of skin and soft tissue catheter related biofilm infection. Catheter segments infected with A. baumannii were implanted subcutaneously into mice; animals were treated with imipenem alone or in combination with TRL1068. The combination showed a significant reduction of catheter-adherent bacteria versus the antibiotic alone (P < 0.001). TRL1068 shows excellent promise as an adjunct to standard-of-care antibiotics for a broad range of difficult-to-treat bacterial infections. PMID- 28717039 TI - Deletion of sigB Causes Increased Sensitivity to para-Aminosalicylic Acid and Sulfamethoxazole in Mycobacterium tuberculosis. AB - Although the de novo folate biosynthesis pathway has been well studied in bacteria, little is known about its regulation. In the present study, the sigB gene in Mycobacterium tuberculosis was deleted. Subsequent drug susceptibility tests revealed that the M. tuberculosis DeltasigB strain was more sensitive to para-aminosalicylic acid (PAS) and sulfamethoxazole. Comparative transcriptional analysis was performed, and downregulation of pabB was observed in the DeltasigB strain, which was further verified by a quantitative reverse transcription-PCR and Western blot assay. Then, the production levels of para-aminobenzoic acid (pABA) were compared between the sigB deletion mutant and wild-type strain, and the results showed that sigB deletion resulted in decreased production of pABA. In addition, SigB was able to recognize the promoter of pabB in vitro Furthermore, we found that deleting pabC also caused increased susceptibility to PAS. Taken together, our data revealed that, in M. tuberculosis, sigB affects susceptibility to antifolates through multiple ways, primarily by regulating the expression of pabB To our knowledge, this is the first report showing that SigB modulates pABA biosynthesis and thus affecting susceptibility to antifolates, which broadens our understanding of the regulation of bacterial folate metabolism and mechanisms of susceptibility to antifolates. PMID- 28717040 TI - Flucloxacillin Results in Suboptimal Plasma Voriconazole Concentrations. AB - Combining voriconazole and flucloxacillin is indicated in patient cohorts experiencing both invasive aspergillosis and Gram-positive infections (e.g., patients with chronic granulomatous disease or postinfluenza pulmonary aspergillosis). We report a highly relevant interaction between voriconazole and flucloxacillin, resulting in subtherapeutic plasma voriconazole concentrations in more than 50% of patients, that poses a severe threat if not managed properly. PMID- 28717041 TI - Activation of Stimulator of Interferon Genes in Hepatocytes Suppresses the Replication of Hepatitis B Virus. AB - Induction of interferon and proinflammatory cytokines is a hallmark of the infection of many different viruses. However, hepatitis B virus (HBV) does not elicit a detectable cytokine response in infected hepatocytes. In order to investigate the molecular mechanism underlying the innate immune evasion, a functional cyclic GMP-AMP (cGAMP) synthase (cGAS)-stimulator of interferon genes (STING) pathway was reconstituted in a human hepatoma cell line supporting tetracycline-inducible HBV replication. It was demonstrated that induction of HBV replication neither activated nor inhibited this cytosolic DNA sensing pathway. However, human hepatoma cells, as well as immortalized mouse hepatocytes, express low levels of STING, which upon activation by cGAMP, the natural ligand of STING, led to induction of a proinflammatory cytokine response. Treatment of immortalized mouse hepatocytes supporting HBV replication with either cGAMP or a small molecule pharmacologic STING agonist significantly reduced viral DNA in a STING- and Janus kinase 1-dependent manner. Moreover, cGAMP treatment was able to induce inflammatory cytokine gene expression and inhibit the transcription of covalently closed circular DNA in HBV-infected human hepatoma cells expressing sodium taurocholate cotransporting polypeptide, an essential receptor for HBV infection of hepatocytes. The studies reported here and previously (F. Guo et al., Antimicrob Agents Chemother 59:1273-1281, 2015, https://doi.org/10.1128/AAC.04321-14) thus support the notion that pharmacological activation of STING in macrophages and hepatocytes induces host innate responses that can efficiently control HBV replication. Hence, despite not playing a significant role in host innate immune response to HBV infection of hepatocytes, STING is potentially a valuable target for immunotherapy of chronic hepatitis B. PMID- 28717042 TI - Modeling the Kinetics of the Permeation of Antibacterial Agents into Growing Bacteria and Its Interplay with Efflux. AB - A mathematical model of the passive permeation of a novel solute into bacteria that explicitly accounts for intracellular dilution through growth was developed. A bacterial cell envelope permeability coefficient of approximately >10-8 cm2 . s 1 is predicted to ensure passive permeation into rapidly replicating bacterial cells. The relative importance of the permeability coefficients of the cytoplasmic and outer membranes of Gram-negative bacteria in determining the overall envelope permeability coefficient was analyzed quantitatively. A mathematical description of the balance between passive influx and active efflux was also developed and shows that bacterial expansion through growth can usually be neglected for compounds likely to be prepared in antibacterial drug discovery programs and the balance between passive inward permeation and active outwardly directed efflux predominates. A new parameter, efflux efficiency (eta, where eta is equal to k/P, in which k is the rate coefficient for the efflux pump and P is the permeability coefficient for the membrane across which the pump acts), is introduced, and the consequences for the efficiency of efflux pumping by a single pump, two pumps in parallel across either the cytoplasmic or the outer membrane, and two pumps in series, one across the cytoplasmic membrane and one across the outer membrane of Gram-negative bacteria, are explored. The results, showing additive efficiency for two pumps acting across a single membrane and multiplicative efficiency for two pumps acting in series across the cytoplasmic and outer membranes, can be quantitatively related to the ratios between MICs measured against pump-sufficient and pump deletion strains and agree with those of previous experimental and theoretical studies. PMID- 28717043 TI - Tandem Amplification of the Staphylococcal Cassette Chromosome mec Element Can Drive High-Level Methicillin Resistance in Methicillin-Resistant Staphylococcus aureus. AB - Hospital-associated methicillin-resistant Staphylococcus aureus (MRSA) strains typically express high-level, homogeneous (HoR) beta-lactam resistance, whereas community-associated MRSA (CA-MRSA) more commonly express low-level heterogeneous (HeR) resistance. Expression of the HoR phenotype typically requires both increased expression of the mecA gene, carried on the staphylococcal cassette chromosome mec element (SCCmec), and additional mutational event(s) elsewhere on the chromosome. Here the oxacillin concentration in a chemostat culture of the CA MRSA strain USA300 was increased from 8 MUg/ml to 130 MUg/ml over 13 days to isolate highly oxacillin-resistant derivatives. A stable, small-colony variant, designated HoR34, which had become established in the chemostat culture was found to have acquired mutations in gdpP, clpX, guaA, and camS Closer inspection of the genome sequence data further revealed that reads covering SCCmec were ~10 times overrepresented compared to other parts of the chromosome. Quantitative PCR (qPCR) confirmed >10-fold-higher levels of mecA DNA on the HoR34 chromosome, and MinION genome sequencing verified the presence of 10 tandem repeats of the SCCmec element. qPCR further demonstrated that subculture of HoR34 in various concentrations of oxacillin (0 to 100 MUg/ml) was accompanied by accordion-like contraction and amplification of the SCCmec element. Although slower growing than strain USA300, HoR34 outcompeted the parent strain in the presence of subinhibitory oxacillin. These data identify tandem amplification of the SCCmec element as a new mechanism of high-level methicillin resistance in MRSA, which may provide a competitive advantage for MRSA under antibiotic selection. PMID- 28717044 TI - Congenital myotonic dystrophy-an RNA-mediated disease across a developmental continuum. AB - Thomas and colleagues (pp. 1122-1133) demonstrate severe dysregulation of developmentally regulated alternative splicing and polyadenylation in congenital myotonic dystrophy (CDM). In doing so, they also highlight the importance of these post-transcriptional processes during normal fetal muscle development. Finally, they generate and characterize a mouse model of CDM that lacks all three Muscleblind-like proteins. PMID- 28717045 TI - Multitasking by Polycomb response elements. AB - Development requires the expression of master regulatory genes necessary to specify a cell lineage. Equally significant is the stable and heritable silencing of master regulators that would specify alternative lineages. This regulated gene silencing is carried out by Polycomb group (PcG) proteins, which must be correctly recruited only to the subset of their target loci that requires lineage specific silencing. A recent study by Erceg and colleagues (pp. 590-602) expands on a key aspect of that targeting: The same DNA elements that recruit PcG complexes to a repressed locus also encode transcriptional enhancers that function in different lineages where that locus must be expressed. Thus, PcG targeting elements overlap with enhancers. PMID- 28717049 TI - Regulation of Small Mitochondrial DNA Replicative Advantage by Ribonucleotide Reductase in Saccharomyces cerevisiae. AB - Small mitochondrial genomes can behave as selfish elements by displacing wild type genomes regardless of their detriment to the host organism. In the budding yeast Saccharomyces cerevisiae, small hypersuppressive mtDNA transiently coexist with wild-type in a state of heteroplasmy, wherein the replicative advantage of the small mtDNA outcompetes wild-type and produces offspring without respiratory capacity in >95% of colonies. The cytosolic enzyme ribonucleotide reductase (RNR) catalyzes the rate-limiting step in dNTP synthesis and its inhibition has been correlated with increased petite colony formation, reflecting loss of respiratory function. Here, we used heteroplasmic diploids containing wild-type (rho+) and suppressive (rho-) or hypersuppressive (HS rho-) mitochondrial genomes to explore the effects of RNR activity on mtDNA heteroplasmy in offspring. We found that the proportion of rho+ offspring was significantly increased by RNR overexpression or deletion of its inhibitor, SML1, while reducing RNR activity via SML1 overexpression produced the opposite effects. In addition, using Ex Taq and KOD Dash polymerases, we observed a replicative advantage for small over large template DNA in vitro, but only at low dNTP concentrations. These results suggest that dNTP insufficiency contributes to the replicative advantage of small mtDNA over wild-type and cytosolic dNTP synthesis by RNR is an important regulator of heteroplasmy involving small mtDNA molecules in yeast. PMID- 28717048 TI - RNA-seq of Rice Yellow Stem Borer Scirpophaga incertulas Reveals Molecular Insights During Four Larval Developmental Stages. AB - The yellow stem borer (YSB), Scirpophaga incertulas, is a prominent pest in rice cultivation causing serious yield losses. The larval stage is an important stage in YSB, responsible for maximum infestation. However, limited knowledge exists on the biology and mechanisms underlying the growth and differentiation of YSB. To understand and identify the genes involved in YSB development and infestation, so as to design pest control strategies, we performed de novo transcriptome analysis at the first, third, fifth, and seventh larval developmental stages employing Illumina Hi-seq. High-quality reads (HQR) of ~229 Mb were assembled into 24,775 transcripts with an average size of 1485 bp. Genes associated with various metabolic processes, i.e., detoxification mechanism [CYP450, GSTs, and carboxylesterases (CarEs)], RNA interference (RNAi) machinery (Dcr-1, Dcr-2, Ago 1, Ago-2, Sid-1, Sid-2, Sid-3, and Sid-1-related gene), chemoreception (CSPs, GRs, OBPs, and ORs), and regulators [transcription factors (TFs) and hormones] were differentially regulated during the developmental stages. Identification of stage-specific transcripts made it possible to determine the essential processes of larval development. Comparative transcriptome analysis revealed that YSB has not evolved much with respect to the detoxification mechanism, but showed the presence of distinct RNAi machinery. The presence of strong specific visual recognition coupled with chemosensory mechanisms supports the monophagous nature of YSB. Designed expressed sequenced tags-simple-sequence repeats (EST-SSRs) will facilitate accurate estimation of the genetic diversity of YSB. This is the first report on characterization of the YSB transcriptome and the identification of genes involved in key processes, which will help researchers and industry to devise novel pest control strategies. This study also opens up a new avenue to develop next-generation resistant rice using RNAi or genome editing approaches. PMID- 28717050 TI - Which azithromycin regimen should be used for treating Mycoplasma genitalium? A meta-analysis. AB - BACKGROUND: There is increasing evidence that azithromycin 1 g is driving the emergence of macrolide resistance in Mycoplasma genitalium worldwide. We undertook a meta-analysis of M. genitalium treatment studies using azithromycin 1 g single dose and azithromycin 500 mg on day 1 then 250 mg daily for 4 days (5 day regimen) to determine rates of treatment failure and resistance in both regimens. METHODS: The online databases PubMed and Medline were searched using terms "Mycoplasma genitalium", "macrolide" or "azithromycin" and "resistance" up to April 2016. Studies were eligible if they: used azithromycin 1 g or 5 days, assessed patients for macrolide resistant genetic mutations prior to treatment and patients who failed were again resistance genotyped. Random effects meta analysis was used to estimate failure and resistance rates. RESULTS: Eight studies were identified totalling 435 patients of whom 82 (18.9%) had received the 5-day regimen. The random effects pooled rate of treatment failure and development of macrolide antimicrobial resistance mutations with azithromycin 1 g was 13.9% (95% CI 7.7% to 20.1%) and 12.0% (7.1% to 16.9%), respectively. Of individuals treated with the 5-day regimen, with no prior doxycycline treatment, fewer (3.7%; 95% CI 0.8% to 10.3%, p=0.012) failed treatment, all of whom developed resistance (p=0.027). CONCLUSION: Azithromycin 1 g is associated with high rates of treatment failure and development of macrolide resistance in M. genitalium infection with no pre-existing macrolide mutations. There is moderate but conflicting evidence that the 5-day regimen may be more effective and less likely to cause resistance. PMID- 28717047 TI - Annotated Draft Genome Assemblies for the Northern Bobwhite (Colinus virginianus) and the Scaled Quail (Callipepla squamata) Reveal Disparate Estimates of Modern Genome Diversity and Historic Effective Population Size. AB - Northern bobwhite (Colinus virginianus; hereafter bobwhite) and scaled quail (Callipepla squamata) populations have suffered precipitous declines across most of their US ranges. Illumina-based first- (v1.0) and second- (v2.0) generation draft genome assemblies for the scaled quail and the bobwhite produced N50 scaffold sizes of 1.035 and 2.042 Mb, thereby producing a 45-fold improvement in contiguity over the existing bobwhite assembly, and >=90% of the assembled genomes were captured within 1313 and 8990 scaffolds, respectively. The scaled quail assembly (v1.0 = 1.045 Gb) was ~20% smaller than the bobwhite (v2.0 = 1.254 Gb), which was supported by kmer-based estimates of genome size. Nevertheless, estimates of GC content (41.72%; 42.66%), genome-wide repetitive content (10.40%; 10.43%), and MAKER-predicted protein coding genes (17,131; 17,165) were similar for the scaled quail (v1.0) and bobwhite (v2.0) assemblies, respectively. BUSCO analyses utilizing 3023 single-copy orthologs revealed a high level of assembly completeness for the scaled quail (v1.0; 84.8%) and the bobwhite (v2.0; 82.5%), as verified by comparison with well-established avian genomes. We also detected 273 putative segmental duplications in the scaled quail genome (v1.0), and 711 in the bobwhite genome (v2.0), including some that were shared among both species. Autosomal variant prediction revealed ~2.48 and 4.17 heterozygous variants per kilobase within the scaled quail (v1.0) and bobwhite (v2.0) genomes, respectively, and estimates of historic effective population size were uniformly higher for the bobwhite across all time points in a coalescent model. However, large-scale declines were predicted for both species beginning ~15-20 KYA. PMID- 28717051 TI - Detection of markers predictive of macrolide and fluoroquinolone resistance in Mycoplasma genitalium from patients attending sexual health services in England. AB - OBJECTIVES: Resistance to both macrolides and fluoroquinolones has been reported in Mycoplasma genitalium; however, due to limited diagnostics, studies are often small and confined to specific geographical areas. This study sought to determine the rate of predicted resistance in M. genitalium-positive specimens referred for diagnostic testing. METHODS: Seventy-four M. genitalium-positive specimens, referred to the national reference laboratory (2010-2013) from 19 centres across England, were blinded and anonymised. Specimens were examined for markers predictive of resistance to macrolides and fluoroquinolones using PCR followed by sequence analysis of 23S rRNA gene, or gyrA and parC, respectively. RESULTS: 23S rRNA gene PCR sequencing revealed that 82.4% (61/74) of specimens harboured a single nucleotide polymorphism (SNP) associated with macrolide resistance. Differences were observed between the rates of predicted macrolide resistance in male (95.1% (58/61)) and female (23.1% (3/13)) patients (P = <0.001). By contrast, all specimens for which sequencing data were available (73/74) yielded wild-type gyrA sequences; and 58/61 (95.1%) had wild-type parC genes. Three specimens (3/61 4.9%) had SNPs in the parC gene associated with fluoroquinolone treatment failure, and all three also had predicted resistance to macrolides. CONCLUSIONS: Eighty-two per cent and 4.9% of M. genitalium specimens had SNPs associated with macrolide and fluoroquinolone resistance, respectively. Due to lack of widespread availability of testing for M. genitalium in the UK, this study sample was likely to be sourced from patients who may have already failed first-line macrolide therapy. Nevertheless, this study highlights the need for both greater access to M. genitalium diagnostics and genetic antimicrobial resistance testing. PMID- 28717046 TI - From structure to mechanism-understanding initiation of DNA replication. AB - DNA replication results in the doubling of the genome prior to cell division. This process requires the assembly of 50 or more protein factors into a replication fork. Here, we review recent structural and biochemical insights that start to explain how specific proteins recognize DNA replication origins, load the replicative helicase on DNA, unwind DNA, synthesize new DNA strands, and reassemble chromatin. We focus on the minichromosome maintenance (MCM2-7) proteins, which form the core of the eukaryotic replication fork, as this complex undergoes major structural rearrangements in order to engage with DNA, regulate its DNA-unwinding activity, and maintain genome stability. PMID- 28717052 TI - Withdrawal of tracheostomy ventilation in motor neurone disease: implementing advance directives. PMID- 28717053 TI - Pure autonomic failure. AB - Pure autonomic failure is a degenerative disorder of the peripheral autonomic nervous system. Patients experience symptomatic hypotension that requires them to sit, squat or lie down to prevent syncope. It is associated with characteristic histopathological findings, resulting in neuronal cytoplasmic inclusions in the peripheral autonomic nerves. These lesions are responsible for defects in the synthesis and release of norepinephrine from sympathetic nerve terminals, resulting in significant hypotension. Patients with autonomic failure also have exaggerated blood pressure responses to common stimuli such as food or fluid intake, heat, exercise and medications. Tilt table (head-up) testing is probably the test most commonly used to establish the diagnosis. However, simple office testing is also useful, such as having the patient stand after lying supine with blood pressure monitoring. Treatment options range from simply increasing fluid and salt intake, and using compressive garments, to medications administered orally, subcutaneously or intravenously in more severe cases. PMID- 28717054 TI - Simple generation of hairless mice for in vivo imaging. AB - The in vivo imaging of mice makes it possible to analyze disease progress non invasively through reporter gene expression. As the removal of hair improves the accuracy of in vivo imaging, gene-modified mice with a reporter gene are often crossed with Hos:HR-1 mutant mice homozygous for the spontaneous Hrhr mutation that exhibit a hair loss phenotype. However, it is time consuming to produce mice carrying both the reporter gene and mutant Hrhr gene by mating. In addition, there is a risk that genetic background of the gene-modified mice would be altered by mating. To resolve these issues, we established a simple method to generate hairless mice maintaining the original genetic background by CRISPR technology. First, we constructed the pX330 vector, which targets exon 3 of Hr. This DNA vector (5 ng/ul) was microinjected into the pronuclei of C57BL/6J mice. Induced Hr gene mutations were found in many founders (76.1%) and these mutations were heritable. Next, we performed in vivo imaging using these gene-modified hairless mice. As expected, luminescent objects in their body were detected by in vivo imaging. This study clearly showed that hairless mice could be simply generated by the CRISPR/Cas9 system, and this method may be useful for in vivo imaging studies with various gene-modified mice. PMID- 28717055 TI - Incidence of anaphylactic reactions after propofol administration in dogs. AB - Propofol is an anesthetic agent suspended in an emulsion system that includes egg yolk lecithin and soybean oil, because of which, there is concern about the use of propofol in patients allergic to these substances. We examined the association between propofol administration and incidence of adverse events in dogs with allergy to egg yolk lecithin and soybean oil. On the basis of the findings of an allergen-specific immunoglobulin E (IgE) test, 14 dogs with high levels (high-IgE group) and 7 dogs with low levels (normal-IgE group) of IgE were selected. Following intravenous administration of propofol, the incidence of anaphylactic reactions and plasma histamine concentrations under general anesthesia maintained with isoflurane throughout surgery were compared between the two groups. The frequency of anaphylactic reactions and plasma histamine concentrations were compared by the chi-square test and Student t-test, respectively. The statistical significance for both tests was set at P<0.05. In the high- and normal-IgE groups, the average frequencies of anaphylactic reactions after propofol administration were 21.4 and 14.3%, and the mean plasma histamine concentrations were 167.9 +/- 94.5 nM and 65.7 +/- 40.3 nM, respectively. Animals of neither groups experienced shock-like symptoms. These results revealed that propofol might be relatively safe, although careful perioperative anesthesia monitoring and standby protocols are required when using propofol in dogs with a history of allergic diseases or high chicken- or soybean-specific IgE levels. PMID- 28717056 TI - Infection with Paragonimus westermani of boar-hunting dogs in Western Japan maintained via artificial feeding with wild boar meat by hunters. AB - Infection of boar-hunting dogs with Paragonimus westermani was investigated in Western Japan. Blood and rectal feces were collected from 441 dogs in the three districts (205 in Kinki, 131 in Chugoku and 105 in Shikoku District). In a screening ELISA for serum antibody against P. westermani antigen, 195 dogs (44.2%) showed positive reaction. In the 195 dogs, 8 dogs were found excreting P. westermani eggs after molecular analysis of fecal eggs, and additional 7 were identified serologically for the parasite infection because of their stronger reactivity against P. westermani antigen than against antigens of other species of Paragonimus. A spatial analysis showed that all of the P. westermani infections were found in Kinki and Chugoku Districts. In this area, dogs' experience of being fed with raw boar meat showed high odds ratio (3.35) to the sero-positivity in the screening ELISA, and the frequency of such experiences was significantly higher in sero-positive dogs. While clear relationship was not obtained between predation of boars by dogs during hunting and their sero positivity. Therefore, it is suggested that human activity of feeding with wild boar meat is the risk factor for P. westermani infection in boar-hunting dogs. Considering that hunting dogs could play as a major definitive host and maintain the present distribution of P. westermani in Western Japan, control measures for the infection in hunting dogs, such as prohibition of raw meat feeding and regular deworming, should be undertaken. PMID- 28717058 TI - Lumbosacral Transitional Vertebrae Cause Spinal Level Misconception in Surgeries for Degenerative Lumbar Spine Disorders. AB - Human lumbar spine usually consists of five vertebrae; however, some individuals have vertebral anomalies with four or six lumbar vertebrae because of sacralized fifth lumbar vertebra (L5 sacralization) or lumbarized first sacral vertebra (S1 lumbarization), respectively. These vertebral anomalies are called lumbosacral transitional vertebra (LSTV). Although LSTV is an asymptomatic anomaly, it is known to cause misconception in spinal counts and in spinal level at lumbar spinal surgery. The purpose of this study is to evaluate how LSTV affects the diagnosis and surgeries in lumbar spine disorders. In 550 consecutive patients who underwent lumbar spinal surgeries, a whole-spine X-ray was taken on admission to assess the true number of lumbar vertebrae. We assessed the coherence between the neurological level diagnosis and the level of spinal canal stenosis on imaging studies before and after the recognition of LSTV to clarify how recognition of LSTV affected pre-operative surgical planning. Out of 550 patients, LSTV was found in 71 (12.9%) patients: 37 cases with L5 sacralization and 34 cases with S1 lumbarization. The number of vertebrae was miscounted at the outpatient department (OPD) in 38 cases (54%): 10 L5-sacralization cases and 28 S1-lumbarization cases. Moreover, surgical spinal levels were altered from the original surgical plans at OPD in 11 cases (15%; 3 L5-sacralization and 8 S1 lumbarization cases), after recognizing the true spinal counts by the whole spine X-ray. To avoid errors in spinal level diagnosis, we should recognize the possibility of LSTV that could be assessed by a whole spine X-ray. PMID- 28717057 TI - Glucose Variability Based on Continuous Glucose Monitoring Assessment Is Associated with Postoperative Complications after Cardiovascular Surgery. AB - PURPOSE: This purpose of this prospective study was to use a continuous glucose monitoring (CGM) system to evaluate the suitability of our institution's glucose management protocol after cardiovascular surgery and to clarify the impact of glycemic variability on postoperative complications. METHODS: In all, 76 patients who underwent elective cardiovascular surgery and were monitored perioperatively using a CGM system were evaluated. Postoperative glucose management consisted of continuous intravenous insulin infusion (CIII) in the intensive care unit, and subcutaneous insulin injections (SQII) after oral food intake started. CIII and subcutaneous injections were initiated when blood glucose level exceeded 150 mg/dL. CGM data were used to analyze perioperative glycemic variability and association with postoperative complications. RESULTS: Target glucose levels (71 180 mg/dL) were achieved during 97.1 +/- 5.5% and 86.4 +/- 19.0% of the continuous insulin infusion and subcutaneous injection periods, respectively. Major postoperative complications were surgical site infections, found in 6.6% of total patients, and atrial fibrillation, found in 44% of patients with off-pump coronary artery bypass grafting. High glycemic variability during SQII was associated with increased risk for both complications. CONCLUSION: Data analysis revealed that our glucose management protocol during CIII was adequate. However, the management protocol during SQII required improvement. PMID- 28717059 TI - Pharmacological effects of a vitamin K1 2,3-epoxide reductase (VKOR) inhibitor, 3 acetyl-5-methyltetronic acid, on cisplatin-induced fibrosis in rats. AB - Cisplatin (CDDP) is a chemotherapeutic agent that is widely used in the treatment of lymphomas and solid malignancies. However, its clinical usage is limited by its severe side effects in the kidneys. Glomerular and tubular injuries in the kidneys commonly progress to interstitial fibrosis and, ultimately, the end stage of renal failure. We previously reported that 3-acetyl-5-methyltetronic acid (AMT) had inhibitory effects on rat renal vitamin K1 2,3-epoxide reductase (VKOR) in vitro and also suppressed mesangial cell proliferation and, consequently, the formation of fibrosis via the vitamin K-dependent activation of the growth arrest specific 6 (Gas6)/Axl pathway in anti-Thy-1 glomerulonephritis (Thy-1 GN) in rats. In the present study, we demonstrated that AMT alleviated the progression of renal fibrosis in CDDP-treated rats. The repeated intravenous administration of AMT for 28 days dose-dependently suppressed increases in plasma urea nitrogen and plasma creatinine levels as well as creatinine clearance in CDDP-treated rats. Furthermore, the treatment suppressed the expression of alpha-smooth muscle actin (SMA)-positive cells and ameliorated the extracellular matrix accumulation of collagen III, indicating an antifibrotic effect. In conclusion, our toxicological and histopathological results demonstrated quantitatively the pharmacological inhibitory effects of AMT on the progression of renal fibrosis in CDDP-treated rats. PMID- 28717060 TI - Clinical data analysis of genotypes and phenotypes of deafness gene mutations in newborns: A retrospective study. AB - We retrospectively analyzed newborns with deafness gene mutations and summarized the relationship between genotype and phenotype to provide a basis for genetic counseling. We studied 582 subjects positive for deafness gene mutations that were treated in the otology outpatient department of Beijing Tongren Hospital, Capital Medical University, between April 2012 and April 2016. The subjects were divided into 3 categories: a diagnosed group (group A), which was further subdivided into subgroups A1 (homozygous and compound heterozygous GJB2 mutations) and A2 (homozygous and compound heterozygous SLC26A4 mutations); a drug-induced deafness group (group B, mitochondrial (Mt) gene mutations); and a mutation carrier group (group C), which was further subdivided into the subgroups C1 (GJB2 heterozygous mutations), C2 (SLC26A4 heterozygous mutations), C3 (GJB3 heterozygous mutations), and C4 (double gene mutations). Partial sequences positive for GJB2 or SLC26A4 were sequenced and analyzed for mutations. Subjects underwent otoscopic examination and comprehensive audiological evaluation, and temporal bone computerized tomography and/or inner ear magnetic resonance imaging were performed. GJB2 235delC was the most common mutation locus. The highest proportion of deafness detected during universal newborn hearing screening was for drug-induced deafness, whereas the lowest was for the diagnosed group. GJB2 gene mutations mainly resulted in flat-type, profound-to-severe sensorineural hearing loss (SNHL). SLC26A4 gene mutation was mainly associated with high frequency drop-type and profound-severe SNHL and was closely related to enlargement of the vestibular aqueduct. PMID- 28717061 TI - APOBEC-mediated genomic alterations link immunity and viral infection during human papillomavirus-driven cervical carcinogenesis. AB - Cervical cancer is one of the most frequently diagnosed cancers and is a major cause of death from gynecologic cancers worldwide; the cancer burden from cervical cancer is especially heavy in less developed countries. Most cases of cervical cancer are caused by persistent infection with carcinogenic human papillomavirus (HPV) genotypes 16 and 18. Non-resolving inflammation caused by HPV infection provides a microenvironment that facilitates cancer development. Molecular alterations during the process of HPV-induced carcinogenesis are characterized by DNA methylation within the HPV genome, promoter hypermethylation of tumor suppressor genes in the host genome, as well as genomic instability caused by viral DNA integrating into the host genome. Catalytic polypeptide-like apolipoprotein B mRNA editing enzymes (APOBECs) normally function as part of the innate immune system. APOBEC expression is stimulated upon viral infection and plays an important role in HPV-induced cervical cancer. APOBECs catalyze the deamination of cytosine bases in nucleic acids, which leads to a conversion of target cytosine (C) to uracil (U) and consequently a change in the single stranded DNA/RNA sequence. APOBEC proteins mediate the complex interactions between HPV and the host genome and link immunity and viral infection during HPV driven carcinogenesis. Understanding the effects of APOBECs in HPV-induced cervical carcinogenesis will enable the development of better tools for HPV infection control and personalized prevention and treatment strategies. PMID- 28717063 TI - Effective waist circumference reduction rate necessary to avoid the development of type 2 diabetes in Japanese men with abdominal obesity. AB - The aim of this study was to determine the effective waist circumference (WC) reduction rate in avoiding the development of type 2 diabetes mellitus (T2DM) in <55 years and >=55 years Japanese men with abdominal obesity. The study subjects were 795 men with WC >=85 cm, fasting plasma glucose <126 mg/dL, 2-hr plasma glucose on 75 g of oral glucose tolerance test <200 mg/dL, and HbA1c 5.6-6.4 % (38-40 mmol/mol) at baseline who underwent general health checkups more than twice between April 2007 and May 2015. They were divided into 5 groups based on the change in WC during the observation period (WC gain group, and four groups stratified according the rate of WC loss). The subjects were also divided into the <55 years and >=55 years (at baseline) subgroups. The cumulative incidence rate of T2DM was analyzed and compared among the groups. The cumulative incidence rates of the largest WC loss quartile (>=5.45 %) in all age, of the largest WC loss quartile (>=5.60 %) and second largest WC loss quartile (3.44-5.59 %) in the <55 years subgroup, and of the largest WC loss quartile (>=5.37 %) in the >=55 years subgroup were significantly lower than that of the gain group (p<0.001, p=0.009, 0.012, and 0.012, respectively). WC reduction rate of at least about 3 % in the younger (<55 years) and at least about 5 % in the older (>=55 years) non diabetic Japanese men with abdominal obesity can effectively reduce the chance of development of T2DM. PMID- 28717062 TI - The effect of DHEA on apoptosis and cohesin levels in oocytes in aged mice. AB - Female fertility declines with age as the number of ovarian follicles decreases and aneuploidy increases. Degradation of the cohesin complex might be responsible for age-related aneuploidy. Dehydroepiandrosterone (DHEA) can improve the ovarian reserve and reduce the rate of aneuploidy, but the relationship between DHEA and cohesin levels in oocytes is still unknown. The aim of the current study was to evaluate the effect of the supplement DHEA on ovarian function, including the number of follicles and cohesin levels in oocytes. C57BL/6J mice at 3 weeks, 6 weeks, 12 weeks, 6 months, and 10 months of age were used to obtain a systematic view into follicle apoptosis and cohesin levels in oocytes. Nine-month-old C57BL/6J mice were administered saline (n = 5), 17beta-estradiol (100 ug/kg per day, n = 5), or DHEA (5mg/Kg per day, n = 5). After 4 weeks, aged mice were weighed and sacrificed, and ovarian tissue samples were prepared. Anti-VASA staining and HE staining were used to count the number of follicles. Anti gammaH2AX staining and TUNEL were used to measure follicle apoptosis and immunofluorescent staining was used to detect the levels of three oocyte cohesin subunits: REC8, SMC1beta, and SMC3. Administration of the supplements 17beta estradiol and DHEA to aged mice increased the number of primordial and primary follicles and decreased the age-related apoptosis of follicles. Levels of the cohesin subunits REC8 and SMC1beta declined with age, but DHEA and 17beta estradiol tended to delay that decline. The supplement DHEA increased the number of primordial and primary follicles in aged mice by inhibiting follicle apoptosis and tended to delay the decrease in cohesin levels in oocytes. PMID- 28717064 TI - Sildenafil improves heart rate variability in dogs with asymptomatic myxomatous mitral valve degeneration. AB - Myxomatous mitral valve degeneration (MMVD) causes an imbalance of sympathovagal activity resulted in poor cardiac outcomes. Phosphodiesterase-5 inhibitors have been revealed cardioprotective effect in patients with heart diseases. This study aimed to 1) compare the heart rate variability (HRV) between asymptomatic MMVD and healthy dogs and 2) assess long-term effects of sildenafil and enalapril on time- and frequency-domains analyzes. Thirty-four dogs with MMVD stage B1 or B2 and thirteen healthy dogs were recruited into the study. MMVD dogs were divided into 3 subgroups: control (n=13), sildenafil (n=12) and enalapril (n=9). HRV was analyzed from 1-hr Holter recording at baseline (D0) in all dogs and at 30, 90 and 180 days after treatment. The results showed that MMVD dogs had significant higher heart rate (HR), systemic blood pressures, the ratio of low to high frequency (LF/HF) and had significant decreased standard deviation of all normal to normal RR intervals (SDNN) and the percentage of the number of normal-to normal sinus RR intervals with differences >50 msec computed over the entire recording (pNN50) when compared with healthy dogs (P<0.05). Neither time nor frequency domain parameters were different among subgroups of MMVD dogs at D0. After treatment with sildenafil for 90 days, both time- and frequency-domain parameters were significantly increased when compared with control and enalapril groups. This study demonstrated that sildenafil improves HRV in asymptomatic MMVD dogs suggesting that sildenafil should be used in the MMVD dogs to restore the sympathovagal balance. PMID- 28717066 TI - A Heart-shaped Sleeve Simplifies Intramedullary Tibial Nail Insertion when Using the Suprapatellar Approach. AB - The suprapatellar approach for intramedullary tibial nailing has become widely accepted over the past decade. A round sleeve is passed beneath the patella to protect the surface of the patellofemoral joint (PFJ). However, the round sleeve cannot be easily stabilized in the PFJ because it does not conform to the shape of the patellar apex. Consequently, we produced a heart-shaped sleeve to simplify the insertion of the entry sleeve during the suprapatellar approach. Using the new sleeve, the following procedure is used: (1) make a longitudinal 4 cm skin incision proximal to the patella to reach the PFJ, (2) insert the guide pin manually to the ventral edge of the tibial plateau, (3) insert the cannulated trocar along the guide pin, (4) insert the heart-shaped sleeve along the cannulated trocar, (5) remove the cannulated trocar, (6) ream the entry point through the heart-shaped sleeve. Then, continue insertion of the nail in the standard manner. Among 44 patients (29 men, mean age 45.6 years, range 26-87 years) with tibial fractures treated between 2010 and 2015, the first 18 consecutive cases were performed using a round sleeve and the rest were performed using the heart-shaped sleeve. The surgery time until entry reaming commenced was 8.9 min (range 6-12 min) using the round sleeve and 6.2 min (range 3-12 min) using the heart-shaped sleeve (P < 0.05). The heart-shaped sleeve is easily stabilized in the PFJ and greatly simplifies the intramedullary nailing of tibial shaft fractures using the suprapatellar approach. PMID- 28717067 TI - Barthel Index and Outcome of Open Bypass for Critical Limb Ischemia. AB - BACKGROUND: Daily activity should be an important factor to consider when deciding on a treatment strategy for critical limb ischemia (CLI), and we hypothesized that there was a close relationship between activities of daily living (ADL) and prognosis. The aim of this study was to investigate the association between ADL and outcomes of open bypass for CLI.Methods and Results:A total of 226 patients undergoing infrainguinal bypass for CLI between January 2005 and December 2015 were reviewed. They were divided into 2 groups based on Barthel index (BI) at admission (pre-BI; >=60 and <60) and compared with respect to the incidence of early adverse events and 3-year overall survival and amputation-free survival. Adverse events were more frequently observed in patients with pre-BI <60. Patients with pre-BI <60 had worse long-term outcomes. On multivariable analysis, hypoalbuminemia, end-stage renal disease, and BI at discharge <60 were significant predictors of 3-year outcomes, whereas pre-BI <60 was not a significant predictor of either outcome. CONCLUSIONS: It is not BI at admission, but BI at discharge that determines long-term outcome. PMID- 28717065 TI - Comparison of postoperative pain and inflammation reaction in dogs undergoing preventive laparoscopic-assisted and incisional gastropexy. AB - This study compared the effects of postoperative pain and inflammation reaction after preventive laparoscopic-assisted gastropexy (LAG) and incisional gastropexy (IG) in 10 clinically normal Beagles. Surgical time, incision length, visual analog scale (VAS) score, University of Melbourne Pain Scale (UMPS) score, and plasma C-reactive protein (CRP), plasma cortisol (COR), and serum interleukin-6 (IL-6) levels were evaluated. The VAS and UMPS scores and COR and IL-6 levels were recorded at 0.5, 1, 2, 4, 8, 12, 18 and 24 hr after surgery. CRP level was recorded at 12, 24 and 48 hr after surgery. The VAS and UMPS scores showed no significant intergroup differences. Compared to IG, LAG had significantly lower surgical time (45 +/- 9.91 min vs 64 +/- 5.30 min; P<0.05), incision length (46 +/- 8.21 mm vs 129 +/- 19.49 mm; P<0.05), CRP level (12 hr after surgery; 4.58 +/ 1.58 mg/dl vs 12.4 +/- 1.34 mg/dl; P<0.01), and COR level (1 hr after surgery; 10.79 +/- 3.07 ug/dl vs 15.9 +/- 3.77 ug/dl; P<0.05). IL-6 levels showed no significant intergroup differences at any time point. However, LAG resulted in lower IL-6 levels than did IG at all postoperative time points. Neither procedure resulted in significant surgical complications. LAG produced lower surgical stress than did IG, suggesting that LAG is a safe, minimally invasive, and highly useful technique for preventing canine gastric dilatation-volvulus. Nevertheless, since this study used experimental models, its usefulness should be evaluated in future cases. PMID- 28717068 TI - First-in-Man Trial of SiO2 Inert-Coated Bare Metal Stent System in Native Coronary Stenosis - The AXETIS FIM Trial. AB - BACKGROUND: A novel bare metal stent with an SiO2coating was developed to prevent excessive neointimal hyperplasia by inertization of the metallic stent surface. The efficacy of the device was demonstrated in a preclinical model. The aim of this first-in-man trial was to assess the safety and feasibility of the new device.Methods and Results:This prospective non-randomized single-arm trial was designed to enroll 35 patients with a de novo coronary lesion. Quantitative coronary angiography and optical coherence tomography (OCT) were performed at the baseline procedure and at the 6-month follow-up. Stent implantation was performed with OCT guidance according to optimal stent implantation criteria. The trial was terminated upon the advice of the data safety monitoring board after enrolling 14 patients due to the high incidence of re-intervention. Optimal OCT implantation criteria were achieved in only 8.3% of lesions. At 6 months, angiographic in stent late lumen loss as the primary endpoint was 0.77+/-0.44 mm, and binary restenosis occurred in 33.3% of lesions. At the 6-month OCT, neointimal volume obstruction was 32.8+/-15.6% with a neointimal thickness of 237+/-117 um. At 12 months, the device-oriented composite endpoint (defined as cardiac death, target vessel myocardial infarction, and clinically indicated target lesion revascularization rate) was 33.3%. CONCLUSIONS: In contrast with the preclinical study, the Axetis stent did not efficiently suppress neointimal hyperplasia in humans in this trial. PMID- 28717069 TI - Atypical Clival Fracture Due to Minor Trauma and Cerebrospinal Fluid Rhinorrhea. PMID- 28717071 TI - Anti-mitochondrial M2 Antibodies Enhance the Risk of Supraventricular Arrhythmias in Patients with Elevated Hepatobiliary Enzyme Levels. AB - Objective Supraventricular arrhythmias are commonly detected in patients with anti-mitochondrial antibody M2 (AMA-M2)-associated myopathy. However, the prevalence of supraventricular arrhythmias in unselected AMA-M2-positive patients and the impact of AMA-M2 on supraventricular arrhythmias have yet to be fully investigated. Methods We analyzed 384 patients (116 men; age, 60 [48-69] years), who underwent AMA-M2 testing following the detection of elevated hepatobiliary enzymes. Supraventricular arrhythmias involving atrial fibrillation, atrial flutter, atrial tachycardia, sick sinus syndrome, and atrial standstill were confirmed by a 12-lead electrocardiogram, 24-hour ambulatory monitoring, and physician-assigned diagnoses within the three years before and two years after the AMA-M2 test. Results Seventy-seven (20%) patients were positive for AMA-M2. The prevalence of supraventricular arrhythmias among AMA-M2-positive patients was higher than that among AMA-M2-negative patients (14% vs. 6%, p=0.008). A univariate analysis showed that supraventricular arrhythmias were associated with AMA-M2 positivity, aging, congestive heart failure, and the CHADS2 score. The multivariate analysis determined that AMA-M2 positivity was an independent risk factor for supraventricular arrhythmias (odds ratio 3.52, p=0.011). Among the AMA M2-positive patients, the AMA-M2 titer did not differ to a statistically significant extent, regardless of the presence or absence of supraventricular arrhythmias. Multiple supraventricular arrhythmias with extremely low atrial deflections was a characteristic finding in AMA-M2-positive patients with supraventricular arrhythmias. Conclusion AMA-M2 enhances the risk of supraventricular arrhythmias, indicating the possible involvement of the atrial myocardium and the formation of an arrhythmogenic substrate. The results highlight the need for clinical attention to supraventricular arrhythmias in AMA M2-positive patients. PMID- 28717070 TI - Clinical Features, Pathogenesis, and Treatment of Large Granular Lymphocyte Leukemias. AB - Large granular lymphocytes (LGLs) are large lymphocytes with azurophilic granules in their cytoplasm. LGLs are either natural killer (NK) cells or T lymphocytes. Expansions of the LGLs in the peripheral blood are seen in various conditions, including three clonal disorders: T-cell LGL (T-LGL) leukemia, chronic lymphoproliferative disorders of NK cells (CLPD-NK), and aggressive NK-cell leukemia (ANKL). However, the monoclonal and polyclonal expansion of LGLs has been associated with many other conditions. The present article describes these LGL disorders, with special emphasis on the clinical features, pathogenesis, and treatments of the three above-mentioned clonal disorders. PMID- 28717072 TI - The Relationship of Bone Mineral Density in Men with Chronic Obstructive Pulmonary Disease Classified According to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) Combined Chronic Obstructive Pulmonary Disease (COPD) Assessment System. AB - Objective Osteoporosis, which is now recognized as a major comorbidity of chronic obstructive pulmonary disease (COPD), must be diagnosed by appropriate methods. The aims of this study were to clarify the relationships between bone mineral density (BMD) and COPD-related clinical variables and to explore the association of BMD with the updated Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification in men. Methods We enrolled 50 Japanese men with clinically stable COPD who underwent dual-energy X-ray absorptiometry (DEXA), pulmonary function testing, and computerized tomography (CT) and who had completed a questionnaire (COPD assessment test [CAT]). We determined the association between the T-score and other tested parameters and compared the BMD of patients in each GOLD category. Results Twenty-three of the 50 patients (46.0%) were diagnosed with osteopenia, and 7 (14.0%) were diagnosed with osteoporosis. The BMD findings were significantly correlated with the CAT score, forced expiratory volume in 1 second percentage predicted (FEV1% predicted), low attenuation volume percentage (LAV%), and percentage of cross-sectional area of small pulmonary vessels (%CSA) on CT images. Notably, the median T-score of the GOLD category D participants was significantly lower than that of the participants in each of the other categories (A [-0.98], B [-1.06], C [-1.05], and D [-2.19], p<0.05). Conclusion Reduced BMD was associated with airflow limitation, extent of radiographic findings, and a poor quality of life (QOL) in patients with COPD. The BMD of GOLD category D patients was the lowest of all of the patients evaluated, and category D patients may benefit from active intervention for osteoporosis. PMID- 28717073 TI - Interstitial Lung Disease after Pleurodesis for Malignant Pleural Effusion. AB - Objective Pleurodesis is an effective therapy for malignant pleural effusion (MPE). While interstitial lung disease (ILD) has been regarded as a serious complication of pleurodesis, its clinicopathological characteristics have not been fully understood. This study was conducted to elucidate the incidence of ILD and the risk factors for ILD in patients who underwent pleurodesis to control MPE. Methods The medical records of patients who underwent pleurodesis in Aichi Medical University between March 2008 and February 2013, the period before the approval of talc in Japan, were retrospectively analyzed. Results A total of 84 patients underwent pleurodesis, all using OK-432. ILD occurred in 13 patients (15.5%). The development of ILD after pleurodesis was significantly associated with old age (odds ratio [OR]: 4.82, 95% confidence interval [CI]: 1.22-19.08) and epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) treatment (OR: 5.97, CI: 1.7-20.9). A multivariate analysis revealed that >67 years of age (p=0.01) and EGFR-TKI treatment (p=0.02) were significantly associated with the development of pleurodesis-related ILD. Among the patients who received both pleurodesis and EGFR-TKIs (n=23), 8 patients developed ILD. All of these patients were receiving EGFR-TKI therapy at the time of pleurodesis or within 30 days after pleurodesis. In contrast, no cases of ILD were observed among the patients who stopped EGFR-TKIs before pleurodesis or started EGFR-TKIs at more than 30 days after pleurodesis. Conclusion ILD seemed to be a frequent complication of pleurodesis in patients using OK-432, especially elderly patients and those who underwent pleurodesis while receiving EGFR-TKI therapy or who started EGFR-TKI therapy within 30 days after pleurodesis. PMID- 28717074 TI - Effect of Thrombomodulin Alfa on Disseminated Intravascular Coagulation in Patients with Lung Cancer. AB - Objective The mortality rate due to disseminated intravascular coagulation (DIC) is higher in patients with lung cancer than in those without. We examined the effect of treatment with thrombomodulin alfa (TM-alpha) for DIC in lung cancer patients. Methods Subjects were 57 patients with DIC (43 men, 14 women; mean age, 71.7 years), comprising 31 with lung cancer and 26 without. DIC patients with or without lung cancer did not differ significantly in their background characteristics. Results No significant difference was noted in the mortality rate between patients with lung cancer (61.3%) and those without (57.7%). However, the dose of TM-alpha was higher for survivors with lung cancer than for non-survivors (473.1 U/kg/day vs. 380.6 U/kg/day; p<0.01). Although no significant difference was noted in the DIC score between these four groups, the serum C-reactive protein level (6.9 mg/dL vs. 11.6 mg/dL; p<0.05) and prothrombin time-international normalized ratio (PT-INR; 1.10 vs. 1.52; p<0.05) were lower in survivors with lung cancer than in the non-survivors with lung cancer. The initial body temperature in non-survivors without lung cancer was lower than that in survivors without lung cancer (37.2 degrees C vs. 37.9 degrees C, p<0.01), and the platelet count and the time to recovery from DIC in patients without lung cancer showed a significant negative correlation (r2=0.438, p<0.05). Conclusion Our findings suggest that although 380 U/kg/day of TM-alpha is the recommended dose for DIC treatment, a higher dose may reduce the mortality rate of lung cancer patients with DIC. Furthermore, TM-alpha should be initiated before worsening of DIC parameters. PMID- 28717075 TI - Clinical Characteristics of Bacteremia Caused by Extended-spectrum Beta-lactamase producing Escherichia coli at a Tertiary Hospital. AB - Objective In recent years, infection caused by extended-spectrum beta-lactamase (ESBL)-producing organisms has become an important issue. However, comparative studies of the bacteremia caused by ESBL Enterobacteriaceae and non-ESBL Enterobacteriaceae are extremely rare in Japan. This study aimed to assess the risk factors and prognosis of patients with bacteremia due to ESBL Escherichia coli (E. coli). Methods The medical records of 31 patients with ESBL E. coli bacteremia and 98 patients with non-ESBL E. coli bacteremia who had been admitted to Osaka City University Hospital between January 2011 and June 2015 were retrospectively reviewed. The patient backgrounds, risk factors for infection, and prognosis were evaluated. Results The male-to-female ratio, mean age, underlying disease, leukocyte count, and C-reactive protein (CRP) level did not differ between the patients in the ESBL E. coli bacteremia and non-ESBL E. coli bacteremia groups. The mean Sequential Organ Failure Assessment (SOFA) score for patients with ESBL and non-ESBL E. coli bacteremia were 3.6 and 3.8, respectively. Further, the mortality did not differ between the two groups (9.7% vs 9.2%). However, the independent predictors associated with ESBL E. coli bacteremia according to a multivariate analysis were the use of immunosuppressive drugs or corticosteroids (p=0.048) and quinolones (p=0.005) prior to isolation. The mortality did not differ between the carbapenem and tazobactam/piperacillin (TAZ/PIPC) or cefmetazole (CMZ) groups for the patients with ESBL E. coli bacteremia. Conclusion Whenever we encountered patients with a history of immunosuppressive drug, corticosteroid, quinolone administration, it was necessary to perform antibiotic therapy while keeping the risk of ESBL E. coli in mind. PMID- 28717076 TI - Increase in the Regional Cerebral Blood Flow following Waon Therapy in Patients with Chronic Fatigue Syndrome: A Pilot Study. AB - Objective Chronic fatigue syndrome (CFS) is a complex disorder, with no consensus on therapeutic options. However, Waon therapy has been reported to be an effective treatment. The purpose of this study was to evaluate changes in the cerebral blood flow (CBF) before and after Waon therapy in CFS patients and to investigate the correlation between such changes and the therapeutic efficacy of Waon therapy. Methods Eleven patients (2 men and 9 women, mean age 27 years old) diagnosed with CFS participated in the study. The disease duration was 8-129 months, and the performance status was 5-8 (on a scale of 0-9). All patients underwent CBF scintigraphy using brain single-photon emission computed tomography (SPECT) with technetium-99m ethyl cysteinate dimer (99mTc-ECD) before and after Waon therapy. CBF changes after Waon therapy were evaluated using a statistical analysis of imaging data, which was performed with a statistical parametric mapping software program (SPM5). Results Waon therapy reduced symptoms in all 11 patients. We also observed an increase in the CBF within the prefrontal region, orbitofrontal region, and right temporal lobe. These results indicated that an improvement in clinical symptoms was linked to an increase in the CBF. Conclusion The results indicated abnormalities of the cerebral function in the prefrontal region, orbitofrontal region, and right temporal lobe in CFS patients and that Waon therapy improved the cerebral function and symptoms in CFS patients by increasing the regional CBF. To our knowledge, this is the first report to clarify the CBF changes in CFS patients before and after Waon therapy. PMID- 28717077 TI - Gastric Hyperplastic Polyps Associated with Proton Pump Inhibitor Use in a Case without a History of Helicobacter pylori Infection. AB - A 56-year-old man with gastroesophageal reflux disease (GERD) was referred to our hospital. Esophagogastroduodenoscopy (EGD) revealed no evidence of any polypoid lesions in the stomach, and the patient had no history of Helicobacter pylori infection. He received omeprazole (20 mg) once daily for the GERD. EGD was performed at 1 year after the start of omeprazole administration, and this time, gastric hyperplastic polyps (GHPs) were detected. The GHPs increased in size as the omeprazole treatment continued, but they markedly decreased in size following omeprazole discontinuation. Thus, the administration of proton pump inhibitors may be a risk factor for the development of GHP independent of H. pylori infection. PMID- 28717078 TI - Dermatomyositis Induced by Hepatitis B Virus-related Hepatocellular Carcinoma: A Case Report and Review of the Literature. AB - Dermatomyositis or polymyositis as a paraneoplastic syndrome of hepatocellular carcinoma (HCC) is an uncommon event. Few cases have been reported in the literature. We herein report the case of a 55-year-old man with chronic hepatitis B and alcoholism who presented with skin rash. Abdominal computed tomography revealed multiple hypervascular liver tumors consistent with HCC. He subsequently developed dysphagia with proximal limb weakness. Laboratory tests and electromyography demonstrated inflammatory myopathy. We therefore diagnosed the patient with HCC-induced dermatomyositis. Prednisolone and anti-viral therapy were administered; however, the patient died two months later due to the progression of the disease. We review the cases of HCC-induced dermatomyositis and polymyositis in the literature. PMID- 28717079 TI - Severe Hypocalcemia in a Patient with Recurrent Chondrosarcoma. AB - Hypocalcemia is relatively uncommon paraneoplastic syndrome. Only one case of hypocalcemia has been reported in a patient with chondrosarcoma. We herein report a case of a 32-year-old woman with metastatic chondrosarcoma with tetany. Her imaging findings revealed multiple calcific metastatic lesions in the lungs, pancreas, left atrium, and pulmonary vein. A laboratory examination showed hypocalcemia with no evidence of any other disease that could induce hypocalcemia. On the basis of the laboratory and clinical findings, we concluded the etiology of her severe hypocalcemia to be excessive calcium consumption by the tumor itself. PMID- 28717080 TI - Addison's Disease Caused by Tuberculosis with Atypical Hyperpigmentation and Active Pulmonary Tuberculosis. AB - We herein report a case of Addison's disease caused by tuberculosis characterized by atypical hyperpigmentation, noted as exacerbation of the pigmentation of freckles and the occurrence of new freckles, that was diagnosed in the presence of active pulmonary tuberculosis. The clinical condition of the patient was markedly ameliorated by the administration of hydrocortisone and anti tuberculosis agents. When exacerbation of the pigmentation of the freckles and/or the occurrence of new freckles are noted, Addison's disease should be considered as part of the differential diagnosis. In addition, the presence of active tuberculosis needs to be assumed whenever we treat patients with Addison's disease caused by tuberculosis, despite its rarity. PMID- 28717081 TI - Severe Glomerular Endothelial Injury Associated with a Short D4Z4 Repeat on Chromosome 4q35. AB - The short D4Z4 repeat on chromosome 4q35 is a confirmatory genetic cause of facioscapulohumeral muscular dystrophy (FSHD), which presents with no renal complications. We herein report a five-year-old girl previously diagnosed with Coat's-like retinopathy, deafness, and mental retardation, who was found to have early-onset, severe FSHD. Despite the absence of muscle weakness, a Southern blot analysis showed a short D4Z4 repeat on chromosome 4q35. She presented with steroid-resistant nephrotic syndrome, and her renal histopathological findings were severe glomerular endothelial injury, which is a new complication associated with this genetic abnormality. Screening of renal complications may be necessary for FSHD patients. This patient requires close follow-up for her muscle symptoms. PMID- 28717082 TI - Post-cytokine-release Salt Wasting as Inverse Tumor Lysis Syndrome in a Non cerebral Natural Killer-cell Neoplasm. AB - The pathogenesis of cerebral/renal salt-wasting syndrome remains unknown. We herein present a case of salt-wasting syndrome with a natural killer-cell neoplasm without cerebral invasion. A 78-year-old man with hemophagocytic syndrome received two cycles of chemotherapy that did not induce tumor lysis syndrome, but repeatedly caused polyuria and natriuresis. The expression of tumor necrosis factor-alpha in the neoplasm led us to hypothesize that an oncolysis induced cytokine storm may have caused renal tubular damage and salt wasting. Our theory may explain the pathogenic mechanism of cerebral/renal salt-wasting syndrome associated with other entities, including cerebral disorders, owing to the elevation of cytokine levels after subarachnoid hemorrhage. PMID- 28717083 TI - Pirfenidone-induced Eosinophilic Pleurisy. AB - The patient was a 69-year-old man with idiopathic pulmonary fibrosis who was taking pirfenidone. After 7 weeks of treatment, he suffered from left-sided eosinophilic pleurisy. Medical thoracoscopy was performed and the histopathological examination of the parietal pleura revealed the massive infiltration of eosinophils and lymphoid follicles. After stopping pirfenidone therapy, the patient's pleural effusion disappeared without additional treatment, and never recurred. This is the first case report of pirfenidone-induced pleurisy. PMID- 28717084 TI - Pathologically Proven Spontaneous Remission of IgG4-related Retroperitoneal Fibrosis. AB - Some forms of idiopathic retroperitoneal fibrosis (RF) have recently been considered to be a part of the spectrum of immunoglobulin G4 (IgG4)-related disease. This case report is the first description of a spontaneous remission in a patient with pathologically proven IgG4-related RF. Although the pathogenesis and long-term disease behavior of IgG4-related RF remains unknown, we believe that an initial assessment consisting of only careful monitoring might be one important strategy, especially in asymptomatic IgG4-related RF patients without nephropathy, while carefully monitoring these patients for the risk of recurrence. PMID- 28717085 TI - High-dose Chemotherapy with Stem Cell Rescue Provided Durable Remission for Classical Hodgkin Lymphoma-type Post-transplant Lymphoproliferative Disorder after Unrelated Cord Blood Transplantation: A Case Report and Review of the Literature. AB - An adult woman developed polymorphic post-transplant lymphoproliferative disorder (PTLD) 58 months after unrelated cord blood transplantation. She was treated successfully with chemotherapy and radiation therapy but presented with lymphadenopathy and splenomegaly 74 months after transplantation. A lymph node biopsy confirmed the diagnosis of nodular sclerosis type Hodgkin lymphoma (classical Hodgkin lymphoma [CHL]-type PTLD). After salvage therapy and hematopoietic stem cell harvesting, she was subsequently treated with consolidative high-dose chemotherapy with melphalan followed by stem cell rescue, which resulted in durable remission. High-dose chemotherapy using stem cell rescue has potential as a therapeutic option for subsequent CHL-type PTLD. PMID- 28717086 TI - Therapy-related Acute Myeloid Leukemia after the Long-term Administration of Low dose Etoposide for Chronic-type Adult T-cell Leukemia-lymphoma: A Case Report and Literature Review. AB - A 61-year-old woman with chronic-type adult T-cell leukemia-lymphoma (ATL) had been taking low-dose oral etoposide for progressive lymphocytosis. After taking this for 3.5 years, she was diagnosed with therapy-related acute myeloid leukemia (t-AML), with a chromosomal translocation of t (6:11) (q27; q23). She thus received remission induction therapy, consolidation therapy, and allogeneic hematopoietic stem cell transplantation. Although both t-AML and ATL were in remissive states, she died of a therapy-related infection within 1 year. We reviewed 12 reported cases of AML complicating ATL to better characterize this unusual disease. We should therefore include t-AML in the differential diagnosis when administering low-dose etoposide for ATL over a long period of time. PMID- 28717088 TI - Long-term Effects of Intravenous Cyclophosphamide in Combination with Mesna Provided Intravenously and via Bladder Perfusion in a Patient with Severe Multifocal Motor Neuropathy. AB - A 25-year-old woman presenting with progressive muscle weakness in the distal extremities in the absence of sensory involvement for 2 years was diagnosed with multifocal motor neuropathy (MMN). Her disease was difficult to manage with various immunosuppressants, and the muscle weakness eventually progressed to involve the respiratory muscles, necessitating mechanical ventilation. Intravenous cyclophosphamide (CY) dramatically improved her symptoms, and she has since maintained her ambulatory status for 18 years with intermittent CY therapy. Because the patient presented with hemorrhagic cystitis due to CY, we also implemented mesna administration by bladder perfusion. The administration of CY should therefore be considered in patients with severe MMN that is unresponsive to standard therapy. PMID- 28717087 TI - Pulmonary Intravascular Large B-cell Lymphoma (IVLBCL) Disguised as an Asthma Exacerbation in a Patient with Asthma. AB - A 62-year-old man with asthma presented with a 1-month history of wheezing and exertional dyspnea. Although the wheezing symptoms disappeared after systemic corticosteroid therapy, the exertional dyspnea and hypoxemia did not improve. A diagnosis of intravascular large B-cell lymphoma (IVLBCL) with pulmonary involvement was suspected because of the increased serum lactic dehydrogenase (LDH) and soluble interleukin-2 receptor (sIL-2R) level, increased alveolar arterial oxygen difference (AaDO2), decreased pulmonary diffusing capacity for carbon monoxide (DLCO) and scintigraphic, computed tomography (CT) and 18F fluorodeoxyglucose (FDG) positron emission tomography (PET)-CT findings. The patient was diagnosed as having IVLBCL with pulmonary involvement based on a pathological analysis of a random skin biopsy and a transbronchial lung biopsy. IVLBCL should be considered in patients with symptoms of asthma that are refractory to corticosteroid treatment. PMID- 28717089 TI - An Autopsy Case of Fulminant Hepatitis in a Patient with Multiple Sclerosis Treated by Interferon-Beta-1a. AB - A 44-year-old woman with multiple sclerosis (MS) receiving interferon (IFN)-beta 1a treatment was admitted to a local hospital for severe icterus and liver injury. She was transferred to our university hospital because fulminant hepatitis (FH) was suspected. She was diagnosed with acute-type FH based on hepatic coma, severe liver injury and liver failure, and she received plasma exchange and continuous hemodiafiltration therapy. On hospital day 6, she died from liver failure despite intensive care. An autopsy revealed histological findings consistent with FH. Physicians should monitor the hepatic function of MS patients receiving IFN-beta-1a treatment, as serious events can occur in rare cases. PMID- 28717090 TI - Delayed Polyneuropathy Induced by Organophosphate Poisoning. AB - An 89-year-old man attempted suicide by ingesting a pesticide (trichlorfon). After surviving the initial critical period in the intensive care unit, he developed rapidly progressive distal weakness and sensory disturbance. Electrophysiological examinations revealed sensory motor axonal polyneuropathy. Delayed polyneuropathy is a rare manifestation of organophosphate poisoning. Nerve conduction studies play an important role in the diagnosis of this rare clinical condition. PMID- 28717091 TI - Thrombolysis-related Multiple Lobar Hemorrhaging in Cerebral Amyloid Angiopathy with Extensive Strictly Lobar Cerebral Microbleeding. AB - A hemi-paralyzed 86-year-old man was diagnosed with ischemic stroke and underwent thrombolysis. Pre-thrombolysis brain magnetic resonance imaging revealed extensive strictly lobar cerebral microbleeding (CMB). Post-thrombolytic computed tomography revealed asymptomatic multiple intracerebral hemorrhaging (ICH). His age, CMB topography, and decreased cerebral spinal fluid amyloid-beta 40 and 42 levels were compatible with a diagnosis of cerebral amyloid angiopathy (CAA). There is no consensus on the safety of thrombolysis for acute stroke patients with CAA. Patients with CAA might have a higher incidence of thrombolysis-related ICH than those without CAA. PMID- 28717092 TI - Cerebrospinal Fluid Rhinorrhea and Subsequent Bacterial Meningitis due to an Atypical Clival Fracture. AB - Cases of cerebrospinal fluid (CSF) rhinorrhea due to clival fracture are rare. We present a case of bacterial meningitis with CSF rhinorrhea after a clival fracture. Heavily T2-weighted images showed a bone flap in the thinned clivus and fluid collection in the sphenoid sinus. CSF rhinorrhea developed at 1 month after mild trauma. The fracture may have been caused by the trauma and/or by the pressure gradient between the intracranial CSF space and the sphenoid sinus. A detailed history to identify trauma and an examination to detect bone defects in the skull base are necessary when patients present with bacterial meningitis and persistent rhinorrhea. PMID- 28717093 TI - Paraneoplastic Anti-3-hydroxy-3-methylglutary-coenzyme A Reductase Antibody positive Immune-mediated Necrotizing Myopathy in a Patient with Uterine Cancer. AB - We report the case of a 69-year-old woman with proximal limb muscle weakness, who received post-operative chemotherapy for uterine cancer. Her serum creatinine kinase level was high (10,779 mg/dL) and a muscle biopsy from her left biceps revealed various sizes of muscle fibers accompanied by necrotic and regenerating fibers. She was positive for anti-3 hydroxy-3-methylglutary-coenzyme A reductase (anti-HMGCR) antibodies, but negative for anti-signal recognition particle (anti SRP) antibodies. She was diagnosed with immune-mediated necrotizing myopathy (IMNM) and treated with prednisolone. Our findings indicate that not only drug induced myopathy but also paraneoplastic myopathy can be involved in the pathogenesis of IMNM. PMID- 28717094 TI - Limbic Encephalitis Associated with Human Herpesvirus-7 (HHV-7) in an Immunocompetent Adult: The First Reported Case in Japan. AB - A 35-year-old male who had not previously suffered any major illnesses was admitted to our hospital because of general fatigue, fever, headache, vomiting, consciousness disturbance, and seizures. A neurological examination showed that he was in a semi-comatose state and exhibited neck stiffness. Brain magnetic resonance imaging detected high-intensity areas in the bilateral hippocampi and periventricular white matter. A cerebrospinal fluid examination revealed mononuclear pleocytosis, an elevated protein level, and positivity for human herpesvirus-7 (HHV-7) DNA. The patient's condition improved after the administration of methylprednisolone, intravenous immunoglobulins, and acyclovir. This is the first known case of limbic encephalitis associated with HHV-7 in an immunocompetent Japanese adult. PMID- 28717095 TI - Encephalopathy Associated with Influenza B in a Healthy Young Man. AB - A 19-year-old man presented with a fever, convulsions, and loss of consciousness at our hospital. The patient had a Glasgow Coma Scale score of 12. Influenza B virus infection was diagnosed using the rapid test kit, and an eight-fold increase in the serum levels of anti-influenza B virus antibody was confirmed using the complement fixation test. Brain magnetic resonance imaging showed multifocal high-signal lesions, and an electroencephalogram showed diffuse slowing of the background activity, indicating acute encephalopathy. After treatment with peramivir and methylprednisolone for 3 days, the patient was discharged without any neurological impairment. This was a case of influenza B infection associated with acute encephalopathy in a healthy young man. PMID- 28717096 TI - Disseminated Mycobacterium scrofulaceum Infection in an Immunocompetent Host. AB - A 56-year-old woman, without any immunocompromising diseases, was referred to our hospital because of a recurrence of pyogenic spondylitis. Computed tomography revealed multiple osteolytic changes in the whole body. Vertebral magnetic resonance imaging revealed osteomyelitis and spondylitis. Mycobacterium scrofulaceum was detected in sputum cultures, in abscesses from the right knee, and in a subcutaneous forehead abscess. Therefore, the patient was diagnosed with disseminated Mycobacterium scrofulaceum infection. The patient was treated with rifampicin, ethambutol, and clarithromycin, which resulted in symptomatic relief and radiological improvement. We herein report a rare case of disseminated Mycobacterium scrofulaceum infection in an immunocompetent host. PMID- 28717097 TI - Plasma 2-hydroxyglutarate and hexanoylcarnitine levels are potential biomarkers for skeletal muscle toxicity in male Fischer 344 rats. AB - To identify new candidate biomarkers for skeletal muscle toxicity, an unbiased metabolomic analysis was performed in rats treated with two distinct myotoxicants, cerivastatin (CER) and tetramethyl-p-phenylenediamine (TMPD). Skeletal muscle toxicity was induced in male Fischer 344 rats by administering CER or TMPD and monitored using established endpoints, such as increased plasma creatine kinase (CK) activity and histopathology, and a metabolomic analysis of skeletal muscle and plasma samples. Plasma CK levels in CER-treated rats were markedly elevated at Day 11; however, those in TMPD-treated rats showed a statistically significant decrease at 24 hr after dosing. Light microscopy revealed that vacuolated or necrotic fibers were evident in all CER-treated rats on Day 11, and slightly vacuolated fibers were observed in TMPD-treated rats at 6 and 24 hr after dosing. Metabolomic analysis of the rectus femoris indicated increases in 2-hydroxyglutarate (2HG) in CER-treated rats and hexanoylcarnitine in CER- and TMPD-treated rats. There were also increases in plasma 2HG in CER treated rats on Days 8 and 11 and in TMPD-treated rats at 24 hr after dosing and increases in plasma hexanoylcarnitine in CER-treated rats on Day 11 and in TMPD treated rats at 6 and 24 hr after dosing. These experiments demonstrated the potential of plasma 2HG and hexanoylcarnitine as specific and easily detectable biomarkers for skeletal muscle toxicity in rats and demonstrated the value of metabolomics for biomarker detection and identification in toxicological studies. PMID- 28717098 TI - Evaluation of drug-induced hematotoxicity using novel in vitro monkey CFU-GM and BFU-E colony assays. AB - In order to evaluate drug-induced hematotoxicity in monkey cells in vitro, colony forming unit-granulocyte, macrophage (CFU-GM), and burst-forming unit-erythroid (BFU-E) colony assays were established using mononuclear cells in the bone marrow collected from male cynomolgus monkeys. Furthermore, the effects of doxorubicin, chloramphenicol, and linezolid on CFU-GM and BFU-E colony formation were investigated using established monkey CFU-GM and BFU-E colony assays in comparison with those on human CFU-GM and BFU-E colonies acquired from human umbilical cord blood cells. Bone marrow mononuclear cells were collected from the ischial or iliac bone of male cynomolgus monkeys. The cells were subsequently processed by density gradient separation at 1.067, 1.070, or 1.077 g/mL for CFU GM or 1.077 g/mL for BFU-E, and then cultured in methylcellulose medium for 9 or 13 days, respectively. A sufficient number of CFU-GM colonies were formed from mononuclear cells processed at a density of 1.070 g/mL. Moreover, the number of BFU-E colonies from the cells processed at a density of 1.077 g/mL was sufficient for the colony assay. The number of CFU-GM or BFU-E colonies decreased after treatment with the drugs of interest in a concentration-dependent manner. Compared with human CFU-GM, monkey CFU-GM were more sensitive to chloramphenicol and resistant to doxorubicin, whereas monkey BFU-E were more sensitive to all compounds in comparison to the sensitivity of human BFU-E. In conclusion, monkey CFU-GM and BFU-E colony assays were established and considered useful tools to evaluate the differences in drug-induced hematotoxicity between species. PMID- 28717099 TI - Differential neurotoxic effects of in utero and lactational exposure to hydroxylated polychlorinated biphenyl (OH-PCB 106) on spontaneous locomotor activity and motor coordination in young adult male mice. AB - We investigated whether in utero or lactational exposure to 4-hydroxy 2',3,3',4',5'-pentachlorobiphenyl (OH-PCB 106) affects spontaneous locomotor activity and motor coordination in young adult male mice. For in utero exposure, pregnant C57BL/6J mice received 0.05 or 0.5 mg/kg body weight of OH-PCB 106 or corn oil vehicle via gavage every second day from gestational day 10 to 18. For lactational exposure, the different groups of dams received 0.05 or 0.5 mg/kg body weight of OH-PCB 106 or corn oil vehicle via gavage every second day from postpartum day 3 to 13. At 6-7 weeks of age, the spontaneous locomotor activities of male offspring were evaluated for a 24-hr continuous session in a home cage and in an open field for 30-min. Motor coordination function on an accelerating rotarod was also measured. Mice exposed prenatally to OH-PCB 106 showed increased spontaneous locomotor activities during the dark phase in the home cage and during the first 10-min in the open field compared with control mice. Mice exposed lactationally to OH-PCB 106, however, did not show a time-dependent decrease in locomotor activity in the open field. Instead, their locomotor activity increased significantly during the second 10-min block. In addition, mice exposed lactationally to OH-PCB 106 displayed impairments in motor coordination in the rotarod test. These results suggest that perinatal exposure to OH-PCB 106 affects motor behaviors in young adult male mice. Depending on the period of exposure, OH-PCB 106 may have different effects on neurobehavioral development. PMID- 28717100 TI - Inhibitory modulation of human estrogen receptor alpha and beta activities by dicyclohexyl phthalate in human breast cancer cell lines. AB - Phthalate esters (PAEs) are man-made compounds that are used widely in industry, and the ubiquitous exposure of humans to PAEs has been reported. Although some PAEs have been suggested to function as xenoestrogens in in vitro systems, such as human estrogen receptors (ERs) expressed in Chinese hamster ovary (CHO)-K1 cells, few studies have attempted to elucidate whether PAEs affect human ERalpha/ERbeta-mediated signaling in human breast cancer cells (i.e., combination between human ERs and human cells). Thus, further experiments are needed in order to clarify the activities of PAEs. Among the 9 PAEs (carbon# in the side chains: 2-8) investigated, dibutyl phthalate (DBP), dipentyl phthalate (DPENP), and dicyclohexyl phthalate (DCHP) were found to exhibit strong anti-estrogenic activities in MCF-7 cells (ER-positive) in the presence of 1 nM 17beta-estradiol (E2). Since limited information is currently available on DPENP and DCHP, we herein focused on these two PAEs. Experiments using MDA-MB-231 cells (ER negative) transfected with human ERalpha or ERbeta expression plasmids revealed that DCHP was a markedly stronger anti-estrogenic PAE than DPENP; DCHP inhibited ERalpha and ERbeta activities stimulated by 1 nM E2 with IC50 values of ~5 and 11.2 uM, respectively. Furthermore, DCHP abrogated diarylpropionitrile (DPN) stimulated ERbeta activity with an IC50 value of 5.17 uM, which was approximately 2-fold stronger than that of DPENP (IC50 = 10 uM). The results of the present study suggest that PAEs (DCHP) function not only as an anti-estrogen for ERalpha, but also for ERbeta, at least in human breast cancer cell lines. PMID- 28717101 TI - Mechanism-based risk assessment strategy for drug-induced cholestasis using the transcriptional benchmark dose derived by toxicogenomics. AB - Cholestasis is one of the major causes of drug-induced liver injury (DILI), which can result in withdrawal of approved drugs from the market. Early identification of cholestatic drugs is difficult due to the complex mechanisms involved. In order to develop a strategy for mechanism-based risk assessment of cholestatic drugs, we analyzed gene expression data obtained from the livers of rats that had been orally administered with 12 known cholestatic compounds repeatedly for 28 days at three dose levels. Qualitative analyses were performed using two statistical approaches (hierarchical clustering and principle component analysis), in addition to pathway analysis. The transcriptional benchmark dose (tBMD) and tBMD 95% lower limit (tBMDL) were used for quantitative analyses, which revealed three compound sub-groups that produced different types of differential gene expression; these groups of genes were mainly involved in inflammation, cholesterol biosynthesis, and oxidative stress. Furthermore, the tBMDL values for each test compound were in good agreement with the relevant no observed adverse effect level. These results indicate that our novel strategy for drug safety evaluation using mechanism-based classification and tBMDL would facilitate the application of toxicogenomics for risk assessment of cholestatic DILI. PMID- 28717102 TI - Human lung adenocarcinoma cells with an EGFR mutation are sensitive to non autophagic cell death induced by zinc oxide and aluminium-doped zinc oxide nanoparticles. AB - Lung cancer, mostly non-small cell lung cancer (NSCLC), is the leading cause of cancer deaths; however, efficient treatments for NSCLC remain insufficient. The objective of this study was to investigate the effects of an epidermal growth factor receptor (EGFR) mutation on autophagic cell death in human lung adenocarcinoma cells by 20-nm zinc oxide nanoparticles (ZnONP20) and aluminum doped ZnONPs (Al-ZnONP20). Two types of human lung adenocarcinoma cells were used throughout the study: wild-type EGFR A549 cells and EGFR-mutated CL1-5 cells. We observed that a significant reduction in cell viability resulting from ZnONP20 and Al-ZnONP20 occurred in A549 and CL1-5 cells after 18 and 24 hr of exposure. A colony formation analysis showed that A549 cells re-grew after exposure to 20 MUg/mL Al-ZnONP20. Levels of light chain 3 (LC3) II conversion were activated by ZnONP20 and Al-ZnONP20 in A549 cells, whereas LC3 II was inhibited by ZnONP20 and Al-ZnONP20 in CL1-5 cells. In conclusion, we have shown that human lung adenocarcinoma cells with an EGFR mutation are sensitive to ZnONP20 and Al ZnONP20, which may have resulted in non-autophagic cell death. ZnONP20 and Al ZnONP20 may have the potential for personalized therapeutics in NSCLC with an EGFR mutation. PMID- 28717103 TI - Metabolomics of an in vitro liver model containing primary hepatocytes assembling around an endothelial cell network: comparative study on the metabolic stability and the effect of acetaminophen treatment. AB - Recently, a novel culture system consisting of primary hepatocytes structured over a network of endothelial cells on the Engelbreth-Holm-Swarm (EHS) gel has been reported. This in vitro liver model on the EHS gel (IVLEHS) has been shown to maintain the expression of hepatic genes and their functional activity. Moreover, the IVLEHS was more sensitive to xenobiotics than hepatocyte monocultures, suggesting the potential utility of this culture system for compound hepatotoxicity screening. However, the effect of this three-dimensional structure formation on the cellular metabolic profile of hepatocytes in the IVLEHS is not well understood. To address this concern, we performed metabolome analysis using capillary electrophoresis-time of flight mass spectrometry. Between the IVLEHS and mono-cultured hepatocytes on the EHS gel, there was no significant difference in the levels of metabolites of the urea cycle and the tricarboxylic acid cycle, essential amino acids, and adenylate energy charge (AEC) which is an important indicator of cellular energy status. On the other hand, acetaminophen-dependent decrease of the AEC in the IVLEHS was greater than that in the monoculture, suggesting the higher sensitivity of IVLEHS to acetaminophen-induced hepatotoxicity which is caused by metabolic activation of this drug. Further analysis showed that the levels of taurocholate, one of the major conjugated bile acids, were higher in the IVLEHS than in the monoculture. Considering that the construction of the IVLEHS did not seem to disturb the major cellular metabolism, our findings would strengthen the concept that IVLEHS would have beneficial effects on the maintenance of hepatic functions. PMID- 28717104 TI - Dexamethasone-induced hepatomegaly and steatosis in larval zebrafish. AB - Fish hepatobiliary syndrome, characterized by hepatomegaly and fatty liver, has been frequently reported in many cultured fish species and has caused a dramatic economic loss in China. Glucocorticoids are thought to be important non nutritional factors for hepatomegaly and fatty liver development. In the present study, a dexamethasone-induced zebrafish model of fatty liver and hepatomegaly was established, and the role of glucocorticoid receptor (GR) in the development of hepatomegaly and fatty liver was investigated using developing zebrafish. Exposure of larval zebrafish at 5 days post fertilization (dpf) to dexamethasone for 24 hr caused significant increases of liver size and number of fish with hepatic steatosis at 6 dpf. The increase of liver size caused by dexamethasone was significantly reversed by treatment with RU486, a GR antagonist, and by gene knock-down with a morpholino against the GR. The dexamethasone-induced hepatic steatosis was also inhibited by treatment with RU486. Overall, the results highlight larval zebrafish as a useful model for stress-induced liver failure. PMID- 28717105 TI - Ephedrine-induced mitophagy via oxidative stress in human hepatic stellate cells. AB - The herb Ephedra sinica (also known as Chinese ephedra or Ma Huang), used in traditional Chinese medicine, contains alkaloids identical to ephedrine and pseudoephedrine as its principal active constituents. Recent studies have reported that ephedrine has various side effects in the cardiovascular and nervous systems. In addition, herbal Ephedra, a plant containing many pharmacologically active alkaloids, principally ephedrine, has been reported to cause acute hepatitis. Many studies reported clinical cases, however, the cellular mechanism of liver toxicity by ephedrine remains unknown. In this study, we investigated hepatotoxicity and key regulation of mitophagy in ephedrine treated LX-2 cells. Ephedrine triggered mitochondrial oxidative stress and depolarization. Mitochondrial swelling and autolysosome were observed in ephedrine-treated cells. Ephedrine also inhibited mitochondrial biogenesis, and the mitochondrial copy number was decreased. Parkin siRNA recovered the ephedrine induced mitochondrial damage. Excessive mitophagy lead to cell death through imbalance of autophagic flux. Moreover, antioxidants and reducing Parkin level could serve as therapeutic targets for ephedrine-induced hepatotoxicity. PMID- 28717106 TI - A carcinogenicity study of diphenylarsinic acid in F344 rats in drinking water for 104 weeks. AB - Diphenylarsinic acid (DPAA), a neurotoxic organic arsenical used as a chemical warfare agent, is present in the groundwater and soil in some regions of Japan due to illegal dumping after World War II. We previously demonstrated that DPAA promotes diethylnitrosamine-induced liver carcinogenesis in a medium-term rat liver bioassay. The purpose of the present study was to evaluate the potential carcinogenicity of DPAA, including investigation of whether the bile duct hyperplasia in the liver that was observed in a previous 52 week rat chronic study develops into a tumor, when administered to rats in their drinking water for 104 weeks. DPAA was administered to groups 1-4 at concentrations of 0, 5, 10, and 20 ppm in their drinking water for 104 weeks. A significant decrease in survival rate was found for females in the 20 ppm DPAA group. Body weights of males in the 20 ppm and females in the 10 and 20 ppm DPAA groups were significantly decreased compared to the controls. Overall histopathological evaluation of neoplasms in all tissues showed no significant increase of tumor incidence in any organ or tissue of the 5, 10, or 20 ppm DPAA-treated male or female F344 rats. In conclusion, the present study demonstrated that DPAA is not a complete carcinogen in male or female F344 rats. PMID- 28717107 TI - Human plasma and urinary metabolic profiles of trimethylamine and trimethylamine N-oxide extrapolated using a simple physiologically based pharmacokinetic model. AB - Trimethylamine, a dietary- and medicinal carnitine-derived amine, is extensively metabolized by liver to non-malodorous trimethylamine N-oxide. Although trimethylamine and trimethylamine N-oxide under daily dietary consumption or carnitine treatment are generally regarded as nontoxic, they have been, and remain, of toxicological and clinical interest because of their potential association with atherosclerosis. The aim of the current study was to model the pharmacokinetics of trimethylamine after oral administration of trimethylamine in humans and compare the results with reported measured values. Adjusted biomonitoring equivalents from rat studies based on reported plasma concentrations were scaled to human equivalents using known species allometric scaling factors. In vitro metabolic clearance data were obtained using rat and human liver microsomal preparations. Renal clearances in humans for trimethylamine and trimethylamine N-oxide were calculated with a clearance concept approach using reported 24-hr urinary excretion rates and assumed areas under plasma concentration curves. The resulting modeled plasma and urinary concentration curves by simple physiologically based pharmacokinetic models (or semi-physiological pharmacokinetic models) were consistent with reported concentrations. This study provides important information to help simulate human plasma levels of trimethylamine and trimethylamine N-oxide in trimethylamine loading tests and during treatment with prescribed medicinal l-carnitine, showing the similar range as that resulting from daily dietary foodstuff consumption along with little toxicological impacts. The present models could estimate relationship between plasma and urine concentrations of trimethylamine or trimethylamine N-oxide and the daily oral doses by both forward and reverse dosimetry from viewpoint of human risk assessment. PMID- 28717108 TI - Isoflurane is a suitable alternative to ether for anesthetizing rats prior to euthanasia for gene expression analysis. AB - Diethyl ether (ether) had been widely used in Japan for anesthesia, despite its explosive properties and toxicity to both humans and animals. We also had used ether as an anesthetic for euthanizing rats for research in the Toxicogenomics Project (TGP). Because the use of ether for these purposes will likely cease, it is required to select an alternative anesthetic which is validated for consistency with existing TGP data acquired under ether anesthesia. We therefore compared two alternative anesthetic candidates, isoflurane and pentobarbital, with ether in terms of hematological findings, serum biochemical parameters, and gene expressions. As a result, few differences among the three agents were observed. In hematological and serum biochemistry analysis, no significant changes were found. In gene expression analysis, four known genes were extracted as differentially expressed genes in the liver of rats anesthetized with ether, isoflurane, or pentobarbital. However, no significant relationships were detected using gene ontology, pathway, or gene enrichment analyses by DAVID and TargetMine. Surprisingly, although it was expected that the lung would be affected by administration via inhalation, only one differentially expressed gene was extracted in the lung. Taken together, our data indicate that there are no significant differences among ether, isoflurane, and pentobarbital with respect to effects on hematological parameters, serum biochemistry parameters, and gene expression. Based on its smallest affect to existing data and its safety profile for humans and animals, we suggest isoflurane as a suitable alternative anesthetic for use in rat euthanasia in toxicogenomics analysis. PMID- 28717109 TI - Utility of human hepatocyte spheroids without feeder cells for evaluation of hepatotoxicity. AB - We investigated the utility of three-dimensionally cultured hepatocytes (spheroids) without feeder cells (Sph(f-)) for the prediction of drug-induced liver injury (DILI) in humans. Sph(f-) and spheroids cultured on feeder cells (Sph(f+)) were exposed to the hepatotoxic drugs flutamide, diclofenac, isoniazid and chlorpromazine at various concentrations for 14 days, and albumin secretion and cumulative leakages of toxicity marker enzymes, aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH) and gamma glutamyl transpeptidase (gamma-GTP), were measured. The cumulative AST, LDH or gamma-GTP leakages from Sph(f-) were similar to or greater than those from Sph(f+) for all drugs tested, although ALT leakages showed no consistent difference between Sph(f+) and Sph(f-). In the case of Sph(f-), significant correlations among all the toxicity markers except for gamma-GTP were observed. As regards the drug concentrations causing 1.2-fold elevation of enzyme leakage (F1.2), no consistent difference between Sph(f+) and Sph(f-) was found, although several F1.2 values were undetermined, especially in Sph(f+). The IC50 of albumin secretion and F1.2 of AST leakage from Sph(f-) were equal to or lower than those of Sph(f+) for all the tested drugs. These results indicate that feeder cells might contribute to resistance to hepatotoxicity, suggesting DILI could be evaluated more accurately by using Sph(f-). We suggest that long-term exposure of Sph(f-) to drugs might be a versatile method to predict and reproduce clinical chronic toxicity, especially in response to repeated drug administration. PMID- 28717110 TI - Mercury and selenium levels, and their molar ratios in several species of commercial shrimp in Japan regarding the health risk of methylmercury exposure. AB - The Japanese shrimp industry depends on importing shrimp from other countries. However, little information is available on mercury speciation and selenium (Se) concentrations in commercial shrimp available in Japan. The present study determined the concentrations of total mercury (T-Hg), methylmercury (MeHg), and Se in the muscles (wet weight) of imported and domestic commercial shrimp from Kumamoto and Kagoshima prefectures to obtain information for assessing the risk of MeHg exposure. The median concentrations of T-Hg, MeHg and Se in shrimp imported from three different countries were, respectively: black tiger shrimp (n = 18), 15.8, 14.4, and 415 ng/g; Vannamei shrimp (n = 25), 11.4, 11.2, and 292 ng/g; and white shrimp (n = 26), 26.8, 26.1, and 396 ng/g. There were significant differences in T-Hg and MeHg concentrations between shrimp imported from different countries. The median concentrations of T-Hg, MeHg and Se in shrimp of Japanese origin were, respectively: Shiba shrimp (n = 10), 15.9, 15.0, and 270 ng/g; Kuruma shrimp (n = 10), 79.9, 75.9, and 390 ng/g; and Ashiaka shrimp (n = 10), 36.1, 34.1, and 303 ng/g. The percentages of MeHg in T-Hg were between 90% and 99%, with MeHg levels in the imported and domestic commercial shrimp lower than the Japanese regulation of 300 ng/g for fish. The mean Se/T-Hg molar ratios (16-160) were comparatively higher than those previously reported in fish. Overall, this survey suggests that shrimp commercially available in Japan will not pose a particularly high risk regarding MeHg exposure to consumers. PMID- 28717111 TI - Usefulness of cardiotoxicity assessment using calcium transient in human induced pluripotent stem cell-derived cardiomyocytes. AB - Monitoring dramatic changes in intracellular calcium ion levels during cardiac contraction and relaxation, known as calcium transient, in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) would be an attractive strategy for assessing compounds on cardiac contractility. In addition, as arrhythmogenic compounds are known to induce characteristic waveform changes in hiPSC-CMs, it is expected that calcium transient would allow evaluation of not only compound-induced effects on cardiac contractility, but also compound arrhythmogenic potential. Using a combination of calcium transient in hiPSC-CMs and a fast kinetic fluorescence imaging detection system, we examined in this study changes in calcium transient waveforms induced by a series of 17 compounds that include positive/negative inotropic agents as well as cardiac ion channel activators/inhibitors. We found that all positive inotropic compounds induced an increase in peak frequency and/or peak amplitude. The effects of a negative inotropic compound could clearly be detected in the presence of a beta-adrenergic receptor agonist. Furthermore, most arrhythmogenic compounds raised the ratio of peak decay time to peak rise time (D/R ratio) in calcium transient waveforms. Compound concentrations at which these parameters exceeded cutoff values correlated well with systemic exposure levels at which arrhythmias were reported to be evoked. In conclusion, we believe that peak analysis of calcium transient and determination of D/R ratio are reliable methods for assessing compounds' cardiac contractility and arrhythmogenic potential, respectively. Using these approaches would allow selection of compounds with low cardiotoxic potential at the early stage of drug discovery. PMID- 28717112 TI - Effect of a single point mutation on equine herpes virus 9 (EHV-9) neuropathogenicity after intranasal inoculation in a hamster model. AB - This study aimed to investigate the neuropathogenesis of equine herpes virus 9 (EHV-9) by studying the effects of a single point mutation introduced in two different EHV-9 genes. The two EHV-9 mutants, 14R and 19R, were generated carrying a point mutation in two separate EHV-9 genes. These mutants, along with the wild-type EHV-9, were used to infect a hamster model. The EHV-9- and 19R infected groups showed earlier and more severe clinical signs of infection than the 14R-infected group. The white blood cells (WBCs) count was significantly increased in both EHV-9- and 19R-infected groups compared to the 14R-infected group at the 4th day post infection (DPI). Viremia was also detected earlier in both EHV-9- and 19R-infected groups than 14R-infected group. There were differences in the anterograde transmission pattern of both EHV-9 and 19R compared to 14R inside the brain. Serum TNF-alpha, IL-6 and IFN-gamma levels were significantly increased in both EHV-9- and 19R-infected groups compared to the 14R-infected group. Histopathological and immunohistochemical analyses revealed that the mean group scores for the entire brain were significantly higher in both EHV-9- and 19R- infected groups than 14R-infected group. Collectively, these results confirm that the gene product of Open Reading Frame 19 (ORF19) plays an important role in EHV-9 neuropathogenicity and that the mutation in ORF19 is responsible for the attenuation of EHV-9. PMID- 28717114 TI - The Efficacy of Isochronal 3D Mapping-Based Ablation of Ventricular Arrhythmia. AB - Treatment of ventricular arrhythmias (VAs) commonly involves ablating sites showing electrograms with the earliest activity relative to the VA, but there is no threshold value for prematurity guaranteeing success. Ablation of sites with great prematurity can still result in failure.We hypothesized that isochronal map area (ISCA), derived from isochrones indicating electrogram prematurity, could help identify ablation targets in VA patients, as well as predict outcome. Specifically, we hypothesized that smaller ICSA for a given prematurity value would indicate a shallower arrhythmogenic focus leading to a higher likelihood of successful ablation.We studied ICSA in 29 patients (12 males, 57 [17-65] years old) undergoing VA ablation. The VAs originated from the right and left ventricles in 11 and 18 patients, respectively. The earliest activation site of the VAs, ECG morphology of sinus beats and premature ventricular complexes (PVCs), and ISCA of activation preceding PVCs were evaluated.RF ablation at the site showing earliest prematurity resulted in VA elimination in 21 patients (success group). The 5-ms ISCA was smaller in the success group than in the failure group (0.2 [0.1-0.6] versus 1.0 [0.8-1.5] cm2, respectively; P < 0.01). No significant difference was noted in prematurity itself (36 [30-45] versus 30 [29-33] ms, respectively; P = 0.07). The cut-off value of the 5 ms ISCA for successful RF ablation was 0.7 cm2 with 87.5% sensitivity and 85.6% specificity.Isochrones of activity preceding PVCs appear to contain information beyond prematurity values and may help dictate suitable areas for successful ablation of VAs. PMID- 28717113 TI - Add-on Antiplatelet Effects of Eicosapentaenoic Acid With Tailored Dose Setting in Patients on Dual Antiplatelet Therapy. AB - The aim of this study was to investigate the antiplatelet effects of eicosapentaenoic acid (EPA) at a sufficient dose following coronary stent implantation. Thirty-one patients on dual antiplatelet therapy with aspirin and clopidogrel were treated with highly purified EPA-E (Epadel(r)) for 12 weeks. Based on our previous study, patients with a high baseline EPA/arachidonic acid (AA) ratio (>= 0.37; n = 11) were given a standard dose (1800 mg daily) of EPA-E, whereas those with a low EPA/AA ratio (< 0.37; n = 20) were given a high dose (2700 mg daily) to reach the target value of > 0.92. Platelet function was then evaluated with agonist-induced aggregation using light transmittance aggregometry and VerifyNow(r). After EPA-E treatment, the EPA/AA ratio significantly increased from 0.28 to 1.31 (P < 0.001). Collagen (1, 2, and 4 MUg/mL)-induced maximal platelet aggregation (MPA) was significantly suppressed after EPA-E administration (from 28.0 to 24.0, P = 0.033; from 44.0 to 40.0, P = 0.016; from 60.0 to 56.0, P = 0.010; respectively). However, there were no changes in MPA induced by adenosine diphosphate and AA and in P2Y12 reaction units (PRU) and aspirin reaction units. After EPA-E treatment, PRU was significantly suppressed in 8 patients showing high on-treatment platelet reactivity (HTPR) (baseline 305; 266-321 versus on-treatment 256; 233-261, P = 0.012), but not in those without HTPR (201; 156-220 versus 183; 159-233, P = 0.212). In conclusion, EPA treatment at a sufficient dose suppressed platelet aggregation and showed possible add-on effects in patients with clopidogrel hyporesponsiveness. PMID- 28717115 TI - Coronary Artery Disease and Type 2 Diabetes Mellitus. AB - Type 2 diabetes mellitus (T2DM) is a major risk factor of coronary artery diseases (CAD). Clinical outcomes in CAD with T2DM are poor despite improvement in medications and intervention devices. Coronary artery bypass grafting (CABG) is superior to percutaneous coronary intervention (PCI) in treating diabetic patients with multivessel coronary artery diseases (MVD). However, selecting a revascularization strategy should depend not only on the lesion complexity but also on the patient's background and comorbidities. In addition, comprehensive risk management with medical and non-pharmacological therapies is important, as is confirmation of whether risk managements are appropriately achieved. Recently, novel anti-diabetic drugs have been demonstrated to have effectiveness in reducing cardiovascular events, which was independent of their glucose-lowering effect. Furthermore, non-pharmacological interventions using exercise and diet during the earlier stages of abnormal glucose metabolism might be beneficial in preventing the development or progression of T2DM and reducing the incidence of cardiovascular events. PMID- 28717116 TI - Novel Predictor of Lung Injury After Balloon Pulmonary Angioplasty in Patients With Chronic Thromboembolic Pulmonary Hypertension. PMID- 28717117 TI - Is Serum Uric Acid a Biomarker, but not a Mediator in Patients With Lifestyle and Cardiovascular Diseases? PMID- 28717118 TI - Can Statins Modify the Wound Healing Process After Myocardial Infarction? PMID- 28717119 TI - Nephron Sparing Surgery Has Better Oncologic Outcomes Than Extirpative Nephrectomy in T1a but Not in T1b or T2 Stage Renal Cell Carcinoma. AB - BACKGROUND The aim of this study was to investigate the benefit of nephron sparing surgery (NSS) compared with extirpative nephrectomy in different tumor stages of renal cell carcinoma. MATERIAL AND METHODS We reviewed the Surveillance, Epidemiology and End Results (SEER) database for NSS and extirpative nephrectomy in localized (stages T1-2N0M0) renal cell carcinoma diagnosed after 2004. We used the variable screening function of the SEER database to identified 55,947 cases that met inclusion and exclusion criteria for survival analysis. Overall mortality and cancer-specific mortality were the primary index outcomes. Stratification analysis was done by T stage subgroups. We also performed survival analysis using propensity score analysis, and changed the survival model to the competing-risk model for cancer-specific mortality analysis. RESULTS Overall, NSS significantly decreased the risk of overall mortality (HR 0.717, 0.668-0.769) and cancer-specific mortality (HR 0.604, 0.525 0.694) when compared to extirpative nephrectomy. In subgroup analysis, NSS had a lower overall mortality risk and cancer-specific mortality compared to extirpative nephrectomy only for T1a stage renal cell carcinoma (HR 0.654, 0.599 0.714, p<0.01 and HR 0.554, 0.458-0.670, p<0.01, respectively), but not for T1b or T2 stage. The propensity score analysis, which included standardized mortality ratio weight adjustment, showed the same results. Additionally, for cancer specific mortality, a competing-risk model gave the exactly same outcome. CONCLUSIONS Compared to extirpative nephrectomy, NSS provided superior overall survival and cancer-specific survival for localized renal cell carcinoma only in T1a stage, not in T1b or T2 stage. NSS should be recommended when the surgery is possible. Further prospective study is needed to confirm this result. PMID- 28717120 TI - New Delhi Metallo-Beta-Lactamase (NDM-1)-Producing Klebsiella Pneumoniae Isolated from a Burned Patient. AB - BACKGROUND Infections affecting burn patients are frequently caused by Staphylococcus aureus, Pseudomonas aeruginosa, and Enterobacteriaceae species. Infections with these pathogens have become increasingly difficult to treat due to evolving antibiotic resistance mechanisms, including the production of carbapenemases. CASE REPORT The present case report describes the evolution of a burn patient with polymicrobial healthcare-associated burn infections, including a bloodstream infection due to an emergent multidrug-resistant New Delhi metallo beta-lactamase (NDM-1)-producing Klebsiella pneumoniae. During hospitalization, initial antibiotic treatment eradicated some of the infecting species. Newer isolates were found to be multidrug-resistant and required unique antibiotic combinations. The patient's condition continued to deteriorate after the isolation of multidrug-resistant P. aeruginosa and NDM-1-positive K. pneumoniae from the blood. CONCLUSIONS This case report illustrates the need for adequate antibiotic therapies in burn patients with subsequent infections due to a carbapenemase-producing multidrug-resistant bacteria. The potential danger of new bacterial pathogens should be considered in this group of susceptible patients. PMID- 28717121 TI - Impact of Doppler Ultrasound on Diagnosis and Therapy Control of Lienalis Steal Syndrome After Liver Transplantation. AB - BACKGROUND Lienalis steal syndrome is a rare complication after orthotopic liver transplantation leading to severe complications. Routine duplex sonography allows early and safe detection of lienalis steal syndrome and secondarily helps to monitor the outcome by evaluating the hemodynamics. MATERIAL AND METHODS This analysis included eight patients who after orthotopic liver transplantation needed splenic artery embolization due to lienalis steal syndrome. Lienalis steal syndrome was assumed in case of elevated transaminases, bilirubinemia or persistent ascites, and the absence of further pathologies. Diagnosis was supported by ultrasound, confirmed by digital subtraction angiography, and followed by splenic artery embolization for treatment. We analyzed blood levels and ultrasound findings before and after splenic artery embolization as well as during follow-up and evaluated for incidence of severe biliary complications and survival. RESULTS Arterial resistive index (RI) significantly regularized after splenic artery embolization while the maximum arterial velocity increased. The portal venous flow volume and maximum velocity decrease. Laboratory parameters normalized. Two of eight patients developed ischemic-type biliary disease. Survival rate was 88% over a median follow-up of 33 months. CONCLUSIONS Beside unspecific clinical findings, bedside ultrasound examination enabled a quick verification of the diagnosis and allowed direct treatment to minimize further complications. Furthermore, ultrasound can immediately monitor the therapeutic effect of splenic artery embolization. PMID- 28717122 TI - Disentangling environmental and spatial effects on phylogenetic structure of angiosperm tree communities in China. AB - Niche-based and neutrality-based theories are two major classes of theories explaining the assembly mechanisms of local communities. Both theories have been frequently used to explain species diversity and composition in local communities but their relative importance remains unclear. Here, we analyzed 57 assemblages of angiosperm trees in 0.1-ha forest plots across China to examine the effects of environmental heterogeneity (relevant to niche-based processes) and spatial contingency (relevant to neutrality-based processes) on phylogenetic structure of angiosperm tree assemblages distributed across a wide range of environment and space. Phylogenetic structure was quantified with six phylogenetic metrics (i.e., phylogenetic diversity, mean pairwise distance, mean nearest taxon distance, and the standardized effect sizes of these three metrics), which emphasize on different depths of evolutionary histories and account for different degrees of species richness effects. Our results showed that the variation in phylogenetic metrics explained independently by environmental variables was on average much greater than that explained independently by spatial structure, and the vast majority of the variation in phylogenetic metrics was explained by spatially structured environmental variables. We conclude that niche-based processes have played a more important role than neutrality-based processes in driving phylogenetic structure of angiosperm tree species in forest communities in China. PMID- 28717123 TI - Fungal infestation boosts fruit aroma and fruit removal by mammals and birds. AB - For four decades, an influential hypothesis has posited that competition for food resources between microbes and vertebrates selects for microbes to alter these resources in ways that make them unpalatable to vertebrates. We chose an understudied cross kingdom interaction to experimentally evaluate the effect of fruit infection by fungi on both vertebrate (mammals and birds) fruit preferences and on ecologically relevant fruit traits (volatile compounds, toughness, etc). Our well-replicated field experiments revealed that, in contrast to previous studies, frugivorous mammals and birds consistently preferred infested over intact fruits. This was concordant with the higher level of attractive volatiles (esters, ethanol) in infested fruits. This investigation suggests that vertebrate frugivores, fleshy-fruited plants, and microbes form a tripartite interaction in which each part could interact positively with the other two (e.g. both orange seeds and fungal spores are likely dispersed by mammals). Such a mutualistic view of these complex interactions is opposed to the generalized idea of competition between frugivorous vertebrates and microorganisms. Thus, this research provides a new perspective on the widely accepted plant evolutionary dilemma to make fruits attractive to mutualistic frugivores while unattractive to presumed antagonistic microbes that constrain seed dispersal. PMID- 28717124 TI - Hyper-Stain Inspector: A Framework for Robust Registration and Localised Co Expression Analysis of Multiple Whole-Slide Images of Serial Histology Sections. AB - In this paper, we present a fast method for registration of multiple large, digitised whole-slide images (WSIs) of serial histology sections. Through cross slide WSI registration, it becomes possible to select and analyse a common visual field across images of several serial section stained with different protein markers. It is, therefore, a critical first step for any downstream co-localised cross-slide analysis. The proposed registration method uses a two-stage approach, first estimating a fast initial alignment using the tissue sections' external boundaries, followed by an efficient refinement process guided by key biological structures within the visual field. We show that this method is able to produce a high quality alignment in a variety of circumstances, and demonstrate that the refinement is able to quantitatively improve registration quality. In addition, we provide a case study that demonstrates how the proposed method for cross-slide WSI registration could be used as part of a specific co-expression analysis framework. PMID- 28717125 TI - MicroRNAs with prognostic significance in bladder cancer: a systematic review and meta-analysis. AB - The aim of this study was to systematically review articles that investigated the prognostic significance of different microRNAs in bladder cancer (BC). We systematically searched PubMed, Web of Science, and Embase to identify relevant studies until March 2016. After screening, 26 studies that involved 2753 patients were included. Results suggested that many miRs expression aberration may predict prognosis in patients with BC. There are six miRs (miR-21, miR-143, miR-155, miR 200, miR-214, and miR-222) were reported by at least two studies, and we performed meta-analysis in the corresponding studies. Accordingly, we found that high miR-21 expression was associated with poor overall survival [OS; hazard ratio (HR) = 3.94, 95% CI 2.08-7.44]. High miR-143 expression was associated with poor progression-free survival (PFS; HR = 3.78, 95% CI 1.61-8.89). High miR-155 expression was associated with poor PFS (HR = 8.10, 95% CI 2.92-22.48). High miR 222 expression was associated with poor OS (HR = 3.39, 95% CI 1.10-10.41). Meanwhile, low miR-214 expression was correlated with poor RFS(HR = 0.34, 95% CI 0.22-0.53). Our comprehensive systematic review concluded that microRNAs, particularly miR-21, miR-143, miR-155, miR-214, and miR-222, could serve as meticulous follow-up markers for early detection of progression or recurrence and even useful therapeutic targets for the treatment in patients with BC. PMID- 28717126 TI - 2D/0D graphene hybrids for visible-blind flexible UV photodetectors. AB - Nitrogen-functionalized graphene quantum dots (NGQDs) are attractive building blocks for optoelectronic devices because of their exceptional tunable optical absorption and fluorescence properties. Here, we developed a high-performance flexible NGQD/graphene field-effect transistor (NGQD@GFET) hybrid ultraviolet (UV) photodetector, using dimethylamine-functionalized GQDs (NMe2-GQDs) with a large bandgap of ca. 3.3 eV. The NMe2-GQD@GFET photodetector exhibits high photoresponsivity and detectivity of ca. 1.5 * 104 A W-1 and ca. 5.5 * 1011 Jones, respectively, in the deep-UV region as short as 255 nm without application of a backgate voltage. The feasibility of these flexible UV photodetectors for practical application in flame alarms is also demonstrated. PMID- 28717127 TI - Experimental evidence reveals the UCP1 genotype changes the oxygen consumption attributed to non-shivering thermogenesis in humans. AB - Humans have spread out all over the world adapting to many different cold environments. Recent worldwide genome analyses and animal experiments have reported dozens of genes associated with cold adaptation. The uncoupling protein 1 (UCP1) gene enhances thermogenesis reaction in a physiological process by blocking ATP (adenosine triphosphate) synthesis on a mitochondrial membrane in brown adipose tissues. To our knowledge, no previous studies have shown an association between variants of the UCP1 gene and physiological phenotypes concerning non-shivering thermogenesis (NST) under the condition of low temperature in humans. We showed that the degree of NST for healthy subjects in an artificial climate chamber is significantly different among UCP1 genotypes. Defining the haplotypes covering the UCP1 region (39.4 kb), we found that the frequency of the haplotype with the highest NST was significantly correlated with latitudes and ambient temperature. Thus, the data in this study provide the first evidence that the UCP1 genotype alters the efficiency of NST in humans, and likely supports the hypothesis that the UCP1 gene has been related to cold adaptation in human evolutionary history. PMID- 28717128 TI - Mother's Pre-pregnancy BMI and Placental Candidate miRNAs: Findings from the ENVIRONAGE Birth Cohort. AB - There is increasing evidence that the predisposition for development of chronic diseases arises at the earliest times of life. In this context, maternal pre pregnancy weight might modify fetal metabolism and the child's predisposition to develop disease later in life. The aim of this study is to investigate the association between maternal pre-pregnancy body mass index (BMI) and miRNA alterations in placental tissue at birth. In 211 mother-newborn pairs from the ENVIRONAGE birth cohort, we assessed placental expression of seven miRNAs important in crucial cellular processes implicated in adipogenesis and/or obesity. Multiple linear regression models were used to address the associations between pre-pregnancy BMI and placental candidate miRNA expression. Maternal pre pregnancy BMI averaged (+/-SD) 23.9 (+/-4.1) kg/m2. In newborn girls (not in boys) placental miR-20a, miR-34a and miR-222 expression was lower with higher maternal pre-pregnancy BMI. In addition, the association between maternal pre pregnancy BMI and placental expression of these miRNAs in girls was modified by gestational weight gain. The lower expression of these miRNAs in placenta in association with pre-pregnancy BMI, was only evident in mothers with low weight gain (<14 kg). The placental expression of miR-20a, miR-34a, miR-146a, miR-210 and miR-222 may provide a sex-specific basis for epigenetic effects of pre pregnancy BMI. PMID- 28717129 TI - 3D printed scaffolds of calcium silicate-doped beta-TCP synergize with co cultured endothelial and stromal cells to promote vascularization and bone formation. AB - Synthetic bone scaffolds have potential application in repairing large bone defects, however, inefficient vascularization after implantation remains the major issue of graft failure. Herein, porous beta-tricalcium phosphate (beta-TCP) scaffolds with calcium silicate (CS) were 3D printed, and pre-seeded with co cultured human umbilical cord vein endothelial cells (HUVECs) and human bone marrow stromal cells (hBMSCs) to construct tissue engineering scaffolds with accelerated vascularization and better bone formation. Results showed that in vitro beta-TCP scaffolds doped with 5% CS (5%CS/beta-TCP) were biocompatible, and stimulated angiogenesis and osteogenesis. The results also showed that 5%CS/beta TCP scaffolds not only stimulated co-cultured cells angiogenesis on Matrigel, but also stimulated co-cultured cells to form microcapillary-like structures on scaffolds, and promoted migration of BMSCs by stimulating co-cultured cells to secrete PDGF-BB and CXCL12 into the surrounding environment. Moreover, 5%CS/beta TCP scaffolds enhanced vascularization and osteoinduction in comparison with beta TCP, and synergized with co-cultured cells to further increase early vessel formation, which was accompanied by earlier and better ectopic bone formation when implanted subcutaneously in nude mice. Thus, our findings suggest that porous 5%CS/beta-TCP scaffolds seeded with co-cultured cells provide new strategy for accelerating tissue engineering scaffolds vascularization and osteogenesis, and show potential as treatment for large bone defects. PMID- 28717130 TI - Polymicrobial Infections In Brain Tissue From Alzheimer's Disease Patients. AB - Several studies have advanced the idea that the etiology of Alzheimer's disease (AD) could be microbial in origin. In the present study, we tested the possibility that polymicrobial infections exist in tissue from the entorhinal cortex/hippocampus region of patients with AD using immunohistochemistry (confocal laser scanning microscopy) and highly sensitive (nested) PCR. We found no evidence for expression of early (ICP0) or late (ICP5) proteins of herpes simplex virus type 1 (HSV-1) in brain sections. A polyclonal antibody against Borrelia detected structures that appeared not related to spirochetes, but rather to fungi. These structures were not found with a monoclonal antibody. Also, Borrelia DNA was undetectable by nested PCR in the ten patients analyzed. By contrast, two independent Chlamydophila antibodies revealed several structures that resembled fungal cells and hyphae, and prokaryotic cells, but most probably were unrelated to Chlamydophila spp. Finally, several structures that could belong to fungi or prokaryotes were detected using peptidoglycan and Clostridium antibodies, and PCR analysis revealed the presence of several bacteria in frozen brain tissue from AD patients. Thus, our results show that polymicrobial infections consisting of fungi and bacteria can be revealed in brain tissue from AD patients. PMID- 28717131 TI - Lactobacillus acidophilus/Bifidobacterium infantis probiotics are associated with increased growth of VLBWI among those exposed to antibiotics. AB - We performed an observational study with very-low-birth weight infants (VLBWI) <=33 weeks of gestation born in centers of the German Neonatal Network (GNN; (total n = 8534, n = 6229 received probiotics). The primary objectives of our study were (a) to assess the effect of Lactobacillus acidophilus/Bifidobacterium infantis probiotics on growth in VLBWI during primary stay in hospital and (b) to determine whether this effect is modified by antibiotic exposure. In linear regression models the administration of probiotics was independently associated with improved weight gain [g/d; effect size B = 0.62 (95% CI: 0.37-0.87), p < 0.001], and higher growth rates for body length [(mm/d; B = 0.06 (95% CI: 0.04 0.08), p < 0.001] and head circumference [mm/d; B = 0.03, 95% CI: 0.02-0.04, p < 0.001]. This effect was pronounced in infants with postnatal exposure to antibiotics; i.e. weight gain [g/d; B = 0.66 (95% CI: 0.32-1), p < 0.001], growth rate body length [(mm/d; B = 0.09 (95% CI: 0.06-0.12), p < 0.001] and head circumference [mm/d; B = 0.04, 95% CI: 0.02-0.06, p < 0.001]. In the small subgroup that was available for analysis at 5-year-follow-up (with probiotics: n = 120 vs. without probiotics: n = 54) we noted a sustained effect of probiotics in infants who received postnatal antibiotics. Probiotics may improve growth in antibiotic-treated infants which needs to be confirmed in randomized-controlled trials. PMID- 28717132 TI - Fiber cavities with integrated mode matching optics. AB - In fiber based Fabry-Perot Cavities (FFPCs), limited spatial mode matching between the cavity mode and input/output modes has been the main hindrance for many applications. We have demonstrated a versatile mode matching method for FFPCs. Our novel design employs an assembly of a graded-index and large core multimode fiber directly spliced to a single mode fiber. This all-fiber assembly transforms the propagating mode of the single mode fiber to match with the mode of a FFPC. As a result, we have measured a mode matching of 90% for a cavity length of ~400 MUm. This is a significant improvement compared to conventional FFPCs coupled with just a single mode fiber, especially at long cavity lengths. Adjusting the parameters of the assembly, the fundamental cavity mode can be matched with the mode of almost any single mode fiber, making this approach highly versatile and integrable. PMID- 28717133 TI - Insulin upregulates betatrophin expression via PI3K/Akt pathway. AB - Betatrophin is regarded as a liver-produced hormone induced by insulin resistance (IR). However, it remains largely unknown how IR regulates betatrophin expression. To study whether IR could regulate betatrophin expression and the corresponding molecular mechanisms, betatrophin levels were examined in 6 in vitro IR models which were established using human hepatocytes L02 with different agents, including tumor necrosis factor-alpha, interleukin-1beta, dexamethasone, palmitate, high glucose and insulin and betatrophin levels were elevated only in the insulin group. These results suggest that it is insulin, not IR that promotes betatrophin expression. In the meantime, PI3K/Akt pathway was activated by insulin and suppressed by above agents that caused IR. Insulin-upregulated betatrophin expression was suppressed by PI3K/Akt inhibitors and IR, suggesting that insulin upregulates and IR decreases betatrophin production through PI3K/Akt pathway. Consistently, the treatment of insulin in mice dose-dependently upregulated betatrophin levels, and the administration of metformin in IR mice also stimulated betatrophin production since published study showed metformin improved PI3K/Akt pathway and IR. In humans, compared with those without insulin treatment, serum betatrophin levels were increased in type 2 diabetic patients with insulin treatment. In conclusion, insulin stimulates betatrophin secretion through PI3K/Akt pathway and IR may play an opposite role. PMID- 28717134 TI - Ash production by attrition in volcanic conduits and plumes. AB - Tephra deposits result from explosive volcanic eruption and serve as indirect probes into fragmentation processes operating in subsurface volcanic conduits. Primary magmatic fragmentation creates a population of pyroclasts through volatile-driven decompression during conduit ascent. In this study, we explore the role that secondary fragmentation, specifically attrition, has in transforming primary pyroclasts upon transport in volcanic conduits and plumes. We utilize total grain size distributions from a suite of natural and experimentally produced tephra to show that attrition is likely to occur in all explosive volcanic eruptions. Our experimental results indicate that fine ash production and surface area generation is fast (<15 min) thereby rapidly raising the fractal dimension of tephra deposits. Furthermore, a new metric, the Entropy of Information, is introduced to quantify the degree of attrition (secondary fragmentation) from grain size data. Attrition elevates fine ash production which, in turn, has consequences for eruption column stability, tephra dispersal, aggregation, volcanic lightening generation, and has concomitant effects on aviation safety and Earth's climate. PMID- 28717135 TI - Projection of American dustiness in the late 21st century due to climate change. AB - Climate models project rising drought risks over the southwestern and central U.S. in the twenty-first century due to increasing greenhouse gases. The projected drier regions largely overlay the major dust sources in the United States. However, whether dust activity in U.S. will increase in the future is not clear, due to the large uncertainty in dust modeling. This study found that changes of dust activity in the U.S. in the recent decade are largely associated with the variations of precipitation, soil bareness, and surface winds speed. Using multi-model output under the Representative Concentration Pathways 8.5 scenario, we project that climate change will increase dust activity in the southern Great Plains from spring to fall in the late half of the twenty-first century - largely due to reduced precipitation, enhanced land surface bareness, and increased surface wind speed. Over the northern Great Plains, less dusty days are expected in spring due to increased precipitation and reduced bareness. Given the large negative economic and societal consequences of severe dust storms, this study complements the multi-model projection on future dust variations and may help improve risk management and resource planning. PMID- 28717137 TI - Phonon Surface Scattering and Thermal Energy Distribution in Superlattices. AB - Thermal transport at small length scales has attracted significant attention in recent years and various experimental and theoretical methods have been developed to establish the reduced thermal conductivity. The fundamental understanding of how phonons move and the physical mechanisms behind nanoscale thermal transport, however, remains poorly understood. Here we move beyond thermal conductivity calculations and provide a rigorous and comprehensive physical description of thermal phonon transport in superlattices by solving the Boltzmann transport equation and using the Beckman-Kirchhoff surface scattering theory with shadowing to precisely describe phonon-surface interactions. We show that thermal transport in superlattices can be divided in two different heat transport modes having different physical properties at small length scales: layer-restricted and extended heat modes. We study how interface conditions, periodicity, and composition can be used to manipulate the distribution of thermal energy flow among such layer-restricted and extended heat modes. From predicted frequency and mean free path spectra of superlattices, we also investigate the existence of wave effects. The results and insights in this paper advance the fundamental understanding of heat transport in superlattices and the prospects of rationally designing thermal systems with tailored phonon transport properties. PMID- 28717136 TI - Association Of Plasma And Urinary Mutant DNA With Clinical Outcomes In Muscle Invasive Bladder Cancer. AB - Muscle Invasive Bladder Cancer (MIBC) has a poor prognosis. Whilst patients can achieve a 6% improvement in overall survival with Neo-Adjuvant Chemotherapy (NAC), many do not respond. Body fluid mutant DNA (mutDNA) may allow non-invasive identification of treatment failure. We collected 248 liquid biopsy samples including plasma, cell pellet (UCP) and supernatant (USN) from spun urine, from 17 patients undergoing NAC. We assessed single nucleotide variants and copy number alterations in mutDNA using Tagged-Amplicon- and shallow Whole Genome- Sequencing. MutDNA was detected in 35.3%, 47.1% and 52.9% of pre-NAC plasma, UCP and USN samples respectively, and urine samples contained higher levels of mutDNA (p = <0.001). Longitudinal mutDNA demonstrated tumour evolution under the selective pressure of NAC e.g. in one case, urine analysis tracked two distinct clones with contrasting treatment sensitivity. Of note, persistence of mutDNA detection during NAC predicted disease recurrence (p = 0.003), emphasising its potential as an early biomarker for chemotherapy response. PMID- 28717138 TI - Airborne Bacterial Communities in Three East Asian Cities of China, South Korea, and Japan. AB - The global diversity of airborne bacteria has not yet been studied, despite its importance in human health and climate change. Here, we focused on the diversity of airborne bacteria and their correlations with meteorological/environmental conditions in China, South Korea, and Japan. Beijing (China) had more diverse airborne bacteria, followed by Seoul (South Korea) and Nagasaki (Japan), and seasonal variations were observed. Beijing and Seoul had more diverse airborne bacteria during the winter, whereas Nagasaki showed greater diversity during the summer. According to principal component analysis and Bray-Curtis similarity, higher similarity was observed between Beijing and Seoul than between Seoul and Nagasaki during all seasons except summer. Among meteorological/environmental variables, temperature and humidity were highly correlated with the diversity of airborne bacteria on the measurement day, whereas wind speeds and the frequency of northwest winds were highly correlated for 2-3-day moving averages. Thus, proximity and resuspension could enhance bacterial diversity in East Asian cities. PMID- 28717139 TI - Relationship between Retinal Inner Nuclear Layer Thickness and Severity of Visual Field Loss in Glaucoma. AB - Glaucoma is a disease characterized by pathologic changes in inner retinal layers, which are comprised of retinal ganglion cells (RGCs). As retinal ganglion cells (RGCs) cross over other retinal neurons that are connected by synapses, it is meaningful to investigate the outer retinal changes in glaucoma. We evaluated the association between thicknesses of segmented retinal layers in macular region and severity of visual field loss in open-angle glaucoma (OAG). This study involved 103 glaucomatous eyes. Retinal nerve fiber layer (RNFL), ganglion cell layer (GCL), inner plexiform layer (IPL), inner nuclear layer (INL), outer plexiform layer (OPL), and outer nuclear layer (ONL) thicknesses were measured at the macular level using the Spectral-domain optical coherence tomography with segmentation software. The functional losses were measured using 24-2 standard automated perimetry. Macular structure losses were positively correlated with functional loss for RNFL, GCL, and IPL (R = 0.550, 0.637, and 0.649, respectively, P < 0.001) and negatively correlated with INL (R = -0.295, P = 0.041). By multivariate regression analysis, INL thickness was significantly associated with visual field mean deviation (dB) and optic disc hemorrhage. These finding carefully suggest reactive responses of neuronal or glial cells located in the INL occur during glaucoma progression. PMID- 28717140 TI - Common variants of T-cells contribute differently to phenotypic variation in sarcoidosis. AB - The involvement of the immune system, particularly the role of T-cells, in sarcoidosis is unclear. The existence of higher CD4+ T-cells and increased CD4/CD8 ratio may indicate a pathogenic role of T-cells in the disease. In this study, we quantified the contribution of T-cells associated variants and of CD4/CD8 ratio in sarcoidosis phenotypes, Lofgren's syndrome (LS) and non- Lofgren's syndrome (non-LS). We employed a polygenic-based approach using genome wide association studies results on relative levels of T-cells in healthy individuals to measure the genetic contribution of T-cells in sarcoidosis entities. Results revealed that the genetic architecture of LS is highly influenced by genetic variants associated with CD8+ T-cells and CD4/CD8 ratio, explaining up to 7.94% and 6.49% of LS variation, respectively; whereas, the genetic architecture of non-LS is minimally influenced by T-cells, explaining a phenotypic variation of <1%. Moreover, pleiotropy assessment between T-cells and LS/non-LS associated-variants led to the discovery of highly scored pathway maps that shared common factors related to antigen presentation and T-cell regulatory mechanisms. Differences in significant polygenic scores, presence of pleiotropy, and distinct genetic factors provide further insights on how genetic variants and genes associated with relative levels of T-cell subtypes contribute differently to sarcoidosis phenotypes. PMID- 28717141 TI - Children's first handwriting productions show a rhythmic structure. AB - Although much research has been concerned with the development of kinematic aspects of handwriting, little is known about the development along with age of two principles that govern its rhythmic organization: Homothety and Isochrony. Homothety states that the ratio between the durations of the single motor events composing a motor act remains invariant and independent from the total duration of the movement. Isochrony refers to the proportional relationship between the speed of movement execution and the length of its trajectory. The current study shows that children comply with both principles since their first grade of primary school. The precocious adherence to these principles suggests that an internal representation of the rhythm of handwriting is available before the age in which handwriting is performed automatically. Overall, these findings suggest that despite being a cultural acquisition, handwriting appears to be shaped by more general constraints on the timing planning of the movements. PMID- 28717142 TI - Photonic Needles for Light Delivery in Deep Tissue-like Media. AB - We demonstrate a new platform for minimally invasive, light delivery probes leveraging the maturing field of silicon photonics, enabling massively parallel fabrication of photonic structures. These Photonic Needles probes have sub-10 MUm cross-sectional dimensions, lengths greater than 3 mm-surpassing 1000 to 1 aspect ratio, and are released completely into air without a substrate below. We show the Photonic Needles to be mechanically robust when inserted into 2% agarose. The propagation loss of these waveguides is low-on the order of 4 dB/cm. PMID- 28717143 TI - Fish oil supplementation to rats fed high-fat diet during pregnancy prevents development of impaired insulin sensitivity in male adult offspring. AB - We examined whether maternal fish oil supplementation during pregnancy could prevent development of insulin resistance in adult male offspring of rat dams fed a high-fat diet. Time-mated Sprague-Dawley rat dams were randomised into four treatment groups: Con-Con, dams fed a control diet (fat: 15% kcal) and administered water by gavage; Con-FO, control diet with unoxidised fish oil by gavage; HF-Con, high-fat diet (fat: 45% kcal) and water by gavage; and HF-FO, high-fat diet and unoxidised fish oil by gavage. Dams were fed the allocated diet ad libitum during pregnancy and lactation, but daily gavage occurred only during pregnancy. After weaning, male offspring consumed a chow diet ad libitum until adulthood. Maternal high-fat diet led to increased food consumption, adiposity, systolic blood pressure, and triglycerides and plasma leptin in adult HF-Con offspring. HF-Con offspring also exhibited lower insulin sensitivity than Con-Con rats. Male offspring from HF-FO group were similar to HF-Con regarding food consumption and most metabolic parameters. However, insulin sensitivity in the HF FO group was improved relative to the HF-Con offspring. Supplementation with unoxidised n-3 PUFA rich oils in the setting of a maternal obesogenic diet improved insulin sensitivity, but had no impact on body composition of adult male offspring. PMID- 28717144 TI - RADseq provides evidence for parallel ecotypic divergence in the autotetraploid Cochlearia officinalis in Northern Norway. AB - Speciation encompasses a continuum over time from freely interbreeding populations to reproductively isolated species. Along this process, ecotypes - the result of local adaptation - may be on the road to new species. We investigated whether three autotetraploid Cochlearia officinalis ecotypes, adapted to different habitats (beach, estuary, spring), are genetically differentiated and result from parallel ecotypic divergence in two distinct geographical regions. We obtained genetic data from thousands of single nucleotide polymorphisms (SNPs) from restriction-site associated DNA sequencing (RADseq) and from six microsatellite markers for 12 populations to assess genetic divergence at ecotypic, geographic and population level. The genetic patterns support differentiation among ecotypes as suggested by morphology and ecology. The data fit a scenario where the ancestral beach ecotype has recurrently and polytopically given rise to the estuary and spring ecotypes. Several ecologically relevant loci with consistent non-random segregating patterns are identified across the recurrent origins, in particular around genes related to salt stress. Despite being ecologically distinct, the Cochlearia ecotypes still represent an early stage in the process of speciation, as reproductive isolation has not (yet) developed. A sequenced annotated genome is needed to specifically target candidate genes underlying local adaptation. PMID- 28717145 TI - Acetylsalicylic acid differentially limits the activation and expression of cell death markers in human platelets exposed to Staphylococcus aureus strains. AB - Beyond their hemostatic functions, platelets alter their inflammatory response according to the bacterial stimulus. Staphylococcus aureus is associated with exacerbated inflammation and thrombocytopenia, which is associated with poor prognosis during sepsis. Acetylsalicylic acid and statins prevent platelet aggregation and decrease the mortality rate during sepsis. Therefore, we assessed whether these two molecules could reduce in vitro platelet activation and the inflammatory response to S. aureus. Platelets were exposed to clinical strains of S. aureus in the presence or absence of acetylsalicylic acid or fluvastatin. Platelet activation, aggregation, and release of soluble sCD62P, sCD40 Ligand, RANTES and GROalpha were assessed. Platelet cell death was evaluated by analyzing the mitochondrial membrane potential, phosphatidylserine exposure, platelet microparticle release and caspase-3 activation. All S. aureus strains induced platelet activation but not aggregation and decreased the platelet count, the expression of cell death markers and the release of RANTES and GROalpha. Acetylsalicylic acid but not fluvastatin limited platelet activation and inflammatory factor release and restored the platelet count by protecting platelets from Staphylococcus-induced expression of cell death markers. This study demonstrates that acetylsalicylic acid limits S. aureus-induced effects on platelets by reducing cell death, revealing new strategies to reduce the platelet contribution to bacteremia-associated inflammation. PMID- 28717147 TI - Information processing in patterned magnetic nanostructures with edge spin waves. AB - Low dissipation data processing with spins is one of the promising directions for future information and communication technologies. Despite a significant progress, the available magnonic devices are not broadband yet and have restricted capabilities to redirect spin waves. Here we propose a breakthrough approach to spin wave manipulation in patterned magnetic nanostructures with unmatched characteristics, which exploits a spin wave analogue to edge waves propagating along a water-wall boundary. Using theory, micromagnetic simulations and experiment we investigate spin waves propagating along the edges in magnetic structures, under an in-plane DC magnetic field inclined with respect to the edge. The proposed edge spin waves overcome important challenges faced by previous technologies such as the manipulation of the spin wave propagation direction, and they substantially improve the capability of transmitting information at frequencies exceeding 10 GHz. The concept of the edge spin waves allows to design a broad of logic devices such as splitters, interferometers, or edge spin wave transistors with unprecedented characteristics and a potentially strong impact on information technologies. PMID- 28717146 TI - Concise and Stereodivergent Synthesis of Carbasugars Reveals Unexpected Structure Activity Relationship (SAR) of SGLT2 Inhibition. AB - Carbasugar sodium-glucose cotransporter 2 (SGLT2) inhibitors are highly promising drug candidates for the treatment of Type 2 diabetes mellitus (T2DM). However, the clinical usage of carbasugar SGLT2 inhibitors has been underexplored, due to the lengthy synthetic routes and the lack of structure-activity relationship (SAR) studies of these compounds. Herein, we report a concise and stereodivergent synthetic route towards some novel carbasugar SGLT2 inhibitors, featuring an underexploited, regioselective, and stereospecific palladium-catalyzed allyl-aryl coupling reaction. This synthetic strategy, together with computational modeling, revealed the unexpected SAR of these carbasugar SGLT2 inhibitors, and enabled the discovery of a highly selective and potent SGLT2 inhibitor. PMID- 28717148 TI - Human ribosomal P1-P2 heterodimer represents an optimal docking site for ricin A chain with a prominent role for P1 C-terminus. AB - The eukaryotic P-stalk contains two P1-P2 protein dimers with a conserved C- terminal domain (CTD) critical for the interaction with external factors. To understand the role of the individual CTD of human P1/P2 proteins, we examined the interaction of reconstituted human P-protein complexes and C-terminally truncated forms with ricin A chain (RTA), which binds to the stalk to depurinate the sarcin/ricin loop (SRL). The interaction between P-protein complexes and RTA was examined by surface plasmon resonance, isothermal titration calorimetry, microscale thermophoresis and bio-layer interferometry. The P1-P2 heterodimer missing a CTD on P2 was able to bind RTA. In contrast, the P1-P2 heterodimer missing the CTD of P1 protein displayed almost no binding toward RTA. Very low interaction was detected between RTA and the non-truncated P2-P2 homodimer, suggesting that the structural architecture of the P1-P2 heterodimer is critical for binding RTA. The reconstituted pentameric human stalk complex had higher affinity for RTA than the P1-P2 dimer. Deletion of P1 CTD, but not P2 CTD reduced the affinity of the pentamer for RTA. These results highlight the importance of the heterodimeric organization of P1-P2 in the human stalk pentamer and functional non-equivalence of the individual P-protein CTDs in the interaction with RTA. PMID- 28717149 TI - Transcriptome Analysis of Rice Seedling Roots in Response to Potassium Deficiency. AB - Rice is one of the most important food crops in the world, and its growth, development, yield, and grain quality are susceptible to a deficiency of the macronutrient potassium (K+). The molecular mechanism for K+ deficiency tolerance remains poorly understood. In this study, K+ deficient conditions were employed to investigate the resulting changes in the transcriptome of rice seedling roots. Using ribonucleic acid sequencing (RNA-Seq) and analysis, a total of 805 differentially expressed genes were obtained, of which 536 genes were upregulated and 269 were downregulated. Gene functional classification showed that the expression of genes involved in nutrient transport, protein kinases, transcription processes, and plant hormones were particularly altered in the roots. Although these changes were significant, the expression of most genes remained constant even in K+-deficient conditions. Interestingly, when our RNA Seq results were compared to public microarray data, we found that most of the genes that were differentially expressed in low K+ conditions also exhibited changes in expression in other environmental stress conditions. PMID- 28717150 TI - A comparison of traditional and novel metrics to quantify resistance training. AB - Common estimates of external training intensity for resistance exercise do not incorporate inter-set recovery duration, and might not reflect the overall demands of training. This study aimed to assess novel metrics of exercise density (ED) during resistance exercise, and how these related to a physiological marker of internal training intensity as well as traditional measures of external training intensity and volume. Thirteen males and seven females performed two bouts of resistance exercise focused on developing strength (5 sets of 5 repetitions with 5-repetition maximum; 180 s recovery) and hypertrophy (3 sets of 10 repetitions with 10-repetition maximum; 60 s recovery). Blood lactate concentration was measured to quantify internal training intensity. Specific metrics of external volume (mechanical work, volume load and total repetitions) and intensity (average weight lifted and ED) were calculated. Despite lower average weights and no difference in mechanical work or volume load, blood lactate was greater following hypertrophy compared with the strength condition. This finding was consistent with higher measures of ED in the hypertrophy compared with the strength condition. Greater ED during hypertrophy resistance exercise, along with the significant association with changes in blood lactate, indicates that ED metrics are reflective of the sessional intensity for resistance exercise. PMID- 28717151 TI - What drives sound symbolism? Different acoustic cues underlie sound-size and sound-shape mappings. AB - Sound symbolism refers to the non-arbitrary mappings that exist between phonetic properties of speech sounds and their meaning. Despite there being an extensive literature on the topic, the acoustic features and psychological mechanisms that give rise to sound symbolism are not, as yet, altogether clear. The present study was designed to investigate whether different sets of acoustic cues predict size and shape symbolism, respectively. In two experiments, participants judged whether a given consonant-vowel speech sound was large or small, round or angular, using a size or shape scale. Visual size judgments were predicted by vowel formant F1 in combination with F2, and by vowel duration. Visual shape judgments were, however, predicted by formants F2 and F3. Size and shape symbolism were thus not induced by a common mechanism, but rather were distinctly affected by acoustic properties of speech sounds. These findings portray sound symbolism as a process that is not based merely on broad categorical contrasts, such as round/unround and front/back vowels. Rather, individuals seem to base their sound-symbolic judgments on specific sets of acoustic cues, extracted from speech sounds, which vary across judgment dimensions. PMID- 28717152 TI - Effects of Population Bottleneck and Balancing Selection on the Chinese Alligator Are Revealed by Locus-Specific Characterization of MHC Genes. AB - Chinese alligator (Alligator sinensis) is an endangered freshwater crocodilian endemic to China, which experienced a severe bottleneck about 30 years ago. In this study, we developed locus-specific primers to investigate the polymorphism of 3 major histocompatibility complex (MHC) loci in 3 Chinese alligator populations, in combination with 6 neutral microsatellite markers as a contrast. We found the genetic trace for the bottleneck effect on the endangered Chinese alligator: the low allelic diversity (2 alleles at each locus), the low nucleotide substitution rate (no more than 0.009) at all sites, the deviation from Hardy-Weinberg Equilibrium/heterozygote deficiency, and the significant Tajima's D values, indicating the MHC class I and class II loci being at different stages of bottleneck. We also obtained 3 pieces of evidence for balancing selection on this severely bottlenecked reptile: an obvious excess of nonsynonymous substitutions over synonymous at the antigen-binding positions, the mean synonymous substitution rate of MHC exons significantly higher than mean nucleotide substitution rate of introns, and the differentiation coefficient F ST of MHC loci significantly lower than that of microsatellite loci. Consequently, we emphasize that the Chinese alligator holds a pretty low adaptive ability and requires scientific conservation strategies to ensure the long-term population development. PMID- 28717153 TI - Proton Pump Inhibitors and the Risk for Fracture at Specific Sites: Data Mining of the FDA Adverse Event Reporting System. AB - Proton pump inhibitors (PPIs) are widely used to treat gastric acid-related disorders. Concerns have been raised about potential fracture risk, especially at the hip, spine and wrist. However, fracture risk at other bone sites has not been as well studied. We investigated the association between PPIs and specific fracture sites using an aggregated knowledge-enhanced database, the Food and Drug Administration Adverse Event Reporting System Data Mining Set (AERS-DM). Proportional reporting ratio (PRR) was used to detect statistically significant associations (signals) between PPIs and fractures. We analyzed both high level terms (HLT) and preferred terms (PT) for fracture sites, defined by MedDRA (Medical Dictionary for Regulatory Activities). Of PPI users reporting fractures, the mean age was 65.3 years and the female to male ratio was 3.4:1. Results revealed signals at multiple HLT and PT fracture sites, consistent for both sexes. These included fracture sites with predominant trabecular bone, not previously reported as being associated with PPIs, such as 'rib fractures', where signals were detected for overall PPIs as well as for each of 5 generic ingredients (insufficient data for dexlansoprazole). Based on data mining from AERS-DM, PPI use appears to be associated with an increased risk for fractures at multiple sites. PMID- 28717154 TI - Thermal Diffusivity Mapping of Graphene Based Polymer Nanocomposites. AB - Nanoparticle dispersion is widely recognised as a challenge in polymer nanocomposites fabrication. The dispersion quality can affect the physical and thermomechanical properties of the material system. Qualitative transmission electronic microscopy, often cumbersome, remains as the 'gold standard' for dispersion characterisation. However, quantifying dispersion at macroscopic level remains a difficult task. This paper presents a quantitative dispersion characterisation method using non-contact infrared thermography mapping that measures the thermal diffusivity (alpha) of the graphene nanocomposite and relates alpha to a dispersion index. The main advantage of the proposed method is its ability to evaluate dispersion over a large area at reduced effort and cost, in addition to measuring the thermal properties of the system. The actual resolution of this thermal mapping reaches 200 um per pixel giving an accurate picture of graphene nanoplatelets (GNP) dispersion. The post-dispersion treatment shows an improvement in directional thermal conductivity of the composite of up to 400% increase at 5 wt% of GNP. The Maxwell-Garnet effective medium approximation is proposed to estimate thermal conductivity that compare favourably to measured data. The development of a broadly applicable dispersion quantification method will provide a better understanding of reinforcement mechanisms and effect on performance of large scale composite structures. PMID- 28717155 TI - Neighbor-Neighbor Correlations Explain Measurement Bias in Networks. AB - In numerous physical models on networks, dynamics are based on interactions that exclusively involve properties of a node's nearest neighbors. However, a node's local view of its neighbors may systematically bias perceptions of network connectivity or the prevalence of certain traits. We investigate the strong friendship paradox, which occurs when the majority of a node's neighbors have more neighbors than does the node itself. We develop a model to predict the magnitude of the paradox, showing that it is enhanced by negative correlations between degrees of neighboring nodes. We then show that by including neighbor neighbor correlations, which are degree correlations one step beyond those of neighboring nodes, we accurately predict the impact of the strong friendship paradox in real-world networks. Understanding how the paradox biases local observations can inform better measurements of network structure and our understanding of collective phenomena. PMID- 28717156 TI - Patterned Arrangements of Olfactory Receptor Gene Expression in Zebrafish are Established by Radial Movement of Specified Olfactory Sensory Neurons. AB - Spatial restriction of olfactory receptor (OR) gene expression in peripheral sense organs is a common phenomenon across species, suggesting that zonal OR expression somehow contributes to olfactory function. In zebrafish OR expression patterns reminiscent of zones occur as concentric domains with preferred diameters for different ORs. However, the function and the developmental origin of the pattern are unknown. Here we investigate olfactory sensory neuron (OSN) neurogenesis in the adult zebrafish olfactory epithelium (OE) to understand how the zonally organized OR pattern is established and maintained during the lifetime of the animal. We find that OSNs are generated from two discontinuous proliferation zones located at the central and peripheral edge of the sensory OE. OSNs turn on OR expression soon after they exit mitosis and invade the sensory tissue, approaching each other from both ends of the OE. Biased generation of OSN subpopulations at both neurogenic sites and elimination of OSNs along their route across the OE generates the impression of OR-specific expression domains. We formulated a simple mathematical model based on exact parameters derived from our analysis of OSN neurogenesis, which accurately generates OR-like distributions without the need to invoke molecular signals to pattern the OE. PMID- 28717157 TI - Cellular uptake pathways of sepiolite nanofibers and DNA transfection improvement. AB - Sepiolite is a nanofibrous natural silicate that can be used as a nanocarrier because it can be naturally internalized into mammalian cells, due to its nano size dimension. Therefore, deciphering the mechanisms of sepiolite cell internalization constitutes a question interesting biotechnology, for the use of sepiolite as nanocarrier, as well as environmental and public health concerns. Though it is low, the perfectly stable and natural intrinsic fluorescence of sepiolite nanofibers allows to follow their fate into cells by specifically sensitive technics. By combining fluorescence microscopy (including confocal analysis), time-lapse video microscopy, fluorescence activated cell sorting and transmission electron microscopy, we show that sepiolite can be spontaneously internalized into mammalian cells through both non-endocytic and endocytic pathways, macropinocytosis being one of the main pathways. Interestingly, exposure of the cells to endocytosis inhibitors, such as chloroquine, two-fold increase the efficiency of sepiolite-mediated gene transfer, in addition to the 100-fold increased resulting from sepiolite sonomechanical treatment. As sepiolite is able to bind various biological molecules, this nanoparticulate silicate could be a good candidate as a nanocarrier for simultaneous vectorization of diverse biological molecules. PMID- 28717158 TI - Neural processing of biological motion in autism: An investigation of brain activity and effective connectivity. AB - The superior temporal sulcus (STS) forms a key region for social information processing and disruptions of its function have been associated with socio communicative impairments characteristic of autism spectrum disorders (ASD). Task based fMRI was applied in 15 adults with ASD and 15 matched typical-controls (TC) to explore differences in activity and effective connectivity of STS while discriminating either 'intact' versus 'scrambled' biological motion point light displays (explicit processing) or responding to a color-change while the 'intact' versus 'scrambled' nature of the stimulus was irrelevant for the task (implicit processing). STS responded stronger to 'intact' than 'scrambled' stimuli in both groups, indicating that the basic encoding of 'biological' versus 'non biological' motion seems to be intact in ASD. Only in the TC-group however, explicit attention to the biological motion content induced an augmentation of STS-activity, which was not observed in the ASD-group. Overall, these findings suggest an inadequacy to recruit STS upon task demand in ASD, rather than a generalized alteration in STS neural processing. The importance of attention orienting for recruiting relevant neural resources was further underlined by the observation that connectivity between STS and medial prefrontal cortex (mPFC), a key region in attention regulation, effectively modulated STS-recruitment in the ASD-group. PMID- 28717160 TI - Differential electron emission from polycyclic aromatic hydrocarbon molecules under fast ion impact. AB - Interaction between polycyclic aromatic hydrocarbon (PAH) molecule and energetic ion is a subject of interest in different areas of modern physics. Here, we present measurements of energy and angular distributions of absolute double differential electron emission cross section for coronene (C24H12) and fluorene (C13H10) molecules under fast bare oxygen ion impact. For coronene, the angular distributions of the low energy electrons are quite different from that of simpler targets like Ne or CH4, which is not the case for fluorene. The behaviour of the higher electron energy distributions for both the targets are similar to that for simple targets. In case of coronene, a clear signature of plasmon resonance is observed in the analysis of forward-backward angular asymmetry of low energy electron emission. For fluorene, such signature is not identified probably due to lower oscillator strength of plasmon compared to the coronene. The theoretical calculation based on the first-order Born approximation with correct boundary conditions (CB1), in general, reproduced the experimental observations qualitatively, for both the molecules, except in the low energy region for coronene, which again indicates the role of collective excitation. Single differential and total cross sections are also deduced. An overall comparative study is presented. PMID- 28717159 TI - The essential genomic landscape of the commensal Bifidobacterium breve UCC2003. AB - Bifidobacteria are common gut commensals with purported health-promoting effects. This has encouraged scientific research into bifidobacteria, though recalcitrance to genetic manipulation and scarcity of molecular tools has hampered our knowledge on the precise molecular determinants of their health-promoting attributes and gut adaptation. To overcome this problem and facilitate functional genomic analyses in bifidobacteria, we created a large Tn5 transposon mutant library of the commensal Bifidobacterium breve UCC2003 that was further characterized by means of a Transposon Directed Insertion Sequencing (TraDIS) approach. Statistical analysis of transposon insertion distribution revealed a set of 453 genes that are essential for or markedly contribute to growth of this strain under laboratory conditions. These essential genes encode functions involved in the so-called bifid-shunt, most enzymes related to nucleotide biosynthesis and a range of housekeeping functions. Comparison to the Bifidobacterium and B. breve core genomes highlights a high degree of conservation of essential genes at the species and genus level, while comparison to essential gene datasets from other gut bacteria identified essential genes that appear specific to bifidobacteria. This work establishes a useful molecular tool for scientific discovery of bifidobacteria and identifies targets for further studies aimed at characterizing essential functions not previously examined in bifidobacteria. PMID- 28717161 TI - Development and Characterization of A Novel Prox1-EGFP Lymphatic and Schlemm's Canal Reporter Rat. AB - The lymphatic system plays a key role in tissue fluid homeostasis, immune cell trafficking, and fat absorption. We previously reported a bacterial artificial chromosome (BAC)-based lymphatic reporter mouse, where EGFP is expressed under the regulation of the Prox1 promoter. This reporter line has been widely used to conveniently visualize lymphatic vessels and other Prox1-expressing tissues such as Schlemm's canal. However, mice have a number of experimental limitations due to small body size. By comparison, laboratory rats are larger in size and more closely model the metabolic, physiological, and surgical aspects of humans. Here, we report development of a novel lymphatic reporter rat using the mouse Prox1 EGFP BAC. Despite the species mismatch, the mouse Prox1-EGFP BAC enabled a reliable expression of EGFP in Prox1-expressing cells of the transgenic rats and allowed a convenient visualization of all lymphatic vessels, including those in the central nervous system, and Schlemm's canal. To demonstrate the utility of this new reporter rat, we studied the contractile properties and valvular functions of mesenteric lymphatics, developed a surgical model for vascularized lymph node transplantation, and confirmed Prox1 expression in venous valves. Together, Prox1-EGFP rat model will contribute to the advancement of lymphatic research as a valuable experimental resource. PMID- 28717162 TI - Ultra-low threshold polariton lasing at room temperature in a GaN membrane microcavity with a zero-dimensional trap. AB - Polariton lasers are coherent light sources based on the condensation of exciton polaritons in semiconductor microcavities, which occurs either in the kinetic or thermodynamic (Bose-Einstein) regime. Besides their fundamental interest, polariton lasers have the potential of extremely low operating thresholds. Here, we demonstrate ultra-low threshold polariton lasing at room temperature, using an all-dielectric, GaN membrane-based microcavity, with a spontaneously-formed zero dimensional trap. The microcavity is fabricated using an innovative method, which involves photo-electrochemical etching of an InGaN sacrificial layer and allows for the incorporation of optimally-grown GaN active quantum wells inside a cavity with atomically-smooth surfaces. The resulting structure presents near theoretical Q-factors and pronounced strong-coupling effects, with a record-high Rabi splitting of 64 meV at room-temperature. Polariton lasing is observed at threshold carrier densities 2.5 orders of magnitude lower than the exciton saturation density. Above threshold, angle-resolved emission spectra reveal an ordered pattern in k-space, attributed to polariton condensation at discrete levels of a single confinement site. This confinement mechanism along with the high material and optical quality of the microcavity, accounts for the enhanced performance of our polariton laser, and pave the way for further developments in the area of robust room temperature polaritonic devices. PMID- 28717163 TI - Titin-mediated thick filament activation, through a mechanosensing mechanism, introduces sarcomere-length dependencies in mathematical models of rat trabecula and whole ventricle. AB - Recent experimental evidence in skeletal muscle demonstrated the existence of a thick-filament mechanosensing mechanism, acting as a second regulatory system for muscle contraction, in addition to calcium-mediated thin filament regulation. These two systems cooperate to generate force, but the extent to which their interaction is relevant in physiologically contracting muscle was not yet assessed experimentally. Therefore, we included both regulatory mechanisms in a mathematical model of rat trabecula and whole ventricle. No additional regulatory mechanisms were considered in our model. Our simulations suggested that mechanosensing regulation is not limited to the initial phases of contraction but, instead, is crucial during physiological contraction. An important consequence of this finding is that titin mediated thick filament activation can account for several sarcomere length dependencies observed in contracting muscle. Under the hypothesis that a similar mechanism is acting on cardiac muscle, and within the limits of a finite element left ventricle model, we predict that these two regulatory mechanisms are crucial for the molecular basis of the Frank Starling law of the heart. PMID- 28717164 TI - Glucagon-like peptide-1 reduces pancreatic beta-cell mass through hypothalamic neural pathways in high-fat diet-induced obese rats. AB - We examined whether glucagon-like peptide-1 (GLP-1) affects beta-cell mass and proliferation through neural pathways, from hepatic afferent nerves to pancreatic efferent nerves via the central nervous system, in high-fat diet (HFD)-induced obese rats. The effects of chronic administration of GLP-1 (7-36) and liraglutide, a GLP-1 receptor agonist, on pancreatic morphological alterations, c fos expression and brain-derived neurotrophic factor (BDNF) content in the hypothalamus, and glucose metabolism were investigated in HFD-induced obese rats that underwent hepatic afferent vagotomy (VgX) and/or pancreatic efferent sympathectomy (SpX). Chronic GLP-1 (7-36) administration to HFD-induced obese rats elevated c-fos expression and BDNF content in the hypothalamus, followed by a reduction in pancreatic beta-cell hyperplasia and insulin content, thus resulting in improved glucose tolerance. These responses were abolished by VgX and SpX. Moreover, administration of liraglutide similarly activated the hypothalamic neural pathways, thus resulting in a more profound amelioration of glucose tolerance than native GLP-1 (7-36). These data suggest that GLP-1 normalizes the obesity-induced compensatory increase in beta-cell mass and glucose intolerance through a neuronal relay system consisting of hepatic afferent nerves, the hypothalamus, and pancreatic efferent nerves. PMID- 28717165 TI - Fabricating fast triggered electro-active shape memory graphite/silver nanowires/epoxy resin composite from polymer template. AB - In recent years shape-memory polymers have been under intense investigation due to their unique mechanical, thermal, and electrical properties that could potentially make them extremely valuable in numerous engineering applications. In this manuscript, we report a polymer-template-assisted assembly manufacturing strategy used to fabricate graphite/silver nanowires/epoxy resin (PGSE) composite. In the proposed method, the porous polymer foams work as the skeleton by forming three-dimensional graphite structure, whereas the silver nanowires act as the continuous conductive network. Preliminary testing on hybrid foams after vacuum infusion showed high electrical conductivity and excellent thermal stability. Furthermore, the composites were found to recover their original shape within 60 seconds from the application of a 0.8 V mm-1 electric field. Notably, the reported shape-memory polymer composites are manufactured with readily available raw materials, they are fast to manufacture, and are shape-controlled. PMID- 28717166 TI - Targeting Cellular Calcium Homeostasis to Prevent Cytokine-Mediated Beta Cell Death. AB - Pro-inflammatory cytokines are important mediators of islet inflammation, leading to beta cell death in type 1 diabetes. Although alterations in both endoplasmic reticulum (ER) and cytosolic free calcium levels are known to play a role in cytokine-mediated beta cell death, there are currently no treatments targeting cellular calcium homeostasis to combat type 1 diabetes. Here we show that modulation of cellular calcium homeostasis can mitigate cytokine- and ER stress mediated beta cell death. The calcium modulating compounds, dantrolene and sitagliptin, both prevent cytokine and ER stress-induced activation of the pro apoptotic calcium-dependent enzyme, calpain, and partly suppress beta cell death in INS1E cells and human primary islets. These agents are also able to restore cytokine-mediated suppression of functional ER calcium release. In addition, sitagliptin preserves function of the ER calcium pump, sarco-endoplasmic reticulum Ca2+-ATPase (SERCA), and decreases levels of the pro-apoptotic protein thioredoxin-interacting protein (TXNIP). Supporting the role of TXNIP in cytokine mediated cell death, knock down of TXNIP in INS1-E cells prevents cytokine mediated beta cell death. Our findings demonstrate that modulation of dynamic cellular calcium homeostasis and TXNIP suppression present viable pharmacologic targets to prevent cytokine-mediated beta cell loss in diabetes. PMID- 28717167 TI - Spatial distribution of Qinghai spruce forests and the thresholds of influencing factors in a small catchment, Qilian Mountains, northwest China. AB - Forest restoration in dryland mountainous areas is extremely difficult due to dry climate, complex topography and accelerating climate change. Thus, exact identification of suitable sites is required. This study at a small watershed of Qilian Mountains, Northwest China, aimed to determine the important factors and their thresholds limiting the spatial distribution of forests of Qinghai spruce (Picea crassifolia), a locally dominant tree species. The watershed was divided into 342 spatial units. Their location, terrain and vegetation characteristics were recorded. Statistical analysis showed that the potential distribution area of Qinghai spruce forests is within an ellipse with the axes of elevation (from 2673.6 to 3202.2 m a.s.l.) and slope aspect (from -162.1 degrees to 75.1 degrees deviated from North). Within this ellipse, the forested sites have a soil thickness >=40 cm, and slope positions of lower-slope, lower- or middle-slope, anywhere if the elevation is <2800, 2800-2900, >2900 m a.s.l, respectively. The corresponding mean annual air temperature at upper elevation boundary is -2.69 degrees C, while the mean annual precipitation at lower elevation boundary is 374 (331) mm within the small watershed (study area). The high prediction accuracy using these 4 factors can help to identify suitable sites and increase the success of afforestation. PMID- 28717169 TI - How transfer flights shape the structure of the airline network. AB - In this paper, we analyse the gravity model in the global passenger air-transport network. We show that in the standard form, the model is inadequate for correctly describing the relationship between passenger flows and typical geo-economic variables that characterize connected countries. We propose a model for transfer flights that allows exploitation of these discrepancies in order to discover hidden subflows in the network. We illustrate its usefulness by retrieving the distance coefficient in the gravity model, which is one of the determinants of the globalization process. Finally, we discuss the correctness of the presented approach by comparing the distance coefficient to several well-known economic events. PMID- 28717168 TI - Dynamics and function of CXCR4 in formation of the granule cell layer during hippocampal development. AB - In the developing hippocampus, granule cell progenitors (GCPs) arising in the ventricular zone (VZ) migrate to the subpial region, and form the granule cell layer (GCL) of the dentate gyrus (DG). To understand the mechanism of GCL formation, we investigated the dynamics and function of CXCR4 which is expressed by the GCPs and is a receptor of the CXCL12 chemokine secreted by cells surrounding the DG. In the VZ, CXCR4 was expressed on the plasma membrane of the GCPs. During their migration and in the DG, CXCR4 was internalized and accumulated as puncta close to the centrosomes, Golgi apparatus, and lysosomes. Phosphatase analysis suggested that both phosphorylated and dephosphorylated CXCR4 exist on the plasma membrane, whereas CXCR4 in intracellular puncta was mainly dephosphorylated. Intraventricular administration of the CXCR4 antagonist AMD3100 resulted in the disappearance of CXCR4 expression from the intracellular puncta, and its appearance on the plasma membranes. Furthermore, AMD3100 treatment resulted in precocious differentiation, delayed migration, and ectopic GCPs. Taken together, these results suggest that during the development and migration of GCPs, CXCR4 on the plasma membrane is phosphorylated, internalized, sorted to the centrosomes, Golgi apparatus, and lysosomes, and functionally regulates GCP differentiation, migration and positioning. PMID- 28717170 TI - Population structure of an orchid mycorrhizal fungus with genus-wide specificity. AB - Fundamental life history processes of mycorrhizal fungi with inconspicuous fruiting bodies can be difficult to elucidate. In this study we investigated the species identities and life history of the orchid mycorrhizal Tulasnella fungi, which associate with the south eastern Australia orchid genus Chiloglottis. Tulasnella prima was the primary partner and was found to be associated with all 17 Chiloglottis species across a range of >1000 km, and to occur in the two edaphic conditions investigated (soil and sphagnum hammocks). Another Tulasnella species (T. sphagneti) appears to be restricted to moist conditions of alpine sphagnum hammocks. The population genetic structure of the widespread species T. prima, was investigated at 10 simple sequence repeat (SSR) markers and at four cross-amplified SSR loci for T. sphagneti. For both taxa, no sharing of multilocus genotypes was found between sites, but clones were found within sites. Evidence for inbreeding within T. prima was found at 3 of 5 sites. Significant genetic differentiation was found within and between taxa. Significant local positive spatial genetic autocorrelation was detected among non-clonal isolates at the scale of two metres. Overall, the population genetic patterns indicated that in Tulasnella mating occurs by inbreeding and dispersal is typically restricted to short-distances. PMID- 28717171 TI - The aspirin metabolite salicylate inhibits lysine acetyltransferases and MUC1 induced epithelial to mesenchymal transition. AB - MUC1 is a transmembrane mucin that can promote cancer progression, and its upregulation correlates with a worse prognosis in colon cancer. We examined the effects of overexpression of MUC1 in colon cancer cells, finding that it induced epithelial to mesenchymal transition (EMT), including enhanced migration and invasion, and increased Akt phosphorylation. When the clones were treated with the aspirin metabolite salicylate, Akt phosphorylation was decreased and EMT inhibited. As the salicylate motif is necessary for the activity of the lysine acetyltransferase (KAT) inhibitor anacardic acid, we hypothesized these effects were associated with the inhibition of KAT activity. This was supported by anacardic acid treatment producing the same effect on EMT. In vitro KAT assays confirmed that salicylate directly inhibited PCAF/Kat2b, Tip60/Kat5 and hMOF/Kat8, and this inhibition was likely involved in the reversal of EMT in the metastatic prostate cancer cell line PC-3. Salicylate treatment also inhibited EMT induced by cytokines, illustrating the general effect it had on this process. The inhibition of both EMT and KATs by salicylate presents a little explored activity that could explain some of the anti-cancer effects of aspirin. PMID- 28717172 TI - Evolution of the Pseudomonas aeruginosa mutational resistome in an international Cystic Fibrosis clone. AB - Emergence of epidemic clones and antibiotic resistance development compromises the management of Pseudomonas aeruginosa cystic fibrosis (CF) chronic respiratory infections. Whole genome sequencing (WGS) was used to decipher the phylogeny, interpatient dissemination, WGS mutator genotypes (mutome) and resistome of a widespread clone (CC274), in isolates from two highly-distant countries, Australia and Spain, covering an 18-year period. The coexistence of two divergent CC274 clonal lineages was revealed, but without evident geographical barrier; phylogenetic reconstructions and mutational resistome demonstrated the interpatient transmission of mutators. The extraordinary capacity of P. aeruginosa to develop resistance was evidenced by the emergence of mutations in >100 genes related to antibiotic resistance during the evolution of CC274, catalyzed by mutator phenotypes. While the presence of classical mutational resistance mechanisms was confirmed and correlated with resistance phenotypes, results also showed a major role of unexpected mutations. Among them, PBP3 mutations, shaping up beta-lactam resistance, were noteworthy. A high selective pressure for mexZ mutations was evidenced, but we showed for the first time that high-level aminoglycoside resistance in CF is likely driven by mutations in fusA1/fusA2, coding for elongation factor G. Altogether, our results provide valuable information for understanding the evolution of the mutational resistome of CF P. aeruginosa. PMID- 28717173 TI - Liquid-phase sequence capture and targeted re-sequencing revealed novel polymorphisms in tomato genes belonging to the MEP carotenoid pathway. AB - Tomato (Solanum lycopersicum L.) plants are characterized by having a variety of fruit colours that reflect the composition and accumulation of diverse carotenoids in the berries. Carotenoids are extensively studied for their health promoting effects and this explains the great attention these pigments received by breeders and researchers worldwide. In this work we applied Agilent's SureSelect liquid-phase sequence capture and Illumina targeted re-sequencing of 34 tomato genes belonging to the methylerythritol phosphate (MEP) carotenoid pathway on a panel of 48 genotypes which differ for carotenoid content calculated as the sum of beta-carotene, cis- and trans-lycopene. We targeted 230 kb of genomic regions including all exons and regulatory regions and observed ~40% of on-target capture. We found ample genetic variation among all the genotypes under study and generated an extensive catalog of SNPs/InDels located in both genic and regulatory regions. SNPs/InDels were also classified based on genomic location and putative biological effect. With our work we contributed to the identification of allelic variations possibly underpinning a key agronomic trait in tomato. Results from this study can be exploited for the promotion of novel studies on tomato bio-fortification as well as of breeding programs related to carotenoid accumulation in fruits. PMID- 28717174 TI - Over-expression of KdSOC1 gene affected plantlet morphogenesis in Kalanchoe daigremontiana. AB - Kalanchoe daigremontiana reproduces asexually by producing plantlets along the leaf margin. The aim of this study was to identify the function of the SUPPRESSOR OF OVEREXPRESSION OF CONSTANS 1 gene in Kalanchoe daigremontiana (KdSOC1) during plantlet morphogenesis. In this study, KdSOC1 gene expression was detected at stem cell niche during in vitro somatic embryogenesis and plantlet morphogenesis. Disrupting endogenous auxin transportation suppressed the KdSOC1 gene response. Knockdown of the KdSOC1 gene caused a defect in cotyledon formation during the early heart stage of somatic embryogenesis. Over-expression (OE) of the KdSOC1 gene resulted in asymmetric plantlet distribution, a reduced number of plantlets, thicker leaves, and thicker vascular fibers. Higher KdPIN1 gene expression and auxin content were found in OE plant compared to those of wild-type plant leaves, which indicated possible KdSOC1 gene role in affecting auxin distribution and accumulation. KdSOC1 gene OE in DR5-GUS Arabidopsis reporting lines resulted in an abnormal auxin response pattern during different stages of somatic embryogenesis. In summary, the KdSOC1 gene OE might alter auxin distribution and accumulation along leaf margin to initiate plantlet formation and distribution, which is crucial for plasticity during plantlet formation under various environmental conditions. PMID- 28717175 TI - Snake venom VEGF Vammin induces a highly efficient angiogenic response in skeletal muscle via VEGFR-2/NRP specific signaling. AB - Vascular Endothelial Growth Factors (VEGFs) are promising molecules for the treatment of ischemic diseases by pro-angiogenic therapy. Snake venom VEGFs are a novel subgroup with unique receptor binding profiles and as such are potential new therapeutic agents. We determined the ligand-receptor interactions, gene regulation and angiogenic properties of Vipera ammodytes venom VEGF, Vammin, and compared it to the canonical angiogenic factor VEGF-A to evaluate the use of Vammin for therapeutic angiogenesis. Vammin efficiently induced VEGFR-2 mediated proliferation and expression of genes associated with proliferation, migration and angiogenesis. VEGF-A165 and especially VEGF-A109 induced less pronounced effects. Vammin regulates a number of signaling pathways by inducing the expression of NR4A family nuclear receptors and regulators of calcium signaling and MAP kinase pathways. Interestingly, MARC1, which encodes an enzyme discovered to catalyze reduction of nitrate to NO, was identified as a novel VEGFR-2 regulated gene. In rabbit skeletal muscle adenoviral delivery of Vammin induced prominent angiogenic responses. Both the vector dose and the co-receptor binding of the ligand were critical parameters controlling the type of angiogenic response from sprouting angiogenesis to vessel enlargement. Vammin induced VEGFR 2/NRP-1 mediated signaling more effectively than VEGF-A, consequently it is a promising candidate for development of pro-angiogenic therapies. PMID- 28717176 TI - Negative velocity fluctuations and non-equilibrium fluctuation relation for a driven high critical current vortex state. AB - Under the influence of a constant drive the moving vortex state in 2H-NbS2 superconductor exhibits a negative differential resistance (NDR) transition from a steady flow to an immobile state. This state possesses a high depinning current threshold ([Formula: see text]) with unconventional depinning characteristics. At currents well above [Formula: see text], the moving vortex state exhibits a multimodal velocity distribution which is characteristic of vortex flow instabilities in the NDR regime. However at lower currents which are just above [Formula: see text], the velocity distribution is non-Gaussian with a tail extending to significant negative velocity values. These unusual negative velocity events correspond to vortices drifting opposite to the driving force direction. We show that this distribution obeys the Gallavotti-Cohen Non Equilibrium Fluctuation Relation (GC-NEFR). Just above [Formula: see text], we also find a high vortex density fluctuating driven state not obeying the conventional GC-NEFR. The GC-NEFR analysis provides a measure of an effective energy scale (E eff ) associated with the driven vortex state. The E eff corresponds to the average energy dissipated by the fluctuating vortex state above [Formula: see text]. We propose the high E eff value corresponds to the onset of high energy dynamic instabilities in this driven vortex state just above [Formula: see text]. PMID- 28717177 TI - Physical mechanism of delta-delta'-epsilon phase stability in plutonium. AB - Based on first-principle calculations, we have systematically explored the nature of the elastic stability and the delta-delta'-epsilon phase transitions in pure Pu at high temperature. It is found that, both the electron-phonon coupling and the spin fluctuation effects tend to decrease the tetragonal elastic constant (C') of delta-Pu, accounting for its anomalous softening at high temperature. The lattice thermal expansion together with the electron-phonon coupling can stiffen C' of epsilon-Pu, promoting its mechanical stability at high temperature. The delta-epsilon transition is calculated to take place around 750-800 K, and is dominated by the phonon vibration. The delta' intermediate phase is realized around 750 K mainly because of the thermal spin fluctuation. PMID- 28717178 TI - Prevalence of metabolic syndrome among adults with liver function injury in rural area of Southwest China: A cross-sectional study. AB - Abnormal liver function (ALF) plays a key role in metabolic syndrome (MetS), but only few data on the relationship between MetS and the risk factors for ALF (e.g., biotoxins) are available. We aimed to provide the prevalence of MetS and its association with the risk factors for ALF in rural area of Southwest China. A cross-sectional study within the hepatocellular carcinoma cohort was conducted, and included 5493 people with age from 30 to 85 years old. MetS was defined according to the Joint Scientific Statement. We observed that the prevalence of MetS was 31.8% (39.0% in women and 19.8% in men). Logistic regression analysis showed that significantly increased risk of MetS was found in those showing ALF (OR = 3.00, 95% CI: 2.43-3.71). Significantly decreased risk of MetS was found in those with higher HBV DNA titers (OR = 0.49, 95% CI: 0.33-0.74), and in those with higher aflatoxin B1 exposure (estimated daily intake, EDI) (OR = 0.60, 95% CI: 0.53-0.67). No significant change was found in those with higher microcystin LR exposure (EDI). Therefore, the different risk factors for ALF might exert different effects on MetS. However, there should be an interaction effect existing that might decide the severity of MetS. PMID- 28717180 TI - A three miRNAs signature predicts survival in cervical cancer using bioinformatics analysis. AB - Growing evidences showed that a large number of miRNAs were abnormally expressed in cervical cancer tissues and played irreplaceable roles in tumorigenesis, progression and metastasis. The aim of the present study was to identify the differential miRNAs expression between cervical cancer and normal cervical tissues by analyzing the high-throughput miRNA data downloaded from TCGA database. Additionally, we evaluated the prognostic values of the differentially expressed miRNAs and constructed a three-miRNA signature that could effectively predict patient survival. According to the cut-off criteria (P < 0.05 and |log2FC| > 2.0), a total of 78 differentially expressed miRNAs were identified between cervical cancer tissues and matched normal tissues, including 37 up regulated miRNAs and 41 down-regulated miRNAs. The Kaplan-Meier survival method revealed the prognostic function of the three miRNAs (miRNA-145, miRNA-200c, and miRNA-218-1). Univariate and multivariate Cox regression analysis showed that the three-miRNA signature was an independent prognostic factor in cervical cancer. The functional enrichment analysis suggested that the target genes of three miRNAs may be involved in various pathways related to cancer, including MAPK, AMPK, focal adhesion, cGMP-PKG, wnt, and mTOR signaling pathway. Taken together, the present study suggested that three-miRNA signature could be used as a prognostic marker in cervical cancer. PMID- 28717179 TI - Genetic Polymorphisms and Platinum-based Chemotherapy Treatment Outcomes in Patients with Non-Small Cell Lung Cancer: A Genetic Epidemiology Study Based Meta analysis. AB - Data regarding genetic polymorphisms and platinum-based chemotherapy (PBC) treatment outcomes in patients with NSCLC are published at a growing pace, but the results are inconsistent. This meta-analysis integrated eligible candidate genes to better evaluate the pharmacogenetics of PBC in NSCLC patients. Relevant studies were retrieved from PubMed, Chinese National Knowledge Infrastructure and WANFANG databases. A total of 111 articles comprising 18,196 subjects were included for this study. The associations of genetic polymorphisms with treatment outcomes of PBC including overall response rate (ORR), overall survival (OS) and progression-free survival (PFS) were determined by analyzing the relative risk (RR), hazard ration (HR), corresponding 95% confidence interval (CI). Eleven polymorphisms in 9 genes, including ERCC1 rs11615 (OS), rs3212986 (ORR), XPA rs1800975 (ORR), XPD rs1052555 (OS, PFS), rs13181 (OS, PFS), XPG rs2296147 (OS), XRCC1 rs1799782 (ORR), XRCC3 rs861539 (ORR), GSTP1 rs1695 (ORR), MTHFR rs1801133 (ORR) and MDR1 rs1045642 (ORR), were found significantly associated with PBC treatment outcomes. These variants were mainly involved in DNA repair (EXCC1, XPA, XPD, XPG, XRCC1 and XRCC3), drug influx and efflux (MDR1), metabolism and detoxification (GSTP1) and DNA synthesis (MTHFR), and might be considered as potential prognostic biomarkers for assessing objective response and progression risk in NSCLC patients receiving platinum-based regimens. PMID- 28717181 TI - Discovery of Novel Human Gene Regulatory Modules from Gene Co-expression and Promoter Motif Analysis. AB - Deciphering gene regulatory networks requires identification of gene expression modules. We describe a novel bottom-up approach to identify gene modules regulated by cis-regulatory motifs from a human gene co-expression network. Target genes of a cis-regulatory motif were identified from the network via the motif's enrichment or biased distribution towards transcription start sites in the promoters of co-expressed genes. A gene sub-network containing the target genes was extracted and used to derive gene modules. The analysis revealed known and novel gene modules regulated by the NF-Y motif. The binding of NF-Y proteins to these modules' gene promoters were verified using ENCODE ChIP-Seq data. The analyses also identified 8,048 Sp1 motif target genes, interestingly many of which were not detected by ENCODE ChIP-Seq. These target genes assemble into house-keeping, tissues-specific developmental, and immune response modules. Integration of Sp1 modules with genomic and epigenomic data indicates epigenetic control of Sp1 targets' expression in a cell/tissue specific manner. Finally, known and novel target genes and modules regulated by the YY1, RFX1, IRF1, and 34 other motifs were also identified. The study described here provides a valuable resource to understand transcriptional regulation of various human developmental, disease, or immunity pathways. PMID- 28717183 TI - The characterization of hippocampal theta-driving neurons - a time-delayed mutual information approach. AB - Interneurons are important for computation in the brain, in particular, in the information processing involving the generation of theta oscillations in the hippocampus. Yet the functional role of interneurons in the theta generation remains to be elucidated. Here we use time-delayed mutual information to investigate information flow related to a special class of interneurons-theta driving neurons in the hippocampal CA1 region of the mouse-to characterize the interactions between theta-driving neurons and theta oscillations. For freely behaving mice, our results show that information flows from the activity of theta driving neurons to the theta wave, and the firing activity of theta-driving neurons shares a substantial amount of information with the theta wave regardless of behavioral states. Via realistic simulations of a CA1 pyramidal neuron, we further demonstrate that theta-driving neurons possess the characteristics of the cholecystokinin-expressing basket cells (CCK-BC). Our results suggest that it is important to take into account the role of CCK-BC in the generation and information processing of theta oscillations. PMID- 28717182 TI - Widespread alternative exon usage in clinically distinct subtypes of Invasive Ductal Carcinoma. AB - Cancer cells can have different patterns of exon usage of individual genes when compared to normal tissue, suggesting that alternative splicing may play a role in shaping the tumor phenotype. The discovery and identification of gene variants has increased dramatically with the introduction of RNA-sequencing technology, which enables whole transcriptome analysis of known, as well as novel isoforms. Here we report alternative splicing and transcriptional events among subtypes of invasive ductal carcinoma in The Cancer Genome Atlas (TCGA) Breast Invasive Carcinoma (BRCA) cohort. Alternative exon usage was widespread, and although common events were shared among three subtypes, ER+ HER2-, ER- HER2-, and HER2+, many events on the exon level were subtype specific. Additional RNA-seq analysis was carried out in an independent cohort of 43 ER+ HER2- and ER- HER2- primary breast tumors, confirming many of the exon events identified in the TCGA cohort. Alternative splicing and transcriptional events detected in five genes, MYO6, EPB41L1, TPD52, IQCG, and ACOX2 were validated by qRT-PCR in a third cohort of 40 ER+ HER2- and ER- HER2- patients, showing that these events were truly subtype specific. PMID- 28717184 TI - Magnetic anisotropy control by applying an electric field to the side surface of ferromagnetic films. AB - Reducing the power consumption necessary for magnetization reversal is one of the most crucial issues facing spintronics devices. Electric field control of the magnetic anisotropy of ferromagnetic thin films is a promising method to solve this problem. However, the electric field is believed to be effective only within several nanometres of the surface in ferromagnetic metals because of its short Thomas-Fermi screening length, which prevents its practical application to devices. Herein, we successfully modulate the magnetic anisotropy of the entire region of the ferromagnetic layers in the elongated mesas of vertical spin field effect transistors with widths as large as ~500 nm by applying an electric field to the side surface of the metallic GaMnAs-based mesas through an electric double layer. Our results will open up a new pathway for spintronics devices with ultra low power consumption. PMID- 28717185 TI - Clinical Significance and Effect of lncRNA HOXA11-AS in NSCLC: A Study Based on Bioinformatics, In Vitro and in Vivo Verification. AB - HOXA11 antisense RNA (HOXA11-AS) has been shown to be involved in tumorigenesis and development of different cancers. However, the role of HOXA11-AS in non-small cell lung cancer (NSCLC) remains unclear. In this study, we firstly explored and confirmed the expression of HOXA11-AS in NSCLC tissues and cells. Cytometry, CCK 8, cell scratch, migration, Matrigel invasion and flow cytometry assays were performed to determine the biological impact of HOXA11-AS in vitro. Furthermore, a chick embryo chorioallantoic membrane (CAM) model of NSCLC was constructed to explore the effect of HOXA11-AS on tumorigenicity and angiogenesis in vivo. Additionally, bioinformatics analyses were performed to investigate the prospective pathways of HOXA11-AS co-expressed genes. As results, HOXA11-AS was markedly highly expressed in NSCLC tissues and cells. Furthermore, the proliferation, migration, invasion, tumorigenic and angiogenic ability of NSCLC cells were all inhibited and apoptosis was induced after HOXA11-AS knock-down. HOXA11-AS RNAi also led to cell cycle arrest on G0/G1 or G2/M phase. In addition, the non-small cell lung cancer pathway might be involved in regulating the co expressed genes of HOXA11-AS in NSCLC. These results indicate that HOXA11-AS plays pivotal roles in NSCLC and it can become a novel therapeutic direction for treating NSCLC. PMID- 28717186 TI - Overstepping the upper refractive index limit to form ultra-narrow photonic nanojets. AB - In general, photonic nanojets (PNJs) occur only when the refractive index (Ri) difference between the microparticle and background media is less than 2. The minimum full width at half-maximum (FWHM) of the PNJ is ~130 nm (approximately one-third of the illumination wavelength lambda = 400 nm) formed within the evanescent field region. This paper proposes and studies a method to overstep the Ri upper bound and generate ultra-narrow PNJs. Finite element method based numerical investigations and ray-optics theoretical analyses have realized ultra narrow PNJs with FWHM as small as 114.7 nm (0.287 lambda) obtained from an edge cut, length-reduced and parabolic-profiled microparticle with Ri = 2.5 beyond evanescent decay length. Using simple strain or compression operations, sub diffraction-limited PNJs can be flexibly tuned on the order of several wavelengths. Such ultra-narrow PNJs offer great prospects for optical nonlinearity enhancements of greater enhancing effect, optical nanoscopy of higher spatial resolution, optical microprobes of smaller measurement accuracy, nano/micro-sized sample detections of higher sensing sensitivity, nanoscale objects of more accurate control, advanced manufactures of smaller processing size, optical-disk storage of larger data capacity and all-optical switching of lower energy consumption. PMID- 28717187 TI - The inducible blockage of RNAi reveals a role for polyunsaturated fatty acids in the regulation of dsRNA-endocytic capacity in Bactrocera dorsalis. AB - Exogenous double-stranded RNA (dsRNA) can trigger gene silencing through the RNA interference (RNAi) pathway. Our previous research established that Bactrocera dorsalis can block RNAi after an initial priming of exposure to dsRNA. However, the mechanism underlying this phenomenon is not yet fully understood. Here, we demonstrate that fatty acid biosynthesis and metabolism pathways play important roles in the blockage of RNAi induced by dsRNA priming. The ratio of linoleic acid (LA) to arachidonic acid (AA) was significantly increased in the hemolymph of B. dorsalis following dsRNA priming, and further, the endocytosis of dsRNA into the midgut cells of B. dorsalis was inhibited in these samples. The expression levels of most genes involved in the fatty acid biosynthesis and metabolism pathways were altered following priming with dsRNA. Furthermore, altering the composition of fatty acids via the injection of AA can facilitate the uptake of ingested dsRNA into the midgut cells of Drosophila melanogaster and successfully induce an RNAi effect, which cannot be achieved via feeding in fruit flies. Our results suggest that polyunsaturated fatty acids are involved in the regulation of the dsRNA-endocytic ability in B. dorsalis. PMID- 28717188 TI - Targeting PTPRZ inhibits stem cell-like properties and tumorigenicity in glioblastoma cells. AB - The R5 subfamily of receptor-type protein tyrosine phosphatases (RPTPs) comprises PTPRZ and PTPRG. A recent study on primary human glioblastomas suggested a close association between PTPRZ1 (human PTPRZ) expression and cancer stemness. However, the functional roles of PTPRZ activity in glioma stem cells have remained unclear. In the present study, we found that sphere-forming cells from the rat C6 and human U251 glioblastoma cell lines showed high expression levels of PTPRZ-B, the short receptor isoform of PTPRZ. Stable PTPRZ knockdown altered the expression levels of stem cell transcription factors such as SOX2, OLIG2, and POU3F2 and decreased the sphere-forming abilities of these cells. Suppressive effects on the cancer stem-like properties of the cells were also observed following the knockdown of PTPRG. Here, we identified NAZ2329, a cell-permeable small molecule that allosterically inhibits both PTPRZ and PTPRG. NAZ2329 reduced the expression of SOX2 in C6 and U251 cells and abrogated the sphere-forming abilities of these cells. Tumor growth in the C6 xenograft mouse model was significantly slower with the co-treatment of NAZ2329 with temozolomide, an alkylating agent, than with the individual treatments. These results indicate that pharmacological inhibition of R5 RPTPs is a promising strategy for the treatment of malignant gliomas. PMID- 28717189 TI - CDK5-mediated phosphorylation of XBP1s contributes to its nuclear translocation and activation in MPP+-induced Parkinson's disease model. AB - Parkinson's disease (PD) is an irreversible and progressive neurodegenerative disorder characterized by the selective loss of dopaminergic neurons of the substantia nigra pars compacta. Growing evidence indicates that endoplasmic reticulum stress is a hallmark of PD; however, its exact contribution to the disease process remains poorly understood. Here, we used molecular biology methods and RNA-Seq analysis to explored an unexpected role of spliced X-Box binding protein 1 (XBP1s) in the nervous system. In this study, we determined that the IRE1alpha/XBP1 pathway is activated in MPP+-treated neurons. Furthermore, XBP1s was identified as a substrate of CDK5 and that the phosphorylation of XBP1s at the Ser61 residue enhances its nuclear migration, whereas mutation of the residue to alanine substantially reduces its nuclear translocation and activity. Importantly, phosphorylated XBP1s acts as a nuclear transcription factor for multiple target genes, including metabolic-related genes, FosB, and non-coding RNAs. Our findings confirm that the IRE1alpha/XBP1 pathway is activated in PD, and reveal a novel role of XBP1s in the pathogenesis of PD. This pathway may be a new therapeutic strategy for PD. PMID- 28717190 TI - Interocular contrast difference drives illusory 3D percept. AB - Any processing delay between the two eyes can result in illusory 3D percepts for moving objects because of either changes in the pure disparities over time for disparity sensors or by changes to sensors that encode motion/disparity conjointly. This is demonstrated by viewing a fronto-parallel pendulum through a neutral density (ND) filter placed over one eye, resulting in the illusory 3D percept of the pendulum following an elliptical orbit in depth, the so-called Pulfrich phenomenon. Here we use a paradigm where a cylinder rotating in depth, defined by moving Gabor patches is presented at different interocular phases, generating strong to ambiguous depth percepts. This paradigm allows one to manipulate independently the contrast and the luminance of the patches to determine their influence on perceived motion-in-depth. Thus we show psychophysically that an interocular contrast difference can itself result in a similar illusory 3D percept of motion-in-depth. We argue that contrast, like luminance (ND filter) can modify the dynamics of visual neurons resulting in an interocular processing delay or an interocular velocity difference. PMID- 28717191 TI - MLN4924 (Pevonedistat), a protein neddylation inhibitor, suppresses proliferation and migration of human clear cell renal cell carcinoma. AB - Neddylation is a post-translational protein modification associated with cancer development. MLN4924 is a neddylation inhibitor currently under investigation in multiple phase I studies on various malignancies, and its clincal name is Pevonedistat. It has been documented that MLN4924 blocks Cullins neddylation and inactivates CRLs and, in turn, triggers cell-cycle arrest, apoptosis, senescence and autophagy in many cancer cells. In this study, we investigated the anti-tumor effect of MLN4924 in human clear cell renal carcinoma (ccRCC). Levels of both Nedd8 activating enzyme E1 and Nedd8-conjugating enzyme E2 were higher in ccRCC tissues and RCC cancer cells than in normal. Moreover, MLN4924 treatment led to rapid inhibition of Cullin1 neddylation and notably suppressed growth and survival as well as migration in a dose-and time-dependent manner. Mechanistic studies revealed that MLN4924 induced the accumulation of a number of CRL substrates, including p21, p27 and Wee1 to trigger DNA damage and induce growth arrest at the G2/M phase. MLN4924 also induced anti-migration and anti-invasion by activating E-cadherin and repressing Vimentin. Taken together, this study provides the first evidence that neddylation pathway is overactive in ccRCC and that MLN4924 induces dose-dependent anti-proliferation, anti-migration, anti invasion in ccRCC cells. The study thus indicates that MLN4924 has potential therapeutic value for the clinical treatment of renal cancer. PMID- 28717192 TI - Torque, but not FliL, regulates mechanosensitive flagellar motor-function. AB - The stator-complex in the bacterial flagellar motor is responsible for surface sensing. It remodels in response to perturbations in viscous loads, recruiting additional stator-units as the load increases. Here, we tested a hypothesis that the amount of torque generated by each stator-unit modulates its association with the rotor. To do this, we measured stator-binding to the rotor in mutants in which motors reportedly develop lower torque compared to wildtype motors. First, we employed a strain lacking fliL. Contrary to earlier reports, measurements indicated that the torque generated by motors in the fliL strain was similar to that in the wildtype, at high loads. In these motors, stator-binding was unchanged. Next, experiments with a paralyzed strain indicated that the stator binding was measurably weaker when motors were unable to generate torque. An analytical model was developed that incorporated an exponential dependence of the unit's dissociation rate on the force delivered to the rotor. The model provided accurate fits to measurements of stator-rotor binding over a wide range of loads. Based on these results, we propose that the binding of each stator-unit is enhanced by the force it develops. Furthermore, FliL does not play a significant role in motor function in E. coli. PMID- 28717193 TI - Adhesive Capsulitis of the Shoulder: Evaluation With US-Arthrography Using a Sonographic Contrast Agent. AB - Adhesive capsulitis (AC) is a painful and disabling disorder, which caused restricted motion and chronic pain of shoulder. Intracavitary contrast-enhanced ultrasound has been recently applied to assess obstructive bile duct diseases, tubal patency, vesicoureteric reflux and so on. The aim of this study was to detect the value of US-arthrography by injecting the contrast agent SonoVue into glenohumeral joint compared with US in diagnosing AC. Utrasound (US) and US arthrography images of 45 patients with AC were compared with that of 45 control subjects without AC with MRI as a gold standard. Patients with AC had a significantly thickened coracohumeral ligment (CHL, 3.1 mm) and inferior capsule (3.5 mm) on US, and a decreased volume of axillary recess (1.14 ml) on US arthrography compared with the control subjects (1.59 ml). Filling defect (91.1%) and synovitis-like abnormality (75.6%) in the joint on US-arthrography were more sensitive than that of rotator interval abnormality (71.1%), thickened CHL more than 3 mm (64.4%), thickened inferior capsule more than 3.5 mm (66.7%) on US respectively for diagnosis of AC. Consequently, US-arthrography was more effective method than US for assessment of AC. Filling defects of joint cavity and synovitis-like abnormality in the joint are characteristic US-arthrography findings for diagnosing AC. PMID- 28717194 TI - Rapid production of human liver scaffolds for functional tissue engineering by high shear stress oscillation-decellularization. AB - The development of human liver scaffolds retaining their 3-dimensional structure and extra-cellular matrix (ECM) composition is essential for the advancement of liver tissue engineering. We report the design and validation of a new methodology for the rapid and accurate production of human acellular liver tissue cubes (ALTCs) using normal liver tissue unsuitable for transplantation. The application of high shear stress is a key methodological determinant accelerating the process of tissue decellularization while maintaining ECM protein composition, 3D-architecture and physico-chemical properties of the native tissue. ALTCs were engineered with human parenchymal and non-parenchymal liver cell lines (HepG2 and LX2 cells, respectively), human umbilical vein endothelial cells (HUVEC), as well as primary human hepatocytes and hepatic stellate cells. Both parenchymal and non-parenchymal liver cells grown in ALTCs exhibited markedly different gene expression when compared to standard 2D cell cultures. Remarkably, HUVEC cells naturally migrated in the ECM scaffold and spontaneously repopulated the lining of decellularized vessels. The metabolic function and protein synthesis of engineered liver scaffolds with human primary hepatocytes reseeded under dynamic conditions were maintained. These results provide a solid basis for the establishment of effective protocols aimed at recreating human liver tissue in vitro. PMID- 28717195 TI - Stability of the PHF10 subunit of PBAF signature module is regulated by phosphorylation: role of beta-TrCP. AB - The PBAF chromatin-remodeling complexes are multi-protein machines, regulating expression of genes involved in proliferation and differentiation. PHF10 is a subunit of the PBAF essential for its association with chromatin. Mammalian PHF10 is expressed as four ubiquitous isoforms, which are alternatively incorporated in the complex and differ by their influence on transcription of target genes. PHF10 have different domain structure and two of them (PHF10-S isoforms) lack C terminal PHD domains, which enables their phosphorylation by CK-1. Here we have found that PBAF subunits have low turnover rate, except for PHF10 which has much lower half-life, and is degraded by beta-TrCP. The beta-TrCP knockdown stabilizes PBAF core subunits - BRG1 and BAF155 and specific subunits - PHF10, BAF200, BAF180 and BRD7. PHF10 isoforms contain two non-canonical beta-TrCP degrons and are degraded by beta-TrCP in a phospho-dependent manner. But phosphorylation of PHF10-S degrons by CK-1, contrary to previously described degrons, prevents their degradation. Targeted molecular docking demonstrated that phosphorylated forms of PHF10 bind to beta-TrCP with much lower affinity than non-phosphorylated ones, contrary to previously described degrons. This unorthodox mechanism proposes that phosphorylation of beta-TrCP degrons by CK-1 could not only degrade a set of proteins, but also stabilize a different set of targets. PMID- 28717196 TI - TRIB1 is a positive regulator of hepatocyte nuclear factor 4-alpha. AB - The TRIB1 locus has been linked to both cardiovascular disease and hepatic steatosis. Recent efforts have revealed TRIB1 to be a major regulator of liver function, largely, but not exclusively, via CEBPA degradation. We recently uncovered a functional interaction between TRIB1 and HNF4A, another key regulator of hepatic function, whose molecular underpinnings remained to be clarified. Here we have extended these findings. In hepatoma models, HNF4A levels were found to depend on TRIB1, independently of its impact on CEBPA. Using a reporter assay model, MTTP reporter activity, which depends on HNF4A, positively correlated with TRIB1 levels. Confocal microscopy demonstrated partial colocalization of TRIB1 and HNF4A. Using overexpressed proteins we demonstrate that TRIB1 and HNF4A can form complexes in vivo. Mapping of the interaction interfaces identified two distinct regions within TRIB1 which associated with the N-terminal region of HNF4A. Lastly, the TRIB1-HNF4A interaction resisted competition with a CEPBA derived peptide, suggesting different binding modalities. Together these findings establish that TRIB1 is required for HNF4A function. This regulatory axis represents a novel CEBPA-independent aspect of TRIB1 function predicted to play an important role in liver physiology. PMID- 28717197 TI - Subcortical volume and white matter integrity abnormalities in major depressive disorder: findings from UK Biobank imaging data. AB - Previous reports of altered grey and white matter structure in Major Depressive Disorder (MDD) have been inconsistent. Recent meta-analyses have, however, reported reduced hippocampal grey matter volume in MDD and reduced white matter integrity in several brain regions. The use of different diagnostic criteria, scanners and imaging sequences may, however, obscure further anatomical differences. In this study, we tested for differences in subcortical grey matter volume (n = 1157) and white matter integrity (n = 1089) between depressed individuals and controls in the subset of 8590 UK Biobank Imaging study participants who had undergone depression assessments. Whilst we found no significant differences in subcortical volumes, significant reductions were found in depressed individuals versus controls in global white matter integrity, as measured by fractional anisotropy (FA) (beta = -0.182, p = 0.005). We also found reductions in FA in association/commissural fibres (beta = -0.184, pcorrected = 0.010) and thalamic radiations (beta = -0.159, pcorrected = 0.020). Tract specific FA reductions were also found in the left superior longitudinal fasciculus (beta = -0.194, pcorrected = 0.025), superior thalamic radiation (beta = -0.224, pcorrected = 0.009) and forceps major (beta = -0.193, pcorrected = 0.025) in depression (all betas standardised). Our findings provide further evidence for disrupted white matter integrity in MDD. PMID- 28717198 TI - Controlled modification of biomolecules by ultrashort laser pulses in polar liquids. AB - Targeted chemical modification of peptides and proteins by laser pulses in a biologically relevant environment, i.e. aqueous solvent at room temperature, allows for accurate control of biological processes. However, the traditional laser methods of control of chemical reactions are applicable only to a small class of photosensitive biomolecules because of strong and ultrafast perturbations from biomolecule-solvent interactions. Here, we report excitation of harmonics of vibration modes of solvent molecules by femtosecond laser pulses to produce controlled chemical modifications of non-photosensitive peptides and proteins in polar liquids under room conditions. The principal modifications included lysine formylation and methionine sulfoxidation both of which occur with nearly 100% yield under atmospheric conditions. That modification occurred only if the laser irradiance exceeded certain threshold level. The threshold, type, and extent of the modifications were completely controlled by solvent composition, laser wavelength, and peak irradiance of ultrashort laser pulses. This approach is expected to assist in establishing rigorous control over a broad class of biological processes in cells and tissues at the molecular level. PMID- 28717199 TI - Association between allergic conditions and colorectal cancer risk/mortality: a meta-analysis of prospective studies. AB - We aimed to assess the association between allergic conditions and risk/mortality of colorectal cancer (CRC). A systematic literature search was conducted using Pubmed and Embase to identify relevant studies. Prospective studies assessing the association between allergic conditions and risk/mortality of CRC were included. Risk ratios (RRs) were pooled with either a fixed- or a random-effects model according to heterogeneity. A total of 515379 participants and 10345 CRC cases from 12 studies were included in the analysis of CRC risk, while four studies with 1484741 individuals and 30040 CRC deaths were included in the analysis of CRC mortality. The pooled RR for the association between allergic conditions and CRC risk was 0.88 (95% CI 0.83-0.92). The inverse association was observed both in colon cancer (pooled RR = 0.83, 95% CI 0.72-0.97) and rectal cancer (pooled RR = 0.83, 95% CI 0.74-0.93). Moreover, no gender difference was observed in the analysis of CRC risk (for males, pooled RR = 0.88, 95% CI 0.81-0.96; for females, pooled RR = 0.88, 95% CI 0.82-0.95). And allergic conditions were also found to be inversely associated with CRC mortality (pooled RR = 0.88, 95% CI 0.83-0.92). In conclusion, the current meta-analysis provides further evidence that allergic conditions were inversely associated with CRC risk and mortality. PMID- 28717200 TI - Genome-wide RNA-Sequencing analysis identifies a distinct fibrosis gene signature in the conjunctiva after glaucoma surgery. AB - Fibrosis-related events play a part in most blinding diseases worldwide. However, little is known about the mechanisms driving this complex multifactorial disease. Here we have carried out the first genome-wide RNA-Sequencing study in human conjunctival fibrosis. We isolated 10 primary fibrotic and 7 non-fibrotic conjunctival fibroblast cell lines from patients with and without previous glaucoma surgery, respectively. The patients were matched for ethnicity and age. We identified 246 genes that were differentially expressed by over two-fold and p < 0.05, of which 46 genes were upregulated and 200 genes were downregulated in the fibrotic cell lines compared to the non-fibrotic cell lines. We also carried out detailed gene ontology, KEGG, disease association, pathway commons, WikiPathways and protein network analyses, and identified distinct pathways linked to smooth muscle contraction, inflammatory cytokines, immune mediators, extracellular matrix proteins and oncogene expression. We further validated 11 genes that were highly upregulated or downregulated using real-time quantitative PCR and found a strong correlation between the RNA-Seq and qPCR results. Our study demonstrates that there is a distinct fibrosis gene signature in the conjunctiva after glaucoma surgery and provides new insights into the mechanistic pathways driving the complex fibrotic process in the eye and other tissues. PMID- 28717201 TI - Cognitive brain responses during circadian wake-promotion: evidence for sleep pressure-dependent hypothalamic activations. AB - The two-process model of sleep-wake regulation posits that sleep-wake-dependent homeostatic processes interact with the circadian timing system to affect human behavior. The circadian timing system is fundamental to maintaining stable cognitive performance, as it counteracts growing homeostatic sleep pressure during daytime. Using magnetic resonance imaging, we explored brain responses underlying working memory performance during the time of maximal circadian wake promotion under varying sleep pressure conditions. Circadian wake-promoting strength was derived from the ability to sleep during an evening nap. Hypothalamic BOLD activity was positively linked to circadian wake-promoting strength under normal, but not under disproportionally high or low sleep pressure levels. Furthermore, higher hypothalamic activity under normal sleep pressure levels predicted better performance under sleep loss. Our results reappraise the two-process model by revealing a homeostatic-dose-dependent association between circadian wake-promotion and cognition-related hypothalamic activity. PMID- 28717202 TI - beta-caryophyllene emitted from a transgenic Arabidopsis or chemical dispenser repels Diaphorina citri, vector of Candidatus Liberibacters. AB - Production of citrus, the main fruit tree crop worldwide, is severely threatened by Huanglongbing (HLB), for which as yet a cure is not available. Spread of this bacterial disease in America and Asia is intimately connected with dispersal and feeding of the insect vector Diaphorina citri, oligophagous on rutaceous host plants. Effective control of this psyllid is an important component in successful HLB management programs. Volatiles released from the non-host guava have been shown to be repellent to the psyllid and to inhibit its response to citrus odour. By analysing VOC emission from guava we identified one volatile compound, (E) beta-caryophyllene, which at certain doses exerts a repellent effect on D. citri. Non-host plant rejection mediated by (E)-beta-caryophyllene is demonstrated here by using Arabidopsis over-expression and knock-out lines. For the first time, results indicate that genetically engineered Arabidopsis plants with modified emission of VOCs can alter the behaviour of D. citri. This study shows that transgenic plants with an inherent ability to release (E)-beta-caryophyllene can potentially be used in new protection strategies of citrus trees against HLB. PMID- 28717203 TI - Genome-wide identification and characterization of circular RNAs by high throughput sequencing in soybean. AB - Circular RNAs (circRNAs) arise during pre-mRNA splicing, in which the 3' and 5' ends are linked to each other by a covalent bond. Soybean is an ancient tetraploid, which underwent two whole genome duplications. Most of soybean genes are paralogous genes with multiple copies. Although many circRNAs have been identified in animals and plants, little is known about soybean circRNAs, especially about circRNAs derived from paralogous genes. Here, we used deep sequencing technology coupled with RNase R enrichment strategy and bioinformatic approach to uncover circRNAs in soybean. A total of 5,372 circRNAs were identified, approximately 80% of which were paralogous circRNAs generated from paralogous genes. Despite high sequence homology, the paralogous genes could produce different paralogous circRNAs with different expression patterns. Two thousand and one hundred thirty four circRNAs were predicted to be 92 miRNAs target mimicry. CircRNAs and circRNA isoforms exhibited tissue-specific expression patterns in soybean. Based on the function of circRNA-host genes, the soybean circRNAs may participate in many biological processes such as developmental process, multi-organism process, and metabolic process. Our study not only provided a basis for research into the function of circRNAs in soybean but also new insights into the plant circRNA kingdom. PMID- 28717204 TI - A Drug Carrier for Sustained Zero-Order Release of Peptide Therapeutics. AB - Peptides have great potential as therapeutic agents, however, their clinic applications are severely hampered by their instability and short circulation half-life. Zero-order release carriers could not only extend the circulation lifetime of peptides, but also maintain the plasma drug level constant, and thus maximize their therapeutic efficacy and minimize their toxic effect. Here using PEGylated salmon calcitonin (PEG-sCT)/tannic acid (TA) film as an example, we demonstrated that hydrogen-bonded layer-by-layer films of a PEGylated peptide and a polyphenol could be a platform for zero-order peptide release. The films were fabricated under mild conditions. The second component, TA, is a natural product and presents potential therapeutic activities itself. Unlike common carriers, the new carrier releases the peptide via gradual disintegration of the film because of its dynamic nature. The release of PEG-sCT follows a perfect zero-order kinetics without initial burst release. In addition the release rate could be tuned via external stimuli, such as pH and temperature. When implanted in rats, the films could remain the plasma level of PEG-sCT constant over an extended period. Accordingly, the serum calcium level was reduced and maintained constant over the same period, suggesting an improved therapeutic efficacy of the released drug. PMID- 28717206 TI - An Amino Acid Signature Associated with Obesity Predicts 2-Year Risk of Hypertriglyceridemia in School-Age Children. AB - Childhood obesity is associated with a number of metabolic abnormalities leading to increased cardiovascular risk. Metabolites can be useful as early biomarkers and new targets to promote early intervention beginning in school age. Thus, we aimed to identify metabolomic profiles associated with obesity and obesity related metabolic traits. We used data from the Obesity Research Study for Mexican children (ORSMEC) in Mexico City and included a case control (n = 1120), cross-sectional (n = 554) and a longitudinal study (n = 301) of 6-12-year-old children. Forty-two metabolites were measured using electrospray MS/MS and multivariate regression models were used to test associations of metabolomic profiles with anthropometric, clinical and biochemical parameters. Principal component analysis showed a serum amino acid signature composed of arginine, leucine/isoleucine, phenylalanine, tyrosine, valine and proline significantly associated with obesity (OR = 1.57; 95%CI 1.45-1.69, P = 3.84 * 10-31) and serum triglycerides (TG) (beta = 0.067, P = 4.5 * 10-21). These associations were validated in the cross-sectional study (P < 0.0001). In the longitudinal cohort, the amino acid signature was associated with serum TG and with the risk of hypertriglyceridemia after 2 years (OR = 1.19; 95%CI 1.03-1.39, P = 0.016). This study shows that an amino acid signature significantly associated with childhood obesity, is an independent risk factor of future hypertriglyceridemia in children. PMID- 28717205 TI - Genome reconstruction in Cynara cardunculus taxa gains access to chromosome-scale DNA variation. AB - The genome sequence of globe artichoke (Cynara cardunculus L. var. scolymus, 2n = 2x = 34) is now available for use. A survey of C. cardunculus genetic resources is essential for understanding the evolution of the species, carrying out genetic studies and for application of breeding strategies. We report on the resequencing analyses (~35*) of four globe artichoke genotypes, representative of the core varietal types, as well as a genotype of the related taxa cultivated cardoon. The genomes were reconstructed at a chromosomal scale and structurally/functionally annotated. Gene prediction indicated a similar number of genes, while distinctive variations in miRNAs and resistance gene analogues (RGAs) were detected. Overall, 23,5 M SNP/indel were discovered (range 6,34 M -14,50 M). The impact of some missense SNPs on the biological functions of genes involved in the biosynthesis of phenylpropanoid and sesquiterpene lactone secondary metabolites was predicted. The identified variants contribute to infer on globe artichoke domestication of the different varietal types, and represent key tools for dissecting the path from sequence variation to phenotype. The new genomic sequences are fully searchable through independent Jbrowse interfaces (www.artichokegenome.unito.it), which allow the analysis of collinearity and the discovery of genomic variants, thus representing a one-stop resource for C. cardunculus genomics. PMID- 28717207 TI - Barcoding utility in a mega-diverse, cross-continental genus: keeping pace with Cyrtodactylus geckos. AB - Over the past decade, DNA barcoding has become a staple of low-cost molecular systematic investigations. The availability of universal primers and subsidized sequencing projects (PolarBOL, SharkBOL, SpongeBOL) have driven this popularity, often without appropriate investigation into the utility of barcoding data for the taxonomic group of interest. Here, our primary aim is to determine the phylogenetic value of DNA barcoding (mitochondrial locus COI) within the gecko genus Cyrtodactylus. With >40 new species described since last systematic investigation, Cyrtodactylus represents one of the most diverse extant squamate genera, and their contemporary distribution spans the Indian subcontinent, eastward through Indochina, and into AustraloPapua. The complex biogeographic history of this group, and morphology-only designation of many species have complicated our phylogenetic understanding of Cyrtodactylus. To highlight the need for continued inclusive molecular assessment, we use Vietnamese Cyrtodactylus as a case study showing the geopolitically paraphyletic nature of their history. We compare COI to the legacy marker ND2, and discuss the value of COI as an interspecific marker, as well as its shortcomings at deeper evolutionary scales. We draw attention back to the Cold Code as a subsidized method for incorporating molecular methods into species descriptions in the effort to maintain accurate phylogenies. PMID- 28717208 TI - Macroscopic Singlet-Triplet Qubit in Synthetic Spin-One Chain in Semiconductor Nanowires. AB - We show here how to create macroscopic quantum states in a semiconductor device: a chain of InAs quantum dots embedded in an InP nanowire. Filling the nanowire with 4 electrons per dot creates a synthetic spin-one chain, with four-fold degenerate topological ground state protected by a Haldane gap. The four states correspond to two spin-1/2 quasiparticles localised at the ends of the macroscopic wire. The quasiparticle spins are mapped onto a robust, macroscopic, singlet-triplet qubit. These predictions are supported by a microscopic theory and extensive numerical simulations. PMID- 28717209 TI - Non-target effects on soil microbial parameters of the synthetic pesticide carbendazim with the biopesticides cantharidin and norcantharidin. AB - Considering the fact that biopesticides are increasingly used to replace synthetic pesticides in pest control, it is necessary to assess their ecotoxicity and especially their non-target effects on soil microorganisms, which is largely unknown. In this study, the effects of the synthetic pesticide carbendazim and the biopesticides (cantharidin and norcantharidin) on soil microbial parameters in a silt loam soil were evaluated. By using commercial formulations at the recommended and higher rates, both cantharidin and norcantharidin induced adverse effects on soil invertase, phosphatase activities and fungal gene structure, but these changes were transient. After about two weeks, the harmful effects owing to the application of pesticides phased out and eventually became comparable with non-treated samples. The degradation of cantharidin and norcantharidin was rapid and can be completed within a few days in the soil. None of the three pesticides caused significant shifts in urease activity. This study provides a comprehensive assessment of the soil microbial toxicity of these biopesticides for reasonable and efficient usage. PMID- 28717210 TI - Linked colour imaging benefits the endoscopic diagnosis of distal gastric diseases. AB - Gastric diseases are common in China, and gastroduodenoscopy could provide accurate diagnoses. Our previous study verified that linked colour imaging (LCI) can improve endoscopic diagnostic accuracy. This study aimed for the first time to establish an LCI-based endoscopic model called colour-microstructure-vessel (CMV) criteria and validated its clinical feasibility for detecting distal gastric diseases manifested as red mucosal lesions under endoscopy in a cohort of 62 patients. Colour features were extracted from the endoscopic images and categorized into 3 types. Colour type 1 was a typical red; Colour type 2 was red ringed with purple and Colour type 3 was red with yellow in the centre and purple around the periphery, allowing for predicting chronic nonatrophic gastritis, chronic atrophic gastritis and gastric cancer. The sensitivity, specificity and Youden index of Colour type 3 with abnormal M or V for gastric cancer were 100.0%, 98.2% and 98.2%. The kappa values for intra-observer and inter-observer agreement for predicting the pathology were 0.834 and 0.791 for experienced endoscopists and 0.788 and 0.732 for endoscopy learners, and these values were comparable regardless of the experience of the endoscopists (P > 0.05). These findings support that the CMV criteria are a promising model for accurate endoscopic diagnosis. PMID- 28717211 TI - Epithelial cell specific Raptor is required for initiation of type 2 mucosal immunity in small intestine. AB - Intestinal tuft cells are one of 4 secretory cell linages in the small intestine and the source of IL-25, a critical initiator of the type 2 immune response to parasite infection. When Raptor, a critical scaffold protein for mammalian target of rapamycin complex 1 (mTORC1), was acutely deleted in intestinal epithelium via Tamoxifen injection in Tritrichomonas muris (Tm) infected mice, tuft cells, IL-25 in epithelium and IL-13 in the mesenchyme were significantly reduced, but Tm burden was not affected. When Tm infected mice were treated with rapamycin, DCLK1 and IL-25 expression in enterocytes and IL-13 expression in mesenchyme were diminished. After massive small bowel resection, tuft cells and Tm were diminished due to the diet used postoperatively. The elimination of Tm and subsequent re-infection of mice with Tm led to type 2 immune response only in WT, but Tm colonization in both WT and Raptor deficient mice. When intestinal organoids were stimulated with IL-4, tuft cells and IL-25 were induced in both WT and Raptor deficient organoids. In summary, our study reveals that enterocyte specific Raptor is required for initiating a type 2 immune response which appears to function through the regulation of mTORC1 activity. PMID- 28717212 TI - A clinicopathological analysis of 153 acral melanomas and the relevance of mechanical stress. AB - The pathogenesis of melanomas emerging in plantar surfaces remains unclear; however, mechanical stress has been reported to increase the formation of melanomas. In this study, we conducted a multicenter retrospective analysis of 153 acral melanomas diagnosed between 2000 and 2015 in Taiwan. The male-to-female ratio of the patients in question was 1:1.28, and the mean age at diagnosis was 68 years. We examined whether melanomas which developed in different areas of the patients' soles differed in their associations with various clinicopathological characteristics and survival. Testing by goodness of fit indicated that stress bearing areas were significantly more conducive to the generation of melanomas than non-stress-bearing areas (P < 0.0001). More specifically, compared to the arch, the rear of the foot and front of the foot were significantly more conducive to the generation of melanomas (P < 0.0001 and P < 0.0001, respectively). The distribution pattern was not associated with differences in age, gender, right/left foot involvement, ulceration, mitosis, lymph node metastasis, tumor thickness, or stage. The overall, distant metastasis-free, and recurrence-free survival rates did not differ significantly between the stress bearing and non-stress-bearing areas. Furthermore, while acral melanomas tended to develop on stress-bearing areas, the distribution pattern was not associated with the prognostic index or survival. PMID- 28717213 TI - Ferroelectric-Paraelectric Transition In A Membrane With Quenched-Induced delta Phase Of PVDF. AB - The stabilization of delta-phase of poly(vinylidene fluoride) PVDF in a 14 um thickness ferroelectric membrane is achieved by a simple route based on the use of a dimethylformamide (DMF)/acetone solvent, in which the application of external electric field is not required. X-ray diffraction and calorimetric experiments on heating reveal that, at 154 degrees C, the original mixture between ferroelectric delta-phase and paraelectric alpha-phase transits to a system with only this latter phase in the crystalline fraction. A gradual and slight increment of amorphous fraction up to the melting at 161 degrees C is also observed. The existence of delta-phase is corroborated by the occurrence of a broad maximum around 154 degrees C in dielectric permittivity measurements, as well as the hysteresis loops observed at room temperature. These results suggest a wide thermal window for a stable delta-phase, between room temperature and 154 degrees C, a subsequent transition into alpha-phase and the corresponding melting at 161 degrees C. The broad dielectric maximum observed around 154 degrees C in dielectric and calorimetric measurements, can be associated with a diffuse ferroelectric-paraelectric transition. PMID- 28717214 TI - Cumulative Dynamics of Independent Information Spreading Behaviour: A Physical Perspective. AB - The popularization of information spreading in online social networks facilitates daily communication among people. Although much work has been done to study the effect of interactions among people on spreading, there is less work that considers the pattern of spreading behaviour when people independently make their decisions. By comparing microblogging, an important medium for information spreading, with the disordered spin glass system, we find that there exist interesting corresponding relationships between them. And the effect of aging can be observed in both systems. Based on the analogy with the Trap Model of spin glasses, we derive a model with a unified power-function form for the growth of independent spreading activities. Our model takes several key factors into consideration, including memory effect, the dynamics of human interest, and the fact that older messages are more difficult to discover. We validate our model by a real-world microblogging data set. Our work indicates that, other than various features, some invariable rules should be considered during spreading prediction. This work also contributes a useful methodology for studying human dynamics. PMID- 28717215 TI - Spot variation fluorescence correlation spectroscopy by data post-processing. AB - Spot variation fluorescence correlation spectroscopy (SV-FCS) is a variant of the FCS techniques which may give useful information about the structural organisation of the medium in which the diffusion takes place. We show that the same results can be obtained by post-processing the photon count data from ordinary FCS measurements. By using this method, one obtains the fluorescence autocorrelation functions for sizes of confocal volume, which are effectively smaller than that of the initial FCS measurement. The photon counts of the initial experiment are first transformed into smooth intensity trace using kernel smoothing method or to a piecewise-continuous intensity trace using binning and then a non-linear transformation is applied to this trace. The result of this transformation mimics the photon count rate in an experiment performed with a smaller confocal volume. The applicability of the method is established in extensive numerical simulations and directly supported in in-vitro experiments. The procedure is then applied to the diffusion of AlexaFluor647-labeled streptavidin in living cells. PMID- 28717216 TI - Random mutagenesis analysis and identification of a novel C2H2-type transcription factor from the nematode-trapping fungus Arthrobotrys oligospora. AB - Arthrobotrys oligospora is a typical nematode-trapping fungus. In this study, 37 transformants of A. oligospora were obtained by REMI (restriction enzyme mediated integration) method and phenotypic properties of nine transformants were analyzed. The nine transformants showed differences in growth, conidiation, trap formation, stress tolerance, and/or pathogenicity among each other and with those of the parental wild-type strain (WT). The insertional sites of the hph cassette were identified in transformants X5 and X13. In X5, the cassette was inserted in the non-coding region between AOL_s00076g273 (76g273) and AOL_s00076g274 (76g274) and the transcription of 76g274, but not 76g273, was enhanced in X5. 76g274p had two conserved domains and was predicted as a nucleoprotein, which we confirmed by its nuclear localization in Saccharomyces cerevisiae using the green fluorescent protein-fused 76g274p. The transcription of 76g274 was stimulated or inhibited by several environmental factors. The sporulation yields of 76g274-deficient mutants were decreased by 70%, and transcription of several sporulation-related genes was severely diminished compared to the WT during the conidiation. In summary, a method for screening mutants was established in A. oligospora and using the method, we identified a novel C2H2-type transcription factor that positively regulates the conidiation of A. oligospora. PMID- 28717217 TI - TKI-addicted ROS1-rearranged cells are destined to survival or death by the intensity of ROS1 kinase activity. AB - ROS1 rearrangement is observed in 1-2% of non-small cell lung cancers (NSCLC). The ROS1 tyrosine kinase inhibitor (TKI) crizotinib has induced marked tumour shrinkage in ROS1-rearranged cancers. However, emergence of acquired resistance to TKI is inevitable within a few years. Previous findings indicate that cabozantinib overcomes secondary mutation-mediated crizotinib-resistance in ROS1 fusion-positive cells. Here we attempted to establish cabozantinib-resistant cells by N-ethyl-N-nitrosourea mutagenesis screening using CD74-ROS1-expressing Ba/F3 cells. Two resistant cell lines with CD74-ROS1 F2004V or F2075C mutations, which are homologous to ALK F1174 or F1245 mutations, survived in the presence of a low dose of ROS1-TKI. Removal of ROS1-TKI from these TKI-addicted cells induced excessive activation of ROS1 tyrosine kinase followed by apoptosis. We succeeded in recapturing the TKI-addicted phenotype using doxycycline-inducible CD74-ROS1 mutant over-expression in Ba/F3 cells, suggesting that excessive ROS1 oncogenic signaling itself induced apoptosis instead of cell growth. Phosphoproteomic analysis and high-throughput inhibitor screening revealed that excessive ROS1 signaling in the TKI-addicted cells phosphorylated or activated apoptosis-related molecules such as FAF1 or p38. Collectively, our findings partly clarify molecular mechanisms of excessive ROS1 oncogenic signaling that mediates paradoxical induction of apoptosis. PMID- 28717218 TI - NMR and DFT investigations of structure of colchicine in various solvents including density functional theory calculations. AB - A detailed NMR investigation of the chemical shifts of hydrogen and carbon atoms associated with the structure of the naturally occurring alkaloid colchicine was conducted using high field NMR. Initially, the experimental chemical shifts for colchicine in chloroform and DMSO were compared to the values calculated using density functional theory (DFT). There were significant deviations observed for the chloroform solvent, but these were only slight in the DMSO solution. Dilution of the chloroform solution changed the experimental chemical shifts and improved agreement with the DFT calculations, suggesting self-aggregation at higher concentrations. A dimeric model was proposed for which agreement with the DFT calculated chemical shifts was better than for corresponding monomeric structures. Three further solvents were studied to evaluate changes in chemical shift values at different dilutions. Chloroform, benzene and water showed significant chemical shift changes implying self-aggregation, whereas DMSO and acetone did not show significant change upon dilution. PMID- 28717219 TI - Versatile functional roles of horizontal cells in the retinal circuit. AB - In the retinal circuit, environmental light signals are converted into electrical signals that can be decoded properly by the brain. At the first synapse of the visual system, information flow from photoreceptors to bipolar cells is modulated by horizontal cells (HCs), however, their functional contribution to retinal output and individual visual function is not fully understood. In the current study, we investigated functional roles for HCs in retinal ganglion cell (RGC) response properties and optokinetic responses by establishing a HC-depleted mouse line. We observed that HC depletion impairs the antagonistic center-surround receptive field formation of RGCs, supporting a previously reported HC function revealed by pharmacological approaches. In addition, we found that HC loss reduces both the ON and OFF response diversities of RGCs, impairs adjustment of the sensitivity to ambient light at the retinal output level, and alters spatial frequency tuning at an individual level. Taken together, our current study suggests multiple functional aspects of HCs crucial for visual processing. PMID- 28717221 TI - Individual recognition of opposite sex vocalizations in the zebra finch. AB - Individual vocal recognition plays an important role in the social lives of many vocally active species. In group-living songbirds the most common vocalizations during communal interactions are low-intensity, soft, unlearned calls. Being able to tell individuals apart solely from a short call would allow a sender to choose a specific group member to address, resulting in the possibility to form complex communication networks. However, little research has yet been carried out to discover whether soft calls contain individual identity. In this study, males and females of zebra finch pairs were tested with six vocalization types - four different soft calls, the distance call and the male song - to investigate whether they are able to distinguish individuals of the opposite sex. For both sexes, we provide the first evidence of individual vocal recognition for a zebra finch soft unlearned call. Moreover, while controlling for habituation and testing for repeatability of the findings, we quantify the effects of hitherto little studied variables such as partners' vocal exchange previous to the experiment, spectral content of playback calls and quality of the answers. We suggest that zebra finches can recognize individuals via soft vocalizations, therefore allowing complex directed communication within vocalizing flocks. PMID- 28717220 TI - Imaging mass spectrometry and MS/MS molecular networking reveals chemical interactions among cuticular bacteria and pathogenic fungi associated with fungus growing ants. AB - The fungus-growing ant-microbe symbiosis is an ideal system to study chemistry based microbial interactions due to the wealth of microbial interactions described, and the lack of information on the molecules involved therein. In this study, we employed a combination of MALDI imaging mass spectrometry (MALDI-IMS) and MS/MS molecular networking to study chemistry-based microbial interactions in this system. MALDI IMS was used to visualize the distribution of antimicrobials at the inhibition zone between bacteria associated to the ant Acromyrmex echinatior and the fungal pathogen Escovopsis sp. MS/MS molecular networking was used for the dereplication of compounds found at the inhibition zones. We identified the antibiotics actinomycins D, X2 and X0beta, produced by the bacterium Streptomyces CBR38; and the macrolides elaiophylin, efomycin A and efomycin G, produced by the bacterium Streptomyces CBR53.These metabolites were found at the inhibition zones using MALDI IMS and were identified using MS/MS molecular networking. Additionally, three shearinines D, F, and J produced by the fungal pathogen Escovopsis TZ49 were detected. This is the first report of elaiophylins, actinomycin X0beta and shearinines in the fungus-growing ant symbiotic system. These results suggest a secondary prophylactic use of these antibiotics by A. echinatior because of their permanent production by the bacteria. PMID- 28717222 TI - FTY720 Induces Autophagy-Associated Apoptosis in Human Oral Squamous Carcinoma Cells, in Part, through a Reactive Oxygen Species/Mcl-1-Dependent Mechanism. AB - In this study, we interrogated the mechanism by which the immunosuppressant FTY720 mediates anticancer effects in oral squamous cell carcinoma (OSCC) cells. FTY720 differentially suppressed the viability of the OSCC cell lines SCC4, SCC25, and SCC2095 with IC50 values of 6.1, 6.3, and 4.5 MUM, respectively. This antiproliferative effect was attributable to the ability of FTY720 to induce caspase-dependent apoptosis. Mechanistic evidence suggests that FTY720-induced apoptosis was associated with its ability to inhibit Akt-NF-kappaB signaling, to facilitate the proteasomal degradation of the antiapoptotic protein Mcl-1, and to increase reactive oxygen species (ROS) generation. Both overexpression of Mcl-1 and inhibition of ROS partially protected cells from FTY720-induced caspase-9 activation, PARP cleavage and cytotoxicity. In addition, FTY720 induced autophagy in OSCC cells, as manifested by LC3B-II conversion, decreased p62 expression, and accumulation of autophagosomes. Inhibition of autophagy by bafilomycin A1 protected cells from FTY720-induced apoptosis. Together, these findings suggest an intricate interplay between autophagy and apoptosis in mediating the tumor suppressive effect in OSCC cells, which underlies the translational potential of FTY720 in fostering new therapeutic strategies for OSCC. PMID- 28717224 TI - Fibulin-4 deposition requires EMILIN-1 in the extracellular matrix of osteoblasts. AB - Tissue microenvironments formed by extracellular matrix networks play an important role in regulating tissue structure and function. Extracellular microfibrillar networks composed of fibrillins and their associated ligands such as LTBPs, fibulins, and EMILINs are of particular interest in this regard since they provide a specialized cellular microenvironment guiding proper morphology and functional behavior of specialized cell types. To understand how cellular microenvironments composed of intricate microfibrillar networks influence cell fate decisions in a contextual manner, more information about the spatiotemporal localization, deposition, and function of their components is required. By employing confocal immunofluorescence and electron microscopy we investigated the localization and extracellular matrix deposition of EMILIN-1 and -2 in tissues of the skeletal system such as cartilage and bone as well as in in vitro cultures of osteoblasts. We found that upon RNAi mediated depletion of EMILIN-1 in primary calvarial osteoblasts and MC3T3-E1 cells only fibulin-4 matrix deposition was lost while other fibulin family members or LTBPs remained unaffected. Immunoprecipitation and ELISA-style binding assays confirmed a direct interaction between EMILIN-1 and fibulin-4. Our data suggest a new function for EMILIN-1 which implies the guidance of linear fibulin-4 matrix deposition and thereby fibulin-4 fiber formation. PMID- 28717223 TI - Investigation of the Changes in the Power Distribution in Resting-State Brain Networks Associated with Pure Conduct Disorder. AB - Conduct disorder (CD) is a psychiatric disorder in children and adolescence. To investigate changes in the power distribution in brain networks between CD and typically developing (TD) groups, resting-state functional magnetic resonance imaging (rsfMRI) data of thirty-six subjects were first recorded, and then the data were preprocessed using DPARSF and SPM8. Meanwhile, the power of the blood oxygenation level-dependent (BOLD) signals of ninety brain regions was acquired using the integral of the Welch power spectral density (PSD). Additionally, the powers of the brain regions that reached significance (p < 0.05) were extracted using the bootstrap statistics, in which the standardized z-scores of the powers were used as a reference. The results of the analysis of the changes in power exhibited that there were significant power differences in some pairs of brain regions between the CD and TD groups, indicating a change in the power distribution. In addition, the results also suggest that the total power consumption of brain networks in CD patients is less than that observed in the TD group. Consequently, the study provided a paradigm for establishing quantifiable indicators via the power spectrum approach for the comparison and analysis of the BOLD signal power between CD patients and healthy controls. PMID- 28717225 TI - A mammalian mirtron miR-1224 promotes tube-formation of human primary endothelial cells by targeting anti-angiogenic factor epsin2. AB - Angiogenesis, new vessel formation from pre-existing vessels, is a highly conserved event through vertebrates. However, the system for tuning angiogenesis by species-intrinsic factors is totally unknown. miR-1224 is a member of mammal specific mirtrons, which were identified as non-canonical microRNAs. We found that the expression of miR-1224 was upregulated in capillary-like tube-forming human umbilical vein endothelial cells on Matrigel. Enforced expression of miR 1224 stimulated tube formation, whereas repression of endogenous miR-1224 inhibited formation. Enforced expression of miR-1224 enhanced VEGF signaling and repressed NOTCH signaling. The adaptor protein of clathrin-dependent endocytosis, epsin2, which has been shown to be a suppressor of angiogenesis, was a direct target of miR-1224. Knockdown of EPN2 stimulated tube formation, while overexpression of EPN2 repressed miR-1224-mediated stimulation. Our findings indicate that miR-1224 is a mammal specific modulator of angiogenesis. PMID- 28717226 TI - Safe Brain Tumor Resection Does not Depend on Surgery Alone - Role of Hemodynamics. AB - Aim of this study was to determine if perioperative hemodynamics have an impact on perioperative infarct volume and patients' prognosis. 201 cases with surgery for a newly diagnosed or recurrent glioblastoma were retrospectively analyzed. Clinical data and perioperative hemodynamic parameters, blood tests and time of surgery were recorded. Postoperative infarct volume was quantitatively assessed by semiautomatic segmentation. Mean diastolic blood pressure (dBP) during surgery (rho -0.239, 95% CI -0.11 - -0.367, p = 0.017), liquid balance (rho 0.236, 95% CI 0.1-0.373, p = 0.017) and mean arterial pressure (MAP) during surgery (rho 0.206, 95% CI -0.07 - -0.34, p = 0.041) showed significant correlation to infarct volume. A rank regression model including also age and recurrent surgery as possible confounders revealed mean intraoperative dBP, liquid balance and length of surgery as independent factors for infarct volume. Univariate survival analysis showed mean intraoperative dBP and MAP as significant prognostic factors, length of surgery also remained as significant prognostic factor in a multivariate model. Perioperative close anesthesiologic monitoring of blood pressure and liquid balance is of high significance during brain tumor surgery and should be performed to prevent or minimize perioperative infarctions and to prolong survival. PMID- 28717227 TI - A Fluctuation Equation of State for Prediction of High-Pressure Densities of Ionic Liquids. AB - During this work, we demonstrate, for the first time, that the volumetric properties of pure ionic liquids could be truly predicted as a function of temperature from 219 K to 473 K and pressure up to 300 MPa. This has been achieved by using only density and isothermal compressibility data at atmospheric pressure through the Fluctuation Theory-based Tait-like Equation of State (FT EoS). The experimental density data of 80 different ionic liquids, described in the literature by several research groups as a function of temperature and pressure, was then used to provide comparisons. Excellent predictive capability of FT-EoS was observed with an overall relative absolute average deviation close to 0.14% for the 15,298 data points examined during this work. PMID- 28717228 TI - Transformation of patchouli alcohol to beta-patchoulene by gastric juice: beta patchoulene is more effective in preventing ethanol-induced gastric injury. AB - Pogostemonis Herba is a functional food approved in Asian countries. Its major constituent, patchouli alcohol (PA), possesses a gastroprotective effect and is reported to transform into beta-patchoulene (beta-PAE) under acidic conditions. To investigate whether beta-PAE, the metabolite of PA, has a protective effect on the gastrointestinal tract, the formation of beta-PAE by gastric juice and the anti-ulcerogenic potential of beta-PAE against ethanol-induced gastric injury were evaluated. The Results indicated that PA was converted to beta-PAE by rat gastric juice. Additionally, beta-PAE was significantly better than PA at reducing the area of gastric ulcer. The overproduction of malondialdehyde, tumour necrosis factor-alpha, interleukin (IL)-1beta, IL-6, Fas, FasL and caspase-3 was markedly inhibited by beta-PAE while the underproduction of superoxide dismutase, glutathione and catalase was significantly improved. beta-PAE also regulated the NF-kappaB and ERK1/2 signalling pathways. Our findings suggest that beta-PAE has potential therapeutic efficacy for antiulcer treatment. PMID- 28717229 TI - Investigation of autistic traits through strategic decision-making in games with adaptive agents. AB - Autism Spectrum Disorders are characterized by difficulties in communicating and cooperating with other people. Impairment in Theory of Mind (ToM), the ability to infer what another person is thinking, may contribute to these social deficits. The present study assesses the relationship between autistic traits and decision making in a socioeconomic game environment that measures ToM and cooperation. We quantified participant strategy during game play with computer agents that simulated aspects of ToM or fixed strategy agents with static behaviors or heuristics. Individuals with higher Autism Quotient (AQ) scores cooperated less than subjects with low AQ scores with the ToM agents. In contrast, subjects with higher AQ scores cooperated more with fixed strategy agents. Additionally, subjects with higher AQ scores spent more time than low AQ subjects signaling cooperative intent in games with fixed strategy agents while spending less time signaling cooperation with adaptive agents, indicating a preference toward systemizing behaviors in the face of uncertainty. We conclude that individuals with high levels of autistic traits are less likely to utilize ToM as a cognitive strategy, even when it is beneficial, to achieve a desired outcome. PMID- 28717230 TI - Activin signaling is an essential component of the TGF-beta induced pro metastatic phenotype in colorectal cancer. AB - Advanced colorectal cancer (CRC) remains a critical health care challenge worldwide. Various TGF-beta superfamily members are important in colorectal cancer metastasis, but their signaling effects and predictive value have only been assessed in isolation. Here, we examine cross-regulation and combined functions of the two most prominent TGF-beta superfamily members activin and TGF beta in advanced colorectal cancer. In two clinical cohorts we observed by immune based assay that combined serum and tissue activin and TGF-beta ligand levels predicts outcome in CRC patients and is superior to single ligand assessment. While TGF-beta growth suppression is independent of activin, TGF-beta treatment leads to increased activin secretion in colon cancer cells and TGF-beta induced cellular migration is dependent on activin, indicating pathway cross-regulation and functional interaction in vitro. mRNA expression of activin and TGF-beta pathway members were queried in silico using the TCGA data set. Coordinated ligand and receptor expression is common in solid tumors for activin and TGF-beta pathway members. In conclusion, activin and TGF-beta are strongly connected signaling pathways that are important in advanced CRC. Assessing activin and TGF beta signaling as a unit yields important insights applicable to future diagnostic and therapeutic interventions. PMID- 28717231 TI - A connection from stratospheric ozone to El Nino-Southern Oscillation. AB - We use reanalysis and observational data to link the lower stratospheric ozone regulation of the ultraviolet radiation (UV-B) component of solar energy to ENSO modulation. Results indicate that during ENSO extremes, the Walker Circulation (WC) and Brewer Dobson Circulation are related to lower stratospheric ozone alterations east of the date line over the Pacific. These in turn are linked to upper tropospheric anomalous dipole temperature patterns on either side of the equator. The ensuing changes in geopotential height values do not only drive equatorial zonal wind anomalies in the upper troposphere that are reversed at the equatorial surface, but also impact on the intensity of the South Pacific High circulation. When the WC is enhanced, a La Nina type of circulation is indentified but if the circulation cell is inverted, the anomalous circulation results in an El Nino. Though the anomalous lower stratospheric ozone peaks during austral summer it is significant throughout the ENSO lifecycle. Hence, ENSO structure and variability are mainly linked to the lower stratospheric ozone instigated internal dynamics of the Pacific atmosphere. The ENSO forcing most likely originates from the ozone related regulation of the incoming solar UV-B radiation rather than the Pacific Ocean surface. PMID- 28717232 TI - The Epichloe festucae antifungal protein has activity against the plant pathogen Sclerotinia homoeocarpa, the causal agent of dollar spot disease. AB - Epichloe spp. are naturally occurring fungal endophytic symbionts of many cool season grasses. Infection by the fungal endophytes often confers biotic and abiotic stress tolerance to their hosts. Endophyte-mediated disease resistance is well-established in the fine fescue grass Festuca rubra subsp. rubra (strong creeping red fescue) infected with E. festucae. Resistance to fungal pathogens is not an established effect of endophyte infection of other grass species, and may therefore be unique to the fine fescues. The underlying mechanism of the disease resistance is unknown. E. festucae produces a secreted antifungal protein that is highly expressed in the infected plant tissues and may therefore be involved in the disease resistance. Most Epichloe spp. do not have a gene for a similar antifungal protein. Here we report the characterization of the E. festucae antifungal protein, designated Efe-AfpA. The antifungal protein partially purified from the apoplastic proteins of endophyte-infected plant tissue and the recombinant protein expressed in the yeast Pichia pastoris was found to have activity against the important plant pathogen Sclerotinia homoeocarpa. Efe-AfpA may therefore be a component of the disease resistance seen in endophyte-infected strong creeping red fescue. PMID- 28717233 TI - Effect of LDL cholesterol, statins and presence of mutations on the prevalence of type 2 diabetes in heterozygous familial hypercholesterolemia. AB - Patients with heterozygous familial hypercholesterolemia (HeFH) have been reported to be less vulnerable to type 2 diabetes mellitus (T2DM), although the mechanism is unknown. The aims of the present study were to assess the effects of low density lipoprotein (LDL) cholesterol concentration and the presence of FH causing mutations on T2DM prevalence in HeFH. Data were collected from the Dyslipidemia Registry of the Spanish Arteriosclerosis Society. Inclusion criteria were definite or probable HeFH in patients aged >=18 years. T2DM prevalence in HeFH patients was compared with data of the general population. 1732 patients were included. The prevalence of T2DM was lower in patients with HeFH compared with the general population (5.94% vs 9.44%; OR: 0.606, 95% CI 0.486-0.755, p < 0.001). Risk factors for developing T2DM were male sex, age, body mass index, hypertension, baseline triglyceride levels and years on statin therapy. The prevalence of T2DM in HeFH patients was 40% lower than that observed in the general population. Gene mutations and LDL cholesterol concentrations were not risk factors associated with the prevalence of T2DM in patients with HeFH. The prevalence of T2DM in patients with HeFH was 40% lower than in the general population matched for age and sex. PMID- 28717234 TI - Dietary lipid content reorganizes gut microbiota and probiotic L. rhamnosus attenuates obesity and enhances catabolic hormonal milieu in zebrafish. AB - In the present study, we explored whether dietary lipid content influences the gut microbiome in adult zebrafish. Diets containing three different lipid levels (high [HFD], medium [MFD], and low [LFD]) were administered with or without the supplementation of Lactobacillus rhamnosus (P) to zebrafish in order to explore how the dietary lipid content may influence the gut microbiome. Dietary lipid content shifted the gut microbiome structure. The addition of L. rhamnosus in the diets, induced transcriptional reduction of orexigenic genes, upregulation of anorexigenic genes, and transcriptional decrease of genes involved in cholesterol and triglyceride (TAG) metabolism, concomitantly with lower content of cholesterol and TAG. Probiotic feeding also decreased nesfatin-1 peptide in HFD-P and attenuated weight gain in HFD-P and MFD-P fed zebrafish, but not in LFD-P group. Intestinal ultrastructure was not affected by dietary fat level or probiotic inclusion. In conclusion, these findings underline the role of fat content in the diet in altering gut microbiota community by shifting phylotype composition and highlight the potential of probiotics to attenuate high-fat diet related metabolic disorder. PMID- 28717235 TI - Protein-protein binding selectivity and network topology constrain global and local properties of interface binding networks. AB - Protein-protein interactions networks (PPINs) are known to share a highly conserved structure across all organisms. What is poorly understood, however, is the structure of the child interface interaction networks (IINs), which map the binding sites proteins use for each interaction. In this study we analyze four independently constructed IINs from yeast and humans and find a conserved structure of these networks with a unique topology distinct from the parent PPIN. Using an IIN sampling algorithm and a fitness function trained on the manually curated PPINs, we show that IIN topology can be mostly explained as a balance between limits on interface diversity and a need for physico-chemical binding complementarity. This complementarity must be optimized both for functional interactions and against mis-interactions, and this selectivity is encoded in the IIN motifs. To test whether the parent PPIN shapes IINs, we compared optimal IINs in biological PPINs versus random PPINs. We found that the hubs in biological networks allow for selective binding with minimal interfaces, suggesting that binding specificity is an additional pressure for a scale-free-like PPIN. We confirm through phylogenetic analysis that hub interfaces are strongly conserved and rewiring of interactions between proteins involved in endocytosis preserves interface binding selectivity. PMID- 28717236 TI - High performance micro-flow cytometer based on optical fibres. AB - Flow cytometry is currently the gold standard for analysis of cells in the medical laboratory and biomedical research. Fuelled by the need of point-of-care diagnosis, a significant effort has been made to miniaturize and reduce cost of flow cytometers. However, despite recent advances, current microsystems remain less versatile and much slower than their large-scale counterparts. In this work, an all-silica fibre microflow cytometer is presented that measures fluorescence and scattering from particles and cells. It integrates cell transport in circular capillaries and light delivery by optical fibres. Single-stream cell focusing is performed by Elasto-inertial microfluidics to guarantee accurate and sensitive detection. The capability of this technique is extended to high flow rates (up to 800 ul/min), enabling a throughput of 2500 particles/s. The robust, portable and low-cost system described here could be the basis for a point-of-care flow cytometer with a performance comparable to commercial systems. PMID- 28717237 TI - Fat binding capacity and modulation of the gut microbiota both determine the effect of wheat bran fractions on adiposity. AB - The aim of this study was to determine the impact of different wheat bran fractions on the gut microbiota and fat binding capacity to explain their differential effects on metabolic and inflammatory disorders induced by a western diet (WD) in mice. Wheat bran derived arabinoxylan oligosaccharides (AXOS), a crude fraction of wheat bran (WB), or the same wheat bran with reduced particle size (WBs) were added to the WD of mice for 8 weeks. AXOS shifted the gut microbiota composition, blunted Clostridium and Turicibacter genera and strongly promoted Bifidobacterium and Butyricicoccus genera, independently of changes in gut antimicrobial peptide expression. AXOS was the most efficient to reduce adiposity. Only WB fraction promoted fat excretion and differed from the other fractions by the capacity to increase the Akkermansia genus and to counteract gut interleukin 1 beta (IL1beta) overexpression. Strikingly, WBs promoted steatosis and adipose tissue inflammation, despite its ability -like WB- to increase bacterial diversity. In conclusion, wheat bran fractions differently affect metabolic and inflammatory disorders associated with WD feeding, depending on their particle size, their fat binding capacity and their influence on the gut microbiota. Those results might be useful to take into account in nutritional advices to control obesity. PMID- 28717238 TI - Molecular mechanism of PD-1/PD-L1 blockade via anti-PD-L1 antibodies atezolizumab and durvalumab. AB - In 2016 and 2017, monoclonal antibodies targeting PD-L1, including atezolizumab, durvalumab, and avelumab, were approved by the FDA for the treatment of multiple advanced cancers. And many other anti-PD-L1 antibodies are under clinical trials. Recently, the crystal structures of PD-L1 in complex with BMS-936559 and avelumab have been determined, revealing details of the antigen-antibody interactions. However, it is still unknown how atezolizumab and durvalumab specifically recognize PD-L1, although this is important for investigating novel binding sites on PD-L1 targeted by other therapeutic antibodies for the design and improvement of anti-PD-L1 agents. Here, we report the crystal structures of PD-L1 in complex with atezolizumab and durvalumab to elucidate the precise epitopes involved and the structural basis for PD-1/PD-L1 blockade by these antibodies. A comprehensive comparison of PD-L1 interactions with anti-PD-L1 antibodies provides a better understanding of the mechanism of PD-L1 blockade as well as new insights into the rational design of improved anti-PD-L1 therapeutics. PMID- 28717239 TI - A Novel Pathogen Capturing Device for Removal and Detection. AB - A simple technique that employs an antibody coated polydimethylsiloxane tube is used for effective capturing of bloodborne and foodborne pathogens. By recirculating the entire sample through the antibody coated tube, accumulation of target pathogens is achieved, thereby delivering a higher concentration of pathogens in a small volume. The described method can provide an effective and economical solution to microbiology techniques that rely on enrichment, thereby expediting diagnostics. Using this method 80.3 +/- 5.6% of Staphylococcus aureus with a starting concentration of ~107 CFU/mL and 95.4 +/- 1.0% of Methicillin resistant Staphylococcus aureus with starting concentration of ~104 CFU/mL were removed from 5 mL blood in a few hours. This concept was extended to live rats with an induced bloodstream S. aureus infection. A reduction of two orders of magnitude in the bacterial load of the rats was observed within a few hours. The same technique was used to capture a food pathogen, Salmonella typhimurium, with starting concentrations as low as ~100 CFU, from 100 or 250 mL of culture broth within similar timeframes as above. The feasibility for food pathogen testing applications was additionally confirmed by capturing and detecting S. typhimurium in ground chicken and ground beef. PMID- 28717240 TI - Elemental compositions of lichens from Duolun County, Inner Mongolia, China: Origin, road effect and species difference. AB - To assess the response of lichen elemental compositions to road traffic and species difference in the context of high dust input and anthropogenic emissions, two foliose epiphytic lichens (Phaeophyscia hirtuosa, PHh; Candelaria fibrosa, CAf) were sampled near a road adjacent to Dolon Nor Town (Duolun County, Inner Mongolia, China). Twenty elements (Ba, Ca, Cd, Co, Cr, Cu, Fe, K, Mg, Mn, Mo, Na, Ni, P, Pb, Sb, Sr, Ti, V and Zn) in lichen and surface soil samples were analysed using inductively coupled plasma mass spectrometer (ICP-MS). The results demonstrate that lichen elemental compositions are highly influenced by both their natural environment and anthropogenic input. Windblown dust associated with sand dunes and degraded/desertified steppes represents the predominant source of lichen elements. Road traffic can enhance the lichen elemental burden by increasing the number of soil particles. Anthropogenic emissions from the town and road traffic have also led to the enrichment of Cd and Zn in lichens. PHh was higher than CAf in concentrations of 14 terrigenous metals. Both lichens are applicable to biomonitoring of atmospheric element deposition and, in most cases, yield comparable results. PMID- 28717242 TI - A New Solution Concept for the Ultimatum Game leading to the Golden Ratio. AB - The Ultimatum Game is a paradigmatic two-player game. A proposer can offer a certain fraction of some valuable good. A responder can accept the offer or reject it, implying that the two players receive nothing. The only subgame perfect Nash equilibrium is to only offer an infinitesimal amount and to accept this. However, this equilibrium is not in agreement with experimental observations, which show varying accepted offers around 40%. While some authors suggest that the fairest split of 50% vs. 50% would be explainable on theoretical grounds or by computer simulation, a few authors (including myself) have recently suggested that the Golden Ratio, about 0.618 vs. about 0.382, would be the solution, in striking agreement with observations. Here we propose a solution concept, based on an optimality approach and epistemic arguments, leading to that suggested solution. The optimality principle is explained both in an axiomatic way and by bargaining arguments, and the relation to Fibonacci numbers is outlined. Our presentation complements the Economic Harmony theory proposed by R. Suleiman and is based on infinite continued fractions. The results are likely to be important for the theory of fair salaries, justice theory and the predictive value of game theory. PMID- 28717241 TI - Sca-1 identifies a trophoblast population with multipotent potential in the mid gestation mouse placenta. AB - Trophoblast stem (TS) cells in the mouse derive from the polar trophectoderm of the blastocyst and persist through early gestation (to E8.5) to support placental development. Further development and growth is proposed to rely on layer restricted progenitor cells. Stem cell antigen (Sca) -1 is a member of the Ly6 gene family and a known marker of stem cells in both hematopoietic and non hematopoietic mouse tissues. Having identified that Sca-1 mRNA was highly expressed in mouse TS cells in culture, we found that it was also expressed in a subset of trophoblast within the chorion and labyrinth layer of the mouse placenta. Isolation and in vitro culture of Sca-1+ trophoblast cells from both differentiated TS cell cultures and dissected mouse placentae resulted in proliferating colonies that expressed known markers of TS cells. Furthermore, these cells could be stimulated to differentiate and expressed markers of both junctional zone and labyrinth trophoblast subtypes in a manner comparable to established mouse TS cell lines. Our results suggest that we have identified a subpopulation of TS cell-like cells that persist in the mid- to late- gestation mouse placenta as well as a cell surface protein that can be used to identify and isolate these cells. PMID- 28717243 TI - The long non-coding RNA LOC441204 enhances cell growth in human glioma. AB - Glioma is the most common and aggressive type of brain tumor. While long non coding RNAs (lncRNAs) are clearly more abundant in human brain than protein coding genes, the specific roles of lncRNAs and mechanisms underlying their dysregulation in glioma remain unclear. Here, we focused on lncRNAs that are differentially expressed in brain tumor and their potential biological functions. LOC441204, a novel non-coding RNA gene displaying high expression in clinical specimens of brain tumor and significant upregulation in glioma cell lines in microarray analyses, was selected for further study. Notably, knockdown of LOC441204 suppressed tumor cell proliferation in two glioma cell lines. Moreover, LOC441204-induced tumor cell growth was mediated the stabilization of beta catenin pathway. Briefly, LOC441204 bound to beta-catenin preventing its degradation, resulting in downstream p21 repression and cdk4 activation to enhance glioma cell proliferation. Collectively, our findings indicate a pro oncogenic role of LOC441204 in tumor cell growth through activation of the beta catenin/p21/cdk4 cascade to act as a potential diagnostic marker or therapeutic target in brain tumor. PMID- 28717244 TI - TRAIL regulatory receptors constrain human hepatic stellate cell apoptosis. AB - The TRAIL pathway can mediate apoptosis of hepatic stellate cells to promote the resolution of liver fibrosis. However, TRAIL has the capacity to bind to regulatory receptors in addition to death-inducing receptors; their differential roles in liver fibrosis have not been investigated. Here we have dissected the contribution of regulatory TRAIL receptors to apoptosis resistance in primary human hepatic stellate cells (hHSC). hHSC isolated from healthy margins of liver resections from different donors expressed variable levels of TRAIL-R2/3/4 (but negligible TRAIL-R1) ex vivo and after activation. The apoptotic potential of TRAIL-R2 on hHSC was confirmed by lentiviral-mediated knockdown. A functional inhibitory role for TRAIL-R3/4 was revealed by shRNA knockdown and mAb blockade, showing that these regulatory receptors limit apoptosis of hHSC in response to both oligomerised TRAIL and NK cells. A close inverse ex vivo correlation between hHSC TRAIL-R4 expression and susceptibility to apoptosis underscored its central regulatory role. Our data provide the first demonstration of non-redundant functional roles for the regulatory TRAIL receptors (TRAIL-R3/4) in a physiological setting. The potential for these inhibitory TRAIL receptors to protect hHSC from apoptosis opens new avenues for prognostic and therapeutic approaches to the management of liver fibrosis. PMID- 28717245 TI - Development and Validation of a Three-gene Prognostic Signature for Patients with Hepatocellular Carcinoma. AB - Hepatocellular carcinoma (HCC) is the leading cause of cancer-related death worldwide, because recurrence often occurs in most HCC patients undergoing hepatectomy. It is necessary to identify patients with high risk for recurrence and adopt effective therapies. An obstacle to monitor patients at high risk for poor prognosis has been the lack of useful predictive biomarkers. Fortunately, recent progress in system biology allows to screen the biomarkers for HCC prognosis in a high-throughput manner. In this study, we performed systematic Kaplan-Meier survival analysis of the whole mRNA transcriptomics based on the Cancer Genome Atlas project (TCGA) and developed a three-gene prognostic signature composing of three genes UPB1, SOCS2 and RTN3. The model was validated in two independent microarray data sets retrieved from Gene Expression Omnibus (GEO) and the expression pattern of these three predictive genes in HCC was confirmed by western blot and immunohistochemistry with our HCC samples. In conclusion, our results showed that this three-gene signature has prognostic value for HCC patients. PMID- 28717246 TI - Estimating utility weights and quality-adjusted life year loss for colorectal cancer-related health states in Korea. AB - We aimed to assess utility weight of health states associated with colorectal cancer (CRC) that reflect the societal preference of the Korean population and to estimate the quality-adjusted life year (QALY) loss with CRC. We recruited 607 individuals from the Korean population; they were surveyed via face-to-face computer-assisted interviews. The participants evaluated each CRC-associated health state using standard gamble. Utility weight for each health state was calculated as the possibility of full health restoration. Moreover, we estimated total QALY loss due to CRC in Korean individuals aged >=30 years in 2013. To calculate QALY due to morbidity, we yielded utility weights and used epidemiologic data of CRC on severity from the National Cancer Control Institute. QALY loss due to mortality was calculated using mortality of CRC and life expectancy data from the Korean Statistical Information Service. The highest and lowest utility weights were assigned to "adenomatous polyps" and "metastatic colon cancer", respectively. Total QALY loss due to CRC in Korea was 173,662; these patients were more likely to be men or be included in the 70-74-year age group. These utility weights may be useful for conducting cost-utility studies of cancer screening for CRC and for measuring disease burden with QALY. PMID- 28717247 TI - Characterization of HIV-1 integrase interaction with human Ku70 protein and initial implications for drug targeting. AB - Human Ku70/Ku80 protein is known to influence HIV-1 replication. One of the possible reasons may be the protection of integrase from proteasomal degradation by Ku70 subunit. We demonstrated that recombinant HIV-1 integrase and Ku70 form a stable complex, while no interaction of Ku70 with integrase from prototype foamy virus was observed. By analyzing protein subdomains we determined two binding sites in the structure of both Ku70 and integrase: the 51-160 a.a. region of integrase interacts with residues 251-438 of Ku70, whereas Ku70 N-terminal domain (1-250 a.a.) contacts an alpha6-helix in the 200-220 a.a. integrase region. Single substitutions within integrase (E212A or L213A) block the interaction with Ku70 thus indicating that the binding site formed by the 200-220 a.a. integrase region is crucial for complex formation. E212A/L213A substitutions decreased the integrase capacity to bind Ku70 in HEK293T cells. A conjugate of 2'-OMe GGUUUUUGUGU oligonucleotide with eosin is shown by molecular modeling to shield integrase residues E212/L213 and is effective in blocking complex formation of Ku70 with integrase what makes the complex between alpha6-helix and Ku70(1-250) a possible target for drug development. PMID- 28717248 TI - Loss of type 9 adenylyl cyclase triggers reduced phosphorylation of Hsp20 and diastolic dysfunction. AB - Adenylyl cyclase type 9 (AC9) is found tightly associated with the scaffolding protein Yotiao and the IKs ion channel in heart. But apart from potential IKs regulation, physiological roles for AC9 are unknown. We show that loss of AC9 in mice reduces less than 3% of total AC activity in heart but eliminates Yotiao associated AC activity. AC9-/- mice exhibit no structural abnormalities but show a significant bradycardia, consistent with AC9 expression in sinoatrial node. Global changes in PKA phosphorylation patterns are not altered in AC9-/- heart, however, basal phosphorylation of heat shock protein 20 (Hsp20) is significantly decreased. Hsp20 binds AC9 in a Yotiao-independent manner and deletion of AC9 decreases Hsp20-associated AC activity in heart. In addition, expression of catalytically inactive AC9 in neonatal cardiomyocytes decreases isoproterenol stimulated Hsp20 phosphorylation, consistent with an AC9-Hsp20 complex. Phosphorylation of Hsp20 occurs largely in ventricles and is vital for the cardioprotective effects of Hsp20. Decreased Hsp20 phosphorylation suggests a potential baseline ventricular defect for AC9-/-. Doppler echocardiography of AC9 /- displays a decrease in the early ventricular filling velocity and ventricular filling ratio (E/A), indicative of grade 1 diastolic dysfunction and emphasizing the importance of local cAMP production in the context of macromolecular complexes. PMID- 28717249 TI - Spectral characteristics of cotton seeds treated by a dielectric barrier discharge plasma. AB - Cold atmospheric plasma has recently emerged as a simple, low-cost and efficient physical method for inducing significant biological responses in seeds and plants without the use of traditional, potentially environmentally-hazardous chemicals, fungicides or hormones. While the beneficial effects of plasma treatment on seed germination, disease resistance and agricultural output have been reported, the mechanisms that underpin the observed biological responses are yet to be fully described. This study employs Fourier Transform Infrared (FTIR) spectroscopy and emission spectroscopy to capture chemical interactions between plasmas and seed surfaces with the aim to provide a more comprehensive account of plasma-seed interactions. FTIR spectroscopy of the seed surface confirms plasma-induced chemical etching of the surface. The etching facilitates permeation of water into the seed, which is confirmed by water uptake measurements. FTIR of exhaust and emission spectra of discharges show oxygen-containing species known for their ability to stimulate biochemical processes and deactivate pathogenic microorganisms. In addition, water gas, CO2, CO and molecules containing -C(CH3)3 moieties observed in FTIR spectra of the exhaust gas during plasma treatment may be partly responsible for the plasma chemical etching of seed surface through oxidizing the organic components of the seed coat. PMID- 28717250 TI - Plk1 phosphorylation of CAP-H2 triggers chromosome condensation by condensin II at the early phase of mitosis. AB - Condensin complexes play crucial roles in chromosome condensation that is a fundamental process to establish the "rod-like" shape of chromosome structure in mitosis. Failure of the chromosome assembly causes chromosome segregation errors and subsequent genomic instability. However, a molecular mechanism that controls condensin function for the chromosomal organization has not been fully understood. Here, we show that the abundance of CAP-H2, one of the condensin II subunits, is fluctuated during the cell cycle in accordance with Plk1 kinase activity. Inhibition of Plk1 leads to Cdc20-mediated degradation of CAP-H2 in mitosis. Plk1 phosphorylation of CAP-H2 at Ser288 is required for the accumulation of CAP-H2 and accurate chromosomal condensation during prophase. These findings suggest that Plk1 phosphorylation regulates condensin II function by modulating CAP-H2 expression levels to facilitate proper mitotic chromosome organization. PMID- 28717251 TI - Transdifferentiated Human Vascular Smooth Muscle Cells are a New Potential Cell Source for Endothelial Regeneration. AB - Endothelial dysfunction is widely implicated in cardiovascular pathological changes and development of vascular disease. In view of the fact that the spontaneous endothelial cell (EC) regeneration is a slow and insufficient process, it is of great interest to explore alternative cell sources capable of generating functional ECs. Vascular smooth muscle cell (SMC) composes the majority of the vascular wall and retains phenotypic plasticity in response to various stimuli. The aim of this study is to test the feasibility of the conversion of SMC into functional EC through the use of reprogramming factors. Human SMCs are first dedifferentiated for 4 days to achieve a vascular progenitor state expressing CD34, by introducing transcription factors OCT4, SOX2, KLF4 and c-MYC. These SMC-derived progenitors are then differentiated along the endothelial lineage. The SMC-converted ECs exhibit typical endothelial markers expression and endothelial functions in vitro, in vivo and in disease model. Further comprehensive analysis indicates that mesenchymal-to-epithelial transition is requisite to initiate SMCs reprogramming into vascular progenitors and that members of the Notch signalling pathway regulate further differentiation of the progenitors into endothelial lineage. Together, we provide the first evidence of the feasibility of the conversion of human SMCs towards endothelial lineage through an intermediate vascular progenitor state induced by reprogramming. PMID- 28717252 TI - Rain-induced changes in soil CO2 flux and microbial community composition in a tropical forest of China. AB - Rain-induced soil CO2 pulse, a rapid excitation in soil CO2 flux after rain, is ubiquitously observed in terrestrial ecosystems, yet the underlying mechanisms in tropical forests are still not clear. We conducted a rain simulation experiment to quantify rain-induced changes in soil CO2 flux and microbial community composition in a tropical forest. Soil CO2 flux rapidly increased by ~83% after rains, accompanied by increases in both bacterial (~51%) and fungal (~58%) Phospholipid Fatty Acids (PLFA) biomass. However, soil CO2 flux and microbial community in the plots without litters showed limited response to rains. Direct releases of CO2 from litter layer only accounted for ~19% increases in soil CO2 flux, suggesting that the leaching of dissolved organic carbon (DOC) from litter layer to the topsoil is the major cause of rain-induced soil CO2 pulse. In addition, rain-induced changes in soil CO2 flux and microbial PLFA biomass decreased with increasing rain sizes, but they were positively correlated with litter-leached DOC concentration rather than total DOC flux. Our findings reveal an important role of litter-leached DOC input in regulating rain-induced soil CO2 pulses and microbial community composition, and may have significant implications for CO2 losses from tropical forest soils under future rainfall changes. PMID- 28717253 TI - Prostacyclin reverses platelet stress fibre formation causing platelet aggregate instability. AB - Prostacyclin (PGI2) modulates platelet activation to regulate haemostasis. Evidence has emerged to suggest that thrombi are dynamic structures with distinct areas of differing platelet activation. It was hypothesised that PGI2 could reverse platelet spreading by actin cytoskeletal modulation, leading to reduced capability of platelet aggregates to withstand a high shear environment. Our data demonstrates that post-flow of PGI2 over activated and spread platelets on fibrinogen, identified a significant reduction in platelet surface area under high shear. Exploration of the molecular mechanisms underpinning this effect revealed that PGI2 reversed stress fibre formation in adherent platelets, reduced platelet spreading, whilst simultaneously promoting actin nodule formation. The effects of PGI2 on stress fibres were mimicked by the adenylyl cyclase activator forskolin and prevented by inhibitors of protein kinase A (PKA). Stress fibre formation is a RhoA dependent process and we found that treatment of adherent platelets with PGI2 caused inhibitory phosphorylation of RhoA, reduced RhoA GTP loading and reversal of myosin light chain phosphorylation. Phospho-RhoA was localised in actin nodules with PKA type II and a number of other phosphorylated PKA substrates. This study demonstrates that PGI2 can reverse key platelet functions after their initial activation and identifies a novel mechanism for controlling thrombosis. PMID- 28717254 TI - The molecular mechanisms of Monascus purpureus M9 responses to blue light based on the transcriptome analysis. AB - Light is an important environmental factor that regulates various physiological processes of fungi. To thoroughly study the responses of Monascus to blue light, transcriptome sequencing was performed on mRNAs isolated from samples of Monascus purpureus M9 cultured under three conditions: darkness (D); exposure to blue light for 15 min/d (B15); and exposure to blue light for 60 min/d over 8 days (B60). The number of differentially expressed genes between the three pairs of samples-B15 vs D, B60 vs B15, and B60 vs D-was 1167, 1172, and 220, respectively. KEGG analysis showed the genes involved in primary metabolism including carbon and nitrogen metabolism were downregulated by B15 light treatment, whereas B15 upregulated expression of genes involved with aromatic amino acid metabolism, which associated with development, and branched chain amino acid metabolism, and fatty acid degradation, which can produce the biosynthetic precursors of pigments. When exposed to B60 conditions, genes with roles in carbohydrate metabolism and protein synthesis were upregulated as part of a stress response to blue light. Based on this study, we propose a predicted light-stimulated signal transduction pathway in Monascus. Our work is the first comprehensive investigation concerning the mechanism of Monascus responses to blue light. PMID- 28717255 TI - Sequential stable isotope analysis reveals differences in multi-year dietary history of three sympatric equid species in SW Mongolia. AB - 1. Competition among sympatric wild herbivores is reduced by different physiological, morphological, and behavioral traits resulting in different dietary niches. Wild equids are a rather uniform group of large herbivores which have dramatically declined in numbers and range. Correlative evidence suggests that pasture competition with livestock is one of the key factors for this decline, and the situation may be aggravated in areas where different equid species overlap. 2. The Dzungarian Gobi is currently the only place where two wild equid species coexist and share the range with the domesticated form of a third equid species. In the arid and winter cold Gobi, pasture productivity is low, highly seasonal, and wild equids additionally face increasing livestock densities. 3. We used stable isotope chronologies of tail hairs to draw inferences about multi-year diet seasonality, isotopic dietary niches, and physiological adaptations in the Asiatic wild ass (khulan), reintroduced Przewalski's horse, and domestic horse in the Mongolian part of the Dzungarian Gobi. 4. Our results showed that even in the arid Gobi, both horse species are predominantly grazers, whereas khulan are highly seasonal, switching from being grazers in summer to mixed feeders in winter. The isotopic dietary niches of the two horse species were almost identical, did not vary with season as in khulan, and were narrower than in the latter. Higher delta15N values point towards higher water use efficiency in khulan, which may be one reason why they can exploit pastures further away from water. 5. Synthesis and applications: The high degree of isotopic dietary niche overlap in the two horses points towards a high potential for pasture competition during the critical nutritional bottleneck in winter and highlights the need to severely restrict grazing of domestic horses on the range of the Przewalski's horses. Khulan are less constrained by water and seem more flexible in their choice of diet or less successful in exploiting grass dominated habitats in winter due to human presence. Providing additional water sources could increase the competition between khulan and livestock, and should therefore be only done following careful consideration. PMID- 28717257 TI - Beyond breadth: The contributions of vocabulary depth to reading comprehension among skilled readers. AB - This study investigated the relationships among vocabulary breadth, vocabulary depth, reading comprehension, and reading rate among college-aged students. While the relationships of some of these variables have been explored in previous research, the current study's focus on the role of vocabulary depth on the literacy measures within a sample of skilled readers is new and produced several interesting findings. First, consistent with the hypotheses, both vocabulary breadth and depth were significantly correlated with reading comprehension and reading rate. Second, while both types of vocabulary knowledge explained unique variance in reading comprehension, only vocabulary breadth explained unique variance in reading rate. Finally, although vocabulary breadth was significantly correlated with both of the vocabulary depth measures, the two depth measures were not significantly correlated with each other. This work implies that a strong depth of vocabulary affects reading comprehension, in addition to the well established relationship between vocabulary breadth and comprehension. PMID- 28717256 TI - Ketone-catalyzed photochemical C(sp3)-H chlorination. AB - Photoexcited arylketones catalyze the direct chlorination of C(sp3)-H groups by N chlorosuccinimide. Acetophenone is the most effective catalyst for functionalization of unactivated C-H groups while benzophenone provides better yields for benzylic C-H functionalization. Activation of both acetophenone and benzophenone can be achieved by irradiation with a household compact fluorescent lamp. This light-dependent reaction provides a better control of the reaction as compared to the traditional chlorination methods that proceed through a free radical chain propagation mechanism. PMID- 28717259 TI - A Computerized Tutor Prototype for Prostate Cryotherapy: Key Building Blocks and System Evaluation. AB - This paper focuses on the evaluation of a prototype for a computer-based tutoring system for prostate cryosurgery, while reviewing its key building blocks and their benchmark performance. The tutoring system lists geometrical constraints of cryoprobe placement, displays a rendered shape of the prostate, simulates cryoprobe insertion, enables distance measurements, simulates the corresponding thermal history, and evaluates the mismatch between the target region shape and a pre-selected planning isotherm. The quality of trainee planning is measured in comparison with a computer-generated plan, created for each case study by a previously developed planning algorithm, known as bubble-packing. While the tutoring level in this study aims only at geometrical constraints on cryoprobe placement and the resulting thermal history, it creates a unique opportunity to gain insight into the process outside of the operation room. System validation of the tutor has been performed by collecting training data from surgical residents, having no prior experience or advanced knowledge of cryotherapy. Furthermore, the system has been evaluated by graduate engineering students having no formal education in medicine. In terms of match between a planning isotherm and the target region shape, results demonstrate medical residents' performance improved from 4.4% in a pretest to 37.8% in a posttest over a course of 50 minutes of training (within 10% margins from a computer-optimized plan). Comparing those results with the performance of engineering students indicates similar results, suggesting that planning of the cryoprobe layout essentially revolves around geometric considerations. PMID- 28717258 TI - Children's Perceptions of Social Resource Inequality. AB - Children's perceptions of social resource inequalities were investigated by measuring spontaneous explanations for race-based disparities in access to societal resources. Fifth graders (N = 139, M = 11.14 years, SD = .61 years) viewed animated vignettes depicting hypothetical resource inequalities between institutions serving children of African-American and European-American background. Children frequently explained disparities in terms of institutions' differing financial resources, revealing awareness that economic inequalities often underlie groups' differential access to societal resources. Further, children attributed inequalities to preferential treatment more often when they witnessed African-Americans at a disadvantage than when they witnessed European Americans at a disadvantage, demonstrating awareness that racial minority groups are more likely to experience restricted access to resources. Finally, children who reasoned about preferential treatment judged inequality, and actions that perpetuated inequality, more negatively than children who attributed inequalities to institutions' differing needs, revealing a link between awareness of discrimination and rejection of social inequalities. PMID- 28717260 TI - Faculty Motivation to Mentor Students Through Undergraduate Research Programs: A Study of Enabling and Constraining Factors. AB - Undergraduate research experiences are a "high impact" educational practice that confer benefits to students. However, little attention has been paid to understanding faculty motivation to mentor undergraduate students through research training programs, even as the number of programs has grown, requiring increasing numbers of faculty mentors. To address this, we introduce a conceptual model for understanding faculty motivation to mentor and test it by using empirical data to identify factors that enable and constrain faculty engagement in an undergraduate research program. Using cross-sectional survey data collected in 2013, we employed generalized linear modeling to analyze data from 536 faculty across 13 research institutions to examine how expected costs/benefits, dispositional factors, situational factors, previous experience, and demographic factors predicted faculty motivation to mentor. Results show that faculty who placed greater value on the opportunity to increase diversity in the academy through mentorship of underrepresented minorities were more likely to be interested in serving as mentors. Faculty who agreed more strongly that mentoring undergraduate students was time consuming and their institution's reward structures were at odds with mentoring, or who had more constrained access to undergraduate students were less likely to be interested in serving as mentors. Mid-career faculty were more likely than late-career faculty to be interested in serving as mentors. Findings have implications for improving undergraduate research experiences, since the success of training programs hinges on engaging highly motivated faculty members as mentors. PMID- 28717262 TI - Three-dimensional graphene nanosheets as cathode catalysts in standard and supercapacitive microbial fuel cell. AB - Three-dimensional graphene nanosheets (3D-GNS) were used as cathode catalysts for microbial fuel cells (MFCs) operating in neutral conditions. 3D-GNS catalysts showed high performance towards oxygen electroreduction in neutral media with high current densities and low hydrogen peroxide generation compared to activated carbon (AC). 3D-GNS was incorporated into air-breathing cathodes based on AC with three different loadings (2, 6 and 10 mgcm-2). Performances in MFCs showed that 3D-GNS had the highest performances with power densities of 2.059 +/- 0.003 Wm-2, 1.855 +/- 0.007 Wm-2 and 1.503 +/- 0.005 Wm-2 for loading of 10, 6 and 2 mgcm-2 respectively. Plain AC had the lowest performances (1.017 +/- 0.009 Wm-2). The different cathodes were also investigated in supercapacitive MFCs (SC-MFCs). The addition of 3D-GNS decreased the ohmic losses by 14-25%. The decrease in ohmic losses allowed the SC-MFC with 3D-GNS (loading 10 mgcm-2) to have the maximum power (Pmax) of 5.746 +/- 0.186 Wm-2. At 5 mA, the SC-MFC featured an "apparent" capacitive response that increased from 0.027 +/- 0.007 F with AC to 0.213 +/- 0.026 F with 3D-GNS (loading 2 mgcm-2) and further to 1.817 +/- 0.040 F with 3D GNS (loading 10 mgcm-2). PMID- 28717263 TI - On generic prescriptions and live surgeries. PMID- 28717264 TI - What's inside. PMID- 28717261 TI - Microbial fuel cells: From fundamentals to applications. A review. AB - In the past 10-15 years, the microbial fuel cell (MFC) technology has captured the attention of the scientific community for the possibility of transforming organic waste directly into electricity through microbially catalyzed anodic, and microbial/enzymatic/abiotic cathodic electrochemical reactions. In this review, several aspects of the technology are considered. Firstly, a brief history of abiotic to biological fuel cells and subsequently, microbial fuel cells is presented. Secondly, the development of the concept of microbial fuel cell into a wider range of derivative technologies, called bioelectrochemical systems, is described introducing briefly microbial electrolysis cells, microbial desalination cells and microbial electrosynthesis cells. The focus is then shifted to electroactive biofilms and electron transfer mechanisms involved with solid electrodes. Carbonaceous and metallic anode materials are then introduced, followed by an explanation of the electro catalysis of the oxygen reduction reaction and its behavior in neutral media, from recent studies. Cathode catalysts based on carbonaceous, platinum-group metal and platinum-group-metal free materials are presented, along with membrane materials with a view to future directions. Finally, microbial fuel cell practical implementation, through the utilization of energy output for practical applications, is described. PMID- 28717265 TI - Round-up. PMID- 28717266 TI - Clinical andrology: The missing jigsaw pieces. PMID- 28717267 TI - Semen culture and the assessment of genitourinary tract infections. AB - The male factor contributes approximately 50% to infertility-related cases in couples with an estimated 12%-35% of these cases attributable to male genital tract infections. Depending on the nature of the infection, testicular sperm production, sperm transport, and sperm function can be compromised. Yet, infections are potentially treatable causes of infertility. Male genital tract infections are increasingly difficult to detect. Moreover, they often remain asymptomatic ("silent") with the result that they are then passed on to the relevant sexual partner leading to fertilization and pregnancy failure as well as illness of the offspring. With the worldwide increasing problem of antibiotic resistance of pathogens, proper diagnosis and therapy of the patient is important. This testing, however, should include not only aerobic microbes but also anaerobic as these can be found in almost all ejaculates with about 71% being potentially pathogenic. Therefore, in cases of any indication of a male genital tract infection, a semen culture should be carried out, particularly in patients with questionable semen quality. Globally, an estimate of 340 million new infections with sexually transmitted pathogens is recorded annually. Among these, the most prevalent pathogens including Chlamydia trachomatis, Ureaplasma urealyticum, Neisseria gonorrhoeae, and Mycoplasma hominis. Escherichia coli are considered the most common nonsexually transmitted urogenital tract microbes. These pathogens cause epididymitis, epididymo-orchitis, or prostatitis and contribute to increased seminal leukocyte concentrations. PMID- 28717268 TI - Empiric medical therapy with hormonal agents for idiopathic male infertility. AB - INTRODUCTION: Infertility affects approximately 15% of all couples, and male factor contribute to up to 50% of cases. Unfortunately, the cause of male infertility is unknown in about 30% of these cases. Infertility of unknown origin is classified as idiopathic male infertility when abnormal semen parameters are present. Despite not having a definable cause, these men may respond to treatment. This review focuses on the use of empiric hormonal therapies for idiopathic male infertility. METHODS: A detailed PubMed/MEDLINE search was conducted to identify all publications pertaining to empiric use of hormonal therapies in the treatment of idiopathic male infertility using the keywords "idiopathic," "male infertility," "empiric treatment," "clomiphene," "SERM," "gonadotropin," "aromatase inhibitor," and "androgen." These manuscripts were reviewed to identify treatment modalities and results. RESULTS: Gonadotropins, androgens, aromatase inhibitors, and selective estrogen receptor modulators (SERMs) have all been used with varying results. The studies on these treatments are of variable quality. The most well-studied agents are the SERMs which show a modest increase in semen parameters and pregnancy rates. Aromatase inhibitors are most effective in non-idiopathic patients. Gonadotropin treatment is limited by their inconvenience and relative ineffectiveness in this population. Testosterone suppresses spermatogenesis and should not be used to treat infertility. CONCLUSION: Gonadotropins, SERMs, and aromatase inhibitors may improve semen parameters and hormone levels in men with idiopathic infertility with the best results from SERMs. Testosterone should never be used to treat infertility. Large multicenter randomized controlled studies are needed to better determine the success of empiric use of hormonal therapy on pregnancy rates. PMID- 28717271 TI - Vitamins and antioxidants in the management of male fertility. PMID- 28717269 TI - Laboratory tests for oxidative stress. AB - INTRODUCTION: Oxidative stress (OS) is considered a significant contributor to male infertility. A number of laboratory techniques have been developed to evaluate oxidative stress in the semen. We review these tests and their current use. METHODS: A literature review was performed utilizing the PubMed search engine for articles studying OS etiology and impact on male fertility, and the laboratory tests used in its assessment. RESULTS: The state of OS results from exaggerated production of oxygen-derived free radicals, also known as reactive oxygen species, to an extent overwhelming the body's antioxidant defense mechanisms. Several laboratory tests have been utilized in OS measurement during male fertility evaluation. These tests are classified into direct assays which measure the degree of oxidation within a sperm cell and indirect assays which estimate the detrimental effects of OS. The chemiluminescence assay, flow cytometry, nitroblue tetrazolium assay, and cytochrome c reduction are examples of direct assays while the myeloperoxidase test and measurements of lipid peroxidation, oxidation-reduction potential, and total antioxidant capacity are examples of the indirect assays. CONCLUSION: OS measurement is an important tool that may help in understanding the pathophysiology of male infertility and provide valuable information that would guide treatment decisions and patient follow-up. PMID- 28717270 TI - Antioxidant therapy in idiopathic oligoasthenoteratozoospermia. AB - INTRODUCTION: Idiopathic oligoasthenoteratozoospermia (iOAT) is commonly encountered during the evaluation of men with infertility. Antioxidants have been utilized empirically in the treatment of iOAT based on their ability to reverse oxidative stress (OS)-induced sperm dysfunction often encountered in this patient population. METHODS: A literature search was performed using MEDLINE/PubMed, focusing on publications of antioxidant therapies for iOAT. The main objective of our review article was to report the rationale and available evidence supporting the use of antioxidants. RESULTS: Antioxidants such as glutathione, vitamins E and C, carnitines, coenzyme-Q10, N-acetylcysteine, selenium, zinc, folic acid, and lycopene have been shown to reduce OS-induced sperm damage. While rigorous scientific evidence in the form of double-blind, placebo-controlled clinical trials is limited, recent systematic reviews and meta-analyses have reported a beneficial effect of antioxidants on semen parameters and live birth rates. CONCLUSION: Additional randomized controlled studies are required to confirm the efficacy and safety of antioxidant supplementation in the medical treatment of idiopathic male infertility as well as the dosage required to improve semen parameters, fertilization rates, and pregnancy outcomes in iOAT. PMID- 28717272 TI - Have we overcome the complications of laparoscopic nephrectomy? A prospective, cohort study using the modified Clavien-Dindo scale. AB - INTRODUCTION: Apart from the complexity of procedure and surgeon's experience, surgical complication rates depend on case definition and method of recording data. We prospectively evaluated the complications of laparoscopic nephrectomy (LN) in a current cohort of patients, graded on the modified Clavien-Dindo (CD) scale and compared them with historical cohorts. METHODS: In the Institutional Review Board approved protocol, all patients undergoing LN over a 30-month were enrolled in the study. Clinical parameters, operative data, inhospital course, and 30-day follow-up were recorded prospectively in an electronic database by a resident who did not perform any of the surgeries. The complications were analyzed using the CD scale. RESULTS: A total of 103 patients (age 14-80 years) underwent LN (30 radical, 73 simple) during the study period. Forty-three of these procedures were for inflammatory conditions (stone disease or tuberculosis). Six procedures were converted to open surgery due to vascular injury (2), bowel injury (1), and adhesions (3). There were 45 (46%) complications in the 97 procedures completed laparoscopically including 34 low grade (CD grade 1, 2) and 11 high-grade (CD grade 3, 4) complications. There was no mortality. Complications were similar in patients undergoing surgery for inflammatory or noninflammatory conditions. CONCLUSIONS: LN continues to be associated with postoperative complications in 46% of cases. However, the complication rates appear to be higher than historical series, possibly due to the more rigorous case-definition and prospective recording. PMID- 28717273 TI - Outcome and complications of living donor pediatric renal transplantation: Experience from a tertiary care center. AB - INTRODUCTION: We retrospectively reviewed the patient characteristics, outcome, and complications of renal transplantation in pediatric age group performed at our center and compared the results with various centers in India and other developed countries. MATERIALS AND METHODS: Patients younger than eighteen years of age who underwent renal transplantation from 2003 to 2014 at our institute were reviewed. Demographic data of the transplant recipients and donors, etiology of ESRD, mode of dialysis, surgical details of renal transplantation, immunosuppression, medical and surgical complications, and post-transplant follow up were assessed. Graft survival was determined at 1, 3 and 5 years post transplant. All data collected were entered into Microsoft excel program and analyzed using SPSS 20. Kaplan-Meier method was applied to determine the graft survival at 1, 3, and 5 years. The log-rank test was applied to test the statistical significance of the difference in survival between groups. RESULTS: Thirty-two children underwent transplantation comprising of 18 females and 14 males. The mean age was 14.5 years (range 10-17 years). The primary cause of renal failure was glomerular diseases in 53% (17/32) of patients. Seventeen postsurgical complications were noted in our series. Two grafts were lost over a follow-up of 5 years. The 1, 3, and 5 year graft survival rates were 96.7%, 92.9%, and 85%, respectively. There was no mortality. CONCLUSION: The etiology of ESRD in our region is different from that of developed countries. The mean age at which children undergo renal transplantation is higher. Graft survival at our center is comparable to that of developed nations. Renal transplantation can be safely performed in children with ESRD. PMID- 28717274 TI - Three-dimensional versus two-dimensional laparoscopy in urology: A randomized study. AB - INTRODUCTION: Conventional two-dimensional (2D) laparoscopy systems have the drawback of poor depth perception and spatial orientation. Three-dimensional (3D) laparoscopic systems have stereoscopic vision in which depth perception is achieved by different unique images received by each eye. We evaluated 3D laparoscopy in comparison with conventional 2D laparoscopy in urological procedures in a prospective randomized study. MATERIALS AND METHODS: Over a 19 month study period, 108 patients scheduled to undergo various urological procedures were randomized to either conventional 2D or 3D laparoscopy (2D n = 53; 3D n = 55). A single senior surgeon performed all the surgeries. Parameters such as total operative time, dissection and suturing time, blood loss, hospital stay, complications (Clavien-Dindo), and visual analog scale (VAS) score for pain were assessed. The subjective assessment of the operating surgeon of superiority and inferiority of either technology on parameters defining surgical skills was recorded using a Likert scale. RESULTS: The total operative time (P < 0.0003), blood loss (P < 0.028), dissection, suturing and stenting time (P < 0.0001), and the State-Trait Anxiety Inventory for Adults score (P < 0.0001) was significantly in favor of 3D laparoscopy. CONCLUSION: Our study showed significant advantages of the 3D system over 2D laparoscopy. These advantages include enhanced operative performance and greater surgeon comfort. PMID- 28717275 TI - Initial experience of robotic nephron sparing surgery in cases of high renal nephrometry scores. AB - INTRODUCTION: The renal nephrometry scoring (RNS) system enables prediction the feasibility of nephron-sparing surgery (NSS) in renal masses. There is insufficient data regarding the outcome of robot-assisted NSS in tumors with RNS >=10. We reviewed the trifecta outcomes of patients undergoing robotic NSS with high RNS and compare it with tumors of low and intermediate RNS. MATERIALS AND METHODS: Our prospectively maintained data of all robot-assisted NSS were reviewed, and those with RNS of >=10 were identified. Patient data, outcomes and postoperative estimated glomerular filtration rate were compared between high, intermediate and low RNS patients. RESULTS: In high RNS group, the mean age of the patients was 53 years (male:female = 15:3). Mean diameter of tumors was 6.28 cm (3.0-10.5 cm). Mean operative time was 173.61 +/- 52.66 min and mean warm ischemia time was 27.85 +/- 5.27 min. Mean estimated blood loss (EBL) was 363.89 +/- 296.45 ml. Mean hospital length of stay was 5.39 +/- 1.91 days (3-9 days). When compared with low and intermediate RNS, only EBL and need for pelvicalyceal system repair was significantly higher in high RNS group. Postoperative complications, renal function preservation and oncological outcomes at 3 months were comparable in all the three groups. CONCLUSION: Robot-assisted NSS is feasible with comparable outcomes in tumors with high RNS. PMID- 28717276 TI - Testosterone versus clomiphene citrate in managing symptoms of hypogonadism in men. AB - INTRODUCTION: Both clomiphene citrate (CC) and testosterone supplementation therapy (TST) are effective treatments for men with hypogonadism. We sought to compare changes in symptoms and treatment efficacy in hypogonadal men before and after receiving CC and TST. PATIENTS AND METHODS: 52 men who received TST and 23 men who received CC for symptomatic hypogonadism were prospectively followed for change in hormone levels and symptoms after treatment. These men were also compared to eugonadal men who were not on CC or TST during the same period. Comparisons were made between baseline and posttreatment hormone levels and symptoms. Symptoms were evaluated using the androgen deficiency in aging male (ADAM) and quantitative ADAM (qADAM) questionnaires. RESULTS: Serum total testosterone increased from pretreatment levels in all men (P < 0.05), regardless of therapy type (TST: 281-541 ng/dL, CC: 235.5-438 ng/dL). Men taking TST reported fewer ADAM symptoms after treatment (5-2, P < 0.05). Similarly, men taking CC reported fewer ADAM symptoms after treatment (3.5-1.5, P < 0.05). Conversely, eugonadal men had similar T levels (352 vs. 364 ng/dL) and hypogonadal symptoms (1.5 vs. 1.4) before and after follow-up. When we evaluated individual symptoms, men treated with TST showed significant increases in qADAM scores in libido, erectile function, and sports performance. However, among the men who received CC, qADAM subscore for libido was lower following treatment (3.75-3.2, P = 0.04), indicating that CC could have an adverse effect on libido in hypogonadal men. CONCLUSIONS: Both TST and CC are effective medications in treating hypogonadism; however, our study indicates that TST is more effective in raising serum testosterone levels and improving hypogonadal symptoms. CC remains a viable treatment modality for hypogonadal men but its adverse effect on libido warrant further study. PMID- 28717277 TI - Contrast-induced nephropathy in urological imaging: A comparison with cardiology interventions. AB - INTRODUCTION: Published studies about contrast-induced nephropathy (CIN) mainly focus on cardiac intervention and rarely focus on patients undergoing urological contrast investigations. We aimed to determine the association and effect of intravenous (IV) iodinated contrast material on the incidence of CIN in a group of patients undergoing urology investigation and compare the results with that of cardiology interventions. METHODS: This prospective study was performed in patients undergoing IV contrast studies in Urology and those undergoing coronary interventions, in our institution for 1 year. Association between the occurrence of CIN and the risk factors such as age (>=60 years), sex, diabetes mellitus, hypertension, anemia, left ventricular ejection fraction <40%, estimated glomerular filtration rate (eGFR), and volume of contrast used were studied using Chi-square tests or Fisher exact test and Student's t-test. RESULTS: A total of 339 cases (168 urology and 171 cardiology) were studied. CIN was noted in 8.3% of urology patients whereas it was 29.8% in cardiology patients. In urology patients, statistically significant association was noted between CIN and eGFR <60 ml/min/1.73 m2 and volume of contrast used. In cardiology patients, statistically significant association (P < 0.05) was noted for diabetes, hypertension, eGFR <60 ml/min/1.73 m2, volume of contrast used. CONCLUSION: Although CIN was found to occur with contrast studies, the deleterious effects of contrast in urological procedures were lower than cardiology patients. The association between the occurrence of CIN and patient factors were also different in the two groups. PMID- 28717278 TI - Dihydroxyadenine stone with adenine phosphoribosyltransferase deficiency: A case report. AB - Adenine phosphoribosyltransferase (APRT) deficiency is a rare autosomal recessive error of purine metabolism resulting in the generation of 2,8-dihydroxyadenine (DHA), a highly insoluble metabolite of adenine, which can cause radiolucent urolithiasis. This is the second case of DHA stone being reported in India and the first case in India to document the mutation of the APRT gene on blood DNA analysis. PMID- 28717279 TI - Cystitis glandularis: Management and challenges in a renal transplant recipient. AB - Cystitis cystica or glandularis is a clinical and pathological entity of the bladder mucosa occurring secondary to inflammation or chronic obstruction. Its premalignant nature remains controversial, especially in an immunocompromised transplant recipient. We present a rare case where a chronic kidney disease patient was found to have cystitis glandularis while being worked up for living related donor renal transplant and describe its subsequent management. PMID- 28717280 TI - Priapism with penile gangrene: An unusual presentation of multiple myeloma. AB - Penile gangrene is very rare sequel of ischemic priapism. Previous published reports have shown its occurrence in patients with sickle cell disease, urethral carcinoma, bladder carcinoma, thrombotic thrombocytopenic purpura, idiopathic, traumatic, etc. Ischemic priapism with penile gangrene as an initial presentation of multiple myeloma has not been reported. We present a 44-year-old patient of multiple myeloma presenting with ischemic priapism and penile gangrene requiring partial penectomy. PMID- 28717281 TI - Cystoscopic stent removal using a guidewire loop. AB - Stent removal is a simple procedure performed with a rigid cystoscope and a stent removal forceps. In the rare event when the stent removal forceps does not work or breaks down, a guidewire loop can be used to remove the stent. PMID- 28717282 TI - Re: Silicate urolithiasis in a pediatric patient. PMID- 28717283 TI - Training Pathways in Oral and Maxillofacial Surgery Across the Globe-A Mini Review. AB - Due to historical reasons, many different training pathways exist across countries that lead to a degree in oral and maxillofacial surgery. Although it is generally accepted to be a specialty of dentistry, the complex nature of procedures being performed by OMF surgeons today, has necessitated extensive general surgical training. Many countries have thus made dual qualification mandatory, while others have extended training programs in OMFS with integrated medical teaching. In India, frequent contact with foriegn experts, availability of world-class equipment and efforts of individual surgeons has ensured that the full scope of OMFS is practised in select centres of learning. However, the MDS curriculum dictated by DCI has not conformed to the requirements of the specialty as practiced today. This brief mini-review of the various training pathways aims at comparing our system with other countries and attempts to draw lessons which could help improve future OMFS training in India. PMID- 28717284 TI - Is the Mandibular Growth Affected by Internal Rigid Fixation?: A Systematic Review. AB - PURPOSE: The purpose of this systematic review was to evaluate, in animal model based studies, whether there are mandibular growth alterations, after open reduction and internal rigid fixation with titanium plates and screws. METHODS: A literature search was conducted using the MEDLINE, EMBASE, and LILACS databases, up to and including August 2015. Surgical reduction and internal rigid fixation (IRF) of induced fractures were compared to non-invasive procedures, in order to investigate if there were alterations in the mandibular growth patterns. RESULTS: Of a total of 624 potentially relevant papers identified through the searching process, five were eligible for inclusion. Three studies using 3-month old New Zealand white rabbits induced fractures of mandibular body or symphysis and internal fixation with titanium microplates and screws, whereas two were based on 6-month old goats with condylar fracture. None of the studies showed statistically significant difference between experimental and control groups. CONCLUSION: As literature regarding this subject is scarce, and the included studies show low level of evidence, it is not possible to conclude that open reduction and internal rigid fixation with titanium plates and screws cause significant growing alteration of the mandible. PMID- 28717285 TI - Orthognathic Surgery: A Review of Articles Published in 2014-2015. AB - OBJECTIVES: We did a retrospective study and reviewed some of the orthognathic surgery related papers that were published between January 2014 and December 2015 in a leading International Maxillofacial Surgery Journal. It was conducted to ascertain the trends of articles being published. METHOD: A total of around 57 articles were reviewed, of which most of the full length articles were on post operative outcomes and obstructive sleep apnoea. RESULTS: Bulk of the studies were retrospective, and less interest was shown onto experimental researches. CONCLUSION: A thorough review and analysis thus gives an impression that there is a high requirement of well designed clinical studies. PMID- 28717286 TI - Histological Changes in Nasolabial Cutaneous Flaps Employed in Intraoral Reconstruction. AB - INTRODUCTION: Nasolabial cutaneous flaps have been routinely used to reconstruct intraoral defects. The purpose of this study was to study histological changes that may occur in the skin flap as a result of its exposure to a new environment. PATIENTS AND METHODS: Thirteen patients took part in this study. Fusiform tissue specimens were obtained from the intraoral cutaneous portion of the flap. Biopsy specimens were also taken from the skin of nasolabial region and from the buccal mucosa to serve as control. Thickness of stratum corneum, degree of inflammatory infiltration and number of skin appendages were evaluated. Periodic-acid Schiff (PAS) staining was also performed to identify the presence of hyphae. RESULTS: The characteristic features of the skin are almost always maintained, although the thickness of stratum corneum and the number of skin appendages are often significantly reduced. In two patients the inflammatory infiltration was intense and accompanied by elimination of skin appendages and stratum corneum. These flaps tend to mimic mucosa macroscopically. In four patients fibrosis was histologically demonstrated. These flaps resembled atrophic skin macroscopically. Hyphae could not be identified with PAS staining in this study. Koilocytes, which are indicative of HPV infection, were identified in two flap specimens. CONCLUSIONS: Intraorally placed nasolabial flaps may undergo a variety of histological and macroscopical changes. In the majority of cases the intraoral cutaneous flap maintains skin features, except if it becomes heavily infiltrated with inflammatory cells. Inflammation occurs for unknown reasons and results in a mucosa-like microscopic and macroscopic appearance of the intraorally placed flap. PMID- 28717287 TI - Cervical Metastases Behavior of T1-2 Squamous Cell Carcinoma of the Tongue. AB - INTRODUCTION: The cervical lymph node metastasis (CM) is one of the most important prognostic factors for oral squamous cell carcinoma. Although the frequency and distribution of CM for tongue carcinoma (TC) are well documented in the literature, there is only little data on metastasis patterns depending on the location of the cancer within the tongue. MATERIALS AND METHODS: In a retrospective study all patients with a T1-T2 TC who were treated between 1997 and 2013 were analysed regarding epidemiological data, risk factors, and tumour parameters such as exact localization, CM. RESULTS: 204 patients (59 +/- 15 years; ?37 %, ?63 %) were included. At the initial diagnosis 23 % had an advanced tumour stage (III-IV) due to CM. The occurrence of CM was significantly higher for T2, advanced G-status and the localization in the posterior area of the tongue. The presence of CM-but not the recurrence-had a significant influence on the survival rate. CONCLUSION: The small TC has an aggressive metastatic behaviour depending not only on the classical prognostic factors such as grading and tumour size, but is also strongly influenced by the posterior location within the tongue. PMID- 28717288 TI - Cone Beam Computed Tomographic Analysis of the Course and Position of Mandibular Canal. AB - PURPOSE: Estimation of the relative position of infra alveolar nerve (IAN) canal and its relation to the mandibular anatomical landmarks can be clinically useful in minimizing the risk of surgery complications such as neurosensory disturbances that may occur after invasive mandibular surgical procedures. The purpose of the present study was to investigate the anatomic location and radiographic course of the mandibular canal compared to anatomic landmarks on CBCT and to discuss its clinical significance and also to determine the possible correlations between the mandibular position and the age of the patients. METHODS: This cross sectional study was conducted on 242 CBCT of patients (99 males and 143 females). The location of canal was evaluated in 4 different regions. The first section in trans-axial view after mental foramen, in which the loop of mandibular canal is formed, was selected as point 1 for measurement and intervals of 10 mm, respectively, points 2, 3, 4 were selected for measurement. On these sections, the shortest linear distances (mm) from the most buccal and lingual aspects of the canal to the corresponding cortical plates of the mandible and also the minimum linear distance between the inferior aspect of canal and inferior border of mandible in these regions were calculated. RESULTS: There was statistically significant correlation between the anatomic course of the canal and the patients' gender. The mean vertical position of the canal, as measured from the lower border of the IAN canal to the inferior border of the mandible, was 8.50 mm, ranging from 4.80 to 14.50 mm. On average, the mandibular canal was situated more lingually at all sites to the point it reached the mental foramen. However, at the mental foramen region (Point 1), it was located closer to the buccal cortical plate. CONCLUSION: Assessment of the exact course of the IAN preoperatively along the body of the mandible by using CBCT might contribute to efficient and accurate surgical planning and therefore positively influence the surgical results. The results of this study confirm the necessity of using CBCT before invasive surgical procedures to determine the variations in the relative position and course of IAN canal. PMID- 28717290 TI - To Compare the Efficacy of C-Reactive Protein and Total Leucocyte Count as Markers for Monitoring the Course of Odontogenic Space Infections. AB - OBJECTIVE: To compare the efficacy of CRP and TLC as markers for monitoring the course of odontogenic space infections (OSI) in 50 patients. METHODS: A Clinical severity scale (CSS) was developed to grade the severity of infections in patients. Blood samples were taken preoperatively and postoperatively at day 1, day 2, day 3 and day 7 for measuring the levels of CRP and TLC. The trends of CRP and TLC were analysed against the CSS. The data was subjected to paired "t" test, ANOVA, Spearman rank correlation, Pearson's bivariate correlation as appropriate. RESULTS: The CRP values were elevated in all 50/50 (100 %) patients as compared to TLC which were elevated in 32/50 (64 %) patients only. The CSS displayed a high internal consistency and reliability (Cronbach alpha = 0.748). A significant strong positive correlation (rho = 0.754) was found between CRP and CSS as compared to a moderate correlation (rho = .607) between TLC and CSS. CONCLUSION: CRP displayed a more consistent relation with clinical severity of the infection than TLC. Hence it could be more reliably employed to judge the progress in a patient with OSI. PMID- 28717289 TI - Comparison of Extended Nasolabial Flap Versus Buccal Fat Pad Graft in the Surgical Management of Oral Submucous Fibrosis: A Prospective Pilot Study. AB - AIM: To evaluate the application of extended nasolabial flap versus buccal fat pad graft in the surgical management of oral submucous fibrosis. SETTINGS AND DESIGN: This prospective study was carried out in the Department of Oral and Maxillofacial Surgery, Tamil Nadu Government Dental College and Hospital, Chennai. MATERIAL AND METHODS: A total of 8 patients (6 men and 2 women) with age range from 21 to 65 years were selected for study. These 8 patients were randomly divided into two groups of four namely group 1 and group 2. In group 1 patients, reconstruction was planned with extended nasolabial flaps and in group 2 patients, reconstruction was planned with buccal fat pad graft respectively. STATISTICAL ANALYSIS USED: Paired t test, Independent sample t test, ANOVA test. RESULTS: The mean preoperative mouth opening in group 1 was 8.5 mm and in group 2 was 11.75 mm. The mean increase in group 1 after one year of postoperative period was 21.50 mm and in group 2 was 24.75 mm. CONCLUSIONS: In the present study, buccal fat pad graft proved to give better results as the interposition material as it has good patient acceptance, rapid epithelization, minimal donor site morbidity and minimal intra and postoperative complications. PMID- 28717291 TI - Risk Factors for Post-operative Infection Following Single Piece Osteotomy. AB - OBJECTIVE: The aim of this retrospective study was to identify the significant risk factors that contribute towards postoperative infection in patients recovering from orthognathic surgery. METHODS: Retrospective records of 522 patients who underwent orthognathic surgery over 9 year period were evaluated for postoperative infection within 3 months of surgery and after 3 months of surgery. The variables of interest included age, gender, habits like smoking and alcohol consumption and incidence of postoperative infection. RESULTS: The overall infection rate was 4.60%. Patients who underwent bilateral sagittal split osteotomy to advance the mandible had an infection rate of 10.4%. Statistically significant predictor variables (P < 0.05) included patients who had the smoking habit, and those that received bone grafts in both the time periods. CONCLUSION: In conclusion, the occurrence of infection after orthognathic surgery is influenced by multiple factors, among which are the type of osteotomy, smoking habit and bone grafting procedures. PMID- 28717293 TI - Utility of Vaccum Pressed Silicon Sheet as a Bite Raising Appliance in the Management of TMJ Dysfunction Syndrome. AB - INTRODUCTION: Temporomandibular disorders (TMDs) represent a group of painful conditions involving the muscles of mastication and the temporomandibular joint (TMJ) that frequently encountered in general clinical practice. This study is designed to assess the utility of vacuum pressed silicon sheet as a bite raising appliance in the management of TMJ dysfunction syndrome. METHODOLOGY: The patients for this study were selected from those with the chief complaint of TMJ disorder. Out of 200 patients, 104 patients were diagnosed with subluxation and 96 patients were diagnosed with internal derangement of temporomandibular joint. All the reported cases were managed conservatively with physiotherapy and muscle relaxant therapy for one week period and followed with silicon bite raising appliance over both the arches in the subsequent period. RESULTS: All the patients had pain relief within six months duration as graded over verbal analog scale. ANOVA scale was used for comparision of VAS scores. CONCLUSION: The use of vacuum pressed bite raising appliance in the management of TMJ disorder was found to be satisfactorily effective in alleviation of pain symptom in our study group. PMID- 28717292 TI - Conservative Management of Unicystic Ameloblastoma in Young Patients: A Prospective Single-Center Trial and Review of Literature. AB - AIMS: The study intends to evaluate the clinical outcome of treating young patients of unicystic ameloblastoma, by various conservative treatment modalities such as marsupialization, enucleation with bone curettage and aid in establishing sound treatment guidelines. MATERIALS AND METHODS: A case series of fifteen patients is presented of unicystic ameloblastoma, who presented to our Department over the past 6 years (2010-2015) and conservative method of treatment elected in all the patients. Also, a methodical literature review of studies discussing treatment of unicystic ameloblastoma in young age group (<20 years) patients over the last 15 years from 2001 to 2015 is added. RESULTS: Faster osseous regeneration after conservative treatment was noted, owing to the young age and growth potential. Over a mean follow-up of 4 years, uneventful secondary healing, no clinical or radiographic evidence of recurrence and no apparent deformity were noted in any of the cases. CONCLUSION: Unicystic ameloblastoma is a benign, locally invasive odontogenic neoplasm of young age which can develop during the stage of tooth formation and hence its early inception and vast proliferation is not uncommon in this age group, due to which it can grow into a huge lesion causing significant morbidity. Conservative surgical management may be a viable option to reduce morbidity and increase the probability of uneventful secondary healing and bone regeneration in the younger population. PMID- 28717294 TI - Study of Distracted Bone in Maxilla: A Comparative Analysis. AB - INTRODUCTION: Anterior maxillary distraction is one of the accepted modalities to treat hypoplastic maxilla. The study was undertaken to assess the maturation of the bone formed, which is measured by analyzing the amount of mineralization of the bone. MATERIALS AND METHODS: For the study 29 patients were chosen, who were divided into three groups. First group consist of patients who had undergone distraction osteogenesis. Second group has cleft patients and third group is the control group. A bone biopsy using trephine drill is obtained from the subjects. This sample is subjected to Fourier transform infrared spectroscopy (FTIR). RESULTS: From the results a mineral to matrix ratio is obtained which is then compared between the three groups. There is a statistically significant difference between the mineralization of the three groups. The distracted bone shows the lowest mineralization while mineralization of the cleft bone is also less than the normal bone. CONCLUSION: The study conclusively establishes that the distracted bone is not as mineralized as the normal bone. Although functionally the distracted bone is as good as the native bone and grafted bone as proved by the success rate of the implants placed. The study also highlights the use of FTIR for assessing the bone quality. PMID- 28717295 TI - Animal Inflicted Maxillofacial Injuries: Treatment Modalities and Our Experience. AB - INTRODUCTION: Animal inflicted injuries to the face and neck are becoming much more common as people lavish affection on pets. Injuries caused by animal attacks to the face can cause complex injuries to soft and hard tissues, presented as perforations, lacerations, crushes, avulsion or fractures. An uncountable number of bacteria and virus can be found in such injuries, with a potential pathological effect to humans, regarding infections. Although the infection rate is low due to excellent blood supply to face, the injuries have disfiguring effect with possible psychological repercussion to the patients. The treatment of animal inflicted injuries must address the soft tissue defect, neurovascular injuries, and bone injuries as well as prevention of post treatment infection. Primary wound repair is the treatment of choice for most clinically uninfected bite wound where as delayed closure should be reserved for wounds at high risk of infection or already infected wounds and tissue defect may require local flap or micro-vascular re-implantations. MATERIAL AND METHODS: In this article, we have elicited up to date considerations regarding the management of animal inflicted injuries to the face based on literature search and exemplified by multiple case reports. CONCLUSION: For bite injuries on face, immediate primary wound repair after meticulous wound debridement and irrigation with sufficient volume added by antibiotic prophylaxis gives good cosmetic results with minimum risk of infection. Depending upon type of attack and age of victims, psychiatric or social counseling may also be required. PMID- 28717297 TI - Air Leak into the Soft Tissues During the Puffed Cheek CT Evaluation of Oral Cavity: Diagnosis and Implication of a Rare Phenomenon. AB - Leakage of small pockets of air in to soft tissues of cheek along vascular bundle is reported in a patient with ulcerated oral malignancy with history of recent biopsy. Leakage occurred during an attempt to puff the cheek during CT examination of oral cavity. Hereto undocumented phenomenon was self limiting and did not lead to clinical disability. Imaging appearance and likely mechanism of the complication are discussed. PMID- 28717296 TI - Surgical Management of Laterognathia in Orthofacial Surgery. AB - INTRODUCTION: Each year around the world, various surgical procedures are carried out with the goal of correcting laterognathia; both the intraoral vertical ramus osteotomy (IVRO) and bilateral sagittal split ramus osteotomy (OSB) have been the most used techniques in mandibular surgery. These techniques have advantages and disadvantages; for example the advantages of the OSB include: increased coefficient of friction between bony segments, for both the forward and the retroposition, as well as decrease in the time of intermaxillary fixation (IMF). Disadvantages include injury to the inferior alveolar nerve (IAN), hemorrhage, bad split, among others. The advantages of IVRO include decrease of possibility of injury to the IAN, ease of implementation of the technique, a lower incidence of hemorrhage and the short duration of the surgical procedure. Their disadvantages include: lower coefficient of friction between bony segments, requires a relatively long period of IMF. The combination between the techniques of mandibular osteotomy for the correction of minor 10 mm laterognathia is the ideal treatment, since it avoids potential recurrence. MATERIALS AND METHODS: We describe two cases of patients with laterognathia greater than 6 mm associated with maxilla deformity, which were treated with combined osteotomies. At Maxillofacial Surgery Service, Specialty Hospital, National Medical Center XXI Century, we describe the advantages and disadvantages, pre and postoperative nosocomial, by comparing them with the reports of the literature. CONCLUSION: The combination of techniques in the correction of laterognathias greater than 4 mm (smaller than 10 mm) is the ideal treatment, eliminating problems of articular compression, recurrence and damage to the alveolar nerve. PMID- 28717298 TI - Ameloblastic Carcinoma: A Rare Malignant Tumour in Maxillofacial Region. AB - Ameloblastic carcinoma (AC) is a rare malignant odontogenic tumor with poor prognosis. It has an aggressive clinical course with extensive local destruction. It occurs primarily in the mandible. It may clinically present as a cystic lesion with benign clinical feature or as a large mass with ulceration, significant bone resorption and mobility of teeth in the affected region. Reliable evidence of it's biological activity along with extensive local destruction, direct extension of tumor, lymph node involvement and metastasis to various sites (frequently lung) have been reported. Wide local excision is the treatment of choice along with regional lymph node dissection. Because of recurrence close periodic assessment of the patient is advocated. The authors discussed a rare case of AC of mandible; with metastasis to regional lymph nodes in a 45 year old male along with a long-term follow up. PMID- 28717299 TI - Giant Solitary Schwannoma of Submandibular Salivary Gland-A Rare Entity. AB - Submandibular gland tumours, especially mesenchymal tumours, are extremely rare. Schwannoma of the salivary gland is a particularly rare form of an extracranial neurogenic tumor, of which ancient schwannoma is one of five variants. Since the first description, only a few ancient schwannomas have been reported in different locations in the head and neck region. In the submandibular gland it is very rare. This report presents a case of 26 year old male patient with an ancient schwannoma of the submandibular gland seems to be arising from parasympathetic fibers. PMID- 28717300 TI - Synovial Osteochondromatosis of the Temporomandibular Joint Manifesting as a Large Infratemporal Space Occupying Lesion. PMID- 28717301 TI - Simplified Technique to Change the Endotracheal Tube from Nasal to Oral Cavity. AB - We introduce modified nasal to oral tube switch technique for modified alar cinching to prevent alar flare after orthognathic and nasal corrective surgeries. The technique is beneficial to prevent alar flare. Modified alar base cinching is effective in patients with modified tube switch technique. It increased positive results. The technique of tube switch is effective in prevention of alar flare. We suggest multi center randomized studies to know the technical difficulties of tube switch for cinching. PMID- 28717302 TI - Frazier Metallic Suction Tube: An Adjunct in Irrigation of Deep Fascial Spaces. AB - Once incision and drainage of fascial space abscess is performed, irrigation of deep spaces with saline and antibiotic solution should be done daily for effective elimination or reduction of infection. Various advocated aids for irrigation into deeper areas are: small pediatric nasogastric feeding tubes, French catheter, polyethylene irrigation tubes and scalp vein infusion set. All these aids have major inherent disadvantages like, they tend to kink inside the deep spaces limiting the reach of irrigating solution into deeper spaces, are not readily available in dental departments and have to be discarded after every use. Overcoming these disadvantages, a simple yet an effective method is proposed here use of a Frazier suction tube. PMID- 28717303 TI - Preservation of the Vascularised Nasal Lining During Palatal Fenestration Procedures: A Simple 2 Step Technique. AB - PROBLEM: During palatal fenestration procedure the vascularised, respiratory nasal lining is often sacrificed inadvertently. It normally functions to keep the inhaled air warm, humid and dust free. CONCLUSION: This vascularised nasal lining when uninvolved oncologically can easily be preserved. Preservation of the vascularised nasal lining shall decrease the leakage of nasal secretions and aid in the healing of reconstruction of the defect when local or regional flaps are used. PMID- 28717304 TI - Letter to the Editor: Can Vagus Nerve Schwannoma Masquerade as a Carotid Chemodectoma? PMID- 28717305 TI - Efficacy of early chick nutrition with Aloe vera and Azadirachta indica on gut health and histomorphometry in chicks. AB - AIM: This study was conducted with an aim of studying the efficacy of water supplements of Aloe vera and Azadirachta indica (neem) during pre-starter age (0 2 weeks) on gut health and histomorphometry in Vanaraja chicks. MATERIALS AND METHODS: A total of 192 day old Vanaraja chicks were randomly assigned to one of four herbal water treatments throughout the experimental pre-starter stage (0-2 weeks) in a completely randomized design. Each treatment was given four replicates consisting of 12 chicks per replicate. Water treatments comprised T1: Control with regular antibiotic supplement, T2: 3 ml Aloe juice per chick per day, T3: 3 ml neem extract per chick per day, T4: 1.5 ml Aloe and 1.5 ml neem per chick per day. Gut culture was done for Escherichia coli and Lactobacillus sps. and gut histomorphometry in 24 gut samples at 14 days of age. RESULTS: This study revealed that supplementation of A. vera and neem in water significantly (p<0.05) reduced and increased the number of gut E. coli and Lactobacillus sps. Colonies, respectively, as compared to that of control groups; Villi was significantly (p<0.05) taller and broader on 14 days of age across the jejunum of chicks fed with neem supplementation as compared to that of control chicks. Significantly lower crypt depth (p<0.05) was observed in the duodenum of Aloe supplementation. Villus height: Crypt depth ratio of duodenum and jejunum was significantly (p<0.05) increased neem and Aloe supplementation in chicks as compared to their combination and control. CONCLUSION: Immediate post hatch supplementation of Aloe juice and neem extract in chicks improved the development and health of their gut. PMID- 28717306 TI - Prevalence of paratuberculosis in organized and unorganized dairy cattle herds in West Bengal, India. AB - AIM: The aim of this study was to determine the prevalence pattern of Mycobacterium avium subsp. paratuberculosis, the causative agent of paratuberculosis or Johne's disease, in unorganized as well as organized cattle herds in West Bengal. MATERIALS AND METHODS: Four organized cattle farms with identical management practice in Nadia (n=3) and South 24 Parganas (n=1) districts and three unorganized cattle herds, one each from three districts, namely, Burdwan, North 24 Parganas, and Purba Midnapur, were selected randomly and screened for paratuberculosis by delayed-type hypersensitivity (DTH) and enzyme-linked immunosorbent assay (ELISA). RESULTS: Of 191 animals tested by DTH, 57 (29.8%) were found to be positive in comparison to 72 (37.7%) by ELISA. In organized farms, seropositivity varied from 13.3% to 53.1%, whereas in unorganized sector, it ranged from 5% to 6.7% with one area having exceptionally high prevalence, i.e. 53.3%. The range of positivity detected by DTH both in organized farms and backyard sectors varied from 0% to 46.7%. By employing both DTH and ELISA together, the positivity of animals in organized and unorganized herds was 19.9% and 8%, respectively. CONCLUSION: The results indicate that animals in organized farms are much more prone to paratuberculosis than others. For screening the herd, both DTH and ELISA should be used simultaneously to increase the test sensitivity in order to minimize its further spread adopting control programs. PMID- 28717308 TI - Prevalence of methicillin-resistant Staphylococcus aureus skin and nasal carriage isolates from bovines and its antibiogram. AB - AIM: This study was conducted to determine the prevalence of methicillin resistant Staphylococcus aureus (MRSA) in cattle and buffalo and to study their antibiotic resistance pattern. MATERIALS AND METHODS: A total of 136 samples (skin and nasal swab) from cattle and buffalo were collected. MRSA was identified by conventional bacterial culture techniques which were further confirmed by amplification of S. aureus-specific 16S rRNA by polymerase chain reaction (PCR). The isolates were further analyzed for the presence of mec A gene by PCR. The antimicrobial susceptibility profiling was performed by disc diffusion method. RESULTS: The prevalence of MRSA in the current study was 28.57% and 34.28% in cattle nasal and skin swab, respectively, with an overall prevalence of 31.43% MRSA among cattle. Buffalo nasal and skin sample showed MRSA prevalence of 54.55% and 39.4%, respectively, with 46.9% overall prevalence. PCR could detect mec A gene in 36.4% and 58% MRSA isolates from cattle and buffalo, respectively. Antimicrobial susceptibility test found MRSA resistant to penicillin and oxytetracycline (88% each), cefoxitin (75%), cotrimoxazole (62%), and amoxyclav (50%). 100% sensitivity was observed against ciprofloxacin, amikacin, chloramphenicol, and gentamicin. Three (16.7%) MRSA isolates from buffalo were found resistant to vancomycin. CONCLUSION: Cattle and buffalo were identified as a potential carrier of MRSA in Bihar (India). The isolation of vancomycin resistant S. aureus (VRSA) in the current study indicates the emergence of VRSA in animal population which may be transmitted to the human beings working in close contact to the animals. PMID- 28717307 TI - Traditional treatment of human and animal salmonelloses in Southern Benin: Knowledge of farmers and traditherapists. AB - AIM: This study aimed to report medicinal plants that are likely to be used in the control of salmonellosis. MATERIALS AND METHODS: A cross-sectional study was conducted in Southern Benin. Semi-structured questionnaires were administered to 150 farmers and 100 traditional therapists in seven high municipalities. This step helped to collect plants that are used in the treatment of animal salmonellosis and typhoid fever in human. RESULTS: The results revealed a low level of use of medicinal plants among breeders who prefer antibiotics such as oxytetracycline (53.55%), tylosine + sulfadimerazine (15.30%), and alphaceryl (19.13%). However, plants such as Moringa oleifera (leaves), Carica papaya (leaves and seeds), and Vernonia amygdalina (leaves) were mostly used by some farmers. From traditional therapists, 57 plant species of 32 families were identified as typhoid fever cures; among which Leguminosae, Asteraceae, and Euphorbiaceae were predominant. Persea americana (22.72%), V. amygdalina (7.57%), and Corchorus olitorius (7.57%) were the most cited by traditherapists for the treatment of typhoid fever in human. CONCLUSION: This study provides a database for further studies on the in vitro and in vivo efficacy of Benin plant species on Salmonellaspp. These evaluations will guarantee the availability of new therapeutic solutions for populations. PMID- 28717309 TI - Molecular characterization of antibiotic-resistant Staphylococcus aureus from livestock (bovine and swine). AB - AIM: The aim of this study was to figure the prevalence, phenotypic and genotypic antibiotic resistance (AR) pattern of Staphylococcus aureus isolated from bovine and swine nares. MATERIALS AND METHODS: Colonies with typical morphology on Baird Parker agar supplemented with egg-yolk tellurite emulsion were selected and biochemically/genotypically identified as S. aureus. These strains were further subjected to epsilometer test for their sensitivity to various clinically important antibiotics and antibiotic susceptibility testing for amoxicillin/clavulanic acid, and double-disk diffusion testing was performed by the standard disc diffusion method following CLSI guidelines. S. aureus strains were also tested for the presence of AR genes, viz., blaZ, mecA, aacA-aphD, erm (ermA, ermB, ermC), tet (efflux genes tetK and tetL, tetM and tetO of the ribosomal protection family), and vanA. RESULTS: The nasal cavities of 17 out of 47 randomly selected bovine and 20 out of 28 randomly selected swine were positive for S. aureus, representing the prevalence of 36.2% (95% confidence interval [CI]: 22.5-49.9) and 71.4% (95% CI: 54.7-88.1), respectively. Most of the S. aureus strains showed higher resistance to penicillin (94.6%, minimal inhibitory concentration [MIC] >=1.5 ug/ml) followed by ciprofloxacin (56.7%, MIC >=32 ug/ml) and tetracycline (18.9%, MIC >=32 ug/ml). About 10-15% of the strains were resistant to gentamicin (MIC 16 ug/ml) and oxacillin (MIC 6-8 ug/ml). None of the strains were resistant to vancomycin (MIC 0.25-1.5 ug/ml). In this study, 32.4% strains were resistant to three or more than three antibiotics and prevalence of this multi-drug resistant S. aureus was 45% (95%CI: 26.6-63.4) and 17.6% (95%CI: 6.7-28.5) in swine and bovine nasal samples, respectively. Four strains from pigs were borderline oxacillin-resistant S. aureus MIC 6-8 ug/ml, but none were mecA positive. Two of these strains were beta-lactamase hyperproducers. Among the resistance genes blaZ, tetK, tetL, tetM, ermB, and aacA aphD were found. CONCLUSION: Our results demonstrated the absence of mecA and pvl gene, but the presence of multi-drug resistant S. aureus in the nares of healthy animals which has a potential to spread in a community. PMID- 28717310 TI - Cytological endometritis and its agreement with ultrasound examination in postpartum beef cows. AB - BACKGROUND: Endometritis, which is one of the most common diseases in dairy cows postpartum, causes severe economic losses, including increased open days, calving intervals, and numbers of services to achieve conception. AIM: This study aimed to evaluate the ultrasound method and its agreement with the endometrium cytology method, which is used to diagnose cytological endometritis in beef cows. Moreover, we determined which method has higher sensitivity and specificity at 4 and 5 weeks postpartum. MATERIALS AND METHODS: The study was conducted 20-35 days postpartum. A total of 53 clinically healthy beef cows (28 Brangus and 25 Kedah Kelantan breeds) from three beef farms were obtained. All cows were evaluated at 4 and 5 weeks postpartum, using ultrasound and cytobrush endometrial examination methods to diagnose cytological endometritis. RESULTS: Endometrial cytology result showed that 11.3% (6/53) and 9.4% (5/53) of the cows exhibited cytological endometritis 4 and 5 weeks postpartum, respectively. A weak-to-moderate agreement found between the diagnostic methods (k=0.29 - 0.50; p<0.01 and k=0.38 - 0.49) at 4 and 5 weeks postpartum respectively. CONCLUSION: The percentage of beef cows that were positive to cytological endometritis was low (polymorphonuclear cells, >=8%) at 4 and 5 weeks postpartum. Results showed that the ultrasound method is useful and practical for diagnosing endometritis 4 and 5 weeks postpartum. This method exhibited 60% sensitivity, 93.8% specificity, and a 0.50 kappa value, especially when presence of intrauterine fluids and measurement of cervix diameter used in combination. PMID- 28717311 TI - Using real-time polymerase chain reaction as an alternative rapid method for enumeration of colony count in live Brucella vaccines. AB - AIM: Brucellosis is a major bacterial zoonosis of global importance affecting a range of animal species and man worldwide. It has economic, public health, and bio-risk importance. Control and prevention of animal brucellosis mainly depend on accurate diagnostic tools and implementation of effective and safe animal vaccination program. There are three types of animal Brucella live vaccines - Brucella melitensis Rev-1 vaccine, Brucella abortus S19, and B. abortus RB51. Evaluation of these vaccines depends mainly on enumeration of Brucella viable count. At present, used colony count method is time consuming, costly and requires especial skills. Hence, the aim of this study is to use and standardize real-time polymerase chain reaction (RT-PCR) as an alternative, quantitative, sensitive, and rapid method to detect the colony count of Brucella in live Brucella vaccine. MATERIALS AND METHODS: Four batches of different live Brucella vaccines were evaluated using of conventional bacterial count and RT-quantitative PCR (RT-qPCR) using BSCP31 gene specific primers and probe. Standard curve was generated from DNA template extracted from 10-fold serial dilution of living B. abortus RB51 vaccine to evaluate the sensitivity of RT-qPCR. RESULTS: Results revealed that three batches of living Brucella vaccines were acceptable for Brucella colony count when traditional bacterial enumeration method was used. Results of RT-qPCR were identical to that of conventional bacterial count. CONCLUSIONS: Results concluded that RT-qPCR was relatively sensitive compared to traditional bacterial colony count of these vaccines. PMID- 28717312 TI - Effect of high and low roughage total mixed ration diets on rumen metabolites and enzymatic profiles in crossbred cattle and buffaloes. AB - AIM: A comparative study was conducted on crossbred cattle and buffaloes to investigate the effect of feeding high and low roughage total mixed ration (TMR) diets on rumen metabolites and enzymatic profiles. MATERIALS AND METHODS: Three rumen-fistulated crossbred cattle and buffalo were randomly assigned as per 3*3 switch over design for 21-days. Three TMR diets consisting of concentrate mixture, wheat straw and green maize fodder in the ratios of (T1) 60:20:20, (T2) 40:30:30, and (T3) 20:40:40, respectively, were fed to the animals ad libitum. Rumen liquor samples were collected at 0, 2, 4, 6, and 8 h post feeding for the estimation of rumen biochemical parameters on 2 consecutive days in each trial. RESULTS: The lactic acid concentration and pH value were comparable in both species and treatments. Feed intake (99.77+/-2.51 g/kg body weight), ruminal ammonia nitrogen, and total nitrogen were significantly (p<0.05) higher in buffalo and in treatment group fed with high concentrate diet. Production of total volatile fatty acids (VFAs) was non-significant (p>0.05) among treatments and significantly (p<0.05) greater in crossbred cattle than buffaloes. Molar proportions of individual VFAs propionate (C3), propionate:butyrate (C3:C4), and (acetate+butyrate):propionate ([C2+C4]:C3) ratio in both crossbred cattle and buffalo were not affected by high or low roughage diet, but percentage of acetate and butyrate varied significantly (p<0.05) among treatment groups. Activities of microbial enzymes were comparable among species and different treatment groups. A total number of rumen protozoa were significantly (p<0.05) higher in crossbred cattle than buffaloes along with significantly (p<0.05) higher population in animal fed with high concentrate diet (T1). CONCLUSION: Rumen microbial population and fermentation depend on constituents of the treatment diet. However, microbial enzyme activity remains similar among species and different treatments. High concentrate diet increases number of rumen protozoa, and the number is higher in crossbred cattle than buffaloes. PMID- 28717313 TI - Study of morphology, chemical, and amino acid composition of red deer meat. AB - AIM: The aim of this study was to evaluate red deer (maral) meat quality based on chemical composition, pH, water-binding capacity (WBC), and amino acid content. MATERIALS AND METHODS: Maral meat surface morphology measurements were obtained by scanning electron microscopy. Active acidity (pH) was determined by potentiometry. Samples were analyzed for WBC by exudation of moisture to a filter paper by the application of pressure. Chemical composition (moisture, protein, fat, and ash fractions) was obtained by drying at 150 degrees C and by extraction, using ethylic ether, and ashing at 500-600 degrees C. The amino acid composition was obtained by liquid chromatography. RESULTS: Maral meat, with a pH of 5.85 and an average moisture content of 76.82%, was found to be low in fat (2.26%). Its protein content was 18.71% while its ash content was 2.21%. The amino acid composition showed that lysine (9.85 g/100 g), threonine (5.38 g/100 g), and valine (5.84 g/100 g) predominated in maral meat, while phenylalanine (4.08 g/100 g), methionine (3.29 g/100 g), and tryptophan (0.94 g/100 g) were relatively low in maral meat compared to other meats. The average WBC was found to be 65.82% and WBC was found to inversely correlate with moisture content. CONCLUSION: Low-fat content, high mineral content, and balanced amino-acid composition qualify maral meat as a worthy dietary and functional food. PMID- 28717314 TI - Enhancing the growth performance of replacement female breeder goats through modification of feeding program. AB - AIM: The study was conducted at a smallholder goat farm located in Labu, Negeri Sembilan, Malaysia. The objective of this study was to evaluate the effect of proper feeding program on growth performances of replacement breeder goats. MATERIALS AND METHODS: A total of 30 healthy female boer cross goats at the age of 4 months old with average initial live body weight (BW) of 20.05+/-0.5 kg were used for on-farm feeding trial to evaluate the growth performance as preparation for breeding purposes. The experimental goats were divided into two groups of 15 animals each labeled as control and treatment groups, which were kept under intensive farming system. Goats in control group were fed with normal routine feeding protocol practiced by the farmer, while goats in the treatment group were fed with new feed formulation. Throughout the experimental period, on-farm monitoring and data collection were carried out. Initial BW and body condition score (BCS) were recorded before the start of the experiment while final BW and BCS were gained after 7 months of the experimental period. Average daily gain (ADG) was calculated after the experiment end. Data on BW, ADG, and BCS were recorded from both groups for every 2 weeks and reported monthly. The feed intake for the control group was 2.8 kg/animal/day which practiced by the farmer and 3.2 kg/animal/day as new feed formulation for the treatment group. RESULTS: After 7 months of the experimental period, final BW shows an improvement in treatment group (39.1+/-1.53 kg) compared with control group (32.3+/-1.23 kg). The ADG in treatment group also gives promising result when comparing with control group. Goats in treatment group significantly attained better ADG than control group which were 126.7 g/day and 83.3 g/day, respectively. For the BCS, goats in the treatment group had shown an improvement where 86.67% (13 out of 15) of the group had BCS >=3 (1-5 scoring scale) and only 66.67% (10 out of 15) of the control group had BCS >=3. CONCLUSION: Therefore, it was concluded that implementation of proper feeding program as shown in treatment group give promising result to improve the growth performance of replacement breeder goats which can be adopted by the farmers to improve farm productivity. PMID- 28717315 TI - Seroprevalence of antibodies to astrovirus in chickens in Grenada, West Indies. AB - AIM: Chicken astroviruses (CAstV) are known to cause mild gastroenteritis, growth depression, and even mortality in poultry, especially in chickens, turkeys, and ducks. To the best our knowledge, there is no published information on CAstV in Grenada. This study was conducted to determine the prevalence of astrovirus in chickens in Grenada. MATERIALS AND METHODS: Blood samples from 366 indigenous chickens and 92 commercial chicken layers were collected from all parishes of the island and tested for antibodies against CAstV using commercial enzyme-linked immunosorbent assay. RESULTS: The seroprevalence of antibodies against astrovirus was 57.6% (95%, Confidence interval [CI]: 47.4-67.2) in commercial layers and 61.5% (95%, CI: 56.4-66.3) in indigenous chickens. The results show the presence of infection throughout the island. CONCLUSION: The results show the infection with CAstV in approximately half of the chicken population in Grenada. This is the first report on the prevalence of CAstV in chickens in Grenada and the Caribbean region. PMID- 28717317 TI - Effect of season on physiological, biochemical, hormonal, and oxidative stress parameters of indigenous sheep. AB - AIM: This study was conducted to evaluate the impact of summer and winter season on physiological, biochemical, hormonal, and antioxidant parameters in Indigenous sheep. MATERIALS AND METHODS: The research was carried out during summer and winter season. 8 adult apparently healthy female sheep (aged 2-4 years) of similar physiological status were selected. Daily ambient temperature and relative humidity were recorded to calculate the temperature-humidity index (THI). The THI value of summer and winter season were 82.55 and 59.36, respectively, which indicate extreme hot condition during summer season and extreme cold condition during winter season. Physiological parameters were recorded daily during the experimental periods. Blood samples were collected at weekly interval and analyzed for biochemical, hormonal, and antioxidant parameters. The results were analyzed using completely randomized design. RESULTS: From data obtained in this study, we found that higher THI during summer have significant effect over various physiological, biochemical, hormonal, and enzymatic indices of indigenous sheep. The physiological response such as rectal temperature, respiration rate (RR), pulse rate (PR), and skin temperature (ST) was increased significantly. We also found a significant increase in some biochemical parameters such as blood urea nitrogen (BUN), uric acid, creatinine (Cr), alanine transaminase (ALT), aspartate transaminase (AST), sodium (Na), and potassium (K). The level of cortisol hormone and superoxide dismutase (SOD), glutathione peroxidase (GPx), and lipid peroxidase (LPO) antioxidants increased significantly during summer. Whereas, some parameters such as glucose, cholesterol, calcium (Ca), inorganic phosphorus (IP), triiodothyronine (T3), and thyroxine (T4) were decreased significantly during summer season. CONCLUSION: It was concluded that the THI is a sensitive indicator of heat stress and is impacted by ambient temperature more than the relative humidity in Indigenous sheep. Higher THI is associated with significant increase in RT, RR, PR, ST, BUN, uric acid, Cr, ALT, AST, Na, K, cortisol, SOD, GPx, and LPO and with a significant decrease in glucose, cholesterol, Ca, IP, T3 and T4. PMID- 28717316 TI - Induced pluripotent stem cell: A headway in reprogramming with promising approach in regenerative biology. AB - Since the embryonic stem cells have knocked the doorsteps, they have proved themselves in the field of science, research, and medicines, but the hovered restrictions confine their application in human welfare. Alternate approaches used to reprogram the cells to the pluripotent state were not up to par, but the innovation of induced pluripotent stem cells (iPSCs) paved a new hope for the researchers. Soon after the discovery, iPSCs technology is undergoing renaissance day by day, i.e., from the use of genetic material to recombinant proteins and now only chemicals are employed to convert somatic cells to iPSCs. Thus, this technique is moving straightforward and productive at an astonishing pace. Here, we provide a brief introduction to iPSCs, the mechanism and methods for their generation, their prevailing and prospective applications and the future opportunities that can be expected from them. PMID- 28717318 TI - Hemogram responses in goats toward challenged with Corynebacterium pseudotuberculosis and its immunogen mycolic acids. AB - AIM: This study was conducted to analyze the changes in blood profile of goats inoculated with Corynebacterium pseudotuberculosis and its immunogen mycolic acid (MA) extract. MATERIALS AND METHODS: A total of 12 clinically healthy crossbred Boer female goats were divided into three groups; A, B and C (4 goats each per group). Group A was inoculated with 2 ml sterile phosphate buffered saline via intradermal route as the negative control group whilst Group B was inoculated with 2 ml of MA extract (1 g/ml) intradermally and Group C was then inoculated with 2 ml (1*109) colony forming unit of active C. pseudotuberculosis intradermally. Blood sample was collected aseptically from the jugular vein periodically for complete blood count (CBC) analysis throughout the experimental period (3 months). RESULT: A significant decrease (p<0.05) was observed in red blood cells, hemoglobin (Hb), packed cell volume, mean corpuscular volume and mean corpuscular Hb concentration in Groups B and C as compared to the control while WBCs, neutrophil, lymphocyte and basophil showed a significant increase (p<0.05) as compared to the control. CONCLUSION: The inoculation of C. pseudotuberculosis and MA resulted in a significant change in the CBC, thereby, indicating that MA has a role in caseous lymphadenitis pathogenesis. PMID- 28717319 TI - Changes in histopathology and cytokeratin AE1/AE3 expression in skin graft with different time on Indonesian local cats. AB - AIM: A good skin graft histopathology is followed by formation of hair follicle, sweat gland, sebaceous gland, blood vessel, lightly dense connective tissue, epidermis, and dermis layer. This research aimed to observe histopathology feature and cytokeratin AE1/AE3 expression on cat skin post skin grafting within a different period of time. MATERIALS AND METHODS: Nine male Indonesian local cats aged 1-2 years old weighing 3-4 kg were separated into three groups. First surgery created defect wound of 2 cm * 2 cm in size to whole groups. The wounds were left alone for several days, differing in interval between each group, respectively: Group I (for 2 days), Group II (for 4 days), and Group III (for 6 days). The second surgery was done to each group which harvested skin of thoracic area and applied it on recipient wound bed. On day 24th post skin graft was an examination of histopathology and cytokeratin AE1/AE3 immunohistochemistry. RESULTS: Group I donor skin's epidermis layer had not formed completely whereas epidermis of donor skin of Groups II and III had completely formed. In all group hair follicle, sweat gland, sebaceous gland, and neovascularization were found. The density of connective tissue in Group I was very solid than other groups. Cytokeratin AE1/AE3 expression was found on donor skin's epithelial cell in epidermis and dermis layer with very brown intensity for Group II, brown intensity for Group II, and lightly brown for Group I. CONCLUSION: Histopathological structure and cytokeratin AE1/AE3 expression post skin graft are better in Groups II and III compared to Group I. PMID- 28717320 TI - Coxiellosis in domestic livestock of Puducherry and Tamil Nadu: Detection of Coxiella burnetii DNA by polymerase chain reaction in slaughtered ruminants. AB - BACKGROUND AND AIM: In the course of our Indian Council of Medical Research project on coxiellosis in Puducherry and Tamil Nadu, 5.64% goat, 1.85% sheep, 1.06% buffaloes, and 0.97% cattle were positive for Coxiella burnetii antibodies by enzyme linked immunosorbent assay kit (IDEXX, Liebefeld, Switzerland). In this preliminary study, we have proceeded to look for C. burnetii DNA in those antibody positive specimens employing an imported commercial C. burnetii polymerase chain reaction (PCR) kit. MATERIALS AND METHODS: Blood samples were collected during slaughtering. All 15 blood samples of antibody positive ruminants and three antibody negative samples were subjected to conventional Trans-PCR assay with a commercial PCR kit (Genekam Biotechnology AG, Duisburg, Germany). An in-house Trans-PCR was included in the study for comparison. RESULTS: A total of 15 antibody positive and three antibody-negative serum samples belonging to 11 goat, 4 sheep, 1 cattle, and 2 buffaloes were tested in duplicate for the presence of C. burnetii DNA by the commercial agar gel PCR kit and an in-house Trans-PCR. Only one buffalo serum sample was positive for C. burnetii with a band at 243 bp in in-house Trans-PCR. DISCUSSION: Seropositivity for C. burnetii need not necessarily translate into infectivity status of the animal. Conversely, seronegative ruminants can shed C. burnetii. Rapid disintegration of C. burnetii DNA during the storage period is an important impediment in QF-PCR research. This is the first time the performance of this commercial PCR kit is being validated in India. CONCLUSION: Commercial PCR kit, Genekam did not identify any positive sample, probably because it targeted a larger amplicon of 687 bp. PMID- 28717321 TI - Effect of different concentrations of soybean lecithin and virgin coconut oil in Tris-based extender on the quality of chilled and frozen-thawed bull semen. AB - AIM: The objective of this study was to evaluate the effects of different concentrations of soybean lecithin (SL) and virgin coconut oil (VCO) in Tris based extender on chilled and frozen-thawed bull semen quality parameters. MATERIALS AND METHODS: A total of 24 ejaculates were collected from four bulls via an electroejaculator. Semen samples were diluted with 2% VCO in Tris-based extender which consists of various concentrations of SL (1, 1.25, 1.5, and 1.75%). A 20% egg yolk in Tris used as a positive control (C+). The diluted semen samples were divided into two fractions; one for chilling which were stored at 4 degrees C for 24, 72, and 144 h before evaluated for semen quality parameters. The second fraction used for freezing was chilled for 3 h at 4 degrees C, packed into 0.25 mL straws and then cryopreserved in liquid nitrogen. The samples were then evaluated after 7 and 14 days. Chilled and frozen semen samples were thawed at 37 degrees C and assessed for general motility using computer-assisted semen analysis, viability, acrosome integrity and morphology (eosin-nigrosin stain), membrane integrity, and lipid peroxidation using thiobarbituric acid reaction test. RESULTS: The results showed that all the quality parameters assessed were significantly (p<0.05) improved at 1.5% SL concentration in chilled semen. Treatment groups of 1, 1.25, 1.5, and 1.75% SL were higher in quality parameters than the control group (C+) in chilled semen. However, all the quality parameters in frozen-thawed semen were significantly higher in the C+ than the treated groups. CONCLUSION: In conclusion, supplementation of 1.5% SL in 2% VCO Tris based extender enhanced the chilled bull semen. However, there was no marked improvement in the frozen-thawed quality parameters after treatment. PMID- 28717322 TI - Th1/Th2 balance and humoral immune response to potential antigens as early diagnostic method of equine Strongylus nematode infection. AB - AIM: The aim of this study was to investigate the early diagnosis of strongyle infection based on early changes in Th1 and Th2 cytokines beside the diagnostic accuracy values and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and western blotting profiles using prepared strongyles antigens. MATERIALS AND METHODS: A total of 73 donkeys had a mean age of 4-32 years old were parasitologically examined for strongyle infection. The early changes in Th1 and Th2 cytokines were determined, and the diagnostic accuracy values and SDS PAGE and western blotting profiles were performed using prepared strongyles antigens; crude somatic Strongylusvulgaris (CSS), excretory-secretory S. vulgaris (ESS), crude somatic Cyathostomins (CSC), and excretory-secretory Cyathostomins (ESC). RESULTS: The results revealed highest 437.04% and lowest 37.81% immunoglobulin G (IgG) in high and low egg shedder groups when using ESC and CSS antigens, respectively. Antibodies index for ESS and CSC were significantly higher in moderate egg shedder group while that for ESS and CSC, ESC was significantly higher in high egg shedder group. Tumor necrosis factor alpha (TNF alpha)/interleukin-4 (IL-4) balance in S. vulgaris infected donkeys was approximately equal in apparently healthy, low and high egg shedder groups while TNF-alpha < IL-4 in moderate egg shedder. In Cyathostomins infected animals, TNF alpha/IL-4 balance was approximately equal in apparently healthy group while it was low in moderate and high egg shedder groups. The diagnostic accuracy showed that the higher specificity (46.6%) and prevalence (95.40%) were recorded by CSS and ESC antigens, respectively. However, SDS-PAGE and western blotting profiling proved that the band at molecular weight 25 kDa is exhibited by CSS antigen. CONCLUSION: Combination of detecting level of TNF-alpha/IL-4 balance, CSS antigen and IgG concentration is good tool for appropriate diagnosis of such infection. More advancement research must be done concerning Th1/Th2 balance and cross reactivity of S. vulgaris and Cyathostomins spp. at the base of serological and molecular investigation. PMID- 28717323 TI - Epidemiological study of tick infestation in buffalo of various regions of district Khairpur, Pakistan. AB - AIM: The aim of this study was to determine the epidemiological infestation and identification of Ixodidae and Argasidae ticks species in buffalo of different parts of district Khairpur, Pakistan. MATERIALS AND METHODS: A total of 720 Water buffaloes from three tehsils (subdivisions) were selected randomly and examined from organized and unorganized dairy farms for tick infestation in district Khairpur, Pakistan. This epidemiological survey was conducted during April to September 2015. RESULTS: The overall mean population and preferred site of tick attachment to infested animals, in Gambat, Sobhodero, and Kot Diji tehsils, were observed on different body parts. The primary body area of infestation by ticks (head, thorax, abdomen, udder, and tail) ranged from highest in tail and udder part compared to lowest in the abdomen, head, and thorax. In all study areas, the infestation was higher (p<0.05) in tail and udder than other parts of the body. In all the study areas, the overall highest population was found in the month of July. In addition, we first time identify four new species of ticks (Hyalomma anatolicum, H. anatolicum excavatum, Hyalomma Ixodes excavatum, and Ixodes ricinus) in district Khairpur, Pakistan. CONCLUSION: Results of this study provide additional information of epidemiological tick infestation, and will be helpful for evolving effective control policy for the management of tick infestation in study district. PMID- 28717324 TI - Investigation of avian influenza infection in wild birds in Ismailia and Damietta cities, Egypt. AB - AIM: This study was carried out to monitor avian influenza (AI) infection in wild birds in Egypt. MATERIALS AND METHODS: A total of 135 wild birds were examined for the presence of H5, H7, and H9 hemagglutination inhibition antibodies. Organs and swab samples of 75 birds were screened by multiplex real-time reverse transcriptase-polymerase chain reaction (RRT-PCR) to detect AI subtypes H5, H7, and H9 matrix genes. RESULTS: The highest seropositive result was recorded in cattle egrets (90.9%) followed by crows (88.6%), semi-captive pigeons (44.8%), and moorhens (39.1%). In cattle egrets, semi-captive pigeons and moorhens, H5 antibodies predominated. In crows, H9 antibodies predominated. Multiple infections with two or three virus subtypes were highest in crows (6/39, 15.4%) followed by cattle egrets (3/30, 10%) and moorhens' (1/9, 11.1%) positive samples. Multiplex RRT-PCR results revealed two positive samples in cattle egrets and moorhens. CONCLUSION: The results indicated high seropositive rates against AI virus subtypes H5 and H9 in the examined wild birds. Multiple infections with more than one AI virus (AIV) subtypes were detected in some birds. This requires a collaboration of efforts to monitor AIV infection in wild birds and implement suitable early intervention measures. PMID- 28717325 TI - Tetracycline resistance phenotypes and genotypes of coagulase-negative staphylococcal isolates from bubaline mastitis in Egypt. AB - AIM: This study was devoted to elucidate the tetracycline resistance of coagulase negative staphylococci (CNS) derived from normal and subclinical mastitic (SCM) buffaloes' milk in Egypt. MATERIALS AND METHODS: A total of 81 milk samples from 46 normal buffalo milk samples and 35 SCM buffalo milk samples at private dairy farms of Egypt were used in this study. CNS were identified using phenotypic and molecular methods (polymerase chain reaction [PCR]). CNS isolates were tested for tetracycline resistance using routine methods and multiplex PCR targeting tetracycline (tet) resistance genes followed by sequencing of positive PCR products and phylogenetic analysis. RESULTS: Isolation and identification of 28 (34.5%) CNS from normal and SCM buffaloes' milk, namely, Staphylococcus intermedius (39.2%), Staphylococcus xylosus (25.0%), Staphylococcus epidermidis (10.7%), Staphylococcus hominis (10.7%), and 3.5% to each of Staphylococcus sciuri, Staphylococcus hyicus, Staphylococcus lugdunensis, and Staphylococcus simulans. Using nested PCR, all the 28 CNS isolates revealed positive for 16srRNA gene specific for genus staphylococci and negative for thermonuclease (nuc) gene specific for Staphylococcus aureus species. The presence of tetracycline resistance-encoding genes (tetK, tetL, tetM, and tetO) was detected by multiplex PCR. All isolates were negative for tetL, M, and O genes while 14 (50%) CNS isolates were positive for tetK gene, namely, S. lugdunensis (100%), S. hominis (100%), S. epidermidis (66.6%), S. intermedius (45.4%), and S. xylosus (42.8%). Nucleotide sequencing of tetK gene followed by phylogenetic analysis showed the high homology between our CNS isolates genes of tetracycline resistance with S. aureus isolates including Egyptian ones. This proves the transfer of the tetracycline resistance encoding genes between coagulase-negative and coagulase positive Staphylococcus spp. CONCLUSION: CNS isolates have distinguishingly high resistance to tetracycline. Abundant tetracycline usage for mastitis treatment leads to the spread of genetic resistance mechanisms inside CNS strains and among all Staphylococcus spp. Consequently, tetracycline is not effective anymore. PMID- 28717326 TI - Honey can repairing damage of liver tissue due to protein energy malnutrition through induction of endogenous stem cells. AB - AIM: This study was to evaluate effect of honey in repairing damage of liver tissue due to energy protein malnutrition and in mobilization of endogenous stem cells. MATERIALS AND METHODS: Male mice model of degenerative liver was obtained through food fasting but still have drinking water for 5 days. It caused energy protein malnutrition and damage of liver tissue. The administration of 50% (v/v) honey was performed for 10 consecutive days, while the positive control group was fasted and not given honey and the negative control not fasted and without honey. Observations of regeneration the liver tissue based on histologically examination, observation of Hsp70 expression, and homing signal based on vascular endothelial growth factor-1 (VEGF-1) expression using immunohistochemistry technique. Observation on expression of CD34 and CD45 as the marker of auto mobilization of hematopoietic stem cells using flow cytometry technique. RESULTS: There is regeneration of the liver tissue due to protein energy malnutrition, decrease of Hsp70 expression, increase of VEGF-1 expression, and high expression of CD34 and CD45. CONCLUSION: Honey can improve the liver tissue based on: (1) Mobilization of endogenous stem cells (CD34 and CD45); (2) Hsp70 and VEGF-1 expressions as regeneration marker of improvement, and (3) regeneration histologically of liver tissue. PMID- 28717327 TI - Virulence gene profiles of Arcobacter species isolated from animals, foods of animal origin, and humans in Andhra Pradesh, India. AB - AIM: This study aimed to detect putative virulence genes in Arcobacter species of animal and human origin. MATERIALS AND METHODS: A total of 41 Arcobacter isolates (16 Arcobacter butzleri, 13 Arcobacter cryaerophilus, and 12 Arcobacter skirrowii) isolated from diverse sources such as fecal swabs of livestock (21), raw foods of animal origin (13), and human stool samples (7) were subjected to a set of six uniplex polymerase chain reaction assays targeting Arcobacter putative virulence genes (ciaB, pldA, tlyA, mviN, cadF, and cj1349). RESULTS: All the six virulence genes were detected among all the 16 A. butzleri isolates. Among the 13 A. cryaerophilus isolates, cadF, ciaB, cj1349, mviN, pldA, and tlyA genes were detected in 61.5, 84.6, 76.9, 76.9, 61.5, and 61.5% of isolates, respectively. Among the 12 A. skirrowii isolates, cadF, ciaB, cj1349, mviN, pldA, and tlyA genes were detected in 50.0, 91.6, 83.3, 66.6, 50, and 50% of isolates, respectively. CONCLUSION: Putative virulence genes were detected in majority of the Arcobacter isolates examined. The results signify the potential of Arcobacter species as an emerging foodborne pathogen. PMID- 28717328 TI - Fine tune your review works please! PMID- 28717330 TI - An Experimental Evaluation of Adaptogenic Potential of Standardized Epipremnum Aureum Leaf Extract. AB - BACKGROUND: Stress is a normal part of everyday life but chronic stress can lead to a variety of stress-related illnesses including hypertension, anxiety, and depression. In the present investigation, standardized leaf extract of Epipremnumaureum was evaluated for its anti-stress potential. MATERIALS AND METHODS: For the evaluation of anti-stress activity, groups of mice (n = 6) were subjected to forced swim stress and anoxic stress tolerance test in mice 1h after daily treatment of E.aureumextract. Diazepam (5 mg/kg) was taken as a reference standard. Urinary vanillylmandelic acid (VMA) and ascorbic acid were selected as noninvasive biomarkers to assess the anti-stress activity and plasma cortisol, blood ascorbic acid, and weight of adrenal were measured. The 24 h urinary excretion of VMA and ascorbic acid were determined by spectrophotometric methods in all groups under normal and stressed conditions. The hematological parameters (neutrophils, lymphocytes, and eosinophils) were also determined. RESULTS: Administration of E.aureumat doses of 400 and 600 mg/kg wasfound to be effective in inhibiting the stress induced urinary biochemical changes in a dose-dependent manner. Treatment with E. aureum extract prevents the rise in blood ascorbic acid and plasma cortisol. Moreover, the extract prevented the increase in weight of adrenal gland also significantly increased the anoxia stress tolerance time. Dose dependent significant reduction in white blood cell count was observed in anoxic stress tolerance test as compared to stressed group. CONCLUSION: Hence, the present study provides scientific support for the positiveadaptogenic effect of E. aureum extract. PMID- 28717329 TI - Statin Therapy Prescribing for Patients with Type 2 Diabetes Mellitus: A Review of Current Evidence and Challenges. AB - Use of statin therapy in patients with type 2 diabetes mellitus (T2DM) has been recommended by most clinical guidelines. Cardiovascular disease (CVD) is a leading cause of morbidity and mortality among T2DM patients. It has been proved that statins are effective for primary or secondary CVD prophylaxis. Reports have highlighted the underutilization of statins in clinical practice and the suboptimal adherence to guideline recommendations. This review article points to summarize the current evidence confirming the role of statins in T2DM patients and to provide an overview of factors that may affect statins' prescribing patterns and compliance in clinical practice. Initiatives to enhance statin therapy prescribing should recognize the comprehensive nature of the prescribing process. Attempts to assure proper statin prescribing and utilization can help in achieving better clinical outcomes of statin therapy. PMID- 28717331 TI - Knowledge and Awareness of First Aid of Avulsed Tooth among Physicians and Nurses of Hospital Emergency Department. AB - INTRODUCTION: Physicians and nurses of emergency department are often the first line of qualified health-care providers attending the patient in person or parent's query over phone reporting immediately following the dental avulsion. Prompt action by them becomes the decisive factor in survival and prognosis of the tooth. Although a few researchers have evaluated knowledge of emergency room physicians, there is scanty of reports concerning nurses who play a climacteric role. MATERIALS AND METHODS: A 10-item questionnaire regarding clinical situation apropos dental injury and tooth avulsion, inquiring knowledge of physicians and nurses was administered to 150 each of nursing professionals and physicians of the emergency department. RESULTS: With 100% response rate, the data obtained was subjected to statistical analysis. Results showed lack of knowledge and confidence in both groups. About 66.7% (n = 100) nurses and 74.7% (n = 112) considered reimplantation of avulsed tooth. There was overbalanced confusion regarding storage/transport media and handling of avulsed tooth. CONCLUSION: The findings from the results suggested a definite inadequacy in knowledge, demanding need for appropriate training for delivering treatment with more predictability and better prognosis. PMID- 28717332 TI - Homology Modeling of Leishmania donovani Enolase and its Molecular Interaction with Novel Inhibitors. AB - INTRODUCTION: The treatment of Indian tropical disease such as kala-azar is likely to be troublesome to the clinicians as AmpB- and miltefosine-resistant Leishmania donovani has been reported. The rationale behind designed a novel inhibitors of model of L. donovani enolase and performing a binding study with its inhibitors to gain details of the interaction between protein residues and ligand molecules. METHODS AND MATERIALS: The L. donovani enolase model consists of two typical domains. The N-terminal one contains three-stranded antiparallel beta-sheets, followed by six alpha-helices. The C-terminal domain composes of eleven-stranded mixed alpha/beta-barrel with connectivity. The first alpha-helix within the C-terminal domain, H7, and the second beta-strand, S7, of the barrel domain was arranged in an antiparallel fashion compared to all other alpha helices and beta-strands. The root-mean-square deviation between predicted model and template is 0.4 A. The overall conformation of L. donovani enolase model is similar to those of Trypanosoma cruzi enolase and Streptococcus pneumoniae enolase crystal structures. RESULT: The key amino acid residues within the docking complex model involved in the interaction between model enolase structure and ligand molecule are Lys70, Asn165, Ala168, Asp17, and Asn213. CONCLUSION: Our theoretical prediction may lead to the establishment of prophylactic and therapeutic approaches for the treatment of kala-azar. This biomedical informatics analysis will help us to combat future kala-azar. PMID- 28717333 TI - Analysis of Chemical Signatures of Alkaliphiles using Fatty Acid Methyl Ester Analysis. AB - BACKGROUND: Fatty acids occur in nearly all living organisms as the important predominant constituents of lipids. While all fatty acids have essentially the same chemical nature, they are an extremely diverse group of compounds. MATERIALS AND METHODS: To test the hypothesis, fatty acids of alkaliphiles isolates, Bacillus subtilis SVUNM4, Bacillus licheniformis SVUNM8, Bacillus methylotrohicus SVUNM9, and Paenibacillus dendritiformis SVUNM11, were characterized compared using gas chromatography-mass spectrometry (GC-MS) analysis. RESULTS: The content of investigated ten fatty acids, 1, 2-benzenedicarboxylic acid butyl 2 methylpropyl ester, phthalic acid, isobutyl 2-pentyl ester, dibutyl phthalate, cyclotrisiloxane, hexamethyl, cyclotetrasiloxane, octamethyl, dodecamethyl, heptasiloxane 1,1,3,3,5,5,7,7,9,9,11,11,13,13-etradecamethyl, 7,15 dihydroxydehydroabietic acid, methyl ester, di (trimethylsilyl) ether, hentriacontane, 2-thiopheneacetic acid, undec-2-enyl ester, obviously varied among four species, suggesting each species has its own fatty acid pattern. CONCLUSIONS: These findings demonstrated that GC-MS-based fatty acid profiling analysis provides the reliable platform to classify these four species, which is helpful for ensuring their biotechnological interest and novel chemotaxonomic. PMID- 28717334 TI - Osteoporosis Knowledge among Future Healthcare Practitioners: Findings from a Malaysian Public University. AB - BACKGROUND AND OBJECTIVES: Students in relevant health-care academic programs are the future professionals who should play an active role in increasing community awareness regarding chronic diseases such as osteoporosis. This research aimed to evaluate the knowledge of osteoporosis, one of the growing health-care burdens in Malaysia, among students belong to three different health occupations programs in a Malaysian University. METHODS: A cross-sectional study design was conducted to assess the level of knowledge on osteoporosis and to explore the potential association between the study program and osteoporosis-related knowledge among medicine, pharmacy, and allied health sciences students in a Malaysian University. A total of 348 students were approached. The data were collected using validated revised Osteoporosis Knowledge Test questionnaire. RESULTS: The results showed variability in knowledge score between students belonging to different study programs. allied health sciences students have the highest overall total score (median = 20) and nutrition score (median = 16), but for exercise score, both students in allied health sciences and medicine programs shared a similar median score (median = 11.5). More than half of the respondents showed adequate knowledge on osteoporosis. The students from allied health sciences exhibited more knowledge on osteoporosis compared to students in other study programs. Among the Kulliyyah of Pharmacy respondents, the majority did not manage to answer correctly on the whole scale. This was evident by total percentage of 69.91% of the respondents scored below than median score. CONCLUSION: There is a considerable gap of knowledge regarding osteoporosis among students in various health occupations academic programs. Pharmacy students particularly need focused learning related to exercise and nutrition in preventing osteoporosis during their academic program. PMID- 28717335 TI - Evaluation of Therapeutic Effectiveness of Prescribed Medications in Patients with Type 2 Diabetes Mellitus: Findings from a Tertiary Care Hospital, Lahore, Pakistan. AB - AIM: The present study was aimed to highlight the current prescribing pattern of oral hypoglycemia in type 2 diabetes mellitus and to evaluate the therapeutic effectiveness of these therapeutic categories in achieving target glycemic control. METHODS: This is a prospective, cross-sectional, observational study of 6 months' duration conducted in a tertiary care hospital of Lahore, Pakistan. RESULTS: The current research recruited 145 patients presented in diabetes management center of a tertiary care hospital in Lahore, Pakistan. Mean age of the participants was 50.2 (+/- 8.5) years. Out of the 145 patients, 63% were females and 37% were males. Most patients were diagnosed to have diabetes within the past 5 years. Diabetes-induced neuropathy was the most common complication (71.7%) among the patients. A large proportion of these patients (70.3%) were also suffering from other comorbidities among which the most common one is hypertension. The average number of prescribed medications was 1.31. Metformin was prescribed to a majority of patients (64%) as monotherapy while 28.96% received combination therapy. Mean glycated hemoglobin (HBA1c) before and after 3 months of treatment was 8.5 (+/- 2.3) and 8.04 (+/- 2.1), respectively. Inferential statistics show a strong association between HBA1c and life style modifications and adherence to medication therapy (P = 0.05). However, the correlation between HBA1c and Morisky score and duration of disease was inverse and weak (P = 0.6, 0.4). The t-test values show a small difference between HBA1c values before and after 3 months (t = 0.440 and 0.466, respectively). CONCLUSION: Optimization of medication regimen and continuous patient education regarding life style modification and adherence to medication therapy are necessitated to bring HBA1c values near to target. PMID- 28717336 TI - Validation of a Stability-Indicating Spectrometric Method for the Determination of Sulfacetamide Sodium in Pure Form and Ophthalmic Preparations. AB - INTRODUCTION: Sulfacetamide sodium is a widely used sulfonamide for ophthalmic infections. OBJECTIVE: A number of analytical methods have been reported for the analysis of sulfacetamide but they lack the ability to determine both the active drug and its major degradation product, sulfanilamide, simultaneously in a sample. MATERIALS AND METHODS: In the present study a simple, rapid and economical stability-indicating UV spectrometric method has been validated for the simultaneous assay of sulfacetamide sodium and sulfanilamide in pure form and in ophthalmic preparations. RESULTS: The method has been found to be accurate (recovery 100.03 +/-0.589%) and precise (RSD 0.587%) with detectable and quantifiable limits of 1.67*10-6 M (0.04 mg%) and 5.07*10-6 M (0.13 mg%), respectively for the assay of pure sulfacetamide sodium. The method is also found to be accurate and precise to small changes in wavelength, pH and buffer concentration as well as to forced degradation. The study further includes the validation of the method for the assay of pure sulfanilamide in solution, which has been found to be accurate, precise and robust. CONCLUSION: The results indicate that the proposed two-component spectrometric method is stability indicating and can be used for the simultaneous assay of both sulfacetamide sodium and sulfanilamide in synthetic mixtures and degraded solutions. PMID- 28717337 TI - Effect of Surface Modification on the In vitro Protein Adsorption and Cell Cytotoxicity of Vinorelbine Nanoparticles. AB - CONTEXT: Nanocarriers possessing long-circulating abilities could take advantage of the pathophysiology of tumor vasculature to achieve spatial placement. To attain such qualities, the drug carriers should possess suitable physicochemical properties such as size and surface hydrophilicity. AIM: The aim of this study was to prepare poly(epsilon-caprolactone) nanoparticles (NPs) loaded with vinorelbine bitartrate (VB) and to modify its steric properties using polyethylene glycol and poloxamer. Furthermore, the influence of surface modification of NPs on their physicochemical and cell interactive properties was evaluated. MATERIALS AND METHODS: NPs were prepared by double emulsion solvent extraction-evaporation technique. The prepared NPs were evaluated for their physicochemical properties, in vitro protein adsorption and cell cytotoxicity. RESULTS AND DISCUSSION: The NPs were <250 nm with an entrapment efficiency ranging between 40% and 52%. The zeta potential of the NPs varied from -7.52 mV to -1.27 mV depending on the surface modification. The in vitro release studies exhibited a biphasic pattern with an initial burst release followed by controlled release of the drug over 72 h. The protein adsorption studies revealed that the ability to resist protein adsorption was influenced by the concentration of surface-modifying agents and the amount of proteins available for interaction. The surface-modified NPs produced cell cytotoxicity comparable to free VB at higher concentrations owing to sustained release of the drug into the cellular environment. CONCLUSION: The results emphasize that surface modification of nanocarriers is an essential and effective tool to dodge opsonization and phagocytosis in the physiological milieu. PMID- 28717338 TI - Perspectives about Pandemic Influenza and Its Prophylactic Measures among Final Year Pharmacy Students in Karachi, Pakistan. AB - AIMS: In flu pandemics, pharmacy students' knowledge, attitudes, and practices are critical to save patients life. The objective of study was to determine the knowledge of and attitude toward the pandemic influenza among the pharmacy students of Karachi, Pakistan. SETTINGS AND DESIGNS: The cross-sectional study was conducted from September to December 2014 by adopting a prevalidated questionnaire distributed to senior pharmacy students (final year) in seven private and public sector universities of Karachi. MATERIALS AND METHODS: A total of 443 pharmacy students responded the survey. Data regarding sociodemographic characteristics of the students, perceptions, level of knowledge and attitudes toward influenza, and prophylactic measures were collected. STATISTICAL ANALYSIS: To compute the correlation between different variables, data were analyzed using Pearson's Chi-square statistic method. P < 0.05 was considered statistical significance for all analysis. RESULTS: Influenza was identified as a viral disease (n = 423; 95.48%) and 282 (71.2%) students correctly identified it as disease affecting humans and pigs. Textbooks reported as most common source of knowledge (n = 282; 64%). Most common symptoms identified were fever (81.94%), sore throat (64.1%), and nonproductive cough (43.34%). The most common preventive measures were covering nose and mouth (268; 60.5%) and wearing protective coverings (254; 57.3%). Only half of the students correctly reported about the route of administration (180; 40.6%) and strains in vaccine (186; 41.98%). The best time for administration of such vaccine was known by only 156 pharmacy students (35.34%). The majority of the students (82.6%) had no idea about the manifestation of influenza pandemic. Knowledge regarding influenza differed according to gender and institutions differing in their affiliation with tertiary care hospitals. CONCLUSION: It was observed that knowledge about disease progression, transmission, vaccination, and treatment in pharmacy students, especially those who are not getting clinical training in tertiary care hospitals was limited. There is an urgent need to develop awareness programs to increase knowledge of influenza among clinical pharmacists as they are more susceptible to infections and community as a whole. PMID- 28717339 TI - Pregabalin and Uremic Pruritus. PMID- 28717340 TI - Erratum: What is the Process of Obtaining Informed Consent in a Clinical Trial? Is it Ever Justifiable to Include Someone in a Clinical Trial without Prior Informed Consent from the Individual? AB - [This corrects the article on p. 262 in vol. 8, PMID: 27413357.]. PMID- 28717341 TI - [An ethics call to include pregnant women in research: Reflections from the Global Forum on Bioethics in Research]. PMID- 28717342 TI - Prevalence of High-Risk Genotypes of Human Papillomavirus: Women Diagnosed with Premalignant and Malignant Pap Smear Tests in Southern Ecuador. AB - Human papillomavirus (HPV) is the primary infectious agent for the development of cervical cancer, although the presence of the virus alone is insufficient for viral development and proliferation; this can be attributed to the increase in potential oncogenic risk, along with other risk factors. In the present investigation, the prevalence of high-risk HPV was determined from samples of premalignant or malignant cervical cytology in women from the southern region of Ecuador. The kit we used was able to detect genotypes 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59. In addition, 64.5% of the analyzed samples were positive for HPV, with genotypes 16 and 18 being the most prevalent (16 was detected in 148 samples and 18 in 108). Genotypes 58 and 51 were the third most frequent simple and multiple infections, respectively. The data are very similar to those obtained worldwide, suggesting that the strategy of sex education, and the use of vaccines as primary prevention agents, could significantly decrease the incidence and mortality rate of cervical cancer in the southern region of Ecuador. PMID- 28717343 TI - Geographical Variation and Factors Associated with Non-Small Cell Lung Cancer in Manitoba. AB - BACKGROUND: Screening decreases non-small cell lung cancer (NSCLC) deaths and is recommended by the Canadian Task Force on Preventive Health Care. We investigated risk factor prevalence and NSCLC incidence at a small region level to inform resource allocation for lung cancer screening. METHODS: NSCLC diagnoses were obtained from the Canadian Cancer Registry, then geocoded to 283 small geographic areas (SGAs) in Manitoba. Sociodemographic characteristics of SGAs were obtained from the 2006 Canadian Census and Canadian Community Health Survey. Geographical variation was modelled using a Bayesian spatial Poisson model. RESULTS: NSCLC incidence in SGAs ranged from 1 to 343 cases per 100,000 population per year. The highest incidence rates were in the Southeastern, Southwestern, and Central regions of Manitoba, while most of Northern Manitoba had lower rates. Poisson regression suggested areas with higher proportions of Aboriginal people and higher average income, and immigrants had lower NSCLC incidence whereas areas with higher proportions of smokers had higher incidence. CONCLUSION: On an SGA level, smoking rates remain the most significant factor driving NSCLC incidence. Socioeconomic status and proportions of immigrants or Aboriginal peoples independently impact NSCLC rates. We have identified SGAs in Manitoba to target in policy and infrastructure planning for lung cancer screening. PMID- 28717345 TI - Erratum to: Regulation of the hypoxic tumor environment in hepatocellular carcinoma using RNA interference. AB - [This corrects the article DOI: 10.1186/s12935-016-0374-6.]. PMID- 28717344 TI - Biomaterials for 4D stem cell culture. AB - Stem cells reside in complex three-dimensional (3D) environments within the body that change with time, promoting various cellular functions and processes such as migration and differentiation. These complex changes in the surrounding environment dictate cell fate yet, until recently, have been challenging to mimic within cell culture systems. Hydrogel-based biomaterials are well suited to mimic aspects of these in vivo environments, owing to their high water content, soft tissue-like elasticity, and often-tunable biochemical content. Further, hydrogels can be engineered to achieve changes in matrix properties over time to better mimic dynamic native microenvironments for probing and directing stem cell function and fate. This review will focus on techniques to form hydrogel-based biomaterials and modify their properties in time during cell culture using select addition reactions, cleavage reactions, or non-covalent interactions. Recent applications of these techniques for the culture of stem cells in four dimensions (i.e., in three dimensions with changes over time) also will be discussed for studying essential stem cell processes. PMID- 28717346 TI - Inflammatory Wnt5A signalling pathways affecting barrier function of human vascular endothelial cells. AB - Wnt5A is a chemokine secreted by inflammatory-activated human macrophages that sustains their inflammatory response in an autocrine manner. High levels of Wnt5A are found in sera of patients with sepsis and septic shock. Here, we comment on recently reported Wnt5A signalling pathways in human vascular endothelial cells (VEC). In human VEC, Wnt5A regulates cytoskeleton remodelling and barrier function through Ryk receptor and Rho-associated protein serine/threonine kinase, targeting LIMK2 and CFL1 involved in actin polymerisation. Wnt5A/Ryk signalling in VEC can be antagonised by the naturally occurring Wnt inhibitory factor (WIF) 1 (WIF1). Therapeutic targeting of this mechanism may reduce vascular leakage and edema in severe systemic inflammation and therefore should be subject of further investigations. PMID- 28717347 TI - Effect of eicosapentaenoic acids-rich fish oil supplementation on motor nerve function after eccentric contractions. AB - BACKGROUND: This study investigated the effect of supplementation with fish oil rich in eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on the M-wave latency of biceps brachii and muscle damage after a single session of maximal elbow flexor eccentric contractions (ECC). METHODS: Twenty-one men were completed the randomized, double-blind, placebo-controlled, and parallel-design study. The subjects were randomly assigned to the fish oil group (n = 10) or control group (n = 11). The fish oil group consumed eight 300-mg EPA-rich fish oil softgel capsules (containing, in total, 600 mg EPA and 260 mg DHA) per day for 8 weeks before the exercise, and continued this for a further 5 days. The control group consumed an equivalent number of placebo capsules. The subjects performed six sets of ten eccentric contractions of the elbow flexors using a dumbbell set at 40% of their one repetition maximum. M-wave latency was assessed as the time taken from electrical stimulation applied to Erb's point to the onset of M-wave of the biceps brachii. This was measured before and immediately after exercise, and then after 1, 2, 3, and 5 days. Changes in maximal voluntary isometric contraction (MVC) torque, range of motion (ROM), upper arm circumference, and delayed onset muscle soreness (DOMS) were assessed at the same time points. RESULTS: Compared with the control group, M-wave latency was significantly shorter in the fish oil group immediately after exercise (p = 0.040), MVC torque was significantly higher at 1 day after exercise (p = 0.049), ROM was significantly greater at post and 2 days after exercise (post; p = 0.006, day 2; p = 0.014), and there was significantly less delayed onset muscle soreness at 1 and 2 days after exercise (day 1; p = 0.049, day 2; p = 0.023). CONCLUSION: Eight weeks of EPA and DHA supplementation may play a protective role against motor nerve function and may attenuate muscle damage after eccentric contractions. TRIAL REGISTRATION: This trial was registered on July 14th 2015 (https://upload.umin.ac.jp/cgi-open-bin/ctr/index.cgi). PMID- 28717348 TI - The Synergistic Effect of Microwave Radiation and Hypergravity on Rats and the Intervention Effect of Rana Sylvatica Le Conte Oil. AB - AIM: The phenomena of hypergravity and microwave radiation are widespread, which cause more and more concern for the hazards to human health. The aim of this study was to investigate the synergistic effect of microwave radiation and hypergravity on rats and observe the protective effect of Rana sylvatica Le conte oil. METHODS: Rats were exposed to microwave radiation and hypergravity, and the rat weight, the climbing pole height, serum enzyme activities, blood urea nitrogen concentration, and total antioxidant capacity were detected. RESULTS: The climbing pole height, the activities of choline acetyl transferase and cholinesterase, and the total antioxidant capacity decreased, whereas the activities of alanine aminotransferase, aspartate aminotransferase, areatine kinase, isocitric dehydrogenase, hydroxybutyrate dehydrogenase, and the blood urea nitrogen concentration increased in the hypergravity irradiation group as compared with the others. CONCLUSION: These results imply that the motion and nervous system of rats might be affected critically by the synergistic effect of microwave radiation and hypergravity, and it causes damage to most rat organs, such as the bone, skeletal muscle, liver, heart, and kidney, and the antioxidant effect is also damaged, while the injury resulted from it could be protected by Rana sylvatica Le conte oil. PMID- 28717349 TI - "Bad Luck Mutations": DNA Mutations Are not the Whole Answer to Understanding Cancer Risk. AB - It has been proposed that many human cancers are generated by intrinsic mechanisms that produce "Bad Luck" mutations by the proliferation of organ specific adult stem cells. There have been serious challenges to this interpretation, including multiple extrinsic factors thought to be correlated with mutations found in cancers associated with these exposures. While support for both interpretations provides some validity, both interpretations ignore several concepts of the multistage, multimechanism process of carcinogenesis, namely, (1) mutations can be generated by both "errors of DNA repair" and "errors of DNA replication," during the "initiation" process of carcinogenesis; (2) "initiated" stem cells must be clonally amplified by nonmutagenic, intrinsic or extrinsic epigenetic mechanisms; (3) organ-specific stem cell numbers can be modified during in utero development, thereby altering the risk to cancer later in life; and (4) epigenetic tumor promoters are characterized by species, individual genetic-, gender-, developmental state-specificities, and threshold levels to be active; sustained and long-term exposures; and exposures in the absence of antioxidant "antipromoters." Because of the inevitability of some of the stem cells generating "initiating" mutations by either "errors of DNA repair" or "errors of DNA replication," a tumor is formed depending on the promotion phase of carcinogenesis. While it is possible to reduce our frequencies of mutagenic "initiated" cells, one can never reduce it to zero. Because of the extended period of the promotion phase of carcinogenesis, strategies to reduce the appearance of cancers must involve the interruption of the promotion of these initiated cells. PMID- 28717350 TI - Properties of Native High-Density Lipoproteins Inspire Synthesis of Actively Targeted In Vivo siRNA Delivery Vehicles. AB - Efficient systemic administration of therapeutic short interfering RNA (siRNA) is challenging. High-density lipoproteins (HDL) are natural in vivo RNA delivery vehicles. Specifically, native HDLs: 1) Load single-stranded RNA; 2) Are anionic, which requires charge reconciliation between the RNA and HDL, and 3) Actively target scavenger receptor type B-1 (SR-B1) to deliver RNA. Emphasizing these particular parameters, we employed templated lipoprotein particles (TLP), mimics of spherical HDLs, and self-assembled them with single-stranded complements of, presumably, any highly unmodified siRNA duplex pair after formulation with a cationic lipid. Resulting siRNA templated lipoprotein particles (siRNA-TLP) are anionic and tunable with regard to RNA assembly and function. Data demonstrate that the siRNA-TLPs actively target SR-B1 to potently reduce androgen receptor (AR) and enhancer of zeste homolog 2 (EZH2) proteins in multiple cancer cell lines. Systemic administration of siRNA-TLPs demonstrated no off-target toxicity and significantly reduced the growth of prostate cancer xenografts. Thus, native HDLs inspired the synthesis of a hybrid siRNA delivery vehicle that can modularly load single-stranded RNA complements after charge reconciliation with a cationic lipid, and that function due to active targeting of SR-B1. PMID- 28717352 TI - Editorial: Pitfalls in the Neuro-Imaging of Glioblastoma in the Era of Antiangiogenic and Immune-Targeted Therapy-Detecting Elusive Disease, Defining Response. PMID- 28717353 TI - A Proposal for a Patient-Oriented Five-Dimensional Approach for Surveillance and Therapy in Multiple Sclerosis. PMID- 28717351 TI - Serial Sampling of Serum Protein Biomarkers for Monitoring Human Traumatic Brain Injury Dynamics: A Systematic Review. AB - BACKGROUND: The proteins S100B, neuron-specific enolase (NSE), glial fibrillary acidic protein (GFAP), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), and neurofilament light (NF-L) have been serially sampled in serum of patients suffering from traumatic brain injury (TBI) in order to assess injury severity and tissue fate. We review the current literature of serum level dynamics of these proteins following TBI and used the term "effective half-life" (t1/2) in order to describe the "fall" rate in serum. MATERIALS AND METHODS: Through searches on EMBASE, Medline, and Scopus, we looked for articles where these proteins had been serially sampled in serum in human TBI. We excluded animal studies, studies with only one presented sample and studies without neuroradiological examinations. RESULTS: Following screening (10,389 papers), n = 122 papers were included. The proteins S100B (n = 66) and NSE (n = 27) were the two most frequent biomarkers that were serially sampled. For S100B in severe TBI, a majority of studies indicate a t1/2 of about 24 h, even if very early sampling in these patients reveals rapid decreases (1-2 h) though possibly of non-cerebral origin. In contrast, the t1/2 for NSE is comparably longer, ranging from 48 to 72 h in severe TBI cases. The protein GFAP (n = 18) appears to have t1/2 of about 24 48 h in severe TBI. The protein UCH-L1 (n = 9) presents a t1/2 around 7 h in mild TBI and about 10 h in severe. Frequent sampling of these proteins revealed different trajectories with persisting high serum levels, or secondary peaks, in patients with unfavorable outcome or in patients developing secondary detrimental events. Finally, NF-L (n = 2) only increased in the few studies available, suggesting a serum availability of >10 days. To date, automated assays are available for S100B and NSE making them faster and more practical to use. CONCLUSION: Serial sampling of brain-specific proteins in serum reveals different temporal trajectories that should be acknowledged. Proteins with shorter serum availability, like S100B, may be superior to proteins such as NF-L in detection of secondary harmful events when monitoring patients with TBI. PMID- 28717355 TI - Correlation of Creatine Kinase Levels with Clinical Features and Survival in Amyotrophic Lateral Sclerosis. AB - OBJECTIVE: To evaluate serum creatine kinase (CK) levels of amyotrophic lateral sclerosis (ALS) patients and to explore the relationship between CK levels and the clinical characteristics and survival prognosis of ALS patients. METHODS: We analyzed the CK levels of 185 ALS patients who underwent long-term follow-up. The relationship between CK levels and clinical features including sex, age, disease duration, site of onset, body mass index (BMI), serum creatinine (Cr), and spontaneous electromyographic activity was analyzed by univariate analysis and multiple linear regression. Kaplan-Meier and Cox proportional hazards models were used to explore whether CK levels were independently correlated with survival prognosis of ALS. RESULTS: Baseline serum CK was raised in 43% of participants. The median CK level was 160 U/L (range: 20-2,574 U/L), and 99% of patients had a baseline serum CK level less than 1,000 U/L. CK levels were significantly higher in male patients than in female patients [204 (169) versus 117 (111) U/L, p < 0.001] and in patients with limb onset ALS than with bulbar onset ALS (p < 0.001). CK levels were also correlated with serum Cr (p = 0.011) and the spontaneous potential score of electromyography (EMG) (p = 0.037) but not correlated with age (p = 0.883), disease duration (p = 0.116), or BMI (p = 0.481). Log CK was independently correlated with survival of ALS patients (HR = 0.457, 95% confidence interval 0.221-0.947, p = 0.035) after adjusting for age, sex, site of onset, serum Cr, and BMI. CONCLUSION: Serum CK levels of ALS patients were correlated with sex, site of onsite, serum Cr, and spontaneous activity in EMG. Serum CK could be an independent prognostic factor for survival of ALS patients. PMID- 28717356 TI - Thermoplasmatales and Methanogens: Potential Association with the Crenarchaeol Production in Chinese Soils. AB - Crenarchaeol is a unique isoprenoid glycerol dibiphytanyl glycerol tetraether (iGDGT) lipid, which is only identified in cultures of ammonia-oxidizing Thaumarchaeota. However, the taxonomic origins of crenarchaeol have been debated recently. The archaeal populations, other than Thaumarchaeota, may have associations with the production of crenarchaeol in ecosystems characterized by non-thaumarchaeotal microorganisms. To this end, we investigated 47 surface soils from upland and wetland soils and rice fields and another three surface sediments from river banks. The goal was to examine the archaeal community compositions in comparison with patterns of iGDGTs in four fractional forms (intact polar-, core , monoglycosidic- and diglycosidic-lipid fractions) along gradients of environments. The DistLM analysis identified that Group I.1b Thaumarchaeota were mainly responsible for changes in crenarchaeol in the overall soil samples; however, Thermoplasmatales may also contribute to it. This is further supported by the comparison of crenarchaeol between samples characterized by methanogens, Thermoplasmatales or Group I.1b Thaumarchaeota, which suggests that the former two may contribute to the crenarchaeol pool. Last, when samples containing enhanced abundance of Thermoplasmatales and methanogens were considered, crenarchaeol was observed to correlate positively with Thermoplasmatales and archaeol, respectively. Collectively, our data suggest that the crenarchaeol production is mainly derived from Thaumarchaeota and partly associated with uncultured representatives of Thermoplasmatales and archaeol-producing methanogens in soil environments that may be in favor of their growth. Our finding supports the notion that Thaumarchaeota may not be the sole source of crenarchaeol in the natural environment, which may have implication for the evolution of lipid synthesis among different types of archaea. PMID- 28717354 TI - Blood Pressure and Penumbral Sustenance in Stroke from Large Vessel Occlusion. AB - The global burden of stroke remains high, and of the various subtypes of stroke, large vessel occlusions (LVOs) account for the largest proportion of stroke related death and disability. Several randomized controlled trials in 2015 changed the landscape of stroke care worldwide, with endovascular thrombectomy (ET) now the standard of care for all eligible patients. With the proven success of this therapy, there is a renewed focus on penumbral sustenance. In this review, we describe the ischemic penumbra, collateral circulation, autoregulation, and imaging assessment of the penumbra. Blood pressure goals in acute stroke remain controversial, and we review the current data and suggest an approach for induced hypertension in the acute treatment of patients with LVOs. Finally, in addition to reperfusion and enhanced perfusion, efforts focused on developing therapeutic targets that afford neuroprotection and augment neural repair will gain increasing importance. ET has revolutionized stroke care, and future emphasis will be placed on promoting penumbral sustenance, which will increase patient eligibility for this highly effective therapy and reduce overall stroke-related death and disability. PMID- 28717357 TI - High Levels of CXCL8 and Low Levels of CXCL9 and CXCL10 in Women with Maternal RhD Alloimmunization. AB - Maternal RhD alloimmunization is an inflammatory response against protein antigens in fetal red blood cells (RBC). However, not all women become alloimmunized when exposed to RhD+ fetal RBC. Thus, this study aimed to evaluate levels of inflammatory chemokines in RhD- pregnant women with erythrocyte alloimmunization. CXCL8, CXCL9, CCL5, and CXCL10 levels were determined from cell culture supernatants by flow cytometry in 46 (30 non-alloimmunized RhD- and 16 previously alloimmunized RhD-) pregnant women. CXCL8 levels were significantly higher (P < 0.004), and CXCL9 (P < 0.008) and CXCL10 (P < 0.003) levels were significantly lower in alloimmunized pregnant women. No significant difference in CCL5 levels was detected between the groups. Fetal RHD genotyping was performed in the alloimmunized RhD- group by real-time PCR. Anti-D alloantibody was detected in 10 mothers and anti-D and -C in six mothers. Twelve fetuses were RHD positive and four were RHD negative. Further studies of serum chemokines and placenta tissue could provide a better understanding of the cells involved in the pathogenesis of maternal erythrocyte alloimmunization. PMID- 28717358 TI - Clinical Response to Vedolizumab in Ulcerative Colitis Patients Is Associated with Changes in Integrin Expression Profiles. AB - BACKGROUND: Despite large clinical success, deeper insights into the immunological effects of vedolizumab therapy for inflammatory bowel diseases are scarce. In particular, the reasons for differential clinical response in individual patients, the precise impact on the equilibrium of integrin-expressing T cell subsets, and possible associations between these issues are not clear. METHODS: Blood samples from patients receiving clinical vedolizumab therapy were sequentially collected and analyzed for expression of integrins and chemokine receptors on T cells. Moreover, clinical and laboratory data from the patients were collected, and changes between homing marker expression and clinical parameters were analyzed for possible correlations. RESULTS: While no significant correlation of changes in integrin expression and changes in outcome parameters were identified in Crohn's disease (CD), increasing alpha4beta7 levels in ulcerative colitis (UC) seemed to be associated with favorable clinical development, whereas increasing alpha4beta1 and alphaEbeta7 correlated with negative changes in outcome parameters. Changes in alpha4beta1 integrin expression after 6 weeks were significantly different in responders and non responders to vedolizumab therapy as assessed after 16 weeks with a cutoff of +4.2% yielding 100% sensitivity and 100% specificity in receiver-operator characteristic analysis. DISCUSSION: Our data show that clinical response to vedolizumab therapy in UC but not in CD is associated with specific changes in integrin expression profiles opening novel avenues for mechanistic research and possibly prediction of response to therapy. PMID- 28717359 TI - The C-Terminal Effector Domain of Non-Structural Protein 1 of Influenza A Virus Blocks IFN-beta Production by Targeting TNF Receptor-Associated Factor 3. AB - Influenza A virus non-structural protein 1 (NS1) antagonizes interferon response through diverse strategies, particularly by inhibiting the activation of interferon regulatory factor 3 (IRF3) and IFN-beta transcription. However, the underlying mechanisms used by the NS1 C-terminal effector domain (ED) to inhibit the activation of IFN-beta pathway are not well understood. In this study, we used influenza virus subtype of H5N1 to demonstrate that the NS1 C-terminal ED but not the N-terminal RNA-binding domain, binds TNF receptor-associated factor 3 (TRAF3). This results in an attenuation of the type I IFN signaling pathway. We found that the NS1 C-terminal ED (named NS1/126-225) inhibits the active caspase activation and recruitment domain-containing form of RIG-I [RIG-I(N)]-induced IFN beta reporter activity, the phosphorylation of IRF3, and the induction of IFN beta. Further analysis showed that NS1/126-225 binds to TRAF3 through the TRAF domain, subsequently decreasing TRAF3 K63-linked ubiquitination. NS1/126-225 binding also disrupted the formation of the mitochondrial antiviral signaling (MAVS)-TRAF3 complex, increasing the recruitment of IKKepsilon to MAVS; ultimately shutting down the RIG-I(N)-mediated signal transduction and cellular antiviral responses. This attenuation of cellular antiviral responses leads to evasion of the innate immune response. Taken together, our findings offer an important insight into the interplay between the influenza virus and host innate immunity. PMID- 28717360 TI - Ethanol Enhances High-Salinity Stress Tolerance by Detoxifying Reactive Oxygen Species in Arabidopsis thaliana and Rice. AB - High-salinity stress considerably affects plant growth and crop yield. Thus, developing techniques to enhance high-salinity stress tolerance in plants is important. In this study, we revealed that ethanol enhances high-salinity stress tolerance in Arabidopsis thaliana and rice. To elucidate the molecular mechanism underlying the ethanol-induced tolerance, we performed microarray analyses using A. thaliana seedlings. Our data indicated that the expression levels of 1,323 and 1,293 genes were upregulated by ethanol in the presence and absence of NaCl, respectively. The expression of reactive oxygen species (ROS) signaling-related genes associated with high-salinity tolerance was upregulated by ethanol under salt stress condition. Some of these genes encode ROS scavengers and transcription factors (e.g., AtZAT10 and AtZAT12). A RT-qPCR analysis confirmed that the expression levels of AtZAT10 and AtZAT12 as well as AtAPX1 and AtAPX2, which encode cytosolic ascorbate peroxidases (APX), were higher in ethanol treated plants than in untreated control plants, when exposure to high-salinity stress. Additionally, A. thaliana cytosolic APX activity increased by ethanol in response to salinity stress. Moreover, histochemical analyses with 3,3' diaminobenzidine (DAB) and nitro blue tetrazolium (NBT) revealed that ROS accumulation was inhibited by ethanol under salt stress condition in A. thaliana and rice, in which DAB staining data was further confirmed by Hydrogen peroxide (H2O2) content. These results suggest that ethanol enhances high-salinity stress tolerance by detoxifying ROS. Our findings may have implications for improving salt-stress tolerance of agriculturally important field-grown crops. PMID- 28717361 TI - Research of Hubs Location Method for Weighted Brain Network Based on NoS-FA. AB - As a complex network of many interlinked brain regions, there are some central hub regions which play key roles in the structural human brain network based on T1 and diffusion tensor imaging (DTI) technology. Since most studies about hubs location method in the whole human brain network are mainly concerned with the local properties of each single node but not the global properties of all the directly connected nodes, a novel hubs location method based on global importance contribution evaluation index is proposed in this study. The number of streamlines (NoS) is fused with normalized fractional anisotropy (FA) for more comprehensive brain bioinformation. The brain region importance contribution matrix and information transfer efficiency value are constructed, respectively, and then by combining these two factors together we can calculate the importance value of each node and locate the hubs. Profiting from both local and global features of the nodes and the multi-information fusion of human brain biosignals, the experiment results show that this method can detect the brain hubs more accurately and reasonably compared with other methods. Furthermore, the proposed location method is used in impaired brain hubs connectivity analysis of schizophrenia patients and the results are in agreement with previous studies. PMID- 28717362 TI - Treatment of Advanced Hepatocellular Carcinoma after Failure of Sorafenib Treatment: Subsequent or Additional Treatment Interventions Contribute to Prolonged Survival Postprogression. AB - BACKGROUND: Sorafenib is a first-line treatment option for advanced hepatocellular carcinoma (HCC) patients; however, survival predictors upon progression have not been well characterized. In the present study, we aimed to show the efficacy of multidisciplinary therapy for patients who had failed to respond to sorafenib treatment. METHODS: Among 146 BCLC stage B or C HCC patients treated with sorafenib monotherapy between July 2009 and August 2014, the first radiological progression according to the modified RECIST was identified in 71 patients; factors predicting overall survival (OS) and survival postprogression (SPP) were analyzed in these patients. RESULTS: The median OS and SPP for patients who failed to respond to sorafenib treatment were 10.5 and 6.2 months, respectively, and the SPP was strongly correlated with the OS (r = 0.982, P < 0.01, and R2 = 0.965). The independent predictors of OS and SPP were identical. The predictors of SPP were des-gamma-carboxy prothrombin, progression of portal vein thrombosis, and subsequent second-line or additional treatment. CONCLUSIONS: SPP is closely associated with OS and might be notable in patients who have failed to respond to initial sorafenib treatment. Furthermore, interventions consisting of other treatment options upon the appearance of progression might prolong OS. PMID- 28717363 TI - Development of an Autonomous Endoscopically Implantable Submucosal Microdevice Capable of Neurostimulation in the Gastrointestinal Tract. AB - Gastric dysmotility can be a sign of common diseases such as longstanding diabetes mellitus. It is known that the application of high-frequency low energetic stimulation can help to effectively moderate and alleviate the symptoms of gastric dysmotility. The goal of our research was the development of a miniature, endoscopically implantable device to a submucosal pocket. The implantable device is a fully customized electronics package which was specifically designed for the purpose of experiments in the submucosa. The device was endoscopically inserted into the submucosal pocket of a pig stomach and partially severed pig side in order to adequately simulate a live animal model. The experiment confirmed that the designed device can be implanted into the submucosa and is capable of the measurement of sensor data and the transmission of this data wirelessly in real time to a computer outside of the body. After proving that the device can be implanted submucosally and transmit data, further experiments can now be performed, primarily with an electrogastrography (EGG) instrument and implantable device with tissue stimulation capability. PMID- 28717364 TI - Serum-Free Thyroxine Levels Were Associated with Pulmonary Hypertension and Pulmonary Artery Systolic Pressure in Euthyroid Patients with Coronary Artery Disease. AB - The aim of this study was to evaluate the association between thyroid hormone levels, pulmonary hypertension (PH), and pulmonary artery systolic pressure (PASP) in euthyroid patients with coronary artery disease (CAD). A cross sectional study was conducted in individuals who underwent coronary angiography and were diagnosed as CAD from March 2013 to November 2013. 811 subjects (185 women and 626 men) were included in this study. PASP was measured by transthoracic Doppler echocardiography. 86 patients were diagnosed as PH and had significantly higher free thyroxine (FT4) levels than those without PH. Multiple logistic regression analysis demonstrated an independent association of FT4 levels with PH after adjustment of gender, age, body mass index, systolic blood pressure, left ventricular ejection fraction, hypertension, and medication use of calcium channel blockers, ACE inhibitors, angiotensin II receptor antagonists, and nitrates. Serum-free triiodothyronine (FT3) and thyroid-stimulating hormone (TSH) were not associated with PH. Furthermore, multivariate linear regression analysis showed that FT4 levels emerged as an independent predictor for PASP, while FT3 and TSH levels were not associated with PASP. Our study demonstrated that, in euthyroid patients with CAD, FT4 was an independent risk factor for PH, and FT4 levels were independently associated with PASP. PMID- 28717365 TI - Behavioural Problems in Children with 46XY Disorders of Sex Development. AB - The aim of this study is to determine the behavioural problems of children with 46XY disorders of sex development (DSD) with genital ambiguity and to identify the risk factors that may influence behaviour. The 27 participants (aged 6-18 years) consisted of 21 patients raised as boys and 6 patients raised as girls. Control data were obtained from a representative sibling of each patient who was matched for age and gender. The study tool used was the Child Behaviour Checklist (CBCL), which is a parent-administered questionnaire. The analysis of the behavioural scores revealed that the patient group had poorer scores in the total, externalizing, and internalizing realms. This group also had poorer scores in the anxious-depressed, social, and rule-breaking realms as compared to the control group. In addition, the XY-F group had higher scores (more pathological) than the XY-M group, although the difference in the scores was not statistically significant. A comparison of the prevalence of patients with scores in the clinical range with that of the control group was not statistically significant. These findings support the current recommendations that psychological counselling should be an integral part of the professional support offered to patients with DSD. PMID- 28717366 TI - Interrelationship between Climatic, Ecologic, Social, and Cultural Determinants Affecting Dengue Emergence and Transmission in Puerto Rico and Their Implications for Zika Response. AB - OBJECTIVE: The global resurgence of dengue has been attributed to rapid population growth, urban expansion, increased air travel, globalization, and climate change. Dengue is now endemic in Puerto Rico. Puerto Rico is at risk for Zika, another emerging arbovirus. The interrelationship between climatic, ecological, social, and cultural factors that affect dengue and other arboviruses' transmission is understudied. DESIGN: The objective of this systematic review is to examine the interrelationship between climatic, ecological, social, and cultural factors on dengue transmission in Puerto Rico and to draw lessons for Zika response. RESULTS: A comprehensive search of peer reviewed journal articles was performed, producing 562 articles; 26 were selected for this review. Findings indicate that human activities and behaviors (urbanization, migration, and consumption) as well as climate have a significant impact on the abundance and the transmission potential of Ae. aegypti, the vector for dengue, Zika, and other viruses. CONCLUSION: Despite the public health burden of dengue limited investments have been made in research and surveillance. Future research is needed to develop models that integrate the multivariate effects of climatic, ecological, social, and cultural factors, which for Puerto Rico have mostly been examined independently. Such models have the potential to inform response to dengue, Zika, and other arboviruses. PMID- 28717368 TI - Community-acquired methicillin-resistant Staphylococcus aureus carriage rate and antimicrobial susceptibility in a tertiary center, Iran. AB - BACKGROUND: This study was aimed to determine frequency and antimicrobial susceptibility of Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) among colonized patients in outpatient status. MATERIALS AND METHODS: A total of 2000 nasal nares specimens were collected and inoculated on mannitol salt agar. MRSAs were identified based on mannitol positivity and coagulase test followed by cefoxitin disc diffusion test. Antimicrobial susceptibility of MRSA isolates was performed by E-test method for vancomycin and doxycycline as well as disc diffusion method for sulfamethoxazole-trimethoprim (SMX-TMP), erythromycin, linezolid, and clindamycin. D-test was performed for detection of inducible resistance to clindamycin. RESULTS: Overall, nasal carrier rate of S. aureus and CA-MRSA was estimated 22% and 1.25%, respectively. Out of the 440 S. aureus isolates, 25 isolates were MRSA. All were susceptible to vancomycin and linezolid, and susceptibility rates to SMX-TMP, erythromycin, levofloxacin, doxycycline, and clindamycin were 68%, 44%, 48%, 40% and 44%, respectively; furthermore, 28.5% of resistant isolates to erythromycin had inducible resistance to clindamycin. CONCLUSION: It seems susceptibility to clindamycin and SMX-TMP, recommended agents for empirical treatment of suspected CA-MRSA, are not promising. Vancomycin and linezolid are effective and reliable antibiotics for the treatment of S. aureus infections. PMID- 28717367 TI - Cells of human breast milk. AB - Human milk is a complex fluid that has developed to satisfy the nutritional requirements of infants. In addition to proteins, lipids, carbohydrates and other biologically active components, breast milk contains a diverse microbiome that is presumed to colonize the infant gastrointestinal tract and a heterogeneous population of cells with unclear physiological roles and health implications. Noteworthy cellular components of breast milk include progenitor/stem cells. This review summarizes the current state of knowledge of breast milk cells, including leukocytes, epithelial cells, stem cells and potentially probiotic bacteria. PMID- 28717369 TI - Association of irritable bowel syndrome and sleep apnea in patients referred to sleep laboratory. AB - BACKGROUND: Irritable bowel syndrome (IBS) is assumed as one of the most frequent gastrointestinal disorders, which decreases the patient's quality of life. IBS pathogenesis, however, is not clearly defined. It seems that sleep apnea induces or escalates IBS clinical symptoms. This study aims at evaluating of IBS prevalence in patients, who are afflicted or are not afflicted with sleep apnea. MATERIALS AND METHODS: This was a case-control study, which was implemented in a sleep laboratory located in Isfahan, Iran. We recruited 200 patients being more than 15 years from 2014 to 2015. Based on the apnea-hypopnea index (AHI), we recruited 100 patients in each of two groups: negative sleep apnea (NSA) (AHI <=4) and positive sleep apnea (PSA) (AHI >4). IBS was diagnosed through a Rome III diagnostic questionnaire. RESULTS: Overall, the prevalence of IBS among patients referred to sleep laboratory was 17.6%. Indeed, IBS prevalence in NSA and PSA groups were 8.2% and 27.1%, respectively. Furthermore, odds ratio of IBS in PSA group versus NSA was 3.92 (95% confidence interval = 1.58-9.77, P = 0.003). Our results showed that the prevalence of IBS did not differ significantly between various severity of sleep apnea (P = 0.452). CONCLUSION: This study showed that there was a positive association between sleep apnea and IBS. PMID- 28717370 TI - Classic high lateral tension and triangular resection methods to prevent dog ear and elongation scar in patients undergoing abdominoplasty: A comparative open label clinical trial. AB - BACKGROUND: One of the most common operations in the plastic surgery curse is abdominoplasty. Several methods were recommended for achieving better results. In the present study, efficacy of a new method compared with classical high lateral tension on preventing dog ear and elongation scar was evaluated. MATERIALS AND METHODS: in an open-label, randomized clinical trial, seventy patients who were candidates for abdominoplasty were selected and randomly divided into two groups. The first group was operated by classic high lateral method and the second group was operated by a new method concentrating on changing incision line and angle. Dog ear prevention, length of scar, improvement, and postoperative complications were compared between the two groups. RESULTS: The mean +/- standard deviation (SD) length of scar in treated patients with classical and new abdominoplasty surgical methods was 53.68 +/- 6.34 and 41.71 +/- 1.78 cm, respectively, and the length of scar in the group treated with the new method was significantly shorter (P < 0.001). The mean +/- SD distance between two anterior superior iliac spine in group treated by new method was significantly decreased after surgery (31.3 +/ 1.3 cm) compared to before intervention (36.7 +/- 3.9 cm) (P < 0.01). CONCLUSION: The new method is more likely to be successful in patients with high lateral tension abdominoplasty. However, according to the lack of similar studies in this regard and the fact that this method was introduced for the first time, it is recommended that further studies in this area are needed and patients in term of complications after surgery need a longer period of follow-up. PMID- 28717371 TI - The effects of probiotic supplement on hemoglobin in chronic renal failure patients under hemodialysis: A randomized clinical trial. AB - BACKGROUND: Chronic inflammation is one of the causes of anemia in chronic renal failure patients under hemodialysis. Probiotics probably establish a balance between pro- and anti-inflammatory cytokines. The study was conducted to determine the effects of probiotic supplementation on hemoglobin (Hb) in hemodialysis patients. MATERIALS AND METHODS: A parallel clinical trial was conducted in which patients were randomly allocated into two groups. The intervention group (n = 18) was given a 500 mg probiotic supplement (a capsule) every day whereas the control group (n = 18) received placebo (a capsule), both for 3 months. Hb levels and C-reactive protein (CRP) levels were measured for three periods. The data were analyzed in SPSS-16 using statistical tests including the t-test and repeated-measures ANOVA. RESULTS: In the probiotic supplementation group, the mean Hb was 9.22 +/- 1.04 mg/dl before the intervention and reached 10.85 +/- 1.177 mg/dl afterward, while in the placebo group, the mean Hb level was 9.38 +/- 0.97 mg/dl before the intervention and reached 10.03 +/- 1.97 mg/dl afterward (P > 0.05). During the study, the placebo caused to increase of Hb temporary, but in longer term, the effect of probiotic was more manifested. Hb levels increased in both groups although the change was not statistically significant (P > 0.05). The findings showed no significant differences between the two groups in either the pre- or post-intervention CRP levels (P = 0.239). CONCLUSION: Probiotic supplementation decreased Hb fluctuations in hemodialysis patients but did not result in a significant increase in Hb levels. Similar studies are therefore recommended to be conducted with a prolonged duration of the study or an increased probiotic dose with larger sample size to complete the results of the present study. PMID- 28717372 TI - Comparison of platelet number and function between nonalcoholic fatty liver disease and normal individuals. AB - BACKGROUND: There is interest about the role of platelet (PLT) number and function in nonalcoholic fatty liver disease (NAFLD). NAFLD patients have abnormalities of PLT number and function, especially mean platelet volume (MPV) which is known as a novel biomarker for atherosclerosis. We decided to compare PLT number and function between NAFLD and healthy participants. MATERIALS AND METHODS: In this case-control study, two groups of patients (65 cases with NAFLD and 65 cases without NAFLD) were included consecutively. The diagnosis of NAFLD was made using ultrasound examination of the liver. Venous blood samples were taken, and the required laboratory markers including PLT number and function (MPV, platelet distribution width [PDW]), prothrombin time (PT), partial thromboplastin time (PTT), lipid profile, hepatic transaminases, ferritin, and fasting blood sugar were assayed. RESULTS: Mean (+/- standard deviation [SD]) MPV in NAFLD group (10.29 +/- 0.95 fL) was significantly higher than in control group (9.56 +/- 1.18 fL); P < 0.001. No significant difference was observed regarding mean (+/- SD) PLT count between NAFLD (271.20 +/- 52.11 * 103/mm3) and healthy participants (262.86 +/- 75.81 * 103/mm3) (P = 0.46). Mean (+/- SD) PDW values were not significantly different between NAFLD and control groups. Logistic regression showed that NAFLD was positively associated with higher MPV (odds ratio [OR] =1.9, 95% confidence interval [CI] =1.20-3.02) and body mass index (OR = 1.5, 95% CI = 1.05-2.15) values. However, PT (OR = 0.14, 95% CI = 0.02-0.82) and PTT (OR = 0.72, 95% CI = 0.58-0.88) had negative association with NAFLD. CONCLUSION: Higher MPV was found to be significantly associated with NAFLD. However, such significant association was not detected regarding PLT count or PDW. As MPV is a reported risk factor for atherosclerosis, this marker may be useful in follow-up of patients with NAFLD. These findings provide basis for further studies to address this marker in long-term follow-up of NAFLD patients. PMID- 28717373 TI - Diagnostic value of alarm symptoms for upper GI malignancy in patients referred to GI clinic: A 7 years cross sectional study. AB - BACKGROUND: Early upper gastrointestinal (UGI) cancer detection had led to organ preserving endoscopic therapy. Endoscopy is a suitable method of early diagnosis of UGI malignancies. In Iran, exclusion of malignancy is the most important indication for endoscopy. This study is designed to see whether using alarm symptoms can predict the risk of cancer in patients. MATERIALS AND METHODS: A total of 3414 patients referred to a tertiary gastrointestinal (GI) clinic in Isfahan, Iran, from 2009 to 2016 with dyspepsia, gastroesophageal reflux disease (GERD), and alarm symptoms, such as weight loss, dysphagia, GI bleeding, vomiting, positive familial history for cancer, and anorexia. Each patient had been underwent UGI endoscopy and patient data, including histology results, had been collected in the computer. We used logistic regression models to estimate the diagnostic accuracy of each alarm symptoms. RESULTS: A total of 3414 patients with alarm symptoms entered in this study, of whom 72 (2.1%) had an UGI malignancy. According to the logistic regression model, dysphagia (P < 0.001) and weight loss (P < 0.001) were found to be significant positive predictive factors for malignancy. Furthermore, males were in a significantly higher risk of developing UGI malignancy. Through receiver operating characteristic curve and the area under the curve (AUC) with adequate overall calibration and model fit measures, dysphagia and weight loss as a related cancer predictor had a high diagnostic accuracy (accuracy = 0. 72, AUC = 0. 881). Using a combination of age, alarm symptoms will lead to high positive predictive value for cancer. CONCLUSION: We recommend to do an early endoscopy for any patient with UGI symptoms and to take multiple biopsies from any rudeness or suspicious lesion, especially for male gender older than 50, dysphagia, or weight loss. PMID- 28717374 TI - Performance of urinalysis tests in screening for significant bacteriuria among human immunodeficiency virus-infected subjects in South India. PMID- 28717375 TI - World Health Organization validated websites provide reliable information on vaccine safety. PMID- 28717376 TI - Noting a black ring at bending: A postcataract surgery symptom! PMID- 28717377 TI - Appropriate blood component therapy can reduce postcardiac surgery acute kidney injury through packed cell transfusion reduction. AB - BACKGROUND: Acute kidney injury (AKI) can happen due to different factors such as anemia. Packed cell (PC) transfusion is an important cause of AKI occurrence. The aim of the study is to investigate whether appropriate blood component (BC) therapy can reduce blood transfusion and it would result in AKI decreasing. MATERIALS AND METHODS: We conducted a cohort study of 1388 patients who underwent cardiac surgery in one university hospital. A serum creatinine higher than 2 mg/dl, renal disease history, renal replacement therapy (chronic dialysis) were our exclusion criteria. RESULTS: From our 1088 samples, 701 (64.43%) patients had normal kidney function, 277 (25.45%) were in the AKI-1 group, 84 (7.72%) had an AKI-2 function, and the rest of patients were classified as end stage. A mean of more than three PC units were transfused for the second and third stage of AKI, which was significantly higher than other AKI groups (P = 0.009); this higher demand of blood product was also true about the fresh frozen plasma, platelet, and fibrinogen. However, there were no needs of fibrinogen in the patients with normal kidney function. The cardiopulmonary bypass time had an average of 142 +/- 24.12, which obviously was higher than other groups (P = 0.032). Total mortality rate was 14 out of 1088 (1.28%), and expiration among the AKI stages 2 and 3 was meaningfully (P = 0.001) more than the other groups. CONCLUSION: A more occurrence of AKI reported for the patients who have taken more units of blood. However, BC indicated to be safer for compensating blood loss because of low AKI occurrence among our patients. PMID- 28717378 TI - Evaluation of shoulder girdle strength more than 12 month after modified radical mastectomy and axillary nodes dissection. AB - BACKGROUND: Muscle strength is necessary for upper body normal function. Upper extremity function impairments have been reported in breast cancer (BC) survivors. It is not possible to know precisely if cancer adjuvant therapy such as radiation and chemotherapy had any effect on the unaffected arm. The aim of this study was to compare shoulder girdle strength among women with BC and similarly aged women without cancer. MATERIALS AND METHODS: Thirty-three postmenopausal women (51 +/- 6.46 years) with BC who underwent surgery, chemotherapy, and radiation therapy and 30 healthy postmenopausal women (53.26 +/ 5.05 years) were selected. Muscle strength was measured using a handheld dynamometer for flexion, horizontal adduction, internal and external rotation, scapular abduction and upward rotation, scapular depression, and adduction. Data were analyzed by multivariate analysis of variance (P < 0.05). RESULTS: The findings indicated significant differences between groups of 6 of the shoulder girdle strength measure (flexion (P = 0.003), internal rotation (P = 0.001), external rotation (P = 0.040), scapular abduction and upward rotation (P = 0.001), scapular depression and adduction (P = 0.025), and shoulder horizontal adduction (P = 0.00)). Patients showed significantly lower strength compared with healthy controls (flexion = 34.3%, abd = 64.2%, int.rot = 51.2%, ext.rot = 32.4%, hor.add = 58.06, and depression = 35.2%). CONCLUSION: The results indicate that the shoulder girdle strength in women with BC decreased compared with healthy women without BC. Therefore, during the treatment of patients with BC, designing of training programs and rehabilitation programs need to be performed on shoulder girdle strength factors in patients undergoing mastectomy with axillary surgery and radiation therapy. PMID- 28717379 TI - Hepatoprotective Effect of Citral on Acetaminophen-Induced Liver Toxicity in Mice. AB - High doses of acetaminophen (APAP) lead to acute liver damage. In this study, we evaluated the effects of citral in a murine model of hepatotoxicity induced by APAP. The liver function markers alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and gamma-glutamyl transferase (gammaGT) were determined to evaluate the hepatoprotective effects of citral. The livers were used to determine myeloperoxidase (MPO) activity and nitric oxide (NO) production and in histological analysis. The effect of citral on leukocyte migration and antioxidant activity was evaluated in vitro. Citral pretreatment decreased significantly the levels of ALT, AST, ALP, and gammaGT, MPO activity, and NO production. The histopathological analysis showed an improvement of hepatic lesions in mice after citral pretreatment. Citral inhibited neutrophil migration and exhibited antioxidant activity. Our results suggest that citral protects the liver against liver toxicity induced by APAP. PMID- 28717380 TI - Response of Local Nitric Oxide Release to Manual Acupuncture and Electrical Heat in Humans: Effects of Reinforcement Methods. AB - This study was to examine the influences of manual acupuncture (MA) and electrical heat corresponding to reinforcing methods on nitric oxide (NO) release over the skin regions in humans. A device with collecting solution was taped to the skin surface along pericardium (PC) or lung (LU) meridian. Acupuncture needles were gently inserted into PC 4 with reinforcing stimulation (low force/rate) for 20 minutes in the MA group. LU11 on the finger was heated (43-44 degrees C) by electrical heat for 20 minutes. Biocapture was consecutively conducted for two 20-minute intervals during and after each treatment. Total nitrite and nitrate (NO x-) in the collecting samples were quantified using chemiluminescence in blinded fashion. Baseline NO x- levels are higher and tended to be higher over PC and LU acupoints during the 1st biocapture. NO x- levels over PC regions were consistently increased by MA during both intervals. NO x- concentrations over LU acupoints were increased and tended to be increased by electrical heat in the 1st and 2nd biocapture. The results suggest that reinforcing MA and electrical heat induce NO released from the local skin regions with higher levels at acupoints, which improve local circulation and contribute to the beneficial effects of the therapies. PMID- 28717381 TI - Patterns and dynamics of neutral lipid fatty acids in ants - implications for ecological studies. AB - BACKGROUND: Trophic interactions are a fundamental aspect of ecosystem functioning, but often difficult to observe directly. Several indirect techniques, such as fatty acid analysis, were developed to assess these interactions. Fatty acid profiles may indicate dietary differences, while individual fatty acids can be used as biomarkers. Ants are among the most important terrestrial animal groups, but little is known about their lipid metabolism, and no study so far used fatty acids to study their trophic ecology. We set up a feeding experiment with high- and low-fat food to elucidate patterns and dynamics of neutral lipid fatty acids (NLFAs) assimilation in ants. We asked whether dietary fatty acids are assimilated through direct trophic transfer, how diet influences NLFA total amounts and patterns over time, and whether these assimilation processes are similar across species and life stages. RESULTS: Ants fed with high-fat food quickly accumulated specific dietary fatty acids (C18:2n6, C18:3n3 and C18:3n6), compared to ants fed with low-fat food. Dietary fat content did not affect total body fat of workers or amounts of fatty acids extensively biosynthesized by animals (C16:0, C18:0, C18:1n9). Larval development had a strong effect on the composition and amounts of C16:0, C18:0 and C18:1n9. NLFA compositions reflected dietary differences, which became more pronounced over time. Assimilation of specific dietary NLFAs was similar regardless of species or life stage, but these factors affected dynamics of other NLFAs, composition and total fat. CONCLUSIONS: We showed that ants accumulated certain dietary fatty acids via direct trophic transfer. Fat content of the diet had no effect on lipids stored by ants, which were able to synthesize high amounts of NLFAs from a sugar-based diet. Nevertheless, dietary NLFAs had a strong effect on metabolic dynamics and profiles. Fatty acids are a useful tool to study trophic biology of ants, and could be applied in an ecological context, although factors that affect NLFA patterns should be taken into account. Further studies should address which NLFAs can be used as biomarkers in natural ant communities, and how factors other than diet affect fatty acid dynamics and composition of species with distinct life histories. PMID- 28717382 TI - Neurological soft signs in Tunisian patients with first-episode psychosis and relation with cannabis use. AB - BACKGROUND: Neurological soft signs (NSS) are minor non-localizing neurological abnormalities that are conceptualized as neurodevelopmental markers that mediate the biological risk for psychosis. We aimed to explore the relationship between NSS and cannabis use, an environmental risk factor of psychosis. METHODS: This was a cross-sectional study in consecutively admitted patients hospitalized for first-episode psychosis. NSS were assessed by the NSS scale (23 items exploring motor coordination, motor integrative function, sensory integration, involuntary movements or posture, quality of lateralization). Presence of NSS was defined as a NSS scale total score >=9.5. Cannabis use was ascertained with the cannabis subsection in the Composite International Diagnostic Interview. RESULTS: Among 61 first-episode psychosis patients (mean age = 28.9 +/- 9.4 years; male = 86.9%, antipsychotic-naive = 75.4%), the prevalence of current cannabis use was 14.8% (heavy use = 8.2%, occasional use = 6.6%). NSS were present in 83.6% of the sample (cannabis users = 66.7% versus cannabis non-users = 85.5%, p = 0.16). The mean total NSS score was 15.3 +/- 6.7, with a significant lower total NSS score in cannabis users (11.2 +/- 5.6 versus 16.0 +/- 6.7, p = 0.048). Differences were strongest for the "motor coordination" (p = 0.06) and "involuntary movements" (p = 0.07) sub-scores. CONCLUSIONS: This study demonstrated a negative association between cannabis use and NSS, especially regarding motor discoordination. This finding supports the hypothesis that a strong environmental risk factor, such as cannabis, may contribute to the onset of psychosis even in the presence of lower biological and genetic vulnerability, as reflected indirectly by lower NSS scores. Nevertheless, additional studies are needed that explore this interaction further in larger samples and considering additional neurobiological and environmental risk factors. PMID- 28717383 TI - What influences feeding decisions for HIV-exposed infants in rural Kenya? AB - BACKGROUND: Infant feeding in the context of human immunodeficiency virus (HIV) poses unique challenges to mothers and healthcare workers in balancing the perceived risks of HIV transmission and nutritional requirements. We aimed to describe the decision-making processes around infant feeding at a rural HIV clinic in Kenya. METHODS: We used a qualitative study design. Between March and August 2011, we conducted in-depth interviews (n = 9) and focus group discussions (n = 10) with purposively selected hospital and community respondents at Kilifi County Hospital, Kenya. These respondents had all experienced of infant feeding in the context of HIV. These interviews were informed by prior structured observations of health care worker interactions with carers during infant feeding counselling sessions. RESULTS: Overall, women living with HIV found it difficult to adhere to the HIV infant feeding guidance. There were three dominant factors that influenced decision making processes: 1) Exclusive breastfeeding was not the cultural norm, therefore practising it raised questions within the family and community about a mother's parenting capabilities and HIV status. 2) Women living with HIV lacked autonomy in decision-making on infant feeding due to socio cultural factors. 3) Non-disclosure of HIV status to close members due to the stigma. CONCLUSION: Infant feeding decision-making by women living with HIV in rural Kenya is constrained by a lack of autonomy, stigma and poverty. There is an urgent need to address these challenges through scaling up psycho-social and gender empowerment strategies for women, and introducing initiatives that promote the integration of HIV infant feeding strategies into other child health services. PMID- 28717384 TI - Accelerating root system phenotyping of seedlings through a computer-assisted processing pipeline. AB - BACKGROUND: There are numerous systems and techniques to measure the growth of plant roots. However, phenotyping large numbers of plant roots for breeding and genetic analyses remains challenging. One major difficulty is to achieve high throughput and resolution at a reasonable cost per plant sample. Here we describe a cost-effective root phenotyping pipeline, on which we perform time and accuracy benchmarking to identify bottlenecks in such pipelines and strategies for their acceleration. RESULTS: Our root phenotyping pipeline was assembled with custom software and low cost material and equipment. Results show that sample preparation and handling of samples during screening are the most time consuming task in root phenotyping. Algorithms can be used to speed up the extraction of root traits from image data, but when applied to large numbers of images, there is a trade-off between time of processing the data and errors contained in the database. CONCLUSIONS: Scaling-up root phenotyping to large numbers of genotypes will require not only automation of sample preparation and sample handling, but also efficient algorithms for error detection for more reliable replacement of manual interventions. PMID- 28717385 TI - Changes in diet associated with cancer: An evolutionary perspective. AB - Changes in diet are frequently correlated with the occurrence and progression of malignant tumors (i.e., cancer) in both humans and other animals, but an integrated conceptual framework to interpret these changes still needs to be developed. Our aim is to provide a new perspective on dietary changes in tumor bearing individuals by adapting concepts from parasitology. Dietary changes may occur alongside tumor progression for several reasons: (i) as a pathological side effect with no adaptive value, (ii) as the result of self-medication by the host to eradicate the tumor and/or to slow down its progression, (iii) as a result of host manipulation by the tumor that benefits its progression, and finally (iv) as a host tolerance strategy, to alleviate and repair damages caused by tumor progression. Surprisingly, this tolerance strategy can be beneficial for the host even if diet changes are beneficial to tumor progression, provided that cancer induced death occurs sufficiently late (i.e., when natural selection is weak). We argue that more data and a unifying evolutionary framework, especially during the early stages of tumorigenesis, are needed to understand the links between changes in diet and tumor progression. We argue that a focus on dietary changes accompanying tumor progression can offer novel preventive and therapeutic strategies against cancer. PMID- 28717386 TI - Understanding low radiation background biology through controlled evolution experiments. AB - Biological experiments conducted in underground laboratories over the last decade have shown that life can respond to relatively small changes in the radiation background in unconventional ways. Rapid changes in cell growth, indicative of hormetic behaviour and long-term inheritable changes in antioxidant regulation have been observed in response to changes in the radiation background that should be almost undetectable to cells. Here, we summarize the recent body of underground experiments conducted to date, and outline potential mechanisms (such as cell signalling, DNA repair and antioxidant regulation) that could mediate the response of cells to low radiation backgrounds. We highlight how multigenerational studies drawing on methods well established in studying evolutionary biology are well suited for elucidating these mechanisms, especially given these changes may be mediated by epigenetic pathways. Controlled evolution experiments with model organisms, conducted in underground laboratories, can highlight the short- and long-term differences in how extremely low-dose radiation environments affect living systems, shining light on the extent to which epimutations caused by the radiation background propagate through the population. Such studies can provide a baseline for understanding the evolutionary responses of microorganisms to ionizing radiation, and provide clues for understanding the higher radiation environments around uranium mines and nuclear disaster zones, as well as those inside nuclear reactors. PMID- 28717387 TI - Human-mediated evolution in a threatened species? Juvenile life-history changes in Snake River salmon. AB - Evaluations of human impacts on Earth's ecosystems often ignore evolutionary changes in response to altered selective regimes. Freshwater habitats for Snake River fall Chinook salmon (SRFCS), a threatened species in the US, have been dramatically changed by hydropower development and other watershed modifications. Associated biological changes include a shift in juvenile life history: Historically essentially 100% of juveniles migrated to sea as subyearlings, but a substantial fraction have migrated as yearlings in recent years. In contemplating future management actions for this species should major Snake River dams ever be removed (as many have proposed), it will be important to understand whether evolution is at least partially responsible for this life-history change. We hypothesized that if this trait is genetically based, parents who migrated to sea as subyearlings should produce faster-growing offspring that would be more likely to reach a size threshold to migrate to sea in their first year. We tested this with phenotypic data for over 2,600 juvenile SRFCS that were genetically matched to parents of hatchery and natural origin. Three lines of evidence supported our hypothesis: (i) the animal model estimated substantial heritability for juvenile growth rate for three consecutive cohorts; (ii) linear modeling showed an association between juvenile life history of parents and offspring growth rate; and (iii) faster-growing juveniles migrated at greater speeds, as expected if they were more likely to be heading to sea. Surprisingly, we also found that parents reared a full year in a hatchery produced the fastest growing offspring of all-apparently an example of cross-generational plasticity associated with artificial propagation. We suggest that SRFCS is an example of a potentially large class of species that can be considered to be "anthro-evolutionary" signifying those whose evolutionary trajectories have been profoundly shaped by altered selective regimes in human-dominated landscapes. PMID- 28717388 TI - Heritability of behavioural tolerance to high CO2 in a coral reef fish is masked by nonadaptive phenotypic plasticity. AB - Previous studies have demonstrated limited potential for acclimation of adversely affected olfactory behaviours in reef fishes under elevated CO 2, indicating that genetic adaptation will be required to maintain behavioural performance in the future. Adaptation depends on the presence of heritable phenotypic variation in the trait, which may differ between populations and environments. We used parent offspring regressions to estimate the heritability (h2) of variation in behavioural tolerance to high CO 2 (754 MUatm) in both field-collected and laboratory-reared families of Acanthochromis polyacanthus. Tolerance to elevated CO 2 was measured by determining the behavioural response of individuals to chemical alarm cues. Both populations exhibited high heritability of olfactory behaviour phenotype (father-mid-offspring h2 = 0.56 & 0.65, respectively) when offspring were acutely exposed to high CO 2 for 4 days. However, there was no heritability in the behavioural phenotype when juveniles were chronically exposed to high CO 2 for 6 weeks in the laboratory-reared families. Parental exposure to high CO 2 during the breeding season did not alter this relationship between heritability and length of juvenile exposure to high CO 2. These results demonstrate that variation in behavioural tolerance to high CO 2 is heritable, but adaptive potential may be constrained by a loss of phenotypic variation when juveniles permanently experience a high-CO 2 environment, as will occur with rising CO 2 levels in the ocean. PMID- 28717389 TI - Sexual selection reinforces a higher flight endurance in urban damselflies. AB - Urbanization is among the most important and globally rapidly increasing anthropogenic processes and is known to drive rapid evolution. Habitats in urbanized areas typically consist of small, fragmented and isolated patches, which are expected to select for a better locomotor performance, along with its underlying morphological traits. This, in turn, is expected to cause differentiation in selection regimes, as populations with different frequency distributions for a given trait will span different parts of the species' fitness function. Yet, very few studies considered differentiation in phenotypic traits associated with patterns in habitat fragmentation and isolation along urbanization gradients, and none considered differentiation in sexual selection regimes. We investigated differentiation in flight performance and flight-related traits and sexual selection on these traits across replicated urban and rural populations of the scrambling damselfly Coenagrion puella. To disentangle direct and indirect paths going from phenotypic traits over performance to mating success, we applied a path analysis approach. We report for the first time direct evidence for the expected better locomotor performance in urban compared to rural populations. This matches a scenario of spatial sorting, whereby only the individuals with the best locomotor abilities colonize the isolated urban populations. The covariation patterns and causal relationships among the phenotypic traits, performance and mating success strongly depended on the urbanization level. Notably, we detected sexual selection for a higher flight endurance only in urban populations, indicating that the higher flight performance of urban males was reinforced by sexual selection. Taken together, our results provide a unique proof of the interplay between sexual selection and adaptation to human-altered environments. PMID- 28717390 TI - Tracing the origin of the early wet-season Anopheles coluzzii in the Sahel. AB - In arid environments, the source of the malaria mosquito populations that re establish soon after first rains remains a puzzle and alternative explanations have been proposed. Using genetic data, we evaluated whether the early rainy season (RS) population of Anopheles coluzzii is descended from the preceding late RS generation at the same locality, consistent with dry season (DS) dormancy (aestivation), or from migrants from distant locations. Distinct predictions derived from these two hypotheses were assessed, based on variation in 738 SNPs in eleven A. coluzzii samples, including seven samples spanning 2 years in a Sahelian village. As predicted by the "local origin under aestivation hypothesis," temporal samples from the late RS and those collected after the first rain of the following RS were clustered together, while larger genetic distances were found among samples spanning the RS. Likewise, multilocus genotype composition of samples from the end of the RS was similar across samples until the following RS, unlike samples that spanned the RS. Consistent with reproductive arrest during the DS, no genetic drift was detected between samples taken over that period, despite encompassing extreme population minima, whereas it was detected between samples spanning the RS. Accordingly, the variance in allele frequency increased with time over the RS, but not over the DS. However, not all the results agreed with aestivation. Large genetic distances separated samples taken a year apart, and during the first year, within-sample genetic diversity declined and increased back during the late RS, suggesting a bottleneck followed by migration. The decline of genetic diversity followed by a mass distribution of insecticide-treated nets was accompanied by a reduced mosquito density and a rise in the mutation conferring resistance to pyrethroids, indicating a bottleneck due to insecticidal selection. Overall, our results support aestivation in A. coluzzii during the DS that is accompanied by long distance migration in the late RS. PMID- 28717391 TI - Transcriptional mechanisms underlying life-history responses to climate change in the three-spined stickleback. AB - Phenotypic plasticity, the ability of an organism to express different phenotypes depending on the environment, provides an important mechanism by which an animal population can persist under rapid climate change. We experimentally tested both life-history and transcriptional responses of an ecological model species, the three-spined stickleback, to warm acclimation at the southern edge of its European range. We explored cross-environment genetic correlations of key life history traits in male sticklebacks exposed to long-term temperature changes to examine whether the plasticity pattern was variable among genotypes by using a character-state approach. We also studied gene expression plasticity by analysing both whole-transcriptome and candidate gene expression in brain and liver. Male sticklebacks that developed under warmer conditions during winter were smaller in size and invested less in nuptial coloration at the beginning of the breeding season, showing similar responses across different genotypes. The lack of genetic variation in life-history responses may limit any future evolution of the thermal reaction norm in the study population. After long-term exposure to increased winter temperatures, genes responsible for several metabolic and oxidation reduction processes were upregulated, and some hormone genes involved in growth and reproduction were downregulated in the brain. In the liver, there was no significantly represented gene ontology by the differentially expressed genes. Since a higher temperature leads to a higher resting metabolic rate, living in warmer environments may incur higher energetic costs for ectotherms to maintain cellular homoeostasis, resulting in negative consequences for life-history traits. The expression of genes related to metabolism, cellular homoeostasis and regulatory signalling may underlie temperature-induced changes in life history. PMID- 28717393 TI - Erratum to: Prevalence of child and adolescent psychiatric disorders in India: a systematic review and meta-analysis. AB - [This corrects the article DOI: 10.1186/1753-2000-8-22.]. PMID- 28717392 TI - The power of evolutionary rescue is constrained by genetic load. AB - The risk of extinction faced by small isolated populations in changing environments can be reduced by rapid adaptation and subsequent growth to larger, less vulnerable sizes. Whether this process, called evolutionary rescue, is able to reduce extinction risk and sustain population growth over multiple generations is largely unknown. To understand the consequences of adaptive evolution as well as maladaptive processes in small isolated populations, we subjected experimental Tribolium castaneum populations founded with 10 or 40 individuals to novel environments, one more favorable, and one resource poor, and either allowed evolution, or constrained it by replacing individuals one-for-one each generation with those from a large population maintained in the natal environment. Replacement individuals spent one generation in the target novel environment before use to standardize effects due to the parental environment. After eight generations we mixed a subset of surviving populations to facilitate admixture, allowing us to estimate drift load by comparing performance of mixed to unmixed groups. Evolving populations had reduced extinction rates, and increased population sizes in the first four to five generations compared to populations where evolution was constrained. Performance of evolving populations subsequently declined. Admixture restored their performance, indicating high drift load that may have overwhelmed the beneficial effects of adaptation in evolving populations. Our results indicate that evolution may quickly reduce extinction risk and increase population sizes, but suggest that relying solely on adaptation from standing genetic variation may not provide long-term benefits to small isolated populations of diploid sexual species, and that active management facilitating gene flow may be necessary for longer term persistence. PMID- 28717394 TI - Immunohistochemical expression of ER-alpha and PR in papillary thyroid carcinoma. AB - Papillary thyroid carcinoma (PTC) is the most common thyroid cancer with multiple risk factors including exposure to ionising radiation. Oestrogens contribute to papillary carcinoma development by promoting cell proliferation and invasion of mutated epithelial follicular cells. The present study aimed to assess ER-alpha and PR expression in PTC and to correlate their expression with the clinicopathological parameters in this cancer. This study included 62 primary and six metastatic papillary thyroid carcinoma cases. Nineteen and 38.7% of primary PTC cases showed positive nuclear expression for ER and PR, respectively. Metastatic cases showed 66.7% positive ER expression and all were negative for PR. Oestrogen receptor expression showed significant higher positivity in metastatic compared to primary PTC (p = 0.02) and it was significantly associated with primary PTC associated with thyroiditis (p = .002). Progesterone receptor expression was significantly associated with old age in primary PTC (p = .003) and it showed significant coparallel expression with ER (p = .000). Oestrogen and progesterone receptors expressed in papillary thyroid carcinoma opening the door for further studies to verify if those patients could benefit from hormonal therapy. Oestrogen receptor seems to have a role in metastatic process of PTC as malignant cells express it in metastatic more than primary site. The presence of lymphocytes in the stroma may promote ER expression in adjacent PTC, necessitating further studies on PTC cases associated with Hashimoto thyroiditis to verify this assumed relationship. PMID- 28717395 TI - Brain imaging before primary lung cancer resection: a controversial topic. AB - OBJECTIVE: International and national recommendations for brain imaging in patients planned to undergo potentially curative resection of non-small-cell lung cancer (NSCLC) are variably implemented throughout the United Kingdom [Hudson BJ, Crawford MB, and Curtin J et al (2015) Brain imaging in lung cancer patients without symptoms of brain metastases: a national survey of current practice in EnglandClin Radiol https://doi.org/10.1016/j.crad.2015.02.007]. However, the recommendations are not based on high-quality evidence and do not take into account cost implications and local resources. Our aim was to determine local practice based on historic outcomes in this patient cohort. METHODS: This retrospective study took place in a regional thoracic surgical centre in the United Kingdom. Pathology records for all patients who had undergone lung resection with curative intent during the time period January 2012-December 2014 were analysed in October 2015. Electronic pathology and radiology reports were accessed for each patient and data collected about their histological findings, TNM stage, resection margins, and the presence of brain metastases on either pre operative or post-operative imaging. From the dates given on imaging, we calculated the number of days post-resection that the brain metastases were detected. RESULTS: 585 patients were identified who had undergone resection of their lung cancer. Of these, 471 had accessible electronic radiology records to assess for the radiological evidence of brain metastases. When their electronic records were evaluated, 25/471 (5.3%) patients had radiological evidence of brain metastasis. Of these, five patients had been diagnosed with a brain metastasis at initial presentation and had undergone primary resection of the brain metastasis followed by resection of the lung primary. One patient had been diagnosed with both a primary lung and a primary bowel adenocarcinoma; on review of the case, it was felt that the brain metastasis was more likely to have originated from the bowel cancer. One had been clinically diagnosed with a cerebral abscess while the radiology had been reported as showing a metastatic deposit. Of the remaining 18/471 (3.8%) patients who presented with brain metastases after their surgical resection, 12 patients had adenocarcinoma, four patients had squamous cell carcinoma, one had basaloid, and one had large-cell neuroendocrine. The mean number of days post-resection that the brain metastases were identified was 371 days, range 14-1032 days, median 295 days (date of metastases not available for two patients). CONCLUSION: The rate of brain metastases identified in this study was similar to previous studies. This would suggest that preoperative staging of the central nervous system may change the management pathway in a small group of patients. However, for this group of patients, the change would be significant either sparing them non-curative surgery or allowing aggressive management of oligometastatic disease. Therefore, we would recommend pre-operative brain imaging with MRI for all patients undergoing potentially curative lung resection. PMID- 28717397 TI - How do we avoid disaster when exiting the European Medicines Agency? Making the most of Brexit in pharmaceutical regulation. AB - As the UK prepares to leave the EU, it must decide what path it is to take with a large number of regulatory and technical agencies who provide collaboration at the European level. In the case of pharmaceuticals, the European Medicines Agency (EMA) provides pan-European licencing for novel pharmaceuticals. Should the UK depart from the EMA system, this article highlights the loss to patients immediately (slower access to novel treatments), and in the long term by having no access to some novel products as companies choose not to launch in the UK. The lack of access then may also preclude the access to these treatments as generic medicines, causing harm far into the future. The other costs considered are the cost for duplicating the functions of the EMA, or the alternative of using the decisions of other regulators without input to decisions made. An alternative is then set out, of how the UK can prosper under 'Brexit', by remaining a member of the EMA, but accepting the decisions without political oversight (as currently happens with the European Commission). Additional freedom could be given to a UK regulator to accept decisions (where appropriate) from other agencies such as the Food & Drug Administration-further speeding access and making the UK a more attractive market. Such an arrangement would put the UK in a better position than the good position it is in currently. This would give patients (both now and in the future) the best access to treatment possible, and promote/attract an industry which employs (directly and indirectly) 500,000 jobs. PMID- 28717396 TI - Intraoperative radiotherapy: review of techniques and results. AB - Intraoperative radiotherapy (IORT) is a technique that involves precise delivery of a large dose of ionising radiation to the tumour or tumour bed during surgery. Direct visualisation of the tumour bed and ability to space out the normal tissues from the tumour bed allows maximisation of the dose to the tumour while minimising the dose to normal tissues. This results in an improved therapeutic ratio with IORT. Although it was introduced in the 1960s, it has seen a resurgence of popularity with the introduction of self-shielding mobile linear accelerators and low-kV IORT devices, which by eliminating the logistical issues of transport of the patient during surgery for radiotherapy or building a shielded operating room, has enabled its wider use in the community. Electrons, low-kV X-rays and HDR brachytherapy are all different methods of IORT in current clinical use. Each method has its own unique set of advantages and disadvantages, its own set of indications where one may be better suited than the other, and each requires a specific kind of expertise. IORT has demonstrated its efficacy in a wide variety of intra-abdominal tumours, recurrent colorectal cancers, recurrent gynaecological cancers, and soft-tissue tumours. Recently, it has emerged as an attractive treatment option for selected, early-stage breast cancer, owing to the ability to complete the entire course of radiotherapy during surgery. IORT has been used in a multitude of roles across these sites, for dose escalation (retroperitoneal sarcoma), EBRT dose de-escalation (paediatric tumours), as sole radiation modality (early breast cancers) and as a re irradiation modality (recurrent rectal and gynaecological cancers). This article aims to provide a review of the rationale, techniques, and outcomes for IORT across different sites relevant to current clinical practice. PMID- 28717398 TI - Preclinical evaluation of NF-kappaB-triggered dendritic cells expressing the viral oncogenic driver of Merkel cell carcinoma for therapeutic vaccination. AB - BACKGROUND: Merkel cell carcinoma (MCC) is a rare but very aggressive skin tumor that develops after integration of a truncated form of the large T-antigen (truncLT) of the Merkel cell polyomavirus (MCV) into the host's genome. Therapeutic vaccination with dendritic cells (DCs) loaded with tumor antigens is an active form of immunotherapy, which intends to direct the immune system towards tumors which express the respective vaccination antigens. METHODS: Cytokine-matured monocyte-derived DCs of healthy donors and MCC patients were electroporated with mRNA encoding the truncLT. To permit major histocompatibility complex (MHC) class II next to class I presentation, we used an RNA construct in which the antigen was fused to a DCLamp sequence in addition to the unmodified antigen. To further improve their immunogenicity, the DCs were additionally activated by co-transfection with the constitutively active nuclear factor (NF) kappaB activator caIKK. These DCs were used to stimulate autologous CD8+ T-cells or a mixture of CD4+ and CD8+ T-cells. Then the percentage of T-cells, specific for the truncLT, was quantified by interferon (IFN)gamma ELISpot assays. RESULTS: Both the truncLT and its DCLamp-fusion were detected within the DCs by flow cytometry, albeit the latter required blocking of the proteasome. The transfection with caIKK upregulated maturation markers and induced cytokine production. After 2-3 rounds of stimulation, the T-cells from 11 out of 13 healthy donors recognized the antigen. DCs without caIKK appeared in comparison less potent in inducing such responses. When using cells derived from MCC patients, we could induce responses for 3 out of 5 patients; however, here the caIKK-transfected DCs did not display their superiority. CONCLUSION: These results show that optimized DCs are able to induce MCV-antigen-specific T-cell responses. Therapeutic vaccination with such transfected DCs could direct the immune system against MCC. PMID- 28717399 TI - Fulvestrant in advanced breast cancer: evidence to date and place in therapy. AB - Breast cancer is a classical hormone-dependent tumour; therefore, endocrine therapy is the mainstay of treatment for hormone receptor-positive, human epidermal growth factor 2-negative advanced breast cancer. Until recently, classical endocrine agents such as tamoxifen, steroidal and nonsteroidal aromatase inhibitors and fulvestrant have been widely used in postmenopausal patients to treat locally advanced or metastatic disease. However, for patients with this subtype of breast cancer, the landscape of endocrine therapy is rapidly changing. Therapies targeting oestrogen modulation have evolved in recent years following the introduction of targeted agents, mTOR and CDK 4/6 inhibitors that are administered in combination with hormone therapy. As a result, options for endocrine therapy have expanded in recent years, and a variety of single-agent or combinations of targeted drugs and endocrine therapies are accepted. Fulvestrant is a selective oestrogen receptor downregulator (SERD) which was introduced to clinical practice in 2002, initially with the indication to treat postmenopausal women with hormone-receptor-positive advanced breast cancer as second-line therapy postdisease progression after aromatase inhibitors or tamoxifen. Additionally, fulvestrant has also been shown to be active in patients previously untreated with endocrine therapy, either both in the neoadjuvant and the metastatic setting, alone or in combination with other targeted therapies. Currently, the standard dose is 500 mg, which is administered with a loading dose. Fulvestrant received a new FDA indication in December 2016, in combination with palbociclib, both in pre/peri/postmenopausal women with breast cancer progressing after endocrine therapy. This manuscript aims to give an overview of new efficacy data and the current role of fulvestrant in the systemic therapy of hormone-receptor-positive advanced breast cancer, in the context of other available therapeutic modalities. PMID- 28717400 TI - Treatment of NRAS-mutated advanced or metastatic melanoma: rationale, current trials and evidence to date. AB - The disease course of BRAF (v-raf murine sarcoma viral oncogene homolog B1) mutant melanoma has been drastically improved by the arrival of targeted therapies. NRAS (neuroblastoma RAS viral oncogene homolog)-mutated melanoma represents 15-25% of all metastatic melanoma patients. It currently does not have an approved targeted therapy. Metastatic patients receive immune-based therapies as first-line treatments, then cytotoxic chemotherapy like carboplatin/paclitaxel (C/P), dacarbazine (DTIC) or temozolomide (TMZ) as a second-line treatment. We will review current preclinical and clinical developments in NRAS-mutated melanoma, and analyze ongoing clinical trials that are evaluating the benefit of different targeted and immune-based therapies, either tested as single agents or in combination, in NRAS-mutant melanoma. PMID- 28717401 TI - Novel therapeutic strategies in the treatment of triple-negative breast cancer. AB - Triple-negative breast cancer (TNBC) is a heterogeneous subtype of breast cancer that is defined by negative estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) status. Treating patients with TNBC remains clinically challenging, as patients are not candidates for endocrine or HER2-directed therapy. As a result, chemotherapy with traditional agents such as anthracyclines and taxanes remains the only available option with moderate success. Recent discoveries have revealed that TNBC is a heterogeneous disease at the clinical, histological and molecular levels. The use of biomarkers to identify distinct subsets of TNBC that derive the greatest benefit from presently approved as well as novel therapeutics has become the main focus of current research. The aim of this review is to explore the clinical and biological complexity of TNBC as well as identify novel therapeutic options that target the various molecular subsets of TNBC. PMID- 28717402 TI - Fracture liaison services: do they reduce fracture rates? AB - The fracture liaison service (FLS) care is considered the most appropriate organizational approach for secondary fracture prevention. We performed a literature search to evaluate to what extent the introduction of a FLS reduced subsequent fracture rates. We identified five studies that compared subsequent fracture rates. These studies varied in study design, proportion of women, baseline and subsequent fracture type [vertebral fracture (VF), non-VF (NVF) or hip fractures], duration of follow-up, response rates of attending the FLS, as well as variables included in adjusted analyses (age, sex, baseline fracture, time dependency). In two studies comparing hospitals with and without a FLS, the adjusted hazard ratio (HR) for subsequent fractures was significantly lower in the FLS hospitals (HR: 0.84 during the first year, 0.44 during the second year for subsequent NVFs after baseline NVF, and 0.67 during the third year for subsequent VFs + NVFs after baseline VFs + NVFs). When comparing fracture rates before (pre-FLS) and after (post-FLS) introduction of a FLS, the adjusted HR for subsequent NVFs after baseline NVF was significantly lower in the post-FLS group after 2 years in one study (HR = 0.65) and nonsignificant in another study for subsequent hip fractures after baseline hip fracture. One study comparing pre-FLS and post-FLS with a follow-up of less than a year did not demonstrate a significant difference in subsequent fracture risk. In conclusion, only five FLS studies with heterogeneous study designs are available, three of them reported a lower subsequent fracture rate related to FLS care. Larger and long-term studies will be needed to further quantify the effect of FLS care on subsequent fracture risk. PMID- 28717404 TI - Physical activity does not alter prolactin levels in post-menopausal women: results from a dose-response randomized controlled trial. AB - BACKGROUND: Increased circulating levels of prolactin have been associated with increased risk of both in situ and invasive breast cancer. We investigated whether or not physical activity had a dose-response effect in lowering plasma levels of prolactin in postmenopausal women. METHODS: Four hundred previously inactive but healthy postmenopausal women aged 50-74 years of age were randomized to 150 or 300 min per week of aerobic physical activity in a year-long intervention. Prolactin was measured from fasting samples with a custom-plex multiplex assay. RESULTS: A high compared to moderate volume of physical activity did not reduce plasma prolactin levels in intention-to-treat (Treatment Effect Ratio (TER) 1.00, 95% Confidence Interval (CI) 0.95 - 1.06) or per-protocol analyses (TER 1.02, 95% CI 0.93 - 1.13). CONCLUSIONS: It is unlikely that changes in prolactin levels mediate the reduced risk of breast cancer development in post menopausal women associated with increased levels of physical activity. TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT01435005. PMID- 28717405 TI - My Command, My Act: Observation Inflation in Face-To-Face Interactions. AB - When observing another agent performing simple actions, these actions are systematically remembered as one's own after a brief period of time. Such observation inflation has been documented as a robust phenomenon in studies in which participants passively observed videotaped actions. Whether observation inflation also holds for direct, face-to-face interactions is an open question that we addressed in two experiments. In Experiment 1, participants commanded the experimenter to carry out certain actions, and they indeed reported false memories of self-performance in a later memory test. The effect size of this inflation effect was similar to passive observation as confirmed by Experiment 2. These findings suggest that observation inflation might affect action memory in a broad range of real-world interactions. PMID- 28717403 TI - The potential role of adult stem cells in the management of the rheumatic diseases. AB - Adult stem cells are considered as appealing therapeutic candidates for inflammatory and degenerative musculoskeletal diseases. A large body of preclinical research has contributed to describing their immune-modulating properties and regenerative potential. Additionally, increasing evidence suggests that stem cell differentiation and function are disrupted in the pathogenesis of rheumatic diseases. Clinical studies have been limited, for the most part, to the application of adult stem cell-based treatments on small numbers of patients or as a 'salvage' therapy in life-threatening disease cases. Nevertheless, these preliminary studies indicate that adult stem cells are promising tools for the long-term treatment of rheumatic diseases. This review highlights recent knowledge acquired in the fields of hematopoietic and mesenchymal stem cell therapy for the management of systemic sclerosis (SSc), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and osteoarthritis (OA) and the potential mechanisms mediating their function. PMID- 28717406 TI - Neurogenic Bowel Dysfunction in Patients with Neurogenic Bladder. AB - Patients with primary neurologic conditions often experience urinary and bowel dysfunction due to loss of sensory and/or motor control. Neurogenic bowel dysfunction is frequently characterized by both constipation and fecal incontinence. In general, the management of neurogenic bowel dysfunction has been less well studied than bladder dysfunction despite their close association.. It is widely accepted that establishment of a multifaceted bowel regimen is the cornerstone of conservative management. Continuing assessment is necessary to determine need for more invasive interventions. In the clinical setting, the Urologist may be the principle provider addressing bowel concerns in addition to bladder dysfunction, and furthermore, treatment of one often impacts the other. Future directions should include development of follow up and management guidelines that address the comprehensive care of this patient population. PMID- 28717407 TI - Effects of a Community-based Lifestyle Intervention on Change in Physical Activity Among Economically Disadvantaged Adults With Prediabetes. PMID- 28717408 TI - SIRT3 Enhances Mesenchymal Stem Cell Longevity and Differentiation. AB - Mesenchymal stem cells (MSCs) are multipotent cells that are currently being investigated in a wide variety of clinical trials for their anti-inflammatory and immunomodulatory properties as well as their osteogenic and chondrogenic capabilities. However, there are considerable interdonor variability and heterogeneity of MSC populations, making it challenging to compare different products. Furthermore, proliferation, differentiation, and immunomodulation of MSCs decrease with aging and ex vivo expansion. The sirtuins have emerged as a class of protein deacylases involved in aging, oxidative stress, and metabolism. Sirtuin 3 (SIRT3) is the major mitochondrial deacetylase involved in reducing oxidative stress while preserving oxidative metabolism, and its levels have been shown to decrease with age. This study investigated the role of SIRT3 in MSC differentiation and aging. As MSCs were expanded ex vivo, SIRT3 levels decreased. In addition, SIRT3 depletion reduced MSC differentiation into adipocytes and osteoblasts. Furthermore, overexpression of SIRT3 in later-passage MSCs reduced aging-related senescence, reduced oxidative stress, and enhanced their ability to differentiate. These data suggest that overexpressing SIRT3 might represent a strategy to increase the quality and quantity of MSCs utilized for clinical applications. PMID- 28717409 TI - Influence of the Microstructure and Silver Content on Degradation, Cytocompatibility, and Antibacterial Properties of Magnesium-Silver Alloys In Vitro. AB - Implantation is a frequent procedure in orthopedic surgery, particularly in the aging population. However, it possesses the risk of infection and biofilm formation at the surgical site. This can cause unnecessary suffering to patients and burden on the healthcare system. Pure Mg, as a promising metal for biodegradable orthopedic implants, exhibits some antibacterial effects due to the alkaline pH produced during degradation. However, this antibacterial effect may not be sufficient in a dynamic environment, for example, the human body. The aim of this study was to increase the antibacterial properties under harsh and dynamic conditions by alloying silver metal with pure Mg as much as possible. Meanwhile, the Mg-Ag alloys should not show obvious cytotoxicity to human primary osteoblasts. Therefore, we studied the influence of the microstructure and the silver content on the degradation behavior, cytocompatibility, and antibacterial properties of Mg-Ag alloys in vitro. The results indicated that a higher silver content can increase the degradation rate of Mg-Ag alloys. However, the degradation rate could be reduced by eliminating the precipitates in the Mg-Ag alloys via T4 treatment. By controlling the microstructure and increasing the silver content, Mg-Ag alloys obtained good antibacterial properties in harsh and dynamic conditions but had almost equivalent cytocompatibility to human primary osteoblasts as pure Mg. PMID- 28717410 TI - Fish Scale Collagen Peptides Protect against CoCl2/TNF-alpha-Induced Cytotoxicity and Inflammation via Inhibition of ROS, MAPK, and NF-kappaB Pathways in HaCaT Cells. AB - Skin diseases associated with inflammation or oxidative stress represent the most common problem in dermatology. The present study demonstrates that fish scale collagen peptides (FSCP) protect against CoCl2-induced cytotoxicity and TNF-alpha induced inflammatory responses in human HaCaT keratinocyte cells. Our study is the first to report that FSCP increase cell viability and ameliorate oxidative injury in HaCaT cells through mechanisms mediated by the downregulation of key proinflammatory cytokines, namely, TNF-alpha, IL-1beta, IL-8, and iNOS. FSCP also prevent cell apoptosis by repressing Bax expression, caspase-3 activity, and cytochrome c release and by upregulating Bcl-2 protein levels in CoCl2- or TNF alpha-stimulated HaCaT cells. In addition, the inhibitory effects of FSCP on cytotoxicity and the induction of proinflammatory cytokine expression were found to be associated with suppression of the ROS, MAPK (p38/MAPK, ERK, and JNK), and NF-kappaB signaling pathways. Taken together, our data suggest that FSCP are useful as immunomodulatory agents in inflammatory or immune-mediated skin diseases. Furthermore, our results provide new insights into the potential therapeutic use of FSCP in the prevention and treatment of various oxidative- or inflammatory stress-related inflammation and injuries. PMID- 28717411 TI - Skeletal muscle generated from induced pluripotent stem cells - induction and application. AB - Human induced pluripotent stem cells (hiPS cells or hiPSCs) can be derived from cells of patients with severe muscle disease. If skeletal muscle induced from patient-iPSCs shows disease-specific phenotypes, it can be useful for studying the disease pathogenesis and for drug development. On the other hand, human iPSCs from healthy donors or hereditary muscle disease-iPSCs whose genomes are edited to express normal protein are expected to be a cell source for cell therapy. Several protocols for the derivation of skeletal muscle from human iPSCs have been reported to allow the development of efficient treatments for devastating muscle diseases. In 2017, the focus of research is shifting to another stage: (1) the establishment of mature myofibers that are suitable for study of the pathogenesis of muscle disease; (2) setting up a high-throughput drug screening system; and (3) the preparation of highly regenerative, non-oncogenic cells in large quantities for cell transplantation, etc. PMID- 28717412 TI - Diffusion magnetic resonance imaging: A molecular imaging tool caught between hope, hype and the real world of "personalized oncology". AB - "Personalized oncology" is a multi-disciplinary science, which requires inputs from various streams for optimal patient management. Humongous progress in the treatment modalities available and the increasing need to provide functional information in addition to the morphological data; has led to leaping progress in the field of imaging. Magnetic resonance imaging has undergone tremendous progress with various newer MR techniques providing vital functional information and is becoming the cornerstone of "radiomics/radiogenomics". Diffusion-weighted imaging is one such technique which capitalizes on the tendency of water protons to diffuse randomly in a given system. This technique has revolutionized oncological imaging, by giving vital qualitative and quantitative information regarding tumor biology which helps in detection, characterization and post treatment surveillance of the lesions and challenging the notion that "one size fits all". It has been applied at various sites with different clinical experience. We hereby present a brief review of this novel functional imaging tool, with its application in "personalized oncology". PMID- 28717413 TI - Revisions to the Tumor, Node, Metastasis staging of lung cancer (8th edition): Rationale, radiologic findings and clinical implications. AB - The Tumor, Node, Metastasis (TNM) staging system, adopted by the Union for International Cancer Control (UICC) and the American Joint Committee on Cancer (AJCC), has been recently revised, with the new 8th edition of the staging manual being published in January 2017. This edition has few but important evidence based changes to the TNM staging system used for lung cancer. Radiologists should be aware of the updated classification system to accurately provide staging information to oncologists and oncosurgeons. In this article, we discuss the rationale, illustrate the changes with relevance to Radiology, and review the clinical implications of the 8th edition of the UICC/AJCC TNM staging system with regards to lung cancer. PMID- 28717414 TI - Cardiac magnetic resonance in patients with acute cardiac injury and unobstructed coronary arteries. AB - AIM: To define the role of cardiac magnetic resonance (CMR) by analyzing a particular group of patients with suspected acute coronary syndrome (ACS) and normal coronary angiogram. METHODS: From January 2009 to December 2015, we examined 220 patients with clinical suspicion of ACS, Troponin elevation [the threshold used to define a positive Troponin T test (TnT) was 0.1 ng/mL] and no significant coronary disease at angiography (the patients were considered to have significant angiographic disease only a 50% stenosis was detected in any of their coronary arteries). The role of CMR with the late gadolinium enhancement was evaluated. RESULTS: CMR was performed to 190 patients (86%) of this group which reveals: Myocarditis in 90 patients (47%); apical ballooning (Tako-Tsubo syndrome) in 32 patients (17%); myocardial infarction (MI) in 40 patients (21%) and no clear diagnosis identified by CMR in 28 patients (15%). A comparison with previous studies was also made. Clinical and echocardiographic follow-ups were performed at 12 +/- 2 mo and no major adverse cardiac events were revealed. CONCLUSION: There is a group of patients with clinical suspicion of ACS displaying normal coronary angiograms. CMR was demonstrated to be a valuable tool in the differential diagnosis evaluation of myocarditis, apical ballooning and MI. PMID- 28717415 TI - Chronic antiepileptic drug use and functional network efficiency: A functional magnetic resonance imaging study. AB - AIM: To increase our insight in the neuronal mechanisms underlying cognitive side effects of antiepileptic drug (AED) treatment. METHODS: The relation between functional magnetic resonance-acquired brain network measures, AED use, and cognitive function was investigated. Three groups of patients with epilepsy with a different risk profile for developing cognitive side effects were included: A "low risk" category (lamotrigine or levetiracetam, n = 16), an "intermediate risk" category (carbamazepine, oxcarbazepine, phenytoin, or valproate, n = 34) and a "high risk" category (topiramate, n = 5). Brain connectivity was assessed using resting state functional magnetic resonance imaging and graph theoretical network analysis. The Computerized Visual Searching Task was used to measure central information processing speed, a common cognitive side effect of AED treatment. RESULTS: Central information processing speed was lower in patients taking AEDs from the intermediate and high risk categories, compared with patients from the low risk category. The effect of risk category on global efficiency was significant (P < 0.05, ANCOVA), with a significantly higher global efficiency for patient from the low category compared with the high risk category (P < 0.05, post-hoc test). Risk category had no significant effect on the clustering coefficient (ANCOVA, P > 0.2). Also no significant associations between information processing speed and global efficiency or the clustering coefficient (linear regression analysis, P > 0.15) were observed. CONCLUSION: Only the four patients taking topiramate show aberrant network measures, suggesting that alterations in functional brain network organization may be only subtle and measureable in patients with more severe cognitive side effects. PMID- 28717416 TI - Feasibility of urinary extracellular vesicle proteome profiling using a robust and simple, clinically applicable isolation method. AB - Extracellular vesicles (EVs) secreted by prostate cancer (PCa) cells contain specific biomarkers and can be isolated from urine. Collection of urine is not invasive, and therefore urinary EVs represent a liquid biopsy for diagnostic and prognostic testing for PCa. In this study, we optimised urinary EV isolation using a method based on heat shock proteins and compared it to gold-standard ultracentrifugation. The urinary EV isolation protocol using the Vn96-peptide is easier, time convenient (~1.5 h) and no special equipment is needed, in contrast to ultracentrifugation protocol (>3.5 h), making this protocol clinically feasible. We compared the isolated vesicles of both ultracentrifugation and Vn96 peptide by proteome profiling using mass spectrometry-based proteomics (n = 4 per method). We reached a depth of >3000 proteins, with 2400 proteins that were commonly detected in urinary EVs from different donors. We show a large overlap (>85%) between proteins identified in EVs isolated by ultracentrifugation and Vn96-peptide. Addition of the detergent NP40 to Vn96-peptide EV isolations reduced levels of background proteins and highly increased the levels of the EV markers TSG101 and PDCD6IP, indicative of an increased EV yield. Thus, the Vn96 peptide-based EV isolation procedure is clinically feasibly and allows large scale protein profiling of urinary EV biomarkers. PMID- 28717417 TI - Analysis of extracellular RNA in cerebrospinal fluid. AB - We examined the extracellular vesicle (EV) and RNA composition of pooled normal cerebrospinal fluid (CSF) samples and CSF from five major neurological disorders: Alzheimer's disease (AD), Parkinson's disease (PD), low-grade glioma (LGG), glioblastoma multiforme (GBM), and subarachnoid haemorrhage (SAH), representing neurodegenerative disease, cancer, and severe acute brain injury. We evaluated: (I) size and quantity of EVs by nanoparticle tracking analysis (NTA) and vesicle flow cytometry (VFC), (II) RNA yield and purity using four RNA isolation kits, (III) replication of RNA yields within and between laboratories, and (IV) composition of total and EV RNAs by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and RNA sequencing (RNASeq). The CSF contained ~106 EVs/MUL by NTA and VFC. Brain tumour and SAH CSF contained more EVs and RNA relative to normal, AD, and PD. RT-qPCR and RNASeq identified disease-related populations of microRNAs and messenger RNAs (mRNAs) relative to normal CSF, in both total and EV fractions. This work presents relevant measures selected to inform the design of subsequent replicative CSF studies. The range of neurological diseases highlights variations in total and EV RNA content due to disease or collection site, revealing critical considerations guiding the selection of appropriate approaches and controls for CSF studies. PMID- 28717418 TI - A novel community driven software for functional enrichment analysis of extracellular vesicles data. AB - Bioinformatics tools are imperative for the in depth analysis of heterogeneous high-throughput data. Most of the software tools are developed by specific laboratories or groups or companies wherein they are designed to perform the required analysis for the group. However, such software tools may fail to capture "what the community needs in a tool". Here, we describe a novel community-driven approach to build a comprehensive functional enrichment analysis tool. Using the existing FunRich tool as a template, we invited researchers to request additional features and/or changes. Remarkably, with the enthusiastic participation of the community, we were able to implement 90% of the requested features. FunRich enables plugin for extracellular vesicles wherein users can download and analyse data from Vesiclepedia database. By involving researchers early through community needs software development, we believe that comprehensive analysis tools can be developed in various scientific disciplines. PMID- 28717419 TI - Platelet extracellular vesicles induce a pro-inflammatory smooth muscle cell phenotype. AB - Extracellular vesicles (EVs) are mediators of cell communication during health and disease, and abundantly released by platelets upon activation or during ageing. Platelet EVs exert modulatory effects on immune and vascular cells. Platelet EVs may modulate the function of vascular smooth muscle cells (SMC). Platelet EVs were isolated from platelet-rich plasma and incubated with SMC in order to assess binding, proliferation, migration and pro-inflammatory phenotype of the cells. Platelet EVs firmly bound to resting SMC through the platelet integrin alphaIIbbeta3, while binding also occurred in a CX3CL1-CX3CR1-dependent manner after cytokine stimulation. Platelet EVs increased SMC migration comparable to platelet derived growth factor or platelet factor 4 and induced SMC proliferation, which relied on CD40- and P-selectin interactions. Flow-resistant monocyte adhesion to platelet EV-treated SMC was increased compared with resting SMC. Again, this adhesion depended on integrin alphaIIbbeta3 and P-selectin, and to a lesser extent on CD40 and CX3CR1. Treatment of SMC with platelet EVs induced interleukin 6 secretion. Finally, platelet EVs induced a synthetic SMC morphology and decreased calponin expression. Collectively, these data indicate that platelet EVs exert a strong immunomodulatory activity on SMC. In particular, platelet EVs induce a switch towards a pro-inflammatory phenotype, stimulating vascular remodelling. PMID- 28717420 TI - Comprehensive toxicity and immunogenicity studies reveal minimal effects in mice following sustained dosing of extracellular vesicles derived from HEK293T cells. AB - Extracellular vesicles (EVs) are under evaluation as therapeutics or as vehicles for drug delivery. Preclinical studies of EVs often use mice or other animal models to assess efficacy and disposition. However, as most EVs under evaluation are derived from human cells, they may elicit immune responses which may contribute to toxicities or enhanced EV clearance. Furthermore, EVs from different cell sources or EVs comprising various cargo may differ with respect to immunogenicity or toxicity. To assess EV-induced immune response and toxicity, we dosed C57BL/6 mice with EVs intravenously and intraperitoneally for 3 weeks. EVs were harvested from wild type or engineered HEK293T cells which were modified to produce EVs loaded with miR-199a-3p and chimeric proteins. Blood was collected to assess hematology, blood chemistry, and immune markers. Spleen cells were immunophenotyped, and tissues were harvested for gross necropsy and histopathological examination. No signs of toxicity were observed, and minimal evidence of changes in immune markers were noted in mice dosed with engineered, but not with wild type EVs. This study provides a framework for assessment of immunogenicity and toxicity that will be required as EVs from varying cell sources are tested within numerous animal models and eventually in humans. PMID- 28717421 TI - Isolation of membrane vesicles from prokaryotes: a technical and biological comparison reveals heterogeneity. AB - Prokaryotes release membrane vesicles (MVs) with direct roles in disease pathogenesis. MVs are heterogeneous when isolated from bacterial cultures so Density Gradient Centrifugation (DGC) is valuable for separation of MV subgroups from contaminating material. Here we report the technical variability and natural biological heterogeneity seen between DGC preparations of MVs for Mycobacterium smegmatis and Escherichia coli and compare these DGC data with size exclusion chromatography (SEC) columns. Crude preparations of MVs, isolated from cultures by ultrafiltration and ultracentrifugation were separated by DGC with fractions manually collected as guided by visible bands. Yields of protein, RNA and endotoxin, protein banding and particle counts were analysed in these. DGC and SEC methods enabled separation of molecularly distinct MV populations from crude MVs. DGC banding profiles were unique for each of the two species of bacteria tested and further altered by changing culture conditions, for example with iron supplementation. SEC is time efficient, reproducible and cost effective method that may also allow partial LPS removal from Gram-negative bacterial MVs. In summary, both DGC and SEC are suitable for the separation of mixed populations of MVs and we advise trials of both, coupled with complete molecular and single vesicle characterisation prior to downstream experimentation. PMID- 28717422 TI - Exosomes purified from a single cell type have diverse morphology. AB - Extracellular vesicles (EVs) are produced by all known organisms and are important for cell communication and physiology. Great morphological diversity has been described regarding EVs found in body fluids such as blood plasma, breast milk, and ejaculate. However, a detailed morphological analysis has never been performed on exosomes when purified from a single cell type. In this study we analysed and quantified, via multiple electron microscopy techniques, the morphology of exosomes purified from the human mast cell line HMC-1. The results revealed a wide diversity in exosome morphology, suggesting that subpopulations of exosomes with different and specific functions may exist. Our findings imply that a new, more efficient way of defining exosome subpopulations is necessary. A system was proposed where exosomes were classified into nine different categories according to their size and shape. Three additional morphological features were also found in exosomes regardless of their morphological classification. These findings show that exosomes purified from a single cell line are also morphologically diverse, similar to previous observations for EVs in body fluids. This knowledge can help to improve the interpretation of experimental results and widen our general understanding of the biological functions of exosomes. PMID- 28717423 TI - Contribution of neuroblastoma-derived exosomes to the production of pro tumorigenic signals by bone marrow mesenchymal stromal cells. AB - The bone marrow (BM) niche is a microenvironment promoting survival, dormancy and therapeutic resistance in tumor cells. Central to this function are mesenchymal stromal cells (MSCs). Here, using neuroblastoma (NB) as a model, we demonstrate that NB cells release an extracellular vesicle (EVs) whose protein cargo is enriched in exosomal proteins but lacks cytokines and chemokines. Using three different purification methods, we then demonstrate that NB-derived exosomes were captured by MSCs and induced the production of pro-tumorigenic cytokines and chemokines, including interleukin-6 (IL-6), IL-8/CXCL8, vascular endothelial cell growth factor and monocyte-chemotactic protein-1, with exosomes prepared by size exclusion chromatography having the highest activity. We found no correlation between the IL-6 and IL-8/CXCL8 stimulatory activity of exosomes from eight NB cell lines and their origin, degree of MYCN amplification, drug resistance and disease status. We then demonstrate that the uptake of NB exosomes by MSCs was associated with a rapid increase in ERK1/2 and AKT activation, and that blocking ERK1/2 but not AKT activation inhibited the IL-6 and IL-8/CXCL8 production by MSCs without affecting exosome uptake. Thus, we describe a new mechanism by which NB cells induce in MSCs an inflammatory reaction that contributes to a favorable microenvironment in the BM. PMID- 28717424 TI - Low active loading of cargo into engineered extracellular vesicles results in inefficient miRNA mimic delivery. AB - Extracellular vesicles (EVs) hold great potential as novel systems for nucleic acid delivery due to their natural composition. Our goal was to load EVs with microRNA that are synthesized by the cells that produce the EVs. HEK293T cells were engineered to produce EVs expressing a lysosomal associated membrane, Lamp2a fusion protein. The gene encoding pre-miR-199a was inserted into an artificial intron of the Lamp2a fusion protein. The TAT peptide/HIV-1 transactivation response (TAR) RNA interacting peptide was exploited to enhance the EV loading of the pre-miR-199a containing a modified TAR RNA loop. Computational modeling demonstrated a stable interaction between the modified pre-miR-199a loop and TAT peptide. EMSA gel shift, recombinant Dicer processing and luciferase binding assays confirmed the binding, processing and functionality of the modified pre miR-199a. The TAT-TAR interaction enhanced the loading of the miR-199a into EVs by 65-fold. Endogenously loaded EVs were ineffective at delivering active miR 199a-3p therapeutic to recipient SK-Hep1 cells. While the low degree of miRNA loading into EVs through this approach resulted in inefficient distribution of RNA cargo into recipient cells, the TAT TAR strategy to load miRNA into EVs may be valuable in other drug delivery approaches involving miRNA mimics or other hairpin containing RNAs. PMID- 28717425 TI - High throughput nanoparticle tracking analysis for monitoring outer membrane vesicle production. AB - Outer membrane vesicles (OMVs) are spherical membrane nanoparticles released by Gram-negative bacteria. OMVs can be quantified in complex matrices by nanoparticle tracking analysis (NTA). NTA can be performed in static mode or with continuous sample flow that results in analysis of more particles in a smaller time-frame. Flow measurements must be performed manually despite the availability of a sample changer on the NanoSight system. Here we present a method for automated measurements in flow mode. OMV quantification in flow mode results in lower variance in particle quantification (coefficient of variation (CV) of 6%, CV static measurements of 14%). Sizing of OMVs was expected to be less favorable in flow mode due to the increased movement of the particles. However, we observed a CV of 3% in flow mode and a CV of 8% in static measurements. Flow rates of up to 5 uL/min displayed correct size and particle measurements, however, particle concentration was slightly lower than in static measurements. The automated method was used to assess OMV release of batch cultures of Neisseria meningitidis. The bacteria released more OMVs in stationary growth phase, while the size of the vesicles remained constant throughout the culture. Taken together, this study shows that automated measurements in flow mode can be established with advanced scripting to reduce the workload for the user. PMID- 28717427 TI - Comparison of the effects of low dose interferon and high dose interferon on reduction of the number and size of plaques in patients with Multiple Sclerosis: A historical cohort. AB - Background: This study was performed to compare the effects of low dose interferon beta-1 (IFN-beta-1) (CinnoVex, 30 mcg) and high dose IFN-beta-1 (REBIF, 44 mcg) on the reduction of the number and size of plaques in magnetic resonance imaging (MRI) in patients with multiple sclerosis (MS). Methods: This historical cohort study, which was performed in 2014 in Sanandaj (western part of Iran). 43 MS patients in two groups were investigated. The first group, which included 19 patients, was treated using high dose IFN (44 mcg) and the second group, which was consisted of 24 patients, was treated using low dose IFN (30 mcg). Patients' data were collected and analyzed by the Stata version 11 software; the analyses were performed using statistical t-test, chi-square test, Fisher test, and logistic regression. Results: Both drugs were effective in controlling active demyelinating plaque and in preventing plaque activation (P = 0.633). The impact of both drugs in the reduction of the number and size of plaques was evaluated. Based on the results of the MRI, high dose IFN therapy was more effective than the low dose IFN drugs and had a better performance in terms of reducing the number of plaques and in stop-and-recovery (P = 0.039), as well as in reducing the plaque size (P = 0.050). Conclusion: The high dose IFN therapy was more effective than the low dose IFN therapy in reducing the number and size of brain plaques in patients with relapsing-remitting MS (RRMS). PMID- 28717426 TI - Extracellular vesicles released following heat stress induce bystander effect in unstressed populations. AB - Cells naive to stress can display the effects of stress, such as DNA damage and apoptosis, when they are exposed to signals from stressed cells; this phenomenon is known as the bystander effect. We previously showed that bystander effect induced by ionising radiation are mediated by extracellular vesicles (EVs). Bystander effect can also be induced by other types of stress, including heat shock, but it is unclear whether EVs are involved. Here we show that EVs released from heat shocked cells are also able to induce bystander damage in unstressed populations. Naive cells treated with media conditioned by heat shocked cells showed higher levels of DNA damage and apoptosis than cells treated with media from control cells. Treating naive cells with EVs derived from media conditioned by heat shocked cells also induced a bystander effect when compared to control, with DNA damage and apoptosis increasing whilst the level of cell viability was reduced. We demonstrate that treatment of naive cells with heat shocked cell derived EVs leads to greater invasiveness in a trans-well Matrigel assay. Finally, we show that naive cells treated with EVs from heat-shocked cells are more likely to survive a subsequent heat shock, suggesting that these EVs mediate an adaptive response. We propose that EVs released following stress mediate an intercellular response that leads to apparent stress in neighbouring cells but also greater robustness in the face of a subsequent insult. PMID- 28717428 TI - Awareness toward stroke in a population-based sample of Iranian adults. AB - Background: Stroke is the leading cause of death and functional disability. While there have been major advances regarding the management of stroke, a significant proportion of people are still unaware of stroke-related symptoms and risk factors. This study was performed to assess the awareness of stroke's warning signs and risk factors among a sample of Iranian population. Methods: A total of 649 participants were randomly selected using systematic randomization from the list of telephone numbers obtained from the telephone directory. Demographic characteristics were recorded. Participants were asked to answer questions regarding the awareness about stroke, its warning signs and risk factors. Results: Patients' mean age was 32.0 +/- 12.2 years old, and 56.4% were women. Hypertension and history of stroke were major risk factors, and loss of consciousness, vertigo and ataxia were major warning signs of stroke correctly identified by respondents. Multiple linear regressions showed that age (beta = 0.277, P < 0.001), academic level of education (beta = 6.41, P = 0.01), housewifery (beta = 8.9, P < 0.001), jobs related to medical care (beta = 13.17, P = 0.016) and previous information about stroke (beta = 18.71, P < 0.001) were significant predictors of the overall awareness about stroke. Conclusion: The awareness of people about stroke, its risk factors and warning signs were good in this study. The awareness toward stroke can be associated with factors such as age, academic level of education, job and previous information about stroke. Further studies are recommended to program public multimedia and health education in academies and colleges. PMID- 28717430 TI - Knowledge, attitude, and practices among Iranian neurologists toward evidence based medicine. AB - Background: Evidence-based medicine (EBM) is a current practice in medicine to produce clinical practice guidelines from well-designed, randomized, controlled trials. We studied knowledge, attitude, and practice of EBM of neurologists who participated in the Iranian congress of neurology. Methods: A self-administered anonymous questionnaire was distributed and filled by neurologists. Results: A total of 200 neurologists were randomly sampled and with response rate of 56%. 33.9% of responder had previously participated in EBM courses. The average total knowledge score was 4.05 +/- 0.80 out of a maximum possible score of 5.0. Textbooks were still the most favorite source of knowledge for our neurologists. A lack of time was the highest, and motivation the least mentioned barrier in using EBM. Conclusion: Overall, the Iranian neurologist had acceptable knowledge and attitude toward EBM and had same similar as found in other studies. PMID- 28717429 TI - Circulating concentrations of interleukin (IL)-17 in patients with multiple sclerosis: Evaluation of the effects of gender, treatment, disease patterns and IL-23 receptor gene polymorphisms. AB - Background: Interleukin (IL)-17/IL-23 axis performs a prominent role in the pathogenesis of several autoimmune disorders. This study aimed to investigate the concentrations of IL-17 in patients with multiple sclerosis (MS) and its relationship with gender, medication, disease forms and single nucleotide polymorphisms (SNP) in IL-23R gene, including rs11209026 and rs1004819. Methods: The blood specimens were obtained from 135 healthy individuals and 135 MS patients. The patients exhibited relapsing-remitting (RRMS; n = 65), primary progressive (PPMS; n = 19), secondary progressive (SPMS; n = 35) or progressive relapsing (PRMS; n = 14) MS. The DNA was analyzed for SNPs using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and IL-17 concentrations were measured by enzyme-linked immunosorbent assay (ELISA). Results: We have observed elevated serum IL-17 concentrations in MS patients compared with healthy individuals (P < 0.001). The men with MS had higher IL-17 concentrations than women patients (P < 0.050). Untreated patients had significantly higher IL-17 concentrations than healthy individuals and treated patients (P < 0.001 and P < 0.010, respectively). The IL-17 concentrations were significantly decreased in patients treated with interferon-beta (IFN-beta), methylprednisolone or both drugs as compared with untreated MS patients (P < 0.050, P < 0.020 and P < 0.050, respectively). The IL-17 concentrations were also significantly higher in patients with RRMS and PRMS compared with healthy individuals (P < 0.005 and P < 0.010, respectively). The genetic variations at SNPs rs11209026 and rs1004819 were not significantly different between healthy individuals and patients. The IL-17 concentrations were not influenced by genetic variations at investigated SNPs. Conclusion: These results indicated higher levels of IL-17 in MS patients that may be influenced by disease patterns, medication and gender. No association was observed between investigated SNPs and MS. PMID- 28717431 TI - Polymorphisms at activated protein C cleavage sites of factor V: Are they important in the absence of factor V Leiden? AB - Background: Activated protein C (APC) inactivates factor V (FV) by cleavage of its heavy chain at Arg306, Arg506, Arg679, and Lys994. Mutational changes, which abolish APC cleavage sites, may predispose thrombosis by altering the inactivation process of FV. FV Leiden (FVL) (Arg506Glu) has been demonstrated as a strong risk factor for thrombosis. In the current study, we have studied whether mutations in the cleavage sites of FV for APC, not due to FVL, would have a role in presenting APC resistance (APCR) and initiation of a cerebral thrombotic event. Methods: A group of 22 patients with a history of cerebral venous thrombosis (CVT), who were not carriers of FVL enrolled in the study. The patients who had conditions associated with acquired APCR were excluded from the study. APCR test was performed on the remaining 16 patients, which showed APCR in 4 plasma samples. DNA sequencing was performed on four exons of FV of APCR patients, encoding Arg306, Arg506, Arg679, and Lys994. Results: Mutations were not found within nucleotides encoding the cleavage sites; neither was found within their close upstream and downstream sequences. Conclusion: Our results show that polymorphisms affecting cleavage sites of FV other than Arg506Glu it would be less likely to be the basis for APCR and its increased thrombosis susceptibility. In addition, it emphasizes on the importance of screening for APCR in the patients diagnosed with CVT. PMID- 28717433 TI - The first attack of multiple sclerosis presented immediately after voluntary and intensive weight loss: A case series. PMID- 28717434 TI - The effects of intensive language therapy in aphasic patients. PMID- 28717432 TI - Multiple sclerosis-A disease on a dramatically rising trend in Iran: Review of possible reasons. AB - There has been a global rising trend in recent years in the incidence of multiple sclerosis (MS). Despite being an MS low-risk region, this disease has also been recently on the rise in the Middle East. As part of the Middle East, Iran has not been spared either; however, the cause of this dramatic increase remains to be discovered. This study reviews possible reasons for this increase in Iran. Although many factors such as the increased rate of smoking, lifestyle changes, modernization, and contact with toxic solvents can be proposed as reasons for this sudden rise in the prevalence of MS in Iran, these factors cannot be taken as definite causes and further studies are required to prove their impact. PMID- 28717435 TI - Psoriasis, bulbar involvement, and diarrhea in late myoclonic epilepsy with ragged-red fibers-syndrome due to the m.8344A > G tRNA (Lys) mutation. PMID- 28717436 TI - Endovascular management of chronic internal carotid occlusion with Penumbra system. PMID- 28717437 TI - Fahr disease: Idiopathic basal ganglia calcification. PMID- 28717438 TI - Emerging potential for bisphosphonates in the treatment of axial spondyloarthritis. PMID- 28717439 TI - Achalasia: current therapeutic options. AB - Achalasia is a chronic incurable esophageal motility disorder characterized by impaired lower esophageal sphincter (LES) relaxation and loss of esophageal peristalsis. Although rare, it is currently the most common primary esophageal motility disorder, with an annual incidence of around 1.6 per 100,000 persons and prevalence of around 10.8/100,000 persons. Symptoms of achalasia include dysphagia to both solids and liquids, regurgitation, aspiration, chest pain and weight loss. As the underlying etiology of achalasia remains unclear, there is currently no curative treatment for achalasia. Management of achalasia mainly involves improving the esophageal outflow in order to provide symptomatic relief to patients. The most effective treatment options for achalasia include pneumatic dilation, Heller myotomy and peroral endoscopic myotomy (POEM), with the latter increasingly emerging as the treatment of choice for many patients. This review focusses on evidence for current and emerging treatment options for achalasia with a particular emphasis on POEM. PMID- 28717440 TI - Stigmatic limitations on reproductive success in a paleotropical tree: causes and consequences. AB - Success in reproduction is subject to the successful initiation as well as successful completion of a chain of consecutive events starting from flower formation and ending with viable seed production. A pivotal role in this chain is played by the stigma which is the seat of pollen recognition and initiation of pollen-pistil interaction. An interesting feature of the family Bignoniaceae is the presence of thigmosensitive stigmas which open, close and re-open in response to touch. Kigelia pinnata bears a touch sensitive stigma and is a low fruit setter in Jammu and Kashmir (India). One possible reason might be pollen limitation coupled with reported self-incompatibility. However, not much is known about the mechanism of self-incompatibility in K. pinnata or of the role of its thigmotropic stigma. Carefully designed manual pollination experiments along with critical field observations revealed naturally deposited pollen load to be too low to cause permanent closure of stigma lobes. A strong relationship exists between the threshold pollen load on stigma, its permanent closure and fertilization. Of the various pollination treatments undertaken, fruits were formed only in open and manual cross pollinations when ~9200 pollen of legitimate type is deposited on the stigma. Thigmosensitivity further limited the opportunity for the deposition of optimum pollen loads. Although, frequented by as many as seven different visitors, an average of 8 bats per night are available for as many as 30 trees which reflects a baseline deficiency of effective pollinators. This limitation in pollen and pollinator availability affects pollination success of this species and ends up with low fruit set. Fluorescence microscopy reveals successful germination and tube growth of pollen grains of both self and cross type but fruit-set is 100 % in cross-pollinated pistils only. Despite slower rates of ovule penetration and evidence of delayed fertilization, absolutely no fruit initiation occurs in self-pollinated pistils. This strongly points towards self incompatibility being late acting. PMID- 28717441 TI - Direct arylation and heterogeneous catalysis; ever the twain shall meet. AB - The formation of aryl-aryl bonds and heteroaryl analogues is one of the most important C-C bond forming processes in organic chemistry. Recently, a methodology termed Direct Arylation (DA) has emerged as an attractive alternative to traditional cross-coupling reactions (Suzuki-Miyaura, Stille, Negishi, etc.). A parallel focus of the pharmaceutical and other chemical industries has been on the use heterogeneous catalysis as a favourable substitute for its homogeneous counterpart in cross-coupling reactions. Only very recently has heterogeneous catalysis been proposed and applied, to DA reactions. In this perspective, we consider the terms 'heterogeneous' and 'homogeneous' and the problems associated with their delineation in transition-metal catalysed reactions. We highlight the reports at the interface of DA and heterogeneous catalysis and we comment briefly on the methods used which attempt to classify reaction types as homo- or heterogeneous. In future work we recommend an emphasis be placed on kinetic methods which provide an excellent platform for analysis. In addition two analytical techniques are described which if developed to run in situ with DA reactions would illuminate our understanding of the catalysis. Overall, we provide an entry point, and bring together the mature, yet poorly-understood, subject of heterogeneous catalysis with the rapidly expanding area of DA, with a view towards the acceleration of catalyst design and the understanding of catalyst behaviour. PMID- 28717442 TI - Aggregation-induced emission of siloles. AB - Aggregation-induced emission (AIE) is a unique and significant photophysical phenomenon that differs greatly from the commonly acknowledged aggregation-caused emission quenching observed for many pi-conjugated planar chromophores. The mechanistic decipherment of the AIE phenomenon is of high importance for the advance of new AIE systems and exploitation of their potential applications. Propeller-like 2,3,4,5-tetraphenylsiloles are archetypal AIE-active luminogens, and have been adopted as a core part in the design of numerous luminescent materials with diverse functionalities. In this review article, we elucidate the impacts of substituents on the AIE activity and shed light on the structure property relationship of siloles, with the aim of promoting the judicious design of AIE-active functional materials in the future. Recent representative advances of new silole-based functional materials and their potential applications are reviewed as well. PMID- 28717443 TI - Boron chemistry in a new light. AB - Photocatalysis has recently opened up new avenues for the generation of radical species under visible light irradiation conditions. A particularly fascinating class of photocatalyzed transformations relies on the activation of stable boron species with visible-light since it allows the creation of boryl and/or carbon radicals through single electron transfer or energy transfer without the need for specific and costly equipment. This new paradigm has found numerous applications in synthetic organic chemistry, catalysis, and macromolecular chemistry. In this minireview, the concepts underlying photoactivation of boron-species as well as applications to the creation of C-H, C-C, C-O, B-C and B-S bond are discussed. PMID- 28717444 TI - Protein recognition by bivalent, 'turn-on' fluorescent molecular probes. AB - We show that the conversion of a known intercalating dye (i.e., thiazole orange) into a bivalent protein binder could lead to the realization of a novel class of 'turn-on' fluorescent molecular probes that detect proteins with high affinity, selectivity, and a high signal-to-noise (S/N) ratio. The feasibility of the approach is demonstrated with monomolecular probes that light-up in the presence of three different proteins: acetylcholinesterase (AChE), glutathione-s transferase (GST), or avidin (Av) at low concentrations and with minimal background signal. The way by which such probes can be used to detect individual protein isoforms and be applied in inhibitor screening, cell imaging, and biomarker detection is described. PMID- 28717445 TI - A hexanuclear gold carbonyl cluster. AB - The hexanuclear gold carbonyl cluster [PPh4]2[Au6(CF3)6Br2(CO)2] (4) has been obtained by spontaneous self-assembly of the following independent units: CF3AuCO (1) and [PPh4][Br(AuCF3)2] (3). The cyclo-Au6 aggregate 4, in which the components are held together by unassisted, fairly strong aurophilic interactions (Au...Au ~310 pm), exhibits a cyclohexane-like arrangement with chair conformation. These aurophilic interactions also result in significant nu(CO) lowering: from 2194 cm-1 in the separate component 1 to 2171 cm-1 in the mixed aggregate 4. Procedures to prepare the single-bridged dinuclear component 3 as well as the mononuclear derivative [PPh4][CF3AuBr] (2) are also reported. PMID- 28717446 TI - A supramolecular nanovehicle toward systematic, targeted cancer and tumor therapy. AB - A supramolecular nanovehicle (denoted as SNV) was fabricated by encapsulating zinc phthalocyanine (ZnPc) and doxorubicin (DOX) into a copolymer (PVP-b-PAA-g FA), so as to achieve systematic and synergistic chemotherapy-photodynamic therapy (PDT), targeted tumor imaging and therapy. The sophisticated copolymer designed in this work can load the PDT photosensitizer (ZnPc) and chemotherapy drug (DOX) simultaneously, which exhibits an excellent performance in chemotherapy-PDT targeted cancer and tumor therapy for both in vitro studies performed with HepG2 cells and in vivo tests with mice. This work provides a new drug formulation with a chemotherapy-PDT synergistic effect by virtue of the supramolecular material design, which possesses the advantages of an ultra-low drug dosage and highly-efficient in vivo targeted tumor imaging/therapy. PMID- 28717447 TI - Molecular computing: paths to chemical Turing machines. AB - To comply with the rapidly increasing demand of information storage and processing, new strategies for computing are needed. The idea of molecular computing, where basic computations occur through molecular, supramolecular, or biomolecular approaches, rather than electronically, has long captivated researchers. The prospects of using molecules and (bio)macromolecules for computing is not without precedent. Nature is replete with examples where the handling and storing of data occurs with high efficiencies, low energy costs, and high-density information encoding. The design and assembly of computers that function according to the universal approaches of computing, such as those in a Turing machine, might be realized in a chemical way in the future; this is both fascinating and extremely challenging. In this perspective, we highlight molecular and (bio)macromolecular systems that have been designed and synthesized so far with the objective of using them for computing purposes. We also present a blueprint of a molecular Turing machine, which is based on a catalytic device that glides along a polymer tape and, while moving, prints binary information on this tape in the form of oxygen atoms. PMID- 28717448 TI - A thorough experimental study of CH/pi interactions in water: quantitative structure-stability relationships for carbohydrate/aromatic complexes. AB - CH/pi interactions play a key role in a large variety of molecular recognition processes of biological relevance. However, their origins and structural determinants in water remain poorly understood. In order to improve our comprehension of these important interaction modes, we have performed a quantitative experimental analysis of a large data set comprising 117 chemically diverse carbohydrate/aromatic stacking complexes, prepared through a dynamic combinatorial approach recently developed by our group. The obtained free energies provide a detailed picture of the structure-stability relationships that govern the association process, opening the door to the rational design of improved carbohydrate-based ligands or carbohydrate receptors. Moreover, this experimental data set, supported by quantum mechanical calculations, has contributed to the understanding of the main driving forces that promote complex formation, underlining the key role played by coulombic and solvophobic forces on the stabilization of these complexes. This represents the most quantitative and extensive experimental study reported so far for CH/pi complexes in water. PMID- 28717449 TI - Dielectric-dependent electron transfer behaviour of cobalt hexacyanides in a solid solution of sodium chloride. AB - Here we emphasise the importance of the dielectric environment on the electron transfer behavior in interfacial electrochemical systems. Through doping cobalt hexacyanide (Co(CN)63-) into single microcrystals of sodium chloride (NaCl), for the first time, we obtained the direct electrochemical behavior of Co(CN)63- which is hardly ever obtained in either aqueous or conventional nonaqueous solutions. DFT calculations elucidate that, as the Co(CN)63- anions occupy the lattice units of NaCl65- in the NaCl microcrystal, the redox energy barrier of Co(CN)63-/4- is decreased dramatically due to the low dielectric constant of NaCl. Meanwhile, the low-spin Co(CN)64- anions are stabilized in the lattices of the NaCl microcrystal. The results also show that the NaCl microcrystal is a potential solvent for solid-state electrochemistry at ambient temperature. PMID- 28717450 TI - An ambient stable core-substituted perylene bisimide dianion: isolation and single crystal structure analysis. AB - Here we report the first example of an isolable, ambient stable perylene bisimide (PBI) dianion which was synthesized by catalytic reduction of a highly electron deficient PBI derivative. The remarkable stability of this unprecedented dianion in air for months facilitated its complete characterization by different methods, including single crystal X-ray analysis. Furthermore, solvent dependent cyclic and square wave voltammetry studies revealed that the formation of PBI dianions is preferred in more polar solvents, whereas the generation of PBI radical anions should be favoured in less polar solvents. PMID- 28717451 TI - 5,20-Bis(alpha-oligothienyl)-substituted [26]hexaphyrins possessing electronic circuits strongly perturbed by meso-oligothienyl substituents. AB - A series of [26]hexaphyrins(1.1.1.1.1.1) bearing two alpha-oligothienyl substituents at 5,20-positions have been synthesised and are shown to have a dumbbell hexaphyrin conformation, to which the alpha-oligothienyl groups are linked with small dihedral angles to form an acyclic helix-like conjugated network. While their distinct diatropic ring currents and four reversible reduction waves characteristic of aromatic [26]hexaphyrins indicate that the [26]hexaphyrin aromatic circuits are viable, the absorption spectra and excited state dynamics are significantly perturbed, which becomes increasingly evident with elongation of the oligothienyl substituents. DFT calculations of these hexaphyrins indicated that the LUMO and LUMO + 1 are localised on the hexaphyrin circuit and the HOMO and HOMO - 1 are spread over the acyclic helix-like conjugation network, which can explain the perturbed absorption spectra. PMID- 28717452 TI - Increased carrier mobility in end-functionalized oligosilanes. AB - We show that a class of oligosilane-arene sigma, pi-hybrid materials exhibits distinct and enhanced solid-state electronic properties relative to its parent components. In the single crystal structure, the sigma-conjugation axis of one molecule points towards the pi-face of a neighboring molecule due to an unusual gauche conformation. This organization is hypothesized to be beneficial for charge transport. We show that solution-deposited crystalline films of the hybrid materials show up to a 100-fold increase in space-charge limited current (SCLC) mobility relative to literature reports of photoinduced hole transport in oligosilane films. The discovery that sigma, pi-hybrids are more than the sum of their parts offers a design opportunity for new materials. PMID- 28717453 TI - Tetraphenylpyrazine-based AIEgens: facile preparation and tunable light emission. AB - Research on aggregation-induced emission (AIE) has been a hot topic. Due to enthusiastic efforts by many researchers, hundreds of AIE luminogens (AIEgens) have been generated which were mainly based on archetypal silole, tetraphenylethene, distyrylanthracene, triphenylethene, and tetraphenyl-1,4 butadiene, etc. To enlarge the family of AIEgens and to enrich their functions, new AIEgens are in high demand. In this work, we report a new kind of AIEgen based on tetraphenylpyrazine (TPP), which could be readily prepared under mild reaction conditions. Furthermore, we show that the TPP derivatives possess a good thermal stability and their emission could be fine-tuned by varying the substituents on their phenyl rings. It is anticipated that TPP derivatives could serve as a new type of widely utilized AIEgen, based on their facile preparation, good thermo-, photo- and chemostabilities, and efficient emission. PMID- 28717454 TI - Magnetic MOF microreactors for recyclable size-selective biocatalysis. AB - In this contribution we report a synthetic strategy for the encapsulation of functional biomolecules within MOF-based microcapsules. We employ an agarose hydrogel droplet Pickering-stabilised by UiO-66 and magnetite nanoparticles as a template around which to deposit a hierarchically structured ZIF-8 shell. The resulting microcapsules are robust, highly microporous and readily attracted to a magnet, where the hydrogel core provides a facile means to encapsulate enzymes for recyclable size-selective biocatalysis. PMID- 28717455 TI - Self-assembly of tetrareduced corannulene with mixed Li-Rb clusters: dynamic transformations, unique structures and record 7Li NMR shifts. AB - Self-assembly processes of the highly reduced bowl-shaped corannulene generated by the chemical reduction with a binary combination of alkali metals, namely Li Rb, have been investigated by variable-temperature 1H and 7Li NMR spectroscopy. The formation of several unique mixed metal sandwich products based on tetrareduced corannulene, C20H104- (14-), has been revealed followed by investigation of their dynamic transformations in solutions. Analysis of NMR data allowed to propose the mechanism of stepwise alkali metal substitution as well as to identify experimental conditions for the isolation of intermediate and final supramolecular products. As a result, two new triple-decker aggregates with a mixed Li-Rb core, [{Rb(THF)2}2]//[Li3Rb2(C20H10)2{Li+(THF)}] (2) and [{Rb(diglyme)}2]//[Li3Rb3(C20H10)2(diglyme)2].0.5THF (3.0.5THF), have been crystallized and structurally characterized. The Li3Rb2-product has an open coordination site at the sandwich periphery and thus is considered transient on the way to the Li3Rb3-sandwich having the maximized intercalated alkali metal content. Next, the formation of the LiRb5 self-assembly with 14- has been identified by 7Li NMR as the final step in a series of dynamic transformations in this system. This product was also isolated and crystallographically characterized to confirm the LiRb5 core. Notably, all sandwiches have their central cavities, located in between the hub-sites of two C20H104- decks, occupied by an internal Li+ ion which exhibits the record high negative shift (ranging from -21 to -25 ppm) in 7Li NMR spectra. The isolation of three novel aggregates having different Li-Rb core compositions allowed us to look into the origin of the unusual 7Li NMR shifts at the molecular level. The discussion of formation mechanisms, dynamic transformations as well as unique electronic structures of these remarkable mixed alkali metal organometallic self-assemblies is provided and supported by DFT calculations. PMID- 28717456 TI - Transformable H-bonds and conformation in compressed glucose. AB - In response to external stimuli the alpha-d-glucose molecule extensively transforms its H-bonding pattern and conformation. High-pressure reverses the linear compressibility and changes the hierarchy of intermolecular interactions in crystalline alpha-d-glucose. At 5.40(2) GPa it undergoes an isostructural phase transition rearranging the OH...O hydrogen bonds, promoting the role of CH...O contacts and eliminating voids in the structure. Such monotonic and abrupt transformations may be characteristic of sugars and polysaccharides. PMID- 28717457 TI - Electrophilic bis-fluorophosphonium dications: Lewis acid catalysts from diphosphines. AB - Stepwise oxidation of 1,8-bis(diphenylphosphino)naphthalene and a series of (oligo)methylene-linked diphosphines with XeF2 followed by fluoride abstraction yields a family of compounds featuring phosphine, phosphonium and phosphorane moieties in close proximity. The bisphosphonium ions [(C10H6)(Ph2PF)2]2+ (5) and [CH2(Ph2PF)2]2+ (9a) exhibit remarkable Lewis acidity arising from the proximity of the phosphonium centers. The effectiveness of bisphosphonium dications (5, 9a e) is examined in a series of Lewis acid catalysed transformations. PMID- 28717458 TI - Formation of a C-C double bond from two aliphatic carbons. Multiple C-H activations in an iridium pincer complex. AB - The search for novel, atom-economic methods for the formation of C-C bonds is of crucial importance in synthetic chemistry. Especially attractive are reactions where C-C bonds are formed through C-H activation, but the coupling of unactivated, alkane-type Csp3 -H bonds remains an unsolved challenge. Here, we report iridium-mediated intramolecular coupling reactions involving up to four unactivated Csp3 -H bonds to give carbon-carbon double bonds under the extrusion of dihydrogen. The reaction described herein is completely reversible and the direction can be controlled by altering the reaction conditions. With a hydrogen acceptor present a C-C double bond is formed, while reacting under dihydrogen pressure leads to the reverse process, with some of the steps representing net Csp3 -Csp3 bond cleavage. Mechanistic investigations revealed a conceptually novel overall reactivity pattern where insertion or deinsertion of an Ir carbene moiety, formed via double C-H activation, into an Ir-C bond is responsible for the key C-C bond formation and cleavage steps. PMID- 28717459 TI - Semi-synthesis of a HGF/SF kringle one (K1) domain scaffold generates a potent in vivo MET receptor agonist. AB - The development of MET receptor agonists is an important goal in regenerative medicine, but is limited by the complexity and incomplete understanding of its interaction with HGF/SF (Hepatocyte Growth Factor/Scatter Factor). NK1 is a natural occurring agonist comprising the N-terminal (N) and the first kringle (K1) domains of HGF/SF. In the presence of heparin, NK1 can self-associate into a "head to tail" dimer which is considered as the minimal structural module able to trigger MET dimerization and activation whereas isolated K1 and N domains showed a weak or a complete lack of agonistic activity respectively. Starting from these structural and biological observations, we investigated whether it was possible to recapitulate the biological properties of NK1 using a new molecular architecture of isolated N or K1 domains. Therefore, we engineered multivalent N or K1 scaffolds by combining synthetic and homogeneous site-specifically biotinylated N and K1 domains (NB and K1B) and streptavidin (S). NB alone or in complex failed to activate MET signaling and to trigger cellular phenotypes. Importantly and to the contrary of K1B alone, the semi-synthetic K1B/S complex mimicked NK1 MET agonist activity in cell scattering, morphogenesis and survival phenotypic assays. Impressively, K1B/S complex stimulated in vivo angiogenesis and, when injected in mice, protected the liver against fulminant hepatitis in a MET dependent manner whereas NK1 and HGF were substantially less potent. These data reveal that without N domain, proper multimerization of K1 domain is a promising strategy for the rational design of powerful MET agonists. PMID- 28717460 TI - Aggregation-induced emission and aggregation-promoted photochromism of bis(diphenylmethylene)dihydroacenes. AB - Reported herein is a new class of pure polycyclic hydrocarbon molecules, designed through a novel aggregation-induced emission (AIE) strategy, with unexpected photochromic properties. The restriction of intramolecular motion was found as a comprehensive mechanism for the AIE effect. The photochromism mechanism study revealed that the photocyclization reaction of cis-stilbene, the molecular conformation in the single crystal and the tetracene backbone should contribute to the unique photo behavior. In particular, the fast responsive, photo reversible and thermo-irreversible photochromic effect facilitated in the solid state opens a new field of aggregation-promoted photochromism. PMID- 28717461 TI - Tissue distribution and urinary excretion of intravenously administered chemically functionalized graphene oxide sheets. AB - The design of graphene-based materials for biomedical purposes is of great interest. Graphene oxide (GO) sheets represent the most widespread type of graphene materials in biological investigations. In this work, thin GO sheets were synthesized and further chemically functionalized with DOTA (1,4,7,10 tetraazacyclododecane-1,4,7,10-tetraacetic acid), a stable radiometal chelating agent, by an epoxide opening reaction. We report the tissue distribution of the functionalized GO sheets labeled with radioactive indium (111In) after intravenous administration in mice. Whole body single photon emission computed tomography (SPECT/CT) imaging, gamma counting studies, Raman microscopy and histological investigations indicated extensive urinary excretion and predominantly spleen accumulation. Intact GO sheets were detected in the urine of injected mice by Raman spectroscopy, high resolution transmission electron microscopy (HR-TEM) and electron diffraction. These results offer a previously unavailable pharmacological understanding on how chemically functionalized GO sheets transport in the blood stream and interact with physiological barriers that will determine their body excretion and tissue accumulation. PMID- 28717462 TI - Oxygen deficient alpha-Fe2O3 photoelectrodes: a balance between enhanced electrical properties and trap-mediated losses. AB - Intrinsic doping of hematite through the inclusion of oxygen vacancies (VO) is being increasingly explored as a simple, low temperature route to preparing active water splitting alpha-Fe2O3-x photoelectrodes. Whilst it is widely accepted that the introduction of VO leads to improved conductivities, little else is verified regarding the actual mechanism of enhancement. Here we employ transient absorption (TA) spectroscopy to build a comprehensive kinetic model for water oxidation on alpha-Fe2O3-x . In contrast to previous suggestions, the primary effect of introducing VO is to block very slow (ms) surface hole - bulk electron recombination pathways. In light of our mechanistic research we are also able to identify and address a cause of the high photocurrent onset potential, a common issue with this class of electrodes. Atomic layer deposition (ALD) of Al2O3 is found to be particularly effective with alpha-Fe2O3-x , leading to the photocurrent onset potential shifting by ca. 200 mV. Significantly TA measurements on these ALD passivated electrodes also provide important insights into the role of passivating layers, that are relevant to the wider development of alpha-Fe2O3 photoelectrodes. PMID- 28717463 TI - Cyclo-oligomerization of isocyanates with Na(PH2) or Na(OCP) as "P-" anion sources. AB - We show that the 2-phosphaethynolate anion, OCP-, is a simple and efficient catalyst for the cyclotrimerization of isocyanates. This process proceeds step wise and involves five-membered heterocycles, namely 1,4,2-diazaphospholidine-3,5 dionide anions and spiro-phosphoranides as detectable intermediates, both of which were also found to be involved in the catalytic conversion. These species can be considered as adducts of a phosphide anion with two and four isocyanate molecules, respectively, demonstrating that the OCP- anion acts as a formal "P-" source. The interconversion between these anionic species was found to be reversible, allowing them to serve as reservoirs for unique phosphorus-based living-catalysts for isocyanate trimerization. PMID- 28717464 TI - pH-Controlled selection between one of three guests from a mixture using a coordination cage host. AB - We demonstrate the use of a simple pH swing to control the selection of one of three different guests from aqueous solution by a coordination cage host. Switching between different guests is based on the fact that neutral organic guests bind strongly in the cage due to the hydrophobic effect, but for acidic or basic guests, the charged (protonated or deprotonated) forms are hydrophilic and do not bind. The guests used are adamantane-1,3-dicarboxylic acid (H2A) which binds at low pH when it is neutral but not when it is deprotonated; 1-amino adamantane (B) which binds at high pH when it is neutral but not when it is protonated; and cyclononanone (C) whose binding is not pH dependent and is therefore the default guest at neutral pH. Thus an increase in pH can reversibly switch the host between the three different bound states cage.H2A (at low pH), cage.C (at medium pH), and cage.B (at high pH) in succession. PMID- 28717465 TI - Sub-5 nm porous nanocrystals: interfacial site-directed growth on graphene for efficient biocatalysis. AB - The direct production of macromolecular scale (sub-5 nm) porous nanocrystals with high surface area has been a considerable challenge over the past two decades. Here we report an interfacial site-directed capping agent-free growth method to directly produce porous ultrasmall (sub-5 nm), fully crystalline, macromolecular scale nanocrystals. The porous sub-5 nm Prussian blue nanocrystals exhibit uniform sizes (~4 +/- 1 nm), high surface area (~855 m2 g-1), fast electron transfer (rate constant of ~9.73 s-1), and outstanding sustained catalytic activity (more than 450 days). The nanocrystal-based biointerfaces enable unprecedented sub-nanomolar level recognition of hydrogen peroxide (~0.5 nM limit of detection). This method also paves the way towards the creation of ultrasmall porous nanocrystals for efficient biocatalysis. PMID- 28717466 TI - Doping-induced memory effect in Li-ion batteries: the case of Al-doped Li4Ti5O12. AB - In Li-ion batteries (LIBs), a memory effect has been revealed in two-phase electrode materials such as olivine LiFePO4 and anatase TiO2, which complicates the two-phase transition and influences the estimation of the state of charge. Practical electrode materials are usually optimized by the element doping strategy, however, its impact on the memory effect has not been reported yet. Here we firstly present the doping-induced memory effect in LIBs. Pristine Li4Ti5O12 is free from the memory effect, while a distinct memory effect could be induced by Al-doping. After being discharged to a lower cutoff potential, Al doped Li4Ti5O12 exhibits poorer electrochemical kinetics, delivering a larger overpotential during the charging process. This dependence of the overpotential on the discharging cutoff leads to the memory effect in Al-doped Li4Ti5O12. Our discovery emphasizes the impact of element doping on the memory effect of electrode materials, and thus has implications for battery design. PMID- 28717467 TI - Capping nanoparticles with graphene quantum dots for enhanced thermoelectric performance. AB - Graphene quantum dots (GQDs) are shown to serve as phase transfer agents to transfer various types of nanoparticles (NPs) from non-polar to polar solvents. Thorough characterization of the NPs proves complete native ligand exchange. Pellets of this GQD-NP composite show that the GQDs limit the crystal size during spark plasma sintering, yielding enhanced thermoelectric performance compared with NPs exchanged with inorganic ions. A photoluminescence study of the GQD-NP composite also suggests energy transfer from GQDs to NPs. PMID- 28717468 TI - Natural products triptolide, celastrol, and withaferin A inhibit the chaperone activity of peroxiredoxin I. AB - Peroxiredoxin I (Prx I) plays an important role in cancer development and inflammation. It is a dual-functional protein which acts as both an antioxidant enzyme and a molecular chaperone. While there have been intensive studies on its peroxidase activity, Prx I's chaperone activity remains elusive, likely due to the lack of chaperone inhibitors. Here we report that natural product triptolide selectively inhibits the chaperone activity of Prx I, but not its peroxidase activity. Through direct interaction with corresponding cysteines, triptolide triggers dissociation of high-molecular-weight oligomers of Prx I, and thereby inhibits its chaperone activity in a dose-dependent manner. We have also identified celastrol and withaferin A as novel Prx I chaperone inhibitors that are even more potent than triptolide in the chaperone activity assay. By revealing the exact molecular mechanisms of interaction and inhibition, the current study provides the first Prx I chaperone inhibitors as promising pharmacological tools for modulating and dissecting the chaperone function of Prx I. PMID- 28717469 TI - Solid-phase synthesis provides a modular, lysine-based platform for fluorescent discrimination of nitroxyl and biological thiols. AB - We describe a modular, synthetically facile solid-phase approach aimed at separating the fluorescent reporter and binding unit of small-molecule metal based sensors. The first representatives contain a lysine backbone functionalized with a tetramethylrhodamine fluorophore, and they operate by modulating the oxidation state of a copper ion ligated to an [N4] (cyclam) or an [N2O] (quinoline-phenolate) moiety. We demonstrate the selectivity of their Cu(ii) complexes for sensing nitroxyl (HNO) and thiols (RSH), respectively, and investigate the mechanism responsible for the observed reactivity in each case. The two lysine conjugates are cell permeable in the active, Cu(ii)-bound forms and retain their analyte selectivity intracellularly, even in the presence of interfering species such as nitric oxide, nitrosothiols, and hydrogen sulfide. Moreover, we apply the new probes to discriminate between distinct levels of intracellular HNO and RSH generated upon stimulation of live HeLa cells with ascorbate and hydrogen sulfide, respectively. The successful implementation of the lysine-based sensors to gain insight into biosynthetic pathways validates the method as a versatile tool for producing libraries of analogues with minimal synthetic effort. PMID- 28717470 TI - 3D electrogenerated chemiluminescence: from surface-confined reactions to bulk emission. AB - Among luminescence techniques, electrogenerated chemiluminescence (ECL) provides a unique level of manipulation of the luminescent process by controlling the electrochemical trigger. Despite its attractiveness, ECL is by essence a 2D process where light emission is strictly confined to the electrode surface. To overcome this intrinsic limitation, we added a new spatial dimension to the ECL process by generating 3D ECL at the level of millions of micro-emitters dispersed in solution. Each single object is addressed remotely by bipolar electrochemistry and they generate collectively the luminescence in the bulk. Therefore, the entire volume of the solution produces light. To illustrate the generality of this concept, we extended it to a suspension of multi-walled carbon nanotubes where each one acts as an individual ECL nano-emitter. This approach enables a change of paradigm by switching from a surface-limited process to 3D electrogenerated light emission. PMID- 28717471 TI - Targeting virulence: salmochelin modification tunes the antibacterial activity spectrum of beta-lactams for pathogen-selective killing of Escherichia coli. AB - New antibiotics are required to treat bacterial infections and counteract the emergence of antibiotic resistance. Pathogen-specific antibiotics have several advantages over broad-spectrum drugs, which include minimal perturbation to the commensal microbiota. We present a strategy for targeting antibiotics to bacterial pathogens that utilises the salmochelin-mediated iron uptake machinery of Gram-negative Escherichia coli. Salmochelins are C-glucosylated derivatives of the siderophore enterobactin. The biosynthesis and utilisation of salmochelins are important for virulence because these siderophores allow pathogens to acquire iron and evade the enterobactin-scavenging host-defense protein lipocalin-2. Inspired by the salmochelins, we report the design and chemoenzymatic preparation of glucosylated enterobactin-beta-lactam conjugates that harbour the antibiotics ampicillin (Amp) and amoxicillin (Amx), hereafter GlcEnt-Amp/Amx. The GlcEnt scaffolds are based on mono- and diglucosylated Ent where one catechol moiety is functionalized at the C5 position for antibiotic attachment. We demonstrate that GlcEnt-Amp/Amx provide up to 1000-fold enhanced antimicrobial activity against uropathogenic E. coli relative to the parent beta-lactams. Moreover, GlcEnt Amp/Amx based on a diglucosylated Ent (DGE) platform selectively kill uropathogenic E. coli that express the salmochelin receptor IroN in the presence of non-pathogenic E. coli and other bacterial strains that include the commensal microbe Lactobacillus rhamnosus GG. Moreover, GlcEnt-Amp/Amx evade the host defense protein lipocalin-2, and exhibit low toxicity to mammalian cells. Our work establishes that siderophore-antibiotic conjugates provide a strategy for targeting virulence, narrowing the activity spectrum of antibiotics in clinical use, and achieving selective delivery of antibacterial cargos to pathogenic bacteria on the basis of siderophore receptor expression. PMID- 28717472 TI - Photoanodic and photocathodic behaviour of La5Ti2CuS5O7 electrodes in the water splitting reaction. AB - The particulate semiconductor La5Ti2CuS5O7 (LTC) with a band gap energy of 1.9 eV functioned as either a photocathode or a photoanode when embedded onto Au or Ti metal layers, respectively. By applying an LTC/Au photocathode and LTC/Ti photoanode to, respectively, photoelectrochemical (PEC) water reduction and oxidation concurrently, zero-bias overall water splitting was accomplished under visible light irradiation. The band structures of LTC/Au and LTC/Ti calculated using a semiconductor device simulator (AFORS-HET) confirmed the critical role of the solid/solid junction of the metal back contact in the charge separation and PEC properties of LTC photoelectrodes. The prominently long lifetime of photoexcited charge carriers in LTC, confirmed by transient absorption spectroscopy, allowed the utilization of both photoexcited electrons and holes depending on the band structure at the solid/solid junction. PMID- 28717473 TI - A simple and effective "capping" approach to readily tune the fluorescence of near-infrared cyanines. AB - Heptamethine cyanines are favorable for fluorescence imaging applications in biological systems owing to their near-infrared (NIR) absorption and emission. However, it is very difficult to quench the fluorescence of NIR dyes by the classic photoinduced electron transfer mechanism due to their relatively high lying occupied molecular orbital energy levels. Herein, we present a simple and effective "capping" approach to readily tune the fluorescence of NIR cyanines. The resulting new functional NIR CyBX (X = O, N, or S) dyes not only retain the intact tricarbocyanine scaffold, but also have a built-in switch to regulate the fluorescence by spiro-cyclization. When compared to traditional cyanines, novel CyBX dyes have a superior character in that their NIR optical properties can be readily tuned by the intrinsic spiro-cyclization mechanism. We expect that this "capping" strategy can be extended across not only the visual spectrum but also to structurally distinct fluorophores. PMID- 28717474 TI - Palladium carbene complexes as persistent radicals. AB - A series of palladium(ii) radical carbene complexes, [PC(sp2)P]PdI, [PC(sp2)P]PdBr, and [PC(sp2)P]PdCl (PC(sp3)H2P = bis[2-(di-iso-propylphosphino) phenyl]methane), is described. Compound [PC(sp2)P]PdI dimerizes to {[PC(sp2)P]PdI}2 in the solid state, akin to the formation of Gomberg's dimer. While the bromo and the iodo derivatives could be obtained from the oxidation of [PC(sp2)P]Pd(PMe3) by the respective dihalogens, a halogen transfer reaction from CH2Cl2 was used for the formation of [PC(sp2)P]PdCl. The halogen transfer from CH2X2 (X = Cl, Br, I) could be used to obtain all three radical carbene palladium complexes and also allowed the isolation of [PC(CH2)P]Pd(PMe3), which is the result of methylene group transfer from CH2X2. Compound [PC(CH2)P]Pd(PMe3) was independently synthesized from [PC(CH3)HP]PdCl2, which contains a supporting ligand analogous to that of the radical carbene complexes but has one of the hydrogen atoms replaced by a methyl group. All three carbene radical species abstract a hydrogen from 9,10-dihydroanthracene or n Bu3SnH. PMID- 28717475 TI - Image-guided combination chemotherapy and photodynamic therapy using a mitochondria-targeted molecular probe with aggregation-induced emission characteristics. AB - Subcellular targeted cancer therapy and in situ monitoring of therapeutic effect are highly desirable for clinical applications. Herein, we report a series of probes by conjugating zero (TPECM-2Br), one (TPECM-1TPP) and two (TPECM-2TPP) triphenylphosphine (TPP) ligands to a fluorogen with aggregation-induced emission (AIE) characteristics. The probes are almost non-emissive as molecularly dissolved species, but they can light up in cell cytoplasm or mitochondria. TPECM 2TPP is found to be able to target mitochondria, depolarize mitochondria membrane potential and selectively exert potent chemo-cytotoxicity on cancer cells. Furthermore, it can efficiently generate singlet oxygen with strong photo toxicity upon light illumination, which further enhances its anti-cancer effect. On the other hand, TPECM-1TPP can also target mitochondria and generate singlet oxygen to trigger cancer cell apoptosis, but it shows low cytotoxicity in dark. Meanwhile, TPECM-1TPP can report the cellular oxidative stress by visualizing the morphological changes of mitochondria. However, TPECM-2Br does not target mitochondria and shows no obvious anticancer effect either in dark or under light illumination. This study thus highlights the importance of molecular probe design, which yields a new generation of subcellular targeted molecular theranostic agents with multi-function, such as cancer cell imaging, chemotherapy, photodynamic therapy, and in situ monitoring of the therapeutic effect in one go. PMID- 28717476 TI - Cobalt diselenide nanobelts grafted on carbon fiber felt: an efficient and robust 3D cathode for hydrogen production. AB - Design and fabrication of low-cost, highly efficient and robust three-dimensional (3D) hierarchical structure materials for electrochemical reduction of water to make molecular hydrogen is of paramount importance for real water splitting applications. Herein, a 3D hydrogen evolution cathode constructed by in situ growing of cobalt diselenide nanobelts on the surface of commercial carbon fiber felt shows exceptionally high catalytic activity with 141 mV overpotential to afford a current density of 10 mA cm-2, and a high exchange current density of 5.9 * 10-2 mA cm-2. Remarkably, it also exhibits excellent catalytic stability, and could be used for more than 30 000 potential cycles with no decrease in the current density in 0.5 M H2SO4. This easily prepared 3D material with excellent electrocatalytic performance is promising as a realistic hydrogen evolution electrode. PMID- 28717477 TI - Shape and composition control of Bi19S27(Br3-x ,I x ) alloyed nanowires: the role of metal ions. AB - We present the first colloidal synthesis of highly uniform single-crystalline Bi19S27Br3 nanowires (NWs) with a mean diameter of ~9 nm and tunable lengths in the range of 0.15-2 MUm in the presence of foreign metal ions (Al3+). The Al3+ ions not only control the growth of NWs, but also achieve species transformation, i.e., from Bi2S3 to Bi19S27Br3, and are not present in the resulting NWs. This colloidal chemistry approach can be expanded to prepare a family of single crystalline Bi19S27(Br3-x ,I x ) alloyed NWs with controlled compositions (0 <= x <= 3). Interestingly, these alloyed NWs show an unusual composition-independent band gap of ~0.82 eV, and theoretical calculations indicate that this phenomenon comes from the very minor contributions of the halogens to the valence band maximum and conduction band minimum. The photodetectors made of Bi19S27(Br3-x ,I x ) alloyed NWs show a pronounced photoresponse with high stability and reproducibility, which makes the NWs potentially useful candidates in optoelectronic devices. PMID- 28717478 TI - Convergent chemo-enzymatic synthesis of mannosylated glycopeptides; targeting of putative vaccine candidates to antigen presenting cells. AB - The combination of solid phase peptide synthesis and endo-beta-N acetylglucosaminidase (ENGase) catalysed glycosylation is a powerful convergent synthetic method allowing access to glycopeptides bearing full-length N-glycan structures. Mannose-terminated N-glycan oligosaccharides, produced by either total or semi-synthesis, were converted into oxazoline donor substrates. A peptide from the human cytomegalovirus (CMV) tegument protein pp65 that incorporates a well-characterised T cell epitope, containing N-acetylglucosamine at specific Asn residues, was accessed by solid phase peptide synthesis, and used as an acceptor substrate. High-yielding enzymatic glycosylation afforded glycopeptides bearing defined homogeneous high-mannose N-glycan structures. These high-mannose containing glycopeptides were tested for enhanced targeting to human antigen presenting cells (APCs), putatively mediated via the mannose receptor, and for processing by the APCs for presentation to human CD8+ T cells specific for a 9-mer epitope within the peptide. Binding assays showed increased binding of glycopeptides to APCs compared to the non-glycosylated control. Glycopeptides bearing high-mannose N-glycan structures at a single site outside the T cell epitope were processed and presented by the APCs to allow activation of a T cell clone. However, the addition of a second glycan within the T cell epitope resulted in ablation of T cell activation. We conclude that chemo-enzymatic synthesis of mannosylated glycopeptides enhances uptake by human APCs while preserving the immunogenicity of peptide epitopes within the glycopeptides, provided those epitopes are not themselves glycosylated. PMID- 28717479 TI - Near-infrared fluorescence activation probes based on disassembly-induced emission cyanine dye. AB - Currently most of the fluorogenic probes are designed for the detection of enzymes which work by converting the non-fluorescence substrate into the fluorescence product via an enzymatic reaction. On the other hand, the design of fluorogenic probes for non-enzymatic proteins remains a great challenge. Herein, we report a general strategy to create near-IR fluorogenic probes, where a small molecule ligand is conjugated to a novel gamma-phenyl-substituted Cy5 fluorophore, for the selective detection of proteins through a non-enzymatic process. Detail mechanistic studies reveal that the probes self-assemble to form fluorescence-quenched J-type aggregate. In the presence of target analyte, bright fluorescence in the near-IR region is emitted through the recognition-induced disassembly of the probe aggregate. This Cy5 fluorophore is a unique self assembly/disassembly dye as it gives remarkable fluorescence enhancement. Based on the same design, three different fluorogenic probes were constructed and one of them was applied for the no-wash imaging of tumor cells for the detection of hypoxia-induced cancer-specific biomarker, transmembrane-type carbonic anhydrase IX. PMID- 28717480 TI - Graphene related magnetic materials: micromechanical exfoliation of 2D layered magnets based on bimetallic anilate complexes with inserted [FeIII(acac2-trien)]+ and [FeIII(sal2-trien)]+ molecules. AB - The syntheses, structures and magnetic properties of the coordination compounds of formula [FeIII(acac2-trien)][MnIICrIII(Cl2 An)3].(CH3CN)2 (1), [FeIII(acac2 trien)][MnIICrIII(Br2An)3].(CH3CN)2 (2) and [GaIII(acac2 trien)][MnIICrIII(Br2An)3].(CH3CN)2 (3) are reported. They exhibit a 2D anionic network formed by Mn(ii) and Cr(iii) ions linked through anilate ligands, while the [FeIII(acac2-trien)]+ or [GaIII(acac2-trien)]+ charge-compensating cations are placed inside the hexagonal channels of the 2D network, instead of being inserted in the interlamellar spacing. Thus, these crystals are formed by hybrid layers assembled through van der Waals interactions. The magnetic properties indicate that these compounds behave as magnets exhibiting a long-range ferrimagnetic ordering at ca. 11 K, while the inserted Fe(iii) cations remain in the high-spin state. As for graphene, these layered materials can be exfoliated in atomically-thin layers with heights down to 2 nm by using the well-known Scotch tape method. Hence, this micromechanical procedure provides a suitable way to isolate ultrathin layers of this kind of graphene related magnetic materials. Interestingly, this method can also be successfully used to exfoliate the 2D anilate-based compound [FeIII(sal2-trien)][MnIICrIII(Cl2An)3].solv (4), which exhibits the typical alternated cation/anion layered structure. This result shows that the micromechanical exfoliation method, which has been extensively used for exfoliating van der Waals layered solids, can also be useful for exfoliating layered coordination compounds, even when they are formed by ionic components. PMID- 28717481 TI - Cytocompatible in situ cross-linking of degradable LbL films based on thiol exchange reaction. AB - Formation of both mechanically durable and programmably degradable layer-by-layer (LbL) films in a biocompatible fashion has potential applications in cell therapy, tissue engineering, and drug-delivery systems, where the films are interfaced with living cells. In this work, we developed a simple but versatile method for generating in situ cross-linked and responsively degradable LbL films, based on the thiol-exchange reaction, under highly cytocompatible conditions (aqueous solution at pH 7.4 and room temperature). The cytocompatibility of the processes was confirmed by coating individual yeast cells with the cross-linked LbL films and breaking the films on demand, while maintaining the cell viability. In addition, the processes were applied to the controlled release of an anticancer drug in the HeLa cells. PMID- 28717482 TI - Atomistic simulation of the growth of defect-free carbon nanotubes. AB - Atomistic simulation of defect-free single-walled carbon nanotube (SWCNT) growth is essential for the insightful understanding of the SWCNT's growth mechanism. Despite the extensive effort paid in the past two decades, the goal has not been completely achieved, due to the huge timescale discrepancy between atomistic simulation and the experimental synthesis of SWCNTs, as well as the lack of an accurate classical potential energy surface for large scale simulation. Here, we report atomistic simulations of defect-free SWCNT growth by using a new generation of carbon-metal potential and a hybrid method, in which a basin hopping strategy is applied to facilitate the defect healing during the simulation. The simulations reveal a narrow diameter distribution and an even chiral angle distribution of the growth of SWCNTs from liquid catalyst, which is in agreement with most known experimental observations. PMID- 28717483 TI - Achieving dynamic behaviour and thermal expansion in the organic solid state via co-crystallization. AB - Thermal expansion involves a response of a material to an external stimulus that typically involves an increase in a crystallographic axis (positive thermal expansion (PTE)), although shrinking with applied heat (negative thermal expansion (NTE)) is known in rarer cases. Here, we demonstrate a means to achieve dynamic molecular motion and thermal expansions in organic solids via co crystallizations. One co-crystal component is known to exhibit dynamic behaviour in the solid state while the second, when varied systematically, affords co crystals with linear thermal expansion coefficients that range from colossal to nearly zero. Two co-crystals exhibit rare NTE. We expect the approach to guide the design of molecular solids that enable predesigned motion related to thermal expansion processes. PMID- 28717484 TI - Experimental observation of TiN12+ cluster and theoretical investigation of its stable and metastable isomers. AB - TiN n+ clusters were generated by laser ablation and analyzed experimentally by mass spectrometry. The results showed that the mass peak of the TiN12+ cluster is dominant in the spectrum. The TiN12+ cluster was further investigated by photodissociation experiments with 266, 532 and 1064 nm photons. Density functional calculations were conducted to investigate stable structures of TiN12+ and the corresponding neutral cluster, TiN12. The theoretical calculations found that the most stable structure of TiN12+ is Ti(N2)6+ with Oh symmetry. The calculated binding energy is in good agreement with that obtained from the photodissociation experiments. The most stable structure of neutral TiN12 is Ti(N2)6 with D3d symmetry. The Ti-N bond strengths are greater than 0.94 eV in both Ti(N2)6+ and its neutral counterpart. The interaction between Ti and N2 weakens the N-N bond significantly. For neutral TiN12, the Ti(N3)4 azide, the N5TiN7 sandwich structure and the N6TiN6 structure are much higher in energy than the Ti(N2)6 complex. The DFT calculations predicted that the decomposition of Ti(N3)4, N5TiN7, and N6TiN6 into a Ti atom and six N2 molecules can release energies of about 139, 857, and 978 kJ mol-1 respectively. PMID- 28717485 TI - Double-walled pyr topology networks from a novel fluoride-bridged heptanuclear metal cluster. AB - Two isostructural metal-organic materials, Tripp-1-M (Tripp = 2,4,6-tris(4 pyridyl)pyridine; M = Co, Ni), that exhibit binodal 3,6-connected pyr network topology have been prepared and characterized. Tripp-1-M are based upon a novel M7F122+ cluster that possesses 12 connection points but, because of double cross linking by 3-connected Tripp ligands, it functions as a 6-connected supermolecular building block (SBB). PMID- 28717486 TI - UV-activated multilayer nanomatrix provides one-step tunable carbohydrate structural characterization in MALDI-MS. AB - The structure-specific fragmentation of gas-phase ions in tandem mass spectrometry among other techniques provides an efficient analytical method for confirming unknown analytes or for elucidating chemical structures. Using concentration-dependent UV-absorbing matrix-functionalized magnetic nanoparticles and matrix-assisted laser desorption-ionization mass spectrometry (MALDI MS), we developed a single-step pseudo-MS/MS approach for tunable ionization and fragmentation to facilitate structure determination. Without chemical derivatization, we have demonstrated that this approach successfully distinguished isomeric sets of di-, tri- and tetrasaccharides. Low concentration of nanomatrix provided an enhanced signal for accurate mass determination of the intact molecular ions of analytes present in the sample. In contrast, high concentration of nanomatrix induced extensive and unique fragmentation, including high-energy facile bond breakage (A- and X-type cross-ring cleavages), which facilitated the linkage and sequence characterization of oligosaccharides without conventional tandem mass spectrometric instrumentation. The practicality of this approach for complex sample analysis was evaluated by an oligosaccharide mixture, wherein molecular ions are unambiguously observed and signature product ions are distinguishable enough for molecular identification and isomer differentiation by this simple tunable approach. By probing the roles of the multilayer nanomatrix components: matrix (energy absorption), silane-coating (energy pooling and dissipation) and core Fe3O4 (fragmentation), a plausible energy transfer mechanism was proposed based on a computational study and photoelectron experiments. The differentiation of tri- and tetra-oligosaccharide shown in this study not only demonstrated the first step toward glycan characterization by nanoparticle-assisted MALDI-MS, but also shed some insight on the nanoparticle mediated energy transfer dynamics behind our approach. PMID- 28717487 TI - High fidelity sorting of remarkably similar components via metal-mediated assembly. AB - Subtle differences in ligand coordination angle and rigidity lead to high fidelity sorting between individual components displaying identical coordination motifs upon metal-mediated self-assembly. Narcissistic self-sorting can be achieved between highly similar ligands that vary minimally in rigidity and internal coordination angle upon combination with Fe(ii) ions and 2 formylpyridine. Selective, sequential cage formation can be precisely controlled in a single flask from a mix of three different core ligands (and 33 total components) differing only in the hybridization of one group that is uninvolved in the metal coordination process. PMID- 28717488 TI - Synthesis of triazolium-based mono- and tris-branched [1]rotaxanes using a molecular transporter of dibenzo-24-crown-8. AB - We report a diverted route to [1]rotaxane and tris-branched [1]rotaxane that are devoid of any efficient template and which could not be obtained by classical straightforward strategies. The described chemical route relies on the utilization of a "macrocycle transporter", which is able first to bind a macrocycle, second to link temporarily a triazolium-containing molecular axle, and third to deliver the macrocycle around the new docked axle through molecular machinery in a [1]rotaxane structure. The extended encircled thread is eventually cleaved by an amine or a triamine to afford the triazolium-containing [1]rotaxanes, releasing at the same time, the macrocycle transporter as a recyclable species. PMID- 28717489 TI - Structure observation of graphene quantum dots by single-layered formation in layered confinement space. AB - Graphene quantum dots (GQDs) have received much research attention due to their unique optical/electrical/magnetic features. However, the intrinsic relationship between the structure and properties of GQDs remains not fully understood, because the controlled synthesis and the accurate structure determination of GQDs are still a great challenge. Here, single-layered GQDs are successfully obtained by the hydrothermal treatment of intercalated citrate in the confined space of 2D interlayer galleries of layered double hydroxides (LDHs). The distinct molecular structures of the single-layered GQDs reveal that the blue photoluminescence of the GQDs derives from a rigid pi-conjugate plane structure, which is in accordance with theoretical calculations. This work will open the door towards a quantitative understanding of the structure-property effects of GQDs. PMID- 28717490 TI - Operando X-ray absorption and EPR evidence for a single electron redox process in copper catalysis. AB - An unprecedented single electron redox process in copper catalysis is confirmed using operando X-ray absorption and EPR spectroscopies. The oxidation state of the copper species in the interaction between Cu(ii) and a sulfinic acid at room temperature, and the accurate characterization of the formed Cu(i) are clearly shown using operando X-ray absorption and EPR evidence. Further investigation of anion effects on Cu(ii) discloses that bromine ions can dramatically increase the rate of the redox process. Moreover, it is proven that the sulfinic acids are converted into sulfonyl radicals, which can be trapped by 2-arylacrylic acids and various valuable beta-keto sulfones are synthesized with good to excellent yields under mild conditions. PMID- 28717491 TI - Unravelling the pH-dependence of a molecular photocatalytic system for hydrogen production. AB - Photocatalytic systems for the reduction of aqueous protons are strongly pH dependent, but the origin of this dependency is still not fully understood. We have studied the effect of different degrees of acidity on the electron transfer dynamics and catalysis taking place in a homogeneous photocatalytic system composed of a phosphonated ruthenium tris(bipyridine) dye (RuP) and a nickel bis(diphosphine) electrocatalyst (NiP) in an aqueous ascorbic acid solution. Our approach is based on transient absorption spectroscopy studies of the efficiency of photo-reduction of RuP and NiP correlated with pH-dependent photocatalytic H2 production and the degree of catalyst protonation. The influence of these factors results in an observed optimum photoactivity at pH 4.5 for the RuP-NiP system. The electron transfer from photo-reduced RuP to NiP is efficient and independent of the pH value of the medium. At pH <4.5, the efficiency of the system is limited by the yield of RuP photo-reduction by the sacrificial electron donor, ascorbic acid. At pH >4.5, the efficiency of the system is limited by the poor protonation of NiP, which inhibits its ability to reduce protons to hydrogen. We have therefore developed a rational strategy utilising transient absorption spectroscopy combined with bulk pH titration, electrocatalytic and photocatalytic experiments to disentangle the complex pH-dependent activity of the homogenous RuP-NiP photocatalytic system, which can be widely applied to other photocatalytic systems. PMID- 28717492 TI - Rational design of quinones for high power density biofuel cells. AB - Enzymatic fuel cells (EFCs) are devices that can produce electrical energy by enzymatic oxidation of energy-dense fuels (such as glucose). When considering bioanode construction for EFCs, it is desirable to use a system with a low onset potential and high catalytic current density. While these two properties are typically mutually exclusive, merging these two properties will significantly enhance EFC performance. We present the rational design and preparation of an alternative naphthoquinone-based redox polymer hydrogel that is able to facilitate enzymatic glucose oxidation at low oxidation potentials while simultaneously producing high catalytic current densities. When coupled with an enzymatic biocathode, the resulting glucose/O2 EFC possessed an open-circuit potential of 0.864 +/- 0.006 V, with an associated maximum current density of 5.4 +/- 0.5 mA cm-2. Moreover, the EFC delivered its maximum power density (2.3 +/- 0.2 mW cm-2) at a high operational potential of 0.55 V. PMID- 28717493 TI - Water diffusion in atmospherically relevant alpha-pinene secondary organic material. AB - Secondary organic material (SOM) constitutes a large mass fraction of atmospheric aerosol particles. Understanding its impact on climate and air quality relies on accurate models of interactions with water vapour. Recent research shows that SOM can be highly viscous and can even behave mechanically like a solid, leading to suggestions that particles exist out of equilibrium with water vapour in the atmosphere. In order to quantify any kinetic limitation we need to know water diffusion coefficients for SOM, but this quantity has, until now, only been estimated and has not yet been measured. We have directly measured water diffusion coefficients in the water soluble fraction of alpha-pinene SOM between 240 and 280 K. Here we show that, although this material can behave mechanically like a solid, at 280 K water diffusion is not kinetically limited on timescales of 1 s for atmospheric-sized particles. However, diffusion slows as temperature decreases. We use our measured data to constrain a Vignes-type parameterisation, which we extend to lower temperatures to show that SOM can take hours to equilibrate with water vapour under very cold conditions. Our modelling for 100 nm particles predicts that under mid- to upper-tropospheric conditions radial inhomogeneities in water content produce a low viscosity surface region and more solid interior, with implications for heterogeneous chemistry and ice nucleation. PMID- 28717494 TI - HOCl can appear in the mitochondria of macrophages during bacterial infection as revealed by a sensitive mitochondrial-targeting fluorescent probe. AB - Macrophages, important cells of the innate immune system, can produce abundant HOCl in the cytoplasm to fight against bacteria. Recent studies suggest that mitochondria in macrophages play a role in antibacterial responses. During bacterial infection, however, it is uncertain whether HOCl is present in the mitochondria, mainly because of the lack of a suitable research method. Herein, by developing a new mitochondrial-targeting fluorescent HOCl probe, combined with confocal fluorescence imaging, we show for the first time that HOCl can appear in the mitochondria of macrophages (Raw264.7 cells) during bacterial infection, as confirmed with non-phagocytic cells and inhibitors as control experiments. Moreover, the developed probe exhibits an accurate mitochondrial-targeting ability, a fast response, and high selectivity and sensitivity (detection limit 9 nM), and is thus expected to be employed for further revealing the biological function of subcellular mitochondria. PMID- 28717495 TI - Self-assembling 1D core/shell microrods by the introduction of additives: a one pot and shell-tunable method. AB - Herein, we have developed a one-pot method for the fabrication of one-dimensional core/shell microrods with tunable shell compositions by the introduction of additives. Crystalline dimethyl melamine hydrochloride was utilized as the core, while melamine derivatives with different functional groups, such as pyrene, thiophene and naphthalene diimide, served as additives to regulate the core morphology and were adsorbed as the shell. The length and width of these one dimensional structures can be tuned by varying the molar ratio of core and shell molecules as well as their total concentration. Through X-ray diffraction, the detailed molecular arrangements within the core of the microrods were revealed, and the selective effect of additives on specific crystal faces was evaluated. It is anticipated that this work may provide a facile approach for the fabrication of one-dimensional functional materials. PMID- 28717496 TI - Supramolecular hydrogel microcapsules via cucurbit[8]uril host-guest interactions with triggered and UV-controlled molecular permeability. AB - Host-guest assembly in droplet-based microfluidics opens a new avenue for fabricating supramolecular hydrogel microcapsules with high monodispersity and controlled functionality. In this paper, we demonstrate a single emulsion microdroplet platform to prepare microcapsules with supramolecular hydrogel skins from host molecule cucurbit[8]uril and guest polymer anthracene-functionalized hydroxyethyl cellulose. In contrast to construction of microcapsules from a droplet-in-droplet double emulsion, here the electrostatic attraction between charged polymer and surfactant facilitates formation of defined supramolecular hydrogel skins in a single emulsion. Furthermore, by taking advantage of dynamic interactions and the tunable cross-linked supramolecular hydrogel network, it is possible to prepare microcapsules with triggered and UV-controlled molecular permeability. These could be potentially used in a delivery system for e.g. agrochemicals, nutraceuticals or cosmetics. PMID- 28717497 TI - Well-defined aqueous nanoassemblies from amphiphilic meta-terphenyls and their guest incorporation. AB - Spherical molecular assemblies with diameters of ~2 nm were quantitatively formed in water from new amphiphilic meta-terphenyls with two hydrophilic pendants at the central benzene ring. Whereas intermolecular interactions between small aromatic rings are typically weak, the obtained nanoassemblies are stable enough at wide-ranging concentrations and mostly remain intact even in the presence of similar nanoassemblies with polyaromatic frameworks. The nanoassembly with pentamethyl-substituted terminal benzene rings provides superior host capability for fluorescent dyes in water. PMID- 28717498 TI - NKT cell-dependent glycolipid-peptide vaccines with potent anti-tumour activity. AB - It is known that T cells can eliminate tumour cells through recognition of unique or aberrantly expressed antigens presented as peptide epitopes by major histocompatibility complex (MHC) molecules on the tumour cell surface. With recent advances in defining tumour-associated antigens, it should now be possible to devise therapeutic vaccines that expand specific populations of anti-tumour T cells. However there remains a need to develop simpler efficacious synthetic vaccines that possess clinical utility. We present here the synthesis and analysis of vaccines based on conjugation of MHC-binding peptide epitopes to alpha-galactosylceramide, a glycolipid presented by the nonpolymorphic antigen presenting molecule CD1d to provoke the stimulatory activity of type I natural killer T (NKT) cells. The chemical design incorporates an enzymatically cleavable linker that effects controlled release of the active components in vivo. Chemical and biological analysis of different linkages with different enzymatic targets enabled selection of a synthetic vaccine construct with potent therapeutic anti tumour activity in mice, and marked in vitro activity in human blood. PMID- 28717499 TI - CO2 induced phase transitions in diamine-appended metal-organic frameworks. AB - Using a combination of density functional theory and lattice models, we study the effect of CO2 adsorption in an amine functionalized metal-organic framework. These materials exhibit a step in the adsorption isotherm indicative of a phase change. The pressure at which this step occurs is not only temperature dependent but is also metal center dependent. Likewise, the heats of adsorption vary depending on the metal center. Herein we demonstrate via quantum chemical calculations that the amines should not be considered firmly anchored to the framework and we explore the mechanism for CO2 adsorption. An ammonium carbamate species is formed via the insertion of CO2 into the M-Namine bonds. Furthermore, we translate the quantum chemical results into isotherms using a coarse grained Monte Carlo simulation technique and show that this adsorption mechanism can explain the characteristic step observed in the experimental isotherm while a previously proposed mechanism cannot. Furthermore, metal analogues have been explored and the CO2 binding energies show a strong metal dependence corresponding to the M-Namine bond strength. We show that this difference can be exploited to tune the pressure at which the step in the isotherm occurs. Additionally, the mmen-Ni2(dobpdc) framework shows Langmuir like behavior, and our simulations show how this can be explained by competitive adsorption between the new model and a previously proposed model. PMID- 28717500 TI - Beyond a solvent: the roles of 1-butyl-3-methylimidazolium chloride in the acid catalysis for cellulose depolymerisation. AB - In this report, 1-butyl-3-methylimidazolium chloride ([C4C1im]Cl) is demonstrated to enhance the kinetics of acid-catalysed hydrolysis of 1,4-beta-glucans in binary solvent mixtures. [C4C1im]Cl plays other roles in the reaction beyond acting as a solvent for cellulose, as currently accepted. In fact, the presence of the IL increases the Hammett acidity of the catalyst dissolved in the reaction medium. The kinetic data from cellobiose and cellulose hydrolysis directly correlate with the acid strength found for p-toluenesulfonic acid in the different reaction media studied here. The current report identifies neglected, but yet very important phenomena occurring in cellulose depolymerisation. PMID- 28717501 TI - A soluble molecular variant of the semiconducting silicondiselenide. AB - Silicondiselenide is a semiconductor and exists as an insoluble polymer (SiSe2) n which is prepared by reacting elemental silicon with selenium powder in the temperature range of 400-850 degrees C. Herein, we report on the synthesis, isolation, and characterization of carbene stabilized molecular silicondiselenide in the form of (cAAC)2Si2Se4 (3) [cAAC = cyclic alkyl(amino)carbene]. 3 is synthesized via reaction of diatomic silicon(0) compound (cAAC)2Si2 (2) with black selenium powder at -78 degrees C to room temperature. The intensely orange colored compound 3 is soluble in polar organic solvents and stable at room temperature for a month under an inert atmosphere. 3 decomposes above 245 degrees C. The molecular structure of 3 has been confirmed by X-ray single crystal diffraction. It is also characterized by UV-vis, IR, Raman spectroscopy and mass spectrometry. The stability, bonding, and electron density distributions of 3 have been studied by theoretical calculations. PMID- 28717502 TI - An inhibitor of ubiquitin conjugation and aggresome formation. AB - Proteasome inhibitors have revolutionized the treatment of multiple myeloma, and validated the therapeutic potential of the ubiquitin proteasome system (UPS). It is believed that in part, proteasome inhibitors elicit their therapeutic effect by inhibiting the degradation of misfolded proteins, which is proteotoxic and causes cell death. In spite of these successes, proteasome inhibitors are not effective against solid tumors, thus necessitating the need to explore alternative approaches. Furthermore, proteasome inhibitors lead to the formation of aggresomes that clear misfolded proteins via the autophagy-lysosome degradation pathway. Importantly, aggresome formation depends on the presence of polyubiquitin tags on misfolded proteins. We therefore hypothesized that inhibitors of ubiquitin conjugation should inhibit both degradation of misfolded proteins, and ubiquitin dependent aggresome formation, thus outlining the path forward toward more effective anticancer therapeutics. To explore the therapeutic potential of targeting the UPS to treat solid cancers, we have developed an inhibitor of ubiquitin conjugation (ABP A3) that targets ubiquitin and Nedd8 E1 enzymes, enzymes that are required to maintain the activity of the entire ubiquitin system. We have shown that ABP A3 inhibits conjugation of ubiquitin to intracellular proteins and prevents the formation of cytoprotective aggresomes in A549 lung cancer cells. Furthermore, ABP A3 induces activation of the unfolded protein response and apoptosis. Thus, similar to proteasome inhibitors MG132, bortezomib, and carfilzomib, ABP A3 can serve as a novel probe to explore the therapeutic potential of the UPS in solid and hematological malignancies. PMID- 28717503 TI - Self-assembly of a mesoporous ZnS/mediating interface/CdS heterostructure with enhanced visible-light hydrogen-production activity and excellent stability. AB - We designed and successfully fabricated a ZnS/CdS 3D mesoporous heterostructure with a mediating Zn1-x Cd x S interface that serves as a charge carrier transport channel for the first time. The H2-production rate and the stability of the heterostructure involving two sulfides were dramatically and simultaneously improved by the careful modification of the interface state via a simple post annealing method. The sample prepared with the optimal parameters exhibited an excellent H2-production rate of 106.5 mmol h-1 g-1 under visible light, which was 152 and 966 times higher than CdS prepared using ethylenediamine and deionized water as the solvent, respectively. This excellent H2-production rate corresponded to the highest value among the CdS-based photocatalysts. Moreover, this heterostructure showed excellent photocatalytic stability over 60 h. PMID- 28717504 TI - Cucurbit[8]uril directed stimuli-responsive supramolecular polymer brushes for dynamic surface engineering. AB - In situ modification of surfaces with thin layers of polymers is of growing interest as adjustment of surface properties can be made on demand. We present herein a supramolecular 'grafting to' polymer brush via the recognition of surface-bound cucurbit[8]uril (CB[8]) rotaxanes towards end-functionalised polyethylene glycol (PEG). This dynamic supramolecular method represents advantages over traditional approaches, which employ covalent bond formation in the 'grafting to' process. Brush properties can be easily modified post preparation by exchanging the polymers with small molecules in a controlled, reversible manner. Including both redox- and light-responsive guests in a single rotaxane entity, the CB[8]-mediated preparation of the polymer brush offers unique opportunities to switch the brush composition efficiently. While the PEG brushes are well hydrated in a good solvent (water) and stretch away from the surface, they collapse in a poor solvent (toluene), leading to the formation of a dense layer on the surface. This collapsed conformation protects the heteroternary complexes of CB[8]-rotaxane from dissociation and maintains the attachment of polymers on the surface. PMID- 28717505 TI - Correction: Impact of mechanical stretch on the cell behaviors of bone and surrounding tissues. AB - [This corrects the article DOI: 10.1177/2041731415618342.]. PMID- 28717506 TI - Injectable scaffold materials differ in their cell instructive effects on primary human myoblasts. AB - Scaffolds are materials used for delivery of cells for regeneration of tissues. They support three-dimensional organization and improve cell survival. For the repair of small skeletal muscles, injections of small volumes of cells are attractive, and injectable scaffolds for delivery of cells offer a minimally invasive technique. In this study, we examined in vitro the cell instructive effects of three types of injectable scaffolds, fibrin, alginate, and poly(lactic co-glycolic acid)-based microparticles on primary human myoblasts. The myoblast morphology and progression in the myogenic program differed, depending on the type of scaffold material. In alginate gel, the cells obtained a round morphology, they ceased to proliferate, and entered quiescence. In the fibrin gels, differentiation was promoted, and myotubes were observed within a few days in culture, while poly(lactic-co-glycolic acid)-based microparticles supported prolonged proliferation. Myoblasts released from the alginate and fibrin gels were studied, and cells released from these scaffolds had retained the ability to proliferate and differentiate. Thus, the study shows that human myogenic cells combined with injectable scaffold materials are guided into different states depending on the choice of scaffold. This opens for in vivo experiments, including testing of the significance of the cell state on regeneration potential of primary human myoblasts. PMID- 27703668 TI - Protein domain architectures provide a fast, efficient and scalable alternative to sequence-based methods for comparative functional genomics. AB - A functional comparative genome analysis is essential to understand the mechanisms underlying bacterial evolution and adaptation. Detection of functional orthologs using standard global sequence similarity methods faces several problems; the need for defining arbitrary acceptance thresholds for similarity and alignment length, lateral gene acquisition and the high computational cost for finding bi-directional best matches at a large scale. We investigated the use of protein domain architectures for large scale functional comparative analysis as an alternative method. The performance of both approaches was assessed through functional comparison of 446 bacterial genomes sampled at different taxonomic levels. We show that protein domain architectures provide a fast and efficient alternative to methods based on sequence similarity to identify groups of functionally equivalent proteins within and across taxonomic boundaries, and it is suitable for large scale comparative analysis. Running both methods in parallel pinpoints potential functional adaptations that may add to bacterial fitness. PMID- 27990266 TI - Breeding novel solutions in the brain: a model of Darwinian neurodynamics. AB - Background: The fact that surplus connections and neurons are pruned during development is well established. We complement this selectionist picture by a proof-of-principle model of evolutionary search in the brain, that accounts for new variations in theory space. We present a model for Darwinian evolutionary search for candidate solutions in the brain. Methods: We combine known components of the brain - recurrent neural networks (acting as attractors), the action selection loop and implicit working memory - to provide the appropriate Darwinian architecture. We employ a population of attractor networks with palimpsest memory. The action selection loop is employed with winners-share-all dynamics to select for candidate solutions that are transiently stored in implicit working memory. Results: We document two processes: selection of stored solutions and evolutionary search for novel solutions. During the replication of candidate solutions attractor networks occasionally produce recombinant patterns, increasing variation on which selection can act. Combinatorial search acts on multiplying units (activity patterns) with hereditary variation and novel variants appear due to (i) noisy recall of patterns from the attractor networks, (ii) noise during transmission of candidate solutions as messages between networks, and, (iii) spontaneously generated, untrained patterns in spurious attractors. Conclusions: Attractor dynamics of recurrent neural networks can be used to model Darwinian search. The proposed architecture can be used for fast search among stored solutions (by selection) and for evolutionary search when novel candidate solutions are generated in successive iterations. Since all the suggested components are present in advanced nervous systems, we hypothesize that the brain could implement a truly evolutionary combinatorial search system, capable of generating novel variants. PMID- 28663784 TI - The internet trade of counterfeit spirits in Russia - an emerging problem undermining alcohol, public health and youth protection policies? AB - Counterfeit alcohol belongs to the category of unrecorded alcohol not reflected in official statistics. The internet trade of alcoholic beverages has been prohibited by the Russian Federation since 2007, but various sellers still offer counterfeit spirits (i.e., forged brand spirits) over the internet to Russian consumers, mostly in a non-deceptive fashion at prices up to 15 times lower than in regular sale. The public health issues arising from this unregulated trade include potential harm to underage drinkers, hazards due to toxic ingredients such as methanol, but most importantly alcohol harms due to potentially increased drinking volumes due to low prices and high availability on the internet. The internet sale also undermines existing alcohol policies such as restrictions of sale locations, sale times and minimum pricing. The need to enforce measures against counterfeiting of spirits, but specifically their internet trade should be implemented as key elements of alcohol policies to reduce unrecorded alcohol consumption, which is currently about 33 % of total consumption in Russia. PMID- 28717510 TI - Post-obstructive pulmonary edema from aspirated nuts. AB - OBJECTIVES: Post-obstructive pulmonary edema is thought to occur from hemodynamic changes secondary to forced inspiration against the closed airway due to acute or chronic airway obstruction. We report a case of a 13 month-old boy who developed pulmonary edema from aspirated foreign body, nuts. METHODS: He underwent emergency bronchoscopy to confirm the clinical diagnosis of aspirated nuts in the trachea and nuts were removed endoscopically. His trachea was then intubated and he was mechanically ventilated with oxygen. RESULTS: He developed florid pulmonary edema early in the course with tracheal obstruction and during endoscopic removal of nuts. After removal of obstruction he was ventilated mechanically and pulmonary edema cleared rapidly. CONCLUSIONS: Aspirated nuts obstructing trachea can induce obstructive pulmonary edema. Early recognition of foreign body obstruction based on clinical history and its removal resolved pulmonary edema. PMID- 28717511 TI - Thalamotomy for essential tremor: FDA approval brings brain treatment with FUS to the clinic. PMID- 28717512 TI - Trauma-related emotions and radical acceptance in dialectical behavior therapy for posttraumatic stress disorder after childhood sexual abuse. AB - BACKGROUND: Posttraumatic Stress Disorder (PTSD) related to childhood sexual abuse (CSA) is often associated with a wide range of trauma-related aversive emotions such as fear, disgust, sadness, shame, guilt, and anger. Intense experience of aversive emotions in particular has been linked to higher psychopathology in trauma survivors. Most established psychosocial treatments aim to reduce avoidance of trauma-related memories and associated emotions. Interventions based on Dialectical Behavior Therapy (DBT) also foster radical acceptance of the traumatic event. METHODS: This study compares individual ratings of trauma-related emotions and radical acceptance between the start and the end of DBT for PTSD (DBT-PTSD) related to CSA. We expected a decrease in trauma-related emotions and an increase in acceptance. In addition, we tested whether therapy response according to the Clinician Administered PTSD-Scale (CAPS) for the DSM-IV was associated with changes in trauma-related emotions and acceptance. The data was collected within a randomized controlled trial testing the efficacy of DBT-PTSD, and a subsample of 23 women was included in this secondary data analysis. RESULTS: In a multilevel model, shame, guilt, disgust, distress, and fear decreased significantly from the start to the end of the therapy whereas radical acceptance increased. Therapy response measured with the CAPS was associated with change in trauma-related emotions. CONCLUSIONS: Trauma related emotions and radical acceptance showed significant changes from the start to the end of DBT-PTSD. Future studies with larger sample sizes and control group designs are needed to test whether these changes are due to the treatment. TRIAL REGISTRATION: ClinicalTrials.gov, number NCT00481000. PMID- 28717514 TI - Gyrations in African Mortality and their Effect on Economic Growth. AB - I examine recent changes in African mortality and discuss their potential economic and demographic effects. Growth in life expectancy sharply departed from its trend after 1990, and then experienced a sharp acceleration after 2005. This latter acceleration was due overwhelmingly to improvements in HIV and malaria. Economists differ in their estimates of how large the structural effect of health on income is, with many estimates being relatively small. Taking seriously the delays built into many plausible causal channels would lead one to expect that any economic effects of these mortality changes, if they are detectable at all, will not appear for several decades. By contrast, the effect of declining mortality, especially from malaria, should soon be visible in data on population age structure in some countries. PMID- 28717513 TI - Unexpected intensive care transfer of admitted patients with severe sepsis. AB - BACKGROUND: Patients with severe sepsis generally respond well to initial therapy administered in the emergency department (ED), but a subset later decompensate and require unexpected transfer to the intensive care unit (ICU). This study aimed to identify clinical factors that can predict patients at increased risk for delayed transfer to the ICU and the association of delayed ICU transfer with mortality. METHODS: This is a nested case-control study in a prospectively collected registry of patients with severe sepsis and septic shock at two EDs. Cases had severe sepsis and unexpected ICU transfer within 48 h of admission from the ED; controls had severe sepsis but remained in a non-ICU level of care. Univariate and multivariate regression analyses were used to identify predictors of unexpected transfer to the ICU, which was the primary outcome. Differences in mortality between these two groups as well as a cohort of patients directly admitted to the ICU were also calculated. RESULTS: Of the 914 patients in our registry, 358 patients with severe sepsis were admitted from the ED to non-ICU level of care; 84 (23.5%) had unexpected ICU transfer within 48 h. Demographics and baseline co-morbidity burden were similar for patients requiring versus not requiring delayed ICU transfer. In unadjusted analysis, lactate >=4 mmol/L and infection site were significantly associated with unexpected ICU upgrade. In forward selection multivariate logistic regression analysis, lactate >=4 mmol/L (OR 2.0, 95% CI 1.03, 3.73; p = 0.041) and night (5 PM to 7 AM) admission (OR 1.9, 95% CI 1.07, 3.33; p = 0.029) were independent predictors of unexpected ICU transfer. Mortality of patients who were not upgraded to the ICU was 8.0%. Patients with unexpected ICU upgrade had similar mortality (25.0%) to those patients with severe sepsis/septic shock (24.6%) who were initially admitted to the ICU, despite less severe indices of illness at presentation. CONCLUSIONS: Serum lactate >=4 mmol/L and nighttime admissions are associated with unexpected ICU transfer in patients with severe sepsis. Mortality among patients with delayed ICU upgrade was similar to that for patients initially admitted directly to the ICU. PMID- 28717515 TI - Changing Needs for Information and Support in an Online System for Parents of Children With Kidney Disease. AB - BACKGROUND: Pediatric chronic kidney disease is psychologically, financially, and physically demanding on parents providing care. Parents often feel isolated because of the rarity of the condition, and geographic isolation often compounds this perception in Canada. Many parents seek assistance online for both information and social support. OBJECTIVE: This study examines an online portal, titled "Ability Online," which was designed to provide support and information to a diverse group of parents using chat facilities, bulletin boards, and e-mail. Specifically, we sought to identify how the technologies offered in this system related to the support and information seeking needs for parents. Secondary aims of determining possible reasons for attrition over time were explored as well. DESIGN: Mixed methodology sequential exploratory design using the qualitative methodology of descriptive interpretation. SETTING: Telephone interviews. PATIENTS: Twenty parents of pediatric patients with chronic kidney disease from four Canadian centers who engaged in an online social support system "Ability Online." MEASUREMENTS: Interview transcripts generated from 20 taped phone conversations were reviewed from parents who engaged in the online system, and the themes derived from these transcripts served to generate semistructured interview questions that focused on their use of, and perceived benefit from, this technology for social support. Follow-up telephone interviews were then conducted with a 6-person subset of the original group in an effort to further define the impact of technology on their experience. This same smaller cohort provided data on social supports, caregiver satisfaction, and caregiver stress. RESULTS: Many parents experience a progression through which their needs for knowledge and support change over time. Specifically, parents describe a transition from pure information seeking, to seeking parental interaction, mutual support and collaboration, and ultimately to advocacy. Parents described how technology could be used to address those needs. LIMITATIONS: Our cohort was slightly more educated and representative of more urban populations than published data reflecting the population of North American pediatric patients living with kidney disease. CONCLUSIONS: Our data suggest themes of technology use influencing the goals of online support seeking. While our findings are preliminary, further study may inform Web designers to identify the changing needs of participants in designing such online support networks, and minimize the reasons that participants fail to adopt, or terminate their online experiences. PMID- 28717516 TI - Costs Associated With Intravenous Darbepoetin Versus Epoetin Therapy in Hemodialysis Patients: A Randomized Controlled Trial. AB - BACKGROUND: Anemia of chronic kidney disease is associated with adverse outcomes and a reduced quality of life. Erythropoiesis-stimulating agents (ESAs) have improved anemia management, and 2 agents are available in Canada, epoetin alfa (EPO) and darbepoetin alfa (DA). EPO and DA are considered equally effective in achieving target hemoglobin (Hb), but it is not clear whether there is a cost difference. There have been few head-to-head comparisons; most published studies are observational switch studies. OBJECTIVE: To compare the cost of DA and EPO and to determine the dose conversion ratio over a 12-month period. DESIGN: Randomized controlled trial. SETTING: Canadian outpatient hemodialysis center. PATIENTS: Eligible patients were adult hemodialysis patients requiring ESA therapy. MEASUREMENTS: The primary outcome was ESA cost (Can$) per patient over 12 months. Secondary outcomes included the dose conversion ratio, deviation from target ranges in anemia indices, iron dose and cost, and time and number of dose changes. METHODS: An open-label randomized controlled trial of intravenous (IV) DA versus EPO was conducted in 50 hemodialysis patients. Participants underwent a minimum 6-week run-in phase followed by a 12-month active study phase. ESA and iron were dosed using a study algorithm. RESULTS: The median cost was $4179 (interquartile range [IQR]: $2416-$5955) for EPO and $2303 (IQR: $1178-$4219) for DA with a difference of $1876 (P = .02). The dose conversion ratio was 280:1 (95% confidence interval [CI]: 197-362:1) at the end of the run-in phase, 360:1 (95% CI: 262-457:1) at the 3-month point of the active phase, and 382:1 (95% CI: 235 529:1) at the 6-month point of the active phase. There were no significant differences between the 2 groups in weekly iron dose, Hb, serum ferritin, or transferrin saturation. The number of dose changes and the time to Hb stability were similar. LIMITATIONS: Results may not be generalizable to hemodialysis units without algorithm-based anemia management, with subcutaneous ESA administration, or to the nondialysis chronic kidney disease population. The effective conversion ratio between EPO and DA is known to increase at higher doses; the Hb targets used in the study were slightly higher than those recommended today so it is possible that the doses used were also higher. Because of this, the cost savings estimated for DA could differ somewhat from the savings realizable in current practice. CONCLUSIONS: In this study of hemodialysis patients with comparable anemia management, IV DA cost $1876 less per year per patient than IV EPO. The dose conversion ratio was greater than 350:1 by the 3-month point. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02817555). PMID- 28717518 TI - The sharing of radiological images by professional mixed martial arts fighters on social media. AB - BACKGROUND: Mixed martial arts is a sport that has recently enjoyed a significant increase in popularity. This rise in popularity has catapulted many of these "cage fighters" into stardom and many regularly use social media to reach out to their fans. An interesting result of this interaction on social media is that athletes are sharing images of their radiological examinations when they sustain an injury. PURPOSE: To review instances where mixed martial arts fighters shared images of their radiological examinations on social media and in what context they were shared. MATERIAL AND METHODS: An Internet search was performed using the Google search engine. Search terms included "MMA," "mixed martial arts," "injury," "scan," "X-ray," "fracture," and "break." Articles which discussed injuries to MMA fighters were examined and those in which the fighter themselves shared a radiological image of their injury on social media were identified. RESULTS: During our search, we identified 20 MMA fighters that had shared radiological images of their injuries on social media. There were 15 different types of injury, with a fracture of the mid-shaft of the ulna being the most common. The most popular social media platform was Twitter. The most common imaging modality X-ray (71%). The majority of injuries were sustained during competition (81%) and 35% of these fights resulted in a win for the fighter. CONCLUSION: Professional mixed martial artists are sharing radiological images of their injuries on social media. This may be in an attempt to connect with fans and raise their profile among other fighters. PMID- 28717517 TI - Knowledge mapping visualization analysis of the military health and medicine papers published in the web of science over the past 10 years. AB - BACKGROUND: Military medicine is a research field that seeks to solve the medical problems that occur in modern war conditions based on public medicine theory. METHODS: We explore the main research topics of military health and medical research in the web of scienceTM core collection (WoSCC) from 2007 to 2016, and the goal of this work is to serve as a reference for orientation and development in military health and medicine. Based on CiteSpace III, a reference co-citation analysis is performed for 7921 papers published in the WoSCC from 2007 to 2016. In addition, a cluster analysis of research topics is performed with a comprehensive analysis of high-yield authors, outstanding research institutions and their cooperative networks. RESULTS: Currently, the research topics in military health and medicine mainly focus on the following seven aspects: mental health diagnoses and interventions, an army study to assess risk and resilience in service members (STARRS), large-scale military action, brain science, veterans, soldier parents and children of wartime, and wound infection. We also observed that the annual publication rate increased with time. Wessely S, Greenberg N, Fear NT, Smith TC, Smith B, Jones N, Ryan MAK, Boyko EJ, Hull L, and Rona RJ were the top 10 authors in military health and medicine research. The top 10 institutes were the Uniformed Services University of the Health Sciences, the United States Army, the United States Navy, Kings College London, Walter Reed National Military Medical Center, Boston University, Walter Reed Army Institute of Research, Walter Reed Army Medical Center, Naval Health Research Center, and the VA Boston Healthcare System. CONCLUSIONS: We are able to perform a comprehensive analysis of studies in military health and medicine research and summarize the current research climate and the developmental trends in the WoSCC. However, further studies and collaborations are needed worldwide. Overall, our findings provide valuable information and new perspectives and shape future research directions for further research in the area of military health and medicine. PMID- 28717519 TI - The diagnostic accuracy of ultrasonography for soft tissue lipomas: a systematic review. AB - BACKGROUND: Ultrasound has been used in the diagnosis of soft-tissue lesions for well over a decade. Lipomas are the most common, benign, soft-tissue tumor and comprise adipose tissue. The sensitivity and specificity of diagnosing lipomas on ultrasound vary greatly in the literature. PURPOSE: To perform a systematic review on ultrasonography in soft-tissue lipomas to better ascertain the true diagnostic value of this test. MATERIAL AND METHODS: A systematic review of the diagnostic value of ultrasound in lipomas was performed where possible in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A comprehensive search of the literature was conducted using several well-known databases Scopus(r), PubMed(r), Ovid(r) Medline, and Web of Science(r). RESULTS: A total of 455 articles were identified in the initial literature search. Six papers were included in the final systematic review, which revealed an overall sensitivity and specificity of 86.87% (95% confidence interval [CI] = 82.14-90.73) and 95.95% (95% CI = 93.75-97.54), respectively. CONCLUSION: Ultrasound is a useful tool in the diagnosis of superficial lipomas with good sensitivity and even better specificity and should continue to be the first line investigation in such cases. PMID- 28717520 TI - Modeling Chronic Dacryocystitis in Rabbits by Nasolacrimal Duct Obstruction with Self-Curing Resin. AB - We established a chronic dacryocystitis model by injecting of 0.05, 0.1, and 0.15 ml self-curing resin via the lacrimal punctum in rabbits. Animals were randomized into four groups (n = 11 animals/group). The control group received 0.15 ml normal saline. Within three months postinjection, epiphora and eye discharge were observed. At the 90th day postlacrimal passage irrigation, CT dacryocystography was performed to find changes in the lacrimal image, and hematoxylin and eosin staining was made to identify pathological changes of the lacrimal sac. Three months postinjection, the rabbits in control group and those who received 0.05 and 0.1 ml self-curing resin failed to develop chronic dacryocystitis. However, 8/11 (72.7%) rabbits those received 0.15 ml self-curing resin were symptomatic and showed complete reflux in lacrimal passage irrigation, indicating the obstruction of the nasolacrimal duct. CT dacryocystography showed that the obstruction was present only in the animals with chronic dacryocystitis. Pathological examinations of chronic dacryocystitis also revealed significantly inflammatory changes, such as mucus epithelium thickening, irregular papillary proliferation, and submucosal fibrous deposition. Local injection of 0.15 ml self curing resin can induce permanent obstruction of the nasolacrimal duct in rabbits and establish a model of chronic dacryocystitis. PMID- 28717521 TI - Improving and Predicting Outcomes of Traumatic Brain Injury: Neuroplasticity, Imaging Modalities, and Perspective Therapy. PMID- 28717523 TI - Assessment of Emotional Expressions after Full-Face Transplantation. AB - We assessed clinical features as well as sensory and motor recoveries in 3 full face transplantation patients. A frequency analysis was performed on facial surface electromyography data collected during 6 basic emotional expressions and 4 primary facial movements. Motor progress was assessed using the wavelet packet method by comparison against the mean results obtained from 10 healthy subjects. Analyses were conducted on 1 patient at approximately 1 year after face transplantation and at 2 years after transplantation in the remaining 2 patients. Motor recovery was observed following sensory recovery in all 3 patients; however, the 3 cases had different backgrounds and exhibited different degrees and rates of sensory and motor improvements after transplant. Wavelet packet energy was detected in all patients during emotional expressions and primary movements; however, there were fewer active channels during expressions in transplant patients compared to healthy individuals, and patterns of wavelet packet energy were different for each patient. Finally, high-frequency components were typically detected in patients during emotional expressions, but fewer channels demonstrated these high-frequency components in patients compared to healthy individuals. Our data suggest that the posttransplantation recovery of emotional facial expression requires neural plasticity. PMID- 28717524 TI - Anasarca, Fever, Thrombocytopenia, Organomegaly, and Multiorgan Failure in a 24 Year-Old Pregnant Woman. AB - TAFRO syndrome is a distinct idiopathic multicentric Castleman disease characterized by the association of thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly. We report the first case occurring in a Caucasian pregnant woman. At 34 weeks of gestation, our patient presented with all clinical and biological symptoms compatible with a TAFRO syndrome. Tough quick cesarean section was performed as symptoms got worse with onset of multiorgan failure requiring mechanical ventilation for acute respiratory distress, continuous renal replacement, and vasopressors. Nine days after ICU admission, steroid boluses were started and allowed spectacular clinical and biological improvement. As systemic inflammatory manifestations are important, TAFRO syndrome can be mistaken with severe autoimmune diseases, systemic infections, hematological malignancies, or hemophagocytic lymphohistiocytosis. PMID- 28717522 TI - Effect of Hypoxic Injury in Mood Disorder. AB - Hypoxemia is a common complication of the diseases associated with the central nervous system, and neurons are highly sensitive to the availability of oxygen. Neuroplasticity is an important property of the neural system controlling breathing, memory, and cognitive ability. However, the underlying mechanism has not yet been clearly elucidated. In recent years, several pieces of evidence have highlighted the effect of hypoxic injury on neuronal plasticity in the pathogenesis and treatment of mood disorder. Therefore, the present study reviewed the relevant articles regarding hypoxic injury and neuronal plasticity and discussed the pathological changes and physiological functions of neurons in hypoxemia in order to provide a translational perspective to the relevance of hypoxic injury and mood disorder. PMID- 28717525 TI - Differential Effects of Awake Glioma Surgery in "Critical" Language Areas on Cognition: 4 Case Studies. AB - Awake surgery with electrocorticosubcortical stimulation is the golden standard treatment for gliomas in eloquent areas. Preoperatively, mostly mild cognitive disturbances are observed with postoperative deterioration. We describe pre- and postoperative profiles of 4 patients (P1-P4) with gliomas in "critical" language areas ("Broca," "Wernicke," and the arcuate fasciculus) undergoing awake surgery to get insight into the underlying mechanism of neuroplasticity. Neuropsychological examination was carried out preoperatively (at T1) and postoperatively (at T2, T3). At T1, cognition of P1 was intact and remained stable. P2 had impairments in all cognitive domains at T1 with further deterioration at T2 and T3. At T1, P3 had impairments in memory and executive functions followed by stable recovery. P4 was intact at T1, followed by a decline in a language test at T2 and recovery at T3. Intraoperatively, in all patients language positive sites were identified. Patients with gliomas in "critical" language areas do not necessarily present cognitive disturbances. Surgery can either improve or deteriorate (existing) cognitive impairments. Several factors may underlie the plastic potential of the brain, for example, corticosubcortical networks and tumor histopathology. Our findings illustrate the complexity of the underlying mechanism of neural plasticity and provide further support for a "hodotopical" viewpoint. PMID- 28717526 TI - Large Cholesterol Granuloma of the Middle Ear Eroding into the Middle Cranial Fossa. AB - BACKGROUND: Cholesterol granuloma of the middle ear is extremely rare in comparison to cholesterol granuloma of the petrous apex but sometimes shows an aggressive course. CASE REPORT: We report herein a case involving a large, aggressive cholesterol granuloma of the middle ear that eroded the middle cranial fossa. A 64-year-old woman presented with pain in the left ear and hearing loss. Cholesterol granuloma was finally diagnosed from diffusion-weighted imaging, and cortical mastoidectomy was performed with canal wall down tympanoplasty type III. Recovery was uneventful recovery and the patient well at the 3-year follow-up. CONCLUSION: This case demonstrates the rare but clinically important pathology of aggressive cholesterol granuloma of the middle ear. PMID- 28717527 TI - Vagal Paraganglioma Presenting as a Neck Mass Associated with Cough on Palpation. AB - A 70-year-old female presented with a neck mass and sporadic dry cough, often leading to fits of coughing severe enough to cause vomiting. The patient reported that touching the mass triggered the cough. On examination, a 2.5 cm right-sided level two neck mass deep to the sternocleidomastoid was present. Palpation of the mass immediately triggered coughing. Cross-sectional imaging proposed vagal paraganglioma as the chief differential, which was confirmed following surgical excision. The patient reported complete resolution of her severe dry cough after surgery. Vagal paragangliomas are rare neuroendocrine tumors arising from the neural crest-derived paraganglionic tissue surrounding the vagus nerve, typically presenting as a neck mass associated with hoarseness or pulsatile tinnitus. To the best of our knowledge this is a unique description in the English literature. This case is presented to aid physicians should they encounter a neck mass associated with cough. Vagal paraganglioma, although rare, should be part of the differential in such a presentation. PMID- 28717528 TI - The Relationship between Werner Syndrome and Sinonasal Malignant Melanoma: Two Sibling Cases of Werner Syndrome with Malignant Melanoma. AB - Werner syndrome (WS) is an autosomal recessive disease characterized by premature aging. Malignant tumors such as thyroid carcinoma and malignant melanoma occur frequently in WS patients. We describe 2 siblings with WS who suffered from sinonasal malignant melanoma (MM). Both patients initially experienced nasal obstruction and recurrent nasal bleeding and died within 2 years of the diagnosis of MM. Otolaryngologists should recognize that WS patients have a high risk for head and neck malignant disease, particularly sinonasal MM, even if they are aged below the expected age range and undergo periodic examinations. Furthermore, it is important that WS patients are aware that a prompt nasal examination is indicated if they experience continuous nasal obstruction or recurrent nasal bleeding. PMID- 28717529 TI - Daily Variation in the Occurrence of Different Subtypes of Stroke. AB - Three thousand two hundred and ninety-eight patients admitted to our Stroke Unit with hemorrhagic, large artery atherosclerosis, cardioembolic, small-vessel occlusion, and undetermined etiology-cryptogenic strokes were included in the study. The circadian variability in onset in each stroke subgroup and the associations with various risk factors were analyzed. In each subgroup, a significant minority of patients suffered from stroke during sleep. In the ischemic group, hypercholesterolemia, paroxysmal atrial fibrillation, and previous myocardial infarction facilitated the onset during waking. During waking, stroke onset was significantly higher in the morning compared to the afternoon both in the hemorrhagic and in the ischemic type. In hemorrhagic stroke, a previous stroke was associated with a lower early morning occurrence. In large artery atherosclerosis stroke, males were at higher risk of early morning occurrence (p < 0.01). In small-vessel occlusion stroke, hypertension is significantly more present in the morning compared to the afternoon onset (p < 0.005). Circadian patterns of stroke onset were observed both in hemorrhagic and in ischemic stroke, irrespective of the ischemic subgroup. In all groups, stroke was more likely to occur during waking than during sleep and, in the diurnal period, during morning than during afternoon. Moreover, sex and some clinical factors influence the diurnal pattern. PMID- 28717531 TI - The role of vitamin D supplementation on erectile function. AB - In the last few years growing evidence highlighted vitamin D (VD) deficiency is one of the several dynamics that associates with increased atherosclerotic cardiovascular (ASCV) diseases. ASCV diseases and erectile dysfunction (ED) share common risk factors such as diabetes mellitus, hypertension, smoking, hyperlipidemia, and a sedentary lifestyle. The aim of this review was to summarize current progress in VD research by focusing effect of low VD level on different body systems and erectile function. Here we examine research linking VD deficiency and ED and discuss how VD influences ED and its classic risk factors that also associate to increased ED risk. We also summarize research indicating that VD associates with reduced risk of several nonvascular contributing factors for ED. Available literature demonstrates relatively high rates of low VD serum levels in ED patients. Based on the preclinical and clinical data available in the literature, to date, we infer that VD play a critical role in maintaining erectile function in humans. Nevertheless, this should also be tested through randomized controlled studies on the effect of VD supplementation with larger population. PMID- 28717532 TI - Retrograde intrarenal surgery for renal stones - Part 1. AB - The main aim in the treatment of renal stones is to clearance of the stones completely with the least morbidity. Parallel to the improvements in technology during recent years, new flexible ureterorenoscopes and effective lithotripters such as holmium laser have been developed, thus retrograde intrarenal surgery (RIRS) has become an efficient and safe option in the management of urinary system stone disease with a gradually increasing popularity. Therewithal, innovations in auxiliary equipment such as guide-wires, ureteral access sheath and stone baskets have made this procedure more effective. With this modality, nowadays, the vast majority of renal stones can be treated successfully without need of open surgery or percutaneous nephrolithotomy. RIRS can be used as a primary treatment in patients with renal stones smaller than 2 cm, in cases with prior unsuccessful shock wave lithotripsy (SWL), infundibular stenosis, renoureteral malformation, musculoskeletal deformity, bleeding diathesis as well as obese patients. The efficiency of this procedure has been also proved in pediatric patients. In the first part of this detailed review for RIRS, history, indications and contraindications, preoperative preparation, antibiotic prophylaxis, anesthesia, surgical technique related to flexible ureteroscopes and auxiliary equipment being used, postoperative care and complications of this operation are discussed with up-to-date literature. PMID- 28717533 TI - Prevalence of erectile dysfunction in men over 40 years of age in Turkey: Results from the Turkish Society of Andrology Male Sexual Health Study Group. AB - OBJECTIVE: Previous study conducted by the Turkish Society of Andrology in 1999 reported the prevalence of erectile dysfunction (ED) as 69.2% in men of >=40 years of age, using a single-item non-validated question. This rate seemed to be higher compared to the studies reported worldwide. So, there was a need to carry out another epidemiological study by using validated questionnaires. Our aim was to investigate ED prevalence, severity, and its correlates in men aged >=40 years using validated tools. MATERIAL AND METHODS: This cross-sectional, observational, population-based field survey was carried out in randomly selected males of >=40 years from 19 provinces of Turkey. All participant completed a survey included with socio-demographic and socio-economic characteristics, medical and sexual history, associated physical and medical comorbidities. Erectile function was assessed by the International Index of Erectile Function (IIEF) questionnaire based on a total score of 30. The prevalence of ED, its severity and correlates in men aged >=40 years were determined for main outcome measures. Data sets were statistically compared and p<0.05 was considered as significant. RESULTS: Median age of 2.760 males was 54.2 years. The median prevalence of ED was calculated as 33% among all males of >=40 years of age. When subjects were stratified by age; median ED prevalence rates were 17% for 40-49 years, 35.5% for 50-59 years, 68.8% for 60-69 years, and 82.9% for >=70 years. Among all ED men, 76.9% reported mild, 16.3% moderate, and 5.7% severe ED. At logistic regression analyses; age, diabetes, hypertension, atherosclerosis, dyslipidemia, lower urinary tract symptoms, educational status and monthly income were found to be independent risk factors for having ED. CONCLUSION: This population-based survey in Turkish men of >=40 years of age reported the prevalence of ED as 33%. Besides, this study reported age as the main predictor for presence and severity of ED. PMID- 28717530 TI - Comparative and integrative analysis of RNA structural profiling data: current practices and emerging questions. AB - BACKGROUND: Structure profiling experiments provide single-nucleotide information on RNA structure. Recent advances in chemistry combined with application of high throughput sequencing have enabled structure profiling at transcriptome scale and in living cells, creating unprecedented opportunities for RNA biology. Propelled by these experimental advances, massive data with ever-increasing diversity and complexity have been generated, which give rise to new challenges in interpreting and analyzing these data. RESULTS: We review current practices in analysis of structure profiling data with emphasis on comparative and integrative analysis as well as highlight emerging questions. Comparative analysis has revealed structural patterns across transcriptomes and has become an integral component of recent profiling studies. Additionally, profiling data can be integrated into traditional structure prediction algorithms to improve prediction accuracy. CONCLUSIONS: To keep pace with experimental developments, methods to facilitate, enhance and refine such analyses are needed. Parallel advances in analysis methodology will complement profiling technologies and help them reach their full potential. PMID- 28717534 TI - Effect of low-energy shockwave therapy on angiogenic factors in the penile tissue of diabetic rats. AB - OBJECTIVE: The aim of this study is to investigate the effect of low-energy shock wave therapy (LESWT) on angiogenesis factors at penile tissue in a diabetic rat model. MATERIAL AND METHODS: A total of 30 male Sprague-Dawley rats which were allocated into three equal groups were included study. Group 1 (control group) included 10 male rats which did not receive any treatment were randomly chosen to serve as normal control. The remaining rats were injected intraperitoneally with 60 mg/kg of streptozotocin (STZ) to induce diabetes. Diabetic rats were divided into two equal group which constituted diabetic control, and LESWT treatment (DM+LESWT) group. Each rat in the DM+LESWT group received L-ESWT therapy. Endothelial nitric oxide synthase (eNOS) and vascular endothelial growth factor (VEGF) mRNA expression levels of penile tissue were evaluated. RESULTS: Following STZ dosing eNOS level dropped in the diabetic control group relative to the control group. Statistically significant increase in eNOS levels were seen in the LESWT+DM group. Similarly, in the diabetic control group STZ treatment decreased VEGF levels, while in the LESWT+DM group VEGF nearly approached to baseline levels. However variations in VEGF levels were not statistically significant. CONCLUSION: Mechanism action of ESWT in the penile tissue seems to involve angiogenic factors. PMID- 28717535 TI - Evaluation of testicular catch-up growth in adolescent microsurgical varicocelectomy. AB - OBJECTIVE: The incidence of varicocele is approximately 15% in adolecent men. Early treatment with varicocele is aimed to resolve testicular hypotrophy and ensure catch-up growth. The aim of this study was to evaluate ipsilateral catch up growth rates relative to contralateral testicular growth in adolescents with varicocele undergoing microsurgical subinguinal varicocelectomy. MATERIAL AND METHODS: Fifty adolescents with unilateral grade 2-3 varicoceles were included in the study. All patients underwent microsurgical subinguinal left varicocelectomies performed by the same experienced surgeon. All patients were evaluated clinically and using orchidometric measurements to define the grade of varicocele and testicular volume at presentation and follow-up. The number of internal and external spermatic veins, testicular arteries and lymphatic vessels preserved during the subinguinal microsurgical varicocelectomy were recorded. The mean follow-up period was 26 months (range 6-48 months). RESULTS: At presentation, mean patient age was 12.9+/-2.1 years. Mean testicular preoperative volumes were 7.1+/-4.3 mL for the right and 5.4+/-3.4 mL for the left testis. There were significant differences between mean volumes of the right and left testis (p=0.002). At the final postoperative follow-up visit, mean testicular volumes were 10.8+/-5.1 mL (range 3-25) for the right and 9.9+/-4.3 mL (range 2 20) for the left, and the difference between the right and left testicular volumes was insignificant (p=0.47). In our series, catch-up growth was observed in 70% (35/50) of our patients. CONCLUSION: Adolescent varicocelectomy is associated with a higher percentage of patients showing testicular catch-up growth. In our study, similarly to the available literature the catch-up growth rate was found as 70% and observed to have positive effects of adolescent varicocelectomy on testicular growth. PMID- 28717536 TI - Safety and efficacy of bipolar energy for transurethral resection of bladder tumours: a prospective quasi-randomized study. AB - OBJECTIVE: The primary aim of the study was to evaluate the safety and efficacy of bipolar energy in resecting bladder tumors. MATERIAL AND METHODS: The study was done between March 2012 and February 2013. This is a prospective quasi randomized study evaluating the safety and efficacy of bipolar energy in transurethral resection of bladder tumours (TURBT). Institutional Ethics Committee approval was obtained. Informed consent was taken from all patients. Patients were randomized into two groups of 50 each to undergo either monopolar TURBT or bipolar TURBT using glycine and saline irrigation solutions, respectively. RESULTS: Most important of all, the means of variables were compared between the two energy sources to know the difference between them and its significance. Hematocrit level, resection time and obturator jerks had significant values. CONCLUSION: The results of this study indicated that bipolar resection of bladder tumours have lower incidence of complications especially bleeding, TUR syndrome, obturator jerks and bladder perforation. Bipolar TURBT is safe and efficacious in managing bladder tumours. PMID- 28717537 TI - Paraoxonase and arylesterase activity in bladder cancer. AB - OBJECTIVE: Oxidative stress is the main pathogenetic mechanism in bladder cancer among many other causes. We aimed to investigate whether a potential relationship exists between bladder cancer and the activities of paraoxonase (PON1) and arylesterase (ARE) enzymes. MATERIAL AND METHODS: The study included 56 patients with bladder cancer, and 57 healthy individuals. The relationships between enzyme activity and tumour grade, stage, muscular invasion and tumour size were evaluated. For statistical analysis, One-Sample Kolmogorov-Smirnov, Independent T, ANOVA and Post-Hoc Bonferroni tests were used. RESULTS: Serum levels of PON1 and ARE enzymes, and total cholesterol were significantly lower in bladder cancer group. While other lipid parameters were similar in both the patient and the control groups. Levels of ARE were positively correlated with lipid parameters except for HDL cholesterol. CONCLUSION: Our results showed that decreased serum PON1 and ARE enzyme activities are related with tumour load and recurrence. Further studies with larger samples are needed to confirm predictive role of enzymatic activities of PON1 and ARE in the diagnosis and prognosis of bladder cancer. PMID- 28717538 TI - Assessment of prostate cancer with integrated CT-perfusion using a sector-wise approach. AB - OBJECTIVE: The role of computed tomography perfusion (CTP) in characterizing primary prostate cancer (PCa) is not definitely known. The aim of the present study was to investigate the relationship between CTP parameters and histopathological features of PCa tissue, using a sector-wise approach. MATERIAL AND METHODS: Fifty-one patients with biopsy-proven PCa underwent prospectively a CTP scan prior to radical prostatectomy. Blood flow (BF), mean blood volume (BV) and mean transit time (MTT) were calculated, with the prostate being divided into eight sectors. Corresponding sector-wise histopathological analysis of whole mount prostatectomy specimens was performed to determine tumoral area (mm2), mean microvessel density (MVD), Gleason patterns (primary, secondary) and total Gleason score. Spearman's rank correlation coefficient was used to analyze the association between CTP and histopathological parameters. RESULTS: BF correlated weakly with tumoral area [rhos coefficient (p-value): 0.25 (0.00)] and MVD [rhos coefficient (p-value): 0.23 (0.00)]. No valuable correlation was found between CTP parameters and primary and secondary Gleason patterns, whereas total Gleason score was weakly correlated with BV [rhos coefficient (p-value): 0.22 (0.00)] and MTT [rhos coefficient (p-value): 0.25 (0.00)]. CONCLUSION: BF correlates weakly with size and vascularity of PCa. There is a need for further studies to elucidate the association between CTP parameters and other histopathological parameters. PMID- 28717539 TI - Single session vs two sessions of flexible ureterosopy (FURS) for dusting of renal pelvic stones 2-3 cm in diameter: Does stone size or hardness play a role in number of sessions to be applied?" AB - OBJECTIVE: To evaluate the stone hardness in predicting the need for single or two sessions of retrograde intrarenal surgery (RIRS) for renal pelvis stones of 2 3 cm in size. MATERIAL AND METHODS: Ninety-six patients (64 male and 32 female) with only renal stones (2.5+/-0.3 cm) underwent RIRS using flexible 7.5 Fr ureteroscope (FURS). The stone hardness was evaluated by preoperative non contrast computed tomography (NCCT). The patients were divided into two groups based on stone hardness: Group I (n=54) (hard stones - Hounsfield Unit (HU) >1000) and group II (n=42) (not hard stone - HU <1000). The stone-free rate, the operative time, any intra or postoperative complications and the need for second sessions of RIRS were evaluated. RESULTS: All stones were successfully accessed. Intraoperative complications were not reported. The initial stone-free rate was 40% in Group I and 95% in Group II after a single session (p=0.01). A second session FURS was needed in 32 cases of Group I (40%) where postoperative CT showed significant residual stone fragments of 6+/-2 mm, and stone-free rate up to 100 percent. On the contrary only 2 cases from Group II underwent second session FURS (p=0.01). The operative times were 75+/-15 minutes in Group I and 55+/-13 minutes in Group II (p<0.01). Six patients (4 in group I and 2 in group II) had postoperative high-grade fever (Clavien Grade II). CONCLUSION: Stone hardness had a significant impact on the decision of performing single versus two sessions of FURS for renal pelvic stones of 2-3 cm rather than the stone size alone. PMID- 28717540 TI - Totally tubeless percutaneous nephrolithotomy is feasible in morbidly obese patients. AB - OBJECTIVE: Regarding technical difficulties that obese body habitus might impose to percutaneous nephrolithotomy (PNL) success and higher risk of peri-operative complications in this group of patients, we decided to retrospectively gather data from our patients during past 8 years to determine the stone free and complication rates. MATERIAL AND METHODS: Between January 2007-December 2015, seventy-eight obese patients with body mass index over 35 who had indication for PNL including stones larger than 2 cm in pelvi-calyceal system or smaller extracorporeal shock wave lithotripsy (ESWL) resistant stones or who were not a fit candidate for ESWL due to increased skin to target distance, with no contraindication of PNL (including bleeding diathesis, inability to be positioned in prone) were enrolled. They were randomly assigned to group 1 (standard PNL with nephrostomy and ureteral stent) or group 2 (totally tubeless PNL with no ureteral stent and no nephrostomy). The outcomes were compared. RESULTS: The transfusion rate, operation time, and the hemoglobin drop were same across the groups (p>0.05). Total analgesic use was equivalent of 33.8 vs. 14.7 mgs of morphine sulfate (18-77 mg) and was significantly lower in total tubeless group (p=0.001). Return to normal activity was described as total number of in-patient and outpatient days from time of admission to the point which the patients returns to normal life activity such as going to job or school and was 19.4 vs. 9.3 days (6-30 days, p=0.001). CONCLUSION: Totally tubeless PNL in obese subjects would have lower analgesic use and return to normal activity versus standard PNL. Totally tubeless PNL is recommended for obese patients. PMID- 28717541 TI - Is standard percutaneous nephrolithotomy still the standard treatment modality for renal stones less than three centimeters? AB - OBJECTIVE: The aim of study was to compare the efficiency and safety of standard percutaneous nephrolithotomy (sPNL) and miniaturized percutaneous nephrolithotomy (mPNL) in lower calyx and/or pelvic stones smaller than three centimeters. MATERIAL AND METHODS: From October 2010 to August 2015, 108 mPNL and 176 sPNL procedures were performed for renal stones smaller than three cm and located in the lower calyx and/or renal pelvis. All patients were evaluated preoperatively with intravenous pyelography and/or computed tomography. Intraoperative parameters, post-operative results and complications were recorded. Postoperative success was defined as complete stone clearance and/or clinically insignificant residual fragments at 3rd month. RESULTS: Preoperative characteristics were similar between sPNL and mPNL groups except previous renal stone operation history and gender. The mean operation time was significantly shorter in the sPNL group (p<0.001). The mean hemoglobin drop was significantly less in the mPNL group (p=0.001), we found a 1.27+/-1.4 and 0.5+/-1.3 decrease in mean hemoglobin levels (mg/dL) in the sPNL and mPNL groups, respectively. Transfusion rate was 1.9% in mPNL and 5.6% in sPNL groups, and the difference was statistically significant (p=0.048). Only one patient in the sPNL group needed angiography and embolization. Postoperative JJ stent insertion rate was significantly higher in the mPNL group (p=0.03). CONCLUSION: Both sPNL and mPNL are safe and effective surgical procedures for lower calyx and/or pelvis stones smaller than 3 cm. However, use of smaller caliber instruments was associated with a lesser hemoglobin drop and need for transfusion. PMID- 28717542 TI - Evaluation of postoperative hydronephrosis following semirigid ureteroscopy: Incidence and predictors. AB - OBJECTIVE: Hydronephrosis developing following ureteroscopy (URS) is an important issue associated with the long-term postoperative renal functions. Studies investigating the role of postoperative imaging revealed conflicting results. In this study, we aimed to determine the incidence and predictors of hydronephrosis following semirigid URS. MATERIAL AND METHODS: We evaluated the results of 455 patients who underwent U RS a nd postoperative imaging with non-contrast computed tomography (CT). Primary endpoints of the study were to determine the frequency of development of hydronephrosis and factors associated with the development of hydronephrosis. Logistic regression analysis was used to define factors effecting on the development of hydronephrosis. RESULTS: Postoperative non-contrast CT revealed hydronephrosis in 81 (17.8%) patients. Stone-free status was achieved in 415 (91.2%) patients. Univariate analysis revealed history of ipsilateral URS (p=0.001), duration of operation (p=0.022), presence of multiple stones (p=0.001), and occurrence of a renal colic episode postoperatively (p=0.013) as the parameters associated with increased risk of postoperative hydronephrosis. In the multivariate analysis, history of ipsilateral URS (OR: 2.724, p=0.017) and presence of multiple stones (OR: 2.116, p=0.032) were found to be the independent prognostic markers of developing postoperative hydronephrosis. CONCLUSION: Ipsilateral hydronephrosis following URS develops in a significant number of patients. In patients with history of ipsilateral hydronephrosis and multiple stones, risk of development of postoperative hydronephrosis is higher, therefore physicians should be keep these parameters in mind in the decision making process of selective imaging postoperatively. PMID- 28717543 TI - Outcome analysis of transurethral resection versus potassium titanyl phosphate photo selective vaporization of the prostate for the treatment of benign prostatic hyperplasia; a randomized controlled trial with 4 years follow up. AB - OBJECTIVE: Photovaporization of prostate (PVP) is a newer surgical modality of benign prostatic hyperplasia (BPH) which is gaining importance recently. There are a few randomized controlled trials that showed safety and efficacy of PVP in comparison with transurethral resection of prostate (TURP) with limited follow-up period (<2 years). Here, we are presenting a comparative study performed on potassium titanyl phosphate (KTP) PVP laser versus TURP for the treatment of BPH with long-term follow-up period. MATERIAL AND METHODS: After institutional ethical clearance, 150 patients were prospectively included in the study from January 2010 to March, 2012. Improvement of International Prostate Symptoms Score (IPSS), Qmax, post-void residual (PVR) urine, International Index of Erectile Function (IIEF)-5 score and complications were assessed at 12, 24, 36 and 48 months. RESULTS: Mean age of the study group was 65.3+/-7.86 years in the TURP and 63.6+/-8.12 years in the PVP groups (p=0.45). IPSS symptom score improved significantly in both TURP and KTP groups (p<0.003). There was improvement in Q max during follow-up in both groups (p<0.001) which was maintained at 48 months. Most of the patients in both groups were satisfied with symptoms and bothersome at 48 months. All the sexual parameters are similar to both groups except retrograde ejaculation. Overall complication noted in 23 patients (15.33%). CONCLUSION: Both KTP Laser PVP and TURP afford durable relief from symptoms of BPH at 48 months follow-up. Both procedures are safe and associated with minimal complications. Both procedures do not have any detrimental effect on sexual function on long-term follow-up. Quality of life remains high even at 4 years in both groups. PMID- 28717544 TI - Is it safe to prescribe ascorbic acid for urinary acidification in stone-forming patients with alkaline urine? AB - OBJECTIVE: To study the effect of ascorbic acid (AA) supplementation on urinary pH, metabolic stone workup parameters, and development of de novo urolithiasis in stone-forming patients. MATERIAL AND METHODS: A retrospective review of the patients followed-up at a tertiary stone centre between September 2009 and October 2015 was performed. Patients with recurrent urolithiasis who received AA supplementation as a urinary acidifying agent were included in the study. Detailed metabolic stone work-up, including two 24-hour urine collections obtained pre- and post-AA supplementation were compared. In addition, imaging studies were reviewed to assess the development of de novo urolithiasis. RESULTS: Twenty-four patients were included in the study with a mean age of 60.6 years and a median daily AA dose of 1000 mg (range: 500-2000 mg). Median follow-up period was 22.6 months (range: 19.7-32.1). After AA supplementation, there was a significant decrease in urinary pH (7.6 vs. 6.9, p=0.02). Although there was no significant increase in the daily oxalate excretion, two patients (8.3%) had their AA dose reduced or discontinued due to de novo hyperoxaluria (342.9 vs 510.2 umol/day; p=0.75). Other serum and urinary parameters did not show any significant changes. Eight (33.3%) patients developed de novo urolithiasis with struvite and carbonate apatite being the major components. CONCLUSION: AA supplementation resulted in significantly lower urinary pH in patients with recurrent urolithiasis and alkaline urine pH. Prospective studies are needed to assess whether this reduction in urinary pH is associated with lower stone recurrence rates. PMID- 28717545 TI - Low dose lignocaine + butorphanol vs. low dose bupivacaine for spinal anaesthesia in day care urological surgeries: a prospective randomized control trial. AB - OBJECTIVE: A local anaesthetic with fast onset, short and reliable duration of anaesthesia may be preferable for day care urological surgeries. Low dose lignocaine is believed to act faster and to have a shorter duration of action than low dose bupivacaine. Use of lignocaine for spinal anesthesia is discouraged now a days because of rare reports of transient neurological symptoms. The purpose of this study was to compare effectiveness and safety of low dose of lignocaine + butorphanol against low dose of bupivacaine for day care urological surgeries. MATERIAL AND METHODS: A prospective randomized control trial was conducted between December 2012 to November 2015. After taking ethical committe approval and patient consent, total 990 patients were randomized in two groups. Group A received 0.5 mL of 5% lignocaine (25 mg) + 0.3 mL butorphanol (0.3 mg) and group B received 1 mL of 0.5% bupivacaine (5 mg) for spinal anesthesia. Spinal anesthesia was given at the L3-L4 interspace with the patient in the sitting or lateral position. The criteria for evaluation were time till onset of sensory and motor block, duration of sensory and motor block, time till ambulation, time till fit for discharge and any complications. RESULTS: Both the groups were comparable in terms of age, male to female ratio, American Society of Anesthesiologists (ASA) grade and duration surgery. Group A and Group B were statistically different in terms of mean time till onset of sensory block (120+/ 22 sec and 274+/-36 sec), onset of motor block (228+/-34 sec and 372+/-41 sec), duration of sensory block (100+/-21 min and 230+/-28 min), duration of motor block (60+/-15 min and 152+/-23 min), time till ambulation (138+/-24 min and 292+/-48 min), time till fit for discharge (256+/-35 min and 428+/-46 min) respectively (<0.0001). Nausea, vomitings, hypotension, bradycarida and pruritis were less in group A compared to group B (<0.01). None of patient in any group had temporary or permanent neurological defecit. CONCLUSION: Spinal anaesthesia is an effective as well as a safe modality to anaesthetize the patient for day care urological procedures. This study shows lignocaine + butorphanol is preferable over bupivacaine for spinal anesthesia for day care urological procedures. It also favours day care surgery at remote areas with lesser medical facilities. It helps to minimize requirement of medical and paramedical staff, thus further extending scope of day care urological surgeries. PMID- 28717546 TI - Laparoscopic management and its outcomes in cases with nonpalpable testis. AB - OBJECTIVE: Diagnostic laparoscopy is the gold standard in the algorithm of nonpalpable testis. Testicular tissue is examined and treatment is planned accordingly. In this study we reviewed the place of diagnostic laparoscopy, and evaluated the results and effectiveness of laparoscopy in the diagnosis and management of nonpalpable testis. MATERIAL AND METHODS: Children who had diagnostic laparoscopy for nonpalpable testes were included in the study. Physical examination results, ultrasonography (USG) reports, age at surgery, laparoscopic and inguinal exploration findings, surgical procedures, orchiopexy results, early and late-term complications were evaluated. Follow-up visits were performed at 3-month intervals for the first, at 6-month intervals for the 2. year, then at yearly intervals. Testicular size and location was evaluated by during control examination. RESULTS: Overall 58 boys, and 68 testes (26 left: 44.8%; 22 right: 37.9%, and 10 bilateral: 17.2%) were included in the study. Mean age at surgery was 5.5 years (10 months-17 years). Diagnostic value of USG was 15.7%. Diagnostic laparoscopy findings were as follows: Group 1: blind-ended vessels, n=7 (10.2%); Group 2: intraabdominal testes, n=8 (11.7%); Group 3: vas and vessels entering internal ring, n=53 (77.9%). Overall 43 testes underwent orchiopexy, which were normal (n=8) or hypoplastic (n=35). Mean follow-up period was 19 months (1-12 years), and on an average 7 visits were performed (5-14). On follow-up, 5 testes were normal-sized and located in the scrotum, while 4 testes were atrophic and underwent orchiectomy. Two testes were found in the inguinal canal and redo orchiopexy was performed. Control USG revealed reduced testicular blood supply and volume. CONCLUSION: Laparoscopic surgery is safe and effective in the management of nonpalpable testes. In the majority, routine use of diagnostic laparoscopy in the algorithma does not confer any additional contributions in many patients. PMID- 28717547 TI - Emphysematous pyelonephritis: Changing trend of clinical spectrum, pathogenesis, management and outcome. AB - OBJECTIVE: To highlight changing trend of clinical spectrum, comparing management options and predictors of outcome of emphysematous pyelonephritis. MATERIAL AND METHODS: This study included patients who were diagnosed as emphysematous pyelonephritis between August, 2001 to July, 2015. We excluded other possible causes of gas in renal system. Baseline patient characteristics, clinical spectrum, serum and urinary biochemical parameters, radiological findings, management and outcomes were recorded. Patients were classified as "responders" and "non-responders". RESULTS: We studied a total of 74 patients and categorised them as responders (62 patients) and non-responders (12 patients). Women outnumbered men constituting 62.16% of the study population (M: F; 1: 1.6). Fever was the most common presenting symptom followed by flank pain. Diabetes mellitus (85.14%) was the most common comorbidity followed by urolithiasis (32.43%). Escherichia coli was the commonest organism grown in urine culture (79.73%). Non responders had distinct laboratory findings relative to responders as low hemoglobin (7.8+/-2.1/11.2+/-3.2 g/dL; p=0.0007), thrombocytopenia (91.67% vs. 11.29%; p=0.0001), proteinuria >3 g/L (50% vs. 6.45%; p=0.0008) and positive blood culture (100% vs. 67.74%; p=0.0288). CONCLUSION: Advanced age, higher body mass index, renal impairment, thrombocytopenia, altered sensorium, shock at presentation can be used as scores for poor prognosis. Emphysematous pyelonephritis management requires multidisciplinary collaboration including hydration and electrolyte management, broad spectrum antibiotics, strict glycaemic control, effective urinary drainage and lastly it may require emergency nephrectomy as a salvage procedure. PMID- 28717548 TI - Infective complications in patients after transrectal ultrasound-guided prostate biopsy and the role of ciprofloxacin resistant Escherichia coli colonization in rectal flora. AB - OBJECTIVE: In the present study, we aimed to invastigate the ciprofloxacin resistance in rectal flora of the patients undergoing prostate biopsy in our department. Additionally, the possible effects of the presence of ciprofloxacin resistant bacteria in faecal flora on the risk of infective complications after the procedure as well as the effect of antibiotic prophylaxis on such infectious complications have been evaluated. MATERIAL AND METHODS: A total of 142 patients undergoing transrectal ultrasound-guided prostate biopsy were included into the study program. Rectal swab samples were taken from all patients prior to biopsy. The presence of complications have been evaluated after a week following the biopsy procedure. Patients with fever were also evaluated. The possible correlation between the presence of ciprofloxacin-resistant bacteria in faecal flora and the risk of urinary tract infection development and the other complications were evaluated. RESULTS: E. coli bacteria were present in all cultures of rectal swab samples obtained from 142 patients prior to prostate biopsy. Of all these patients, while ciprofloxacin-resistant E. coli (CR E. coli) grew in 76 (53.5%) patients; ciprofloxacin susceptible E. coli (CS E. coli) was obtained in 66 (46.5%) patients. In 16 patients (11.3%), infectious complications were observed. While the infective complications were present in the 14.5% of patients with CR E. coli; they were present in the 7.6% of patients with CS E. coli (p=0.295). High fever was observed in nine patients (6.3%). Of these nine patients, although six had CR E. coli growth as detected during culture sensitivity tests; three had CS E. coli growth in their rectal swab culture tests. Sepsis was observed in three (2.1%) of these patients with high fever. Ciprofloxacin-resistant E. coli grew in all of the rectal swab cultures obtained from these patients with sepsis. CONCLUSION: In the light of our findings we may say that, it will be appropriate to reconsider the ciprofloxacin prophylaxis and prefer to use other prophylactic agents for a certain period of time in populations with higher rates of resistance to this medical agent. Furthermore, it will be appropriate again to obtain rectal swab specimens for culture tests before biopsy procedure in order to perform targeted prophylaxis according to the culture antibiogram test results. This approach will enable us to evaluate the cost-effectiveness of the procedure in detail. PMID- 28717549 TI - 22-year survival following radical nephrectomy and several metastasectomies in a case of renal cell carcinoma. AB - Renal cell carcinoma (RCC) is a common malignancy. Metastases can be seen both synchronously, at the time of diagnosis, and metachronously during follow-up. At the time of diagnosis, 23% of the patients have metastatic disease. and 25% of patients will develop metastasis during follow-up period after nephrectomy. Nearly 80% of them develop within the first 5 years. However late metastasis of RCC have been also reported within the postoperative 10 years in the literature. For metastatic lesions, if surgically feasible, metastasectomy, and targeted pharmaceutical agents have been recommended. However any randomized controlled study which aimed to determine treatment protocol in patients who develop multiple metastases has not been cited in the literature. Herein, we are presenting a case with renal cell carcinoma in whom within 22 years of follow-up after 10 years of survival multiple metastases in different organs were detected which were managed with surgical, and medical treatments. As far as we know, this case is the first patient with the longest survival whose non-pulmonary metastases had been treated with more than one surgical interventions. PMID- 28717550 TI - Metastatic pancreatic adenocarcinoma to the scrotum. AB - Metastatic cancer to the scrotum is a rare occurrence. We describe the first case of cutaneous scrotal lesions consistent with metastatic pancreatic adenocarcinoma. A brief discussion including epidemiologic factors and clinical presentation is presented. PMID- 28717551 TI - Angiomyolipoma of the scrotum: report of a rarely seen case and review of the literature. AB - Angiomyolipoma (AML) is a benign, histologically complex mesenchymal tumor arising mainly from the kidney and liver. The majority (80%) of these tumors arise as sporadic tumors, while 20% of them are associated with tuberous sclerosis. Extra-renal sites of AML, though rare, have been reported in literature. In this report, we describe a case of AML arising from the scrotal skin, and presenting as a scrotal mass. Although skin is the most commonly reported site after kidney and liver, scrotal skin AML presents as an intriguing mass in a region known for germ cell tumors which has been reported only once before. A 35-year-old male presented with scrotal swelling. His physical examination, laboratory investigations and imaging studies were non-specific. Excision of the lesion with subsequent histopathological examination revealed the true nature of the lesion. This lesion should be included in the differential diagnosis of scrotal masses. PMID- 28717553 TI - Meetings & Congresses. PMID- 28717552 TI - Re: Top cited articles in urology from Turkey. PMID- 28717554 TI - Toward On-line Parameter Estimation of Concentric Tube Robots Using a Mechanics based Kinematic Model. AB - Although existing mechanics-based models of concentric tube robots have been experimentally demonstrated to approximate the actual kinematics, determining accurate estimates of model parameters remains difficult due to the complex relationship between the parameters and available measurements. Further, because the mechanics-based models neglect some phenomena like friction, nonlinear elasticity, and cross section deformation, it is also not clear if model error is due to model simplification or to parameter estimation errors. The parameters of the superelastic materials used in these robots can be slowly time-varying, necessitating periodic re-estimation. This paper proposes a method for estimating the mechanics-based model parameters using an extended Kalman filter as a step toward on-line parameter estimation. Our methodology is validated through both simulation and experiments. PMID- 28717555 TI - Adaptive Nonparametric Kinematic Modeling of Concentric Tube Robots. AB - Concentric tube robots comprise telescopic precurved elastic tubes. The robot's tip and shape are controlled via relative tube motions, i.e. tube rotations and translations. Non-linear interactions between the tubes, e.g. friction and torsion, as well as uncertainty in the physical properties of the tubes themselves, e.g. the Young's modulus, curvature, or stiffness, hinder accurate kinematic modelling. In this paper, we present a machine-learning-based methodology for kinematic modelling of concentric tube robots and in situ model adaptation. Our approach is based on Locally Weighted Projection Regression (LWPR). The model comprises an ensemble of linear models, each of which locally approximates the original complex kinematic relation. LWPR can accommodate for model deviations by adjusting the respective local models at run-time, resulting in an adaptive kinematics framework. We evaluated our approach on data gathered from a three-tube robot, and report high accuracy across the robot's configuration space. PMID- 28717556 TI - Thorax Computed Tomography Findings in Patients with Erectile Dysfunction. AB - OBJECTIVE: Diabetes mellitus, smoking, dyslipidemia, and obesity play an important role in the etiology of erectile dysfunction, particularly in cases with vascular insufficiency. These risk factors also target the lungs due to their systemic effects. MATERIALS AND METHODS: Patients with penile vascular insufficiency determined at Doppler ultrasonography and undergoing thoracic computerized tomography for various reasons were included in this study. A history of acute thoracic trauma, pneumonic consolidation, or pelvic surgery and trauma were regarded as exclusion criteria. RESULTS: Thirty-seven male patients with identified vascular insufficiency (age 54.48 +/- 13.62 years) were enrolled. Mass lesions with a malignant morphology were present in two patients. The most common mediastinal/vascular pathology was atherosclerosis, while the most common parenchymal lesion was emphysematous aeration. Other findings included parenchymal fibrotic bands, atelectasis, interstitial thickening, bronchiectasis, air trapping, aortic aneurysm, a dilated pulmonary artery, hiatal hernia, and pericardial effusion. CONCLUSION: Erectile dysfunction may be an early sign of cardiovascular diseases. Care must be taken in terms of existing or potential pulmonary pathologies in these patients due to their sharing common risk factors with systemic effects. PMID- 28717557 TI - Uterine Lipoleiomyoma: A Report of Two Cases. AB - We report two cases of uterine lipoleiomyoma in postmenopausal women of ages 52 and 55 years, who presented with complaints of leukorrhea and lower abdominal pain, respectively. Lipoleiomyoma is a rare benign variant of leiomyoma, having an incidence of 0.03%-0.2%. These are benign pelvic tumors which are usually asymptomatic and commonly occur in obese postmenopausal women. However, they can occasionally present with typical leiomyoma symptoms. Imaging plays a crucial role in the diagnosis of benign pelvic tumors. Ultrasonography is the first imaging modality for diagnosis of pelvic tumors in females. Computed tomography and magnetic resonance imaging are specific in demonstrating the uterine origin and fat component. PMID- 28717558 TI - Single pulse two photon fluorescence lifetime imaging (SP-FLIM) with MHz pixel rate. AB - Two-photon-excited fluorescence lifetime imaging microscopy (FLIM) is a chemically specific 3-D sensing modality providing valuable information about the microstructure, composition and function of a sample. However, a more widespread application of this technique is hindered by the need for a sophisticated ultra short pulse laser source and by speed limitations of current FLIM detection systems. To overcome these limitations, we combined a robust sub-nanosecond fiber laser as the excitation source with high analog bandwidth detection. Due to the long pulse length in our configuration, more fluorescence photons are generated per pulse, which allows us to derive the lifetime with a single excitation pulse only. In this paper, we show high quality FLIM images acquired at a pixel rate of 1 MHz. This approach is a promising candidate for an easy-to-use and benchtop FLIM system to make this technique available to a wider research community. PMID- 28717559 TI - Measuring the effect of a Western diet on liver tissue architecture by FLIM autofluorescence and harmonic generation microscopy. AB - The phasor approach to auto-fluorescence lifetime imaging was used to identify and characterize a long lifetime species (LLS) (~7.8 ns) in livers of mice fed with a Western diet. The size of the areas containing this LLS species depends on the type of diet and the size distribution shows Western diet has much larger LLS sizes. Combination of third harmonic generation images with FLIM identified the LLS species with fat droplets and the droplet size distribution was estimated. Second harmonic generation microscopy combined with phasor FLIM shows that there is an increase in fibrosis with a Western diet. A new decomposition in three components of the phasor plot shows that a Western diet is correlated with a higher fraction of free NADH, signifying more reducing condition and more glycolytic condition. Multiparametric analysis of phasor distribution shows that from the distribution of phasor points, a Western diet fed versus a low fat diet fed samples of mice livers can be separated. The phasor approach for the analysis of FLIM images of autofluorescence in liver specimens can result in discovery of new fluorescent species and then these new fluorescent species can help assess tissue architecture. Finally integrating FLIM and second and third harmonic analysis provides a measure of the advancement of fibrosis as an effect of diet. PMID- 28717560 TI - Ultra-high speed digital micro-mirror device based ptychographic iterative engine method. AB - To reduce the long data acquisition time of the common mechanical scanning based Ptychographic Iterative Engine (PIE) technique, the digital micro-mirror device (DMD) is used to form the fast scanning illumination on the sample. Since the transverse mechanical scanning in the common PIE is replaced by the on/off switching of the micro-mirrors, the data acquisition time can be reduced from more than 15 minutes to less than 20 seconds for recording 12 * 10 diffraction patterns to cover the same field of 147.08 mm2. Furthermore, since the precision of DMD fabricated with the optical lithography is always higher than 10 nm (1 MUm for the mechanical translation stage), the time consuming position-error correction procedure is not required in the iterative reconstruction. These two improvements fundamentally speed up both the data acquisition and the reconstruction procedures in PIE, and relax its requirements on the stability of the imaging system, therefore remarkably improve its applicability for many practices. It is demonstrated experimentally with both USAF resolution target and biological sample that, the spatial resolution of 5.52 MUm and the field of view of 147.08 mm2 can be reached with the DMD based PIE method. In a word, by using the DMD to replace the translation stage, we can effectively overcome the main shortcomings of common PIE related to the mechanical scanning, while keeping its advantages on both the high resolution and large field of view. PMID- 28717561 TI - Diattenuation of brain tissue and its impact on 3D polarized light imaging. AB - 3D-polarized light imaging (3D-PLI) reconstructs nerve fibers in histological brain sections by measuring their birefringence. This study investigates another effect caused by the optical anisotropy of brain tissue - diattenuation. Based on numerical and experimental studies and a complete analytical description of the optical system, the diattenuation was determined to be below 4 % in rat brain tissue. It was demonstrated that the diattenuation effect has negligible impact on the fiber orientations derived by 3D-PLI. The diattenuation signal, however, was found to highlight different anatomical structures that cannot be distinguished with current imaging techniques, which makes Diattenuation Imaging a promising extension to 3D-PLI. PMID- 28717562 TI - Development of thin skin mimicking bilayer solid tissue phantoms for optical spectroscopic studies. AB - In vivo spectroscopic measurements have the proven potential to provide important insight about the changes in tissue during the development of malignancies and thus help to diagnose tissue pathologies. Extraction of intrinsic data in the presence of varying amounts of scatterers and absorbers offers great challenges in the development of such techniques to the clinical level. Fabrication of optical phantoms, tailored to the biochemical as well as morphological features of the target tissue, can help to generate a spectral database for a given optical spectral measurement system. Such databases, along with appropriate pattern matching algorithms, could be integrated with in vivo measurements for any desired quantitative analysis of the target tissue. This paper addresses the fabrication of such soft, photo stable, thin bilayer phantoms, mimicking skin tissue in layer dimensions and optical properties. The performance evaluation of the fabricated set of phantoms is carried out using a portable fluorescence spectral measurement system. The alterations in flavin adenine dinucleotide (FAD) a tissue fluorophore that provides important information about dysplastic progressions in tissues associated with cancer development based on changes in emission spectra-fluorescence with varied concentrations of absorbers and scatterers present in the phantom are analyzed and the results are presented. Alterations in the emission intensity, shift in emission wavelength and broadening of the emission spectrum were found to be potential markers in the assessment of biochemical changes that occur during the progression of dysplasia. PMID- 28717563 TI - Multiphoton in vivo imaging with a femtosecond semiconductor disk laser. AB - We use an ultrafast diode-pumped semiconductor disk laser (SDL) to demonstrate several applications in multiphoton microscopy. The ultrafast SDL is based on an optically pumped Vertical External Cavity Surface Emitting Laser (VECSEL) passively mode-locked with a semiconductor saturable absorber mirror (SESAM) and generates 170-fs pulses at a center wavelength of 1027 nm with a repetition rate of 1.63 GHz. We demonstrate the suitability of this laser for structural and functional multiphoton in vivo imaging in both Drosophila larvae and mice for a variety of fluorophores (including mKate2, tdTomato, Texas Red, OGB-1, and R CaMP1.07) and for endogenous second-harmonic generation in muscle cell sarcomeres. We can demonstrate equivalent signal levels compared to a standard 80 MHz Ti:Sapphire laser when we increase the average power by a factor of 4.5 as predicted by theory. In addition, we compare the bleaching properties of both laser systems in fixed Drosophila larvae and find similar bleaching kinetics despite the large difference in pulse repetition rates. Our results highlight the great potential of ultrafast diode-pumped SDLs for creating a cost-efficient and compact alternative light source compared to standard Ti:Sapphire lasers for multiphoton imaging. PMID- 28717564 TI - Electrically tunable fluidic lens imaging system for laparoscopic fluorescence guided surgery. AB - The addition of fluorescence guidance in laparoscopic procedures has gained significant interest in recent years, particularly through the use of near infrared (NIR) markers. In this work we present a novel laparoscope camera coupler based on an electrically tunable fluidic lens that permits programmable focus control and has desirable achromatic performance from the visible to the NIR. Its use extends the lower working distance limit and improves detection sensitivity, important for work with molecularly targeted fluorescence markers. We demonstrate its superior optical performance in laparoscopic fluorescence guided surgery. In vivo results using a tumor specific molecular probe and a nonspecific NIR dye are presented. PMID- 28717566 TI - Chemical reactivation of resin-embedded pHuji adds red for simultaneous two-color imaging with EGFP. AB - The pH-sensitive fluorescent proteins enabling chemical reactivation in resin are useful tools for fluorescence microimaging. EGFP or EYFP is good for such applications. For simultaneous two-color imaging, a suitable red fluorescent protein is an urgent need. Here a pH-sensitive red fluorescent protein, pHuji, is selected and verified to remain pH-sensitive in HM20 resin. We observe 183% fluorescence intensity of pHuji in resin-embeded mouse brain and 29.08-fold fluorescence intensity of reactivated pHuji compared to the quenched state. pHuji and EGFP can be quenched and chemically reactivated simultaneously in resin, thus enabling simultaneous two-color micro-optical sectioning tomography of resin embedded mouse brain. This method may greatly facilitate the visualization of neuronal morphology and neural circuits to promote understanding of the structure and function of the brain. PMID- 28717567 TI - Introduction to the feature issue on the 25 year anniversary of optical coherence tomography. AB - The guest editors introduce a feature issue commemorating the 25th anniversary of optical coherence tomography. PMID- 28717565 TI - Twenty-five years of optical coherence tomography: the paradigm shift in sensitivity and speed provided by Fourier domain OCT [Invited]. AB - Optical coherence tomography (OCT) has become one of the most successful optical technologies implemented in medicine and clinical practice mostly due to the possibility of non-invasive and non-contact imaging by detecting back-scattered light. OCT has gone through a tremendous development over the past 25 years. From its initial inception in 1991 [Science254, 1178 (1991)] it has become an indispensable medical imaging technology in ophthalmology. Also in fields like cardiology and gastro-enterology the technology is envisioned to become a standard of care. A key contributor to the success of OCT has been the sensitivity and speed advantage offered by Fourier domain OCT. In this review paper the development of FD-OCT will be revisited, providing a single comprehensive framework to derive the sensitivity advantage of both SD- and SS OCT. We point out the key aspects of the physics and the technology that has enabled a more than 2 orders of magnitude increase in sensitivity, and as a consequence an increase in the imaging speed without loss of image quality. This speed increase provided a paradigm shift from point sampling to comprehensive 3D in vivo imaging, whose clinical impact is still actively explored by a large number of researchers worldwide. PMID- 28717568 TI - Robust total retina thickness segmentation in optical coherence tomography images using convolutional neural networks. AB - We developed a fully automated system using a convolutional neural network (CNN) for total retina segmentation in optical coherence tomography (OCT) that is robust to the presence of severe retinal pathology. A generalized U-net network architecture was introduced to include the large context needed to account for large retinal changes. The proposed algorithm outperformed qualitative and quantitatively two available algorithms. The algorithm accurately estimated macular thickness with an error of 14.0 +/- 22.1 um, substantially lower than the error obtained using the other algorithms (42.9 +/- 116.0 um and 27.1 +/- 69.3 um, respectively). These results highlighted the proposed algorithm's capability of modeling the wide variability in retinal appearance and obtained a robust and reliable retina segmentation even in severe pathological cases. PMID- 28717569 TI - Histogram analysis for smartphone-based rapid hematocrit determination. AB - A novel and rapid analysis technique using histogram has been proposed for the colorimetric quantification of blood hematocrits. A smartphone-based "Histogram" app for the detection of hematocrits has been developed integrating the smartphone embedded camera with a microfluidic chip via a custom-made optical platform. The developed histogram analysis shows its effectiveness in the automatic detection of sample channel including auto-calibration and can analyze the single-channel as well as multi-channel images. Furthermore, the analyzing method is advantageous to the quantification of blood-hematocrit both in the equal and varying optical conditions. The rapid determination of blood hematocrits carries enormous information regarding physiological disorders, and the use of such reproducible, cost-effective, and standard techniques may effectively help with the diagnosis and prevention of a number of human diseases. PMID- 28717570 TI - Chip-on-the-tip compact flexible endoscopic epifluorescence video-microscope for in-vivo imaging in medicine and biomedical research. AB - We demonstrate a 60 mg light video-endomicroscope with a cylindrical shape of the rigid tip of only 1.6 mm diameter and 6.7 mm length. A novel implementation method of the illumination unit in the endomicroscope is presented. It allows for the illumination of the biological sample with fiber-coupled LED light at 455 nm and the imaging of the red-shifted fluorescence light above 500 nm in epi direction. A large numerical aperture of 0.7 leads to a sub-cellular resolution and yields to high-contrast images within a field of view of 160 MUm. A miniaturized chip-on-the-tip CMOS image sensor with more than 150,000 pixels captures the multicolor images at 30 fps. Considering size, plug-and-play capability, optical performance, flexibility and weight, we hence present a probe which sets a new benchmark in the field of epifluorescence endomicroscopes. Several ex-vivo and in-vivo experiments in rodents and humans suggest future application in biomedical fields, especially in the neuroscience community, as well as in medical applications targeting optical biopsies or the detection of cellular anomalies. PMID- 28717571 TI - Visible spectrum extended-focus optical coherence microscopy for label-free sub cellular tomography. AB - We present a novel extended-focus optical coherence microscope (OCM) attaining 0.7 MUm axial and 0.4 MUm lateral resolution maintained over a depth of 40 MUm, while preserving the advantages of Fourier domain OCM. Our system uses an ultra broad spectrum from a supercontinuum laser source. As the spectrum spans from near-infrared to visible wavelengths (240 nm in bandwidth), we call the system visOCM. The combination of such a broad spectrum with a high-NA objective creates an almost isotropic 3D submicron resolution. We analyze the imaging performance of visOCM on microbead samples and demonstrate its image quality on cell cultures and ex-vivo brain tissue of both healthy and alzheimeric mice. In addition to neuronal cell bodies, fibers and plaques, visOCM imaging of brain tissue reveals fine vascular structures and sub-cellular features through its high spatial resolution. Sub-cellular structures were also observed in live cells and were further revealed through a protocol traditionally used for OCT angiography. PMID- 28717572 TI - Multiphoton microscopy for label-free identification of intramural metastasis in human esophageal squamous cell carcinoma. AB - For complete removal of cancerous tissue in esophageal squamous cell carcinoma (ESCC), intramural metastasis (IM) should be identified preoperatively or intraoperatively. Here, multiphoton microscopy (MPM) was introduced for label free identification of IM in the esophageal wall, by a combination of two-photon excited fluorescence (TPEF), second harmonic generation (SHG) imaging, and spectral analysis. Three-dimensional (3D) imaging of the IM region was also performed. Quantitative parameters, including 3D fiber orientation, were measured by 3D-weighted orientation vector summation. Overall, MPM showed the potential to identify IM. With the development of the advanced MPM endoscope, clinical identification of IM by MPM will be possible. PMID- 28717573 TI - In-vivo digital wavefront sensing using swept source OCT. AB - Sub-aperture based digital adaptive optics is demonstrated in a fiber based point scanning optical coherence tomography system using a 1060 nm swept source laser. To detect optical aberrations in-vivo, a small lateral field of view of ~[Formula: see text] is scanned on the sample at a high volume rate of 17 Hz (~1.3 kHz B-scan rate) to avoid any significant lateral and axial motion of the sample, and is used as a "guide star" for the sub-aperture based DAO. The proof of principle is demonstrated using a micro-beads phantom sample, wherein a significant root mean square wavefront error (RMS WFE) of 1.48 waves (> 1[Formula: see text]) is detected. In-vivo aberration measurement with a RMS WFE of 0.33 waves, which is ~5 times higher than the Marechal's criterion of [Formula: see text] waves for the diffraction limited performance, is shown for a human retinal OCT. Attempt has been made to validate the experimental results with the conventional Shack-Hartmann wavefront sensor within reasonable limitations. PMID- 28717574 TI - Detection of rotavirus in clinical specimens using an immunosensor prototype based on the photon burst counting technique. AB - In this study, a sensitive fluorescence sensor was developed for the detection of small, fluorescence-labeled particles dispersed in a solution. The prototype system comprises of a laser confocal optical system and a mechanical sample stage to detect photon bursting of fluorescence-labeled small particles in sample volumes less than 5 MUL within 3 minutes. To examine the feasibility of the prototype system as a diagnostic tool, assemblages of rotavirus and fluorescence labeled antibody were analyzed. The detection sensitivity for rotavirus was 1 * 104 pfu/mL. Rotavirus in stool samples from patients with acute gastroenteritis was also detected. The advantages and disadvantages of this immunosensor with respect to ELISA and RT-PCR, the current gold standards for virus detection, are discussed. PMID- 28717575 TI - Flow-mediated dilatation test using optoacoustic imaging: a proof-of-concept. AB - Label-free multispectral optoacoustic tomography (MSOT) has recently shown superior performance in visualizing the morphology of human vasculature, especially of smaller vessels, compared to ultrasonography. Herein, we extend these observations towards MSOT interrogation of macrovascular endothelial function. We employed a real-time handheld MSOT scanner to assess flow-mediated dilatation (FMD), a technique used to characterize endothelial function. A data processing scheme was developed to quantify the dimensions and diameter changes of arteries in humans and determine wall distensibility parameters. By enabling high-resolution delineation of the blood-vessel wall in a cross-sectional fashion, the findings suggest MSOT as a capable alternative to ultrasonography for clinical FMD measurements. PMID- 28717576 TI - Demodulation of quasi-quadrature interferometric signals for use in the totally implantable hearing aids. AB - We propose and experimentally prove an algorithm for demodulation of interferometric signals, modified for use in a totally implantable hearing aid device. A fiber optic configuration, which generates two quasi-quadrature signals by a passive 3x3 coupler, for a non-contact detection of the middle ear ossicle vibration is employed. We simulated the ossicle vibration and large movements and demonstrated the effectiveness of the algorithm to compensate changes of the signal DC values and the phase shift introduced by the coupler. Applying the proposed algorithm we obtained the output signal stability better than 0.5 dB, and the system equivalent input noise of about 31 dB (A) SPL @ 1 kHz. PMID- 28717577 TI - Temporal multiplexing to simulate multifocal intraocular lenses: theoretical considerations. AB - Fast tunable lenses allow an effective design of a portable simultaneous vision simulator (SimVis) of multifocal corrections. A novel method of evaluating the temporal profile of a tunable lens in simulating different multifocal intraocular lenses (M-IOLs) is presented. The proposed method involves the characteristic fitting of the through-focus (TF) optical quality of the multifocal component of a given M-IOL to a linear combination of TF optical quality of monofocal lenses viable with a tunable lens. Three different types of M-IOL designs are tested, namely: segmented refractive, diffractive and refractive extended depth of focus. The metric used for the optical evaluation of the temporal profile is the visual Strehl (VS) ratio. It is shown that the time profiles generated with the VS ratio as a metric in SimVis resulted in TF VS ratio and TF simulated images that closely matched the TF VS ratio and TF simulated images predicted with the M-IOL. The effects of temporal sampling, varying pupil size, monochromatic aberrations, longitudinal chromatic aberrations and temporal dynamics on SimVis are discussed. PMID- 28717578 TI - In vivo analysis of mucosal lipids reveals histological disease activity in ulcerative colitis using endoscope-coupled Raman spectroscopy. AB - The goal of this study is to evaluate endoscopic Raman spectroscopy as a noninvasive technique to determine histological inflammatory status of colitis. Colon mucosal composition was investigated in vivo from patients with ulcerative colitis (UC) and from age- and body mass index (BMI) matched controls using endoscope-coupled Raman spectroscopy. The results were co-registered with histological assessment of inflammatory status at the same locations. Substantial decreases (50-60%) in the content of phosphotidylcholines (PCs) and total lipids were observed in inflamed colon tissue (histology grade 1, 2 and 3) compared to those from the quiescent (histology grade 0) and from the controls. No significant difference was observed in lipids or PC contents between control and grade 0, or among grades 1 - 3. The degree of lipid unsaturation increased in the inflamed tissue regardless of disease severity. The inflammation-associated alterations in lipids and PC are observed independent of BMI or the anatomical locations for data collection. Multivariate analysis using support vector machine (SVM) algorithm classified the spectra of the controls or the inactive colitis from those of inflamed tissue with a sensitivity of 83.5% and 97.1% respectively. Our results showed that mucosal lipid content is related to the microscopic disease activity, and thus could serve as a valuable spectral marker to differentiate active colitis from the quiescent. PMID- 28717579 TI - Deep-learning based, automated segmentation of macular edema in optical coherence tomography. AB - Evaluation of clinical images is essential for diagnosis in many specialties. Therefore the development of computer vision algorithms to help analyze biomedical images will be important. In ophthalmology, optical coherence tomography (OCT) is critical for managing retinal conditions. We developed a convolutional neural network (CNN) that detects intraretinal fluid (IRF) on OCT in a manner indistinguishable from clinicians. Using 1,289 OCT images, the CNN segmented images with a 0.911 cross-validated Dice coefficient, compared with segmentations by experts. Additionally, the agreement between experts and between experts and CNN were similar. Our results reveal that CNN can be trained to perform automated segmentations of clinically relevant image features. PMID- 28717580 TI - Photoacoustic/ultrasound dual imaging of human thyroid cancers: an initial clinical study. AB - We reported an initial clinical study of in vivo human thyroid by a photoacoustic/ultrasound handheld probe. Our dual-modality system is based on a high-end clinical ultrasound machine. Both healthy and cancerous thyroids were imaged non-invasively, and we compared the photoacoustic imaging with color Doppler ultrasound. The results of photoacoustic thyroid imaging could reveal many blood vessels that were not sensitive for Doppler ultrasound. Our study demonstrated that photoacoustic imaging could provide important complementary information for traditional ultrasound thyroid examination, which has a great potential for clinical diagnosis. PMID- 28717581 TI - Detection of Echinococcus granulosus antigen by a quantum dot/porous silicon optical biosensor. AB - Highly sensitive labeled detection of Echinococcus granulosus using colloidal quantum dots (QDs) based on a porous silicon Bragg mirror sensor are demonstrated. Rabbit anti-p38 labeled CdSe/ZnS QDs was infiltrated in porous silicon pores immobilized Egp38 antigen. QD-antibodies are specifically bound to antigens linked covalently to the pore walls of PSi after the immune reaction. By the design of the transfer matrix method and the preparation of the electrochemical etching method, the fluorescence peak wavelength of the quantum dots is located in the forbidden band of the Bragg mirror. The fluorescence of QDs are enhanced by PSi Bragg mirror. Egp38 antigen detection limit of 300fg/mL is achievable. Our results exhibit that the biosensor combining PSi Bragg mirror and QDs can potentially be applied to the clinical detection of hydatid disease. PMID- 28717582 TI - In vivo multiphoton imaging of a diverse array of fluorophores to investigate deep neurovascular structure. AB - We perform high-resolution, non-invasive, in vivo deep-tissue imaging of the mouse neocortex using multiphoton microscopy with a high repetition rate optical parametric amplifier laser source tunable between lambda=1,100 and 1,400 nm. By combining the high repetition rate (511 kHz) and high pulse energy (400 nJ) of our amplifier laser system, we demonstrate imaging of vasculature labeled with Texas Red and Indocyanine Green, and neurons expressing tdTomato and yellow fluorescent protein. We measure the blood flow speed of a single capillary at a depth of 1.2 mm, and image vasculature to a depth of 1.53 mm with fine axial steps (5 MUm) and reasonable acquisition times. The high image quality enabled analysis of vascular morphology at depths to 1.45 mm. PMID- 28717583 TI - In vivo photothermal treatment with real-time monitoring by optical fiber-needle array. AB - Photothermal treatment (PTT) using gold nanoshells (gold-NSs) is accepted as a method for treating cancer. However, owing to restrictions in therapeutic depth and skin damage caused by excessive light exposure, its application has been limited to lesions close to the epidermis. Here, we demonstrate an in vivo PTT method that uses gold-NSs with a flexible optical fiber-needle array (OFNA), which is an array of multiple needles in which multimode optical fibers are inserted, one in each, for light delivery. The light for PTT was directly administrated to subcutaneous tissues through the OFNA, causing negligible thermal damage to the skin. Enhancement of light energy delivery assisted by the OFNA in a target area was confirmed by investigation using artificial tissues. The ability of OFNA to treat cancer without causing cutaneous thermal damage was also verified by hematoxylin and eosin (H&E) staining and optical coherence tomography in cancer models in mice. In addition, the OFNA allowed for observation of the target site through an imaging fiber bundle. By imaging the activation of the injected gold-NSs, we were able to obtain information on the PTT process in real-time. PMID- 28717584 TI - Pulse wave analysis with diffusing-wave spectroscopy. AB - Hypertension is a major risk factor for cardiovascular disease and thus at the origin of many deaths by e.g. heart attack or stroke. Hypertension is caused by many factors including an increase in arterial stiffness which leads to changes in pulse wave velocity and wave reflections. Those often result in an increased left ventricular load which may result in heart failure as well as an increased pulsatile pressure in the microcirculation l to damage to blood vessels. In order to specifically treat the different causes of hypertension it is desirable to perform a pulse wave analysis as a complement to measurements of systolic and diastolic pressure by brachial cuff sphygmomanometry. Here we show that Diffusing Wave Spectroscopy, a novel non-invasive portable tool, is able to monitor blood flow changes with a high temporal resolution. The measured pulse travel times give detailed information of the pulse wave blood flow profile. PMID- 28717585 TI - Erratum: Measuring the effect of Western diet on liver tissue architecture by FLIM autofluorescence and harmonic generation microscopy: erratum. AB - [This corrects the article on p. 3143 in vol. 8.]. PMID- 28717586 TI - Evaluating platelet aggregation dynamics from laser speckle fluctuations. AB - Platelets are key to maintaining hemostasis and impaired platelet aggregation could lead to hemorrhage or thrombosis. We report a new approach that exploits laser speckle intensity fluctuations, emanated from a drop of platelet-rich plasma (PRP), to profile aggregation. Speckle fluctuation rate is quantified by the speckle intensity autocorrelation, g2(t), from which the aggregate size is deduced. We first apply this approach to evaluate polystyrene bead aggregation, triggered by salt. Next, we assess dose-dependent platelet aggregation and inhibition in human PRP spiked with adenosine diphosphate and clopidogrel. Additional spatio-temporal speckle analyses yield 2-dimensional maps of particle displacements to visualize platelet aggregate foci within minutes and quantify aggregation dynamics. These findings demonstrate the unique opportunity for assessing platelet health within minutes for diagnosing bleeding disorders and monitoring anti-platelet therapies. PMID- 28717587 TI - Closed-Incision Negative-Pressure Therapy in Obese Patients Undergoing Cesarean Delivery: A Randomized Controlled Trial. AB - Background Postcesarean wound morbidity is a costly complication of cesarean delivery for which preventative strategies remain understudied. Objective We compared surgical site occurrences (SSOs) in cesarean patients receiving closed incision negative-pressure therapy (ciNPT) or standard-of-care (SOC) dressing. Study Design A single-center randomized controlled trial compared ciNPT (5-7 days) to SOC dressing (1-2 days) in obese women (body mass index [BMI] >= 35), undergoing cesarean delivery between 2012 and 2014. Participants were randomized 1:1 and monitored 42 +/- 10 days postoperatively. The primary outcome SSOs included unanticipated local inflammation, wound infection, seroma, hematoma, dehiscence, and need for surgical or antibiotic intervention. Results Of the 92 randomized patients, 82 completed the study. ciNPT and SOC groups had similar baseline characteristics. Mean BMI was 46.5 +/- 6.5 and no treatment-related serious adverse events. Compared with SOC, the ciNPT group had fewer SSOs (7/43 [16.3%] vs. 2/39 [5.1%], respectively; p = 0.16); significantly fewer participants with less incisional pain both at rest (39/46 [84.8%] vs. 20/46 [43.5%]; p < 0.001) and with incisional pressure (42/46 [91.3%] vs. 25/46 [54.3%]; p < 0.001); and a 30% decrease in total opioid use (79.1 vs. 55.9 mg morphine equivalents, p = 0.036). Conclusion A trend in SSO reduction and a statistically significant reduction in postoperative pain and narcotic use was observed in women using ciNPT. PMID- 28717588 TI - Erratum. AB - [This corrects the article on p. 3 in vol. 6.]. PMID- 28717589 TI - Association of polymorphic markers of genes FTO, KCNJ11, CDKAL1, SLC30A8, and CDKN2B with type 2 diabetes mellitus in the Russian population. AB - BACKGROUND: The association of type 2 diabetes mellitus (T2DM) with the KCNJ11, CDKAL1, SLC30A8, CDKN2B, and FTO genes in the Russian population has not been well studied. In this study, we analysed the population frequencies of polymorphic markers of these genes. METHODS: The study included 862 patients with T2DM and 443 control subjects of Russian origin. All subjects were genotyped for 10 single nucleotide polymorphisms (SNPs) of the genes using real-time PCR (TaqMan assays). HOMA-IR and HOMA-beta were used to measure insulin resistance and beta-cell secretory function, respectively. RESULTS: The analysis of the frequency distribution of polymorphic markers for genes KCNJ11, CDKAL1, SLC30A8 and CDKN2B showed statistically significant associations with T2DM in the Russian population. The association between the FTO gene and T2DM was not statistically significant. The polymorphic markers rs5219 of the KCNJ11 gene, rs13266634 of the SLC30A8 gene, rs10811661 of the CDKN2B gene and rs9465871, rs7756992 and rs10946398 of the CDKAL1 gene showed a significant association with impaired glucose metabolism or impaired beta-cell function. CONCLUSION: In the Russian population, genes, which affect insulin synthesis and secretion in the beta-cells of the pancreas, play a central role in the development of T2DM. PMID- 28717590 TI - Construction of a fur null mutant and RNA-sequencing provide deeper global understanding of the Aliivibrio salmonicida Fur regulon. AB - BACKGROUND: The ferric uptake regulator (Fur) is a transcription factor and the main regulator of iron acquisition in prokaryotes. When bound to ferric iron, Fur recognizes its DNA binding site and generally executes its function by repressing transcription of its target genes. Due to its importance in virulence, the Fur regulon is well studied for several model bacteria. In our previous work, we used computational predictions and microarray to gain insights into Fur-regulation in Aliivibrio salmonicida, and have identified a number of genes and operons that appear to be under direct control of Fur. To provide a more accurate and deeper global understanding of the biological role of Fur we have now generated an A. salmonicida fur knock-out strain and used RNA-sequencing to compare gene expression between the wild-type and fur null mutant strains. RESULTS: An A. salmonicida fur null mutant strain was constructed. Biological assays demonstrate that deletion of fur results in loss of fitness, with reduced growth rates, and reduced abilities to withstand low-iron conditions, and oxidative stress. When comparing expression levels in the wild-type and the fur null mutant we retrieved 296 differentially expressed genes distributed among 18 of 21 functional classes of genes. A gene cluster encoding biosynthesis of the siderophore bisucaberin represented the highest up-regulated genes in the fur null mutant. Other highly up-regulated genes all encode proteins important for iron acquisition. Potential targets for the RyhB sRNA was predicted from the list of down-regulated genes, and significant complementarities were found between RyhB and mRNAs of the fur, sodB, cysN and VSAL_I0422 genes. Other sRNAs with potential functions in iron homeostasis were identified. CONCLUSION: The present work provides by far the most comprehensive and deepest understanding of the Fur regulon in A. salmonicida to date. Our data also contribute to a better understanding of how Fur plays a key role in iron homeostasis in bacteria in general, and help to show how Fur orchestrates iron uptake when iron levels are extremely low. PMID- 28717591 TI - Nectar-living yeasts of a tropical host plant community: diversity and effects on community-wide floral nectar traits. AB - We characterize the diversity of nectar-living yeasts of a tropical host plant community at different hierarchical sampling levels, measure the associations between yeasts and nectariferous plants, and measure the effect of yeasts on nectar traits. Using a series of hierarchically nested sampling units, we extracted nectar from an assemblage of host plants that were representative of the diversity of life forms, flower shapes, and pollinator types in the tropical area of Yucatan, Mexico. Yeasts were isolated from single nectar samples; their DNA was identified, the yeast cell density was estimated, and the sugar composition and concentration of nectar were quantified using HPLC. In contrast to previous studies from temperate regions, the diversity of nectar-living yeasts in the plant community was characterized by a relatively high number of equally common species with low dominance. Analyses predict highly diverse nectar yeast communities in a relatively narrow range of tropical vegetation, suggesting that the diversity of yeasts will increase as the number of sampling units increases at the level of the species, genera, and botanical families of the hosts. Significant associations between specific yeast species and host plants were also detected; the interaction between yeasts and host plants impacted the effect of yeast cell density on nectar sugars. This study provides an overall picture of the diversity of nectar-living yeasts in tropical host plants and suggests that the key factor that affects the community-wide patterns of nectar traits is not nectar chemistry, but rather the type of yeasts interacting with host plants. PMID- 28717592 TI - EPAS1 variants in high altitude Tibetan wolves were selectively introgressed into highland dogs. AB - BACKGROUND: Admixture can facilitate adaptation. For example, black wolves have obtained the variant causing black coat color through past hybridization with domestic dogs and have higher fitness than gray colored wolves. Another recent example of the transfer of adaptive variation between the two species has been suggested by the similarity between high altitude Tibetan mastiffs and wolves at the EPAS1 gene, a transcription factor induced in low oxygen environments. METHODS: Here, we investigate the directionality of admixture in EPAS1 between 28 reference highland gray wolves, 15 reference domestic dogs, and 21 putatively admixed highland wolves. This experimental design represents an expanded sample of Asian dogs and wolves from previous studies. Admixture was inferred using 17,709 publicly available SNP genotypes on canine chromosome 10. We additionally conducted a scan for positive selection in the highland dog genome. RESULTS: We find an excess of highland gray wolf ancestry at the EPAS1 locus in highland domestic dogs, suggesting adaptive introgression from wolves to dogs. The signal of admixture is limited in genomic extent to a small region on chromosome 10, indicating that it is the focus of selection in an oxygen-limited environment. DISCUSSION: Our results suggest that an adaptive variant of EPAS1 in highland wolves was transferred to highland dogs, carrying linked variants that potentially function in hypoxia response at high elevation. The intertwined history of dogs and wolves ensures a unique evolutionary dynamic where variants that have appeared in the history of either species can be tested for their effects on fitness under natural and artificial selection. Such coupled evolutionary histories may be key to the persistence of wild canines and their domesticated kin given the increasing anthropogenic modifications that characterize the future of both species. PMID- 28717593 TI - Short reads from honey bee (Apis sp.) sequencing projects reflect microbial associate diversity. AB - High throughput (or 'next generation') sequencing has transformed most areas of biological research and is now a standard method that underpins empirical study of organismal biology, and (through comparison of genomes), reveals patterns of evolution. For projects focused on animals, these sequencing methods do not discriminate between the primary target of sequencing (the animal genome) and 'contaminating' material, such as associated microbes. A common first step is to filter out these contaminants to allow better assembly of the animal genome or transcriptome. Here, we aimed to assess if these 'contaminations' provide information with regard to biologically important microorganisms associated with the individual. To achieve this, we examined whether the short read data from Apis retrieved elements of its well established microbiome. To this end, we screened almost 1,000 short read libraries of honey bee (Apis sp.) DNA sequencing project for the presence of microbial sequences, and find sequences from known honey bee microbial associates in at least 11% of them. Further to this, we screened ~500 Apis RNA sequencing libraries for evidence of viral infections, which were found to be present in about half of them. We then used the data to reconstruct draft genomes of three Apis associated bacteria, as well as several viral strains de novo. We conclude that 'contamination' in short read sequencing libraries can provide useful genomic information on microbial taxa known to be associated with the target organisms, and may even lead to the discovery of novel associations. Finally, we demonstrate that RNAseq samples from experiments commonly carry uneven viral loads across libraries. We note variation in viral presence and load may be a confounding feature of differential gene expression analyses, and as such it should be incorporated as a random factor in analyses. PMID- 28717595 TI - Egg clutch dehydration induces early hatching in red-eyed treefrogs, Agalychnis callidryas. AB - Terrestrial eggs have evolved repeatedly in tropical anurans exposing embryos to the new threat of dehydration. Red-eyed treefrogs, Agalychnis callidryas, lay eggs on plants over water. Maternally provided water allows shaded eggs in humid sites to develop to hatching without rainfall, but unshaded eggs and those in less humid sites can die from dehydration. Hatching responses of amphibian eggs to dry conditions are known from two lineages with independent origins of terrestrial eggs. Here, we experimentally tested for dehydration-induced early hatching in another lineage (Agalychnis callidryas, Phyllomedusidae), representing a third independent origin of terrestrial eggs. We also investigated how dehydration affected egg and clutch structure, and egg mortality. We collected clutches from a pond in Gamboa, Panama, and randomly allocated them to wet or dry treatments at age 1 day. Embryos hatched earlier from dry clutches than from wet clutches, accelerating hatching by ~11%. Clutch thickness and egg diameter were affected by dehydration, diverging between treatments over time. Meanwhile, mortality in dry clutches was six-fold higher than in control clutches. With this study, early hatching responses to escape mortality from egg dehydration are now known from three anuran lineages with independent origins of terrestrial eggs, suggesting they may be widespread. Further studies are needed to understand how terrestrial amphibian eggs can respond to, or will be affected by, rapid changes in climate over the next decades. PMID- 28717594 TI - Effect of freshwater mussels on the vertical distribution of anaerobic ammonia oxidizers and other nitrogen-transforming microorganisms in upper Mississippi river sediment. AB - Targeted qPCR and non-targeted amplicon sequencing of 16S rRNA genes within sediment layers identified the anaerobic ammonium oxidation (anammox) niche and characterized microbial community changes attributable to freshwater mussels. Anammox bacteria were normally distributed (Shapiro-Wilk normality test, W statistic =0.954, p = 0.773) between 1 and 15 cm depth and were increased by a factor of 2.2 (p < 0.001) at 3 cm below the water-sediment interface when mussels were present. Amplicon sequencing of sediment at depths relevant to mussel burrowing (3 and 5 cm) showed that mussel presence reduced observed species richness (p = 0.005), Chao1 diversity (p = 0.005), and Shannon diversity (p < 0.001), with more pronounced decreases at 5 cm depth. A non-metric, multidimensional scaling model showed that intersample microbial species diversity varied as a function of mussel presence, indicating that sediment below mussels harbored distinct microbial communities. Mussel presence corresponded with a 4-fold decrease in a majority of operational taxonomic units (OTUs) classified in the phyla Gemmatimonadetes, Actinobacteria, Acidobacteria, Plantomycetes, Chloroflexi, Firmicutes, Crenarcheota, and Verrucomicrobia. 38 OTUs in the phylum Nitrospirae were differentially abundant (p < 0.001) with mussels, resulting in an overall increase from 25% to 35%. Nitrogen (N)-cycle OTUs significantly impacted by mussels belonged to anammmox genus Candidatus Brocadia, ammonium oxidizing bacteria family Nitrosomonadaceae, ammonium oxidizing archaea genus Candidatus Nitrososphaera, nitrite oxidizing bacteria in genus Nitrospira, and nitrate- and nitrite-dependent anaerobic methane oxidizing organisms in the archaeal family "ANME-2d" and bacterial phylum "NC10", respectively. Nitrosomonadaceae (0.9-fold (p < 0.001)) increased with mussels, while NC10 (2.1-fold (p < 0.001)), ANME-2d (1.8-fold (p < 0.001)), and Candidatus Nitrososphaera (1.5-fold (p < 0.001)) decreased with mussels. Co-occurrence of 2 fold increases in Candidatus Brocadia and Nitrospira in shallow sediments suggests that mussels may enhance microbial niches at the interface of oxic anoxic conditions, presumably through biodeposition and burrowing. Furthermore, it is likely that the niches of Candidatus Nitrososphaera and nitrite- and nitrate-dependent anaerobic methane oxidizers were suppressed by mussel biodeposition and sediment aeration, as these phylotypes require low ammonium concentrations and anoxic conditions, respectively. As far as we know, this is the first study to characterize freshwater mussel impacts on microbial diversity and the vertical distribution of N-cycle microorganisms in upper Mississippi river sediment. These findings advance our understanding of ecosystem services provided by mussels and their impact on aquatic biogeochemical N-cycling. PMID- 28717596 TI - Phenotypic and microRNA transcriptomic profiling of the MDA-MB-231 spheroid enriched CSCs with comparison of MCF-7 microRNA profiling dataset. AB - Breast cancer spheroids have been widely used as in vitro models of cancer stem cells (CSCs), yet little is known about their phenotypic characteristics and microRNAs (miRNAs) expression profiles. The objectives of this research were to evaluate the phenotypic characteristics of MDA-MB-231 spheroid-enriched cells for their CSCs properties and also to determine their miRNAs expression profile. Similar to our previously published MCF-7 spheroid, MDA-MB-231 spheroid also showed typical CSCs characteristics namely self-renewability, expression of putative CSCs-related surface markers and enhancement of drug resistance. From the miRNA profile, miR-15b, miR-34a, miR-148a, miR-628 and miR-196b were shown to be involved in CSCs-associated signalling pathways in both models of spheroids, which highlights the involvement of these miRNAs in maintaining the CSCs features. In addition, unique clusters of miRNAs namely miR-205, miR-181a and miR 204 were found in basal-like spheroid whereas miR-125, miR-760, miR-30c and miR 136 were identified in luminal-like spheroid. Our results highlight the roles of miRNAs as well as novel perspectives of the relevant pathways underlying spheroid enriched CSCs in breast cancer. PMID- 28717597 TI - Cuticle hydrocarbons in saline aquatic beetles. AB - Hydrocarbons are the principal component of insect cuticle and play an important role in maintaining water balance. Cuticular impermeability could be an adaptative response to salinity and desiccation in aquatic insects; however, cuticular hydrocarbons have been poorly explored in this group and there are no previous data on saline species. We characterized cuticular hydrocarbons of adults and larvae of two saline aquatic beetles, namely Nebrioporus baeticus (Dytiscidae) and Enochrus jesusarribasi (Hydrophilidae), using a gas chromatograph coupled to a mass spectrometer. The CHC profile of adults of both species, characterized by a high abundance of branched alkanes and low of unsaturated alkenes, seems to be more similar to that of some terrestrial beetles (e.g., desert Tenebrionidae) compared with other aquatic Coleoptera (freshwater Dytiscidae). Adults of E. jesusarribasi had longer chain compounds than N. baeticus, in agreement with their higher resistance to salinity and desiccation. The more permeable cuticle of larvae was characterized by a lower diversity in compounds, shorter carbon chain length and a higher proportion of unsaturated hydrocarbons compared with that of the adults. These results suggest that osmotic stress on aquatic insects could exert a selection pressure on CHC profile similar to aridity in terrestrial species. PMID- 28717598 TI - Development rate rather than social environment influences cognitive performance in Australian black field crickets, Teleogryllus commodus. AB - Cognitive functioning is vital for enabling animals of all taxa to optimise their chances of survival and reproductive success. Learning and memory in particular are drivers of many evolutionary processes. In this study, we examine how developmental plasticity can affect cognitive ability by exploring the role the early social environment has on problem solving ability and learning of female black field crickets, Teleogryllus commodus. We used two learning paradigms, an analog of the Morris water maze and a novel linear maze, to examine cognitive differences between individuals reared in two acoustic treatments: silence or calling. Although there was no evidence of learning or memory, individuals that took longer to mature solved the Morris water maze more quickly. Our results suggest that increased investment into cognitive development is likely associated with increased development time during immature stages. Inconsistent individual performance and motivation during the novel linear maze task highlights the difficulties of designing ecologically relevant learning tasks within a lab setting. The role of experimental design in understanding cognitive ability and learning in more natural circumstances is discussed. PMID- 28717599 TI - Improving the trajectory of transpedicular transdiscal lumbar screw fixation with a computer-assisted 3D-printed custom drill guide. AB - Transpedicular transdiscal screw fixation is an alternative technique used in lumbar spine fixation; however, it requires an accurate screw trajectory. The aim of this study is to design a novel 3D-printed custom drill guide and investigate its accuracy to guide the trajectory of transpedicular transdiscal (TPTD) lumbar screw fixation. Dicom images of thirty lumbar functional segment units (FSU, two segments) of L1-L4 were acquired from the PACS system in our hospital (patients who underwent a CT scan for other abdomen diseases and had normal spine anatomy) and imported into reverse design software for three-dimensional reconstructions. Images were used to print the 3D lumbar models and were imported into CAD software to design an optimal TPTD screw trajectory and a matched custom drill guide. After both the 3D printed FSU models and 3D-printed custom drill guide were prepared, the TPTD screws will be guided with a 3D-printed custom drill guide and introduced into the 3D printed FSU models. No significant statistical difference in screw trajectory angles was observed between the digital model and the 3D-printed model (P > 0.05). Our present study found that, with the help of CAD software, it is feasible to design a TPTD screw custom drill guide that could guide the accurate TPTD screw trajectory on 3D-printed lumbar models. PMID- 28717600 TI - Implementation of the Xpert MTB/RIF assay for tuberculosis in Mongolia: a qualitative exploration of barriers and enablers. AB - OBJECTIVE: The aim of our study was to identify barriers and enablers to implementation of the Xpert MTB/RIF test within Mongolia's National Tuberculosis Program. METHODS: Twenty-foursemi-structured interviews were conducted between June and September 2015 with laboratory staff and tuberculosis physicians in Mongolia's capital Ulaanbaatar and regional towns where Xpert MTB/RIF testing had been implemented. Interviews were recorded, transcribed, translated and analysed thematically using NVIVO qualitative analysis software. RESULTS: Eight laboratory staff (five from the National Tuberculosis Reference Laboratory in Ulaanbaatar and three from provincial laboratories) and sixteen tuberculosis physicians (five from the Mongolian National Center for Communicable Diseases in Ulaanbaatar, four from district tuberculosis clinics in Ulaanbaatar and seven from provincial tuberculosis clinics) were interviewed. Major barriers to Xpert MTB/RIF implementation identified were: lack of awareness of program guidelines; inadequate staffing arrangements; problems with cartridge supply management; lack of local repair options for the Xpert machines; lack of regular formal training; paper based system; delayed treatment initiation due to consensus meeting and poor sample quality. Enablers to Xpert MTB/RIF implementation included availability of guidelines in the local language; provision of extra laboratory staff, shift working arrangements and additional modules; capacity for troubleshooting internally; access to experts; opportunities for peer learning; common understanding of diagnostic algorithms and decentralised testing. CONCLUSION: Our study identified a number of barriers and enablers to implementation of Xpert MTB/RIF in the Mongolian National Tuberculosis Program. Lessons learned from this study can help to facilitate implementation of Xpert MTB/RIF in other Mongolian locations as well as other low-and middle-income countries. PMID- 28717601 TI - Investigation on papillomavirus infection in dromedary camels in Al-Ahsa, Saudi Arabia. AB - We investigated two outbreaks of papillomatosis between 2013 and 2015 in Al Ahsa region of eastern Saudi Arabia involving fourteen dromedary camels. The disease affected both young and adult animals and occurred in coincidence with demodectic mange infestation. Diagnosis was made based on gross and histopathological characteristics of the wart lesion and was confirmed by PCR. Rolling circle amplification followed by degenerate primer PCR and sequencing of the amplicons revealed the presence of both Camelus dromedarius papillomavirus types 1 and 2, previously identified in infected dromedaries in Sudan. PMID- 28717602 TI - Expression of various sarcomeric tropomyosin isoforms in equine striated muscles. AB - In order to better understand the training and athletic activity of horses, we must have complete understanding of the isoform diversity of various myofibrillar protein genes like tropomyosin. Tropomyosin (TPM), a coiled-coil dimeric protein, is a component of thin filament in striated muscles. In mammals, four TPM genes (TPM1, TPM2, TPM3, and TPM4) generate a multitude of TPM isoforms via alternate splicing and/or using different promoters. Unfortunately, our knowledge of TPM isoform diversity in the horse is very limited. Hence, we undertook a comprehensive exploratory study of various TPM isoforms from horse heart and skeletal muscle. We have cloned and sequenced two sarcomeric isoforms of the TPM1 gene called TPM1alpha and TPM1kappa, one sarcomeric isoform of the TPM2 and one of the TPM3 gene, TPM2alpha and TPM3alpha respectively. By qRT-PCR using both relative expression and copy number, we have shown that TPM1alpha expression compared to TPM1kappa is very high in heart. On the other hand, the expression of TPM1alpha is higher in skeletal muscle compared to heart. Further, the expression of TPM2alpha and TPM3alpha are higher in skeletal muscle compared to heart. Using western blot analyses with CH1 monoclonal antibody we have shown the high expression levels of sarcomeric TPM proteins in cardiac and skeletal muscle. Due to the paucity of isoform specific antibodies we cannot specifically detect the expression of TPM1kappa in horse striated muscle. To the best of our knowledge this is the very first report on the characterization of sarcmeric TPMs in horse striated muscle. PMID- 28717603 TI - Isolated limb perfusion electrochemotherapy for the treatment of an advanced squamous cell carcinoma of the hoof in a mare. AB - A twenty-year-old female saddle horse was referred for evaluation of a seven month, non-healing erosive lesion of the right hind hoof with proliferation and bleeding of the underlying soft tissues. This lesion had been twice surgically treated as a canker but rapidly recurred. Histological examination of the second excision revealed a well-differentiated squamous cell carcinoma. At presentation, the horse was mildly depressed, lame and partially non-weight-bearing on the right hind leg, which exhibited a 10 x 10 cm erosive and proliferative lesion remodeling the hoof. After completing staging procedures, the lesion was approached with surgery and intraoperative electrochemotherapy (ECT) administration of bleomycin in isolated limb perfusion. A second session of surgery and ECT was performed one month later, followed by three additional monthly sessions of ECT. During periodic recheck, the mare showed continuous improvement. One year after presentation, the mare was in complete remission and her gait markedly improved. ECT was well-tolerated and resulted in improved local control of a tumor in a challenging anatomical district. PMID- 28717604 TI - Central vestibular syndrome in a red fox (Vulpes vulpes) with presumptive right caudal cerebral artery ischemic infarct and prevalent midbrain involvement. AB - A wild young male red fox (Vulpes vulpes) was found in the mountainous hinterland of Rome (Italy) with a heavily depressed mental status and unresponsive to the surrounding environment. Neurological examination revealed depression, left circling, right head tilt, ventromedial positional strabismus and decreased postural reactions on the left side. Neurological abnormalities were suggestive of central vestibular syndrome. Two consecutive MRIs performed with 30 days interval were compatible with lacunar ischemic infarct in the territory of right caudal cerebral artery and its collateral branches. The lesion epicentre was in the right periaqueductal portion of the rostral mesencephalic tegmentum. Neuroanatomical and neurophysiological correlation between lesion localization and clinical presentation are discussed. PMID- 28717606 TI - Combined supplementation of ascorbic acid and thyroid hormone T3 affects tenocyte proliferation. The effect of ascorbic acid in the production of nitric oxide. AB - BACKGROUND: Tissue engineering is now increasingly focusing on cell-based treatments as promising tools to improve tendon repair. However, many crucial aspects of tendon biology remain to be understood before adopting the best experimental approach for cell-tissue engineering. METHODS: The role played by Ascorbic Acid (AA) alone and in combination with thyroid hormone T3 in the viability and proliferation of primary human tendon-derived cells was investigated. Human tenocyte viability was detected by Trypan blue exclusion test and cellular proliferation rate was evaluated by CFSE CellTraceTM. In addition, the potential role of the AA in the production of Nitric Oxide (NO) was also examined. RESULTS: In this in vitro model, an increase in tenocyte proliferation rate was observed as a consequence of progressively increased concentrations of AA (from 10 to 50 ug/ml). The addition of the T3 hormone to the culture further increased tenocyte proliferation rate. In detail, the most evident effect on cellular growth was achieved using the combined supplementation of 50 ug/ml AA and 10-7 M T3. CONCLUSION: We showed that the highest concentration of AA (100 and 500 ug/ml) caused cytotoxicity to human tenocytes. Moreover, it was shown that AA reduces NO synthesis. These results show that AA is a cell proliferation inducer that triggers tenocyte growth, while it reduces NO synthesis. PMID- 28717607 TI - Arthroscopic trans-osseous rotator cuff repair. AB - BACKGROUND: Mechanical factors are at the basis of any tendon healing process, being pressure an aspect able to positively influence it. For this reason transosseous rotator cuff repair represents the gold standard procedure for patients affected by a cuff tear, maximizing the tendon footprint contact area and reducing motion at the tendon to bone interface. METHODS: The Authors present an all arthroscopic suture bridge-like transosseous repair with the preparation of a single transosseous tunnel perfor med thanks to a precise dedicated instrument (Compasso(r)) and one implant (Elite-SPK(r)) with the use of only 3 suture wires. In addition this technique permits to accurately prepare the bony side of the lesion without any risk or complication, such as anchor pull-out and greater tuberosity bone osteolysis. CONCLUSIONS: However, even if this technique seems less demanding, the arthroscopic transosseous repair is still an advanced procedure, and should be performed only by well prepared arthroscopic shoulder surgeons. LEVEL OF EVIDENCE: V. PMID- 28717605 TI - I.S.Mu.L.T. first-time patellar dislocation guidelines. AB - : Primary traumatic patellar dislocation is common, particularly in young active individuals. A consensus on its management is still lacking. The present work provides easily accessible guidelines to be considered as recommendations for a good clinical practice developed through a process of systematic review of the literature and expert opinion, to improve the quality of care and rationalize the use of resources. LEVEL OF EVIDENCE: Ia. PMID- 28717608 TI - Computerized tomographic assessment and clinical evaluation in shoulder instability treated with the Latarjet-Patte procedure using one screw and washer. AB - BACKGROUND: The Latarjet-Patte (L-P) procedure is indicated in anterior instability of the shoulder with a glenoid or humeral bone loss. Our purpose is to evaluate clinical outcome and computerized tomographic (CT) findings as position and resorption of the graft and articular degeneration. METHODS: From 2006 to 2009 50 patients underwent to L-P, 48 was contacted by telephone and 26 were available for follow-up (3 to 6 years). Quick-DASH and Rowe scores was used, 22 patients perform CT. RESULTS: None of contacted patients reported a new dislocation. The clinical outcome in the 26 followed patients was excellent: mean Quick DASH score: 1.9; mean ROWE score was 94.7. CT scans showed no evidence of articular degeneration of humeral head. There was partial resorption of the graft in 13 patients. We found a correlation between the zone of partial resorption and position of the graft. CONCLUSIONS: CT scan is appropriate to study position and the healing of coracoid graft. A correct choice of where to place the graft together with a wide bone contact and stable synthesis does not cause degenerative changes after 6 years in our series. LEVEL OF THE EVIDENCE: IV. PMID- 28717609 TI - Pre-operative corticosteroid injections improve functional outcomes in patients undergoing arthroscopic repair of high-grade partial-thickness rotator cuff tears. AB - BACKGROUND: Subacromial corticosteroid injections (CSI's) are a common non surgical treatment for rotator cuff tears. Few studies have assessed the effects of pre-operative CSI's on postoperative functional outcomes. METHODS: A retrospective analysis was conducted of 132 patients with high-grade, partial thickness rotator cuff tears (PTRCT's). The subjects were divided into two groups based on whether they received a CSI or not. The CSI group was further divided into three subgroups based on when they received a pre-operative injection: 0-3 months, 3-6 months, >6 months before surgery. The Visual Analog Scores (VAS), American Shoulder and Elbow Surgeon scores (ASES), and Constant scores were recorded prior to surgery and at a one-year post-operative follow-up appointment for each subject. RESULTS: Patients who received a pre-operative CSI (n=92) improved significantly more than the non-injection group (n=40) in all outcome measures. The 0-3 months injection subgroup experienced a significant increase in ASES and Constant score (p=0.019 and 0.014, respectively) compared to the other two subgroups, but the VAS score decrease only trended toward significance (p=0.091). The sample as a whole experienced significant improvement in all three outcome measures. CONCLUSION: Patients undergoing arthroscopic repair of a high grade PTRCT may benefit from a pre-operative CSI 0-3 months before surgery. LEVEL OF EVIDENCE: IIb. PMID- 28717610 TI - Functional treatment in rotator cuff tears: is it safe and effective? A retrospective comparison with surgical treatment. AB - BACKGROUND: The aim of this study was to compare rehabilitation protocol and operative treatment in a population of patients with a diagnosis of small to medium rotator cuff tears (<=3 cm), the null hypothesis being that there would been no difference in terms of clinical outcomes and patient's satisfaction between the rehabilitation protocol and the surgical treatment. METHODS: Patients with small to medium supraspinatus tears were retrospectively enrolled in this study and divided in 2 groups: arthroscopic repair (group A, 20 patients) and reinstated (group B, 18 patients). At a mean follow-up of 18 months, both groups underwent clinical (Constant, QuickDash, VAS), dynamometric and ultrasonographic evaluation. RESULTS: In both groups a significant clinical improvement was registered compared to baseline. However, surgical treatment yielded better results in Constant (p=0.004), Quick-Dash (p=0.0012), VAS (p=0.048) and strength evaluation (p=0.0014). In group A the re-tear rate was 10%, while in group B only 11% of increased tear size was registered. CONCLUSION: At a short term follow-up, the surgical treatment of small to medium supraspinatus tears yielded better clinical outcomes compared to the rehabilitation protocol, with better strength outcomes and 10% re-tear rate. Nevertheless, physiotherapy still offers acceptable results and could be a valuable option in patients not undergoing surgery. LEVEL OF EVIDENCE: III. PMID- 28717611 TI - Conservative, minimally invasive and open surgical repair for management of acute ruptures of the Achilles tendon: a clinical and functional retrospective study. AB - BACKGROUND: At present, it is unclear which is the best management for Achilles tendon rupture. PURPOSE: We assess the clinical, functional and imaging outcomes of active patients undergoing 3 different types of management for acute subcutaneous rupture of the Achilles tendon, including conservative cast immobilization, traditional open surgery and percutaneous repair. METHODS: 26 active patients were managed for a rupture of the Achilles Tendon from January 2007 to March 2008. Anthropometric measurements, Functional assessment, Isometric strength, Ultrasonographic assessment, Patient satisfaction, Working life, Physical activity, Functional score and Complications were recorded retrospectively. RESULTS: All 23 (21 men, 2 women) patients were reviewed at a minimum follow-up of 24 months (average 25.7, range 24 to 32 months, SD: 6.3) from the index injury. Thermann scores and patient satisfaction were significantly higher following surgery than conservative management with no significance between open and minimally invasive operated patients. Sensitive disturbances occur in up to 12% of open repairs and 1.8% of patients managed nonsurgically. CONCLUSIONS: Clinical and functional outcomes following surgical repair, percutaneous and open, of the Achilles tendon are significantly improved than following conservative management. LEVEL OF EVIDENCE: Level III. PMID- 28717612 TI - Intratendinous tears of the Achilles tendon - a new pathology? Analysis of a large 4-year cohort. AB - BACKGROUND: Achillodynia is common and includes Achilles tendinopathy, partial Achilles tears and Achilles tendon ruptures. However, we believe an additional pathology should be considered for Achillodynia differentials - the intratendinous tear (ITT). METHODS: Examinations of 740 achillodynic patients in one specialist centre were reviewed. ITTs were defined as a clearly visualised echopoor area situated centrally and extending to, but not through the tendon periphery, with pain on palpation and no clinical findings consistent with Achilles rupture. Descriptive statistics were used to analyse differences between pathological sub-groups, and images described qualitatively. RESULTS: 5% (29 males, 8 females) of 740 patients had an ITT. Patients typically presented with a history of sudden onset localised pain and the ability to train but not reach maximal loading. Average age was 36.3 years (range 20-64), significantly lower than mid-tendon tendinopathy (8.48 years; p<0.01). 92% had concurrent Achilles tendinopathy. Elite sportspeople were more highly represented in the ITT than mid tendon tendi nopathy groups (86.2% ITT group vs 13.8% mid-tendon AT group; p<0.01). CONCLUSIONS: ITTs should be actively searched for in patients with Achilles pathology, especially in elite male athletes with a history of high impact pain. Prospective research is warranted concerning diagnosis and management. LEVEL OF EVIDENCE: IV. PMID- 28717613 TI - Morphometric evaluation of human tendocalcaneus: a cadaveric study of south indian male population. AB - INTRODUCTION: Tendocalcaneus or Achilles tendon is formed by the fusion of the tendons of gastrocnemius and soleus muscles. Normal morphometric measurements of tendo-calcaneus serves an important landmark in its anthropometric evaluation and biomechanical characteristics. Hence the objective of this study was to provide detailed morphometric profile of tendocalcaneus in south indian cadaveric male population. MATERIALS AND METHOD: A total of 64 dissected adult limbs was studied. Out of the 64 limbs: 37 belonged to right side while 27 were of the left side. These limbs were dissected to expose the extent of tendocalcaneus. Total length, proximal width and proximal circumference of the tendon, distal width and distal circumference of the tendon was measured. Results were tabulated and correlated using SPSS. RESULTS: Tendon length, width and circumference showed no statistically significant differences between the right and left side. However significant correlation was observed between proximal width and distal widths, proximal circumference and distal circumference, proximal width and proximal circumference and distal width and distal circumference of the tendon. CONCLUSION: This cadaveric morphometric study of tendo-calcaneus would be very helpful to sports medicine physicians for diagnosis and treatment of tendo Achilles overuse injuries and tendinopathy. LEVEL OF EVIDENCE: IV. PMID- 28717614 TI - Activity level recovery after acute Achilles tendon rupture surgically repaired: a series of 29 patients with a mean follow-up of 46 months. AB - BACKGROUND: Achilles tendon rupture is a common injury but its optimal management is still controversial. When decided, surgical repair can be performed by open or percutaneous techniques. Till now, there is no agreement on the ideal type of surgical management. PURPOSE: To compare the outcomes of the percutaneous and open surgical treatment for acute Achilles tendon rupture and to assess the postoperative activity level recovery. METHODS: Between 2008 and 2013, 29 patients were surgically treated for acute Achilles tendon rupture in our institution. 16 patients were operated by percutaneous technique and 13 by open repair. All patients received the same postoperative rehabilitation protocol. Patients were evaluated objectively and subjectively after an average of 46 months (23-91). RESULTS: 96.6% of patients had excellent and good results according to subjective assessment. No significant difference was observed with respect to the examined clinical variables between the open and percutaneous repair groups. 20.68% of patients had minor complications related to the operation with lesser complications in the percutaneous group. 89.6% of patients resumed sport activity with an average delay of 7,7 months (4-24) and 57,7% of them resumed at a level equal or superior to their level before injury, with higher rate in the percutaneous group. CONCLUSION: Percutaneous technique has similar satisfactory outcomes to open surgery in repairing acute ruptured Achilles tendon with lesser complications and higher activity level recovery rate. LEVEL OF EVIDENCE: Retrospective comparative study. Level III. PMID- 28717615 TI - Outcomes of prolotherapy for intra-tendinous Achilles tears: a case series. AB - BACKGROUND: The intra-tendinous tear is a new pathology that is defined as a discontinuity of fibres situated entirely within the tendon. Prolotherapy involves injecting an irritant, such as hyperosmolar dextrose, to stimulate a tissue healing response and ultimately reduce pain. METHODS: 43 consecutive patients diagnosed with an intra-tendinous tear were included (27 males: 16 females, mean (SD) age 41 (11.3). Patients were injected with 0.4ml-1.5ml (mean 0.8ml) of 50% dextrose and 0.5% marcaine mixed in a 1:1 ratio. A 4-6 week period of walking boot immobilisation was followed by progressive rehabilitation (6-8 weeks). Outcomes were assessed with a VISA-A questionnaire at baseline, 3 months and a mean 12.6 (7.0) months post-treatment. Ultrasound scans were conducted before treatment and 5.2 (2.3) weeks later to assess sonographic changes. RESULTS: 30 patients (70%) responded with VISA-A scores increasing by 31 (30.5) points after 3 months (f=0.62, p<0.05) and by 40 (29.3) points after 12.60 (7.0) months (f=0.87, p<0.05). After 5.2 (2.3) weeks, echogenicity was significantly reduced (p<0.05) and 27% of tears were no longer detectable. No significant differences were observed in remaining tears with respect to tear size, tendon thickness or neovascularisation. CONCLUSION: Treatment resulted in clinically significant improvements and controlled trials are warranted. LEVEL OF EVIDENCE: IV. PMID- 28717616 TI - Topical polidocanol application in combination with static stretching in tendinopathies: a prospective pilot study. AB - BACKGROUND: Highly operator-based injection therapy with vasosclerosing and anesthetic polidocanol is used for tendinopathies. This pilot-study evaluates the topical application of polidocanol gel. METHODS: Prospective case series. 39 patients with tendinopathies (14 Achilles, 14 patella, 11 wrist extensors) with a symptom duration > 6 months were included. Polidocanol and static stretching were the therapy in the first 2 weeks, while static stretching was continuously performed for 6 months. Clinical outcome was evaluated with VISA-A, VISA-P and DASH Scores and sonographically with B-Mode (B-Mode), Power Doppler (PD) and Shearwave Elastography (SWE). RESULTS: 22 patients clinically improved (>+10 score points), 11 patients were without improvement (<+ 10) and 1 patient worsened during 6 months. The VISA-A Score increased in average 19 points from 56 to 75 (p< 0.01), VISA-P Score increased 13 points from 59 to 72 (p< 0,01) and the DASH-Score decreased 20 points from 40 to 20 (p< 0,01). SWE correlates better than B-Mode or PD with symptom improvement. CONCLUSION: The combination of static training and topical polidocanol application seems to be successful in the treatment of tendinopathies. Further RCT studies need to evaluate the efficiency of topical polidocanol application. SWE is a more sensitive tool to describe symptom development than PD or B-Mode. LEVEL OF EVIDENCE: IV. PMID- 28717617 TI - Conservative treatment for Insertional Achilles Tendinopathy: platelet-rich plasma and focused shock waves. A retrospective study. AB - BACKGROUND: Insertional Achilles tendinopathy (IAT) represents a serious challenge for both physiatrists and surgeons. Here we analyse the results obtained by two conservative treatments [platelet-rich plasma (PRP) injections and focused extracorporeal shock-wave therapy (ESWT)] in physically active patients with IAT. METHODS: During two consecutive periods, 45 consecutive patients with IAT were treated with 3 sessions of ESWT (2400 impulses at 0.17 0.25 mJ/mm2 per session) (24 cases between September 2011 and July 2013) or with 2 autologous PRP injections over two weeks (21 cases between September 2013 and July 2015). All patients were evaluated at 0, 2-, 4-, 6-month follow-up after therapy. The outcome measures were VISA-A, VAS, Patient Satisfaction. RESULTS: Intra-group analysis showed a significant improvement of VISA-A and VAS scores in both groups at all time-points. No differences between groups were observed for VAS and VISA-A scores at all time-points, excepted for VISA-A at 4-months in favour of ESWT group (P=0.049). Patient satisfaction increased progressively (>70% at 6 months) and with no differences between two groups. CONCLUSION: Both ESWT and PRP therapy are effective and safe. Our study confirms the success of these conservative treatments in Achilles tendinopathy, even in the insertional one. LEVEL OF EVIDENCE: IIIa. PMID- 28717618 TI - Plantar fasciitis in athletes: diagnostic and treatment strategies. A systematic review. AB - BACKGROUND: Plantar fasciitis (PF) is reported in different sports mainly in running and soccer athletes. Purpose of this study is to conduct a systematic review of published literature concerning the diagnosis and treatment of PF in both recreational and elite athletes. The review was conducted and reported in accordance with the PRISMA statement. METHODS: The following electronic databases were searched: PubMed, Cochrane Library and Scopus. As far as PF diagnosis, we investigated the electronic databases from January 2006 to June 2016, whereas in considering treatments all data in literature were investigated. RESULTS: For both diagnosis and treatment, 17 studies matched inclusion criteria. The results have highlighted that the most frequently used diagnostic techniques were Ultrasonography and Magnetic Resonance Imaging. Conventional, complementary, and alternative treatment approaches were assessed. CONCLUSIONS: In reviewing literature, we were unable to find any specific diagnostic algorithm for PF in athletes, due to the fact that no different diagnostic strategies were used for athletes and non-athletes. As for treatment, a few literature data are available and it makes difficult to suggest practice guidelines. Specific studies are necessary to define the best treatment algorithm for both recreational and elite athletes. LEVEL OF EVIDENCE: Ib. PMID- 28717619 TI - Comparison of dynamic postural stability scores between athletes with and without chronic ankle instability during lateral jump landing. AB - BACKGROUNDS: Many ankle injuries occur while participating in sports that require jumping and landing such as basketball, volleyball and soccer. Most recent studies have investigated dynamic postural stability of patients with chronic ankle instability after landing from a forward jump. The present study aimed to investigate the dynamic postural stability of the athletes who suffer from chronic ankle sprain while landing from a lateral jump. METHODS: Twelve athletes with self-reported unilateral chronic ankle instability (4 females and 8 males) and 12 matched controls (3 females and 9 males) voluntarily participated in the study. Dynamic postural stability index and its directional indices were measured while performing lateral jump landing test. RESULTS: No differences were found between athletes with and without chronic ankle instability during our landing protocol by means of the dynamic postural stability index and its directional indices. Findings showed that in each group, medial/lateral stability index is significantly higher than anterior/posterior and vertical stability indexes. CONCLUSION: Findings showed that dynamic postural stability was not significantly different between the two groups. Future studies should examine chronic ankle instability patients with more severe disabilities and expose them to more challenging dynamic balance conditions to further explore postural stability. LEVEL OF EVIDENCE: IIIa. PMID- 28717620 TI - The influence of muscle-tendon forces on ACL loading during jump landing: a systematic review. AB - BACKGROUND: The goal of this review is to summarise and discuss the reported influence of muscle-tendon forces on anterior cruciate ligament (ACL) loading during the jump-landing task by means of biomechanical analyses of the healthy knee. METHODS: A systematic review of the literature was conducted using different combinations of the terms "knee", "ligament", "load", "tension ", "length", "strain", "elongation" and "lengthening". 26 original articles (n=16 in vitro studies; n=10 in situ studies) were identified which complied with all inclusion/exclusion criteria. RESULTS: No apparent trend was found between ACL loading and the ratio between hamstrings and quadriceps muscle-tendon forces prior to or during landing. Four in vitro studies reported reduced peak ACL strain if the quadriceps force was increased; while one in vitro study and one in situ study reported reduced ACL loading if the hamstrings force was increased. A meta-analysis of the reported results was not possible because of the heterogeneity of the confounding factors. CONCLUSION: The reported results suggest that increased hip flexion during landing may help in reducing ACL strain by lengthening the hamstrings, and thus increasing its passive resistance to stretch. Furthermore, it appears that increased tensile stiffness of the quadriceps may help in stabilising the knee joint during landing, and thus protecting the passive soft-tissue structures from overloading. LEVEL OF EVIDENCE: Ib. PMID- 28717621 TI - Effects of the menstrual cycle on lower-limb biomechanics, neuromuscular control, and anterior cruciate ligament injury risk: a systematic review. AB - OBJECTIVE: Anterior cruciate ligament (ACL) injury has a devastating impact on physical and psychological disability. Rates of ACL rupture are significantly greater in females than males during the same sports. Hormonal mechanisms have been proposed but are complex and poorly understood. This systematic review evaluates the effects of menstrual cycle on: 1) lower-limb biomechanics, 2) neuromuscular control, and 3) ACL injury risk. METHODS: The MEDLINE, CINAHL, SPORTSDiscus, Web of Science, and Google Scholar databases were searched from inception to August 2016 for studies investigating the effects of the menstrual cycle on lower-limb biomechanics, neuromuscular control, and ACL injury risk in females. Three independent reviewers assessed each paper for inclusion and two assessed for quality. RESULTS: Seventeen studies were identified. There is strong evidence that: 1) greatest risk of ACL injury is within the pre-ovulatory phase of the menstrual cycle, and 2) females with greater ACL laxity in the pre ovulatory phase experience greater knee valgus and greater tibial external rotation during functional activity. CONCLUSION: Females are at greatest risk of ACL injury during the pre-ovulatory phase of the menstrual cycle through a combination of greater ACL laxity, greater knee valgus, and greater tibial external rotation during functional activity. LEVEL OF EVIDENCE: Ib. PMID- 28717622 TI - Semitendinosus muscle architecture during maximum isometric contractions in individuals with anterior cruciate ligament reconstruction and controls. AB - BACKGROUND: The most widely used graft as a replacement in anterior cruciate ligament (ACL) reconstruction is the semitendinosus (ST) tendon graft. After harvesting for ACL reconstruction, the hamstring tendon regenerates in most people and becomes similar to normal. The effect of graft harvest on muscle morphology and function remains unclear. The present study aimed to examine the morphology of the ST during isometric contraction after harvesting the ST tendon for ACL reconstruction. METHODS: Maximal isometric contractions of the knee flexors from two angular positions were performed by 8 participants, at least 1 year after ACL reconstruction with an ST tendon graft and 8 matched controls. Ultrasonographic images were used to measure the pennation angle and muscle thickness of the ST muscle. RESULTS: There was not a statistically significant difference in pennation angle values between the control group and the group who underwent ACL reconstruction (p >0.05). Muscle thickness was significantly higher in the ACLR group compared with controls (p< 0.05). CONCLUSIONS: Individuals who underwent ACL reconstruction display a higher ST muscle thickness but similar pennation angle compared with controls. This indicates that ACL reconstruction has an effect on ST muscle belly but effect on force generation capacity is rather limited. LEVEL OF EVIDENCE: IIb. PMID- 28717623 TI - Chondrocytes treated with different shock wave devices. AB - BACKGROUND: Shock wave treatment is used for several orthopedic diseases and there are different devices available. Until now, there have been no experimental studies on the effects of these different generators. METHODS: We carried out an experimental study to compare the effects of three focused generators (electro magnetic, piezoelectric and electro-hydraulic) as well as a radial generator on healthy and osteoarthritis chondrocytes. RESULTS: By the analysis of our results, we may exclude significant differences between the different generators, even though there is a greater action specificity for electro-magnetic and piezoelectric generators. CONCLUSIONS: The smaller size of the focus of the latter two generators guarantees a greater concentration of energy in the target. The biological effect of the increase of IL-10 and reduction of both N-Cadherin and B-Catenin in chondrocytes in healthy subjects and those affected by osteoarthritis confirms the therapeutic potential of ESWT in cartilage diseases, such as osteoarthritis. In clinical practice it is important to introduce the parameter of total energy. This allows us to standardize the treatment and to manage the variability related to the different types of device and size of the focus. LEVEL OF EVIDENCE: IIb. PMID- 28717624 TI - Ipsilateral hamstring tendon graft reconstruction for chronic patellar tendon ruptures: surgical technique. AB - BACKGROUND: Patellar tendon chronic ruptures are more debated to manage that acute injuries as the patella tends to retract proximally (after 2 weeks), and surrounding soft tissues may make the repair more complicate. PURPOSE: We propose a novel technique in which the patellar tendon is reconstructed using ipsilateral hamstring tendons. This surgical procedure implies to drill a single tunnel through the patella and another through the tibia to reduce the risk of bony breakage. In addition, the tendon is secured to the bone, at the tunnel exit points, by periostium sutures without requiring any additional surgery for hardware removal. METHODS: We assessed 19 patients (16 men and 3 women) who underwent PT reconstruction at an average of 5.8 years (range, 4 to 7.8 years, SD: 3.5) from the index surgery. The mean age at surgery was 46 +/- 9.2 years (range, 38-59 years). RESULTS: All patients had a complete tear of the patellar tendon. CONCLUSIONS: The main indication for this procedure is the reconstruction of the PT in patients with chronic rupture (>6 weeks) in which the tendon gap is greater than 2 centimeters and the scar tissues and degenerated tendon ends do not allow to juxtapose the tendon stumps to each other. LEVEL OF EVIDENCE: Level IV. PMID- 28717625 TI - Assessment of different fitting methods for in-vivo bi-component T2* analysis of human patellar tendon in magnetic resonance imaging. AB - PURPOSE: To investigate the robustness of four fitting methods for bi-component effective spin-spin T2 (T2*) relaxation time analysis of human patellar tendon. METHODS: A three-dimensional (3D) cone ultra-short echo-time (UTE) sequence was performed on the knees of ten healthy volunteers at 3.0T. Four fitting methods incorporating either Gaussian or Rician noise distribution were used for voxel-by voxel bi-component T2* analysis of the patellar tendon. The T2* for the short relaxing (T**,s ) and long relaxing (T*2,l ) water components and the fraction of the short relaxing water component (fs ) were measured, and different fitting methods were compared using Friedman's and Wilcoxon signed rank tests. A numerical simulation study was also performed to predict the accuracy and precision of bi-component T2* parameter estimation in tendon at different signal to-noise ratios (SNR) levels. RESULTS: The average T*2,s , T*2,l , fs of human patellar tendon were 1.5ms, 30ms, and 80% respectively. Incorporating different noise models and fitting methods influenced the measured bi-component T2* parameters. Fitting methods incorporating Rician noise were superior to traditional fitting methods for bi-component T2* analysis especially at lower SNR. fs and T*2,s were less sensitive than T*2,1 to noise at even moderate and low SNR. The result of the in-vivo bi-component T2* analysis of tendon agreed well with numerical simulations. CONCLUSION: Our study demonstrated the use of a 3D cone UTE sequence to perform in vivo voxel-by-voxel bi-component T2* analysis of human patellar tendon. Incorporating Rician noise was useful for improving bi component T2* analysis especially at lower SNR. LEVEL OF EVIDENCE: IV. PMID- 28717626 TI - Muscle fatigue in participants of indoor cycling. AB - BACKGROUND: Indoor Cycling (IC) has been gaining recognition and popularity within recent years and few studies have investigated its benefits for sedentary participants. OBJECTIVE: The aim of this study was to evaluate differences in the surface electromyography (sEMG) variables, heart rate (HR), and subjective effort in sedentary participants while they performed an IC session and to compare their results with the trained subjects, to answer the question: Are trained cyclists less susceptible to muscle fatigue, since it is expected that they make less effort? DESIGN: Twenty-six volunteers were split into two groups according to their fitness status and weekly training load. Each participant completed an IC session in a private gym, lasting 45 minutes and were encouraged to follow the pedaling frequency and cycle resistance, within their limitations. Main Outcome Measures: HR, participants' subjective effort on the Borg Scale of Perceived Exertion (Borg Scale) and sEMG data were compared between groups. RESULTS: 28.6% of the sedentary participants withdrew from the study. Exercise intensity, assessed using the HR, was similar in both groups. The subjective perceived effort, assessed using the Borg Scale, was significantly higher in the sedentary group. All muscles considered in the sedentary group had higher variation levels of Root Mean Square (RMS) and Median Frequency (MF) than those in the trained group. CONCLUSION: Sedentary participants are more likely to present fatigue and IC can be incorporated into protocols for this population, but their fitness levels should be taken into account because each performance depends on the individual's physical fitness. LEVEL OF EVIDENCE: IIIb. PMID- 28717627 TI - The influence of playing surface on injury risk in italian elite rugby players. AB - BACKGROUND: There is a growing interest in the use of artificial turf surfaces in rugby. In particular, artificial surfaces may be an useful means of increasing participation in the sport by allowing greater usage of a given pitch, especially in regions where natural turf pitches are difficult to maintain. METHODS: The incidence of site, nature, cause, and severity of training and match injuries was prospectively recorded in two professional teams (one equipped with World Rugby certified third generation artificial turf and the other with natural grass over the 2014-2015 season). RESULTS: A total of 23,840 minutes of exposure was displayed for the whole sample, 1,440 minutes during matches and 22,400 during training sessions. We recorded 37 (48%) traumatic injuries and 39 (52%) overuse injuries. For traumatic injuries, we did not find significant differences in the overall risk injury between grass and artificial turf considering match exposure and training sessions. For overuse injuries, there were significant differences in the overall risk injury between grass and artificial turf considering match exposure (p=0.03) and training sessions (p=0.02). CONCLUSION: In elite Italian rugby players, artificial turf seems to be safe in regards to traumatic injury while it seems to be a risk factor for overuse injuries. LEVEL OF EVIDENCE: II. PMID- 28717628 TI - Does combined strength training and local vibration improve isometric maximum force? A pilot study. AB - BACKGROUND: The aim of the study was to determine whether a combination of strength training (ST) and local vibration (LV) improved the isometric maximum force of arm flexor muscles. ST was applied to the left arm of the subjects; LV was applied to the right arm of the same subjects. The main aim was to examine the effect of LV during a dumbbell biceps curl (Scott Curl) on isometric maximum force of the opposite muscle among the same subjects. It is hypothesized, that the intervention with LV produces a greater gain in isometric force of the arm flexors than ST. METHODS: Twenty-seven collegiate students participated in the study. The training load was 70% of the individual 1 RM. Four sets with 12 repetitions were performed three times per week during four weeks. The right arm of all subjects represented the vibration trained body side (VS) and the left arm served as the traditional trained body side (TTS). RESULTS: A significant increase of isometric maximum force in both body sides (Arms) occurred. VS, however, significantly increased isometric maximum force about 43% in contrast to 22% of the TTS. CONCLUSION: The combined intervention of ST and LC improves isometric maximum force of arm flexor muscles. LEVEL OF EVIDENCE: III. PMID- 28717629 TI - Ultrasound measures of tendon thickness: Intra-rater, Inter-rater and Inter machine reliability. AB - BACKGROUND: Ultrasound imaging is often used by physiotherapists and other healthcare professionals but the reliability of image acquisition with different ultrasound machines is unknown. The objective was to compare the intra-rater, inter-rater and intermachine reliability of thickness measurements of the plantar fascia (PF), Achilles tendon (AT), patellar tendon (PT) and elbow common extensor tendon (ECET) with musculoskeletal ultrasound imaging (MSUS). METHODS: Tendon thickness was measured in four anatomical structures (14 participants, 28 images per tendon) by two sonographers and with two different ultrasound machines. Intraclass Correlation Coefficients (ICCs) and Bland-Altman plots were calculated. The standard error of measurement (SEM) and minimum detectable difference (MDD) were calculated. RESULTS: Inter-rater reliability was excellent for AT (ICC=0.98; 95% CI= 0.96-0.99) and very good for PT (ICC=0.85; 95% CI = 0.67-0.93) and ECET (ICC=0.81; 95% CI= 0.72-0.94). Reliability for PF was moderate, with an ICC of 0.63 (CI 95%= 0.20-0.83). Bland-Altman plot for inter machine reliability showed a mean difference of 1 m for PF measurements and a mean difference of 4 m and 20 m for AT and PT. The relative SEMs were below 7% and the MDCs were below 0.7 mm. CONCLUSION: The MSUS reliability in measuring thickness of the four tendons is confirmed by the homogeneous readings intra sonographers, between operators and between different machines. Level of evidence: Tendon thickness can be measured reliably on different ultrasound devices, which is an important step forward in the use of this technique in daily clinical practice and research. LEVEL OF EVIDENCE: III. PMID- 28717630 TI - PTX3: a new mediator of bone metabolism and osteoporosis. PMID- 28717631 TI - Orthodontic view in the diagnoses of obstructive sleep apnea. AB - Obstructive sleep apnea is an exciting area for orthodontists to be involved. The level of awareness of sleep apnea and related health issues is growing rapidly. The demand of integrating sleep into the orthodontic practice shortly will be driven by the need of the societies as some of our patients will be shortly coming into our offices aware of sleep apnea. However, with our busy clinical orthodontic practice, the need of condense short review become more demanding. Therefore, this review will try to summarize the clinical and orthodontic observation in the diagnoses of adult obstructive sleep apnea with clinical application in orthodontic practice. PMID- 28717633 TI - Cementum and dentin repair following root damage caused by the insertion of self tapping and self-drilling miniscrews. AB - OBJECTIVE: The aim of this study was to evaluate the histological responses of cementum, root dentin, and pulp following intentional root injuries caused via self-tapping and self-drilling miniscrews. MATERIALS AND METHODS: Fourteen patients (with a mean age of 15.7 years and age range of 14-18 years) who were scheduled for the extraction of all four first premolars as part of their orthodontic treatment plan participated in this study. The roots of the right and the left quadrants' first premolars were designedly injured using self-tapping miniscrews and self-drilling miniscrews, respectively. Teeth were extracted eight weeks after the injury. Cementum repair was assessed through histological examinations. RESULTS: In this study, 40 teeth (75.4%) showed reparative cementum formation and 13 teeth (24.5%) showed no repair. There was no significant difference between the two groups regarding the formation of reparative cementum (P = 0.3). In all examined teeth, the inflammatory response of the pulp to the cold test was within the normal range. CONCLUSION: This study showed that in most cases, the healing of cementum was observed eight weeks after the injury and the two methods of miniscrew insertion showed no significant difference when it comes to the healing process. PMID- 28717632 TI - Effect of different intracoronal bleaching methods on shear bond strength of ceramic brackets bonded to bleached enamel: An in-vitro study. AB - OBJECTIVE: To investigate the effect of different intracoronal bleaching methods on the shear bond strength and site of failure of ceramic brackets. MATERIALS AND METHODS: Sixty freshly extracted human maxillary incisors were randomly divided into four groups (n = 15). Endodontic access cavity was prepared and root canals were filled, root fillings were removed 2mm apical to the cementoenamel junction, and a 2-mmthick layer of glass ionomer cement base was applied. Group 1 served as the control. Intracoronal bleaching was performed with 35% carbamide peroxide in group 2, sodium perborate in group 3, and 37.5% hydrogen peroxide in group 4. The teeth were immersed in artificial saliva for 4 weeks before bracket bonding. Ceramic brackets were bonded with composite resin and cured with LED light. After bonding, the shear bond strength of the brackets was tested with a universal testing machine. The site of bond failure was determined by modified ARI (Adhesive Remnant Index). RESULTS: The highest value of shear bond strength was measured in control group (18.67 +/- 1.59 MPa), which was statistically significant from groups 2,3, and 4. There was no significant difference between groups 2 and 4. The lowest shear bond strength was measured in group 3. ARI scores were not significant from each other. CONCLUSIONS: Intracoronal bleaching significantly affected the shear bond strength of ceramic brackets even after 4 weeks of bleaching. Bleaching with sodium perborate affects shear bond strength more adversely than does bleaching with other agents like hydrogen peroxide and carbamide peroxide. PMID- 28717634 TI - Molar distalization with 2K appliance: one-year follow-up. AB - Correction of class II molars in growing patients with acceptable facial profile can be performed by distalization of maxillary first molars. However, in patients where compliance is difficult intraoral means of molar distalization is required. This case report describes the use and effectiveness of a novel 2K appliance in an 11-year-old female having an orthognathic profile, skeletal Class I relation, and Angle's Class II division 1 malocclusion with crowding of 8 mm and 3 mm in the maxillary and mandibular arches, respectively. Nonextraction treatment was planned with bilateral distalization of the maxillary first molars. The amount of distalization achieved by 2K appliance was 3.5 mm with only 1 degrees distal tipping. The 2K appliance required minimal patient cooperation, produced bodily movement of molars with minimal tipping/rotation, and prevented anchorage loss of the anterior teeth. This 2K molar distalization appliance was found to be an effective technique to control molars in all three planes of space. PMID- 28717635 TI - The fabrication of a customized occlusal splint based on the merging of dynamic jaw tracking records, cone beam computed tomography, and CAD-CAM digital impression. AB - OBJECTIVES: The aim of this case report was to present the procedure of fabricating a customized occlusal splint, through a revolutionary software that combines cone beam computed tomography (CBCT) with jaw motion tracking (JMT) data and superimposes a digital impression. MATERIALS AND METHODS: The case report was conducted on a 46-year-old female patient diagnosed with the temporomandibular disorder. A CBCT scan and an optical impression were obtained. The range of the patient's mandibular movements was captured with a JMT device. The data were combined in the SICAT software (SICAT, Sirona, Bonn, Germany). RESULTS: The software enabled the visualization of patient-specific mandibular movements and provided a real dynamic anatomical evaluation of the condylar position in the glenoid fossa. After the assessment of the range of movements during opening, protrusion, and lateral movements all the data were sent to SICAT and a customized occlusal splint was manufactured. CONCLUSIONS: The SICAT software provides a three-dimensional real-dynamic simulation of mandibular movements relative to the patient-specific anatomy of the jaw; thus, it opens new possibilities and potentials for the management of temporomandibular disorders. PMID- 28717636 TI - Orthodontic treatment for a patient with multiple sclerosis. AB - Multiple sclerosis (MS) is a chronic, autoimmune inflammatory disorder of the central nervous system (CNS) that affects myelinated axons, destroying the myelin and damaging axons to varying degrees. The course of MS is highly varied and unpredictable. Metals used during orthodontic treatment can negatively affect imaging techniques used to diagnose and monitor the progression of MS, while medications used to treat MS can negatively affect orthodontic tooth movement. The present case report highlights some of the challenges encountered during orthodontic treatment of a patient with MS and how to overcome them. The patient was a 20-year-old woman with complaints of diastema and spacing in the upper arch. Although closing the spaces was challenging due to some of the MS medications, she was treated successfully, without complications, within 20 months using closing loops. PMID- 28717637 TI - Phage Therapy in a 16-Year-Old Boy with Netherton Syndrome. AB - Netherton syndrome (NS) is a rare autosomal recessive disorder, characterized by a classical triad of clinical features, including congenital ichthyosiform erythroderma, trichorrhexis invaginata, and atopic diathesis coupled with frequent bacterial infections (1). The genetic basis for the disease has been recently identified with mutations in gene SPINK5, which is involved in the regulation of formation of skin barriers. We report on a 16-year-old male with all the typical manifestations of NS, including atopic diathesis and ongoing serious staphylococcal infections and allergy to multiple antibiotics whose family sought help at the Eliava Phage Therapy Center when all other treatment options were failing. Treatment with several antistaphylococcal bacteriophage preparations led to significant improvement within 7 days and very substantial changes in his symptoms and quality of life after treatment for 6 months, including return visits to the Eliava Phage Therapy Center after 3 and 6 months of ongoing use of phage at home. PMID- 28717638 TI - Spatial Patterns and Impacts of Environmental and Climatic Factors on Canine Sinonasal Aspergillosis in Northern California. AB - Sinonasal aspergillosis (SNA) causes chronic nasal discharge in dogs and has a worldwide distribution, although most reports of SNA in North America originate from the western USA. SNA is mainly caused by Aspergillus fumigatus, a ubiquitous saprophytic filamentous fungus. Infection is thought to follow inhalation of spores. SNA is a disease of the nasal cavity and/or sinuses with variable degrees of local invasion and destruction. While some host factors appear to predispose to SNA (such as belonging to a dolichocephalic breed), environmental risk factors have been scarcely studied. Because A. fumigatus is also the main cause of invasive aspergillosis in humans, unraveling the distribution and the environmental and climatic risk factors for this agent in dogs would be of great benefit for public health studies, advancing understanding of both distribution and risk factors in humans. In this study, we reviewed electronic medical records of 250 dogs diagnosed with SNA between 1990 and 2014 at the University of California Davis Veterinary Medical Teaching Hospital (VMTH). A 145-mile radius catchment area around the VMTH was selected. Data were aggregated by zip code and incorporated into a multivariate logistic regression model. The logistic regression model was compared to an autologistic regression model to evaluate the effect of spatial autocorrelation. Traffic density, active composting sites, and environmental and climatic factors related with wind and temperature were significantly associated with increase in disease occurrence in dogs. Results provide valuable information about the risk factors and spatial distribution of SNA in dogs in Northern California. Our ultimate goal is to utilize the results to investigate risk-based interventions, promote awareness, and serve as a model for further studies of aspergillosis in humans. PMID- 28717639 TI - Commentary: Complete Cranial Iliac Osteotomy to Approach the Lumbosacral Foramen. PMID- 28717640 TI - Lung microbiome and host immune tone in subjects with idiopathic pulmonary fibrosis treated with inhaled interferon-gamma. AB - Therapies targeting inflammation reveal inconsistent results in idiopathic pulmonary fibrosis (IPF). Aerosolised interferon (IFN)-gamma has been proposed as a novel therapy. Changes in the host airway microbiome are associated with the inflammatory milieu and may be associated with disease progression. Here, we evaluate whether treatment with aerosolised IFN-gamma in IPF impacts either the lower airway microbiome or the host immune phenotype. Patients with IPF who enrolled in an aerosolised IFN-gamma trial underwent bronchoscopy at baseline and after 6 months. 16S rRNA sequencing of bronchoalveolar lavage fluid (BALF) was used to evaluate the lung microbiome. Biomarkers were measured by Luminex assay in plasma, BALF and BAL cell supernatant. The compPLS framework was used to evaluate associations between taxa and biomarkers. IFN-gamma treatment did not change alpha or beta diversity of the lung microbiome and few taxonomic changes occurred. While none of the biomarkers changed in plasma, there was an increase in IFN-gamma and a decrease in Fit-3 ligand, IFN-alpha2 and interleukin-5 in BAL cell supernatant, and a decrease in tumour necrosis factor-beta in BALF. Multiple correlations between microbial taxa common to the oral mucosa and host inflammatory biomarkers were found. These data suggest that the lung microbiome is independently associated with the host immune tone and may have a potential mechanistic role in IPF. PMID- 28717641 TI - Information and communication technology use in asthmatic patients: a cross sectional study in Latin America. AB - Rapid diffusion, low cost and broad availability of information and communication technologies (ICTs) make them an attractive platform for managing care, communication and interventions in asthma. There is little information in Latin America about usage frequency of ICTs in asthmatic patients. The analysis undertaken consisted of an observational, cross-sectional study that aimed to identify the frequency and type of ICTs most often used by asthmatics. The Spanish version of the Michigan questionnaire was employed in five Latin American countries. Age and educational level was categorised. Logistic regression was performed among these groups concerning the frequency of ICT usage and the level of interest shown in seeking and receiving information about asthma. In total, 673 asthma patients were surveyed. The mean age was 43.44 years. Over two-thirds of the participants were female (68.4%). The most used ICT was the short message service (SMS) (69.9%). SMS and E-mail are useful tools for communicating (i.e. receiving and seeking information) with all asthma patients, irrespective of their age. WhatsApp (61.5%) and Facebook (32.0%) were rated as being the most interesting channels of communication for receiving information. Regression analysis showed that younger asthmatics and asthmatics with higher educational levels were most likely to use almost all forms of ICTs. ICTs are generally an attractive platform for managing care, communication and interventions to improve asthma care. SMS and E-mail were found to be the preferred ICT forms among users. However, social media forms such as WhatsApp and Facebook may also be appropriate for certain types of patient. PMID- 28717642 TI - Lung adenocarcinoma patients of young age have lower EGFR mutation rate and poorer efficacy of EGFR tyrosine kinase inhibitors. AB - Patients aged <=50 years are rarely diagnosed with nonsmall cell lung cancer. We conducted a retrospective cohort study to understand the mutation status of EGFR and the efficacy of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) treatment in young Asian patients with lung adenocarcinoma. We collected tumour specimens and malignant pleural effusions from lung adenocarcinoma patients from June 2005 to April 2014, recorded their clinical demographic data, and analysed EGFR mutations by reverse transcriptase PCR. EGFR mutation data were collected from 1039 lung adenocarcinoma patients, including 161 patients aged <=50 years and 878 patients aged >50 years. Fewer patients aged <=50 years had EGFR mutations than older patients (p=0.043), but they showed a higher rate of uncommon EGFR mutations (p=0.035). A total of 524 patients with EGFR mutations received EGFR-TKI treatment, including 81 patients aged <=50 years. Younger patients had a lower response rate than older patients (p=0.038) and had the shortest progression-free survival compared with other predefined age categories (p=0.033). Multivariate analysis of overall survival revealed age <=50 years as a poor prognostic factor. In conclusion, fewer Asian patients aged <=50 years had EGFR mutations, but the EGFR mutation types were more uncommon. Age <=50 years is associated with poorer efficacy of EGFR-TKI treatment. PMID- 28717643 TI - Chronic airflow obstruction after successful treatment of multidrug-resistant tuberculosis. AB - Cross-sectional studies reveal an association between tuberculosis (TB) and chronic airflow obstruction, but cannot adequately address confounding. We hypothesised that treated pulmonary TB is an independent risk factor for chronic airflow obstruction. The Pulmones Post TB cohort study enrolled participants from Lima, Peru, aged 10-70 years with a history of drug-susceptible (DS)- or multidrug-resistant (MDR)-TB who had completed treatment and were clinically cured. Unexposed participants without TB were randomly selected from the same districts. We assessed respiratory symptoms, relevant environmental exposures, and spirometric lung function pre- and post-bronchodilator. In total, 144 participants with DS-TB, 33 with MDR-TB and 161 unexposed participants were fully evaluated. Compared with unexposed participants, MDR-TB patients had lower lung volumes (adjusted mean difference in forced vital capacity -370 mL, 95% CI -644- 97) and post-bronchodilator airflow obstruction (adjusted OR 4.89, 95% CI 1.27 18.78). Participants who had recovered from DS-TB did not have lower lung volumes than unexposed participants, but were more likely to have a reduced forced expiratory volume in 1 s/forced vital capacity ratio <0.70 (adjusted OR 2.47, 95% CI 1.01-6.03). Individuals successfully treated for TB may experience long lasting sequelae. Interventions facilitating earlier TB treatment and management of chronic respiratory disease should be explored. PMID- 28717644 TI - Optimization of a Functionally Graded Material Stem in the Femoral Component of a Cemented Hip Arthroplasty: Influence of Dimensionality of FGM. AB - The longevity of hip prostheses is contingent on the stability of the implant within the cavity of the femur bone. The cemented fixation was mostly adopted owing to offering the immediate stability from cement-stem and cement-bone bonding interfaces after implant surgery. Yet cement damage and stress shielding of the bone were proven to adversely affect the lifelong stability of the implant, especially among younger subjects who tend to have an active lifestyle. The geometry and material distribution of the implant can be optimized more efficiently with a three-dimensional realistic design of a functionally graded material (FGM). We report an efficient numerical technique for achieving this objective, for maximum performance stress shielding and the rate of early accumulation of cement damage were concurrently minimized. Results indicated less stress shielding and similar cement damage rates with a 2D-FGM implant compared to 1D-FGM and Titanium alloy implants. PMID- 28717645 TI - Whole Genome Amplification of Day 3 or Day 5 Human Embryos Biopsies Provides a Suitable DNA Template for PCR-Based Techniques for Genotyping, a Complement of Preimplantation Genetic Testing. AB - Our objective was to determine if whole genome amplification (WGA) provides suitable DNA for qPCR-based genotyping for human embryos. Single blastomeres (Day 3) or trophoblastic cells (Day 5) were isolated from 342 embryos for WGA. Comparative Genomic Hybridization determined embryo sex as well as Trisomy 18 or Trisomy 21. To determine the embryo's sex, qPCR melting curve analysis for SRY and DYS14 was used. Logistic regression indicated a 4.4%, 57.1%, or 98.8% probability of a male embryo when neither gene, SRY only, or both genes were detected, respectively (accuracy = 94.1%, kappa = 0.882, and p < 0.001). Fluorescent Capillary Electrophoresis for the amelogenin genes (AMEL) was also used to determine sex. AMELY peak's height was higher and this peak's presence was highly predictive of male embryos (AUC = 0.93, accuracy = 81.7%, kappa = 0.974, and p < 0.001). Trisomy 18 and Trisomy 21 were determined using the threshold cycle difference for RPL17 and TTC3, respectively, which were significantly lower in the corresponding embryos. The Ct difference for TTC3 specifically determined Trisomy 21 (AUC = 0.89) and RPL17 for Trisomy 18 (AUC = 0.94). Here, WGA provides adequate DNA for PCR-based techniques for preimplantation genotyping. PMID- 28717646 TI - Genetic Variation and Its Reflection on Posttranslational Modifications in Frequency Clock and Mating Type a-1 Proteins in Sordaria fimicola. AB - Posttranslational modifications (PTMs) occur in all essential proteins taking command of their functions. There are many domains inside proteins where modifications take place on side-chains of amino acids through various enzymes to generate different species of proteins. In this manuscript we have, for the first time, predicted posttranslational modifications of frequency clock and mating type a-1 proteins in Sordaria fimicola collected from different sites to see the effect of environment on proteins or various amino acids pickings and their ultimate impact on consensus sequences present in mating type proteins using bioinformatics tools. Furthermore, we have also measured and walked through genomic DNA of various Sordaria strains to determine genetic diversity by genotyping the short sequence repeats (SSRs) of wild strains of S. fimicola collected from contrasting environments of two opposing slopes (harsh and xeric south facing slope and mild north facing slope) of Evolution Canyon (EC), Israel. Based on the whole genome sequence of S. macrospora, we targeted 20 genomic regions in S. fimicola which contain short sequence repeats (SSRs). Our data revealed genetic variations in strains from south facing slope and these findings assist in the hypothesis that genetic variations caused by stressful environments lead to evolution. PMID- 28717647 TI - Intracranial Hematoma Detection by Near Infrared Spectroscopy in a Helicopter Emergency Medical Service: Practical Experience. AB - In (helicopter) emergency medical services, (H)EMS, the prehospital detection of intracranial hematomas should improve patient care and the triage to specialized neurosurgical hospitals. Recently, noninvasive detection of intracranial hematomas became possible by applying transcranial near infrared spectroscopy (NIRS). Herein, second-generation devices are currently available, for example, the Infrascanner 2000 (Infrascan), that appear suited also for prehospital (H)EMS applications. Since (H)EMS operations are time-critical, we studied the Infrascanner 2000 as a "first-time-right" monitor in healthy volunteers (n = 17, hospital employees, no neurologic history). Further, we studied the implementation of the Infrascanner 2000 in a European HEMS organization (Lifeliner 1, Amsterdam, The Netherlands). The principal results of our study were as follows: The screening for intracranial hematomas in healthy volunteers with first-time-right intention resulted in a marked rate of virtual hematomas (false positive results, i.e., 12/17), rendering more time consuming repeat measurements advisable. The results of the implementation of the Infrascanner in HEMS suggest that NIRS-based intracranial hematoma detection is feasible in the HEMS setting. However, some drawbacks exist and their possible solutions are discussed. Future studies will have to demonstrate how NIRS-based intracranial hematoma detection will improve prehospital decision making in (H)EMS and ultimately patient outcome. PMID- 28717648 TI - Response Detection of Castrate-Resistant Prostate Cancer to Clinically Utilised and Novel Treatments by Monitoring Phospholipid Metabolism. AB - Androgen receptor (AR) activation is the primary driving factor in prostate cancer which is initially responsive to castration but then becomes resistant (castration-resistant prostate cancer (CRPC)). CRPC cells still retain the functioning AR which can be targeted by other therapies. A recent promising development is the use of inhibitors (Epi-1) of protein-protein interaction to inhibit AR-activated signalling. Translating novel therapies into the clinic requires sensitive early response indicators. Here potential response markers are explored. Growth inhibition of prostate cancer cells with flutamide, paclitaxel, and Epi-1 was measured using the MTT assay. To simulate choline-PET scans, pulse chase experiments were carried out with [3H-methyl]choline and proportion of phosphorylated activity was determined after treatment with growth inhibitory concentrations of each drug. Extracts from treated cells were also subject to 31P NMR spectroscopy. Cells treated with flutamide demonstrated decreased [3H methyl]choline phosphorylation, whilst the proportion of phosphorylated [3H methyl]choline that was present in the lipid fraction was increased in Epi-1 treated cells. Phospholipid breakdown products, glycerophosphorylcholine and glycerophosphoethanolamine levels, were shown by 31P-NMR spectroscopy to be decreased to undetectable levels in cells treated with Epi-1. LNCaP cells responding to treatment with novel protein-protein interaction inhibitors suggest that 31P-NMR spectroscopy may be useful in detecting response to this promising therapy. PMID- 28717649 TI - Circular RNA Profiling and Bioinformatic Modeling Identify Its Regulatory Role in Hepatic Steatosis. AB - Circular RNAs (circRNAs) exhibit a wide range of physiological and pathological activities. To uncover their role in hepatic steatosis, we investigated the expression profile of circRNAs in HepG2-based hepatic steatosis induced by high fat stimulation. Differentially expressed circRNAs were subjected to validation using QPCR and functional analyses using principal component analysis, hierarchical clustering, target prediction, gene ontology (GO), and pathway annotation, respectively. Bioinformatic integration established the circRNA-miRNA mRNA regulatory network so as to identify the mechanisms underlying circRNAs' metabolic effect. Here we reported that hepatic steatosis was associated with a total of 357 circRNAs. Enrichment of transcription-related GOs, especially GO: 0006355, GO: 004589, GO: 0045944, GO: 0045892, and GO: 0000122, demonstrated their specific actions in transcriptional regulation. Lipin 1 (LPIN1) was recognized to mediate the transcriptional regulatory effect of circRNAs on metabolic pathways. circRNA-miRNA-mRNA network further identified the signaling cascade of circRNA_021412/miR-1972/LPIN1, which was characterized by decreased level of circRNA_021412 and miR-1972-based inhibition of LPIN1. LPIN1-induced downregulation of long chain acyl-CoA synthetases (ACSLs) expression finally resulted in the hepatosteatosis. These findings identify circRNAs to be important regulators of hepatic steatosis. Transcription-dependent modulation of metabolic pathways may underlie their effects, partially by the circRNA_021412/miR 1972/LPIN1 signaling. PMID- 28717650 TI - Removal of Cu, Zn, Pb, and Cr from Yangtze Estuary Using the Phragmites australis Artificial Floating Wetlands. AB - Contamination of heavy metals would threaten the water and soil resources; phytoremediation can be potentially used to remediate metal contaminated sites. We constructed the Phragmites australis artificial floating wetlands outside the Qingcaosha Reservoir in the Yangtze Estuary. Water characteristic variables were measured in situ by using YSI Professional Pro Meter. Four heavy metals (copper, zinc, lead, and chromium) in both water and plant tissues were determined. Four heavy metals in estuary water were as follows: 0.03 mg/Kg, 0.016 mg/Kg, 0.0015 mg/Kg, and 0.004 mg/Kg. These heavy metals were largely retained in the belowground tissues of P. australis. The bioaccumulation (BAF) and translation factor (TF) value of four heavy metals were affected by the salinity, temperature, and dissolved oxygen. The highest BAF of each metal calculated was as follows: Cr (0.091 in winter) > Cu (0.054 in autumn) > Pb (0.016 in summer) > Zn (0.011 in summer). Highest root-rhizome TF values were recorded for four metals: 6.450 for Cu in autumn, 2.895 for Zn in summer, 7.031 for Pb in autumn, and 2.012 for Cr in autumn. This indicates that the P. australis AFW has potential to be used to protect the water of Qingcaosha Reservoir from heavy metal contamination. PMID- 28717651 TI - Comparison of Nonspherical Polyvinyl Alcohol Particles and Microspheres for Prostatic Arterial Embolization in Patients with Benign Prostatic Hyperplasia. AB - PURPOSE: To report early results following prostatic artery embolization (PAE) and compare outcomes between nonspherical polyvinyl alcohol (PVA) particles and microspheres to treat lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH). METHODS: PAE was performed in nine patients (mean age: 78.1 years) with symptomatic BPH. Embolization was performed using nonspherical PVA particles (250-355 MUm) in four patients and microspheres (300-500 MUm) in five patients. RESULTS: PAE was technically successful in all nine patients (100%). During a mean follow-up of 10.1 months, improvements in mean International Prostate Symptom Score (IPSS), Quality of Life (QoL), prostatic volume (total volume and transition zone), and peak urinary flow (Qmax) were 9.8 points, 2.3 points, 28.1 mL, 17.8 mL, and 4.5 mL/s, respectively. Clinical success was obtained in seven of nine patients (78%). Patients in the microsphere group showed greater improvement in IPSS, QoL, prostatic volume, and Qmax compared to patients in the nonspherical PVA particle group. However, significant difference was noted only in the prostatic volume. CONCLUSION: PAE is a feasible, effective, and safe treatment option for BPH with LUTS. Use of microspheres showed greater prostatic volume reduction compared to nonspherical PVA particles. PMID- 28717652 TI - Morphological Study of the Anterior Surface of the Distal Radius. AB - The shape of the anterior surface of the distal radius is important for designing a distal radius plate for wrist fracture surgery. The aim of this study was to describe the shape of the anterior surface of the distal radius and to compare the results between female and male. We used 90 sides from three-dimensional radial models based on computer tomography images from Korean adult cadavers for this study. The anterior surface was measured in two dimensions in the coronal view, and we sectioned the anterior surface of the models to obtain intermediate and radial sections to measure the curved shape of the anterior surface in sagittal view. Several parameters were statistically different between females and males; however, there were no differences between the right and left sides for any parameters. The width of the anterior surface in the coronal view was larger in males than females, and the curved part of the anterior surface of the males was longer and more concave than that of females. In both the female and male specimens, the intermediate section was longer and more concave than the radial section. Our results are useful for anthropological studies and for designing distal radial plates. PMID- 28717653 TI - Individual, Social, and Environmental Correlates of Active Transportation Patterns in French Women. AB - The objectives were (1) to define physical activity (PA) and sedentary behaviors (SB) patterns in daily life contexts (work, leisure, and transportation) in French working women from NutriNet-Sante web-cohort and (2) to identify pattern(s) of active transportation and their individual, social, and environmental correlates. 23,432 participants completed two questionnaires to evaluate PA and SB in daily life contexts and individual representations of residential neighborhood and transportation modes. Hierarchical cluster analysis was performed which identified 6 distinct movement behavior patterns: (i) active occupation, high sedentary leisure, (ii) sedentary occupation, low leisure, (iii) sedentary transportation, (iv) sedentary occupation and leisure, (v) active transportation, and (vi) active leisure. Multinomial logistic regressions were performed to identify correlates of the "active transportation" cluster. The perceived environmental characteristics positively associated with "active transportation" included "high availability of destinations around home," "presence of bicycle paths," and "low traffic." A "positive image of walking/cycling," the "individual feeling of being physically active," and a "high use of active transport modes by relatives/friends" were positively related to "active transportation," identified as a unique pattern regarding individual and environmental correlates. Identification of PA and SB context-specific patterns will help to understand movement behaviors' complexity and to design interventions to promote active transportation in specific subgroups. PMID- 28717655 TI - The neck burn scar contracture: a concept of effective treatment. AB - A neck scar contracture can severely and negatively affect the function of mastication, phonic, or breathing and result in neck pain and issues with esthetics. The best way is of course to avoid such contracture by means of non surgical treatment such as use of a growth factor. The basic fibroblastic growth factor is clinically well proven in decreasing scar formation and improving healing. There are numerous reconstructive methods for neck contracture, especially when the lesions are relatively limited in part of the neck. However, a very severe and full circumferential scar contracture requires extensive reconstruction. The thin groin flap is one of the answers and well matches with the tissue texture and maintains the flexibility. Even with extensive burns and delayed reconstructions due to resuscitation first, the groin area is well preserved and can be safely harvested by dual vasculature systems of the superficial circumflex iliac artery and superficial epigastric artery, which warrant more reliability compared to the perforator flaps in this area. More demanding and stringent forms of the neck burn scar contracture are the sequelae of radiation. A radiation burn or radiation injury can be progressing and hard to heal. Adipose-derived stem cells can reverse the scar contracture as the surrounding tissue is softened and can accelerate wound healing. In this review, different types of neck burn scar contracture and reconstructive methods are summarized, including innovative use of bFGF and ADSCs in the management of difficult wound healing and scar contracture. PMID- 28717654 TI - Fusion to Flaviviral Leader Peptide Targets HIV-1 Reverse Transcriptase for Secretion and Reduces Its Enzymatic Activity and Ability to Induce Oxidative Stress but Has No Major Effects on Its Immunogenic Performance in DNA-Immunized Mice. AB - Reverse transcriptase (RT) is a key enzyme in viral replication and susceptibility to ART and a crucial target of immunotherapy against drug resistant HIV-1. RT induces oxidative stress which undermines the attempts to make it immunogenic. We hypothesized that artificial secretion may reduce the stress and make RT more immunogenic. Inactivated multidrug-resistant RT (RT1.14opt-in) was N-terminally fused to the signal providing secretion of NS1 protein of TBEV (Ld) generating optimized inactivated Ld-carrying enzyme RT1.14oil. Promotion of secretion prohibited proteasomal degradation increasing the half-life and content of RT1.14oil in cells and cell culture medium, drastically reduced the residual polymerase activity, and downmodulated oxidative stress. BALB/c mice were DNA-immunized with RT1.14opt-in or parental RT1.14oil by intradermal injections with electroporation. Fluorospot and ELISA tests revealed that RT1.14opt-in and RT1.14oil induced IFN-gamma/IL-2, RT1.14opt-in induced granzyme B, and RT1.14oil induced perforin production. Perforin secretion correlated with coproduction of IFN-gamma and IL-2 (R = 0,97). Both DNA immunogens induced strong anti-RT antibody response. Ld peptide was not immunogenic. Thus, Ld-driven secretion inferred little change to RT performance in DNA immunization. Positive outcome was the abrogation of polymerase activity increasing safety of RT-based DNA vaccines. Identification of the molecular determinants of low cellular immunogenicity of RT requires further studies. PMID- 28717656 TI - Commentary to medical genetics and genomic medicine in Chile: Chilean experience on molecular diagnosis for neurodegenerative disorders. AB - In this article, the experience in the molecular diagnosis in neurodegenerative disorders in Chile, including present challenges and potential new pathways for development, is explained. PMID- 28717657 TI - Medical genetics and genomic medicine in the United States of America. Part 1: history, demographics, legislation, and burden of disease. AB - Medical genetics and genomic medicine in the United States of America. Part 1: history, demographics, legislation, and burden of disease. PMID- 28717658 TI - Targeting breast cancer outcomes-what about the primary relatives? AB - BACKGROUND: Up to 65% of newly diagnosed breast cancer patients had not been screened correctly before diagnosis resulting in increased stage of cancer at presentation. This study assessed whether their primary relatives are, in turn, assessed appropriately. METHODS: An ethically approved prospective study involving 274 primary relatives of women diagnosed with breast cancer, between 2009-2012, at a symptomatic breast unit in Ireland. Telephone interview established: demographics, menstrual history, family history verification, breast screening history. Personal risk level was calculated and whether current screening met screening guidelines. Participants were enrolled into appropriate screening programs if currently not in one and results analyzed. RESULTS: Two hundred and fifteen of the 280 (76.8%) newly diagnosed patients responded giving details of their 274 primary relatives; this made up the study cohort. Mean age 50 +/- 10 (35-75). Thirty two percent were low risk, 64% moderate and 4% high. 190/274 (69%) were being screened appropriately. Seventy five relatives were then assessed with: mammography in 55, Mg and US in 16. Four underwent a biopsy and to date none had cancer. Surveillance was: annual screening in 48%; national screening program and General Practitioner (GP) in 33%; GP only in over 65s in 13%; 6% await further assessment at specialist genetics clinics where their surveillance will be decided. CONCLUSIONS: This study has identified an opportunity to improve the delivery of appropriate screening to higher risk primary relatives of patients with breast cancer. This necessitates an integrated national approach involving providers of primary care, patients and screening breast programs. PMID- 28717659 TI - Identification and characterization of variants and a novel 4 bp deletion in the regulatory region of SIX6, a risk factor for primary open-angle glaucoma. AB - BACKGROUND: Primary open-angle glaucoma (POAG) is a complex disease of multigenic inheritance and the most common subtype of glaucoma. SIX6 encodes a transcription factor involved in retina, optic nerve, and pituitary development. Previous studies showed a genetic association between the SIX6 locus and POAG, identifying risk alleles. Whether these alleles are present also in the south Indian population is unclear. METHODS: To address this question, the SIX6 gene and an already characterized and highly conserved SIX6 enhancer (Ch14:60974427-60974430) were sequenced in two south Indian cohorts, respectively, composed of 65/65 and 200/200 POAG cases/age-matched controls. We next used Taqman-based allelic discrimination assay to genotype a common variant (rs33912345: c.421A>C) and the rs1048372 SNP in two cohorts, respectively, composed of 557/387 and 590/448 POAG cases/age-matched controls. An additional cohort of 153 POAG cases was subsequently recruited to assess the association of the rs33912345:c.421A>C and rs10483727 variants with more prominent changes in two POAG diagnostic parameters: retinal nerve fiber layer thickness and vertical cup/disc ratio, using spectral domain optical coherence tomography. The activity of the newly identified enhancer variants was assessed by transgenesis in zebrafish and luciferase assays. RESULTS: We identified two known rare and two common variants in the SIX6 locus and a novel 4 bp deletion in the analyzed enhancer. Contrary to previous studies, we could not establish a significant association between the rs10483727 and rs33912345:c.421A>C variants and PAOG in the south Indian ethnicity but patients carrying the corresponding C or T risk alleles exhibited a dose-dependent reduction of the thickness of the retinal nerve fiber layer and a significant increase in the vertical cup/disc ratio. Transgenesis in zebrafish and luciferase assays demonstrated that the newly identified 4 bp deletion significantly reduced reporter expression in cells of the retinal ganglion and amacrine layers, where human SIX6 is expressed. CONCLUSION: Altogether, our data further support the implication of SIX6 variants as POAG risk factors and implicates SIX6 haploinsufficiency in POAG pathogenesis. PMID- 28717660 TI - A novel molecular diagnostics platform for somatic and germline precision oncology. AB - BACKGROUND: Next-generation sequencing (NGS) opens new options in clinical oncology, from therapy selection to genetic counseling. However, realization of this potential not only requires succeeding in the bioinformatics and interpretation of the results, but also in their integration into the clinical practice. We have developed a novel NGS diagnostic platform aimed at detecting (1) somatic genomic alterations associated with the response to approved targeted cancer therapies and (2) germline mutations predisposing to hereditary malignancies. METHODS: Next-generation sequencing libraries enriched in the exons of 215 cancer genes (97 for therapy selection and 148 for predisposition, with 30 informative for both applications), as well as selected introns from 17 genes involved in drug-related rearrangements, were prepared from 39 tumors (paraffin embedded tissues/cytologies), 36 germline samples (blood) and 10 cell lines using hybrid capture. Analysis of NGS results was performed with specifically developed bioinformatics pipelines. RESULTS: The platform detects single-nucleotide variants (SNVs) and insertions/deletions (indels) with sensitivity and specificity >99.5% (allelic frequency >=0.1), as well as copy-number variants (CNVs) and rearrangements. Somatic testing identified tailored approved targeted drugs in 35/39 tumors (89.74%), showing a diagnostic yield comparable to that of leading commercial platforms. A somatic EGFR p.E746_S752delinsA mutation in a mediastinal metastasis from a breast cancer prompted its anatomopathologic reassessment, its definite reclassification as a lung cancer and its treatment with gefitinib (partial response sustained for 15 months). Testing of 36 germline samples identified two pathogenic mutations (in CDKN2A and BRCA2). We propose a strategy for interpretation and reporting of results adaptable to the aim of the request, the availability of tumor and/or normal samples and the scope of the informed consent. CONCLUSION: With an adequate methodology, it is possible to translate to the clinical practice the latest advances in precision oncology, integrating under the same platform the identification of somatic and germline genomic alterations. PMID- 28717661 TI - A strategy for molecular diagnostics of Fanconi anemia in Brazilian patients. AB - BACKGROUND: Fanconi anemia (FA) is a predominantly autosomal recessive disease with wide genetic heterogeneity resulting from mutations in several DNA repair pathway genes. To date, 21 genetic subtypes have been identified. We aimed to identify the FA genetic subtypes in the Brazilian population and to develop a strategy for molecular diagnosis applicable to routine clinical use. METHODS: We screened 255 patients from Hospital de Clinicas, Universidade Federal do Parana for 11 common FA gene mutations. Further analysis by multiplex ligation-dependent probe amplification (MLPA) for FANCA and Sanger sequencing of all coding exons of FANCA, -C, and -G was performed in cases who harbored a single gene mutation. RESULTS: We identified biallelic mutations in 128/255 patients (50.2%): 89, 11, and 28 carried FANCA,FANCC, and FANCG mutations, respectively. Of these, 71 harbored homozygous mutations, whereas 57 had compound heterozygous mutations. In 4/57 heterozygous patients, both mutations were identified by the initial screening, in 51/57 additional analyses was required for classification, and in 2/57 the second mutation remained unidentified. We found 52 different mutations of which 22 were novel. CONCLUSION: The proposed method allowed genetic subtyping of 126/255 (49.4%) patients at a significantly reduced time and cost, which makes molecular diagnosis of FA Brazilian patients feasible. PMID- 28717662 TI - Clinical and molecular characterization of cystinuria in a French cohort: relevance of assessing large-scale rearrangements and splicing variants. AB - BACKGROUND: Cystinuria is an autosomal recessive disorder of dibasic amino acid transport in the kidney and the intestine leading to increased urinary cystine excretion and nephrolithiasis. Two genes, SLC3A1 and SLC7A9, coding respectively for rBAT and b0,+AT, account for the genetic basis of cystinuria. METHODS: This study reports the clinical and molecular characterization of a French cohort including 112 cystinuria patients and 25 relatives from 99 families. Molecular screening was performed using sequencing and Quantitative Multiplex PCR of Short Fluorescent Fragments analyses. Functional minigene-based assays have been used to characterize splicing variants. RESULTS: Eighty-eight pathogenic nucleotide changes were identified in SLC3A1 (63) and SLC7A9 (25) genes, of which 42 were novel. Interestingly, 17% (15/88) and 11% (10/88) of the total number of variants correspond, respectively, to large-scale rearrangements and splicing mutations. Functional minigene-based assays were performed for six variants located outside the most conserved sequences of the splice sites; three variants affect splice sites, while three others modify exonic splicing regulatory elements (ESR), in good agreement with a new in silico prediction based on DeltatESRseq values. CONCLUSION: This report expands the spectrum of SLC3A1 and SLC7A9 variants and supports that digenic inheritance is unlikely. Furthermore, it highlights the relevance of assessing large-scale rearrangements and splicing mutations to fully characterize cystinuria patients at the molecular level. PMID- 28717663 TI - Refining genotype-phenotype correlation in Alstrom syndrome through study of primary human fibroblasts. AB - BACKGROUND: Alstrom syndrome (AS), featuring retinal dystrophy, neuronal deafness, cardiomyopathy, metabolic syndrome, and diffuse fibrosis, is caused by biallelic mutations in the centrosomal protein ALMS1. Genotype-phenotype correlation has been suggested without assessment of ALMS1 expression. METHODS: ALMS1 expression (real-time PCR and immunocytochemistry) and cilia formation (immunocytochemistry) were assessed in fibroblasts from deeply phenotyped volunteers diagnosed with AS recruited from a dedicated AS Service. Exome sequencing was used in two participants without convincing biallelic ALMS1 mutations, and BBS2 (Bardet-Biedl syndrome 2) protein expression was assessed in one patient with biallelic BBS2 mutations. Hedgehog-induced GLI1 expression and PDGFA signaling was assessed using quantitative real-time PCR, immunoblotting, or immunostaining of fixed cells after stimulation. RESULTS: In 16 of the patient cell lines examined, ALMS1 protein was undetectable (14 with biallelic loss-of function (LoF) mutations), and in two, ALMS1 staining was equivocal (one with biallelic LoF mutations). In five lines, ALMS1 expression was normal using at least one fixation method (one with biallelic LoF mutations). These differences were not accounted for by major differences in ALMS1 mRNA expression. Exome sequencing of two participants with normal ALMS1 expression identified biallelic LoF BBS2 mutations in one. No second, known ciliopathy mutation was found in the other patient, who had one LoF ALMS1 mutation. Phenotypes were milder or atypical in participants with preserved ALMS1 immunostaining, even when two with likely alternative genetic diagnoses were excluded. All cells studied developed normal cilia, ALMS1 and BBS2 mutant cells showed normal Hedgehog-induced upregulation of GLI1 expression, and PDGFA signaling was normal in ALMS1-deficient cells. CONCLUSION: Milder or atypical presentations of AS should prompt genetic evaluation for alternative, clinically overlapping ciliopathies. A subgroup of patients with bona fide ALMS1 defects have milder phenotypes due to residual ALMS1 expression, which may be more important than mutation site. PMID- 28717664 TI - Genetic variation spectrum in ATP7B gene identified in Latvian patients with Wilson disease. AB - BACKGROUND: Wilson disease (WD) is an autosomal recessive disorder of copper metabolism caused by allelic variants in ATP7B gene. More than 500 distinct variants have been reported, the most common WD causing allelic variant in the patients from Central, Eastern, and Northern Europe is H1069Q. METHODS: All Latvian patients with clinically confirmed WD were screened for the most common mutation p.H1069Q by PCR Bi-PASA method. Direct DNA sequencing of gene ATP7B (all 21 exons) was performed for the patients with WD symptoms, being either heterozygous for H1069Q or without it on any allele. RESULTS: We identified 15 different allelic variants along with eight non-disease-causing allelic variants. Based on the gene molecular analysis and patients' clinical data variant p.His1069Gln was found in 66.9% of WD alleles. Wide clinical variability was observed among individuals with the same ATP7B genotype. The results of our study confirm that neurological manifestations of WD are typically present later than the liver disease but no significant association between the presence/absence of the most common genetic variant and mode of initial WD presentation or age at presentation was identified. CONCLUSIONS: (1) The most prevalent mutation in Latvian patients with Wilson disease was c.3207C>A (p.His1069Gln); (2) No significant phenotype-genotype correlation was found in Latvian patients with Wilson disease; (3) The estimated prevalence of Wilson disease in Latvia is 1 of 24,000 cases which is higher than frequently quoted prevalence of 1: 30,000. PMID- 28717665 TI - Identification of an Alu element-mediated deletion in the promoter region of GNE in siblings with GNE myopathy. AB - BACKGROUND: GNE myopathy is a rare genetic disease characterized by progressive muscle atrophy and weakness. It is caused by biallelic mutations in the GNE gene that encodes for the bifunctional enzyme, uridine diphosphate (UDP)-N acetylglucosamine (GlcNAc) 2-epimerase/N-acetylmannosamine (ManNAc) kinase. Typical characteristics of GNE myopathy include progressive myopathy, first involving anterior tibialis muscle and sparing the quadriceps, and rimmed vacuoles on muscle biopsy. Identifying biallelic mutations by sequencing of the GNE gene confirms the diagnosis of GNE myopathy. In a subset of patients, diagnostic confirmation is challenged by the identification of mutations in only one allele, suggesting mutations in deep intronic regions or regulatory regions. METHODS: We performed targeted sequencing and copy number variant (CNV) analysis of GNE in two siblings who clinically presented with GNE myopathy. Further molecular and biochemical studies were done to characterize the effect of a previously uncharacterized GNE mutation. RESULTS: We report two siblings of Indian descent with characteristic features of GNE myopathy, including progressive skeletal muscle weakness initially involving the anterior tibialis, and rimmed vacuoles on muscle biopsy, in which a heterozygous mutation, p.Val727Met, was identified in both affected siblings, but no other deleterious variants in either coding region or exon-intron boundaries of the gene. Subsequent insertion/deletion analysis identified a novel 11.3-kb deletion (Chr9 [GRCh37]: g.36257583_36268910del) encompassing the GNE promoter region, with breakpoints residing in Alu repeats. Gene expression analysis revealed reduced GNE mRNA and protein levels, confirming decreased expression of the deleted allele harboring the deletion. CONCLUSIONS: We have identified GNE as one of the genes susceptible to Alu-mediated recombination. Our findings suggest that the deletion may encompass the promoter or another region necessary for GNE expression. In patients with typical manifestations of GNE myopathy and a single GNE variant identified, copy number variant (CNV) analysis may be useful in arriving at the diagnosis. PMID- 28717666 TI - Whole exome sequencing and DNA methylation analysis in a clinical amyotrophic lateral sclerosis cohort. AB - BACKGROUND: Gene discovery has provided remarkable biological insights into amyotrophic lateral sclerosis (ALS). One challenge for clinical application of genetic testing is critical evaluation of the significance of reported variants. METHODS: We use whole exome sequencing (WES) to develop a clinically relevant approach to identify a subset of ALS patients harboring likely pathogenic mutations. In parallel, we assess if DNA methylation can be used to screen for pathogenicity of novel variants since a methylation signature has been shown to associate with the pathogenic C9orf72 expansion, but has not been explored for other ALS mutations. Australian patients identified with ALS-relevant variants were cross-checked with population databases and case reports to critically assess whether they were "likely causal," "uncertain significance," or "unlikely causal." RESULTS: Published ALS variants were identified in >10% of patients; however, in only 3% of patients (4/120) could these be confidently considered pathogenic (in SOD1 and TARDBP). We found no evidence for a differential DNA methylation signature in these mutation carriers. CONCLUSIONS: The use of WES in a typical ALS clinic demonstrates a critical approach to variant assessment with the capability to combine cohorts to enhance the largely unknown genetic basis of ALS. PMID- 28717667 TI - Haploinsufficiency of BCL11A associated with cerebellar abnormalities in 2p15p16.1 deletion syndrome. AB - BACKGROUND: Chromosome 2p15p16.1 deletion syndrome is a rare genetic disorder characterized by intellectual disability (ID), neurodevelopmental delay, language delay, growth retardation, microcephaly, structural brain abnormalities, and dysmorphic features. More than 30 patients with 2p15p16.1 microdeletion syndrome have been reported in the literature. METHODS: Molecular analysis was performed using microarray-based comparative genomic hybridization (array CGH). Clinical characteristics and brain magnetic resonance imaging features of these patients were also reviewed. RESULTS: We identified four patients with ID, neurodevelopmental delay, brain malformations, and dysmorphic features; two patients with 2p15p16.1 deletions (3.24 Mb, 5.04 Mb), one patient with 2p16.1 deletion (1.12 Mb), and one patient with 2p14p16.1 deletion (5.12 Mb). Three patients with 2p15p16.1 deletions or 2p16.1 deletions encompassing BCL11A,PAPOLG, and REL showed hypoplasia of the pons and cerebellum. The patient with 2p14p16.1 deletion, which did not include three genes showed normal size and shape of the cerebellar hemispheres and pons. CONCLUSION: The zinc finger transcription factor BCL11A associated with the BAF chromatin remodeling complex has been identified to be critical for neural development and BCL11A haploinsufficiency is closely related to cerebellar abnormalities. PMID- 28717668 TI - Different renal phenotypes in related adult males with Fabry disease with the same classic genotype. AB - BACKGROUND: Fabry disease related patients with classical mutation usually exhibit similar severe phenotype especially concerning renal manifestation. METHODS: A dry blood spot screening (DBS) and the DNA analysis has been performed in a 48-year-old man (Patient 1) because of paresthesia. RESULTS: The DBS revealed absent leukocyte alpha-Gal A enzyme activity while DNA analysis identified the I354K mutation. Serum creatinine and e-GFR were in normal range and also albuminuria and proteinuria were absent. The brain MRI showed ischemic lesions and a diffuse focus of gliosis in the white matter, while the echocardiogram showed a left ventricular hypertrophy. The renal biopsy performed in the case index showed a massive deposition of zebra bodies. By a familiar investigation, it was recognized that his brother (Patient 2) died 2 years before from sudden death syndrome at the age of 49. He had suffered sporadic and undiagnosed pain at the extremities, a prior cataract, bilateral neurosensorial hearing loss and left ventricular hypertrophy on Echocardiogram. His previous laboratory examinations revealed a normal serum creatinine and the absence of proteinuria. Pedigree analysis of the brothers revealed a high disease burden among family members, with an affected cousin (Patient 3) who progressed early to end-stage renal disease (ESRD) that required renal transplantation. CONCLUSIONS: Here we describe the clinical history of three adult male members of the same family with the same genotype who manifested different presentation and progression of the disease, particularly concerning the renal involvement. PMID- 28717669 TI - Pitfalls in genetic testing: a case of a SNP in primer-annealing region leading to allele dropout in BRCA1. AB - BACKGROUND: Hereditary breast and ovarian cancer is characterized by mutations in BRCA1 or BRCA2 genes and PCR-based screening techniques, such as capillary sequencing and next-generation sequencing (NGS), are considered gold standard methods for detection of pathogenic mutations in these genes. Single-nucleotide polymorphisms (SNPs) constitute a vast source of variation in the human genome and represent a risk for misdiagnosis in genetic testing, since the presence of a SNP in primer-annealing sites may cause false negative results due to allele dropout. However, few reports are available and the frequency of this phenomenon in diagnostic assays remains unknown. METHODS AND RESULTS: In this article, we investigated the causes of a false negative capillary sequencing result in BRCA1 involving a mother-daughter dyad. Using several molecular strategies, including different DNA polymerases, primer redesign, allele-specific PCR and NGS, we established that the initial misdiagnosis was caused by a SNP located in the primer-annealing region, leading to allele dropout of the mutated allele. CONCLUSION: Assuming that this problem can also occur in any PCR-based method that are widely used in diagnostic settings, the clinical report presented here draws attention for one of the limitations of genetic testing in general, for which medical and laboratory communities need to be aware. PMID- 28717670 TI - Biomechanical Comparison Between the Cruciate Suture and a Single Vertical Suture Used for Arthroscopic Meniscal Repair: Letter to the Editor. PMID- 28717671 TI - Biomechanical Comparison Between the Cruciate Suture and a Single Vertical Suture Used for Arthroscopic Meniscal Repair: Response. PMID- 28717672 TI - Coccidioidomycosis A Cause of Sarcoidosis. AB - BACKGROUND: Sarcoidosis is a granulomatous disease of unknown etiology and coccidioidomycosis is a granulomatous fungal infection endemic to the southwestern United States. Clinical observations on patients with sarcoidosis and coccidioidomycosis simultaneously led to the hypothesis that sarcoidosis can be caused by the fungus Coccidioides. METHODS: Two patients with sarcoidosis and coccidioidomycosis were studied, one prospectively (ie, a patient with sarcoidosis was predicted to develop coccidioidomycosis) and the other retrospectively (ie, a patient with coccidioidomycosis develops sarcoidosis). In addition, a literature review found 5 patients with these 2 diseases, and they were analyzed to establish an archived relationship between the 2 entities. In addition, polymerase chain reaction (PCR) testing for Coccidioides deoxyribonucleic acid (DNA) was performed on tissue from 15 Arizona patients diagnosed with sarcoidosis. RESULTS: Patient 1 was diagnosed with sarcoid in Arizona and followed prospectively. There was no evidence for coccidioidomycosis at diagnosis. This patient was observed for 8 years before he was documented to have disseminated coccidioidomycosis. Patient 2 was retrospectively studied. He was diagnosed with disseminated coccidioidomycosis, but after 3 years, while on antifungal therapy, he developed respiratory failure. A lung biopsy was consistent with sarcoidosis with no evidence of Coccidioides; cultures, histopathology, and serology were all negative. Paradoxically, PCR testing for Coccidioides DNA on tissue taken at the time of the sarcoidosis diagnosis were all negative, including Patient 2 who had proven coccidioidomycosis. CONCLUSIONS: The 2 study patients and 5 case reports from the literature support the hypothesis that Coccidioides can cause sarcoidosis in Arizona. There are similar reports in the literature that Histoplasma can be associated with sarcoidosis. Based on these observations, we propose that sarcoidosis can be caused by endemic fungi in different areas of the United States, coccidioidomycosis in the Southwest and histoplasmosis in the Midwest. PMID- 28717673 TI - Sex and Race/Ethnic Disparities in Food Security and Chronic Diseases in U.S. Older Adults. AB - Objective: The purpose of this study was to determine the relationships among sex, race/ethnicity, and food security with the likelihood of cancer, diabetes, cardiovascular disease, and lung disease for older adults. Method: Complex sample analysis by logistic regression models for chronic diseases were conducted from National Health and Nutrition Examination Surveys, 2011 to 2012 and 2013 to 2014, for N = 3,871 adults aged >=55 years. Results: Being female with low food security was associated with lung disease and diabetes. Poverty, rather than low food security, was associated with cardiovascular diseases. Minority status was independently associated with low food security and diabetes. Discussion: Food insecurity, sex, and race/ethnicity were associated with chronic diseases in a representative sample of U.S. older adults. PMID- 28717674 TI - ExACtly zero or once: A clinically helpful guide to assessing genetic variants in mild epilepsies. AB - OBJECTIVE: To assist the interpretation of genomic data for common epilepsies, we asked whether variants implicated in mild epilepsies in autosomal dominant families are present in the general population. METHODS: We studied 12 genes for the milder epilepsies and identified published variants with strong segregation support (de novo germline mutation or >=4 affected family members). These variants were checked in the Exome Aggregation Consortium (ExAC), a database of genetic variation in over 60,000 individuals. We subsequently evaluated variants in these epilepsy genes that lacked strong segregation support. To determine whether the findings in epilepsies were representative of other diseases, we also assessed the presence of variants in other dominant neurologic disorders (e.g., CADASIL). RESULTS: Published epilepsy variants with strong segregation support (n = 65) were absent (n = 61) or present once (n = 4) in ExAC. By contrast, of 46 published epilepsy variants without strong segregation support, 8 occurred recurrently (2-186 times). Similarly, none of the 45 disease-associated variants from other neurologic disorders with strong segregation support occurred more than once in ExAC. Reanalysis using the larger ExAC V2 plus gnomAD reference cohort showed consistent results. CONCLUSIONS: Variants causing autosomal dominant epilepsies are ultra-rare in the general population. Variants observed more than once in ExAC were only found among reports without strong segregation support, suggesting that they may be benign. Clinicians are increasingly faced with the interpretation of genetic variants of unknown significance. These data illustrate that variants present more than once in ExAC are less likely to be pathogenic, reinforcing the valuable clinical role of ExAC. PMID- 28717675 TI - Ethics of Clinical Trials in Low-Resource Settings: Lessons From Recent Trials in Cancer Medicine. PMID- 28717676 TI - Breast Cancer Screening in Low- and Middle-Income Countries: A Perspective From Malawi. PMID- 28717677 TI - Development of a Breast Cancer Treatment Program in Port-au-Prince, Haiti: Experiences From the Field. AB - PURPOSE: The nonprofit Project Medishare launched a breast cancer treatment program in Port-au-Prince in July 2013 to address the demand for breast cancer care in Haiti. We outline the development of the program, highlight specific challenges, and discuss key considerations for others working in global oncology. METHODS: We reflected on our experiences in the key areas of developing partnerships, building laboratory capacity, conducting medical training, using treatment algorithms, and ensuring access to safe, low-cost chemotherapy drugs. We also critically reviewed our costs and quality measures. RESULTS: The program has treated a total of 139 patients with breast cancer with strong adherence to treatment regimens in 85% of patients. In 273 chemotherapy administrations, no serious exposure or adverse safety events were reported by staff. The mortality rate for 94 patients for whom we have complete data was 24% with a median survival time of 53 months. Our outcome data were likely influenced by stage at presentation, with more than half of patients presenting more than 12 months after first noticing a tumor. Future efforts will therefore focus on continuing to improve the level of care, while working with local partners to spread awareness, increase screening, and get more women into care earlier in the course of their disease. CONCLUSION: Our experiences may inform others working to implement protocol-based cancer treatment programs in resource-poor settings and can provide valuable lessons learned for future global oncology efforts. PMID- 28717679 TI - Tuberculosis Diagnosis Delaying Treatment of Cancer: Experience From a New Oncology Unit in Blantyre, Malawi. AB - PURPOSE: Malawi is a low-income country in sub-Saharan Africa with limited health care infrastructure and high prevalance of HIV and tuberculosis. This study aims to determine the characteristics of patients presenting to Queen Elizabeth Central Hospital Oncology Unit, Blantyre, Malawi, who had been treated for tuberculosis before they were diagnosed with cancer. METHODS: Clinical data on all patients presenting to the oncology unit at Queen Elizabeth Central Hospital from 2010 to 2014 after a prior diagnosis of tuberculosis were prospectively recorded, and a descriptive analysis was undertaken. RESULTS: Thirty-four patients who had been treated for tuberculosis before being diagnosed with cancer were identified between 2010 and 2014, which represents approximately 1% of new referrals to the oncology unit. Forty-one percent of patients were HIV positive. Mean duration of tuberculosis treatment before presentation to the oncology unit was 3.6 months. The most common clinical presentation was a neck mass or generalized lymphadenopathy. Lymphoma was the most common malignancy that was subsequently diagnosed in 23 patients. CONCLUSION: Misdiagnosis of cancer as tuberculosis is a significant clinical problem in Malawi. This study underlines the importance of closely monitoring the response to tuberculosis treatment, being aware of the possibility of a cancer diagnosis, and seeking a biopsy early if cancer is suspected. PMID- 28717678 TI - Impact of the Bim Deletion Polymorphism on Survival Among Patients With Completely Resected Non-Small-Cell Lung Carcinoma. AB - PURPOSE: A deletion polymorphism of the Bim gene has been reported to be a prognostic factor for patients with non-small-cell lung cancer (NSCLC) treated with epidermal growth factor receptor-tyrosine kinase inhibitors in the Asian population. We investigated the impact of the Bim deletion polymorphism on survival among patients with completely resected NSCLC. PATIENTS AND METHODS: The Bim polymorphism was detected by polymerase chain reaction analysis. We measured overall survival (OS) and recurrence-free survival rates in 411 patients and postrecurrence survival (PRS) in 94 patients who experienced recurrence and received additional anticancer therapy. RESULTS: The Bim deletion polymorphism was detected in 61 patients (14.8%). OS rates were significantly lower for patients with the Bim deletion polymorphism than for those with the wild-type sequence. On multivariable analysis, the Bim deletion polymorphism was identified as an independent prognostic factor for OS (hazard ratio, 1.98; 95% CI, 1.17 to 3.36; P = .011). Among the 94 patients who experienced recurrence and were treated with anticancer therapy, patients with the Bim deletion polymorphism showed significantly poorer PRS than those with the wild-type sequence (median, 9.8 months v 26.9 months, respectively; P < .001). Multivariable analysis revealed that the Bim deletion polymorphism was an independent predictor of PRS (hazard ratio, 3.36; 95% CI, 1.75 to 6.47; P < .001). This trend remained apparent in subgroup analyses stratified by EGFR status, histology, and therapeutic modality. CONCLUSION: The Bim deletion polymorphism is a novel indicator of shortened PRS among patients with recurrent NSCLC treated with anticancer therapy in the Asian population. PMID- 28717680 TI - Lung Cancer Survival Among Chinese Americans, 2000 to 2010. AB - PURPOSE: Despite being the leading cause of cancer death, no prior studies have characterized survival patterns among Chinese Americans diagnosed with lung cancer. This study was conducted to identify factors associated with survival after lung cancer in a contemporary cohort of Chinese patients with lung cancer. METHODS: The study design is a prospective descriptive analysis of population based California Cancer Registry data. Multivariable Cox proportional hazards models were used to estimate hazard ratios (HRs) for overall mortality. Participants were Chinese American residents diagnosed with first primary invasive lung cancer from 2000 to 2010 (2,216 men and 1,616 women). RESULTS: Among Chinese men, decreased mortality was associated with care at a National Cancer Institute cancer center (HR, 0.85; 95% CI, 0.73 to 0.99) and adenocarcinoma versus small-cell carcinoma (HR, 0.78; 95% CI, 0.65 to 0.92). Women had better survival compared with men (HR, 0.82; 95% CI, 0.75 to 0.89), with mortality associated with never married versus currently married status (HR, 1.36; 95% CI, 1.11 to 1.66), lower versus higher neighborhood socioeconomic status (HR, 1.38; 95% CI, 1.10 to 1.72 comparing lowest to highest quintile), care at a cancer center (HR, 0.80; 95% CI, 0.67 to 0.96), and squamous cell relative to small-cell carcinoma (HR, 1.60; 95% CI, 1.04 to 2.48). CONCLUSION: Focusing on factors associated with marital status, community socioeconomic status, and characteristics unique to National Cancer Institute-designated cancer centers may help to identify potential strategies for improving the length of survival for Chinese Americans. PMID- 28717681 TI - Increasing Access to Oral Anticancer Medicines in Middle-Income Countries: A Case Study of Private Health Insurance Coverage in Brazil. AB - The World Health Organization estimates that approximately 60% of the world's new annual cancer cases occur in Asia, Africa, and Central and South America, and that 70% of cancer deaths occur in these regions. Although oral chemotherapy is a promising intervention for cancer treatment, given its high cost, it is usually unavailable in middle-income countries. In 2013, after strong lobbying from civil society, Brazil's Congress passed legislation mandating that all private health insurance companies provide access to oral antineoplastic treatment. The decision to scale up the provision of oral chemotherapy was a watershed event in the regulation of private health insurance in Brazil. Until then, private insurers, which cover 25% of the population, were exempted from the provision of pharmaceutical drugs for home care treatments. This article explores the political process involved in regulating the provision of oral chemotherapy medicines by private health insurers. Elements of this successful advocacy case included investment in strategic communication, specialized knowledge of regulatory policy, and the ability to act via democratic channels of political representation. In turn, the receptiveness of government branches such as the Congress and regulating bodies, as well as the Cancer Awareness Month campaign, opened a window of opportunity. However, prospects for expanded access to such medicines in the public health system are bleak in the short term because of the ongoing political and economic crisis. PMID- 28717682 TI - Collision of Three Pandemics: The Coexistence of Cervical Cancer, HIV Infection, and Prior Tuberculosis in the Sub-Saharan Country of Botswana. AB - Cervical cancer is the leading cause of cancer-related mortality in the developing world, where HIV and Mycobacterium tuberculosis (TB) infection are also endemic. HIV infection is independently associated with increased morbidity and mortality among women with cervical cancer. TB is believed to increase the risk of malignancies and could cause chronic inflammation in the gynecologic tract. However, the relationship between cervical cancer and TB in settings hyperendemic for HIV is unknown. We found that 18 (10%) of a cohort of 180 women with cervical cancer in Botswana had a history of TB disease. Age and HIV infection were also associated with a history of TB disease. Our data show that prior TB disease is highly prevalent among patients with cervical cancer infected with HIV. The coexistence of cervical cancer, HIV infection, and prior TB infection might be higher than expected in the general population. Prospective studies are needed to better determine the impact of the collision of these three world health epidemics. PMID- 28717683 TI - How Context Matters: A Dissemination and Implementation Primer for Global Oncologists. PMID- 28717684 TI - Maya Healers' Conception of Cancer as Revealed by Comparison With Western Medicine. AB - PURPOSE: Cultural diversity in clinical encounters is common, yet mental constructions regarding cancer that influence expected treatment are poorly studied for indigenous people. We explored Maya healers' conceptions, diagnosis, and treatment of cancer to remedy this problem. METHODS: In-depth structured interviews with 67 traditional Maya healers in Guatemala across Kaqchikel, Kiche', Mam, Mopan, and Q'eqchi' ethnolinguistic groups were conducted by using a transdisciplinary format. Analysis of qualitative data in categorized matrixes allowed for statistical examination of tendencies and the results were complemented by validation workshops with Maya representatives. RESULTS: Maya classification of diseases has broad categories of malignant diseases including cancer. Specific Maya terms might equate to particular cancer types, which would open new avenues for research. Notions of malignancy and metastasis were expressed by healers as core characteristics of cancer, a disease believed to be both material and spiritual. Resolution of and/or treatment for cancer is based on restoring physical, mental, emotional, and spiritual equilibrium of the patient and extending that equilibrium to his larger social circle. CONCLUSION: Maya conceptions of cancer determine how traditional diagnostic tools are used and dictate treatment options that include the patient's social-spiritual support system. Official health care providers' understanding of these principles can improve implementation of culturally appropriate protocols that increase indigenous patients' compliance and reduce rates of treatment abandonment. PMID- 28717685 TI - Trends in the Aggressiveness of End-of-Life Cancer Care in the State of Qatar. AB - PURPOSE: Quality of end-of-life (EOL) care is a key component of excellence in cancer care, and monitoring indicators for quality of EOL cancer care is crucial to providing excellent care. The aim of the current study is to describe the relative aggressiveness of EOL cancer care in the state of Qatar and to compare it with international figures. METHODS: We analyzed all deaths from cancer in Qatar between January 1, 2009 and December 31, 2013. A total of 784 eligible patients were studied to assess aggressiveness of cancer care at EOL. RESULTS: The average number of intensive care unit admissions per person decreased from 0.44 to 0.22 (P < .001) over the period of study. In addition, patients spent fewer days in the intensive care unit (2.79 to 1.82 days; P = .006) and made fewer visits to the emergency department (1.00 to 0.52 visits; P < .001) in the last 30 days of life. Fewer patients had at least one aggressive treatment measure at EOL during the 5-year period (82.3% to 71.0%; P = .038). The mean composite score for aggressiveness of EOL care decreased from 2.24 to 1.92 (P < .01). CONCLUSION: The aggressiveness of EOL cancer care has significantly decreased over time in Qatar; however, despite this decrease, the rate is still higher than that reported internationally. The integration of community palliative care services in Qatar may further decrease the aggressiveness of cancer care at EOL. PMID- 28717686 TI - Implementation and Validation of Telepathology Triage at Cancer Referral Center in Rural Rwanda. AB - PURPOSE: Connecting a cancer patient to the appropriate treatment requires the correct diagnosis provided in a timely manner. In resource-limited settings, the anatomic pathology bridge to efficient, accurate, and timely cancer care is often challenging. In this study, we present the first phase of an anatomic telepathology triage system, which was implemented and validated at the Butaro District Hospital in northern rural Rwanda. METHODS: Select cases over a 9-month period in three segments were evaluated by static image telepathology and were independently evaluated by standard glass slide histology. Each case via telepathology was classified as malignant, benign, infectious/inflammatory, or nondiagnostic and was given an exact histologic diagnosis. RESULTS: For cases triaged as appropriate for telepathology, correlation with classification and exact diagnosis demonstrated greater than 95% agreement over the study. Cases in which there was disagreement were analyzed for cause, and the triage process was adjusted to avoid future problems. CONCLUSION: Challenges to obtaining a correct and complete diagnosis with telepathology alone included the need for immunohistochemistry, assessment of the quality of images, and the lack of images representing an entire sample. The next phase of the system will assess the effect of telepathology triage on turnaround time and the value of on-site immunohistochemistry in reducing that metric and the need for evaluation outside of telepathology. PMID- 28717687 TI - Could African and Low- and Middle-Income Countries Contribute Scientifically to Global Cancer Care? The Answer Is Yes! PMID- 28717688 TI - Me, Too. PMID- 28717689 TI - Treating Nephroblastoma in Rwanda: Using International Society of Pediatric Oncology Guidelines in a Novel Oncologic Care Model. AB - PURPOSE: Success in treating nephroblastoma in high-income countries has been transferred to some resource-constrained settings; multicenter studies report disease-free survival of greater than 70%. However, few reports present care models with rural-based components, care tasks shifted to internists and pediatricians, and data collection structured for monitoring and evaluation. Here, we report clinical outcomes and protocol compliance for patients with nephroblastoma evaluated at Butaro Cancer Center of Excellence in Rwanda. PATIENTS AND METHODS: This retrospective study reports the care of 53 patients evaluated between July 1, 2012, and June 30, 2014. Patients receiving less than half of their chemotherapy at Butaro Cancer Center of Excellence were excluded. RESULTS: Of the 53 patients included, 9.4% had stage I, 13.2% had stage II, 24.5% had stage III, 26.4% had stage IV, and 5.7% had stage V disease; the remaining 20.8% had unknown stage disease from inadequate work-up or unavailable surgical report. The incidence of neutropenia increased with treatment progression, and the greatest proportion of delays occurred during the surgical referral phase. At the end of the study period, 32.1% of patients (n = 17) remained alive after treatment; 24.5% (n = 13) remained alive while continuing treatment, including one patient with recurrent disease; 30.2% (n = 16) died; and 13.2% (n = 7) were lost to follow-up. CONCLUSION: Our findings confirm that nephroblastoma can be effectively treated in resource-constrained settings. Using an approach in which chemotherapy is delivered at a rural-based center by nononcologists and data are used for routine evaluation, care can be delivered in safe, novel ways. Protocol modifications to mitigate chemotherapy toxicities and strong communication between the multidisciplinary team members will likely minimize delays and further improve outcomes in similar settings. PMID- 28717690 TI - Screening by Clinical Breast Examination in Western Kenya: Who Comes? AB - PURPOSE: More than 80% of women with breast cancer in Kenya present to medical care with established late-stage disease. We sought to understand why women might not participate in breast cancer screening when it is offered by comparing the views of a cohort of those who attended a screening special event with those of community controls who did not attend. METHODS: All residents living close to three health centers in western Kenya were invited to participate in screening. Participants (attendees) underwent clinical breast examination by trained physician oncologists. In addition, women who consented were interviewed by using a modified Breast Cancer Awareness Module questionnaire. Nonattendees were interviewed in their homes the following day. RESULTS: A total of 1,511 attendees (1,238 women and 273 men) and 467 nonattendee women participated in the study. Compared with nonattendees, the women attendees were older, more often employed, knew that breast cancer presented as a lump, and were more likely to have previously felt a lump in a breast. In addition, they were more likely to report previously participating in screening activities, were more likely to have performed breast self-examination, and were less concerned about wasting a doctor's time. Almost all those surveyed (attendees and nonattendees) expressed interest in future breast cancer screening opportunities. CONCLUSION: The women who volunteer for breast cancer screening in western Kenya are more aware of breast cancer than those who do not volunteer. Screening recruitment should seek to close these knowledge gaps to increase participation. PMID- 28717691 TI - Outcomes of Saudi Arabian Patients With Nasopharyngeal Cancer Treated With Primarily Neoadjuvant Chemotherapy Followed by Concurrent Chemoradiotherapy. AB - PURPOSE: Nasopharyngeal cancer (NPC) is the most common head and neck cancer in Saudi Arabia. This study reports the locoregional disease control and survival outcomes in patients with NPC treated in King Abdulaziz University Hospital. METHODS: Patients treated for NPC between June 2007 and October 2014 were retrospectively reviewed. Demographic information, clinicopathologic variables, and chemotherapy data were collected and analyzed. Cumulative survival and disease control rates were calculated by Kaplan-Meier product-limit actuarial method. RESULTS: Thirty-nine patients with NPC were reviewed. Thirty-five (90%) patients received definitive radiotherapy (RT) and four (10%) had palliative RT. Mean prescribed dose for definitive RT was 68 Gy (range, 60 to 70.2 Gy), delivered with mean doses per fraction of 1.9 Gy (range, 1.8 to 2.1 Gy). After a median follow-up of 15 months (range, 1 to 84 months), 22 (63%) patients who underwent definitive RT were disease free and 13 (37%) were still with disease. During this period, seven (18%) patients died of the disease; five (13%) of them received definitive RT. After 2 years' follow-up, the actuarial estimate rates were: 85.7% for local control, 91.4% for nodal control, and 85.7% for distant control. CONCLUSION: Our study showed a disease with clinical behavior similar to what has been observed in East and Southeast Asia. Further it explored the neoadjuvant chemotherapy approach in treating NPC with results that are comparable to literature. However, little is known about the molecular pathogenesis of this disease in this region, and further research integrating clinical and molecular biomarkers is required. PMID- 28717692 TI - Treatment of Chronic Myeloid Leukemia in Rural Rwanda: Promising Early Outcomes. AB - PURPOSE: The burden of cancer is rising in low- and middle-income countries, yet cancer treatment requires resources that are often not available in these settings. Although management of chronic myeloid leukemia (CML) has been described in low- and middle-income countries, few programs involve patients treated in rural settings. We describe characteristics and early outcomes of patients treated for CML at rural district hospitals in Rwanda. METHODS: We conducted a retrospective review of patients with confirmed BCR-ABL-positive CML who were enrolled between July 1, 2009 and June 30, 2014. Types of data included patient demographics, diagnostic work up, treatment, clinical examination, laboratory testing, and death. RESULTS: Forty-three patients were included, with a maximum follow-up of 58 months. Of 31 patients who were imatinib-naive at enrollment, 54.8% were men and the median age at diagnosis was 36.9 years (interquartile range: 29-42 years). Approximately two-thirds of patients (67.7%) were on the national public insurance scheme. The imatinib dose was reduced for 16 patients and discontinued for five. Thirty-two of the 43 patients continued to have normal blood counts at last follow-up. Four patients have died and four are lost to follow-up. CONCLUSION: Our experience indicates that CML can be effectively managed in a resource-constrained rural setting, despite limited availability of on-site diagnostic resources or specialty oncology personnel. The importance of model public-private partnerships as a strategy to bring high-cost, life-saving treatment to people who do not have the ability to pay is also highlighted. PMID- 28717693 TI - Pulmonary Nodules in Patients With Nonpulmonary Cancer: Not Always Metastases. AB - INTRODUCTION: The differential diagnosis of pulmonary nodules (PNs) includes metastases, lung cancers, infectious diseases, and scar tissue, among others. Because data regarding whether and when to perform a PN biopsy in patients with cancer are scarce, clinicians tend to assume that PNs are metastatic disease based solely on imaging. The current study evaluated the findings of PN biopsies in a population of patients with cancer and sought to determine the variables that correlated with higher odds of metastatic disease. PATIENTS AND METHODS: We conducted a retrospective, single-institution study that included consecutive patients with nonpulmonary solid malignancies who underwent PN biopsy from January 2011 to December 2013. Imaging and clinical variables were analyzed by logistic regression to determine the correlation between such variables and the odds of metastatic disease. Patients with previously known metastatic disease or primary hematologic malignancies were excluded. RESULTS: Two hundred twenty-eight patients were included in the study. Metastatic disease was found in 146 patients (64%), 60 patients (26.3%) were diagnosed with a second primary lung tumor, and 22 patients (9.6%) had no cancer on biopsy. On multivariate analysis, the presence of multiple PNs (> 5 mm) and cavitation/necrosis were the only variables associated with higher odds (P < .05) of metastatic disease. We registered six (2.6%) procedure complications demanding active interventions, and no procedure related death occurred. CONCLUSION: Multiple PNs (> 5 mm) and cavitation were the two characteristics associated with the highest chances of metastatic disease. Our findings demonstrate that PNs should not be assumed to be metastases without performing a biopsy. This assumption may lead to high rates of misdiagnosis. Tissue sampling is fundamental for accurately diagnosing patients with cancer. PMID- 28717694 TI - Cheaper Options in the Prevention of Chemotherapy-Induced Nausea and Vomiting. AB - Chemotherapy-induced nausea and vomiting (CINV) is a common challenge in oncology practice for which there are expensive guideline-based treatment options. Although supportive care in cancer adds significantly to the overall cost, the discussion of unaffordability of anticancer treatment frequently only revolves around the targeted drugs and immunotherapies. In this review, we highlight the available cost-saving strategies and recent updates in preventing CINV in patients with cancer. This is the first work, to our knowledge, to review specifically the less expensive alternatives in CINV prevention, which is particularly important for those working in resource-limited settings. Whereas patients in these settings often cannot afford expensive antiemetics, we now have the science to offer cheaper, more affordable options without necessarily compromising efficacy. PMID- 28717696 TI - Nasopharyngeal Cancer Outcomes From Saudi Arabia. PMID- 28717695 TI - Nursing's Potential to Address the Growing Cancer Burden in Low- and Middle Income Countries. PMID- 28717697 TI - More Convoluted Than a Brazilian Soap Opera: How an Eager Chemistry Professor and a Well-Intended but Misguided Federal Judge Ignited an Industry of False Hopes. PMID- 28717698 TI - Neuroblastoma in Africa: A Survey by the Franco-African Pediatric Oncology Group. AB - PURPOSE: Neuroblastoma is a sympathoadrenal lineage neural crest-derived tumor. It is the third most common childhood malignancy in the Western world. Studies from the United States show that black patients with neuroblastoma have a greater proportion of high-risk neuroblastoma with poorer prognosis compared with white patients. In Africa, there are few published data on the epidemiology and management of neuroblastoma. The primary aim of this study was to assess the diagnostic and therapeutic resources available for the management of neuroblastoma within the Franco-African Pediatric Oncology Group (GFAOP). METHODS: A survey was conducted in the pediatric oncology centers of the GFAOP. Participating GFAOP centers were Abidjan, Algiers, Bamako, Dakar, Lubumbashi, Lome, Ouagadougou, Rabat, Tananarive Antananarivo, and Tunis. Questionnaires were sent out by e-mail to the principal investigators at each participating GFAOP center in December 2013. RESULTS: Ten (62%) of 16 GFAOP centers responded to the questionnaire. Neuroblastoma represented only 3% to 5% of childhood cancers in the sub-Saharan African centers, with the exception of Antananarivo, where it represented 7.5%. In contrast, in the northern African centers of Tunis, Rabat, and Algiers, neuroblastoma accounted for 30%,10%, and 7% of childhood cancer, respectively. At initial diagnosis, 50% to 80% of patients had metastatic neuroblastoma in eight of 10 centers. CONCLUSION: Based on this survey, neuroblastoma seems to be less common in sub-Saharan Africa. The proportion of patients with metastatic neuroblastoma seems to be higher than reported in Western countries. PMID- 28717699 TI - Opportunistic Breast Cancer Education and Screening in Rural Honduras. AB - PURPOSE: In Honduras, the breast cancer burden is high, and access to women's health services is low. This project tested the connection of community-based breast cancer detection with clinical diagnosis and treatment in a tightly linked and quickly facilitated format. METHODS: The Norris Cotton Cancer Center at Dartmouth College partnered with the Honduran cancer hospital La Liga Contra el Cancer to expand a cervical cancer screening program, which included self-breast exam (SBE) education and clinical breast exams (CBEs), to assess patient attitudes about and uptake of breast cancer education and screening services. The cervical cancer screening event was held in Honduras in 2013; 476 women from 31 villages attended. RESULTS: Half of the women attending elected to receive a CBE; most had concerns about lactation. Clinicians referred 12 women with abnormal CBEs to La Liga Contra el Cancer for additional evaluation at no cost. All referred patients were compliant with the recommendation and received follow-up care. One abnormal follow-up mammogram/ultrasound result was negative on biopsy. One woman with an aggressive phyllodes tumor had a mastectomy within 60 days. Multimodal education about breast cancer screening maximized delivery of women's health services in a low-tech rural setting. CONCLUSION: The addition of opportunistic breast cancer education and screening to a cervical cancer screening event resulted in high uptake of services at low additional cost to program sponsors. Such novel strategies to maximize delivery of women's health services in low-resource settings, where there is no access to mammography, may result in earlier detection of breast cancer. Close follow-up of positive results with referral to appropriate treatment is essential. PMID- 28717700 TI - Prostate Cancer Burden at the Uganda Cancer Institute. AB - PURPOSE: In Uganda, the incidence of prostate cancer is increasing at a rate of 5.2% annually. Data describing presentation and outcomes for patients with prostate cancer are lacking. METHODS: A retrospective review of medical records for men with histologically confirmed prostate cancer at the Uganda Cancer Institute (UCI) from January 1 to December 17, 2012, was performed. RESULTS: Our sample included 182 men whose mean age was 69.5 years (standard deviation, 9.0 years). Patients who presented to the UCI had lower urinary tract symptoms (73%; n = 131), bone pain (18%; n = 32), increased prostate-specific antigen (PSA; 3%; n = 5), and other symptoms (6%; n = 11). Median baseline PSA was 91.3 ng/mL (interquartile range, 19.5-311.3 ng/mL), and 51.1% of the patients (n = 92) had a PSA value above 100 ng/mL. Gleason score was 9 or 10 in 66.7% of the patients (n = 120). Ninety percent (n = 136) had stage IV disease, and metastatic sites included bone (73%; n = 102), viscera (21%; n = 29), and lymph nodes (4%; n = 5). Spinal cord compression occurred in 30.9% (n = 55), and 5.6% (n = 10) experienced a fracture. A total of 14.9% (n = 27) underwent prostatectomy, and 17.7% (n = 32) received radiotherapy. Gonadotropin-releasing hormone agonist was given to 45.3% (n = 82), 29.2% (n = 53) received diethylstilbestrol, and 26% (n = 47) underwent orchiectomy. Chemotherapy was administered to 21.6% (n = 39), and 52.5% (n = 95) received bisphosphonates. During the 12 months of study, 23.8% of the men (n = 43) died, and 54.4% (n = 98) were lost to follow-up. CONCLUSION: UCI patients commonly present with high PSA, aggressive Gleason scores, and stage IV disease. The primary treatments are hormonal manipulation and chemotherapy. Almost 25% of patients succumb within a year of presentation, and a large number of patients are lost to follow-up. PMID- 28717701 TI - Cost Effectiveness of Universal Hepatitis B Virus Screening in Patients Beginning Chemotherapy for Sarcomas or GI Stromal Tumors. AB - PURPOSE: The value of screening for hepatitis B virus (HBV) infection before chemotherapy for nonhematopoietic solid tumors remains unsettled. We evaluated the cost effectiveness of universal screening before systemic therapy for sarcomas, including GI stromal tumors (GISTs). PATIENTS AND METHODS: Drawing from the National Cancer Centre Singapore database of 1,039 patients with sarcomas, we analyzed the clinical records of 485 patients who received systemic therapy. Using a Markov model, we compared the cost effectiveness of a screen-all versus screen-none strategy in this population. RESULTS: A total of 237 patients were screened for HBV infection. No patients developed HBV reactivation during chemotherapy. The incremental cost-effectiveness ratio per quality-adjusted life year (QALY) of offering HBV screening to all patients with sarcomas and patients with GISTs exceeded the cost-effectiveness threshold of SG$100,000 per QALY. This result was robust in one-way sensitivity analysis. Our results show that only changes in mortality rate secondary to HBV reactivation could make the incremental cost-effectiveness ratio cross the cost-effectiveness threshold. CONCLUSION: Universal HBV screening in patients with sarcomas or GISTs undergoing chemotherapy is not cost effective at a willingness to pay of SG$100,000 per QALY and may not be required. PMID- 28717702 TI - Management of Chemoradiation-Induced Mucositis in Head and Neck Cancers With Oral Glutamine. AB - PURPOSE: Head and neck cancers are the third most common cancers worldwide. Oral mucositis is the most common toxicity seen in patients who receive chemoradiation to treat head and neck cancer. The aim of this study was to evaluate the efficacy and safety of oral glutamine supplementation in these patients. MATERIALS AND METHODS: From December 2013 to December 2014, we randomly assigned to two arms 162 patients who had squamous cell carcinoma of the head and neck. Patients in arm A were given oral glutamine once per day, whereas those in arm B served as negative control subjects. All patients received radiotherapy given as 70 Gy in 35 fractions over 7 weeks with an injection of cisplatin once per week. Patients were assessed once per week to evaluate for the onset and severity of mucositis, pain, use of analgesics, and for Ryle tube feeding. RESULTS: We observed that 53.1% of patients developed mucositis toward the fifth week in the glutamine arm compared with 55.5% of patients in the control arm at the third week. None in the glutamine arm compared with 92.35% of patients in the control arm developed G3 mucositis. Rates of adverse events like pain, dysphagia, nausea, edema, and cough, as well as use of analgesics and Ryle tube feeding, were significantly lower in the glutamine arm than in the control arm. CONCLUSION: This study highlights that the onset as well as the severity of mucositis in patients receiving glutamine was significantly delayed. None of the patients receiving glutamine developed G3 mucositis. Hence, the findings emphasize the use of oral glutamine supplementation as a feasible and affordable treatment option for mucositis in patients with head and neck cancers who are receiving chemoradiation. PMID- 28717703 TI - Global Access to Radiotherapy Services: Have We Made Progress During the Past Decade? AB - PURPOSE: The global incidence of cancer is rising, particularly in low- and middle-income countries. Radiotherapy is an important cancer treatment in the curative and palliative setting. We aimed to estimate the global demand for and supply of radiotherapy megavoltage machines (MVMs) and assess the changes in supply and demand during the past decade. MATERIALS AND METHODS: Cancer incidences for 27 cancer types in 184 countries were extracted from the International Agency for Research on Cancer GLOBOCAN database. The Collaboration for Cancer Outcomes Research and Evaluation radiotherapy utilization rate (RTU) model was used to estimate the number of patients in each country with an indication for radiotherapy for each cancer type and estimate the demand for MVMs. The radiotherapy supply data were accessed from Directory of Radiotherapy Centres database maintained by the International Atomic Energy Agency. RESULTS: RTU varied by country, from 32% in Mongolia to 59% in Comoros. The average optimal world RTU was 50%, equating to 7 million people in 2012 who would benefit from radiotherapy. There remains a deficit of more than 7,000 machines worldwide. During the past decade, the gap between radiotherapy demand and supply has widened in low-income countries. CONCLUSION: RTU varies significantly between countries. Approximately half of all patients with cancer worldwide should receive radiotherapy; however, more than 2 million people are unable to access it because of a lack of MVMs. Low- and middle-income countries are particularly disadvantaged by this deficit. PMID- 28717704 TI - Significance of Magnetic Resonance Imaging-Assessed Tumor Response for Locally Advanced Rectal Cancer Treated With Preoperative Long-Course Chemoradiation. AB - PURPOSE: To study the predictive and prognostic value of magnetic resonance imaging (MRI)-assessed tumor response after long-course neoadjuvant therapy for locally advanced rectal cancer. METHODS: This study included 79 patients who had T3 or T4 and/or N+ rectal cancer treated with long-course neoadjuvant chemoradiation. MRI-assessed tumor regression grade (mrTRG) was assessed in 64 patients. MRIs were reviewed by the study radiologist. Surgical and pathologic reports for those who underwent surgery were reviewed. Disease-free survival (DFS) was estimated. Progression during therapy, local relapse, metastasis, and death resulting from the tumor were classified as events. Statistical significance was calculated. RESULTS: In 11 patients, the tumor completely disappeared on MRI; that is, it had an mrTRG of 1. All but one patient, who chose deferred surgery, had a complete pathologic response (pCR), with a positive predictive value of nearly 100%. Of the 20 patients who had an mrTRG of 2 on MRI, six had a pCR. mrTRG 3, mrTRG 4, and mrTRG 5 were detected in 24, six, and three patients, respectively, of whom only one patient had a pCR. The 2-year DFS was 77%. The mrTRG was significant for DFS. The 2-year DFS was 88% for patients with a good response versus 66% for those with a poor response (P = .046). CONCLUSION: MRI-assessed complete tumor response was strongly correlated with pCR and, therefore, can be used as a surrogate marker to predict absence of viable tumor cells. Our results can be used to implement use of mrTRGs in larger prospective correlative studies as a tool to select patients for whom deferred surgery may be appropriate. Also, those with a poor response may be offered further treatment options before definitive surgery. PMID- 28717705 TI - Adoption of Information and Communication Technologies for Early Detection of Breast and Cervical Cancers in Low- and Middle-Income Countries. AB - PURPOSE: In response to the growing burden of breast and cervical cancers, low- and middle-income countries (LMICs) are beginning to implement national cancer prevention programs. We reviewed the literature on information and communication technology (ICT) applications in the prevention of breast and cervical cancers in LMICs to examine their potential to enhance cancer prevention efforts. METHODS: Ten databases of peer-reviewed and gray literature were searched using an automated strategy for English-language articles on the use of mobile health (mHealth) and telemedicine in breast and cervical cancer prevention (screening and early detection) published between 2005 and 2015. Articles that described the rationale for using these ICTs and/or implementation experiences (successes, challenges, and outcomes) were reviewed. Bibliographies of articles that matched the eligibility criteria were reviewed to identify additional relevant references. RESULTS: Of the initial 285 citations identified, eight met the inclusion criteria. Of these, four used primary data, two were overviews of ICT applications, and two were commentaries. Articles described the potential for mHealth and telemedicine to address both demand- and supply-side challenges to cancer prevention, such as awareness, access, and cost, in LMICs. However, there was a dearth of evidence to support these hypotheses. CONCLUSION: This review indicates that there are few publications that reflect specifically on the role of mHealth and telemedicine in cancer prevention and even fewer that describe or evaluate interventions. Although articles suggest that mHealth and telemedicine can enhance the implementation and use of cancer prevention interventions, more evidence is needed. PMID- 28717706 TI - Cancer Pain Management Insights and Reality in Southeast Asia: Expert Perspectives From Six Countries. AB - This expert opinion report examines the current realities of the cancer pain management landscape and the various factors that hinder optimal pain control in six countries in Southeast Asia, describes ongoing efforts to advance patient care, and discusses approaches for improving cancer pain management. Information was gathered from leading experts in the field of cancer pain management in each country through an initial meeting and subsequent e-mail discussions. Overall, there are vast disparities in cancer pain management practices and access to opioids in the Southeast Asian countries. The experts considered cancer pain as being generally undermanaged. Access to opioids is inadequate in most countries, and opioid use for analgesia remains inadequate in the region. Several system-, physician-, and patient-related barriers to adequate pain relief were identified, including widespread over-regulation of opioid use, shortage of trained health care workers, inadequacies in pain assessment and knowledge about managing pain, and widespread resistance among patients and physicians toward opioid treatment. According to the experts, many of the ongoing initiatives in the Southeast Asian countries are related to educating patients and physicians on cancer pain management and opioid use. Efforts to improve opioid availability and reduce regulatory barriers in the region are limited, and much work is still needed to improve the status of cancer pain management in the region. Enacting necessary change will require recognition of the unique needs and resources of each country and collaboration across interdisciplinary professional teams to improve cancer pain care in this region. PMID- 28717707 TI - Misdiagnosis of Cancer as Tuberculosis in Low- to Middle-Income Countries: A Tip of the Iceberg! PMID- 28717708 TI - Researchers' First Duty Is to the Participants. PMID- 28717709 TI - Beyond Me, Too. PMID- 28717710 TI - Zika Virus in a Patient With Cancer: How Much Do We Know? PMID- 28717711 TI - Breast Cancer Among Iraqi Women: Preliminary Findings From a Regional Comparative Breast Cancer Research Project. PMID- 28717712 TI - EGFR Mutations in Latinos From the United States and Latin America. AB - PURPOSE: Epidermal growth factor receptor (EGFR) mutations confer sensitivity to EGFR tyrosine kinase inhibitors in patients with advanced non-small-cell lung cancer (NSCLC). There are limited and conflicting reports on the frequency of EGFR mutations in Latinos. PATIENTS AND METHODS: Samples from 642 patients with NSCLC from seven institutions in the United States and Latin America were assessed for EGFR mutations (exons 18 to 21) at Clinical Laboratory Improvement Amendments-certified central laboratories. RESULTS: EGFR mutation analysis was successfully performed in 480 (75%) of 642 patients; 90 (19%) were Latinos, 318 (66%) were non-Latino whites, 35 (7%) were non-Latino Asians, 30 (6%) were non Latino blacks, and seven (2%) were of other races or ethnicities. EGFR mutations were found in 21 (23%) of 90 Latinos with varying frequencies according to the country of origin; Latinos from Peru (37%), followed by the United States (23%), Mexico (18%), Venezuela (10%), and Bolivia (8%). In never-smoker Latinos and Latinos with adenocarcinoma histology, EGFR mutation frequencies were 38% and 30%, respectively. There was a significant difference in the frequency of EGFR mutations among the different racial and ethnic subgroups analyzed (P < .001), with non-Latino Asians having the highest frequency (57%) followed by Latinos (23%), non-Latino whites (19%), and non-Latino blacks (10%). There was no difference between Latinos (23%) and non-Latinos (22%; P = .78) and Latinos and non-Latino whites (P = .37). Patients from Peru had an overall higher frequency of mutations (37%) than all other Latinos (17%), but this difference only exhibited a trend toward significance (P = .058). CONCLUSION: There was no significant difference between the frequency of EGFR mutations in NSCLC in Latinos and non-Latinos. PMID- 28717713 TI - Breaking Cancer Bad News to Patients With Cancer: A Comprehensive Perspective of Patients, Their Relatives, and the Public-Example From a Middle Eastern Country. AB - PURPOSE: Empowering patients with cancer requires that they be continuously informed about their condition. In some Eastern cultures, this concept is often opposed by caregivers. We aim to compare the extent of disclosure desired by actual and presumed patients with cancer and their relatives in our practice. METHODS: Nine questions reflecting possible bad news communication to patients from diagnosis to the end of life were designed to investigate the extent of desired disclosure and were answered by 100 patients (cohort I) and 103 accompanying relatives (cohort II) in an outpatient setting. In addition, 103 public participants attending a family medicine clinic (cohort III) each answered the questions from the perspective of a presumed patient (cohort IIIA) and the perspective of a relative (cohort IIIB). The primary end point was affirmative response to six or more questions (AR >= 6), reflecting a preference to be informed of the majority (>= 67%) of possible bad news. RESULTS: AR >= 6 was reported in 85% of cohort I and 52% of cohort II (chi2P < .001). On multivariable analysis, AR >= 6 showed significant association with being a patient (in cohorts I and II) and having nonmetastatic disease (only in cohort I). In the public cohort, AR >= 6 was reported in 91% in cohort IIIA and 63% in cohort IIIB (chi2P < .001). On multivariable analysis, AR >= 6 in cohort III was significantly associated with being a presumed patient and having at least a college education. CONCLUSION: Patients desire disclosure of the majority of cancer-related bad news. This is in contrast to the views and requests of relatives. The public participants would also desire similar disclosure if they were to be diagnosed with cancer. PMID- 28717714 TI - Phenotype and Treatment of Breast Cancer in HIV-Positive and -Negative Women in Cape Town, South Africa. AB - PURPOSE: An estimated 5.9 million people in South Africa are infected with HIV. Because antiretroviral therapy has made infection with HIV a treatable, chronic condition, HIV-infected individuals are now surviving to middle and older age. We investigated the implications of HIV status for breast cancer in South Africa. METHODS: We compared clinical and demographic characteristics of women newly diagnosed with a first primary breast cancer at Tygerberg Hospital, Cape Town, South Africa, from January 2010 to December 2011 by HIV status. We then compared HIV-positive patients with HIV-negative controls, matched 2:1 on age and ethnicity, with respect to chemotherapy regimens, toxicities, completion of systemic chemotherapy, and changes in CD4 cell count. RESULTS: Of 586 women with breast cancer, 31 (5.3%) were HIV positive, 420 (71.7%) were HIV negative, and 135 (23%) were untested for HIV. Women with HIV were younger than other women (P < .001). The groups did not differ in regard to stage at presentation, histologic subtype, tumor grade, nodal involvement, or hormone receptor positivity. More than 84% of patients who initiated systemic chemotherapy, regardless of HIV status, completed it without serious toxicity. Among HIV-positive patients receiving chemotherapy, the mean baseline CD4 cell count was 477 cells/uL (standard deviation, 160 cells/uL), and the mean nadir was 333 cells/uL (standard deviation, 166 cells/uL). CONCLUSION: HIV-infected women were younger at breast cancer diagnosis than HIV-negative women but otherwise similar in phenotype and completion of chemotherapy. Longer term follow-up is needed to evaluate the effects of HIV, antiretroviral therapy, and chemotherapy on the survival and quality of life of patients with breast cancer. PMID- 28717715 TI - Compulsory Licenses for Cancer Drugs: Does Circumventing Patent Rights Improve Access to Oncology Medications? AB - Worldwide, there are enormous inequities in cancer control that cause poor outcomes among patients with cancer who live in low- and middle-income countries (LMICs). One of the biggest challenges that oncology faces today is how to increase patient access to expensive, but life-saving, therapies in LMICs. Access to cancer medications in LMICs is a major problem, especially in recent years, as the costs of these therapies continue to rise exponentially. One mechanism available to LMICs to improve access to cancer medications allows a country to pursue a compulsory license for a given drug. Here, we will review how the legal framework in the World Trade Organization's Trade-Related Aspects of Intellectual Property Rights Agreement and the Doha Declaration supports countries to circumvent patent laws and acquire compulsory licenses for essential medicines. We will also discuss the current and future role of compulsory licenses in oncology and how compulsory licenses may improve access to cancer drugs in LMICs. PMID- 28717716 TI - Breast Cancer and African Ancestry: Lessons Learned at the 10-Year Anniversary of the Ghana-Michigan Research Partnership and International Breast Registry. AB - Women with African ancestry in western, sub-Saharan Africa and in the United States represent a population subset facing an increased risk of being diagnosed with biologically aggressive phenotypes of breast cancer that are negative for the estrogen receptor, the progesterone receptor, and the HER2/neu marker. These tumors are commonly referred to as triple-negative breast cancer. Disparities in breast cancer incidence and outcome related to racial or ethnic identity motivated the establishment of the International Breast Registry, on the basis of partnerships between the Komfo Anokye Teaching Hospital in Kumasi, Ghana, the University of Michigan Comprehensive Cancer Center in Ann Arbor, Michigan, and the Henry Ford Health System in Detroit, Michigan. This research collaborative has featured educational training programs as well as scientific investigations related to the comparative biology of breast cancer in Ghanaian African, African American, and white/European American patients. Currently, the International Breast Registry has expanded to include African American patients throughout the United States by partnering with the Sisters Network (a national African American breast cancer survivors' organization) and additional sites in Ghana (representing West Africa) as well as Ethiopia (representing East Africa). Its activities are now coordinated through the Henry Ford Health System International Center for the Study of Breast Cancer Subtypes. Herein, we review the history and results of this international program at its 10-year anniversary. PMID- 28717718 TI - Gallbladder Adenomyomatosis Mimicking Carcinoma: A Diagnostic Dilemma. PMID- 28717717 TI - Management and Care of Women With Invasive Cervical Cancer: American Society of Clinical Oncology Resource-Stratified Clinical Practice Guideline. AB - PURPOSE: To provide evidence-based, resource-stratified global recommendations to clinicians and policymakers on the management and palliative care of women diagnosed with invasive cervical cancer. METHODS: ASCO convened a multidisciplinary, multinational panel of cancer control, medical and radiation oncology, health economic, obstetric and gynecologic, and palliative care experts to produce recommendations reflecting resource-tiered settings. A systematic review of literature from 1966 to 2015 failed to yield sufficiently strong quality evidence to support basic- and limited-resource setting recommendations; a formal consensus-based process was used to develop recommendations. A modified ADAPTE process was also used to adapt recommendations from existing guidelines. RESULTS: Five existing sets of guidelines were identified and reviewed, and adapted recommendations form the evidence base. Eight systematic reviews, along with cost-effectiveness analyses, provided indirect evidence to inform the consensus process, which resulted in agreement of 75% or greater. RECOMMENDATIONS: Clinicians and planners should strive to provide access to the most effective evidence-based antitumor and palliative care interventions. If a woman cannot access these within her own or neighboring country or region, she may need to be treated with lower-tier modalities, depending on capacity and resources for surgery, chemotherapy, radiation therapy, and supportive and palliative care. For women with early-stage cervical cancer in basic settings, cone biopsy or extrafascial hysterectomy may be performed. Fertility-sparing procedures or modified radical or radical hysterectomy may be additional options in nonbasic settings. Combinations of surgery, chemotherapy, and radiation therapy (including brachytherapy) should be used for women with stage IB to IVA disease, depending on available resources. Pain control is a vital component of palliative care. Additional information is available at www.asco.org/rs-cervical cancer-treatment-guideline and www.asco.org/guidelineswiki. It is the view of ASCO that health care providers and health care system decision makers should be guided by the recommendations for the highest stratum of resources available. The guideline is intended to complement but not replace local guidelines. PMID- 28717719 TI - Twenty-Year Collaboration Between North American and South American Retinoblastoma Programs. PMID- 28717720 TI - First of All, I Feel Very Loved: Humanism and Cancer Care in South India. PMID- 28717721 TI - Evaluation of a Smartphone-Based Training Strategy Among Health Care Workers Screening for Cervical Cancer in Northern Tanzania: The Kilimanjaro Method. AB - PURPOSE: Almost nine of 10 deaths resulting from cervical cancer occur in low income countries. Visual inspection under acetic acid (VIA) is an evidence-based, cost-effective approach to cervical cancer screening (CCS), but challenges to effective implementation include health provider training costs, provider turnover, and skills retention. We hypothesized that a smartphone camera and use of cervical image transfer for real-time mentorship by experts located distantly across a closed user group through a commercially available smartphone application would be both feasible and effective in enhancing VIA skills among CCS providers in Tanzania. METHODS: We trained five nonphysician providers in semirural Tanzania to perform VIA enhanced by smartphone cervicography with real time trainee support from regional experts. Deidentified images were sent through a free smartphone application on the available mobile telephone networks. Our primary outcomes were feasibility of using a smartphone camera to perform smartphone-enhanced VIA and level of agreement in diagnosis between the trainee and expert reviewer over time. RESULTS: Trainees screened 1,072 eligible women using our methodology. Within 1 month of training, the agreement rate between trainees and expert reviewers was 96.8%. Providers received a response from expert reviewers within 1 to 5 minutes 48.4% of the time, and more than 60% of the time, feedback was provided by regional expert reviewers in less than 10 minutes. CONCLUSION: Our method was found to be feasible and effective in increasing health care workers' skills and accuracy. This method holds promise for improved quality of VIA-based CCS programs among health care providers in low income countries. PMID- 28717722 TI - Gestational Trophoblastic Neoplasia Treatment at the Butaro Cancer Center of Excellence in Rwanda. AB - PURPOSE: Gestational trophoblastic neoplasia (GTN) is a highly treatable disease, most often affecting young women of childbearing age. This study reviewed patients managed for GTN at the Butaro Cancer Center of Excellence (BCCOE) in Rwanda to determine initial program outcomes. PATIENTS AND METHODS: A retrospective medical record review was performed for 35 patients with GTN assessed or treated between May 1, 2012, and November 30, 2014. Stage, risk score, and low or high GTN risk category were based on International Federation of Gynecology and Obstetrics staging and the WHO scoring system and determined by beta human chorionic gonadotropin level, chest x-ray, and ultrasound per protocol guidelines for resource-limited settings. Pathology reports and computed tomography scans were assessed when possible. Treatment was based on a predetermined protocol stratified by risk status. RESULTS: Of the 35 patients (mean age, 32 years), 26 (74%) had high-risk and nine (26%) had low-risk disease. Nineteen patients (54%) had undergone dilation and curettage and 11 (31%) had undergone hysterectomy before evaluation at BCCOE. Pathology reports were available in 48% of the molar pregnancy surgical cases. Systemic chemotherapy was initiated in 30 of the initial 35 patients: 13 (43%) received single-agent oral methotrexate, 15 (50%) received EMACO (etoposide, methotrexate, dactinomycin, cyclophosphamide, and vincristine), and two (7%) received alternate regimens. Of the 13 patients initiating methotrexate, three had their treatment intensified to EMACO. Four patients experienced treatment delays because of medication stockouts. At a median follow-up of 7.8 months, the survival probability for low risk patients was 1.00; for high-risk patients, it was 0.63. CONCLUSION: This experience demonstrates the feasibility of GTN treatment in rural, resource limited settings. GTN is a curable disease and can be treated following the BCCOE model of cancer care. PMID- 28717723 TI - Cervical Abnormalities in South African Women Living With HIV With High Screening and Referral Rates. AB - PURPOSE: To determine the prevalence of screening, cervical dysplasia, and malignancy on the basis of histologic diagnoses from colposcopy and large loop excision of the transformation zone among women living with HIV (WLWH) who attended an urban antiretroviral treatment (ART) clinic in KwaZulu-Natal, South Africa. MATERIALS AND METHODS: We performed a retrospective cohort study to examine a random sample of 462 WLWH during a 5-year period from 2004 to 2009. Women on ART for < 3 months were excluded. Data were abstracted from electronic records and paper charts to assess rates of cervical abnormalities detected on Pap smears as well as time to colposcopy. RESULTS: During the study period, 432 women (93.5%) had at least one evaluable Papanicolau test. At baseline, 237 women (54.9%) had an abnormal Papanicolau test, and of these patients, 181 (76.3%) had a Papanicolau test that qualified for further colposcopic evaluation. In addition, 115 women (63.5%) received colposcopy within a median of 39 days from referral. This yielded 74 evaluable histologic samples (64.3%), of which 21.6%, 27.0%, 27.0%, and 1.4% had cervical intraepithelial neoplasia (CIN) 1, CIN2, CIN3, and invasive cervical cancer, respectively. CONCLUSION: In a large sample of WLWH who received ART in KwaZulu-Natal, South Africa, where Papanicolau test coverage and rates of referral for colposcopy and large loop excision of the transformation zone were high, > 75% of women with evaluable histologic samples had evidence of cervical dysplasia or malignancy. These findings underscore the importance of routine cervical screening upon entry into HIV care to optimize survival. PMID- 28717724 TI - Validation and Quality Assessment of the Kilimanjaro Cancer Registry. AB - PURPOSE: Global cancer burden has increasingly shifted to low- and middle-income countries and is particularly pronounced in Africa. There remains a lack of comprehensive cancer information as a result of limited cancer registry development. In Moshi, Tanzania, a regional cancer registry exists at Kilimanjaro Christian Medical Center. Data quality is unknown. Our objective was to evaluate the completeness and quality of the Kilimanjaro Cancer Registry (KCR). METHODS: In October 2015, we conducted a retrospective review of KCR by validating the internal consistency of registry records with medical and pathology records. We randomly sampled approximately 100 total registry cases. Four reviewers not associated with the KCR manually collected data elements from medical records and compared them with KCR data. RESULTS: All 100 reviewed registry cases had complete cancer site and morphology included in the registry. Six had a recorded stage. For the majority (n = 92), the basis of diagnosis was pathology. Pathology reports were found in the medical record for 40% of patients; for the remainder, these were stored separately in the pathology department. Of sampled registry cases, the KCR and medical records were 98% and 94% concordant for primary cancer site and morphology, respectively. For 28%, recorded diagnosis dates were within 14 days of what was found in the medical record, and for 32%, they were within 30 days. CONCLUSION: The KCR has a high level of concordance for classification and coding when data are retrieved for validation. This parameter is one of the most important for measuring data quality in a regional cancer registry. PMID- 28717725 TI - Minding the Gaps in Cancer Pain Management Education: A Multicenter Study of Clinical Residents and Fellows in a Low- Versus High-Resource Setting. AB - PURPOSE: Inadequate pain management training has been reported as a major cause of undertreatment of cancer pain. Yet, past research has not comprehensively compared the quality of cancer pain management education among physicians in training in high-resource countries (HRCs) with those in low-resource countries (LRCs). The purpose of this study was to examine and compare gaps in cancer pain management education among physician trainees in an HRC (United States) versus an LRC (Ghana). METHODS: A cross section of physicians at four major academic medical centers completed surveys about the adequacy of cancer pain training. Participation in the study was completely voluntary, and paper or online surveys were completed anonymously. RESULTS: The response rate was 60% (N = 120). Major gaps were identified in cancer pain management education across the spectrum of medical school training. Training was rated as inadequate (by approximately 80% of trainees), although approximately 10% more trainees in HRCs versus LRCs felt this way; 35% said residency training was inadequate in both settings; and 50% in LRCs versus 44% in HRCs said fellowship training was less than good. On the basis of the lowest group means, the three key areas of perceived deficits included interventional pain procedures (2.34 +/- 1.12), palliative care interventions (2.39 +/- 1.12), and managing procedural and postoperative pain (2.94 +/- 0.97), with significant differences in the distribution of deficits in 15 cancer-pain competencies between LRCs and HRCs (P < .05). CONCLUSION: This study identifies priority areas that could be targeted synergistically by LRCs and HRCs to advance cancer care globally. The findings underscore differential opportunities to broaden and improve competencies in cancer pain management via exchange training, in which physicians from HRCs spend time in LRCs and vice versa. PMID- 28717726 TI - Breast Cancer Reporting in Lagos, Nigeria: Implications for Training and Education in Africa. AB - PURPOSE: To assess the completeness and accuracy of breast cancer pathologic reporting in Nigeria. MATERIALS AND METHODS: The histologic parameters provided in breast cancer pathology reports at a large teaching hospital in Nigeria were assessed. The corresponding slides were reviewed after the United Kingdom Royal College of Pathologists guidelines, and results were compared. RESULTS: Out of 115 breast cancer cases, histologic type of breast carcinoma was concordant with the review type in 53.1% of cases and discordant in 46.9%. Grading was stated in 89.62% of cases, of which 50.5% were correctly graded, 35.8% were under-graded, and 8.5% were over-graded. Poor fixation and omission of the mitotic count were the main reasons for discordant grades. A comment on lymph node status was included in 40% of cases, and lymphovascular invasion was not commented on in 97.4% of cases. Only 26% of the tumors had hormone receptors and/or HER2 tested. CONCLUSION: Some essential histologic parameters were absent from the histologic reports, and where present, a proportion were inaccurate. Attention to specimen fixation and method of grading and familiarity with uncommon breast cancer types are required; all can be facilitated by education and training. The use of a template/proforma is recommended to ensure cancer data set parameters are included in the pathology reports. PMID- 28717727 TI - Childhood Cancer Mortality in India: Direct Estimates From a Nationally Representative Survey of Childhood Deaths. AB - PURPOSE: Although most children with cancer live in low- and middle-income countries, measurements of childhood cancer burden in such countries have been restricted to incidence rates from a few subnational cancer registries and mortality rates from vital statistics. We aimed to provide alternative burden estimates by using nationally representative longitudinal survey-derived mortality rates. METHODS: We examined cancer deaths in childhood (1 month to 14 years of age) in the Million Death Study, a cohort of > 27,000 pediatric deaths in India on the basis of enhanced verbal autopsies. All deaths potentially due to childhood cancer were identified. Two pediatric specialists independently categorized deaths as definite, probable, possible, or unlikely cancer related. From definite and probable deaths, we estimated national and regional mortality rates attributable to childhood malignancies. Data on symptoms and health care seeking behavior were abstracted from closed-ended questions and caregiver narratives. RESULTS: Of 700 included deaths, 189 were classified as definite or possibly cancer related. The kappa-statistic between reviewers was 0.75 (95% CI, 0.71 to 0.78). From these deaths, we estimated that in 2010, 13,700 were a result of childhood cancer in India, which led to a mortality rate of 37 (95% CI, 31 to 42) per million population per year, which exceeds many prior estimates of mortality and even some estimates of incidence. Disparities between mortality estimates were widest in northeast India and for brain tumors. A preponderance of male deaths was seen (male:female ratio, 1.6:1). CONCLUSION: The burden of childhood cancer in India is substantially higher than previously suggested. This information will aid advocacy for national strategies aimed at improving outcomes for Indian children with cancer. PMID- 28717728 TI - Prevalence of Triple-Negative Breast Cancer in India: Systematic Review and Meta Analysis. AB - PURPOSE: There is considerable variation in prevalence rates of triple-negative breast cancer (TNBC) reported by various studies from India. We performed a systematic review and literature-based meta-analysis of these studies. METHODS: We searched databases of Medline, Scopus, EMBASE, and Web of Science for studies that reported on the prevalence of TNBC in India that were published between January 1, 1999, and December 31, 2015. We extracted relevant information from each study by using a standardized form. We pooled study-specific estimates by using random-effects meta-analysis to provide summary estimates. We explored sources of heterogeneity by using subgroup analyses and metaregression. RESULTS: Data were obtained from 17 studies that involved 7,237 patients with breast cancer. Overall combined prevalence of TNBC was 31% (95% CI, 27% to 35%). There was substantial heterogeneity across the studies (I2 of 91% [95% CI, 88% to 94%]; P < .001) that was not explained by available study level characteristics, including study location, definition of human epidermal growth factor receptor 2 or estrogen receptor, mean age of participants, proportion of patients with premenopausal cancer, grade 3 disease, or tumor size > 5 cm. Overall combined prevalence of hormone receptor-positive and human epidermal growth factor receptor 2-positive breast cancer was 48% (95% CI, 42% to 54%) and 27% (95% CI, 24% to 31%), respectively. There was no evidence of publication bias. CONCLUSION: Prevalence of TNBC in India is considerably higher compared with that seen in Western populations. As many as as one in three women with breast cancer could have triple-negative disease. This finding has significant clinical relevance as it may contribute to poor outcomes in patients with breast cancer in India. Additional research is needed to understand the determinants of TNBC in India. PMID- 28717729 TI - Middle Eastern Conflicts: Implications for Refugee Health in the European Union and Middle Eastern Host Countries. AB - Until very recently, health care in conflict settings was based on a model developed in the second half of the twentieth century. Things have changed, and present civil wars, such as those that are currently taking place in the Middle East, do not address the complexity of the ongoing armed conflicts in countries such as Syria, Iraq, and Afghanistan. These conflicts have caused a significant increase in the number of refugees in the region, as well as in Europe. Hundreds of thousands of refugees succeed in settling in mid- and north-European countries, and their health issues are becoming of great importance. Refugees in Europe in the twenty-first century do not suffer so much from infectious diseases but more from noninfectious chronic diseases such as diabetes, cardiac disease, and cancer. These facts profoundly alter the demographics and disease burden of hostility-derived migrants. Thus, host European countries face situations they have never faced before. Hence, new approaches and strategies are urgently needed to cope with this new situation. The efforts to absorb refugees of different traditions and cultural backgrounds often cause increasing ethnic and religious tensions, which frequently escort the emergence of social violence. To date, little attention has been paid to the overall load of distress being experienced, especially among the first-generation refugees. The current ongoing hostilities in the Middle East induce a long-term health impact on people expelled from their homes, communities, traditions, and cultural environment. The realization of collective suffering forces communities and governmental health agencies to develop new programs that include social determinants to overcome the severe cultural gaps of the newcomers in their new European host countries. PMID- 28717730 TI - Multicompartmental Trigeminal Schwannomas: Dumbbell Tumors Revisited. AB - Multicompartmental trigeminal schwannomas (MTSs) are a rare and complex but treatable group of tumors. Herein, we describe the clinicoradiologic presentation of two patients with MTS. The two illustrated distinct case reports highlight the role of imaging and the outcome of two different types of MTS. The Discussion summarizes the literature to date, which will help the reader diagnose these tumors in a timely manner and manage them appropriately. PMID- 28717731 TI - Not All Body Surface Area Formulas Are the Same, but Does It Matter? PMID- 28717732 TI - Androgen Deprivation Therapy-Induced Cardiovascular Disease. PMID- 28717733 TI - Misuse of Pirated Drugs: Why China? What Is Next? PMID- 28717734 TI - Arsenic as Traditional Chinese Medicine Provides New Hope for Overcoming High Treatment Costs of Acute Promyelocytic Leukemia. PMID- 28717735 TI - Investigating the Two-Tiered System of Psychosocial Cancer Care in Brazil Using a Distress Screening Measure. PMID- 28717736 TI - Cardiovascular Disease Risk Factors: How Relevant in African Men With Prostate Cancer Receiving Androgen-Deprivation Therapy? AB - PURPOSE: Cardiovascular disease risk factors have been associated with androgen deprivation therapy (ADT) in white and Hispanic populations. It is therefore relevant to determine if there exists a relationship between these parameters in the African population. PATIENTS AND METHODS: The design of the study was cross sectional. Prostate-specific antigen concentration, waist circumference, body mass index (BMI), lipid profile, glucose level, and insulin level were determined in 153 patients with prostate cancer and 80 controls. The patients with prostate cancer were divided into subgroups of treatment-naive patients and those receiving ADT. RESULTS: Mean total cholesterol (P = .010), LDL cholesterol (P = .021), BMI (P = .001), and waist circumference (P = .029) values were significantly higher in patients treated with ADT when compared with treatment naive patients. In patients treated with ADT for up to 1 year, only mean BMI was significantly higher than in treatment-naive patients, whereas those treated with ADT for more than 1 year had significantly higher mean BMI, waist circumference, total cholesterol, and LDL cholesterol values when compared with treatment-naive patients. There were no significant differences in insulin or glucose levels. Those undergoing hormone manipulation after orchiectomy had fewer cardiovascular risk factors compared with those undergoing hormone manipulation alone. CONCLUSION: This study shows that ADT results in elevated total cholesterol, LDL cholesterol, BMI, and waist circumference values, all of which are risk factors of cardiovascular disease. Screening for cardiovascular risk factors should be included in treatment plans for patients with prostate cancer. PMID- 28717737 TI - Rivaroxaban: An Affordable and Effective Alternative in Cancer-Related Thrombosis? AB - BACKGROUND: Venous thromboembolic events (VTEs) are common and potentially fatal complications in cancer patients, and they are responsible for the second most common cause of death. Low molecular weight heparin (LMWH) is the gold-standard treatment, but the costs involved limit its use, especially in developing countries. Recently, the oral anticoagulant rivaroxaban, which directly inhibits factor Xa, was approved for VTE treatment. METHODS: We conducted a retrospective analysis from January 2009 to February 2014 with patients who had cancer and VTE who were receiving rivaroxaban. We compared the efficacy, safety, and cost of rivaroxaban and low molecular weight heparin (LMWH) alone or followed by vitamin K antagonists. RESULTS: Forty-one patients were identified, with a median age of 62.5 years. The most frequent tumor histology was adenocarcinoma (78%), which was most often found in the colon (26.8%). Most participants had advanced disease and an implanted central venous catheter. Patients' VTE risk-assessment scores were low (12.5%), intermediate (50%), and high (35.5%). Pulmonary thromboembolism was reported in 41.4% of patients, but inferior limb thrombosis was reported only in 14.6%; 43.9% of patients received enoxaparin before starting rivaroxaban. Rivaroxaban was used for a median time of 5.5 months. Nonmajor bleeding was reported in 12.2% of patients, and rethrombosis was reported in 12.2%. In our study, rivaroxaban was as safe and effective as enoxaparin/vitamin K antagonists (P = .54 and P = .25, respectively) or LMWH (P = .46 and P = .29, respectively). CONCLUSION: Although our study was a retrospective analysis, our results suggest that in this cohort of oncologic patients, rivaroxaban was safe and effective. Its oral route and lower cost make it an attractive alternative to LMWH, improving management of patients with cancer in low-income countries. Additional studies are necessary to confirm our data. PMID- 28717739 TI - Liver Metastasectomy and Systemic Therapy Improve Overall Survival Compared With Surgery Alone After Curative Liver Resection of Colorectal Metastases in a Developing Country (Costa Rica). AB - BACKGROUND: Resection of liver-isolated metastases of colorectal cancer (CRC) offers the greatest likelihood of cure. Nevertheless, recurrence rates after this procedure are high, and chemotherapy is a reasonable choice with inconclusive evidence. We aimed to determine if there is a survival difference between patients receiving systemic therapy with surgery versus surgery alone for resection of liver metastases. METHODS: From a source population of 170 patients treated in our National Centre (Centro Nacional de Cirugia Hepatobiliar, San Jose, Costa Rica), with liver metastases from various primary sites, we selected 51 patients with CRC who underwent hepatic resection with curative intent. We categorized patients according to the treatment received (fluoropyrimidine-based chemotherapy plus or minus monoclonal antibody and surgery v surgery alone) and then calculated the overall survival (OS) rate according to the Kaplan-Meier method. A Cox proportional hazard model was used to assess the influence of potential confounding variables on OS. RESULTS: After a median follow-up of 41.6 months, OS was significantly better for patients treated with systemic therapy (before and/or after hepatic resection) versus surgery alone (3-year OS: 66.7% v 41.7%; hazard ratio, 0.37; 95% CI, 0.15 to 0.91; log-rank test: P = .025). There were no differences among patients who underwent neoadjuvant (48.7%), perioperative (46.2%), and adjuvant therapy (5.1%). The use of systemic therapy was significantly associated with better OS after adjustment for confounding variables (hazard ratio, 0.23; 95% CI, 0.07 to 0.92; P = .03). CONCLUSION: Our findings support the use of systemic therapy (either perioperative, neoadjuvant, or adjuvant) as part of isolated hepatic metastasectomy from CRC. PMID- 28717738 TI - Collaborative Pediatric Bone Tumor Program to Improve Access to Specialized Care: An Initiative by the Lebanese Children's Oncology Group. AB - BACKGROUND: Children with malignant bone tumors have average 5-year survival rates of 60% to 70% with current multimodality therapy. Local control modalities aimed at preserving function greatly influence the quality of life of long-term survivors. In developing countries, the limited availability of multidisciplinary care and limited expertise in specialized surgery and pediatric radiation therapy, as well as financial cost, all form barriers to achieving optimal outcomes in this population. METHODS: We describe the establishment of a collaborative pediatric bone tumor program among a group of pediatric oncologists in Lebanon and Syria. This program provides access to specialized local control at a tertiary children's cancer center to pediatric patients with newly diagnosed bone tumors at participating sites. Central review of pathology, staging, and treatment planning is performed in a multidisciplinary tumor board setting. Patients receive chemotherapy at their respective centers on a unified treatment plan. Surgery and/or radiation therapy are performed centrally by specialized staff at the children's cancer center. Cost barriers were resolved through a program development initiative led by St Jude Children's Research Hospital. Once program feasibility was achieved, the Children's Cancer Center of Lebanon Foundation, via fundraising efforts, provided continuation of program-directed funding. RESULTS: Findings over a 3-year period showed the feasibility of this project, with timely local control and protocol adherence at eight collaborating centers. We report success in providing standard-of-care multidisciplinary therapy to this patient population with complex needs and financially challenging surgical procedures. CONCLUSION: This initiative can serve as a model, noting that facilitating access to specialized multidisciplinary care, resolution of financial barriers, and close administrative coordination all greatly contributed to the success of the program. PMID- 28717740 TI - Curative-Intent Surgery for Pancreatic Tumors: A Review of Procedures From the Brazilian National Health System. AB - PURPOSE: In Brazil, a country with major health access disparities, resource limitations make management of pancreatic cancer (PC) challenging. This study evaluated curative-intent surgery for PC in the Brazilian public health care system. METHODS: We collected data for PC surgical procedures with curative intent in Brazil's public health care system (DATASUS) and from the demographic database. Costs, lengths of stay, number of perioperative deaths, and PC deaths were analyzed for each state and then associated with population, gross domestic product (GDP) per capita, and number of procedures. RESULTS: A total of 37,142 patients died as a result of PC in Brazil between 2008 and 2012. The number of deaths (per 100,000 person-years) was highest in the south and southeast regions. Mortality from PC had a positive association with the number of procedures and GDP per capita. Between January 2008 and July 2014, 3,386 procedures were performed, the majority (51.2%) in the southeast region. Four hundred ninety three patients died, which translates to an inpatient mortality rate of 14.6%. The northern states had the highest perioperative mortality (mean, 25%). The number of procedures per 100,000 residents was higher in the southeast and south. Overall, cost tended to increase as the number of procedures or population increased. For fixed GDP per capita and population, cost tended to increase as the number of procedures increased, whereas for a fixed number of procedures and GDP per capita, cost tended to decrease as population increased. The mean length of hospital stay was 16.9 days, which was higher than in major international centers. CONCLUSION: This study is the first to our knowledge to evaluate regional disparities in PC care in Brazil. Perioperative mortality was high in the public health care system. Regionalized policies that improve care are needed. PMID- 28717741 TI - Patient-Reported Burden of a Neuroendocrine Tumor (NET) Diagnosis: Results From the First Global Survey of Patients With NETs. AB - PURPOSE: Despite the considerable impact of neuroendocrine tumors (NETs) on patients' daily lives, the journey of the patient with a NET has rarely been documented, with published data to date being limited to small qualitative studies. NETs are heterogeneous malignancies with nonspecific symptomology, leading to extensive health care use and diagnostic delays that affect survival. A large, international patient survey was conducted to increase understanding of the experience of the patient with a NET and identify unmet needs, with the aim of improving disease awareness and care worldwide. METHODS: An anonymous, self reported survey was conducted (online or on paper) from February to May 2014, recruiting patients with NETs from > 12 countries as a collaboration between the International Neuroendocrine Cancer Alliance and Novartis Pharmaceuticals. Survey questions captured information on sociodemographics, clinical characteristics, NET diagnostic experience, disease impact/management, interaction with medical teams, NET knowledge/awareness, and sources of information. This article reports the most relevant findings on patient experience with NETs and the impact of NETs on health care system resources. RESULTS: A total of 1,928 patients with NETs participated. A NET diagnosis had a substantially negative impact on patients' personal and work lives. Patients reported delayed diagnosis and extensive NET related health care resource use. Patients desired improvement in many aspects of NET care, including availability of a wider range of NET-specific treatment options, better access to NET experts or specialist centers, and a more knowledgeable, better-coordinated/-aligned NET medical team. CONCLUSION: This global patient-reported survey demonstrates the considerable burden of NETs with regard to symptoms, work and daily life, and health care resource use, and highlights considerable unmet needs. Further intervention is required to improve the patient experience among those with NETs. PMID- 28717742 TI - Simplified Graded Baseline Symptom Assessment in Patients With Lung Cancer Undergoing First-Line Chemotherapy: Correlations and Prognostic Role in a Resource-Constrained Setting. AB - PURPOSE: There are limited data from developing countries on graded baseline symptom (BS) assessment in lung cancer. This prospective study aimed to assess the prognostic role of BS and correlation of BS with comorbidity, demographic, and investigation profiles in a cohort of 238 patients with lung cancer undergoing first-line chemotherapy over a 15-month period. METHODS: The Medical Research Council (MRC) scale was used to assess dyspnea, whereas the visual analog scale (VAS; score of 1 to 10) was used to assess anorexia, fatigue, chest pain, and cough. Weight loss (WL) was noted as percentage of pre-illness baseline. All patients received histology-guided platinum doublet chemotherapy. Outcomes assessed were overall survival (OS) and radiologic responses by RECIST. RESULTS: Significant correlations (Spearman rho) were noted for fatigue and anorexia with all other BSs. Dyspnea differed significantly among groups on the basis of either the simplified comorbidity score or Charlson comorbidity index. Median OS was 287 days (95% CI, 232 to 342 days). OS was significantly higher for anorexia VAS score less than 4 (388 v 229 days for VAS score >= 4), fatigue VAS score less than 3 (388 v 213 days for VAS score >= 3), WL less than 5% (410 v 259 days for WL >= 5%), and MRC dyspnea grade less than 3 (377 v 187 days for MRC grade >= 3). On univariable Cox proportional hazards analysis, worse OS was noted for all BSs, stage, and performance status, but on multivariable analysis, only fatigue (hazard ratio [HR], 1.21), Eastern Cooperative Oncology Group performance status >= 2 (HR, 1.57), and stage IV disease (HR, 1.61) were significant. Nonresponders (stable disease and progressive disease [PD]) had a higher percentage of WL and higher mean VAS scores for cough, chest pain, anorexia, and fatigue. On multivariable logistic regression analysis, PD was associated with fatigue and percentage of WL. CONCLUSION: BSs are prognostic for patients with lung cancer on first-line chemotherapy. Fatigue is prognostic for worse OS and PD. Comorbidity and investigation profiles do not correlate with either OS or response rates. PMID- 28717743 TI - Chronic Myeloid Leukemia in India. AB - BACKGROUND: In the last decade, the use of imatinib has brought a paradigm shift in the management of chronic myeloid leukemia (CML). In India, imatinib has been available for more than a decade and has been made accessible to all segments of the population because of patient assistance programs and cheaper generic versions. Despite improvements in survival, there are unique challenges in the Indian context. METHODS: We reviewed published data pertaining to CML in India for the period of 1990 to 2016, using PubMed advanced search with the terms chronic myeloid leukemia and India, and included studies that reported on epidemiology, monitoring for therapy, treatment outcomes, and resistance. Additionally, the references in retrieved articles were also reviewed. RESULTS: Thirty-seven studies were identified. The incidence of CML may be slightly lower in India than in the West, but there was only a single article reporting population-based data. Indian patients presented with more advanced disease. Most centers have access to imatinib as first-line therapy, but there is limited availability of molecular monitoring and second-line therapy. Most of the outcome data were retrospective but seemed comparable with that reported in Western centers. Drug adherence was impaired in at least one third of patients and contributed to poor survival. CONCLUSION: Focused prospective studies and cooperative studies might improve the quality of data available. Future studies should focus on adherence, its effects on outcomes, and methods to address this problem. PMID- 28717744 TI - Influence of HIV/AIDS on Cervical Cancer: A Retrospective Study From Tanzania. AB - PURPOSE: Cervical cancer is the leading cause of cancer-related morbidity and mortality in women in Tanzania. Any impact of the HIV/AIDS epidemic on cervical precancerous lesions and invasive cervical cancer has a significant implication, as for any public health concern, especially in an area such as the Morogoro region in Tanzania, which has one of the highest rates of cervical cancer in the world. METHODS: A comparative retrospective study was performed of 536 women screened for cervical cancer by visual inspection methods at the Morogoro Regional Referral Hospital over a period of 3 years; the women were grouped according to their HIV status. The odds ratios (OR) with 95% CIs were estimated using chi2 test and multivariate analysis. The test statistics were evaluated with a significance level of P < .05. RESULTS: The prevalence of precancerous lesions was 71.8% in HIV-positive women and 27.3% in HIV-seronegative women. Furthermore, the prevalence of extensive or large precancerous lesions was 40.5% in HIV-positive women and 13.5% in HIV-seronegative women. The prevalence of invasive cervical cancer was 8% in HIV-seronegative women and 11% in HIV-positive women. The risk factors for the cervical lesions were HIV-positive status (OR, 6.8; 95% CI, 4.2 to 11.2; P < .001) and being older than 30 years of age (OR, 11.99; 95% CI, 6.86 to 21.21; P < .001). CONCLUSION: HIV/AIDS has a highly statistically significant association with (P < .001) and a great influence on the development of cervical precancerous lesions in HIV-positive women; however, its direct involvement in the progression to invasive cervical cancer, especially in this era of highly active antiretroviral therapy, is questionable. PMID- 28717745 TI - Desmoplastic Small Round-Cell Tumor in a Young Indigenous Australian Man: A Case Report. PMID- 28717746 TI - New Expensive Anticancer Agents: Which Role Is Played by Quality-Adjusted Life Years in the Selection of a Specific Treatment? PMID- 28717747 TI - Resource-Stratified Guidelines for Cancer Management: Correction and Commentary. PMID- 28717748 TI - Bevacizumab in Advanced Cervical Cancer: Issues and Challenges for Low- and Middle-Income Countries. AB - Bevacizumab became the first molecular antibody to show survival benefit in advanced cervical cancer. In the GOG-0240 (Paclitaxel and Cisplatin or Topotecan With or Without Bevacizumab in Treating Patients With Stage IVB, Recurrent, or Persistent Cervical Cancer) trial, it improved overall survival by a significant 3.7 months over platinum doublet chemotherapy alone. However, this discovery is not likely to improve the status of global cervical cancer because more than 85% of patients with cervical cancer live in low- and middle-income countries and cannot afford bevacizumab. This commentary looks at the options by which this drug can be made more affordable and cost-effective for patients in low- and middle-income countries. We also discuss other important questions related to its affordability and cost issues such as the optimal number of cycles and personalizing the treatment. Finally, we emphasize that although the unaffordability of bevacizumab in cervical cancer seems to be a very important issue, the best cost-effective strategy against cervical cancer is prevention with screening and vaccination. PMID- 28717749 TI - Perceptions and Barriers of Survivorship Care in Asia: Perceptions From Asian Breast Cancer Survivors. AB - PURPOSE: With the long-term goal to optimize post-treatment cancer care in Asia, we conducted a qualitative study to gather in-depth descriptions from multiethnic Asian breast cancer survivors on their perceptions and experiences of cancer survivorship and their perceived barriers to post-treatment follow-up. METHODS: Twenty-four breast cancer survivors in Singapore participated in six structured focus group discussions. The focus group discussions were voice recorded, transcribed verbatim, and analyzed by thematic analysis. RESULTS: Breast cancer survivors were unfamiliar with and disliked the term "survivorship," because it implies that survivors had undergone hardship during their treatment. Cognitive impairment and peripheral neuropathy were physical symptoms that bothered survivors the most, and many indicated that they experienced emotional distress during survivorship, for which they turned to religion and peers as coping strategies. Survivors indicated lack of consultation time and fear of unplanned hospitalization as main barriers to optimal survivorship care. Furthermore, survivors indicated that they preferred receipt of survivorship care at the specialty cancer center. CONCLUSION: Budding survivorship programs in Asia must take survivor perspectives into consideration to ensure that survivorship care is fully optimized within the community. PMID- 28717750 TI - Fear of Treatments Surpasses Demographic and Socioeconomic Factors in Affecting Patients With Breast Cancer in Urban South Africa. AB - PURPOSE: Breast cancer is the most common cause of cancer in women in South Africa, and often patients present late. There is little understanding of the psychosocial stresses affecting women with breast cancer in Africa. METHODS: A questionnaire was distributed to 263 patients with breast cancer at two sites (one government and one private facility) in Johannesburg. Self-reported levels of fear were recorded on summative scales and their relationship to demographic variables assessed through univariable and multivariable modified Poisson regression. RESULTS: Fears related to treatments and prognosis, particularly radiation, loss of hair, and loss of breast, were far stronger than those related to socioeconomic barriers. Relative risk (RR) of most fears was higher in women younger than age 40 years, including treatment affordability (RR, 1.80; 95% CI, 1.26 to 2.56), hair loss (RR, 1.48; 95% CI, 1.12 to 2.95), and surgery (RR, 1.31; 95% CI, 1.02 to 1.68). Difficulty taking time off work predicted fear of job loss (RR, 2.59; 95% CI, 1.59 to 4.21) and missing appointments because of transport (RR, 2.46; 95% CI, 1.52 to 3.96) or family commitments (RR, 2.46; 95% CI, 1.52 to 3.96). Women with dependents and black women were more afraid of dying (RR, 1.73; 95% CI, 1.03 to 2.90; and RR, 1.79; 95% CI, 1.33 to 2.24, respectively); however, socioeconomic status in this sample was a strong confounder of race and explained most of the racial differences in levels of fear. CONCLUSION: The most significant fears around breast cancer were related to treatment modalities and adverse effects rather than transport, financial, or work concerns. Young age and job insecurity were predictive of increased fears. Education about treatments has a key role to play in improving access to breast cancer care in South Africa. PMID- 28717751 TI - Second Primary Cancers After Primary Breast Cancer Diagnosis in Israeli Women, 1992 to 2006. AB - PURPOSE: Improvements in early detection and treatment have resulted in improved long-term survival from breast cancer, which increases the likelihood of the occurrence of second primary cancers. We calculated the risk of second primary cancers among Israeli women receiving a first primary breast cancer diagnosis. METHODS: By using data from the Israel National Cancer Registry, we identified 46,090 women with invasive breast cancer diagnosed between 1990 and 2006 and non breast primary cancers diagnosed subsequent to breast cancer diagnosis. We used life table analysis to calculate the risk of a second primary cancer and calculated standardized incidence ratios (SIRs) by using age-specific cancer risk in the general population of Israeli women as the standard and stratifying by diagnosis period (1992 to 1996, 1997 to 2001, 2002 to 2006) and age at diagnosis (< 50 and >= 50 years). RESULTS: The probability of a second malignancy was 3.6% within 5 years, 8.2% within 10 years, and 13.9% within 15 years. The SIR for any second non-breast primary cancer was 1.26 (95% CI, 1.23 to 1.30). Significantly increased risks of colorectal, uterine, lung, ovarian, and thyroid cancer and leukemia were observed for the full follow-up period, which persisted after excluding the first 6 months after index diagnosis, although increased leukemia and colorectal cancer risks were no longer statistically significant. Women younger than age 50 years at initial diagnosis had a greater excess risk than women age 50 years and older (SIR, 1.77 [95% CI, 1.63 to 1.91] and 1.20 [95% CI, 1.15 to 1.24], respectively). CONCLUSION: The findings likely reflect a combination of personal risk factors (genetics, hormonal therapy, environmental exposures) as well as the effects of the initial cancer treatment and are unlikely to be explained by enhanced surveillance alone. PMID- 28717752 TI - Challenges of Treating Childhood Medulloblastoma in a Country With Limited Resources: 20 Years of Experience at a Single Tertiary Center in Malaysia. AB - PURPOSE: Pediatric medulloblastoma (MB) treatment has evolved over the past few decades; however, treating children in countries with limited resources remains challenging. Until now, the literature regarding childhood MB in Malaysia has been nonexistent. Our objectives were to review the demographics and outcome of pediatric MB treated at the University Malaya Medical Center between January 1994 and December 2013 and describe the challenges encountered. METHODS: Fifty-one patients with childhood MB were seen at University Malaya Medical Center. Data from 43 patients were analyzed; eight patients were excluded because their families refused treatment after surgery. RESULTS: Headache and vomiting were the most common presenting symptoms, and the mean interval between symptom onset and diagnosis was 4 weeks. Fourteen patients presented with metastatic disease. Five year progression-free survival (+/- SE) for patients >= 3 years old was 41.7% +/- 14.2% (95% CI, 21.3% to 81.4%) in the high-risk group and 68.6% +/- 18.6% (95% CI, 40.3% to 100%) in the average-risk group, and 5-year overall survival (+/- SE) in these two groups was 41.7% +/- 14.2% (95% CI, 21.3% to 81.4%) and 58.3% +/ 18.6% (95% CI, 31.3% to 100%), respectively. Children younger than 3 years old had 5-year progression-free and overall survival rates (+/- SE) of 47.6% +/- 12.1% (95% CI, 28.9% to 78.4%) and 45.6% +/- 11.7% (95% CI, 27.6% to 75.5%), respectively. Time to relapse ranged from 4 to 132 months. Most patients who experienced relapse died within 1 year. Febrile neutropenia, hearing loss, and endocrinopathy were the most common treatment-related complications. CONCLUSION: The survival rate of childhood MB in Malaysia is inferior to that usually reported in the literature. We postulate that the following factors contribute to this difference: lack of a multidisciplinary neuro-oncology team, limited health care facilities, inconsistent risk assessment, insufficient data in the National Cancer Registry and pathology reports, inadequate long-term follow-up, and cultural beliefs leading to treatment abandonment. PMID- 28717753 TI - Surgery for CNS Tumors in the Brazilian National Health Care System. AB - PURPOSE: Resource limitations in low- and middle-income countries make the management of CNS tumors challenging, particularly in Brazil, a country with major disparities in socioeconomic status and access to health care. We aimed to evaluate cancer-related neurosurgical procedures in the public health care system. METHODS: On the basis of Brazil's public health system database, we collected data for neurosurgical procedures related to CNS tumors performed between January 2008 and November 2013. Information about the number of procedures, costs, length of stay, and number of inpatient deaths were analyzed for each state and then correlated to the state-specific population, gross domestic product per capita, and number of procedures. RESULTS: In all, 57,361 procedures were performed, the majority of them in the Southeast region. The mean length of hospital stay was 14.4 days, but longer hospital stay was reported for patients treated in the North. The inpatient mortality rate was 7.11%. Mortality rates decreased as the number of procedures (P < .001), gross domestic product per capita (P < .001), or state population increased (P < .001). On multivariate analysis, only the number of procedures (odds ratio, 0.93; 95% CI, 0.91 to 0.96; P < .001) and state population (odds ratio, 1.25; 95% CI, 1.13 to 1.38; P < .001) had an independent association with mortality. CONCLUSION: To the best of our knowledge, this is the first study to evaluate disparities in CNS tumor surgery in a middle-income country, confirming that regional disparities exist and that clinical and economic outcomes correlate with income level, number of procedures, and state population. PMID- 28717754 TI - Surgical Management of Breast Cancer in Africa: A Continent-Wide Review of Intervention Practices, Barriers to Care, and Adjuvant Therapy. AB - Breast cancer has emerged as a leading cancer among women in Africa, necessitating improved understanding of its management across the continent. Although previous studies have described regional trends in therapy, this review aims to summarize continent-wide management and focus specifically on surgical interventions. Current literature shows that the rates of surgery, chemotherapy, and radiation therapy vary across different countries and institutions, indicating the need for greater use of standardized cancer treatment guidelines. Surgery, primarily modified radical mastectomy, is the most common form of therapy described. When chemotherapy is offered, the limited availability and cost of treatment lead to high rates of interruption and premature termination of cycles. Few patients have access to radiation or hormonal therapy because these treatments are not available in many countries. Significant delays in seeking treatment are common and contribute to patients presenting with advanced disease. Although limited infrastructure favors surgical management, interventions to improve early detection behavior, provide timely referrals to medical care, and initiate early treatment with access to clinically justified neo-adjuvant and adjuvant therapy are key to improving prognosis. PMID- 28717755 TI - Innovative Breast Cancer Awareness and Advocacy Campaign. AB - Breast cancer is a major disease in Nigeria; in 2012, 27,304 new occurrences were diagnosed, and the number of mortalities was 13,960. Greater than 70% of patients present with advanced disease, which has a poor survival outcome. The mortality rates are high mainly because of a lack of awareness about breast health, screening guidelines, and treatment centers, and because of sociocultural barriers. In Nigeria, health care professionals remain the backbone for the provision of medical information to the public. This is a study of the innovative ways that breast health and cancer awareness were promoted across communities and institutions in Lagos State, Nigeria, in 2015. Several community awareness campaigns were carried out in the forms of health talks, breast cancer screenings, radio and television interviews, and campaigns on social media. Anomalies noticed during the screenings were promptly referred to appropriate hospitals for additional treatment. The campaign culminated in the #12KLLP, or 12,000 people light Lagos pink, which was a Guinness World Record attempt for the largest human awareness ribbon formed for breast cancer. There was a total reach of 28,774,812 people across platforms: 285,318 were on social media, 3,620 were in communities, 7,466,276 were on the website, 20 million were through media events, 12,000 were through publications, 7,598 were verified participants at the Guinness World Record, and approximately 1 million were through blogs. Eighty partnerships were made with various private and government institutions to facilitate different aspects of the campaign. The community members were able to learn about the need for early detection and awareness; volunteerism and corporate social responsibility were promoted among individuals and corporate institutions. PMID- 28717756 TI - Primary Cervicomedullary Junction Melanocytic Melanoma: An Illustrated Case Report. PMID- 28717757 TI - Immunohistochemistry Heterogeneity in Reported Breast Cancer Demographics From India: Triple-Negative Breast Cancer Rates Could Be Lower Than Suggested in Pooled Meta-Analysis. PMID- 28717758 TI - Organization of Chemotherapy and Systemic Therapy Services in India: The Devil Lies in the Details. PMID- 28717759 TI - Quality Oncology Practice Initiative Can Guide and Improve Oncology Providers' Training in Brazil. AB - PURPOSE: It has become crucial to translate scientific findings and to find ways by which to mobilize local resources to improve the quality and accessibility of cancer care in developing countries. This study seeks to provide insight into challenge through examining differences in clinician documentation of patients with cancer treated at a Brazilian Public University Hospital. METHODS: ASCO Quality Oncology Practice Initiative (QOPI) measures were used to examine the care provided in the departments of breast, colorectal, lymphoma, gynecology, and lung cancers. For this study, data from a representative sample of patients receiving chemotherapy in the previous month were extracted and quality of cancer care indicators examined. RESULTS: Certain elements of medical care were consistently and appropriately documented, including cancer diagnosis and stage, chemotherapy planning, administration, and summary. In general, considering the specific cancer management measures, patients received recommended care in accordance with recognized guidelines. Despite this, a number of important gaps in care were identified, including the assessment and treatment of pain, documentation of chemotherapy intention, symptom and toxicity management, patients' psychosocial status, and provision of a treatment summary at care completion. CONCLUSION: These findings are encouraging in terms of adherence to core treatment guidelines in cancer care in Brazil. However, results suggest important opportunities for improving care across a number of domains, many of which represent a challenge throughout both developing and developed countries. This study may also provide preliminary guidance for enhancing educational and training programs for professionals and students alike, to implement high quality, comprehensive cancer care. PMID- 28717760 TI - Pilot Survey of Breast Cancer Management in Sub-Saharan Africa. AB - PURPOSE: To understand the current state of breast cancer management in sub Saharan Africa. METHODS: We conducted an anonymous online survey of breast cancer management among African Organization for Research and Treatment in Cancer (AORTIC) members by using a 42-question structured questionnaire in both English and French in 2013. RESULTS: Twenty members from 19 facilities in 14 countries responded to the survey. Twelve members (60%) belonged to a multidisciplinary breast cancer team. Radiotherapy equipment was available in seven facilities (36%), but equipment had down time at least once a week in four facilities. Available chemotherapy drugs included methotrexate, cyclophosphamide, fluorouracil, anthracyclines, and vincristine, whereas trastuzumab, taxanes, vinorelbine, and gemcitabine were available in few facilities. Core-needle biopsy was available in 16 facilities (84%); mammogram, in 17 facilities (89%); computed tomography scan, in 15 facilities (79%); magnetic resonance imaging, in 11 facilities (58%); and bone scans, in nine facilities (47%). It took an average of 1 to 3 weeks to report histopathology. Immunohistochemistry was available locally in eight facilities (42%), outside hospitals but within the country in seven facilities (37%), and outside the country in four facilities (21%). Thirteen facilities (68%) performed axillary node dissections as part of a breast protocol. Neoadjuvant chemotherapy was the most common therapy for locally advanced breast cancer in 13 facilities (68%). In three facilities (16%), receptor status did not influence the prescription of hormone treatment. CONCLUSION: This pilot survey suggests that AORTIC members in sub-Saharan Africa continue to make gains in the provision of access to multidisciplinary breast cancer care, but the lack of adequate pathology and radiotherapy services is a barrier. Focused attention on in-country and regional training needs and improvement of health systems deliverables is urgently needed. PMID- 28717761 TI - Estimation of Premature Deaths From Lack of Access to Anti-HER2 Therapy for Advanced Breast Cancer in the Brazilian Public Health System. AB - PURPOSE: Patients with human epidermal growth factor receptor 2 (HER2) -positive metastatic tumors treated in the public health system in Brazil do not have access to trastuzumab. This study aimed to estimate the impact of the lack of access to anti-HER2 therapies on the mortality of these patients. METHODS: On the basis of published data, the number of patients with HER2-positive advanced breast cancer in 2016 who should receive anti-HER2 targeted therapy was estimated. Three different treatment groups were considered for this hypothetical cohort: chemotherapy alone, chemotherapy plus trastuzumab, and chemotherapy plus trastuzumab and pertuzumab. The number of patients alive after 2 years of follow up was estimated on the basis of the efficacy results of the pivotal trials considering these interventions. RESULTS: It was calculated that 2,008 women will be diagnosed with advanced HER2-positive breast cancer in Brazil in 2016. It was estimated that only 808 women would be alive in 2018 if they receive only chemotherapy (which is the treatment offered by the public health system). On the other hand, the bar rises to 1,408 women alive in 2018 if they receive chemotherapy plus trastuzumab and 1,576 women alive in 2018 if they receive the gold standard of chemotherapy plus trastuzumab and pertuzumab. CONCLUSION: Trastuzumab is included in the WHO's list of essential medications, but the Brazilian public health system does not yet provide this treatment to its population with advanced disease. The introduction of trastuzumab and pertuzumab would have a positive effect, preventing premature deaths in women with metastatic HER2-positive breast cancer in Brazil. PMID- 28717762 TI - Epidermal Growth Factor Receptor Mutational Status and Brain Metastases in Non Small-Cell Lung Cancer. AB - INTRODUCTION: Epidermal growth factor receptor (EGFR) mutations in non-small-cell lung cancers (NSCLC) may be more common in patients with brain metastases. Previous studies, however, did not adjust for effects of confounding variables. METHODS: This retrospective study included 1,522 consecutive patients with NSCLC, whose tumors were diagnosed and tested for EGFR mutations at the University of Nebraska Medical Center (Omaha, NE) and Tata Memorial Hospital (Mumbai, India). Multivariate logistic regression was used to identify any association between EGFR status and clinical factors. RESULTS: EGFR mutations were more common in females than males (38.7% v 24.8%), Asians than whites (31.3% v 13.4%), nonsmokers than smokers (40.2% v 14.6%), alcohol nonconsumers than users (32.4% v 15.8%), adenocarcinoma than other histology types (32.7% v 10.3%), and patients with brain metastases than extracranial or no metastases (39.4% v 29.8% v 15.1%; P < .001 for all comparisons). There was a higher likelihood of an EGFR mutation among patients with brain metastases (odds ratio, 1.8; P < .001). The median overall survival (OS) was 19.8 months. Patients with brain metastases had a shorter median OS (15 v 20.6 months; P = .02). However, in the cohort of EGFR mutation-positive patients, there was no difference in median OS between patients with and without brain metastases (20.8 v 25.1 months; P = .11). CONCLUSION: There is a nearly two-fold higher incidence of EGFR mutations in NSCLC among patients with brain metastases at diagnosis. EGFR mutations did not predict for outcomes from brain metastases. PMID- 28717763 TI - Burkitt's Lymphoma and B-Cell Lymphoma Unclassifiable With Features Intermediate Between Diffuse Large B-Cell Lymphoma and Burkitt's Lymphoma in Patients With HIV: Outcomes in a South African Public Hospital. AB - PURPOSE: Burkitt's lymphoma (BL) is a common HIV-associated lymphoma in South Africa. B-cell lymphoma unclassifiable with features intermediate between diffuse large B-cell lymphoma and Burkitt's lymphoma (BL/DLBCL) also occurs in HIV infection. Outcomes of HIV-infected patients with BL or BL/DLBCL in a resource constrained setting are not defined. METHODS: We performed a retrospective study of HIV-positive patients with BL or BL/DLBCL treated from 2004 to 2012 with curative intent at a publically funded academic medical center in South Africa. Differences between BL and BL/DLBCL, survival outcomes, and factors associated with survival were analyzed. RESULTS: There were 35 patients with either HIV associated BL (24) or BL/DLBCL (11) who met study criteria. Median CD4+ T lymphocyte count at lymphoma diagnosis was 188 cells/MUL (range, 10 to 535 cells/MUL). Patients with BL/DLBCL were significantly older and had less bone marrow involvement and lower baseline serum lactase dehydrogenase than patients with BL. Eighty-nine percent of patients presented with advanced disease, and 25% had baseline CNS involvement. Chemotherapy regimens consisted of cytoreduction with low-dose cyclophosphamide, vincristine, and prednisone followed by induction with vincristine, methotrexate, cyclophosphamide, doxorubicin and prednisone (LMB 86; 57%); hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, and cytarabine (hyper-CVAD; 20%); cyclophosphamide, doxorubicin, vincristine, and prednisone and high-dose methotrexate with leucovorin rescue on day 10 with accompanying prophylactic IT chemotherapy (Stanford regimen; 14%); and cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP-like; 9%) regimens. Twenty-three patients received CNS treatment or prophylaxis, and 31 received concurrent combination antiretroviral therapy. Two-year overall survival was 38% (95% CI, 22% to 54%) and 2-year event-free survival was 23% (95% CI, 11% to 38%), with no difference between histologic subtypes. Common causes of death were infection (41%) and CNS disease progression or systemic relapse (41%). CONCLUSION: Cure of HIV-associated BL and BL/DLBCL with intensive regimens is possible in resource-limited settings, but lower toxicity regimens, improved CNS prophylaxis, and increased resources for supportive care are required. PMID- 28717765 TI - Assessment of Adequacy of Pain Management and Analgesic Use in Patients With Advanced Cancer Using the Brief Pain Inventory and Pain Management Index Calculation. AB - PURPOSE: The objective of this cross-sectional, noninterventional, 6-month observational study was to assess the adequacy of pain management in patients with cancer admitted to the Oncology Department of Guru Gobind Singh Medical College in Faridkot, India. METHODS AND MATERIALS: A total of 348 patients with cancer were recruited for evaluation of the prevalence of inadequate cancer pain management using the Brief Pain Inventory Pain Management Index. RESULTS: The current study included 127 males (36.5%) and 221 females (63.5%). The most prevalent cancer type was genitourinary; 268 patients (77%) had inadequately managed pain. A significant correlation was observed between poorly managed pain and age groups, analgesic used, and body mass index. CONCLUSION: Our observation of inadequate pain management among 77% of patients indicates that pain management was insufficient in three quarters of the patients in this study. Accumulating data regarding the inadequacy of cancer pain management is crucial to improve symptom management. Better management of pain not only alleviates pain symptoms but also increases the quality of life for patients with cancer. PMID- 28717764 TI - Comprehensive Human Papillomavirus Genotyping in Cervical Squamous Cell Carcinomas and Its Relevance to Cervical Cancer Prevention in Malawian Women. AB - PURPOSE: Cervical squamous cell carcinoma (SCC) continues to be a significant cause of cancer morbidity and is the third leading cause of cancer-related death in women worldwide. In sub-Saharan Africa, cervical cancer is not only the most common female cancer but also the leading cause of cancer-related deaths in women. Malawi, in particular, has the highest burden of cervical cancer. With the increasing use of human papillomavirus (HPV) vaccination, documenting the prevalent HPV types in those high-risk populations is necessary to both manage expectations of HPV vaccination and guide future vaccine development. MATERIALS AND METHODS: In this study, we performed HPV typing on 474 cervical SCC samples and analyzed the potential impact of HPV vaccination in this population. RESULTS: Ninety-seven percent of tumors were positive for at least one HPV type, and 54% harbored more than one HPV type. HPV 16 was the most common type (82%), followed by HPV 18 (34%), HPV 35 (24%), and HPV 31 (12%). A vaccine against HPV 16 and 18 would ideally prevent 53% of cervical SCC, and the nonavalent HPV vaccine (covering HPV 16, 18, 31, 33, 45, 52, and 58) would prevent 71% of cervical SCC in Malawi (assuming 100% vaccine efficacy). The main reason for a lack of coverage was high prevalence of HPV 35, which was also present as a single infection in a small subset of patients. CONCLUSION: Although any HPV vaccination in this population would likely prevent a significant proportion of cervical cancer, the nonavalent vaccine would provide better coverage. Furthermore, investigation of the role of HPV 35 in this population, including possible cross protection with other HPV types, should be pursued. PMID- 28717766 TI - Practice and Impact of Multidisciplinary Tumor Boards on Patient Management: A Prospective Study. AB - PURPOSE: Multidisciplinary tumor boards (MTBs) have become commonplace. The use, attendance, and function of MTBs need continued assessment and improvement. METHODS: We prospectively recorded and assessed all cases presented at MTBs between October 2013 and December 2014. Data were collected before and during each MTB. Data were analyzed using SPSS for Windows version 23 (SPSS, Chicago, IL). RESULTS: Five hundred three cases were presented: 234 cases (46%) at GI cancer MTBs, 149 cases (29.6%) at breast cancer MTBs, 69 cases (13.7%) at thoracic/head and neck cancer MTBs, and 51 cases (10.7%) at neuro-oncology MTBs. A total of 86.7% of MTB cases were presented to make plans for management. Plans for upfront management were made in 67% of the breast cancer cases, 63% of GI cases, 59% of thoracic/head and neck cases, and 49% of neuro-oncology cases. Three hundred ninety-four cases (78.3%) were presented by medical oncologists, whereas only 74 cases (14.7%) were presented by surgeons, and 10 cases (2%) were presented by radiation oncologists. The majority of MTBs, with the exception of the neurosurgery MTBs, were led by medical oncologists. Surgeons presented the least number of cases but attended the most, and their contributions to discussions and decision making were essential. CONCLUSION: MTBs enhance the multidisciplinary management of patients with cancer. Upfront multidisciplinary decision making should be considered as an indicator of benefit from MTBs, in addition to changes in management plans made at MTBs. Increasing the contributions of surgeons to MTBs should include bringing more of their own cases for discussion. PMID- 28717767 TI - Breaking Bad News in Ethnic Settings: Perspectives of Patients and Families in Northern Sri Lanka. AB - PURPOSE: The discussion of a cancer diagnosis and prognosis often is difficult. This study explored the expectations of Tamil-speaking patients with cancer and their families with respect to receiving their cancer diagnosis in northern Sri Lanka. METHODS: This exploratory, descriptive, qualitative study used semistructured interviews. RESULTS: Thematic analysis identified two major themes: communication and information seeking. The findings illustrate a discrepancy between patient preference for direct disclosure of the diagnosis and that of families. Ninety-five percent of patients wanted medical staff to disclose their cancer diagnosis, whereas only 45% of family members believed that the diagnosis should be disclosed to the patient rather than to the family. CONCLUSION: Although patients and their family members' views and expectations of the disclosure of diagnosis and prognosis differ, a majority of patients want to be told directly about their diagnosis rather than to learn of it from a relative. The findings are similar to the literature on other ethnic groups from Sri Lanka and studies from English-speaking developed countries. Therefore, the main questions are how to educate families and physicians about the benefits of open disclosure to patients and how to change culture. Results of this study along with a previous study call for the development of strategies and guidelines to improve societal views, educate patients and families, and train health professionals in the area of breaking bad news and discussing prognosis in the Sri Lankan setting. PMID- 28717768 TI - Symptom Levels in Care-Seeking Bangladeshi and Nepalese Adults With Advanced Cancer. AB - PURPOSE: Three-fourths of patients with advanced cancer are reported to suffer from pain. A primary barrier to provision of adequate symptom treatment is failure to appreciate the intensity of the symptoms patients are experiencing. Because data on Bangladeshi and Nepalese patients' perceptions of their symptomatic status are limited, we sought such information using a cell phone questionnaire. METHODS: At tertiary care centers in Dhaka and Kathmandu, we recruited 640 and 383 adult patients, respectively, with incurable malignancy presenting for outpatient visits and instructed them for that single visit on one time completion of a cell phone platform 15-item survey of questions about common cancer-associated symptoms and their magnitudes using Likert scales of 0 to 10. The questions were taken from the Edmonton Symptom Assessment System and the Brief Pain Inventory instruments. RESULTS: All but two Bangladeshi patients recruited agreed to study participation. Two-thirds of Bangladeshi patients reported usual pain levels >= 5, and 50% of Nepalese patients reported usual pain levels >= 4 (population differences significant at P < .001). CONCLUSION: Bangladeshi and Nepalese adults with advanced cancer are comfortable with cell phone questionnaires about their symptoms and report high levels of pain. Greater attention to the suffering of these patients is warranted. PMID- 28717769 TI - End-of-Life Care in Latin America. AB - Cancer has become a global pandemic with disproportionately higher mortality rates in low- and middle- income countries, where a large fraction of patients present in advanced stages and in need of end-of-life care. Globally, the number of adults needing end-of-life care is greater than 19 million, and up to 78% of these patients are living in low- and middle- income countries. In the Americas alone, more than one million people are in need of end-of-life care, placing an enormous burden on local health systems, which are often unprepared to meet the challenge presented by this complex patient population. In Latin America, cancer care is characterized by the presence of vast inequalities between and within countries, and the provision of end-of-life care is no exception. Disparities in access to advanced care planning, with a lack of provision of adequate palliative care and pain medication, are common in the region. These shortcomings are related in large part to inadequate or inappropriate legislation, lack of comprehensive national palliative care plans, insufficient infrastructure, lack of opportunities for clinical training, unreliable reporting of data, and cultural barriers. This report reviews the current status of end-of-life care in Latin America, focusing on identifying existing deficiencies and providing a framework for improvement. PMID- 28717770 TI - National Cancer Control Programme in India: Proposal for Organization of Chemotherapy and Systemic Therapy Services. AB - Cancer is a major health problem in India, with an estimated incidence of 1 million cases in 2012 that is likely to double in 2035 to approximately 1.7 million. The majority of cases are diagnosed in advanced stages, and approximately two thirds of patients die as a result of their disease. The mortality-to-incidence ratio is 0.68 in India, which is far higher than that in developed countries (approximately 0.38). One of the important reasons for this discrepancy is inequitable distribution and inaccessibility of health care resources in India. One component of scarce health care resources is the low ratio of oncologists to patients with cancer (1:2,000), which leads to delivery of systemic anticancer therapy in many hospitals by health care professionals who do not have required training. Given these facts, there is a need to focus on organization of medical oncology services in terms of manpower and infrastructure to standardize the delivery of systemic anticancer therapy. Redistribution of resources can streamline the delivery of cancer care, preferably close to the patient's home. This article describes the blueprint for organization of medical oncology services and delivery of chemotherapy and other systemic therapies to Indian patients. The model uses existing health care services in the country and is a four-tiered system of increasing sophistication: District Hospitals, Medical College Hospitals, Regional Cancer Centres, and Apex Cancer Centres. Delivery of quality care to patients with cancer through standardized protocols is crucial in improving cancer outcomes in India. PMID- 28717771 TI - Human Papillomavirus-Induced Cancer: Late Relapse in a Patient Treated With Tumor Necrosis Factor-Alpha Inhibitor. PMID- 28717772 TI - Care of the Terminally Ill Patient in India: Comments on the Proposed Legislation. PMID- 28717773 TI - Child Trauma Exposure and Posttraumatic Stress Disorder: Identification in Community Mental Health Clinics. AB - We examined the identification of trauma exposure and post-traumatic stress disorder (PTSD) in help-seeking urban children (N=157) presenting for care in community mental health clinics. Children and their parents completed a standard intake assessment conducted by a community clinician followed by a structured trauma-focused assessment conducted by a study clinician. Clinicians provided ratings of child functional impairment, parents reported on internalizing/externalizing problems, and children provided self-reports of PTSD symptom severity. Although community clinicians were mandated by clinic policy to ask about exposure to physical abuse, sexual abuse, and witnessed domestic violence, they identified exposure to these at significantly lower rates than study clinicians. Rates of PTSD based on community clinician diagnosis (1.9%) were also much lower than rates obtained by study clinicians (19.1%). A review of clinical charts one year after intake revealed no change in PTSD diagnosis rate following additional clinical contacts. Clinician-rated impairment, parent-rated emotional/behavioral problems, and child-rated PTSD symptom severity measures provided support for the validity of trauma exposure and PTSD as identified by study clinicians. Trauma exposure and PTSD diagnosis among help-seeking urban youth appear to be under-identified by community clinicians, which may compromise clinicians' ability to respond to environmental risks and provide appropriate evidence-based treatments. PMID- 28717774 TI - Role of Oral Proficiency on Reading Comprehension: Within-Language and Cross Language Relationships. AB - This longitudinal study examined the role of oral proficiency, as measured with elicited narratives using a wordless picture book, Frog Where are You? (Meyer, 1969/1994), on English reading comprehension with a total of 102 English Language Learners (ELLs), including both Spanish and Cantonese speakers. Narrative samples were collected in the winter of first grade and reading skills were assessed on the same children one year later in second grade. Children were enrolled in either bilingual programs or mainstream programs. Multiple regression results show it was not the quantity and variety of words used in the narratives that predicted English reading comprehension one year later. Instead, the ability to produce a coherent oral narrative, in either the home language or English, explained a small variance in English reading comprehension for both English learner groups. These findings highlight the importance of examining narrative skills, especially as measured by narrative structure. Implications for parents and educators are discussed. PMID- 28717775 TI - Impact of early coronary angiography on the survival to discharge after out-of hospital cardiac arrest. AB - OBJECTIVE: Acute myocardial infarction is a major cause of out-of-hospital cardiac arrest (OHCA). Coronary angiography (CAG) enables diagnostic confirmation of coronary artery disease and subsequent revascularization, which might improve the prognosis of OHCA survivors. Non-randomized data has shown a favorable impact of CAG on prognosis for this population. However, the optimal timing of CAG has been debated. METHODS: The clinical outcomes of 607 OHCA patients registered in CAPTURES (Cardiac Arrest Pursuit Trial with Unique Registration and Epidemiologic Surveillance), a nationwide multicenter registry performed in 27 hospitals, were analyzed. Early CAG was defined as CAG performed within 24 hours of emergency department admission. The primary outcome was survival to discharge, with neurologically favorable status defined by cerebral performance category scores <=2. RESULTS: Compared to patients without CAG (n=469), patients who underwent early CAG (n=138) were younger, more likely to be male, and more likely to have received bystander cardiopulmonary resuscitation, pre-hospital defibrillation, and revascularization (P<0.01 for all). Analysis of 115 propensity score-matched pairs showed that early CAG is associated with a 2.3-fold increase in survival to discharge with neurologically favorable status (P<0.001, all). Survival to discharge increased consistently according to the time interval between emergency department visit and CAG (P<0.05). CONCLUSION: Early CAG of OHCA patients was associated with better survival and favorable neurologic outcomes at discharge. However, there was no clear time threshold for CAG that predicted survival to discharge. PMID- 28717776 TI - A retrospective study of emergency department potassium disturbances: severity, treatment, and outcomes. AB - OBJECTIVE: Disturbances in potassium (K) levels are relatively common and may be associated with significant morbidity and mortality; however, treatments vary. Our purpose was to determine the incidence, treatments, and outcomes associated with hyperkalemia and hypokalemia in emergency department (ED) patients. METHODS: We performed a structured, retrospective review of electronic medical records of consecutive adult ED patients with K measured while in the ED. Demographic, clinical, and laboratory data as well as treatments, disposition, and in-hospital complications were collected. Univariate and multivariate analyses, presented as adjusted odds ratios, were used to compare outcomes by K levels. RESULTS: Of 100,260 visits in 2014, an ED K level was ordered in 48,827 (49%). A total of 1,738 patients (3.6%) were excluded because of sample hemolysis. The K was low (<3.5 mEq/L) in 5.5%, normal (3.5 to 5.0 mEq/L) in 90.9%, and elevated (>5.0 mEq/L) in 3.6% of patients. Patients with hyperkalemia were older (64 vs. 49 years, P<0.001) and more likely male (58% vs. 40%, P<0.001). Treatment for hyperkalemia varied greatly. After adjusting for confounders, both hyperkalemia and hypokalemia were associated with inpatient hospitalization and death. At least one medication was used to manage hyperkalemia in 11.5% of patients with a K of 5.1 to 5.4 mEq/L, 36.4% of those with a K 5.5 to 6 mEq/L and 77.0% of the cohort with K >6 mEq/L. CONCLUSION: Hyperkalemia or hypokalemia occur in 1 of 11 ED patients and are associated with inpatient admission and mortality. Treatment of hyperkalemia varies greatly suggesting the need for evidence-based treatment guidelines. PMID- 28717777 TI - Association between public cardiopulmonary resuscitation education and the willingness to perform bystander cardiopulmonary resuscitation: a metropolitan citywide survey. AB - OBJECTIVE: Bystander cardiopulmonary resuscitation (CPR) is an important factor associated with improved survival rates and neurologic prognoses in cases of out of-hospital cardiac arrest. We assessed how factors related to CPR education including timing of education, period from the most recent education session, and content, affected CPR willingness. METHODS: In February 2012, trained interviewers conducted an interview survey of 1,000 Daegu citizens through an organized questionnaire. The subjects were aged >=19 years and were selected by quota sampling. Their social and demographic characteristics, as well as CPR and factors related to CPR education, were investigated. Chi-square tests and multivariate logistic regression analyses were used to evaluate how education related factors affected the willingness to perform CPR. RESULTS: Of total 1,000 cases, 48.0% were male. The multivariate analyses revealed several factors significantly associated with CPR willingness: didactic plus practice group (adjusted odds ratio [AOR], 3.38; 95% confidence interval [CI], 2.3 to 5.0), group with more than four CPR education session (AOR, 7.68; 95% CI, 3.21 to 18.35), interval of less than 6 months from the last CPR education (AOR, 4.47; 95% CI 1.29 to 15.52), and education with automated external defibrillator (AOR, 5.98; 95% CI 2.30 to 15.53). CONCLUSION: The following were associated with increased willingness to perform CPR: practice sessions and automated electrical defibrillator training in public CPR education, more frequent CPR training, and shorter time period from the most recent CPR education sessions. PMID- 28717778 TI - Retention of cardiopulmonary resuscitation skills after hands-only training versus conventional training in novices: a randomized controlled trial. AB - OBJECTIVE: Cardiopulmonary resuscitation (CPR) training can improve performance during simulated cardiac arrest; however, retention of skills after training remains uncertain. Recently, hands-only CPR has been shown to be as effective as conventional CPR. The purpose of this study is to compare the retention rate of CPR skills in laypersons after hands-only or conventional CPR training. METHODS: Participants were randomly assigned to 1 of 2 CPR training methods: 80 minutes of hands-only CPR training or 180 minutes of conventional CPR training. Each participant's CPR skills were evaluated at the end of training and 3 months thereafter using the Resusci Anne manikin with a skill-reporting software. RESULTS: In total, 252 participants completed training; there were 125 in the hands-only CPR group and 127 in the conventional CPR group. After 3 months, 118 participants were randomly selected to complete a post-training test. The hands only CPR group showed a significant decrease in average compression rate (P=0.015), average compression depth (P=0.031), and proportion of adequate compression depth (P=0.011). In contrast, there was no difference in the skills of the conventional CPR group after 3 months. CONCLUSION: Conventional CPR training appears to be more effective for the retention of chest compression skills than hands-only CPR training; however, the retention of artificial ventilation skills after conventional CPR training is poor. PMID- 28717779 TI - Impact of Middle East respiratory syndrome outbreak on the use of emergency medical resources in febrile patients. AB - OBJECTIVE: Outbreaks of transmissible respiratory infection are suspected to have significant effects on the health of pediatric and geriatric patients. The objective was to assess the impact of the Middle East respiratory syndrome (MERS) outbreak on the use of emergency resources. METHODS: An ecologic analysis of emergency department (ED) records between September and December 2015, was performed. Data was obtained from the National Emergency Department Information System database for Korea. All demographic and diagnostic data from patients presenting with febrile symptoms as a main complaint were collected. The data were compared to the equivalent period in the three years preceding the MERS outbreak in Korea. RESULTS: Following the MERS outbreak, there was an increase in overall ED visits by febrile patients and the proportion of visits by febrile patients, relative to total ED attendances. This effect was more prominent in the children under five years. The duration of the chief complaint before ED arrival and the length of ED stay were significantly increased among younger pediatric patients. Decreased body temperature on arrival was observed in younger pediatric patients. CONCLUSION: MERS outbreak appears to have had a significant effects on ED use by febrile patients. The use of emergency care services by pediatric patients makes them more vulnerable to an outbreak of a transmissable disease. An effective strategy to control emergency center visits by non-urgent febrile patients and provide proper medical services is urgently needed. PMID- 28717780 TI - Epidemiology of prehospital emergency medical service use in Korean children. AB - OBJECTIVE: The aim of this study was to elucidate the epidemiology of pediatric patients transported by the National 119 Rescue Services in Korea. METHODS: We enrolled all pediatric patients (<16 years old) who used the National 119 Rescue Services in Korea between January 2006 and December 2008, and analyzed the 119 ambulance patient care record databases. RESULTS: The total number of the cases was 238,644 for 3 years. The median age was 6 years old and 59.0% were male, and the 2- to 5-year-old group was the largest (31.0%). The peak transport times were in the afternoon (from 12:00 p.m. to 17:59 p.m., 36.3%), on Saturday and Sunday (15.9% and 15.7%), and in summer (June to August, 27.3%). The ratio of disease versus injury as the cause of the transports was 42.3% vs. 57.7%. Among the 16 metropolitan cities and provinces, Gyeonggi (25.7%), Seoul (17.6%), and Incheon (7.0%) account for almost half of the all transported children. Regarding the annual transport rates per 100,000 children standardized by age, and gender to the Korean child population, Jeju was the largest (1,650.2) followed by Gangwon (1,201.3), and Jeonnam (1,178.1). CONCLUSION: This report presents comprehensive epidemiologic data of pediatric patients transported by 119 rescue services in Korea. PMID- 28717781 TI - Spinal cord infarction mimicking ischemic heart disease. AB - Spinal cord infarction is a rare condition and is easily misdiagnosed owing to its initial non-specific manifestation. We report a case of a 77-year-old man who presented with chest pain and upper back pain initially, and was misdiagnosed with a myocardial infarction. Four hours after admission, he complained of numbness in his entire left leg below the knee, with rapid deterioration of neurological symptoms. After 9 hours, loss of sensation progressed up to the T4 dermatome, strength of both lower extremities deteriorated to grade 0, and decrease in anal tone and deep tendon reflex was observed. Initial magnetic resonance imaging findings were normal; however, a signal change occurred 3 days after symptom onset. When patients present with acute chest pain and neurologic symptoms, the possibility of ischemic cardiac disease as well as any neurological manifestations must be investigated. Emergency physicians must remember the value of serial physical examinations. PMID- 28717782 TI - Splenic artery aneurysm with the double-rupture phenomenon. AB - Splenic artery aneurysm is the third most common type of intra-abdominal aneurysm, with a prevalence rate of 0.01% to 10.4% in the general population. Splenic artery aneurysm is usually asymptomatic and is typically detected by chance and does not require surgical management; however, if rupture occurs, although rare, the patient's situation can become critical. We report our experience with a man who presented with left flank and left shoulder pain. His symptoms were caused by multiple hematomas confined to the spleen, but 2 days after admission, he developed delayed hemoperitoneum and required surgical management. We believe that his condition was due to delayed intraperitoneal bleeding called the double-rupture phenomenon; emergency physicians must consider this phenomenon when taking care of splenic artery aneurysm patients. PMID- 28717783 TI - Acute pulmonary thromboemboli due to a giant mobile thrombus. PMID- 28717784 TI - Incorporating FOAM into medical student and resident education. PMID- 28717785 TI - The effects of high concentrations of ionic liquid on GB1 protein structure and dynamics probed by high-resolution magic-angle-spinning NMR spectroscopy. AB - Ionic liquids have great potential in biological applications and biocatalysis, as some ionic liquids can stabilize proteins and enhance enzyme activity, while others have the opposite effect. However, on the molecular level, probing ionic liquid interactions with proteins, especially in solutions containing high concentration of ionic liquids, has been challenging. In the present work the 13C, 15N-enriched GB1 model protein was used to demonstrate applicability of high resolution magic-angle-spinning (HR-MAS) NMR spectroscopy to investigate ionic liquid - protein interactions. Effect of an ionic liquid (1-butyl-3 methylimidazolium bromide, [C4-mim]Br) on GB1was studied over a wide range of the ionic liquid concentrations (0.6 to 3.5 M, which corresponds to 10%-60% v/v). Interactions between GB1 and [C4-mim]Br were observed from changes in the chemical shifts of the protein backbone as well as the changes in 15N ps-ns dynamics and rotational correlation times. Site-specific interactions between the protein and [C4-mim]Br were assigned using 3D methods under HR-MAS conditions. Thus, HR-MAS NMR is a viable tool that could aid in elucidation of the molecular mechanism of ionic liquid - protein interactions. PMID- 28717786 TI - Setting Priorities for Diabetic Retinopathy Clinical Research and Identifying Evidence Gaps. AB - PURPOSE: Prioritizing comparative effectiveness research may contribute to obtaining answers that clinicians perceive they need and may minimize research that could be considered wasteful. Our objective was to identify evidence gaps and set priorities for new systematic reviews and randomized controlled trials for managing diabetic retinopathy (DR), including diabetic macular edema (DME). DESIGN: Cross-sectional study. PARTICIPANTS: Diabetic Retinopathy Clinical Research Network (DRCR.net) investigators. METHODS: We provided recommendations from the American Academy of Ophthalmology's 2012 Preferred Practice Patterns for Diabetic Retinopathy as 91 answerable clinical research questions about intervention effectiveness to 410 DRCR.net investigators to rate each question's importance from 0 (not important) to 10 (very important) using a 2-round Delphi survey and to suggest additional questions. We considered questions as high priority if at least 75% of respondents to both rounds assigned an importance rating of 5 or more in round 2. We also extracted outcome measures relevant to DR and asked respondents to identify those that must be measured in all studies. We mapped Cochrane reviews published up to March 2016 to high-priority clinical research questions. MAIN OUTCOME MEASURE: Ranking of importance of each clinical question. RESULTS: Thirty-two individuals completed rounds 1 and 2 and suggested 15 questions. Among the final list of 106 clinical research questions, 22 questions met our definition of high priority: 9 of 22 concerned the effectiveness of anti-VEGF therapy, and 13 of 22 focused on how often patients should be followed up (re-examination) and treatment effectiveness in patients with specific characteristics (e.g., DME). Outcomes that 75% or more of respondents marked as "must be measured in all studies" included visual acuity and visual loss, death of participants, and intraocular pressure. Only 1 prioritized question was associated with conclusive evidence from a Cochrane systematic review. CONCLUSIONS: A limited response rate among DRCR.net members identified 22 comparative effectiveness research questions as high priority for the management of DR, including DME, but few were associated with Cochrane reviews. These results support the need of systematic reviews and randomized controlled trials to address evidence gaps. PMID- 28717787 TI - A Prospective Study of Infectious Mononucleosis in College Students. AB - BACKGROUND: The present study aims to prospectively investigate possible biological and psychological factors present in college students who will go on to develop chronic fatigue syndrome (CFS) following Infectious Mononucleosis (IM). Identification of risk factors predisposing patients towards developing CFS may help to understand the underlying mechanisms and ultimately prevent its occurrence. Our study is enrolling healthy college students over the age of 18. Enrollment began in March of 2013 and is ongoing. METHODS: Biological and psychological data are collected when students are well (Stage 1), when they develop IM (Stage 2), and approximately 6 months after IM diagnosis (Stage 3). RESULTS: Two case studies demonstrate the progression of student symptomology across all three stages. CONCLUSION: The Case Studies presented illustrate the usefulness of a prospective research design that tracks healthy students, following their trajectory of IM illness to either a) full recovery or b) diagnosis with CFS. PMID- 28717788 TI - Disentangling Disease Heterogeneity with Max-Margin Multiple Hyperplane Classifier. AB - There is ample evidence for the heterogeneous nature of diseases. For example, Alzheimer's Disease, Schizophrenia and Autism Spectrum Disorder are typical disease examples that are characterized by high clinical heterogeneity, and likely by heterogeneity in the underlying brain phenotypes. Parsing this heterogeneity as captured by neuroimaging studies is important both for better understanding of disease mechanisms, and for building subtype-specific classifiers. However, few existing methodologies tackle this problem in a principled machine learning framework. In this work, we developed a novel non linear learning algorithm for integrated binary classification and subpopulation clustering. Non-linearity is introduced through the use of multiple linear hyperplanes that form a convex polytope that separates healthy controls from pathologic samples. Disease heterogeneity is disentangled by implicitly clustering pathologic samples through their association to single linear sub classifiers. We show results of the proposed approach from an imaging study of Alzheimer's Disease, which highlight the potential of the proposed approach to map disease heterogeneity in neuroimaging studies. PMID- 28717789 TI - Editorial: EAED photo contest. PMID- 28717790 TI - Soft and hard tissue response ?to an implant with a convergent ?collar in the esthetic area: ?preliminary report at 18 months. AB - AIM: The purpose of this prospective cohort study was to investigate, over an 18 month period, soft and hard tissue response to a transmucosal implant with a convergent collar inserted in the anterior maxillary esthetic area. MATERIALS AND METHODS: From June 2013 to January 2014, 14 consecutive patients were enrolled (7 men and 7 women; mean age 63.7 +/- 14 years) with 20 implants, needing at least one implant-supported restoration between the canines in the maxillary anterior esthetic area. Six months after hopeless tooth extraction and an alveolar socket graft, a transmucosal-type implant with convergent collar walls was inserted in a midcrestal position with mini-flap surgery. An impression was taken 2 months later, and a definitive abutment with a provisional restoration was positioned. The final restoration was seated 2 weeks later. Clinical parameters, photographs, radiographs, and impressions were taken at this timepoint, and after 6 and 18 months. Using dedicated software, radiographic analysis (to detect marginal bone level changes) and cast analysis (to detect soft tissue vertical and horizontal changes) were performed. RESULTS: At the 18-month follow-up, all implants were clinically osseointegrated, stable, and showed no sign of infection. At baseline, interproximal radiographs revealed no bone defect around the implant. After an initial minimal bone loss (0.09 +/- 0.144 mm), radiographic analysis showed a stable condition of bone remodeling (mean value 0.09 +/- 0.08; range 0.0 to 0.5 mm) at the 18-month follow-up. No statistically significant horizontal dimensional changes of the alveolar ridge were observed between each timepoint. Mean soft tissue levels significantly improved between baseline and 18 months. The mean heights of the mesial papilla (MP) and distal papilla (DP) changes were 0.38 +/- 0.22 and 0.47 +/- 0.31, respectively. The level of the labial gingival margin (LGM) was 1.01 +/- 0.63. Periodontal parameters never exceeded the physiological levels. CONCLUSIONS: Within the limitations of this preliminary study, the analyzed implants produced positive results in these esthetically demanding cases. This outcome should encourage long-term studies in order to assess, through controlled clinical trials, whether this convergent collar design offers advantages over other designs. Furthermore, due to the peculiar crestal module, together with the use of delayed implant insertion and a postextraction ridge preservation technique with biomimetic hydroxyapatite, the analyzed implants seem to help prevent the negative bone remodeling typically associated with two-piece implant systems, but without the well-known drawbacks of traditionally designed transmucosal implants. Therefore, wherever crestal bone preservation is a critical issue for clinical success in the anterior maxillary area can be considered of particular interest. PMID- 28717791 TI - Residual root preparation ?for socket-shield procedures: ?a facial window approach. AB - Two common complications that occur following immediate implant placement and provisionalization procedures in the anterior maxilla are changes to the facial periimplant soft tissue levels and the facial contours. To counteract these changes, different techniques and treatments have been recommended. The recently introduced socket-shield technique (SST) appears to be a viable treatment option for stabilizing the facial osseous and gingival architecture; however, preparation of the root fragment can present challenges. This article describes a surgical approach designed to facilitate preparation of the facial root fragment. PMID- 28717792 TI - Accelerated fatigue resistance ?of novel-design histoanatomic ?implant restorations made of ?CAD/CAM bilaminar assemblies. AB - OBJECTIVES: Evaluate the fatigue resistance and failure mode of novel-design implant restorations made of histoanatomic computer-assisted design/computer assisted manufacturing (CAD/CAM) bilaminar bonded assemblies. MATERIAL AND METHODS: 60 screw-retained implant restorations were fabricated. Monolithic restorations were used as a control group (15 lithium disilicate: group CE; and 15 nanofilled composite resin: group CL), and compared with bilaminar restorations (15 dentin-shaped lithium disilicate mesostructures with a bonded nanofilled composite resin veneer: group CEL; and 15 dentin-shaped nanofilled composite resin mesostructures with a bonded lithium disilicate veneer: group CLE). All monolithic and bilaminar restorations were assembled and bonded to a customized metal implant abutment. Cyclic isometric chewing (5 Hz) at a 30-degree angle was simulated, starting with 5,000 cycles at a load of 150 N, followed by 20,000 cycles with increments of 50 N. Samples were loaded until fracture or to a maximum of 160,000 cycles. The groups were compared using the Life Table survival analysis (logrank test at P = 0.05; post hoc tests at P = 0.008). RESULTS: In the CL group, restorations failed at an average load of 347.39 N (98.361 cycles), and in the CLE group at an average load of 313.20 N (83.105 cycles), and none of the specimens withstood all 160,000 load cycles. In the CE group, restorations failed at an average load of 381.47 N (119.115 cycles), and in the CEL group at an average load of 415.20 N (132.873 cycles), with survival rates of 26% and 33%, respectively. Post hoc tests from the load step data showed higher fatigue resistance of CEL compared with CLE (P = 0.003). CONCLUSION: Lithium disilicate monolithic restorations and mesostructures with nanofilled composite resin veneer presented higher survival rates when compared with nanofilled composite resin restorations. PMID- 28717793 TI - Altered passive eruption (APE) ?and active secondary eruption (ASE): differential diagnosis and management. AB - The process of tooth eruption consists of two phases, active and passive. While the distinction is unequivocal, the mechanism is ambiguous. This article compares and contrasts altered passive eruption (APE) and active secondary eruption (ASE). Although these phases present with similar clinical manifestations, each has its own etiology, physiogenesis, and pathogenesis. Furthermore, the differential diagnosis between the two, and that between other mirroring conditions, is essential for arriving at a definite diagnosis and correct treatment strategies, which may be similar but have different consequences. This article concludes with two case studies that show the management of APE and ASE, highlighting the treatment similarities and differences that are dependent on the specific etiology. PMID- 28717794 TI - The influence of maxillary incisor torque on the esthetic perception ?of the smile. AB - PURPOSE: An esthetically pleasing smile is one of our patients' main goals. However, it is not always clear that the esthetic perceptions of patients and clinicians are the same. The purpose of this study was to evaluate and quantify the discrepancies in the esthetic perception of maxillary incisor torque among professionals, and between professionals and the general public. MATERIALS AND METHODS: A photograph of a 30-year-old woman was digitally manipulated to obtain nine smile images and nine full-profile images with various maxillary incisor torques, while maintaining the overjet. The images were evaluated in an online survey by three different groups: laypersons (LP, n = 21), orthodontists (OR, n = 20), and specialists in dental esthetics (SDE, n = 19). RESULTS: From among the smile images, the LP group preferred the 80-degree option (the angle that forms the tangent between the crown of the maxillary incisor and the functional occlusal plane), the SDE group preferred the 75-degree option, and the OR group preferred the 70-degree option. From among the full-profile images, both the LP and the SDE groups preferred the 80-degree option, while the OR group preferred the 75-degree option. To analyze the data and verify or reject the hypotheses of normality and homoscedasticity, ANOVA and Kruskal-Wallis tests were used. CONCLUSIONS: The LP and SDE groups coincided, in contrast to the OR group, which preferred more protrusive torques and was less tolerant of retroclined maxillary incisors. PMID- 28717795 TI - Comparison of visual shade ?matching and electronic color ?measurement device. AB - OBJECTIVE: The objective of this study was to compare the performance of visual shade matching and spectrophotometric measurements. MATERIALS AND METHODS: A total of 100 observers matched pairs of corresponding shade tabs from two VITA classical A1-D4 shade guides. The tab identifiers on one shade guide were masked. Lack of visible color differences between the corresponding tabs was confirmed by means of an intraoral spectrophotometer. Means and standard deviations were calculated. Analysis of variance (ANOVA) (alpha = 0.05) with a Bonferroni correction was performed to detect significance of differences between groups. RESULTS: A total of 72.5% of tab pairs (or 11.6 tabs) were matched using the visual method, and 98.9% were matched using the spectrophotometer (P < 0.001). Female observers showed significantly better results than male observers (P = 0.027). Both genders showed the highest visual scores in group B, followed by groups C, A, and D. CONCLUSIONS: Instrumental shade-matching systems have the potential to improve color matching in dentistry. Results were influenced by gender. CLINICAL RELEVANCE: The dental spectrophotometer exhibited a significantly higher percentage of correct matches of corresponding shade tabs compared with conventional visual shade matching. PMID- 28717796 TI - Tri- and hexaferrocenyl-substituted subphthalocyanines in the quest for the optimum electron donor-acceptor distances. AB - Three and six ferrocenyl subunits have been attached to the periphery of subphthalocyanines (SubPcs). Unlike axially coordinated ferrocenes, peripherally bonded ferrocenes have an impact on the electronic features of SubPcs, which show a 44 to 70 nm red-shift of their Q-bands. The unusually deep and narrow ferrocenyl-SubPc is able to host C60, giving rise to atypical SubPc*C60 cocrystallates, through a combination of concave-convex and convex-convex pi-pi interactions. PMID- 28717797 TI - Copper-catalyzed synthesis of arylcarboxamides from aldehydes and isocyanides: the isocyano group as an N1 synthon. AB - An interesting radical coupling reaction of aromatic aldehydes with isocyanides was disclosed for the synthesis of amides catalyzed by copper. According to the experimental results and mechanistic study, the isocyano group acted as an N1 synthon rather than exhibiting the carbene-like reactivity, exploiting a new reactivity profile of isocyanides. PMID- 28717798 TI - Correction: Phase behavior of colloid-polymer depletion mixtures with unary or binary depletants. AB - Correction for 'Phase behavior of colloid-polymer depletion mixtures with unary or binary depletants' by Nayoung Park et al., Soft Matter, 2017, 13, 2781-2792. PMID- 28717799 TI - Interface interactions and enhanced room temperature ferromagnetism of Ag@CeO2 nanostructures. AB - Enhancement of room temperature ferromagnetism (RTFM) has been achieved with core shell metal-oxide nanoparticles (Ag@CeO2). To enhance the magnetic properties, interfacial charge transfer is achieved via the formation of a core-shell interface. Furthermore, by varying the shell thicknesses, additional control of the RTFM can be obtained. The Ag@CeO2 core-shell nanoparticles are synthesized successfully via a two-step method. Ag nanoparticles (NPs) are first synthesized on a TiO2 substrate by a thermally assisted photoreduction method, and then CeO2 NPs are deposited on the surface of Ag NPs by chemical reduction. No surfactants or organic compounds are used during the synthesis. At the interface between the core and the shell, electron transfers from the Ag-p orbital to the Ag-d and Ce-f orbitals are evidenced by X-ray absorption spectroscopy and electron energy loss spectroscopy. Such interfacial charge transfer results in enhanced room temperature ferromagnetism in the Ag@CeO2 core-shell NPs compared to the magnetism arising for bare Ag or CeO2 NPs. This study suggests that tailoring the interface, the surface and their coupling in nanostructured metal-oxide core shell nanoparticles is an effective way to enhance their magnetic properties. PMID- 28717800 TI - From molecules to macrostructures: recent development of bioinspired hard tissue repair. AB - Enamel, dentin and bone are calcified hard tissues in the human body that play significant roles in food mastication and movement support. Generally, hard tissues lack the ability of self-repair, except for the regeneration ability of bone for small-scale defects. Fabrication of man-made repair materials is therefore highly demanded. In this review, following a bioinspired strategy, we describe the composition and multiscale structures of different hard tissues, and highlight the key points for the reconstruction of hard tissues. Finally, bioinspired tissue repair techniques ranging from molecule-induced mineralization, to microscale assembly to macroscaffold fabrication are summarised. PMID- 28717802 TI - A computational study on the mechanism of ynamide-mediated amide bond formation from carboxylic acids and amines. AB - This paper reports a computational study elucidating the reaction mechanism for ynamide-mediated amide bond formation from carboxylic acids and amines. The mechanisms have been studied in detail for ynamide hydrocarboxylation and the subsequent aminolysis of the resulting adduct by an amine. Ynamide hydrocarboxylation is kinetically favorable and thermodynamically irreversible, resulting in the formation of a key low-lying intermediate CP1 featuring geminal vinylic acyloxy and sulfonamide groups. The aminolysis of CP1 by the amine is proposed to be catalyzed by the carboxylic acid itself that imparts favourable bifunctional effects. In the proposed key transition state TSaminolysis-acid iso2, the amine undergoes direct nucleophilic substitution at the acyl of CP1 to replace the enolate group in a concerted way, which is promoted by secondary hydrogen bonding of carboxylic acid with both the amine and CP1. These secondary interactions are suggested to increase the nucleophilicity of the amine and to activate the Cacyl-O bond to be cleaved, thereby stabilizing the aminolysis transition state. The concerted aminolysis mechanism is competitive with the classic stepwise nucleophilic acyl substitution mechanism that features sequential amine addition to acyl/intramolecular proton transfer/C-O bond cleavage and a key tetrahedral intermediate. Based on the mechanistic model, the carboxylic acid substrate effect and studies of more acidic CF3SO3H as the catalyst are in good agreement with the experimental observations, lending further support for the mechanistic model. The bifunctional catalytic effect of the carboxylic acid substrate may widely play a role in related amide bond forming reactions and peptide formation chemistry. PMID- 28717801 TI - Mimicking arterial thrombosis in a 3D-printed microfluidic in vitro vascular model based on computed tomography angiography data. AB - Arterial thrombosis is the main instigating factor of heart attacks and strokes, which result in over 14 million deaths worldwide every year. The mechanism of thrombosis involves factors from the blood and the vessel wall, and it also relies strongly on 3D vessel geometry and local blood flow patterns. Microfluidic chip-based vascular models allow controlled in vitro studies of the interaction between vessel wall and blood in thrombosis, but until now, they could not fully recapitulate the 3D geometry and blood flow patterns of real-life healthy or diseased arteries. Here we present a method for fabricating microfluidic chips containing miniaturized vascular structures that closely mimic architectures found in both healthy and stenotic blood vessels. By applying stereolithography (SLA) 3D printing of computed tomography angiography (CTA) data, 3D vessel constructs were produced with diameters of 400 MUm, and resolution as low as 25 MUm. The 3D-printed templates in turn were used as moulds for polydimethylsiloxane (PDMS)-based soft lithography to create microfluidic chips containing miniaturized replicates of in vivo vessel geometries. By applying computational fluid dynamics (CFD) modeling a correlation in terms of flow fields and local wall shear rate was found between the original and miniaturized artery. The walls of the microfluidic chips were coated with human umbilical vein endothelial cells (HUVECs) which formed a confluent monolayer as confirmed by confocal fluorescence microscopy. The endothelialised microfluidic devices, with healthy and stenotic geometries, were perfused with human whole blood with fluorescently labeled platelets at physiologically relevant shear rates. After 15 minutes of perfusion the healthy geometries showed no sign of thrombosis, while the stenotic geometries did induce thrombosis at and downstream of the stenotic area. Overall, the novel methodology reported here, overcomes important design limitations found in typical 2D wafer-based soft lithography microfabrication techniques and shows great potential for controlled studies of the role of 3D vessel geometries and blood flow patterns in arterial thrombosis. PMID- 28717803 TI - Hot off the Press. AB - A personal selection of 32 recent papers is presented covering various aspects of current developments in bioorganic chemistry and novel natural products such as svetamycin B from a Streptomyces species. PMID- 28717804 TI - Relationship between Total Fruit and Vegetable Intake and Self-Reported Knee Pain in Older Adults. AB - OBJECTIVES: Knee pain is one of the most common symptoms of knee osteoarthritis (OA) that affects the quality of life in the older adults, and identifying the contributing factors of knee pain is important. We hypothesized that higher fruit and vegetable consumption might be associated with the severity of knee pain lower prevalence of severe knee pain by affecting pain perception in the knee joint. Therefore, we investigated the relationship between self-reported knee pain and the consumption of fruits vegetables, carotenoids and vitamin C and self reported knee pain. DESIGN: Nationally representative cross sectional study. SETTING: 2010-2011 rounds of the Korean National Health and Nutrition Examination Survey. PARTICIPANTS: A total of 6588 subjects aged >=50 years were participated. METHODS: Severity of knee pain was estimated using a 10-point numeric rating scale (NRS). Daily intake of fruits, vegetables, and vitamins were estimated using data from 24-hour recalls and food frequency questionnaires. RESULTS: The NRS scores of knee pain decreased significantly with increasing fruit and vegetable intake quartiles. A multivariate logistic regression analysis showed that the fourth quartile of vegetable and fruit consumption was associated with decreased prevalence of severe knee pain (OR 0.59, 95% CI 0.48-0.73) compared with first quartile of vegetable and fruit consumption; however, carotenoids and vitamin C consumption was not associated with the severity of knee pain. CONCLUSIONS: In conclusion, severe knee pain was independently associated with fruit and vegetable consumption. Our findings suggest that intake of whole fruits and vegetables may help improve knee pain in older adults. PMID- 28717805 TI - Relationship between diet-related indicators and overweight and obesity in older adults in rural Japan. AB - OBJECTIVES: To identify the relationship between diet-related indicators and overweight and obesity in older adults in rural Japan. DESIGN: Cross-sectional survey. SETTING: Obira, Hokkaido, Japan. PARTICIPANTS: Local residents aged between 65 and 74 years, except for those with poor health, were included. INTERVENTION: A health- and diet-related questionnaire was applied to participants house-to-house by trained health professionals. MEASUREMENTS: The following indicators were examined: number of meals, number of balanced meals, food diversity, food group diversity, chewing ability, alcohol intake habit, smoking habit, instrumental activities of daily living scores, age, and residing alone or with family. RESULTS: Of 550 residents, 317 residents completely responded to the questionnaire. Of these, 41 were had low body mass index (BMI<=20) and were excluded. This resulted in a sample of 307 subjects comprising 117 men and 190 women; 37.6% and 46.8% of men and women were classified as obese (BMI>=25), respectively. Women with a normal BMI (20=75). Linear trend was estimated using continuous 25(OH)D concentrations. ORs were adjusted for age, race, and smoking status. We further adjusted for hypertension status to examine if vitamin D status influenced early AMD via its effects on blood pressure. Exploratory analyses of effect modification by age, sex, race and high risk genotypes [Y402H complement factor H (CFH) rs1061170 and the A69S age-related maculopathy susceptibility 2 (ARMS2) rs10490924 polymorphisms] were conducted. RESULTS: The prevalence of early AMD was 5%, and 5% of participants were vitamin D deficient. The adjusted OR (95% CIs) for early AMD among those with adequate (>=75 nmol/L) compared to deficient (<30 nmol/L) vitamin D status was 0.94 (0.59-1.50), p-trend=0.86. Further adjustment for hypertension status did not influence results (OR [95% CI]=0.95 [0.59-1.52], p-trend=0.84). Results did not vary significantly by age, race, sex, early AMD subtype (soft drusen or retinal pigment epithelium depigmentation), or ARMS2 genotype. Results did not vary significantly by CFH genotype in African Americans. The p for multiplicative interaction between 25(OH)D and CFH genotype was 0.06 in Caucasians, but OR [95% CIs] for AMD by vitamin D status were similar in each CFH genotype and not statistically significant. CONCLUSIONS: Vitamin D status was not associated with early AMD in this cohort sample. PMID- 28717808 TI - The Impact of Multimorbidity on Resting Metabolic Rate in Community-Dwelling Women over a Ten-Year Period: A Cross-Sectional and Longitudinal Study. AB - OBJECTIVES: Ageing has been associated with increasing multimorbidity. This study investigated whether the number of diseases is a predictor of resting metabolic rate (RMR) and its long-term changes in community-dwelling elderly women. SUBJECTS AND DESIGN: Cross-sectional and longitudinal data, obtained over ten years with repeated follow-ups, from 180 women aged 60 - 86 years and with a BMI of 18 - 43 kg/m2 at baseline were analyzed. MEASUREMENTS: RMR was measured using indirect calorimetry and body composition by bioelectrical impedance analysis. Diagnosed diseases were assessed by a questionnaire comprising 23 disease categories. Subjects with 0 - 2 diseases were classified as relatively healthy and with > 2 diseases as multimorbid. RESULTS: At baseline, relatively healthy (N = 75) and multimorbid (N = 105) women did not differ in RMR. During the ten-year follow-up, the median (range) number of diseases increased from 2 (0 - 2) to 4 (0 - 8) in relatively healthy and from 5 (3 - 11) to 7 (3 - 15) in multimorbid women. In the longitudinal analyses, only women who were multimorbid at baseline showed a significant increase in RMR of 31 kJ/d per additional disease (P = 0.015), adjusted for fat-free mass, fat mass, waist circumference and age. CONCLUSION: Increasing multimorbidity in community-dwelling women is associated with an increase in RMR independently of body composition and age. PMID- 28717809 TI - Racial Differences in Misclassification of Healthy Eating Based on Food Frequency Questionnaire and 24-Hour Dietary Recalls. AB - OBJECTIVES: To examine the agreement in nutrient intake and alternate healthy eating indices (AHEI) between a self-administered Food Frequency Questionnaire (FFQ) and 24-hour recall (24HR) measurements of diet by race, among urban older women. DESIGN: Cross-sectional observational study. SETTING: Urban neighborhoods in Washington, DC, USA. PARTICIPANTS: Community-dwelling White and Black women aged 65 and older. MEASUREMENTS: In 2014 and 2015, 49 White and 44 Black older women were queried on diet using both FFQ and 24-hour recalls. The correlation coefficients of 55 nutrient intake measures and agreements on healthy eating classification between the two instruments were compared overall and by race. RESULTS: The mean correlation coefficient (rho) was 0.46 for Whites and 0.23 for Blacks. For 47 measures, rho was lower for Blacks. Whites had a strong correlation of >=0.5 for 28 items, while Blacks had strong correlations for only 3 items. Based on FFQ, the mean (SD) of AHEI were 54.0 (10.3) for Whites and 45.9 (8.8) for Blacks (p<0.001). Based on 24HR, the mean (SD) were 43.9 (10.8) for Whites and 33.2 (9.6) for Blacks (p<0.001). Using 32 as the cutoff (40% of maximum AHEI score), 50% of Blacks and 14% of Whites were classified as eating unhealthy based on the 24HR, versus 2.6% and 0% based on the FFQ. CONCLUSION: The FFQ has limited ability to accurately assess nutrient intake among older Black women, and tends to underestimate racial differences in healthy eating. The FFQ should be further improved for use in racial disparities research of healthy eating in older age, using a larger sample of older women with racial and geographic diversities. PMID- 28717810 TI - Association between Adiposity and disability in the Lc65+ Cohort. AB - OBJECTIVES: To examine the longitudinal association between body mass index (BMI) and waist circumference (WC) with mortality and incident disability in Lc65+ cohort. DESIGN: Population-based cohort of non-institutionalized adults with up to 8.9 years of follow-up. SETTING: City of Lausanne, Switzerland. PARTICIPANTS: 1,293 individuals aged 65 to 70 at baseline (58% women). MEASUREMENTS: BMI, WC and covariates were measured at baseline in 2004-2005. Vital status was obtained up to the 31st December 2013 and difficulty with basic activities of daily living (BADL) was reported in a self-administered questionnaire sent to participants every year. Main outcomes were total mortality and disability, defined as difficulty with BADL for >=2 years or institutionalization. Cox regression was used with BMI/WC quintiles 2 as the reference. RESULTS: 130 persons died over a median follow-up of 8.47 years (crude mortality rate, men: 16.5/1,000 person years, women: 9.7/1,000 person-years). In Cox regression adjusted for age, sex, education, financial situation, smoking and involuntary weight loss (IWL) at baseline, mortality was significantly associated with neither BMI nor WC, but there were trends towards non-significant J-curves across both BMI and WC quintiles. Disability (231 cases) tended to increase monotonically across both BMI and WC quintiles and was significantly associated with BMI quintile 5 (HR=2.44, 95% CI [1.65-3.63]), and WC quintiles 4 (HR=1.81 [1.15-2.85]) and 5 (HR=2.58, [1.67-4.00]). CONCLUSION: Almost half of the study population had a substantially increased HR of disability, as compared to the reference BMI/WC categories. This observation emphasizes the need for life-long strategies aimed at preventing excess weight, muscle loss and functional decline through adequate nutrition and regular physical activity, starting at early age and extending throughout life. PMID- 28717811 TI - Effect on Body Weight, Quality of Life and Appetite Following Individualized, Nutritional Counselling to Home-Living Elderly after Rehabilitation - An Open Randomized Trial. AB - OBJECTIVES: We examined if individually-adapted nutritional counselling could prevent > 5% weight loss among elderly patients 3 months after discharge from a rehabilitation institution. In addition we assessed quality of life (QoL) and appetite. DESIGN: An open, randomized trial. SETTING: Godthaab Health and Rehabilitation Institution in Baerum, Norway. PARTICIPANTS: Patients identified as being undernourished or at risk of disease-related malnutrition using the Nutritional Risk Screening tool NRS-2002. INTERVENTION: Shortly before discharge, patients in the intervention group received an individually-tailored nutrition plan. During the subsequent 3 months these patients were contacted 3 times via telephone calls and they received one visit at their homes, for nutrition counselling. Focus on this counselling was on optimizing meal environment, improving appetite, increasing food intake, advice on food preparation, and motivation and support. MEASUREMENTS: In addition to weight, QoL and appetite were assessed using the EQ-5D questionnaire and a modified version of the Disease Related Appetite Questionnaire, respectively. RESULTS: Among 115 considered eligible for the study, 100 were enrolled (72 women and 28 men), with a mean age of 75 years and a mean body mass index of 20 kg/m2. Two in the intervention group (n = 52) and 5 in the control group (n = 48) lost > 5% of their body weight, giving an odds ratio of 0.34 (95% CI: 0.064 - 1.86; p = 0.22). We did not detect any significant differences in the QoL- or appetite scores between the two study groups after three months. CONCLUSION: An individually-adapted nutritional counselling did not improve body mass among elderly patients 3 months after discharge from a rehabilitation institution. Neither quality of life nor appetite measures were improved. Possibly, nutritional counselling should be accompanied with nutritional supplementation to be effective in this vulnerable group of elderly. The trial is registered in Clinical Trials (ID: NCT01632072). PMID- 28717812 TI - A New Adaptive Home-based Exercise Technology among Older Adults Living in Nursing Home: A Pilot Study on Feasibility, Acceptability and Physical Performance. AB - OBJECTIVES: To explore the feasibility and acceptability of a new home-based exercise technology among older adults and to evaluate its efficacy on physical performance measures. DESIGN: Longitudinal clinical trial. SETTING: Oak Hammock at the University of Florida, a nursing home located in Gainesville, Florida. PARTICIPANTS: Twelve pre-disabled older adults (>=75 years) living in a nursing home with a Short Physical Performance Battery (SPPB) score between 6 and 9 and no diagnosis of dementia. INTERVENTION: Thirty minutes of light intensity exercise (aerobic, strength and balance) two times per week for four weeks using a home-based physical activity technology called Jintronix. MEASUREMENTS: Feasibility and acceptability were assessed through a 9-item self-administered questionnaire and by exploring the percentage of quality of movements and time performing exercise which was calculated automatically by Jintronix technology. Physical performance measures were assessed through the SPPB score at baseline, after 4 weeks of intervention and after 3 months from the completion of the intervention. RESULTS: Twelve older adults (80.5+/-4.2 years old) performed light intensity exercise with Jintronix for a total of 51.9+/-7.9 minutes per week. Participants reached 87% score of quality of movements in strength and balance exercises, a global appreciation score of 91.7% and a global difficulty score of 36%. Compared to baseline, there was a significant improvement in SPPB score at the end of the intervention and at 3 months following the completion of the exercise program (0.67+/-0.98 and 1.08+/-0.99 respectively, p-value <0.05). CONCLUSION: Jintronix technology is feasible and acceptable among pre-disabled older adults without dementia living in nursing home and is beneficial in improving their physical performance. PMID- 28717813 TI - Cut-off Points for Muscle Mass - Not Grip Strength or Gait Speed - Determine Variations in Sarcopenia Prevalence. AB - OBJECTIVES: The European Working Group on Sarcopenia in Older People (EWGSOP) has proposed different methods and cut-off points for the three parameters that define sarcopenia: muscle mass, muscle strength and physical performance. Although this facilitates clinical practice, it limits comparability between studies and leads to wide differences in published prevalence rates. The aim of this study was to assess how changes in cut-off points for muscle mass, gait speed and grip strength affected sarcopenia prevalence according to EWGSOP criteria. METHODS: Cross-sectional analysis of elderly individuals recruited from outpatient clinics (n=298) and nursing homes (n=276). We measured muscle mass, grip strength and gait speed and assessed how changes in cut-off points changed sarcopenia prevalence in both populations. RESULTS: An increase from 5.45 kg/m2 to 6.68 kg/m2 in the muscle mass index for female outpatients and nursing-home residents increased sarcopenia prevalence from 4% to 23% and from 9% to 47%, respectively; for men, for an increase from 7.25 kg/m2 to 8.87 kg/m2, the corresponding increases were from 1% to 22% and from 6% to 41%, respectively. Changes in gait speed and grip strength had a limited impact on sarcopenia prevalence. CONCLUSION: The cut-off points used for muscle mass affect the reported prevalence rates for sarcopenia and, in turn, affect comparability between studies. The main factors influencing the magnitude of the change are muscle mass index distribution in the population and the absolute value of the cut-off points: the same difference between two references (e.g., 7.5 kg/m2 to 7.75 kg/m2 or 7.75 kg/m2 to 8 kg/m2) may produce different changes in prevalence. Changes in cut-off points for gait speed and grip strength had a limited impact on sarcopenia prevalence and on study comparability. PMID- 28717814 TI - Malnutrition in Hospitalised Older Adults: A Multicentre Observational Study of Prevalence, Associations and Outcomes. AB - BACKGROUND: Malnutrition is common in older adults and is associated with high costs and adverse outcomes. The prevalence, predictors and outcomes of malnutrition on admission to hospital are not clear for this population. DESIGN: Prospective Cohort Study. SETTING: Six hospital sites (five public, one private). PARTICIPANTS: In total, 606 older adults aged 70+ were included. All elective and acute admissions to any speciality were eligible. Day-case admissions and those moribund on admission were excluded. MEASUREMENTS: Socio-demographic and clinical data, including nutritional status (Mini-Nutritional Assessment - short form), was collected within 36 hours of admission. Outcome data was collected prospectively on length of stay, in-hospital mortality and new institutionalisation. RESULTS: The mean age was 79.7; 51% were female; 29% were elective admissions; 67% were admitted to a medical specialty. Nutrition scores were available for 602/606; 37% had a 'normal' status, 45% were 'at-risk', and 18% were 'malnourished'. Malnutrition was more common in females, acute admissions, older patients and those who were widowed/ separated. Dementia, functional dependency, comorbidity and frailty independently predicted a) malnutrition and b) being at-risk of malnutrition, compared to normal status (p < .001). Malnutrition was associated with outcomes including an increased length of stay (p < .001), new institutionalisation (p =<0.001) and in-hospital mortality (p < .001). CONCLUSIONS: These findings support the prioritisation of nutritional screening in clinical practice and public health policy, for all patients >=70 on admission to hospital, and in particular for people with dementia, increased functional dependency and/or multi-morbidity, and those who are frail. PMID- 28717815 TI - Hip Fractures in Older Patients: Trajectories of Disability after Surgery. AB - BACKGROUND: Hip fracture in older patients often lead to permanent disabilities and can result in mortality. OBJECTIVE: To identify distinct disability trajectories from admission to one-year post-discharge in acutely hospitalized older patients after hip fracture. DESIGN: Prospective cohort study, with assessments at admission, three-months and one-year post-discharge. SETTING AND PARTICIPANTS: Patients >= 65 years admitted to a 1024-bed tertiary teaching hospital in the Netherlands. METHODS: Disability was the primary outcome and measured with the modified Katz ADL-index score. A secondary outcome was mortality. Latent class growth analysis was performed to detect distinct disability trajectories from admission and Cox regression was used to analyze the effect of the deceased patients to one-year after discharge. RESULTS: The mean (SD) age of the 267 patients was 84.0 (6.9) years. We identified 3 disability trajectories based on the Katz ADL-index score from admission to one-year post discharge: 'mild'- (n=54 (20.2%)), 'moderate'- (n=110 (41.2%)) and 'severe' disability (n=103 (38.6%)). Patients in all three trajectories showed an increase of disabilities at three months, in relation to baseline and 80% did not return to baseline one-year post-discharge. Seventy-three patients (27.3%) deceased within one-year post-discharge, particularly in the 'moderate'- (n=22 (8.2%)) and 'severe' disability trajectory (n=47 (17.6%)). CONCLUSIONS: Three disability trajectories were identified from hospital admission until one-year follow-up in acutely hospitalized older patients after hip fracture. Most patients had substantial functional decline and 27% of the patient's deceased one-year post discharge, mainly patients in the 'moderate'- 'and severe' disability trajectories. PMID- 28717816 TI - Prospective Associations of Low Muscle Mass and Function with 10-Year Falls Risk, Incident Fracture and Mortality in Community-Dwelling Older Adults. AB - OBJECTIVES: Purpose: To compare the performance of low muscle mass and function with falls risk, incident fracture and mortality over 10 years. METHODS: 1041 participants (50% women; mean age 63+/-7.5 years) were prospectively followed for 10 years. Falls risk was measured using the Physiological Profile Assessment, fractures were self-reported and mortality was ascertained from the death registry. Appendicular lean mass (ALM) was assessed using dual energy X-ray absorptiometry. Four anthropometric: (ALM/height2, ALM/body mass index, ALM/weight*100, a residuals method of ALM on height and total body fat) and four performance-based measures: (handgrip strength, lower-limb muscle strength, upper and lower-limb muscle quality) were examined. Participants in the lowest 20% of the sex-specific distribution for each anthropometric and performance-based measure were classified has having low muscle mass or function. Regression analyses were used to estimate associations between each anthropometric and performance-based measure at baseline and 10-year falls risk, incident fractures and mortality. RESULTS: Mean falls risk z-score at 10 years was 0.64 (SD 1.12), incident fractures and mortality over 10 years were 16% and 14% respectively. All baseline performance-based measures were significantly associated with higher falls risk score at 10 years. Low handgrip (RR 1.55, 95% CI: 1.09, 2.20) and ALM/body mass index (RR 1.54, 95% CI: 1.14, 2.08) were the only significant predictors of fracture and mortality respectively. CONCLUSIONS: Low handgrip strength, a simple and inexpensive test could be considered in clinical settings for identifying future falls and fractures. ALM/ body mass index could be most suitable in estimating 10-year mortality risk, but requires specialised equipment. PMID- 28717818 TI - Photoacoustic imaging using genetically encoded reporters: a review. AB - Genetically encoded contrast in photoacoustic imaging (PAI) is complementary to the intrinsic contrast provided by endogenous absorbing chromophores such as hemoglobin. The use of reporter genes expressing absorbing proteins opens the possibility of visualizing dynamic cellular and molecular processes. This is an enticing prospect but brings with it challenges and limitations associated with generating and detecting different types of reporters. The purpose of this review is to compare existing PAI reporters and signal detection strategies, thereby offering a practical guide, particularly for the nonbiologist, to choosing the most appropriate reporter for maximum sensitivity in the biological and technological system of interest. PMID- 28717817 TI - Quantifying three-dimensional rodent retina vascular development using optical tissue clearing and light-sheet microscopy. AB - Retinal vasculature develops in a highly orchestrated three-dimensional (3-D) sequence. The stages of retinal vascularization are highly susceptible to oxygen perturbations. We demonstrate that optical tissue clearing of intact rat retinas and light-sheet microscopy provides rapid 3-D characterization of vascular complexity during retinal development. Compared with flat mount preparations that dissect the retina and primarily image the outermost vascular layers, intact cleared retinas imaged using light-sheet fluorescence microscopy display changes in the 3-D retinal vasculature rapidly without the need for point scanning techniques. Using a severe model of retinal vascular disruption, we demonstrate that a simple metric based on Sholl analysis captures the vascular changes observed during retinal development in 3-D. Taken together, these results provide a methodology for rapidly quantifying the 3-D development of the entire rodent retinal vasculature. PMID- 28717819 TI - Atrophic degeneration of cerebellum impairs both the reactive and the proactive control of movement in the stop signal paradigm. AB - The cognitive control of movement suppression, including performance monitoring, is one of the core properties of the executive system. A complex cortical and subcortical network involving cerebral cortex, thalamus, subthalamus, and basal ganglia has been regarded as the neural substrate of inhibition of programmed movements. Using the countermanding task, a suitable tool to explore behavioral components of movement suppression, the contribution of the cerebellum in the proactive control and monitoring of voluntary action has been recently described in patients affected by focal lesions involving in particular the cerebellar dentate nucleus. Here, we evaluated the performance on the countermanding task in a group of patients with cerebellar degeneration, in which the cerebellar cortex was diffusely affected, and showed that they display additionally a longer latency in countermanding engaged movements. Overall, the present data confirm the role of the cerebellum in executive control of action inhibition by extending the contribution to reactive motor suppression. PMID- 28717821 TI - [Perihilar cholangiocarcinoma Bismuth type IV: Resection frequently possible]. PMID- 28717822 TI - [Q14 pain medicine in medical studies: glass half full or half empty?] PMID- 28717820 TI - Differences between endogenous attention to spatial locations and sensory modalities. AB - Vibell et al. (J Cogn Neurosci 19:109-120, 2007) reported that endogenously attending to a sensory modality (vision or touch) modulated perceptual processing, in part, by the relative speeding-up of neural activation (i.e., as a result of prior entry). However, it was unclear whether it was the fine temporal discrimination required by the temporal-order judgment task that was used, or rather, the type of attentional modulation (spatial locations or sensory modalities) that was responsible for the shift in latencies that they observed. The present study used a similar experimental design to evaluate whether spatial attention would also yield similar latency effects suggestive of prior entry in the early visual P1 potentials. Intriguingly, while the results demonstrate similar neural latency shifts attributable to spatial attention, they started at a somewhat later stage than seen in Vibell et al.'s study. These differences are consistent with different neural mechanisms underlying attention to a specific sensory modality versus to a spatial location. PMID- 28717823 TI - [Interdisciplinary pain assessment in the hospital setting : Merely a door-opener to multimodal pain therapy?] AB - BACKGROUND: Chronic pain is characterized by a complex interaction of somatic, mental and social factors. Assessing these factors in patients with chronic pain is vital during the diagnostic work-up and when making a structured treatment plan. Interdisciplinary pain assessment (ISA) is the most promising method to deal with these challenges. This article presents our experience in performing pain assessments in the hospital setting and also illustrates the characteristic features of chronic pain patients undergoing such assessments. METHODS: This study reviews and evaluates patient data from 2704 ISAs performed at the Interdisciplinary Pain Centre of the Zentralklinik Bad Berka, Germany, between 2008 and 2015. RESULTS: The majority of our ISA patients are severely handicapped and show distinct signs of chronic disease. A large proportion of patients is either unable to work or receiving benefits (invalidity pension or retirement pension). In addition, patients reported long disease durations and high emotional distress. Treatment recommendations were based on the patients' individual clinical presentations and examination results. More than half of the patients required multimodal pain management, while adjustments or therapeutic withdrawal of pain medications, in particular of opioids, were indicated in many patients. DISCUSSION: Our study shows that ISA enables fast, high-quality diagnostic assessments of chronic pain while taking the biopsychosocial model of pain in particular into account. In addition, ISA is not biased with regard to outcome results and recommends the further treatment that appears best for the individual patient. ISA leads not only to inpatient treatment, but also to treatment in other therapeutic settings and, as such, is not merely a door-opener to multimodal pain therapy. PMID- 28717824 TI - Follow-up after radical vaginal trachelectomy (RVT): patients' problems and physicians' difficulties. AB - PURPOSE: Patients after radical vaginal trachelectomy (RVT) need specific follow up treatment because their problems differ from those of other gyneco-oncologic patients. Anatomic changes after surgery complicate examinations. Recognition and treatment of these issues require physician's expertise. PATIENTS AND METHODS: We evaluated the follow-up data of 70 patients who underwent RVT for early cervical cancer between 03/2010 and 12/2013. The follow-up interval in the first 2 years was 3 and 6 months in the following 2 years. We used a tailored protocol to describe the special problems after RVT. RESULTS: Cervical stenosis was one of the central problems independent of time interval to RVT. Physicians' most significant problem was to locate the exact position of the neo-cervix and thus to receive valid pap smears. CONCLUSIONS: Follow-up of patients after RVT needs special expertise because the symptoms differ from those after hysterectomy and examinations ensuring oncologic safety require special attention. PMID- 28717825 TI - [Current developments in telemedicine : Expectations, disappointments and hopes]. PMID- 28717826 TI - Operator radiation exposure during transradial coronary angiography : Effect of single vs. double catheters. AB - BACKGROUND: The right radial artery has gained popularity as the preferred access site for coronary angiography. To save time and limit the radiation exposure of operators and patients, newly designed catheters can be used to access both the right and left coronary arteries. The aim of this study was to compare operator radiation exposure between single-catheter (SCA) and two-catheter approaches (TCA). METHODS: In all, 256 patients undergoing diagnostic coronary angiography via the right radial artery in a high-volume medical center were randomized to either the SCA or TCA group. The dose of radiation exposure of the operators was measured by an electronic dosimeter attached to the breast pocket of the operator's apron. The dose-area product and air kerma were used as indices of patient exposure to radiation. The duration of fluoroscopy "beam-on" time, acquisition time, and total duration of the procedure were measured and analyzed for the two groups. RESULTS: Operator radiation exposure was 21.6 +/- 11.4 uSv in the SCA group, which was significantly less than 28.0 +/- 14.9 uSv in the TCA group. The duration of fluoroscopy was significantly shorter in the SCA group than in the TCA group (152 +/- 83 vs. 203 +/- 121 s; p < 0.001). Moreover, the total duration of the diagnostic procedure was also shorter in the SCA group compared with the TCA group (9.5 +/- 3.2 vs. 11.4 +/- 4.0 min; p < 0.001). CONCLUSION: The use of SCA is advantageous over TCA in reducing the exposure of operators to radiation. The shorter duration of fluoroscopy beam-on time and total procedure time may contribute to the lower exposure of operators to radiation. PMID- 28717827 TI - Individual and environmental correlates of objectively measured physical activity and sedentary time in adults from Curitiba, Brazil. AB - OBJECTIVES: This study assessed the association of individual and neighborhood environment characteristics and objectively measured physical activity (PA) and sedentary time (ST) in adults from Curitiba, Brazil. METHODS: A population-based cross-sectional study was conducted through face-to-face household interviews in 2010. The analytic sample included 305 adults aged 20-65 years recruited from 32 census tracts selected according to neighborhood walkability and socioeconomic status. Individual and environmental PA correlates were evaluated through standardized and valid self-reported measures, including the Neighborhood Environment Walkability Scale. Minutes per week of PA and ST were assessed through accelerometry. Multi-level regression models were used in the analyses. RESULTS: After adjusting for confounders the strongest individual and environmental correlates associated with ST was residential density (B = 0.14; p = 0.008), light-intensity PA was being a father/mother (B = 35.71; p = 0.025) and moderate-to-vigorous PA was sex (B = 0.91; p < 0.001) and number of cars (one car, B = -1.05; two cars, B = -1.14; p < 0.001). CONCLUSIONS: The associations found with individual and environmental correlates varied accordingly across all outcomes. Future changes in policies and infrastructure should consider the social context of the community and improvements to promote a safer environment in the neighborhood. PMID- 28717828 TI - Statistical challenges in modelling the health consequences of social mobility: the need for diagonal reference models. AB - OBJECTIVES: Various studies on the health consequences of socio-economic position address social mobility. They aim to uncover whether health outcomes are affected by: (1) social mobility, besides, (2) social origin, and (3) social destination. Conventional methods do not, however, estimate these three effects separately, which may produce invalid conclusions. We highlight that diagonal reference models (DRMs) overcome this problem, which we illustrate by focusing on overweight/obesity (OWOB). METHODS: Using conventional methods (logistic regression analyses with dummy variables) and DRMs, we examine the effects of intergenerational educational mobility on OWOB (BMI >= 25 kg/m2) using survey data representative of the Dutch population aged 18-45 (1569 males, 1771 females). RESULTS: Conventional methods suggest that mobility effects on OWOB are present. Analyses with DRMs, however, indicate that no such effects exist. CONCLUSIONS: Conventional analyses of the health consequences of social mobility may produce invalid results. We, therefore, recommend the use of DRMs. DRMs also validly estimate the health consequences of other types of social mobility (e.g. intra- and intergenerational occupational and income mobility) and status inconsistency (e.g. in educational or occupational attainment between partners). PMID- 28717829 TI - Configured-groups hypothesis: fast comparison of exact large quantities without counting. AB - Our innate number sense cannot distinguish between two large exact numbers of objects (e.g., 45 dots vs 46). Configured groups (e.g., 10 blocks, 20 frames) are traditionally used in schools to represent large numbers. Previous studies suggest that these external representations make it easier to use symbolic strategies such as counting ten by ten, enabling humans to differentiate exactly two large numbers. The main hypothesis of this work is that configured groups also allow for a differentiation of large exact numbers, even when symbolic strategies become ineffective. In experiment 1, the children from grade 3 were asked to compare two large collections of objects for 5 s. When the objects were organized in configured groups, the success rate was over .90. Without this configured grouping, the children were unable to make a successful comparison. Experiments 2 and 3 controlled for a strategy based on non-numerical parameters (areas delimited by dots or the sum areas of dots, etc.) or use symbolic strategies. These results suggest that configured grouping enables humans to distinguish between two large exact numbers of objects, even when innate number sense and symbolic strategies are ineffective. These results are consistent with what we call "the configured group hypothesis": configured groups play a fundamental role in the acquisition of exact numerical abilities. PMID- 28717830 TI - A review of drug-induced liver injury databases. AB - Drug-induced liver injuries have been a major focus of current research in drug development, and are also one of the major reasons for the failure and withdrawal of drugs in development. Drug-induced liver injuries have been systematically recorded in many public databases, which have become valuable resources in this field. In this study, we provide an overview of these databases, including the liver injury-specific databases LiverTox, LTKB, Open TG-GATEs, LTMap and Hepatox, and the general databases, T3DB, DrugBank, DITOP, DART, CTD and HSDB. The features and limitations of these databases are summarized and discussed in detail. Apart from their powerful functions, we believe that these databases can be improved in several ways: by providing the data about the molecular targets involved in liver toxicity, by incorporating information regarding liver injuries caused by drug interactions, and by regularly updating the data. PMID- 28717831 TI - A reply to the letter to the editor by Nima Derakhshan and Mahsa Roshanfarzad with regard to the paper "Pandora's box: eosinophilic granuloma at the cerebellopontine angle-should we open it?" PMID- 28717832 TI - Endoscopic surgery for intraventricular arachnoid cysts in children: clinical presentation, radiological features, management, and outcomes over a 12-year period. AB - PURPOSE: Less than 0.5% of arachnoid cysts are intraventricular in origin. We review our experience with endoscopic surgery for intraventricular arachnoid cysts in children. METHODS: This is a retrospective review of children with intraventricular arachnoid cysts who underwent surgery between 2005 and 2016. Clinical notes and imaging were reviewed. RESULTS: Twenty-nine patients with endoscopically treated intraventricular arachnoid cysts were identified (M/F = 17:12; median age = 1.47 years, range = 7 days-13 years). All had hydrocephalus at presentation, many had symptoms/signs of raised intracranial pressure, and five (17%) were asymptomatic. Cysts were treated with fenestration into the ventricle alone (ventriculocystostomy [VC], n = 14), fenestration into the ventricle and cisternostomy (ventriculocystostomy plus cisternostomy [VC + C], n = 14), or endoscopic third ventriculostomy alone (n = 1). Six (21%) patients experienced transient and/or conservatively managed complications. Further surgery was required in 12 (41%). Revision-free survival was significantly shorter with VC compared to VC + C (log rank p = 0.049), and the majority of VC/VC + C revisions (n = 8 of 11, 73%) were required within 6 months of initial endoscopic surgery. One (3%) patient died during follow-up, from unrelated pathology. After a median follow-up of 67.5 months in survivors (range = 5.5 133.5 months), 24 (83%) cases were clinically and radiologically stable without a shunt in situ. CONCLUSIONS: Endoscopic fenestration is safe and effective in most intraventricular arachnoid cysts. Additional cisternostomy at the time of cyst fenestration into the ventricle significantly improved revision-free survival in our cohort. Endoscopic surgery should be the first-line therapy when considering intervention for symptomatic intraventricular arachnoid cysts and for asymptomatic cysts increasing in size on serial imaging. PMID- 28717833 TI - An interdigital array microelectrode aptasensor based on multi-walled carbon nanotubes for detection of tetracycline. AB - In this study an impedance aptasensor was designed for sensitive, selective, and fast detection of tetracycline (TET) based on an interdigital array microelectrode (IDAM). The IDAM was integrated with impedance detection to miniaturize the conventional electrodes, enhance the sensitivity, shorten the detection time, and minimize interfering effects of non-target analytes in the solution. Due to their excellent conductivity, good biocompatibility, the multi walled carbon nanotubes (MWCNTs) were used to modify the IDAM to immobilize TET aptamer effectively. The proposed aptasensor produced a sensitive impedance change which was characterized by the electrochemical impedance spectroscopy (EIS). With the addition of TET, the formation of TET-aptamer complex on the surface of MWCNTs modified electrode resulted in an increase of electron transfer resistance (R et). The change of R et depends on the concentration of TET, which is applied for the quantification of TET. A wide linear range was obtained from 10-9 to 10-3 M. The linear regression equation was y(DeltaR) = 21.310 * x(LogC) (M) + 217.25. It was successfully applied to detect TET in real milk samples. PMID- 28717835 TI - Focus on ECMO and ECCO2R in ARDS patients. PMID- 28717834 TI - Characterizing the Adherence Profiles of Virulent Vibrio parahaemolyticus Isolates. AB - The human pathogen Vibrio parahaemolyticus is a leading cause of seafood-borne illness in the USA, and infections with V. parahaemolyticus typically result from eating raw or undercooked oysters. V. parahaemolyticus has been shown to be highly resistant to oyster depuration, suggesting that the bacterium possesses specific mechanisms or factors for colonizing oysters and persisting during depuration. In this study, we characterized eight different V. parahaemolyticus strains for differences in resistance to oyster depuration, biofilm formation, and motility. While each strain exhibited distinct phenotypes in the various assays, we determined that biofilm formation on abiotic surfaces, such as glass or plastic, does not directly correlate with bacterial retention in oysters during depuration. However, we did observe that the motility phenotype of a strain appeared to be a better indicator for persistence in the oyster. Further studies examining the molecular mechanisms underlying the observed colonization differences by these and other V. parahaemolyticus strains may provide beneficial insights into what critical factors are required for proficient colonization of the Pacific oyster. PMID- 28717836 TI - Risk factors of percutaneous cannulation failure by intensivists for veno arterial extracorporeal life support for refractory cardiac arrest. PMID- 28717837 TI - The dark side of the swan. PMID- 28717839 TI - Lung Biopsy: Don't Forget Air Embolism! : Letter Reply to "Comment on CIRSE Guidelines on Percutaneous Needle Biopsy (PNB)". PMID- 28717838 TI - The triterpenoid alpha, beta-amyrin prevents the impaired aortic vascular reactivity in high-fat diet-induced obese mice. AB - To characterize the protective effects of the triterpenoid mixture alpha, beta amyrin (AMY, 20 mg/kg, during 15 days) on the reactivity of isolated aorta of high-fat diet (HFD)-induced obese mice. Male Swiss mice were fed with HFD or normal diet (ND) for 15 weeks. Contractions of thoracic aorta in response to KCl or phenylephrine (PHE) and relaxation by acetylcholine (ACh) or sodium nitroprusside (SNP) were analyzed. HFD-fed mice developed hyperglycemia, hyperlipidemia, and significant body weight gain, parameters prevented by AMY treatment. Whereas aortic contractility did not differ in response to KCl, contractions induced by PHE (1 MUM) as well as relaxation induced by ACh (1-30 MUM) or SNP (1 nM-0.1 mM) on PHE-contracted aorta were decreased (p < 0.05) in tissues of HFD compared to ND mice, phenomenon significantly (p < 0.05) diminished in HFD mice treated with AMY. The relaxant actions of ACh and SNP were inhibited (p < 0.05) by tetraethylammonium (TEA, 5 mM), apamin (0.1 MUM), and 4 aminopyridine (4-AP; 3 mM) in aortae from ND group, but not from HFD. Treatment of HFD mice with AMY rescued the inhibitory effect of TEA (p < 0.05) on vasorelaxant actions of ACh and SNP. 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) inhibited similarly the relaxant effects of SNP in all groups. 8-Br-cGMP relaxed with similar profile aortae of all groups. By preventing HFD-induced obesity in mice, AMY rescued the blunted contractile response to PHE, and the attenuated vasorelaxation and K+ channel activation (opening) induced by ACh and SNP in isolated aorta. PMID- 28717840 TI - Nonoperative management of perforated acute diverticulitis with extraluminal air: results and risk factors of failure. AB - AIM: The aim of this study was to analyze the results of nonoperative management of patients with perforated acute diverticulitis with extraluminal air and to identify risk factors that may lead to failure and necessity of surgery. METHODS: Methods included observational retrospective cohort study of patients between 2010 and 2015 with diagnosis of diverticulitis with extraluminal air and with nonoperative management initial. Patient demographics, clinical, and analytical data were collected, as were data related with computed tomography. Univariate and multivariate analyses with Wald forward stepwise logistic regression were performed to analyze results and to identify risk factors potentially responsible of failure of nonoperative management. RESULTS: Nonoperative management was established in 83.12% of patients diagnosed with perforated diverticulitis (64 of 77) with an overall success rate of 84.37%, a mean hospital stay of 11.98 +/- 7.44 days and only one mortality (1.6%). Patients with pericolic air presented a greater chance of success (90.2%) than patients with distant air (61.5%). American Society of Anesthesiologists (ASA) grade III-IV (OR, 5.49; 95% CI, 1.04 29.07) and the distant location of air (OR, 4.81; 95% CI, 1.03-22.38) were the only two factors identified in the multivariate analysis as risk factors for a poor nonoperative treatment outcome. Overall recurrence after conservative approach was 20.4%; however, recurrence rate of patients with distant air was twice than that of patients with pericolic air (37.5 vs 17.39%). Only 14.8% of successfully treated patients required surgery after the first episode. CONCLUSION: Nonoperative management of perforated diverticulitis is safe and efficient. Special follow-up must be assumed in patients ASA III-IV and with distant air in CT. PMID- 28717841 TI - Variation in care for surgical patients with colorectal cancer: protocol adherence in 12 European hospitals. AB - PURPOSE: Surgical care for patients with colorectal cancer has become increasingly standardized. The Enhanced Recovery After Surgery (ERAS) protocol is a widely accepted structured care method to improve postoperative outcomes of patients after surgery. Despite growing evidence of effectiveness, adherence to the protocol remains challenging in practice. This study was designed to assess the adherence rate in daily practice and examine the relationship between the importance of interventions and adherence rate. METHODS: This international observational, cross-sectional multicenter study was performed in 12 hospitals in four European countries. Patients were included from January 1, 2014. Data was retrospectively collected from the patient record by the local study coordinator. RESULTS: A total of 230 patients were included in the study. Protocol adherence was analyzed for both the individual interventions and on patient level. The interventions with the highest adherence were antibiotic prophylaxis (95%), thromboprophylaxis (87%), and measuring body weight at admission (87%). Interventions with the lowest adherence were early mobilization-walking and sitting (9 and 6%, respectively). The adherence ranged between 16 and 75%, with an average of 44%. CONCLUSION: Our results show that the average protocol adherence in clinical practice is 44%. The variation on patient and hospital level is considerable. Only in one patient the adherence rate was >70%. In total, 30% of patients received 50% or more of the key interventions. A solid implementation strategy seems to be needed to improve the uptake of the ERAS pathway. The importance-performance matrix can help in prioritizing the areas for improvement. PMID- 28717842 TI - Selective matrix metalloproteinase inhibition increases breaking strength and reduces anastomotic leakage in experimentally obstructed colon. AB - PURPOSE: Colonic obstruction causes loss of collagen and impairment of anastomotic integrity by matrix metalloproteinases (MMPs). Unexpectedly, pharmacological MMP inhibition increased anastomotic leakage (AL) in obstructed colon possibly due to the non-selective nature of these compounds and the experimental model applied. We therefore studied the effects of selective MMP inhibition on the healing of anastomoses in colon obstructed by a novel laparoscopic technique. METHODS: Left colon was obstructed in 38 male Sprague Dawley rats (226-284 g). After 12 h, stenoses were resected and end-to-end anastomoses constructed. Baseline breaking strength was determined in 6 animals on day 0. The remaining 32 rats were randomized to daily treatment with the selective MMP-8, MMP-9, and MMP-12 inhibitor AZD3342 (n = 16) or vehicle (n = 16). On day 3, anastomoses were evaluated for AL and breaking strength. Isolated anastomotic wound tissue was analyzed on total collagen and pepsin-insoluble and pepsin-soluble collagen by hydroxyproline. The soluble collagens were further differentiated into native, measured by Sircol, and fragmented forms. RESULTS: Baseline breaking strength was maintained with AZD3342 but decreased by 25% (P = 0.023) in the vehicle group. The anastomotic breaking strength of AZD3342-treated rats was 44% higher (P = 0.008) than the vehicle-treated rats. Furthermore, the AL rate was reduced (P = 0.037) with AZD3342 compared with vehicle treatment. AZD3342 treatment influenced neither the total or insoluble collagen concentrations nor the degree of fragmentation of the soluble collagen triple helices. CONCLUSION: Selective MMP inhibition increased anastomotic breaking strength and reduced AL after resection of colonic obstruction. PMID- 28717843 TI - Septic arthritis associated with systemic sepsis. AB - PURPOSE: Septic arthritis presents with good joint function, but sometimes leads to poor outcomes. Concurrent systemic sepsis has been regarded as the poor outcome, and the exact cause remains unclear. This paper was performed to identify factors associated with concurrent systemic sepsis and to research results to predict poor outcomes in patients with septic arthritis. METHODS: Laboratory and medical data were reviewed for 137 adults with acute septic arthritis who underwent open or arthroscopic surgical debridement at our institution between January 2005 and December 2014. The patients were divided according to whether they had septic arthritis alone (Group A) or in combination with systemic sepsis (Group B). Systemic sepsis was defined as two more systemic inflammatory signs in response to an infectious process. Patient characteristics, laboratory findings, synovial fluid findings and cultures, and surgical results were compared between two groups. RESULTS: Of the 137 patients, 41 (29.9%) had initial systemic sepsis at the diagnosis of septic arthritis. Independent t test revealed that duration of prodromal symptom (p = 0.012), serum neutrophil percent (p = 0.008), C-reactive protein (p = 0.001), Charlson comorbidity index (p = 0.001), positive culture in synovial fluid (p = 0.001), and methicillin-sensitive Staphylococcus aureus (MSSA) isolate in synovial fluid (p = 0.001) had significant correlations with the group B. Repeated debridement was performed for those who had recurrence of infection, and this procedure was more often in group B (23 versus 21 joints, 23.9 versus 51.2%, p = 0.012). Progression of arthritis occurred more often in group B (16 versus 17 joints, 16.7 versus 41.5%, p = 0.001). CONCLUSION: Septic arthritis combined with systemic sepsis was related to duration of prodromal symptom, serum neutrophil percent, C-reactive protein, Charlson comorbidity index, positive culture in synovial fluid, and a MSSA isolate in synovial fluid. Concurrent systemic sepsis led to poor outcomes in patients with septic arthritis in terms of recurrence of infection and progression of arthritis. LEVEL OF EVIDENCE: III Case control study. PMID- 28717844 TI - Application of the Biopsy-Sparing ESPGHAN Guidelines for Celiac Disease Diagnosis in Adults: A Real-Life Study. AB - BACKGROUND: Current adult celiac disease diagnosis requires histological confirmation. However, pediatric guidelines have proposed biopsy-sparing algorithms. AIMS: To explore the applicability of the ESPGHAN criteria and assess the accuracy of serology in predicting disease in adults. METHODS: We evaluated 234 consecutive adults showing elevated anti-tTG titers, EMA-positivity, and genetic susceptibility. Patients underwent upper endoscopy with duodenal biopsy. We determined optimal anti-tTG cutoff levels using ROC curves. RESULTS: Mean anti tTG levels were 71.1 +/- 66.5 U/ml; mean normalized levels were 14.8 +/- 14.1 * ULN (mean +/- SD). Partial/total villous atrophy was present in 36%/55% of cases, respectively. Anti-tTG levels correlated with histology (r s = 0.397, p < 0.001). AUC was similar before and after normalization (0.803 vs 0.807). Applying the ESPGHAN criterion (>=10 * ULN), we calculated a 97.66% PPV. ROC curve analysis showed an optimal cutoff of >=16 * ULN, with a PPV of 98.86%. Eleven different assays were used for anti-tTG titer determination: Two were prevalent, labeled A (n = 141) and B (n = 59). They performed differently regarding disease prediction (AUC = 0.689 vs 0.925, p < 0.01), showing distinct optimal cutoff values (14.3 * ULN vs 3.7 * ULN), even after standardization (-0.14 vs -1.2). CONCLUSION: In adult symptomatic patients showing EMA-positivity and genetic susceptibility, anti-tTG titers correlated with histology. ESPGHAN criteria performed similarly to previous studies. However, a calculated 16 * ULN cutoff showed an improved PPV. Among prevalent assays, PPV peaked differently both after normalization and standardization, indicating intrinsic differences in performance, thus preventing uniform prediction of disease in a real-life setting. Assay-specific optimal cutoffs seem possible, but would complicate diagnostic criteria. However, biopsy sparing strategies in adults could prove useful in challenging patients. PMID- 28717845 TI - Proteomics in Inflammatory Bowel Disease: Approach Using Animal Models. AB - Recently, proteomics studies have provided important information on the role of proteins in health and disease. In the domain of inflammatory bowel disease, proteomics has shed important light on the pathogenesis and pathophysiology of inflammation and has contributed to the discovery of some putative clinical biomarkers of disease activity. By being able to obtain a large number of specimens from multiple sites and control for confounding environmental, genetic, and metabolic factors, proteomics studies using animal models of colitis offered an alternative approach to human studies. Our aim is to review the information and lessons acquired so far from the use of proteomics in animal models of colitis. These studies helped understand the importance of different proteins at different stages of the disease and unraveled the different pathways that are activated or inhibited during the inflammatory process. Expressed proteins related to inflammation, cellular structure, endoplasmic reticulum stress, and energy depletion advanced the knowledge about the reaction of intestinal cells to inflammation and repair. The role of mesenteric lymphocytes, exosomes, and the intestinal mucosal barrier was emphasized in the inflammatory process. In addition, studies in animal models revealed mechanisms of the beneficial effects of some therapeutic interventions and foods or food components on intestinal inflammation by monitoring changes in protein expression and paved the way for some new possible inflammatory pathways to target in the future. Advances in proteomics technology will further clarify the interaction between intestinal microbiota and IBD pathogenesis and investigate the gene-environmental axis of IBD etiology. PMID- 28717846 TI - Effects of Xylitol and Sucrose Mint Products on Streptococcus mutans Colonization in a Dental Simulator Model. AB - Few laboratory methods exist for evaluating the cariogenicity of food ingredients. In this study, a dental simulator was used to determine the effects of commercial sucrose and xylitol mint products on the adherence and planktonic growth of Streptococcus mutans. Solutions (3% w/v) of sucrose, xylitol, sucrose mints, xylitol mints, xylitol with 0.02% peppermint oil (PO), and 0.02% PO alone were used to test the levels of planktonic and adhered S. mutans. A dental simulator with continuous artificial saliva flow, constant temperature, and mixing was used as a test environment and hydroxyapatite (HA) discs were implemented into the model to simulate the tooth surface. Bacterial content was quantified by qPCR. Compared with the artificial saliva alone, sucrose and sucrose mints increased the numbers of HA-attached S. mutans, whereas xylitol decreased them. Similarly, planktonic S. mutans quantities rose with sucrose and declined with xylitol and xylitol mints. Versus sucrose mints, xylitol mints significantly reduced the counts of HA-bound and planktonic S. mutans. Similar results were observed with the main ingredients of both types of mints separately. PO-supplemented artificial saliva did not influence the numbers of S. mutans that attached to HA or planktonic S. mutans compared with artificial saliva control. In our dental simulator model, xylitol reduced the counts of adhering and planktonic S.mutans. The mints behaved similarly as their pure, main ingredients-sucrose or xylitol, respectively. PO, which has been suggested to have antimicrobial properties, did not influence S. mutans colonization. PMID- 28717848 TI - New Identification of Three or More Campylobacter Species on the Basis of a Degenerate PCR-RFLP Method Targeting gyrB Gene. AB - This method was aimed targeting more Campylobacter species than conventional PCR based identifications. They generally use species-specific primers focusing on clinically common species like C. jejuni, resulting in failure to recognize other species. We made the PCR-based identification more flexible using degenerate primers and DdeI- and MboI-separately used RFLP assay, which were designed on the basis of gyrB nucleotide sequence data of 14 Campylobacter species including C. jejuni, C. coli, and C. fetus. Ninety-four clinical isolates from patients with Campylobacter gastroenteritis and 13 biochemically identified C. fetus were used for its evaluation. In consequence, this method succeeded in identifying C. jejuni, C. coli, and C. fetus with tentative sensitivity (93.4-98.0%) and specificity (89.0-99.0%). According to our data-based analysis, the primers can possibly target other related species including Helicobacter and Arcobacter. This method may be a universal identification for Campylobacter and related organisms and would provide an alternative identification in clinical microbiology. PMID- 28717847 TI - Exploring the Genomic Diversity and Cariogenic Differences of Streptococcus mutans Strains Through Pan-Genome and Comparative Genome Analysis. AB - Pan-genome refers to the sum of genes that can be found in a given bacterial species, including the core-genome and the dispensable genome. In this study, the genomes from 183 Streptococcus mutans (S. mutans) isolates were analyzed from the pan-genome perspective. This analysis revealed that S. mutans has an "open" pan genome, implying that there are plenty of new genes to be found as more genomes are sequenced. Additionally, S. mutans has a limited core-genome, which is composed of genes related to vital activities within the bacterium, such as metabolism and hereditary information storage or processing, occupying 35.6 and 26.6% of the core genes, respectively. We estimate the theoretical core-genome size to be about 1083 genes, which are fewer than other Streptococcus species. In addition, core genes suffer larger selection pressures in comparison to those that are less widely distributed. Not surprisingly, the distribution of putative virulence genes in S. mutans strains does not correlate with caries status, indicating that other factors are also responsible for cariogenesis. These results contribute to a more understanding of the evolutionary characteristics and dynamic changes within the genome components of the species. This also helps to form a new theoretical foundation for preventing dental caries. Furthermore, this study sets an example for analyzing large genomic datasets of pathogens from the pan-genome perspective. PMID- 28717849 TI - An assessment of benzimidazole resistance against caprine nematodes in Central India. AB - Current status of resistance to benzimidazole (BZ) group of anthelmintic drugs against caprine nematodes in Central India at Amanala goat farm, Jabalpur, Madhya Pradesh (M. P.), was systematically investigated using faecal egg count reduction (FECR) test and egg hatch test (EHT). Besides, allele-specific PCR (AS-PCR) was deployed to ascertain the susceptible genotype (alleles) especially of the Haemonchus contortus. Randomly selected 30 goats, irrespective of age and sex, were divided into three groups of 10 each, to serve as treated and untreated controls. It was ensured that the animals were not administered with an anthelmintic drug for the past 3 months prior to undertaking the study, and faecal egg counts were estimated. FECR test evidenced fenbendazole resistance by partial elimination (24.90%) copro-egg counts in the treated group of animals vis a-vis controls with a lower confidence interval of -26%. Further, EHT revealed ED 50 value of 0.335 MUg of thiabendazole/ml, confirming benzimidazole resistance in the animals of that farm. AS-PCR showed that 62% of H. contortus larvae were homozygous resistant (rr), 24% heterozygous (rS) and 14% homozygous susceptible (SS). The genotypic frequencies of three genotypes (rr, rS and SS) were significantly (P < 0.01) different. The prevalence of benzimidazole resistance allele (r) was also significantly (P < 0.01) higher (74%) as compared to susceptible allele (S) (26%). The resistance to benzimidazole has been discussed while emphasizing improved managemental practices designed to reduce exposure of the goat population to parasites, minimize frequency of anthelmintic use at optimum dose and rotational use of different chemical groups of medicines with different mode of action, so as to overcome and combat the upcoming problem in the field. PMID- 28717850 TI - Physio-biochemical parameters: a potential tool for target-selective treatment of haemonchosis in the small ruminants. AB - This study aims to evaluate the conjunctiva colour-based FAMACHA score (FS) coupled with a body condition score (BCS), haemogram and stressor hormone level estimation, in identifying post-mortem (PM)/coproscopically proven individuals wanting therapy for economically important gastrointestinal (GI) helminths, Haemonchus contortus, in the small ruminants. The incidence of haemonchosis was significantly (p < 0.05) higher (60.81%) in the ruminants with FS = 3. The H. contortus count in the animals with FS 2, 3 and 4 was 23.2 +/- 0.37, 62 +/- 2.5 and 74 +/- 3.2 (p < 0.05) [positive correlation (r = 0.841 in goats; r = 0.828 in sheep, p < 0.05)], respectively, with corresponding 2.8 +/- 0.15, 2 +/- 0.3 and 2 +/- 0.16 BCS (negative correlation, p > 0.05). The infected animals of FS 2, 3 and 4 measured 8.2 +/- 0.0, 7.5 +/- 0.23 and 6.7 +/- 0.34 g/dl Hb (r = -0.452, p = 0.01) in goats/9.3 +/- 0.8, 8.6 +/- 0.5 and 7.6 +/- 0.3 g/dl Hb (r = -0.511, p = 0.05) in sheep with 21.2, 19.8 +/- 1.8 and 17.8 +/- 0.2% PCV (r = -0.369, p = 0.05) in goats/26.7 +/- 1.2, 22.2 +/- 0.2 and 20.9 +/- 0.6% PCV (r = -0.251, p = 0.03) in sheep, respectively. The FS 2, 3 and 4 infected goats/sheep measured 6.1 +/- 0, 7.9 +/- 1.0 and 9.5 +/- 0.9 (p < 0.05)/5.8 +/- 2.3, 6.9 +/- 1.2 and 7.8 +/ 0.2% (p < 0.05) mid-granulocyte [(r = 0.928 (goats)/0.834 (sheep), p < 0.05], while the cortisol level was 15.6, 23 +/- 4.5 and 42 +/- 2.3 (p = 0.23)/12.1 +/- 0, 15.9 +/- 1.2 and 24 +/- 3.4 (p = 0.29) MUg/dl, respectively. The infected ruminants recorded low (p < 0.05) level of Hb/PCV while high level of mid granulocytes/cortisol. Specificity of FAMACHA test was maximized (100%) when FS = 4 was considered anaemic, but sensitivity was low (35.29% in goats; 25% in sheep). The false negatives was 5.9 (goat)/12.5 (sheep)% when FS >= 3 was considered anaemic. The small ruminants with FS >= 3, BCS <= 2.5, Hb <= 7.5 g/dl (goats)/8.6 g/dl (sheep), PCV <= 19.8% (goats)/22.2% (sheep) and mid-granulocyte >=7.9% (goats)/6.9 +/- 1.2% (sheep) can be subjected to target-selective treatment for haemonchosis in the field simultaneously maximizing the economic benefit to the farmers. PMID- 28717851 TI - Multidrug-resistant Salmonellae isolated in Japanese quails reared in Abeokuta, Nigeria. AB - Salmonellosis is a major bacterial disease causing huge economic losses in the poultry industry worldwide. This study was carried out to determine the period prevalence and antimicrobial susceptibility of Salmonella enterica in Japanese quails in Abeokuta, Nigeria. Four hundred cloacal swabs of quail birds were collected from 4 locations within Abeokuta. Salmonella was isolated from the samples using conventional methods for selective isolation of Salmonella and biochemical identification. Isolates were confirmed by polymerase chain reaction assays for the amplification and detection of Salmonella-associated virulence genes (invA and stn) using specific primers. Antimicrobial susceptibility testing was done using the Kirby-Bauer disk diffusion method. In all, Salmonella was isolated from 14 (3.5%) cloacal swabs. All 14 isolates possessed invA and stn genes. The Salmonella isolates showed resistance to tetracycline (100%), doxycycline (100%), ampicillin (100%), sulphamethoxazole (92.9%), nalidixic acid (85.8%), ceftazidime (78.6%), neomycin (64.3%), streptomycin (50%) and gentamycin (28.6%) but all the isolates were susceptible to ciprofloxacin. The isolates were resistant to at least three antimicrobials indicating multidrug resistance. The results concluded that Japanese quails harbour multidrug-resistant Salmonella which could be transmitted to humans through consumption of contaminated food or by direct and indirect contact with the carrier birds. Antimicrobial resistance could be due to overdependence on antimicrobials. Ciprofloxacin could be considered in the treatment of zoonotic Salmonellosis in humans. PMID- 28717852 TI - Elevated S100A8 protein expression in breast cancer cells and breast tumor stroma is prognostic of poor disease outcome. AB - PURPOSE: Elevated S100A8 expression has been observed in cancers of the bladder, esophagus, colon, ovary, and breast. S100A8 is expressed by breast cancer cells as well as by infiltrating immune and myeloid cells. Here we investigate the association of elevated S100A8 protein expression in breast cancer cells and in breast tumor stroma with survival outcomes in a cohort of breast cancer patients. PATIENTS AND METHODS: Tissue microarrays (TMA) were constructed from breast cancer specimens from 417 patients with stage I-III breast cancer treated at the University of Michigan Comprehensive Cancer Center between 2004 and 2006. Representative regions of non-necrotic tumor and distant normal tissue from each patient were used to construct the TMA. Automated quantitative immunofluorescence (AQUA) was used to measure S100A8 protein expression, and samples were scored for breast cancer cell and stromal S100A8 expression. S100A8 staining intensity was assessed as a continuous value and by exploratory dichotomous cutoffs. Associations between breast cancer cell and stromal S100A8 expression with disease-free survival and overall survival were determined using the Kaplan-Meier method and Cox proportional hazard models. RESULTS: High breast cancer cell S100A8 protein expression (as indicated by AQUA scores), as a continuous measure, was a significant prognostic factor for OS [univariable hazard ratio (HR) 1.24, 95% confidence interval (CI) 1.00-1.55, p = 0.05] in this patient cohort. Exploratory analyses identified optimal S100A8 AQUA score cutoffs within the breast cancer cell and stromal compartments that significantly separated survival curves for the complete cohort. Elevated breast cancer cell and stromal S100A8 expression, indicated by higher S100A8 AQUA scores, significantly associates with poorer breast cancer outcomes, regardless of estrogen receptor status. CONCLUSIONS: Elevated breast cancer cell and stromal S1008 protein expression are significant indicators of poorer outcomes in early stage breast cancer patients. Evaluation of S100A8 protein expression may provide additional prognostic information beyond traditional breast cancer prognostic biomarkers. PMID- 28717853 TI - Radiation-related heart disease after breast cancer radiation therapy in Korean women. AB - PURPOSE: To study the late cardiac toxicity of breast radiation therapy (RT) in Asian women. METHODS: Female breast cancer patients in Korea who underwent breast conservation surgery followed by RT from 1990-2012 were identified from two large registries at institution and population levels. Cumulative incidences of acute coronary events (ACE) or cardiac mortality were estimated in relation to the laterality of breast cancer using a competing risks analysis. RESULTS: In an analysis of 2577 women from a single institution, 3.7% were obese (body mass index >=30), and 3.4% were ever-smokers. Patients with a history of hypertension, diabetes, or coronary artery disease were 17.5, 5.7, and 2.8%, respectively. The mean heart doses were 6.2 and 1.5 Gy for left- and right-sided tumors, respectively. With a median follow-up of 7 (range 1-23) years, the overall and breast cancer-specific survivals at 10 years were 94.9 and 96.5%, respectively. The 10-year cumulative incidence of ACE was 2.96%. The mean time to ACE was 5.2 +/- 3.9 years (range 1-17). There was no clinically relevant difference in rates of ACE between left-sided and right-sided patients, with an adjusted hazard ratio of 1.16 (CI 0.59-2.29). An analysis of 24,235 women in a nationwide registry validated these negative findings with respect to cardiac mortality, with an adjusted hazard ratio of 1.52 (CI 0.37-6.25). Increasing age, a higher body mass index, and a history of hypertension or ischemic heart disease were identified as risk factors. CONCLUSIONS: Our findings reassure that excess risk from breast RT may be small in healthy women, most of who not smoke, weigh less, and have fewer risk factors. A validation using a larger data set of National Health Insurance Corporation is ongoing. PMID- 28717854 TI - Pharmaceutically treated anxiety but not depression prior to cancer diagnosis predicts the onset of cardiovascular disease among breast cancer survivors. AB - PURPOSE: To examine the associations between pharmaceutically treated anxiety and depression present in the year prior to breast cancer diagnosis and the risk of incident cardiovascular disease (CVD), while controlling for traditional cardiovascular risk factors and clinical characteristics in a population-based observational study. METHODS: Adult 1-year breast cancer survivors (n = 7227), diagnosed between 01-01-1999 and 12-31-2010, with no history of CVD, were selected from the Netherlands Cancer Registry. Drug dispensing data were derived from the PHARMO Database Network and used as proxy for CVD, anxiety, and depression. By multivariable Cox regression analysis, we examined the risk associated with pharmaceutically treated anxiety and depression for developing CVD after cancer diagnosis, adjusting for age, pharmaceutically treated hypertension, hypercholesterolemia, and diabetes mellitus in the year prior to cancer diagnosis, tumor stage, and cancer treatment. RESULTS: During the 13-year follow-up period, 193 (3%) breast cancer survivors developed CVD. Women pharmaceutically treated for anxiety in the year prior to their cancer diagnosis had a 48% increased hazard for CVD [HR = 1.48; 95% CI 1.05-1.08] after full adjustment. This association was restricted to breast cancer survivors who were 65 years or younger. Depression was not associated with CVD risk [HR = 0.89; 95% CI 0.52-1.53]. Older age [HR = 1.06; 95% CI 1.05-1.08], hypertension [HR = 1.80; 95% CI 1.32-2.46], and hypercholesterolemia [HR = 1.63; 95% CI 1.15-2.33] were associated with an increased hazard for incident CVD, whereas hormone therapy [HR = 0.59; 95% CI 0.42-0.83] was protective. CONCLUSIONS: Anxiety present in the year prior to breast cancer diagnosis increases the risk of incident CVD in 1 year breast cancer survivors, after adjustment for depression, traditional cardiovascular risk factors, and clinical characteristics. PMID- 28717856 TI - Intraoperative radiotherapy for extremity soft-tissue sarcomas: can long-term local control be achieved? AB - BACKGROUND: Intraoperative electron-beam radiation therapy (IOERT) during limb sparing surgery has the advantage of delivering a single high boost dose to sarcoma residues and surgical bed area near to radiosensitive structures with limited toxicity. Retrospective studies have suggested that IOERT may improve local control compared to standard radiotherapy and we aimed to demonstrate this theory. Therefore, we performed an observational prospective study to determine (1) if it is possible to achieve high local control by adding IOERT to external beam radiation therapy (EBRT) in extremity soft-tissue sarcomas (STS), (2) if it is possible to improve long-term survival rates, and (3) if toxicity could be reduced with IOERT MATERIALS AND METHODS: From 1995-2003, 39 patients with extremity STS were treated with IOERT and postoperative radiotherapy. The median follow-up time was 13.2 years (0.7-19). Complications, locoregional control and survival rates were collected. RESULTS: Actuarial local control was attained in 32 of 39 patients (82%). Control was achieved in 88% of patients with primary disease and in 50% of those with recurrent tumors (p = 0.01). Local control was shown in 93% of patients with negative margins and in 50% of those with positive margins (p = 0.002). Limb-sparing was achieved in 32 patients (82%). The overall survival rate was 64%. 13% of patients had grade >=3 acute toxicity, and 12% developed grade >=3 chronic toxicity. CONCLUSION: IOERT used as a boost to EBRT provides high local control and limb-sparing rates in patients with STS of the extremities, with less toxicity than EBRT alone. PMID- 28717857 TI - Concordance of HPV load and HPV mRNA for 16 carcinogenic/possibly carcinogenic HPV types in paired smear/tissue cervical cancer specimens. AB - HPV types with high viral load are associated with cervical abnormalities. However, viral load measurements and concordance of HPV loads and viral mRNA have not been demonstrated for all high-risk/possibly high-risk (HR-/pHR-)HPV types in cervical cancer (CxCa). Especially, the biological role of co-infecting HR-/pHR HPV types with low viral load has not been thoroughly investigated. Using BSGP5+/6+-PCR/MPG genotyping, we analyzed viral loads for all currently defined 51 mucosal HPV types in 74 cervical smears from patients with CxCa and compared this data with HPV DNA and mRNA status in these patients' corresponding CxCa tissues. All cervical smear/tissue pairs were HPV DNA+. Overall HPV type agreement within pairs was 99% (complete agreement in 50%, partial agreement in 49%, and complete disagreement in 1% of cases). The proportion of multiple HPV types was significantly higher in smears compared to tissues (p<0.0001). High load HPV infections (>1 copy/cell) were found in 88% of HPV DNA+ smears, and were significantly associated with the presence of respective HPV DNA (kappa=0.685, CI: 0.567-0.803), and HPV mRNA (kappa=0.693, CI: 0.566-0.820) in CxCa tissues. In total, 93% (67/72) of high load HR-/pHR-HPV infections identified in smears were also present in corresponding CxCa tissues, and 93% (62/67) of these were HPV mRNA+. On the other hand, 78% (42/54) of low load HR-/pHR-HPV infections identified in smears were not detectable in tissues, including 11 out of 15 low load HPV16 infections. This data demonstrates that the presence of high HPV loads in CxCa smears predicts biologically active HR-/pHR-HPV types in tumor tissues. PMID- 28717855 TI - Esophageal stenosis and the Glasgow Prognostic Score as independent factors of poor prognosis for patients with locally advanced unresectable esophageal cancer treated with chemoradiotherapy (exploratory analysis of JCOG0303). AB - BACKGROUND: The aim of this study was to investigate the possible prognostic factors and predictive accuracy of the Glasgow Prognostic Score (GPS) for patients with unresectable locally advanced esophageal squamous cell carcinoma (LAESCC) treated with chemoradiotherapy. METHODS: One hundred forty-two patients were enrolled in JCOG0303 and assigned to the standard cisplatin and 5 fluorouracil (PF)-radiotherapy (RT) group or the low-dose PF-RT group. One hundred thirty-one patients with sufficient data were included in this analysis. A Cox regression model was used to analyze the prognostic factors of patients with unresectable LAESCC treated with PF-RT. The GPS was classified based on the baseline C-reactive protein (CRP) and serum albumin levels. Patients with CRP <=1.0 mg/dL and albumin >=3.5 g/dL were classified as GPS0. If only CRP was increased or only albumin was decreased, the patients were classified as GPS1, and the patients with CRP >1.0 mg/dL and albumin <3.5 g/dL were classified as GPS2. RESULTS: The patients' backgrounds were as follows: median age (range), 62 (37-75); male/female, 119/12; ECOG PS 0/1/2, 64/65/2; and clinical stage (UICC 5th) IIB/III/IVA/IVB, 3/75/22/31. Multivariable analyses indicated only esophageal stenosis as a common factor for poor prognosis. In addition, overall survival tended to decrease according to the GPS subgroups (median survival time (months): GPS0/GPS1/GPS2 16.1/14.9/8.7). CONCLUSIONS: Esophageal stenosis was identified as a candidate stratification factor for randomized trials of unresectable LAESCC patients. Furthermore, GPS represents a prognostic factor for LAESCC patients treated with chemoradiotherapy. CLINICAL TRIAL INFORMATION: UMIN000000861. PMID- 28717858 TI - Complete nucleotide sequence of a novel bovine viral diarrhea virus subtype 1 isolate from Italy. AB - To gain further insight into the genomic features of bovine viral diarrhea virus 1 (BVDV-1) subtypes, we sequenced the complete genome of the BVDV-1 isolate VE/245/12. This is an uncommon subtype that was isolated from a persistently infected animal. Here, we report the complete genome sequence, consisting of 12,295 nucleotides (nt) with an open reading frame of 11,694 nt encoding 3,898 amino acids. Phylogenetic analysis of the full-length genome, 5'-UTR, and Npro region confirmed that the BVDV-1 isolate differed significantly from all of the bovine pestiviruses identified so far, providing evidence for the presence of a distinct novel genetic group. PMID- 28717859 TI - Estimated Costs of Clinical and Surgical Treatment of Severe Obesity in the Brazilian Public Health System. AB - BACKGROUND: Obesity is a major global epidemic and a burden to society and health systems. This study aimed to estimate and compare the anual costs of clinical and surgical treatment of severe obesity from the perspective of the Brazilian Public Health System. METHODS: An observational and cross-sectional study was performed in three reference centers. Data collection on health resources utilization and productivity loss was carried out through an online questionnaire. Participants were divided in clinical (waiting list for a bariatric surgery) and surgical groups (open Roux-en-Y gastric bypass), and then allocated by the time of surgery (up to 1 year; 1-2 years; 2-3 years; and >3 years). Costs of visits, medications, exams, and surgeries were obtained from government sources. Data on non-medical costs, such as transportation, special diets, and caregivers, were also colleted. Productivity loss was estimated using self-reported income. Costs in local currency (Real) were converted to international dollars (Int$ 2015). RESULTS: Two hundred and seventy-four patients, 140 in surgical group and 134 in clinical group were included. In first postoperative year, the surgical group had higher costs than clinical group (Int$6005.47 [5000.18-8262.36] versus 2148.14 [1412.2 3506.8]; p = 0.0002); however, from the second year, the costs decreased progressively. In the same way, indirect costs decreased significantly after surgery (259.08 [163.63-662.72] versus 368.17 [163.62-687.27]; p = 0.06). CONCLUSION: Total costs were higher in the surgical group in the first 2 years after surgery. However, from the third year on, the costs were lower than in the clinical group. PMID- 28717860 TI - Performance of the DiaRem Score for Predicting Diabetes Remission in Two Health Systems Following Bariatric Surgery Procedures in Hispanic and non-Hispanic White Patients. AB - OBJECTIVE: The objective of this study was to determine whether the DiaRem, a score that predicts type 2 diabetes (T2D) remission following roux-en-y gastric bariatric surgery (RYGB), also predicts remission following laparoscopic adjustable gastric banding (LAGB) and laparoscopic sleeve gastrectomy (LSG) in white and Hispanic patients. BACKGROUND: While bariatric surgery is highly effective in reversing insulin resistance, there are patients for whom surgery will not lead to remission. To date, there is no score for predicting remission following LAGB or LSG surgery. Additionally, there is little known about how to predict whether Hispanic patients will experience remission. METHODS: We conducted a retrospective cohort study of white and Hispanic patients with T2D who received bariatric surgery. There were 361 white and 130 Hispanic patients among whom 328 had RYGB surgery, 107 had LSG surgery, and 56 had LAGB surgery. We used age, diabetes treatment, and hemoglobin A1c to calculate DiaRem scores. Mann Whitney U test was used to determine the association between DiaRem scores and remission. Area under the receiver operant curve (AUC) was used to assess the ability of the DiaRem to discriminate between patients who did and did not remit. RESULTS: The DiaRem was associated with partial remission in all surgery types for white and Hispanic patients (Mann-Whitney, p < 0.001). The DiaRem had moderate to high discriminant ability (AUC > 0.70) for all surgical and racial/ethnic groups. CONCLUSIONS: The DiaRem distinguishes between patients likely and unlikely to experience remission, informing expectations of patients making T2D treatment decisions. PMID- 28717861 TI - Patient Perspectives on Gene Transfer Therapy for Sickle Cell Disease. AB - INTRODUCTION: Sickle cell disease (SCD) is a chronic genetic disease with high morbidity and early mortality; it affects nearly 100,000 individuals in the USA. Bone marrow transplantation, the only curative treatment, is available to less than 20% of patients because of a number of access barriers. Gene transfer therapy (GTT) has been shown to be curative in animal models and is approved for use in humans for early-phase studies at a few centers. GTT would offer a more accessible treatment option available to all patients. It is important to understand patient perspectives on GTT to help ensure human clinical trial success. METHODS: Two focus groups were conducted with younger (18-30 years) and older (31 years and older) adults with SCD to obtain data on patient knowledge and beliefs about GTT. Data from these two focus groups was used to develop a GTT educational brochure. A third focus group was conducted to obtain participant feedback on acceptability and feasibility of education and the brochure. RESULTS: Most adults, especially young adults, had little knowledge about GTT and expressed fear and uncertainty about the side effects of chemotherapy (e.g., hair loss, infertility), use of a human immunodeficiency virus (HIV)-derived viral vector, and potential for cancer risk. Participants wanted full transparency in educational materials, but advised researchers not to share the vector's relation to HIV because of cultural stigma and no HIV virus is used for the GTT vector. CONCLUSION: Older adults had more desire to participate in human clinical GTT trials than younger participants. When recruiting for trials, researchers should develop GTT educational materials that address participant lack of trust in the healthcare system, cultural beliefs, fears related to side effects, and include visual illustrations. Use of such materials will provide adults with SCD the information they need to fully evaluate GTT. PMID- 28717863 TI - Global Mental Health and Adolescent Anxiety: Kin, Care and Struggle in New Mexico. AB - While recent developments within the field of global mental health have illuminated the reality of serious mental health difficulties worldwide, particularly in low-income settings, research that focuses on children and adolescents remains underdeveloped. This is especially the case with respect to ethnographic studies of lived experience of adolescents diagnosed with serious mental health conditions. Drawing from an interdisciplinary study of adolescents in New Mexico who were afflicted with a broad range of disorders according to contemporary research diagnostic criteria, this article focuses on anxiety related conditions with respect to subjective experience and social-ecological contexts of living with such conditions. We offer preliminary observations regarding the value of linking ethnographic and research diagnostic data to address questions of resilience, endurance, capacity and struggle. These observations are intended as the basis for the formulation of more precise hypotheses about adolescent anxiety, kin, and care under conditions of structural violence marked by psychological, residential, and intergenerational adversity. PMID- 28717862 TI - Practical Considerations for the Use of Subcutaneous Treatment in the Management of Dyslipidaemia. AB - Suboptimal drug adherence represents a major challenge to effective primary and secondary prevention of cardiovascular disease. While adherence is influenced by multiple considerations, polypharmacy and dosing frequency appear to be rate limiting factors in patient satisfaction and subsequent adherence. The cardiovascular and metabolic therapeutic areas have recently benefited from a number of advances in drug therapy, in particular protease proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and incretin-based therapies, respectively. These drugs are administered subcutaneously and offer efficacious treatment options with reduced dosing frequency. Whilst patients with diabetes and diabetologists are well initiated to injectable therapies, the cardiovascular therapeutic arena has traditionally been dominated by oral agents. It is therefore important to examine the practical aspects of treating patients with these new lipid-lowering agents, to ensure they are optimally deployed in everyday clinical practice. PMID- 28717864 TI - Diagnosing developmental dysplasia of the hip using the Graf ultrasound method: risk and protective factor analysis in 11,820 universally screened newborns. AB - : The essential role of ultrasound examinations in diagnosis and treatment of developmental dysplasia of the hip (DDH) is widely accepted while the weighting and correlation of protective factors and perinatal risk for DDH still give rise to debate. Our aim was to investigate the impact of single and twofold combined risk and protective factors on the newborns' hip maturity, assessed with the Graf ultrasound method. Therefore, data sets of 11,820 universally screened newborns were analyzed. Univariate and logistic regression analyses were performed to correlate risk and protective factors with mature or immature but appropriate for age and pathologic hip types. Thereby, female gender (OR 4.07 (95% CI 3.01-5.51), p < 0.001), breech presentation (4.98 (3.71-6.71), p < 0.001), and positive family anamnesis (5.05 (3.49-7.31), p < 0.001) as well as the combination of female gender with high birth weight (3.51 (2.45-5.03), p < 0.001) could be identified as independent predictive risk factors. Only low birth weight (0.27 (0.11-0.66), p = 0.004) could be identified as a single protective factor, while no combination of protective factors was significant. CONCLUSION: The significance and the informative value of risk and protective factor combinations, e.g., for selective ultrasound surveys, are limited. Early universal ultrasound screening using the Graf method is advised to timely detect hip immaturity and pathologies and to provide the optimal approach for mature or immature but appropriate for age and pathologic hips. What is Known: * Ultrasound screening is essential for diagnosis and treatment of DDH in time while the weighting and correlation of protective factors and perinatal risk and their role for the ultrasound screening protocol still give rise to debate. What is New: * The effects of single risk and protective factors for DDH do not cumulate or counteract, resulting in a limited value of a selective screening protocol based on risk and protective factors. * A universal screening protocol using the Graf ultrasound method is recommended. PMID- 28717865 TI - Heavy metal concentrations in water and soil along the Hun River, Liaoning, China. AB - Water and soil samples were collected along the Hun River to study the concentrations of Cr, Cu and Zn during the dry season, medium season and wet season in 2013. The concentrations of Cr, Cu, and Zn in Hun River were 0.0010 to 0.1298, 0.0057 to 0.1533 and 0.0162 to 0.5004 mg/L, respectively. The concentrations of Cr, Cu, and Zn in soil from around the Dahuofang reservoir were 0.0033 to 0.2149, 0.0054 to 0.2218 and 0.0135 to 0.3544 mg/g, respectively. The results indicated that the concentrations of Cr, Cu and Zn in water from the Hun River and soil from around the Dahuofang reservoir were significantly different at different sample stations and seasons. The pollution indexes of Cr, Cu and Zn in water and soil along the Hun River were calculated using principal component analysis in order to enact future measures against heavy metal pollution. According to the pollution characteristics of heavy metals along the Hun River, a treatment strategy was formulated to provide a scientific basis for the prevention and control of heavy metal pollution along the Hun River. PMID- 28717867 TI - Totally laparoscopic living donor left hepatectomy for liver transplantation in a child. AB - BACKGROUND: Minimally invasive surgery has been validated to be a new standard in living donor hepatectomy for adult-to-pediatric transplantation with less morbidity [1]. Laparoscopic donor hepatectomy can reduce the major concerns about pain and morbidity associated with open surgery and a slow return to daily activities of donors [2]. Herein, we present one case of totally laparoscopic living donor left hepatectomy including the middle hepatic vein (MHV). DONOR AND METHOD: A 37-year-old mother volunteered to donate to her 3-year-old son with biliary atresia (PELD score 7). Total donor liver volume was 833 cm3 and left liver, including MHV, was 290 cm3. Graft to recipient body weight ratio was 2.07. Our operative technique has been published previously [2]. The left hepatic artery and portal vein were dissected and encircled with two vessel loops. Pringle's maneuver was used during parenchymal transection. The transection of the liver was performed using an alternating combination of laparoscopic ultrasonic aspirator (CUSA) and THUNDERBEATTM (Olympus, Japan). The MHV was identified and parenchymal transection was performed right side to it. Several small tributaries from segment V and VIII were identified and divided. Finally, left bile duct was identified and divided after performing intraoperative cholangiography using a mobile C-arm. RESULTS: Totally laparoscopic living donor left hepatectomy was performed successfully without intraoperative complications and transfusion. The operation time was 300 min, the estimated blood loss was less than 125 ml and Graft weight was 314 g. Oral intake was resumed on the first postoperative day (POD). On POD 4, CT scan showed no pathological findings. The patient was discharged on POD 8 without complications. CONCLUSION: The authors conclude that the laparoscopic living donor left hepatectomy is a safe and feasible procedure but should be performed in selected patients with a favorable anatomy. PMID- 28717866 TI - MiR-30a Positively Regulates the Inflammatory Response of Microglia in Experimental Autoimmune Encephalomyelitis. AB - Multiple sclerosis (MS) is a classical inflammatory demyelinating disease of the central nervous system (CNS). Microglia are the main resident immune cells in the CNS and are closely associated with the pathogenesis of MS. In the present study, we found that miR-30a was highly expressed in jellyfish-like microglia in chronic active lesions of MS patients, as well as in the microglia of mice with experimental autoimmune encephalomyelitis (EAE) at the chronic phase. In vitro, the conditioned supernatant of mouse microglia overexpressing miR-30a promoted the apoptosis of oligodendrocyte precursor cells (OPCs), and inhibited OPC differentiation. In vivo, overexpressing miR-30a in transplanted microglia exacerbated the progression of EAE. Overexpression and knock-down experiments in primary cultured mouse microglia showed that miR-30a increased the expression of IL-1beta and iNOS, which are pro-inflammatory, while inhibiting the expression of Ym-1 and CD206. Mechanistically, miR-30a inhibited the expression of Ppargc1b, which is the co-activator of peroxisome proliferator-activated receptor gamma, resulting in pro-inflammatory effects. Our work shows that miR-30a is an important regulator of the inflammatory response in microglia, and may be a promising therapeutic target for inflammatory diseases like MS in the CNS. PMID- 28717868 TI - Erratum to: EUS-guided gastroenterostomy is comparable to enteral stenting with fewer re-interventions in malignant gastric outlet obstruction. PMID- 28717869 TI - Transoral endoscopic thyroidectomy vestibular approach (TOETVA): indications, techniques and results. AB - INTRODUCTION: The Transoral Neck Surgery (TONS) Study Group was established at the 1st International Thyroid NOTES Conference in February 2016 with the intention of standardizing and refining thyroid NOTES techniques, including both transoral endoscopic and robotic thyroidectomy approaches. Herein, the authors report the modification of indications, preparation, and step-by-step explanations for operative techniques, as well as results and postoperative care for transoral endoscopic thyroidectomy vestibular approach (TOETVA). METHODS: Between February 2015 and December 2015, a total of 200 patients comprising 8 males (4%) and 192 females (96%) underwent TOETVA using 3 laparoscopic ports inserted at the oral vestibule. Of these patients, 111 presented with single thyroid nodules (55.5%), while 66 patients had multinodular goiters (33%), 12 had Graves' disease (6%) and 11 had papillary microcarcinoma (5.5%). The CO2 insufflation pressure was maintained at 6 mmHg. Each surgery was performed using laparoscopic instruments and ultrasonic devices. RESULTS: TOETVA was performed on 200 consecutive patients. No conversion to conventional open surgery was necessary. Average tumor size was 4.1 +/- 1.78 cm (1-10 cm). Median operative time was 97 +/- 40.5 min (45-300 min). Median blood loss was 30 +/- 46.25 mL (6 300 mL). Mean visual analog scale measurements were 2.41 +/- 2.04 (2-7), 1.17 +/- 1.4 (0-5), and 0.47 +/- 0.83 (0-3) on the first, second, and third days, respectively. Temporary hoarseness and hypoparathyroidism occurred in 8 patients (4%) and 35 patients (17.5%), respectively. No permanent hoarseness or hypoparathyroidism occurred. Mental nerve injury occurred in 3 patients (1.5%). One patient (0.5%) developed a post-operative hematoma that required open surgery. No infection was identified. CONCLUSION: TOETVA was shown to be safe and feasible with a reasonable surgical duration and minimal pain scores. This approach shows promise for those patients who are motivated to avoid a neck scar. PMID- 28717870 TI - Laparoscopic liver resections for hepatocellular carcinoma. Can we extend the surgical indication in cirrhotic patients? AB - BACKGROUND: Evidence on the value of laparoscopic liver resections (LLR) for hepatocellular carcinoma (HCC) and severe cirrhosis is still lacking. The aim of this study is to assess surgical and oncological outcomes of LLR in cirrhotic HCC patients. METHODS: The analysis included 403 LLR for HCC from seven European centres. 333 cirrhotic and 70 non-cirrhotic patients were compared. A matched comparison was performed between 100 Child-Pugh A and 25 Child-Pugh B patients. RESULTS: There was no difference in blood loss (250 vs. 250 mL, p 0.465) and morbidity (28.6 vs. 26.4%, p 0.473) between cirrhotics and non-cirrhotics, and liver-specific complications were similar (12.8 vs. 12%, p 0.924). The sub analysis revealed similar perioperative outcomes in either Child-Pugh A or B patients. Noteworthy, ascitis (11 vs. 12%, p 0.562) and liver failure (3 vs. 4%, p 0.595) were not different. ASA score (OR 1.76, p 0.034) and conversion (OR 2.99, p 0.019) were risk factors for major morbidity. Despite lower recurrence free survival in cirrhotics (43 vs. 55 months, p 0.034), overall survival was similar to non-cirrhotic patients (84 vs. 76.5, p 0.598). CONCLUSION: LLR for HCC appear equally safe in cirrhotic and non-cirrhotic patients, and the advantages can be witnessed in those with advanced cirrhosis. Severe comorbidities and conversion should be considered risk factors for complications-rather than the severity of cirrhosis and portal hypertension-when liver resection is performed laparoscopically. Such results may be of great interest to liver surgeons and hepatologists when deciding on the management of HCC within cirrhosis. PMID- 28717871 TI - Sleeve gastrectomy telementoring: a SAGES multi-institutional quality improvement initiative. AB - BACKGROUND: Sleeve gastrectomy is a relatively new procedure that developed as a result of rapid innovation in the field of bariatric surgery. As with any newly developed operation, there is a learning curve that potentially can be associated with higher morbidity. Real-time surgical mentoring reduces the learning curve effect but can be time intensive for the mentor. The aim of this initiative was to evaluate the feasibility, effectiveness, and satisfaction of surgical telementoring for laparoscopic sleeve gastrectomy. This is the first national specialty society effort to determine if the "remote presence" of an expert surgeon (mentor) can help practicing surgeons improve skills. METHODS: The experience of 15 surgical trainees (mentees) who performed laparoscopic sleeve gastrectomy under real-time telementoring by 7 mentors was reviewed. Telementoring was implemented using the Visitor1(r) remote presence system with two-way live audio and video communication. The receiving platform utilized a conventional laptop, iPad, or iPhone. The mentee followed a structured telementoring program including didactic learning, live case teleobservation, and telementoring of 2-3 cases. A survey on the quality of the telecommunication and effectiveness of the mentoring was performed by the mentor and mentee on a scale of "exceeded," "met," "almost met," or "failed to meet" expectations. The overall telementoring experience was rated on a scale of 1 for "poor" to 5 for "excellent." RESULTS: Based on the mentees' survey, the overall telementoring experience was rated as 4.8. Despite the mentees having experience with laparoscopic sleeve gastrectomy, most commented that the telementoring experience was an excellent educational tool and they learned some new techniques they plan to apply it in their practice. Based on the mentors' survey, the overall telementoring experience was rated as 4.7. All mentors stated that they were satisfied with the telementoring sessions and there were no unexpected intraoperative occurrences. There were some logistical limitations including difficulties in scheduling of cases or the delay of cases. CONCLUSIONS: Surgical instruction by telementoring was shown to be feasible, practical, and successful, and was highly rated in this study by both the mentors and mentees. The currently utilized telementoring platform is thus an effective educational tool that can facilitate acquisition of surgical skills and assist with the conventional on site surgical mentoring model. PMID- 28717872 TI - Stress-induced changes in miRNA biogenesis and functioning. AB - MicroRNAs (miRNAs) are small, noncoding RNAs that play key roles in the regulation of cellular homeostasis in eukaryotic organisms. There is emerging evidence that some of these processes are influenced by various forms of cellular stresses, including DNA damage, pathogen invasion or chronic stress associated with diseases. Many reports over the last decade demonstrate examples of stress induced miRNA deregulation at the level of transcription, processing, subcellular localization and functioning. Moreover, core miRNA biogenesis proteins and their interactions with partners can be selectively regulated in response to stress signaling. However, little is known about the role of isomiRs and the interactions of miRNA with non-canonical targets in the context of the stress response. In this review, we summarize the current knowledge on miRNA functions under various stresses, including chronic stress and miRNA deregulation in the pathogenesis of age-associated neurodegenerative disorders. PMID- 28717874 TI - Distinct functions of Crumbs regulating slit diaphragms and endocytosis in Drosophila nephrocytes. AB - Mammalian podocytes, the key determinants of the kidney's filtration barrier, differentiate from columnar epithelial cells and several key determinants of apical-basal polarity in the conventional epithelia have been shown to regulate podocyte morphogenesis and function. However, little is known about the role of Crumbs, a conserved polarity regulator in many epithelia, for slit-diaphragm formation and podocyte function. In this study, we used Drosophila nephrocytes as model system for mammalian podocytes and identified a conserved function of Crumbs proteins for cellular morphogenesis, nephrocyte diaphragm assembly/maintenance, and endocytosis. Nephrocyte-specific knock-down of Crumbs results in disturbed nephrocyte diaphragm assembly/maintenance and decreased endocytosis, which can be rescued by Drosophila Crumbs as well as human Crumbs2 and Crumbs3, which were both expressed in human podocytes. In contrast to the extracellular domain, which facilitates nephrocyte diaphragm assembly/maintenance, the intracellular FERM-interaction motif of Crumbs is essential for regulating endocytosis. Moreover, Moesin, which binds to the FERM binding domain of Crumbs, is essential for efficient endocytosis. Thus, we describe here a new mechanism of nephrocyte development and function, which is likely to be conserved in mammalian podocytes. PMID- 28717873 TI - Orchestration of H3K27 methylation: mechanisms and therapeutic implication. AB - Histone proteins constitute the core component of the nucleosome, the basic unit of chromatin. Chemical modifications of histone proteins affect their interaction with genomic DNA, the accessibility of recognized proteins, and the recruitment of enzymatic complexes to activate or diminish specific transcriptional programs to modulate cellular response to extracellular stimuli or insults. Methylation of histone proteins was demonstrated 50 years ago; however, the biological significance of each methylated residue and the integration between these histone markers are still under intensive investigation. Methylation of histone H3 on lysine 27 (H3K27) is frequently found in the heterochromatin and conceives a repressive marker that is linked with gene silencing. The identification of enzymes that add or erase the methyl group of H3K27 provides novel insights as to how this histone marker is dynamically controlled under different circumstances. Here we summarize the methyltransferases and demethylases involved in the methylation of H3K27 and show the new evidence by which the H3K27 methylation can be established via an alternative mechanism. Finally, the progress of drug development targeting H3K27 methylation-modifying enzymes and their potential application in cancer therapy are discussed. PMID- 28717875 TI - MAST-like protein kinase IREH1 from Arabidopsis thaliana co-localizes with the centrosome when expressed in animal cells. AB - MAIN CONCLUSION: The similarity of IREH1 (Incomplete Root Hair Elongation 1) and animal MAST kinases was confirmed; IREH1cDNA was cloned while expressing in cultured animal cells co-localized with the centrosome. In mammals and fruit flies, microtubule-associated serine/threonine-protein kinases (MAST) are strongly involved in the regulation of the microtubule system. Higher plants also possess protein kinases homologous to MASTs, but their function and interaction with the cytoskeleton remain unclear. Here, we confirmed the sequence and structural similarity of MAST-related putative protein kinase IREH1 (At3g17850) and known animal MAST kinases. We report the first cloning of full-length cDNA of the IREH1 from Arabidopsis thaliana. Recombinant GFP-IREH1 protein was expressed in different cultured animal cells. It revealed co-localization with the centrosome without influencing cell morphology and microtubule arrangement. Structural N-terminal region of the IREH1 molecule co-localized with centrosome as well. PMID- 28717876 TI - Structural and Ultrastructural Changes to Type I Spiral Ganglion Neurons and Schwann Cells in the Deafened Guinea Pig Cochlea. AB - Sensorineural hearing loss is commonly caused by damage to cochlear sensory hair cells. Coinciding with hair cell degeneration, the peripheral fibres of type I spiral ganglion neurons (SGNs) that normally form synaptic connections with the inner hair cell gradually degenerate. We examined the time course of these degenerative changes in type I SGNs and their satellite Schwann cells at the ultrastructural level in guinea pigs at 2, 6, and 12 weeks following aminoglycoside-induced hearing loss. Degeneration of the peripheral fibres occurred prior to the degeneration of the type I SGN soma and was characterised by shrinkage of the fibre followed by retraction of the axoplasm, often leaving a normal myelin lumen devoid of axoplasmic content. A statistically significant reduction in the cross-sectional area of peripheral fibres was evident as early as 2 weeks following deafening (p < 0.001, ANOVA). This was followed by a decrease in type I SGN density within Rosenthal's canal that was statistically significant 6 weeks following deafening (p < 0.001, ANOVA). At any time point examined, few type I SGN soma were observed undergoing degeneration, implying that once initiated, soma degeneration was rapid. While there was a significant reduction in soma area as well as changes to the morphology of the soma, the ultrastructure of surviving type I SGN soma appeared relatively normal over the 12-week period following deafening. Satellite Schwann cells exhibited greater survival traits than their type I SGN; however, on loss of neural contact, they reverted to a non-myelinating phenotype, exhibiting an astrocyte-like morphology with the formation of processes that appeared to be searching for new neural targets. In 6- and 12-week deafened cochlea, we observed cellular interaction between Schwann cell processes and residual SGNs that distorted the morphology of the SGN soma. Understanding the response of SGNs, Schwann cells, and the complex relationship between them following aminoglycoside deafening is important if we are to develop effective therapeutic techniques designed to rescue SGNs. PMID- 28717877 TI - Temporal Envelope Coding by Inferior Colliculus Neurons with Cochlear Implant Stimulation. AB - Modulations in temporal envelopes are a ubiquitous property of natural sounds and are especially important for hearing with cochlear implants (CIs) because these devices typically discard temporal fine structure information. With few exceptions, neural temporal envelope processing has been studied in both normal hearing (NH) and CI animals using only pure sinusoidal amplitude modulation (SAM) which poorly represents the diversity of envelope shapes contained in natural sounds because it confounds repetition rate and the width of each modulation cycle. Here, we used stimuli that allow independent manipulation of the two parameters to characterize envelope processing by inferior colliculus (IC) neurons in barbiturate-anesthetized cats with CIs. Specifically, the stimuli were amplitude modulated, high rate pulse trains, where the envelope waveform interleaved single cycles ("bursts") of a sinusoid with silent intervals. We found that IC neurons vary widely with respect to the envelope parameters that maximize their firing rates. In general, pure SAM was a relatively ineffective stimulus. The majority of neurons (60 %) preferred a combination of short bursts and low repetition rates (long silent intervals). Others preferred low repetition rates with minimal dependence on envelope width (17 %), while the remainder responded most strongly to brief bursts with lesser sensitivity to repetition rate (23 %). A simple phenomenological model suggests that a combination of inhibitory and intrinsic cellular mechanisms suffices to account for the wide variation in optimal envelope shapes. In contrast to the strong dependence of firing rate on envelope shape, neurons tended to phase lock precisely to the envelope regardless of shape. Most neurons tended to fire specifically near the peak of the modulation cycle, with little phase dispersion within or across neurons. Such consistently precise timing degrades envelope coding compared to NH processing of real-world sounds, because it effectively eliminates spike timing as a cue to envelope shape. PMID- 28717878 TI - The isolation of primary hepatocytes from human tissue: optimising the use of small non-encapsulated liver resection surplus. AB - Two-step perfusion is considered the gold standard method for isolating hepatocytes from human liver tissue. As perfusion may require a large tissue specimen, which is encapsulated and has accessible vessels for cannulation, only a limited number of tissue samples may be suitable. Therefore, the aim of this work was to develop an alternative method to isolate hepatocytes from non encapsulated and small samples of human liver tissue. Healthy tissue from 44 human liver resections were graded for steatosis and tissue weights between 7.8 and 600 g were used for hepatocyte isolations. Tissue was diced and underwent a two-step digestion (EDTA and collagenase). Red cell lysis buffer was used to prevent red blood cell contamination and toxicity. Isolated hepatocyte viability was determined by trypan blue exclusion. Western blot and biochemical analyses were undertaken to ascertain cellular phenotype and function. Liver tissue that weighed >=50 g yielded significantly higher (P < 0.01) cell viability than tissue <50 g. Viable cells secreted urea and displayed the phenotypic hepatocyte markers albumin and cytochrome P450. Presence of steatosis in liver tissue or intra hepatocellular triglyceride content had no effect on cell viability. This methodology allows for the isolation of viable primary human hepatocytes from small amounts of "healthy" resected liver tissue which are not suitable for perfusion. This work provides the opportunity to increase the utilisation of resection surplus tissue, and may ultimately lead to an increased number of in vitro cellular studies being undertaken using the gold-standard model of human primary hepatocytes. PMID- 28717879 TI - Comparison of the effect of activated or non-activated PRP in various concentrations on osteoblast and fibroblast cell line proliferation. AB - Platelet-rich plasma (PRP) contains growth factors which positively affect cell proliferation, cell differentiation, chemotaxis and intracellular matrix synthesis. All these processes are involved in wound healing and tissue regeneration; thus, PRP as a source of growth factors can be used in periodontal regenerative therapies. The purpose of the present study was to assess the effect of various concentrations of activated and non-activated PRP on proliferation of osteoblasts and fibroblasts in vitro. PRP was obtained from three healthy volunteers. 75, 50, 25, and 10% concentrations of f PRP were prepared by dilution in Dulbecco's modified Eagle's medium. In activated PRP groups, PRP concentrations were activated by adding calcium gluconate. Human gingival fibroblast (HGF) cell line and MG-63 (osteosarcoma) human osteoblast-like cell line were used in the study. The MTT proliferation assay was used to assess the effect of different types of PRP concentrates on proliferation of HGF and MG-63 cells, in 24, 48 and 72 h. After 24, 48, and 72 h, the proliferation rate of both cell lines was higher in the positive control group, except in 72 h in HGF cell lines, that 10% non-activated PRP group and 10 and 25% activated PRP groups has higher proliferation rate than the positive control group, which it was not significant. Proliferation rate in cells with 10% activated PRP was highest among samples containing PRP. The current study failed to show the significant effect of activated or non-activated PRP on proliferation of HGFs or MG-63 osteoblast like cells. However, our results showed that activated PRP had a greater effect than non-activated PRP. PMID- 28717880 TI - Environmental exposure does not explain putative maladaptation in road-adjacent populations. AB - While the ecological consequences of roads are well described, little is known of their role as agents of natural selection, which can shape adaptive and maladaptive responses in populations influenced by roads. This knowledge gap persists despite a growing appreciation for the influence of evolution in human altered environments. There, insights indicate that natural selection typically results in local adaptation. Thus, populations influenced by road-induced selection should evolve fitness advantages in their local environment. Contrary to this expectation, wood frog tadpoles from roadside populations show evidence of a fitness disadvantage, consistent with local maladaptation. Specifically, in reciprocal transplants, roadside populations survive at lower rates compared to populations away from roads. A key question remaining is whether roadside environmental conditions experienced by early stage embryos induce this outcome. This represents an important missing piece in evaluating the evolutionary nature of this maladaptation pattern. Here, I address this gap using a reciprocal transplant experiment designed to test the hypothesis that embryonic exposure to roadside pond water induces a survival disadvantage. Contrary to this hypothesis, my results show that reduced survival persists when embryonic exposure is controlled. This outcome indicates that the survival disadvantage is parentally mediated, either genetically and/or through inherited environmental effects. This result suggests that roadside populations are either truly maladapted or potentially locally adapted at later life stages. I discuss these interpretations, noting that regardless of mechanism, patterns consistent with maladaptation have important implications for conservation. In light of the pervasiveness of roads, further resolution explaining maladaptive responses remains a critical challenge in conservation. PMID- 28717882 TI - Taiwan: Pioneer of the Health and Well-Being of Sexual Minorities in Asia. PMID- 28717881 TI - A retrospective comparison of inhaled milrinone and iloprost in post-bypass pulmonary hypertension. AB - During cardiac operations, weaning from cardiopulmonary bypass (CPB) may prove challenging as a result of superimposed acute right ventricular dysfunction in the setting of elevated pulmonary vascular resistance (PVR). The aim of this study was to retrospectively evaluate the effect of inhaled milrinone versus inhaled iloprost in patients with persistent pulmonary hypertension following discontinuation of CPB. Eighteen patients with elevated PVR post-bypass were administered inhaled milrinone at a cumulative dose of 50 MUg kg-1. These patients were retrospectively matched with 18 patients who were administered 20 MUg of inhaled iloprost. Both drugs were administered through a disposable aerosol-generating jet nebulizer device and inhaled for a 15-min period. Hemodynamic measurements were performed before and after cessation of the inhalation period. Both inhaled milrinone and inhaled iloprost induced significant reductions in mean pulmonary artery pressure and PVR and significant increases in cardiac index in patients with post-CPB pulmonary hypertension. The favorable effect of both agents on the pulmonary vasculature was confirmed by echocardiographic measurements. Both agents were devoid of systemic side effects, since mean arterial pressure and systemic vascular resistance were not affected. A decrease in intrapulmonary shunt by inhalation of both agents was also demonstrated. Pulmonary vasodilatation attributed to iloprost seems to be of greater magnitude and of longer duration as compared to that of inhaled milrinone. Both substances proved to be selective pulmonary vasodilators. The greater magnitude and of longer duration vasodilatation attributed to iloprost may be due to its longer duration of action. PMID- 28717883 TI - First Postpubertal Male Same-Sex Sexual Experience in the National Health and Social Life Survey: Current Functioning in Relation to Age at Time of Experience and Partner Age. AB - This study used an important data set to examine long-term adjustment and functioning in men, who as adolescents had sexual experiences with men. The data came from the National Health and Social Life Survey, which used a national probability sample (Laumann, Gagnon, Michael, & Michaels, 1994). Three perspectives were considered, which offered different predictions. From the "child sexual abuse" (CSA) paradigm, which dominates clinical, legal, and lay views, expected was robust evidence for poorer adjustment, given that intense harm is assumed to be intrinsic. From the "mainstream psychological" perspective, derived from the CSA paradigm but more scientifically based, poorer adjustment was also expected, but with less magnitude, given that minor-adult sex is seen as posing a serious risk of harm, which may not universally apply. From the "relevant-empirical" perspective, which infers response to male adolescent-adult same-sex sex from relevant prior empirical research (as opposed to clinical cases or the female experience), expected was little or no evidence for poorer adjustment. Results supported the relevant-empirical perspective. Compared to several control groups (i.e., men whose first postpubertal same-sex sex was as men with other men; men with no postpubertal same-sex sexual experience or child adult sex), men whose first postpubertal same-sex sex was as adolescents with men were just as well adjusted in terms of health, happiness, sexual functioning, and educational and career achievement. Results are discussed in relation to cultural influences, other cultures, and comparative data from primates. PMID- 28717884 TI - Serum concentrations of glial fibrillary acidic protein (GFAP) do not indicate tumor recurrence in patients with glioblastoma. AB - Recent studies identified serum concentrations of the astroglial protein glial fibrillary acidic protein (GFAP) to be indicative of glioblastoma (GBM) in patients with newly diagnosed space occupying cerebral mass lesions. Until now, no data is available whether GFAP serum concentrations decrease after first therapy and whether GFAP may be used as a predictor of survival and an indicator of tumor recurrence. In this prospective study, we included 44 patients with a single space occupying cerebral mass lesion suspicious for GBM. GBM was histopathologically proven in 33 cases. After initial therapy, patients were followed up until tumor recurrence (defined according to the RANO criteria) or death (maximum observation period 78 weeks). Blood was sampled on a regular basis, and GFAP serum levels were determined using an immunofluorescence assay. Prior to any intervention, 14 of the 33 GBM patients had elevated GFAP serum concentrations (median 0.25 ug/L, interquartile range 0.13-0.53), whereas only one out of 11 patients having other tumor entities revealed a slightly increased GFAP serum level (0.06 ug/L). Following surgery (i.e., biopsy, full or partial resection), all initially GFAP positive GBM patients showed decreased serum concentrations. During the follow-up period, we found a minimal GFAP increase in one patient only (0.04 ug/L; week 52), although 23 out of 31 available GBM patients developed tumor progression or died. No difference was found regarding the survival rate and the time to tumor recurrence between initially GFAP positive and GFAP negative GBM patients. In GBM patients, initially elevated GFAP serum concentrations decrease after the first diagnostic or therapeutic intervention. GFAP was not predictive for tumor recurrence. PMID- 28717885 TI - Risk of severe acute liver injury among patients with brain cancer treated with temozolomide: a nested case-control study using the healthcore integrated research database. AB - Temozolomide (TMZ) is used to treat adult patients with glioblastoma multiforme (GBM). Cases of hepatotoxicity have been reported among patients using TMZ. The objective of the study was to assess the relation, if any, between exposure to TMZ and serious acute liver injury (SALI). We used the HealthCore Integrated Research Database to perform a case-control study nested within a retrospective cohort of adult patients aged 18-100 years with at least two diagnoses of brain cancer anytime between 2006 and 2014. Patients without continuous eligibility or with a SALI diagnosis within 6 months prior to the date of incident brain cancer diagnosis were excluded. Medical records were sought for potential SALI cases and reviewed by two hepatologists. Five controls were selected for each case using incidence density sampling, matched on age and calendar year of index date. The analysis included 61 confirmed SALI cases and 305 selected controls. Exposure to TMZ was classified according to dispensing date and days supply of medication dispensed. We estimated odds ratios using conditional logistic regression models. The odds ratio for any exposure to TMZ was 0.91 (95% CI 0.44-1.91), for recent exposure to TMZ was 0.62 (95% CI 0.21-1.85). There was no increased risk of SALI with increasing duration of exposure to TMZ. When patients with unconfirmed SALI were included in the analysis, results were similar (OR 1.04; 95% CI 0.70-1.54). In conclusion, this study did not find an association between TMZ and SALI risk among patients with brain cancer. PMID- 28717887 TI - Erratum to: The German Lipoprotein Apheresis Registry (GLAR) - almost 5 years on. PMID- 28717886 TI - Endoplasmic Reticulum Stress, a Driver or an Innocent Bystander in Endothelial Dysfunction Associated with Hypertension? AB - PURPOSE OF REVIEW: Hypertension (htn) is a polygenic disorder that effects up to one third of the US population. The endoplasmic reticulum (ER) stress response is a homeostatic pathway that regulates membrane structure, protein folding, and secretory function. Emerging evidence suggests that ER stress may induce endothelial dysfunction; however, it is unclear whether ER stress-associated endothelial dysfunction modulates htn. RECENT FINDINGS: Exogenous and endogenous molecules activate ER stress in the endothelium, and ER stress mediates some forms of neurogenic htn, such as angiotensin II-dependent htn. Human studies suggest that ER stress induces endothelial dysfunction, though direct evidence that ER stress augments blood pressure in humans is lacking. However, animal and cellular models demonstrate direct evidence that ER stress influences htn. ER stress is likely one of many players in a complex interplay among molecular pathways that influence the expression of htn. Targeted activation of specific ER stress pathways may provide novel therapeutic opportunities. PMID- 28717888 TI - Acetabular labral reconstruction using the indirect head of the rectus femoris tendon significantly improves patient reported outcomes. AB - PURPOSE AND HYPOTHESIS: The aim of this study was to evaluate outcomes after acetabular labral reconstruction using the indirect head of the rectus femoris tendon. The study hypothesis stated that arthroscopic acetabular labral reconstruction may improve patient reported outcomes in patients with labral tears that were not amenable to repair. METHODS: Between 2009 and 2015, the senior author performed 31 acetabular labral reconstructions using the indirect head of the rectus femoris tendon. The graft is harvested through the same arthroscopic portals established for the procedure. The graft was gradually secured to the acetabular rim starting at its origin to the myotendinous junction, reestablishing the suction seal of the joint. Medical records and surgical reports were reviewed for demographic data, and outcome measures were assessed with pre- and postoperative modified Harris Hip Scores (mHHS). RESULTS: Twenty-two patients with follow-up of more than 2 years were evaluated. Fourteen procedures were revision hip arthroscopy and 8 were primary labral reconstruction in 13 males and 9 females. The median age was 43 (range 22-68 years old). The median follow-up time was 36.2 months with a range from 24 to 72 months. The median preoperative mHHS was 67.1. Postoperatively, patients improved to a median mHHS of 97.8 (range 73.7-100) (p < 0.0001). CONCLUSION: Acetabular labral reconstruction using the indirect head of the rectus femoris tendon is a minimally invasive surgical procedure. The technique was applicable in all patients in this study with good outcomes. This procedure is clinically relevant for patients with large labral tears not amendable to labral repair as it offers good results using a local allograft. The local allograft is clinically advantageous as there is no additional donor-site morbidity and no risk of disease transmission. LEVEL OF EVIDENCE: IV. PMID- 28717889 TI - Combined arthroscopically assisted coraco- and acromioclavicular stabilization of acute high-grade acromioclavicular joint separations. AB - PURPOSE AND HYPOTHESIS: Due to high rate of persisting dynamic posterior translation (DPT) following isolated coracoclavicular double-button technique for reconstruction of the acromioclavicular (AC) joint reported in the literature, an additional acromioclavicular cerclage was added to the procedure. The aim of this study was to evaluate the clinical and radiological results of patients with high grade AC-joint instability treated with a double TightRope technique with an additional percutaneous acromioclavicular cerclage. METHODS: Fifty-nine patients (6 f/53 m; median age 38.3 (range 21.5-63.4 years) who sustained an acute high grade AC-joint dislocation (Rockwood type V) were treated using the above mentioned technique. At the final follow-up, the constant score (CS), the subjective shoulder value (SSV), the Taft score (TF) and the acromioclavicular joint instability score (ACJI) as well as bilateral anteroposterior stress views with 10 kg of axial load and bilateral modified Alexander views were obtained. RESULTS: At a median follow-up of 26.4 (range 20.3-61.0) months, 34 patients scored a median of 90 (33-100) points in the CS, 90 (25-100) % in the SSV, 11 (4 12) points in the TF and 87 (43-100) points in the ACJI. The coracoclavicular (CC) distance was 12.1 (6.5-19.8) mm and the CC difference 2.0 (0.0-11.0) mm. Two patients (5.8%) showed a complete DPT of the AC joint, and fourteen patients (41.1%) displayed a partial DPT. The overall revision rate was 11.7%. Two patients presented implant irritation, one patient a recurrent instability, and one patient suffered from a local infection. CONCLUSION: The arthroscopically assisted and image-intensifier-controlled double TightRope technique with an additional percutaneous acromioclavicular cerclage leads to good and excellent clinical results after a follow-up of 2 years. The incidence of persisting dynamic horizontal translation is lower compared to isolated coracoclavicular stabilization. Thus, we recommend using the double TightRope implant with an additional acromioclavicular cerclage. LEVEL OF EVIDENCE: IV. PMID- 28717890 TI - Application of phototherapy for the healing of the navels of neonatal dairy calves. AB - The present work evaluated the effects of LED light irradiation on the healing of the navels of neonatal dairy calves. Fifty-seven neonatal calves were divided into two groups. Animals had their umbilical stumps immersed in 10% iodine tincture for 60 s, and this process was repeated every 24 h for three consecutive days. The 29 animals in the first group did not receive LED therapy. The 28 animals in the second group received LED light irradiation at 640 nm with 300 mW power, 46.8 J/cm2 energy density, 60 s irradiation time, and 0.385 cm2 spot size. The animals were irradiated at four points (46.8 J/cm2 per point) evenly distributed around the insertion site of the umbilical stump every 24 h for three consecutive days. Irradiation with LED light was applied before the umbilical stumps were immersed in the iodine solution. The time after birth at which the umbilical stump fell off of each calf was noted. The umbilical stumps of all animals fell off by the 25th day of age. After the umbilical stump fell off, the healing of the remnant wound was followed up to the 30th day after birth. The area of the wound was measured on the 15th, 20th, and 25th day after birth using digital photographs and computer-assisted area measurements. A two-tailed unpaired t test was applied to analyze the falling off the umbilical stump, whereas a Kruskal-Wallis one-way ANOVA test with a Dunn's multiple comparison test was used for the wound size evolution. GraphPad Prisma 5.0(r) and GraphPad StatMate 2.00(r) were used for the statistical analysis. The results revealed that phototherapy hastened the falling off the umbilical stump, accelerated navel healing, and reduced the mortality rate in newborn calves. Therefore, this study introduced a preventive and adjuvant after birth treatment that proved to be effective in reducing the incidences of omphalitis and newborn mortality. PMID- 28717891 TI - Surgery for spinal intramedullary tumors: technique, outcome and factors affecting resectability. AB - Intramedullary spinal cord tumors (IMSCTs) are relatively infrequent lesions with ependymomas and astrocytomas representing the most common types. Microsurgical resection is established as the treatment of choice for these challenging lesions. We reviewed the surgical outcome of 29 cases operated for IMSCTs by the same surgeon between 2009 and 2015. The median follow-up period was 31 months, and all patients were followed up at least for 1 year. Among these 29 cases, 5 patients were previously operated for partial resection elsewhere. Age ranged from 9 to 62 years with a median of 39 years. All patients were symptomatic before surgery. The most common pathology was ependymoma (16 cases), and the most common tumor location was the cervical spine (18 cases). Gross total resection was achieved in 20 out of 29 cases (68.9%). Tumors were totally excised in all cases of ependymoma except in two patients; one was previously operated and irradiated and the second had an extensive anaplastic ependymoma. Sixteen cases experienced immediate post-operative worsening which was temporary in all but one case. At 1-year follow up, 23 patients (79.3%) maintained their pre-operative McCormick grade, 5 patients (17.2%) had a better grade, and 1 patient (3.5%) deteriorated. Surgery still represents the mainstay in the management of IMSCT. Gross total resection can be achieved safely in many cases especially in the presence of an identifiable plane of cleavage between the tumor and the normal spinal cord. PMID- 28717892 TI - A population-based study of injuries to the brachial plexus and to the peripheral nerves of the shoulder girdle and upper limb in the Italian region Friuli Venezia Giulia. AB - The aim of this study was to estimate the incidence, identify the causes, and explore treatments of the injuries to the brachial plexus and peripheral nerves of the shoulder girdle and upper limb in the 1,220,000-inhabitant Italian region Friuli Venezia Giulia.We linked at the individual patient level various administrative databases using an anonymous stochastic key: list of residents, hospital discharge, emergency department, and outpatient care prescriptions database. We abstracted hospital discharge records with at least one discharge diagnosis code ICD-9-CM 953.4 (brachial plexus) or 955.0-955.9 (upper limb). For hospitalized patients, we investigated the prescriptions of ambulatory care during the following year. Emergency department visits in the month prior to hospital admission were also assessed.From 2000 to 2015, we observed 474 hospitalizations (annual average: 61); 48% of patients received at least one prescription of outpatient physical therapy and rehabilitation in the following year, accounting for more than 25,000 visits and interventions. According to emergency department data, falls were the most common mechanism among the elderly; cuts were common among the young.This is the first population study of peripheral nerve injuries to the brachial plexus and peripheral nerves of the shoulder girdle and upper limb in Italy. PMID- 28717893 TI - Normal-phase liquid chromatography retention behavior of polycyclic aromatic hydrocarbon and their methyl-substituted derivatives on an aminopropyl stationary phase. AB - Retention indices for 124 polycyclic aromatic hydrocarbons (PAHs) and 62 methyl substituted (Me-) PAHs were determined using normal-phase liquid chromatography (NPLC) on a aminopropyl (NH2) stationary phase. PAH retention behavior on the NH2 phase is correlated to the total number of aromatic carbons in the PAH structure. Within an isomer group, non-planar isomers generally elute earlier than planar isomers. MePAHs generally elute slightly later but in the same region as the parent PAHs. Correlations between PAH retention behavior on the NH2 phase and PAH thickness (T) values were investigated to determine the influence of non planarity for isomeric PAHs with four to seven aromatic rings. Correlation coefficients ranged from r = 0.19 (five-ring peri-condensed molecular mass (MM) 252 Da) to r = -0.99 (five-ring cata-condensed MM 278 Da). In the case of the smaller PAHs (MM <= 252 Da), most of the PAHs had a planar structure and provided a low correlation. In the case of larger PAHs (MM >= 278 Da), nonplanarity had a significant influence on the retention behavior and good correlation between retention and T was obtained for the MM 278 Da, MM 302 Da, MM 328 Da, and MM 378 Da isomer sets. Graphical abstract NPLC separation of the three-, four-, five-, and six-ring PAH isomers with different number of aromatic carbon atoms and degrees of non-planarity (Thickness, T). The inserted figure plots the number of aromatic carbon atoms vs. the log I value for the 124 parent PAHs. PMID- 28717894 TI - Determination of ketones and ethyl acetate-a preliminary study for the discrimination of patients with lung cancer. AB - In this work, ten possible volatile biomarkers of lung cancer (acetone, 2 butanone, ethyl acetate, 2-pentanone, 4-methyl-2-pentanone, 2-hexanone, 3 heptanone, 2-heptanone, 3-octanone, and 2-nonanone) have been analyzed to evaluate their different concentration levels in urine samples from lung cancer patients (n = 12) and healthy controls (n = 12). The volatile compounds were generated with a headspace autosampler and analyzed with a gas chromatograph equipped with a programmed temperature vaporizer and mass spectrometry detector (HS-PTV-GC-MS). With the aim of evaluating the aforementioned differences, a Mann Whitney U test and box-plots were obtained. Very good discrimination between cancer and control groups was achieved for three (ethyl acetate, 3-heptanone, and 3-octanone) of the ten analytes studied. With a view to assigning samples to the group of healthy or ill individuals, the Wilcoxon signed-rank test has been used. In spite of the small number of urine samples assayed, the results may suggest that the studied compounds could be considered useful tools in order to discern samples and they could be employed as a complementary test in a diagnosis. Graphical abstract Classification of samples (lung cancer patients and controls) with the Wilcoxon signed rank test. PMID- 28717895 TI - Correlating uptake and activity of proline-rich antimicrobial peptides in Escherichia coli. AB - Increasing death tolls accounted for by antimicrobial drug resistance demand novel antibiotic lead compounds. Among different promising candidate classes, proline-rich antimicrobial peptides (PrAMPs) are very favorable due to their intracellular mechanism, i.e., binding to the 70S ribosome and DnaK, after active uptake relying on bacterial transporters like SbmA and MdtM. Studies on peptide internalization as the first step of their complex mode of action rely typically on fluorophore or radioactive labeling and quantification using microscopy, flow cytometry, or radioactivity. Here, a liquid chromatography based assay was applied to quantify the unlabeled internalized full-length peptides and their proteolytic degradation products (metabolites) using UV absorbance and mass spectrometry. Knockout mutants lacking transporter proteins showed reduced PrAMP uptakes, explaining their reduced susceptibility against PrAMPs. Interestingly, major metabolites produced by bacterial proteases still bound to the 70S ribosome provide evidence that degradation by cytosolic proteases as a possible resistance mechanism is not very efficient. Graphical abstract The uptake of unlabeled proline-rich antimicrobial peptides (PrAMPs) is analyzed in Escherichia coli BW25113 wild-type and transporter knockout mutants DeltasbmA and BS2 (DeltasbmA yjiL::Tn10) by reversed-phase chromatography and quantified by UV detection or mass spectrometry with multi-reaction monitoring (scheme right). Internalized peptide amounts correlated to minimal inhibitory concentrations and bacterial transport activities based on the present transporter proteins (scheme left). PMID- 28717896 TI - Optimization of lipid extraction and analytical protocols for UHPLC-ESI-HRMS based lipidomic analysis of adherent mammalian cancer cells. AB - Lipidomics, which reveals comprehensive characterization of molecular lipids, is a rapidly growing technology used in biomedical research. Lipid extraction is a critical step in lipidomic analysis. However, the effectiveness of different lipid extract solvent systems from cellular samples still remains unclear. In the current study, the protocol of reverse-phase liquid chromatography mass spectrometry (LC/MS)-based lipidomics was optimized for extraction and detection of lipids from human pancreatic cancer cell line PANC-1. Four different extraction methods were compared, including methanol/methyl-tert-butyl ether (MTBE)/H2O, methanol/chloroform, methanol/MTBE/chloroform, and hexane/isopropanol. Data were acquired using high-resolution mass spectrometry in positive and negative ion modes respectively. The number of total detected and identified lipids was assessed with the aid of automated lipid identification software LipidSearch. Results demonstrated that methanol/MTBE/H2O provided a better extraction efficiency for different lipid classes, which was chosen as the optimized extraction solvent system. This validated method enables highly sensitive and reproducible analysis for a variety of cellular lipids, which was further applied to an untargeted lipidomic study on human pancreatic cancer PANC 1 cell lines. Moreover, this optimized extraction solvent system can be further applied to other cancer cell lines with similar chemical and physical properties. Graphical abstract Optimized UHPLC-ESI-HRMS-based lipidomic analysis of cancer cells. PMID- 28717897 TI - Development of a fast and cost-effective gas chromatography-mass spectrometry method for the quantification of short-chain and medium-chain fatty acids in human biofluids. AB - The quantification of short-chain and medium-chain fatty acids is becoming more and more relevant in fecal and plasma samples due to their biological impact, which has been associated with colon rectal cancer and fiber consumption. For these reasons, a fast, cost-effective, and reproducible analytical method is highly required. In this research, a gas chromatography-mass spectrometry method based on full scan and multiple reaction monitoring (MRM) acquisition modes were optimized and validated for the analysis of short-chain and medium-chain fatty acids in three biological samples: human fecal water, fecal fermentation supernatants, and human plasma. Several extraction solvents (acidified water, diethyl ether, dichloromethane, ethyl acetate, and methyl tert-butyl ether (MTBE) were further evaluated, demonstrating that the latter was clearly the most suitable solvent with recoveries from 75.4 to 124.4% and coefficient of variations lower than 20%. The applicability of the GC-MS method was tested, for instance, acetic acid was quantified by using samples of plasma and feces from healthy donors at mean values of 66.9 MUM and 24.5 mM, respectively. The optimized protocol could successfully find applications within multi-compartment human studies. In parallel, a second pilot experiment on fecal fermentation supernatants indicated that the proposed protocol is suitable to follow the formation of SCFAs during in vitro fermentation by the human gut microbiota. In summary, the present work provided an improved GC-MS method for precise and accurate quantification of SCFAs and MCFAs in human feces and plasma. PMID- 28717898 TI - Thiophene-based rhodamine as selectivef luorescence probe for Fe(III) and Al(III) in living cells. AB - The thiophene-modified rhodamine 6G (GYJ) has been synthesized as a novel chemosensor. The sensor has sufficiently high selectivity and sensitivity for the detection of Fe3+ and Al3+ ions (M3+) by fluorescence and ultraviolet spectroscopy with a strong ability for anti-interference performance. The binding ratio of M3+-GYJ complex was determined to be 2:1 according to the Job's plot. The binding constants for Fe3+ and Al3+ were calculated to be 3.91 * 108 and 5.26 * 108 M-2, respectively. All these unique features made it particularly favorable for cellular imaging applications. The obvious fluorescence microscopy experiments demonstrated that the probes could contribute to the detection of Fe3+ and Al3+ in related cells and biological organs with satisfying resolution. Graphical abstract GYJ has high selectivity and sensitivity for the detection of Fe(III) and Al(III) with the binding ratio of 2:1. PMID- 28717899 TI - The Effects of Public Disclosure of Industry Payments to Physicians on Patient Trust: A Randomized Experiment. AB - BACKGROUND: Financial ties between physicians and the pharmaceutical and medical device industry are common, but little is known about how patient trust is affected by these ties. OBJECTIVE: The purpose of this study was to evaluate how viewing online public disclosure of industry payments affects patients' trust ratings for physicians, the medical profession, and the pharmaceutical and medical device industry. DESIGN: This was a randomized experimental evaluation. PARTICIPANTS: There were 278 English-speaking participants over age 18 who had seen a healthcare provider in the previous 12 months who took part in the study. INTERVENTIONS: Participants searched for physicians on an online disclosure database, viewed payments from industry to the physicians, and assigned trust ratings. Participants were randomized to view physicians who received no payment ($0), low payment ($250-300), or high payment (>$13,000) from industry, or to a control arm in which they did not view the disclosure website. They also were asked to search for and then rate trust in their own physician. MAIN MEASURES: Primary outcomes were trust in individual physician, medical profession, and industry. These scales measure trust as a composite of honesty, fidelity, competence, and global trust. KEY RESULTS: Compared to physicians who received no payments, physicians who received payments over $13,000 received lower ratings for honesty [mean (SD): 3.36 (0.86) vs. 2.75 (0.95), p < 0.001] and fidelity [3.19 (0.65) vs. 2.89 (0.68), p = 0.01]. Among the 7.9% of participants who found their own physician on the website, ratings for honesty and fidelity decreased as the industry payment to the physician increased (honesty: Spearman's rho = -0.52, p = 0.02; fidelity: Spearman's rho = -0.55, p = 0.01). Viewing the disclosure website did not affect trust ratings for the medical profession or industry. CONCLUSIONS: Disclosure of industry payments to physicians affected perceptions of individual physician honesty and fidelity, but not perceptions of competence. Disclosure did not affect trust ratings for the medical profession or the pharmaceutical and medical device industry. ClinicalTrials.gov identifier: NCT02179632 ( https://clinicaltrials.gov/ct2/show/NCT02179632 ). PMID- 28717901 TI - Performance assessment of a programmable five degrees-of-freedom motion platform for quality assurance of motion management techniques in radiotherapy. AB - Inter-fraction and intra-fraction motion management methods are increasingly applied clinically and require the development of advanced motion platforms to facilitate testing and quality assurance program development. The aim of this study was to assess the performance of a 5 degrees-of-freedom (DoF) programmable motion platform HexaMotion (ScandiDos, Uppsala, Sweden) towards clinically observed tumor motion range, velocity, acceleration and the accuracy requirements of SABR prescribed in AAPM Task Group 142. Performance specifications for the motion platform were derived from literature regarding the motion characteristics of prostate and lung tumor targets required for real time motion management. The performance of the programmable motion platform was evaluated against (1) maximum range, velocity and acceleration (5 DoF), (2) static position accuracy (5 DoF) and (3) dynamic position accuracy using patient-derived prostate and lung tumor motion traces (3 DoF). Translational motion accuracy was compared against electromagnetic transponder measurements. Rotation was benchmarked with a digital inclinometer. The static accuracy and reproducibility for translation and rotation was <0.1 mm or <0.1 degrees , respectively. The accuracy of reproducing dynamic patient motion was <0.3 mm. The motion platform's range met the need to reproduce clinically relevant translation and rotation ranges and its accuracy met the TG 142 requirements for SABR. The range, velocity and acceleration of the motion platform are sufficient to reproduce lung and prostate tumor motion for motion management. Programmable motion platforms are valuable tools in the investigation, quality assurance and commissioning of motion management systems in radiation oncology. PMID- 28717900 TI - Elements of Program Design in Medicare's Value-based and Alternative Payment Models: a Narrative Review. AB - Increasing emphasis on value in health care has spurred the development of value based and alternative payment models. Inherent in these models are choices around program scope (broad vs. narrow); selecting absolute or relative performance targets; rewarding improvement, achievement, or both; and offering penalties, rewards, or both. We examined and classified current Medicare payment models-the Hospital Readmissions Reduction Program (HRRP), Hospital Value-Based Purchasing Program (HVBP), Hospital-Acquired Conditions Reduction Program (HACRP), Medicare Advantage Quality Star Rating program, Physician Value-Based Payment Modifier (VM) and its successor, the Merit-Based Incentive Payment System (MIPS), and the Medicare Shared Savings Program (MSSP) on these elements of program design and reviewed the literature to place findings in context. We found that current Medicare payment models vary significantly across each parameter of program design examined. For example, in terms of scope, the HRRP focuses exclusively on risk-standardized excess readmissions and the HACRP on patient safety. In contrast, HVBP includes 21 measures in five domains, including both quality and cost measures. Choices regarding penalties versus bonuses are similarly variable: HRRP and HACRP are penalty-only; HVBP, VM, and MIPS are penalty-or-bonus; and the MSSP and MA quality star rating programs are largely bonus-only. Each choice has distinct pros and cons that impact program efficacy. Unfortunately, there are scant data to inform which program design choice is best. While no one approach is clearly superior to another, the variability contained within these programs provides an important opportunity for Medicare and others to learn from these undertakings and to use that knowledge to inform future policymaking. PMID- 28717902 TI - Fusion of heart rate variability and pulse rate variability for emotion recognition using lagged poincare plots. AB - Designing an efficient automatic emotion recognition system based on physiological signals has attracted great interests within the research of human machine interactions. This study was aimed to classify emotional responses by means of a simple dynamic signal processing technique and fusion frameworks. The electrocardiogram and finger pulse activity of 35 participants were recorded during rest condition and when subjects were listening to music intended to stimulate certain emotions. Four emotion categories, including happiness, sadness, peacefulness, and fear were chosen. Estimating heart rate variability (HRV) and pulse rate variability (PRV), 4 Poincare indices in 10 lags were extracted. The support vector machine classifier was used for emotion classification. Both feature level (FL) and decision level (DL) fusion schemes were examined. Significant differences have been observed between lag 1 Poincare plot indices and the other lagged measures. The mean accuracies of 84.1, 82.9, 79.68, and 76.05% were obtained for PRV, DL, FL, and HRV measures, respectively. However, DL outperformed others in discriminating sadness and peacefulness, using SD1 and total features, correspondingly. In both cases, the classification rates improved up to 92% (with the sensitivity of 95% and specificity of 83.33%). Totally, DL resulted in better performances compared to FL. In addition, the impact of the fusion rules on the classification performances has been confirmed. PMID- 28717903 TI - High Expression of Angiopoietin-1 is Associated with Lymph Node Metastasis and Invasiveness of Papillary Thyroid Carcinoma. AB - BACKGROUND: We investigated the expression of angiopoietins in patients with papillary thyroid carcinoma (PTC) and the role of angiopoietins as biomarkers predicting the aggressiveness of PTC. METHODS: Expression of angiopoietins was evaluated by immunohistochemistry of tumor specimens from patients with PTC. We demonstrated potential correlations between expression of angiopoietins and clinicopathologic features. RESULTS: High expression of Ang-1 was positively correlated with a tumor size >1 cm, capsular invasion, extrathyroid extension, lymphovascular invasion, lymph node metastasis, and recurrence (P < 0.05). Moreover, multivariate analysis revealed that high expression of Ang-1 was an independent risk factor for lymph node metastasis (P < 0.001, odds ratio [OR] = 62.113) and lymphovascular invasion (P = 0.027, OR 4.405). However, there was no significant correlation between Ang-2 and clinicopathologic features. CONCLUSIONS: Our results suggest that Ang-1 can serve as a valuable prognostic biomarker for lymph node metastasis and invasiveness in patients with PTC. PMID- 28717904 TI - A Description of Deaths Following Emergency Abdominal Surgery. AB - OBJECTIVE: Emergency major abdominal surgery carries a high mortality rate. The aim of this present study was to characterize a population of deceased abdominal surgical patients, to examine how many died unexpectedly and how many were subject to treatment limitations. MATERIALS AND METHODS: We included adult emergency abdominal surgical patients who died within 30 days postoperatively. We collected data from January 1, 2013, to December 31, 2014, in a Danish tertiary care hospital (Herlev). RESULTS: A total of 138 patients were included which corresponded to a crude mortality rate of 16.5% in the population. Four percent (5 of 138) of the patients died unexpectedly without any prior signs of deterioration and 46% (65 of 138) experienced a complicated treatment course, 67% of which was treated in the intensive care unit (ICU). The remaining 50% (68 of 138) had treatment limitations, applied pre- or postoperatively, of which 4% were treated in the ICU ward. CONCLUSIONS: In the present study, we found a high number of patients with treatment limitations, offering one explanation to why so relatively few high-risk surgical patients are admitted to the ICU ward. Whether intermediary wards could serve as a viable alternative for these patients, securing a sufficient level of treatment without taking up scarce beds in the intensive care unit, remains an important question for future studies. Furthermore, five patients died unexpectedly, without any clear cause of death, proving that continual strides toward improving the overall process of postoperative care are still demanded. PMID- 28717905 TI - Analysis of Injury and Mortality Patterns in Deceased Patients with Road Traffic Injuries: An Autopsy Study. AB - BACKGROUND: Despite improvements in prevention and rescue, mortality rates after severe blunt trauma continue to be a problem. The present study analyses mortality patterns in a representative blunt trauma population, specifically the influence of demographic, injury pattern, location and timing of death. METHODS: Patients that died between 1 January 2004 and 31 December 2005 were subjected to a standardised autopsy. INCLUSION CRITERIA: death from blunt trauma due to road traffic injuries (Injury Severity Score >= 16), patients from a defined geographical area and death on scene or in hospital. EXCLUSION CRITERIA: suicide, homicide, penetrating trauma and monotrauma including isolated head injury. Statistical analyses included Student's t test (parametric), Mann-Whitney U test (nonparametric) or Chi-square test. RESULTS: A total of 277 consecutive injured patients were included in this study (mean age 46.1 +/- 23 years; 67.5% males), 40.5% of which had an ISS of 75. A unimodal distribution of mortality was observed in blunt trauma patients. The most frequently injured body regions with the highest severity were the head (38.6%), chest (26.7%), or both head and chest (11.0%). The cumulative analysis of mortality showed that several factors, such as injury pattern and regional location of collisions, also affected the pattern of mortality. CONCLUSIONS: The majority of patients died on scene from severe head and thoracic injuries. A homogenous distribution of death was observed after an initial peak of death on scene. Moreover, several factors such as injury pattern and regional location of collisions may also affect the pattern of mortality. PMID- 28717906 TI - Undiagnosed Liver Fibrosis in Patients Undergoing Pancreatoduodenectomy for Pancreatic Adenocarcinoma. AB - BACKGROUND: Chronic obstruction of the biliary system may cause hepatic fibrosis and liver failure. The purpose of this study was to define the incidence of unrecognized liver fibrosis in patients undergoing pancreaticoduodenectomy (PD). METHODS: Retrospective data were collected on patients undergoing PD during a 21 month period. Each patient had a core needle biopsy at the time of surgery by a hepatobiliary surgeon. RESULTS: This study identified 36 consecutive patients who were referred to a tertiary center and underwent pancreatoduodenectomy during a period of 21 months. The majority of patients, 32 (88.8%), were diagnosed with pancreatic adenocarcinoma. Liver fibrosis was diagnosed in 23 (63.9%) patients. A total of 25 (69.4%) patients were found to have pathological evidence of cholestasis consistent with bile obstruction. Patients that were found to have evidence of obstruction had significantly increased odds that fibrosis stage 2 would be found on pathological diagnosis (OR 6.75, 95% CI 1.20-38.02, Fisher's exact test P value = 0.0312). There was no significant association in patients who were stented compared to non-stented patients and their diagnosis of high grade fibrosis stage 2 (OR 1.5238, 95% CI 0.4019-5.7769, Fisher's exact test P value = 0.7360). CONCLUSIONS: An astonishing 63.9% of patients who underwent PD were diagnosed with stage 1-4 liver fibrosis and half (47.2%) had fibrosis stage of 2 or more. Further, stent status had no significant impact on the degree of liver fibrosis. Liver fibrosis is currently underrecognized in patients undergoing PD, which is important for physicians to be conscious of as it is known that liver fibrosis increases morbidity and mortality. PMID- 28717907 TI - Elevated Lactate is Independently Associated with Adverse Outcomes Following Hepatectomy. AB - BACKGROUND: Arterial lactate is frequently monitored to indicate tissue hypoxia and direct therapy. We sought to determine whether early post-hepatectomy lactate (PHL) is associated with adverse outcomes and define factors associated with PHL. METHODS: Hepatectomy patients at a single institution from 2003 to 2012 with PHL available were included. Univariable and multivariable analyses examined factors associated with PHL and the relationship between PHL and 30-day major morbidity (Clavien grade III-V), 90-day mortality, and length of stay (LOS). RESULTS: Of 749 hepatectomies, 490 were included of whom 71.4% had elevated PHL (>=2 mmol/L). Cirrhosis (coefficient 0.31, p = 0.039), Charlson comorbidity index (coefficient 0.05, p < 0.001), major resections (coefficient 0.34, p < 0.001), procedure time (coefficient 0.08, p < 0.001), and blood loss (coefficient 0.11, p < 0.001) were associated with PHL. As lactate increased from <2 to >=6 mmol/L, morbidity rose from 11.6 to 40.6%, and mortality from 0.7 to 22.7%. PHL was independently associated with 90-day mortality (OR 1.52 p < 0.001) and 30-day morbidity (OR 1.19, p = 0.002), but not LOS (rate ratio 1.03, p = 0.071). CONCLUSION: Patients with elevated PHL in the initial postoperative period should be carefully monitored due to increased risk of major morbidity and mortality. Further research on the impact of lactate-directed fluid therapy is warranted. PMID- 28717908 TI - Systematic Review and Meta-Analysis of Laparoscopic Versus Open Appendicectomy in Adults with Complicated Appendicitis: an Update of the Literature. AB - AIMS: To review and compare the outcomes of laparoscopic (LA) versus open appendicectomy (OA) in complicated appendicitis in adult patients, eight years after the last literature review. METHODS: The PRISMA guidelines were adhered to. Pre-defined inclusion and exclusion criteria were used to search the PubMed, Scopus and Cochrane databases and extract relevant data. Methodological and quality assessment was undertaken with outcome meta-analysis and subgroup analyses of methodological quality, type of study and year of study. Assessment of clinical and statistical heterogeneity and publication bias was conducted. RESULTS: Three randomised control trials (RCTs) (154LA vs 155OA) and 23 case control trials were included (2034LA vs 2096OA). Methodological quality was low to average but with low statistical heterogeneity. Risk of publication bias was low, and meta-regression indicated shorter length of hospital stay (LOS) in more recent studies, Q = 7.1, P = 0.007. In the combined analysis LA had significantly less surgical site infections [OR = 0.30 (0.22,0.40); p < 0.00001] with reduced time to oral intake [WMD = -0.98 (-1.09,-0.86); P < 0.00001] and LOS [WMD = 3.49(-3.70,-3.29); p < 0.00001]. There was no significant difference in intra abdominal abscess rates [OR = 1.11(0.85,1.45); p = 0.43]. Operative time was longer during LA [WMD = 10.51 (5.14,15.87); p = 0.0001] but did not reach statistical significance (p = 0.13) in the RCT subgroup analysis. CONCLUSIONS: LA appears to have significant benefits with improved morbidity compared to OA in complicated appendicitis (level of evidence II). PMID- 28717909 TI - Scientific Integrity Issues to Discuss. PMID- 28717910 TI - Is Laparoscopy Really Advantageous for Splenectomy Patients? PMID- 28717912 TI - Management of the Open Abdomen after Liver Transplantation. AB - INTRODUCTION: The optimal management of the open abdomen (OA) after liver transplantation (LT) is unclear. The negative pressure wound therapy (NPWT) has been shown to be safe and can increase the chance for early fascial closure in trauma or septic patients. However, little data are available on the specific setting of LT. We aimed to report our experience of OA after LT, marked by the recent use of NPWT. METHODS: All patients with postponed wall closure after LT, from 2002 to 2014, in a single institution were included and retrospectively analyzed. Our management of OA after LT has shifted from skin-only closure (SOC) followed by abdominal wall reconstruction at a distance to the use of NPWT with early fascial closure. RESULTS: Of the 1559 LTs performed during the study period, immediate abdominal wall closure at the end of transplantation could not be achieved in 46 (2.9%) patients. Of them, SOC was performed in 22 (47.8%) patients, whereas vacuum-assisted closure (VAC) therapy was used in 24 (52.1%) patients. The comprehensive complication indexes (CCI) were similar [CCI: 66 (0 100) in the SOC group vs. 56 (0-100) in the VAC group; p = 0.55]. No evisceration or fistula occurred in both groups. One (4.2%) postoperative bleeding case was reported in the VAC group. Early fascial closure was achieved within a median of 5.5 days (1-12) for the 24 patients (100%) of the VAC group. In four of them, a biological mesh was necessary. Only nine patients (52.9%) of the survivors in the SOC group underwent abdominal reconstruction. CONCLUSION: The NPWT in patients with OA after LT enables early fascial closure with limited morbidity provided a specific attention is given to the risk of bleeding. These results support the use of NPWT as the first option in OA patients after LT. PMID- 28717911 TI - Laparoscopic Compared to Open Repeat Hepatectomy for Colorectal Liver Metastases: a Multi-institutional Propensity-Matched Analysis of Short- and Long-Term Outcomes. AB - INTRODUCTION: While uptake of laparoscopic hepatectomy has improved, evidence on laparoscopic re-hepatectomy (LRH) for colorectal liver metastases (CRLMs) is limited and has never been compared to the open approach. We sought to define outcomes of LRH compared to open re-hepatectomy (ORH). METHODS: Patients undergoing re-hepatectomy for CRLM at 39 institutions (2006-2013) were identified. Primary outcomes were 30-day post-operative overall morbidity, mortality, and length of stay. Secondary outcomes were recurrence and survival at latest follow-up. LRHs were matched to ORHs (1:3) using a propensity score created by comparing pre-operative clinicopathologic factors (number and size of liver metastases and major hepatectomy). RESULTS: Of 376 re-hepatectomies included, 27 were LRH, including 1 (3.7%) conversion. The propensity-matched cohort included 108 patients. Neither median operative time (252 vs. 230 min; p = 0.82) nor overall 30-day morbidity (48.1 vs. 38.3%; p = 0.37) differed. Non specific morbidity (including cardiac, respiratory, infectious, and renal events) decreased with LRH (11.1 vs. 30.9%, p = 0.04), while surgical-specific morbidity, including liver insufficiency, was higher (44.4 vs. 22.2%, p = 0.03). One ORH and 0 LRH suffered 30-day mortality. Median length of stay (9 vs. 12 days; p = 0.60) was comparable. At latest follow-up, 26 (96.3%) LRH and 67 (82.7%) ORH patients were alive. Eight (29.6%) LRH and 36 (44.4%) ORH patients were alive without disease. CONCLUSION: LRH for recurrent CRLM was associated with overall short term outcomes comparable to ORH, but different morbidity profiles. While it may offer a safe and feasible approach, further insight is necessary to better define patient selection. PMID- 28717913 TI - Survival Benefits of Surgical Resection in Patients with Recurrent Biliary Tract Carcinoma. AB - BACKGROUND: Whether surgical resection for recurrent biliary tract carcinoma (BTC) prolongs survival and the patients who are most likely to benefit from such treatment remain unclear. METHODS: Among 251 patients with recurrences after the initial resection of BTC, a total of 21 patients (8.4%) underwent surgical resection for the recurrence, with a zero mortality rate. The clinicopathological features of these patients were compared with those of patients who did not undergo surgery. RESULTS: The median survival time (MST) after the first recurrence and the 5-year post-recurrent survival (PRS) rate were 19.8 months and 32.8%, respectively, for patients who underwent re-resection. Fourteen patients (66.7%) experienced second recurrences; however, none of these patients underwent further surgical resection. Surgical resection for recurrence was identified as an independent prognostic factor for survival after recurrence (hazard ratio of 0.33, 95% CI of 0.17-0.58, p < 0.001). Patients with less than three liver metastases had a significantly better PRS after surgical resection than after chemotherapy (p = 0.015). Among the patients with an isolated solitary liver metastasis, patients who underwent resection had a significantly longer MST after the first recurrence than patients receiving chemotherapy (22.8 vs. 10.9 months, p = 0.025), whereas the PRS was similar between the two groups among patients with two liver lesions. CONCLUSIONS: Surgical resection for recurrent BTC may prolong survival in highly selected patients. A hepatectomy might offer a survival benefit for patients with a solitary liver metastasis. PMID- 28717915 TI - International Hernia Collaboration Consensus on Nomenclature of Abdominal Wall Hernia Repair. PMID- 28717914 TI - Association of Elevated Pre-operative Hemoglobin A1c and Post-operative Complications in Non-diabetic Patients: A Systematic Review. AB - IMPORTANCE: Pre-operative hyperglycemia is associated with post-operative adverse outcomes in diabetic and non-diabetic patients. Current pre-operative screening includes random plasma glucose, yet plasma glycated hemoglobin (HbA1c) is a better measure of long-term glycemic control. It is not clear whether pre operative HbA1c can identify non-diabetic patients at risk of post-operative complications. OBJECTIVE: The systematic review summarizes the evidence pertaining to the association of suboptimal pre-operative HbA1c on post-operative outcomes in adult surgical patients with no history of diabetes mellitus. EVIDENCE REVIEW: A detailed search strategy was developed by a librarian to identify all the relevant studies to date from the major online databases. FINDINGS: Six observational studies met all the eligibility criteria and were included in the review. Four studies reported a significant association between pre-operative HbA1c levels and post-operative complications in non-diabetic patients. Two studies reported increased post-operative infection rates, and two reported no difference. Of four studies assessing the length of stay, three did not observe any association with HbA1c level and only one study observed a significant impact. Only one study found higher mortality rates in patients with suboptimal HbA1c. CONCLUSIONS AND RELEVANCE: Based on the limited available evidence, suboptimal pre-operative HbA1c levels in patients with no prior history of diabetes predict post-operative complications and represent a potentially modifiable risk factor. PMID- 28717916 TI - Colon Perfusion Patterns During Colorectal Resection Using Visible Light Spectroscopy. AB - BACKGROUND: The impact of blood supply to the anastomosis on development of anastomotic leakage is still a matter of debate. Considering that bowel perfusion may be affected by manipulation during surgery, perfusion assessment of the anastomosis alone may be of limited value. We propose perfusion assessment at different time points during surgery to explore the dynamics of bowel perfusion during colorectal resection and its impact on outcome. METHODS: In this prospective cohort study, patients undergoing elective colorectal resection were eligible. Colon perfusion was evaluated using visible light spectroscopy. Main outcome was the difference in colon perfusion, quantified by measuring tissue oxygen saturation (StO2) in the colonic serosa, before and after anastomosis during surgery. RESULTS: We included 58 patients between July 2013 and November 2015. Colon perfusion increased by an average of 5.9% StO2 during surgery (95% confidence interval 3.1, 8.8; P < 0.001). The number of patients with abnormal perfusion (defined as StO2 < 65%) decreased from 50% at the beginning to 24% by the end of surgery. Six patients (10%) developed anastomotic leaks (AL), of which five patients had abnormal perfusion at the beginning of surgery, whereas four patients had normal StO2 at the anastomosis. CONCLUSION: Colon perfusion significantly increased during colorectal surgery. Considering that one quarter of patients had suboptimal anastomotic perfusion without developing AL, impaired blood flow at the anastomosis alone does not seem to be critical. Further investigations including more patients are necessary to evaluate the impact of perioperative parameters on colon perfusion, anastomotic healing and surgical outcome. PMID- 28717917 TI - [Acute right-sided upper abdominal pain in a 46-year-old woman]. AB - A 46-year-old woman presented with acute abdominal pain in the right upper quadrant. Esophagogastroduodenoscopy revealed a duodenal stenosis within the horizontal part of the duodenum. Based on the findings of abdominal computed tomography (CT), endosonography, Doppler duplex sonography and angiography, the diagnosis of an aneurysm of a branch of the inferior pancreaticoduodenal artery was established. This arterial branch was part of a collateral circulation between the superior mesenteric artery and the proper hepatic artery caused by obturation of the celiac artery. The symptomatic duodenal stenosis was the result of a local hematoma due to prior rupture of an aneurysm. After successful coiling of the afferent vessels to the aneurysm follow-up examinations showed progredient resorption of the hematoma and the patient was free of complaints. PMID- 28717918 TI - [Syncope, falls and vertigo]. AB - Dizziness/vertigo, falls and syncope are among the most common reasons for seeking medical care. As clinical entities they share common pathogenetic and clinical features and differences. The diagnostic work-up can often be initiated in a general practitioner's or internist's practice and, if necessary, completed in an interdisciplinary emergency unit. Simple diagnostic tools can be used in an outpatient setting to obtain valuable diagnostic information. First and foremost, it is important to differentiate between prognostically favorable clinical events and potentially serious disease. In younger patients diagnostic procedures should primarily focus on potential structural cardiac disease and/or primary arrhythmia. The same applies to elderly patients in whom, however, multicausal clinical symptoms and severe complications in the case of falls are characteristic. Elderly patients frequently require the involvement of various clinical specialties to investigate a broad spectrum of potential differential diagnoses in an interdisciplinary diagnostic approach, which is not always available in practice. In the emergency unit, decisions regarding inpatient care need to be made individually. In elderly patients, inpatient care is sometimes necessary not only due to acute disease, but also in order to ensure social care. Geriatric day hospitals may be a suitable option for some of these patients. PMID- 28717919 TI - [Imaging in vascular medicine]. PMID- 28717920 TI - Mother and Adolescent Eating in the Context of Food Insecurity: Findings from Urban Public Housing. AB - Introduction Anecdotal evidence suggests that parents protect their children from food insecurity and its effects, but few studies have concurrently assessed food insecurity among youth and parents. The purpose of this study was to examine food insecurity and eating behaviors among an urban sample of mother-adolescent dyads. Methods Mother-adolescent dyads (n = 55) were from six public housing sites in Phoenix, Arizona who completed surveys during 2014. Multivariate mixed linear and logistic regression models assessed the relationship between mother and adolescent eating behaviors in the context of food insecurity. Results Food insecurity was prevalent with 65.4% of parents and 43.6% of adolescents reporting food insecurity; 34.5% of parents and 14.5% of adolescents reported very low food security. After adjusting for food insecurity status, parents' and adolescents' fruit, vegetable, and sugar-sweetened beverage consumption was not associated. However, significant associations were observed between mothers' and adolescents' fast food intake (beta = 0.52; p < 0.001), family meal intake (beta = 0.52; p = 0.001), mindful eating (beta = 0.51; p = 0.032), and binge eating (OR 8.05; p = 0.011). Discussion Parents may protect their adolescent children against food insecurity given the lower prevalence of food insecurity observed among adolescents. Interventions addressing food insecurity among mothers and adolescents may want to capitalize on shared eating patterns and address issues related to binge eating and leverage site-based strengths of public housing. PMID- 28717921 TI - Female-Headed Households Associated with Lower Childhood Stunting Across Culturally Diverse Regions of Pakistan: Results from a Cross-Sectional Household Survey. AB - Objectives Early childhood stunting adversely influences long-term cognitive and health outcomes. There is limited evidence on whether female empowerment within households could reduce its prevalence. We investigated this relationship in Punjab, Pakistan, which has high stunting rates and a sizeable proportion of female-headed households, and whether this relationship differed across three provincial regions with diverse cultural attitudes towards the role of women in society. Methods Using cross-sectional data from the 2011 Multiple Indicator Cluster Survey, we identified 13,412 children aged 1-4 from 8985 two-parent households in three culturally distinct regions in Punjab, Pakistan. Logistic regression models assessed whether the likelihood of stunting was associated with female-headed households, a proxy for female empowerment, and whether this relationship differed by region. Regressions controlled for child- and household level covariates. Results Children had 26% lower odds of stunting among female headed households (OR 0.74, CI 0.60, 0.90). The interaction term for female headed households and child stunting by provincial region was not statistically significant, suggesting that the relationship holds across the three culturally distinct regions. Conclusions for Practice Female empowerment was associated with lower rates of stunting among young children, and the results did not vary by provincial region. This suggests that women can play important roles as agents of change, even in areas where females have limited freedoms. Greater investments in public education and awareness campaigns to improve health literacy might have important spillover effects for child health and improve the success of existing public health interventions targeting childhood stunting. PMID- 28717922 TI - Healthy Living Behaviors Among Chinese-American Preschool-Aged Children: Results of a Parent Survey. AB - Associations between diet, physical activity, parenting, and acculturation among Chinese-American children are understudied. Parents/caregivers of children attending child-care programs in Boston Chinatown completed a self-administered survey on demographics, child's diet, physical activities, anthropometrics, and parenting practices. Associations were evaluated in multivariable regression analysis, stratified by survey language preference, a proxy for acculturation. Responding Asian families = 132; 86.4% were immigrants; 75.8% completed the Chinese-version survey. Children (mean +/- SD: 4.9 +/- 1.1 years) did not eat vegetables (31.8%), or play actively outside (45.4%) daily, 64.8% watched television/screens daily; 32.6% were overweight/obese (based on parent report). Parenting practices associated with obesity were apparent. Although healthy living behavioral outcomes were less prevalent among less acculturated parents; multivariable adjustment attenuated the observed significant differences. Findings suggest opportunities for improvement in study children's diet and healthy-living behaviors, and underscore the need for further research on acculturation, and parenting styles in this population. PMID- 28717923 TI - MiRNA-200a induce cell apoptosis in renal cell carcinoma by directly targeting SIRT1. AB - Accumulating evidence indicates that microRNAs are implicated in tumor initiation and progression through negatively regulating oncogenes or tumor suppressor genes. In the present study, we report that the expression of miR-200a was significantly lower in renal cell carcinoma (RCC) specimens and RCC cell lines. Restoration of miR-200a suppressed cell growth, arrested cell cycle progression, and promoted cell apoptosis in RCC cell lines. We next used qRT-PCR array technology to identify Sirtuin 1 (SIRT1) as one of the downregulated proteins during miR-200a overexpression in 786-O cells. Following a further assay by luciferase reporter system, SIRT1 was validated as a direct target of miR-200a. Moreover, siRNA-mediated knockdown of SIRT1 could partially phenocopy the effects of miR-200a overexpression. In contrast, overexpression of truncated SIRT1 (without an endogenous 3'-UTR) could rescue the effect of miR-200a overexpression on 786-O cells, which suggested that SIRT1 3'-UTR is targeted by miR-200a specifically. These observations provide further evidence for a critical tumor suppressive role of the miR-200a in RCC in addition to identifying a novel regulatory mechanism, which may contribute to SIRT1 upregulation in RCC. PMID- 28717924 TI - Hypertrophic cardiomyopathy and the myosin mesa: viewing an old disease in a new light. AB - The sarcomere is an exquisitely designed apparatus that is capable of generating force, which in the case of the heart results in the pumping of blood throughout the body. At the molecular level, an ATP-dependent interaction of myosin with actin drives the contraction and force generation of the sarcomere. Over the past six decades, work on muscle has yielded tremendous insights into the workings of the sarcomeric system. We now stand on the cusp where the acquired knowledge of how the sarcomere contracts and how that contraction is regulated can be extended to an understanding of the molecular mechanisms of sarcomeric diseases, such as hypertrophic cardiomyopathy (HCM). In this review we present a picture that combines current knowledge of the myosin mesa, the sequestered state of myosin heads on the thick filament, known as the interacting-heads motif (IHM), their possible interaction with myosin binding protein C (MyBP-C) and how these interactions can be abrogated leading to hyper-contractility, a key clinical manifestation of HCM. We discuss the structural and functional basis of the IHM state of the myosin heads and identify HCM-causing mutations that can directly impact the equilibrium between the 'on state' of the myosin heads (the open state) and the IHM 'off state'. We also hypothesize a role of MyBP-C in helping to maintain myosin heads in the IHM state on the thick filament, allowing release in a graded manner upon adrenergic stimulation. By viewing clinical hyper contractility as the result of the destabilization of the IHM state, our aim is to view an old disease in a new light. PMID- 28717925 TI - Complex biomembrane mimetics on the sub-nanometer scale. AB - Biomimetic lipid vesicles are indispensable tools for gaining insight into the biophysics of cell physiology on the molecular level. The level of complexity of these model systems has steadily increased, and now spans from domain-forming lipid mixtures to asymmetric lipid bilayers. Here, we review recent progress in the development and application of elastic neutron and X-ray scattering techniques for studying these systems in situ and under physiologically relevant conditions on the nanometer to sub-nanometer length scales. In particular, we focus on: (1) structural details of coexisting liquid-ordered and liquid disordered domains, including their thickness and lipid packing mismatch as a function of a size transition from nanoscopic to macroscopic domains; (2) membrane-mediated protein partitioning into lipid domains; (3) the role of the aqueous medium in tuning interactions between membranes and domains; and (4) leaflet-specific structure in asymmetric bilayers and passive lipid flip-flop. PMID- 28717927 TI - Erratum to: Ethical aspects of clinical trials in rare diseases. PMID- 28717928 TI - Routine clinical knee MR reports: comparison of diagnostic performance at 1.5 T and 3.0 T for assessment of the articular cartilage. AB - OBJECTIVE: Accurate assessment of knee articular cartilage is clinically important. Although 3.0 Tesla (T) MRI is reported to offer improved diagnostic performance, literature regarding the clinical impact of MRI field strength is lacking. The purpose of this study is to compare the diagnostic performance of clinical MRI reports for assessment of cartilage at 1.5 and 3.0 T in comparison to arthroscopy. MATERIALS AND METHODS: This IRB-approved retrospective study consisted of 300 consecutive knees in 297 patients who had routine clinical MRI and arthroscopy. Descriptions of cartilage from MRI reports of 165 knees at 1.5 T and 135 at 3.0 T were compared with arthroscopy. The sensitivity, specificity, percent of articular surfaces graded concordantly, and percent of articular surfaces graded within one grade of the arthroscopic grading were calculated for each articular surface at 1.5 and 3.0 T. Agreement between MRI and arthroscopy was calculated with the weighted-kappa statistic. Significance testing was performed utilizing the z-test after bootstrapping to obtain the standard error. RESULTS AND CONCLUSIONS: The sensitivity, specificity, percent of articular surfaces graded concordantly, and percent of articular surfaces graded within one grade were 61.4%, 82.7%, 62.2%, and 77.5% at 1.5 T and 61.8%, 80.6%, 59.5%, and 75.6% at 3.0 T, respectively. The weighted kappa statistic was 0.56 at 1.5 T and 0.55 at 3.0 T. There was no statistically significant difference in any of these parameters between 1.5 and 3.0 T. Factors potentially contributing to the lack of diagnostic advantage of 3.0 T MRI are discussed. PMID- 28717926 TI - Clinical Evaluation of Modified Release and Immediate Release Tacrolimus Formulations. AB - The science of drug delivery has evolved considerably and has led to the development of multiple sustained release formulations. Each of these formulations can present particular challenges in terms of clinical evaluation and necessitate careful study to identify their optimal use in practice. Tacrolimus is an immunosuppressive agent that is widely used in organ transplant recipients. However, it is poorly soluble, has an unpredictable pharmacokinetic profile subject to important genetic polymorphisms and drug-drug interactions, and has a narrow therapeutic index. For these reasons, it represents an agent that could benefit from modified release formulations to overcome these limitations. The objective of this review is to discuss the clinical evaluation of immediate and modified release tacrolimus formulations in renal transplant recipients. Clinical trials from early development of immediate release tacrolimus to formulation-specific post-marketing trials of modified release tacrolimus formulations are reviewed with an emphasis on key elements relating to trial design end endpoint assessment. Particular elements that can be addressed with formulation alterations, such as pharmacokinetics, pharmacogenomics, and toxicity and corresponding clinical evaluations are discussed. In addition, current knowledge gaps in the clinical evaluation of immediate and modified release tacrolimus formulations are discussed to highlight potential avenues for the future development of different tacrolimus formulations with outcomes relevant to the regulators, the transplant community, and to transplant recipients. This review shows that new formulations may alter tacrolimus bioavailability, alleviate certain adverse events while potentially enhancing patient convenience. PMID- 28717929 TI - Reduction in targeted potentially inappropriate medication use in elderly inpatients: a pragmatic randomized controlled trial. AB - PURPOSE: The use of potentially inappropriate medications (PIMs) in hospitalized older adults is a complex problem, but the use of computerized alert systems (CAS) has shown some potential. The study's objective is to assess the change in PIM use with a CAS-based pharmacist-physician intervention model compared to usual clinical care. METHODS: Pragmatic single-site randomized controlled trial was conducted at a university teaching hospital. Hospitalizations identified with selected Beers or STOPP criteria were randomized to usual clinical care or to the CAS-based pharmacist-physician intervention. The primary outcome was PIM drug cessation or dosage decrease. Clinical relevance of the CAS alerts was assessed. RESULTS: Analyses included 231 patients who had 128 and 126 hospitalizations in the control and intervention groups, respectively. Patients had a mean age of 81, and 60% were female. In the intervention compared to the control group, drug cessation or dosage decrease were more frequent at 48 h post-alert (45.8 vs 15.9%; absolute difference 30.0%; 95%CI 13.8 to 46.1%) and at discharge from the hospital (48.1 vs 27.3%; absolute difference 20.8%; 95%CI 4.6 to 37.0%). In a post hoc analysis of all alerts, regardless of their clinical relevance, the absolute difference in drug cessation or dosage decrease between the intervention and control groups was 16.2% (95%CI 2.9 to 29.6%) at 48 h and 8.0% (95%CI -4.0 to 20.0%) at discharge from the hospital. CONCLUSIONS: In hospitalized older adults, a CAS-based pharmacist-physician intervention, compared to usual clinical care, resulted in significant higher number of drug cessation and dosage reductions for targeted PIMs. PMID- 28717930 TI - Understanding the phenotypic similarities between IFAP and Olmsted syndrome from a molecular perspective: the interaction of MBTPS2 and TRPV3. AB - Ichthyosis Follicularis, Atrichia, and Photophobia (IFAP) is a severe rare genetic disorder caused by mutations in the gene encoding the Membrane-Bound Transcription Factor Peptidase, Site 2 (MBTPS2). Olmsted syndrome is another rare genetic disease with overlapping clinical features caused by mutations in the gene encoding the Transient Receptor Potential Cation Channel, subfamily V (TRPV3). Mutations in MBTPS2 have been recently reported in Olmsted syndrome, underscoring the overlap and the confusion in separating Olmsted from IFAP syndrome. We studied a Lebanese family with IFAP syndrome both, clinically and molecularly, and investigated whether there is a cross relation between TRPV3 and MBTPS2. We identified a recurrent mutation designated p.F475S in MBTPS2 in the affected individuals. This mutation was not found in 100 control individuals from the same population. We determined that TRPV3 regulatory region is a target for MBTPS2. In addition, there was an increased cell death in the cells transfected with the mutant versus the wild-type MBTPS2. In conclusion, we identified a direct regulatory effect of MBTPS2 on TRPV3 which can partially contribute to the overlapping clinical features of IFAP and Olmsted syndromes under a common signaling pathway. PMID- 28717932 TI - A W-Geometry Ortho-TOF MS with High Resolution and Up to 100% Duty Cycle for MS/MS. AB - Orthogonal injection time-of-flight (orthoTOF) mass spectrometry (MS) is the most prevalent form of TOFMS, owing to its greater control over incoming ion energy, the ability to correct for aberrations in incoming ion velocity and position, and its ability to provide an entire mass spectrum within a single scan. However, the duty cycle of orthoTOFMS is low compared with scanning analyzers, which can have 100% duty cycle when measuring a single type of ion. Typical duty cycles for orthoTOFMS range from 1% to 30%, depending on instrument geometry. Generally, as instrument resolution increases, duty cycle decreases. Additionally, the greatest duty cycle is achieved for the highest m/z ion recorded in the spectrum, and decreases for all other ions as a function of m/z. In a prior publication [Loboda, A.V.; Chernushevich, I.V. J. Am. Soc. Mass Spectrom. 20, 1342-1348 (20)], a novel trapping/release method for restoring the duty cycle of a V geometry orthoTOFMS to near 100% (referred to as "Zeno pulsing") was presented. Here, we apply that method to a W-TOF geometry analyzer with analog detection. Across a m/z range of 100-2000, sensitivity gains of ~5-20 are observed, for total ion currents approaching ~107 ions.s-1. Zeno pulsing, or similar strategies for restoring duty cycle, will continue to be important as instrument resolution in orthoTOFMS is increased through the use of ion mirrors. Graphical Abstract ?. PMID- 28717931 TI - Noncovalent Halogen Bonding as a Mechanism for Gas-Phase Clustering. AB - Gas-phase clustering of nonionizable iodylbenzene (PhIO2) is attributed to supramolecular halogen bonding. Electrospray ionization results in the formation of ions of proton-charged and preferably sodium-charged clusters assignable to [H(PhIO2) n ]+, n = 1-7; [Na(PhIO2) n ]+, n = 1-6; [Na2(PhIO2) n ]2+, n = 7-20; [HNa(PhIO2) n ]2+, n = 6-19; [HNa2(PhIO2) n ]3+, n = 15-30; and [Na3(PhIO2) n ]3+, n = 14-30. The largest cluster detected has a supramolecular mass of 7147 Da. Electronic structure calculations using the M06-2X functional with the 6 311++G(d,p) basis set for C, H, and O, and LANL2DZ basis set for I and Na predict 298 K binding enthalpies for the protonated and sodiated iodylbenzene dimers and trimers are greater than 180 kJ/mol. This is exceptionally high in comparison with other protonated and sodiated clusters with well-established binding enthalpies. Strongly halogen-bonded motifs found in the crystalline phases of PhIO2 and its derivatives serve as models for the structures of larger gas-phase clusters, and calculations on simple model gas-phase dimer and trimer clusters result in similar motifs. This is the first account of halogen bonding playing an extensive role in gas-phase associations. Graphical Abstract ?. PMID- 28717933 TI - A Novel MS-Cleavable Azo Cross-Linker for Peptide Structure Analysis by Free Radical Initiated Peptide Sequencing (FRIPS). AB - The chemical cross-linking/mass spectrometry (MS) approach is a growing research field in structural proteomics that allows gaining insights into protein conformations. It relies on creating distance constraints between cross-linked amino acid side chains that can further be used to derive protein structures. Currently, the most urgent task for designing novel cross-linking principles is an unambiguous and automated assignment of the created cross-linked products. Here, we introduce the homobifunctional, amine-reactive, and water soluble cross linker azobisimidoester (ABI) as a prototype of a novel class of cross-linkers. The ABI-linker possesses an innovative modular scaffold combining the benefits of collisional activation lability with open shell chemistry. This MS-cleavable cross-linker can be efficiently operated via free radical initiated peptide sequencing (FRIPS) in positive ionization mode. Our proof-of-principle study challenges the gas phase behavior of the ABI-linker for the three amino acids, lysine, leucine, and isoleucine, as well as the model peptide thymopentin. The isomeric amino acids leucine and isoleucine could be discriminated by their characteristic side chain fragments. Collisional activation experiments were conducted via positive electrospray ionization (ESI) on two Orbitrap mass spectrometers. The ABI-mediated formation of odd electron product ions in MS/MS and MS3 experiments was evaluated and compared with a previously described azo based cross-linker. All cross-linked products were amenable to automated analysis by the MeroX software, underlining the future potential of the ABI-linker for structural proteomics studies. Graphical Abstract ?. PMID- 28717934 TI - Why should we screen for arterial hypertension in children and adolescents? PMID- 28717936 TI - Neonatal stroke and haematuria: Questions. AB - This is a report of an infant born near term with neonatal stroke and haematuria. Changes were noted on foetal magnetic resonance images, and these persisted postnatally. A routine renal ultrasound scan during follow-up detected haematuria with no associated proteinuria. A likely pathogenic genetic mutation was identified. This case highlights a relatively newly discovered cause for hereditary nephropathy affecting the basement membrane, initially affecting the glomerular but later the renal tubular basement membranes. The renal phenotype, pathogenic genotype and pathological findings on renal biopsy are discussed. PMID- 28717935 TI - Rabbit anti-human thymocyte immunoglobulin for the rescue treatment of chronic antibody-mediated rejection after pediatric kidney transplantation. AB - BACKGROUND: Chronic antibody-mediated rejection (cAMR) is the leading cause of late kidney graft loss, but current therapies are often ineffective. Rabbit anti human thymocyte immunoglobulin (rATG) may be helpful, but its use is virtually undocumented. METHODS: Data were analyzed retrospectively from nine pediatric kidney transplant patients with cAMR were treated with rATG (1.5 mg/kg * 5 days) at our center after non-response to pulsed prednisolone, intravenous immunoglobulin, rituximab, and increased immunosuppressive intensity (including switching to belatacept in some cases), with or without bortezomib. RESULTS: The median time from diagnosis to cAMR was 179 days. rATG was started 5-741 days after diagnosis. Median estimated glomerular filtration rate (eGFR) increased from 40 mL/min/1.73 m2 when rATG was started to 62 mL/min/1.73 m2 9 months later (p = 0.039). Four patients showed substantially higher eGFR after 9 months and 2 patients showed a small improvement; eGFR continued to decline in 3 patients after starting rATG. No grafts were lost during follow-up. At last follow-up, donor-specific antibodies (DSAs) were no longer detectable in 4 out of 8 patients for whom data were available, median fluorescence intensity had decreased substantially in 1 out of 8 patients; anti-HLA DQ DSAs persisted in 2 out of 8 patients. No adverse events with a suspected relation to rATG, including allergic reactions, leukocytopenia or infections, were observed in any of the patients. CONCLUSIONS: In this small series of patients, rATG appears a promising treatment for unresponsive cAMR. Further evaluation, including earlier introduction of rATG, is warranted. PMID- 28717937 TI - Clinical presentation and outcomes of childhood-onset membranous lupus nephritis. AB - BACKGROUND: Best practices for managing childhood-onset membranous lupus nephritis (MLN) are not yet established. Most studies involve primarily or exclusively adult cohorts or pediatric cohorts with combinations of pure or mixed membranous and proliferative nephritis. METHODS: We performed a single-center cohort study of consecutively diagnosed children with pure MLN from 1990 and 2016. Patients received care in Houston, Texas, one of the most diverse metropolitan areas in North America. Renal outcomes were obtained using consensus definitions from the Childhood Arthritis and Rheumatology Research Alliance (CARRA). Logistic regression was used to detect predictors of complete renal response. RESULTS: A total of 56 children with MLN were identified (82% females, 44% black, 35% Hispanic) with a median follow-up time of 4.1 years. The mean age of MLN onset was 13.7 +/- 3.4 years. On initial presentation 69% had nephrotic syndrome and 11% had acute kidney injury. Glucocorticoids were prescribed in 96% of patients and anti-malarials in 88%. Mycophenolate mofetil was the most common non-steroid immunosuppressive agent (69%), followed by rituximab (25%), cyclophosphamide (18%), and azathioprine (9%). Renin-angiotensin aldosterone system blocking agents were prescribed in 78% of patients. Of 37 patients with >=2 years of follow-up, 74% achieved complete renal response at 24 months. No predictor variable of complete renal response was identified in this small cohort. Renal flares occurred in 48% of patients (86% proteinuric, 14% nephritic). On subsequent renal biopsy, 13% patients had developed proliferative nephritis. CONCLUSIONS: This single-center cohort of childhood-onset MLN showed favorable outcomes. Utilizing pediatric renal outcomes definitions, we found that response rates were high, as were rates of renal flare. PMID- 28717938 TI - Rituximab in steroid-sensitive nephrotic syndrome: lessons from clinical trials. AB - Idiopathic nephrotic syndrome is the most common chronic glomerular disease in children. A total of 80-90% of patients with childhood idiopathic nephrotic syndrome achieve remission with steroid therapy [steroid-sensitive nephrotic syndrome (SSNS)]. However, approximately 50% of children with SSNS develop frequently relapsing nephrotic syndrome (FRNS) or steroid-dependent nephrotic syndrome (SDNS). Children with FRNS or SDNS are usually treated with immunosuppressive agents, but 10-20% of children receiving immunosuppressive agents still show frequent relapses or steroid dependence during or after treatment, defined as complicated FRNS or SDNS. Rituximab, a chimeric anti-CD20 monoclonal antibody that was originally developed to treat patients with B-cell non-Hodgkin's lymphoma, is currently used for treating SSNS. In this review we highlight recent studies, mainly randomized controlled trials of rituximab for SSNS, including complicated and uncomplicated forms of FRNS or SDNS in children. We also discuss the effects of these studies on the management of patients suffering from these conditions. PMID- 28717939 TI - Neonatal stroke and haematuria: Answers. AB - BACKGROUND: This is a report of an infant born near term with neonatal stroke and haematuria. The renal phenotype, pathogenic genotype and pathological findings on renal biopsy are discussed. CASE-DIAGNOSIS: Prenatal magnetic resonance imaging revealed anomalies which persisted postnatally. Haematuria was detected during follow-up. The posttnatal renal ultrasound scan was normal, and there was no associated proteinuria. A likely pathogenic genetic mutation was detected. CONCLUSIONS: This case highlights a relatively newly discovered cause of hereditary nephropathy in which the basement membrane is affected, with initial effects on the glomerular membranes and subsequent effects on the renal tubular basement membranes. PMID- 28717942 TI - Erratum to: Animal and cellular models of familial dysautonomia. PMID- 28717941 TI - The Comparative Safety of TNF Inhibitors in Ankylosing Spondylitis-a Meta Analysis Update of 14 Randomized Controlled Trials. AB - TNF inhibitors have been used in ankylosing spondylitis (AS). The efficacy of TNF inhibitors was already evaluated by meta-analysis of randomized controlled trials (RCTs). However, the safety of TNF inhibitors is still unclear. Therefore, we aimed to evaluate and update the safety data from RCTs of TNF inhibitors in patients treated for AS. A systematic literature search was conducted from 1990 through May 31, 2016. All studies included were randomized, double-blind, controlled trials of patients with ankylosing spondylitis that evaluated adalimumab, certolizumab pegol, etanercept, golimumab, or infliximab treatment. The overall serious adverse events, the risk of serious infection events, and the risk of malignancy and discontinuation rates were abstracted, and risk estimates were calculated by Peto odds ratios (ORs). Fourteen randomized controlled trials involving 2032 subjects receiving TNF inhibitors and 1030 subjects receiving placebo and/or traditional disease-modifying anti-rheumatic drugs (DMARDs) were included. The overall serious adverse events (OR, 1.34; 95% CI, 0.87-2.05), the risk of serious infection events (OR, 1.59; 95% CI, 0.63-4.01), the risk of malignancy (OR, 0.98; 95% CI, 0.25-3.85), and discontinuation due to adverse events (OR, 1.55; 95% CI, 0.95-2.54) in patients treated with TNF inhibitors as a group were not significantly different from those treated with placebo in the control group. TNF inhibitors were generally safe for treatment of ankylosing spondylitis. These data may help guide clinical comparative decision making in the management of AS. PMID- 28717940 TI - Alopecia Areata: a Comprehensive Review of Pathogenesis and Management. AB - Alopecia areata is a common hair loss condition that is characterized by acute onset of non-scarring hair loss in usually sharply defined areas ranging from small patches to extensive or less frequently diffuse involvement. Depending on its acuity and extent, hair loss is an important cause of anxiety and disability. The current understanding is that the condition represents an organ-specific autoimmune disease of the hair follicle with a genetic background. Genome-wide association studies provide evidence for the involvement of both innate and acquired immunity in the pathogenesis, and mechanistic studies in mouse models of alopecia areata have specifically implicated an IFN-gamma-driven immune response, including IFNgamma, IFNgamma-induced chemokines and cytotoxic CD8 T cells as the main drivers of disease pathogenesis. A meta-analysis of published trials on treatment of alopecia areata states that only few treatments have been well evaluated in randomized trials. Nevertheless, depending on patient age, affected surface area and disease duration, an empiric treatment algorithm can be designed with corticosteroids and topical immunotherapy remaining the mainstay of therapy. The obviously limited success of evidence-based therapies points to a more important complexity of hair loss. At the same time, the complexity of pathogenesis offers opportunities for the development of novel targeted therapies. New treatment opportunities based on the results of genome-wide association studies that implicate T cell and natural killer cell activation pathways are paving the way to new approaches in future clinical trials. Currently, there are ongoing studies with the CTLA4-Ig fusion protein abatacept, anti-IL15Rbeta monoclonal antibodies and the Janus kinase inhibitors tofacitinib, ruxolitinib and baricitinib. Ultimately, the options available for adapting to the disease rather than treating it in an effort to cure may also be taken into consideration in selected cases of long-standing or recurrent small spot disease. PMID- 28717944 TI - Evaluation of the Persistent Preventive Efficacy of 2.5 % Moxidectin/10 % Imidacloprid Spot-on (Advocate(r), Advantage(r) Multi) in Dogs Experimentally Infected with Angiostrongylus vasorum. PMID- 28717943 TI - A pyrrole-based natural small molecule mitigates HSP90 expression in MDA-MB-231 cells and inhibits tumor angiogenesis in mice by inactivating HSF-1. AB - Heat shock proteins (HSPs), molecular chaperones, are crucial for the cancer cells to facilitate proper functioning of various oncoproteins involved in cell survival, proliferation, migration, and tumor angiogenesis. Tumor cells are said to be "addicted" to HSPs. HSPs are overexpressed in many cancers due to upregulation of transcription factor Heat-shock factor 1 (HSF-1), the multifaceted master regulator of heat shock response. Therefore, pharmacological targeting of HSPs via HSF-1 is an effective strategy to treat malignant cancers like triple negative breast cancer. In the current study, we evaluated the efficacy of a pyrrole derivative [bis(2-ethylhexyl)1H-pyrrole-3,4-dicarboxylate], TCCP, purified from leaves of Tinospora cordifolia for its ability to suppress heat shock response and angiogenesis using MDA-MB-231 cells and the murine mammary carcinoma: Ehrlich ascites tumor model. HSP90 was downregulated by TCCP by inactivation of HSF-1 resulting in inhibition of tumor cell proliferation, VEGF-induced cell migration, and concomitant decrease in tumor burden and neo angiogenesis in vivo. The mechanism of suppression of HSPs involves inactivation of PI3K/Akt and phosphorylation on serine 307 of HSF-1 by the activation of ERK1. HSF-1 and HSP90 and 70 localization and expression were ascertained by immunolocalization, immunoblotting, and qPCR experiments. The anti-angiogenic effect of TCCP was studied in vivo in tumor-bearing mice and ex vivo using rat corneal micro-pocket assay. All the results thus corroborate the logic behind inactivating HSF-1 using TCCP as an alternative approach for cancer therapy. PMID- 28717945 TI - Lungworms in Germany 2002 - 2016: Is there an Increase in Occurrence and Geographical Spread? PMID- 28717946 TI - Spontaneous Shedding of Metastrongyloid Third-Stage Larvae by Experimentally Infected Limax maximus. PMID- 28717947 TI - Angiostrongylus vasorum, "The French Heartworm": a Serological Survey in Dogs from France Introduced by a Brief Historical Review. PMID- 28717948 TI - Evaluation of the Efficacy and Safety of an Imidacloprid 10 % / Moxidectin 1 % Spot-on Formulation (Advocate(r), Advantage(r) Multi) in Cats Naturally Infected with Capillaria aerophila. PMID- 28717949 TI - Evaluation of the Clinical Efficacy and Safety of a Spot-on Combination of Imidacloprid 10 % / Moxidectin 2.5 % (Advocate(r), Advantage(r) Multi) in Comparison to an Untreated Control Group in the Treatment of Capillaria boehmi in Naturally Infected Dogs. PMID- 28717950 TI - Specific Antibody Detection in Dogs with Filarial Infections. PMID- 28717951 TI - Periodicity of Dirofilaria immitis in Longterm Infections. PMID- 28717952 TI - Temporal Pattern of Circulating Antigens and Antibody Responses in Cats Experimentally Infected with Dirofilaria immitis. PMID- 28717953 TI - Evaluation of the Efficacy and Safety of Flumethrin 275 mg Bee-hive Strips (PolyVar Yellow(r)) against Varroa destructor in Naturally Infested Honey Bee Colonies in a Controlled Study. PMID- 28717954 TI - Evaluation of 40 % Diazinon Impregnated Ear Tag (PatriotTM) for Controlling Horn Flies and Face Flies among Cow-Calf Pairs in the United States. PMID- 28717955 TI - Occurrence of Spirocerca lupi Infection in Hungarian Dogs Referred for Gastroscopy. PMID- 28717956 TI - Retrospective Analysis of Canine Vector-borne Diseases (CVBD) in Germany with Emphasis on the Endemicity and Risk Factors of Leishmaniosis. PMID- 28717957 TI - Repellency Effect of an Imidacloprid / Flumethrin (Seresto(r)) Controlled Release Polymer Matrix Collar against the Australian Paralysis Tick (Ixodes holocyclus) in Dogs. PMID- 28717958 TI - [The 8th edition of the AJCC Cancer Staging Manual : Updates in otorhinolaryngology, head and neck surgery]. AB - BACKGROUND: The TNM system is an established tool for classification of solid tumors by means of tumor size and extent, the involvement of local lymph nodes, and the presence of distant metastases. The classification was established in order to visualize prognostic implications and to allow establishment of systematic therapeutic algorithms. Since the beginning of 2017 a revised version of the classification has applied. Particularly the classification of otorhinolaryngologic tumors has been thoroughly revised in the 8th edition, partly on the basis of new prognostically relevant parameters, such as infection with oncogenic human papillomavirus (HPV) subtypes. MATERIALS AND METHODS: The 8th edition of the American Joint Committee on Cancer (AJCC) served as a basis for the review. The highlighted changes were supplemented by a literature review and the most important elements were summarized. RESULTS: Substantial changes were made for oropharyngeal carcinomas caused by HPV, for the classification of lymph node metastases under consideration of extranodal extension, and for classification of tumors of the oral cavity. Due to their frequency and special biology, skin tumors in the head and neck area are now described in a separate chapter. CONCLUSION: The new classification is a challenge for all specialties involved in tumor staging and therapy. The advantage for the patient lies in a more accurately adjustable treatment modality through more precise classification of tumors. Good collaboration and rapid implementation of the new classification is required in all disciplines involved in head neck tumor diagnostics and therapy. PMID- 28717959 TI - [Development and validation of the Stapesplasty Outcome Test 25 (SPOT-25)]. AB - BACKGROUND: Otosclerosis affects health-related quality of life (HRQOL). Until now, measurements have only been performed using audiometric data or non validated quality of life questionnaires. OBJECTIVE: The objective of this study was to develop the first validated disease-specific HRQOL measuring instrument to determine HRQOL in otosclerosis. MATERIALS AND METHODS: After sequential analysis and item reduction of the initial Stapesplasty Outcome Test 47 (SPOT-47), the SPOT-25 was validated prospectively on 52 otosclerosis patients undergoing stapes surgery. In addition to the overall score, four subscores were defined (hearing function, tinnitus, social restrictions, mental condition). RESULTS: The SPOT-25 showed a high internal consistency (Cronbach's alpha > 0.7), allowed discrimination between otosclerosis patients and healthy subjects, and demonstrated acceptable test-retest reliability (r = 0.85). After stapes surgery, the HRQOL improved significantly. The responsiveness was high. CONCLUSION: The SPOT-25 is the first validated disease-specific instrument for HRQOL measurement in otosclerosis patients. It should be used routinely for quality control. PMID- 28717960 TI - Population genetic analysis of the Globalfiler STR loci in 3032 individuals from the Altay Han population of Xinjiang in northwest China. AB - The genetic polymorphisms of 21 autosomal short tandem repeat (STR) loci included in the GlobalFilerTM PCR Amplification Kit were evaluated in 3032 unrelated individuals Altay Han of Xinjiang, northwest China. All of the loci reached the Hardy-Weinberg equilibrium. These loci were examined to determine allele frequencies and forensic statistical parameters. SE33 showed the greatest power of discrimination in Altay Han population, whereas TPOX showed the lowest. The combined discrimination power and probability of excluding paternity of the 21 autosomal STR loci were 0.999999999999999999999999889838 and 0.999999996664704, respectively. Both pairwise genetic distance and phylogenetic methods indicated that the Altay Han had the closest genetic relationship with the Han origin and Hui populations. The present results revealed that the GlobalFiler system had a high level of polymorphism in Altay Han population and hence could be a powerful tool for forensic application and population genetic study. PMID- 28717961 TI - Determining the optimal forensic DNA analysis procedure following investigation of sample quality. AB - Crime scene traces of various types are routinely sent to forensic laboratories for analysis, generally with the aim of addressing questions about the source of the trace. The laboratory may choose to analyse the samples in different ways depending on the type and quality of the sample, the importance of the case and the cost and performance of the available analysis methods. Theoretically well founded guidelines for the choice of analysis method are, however, lacking in most situations. In this paper, it is shown how such guidelines can be created using Bayesian decision theory. The theory is applied to forensic DNA analysis, showing how the information from the initial qPCR analysis can be utilized. It is assumed the alternatives for analysis are using a standard short tandem repeat (STR) DNA analysis assay, using the standard assay and a complementary assay, or the analysis may be cancelled following quantification. The decision is based on information about the DNA amount and level of DNA degradation of the forensic sample, as well as case circumstances and the cost for analysis. Semi-continuous electropherogram models are used for simulation of DNA profiles and for computation of likelihood ratios. It is shown how tables and graphs, prepared beforehand, can be used to quickly find the optimal decision in forensic casework. PMID- 28717963 TI - The role of multislice computed tomography of the costal cartilage in adult age estimation. AB - To establish population-specific age estimation models in adults from costal cartilage for contemporary Chinese by using three-dimensional volume-rendering technique. Five hundred and twelve individuals (254 females and 258 males) with documented ages between 20 and 85 years were retrospectively included. Their clinical CT examinations (1 mm slice thickness) were used to develop the sex specific age prediction model. A validation sample comprising 26 female and 24 male individuals was then used to test the predictive accuracy of the established models. Simple linear regression (SLR), multiple linear regression (MLR), gradient boosting regression (GBR), support vector machine (SVM), and decision tree regression (DTR) were utilized to build the age diagnosis models from calibration samples. By comparison, the decision tree regression was the relatively more accurate age prediction model for male, with mean absolute error = 5.31 years, least absolute error = 0.10 years, correct percentage within 5 years = 54%, and the correct percentage within 10 years = 88%. The stepwise multiple linear regression equations was the relatively more accurate one for female, with mean absolute error = 6.72 years, least absolute error = 0.68 years, correct percentage within 5 years = 42%, and correct percentage within 10 years = 77%. Our results indicated that the present established age estimation model can be applied as an additional guidance for age estimation in adults. PMID- 28717962 TI - Comparative proteome analysis for identification of differentially abundant proteins in SIDS. AB - Sudden infant death syndrome (SIDS) remains one of the most common causes of post neonatal infant mortality in developed countries. Its pathogenesis is still poorly understood. The goal of the present study was to characterize changes in the proteome of SIDS compared to age-matched controls in heart and medulla tissues as well as in blood samples using two complementary quantitative proteomic techniques: 2D-DIGE and iTRAQ aiming to provide new insights into the mechanism of SIDS and to find diagnostic protein patterns. Our results revealed collectively 122 modulated proteins in SIDS of which 83 proteins were up regulated. They are involved in metabolic processes, cellular processes, and localization. Gene expression patterns of selected proteins were further validated by reverse transcription quantitative real-time PCR (RT-qPCR). The role of hypoxia, inflammation, and apoptosis in SIDS was demonstrated by exploring some candidate proteins especially APOA1, GAPDH, S100B, zyxin, and complement component C4A. According to the results of this study, these proteins might be used as diagnostic biomarkers for SIDS. All of them were up-regulated in SIDS except for C4A that was down-regulated. PMID- 28717964 TI - Wound morphology in contact shots from blank cartridge handguns: a study on composite models. AB - It is a well-known fact that blank cartridge guns can cause penetrating and even fatal injuries when discharged in contact or at very close ranges. In these cases, the gas jet perforates the skin leaving an entrance wound similar to that from a conventional gun. In order to investigate the wound morphology in contact shots from blank firearms, test shots were fired at composite models of pig skin and gelatin blocks using three different calibre 9-mm blank cartridge handguns (two pistols and one revolver) and two types of ammunition. It turned out that the penetrating gas jet produced roundish skin defects resembling bullet entrance holes. Small skin particles from the perforation site were dispersed in the underlying simulant where radiating cracks containing greyish gunshot residues indicated the original expansion of the inrushing combustion gases. Apart from the size of the permanent entrance hole in the skin and the final position of the displaced tissue particles, the penetration depth of the gas jet was determined. Under the specified conditions of the test shots, the zone of mechanical destruction within the simulant was 2.2 to 6.1 cm in length, which illustrates the injuring potential of contact shots inflicted with blank cartridge handguns. PMID- 28717965 TI - Genomic properties of chromosomal bands are linked to evolutionary rearrangements and new centromere formation in primates. AB - Chromosomal rearrangements in humans are largely related to pathological conditions, and phenotypic effects are also linked to alterations in the expression profile following nuclear relocation of genes between functionally different compartments, generally occupying the periphery or the inner part of the cell nuclei. On the other hand, during evolution, chromosomal rearrangements may occur apparently without damaging phenotypic effects and are visible in currently phylogenetically related species. To increase our insight into chromosomal reorganisation in the cell nucleus, we analysed 18 chromosomal regions endowed with different genomic properties in cell lines derived from eight primate species covering the entire evolutionary tree. We show that homologous loci, in spite of their evolutionary relocation along the chromosomes, generally remain localised to the same functional compartment of the cell nuclei. We conclude that evolutionarily successful chromosomal rearrangements are those that leave the nuclear position of the regions involved unchanged. On the contrary, in pathological situations, the effect typically observed is on gene structure alteration or gene nuclear reposition. Moreover, our data indicate that new centromere formation could potentially occur everywhere in the chromosomes, but only those emerging in very GC-poor/gene-poor regions, generally located in the nuclear periphery, have a high probability of being retained through evolution. This suggests that, in the cell nucleus of related species, evolutionary chromosomal reshufflings or new centromere formation does not alter the functionality of the regions involved or the interactions between different loci, thus preserving the expression pattern of orthologous genes. PMID- 28717966 TI - Association between aspirin use and deep venous thrombosis in mechanically ventilated ICU patients. AB - Deep venous thrombosis (DVT) is common in intensive care unit (ICU) patients. It is often silent and may be complicated by pulmonary embolism and death. Thromboprophylaxis with heparin does not always prevent venous thromboembolism (VTE). Aspirin (ASA) reduces the risk of VTE in surgical and high-risk medical patients but it is unknown if ASA may prevent DVT in mechanically ventilated ICU patients. We performed a retrospective chart review of critically ill patients who received mechanical ventilation for >72 h and underwent venous ultrasonography for suspected DVT between Jan 2012 and Dec 2013. We excluded patients who were on therapeutic doses of anticoagulation or had coagulopathy. We used multivariable logistic regression to evaluate association between aspirin use and DVT during hospitalization. There were 193 patients. The mean +/- SD age was 58 +/- 15.7 years. Half were male. DVT was found in 49 (25.4%). DVT was found in the first 15 days of hospitalization in 67.3% of the patients. The majority (82.8%) received thromboprophylaxis with unfractionated or low molecular weight heparin. Fifty-six (29%) were on ASA. On multivariable regression analysis, ASA use was associated with a significant reduction in the odds of finding DVT (OR 0.39, 95% CI 0.16-0.94; p = 0.036). DVT is common in mechanically ventilated ICU patients despite the use of thromboprophylaxis. Aspirin may prevent DVT in such patients. PMID- 28717967 TI - Orexin A/Hypocretin Modulates Leptin Receptor-Mediated Signaling by Allosteric Modulations Mediated by the Ghrelin GHS-R1A Receptor in Hypothalamic Neurons. AB - The hypothalamus is a key integrator of nutrient-seeking signals in the form of hormones and metabolites originated in both the central nervous system and the periphery. The main autocrine and paracrine target of orexinergic-related hormones such as leptin, orexin/hypocretin, and ghrelin are neuropeptide Y neurons located in the arcuate nucleus of the hypothalamus. The aim of this study was to investigate the expression and the molecular and functional relationships between leptin, orexin/hypocretin and ghrelin receptors. Biophysical studies in a heterologous system showed physical interactions between them, with potential formation of heterotrimeric complexes. Functional assays showed robust allosteric interactions particularly different when the three receptors are expressed together. Further biochemical and pharmacological assays provided evidence of heterotrimer functional expression in primary cultures of hypothalamic neurons. These findings constitute evidence of close relationships in the action of the three hormones already starting at the receptor level in hypothalamic cells. PMID- 28717968 TI - Deletion of Type-2 Cannabinoid Receptor Induces Alzheimer's Disease-Like Tau Pathology and Memory Impairment Through AMPK/GSK3beta Pathway. AB - Although several studies have shown that type-2 cannabinoid receptor (CB2R) is involved in Alzheimer's disease (AD) pathology, the effects of CB2R on AD-like tau abnormal phosphorylation and its underlying mechanism remain unclear. Herein, we employed the CB2R-/- mice as the animal model to explore roles of CB2R in regulating tau phosphorylation and brain function. We found that CB2R-/- mice display AD-like tau hyperphosphorylation, hippocampus-dependent memory impairment, increase of GSK3beta activity, decrease of AMPK and Sirt1 activity and mitochondria dysfunction. Interestingly, AICAR or resveratrol (AMPK agonist) could efficiently rescue most alternations caused by solo deletion of CB2R in CB2R-/- mice. Moreover, JWH133, a selective agonist of CB2R, reduces phosphorylation of tau and GSK3beta activity in HEK293 tau cells, but the effects of JWH133 on phosphorylation of tau and GSK3beta disappeared while blocking AMPK activity with compound C or Prkaa2-RNAi. Taken together, our study indicated that deletion of CB2R induces behavior damage and AD-like pathological alternation via AMPK/GSK3beta pathway. These findings proved that CB2R/AMPK/GSK3beta pathway can be a promising new drug target for AD. PMID- 28717969 TI - Decreasing the Expression of GABAA alpha5 Subunit-Containing Receptors Partially Improves Cognitive, Electrophysiological, and Morphological Hippocampal Defects in the Ts65Dn Model of Down Syndrome. AB - Trisomy 21 or Down syndrome (DS) is the most common cause of intellectual disability of a genetic origin. The Ts65Dn (TS) mouse, which is the most commonly used and best-characterized mouse model of DS, displays many of the cognitive, neuromorphological, and biochemical anomalies that are found in the human condition. One of the mechanisms that have been proposed to be responsible for the cognitive deficits in this mouse model is impaired GABA-mediated inhibition. Because of the well-known modulatory role of GABAA alpha5 subunit-containing receptors in cognitive processes, these receptors are considered to be potential targets for improving the intellectual disability in DS. The chronic administration of GABAA alpha5-negative allosteric modulators has been shown to be procognitive without anxiogenic or proconvulsant side effects. In the present study, we use a genetic approach to evaluate the contribution of GABAA alpha5 subunit-containing receptors to the cognitive, electrophysiological, and neuromorphological deficits in TS mice. We show that reducing the expression of GABAA alpha5 receptors by deleting one or two copies of the Gabra5 gene in TS mice partially ameliorated the cognitive impairments, improved long-term potentiation, enhanced neural differentiation and maturation, and normalized the density of the GABAergic synapse markers. Reducing the gene dosage of Gabra5 in TS mice did not induce motor alterations and anxiety or affect the viability of the mice. Our results provide further evidence of the role of GABAA alpha5 receptor-mediated inhibition in cognitive impairment in the TS mouse model of DS. PMID- 28717970 TI - Prostaglandin EP2 Receptors Mediate Mesenchymal Stromal Cell-Neuroprotective Effects on Dopaminergic Neurons. AB - Mesenchymal stromal cells (MSCs) have been shown to have useful properties for cell therapy and have been proposed for treatment of neurodegenerative diseases, including Parkinson's disease. However, the mechanisms involved in recovering dopaminergic neurons are not clear. The present study aims to evaluate the pathways and molecules involved in the neuroprotective effect of MSCs. We analyzed the viability of dopaminergic cells from different sources in response to conditioned medium derived from bone marrow MSC (MSC-CM). MSC-CM increased the viability of dopaminergic cells of rat and human origins, having both neuroprotective and neurorescue activities against effects of dopaminergic neurotoxin 6-hydroxydopamine. We found that lipid removal, inhibition of the prostaglandin E2 receptor 2 (EP2), and its signaling pathway were able to block the effects of MSC-CM on a pure population of dopaminergic neurons. Moreover, in primary mesencephalic cultures and hiPSC-derived neurons, inhibition of EP2 signaling caused a reduction in the number of dopaminergic neurons obtained in culture. Taken together, our results demonstrate for the first time the involvement of prostaglandin signaling from MSC in dopaminergic neuron survival through EP2 receptors, and suggest new approaches for treatment of Parkinson's disease. PMID- 28717971 TI - Subnetwork mining on functional connectivity network for classification of minimal hepatic encephalopathy. AB - Hepatic encephalopathy (HE), as a complication of cirrhosis, is a serious brain disease, which may lead to death. Accurate diagnosis of HE and its intermediate stage, i.e., minimal HE (MHE), is very important for possibly early diagnosis and treatment. Brain connectivity network, as a simple representation of brain interaction, has been widely used for the brain disease (e.g., HE and MHE) analysis. However, those studies mainly focus on finding disease-related abnormal connectivity between brain regions, although a large number of studies have indicated that some brain diseases are usually related to local structure of brain connectivity network (i.e., subnetwork), rather than solely on some single brain regions or connectivities. Also, mining such disease-related subnetwork is a challenging task because of the complexity of brain network. To address this problem, we proposed a novel frequent-subnetwork-based method to mine disease related subnetworks for MHE classification. Specifically, we first mine frequent subnetworks from both groups, i.e., MHE patients and non-HE (NHE) patients, respectively. Then we used the graph-kernel based method to select the most discriminative subnetworks for subsequent classification. We evaluate our proposed method on a MHE dataset with 77 cirrhosis patients, including 38 MHE patients and 39 NHE patients. The results demonstrate that our proposed method can not only obtain the improved classification performance in comparison with state-of-the-art network-based methods, but also identify disease-related subnetworks which can help us better understand the pathology of the brain diseases. PMID- 28717972 TI - Characteristics of patients in an eating disorder sample who dropped out: 2-year follow-up. AB - OBJECTIVE: This manuscript explores the characteristics of individuals diagnosed with an eating disorder who dropped out of treatment, compared with those who completed it. METHOD: The participants were 196 patients diagnosed with eating disorders (according to DSM-IV-TR criteria) who consecutively began treatment for the first time in an eating disorders unit. They were assessed at baseline with a set of questionnaires evaluating eating habits, temperament, and general psychopathology. During the follow-up period, patients who dropped out were re assessed via a telephone interview. RESULTS: In the course of a 2-year follow-up, a total of 80 (40.8%) patients were labeled as dropouts, and 116 (59.2%) remaining subjects were considered completers. High TCI scores in the character dimensions of Disorderliness (NS4) (p < .01) and total Novelty Seeking (NST), along with low scores in Dependency (RD4), were significantly associated with dropout in the course of 2 years. Once the results were submitted to logistic regression analysis, dropout only remained associated with high scores in Disorderliness (NS4) and, inversely, with an initial Anorexia Nervosa (AN) diagnosis (p < .05). Reasons for dropout stated by the patients included logistic difficulties, subjective improvement of their condition, and lack of motivation. DISCUSSION: Clinicians should handle the first therapeutic intervention with particular care in order to enhance their understanding of clients and their ability to rapidly identify those who are at risk of dropping out of treatment. LEVEL OF EVIDENCE: Level III: Cohort Study. PMID- 28717973 TI - Design and Development of Repaglinide Microemulsion Gel for Transdermal Delivery. AB - Microemulsion formulation of repaglinide, a BCS class II hypoglycemic agent with limited oral bioavailability, was developed considering its solubility in various oils, surfactants, and cosurfactants. The pseudo-ternary phase diagrams for microemulsion regions were constructed by water titration method at K m 1:1 and characterized for optical birefringence, percentage transmittance, pH, refractive index, globule size, zeta potential, viscosity, drug content, and thermodynamic stability. To enhance the drug permeation and residence time, the optimized microemulsions having mean globule size of 36.15 +/- 9.89 nm was gelled with xanthan gum. The developed microemulsion-based gel was characterized for globule size, zeta potential, pH, and drug content. All evaluation parameters upon gelling were found to be satisfactory. Ex vivo permeability study across rat skin demonstrated higher steady-state flux (P < 0.05) for microemulsion of repaglinide in comparison to the repaglinide microemulsion gel. At the end of 24 h, the cumulative drug permeation from microemulsion and microemulsion gel was found to be 229.19 +/- 24.34 and 180.84 +/- 17.40 MUg/cm2, respectively. The microemulsion formulation showed 12.30-fold increase in flux as compared to drug suspension with highest enhancement ratio (E r ) of 12.36. Whereas microemulsion gel exhibited 10.97-fold increase in flux (with highest E r , 11.78) as compared to repaglinide (RPG) suspension. In vivo efficacy study was performed in normal Sprague-Dawley rats by using oral glucose tolerance test. Results of RPG transdermal microemulsion gel demonstrated remarkable advantage over orally administered RPG by reducing the glucose level in controlled manner. Hence, it could be a new, alternative dosage form for effective therapy of type 2 diabetes mellitus. PMID- 28717974 TI - Improvement of Oral Bioavailability of Lopinavir Without Co-administration of Ritonavir Using Microspheres of Thiolated Xyloglucan. AB - Lopinavir is a BCS Class IV drug exhibiting poor bioavailability due to P-gp efflux and limited permeation. The aim of this research was to formulate and characterize microspheres of lopinavir using thiolated xyloglucan (TH-MPs) as carrier to improve its oral bioavailability without co-administration of ritonavir. Thiomeric microspheres were prepared by ionotropic gelation between alginic acid and calcium ions. Interaction studies were performed using Fourier transform infrared spectroscopy (FT-IR). The thiomeric microspheres were characterized for its entrapment efficiency, T80, surface morphology, and mucoadhesion employing in vitro wash off test. The microspheres were optimized by 32 factorial design. The optimized thiomeric microsphere formulation revealed 93.12% entrapment efficiency, time for 80% drug release (T80) of 358.1 min, and 88% mucoadhesion after 1 h. The permeation of lopinavir from microspheres was enhanced 3.15 times as determined by ex vivo study using everted chick intestine and increased relative bioavailability over 3.22-fold over combination of lopinavir and ritonavir as determined by in vivo study in rat model. PMID- 28717976 TI - [Trauma surgery in Pacific Small Island Developing States (SIDS)]. AB - BACKGROUND: The small developing countries in the Pacific are grouped together as Small Island Development States (SIDS) because they face similar problems which they cannot cope with nationally. They are developing countries, so-called low and lower middle income countries (LMIC), are economically weak and the islands of the different nations are widely scattered. Approximately 80% of the 10 million inhabitants live in rural regions. EPIDEMIOLOGY AND SURGICAL CAPACITY: Over 40% of patients in the surgical departments of hospitals are hospitalized for injuries, and this tendency is increasing. Fractures of the upper extremities are relatively more frequent in the Pacific than in the countries of the North. Long distances, lack of possibilities for treatment and lack of transport often cause complications, such as infected open fractures, pseudarthrosis and posttraumatic malformations. There are too few hospitals with sufficiently competent surgeons, anesthetists and obstetricians (SAO) and appropriate equipment. PACIFIC ISLANDS ORTHOPEDIC ASSOCIATION (PIOA): The PIOA was founded in Honiara, Solomon Islands, and offers surgeons of the Pacific SIDS a comprehensive, structured trauma and orthopedic surgery training in their own countries. It lasts 4 years and leads to an M-Med (orthopaedic surgery) diploma and to a Fellowship of the International College of Surgeons (FICS), which are both recognized by the participating hospitals. It is free for participants. THE AO ALLIANCE FOUNDATION (AOAF): The AOAF is an independent organization with the only aim to enhance trauma surgery capacity in LMICs. The AOAF supports the PIOA program together with the Wyss Medical Foundation. Currently, 18 trainees from 8 Pacific SIDS are participating in the PIOA training program. PMID- 28717975 TI - Development of a Novel Polymeric Nanocomposite Complex for Drugs with Low Bioavailability. AB - Semi-synthetic biopolymer complex (SSBC) nanoparticles were investigated as a potential oral drug delivery system to enhance the bioavailability of a poorly water-soluble model drug acyclovir (ACV). The SSBCs were prepared from cross linking of hydroxyl groups on hyaluronic acid (HA) with poly(acrylic acid) (PAA) resulting in ether linkages. Thereafter, conjugation of 2-hydroxypropyl-beta cyclodextrin (HP-beta-CD) onto HA-PAA was accomplished using a 1-ethyl-3-(3 dimethylaminopropyl) carbodiimide (EDC)/N-hydroxysuccinimide (NHS)-promoted coupling reaction. Nanoparticle powders were prepared by spray drying of drug loaded SSBC emulsions in a laboratory nano spray dryer. The prepared SSBC was characterized by Fourier transform infrared (FT-IR) spectroscopy, differential scanning calorimetry (DSC), 1H nuclear magnetic resonance (NMR) imaging, and X ray diffraction (XRD) spectroscopy. The average particle size was found to be 257.92 nm. An entrapment efficiency of 85% was achieved as ACV has enhanced affinity for the hydrophobic inner core of the complex. It was shown that SSBC improved the solubility of ACV by 30% and the ex vivo permeation by 10% compared to the conventional ACV formulation, consequentially enhancing its bioavailability. Overall, this study resulted in the successful preparation of a hybrid chemically conjugated SSBC which has great potential for enhanced oral absorption of ACV with possible tuneable ACV permeability and solubility, producing an "intelligent" nanoenabled drug delivery system. PMID- 28717977 TI - [Challenges of implementing a geriatric trauma network : A regional structure]. AB - BACKGROUND: At present, there is a high percentage and increasing tendency of patients presenting with orthogeriatric injuries. Moreover, significant comorbidities often exist, requiring increased interdisciplinary treatment. These developments have led the German Society of Trauma Surgery, in cooperation with the German Society of Geriatrics, to establish geriatric trauma centers. METHODS: As a conglomerate hospital at two locations, we are cooperating with two external geriatric clinics. In 2015, a geriatric trauma center certification in the form of a conglomerate network structure was agreed upon for the first time in Germany. For this purpose, the requirements for certification were observed. Both structure and organization were defined in a manual according to DIN EN ISO 9001:2015. RESULTS: Between 2008 and 2016, an increase of 70% was seen in geriatric trauma cases in our hospital, with a rise of up to 360% in specific diagnoses. The necessary standards and regulations were compiled and evaluated from our hospitals. After successful certification, improvements were necessary, followed by a planned re-audit. These were prepared by multiprofessional interdisciplinary teams and implemented at all locations. CONCLUSIONS: A network structure can be an alternative to classical cooperation between trauma and geriatric units in one clinic and help reduce possible staffing shortage. Due to the lack of scientific evidence, future evaluations of the geriatric trauma register should reveal whether network structures in geriatric trauma surgery lead to a valid improvement in medical care. PMID- 28717978 TI - [Treatment strategy and planning for pilon fractures]. AB - BACKGROUND: Pilon fractures are mainly severe and prognostically serious injuries with a high rate of relevant soft tissue involvement. The adequate decision making and choice of treatment in the early phase of trauma are of paramount importance for the final outcome. This essentially encompasses the management of the soft tissue damage, the surgical planning and the differentiated selection of procedures. GOALS/MATERIAL AND METHODS: Most concepts of staged treatment nowadays offer a wide range of options which are integrated into expert-based algorithms. The aim of the present analysis was to display the strategy variations for the treatment of pilon fractures taking into account the advantages and disadvantages of the corresponding treatment concepts. RESULTS: A staged procedure including primary closed reduction employing ligamentotaxis and fixation of the joints of the hindfoot via tibiocalcaneal metatarsal fixation offers a safe basis for consecutive imaging and the selection of specific approaches for definitive reconstruction. A simultaneous reconstruction and fixation of the fibula during the primary intervention are generally not recommended in order to avoid any limitations for subsequent reconstructive procedures. A time frame for definitive reconstruction covers a period of up to 3 weeks after trauma and allows a detailed planning considering the individual dynamics of the soft tissue situation and any logistic requirements. For the choice of the definitive treatment concept a wide range of procedures and implants are available. There are also valid concepts for primary treatment of defined fracture constellations while primary arthrodesis represents a solution in cases of major destruction of the joint surface. DISCUSSION AND CONCLUSION: Knowledge of the multiple procedural variations for pilon fracture treatment creates the basis to optimize the treatment modalities and to take into account individual parameters of the fracture. PMID- 28717980 TI - When Science and Values Collide: Recalling the Lessons of Evidence-Based HIV Prevention. PMID- 28717979 TI - Impact of age on laryngopharyngeal reflux disease presentation: a multi-center prospective study. AB - The objective is to assess the differences in the severity of symptoms, signs, voice quality, and quality of life before and after treatment according to age in suspected laryngopharyngeal reflux (LPR) patients. The design used in this paper is prospective multi-center study. Eighty clinically diagnosed LPR patients with a reflux finding score (RFS) >7 and a reflux symptom index (RSI) >13 were treated with pantoprazole and diet recommendations for 3 months. Patients were subdivided into three groups according their age: group 1 (18-39 years, N = 21), group 2 (40 59 years, N = 31), and group 3 (>=60 years, N = 28). RSI, RFS, Voice Handicap Index (VHI), Short Form 36 questionnaire (SF36), aerodynamic, and acoustic measurements were evaluated at baseline and after treatment. The response to the empiric treatment was also assessed. Significant improvements in RSI, RFS, and VHI were found in all patient groups. The elderly patients showed a significantly lower RSI score than younger subjects (p = 0.035) without RFS difference among groups. At baseline, the SF36 score was better in group 3 with respect to social functioning (p = 0.049). At the 3-month follow-up, we found significant improvement of acoustic parameters only in the younger age groups (group 1 and group 2). The rate of resistant patients to the empiric treatment was higher in the younger group than in the elderly patient group (42.9 versus 28.6%). Age appears to reduce the subjective LPR symptom perception, leading to a lower rate of uncured patients. The utilization of acoustic parameters as an indicator of treatment effectiveness seems less useful for elderly subjects, probably due to an overlap between an aging voice and LPR. PMID- 28717981 TI - Effects of Counselling on Adherence to Antiretroviral Treatment Among People with HIV in Estonia: A Randomized Controlled Trial. AB - To assess the efficacy of an education- and strengths-based counselling programme to promote antiretroviral therapy (ART) adherence in a cohort of HIV-infected individuals with high prevalence of injection drug use in Estonia. Parallel-group randomized (1:1) controlled trial (RCT). Adults receiving ART in two clinics were followed for 12 months. The trial compared: (i) an intervention (three sessions) incorporated into routine clinic visits, providing education about HIV, ART, the role of adherence, and tailoring regimen to daily routines using problem-solving skills to address adherence barriers versus (ii) usual care (control). Primary and secondary outcomes were self-reported ART adherence (3-day recall) and viral load (respectively). 519 patients were randomized and 82% completed the study. Recent optimal ART adherence (3-day recall >=95%) was reported by 75.6% in the intervention group and 72.9% of controls at baseline and 76.7% and 67.5%, respectively, at 12 months (RR 1.14, 95% CI 1.00-1.28; adjusted RR 1.13, 95% CI 1.00-1.27). There was no difference in the proportion of patients with undetectable viral load. At 12 months the intervention group reported significantly higher perceptions of ART necessity versus ART concerns [mean ART necessity-concerns differential: intervention group 1.32 (SD 1.22) vs control group 1.08 (SD 1.12); p = 0.048]. All-cause mortality among study participants was 27.7 per 1000 person years (95% CI 15.6-44.8). A brief, clinic-based adherence intervention alone may assist with adherence but lacks impact on viral load at 12 months. PMID- 28717982 TI - Characterization of zinc amino acid complexes for zinc delivery in vitro using Caco-2 cells and enterocytes from hiPSC. AB - Zn is essential for growth and development. The bioavailability of Zn is affected by several factors such as other food components. It is therefore of interest, to understand uptake mechanisms of Zn delivering compounds to identify ways to bypass the inhibitory effects of these factors. Here, we studied the effect of Zn amino acid conjugates (ZnAAs) on the bioavailabilty of Zn. We used Caco-2 cells and enterocytes differentiated from human induced pluripotent stem cells from a control and Acrodermatitis enteropathica (AE) patient, and performed fluorescence based assays, protein biochemistry and atomic absorption spectrometry to characterize cellular uptake and absorption of ZnAAs. The results show that ZnAAs are taken up by AA transporters, leading to an intracellular enrichment of Zn mostly uninhibited by Zn uptake antagonists. Enterocytes from AE patients were unable to gain significant Zn through exposure to ZnCl2 but did not show differences with respect to ZnAAs. We conclude that ZnAAs may possess an advantage over classical Zn supplements such as Zn salts, as they may be able to increase bioavailability of Zn, and may be more efficient in patients with AE. PMID- 28717983 TI - Evaluation of acute kidney injury (AKI) with RIFLE, AKIN, CK, and KDIGO in critically ill trauma patients. AB - PURPOSE: The aim of our study was to evaluate the effects of AKI development on mortality with four different classification systems (RIFLE, AKIN, CK, KDIGO) in critically ill trauma patients followed in the intensive care unit. METHODS: A retrospective review of 2034 patients in our intensive care unit was conducted between July 2010 and August 2013. A total of 198 patients with primary trauma were included in the study to evaluate the development of AKI. RESULTS: When the presence of AKI was investigated according to the four criteria (RIFLE, AKIN, CK, and KDIGO), the highest incidence of AKI was found according to the KDIGO classification (74.2%), followed by AKIN (72.2%), RIFLE (69.7%), and CK (59.1%). It was observed that more AKI developed according to KDIGO in patients with multiple trauma and thoracic trauma (p = 0.031, p = 0.029). Sixty-two (31%) of the 198 trauma patients monitored in the intensive care unit died; mortality was frequently found high in AKI stage 2 and 3 patients. According to the CK classification, there was a significant increase in mortality in patients with AKI on the first day (p = 0.045). AKI classifications by RIFLE, AKIN, CK, and KDIGO were independently associated with the risk of in-hospital death. CONCLUSION: In this study, the presence of AKI was found to be an independent risk factor in the development of in-hospital mortality according to all classification systems (RIFLE, AKIN, CK, and KDIGO) in critically traumatic patients followed in ICU, and the compatibility between RIFLE, AKIN, and KDIGO was the highest among the classification systems. PMID- 28717984 TI - Falls in older people: comparing older and younger fallers in a developing country. AB - PURPOSE: While falls are common in older people, causing significant mortality and morbidity, this phenomenon has not been extensively studied in the Caribbean. This study aimed to compare falls in older and younger people in this setting. METHODS: We conducted a prospective observational study of older trauma patients in Trinidad, comparing older and younger patients sustaining falls. RESULTS: 1432 adult trauma patients were included (1141 aged 18-64 years and 291 aged 65 years and older). Older fallers were more likely to be female (66.7 vs 47.2%; p < 0.001), suffer from multiple pre-existing diseases (24.7 vs 2.4%; p < 0.001) and take multiple medications (16.1 vs 0.8%; p < 0.001). They also sustained more severe injuries and presented with higher acuity than younger fallers. Admission rates were higher among older fallers (29.9 vs 13.1%; p < 0.001). CONCLUSIONS: In our study, older patients who fell were a distinct group from younger falls victims, with unique demographic, clinical and injury related characteristics. Their increased risk of injury within the home, coupled with their propensity for more severe injuries made them a high risk patient group. More research is needed to better understand this patient group and plan specific preventive interventions. PMID- 28717985 TI - Basic echocardiography for undergraduate students: a comparison of different peer teaching approaches. AB - BACKGROUND: The aim of this study was to assess the impact of different teaching interventions in a peer-teaching environment on basic echocardiography skills and to examine the influence of gender on learning outcomes. METHODS: We randomly assigned 79 s year medical students (55 women, 24 men) to one of four groups: peer teaching (PT), peer teaching using Peyton's four-step approach (PPT), team based learning (TBL) and video-based learning (VBL). All groups received theoretical and practical hands-on training according to the different approaches. Using a pre-post-design we assessed differences in theoretical knowledge [multiple choice (MC) exam], practical skills (Objective Structured Practical Examination, OSPE) and evaluation results with respect to gender. RESULTS: There was a significant gain in theoretical knowledge for all students. There were no relevant differences between the four groups regarding the MC exam and OSPE results. The majority of students achieved good or very good results. Acceptance of the peer-teaching concept was moderate and all students preferred medical experts to peer tutors even though the overall rating of the instructors was fairly good. Students in the Video group would have preferred a different training method. There was no significant effect of gender on evaluation results. CONCLUSIONS: Using different peer-teaching concepts proved to be effective in teaching basic echocardiography. Gender does not seem to have an impact on effectiveness of the instructional approach. Qualitative analysis revealed limited acceptance of peer teaching and especially of video-based instruction. PMID- 28717986 TI - Thrombolysis for stroke in Ireland: increasing access and maintaining safety in a challenging environment. AB - BACKGROUND: In the setting of a national audit of acute stroke services, we examined the delivery of thrombolytic therapy for ischaemic stroke and whether current practice was achieving safe outcomes and consistent delivery for patients. METHOD: Data obtained from the recent national stroke audit was compared against previous Irish audit, the most recent SSNAP UK stroke audit and the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST) study. RESULTS: Thrombolysis was provided in 27 acute hospitals throughout Ireland during the period assessed with 82% (22/27) providing 24/7 access, the remaining sites using redirect policies. Decision to thrombolyse was made by stroke trained consultants in 63% (17/27) of units, with general physicians and emergency medicine consultants covering the other units. Thrombolysis rate for non-haemorrhagic stroke was 11% (n = 80/742, CI 95% +/-2.23) versus a 1% rate in the 2008 audit. Sites receiving patients through a redirect policy had the highest thrombolysis rate, an average of 24%. Nearly 30% of cases were thrombolysed on the weekend. Eighty-three percent of cases were managed in a stroke unit at some time during admission versus 54% of the national total cases. Thirty-seven percent of patients were >=80 years old. The mortality rate was 11.3% versus the national mortality rate for non-thrombolysed ischaemic strokes of 10% (p > 0.5), and this is comparable to the SITS-MOST 2007 study 3-month mortality rate of 11.3% (p > 0.5). CONCLUSION: Stroke thrombolysis is being effectively and safely provided in acute stroke services in Ireland despite regular involvement of non-specialist staff. There is still potential to improve thrombolysis rate. PMID- 28717987 TI - Interventions for Refractory Trigeminal Neuralgia: A Bayesian Mixed Treatment Comparison Network Meta-Analysis of Randomized Controlled Clinical Trials. AB - INTRODUCTION: Patients with trigeminal neuralgia (TN) are often refractory to recommended first-line agents. Due to the absence of a systematic review, we undertook a network meta-analysis to assess various interventions that can be used to manage refractory TN. METHODS: Electronic databases were searched using appropriate strategies to identify randomized controlled clinical trials in patients with refractory TN, evaluating the proportion of patients with a minimum of 50% reduction in pain or a minimum of 2 cm reduction in score in an appropriate pain scale or complete pain relief by subjective pain scales. Mixed treatment comparisons were carried out using a Bayesian approach and a random effects model was developed with Monte-Carlo simulation with 1,000 iterations. Odds ratios with 95% credible intervals were assessed for each comparison. Consistency of direct and indirect results was checked with deviance plots. Rankogram was generated based on the surface area under the cumulating ranking curve (SUCRA). RESULTS: A total of 13 studies were included in this systematic review, of which 11 were finally included for the final network meta-analysis. Two different interventions were analyzed: drug-related and radiofrequency related interventions. In the former group, sumatriptan, intranasal lidocaine, botulinum toxin, and intravenous lidocaine were observed to perform better than ophthalmic proparacaine and placebo based on pooled estimates in a Forest plot. In the latter group, conventional radiofrequency (both standalone and in combination with pulsed radiofrequency) was found to be better than pulsed radiofrequency alone. Rankogram plots revealed sumatriptan and combined continuous and pulsed radiofrequency thermocoagualtion have the highest probability of being the best treatments in the respective group of interventions. No inconsistency was observed between direct and indirect comparisons. CONCLUSION: We found that drug-related interventions that include sumatriptan, intranasal lidocaine, intravenous lidocaine, and botulinum toxin and combined continuous and pulsed radiofrequency thermocoagulation had significant effects in reducing pain in patients with refractory TN. However, the quality of evidence was graded as very low for all except botulinum toxin. PMID- 28717988 TI - Bioabsorbable implants for subtalar arthroereisis in pediatric flatfoot. AB - Flatfoot is a common condition in growing-age patients. Despite its common presentation, nowadays surgical indications and treatments are still debated. Arthroereisis is a widely used technique, and several implants designs have been proposed over time. Despite the good results shown in the literature, the main drawback of these techniques has always been the need for a second surgery for implant removal. Bioabsorbable devices have been introduced to overcome this necessity.Correct approach to the patient, indications and contraindications and available studies on bioabsorbable implants for subtalar arthroereisis in pediatric flatfoot were analyzed in this narrative review. Even if only a few studies have been published in the literature, bioabsorbable implants showed good clinical results comparable to non-absorbable implants and with a rare necessity for implant removal or revision. When correct indications and proper surgical technique are followed, arthroereisis with bioabsorbable implants appears to be an effective solution for the treatment of pediatric flexible flatfoot. PMID- 28717989 TI - The CARMA3-BCL10-MALT1 (CBM) complex contributes to DNA damage-induced NF-kappaB activation and cell survival. PMID- 28717990 TI - Iron-based phosphate binders: a paradigm shift in the treatment of hyperphosphatemic anemic CKD patients? AB - The partial correction of anemia and the normalization of phosphate and blood pressure are the mainstay of treatment of patients with chronic kidney disease (CKD). Available anti-hypertensive drugs, erythropoiesis stimulating agents (ESAs) and iron supplements have resolved quite satisfactorily the goal of controlling hypertension and partially correcting anemia. Unfortunately, the treatment of hyperphosphatemia is still far from resolved. Phosphate binders have poor tolerability and/or limited efficacy, leading to the prescription of many tablets that achieve only a mild-to-moderate effect. Moreover, increased consumption of tablets is associated with increased low tolerability, thus jeopardizing patient compliance and, in turn, the efficacy of phosphate binding. Compared to calcium-free binders, the cheaper calcium salts increase the risk of hypercalcemia, calciphylaxis and vascular calcification and possibly all-cause mortality. Calcium-free phosphate binders decrease serum phosphate levels without increasing the serum calcium concentration. The higher phosphate-binding efficacy of lanthanum carbonate compared to sevelamer should be balanced against its lack of pleiotropic effects on lipid metabolism and inflammation and the accumulation in bones. New iron-based phosphate binders are available. In addition to their phosphate binding capacity, they could also be useful to treat anemia. Iron citrate is seeking for such an indication because its iron absorption is significant. This could be of clinical importance, particularly in CKD patients not on dialysis, obviating the need for extra oral iron administration and possibly favoring compliance. In conclusion, the use of iron-based phosphate binders with significant iron absorption properties could represent a novel paradigm for correcting anemia and hyperphosphatemia in CKD patients. PMID- 28717991 TI - Prolonged bed rest impairs rapid CPI-17 phosphorylation and contraction in rat mesenteric resistance arteries to cause orthostatic hypotension. AB - Prolonged bed rest (PBR) causes orthostatic hypotension (OH). Rapid constriction of splanchnic resistance arteries in response to a sudden increase in sympathetic tone contributes to the recovery of orthostatic arterial pressure upon standing. However, the molecular mechanism of PBR-induced dysfunction in arterial constriction is not fully understood. Previously, we showed that CPI-17, a regulatory protein for myosin phosphatase, mediates alpha1A-adrenergic receptor induced rapid contraction of small mesenteric arteries. Here, we tested whether PBR associated with OH affects the alpha1-adrenergic receptor-induced CPI-17 signaling pathway in mesenteric arteries using rats treated by head-down tail suspension hindlimb unloading (HDU), an experimental OH model. In normal anesthetized rats, mean arterial pressure (MAP) rapidly reduced upon 90 degrees head-up tilt from supine position and then immediately recovered without change in heart rate, suggesting a rapid arterial constriction. On the other hand, after a 4-week HDU treatment, the fast orthostatic MAP recovery failed for 1 min. Alpha1A subtype-specific antagonist suppressed the orthostatic MAP recovery with a small decrease in basal blood pressure, whereas non-specific alpha1-antagonist prazosin strongly reduced both basal MAP and orthostatic recovery. The HDU treatment resulted in 68% reduction in contraction in parallel with 83% reduction in CPI-17 phosphorylation in denuded mesenteric arteries 10 s after alpha1 agonist stimulation. The treatment with either Ca2+-release channel opener or PKC inhibitor mimicked the deficiency in HDU arteries. These results suggest that an impairment of the rapid PKC/CPI-17 signaling pathway downstream of alpha1A adrenoceptors in peripheral arterial constriction, as an end organ of orthostatic blood pressure reflex, is associated with OH in prolonged bed rest patients. PMID- 28717992 TI - Melting of polymeric DNA double helix at elevated temperature: a molecular dynamics approach. AB - Genomic DNA of higher organisms exists as extremely long polymers, while in bacteria and other lower organisms it is circular with no terminal base pairs. Temperature-induced melting of the DNA double helix by localized strand separation has been unattainable by molecular dynamic simulations due to more rapid fraying of the terminal base pairs in oligomeric DNA. However, local sequence-dependent unfolding of the DNA double helix is extremely important for understanding various biochemical phenomena, and can be addressed by simulating a model polymeric DNA duplex. Here, we present simulations of polymeric B-DNA of sequence d(CGCGCGCGAATTCGCGCGCG)2 at elevated temperatures, along with its equivalent oligomeric constructs for comparison. Initiation of temperature induced DNA melting was observed with higher fluctuations of the central d(AATT) region only in the model polymer. The polymeric construct shows a definite melting start site at the weaker A/T stretch, which propagates slowly through the CG rich regions. The melting is reflected in the hydrogen bond breaking, i.e. basepair opening, and by disruption of stacking interaction between successive basepairs. Melting at higher temperature of the oligomer, however, was only through terminal fraying, as also reported earlier. PMID- 28717993 TI - Probing the binding affinities of imipenem and ertapenem for outer membrane carboxylate channel D1 (OccD1) from P. aeruginosa: simulation studies. AB - Pseudomonas aeruginosa is an important nosocomial human pathogen. The major difficulty in the fight against this pathogen is the relative impermeability of its outer membrane (OM). Only specific substrates can penetrate through the OM of P. aeruginosa via substrate-specific porins, so this has become one of the most problematic drug-resistant pathogens. Carbapenems are the most effective drugs for treating P. aeruginosa infections. One such carbapenem that is applied in cases of P. aeruginosa infection is imipenem (IMI), which uses outer membrane carboxylate channel D1 (OccD1) as a point of entry into the pathogen. Unlike IMI, ertapenem (ERTA, another carbapenem) shows only weak activity towards P. aeruginosa, as it is blocked from penetrating through the OM. However, it is currently unclear as to why IMI is allowed to pass through the OM while ERTA is not. Therefore, we conducted molecular dynamics (MD) simulations to elucidate the behavior of these drugs inside OccD1 as compared to the ligand-free state. We discovered another possible binding site in the constriction region close to the side-pore opening. Both drugs employ the core lactam part to tether themselves to the binding site, whereas the tail governs the direction of permeation. L132 and F133 appear to be involved in interactions that are key to core attachment. At least four hydrogen bonds are required for drug binding. The direction of motion of L2 also plays a role: inward flipping traps IMI in the constriction area, while a shift of L2 towards the membrane brings ERTA into contact with more water, which prompts the expulsion of ERTA to the mouth of the channel protein. The opening of L2 seems to facilitate the rejection of ERTA. PMID- 28717994 TI - Modeling and investigation of new explosive materials based on N-(3,5-dimethyl 2,4,6-trinitrophenyl)-1H-1,2,4-triazol-3-amine. AB - This study presents an investigation of the effects of adding extra nitro group substituents to N-(3,5-dimethyl-2,4,6-trinitrophenyl)-1H-1,2,4-triazol-3-amine (HEM-II) on its thermal and chemical stability as well as its explosive performance. An analysis of the thermal stabilities of HEM-II and HEM-II-based molecules based on an investigation of the binding energy per atom for each molecule was performed. The values of the gap between the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) as well as those of the chemical hardness and softness for HEM-II and the HEM-II based molecules were studied to determine the chemical stabilities of these molecules. The detonation velocity and oxygen balance of each HEM-II-based molecule were investigated to elucidate its explosive properties. The results of our investigation show that the presence of additional nitro groups suppresses the tendency of the new HEM-II-based explosive material to react with other materials, improves its explosive properties (strength), decreases the likelihood that it will degrade, and enhances its toxicity and thermal stability. We also found that zero-point correction does not need to be performed when molecules with different substituents are investigated and compared. PMID- 28717995 TI - Ovomucin nanoparticles: promising carriers for mucosal delivery of drugs and bioactive compounds. AB - Ovomucin, with a similar structure to mucin and gelation ability at room temperature, is a potential mucosal carrier. To evaluate this potential, the mucoadhesive property of ovomucin was studied by the tensile strength and rheology methods, and compared with three known mucoadhesive polymers, chitosan, polyacrylic acid (PAA), and alginate. Ovomucin particles were basically spherical in shape with an average size of ~572, 235 and 54 nm prepared at pH 5, 6.5, and 9, respectively. The absolute value of the zeta potential increased from ~ -51 mV at pH 5 to ~ -59 and -91 mV at pH 6.5 and 9, respectively. Drug loading efficiency of ovomucin particles for brilliant blue (negatively charged), riboflavin (non-ionic), and ciprofloxacin (positively charged) were ~87.7, 25.4, and 89.1%, respectively. The release of encapsulated ciprofloxacin was evaluated in phosphate-buffered saline (PBS), simulated intestinal fluid (SIF), and simulated gastric fluid (SGF). The mechanism of the releases was studied using different mathematical models: zero-order, first-order, Higuchi, Hixson-Crowell, and Korsmeyer-Peppas models. Approximately 61 and 67% of loaded ciprofloxacin were released from the particles over 7 h of incubation in PBS and SIF, respectively. The kinetics of drug releases in PBS and SIF followed the Fickian diffusion mechanism (Korsmeyer-Peppas model). Therefore, ovomucin could function as a mucoadhesive carrier to efficiently encapsulate drugs and sustainably release them in the non-digestive and intestinal mucosal tissues. PMID- 28717996 TI - Patterns of oribatid mite species diversity: testing the effects of elevation, area and sampling effort. AB - Elevational gradients in species diversity and species area relationships are two well established patterns that are not mutually exclusive in space and time. Elevation and area are both considered as good proxies to detect and characterize the patterns of species diversity distribution. However, such studies are hampered by the incomplete biodiversity data available for ecologists, which may affect the pattern perceptions. Using the large dataset of oribatid mite communities sampled in Georgia, we tested the effects of altitude and area on species distribution using various approaches, while explicitly considering the biases from sampling effort. Our results showed that elevation and area are strongly correlated (with increasing absolute elevation, land area decreases) and both have strong linear effects on species diversity distribution when studied separately. Approaches based on multiple regression and direct removal of co varied factors, indicated that the effect of area can actually override the effect of elevation in describing the oribatid species diversity distribution along with elevation. On the other hand, the bias of sampling proved significant in perception of elevational species richness pattern with less effect on elevational species area relationship. We suggest that the sampling alone may be responsible for patterns observed and thus should be considered in ecological studies when eligible. PMID- 28717997 TI - An enhanced sensitivity methyl 1H triple-quantum pulse scheme for measuring diffusion constants of macromolecules. AB - We present a pulse scheme that exploits methyl 1H triple-quantum (TQ) coherences for the measurement of diffusion rates of slowly diffusing molecules in solution. It is based on the well-known stimulated echo experiment, with encoding and decoding of TQ coherences. The size of quantifiable diffusion coefficients is thus lowered by an order of magnitude with respect to single-quantum (SQ) approaches. Notably, the sensitivity of the scheme is high, approximately 3/4 that of the corresponding single quantum experiment, neglecting relaxation losses, and on the order of a factor of 4 more sensitive than a previously published sequence for AX3 spin systems (Zheng et al. in JMR 198:271-274, 2009) for molecules that are only 13C labeled at the methyl carbon position. Diffusion coefficients measured from TQ- and SQ-based experiments recorded on a range of protein samples are in excellent agreement. We present an application of this technique to the study of phase-separated proteins where protein concentrations in the condensed phase can exceed 400 mg/mL, diffusion coefficients can be as low as ~10-9 cm2s-1 and traditional SQ experiments fail. PMID- 28717998 TI - Locust displacing winds in eastern Australia reassessed with observations from an insect monitoring radar. AB - Based on previous investigations, adult Australian plague locusts are believed to migrate on warm nights (with evening temperatures >25 degrees C), provided daytime flight is suppressed by surface winds greater than the locusts' flight speed, which has been shown to be 3.1 m s-1. Moreover, adult locusts are believed to undertake briefer 'dispersal' flights on nights with evening temperature >20 degrees C. To reassess the utility of these conditions for forecasting locust flight, contingency tests were conducted comparing the nights selected on these bases (predicted nights) for the months of November, January, and March and the nights when locust migration were detected with an insect monitoring radar (actual nights) over a 7-year period. In addition, the wind direction distributions and mean wind directions on all predicted nights and actual nights were compared. Observations at around 395 m above ground level (AGL), the height at which radar observations have shown that the greatest number of locusts fly, were used to determine the actual nights. Tests and comparisons were also made for a second height, 990 m AGL, as this was used in the previous investigation. Our analysis shows that the proposed criteria are successful from predicting migratory flight only in March, when the surface temperature is effective as a predicting factor. Surface wind speed has no predicting power. It is suggested that a strong daytime surface wind speed requirement should not be considered and other meteorological variables need to be added to the requirement of a warm surface temperature around dusk for the predictions to have much utility. PMID- 28717999 TI - Macro- and microclimate conditions may alter grapevine deacclimation: variation in thermal amplitude in two contrasting wine regions from North and South America. AB - Low temperature is a limiting factor that affects vineyard distribution globally. The level of cold hardiness acquired during the dormant season by Vitis sp. is crucial for winter survival. Most research published on this topic has been generated beyond 40 degrees N latitude, where daily mean temperatures may attain injurious levels during the dormant season resulting in significant damage to vines and buds. Symptoms of cold injury have been identified in Mendoza (32-35 degrees S latitude), a Southern Hemisphere wine region characterized by a high thermal amplitude, and warm winds during the dormant season. These symptoms have usually been attributed to drought and/or pathogens, but not to rapid deacclimation followed by injurious low temperatures. Because local information on meteorological events as probable causes is scarce, this research was designed to test and study this assumption by comparing macro-, meso-, and microclimatic data from Mendoza, Argentina, and eastern Washington, USA. The goal was to unveil why freezing damage has occurred in both regions, despite the existence of large climatic differences. Because environmental parameters under field conditions may not correspond to data recorded by conventional weather stations, sensors were installed in vineyards for comparison. Microclimatic conditions on grapevines were also evaluated to assess the most vulnerable portions of field-grown grapevines. In order to better understand if it may be possible to modify cold hardiness status in a short period with high thermal amplitude conditions, deacclimation was induced using a thermal treatment. Hence, despite the fact that Mendoza is warmer, and temperatures are not as extreme as in Washington, high daily thermal amplitude might be partially involved in plant deacclimation, leading to a differential cold hardiness response. PMID- 28718000 TI - Phenological model of bird cherry Padus racemosa with data assimilation. AB - The accuracy of the operational models can be improved by using observational data to shift the model state in a process called data assimilation. Here, a data assimilation approach using the temperature similarity to control the extent of extrapolation of point-like phenological observations is explored. A degree-day model is used to describe the spring phenology of the bird cherry Padus racemosa in the Baltic region in 2014. The model results are compared to phenological observations that are expressed on a continuous scale based on the BBCH code. The air temperature data are derived from a numerical weather prediction (NWP) model. It is assumed that the phenology at two points with a similar temperature pattern should be similar. The root mean squared difference (RMSD) between the time series of hourly temperature data over a selected time interval are used to measure the temperature similarity of any two points. A sigmoidal function is used to scale the RMSD into a weight factor that determines how the modelled and observed phenophases are combined in the data assimilation. The parameter space for determining the weight of observations is explored. It is found that data assimilation improved the accuracy of the phenological model and that the value of the point-like observations can be increased through using a weighting function based on environmental parameters, such as temperature. PMID- 28718001 TI - A new device for fiducial registration of image-guided navigation system for liver RFA. AB - PURPOSE: Radiofrequency ablation for liver tumors (liver RFA) is widely performed under ultrasound guidance. However, discriminating between the tumor and the needle is often difficult because of cavitation caused by RFA-induced coagulation. An unclear ultrasound image can lead to complications and tumor residue. Therefore, image-guided navigation systems based on fiducial registration have been developed. Fiducial points are usually set on a patient's skin. But the use of internal fiducial points can improve the accuracy of navigation. In this study, a new device is introduced to use internal fiducial points using 2D US. METHODS: 3D Slicer as the navigation software, Polaris Vicra as the position sensor, and two target tumors in a 3D abdominal phantom as puncture targets were used. Also, a new device that makes it possible to obtain tracking coordinates in the body was invented. First, two-dimensional reslice images from the CT images using 3D Slicer were built. A virtual needle was displayed on the two-dimensional reslice image, reflecting the movement of the actual needle after fiducial registration. A phantom experiment using three sets of fiducial point configurations: one conventional case using only surface points, and two cases in which the center of the target tumor was selected as a fiducial point was performed. For each configuration, one surgeon punctured each target tumor ten times under guidance from the 3D Slicer display. Finally, a statistical analysis examining the puncture error was performed. RESULTS: The puncture error for each target tumor decreased significantly when the center of the target tumor was included as one of the fiducial points, compared with when only surface points were used. CONCLUSION: This study introduces a new device to use internal fiducial points and suggests that the accuracy of image-guided navigation systems for liver RFA can be improved by using the new device. PMID- 28718003 TI - Molecular Pathogenesis of Liver Cancer. PMID- 28718002 TI - Infectious pathogens may trigger specific allo-HLA reactivity via multiple mechanisms. AB - Transplant recipients can be sensitized against allo-HLA antigens by previous transplantation, blood transfusion, or pregnancy. While there is growing awareness that multiple components of the immune system can act as effectors of the alloresponse, the role of infectious pathogen exposure in triggering sensitization and allograft rejection has remained a matter of much debate. Here, we describe that exposure to pathogens may enhance the immune response to allogeneic HLA antigens via different pathways. The potential role of allo-HLA cross-reactivity of virus-specific memory T cells, activation of innate immunity leading to a more efficient induction of the adaptive alloimmune response by antigen-presenting cells, and bystander activation of existing memory B cell activation will be discussed in this review. PMID- 28718004 TI - Impact of gastrointestinal events on patient-reported outcomes in Asia-Pacific women with osteoporosis: baseline results of the MUSIC OS-AP study. AB - : The purpose of this study was to describe the impact of gastrointestinal events on patient-reported outcomes and health care resource use among Asia-Pacific women with postmenopausal osteoporosis. The results of this study show that gastrointestinal events decreased adherence, treatment satisfaction, and quality of life in Asia-Pacific women with postmenopausal osteoporosis. PURPOSE: This study aimed to describe the impact of gastrointestinal (GI) events on patient reported outcomes and health care resource use among Asia-Pacific women with postmenopausal osteoporosis. METHODS: The MUSIC OS-AP study included an observational cohort study of postmenopausal women with osteoporosis. Women were classified as untreated or treated, with treated patients further classified as new or experienced users. Adherence was measured by the Adherence Evaluation of Osteoporosis treatment (ADEOS) questionnaire, treatment satisfaction by the Osteoporosis Patient Satisfaction Questionnaire (OPSAT) while general health related and osteoporosis-specific quality of life were measured by the European Quality of Life-5 Dimensions (EQ-5D) questionnaire and the Osteoporosis Assessment Questionnaire (OPAQ), respectively. The association of GI events with these outcomes was determined by covariate-adjusted regression analysis of least squares mean differences in the scores of treated patients with and without GI events. Resource utilization was measured as the number of physician visits over the past 3 months, and multivariate regression analysis was used to assess the association of GI events with the likelihood of a visit. RESULTS: The GI event profile, quality of life scores, and resource use were numerically similar in untreated and treated women. The rate of adherence among treated women was higher in experienced than in new users. As indicated by mean scores, experienced users had better quality of life and slightly higher treatment satisfaction and fewer physician visits than new users. Except for adherence in new users, all measures were similarly adversely affected by GI events in both new and experienced users. CONCLUSIONS: GI events decreased adherence, treatment satisfaction, and quality of life in Asia-Pacific women with postmenopausal osteoporosis. PMID- 28718005 TI - Sunscreens block cutaneous vitamin D production with only a minimal effect on circulating 25-hydroxyvitamin D. AB - : A 50+ SPF sunscreen decreased significantly cutaneous vitamin D production following a single narrow-band (nb)UVB exposure, independently from the body surface area exposed. In contrast, the circulating 25(OH)D3 levels were only minimally affected. It is probable that another endogenous source of precursors is selected when skin-originated precursors are lacking. PURPOSE: Sunscreen use, highly advocated for preventing cutaneous carcinogenesis, is potentially leading to an aggravation of vitamin D deficiency with its consequences on bone health. The effect of sunscreens on circulating vitamin D levels remains debated. This study investigated the effect of sunscreen on cutaneous vitamin D production and circulating 25(OH)D3 levels, according to different body surface areas (BSA). METHODS: Vitamin D and 25(OH)D3 levels were measured in four groups exposed to a single nbUVB exposure on 9% (group I: head and hands), 23% (group II: head, hands and arms), 50% (group III: head, hands, arms and legs) and 96% (group IV: total body) of the body surface without and with a 50+ sun protection factor sunscreen. RESULTS: Sunscreen use decreased by 83, 88.3, 75.7 and 92.5% the cutaneous vitamin D production in groups I to IV, respectively, but only by 13.2, 10.5, 7.7 and 10.4% the values of circulating 25(OH)D3, correspondingly. CONCLUSIONS: Although a 50+ sunscreen decreases significantly cutaneous vitamin D production following a single nbUVB exposure, and independently from the BSA, the circulating 25(OH)D3 levels were only minimally affected. This could be explained by a switch to another endogenous source of precursors. Short-term sunscreen use probably does not affect circulating vitamin D levels and hence does not increase the risk for osteoporosis. The effect of long-term sunscreen use remains however to be determined. PMID- 28718006 TI - [Extracorporeal irradiation : Reimplantation of bone segments in the treatment of malignant bone tumours]. AB - BACKGROUND: Malignant bone tumors themselves and the wide resection required because of them may cause huge bone defects in the bone segment involved. Autologous bone grafts are a reliable option to cover these defects in many cases but their availability is limited. Besides common alternative reconstruction methods, including the use of allografts and/or prostheses, especially extracoroporeal irradiation (ECI) and reimplantation of the bone segment involved is attracting increasingly more attention nowadays. DISCUSSION: In the following, we report on indications/contraindications, details of the operative technique, as well as the recommended rehabilitation regime of ECI. Furthermore, we compare our own results with those published in the recent literature. Especially the advantages and disadvantages of this method, the risks and the complications are illustrated and critically discussed. CONCLUSION: Extracorporeal irradiation of a tumor bearing bone segment is a valuable alternative reconstruction technique following tumor resections of the pelvis, femur and tibia, with encouraging results with respect to local control, complication risks and functional outcome. PMID- 28718007 TI - [Basic principles of fracture healing]. AB - BACKGROUND: In contrast to other tissues, bone has the remarkable ability to heal without scarring. After union of the fracture, the remodeled bone ideally does not differ from the original bone, especially in terms of biomechanical properties. The healing of a fracture resembles the embryonic development of bone. Depending on the biomechanical properties of the fracture, bone heals directly or indirectly, which refers to the formation of cartilage as a step before new bone appears. Currently, treatment of the patient is often limited to anatomical reduction and optimization of the fracture environment with respect to biomechanics. PROSPECTS: Future treatment strategies, however, could include systemic medication that could be especially beneficial for patients at risk of complications in fracture healing. The aim of this review is to provide an overview on the process of fracture healing and to depict possibilities for current and future treatment strategies. PMID- 28718008 TI - The effect of vitamin D and calcium supplementation on falls in older adults : A systematic review and meta-analysis. AB - OBJECTIVES: A number of studies have hypothesized that vitamin D is a potential factor in the prevention of falls in the elderly; however, the effect of vitamin D is still inconsistent and not quantitative. We conducted this meta-analysis to assess the effect of vitamin D on falls among elderly individuals. METHODS: The PubMed and Cochrane Library databases were searched from the earliest possible year up to December 2016. Two authors working independently reviewed the trials, and odds ratios (ORs) were calculated using a fixed-effect or random-effect model by Review Manager 5.3. We included only double-blind randomized, controlled trials (RCTs) of vitamin D in elderly populations that examined fall results. RESULTS: A total of 26 articles were included in which 16,540 elderly individuals received vitamin D supplementation, while 16,146 were assigned to control groups. The meta-analysis showed that combined vitamin D plus calcium supplementation has a significant effect on the reduction in the risk of falls (OR for the risk of suffering at least one fall, 0.87; 95% CI, 0.80-0.94). However, no significant association between vitamin D2 or D3 and a reduction in the risk of falls was found (OR, 0.77; 95% CI, 0.58-1.03 for vitamin D2, and OR, 1.08; 95% CI, 0.98 1.20 for vitamin D3). CONCLUSIONS: Combined calcium plus vitamin D supplementation is statistically significantly associated with a reduction in fall risks across various populations. PMID- 28718010 TI - Peter Sitte (1929-2015): a theistic cell biologist. PMID- 28718009 TI - Relative salinity tolerance of rice cultivars native to North East India: a physiological, biochemical and molecular perspective. AB - Salinity is the second most prevalent abiotic stress faced by plants, and rice is not an exception. Through this study, it has been tried upon, to study the relative salinity tolerance of eight local varieties of North East India. Preliminary screening was based on their dose- and time-dependent physiological responses to salinity stress. Among the cultivars, Tampha was found to be relatively more tolerant, whereas MSE9 the most sensitive. To further ascertain their tolerance capacity, MDA and H2O2 content was determined, which also confirmed the tolerance level of the two cultivars. Histochemical assays for root plasma membrane integrity and leaf and root H2O2 and O2- content also showed more damage in Tampha in comparison to MSE9. Finally, gene expression analysis for Na+/K+ co-transporters, OsHKT2;1, OsHKT2;3 and OsHKT2;4, was performed to observe how the expression level of these transporters varies with the tolerance capacity of these two cultivars in leaves and roots under different time frames. The study reveals Tampha to be the most tolerant and MSE9 the most sensitive when compared to the other six screened cultivars for salinity stress. PMID- 28718011 TI - Case series on the association between blood levels and side effects of afatinib maleate. AB - PURPOSE: Afatinib maleate (AFA) is a second-generation, tyrosine kinase inhibitor (TKI) treatment for specific variants of non-small cell lung cancer exhibiting epidermal growth factor receptor (EGFR) mutations. In this study, we measured the blood AFA levels in six patients with lung cancer and investigated the association between blood levels and side effects of this drug. METHODS: The study subjects were patients who were administered AFA for non-small cell lung cancer. Of these subjects, six patients agreed to participate in the study. The starting dose of AFA was 40 mg/day. We measured trough blood AFA levels on day 1 and 3 after AFA administration, on day 8-12, and every month until AFA administration was discontinued. Side effects were evaluated according to the adverse event codialect standard (CTCAE v.4.0). RESULTS: A temporary discontinuation and/or reduction in AFA dose (within 2 months) because of diarrhea and stomatitis was needed in four patients. Mean blood AFA levels on day 8-12 in these four patients were significantly higher than in other patients (47.0 +/- 9.5 vs. 24.4 +/- 0.1 ng/mL, P = 0.017). In addition, mean renal function prior to AFA administration in these four patients was significantly lower than that in the other patients (49.0 +/- 9.6 mL/min/1.73 m2 vs. 77.2 +/- 9.0, P = 0.026). CONCLUSIONS: High blood AFA levels were associated with the early discontinuation and/or dose reduction of AFA because of untoward side effects, which may also be associated with decreased renal function. PMID- 28718012 TI - Implant decontamination with phosphoric acid during surgical peri-implantitis treatment: a RCT. AB - BACKGROUND: Peri-implantitis is known as an infectious disease that affects the peri-implant soft and hard tissue. Today, scientific literature provides very little evidence for an effective intervention protocol for treatment of peri implantitis. The aim of the present randomized controlled trial is to evaluate the microbiological and clinical effectiveness of phosphoric acid as a decontaminating agent of the implant surface during surgical peri-implantitis treatment. METHODS: Peri-implantitis lesions were treated with resective surgical treatment aimed at peri-implant granulation tissue removal, bone recontouring, and pocket elimination. Fifty-three implant surfaces in 28 patients were mechanically cleaned and treated with either 35% phosphoric etching gel (test group) or sterile saline (control group). Microbiological samples were obtained during surgery; clinical parameters were recorded at baseline and at 3 months after treatment. Data were analyzed using multi-variable linear regression analysis and multilevel statistics. RESULTS: Significant immediate reductions in total anaerobic bacterial counts on the implant surface were found in both groups. Immediate reduction was greater when phosphoric acid was used. The difference in log-transformed mean anaerobic counts between both procedures was not statistical significant (p = 0.108), but there were significantly less culture-positive implants after the decontamination procedure in the phosphoric acid group (p = 0.042). At 3 months post-surgery, 75% of the implants in the control group and 63.3% of the implants in the test group showed disease resolution. However, no significant differences in clinical and microbiological outcomes between both groups were found. CONCLUSIONS: The application of 35% phosphoric acid after mechanical debridement is superior to mechanical debridement combined with sterile saline rinsing for decontamination of the implant surface during surgical peri-implantitis treatment. However, phosphoric acid as implant surface decontaminant does not seem to enhance clinical outcomes on a 3-month follow-up. TRIAL REGISTRATION: Netherlands National Trial Register, NTR5185 (www.trialregister.nl). PMID- 28718013 TI - Brain abscess due to Nocardia infection in an immunocompetent patient with asymptomatic pulmonary alveolar proteinosis. PMID- 28718014 TI - Protein hydrolysate from canned sardine and brewing by-products improves TNF alpha-induced inflammation in an intestinal-endothelial co-culture cell model. AB - PURPOSE: The anti-inflammatory activity of sardine protein hydrolysates (SPH) obtained by hydrolysis with proteases from brewing yeast surplus was ascertained. METHODS: For this purpose, a digested and desalted SPH fraction with molecular weight lower than 10 kDa was investigated using an endothelial cell line (EA.hy926) as such and in a co-culture model with an intestinal cell line (Caco 2). Effects of SPH <10 kDa on nitric oxide (NO) production, reactive oxygen species (ROS) inhibition and secretion of monocyte chemoattractant protein 1 (MCP 1), vascular endothelial growth factor (VEGF), chemokine IL-8 (IL-8) and intercellular adhesion molecule-1 (ICAM-1) were evaluated in TNF-alpha-treated and untreated cells. RESULTS: Upon TNF-alpha treatment, levels of NO, MCP-1, VEGF, IL-8, ICAM-1 and endothelial ROS were significantly increased in both mono- and co-culture models. Treatment with SPH <10 kDa (2.0 mg peptides/mL) significantly decreased all the inflammation markers when compared to TNF-alpha treated control. This protective effect was more pronounced in the co-culture model, suggesting that SPH <10 kDa Caco-2 cells metabolites produced in the course of intestinal absorption may provide a more relevant protective effect against endothelial dysfunction. Additionally, indirect cross-talk between two cell types was established, suggesting that SPH <10 kDa may also bind to receptors on the Caco-2 cells, thereby triggering a pathway to secrete the pro inflammatory compounds. CONCLUSION: Overall, these in vitro screening results, in which intestinal digestion, absorption and endothelial bioactivity are simulated, show the potential of SPH to be used as a functional food with anti-inflammatory properties. PMID- 28718015 TI - Capable and credible? Challenging nutrition science. AB - Nutrition science has enriched our understanding of how to stay healthy by producing valuable knowledge about the interaction of nutrients, food, and the human body. Nutrition science also has raised societal awareness about the links between food consumption and well-being, and provided the basis for food regulations and dietary guidelines. Its collaborative and interdisciplinary research has accomplished much, scientifically and socially. Despite this, nutrition science appears to be in crisis and is currently confronted with a public reluctance to trust nutritional insights. Though deflating trust is a general phenomenon surrounding the scientific community, its impact on nutrition science is particularly strong because of the crucial role of nutrition in everyone's daily life. We, a Dutch collective of nutritionists, medical doctors, philosophers and sociologists of science ( http://www.nutritionintransition.nl ), have diagnosed that nutrition science is meeting inherent boundaries. This hampers conceptual and methodological progress and the translation of novel insights into societal benefit and trust. In other words, nutrition science is facing limitations to its capability and credibility, impeding its societal value. We take up the challenge to halt the threatening erosion of nutrition science's capability and credibility, and explore a way forward. We analyse limitations to capability and credibility, then argue that nutrition science is caught in a vicious circle, and end by offering some suggestions to transcend the limitations and escape the current deadlock. We invite nutritional experts as well as scholars from adjacent disciplines to engage in the discussion. PMID- 28718017 TI - Occurrence and transformations of carbon, nitrogen, and phosphorus related to particle size fraction of sweet potato starch wastewater during hydrolytic acidification processes. AB - Sweet potato starch wastewater (SPSW) is an industrial food-processing waste product, which is a significant pollution source due to its high chemical oxygen demand (COD), nitrogen, and phosphorus loads. The influence of hydrolytic acidification (HA) process on C, N, and P as well as other main parameters were evaluated. It is essential to treat these wastewaters with effective methods such as HA, a general pretreatment application. In this study, we investigate the scientific link between the changes of different fractions of C, N, and P with particle size distribution in response to the newly introduced HA process. Results showed that the levels of COD, TN, and TP remained ultimately stable; pH and suspended solids (SSs) decreased obviously. HA process exhibits excellent capability of reducing the larger particulars (with diameter of >5 MUm) into smaller ones (with diameter of <0.1 MUm). The most significant initial concentration contribution to COD, TN, and TP pollution came from particles and matter with a diameter of >5 MUm, at 41.8, 57.3, and 43.5%, respectively. While the most significant contribution to COD, TN, and TP was resulting from micro molecular size particles (<0.1 MUm) after 48 h. The smallest particles (<0.1 MUm) were the most dominant contribution to all pollutants measured, with COD, TN, and TP contributions of 63.2, 50.4, and 59.3%, respectively. While the contribution of larger particles (particle size >5 MUm) reduced to 10.2, 15.3, and 7.1%, respectively. PMID- 28718016 TI - Blackcurrant anthocyanins stimulated cholesterol transport via post transcriptional induction of LDL receptor in Caco-2 cells. AB - PURPOSES: We previously showed that polyphenol-rich blackcurrant extract (BCE) showed a hypocholesterolemic effect in mice fed a high fat diet. As direct cholesterol removal from the body via the intestine has been recently appreciated, we investigated the effect of BCE on the modulation of genes involved in intestinal cholesterol transport using Caco-2 cells as an in vitro model. METHODS: Caco-2 cells were treated with BCE to determine its effects on mRNA and protein expression of genes important for intestinal cholesterol transport, low-density lipoprotein (LDL) uptake, cellular cholesterol content, and cholesterol transport from basolateral to apical membrane of Caco-2 cell monolayers. Cells were also treated with anthocyanin-rich or -poor fraction of BCE to determine the role of anthocyanin on BCE effects. RESULTS: BCE significantly increased protein levels of LDL receptor (LDLR) without altering its mRNA, which consequently increased LDL uptake into Caco-2 cells. This post transcriptional induction of LDLR by BCE was markedly attenuated in the presence of rapamycin, an inhibitor of mechanistic target of rapamycin complex 1 (mTORC1). In addition, BCE altered genes involved in cholesterol transport in the enterocytes, including apical and basolateral cholesterol transporters, in such a way that could enhance cholesterol flux from the basolateral to apical side of the enterocytes. Indeed, BCE significantly increased the flux of LDL-derived cholesterol from the basolateral to the apical chamber of Caco-2 monolayer. LDLR protein levels were markedly increased by anthocyanin-rich fraction, but not by anthocyanin-free fraction. CONCLUSION: mTORC1-dependent post-transcriptional induction of LDLR by BCE anthocyanins drove the transport of LDL-derived cholesterol to the apical side of the enterocytes. This may represent a potential mechanism for the hypocholesterolemic effect of BCE. PMID- 28718018 TI - The environmental legacy of historic Pb-Zn-Ag-Au mining in river basins of the southern edge of the Massif Central (France). AB - The main rivers (Aude, Orb, Herault) that discharge into the Gulf of Lions and the west bank tributaries of the Rhone River including the Gardon have former non ferrous metal mines in their upper drainage basin. Using unpublished data and data from the literature, this study provides an integrated overview of the contamination of water and sediment along the continent-sea continuum and of its impacts on the biota and on human health. In the upper part of these basins, water and stream sediments are enriched in metal(-loids) compared to median European concentrations. Arsenic is the main contaminant in the rivers Aude and Gardon d'Anduze, Sb in the Orb and Gardon d'Ales, and Tl in the Herault river. A rapid reduction in dissolved and particulate concentrations was systematically observed along the river due to dilution and precipitation. The high concentrations of metal(-loid)s observed suggest that the former mining activity still represents a potential threat for the environment, but the lack of high temporal resolution monitoring, especially during Mediterranean floods, prevents accurate assessment of metal fluxes from these rivers to the Mediterranean Sea. Studies dedicated to the impacts on human health are too rare, given that studies have shown a higher rate of arsenic-specific cancer near Salsigne mine in the Aude River basin and cases of saturnism in children in the upper Herault River basin. These studies underline the need to take environmental health issues into consideration not only in these watersheds but around the entire Mediterranean basin, which harbors numerous metalliferous ores that have been mined for millennia. PMID- 28718019 TI - Neonatal, placental, and umbilical cord blood parameters in pregnant women residing in areas with intensive pesticide application. AB - In rural populations, the proximity to areas with intensive pesticide application represents a risk factor of xenobiotic exposure. Here, we investigated whether newborns born to mothers residing in an area with intensive pesticide application show alterations in placental and neonatal morphometric standards, umbilical cord blood (UCB) biochemical parameters, and/or biomarkers related to oxidative stress and oxidative damage. Samples were collected from 151 healthy pregnant women residing in a rural area (rural group; RG) during the pesticide spraying (SS) and nonspraying (NSS) seasons, as well as from women from an urban population (control group; CG), and grouped according to the delivery type (vaginal or cesarean). In the vaginal delivery group, the placental weight and placental index were higher in the RG groups than in the CG (p = 0.01), whereas in the cesarean delivery group, newborn weight was lower in the RG-SS group than in the CG. In the RG-SS group, UCB erythrocyte osmotic fragility and the DNA damage index (DI) were higher, and superoxide dismutase (SOD) activity was lower than in the RG-NSS group. Acetylcholinesterase and SOD activities were found to be inversely correlated with the DI. PMID- 28718020 TI - Critical aggregates concentration of fatty esters present in biodiesel determined by turbidity and fluorescence. AB - Biodiesel for combustible engine is available as mixture of fossil diesel and fatty esters obtained by transesterification of vegetable oils. The use of biodiesel reduces the amount of SOx, mainly. However, it was already observed that biodiesel has a different behavior in environment in cases of accidental spill and groundwater contamination. It was noticed that the biodegradation of hydrocarbons (cyclic and aliphatic) in the presence of biodiesel are speeded, although the mechanism is still unclear. Considering the chemical structure of fatty esters, it was investigated the formation of aggregates in water solution by fatty esters present in commercial biodiesel. In Brazil, biodiesel is composed by 95% of fossil diesel and 5% of fatty esters mixture. In this work, fatty esters were treated as neutral surfactant, i.e., it was treated as a molecule with polar and non-polar part. Turbidity and fluorescence were used to determine the critical aggregates concentration (CAC). Water solutions containing fatty esters were examined exploiting changes in turbidity and fluorescence intensity of pyrene. Abrupt changes were attributed to aggregates formation, following the same behavior of traditional amphiphilic compounds. It was determined the CAC for ethyl palmitate, ethyl stearate, ethyl oleate, and ethyl linoleate. The values of CAC for fatty esters varied from 1.91 to 4.27 MUmol/L, while CAC for the mixture of esters (biodiesel) was 2.01 for methyl esters and 1.19 for ethyl esters, both prepared using soybean oil. The aggregates formation was also determined by fluorescence measurements considering the changes in intensity of peaks I and III of pyrene. Pyrene senses the changes in environment polarity. The values found of CAC by fluorescence for individual ethyl esters varied from 1.85 to 3.21 MUmol/L, while mixtures of ethyl esters was 2.23 and 2.07 MUmol/L for mixture of methyl esters. The results clearly showed that fatty esters form aggregates and might be responsible for speed degradation of compounds by accommodation of them in inner part of aggregates. PMID- 28718021 TI - Evidence for photolytic and microbial degradation processes in the dissipation of leptospermone, a natural beta-triketone herbicide. AB - Bioherbicides appear as an ecofriendly alternative to synthetic herbicides, generally used for weed management, because they are supposed to have low side on human health and ecosystems. In this context, our work aims to study abiotic (i.e., photolysis) and biotic (i.e,. biodegradation) processes involved in the fate of leptospermone, a natural beta-triketone herbicide, by combining chemical and microbiological approaches. Under controlled conditions, the photolysis of leptospermone was sensitive to pH. Leptospermone has a half-life of 72 h under simulated solar light irradiations. Several transformation products, including hydroxy-leptospermone, were identified. For the first time, a bacterial strain able to degrade leptospermone was isolated from an arable soil. Based on its 16S ribosomal RNA (rRNA) gene sequence, it was affiliated to the Methylophilus group and was accordingly named as Methylophilus sp. LS1. Interestingly, we report that the abundance of OTUs, similar to the 16S rRNA gene sequence of Methylophilus sp. LS1, was strongly increased in soil treated with leptospermone. The leptospermone was completely dissipated by this bacteria, with a half-life time of 6 days, allowing concomitantly its growth. Hydroxy-leptospermone was identified in the bacterial culture as a major transformation product, allowing us to propose a pathway of transformation of leptospermone including both abiotic and biotic processes. PMID- 28718022 TI - Identifying nitrate sources and transformations in Taizi River Basin, Northeast China. AB - The nitrate (NO3-) pollution of aquatic systems in Northeast China is a severe problem. To identify NO3- sources and transformations in different zones with different land uses in the Taizi River Basin, ion-exchange methods were utilized to determine the concentrations and isotopic compositions (delta15N and delta18O) of NO3- and chloride (Cl-). Results showed that Cl- concentrations ranged from 2.7 to 73.4 mg/L. Cl- concentrations were the highest in zone 8 and the lowest in zone 1. NO3- concentrations ranged from 0.3 to 27.4 mg/L and were the highest in zone 1 and the lowest in zone 8. During the sampling period, delta15N-NO3- values varied from 3.8 to 37.20/00, and delta18O-NO3- values ranged from -0.5 to 10.40/00. delta15N-NO3- values were the highest in zone 9 and the lowest in zone 1. The differences in physicochemical parameters and NO3- isotopes may be affected by land use and biogeochemical nitrogen processes in different zones. The combined analysis of dual isotopes (delta15N-NO3- and delta18O-NO3-) and NO3 /Cl- versus Cl- showed that different sources contributed NO3- to different zones during the sampling period. Soil N, manure, and sewage were the main NO3- sources in the Taizi River Basin. In zones 1 to 6, the delta15N-NO3- values of almost all samples were more than 100/00, NO3-/Cl- values were high, and Cl- molar concentration was low during the sampling period. These findings suggested that the volatilization and nitrification of soil NH4+ might be related to NO3- sources in zones 1 to 6. A 1:1 to 2:1 linear relationship between delta15N-NO3- and delta18O-NO3- combined with the significantly negative relationship between ln (NO3-) and delta18O-NO3- indicated that denitrification affected NO3- distribution in zones 8 to 9 during the sampling period. These results can provide useful information to control NO3- concentrations in different zones in Taizi River Basin. PMID- 28718023 TI - Two-year survey of specific hospital wastewater treatment and its impact on pharmaceutical discharges. AB - It is well known that pharmaceuticals are not completely removed by conventional activated sludge wastewater treatment plants. Hospital effluents are of major concern, as they present high concentrations of pharmaceutically active compounds. Despite this, these specific effluents are usually co-treated with domestic wastewaters. Separate treatment has been recommended. However, there is a lack of information concerning the efficiency of separate hospital wastewater treatment by activated sludge, especially on the removal of pharmaceuticals. In this context, this article presents the results of a 2-year monitoring of conventional parameters, surfactants, gadolinium, and 13 pharmaceuticals on the specific study site SIPIBEL. This site allows the characterization of urban and hospital wastewaters and their separate treatment using the same process. Flow proportional sampling, solid-phase extraction, and liquid chromatography coupled with tandem mass spectrometry were used in order to obtain accurate data and limits of quantification consistent with ultra-trace detection. Thanks to these consolidated data, an in-depth characterization of urban and hospital wastewaters was realized, as well as a comparison of treatment efficiency between both effluents. Higher concentrations of organic carbon, AOX, phosphates, gadolinium, paracetamol, ketoprofen, and antibiotics were observed in hospital wastewaters compared to urban wastewaters. Globally higher removals were observed in the hospital wastewater treatment plant, and some parameters were shown to be of high importance regarding removal efficiencies: hydraulic retention time, redox conditions, and ambient temperature. Eleven pharmaceuticals were still quantified at relevant concentrations in hospital and urban wastewaters after treatment (e.g., up to 1 MUg/L for sulfamethoxazole). However, as the urban flow was about 37 times higher than the hospital flow, the hospital contribution appeared relatively low compared to domestic discharges. Thanks to the SIPIBEL site, data obtained from this 2-year program are useful to evaluate the relevance of separate hospital wastewater treatment. PMID- 28718024 TI - Propositional modification for the USEPA models for human exposure assessment on chemicals in settled dust or soil. PMID- 28718025 TI - Reduction of individual or combined toxicity of fumonisin B1 and zearalenone via dietary inclusion of organo-modified nano-montmorillonite in rats. AB - Fusarium mycotoxins are nature environmental contaminants worldwide in animal feed and human food resulting in a serious health risk. The present study aimed to evaluate the potential role of organo-modified nano-montmorillonite (OMNM) against the health risk and the oxidative stress resulted from the exposure of fumonisin (FB1) and zearalenone (ZEN) individually and in combination in rats. Eight groups of female Sprague Dawley rats were treated orally for 3 weeks including the control group, FB1 alone-treated group (50 mg/kg b.w.), ZEN alone treated group (40 MUg/kg b.w), FB1 plus ZEN-treated group, the group fed basal diet supplemented with OMNM (5 g/kg diet), and the groups fed basal diet supplemented with OMNM and treated with FB1 and/or ZEN. At the end of the experimental period, samples of blood and tissues were collected for different biochemical and histological analyses. The results revealed that administration of FB1 and/or ZEN resulted in significant disturbances in the biochemical parameters tested, lipid profiles, serum cytokines, oxidative stress indices, the activity of antioxidant enzymes, and the histological status of the liver and kidney. Co-administration of both mycotoxins indicated a synergistic effect. OMNM alone was safe and succeeded to reduce and/or prevent most of the toxicity of both mycotoxins. It could be concluded that OMNM is a novel and promising nanograde adsorbent suitable for the protection against the combined exposure to FB1 and ZEN. PMID- 28718026 TI - Solid-phase extraction of multi-class pharmaceuticals from environmental water samples onto modified multi-walled carbon nanotubes followed by LC-MS/MS. AB - In this paper, pristine and chemically treated multi-walled carbon nanotubes (MWCNTs) were employed as solid-phase extraction sorbents for the isolation and enrichment of multi-class pharmaceuticals from the surface water and groundwater, prior to liquid chromatography-tandem mass spectrometry analysis. Thirteen pharmaceuticals that belong to different therapeutical classes (erythromycin, azithromycin, sulfamethoxazole, diazepam, lorazepam, carbamazepine, metoprolol, bisoprolol, enalapril, cilazapril, simvastatin, clopidogrel, diclofenac) and two metabolites of metamizole (4-acetylaminoantipyrine and 4-formylaminoantipyrine) were selected for this study. The influence of chemical treatment on MWCNT surface characteristics and extraction efficiency was studied, and it was shown that HCl treatment of MWCNT leads to a decrease in the amount of surface oxygen groups and at the same time favorably affects the efficiency toward extraction of selected pharmaceuticals. After the optimization of the SPE procedure, the following conditions were chosen: 50 mg of HCl-treated MCWNT as a sorbent, 100 mL of water sample at pH 6, and 15 mL of the methanol-dichloromethane mixture (1:1, v/v) as eluent. Under optimal conditions, high recoveries (79-119%), as well as low detection (0.2 to 103 ng L-1) and quantitation (0.5-345 ng L-1) limits, were obtained. The optimized method was applied to the analysis of five surface water and two groundwater samples, and three pharmaceuticals were detected, the antiepileptic drug carbamazepine and two metabolites of antipyretic metamizole. PMID- 28718027 TI - Comprehensive analysis of mercury pollution in the surface riverine sediments in the Haihe Basin, China. AB - The Haihe Basin extends over 318,000 km2 or 3.3% of the total area of China, has a population of over 120 million, and is one of China's most polluted river basins. We investigated the pollution and risks from mercury (Hg) in surface riverine sediments of this basin and found that total Hg concentrations in surface sediments ranged from 0.001 to 1.05 mg/kg and averaged 0.054 mg/kg. Using the modified European Community Bureau of Reference standard method, we found that the exchangeable/acid-soluble, reducible, oxidizable, and residual fractions of Hg accounted for 9.86, 6.54, 11.0, and 72.6% of total Hg, respectively. The riverine sediments in the Da Qing He watershed had the highest anthropogenic enrichment of Hg (enrichment factor >1.5). There was a high potential ecological risk from Hg in the riverine sediments in the upper reaches of the Bei San He and Da Qing He watersheds, the middle reaches of the Luan He and Hei Long Gang watersheds, and the lower reaches of the Zi Ya He watershed. Comparison with risk assessment code showed that the riverine sediments in the Da Qing He, Luan He, and Tu-Hai Ma-Xia He watersheds represented a medium risk, with 16.6, 11.9, and 11.8% of Hg in the exchangeable/acid-soluble fraction, respectively. PMID- 28718028 TI - Predicting attenuation of solar radiation (UV-B, UV-A and PAR) in waste stabilization ponds under Sahelian climatic conditions. AB - Because of its importance in pathogen removal and algal productivity in waste stabilization ponds, sunlight penetration was measured in microcosms and in situ under Sahelian climatic conditions. The different wavelengths were detected using a submersible radiometer equipped with three sensors: UV-B (311 nm), UV-A (369 nm) and photosynthetically available radiation (PAR, 400-700 nm). UV-B was more attenuated than UV-A and PAR. Facultative pond was more light-attenuating than maturation pond. The mean euphotic depths for UV-B were 0.20 and 0.31 m, respectively, in the facultative and maturation ponds; PAR penetrated deeper with mean euphotic depths of 0.27 and 0.42 m, respectively. The mean Secchi depths were 0.16 and 0.10 m in the maturation and facultative ponds waters, respectively. In view of the reported results, the contribution of the deeper sections of ponds to pathogen removal mediated by sunlight seems negligible. Therefore, when designing WSPs, these findings should be considered to increase the penetration of damaging wavelengths in order to ensure efficient microbial removal. For more pathogen elimination, downstream shallow ponds could be considered. The paper also shows how suspended solids, turbidity, and Secchi depth are related to the attenuation coefficients and euphotic depths. The developed models could be used to predict light penetration and then algal growth and pathogen removal mediated by sunlight in waste stabilization ponds located in Sahelian climate. PMID- 28718029 TI - Serum C-reactive protein increases the risk of venous thromboembolism: a prospective study and meta-analysis of published prospective evidence. AB - Evolving debate suggests that C-reactive protein (CRP) might be associated with the development of venous thromboembolism (VTE); however, the evidence is conflicting. We aimed to assess the prospective association of CRP with VTE risk. C-reactive protein was measured in serum samples at baseline from 2420 men aged 42-61 years, from the Kuopio Ischemic Heart Disease study. Within-person variability in CRP levels was corrected for using repeat measurements of CRP taken 11 years after baseline. Incident VTE events (n = 119) were recorded during a median follow-up of 24.7 years. The age-adjusted regression dilution ratio for loge CRP was 0.57 [95% confidence interval (CIs): 0.51-0.64]. In age-adjusted Cox regression analysis, the hazard ratio (95% CIs) for VTE per 1 standard deviation (SD) increase in loge baseline CRP was 1.17 (0.98-1.40). Further adjustment for several established and emerging risk factors did not alter the association. In a meta-analysis of nine population-based studies (including the current study) comprising 81,625 participants and 2225 VTE cases, the fully-adjusted risk estimate for VTE was 1.14 (1.08-1.19) per SD increase in loge baseline CRP. In a pooled dose-response analysis, a linear association between CRP and VTE risk was suggested (P for nonlinearity = 0.272). The pooled risk estimate for VTE per 5 mg/l increment in CRP levels was 1.23 (1.09-1.38). C-reactive protein was only modestly associated with VTE risk in the primary analysis. Pooled evidence, however, suggests that elevated CRP is associated with greater VTE risk, consistent with a linear dose-response relationship. PMID- 28718030 TI - Precision Stroke Animal Models: the Permanent MCAO Model Should Be the Primary Model, Not Transient MCAO. AB - An argument for preclinical stroke research to make more use of the permanent middle cerebral artery occlusion (MCAO) model, rather than transient MCAO, is presented. Despite STAIR recommending permanent MCAO as the primary model, preclinical stroke research has not been listened. In 2012, Hossmann reported that 64% of the treatment studies for MCAO used prompt transient MCAO models and only 36% of the studies used permanent MCAO or gradual transient MCAO (i.e., embolic stroke model). Then, in 2014 and 2015, 88% of published basic science studies on large vessel occlusion used the transient MCAO model. However, this model only represents 2.5-11.3% of large vessel stroke patients. Therefore, the transient MCAO model, which mimics stroke with reperfusion, does not accurately reflect the majority of clinical stroke cases. Thus, once again, the argument for studying permanent MCAO as a primary model is made and supported. PMID- 28718032 TI - Erratum to: Axillary Micrometastases and Isolated Tumor Cells Are Not an Indication for Post-mastectomy Radiotherapy in Stage 1 and 2 Breast Cancer. PMID- 28718031 TI - Newcomers in paediatric GI pathology: childhood enteropathies including very early onset monogenic IBD. AB - Childhood enteropathies are a group of diseases causing severe chronic (>2-3 weeks) diarrhoea often starting in the first week of life with the potential for fatal complications for the affected infant. Early identification and accurate classification of childhood enteropathies are, therefore, crucial for making treatment decisions to prevent life-threatening complications. Childhood enteropathies are classified into four groups based on the underlying pathology: (i) conditions related to defective digestion, absorption and transport of nutrients and electrolytes; (ii) disorders related to enterocyte differentiation and polarization; (iii) defects of enteroendocrine cell differentiation; and (iv) disorders associated with defective modulation of intestinal immune response. While the intestinal mucosa is usually normal in enteropathies related to congenital transport or enzyme deficiencies, the intestinal biopsy in other disorders may reveal a wide range of abnormalities varying from normal villous architecture to villous atrophy and/or inflammation, or features specific to the underlying disorder including epithelial abnormalities, lipid vacuolization in the enterocytes, absence of plasma cells, lymphangiectasia, microorganisms, and mucosal eosinophilic or histiocytic infiltration. This review intends to provide an update on small intestinal biopsy findings in childhood enteropathies, the "newcomers", including very early onset monogenic inflammatory bowel disease (IBD), in particular, for the practicing pathologist. PMID- 28718033 TI - A New Clinical Trial of Neoadjuvant Chemotherapy Combined With Transoral Robotic Surgery and Customized Adjuvant Therapy for Patients With T3 or T4 Oropharyngeal Cancer. AB - BACKGROUND: A prospective clinical trial of combination neoadjuvant chemotherapy, transoral robotic surgery (TORS), and customized adjuvant therapy for patients with locally advanced oropharyngeal cancer was conducted. METHODS: Between July 2009 and October 2016, 31 patients were enrolled in this clinical trial. RESULTS: The primary lesions were located in the tonsils of 27 patients and in the base of the tongue of 4 patients. Of the 31 patients, 16 (51.6%) were classified as T3 and 15 patients (48.4%) as T4a. Three patients (9.7%) had stage 3 disease, and 28 (90.3%) had stage 4 disease. The 5-year overall survival rate was 78.7%; the 5 year disease-specific survival rate was 85%; and the 5-year disease-free survival rate was 80.8%. At the final follow-up visit, 26 patients were alive with no evidence of disease, and 1 was alive with disease. Four patients died during the study: two of tumor-node-metastasis (TNM)-related disease and two of another condition. All the patients tolerated an oral diet at an average of 7.4 days postoperatively. At the subjective swallowing evaluation using the Functional Outcome Swallowing Scale score, 83.9% of the patients exhibited favorable outcomes. No patient was permanently dependent on a feeding tube. All the patients breathed and phonated in the absence of a permanent tracheotomy at the final follow-up evaluation. CONCLUSIONS: The treatment strategy in this study afforded good oncologic and functional outcomes for patients with locally advanced oropharyngeal cancer. Although future large-scale multicenter studies with longer follow-up periods are needed, this study showed that neoadjuvant chemotherapy combined with TORS is useful for treating advanced oropharyngeal cancer. PMID- 28718034 TI - Hepatoceliac Lymph Node Involvement in Advanced Ovarian Cancer Patients: Prognostic Role and Clinical Considerations. AB - BACKGROUND: The study aimed too investigate the rate of hepatoceliac lymph node (HCLN) involvement, as well as its association with clinicopathologic features, together with morbidity of HCLN resection and the prognostic impact of metastatic HCLN status on patients with advanced ovarian cancer (OC) undergoing cytoreductive surgery. METHODS: All consecutive patients with stages 3c to 4 epithelial OC who underwent HCLN surgery from January 2010 to September 2016 were analyzed for surgical procedures, pathology, and oncologic outcomes. RESULTS: During the study period, 85 patients underwent HCLN resection. Absence of visible tumor at the end of surgery was documented for 73 of the patients (85.9%). The median number of HCLNs removed was 6 (range 1-18). Histopathologic evaluation was able to identify HCLN metastasis in 45 (52.9%) of the 85 cases. No difference in the rate of surgical morbidity according to pathologic status of HCLN was observed. As of December 2016, the median follow-up period was 36 months (range 6 54 months). Recurrence of disease was observed in 35 (41.2%) of the 85 cases. Relapse of disease most frequently occurred for the patients with metastatic HCLN involvement (65.7%) compared with the patients who had no HCLN involvement (34.3%) (p = 0.048). The median progression-free survival values were 16 months (95% confidence interval [CI], 12-19 months) for the patients with metastatic HCLNs and 22 months (95% CI, 12-19 months) for the patients with no HCLN involvement (p = 0.035). CONCLUSIONS: The study confirmed that HCLN surgery is feasible with acceptable morbidities for patients with advanced OC. Metastatic HCLNs are a marker of disease severity associated with worst oncologic outcome. PMID- 28718035 TI - Elevated Preoperative Neutrophil-Lymphocyte Ratio is Predictive of a Poorer Prognosis for Pediatric Patients with Solid Tumors. AB - BACKGROUND: An elevated neutrophil-lymphocyte ratio (NLR) has been shown to indicate poorer prognosis for adults with solid tumors and potentially represents an independent, universal adjunct prognostic factor. The value of NLR in a pediatric setting has not been evaluated. This study sought to determine the prognostic value of NLR for pediatric patients with solid tumors. METHODS: Pediatric patients with solid tumors undergoing neoadjuvant chemotherapy followed by surgery with curative intent between 2000 and 2014 were eligible for this study. A preoperative peripheral blood count within 1 month of surgery taken after recovery from recent chemotherapy was analyzed in relation to overall survival (OS) and event-free survival (EFS). RESULTS: This retrospective study enrolled 293 patients. The median age at diagnosis was 46.5 months (range 0.1 206.1 months). Males accounted for 58% of the patients. The median OS was 49 months. An NLR cutoff of 2.5 was used in the analysis. In the univariate analysis, a high NLR was associated with low OS (p = 0.001) and low EFS (p = 0.020). Other factors identified in the univariate analysis that affected survival included metastatic disease at diagnosis (p < 0.001) and tumor type (p = 0.012). The multivariate analyses showed that a high NLR was associated with low OS (p = 0.014) but not with EFS (p = 0.270). The multivariate analysis of neuroblastoma patients found that a high NLR was associated with low OS (p = 0.013). CONCLUSIONS: An elevated NLR is prognostic of a poorer outcome for pediatric patients with solid tumors and potentially represents an independent, universal adjunct prognosticator in such cases. PMID- 28718036 TI - Paravertebral Blocks Reduce Narcotic Use Without Affecting Perfusion in Patients Undergoing Autologous Breast Reconstruction. AB - BACKGROUND: Autologous breast reconstruction offers excellent long term outcomes after mastectomy. However, maintaining adequate postoperative analgesia remains challenging. Use of paravertebral blocks (PVBs) reduces postoperative narcotic use and length of stay, and enhanced recovery protocols with mixed analgesia methods are gaining popularity, but few studies have explored the intraoperative effects of these interventions. METHODS: Patients who underwent abdominally based autologous breast reconstruction between 2010 and 2016 were compiled into a retrospective database. We used electronic medical records to determine demographics, as well as perioperative and intraoperative vital signs and narcotic, anxiolytic, crystalloid, colloid, blood product, and vasopressor requirements, and postoperative complications. Results were compared between patients who had a PVB and those who did not and those who had a PVB alone and those who followed our enhanced recovery protocol using standard statistical methods and adjusting for preoperative values. RESULTS: A total of 170 patients were included in the study. Sixty-six had a PVB, and 104 did not. Of the 66 who had a PVB, 19 followed our enhanced recovery protocol. Patients who did not have a PVB required 171.6 mg of total narcotic medication in the perioperative period, those with a PVB alone required 146.9 mg, and those who followed the ERAS protocol 95.2 mg (p = 0.01). There was no difference in intraoperative mean arterial pressure, time with mean arterial pressure <80% of baseline, vasopressor use, or fluid requirement. There was no difference in complication rate. CONCLUSIONS: PVBs and an enhanced recovery protocol reduce the use of narcotic medications in autologous breast reconstruction without impacting intraoperative hemodynamics. Breast reconstruction after mastectomy restores body image and improves health-related quality of life, satisfaction with appearance and physical, psychosocial, and sexual well-being (Donovan et al. in J Clin Oncol 7(7):959-968, 1989; Eltahir et al. in Plast Reconstr Surg 132(2):201e-209e, 2013; Jagsi et al. in Ann Surg 261(6):1198-1206, 2015). For patients pursuing breast reconstruction, there are two major options: prosthetic (tissue expander/implant) or autologous reconstruction. However, while providing exceptional long-term outcomes, postoperative pain and length of hospital stay remains a major challenge preventing more widespread adoption of autologous breast reconstruction (Albornoz et al. in Plast Reconstr Surg 131(1):15-23, 2013; Gurunluoglu et al. in Ann Plast Surg 70(1):103-110, 2013; Kulkarni et al. in Plast Reconstr Surg 132(3):534-541, 2013; Sbitany et al. in Plast Reconstr Surg 124(6):1781-1789, 2009). Acute postoperative pain contributes to prolonged hospital stays, increased narcotic use, and associated risks of the aforementioned. PMID- 28718037 TI - Cost-Effectiveness of Surveillance for Distant Recurrence in Extremity Soft Tissue Sarcoma. AB - BACKGROUND: Optimal distant recurrence (DR) surveillance strategies for extremity soft tissue sarcoma (STS) are unknown. We performed a cost-effectiveness analysis of different imaging modalities performed at guideline-specified intervals. METHODS: We developed a Markov model simulating lifetime outcomes for 54-year-old patients after definitive treatment for American Joint Committee on Cancer stage II-III extremity STS using four surveillance strategies: watchful waiting (WW), chest X-ray (CXR), chest computed tomography (CCT), and positron emission tomography-computed tomography (PET/CT). Probabilities, utilities, and costs were extracted from the literature and Medicare claims to determine incremental cost effectiveness ratios (ICER). RESULTS: CCT was the most effective and most costly strategy with CXR the most cost-effective strategy at a societal willing-to-pay (WTP) of $100,000/quality-adjusted life year (QALY). The ICER was $12,113/QALY for CXR versus $104,366/QALY for CCT while PET/CT was never cost-effective. Sensitivity analyses demonstrated CCT becomes the preferred imaging modality as the lifetime risk of DR increases beyond 33% or as the WTP increases beyond $120,000/QALY. CONCLUSIONS: Optimal DR surveillance imaging for stage II-III extremity STS should be individualized based on patients' risks for DR. These results suggest CXR, or CCT performed at more protracted intervals, may be preferred for lower-risk patients (i.e., DR risk <33%), whereas CCT may be preferred for higher-risk patients (i.e., DR risk >33%). Further study of optimal strategies is needed. In the interim, these findings may help to refine guidelines to reduce resource overutilization during routine surveillance of lower-risk sarcoma patients. PMID- 28718038 TI - Reappraisal of Staging Laparoscopy for Patients with Pancreatic Adenocarcinoma: A Contemporary Analysis of 1001 Patients. AB - BACKGROUND: Recent advances in imaging and the increasing use of neoadjuvant therapy puts the contemporary utility of staging laparoscopy for patients with pancreatic adenocarcinoma (PDAC) into question. This study aimed to develop a prognostic score to optimize prevention of an unnecessary laparotomy and minimize the rate for unnecessary laparoscopy. METHODS: Clinicopathologic data were evaluated for all patients undergoing surgical intervention for PDAC between 2001 and 2015, who were stratified into group 1 (2001-2008) and group 2 (2009-2014). RESULTS: The study identified 1001 patients eligible for analysis, 331 (33%) of whom underwent a staging laparoscopy before exploration. An unnecessary laparotomy was prevented for 44.4% of the patients in period 1 and for 24% of the patients in period 2 (p < 0.001). Male gender [odds ratio (OR), 1.8; p < 0.05], preoperative resectability (borderline resectable OR 2.1; p < 0.019; locally advanced OR 7.6; p < 0.001), CA 19-9 levels higher than 394 U/L (OR 3.1; p < 0.001), no neoadjuvant chemotherapy (OR 2.7; p = 0.012), and pancreatic body or tail lesions (OR 1.8; p = 0.063) were predictive of occult metastatic disease. The developed scoring index demonstrated a c-statistic of 0.729. The observed-to expected ratio for the index at every score level validated the index's model. A score cutoff at 4 was able to detect 76.1% of radiographically occult metastatic disease. CONCLUSION: The rate for unnecessary laparotomy among patients with PDAC has decreased in contemporary times, but unnecessary laparotomy still occurs for 1 in 4 patients. Using our scoring system, a cutoff of 4 allows 76% of radiographically occult metastases to be predicted, thereby selecting high-risk patients for laparoscopic biopsy and potentially avoiding a non-therapeutic laparotomy. PMID- 28718039 TI - A decade of atrial fibrillation ablation : Shifts in patient characteristics and procedural outcomes. AB - BACKGROUND: Over the past decade, radiofrequency catheter ablation (RFCA) of atrial fibrillation (AF) has evolved into a frequently performed procedure. The aim of this study was to monitor changes in patient characteristics, procedural characteristics, outcomes and complications over the past 10 years. METHODS: All consecutive patients who underwent primary RFCA treatment of AF in the University Medical Center Utrecht from 2005-2015 were included. In all patients, the primary ablation strategy was pulmonary vein (PV) antrum isolation without additional substrate modification. Baseline patient and procedure characteristics, and 1 year follow-up data of 975 patients were prospectively collected. RESULTS: In 2005, 73.4% of patients suffered from paroxysmal AF, which decreased to 45.3% in 2014. Mean age increased from 54 +/- 9 to 61 +/- 10 years and CHA2DS2-VASc score >=2 from 18 to 40.6%. History of AF decreased significantly from 7 to 4 years. Mean procedure duration was 237 +/- 53 min in 2005 and 163 +/- 41 min in 2014. Fluoroscopy time significantly decreased from 41 +/- 17 to 19 +/- 8 min and total radiation exposure from 465 (263-687) to 210 (118-376) mGy. One-year success remained similar (2005: 55.6%, 2014: 54.8%), as did the amount of PV reconnection observed during redo procedures. Due to a marked reduction in vascular complications and moderate PV stenosis, the total complication rate decreased significantly. CONCLUSION: Over the past decade, AF ablation has increasingly been performed in older patients with persistent AF and more comorbidity. Moreover, it has been performed earlier after AF diagnosis. Although several performance parameters, such as procedure duration and complication rate, improved, 1-year single procedure success remained unchanged. PMID- 28718040 TI - Erratum to: Phylogeny and biogeography of the genus Stevia (Asteraceae: Eupatorieae): an example of diversification in the Asteraceae in the new world. PMID- 28718042 TI - Contrast enhanced ultrasound for focal liver lesions: how accurate is it? AB - With the recent FDA approval for characterization of focal liver lesions (FLL) in both pediatric and adult patients using Lumason (sulfur hexafluoride microbubbles), increased use of ultrasound contrast for routine clinical use is expected. This agent has been available for many years in Europe and Asia, and a large body of literature is available regarding the sensitivity and specificity of this agent. In addition, a few studies have directly compared CEUS to CECT and CEMRI for the characterization of focal liver lesions. This paper reviews the literature to provide a background to investigators in the United States as to the accuracy of CEUS in the characterization of FLL. This paper reviews the literature regarding sulfur hexafluoride microbubbles (Lumason in the USA and Sonovue in the rest of the world) since it is the only FDA approved agent in the USA for characterization of FLL. The results of other ultrasound contrast agents which are not FDA approved for abdominal indications (approval for cardiac indications) most likely will have similar results. PMID- 28718041 TI - Quality of vision, patient satisfaction and long-term visual function after bilateral implantation of a low addition multifocal intraocular lens. AB - PURPOSE: The aim of the current study was to compare the quality of vision, contrast sensitivity and patient satisfaction with a biaspheric, segmented, rotationally asymmetric IOL (Lentis Comfort LS-313 MF 15-Oculentis GmbH, Berlin, Germany) as opposed to those of a monofocal IOL. METHODS: This prospective single blind comparative study included two groups of patients affected by bilateral senile cataract who underwent lens extraction and IOL implantation. The first group received a bilateral implantation of a monofocal IOL, and the second group received a bilateral implantation of the Comfort IOL. Twelve months after surgery uncorrected and corrected visual acuity at different distances (30, 50, 70 cm and 4 m), defocus curve and contrast sensitivity were assessed. Patient's satisfaction and spectacle independence were evaluated by mean of the NEI RQL-42 questionnaire. RESULTS: No significant differences were found between the groups in terms of near vision. The group of patients implanted with a Comfort IOL obtained the best results at intermediate distances (50 and 70 cm P < .001). Both groups showed an excellent uncorrected distance visual acuity (4 m). No statistically significant differences were found in terms of corrected near, intermediate and distance visual acuity. Concerning contrast sensitivity, no statistically significant differences between the groups were observed at any cycles per degree. The NEI RQL-42 questionnaire showed statistically significant differences between the group for "near vision" (P = .015), "dependence on correction" (P = .048) and "suboptimal correction" (P < .001) subscales. CONCLUSION: Our findings indicated that the Comfort IOL +1.5 D provides a good intermediate spectacle independence together with a high quality of vision, with a low amount of subjective symptoms and a contrast sensitivity similar to those obtained with a monofocal IOL. PMID- 28718043 TI - Impact of rituximab on patient-reported outcomes in patients with rheumatoid arthritis from the US Corrona Registry. AB - To evaluate the impact of rituximab on patient-reported outcomes (PROs) in a US based observational cohort of patients with rheumatoid arthritis (RA). Patients with active RA, prior exposure to >=1 tumor necrosis factor inhibitor (TNFi) and who newly initiated rituximab were identified. Changes in PROs were assessed 1 year after rituximab initiation. PRO measures included Clinical Disease Activity Index (CDAI); patient global disease activity, pain and fatigue (visual analog score; 0-100); morning stiffness (hours); modified Health Assessment Questionnaire (mHAQ; 0-3); and EuroQoL EQ-5D. Of the 667 patients who newly initiated rituximab, baseline PRO and clinical measures indicated that patients were substantially impacted by their RA disease and quality of life; 54% of patients had high disease activity. One year after rituximab initiation, 49.0, 47.1, 49.8, and 23.2% of patients reported clinically meaningful improvements in patient global, pain, fatigue, and mHAQ, respectively. Morning stiffness and EuroQol EQ-5D domains improved in 48 and 19-32% of patients, respectively. These real-world registry data demonstrated that patients with long-standing, refractory RA experienced improvements in PROs 1 year after initiating rituximab. PMID- 28718044 TI - Enthesis as a target organ in rheumatic diseases: an expanding frontier. PMID- 28718045 TI - Full-length genome sequence analysis of four subgroup J avian leukosis virus strains isolated from chickens with clinical hemangioma. AB - Since 2014, cases of hemangioma associated with avian leukosis virus subgroup J (ALV-J) have been emerging in commercial chickens in Guangxi. In this study, four strains of the subgroup J avian leukosis virus (ALV-J), named GX14HG01, GX14HG04, GX14LT07, and GX14ZS14, were isolated from chickens with clinical hemangioma in 2014 by DF-1 cell culture and then identified with ELISA detection of ALV group specific antigen p27, the detection of subtype specific PCR and indirect immunofluorescence assay (IFA) with ALV-J specific monoclonal antibody. The complete genomes of the isolates were sequenced and it was found that the gag and pol were relatively conservative, while env was variable especially the gp85 gene. Homology analysis of the env gene sequences showed that the env gene of all the four isolates had higher similarities with the hemangioma (HE)-type reference strains than that of the myeloid leukosis (ML)-type strains, and moreover, the HE type strains' specific deletion of 205-bp sequence covering the rTM and DR1 in 3'UTR fragment was also found in the four isolates. Further analysis on the sequences of subunits of env gene revealed an interesting finding: the gp85 of isolates GX14ZS14 and GX14HG04 had a higher similarity with HPRS-103 and much lower similarity with the HE-type reference strains resulting in GX14ZS14, GX14HG04, and HPRS-103 being clustered in the same branch, while gp37 had higher similarities with the HE-type reference strains when compared to that of HPRS 103, resulted in GX14ZS14, GX14HG04, and HE-type reference strains being clustered in the same branch. The results suggested that isolates GX14ZS14 and GX14HG04 may be the recombinant strains of the foreign strain HPRS-103 with the local epidemic HE-type strains of ALV-J. PMID- 28718046 TI - Complete genome sequencing and characterization revealed a recombinant subgroup B isolate of avian leukosis virus with a subgroup J-like U3 region. AB - One natural recombinant subgroup B avian leukosis virus (ALV) with a subgroup J like U3 region was isolated from commercial native chickens that experienced disease in 2014 and named GX14FF03. GX14FF03 was isolated by DF-1 cell culture and then identified with ELISA detection of avian leukosis virus p27 group specific antigen, the detection of subtype specific PCR, and indirect immunofluorescence assay with ALV-B-specific monoclonal antibody. Its complete proviral genome was sequenced and compared with the reference strains of ALVs and found that the gag and pol were relatively conservative. The gp85 of GX14FF03 showed 91.3-96.2% amino acid identity to the other ALV-B reference strains and 36.0-37.1% identity to the ALV-J reference strains, and its U3 region showed 49.4 89.3% nucleotide identity to ALV-A, B, C, D, E, K reference strains and 91.6 95.3% identity to ALV-J reference strains. Phylogenetic analysis of U3 region showed that GX14FF03 and ALV-J reference strains were in the same cluster. Moreover, an additional AIB REP1 retroviral transcription regulatory element was found in GX14FF04 U3 region which was only presenting in ALV-J strains. These results suggested that isolate GX14FF03 may be a recombinant ALV-B with the ALV-J like U3 region. PMID- 28718047 TI - Antigenic variability of foot-and-mouth disease virus serotype O during serial cytolytic passage. AB - The emergence and disappearance of antigenic variants of foot-and-mouth disease virus (FMDV) during a field outbreak occurs periodically due to the volatile nature of its genome. In the present analysis, change in antigenic behavior of serotype O FMDV during the serial cytolytic passage in the absence of immune pressure was observed. Initially, the isolate showed a poor antigenic match (relationship value <0.3) with the serotype O vaccine strain and upon serial passage increase in relationship value was observed. Comparison of capsid sequence revealed substitution at four positions (VP3:K58 -> E and P158 -> S, VP1:E83 -> K and R172 -> Q) acquired during the serial passage. Examination of passage level and amino acid substitution revealed the critical role of position VP3-58 that was identified earlier as crucial for antigenic site IV, in the observed antigenic variability. The role of position VP3-58 was further confirmed using reverse genetics approach. PMID- 28718048 TI - Joint Effects of GWAS SNPs in Coagulation System Confer Risk to Hypertensive Intracerebral Hemorrhage. AB - Recent genome-wide association studies (GWAS) have identified numerous single nucleotide polymorphisms (SNPs) associated with coagulation system, including hemostatic factors and hematological phenotypes. However, few articles described the relationships between these SNPs and the risk of hemorrhagic stroke. The aim of our study was to evaluate the roles of these SNPs as risk factors and survival predictors for hemorrhagic stroke. Thirteen SNPs from GWAS in coagulation system were genotyped in a Chinese Han population including 1000 patients with hemorrhagic stroke (intracerebral hemorrhage, ICH = 743; subarachnoid hemorrhage, SAH = 257) and 1044 population-based controls. The associations between the genetics risk score (GRS) and risk of hemorrhagic stroke as well as post-stroke adverse outcomes were determined. No individual SNP was associated with the risk of hemorrhagic stroke. The GRS was calculated by summing the number of risk alleles of each SNP, and a total of 13 SNPs were included. Meanwhile, the GRS cutoffs values were defined to be close to quartiles or tertiles in control subjects. For quartiles, individuals with GRS about 8-9, 10-11, >=12 had 1.28 (OR 1.28, 95% CI 0.98-1.68, p = 0.067)-, 1.36 (OR 1.36, 95% CI 1.04-1.79, p = 0.026) , 1.53 (OR 1.53, 95% CI 1.13-2.07, p = 0.006)-fold increase in ICH risk compared to those with GRS <=7, respectively; for tertiles, individuals with GRS about GRS 9-10, >=11 had 0.98 (OR 0.98, 95% CI 0.78-1.23, p = 0.067)- and 1.26 (OR 1.26, 95% CI 1.00-1.59, p = 0.048)-fold increase in ICH risk compared to those with GRS <=8, respectively. Further stratification analyses indicated that this association was only found in hypertensive ICH subjects. However, no statistical difference was found in the volume of hematoma, activities of daily living scale as well as hospital death in the ICH patients based on GRS values. Joint effects of SNPs associated with low coagulation factor levels might confer risk to ICH patients with hypertension. However, the clinical value on risk stratification and survival prediction was limited. PMID- 28718049 TI - Good Things in Small Packages: an Innovative Delivery Approach for Inhaled Insulin. AB - PURPOSE: The design development of a small, hand held, battery operated, breath actuated inhaler as a drug/device platform for inhaled insulin posed a number of technical challenges. Our goal was to optimize lung deposition and distribution with aerosol generators producing 3-6 MUm particle size distribution. METHODS: In silico modeling with computational fluid dynamics (CFD) and in vitro testing of device components were assessed using an Alberta idealized adult airway (Copley, UK) to optimize mouthpiece and aerosol path design for dose delivered distal to the trachea. Human factors use testing was designed to determine the ability to perform inspiratory manuevers with LED guidance within target flow limits. In vivo testing with healthy normal subjects of radiolabeled aerosol compared 2 breathing patterns for lung deposition efficiency, distribution, and subject preference. RESULTS: CFD demonstrated that flows <=5 L/min and >=15 L/min reduced the delivery efficiencg. Prototypes tested with inspiratory flow of 10 L/min provided up to 70% of dose delivered distal to the model throat with aerosols of 3 to 6 MUm. Users guided by LED were able to inhale for 8-24 s with 5 s breath hold. Lung dose >70% with peripheral to central ratios >2.0 were achieved, with subject preference for the longer inspiratory time with breath hold. CONCLUSION: The device design phase integration led to a novel design and inspiratory pattern with greater levels of peripheral deposition than previously reported with commercial inhalers. The rationale and process of the application of these methods are described with implications for use in future device development. PMID- 28718051 TI - Coronary Heart Disease Preoperative Gesture Interactive Diagnostic System Based on Augmented Reality. AB - Coronary heart disease preoperative diagnosis plays an important role in the treatment of vascular interventional surgery. Actually, most doctors are used to diagnosing the position of the vascular stenosis and then empirically estimating vascular stenosis by selective coronary angiography images instead of using mouse, keyboard and computer during preoperative diagnosis. The invasive diagnostic modality is short of intuitive and natural interaction and the results are not accurate enough. Aiming at above problems, the coronary heart disease preoperative gesture interactive diagnostic system based on Augmented Reality is proposed. The system uses Leap Motion Controller to capture hand gesture video sequences and extract the features which that are the position and orientation vector of the gesture motion trajectory and the change of the hand shape. The training planet is determined by K-means algorithm and then the effect of gesture training is improved by multi-features and multi-observation sequences for gesture training. The reusability of gesture is improved by establishing the state transition model. The algorithm efficiency is improved by gesture prejudgment which is used by threshold discriminating before recognition. The integrity of the trajectory is preserved and the gesture motion space is extended by employing space rotation transformation of gesture manipulation plane. Ultimately, the gesture recognition based on SRT-HMM is realized. The diagnosis and measurement of the vascular stenosis are intuitively and naturally realized by operating and measuring the coronary artery model with augmented reality and gesture interaction techniques. All of the gesture recognition experiments show the distinguish ability and generalization ability of the algorithm and gesture interaction experiments prove the availability and reliability of the system. PMID- 28718050 TI - Dissolving Microneedle Patches for Dermal Vaccination. AB - The dermal route is an attractive route for vaccine delivery due to the easy skin accessibility and a dense network of immune cells in the skin. The development of microneedles is crucial to take advantage of the skin immunization and simultaneously to overcome problems related to vaccination by conventional needles (e.g. pain, needle-stick injuries or needle re-use). This review focuses on dissolving microneedles that after penetration into the skin dissolve releasing the encapsulated antigen. The microneedle patch fabrication techniques and their challenges are discussed as well as the microneedle characterization methods and antigen stability aspects. The immunogenicity of antigens formulated in dissolving microneedles are addressed. Finally, the early clinical development is discussed. PMID- 28718052 TI - Zen and the Art of Living Mindfully: The Health-Enhancing Potential of Zen Aesthetics. AB - Amidst the burgeoning enthusiasm for mindfulness in the West, there is a concern that the largely secular 'de-contextualized' way in which it is being harnessed is denuding it of its potential to improve health and well-being. As such, efforts are underway to 're-contextualize' mindfulness, explicitly drawing on the wider framework of Buddhist ideas and practices in which it was initially developed. This paper aims to contribute to this, doing so by focusing on Zen Buddhism, and in particular on Zen aesthetic principles. The article concentrates on the seven principles identified by Hisamatsu (1971) in his classic text Zen and the Fine Arts: kanso (simplicity); fukinsei (asymmetry); koko (austere sublimity); shizen (naturalness); daisuzoku (freedom from routine); sei-jaku (tranquillity); and yugen (profound grace). The presence of these principles in works of art is seen as reflecting and communicating insights that are central to Buddhism, such as non-attachment. Moreover, these principles do not only apply to the creation and appreciation of art, but have clear applications for treating health-related issues, and improving quality of life more generally. This paper makes the case that embodying these principles in their lives can help people enhance their psychosomatic well-being, and come to a truer understanding of the essence of mindful living. PMID- 28718053 TI - Family Interdependence, Spiritual Perspective, Self-Transcendence, and Depression Among Korean College Students. AB - The purpose of this study was to examine the mechanisms that might account for the effects of spirituality and self-transcendence on Korean college students' depression among 197 Korean fathers, mothers, and children. A structural equation analysis indicated that spiritual perspective related to lower depression through the mediating pathway of self-transcendence for individuals. Mothers' spiritual perspective and self-transcendence related to their children's depression through the mediating pathway of their own depression, but the same was not true for fathers. Findings help explicate the intergenerational transmission of depression and important predictors of depression related to spirituality. PMID- 28718054 TI - Mass attenuation coefficient of tannin-added Rhizophora spp. particleboards at 16.59-25.56 keV photons, and 137Cs and 60Co gamma energies. AB - The aim of this study was to determine the suitability of tannin-added Rhizophora spp. particleboards as phantom materials in the application of low- and high energy photons. The tannin-added Rhizophora spp. particleboards and density plug phantoms were created with a target density of 1.0 g/cm3. The elemental composition and effective atomic number of the particleboards were measured using energy dispersive X-ray analysis. The mass attenuation coefficient of the particleboards for low-energy photons were measured using the attenuation of X ray fluorescence. The mass attenuation coefficients of high-energy photons were measured using the attenuation of 137Cs and 60Co gamma energies. The results were compared to the calculated value of water using XCOM calculations. The results showed that the effective atomic number and mass attenuation coefficients of tannin-added Rhizophora spp. particleboards were similar to those of water, indicating the suitability of tannin-added Rhizophora spp. particleboards as phantom materials for low- and high-energy photons. PMID- 28718055 TI - Early Anti-inflammatory and Pro-angiogenic Myocardial Effects of Intravenous Serelaxin Infusion for 72 H in an Experimental Rat Model of Acute Myocardial Infarction. AB - Sprague Dawley rats were subjected to acute myocardial infarction (AMI) by permanent ligation of the left anterior descending coronary artery. At the time of AMI, a subcutaneous mini-osmotic pump was implanted and animals were randomized into three groups, according to the intravenous therapy received during the first 72 h: placebo-treated (saline), serelaxin10-treated (SRLX10 = 10 MUg/kg/day), or serelaxin30-treated (SRLX30 = 30 MUg/kg/day). Treatment with SRLX30 reduced the expression of inflammatory cytokines and chemokines, as well as the infiltration of macrophages, and increased the expression of pro angiogenic markers and vessel density in the infarcted myocardium after 7 days. SRLX30 did not reduce early myocardial fibrosis but reduced myocardial levels of sST2 and galectin-3. No significant effects were observed with SRLX10 treatment. A significant correlation was observed between plasma levels of serelaxin and effect measures. The results suggest serelaxin has a protective effect in early processes of cardiac remodeling after AMI. PMID- 28718056 TI - Aeration control strategies to stimulate simultaneous nitrification denitrification via nitrite during the formation of aerobic granular sludge. AB - In this study, a sequencing batch reactor (SBR), treating synthetic wastewater (COD/N = 5), was operated in two stages. During stage I, an aeration control strategy based on oxygen uptake rate (OUR) was applied, to accomplish nitrogen removal via nitrite >80%. In stage II, the development of aerobic granular sludge (AGS) was examined while two aeration control strategies (OUR and pH slope) maintained the nitrite pathway and optimized the simultaneous nitrification denitrification (SND) performance. Stimulation of slow-growing organisms, (denitrifying) polyphosphate-accumulating organisms (D)PAO and (denitrifying) glycogen-accumulating organisms (D)GAO leads to full granulation (at day 200, SVI10 = 47.0 mL/g and SVI30 = 43.1 mL/g). The average biological nutrient removal efficiencies, for nitrogen and phosphorus, were 94.6 and 83.7%, respectively. Furthermore, the benefits of an increased dissolved oxygen concentration (1.0-2.0 mg O2/L) were shown as biomass concentrations increased with approximately 2 g/L, and specific ammonium removal rate and phosphorus uptake rate increased with 33 and 44%, respectively. It was shown that the combination of both aeration phase length control strategies provided an innovative method to achieve SND via nitrite in AGS. PMID- 28718057 TI - Immobilized enzymes from Geotrichum spp. improve wine quality. AB - Higher alcohols are the byproducts of yeasts in alcohol fermentation and are harmful to human health at high concentrations. In this study, immobilized crude enzymes extracted from Geotrichum spp. strains S12 and S13 were separately employed to treat red wine, then GC and GC-MS analyses were used to determine the profiles of volatile compounds in untreated and treated wine samples. Immobilized enzymes from S13 (SA-S13E) were more active in decreasing higher alcohols than enzymes from S12. Conditions for preparing SA-S13E were optimized, and best results were obtained at a sodium alginate concentration of 35 g/L, calcium chloride of 20 g/L, and crude enzyme dosage of 3 mL. Treatment with SA-S13E significantly increased the ester content and sensory quality of wine. After being reused three times, SA-S13E still exhibited approximately 80% activity towards 1-propanol, isobutanol, and hexanol and had certain activity even after 3 months storage at -20 degrees C, indicating high stability in application and storage and thus showing potential in wine processing. PMID- 28718058 TI - Cultural Biases in Current Medical Practices with a Specific Attention to Orthopedic Surgery: a Review. AB - Due to the increasing diversity within the United States population, there is an ever-increasing need for increased education on cultural literacy and tolerance in medical schools and residency programs. The purpose of this article was to review how a person's culture can play a substantive role in effecting and influencing (1) medical diagnosis, (2) patient and health provider medical decision-making, (3) the patient's perception of disease, and (4) the doctor patient relationships. Many of the decisions we make as orthopedic surgeons must account for the patient's cultural needs, as much of our work impacts patients' daily activities and function. When considering the patient's perception of disease, validated tools have been developed, such as the Patient-Specific Index, which can be used to assess the feelings, goals, and expectations of patients. Cultural competency should be a part of curricula at every level of medical education. PMID- 28718059 TI - Recent Advances in Tissue Engineering Strategies for the Treatment of Joint Damage. AB - PURPOSE OF REVIEW: While the clinical potential of tissue engineering for treating joint damage has yet to be realized, research and commercialization efforts in the field are geared towards overcoming major obstacles to clinical translation, as well as towards achieving engineered grafts that recapitulate the unique structures, function, and physiology of the joint. In this review, we describe recent advances in technologies aimed at obtaining biomaterials, stem cells, and bioreactors that will enable the development of effective tissue engineered treatments for repairing joint damage. RECENT FINDINGS: 3D printing of scaffolds is aimed at improving the mechanical structure and microenvironment necessary for bone regeneration within a damaged joint. Advances in our understanding of stem cell biology and cell manufacturing processes are informing translational strategies for the therapeutic use of allogeneic and autologous cells. Finally, bioreactors used in combination with cells and biomaterials are promising strategies for generating large tissue grafts for repairing damaged tissues in pre-clinical models. Together, these advances along with ongoing research directions are making tissue engineering increasingly viable for the treatment of joint damage. PMID- 28718061 TI - Schnitzler Syndrome: a Review. AB - PURPOSE OF REVIEW: We focus on recent advances in diagnosis and therapeutic strategies, as well as on pathogenesis of Schnitzler syndrome. RECENT FINDINGS: New diagnostic criteria were established, and their external validity was assessed in a retrospective cohort study. The cytokine interleukin-1 (IL-1) plays a crucial role in the pathogenesis of the Schnitzler syndrome, and this explains the spectacular efficiency of IL-1 blocking therapies. The Schnitzler syndrome is now considered as a late-onset acquired autoinflammatory syndrome in which the cytokine IL-1 plays a crucial role. IL-1 blocking therapies are efficient on the inflammation-linked symptoms but not on the monoclonal component. Therefore, they probably don't reduce the risk of the development of lymphoproliferative disorders that remains the main prognostic issue. The link between autoinflammation and the monoclonal component needs to be further elucidated. PMID- 28718060 TI - Innate Immune Responses and Osteoarthritis. AB - PURPOSE OF THE REVIEW: Osteoarthritis (OA) is a chronic, painful joint disease that affects approximately 40% of adults over 70 year. Age is the strongest predictor of OA, while obesity is considered the primary preventable risk factor for OA. Both conditions are associated with abnormal innate immune inflammatory responses that contribute to OA progression and are the focus of this review. RECENT FINDINGS: Recent studies have identified risk factors for OA progression including increased innate immune responses secondary to aging-associated myeloid skewing, obesity-related myeloid activation, and synovial tissue hyperplasia with activated macrophage infiltration. Toll-like receptor (TLR)4-induced catabolic responses also play a significant role in OA. The complex interplay between obesity and aging-associated macrophage activation, pro-inflammatory cytokine production from TLR-driven responses, and adipokines leads to a vicious cycle of synovial hyperplasia, macrophage activation, cartilage catabolism, infrapatellar fat pad fibrosis, and joint destruction. PMID- 28718062 TI - Update on Biosimilars in Asia. AB - PURPOSE OF REVIEW: This review provides an update on the evolution of, manufacturing of, and regulations for biosimilars in Asian countries. RECENT FINDINGS: The use of biologics revolutionized the treatment of various diseases. However, the high cost of biologics remained unaffordable for most Asian patients and increases the financial burden of Asian governments. The development of biosimilars provides the best solution for this predicament. A great boom of biosimilars is developing in Asia. Hundreds of biopharmaceutical companies have established their manufacturing facilities and provide affordable products for Asian patients. Regulation guidelines and international harmonization are evolving. Better manufacturing quality and post-market pharmacovigilance are needed in Asia despite the rapid evolution of biosimilar development. PMID- 28718064 TI - Contribution of Circulatory Disturbances in Subchondral Bone to the Pathophysiology of Osteoarthritis. AB - PURPOSE OF REVIEW: This review describes the contributions of abnormal bone circulation to the pathophysiology of osteoarthritis. Combining dynamic imaging with MRI and PET with previous observations reveals that venous stasis and a venous outlet syndrome is most likely the key circulatory pathology associated with the initiation or progression of osteoarthritis. RECENT FINDINGS: MRI and PET have revealed that venous outflow obstruction results in physicochemical changes in subchondral bone to which osteoblasts are responsive. The osteoblasts express an altered pattern of cytokines, many of which can serve as structural or signaling molecules contributing to both bone remodeling and cartilage degeneration. The patterns of circulatory changes are associated with alterations in the physicochemical environment of subchondral bone, including hypoxia. Osteoblast cytokines can transit the subchondral bone plate and calcified cartilage and communicate with chondrocytes. PMID- 28718065 TI - Structure-function relationships of protein-lipopeptide complexes and influence on immunogenicity. AB - The lipopeptide, R4Pam2Cys, associates electrostatically with soluble protein antigens and significantly enhances their ability to induce protective humoral and cell-mediated responses. We demonstrate that antibody titers elicited by the antigen ovalbumin (OVA) associated with R4Pam2Cys are higher than those elicited by OVA in the presence of alum and comparable to those elicited by OVA formulated with complete Freund's adjuvant (CFA). The hierarchy of anti-OVA antibody avidities was CFA > R4Pam2Cys = alum. Each of the three adjuvants facilitated IgG class-switching with significantly more IgG1 elicited by OVA when formulated with R4Pam2Cys. The effects of substituting naturally occurring L-stereoisomers of the cationic residues within R4Pam2Cys with D-stereoisomers revealed that substitution did not affect the ability of R4Pam2Cys to stimulate dendritic cell maturation or its ability to elicit antibody production when used as an adjuvant. Minor detrimental effects were, however, observed in the ensuing CD8+ T cell responses suggesting that the use of D-amino acids affects antigen processing and presentation pathways involved in generation of cell-mediated immunity at least when facilitated through TLR2. Both D- and L-forms were found to be resistant to digestion by trypsin, indicating resistance of the branched structure to protease activity. PMID- 28718063 TI - New Insights on Platelets and Platelet-Derived Microparticles in Systemic Lupus Erythematosus. AB - PURPOSE OF REVIEW: Current knowledge on the role of platelets and platelet derived microparticles (PMPs) on the immune system has been fast-growing. Systemic lupus erythematosus (SLE) is a systemic auto-immune disorder characterized by a loss of tolerance toward nuclear auto-antigens. Although recent studies allowed a better understanding of SLE pathogenesis, there is an urgent need for the development of new treatments and the identification of new biomarkers to assess the disease activity. We describe here the state-of-the-art knowledge linking platelets and PMPs to SLE. RECENT FINDINGS: Platelet system activation is a key event in the pathogenesis of SLE. Circulating immune complexes, anti-phospholipid antibodies, and infectious agents such as virus are the main activators of platelets in SLE. Platelet activation can be monitored through different ways such as P-selectin expression, mean platelet volume, or circulating PMP levels, suggesting their potential use as biomarkers. Upon activation, platelets promote type I interferon production, NETosis, dendritic cell activation, and T and B lymphocyte activation, all essential events contributing to the development of SLE. Of interest, platelets also play a fundamental role in SLE organ disease such as the development of cardiovascular, thrombotic, and renal diseases. Finally, we review current knowledge on drugs targeting platelet activation and their potential impact on SLE pathogenesis. Platelets play a major role in SLE pathogenesis and organ disease and represent a great potential for novel biomarkers and drug development. PMID- 28718066 TI - The preventive effects of taurine on neural tube defects through the Wnt/PCP-Jnk dependent pathway. AB - The aim of this study was to clarify the protective role of taurine in neuronal apoptosis and the role of the Wnt/PCP-Jnk pathway in mediating the preventive effects of taurine on neural tube defects (NTDs). HT-22 cells (a hippocampal neuron cell line) were divided into a control group, a glutamate-induced apoptosis group, and glutamate (4.0 mmol/L) plus low-dose taurine (L; 0.5 mmol/L) and high-dose taurine (H; 2.0 mmol/L) groups. The MTT assay was used to monitor cell proliferation and cell survival. Immunofluorescence and Western blot analyses were used to determine caspase 9 expression. Retinoic acid (RA) induced embryonic NTDs in Kunming mice, thus establishing an NTD model. Pregnant mice were divided into a control group, an RA (30 mg/kg body weight) group, and an RA (30 mg/kg body weight) plus taurine (free drinking of 2 g/L solution) group. Immunohistochemistry and Western blot analyses were used to detect the expression of Dvl, RhoA and phosphorylated (p)-Jnk/Jnk in the embryonic neural tubes. In HT 22 cells, the apoptosis rate was significantly higher and caspase 9 activation was also significantly increased in the glutamate-induced apoptosis group compared to the L and H taurine groups. In the NTD model, the expression levels of Dvl, RhoA, and p-Jnk were significantly higher in the RA group than in the control group, whereas they were significantly reduced in the RA + taurine group. This study suggests that taurine has positive effects on neuronal protection and NTD prevention. Moreover, the Wnt/PCP-Jnk-dependent pathway plays an important role in taurine-mediated prevention of NTDs. PMID- 28718067 TI - Theoretical and Experimental in vivo Study of Antioxidant Activity of Crocin in Order to Propose Novel Derivatives with Higher Antioxidant Activity and Their Delivery via Nanotubes and Nanocones. AB - In this study, the antioxidant activity of crocin via experimental and theoretical methods was investigated. In order to induce oxidative stress, 30-min renal ischemia and 24-h reperfusion were used in male Wistar rats. Oxidative stress was assessed by measuring tissue malondialdehyde (MDA) and ferric reducing/antioxidant power (FRAP). The results showed that following ischemia/reperfusion, the level of MDA was increased and FRAP decreased. Both of these changes were alleviated by crocin administration. The bond dissociation enthalpy and ionization potential values as enthalpies of mechanism of antioxidant activity of crocin were calculated by density functional theory method. According to obtained results, the novel structures of crocin with higher antioxidant activity for synthesis were proposed. Results indicated that NH2, OMe, and F substituents can improve the antioxidant activity of crocin. The crocin delivery via carbon and boron nitride nanotubes and nanocones was investigated. The results confirm that the calculated adsorption and free Gibbs energies of crocin on the surface of studied nanostructures were negative meaningfully, so these processes were exothermic and experimentally possible from the energetic viewpoint. PMID- 28718068 TI - Dengue encephalopathy: very unusual neuroimaging findings. AB - Neuroimaging, in many patients with dengue encephalopathy, may reveal periventricular signal changes. We report a 25-year-old man, who presented with altered sensorium. Dengue-IgM test in serum was positive. Cerebrospinal fluid examination was normal. MRI brain revealed presence of bilateral parieto occipital intraparenchymal bleed with mass effect. Neuroimaging was consistent with posterior reversible encephalopathy syndrome. We report posterior reversible encephalopathy syndrome in a normotensive patient with dengue encephalopathy and systemic metabolic alterations. PMID- 28718069 TI - Neurological involvement in patients with acute/recent HIV-1 infection. A case control study. AB - Primary HIV-1 infection is a relevant period for its virological and epidemiological consequences. Most patients present a symptomatic disease that can be potentially serious, but neurological involvement during primary HIV-1 infection has been poorly studied. The aim of this study was to describe the characteristics and outcomes of primary HIV-1 infection patients presenting neurological symptoms and to compare them with primary HIV-1 infection patients without neurological involvement. Retrospective case-control study (1:3) comparing primary HIV-1 infection patients with and without neurological involvement enrolled in the Acute/Recent Hospital Clinic PHI Cohort between 1997 and 2016. Matching criteria included age (+/-10 years), gender, year of diagnosis (+/-4 years), and Fiebig stage. The conditional logit model was used for comparisons. Fourteen out of 463 patients (3.02%) enrolled in the Acute/Recent Hospital Clinic PHI Cohort between 1997 and 2016 presented neurological symptoms. 28.5% of cases presented as meningitis and 71.5% as meningoencephalitis. Cerebrospinal fluid showed non-specific findings, including pleocytosis with lymphocyte predominance and increased protein levels. All cases required hospitalisation, whereas only 19% of the controls did. No other pathogen was identified in any case, but five patients initiated empirically antimicrobial treatment for other aetiologies until diagnosis was confirmed. CD4/CD8 ratio was significantly lower (p = 0.039) and plasmatic viral load significantly higher in the case group, compared to controls (p = 0.028). Risk factors, HIV-1 tropism, subtype distribution, and prescribed ART regimens were comparable between cases and controls. After 6 months on ART, 92% of cases had undetectable viral load, similar to controls, and CD4/CD8 ratio became also comparable between groups. All cases recovered rapidly with ART and were discharged without sequels. Neurological involvement during primary HIV-1 infection is unusual but serious, always requiring hospitalisation. Diagnosis is difficult because of the wide range of symptoms and similarities with other viral aetiologies. Neurological manifestations during primary HIV-1 infection are associated with a lower CD4/CD8 ratio and with a higher viral load than controls. Immediate ART initiation and rapid viral load decrease are required, allowing complete clinical recovery. PMID- 28718070 TI - Platelet-lymphocyte and neutrophil-lymphocyte ratios are prognostic but not predictive of response to abiraterone acetate in metastatic castration-resistant prostate cancer. AB - PURPOSE: Recently neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) have been reported to be inflammatory parameters that confer poorer outcome in metastatic castration-resistant prostate cancer (mCPRPC). However, these ratios have not been analyzed in patients treated with abiraterone acetate. We explored the relationship between different values of PLR and NLR and survival in mCPRCP treated with abiraterone and their possible relation with a prostate specific antigen (PSA) response. METHODS: We retrospectively analyzed 101 patients with mCRPC treated with abiraterone from January of 2012 to November of 2015 in two different hospitals. A cut-off value of 5 for NLR and 150 for PLR were used to compare survival by Kaplan-Meier method. Moreover, an association between these cut-off values and the PSA response was analyzed by a chi 2 test. RESULTS: In the case of NLR, the median DFS were 12, 1 months for NLR <5 and 7 months for NLR >=5, p = 0.061. The median OS were 23.9 months for NLR <5 and 16.3 months for NLR >=5, p = 0.046. In the case of PLR, the median DFS were 11.8 months for PLR <150 and 10.6 months for PLR >=150, p = 0.549. The median OS were 27.4 months for PLR <150 and 15.9 months for PLR >=150, p = 0.005. It was not observed a correlation between the different cut-off values of PLR or NLR and a PSA response >=25% (p = 0.31). CONCLUSIONS: It is shown a better prognostic relationship between PLR and NLR low values and OS that is statistically significant in mCPRC patients treated with abiraterone. Furthermore, it was not shown a relation between PLR and NLR values and PSA response. PMID- 28718071 TI - Cancer survival in adult patients in Spain. Results from nine population-based cancer registries. AB - INTRODUCTION: With the aim of providing cancer control indicators, this work presents cancer survival in adult (>=15 years) patients in Spain diagnosed during the period 2000-2007 from Spanish cancer registries participating in the EUROCARE project. METHODS: Cancer cases from nine Spanish population-based cancer registries were included and analysed as a whole. All primary malignant neoplasms diagnosed in adult patients were eligible for the analysis. Cancer patients were followed until 31 December 2008. For each type of cancer, 1-, 3- and 5-year observed and relative survival were estimated by sex, age and years from diagnosis. Furthermore, age-standardized 5-year relative survival for the period 2000-2007 has been compared with that of the period 1995-1999. RESULTS: Skin melanoma (84.6 95% CI 83.0-86.2), prostate (84.6% 95% CI 83.6-85.6) and thyroid (84.2% CI 95% 82.0-86.6) cancers showed the highest 5-year relative survival, whereas the worst prognosis was observed in pancreatic (6% 95% CI 5.1-7.0) and oesophageal (9.4% 95% CI 7.9-11.1) cancers. Overall, survival is higher in women (58.0%) than in men (48.9%). The absolute difference in relative survival between 2000-2007 and 1995-1999 was positive for all cancers as a whole (+4.8% in men, +1.6% in women) and for most types of tumours. Survival increased significantly for chronic myeloid leukaemia, non-Hodgkin's lymphoma and rectum cancer in both sexes, and for acute lymphoid leukaemia, prostate, liver and colon cancers in men and Hodgkin's lymphoma and breast cancer in women. Survival patterns by age were similar in Europe and Spain. A decline in survival by age was observed in all tumours, being more pronounced for ovarian, corpus uteri, prostate and urinary bladder and less for head and neck and rectum cancers. CONCLUSION: High variability and differences have been observed in survival among adults in Spain according to the type of cancer diagnosed, from above 84% to below 10%, reflecting high heterogeneity. The differences in prognosis by age, sex and period of diagnosis reveal opportunities for improving cancer care in Spain. PMID- 28718074 TI - Advances in imaging instrumentation for nuclear cardiology. AB - Advances in imaging instrumentation and technology have greatly contributed to nuclear cardiology. Dedicated cardiac SPECT cameras incorporating novel, highly efficient detector, collimator, and system designs have emerged with the expansion of nuclear cardiology. Solid-state radiation detectors incorporating cadmium zinc telluride, which directly convert radiation to electrical signals and yield improved energy resolution and spatial resolution and enhanced count sensitivity geometries, are increasingly gaining favor as the detector of choice for application in dedicated cardiac SPECT systems. Additionally, hybrid imaging systems in which SPECT and PET are combined with X-ray CT are currently widely used, with PET/MRI hybrid systems having also been recently introduced. The improved quantitative SPECT/CT has the potential to measure the absolute quantification of myocardial blood flow and flow reserve. Rapid development of silicon photomultipliers leads to enhancement in PET image quality and count rates. In addition, the reduction of emission-transmission mismatch artifacts via application of accurate time-of-flight information, and cardiac motion de blurring aided by anatomical images, are emerging techniques for further improvement of cardiac PET. This article reviews recent advances such as these in nuclear cardiology imaging instrumentation and technology, and the corresponding diagnostic benefits. PMID- 28718072 TI - Diabetes Mellitus Following Renal Transplantation: Clinical and Pharmacological Considerations for the Elderly Patient. AB - Post-transplant diabetes mellitus occurs in 30-50% of cases during the first year post-renal transplantation. It is associated with increased morbidity, mortality and healthcare costs. Risk factors include age and specific immunosuppression regimens. At the same time, renal transplantation is increasingly indicated in elderly (aged >65 years) patients as this proportion of older patients in the prevalent dialysis population has increased. The immune system and beta cells undergo senescence and this impacts on the risk for developing post-transplant diabetes and our ability to prevent such development. It may, however, be possible to identify patients at risk of developing post-transplant diabetes, enabling treatment protocols that prevent or reduce the impact of post-transplant diabetes. Much work remains to be completed in this area and is facilitated by the growing base of knowledge regarding the pathophysiology of post-transplant diabetes. Should post-transplant diabetes develop, there are a range of treatment options available. There is increasing interest in using newer agents, although their safety and efficacy in transplant recipients remains to be conclusively established. PMID- 28718073 TI - A randomised Phase II/III study to evaluate the efficacy and safety of orally administered Oxalobacter formigenes to treat primary hyperoxaluria. AB - Primary hyperoxaluria (PH) patients overproduce oxalate because of rare genetic errors in glyoxylate metabolism. Recurrent urolithiasis and/or progressive nephrocalcinosis are PH hallmarks and can lead to kidney damage, systemic oxalosis and death. Based on previous studies, we hypothesised that treatment with the oxalate-metabolizing bacterium Oxalobacter formigenes would mediate active elimination of oxalate from the plasma to the intestine of PH patients, thereby reducing urinary oxalate excretion (Uox). The efficacy and safety of O. formigenes (OxabactTM OC3) were evaluated for 24 weeks in a randomised, placebo controlled, double-blind study. The primary endpoint was reduction in Uox. Secondary endpoints included change in plasma oxalate (Pox) concentration, frequency of stone events, number of responders, and Uox in several subgroups. Additional post hoc analyses were conducted. Thirty-six patients were randomised; two patients withdrew from placebo treatment. Both OC3 and placebo groups demonstrated a decrease in Uox/urinary creatinine ratio, but the difference was not statistically significant. No differences were observed with respect to change in Pox concentration, stone events, responders' number or safety measures. In patients with estimated glomerular filtration rate (eGFR) < 90 mL/min/1.73 m2, Pox increased by 3.25 umol/L in the placebo group and decreased by -1.7 umol/L in the OC3 group (p = 0.13). After 24 weeks, eGFR had declined to a greater degree in the placebo than in the OC3 group: -8.00 +/- 2.16 versus -2.71 +/- 2.50; p = 0.01. OC3 treatment did not reduce urinary oxalate over 24 weeks of treatment compared with placebo in patients with PH. The treatment was well tolerated. PMID- 28718075 TI - Does time-of-flight improve image quality in the heart? PMID- 28718076 TI - Adenosine MPS in octogenarians: Looking safely into the future. PMID- 28718077 TI - Early risk stratification using Rubidium-82 positron emission tomography in STEMI patients. AB - BACKGROUND: Assessment of infarct size after myocardial infarction is predictive of subsequent morphological changes and clinical outcome. This study aimed to assess subacute post-intervention Rubidium-82 (82Rb)-PET imaging in predicting left ventricle ejection fraction, regional wall motion, and final infarct size by CMR at 3-months after STEMI. METHODS: STEMI patients undergoing percutaneous coronary intervention were included prospectively. Rest-only 82Rb-PET perfusion imaging was performed at median 36 hours [IQR: 22 to 50] after the treatment. The extent of hypoperfusion and absolute blood flow (mL.min.g) were estimated on a global and a 17-segment model with dedicated software. At 3-months follow-up patients completed the CMR functional and late gadolinium enhancement imaging. RESULTS: 42 patients were included, but only 35 had follow-up CMR and constituted the study population. Absolute blood flow was significantly lower in the infarct related territory compared to remote myocardium, P < .005. Extent of hypoperfusion correlated with final infarct size, r = 0.58, P < .001, while blood flow correlated with ejection fraction, r = 0.41, P < .05. In linear mixed models, higher subacute absolute blood flow (beta = 4.6, confidence interval [3.5; 5.2], P < .001, R 2 = 0.67) was associated with greater wall motion. Segmental extent of subacute hypoperfusion (beta = 0.43 [0.38; 0.49], P < .001, R 2 = 0.58) was associated with the degree of late gadolinium enhancement at 3 months. CONCLUSIONS: Subacute rest-only 82Rb-PET is feasible following STEMI and seems predictive of myocardial function and infarct size at 3-months. PMID- 28718078 TI - Relationship between daily pain and affect in women with rheumatoid arthritis: lower optimism as a vulnerability factor. AB - The aim of the study was to examine the moderating effect of optimism on the relationship between daily pain-daily affect. Fifty-four female patients with rheumatoid arthritis completed self-report measures of optimism (once), daily pain and daily positive and negative affect for 7 consecutive days during hospitalization. Results of multilevel random coefficients modeling demonstrated a significant cross-level interaction for daily negative affect only. Simple slopes analysis revealed that low optimism was related to a stronger positive relationship between daily pain and daily negative affect, whereas this effect was insignificant for higher optimism. High optimism was also related to higher daily positive affect, regardless of pain level. These findings suggest that low optimism may be a vulnerability factor in the daily pain-daily affect relationship rather than high optimism acting as a protective factor. PMID- 28718079 TI - Symptom self-management strategies reported by adolescents and young adults with cancer receiving chemotherapy. AB - PURPOSE: Adolescents and young adults (AYAs) with cancer experience multiple symptoms related to their cancer and its treatment which can negatively impact their development and quality of life. An understanding of the strategies AYAs use to self-manage their symptoms is limited. This study described symptom self management strategies reported by AYAs with cancer using an iPad-based symptom heuristics tool, the Computerized Symptom Capture Tool. METHODS: The study used a cross-sectional, descriptive design. AYAs' free text responses relating their symptom self-management strategies were explored using qualitative content analysis procedures. Strategies were examined overall and by individual symptoms. RESULTS: Seventy-two AYAs 13-29 years of age (mean 18.4 years) reported a total of 772 symptom self-management codes for 585 individual symptoms. These codes were organized into 119 distinct categories. These categories were further organized into 16 subthemes and 3 overarching themes: "Things I Take ... or Not" (n = 209 codes), "Physical Care Things I Do" (n = 367 codes), and "Psychosocial Care Things I Do" (n = 132 codes). AYAs frequently reported strategies from all three of the symptom self-management themes to manage individual symptoms; however, "medications" was the most frequently reported strategy. CONCLUSION: AYAs receiving chemotherapy use multiple common, yet uniquely individual symptom self-management strategies. AYAs' reported strategies range from those that involve shared management with a healthcare provider to those that AYAs implement independently. The study provides a foundation for future research to empower AYAs to engage in symptom self-management and to guide healthcare providers as they discuss developmentally relevant and evidence-based symptom self-management strategies. PMID- 28718080 TI - A comparison of live birth rates and perinatal outcomes between cryopreserved oocytes and cryopreserved embryos. AB - PURPOSE: Prior studies suggest that pregnancy outcomes after autologous oocyte cryopreservation are similar to fresh in vitro fertilization (IVF) cycles. It is unknown whether there are differences in pregnancy and perinatal outcomes between cryopreserved oocytes and cryopreserved embryos. METHODS: This is a retrospective cohort study comparing pregnancy and perinatal outcomes between oocyte and embryo cryopreservation at a university-based fertility center. We included 42 patients and 68 embryo transfers in patients who underwent embryo transfer after elective oocyte preservation (frozen oocyte-derived embryo transfer (FOET)) from 2005 to 2015. We compared this group to 286 patients and 446 cycles in women undergoing cryopreserved embryo transfer (frozen embryo transfer (FET)) from 2012 to 2015. RESULTS: Five hundred fourteen transfer cycles were included in our analysis. The mean age was lower in the FOET vs FET group (34.3 vs 36.0 years), but there were no differences in ovarian reserve markers. Thawed oocytes had lower survival than embryos (79.1 vs 90.1%); however, fertilization rates were similar (76.2 vs 72.8%). In the FOET vs FET groups, clinical pregnancies were 26.5 and 30%, and live birth rates were 25 and 25.1%. Miscarriages were higher in the FET group, 8.1 vs 1.5%. There were no differences in perinatal outcomes between the two groups. The mean gestational age at delivery was 39.1 vs 38.6 weeks, mean birth weight 3284.2 vs 3161.1 gms, preterm gestation rate 5.9 vs 13.4%, and multiple gestation rate 5.9 vs 11.6%. CONCLUSIONS: In our study, live birth rates and perinatal outcomes were not significantly different in patients after oocyte and embryo cryopreservation. PMID- 28718081 TI - Blastocyst utilization rates after continuous culture in two commercial single step media: a prospective randomized study with sibling oocytes. AB - PURPOSE: The aim of this study is to determine whether blastocyst utilization rates are different after continuous culture in two different commercial single step media. METHODS: This is a paired randomized controlled trial with sibling oocytes conducted in infertility patients, aged <=40 years with >=10 oocytes retrieved assigned to blastocyst culture and transfer. Retrieved oocytes were randomly allocated to continuous culture in either Sage one-step medium (Origio) or Continuous Single Culture (CSC) medium (Irvine Scientific) without medium renewal up to day 5 post oocyte retrieval. Main outcome measure was the proportion of embryos suitable for clinical use (utilization rate). RESULTS: A total of 502 oocytes from 33 women were randomly allocated to continuous culture in either Sage one-step medium (n = 250) or CSC medium (n = 252). Fertilization was performed by either in vitro fertilization or intracytoplasmic sperm injection, and embryo transfers were performed on day 5. Two patients had all blastocysts frozen due to the occurrence of severe ovarian hyperstimulation syndrome. Fertilization and cleavage rates, as well as embryo quality on day 3, were similar in the two media. Blastocyst utilization rates (%, 95% CI) [55.4% (46.4-64.1) vs 54.7% (44.9-64.6), p = 0.717], blastocyst formation rates [53.6% (44.6-62.5) vs 51.9 (42.2-61.6), p = 0.755], and proportion of good quality blastocysts [36.8% (28.1-45.4) vs 36.1% (27.2-45.0), p = 0.850] were similar in Sage one-step and CSC media, respectively. CONCLUSIONS: Continuous culture of embryos in Sage one-step and CSC media is associated with similar blastocyst development and utilization rates. Both single-step media appear to provide adequate support during in vitro preimplantation embryo development. Whether these observations are also valid for other continuous single medium protocols remains to be determined. CLINICAL TRIAL REGISTRATION NUMBER: NCT02302638. PMID- 28718082 TI - Low first-trimester PAPP-A in IVF (fresh and frozen-thawed) pregnancies, likely due to a biological cause. AB - PURPOSE: The purpose of this study is to confirm a difference in the first trimester screen maternal biochemistry and false-positive rates (FPR) between pregnancies conceived spontaneously and those conceived via assisted reproductive technologies (ART). METHODS: Retrospective analysis of the complete population of women (17,889 pregnancies) who had undergone first-trimester screening between January 2004 and September 2009 at three private ultrasound clinics in Queensland, Australia was used in the study. The age, gestation, method of conception, ultrasound markers, biochemistry markers (PAPP-A, fbeta-hCG), and type of biochemical analyzer platform (Brahms Kryptor, Immulite 2000) data was collated. Univariate analysis of variance (ANOVA), Spearman's rank nonparametric correlation analysis, and Binary Logistic Regression analysis were used to analyze data. Spontaneous pregnancies were used as controls. Results were considered significant when the p value was less than 0.05. RESULTS: After exclusions, 16,363 singleton pregnancies, including 1543 conceived via ART, were analyzed. Results from the two biochemistry platforms, Brahms Kryptor and Immulite 2000 were significantly different (p < 0.001); thus, the data was divided for analysis purposes. PAPP-A was universally significantly lower in IVF pregnancies compared to spontaneously conceived pregnancies (p < 0.001). Using the Brahms Kryptor platform, ICSI was associated with significantly decreased PAPP-A (p < 0.046), and a significantly increased FPR (p = 0.012). CONCLUSIONS: Consistent with previous studies IVF pregnancies had significantly lower PAPP-A levels supporting the need to appropriately adjust the combined first-trimester screening (cFTS) risk algorithm for IVF conceptions. The Brahms Kryptor and Immulite 2000 platforms are significantly different; however, the universally lower PAPP-A findings support the hypothesis that the lower PAPP-A is due to a biological cause. PMID- 28718084 TI - Pancreatic Neuroendocrine Tumor Producing Insulin and Vasopressin. AB - The objective of the study is to report a rare case of pancreatic neuroendocrine tumor (pNET) producing insulin and vasopressin. We describe the clinical presentation and management of a metastatic pNET with refractory hypoglycemia and progressive severe hyponatremia. A 52-year-old patient had abdominal pain leading to the diagnosis of a tumor that was initially presumed to be splenic in origin. Investigations ultimately identified a pancreatic mass that on biopsy proved to be a pNET. Eventually, he developed extensive liver metastases, and with tumor progression, he manifested hypoglycemia and severe hyponatremia. He was managed with multiple therapies including somatostatin analogue, peptide-receptor radionuclide-therapy (PRRT), diazoxide, and everolimus; none of these therapeutic modalities was successful in controlling functional and structural progression of the tumor. Ultimately, the pNET proved fatal and autopsy confirmed widely metastatic disease that stained strongly and diffusely for vasopressin, a feature not seen in the previous liver biopsy. This case illustrates the challenges of diagnosis and management of aggressive insulin-producing pNETs and highlights the potential concomitant ectopic production of vasopressin leading to refractory hyponatremia. PMID- 28718085 TI - Erratum to: The Montreal Protocol for Identification of Amusia. PMID- 28718083 TI - Erratum to: Practice of hemodynamic monitoring and management in German, Austrian, and Swiss intensive care units: the multicenter cross-sectional ICU CardioMan Study. PMID- 28718086 TI - Erratum to: A brief assessment tool for investigating facets of moral judgment from realistic vignettes. PMID- 28718087 TI - Speaking two "Languages" in America: A semantic space analysis of how presidential candidates and their supporters represent abstract political concepts differently. AB - In this article we report a computational semantic analysis of the presidential candidates' speeches in the two major political parties in the USA. In Study One, we modeled the political semantic spaces as a function of party, candidate, and time of election, and findings revealed patterns of differences in the semantic representation of key political concepts and the changing landscapes in which the presidential candidates align or misalign with their parties in terms of the representation and organization of politically central concepts. Our models further showed that the 2016 US presidential nominees had distinct conceptual representations from those of previous election years, and these patterns did not necessarily align with their respective political parties' average representation of the key political concepts. In Study Two, structural equation modeling demonstrated that reported political engagement among voters differentially predicted reported likelihoods of voting for Clinton versus Trump in the 2016 presidential election. Study Three indicated that Republicans and Democrats showed distinct, systematic word association patterns for the same concepts/terms, which could be reliably distinguished using machine learning methods. These studies suggest that given an individual's political beliefs, we can make reliable predictions about how they understand words, and given how an individual understands those same words, we can also predict an individual's political beliefs. Our study provides a bridge between semantic space models and abstract representations of political concepts on the one hand, and the representations of political concepts and citizens' voting behavior on the other. PMID- 28718088 TI - How well do network models predict observations? On the importance of predictability in network models. AB - Network models are an increasingly popular way to abstract complex psychological phenomena. While studying the structure of network models has led to many important insights, little attention has been paid to how well they predict observations. This is despite the fact that predictability is crucial for judging the practical relevance of edges: for instance in clinical practice, predictability of a symptom indicates whether an intervention on that symptom through the symptom network is promising. We close this methodological gap by introducing nodewise predictability, which quantifies how well a given node can be predicted by all other nodes it is connected to in the network. In addition, we provide fully reproducible code examples of how to compute and visualize nodewise predictability both for cross-sectional and time series data. PMID- 28718089 TI - Eye blink detection for different driver states in conditionally automated driving and manual driving using EOG and a driver camera. AB - In this article, we examine the performance of different eye blink detection algorithms under various constraints. The goal of the present study was to evaluate the performance of an electrooculogram- and camera-based blink detection process in both manually and conditionally automated driving phases. A further comparison between alert and drowsy drivers was performed in order to evaluate the impact of drowsiness on the performance of blink detection algorithms in both driving modes. Data snippets from 14 monotonous manually driven sessions (mean 2 h 46 min) and 16 monotonous conditionally automated driven sessions (mean 2 h 45 min) were used. In addition to comparing two data-sampling frequencies for the electrooculogram measures (50 vs. 25 Hz) and four different signal-processing algorithms for the camera videos, we compared the blink detection performance of 24 reference groups. The analysis of the videos was based on very detailed definitions of eyelid closure events. The correct detection rates for the alert and manual driving phases (maximum 94%) decreased significantly in the drowsy (minus 2% or more) and conditionally automated (minus 9% or more) phases. Blinking behavior is therefore significantly impacted by drowsiness as well as by automated driving, resulting in less accurate blink detection. PMID- 28718090 TI - A large retroperitoneal lymphatic malformation successfully treated with traditional Japanese Kampo medicine in combination with surgery. AB - BACKGROUND: Current treatment options for lymphatic malformations (LMs) are multimodal. Recently, the effectiveness of treating LMs with Eppikajyutsuto (TJ 28) has been reported. TJ-28 is a kind of oral herbal medicine classified as the traditional Japanese Kampo medicine. CASE PRESENTATION: A 12-year-old girl was admitted to our hospital for intermittent upper abdominal pain. Radiological examinations revealed a large (9.5 * 5.8 * 10.0 cm) retroperitoneal LM, which was suspected to adhering and stretching both pancreas head and duodenum. The large retroperitoneal tumor resection might induce involving complications because of the size and the location. Therefore, we used TJ-28 in order to diminish the tumor size before surgery. The patient received oral doses of 7.5 g/day (2.5 g * 3 times/day) of TJ-28. Six months after the medication, the tumor decreased markedly to 3.5 * 1.5 * 1.2 cm in size. Thereafter, the mass was sub-totally resected (95%) via a 3 cm trans-umbilical incision without any surgical complications. CONCLUSIONS: We reported a case of successfully treated retroperitoneal LM with the combination treatment of TJ-28 and surgery. Based on our experience, this TJ-28 treatment option may be very useful in treating cases of LMs having surgical difficulties because of size and/or location. PMID- 28718091 TI - Nutritional and Micronutrient Care of Bariatric Surgery Patients: Current Evidence Update. AB - PURPOSE OF REVIEW: The continued success of bariatric surgery to treat obesity and obesity-associated metabolic conditions creates a need for a strong understanding of clinical nutrition both before and after these procedures. RECENT FINDINGS: Surgically induced alteration of gastrointestinal physiology can affect the nutrition of individuals, especially among those who have undergone malabsorptive procedures. While uncommon, a subset of patients may develop protein-calorie malnutrition. In these cases, nutrition support should be tailored to the severity of malnutrition. Among all patients who undergo bariatric surgery, high rates of micronutrient deficiencies have been observed. To mitigate these deficiencies, empiric supplementation with multivitamins, calcium citrate, and vitamin D is generally recommended. Periodic surveillance should be performed for commonly deficient micronutrients, including thiamin (B1), folate (B9), cobalamin (B12), iron, and vitamin D. Following Roux-en-Y gastric bypass, serum levels of copper and zinc should also be monitored. In addition, lipid-soluble vitamins should be monitored following biliopancreatic diversion with/without duodenal switch. PMID- 28718092 TI - No significant impact of prior treatment profile with docetaxel on the efficacy of cabazitaxel in Japanese patients with metastatic castration-resistant prostate cancer. AB - The objective of this study was to retrospectively analyze the oncological outcomes of Japanese patients with metastatic castration-resistant prostate cancer (mCRPC) who received cabazitaxel. This study included a total of 63 consecutive Japanese mCRPC patients treated with cabazitaxel following the failure of docetaxel, and assessed the prognostic significance of cabazitaxel therapy in these patients focusing on the association of efficacies between two taxane agents. After treatment with cabazitaxel (median 5 cycles), prostate specific antigen (PSA) decline was observed in 39 patients (61.9%), including 13 (27.0%) achieving the response defined by PSA decline >=50%. The median progression-free survival (PFS) and overall survival (OS) periods after the introduction of cabazitaxel were 4.1 and 14.8 months, respectively. The response rate to cabazitaxel was not significantly different between responders and non responders to prior docetaxel, and there was no significant correlation between the PFSs with docetaxel and cabazitaxel. Furthermore, univariate analyses of several parameters identified the performance status (PS) and clinical symptoms, but not the cycles of docetaxel therapy, total amount of administered docetaxel or objective response to docetaxel therapy, as significant predictors of OS on cabazitaxel therapy, of which only PS was independently associated with OS on multivariate analysis. These findings suggest that oncological outcomes in Japanese mCRPC patients receiving cabazitaxel are generally satisfactory, irrespective of the profiles related to prior treatment with docetaxel, and that it might be preferable to introduce cabazitaxel to mCRPC patients with a good PS to maximize the prognostic benefit of this agent. PMID- 28718093 TI - Evolvement rules of basin flood risk under low-carbon mode. Part II: risk assessment of flood disaster under different land use patterns in the Haihe basin. AB - Land use pattern contains a large amount of information about the flood hazard formative environments, which is the most sensitive factor in hazard-formative environments. In this paper, based on the land use pattern in 2008 (the base year) and in 2020 (the planning year), the comparative analysis of flood disaster risk changes in Haihe basin were studied by the spatial analysis function of ARCGIS and the analytic hierarchy process (AHP). The results showed the flood disaster risk in Haihe basin had an obvious zonality in the space, among which low risk was located in the northwest regions, and high risk was located in the southeast regions. Flood disaster risk in planning year was lower than in the base year. The risk value of 2020 in the mountain decreases from 0.445 to 0.430, while the risk value of the plain increases from 0.562 to 0.564. For the plain, high-risk area in 2020 is increased by 13.2%, which is the biggest change in risk grades. For the mountain, low-risk area and low risk area in 2020 are increased, and the low-risk area is the biggest increase, up to 37.7%. Meanwhile, high-risk area, high risk area, and medium risk area all tend to decrease, and the high risk area is the biggest decrease, up to 32.6%. Overall, land use planning pattern under low-carbon mode is conducive to the Haihe basin flood control. The research can provide scientific foundations for basin land use planning and flood disaster risk management. PMID- 28718094 TI - Distribution, source analysis, and ecological risk assessment of polycyclic aromatic hydrocarbons in the typical topsoil of the Issyk-Kul Lake Basin. AB - The concentration, distribution, compositional characteristics, and pollution sources of 16 polycyclic aromatic hydrocarbons (PAHs) in the topsoil of Issyk-Kul Lake Basin were studied, and their ecological risks were evaluated in this paper. The total concentration of the 16 PAHs was 68.58-475.95 ng g-1, with an average of 134.45 ng g-1. Four-ring PAHs accounted for 43.2% of the total PAHs, two- and three-ring PAHs accounted for 39.4%, and five- and six-ring PAHs accounted for 15.8%. The total concentration of the seven carcinogenic PAHs was 7.66-76.04 ng g 1, with an average of 30.97 ng g-1. An analysis of the PAH sources through diagnostic ratio analysis and principal component analysis was carried out. The results showed that the regional soil PAHs were mainly derived from coal, wood, and grass combustion, while traffic and regional industry also had small contributions to the PAHs. The pollution-free samples accounted for 75% and the slightly polluted samples accounted for 25% based on the total concentration of the 16 PAHs. An ecological risk assessment showed that 26.7% of Ac and 3.3% of Pyr and DahA might occasionally produce ecological risks. The toxicity was calculated on the basis of benzo[a]pyrene, and the toxicity equivalent was between 2.48 and 13.78 ng g-1 with an average of 6.23 ng g-1, which currently does not pose any health risk to human life. PMID- 28718095 TI - Changes in sub-soil river water quality upon its open storage-a case study. AB - A study was carried out to investigate the changes in the physicochemical and biological properties of sub-soil river water upon its storage in a man-made reservoir. Palar sub-soil and reservoir water samples were collated fortnightly for a period of 5 years (2010-2014). The open reservoir is used as a reliable raw water source for condenser cooling systems and for the demineralizing (DM) plant input of Fast Breeder Test Reactor (FBTR), Madras Atomic Power Station (MAPS), and other laboratories at Kalpakkam, southeast coast of India. Relatively high nutrient concentration was observed in the Palar sub-soil water, and a significant reduction in average concentration (MUmol l-1) of phosphate (Palar 1.92; open reservoir 1.54) and nitrate (Palar 9.78; open reservoir 5.67) was observed from Palar to open reservoir. Substantial increase in pH (Palar 8.05; open reservoir 8.45), dissolved oxygen (mg l-1) (Palar 6.07; open reservoir 8.47), and chlorophyll-a (mg m-3) (Palar 1.66; open reservoir 8.43) values were noticed from the Palar sub-soil water to open reservoir water. It is concluded that sub-soil water with higher nutrient concentrations when stored openly, exposing to the sun, resulted in growth of plants, planktonic, and macrophytes, which led to substantial deterioration in water quality from its utility point of view as a condenser cooling medium and raw water input for DM plant. PMID- 28718096 TI - Contamination status of arsenic in fish and shellfish from three river basins in Ghana. AB - Fish and shellfish are regularly consumed and sold in Ghana, yet studies on arsenic pollution in Ghana are limited largely to ground water. This study evaluated arsenic concentrations in seven species of shellfish and 10 species of fish inhabiting the mouth of Ankobra, Densu and Volta basins in Ghana and assessed the public health implications. Arsenic levels varied from 0.2 to 2.2 mg L-1 in the three rivers and were higher than WHO recommended values of 10 MUg L-1 for drinking water. Except for Periophthalmus sp. and Tympanotonus fuscatus from the Ankobra in which arsenic was not detected, concentrations in the organisms ranged from 0.2 to 2.8 mg kg-1. The maximum quantities of the organisms considered safe for consumption ranged from 375 to 5250 g per week. Caution however needs to be exercised as PTWI for arsenic needs revision, and some heavy metals such as mercury are more toxic than arsenic. PMID- 28718098 TI - Massive hemorrhage and transfusion in the operating room. AB - PURPOSE: In this Continuing Professional Development module, we review the pathophysiology and clinical manifestations associated with massive hemorrhage as well as laboratory investigations and appropriate therapeutic measures. In addition to reviewing the available blood/plasma products and adjunct therapy, we also explore the role of the anesthesiologist in a massive transfusion protocol scenario. PRINCIPAL FINDINGS: Massive hemorrhage can be either anticipated or unexpected. The coinciding presence of acidosis, hypothermia, and hypotension contribute greatly to a poor outcome. Red blood cells not only increase oxygen carrying capacity, but they also play a role in providing hemostasis. While timely laboratory results, including point-of-care testing, are important, transfusion remains a clinical decision. Adjunct therapies other than blood components have contributed to improved outcomes. The pathophysiology of massive obstetric hemorrhage is unique when compared with the non-obstetric population. The approach to massive hemorrhage and its treatment vary considerably from institution to institution. CONCLUSIONS: Massive hemorrhage is a multidisciplinary challenge that requires immediate response and communication between clinicians, nurses, other healthcare providers, laboratory testing, and blood banks. Basic knowledge and utilization of available products and therapies are inconsistent. A massive transfusion protocol can be used effectively to reduce chaos and ensure that correct treatments and proper dosing occur in a timely manner. PMID- 28718099 TI - Mapping intracerebral steal during a hypercapnic challenge. PMID- 28718097 TI - Regulatory genes and their roles for improvement of antibiotic biosynthesis in Streptomyces. AB - The numerous secondary metabolites in Streptomyces spp. are crucial for various applications. For example, cephamycin C is used as an antibiotic, and avermectin is used as an insecticide. Specifically, antibiotic yield is closely related to many factors, such as the external environment, nutrition (including nitrogen and carbon sources), biosynthetic efficiency and the regulatory mechanisms in producing strains. There are various types of regulatory genes that work in different ways, such as pleiotropic (or global) regulatory genes, cluster situated regulators, which are also called pathway-specific regulatory genes, and many other regulators. The study of regulatory genes that influence antibiotic biosynthesis in Streptomyces spp. not only provides a theoretical basis for antibiotic biosynthesis in Streptomyces but also helps to increase the yield of antibiotics via molecular manipulation of these regulatory genes. Currently, more and more emphasis is being placed on the regulatory genes of antibiotic biosynthetic gene clusters in Streptomyces spp., and many studies on these genes have been performed to improve the yield of antibiotics in Streptomyces. This paper lists many antibiotic biosynthesis regulatory genes in Streptomyces spp. and focuses on frequently investigated regulatory genes that are involved in pathway-specific regulation and pleiotropic regulation and their applications in genetic engineering. PMID- 28718102 TI - ? PMID- 28718104 TI - ? PMID- 28718103 TI - ? PMID- 28718101 TI - Flexible bronchoscopic intubation through the AuraGainTM laryngeal mask versus a slit Guedel tube: a non-inferiority randomized-controlled trial. AB - PURPOSE: AuraGainTM, a novel third-generation laryngeal mask, can facilitate insertion of a gastric tube and provide the potential advantage of intubation. Data are lacking on intubation through the AuraGain laryngeal mask. METHODS: Eighty-eight hip or knee surgery patients were enrolled in this parallel randomized-controlled trial. We hypothesized that intubation time using the AuraGain laryngeal mask would be no longer than that for standard flexible bronchoscopic intubation over a slit Guedel tube, with a non-inferiority margin of five seconds. The following data were recorded during a maximum of three intubation attempts: intubation time, number of intubation attempts, degree of resistance to advance the endotracheal tube, and mask placement (i.e., Brimacombe score). Follow-up outcomes, including neck pain, hoarseness, and dysphagia, were also measured two and 24 hr postoperatively. Patients and outcome assessors remained blinded until the last examination. RESULTS: Mean intubation time was similar between the Guedel tube and AuraGain groups (23.6 sec vs 21.4 sec, respectively). The upper limit of the 95% confidence interval (CI) of the difference in mean intubation time between groups fell below our pre-specified non-inferiority margin; therefore, we found the AuraGain laryngeal mask to be non inferior to the slit Guedel tube (adjusted group difference, -1.6 sec; 95% CI, 3.7 to 0.5). Successful intubation was achieved in the majority of patients (>= 95%) in each group on the first attempt. No resistance to insertion of the endotracheal tube was encountered in the majority of patients in each group, and no complications were reported during the 24-hr postoperative period. There was no difference in the Brimacombe score or in the status of postoperative morbidity between the two groups. CONCLUSION: We conclude that flexible bronchoscopic intubation through an AuraGain laryngeal mask can be achieved at least as fast as standard bronchoscopic intubation without contributing to additional patient morbidity or postoperative discomfort. TRIAL REGISTRATION: www.clinicaltrials.gov , NCT 02570269. Registered 23 September 2015. PMID- 28718100 TI - Risk factors for delirium after cardiac surgery: a historical cohort study outlining the influence of cardiopulmonary bypass. AB - PURPOSE: Cardiopulmonary bypass (CPB) induces a significant inflammatory response that may increase the risk for delirium. We hypothesized that exposure to CPB during coronary artery bypass grafting (CABG) surgery would correlate with an increased risk of delirium. METHODS: We reviewed clinical data from two databases at our medical centre - the Cardiac Surgery Perioperative Outcomes Database and the Society of Thoracic Surgeons Database. Patients undergoing elective CABG surgery (on-pump and off-pump) from November 1, 2009 to September 30, 2015 were included in the study. Delirium was defined as any postoperative positive Confusion Assessment Method for the Intensive Care Unit exam during the intensive care unit stay. We performed logistic regression to isolate the association between CPB exposure and delirium adjusted for predetermined risk factors and potential confounders. RESULTS: During the study period, 2,280 patients underwent elective CABG surgery, with 384 patients (16.9%) exposed to CPB. Delirium was diagnosed in 451 patients (19.8%). Exposure to CPB showed a significant independent association with delirium. Patients exposed to CPB for 142 min (90th percentile of CPB duration) vs those exposed for 54 min (10th percentile) had an adjusted relative risk (RR) of delirium of 2.18 (95% confidence interval [CI], 1.39 to 3.07; P = 0.002) vs a RR of 1.51 (95% CI, 0.92 to 2.29; P = 0.10), respectively. CONCLUSIONS: The use and duration of cardiopulmonary bypass were associated with an increased risk of delirium in patients undergoing CABG surgery. TRIAL REGISTRATION: www.clinicaltrials.gov , NCT02548975. Registered 4 September 2015. PMID- 28718105 TI - ? PMID- 28718106 TI - ? PMID- 28718107 TI - ? PMID- 28718108 TI - ? PMID- 28718109 TI - ? PMID- 28718110 TI - ? PMID- 28718111 TI - ? PMID- 28718112 TI - ? PMID- 28718113 TI - [Stroke and myocardial infarction after herpes zoster]. PMID- 28718114 TI - [Obstructive sleep apnea and hypertension]. PMID- 28718115 TI - [Carpal tunnel syndrome]. PMID- 28718116 TI - [Combination of oral antidiabetic drugs: What fits together?] PMID- 28718117 TI - ? PMID- 28718118 TI - [More heat stress and air pollution for the lungs in view of climate change]. PMID- 28718120 TI - ? PMID- 28718119 TI - [Global warming - more and other infectious diseases in Germany?] PMID- 28718121 TI - ? PMID- 28718122 TI - ? PMID- 28718123 TI - ? PMID- 28718124 TI - ? PMID- 28718125 TI - ? PMID- 28718126 TI - ? PMID- 28718127 TI - ? PMID- 28718128 TI - ? PMID- 28718129 TI - ? PMID- 28718130 TI - ? PMID- 28718131 TI - ? PMID- 28718132 TI - ? PMID- 28718133 TI - ? PMID- 28718134 TI - ? PMID- 28718135 TI - ? PMID- 28718136 TI - ? PMID- 28718137 TI - ? PMID- 28718138 TI - ? PMID- 28718140 TI - ? PMID- 28718141 TI - ? PMID- 28718139 TI - ? PMID- 28718142 TI - ? PMID- 28718143 TI - ? PMID- 28718144 TI - ? PMID- 28718145 TI - ? PMID- 28718146 TI - ? PMID- 28718147 TI - ? PMID- 28718148 TI - ? PMID- 28718149 TI - ? PMID- 28718151 TI - ? PMID- 28718150 TI - ? PMID- 28718153 TI - ? PMID- 28718155 TI - ? PMID- 28718156 TI - ? PMID- 28718154 TI - ? PMID- 28718157 TI - [Falls in elderly people]. PMID- 28718158 TI - The Extent of Heavy Metal Pollution and Their Potential Health Risk in Topsoils of the Massively Urbanized District of Shanghai. AB - Urbanization and industrialization increase the concentrations of heavy metals in soils, which affect human health. A total of 127 topsoil samples were collected from the massively urbanized and industrialized district of Shanghai: Baoshan District. The sampling sites were isolated based on the land-use practice: industrial area, roadside area, residential area, and agricultural area. The absolute concentrations of heavy metals (Zn, Cr, Ni, Mn, Cu, Pb, and Cd) were determined using atomic absorption spectrometry and compared with Shanghai and the National soil background values. The geoaccumulation index (Igeo) and Nemerow pollution index were used to determine the existence and severity of the pollution of heavy metals. Enrichment factor (EF) analysis, spatial variability of pollution, and multivariate statistical analyses also were employed to determine the anthropogenic loading of heavy metals, their spatial dependency, and correlation among their sources, respectively. Moreover, potential ecological risk and human health risk [carcinogenic risk (RI) and noncarcinogenic hazard (HI)] were evaluated. The average concentration of all the metals (accounted as 229, 128, 56, 719, 55, 119, and 0.3 mg kg-1 for Zn, Cr, Ni, Mn, Cu, Pb, and Cd, respectively) was many folds higher than the background values. The indices depicted that the pollution exists in all the sites and severity decreases in the following order: industrial soils > roadside soil > residential soils > agricultural soils. However, Zn, Pb, and Cd showed high levels of pollution in all the soils. The EF values suggested that the majority of heavy metals are anthropogenically loaded; spatial variability showed that the pollution is more concentrated in Songnan town; Pearson's correlation, principal component analysis (PCA), and cluster analysis suggested different sources of origin for the majority of the heavy metals. RI of Cr and Pb ranged between 2.8E-04 and 2.7E-07. However, HI was site-specific (only for Cr, Pb, Mn), and most of the sites were in Songnan town. This study could be used as a significant piece of information for management purposes to prevent heavy metal pollution and to protect human health. PMID- 28718159 TI - The Role of Varicocele in Male Factor Subfertility. AB - PURPOSE OF REVIEW: Varicocele may play a significant role in a subset of patients presenting with male factor infertility. Despite its relatively high prevalence amongst subfertile men, there has been controversy over the effectiveness of surgical treatments, patient selection, and when to administer treatment, particularly in the era of assisted reproductive technology. RECENT FINDINGS: In line with earlier finding, recent evidence strongly suggests that varicocelectomy improves pregnancy rates and semen parameters. The currently available literature still does not clearly elucidate the answer to this question, due to flaws in retrospective study design. Patients undergoing subinguinal microsurgical varicocelectomy appear to have the highest pregnancy rates, and lowest complication rates, compared to other surgical approaches. Current research has given us a better understanding of the relationship between varicocele and infertility. Amongst men presenting with semen analysis abnormalities and varicoceles, including those patients presenting with non-obstructive azoospermia or couples with a significant male factor component failing previous attempts at in vitro fertilization, varicocelectomy may improve take home baby rates. More robust, prospective, controlled studies are needed to further clarify the population of subfertile men with varicocele most likely to benefit from varicocelectomy. PMID- 28718160 TI - Validity of Claims Data for the Identification of Male Infertility. AB - PURPOSE OF REVIEW: We sought to determine whether infertile men can accurately be identified within a large insurance claims database to validate its use for reproductive health research. RECENT FINDINGS: Prior literature suggests that men coded for infertility are at higher risk for chronic disease though it was previously unclear if these diagnostic codes correlated with true infertility. We found that the specificity of one International Classification of Disease (9th edition) code in predicting abnormal semen parameters was 92.4%, rising to 99.8% if a patient had three different codes for infertility. The positive predictive value was as high as 85%. The use of claims data for male infertility research has been rapidly progressing due to its high power and feasibility. The high specificity of ICD codes for men with abnormal semen parameters is reassuring and validates prior studies as well as future investigation into men's health. PMID- 28718161 TI - Frailty and Lower Urinary Tract Symptoms. AB - The incidence of both frailty and lower urinary tract symptoms, including urinary incontinence, overactive bladder, underactive bladder, and benign prostatic hyperplasia, increases with age. However, our understanding of the relationship between frailty and lower urinary tract symptoms, both in terms of pathophysiology and in terms of the evaluation and management of such symptoms, is greatly lacking. This brief review will summarize definitions and measurement tools associated with frailty and will also review the existing state of the literature on frailty and lower urinary tract symptoms in older individuals. PMID- 28718162 TI - Robotic Sacrocolpopexy-Is It the Treatment of Choice for Advanced Apical Pelvic Organ Prolapse? AB - PURPOSE OF REVIEW: Pelvic organ prolapse (POP) is a highly prevalent condition among women that, although non-life threatening, can significantly impact daily activities and quality of life (QOL). Sacrocolpopexy (SC) has been touted by many as the "gold standard," citing superior anatomic success rates compared to transvaginal approaches for apical prolapse repair. In line with current trends throughout the surgical field, robotic-assisted laparoscopic sacrocolpopexy (RSC) has rapidly gained popularity. This review will present the most contemporary evidence examining RSC and discuss whether it has met criteria to qualify as the "treatment of choice" for advanced apical vaginal prolapse. RECENT FINDINGS: Recent findings support the superior durability of SC for apical prolapse repair compared to native tissue vaginal approaches. Recent evidence demonstrates that anatomic outcomes of minimally invasive sacrocolpopexy, including RSC, are no different than those of traditional ASC. Low quality evidence suggests lower rates of dyspareunia with SC compared to vaginal repairs. RSC may be cost effective when compared to ASC. When compared to LSC, however, RSC is more expensive and associated with longer operating times. RSC is an excellent option for many women who desire the most durable option for definitive repair of advanced apical POP. PMID- 28718163 TI - Incidence and Management of Lower Urinary Tract Symptoms After Urethral Stricture Repair. AB - Lower urinary tract symptoms (LUTS) after urethral stricture repair are not uncommon. Urgency has been reported in 40% of men and urge incontinence in 12% of men after anterior urethroplasty. De novo urgency and urge incontinence is seen in 9 and 5% of men, respectively, after urethroplasty. Once a complication of urethroplasty (such as recurrent urethral stricture or diverticulum) has been excluded as a cause, evaluation of LUTS in such patients should focus on differentiating bladder dysfunction (overactive bladder, underactive bladder), from other outlet obstruction (such as benign prostatic obstruction), dysfunctional voiding, or medical causes (such as nocturnal polyuria). Management of overactive bladder may include behavioural modification, physical therapy, anticholinergic and/or beta-3 agonist medications, intravesical onabolulinum toxin, sacral neuromodulation or peripheral tibial nerve stimulation. Definitive treatment for underactive bladder is limited. Treatment of benign prostatic obstruction may include alpha-blocker and/or 5-alpha reductase inhibitor medication, or surgery to cavitate the prostate. Minimally invasive prostatic procedures are also an option. Although management of LUTS for patients after urethral stricture repair can usually proceed similarly as for patients without prior history of urethral reconstruction, special consideration and alterations in management need to be made when instrumenting the urethra, as the urethral lumen may be narrower in these patients. PMID- 28718164 TI - Advances in Imaging in Prostate and Bladder Cancer. AB - Recent advancements in urologic imaging techniques aim to improve the initial detection of urologic malignancies and subsequent recurrence and to more accurately stage disease. This allows the urologist to make better informed treatment decisions. In particular, exciting advances in the imaging of prostate cancer and bladder cancer have recently emerged including the use of dynamic, functional imaging with MRI and PET. In this review, we will explore these imaging modalities, in addition to new sonography techniques and CT, and how they hope to improve the diagnosis and management of prostate and bladder cancer. PMID- 28718166 TI - Can Long-term LUTS/BPH Pharmacological Treatment Alter the Outcomes of Surgical Intervention? AB - PURPOSE OF REVIEW: We have reviewed the available evidence on the impact of long term pharmacological treatment of lower urinary tract symptoms on the outcomes of benign prostatic hyperplasia surgery. EVIDENCE ACQUISITION: A systematic literature search from January 1990 to May 2017 was performed. Only references in the English language and peer-reviewed manuscripts were considered. RECENT FINDINGS: Over time, the ever-increasing use of long-term pharmaceutical treatments has considerably reduced the rate of BPH surgery in most countries. In addition, patients undergoing surgery are now generally older, more fragile and with larger prostates. Nevertheless, progress in the surgical field may have compensated for this critical picture and no pejorative trend has been recorded in peri- and post-operative complications and functional outcomes. The question whether long-term pharmacological treatment has altered the outcomes of surgical interventions of BPH remains with no clear answer. The call for randomized studies of long-term pharmacological vs surgical treatment of lower urinary tract symptoms due to BPH pharmacological treatment remains valid. PMID- 28718165 TI - Surgical Techniques to Optimize Early Urinary Continence Recovery Post Robot Assisted Radical Prostatectomy for Prostate Cancer. AB - PURPOSE OF REVIEW: A variety of different surgical techniques are thought to impact on urinary continence (UC) recovery in patients undergoing robot assisted radical prostatectomy (RARP) for prostate cancer. Herein, we review current evidence and propose a composite evidence-based technique to optimize UC recovery after RARP. RECENT FINDINGS: A literature search on studies reporting on surgical techniques to improve early continence recovery post robotic prostatectomy was conducted on PubMed and EMBASE. The available data from studies ranging from randomized control trials to retrospective cohort studies suggest that minimizing damage to the internal and external urinary sphincters and their neural supply, maximal sparing of urethral length, creating a secure vesicourethral anastomosis, and providing anterior and posterior myo- fascio-ligamentous support to the anastomosis can improve early UC recovery post RARP. A composite evidence-based surgical technique incorporating the above principles could optimize early UC recovery post RARP. Evidence from randomized studies is required to prove benefit. PMID- 28718167 TI - Are computer numerical control (CNC)-manufactured patient-specific metal templates available for posterior thoracic pedicle screw insertion? Feasibility and accuracy evaluation. AB - PURPOSE: Accurate and safe posterior thoracic pedicle insertion (PTPI) remains a challenge. Patient-specific drill templates (PDTs) created by rapid prototyping (RP) can assist in posterior thoracic pedicle insertion, but pose biocompatibility risks. The aims of this study were to develop alternative PDTs with computer numerical control (CNC) and assess their feasibility and accuracy in assisting PTPI. METHODS: Preoperative CT images of 31 cadaveric thoracic vertebras were obtained and then the optimal pedicle screw trajectories were planned. The PDTs with optimal screw trajectories were randomly assigned to be designed and manufactured by CNC or RP in each vertebra. With the guide of the CNC- or RP-manufactured PDTs, the appropriate screws were inserted into the pedicles. Postoperative CT scans were performed to analyze any deviations at entry point and midpoint of the pedicles. RESULTS: The CNC group was found to be significant manufacture-time-shortening, and cost-decreasing, when compared with the RP group (P < 0.01). The PDTs fitted the vertebral laminates well while all screws were being inserted into the pedicles. There were no significant differences in absolute deviations at entry point and midpoint of the pedicle on either axial or sagittal planes (P > 0.05). The screw positions were grade 0 in 90.3% and grade 1 in 9.7% of the cases in the CNC group and grade 0 in 93.5% and grade 1 in 6.5% of the cases in the RP group (P = 0.641). CONCLUSION: CNC manufactured PDTs are viable for assisting in PTPI with good feasibility and accuracy. PMID- 28718169 TI - Predicting elderly patient length of stay in hospital and community care using a series of conditional Coxian phase-type distributions, further conditioned on a survival tree. AB - Increasing demand on hospital resources by an ageing population is impacting significantly on the number of beds available and, in turn, the length of time that elderly patients must wait for a bed before being admitted to hospital. This research presents a new methodology that models patient pathways and allows the accurate prediction of patient length of stay in hospital, using a phase-type survival tree to cluster patients based on their covariates and length of stay in hospital. A type of Markov model, called the conditional Coxian phase-type distribution is then implemented, with the probability density function for the time spent at a particular stage of care, for example, the first community discharge, conditioned on the length of stay experienced at the previous stage, namely the initial hospital admission. This component of the methodology is subsequently applied to each cohort of patients over a number of hospital and community stages in order to build up the profile of patient readmissions and associated timescales for each cohort. It is then possible to invert the methodology, so that the length of stay for an observation representing a new patient admission may be estimated at each stage of care, based on the assigned cohort at the initial hospital stage. This approach provides hospital managers with an accurate understanding of the rates with which different groups of patients move between hospital and community care, which may be used to reduce the negative effects of bed-blocking and the premature discharge of patients without a required period of convalescence. This has the benefit of assisting hospital managers with the effective allocation of vital healthcare resources. The approach presented is different to previous research in that it allows the inclusion of patient covariate information into the methodology describing patient transitions between hospital and community care stages in an aggregate Markov process. A data set containing hospital readmission data for elderly patients from the Abruzzo region of Italy is used as a case study in the application of the presented methodology. PMID- 28718168 TI - Higher reoperation rate following cervical disc replacement in a retrospective, long-term comparative study of 715 patients. AB - PURPOSE: To evaluate rates of secondary surgical interventions in a cohort treated with fusion (ACDF), artificial disc replacement (ADR) or a posterior surgical procedure (PP) because of a cervical degenerative pathology. METHODS: 715 patients treated with any primary cervical surgical intervention between the years 2000 and 2010 were retrospectively evaluated regarding frequency of secondary surgery between the years 2000 and 2015, thus giving a follow-up time of minimum 5 years. Reasons for secondary surgery as well as choice of new intervention were evaluated. Data were collected from a single-center setting. RESULTS: Follow-up rate was 94%. 79 (11%) patients in total underwent a new operation during follow-up. 50/504 (10%), 27/172 (15%), and 2/39 (5%) of the patients had a second surgical intervention in the ACDF, ADR, and PP groups, respectively. There was a statistically significant higher rate of repeated surgery in the ADR group compared to the ACDF group, OR 1.7 (CI 1.06-2.8), p = 0.03. Risk for repeated surgery at index level was even higher for ADR, OR 5.1 (CI 2.4-10.7), p < 0.001. Reoperation rate because of ASD in the whole cohort did not differ between ACDF and ADR groups, p = 0.40. CONCLUSION: The group initially treated with artificial disc replacement showed higher rate of reoperations and more implant-related complications. In this cohort, artificial disc replacement was not protective against reoperation because of adjacent segment pathology. PMID- 28718170 TI - Your Best Life: Resiliency Builder: Delivering Orthopaedic Care Abroad. PMID- 28718172 TI - Components of competitor priming in task switching. AB - Executing an action in response to a stimulus is thought to result in the creation of an event code that integrates stimulus and action features (Allport, 1987; Hommel in Visual Cognition 5: 183-216, 1998). When switching between tasks, competitor priming occurs if a distractor stimulus cues the retrieval of a previously established event code in which that distractor is bound to a competing task, creating a source of interference with the current task whereby the observer is encouraged to apply the competing task to the distractor. We propose a second aspect of competitor priming: the misapplication of the retrieved competing task to the target stimulus. We report two task-switching experiments in which tasks applied to picture-word compound stimuli were manipulated to create conditions in which this second aspect of competitor priming could be revealed and distinguished from other sources of task- and stimulus-based priming. A substantial increase in competitor priming was observed when subjects switched between tasks that required very different processing operations and the competing task was highly relevant to the target stimulus. These results are consistent with our claim that competitor priming can result from applying the competing task either to the distractor that cued it or to the target stimulus. PMID- 28718171 TI - Younger Patients and Men Achieve Higher Outcome Scores Than Older Patients and Women After Anterior Cruciate Ligament Reconstruction. AB - BACKGROUND: There is some evidence that functional performance and validated outcome scores differ according to the gender, age, and sport participation status of a patient after anterior cruciate ligament (ACL) reconstruction. However, the impact of these three factors, and interaction among them, has not been studied across a large relatively homogeneous group of patients to better elucidate their impact. QUESTIONS/PURPOSES: We reviewed a large cohort of patients who had undergone ACL reconstruction to determine if ROM, knee laxity, objective performance measures, and validated outcome scores differed according to (1) gender; (2) age; and (3) sport participation status. METHODS: This was a retrospective analysis of prospectively collected data. Between 2007 and 2016, we performed 3452 single-bundle ACL reconstructions in patients who participated in sport before ACL injury. Of those, complete followup (including preoperative scores and scores at 1 year after surgery; mean, 14 months; range, 12-20 months) was available on 2672 (77%) of patients. Those lost to followup and those accounted for were not different in terms of age, gender, and sports participation at baseline. The study group consisted of 1726 (65%) men and 946 (35%) women with a mean +/- SD age of 28 +/- 10 years. For these patients, the following measures were obtained: knee ROM (flexion and extension deficit), instrumented knee laxity, single and triple hop for distance limb symmetry index (LSI), International Knee Documentation Committee (IKDC) subjective evaluation, and Single Assessment Numeric Evaluation score. Mean scores and measures of variability were calculated for each outcome measure. Comparisons were made among gender, age, and sport status. RESULTS: Men had less knee laxity after reconstruction (men 1.1 +/- 2.2 mm, women 1.3 +/- 2.4 mm; mean difference 0.2 mm [0.1-0.4], p < 0.001), greater limb symmetry (single limb hop men: 94% +/- 12%, women 91% +/- 13%, mean difference 3% [2%-4%], p < 0.001), and higher IKDC scores than did women (men 84 +/- 12, women 82 +/- 12, mean difference 2 [1-3], p < 0.001). With the exception of instrumented laxity, all outcome measures showed reduced deficits and higher scores in younger patients. This was most marked for LSI scores between the youngest and oldest aged patient groups (crossover hop: < 16 years 99% +/- 10%, > 45 years 90% +/- 16%, mean difference: 9 [5-11], p < 0.001). Patients who had returned to their preinjury sport also scored higher and had smaller deficits for all outcomes except ROM compared with patients who had not returned to sport at the time of followup (IKDC subjective: returned 90 +/- 9, no sport 79 +/- 12, mean difference 11 points [9-12], p < 0.001; single limb hop: returned 97 +/- 10, no sport 91 +/- 14, mean difference 6% [5%-7%], p < 0.001). CONCLUSIONS: This study showed that some of the most commonly used functional performance and validated clinical scores for ACL reconstruction are superior for patients who are younger, male, and have returned to preinjury sport. Reference to these data allows clinicians to more effectively evaluate a patient based on their age, gender, and sport status when making return to sport and rehabilitation decisions. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 28718173 TI - Temporal trimming: Evidence that common-onset masking shortens perceptual sampling of conscious object representations. AB - Common-onset masking (COM) refers to a methodology where a mask can impair awareness of an object if the mask's offset is delayed relative to the offset of the object. This method has classically been used to understand how discontinuities in visual input lead to the discrete removal of object representations before they reach conscious awareness. However, COM has recently been shown to reduce the precision of conscious object representations (Harrison, Rajsic, & Wilson, Psychonomic Bulletin & Review, 23(1), 180-186, 2016). As a result, Harrison et al. proposed that COM shortens the temporal window for perceptual sampling of an object's representation, an account consistent with interruption-based theories of masking. In the present study we modified the standard COM methodology to assess the impact of a delayed mask offset on the temporal perception of an object's representation. Across two experiments we provide novel evidence that a delayed mask offset can impair temporal perception of a conscious percept, such that it reduces the percept's perceived duration (Experiment 1), and prematurely terminates updating of the percept's dynamic orientation (Experiment 2). We refer to these results as temporal trimming, and suggest that the mechanism responsible for COM operates during the sustained perception of an object. PMID- 28718174 TI - Object-substitution masking weakens but does not eliminate shape interactions. AB - At any moment, some objects in the environment are seen clearly, whereas others go unnoticed. Whether or not these gaps in awareness are actually problematic may depend on the extent that information about unseen objects is lost. Determining when and how visual awareness and visual processing become linked is thus of great importance. Previous research using object-substitution masking (OSM) demonstrated that relatively simple visual features, such as size or orientation, are still processed even when they are not visible. Yet this does not appear to be the case for more complex features like faces. This suggests that, during OSM, disruptions of visual processing and awareness may tend to co-occur beginning at some intermediate stage along the ventral pathway. We tested this hypothesis by evaluating the extent to which OSM disrupted the perception and processing of two dimensional objects. Specifically, we evaluated whether an unseen shape's aspect ratio would influence the appearance of another shape that was briefly visible nearby. As expected, the aspect ratios of two shapes appeared to be more similar to each other when both were visible. This averaging effect was weakened, but not eliminated, when one ellipse in each pair received OSM. These shape interactions persisted even when one ellipse from each pair was invisible. When combined with previous work, these results suggest that during object-substitution masking, disruptions of visual processing tend to strengthen with increases in stimulus complexity, becoming more tightly bound to the mechanisms of visual awareness at intermediate stages of visual analysis. PMID- 28718175 TI - Deployment of spatial attention to a structural framework: exogenous (alerting) and endogenous (goal-directed) factors. AB - The main question examined in the present work was whether spatial attention can be deployed to an appropriate structural framework not only endogenously when the framework is displayed continuously, as in previous work, but also exogenously, when it is displayed transiently 100 ms before the target. The results of five experiments answered that question in the negative. We found that the onset transient triggered by a brief presentation of the structural framework did enhance the response to the upcoming target. That enhancement, however, was due not to the framework itself but to the alerting effect produced by its sudden onset, witness the finding that the same enhancement was produced by an onset transient triggered by a featureless stimulus (i.e., by a brief dimming of the entire screen, in the absence of a structural framework). We conclude that spatial attention can be deployed to the region demarcated by a structural framework when it is deployed endogenously but not when it is deployed exogenously. A theoretical account of the results is proposed in terms of the temporal dynamics of the locus coeruleus/norepinephrine neuromodulatory system. PMID- 28718176 TI - Encouraging top-down attention in visual search:A developmental perspective. AB - Four experiments are reported in which 60 younger children (7-8 years old), 60 older children (10-11 years old), and 60 young adults (18-25 years old) performed a conjunctive visual search task (15 per group in each experiment). The number of distractors of each feature type was unbalanced across displays to evaluate participants' ability to restrict search to the smaller subset of features. The use of top-down attention processes to restrict search was encouraged by providing external aids for identifying and maintaining attention on the smaller set. In Experiment 1, no external assistance was provided. In Experiment 2, precues and instructions were provided to focus attention on that subset. In Experiment 3, trials in which the smaller subset was represented by the same feature were presented in alternating blocks to eliminate the need to switch attention between features from trial to trial. In Experiment 4, consecutive blocks of the same subset features were presented in the first or second half of the experiment, providing additional consistency. All groups benefited from external support of top-down attention, although the pattern of improvement varied across experiments. The younger children benefited most from precues and instruction, using the subset search strategy when instructed. Furthermore, younger children benefited from blocking trials only when blocks of the same features did not alternate. Older participants benefited from the blocking of trials in both Experiments 3 and 4, but not from precues and instructions. Hence, our results revealed both malleability and limits of children's top-down control of attention. PMID- 28718177 TI - Saliency maps for finding changes in visual scenes? AB - Sudden changes in the environment reliably summon attention. This rapid change detection appears to operate in a similar fashion as pop-out in visual search, the phenomenon that very salient stimuli are directly attended, independently of the number of distracting objects. Pop-out is usually explained by the workings of saliency maps, i.e., map-like representations that code for the conspicuity at each location of the visual field. While past research emphasized similarities between pop-out search and change detection, our study highlights differences between the saliency computations in the two tasks: in contrast to pop-out search, saliency computation in change detection (i) operates independently across different stimulus properties (e.g., color and orientation), and (ii) is little influenced by trial history. These deviations from pop-out search are not due to idiosyncrasies of the stimuli or task design, as evidenced by a replication of standard findings in a comparable visual-search design. To explain these results, we outline a model of change detection involving the computation of feature-difference maps, which explains the known similarities and differences with visual search. PMID- 28718178 TI - Body Composition is Different After Surgical or Pharmacological Remission of Cushing's Syndrome: A Prospective DXA Study. AB - Patients with active Cushing's syndrome (CS) exhibit an increase of the visceral adipose tissue, increasing the risk of cardiovascular events. Until now, it is not yet clear whether remission of CS leads to a normalization of body composition, or if different strategies to control hypercortisolism could result in a different clinical outcome concerning adipose tissue distribution. Therefore, we analyzed body composition changes using dual-energy X-ray absorptiometry (DXA) in patients with CS in a prospective and controlled study. We considered 23 patients with CS, whose remission was achieved after surgery in 14 or gained with pharmacological treatment in 9 subjects. Clinical and DXA data (lean and fat mass in total body, trunk, and R1 box) were collected during active hypercortisolism and after sustained remission, defined as the normalization of both late night salivary and 24-h urinary cortisol levels, at least for 6 consecutive months. Healthy subjects, matched with CS for gender, age, and BMI, were considered as controls (n=25). After remission of hypercortisolism, body compositions of patients were similar to matched controls; fat mass in total body (-7.53%), trunk (-3.24%), and R1- box (-12.82%, all p<0.01) were decreased from baseline levels. Dividing patients by type of treatment, fat mass reduction was higher in those that achieved surgical remission of CS (total body -17.26%, trunk -22.73%, and R1 box -21.21%, all p<0.05). Surgical remission of hypercortisolism is characterized by improvement of body composition, particularly fat reduction, easily detectable with DXA during routine clinical practice. PMID- 28718179 TI - Genetic Alterations in Pendrin (SLC26A4) Gene in Adult Hypothyroid Patients. AB - Current study was aimed to screen the SLC26A4 gene in 127 nonautoimmune and noncongenital hypothyroid patients, who were under optimal iodine nutrition and devoid of any characteristics of Pendred syndrome from eastern part of Indian population. 8 single nucleotide variants/mutations were identified in heterozygous state in 20% patient population, which include 1 novel nonsynonymous (p.C18S), 1 novel intronic (g.942C>A), 3 known nonsynonymous (p.S23X, p.V239D, and p.I455F), and 3 known intronic (g.23034G>T, g.29641C>G, and g.33893T>C) variants. Only g.23034G>T was noted also in homozygous state in 2% patient population. However, Controls exhibited only the variations g.23034G>T and p.I455F. Therefore, present study reports for the first time that the observed novel variants in pendrin gene might be linked with autoimmune negative hypothyroidism, without any characteristics of Pendred syndrome and/or congenital hypothyroidism. While, all observed known variants/mutations were reported with either Pendred syndrome and/or congenital hypothyroidism earlier, but never with nonautoimmune adult hypothyroidism solely. Thereby, the absence of any features of Pendred syndrome and/or congenital hypothyroidism in patients with observed known nonsynonymous variants/mutations may be due to either heterozygous state of each variant or differential domain specific activity of ions trafficking in the respective organ. The analysis of amino acid change at least for p.C18S, p.S23X, and p.V239D in correlation with phenotypic characteristics of respective patients might assume a possible effect on protein structure and function. Altogether, we report for the first time that genetical variations in SLC26A4 gene could play an important role in development of nonautoimmune adult hypothyroidism. PMID- 28718180 TI - Changing Face of Invasive Diagnostic Testing in the Era of Cell-Free DNA. PMID- 28718181 TI - Erythropoietin for Cognitive Deficits Associated with Schizophrenia, Bipolar Disorder, and Major Depression: A Systematic Review. AB - INTRODUCTION: The purpose of this study is to systematically review the efficacy and safety of adjunctive erythropoietin (EPO) in treating cognitive deficits associated with schizophrenia, bipolar disorder, and major depression based on randomized controlled trials (RCTs). METHODS: Two evaluators independently and systematically searched and selected studies, extracted data, and conducted quality assessment. RESULTS: Four RCTs with 144 patients (71 in the EPO group and 73 in the placebo group) met the study entry criteria. Adjunctive EPO could improve schizophrenia-related cognitive performance. In patients with bipolar disorder, EPO could also enhance sustained attention, recognition of happy faces, and speed of complex information processing across learning, attention, and executive function when compared with placebo. In addition, EPO could enhance verbal recall, recognition, and memory in patients with major depression. DISCUSSION: This preliminary study found that adjunctive EPO appears to be effective in treating cognitive deficits associated with schizophrenia, bipolar disorder, and major depression without major adverse effects observed. Further higher quality RCTs with larger samples are needed to confirm the findings. REVIEW REGISTRATION: CRD42017058094. PMID- 28718182 TI - Driving Under the Influence of Antidepressants: A Systematic Review and Update of the Evidence of Experimental and Controlled Clinical Studies. AB - Introduction This review provides an update of experimental and clinical studies on the effects of antidepressants on driving performance. Methods A systematic literature search on the PubMed database (1980-2016) was performed. Results Twenty-eight studies could be included in this review, whereas only 5 studies investigated driving performance under antidepressants in patients. Most tri- and tetracyclics have acute deleterious effects on driving performance that, except for mianserin, attenuate after subchronic use. Selective serotonin reuptake inhibitors and the serotonin norepinephrine reuptake inhibitor's venlafaxine and milnacipran did not affect driving ability. Trazodone appears to have dose related acute effects on driving skills. Acute use of mirtazapine does produce impairments that diminish when given as a nocturnal dose and cannot be seen in healthy subjects when initially given as a low dose or after repeated dosing. Additive effects with alcohol were most pronounced with sedating antidepressants. Most patients definitely benefit from treatment with newer antidepressants with respect to driving skills. Discussion Much more patient studies are needed to elucidate a crucial question: from which antidepressant treatment do patients benefit most with respect to driving performance? PMID- 28718183 TI - ? PMID- 28718184 TI - [Natriuretic Propeptide as an Early Marker for Bronchopulmonary Dysplasia in Very Preterm Neonates?] PMID- 28718185 TI - Congenital Pulmonary Lymphangiectasia: A Disorder not only of Fetoneonates. AB - Congenital pulmonary lymphangiectasia (CPL) is a rare developmental disorder of the lung, characterized by dilation of pulmonary subpleural, interlobar, perivascular and peribronchial lymphatics. The incidence of CPL among stillborn and neonates was estimated to be <1%. The etiology of CPL is unknown. However, it has been suspected to be of a genetic background. Recent basic studies revealed that it might be caused by the FOXC2, Vegfr-3 and integrin alpha9beta1gene mutations. A clinical diagnosis of CPL can be made much easier in full-term neonates who present with respiratory distress, pleural (especially chylous) effusions with or without generalized edema. In infancy, the diagnosis seems to be more difficult due to the nonspecific respiratory symptoms like persistent tachypnea, cough and wheeze. Lung biopsy with subsequent histological and immunohistochemical studies is the golden diagnostic method of CPL. Immunohistochemical staining for endothelial cell markers CD31, CD34 and D2-40 confirms lymphatic origin. Therapeutic strategies include supportive, nutritional, investigational, aggressively interventional and surgical regimens, most of which have shown promising outcomes. Although CPL was once regarded as a disorder of very poor prognosis in neonatal onset cases, teenager and adult patients have shown good outcomes upon long-term follow-up.Die angeborene pulmonale Lymphangiektasie (CPL) ist eine seltene Entwicklungsstorung der Lunge, die durch eine Dilatation der pulmonalen subpleuralen, interlobaren, perivaskularen und peribronchialen Lymphgefabetae charakterisiert ist. Die Inzidenz der CPL bei Totgeburten und Neugeborenen wird <1% geschatzt. Die Atiologie der CPL ist unbekannt. Allerdings wird ein genetischer Hintergrund vermutet. Neuere Grundlagenstudien zeigten, dass die CPL durch FOXC2, Vegfr-3 und Integrin alpha9beta1-Genmutationen verursacht sein konnte. Die klinische Diagnose der CPL ist sehr viel einfacher in Reifgeborenen zu stellen, die Atemnot, Pleuraergusse (vor allem chylose) mit und ohne generalisiertem Odem aufweisen. In der fruhen Kindheit ist die Diagnose aufgrund der unspezifischen respiratorischen Symptomatik wie persistierende Tachypnoen, Husten oder Rocheln schwerer zu stellen. Die Lungenbiopsie mit anschliebetaenden histologischen und immunhistochemischen Untersuchungen ist der Goldstandard fur die Diagnose der CPL. Die immunhistochemische Farbung der Endothelzellmarker CD31, CD34 und D2-40 bestatigt den lymphatischen Ursprung. Die Behandlungsstrategien umfassen unterstutzende, alimentare, in Erprobung befindliche, aggressiv-interventionelle und chirurgische Behandlungsplane, von denen die meisten ermutigende Ergebnisse zeigten. Obwohl die CPL einst bei Fallen mit Ausbruch im Neugeborenenalter als Erkrankung mit sehr schlechter Prognose galt, zeigen Teenager und erwachsene Patienten in der Langzeit-Nachbeobachtung gute Verlaufe. PMID- 28718186 TI - Intrauterine Growth Restriction (IUGR) Induces Signs of Subclinical Atherosclerosis in 6-Year-Old Infants Despite Absence Of Excessive Growth. AB - Background Postnatal catch-up growth and rapid weight gain after intrauterine growth restriction (IUGR) seem to increase the risk for later disease. This study aimed to compare features of the metabolic syndrome early in life between IUGR and appropriate for gestational age (AGA) infants. Patients Data for 9 infants with IUGR defined by a birth weight<10th percentile and ultrasound-proven placental insufficiency and 11 AGA children were available. Method Postnatal growth, auxological, cardiovascular, and metabolic parameters up to a chronological age of 6 years were assessed: Fasting serum concentrations of LDL cholesterol, insulin, leptin, IGF-I, DHEAS, skinfold thicknesses, blood pressure, and mean carotid intima-media thickness (cIMT). Results All IUGR infants showed catch-up growth, although mean BMI SDS and total subcutaneous fat mass at the age of 6 years were still slightly lower compared to the AGA cohort. Reduced serum leptin concentrations were observed in IUGR infants (p=0.02), whereas no significant difference was found for IGF-I, insulin, LDL-cholesterol and DHEAS concentrations. Mean cIMT was significantly higher in IUGR infants (p<0.05). Mean arterial pressure did no differ. Discussion and Conclusion In 6-year-old IUGR infants with catch-up growth, who still had a slightly reduced BMI SDS compared to the AGA group, signs of subclinical atherosclerosis were detectable suggesting that cardiovascular risk in IUGR may be present even in the absence of excessive growth. PMID- 28718187 TI - Brain Natriuretic Propeptide as an Early Marker of Bronchopulmonary Dysplasia or Death in the Preterm Newborn. AB - Aim To investigate whether increased brain natriuretic propeptide (NT-proBNP) levels at 48 to 72 h of life are associated with the development of bronchopulmonary dysplasia (BPD) or death in premature neonates. Methods A retrospective study was performed in neonates born before 32 weeks' gestation or with birth weight below 1500 grams, in whom NT-proBNP determination and echocardiography were performed at 48 to 72 h of life. Associations between NT proBNP levels and the combined outcome BPD or death were analyzed using multivariate logistic regression analysis. Results 117 neonates with mean gestational age 27.8+/-2.1 weeks and birth weight 949.7+/-267.5 grams were included. Forty (34.2%) had an outcome of BPD or death. The risk of this combined outcome was found to be 3.95-fold higher (OR 3.95; 95% CI 1.1-14.6) in neonates with NT-proBNP levels above 17800 pg/mL. Conclusion Increased NT-proBNP levels may be associated with a significant decrease in BPD-free survival in very immature newborns. PMID- 28718188 TI - Weaning Premature Infants from Nasal Continuous Positive Airway Pressure - Current Practice and Scientific Evidence. AB - Objective In the past decade, a number of trials have been conducted to determine the optimal strategy of weaning premature infants from nasal continuous airway pressure (nCPAP). However, a paucity of information exists on how weaning is actually performed in clinical routine. Aim of this study was to investigate the current practice of weaning premature infants from nCPAP in Germany. Methods An online survey was performed in German tertiary care neonatal units. Results All 160 German tertiary care units were contacted. Replies were retrieved from 85/160 (53%) units, of which 83/160 (52%) completed the questionnaire. 66/83 (80%) respondents indicated to wean without the use of formal written policies. In 44/83 (53%) units weaning decisions are made jointly between physicians and nurses, whereas physicians are the sole decision makers in 33/83 (40%) as are nurses in 6/83 (7%) units. Many units use more than one weaning strategy. 81/83 units (98%) gradually reduce nCPAP pressure as the initial step in the weaning process. 9/83 (11%) units stop nCPAP at standard criteria [CICADA (CeasIng nCpap At standarD criteriA) method] and 58/83 (70%) units use a cycling nCPAP on/off strategy. 52/83 (63%) of the responding units use nasal high flow at least at some point during the weaning process, either as a gradual weaning method or during nCPAP breaks. Conclusion Weaning strategies from nCPAP vary widely in German tertiary care neonatal units. It appears that evidence is still insufficient to promote a distinct weaning strategy which in turn highlights the urgent need for further adequately powered clinical trials. PMID- 28718189 TI - [Health Related Quality of Life, Self-Esteem and Health Behaviour on Average 6 Years after an Obesity Outpatient Lifestyle Program]. AB - Background Multimodal programs focusing on weight reduction are recommended in guidelines for the treatment of obese children. However, studies investigating the effects of such programs over time are still missing; there is especially a lack of studies considering longer periods after treatment. In the present study, adolescents' bodyweight, health-related quality of life (HRQoL), self-esteem and health behavior were assessed before and directly after the treatment as well as 3 years after the treatment. Methods Between 2005 and 2009 84 children and adolescents took part in a 10-month, multimodal training programme. A number of 55 participants were assessed before (T0), after (T1) and at least 3 years after the beginning of the programme (T2). Based on height and weight the Body mass index standard deviation score (BMI-SDS) was calculated. Further, HRQoL, self esteem, physical activity and eating behavior were measured by means of standardized questionnaires. Results On average 6 years after program beginning the BMI-SDS decreased by 0.4 compared to program beginning (p<0.01). The HRQoL total score increased from 70.1+/-12.1 at T0 to 76.2+/-12.8 at T2 (p<0.05). The self-esteem also increased from 54.0+/-23.4 (T0) to 65.0+/-21.5 (T2; p<0.05). In addition, in the long run the physical activity (p<0.05) and the interest in sports (p<0.001) increased. However, the eating behavior did not improve significantly. Conclusion In addition to weight and health behaviour improvements participating in a multimodal training program is associated with a clinical relevant increase of HRQoL and self-esteem. These improvements of protective factors can diminish the risk of discrimination and should be analysed in further controlled studies. PMID- 28718191 TI - [Treatment of obstructive sleep apnea by orthodontic treatment - a thought provoking impulse]. PMID- 28718190 TI - [Prevalence and Risk Factors of Myopia in Children and Adolescents in Germany - Results of the KiGGS Survey]. AB - Purpose To determine the population prevalence and risk factors of myopia in children and adolescents in Germany. Methods The prevalence of myopia in Germany was computed using data from the 2003-2006 German Health Interview and Examination Survey for Children and Adolescents (N=17 640, 49% girls). Status of myopia was derived from parental questionnaire responses for myopia and the use of spectacles. Potential risk factors were identified using directed acyclic graphs and evaluated using multivariable logistic regression analysis. Results The population prevalence of myopia in the age group 3-17 years was estimated at 13.3% (95%-confidential interval 12.6-14.0%). In the age group 3-10 years, myopia was positively associated with age (per 2 years: OR=1.78 [1.59; 2.00]) and negatively associated with male gender (OR=0.73 [0.57; 0.95]), but neither with leisure-time activities nor with media use. In the age group 11-17 years, attending a High School was positively associated with myopia (OR=1.69 [1.32; 2.16]), while regular physical activity (OR=0.67 [0.53; 0.84]) was negatively associated. Media use was not associated. Conclusions In Germany, myopia is one of the most frequent chronic medical conditions among children and adolescents. Girls, adolescents, and pupils attending a Gymnasium are at higher risk of developing myopia while being physically active may be protective. PMID- 28718192 TI - Cardiometabolic risks vary by weight status in pediatric kidney and liver transplant recipients: A cross-sectional, single-center study in the USA. AB - There is an increasing need to understand long-term metabolic changes and resultant comorbidities because life expectancy is increasing after pediatric kidney and liver transplants. We evaluated differences in classic and novel cardiometabolic biomarkers among obese and normal weight adolescent transplant recipients. We enrolled a total of 80 adolescent (mean+/-SD, 14.8 years +/-3.0) transplant recipients (63 kidney, 17 liver) with mean duration from transplantation of 6.0 (+/-4.1) years. Among kidney transplant recipients, overweight and obese individuals had higher leptin (16.7 vs 7.5 MUg/mL, P<.001), lower HDL (1.1 vs 1.3 mmol/L, P=.02), higher free fatty acid (0.6 vs 0.5 mmol/L, P=.03), higher apoB-to-apoA1 ratio (0.8 vs 0.6, P=.03), and higher glucose (5.8 vs 4.3 mmol/L, P=.03) concentrations compared to normal weight individuals. Regardless of obesity status, over half of all participants (57.5%) were considered at high cardiometabolic risk using consensus guidelines, and this was more pronounced for kidney transplant recipients (61.9%). Post-transplantation adolescents have increased cardiometabolic risk characterized by traditional risk factors of obesity and diabetes. The presence of obesity significantly worsens biomarkers of cardiometabolic risk. Future studies should explore whether treatment of obesity can improve the health and long-term outcomes for children undergoing solid organ transplant. PMID- 28718193 TI - Metacommunity theory meets restoration: isolation may mediate how ecological communities respond to stream restoration. AB - An often-cited benefit of river restoration is an increase in biodiversity or shift in composition to more desirable taxa. Yet, hard manipulations of habitat structure often fail to elicit a significant response in terms of biodiversity patterns. In contrast to conventional wisdom, the dispersal of organisms may have as large an influence on biodiversity patterns as environmental conditions. This influence of dispersal may be particularly influential in river networks that are linear branching, or dendritic, and thus constrain most dispersal to the river corridor. As such, some locations in river networks, such as isolated headwaters, are expected to respond less to environmental factors and less by dispersal than more well-connected downstream reaches. We applied this metacommunity framework to study how restoration drives biodiversity patterns in river networks. By comparing assemblage structure in headwater vs. more well-connected mainstem sites, we learned that headwater restoration efforts supported higher biodiversity and exhibited more stable ecological communities compared with adjacent, unrestored reaches. Such differences were not evident in mainstem reaches. Consistent with theory and mounting empirical evidence, we attribute this finding to a relatively higher influence of dispersal-driven factors on assemblage structure in more well-connected, higher order reaches. An implication of this work is that, if biodiversity is to be a goal of restoration activity, such local manipulations of habitat should elicit a more profound response in small, isolated streams than in larger downstream reaches. These results offer another significant finding supporting the notion that restoration activity cannot proceed in isolation of larger-scale, catchment-level degradation. PMID- 28718194 TI - Prevalence of imaginary companions in Japanese children. AB - Having an imaginary companion (IC) is an example of children's pretend play. However, most research regarding children's ICs is from Western cultures. In this study, the prevalence of ICs was assessed among Japanese children (2- to 9-year old children, N = 800). The developmental (age), biological (sex), and environmental (birth order) effects on Japanese children's ICs were also assessed. Moreover, whether IC status can be an indicator of fantasy orientation in Japanese children was examined. The results revealed that the prevalence of the invisible friend was relatively rare, but the personified object was prevalent in Japanese children. Age and sex, but not birth order, significantly affected the prevalence of ICs in Japan. Moreover, IC status significantly indicated children's fantasy orientation. The results suggest that the characteristics of Japanese children's ICs are partly different from those in Western children. Social-cultural contexts can affect this difference. PMID- 28718195 TI - Correction PMID- 28718197 TI - Mandarin Translations. PMID- 28718196 TI - Retracted: Cannabinoid CB(2) receptors modulate ERK-1/2 kinase signalling and NO release in microglial cells stimulated with bacterial lipopolysaccharide, by S Merighi, S Gessi, K Varani, C Simioni, D Fazzi, P Mirandola and P A Borea. British Journal of Pharmacology, volume 165(6): 1773-1788, published in March 2012; DOI 10.1111/j.1476-5381.2011.01673.x. AB - The above article, published by the British Journal of Pharmacology in March 2012 (http://onlinelibrary.wiley.com/doi/10.1111/j.1476-5381.2011.01673.x/full), has been retracted by agreement between the authors, the Journal Editor in Chief and John Wiley & Sons Ltd. The authors wish to state that in preparation of the original manuscript errors occurred resulting in duplication. This issue relates specifically to Figures 2A and 2B, lanes 3-5 of the pJNK1/2 in Figure 3B and lanes 1-3 of the pJNK1/2 blot from Figure 3C. In addition, duplication has occurred in lanes 1-9 of the total MEK1/2 blot (left) and lanes 1-9 of the tubulin blot from Figure 6G JBC 280 (right). The authors apologize for the mistake. Unfortunately, the authors are not able to provide the original data for these figures. PMID- 28718198 TI - Targeted antenatal anti-D prophylaxis program for RhD-negative pregnant women - outcome of the first two years of a national program in Finland. AB - INTRODUCTION: The aim of this study was to assess the accuracy of the non invasive fetal RHD test at 24-26 weeks of gestation as part of the national antenatal screening program to target routine antenatal anti-D prophylaxis (RAADP) at 28-30 weeks at women carrying an RhD-positive fetus. MATERIAL AND METHODS: A prospective cohort study involving all maternity care centers and delivery hospitals in Finland between February 2014 and January 2016. Fetal RHD genotyping using cell-free fetal DNA in maternal plasma was performed with real time polymerase chain reaction in a centralized setting. The results were systematically compared with the serological newborn RhD typing. The main outcome measure was the accuracy of the fetal RHD assay; the secondary variable was compliance with the newly introduced RAADP program. RESULTS: Fetal RHD was screened from 10 814 women. For the detection of fetal RHD, sensitivity was 99.99% [95% confidence interval (CI) 99.92-99.99] and specificity 99.81% (95% CI 99.60-99.92). One false-negative and seven false-positive results were reported by the delivery hospitals in two years. The negative predictive value of the test was 99.97% (95% CI 99.81-99.99). At the end of the study period, over 98% of the RhD-negative women participated in the new screening program. CONCLUSIONS: The targeted RAAPD program was implemented effectively in the national maternity care program in Finland. An accurate fetal RHD screening test allows discontinuation of newborn testing without risking the postnatal prophylaxis program. In the future, the main area to investigate will be the clinical effect of RAADP on subsequent pregnancies. PMID- 28718199 TI - The CLEC12A receptor marks human basophils: Potential implications for minimal residual disease detection in acute myeloid leukemia. AB - BACKGROUND: The transmembrane receptor C-type lectin domain family 12, member A (CLEC12A) is known to be highly expressed on monocytes and neutrophils and is a reliable leukemia associated marker in acute myeloid leukemia. Consequently, detailed knowledge of the various normal cell types expressing this receptor is essential. We have observed CLEC12A to be expressed on CD45lowSSClowCD14-CD123+ basophils in peripheral blood (PB) and in this study, we aimed at verifying this observation and further delineate the CD45lowSSClowCD14-CD123 + CLEC12A+ subpopulation. METHODS: We analyzed PB from 20 diagnostic chronic myeloid leukemia (CML) samples and eight healthy donors in a six-color multicolor flowcytometry (FCM) based assay. Furthermore, we performed fluorescence activated cell sorting on one CML sample to morphologically confirm the CD45lowSSClowCD14 CD123 + CLEC12A+ subset to be highly enriched for basophils. Finally, to further delineate the CD45lowSSClowCD14-CD123 + CLEC12A+ subpopulation in normal PB, we examined three healthy donors in a 10-color FCM assay enabling further separation of the cell subset into basophils and dendritic cells. RESULTS: The CLEC12A receptor is expressed on basophils. CONCLUSIONS: Identification and enumeration of basophils is of high relevance in diagnostic hematology and immunology. We here show that CLEC12A in a simple FCM assay consistently marks basophils. Importantly, as basophils are characterized by a CD45lowSSClow profile similar to the "blast-gate" used for the evaluation of hematological disorders, awareness of minor normal CLEC12A+ subpopulations is crucial when using CLEC12A as a minimal residual disease marker in myeloid malignancies. (c) 2017 International Clinical Cytometry Society. PMID- 28718200 TI - A case of acquired epidermodysplasia verruciformis in a renal transplant recipient clearing with multimodal treatment including HPV (Gardasil) vaccination. PMID- 28718201 TI - Granulomatous reaction to hyaluronic acid filler material in oral and perioral region: A case report and review of literature. AB - The use of cosmetic fillers agents in orofacial region has become more often used for esthetic concern. Although adverse effects are rare, some patients may develop foreign body reaction to such fillers. Hyaluronic acid (HA) is a biomaterial in the spotlight, because it is normally present in several tissues of human body. The aim of this study was to report a case of a 54-year-old white woman with granulomatous reaction to the HA located in the lips. In addition, a review of the English-language literature of all previously described cases of this condition in oral and perioral region was performed. The location, clinical features, symptoms, time between injection and reaction, type of treatment and treatment outcome of 17 cases were summarized. The clinical and histopathological examination along with a detailed history about this condition is very important to management of patients with nodular lesions in maxillofacial region. PMID- 28718202 TI - Patterns of mortality in a montane mixed-conifer forest in San Diego County, California. AB - We examine spatial patterns of conifer tree mortality and their changes over time for the montane mixed-conifer forests of San Diego County. These forest areas have recently experienced extensive tree mortality due to multiple factors. A spatial contextual image processing approach was utilized with high spatial resolution digital airborne imagery to map dead trees for the years 1997, 2000, 2002, and 2005 for three study areas: Palomar, Volcan, and Laguna mountains. Plot based fieldwork was conducted to further assess mortality patterns. Mean mortality remained static from 1997 to 2002 (4, 2.2, and 4.2 trees/ha for Palomar, Volcan, and Laguna) and then increased by 2005 to 10.3, 9.7, and 5.2 trees/ha, respectively. The increase in mortality between 2002 and 2005 represents the temporal pattern of a discrete disturbance event, attributable to the 2002-2003 drought. Dead trees are significantly clustered for all dates, based on spatial cluster analysis, indicating that they form distinct groups, as opposed to spatially random single dead trees. Other tests indicate no directional shift or spread of mortality over time, but rather an increase in density. While general temporal and spatial mortality processes are uniform across all study areas, the plot-based species and quantity distribution of mortality, and diameter distributions of dead vs. living trees, vary by study area. The results of this study improve our understanding of stand- to landscape level forest structure and dynamics, particularly by examining them from the multiple perspectives of field and remotely sensed data. PMID- 28718203 TI - Landscape effects on pollination networks in Mediterranean gypsum islands. AB - Habitat fragmentation is a major driver of global change that has operated historically on Mediterranean ecosystems. However, more needs to be understood about how fragmentation influences ecological interactions, particularly pollination. Gypsum outcrops are historically fragmented Mediterranean habitats and settings for the evolution of many endangered soil-specialist plants with narrow ranges. In this study, we aimed to determine how fragmentation (area and connectivity) affects: (i) pollinator community composition and (ii) structural properties of pollination networks; and whether there are differences in the effects of fragmentation on: (iii) the number of interactions and visits among pollinator functional groups; and (iv) the number of interactions and specialisation degree between soil-specialist and soil-generalist plants. We characterised the degree of fragmentation and the pollination network structures in 12 gypsum habitat fragments embedded in a cropland matrix during two consecutive years. We found significant relationships between fragmentation and network structure. The effects of fragmentation differed among pollinator functional groups, but not between soil-specialist and soil-generalist plants, in terms of number of interactions. However, the relatively higher pollinator specialisation of soil-specialist plants suggested greater dependence on pollinators. Inter-annual variations in the network structures demonstrated the importance of temporal replication. The observed patterns related to the landscape structure and pollination at both the network and species levels provide insights into the key ecological processes in gypsum islands. These findings may help to identify the potential drivers of species persistence, especially for endangered soil-specialist plants with narrow ranges in a changing scenario with exacerbated habitat fragmentation. PMID- 28718204 TI - Detrital shadows: estuarine food web connectivity depends on fluvial influence and consumer feeding mode. AB - We measured the influence of landscape setting on estuarine food web connectivity in five macrotidal Pacific Northwest estuaries across a gradient of freshwater influence. We used stable isotopes (delta13 C, delta15 N, delta34 S) in combination with a Bayesian mixing model to trace primary producer contributions to suspension- and deposit-feeding bivalve consumers (Mytilus trossulus and Macoma nasuta) transplanted into three estuarine vegetation zones: emergent marsh, mudflat, and eelgrass. Eelgrass includes both Japanese eelgrass (Zostera japonica) and native eelgrass (Zostera marina). Fluvial discharge and consumer feeding mode strongly influenced the strength and spatial scale of observed food web linkages, while season played a secondary role. Mussels displayed strong cross-ecosystem connectivity in all estuaries, with decreasing marine influence in the more fluvial estuaries. Mussel diets indicated homogenization of detrital sources within the water column of each estuary. In contrast, the diets of benthic deposit-feeding clams indicated stronger compartmentalization in food web connectivity, especially in the largest river delta where clam diets were trophically disconnected from marsh sources of detritus. This suggests detritus deposition is patchy across space, and less homogenous than the suspended detritus pool. In addition to fluvial setting, other estuary-specific environmental drivers, such as marsh area or particle transport speed, influenced the degree of food web linkages across space and time, often accounting for unexpected patterns in food web connectivity. Transformations of the estuarine landscape that alter river hydrology or availability of detritus sources can thus potentially disrupt natural food web connectivity at the landscape scale, especially for sedentary organisms, which cannot track their food sources through space. PMID- 28718205 TI - Bcl-2 maturation pattern in T-cells distinguishes thymic neoplasm/hyperplasia, T lymphoblastic lymphoma, and reactive lymph nodes. AB - Anterior mediastinal biopsies consisting predominantly of small lymphocytes can be a diagnostic challenge, especially in small core biopsies. In these cases, immunophenotyping is often employed using flow cytometry, and/or immunohistochemistry. However, due the overlap in T-cell phenotype between thymic neoplasm/hyperplasia (THY), T-lymphoblastic lymphoma (T-LBL), and reactive lymph nodes (RLN), biopsies consisting predominantly of T-cells may still be difficult to differentiate. Previous studies have shown a specific CD3/bcl-2 staining pattern in thymic T cells of humans and mice using flow cytometry. However, the utility of this finding in distinguishing T-cells of THY, T-LBL, and RLN has not been carefully evaluated. Our findings show that the pattern of CD3/bcl-2 expression in thymic T-cells can be used to help diagnose anterior mediastinal biopsies, even when limited specimen is provided. (c) 2017 International Clinical Cytometry Society. PMID- 28718207 TI - Plaque psoriasis is associated with subclinical atherosclerosis in a Chinese population. PMID- 28718209 TI - New knowledge and insights about the malignant transformation of endometriosis. AB - Endometriosis may be a definitive risk factor for ovarian cancer, the most fatal gynecological cancer. The ability of endometriosis to transform into malignancy, first described by Dr. Sampson in 1925, is considered a rare occurrence, affecting approximately 1% of ovarian endometriomas. Recently we conducted a retrospective study regarding the malignant transformation of endometriosis in Japanese women. Many studies have reported a consistent correlation between endometriosis and ovarian cancer according to histological subtypes. However, the existing epidemiological evidence linking this association is insufficient to define the role of endometriosis as a cause of ovarian cancer and to influence changes to current clinical practice. Prospective cohort studies are therefore needed to clarify this issue. Additionally, the results of many molecular studies are conflicting, and earlier studies showing the molecular aberrations involved in genomic instability and mutation that enable malignant transformation have not been replicated in later studies. Careful long-term observation of a patient with endometrioma is required to detect possible subsequent incidence of malignant transformation. More importantly, a precise strategy should be set up for better prevention, early detection, specific diagnosis and treatment targeting molecular pathogenesis to understand the mechanisms of endometriosis-associated ovarian cancer. Clinicians need to be aware of the increased ovarian cancer risk in women with endometriosis. PMID- 28718210 TI - Mean platelet volume may not show the presence and severity of hyperemesis gravidarum. PMID- 28718206 TI - Delta-like protein 1 in the pituitary-adipose axis in the adult male mouse. AB - With the aim of studying delta-like protein 1 (DLK1) with respect to the relationship between adipocyte leptin and adenohypophyseal hormones, we carried out an immunohistochemical study analysing the presence of receptors for these hormones in the pituitary and adipose cells of male wild-type (WT) mice (Dlk1+/+ ) compared to knockout (KO) mice (Dlk1-/- ). The mRNA expression of these molecules was also determined using the reverse transcriptase-polymerase chain reaction. The results obtained showed that, in WT adipose cells, all of the adenohypophyseal hormone receptors were present, with a higher mRNA expression for growth hormone (GH) receptor and thyroid-stimulating hormone (TSH) receptor. Of the total cells in the anterior pituitary lobe, 17.09+/-0.9% were leptin receptor (LEPR) immunoreactive (-IR), mainly in GH-IR and prolactin (PRL)-IR cells (41.5+/-3.8%; 13.5+/-1.7%, respectively). In Dlk1-/- mice, adipocyte cells showed a significant increase in the TSH receptor mRNA expression level. Moreover, the percentage of LEPR-IR GH cells showed a statistically significant increase compared to controls, from 41.5+/-3.8% to 53.1+/-4.0%. By contrast, only 3.0+/-0.6% of LEP-IR anterior pituitary cells were detected in Dlk1 KO mice, as opposed to 6.8+/-1.1% observed in WT mice. The results suggest that relationships exist between adipocytes and pituitary GH, PRL and TSH cells, in addition to an influence with respect to the synthesis and release of pituitary leptin, particularly in PRL cells. PMID- 28718208 TI - Quantification of nasal airflow resistance in English bulldogs using computed tomography and computational fluid dynamics. AB - Stenotic nares, edematous intranasal turbinates, mucosal swelling, and an elongated, thickened soft palate are common sources of airflow resistance for dogs with brachycephalic airway syndrome. Surgery has focused on enlarging the nasal apertures and reducing tissue of the soft palate. However, objective measures of surgical efficacy are lacking. Twenty-one English bulldogs without previous surgery were recruited for this prospective, pilot study. Computed tomography was performed using conscious sedation and without endotracheal intubation using a 128 multidetector computed tomography scanner. Raw multidetector computed tomography data were rendered to create a three dimensional surface mesh model by automatic segmentation of the air-filled nasal passage from the nares to the caudal soft palate. Three-dimensional surface models were used to construct computational fluid dynamics models of nasal airflow resistance from the nares to the caudal aspect of the soft palate. The computational fluid dynamics models were used to simulate airflow in each dog and airway resistance varied widely with a median 36.46 (Pa/mm)/(l/s) and an interquartile range of 19.84 to 90.74 (Pa/mm)/(/s). In 19/21 dogs, the rostral third of the nasal passage exhibited a larger airflow resistance than the caudal and middle regions of the nasal passage. In addition, computational fluid dynamics data indicated that overall measures of airflow resistance may significantly underestimate the maximum local resistance. We conclude that computational fluid dynamics models derived from nasal multidetector computed tomography can quantify airway resistance in brachycephalic dogs. This methodology represents a novel approach to noninvasively quantify airflow resistance and may have utility for objectively studying effects of surgical interventions in canine brachycephalic airway syndrome. PMID- 28718211 TI - Ovarian apoplexy resulting from ruptured heterotopic pregnancy following intrauterine insemination. AB - Heterotopic pregnancy is on the rise with the use of assisted conception and commonly involves the fallopian tube. Ovarian heterotopic pregnancy is rare, with fewer than 40 reported cases in PubMed/Medline; cases of ovarian ectopic pregnancy after intrauterine insemination are even rarer, with only seven published reports. We report here a case of ovarian heterotopic pregnancy following intrauterine insemination; this could possibly be the first such report. Our patient presented with circulatory collapse in the first trimester and laparoscopy disclosed an ovarian pregnancy with hemoperitoneum. Following resection of the ovarian pregnancy, the intrauterine gestation continued undisturbed and the patient delivered at term. Heterotopic pregnancy and unusual ectopic locations should be considered a possibility in pregnant women with pelvic pain, particularly following fertility treatment, including ovarian stimulation and intrauterine insemination. PMID- 28718212 TI - Effectiveness of Helicobacter pylori eradication in pregnant women with idiopathic thrombocytopenic purpura. AB - Platelet counts increase after eradication of Helicobacter pylori (Hp) infection in non-pregnant patients with Hp-associated idiopathic thrombocytopenic purpura (ITP); however, improvement in pregnant patients has not yet been reported. We treated four pregnant women for Hp-positive ITP after Hp eradication. In three of four cases, platelet counts increased to levels exceeding 10 * 109 /L two weeks after eradication, and these levels were maintained until delivery. Vaginal deliveries were uncomplicated, and no excessive blood loss occurred in any of the cases. There were no remarkable side effects of Hp eradication in pregnant women or fetuses. In pregnant women with Hp-associated ITP, Hp eradication might be worthwhile prior to considering steroid administration. PMID- 28718213 TI - Safety and dose-finding trial of tadalafil administered for fetal growth restriction: A phase-1 clinical study. AB - AIM: We designed a safety and dose-finding trial of tadalafil administered for fetal growth restriction (FGR). METHODS: Three cases were initially commenced on 10 mg/day and monitored for major adverse events. Should a major adverse event be observed in one or more of the three cases, an examination into its relation with tadalafil would be conducted by a safety evaluation committee. If one or more of these new cases exhibited the same adverse event, the trial would be stopped completely. If there were no harmful side-effects, the trial would be extended to three cases at 20 mg/day, and the protocol would continue as in the 10-mg/day dose. The 40-mg/day dosage was tried in six cases as the dosage was considered to be high. RESULTS: The study population consisted of pregnant women with FGR. Maternal adverse events in all doses were recorded as least one grade 1 adverse events, as tadalafil was considered acceptable from the viewpoint of the mothers. However, a dose of 40 mg/day increased the number of grade 1 adverse events. The only fetal adverse event was a case of intrauterine fetal death related to the velamentous insertion of the umbilical cord. Neonatal adverse events showed no correlation to tadalafil dose, but were found more frequently in preterm births and, therefore, were correlated to infant prematurity. CONCLUSION: This safety and dose-finding trial showed that tadalafil had a favorable safety profile for pregnant women and fetuses with FGR. PMID- 28718214 TI - A Boron Alkylidene-Alkene Cycloaddition Reaction: Application to the Synthesis of Aphanamal. AB - We describe an unusual net [2+2] cycloaddition reaction between boron alkylidenes and unactivated alkenes. This reaction provides a new method for the construction of carbocyclic ring systems bearing versatile organoboronic esters. Aside from surveying the scope of this reaction, we provide details about the mechanistic underpinnings of this process, and examine its application to the synthesis of the natural product aphanamal. PMID- 28718215 TI - USP18 protects against hepatic steatosis and insulin resistance through its deubiquitinating activity. AB - : Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis, impaired insulin sensitivity, and chronic low-grade inflammation. However, the pathogenic mechanism of NAFLD is poorly understood, which hinders the exploration of possible treatments. Here, we report that ubiquitin-specific protease 18 (USP18), a member of the deubiquitinating enzyme family, plays regulatory roles in NAFLD progression. Expression of USP18 was down-regulated in the livers of nonalcoholic steatohepatitis patients and high-fat diet (HFD)-induced or genetically obese mice. When challenged with HFD, hepatocyte-specific USP18 transgenic mice exhibited improved lipid metabolism and insulin sensitivity, whereas mice knocked out of USP18 expression showed adverse trends regarding hepatic steatosis and glucose metabolic disorders. Furthermore, the concomitant inflammatory response was suppressed in USP18-hepatocyte-specific transgenic mice and promoted in USP18-hepatocyte-specific knockout mice treated with HFD. Mechanistically, hepatocyte USP18 ameliorates hepatic steatosis by interacting with and deubiquitinating transforming growth factorbeta-activated kinase 1 (TAK1), which inhibits TAK1 activation and subsequently suppresses the downstream c-Jun N-terminal kinase and nuclear factor kappa B signaling pathways. This is further validated by alleviated steatotic phenotypes and highly activated insulin signaling in HFD-fed USP18-hepatocyte-specific knockout mice administered a TAK1 inhibitor. The therapeutic effect of USP18 on NAFLD relies on its deubiquitinating activity because HFD-fed mice injected with active-site mutant USP18 failed to inhibit hepatic steatosis. CONCLUSION: USP18 associates with and deubiquitinates TAK1 to protect against hepatic steatosis, insulin resistance, and the inflammatory response. (Hepatology 2017;66:1866-1884). PMID- 28718216 TI - Deep-Red to Near-Infrared Thermally Activated Delayed Fluorescence in Organic Solid Films and Electroluminescent Devices. AB - The design and synthesis of highly efficient deep red (DR) and near-infrared (NIR) organic emitting materials with characteristic of thermally activated delayed fluorescence (TADF) still remains a great challenge. A strategy was developed to construct TADF organic solid films with strong DR or NIR emission feature. The triphenylamine (TPA) and quinoxaline-6,7-dicarbonitrile (QCN) were employed as electron donor (D) and acceptor (A), respectively, to synthesize a TADF compound, TPA-QCN. The TPA-QCN molecule with orange-red emission in solution was employed as a dopant to prepare DR and NIR luminescent solid thin films. The high doped concentration and neat films exhibited efficient DR and NIR emissions, respectively. The highly efficient DR and NIR organic light-emitting devices (OLEDs) were fabricated by regulating TPA-QCN dopant concentration in the emitting layers. PMID- 28718218 TI - Impact of prenatal immune challenge on the demyelination injury during adulthood. AB - AIM: Brain inflammation is associated with several brain diseases such as multiple sclerosis (MS), a disease characterized by demyelination. Whether prenatal immune challenge affects demyelination-induced inflammation in the white matter during adulthood is unclear. In the present study, we used a well established experimental model of focal demyelination to assess whether prenatal immune challenge affects demyelination-induced inflammation. METHODS: Pregnant rats were injected with either lipopolysaccharide (100 MUg/kg, ip) or pyrogen free saline. A 2 MUL solution of the gliotoxin ethidium bromide (0.04%) was stereotaxically infused into the corpus callosum of adult male offspring. The extent of demyelination lesion was assessed using Luxol fast blue (LFB) staining. Oligodendrocyte precursor cells, mature oligodendrocytes, markers of cellular gliosis, and inflammation were monitored in the vicinity of the demyelination lesion area. RESULTS: Prenatal lipopolysaccharide reduced the size of the demyelination lesion during adulthood. This reduced lesion was associated with enhanced density of mature oligodendrocytes and reduced density of microglial cells in the vicinity of the demyelination lesion. Such reduction in microglial cell density was accompanied by a reduced activation of the nuclear factor kappaB signaling pathway. CONCLUSION: These data strongly suggest that prenatal immune challenge dampens the extent of demyelination during adulthood likely by reprogramming the local brain inflammatory response to demyelinating insults. PMID- 28718217 TI - A 3D musculoskeletal model of the western lowland gorilla hind limb: moment arms and torque of the hip, knee and ankle. AB - Three-dimensional musculoskeletal models have become increasingly common for investigating muscle moment arms in studies of vertebrate locomotion. In this study we present the first musculoskeletal model of a western lowland gorilla hind limb. Moment arms of individual muscles around the hip, knee and ankle were compared with previously published data derived from the experimental tendon travel method. Considerable differences were found which we attribute to the different methodologies in this specific case. In this instance, we argue that our 3D model provides more accurate and reliable moment arm data than previously published data on the gorilla because our model incorporates more detailed consideration of the 3D geometry of muscles and the geometric constraints that exist on their lines-of-action about limb joints. Our new data have led us to revaluate the previous conclusion that muscle moment arms in the gorilla hind limb are optimised for locomotion with crouched or flexed limb postures. Furthermore, we found that bipedalism and terrestrial quadrupedalism coincided more regularly with higher moment arms and torque around the hip, knee and ankle than did vertical climbing. This indicates that the ability of a gorilla to walk bipedally is not restricted by musculoskeletal adaptations for quadrupedalism and vertical climbing, at least in terms of moment arms and torque about hind limb joints. PMID- 28718219 TI - Barriers to glaucoma case finding as perceived by optometrists in Ireland. AB - BACKGROUND: This research was designed to provide an in-depth exploration of the perceptions of optometrists relating to the challenges of glaucoma case finding in the Irish health-care system. METHODS: A survey was developed, piloted and distributed for anonymous completion by optometrists registered to practise in Ireland. The survey included 10 five-level Likert items exploring potential barriers to glaucoma detection and a free-text box for participants to comment more broadly. RESULTS: One hundred and ninety-nine optometrists (27 per cent of registrants) responded to the survey. Among the barriers identified, there was notable agreement (71 per cent) with the need for extra training on glaucoma detection. Logistic regression showed that optometrists without postgraduate qualifications were more likely to agree with the need for extra training (OR 3.2, 95 per cent CI 1.3-8.1). Respondents largely agreed (61 per cent) that patient unwillingness to pay additional fees for supplementary glaucoma-specific tests was also a barrier. Appointment times of less than 30 minutes were significantly associated with six of the 10 proposed barriers to glaucoma detection. A logistic regression analysis (n = 179) confirmed that the time allotted per appointment was a significant predictor of the agreement time of optometrists as a barrier (chi2 [1] = 13.52, p < 0.001). Multiple linear regression showed that optometrists with less experience, charging lower fees, and working in large multiples or franchised practices have the shortest appointment times. CONCLUSION: The strong link found between postgraduate education and the confidence of optometrists in detecting glaucoma indicates that optometrists wishing to increase their scope of practice in the new legislative environment in Ireland may more actively seek training in areas of interest. The responses also indicate a lack of funding for the level of diagnostic testing required for accurate glaucoma diagnosis. Recent increases in the state's eye examination fees look likely to address the identified time and financial barriers to glaucoma detection in Ireland. Future work should look to analyse the effects of increased funding on optometric case finding for glaucoma. PMID- 28718220 TI - Long-acting formulation leading to severe long-term adverse effects: a case report of fluphenazine and persistent extrapyramidal symptoms. AB - WHAT IS KNOWN AND OBJECTIVE: Long-acting formulations are an important therapeutic option for non-adherent patients with schizophrenia. There is a commonly held view that management of long-acting formulation-induced side effects is difficult. CASE DESCRIPTION: We present a patient with schizophrenia who developed acute and persistent extrapyramidal symptoms requiring tracheostomy and long-term rehabilitation after long-acting injections of fluphenazine decanoate. Extrapyramidal symptoms improved with declining fluphenazine concentration and antiparkinsonian drug therapy with bromocriptine. WHAT IS NEW AND CONCLUSION: Long-acting formulations may lead to severe persistent adverse effects. For preventing fluphenazine-induced side effects, a possible option might be the antiparkinsonian drug therapy with bromocriptine. PMID- 28718221 TI - Multidimensional assessment of quality of life of children and problems of parents in Indian society after pediatric renal transplant: Beyond the conventional thoughts. AB - This study evaluated multidimensional QoL after renal transplant to find the physical, psychosocial, and economic issues after pediatric transplant. Sixty-two patients under the age of 18 at the time of assessment were asked to complete WHOQOL questionnaires. Assessment of behavioral, emotional status of child, problems of parents, and SEC of family were also performed. The beneficial effect of transplantation was observed across all domains of QoL (physical, psychological, social, environmental, and overall QoL). The greatest change was observed in QoL domains that dealt with overall satisfaction (81.28+/-15.76 vs 45.32+/-10.98; P<.0001). The domain dealing with environmental factors showed the least variation after transplantation (65.58+/-17.45 vs 51.34+/-17.81; P<.0001). Feelings of happiness and peer group socialization were reported in 81% and 69% of patients, respectively. There was no marital disharmony in 52% of families. However, SEC deteriorated in 16% of families and 59% of the families availed financial assistance. Sixty-nine percent of children had not attended school after one year of transplantation, but return to school after transplant was reduced to 8% at 5 years. Pre- and post-transplant social and psychological support may help these patients and their families adjust in society and have a positive outlook for their future. PMID- 28718222 TI - When is a sentinel node biopsy indicated for patients with primary melanoma? An update of the 'Australian guidelines for the management of cutaneous melanoma'. AB - A sentinel lymph node biopsy is a surgical staging procedure performed for patients with primary cutaneous melanoma who are clinically lymph-node negative to determine whether there is low volume nodal metastasis in the draining lymph node field. A systematic review was recently performed to update the Australian clinical practice guidelines for the diagnosis and management of melanoma, addressing the question, 'When is a sentinel lymph node biopsy indicated?' This article discusses the findings of the systematic review and the evidence base for the updated guidelines. PMID- 28718224 TI - Re: Review of knee arthroscopic practice and coding at a major metropolitan centre. PMID- 28718223 TI - Self-management of stress urinary incontinence via a mobile app: two-year follow up of a randomized controlled trial. AB - INTRODUCTION: We investigated the long-term effects of using a mobile app to treat stress urinary incontinence with a focus on pelvic floor muscle training. MATERIAL AND METHODS: A previous randomized controlled trial of 123 women aged 27 72 years found that three months of self-managing stress urinary incontinence with support from the Tat(r) app was effective. We followed up the women in the app group (n = 62) two years after the initial trial with the same primary outcomes for symptom severity (International Consultation on Incontinence Questionnaire Short Form) and condition-specific quality of life (ICIQ-Lower Urinary Tract Symptom Quality of Life) and compared the scores with those at baseline. RESULTS: Of the 62 women, 61 and 46 (75.4%), respectively, participated in three-month and two-year follow-ups. Baseline data did not differ between responders and non-responders at follow-up. The mean decreases in International Consultation on Incontinence Questionnaire Short Form and ICIQ-Lower Urinary Tract Symptom Quality of Life scores after two years were 3.1 (95% confidence interval 2.0-4.2) and 4.0 (95% confidence interval 2.1-5.9), respectively. Of the 46 women, four (8.7%) rated themselves as very much better, nine (19.6%) as much better, and 16 (34.8%) as a little better. The use of incontinence protection products decreased significantly (p = 0.04), and the proportion of women who felt they could contract their pelvic muscles correctly increased from 14/46 (30.4%) at baseline to 31/46 (67.4%) at follow-up (p < 0.001). CONCLUSIONS: Self management of stress urinary incontinence with support from the Tat(r) app had significant and clinically relevant long-term effects and may serve as first-line treatment. PMID- 28718226 TI - Preparation of Layered-Spinel Microsphere/Reduced Graphene Oxide Cathode Materials for Ultrafast Charge-Discharge Lithium-Ion Batteries. AB - Although Li-rich layered oxides (LLOs) have the highest capacity of any cathodes used, the rate capability of LLOs falls short of meeting the requirements of electric vehicles and smart grids. Herein, a layered-spinel microsphere/reduced graphene oxide heterostructured cathode (LS@rGO) is prepared in situ. This cathode is composed of a spinel phase, two layered structures, and a small amount of reduced graphene oxide (1.08 wt % of carbon). The assembly delivers a considerable charge capacity (145 mA h g-1 ) at an ultrahigh charge- discharge rate of 60 C (12 A g-1 ). The rate capability of LS@rGO is influenced by the introduced spinel phase and rGO. X-ray absorption and X-ray photoelectron spectroscopy data indicate that Cr ions move from octahedral lattice sites to tetrahedral lattice sites, and that Mn ions do not participate in the oxidation reaction during the initial charge process. PMID- 28718227 TI - Anti-Microbial Resistance In Pakistan: A Public Health Issue AB - Anti-microbial or antibiotic resistance is a global public health problem, more dominant in thedeveloping countries. Illiteracy and lack of awareness among the general population is a leadingcause, compounded by lack of concern by the physicians and the pharmacists selling drugs overthe counter. Another side of the phenomenon is attributed to profit making goals ofpharmaceutical companies and weak regulation of the market. Nevertheless, misuse and overuseof antimicrobials accelerates this process. Besides, health issues, anti-microbial resistance also haseconomic implications on the health care system, where the simpler treatments are becomingdifficult, day by day. Enforcement of standard treatment guidelines for the health providers andbehavior changes at the patients' end are likely to bring about a change in the situation. PMID- 28718225 TI - Proteostasis and ageing: insights from long-lived mutant mice. AB - The global increase in life expectancy is creating significant medical, social and economic challenges to current and future generations. Consequently, there is a need to identify the fundamental mechanisms underlying the ageing process. This knowledge should help develop realistic interventions capable of combatting age related disease, and thus improving late-life health and vitality. While several mechanisms have been proposed as conserved lifespan determinants, the loss of proteostasis - where proteostasis is defined here as the maintenance of the proteome - appears highly relevant to both ageing and disease. Several studies have shown that multiple proteostatic mechanisms, including the endoplasmic reticulum (ER)-induced unfolded protein response (UPR), the ubiquitin-proteasome system (UPS) and autophagy, appear indispensable for longevity in many long-lived invertebrate mutants. Similarly, interspecific comparisons suggest that proteostasis may be an important lifespan determinant in vertebrates. Over the last 20 years a number of long-lived mouse mutants have been described, many of which carry single-gene mutations within the growth-hormone, insulin/IGF-1 or mTOR signalling pathways. However, we still do not know how these mutations act mechanistically to increase lifespan and healthspan, and accordingly whether mechanistic commonality occurs between different mutants. Recent evidence supports the premise that the successful maintenance of the proteome during ageing may be linked to the increased lifespan and healthspan of long-lived mouse mutants. PMID- 28718228 TI - Early Initiation Of Beta Blockers Following Primary Endoscopic Therapy For Bleeding Oesophageal Varices In Cirrhotics. AB - BACKGROUND AND AIMS: Beta-blockers provide secondary prophylaxis following endoscopic therapy for variceal bleeding. Guidelines recommend starting beta blockers 6 days after endoscopy to prevent masking hemodynamic signs of re bleeding. We aimed to see safety of earlier initiation of betablockers. METHODS: Cirrhotic patients with upper GI bleed were given intravenous vasoactive agents until undergoing endoscopy. Patients with only oesophageal varices as source of bleed were recruited. Vasoactive agents were discontinued following variceal banding. The patients were observed for 12-18 hours, discharged on oral carvedilol 6.25 mg BID and monitored for 6 weeks for re-bleeding and mortality. RESULTS: Fifty patients were included, 27 (54%) male and 23 (46%) female. Average age was 43+/-3 years. Aetiology of cirrhosis was HCV in 42 (84%), HBV in 6 (12%), HCV & HBV in 2 (4%) and indeterminate in 1 (2%) patient. Seventeen (34%) patients had Child A, 22 (44%) Child B and 11 (22%) had Child C disease. Hospital stay was under 24 hours in 24 (48%), 24-48 hours in 15 (30%) and 48-72 hours in 11 (22%) patients. Five (10%) patients underwent EGD within 6 hours of admission, 28 (56%) within 12 hours, 14 (28%) within 24 hours and 3 (6%) within 36 hours. No re bleeding, mortality or drug related adverse effects were noted during 6 weeks after discharge. CONCLUSIONS: Our study proves possibility of shorter management of variceal bleeding by having a 12-18 hour monitoring after endoscopic banding, followed by beta-blocker initiation and discharge. This will safely reduce physical and financial burden on health services. PMID- 28718229 TI - Comparison Of Pre-Operative Curvature With Postoperative Curvature In Root Canals Treated With K-3 Rotary Systems. AB - BACKGROUND: With root canal treatment, the organic debris and micro-organisms from pulp space is removed and an ideal canal preparation is achieved that is conducive of hermetic obturation. The purpose of this study was to correlate the pre-operative canal curvature with the postoperative curvature in human extracted teeth prepared with K-3 rotary systems. METHODS: The root canal preparation was carried out on extracted human molars and premolars using K-3 endodontic rotary files. A pre and post-operative image of the teeth using digital radiograph were taken in order to compare pre and post-operative canal curvature. The images were saved in an images retrieval system (Gendex software, USA). Change in the canal curvature was measured using the software measuring tool (Vixwin software, USA). Student paired t-test and Pearson correlation test was applied at 0.05 level of significance. RESULTS: There is a statistically significant difference between pre-operative and post-operative canal curvature (p-value <0.001) and a strong positive correlation (91% correlation) between pre-operative and post-operative canal curvature in teeth prepared with the K-3 rotary files. CONCLUSIONS: A significant difference between pre and post instrumentation curvature was found. Degree of canal curvature was not correlated with time taken for canal preparation. PMID- 28718230 TI - Determinants Of Impoverishment Due To Out Of Pocket Payments In Nigeria. AB - BACKGROUND: Poverty is an extreme consequence of out of pocket payments in countries with health systems that do not provide financial risk protection through mandatory health insurance coverage for people in both the formal and informal sectors. The study assessed the determinants of impoverishment due to out of pocket payments in Nigeria. METHODS: Secondary data from the Harmonized Nigeria Living Standard Survey (HNLSS) of 2009/10 was utilized to assess factors associated with impoverishment in Nigeria. Household and individual characteristics associated with impoverishment were determined using binary logistic regression. A significance level of p<0.05 was used. RESULTS: Results show that lack of health insurance, having a member above 65 years, large household size, household socio-economic status, type of illness suffered, type of health facility visited, geo-political zones, education of household heads and location were major determinants of impoverishment due to out of pocket health expenditure. CONCLUSIONS: Findings from the study show that most households and individuals are vulnerable to financial risk due to this regressive source of payments for health care services. This explains why the level of poverty keeps increasing in spite of the numerous poverty alleviation programs across the country. Policy makers and political actors need to design a new health system financing policy that will increase financial risk protection for people in both the formal and informal sectors. Governments and decision makers have to focus on health as a determinant of economic well-being. PMID- 28718231 TI - Endostatin Concentration In Plasma Of Healthy Human Volunteers. AB - BACKGROUND: Angiogenesis is involved in many cardiovascular and cancerous diseases, including atherosclerosis and is controlled by a fine balance between angiogenic and angiostatic mediators. Endostatin is one of the main angiostatic mediators, and inhibits angiogenesis and prevents progression of atherosclerosis. The available literature shows a broad range of concentrations in relatively small samples of healthy controls and is calculated by using different techniques. This study was aimed to determine the basal endostatin concentration in plasma of healthy volunteers, to fully understand its physiological role. METHODS: Fifty healthy adult volunteers were recruited to the study. Participants were advised not to participate in any physical activity on the day before the blood sampling. The volunteers' physical activity, height, weight, heart rate and blood pressure were recorded. The samples were analysed for plasma endostatin concentration, using ELISA. The participants were divided by gender and ethnic groups to calculate any difference. RESULTS: Endostatin and other variables were normally distributed. Most of the participants had a moderate level of physical activity with no gender related difference (p=0.370). The mean value for plasma endostatin in all samples was 105+/-12 ng/ml with range of 81-132 ng/ml. For males, it was 107+/-13 ng/ml, while for females; 102+/-12 ng/ml. There were no significant gender or ethnicity related differences in endostatin concentration. Moreover, endostatin was not significantly related with any anthropometric and physical variable. CONCLUSIONS: This study gives endostatin levels in normal healthy people and show no gender and ethnicity related differences in endostatin levels. Endostatin was not related with any anthropometric and physical variable. PMID- 28718232 TI - Effect Of Preoperative Intravenous Steroids On Seroma Formation After Modified Radical Mastectomy. AB - BACKGROUND: With the steep increase in breast cancer incidence globally and regionally, there has been a trend toward reducing patient morbidity by meticulous surgical techniques to obviate complications like seroma formation; use to pre-operative steroids seems to be convenient, cost effective and shows promising results in trials. METHODS: This randomized clinical trial was conducted at Surgical Department of Khyber Teaching Hospital Peshawar, from January 2012 to April 2014 on 65 patients randomly allocated to Group A and Group B using lottery method. Group A underwent MRM+AD in the conventional manner while Group B received a 120 mg of injection Depomedrol intravenously 1 hour before the surgery. The two were compared in terms of total drainage, days of drainage, wound complications and incidence of seroma. Data was entered and analysed using statistical program SPSS-21. RESULTS: The mean age in group A was 34.2+/-10.1 years and B was 32.3+/-9.1 years. The mean drainage in intervention group was significantly reduced as compared to control group (755.4+/-65ml vs 928.3+/ 102.5). Total drainage days were reduced (6.5+/-1.6 days vs 10.2+/-2.2 days) and incidence of seroma was also reduced (A=18.75% vs B=6.06%). However, three patients in group B had wound infection. CONCLUSIONS: Seroma formation is the most common complication of Mastectomy and among the methods used to reduce its incidence, steroid administration seems to be the most cost effective and shows promising results. PMID- 28718233 TI - Haemodynamic Preservation In Caesarean Sections By Low Dose 0.5% Hyperbaric Bupivacaine. AB - BACKGROUND: Spinal anaesthesia is technique of choice for caesarean sections and hyperbaric bupivacaine is a recommended drug for this popular block. Although safe but few complications are haemodynamic changes, postdural puncture headache, cauda equina syndrome and radiculopathy. However, hypotension remains the common side effect which is believed to occur in 95% of patients resulting in reduction of uteroplacental perfusion causing foetal acid-base abnormalities. Various doses regimes are in safe anaesthesia practice for providing regional anaesthesia for such patients with least detrimental effects on foetal outcome. This study was carried out to find the effective dose of 0.5 % hyperbaric bupivacaine in caesarean section patients by comparing two different doses. METHODS: After enrolling two hundred patients of C section (Caesarean section) for this study, 90 patients were selected to compare the effects of 0.5% hyperbaric bupivacaine. Group A (n=45) received 10 mg of drug while group B (n=45) received 12 mg for spinal anaesthesia. Onset of block, sensory and motor level, haemodynamic changes, surgery time, maternal satisfaction, Apgar score and incidence of complications were compared in two groups. RESULTS: Blood pressure decreases were less in Group A (p-0.074) but not statistically significant. Phenylephrine for hypotension was given to 17% vs 5% in group B. Maternal satisfaction was found to be better in group B 33 vs 17 but was statistically significant (p 0.034). 2% patients had bradycardia in group A which was treated by atropine. No complications were reported in either group. CONCLUSIONS: Doses of hyperbaric bupivacaine for spinal anaesthesia in caesarean sections must be at least 12 mg because it produces excellent anaesthesia and maternal satisfaction without complications. PMID- 28718234 TI - Paediatrics Brain Imaging In Epilepsy: Common Presenting Symptoms And Spectrum Of Abnormalities Detected On MRI. AB - BACKGROUND: Epilepsy, a common neurological disorder can present at any age and has a number of aetiologies with underlying brain disease being the most common aetiology. Brain imaging becomes important and mandatory in the work up for epilepsy in localization and lateralization of the seizure focus. METHODS: This cross-sectional study was conducted in the department of Radiology Ayub Medical Teaching Institution Abbottabad from 1st March 2015 to 31st March 2016. A total of 209 children aged 28 days to 14 years were included in the study who presented with seizures to clinicians. Information obtained from history, clinical examination and investigations especially MRI brains were recorded in a prescribed pro forma. The data was analysed in SPSS 20. RESULTS: MRI examination was unremarkable in 44.01% (n=92) and mild generalized brain atrophy was noted in 12.91% (n=27). Arachnoid cysts, mild unilateral brain atrophy and hydrocephalous due to aqueduct stenosis were recorded in 3.82% (n=8) of each group. Neoplastic lesions were the second most common abnormal MRI finding and constituted 5.74% (n=12). Leukodystrophy was diagnosed in 4.78% (n=10). MRI examination showed ring enhancing lesions (tuberculomas) and AVM in 1.43% (n=3) of each group. Perinatal ischemia and intracranial infection, (focal or generalized) were recorded in 2.87% (n=6) of each group. A 0.95% (n=2) of children in each group had agenesis of corpus callosum and cavernoma. The radiological MRI diagnosis of Raussmussen encephalitis was made in 3.34% (n=7). Single case, each of mesial temporal sclerosis, subdural haemorrhage, infarct and craniopharyngioma was recorded making 0.47% of the total patients in each case. CONCLUSIONS: MRI examination was abnormal in significant number of patients (55.86%), so therefore if properly utilized, in a good clinical context, this can identify most of the structural brain abnormalities in paediatric patients presenting with seizures. PMID- 28718235 TI - Quality Assessment Of Focused Antenatal Care Service Delivery In Tertiary Care Health Facility. AB - BACKGROUND: Regardless of high maternal deaths in Pakistan, only 37% of pregnant women make four or more antenatal care visits during pregnancy. This proportion has further been diverged between urban and rural. About 62% of women visit clinics for WHO recommended sets of antenatal care (ANC) check-ups in urban as compared to 26% women in rural areas. This study was conducted with the aim to assess quality of Focused ANC service delivery in terms of examination, screening, treatment, counselling and to determine variation in service delivery with provider's clinical qualification and expertise. METHODS: Cross sectional study design was used. Data was collected from pregnant women when they were visiting hospital for their antenatal visits. Direct observation was also made regarding provision of services. RESULTS: Out of 278, 55% of study women were in 28-33 years age group and 21.2% made at least one visit. While 42.8% reported more than one visit, 98.9% received tetanus toxoid, 82% received proper screening. Counselling was done mostly regarding nutrition and self-care (42.8%), and significant association (p-value <0.05) was observed between provider's clinical qualification and provision of services such as for screening and counselling. CONCLUSIONS: The delivery of antenatal care services to pregnant women varied to some extent. Most of the routine investigation services were in accordance with recommended standards of optimal quality with little divergence from guidelines such as screening for HIV and syphilis. Better quality services were being provided to private participants in terms of counselling and danger sign screening. PMID- 28718236 TI - Dose Comparison And Side Effect Profile Of Metformin Extended Release Versus Metformin Immediate Release. AB - BACKGROUND: Diabetes Mellitus type 2 is very common worldwide, with majority of cases in Asia Pacific region. Metformin is the first line therapy, along with lifestyle modification for all type 2 diabetics as recommended by ADA. Metformin is available as conventional Metformin Immediate Release (MIR) and Metformin Extended Release (MXR). Metformin XR has better gastrointestinal tolerability and fewer side effects as compared to Metformin IR, with similar efficacy regarding anti-hyperglycaemic effects. The objective of this study was to determine whether metformin XR is as effective as Metformin IR in maintaining glycaemic control at equivalent doses or even at reduced doses; and to compare the side effect profile of the two preparations. METHODS: This randomized control trial was conducted at Medical and Endocrinology OPD of Jinnah Hospital Lahore. A total of 90 type 2 diabetics of both genders were recruited using nonprobability purposive sampling. Patients were randomized into 3 groups; 30 in each group. Group 1 received Metformin IR 1000 mg twice daily; group 2 received metformin XR 1000 mg twice daily; and group 3 received metformin XR 500 mg twice daily, for a period of three months. HbA1c was done at baseline and after three months of therapy along with fasting blood sugars and random blood sugars weekly. RESULTS: The mean age of patients was 46+/-9 years, with 54% being males and 46% being females. There was a 1% reduction in HbA1c in group 1, 0.7% reduction in group 2 and only 0.4% reduction in group 3. Similarly, all three therapies were equally effective in reducing blood sugar fasting and blood sugar random at three months. Side effects namely diarrhoea, dyspepsia and flatulence were greatest with Metformin IR (40%) but less than half with Metformin XR at equivalent dose and negligible at half the dose. CONCLUSIONS: All three Metformin groups were effective in reduction of HbA1C and glycaemic control clinically and there is no statistical difference in HbA1c reduction among groups at three months. PMID- 28718237 TI - Accidental Intra Arterial Injection And Limb Ischemia. AB - BACKGROUND: Accidental intra-arterial drug injections usually occur as an iatrogenic complication but it is also found in drug abusers as a result of attempted intravenous (IV) injections. It is estimated that accidental intra arterial injections are found in 1:3500-1:56000 patients visiting emergency department. METHODS: This was cross sectional study performed in cardiovascular department Lady reading Hospital Peshawar from 1.1.2013 to 31.8.2015. Accidental intra-arterial injection was defined as intravenous injection in upper limb for any illness which is followed by sudden severe pain in limb followed by bluish discoloration of any part of limb. Data was analysed using SPSS-20. Frequency and percentage were calculated for categorical variables like while Means+/-SD was calculated for numerical variables. Chi square test was used to compare Categorical variables. RESULTS: Total 30 patients were studied in whom 17 were male. Mean age of the study population was 43.2+/-17.9 years. All patients after admission were put on intravenous Heparin alone or in combination with Dexamethason, Beraprost and Nifedifin on discretion of visiting consultant. Injection diclofenac were found more frequently as cause of limb ischemia (43 %). Amputation of digits or part of limb was noted in 7 (23.1 %) cases. CONCLUSIONS: Accidental intra-arterial injection can lead to limb ischemia and even limb loss so while injecting IV drugs, care should be taken to use venous site away from arterial sites. PMID- 28718238 TI - Bacteriology Of Diabetic Foot In Tertiary Care Hospital; Frequency, Antibiotic Susceptibility And Risk Factors. AB - BACKGROUND: Diabetic foot being one of the frequent and disabling complications of diabetes. In view of widespread regional variation in causative organisms and antimicrobial susceptibility, the current study aimed to determine frequency of causative organisms, their antimicrobial susceptibility and associated risk factors. METHODS: This descriptive cross-sectional study was conducted in 6 months' duration at dept. of Medicine; PIMS Hospital Islamabad. Type 2 Diabetes mellitus patients with diabetic foot ulcer were enrolled after informed consent. Patients already receiving antibiotics, having no growth on culture and >3 weeks' duration of ulcer were excluded. Sample from wound was sent for culture and sensitivity. Antibiotic susceptibility testing identified the susceptible and resistant strains of organisms. RESULTS: Among 114 patients (66.67% males and 33.33% females); mean age was 55.11+/-11.96 years. Staphylococcus aureus was identified in 46%, E. coli in 28%, Pseudomonas in 6%, Klebsiella in 3.5% and other organisms in 17%. 92% of S. aureus was sensitive to Vancomycin and 67% to Clindamycin. Amongst E. coli, 81% showed sensitivity to Imipenem, 69% to Aminoglycosides and 31% to Quinolones. Glycaemic control was unsatisfactory in 65.8%. Peripheral vascular disease was found in 46% patients and sensory neuropathy in 94%. CONCLUSIONS: Staphylococcus aureus was the most frequent isolate amongst gram positive organisms while E. coli amongst gram-negatives. Vancomycin is suggested to be the drug of choice for gram positive and Imipenem for gram negative organisms. Appropriate antimicrobial therapy according to susceptibility patterns would reduce the morbidity and emergence of multidrug resistant organisms in diabetic foot infections. PMID- 28718239 TI - Permanent Pace Maker Implantation Through Axillary Vein Approach. AB - BACKGROUND: Device implantation is an integral part of interventional cardiology particularly electrophysiology. In this study, we are going to shear our experience of device implantation technique at electrophysiology department Hayatabad Medical Complex, Peshawar. METHODS: The study was conducted from June 2011 to December 2015. Axillary vein was used to implant the devices but in some cases when this rout was not convenient due to any reason then subclavian vein was entered through the Seldinger technique. Fluoroscopy time was less than 10 minutes and total procedure time was not more than 45 minutes. Electric cautery was used only in two cases. Pressure dressing was used in a few cases. RESULTS: Total numbers of permanent pacemakers (PPM) remain 800 during the study period. There were 450 single chamber pacemakers and 350 dual chambers pacemakers. No case of any major bleeding was documented and in very few cases there was mild ooze from the procedure site after the operation which was tackled with pressure dressing. Four cases of pneumothorax were noted during the study period and in three cases chest intubation were done and one patient was kept on conservative management. Patient were followed after one moth of discharge from the hospital and then yearly. Eight cases of lead dislodgment were documented during the study period. CONCLUSIONS: Axillary vein approach for implantation of permanent pacemakers is a safe and less time-consuming technique. PMID- 28718240 TI - Ponseti Technique For Management Of Congenital Idiopathic Club Foot. AB - BACKGROUND: Clubfoot or congenital talipes equinovarus, is a congenital deformity of the foot. It consists of cavus, adduction, varus and equinus. This is due to medial displacement of navicular and calcaneus around the talus. Talus is in equinus. Medial deviation of the head and neck of talus is due to force of calcaneus on talus. METHODS: This descriptive case series study was conducted at Orthopaedic unit, Ayub Teaching Hospital, Abbottabad from 1st August 2015 to 31st January 2016 to determine the frequency of idiopathic clubfoot correction, by using the Ponseti method. A total of 177, unilateral and bilateral clubfeet, from both genders were studied. Patients between age of 2 weeks to 2 years were included in the study. Basic pirani score six (06) who were previously untreated were included in the study. Syndromic patients, previously treated and patients with associated neuro-mascular disorders were excluded from the study. Patients who were corrected with serial castings, were put in foot abduction brace. Those who needed some sort of surgery underwent surgery. All the data was collected in the proforma and analysed by SPSS version 16.00. RESULTS: A total of 177 clubfeet were included in the study. Mean age of the patients was 10.28+/-7.45 ranging from 2 weeks 2 years. There were 93 (52.5%) male and 84 (43.5%) female out of total 177 patients. Of these 20 patients were corrected with serial casting only while 150 patients underwent percutaneous tenotomy, which is a minor procedure and done on out -patient department basis. After correction, the feet were put in 70 degree of abduction in abduction brace. Only 7 patients required some sort of surgery, more than tenotomy. CONCLUSIONS: Ponseti is very effective, economical and non-invasive way of treating congenital idiopathic clubfoot. Only resistant cases may need some sort of extensive surgery. PMID- 28718241 TI - C-Reactive Protein: An Aid For Diagnosis Of Acute Appendicitis. AB - BACKGROUND: Delayed or wrong diagnosis of acute appendicitis in patients results in complications like perforation, gangrene, etc. which carries a significant amount of morbidity and mortality to the patients. Thus, timely diagnosis of acute appendicitis is crucial to prevent these complications. Recently, it was found that serum C-reactive protein (CRP) individually can be a useful marker, thus in resource limited settings (i.e., access to ultrasonography) simple laboratory investigation can be of extreme utility for the diagnosis of acute appendicitis. Current study aimed to ascertain and determine the role of C Reactive Protein (CRP) as a complementary test to decrease the rate of negative appendectomies in tertiary care hospitals of Pakistan. METHODS: Using non probability consecutive sampling, 112 patients with the initial diagnosis of acute appendicitis on history and clinical examination were enrolled. A blood sample was taken for serum level of CRP. RESULTS: Mean age was 20.8+/-8.6 years and 51 (45.5 %) patients were males. Pathologic review revealed 100 cases (89.3%) of acute appendicitis, 4 patients (3.6%) had perforated appendix while 8 patients (7.1%) had normal appendix. Sensitivity, specificity, positive and negative predictive value and diagnostic accuracy of C reactive protein >24 mg/lit taking histology as gold standard came out 25.9%, 100%, 100%, 9.4% and 31.25% respectively. CONCLUSIONS: It was concluded that CRP >48 mg/lit is an indication of perforated appendix and when the surgeon is in fix whether to go conservatively or apply some intervention, CRP can be a good diagnostic aid. PMID- 28718242 TI - Ectopic Pregnancy With Tubal Rupture: An Analysis Of 80 Cases. AB - BACKGROUND: Ectopic pregnancy (EP) is a major problem in obstetrics as there is evidence of increasing incidence throughout the world. It is an important cause of maternal morbidity and mortality. In Pakistan, the care seeking behaviour among female is limited that makes female vulnerable to die due to complication of ectopic pregnancy. The aim of this study is to determine the frequency of tubal rupture in ectopic pregnancy in Pakistani patients. METHODS: In this crosssectional study data pertaining to age, gestational age, parity and duration of presenting symptoms were collected and analysed. RESULTS: 80 patients were diagnosed to have ectopic pregnancy. The frequency of tubal rupture was 91.25%. It is encountered significantly more often in women with age of 26 years. More tubal rupture is found in patient with low parity, in which the frequency of tubal rupture is up to 100% and decrease up to 78.6% with increasing parity up to four. Furthermore, it is noted that increase in gestational age from 8 weeks to 10 weeks caused an increase in frequency of tubal rupture from 80 to 100% respectively. It is also noted that earlier the patient presents the lesser is the frequency of tubal rupture, as compared to late presentation beyond 3-4 days which make frequency up to 95%. CONCLUSIONS: Tubal rupture is still common cause of maternal morbidity and mortality, and is still a major challenge in gynaecological practice. Creating awareness amongst midwives and GPs regarding early diagnosis can contribute to decrease the mortality, morbidity and fertility loss related to EP. PMID- 28718243 TI - Type-I Tympanoplasty By Underlay Technique - Factors Affecting Outcome. AB - BACKGROUND: Type-I Tympanoplasty is an operation which is widely done to close a persistent tympanic membrane perforation after clearing the disease from the middle ear. It is very safe and effective procedure. The success rate varies in different setups and there are some confounding factors which affect the result of Type-I tympanoplasty like the size, type and location of perforation. By conducting this study, we aimed to calculate the success rate of Type-I Tympanoplasty in Ayub Teaching Hospital and assess which confounding factors affect the success rate. METHODS: This case series study was conducted at Ayub teaching hospital from 1st January 2014 to 31st December 2015. All the patients who presented with dry ears, no nasal disease and persistent tympanic membrane perforations during this period were operated upon and overall success rate was calculated. In addition, the relationship between the site of perforation, size of perforation and the type of perforation and the success rate of Type-I Tympanoplasty was also calculated. RESULTS: One hundred and thirteen patients were included in this study. Out of these 91 (80.5%) showed complete healing after surgery. Anterior perforations were found to fail the procedure in 41.7% of the cases, while central perforation failed in only 5.4% of the cases. In cases of marginal perforations healing was significantly decreased, i.e., only 47.1% while it was 94.9% in cases where annulus was not involved. Larger perforations also showed poor surgical outcome. 100% of the small perforation healed completely while only 58.3% of the large perforations showed successful result after surgery. When p-value was calculated all of these findings were more than 95% significant. CONCLUSIONS: There is a significant association between the healing of tympanic membrane after Type-I Tympanoplasty and site, size and type of perforation. Anterior perforations, marginal perforation and large perforations reduce the chances of successful outcome of Type-I Tympanoplasty. PMID- 28718244 TI - Depression In Type-2 Diabetic Patients Presenting To A Tertiary Care Hospital In Pakistan. AB - BACKGROUND: Diabetes affects almost every system including mental health. When depression and diabetes coexist, the outcome is even worse. This study was conducted to find the prevalence of comorbid depression in diabetic patients and its association with diabetic control. METHODS: This was a descriptive cross sectional observational study conducted in the department of general medicine of Pakistan Institute of Medical Sciences, Islamabad from March to September 2014. A total of 223 adult diabetic patients 30-60 years of age were enrolled. Becks Depression score (BDI) and HDRS (Hamilton Depression Rating Score) of each patient was calculated. Patients were stratified into various categories based on their demographics, depressions scores and diabetic control (by means of HbA1C). Percentages, frequencies and means were calculated accordingly using SPSS-16. RESULTS: Out of a total of 223 patients, 55.6% were females while the rest (44.4%) were males. The mean age of the patients was 51 years. Majority of the patients were uneducated (35.9%). Eighty-seven% were married, Mean BMI, duration of diabetes and HbA1C were 27 Kg/m2, 8.3 years+/-6.1 years and 8.15+/-2.13% respectively. Mean BDI and HDRS were 9.97+/-9.42 and 6.27+/-6.74 respectively. 25.6% and 21.1% of the patients had at least some degree of depression when assessed by BDI and HDRS score respectively.. CONCLUSIONS: Depression is common in diabetic patients especially females, uneducated, have social issues like widows, those having long standing diabetes and those who have uncontrolled blood sugars. PMID- 28718245 TI - Left Ventricular Systolic Dysfunction Predicted By Early Troponin I Release After Anthracycline Based Chemotherapy In Breast Cancer Patients. AB - BACKGROUND: Anthracyclines are one of the most effective chemotherapeutic agents in management of Breast cancer, however Anthracycline induced cardiotoxicity remains a matter of special concern. Detection of early toxicity by use of biomarkers like Troponins has been the focus of interest in recent years. We measured Troponin I levels after chemotherapy with anthracyclines and correlated it with ECG, Echocardiography and clinical findings. METHODS: Patients with early Breast cancer eligible for chemotherapy were included in the study. All patients underwent clinical evaluation, Left Ventricular Ejection Fraction (LVEF) measurement by echocardiography at baseline and every 03 monthly for first year. Serum samples for TNI were obtained immediately after chemotherapy and after 24 hrs. RESULTS: A total of 82 patients (all females) were included in the study. Median age was 47 (range 30-64) years. Anthracycline mediated cardiotoxicity occurred in 6 patients (7%) and was more frequent in patients with TNI elevation (p<0.001). Five patients (83%) recovered from cardiotoxicity. At multivariate analysis, TNI elevation was the only independent predictor of cardiotoxicity (95% CI 0.0007879-0.2821) and of lack of LVEF recovery (95% CI 0.002484 to 1.680). CONCLUSIONS: Measurements of Trop I levels after Anthracyclines can be useful in detecting early cardiotoxicity and tailoring further therapy. PMID- 28718246 TI - Effect Of Cobalt-Chromium Alloy Re-Use In Dentistry On Its Castability Value. AB - BACKGROUND: Re-use of dental casting alloy is a routine practice, which is carried out with the motive to conserve resources. There have been studies on the re-use of alloys but a controversy exists as to the proportioning ratio of fresh to used alloy and the number of time an alloy can be recast. The objective of the study was to measure the effect of addition of 50% by weight used alloy to the fresh Cobalt-Chromium alloy on the castability. METHODS: In the present in-vitro experimental study A total of 20 specimens were cast by flame centrifuge, using modified Whitlock's method. The total sample size was divided into four groups of five specimens each. Group 1 was the control group with 100% fresh alloy cast once. In group 2, 3 and 4, a 50% by weight cut off of previous castings were mixed to the fresh alloy. The reused alloy for the group 2 and 3 was further aged or exposed to flame casting separately. The number of completely cast segments were counted and castability value was calculated according to the Whitlock's formula. RESULTS: There was no significant difference of castability value among the entire tested group (p=0.085). CONCLUSIONS: Within the limitations of the present study, it is recommended that commercial Co-Cr-Mo alloy can be re-used six times without affecting its castability, when 50% fresh alloy is added on each re-use. PMID- 28718247 TI - Public Private Partnership And Utilization Of Maternal And Child Health Services In District Abbottabad, Pakistan. AB - BACKGROUND: Public Private Partnership has been experimented as an approach in Pakistan in 2005 and in eighteen districts of Khyber Pakhtunkhwa including Abbottabad in 2011, to improve delivery of maternal and child health services. This study was conducted to assess the utilization of maternal and child health services before and after implementation of Public Private Partnership in district Abbottabad. METHODS: A cross sectional study was conducted in district Abbottabad from July to December 2014. Study included all the 53 basic health units, outsourced to People's Primary Healthcare Initiative in 2011. Data related to selected maternal and child health services indicators (family planning services, antenatal and post-natal care, safe delivery, tetanus toxoid vaccination of pregnant women and child immunization), before and after the introduction of Public Private Partnership, was collected. Significance tests (t test) was applied and p-value <0.05 was taken as significant. RESULTS: Marked improvement was observed in vaccination of target children (127%) and women (42%), respectively. Similarly, utilization of family planning services, antenatal and postnatal care increased by 60%, 9% and 38%, respectively. Public Private Partnership had significant effect on postnatal visits (p<0.001), family planning services (p<0.001), women vaccinated with tetanus toxoid (p<0.001) and children vaccinated in Expanded Program of Immunization (p=0.003). CONCLUSIONS: Public Private Partnership improved the utilization of maternal and child health services, particularly family planning services and maternal & child immunization. The partnership may be scaled up and extended, for an improved coverage of maternal and child health services. PMID- 28718248 TI - Outcome Of 0.2% Glyceryltrinitrate Cream Versus 2% Diltiazem Cream In The Treatment Of Chronic Anal Fissure. AB - BACKGROUND: Anal fissure is a linear tear in the distal anal canal resulting from persistent hypertonia and spasm of the internal sphincter which results in mucosal ischemia. We have conducted a study in order to compare the outcome of 0.2% glyceryl trinitrate cream versus 2% diltiazem cream in the treatment of chronic anal fissure. METHODS: This randomized controlled trial (RCT) was carried out in the Department of Surgical "B" unit, at Ayub Teaching Hospital, Abbottabad, Pakistan from 15th June 2012 to 15th May 2015. One hundred and eighty four patients who visited the outpatient department for the treatment of chronic anal fissure were included in the study. They were divided into two groups with 92 patients in each group. Patients in group "A" included those patients receiving topical glyceryl trinitrate and group "B" patients were those receiving topical diltiazem cream. RESULTS: Out of 184 patients 66.3% were males, 33.7% were females. Mean age of the patients was 43.84+/-7.976 and mean duration of symptoms was 10.55+/-2.524. Overall outcome in terms of healing was 71.2%, among which 80.4% were from diltiazem group while 62% in glyceryl trinitrate group. Complete relief of pain was observed in 67.9%, 26.1% complained of mild pain and 5.4% complained of moderate pain. Only one patient in glyceryl trinitrate group complained with severe pain with no healing after one month of follow up. No statistical association was found between healing outcome and gender as well as age of the patients (p>0.05) although an association was found between healing outcome and duration of symptoms (p<0.05). CONCLUSIONS: This study shows that diltiazem has better outcome in terms of healing of chronic anal fissure and reductions in symptoms, i.e., pain compared with glyceryl trinitrate. PMID- 28718249 TI - Frequency Of Undiagnosed Chronic Obstructive Pulmonary Disease In Patients With Coronary Artery Disease. AB - BACKGROUND: Chronic obstructive airway disease (COPD) is considered as risk factor for coronary artery disease (CAD) along with other risk factors. This study was conducted to determine the frequency of undiagnosed chronic obstructive pulmonary disease in patients with coronary artery disease. METHODS: This cross sectional study was conducted in the Pulmonology and Cardiology wards/OPD's of Khyber Teaching Hospital Peshawar. Patients more than 35 years of age, diagnosed with CAD of either gender were included. Patients already diagnosed with COPD, recent myocardial infarction (within 7 days), left ventricular impairment, pneumothorax, bronchiectasis, comatose patient, asthmatic and those with chest trauma were excluded. All the patients underwent spirometry examination before and after administration of salbutamol (5 mg for 5 minutes) via nebulizer. FEV1/FVC less than 70% confirmed the presence of COPD. RESULTS: Out of 151 patients, 57 (37.7%) were found to have COPD. Among them, 39 (68.42%) were male and 18 (31.57%) were female. Among male patients with COPD, 82.05% (n=32) were smokers and 17.94% (n=7) were nonsmokers while in females with COPD no one was smoker. CONCLUSIONS: COPD is an under-diagnosed progressive disease in patients with high risk patients with coronary artery disease. PMID- 28718250 TI - Qing-Qi Rickshaw : A Boon Or Bane For Public Transportation? A Study Of Road Traffic Injury Patterns Involving Qing-Qi Rickshaws In Karachi Pakistan. AB - BACKGROUND: The three-wheeler Qing-qi and Compressed Natural Gas (CNG) auto rickshaws were introduced in Karachi to meet the transportation demand of the growing population. These vehicles have directly or indirectly been implicated in a number of road traffic violations as well as road accidents. This study aims to describe the crash characteristics and injury patterns for Qing-qi rickshaw occupants and other road users hit by Qing-qi rickshaw in Karachi, Pakistan. METHODS: An Observational/ Descriptive study was conducted at Accident & Emergency and Orthopaedic Surgery Department, Jinnah Post Graduate Medical Centre, Karachi Pakistan from July 2014 to June 2015.All patients who came with Qing-qi rickshaw accident in Accident & Emergency (A&E) of JPMC were included. Crash characteristics, details of injuries, injury severity parameters and outcome were documented in detailed interviews. RESULTS: Four hundred and eighty six rickshaw related injuries were noted in road traffic accidents by Qing-gi rickshaw. Age range was 2-85 (43.5+/-58.68). 350 injured victims were males and 136 were females. By occupation most victims were laborers and daily wage workers (45%) and students (21%). Overloading of vehicle with more than two passengers was found in (28.5%). The most common cause of injury was collision with a moving vehicle (56%), followed by fall from rickshaw. The most common contributing factor was the overloading of rickshaw and roll over on turning (61%). Injury severity on arrival were mild (49%), moderate were (32%), and severe were (19%). Injuries related to head and neck (26%), face (14%), thorax and abdomen (5%), lower extremity and pelvic girdle (31%) and upper extremity (23%) were observed. CONCLUSIONS: Qing-qi rickshaw injuries are common and these vehicles are vulnerable to road traffic accidents. Occupants and road users are both at risk of injuries. PMID- 28718251 TI - Comparison Of Dietary Practices And Body Mass Index Among Educated Housewives And Working Women In Karachi. AB - BACKGROUND: Body Mass Index (BMI) is considered as a major determinant of health. The objective of study was to find out differences between dietary practices, as well as BMI in educated housewives and working woman. It is supposed that both study groups may have difference in work pressures with resultant diverse preferences for food. This can affect health status particularly in relation to obesity in women. Furthermore, we selected participants with 14 years' education expecting basic awareness of healthful diet. METHODS: This cross-sectional study had a convenient sampling method and sample size of 600 with 300 house wives and 300 working women, aged 35-45 years. Dietary habits were recorded by interview. Body Mass Index was calculated by standard formula, and results obtained by Chi Square using SPSS-17. RESULTS: Working women had healthier dietary practices. Number of meals, fruits, fish/ poultry and water consumption was better in working mothers with significant p-value <0.00.1. Intake of vegetables and fast food was found similar. BMI comparison showed that majority of housewives were noted as overweight whereas working women showed normal weight (p-value <0.001). Most housewives responded that they have a sedentary life style as opposed to working women p-value <0.001. Self- assessment of diet quality was comparable as it was mentioned moderate by most of the participants, however more working females accepted that they need to improve their diet and would need expert advice. CONCLUSIONS: Healthier BMI, active life style and better dietary habits were witnessed in working women as compared to housewives. PMID- 28718252 TI - Use Of Complementary And Alternative Medicine Among Asthmatic Patients. AB - BACKGROUND: The prevalence of complementary and alternative medicine (CAM) use in some developed countries is on the rise as surveys conducted on large scale vouch for. This study was conducted with the aim to determine the frequency of complementary and alternative medicine (CAM) use among asthmatic patients at outpatient department of tertiary care hospitals in Peshawar, Khyber Pakhtunkhwa, Pakistan. METHODS: This cross-sectional study was conducted in outpatient department of two tertiary care hospitals. A face to face interview of 423 patients was conducted through a questionnaire. Non-probability consecutive sampling method was used to select the respondents. Stata version 12.1 (StataCorp), College Station, Texas) was used to carry out the statistical analysis. RESULTS: Overall asthmatic patients in the study were 423, in which 232 (54.85%) patients reported as using CAM. There were 177 (41.84%) males and 246 (58.16%) females. The CAM use was significantly more in older age patients, suffering from asthma for more than 5 years, severe persistent type of asthma, married, unemployed, rural and current smokers. CONCLUSIONS: The use of CAM reflects a high CAM use among asthmatic patients in Pakistan. Clinicians should be aware about their patient's use of CAM. PMID- 28718253 TI - Psychological Adjustment To Amputation: Variations On The Bases Of Sex, Age And Cause Of Limb Loss. AB - BACKGROUND: Amputation is the removal of a limb or part of a limb by a surgical procedure in order to save the life of a person. The underlying reasons behind the occurrence of this tragic incidence may be varied. However, irrespective of its cause limb loss is associated with wide range of life challenges. The study was done to investigate the psychological sequel of an individual after losing a limb and to know the level of strain and pressure they experience after this traumatic event. It also attempts to examine the moderating role of some demographic traits such as age, sex and cause of limb loss in psychosocial adjustment to amputation. METHODS: The study includes 100 adult amputees of both genders and the data was collected from major government and private hospitals of Peshawar district. Demographic data sheet was constructed in order to know the demographics traits of amputees and a standardize Psychological Adjustment Scale developed by Sabir (1999) was used to find out the level of psychological adjustment after limb loss. RESULTS: Nearly all the amputees' exhibit signs of psychological maladjustment at varying degrees. Males showed much greater signs of maladjustment than women and young adults were much psychologically shattered and disturbed as a result of limb loss. Amputation caused by planned medical reasons leads to less adjustment issues as compared to unplanned accidental amputation in which patient were not mentally prepare to accept this loss. CONCLUSIONS: Psychological aspect of amputation is an important aspect of limb loss which needs to be addressed properly in order to rehabilitate these patients and helps them to adjust successfully to their limb loss. PMID- 28718254 TI - Reduction Of St Segment Elevation In Diabetic Patients With Myocardial Infarction After Thrombolytic Therapy. AB - BACKGROUND: Acute coronary artery disease (CAD) is one of the main causes of death in today's world. Myocardial infarction (MI) tends to be more common among diabetic patients. One of the most effective and used (in our settings) methods of resolution of MI is administration of streptokinase (SK). This study was conducted with the aim to determine the efficacy of thrombolytic therapy in reduction of ST segment elevation in acute MI patients presenting with diabetes. METHODS: A descriptive case series with selection of 130 patients through nonprobability purposive sampling was conducted at the Medical Departments of Services Hospital Lahore. The study was completed in 6 Months. Patients 18-80 years of age having either gender diagnosed with confirmed acute myocardial infarction were included in this study. All patients were then injected with streptokinase 1.5 mu. Pre S and Post SK ECGs were done and ST segment elevation measured also measuring reduction of ST segment. RESULTS: The mean age of the patients was noted as 54.42+/-8.80 years. There were 62.31% males. Mean reduction in ST-segment elevation of the patients was noted as 58.53+/-26.01. The efficacy was achieved in 47.7% patients. CONCLUSIONS: It is concluded that SK can be effective in almost half of diabetic patients with myocardial infarction. PMID- 28718255 TI - Dural Tears In Patients With Depressed Skull Fractures. AB - BACKGROUND: The presence of skull fracture in patients sustaining traumatic brain injury is an important risk factor for intracranial lesions. Assessment of integrity of dura in depressed skull fracture is of paramount importance because if dura is torn, lacerated brain matter may be present in the wound which needs proper debridement followed by water tight dural closure to prevent meningitis, cerebral abscess, and pseudomeningocoele formation. The objective of this study was to determine the frequency of dural tear in patients with depressed skull fractures. METHODS: This cross-sectional study was conducted at Department of Neurosurgery Ayub Teaching Hospital Abbottabad. All the patients of either patients above 1 year of age with depressed skull fracture were included in this study in consecutive manner. Patients were operated for skull fractures and per operatively dura in the region of depressed skull fracture was closely observed for any dural tear. The data were collected on a predesigned pro forma. RESULTS: A total of 83 patients were included in this study out of which 57 (68.7%) were males and 26 (31.3%) were females. The age of the patients ranged from 1-50 (mean 15.71+/-13.49 years). Most common site of depressed skull fracture was parietal 32 (38.6%), followed by Frontal in 24 (28.9%), 21(25.3%) in temporal region, 5(6.0%) were in occipital region and only 1 (1.2%) in posterior fossa. Dural tear was present in 28 (33.7%) patients and it was absent in 55 (66.3%) of patients. CONCLUSIONS: In depressed skull fractures, there are high chances of associated traumatic dural tears which should be vigilantly managed. PMID- 28718256 TI - Iron Deficiency Anaemia As Risk Factor For Simple Febrile Seizures: A Case Control Study. AB - BACKGROUND: Febrile fits is common problem in children. Among other risk factors, iron deficiency anaemia is considered as aggravating factor for febrile fits. Iron deficiency anaemia is preventable and treatable disease. The objective of the study was to find out iron deficiency anaemia as risk factor for febrile fits. METHODS: It was a case control study. Thirty cases of febrile fits were recorded. Control group of 30 cases was taken at the same time with same variables but without febrile fits. Their temperatures and weights were recorded and laboratory haematological parameters haemoglobin, haematocrit, Mean Corpuscular Volume (MCV), Mean Corpuscular Haemoglobin (MCH), Mean Corpuscular Haemoglobin Concentration (MCHC), Red Blood Count (RBC) and Red Cell Distribution Width values were collected and analysed statistically with SPSS Ver 20.0. RESULTS: In case group 21 had haemoglobin <11.0 gm% while in control group 13 cases had haemoglobin <11.0 gm% (Odd Ratio 3.0513 95% CI 1.0533-8.8390) Mean Haematocrit, RBC, MCV, MCH, MCHC and RDW had statistically significant difference between the two groups (p-value <0.05). CONCLUSIONS: As Iron Deficiency Anaemia is a risk factor for febrile fits, treatment and prevention of iron deficiency anaemia can decrease incidence of febrile fits. PMID- 28718257 TI - Risk Factors For Heat Related Deaths During The June 2015 Heat Wave In Karachi, Pakistan. AB - BACKGROUND: Mortality as a consequence of heat related illness is a public health concern. Emergency department (ED) experiences increased patients' flow and decreased survival as a consequence of heat stroke during the episodes of heat wave. The present study was conducted to identify the risk factors for mortality among victims of heat wave (17th - 23rd June), 2015 evaluated in the Emergency Department of The Indus Hospital (TIH), Karachi. METHODS: In this cross-sectional study data was retrospectively collected. Out of 2278 patients, 150 patients who satisfied the inclusion criteria (core body temperature >38 degrees C, dehydrated and CNS dysfunction without infection) were included. Data was analysed using SPSS version 21 (IBM). RESULTS: Among 150 patients included for analysis, the mortality was observed in twenty-four patients (16%). Majority (64.7%) of the patients included in this retrospective study were males and older with median age of 51.5 years. It was identified that non-survivors had significantly lower diastolic blood pressure and oxygen saturation compared to survivors along with higher median reparatory rate, pulse rate, temperature, and length of stay in emergency, shock index, and proportion of unconscious level. CONCLUSIONS: The study concluded that heat stroke patients with decreased diastolic blood pressure and oxygen saturation as well as patients with increased shock index, low conscious level and higher core temperature, respiratory and pulse rate should be considered for more intensive management in Intensive Care Unit (ICU) to decrease mortality rate during future heat stroke episodes. PMID- 28718258 TI - Variations In The Age Of Fusion Of Ischial Tuberosity; A Radiological Study. AB - BACKGROUND: Human skeleton develops from separate ossification centres which continue to ossify till the bone is completely formed. Radiological techniques are very reliable and useful method for estimating the age of individual for forensic and criminal reasons by observing these ossification centres. External inspection for age determination is liable to error. This study is thus aimed to assess the variation in age of fusion of ischial tuberosity in Pakistani population. METHODS: It was a cross sectional study, wherein data was retrospectively collected at Bahawalpur Victoria Hospital, a tertiary referral centre in which consecutively selected 47 females and 121 males between 10-24 years of age, attending the outpatient, referred from National Database and Registration Authority for the confirmation of age were selected. RESULTS: There were a total of 13 cases in stage I, 98 in stage II, 23 in stage III and 34 in stage IV. In stage II maximum numbers of cases were between the ages of 19-22 years whereas in stage IV the maximum numbers of cases were between 21-24 years of age. CONCLUSIONS: It is concluded that the earliest appearance of epiphyseal centre in males occurred at 12-13 years and in females at 10-11 years. While earliest complete union was seen at the age of 19-20 years in females and 16-17 years in males. All cases in age group of 23-24 years showed complete union. PMID- 28718259 TI - Counterforce Orthosis In The Management Of Lateral Epicondylitis. AB - BACKGROUND: Lateral Epicondylitis (LE), is a condition characterized by the pain and tenderness over the lateral epicondyle of the humerus. LE is commonly seen among people who are involved in sports such as tennis and golf. Any activity that repeatedly overstrains the extensor carpi radialis brevis tendon can lead to LE. The management of lateral epicondylitis generally involves the use of counterforce orthosis. The aim of this review is to summarize the evidence regarding the effectiveness of counterforce orthoses on the clinical outcomes of patients with lateral epicondylitis. METHODS: The PubMed, Ovid, and ProQuest databases were searched for potential studies which explored the use of counterforce orthosis in the management of lateral epicondylitis. RESULTS: To have a better understanding of the effectiveness of various types of orthoses, the review is organized into four sections. The first section explores the use of a single orthotic device, the second section focuses on the combined use of orthotic devices, the third section explore studies that compared the effect of local steroid injection along with orthosis and the last section narrate the studies that compared various types of orthotic devices. The studies support the use of orthotic devices as a treatment modality for lateral epicondylitis. There is rising evidence which supports the use of a comprehensive approach, (by combining routine physiotherapy with orthotic devices) in the management of LE. CONCLUSIONS: Orthosis alone or in combination with routine physical therapy can be considered as an evidence-based treatment strategy for patients with lateral epicondylitis. However, on the basis of the literature review conducted, the authors recommend that further high-quality clinical trials regarding the management of lateral epicondylitis are necessary to strengthen the evidence based physiotherapy practice. PMID- 28718260 TI - Cerebral Oximetry Use For Cardiac Surgery. AB - BACKGROUND: Studies have shown maintaining good cerebral perfusion during Cardiac Surgeries is very important in terms of patient outcomes and reducing the hospital stay, which may have its financial and clinical implications. The aim of this review study was to determine the effectiveness of Cerebral Oximetry (Transcranial Near-Infrared Spectroscopy-NIRS to monitor cerebral oxygenation) for Cardiac Surgery and to propose a possible concluding remark about its potential applications, overall clinical value and whether to keep using it or not. METHODS: Medical database and archives including Pubmed, Embase, index medicus, index copernicus and Medline were searched. Different papers were looked upon and each had an argument, scientific evidence and background. Fifteen research papers were selected and brought under review after carefully consideration. RESULTS: The papers were carefully reviewed and findings were given in favour of not using NIRS technique for Cerebral Oximetry in Cardiac Surgery. CONCLUSIONS: This can rightly be concluded from this study that NIRS Cerebral Oximetry does not carry the clinical significance and relevance which was previously thought. The subject under observation needs further studies and research to evaluate the effectiveness of the Cerebral Oximetry Use for Cardiac Surgery. PMID- 28718261 TI - Modern Management Of Duodenal Variceal Bleeding. AB - Duodenal variceal bleeding is an uncommon cause of gastrointestinal bleeding. Treatment strategies are reliant on case reports and case series with new developments in interventional treatment modalities including endoscopic therapy, radiological intervention, and surgery. Endoscopic treatment includes injection sclerotherapy using various agents, banding of varices and clipping of varices. Interventional radiological procedures include Transjugular Intrahepatic porto systemic shunt (TIPSS), and Balloon- Occluded Retrograde Transvenous Obliteration (BRTO). Surgical treatment could be suture ligation of varices or gastro duodenectomy. In this article, a case report of upper gastrointestinal bleed, and management of duodenal varices is described, with review of the literature to offer optimum modern era treatment to these high risk gastrointestinal bleeds. PMID- 28718262 TI - Laparoscopic Approach To A Rare Interstitial Incisional Hernia Following Appendectomy. AB - Among the complications of an open appendectomy is the presentation of an incisional hernia. An interstitial or interparietal hernia is the one in which the hernia sac is present between the muscle layers of the abdominal wall which makes the presentation of a post-operative incisional interstitial hernia quite a rarity. A 52-year-old female was admitted through the outpatient clinic presenting with the complaints of discomfort and a bulge felt in the right hypochondrium for the last 3 years. Radiological investigations were able to delineate an interstitial incisional hernia through the previous open appendectomy scar. A laparoscopic approach to repair of this hernia was successfully undertaken without any complications. This is an interesting case of incisional hernia that may pose a diagnostic challenge to the unsuspecting surgeon with an unusual presentation which may cause unnecessary delays in treatment as well as unnecessary operations. Very few comparable cases can be found in literature. PMID- 28718263 TI - Multi-Organ Dysfunction Secondary To Yellow Scorpion Sting. AB - Scorpion stings are common in tropical and subtropical regions. The history and clinical manifestation warrant urgent recognition and treatment. The incidence of scorpion stings in Pakistan is not known as there is no published data available in literature. We report our experience of a yellow scorpion sting victim who required intensive care admission after developing multi-organ dysfunction. PMID- 28718264 TI - Malignant Infantile Osteopetrosis. AB - Two main forms of osteopetrosis are recognized, a severe autosomal recessive form (MIM 259700) with an incidence of approximately 1 in 250,000 births and a mild autosomal dominant form (MIM166600) with an incidence of 1 in 20,000 births. Intrinsic disturbances of osteoclastic function due to mutations in genes encoding osteoclast-specific subunits of the vacuolar proton pump (TCIRG1, CLCN7) are found in most patients with recessive form. Mutations of CLCN7 are observed in dominant form of osteopetrosis .The recessive form of ostreopetrosis, i.e., malignant infantile osteopetrosis (MIOP) presents early in life with extreme sclerosis of the skeleton and reduction of marrow space. Signs/symptoms of MIOP appear as early as neonatal age. As there is defect in bone marrow children present with deficiency of red blood cells, white blood cells and platelets. There is extramedullary haemopoiesis, cranial nerve compressions and severe growth failure. The condition also presents with early and late onset neonatal sepsis and is often lethal in the first decade of life due to secondary infections. Treatment is mainly supportive. The only curative treatment is stem cell transplantation. This is a case report of a new-born who was admitted in nursery of Ayub Teaching Hospital initially with complains of neonatal jaundice and sepsis , and a second time with lower respiratory tract infection. Death was eventually due to sepsis. Workup led to diagnosis of Malignant infantile osteopetrosis. PMID- 28718265 TI - Haemoglobinuria And Portal Venous Thrombosis In A Young Male. AB - Paroxysmal nocturnal haemoglobinuria is a non-malignant stem cell disorder due to acquired somatic mutations in cell surface anchored proteins CD55 and CD59. Both have a compliment inhibitory role and their deficiency leads to intravascular haemolysis. This paper reports a challenging case of a 25 years old male who presented with generalized weakness, exertional dyspnoea and episodic early morning haematuria. Recently, he started developing progressive abdominal distention and dull generalized abdominal pain. Investigations revealed haemoglobin 3.5 g/dl with 10% reticulocytes, total bilirubin 54.5 mg/dl, LDH 3155 U/L, negative Coomb's test and erythroid hyperplasia on bone marrow biopsy. Urine complete exam was significant for haemoglobinuria without red blood cells. Doppler scan of abdomen showed portal vein thrombosis. Loss of expression of CD14, CD16, CD55 and CD59 on leukocytes and erythrocytes was seen on PNH analysis, confirming paroxysmal nocturnal haemoglobinuria. He was managed with blood transfusions and was advised folic acid and bone marrow transplant. PMID- 28718266 TI - A Case Of 13-Year-Old Girl With Prolidase Deficiency. AB - Prolidase deficiency is a rare autosomal recessive disorder characterized by recurrent and nonhealing skin ulcers along with facial dysmorphism and mental retardation. We report a 13-year-old girl who has clinical manifestation of Proliodase deficiency. It is a very rare disorder and no such case has been reported so far from Pakistan. PMID- 28718267 TI - Giant Haemangioma Of Nasopharynx: A Rare Case Outcome. AB - A 60-year-old female presented to us with a 5-year history of progressive right sided nasal obstruction and recurrent epistaxis. On examination lesion was seen in the right nostril which was firm and bled on probing. CT-scan paranasal sinuses showed a right sided lesion of nose and naso-pharnyx obstructing posterior nasal choanae. Dimensions were reported to be 9*4.1*3.8 cm. A punch biopsy was taken in operating room under general anaesthesia which resulted in profuse bleeding. Suction cautery was used to control bleeding and the nose was packed. The mass was firm to hard and provided resistance during the time of biopsy. On second post-operative day, the mass visibly changed its colour and became blackish in appearance. Patient had an episode of cough in the evening and expelled out the entire mass orally. PMID- 28718268 TI - Oxymorphone Induced Thrombotic Microangiopathy Mimicking Atypical Haemolytic Uremic Syndrome. AB - BACKGROUND: Atypical Haemolytic Uremic Syndrome (aHUS) is a rare life threatening entity characterized by thrombocytopenia, haemolytic anaemia and renal dysfunction. It is a thrombotic microangiopathy related to genetic mutations in the alternate complement pathway and has a distinct pathophysiology which makes it harder to distinguish from other microangiopathies. We present a case of a 25 year-old male patient with history of polysubstance abuse who presented with chest pain and dyspnoea. He admitted to using injectable oxymorphone (Opana) two weeks before presentation. Patient's vital signs were stable except for tachycardia and high blood pressure. On physical examination, epigastric tenderness and mild splenomegaly was appreciated. Urine Drug Screen was positive for oxycodone and opiates. Laboratory work up revealed haemolytic anaemia, thrombocytopenia and acute kidney injury. Extensive evaluation resulted in our impression of the disease being atypical haemolytic-uremic syndrome. He was managed with dialysis, intravenous steroids and plasmapheresis with improvement in his hematologic parameters. PMID- 28718269 TI - Non-Atherosclerotic Obliteration Of Bilateral Supraclinoid Internal Carotid Arteries; A Classic Case Of Moyamoya Disease. AB - Moyamoya disease is an idiopathic progressive vasculopathy of distal internal carotid artery and circle of Willis which leads to the development of characteristic smoky appearance of the vascular collateral network on angiography. With the highest reported incidence among Japanese population, it has been under recognized as a cause of cerebrovascular accidents in Western countries. Here we report a case of a young 20-year-old Caucasian woman who presented to the emergency department with expressive aphasia, right arm weakness and numbness for three days. Imaging modalities confirmed Moyamoya disease. PMID- 28718270 TI - Salmonella Infection Amongst Food Workers In Lahore. AB - This descriptive observational study was conducted at Pathology lab Jinnah hospital, Lahore, January 2013 to October 2015. We include all the food workers in different restaurants, slaughters, inn, recreation centre and bakeries of Lahore for the purpose to identify the salmonella infection, we used Typhoid IgGI/IgM Rapid test device methods (Serum/Plasma), is a lateral flow chromatographic immunoassay technique were calculated. We analysed 1025 individuals, 62 (6%) were found positive for the said diseases out of which 14 (1.3%) IgG positive, 18 (1.8%) IgG IgM positive and 30 (2.9%) were IgM positive. All the individuals who were found positive were without signs and symptoms. Salmonellosis continues to be an important global cause of infectious intestinal disease and spread readily by means of food personnel, zoonotic and contaminated equipments and surface. The screening of the individuals who are silent carriers, help in controlling the spread of salmonella infection in the public. PMID- 28718271 TI - Focal Hemispheric Central Nervous System Vasculitis: An Unusual Form Of Primary Angiitis. PMID- 28718272 TI - 360 Degree Deep Corneal Vascularization In A Case Of Endophthalmitis With Corneal Abscess. PMID- 28718274 TI - [Microbiome and next generation sequencing]. AB - The human microbiome is an internal ecosystem that refers to the community of microorganisms that populate the human body. These microorganisms are essential to support his health, because the interaction between the host immune system and microorganisms, provide the host with protection against pathogens, and contributes to the preservation of health. Bacteriological culture has been the basis for traditional microbiology; however, most of the bacterial forms observed in nature cannot be isolated with laboratory culture methods. At present, metagenomic applies a suite of genomic technologies, where the microorganisms are identified by their genomic fingerprint. The 16S rRNA subunit is considered as the universal target for bacterial identification from DNA with the aid of sequencing. Sanger sequencing technology had a great impact on the first generation sequencing due to its simplicity and precision. Platforms high throughput known as second generation secuencing technologies are capable to generate hundreds of thousands of sequence reactions in a faster and economic way. However, thanks to the third generation sequencing the greatest advances in nanotechnology have been made. Using the reference gene, the massive sequencing techniques and bioinformatics tools used for the data processing, there has been an important development of the human microbiome, achieving an unprecedented detail level on the taxonomy and microbial function. This has meant an authentic revolution not only in their knowledge but also in their involvement in the health or illness of the human being. PMID- 28718273 TI - 3D quantitative evaluation of spine proprioceptive perception/motor control through instinctive self-correction maneuver in healthy young subjects' posture: an observational study. AB - BACKGROUND: Conservative treatment in spine deformities and spine related disorders is mainly based on proper individual proprioceptive and motor control training. For these reasons, conservative treatment involves the stimulation of individual capability of perceiving/reducing deformities, blocks and/or improper spine posture by voluntary control. The literature describes that habitually adopted relaxed postures often exacerbate low back pain. Typically, youths can be referred to therapeutic programs aimed at improving the quality of body posture along with fostering the awareness of the importance of correct posture. Few studies in literature outline the subject's individual instinctive ability to perceive properly and control his/her posture and produce an improvement through a self-correction maneuver. AIM: How do healthy young adult subjects perceive and control their posture and spine shape? Are they able to modify them in a correct way through an instinctive self-correction maneuver? DESIGN: Cross-sectional observational study. SETTING: A cohort of asymptomatic young adult university students and workers were recruited at Clinic of Rehabilitation, University of Medical Sciences, Poznan, Poland. POPULATION: One hundred and twenty-one healthy subjects (57 females, 64 males), aged 19-34 years (mean age: 23.5+/-3.2 years). METHODS: Subject's full body posture including 3D spine shape reconstruction, identified using 27 retro-reflective markers suitably located on anatomical landmarks has been measured by using a non-ionizing 3D optoelectronic stereo photogrammetric approach and a 3D full skeleton biomechanical model. RESULTS: From the 3D full skeleton and spine reconstruction, eleven quantitative biomechanical parameters describing the nature of body posture have been computed to compare natural erect versus self-corrected standing attitudes. A great number of healthy participants (105, 87%) was unable to modify its spinal shape in the frontal plane. Conversely, the sagittal plane presented significant clinical changes in the thoracic spine, as males reached a greater thoracic spine extension (36.4+/-8.3) than females (40.8+/-8.7). When changes occurred, subjects were not able to focus and control their posture globally, but only on few aspects at a time. CONCLUSIONS: Instinctive posture proprioception and motor control do not produce an effective self-correction maneuver yielding a global improvement of body posture and spine shape. CLINICAL REHABILITATION IMPACT: Self correction maneuver producing an improvement of body posture and spine shape has to be learned with specific postural training. The 3D stereo-photogrammetric approach is effective in quantitatively describe subject's posture, motor control and proprioceptive capability. PMID- 28718275 TI - [Assessment of adherence to antibiotic treatment in Primary Care by determining levels of the drug using a liquid chromatography technique]. AB - OBJECTIVE: The lack of adherence to antibiotic treatments is a matter of special interest, which has important clinical implications, as it is associated with therapeutic failure and increased bacterial resistance causing a high sani-tary cost. The objective of our study was to assess the degree of adherence to prescribed antibiotic treatment in outpatients through the detection of these in blood, urine or sputum. METHODS: Concentrations of antibiotics prescribed in 39 patients (34 with clinical suspicion of urinary tract infection and 5 with clinical suspicion of low respiratory tract infection) treated in Primary Care consultations of the Sanitary District of Almeria (Spain) were determined by ultra-high performance liquid chromatography coupled to tandem mass spectrometry. RESULTS: A 48.7% of the patients did not comply correctly with the indicated treatment due to the complete or partial omission in taking the prescribed antibiotics. This lack of adherence was independent of the age and sex of the patients, the number of daily doses of the antibiotic, and whether or not they were receiving another medication. CONCLUSIONS: Precise analytical techniques such as liquid chromatography can be useful to detect inadequate or incomplete treatments as well as the degree of adherence of outpatients. Thus, adequate measures could be established that affect the control of therapeutic compliance. PMID- 28718276 TI - Recent developments in intraoperative imaging and navigation during aortic interventions. AB - With the advent of endovascular techniques, rapid improvements have been made in intraoperative imaging. This review intends to summarize the latest imaging technologies available and the new leads currently investigated for the future. PMID- 28718277 TI - Clinical implications of long-term ECG monitoring: from loop recorder to devices remote control. AB - Long-term ECG monitoring has become nowadays an indispensable technology for prevention, management and treatment of many cardiac issues. Today long-term ECG monitoring is achievable through loop recorders and cardiac devices like pacemaker, implantable cardioverter-defibrillators and cardiac resynchronization therapy device-defibrillators, all of which associated with remote monitoring. Targeted long-term ECG monitoring patients who have recurrent non-documented episodes of palpitations, unexplained episodes of syncope, cryptogenic stroke or patients with a cardiomyopathy needing a risk stratification, may benefit from long-term ECG monitoring. PMID- 28718278 TI - Matrix Stiffness Differentially Regulates Cellular Uptake Behavior of Nanoparticles in Two Breast Cancer Cell Lines. AB - Matrix stiffness regulates cell behavior in various biological contexts. In breast tumors, the deposition of extracellular matrix correlates with increasing matrix stiffness and poor survival. Nanoparticulate carriers represent a promising therapeutic vehicle for disease diagnosis and efficient anticancer drug delivery. However, how matrix stiffness influences cellular uptake of nanoparticles remains largely unexplored. Here, we selected photopolymerized polyacrylamide gels with varying stiffnesses as model substrates and studied the impact of matrix stiffness on cell morphology and nanoparticle uptake efficiency in two representative breast cancer cell lines with varying invasiveness, that is, MCF-7 with low invasiveness and MDA-MB-231 with high invasiveness. In our study, both cell lines showed similar morphological changes with changing stiffness. MCF-7 cells adhered on compliant substrates (1 kPa) showed a roundlike morphology with the lowest cell uptake efficiency among four stiffnesses under investigation at each given time point, whereas for MDA-MB-231 cells, the uptake efficiency showed no significant differences across varying stiffnesses. The percentages of MCF-7 cell proliferation on a 1 kPa substrate were significantly decreased at 48 and 72 h as compared to those on stiff substrates and coverslips. When treated with pluronic/d-alpha-tocopheryl polyethylene glycol 1000 succinate mixed micelle-loaded paclitaxel, cells on stiff substrates of 7, 20, and 25 kPa showed higher cell apoptosis rates as compared to those of cells on 1 kPa substrates. To sum up, our work presents an example of how physical cues impact specific cellular behavior and function, which may further contribute to engineering nanoparticulate delivery systems for more efficient delivery in vivo. PMID- 28718279 TI - Complex Annulations through Silver Carbenoid Intermediate: An Alternative Entry to Transformations of 1,2,3-Triazoles. AB - An alternative entry to transformations of N-sulfonyl-4-(2-(ethynyl)aryl)-1,2,3 triazoles with various generated in situ or external nucleophiles by means of silver catalysis for producing diverse functionalized isoquinolines is described. Mechanistically, the reaction is proposed to involve a key silver carbenoid intermediate, thus enabling the formation of multiple chemical bonds via ring opening, N2 extrusion, silver carbenoid formation, nucleophilic addition, and complex annulations cascades. PMID- 28718280 TI - Contact Effect of ReS2/Metal Interface. AB - Rhenium disulfide (ReS2) has attracted immense interest as a promising two dimensional material for optoelectronic devices owing to its outstanding photonic response based on its energy band gap's insensitivity to the layer thickness. Here, we theoretically calculated the electrical band structure of mono-, bi-, and trilayer ReS2 and experimentally found the work function to be 4.8 eV, which was shown to be independent of the layer thickness. We also evaluated the contact resistance of a ReS2 field-effect transistor using a Y-function method with various metal electrodes, including graphene. The ReS2 channel is a strong n-type semiconductor, thus a lower work function than that of metals tends to lead to a lower contact resistance. Moreover, the graphene electrodes, which were not chemically or physically bonded to ReS2, showed the lowest contact resistance, regardless of the work function, suggesting a significant Fermi-level pinning effect at the ReS2/metal interface. In addition, an asymmetric Schottky diode device was demonstrated using Ti or graphene for ohmic contacts and Pt or Pd for Schottky contacts. The ReS2-based transistor used in this study on the work function of ReS2 achieved the possibility of designing the next-generation nanologic devices. PMID- 28718281 TI - Long Distance Modulation of Disorder-to-Order Transitions in Protein Allostery. AB - Elucidation of the molecular details of allosteric communication between distant sites in a protein is key to understanding and manipulating many biological regulatory processes. Although protein disorder is acknowledged to play an important thermodynamic role in allostery, the molecular mechanisms by which this disorder is harnessed for long distance communication are known for a limited number of systems. Transcription repression by the Escherichia coli biotin repressor, BirA, is allosterically activated by binding of the small molecule effector biotinoyl-5'-AMP. The effector acts by promoting BirA dimerization, which is a prerequisite for sequence-specific binding to the biotin biosynthetic operon operator sequence. A 30 A distance separates the effector binding and dimerization surfaces in BirA, and previous studies indicate that allostery is mediated, in part, by disorder-to-order transitions on the two coupled sites. In this work, combined experimental and computational methods have been applied to investigate the molecular basis of allosteric communication in BirA. Double mutant cycle analysis coupled with thermodynamic measurements indicates functional coupling between residues in disordered loops on the two distant surfaces. All atom molecular dynamics simulations reveal that this coupling occurs through long distance reciprocal modulation of the structure and dynamics of disorder-to-order transitions on the two surfaces. PMID- 28718282 TI - Metal-Free Three-Component Regioselective Aminofluorination of Styrene Derivatives. AB - The first metal-free, three-component radical aminofluorination of styrene derivatives has been developed, which employs Selectfluor as a fluorine source and azole derivatives as a nitrogen source. This transformation proceeds with high regioselectivity, providing various 1,2-aminofluorination compounds under mild conditions. Mechanistic studies suggest that the aminofluorination process might involve radical fluorination followed by nucleophilic amination. PMID- 28718283 TI - The Disordered Linker in p53 Participates in Nonspecific Binding to and One Dimensional Sliding along DNA Revealed by Single-Molecule Fluorescence Measurements. AB - The tumor suppressor p53 is a multidomain transcription factor that can quickly bind to its target DNA by sliding along the DNA strand. We hypothesized that the intrinsically disordered and positively charged linker of p53 regulates its search dynamics first by directly interacting with DNA and second by modulating hopping of the core domain. To test the two hypotheses, we prepared five variants of p53 in which the length and charge of the linker were modulated. The affinity for and sliding along nonspecific DNA of p53 were altered by the charge of the linker, but not by the linker length. In particular, charge neutralization significantly reduced the affinity, suggesting that the linker directly contacts the DNA. Charge neutralization eliminated the slow mode of sliding, in which the core domain was assumed to contact nonspecific DNA. In contrast, the affinity of p53 for the target DNA was not affected by linker mutations. These results demonstrate that the linker participates in a target search of p53 by contacting nonspecific DNA and recruiting the core domain to contact DNA. PMID- 28718284 TI - Achieving Site Selectivity in Metal-Catalyzed Electron-Rich Carbene Transfer Reactions from N-Tosylhydrazones. AB - Catalyst control of the site-selectivity of electron-rich alkyl, aryl disubstituted carbenes generated in situ from o-alkenyl-substituted N tosylhydrazones was achieved in this study. Exposure of these substrates to copper iodide triggered the formation of alpha-alkoxy 2H-naphthalenones. This investigation established that changing the catalyst to a rhodium(II) carboxylate turned off cyclization and migration of the electron-rich metal carbene with the beta-carboxylate and turned on allylic C-H bond functionalization to diastereoselectively afford 1H-indenes. Examination of the scope of this reaction revealed that ethereal, aminomethylene, and unactivated 2 degrees C-H bonds could be functionalized. PMID- 28718285 TI - Strong Blue Emissive Supramolecular Self-Assembly System Based on Naphthalimide Derivatives and Its Ability of Detection and Removal of 2,4,6-Trinitrophenol. AB - Two simple and novel gelators (G-P with pyridine and G-B with benzene) with different C-4 substitution groups on naphthalimide derivatives have been designed and characterized. Two gelators could form organogels in some solvents or mixed solvents. The self-assembly processes of G-P in a mixed solvent of acetonitrile/H2O (1/1, v/v) and G-B in acetonitrile were studied by means of electron microscopy and spectroscopy. The organogel of G-P in the mixed solvent of acetonitrile/H2O (1/1, v/v) formed an intertwined fiber network, and its emission spectrum had an obvious blue shift compared with that of solution. By contrast, the organogel of G-B in acetonitrile formed a straight fiber, and its emission had an obvious red shift compared with that of solution. G-P and G-B were employed in detecting nitroaromatic compounds because of their electron-rich property. G-P is more sensitive and selective toward 2,4,6-trinitrophenol (TNP) compared with G-B. The sensing mechanisms were investigated by 1H NMR spectroscopic experiments and theoretical calculations. From these experimental results, it is proposed that electron transfer occurs from the electron-rich G-P molecule to the electron-deficient TNP because of the possibility of complex formation between G-P and TNP. The G-P molecule could detect TNP in water, organic solvent media, as well as using test strips. It is worth mentioning that the organogel G-P can not only detect TNP but also remove TNP from the solution into the organogel system. PMID- 28718286 TI - Functionalized Selenium Nanosystem as Radiation Sensitizer of 125I Seeds for Precise Cancer Therapy. AB - Although radiotherapy has been extensively applied in cancer treatment, external beam radiation therapy is still unable to avoid damage to adjacent normal tissues in the process of delivering a sufficient radiation dose to the tumor sites of patients. To overcome this limitation, chemoradiotherapy, as a combination of chemotherapy and radiotherapy of a radioactive seed, has been proposed to decrease the damage to tumor-surrounding tissues and enhance the radiosensitivity of solid tumors. In this study, we designed and synthesized folic acid-conjugated selenium nanoparticles (FA@SeNPs) as a cancer-targeting agent that could be synergistically enhanced by radioactive 125I seeds to realize anticancer efficacy and inhibited colony formation ability. Interestingly, when compared with X-ray irradiation, 125I seeds demonstrate a larger synergistic effect with the FA@SeNPs, drastically increasing reactive oxygen species overproduction to trigger apoptosis and influencing the cell cycle distribution in human breast cancer cells, inducing DNA damage and activating the mitogen-activated protein kinase and p53 signaling pathways. Moreover, this combination treatment demonstrates better in vivo antitumor activity and lower systemic toxicity. Therefore, this study demonstrates a new strategy for using functionalized SeNPs as a radiation sensitizer for 125I seeds for cancer therapy. PMID- 28718287 TI - Preparation of 3-Iodoquinolines from N-Tosyl-2-propynylamines with Diaryliodonium Triflate and N-Iodosuccinimide. AB - 4-Aryl and 4-alkyl substituted 3-iodoquinolines could be smoothly obtained in one pot by treating N-tosyl-2-propynylamines with diaryliodonium triflate in the presence of K3PO4 and a catalytic amount of CuCl at room temperature, followed by treatment with N-iodosuccinimide and BF3.OEt2 at 0 degrees C, and then NaOH in methanol solution. The product, 3-iodo-4-phenylquinoline was smoothly transformed into 4-phenylquinoline with zinc; 4-phenyl-3-toluenesulfenylquinoline with toluenethiol, K2CO3, and CuI; 4-phenyl-3-phenylethynylquinoline with the Sonogashira coupling reaction; 4-phenyl-3-styrylquinoline with the Heck coupling reaction; 3,4-diphenylquinoline with the Suzuki-Miyaura coupling reaction; 2 cyclohexyl-3-iodo-4-phenylquinoline with cyclohexanecarboxylic acid, Ag2CO3, and K2S2O8; and 3-iodo-2-(2',5'-dioxan-1'-yl)-4-phenylquinoline with benzoyl peroxide in dioxane. PMID- 28718288 TI - Iminocyclohexadienylidenes: Carbenes or Diradicals? The Hetero-Wolff Rearrangement of Benzotriazoles to Cyanocyclopentadienes and 1H-Benzo[b]azirines. AB - The thermal rearrangements of benzotriazole 1 to fulvenimine 4 and 1H-benzazirine 7 are investigated at DFT and CASPT2 levels of theory. Ring opening of benzotriazole 1 to 2-diazo-cyclohexadienimine 2 followed by N2 elimination affords Z- and E-2-iminocyclohexadienylidenes 3, which have triplet ground states (3A"). The open-shell singlet (OSS) (1A") and closed-shell singlet (CSS) (1A') of 3 lie ~15 and 40 kcal/mol higher in free energy, respectively. The OSS 3 (1A") is best described as a 1,3-diradical, whereas the CSS (1A') has the character of a carbene. A hetero-Wolff rearrangement of OSS 3 yields fulvenimine 4, which is a precursor of cyanocyclopentadiene 5, with a calculated activation barrier of 38 kcal/mol at the CASPT2(8,8) level, whereby there is a surface crossing from the OSS to the CSS near the transition state. The barrier for cyclization to 1H benzo[b]azirine 7 is only ~13 kcal/mol. Therefore, reaction paths involving the singlet iminocyclohexadienylidene diradicals 3 will necessarily cause equilibration with 1H-benzazirine 7 prior to ring contraction to iminofulvene 4 and cyanocyclopentadiene 5, in agreement with experimental observations based on 13C labeling. The thermolysis of 1-acetylbenzotriazole 7 leads to the analogous N acetyl-diazocyclohexadienimines 8, N-acetyliminocyclohexadienylidene diradicals 9, and N-acetylfulvenimine 10. The E-N-acetyliminocyclohexadienylidene E9 ring closes to the N-acetyl-1H-benzazirine 11 prior to ring contraction to N acetylfulvenimine 10, and the Z-N-acetyl-2-diazocyclohexadienimine Z8 ring closes to 2-methylbenzoxazole 12. 1H-benzazirines are predicted to be spectroscopically observable species. PMID- 28718289 TI - Catalyst-Free "On-Water" Regio- and Stereospecific Ring-Opening of Spiroaziridine Oxindole: Enantiopure Synthesis of Unsymmetrical 3,3'-Bisindoles. AB - A catalyst-free water-mediated regio- and stereospecific ring-opening reaction of nonracemic spiroaziridine oxindoles and indoles has been developed with retention of configuration. This method provides direct access to enantiopure 3,3'-mixed bisindoles with excellent yield and enantioselectivity (up to 98% ee). PMID- 28718290 TI - Enhanced Long-term and Thermal Stability of Polymer Solar Cells in Air at High Humidity with the Formation of Unusual Quantum Dot Networks. AB - Due to the practical applications of polymer solar cells (PSCs), their stability recently has received increasing attention. Herein, a new strategy was developed to largely enhance the long-term and thermal stability of PSCs in air with a relatively high humidity of 50-60% without any encapsulation. In this strategy, semiconductor PbS/CdS core/shell quantum dots (QDs) were incorporated into the photoactive blend of poly(3-hexylthiophene) (P3HT) and phenyl-C61-butyric acid methyl ester (PCBM). By replacing the initial ligands of oleic acid with halide ligands on the surface of PbS/CdS QDs via solution-phase ligand exchange, we were able to form unusual, continuous QD networks in the film of P3HT:PCBM, which effectively stabilized the photoactive layer. Air-processed PSCs based on the stabilized P3HT:PCBM film showed excellent long-term stability under high humidity, providing over 3% of power conversion efficiency (PCE) simultaneously. Around 91% of pristine PCE was retained after 30 days storage in high-humidity air without encapsulation. This constitutes a remarkable improvement compared to ~53% retained PCE for the QD-free devices, which can be ascribed to the efficient suppression of both PCBM aggregation and oxidation of the thiophene ring in P3HT, thanks to the formation of robust QD networks. Furthermore, the presence of QD networks was able to enhance the stability of the P3HT:PCBM film against thermal stress/oxidation under high-humidity environment (50-60%) as well. The device kept 60% of pristine PCE after thermal treatment for 12 h at 85 degrees C in air, which is more than twice higher than that for the QD-free device. To the best of our knowledge, the work represents the first unambiguous demonstration of the formation of QD networks in the photoactive layer and of their important contribution to the stability of PSCs. This strategy is highly promising for other fullerene-based PSCs and opens a new avenue toward achieving PSCs with high PCE and excellent stability. PMID- 28718291 TI - Porous Structured Ni-Fe-P Nanocubes Derived from a Prussian Blue Analogue as an Electrocatalyst for Efficient Overall Water Splitting. AB - Exploring nonprecious metal electrocatalysts to replace the noble metal-based catalysts for full water electrocatalysis is still an ongoing challenge. In this work, porous structured ternary nickel-iron-phosphide (Ni-Fe-P) nanocubes were synthesized through one-step phosphidation of a Ni-Fe-based Prussian blue analogue. The Ni-Fe-P nanocubes exhibit a rough and loose porous structure on their surface under suitable phosphating temperature, which is favorable for the mass transfer and oxygen diffusion during the electrocatalysis process. As a result, Ni-Fe-P obtained at 350 degrees C with poorer crystallinity offers more unsaturated atoms as active sites to expedite the absorption of reactants. Additionally, the introduction of nickel improved the electronic structure and then reduced the charge-transfer resistance, which would result in a faster electron transport and an enhancement of the intrinsic electrocatalytic activities. Benefiting from the unique porous nanocubes and the chemical composition, the Ni-Fe-P nanocubes exhibit excellent hydrogen evolution reaction and oxygen evolution reaction activities in alkaline medium, with low overpotentials of 182 and 271 mV for delivering a current density of 10 mA cm-2, respectively. Moreover, the Ni-Fe-P nanocubes show outstanding stability for sustained water splitting in the two-electrode alkaline electrolyzer. This work not only provides a facile approach for designing bifunctional electrocatalysts but also further extends the application of metal-organic frameworks in overall water splitting. PMID- 28718292 TI - Structural Characterization of Ordered, Non-Close-Packed Functionalized Silica Nanoparticles on Gold Surfaces. AB - Nanostructured surfaces play an important role in modern science and technology. In particular, ordered arrangements of nonclose-packed nanoparticles created by self-assembly offer a versatile route to prepare systems, which can be used in various applications such as sensing, plasmonic devices or antireflection coatings. Self-assembly based systems are particularly appealing as preparation is rather simple. The ability of nanoparticle systems to form nonclosed packed monolayers by self-assembly depends on the balance of various energetic contributions in particular the adsorption energy, the lateral barrier for diffusion and the repulsion between particles. Even for simple model systems such as the monodispersed silica particles adsorbed on a bare gold surface investigated here, none of these quantities is easy to determine experimentally. To this end, we will report on a detailed characterization of the adsorption in particular with respect to the structural properties of the above-mentioned model system. Based on experimental results obtained by using quartz crystal microbalance with dissipation monitoring (QCM-D) as well as scanning electron microscopy (SEM) it is possible to determine the electrostatic pair potential from the lateral arrangement of the nano particles in the limit of low coverage. PMID- 28718293 TI - Functional Design of Dielectric-Metal-Dielectric-Based Thin-Film Encapsulation with Heat Transfer and Flexibility for Flexible Displays. AB - In this study, a new and efficient dielectric-metal-dielectric-based thin-film encapsulation (DMD-TFE) with an inserted Ag thin film is proposed to guarantee the reliability of flexible displays by improving the barrier properties, mechanical flexibility, and heat dissipation, which are considered to be essential requirements for organic light-emitting diode (OLED) encapsulation. The DMD-TFE, which is composed of Al2O3, Ag, and a silica nanoparticle-embedded sol gel hybrid nanocomposite, shows a water vapor transmission rate of 8.70 * 10-6 g/m2/day and good mechanical reliability at a bending radius of 30 mm, corresponding to 0.41% strain for 1000 bending cycles. The electrical performance of a thin-film encapsulated phosphorescent organic light-emitting diode (PHOLED) was identical to that of a glass-lid encapsulated PHOLED. The operational lifetimes of the thin-film encapsulated and glass-lid encapsulated PHOLEDs are 832 and 754 h, respectively. After 80 days, the thin-film encapsulated PHOLED did not show performance degradation or dark spots on the cell image in a shelf lifetime test. Finally, the difference in lifetime of the OLED devices in relation to the presence and thickness of a Ag film was analyzed by applying various TFE structures to fluorescent organic light-emitting diodes (FOLEDs) that could generate high amounts of heat. To demonstrate the difference in heat dissipation effect among the TFE structures, the saturated temperatures of the encapsulated FOLEDs were measured from the back side surface of the glass substrate, and were found to be 67.78, 65.12, 60.44, and 39.67 degrees C after all encapsulated FOLEDs were operated at an initial luminance of 10 000 cd/m2 for sufficient heat generation. Furthermore, the operational lifetime tests of the encapsulated FOLED devices showed results that were consistent with the measurements of real-time temperature profiles taken with an infrared camera. A multifunctional hybrid thin-film encapsulation based on a dielectric-metal dielectric structure was thus effectively designed considering the transmittance, gas-permeation barrier properties, flexibility, and heat dissipation effect by exploiting the advantages of each separate layer. PMID- 28718294 TI - Impact of Social Integration and Living Arrangements on Korean Older Adults' Depression: A Moderation Model. AB - Depression among older adults is a challenging public health concern in Korea. Using panel data from the Korea Institute for Health and Social Affairs on Korean older adults and their family caregivers, this study explores significant predictors of depression among Korean older adults as well as the moderating effect of living arrangements on the association between social integration and depression. A multivariate logistic regression analysis showed that preexisting depression was the most significant predictor of Korean older adults' current depression, followed by health status and family support. In addition, social integration significantly decreased Korean older adults' depression. Importantly, a significant moderation effect of living arrangements between Korean older adults' social integration and depression was observed. This study implies the development of individually tailored and culturally responsive programs to engage marginalized Korean older adults living alone, helping foster their well-being and optimal aging. PMID- 28718295 TI - Accelerometer-Determined Physical Activity and All-Cause Mortality in a National Prospective Cohort Study of Adults Post-Acute Stroke. AB - PURPOSE: No epidemiological study has examined the association of objectively measured physical activity with all-cause mortality among adults who have had a stroke, which was the purpose of this study. DESIGN: Prospective. SETTING: National Health and Nutrition Examination Survey 2003 to 2006. PARTICIPANTS: One hundred eighty-four patients with stroke. MEASURES: Physical activity assessed via accelerometry (ActiGraph 7164), with stroke assessed via self-report of physician diagnosis. Mortality was assessed via linkage with the National Death Index, with follow-up through 2011. ANALYSIS: Cox proportional hazard model. RESULTS: The median follow-up period was 71.96 months, with 13 241 person-months; 53 deaths occurred during this follow-up period. After adjustments, for every 60 min/d increase in total physical activity, adults who have had a stroke had a 28% (hazard ratio = 0.72; 95% confidence interval: 0.59-0.88) reduced risk of all cause mortality. CONCLUSION: Physical activity among stroke survivors is inversely associated with all-cause mortality. PMID- 28718296 TI - Real-Life Management of Venous Thromboembolism With Rivaroxaban: Results From EXperience VTE, an Italian Epidemiological Survey. AB - Two large randomized controlled trials examined the efficacy and safety of rivaroxaban for the treatment of venous thromboembolism (VTE). The aim of this epidemiological study was to analyze a cohort of Italian patients affected by VTE who were treated with rivaroxaban in clinical practice. The data were collected by physicians using an online electronic questionnaire. The study was performed during a 6-month period from January to June 2014. We analyzed the clinical characteristics, risk factors for VTE, comorbidities, diagnostic techniques, and treatments in the whole population and in the subgroups with deep vein thrombosis (DVT) only, pulmonary embolism (PE) only, and DVT+PE. Overall, 75.9% of patients were affected by DVT; 20% of patients had DVT and PE; and 4.8% of patients had only PE. Approximately 90% of patients were symptomatic upon diagnosis, and 46.3% of patients required hospitalization. More than half of the patients switched to rivaroxaban after receiving another anticoagulant therapy. The main reasons for changing treatment included difficulties in managing vitamin K antagonists, patient choice, and prothrombin time-international normalized ratio (PT-INR) instability. The switch to rivaroxaban occurred after a mean of 1.8 PT-INR measurements. Clinical characteristic were overall similar to those of patients enrolled in prior clinical trials evaluating the safety and efficacy of rivaroxaban. PMID- 28718297 TI - Determination of Aerobic Capacity via Cycle Ergometer Exercise Testing in Alzheimer's Disease. AB - BACKGROUND: Older adults with Alzheimer's disease (AD) may be unable to perform treadmill testing due to balance issues. We investigated whether older adults with AD could successfully complete a peak cycle ergometer test. METHODS: Peak oxygen consumption (peak [Formula: see text]) assessed via a cycle ergometer test in 44 participants with AD (age 78.4 +/- 6.8). Physical function was assessed via the incremental shuttle walk, 6-minute walk, and the Short Physical Performance Battery (SPPB). RESULTS: All participants completed the cycle ergometer test successfully. Peak [Formula: see text] was correlated with SPPB ( r = .35, P = .023), shuttle walk ( r = .35, P = .024), 6-minute walk ( r = .31, P = .05), and inversely with age ( r = -.4, P = .009). There was no correlation between peak [Formula: see text] and cognition. CONCLUSION: Older adults with AD are able to safely complete a peak cycle ergometer exercise testing protocol. We provide an individualized cycle ergometer test for determining aerobic capacity in older adults with AD who may be unable to perform treadmill testing due to balance or gait issues. PMID- 28718298 TI - A systematic review of the prevalence of comorbid cancer and dementia and its implications for cancer-related care. AB - OBJECTIVES: A comorbid diagnosis of cancer and dementia (cancer-dementia) may have unique implications for patient cancer-related experience. The objectives were to estimate prevalence of cancer-dementia and related experiences of people with dementia, their carers and cancer clinicians including cancer screening, diagnosis, treatment and palliative care. METHOD: Databases were searched (CINAHL, Psychinfo, Medline, Embase, BNI) using key terms such as dementia, cancer and experience. Inclusion criteria were as follows: (a) English language, (b) published any time until early 2016, (c) diagnosis of cancer-dementia and (d) original articles that assessed prevalence and/or cancer-related experiences including screening, cancer treatment and survival. Due to variations in study design and outcomes, study data were synthesised narratively. RESULTS: Forty seven studies were included in the review with a mix of quantitative (n = 44) and qualitative (n = 3) methodologies. Thirty-four studies reported varied cancer dementia prevalence rates (range 0.2%-45.6%); the others reported reduced likelihood of receiving: cancer screening, cancer staging information, cancer treatment with curative intent and pain management, compared to those with cancer only. The findings indicate poorer cancer-related clinical outcomes including late diagnosis and higher mortality rates in those with cancer-dementia despite greater health service use. CONCLUSIONS: There is a dearth of good-quality evidence investigating the cancer-dementia prevalence and its implications for successful cancer treatment. Findings suggest that dementia is associated with poorer cancer outcomes although the reasons for this are not yet clear. Further research is needed to better understand the impact of cancer-dementia and enable patients, carers and clinicians to make informed cancer-related decisions. PMID- 28718299 TI - Felt Age, Desired, and Expected Lifetime in the Context of Health, Well-Being, and Successful Aging. AB - This study examines the interrelations of three different aspects of the subjective age: felt, desired and expected, as well as their relations with the chronological age (CA), health, and psychological well-being variables. Four hundred and twenty-three community-dwelling Croatian adults, aged 60-95 years, participated in the study. All three subjective age measures significantly correlated with the CA. Self-rated health were better predictors of the subjective age compared to the psychological variables. Among psychological variables, successful aging was the only significant predictor of the felt and expected age, while optimism showed to be the only significant predictor of the desired age. Results indicate the importance of some sociodemographic, psychological, and health variables for understanding older persons' subjective age identity and their desires and expectations regarding length of life. Besides the CA, it is very useful to include subjective age measures in research with elderly people. PMID- 28718300 TI - Clinical Aspects of Systemic Inflammation and Arrhythmogenesis, Especially Atrial Fibrillation. PMID- 28718302 TI - Cardiovascular Risk Factors Among Patients With Vestibular Neuritis. AB - OBJECTIVE: To investigate the correlation between cardiovascular risk factors (CVRFs) and vestibular neuritis (VN) in hospitalized adult patients. METHODS: A cross-sectional retrospective study was conducted in a tertiary hospital setting. The medical records of patients (aged over 18 years old) who were hospitalized between the years 2005 and 2014 with the diagnosis of VN were retrieved. Inclusion criteria were: (1) acute vertigo lasting for at least 24 hours, (2) absence of auditory complaints, (3) horizontal unidirectional nystagmus present during physical examination, and (4) absence of neurological symptoms or signs. The ratio of CVRFs among VN patients was compared to the ratio of those among the general Israeli population. RESULTS: A significantly higher prevalence of CVRFs was found among VN hospitalized patients in comparison to the general population ( P < .05). Furthermore, a significant correlation ( P < .001) was found between the patients' age and the number of CVRFs (r = .387). A positive correlation (r = .643) was found between the number of CVRFs and VN in each age group ( P = .119). CONCLUSION: There may be a possible interrelation between CVRFs and VN. This correlation can be caused by occlusion of small blood vessels leading to labyrinthine ischemia and apparition of symptoms of VN. PMID- 28718301 TI - Web addiction in the brain: Cortical oscillations, autonomic activity, and behavioral measures. AB - Background and aims Internet addiction (IA) was recently defined as a disorder tagging both the impulse control and the reward systems. Specifically, inhibitory deficits and reward bias were considered highly relevant in IA. This research aims to examine the electrophysiological correlates and autonomic activity [skin conductance response (SCR) and heart rate] in two groups of young subjects (N = 25), with high or low IA profile [tested by the Internet Addiction Test (IAT)], with specific reference to gambling behavior. Methods Oscillatory brain activity (delta, theta, alpha, beta, and gamma) and autonomic and behavioral measures [response times (RTs) and error rates (ERs)] were acquired during the performance of a Go/NoGo task in response to high-rewarding (online gambling videos and video games) or neutral stimuli. Results A better performance (reduced ERs and reduced RTs) was revealed for high IAT in the case of NoGo trials representing rewarding cues (inhibitory control condition), probably due to a "gain effect" induced by the rewarding condition. In addition, we also observed for NoGo trials related to gambling and video games stimuli that (a) increased low-frequency band (delta and theta) and SCR and (b) a specific lateralization effect (more left-side activity) delta and theta in high IAT. Discussion Both inhibitory control deficits and reward bias effect were considered to explain IA. PMID- 28718303 TI - Benign Paroxysmal Positional Vertigo: Management and Its Impact on Falls. AB - INTRODUCTION: Benign paroxysmal positional vertigo (BPPV) is the most common cause of dizziness in the elderly. This has been identified as a risk factor in falls. Falls are the leading cause of disability and the leading cause of death from injury among people over 75 in the UK. METHODS: We assessed the effect of BPPV treatment on falls in an elderly population by retrospectively reviewing one unit's experience of BPPV management over an 8-year period from June 2008 to June 2016. We specifically assessed patients who were referred for the primary reason of falls and were aged over 65 years. These patients were evaluated and treated with particle repositioning maneuvers if their positional tests were positive. The frequency of falls prior to their visit and at 6-month clinic follow-up were reviewed. RESULTS: The total number of falls in the cohort reduced significantly ( P < .0001) after the procedure, from 128 to 46 falls (64% reduction). Associated comorbidities were also evaluated in this group. CONCLUSION: A prompt and effective treatment of BPPV is prudent to prevent devastating falls in older people in our communities. PMID- 28718304 TI - The role of surgery in low-grade gliomas: do timing and extent of resection matter? AB - Hugues Duffau is a Professor and Chairman of the Neurosurgery Department in the Montpellier University Medical Center and Head of the INSERM 1051 Team "plasticity of the central nervous system, human stem cells and glial tumors" at the Institute for Neurosciences of Montpellier (France). He is an expert in the awake cognitive neurosurgery of slow-growing brain tumors, such as low-grade gliomas, a routine which he has developed since 20 years. His fundamental approach is centered on the concepts of the brain connectomics and neuroplasticity, breaking with the traditional localizationist view of cerebral processing. For his innovative work in neurosurgery and neurosciences, he was awarded Doctor Honoris Causa several times, and he was the youngest recipient of the prestigious Herbert Olivecrona Award from the Karolinska Institute in Stockholm. He has written four textbooks and over 335 publications in international journals ranging from neurosurgery to fundamental neurosciences, including cognitive sciences and brain plasticity for a total of more than 20,800 citations and with an h-index of 77. He is a member of editorial boards of many journals (as brain and language, neurosurgery or neuro-oncology) and ad hoc reviewer for around 100 journals (over 900 reviews) including: New England Journal of Medicine, Lancet Oncology, Nature Medicine, Nature Reviews Neuroscience, Nature Reviews Neurology; Annals of Neurology, Brain, Cerebral Cortex, Trends in Cognitive Science, Current Biology, among others. He is a member of many societies: member of the French Academy of Medicine, member of the French Academy of Surgery, member of the World Academy of Neurological Surgery, member of the Young Neurosurgeons Award Committee of the World Federation of Neurosurgical Societies, member of the Scientific Committee of the European Association for Neuro-oncology, etc. PMID- 28718306 TI - Our panel of experts highlights the most important research articles across the spectrum of topics relevant to the field of CNS oncology. PMID- 28718305 TI - Outcome evaluation of patients with newly diagnosed anaplastic gliomas treated in a single institution. AB - AIM: To evaluate the outcome of newly diagnosed anaplastic glioma patients treated in our institution in relation to the 2016 WHO classification suggestions. METHODS: This retrospective study included patients who underwent surgery plus adjuvant chemotherapy alone or concomitant and adjuvant chemoradiotherapy. Response was recorded using the Response Assessment in Neuro Oncology criteria. RESULTS: 123 patients were analyzed. The median progression free survival time and the 2, 3 and 5 years progression-free survival rate were 27 months, 65.5, 21.2 and 21.2%; the 2, 3 and 5 years overall survival rate were 89.7, 83.0 and 58.4%. From the univariate/multivariate analysis, the factors conditioning survival were Karnofsky performance scale, extent of resection, IDH1 mutation status and presence of 1p/19q codeletion. CONCLUSION: The choice of adjuvant treatment have to consider molecular assessment and, in our experience, the extent of surgical resection. PMID- 28718307 TI - Late post-treatment radiographic changes 3 years following chemoradiation for glioma: the importance of histopathology. AB - Treatment-related changes can mimic brain tumor progression both clinically and radiographically. Distinguishing these two entities represents a major challenge in neuro-oncology. No single imaging modality is capable of reliably achieving such distinction. While histopathology remains the gold standard, definitive pathological criteria are also lacking which can further complicate such cases. We report a patient with high-grade glioma who, after initially presenting with histopathologically confirmed pseudoprogression 10 months following treatment, re presented 3 years following concurrent chemoradiation with clinical and radiographic changes that were most consistent with progressive disease but for which histopathology revealed treatment effects without active glioma. This case highlights the potential late onset of treatment-related changes and underscores the importance of histopathologic assessment even years following initial therapy. PMID- 28718308 TI - Ulnar Shortening Versus Distal Radius Corrective Osteotomy in the Management of Ulnar Impaction After Distal Radius Malunion. AB - BACKGROUND: Distal radius malunions lead to functional deficits. This study compares isolated ulnar shortening osteotomy (USO) to distal radius osteotomy (DRO) for the treatment of ulnar impaction syndrome following distal radius malunion. METHODS: We retrospectively reviewed 11 patients with extra-articular distal radius malunions treated for ulnar impaction with isolated USO. This group was compared to a 1:1 age- and sex-matched cohort treated with isolated DRO for the same indication. Pain visual analog scale (VAS), wrist motion, grip strength, radiographic parameters, and perioperative complications were analyzed. Mean follow-up was 14.8 months. RESULTS: VAS scores improved. Wrist range of motion improved in both cohorts with the exception of radial deviation, pronation, and supination in the USO cohort, which decreased from a mean of 17 degrees -16 degrees , 67 degrees -57 degrees , and 54 degrees -52 degrees , respectively. There was no significant difference between groups in regard to change in pain or range of motion, with the exception of pronation and ulnar deviation. The mean tourniquet time was shorter in the USO group. The final ulnar variance was 1.8 mm negative in the USO group and 1.1 mm positive in the DRO group. There was 1 reoperation following USO for painful nonunion, while there were 2 reoperations following DRO for persistent ulnar impaction. CONCLUSIONS: An improvement in range of motion, grip strength, and VAS with restoration of the radioulnar length relationship was observed in both cohorts. USO is a simpler procedure with a shorter tourniquet time that can be an attractive alternative to DRO for ulnar impaction syndrome after distal radius malunions. PMID- 28718309 TI - Intra-Articular Fracture of the Base of the First Metacarpal Bone: Treatment Through a Volar Approach. AB - BACKGROUND: Management of Bennett fractures has been controversial. Early reports supported closed reduction and casting with or without percutaneous pinning. Later, open reduction and internal fixation was advocated. The purpose of this article is to assess the surgical treatment using a direct volar approach. METHODS: Between March 2008 and December 2014, 21 patients with intra-articular first metacarpal fractures displaced more than 1 mm were operated on using a direct volar approach. Fixation was done with micro-screws or K-wires, always placed from ulnar to radial during thumb supination. The articular step-off, secondary displacement incidence and consolidation rate time were measured. At final follow-up, we assessed the thumbs for range of motion, residual pain, and grip strength. Sensitive areas around the scar were evaluated. Mean follow-up was 8 months. RESULTS: Anatomical reduction was achieved in all cases. One secondary displacement was registered. The mean distance between the tip of the thumb and the fifth metacarpophalangeal joint was less than 10 mm; reposition was complete. Mean palmar abduction was 63 degrees . Grip strength averaged 84.6% of the opposite side. The mean visual analog scale score was 0. No sensory disturbances around the scar were recorded. CONCLUSIONS: The complete visualization of the first metacarpal articular surface is hard to accomplish from the dorsoradial aspect of the hand. The volar approach offers an excellent fracture exposure. It is possible to place the osteosynthesis in ulna-radial fashion from the smaller fragment achieving correct reduction and stabilization. In spite of the proximity to the radial and median nerve branches, we found no complications. PMID- 28718310 TI - Comparison of Computed Tomography Articular Surface Geometry of Male Versus Female Thumb Carpometacarpal Joints. AB - BACKGROUND: Given the predilection of first carpometacarpal (CMC) joint osteoarthritis in women compared with men, we aim to determine the differences in first CMC joint surface geometry and congruence between young healthy males and females. METHODS: Wrist computed tomographic scan data of 11 men and 11 women aged 20 to 35 years were imported into 3-dimensional software programs. The first metacarpal and the trapezium were aligned in a standardized position according to landmarks at key points on Gaussian and maximum curvature maps. Measurements of joint congruence and surface geometry were analyzed, including joint space volume, distance between the bones at the articular surface edges, area of the joint space, and radii of curvature in the radial-ulnar and volar-dorsal planes. RESULTS: The mean thumb CMC articular space volume was 104.02 +/- 30.96 mm3 for females and 138.63 +/- 50.36 mm3 for males. The mean first metacarpal articular surface area was 144.9 +/- 10.9 mm2 for females and 175.4 +/- 25.3 mm2 for males. After normalizing for size, the mean thumb CMC articular space volume was 119.4 +/- 24.6 mm3 for females and 117.86 +/- 28.5 mm3 for males. There was also no significant difference for the articular space volume, articular surface distances, articular space, and mean radii of curvatures. CONCLUSIONS: This study found that there are sex differences in the first CMC joint articular volume without normalizing for size; however, there are no sex differences in first CMC joint articular volume, curvature characteristics, or joint congruence of young, healthy patients after normalizing for joint size. PMID- 28718311 TI - A Biomechanical Study of a Novel Asymmetric 6-Strand Flexor Tendon Repair Using Porcine Tendons. AB - BACKGROUND: This study evaluated the biomechanical performance of a novel asymmetric 6-strand flexor tendon repair technique without locking loops. METHODS: Twenty porcine flexor tendons were equally repaired by using the asymmetric technique and compared with the modified Lim-Tsai repair technique. The ultimate tensile strength, load to 1-mm gap force, stiffness, and mechanism of failure were measured. RESULTS: The asymmetric repair technique had significantly higher tensile strength (63.3 +/- 3.7 N) than the modified Lim-Tsai repairs (46.7 +/- 8.3 N). CONCLUSIONS: A novel flexor tendon repair technique with improved biomechanical performance may be available for use in flexor tendon repairs. PMID- 28718312 TI - GBM skin metastasis: a case report and review of the literature. AB - Glioblastoma (GBM) is the most common type of malignant tumor found in the brain, and acts very aggressively by quickly and diffusely infiltrating the surrounding brain parenchyma. Despite its aggressive nature, GBM is rarely found to spread extracranially and develop distant metastases. The most common sites of these rare metastases are the lungs, pleura and cervical lymph nodes. There are also a few case reports of skin metastasis. We present the clinical, imaging and pathologic features of a case of a GBM with metastasis to the soft tissue scar and skin near the original craniotomy site. In addition, we discuss the details of this case in the context of the previously reported literature. PMID- 28718313 TI - Massive Embryonal Rhabdomyosarcoma of the Hand in an Infant With Metastasis at Birth: Management Dilemma. AB - BACKGROUND: Rhabdomyosarcomas are malignant tumors arising from striated muscle but can be often confused with primitive neuroectodermal tumors and Ewing sarcoma. They are often classified based on age of presentation and histological features. Three major types of rhabdomyosarcomas are embryonal, alveolar, and pleomorphic with characteristic presentations. METHOD: Here, we present a case of embryonal rhabdomyosarcoma in the hand of a 5-month-old child with lymphatic metastasis, the age, site, and metastasis being unusual feature for this type of rhabdomyosarcoma. RESULT: The child succumbed to the complications soon after initiation of chemotherapy. CONCLUSION: Age, site, metastasis at birth and treatment related complications contribute to the poor outcome. PMID- 28718314 TI - Techniques of Force and Pressure Measurement in the Small Joints of the Wrist. AB - BACKGROUND: The alteration of forces across joints can result in instability and subsequent disability. Previous methods of force measurements such as pressure sensitive films, load cells, and pressure-sensing transducers have been utilized to estimate biomechanical forces across joints and more recent studies have utilized a nondestructive method that allows for assessment of joint forces under ligamentous restraints. METHODS: A comprehensive review of the literature was performed to explore the numerous biomechanical methods utilized to estimate intra-articular forces. RESULTS: Methods of biomechanical force measurements in joints are reviewed. CONCLUSIONS: Methods such as pressure-sensitive films, load cells, and pressure-sensing transducers require significant intra-articular disruption and thus may result in inaccurate measurements, especially in small joints such as those within the wrist and hand. Non-destructive methods of joint force measurements either utilizing distraction-based joint reaction force methods or finite element analysis may offer a more accurate assessment; however, given their recent inception, further studies are needed to improve and validate their use. PMID- 28718315 TI - Ulnar Styloid Base Fractures Cause Distal Radioulnar Joint Instability in a Cadaveric Model. AB - BACKGROUND: The deep portion of the distal radioulnar ligaments (DRUL) inserts on the ulnar fovea and is the most important stabilizer of the distal radioulnar joint (DRUJ). Ulnar styloid base fractures that include the ulnar fovea may cause DRUJ instability. METHODS: DRUJ stability in pronosupination was evaluated in 12 fresh-frozen upper extremities (4 female) aged 52 to 68 years (mean: 58.8 years) using a custom fixture, which allowed free rotation of the radius around the fixed ulna. Optical motion capture was used to record rotation of the radius with respect to the ulna. Each specimen was subjected to 3 N m of torque in both supination and pronation under 4 conditions: intact, ulnar styloid osteotomy with disruption of the foveal insertion of the DRUL, ulnar styloid fixation, and DRUL transection. Group differences were compared using a 1-way repeated-measures analysis of variance and Tukey multiple comparison post hoc tests. RESULTS: When compared with the intact condition, both ulnar styloid osteotomy and DRUL transection significantly increased mean pronation (by 9.40 degrees and 15.21 degrees , respectively) and supination (by 9.05 degrees and 17.42 degrees , respectively) of the forearm. Screw fixation only significantly reduced pronation compared with osteotomy (by 2.62 degrees ). Screw fixation did not significantly affect supination. CONCLUSIONS: Ulnar styloid fractures that disrupt the fovea cause instability of the DRUJ in pronation and supination under 3 N m of torque in a cadaveric model. Screw fixation of ulnar styloid base fractures achieves anatomic reduction; however, it only partially returns rotational stability acutely to the DRUJ and only during pronation. PMID- 28718316 TI - Predictors of complications and readmission following spinal stereotactic radiosurgery. AB - AIM: to identify preoperative factors associated with morbidity/mortality, hospital length of stay (LOS), 30-day readmission and operation rates following spinal stereotactic radiosurgery (SRS) for spinal tumors. METHODS: The American College of Surgeons National Quality Improvement Program was queried from 2012 to 2014 to identify patients undergoing SRS for spinal tumors. Logistic regression was performed to identify predictors. RESULTS: 2714 patients were identified; 6.8% had major morbidity or mortality, 6.9% were readmitted within 30 days and 4.3% had a subsequent operation within 30 days. Age, BMI and American Society of Anesthesiologist (ASA) class were predictive of LOS. Major morbidity was predicted by age >80, BMI >35, high ASA, pretreatment functional dependence and baseline comorbidities. Predictors of operation within 30 days included preoperative steroid use, renal failure, BMI >35 and if the treatment was nonelective. DISCUSSION: 4-7% of patients undergoing SRS for spinal tumors have morbidity following the procedure. Factors predictive of morbidity, LOS, and subsequent operation included age, BMI, baseline comorbidities and functional status. CONCLUSION: Identification of preoperative patient-specific factors that are predictive of post-treatment outcome will aid in patient selection and patient counseling leading to greater patient satisfaction and hospital efficiency. PMID- 28718317 TI - Hand Surgeons and Orthopedic Trauma Surgeons Call Coverage of Acute Upper Extremity Injuries: Where Should the Line Be Drawn? AB - BACKGROUND: There is a lack of consensus as to which subspecialty service should cover acute upper extremity injuries in the emergency department (ED). The purpose of the present study is to understand how upper extremity injuries are currently triaged to specialists and to assess the current opinion among hand and orthopedic trauma specialists as to how these injuries should be best triaged based on injury location and severity. METHODS: The American Association for Hand Surgery (AAHS) membership and Orthopaedic Trauma Association (OTA) membership were surveyed using a 28-item online questionnaire. RESULTS: A total of 103 responses from the AAHS and 114 responses from the OTA were received. Nearly 50% of the respondents report no formal anatomic line as to how upper extremity injuries are triaged to specialists from the ED. Approximately 57% of the AAHS respondents feel that hand call should begin at the distal radius or proximal, while 71% of the OTA respondents feel that hand call should begin at the radiocarpal joint or distal. There was increasing agreement that more complex injuries be assigned to the hand surgeon. CONCLUSIONS: There is agreement that proximal to the elbow, the trauma consultant should be called, and distal to the distal radius, the hand consultant should be called. However, there is a lack of agreement as to who should be responsible for call between the elbow and the hand. To optimize patient care, better allocate consultant resources, and minimize conflict between consultants, establishing anatomic guidelines for consultation should be considered. PMID- 28718318 TI - High glucose-induced endothelial progenitor cell dysfunction. AB - Vascular complications contribute significantly to morbidity and mortality of diabetes mellitus. The primary cause of vascular complications in diabetes mellitus is hyperglycaemia, associated with endothelial dysfunction and impaired neovascularization. Circulating endothelial progenitor cells was shown to play important roles in vascular repair and promoting neovascularization. In this review, we will demonstrate the individual effect of high glucose on endothelial progenitor cells. Endothelial progenitor cells isolated from healthy subjects exposed to high glucose conditions or endothelial progenitor cells isolated from diabetic patients exhibit reduced number of endothelial cell colony forming units, impaired abilities of differentiation, proliferation, adhesion and migration, tubulization, secretion, mobilization and homing, whereas enhanced senescence. Increased production of reactive oxygen species by the mitochondria seems to play a crucial role in high glucose-induced endothelial progenitor cells deficit. Later, we will review the agents that might be used to alleviate dysfunction of endothelial progenitor cells induced by high glucose. The conclusions are that the relationship between hyperglycaemia and endothelial progenitor cells dysfunction is only beginning to be recognized, and future studies should pay more attention to the haemodynamic environment of endothelial progenitor cells and ageing factors to discover novel treatment agents. PMID- 28718319 TI - Medical Modeling for Precision Ulna Reconstruction Using a Microvascular Fibula Free Flap. AB - BACKGROUND: Despite the growing use of medical modeling in other surgical specialties, its utilization in extremity reconstruction has remained limited. METHODS: We present the application of medical modeling for ulna reconstruction using a microvascular fibula free flap. RESULTS: Following a motor vehicle accident, the patient suffered segmental loss of the right radius and ulna with concomitant forearm soft tissue and muscle loss. Using medical modeling, imaging from the unaffected contralateral forearm and lower extremity was used to plan a reconstruction that restored the anatomic length and orientation of the ulna. Accurate ulna length was recreated from the contralateral ulna, which served as a template. CONCLUSIONS: Cutting guides for the osteotomies on both the fibula and ulna maximized surface contact at the native ulna and fibula junction to aid in osseous healing of the fibula flap, stabilized the fibula orientation on the ulna, and allowed for lag screw placement for additional fixation. PMID- 28718320 TI - Oral prednisolone for 4 days does not increase exercise tolerance in men with COPD. AB - One of the primary objectives in management of chronic obstructive pulmonary disease (COPD) is preventing decrease in lung function and reducing the annual number of acute exacerbations of COPD (AECOPD). An oral course of systemic corticosteroids is a commonly used treatment in AECOPD. We hypothesize that this treatment also increases exercise performance and decreases muscle fatigue. In a randomized double-blinded, parallel, placebo-controlled trial, we investigated 14 men (8 on prednisolone 37.5 mg vs. 6 on placebo) with severe and very severe COPD. For 5 consecutive days, the patients performed a submaximal endurance test measuring time to exhaustion (TTE, primary endpoint), spirometry, maximal inspiratory and expiratory pressure and maximal isometric contraction of the quadriceps femoris muscle (maximum voluntary contraction (MVC)). At visits 2, 3 and 4, a fatigue protocol was carried out after 40 minutes of cycling at 40% of maximal effort. No differences between groups were found for TTE, lung function or maximal inspiratory or expiratory pressure, however, patients on prednisolone showed significant increased MVC: median 5.15 [3.35; 9.15] against placebo: -2 [ 5.57; 3.95] ( p = 0.03). This finding indicates an impact of corticosteroids on muscle groups being exposed to submaximal endurance. PMID- 28718321 TI - Breathlessness services as a new model of support for patients with respiratory disease. AB - The complexity of breathlessness in advanced disease requires a diversity of measures ideally tailored to the individual patient needs. 'Breathlessness services' have been systematically developed and tested to provide specific interventions and support for patients and their carers. The aim of this article is (1) to identify and describe components of breathlessness services and (2) to describe the clinical model of one specific service in more detail. This article is based on a systematic review evaluating randomized controlled trials (RCTs) and quasi-RCTs which examine the effectiveness of services aiming to improve breathlessness of patients with advanced disease. The Munich Breathlessness Service (MBS) is described in detail as an example of a recently set-up specialist service. Five service models were identified which were tested in six RCTs. Services varied regarding structure and composition with face-to-face meetings, some with additional telephone contacts. Service duration was median 6 weeks (range 2-12 weeks). Involved professions were nurses, various therapists and, in two models, also physicians. The breathing-thinking-functioning model was targeted by various service components. The MBS is run by a multi-professional team mainly with physicians and physiotherapists. Patients are seen weekly over 5 6 weeks with an individualized management plan. Breathlessness services are a new model for patients with advanced disease integrating symptom management and early access to palliative care. PMID- 28718322 TI - The PROMIS Global Health Questionnaire Correlates With the QuickDASH in Patients With Upper Extremity Illness. AB - BACKGROUND: The objective of this study is to evaluate the construct validity of the Patient-Reported Outcomes Measurement Information System (PROMIS) Global Health instrument by establishing its correlation to the Quick-Disabilities of the Arm, Shoulder and Hand (QuickDASH) questionnaire in patients with upper extremity illness. METHODS: A cohort of 112 patients completed a sociodemographic survey and the PROMIS Global Health and QuickDASH questionnaires. Pearson correlation coefficients were used to evaluate the association of the QuickDASH with the PROMIS Global Health items and subscales. RESULTS: Six of the 10 PROMIS Global Health items were associated with the QuickDASH. The PROMIS Global Physical Health subscale showed moderate correlation with QuickDASH and the Mental Health subscale. There was no significant relationship between the PROMIS Global Mental Health subscale and QuickDASH. CONCLUSIONS: The consistent finding that general patient-reported outcomes correlate moderately with regional patient reported outcomes suggests that a small number of relatively nonspecific patient reported outcome measures might be used to assess a variety of illnesses. In our opinion, the blending of physical and mental health questions in the PROMIS Global Health makes this instrument less useful for research or patient care. PMID- 28718323 TI - Modern approaches to the management of metastatic epidural spinal cord compression. AB - Metastatic epidural spinal cord compression (MESCC) is an oncologic emergency requiring prompt treatment to maximize neurologic function, ambulatory function and local control. Traditionally, options for MESCC included external beam radiation therapy with or without surgery. Surgery has usually been reserved for the patient with optimal performance status, single level MESCC or mechanical instability. Advances in external beam radiation therapy such as the development of stereotactic body radiation therapy have allowed for the delivery of high-dose radiation, allowing for both long-term pain and local control. Surgical advances, such as separation surgery, minimal access spine surgery and percutaneous instrumentation, have decreased surgical morbidity. This review summarizes the latest advances and evidence in MESCC to enable modern management. PMID- 28718324 TI - Physical Health and Drug Safety in Individuals with Schizophrenia. AB - BACKGROUND: While antipsychotic medications are the mainstay of therapy for individuals with schizophrenia and psychotic disorders, their use is associated with adverse effects on physical health that require the attention and care of prescribers. METHODS: We used the ADAPTE process to adapt existing guideline recommendations from the National Institute for Health and Care Excellence (NICE) and Scottish Intercollegiate Guidelines Network (SIGN) guidelines on the dosing of antipsychotics and antipsychotic polypharmacy, screening for adverse effects of antipsychotics, and management of metabolic and extrapyramidal side effects to the Canadian context. RESULTS: Prescribers are encouraged to use the lowest effective dose and to avoid the routine use of multiple antipsychotics. Scheduled monitoring of body mass index, waist circumference, blood pressure, glucose, lipids, prolactin, electrocardiograms, and extrapyramidal symptoms is recommended. Lifestyle interventions are recommended to mitigate antipsychotic induced weight gain. Prescribers should follow Canadian guidelines on the treatment of obesity, dyslipidemia, and diabetes. Recommendations on antipsychotic drug choice are made for users particularly concerned about extrapyramidal symptoms. CONCLUSION: Careful monitoring and attention by prescribers may mitigate adverse effects associated with antipsychotic medications. PMID- 28718325 TI - Collaborative Care for Psychiatric Disorders in Older Adults: A Systematic Review. AB - OBJECTIVE: To evaluate the mode of implementation, clinical outcomes, cost effectiveness, and the factors influencing uptake and sustainability of collaborative care for psychiatric disorders in older adults. DESIGN: Systematic review. SETTING: Primary care, home health care, seniors' residence, medical inpatient and outpatient. PARTICIPANTS: Studies with a mean sample age of 60 years and older. INTERVENTION: Collaborative care for psychiatric disorders. METHODS: PubMed, MEDLINE, Embase, and Cochrane databases were searched up until October 2016. Individual randomized controlled trials and cohort, case-control, and health service evaluation studies were selected, and relevant data were extracted for qualitative synthesis. RESULTS: Of the 552 records identified, 53 records (from 29 studies) were included. Very few studies evaluated psychiatric disorders other than depression. The mode of implementation differed based on the setting, with beneficial use of telemedicine. Clinical outcomes for depression were significantly better compared with usual care across settings. In depression, there is some evidence for cost-effectiveness. There is limited evidence for improved dementia care and outcomes using collaborative care. There is a lack of evidence for benefit in disorders other than depression or in settings such as home health care and general acute inpatients. Attitudes and skill of primary care staff, availability of resources, and organizational support are some of the factors influencing uptake and implementation. CONCLUSIONS: Collaborative care for depressive disorders is feasible and beneficial among older adults in diverse settings. There is a paucity of studies on collaborative care in conditions other than depression or in settings other than primary care, indicating the need for further evaluation. PMID- 28718326 TI - CNS Anticancer Drug Discovery and Development: 2016 conference insights. AB - CNS Anticancer Drug Discovery and Development November 2016, AZ, USA The 2016 second CNS Anticancer Drug Discovery and Development Conference addressed diverse viewpoints about why new drug discovery/development focused on CNS cancers has been sorely lacking. Despite more than 70,000 individuals in the USA being diagnosed with a primary brain malignancy and 151,669-286,486 suffering from metastatic CNS cancer, in 1999, temozolomide was the last drug approved by the US FDA as an anticancer agent for high-grade gliomas. Among the topics discussed were economic factors and pharmaceutical risk assessments, regulatory constraints and perceptions and the need for improved imaging surrogates of drug activity. Included were modeling tumor growth and drug effects in a medical environment in which direct tumor sampling for biological effects can be problematic, potential new drugs under investigation and targets for drug discovery and development. The long trajectory and diverse impediments to novel drug discovery, and expectation that more than one drug will be needed to adequately inhibit critical intracellular tumor pathways were viewed as major disincentives for most pharmaceutical/biotechnology companies. While there were a few unanimities, one consensus is the need for continued and focused discussion among academic and industry scientists and clinicians to address tumor targets, new drug chemistry, and more time- and cost-efficient clinical trials based on surrogate end points. PMID- 28718327 TI - Fibrin Glue Increases the Tensile Strength of Conduit-Assisted Primary Digital Nerve Repair. AB - BACKGROUND: An ideal peripheral nerve repair construct does not currently exist. Our primary goal was to determine whether fibrin glue adds to the tensile strength of conduit-assisted primary digital nerve repairs. Our secondary goal was to evaluate the impact of varying suture number and location on the tensile strength. METHODS: Ninety cadaveric digital nerves were harvested and divided equally into the following repair groups: A (4/4), B (2/2), C (0/2), D (0/1), and E (0/0) with the first number referring to the number of sutures at the coaptation and the second number referring to the number of sutures at each proximal and distal end of the nerve-conduit junction. When fibrin glue was added, the group was labeled prime. The nerve specimens were transected and then repaired with 8-0 nylon suture and conduit. The tensile strength of the repairs was tested, and maximum failure load was determined. The results were analyzed with a 2-way analysis of variance. The Tukey post hoc test compared repair groups if the 2-way analysis of variance showed significance. RESULTS: Both suture group and glue presence significantly affected the maximum failure load. Increasing the number of sutures increased the maximum failure load, and the presence of fibrin glue also increased the failure load. CONCLUSIONS: Fibrin glue was found to increase the strength of conduit-assisted primary digital nerve repairs. Furthermore, the number of sutures correlated to the strength of the repair. Fibrin glue may be added to a conduit-assisted primary digital nerve repair to maintain strength and allow fewer sutures at the primary coaptation site. PMID- 28718328 TI - Primary mono- and bis-sulfonamides obtained via regiospecific sulfochlorination of N-arylpyrazoles: inhibition profile against a panel of human carbonic anhydrases. PMID- 28718329 TI - Assessment of Forearm Rotational Control Using 4 Upper Extremity Immobilization Constructs. AB - BACKGROUND: Forearm immobilization techniques are commonly used to manage distal radius, scaphoid, and metacarpal fractures. The purpose of our study was to compare the degree of rotational immobilization provided by a sugar-tong splint (STS), short arm cast (SAC), Munster cast (MC), and long arm cast (LAC) at the level of the distal radioulnar joint (DRUJ), carpus, and metacarpals. METHODS: Seven cadaveric upper extremity specimens were mounted to a custom jig with the ulnohumeral joint fixated in 90 degrees of flexion. Supination and pronation were unrestricted. K-wires were placed in the distal radius, scaphoid, and metacarpals using fluoroscopic guidance to measure the total arc of rotation referenced to the ulnar ex-fix pin. Baseline measurements followed by sequential immobilization with well-molded STS, SAC, MC, and LAC were obtained with 1.25, 2.5, and 3.75 ft-lb of supination and pronation force directed through the metacarpal K-wire. Each condition was tested 3 times. Digital photographs were taken perpendicular to the ulnar axis to analyze the total arc of motion. RESULTS: The most effective constructs from least to greatest allowed rotational arcs were LAC, MC, SAC, and STS. Above-elbow constructs (MC, LAC) demonstrated superior immobilization compared with below-elbow constructs (SAC) ( P < .001). Circumferential constructs (SAC, MC, LAC) were superior to the noncircumferential construct (STS) ( P < .001). There were no significant differences between the MC and LAC in all conditions tested. CONCLUSIONS: Both circumferential and proximally extended immobilization independently improved rotational control of the wrist. However, extending immobilization proximal to the epicondyles did not confer additional stability. PMID- 28718330 TI - Anatomic Assessment of K-Wire Trajectory for Transverse Percutaneous Fixation of Small Finger Metacarpal Fractures: A Cadaveric Study. AB - BACKGROUND: The purpose of this cadaveric study is to evaluate the trajectory of percutaneous transverse Kirschner wire (K-wire) placement for fifth metacarpal fractures relative to the sagittal profile of the fifth metacarpal in order to develop a targeting strategy for the treatment of fifth metacarpal fractures. METHODS: Using 12 unmatched fresh human upper limbs, we evaluated the trajectory of percutaneous transverse K-wire placement relative to the sagittal profile of the fifth metacarpal in order to develop a targeting strategy for treatment of fifth metacarpal fractures. The midpoint of the small and ring finger metacarpals in the sagittal plane was identified at 3 points. At each point, a K-wire was inserted from the small finger metacarpal into the midpoint of the ring finger metacarpal ("center-center" position). RESULTS: The angle of the transverse K wire relative to the table needed to achieve a center-center position averaged 20.8 degrees , 18.9 degrees , and 16.7 degrees for the proximal diaphysis, middiaphysis, and the collateral recess, respectively. Approximately 80% of transversely placed K-wires obtained purchase in the long finger metacarpal. CONCLUSIONS: These results can serve as a guide to help surgeons in the accurate placement of percutaneous K-wires for small finger metacarpal fractures and may aid in surgeon training. PMID- 28718331 TI - Entinostat for the treatment of breast cancer. AB - INTRODUCTION: Breast cancer accounts for 29% of malignant tumors. It is an heterogenous disease covering a spectrum of different molecular subtypes. Epigenetic aberrations may affect gene expression through DNA and histone proteins modifications thus promoting tumor progression and resistance to anti- tumor treatment. Area covered: This article explores the potential role of entinostat in the treatment of breast cancer. The clinical trials evaluating entinostat are discussed, highlighting preclinical data and early-phase clinical studies results. The emerging activity of entinostat in several clinical settings is evaluated by focusing on endocrine-resistant, HER2 positive and triple negative breast cancer with promising activity in boosting the immune-system. Expert opinion: Entinostat, a synthetic benzamide derivative class I histone deacetylases (HDACs) inhibitor, inhibits cell proliferation and promotes apoptosis in breast cancer. Several results from clinical trials demonstrate that the addition of an epigenetic therapy to antiestrogen therapy may be an effective approach to targeting resistance pathways in breast cancer, particularly in hormone-positive disease. Agents such as entinostat may have a role in immunogenic modulation. Genetic and pharmacological inhibition studies identified HDAC as a key determinant in the reversal of carcinoma immune escape. This offers the rationale for combining HDAC inhibitors with immunotherapy, including therapeutic cancer vaccines. PMID- 28718332 TI - A Peculiar Form of Breast Fat Necrosis Simulating Hyaline Ring Granuloma (So called Pulse Granuloma): A Rare Complication of Hyperparathyroidism. AB - Pulse granuloma is a rare, foreign body inflammatory reaction that occurs mainly in the oral cavity. It is exceedingly rare elsewhere, with only isolated cases described in the literature. We report the case of a 79-year-old woman with a history of normocalcemic hyperparathyroidism who presented to our hospital with a painful 4-cm lump in the upper quadrants-upper outer quadrant of her left breast. The clinical and radiological (BIRADS-5) findings were indicative of a malignant lesion. However, core needle biopsy revealed features simulating hyaline ring granuloma (pulse granuloma-like). A definitive diagnosis of lipomembranous fat necrosis was made by identifying its characteristic histomorphology. Histopathological study is essential to establish an exact diagnosis since clinical and imaging features may mimic breast carcinoma. To our knowledge, this is the first reported case of a hyaline ring granuloma-like in the breast, which may represent a peculiar form of degenerative change of lipomembranous fat necrosis. PMID- 28718333 TI - Anomalous Radial Artery as an Incidental Finding During a Routine Carpal Tunnel Release. AB - BACKGROUND: Compression of the median nerve at the wrist, or carpal tunnel syndrome, is the most commonly recognized nerve entrapment syndrome. Carpal tunnel syndrome is usually caused by compression of the median nerve due to synovial swelling, tumor, or anomalous anatomical structure within the carpal tunnel. METHODS: During a routine carpal tunnel decompression, a large vessel was identified within the carpal tunnel. RESULTS: The large vessel was the radial artery. It ran along the radial aspect of the carpal tunnel just adjacent to the median nerve. CONCLUSIONS: The unusual presence of the radial artery within the carpal tunnel could be a contributing factor to the development of carpal tunnel syndrome. In this case, after surgical carpal tunnel release, all symptoms of carpal tunnel syndrome resolved. PMID- 28718334 TI - The preclinical discovery and development of brexpiprazole for the treatment of major depressive disorder. AB - INTRODUCTION: Brexpiprazole is the most recently approved second-generation antipsychotic, which is used as adjunctive therapy to antidepressants for treating major depressive disorder (MDD) with inadequate response. Brexpiprazole shares pharmacological similarities with other second-generation antipsychotics, especially aripiprazole. Area covered: This review provides a detailed overview of the pre-clinical studies of brexpiprazole, followed by a summary of its clinical studies, and a comparison with other antipsychotics in MDD. Brexpiprazole is superior to placebo in reducing depressive symptoms of patients who have had an inadequate response to a standard antidepressant treatment. The efficacy of brexpiprazole is comparable to aripiprazole and quetiapine-XR, but brexpiprazole has demonstrated a lower risk for akathisia than aripiprazole and a lower risk for somnolence than quetiapine-XR. Expert opinion: Given that different studies have used different criteria to define 'treatment-resistance' or 'inadequate-response', an accurate comparison of the efficacy and safety of brexpiprazole with other antipsychotics is difficult. Preclinical data supports the premise that the antidepressant-like effects of antipsychotics are mainly due to their ability to modulate/regulate the monoamine system. Therefore, antipsychotics with similar pharmacodynamic properties like brexpiprazole could also take the 'me too' approach to treating MDD. PMID- 28718335 TI - Variability of performance status assessment between patients with hematologic malignancies and their physicians. AB - This study was conducted to determine the incidence of inter-observer variability in Eastern Cooperative Oncology Group (ECOG) performance status (PS) rating between patients with leukemia and lymphoma and their physicians. ECOG PS was assessed at diagnosis by patients and their physicians and stratified by disease subtype, gender, age, disease stage and education. Association between patient- and physician-rated PS and overall survival (OS) was stratified by subtype and prognostic risk score. Overall, 65% of patients and physicians rated PS the same. Age, disease stage and disease subtype were significant predictors of PS disagreement. PS was a significant predictor of OS irrespective of assessment by patients or physicians across all subtypes except those with Hodgkin lymphoma. These findings suggest the need for physicians to better communicate with patients when determining PS, as PS is a strong predictor of survival and is critical in treatment decisions, including determining fitness for cancer treatment. PMID- 28718336 TI - Coexistence of Takayasu's arteritis and ankylosing spondylitis may not be accidental - Is there a need for a new subgroup in the spondyloarthritis family? AB - Aortitis of ascending aorta is a recognized complication of ankylosing spondylitis (AS). There are a few published cases of diffuse aortitis and aorta collaterals inflammation that fulfill Takayasu's arteritis (TA) criteria coexisting with AS. We have reviewed published cases from literature and present three new cases of such coexistence. We identified three patients who fulfilled definite AS New York criteria in our Takayasu's vasculitis cohort of eight patients. One of this patients had been diagnosed with Crohn's disease before AS and TA diagnosis. Additionally, two other patients had an inflammatory back pain and suffered of chronic uveitis. One of them had increased sacroiliac uptake of isotope in scintigraphy. Those two patients did not fulfil spondyloarthritis criteria. In this paper, we debate if TA type arteritis might be one of the AS cardiovascular complications. PMID- 28718338 TI - The role of attention at retrieval on the false recognition of negative emotional DRM lists. AB - This study examined the role of attention at retrieval on the false recognition of emotional items using the Deese-Roediger-McDermott (DRM) paradigm. Previous research has shown that divided attention at test increases false remember judgements for neutral critical lures. However, no research has yet directly assessed emotional false memories when attention is manipulated at retrieval. To examine this, participants studied negative (low in valence and high in arousal) and neutral DRM lists and completed recognition tests under conditions of full and divided attention. Results revealed that divided attention at retrieval increased false remember judgements for all critical lures compared to retrieval under full attention, but in both retrieval conditions, false memories were greater for negative compared to neutral stimuli. We believe that this is due to reliance on a more easily accessible (meaning of the word) but less diagnostic form of source monitoring, amplified under conditions of divided attention. PMID- 28718340 TI - Characterization of Sepsis and Sepsis-Associated Encephalopathy. AB - BACKGROUND: Sepsis and sepsis-associated encephalopathy (SAE) are common intensive care unit (ICU) diseases; the morbidity and mortality are high. The present study analyzed the sensitivity of different diagnostic criteria of sepsis 1.0 and 3.0, epidemiological characteristics of sepsis and SAE, and explored its risk factors for death, short-term, and long-term prognosis. METHODS: The retrospective study included patients in ICU from January 2015 to June 2016. After excluding 58 patients, 175 were assigned to either an SAE or a non-SAE group (patients with sepsis but no encephalopathy). The sensitivity of the diagnostic criteria was compared between sepsis 1.0 and 3.0, respectively. Between-group differences in baseline data, Acute Physiology and Chronic Health Evaluation II score (APACHE II score), Sequential Organ Failure Assessment score (SOFA score), etiological data, biochemical indicators, and 28-day and 180-day mortality rates were analyzed. Survival outcomes and long-term prognosis were observed, and risk factors for death were analyzed through 180-day follow-up. RESULTS: The sensitivity did not differ significantly between the diagnostic criteria of sepsis 1.0 and 3.0 ( P = .286). The 42.3% incidence of SAE presented a significantly high APACHE II and SOFA scores as well as 28-day mortality and 180-day mortality (all P < .001). The incidence of death was 37.1%. The multivariate stepwise regression analysis demonstrated that the risk of death in SAE group was significantly higher than the non-SAE group ( P < .001). Sepsis associated encephalopathy is a risk factor for sepsis-related death (relative risk [RR] = 2.868; 95% confidence interval: 1.730-4.754; P < .001). Although males showed a significantly high rate of 28-day and 180-day mortality ( P = .035 and .045), it was not an independent risk factor for sepsis-related death ( P = .072). The long-term prognosis of patients with sepsis was poor with decreased quality of life. No significant difference was observed in prognosis between the SAE and non-SAE groups ( P > .05). CONCLUSION: Both diagnostic criteria cause misdiagnosis, and the sensitivity did not differ significantly. The incidence of SAE was high, and 28-day and 180-day mortality rates were significantly higher than those without SAE. Sepsis-associated encephalopathy is a risk factor for poor outcome. The overall long-term prognosis of patients with sepsis was poor, and the quality of life decreased. PMID- 28718341 TI - Diagnostic Yield and Outcomes of Computed Tomography of the Head in Critically Ill Nontrauma Patients. AB - BACKGROUND: Computed tomography of the head (HCT) is a widely used diagnostic tool, especially for emergency and trauma patients. However, the diagnostic yield and outcomes of HCT for patients on medical intensive care units (MICUs) are largely unknown. METHODS: We retrospectively evaluated all head CTs from patients admitted to a single-center MICU during a 5-year period for CT indications, diagnostic yield, and therapeutic consequences. Uni- and multivariate analyses for the evaluation of risk factors for positive head CT were conducted. RESULTS: Six hundred ninety (18.8%) of all patients during a 5-year period underwent HCT; 78.7% had negative CT results, while 21.3% of all patients had at least 1 new pathological finding. The main indication for acquiring CT scan of the head was an altered mental state (AMS) in 23.5%, followed by a new focal neurology in 20.7% and an inadequate wake up after stopping sedation in 14.9% of all patients. The most common new finding was intracerebral bleeding in 6.4%. In 6.7%, the CT scan itself led to a change of therapy of any kind. Admission after resuscitation or a new focal neurology were independent predictors of a positive CT. Psychic alteration and AMS were both independent predictors of a higher chance of a negative head CT. Positive HCT during MICU is an independent predictor of lower survival. CONCLUSIONS: New onset of focal neurologic deficit seems to be a good predictor for a positive CT, while AMS and psychic alterations seem to be very poor predictors. A positive head CT is an independent predictor of death for MICU patients. PMID- 28718342 TI - Reconsidering the roles of gratitude and indebtedness in social exchange. AB - Receiving favors is often a mixed blessing and commonly triggers two emotions: the positive emotion gratitude and negative emotion indebtedness. In three studies, we examined the hypothesis that gratitude and indebtedness have distinct functions in social exchange. Contrary to current views, we believe that the function of gratitude does not primarily reside in facilitating social exchange. Instead, we propose that indebtedness motivates people to repay favours received, and thus accounts for most of the prosocial effects commonly attributed to gratitude. On the other hand consistent with current views, we believe that gratitude signals the potential for developing a relationship and fosters proximity seeking. Supporting these assumptions, in Study 1 we found that gratitude and indebtedness were associated with aspects of the favour that reflect the concern for relationship and the level of inequity. Studies 2 and 3 provided causal support for these relations, and revealed the unique associations between gratitude and the motivation of proximity seeking, and between indebtedness and the motivation to reciprocate. We argue that this functional distinction has escaped research attention as gratitude and indebtedness are naturally correlated because they stem from the same eliciting event. To appreciate this functional distinction, both emotions should be studied simultaneously in the context of social exchange. PMID- 28718343 TI - Application of t-SNE to human genetic data. AB - The t-distributed stochastic neighbor embedding t-SNE is a new dimension reduction and visualization technique for high-dimensional data. t-SNE is rarely applied to human genetic data, even though it is commonly used in other data intensive biological fields, such as single-cell genomics. We explore the applicability of t-SNE to human genetic data and make these observations: (i) similar to previously used dimension reduction techniques such as principal component analysis (PCA), t-SNE is able to separate samples from different continents; (ii) unlike PCA, t-SNE is more robust with respect to the presence of outliers; (iii) t-SNE is able to display both continental and sub-continental patterns in a single plot. We conclude that the ability for t-SNE to reveal population stratification at different scales could be useful for human genetic association studies. PMID- 28718344 TI - Knee extensor fatigue developed during high-intensity exercise limits lower-limb power production. AB - We investigated the association between changes in vastii electromyography (EMG) and knee extensor fatigue during high-intensity cycling, and the subsequent effect on lower-limb power and intermuscular coordination during all-out cycling. On two separate days, participants completed 30-s all-out cycling or 10-min of high-intensity cycling followed by 30-s all-out cycling. EMG for gluteus maximus (GMAX), rectus femoris (RF), vastii (VAS), hamstrings (HAM) and gastrocnemius (GAS); co-activation for GMAX/RF, VAS/HAM and VAS/GAS; isometric maximal voluntary force (IMVF) and resting twitch (RT) of the knee extensors were measured. VAS EMG increases during high-intensity cycling (6% to 14%, P < 0.05) were negatively correlated (r = -0.791, P < 0.05) with knee extensor IMVF decreases (-2% to-36%, P < 0.05) following the exercise. Knee extensor IMVF decreases were positively correlated (r = 0.757, P < 0.05) with all-out cycling power reductions (0% to -27%, P < 0.05). VAS/GAS co-activation did not change (P > 0.05) during all-out cycling while VAS and GAS EMG decreased. Larger increase in VAS EMG during high-intensity cycling was associated with greater knee extensor fatigue and larger power reduction during all-out cycling. High VAS/GAS co-activation potentially limited power reduction induced by knee extensor fatigue during all-out cycling. PMID- 28718345 TI - The value of quality feedback in formative OSCEs. PMID- 28718346 TI - Effect of desvenlafaxine 50 mg and 100 mg on energy and lassitude in patients with major depressive disorder: A pooled analysis. AB - Nine randomized, double-blind, placebo-controlled studies of major depressive disorder were pooled to evaluate the effects of desvenlafaxine 50- and 100-mg/d on energy and lassitude in adults with major depressive disorder ( n=4279). Changes from baseline to endpoint in 17-item Hamilton Rating Scale for Depression (HAM-D17) Work and Activities, Retardation, and Somatic Symptoms General items, HAM-D17 psychomotor retardation factor, and Montgomery-Asberg Depression Rating Scale Lassitude item were analyzed with a mixed model for repeated measures analysis of variance. Associations between residual energy measures and functional impairment, based on the Sheehan Disability Scale, were modeled using stepwise multiple linear regression. Improvement from baseline was significantly greater for both desvenlafaxine doses versus placebo on all energy symptom outcomes at week 8 (all p?0.005). Both early improvement in HAM-D17 psychomotor retardation at week 2 and residual energy symptoms at week 8 were associated with Sheehan Disability Scale total score at week 8 (all p?0.001). Among Sheehan Disability Scale remitters and responders, the HAM-D17 psychomotor retardation score at week 8 was significantly lower with desvenlafaxine (both doses) than placebo. Desvenlafaxine 50 and 100 mg/d significantly improved energy and lassitude symptoms in patients with major depressive disorder. Both early improvement in energy and fewer residual energy symptoms were associated with functional improvement. PMID- 28718347 TI - Priming involuntary autobiographical memories in the lab. AB - Involuntary autobiographical memories (IAMs) are recollections of personal past that frequently and spontaneously occur in daily life. Initial studies by Mace (2005) showed that deliberately reminiscing about a certain lifetime period (e.g., high school) significantly increased the number of different IAMs from the same period in subsequent days, suggesting that priming may play a significant role in the retrieval of IAMs in everyday life. In the present study, we used a modified experimental paradigm, originally used by Schlagman and Kvavilashvili (2008), to study IAMs under well-controlled laboratory conditions. Participants completed a monotonous vigilance task twice and reported the occurrence of any spontaneous thoughts that were later classed as IAMs or other thoughts. Priming was manipulated by having experimental participants reminiscing about high school period between the two vigilance tasks and control participants playing simple games. Results showed that participants in the experimental group reported IAMs relating to high school period more frequently during the second vigilance task than those in the control group. In the experimental group, the number of high school memories was marginally higher in the second vigilance task compared to the first vigilance task with the medium effect size, but this within subjects effect was not significant in the control group. Finally, priming also enhanced the retrieval of more remote IAMs in the experimental group compared to the control group. These results suggest that priming may play a significant role in the activation and recall of IAMs and open up interesting avenues for future research. PMID- 28718348 TI - Thalidomide has a significant effect in patients with thalassemia intermedia. AB - OBJECTIVE: To investigate the effect of thalidomide in patients with thalassemia intermedia. METHODS: We observed the effect of thalidomide in seven patients with thalassemia intermedia requiring blood transfusion. Four of the patients were transfusion-independent, and three patients were transfusion-dependent. RESULTS: For the four transfusion-independent patients, hemoglobin concentration increased significantly (>=2 g/dl) in three and moderately (1-2 g/dl) in one. After 3 months of treatment, hemoglobin concentration increased 3.2 +/- 1.2 g/dl compared to pretreatment. Among the three transfusion-dependent patients, transfusion was terminated after one month of treatment in one patient and decreased >50% in the other two patients, accompanied by an increase in the average hemoglobin concentration. CONCLUSION: Thalidomide had a significant effect in patients with thalassemia intermedia. Further studies of a larger scale and more rigorous design are warranted. PMID- 28718349 TI - Relationship between moral distress and ethical climate with job satisfaction in nurses. AB - BACKGROUND: Moral distress and ethical climate are important issues in the workplace that appear to affect people's quality of work life. OBJECTIVES: This study was conducted to determine the relationship of moral distress and ethical climate to job satisfaction in critical care nurses. MATERIALS AND METHODS: This descriptive-correlation study was conducted on 142 critical care nurses, selected from five social security hospitals in north Iran through census sampling. Data were collected using a demographic questionnaire, the Moral Distress Scale Revised, the Olson's Hospital Ethical Climate Survey, and the Brayfield and Rothe Job Satisfaction index. Ethical considerations: The research project was approved by the Ethics Committee of Mazandaran University of Medical Sciences and the Medical Deputy of the Social Security Organization. FINDINGS: The mean scores obtained by the critical care nurses for moral distress, ethical climate, and job satisfaction were 87.02 +/- 44.56, 3.51 +/- 0.53, and 62.64 +/- 9.39, respectively. Although no significant relationships were observed between moral distress and job satisfaction, the relationship between ethical climate and job satisfaction was statistically significant (p < 0.05). CONCLUSION: Identifying ethical stressors in the workplace and giving proper feedback to the authorities to eliminate these factors and improve the ethical climate in these workplaces can help enhance job satisfaction in nurses and lead to higher quality care. PMID- 28718350 TI - Tourniquet Deflation Prior to 20 Minutes in Upper Extremity Intravenous Regional Anesthesia. AB - BACKGROUND: Bier blocks, or intravenous regional anesthesia (IVRA), are a method of anesthesia for upper extremity surgeries. This study reports our experience with tourniquet deflation prior to 20 minutes with upper extremity IVRA. METHODS: This study was designed as a retrospective cohort analysis. Records, including intraoperative and immediate postoperative anesthesia notes, of 430 patients who underwent IVRA with an upper extremity Bier block and a corresponding tourniquet time of less than 20 minutes were reviewed. Patient demographics, procedure(s) performed, American Society of Anesthesiologists scores, volume of lidocaine used in Bier block, tourniquet time, and any complications were recorded. RESULTS: This cohort consisted of 127 males and 303 females. The 3 most common procedures performed were carpal tunnel release (315), trigger finger release (47), and excision of masses (34). The average tourniquet time for this cohort was 16 minutes (range, 9-19 minutes), and the average volume of lidocaine (0.5% plain) injected was 44 mL (range, 30-70 mL). A tourniquet time of 17 minutes or less was observed in 339 patients, and 170 patients had tourniquet times of 15 minutes or less. Five complications were recorded: intraoperative vomiting, mild postoperative nausea/vomiting, severe postoperative nausea and vomiting, and transient postoperative hypotension that responded to a fluid bolus. CONCLUSIONS: No major complications were observed in our cohort of upper extremity IVRA and tourniquet times of less than 20 minutes. Several variables play a role in the safety of upper extremity IVRA. PMID- 28718351 TI - Exosomal HSP60: a potentially useful biomarker for diagnosis, assessing prognosis, and monitoring response to treatment. AB - INTRODUCTION: Cell-to-cell communication is imperative for life and it is mediated by sending and receiving information via the secretion and subsequent receptor-mediated detection of biological molecules. Exosomes (EXs) secreted from cells to the extracellular environment play an important role in intercellular communication in normal and pathological conditions. Areas covered: New evidence indicates that tumor cells-derived EXs contribute to cancer progression through the modulation of tumor microenvironment. The exosomal heat shock protein 60 (HSP60) is very likely a key player in intercellular cross-talk, particularly during the progress of diseases, such as cancer. Many studies have focused on the extracellular roles played by HSP60 that pertain to cancer development and immune system stimulation. Our experimental data in vitro and in vivo demonstrated that HSP60 occurs on the surface of EXs secreted by tumour cells. Expert commentary: Exosomal HSP60 has great potential for clinical applications, as a 'liquid biopsy', including its use as biomarker for diagnostics, assessing prognosis, and monitoring disease progression and response to treatment, particularly in cancer. PMID- 28718352 TI - Narratives for Obesity: Effects of Weight Loss and Attribution on Empathy and Policy Support. AB - Despite an urgent need to address the issue of obesity, little research has examined the psychological factors that influence support for obesity-related policy initiatives, which represent an important tool for addressing this complex health issue. In the present study, we measured the degree to which people supported obesity-related policy interventions and empathized with a person struggling with obesity after reading a personal account of his or her situation. The narrative described an obese individual who was portrayed as either successfully losing weight or not, and as attributing his or her weight-loss outcome to personal or environmental factors. We found that protagonists who successfully lost weight and/or took personal responsibility for their situation elicited more empathy from participants, which was associated with support for societal policy interventions for obesity. These findings suggest that specific features of personal narratives influence support for obesity-related policies and highlight empathy as a mechanism through which such narratives affect obesity related attitudes. PMID- 28718353 TI - A Multiyear Assessment of Public Response to a Statewide Drug Take-Back and Disposal Campaign, 2010 to 2012. AB - This study is the first to analyze public response to a drug take-back program, the American Medicine Chest Challenge, in a single state over a period of 3 years (2010-2012). The study utilized a three-wave repeated cross-sectional design and an annual phone survey conducted with a representative sample of adults ( N = 906 in 2010, N = 907 in 2011, and N = 906 in 2012), which assessed exposure to the campaign, drug disposal behaviors, possible mediators of campaign effects (risk appraisal, personal agency, normative influence, and interpersonal talk), and potential confounders. Logistic regression and causal mediation analysis were employed to estimate confounder-adjusted direct and mediated effects of the campaign. Results showed that the campaign reached a sizable portion (50% to 60%) of state adults and that campaign exposure was associated with increased likelihood of having conversations with others about this topic. About 55% of all adults in the state reported taking at least one of the actions recommended by the campaign, and campaign exposure was associated with increased likelihood of disposing of prescription drugs at a drug collection day event (adjusted odds ratio = 4) and of talking to a child about the risks associated with prescription drug abuse (adjusted odds ratio = 2). The causal mediation analysis demonstrated that the campaign influenced audiences by reinforcing their efficacy to safely dispose of prescription drugs, but also potentially by stimulating conversations among community members about this topic. Drug take-back campaigns can be an effective mechanism to decrease the availability of prescription drugs in communities. PMID- 28718356 TI - Comparison of three non-invasive ventilation strategies (NSIPPV/BiPAP/NCPAP) for RDS in VLBW infants. AB - BACKGROUND: Non-invasive ventilation (NIV) significantly changed the management of respiratory distress syndrome (RDS) in preterm infants. Further perspectives for neonatologists regard the assessment of different NIV strategies in terms of availability, effectiveness, and failure. OBJECTIVE: The aim of the present study is to evaluate the effectiveness of three different NIV strategies: nasal continuous positive airway pressure (N-CPAP), nasal synchronized intermittent positive pressure ventilation (N-SIPPV), and nasal bilevel-CPAP (BiPAP), as first intention treatment for RDS in very low birth-weight infants (VLBW). METHODS: A multicenter retrospective study was conducted in three neonatal intensive care unit (NICUs) that enrolled 191 VLBW infants complicated by RDS, who received, as first intention treatment for RDS, three different NIV approaches (N-CPAP: n = 66; N-SIPPV: n = 62, BiPAP: n = 63). We evaluated the performance of different NIV strategies by primary (failure within the first 5 d of life) and some selected secondary end-points. RESULTS: The incidence of NIV failure was significantly higher in the N-CPAP group (22/66) versus N-SIPPV/BiPAP groups (11/62; 11/63) (p < .05 for both), while no difference was observed between N SIPPV and BiPAP groups. Moreover, no differences were found between the three groups regarding secondary outcomes. CONCLUSIONS: The present study shows that first intention N-SIPPV/BiPAP, as NIV support, augment the beneficial effects of N-CPAP contributing to a reduced risk of failure in VLBW infants complicated by RDS. Data open up to further RCTs on a wider population to evaluate NIV effectiveness on long-term outcomes. PMID- 28718357 TI - The influence of staff training and education on prosthetic and orthotic service quality: A scoping review. AB - BACKGROUND: Education and training in prosthetics and orthotics typically comply with International Society for Prosthetics and Orthotics standards based on three categories of prosthetic and orthotic professionals. OBJECTIVE: This scoping study sought to describe the evidence base available to answer the question, How are prosthetic and orthotic services influenced by the training of staff providing them? STUDY DESIGN: Scoping review. METHODS: A structured search of the peer-reviewed literature catalogued in major electronic databases yielded 3039 papers. Following review of title and abstract, 93 articles were considered relevant. Full-text review reduced this number to 25. RESULTS: Only two articles were identified as providing direct evidence of the effects of training and education on service provision. While both suggested that there was an impact, it is difficult to see how the more specific conclusions of either could be generalised. The other 23 articles provide a useful background to a range of issues including the specification of competencies that training programmes should deliver (3 articles), descriptions of a range of training programmes and the effects of training and education on student knowledge and skills. CONCLUSION: Although it is considered axiomatic, the service quality is dependent on practitioner education and training. There is insufficient evidence to establish whether levels of training and education in prosthetics and orthotics have an effect on the quality of prosthetic and orthotic services. Clinical relevance There is very little evidence about the effects of training and education of prosthetists and orthotists on service quality. While this is a somewhat negative finding, we feel that it is important to bring this to the attention of the prosthetics and orthotics community. PMID- 28718354 TI - Mercury-induced motor and sensory neurotoxicity: systematic review of workers currently exposed to mercury vapor. AB - The neurotoxicity of elemental mercury (Hg0) is well-recognized, but it is uncertain whether and for how long neurotoxicity persists; among studies that evaluated previously exposed workers, only one examined workers during and also years after exposure ceased. The aim of this review is to document the type, frequency, and dose-relatedness of objective neurological effects in currently exposed mercury workers and thereby provide first approximations of the effects one would have expected in previously exposed workers evaluated during exposure. We systematically reviewed studies of neurotoxicity in currently exposed mercury workers identified by searching MEDLINE (1950-2015), government reports, textbook chapters, and references cited therein; dental cohorts were not included. Outcomes on physical examination (PE), neurobehavioral (NB) tests, and electrophysiological studies were extracted and evaluated for consistency and dose-relatedness. Forty-five eligible studies were identified, comprising over 3000 workers chronically exposed to a range of Hg0 concentrations (0.002-1.7 mg/m3). Effects that demonstrated consistency across studies and increased frequency across urine mercury levels (<50; 50-99; 100-199; >=200 MUg/L) included tremor, impaired coordination, and abnormal reflexes on PE, and reduced performance on NB tests of tremor, manual dexterity and motor speed. The data suggest response thresholds of UHg ~275 MUg/L for PE findings and ~20 MUg/L for NB outcomes. These results indicate that PE is of particular value for assessing workers with UHg >200 MUg/L, while NB testing is more appropriate for those with lower UHg levels. They also provide benchmarks to which findings in workers with historical exposure can be compared. PMID- 28718359 TI - Noticias para os socios da SPCAL/News for SPCAL members. PMID- 28718358 TI - An updated method for the jugular catheterization of grower pigs for repeated blood sampling following an oral glucose tolerance test. AB - Jugular catheterization is a common procedure used under experimental conditions. However, there is considerable variation in the reported techniques, particularly for grower pigs (>40 kg and <60 kg) when larger volumes of blood per sample (>10 mL) are required. This paper provides a complete methodology including the use of current equipment and anaesthetic regimen for grower pigs. This surgical jugular catheterization method was carried out in 30 large white grower pigs. Firstly, the pigs were habituated to human handling for at least two weeks prior to surgery. Animals were sedated and anesthetized. Following intubation, an incision was made in the jugular fossa, and the jugular vein was located. A catheter was then inserted and fixated. The wound was stapled and the catheter line secured to the back of the neck. The pigs recovered fully from the surgery and the catheters remained patent for the duration of the blood sampling period (min 72 h). Twenty millilitres of blood were collected every 15 min, taking approximately 2 min per pig. No haemolysis was detected in any samples. Jugular catheterization of pigs using this procedure proved successful both in terms of animal recovery and quality of samples. Catheters remained patent and pigs remained calm during sampling. PMID- 28718360 TI - Inflammatory Myopathy in Horses With Chronic Piroplasmosis. AB - Horses affected by chronic piroplasmosis may develop poor performance and muscle atrophy. Here we investigate the pathological and immunopathological aspects of myopathy occurring in chronic equine piroplasmosis. The study included 16 horses serologically positive for equine piroplasms presenting with clinical signs and supporting serum biochemical evidence of a myopathy. Skeletal muscle was evaluated by histopathology, immunohistochemistry, indirect immunofluorescence, and molecular detection of piroplasms and inflammatory cytokines in skeletal muscle. Histologic lesions included muscle fiber atrophy (100% of cases), degenerative changes (13/16, 81%), and perivascular perimysial and endomysial lymphocytic infiltrates (81% of cases). In 15 cases (94%), muscle fibers had strong immunostaining for major histocompatibility complex classes I and II. T lymphocyte populations were mainly CD3+, CD8+, and CD4+ in equal proportions, with a lower number of CD79alpha+ cells. The serum from affected horses was tested by indirect immunofluorescence for binding of IgG, IgM, or IgA to sections of normal equine muscle to detect circulating autoantibodies against muscle antigen(s). In all cases, distinct sarcolemmal staining was detected in sections incubated with serum from affected horses, in contrast to sections incubated with phosphate-buffered saline or equine control sera. Reverse transcription polymerase chain reaction (RT-PCR) testing of muscles from affected animals revealed a significant increase of interferon-gamma, interleukin-12, and tumor necrosis factor-alpha gene expression compared to healthy controls. Theileria equi or Babesia caballi was not detected in samples of affected muscle by RT-PCR. Thus, inflammatory myopathy associated with equine piroplasmosis may involve an autoimmune pathogenesis with upregulation of inflammatory cytokines that may cause myofiber atrophy and degeneration. PMID- 28718362 TI - Adaptive behaviour and motor skills in children with upper limb deficiency. AB - BACKGROUND: The dysfunction of individuals with upper limb deficiencies affects their daily lives and social participation. OBJECTIVES: To clarify the adaptive behaviours and motor skills of children with upper limb deficiencies. STUDY DESIGN: Cross-sectional survey. METHODS: The subjects were 10 children ranging from 1 to 6 years of age with unilateral upper limb deficiencies at the level distal to the elbow who were using only cosmetic or passive prostheses or none at all. To measure their adaptive behaviour and motor skills, the Vineland Adaptive Behavior Scales, Second Edition was used. They were evaluated on the domains of communication, daily living skills, socialization and motor skills. We also examined the relationship of the scores with age. RESULTS: There were no statistically significant scores for domains or subdomains. The domain standard score of motor skills was significantly lower than the median scores of the domains and was negatively correlated with age. CONCLUSION: Children with upper limb deficiencies have individual weaknesses in motor skill behaviours, and these weaknesses increase with age. It may be helpful in considering approaches to rehabilitation and the prescription of prostheses to consider the characteristics and course of children's motor skill behaviours. Clinical relevance Even if children with unilateral upper limb deficiencies seem to compensate well for their affected limb function, they have or will experience individual weaknesses in motor skills. We should take this into consideration to develop better strategies for rehabilitation and prostheses prescriptions. PMID- 28718364 TI - Evaluation of epigenetic inactivation of vascular endothelial growth factor receptors in head and neck squamous cell carcinoma. AB - The aim of this study was to determine the methylation status of the genes encoding the vascular endothelial growth factor receptors and to evaluate the usefulness of VEGFR methylation as a prognostic indicator in head and neck squamous cell carcinoma. VEGFR messenger RNA expression and promoter methylation were examined in a panel of cell lines via quantitative reverse transcription and methylation-specific polymerase chain reaction, respectively. Promoter methylation was compared with clinical characteristics in 128 head and neck squamous cell carcinoma samples. The normalized methylation values for the VEGFR1, VEGFR2 and VEGFR3 promoters tended to be higher in the tumour cell lines than in normal tonsil samples, whereas amounts of VEGFR1, VEGFR2 and VEGFR3 messenger RNA were significantly higher. Methylation of the VEGFR1 promoter (p = 0.003; 66/128 head and neck squamous cell carcinoma samples, 52%) and VEGFR3 promoter (p = 0.043; 53/128 head and neck squamous cell carcinoma samples, 41%) significantly correlated with recurrence, whereas methylation of the VEGFR2 promoter significantly correlated with lymph node metastasis (p = 0.046; 47/128 head and neck squamous cell carcinoma samples, 37%). Concurrent methylation of the VEGFR1 and VEGFR3 promoters significantly correlated with reduced disease free survival (log-rank test, p = 0.009). In a multivariate logistic regression analysis, methylation of the VEGFR1, VEGFR3 and both the VEGFR1 and VEGFR3 promoters independently predicted recurrence (odds ratios and 95% confidence intervals: 3.19, 1.51-6.75 (p = 0.002); 2.24, 1.06-4.76 (p = 0.035); and 2.56, 1.09-6.05 (p = 0.032), respectively). Methylation of the VEGFR promoters predicts poor prognosis in head and neck squamous cell carcinoma patients. PMID- 28718365 TI - TMEM88, CCL14 and CLEC3B as prognostic biomarkers for prognosis and palindromia of human hepatocellular carcinoma. AB - Hepatocellular carcinoma is one of the most mortal and prevalent cancers with increasing incidence worldwide. Elucidating genetic driver genes for prognosis and palindromia of hepatocellular carcinoma helps managing clinical decisions for patients. In this study, the high-throughput RNA sequencing data on platform IlluminaHiSeq of hepatocellular carcinoma were downloaded from The Cancer Genome Atlas with 330 primary hepatocellular carcinoma patient samples. Stable key genes with differential expressions were identified with which Kaplan-Meier survival analysis was performed using Cox proportional hazards test in R language. Driver genes influencing the prognosis of this disease were determined using clustering analysis. Functional analysis of driver genes was performed by literature search and Gene Set Enrichment Analysis. Finally, the selected driver genes were verified using external dataset GSE40873. A total of 5781 stable key genes were identified, including 156 genes definitely related to prognoses of hepatocellular carcinoma. Based on the significant key genes, samples were grouped into five clusters which were further integrated into high- and low-risk classes based on clinical features. TMEM88, CCL14, and CLEC3B were selected as driver genes which clustered high-/low-risk patients successfully (generally, p = 0.0005124445). Finally, survival analysis of the high-/low-risk samples from external database illustrated significant difference with p value 0.0198. In conclusion, TMEM88, CCL14, and CLEC3B genes were stable and available in predicting the survival and palindromia time of hepatocellular carcinoma. These genes could function as potential prognostic genes contributing to improve patients' outcomes and survival. PMID- 28718366 TI - Long non-coding RNA CCAT2 promotes cell proliferation and invasion through regulating Wnt/beta-catenin signaling pathway in clear cell renal cell carcinoma. AB - Clear cell renal cell carcinoma (ccRCC) is a common urologic malignancy. Long non coding RNA colon cancer-associated transcript 2 (CCAT2) has been suggested as serving pivotal roles in tumorigenesis. However, the clinical significance and biological role of CCAT2 in ccRCC remains elusive. The purpose of this study is to identify the function of CCAT2 in ccRCC and its possible molecular mechanism. Expression of CCAT2 was analyzed in 61 ccRCC tissues and two ccRCC cell lines (786-O and ACHN) by quantitative reverse transcription polymerase chain reaction. The functional roles of CCAT2 in ccRCC were determined by 3-(4,5-dimethylthiazol 2-yl)-2,5-diphenyltetrazolium bromide assay, colony formation assay, Transwell assay, and flow cytometric analysis. The influence of CCAT2 on tumorigenesis was monitored by in vivo mice xenograft model. The activation of Wnt/beta-catenin signaling pathway was evaluated by the TOP/FOP Wnt luciferase reporter assay and western blot assay. CCAT2 expression was markedly higher in ccRCC cell lines and tissues, being positively associated with tumor size and tumor stage in ccRCC patients. Patients with higher CCAT2 expression had a markedly poorer overall survival than did patients with low CCAT2 expression. Knocking down CCAT2 expression led to reduced cell proliferation and increased apoptosis of ccRCC cells in vitro as well as the activation of Wnt/beta-catenin signaling pathway, and CCAT2 overexpression remarkably enhanced these oncogenic properties. In vivo mice xenograft model also showed that knocking CCAT2 expression inhibited the growth of ccRCC xenografts. In conclusion, these results indicated that CCAT2 may play a critical role in ccRCC progression and will be further considered as a biomarker for predicting the survival of ccRCC patients and a potential therapeutic target for ccRCC intervention. PMID- 28718367 TI - HBXIP suppression reduces cell proliferation and migration and its overexpression predicts poor prognosis in non-small-cell lung cancer. AB - Emerging evidence has demonstrated that the high expression of HBXIP has been correlated with many cancers. With evaluation of the functional role of HBXIP in non-small-cell lung cancer, the primary aim of this study is to investigate the correlation between HBXIP expression and the prognosis of non-small-cell lung cancer patients. The protein levels of HBXIP were detected using western blotting in non-small-cell lung cancer cells. Cell proliferation and migration assays were measured to evaluate the function of HBXIP in non-small-cell lung cancer cells. A total of 120 non-small-cell lung cancer patients with strict follow-up and 60 adjacent non-tumor lung tissues were selected for immunohistochemical staining of the HBXIP protein. The localization of the HBXIP protein was detected in A549 non small-cell lung cancer cells using immunofluorescence staining. The correlation between HBXIP expression and the clinicopathological features of non-small-cell lung cancer patients was analyzed by a chi-squared and Fisher's exact test. The overall survival rates of all of the non-small-cell lung cancer patients were calculated using the Kaplan-Meier method, and univariate and multivariate analyses were performed using the Cox proportional hazards regression model. In function, we showed that suppression of HBXIP decreased A549 cell proliferation and migration. HBXIP protein showed a mainly cytoplasmic staining pattern in non small-cell lung cancer using immunohistochemical staining in paraffin-embedded non-small-cell lung cancer tissues and immunofluorescence staining in A549 cells. The HBXIP protein had strong positive staining in the non-small-cell lung cancer tissues, which was significantly higher than the percentage of adjacent non-tumor tissues. The overexpression of HBXIP was closely correlated with histological grade, clinical stage, lymph node metastasis, and lower overall survival rates of patients with non-small-cell lung cancer. Moreover, multivariate analysis suggested that HBXIP emerged as a significant independent prognostic factor along with clinical stage in patients with non-small-cell lung cancer. In conclusion, a high level of expression of HBXIP is associated with the progression of non-small cell lung cancer and may be a useful biomarker for poor prognostic evaluation and a potential molecular therapy target for patients with non-small-cell lung cancer. PMID- 28718368 TI - Remodeling of extracellular matrix of the lamina propria in the uninvolved human rectal mucosa 10 and 20 cm away from the malignant tumor. AB - In recent years, it has been demonstrated that malignancy arises and advances through the molecular interplay between tumor cells and non-malignant elements of the tumor stroma, that is, fibroblasts and extracellular matrix. However, in contrast to the mounting evidence about the role of tumor stroma in the genesis and progression of the malignant disease, there are very few data regarding the uninvolved stromal tissue in the remote surrounding of the tumor. Using the objective morphometric approach in patients with adenocarcinoma, we demonstrate the remodeling of extracellular matrix of the lamina propria in the uninvolved rectal mucosa 10 and 20 cm away from the neoplasm. We show that the representation of basic extracellular matrix constituents (reticular and collagen fibers and ground substance) is decreased. Also, the diameter of empty spaces that appear within the extracellular matrix of the lamina propria is increased. These spaces do not represent the blood or lymphatic vessel elements. Very likely, they reflect the development of tissue edema in the remote, uninvolved lamina propria of the mucosa in patients with the malignant tumor of the rectum. We hypothesize that the remodeling of extracellular matrix in lamina propria of the rectal mucosa may increase its stiffness, modulating the mechano-signal transduction, and thus promote the progression of the malignant disease. PMID- 28718369 TI - MiR-143 inhibits cell proliferation and invasion by targeting DNMT3A in gastric cancer. AB - Increasing evidence has suggested that MircroRNAs (miRNAs) dysregulated in pathogenesis and tumorigenicity in human cancers including gastric cancer (GC). MiR-143 had been reported to function as tumor suppressor in GC progression, however, the underlying function of miR-143 in GC still need to be well known. In the study, we revealed that miR-143 was significantly down-regulated in GC cell lines. Upregulation of miR-143 inhibited cell proliferation, invasion, S phase cell proportion and cell cycle related protein levels of Cyclin D1, CDK4 and CDK6 in GC. Furthermore, luciferase reporter assays demonstrated that DNMT3A was a direct target of miR-143 and Upregulation of miR-143 inhibited the DNMT3A mRNA and protein expression levels in GC cells. Moreover, we demonstrated that DNMT3A knockdown rescued the promoting effect of miR-143 inhibitor on cell proliferation in GC. Thus, these results demonstrated that miR-143 targeted DNMT3A in GC cells and inhibit GC tumorigenesis and progression, which may provide a novel therapeutic target of GC. PMID- 28718370 TI - Hook1 inhibits malignancy and epithelial-mesenchymal transition in hepatocellular carcinoma. AB - Hook1 is a member of the hook family of coiled-coil proteins, which is recently found to be associated with malignant tumors. However, its biological function in hepatocellular carcinoma is yet unknown. Here, we evaluated the Hook1 levels in human hepatocellular carcinoma samples and matched peritumoral tissues by real time polymerase chain reaction. Small interfering RNA knockdown and a transforming growth factor-beta-induced epithelial-mesenchymal transition model were employed to investigate the biological effects of Hook1 in hepatocellular carcinoma. Our results indicated that Hook1 levels were significantly lower in hepatocellular carcinoma tissues than in the peritumoral tissues. In addition, Hook1 expression was significantly associated with hepatocellular carcinoma malignancy. Hook1 was downregulated after transforming growth factor-beta-induced epithelial-mesenchymal transition. Moreover, Hook1 knockdown promoted epithelial mesenchymal transition and attenuated the sensitivity of hepatocellular carcinoma cells to doxorubicin. In summary, our results indicate that downregulation of Hook1 plays a pivotal role in hepatocellular carcinoma progression via epithelial mesenchymal transition. Hook1 may be used as a novel marker and therapeutic molecular target in hepatocellular carcinoma. PMID- 28718371 TI - Changes in the expression of genes involved in cell cycle regulation and the relative telomere length in the process of canceration induced by omethoate. AB - Organophosphorous pesticides (OPs), with high efficiency, broad-spectrum and low residue, are widely used in China. Omethoate is a broad category of organophosphorous pesticides and is more domestically utilized which has chronic toxic effect on human health caused by long-term, low-dose exposure to Ops, recently its potential genotoxicity has attracted wide attention which can cause chromosomal DNA damage. Thus, the aim of this study is screen susceptible biomarkers and explore the mechanism of canceration induced by omethoate. 180 long-term organophosphorus pesticide-exposed workers and 115 healthy controls were recruited. Quantitative polymerase chain reaction method was applied to determine the relative telomere length in peripheral lymphocyte DNA as well as p53 and p21 gene expression levels. Genetic polymorphisms were determined by the polymerase chain reaction-restriction fragment length polymorphism method. Multiple linear regression was conducted to explore the effects of exposure, expression levels, and polymorphisms in genes on the telomere length. The results showed the relative telomere lengths in the exposure group were significantly longer than that in the control group. The messenger RNA expression levels of p53 and p21 in exposure group were significantly lower than that in the control group; telomere lengths of the CA genotype individuals of p21 rs1801270 polymorphism locus were significantly longer than that of the CC genotype in the control group that were estimated using the Bonferroni method; and bivariate correlation analysis showed that the messenger RNA expression level of gene p53 was negatively correlated with telomere length, and the messenger RNA expression level of gene p21 was positively correlated with telomere length. Multivariate analysis found that p53 messenger RNA and p21 messenger RNA had an impact on telomere length. These results demonstrated that the messenger RNA expression levels of p53 and p21 may have a relationship with the changes in telomere length induced by omethoate and provided strong evidence for the mechanism of canceration induced by poison. PMID- 28718372 TI - MiR-592 functions as a tumor suppressor in glioma by targeting IGFBP2. AB - A growing body of evidence suggests that microRNA-592 is involved in tumor initiation and development in several types of human cancers. However, the biological functions and molecular mechanism of microRNA-592 in glioma remain unclear. In this study, we explored the potential role of microRNA-592 in glioma as well as the possible molecular mechanisms. Our results proved that microRNA 592 expression was significantly downregulated in glioma tissues and cell lines (p < 0.01). Functional assays revealed that overexpression of microRNA-592 dramatically reduced the cell proliferation, migration, and invasion and induced cell arrest at G1/G0 phase in vitro. Mechanistic investigations defined insulin like growth factor binding protein 2 as a direct and functional downstream target of microRNA-592, which was involved in the microRNA-592-mediated tumor suppressive effects in glioma cells. Moreover, the in vivo study showed that microRNA-592 overexpression produced the smaller tumor volume and weight in nude mice. In summary, these results elucidated the function of microRNA-592 in glioma progression and suggested a promising application of it in glioma treatment. PMID- 28718373 TI - Screening of specific nucleic acid aptamers binding tumor markers in the serum of the lung cancer patients and identification of their activities. AB - Lung cancer is by far the leading cause of cancer death in the world. Despite the improvements in diagnostic methods, the status of early detection was not achieved. So, a new diagnostic method is needed. The aim of this study is to obtain the highly specific nucleic acid aptamers with strong affinity to tumor markers in the serum of the lung cancer patients for targeting the serum. Aptamers specifically binding to tumor markers in the serum of the lung cancer patients were screened from the random single-stranded DNA library with agarose beads as supports and the serum as a target by target-substituting subtractive SELEX technique and real-time quantitative polymerase chain reaction technique. Subsequently, the secondary single-stranded DNA library obtained by 10 rounds of screening was amplified to double-stranded DNA, followed by high-throughput genome sequence analysis to screen aptamers with specific affinity to tumor markers in the serum of the lung cancer patients. Finally, six aptamers obtained by 10 rounds of screening were identified with high specific affinity to tumor markers in the serum of the lung cancer patients. Compared with other five aptamers, the aptamer 43 was identified both with the highest specificity to bind target molecule and without any obvious affinity to non-specific proteins. The screened aptamers have relatively high specificity to combine tumor markers in the serum of the lung cancer patients, which provides breakthrough points for early diagnosis and treatment of lung cancer. PMID- 28718375 TI - EMP3 is induced by TWIST1/2 and regulates epithelial-to-mesenchymal transition of gastric cancer cells. AB - In this study, we aimed to explore new downstream effectors of TWIST1/2 in inducing epithelial-to-mesenchymal transition in gastric cancer. Bioinformatic data mining was performed using data in The Cancer Genome Atlas Stomach Adenocarcinoma. Survival curves were generated using Kaplan-Meier plotter. Gastric cancer cell lines (AGS and SGC-7901) were used as in vitro cell model to investigate the regulative effect of TWIST1/2 on epithelial membrane protein 3 expression and the progression of epithelial-to-mesenchymal transition. Results showed that TWIST1 and TWIST2 are usually co-upregulated in patients with primary gastric cancer. High TWIST1 expression is associated with worse overall survival (hazard ratio = 1.26; 95% confidence interval = 1.06-1.49; p = 0.007) and also worse first progression-free survival (hazard ratio = 1.47; 95% confidence interval = 1.18-1.82; p < 0.0001). Similarly, high TWIST2 expression is associated with unfavorable overall survival (hazard ratio = 1.71; 95% confidence interval = 1.32-2.22; p < 0.0001) and progression-free survival (hazard ratio = 1.99; 95% confidence interval = 1.45-2.72; p < 0.0001). Epithelial membrane protein 3 is negatively correlated to CDH1 expression (Pearson's r = -0.46) but is positively correlated to VIM expression (Pearson's r = 0.83). Knockdown of epithelial membrane protein 3 significantly increased E-cadherin but significantly decreased Vimentin expression in AGS cells. Gastric cancer patients with metastasis have significantly higher epithelial membrane protein 3 expression than the cases without metastasis. In addition, high epithelial membrane protein 3 expression is associated with worse overall survival (hazard ratio = 2.59; 95% confidence interval = 2.06-3.26; p < 0.0001) and also worse progression-free survival (hazard ratio = 2.21; 95% confidence interval = 1.78 2.74; p < 0.0001). In conclusion, epithelial membrane protein 3 is a downstream effector of TWIST1/2 in inducing epithelial-to-mesenchymal transition in gastric cancer. Epithelial membrane protein 3 upregulation might be associated with gastric cancer metastasis and is a potential indicator of unfavorable overall survival and progression-free survival in gastric cancer patients. PMID- 28718374 TI - Cancer-associated fibroblasts secrete FGF-1 to promote ovarian proliferation, migration, and invasion through the activation of FGF-1/FGFR4 signaling. AB - Ovarian cancer is the most lethal gynecologic malignancy, due to its high propensity for metastasis. Cancer-associated fibroblasts, as the dominant component of tumor microenvironment, are crucial for tumor progression. However, the mechanisms underlying the regulation of ovarian cancer cells by cancer associated fibroblasts remain little known. Here, we first isolated cancer associated fibroblasts from patients' ovarian tissues and found that cancer associated fibroblasts promoted SKOV3 cells' proliferation, migration, and invasion. Fibroblast growth factor-1 was identified as a highly increased factor in cancer-associated fibroblasts compared with normal fibroblasts by quantitative reverse transcription polymerase chain reaction (~4.6-fold, p < 0.01) and ELISA assays (~4-fold, p < 0.01). High expression of fibroblast growth factor-1 in cancer-associated fibroblasts either naturally or through gene recombination led to phosphorylation of fibroblast growth factor receptor 4 in SKOV3 cells, which is followed by the activation of mitogen-activated protein kinase/extracellular signal-regulated protein kinase pathway and epithelial-to-mesenchymal transition associated gene Snail1 and MMP3 expression. Moreover, treatment of SKOV3 cell with fibroblast growth factor receptor inhibitor PD173074 terminated cellular proliferation, migration, and invasion, reduced the phosphorylation level of fibroblast growth factor receptor 4, and suppressed the activation of mitogen activated protein kinase/extracellular signal-regulated protein kinase pathway. In addition, the expression level of Snail1 and MMP3 was reduced, while the expression level of E-cadherin increased. These observations suggest a crucial role for cancer-associated fibroblasts and fibroblast growth factor-1/fibroblast growth factor receptor 4 signaling in the progression of ovarian cancer. Therefore, this fibroblast growth factor-1/fibroblast growth factor receptor 4 axis may become a potential target for the treatment of ovarian cancer. PMID- 28718376 TI - RIZ1 and histone methylation status in pituitary adenomas. AB - RIZ1 displays strong tumor-suppressive activities, which has a potential histone methyltransferase activity. The objective of the study was to evaluate the level and the methylation status of RIZ1 and analyze its association with clinicopathological features and the histone in the pituitary adenomas. We found that RIZ1-positive cases were 11/50 and H-Scores 22.75 +/- 11.83 in invasive pituitary adenomas and 26/53 and 66.3 +/- 21.7 in non-invasive pituitary adenomas (chi2 = 8.182, p = 0.004). RIZ1 and C-myc showed the opposite trend in these cases. The methylation levels of RIZ1 were more than 50% in 30.4% (7/23) CpG sites through MALDI-TOF Mass array. There was significant difference (p < 0.01) in 4 CpG sites between invasive pituitary adenoma group and non-invasive pituitary adenoma group; furthermore, the relieved methylation levels of H3K4/H3K9 and enhanced methylation levels of H3K27 in the patients' serum were found. Furthermore, there was statistic difference of H3K4 and H3K27 methylation between invasive pituitary adenoma and non-invasive pituitary adenoma group (p < 0.01). The average progression-free survival in high RIZ1 group was 52.63 +/- 7.62 months and 26.06 +/- 4.23 months in low RIZ1 group (p < 0.05). Promoter region methylation of RIZ1 may play an important role in the epigenetic silencing of RIZ1 expression in pituitary adenomas, which may translate into important diagnostic and therapeutic applications. PMID- 28718378 TI - MicroRNA-613 is downregulated in HCMV-positive glioblastoma and inhibits tumour progression by targeting arginase-2. AB - Glioblastoma is the most common and malignant tumour that occurs primarily in nervous system and has a high morbidity. Research on glioblastoma has recently focused on human cytomegalovirus, belonging to the beta subfamily of Herpesviridae that plays crucial roles in cancer development and progression. This study aimed to investigate the role of human cytomegalovirus-associated microRNA-613 in glioblastoma. In this study, we demonstrate that microRNA-613 expression was frequently reduced in human cytomegalovirus-positive glioblastoma specimens/cells compared with human cytomegalovirus-negative glioblastoma tissue/cells, and a significant correlation was observed between the reduction in microRNA-613 expression and the presence of unfavourable variables, including tumour size (p = 0.0118), World Health Organization stage (p = 0.0169), the overall survival (p = 0.0107) and disease-free (p = 0.0159) survival of patients. Overexpression of microRNA-613 in the glioblastoma cell lines U87 and U251 retarded cell growth and induced cell apoptosis. Upregulation of microRNA-613 inhibited glioblastoma cell clone formation, invasion and migration. Furthermore, we demonstrated that arginase-2 was directly regulated by microRNA-613 and played an essential role in mediating the biological effects of microRNA-613 in glioblastoma. Re-expression of arginase-2 markedly reversed the inhibitory properties of microRNA-613 in glioblastoma cells. Taken together, our data provide compelling evidence that human cytomegalovirus reduced the level of microRNA-613 which functions as an anti-onco-miRNA in glioblastoma, primarily by downregulating the expression of arginase-2. PMID- 28718377 TI - Downregulation of tyrosine threonine kinase inhibits tumor growth via G2/M arrest in human endometrioid endometrial adenocarcinoma. AB - Endometrial cancer is the most common gynecologic malignancy, about 80% of which is endometrial endometrioid carcinoma. Dysregulation of spindle assembly checkpoint plays a vital role in endometrial endometrioid carcinoma tumorigenesis and progression. The purpose of this study was to explore how tyrosine threonine kinase, a spindle assembly checkpoint-related protein, promotes the endometrial endometrioid carcinoma progression. We found that both messenger RNA and protein levels of tyrosine threonine kinase in endometrial endometrioid carcinoma tissues are higher than those in normal endometrial tissues, and its expression is associated with tumor stages. Genetic depletion of tyrosine threonine kinase by RNA interference in two endometrial endometrioid carcinoma cell lines significantly inhibits cell proliferation and induces apoptosis. Mechanistically, depletion of tyrosine threonine kinase induces G2/M cell cycle arrest and triggers caspase-dependent cell apoptosis. Collectively, tyrosine threonine kinase is significantly upregulated in endometrial endometrioid carcinoma, and downregulation of tyrosine threonine kinase can suppress endometrial endometrioid carcinoma cell proliferation and promote apoptosis via G2/M cell cycle arrest. Our study demonstrates that tyrosine threonine kinase can be a potential therapeutic target for endometrial endometrioid carcinoma treatment. PMID- 28718379 TI - Expression of embryonic stem cell markers in acute myeloid leukemia. AB - Acute myeloid leukemia is driven by leukemic stem cells which can be identified by cross lineage expression or arrest of differentiation compared to normal hematopoietic stem cells. Self-renewal and lack of differentiation are also features of stem cells and have been associated with the expression of embryonic genes. The aim of our study was to evaluate the expression of embryonic antigens (OCT4, NANOG, SOX2, SSEA1, SSEA3) in hematopoietic stem cell subsets (CD34+CD38- and CD34+CD38+) from normal bone marrows and in samples from acute myeloid leukemia patients. We observed an upregulation of the transcription factors OCT4 and SOX2 in leukemic cells as compared to normal cells. Conversely, SSEA1 protein was downregulated in leukemic cells. The expression of OCT4, SOX2, and SSEA3 was higher in CD34+CD38- than in CD34+CD38+ subsets in leukemic cells. There was no correlation with biological characteristics of the leukemia. We evaluated the prognostic value of marker expression in 69 patients who received an intensive treatment. The rate of complete remission was not influenced by the level of expression of markers. Overall survival was significantly better for patients with high SOX2 levels, which was unexpected because of the inverse correlation with favorable genetic subtypes. These results prompt us to evaluate the potential role of these markers in leukemogenesis and to test their relevance for better leukemic stem cell identification. PMID- 28718380 TI - The Burden of Genetic and Epigenetic Traits in Prematurity. AB - Despite decades of investigations and accumulated scientific knowledge, preterm birth (PTB) remains a significant burden worldwide. Several mechanisms have been proposed to explain this condition, and a number of risk factors from infectious to behavioral and genetic/epigenetic factors influence this outcome. The heritability of PTB is estimated to be 17% to 36%, which demonstrates that genetic predisposition plays a key role in PTB. Structural DNA modifications without changes in the DNA sequence and post-transcriptional regulation also have an impact on gene expression and thus influence pregnancy outcomes. There is a complex interplay between environmental factors and the individual's genetics and epigenetics that may culminate in PTB, but the complete regulatory pathways and networks involved in this context are still unclear. Here, we outline what is known so far about the genetic and epigenetic factors involved in preterm delivery, including polymorphisms, DNA methylation, and microRNAs, and suggest fields for research. PMID- 28718381 TI - Histological and Immunohistochemical Characterization of the Similarity and Difference Between Ovarian Endometriomas and Deep Infiltrating Endometriosis. AB - Ovarian endometrioma (OMA) and deep infiltrating endometriosis (DIE) have long been recognized to have different histology and, as such, postulated to be 2 separate disease entities. Few studies, however, have attempted to elucidate the causes for their differences. Making use of ectopic endometrial tissue samples from 25 and 20 women with OMA and DIE, respectively, and control endometrial tissue samples from 25 women without endometriosis, we conducted an immunohistochemical analysis to evaluate the expression of a group of carefully chosen markers for epithelial-mesenchymal transition (EMT), fibroblast-to myofibroblast transdifferentiation (FMT), smooth muscle metaplasia (SMM), fibrosis, vascularity, hormonal receptors, and proteins involved in epigenetic modifications. We found that both OMA and DIE lesions exhibited the same cellular changes consistent with EMT, FMT, SMM, and fibrosis as already shown in animal models. Compared to OMA, DIE lesions underwent more thorough and extensive EMT, FMT, and SMM and, consequently, displayed significantly higher fibrotic content but less vascularity. The 2 conditions also showed different expression levels of hormonal receptors. Both OMA and DIE lesions, especially the latter, showed significantly higher staining of enhancer of zeste homolog 2, H3K9me3, and H3K27me3 than that of control endometrium, suggesting progressive epigenetic changes concomitant with cellular ones. Finally, proteins that are known to be involved in fibrogenesis, such as thymocyte differentiation antigen 1 and peroxisome proliferator-activated receptor gamma , were also aberrantly expressed under both conditions. The many similarities shared by both OMA and DIE indicate that the 2 conditions may actually share the same pathogenesis/pathophysiology. Their differences, however, suggest that the source of these differences may result from the different lesional microenvironments. PMID- 28718382 TI - Establishing Clinical Pharmacy Services With Prescribing Privileges in a Federally Qualified Health Center Primary Care Clinic. AB - OBJECTIVES: To describe the process and cost of establishing clinical pharmacy services with prescribing privileges in a federally qualified health center (FQHC) primary care clinic. SETTING: The primary care clinic was located in a low income area of Southern California and served patients with Medicaid and Medicare. The primary care clinic had preventive medicine and family medicine physicians, a family medicine residency program, behavioral health services, and a registered dietician. PRACTICE INNOVATION: New clinical pharmacy services were established at this FQHC primary care clinic. The medication assistance program was a stepping stone to establish rapport with the physicians. Credentialing and privileging was implemented for clinical pharmacists. An open protocol collaborative practice agreement was developed to allow clinical pharmacists to manage ambulatory patients. RESULTS: From August 2014 to June 2015, the clinical pharmacist interacted with 392 patients and spent 336 hours educating patients and providing disease state management. The pharmacist also provided consults to residents and providers. Diabetic patients made up 76% of all clinical pharmacy encounters. There were 86 face-to-face clinical pharmacy appointments with the pharmacist. The average time for clinical pharmacy appointments was 77 minutes. CONCLUSION: By describing ways to develop rapport with providers, how to credential and privilege pharmacists, and explain resources and costs of setting up a service, the hope is that more clinical pharmacists will be able to incorporate into independent or FQHC primary care clinics for improved management of ambulatory patients. PMID- 28718383 TI - Mortality in England - erroneous attribution of excess winter deaths to underlying trend. PMID- 28718384 TI - Response to Jones and Milne. PMID- 28718386 TI - A future of technology and other humans. PMID- 28718388 TI - George Starkey's 1658 challenge to Galenists to compare their treatment results with his. PMID- 28718391 TI - Corrigendum. AB - Operating and environmental performances of commercial-scale waste gasification and melting technology by Nobuhiro Tanigaki, Yasuka Fujinaga, Hirohisa Kajiyama, and Yoshihiro Ishida. Waste Management & Research 2013; 31: 1118-1124, DOI: 10.1177/0734242X13502386. The authors regret that they omitted the following declaration of conflicting interest in the article: Declaration of Conflicting Interest At the time of publication, all authors were employed by Nippon Steel & Sumikin Engineering Co., Ltd. Technology developed by Nippon Steel & Sumikin Engineering Co., Ltd is reported on in this manuscript. PMID- 28718392 TI - Efficient body fat estimation using multistage pair ranked set sampling. AB - Rank-based sampling methods are applicable in settings where precise measurements are expensive, but small sets of units can be accurately ranked at negligible cost. This article introduces one such a design, called multistage pair ranked set sampling. It mitigates ranking burden associated with a competitor scheme, namely multistage ranked set sampling. The mean estimator in multistage pair ranked set sampling is unbiased, and under perfect rankings has variance no larger than its simple random sampling counterpart. Although the suggested mean estimator is outperformed by its multistage ranked set sampling analog in terms of precision under perfect rankings, the situation may be reversed if cost considerations are taken into account. The methodology is illustrated using a medical dataset. PMID- 28718394 TI - Multiple possible inaccuracies cast doubt on a recent report suggesting selective serotonin reuptake inhibitors to be toxic and ineffective. AB - According to a systematic review on the use of selective serotonin reuptake inhibitors (SSRIs) in adult depression that was recently published in BMC Psychiatry, the results of which have been widely disseminated in lay media, these drugs increase the risk for serious adverse events (SAEs) while exerting poor antidepressant efficacy. A cursory analysis, however, suggests the analysis of SAEs conducted by the authors to be marred by both methodological inaccuracies and blatant errors. After having corrected for these apparent mistakes, we conducted a sensitivity analysis in which we also accounted for a possible moderating effect of age; while this suggests SSRIs to be safe drugs in the non elderly, they do confirm what is already known, that is, that they may enhance the risk for SAEs in the old. Given the loose definition of SAE, including also innocuous phenomena, the possible clinical significance of the latter observation, however, remains unclear until the nature and actual impact of the SAEs in question have been clarified. Moreover, with respect to efficacy, we find the paper in BMC Psychiatry misleading: first, the authors seem unaware of the well-established shortcomings associated with the conventional efficacy parameter on which their analysis is based, second, they have included suboptimal SSRI doses and third, they have missed some pivotal trials. Unless there are explanations for the many peculiarities in this paper that have escaped us, and which may be satisfactorily clarified by the authors, it seems important that the conclusions presented in this paper be publicly rectified. PMID- 28718395 TI - Ultrasound-guided wire localisation to facilitate removal of an abnormal neck lymph node - a technical note. AB - BACKGROUND: Ultrasound-guided wire localisation is a technique that is well established in breast surgery, but is not well described in head and neck practice. It can be used to locate impalpable lesions for surgical removal, without the need for more extensive surgery. METHOD: This paper describes a case where the technique was used to assist in the removal of an impalpable but radiologically abnormal lymph node. CONCLUSION: The technique offers a safe and effective method for removing lesions within the head and neck. PMID- 28718396 TI - A structured literature review on the role of mindfulness, mindful eating and intuitive eating in changing eating behaviours: effectiveness and associated potential mechanisms. AB - The role of mindfulness, mindful eating and a newer concept of intuitive eating in modulating eating habits is an area of increasing interest. In this structured literature review, a summary of the current evidence is presented, together with details of interventions undertaken and the tools to measure outcomes. It is broad in scope given the emerging evidence base in this area. The review yielded sixty-eight publications: twenty-three interventions in obese/overweight populations; twenty-nine interventions in normal-weight populations; sixteen observational studies, three of which were carried out in overweight/obese populations. Mindfulness-based approaches appear most effective in addressing binge eating, emotional eating and eating in response to external cues. There is a lack of compelling evidence for the effectiveness of mindfulness and mindful eating in weight management. Mindfulness-based approaches may prevent weight gain. Reduced food intake was seen in some of the studies in overweight and obese populations, but this was less apparent in the studies in normal-weight populations. The evidence base for intuitive eating is limited to date and further research is needed to examine its potential in altering eating behaviours. Mindfulness appears to work by an increased awareness of internal, rather than external, cues to eat. Mindfulness and mindful eating have the potential to address problematic eating behaviours and the challenges many face with controlling their food intake. Encouraging a mindful eating approach would seem to be a positive message to be included in general weight management advice to the public. PMID- 28718397 TI - The Vitamin D Standardization Program (VDSP) Manual for Retrospective Laboratory Standardization of Serum 25-Hydroxyvitamin D Data. AB - Low concentrations of total 25-hydroxyvitamin D [25(OH)D], the principal biological measure of vitamin D status, have been associated with clinical and public health outcomes. The determination of levels under which there is an increase in the risk of disease, as well as comparisons across populations, have been difficult to establish due the large assay variability in measuring 25(OH)D. Accordingly, the Vitamin D Standardization Program (VDSP) includes the retrospective standardization of existing 25(OH)D values collected by epidemiological and clinical studies, as well as clinical trials, as one of its main objectives. We introduce methodology developed by the VDSP that can be used to standardize the measurement of time-stable analytes, including 25(OH)D, in samples that have been banked and maintained appropriately. Sample size estimation formulae are first applied to calculate the required number of banked blood samples to be reanalyzed using either of two approaches. In the first approach, existing samples are remeasured using the current measurement procedure, and an equation relating "old" to "current" measurements is obtained. A second set of sera, usually 40-50 single-donor serum samples, are measured with the current measurement procedure and an assay traceable to a reference measurement procedure and/or certified reference materials, which yields a second calibration equation. These two equations are combined to produce standardized levels from the original old values. This approach is necessary when study restrictions prevent serum samples from being shipped to an external laboratory and is illustrated with samples from the Canadian Health Measures Survey. When serum samples are permitted to be shared with other laboratories, or the study investigators can carry out the measurements with a traceable assay, a single calibration equation method is used. Existing samples are selected and remeasured using the available traceable assay. We outline the statistical theory supporting the VDSP protocol and provide implementation examples. The methods proposed are generalizable to any instance in which banked specimens have been properly prepared and stored and the analyte of interest is stable under those conditions. PMID- 28718398 TI - Comparative Study of NMR Spectral Profiling for the Characterization and Authentication of Cannabis. AB - For the authentication of botanical materials, it is difficult to obtain representative reference materials because botanicals vary significantly with respect to cultivation conditions. Chemical profiling of plant extracts or spectral fingerprinting can differentiate botanicals and group them by their chemical profiles. NMR spectroscopy yields a powerful and useful method for profiling plant extracts. Both 500 MHz 1H and 1H-1H correlation NMR spectroscopy coupled with pattern recognition were used to discriminate among Cannabis samples. A rapid method of analysis was achieved by extracting directly into the deuterated solvent. Spectral ranges including or excluding the downfield region were compared to evaluate the effect on classification accuracy by projected difference resolution. Six classification methods-fuzzy rule-building expert system, linear discriminant analysis (LDA), super partial least-squares discriminant analysis, support vector machine (SVM), and SVM classification trees (SVMTrees)-all gave better classification performance for proton NMR spectra than for proton-proton correlation NMR spectra for seven Cannabis samples. Among the classification methods for a set of 25 Cannabis samples, the 0.5-7.2 plus 7.4 13.0 ppm ranges gave higher prediction rates of greater than 96% when compared to the reduced range of 0.5-7.2 ppm that excluded the downfield range. The LDA method had the best prediction accuracy of 99.8 +/- 0.4%. SVMTree methods provide a robust tool, and classification trees are amenable to interpretation. Hence, NMR spectroscopy combined with chemometrics could be used as a fast screening method for the authentication of Cannabis samples. PMID- 28718399 TI - Certified Reference Material for Use in 1H, 31P, and 19F Quantitative NMR, Ensuring Traceability to the International System of Units. AB - In recent years, quantitative NMR (qNMR) spectroscopy has become one of the most important tools for content determination of organic substances and quantitative evaluation of impurities. Using Certified Reference Materials (CRMs) as internal or external standards, the extensively used qNMR method can be applied for purity determination, including unbroken traceability to the International System of Units (SI). The implementation of qNMR toward new application fields, e.g., metabolomics, environmental analysis, and physiological pathway studies, brings along more complex molecules and systems, thus making use of 1H qNMR challenging. A smart workaround is possible by the use of other NMR active nuclei, namely 31P and 19F. This article presents the development of three classes of qNMR CRMs based on different NMR active nuclei (1H, 31P, and 19F), and the corresponding approaches to establish traceability to the SI through primary CRMs from the National Institute of Standards and Technology and the National Metrology Institute of Japan. These TraceCERT(r) qNMR CRMs are produced under ISO/IEC 17025 and ISO Guide 34 using high-performance qNMR. PMID- 28718401 TI - Targeting ATF5 in Cancer. AB - The expression of activating transcription factor 5 (ATF5) correlates negatively with patient survival in different types of cancer. ATF5 is important for the survival and proliferation of cancer cells, and can be targeted to selectively trigger cancer cell apoptosis while sparing normal cells. Cell-penetrating peptides combined with a dominant negative ATF5 cargo have recently shown efficacy against brain, breast, melanoma, and prostate cancers. PMID- 28718400 TI - Histone H3G34R mutation causes replication stress, homologous recombination defects and genomic instability in S. pombe. AB - Recurrent somatic mutations of H3F3A in aggressive pediatric high-grade gliomas generate K27M or G34R/V mutant histone H3.3. H3.3-G34R/V mutants are common in tumors with mutations in p53 and ATRX, an H3.3-specific chromatin remodeler. To gain insight into the role of H3-G34R, we generated fission yeast that express only the mutant histone H3. H3-G34R specifically reduces H3K36 tri-methylation and H3K36 acetylation, and mutants show partial transcriptional overlap with set2 deletions. H3-G34R mutants exhibit genomic instability and increased replication stress, including slowed replication fork restart, although DNA replication checkpoints are functional. H3-G34R mutants are defective for DNA damage repair by homologous recombination (HR), and have altered HR protein dynamics in both damaged and untreated cells. These data suggest H3-G34R slows resolution of HR mediated repair and that unresolved replication intermediates impair chromosome segregation. This analysis of H3-G34R mutant fission yeast provides mechanistic insight into how G34R mutation may promote genomic instability in glioma. PMID- 28718402 TI - Metabolism during ECM Detachment: Achilles Heel of Cancer Cells? AB - Integrin-mediated attachment to the extracellular matrix (ECM) is required to combat the induction of programmed cell death in a variety of distinct cell types. If cells fail to maintain proper ECM attachment, they become subject to elimination via an apoptotic cell death program known as anoikis. However, anoikis inhibition is not sufficient to promote the long-term survival of ECM detached cells. Several recent studies have unveiled the profound (anoikis independent) impact of cell metabolism on the viability of ECM-detached cells. Thus, we posit that, during metastatic dissemination (when cancer cells are exposed to periods of ECM detachment), cancer cells must alter their metabolism in a fashion that promotes survival and ultimately contributes to metastatic outgrowth. PMID- 28718403 TI - ADAM Metalloprotease-Released Cancer Biomarkers. AB - Identification of early cancer, detection of progression, and monitoring of therapeutic success remain urgent issues in clinical medicine, particularly given the increasing cancer incidence in our aging populations. New methodologies have provided enormous progress over the past decades by defining the genetic and proteomic composition of cancers, yielding putative cancer biomarkers detectable in blood or other body fluids less invasively and more cheaply than using currently available screening techniques that often involve biopsies or surgery. However, the clinical use of these new methodologies is still far off. In this review, we focus on putative soluble cancer biomarkers shed from the cell surface by metalloproteases overexpressed in numerous cancers. Although useful candidates have been identified, their validation and adoption into clinical use remain challenging. PMID- 28718404 TI - Emerging Role of the Unfolded Protein Response in Tumor Immunosurveillance. AB - Disruption of endoplasmic reticulum (ER) homeostasis results in ER stress and activation of the unfolded protein response (UPR). This response alleviates cell stress, and is activated in both tumor cells and tumor infiltrating immune cells. The UPR plays a dual function in cancer biology, acting as a barrier to tumorigenesis at the premalignant stage, while fostering cancer maintenance in established tumors. In infiltrating immune cells, the UPR has been involved in both immunosurveillance and immunosuppressive functions. This review aims to decipher the role of the UPR at different stages of tumorigenesis and how the UPR shapes the balance between immunosurveillance and immune escape. This knowledge may improve existing UPR-targeted therapies and the design of novel strategies for cancer treatment. PMID- 28718405 TI - RNA-Binding Proteins in Cancer: Old Players and New Actors. AB - RNA-binding proteins (RBPs) are key players in post-transcriptional events. The combination of versatility of their RNA-binding domains with structural flexibility enables RBPs to control the metabolism of a large array of transcripts. Perturbations in RBP-RNA networks activity have been causally associated with cancer development, but the rational framework describing these contributions remains fragmented. We review here the evidence that RBPs modulate multiple cancer traits, emphasize their functional diversity, and assess future trends in the study of RBPs in cancer. PMID- 28718406 TI - Targeting Hypoxia-Inducible Factors for Antiangiogenic Cancer Therapy. AB - Hypoxia (low O2) is a pathobiological hallmark of solid cancers, resulting from the imbalance between cellular O2 consumption and availability. Hypoxic cancer cells (CCs) stimulate blood vessel sprouting (angiogenesis), aimed at restoring O2 delivery to the expanding tumor masses through the activation of a transcriptional program mediated by hypoxia-inducible factors (HIFs). Here, we review recent data suggesting that the efficacy of antiangiogenic (AA) therapies is limited in some circumstances by HIF-dependent compensatory responses to increased intratumoral hypoxia. In lieu of this evidence, we discuss the potential of targeting HIFs as a strategy to overcome these instances of AA therapy resistance. PMID- 28718407 TI - Cell and Tissue Biology Paves a Path to Breast Cancer Prevention. AB - We hypothesize that breast cancer susceptibility stems from interactions between difficult-to-modify cultural and dietary habits and aging processes that are modifiable. We propose a pathway to prevention that uses human organotypic systems that recapitulate hallmarks of aging in order to better understand and to modulate the biological consequences of aging in breast. PMID- 28718408 TI - A Common Clinical Dilemma: Management of Persistent hrHPV Infection. AB - Persistent infection with high-risk human papillomavirus (hrHPV) is a key step in the development of cervical cancer. However, making clinical decisions about how to deal with these cases has become a challenge for obstetrics and gynecology (Ob/Gyn) practitioners. Here, we review the latest research findings and propose possible solutions for the management of persistent hrHPV infections. PMID- 28718409 TI - Metronomic Chemotherapy: Direct Targeting of Cancer Cells after all? AB - Metronomic chemotherapy (MC) was initially described as an antiangiogenic therapy more than 15 years ago. Over the past few years, additional data have highlighted the impact of MC on the microenvironment beyond angiogenesis, with, most importantly, a potential impact on the immune system. Here, we review and reappraise the fact that MC might be able to directly kill cancer cells. Although long neglected, this question is of critical importance both fundamentally and clinically, especially when considering future associations with immunotherapies. PMID- 28718410 TI - Plastic Heterogeneity of Innate Lymphoid Cells in Cancer. AB - Innate lymphoid cells (ILCs) fulfill important protective and reparative functions, and have thus been implicated in the maintenance of tissue homeostasis. Dysregulation of their activation is associated with several autoimmune and inflammatory diseases. The current literature on the role of ILCs in cancer is limited and our knowledge is therefore incomplete. Indeed, ILCs have been separately associated with tumor-promoting as well as tumor-suppressing activities, raising the need to understand the mechanisms by which these cells regulate tumor growth and progression toward a rational design of therapeutic approaches. We focus here on the heterogeneity of ILCs and discuss currently known mechanisms of their plasticity. PMID- 28718411 TI - Molecular Events in the Natural History of Pancreatic Cancer. AB - Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest epithelial malignancies. Improvements in our understanding of PDAC carcinogenesis will hopefully improve its detection, management, and outcomes, as has been achieved with other malignancies. Here we review the literature on the natural history of PDAC, including its cell of origin, the initiating somatic mutational events, pathways deranged in the mature tumor, its biological heterogeneity, and the relationship of the primary tumor with metastases. We also suggest areas for further research and highlight translatable findings that are beginning to make clinical inroads. PMID- 28718412 TI - Stem Cells, Cancer, and MUSASHI in Blood and Guts. AB - The mammalian MSI family of RNA-binding proteins (RBPs) have important roles as oncoproteins in an array of tumor types, including leukemias, glioblastomas, and pancreatic, breast, lung, and colorectal cancers. The mammalian Msi genes, Msi1 and Msi2, have been most thoroughly investigated in two highly proliferative tissues prone to oncogenic transformation: the hematopoietic lineage and the intestinal epithelium. Despite their vast phenotypic differences, MSI proteins appear to have an analogous role in governing the stem cell compartment in both of these tissues, potentially providing a paradigm for a broader understanding of MSI function and oncogenic activities. In this review, we focus on the function of MSI in the blood and the intestine, and discuss therapeutic strategies for targeting this pathway. PMID- 28718413 TI - Intrinsic Molecular Processes: Impact on Mutagenesis. AB - Mutations provide resources for genome evolution by generating genetic variability. In addition, mutations act as a driving force leading to disease pathogenesis, and thus have important implications for disease diagnosis, prognosis, and treatment. Understanding the mechanisms underlying how mutations occur is therefore of prime importance for elucidating evolutionary and pathogenic processes. Recent genomics studies have revealed that mutations occur non-randomly across the human genome. In particular, the distribution of mutations is highly associated with intrinsic molecular processes including transcription, chromatin organization, DNA replication timing, and DNA repair. Interplay between intrinsic processes and extrinsic mutagenic exposure may thus imprint a characteristic mutational landscape on tumors. We discuss the impact of intrinsic molecular processes on mutation acquisition in cancer. PMID- 28718414 TI - Epigenetics and Cancer Stem Cells: Unleashing, Hijacking, and Restricting Cellular Plasticity. AB - Epigenetic mechanisms have emerged as key players in cancer development which affect cellular states at multiple stages of the disease. During carcinogenesis, alterations in chromatin and DNA methylation resulting from genetic lesions unleash cellular plasticity and favor oncogenic cellular reprogramming. At later stages, during cancer growth and progression, additional epigenetic changes triggered by interaction with the microenvironment modulate cancer cell phenotypes and properties, and shape tumor architecture. We review here recent advances highlighting the interplay between epigenetics, genetics, and cell-to cell signaling in cancer, with particular emphasis on mechanisms relevant for cancer stem cell formation (CSC) and function. PMID- 28718415 TI - Aging: Fewer Obstacles to DNA Replication? AB - Many cancers are initiated by loss-of-heterozygosity (LOH) events that lead to the replacement of single, functional tumor suppressor genes by the mutant alleles. The underlying mechanisms, of why LOH rates increase with age, are not well understood. We discuss the possible involvement of difficult-to-replicate (fragile) chromosomal sites in this process. PMID- 28718416 TI - The Untold Story of Granzymes in Oncoimmunology: Novel Opportunities with Old Acquaintances. AB - For more than 20 years perforin and granzymes (GZMs) have been recognized as key cell death executors of cytotoxic T (Tc) and natural killer (NK) cells during cancer immunosurveillance. In immune surveillance, perforin and GZMB, the most potent cytotoxic molecules, act mainly as antitumoral and anti-infectious factors. However, when expressed by immune regulatory cells they may contribute to immune evasion of specific cancer types. By contrast, the other major granzyme, GZMA, seems not to play a major role in Tc/NK cell-mediated cytotoxicity, but acts as a proinflammatory cytokine that might contribute to cancer development. Members of the GZM family also regulate other biological processes unrelated to cell death, such as angiogenesis, vascular integrity, extracellular matrix remodeling, and barrier function, all of which contribute to cancer initiation and progression. Thus, a new paradigm is emerging in the field of oncoimmunology. Can GZMs act as protumoral factors under some circumstances? We review the diverse roles of GZMs in cancer progression, and new therapeutic opportunities emerging from targeting these protumoral roles. PMID- 28718417 TI - Exercise and the Hallmarks of Cancer. AB - A wealth of evidence supports an association between regular physical activity (PA) and decreased risk for cancer and cancer mortality. This is clearly an important issue given the growing worldwide incidence of both cancer and physical inactivity. Of further importance is unraveling the biological mechanisms that explain the potential preventive effects of PA against the development of cancer, as this might improve our understanding of cancer biology and assist researchers exploring novel treatment strategies. Here we review mechanistic studies that help explain the anticancer effects of exercise based on how exercise impacts hallmark features of cancer. We also discuss the emerging role of myokines, methodological caveats in the field, and potential questions that remain to be addressed in future research. PMID- 28718418 TI - Novel Insights into Membrane Targeting of B Cell Lymphoma. AB - Standard therapy of patients with B cell non-Hodgkin lymphoma (B-NHL) predominantly consists of chemotherapy combined with anti-CD20 (e.g., rituximab) immunotherapy. However, relapse of aggressive B-NHL occurs frequently, and this may coincide with therapy resistance. This demonstrates the urgent need for exploring new lymphoma-targeted therapies. We review here recent insights in the pathophysiology of B-NHL and discuss CD20 and three alternative membrane targets (B cell receptor, immune checkpoints PD-1/PD-L1, tetraspanin CD37) that are currently in the spotlight for B-NHL treatment. Furthermore, we present a novel concept in which the plasma membrane organization of the lymphoma B cell determines the efficacy of membrane-targeted therapies, and this has consequences for treatment application and clinical outcome in patients with B cell lymphoma. PMID- 28718420 TI - Corrigendum to "One proboscis, two tasks: Adaptations to blood-feeding and nectar extracting in long-proboscid horse flies (Tabanidae, Philoliche)" [Arthropod Struct. Dev. 43 (2014) 403-413]. PMID- 28718419 TI - Targeting PI3K Signaling in Combination Cancer Therapy. AB - Targeting upstream phosphatidylinositol-3-kinases (PI3Ks) in the PI3K/Akt/mTOR pathway appears to be a promising therapy in solid cancers; however, first early clinical trials with PI3K inhibitors in monotherapy have been disappointing. A massive array of preclinical and clinical trials are currently evaluating combinations of PI3K inhibitors in targeted therapies. These combinations include co-treatments with drugs directed against other intra-/extracellular signaling molecules, nuclear hormone receptors, DNA damage repair enzymes, and immune modulators. We review the literature and pinpoint mechanisms of action in different genomic and organ contexts. Combinatorial approaches are potentially superior to monotherapies and should become alternative clinical strategies to treat cancer patients. PMID- 28718421 TI - Corrigendum to "Metal-assisted synthesis of unsymmetrical magnolol and honokiol analogs and their biological assessment as GABAA receptor ligands" [Bioorg. Med. Chem. Lett. 25/2 (2015) 400-403]. PMID- 28718422 TI - Secondary Necrosis: Accidental No More. AB - Recent data demonstrate that secondary necrosis is not an accidental epiphenomenon of apoptosis, but a finely regulated process with prominent pathophysiological and therapeutic implications. The molecular machinery that controls secondary necrosis stands out as a promising target for the development of novel drugs that may increase the immunogenicity of cancer cells succumbing to treatment. PMID- 28718423 TI - Angiogenesis and Metabolism: Entwined for Therapy Resistance. AB - Angiogenesis and metabolism are entwined processes that permit tumor growth and progression. Blood vessel supply is necessary for tumor survival not only by providing oxygen and nutrients for anabolism but also by removing waste products from cellular metabolism. On the other hand, blocking angiogenesis with antiangiogenic therapies shows clinical benefits in treating several tumor types. Nevertheless, resistance to therapy emerges over time. In this review we discuss a novel mechanism of adaptive resistance involving metabolic adaptation of tumor cells, and we also provide examples of tumor adaptation to therapy, which may represent a new mechanism of resistance in several types of cancer. Thus, targeting this metabolic tumor adaptation could be a way to avoid resistance in cancer patients. PMID- 28718424 TI - Targeted Therapy and Immunosuppression in the Tumor Microenvironment. AB - Small-molecule inhibitors offer great promise for targeting pathways that are specifically deregulated in different tumors. However, such 'targeted' therapies also elicit poorly understood effects on protective antitumor immunity. Given the emerging relevance of immunotherapies that boost pre-existing T cell responses, understanding how different immune cells are affected by small-molecule inhibitors could lead to more-effective interventions, alone or combined with immunotherapy. This review discusses the growing array of activities elicited by multiple 'targeted' inhibitors on antitumor immunity, underscoring the complex effects resulting from diverse activities on different immune cell types in vivo, and the need to conduct mechanistic research that identifies drugs performing well not only in immunocompromised mice but also in the presence of spontaneous or therapeutic antitumor immunity. PMID- 28718426 TI - Targeting TGF-beta Signaling in Cancer. AB - The transforming growth factor (TGF)-beta signaling pathway is deregulated in many diseases, including cancer. In healthy cells and early-stage cancer cells, this pathway has tumor-suppressor functions, including cell-cycle arrest and apoptosis. However, its activation in late-stage cancer can promote tumorigenesis, including metastasis and chemoresistance. The dual function and pleiotropic nature of TGF-beta signaling make it a challenging target and imply the need for careful therapeutic dosing of TGF-beta drugs and patient selection. We review here the rationale for targeting TGF-beta signaling in cancer and summarize the clinical status of pharmacological inhibitors. We discuss the direct effects of TGF-beta signaling blockade on tumor and stromal cells, as well as biomarkers that can predict the efficacy of TGF-beta inhibitors in cancer patients. PMID- 28718425 TI - NLRC5/CITA: A Key Player in Cancer Immune Surveillance. AB - Cancer cells need to escape immune surveillance for successful tumor growth. Loss of MHC class I has been described as a major immune evasion strategy in many cancers. MHC class I transactivator (CITA), NLRC5 [nucleotide-binding domain and leucine-rich repeats containing (NLR) family, caspase activation and recruitment domain (CARD) domain containing 5], is a key transcription coactivator of MHC class I genes. Recent genetic studies have revealed that NLRC5 is a major target for cancer immune evasion mechanisms. The reduced expression or activity of NLRC5 caused by promoter methylation, copy number loss, or somatic mutations is associated with defective MHC class I expression, impaired cytotoxic T cell activation, and poor patient prognosis. Here, we review the role of NLRC5 in cancer immune evasion and the future prospects for cancer research. PMID- 28718427 TI - Signatures of Breast Cancer Metastasis: aMENAble to Interpretation? AB - MenaINV, an isoform of the motility regulator protein Mena, contributes to prometastatic phenotypes. Tumor microenvironment of metastasis (TMEM), a three cell structure associated with intravasation, contains a stationary Mena expressing tumor cell. TMEM density and MenaINV expression both correlate with poor clinical outcome in breast cancer patients. However, is MenaINV involved in TMEM assembly and function? PMID- 28718428 TI - IFN Signaling and ICB Resistance: Time is on Tumor's Side. AB - Activation of antitumor immunity upon immune checkpoint blockade (ICB) is one of the most promising strategies in cancer therapy. However, ICB resistance is frequently observed in cancer preclinical models and patients. A recent report in Cell reveals that sustained interferon (IFN) signaling confers tumor resistance to ICB by inducing the expression of an immunosuppressive multigenic program. PMID- 28718429 TI - Activated ERK: An Emerging Player in miRNA Downregulation. AB - To date, the mechanisms underlying global downregulation of miRNAs in cancer remain largely unclear. Recent findings indicate that activated ERK can cause widespread miRNA repression through suppressing the major steps of miRNA biogenesis. Here we discuss how ERK signaling globally downregulates miRNAs and how this contributes to tumorigenesis. PMID- 28718430 TI - Liquid Biopsies in Colorectal Cancer: Monitoring Genetic Heterogeneity. AB - Dynamic changes in the colorectal cancer (CRC) signalome and tumor genetic heterogeneity underlie acquired drug resistance. Improving treatment-related decisions is facilitated by an emerging consensus in the classification of tumor subtypes as well as by real-time monitoring of predictive biomarkers in circulating tumor cells and DNA. PMID- 28718432 TI - Autoantibodies: Opportunities for Early Cancer Detection. AB - Cancer cells can induce an immunological response resulting in the production of tumor-associated (TA) autoantibodies. These serum immunobiomarkers have been detected for a range of cancers at an early stage before the development of clinical symptoms. Their measurement is minimally invasive and cost effective using established technologies. TA autoantibodies are present in a clinically significant number of individuals and could supplement current screening modalities to aid early diagnosis of high-risk populations and assist the clinical management of patients. Here we review their production, discovery, and validation as biomarkers for cancer and their current and future potential as clinical tools. PMID- 28718431 TI - Racial Differences in Cancer Susceptibility and Survival: More Than the Color of the Skin? AB - Epidemiological studies point to race as a determining factor in cancer susceptibility. In US registries recording cancer incidence and survival by race (distinguishing 'black versus white'), individuals of African ancestry have a globally increased risk of malignancies compared with Caucasians and Asian Americans. Differences in socioeconomic status and health-care access play a key role. However, the lesser disease susceptibility of Hispanic populations with comparable lifestyles and socioeconomic status as African Americans (Hispanic paradox) points to the concomitant importance of genetic determinants. Here, we overview the molecular basis of racial disparity in cancer susceptibility ranging from genetic polymorphisms and cancer-driver gene mutations to obesity, chronic inflammation, and immune responses. We discuss implications for race-adapted cancer screening programs and clinical trials to reduce disparities in cancer burden. PMID- 28718434 TI - Undercover Agents: Targeting Tumours with Modified Platelets. AB - Platelets have long been recognised to colocalise with tumour cells throughout haematogenous metastasis. Interactions between these cells contribute to tumour cell survival and motility through the vasculature into other tissues. Now, the research focus is shifting towards developing means to exploit this relationship to provide accurate diagnostics and therapies. Alterations to platelet count, RNA profile, and platelet ultrastructure are associated with the presence of certain malignancies, and may be used for cancer detection. Additionally, nanoparticle based drug delivery systems are enhanced through the use of platelet membranes to specifically target cancer cells and camouflage the foreign particles from the immune system. This review discusses the development of platelets into highly powerful tools for cancer diagnostics and therapies. PMID- 28718433 TI - Mitotic DNA Damage Response: At the Crossroads of Structural and Numerical Cancer Chromosome Instabilities. AB - DNA double-strand breaks (DSBs) prevent cells from entering mitosis allowing cells to repair their genomic damage. Little is known about the response to DSBs once cells have already committed to mitosis. Here, we review the genome protective role of the mitotic DNA damage response (DDR) and evidence suggesting that its untimely activation induces chromosome segregation errors and paradoxically undermines genomic integrity. In contrast to normal cells, cancer cells coopt this pathway to propagate structural and numerical chromosomal instabilities. Cells derived from genomically unstable tumors exhibit evidence for a partially activated DDR during mitosis, which leads to ongoing chromosome segregation errors. Thus, a thorough understanding of the consequences of mitotic DNA damage is key to our ability to devise novel anticancer therapeutic strategies. PMID- 28718435 TI - Agrin to YAP in Cancer and Neuromuscular Junctions. AB - Agrin is utilized by motor neurons to stimulate the LRP4-MuSK receptor in muscles for neuromuscular junction (NMJ) formation. Recent studies of cancer have identified novel functions of the low-density lipoprotein receptor-related protein 4-muscle-specific kinase (LRP4-MuSK) pathway. Agrin may act as a mechanotransduction signal in the extracellular matrix (ECM) to coordinate the cross-talk between the LRP4-MuSK pathway and integrin-focal adhesion pathway. Ensuing Yes-associated protein (YAP) activation promotes hepatocellular carcinoma (HCC). Here, we discuss the implications of the converged pathways in NMJ formation and liver cancer. PMID- 28718436 TI - tRNA Modification: Is Cancer Having a Wobble? AB - Translational control of protein synthesis supports tumor development and progression to metastasis. Wobble tRNA modifications are required during translation elongation and sustain proteome homeostasis. Recent work has highlighted the surprising upregulation of the wobble uridine 34 (U34) tRNA cascade in cancer, which underlies the specific requirement for this pathway in tumor development. PMID- 28718437 TI - Mutations, Cancer and the Telomere Length Paradox. AB - Individuals with short telomeres should be at increased risk for cancer, since short telomeres lead to genomic instability - a hallmark of cancer. However, individuals with long telomeres also display an increased risk for major cancers, thus creating a cancer-telomere length (TL) paradox. The two-stage clonal expansion model we propose is based on the thesis that a series of mutational hits (1st Hit) at the stem-cell level generates a clone with replicative advantage. A series of additional mutational hits (2nd Hit) transforms the expanding clone into cancer. By proposing that the 1st Hit is largely telomere length-independent, while the 2nd Hit is largely TL-dependent, we resolve the paradox, highlighting a regulatory role of telomeres in cancer. PMID- 28718438 TI - Tissue-Intrinsic Tumor Hotspots: Terroir for Tumorigenesis. AB - Epithelial tissues are highly organized systems with a remarkable homeostatic ability to maintain morphology through regulation of cellular proliferation and tissue integrity. This robust self-organizing system is progressively disrupted during tumor development. Recent studies of conserved tumor-suppressor genes in Drosophila showed how protumor cells deviate from the robustly organized tissue microenvironment to take the first steps into becoming aggressive tumors. Here we review the 'tumor hotspot' hypothesis that explains how the tissue-intrinsic local microenvironment has a pivotal role in the initial stage of tumorigenesis in Drosophila epithelia and discuss comparable mechanisms in mammalian tissues. PMID- 28718440 TI - Selective Targeting of RSK Isoforms in Cancer. AB - The p90 ribosomal S6 kinase family (RSK1-4) is a group of highly conserved Ser/Thr kinases that act as downstream effectors of the Ras/Raf/MEK/ERK signaling pathway. The RSKs phosphorylate a range of substrates involved in transcription, translation, cell cycle regulation, and cell survival. Although the RSKs have a high degree of sequence homology, their functional differences in cancer are of great interest. Current RSK inhibitors target more than one RSK isoform, and this may limit their efficacy as anticancer agents. Here, we review the structure and function of the RSK kinases, their role in cancer growth and survival, and their potential as modulators of chemoresistance. In addition, we summarize the development of current RSK inhibitors and their limitations. PMID- 28718439 TI - Super-Enhancer-Driven Transcriptional Dependencies in Cancer. AB - Transcriptional deregulation is one of the core tenets of cancer biology and is underpinned by alterations in both protein-coding genes and noncoding regulatory elements. Large regulatory elements, so-called super-enhancers (SEs), are central to the maintenance of cancer cell identity and promote oncogenic transcription to which cancer cells become highly addicted. Such dependence on SE-driven transcription for proliferation and survival offers an Achilles heel for the therapeutic targeting of cancer cells. Indeed, inhibition of the cellular machinery required for the assembly and maintenance of SEs dampens oncogenic transcription and inhibits tumor growth. In this article, we review the organization, function, and regulation of oncogenic SEs and their contribution to the cancer cell state. PMID- 28718441 TI - Is Intra-Articular Steroid Injection to the Temporomandibular Joint for Juvenile Idiopathic Arthritis More Effective and Efficient When Performed With Image Guidance? AB - PURPOSE: To compare short-term outcomes and procedure times for intra-articular steroid injection (IASI) to the temporomandibular joint (TMJ) with and without the use of intraoperative image guidance for patients with juvenile idiopathic arthritis (JIA). MATERIALS AND METHODS: This is a retrospective study of children with JIA who underwent TMJ IASI at Boston Children's Hospital (Boston, MA). Patients were divided into groups according to IASI technique: 1) "landmark" group if performed by an oral and maxillofacial surgeon using an anatomic landmark technique with no intraoperative image guidance or 2) "image-guided" group if performed by an interventional radiologist using intraoperative ultrasound and computed tomography. Predictor variables included IASI technique (landmark vs image guided), age, gender, JIA subtype, category of medications for arthritis, and presence of family history of autoimmune disease. Outcome variables were changes in patient-reported pain, maximal incisal opening (MIO), synovial enhancement ratio (ER), and total procedure time. RESULTS: Forty-five patients with 71 injected TMJs were included. Twenty-two patients with 36 injected TMJs were in the landmark group and 23 patients with 35 injected joints were in the image-guided group. There were no relevant differences in age, gender, family history of rheumatologic disease, or disease subtype between groups. There were no differences in resolution of pain (P = 1.00), increase in MIO (P = .975), or decrease in ER (P = .492) between groups, but procedure times averaged 49 minutes longer for the image-guided group (P < .008). CONCLUSIONS: There were no statistical differences in short-term outcomes, but procedure times were longer for the image-guided group. Although specific indications for the use of image guidance might exist, routine use of this procedure cannot be justified. PMID- 28718442 TI - Wnt/Planar Cell Polarity Signaling: New Opportunities for Cancer Treatment. AB - Cancer cells are addicted to a large spectrum of extracellular cues implicated in initiation, stem cell renewal, tumor growth, dissemination in the body, and resistance to treatment. Wingless/Int-1 (Wnt) ligands and their associated signaling cascades contribute to most of these processes, paving the way for opportunities in therapeutic development. The developmental Wnt/planar cell polarity (PCP) pathway is the most recently described branch of Wnt signaling strongly implicated in cancer development at early and late stages. We describe here some of the latest knowledge accumulated on this pathway and the pending questions, present the most convincing findings about its role in cancer, and review the most promising strategies currently designed to target its components. PMID- 28718443 TI - Developing Cures: Targeting Ontogenesis in Cancer. AB - Cancer has long been known to histologically resemble developing embryonic tissue. Since this early observation, a mounting body of evidence suggests that cancer mimics or co-opts developmental processes to facilitate tumor initiation and progression. Programs important in both normal ontogenesis and cancer progression broadly fall into three domains: the lineage commitment of pluripotent stem cells, the appropriation of primordial mechanisms of cell motility and invasion, and the influence of multiple aspects of the microenvironment on the parenchyma. In this review we discuss how derangements in these developmental pathways drive cancer progression with a particular focus on how they have emerged as targets of novel treatment strategies. PMID- 28718444 TI - Tumor-Host Cell Interactions in Ovarian Cancer: Pathways to Therapy Failure. AB - Although most ovarian cancer patients are highly responsive to chemotherapy, they frequently present with recurrent metastatic lesions that result in poor overall survival, a situation that has not changed in the last 20 years. This review discusses new insights into the regulation of ovarian cancer chemoresistance with a focus on the emerging role of immune and other host cells. Here, we summarize the complex molecular pathways that regulate the interaction between tumor and host cells, discuss the limitations of current in vitro and in vivo models for translational studies, and present perspectives for the development of innovative therapies. PMID- 28718446 TI - Cancer - An Insurgency of Clones. AB - Oncological therapy resembles a military force that eliminates the central power of a country (dominant clone of a cancer) to create a vacuum where insurgents (subclones) thrive and instigate rebellion (relapse). We suggest that military counterinsurgency doctrine can inspire a discussion of cancer that uniquely embraces both cancer cell evolution and tumour microenvironment. PMID- 28718445 TI - Mouse versus Human Neutrophils in Cancer: A Major Knowledge Gap. AB - Many types of cancer recruit neutrophils that could have protumor or antitumor effects on tumor development. Numerous findings in murine models suggest a predominantly protumoral role for neutrophils in cancer development. However, there are fundamental differences between mouse and human tumors in the evolution of tumors, genetic diversity, immune response, and also in the intrinsic biology of neutrophils that might have a profound impact on tumor development and the function of these cells. A crucial difference is that the majority of mouse tumor models lack the prolonged initial phases of multistage tumor evolution present in humans when antitumoral mechanisms are activated. In this review, we discuss the challenges specific to cross-species extrapolation of neutrophil function during mouse versus human tumor development. PMID- 28718447 TI - Prostaglandin E2 Signaling: Alternative Target for Glioblastoma? AB - Elevated cyclooxygenase-2 (COX-2) and the associated inflammation within the brain contribute to glioblastoma development. However, medical use of COX inhibitors in glioblastoma treatment has been limited due to their well documented vascular toxicity and inconsistent outcomes from recent human studies. Prostaglandin E2 (PGE2) has emerged as a principal mediator for COX-2 cascade driven gliomagenesis. Are PGE2 terminal synthases and receptors feasible therapeutic targets for glioblastoma? PMID- 28718449 TI - The dual-function chaperone HycH improves assembly of the formate hydrogenlyase complex. AB - The assembly of multi-protein complexes requires the concerted synthesis and maturation of its components and subsequently their co-ordinated interaction. The membrane-bound formate hydrogenlyase (FHL) complex is the primary hydrogen producing enzyme in Escherichia coli and is composed of seven subunits mostly encoded within the hycA-I operon for [NiFe]-hydrogenase-3 (Hyd-3). The HycH protein is predicted to have an accessory function and is not part of the final structural FHL complex. In this work, a mutant strain devoid of HycH was characterised and found to have significantly reduced FHL activity due to the instability of the electron transfer subunits. HycH was shown to interact specifically with the unprocessed species of HycE, the catalytic hydrogenase subunit of the FHL complex, at different stages during the maturation and assembly of the complex. Variants of HycH were generated with the aim of identifying interacting residues and those that influence activity. The R70/71/K72, the Y79, the E81 and the Y128 variant exchanges interrupt the interaction with HycE without influencing the FHL activity. In contrast, FHL activity, but not the interaction with HycE, was negatively influenced by H37 exchanges with polar residues. Finally, a HycH Y30 variant was unstable. Surprisingly, an overlapping function between HycH with its homologous counterpart HyfJ from the operon encoding [NiFe]-hydrogenase-4 (Hyd-4) was identified and this is the first example of sharing maturation machinery components between Hyd-3 and Hyd-4 complexes. The data presented here show that HycH has a novel dual role as an assembly chaperone for a cytoplasmic [NiFe] hydrogenase. PMID- 28718451 TI - NaCl-assisted one-step growth of MoS2-WS2 in-plane heterostructures. AB - Transition metal dichalcogenides (TMDs) have attracted considerable interest for exploration of next-generation electronics and optoelectronics in recent years. Fabrication of in-plane lateral heterostructures between TMDs has opened up excellent opportunities for engineering two-dimensional materials. The creation of high quality heterostructures with a facile method is highly desirable but it still remains challenging. In this work, we demonstrate a one-step growth method for the construction of high-quality MoS2-WS2 in-plane heterostructures. The synthesis was carried out using ambient pressure chemical vapor deposition (APCVD) with the assistance of sodium chloride (NaCl). It was found that the addition of NaCl played a key role in lowering the growth temperatures, in which the Na-containing precursors could be formed and condensed on the substrates to reduce the energy of the reaction. As a result, the growth regimes of MoS2 and WS2 are better matched, leading to the formation of in-plane heterostructures in a single step. The heterostructures were proved to be of high quality with a sharp and clear interface. This newly developed strategy with the assistance of NaCl is promising for synthesizing other TMDs and their heterostructures. PMID- 28718452 TI - Role of Al doping in the filament disruption in HfO2 resistance switches. AB - Resistance switching devices, whose operation is driven by formation (SET) and dissolution (RESET) of conductive paths shorting and disconnecting the two metal electrodes, have recently received great attention and a deep general comprehension of their operation has been achieved. However, the link between switching characteristics and material properties is still quite weak. In particular, doping of the switching oxide layer has often been investigated only for looking at performance upgrade and rarely for a meticulous investigation of the switching mechanism. In this paper, the impact of Al doping of HfO2 devices on their switching operations, retention loss mechanisms and random telegraph noise traces is investigated. In addition, phenomenological modeling of the switching operation is performed for device employing both undoped and doped HfO2. We demonstrate that Al doping influences the filament disruption process during the RESET operation and, in particular, it contributes in preventing an efficient restoration of the oxide with respect to undoped devices. PMID- 28718450 TI - Dynamics and energetics of the mammalian phosphatidylinositol transfer protein phospholipid exchange cycle. AB - Phosphatidylinositol-transfer proteins (PITPs) regulate phosphoinositide signaling in eukaryotic cells. The defining feature of PITPs is their ability to exchange phosphatidylinositol (PtdIns) molecules between membranes, and this property is central to PITP-mediated regulation of lipid signaling. However, the details of the PITP-mediated lipid exchange cycle remain entirely obscure. Here, all-atom molecular dynamics simulations of the mammalian StART-like PtdIns/phosphatidylcholine (PtdCho) transfer protein PITPalpha, both on membrane bilayers and in solvated systems, informed downstream biochemical analyses that tested key aspects of the hypotheses generated by the molecular dynamics simulations. These studies provided five key insights into the PITPalpha lipid exchange cycle: (i) interaction of PITPalpha with the membrane is spontaneous and mediated by four specific protein substructures; (ii) the ability of PITPalpha to initiate closure around the PtdCho ligand is accompanied by loss of flexibility of two helix/loop regions, as well as of the C-terminal helix; (iii) the energy barrier of phospholipid extraction from the membrane is lowered by a network of hydrogen bonds between the lipid molecule and PITPalpha; (iv) the trajectory of PtdIns or PtdCho into and through the lipid-binding pocket is chaperoned by sets of PITPalpha residues conserved throughout the StART-like PITP family; and (v) conformational transitions in the C-terminal helix have specific functional involvements in PtdIns transfer activity. Taken together, these findings provide the first mechanistic description of key aspects of the PITPalpha PtdIns/PtdCho exchange cycle and offer a rationale for the high conservation of particular sets of residues across evolutionarily distant members of the metazoan StART-like PITP family. PMID- 28718454 TI - High aspect ratio sharp nanotip for nanocantilever integration at CMOS compatible temperature. AB - In this paper, we demonstrate a novel low temperature nanofabrication approach that enables the formation of ultra-sharp high aspect ratio (HAR) and high density nanotip structures and their integration onto nanoscale cantilever beams. The nanotip structure consists of a nanoscale thermally evaporated Cr Spindt tip on top of an amorphous silicon rod. An apex radius of the tip, as small as 2.5 nm, has been achieved, and is significantly smaller than any other Spindt tips reported so far. 100 nm wide tips with aspect ratio of more than 50 and tip density of more than 5 * 109 tips cm-2 have been fabricated. The HAR tips have been integrated onto an array of 460 nm wide cantilever beams with high precision and yield. In comparison with other approaches, this approach allows the integration of HAR sharp nanotips with nano-mechanical structures in a parallel and CMOS compatible fashion for the first time to our knowledge. Potential applications include on-chip high-speed atomic force microscopy and field emission devices. PMID- 28718455 TI - Unidirectional endotaxial cobalt di-silicide nanowires on Si(110) substrates. AB - Self-organized growth of well-ordered endotaxial silicide nanowires (NWs) on clean Si(110) surfaces has been investigated by in situ scanning tunneling microscopy (STM) and transmission electron microscopy (TEM). Co deposition on clean Si(110) reconstructed surfaces at ~600 degrees C produces unidirectional CoSi2 NWs by reaction of cobalt with the hot silicon substrate. STM investigations reveal four major types of distinct NWs, all growing along the [ 110] in-plane direction except one type growing along the in-plane [-113] direction. There are also some nanodots. The cross-sectional TEM measurements show that the unidirectional NWs are of two types-flat-top and ridged. The NWs grow not only on the substrate but also into the substrate. CoSi2 in flat top NWs are in the same crystallographic orientation as the substrate Si and the buried interfaces between CoSi2 and Si are A-type. In the ridged NWs CoSi2 and Si are in different crystallographic orientations and the interfaces are B-type. The ridged NWs are in general wider and grow deeper into the substrate. PMID- 28718448 TI - Neuronal Activity in Ontogeny and Oncology. AB - The nervous system plays a central role in regulating the stem cell niche in many organs, and thereby pivotally modulates development, homeostasis, and plasticity. A similarly powerful role for neural regulation of the cancer microenvironment is emerging. Neurons promote the growth of cancers of the brain, skin, prostate, pancreas, and stomach. Parallel mechanisms shared in development and cancer suggest that neural modulation of the tumor microenvironment may prove a universal theme, although the mechanistic details of such modulation remain to be discovered for many malignancies. We review here what is known about the influences of active neurons on stem cell and cancer microenvironments across a broad range of tissues, and we discuss emerging principles of neural regulation of development and cancer. PMID- 28718456 TI - Graphene oxide and DNA aptamer based sub-nanomolar potassium detecting optical nanosensor. AB - Quantum-dot (QD) based nanosensors are frequently used by researchers to detect small molecules, ions and different biomolecules. In this article, we present a sensor complex/system comprised of deoxyribonucleic acid (DNA) aptamer, gold nanoparticle and semiconductor QD, attached to a graphene oxide (GO) flake for detection of potassium. As reported herein, it is demonstrated that QD-aptamer quencher nanosensor functions even when tethered to GO, opening the way to future applications where sensing can be accomplished simultaneously with other previously demonstrated applications of GO such as serving as a nanocarrier for drug delivery. Herein, it is demonstrated that the DNA based thrombin binding aptamer used in this study undergoes the conformational change needed for sensing even when the nanosensor complex is anchored to the GO. Analysis with the Hill equation indicates the interaction between aptamer and potassium follows sigmoidal Hill kinetics. It is found that the quenching efficiency of the optical sensor is linear with the logarithm of concentration from 1 pM to 100 nM and decreases for higher concentration due to unavailability of aptamer binding sites. Such a simple and sensitive optical aptasensor with minimum detection capability of 1.96 pM for potassium ion can also be employed in-vitro detection of different physiological ions, pathogens and disease detection methods. PMID- 28718457 TI - Towards production of novel catalyst powders from supported size-selected clusters by multilayer deposition and dicing. AB - A multilayer deposition method has been developed with the potential to capture and process atomic clusters generated by a high flux cluster beam source. In this deposition mode a series of sandwich structures each consisting of three layers-a carbon support layer, cluster layer and polymer release layer-is sequentially deposited to form a stack of isolated cluster layers, as confirmed by through focal aberration-corrected HAADF STEM analysis. The stack can then be diced into small pieces by a mechanical saw. The diced pieces are immersed in solvent to dissolve the polymer release layer and form small platelets of supported clusters. PMID- 28718458 TI - [Correction: Incorrect spelling of last author name in Neuropsychological profile of frontotemporal lobar degeneration]. AB - This corrects the article on p. 79 in volume 38(1), PMID 25963461. PMID- 28718459 TI - Strengthening Global Partnership in Breast Cancer Research. PMID- 28718460 TI - Breast Cancer in Sub-Saharan Africa. PMID- 28718461 TI - [Multidisciplinary treatment approach in a patient with a severe gag reflex]. AB - A patient was referred to a centre for special care dentistry due to problems with a severe gag reflex and dental care-related anxiety. A regular treatment was started with gradual exposure in vivo in combination with breathing exercises, which involved the patient doing exercises at home. In addition, she was referred to an (external) speech therapist. During the treatment the patient suffered from pain in [molar] tooth 27 and a short-term solution was necessary. Regular treatment was not (yet) possible due to the existing severe gag reflex. Treatment with nitrous oxide was chosen to address the pain, in combination with the treatment that had already been started, so that the nitrous oxide could eventually be reduced again. Due in part to the patient's motivation and a multidisciplinary approach a good and stable result has been achieved. PMID- 28718462 TI - [Preventive dentistry 7. Getting rid of halitosis]. AB - Halitosis or bad breath is a problem that affects many people and its source is generally found in the oral cavity (intra-oral halitosis). Bacteria in the oral cavity produce volatile sulphur compounds such as hydrogen sulphide and methyl mercaptan that not only emit an unpleasant odour, but may also have toxic effects on the periodontal tissues. Good oral hygiene, a healthy periodontium and healthy teeth are the basis for the prevention of intra-oral halitosis and dentists and dental hygienists therefore play an essential role in its prevention. PMID- 28718463 TI - [Chewing on bruxism: associations, consequences and management]. AB - In this second part of a diptych on bruxism, the focus is on the associations of this masticatory muscle activity with other sleep-related conditions. Its association with the obstructive sleep apnoea syndrome (OSAS) has been a particular object of study. Bruxism seems to play a protective role in OSAS, although the evidence for this is not yet conclusive. Apart from this possible positive consequence, bruxism also has several negative consequences, for which evidence is available to a greater or lesser extent. For example, bruxism has been associated with temporomandibular pain and dysfunction, periodontal and endodontic problems, failures of restorations and implants, and tooth wear. In some cases, these consequences are severe enough to justify treatment of bruxism. In all other cases, there is no indication for diagnostics and treatment, given the possible positive consequences. If treatment is indicated, modalities should be conservative, like stabilisation appliances, counselling, medication, psychology, and physiotherapy. PMID- 28718464 TI - [Dissertation 25 years after date 48. The effect of saliva on the -colonisation of oral bacteria]. AB - In the research that formed the basis of the dissertation 'Intervention of saliva in the colonization process of oral bacteria' from 1992, the aggregation or clustering of oral bacteria by saliva was investigated. This prevents bacterial colonisation in the mouth. Major individual differences in aggregation activity of different saliva samples were found to exist, partly determined by the blood group of the saliva donor. As well as being found in red blood cells, AB0 blood group antigens also appear on salivary glycoproteins. This does, however, not hold true for all individuals: this is only the case for so-called secretors. Non secretors aggregated fewer bacteria than secretors. Later research showed that this was associated with a higher risk of caries. Subsequent research revealed that the complement system, a defence system in blood, was activated by saliva of secretors, but not of non-secretors. This shows that the oral defence systems are influenced by blood group and secretor status, but in a different way than we originally thought. PMID- 28718465 TI - Structure and molecular packing in smectic BCr and Ad phases of Schiff base liquid crystal compounds through the analyses of layer spacing, entropy and crystal structure. AB - Single-crystal structural analyses and heat capacity measurements were performed on two Schiff base liquid crystal compounds, 5CBAA (4-chlorobenzylidene-4' pentyloxyaniline) and 5ABCA (4-pentyloxybenzylidene-4'-chloroaniline). The alkyloxy-chain of a 5CBAA molecule was conformationally ordered in the crystal at room temperature. While that of 5ABCA was partially disordered in the room temperature phase but ordered in a low-temperature phase at 100 K. The structural phase transition involving the disordering of the conformation was observed at 107 K in the heat capacity of 5ABCA. Both compounds showed two liquid crystalline phases, SmBCr and SmAd. The net entropy change associated with the chain disordering was essentially the same in them despite the difference in the orientation of their central -CH[double bond, length as m-dash]N- moiety. The layer-spacings of SmBCr and SmAd phases were analyzed for their chain-length dependence in both series of mesogens (nCBAA and nABCA), as well as in the case of nBBAA (4-bromobenzylidene-4'-alkyloxyaniline). The results reveal that these smectic structures are composed of alternately stacked core- and chain-layers with an antiparallel arrangement of cores and a bent-form of molecules. PMID- 28718466 TI - Exploring viscosity, polarity and temperature sensitivity of BODIPY-based molecular rotors. AB - Microviscosity is a key parameter controlling the rate of diffusion and reactions on the microscale. One of the most convenient tools for measuring microviscosity is by fluorescent viscosity sensors termed 'molecular rotors'. BODIPY-based molecular rotors in particular proved extremely useful in combination with fluorescence lifetime imaging microscopy, for providing quantitative viscosity maps of living cells as well as measuring dynamic changes in viscosity over time. In this work, we investigate several new BODIPY-based molecular rotors with the aim of improving on the current viscosity sensing capabilities and understanding how the structure of the fluorophore is related to its function. We demonstrate that due to subtle structural changes, BODIPY-based molecular rotors may become sensitive to temperature and polarity of their environment, as well as to viscosity, and provide a photophysical model explaining the nature of this sensitivity. Our data suggests that a thorough understanding of the photophysics of any new molecular rotor, in environments of different viscosity, temperature and polarity, is a must before moving on to applications in viscosity sensing. PMID- 28718467 TI - How to make an efficient and robust molecular catalyst for water oxidation. AB - Energy has been a central subject for human development from Homo erectus to date. The massive use of fossil fuels during the last 50 years has generated a large CO2 concentration in the atmosphere that has led to the so-called global warming. It is very urgent to come up with C-neutral energy schemes to be able to preserve Planet Earth for future generations to come and still preserve our modern societies' life style. One of the potential solutions is water splitting with sunlight (hnu-WS) that is also associated with "artificial photosynthesis", since its working mode consists of light capture followed by water oxidation and proton reduction processes. The hydrogen fuel generated in this way is named as "solar fuel". For this set of reactions, the catalytic oxidation of water to dioxygen is one of the crucial processes that need to be understood and mastered in order to build up potential devices based on hnu-WS. This tutorial describes the different important aspects that need to be considered to come up with efficient and oxidatively robust molecular water oxidation catalysts (Mol-WOCs). It is based on our own previous work and completed with essential contributions from other active groups in the field. We mainly aim at describing how the ligands can influence the properties of the Mol-WOCs and showing a few key examples that overall provide a complete view of today's understanding in this field. PMID- 28718468 TI - DNA melting in the presence of molecular crowders. AB - We study the opening of double stranded DNA (dsDNA) in the presence of molecular crowders using the Peyrard-Bishop-Dauxois (PBD) model. It is a known fact that about 15-20% of the total volume of a cell is occupied by molecular crowders. The presence of crowders in the model is represented through the potential depth in the Morse potential. Using equilibrium statistical calculations we find the melting profile and the melting probabilities of the chain. We found that the melting temperature, Tm, increases in the presence of a crowder. This is due to the fact that the crowders occupy a substantial amount of the system volume and hence reduce the free volume available to the DNA molecule. This restricts the free movement of base pairs and hence the DNA molecule, which results in an increase in the melting temperature of the DNA molecule. We also find a correlation between the melting temperature and the crowder density of the solution. The power law behaviour shows that the melting temperature scales linearly with the crowder density. At a given density, a higher density of crowder may suppress the free movement in the DNA molecule, which will increase Tm. Although the temperature changes occurring in vitro seem to be smaller than those observed in this work, the results demonstrate interesting features of the opening of DNA molecules in crowded environments. PMID- 28718469 TI - Characterization of the thermal/thermal oxidative stability of fluorinated graphene with various structures. AB - Considering practical applications, the thermal/thermal oxidative stability of fluorinated graphene should be given sufficient attention. Herein, X-ray photoelectron spectroscopy (XPS), thermogravimetric analysis (TGA) and Fourier transform infrared spectroscopy (FT-IR) were used to investigate in detail the differences in the thermal stabilities of two types of fluorinated samples, fluorinated graphene (FG) and fluorinated porous graphene (FPG) with various fluorine contents, respectively, as well as the reasons for these differences. It was demonstrated that the thermal stability of FG and FPG was improved upon increasing the fluorine content, which was mainly caused by the enhancement of bond energy of the covalent C-F bonds. Moreover, compared to that of the raw graphene samples, the thermal oxidative stability of FG was reduced due to the defects brought by fluorination, while the thermal oxidative stability of FPG was improved, originating from the inflaming retarding effect of the fluorine element. Interestingly, the thermal oxidative stability of the fluorinated samples was even better than their thermal stability. Using a comparison of the two types of fluorinated samples and support from the computational simulations of the model molecules, it was suggested that a greater amount of CFn (n = 2, 3) groups or defects in the FG samples resulted in its relatively worse thermal stabilities. Furthermore, electron paramagnetic resonance (EPR) spectroscopy was introduced to analyze the thermal stabilities of the fluorinated graphene samples as a novel method. The changes in the spin centers in samples after thermal treatment were studied, which indicated that the lower amount of the more stable spin centers of FPG was another reason leading to its more outstanding thermal stabilities in comparison to FG samples. PMID- 28718470 TI - CO2 activation and dissociation on the low miller index surfaces of pure and Ni coated iron metal: a DFT study. AB - We have used spin polarized density functional theory calculations to perform extensive mechanistic studies of CO2 dissociation into CO and O on the clean Fe(100), (110) and (111) surfaces and on the same surfaces coated by a monolayer of nickel. CO2 chemisorbs on all three bare facets and binds more strongly to the stepped (111) surface than on the open flat (100) and close-packed (110) surfaces, with adsorption energies of -88.7 kJ mol-1, -70.8 kJ mol-1 and -116.8 kJ mol-1 on the (100), (110) and (111) facets, respectively. Compared to the bare Fe surfaces, we found weaker binding of the CO2 molecules on the Ni-deposited surfaces, where the adsorption energies are calculated at +47.2 kJ mol-1, -29.5 kJ mol-1 and -65.0 kJ mol-1 on the Ni-deposited (100), (110) and (111) facets respectively. We have also investigated the thermodynamics and activation energies for CO2 dissociation into CO and O on the bare and Ni-deposited surfaces. Generally, we found that the dissociative adsorption states are thermodynamically preferred over molecular adsorption, with the dissociation most favoured thermodynamically on the close-packed (110) facet. The trends in activation energy barriers were observed to follow that of the trends in surface work functions; consequently, the increased surface work functions observed on the Ni-deposited surfaces resulted in increased dissociation barriers and vice versa. These results suggest that measures to lower the surface work function will kinetically promote the dissociation of CO2 into CO and O, although the instability of the activated CO2 on the Ni-covered surfaces will probably result in CO2 desorption from the nickel-doped iron surfaces, as is also seen on the Fe(110) surface. PMID- 28718471 TI - Two-dimensional metal-organic frameworks with high thermoelectric efficiency through metal ion selection. AB - Two-dimensional (2D) materials have attracted much attention due to their novel properties. An exciting new class of 2D materials based on metal-organic frameworks (MOFs) has recently emerged, displaying high electrical conductivity, a rarity among organic nanoporous materials. The emergence of these materials raises intriguing questions about their fundamental electronic, optical, and thermal properties, but few studies exist in this regard. Here we present an atomistic study of the thermoelectric properties of crystalline 2D MOFs X3(HITP)2 with X = Ni, Pd or Pt, and HITP = 2,3,6,7,10,11-hexaiminotriphenylene, using both ab initio transport models and classical molecular dynamics simulations. We find that these materials have a high Seebeck coefficient and low thermal conductivity, making them promising for thermoelectric applications. Furthermore, we explore the dependence of thermoelectric transport properties on the atomic structure by comparing the calculated band structure, band alignment, and electronic density of states of the three 2D MOFs, and find that the thermoelectric transport properties strongly depend on both the interaction between the ligands and the metal ions, and the d orbital splitting of the metal ions induced by the ligands. This demonstrates that selection of the metal ion is a powerful approach to control and enhance the thermoelectric properties. Interestingly we reveal an unexpected effect where, unlike for electrons, the thermal and electrical current may not be equally carried by the holes, leading to a significant deviation from the Wiedemann-Franz law. The results of this work provide fundamental guidance to optimize the existing 2D MOFs, and to design and discover new families of MOF-like materials for thermoelectric applications. PMID- 28718472 TI - Unveiling the irreversible performance degradation of organo-inorganic halide perovskite films and solar cells during heating and cooling processes. AB - While organo-inorganic halide perovskite solar cells show great potential to meet future energy needs, their thermal instability raises serious questions about their commercialization viability. At present, the stability of perovskite solar cells has been studied under various environmental conditions including humidity and temperature. Nonetheless, understanding of the performance of CH3NH3PbI3-xClx perovskite solar cells is limited. This study reports the irreversible performance degradation of CH3NH3PbI3-xClx perovskite solar cells during the heating and cooling processes under AM 1.5 and unveils what triggers the irreversible performance degradation of solar cells. Particularly, the primary cause of the irreversible performance degradation of CH3NH3PbI3-xClx is quantitatively analyzed by monitoring in real time the development of deteriorated crystallinity, charge trapping/detrapping, trap depth, and the PbI2 phase, namely a critical signal of perovskite degradation while varying the temperature of the perovskite films and solar cells. Most surprisingly, it is revealed that the degradation of both perovskite films and solar cells was triggered at ~70 degrees C. Remarkably, even after the device temperature cooled down to room temperature, the degraded performance of the solar cells persisted with increasing charge trapping and further development of the PbI2 phase. Identification of the irreversible performance degradation of perovskite solar cells provides guidance for future development of more stable perovskite solar cells. PMID- 28718473 TI - Probing the balance between ductility and strength: transition metal silicides. AB - The adjustment of the balance between strength and ductility is still a great challenge for ultrahigh temperature materials. Essentially, the strength depends on the valence electron density of transition metals and the bond strength of chemical bonding. However, the ductility of a solid is mainly determined by the symmetrical slips and crystal structure. Based on the above design principles, we apply first-principles calculations to investigate the structure, elastic properties and brittle-or-ductile behavior of TM3Sis with a cubic structure. Two new TM3Si structures: Ti3Si and W3Si (space group: Pm3[combining macron]n) are predicted. The calculated results show that W3Si exhibits strong volume deformation and shear deformation resistances in comparison to TM5Si3. In particular, W3Si also exhibits excellent ductility due to the symmetrical structure. The calculated electronic structure reveals that a high elastic modulus derives from the strong and symmetrical W-Si and W-W bonds. Therefore, we can control a crystal structure with symmetrical slips and choose a TM metal with a high valence electron density, to improve the correlation between ductility and strength. PMID- 28718474 TI - Alkane-length sorting using activated pillar[5]arene crystals. AB - We report a simple and easy-to-operate method for separating n-alkanes: when we immersed activated pillar[5]arene crystals into a mixture of n-alkanes with various chain lengths, the crystals preferentially took up n-alkanes with longer chain lengths. PMID- 28718475 TI - Nanoscale chemical imaging of the additive effects on the interfaces of high voltage LiCoO2 composite electrodes. AB - X-ray photoemission electron microscopy (X-PEEM) of cycled LiCoO2 composite electrodes has revealed the interfaces of various components within the composite electrodes and their dependence on additives in the electrolyte and the interplay of multiple components in the electrodes. This study visualizes CoF2 distribution and Co-O bonding variation along with local component agglomeration and degradation. The obtained new insights will assist further development of long life high-voltage LiCoO2/C batteries. PMID- 28718476 TI - Strong ferromagnetic exchange coupling in a {Ni} cluster mediated through an air stable tetrazine-based radical anion. AB - A planar tetradentate 3,6-bis(2-pyrimidyl)-1,2,4,5-tetrazine (BpymTz) templating chelate affords the formation of an unprecedented BpymTz- radical anion bridged {Ni} complex. Detailed magnetic measurements performed on the isolated air stable [Ni(BpymTz-)Cl6(DMF)8]Cl.0.5(H2O) compound reveal strong ferromagnetic NiII BpymTz- interactions with a coupling constant of J = 98.84 cm-1. PMID- 28718477 TI - NHC-stabilized 1-hydrosilaimine: synthesis, structure and reactivity. AB - A facile, straightforward synthesis of N-heterocyclic carbene (NHC)-stabilized 1 hydrosilaimine starting from a silicon(iv)-precursor is reported. It has been employed for the addition of an O-H bond of water under ambient conditions without any additional catalyst. PMID- 28718479 TI - Exploring structural complexity in the discovery and self-assembly of a family of nanoscale chalcoxides from {Se8Mo36} to {Se26Mo68}. AB - Herein, we show the controlled generation of multi-component libraries based on the [MoS2O2]2+/MoVIO42-/SeIVO32-/C4O42- system leading to the formation of a whole new family of nanosized molecular chalcoxides, {Se8Mo36} 1, {Se8Mo40} 2, {Se8Mo56} 3, {Se20Mo56} 4 and {Se26Mo68} 5, of the general formula {(MoO2S2)a(OH)b(SeIVO3)c(C4O4)d(MoO7)e}n-, where a, b, c, d, e, n = [16, 20, 8, 6, 2, 20] for 1, [18, 24, 8, 6, 2, 20] for 2, [24, 32, 8, 8, 4, 24] for 3, [28, 32, 20, 8, 0, 32] for 4 and [34, 36, 26, 8, 0, 36] for 5. The coordination modulation effect offered by the SeIVO32- and the C4O42- anions lead to the generation of new building blocks, [(MoO2S2)3(OH)6(C4O4) (MoO7)]4-, and the discovery of a new family of clusters of increasing nuclearity and complexity. PMID- 28718478 TI - GSH-Responsive supramolecular nanoparticles constructed by beta-d-galactose modified pillar[5]arene and camptothecin prodrug for targeted anticancer drug delivery. AB - Supramolecular construction of a targeted and stimuli-responsive drug delivery system is still a challenging task. Herein, GSH-responsive supramolecular prodrug nanoparticles were constructed by the host-guest complexation between a beta-d galactose-functionalized water-soluble pillar[5]arene (GalP5) and a disulfide bond containing camptothecin prodrug (G). The obtained prodrug nanoparticles were stable under physiological conditions, whereas efficient drug release was triggered in a simulated tumor environment with high GSH concentration. In vitro studies revealed that these prodrug nanoparticles preferentially entered asialoglycoprotein receptor-overexpressing HepG2 cells due to the active targeting effect of galactose units. This active targeting effect resulted in the maximization of anticancer efficacy and reduction of the undesirable side effects to normal cells. PMID- 28718480 TI - Visible-light-induced thiotrifluoromethylation of terminal alkenes with sodium triflinate and benzenesulfonothioates. AB - An unconventional reductive quenching cycle was developed to realize the visible light-induced thiotrifluoromethylation of terminal alkenes. CF3SO2Na was used as an easy to handle CF3 radical source to afford the desired products in moderate to good yields. Mild reaction conditions and a broad substrate scope feature in this transformation. PMID- 28718481 TI - Development and photocatalytic mechanism of monolayer Bi2MoO6 nanosheets for the selective oxidation of benzylic alcohols. AB - Monolayer Bi2MoO6 nanosheets have been successfully prepared for the first time via a bottom-top approach with surfactant assistance, and show 8 times higher activity than bulk Bi2MoO6 for the selective oxidation of benzyl alcohol. Ultrafast charge separation and more acid-base active sites on the monolayer nanosheets are considered to be responsible for the robust photoactivity. PMID- 28718482 TI - Molecular insight into the Mullins effect: irreversible disentanglement of polymer chains revealed by molecular dynamics simulations. AB - The debate regarding the possible molecular origins of the Mullins effect has been ongoing since its discovery. Molecular dynamics (MD) simulations were carried out to elucidate the underlying mechanism of the Mullins effect. For the first time, the key characteristics associated with the Mullins effect, including (a) the majority of stress softening occurring in the first stretch, (b) continuous softening with stress increase, (c) a permanent set, and (d) recovery with heat treatment, are captured by molecular modeling. It is discovered that the irreversible disentanglement of polymer chains is physically sufficient to interpret these key characteristics, providing molecular evidence for this long controversial issue. Our results also reveal that filled polymers exhibit three distinct regimes, i.e., the polymer matrix, the interface, and the filler. When subjected to external strain, the polymer matrix suffers from excess deformation, indicating strong heterogeneity within the filled polymer, which offers molecular insight for the formulation of physics-based constitutive relations for filled polymers. PMID- 28718483 TI - Resonant dynamic Stark shift as a tool in strong-field quantum control: calculation and application for selective multiphoton ionization of sodium. AB - A method for determining the resonant dynamic Stark shift (RDSS), based on wave packet calculations of the populations of quantum states, is presented. It is almost insensitive to variations of the laser pulse profile, and this feature ensures generality in applications. This method is used to determine an RDSS data set for 3s -> nl (n <= 6) transitions in sodium induced by laser pulses with peak intensities up to 7.9 * 1012 W cm-2 and wavelengths in the range from 455.6 to 1139 nm. The data are applied to analyze the photoelectron spectra (electron yield versus excess energy) of the sodium atom interacting with 800 nm laser radiation. Substructures observed in the experimentally measured spectra are successfully reproduced and related to the resonantly enhanced multiphoton ionization via specific (P and F) intermediate states. PMID- 28718484 TI - Palladium-catalyzed dearomatizative [2 + 2 + 1] carboannulation of 1,7-enynes with aryl diazonium salts and H2O: facile synthesis of spirocyclohexadienone fused cyclopenta[c]quinolin-4(5H)-ones. AB - A new palladium-catalyzed dearomatizative [2 + 2 + 1] carboannulation of 1,7 enynes with aryl diazonium salts and H2O is presented. The reaction enables the construction of spirocyclohexadienone-fused cyclopenta[c]quinolin-4(5H)-ones through a sequence of Heck-type addition, 6-exo-dig cyclization, ipso cyclization, dearomatization and hydrolysis. PMID- 28718485 TI - Electrochemical potassium-ion intercalation in NaxCoO2: a novel cathode material for potassium-ion batteries. AB - Reversible electrochemical potassium-ion intercalation in P2-type NaxCoO2 was examined for the first time. Hexagonal Na0.84CoO2 platelets prepared by a solution combustion synthesis technique were found to work as an efficient host for K+ intercalation. They deliver a high reversible capacity of 82 mA h g-1, good rate capability and excellent cycling performance up to 50 cycles. PMID- 28718486 TI - What will it take to end AIDS in the Americas? PMID- 28718487 TI - HIV/AIDS prevention, care and treatment in the Region of the Americas: achievements, challenges and perspectives. PMID- 28718488 TI - Infectious disease morbidity and growth among young HIV-exposed uninfected children in Jamaica. AB - Objective: There is a growing body of data that demonstrates increased infectious disease outcomes for HIV-exposed uninfected (HIV-EU) infants as compared to their HIV-unexposed (HU) counterparts. We hypothesized that these HIV-EU infants are at greater risk for infectious morbidity and mortality when compared to the general childhood population. We therefore aimed to characterize infections and growth outcomes among HIV-EU infants in Jamaica during their first two years of life. By identifying these outcomes, specific interventions could be implemented to mitigate this risk of morbidity and mortality. Methods: HIV-EU infants born between 1 January 2004 and 31 December 2006 in Kingston, Jamaica, were enrolled and followed in multicenter health facilities, using standardized protocols. HIV status was determined by RNA/DNA polymerase chain reaction (PCR) and confirmatory HIV enzyme-linked immunoassay (ELISA). Data were collected on demographic and anthropometric characteristics, infectious morbidity and mortality, and hospitalizations. Outcomes (incidence of infections and hospitalizations; growth (z scores for weight)) were determined, using univariate analyses. Results: Of 195 HIV-EU infants followed for 25.9 months (standard deviation, 10.9 months), 102 (52%) were male, 185 (95%) were non-breast-fed, 161 (83%) experienced at least one infection, and 58 (30%) were hospitalized at least once. Infectious disease incidence per 1 000 child-weeks included upper respiratory tract infection of 7.25 (95% confidence interval (CI): 5.92-8.90), otitis media of 4.12 (3.21-5.20), and acute gastroenteritis (AGE) of 1.92 (1.35-2.65). Hospitalization incidence per 1 000 child-weeks included lower respiratory tract infections (LRTIs) of 0.89 (0.53-1.40), sepsis of 0.48 (0.23-0.89), and AGE of 0.43 (0.20 0.81). These infection incidence rates among the HIV-EU infants were higher than those for published community controls. Among the HIV-EU infants, the low birthweight ones and those born via cesarean section had significantly higher hospitalization rates from LRTI and sepsis than did published community controls. The mean z score for weight during the infants' first 6 months ranged from -0.06 to 0.78 in this predominantly non-breast-fed population. That score trended upwards to 24 months of age. Conclusions: Infectious disease morbidity was higher but growth was normal in this cohort of HIV-EU non-breast-fed infants, in comparison to published community controls. Specific interventions should be implemented to mitigate the risk in this setting. PMID- 28718489 TI - [Profile of transvestites and transgender women: tuberculosis and HIV/AIDS in the city of Sao Paulo]. AB - Objective: To characterize the profile of transvestites and transgender women participating in a survey regarding tuberculosis and HIV/Aids in the city of Sao Paulo. Method: This cross-sectional study employed the Knowledge, Attitudes and Practices (KAP) questionnaire adapted for data collection. Sociodemographic aspects as well as aspects related to history of imprisonment, process of gender transition, use of condoms, previous treatment of sexually transmitted diseases and tuberculosis and knowledge regarding HIV/Aids were addressed. Results: The study included 58 transvestites and 66 transgender women. There were differences between the two groups regarding schooling (P = 0.008), prostitution (P < 0.001), imprisonment (P < 0.001), silicone injections (P = 0.005), and hormone therapy without medical guidance (P = 0.004). All trans women (100%) and 80% of transvestites mentioned treatment of syphilis; 25.9% of transvestites reported tuberculosis/HIV co-infection. The investigation regarding knowledge of HIV/AIDS revealed inconsistent use of condoms and mistaken beliefs related to modes of transmission. Conclusion: The present results show that transvestites and trans women were vulnerable to tuberculosis and HIV/AIDS. The differences observed between the two groups suggest the need for different approaches to transvestites and transgender women in future studies. PMID- 28718490 TI - Barriers to HIV testing, linkage to care, and treatment adherence: a cross sectional study from a large urban center of Brazil. AB - Objective: Early, continued engagement with the HIV treatment continuum can help achieve viral suppression, though few studies have explored how risk factors for delays differ across the continuum. The objective of this study was to identify predictors of delayed diagnosis, delayed linkage to care, and nonadherence to treatment in the city of Salvador, Bahia, Brazil. Methods: Data were collected during 2010 in a cross-sectional study with a sample (n = 1 970) of HIV-infected individuals enrolled in care. Multiple logistic regression analyses identified sociodemographic variables, behaviors, and measures of health service quality that were associated with delayed diagnosis, delayed linkage to care, and treatment nonadherence. Results: For delayed diagnosis, male gender (adjusted odds ratio (AOR), 3.02; 95% confidence interval (CI), 2.0-4.6); age 45 years and older (AOR, 1.67; 95% CI, 1.1-2.5); and provider-initiated testing (AOR, 3.00; 95% CI, 2.1-4.4) increased odds, while drug use (AOR, 0.29; 95% CI, 0.2-0.5) and receiving results in a private space (AOR, 0.37; 95% CI, 0.2-0.8) decreased odds. For delayed linkage to care, unemployment (AOR, 1.42; 95% CI, 1.07-1.9) and difficulty understanding or speaking with a health care worker (AOR, 1.61; 95% CI, 1.2-2.1) increased odds, while posttest counseling (AOR, 0.49; 95% CI, 0.3 0.7) decreased odds. For nonadherence, experiencing verbal or physical discrimination related to HIV (AOR, 1.94; 95% CI, 1.3-3.0) and feeling mistreated or not properly attended to at HIV care (AOR, 1.60; 95% CI, 1.0-2.5) increased odds, while posttest counseling (AOR, 0.34; 95% CI, 0.2-0.6) decreased odds. Conclusions: More attention is needed on how policies, programs, and research can provide tailored support across the treatment continuum. PMID- 28718491 TI - [HIV/AIDS surveillance among pregnant women: assessing the quality of the available information]. AB - Objective: To analyze the quality of the information available in the Reportable Disease Information System (SINAN) regarding pregnant women with HIV/AIDS in the state of Rio Grande do Norte, Brazil, between 2007 and 2014. Method: The quality of information was analyzed based on completeness (percentage of fields containing values that were not null) of fields (sociodemographic information, epidemiologic maternal history, pre-natal care, and delivery) and on the existence of discrepancy between the data sources analyzed (Natal and Mossoro municipal departments of health, state department of health, and Unified Health System information database, DATASUS). Completeness was classified as excellent (>90% of fields with values that are not null), regular (70%-89%), and poor (<70%). Dissonance was verified in the presence of differences between the sources regarding the number of pregnant women of reproductive age with HIV/AIDS reported during the study period. Results: In the study period, the State Department of Health recorded 492 cases of pregnant women with HIV/AIDS. Considering the 19 fields of the notification form, completeness was regular or poor in 11 (72%) fields. Completeness was excellent for most sociodemographic variables, but was regular or poor for most fields relating to pre-natal care and delivery. There was dissonance between the sources regarding the number of women of reproductive age with HIV/AIDS, with 482 women reported by DATASUS, 616 by the state department of health, and 663 by the municipal departments of health. Conclusions: The quality of the information regarding pregnant women/women of reproductive age with HIV/AIDS is deficient. Investment in infrastructure and continued qualification of the professionals involved in reporting could help improve the quality of information. PMID- 28718492 TI - [HIV and syphilis coinfection in pregnancy and vertical HIV transmission: a study based on epidemiological surveillance data]. AB - Objective: To estimate the rate of HIV and syphilis coinfection among pregnant women living in Porto Alegre, Brazil, as well as the association of coinfection with vertical HIV transmission and socioeconomic variables. Method: This analytical retrospective cross-sectional study employed data from the regular epidemiological surveillance system for the period from 2010 to 2013. Data were obtained regarding pregnant women with HIV and exposed children, syphilis in pregnancy, and congenital syphilis. Results: The study population included 1 500 HIV-positive women with deliveries from 2010 to 2013. Of these, 155 (10.3%) were also infected with syphilis, corresponding to an HIV and syphilis coinfection rate of 10.2% (+/- 1.5%). The coinfected group had lower education levels, higher prevalence of black women, and greater HIV exposure related to drug use by the woman or a partner. Coinfected women had more delayed HIV diagnosis (for example, during childbirth) and greater prevalence of lacking prenatal care (44%). Crude analysis showed an association between vertical HIV transmission and HIV and syphilis co-infection (PR = 2.1; 95%CI: 1.21-3.74; P = 0.01) that persisted in the adjusted analysis. Conclusion: A profile of increased vulnerability was identified among pregnant women with HIV and syphilis coinfection. A positive impact of the treatment to reduce congenital syphilis and eliminate vertical transmission of HIV depends on enhanced access to qualified health care. PMID- 28718493 TI - The HIV continuum of care in the Bahamas in 2014. AB - Objective: The HIV cascade of care describes the spectrum of engagement in HIV care from diagnosis to viral suppression (VS). The study objective was to develop a baseline HIV cascade of care for new HIV diagnoses in the Bahamas in 2014. Methods: Individuals who were newly diagnosed with HIV in 2014 and known to be alive within a year of that diagnosis were included in the cascade of care (n = 250). Individuals with one CD4 or HIV viral load (VL) measure in 2014 were considered linked to care. Those with at least two CD4 counts in the year were considered retained in care. Eligibility for antiretroviral therapy (ART) was based on having a CD4 count < 350 cells/mm3. ART adherence was defined as filled prescriptions > 11 months/year. VL < 1 000 copies/ml was considered suppressed. Comparisons were made in the cascades by gender and age. Results: Of the 250 persons in the study, 79 of them (32%) were retained in care. Antiretrovirals (ARVs) were prescribed to 116 of the 250 (46%); of those 116, 48 of them (41%) achieved VS. A higher proportion of women achieved VS than did men, but this difference did not reach statistical significance. Similarly, there were differences in VS based on age, but the differences were not statistically significant. Conclusions: In the Bahamas, increased efforts are needed to help people living with HIV to link to and be retained in care. VS may remain suboptimal unless ART is scaled up and adherence interventions are included in measures to improve the treatment cascade. PMID- 28718494 TI - The HIV care cascade in Buenos Aires, Argentina: results in a tertiary referral hospital. AB - Objective: To determine rates of retention, antiretroviral therapy (ART) use, and viral suppression in an adult cohort from a public tertiary referral hospital in the city of Buenos Aires, Argentina. Methods: HIV-positive ART-naive patients >= 18 years old starting care 2011-2013 contributed data until the end of 2014. Three outcomes were assessed in 2014: retention in care, ART use, and viral suppression. Patient characteristics associated with each outcome were assessed through logistic regression. Results: A total of 1 031 patients were included. By the end of 2014, 1.5% had died and 14.8% were transferred to a different center. Of the remaining 859 patients, 563 (65.5%) were retained in 2014. Among those retained, 459 (81.5%) were on ART in 2014. Of those 459 on ART, 270 (58.8%) were virologically suppressed. Younger age was associated with lower retention (OR (odds ratio): 0.67; 95% CI (confidence interval): 0.44-0.92 for >= 35 vs. < 35 years), but unrelated with ART use or viral suppression. Low CD4 count at first visit was associated with ART use (OR: 35.72 for CD4 < 200, 7.13 for CD4 200-499 vs. >= 500, P < 0.001) and with virologic suppression (OR: 2.17 for CD4 < 200, 2.46 for CD4 200-499 vs. >= 500, P: 0.023). Conclusions: Our hospital in Buenos Aires is still below the recommended 90-90-90 targets of the Joint United Nations Programme on HIV/AIDS (UNAIDS) for ART use and viral suppression. We found a major gap in retention in care. Identifying younger age as being associated with worse retention will help in the design of targeted interventions. PMID- 28718495 TI - Comparative effectiveness of single and dual rapid diagnostic tests for syphilis and HIV in antenatal care services in Colombia. AB - Objective: To assess the effectiveness of a dual rapid test compared to a single rapid test for syphilis and HIV screening. Methods: A cluster-randomized open label clinical trial was performed in 12 public antenatal care (ANC) centers in the cities of Bogota and Cali, Colombia. Pregnant women who were over 14 years of age at their first antenatal visit and who had not been previously tested for HIV and syphilis during the current pregnancy were included. Pregnant women were randomized to single HIV and single syphilis rapid diagnostic tests (Arm A) or to dual HIV and syphilis rapid diagnostic tests (Arm B). The four main outcomes measured were: (1) acceptability of the test, (2) uptake in testing, (3) treatment on the same day (that is, timely treatment), and (4) treatment at any time for positive rapid test cases. Bivariate and multivariate analyses were calculated to adjust for the clustering effect and the period. Results: A total of 1 048 patients were analyzed in Arm A, and 1 166 in Arm B. Acceptability of the rapid tests was 99.8% in Arm A and 99.6% in Arm B. The prevalence of positive rapid tests was 2.21% for syphilis and 0.36% for HIV. Timely treatment was provided to 20 of 29 patients (69%) in Arm A and 16 of 20 patients (80%) in Arm B (relative risk (RR), 1.10; 95% confidence interval (CI): (1.00 -1.20). Treatment at any time was given to 24 of 29 patients (83%) in Arm A and to 20 of 20 (100%) in Arm B (RR, 1.11; 95% CI: 1.01-1.22). Conclusions: There were no differences in patient acceptability, testing and timely treatment between dual rapid tests and single rapid tests for HIV and syphilis screening in the ANC centers. Same-day treatment depends also on the interpretation of and confidence in the results by the health providers. PMID- 28718496 TI - [Introduction of rapid syphilis and HIV testing in prenatal care in Colombia: qualitative analysis]. AB - Objective: Interpret perceptions of Colombian health professionals concerning factors that obstruct and facilitate the introduction of rapid syphilis and HIV testing in prenatal care services. Methods: A qualitative study based on semi structured interviews was carried out. A convenience sample was selected with 37 participants, who included health professionals involved in prenatal care services, programs for pregnant women, clinical laboratories, and directors of health care units or centers, as well as representatives from regional departments and the Ministry of Health. Results: Colombia does not do widespread screening with rapid syphilis and HIV tests in prenatal care. The professionals interviewed stated they did not have prior experience in the use of rapid tests except for laboratory staff-or in the course of action in response to a positive result. The insurance system hinders access to timely diagnosis and treatment. Health authorities perceive a need to review existing standards, strengthen the first level of care, and promote comprehensive prenatal care starting with contracts between insurers and health service institutional providers. Participants recommended staff training and integration between health policymaking and academic entities for updating training programs. Conclusions: The market approach and the characteristics of the Colombian health system constitute the main barriers to implementation of rapid testing as a strategy for elimination of mother-to-child transmission of syphilis and HIV. Measures identified include making changes in contracts between insurers and health service institutional providers, adapting the timing and duration of prenatal care procedures, and training physicians and nurses involved in prenatal care. PMID- 28718497 TI - Review of HIV treatment progress, gaps, and challenges in the Caribbean, 2005 2015. AB - Objective: To highlight the current context of the HIV response in the Caribbean and what remains to be addressed to close gaps in HIV treatment and care and end AIDS by 2030. Methods: We reviewed and analyzed reports from peer-reviewed and gray literature for the period of 2005-2015 on HIV treatment progress and gaps in the Caribbean, based on searches done in four bibliographic databases and three organizations' websites and/or libraries. Data were extracted using forms detailing study objectives, thematic areas for HIV care and treatment in the Caribbean, results, and other key information. Before being included in the descriptive review, each publication was assessed for its relevance to the HIV response in the Caribbean. Results: We carefully analyzed a total of 62 sources addressing HIV treatment coverage in the Caribbean, including peer-reviewed articles, gray literature reports, and abstracts. The Caribbean has made remarkable progress in reducing new infections and in increasing health care access. Coverage with antiretroviral (ARV) treatment rose between 2005 and 2015, and HIV-related mortality fell by half. Despite the decline in HIV incidence rates, some Caribbean countries have reported challenges with linkages to care, access and adherence to ARV treatment, and viral suppression. Conclusion: The risk of HIV infection in the Caribbean among at-risk populations, including men who have sex with men, transgender persons, and sex workers, is disproportionately high. Caribbean countries need to work together to face the HIV threat. National programs need to fast-track HIV treatment services and accelerate other responses to HIV by 2020, and then maintain sustained actions up through 2030. PMID- 28718498 TI - Assessing HIV acquisition risks among men who have sex with men in the United States of America. AB - Men who have sex with men (MSM) can reduce their risk of acquiring human immunodeficiency virus (HIV) by using various prevention strategies and by understanding the effectiveness of each option over the short- and long-term. Strategies examined were: circumcision; insertive anal sex only; consistent, 100% self-reported condom use; and pre-exposure prophylaxis (PrEP). PrEP efficacy was based on three levels of adherence. The cumulative HIV acquisition risk among MSM over periods of 1 year and 10 years were estimated with and without single and combinations of prevention strategies. A Bernoulli process model was used to estimate risk. In the base case with no prevention strategies, the 1-year risk of HIV acquisition among MSM was 8.8%. In contrast, the 1-year risk associated with circumcision alone was 6.9%; with insertive sex only, 5.5%; with 100% self reported condom use, 2.7%; and with average, high, and very high PrEP adherence, 5.1%, 2.5%, and 0.7%, respectively. The 10-year risk of HIV acquisition among MSM with no prevention strategy was 60.3%. In contrast, that associated with circumcision alone was 51.1%; with insertive sex only, 43.1%; with 100% self reported condom use, 24.0%; and with average, high, and very high PrEP adherence, 40.5%, 22.2%, and 7.2%, respectively. While MSM face substantial risk of HIV, there are now a number of prevention strategies that reduce risk. Very high adherence to PrEP alone or with other strategies appears to be the most powerful tool for HIV prevention. PMID- 28718499 TI - [Meeting contraceptive needs of HIV-positive women: effect on elimination of vertical transmission of HIV]. AB - Nearly 38% of unplanned pregnancies occur because of unmet contraceptive needs. In HIV-positive women, these figures triple, a phenomenon explained by social determinants such as poverty, access to health services, violence, and forced displacement, all of which are frequent elements in the lives of these women. Unplanned pregnancies represent a psychological burden related to women's fear of transmitting the infection to their children, orphanhood, and assuming risks during pregnancy, in addition to family and social consequences that are expressed in lack of prenatal care, neglect of their health, and an increased likelihood of vertical transmission. Technical assistance for differentiated contraception counseling integrated into HIV care and control services is basic to achieving short- and medium-term elimination of vertical transmission of HIV. These women's characteristics are different from those of the general population, as expressed in their reproductive lives, desires, and intentions regarding motherhood; and their unplanned pregnancies represent a greater psychological, social, and economic burden than that of other women. Recognizing this would allow contraception counseling to be provided by HIV care and follow-up programs, in the same place and time, with trained personnel, capable of understanding and meeting their reproductive needs within a rights-based framework, ensuring that health systems, based on the responsibility they have to society, would be capable of offering quality reproductive care counseling, aimed at meeting the specific needs of HIV-positive women. PMID- 28718500 TI - Neurofilament light as an immune target for pathogenic antibodies. AB - Antibodies to neuronal antigens are associated with many neurological diseases including paraneoplastic neurological disorders, epilepsy, amyotrophic lateral sclerosis and multiple sclerosis. Immunization with neuronal antigens such as neurofilament light (NF-L), a neuronal intermediate filament in axons, has been shown to induce neurological disease and spasticity in mice. Also, although antibodies to NF-L are widely used as surrogate biomarkers of axonal injury in amyotrophic lateral sclerosis and multiple sclerosis, it remains to be elucidated if antibodies to NF-L contribute to neurodegeneration and neurological disease. To address this, we examined the pathogenic role of antibodies directed to NF-L in vitro using spinal cord co-cultures and in vivo in experimental autoimmune encephalomyelitis (EAE) and optic neuritis animal models of multiple sclerosis. Here we show that peripheral injections of antibodies to NF-L augmented clinical signs of neurological disease in acute EAE, increased retinal ganglion cell loss in experimental optic neuritis and induced neurological signs following intracerebral injection into control mice. The pathogenicity of antibodies to NF L was also observed in spinal cord co-cultures where axonal loss was induced. Taken together, our results reveal that as well as acting as reliable biomarkers of neuronal damage, antibodies to NF-L exacerbate neurological disease, suggesting that antibodies to NF-L generated during disease may also be pathogenic and play a role in the progression of neurodegeneration. PMID- 28718501 TI - New imaging tools for an old disease: Secondary syphilis. PMID- 28718503 TI - Assumption Hunting in Groundwater Modeling: Find Assumptions Before They Find You. PMID- 28718504 TI - Air Compressibility Effect on Bouwer and Rice Seepage Meter. AB - Measuring a disconnected streambed seepage flux using a seepage meter can give important streambed information and help understanding groundwater-surface water interaction. In this study, we provide a correction for calculating the seepage flux rate with the consideration of air compressibility inside the manometer of the Bouwer and Rice seepage meter. We notice that the effect of air compressibility in the manometer is considerably larger when more air is included in the manometer. We find that the relative error from neglecting air compressibility can be constrained within 5% if the manometer of the Bouwer and Rice seepage meter is shorter than 0.8 m and the experiment is done in a suction mode in which air is pumped out from the manometer before the start of measurement. For manometers longer than 0.8 m, the relative error will be larger than 5%. It may be over 10% if the manometer height is longer than 1.5 m and the experiment is done in a no-suction mode, in which air is not pumped out from the manometer before the start of measurement. PMID- 28718502 TI - Chansporter complexes in cell signaling. AB - Ion channels facilitate diffusion of ions across cell membranes for such diverse purposes as neuronal signaling, muscular contraction, and fluid homeostasis. Solute transporters often utilize ionic gradients to move aqueous solutes up their concentration gradient, also fulfilling a wide variety of tasks. Recently, an increasing number of ion channel-transporter ('chansporter') complexes have been discovered. Chansporter complex formation may overcome what could otherwise be considerable spatial barriers to rapid signal integration and feedback between channels and transporters, the ions and other substrates they transport, and environmental factors to which they must respond. Here, current knowledge in this field is summarized, covering both heterologous expression structure/function findings and potential mechanisms by which chansporter complexes fulfill contrasting roles in cell signaling in vivo. PMID- 28718505 TI - Immunogenomic approaches to understand the function of immune disease variants. AB - Mapping hundreds of genetic variants through genome wide association studies provided an opportunity to gain insights into the pathobiology of immune-mediated diseases. However, as most of the disease variants fall outside the gene coding sequences the functional interpretation of the exact role of the associated variants remains to be determined. The integration of disease-associated variants with large scale genomic maps of cell-type-specific gene regulation at both chromatin and transcript levels deliver examples of functionally prioritized causal variants and genes. In particular, the enrichment of disease variants with histone marks can point towards the cell types most relevant to disease development. Furthermore, chromatin contact maps that link enhancers to promoter regions in a direct way allow the identification of genes that can be regulated by the disease variants. Candidate genes implicated with such approaches can be further examined through the correlation of gene expression with genotypes. Additionally, in the context of immune-mediated diseases it is important to combine genomics with immunology approaches. Genotype correlations with the immune system as a whole, as well as with cellular responses to different stimuli, provide a valuable platform for understanding the functional impact of disease-associated variants. The intersection of immunogenomic resources with disease-associated variants paints a detailed picture of disease causal mechanisms. Here, we provide an overview of recent studies that combine these approaches to identify disease vulnerable pathways. PMID- 28718506 TI - Felbamate as an add-on therapy for refractory partial epilepsy. AB - BACKGROUND: This review is an update of a previously published review in the Cochrane Database of Systematic Reviews (Issue 7, 2014) on 'Felbamate as an add on therapy for refractory epilepsy'. Epilepsy is a chronic and disabling neurologic disorder, affecting approximately 1% of the population. Up to 30% of people with epilepsy have seizures that are resistant to currently available drugs. Felbamate is one of the second-generation antiepileptic drugs and we have assessed its effects as an add-on therapy to standard drugs in this review. OBJECTIVES: To evaluate the efficacy and tolerability of felbamate versus placebo when used as an add-on treatment for people with refractory partial-onset epilepsy. SEARCH METHODS: For the latest update we searched the Cochrane Epilepsy Specialized Register, CENTRAL, MEDLINE, ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform, up to 20 October 2016. There were no language and time restrictions. We reviewed the reference lists of retrieved studies to search for additional reports of relevant studies. We also contacted the manufacturers of felbamate and experts in the field for information about any unpublished or ongoing studies. SELECTION CRITERIA: Randomised placebo controlled add-on studies of people of any age with refractory partial-onset seizures. The studies could be double-blind, single-blind or unblinded and could be of parallel or cross-over design. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies for inclusion and extracted information. We resolved disagreements by discussion. If disagreements persisted, the third review author arbitrated. We assessed the following outcomes: 50% or greater reduction in seizure frequency; absolute or percentage reduction in seizure frequency; treatment withdrawal; adverse effects; quality of life. MAIN RESULTS: We included four randomised controlled trials with a total of 236 participants. Two trials were parallel design, the third had a two-period cross-over design, and the fourth had a three-period cross-over design. Two studies were at an unclear risk of bias for random sequence generation and allocation concealment. These two studies did not include any description of their methods for outcome assessment and performance blinding (i.e. participants or doctors). Two studies were at high risk of bias for incomplete outcome data. Due to significant methodological heterogeneity, clinical heterogeneity and differences in outcome measures, it was not possible to perform a meta-analysis of the results. Only one study reported 50% or greater reduction in seizure frequency. One study reported absolute and percentage reduction in seizure frequency compared to placebo, P values were 0.046 and 0.018, respectively. One study reported percentage reduction in seizure frequency compared to placebo, but there were no P values. Adverse effects rates were higher during the felbamate period than the placebo period, particularly headache, nausea and dizziness. AUTHORS' CONCLUSIONS: In view of the methodological deficiencies, limited number of individual studies and differences in outcome measures, we have found no reliable evidence to support the use of felbamate as an add-on therapy in people with refractory partial-onset epilepsy. A large-scale, randomised controlled trial conducted over a longer period of time is required to inform clinical practice. PMID- 28718509 TI - Are minimally invasive approaches to ectopic pregnancy underutilized? PMID- 28718508 TI - Development of iFOX-hunting as a functional genomic tool and demonstration of its use to identify early senescence-related genes in the polyploid Brassica napus. AB - Functional genomic studies of many polyploid crops, including rapeseed (Brassica napus), are constrained by limited tool sets. Here we report development of a gain-of-function platform, termed 'iFOX (inducible Full-length cDNA OvereXpressor gene)-Hunting', for inducible expression of B. napus seed cDNAs in Arabidopsis. A Gateway-compatible plant gene expression vector containing a methoxyfenozide inducible constitutive promoter for transgene expression was developed. This vector was used for cloning of random cDNAs from developing B. napus seeds and subsequent Agrobacterium-mediated transformation of Arabidopsis. The inducible promoter of this vector enabled identification of genes upon induction that are otherwise lethal when constitutively overexpressed and to control developmental timing of transgene expression. Evaluation of a subset of the resulting ~6000 Arabidopsis transformants revealed a high percentage of lines with full-length B. napus transgene insertions. Upon induction, numerous iFOX lines with visible phenotypes were identified, including one that displayed early leaf senescence. Phenotypic analysis of this line (rsl-1327) after methoxyfenozide induction indicated high degree of leaf chlorosis. The integrated B. napuscDNA was identified as a homolog of an Arabidopsis acyl-CoA binding protein (ACBP) gene designated BnACBP1-like. The early senescence phenotype conferred by BnACBP1-like was confirmed by constitutive expression of this gene in Arabidopsis and B. napus. Use of the inducible promoter in the iFOX line coupled with RNA-Seq analyses allowed mechanistic clues and a working model for the phenotype associated with BnACBP1-like expression. Our results demonstrate the utility of iFOX-Hunting as a tool for gene discovery and functional characterization of Brassica napus genome. PMID- 28718507 TI - Gene expression analyses reveal metabolic specifications in acute O2 -sensing chemoreceptor cells. AB - KEY POINTS: Glomus cells in the carotid body (CB) and chromaffin cells in the adrenal medulla (AM) are essential for reflex cardiorespiratory adaptation to hypoxia. However, the mechanisms whereby these cells detect changes in O2 tension are poorly understood. The metabolic properties of acute O2 -sensing cells have been investigated by comparing the transcriptomes of CB and AM cells, which are O2 -sensitive, with superior cervical ganglion neurons, which are practically O2 insensitive. In O2 -sensitive cells, we found a characteristic prolyl hydroxylase 3 down-regulation and hypoxia inducible factor 2alpha up-regulation, as well as overexpression of genes coding for three atypical mitochondrial electron transport subunits and pyruvate carboxylase, an enzyme that replenishes tricarboxylic acid cycle intermediates. In agreement with this observation, the inhibition of succinate dehydrogenase impairs CB acute O2 sensing. The responsiveness of peripheral chemoreceptor cells to acute hypoxia depends on a 'signature metabolic profile'. ABSTRACT: Acute O2 sensing is a fundamental property of cells in the peripheral chemoreceptors, e.g. glomus cells in the carotid body (CB) and chromaffin cells in the adrenal medulla (AM), and is necessary for adaptation to hypoxia. These cells contain O2 -sensitive ion channels, which mediate membrane depolarization and transmitter release upon exposure to hypoxia. However, the mechanisms underlying the detection of changes in O2 tension by cells are still poorly understood. Recently, we suggested that CB glomus cells have specific metabolic features that favour the accumulation of reduced quinone and the production of mitochondrial NADH and reactive oxygen species during hypoxia. These signals alter membrane ion channel activity. To investigate the metabolic profile characteristic of acute O2 -sensing cells, we used adult mice to compare the transcriptomes of three cell types derived from common sympathoadrenal progenitors, but exhibiting variable responsiveness to acute hypoxia: CB and AM cells, which are O2 -sensitive (glomus cells > chromaffin cells), and superior cervical ganglion neurons, which are practically O2 -insensitive. In the O2 -sensitive cells, we found a characteristic mRNA expression pattern of prolyl hydroxylase 3/hypoxia inducible factor 2alpha and up regulation of several genes, in particular three atypical mitochondrial electron transport subunits and some ion channels. In addition, we found that pyruvate carboxylase, an enzyme fundamental to tricarboxylic acid cycle anaplerosis, is overexpressed in CB glomus cells. We also observed that the inhibition of succinate dehydrogenase impairs CB acute O2 sensing. Our data suggest that responsiveness to acute hypoxia depends on a 'signature metabolic profile' in chemoreceptor cells. PMID- 28718510 TI - Reproducibility of endometrial cytology by the Osaki Study Group Method: Methodological issues. PMID- 28718511 TI - Genomewide identification of genes involved in the potato response to drought indicates functional evolutionary conservation with Arabidopsis plants. AB - Potato is one of the four most important food crop plants worldwide and is strongly affected by drought. The following two pairs of potato cultivars, which are related in ancestry but show different drought tolerances, were chosen for comparative gene expression studies: Gwiazda/Oberon and Tajfun/Owacja. Comparative RNA-seq analyses of gene expression differences in the transcriptomes obtained from drought-tolerant versus drought-sensitive plants during water shortage conditions were performed. The 23 top-ranking genes were selected, 22 of which are described here as novel potato drought-responsive genes. Moreover, all but one of the potato genes selected have homologues in the Arabidopsis genome. Of the seven tested A. thaliana mutants with altered expression of the selected homologous genes, compared to the wild-type Arabidopsis plants, six showed an improved tolerance to drought. These genes encode carbohydrate transporter, mitogen-activated protein kinase kinase kinase 15 (MAPKKK15), serine carboxypeptidase-like 19 protein (SCPL19), armadillo/beta-catenin-like repeat containing protein, high-affinity nitrate transporter 2.7 and nonspecific lipid transfer protein type 2 (nsLPT). The evolutionary conservation of the functions of the selected genes in the plant response to drought confirms the importance of these identified potato genes in the ability of plants to cope with water shortage conditions. Knowledge regarding these gene functions can be used to generate potato cultivars that are resistant to unfavourable conditions. The approach used in this work and the obtained results allowed for the identification of new players in the plant response to drought. PMID- 28718513 TI - The fine needle aspiration of translocation sarcomas. AB - INTRODUCTION: Soft tissue sarcomas comprise a heterogeneous group of clinically aggressive cancers that are often hard to classify on limited cytological samples. "Translocation sarcomas" (TS) are a diverse subset of such cancers, different from pleomorphic sarcomas, and characterised by unique single chromosomal translocations in each sarcoma subtype. Interestingly, despite their high-grade biological behaviour, TS have deceptively monotonous and bland cytomorphology, therefore creating diagnostic issues on limited samples. MATERIALS AND METHODS: A retrospective search was conducted of the cytopathology archives of The Johns Hopkins Hospital revealing 147 translocation sarcoma cases over a 25-year period. RESULTS: The common morphological denominators for most translocation sarcomas were: hypercellularity, cellular monotony, mostly discohesive and single cells, round-to-oval or short spindled cells and a lack of necrosis. The exceptions were an inflammatory myofibroblastic tumour, in which cellular monotony was not present owing to the prominence of lymphocytes and plasma cells, and low-grade fibromyxoid sarcoma, in which the specimens were generally hypocellular. Ancillary testing, especially immunoperoxidase staining, was often required for primary lesions. CONCLUSION: Distinct morphological clues and subsequent ancillary testing (particularly immunoperoxidase staining) provide an accurate diagnosis on cytological interpretation of both, primary and recurrent/metastatic lesions. PMID- 28718512 TI - Overweight is associated with lower resting state functional connectivity in females after eliminating genetic effects: A twin study. AB - Obesity is related to altered functional connectivity of resting state brain networks that are involved in reward and motivation. It is unknown to what extent these associations reflect genetic confounding and whether the obesity-related connectivity changes are associated with differences in dietary intake. In this study, resting state functional MRI was performed after an overnight fast in 16 female monozygotic twin pairs (aged 48.8 +/- 9.8 years) with a mean BMI discordance of 3.96 +/- 2.1 kg/m2 (range 0.7-8.2). Functional connectivity of the salience, basal ganglia, default mode and anterior cingulate-orbitofrontal cortex networks was examined by independent component analysis. Dietary intake was assessed using 3-day 24-hour recalls. Results revealed that within the basal ganglia network, heavier versus leaner co-twins have decreased functional connectivity strength in bilateral putamen (P < 0.05, FWE-corrected). There were no differences in connectivity in the other networks examined. In the overall group, lower functional connectivity strength in the left putamen was correlated with higher intake of total fat (P < 0.01). It was concluded that, after eliminating genetic effects, overweight is associated with lower resting state functional connectivity in bilateral putamen in the basal ganglia network. The association between lower putamen connectivity and higher fat intake suggests an important role of the putamen in appetitive mechanisms. The cross-sectional nature of our study cannot discriminate cause and consequence, but the findings are compatible with an effect of lower putamen connectivity on increased BMI and associated higher fat intake. Hum Brain Mapp 38:5069-5081, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28718514 TI - Aldehyde dehydrogenase 1 a1 regulates energy metabolism in adipocytes from different species. AB - BACKGROUND: Survival and longevity of xenotransplants depend on immune function and ability to integrate energy metabolism between cells from different species. However, mechanisms for interspecies cross talk in energy metabolism are not well understood. White adipose tissue stores energy and is capable of mobilization and dissipation of energy as heat (thermogenesis) by adipocytes expressing uncoupling protein 1 (Ucp1). Both pathways are under the control of vitamin A metabolizing enzymes. Deficient retinoic acid production in aldehyde dehydrogenase 1 A1 (Aldh1a1) knockout adipocytes (KO) inhibits adipogenesis and increases thermogenesis. Here we test the role Aldh1a1 in regulation of lipid metabolism in xenocultures. METHODS: Murine wide-type (WT) and KO pre-adipocytes were encapsulated into a poly-L-lysine polymer that allows exchange of humoral factors <32kD via nanopores. Encapsulated murine adipocytes were co-incubated with primary differentiated canine adipocytes. Then, expression of adipogenic and thermogenic genes in differentiated canine adipocytes was detected by real-time polymerase chain reaction (PCR). The regulatory factors in WT and KO cells were identified by comparison of secretome using proteomics and in transcriptome by gene microarray. RESULTS: Co-culture of encapsulated mouse KO vs WT adipocytes increased expression of peroxisome proliferator-activated receptor gamma (Pparg), but reduced expression of its target genes fatty acid binding protein 4 (Fabp4), and adipose triglyceride lipase (Atgl) in canine adipocytes, suggesting inhibition of PPARgamma activation. Co-culture with KO adipocytes also induced expression of Ucp1 in canine adipocytes compared to expression in WT adipocytes. Cumulatively, murine KO compared to WT adipocytes decreased lipid accumulation in canine adipocytes. Comparative proteomics revealed significantly higher levels of vitamin A carriers, retinol binding protein 4 (RBP4), and lipokalin 2 (LCN2) in KO vs WT adipocytes. CONCLUSIONS: Our data demonstrate the functional exchange of regulatory factors between adipocytes from different species for regulation of energy balance. RBP4 and LCN2 appear to be involved in the transport of retinoids for regulation of lipid accumulation and thermogenesis in xenocultures. While the rarity of thermogenic adipocytes in humans and dogs precludes their use for autologous transplantation, our study demonstrates that xenotransplantation of engineered cells could be a potential solution for the reduction in obesity in dogs and a strategy for translation to patients. PMID- 28718516 TI - Control of the Fluid Viscosity in a Mock Circulation. AB - A mock circulation allows the in vitro investigation, development, and testing of ventricular assist devices. An aqueous-glycerol solution is commonly used to mimic the viscosity of blood. Due to evaporation and temperature changes, the viscosity of the solution drifts from its initial value and therefore, deviates substantially from the targeted viscosity of blood. Additionally, the solution needs to be exchanged to account for changing viscosities when mimicking different hematocrits. This article presents a method to control the viscosity in a mock circulation. This method makes use of the relationship between temperature and viscosity of aqueous-glycerol solutions and employs the automatic control of the viscosity of the fluid. To that end, an existing mock circulation was extended with an industrial viscometer, temperature probes, and a heating nozzle band. The results obtained with different fluid viscosities show that a viscosity controller is vital for repeatable experimental conditions on mock circulations. With a mixture ratio of 49 mass percent of aqueous-glycerol solution, the controller can mimic a viscosity range corresponding to a hematocrit between 29 and 42% in a temperature range of 30-42 degrees C. The control response has no overshoot and the settling time is 8.4 min for a viscosity step of 0.3 cP, equivalent to a hematocrit step of 3.6%. Two rotary blood pumps that are in clinical use are tested at different viscosities. At a flow rate of 5 L/min, both show a deviation of roughly 15 and 10% in motor current for high rotor speeds. The influence of different viscosities on the measured head pressure is negligible. Viscosity control for a mock circulation thus plays an important role for assessing the required motor current of ventricular assist devices. For the investigation of the power consumption of rotary blood pumps and the development of flow estimators where the motor current is a model input, an integrated viscosity controller is a valuable contribution to an accurate testing environment. PMID- 28718515 TI - Impact of Single Nucleotide Polymorphisms on Plasma Concentrations of Efavirenz and Lopinavir/Ritonavir in Chinese Children Infected with the Human Immunodeficiency Virus. AB - Single nucleotide polymorphisms (SNPs) in the genes that encode the cytochrome P450 (CYP) drug metabolizing enzymes and drug transporters have been reported to influence antiretroviral drug pharmacokinetics. Although primarily metabolized by CYP2B6 and -3A, efavirenz (EFV) and lopinavir/ritonavir (LPV/r) are substrates of P-glycoprotein and the solute carrier organic (SLCO) anion transporter, respectively. We investigated the association between SNPs and efavirenz (EFV) or lopinavir/ritonavir (LPV/r) concentrations in Chinese children infected with the human immunodeficiency virus (HIV). Genotyping was performed on CYP2B6 516G->T, 1459C->T, and -983T->C, ABCB1 3435C->T, and SLCO1B1 521T->C in 229 HIV-infected Chinese pediatric patients (age range 4.0 to 17.5 yrs). Plasma concentrations of EFV and LPV/r were measured using validated high-performance liquid chromatography coupled with the mass spectrum method among 39 and 69 children who received EFV- and LPV/r-containing regimens, respectively. The frequencies of CYP2B6 516G->T in the study participants were 71%, 25%, and 4% for the G/G, G/T, and T/T genotypes, respectively. Among the children under therapeutic drug monitoring, 21% and 39% experienced EFV and LPV concentrations, respectively, above the upper threshold of the therapeutic window. CYP2B6 516G->T was significantly associated with EFV concentrations (p<0.001). Older children (older than 10 yrs) were more likely to have significantly higher EFV concentrations than the younger ones (p=0.0314). CYP2B6 genotyping and EFV concentration monitoring may help optimize antiretroviral therapy in pediatric patients who initiate an EFV-based regimen. PMID- 28718517 TI - Evaluation of fitting models for prostate tissue characterization using extended range b-factor diffusion-weighted imaging. AB - PURPOSE: To compare the fitting and tissue discrimination performance of biexponential, kurtosis, stretched exponential, and gamma distribution models for high b-factor diffusion-weighted images in prostate cancer. METHODS: Diffusion weighted images with 15 b-factors ranging from b = 0 to 3500 s/mm2 were obtained in 62 prostate cancer patients. Pixel-wise signal decay fits for each model were evaluated with the Akaike Information Criterion (AIC). Parameter values for each model were determined within normal prostate and the index lesion. Their potential to differentiate normal from cancerous tissue was investigated through receiver operating characteristic analysis and comparison with Gleason score. RESULTS: The biexponential slow diffusion fraction fslow , the apparent kurtosis diffusion coefficient ADCK , and the excess kurtosis factor K differ significantly among normal peripheral zone (PZ), normal transition zone (TZ), tumor PZ, and tumor TZ. Biexponential and gamma distribution models result in the lowest AIC, indicating a superior fit. Maximum areas under the curve (AUCs) of all models ranged from 0.93 to 0.96 for the PZ and from 0.95 to 0.97 for the TZ. Similar AUCs also result from the apparent diffusion coefficient (ADC) of a monoexponential fit to a b-factor sub-range up to 1250 s/mm2 . For kurtosis and stretched exponential models, single parameters yield the highest AUCs, whereas for the biexponential and gamma distribution models, linear combinations of parameters produce the highest AUCs. Parameters with high AUC show a trend in differentiating low from high Gleason score, whereas parameters with low AUC show no such ability. CONCLUSION: All models, including a monoexponential fit to a lower-b sub-range, achieve similar AUCs for discrimination of normal and cancer tissue. The biexponential model, which is favored statistically, also appears to provide insight into disease-related microstructural changes. Magn Reson Med 79:2346-2358, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28718518 TI - Reduction of Zika virus infectivity in platelet concentrates after treatment with ultraviolet C light and in plasma after treatment with methylene blue and visible light. AB - BACKGROUND: Zika virus (ZIKV) has emerged as a potential threat to transfusion safety worldwide. Pathogen inactivation is one approach to manage this risk. In this study, the efficacy of the THERAFLEX UV-Platelets system and THERAFLEX MB Plasma system to inactivate ZIKV in platelet concentrates (PCs) and plasma was investigated. STUDY DESIGN AND METHODS: PCs spiked with ZIKV were treated with the THERAFLEX UV-Platelets system at 0.05, 0.10, 0.15, and 0.20 J/cm2 UVC. Plasma spiked with ZIKV was treated with the THERAFLEX MB-Plasma system at 20, 40, 60, and 120 J/cm2 light at 630 nm with at least 0.8 umol/L methylene blue (MB). Samples were taken before the first and after each illumination dose and tested for residual virus. For each system the level of viral reduction was determined. RESULTS: Treatment of PCs with THERAFLEX UV-Platelets system resulted in a mean of 5 log reduction in ZIKV infectivity at the standard UVC dose (0.20 J/cm2 ), with dose dependency observed with increasing UVC dose. For plasma treated with MB and visible light, ZIKV infectivity was reduced by a mean of at least 5.68 log, with residual viral infectivity reaching the detection limit of the assay at 40 J/cm2 (one-third the standard dose). CONCLUSIONS: Our study demonstrates that the THERAFLEX UV-Platelets system and THERAFLEX MB-Plasma system can reduce ZIKV infectivity in PCs and pooled plasma to the detection limit of the assays used. These findings suggest both systems have the capacity to be an effective option to manage potential ZIKV transfusion transmission risk. PMID- 28718519 TI - Cookies elaborated with oat and common bean flours improved serum markers in diabetic rats. AB - BACKGROUND: Common beans have been associated with anti-diabetic effects, due to its high content of bioactive compounds. Nevertheless, its consumption has decreased worldwide. Therefore, there is an increasing interest in the development of novel functional foods elaborated with common beans. The aim of this study was to evaluate the anti-diabetic effect of oat-bean flour cookies, and to analyze its bioactive composition, using commercial oat-wheat cookies for comparative purposes. RESULTS: Oat-bean cookies (1.2 g kg-1 ) slightly decreased serum glucose levels (~1.1-fold) and increased insulin levels (~1.2-fold) in diabetic rats, reducing the hyperglycemic peak in healthy rats (~1.1-fold). Oat bean cookies (0.8 and 1.2 g kg-1 ) exerted a greater hypolipidemic effect than commercial oat-wheat cookies (1.2 g kg-1 ), as observed in decreased serum triglycerides and low-density lipoprotein cholesterol. Furthermore, the supplementation with 1.2 g kg-1 oat-bean cookies decreased atherogenic index and serum C-reactive protein levels, suggesting their cardioprotective potential. The beneficial effect of oat-bean cookies was associated with their high content of dietary fiber and galacto oligosaccharides, as well as chlorogenic acid, rutin, protocatechuic acid, beta-sitosterol and soyasaponins. CONCLUSION: These results suggest that common beans can be used as functional ingredients for the elaboration of cookies with anti-diabetic effects. (c) 2017 Society of Chemical Industry. PMID- 28718520 TI - Putting public health infrastructures to the test: introducing HPV vaccination in Austria and the Netherlands. AB - This article presents two cases of policymaking concerning the vaccine against Human Papilloma Virus (HPV), which is sexually transmitted and carcinogenic. Our analysis focuses on its introduction in Austria and the Netherlands. In both contexts, we find prevention and screening to be at once complementary and competing public health logics and we draw on the concept of 'infrastructure' to understand their roles in shaping the reception of the vaccine. We reveal how the HPV vaccine had to be made 'good enough', much like the Pap smear (Casper and Clarke ), by means of diverse tinkering practices that transformed both the technology and the infrastructures in which they emerged. At the same time, it was important that the vaccine would not come to problematise Pap smear-based screening. The article points to the contextually contingent nature of policymaking around new medical technologies, and the skillful care with which public health infrastructures such as immunisation and screening programmes are handled and tinkered with. PMID- 28718521 TI - Nucleic acid storage on FTA cards from cytological samples. PMID- 28718522 TI - T2 -prepared balanced steady-state free precession (bSSFP) for quantifying whole blood oxygen saturation at 1.5T. AB - PURPOSE: To establish a calibration equation to convert human blood T2 to the full range of oxygen saturation levels (HbO2 ) and physiologic hematocrit (Hct) values using a T2 -prepared balanced steady-state free precession sequence (T2 SSFP) at 1.5T. METHODS: Blood drawn from 10 healthy donors (29.1 +/- 3.9 years old) was prepared into samples of varying HbO2 and Hct (n = 79), and imaged using T2 -SSFP sequence at 37 degrees C and interrefocusing interval tau180 = 12 ms. The relationship between blood T2 , HbO2 , and Hct was established based on the model R2=R2,plasma+Hct (R2,RBC-R2,plasma)+k.Hct.(1-Hct).(1-HbO2)2. Measured R2 and HbO2 levels were fit by the model yielding values of R2,plasma, R2,RBC, and k. T2 -SSFP and the established calibration equation were applied to extract HbO2 at the superior sagittal sinus (SSS) in vivo and were compared with susceptometry based oximetry. RESULTS: Constants derived from the fit were: k = 74.2 [s-1 ], R2,plasma = 1.5 [s-1 ], R2,RBC = 11.6 [s-1 ], the R2 of the fit was 0.95. Average HbO2 at the SSS in seven healthy volunteers was 65% +/- 7% and 66% +/- 7% via T2 - and susceptometry-based oximetry, respectively. Bland-Altman analysis indicated agreement between the two oximetric methods with no significant bias. CONCLUSION: The calibration constants presented here should ensure improved accuracy for whole-blood oximetry based on T2 -SSFP at 1.5T. Magn Reson Med 79:1893-1900, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28718524 TI - Erratum. PMID- 28718523 TI - Error rate of automated calculation for wound surface area using a digital photography. AB - BACKGROUND: Although measuring would size using digital photography is a quick and simple method to evaluate the skin wound, the possible compatibility of it has not been fully validated. PURPOSE: To investigate the error rate of our newly developed wound surface area calculation using digital photography. METHODS: Using a smartphone and a digital single lens reflex (DSLR) camera, four photographs of various sized wounds (diameter: 0.5-3.5 cm) were taken from the facial skin model in company with color patches. The quantitative values of wound areas were automatically calculated. The relative error (RE) of this method with regard to wound sizes and types of camera was analyzed. RESULTS: RE of individual calculated area was from 0.0329% (DSLR, diameter 1.0 cm) to 23.7166% (smartphone, diameter 2.0 cm). In spite of the correction of lens curvature, smartphone has significantly higher error rate than DSLR camera (3.9431+/-2.9772 vs 8.1303+/ 4.8236). However, in cases of wound diameter below than 3 cm, REs of average values of four photographs were below than 5%. In addition, there was no difference in the average value of wound area taken by smartphone and DSLR camera in those cases. CONCLUSION: For the follow-up of small skin defect (diameter: <3 cm), our newly developed automated wound area calculation method is able to be applied to the plenty of photographs, and the average values of them are a relatively useful index of wound healing with acceptable error rate. PMID- 28718525 TI - Bayard T. Storey: 1932-2017. PMID- 28718526 TI - Andrology Award 2016. PMID- 28718527 TI - Evaluation of intralesional injection of hyaluronic acid compared with verapamil in Peyronie's disease: preliminary results from a prospective, double-blinded, randomized study. AB - Several intralesional therapeutic protocols have been proposed for the treatment of Peyronie's disease. Among all, hyaluronic acid (HA) and verapamil have been differently tested. We aimed to evaluate the efficacy of intralesional verapamil (ILVI) compared with intralesional HA in patients with early onset of Peyronie's disease (PD). This is a multi-centre prospective double-arm, randomized, double blinded study comparing ILVI vs. intralesional HA after 12-weeks. Sexually active men, older than 18 years and affected by the acute phase of PD were eligible for this study. Patients have been double-blinded randomly divided into two groups (1 : 1 ratio): Group A received intralesional treatment with Verapamil (10 mg in 5 mL of normal saline water) weekly for 12 weeks, while group B received intralesional treatment with HA (0.8% highly purified sodium salt HA 16 mg/2 mL) weekly for 12 weeks. The primary efficacy outcome was the change from the baseline to the endpoint (12 weeks after therapy) for the penile curvature (degree). The secondary outcome was the change in the plaque size and in the International Index of erectile Function (IIEF-5) score. The difference between post- and pre-treatment plaque size was -1.36 mm (SD +/- 1.27) for Group A and 1.80 mm (SD +/- 2.47) for Group B (p-value = NS). IIEF-5 increased of 1.46 points (SD +/- 2.18) in Group A and 1.78 (SD +/- 2.48) in Group B (p-value +/- NS). No difference in penile curvature was observed in Group A, while in Group B the penile curvature decreased of 4.60 degrees (SD +/- 5.63) from the baseline (p < 0.001) and vs. Group A. According to PGI-I results, we found significant difference as concerning patient global impression of improvement (PGI-I) (4.0 vs. 2.0; p < 0.05). This prospective, double-arm, randomized, double-blinded study comparing ILVI vs. HA as intralesional therapy showed greater efficacy of HA in terms of penile curvature and PGI-I. PMID- 28718528 TI - Impairment of sperm DNA methylation in male infertility: a meta-analytic study. AB - Considering the widespread use of assisted reproductive techniques (ART), DNA methylation of specific genes involved in spermatogenesis achieves increasingly clinical relevance, representing a possible explanation of increased incidence of syndromes related to genomic imprinting in medically assisted pregnancies. Several trials suggested a relationship between male sub-fertility and sperm DNA methylation, although its weight on seminal parameters alteration is still a matter of debate. To evaluate whether aberrant sperm DNA methylation of imprinted genes is associated with impaired sperm parameters. Meta-analysis of controlled clinical trials evaluating imprinted genes sperm DNA methylation comparing men with idiopathic infertility to fertile controls. Twenty-four studies were included, allowing a meta-analytic evaluation for H19, MEST, SNRPN, and LINE-1. When a high heterogeneity of the results was demonstrated, the random effect model was used. H19 methylation levels resulted significantly lower in 879 infertile compared with 562 fertile men (7.53%, 95% CI: 5.14-9.93%, p < 0.001), suggesting a 9.91-fold higher risk ratio to show aberrant sperm DNA methylation (95% CI: 5.55-17.70, p < 0.001, I2 = 19%) in infertile men. The mean MEST methylation level was significantly higher in 846 infertile compared with 353 fertile men (3.35%, 95% CI: 1.41-5.29%, p < 0.001), as well as for SNRPN comparing 301 infertile men with 124 controls (3.23%, 95% CI: 0.75-5.72%, p < 0.001). LINE-1 methylation levels did not differ between 291 infertile men and 198 controls (0.44%, 95% CI: -2.04-1.16%, p = 0.63). The meta-analytic approach demonstrated that male infertility is associated with altered sperm methylation at H19, MEST, and SNRPN. Although its role in infertility remains unclear, sperm DNA methylation could be associated with the epigenetic risk in ART. In this setting, before proposing this analysis in clinical practice, an accurate identification of the most representative genes and a cost-effectiveness evaluation should be assessed in ad hoc prospective studies. PMID- 28718530 TI - What I've learned about Andrology: making the most of your opportunities. PMID- 28718529 TI - DNA fragmentation in spermatozoa: a historical review. AB - Sperm DNA Fragmentation has been extensively studied for more than a decade. In the 1940s the uniqueness of the spermatozoa protein complex which stabilizes the DNA was discovered. In the fifties and sixties, the association between unstable chromatin structure and subfertility was investigated. In the seventies, the impact of induced DNA damage was investigated. In the 1980s the concept of sperm DNA fragmentation as related to infertility was introduced as well as the first DNA fragmentation test: the Sperm Chromatin Structure Assay (SCSA). The terminal deoxynucleotidyl transferase nick end labelling (TUNEL) test followed by others was introduced in the nineties. The association between DNA fragmentation in spermatozoa and pregnancy loss has been extensively investigated spurring the need for a therapeutic tool for these patients. This gave rise to an increased interest in the aetiology of DNA damage. The present decade continues within this research area. Some of the more novel methods recently submerging are sorting of cells with increased DNA fragmentation and hyaluronic acid (HA) binding techniques. The clinical value of these tests remains to be elucidated. In spite of half a century of research within the area, this analysis is not routinely implemented into the fertility clinics. The underlying causes are multiple. The abundance of methods has impeded the need for a clinical significant threshold. One of the most promising methods was commercialized in 2005 and has been reserved for larger licensed laboratories. Myriads of reviews and meta-analyses on studies using different assays for analysis of DNA fragmentation, different clinical Artificial Reproductive Treatments (ART), different definitions of successful ART outcome and small patient cohorts have been published. Although the area of DNA fragmentation in spermatozoa is highly relevant in the fertility clinics, the need for further studies focusing on standardization of the methods and clinical implementation persists. PMID- 28718531 TI - Next-generation sequencing for patients with non-obstructive azoospermia: implications for significant roles of monogenic/oligogenic mutations. AB - Azoospermia affects up to 1% of adult men. Non-obstructive azoospermia is a multifactorial disorder whose molecular basis remains largely unknown. To date, mutations in several genes and multiple submicroscopic copy-number variations (CNVs) have been identified in patients with non-obstructive azoospermia. The aim of this study was to clarify the contribution of nucleotide substitutions in known causative genes and submicroscopic CNVs in the genome to the development of non-obstructive azoospermia. To this end, we conducted sequence analysis of 25 known disease-associated genes using next-generation sequencing and genome-wide copy-number analysis using array-based comparative genomic hybridization. We studied 40 Japanese patients with idiopathic non-obstructive azoospermia. Functional significance of molecular alterations was assessed by in silico analyses. As a result, we identified four putative pathogenic mutations, four rare polymorphisms possibly associated with disease risk, and four probable neutral variants in 10 patients. These sequence alterations included a heterozygous splice site mutation in SOHLH1 and a hemizygous missense substitution in TEX11, which have been reported as causes of non-obstructive azoospermia. Copy-number analysis detected five X chromosomal or autosomal CNVs of unknown clinical significance, in addition to one known pathogenic Y chromosomal microduplication. Five patients carried multiple molecular alterations. The results indicate that monogenic and oligogenic mutations, including those in SOHLH1 and TEX11, account for more than 10% of cases of idiopathic non-obstructive azoospermia. Furthermore, this study suggests possible contributions of substitutions in various genes as well as submicroscopic CNVs on the X chromosome and autosomes to non-obstructive azoospermia, which require further validation. PMID- 28718532 TI - Development Without Human Development. PMID- 28718533 TI - Changes Of Intraocular Pressure In Vitrectomised Eyes After Removal Of Silicone Oil. AB - BACKGROUND: Patients with Rhegmatogenous retinal detachment develop raised intraocular pressure (IOP) when they undergo pars plana vitrectomy with silicone oil. The present study was done to document changes in IOP with silicone oil and after its removal. METHODS: The interventional study was conducted at Eye department of Lady Reading Hospital Peshawar, from August 2012 to July 2014 on 30 patients with Rhegmatogenous retinal detachment in whom pars plana vitrectomy with silicone oil injection was indicated. IOP readings were obtained on 1st postoperative day, at one month and at 6 months; the silicone oil was removed after the third reading and the IOP readings obtained after 2 weeks. RESULTS: Of the 30 patients selected for the study, there were 25 (83.3%) males and 5 (16.7%) females with ages ranging from 12-80 years (mean age 41.83+/-21.43 years). The mean of three pre silicone oil removal IOP readings was 27.35+/-9.20 mmHgwhich was reduced to a mean of 16.10+/-6.14mmHg following the removal of silicone oil at 6 months (p<0.001). Postoperative raised IOP values were highly predictive of persistently elevated IOP readings in patients after six months. CONCLUSIONS: Vitrectomised eyes with silicone oil raised intraocular pressure which was reduced after silicone oil removal. PMID- 28718535 TI - Decompressive Craniectomy For Acute Subdural Haematoma With Expansile Duraplasty Versus Dural-Slits. AB - BACKGROUND: Traumatic subdural hematoma is one of the lethal injuries to brain. Various surgical techniques are used to evacuate the acute subdural hematoma. The hematoma evacuation can either be done by opening of dura by multiple slits or by opening of dura in single large c shape and then doing the expansile duraplasty. Present study aimed to compare both these techniques. METHODS: This randomized control study was conducted in department of neurosurgery, Ayub Medical College, Abbottabad from July 2011 to July 2013. A total of 59 patients were included in this study, which were randomly allocated in two groups (i.e., group A and group B) for decompressive craniectomy. Thirty-one patients were operated by craniectomy with full dural flap opening (Group A), and 28 patients were operated by craniectomy with multidural-slits (Group B). Glasgow Outcome score (GOS) at 6 weeks after the surgery was used to determine the outcome. RESULTS: Mean age of the patients was 33.4+/-12.8 years. Majority were males. In group A 51.6 % (16) of the patients survived out of which a favourable outcome (GOC 3-5) was observed in 41.9% of the patients, and 9.1% of patients ended up in vegetative state. While in group B 46.4% (13) of the patients survived among which favourable outcome was seen in 39.3% of patients and 7.1% of patients ended up in vegetative state. The difference in outcome measure is insignificant. CONCLUSIONS: There was no statistically significant difference among the two groups as regards the mortality, GOS, frequency of complications and hospital. While the duration of surgery was significantly shorter in patients operated with dural slits. PMID- 28718534 TI - Effects Of Interferon Therapy On Heart. AB - BACKGROUND: Hepatitis C virus (HCV) infection is a major health problem worldwide. Around 185 million people are suffering from HCV infection all over the world, out of which 10 million people are residing in Pakistan. 4.7% (2-14% by different studies) of Pakistanis are suffering from this deadly disease. Interferon+Ribavarin IFN/RIB is the mainstay of treatment for this infection. Various cardiovascular adverse reactions have been reported of this therapy. We conducted this study at Punjab Institute of cardiology to look for the cardiac safety of interferon therapy in our population. METHODS: We studied HCV infected patients planned for interferon therapy between 21st of November 2012 to 20th of August 2014. Echocardiography was performed before, during and after the completion of therapy. Pegylated interferon once a week plus ribavirin therapy was given to the patients. Patients received 16-40 injections of pegylated interferon depending upon the decision of hepatologist. Patients with prior structural heart disease, patients who did not start the treatment or patients who did not turn up on follow up were excluded from the study. RESULTS: A total of 102 patients planned to have interferon therapy were screened echocardiographically. One patient died after 5 injections due to infection (a non-cardiac cause). 46 patients completed the treatment and the follow up. None of the patients had any acute cardiac event. All patients had normal biventricular systolic function at the end of study. None of the patients had significant valvular heart disease or pulmonary hypertension. Reversal of E/A ratio or E/A ratio>2, parameters of diastolic dysfunction and mild pericardial effusion were noted in a statistically significant number of patients. CONCLUSIONS: Interferon therapy for HCV infection is cardiac safe in patients who have structurally normal heart. Female patients have propensity of adverse events like severe diastolic dysfunction and mild pericardial effusion. The safety of drug in patients already having cardiac ailment needs to be studied. Moreover HCV infection itself is not injurious to the heart. PMID- 28718536 TI - Comparison Of Protective Effect Of Green Tea And Vitamin C Against Cypermethrin Induce Nephrotoxicity In Mice. AB - BACKGROUND: Insecticide toxicity is the problem of every person in under developed countries. It is necessary to counteract its effect by natural and cheap remedies like green tea and vitamin C. In this manner common man can also enjoy blessings of life. The current research was performed to compare the protective function of green tea and vitamin C on experimental cypermethrin provoked nephrotoxicity. METHODS: Forty healthy Balb/C mice purchased from National Institute of Health, Islamabad, Pakistan and divided in to four groups (10 each). Group a was control which received only normal diet. Group B, group C and group D were experimental groups which were given Cypermethrin, Cypermethrin with green tea and Cypermethrin with vitamin C respectively. These groups were also given normal diet. After 1 month blood was drawn by intra-cardiac method to assess renal parameters. RESULTS: One month research showed increase in serum urea to 6.8+/-.48 m.mol/l (n=3.9+/-.44) while green tea and vitamin C normalize them to 4.0+/-.83m.mol/l and 3.4+/-.33m.mol/l respectively. Serum creatinine increased to 42.90+/-3.28m.mol/l (n=29.50+/-3.95) while green tea and vitamin C normalize them to 28.80+/-4.58m.mol/l and 22.60+/-2.06m.mol/l correspondingly. CONCLUSIONS: The results showed that green tea and vitamin C neutralized toxicity induced by Cypermethrin in mice and their effect is comparable. PMID- 28718537 TI - Frequency Of Different Risk Factors Associated With Recurrent Urinary Tract Infection Among Postmenopausal Women. AB - BACKGROUND: Urinary Tract Infection is one of the most common infections encountered by women. These infections have the tendency to recur. In order to identify women at risk of recurrence there is a need to identify risk factors associated with it. Among women, factors predisposing to recurrent infections are not much explored. The study was done with an objective to determine different risk factors associated with recurrent UTI among postmenopausal women. METHODS: This was a cross sectional study conducted at the Out Patient Department of Nephrology in Shifa International Hospital Islamabad over a period of six months, June 6th to December 5th 2012. Information regarding demographics and risk factors were recorded on a predesigned pro forma. A descriptive analysis was done for quantitative variables like age and qualitative variables like marital status and frequency of different risk factors. Stratification of risk factors according to age was also done. RESULTS: Hundred females were enrolled into the study after informed consent. The mean age of the study population was 64.4+/-9.48. 97% of the population was married. Out of 100 patients, 42 had high post-void volume, 35 had urinary incontinence and 17 patients were having cystocele. According to age stratification, most frequently affected age group was between 51-60 years (38%), followed by 61-70 years (36%), then 25% in more than 70 years, whereas only 1% was between 41-50 years. CONCLUSIONS: Recurrent UTI in postmenopausal females is most frequently associated with high post void volume and most frequently affected age group is between 51-60 years. PMID- 28718538 TI - Association Of Tricuspid Regurgitation And Severity Of Mitral Stenosis In Patients With Rheumatic Heart Disease. AB - BACKGROUND: Rheumatic heart disease is a common ailment in Pakistan and Mitral stenosis is its flag bearer Severity of mitral stenosis is the key factor in deciding for mitral valve surgery. METHODS: This case series study was conducted at Ayub Teaching Hospital .Cases of Rheumatic heart disease with mitral stenosis were diagnosed clinically. 2D echocardiography was used to find severity of mitral stenosis. Data was entered into SPSS-17.0 and results were recorded and analysed. Pearson's two tailed correlation was used to find the correlation between presence of tricuspid regurgitation in patients with severe mitral stenosis, p was <0.05. RESULTS: A total 35 patients with pure mitral stenosis were included in study, out of which 8 were male and 27 were females. Mean age in males was 34.5+/-15.85 years while in females it was 31+/-8 years. Twenty-two out of 35 (62.86%) patients had tricuspid regurgitation while 13 out 35 (37.14%) had no tricuspid regurgitation. Mean (MVA) mitral valve area in patients with tricuspid regurgitation was 0.84+/-0.3 cm2 while mean (MVA) mitral valve area in patients without tricuspid regurgitation was 1.83+/-0.7 cm2. Mean left atrial (L.A) size was 45.23+/-1.5 mm2 in patients with tricuspid regurgitation, while it was 44.13+/-6.14 mm2 in patients without tricuspid regurgitation. Mean RSVP was 57.5mmHg in patients with tricuspid regurgitation while RSVP could not be calculated in patients without tricuspid regurgitation. CONCLUSIONS: It was concluded that tricuspid regurgitation was strongly associated with severe mitral stenosis as almost all patients with severe mitral stenosis had tricuspid regurgitation and none of the patients with mild mitral stenosis had tricuspid regurgitation. PMID- 28718539 TI - Screening For Hypothyroidism-Results Of A Study Conducted At District Headquarter Hospital, Abbottabad. AB - BACKGROUND: Sub-clinically hypo-functioning thyroid is a condition in which there is biochemical evidence of hypothyroidism but patient is clinically asymptomatic. This concept is not new. The typical picture of this condition is increased thyroid stimulating hormone and normal thyroxine levels. Subclinical hypothyroidism has been found to have variable prevalence ranging from 4-10% to 10- 26%. METHODS: This cross sectional study was conducted on 378 adult patients coming to outpatient department of District Headquarter Hospital Abbottabad over a period of two years from February 2013 to February 2015. RESULTS: Out of the 378 individuals studied, 37 (9.78%) had subclinical hypothyroidism. Mean age of the patients was 43.5+/-10.5 years. Females outnumbered males, i.e., 24 out of 37 (65%). It was noted that there was no correlation between mean TSH level and gender or age of the patients. CONCLUSIONS: Subclinical hypothyroidism is not an uncommon condition and its diagnosis is established easily by doing thyroid hormone levels in fasting condition. Early diagnosis and therapeutic intervention may not only prevent the progression to clinical hypothyroidism but also help in preventing the wastage of resources on doing unnecessary investigations. PMID- 28718540 TI - Assessment Of Preanalytical Blood Sampling Errors In Clinical Settings. AB - BACKGROUND: Blood sampling is one of the common procedures done in every ward for disease diagnosis and prognosis. Daily hundreds of samples are collected from different wards but lack of appropriate knowledge of blood sampling by paramedical staff and accidental errors make the samples inappropriate for testing. Thus the need to avoid these errors for better results still remains. We carried out this research with an aim to determine the common errors during blood sampling; find factors responsible and propose ways to reduce these errors. METHODS: A cross sectional descriptive study was carried out at the Military and Combined Military Hospital Rawalpindi during February and March 2014. A Venous Blood Sampling questionnaire (VBSQ) was filled by the staff on voluntary basis in front of the researchers. The staff was briefed on the purpose of the survey before filling the questionnaire. Sample size was 228. Results were analysed using SPSS-21. RESULTS: When asked in the questionnaire, around 61.6% of the paramedical staff stated that they cleaned the vein by moving the alcohol swab from inward to outwards while 20.8% of the staff reported that they felt the vein after disinfection. On contrary to WHO guidelines, 89.6% identified that they had a habit of placing blood in the test tube by holding it in the other hand, which should actually be done after inserting it into the stand. Although 86% thought that they had ample knowledge regarding the blood sampling process but they didn't practice it properly. CONCLUSIONS: Pre analytical blood sampling errors are common in our setup. Eighty six percent participants though thought that they had adequate knowledge regarding blood sampling, but most of them were not adhering to standard protocols. There is a need of continued education and refresher courses. PMID- 28718541 TI - Poisons Implicated In Homicidal, Suicidal And Accidental Cases In North-West Pakistan. AB - BACKGROUND: Pakistan has one of the highest prevalence of poisoning in the world. However, limited data exist on the frequency of poisons implicated in homicidal, suicidal, and accidental cases in North-West Pakistan (Khyber Pakhtunkhwa). METHODS: This retrospective study of 353 cases and biological specimens of poisoning received at the department of Forensic medicine and toxicology, Khyber Medical College Peshawar from 13 districts of Khyber Pakhtunkhwa. Frequency of poisoning was assessed by testing each specimen for 17 different poisons. RESULTS: Of all the specimens, 250 (70.8%) specimens tested positive and the rest didn't show any indication of poisoning (n=103, 29.2%). The most frequent poisons detected were benzodiazepines (total n=75), organophosphates (total n=58), phencyclidine (total n=30) and morphine (total n=23). Gender had a significant association with benzodiazepines (p=0.011), tricyclic antidepressants (p=0.001), and organophosphates (p<0.001). Organophosphates were the most common cause of poisoning in females while benzodiazepines were the most common cause of poisoning in males. CONCLUSIONS: Poisoning by benzodiazepines, organophosphates and phencyclidine are the most common causes of intoxication in population of Khyber Pakhtunkhwa. Source of poisoning varies with gender for organophosphates, benzodiazepines and tricyclic antidepressants. PMID- 28718542 TI - Intravitreal Bevacizumab: Indications And Complications. AB - BACKGROUND: Bevacizmab is still an unlicensed drug for intraocular use in spite of the fact that it has shown comparable efficacy to other anti-vascular endothelial growth factors (anti-VEGF) medications in some large sample randomized control trails. Although repackaged bevacizumab has got safety concerns but its use is growing because of easy availability and low cost. Our study focuses on the diverse and growing indications of intravitreal bevacizumab (IVB) and its ocular complications in our geographical setting. METHODS: This interventional case series was carried out at my private practice in Said Anwar Medical Complex, Dabgari, Peshawar, from January 2008 to July 2015. Total of 6107 injections were given to 4352 eyes. Intravitreal bevacizumab was injected in proper operating room setting. Bevacizumab injections were prepared from same vial by multiple withdrawals taking care of aseptic precautions. Follow up was done at 1 week and 20 days and adverse effects were noted. RESULTS: Diabetic macular oedema (36%), central retinal vein occlusion (17.6%) and branched retinal vein occlusion (11%) were the top three indications of IVB. Other common indications were proliferative diabetic retinopathy (9.6%), neo-vascular glaucoma (5.9%), proliferative diabetic retinopathy with vitreous bleed (4.4%), proliferative diabetic retinopathy with tractional retinal detachment (3.7%), neo vascular age related macular degeneration (2.9%), central serous retinopathy (1.48%) and Eale's disease (1.48%). Endohthalmitis occurred in 3 eyes (0.069%) while retinal detachment was found in only 2 eyes (0.046%). CONCLUSIONS: Common indications of bevacizumab are diabetic macular oedema, central retinal vein occlusion and branched retinal vein occlusion. Complications like endophthalmitis and retinal detachment are rare. PMID- 28718543 TI - Drug Non-Adherence In Type 2 Diabetes Mellitus; Predictors And Associations. AB - BACKGROUND: Diabetes being a serious health issue faced by developing countries with drug adherence having pivot role for recommended glycaemic target. This study aims to determine drug non-adherence in type 2 diabetics and its predictors and associations. METHODS: This cross sectional study was conducted after ethical approval at Medicine Dept. Rawal Institute of Health Sciences Islamabad over 10 months duration. Demographic details, duration of diabetes, education, socioeconomic class, glycaemic control, mode of anti-diabetic therapy, number of medications and other modes of therapy documented. Michigan Diabetes Knowledge Questionnaire applied with outcome as good, acceptable and poor knowledge. Drug adherence was assessed by Morisky Medication Adherence Scale (non-adherence at <6 points). Data analysed via SPSS version 17 with significant p-value <0.05. RESULTS: Among 183 diabetics there were 43 (23.5%) males and 140 (76.5%) females. Mean age was 56.6+/-10.6 years and mean duration of diabetes 8.4+/-6.57 years. One hundred and fourteen (62%) cases were non-adherent. Diabetes knowledge was poor in 76 (41.5 %), acceptable in 76 (41.5 %) and good in 31 (16.9%). Un satisfactory glycaemic control present in 149 (81.4%). Non-adherence was found to be associated with poor glycaemic control, poor dietary adherence, poly-pharmacy, illiteracy, practicing other modes of therapy and poor diabetes knowledge (p<0.05). CONCLUSIONS: Nonadherence to medication in type 2 diabetics needs to be addressed. Suggested contributory factors are illiteracy, practicing other modes of therapy, poor diabetes knowledge and poly-pharmacy. Public awareness programs, self-monitoring of blood sugars, regular follow-up visits with focus at patient education may improve glycaemic control and diabetes related complications. PMID- 28718544 TI - Diffusion Lung Capacity Changes In Hodgkin Lymphoma Patients Before And After Abvd Chemotherapy. AB - BACKGROUND: Chemotherapy consisting of Adriamycin, Bleomycin, Vinblastine, and Doxorubicin (ABVD), which is the mainstay of treatment in Hodgkin's Lymphoma (HL), is associated with both acute and long-term pulmonary toxicity primarily due to Bleomycin. Bleomycin induced pulmonary toxicity (BPT) is clinically detected using diffusing lung capacity for carbon monoxide (DLCO). The objective of this study was to evaluate changes in DLCO in HL patients before and after ABVD chemotherapy. METHODS: Medical records of all adult HL patients treated with ABVD chemotherapy at a single centre in Lahore, Pakistan during the entire calendar year 2012 were analysed. Patients with pre-existing pulmonary dysfunction, history of thoracic surgery and smokers were excluded. RESULTS: A total of 179 HL patients were identified during the study period who received ABVD chemotherapy. Out of these, 93 (51.95%) patients had undergone both a pre- and post-chemotherapy DLCO measurements. The remaining patients had only one DLCO reading available and were not included in the analysis. The mean percentage difference between pre- and post-chemotherapy values for DLCO (5.49%; 95% confidence interval [CI] 1.56-9.43%) and for Haemoglobin-adjusted DLCO (8.24%; 95% CI 3.90-12.57%) were statistically significant at p<0.01. Diffusing lung capacity for carbon (DLCO) values declined from pre-treatment to post-treatment by 1-10% in 23 (24.7%) patients, by 10-20% in 19 (20.4%) patients, by 20-30% in 10 (10.8%) patients and >30% in 10 (10.8%) patients. After adjusting for age, a 1mg/m2 increase in dose of Bleomycin was significantly associated with 0.14% (95% CI: 0.03-0.25%) decline in DLCO and 0.13% (95% CI: 0.10-0.26%) decline in haemoglobin-adjusted DLCO from pre-treatment value. CONCLUSIONS: Mild to moderate dysfunction in diffusion lung capacity is common after ABVD chemotherapy. DLCO and haemoglobin-adjusted DLCO value decreased with increasing age and increasing dose of Bleomycin. PMID- 28718546 TI - Effect Of Sitagliptin On Glycemic Control, Body Weight, Blood Pressure And Serum Lipid Profile In Type 2 Diabetic Hyperlipidemic Patients. AB - BACKROUND: Dyslipidaemia is a global health issue in developed as well as in developing countries. People with type 2 Diabetes mellitus are more susceptible to develop dyslipidaemia and its related complications. The objective of the study was to assess the effect of sitagliptin a (DPP-4 inhibitor) oral antidiabetic drug on blood sugar, body weight, blood pressure and dyslipidaemia in type 2 diabetic patients. METHODS: This 12 weeks open label observational study was conducted at outdoor of diabetic clinic of Sheikh Zayed Medical College/Hospital, Rahim Yar Khan in which newly diagnosed type 2 diabetic patients (n=78) with poor glycaemic control(HbA1c >7.2%) were selected. The patient received sitagliptin 50 mg twice daily for 12 weeks. RESULTS: After 12 weeks treatment with sitagliptin, there was a significant reduction in the value of HbA1c from 8.184%+/-0.467 at baseline to 7.0200%+/-0.459 at 12 weeks (p<0.05). Body weight also decreased significantly from 80.21kg+/-7.156 at baseline to 71.74 kg+/-6.567 at 12 weeks (p<0.05).Systolic blood pressure decreased (SBP) decreased significantly from 138.17+/-6.050 mmHg at baseline to 131.22+/-6.311 mmHg at 12 weeks (p<0.05). Significant changes were also seen in diastolic blood pressure which decreased from 83.14+/-6.714 mmHg at baseline to 75.28+/-6.481 mmHg at 12 weeks (p<0.05). Significant reduction in the serum level of total Cholesterol (TC), triglycerides (TG) and Low density lipoprotein cholesterol (LDL C) were detected (TC: 222.09+/-13.538 to 209.41+/-13.475 mg/dl, p<0.05; TG: 170.99+/-6.940 to 143.45+/-8.279 mg/dl, p<0.05; LDL-C 120.00+/-5.804 to 109.06+/ 6.278 mg/dl, p<0.05). High density lipoprotein cholesterol (HDL-C) increased significantly from 42.99+/-4.836 mg/dl at baseline to 49.97+/-3.490 mg/dl at 12 weeks. CONCLUSIONS: Sitagliptin not only improves blood glucose control but also body weight, blood pressure and lipid profile in type 2 diabetic hyperlipidaemia patients. PMID- 28718545 TI - Characteristics And Outcome Of Patients With Diffuse Large B Cell Lymphoma Treated With Chemotherapy Or Chemo-Immunotherapy. AB - BACKROUND: Diffuse large-B-cell lymphoma, is the most common subtype of Non Hodgkin lymphoma. Aim of this study was to look at the characteristics and outcome of DLBCL patients who were treated with chemotherapy or chemotherapy plus rituximab at our institution. METHODS: Data of 750 patients, who got registered at our institute between 2007 and 2014, was reviewed retrospectively. After appropriate exclusions, 337 were included. Disease free survival (DFS) and overall survival (OS) were compared between patients who received rituximab plus CHOP (Cyclophosphamide, Doxorubicine, Vincristine, Prednisolon) (R-Ch) and standard chemotherapy- CHOP (S-Ch). RESULTS: Males and females were 216 (64%) and 121 (36%) respectively, with median age 38 years (Range 18-80 yrs.). R-Ch and S.Ch was received by 129(38.3%) and 197(58.4%) patients, respectively. Complete remission (CR) was achieved by 81 (62.8%) vs. 105 (53.3%) patients in R-Ch vs. S Ch cohorts, respectively. In subset analysis CR was seen in 34 (63.0%) and 45 (58.4%) (p=0.01) in R-Ch/XRT and S-Ch/XRT, respectively. At three years, DFS was 85.3% vs. 74% (p=0.04) and OS was 82.2% vs. 72.6% (p=0.02) in R-Ch and S-Ch cohorts respectively. Deaths observed were 9 Vs.13 in R-Ch/XRT and S-Ch/XRT, respectively. CONCLUSIONS: Based on our study, onset of DLBCL is at younger age in our population with male predominance. Addition of rituximab to CHOP resulted in better DFS and OS in patients with DLBCL. In developing countries, due to cost, large number of patients do not have access to rituximab. Efforts should be made to reduce the price of targeted therapies so that more and more patients are benefitted from these newer agents. PMID- 28718547 TI - Outcomes Of Distal Femur Fracture Treated With Dynamic Condylar Screw. AB - BACKROUND: Implants for open reduction and internal fixation of distal femoral fracture includes angle blade plate, rush nails, enders nail and interlocking nails. But all these devices are technically demanding and less effective in providing inter-fragmentary compression in osteoporotic bones. These problems can be solved with dynamic condylar screw (DCS).The objective of the study was to determine the frequency of different outcomes of distal femoral fracture treated with dynamic condylar screw. METHODS: This case series study was carried out in the Department of Trauma & Orthopaedics, Ayub Teaching Hospital Abbottabad from 1st October 2014 to August 2015, after approval of the ethical committee of the institution. Data of all patients with distal femoral fractures aged 20-70 years, recruited through emergency, OPD or consultant clinic collected on a pro forma. Standard treatment of trauma was given to the patients. Detailed history was taken including the past medical and surgical history. Detailed examination including air-way, breathing and circulation, general physical examination and abdomino-pelvic examination was done in each patient. Investigations including urinalysis, haemoglobin %, full blood count, X-ray (both AP and lateral view) of the involved femur (including hip and knee) was done. RESULTS: Mean age of the patients was 43.18+/-14.647 ranging from 20 to 70 years. Mean duration of hospital stay in days was 2.21+/-1.111 ranging from 1 to 6 days. Patients' follow up assessment after 4 months of surgery for union of femoral fracture treated with dynamic condylar screw was found in 96 (94.1%), wound infection was found in 7 (6.9%), knee stiffness was found in 21 (20.6%) and limb shortening was found in 7 (6.9%). CONCLUSIONS: Dynamic condylar screw is an easy, scientifically less difficult and satisfying method of treatment for fra.ctures of femur. PMID- 28718548 TI - Factors Predictive Of Alcohol Consumption Among Elderly People In A Rural Community: A Case Study In Phayao Province Thailand. AB - BACKROUND: Alcohol consumption is recognized as a public health issue. Study objectives were to identify factors predictive of alcohol consumption among elderly people in Phayao province Thailand, where there was high prevalence of alcohol consumption. METHODS: This was a cross-sectional study. Four hundred elderly people participated in a survey. Data was collected by face-to-face interviews. Chi-square and multivariate logistic regression were used to determine the factors predictive of alcohol consumption among the study subjects. RESULTS: One thirds of elderly (31.7%) had consumed alcohol in their lifetime, and (15.7%) of them were current drinkers. Following univariate analysis, seven factors included gender, working, sickness, smoking, quality of life (QOL), daily activities and economic recession - were identified as being significantly associated with drinking (p<0.05). Multivariate analysis revealed four factors to be predictive of alcohol among elderly people: gender (OR=6.02, 95% CI=3.58 10.13), smoking (OR=4.34, 95% CI=2.57-7.34), economic recession (OR=2.79, 95%, CI=1.66-4.71), and QOL (OR=1.86, 95%, CI=1.09-3.16). CONCLUSIONS: Gender (male) and smoking were strongly predictive factors of elderly alcohol consumption. Hence, an effort to reduce alcohol consumption should be placed on male elderly and those who smoke. PMID- 28718549 TI - Effect Of Intra Vitreal Injection Of Bevacizumab On Intra-Ocular Pressure. AB - BACKROUND: Bevacizumab has been in use as a therapeutic agent for macular oedema for several years. While its efficacy has been well documented, its use has been shown to cause a transient rise in the intra-ocular pressure. The aim of this study was to evaluate the long term effect of intravitreal injection of Bevacizumab on Intra-ocular pressure. METHODS: One hundred eyes (n=100) of one hundred patients, requiring intra-vitreal injection of Bevacizumab for diabetic macular oedema were recruited from Shifa Foundation Community Health Centre (SFCHC) between January and December 2014. Patients of glaucoma, ocular hyper tension, known allergy to Bevacizumab or had injections of Bevacizumab prior to the study were excluded. Intra-ocular pressure was measured using a Goldmann applanation tonometer, prior to, and at six and twelve months after the injection. The pre- and post- injection Intra-ocular pressure was entered into the database. Test of significance was applied to investigate whether there was a significant change in intra-ocular pressure after the injection. RESULTS: The mean age of the patient was 56.97 years (+/-14.97). The mean intra-ocular pressure was 13.86 (+/-3.16) mmHg before injection, while postinjection mean Intra-Ocular pressure was 14.21 (+/-3.12) mmHg and 13.79 (+/-3.07) at six and twelve months respectively. Between baseline and six months there was a statistically significant difference in intra-ocular pressure (p=0.03), while no significant difference existed in the intraocular pressure between baseline and twelve months (p=0.92). CONCLUSIONS: Intra-vitreal injection of Bevacizumab is associated with a statically significant rise in intra-ocular pressure at six months, while no significant difference was seen at twelve months compared to baseline. PMID- 28718550 TI - Upper And Lower Limbs Disability And Personality Traits. AB - BACKGROUND: It is believed that the study of personality has the potentials to enhance our prognostic abilities and can better to expose the etiology of mental illness through the relationship of revealed mechanisms. The focus of this study was to investigate and compare the habitual patterns of behavior, thought and emotions of upper and lower limb physically disabled students in terms of personality traits. METHODS: This cross sectional study consisted of 100 upper limbs and lower limbs disabled students taken from Kingston school Inclusive Education System Abottabad, Mashal special education system Haripur, Syed Ahmed Shaheed special education center Abottabad, Al-Munir Foundation Mansehra and Hera Special Education System Haripur and 100 normal students taken from Islamic International School Abottabad, Falcon Public School Haripur, Iqra Academy Mansehra and Alhamd International School Haripur of Hazara Division by purposive sampling technique. This study was conducted during the month of June 2013 to May 2014. Goldberg five big personality scale was used for measuring personality traits of physically disabled and normal students. RESULTS: The significant difference of personality traits scores between physically disabled students (M = 139.2, SD=12.0) and normal students (M=184.5, SD=13.2), t (198) =25.3, p<.05 was observed. CONCLUSIONS: Normal students have high scores as compared to physically disabled students on big five traits, i.e., Extraversion, Agreeableness, Conscientiousness, Emotional Stability and Openness to Experience. PMID- 28718551 TI - Sociodemographic And Reproductive Factors Affecting Knowledge Of Married Men Accepting Vasectomy. AB - BACKGROUND: Men's attitude is very important in the adoption of methods of contraception and limiting the family size. Men represent half the world's population, but account for less than onethird of contraceptive use. Knowledge of men about vasectomy as contraceptive method is also limited. The objectives of the study were to assess the knowledge of males about vasectomy in age group 25 50 years and to identify the factors affecting the knowledge of men regarding vasectomy. METHODS: It was cross-sectional descriptive study. All the clients coming for vasectomy at Lahore General Hospital and Family Health Hospital were included in the study. Data was collected through questionnaire, which was entered in to computer using SPSS-17. Confidentiality of the data was ensured and verbal consent was obtained before data collection. RESULTS: Majority (85.6%) of the men had adequate knowledge about vasectomy. Major source of knowledge, motivation and decision making regarding vasectomy were healthcare providers followed by friends and colleagues. Socio-demographic factors like age of the wife, education of men, income of men, media, friends and relatives showed association with knowledge about vasectomy. CONCLUSIONS: Almost all the respondents had formal education. Majority of the respondents had knowledge about vasectomy. Respondents acquired knowledge from health personnel, television, radio, newspapers, spouses and friends/colleagues. Misconception of the general population regarding vasectomy needs to be cleared and men should be involved actively in family planning programs. Health education program should be held at community level to educate people about the utilization of procedure. PMID- 28718552 TI - Complementing theory with practice to enhance Students' learning. AB - BACKGROUND: Combining cognitive skills teaching related to the techniques leads to better understanding in a skill training course; but still there a substantial disagreement in curriculum on such combinations. This study aims to help guide the designers in making the outline of instructional plan for a Clinical Skills Module (CSM) for the undergraduates. Objectives were to assess performance of students on a clinical skill after training by two different models of (hands-on only or with cognitive skills) instructions and explore their perception on the employment of educational strategies through Focus Group Discussions (FGD) through a Sequential mixed method study design: (1) Quantitative (Pre- and post assessments and comparing their results (2) Qualitative (Exploration of perspectives through constructivist approach using qualitative phenomenological design) The study was conducted during the month of September, 2015 at Rabigh Medical College, King Abdul Aziz University, Jeddah. METHODS: Students entering fourth year were randomized to two groups to participate in pre-post OSCE using global rating scale and their scores were compared. The examiners were kept blinded to the randomization of students undergoing two separate training methods. The test group (group A) was trained for both procedural as well as cognitive skills whereas the control group (Group-B) was trained only with hands on practice. Later their perception about the addition of cognitive skills to improve of procedural skills was explored through focus group discussions. The recorded audio tapes of FGDs were transcribed and analysed thematically. Triangulation of themes and trends was achieved by relating the content analysis to the relevant frequency of quotes. Auditing of the data verification was done by all the authors separately.. RESULTS: A total of 42 students completed both pre- and post-tests. As a result, student performance in OSCE significantly increased from pre- to post-test (p<0.001) in both the groups; on the other hand no statistically significant difference was found in the pre- and posttest scores between groups A and B (p=0.108). Five themes (1) advantages, (2) disadvantages of combining theory with practice, (3) time balance in teaching a skill, (4) training on skills, (5) skillsassessment, were found prevalent on thematic analysis of the FGDs. CONCLUSIONS: Students' ability to grasp the procedural skills was not significantly different when they acquire the cognitive skills in addition to the practical sessions. Students were more convinced to adopt combination of the two in the learning of procedural skills. PMID- 28718553 TI - Growth Retardation Of Chick Embryo Exposed To A Low Dose Of Electromagnetic Waves. AB - BACKGROUND: The objectives of this study were to explore the effects of low dose of the nonionizing (REW) emitted by a mobile phone on the development of chick embryo. METHODS: one hundred and twenty chick fertilized eggs were equally divided into a control and an exposed group. Sixty fertilized eggs were placed in an egg incubator with a mobile phone (SAR US: 1.10W/kg (head) 0.47 W/kg body) in silent mode having vibration disable mode. Mobile was called for a total of 20 minutes in 24 hours. Twenty embryos each were sacrificed at day 5, 10 and 15, mortality, wet body weight, head to rump length, eye diameter and morphological changes were noted. The control group, 60 eggs were incubated in the same conditions, having removed the phone. RESULTS: No mortality was noted. The experimental group exposed to REW showed subcutaneous haemorrhagic areas and significant growth retardation at day 10 as evidence by smaller eye diameter, wet weight and CR length than the control group. There were no significant growth differences at either day 5 or at day 15. CONCLUSIONS: Electromagnetic waves emitted from mobile phones even though for a very short duration of 20 minutes per day have affected the growth of the chick embryo at day 10 of incubation, Hence exposure of these waves are not 100% safe. PMID- 28718554 TI - Diagnostic Utility Of Pleural Fluid Adenosine Deaminase Level In Tuberculous Pleural Effusion. AB - BACKGROUND: Early diagnosis and management of tuberculosis is essential for decreasing the disease burden. Pakistan is one of the few countries of world with a very high burden of tuberculosis. Many diagnostic tests are available for detection of tuberculosis but each is fraught with certain limitations of its own. METHODS: This study was a cross sectional validation study that sought to determine the validity of pleural fluid adenosine deaminase levels for diagnosis of tuberculous pleural effusion. RESULTS: A total of 160 patients with exudative lymphocytic pleural effusions were enrolled in this study. The mean pleural fluid ADA level was 52.18+/-1.98 U/L. The mean pleural fluid ADA level in patients diagnosed to have tuberculosis on pleural biopsy/histopathology was higher as compared to patients who did not have tuberculous pleural effusion 52.16+/-2.4 U/L vs 38.6+/-3.14 U/L. The difference was found to be statistically significant between the two groups (p<0.05). The sensitivity, specificity, ppv and npv of pleural fluid ADA level were 88.88%, 77.04%, 86.28% and 81.04% respectively. CONCLUSIONS: Despite wide variations in the reported sensitivity and specificity of pleural fluid ADA level, it can be used as a surrogate for pleural biopsy when the latter is not feasible. PMID- 28718555 TI - Tackling The Co-Epidemic Of Diabetes And Tuberculosis: From Evidence To Policy And Practice. AB - With the global increase in the diabetic population there is a resurgence of interest in the dual epidemic of diabetes mellitus (DM) and tuberculosis (TB), which has a bidirectional detrimental relationship with negative consequences for co-infected patients. Pakistan is feared to be hit the hardest, occupying fifth position amidst the 22 high burden TB countries, and ranking seventh in the global diabetic burden. The diabetes tuberculosis treatment outcome (DITTO) study was undertaken to determine the impact of diabetes on tuberculosis treatment outcome in Pakistan. The generation of such scientific evidence is useless if it is not utilized for policy making and practice, especially in a developing country like ours with a dearth of resources. In this paper, we have developed a framework for the transfer of scientific evidence regarding the impact of diabetes on TB treatment outcomes into policy and practice. The framework is divided into three components namely; generation of scientific evidence harnessing international and national efforts, informing health policy and practice and addressing other concerns such as social protection, health education and future research. PMID- 28718556 TI - Association of haematological and radiological Findings with clinical outcome in hospitalized Children 2-36 months old with severe lower Respiratory tract infection. AB - BACKGROUND: Despite reduction in child mortality during last decade, lower respiratory tract infection (LRTI) remained number one killer of under-five. The current study aimed to assess the association of haematological and radiological findings with clinical outcome in hospitalized children 2-36 months old with severe LRTI. METHODS: In the current cross sectional study, 581 children 2-36 months old with severe LRTI were enrolled and followed at the Children Hospital, Islamabad, between 2011 and 2014. At the time of enrolment, complete history of present illness, anthropometric measurements, blood sample and chest radiograph were obtained. The primary outcome was either early clinical response (within 72 hours) or delayed clinical response (>72 hours). Multivariable logistic regression was performed to examine the association between haematological and radiological findings with clinical outcome, adjusted for potential confounding factors. RESULTS: Of 581 enrolled children, 292 (50.3%) children had early, and 289 (49.7%) had delayed clinical response. The multivariable logistic regression showed that leucocytosis (OR 1.79, 95% CI 1.15-2.79), neutrophilia (OR 1.91, 95% CI 1.29-2.84), radiological interstitial pneumonia (OR 2.49, 95%CI 1.70-3.64), and lobar consolidation (OR 6.00, 95%CI 2.41-14.96) were significantly associated with delayed clinical response, after adjusted for potential confounding factors. CONCLUSIONS: Delayed clinical response was significantly associated with abnormal haematological and radiological findings at the time of admission in children 2 36 months old with severe LRTI. Haematological and radiological findings at the time of presentation are useful for predicting delayed clinical response in children 2-36 months old with severe LRTI. PMID- 28718557 TI - Leech Therapy For The Treatment Of Venous Congestion In Flaps, Digital Re-Plants And Revascularizations - A Two-Year Review From A Regional Centre. AB - BACKGROUND: Leeches are a well-recognized treatment for congested tissue. This study reviewed the efficacy of leech therapy for salvage of venous congested flaps and congested replanted or revascularized hand digits over a 2-year period. METHODS: All patients treated with leeches between 1 Oct 2010 and 30 Sep 2012 (two years) at Queen Elizabeth Hospital, Birmingham, UK were included in the study. Details regarding mode of injury requiring reconstruction, surgical procedure, leech therapy duration, subsequent surgery requirement and tissue salvage rates were recorded. RESULTS: Twenty tissues in 18 patients required leeches for tissue congestion over 2 years: 13 men and 5 women. The mean patient age was 41 years (range 17-79). The defect requiring reconstruction was trauma in 16 cases, following tumour resection in two, and two miscellaneous causes. Thirteen cases had flap reconstruction and seven digits in six patients had hand digit replantations or revascularisation. Thirteen of 20 cases (65%) had successful tissue salvage following leech therapy for congestion (77% in 10 out of 13 flaps, and 43% in 3 of 7 digits). The rate of tissue salvage in pedicled flaps was good 6/6 (100%) and so was in digital revascularizations 2/3 (67%), but poor in digital re-plants 1/4 (25%) and free flaps 0/2 (0%). CONCLUSIONS: Leeches are a helpful tool for congested tissue salvage and in this study, showed a greater survival benefit for pedicled flaps than for free flaps or digital replantations. PMID- 28718558 TI - Childhood Idiopathic Steroid Resistant Nephrotic Syndrome, Different Drugs And Outcome. AB - BACKGROUND: The management of steroid resistant nephrotic syndrome (SRNS) is quite difficult in paediatric patients. Not only the remission is difficult but also these patients are at risk of progression to end stage renal disease (ESRD). The goal of treatment is either to achieve complete remission or even partial remission as it is the most important predictor of disease outcome. METHODS: This study was conducted at The Children's Hospital, Lahore from February 2014 to May 2015. The SRNS patients of either sex between ages of 1-12 years were included with histology showing mesangioproliferative glomerulonephritis (MesangioPGN), focal segmental glomerulosclerosis (FSGS) or minimal change disease (MCD). Patients were given different immunosuppressant drugs and steroid 30 mg/m2 alternate day therapy on case to case basis and kept on regular follow up to check for response and adverse effects. RESULTS: Total of 105 patients included, 63 (60%) male and 42 (40%) female patients. The age ranges from 1.08 to 12 years, mean age of 6.53 years and SD of +/-3.17. Tacrolimus was the most common drug used 43 (41%) patients followed by cyclosporine in 38 (36.2%) patients, while Mycophenolate mofetil (MMF) was prescribed in 21 (20%) patients. Complete response was in 96 (91.4%) initially while partial response was seen in 8 (7.6%) patients. On follow up, 92 (87.6%) patients showed complete response and partial response was in 5 (4.7%) patients. Cushingoid features and hypertrichosis were the most common adverse effect seen. CONCLUSIONS: Steroid resistant nephrotic syndrome can be managed well with various immunosuppressant drugs and steroids but treatment should be individualized according to clinical presentation, disease histology and cost/social factors. PMID- 28718559 TI - Revascularization Of Late-Presenting Acute Limb Ischaemia And Limb Salvage. AB - BACKGROUND: Late-presenting acute limb ischaemia represents a challenging vascular emergency. The purpose of this study was to evaluate the outcome in patients following revascularization and management of existing or impending reperfusion injury of ischaemic limbs over a 12-year period (2002-2014). METHODS: Routine procedural codes were used to label consecutive patients admitted 72 hours following onset of symptoms for surgical revascularization of an acutely ischaemic limb. Data collected included demography, clinical presentation, synchronous morbidities, procedural specifics and outcomes of surgical management of all patients. RESULTS: The study sample included 206 patients, (117 male and 89 female, average age =49.4+/-14.6 years) presenting with a diagnosis of acute limb ischemia. The most frequent cause of acute thromboembolic limbs was cardiac disease (n=148). Femoral artery exploration with embolectomy was the most common procedure and was used for aortic, iliac, infrainguinal and distal occlusion. Thirty-four patients required additional vascular surgery due to failure of revascularization by embolectomy. Fasciotomy was performed in 45.6% of cases for existing or impending compartment syndrome when the patient presented very late. Surgical site infection occurred in 8.25% of cases, repeat embolectomy was required in 10.68% of cases; amputation in 13.1% and mortality was 5.8%. Predictors of morbidity and mortality included age of the patient, time of presentation and specific comorbidities. The 5-year amputation-free and survival estimate was 80%. CONCLUSIONS: Our study suggests that late revascularization of acute leg ischaemia improves blood supply to the limb, thereby reducing the number of amputations. The results suggest that revascularization is clinically warranted, even one week following the onset of acute ischaemia. Additional surgical procedures including fasciotomy further reduce the morbidity and mortality. PMID- 28718560 TI - Frequency of epstein-barr virus in classical hodgkin Lymphoma. AB - BACKGROUND: Epstein-Barr virus plays an important role in pathogenesis of Hodgkin lymphoma. The first patient with Epstein-Barr positive Reed Sternberg cells was described in 1985. Since then association between Epstein-Barr virus and Hodgkin lymphoma has been shown in many parts of the world and its occurrence shows significant variation from continent to continent and from country to country. METHODS: The study was carried out at department of histopathology, Armed Forces Institute of Pathology from 27th April 2013 to 10th March 2014. A total of 55 cases of classical Hodgkin lymphoma were included in the study. RESULTS: Out of 55 patients, 38 (69%) were male and 17 (31%) were female. The age of the patients ranged between 4-67 years with an average age of 29.4+/-21.72 years. Out of these, 44 cases (80%) were positive for latent membrane protein-1. Among positive cases 32 (72.72%) were male and 12 (27.28%) were female. Based upon histological subtypes MCHL was the commonest as a whole accounting for 87.3% as well as among both genders. Out of total 55 cases, 79.16% (38/48) of mixed cellularity Hodgkin lymphoma cases showed positivity for latent membrane protein-1 while 83.33% (5/6) cases of nodular sclerosis Hodgkin lymphoma and 100% (1/1) cases of lymphocyte depleted Hodgkin lymphoma showed positivity. No case of lymphocyte predominant classical Hodgkin lymphoma was diagnosed during the study. 80% of our classical Hodgkin lymphoma cases showed association with EBV expression. A total of 79.16% cases of mixed cellularity Hodgkin lymphoma showed LMP1 expression while 100% of lymphocyte depleted Hodgkin lymphoma showed LMP1 expression. CONCLUSIONS: The highest expression seen in lymphocyte depleted Hodgkin lymphoma subtype in contrast to mixed cellularity requires to be confirmed by a larger scale study comprising of substantial number of patients of lymphocyte depleted Hodgkin lymphoma and lymphocyte rich classical Hodgkin lymphoma. PMID- 28718561 TI - Analysis Of 1058 Lumbar Prolapsed Intervertebral Disc Cases In Two Tertiary Care Hospitals Of Pakistan. AB - BACKGROUND: Characteristics of Prolapsed Intervertebral Disc (PID) in two tertiary care hospitals of Pakistan. The objective of this was to study the demographic characteristics of lumbar PID by age, gender, clinical presentation, levels of spinal column involvement, treatment options and post-operative complications for lumber disc prolapse. METHODS: One thousand and fifty eight cases (708 males, 350 females) of prolapsed intervertebral disc over six years between January 2009 and December 2014 were studied for location of prolapsed disks, gender, age, clinical presentation, treatment options and complications of surgery. RESULTS: Of the determined locations L5/S1 was the commonest (34.6%), followed by L4/L5 (33.4%). 24.2%of the patients had prolapsed disks at 2 levels (L3/L4, L4/L5 andL4/L5, L5/S1). Prolapsed disc was commonest in the 31-49 year age group. Male were mostly affected with male to female ratio of 2.02%. Most common surgery performed was discectomy with fenestration (60.64% of total surgeries performed) and most common postoperative complication being mechanical backache (4.8%). CONCLUSIONS: Prolapsed intervertebral disc is common in the lower lumbar region at the level of L4/L5 and L5/S1. The outcome of the patients who underwent surgery is very good with 92.19% of patients, being free of postoperative complications. PMID- 28718562 TI - Clinico-Pathological Profile And Outcomes Of Patients With Polycythaemia Vera, Essential Thrombocythaemia And Idiopathic Myelofibrosis: A Tertiary Care Center Experience From Southern Pakistan. AB - BACKGROUND: The "Philadelphia Negative Classic Myeloproliferative Neoplasms" include polycythaemia vera (PV), essential thrombocythaemia (ET) and idiopathic myelofibrosis (IMF). These three disorders share several clinical and laboratory features including JAK2 V617F mutation. Our objectives were to determine the clinico-pathological profile and outcomes of Pakistani patients with polycythaemia vera (PV), essential thrombocythaemia (ET) and idiopathic myelofibrosis (IMF) in order to have an insight regarding behaviour of these conditions. METHODS: A retrospective analysis of all the cases of PV, ET and IMF diagnosed at our institute from January 1995 to December 2013 was performed. Age, gender, clinical presentation, laboratory investigations, treatment provided and duration of follow-up were included for analysis. Appropriate statistics were utilized for calculation of data. RESULTS: A total of 58 patients were diagnosed as PV, ET or IMF during the study period. Male to female ratio was 1.1:1. Forty five percent (n=27) patients came to medical attention due to abnormal laboratory results, 3 had cerebrovascular events, 3 had pruritus, and 1 patient each with gangrene and Budd-Chiari syndrome. Haemorrhage was not seen in any patient. Sixty percent (n=35) patients were treated with phlebotomy, hydroxyurea and aspirin alone or in combination. None of the patients transformed to myelofibrosis (MF) or myelodysplasia (MDS) during the mean (+/-SD) follow-up period of 57.2+/-50 months. One patient with ET transformed to acute myeloid leukaemia 9 years after the diagnosis. CONCLUSIONS: This study demonstrated a relatively more benign form of PV, ET and IMF with lesser frequency of symptoms, good response to treatment and less likelihood of transformation to MF, MDS or AML. PMID- 28718563 TI - Pattern Of Leukaemia Patients Admitted In Ayub Teaching Hospital Abbottabad. AB - BACKGROUND: Any tissue of the body can give rise to cancer. However, those tissues which multiply rapidly are at high risk of developing cancer and haematopoietic system is one of them. Neoplasms of this system are known as leukaemia and lymphoma, according to the types of white cells involved. Study of cancer patterns in different societies, however can contribute a substantial knowledge about the aetiology of cancer. The present Study was designed and aimed to estimate the frequency of different types of leukaemia in patients admitted in Ayub Teaching hospital Abbottabad. METHODS: Data from the patients admitted at oncology Department of Ayub Teaching Hospital Abbottabad from 2010 to 2015 was collected and analysed to calculate cumulative and year-wise frequency of leukaemia and its major types. Frequency distribution with reference to gender and age was also calculated. RESULTS: In our analysis about 16% patients had acute myelocytic leukaemia and 32% patients had acute lymphocytic leukaemia; while chronic myeloid leukaemia outnumbered chronic lymphocytic leukaemia (11% and 3%); Hodgkin lymphoma was seen in 18% cases while Non Hodgkin lymphoma (NHL) was present in 20% cases. Out of the total, 150 cases (75%) belonged to mountainous areas of Hazara, i.e., 40 cases belonged to Kohistan, another 40 cases were residents of Battagram, 45 cases belonged to hilly areas of Mansehra and 25 cases to Kaghan valley, while only 50 (25%) cases were from the plain areas of Abbottabad and Haripur districts, i.e., 20 and 30 cases respectively. CONCLUSIONS: Leukaemia is more common in hilly areas of Hazara, since majority of the cases belonged to well-known mountainous regions of Kohistan, Battagram, Kaghan or Mansehra and only few cases belonged to the plain areas of Abbottabad and Haripur districts. PMID- 28718564 TI - Correlation Of Deviance In Arterial Oxygenation With Severity Of Chronic Liver Disease. AB - BACKGROUND: Hepatitis B and C related chronic liver diseases have led to development of a serious threat to the people of South Asia. The main aim of this study was to evaluate the correlation of magnitude of arterial deoxygention to the severity of liver disease. METHODS: It was a hospital based cross-sectional descriptive study, carried out in the Medical Department of Khyber Teaching Hospital Peshawar. All in all 115 patients were assessed for the severity of the liver diseases and were correlated with arterial deoxygenation using linear regression models. RESULTS: Male to female ratio was 1.5:1. Males infected with hepatitis B, hepatitis C and both were 9, 60 and 1, while females suffered from hepatitis B, Hepatitis C and both were 2, 42 and 1 respectively. The linear relationship between A-a DO2 with severity of liver disease showed positive correlation while PO2 showed negative correlation with severity of liver disease. CONCLUSIONS: There was a positive correlation between A-a DO2 and severity of liver diseases while PO2 and severity of liver diseases showed negative correlation. PMID- 28718565 TI - Functional Outcome Of Proximal Humeral Fractures Treated With Philos Plate In Adults. AB - BACKGROUND: Proximal humeral fractures account for 4-5% of all fractures. Most fractures are minimally displaced and can be managed non-operatively in adults. Displaced and unstable fractures are difficult to manage and should be treated to achieve painless shoulder and full function. Our aim was to evaluate the functional outcome of proximal humerus fractures (Neers classification 2 part, 3 part and 4 part) treated with PHILOS (Proximal humeral internal locking system). METHODS: We retrospectively reviewed 22 patients who had proximal humerus fractures treated with PHILOS plate from Jan 2012 to June 2013 conducted at Orthopaedic Department Liaquat National Hospital. Clinical outcome was measured using DASH (disability of arm, shoulder and hand) Score System. Radiological union was assessed by serial X rays. RESULTS: Two patients were lost to follow up. Mean age was 40 years (20-70). Mean follow up was 6 months. 4 patients had two-part fracture, 10 patients had three-part and 6 patients had four-part fracture. Radiological union was achieved in average 8.31 weeks (+/-1.37SD). Average DASH score in young patients was 15.14 (+/-1.91SD) and in elderly was 31.66 (+/-4.08SD). One case of implant failure was noted. Better results in younger patients were achieved as compared to elderly proved by DASH score. CONCLUSIONS: Increase in number of fracture parts and delay in treatment did not affect the outcome. Our study concluded that this implant provides stable fixation in younger patients with good quality bone sufficient to allow mobilization. PMID- 28718566 TI - Efficacy And Safety Of Interlocked Intramedullary Nailing For Open Fracture Shaft Of Tibia. AB - BACKGROUND: Due to increasing population and changing human habits the number of accidents and high energy trauma is rising. Management of open fracture tibia is a complex problem and is a challenge for both orthopaedic and plastic surgeons. The study was carried out to ascertain the efficacy and safety of interlocked intra-medullary nailing for open shaft tibial fractures in patients presenting at or after 24hr of injury. METHODS: In this descriptive case series, over a period of 6 moths, 163 consecutive cases of open fracture of tibial shaft were reviewed in terms of clinical profile, time of presentation, and gender distribution. RESULTS: In this study mean age was 30+/-0.02 years. Males comprised 85% of study population while 15% were females. Gustilo-I type fracture and Gustilo-II type fracture was diagnosed in 90% and 10% patients respectively. Thirty three percent patients had wound infection while fracture union was found in 15% cases. Moreover interlocked intramedullary nailing for open fracture shaft of tibia was safe in 80% patients while this procedure was effective in 85%. CONCLUSIONS: Un reamed, interlocked intra-medullary nailing may be considered as a suitable option for treatment of open fractures of tibia. PMID- 28718567 TI - Knowledge Of Maintenance Intravenous Fluid Therapy In Acutely Ill Hospitalized Children Among Residents. AB - BACKGROUND: Isotonic saline is recommended as maintenance intravenous fluid therapy (MIVFT) for most of the acutely ill hospitalized children. The aim of this study is to assess the current knowledge of paediatric residents regarding the selection of MIVFT in hospitalized children. METHODS: We conducted a paper based questionnaire survey to paediatric residents from ten centres asking selection of MIVFT in four common clinical scenarios in 6-month and 10-year old patients as well as monitoring of fluid balance and electrolyte. RESULTS: 445 responses were collected (>90% response rate). Majority [78.3% (n=348)] of them were FCPS-trainees. The 0.9%, 0.45% and 0.2% solution were selected by 45.8%, 43.98% and 10.92% respectively. The isotonic and hypotonic solution was prescribed in 6- mo (35.22% vs. 64.76% [p<0.001]) and 10-year (54.49% vs. 44.98%) in four different clinical scenarios respectively. 0.45% solution was most commonly prescribed MIVFT in pneumonia (50.22%) and meningitis (45.39%) and 0.9% solution was most commonly selected in acute gastroenteritis (55.05%) and post operative patients (51.23%). Fluid balance and electrolyte monitoring were selected by 96.9% and 55.7% respondents respectively. CONCLUSIONS: Our survey reports that more than fifty percent of paediatric residents have inadequate knowledge about maintenance intravenous fluid therapy in acutely ill hospitalized children. PMID- 28718568 TI - Association Of Serum Testosterone And Sex Hormone Binding Globulin Levels In Females With Acne Based On Its Severity. AB - BACKGROUND: Androgens are involved in the development of acne. The aim of this study was to find out if there was an association of serum testosterone and sex hormone binding globulin (SHBG) in females with acne based on its severity. METHODS: It was a cross sectional study, conducted in Dermatology unit of Fauji Foundation Hospital (FFH), Rawalpindi. Duration of study was eight months. Adult females with acne were enrolled in the study. Patients were categorized into minor, mild, moderate groups. Blood samples were taken for serum testosterone and SHBG. RESULTS: Five hundred and thirty-one adult female were enrolled into the study. The mean age was 21.49+/-4.73 years. Acne was graded as minor in 78 (14.7%) cases, mild in 248 (46.7%) and moderate in 205 (38.6%). There was no statistically significant relationship between the levels of serum testosterone (p=0.776) and SHBG (p=0.711) with acne severity. CONCLUSIONS: There was no association of serum testosterone and sex hormone binding globulin levels in females with acne based on its severity. PMID- 28718569 TI - Comparison Of Efficacy Of 10% Potassium Hydroxide Solution Versus Cryotherapy In Treatment Of Molluscum Contagiosum. AB - Background:: Different topical therapies are being used for treating molluscum contagiosum. Potassium hydroxide in varying solution strengths with irritant reaction on the skin can help in eliminating the infection. It is cheap, easily available, can be easily applied at home, with good safety profile and cost effectiveness. This study was conducted to compare the efficacy of 10% potassium hydroxide solution versus cryotherapy in treating molluscum contagiosum. Methodology: This study was a Randomized control trial conducted in the Department of dermatology, Military hospital Rawalpindi. Study included 120 randomly selected patients with molluscum contagiosum divided equally into two groups. Group A were treated with 10% potassium hydroxide aqueous solution applied daily to the lesions twice daily for 6 weeks while Group B received weekly cryotherapy with liquid nitrogen. The status of lesions was documented weekly for 6 weeks. RESULTS: Of the 120 patients enrolled, 67 (55.8%) were male and 53 (44.2%) were female. Mean age of patients was 20.53(+/-8.17) years. At base line Molluscum contagiosum lesion ranged from minimum of 2 lesions to maximum of 26 lesions with a mean of 8.95 (SD +/-4.45) lesions. Of 120 patients, complete clearance was observed in 98(81.6%) of patients, 48(80%) patients had lesion clearance in Group A and 50 (83.3%) patients had lesion clearance was observed in Group B. No statistical significance was observed in the lesion clearance between the two groups (p-0.63). CONCLUSIONS: The efficacy of 10% potassium hydroxide solution and cryotherapy is statistically same over 6 weeks of treatment. Thus less expensive, easily available and cosmetically more acceptable potassium hydroxide solution can be used instead of cryotherapy in treating molluscum contagiosum. PMID- 28718570 TI - Anomalous Origin Of The Epicardial Left Coronary Artery From The Right Coronary Sinus Revealed In A Patient Presenting With Acute Myocardial Infarction. AB - An 84-year-old lady presented with history of syncope and a transient loss of consciousness proceeded by severe chest pain to accident and emergency. Electrocardiogram (ECG) revealed anterolateral ST elevation. She had an emergency coronary angiogram revealing an anomalous left coronary artery with severe tortuosity and occlusion at mid segment. During the course of the angiogram she became asymptomatic and TIMI flow spontaneously restored. These findings were discussed with the patient and she opted for medical management understanding that it would be difficult to negotiate the tortuosity. On follow up she remained well with optimal anti-anginal treatment. PMID- 28718571 TI - A Rare Cause Of Pneumoperitoneum: Perforated Appendicitis. AB - Peptic ulcer perforation is the most common cause of pneumoperitoneum (75%). The rate of the perforation of acute appendicitis is 20-30% and the rate of its co occurrence with pneumoperitoneum is 0-7%. In this report, a patient with sub diaphragmatic free air due to perforated appendicitis. PMID- 28718572 TI - MRI Findings In Acute Wernicke's Encephalopathy, Caused By Hyperemesis Gravidarum. AB - A 25-year old pregnant female with history of confusion and drowsiness for 02 days was referred by neurophysician for MRI brain. MRI demonstrated T2W/FLAIR hyper intensities in medial thalami, periaqueductal areas with variable diffusion restriction, apparent as hyper intense signal on DWI and no signal change on ADC mapping that was typically consistent with Wernicke's encephalopathy. A high index of suspicion is necessary, as delayed or lack of treatment can lead to high morbidity and mortality. PMID- 28718573 TI - Isolated Duodenal Injuries After Blunt Abdominal Trauma. AB - Isolated duodenal injury after blunt abdominal trauma is a very rare entity. In contrast to penetrating injuries, duodenal injuries after blunt trauma are difficult to diagnose. Early diagnosis and management is required to prevent high morbidity and mortality associated with these injuries. We present three young patients of blunt abdominal trauma with an isolated injury to duodenum in which primary repair of perforations were done with good outcomes. PMID- 28718574 TI - Pierre Robin Sequence: A Rare Presentation Of Absent Femur And Inguinal Hernia. AB - Pierre Robin Sequence is a well-recognized case of rarity which presents with a triad of glossoptosis, cleft palate. We report a rare case of Pierre robin Sequence in an Asian child, with the absence of left femur and right sided inguinal hernia. PMID- 28718575 TI - Best Vitelliform Macular Dystrophy In Afghan Twins. AB - Best vitelliform macular dystrophy is the second most common type of hereditary fundus dystrophies. Our case report describes twin brothers of Afghan family who developed Best vitelliform macular dystrophy. One of them developed choroidal neovascularization in one eye which was treated with single intravitreal injection of bevacizumab. The patient showed stable vision and did not have any recurrence until 3 years of follow up. Many cases of familial Best vitelliform macular dystrophy have been described in medical literature but our report is unique as it presents twin brothers with Best vitelliform macular dystrophy which has never been described before. PMID- 28718576 TI - Foriegn Body In Rectum: An Unusual Case. AB - Rectal Foreign bodies have been reported in literature since long. They are inserted as a result of erotic behaviour. Rectal foreign bodies may be inserted as a result of sexual perversion or for nonsexual reasons such as constipation, concealment or in psychiatric patients1.Their insertion may be voluntary or involuntary as in impalement. Usually patients are men in their 40's but it shows a bimodal distribution from teenage up to 80's or 90's. Presentation is usually late due to embarrassment. They can be diagnosed by simple plain radiographs and digital rectal examination. Most of times they can be extracted per rectally after analgesia or general anaesthesia with laparotomy required only for perforation and peritonitis. Here we report a case of a 50 years old man who presented with a steel rod in rectum which was pulled out per rectally. PMID- 28718577 TI - Fallopian Tube Cyst: A Rare Complication Of Tubal Sterilization. AB - Tubal sterilization is one of the most commonly employed permanent method of contraception, although it is considered very safe, rarely a cyst may develop in the fallopian tube after sterilization which may undergo torsion resulting in patient presenting with acute abdomen. We are presenting a case of a middle aged women presenting to emergency room with severe lower abdominal pain, she had past history of tubal ligation done 12 years back. Pelvic ultrasound showed right sided ovarian cyst, emergency laparotomy was performed for suspected torsion of ovarian cyst, which revealed normal ovary, however a right sided fallopian tube cyst was present which had undergone torsion, right sided salpingectomy was performed and the patient was sent home in stable condition on the fourth postoperative day. PMID- 28718578 TI - Atypical Cutaneous Presentation Of Adult Onset Still Disease. AB - Adult onset still disease is a rare systemic inflammatory disease which presents with cardinal symptoms of spiking fever, arthralgia, and characteristic non pruritic evanescent salmon pink rash and neutrophilic leukocytosis. However it can have accompanied atypical cutaneous manifestations of pruritic plaques and papules. Clinicians need to be aware of this condition so that they can correctly diagnose it and prevent its serious complications. PMID- 28718579 TI - Constitutional Reforms In Pakistan: Turning Around The Picture Of Health Sector In Punjab Province. AB - consequences of 2011 reforms on the future roles demarcation between the federation and provinces for steering the health sector. The objective of this assessment study was to conduct an institutional appraisal of the provincial health department in Punjab to mark the achievements, problem areas and issues, as well as to formulate the recommendations in the post-devolution scenario. It was an in-depth literature review comprising papers found on PubMed/Medline, Google Scholar, reports published by the government departments, independent research works, academic papers, and documents produced by the development agencies in Pakistan, covering 18th constitutional amendment and its implications on health sector. Following 18th amendment, the Punjab Government formulated health sector strategy (2012-2017) which is being implemented in a phased approach. All districts have developed their three years rolling out plans. An integrated strategic and operational plan of MNCH, Nutrition and Family Planning is under review for approval. Punjab Health Care Commission has been established and is functional to regulate the health sector. Development agencies have in principle committed to support health sector strategy till 2017. Fair investments in improving governance, service delivery structure, human resource, health information, and medical products are expected more than ever in the post 18th amendment scenario. This is the chance for the health system of Punjab to serve the vulnerable people of the provinces, saving them from health shocks. PMID- 28718580 TI - Appetite Regulation In Relation To Energy Provision. AB - Background: Appetite control is a very complex process which influences the short term feeding behaviour and a long term adaptive process that responds to the energy input. Appetite control and food intake is influenced by a combination of behavioural, psychological and neuro-endocrine influences. METHODS: For identification of articles search engines of the databases EMBASE, OVID, Pub med and MEDLINE were used for papers published from 2002 to 2015 in English language. RESULTS: The higher endogenous peptide YY (PYY) and cholecystokinin (CCK) and lower ghrelin levels are not always associated with subjective feelings of fullness or hunger and a decreased energy intake which highlights the fact that appetite control and food intake is a very intricate process. CONCLUSIONS: When food is ingested, numerous physiological, hormonal, social and psychological processes are triggered in an intricate manner. Therefore, it can be said that ghrelin, PYY and CCK are just few pieces, which contributes to the process of appetite control and energy intake. PMID- 28718581 TI - "Why we could not eradicate polio from pakistan and how can we?" AB - Polio is a major health problem and a deadly infectious disease in the developing countries. It is a viral illness caused by polio virus that can lead to paralysis, limb deformities, breathing problems or even death. Polio virus resides only in humans and passes on to the environment in the faeces of someone who is infected. Polio is still endemic in three countries, i.e., Pakistan, Nigeria and Afghanistan and is eradicated from the rest of the world. Pakistan is considered as the exporter of Wild Polio Virus (WPV) with highest number of polio outbreaks among endemic countries. With the start of World Polio Eradication Initiative in 1988, the number of polio cases has been reduced up to 99% worldwide until now. In 2015, Pakistan has shown a decrease of 70-75% in number of polio cases as compare to last year which is the result of good government's initiatives. Militant organizations such as Tehreek-e-Taliban Pakistan, Al-Qaeda and Boko haram movement of northern Nigeria are a major hurdle in the eradication of polio from these countries. The misconception of people about polio vaccine, insecurity within the country and poor health system are the reasons of failure of polio eradication campaigns in these regions. Awareness campaigns about polio for locals and development of proper health system will help in the eradication of polio. Once polio is eradicated, about 40-50 billion dollars can be saved globally. With the strong commitment, seriousness and good initiatives, polio will be eradicated from Pakistan within two years more likely. PMID- 28718582 TI - Intra-Oral Basal Cell Carcinomaan Immunohistochemical Interpretation Using Ber Ep4. PMID- 28718583 TI - Musculoskeletal Spect-Ct: A Pictorial Review. AB - SPECT-CT being a hybrid imaging scanner provides molecular and anatomical imaging in one go as a one stop shop. The addition of correlative CT scan to the planar skeletal scintigraphy gives better localization of the lesion, its characterization and attenuation correction as well. We present a brief overview of our institutional experience with hybrid SPECT-CT, as an adjunct to planar skeletal scintigraphy. SPECT-CT imaging improves the diagnostic yield and specificity of planar skeletal scintigraphy. PMID- 28718584 TI - Doctor Patient Language Barrier - Compromising On Quality Care. PMID- 28718585 TI - ? PMID- 28718586 TI - [Adverse events of biologic therapies]. AB - Biological therapies have revolutionized the management and the outcome of patients with inflammatory rheumatic diseases. The prescription and the number of patients under biotherapies have greatly increased. Unfortunately, these treatments are occasionally accompanied by side effects usually reversible upon treatment discontinuation. Some are preventable or can be reduced, including through the screening and prevention (tuberculosis screening, vaccination...). It is important to be aware of these different side effects to adapt the prescription of biologics according to the patient's profile (history of infection, malignancy, heart failure...). It is also critical to involve the patients into the decision-making and thus, to inform them thoroughly. PMID- 28718587 TI - [Drugs induced osteopathies]. AB - Drug induced bone diseases concerns : induced osteoporosis, induced osteomalacia (by loss of calcium, phosphate or vitamin D) and induced sarcopenia. Some of these drugs are well known, such as anti-hormones, corticotherapy (which could induce all of osteoporosis, osteomalacia and sarcopenia). In the present article, we will focus on 3 others less known but frequently used drugs : iron replacement, proton pump inhibitors therapy, and serotonin reuptake inhibitor antidepressants treatment. For each of them we will discuss the pathophysiological mechanism leading to bone fragility as well as the recommendations of prevention / management to be proposed in case of absolute necessity of the treatment. PMID- 28718588 TI - [Spinal injection : risks and side effects]. AB - The efficacy of spinal injection for chronic spinal pain is dubious for most conditions. They are however frequently prescribed. Side effects are poorly reported in the literature. In addition to benign and transient problems, serious and lethal side effects have been reported due to infection, hematoma or central and spinal cord infarctions which could be related to intravascular injection of corticoids. Although their frequency is excessively low, they should be discussed with every patient before prescription and should be mentioned in the consent form. PMID- 28718590 TI - [Novelties in ENT - 2016]. AB - These novelties in ENT were selected among more than 15'000 abstracts in the 2016 literature, and dedicated to the practioner Guidelines of the American Academy of ORL will resume the attitude towards chronic otitis media, and reviews of hearing impairment and tinnitus are presented, as well as impact of the pneumoccal vaccine on otitis media. In rhinology, the flora of chronic rhinosinusitis and its non surgical treatments will be discussed, as well as epistaxis and malignant tumor series. 17 Diseases dignanosed only with exhaled air will be also reported. The importance of HPV in head and neck cancer will be again discussed, with the increasing incidence of oropharyngeal cancer. Peritonsillar abcesses, and indications for tonsillectomy, as well as progresses in salivary glands, including sialendoscopy will be finaly presented. PMID- 28718589 TI - [Drug-induced iatrogenic arthropathies]. AB - Arthropathies induced by drugs, especially arthralgias, are very frequently reported in pharmacology. The major difficulty often consists in confirming the accountability of the drug in the occurrence of the symptoms. Stopping the drug when it really responsible of the arthralgia is then likely to lead to the disappearance of the symptoms. The aim of this article is to review some of classical known induced arthropathies and some innovations by describing the clinical characteristics as well as the mechanisms linking the drug to the arthropathies when these have been clarified. PMID- 28718591 TI - ? PMID- 28718592 TI - ? PMID- 28718593 TI - ? PMID- 28718594 TI - ? PMID- 28718595 TI - ? PMID- 28718597 TI - ? PMID- 28718596 TI - ? PMID- 28718598 TI - ? PMID- 28718599 TI - ? PMID- 28718600 TI - [The introduction of sexuality during gynaecological consultation]. AB - Many health organisms recommended to gynaecologists to actively address sexuality issues during consultation. However, physicians do not take systematically sexual history from their patients into account. The objective of this paper is to examine, on the basis of current knowledge and, more specifically on a Swiss study, gynaecologists' perceived obstacles and also patients' expectations with regard to sexuality issues. Findings highlighted a lack of training in sexology within medical programs. Moreover, it emphasized important mismatches on perceptions between gynaecologists and patients concerning the gynaecologist's role ; intimacy and even on the way of introducing sexuality topics. Practical perspectives are suggested to allow futur adjustments. PMID- 28718601 TI - [Interest of a psychosomatic approach Two example of what might be concealed behind gynecological symptoms]. AB - Two situations found in everyday gynecological practice demonstrate how a trustworthy doctor-patient relationship is built. This relationship helps to uncover what is concealed behind physical symptoms, which can perturb daily life (couple, social, family life) beyond a purely medical approach. To understand what is really happening rarely leads to a rapid solution. A stable chronicity that does not involve too many treatments, including surgical ones, can already be considered a success. PMID- 28718602 TI - [Sexual function and clitoral reconstruction after female genital mutilation]. AB - Evidence on sexual function of women living with female genital mutilation (FGM) and on clitoral reconstruction after FGM is limited. Such surgery is performed in case of chronic clitoral pain, clitoral dyspareunia or for female identity reasons. In this article we summarize the anatomical, psychosexual and sociocultural factors that influence sexual function of women with FGM and the available data on clitoral reconstruction. Surgical resection of the fibrous tissue around the clitoris, with eventual excision of painful post-traumatic neuromas, could improve pain and sexual function. In asymptomatic women, multidisciplinary non-surgical management could be equally or more beneficial and less risky than surgery. PMID- 28718603 TI - [Long term consequences of obstetrical anal sphincter injuries on sexual function]. AB - Obstetrical anal sphincter injuries (OASIS) can lead to sexual dysfunction. Literature is poor concerning long-term consequences of OASIS on female sexuality. The objective of this paper is to clarify long-term consequences of OASIS on sexual function. Dyspareunia and lubrication troubles are constantly reported based on articles reviewed in literature through Pubmed. Nevertheless, global sexual function seems not to be influenced by OASIS on a long-term basis. Therefore, sexual dysfunctions must be specifically analysed in women's follow-up after OASIS. PMID- 28718604 TI - [Sexual medicine in Lausanne : past, present and future]. AB - Sexuality is a natural function, part of global health and has to be evaluated in every patient. When difficulties or dyfunctions happen in this domain, a specific mangement should be proposed. Sexual medicine is a " young " transversal discipline developping these last years in the french-speaking area of Switzerland. We present in this article a short history of sexual medicine in Lausanne and the recent activity in the Sexual Medicine Consultation of the Maternity in the CHUV. PMID- 28718605 TI - [When sex hurts the couple : the case of endometriosis]. AB - Sexual health is a critical aspect of quality of life and is also influenced by medical conditions and health care interventions, particularly when gynaecological disorders are involved. Dyspareunia is a common symptom of endometriosis, a cause of personal distress and a main raison for seeking treatment. Endometriosis negatively affects different domains of sexual function and specific biopsychological variables (chronic pain, recurrence, infertility) may further worsen quality of sexual function and relationship. Consequences of endometriosis treatment on global sexual functioning have not been featured prominently in the available literature, assuming wrongly that sexual pain improvement was always translated into a recovered sexual health. PMID- 28718606 TI - [Interventional treatment of venous insufficiency]. AB - Interventional treatment of venous insufficiency has been revolutionized by endovascular techniques. Some of these techniques, and particularly thermal ablation (endovenous laser, radiofrequency) are now recommended as first-line therapy in the latest international guidelines. This is because of less post operative pain, a shorter leave from employment and similar or lower recurrence rate. Endovenous techniques allow safer and more efficient treatment of certain particular conditions : small saphenous vein, ulcers, and recurrent varicose veins. In addition to clinical history and examination, a duplex sonography of deep and superficial veins, performed by an angiologist, is the most important exam in order to determine proper indication and best treatment strategy for each patient. PMID- 28718607 TI - [Interdisciplinarity for obese patient global management]. AB - Obesity is a chronic illness involving serious somatic comorbidities and psychological disorders. Furthermore, obese patients often suffer from personal and / or socio-cultural problems. Taken together these elements amount to a complex illness requiring comprehensive patient care and hence an interdisciplinary approach aimed at integrating and coordinating the interventions of the different health professionals. Through various initiatives, the Interdisciplinary group for the treatment of obesity (GITO) endeavours to apply and promote an interdisciplinary approach both in clinical practice and in the debate on the problems relating to obesity. PMID- 28718608 TI - ? PMID- 28718609 TI - ? PMID- 28718610 TI - ? PMID- 28718611 TI - ? PMID- 28718612 TI - ? PMID- 28718613 TI - ? PMID- 28718614 TI - Emergency management of renal and genitourinary trauma: best practices update AB - In up to 10% of patients who experience abdominal trauma, renal and urogenital systems will be involved. In polytrauma patients with other potentially life threatening injuries, renal and genitourinary trauma may be overlooked initially, but a delayed or missed diagnosis of these injuries may result in preventablecomplications. This review provides a best-practice approach to the diagnosis and management of renal and genitourinary injuries, with an emphasis on the systematic approach needed to identify subtle injuries and avoid long-term urinary sequelae such as hypertension, incontinence, erectile dysfunction, chronic kidney disease, and nephrectomy. PMID- 28718615 TI - Development of Nanofiber Sponges-Containing Nerve Guidance Conduit for Peripheral Nerve Regeneration in Vivo. AB - In the study of hollow nerve guidance conduit (NGC), the dispersion of regenerated axons always confused researchers. To address this problem, filler containing NGC was prepared, which showed better effect in the application of nerve tissue engineering. In this study, nanofiber sponges with abundant macropores, high porosity, and superior compressive strength were fabricated by electrospinning and freeze-drying. Poly(l-lactic acid-co-epsilon caprolactone)/silk fibroin (PLCL/SF) nanofiber sponges were used as filler to prepare three-dimensional nanofiber sponges-containing (NS-containing) NGC. In order to study the effect of fillers for nerve regeneration, hollow NGC was set as control. In vitro cell viability studies indicated that the NS-containing NGC could enhance the proliferation of Schwann cells (SCs) due to the macroporous structure. The results of hematoxylin-eosin (HE) and immunofluorescence staining confirmed that SCs infiltrated into the nanofiber sponges. Subsequently, the NS containing NGC was implanted in a rat sciatic nerve defect model to evaluate the effect in vivo. NS-containing NGC group performed better in nerve function recovery than hollow NGC group. In consideration of the walking track and triceps weight analysis, NS-containing NGC was close to the autograft group. In addition, histological and morphological analyses with HE and toluidine blue (TB) staining, and transmission electron microscope (TEM) were conducted. Better nerve regeneration was observed on NS-containing NGC group both quantitatively and qualitatively. Furthermore, the results of three indexes' immuno-histochemistry and two indexes' immunofluorescence all indicated good nerve regeneration of NS containing NGC as well, compared with hollow NGC. The results demonstrated NS containing NGC had great potential in the application of peripheral nerve repair. PMID- 28718616 TI - Photothermally Driven Refreshable Microactuators Based on Graphene Oxide Doped Paraffin. AB - Actuators based on phase change materials (paraffin) can simultaneously produce large stroke length and large force due to thermal expansion, but the low thermal conductivity of paraffin requires high power input and long actuation time. The graphene oxide (GO) doped paraffin dynamic actuator addresses the key challenges in the design of thermal phase change actuators: Thermal conductivity and light absorbing are increased, and the response time is reduced compared to the standard phase change actuator designed with metal heating resistors. The thermal properties of GO-paraffin composites with varied loading amount are characterized to confirm the optimal loading amount of 1.0%. A multicell phase change actuator was integrated into a digital micromirror controlled optical system. A series of photothermally driven refreshable patterns were generated and confirmed with infrared imaging. PMID- 28718617 TI - Initial Reduction of CO2 on Pd-, Ru-, and Cu-Doped CeO2(111) Surfaces: Effects of Surface Modification on Catalytic Activity and Selectivity. AB - Surface modification by metal doping is an effective treatment technique for improving surface properties for CO2 reduction. Herein, the effects of doped Pd, Ru, and Cu on the adsorption, activation, and reduction selectivity of CO2 on CeO2(111) were investigated by periodic density functional theory. The doped metals distorted the configuration of a perfect CeO2(111) by weakening the adjacent Ce-O bond strength, and Pd doping was beneficial for generating a highly active O vacancy. The analyses of adsorption energy, charge density difference, and density of states confirmed that the doped metals were conducive for enhancing CO2 adsorption, especially for Cu/CeO2(111). The initial reductive dissociation CO2 -> CO* + O* on metal-doped CeO2(111) followed the sequence of Cu > perfect > Pd- > Ru-doped CeO2(111); the reductive hydrogenation CO2 + H -> COOH* followed the sequence of Cu- > perfect > Ru- > Pd-doped CeO2(111), in which the most competitive route on Cu/CeO2(111) was exothermic by 0.52 eV with an energy barrier of 0.16 eV; the reductive hydrogenation CO2 + H -> HCOO* followed the sequence of Ru- > perfect > Pd-doped CeO2(111). Energy barrier decomposition analyses were performed to identify the governing factors of bond activation and scission along the initial CO2 reduction routes. Results of this study provided deep insights into the effect of surface modification on the initial reduction mechanisms of CO2 on metal-doped CeO2(111) surfaces. PMID- 28718618 TI - Graphene Oxide by UV-Ozone Treatment as an Efficient Hole Extraction Layer for Highly Efficient and Stable Polymer Solar Cells. AB - The hole extraction layer has a significant impact on the achievement of high efficiency polymer solar cells (PSCs). Here, we report an efficient approach to direct UV-ozone treatment by larger device performance enhancement employing graphene oxide (GO). The dramatic performance enhancement of PSCs with the P3HT:PCBM blend as an active layer was demonstrated by the UV-ozone treatment of GO for 30 min: best power conversion efficiency (PCE) of 4.18%, fill factor of 0.63, Jsc of 10.94 mA cm-2, and Voc of 0.61 V, which are significantly higher than those of the untreated GO (1.82%) and highly comparable PEDOT:PSS-based PSCs (3.73%). In addition, PSCs with UV-ozone-treated GO showed a longer stability than PSCs with PEDOT:PSS. The significant enhancement of PCEs of PSCs can be attributed to the fact that ozone molecules can oxidize GO into CO2 and leave highly conductive graphene particles. We suggest that this simple UV-ozone treatment can provide an efficient method for highly efficient GO hole extraction in high-performance PSCs. PMID- 28718619 TI - Radial Dopant Placement for Tuning Plasmonic Properties in Metal Oxide Nanocrystals. AB - Doped metal oxide nanocrystals that exhibit tunable localized surface plasmon resonances (LSPRs) represent an intriguing class of nanomaterials that show promise for a variety of applications from spectroscopy to sensing. LSPRs arise in these materials through the introduction of aliovalent dopants and lattice oxygen vacancies. Tuning the LSPR shape and energy is generally accomplished through controlling the concentration or identity of dopants in a nanocrystal, but the lack of finer synthetic control leaves several fundamental questions unanswered regarding the effects of radial dopant placement, size, and nanocrystalline architecture on the LSPR energy and damping. Here, we present a layer-by-layer synthetic method for core/shell nanocrystals that permits exquisite and independent control over radial dopant placement, absolute dopant concentration, and nanocrystal size. Using Sn-doped In2O3 (ITO) as a model LSPR system, we synthesized ITO/In2O3 core/shell as well as In2O3/ITO core/shell nanocrystals with varying shell thickness, and investigated the resulting optical properties. We observed profound influence of radial dopant placement on the energy and linewidth of the LSPR response, noting (among other findings) that core-localized dopants produce the highest values for LSPR energies per dopant concentration, and display the lowest damping in comparison to nanocrystals with shell-localized or homogeneously distributed dopants. Inactive Sn dopants present on ITO nanocrystal surfaces are activated upon the addition of a subnanometer thick undoped In2O3 shell. We show how LSPR energy can be tuned fully independent of dopant concentration, relying solely on core/shell architecture. Finally, the impacts of radial dopant placement on damping, independent of LSPR energy, are explored. PMID- 28718620 TI - High-Performance Cathode Based on Microporous Mo-V-Bi Oxide for Li Battery and Investigation by Operando X-ray Absorption Fine Structure. AB - The development of cathode-active material of Li battery is important for the current emerging energy transferring and saving problems. A stable crystalline microporous complex metal oxide based on Mo, V, and Bi is an active and suitable material for Li battery. High capacity (380 Ah/kg) and stable cycle performance are achieved. X-ray absorption near-edge structure analyses demonstrate that the original Mo6+ and V4+ ions are reduced to Mo4+ and V3+ in the discharging process, respectively, which results in a 70-electron reduction per formula. The reduced metal ions can be reoxidized reversibly in the next charging process. Furthermore, extended X-ray absorption fine structure analyses reveal that the Mo O bonds in the material are lengthened in the discharging process probably due to interaction with Li+ without change of the basic structure. PMID- 28718621 TI - Illuminating the Cell's Biochemical Activity Architecture. AB - All cellular behaviors arise through the coordinated actions of numerous intracellular biochemical pathways. Over the past 20 years, efforts to probe intracellular biochemical processes have undergone a fundamental transformation brought about by advances in fluorescence imaging, such as the development of genetically encoded fluorescent reporters and new imaging technologies; the impact of these approaches on our understanding of the molecular underpinnings of biological function cannot be understated. In particular, the ability to obtain information on the spatiotemporal regulation of biochemical processes unfolding in real time in the native context of a living cell has crystallized the view, long a matter of speculation, that cells achieve specific biological outcomes through the imposition of spatial control over the distribution of various biomolecules, and their associated biochemical activities, within the cellular environment. Indeed, the compartmentalization of biochemical activities by cells is now known to be pervasive and to span a multitude of spatial scales, from the length of a cell to just a few enzymes. In this Perspective, part of this special issue on "Seeing into cells", we highlight several recent imaging studies that provide detailed insights into not just where molecules are but where molecules are active within cells, offering a glimpse into the emerging view of biochemical activity architecture as a complement to the physical architecture of a cell. PMID- 28718622 TI - Graphene Sheet-Induced Global Maturation of Cardiomyocytes Derived from Human Induced Pluripotent Stem Cells. AB - Human induced pluripotent stem cells (hiPSCs) can proliferate infinitely. Their ability to differentiate into cardiomyocytes provides abundant sources for disease modeling, drug screening and regenerative medicine. However, hiPSC derived cardiomyocytes (hiPSC-CMs) display a low degree of maturation and fetal like properties. Current in vitro differentiation methods do not mimic the structural, mechanical, or physiological properties of the cardiogenesis niche. Recently, we present an efficient cardiac maturation platform that combines hiPSCs monolayer cardiac differentiation with graphene substrate, which is a biocompatible and superconductive material. The hiPSCs lines were successfully maintained on the graphene sheets and were able to differentiate into functional cardiomyocytes. This strategy markedly increased the myofibril ultrastructural organization, elevated the conduction velocity, and enhanced both the Ca2+ handling and electrophysiological properties in the absence of electrical stimulation. On the graphene substrate, the expression of connexin 43 increased along with the conduction velocity. Interestingly, the bone morphogenetic proteins signaling was also significantly activated during early cardiogenesis, confirmed by RNA sequencing analysis. Here, we reasoned that graphene substrate as a conductive biomimetic surface could facilitate the intrinsic electrical propagation, mimicking the microenvironment of the native heart, to further promote the global maturation of hiPSC-CMs. Our findings highlight the capability of electrically active substrates to influence cardiomyocyte development. We believe that application of graphene sheets will be useful for simple, fast, and scalable maturation of regenerated cardiomyocytes. PMID- 28718623 TI - A Multimodal Spectroscopic Imaging Method To Characterize the Metal and Macromolecular Content of Proteinaceous Aggregates ("Amyloid Plaques"). AB - Alzheimer's disease (AD) is a major international health and economic concern. A key pathological feature of AD is so-called "amyloid-beta-plaques", or "Abeta plaques", which are deposits of aggregated protein, enriched with the Abeta fragment of amyloid precursor protein. Despite their name, the deposits are not pure Abeta and have a heterogeneous, chemically complex composition that can include multiple proteins, lipids, and metal ions (Fe, Cu, or Zn). Despite extensive research, it is still uncertain whether Abeta-plaques are a cause or a consequence of AD pathology. Further characterization of the elemental and biochemical composition within and surrounding Abeta-plaques, and knowledge of how composition varies with disease state or progression, may provide important insight into the relationship between Abeta-plaques and AD pathology. With this aim in mind, herein we demonstrate a multimodal spectroscopic imaging workflow to better characterize the complex composition of Abeta-plaques. Our approach incorporates several spectroscopic imaging techniques, such as Fourier transform infrared spectroscopic imaging (FTIR), Raman microscopy, and X-ray fluorescence microscopy (XFM). While FTIR, Raman, and XFM have been used previously, mostly in isolation, to study Abeta-plaques, application of all three techniques, in combination with histology and fluorescence microscopy, has not been reported previously. We demonstrate that a multimodal workflow, incorporating all three methods on adjacent or serial tissue sections, can reveal substantial complementary information about the biochemical and elemental composition of Abeta-plaques. Information revealed by the method includes the relative content and distribution of aggregated protein, total lipid, lipid esters, cholesterol, and metals (Fe, Cu, or Zn). PMID- 28718624 TI - Covalent Enzyme Inhibition through Fluorosulfate Modification of a Noncatalytic Serine Residue. AB - Irreversible enzyme inhibitors and covalent chemical biology probes often utilize the reaction of a protein cysteine residue with an appropriately positioned electrophile (e.g., acrylamide) on the ligand template. However, cysteine residues are not always available for site-specific protein labeling, and therefore new approaches are needed to expand the toolkit of appropriate electrophiles ("warheads") that target alternative amino acids. We previously described the rational targeting of tyrosine residues in the active site of a protein (the mRNA decapping scavenger enzyme, DcpS) using inhibitors armed with a sulfonyl fluoride electrophile. These inhibitors subsequently enabled the development of clickable probe technology to measure drug-target occupancy in live cells. Here we describe a fluorosulfate-containing inhibitor (aryl fluorosulfate probe (FS-p1)) with excellent chemical and metabolic stability that reacts selectively with a noncatalytic serine residue in the same active site of DcpS as confirmed by peptide mapping experiments. Our results suggest that noncatalytic serine targeting using fluorosulfate electrophilic warheads could be a suitable strategy for the development of covalent inhibitor drugs and chemical probes. PMID- 28718625 TI - Controlling the Interfacial Environment in the Electrosynthesis of MnOx Nanostructures for High-Performance Oxygen Reduction/Evolution Electrocatalysis. AB - High-performance, nonprecious metal bifunctional electrocatalysts for the oxygen reduction and evolution reactions (ORR and OER, respectively) are of great importance for rechargeable metal-air batteries and regenerative fuel cells. A comprehensive study based on statistical design of experiments is presented to investigate and optimize the surfactant-assisted structure and the resultant bifunctional ORR/OER activity of anodically deposited manganese oxide (MnOx) catalysts. Three classes of surfactants are studied: anionic (sodium dodecyl sulfate, SDS), non-ionic (t-octylphenoxypolyethoxyethanol, Triton X-100), and cationic (cetyltrimethylammonium bromide, CTAB). The adsorption of surfactants has two main effects: increased deposition current density due to higher Mn2+ and Mn3+ concentrations at the outer Helmholtz plane (Frumkin effect on the electrodeposition kinetics) and templating of the MnOx nanostructure. CTAB produces MnOx with nanoneedle (1D) morphology, whereas nanospherical- and nanopetal-like morphologies are obtained with SDS and Triton, respectively. The bifunctional performance is assessed based on three criteria: OER/ORR onset potential window (defined at 2 and -2 mA cm-2) and separately the ORR and OER mass activities. The best compromise among these three criteria is obtained either with Triton X-100 deposited catalyst composed of MnOOH and Mn3O4 or SDS deposited catalyst containing a combination of alpha- and beta-MnO2, MnOOH, and Mn3O4.The interaction effects among the deposition variables (surfactant type and concentration, anode potential, Mn2+ concentration, and temperature) reveal the optimal strategy for high-activity bifunctional MnOx catalyst synthesis. Mass activities for OER and ORR up to 49 A g-1 (at 1556 mVRHE) and -1.36 A g-1 (at 656 mVRHE) are obtained, respectively. PMID- 28718626 TI - Gold Nanoparticle Loaded Split-DNAzyme Probe for Amplified miRNA Detection in Living Cells. AB - A new class of intracellular nanoprobe, termed AuNP loaded split-DNAzyme probe, was developed to sense miRNA in living cells. Briefly, it consists of an AuNP and substrates hybridized with two half of split DNAzymes. In the absence of target miRNA, the split DNAzymes form an inactive DNAzyme motif with their substrate through partial paring at the end of each strand, and the fluorescence is quenched. Inside the cells, the target miRNA binds with both of the two half of split DNAzymes, forming the active secondary structure in the catalytic cores, which can cleave the substrates, resulting in the rupture of the substrate and recovery of the fluorescence. Meanwhile, the target is released and binds to another inactive DNAzyme motif to drive another cycle of activation. During the cyclic process, a very small number of target miRNAs can initiate the cleavage of many fluorophore-labeled substrate strands from AuNP surface, providing an amplified fluorescent signal of the target miRNA and, thus, offering high detection sensitivity. PMID- 28718628 TI - Synthesis and Electrochemical Reaction of Tin Oxalate-Reduced Graphene Oxide Composite Anode for Rechargeable Lithium Batteries. AB - Unlike for SnO2, few studies have reported on the use of SnC2O4 as an anode material for rechargeable lithium batteries. Here, we first introduce a SnC2O4 reduced graphene oxide composite produced via hydrothermal reactions followed by a layer-by-layer self-assembly process. The addition of rGO increased the electric conductivity up to ~10-3 S cm-1. As a result, the SnC2O4-reduced graphene oxide electrode exhibited a high charge (oxidation) capacity of ~1166 mAh g-1 at a current of 100 mA g-1 (0.1 C-rate) with a good retention delivering approximately 620 mAh g-1 at the 200th cycle. Even at a rate of 10 C (10 A g-1), the composite electrode was able to obtain a charge capacity of 467 mAh g-1. In contrast, the bare SnC2O4 had inferior electrochemical properties relative to those of the SnC2O4-reduced graphene oxide composite: ~643 mAh g-1 at the first charge, retaining 192 mAh g-1 at the 200th cycle and 289 mAh g-1 at 10 C. This improvement in electrochemical properties is most likely due to the improvement in electric conductivity, which enables facile electron transfer via simultaneous conversion above 0.75 V and de/alloy reactions below 0.75 V: SnC2O4 + 2Li+ + 2e- > Sn + Li2C2O4 + xLi+ + xe- -> LixSn on discharge (reduction) and vice versa on charge. This was confirmed by systematic studies of ex situ X-ray diffraction, transmission electron microscopy, and time-of-flight secondary-ion mass spectroscopy. PMID- 28718627 TI - Structural Basis for Interaction of the Tandem Zinc Finger Domains of Human Muscleblind with Cognate RNA from Human Cardiac Troponin T. AB - The human muscleblind-like proteins (MBNL) regulate tissue-specific splicing by targeting cardiac troponin T and other pre-mRNAs; aberrant targeting of CUG and CCUG repeat expansions frequently accompanies the neuromuscular disease myotonic dystrophy. We show, using biolayer interferometry (Octet) and NMR spectroscopy, that the zinc finger domains of MBNL isoform 1 (MBNL1) are necessary and sufficient for binding CGCU sequences within the pre-mRNA of human cardiac troponin T. Protein constructs containing zinc fingers 1 and 2 (zf12) and zinc fingers 3 and 4 (zf34) of MBNL1 each fold into a compact globular tandem zinc finger structure that participates in RNA binding. NMR spectra show that the stoichiometry of the interaction between zf12 or zf34 and the CGCU sequence is 1:1, and that the RNA is single-stranded in the complex. The individual zinc fingers within zf12 or zf34 are nonequivalent: the primary RNA binding surface is formed in each pair by the second zinc finger (zf2 or zf4), which interacts with the CGCU RNA sequence. The NMR structure of the complex between zf12 and a 15 base RNA of sequence 95GUCUCGCUUUUCCCC109, containing a single CGCU element, shows the single-stranded RNA wrapped around zf2 and extending to bind to the C terminal helix. Bases C101, U102, and U103 make well-defined and highly ordered contacts with the protein, whereas neighboring bases are less well-ordered in the complex. Binding of the MBNL zinc fingers to cardiac troponin T pre-mRNA is specific and relatively simple, unlike the complex multiple dimer-trimer stoichiometries postulated in some previous studies. PMID- 28718629 TI - Hadamard-Transform Fluorescence Excitation-Emission-Matrix Spectroscopy. AB - We present a fluorescence excitation-emission-matrix spectrometer with superior data acquisition rates over previous instruments. Light from a white light emitting diode (LED) source is dispersed onto a digital micromirror array (DMA) and encoded using binary n-size Walsh functions ("barcodes"). The encoded excitation light is used to irradiate the liquid sample and its fluorescence is dispersed and detected using a conventional array spectrometer. After exposure to excitation light encoded in n different ways, the 2-dimensional excitation emission-matrix (EEM) spectrum is obtained by inverse Hadamard transformation. Using this technique we examined the kinetics of the fluorescence of rhodamine B as a function of temperature and the acid-driven demetalation of chlorophyll-a into pheophytin-a. For these experiments, EEM spectra with 31 excitation channels and 2048 emission channels were recorded every 15 s. In total, data from over 3000 EEM spectra were included in this report. It is shown that the increase in data acquisition rate can be as high as [{n(n + 1)}/2]-fold over conventional EEM spectrometers. Spectral acquisition rates of more than two spectra per second were demonstrated. PMID- 28718630 TI - Designed Formulation of Se-Impregnated N-Containing Hollow Core Mesoporous Shell Carbon Spheres: Multifunctional Potential Cathode for Li-Se and Na-Se Batteries. AB - Nitrogen-containing carbon spheres with hollow core and mesoporous shell (NHCS), capable of confining Se at levels as high as 72 wt % has been demonstrated to exhibit appreciable electrochemical behavior with 52 and 61 wt % Se loading. In particular, 52 wt % Se confined NHCS cathode exhibits 265 mAh/g at 10C rate and retains 75% of initial capacity at 2C rate up to 10 000 cycles with an insignificant decay of 0.0025% per cycle, which is an ever first report on the extended cycle life of Li-Se batteries. Due to the negligible difference found between the transport kinetics of Se and that of Li2Se, irrespective of the cycling rate, 52 wt % Se @ NHCS performs better at high rates. Furthermore, capacity is governed by the extent of utilization of confined Se and cycle life by the extent of mitigation of volume expansion. Accordingly, rate capability studies recommend 52 wt % Se loaded cathode above 2C rate and 61 wt % Se loading up to 2C rate. Furthermore, NHCS/Se-52 cathode demonstrates suitability for Na-Se batteries by exhibiting 339 and 219 mAh/g of capacity at rates of C/5 and 2C rates, respectively. NHCS with select Se concentration could thus be exploited for multifunctional cathode behavior in Li-Se and Na-Se systems. PMID- 28718631 TI - A Copper(II)-Paddlewheel Metal-Organic Framework with Exceptional Hydrolytic Stability and Selective Adsorption and Detection Ability of Aniline in Water. AB - Copper(II)-paddlewheel-based metal-organic frameworks (CP-MOFs) represent a unique subclass of MOFs with highly predictable porous structures, facile syntheses, and functional open metal sites. However, the lack of high hydrolytic stability is an obstacle for CP-MOFs in many practical applications. In this work, we report a new CP-MOF, [Cu4(tdhb)] (BUT-155), which is constructed from a judiciously designed carboxylate ligand with high coordination connectivity (octatopic), abundant hydrophobic substituents (six methyl groups), and substituent constrained geometry (tetrahedral backbone), tdhb8- [H8tdhb = 3,3',5,5'-tetrakis(3,5-dicarboxyphenyl)-2,2',4,4',6,6'-hexamethylbiphenyl)]. BUT 155 shows high porosity with a Brunauer-Emmett-Teller surface area of 2070 m2/g. Quite interestingly, this CP-MOF retains its structural integrity after being treated in water for 10 days at room temperature or in boiling water for 24 h. To the best of our knowledge, BUT-155 represents the first CP-MOF that is demonstrated to retain its structural integrity in boiling water. The high hydrolytic stability of BUT-155 allowed us to carry out adsorption studies of water vapor and aqueous organic pollutants on it. Water-vapor adsorption reveals a sigmoidal isotherm and a high uptake (46.7 wt %), which is highly reversible and regenerable. In addition, because of the availability of soft-acid-type open Cu(II) sites, BUT-155 shows a high performance for selective adsorption of soft base-type aniline over water or phenol, and a naked-eye detectable color change for the MOF sample accompanies this. The adsorption selectivity and high adsorption capacity of aniline in BUT-155 are also well-interpreted by single crystal structures of the water- and aniline-included phases of BUT-155. PMID- 28718632 TI - Systematic Approaches to Efficiently Produce 2,3-Butanediol in a Marine Cyanobacterium. AB - Cyanobacteria have attracted significant interest as a platform for renewable production of fuel and feedstock chemicals from abundant atmospheric carbon dioxide by way of photosynthesis. While great strides have been made in developing this technology in freshwater cyanobacteria, logistical issues remain in scale-up. Use of the cyanobacterium Synechococcus sp. PCC 7002 (7002) as a chemical production chassis could address a number of these issues given the higher tolerance to salt, light, and heat as well as the fast growth rate of 7002 in comparison to traditional model cyanobacteria such as Synechococcus elongatus PCC 7942 and Synechocystis sp. PCC 6803. However, despite growing interest, the development of genetic engineering tools for 7002 continues to lag behind those available for model cyanobacterial strains. In this work we demonstrate the systematic development of a 7002 production strain for the feedstock chemical 2,3 butanediol (23BD). We expand the range of tools available for use in 7002 by identifying and utilizing new integration sites for homologous recombination, demonstrating the inducibility of theophylline riboswitches, and screening a set of isopropyl beta-d-1-thiogalactopyranoside (IPTG) inducible promoters. We then demonstrate improvements of 23BD production with the systematic screening of different conditions including: operon arrangement and copy number, light strength, inducer concentration, cell density at the time of induction, and nutrient concentration. Final production tests yielded titers of 1.6 g/L 23BD after 16 days at a rate of 100 mg/L/day. This work represents great strides in the development of 7002 as an industrially relevant production host. PMID- 28718633 TI - TiO2 Nanorods Decorated with Pd Nanoparticles for Enhanced Liquefied Petroleum Gas Sensing Performance. AB - Development of highly sensitive and selective semiconductor-based metal oxide sensor devices to detect toxic, explosive, flammable, and pollutant gases is still a challenging research topic. In the present work, we systematically enhanced the liquefied petroleum gas (LPG) sensing performance of chemical bath deposited TiO2 nanorods by decorating Pd nanoparticle catalyst. Surface morphology with elemental mapping, crystal structure, composition and oxidation states, and surface area measurements of pristine TiO2 and Pd:TiO2 nanorods was examined by high resolution transmission electron microscopy with energy dispersive X-ray spectroscopy, X-ray diffraction, X-ray photoelectron spectroscopy, and nitrogen adsorption-desorption characterization techniques. LPG sensing performance of pristine TiO2 and Pd:TiO2 nanorods was investigated in different LPG concentration and operating temperature ranges. The LPG response of 21% for pristine TiO2 nanorods is enhanced to 49% after Pd catalyst decoration with reasonably fast response and recovery times. Further, the sensor exhibited long-term stability, which could be due to the strong metal support (Pd:TiO2) interaction and catalytic properties offered by the Pd nanoparticle catalyst. The work described herein demonstrates a general and scalable approach that provides a promising route for rational design of variety of sensor devices for LPG detection. PMID- 28718634 TI - Porous Uranyl Borophosphates with Unique Three-Dimensional Open-Framework Structures. AB - Two novel alkali-metal uranyl borophosphates have been prepared and characterized for the first time, namely, K5(UO2)2[B2P3O12(OH)]2(OH)(H2O)2 and K2(UO2)12[B(H2PO4)4](PO4)8(OH)(H2O)6 denoted as KUPB1 and KUPB2, respectively. KUPB1 was obtained hydrothermally at 220 degrees C and crystallizes in a monoclinic structure in the chiral space group P21. The unit cell parameters of KUPB1 are a = 6.7623(2) A, b = 19.5584(7) A, c = 11.0110(4) A, alpha = gamma = 90 degrees , beta = 95.579(3) degrees , and V = 1449.42(8) A3. It features a unique three-dimensional (3D) open-framework structure, composed of two corner-sharing linked one-dimensional (1D) anionic borophosphates (BP), [B2P3O13]5-, along the a axis and uranyl phosphate (UP), [(UO2)(PO4)3]7-, chains along the c axis, further bridged by PO4 tetrahedra. Multi-intersectional channels can be observed within the structure, in which the largest 11-ring (11-R) tunnel size is ~7.0 A * 8.8 A. Its simplified framework can be described as a new 4-nodal net topological type with a point symbol of {4.84.10}{42.6}2{43.62.83.102}{82.10}. By modification of the synthetic conditions of KUPB1 through an increase in the amount of H3BO3 as flux 4-fold and a reduction of water as the reaction medium, the novel compound KUPB2 is generated. The unit cell parameters of KUPB2 are a = b = 21.8747(3) A, c = 7.0652(2) A, alpha = beta = gamma = 90 degrees , and V = 3380.72(12) A3. KUPB2 crystallizes in a tetragonal structure in the polar space group I42m, and its structure is based on a highly complex 3D framework, {(UO2)12[B(PO4)4](PO4)8}9-, in which 1D 8-R UP [(UO2)(PO4)]- tubes can be observed along the c axis. The [(UO2)(PO4)]- tubes consist of three uranyl chains along the c axis, which are linked alternately by [PO4]3- tetrahedra. Those isolated 1D [(UO2)(PO4)]- tubes are further bridged through [(UO2)4B(PO4)4]- clusters, forming an exceptional 3D open-framework structure. Its simplified cation network is a new 5-nodal net topological type such as {32.43.5.62.7.8}8{34.45.54.62}8{4.62.83}4{42.6}4{44.62}. Their facile hydrothermal synthetic routes, porous structure topology, thermal stability, and Raman spectroscopy properties are reported and discussed. PMID- 28718635 TI - Undervalued N3 Coordination Revealed in the Cisplatin Complex with 2' Deoxyadenosine-5'-monophosphate by a Combined IRMPD and Theoretical Study. AB - The complex obtained by the reaction of cisplatin and 2'-deoxyadenosine-5' monophosphate (5'-dAMP) in water has been isolated and detected by electrospray ionization mass spectrometry. The so-formed cis-[PtCl(NH3)2(5'-dAMP)]+ complex has been studied in detail by infrared multiple photon dissociation (IRMPD) spectroscopy in two spectral ranges, namely, 700-1900 and 2800-3800 cm-1, backed by quantum-chemical calculations at the B3LYP/LACV3P/6-311G** level of theory. In agreement with the computational results, the vibrational spectroscopic characterization of cis-[PtCl(NH3)2(5'-dAMP)]+ shows that the sampled ionic population comprises two major isomers, differentiated in the X-H stretching region by their distinct fragmentation patterns. One of these species presents coordination of the platinum moiety at the N3 position of adenine, whereas in the second one, platinum is bound at the N1 position of adenine. IRMPD kinetics have allowed an estimation of their relative proportions. Surprisingly, the most abundant component of cis-[PtCl(NH3)2(5'-dAMP)]+ is the N3 isomer, although it is slightly less stable than the other potential isomers in the gas phase. In contrast, the lowest-energy species, namely, the one showing cisplatin binding to the N7 position of adenine, seems to be the one less represented in the sampled ionic population. These findings suggest that the reaction of cisplatin with 5' dAMP is governed by the kinetics of the process occurring in solution rather than by the thermodynamic factors. PMID- 28718636 TI - Long Chain Alkyl Esters of Hydroxycinnamic Acids as Promising Anticancer Agents: Selective Induction of Apoptosis in Cancer Cells. AB - Cancer is the major cause of morbidity and mortality worldwide. Hydroxycinnamic acids (HCAs) are naturally occurring compounds and their alkyl esters may possess enhanced biological activities. We evaluated C4, C14, C16, and C18 alkyl esters of p-coumaric, ferulic, sinapic, and caffeic acids (19 compounds) for their cytotoxic activity against four human cancer cells and also examined their effect on cell cycle alteration and apoptosis induction. The tetradecyl (1c) and hexadecyl (1d) esters of p-coumaric acid and tetradecyl ester of caffeic acid (4c), but not the parental HCAs, were selectively effective against MOLT-4 (human lymphoblastic leukemia) cells with IC50 values of 0.123 +/- 0.012, 0.301 +/- 0.069 and 1.0 +/- 0.1 MUM, respectively. Compounds 1c, 1d, and 4c significantly increased apoptotic cells in sub-G1 phase and activated the caspase-3 enzyme in MOLT-4 cells. Compound 1c was 15.4 and 23.6 times more potent than doxorubicin and cisplatin, respectively, against the drug resistant MES-SA-DX5 uterine sarcoma cells. These p-coumarate esters were several times less effective against NIH/3T3 fibroblast cells. Docking studies showed that 1c may cause cytotoxicity by interaction with carbonic anhydrase IX. In conclusion, long chain alkyl esters of p-coumaric acid are promising scaffolds for selective apoptosis induction in cancer cells. PMID- 28718637 TI - Non-Gaussian Brownian Diffusion in Dynamically Disordered Thermal Environments. AB - In this article, we suggest simple alternatives to the methods recently used by Jain and Sebastian [ J. Phys. Chem. B 2016 , 120 , 3988 ] and Chechkin et al. [ Phys. Rev. X 2017 , 7 , 021002 ] to treat a model of non-Gaussian Brownian diffusion based on the dynamics of a particle governed by Ornstein-Uhlenbeck modulated white noise. In addition to substantiating these authors' earlier findings (which show that a particle can execute a simple random walk even when the distribution of its displacements deviates from Gaussianity), our approach identifies another process, two-state white noise, that exhibits the same "anomalous" Brownian behavior. Indeed, we find that the modulation of white noise by any stochastic process whose time correlation function decays exponentially is likely to behave similarly, suggesting that the occurrence of such behavior can be widespread and commonplace. PMID- 28718638 TI - Semisynthesis and Kappa-Opioid Receptor Activity of Derivatives of Columbin, a Furanolactone Diterpene. AB - Columbin (1) is a furanolactone diterpene isolated from the roots of Jateorhiza and Tinospora species. These species generally grow in Asia and Africa and have been used in folk medicine for their apparent analgesic and antipyretic activities. Columbin (1) is of particular interest due to its structural similarity to the known kappa-opioid receptor (KOR) agonist salvinorin A. Given that the KOR is of interest in the study of many serious diseases, such as anxiety, depression, and drug addiction, obtaining natural or semisynthetic molecules with KOR activity recently has gained much interest. For this reason, in the present study, derivatives of 1 were designed and synthesized using known structure-activity relationships of salvinorin A at KORs. The structures of the columbin analogues prepared were elucidated by NMR spectroscopy and mass spectroscopy, and their KOR activity was investigated in vitro by inhibition of forskolin-induced cAMP accumulation. Slight improvements in KOR activity were observed in columbin derivatives over their parent compound. However, despite the structural similarities to salvinorin A, neither columbin (1) nor its derivatives were potent KOR ligands. This work represents not only the first evaluation of columbin (1) at the KOR but also one of the first works to explore synthetic strategies that are tolerated on the columbin core. PMID- 28718639 TI - Regioselective Synthesis, NMR, and Crystallographic Analysis of N1-Substituted Pyrazoles. AB - A systematic study of the N-substitution reactions of 3-substituted pyrazoles under basic conditions has been undertaken. Regioselective N1-alkylation, arylation, and -heteroarylation of 3-substituted pyrazoles have been achieved using K2CO3-DMSO. The regioselectivity is justified by the DFT calculations at the B3LYP/6-31G**(d) level. A consistent steric effect on chemical shift has been observed for N-alkyl pyrazole analogues. Twenty-five X-ray crystallographic structures have been obtained to confirm the regiochemistry of the major products. PMID- 28718640 TI - SmI2(H2O)n Reduction of Electron Rich Enamines by Proton-Coupled Electron Transfer. AB - Samarium diiodide in the presence of water and THF (SmI2(H2O)n) has in recent years become a versatile and useful reagent, mainly for reducing carbonyl-type substrates. This work reports the reduction of several enamines by SmI2(H2O)n. Mechanistic experiments implicate a concerted proton-coupled electron transfer (PCET) pathway, based on various pieces of evidence against initial outer-sphere electron transfer, proton transfer, or substrate coordination. A thermochemical analysis indicates that the C-H bond formed in the rate-determining step has a bond dissociation free energy (BDFE) of ~32 kcal mol-1. The O-H BDFE of the samarium aquo ion is estimated to be 26 kcal mol-1, which is among the weakest known X-H bonds of stable reagents. Thus, SmI2(H2O)n should be able to form very weak C-H bonds. The reduction of these highly electron rich substrates by SmI2(H2O)n shows that this reagent is a very strong hydrogen atom donor as well as an outer-sphere reductant. PMID- 28718641 TI - In-Silico Skin Model: A Multiscale Simulation Study of Drug Transport. AB - Accurate in-silico models are required to predict the release of drug molecules through skin in order to supplement the in-vivo experiments for faster development/testing of drugs. The upper most layer of the skin, stratum corneum (SC), offers the main resistance for permeation of actives. Most of the SC's molecular level models comprise cholesterol and phospholipids only, which is far from reality. In this study we have implemented a multiscale modeling framework to obtain the release profile of three drugs, namely, caffeine, fentanyl, and naphthol, through skin SC. We report for the first time diffusion of drugs through a realistic skin molecular model comprised of ceramides, cholesterol, and free fatty acid. The diffusion coefficients of drugs in the SC lipid matrix were determined from multiple constrained molecular dynamics simulations. The calculated diffusion coefficients were then used in the macroscopic models to predict the release profiles of drugs through the SC. The obtained release profiles were in good agreement with available experimental data. The partition coefficient exhibits a greater effect on the release profiles. The reported multiscale modeling framework would provide insight into the delivery mechanisms of the drugs through the skin and shall act as a guiding tool in performing targeted experiments to come up with a suitable delivery system. PMID- 28718643 TI - Correction to "Chemical Dynamic Thermodynamic Resolution and S/R Interconversion of Unprotected Unnatural Tailor-made alpha-Amino Acids". PMID- 28718642 TI - Predictive Model for Site-Selective Aryl and Heteroaryl C-H Functionalization via Organic Photoredox Catalysis. AB - Direct C-H functionalization of aromatic compounds is a useful synthetic strategy that has garnered much attention because of its application to pharmaceuticals, agrochemicals, and late-stage functionalization reactions on complex molecules. On the basis of previous methods disclosed by our lab, we sought to develop a predictive model for site selectivity and extend this aryl functionalization chemistry to a selected set of heteroaromatic systems commonly used in the pharmaceutical industry. Using electron density calculations, we were able to predict the site selectivity of direct C-H functionalization in a number of heterocycles and identify general trends observed across heterocycle classes. PMID- 28718645 TI - Fourfold-Interpenetrated MOF [Ni(pybz)2] as Coating Material in Gas Chromatographic Capillary Column for Separation. AB - A fourfold interpenetrated diamond-like topological metal-organic framework (MOF), Ni(pybz)2 [pybz = 4-(4-pyridyl)benzoate] was successfully synthesized and fully characterized. This MOF can serve as coating material in gas chromatographic capillary column for the separation of some low boiling point essential oils. The prepared columns have good recognition ability and excellent selectivity toward a series of organic compounds, including alcohols, aldehydes, ketones, carboxylic acid, ethers, ester, and amines. It is found that the strained metal sites, van der Waals interactions, C-H...pi attraction, and weak nonclassical hydrogen bond contribute to the recognition and selectivity of prepared columns. The grand canonical Monte Carlo technique is used to simulate the interactions of the adsorbates with MOF. The calculated van der Waals energies agree with the results of gas chromatographic separation. PMID- 28718644 TI - General and Direct Method for Preparing Oligonucleotide-Functionalized Metal Organic Framework Nanoparticles. AB - Metal-organic frameworks (MOFs) are a class of modular, crystalline, and porous materials that hold promise for storage and transport of chemical cargoes. Though MOFs have been studied in bulk forms, ways of deliberately manipulating the external surface functionality of MOF nanoparticles are less developed. A generalizable approach to modify their surfaces would allow one to impart chemical functionality onto the particle surface that is independent of the bulk MOF structure. Moreover, the use of a chemically programmable ligand, such as DNA, would allow for the manipulation of interparticle interactions. Herein, we report a coordination chemistry-based strategy for the surface functionalization of the external metal nodes of MOF nanoparticles with terminal phosphate-modified oligonucleotides. The external surfaces of nine distinct archetypical MOF particles containing four different metal species (Zr, Cr, Fe, and Al) were successfully functionalized with oligonucleotides, illustrating the generality of this strategy. By taking advantage of the programmable and specific interactions of DNA, 11 distinct MOF particle-inorganic particle core-satellite clusters were synthesized. In these hybrid nanoclusters, the relative stoichiometry, size, shape, and composition of the building blocks can all be independently controlled. This work provides access to a new set of nucleic acid-nanoparticle conjugates, which may be useful as programmable material building blocks and as probes for measuring and manipulating intracellular processes. PMID- 28718646 TI - Exploring the Relationship between Nicotinic Acetylcholine Receptor Ligand Size, Efficiency, Efficacy, and C-Loop Opening. AB - Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels mediating fundamental physiological activities in the nervous system and have become important targets for drug design. For a long time, the acetylcholine binding protein (AChBP) has been used as a surrogate to study the nAChR structure function. Taking advantage of more than 100 AChBP crystal structures in the Protein DataBank (PDB), we explored the relationship between the size, efficiency, and efficacy of nAChR ligands and the C-loop movement. We found that the size of the ligand is correlated with the opening of the C-loop, which can be used in selecting AChBP crystal structures with appropriate C-loop opening to be used for nAChR ligand docking. Ligand size and C-loop opening are reversely correlated with the ligand efficiency rather than the binding affinity. Ligand efficiency could be accurately predicted using simple computational docking, giving a correlation coefficients (R2) up to 0.73. The efficacy of nAChR ligands might be related to ligand size, C-loop opening, and ligand efficiency. Results from this study are useful for engineering the binding affinity and efficacy of nAChR ligands. PMID- 28718647 TI - FeCl3-Catalyzed Allylation Reactions onto 3-Hydroxy-2-oxindoles: Formal Total Syntheses of Bis-cyclotryptamine Alkaloids, (+/-)-Chimonanthine, and (+/-) Folicanthine. AB - An FeCl3-catalyzed efficient strategy for the allylation reactions of 3-hydroxy-2 oxindoles with allyltrimethylsilane has been developed. The reaction affords a variety of 2-oxindoles having quaternary center at the pseudobenzylic position in an operationally simple and inexpensive procedure. Control experiments using enantioenriched 3-hydroxy-2-oxindole show that the reaction proceeds through in situ generated 2H-indol-2-one (8). The methodology presents an efficient and concise access to the pyrroloindoline alkaloids (+/-)-deoxyeseroline (1a), (+/-) esermethole (1b), (+/-)-physostigmine (1c), (+/-)-phenserine (1d), and (+/-) physovenine (1e). Eventually, we extrapolated the scope of this methodology to the formal total syntheses of dimeric cyclotyrptamine alkaloids (+/-) chimonanthine (3a), (+/-)-folicanthine (3c), and (+/-)-calycanthine (4). PMID- 28718648 TI - Multi-imaging of Cytokinin and Abscisic Acid on the Roots of Rice (Oryza sativa) Using Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry. AB - Plant hormones act as important signaling molecules that regulate responses to abiotic stress as well as plant growth and development. Because their concentrations of hormones control the physiological responses in the target tissue, it is important to know the distributions and concentrations in the tissues. However, it is difficult to determine the hormone concentration on the plant tissue as a result of the limitations of conventional methods. Here, we report the first multi-imaging of two plant hormones, one of cytokinin [i.e., trans-zeatin (tZ)] and abscisic acid (ABA) using a new technology, matrix assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) imaging. Protonated signals of tZ (m/z 220.1) and ABA (m/z 265.3) were chosen on longitudinal sections of rice roots for MS imaging. tZ was broadly distributed about 40 mm behind the root apex but was barely detectable at the apex, whereas ABA was mainly detected at the root apex. Multi-imaging using MALDI-TOF-MS enabled the visualization of the localization and quantification of plant hormones. Thus, this tool is applicable to a wide range of plant species growing under various environmental conditions. PMID- 28718649 TI - Ensemble and Single Particle Fluorescence Characterization of Dye-Labeled Cellulose Nanocrystals. AB - Cellulose nanocrystals (CNCs) have been covalently labeled with both fluorescein and rhodamine and studied by a combination of UV-vis absorption spectroscopy and ensemble and single molecule fluorescence spectroscopy. For all samples, the fluorescence anisotropy and lifetimes were consistent with effects expected for covalently bound dye molecules. Low dye loading levels (~0.1 dye/particle) were estimated for the fluorescein-labeled CNC which coupled with the strong pH dependence make this a less suitable fluorophore for most applications. Rhodamine labeled CNCs were prepared from both sulfated and carboxylated CNCs and had loading levels that varied from 0.25 to ~15 dye molecules/CNC. For the sulfated samples, the absorption due to (nonfluorescent) dimeric dye increased with dye loading; in contrast, the carboxylated sample, which had the highest rhodamine content, had a low dimer yield. Single particle fluorescence studies for two of the rhodamine-labeled CNCs demonstrated that individual particles are readily detected by their stepwise blinking/bleaching behavior and by polarization effects. Overall, the results indicate the importance of understanding the effects of loading on dye photophysics to select an optimal dye concentration to maximize sensitivity while minimizing the effect of the dye on the CNC behavior. The results also demonstrate that CNCs with relatively low dye loadings (e.g., ~1 dye/particle) are readily detectable by fluorescence and should be adequate for use in fluorescence-based biological assays or to probe the distribution of CNCs in composite materials. PMID- 28718650 TI - Self-Regulated Nanoparticle Assembly at Liquid/Liquid Interfaces: A Route to Adaptive Structuring of Liquids. AB - The controlled structuring of liquids into arbitrary shapes can be achieved in biphasic liquid media using the interfacial assemblies of nanoparticle surfactants (NP-surfactants), that consist of a polar nanoparticle "head group" bound to one or more hydrophobic polymer "tails". The nonequilibrium shapes of the suspended liquid phase can be rendered permanent by the jamming of the NP surfactants formed and assembled at the interface between the liquids as the system attempts to minimize the interfacial area between the liquids. While critical to the structuring process, little is known of the dynamic mechanical properties of the NP-surfactant monolayer at the interface as it is dictated by the characteristics of the component, including NP size and concentration and the molecular weight and concentration of polymers bound to the NPs. Here we provide the first comprehensive understanding of the dynamic mechanical character of two dimensional NP-surfactant assemblies at liquid/liquid interfaces. Our results indicate that the dynamics of NP-polymer interactions are self-regulated across multiple time scales and are associated with specific mesoscale interactions between self-similar and cross-complementary components. Furthermore, the mechanical properties of the NP-surfactant monolayer are tunable over a broad range and deterministic on the basis of those component inputs. This control is key to tailoring the functional attributes of the reconfigurable structured liquids to suit specific applications. PMID- 28718651 TI - Organization of Microgels at the Air-Water Interface under Compression: Role of Electrostatics and Cross-Linking Density. AB - Poly(N-isopropylacrylamide) (pNIPAM) microgels are soft and deformable particles, which can adsorb at liquid interfaces. In the present paper, we study the two dimensional organization of charged and quasi-neutral microgels with different cross-linking densities, under compression at the air-water interface and the transfer of the microgel monolayer onto a solid substrate at different surface pressures. At low cross-linking densities, the microgels form highly ordered hexagonal lattices on the solid substrate over large areas, with a unique lattice parameter that decreases continuously as the surface pressure increases. We thus prove that the microgel conformation evolves at the air-water interface. The microgels undergo a continuous transition from a highly flattened state at low surface coverage, where the maximal polymer segments are adsorbed at the interface, to entangled flattened microgels, and finally the thickening of the layer up to a dense hydrogel layer of compacted microgels. Moreover, two batches of microgels, with and without charges, are compared. The contribution of electrostatic interactions is assessed via changing the charge density of the microgels or modulating the Debye length. In both cases, electrostatics does not change the lattice parameter, meaning that, despite the microgel different swelling ratio, charges do not affect neither interactions between particles at the interface nor microgels adsorption. Conversely, the cross-linking density has a strong impact on microgel packing at the interface: increasing the cross linking density strongly decreases the extent of microgel flattening and promotes the occurrence of coexisting hexagonally ordered domains with different lattice parameters. PMID- 28718652 TI - Correction to Receptor and Microenvironment Dual-Recognizable Nanogel for Targeted Chemotherapy of Highly Metastatic Malignancy. PMID- 28718653 TI - Vertical versus Lateral Two-Dimensional Heterostructures: On the Topic of Atomically Abrupt p/n-Junctions. AB - The key appeal of two-dimensional (2D) materials such as graphene, transition metal dichalcogenides (TMDs), or phosphorene for electronic applications certainly lies in their atomically thin nature that offers opportunities for devices beyond conventional transistors. It is also this property that makes them naturally suited for a type of integration that is not possible with any three dimensional (3D) material, that is, forming heterostructures by stacking dissimilar 2D materials together. Recently, a number of research groups have reported on the formation of atomically sharp p/n-junctions in various 2D heterostructures that show strong diode-type rectification. In this article, we will show that truly vertical heterostructures do exhibit much smaller rectification ratios and that the reported results on atomically sharp p/n junctions can be readily understood within the framework of the gate and drain voltage response of Schottky barriers that are involved in the lateral transport. PMID- 28718654 TI - Rauvomines A and B, Two Monoterpenoid Indole Alkaloids from Rauvolfia vomitoria. AB - Two unusual normonoterpenoid indole alkaloids rauvomine A (1) and rauvomine B (2), together with two known compounds peraksine (3) and alstoyunine A (4), were isolated from the aerial parts of Rauvolfia vomitoria. The structures with absolute configurations of 1 and 2 were elucidated by spectroscopic analysis, single-crystal X-ray diffraction, and electronic circular dichroism (ECD) calculations. Compound 2 is a novel C18 normonoterpenoid indole alkaloid with a substituted cyclopropane ring that forms an unusual 6/5/6/6/3/5 hexcyclic rearranged ring system. The plausible biogenetic pathways of 1 and 2 were proposed. Compound 2 exhibited significant anti-inflammatory activity. PMID- 28718655 TI - Palladium-Catalyzed C-H Bond Activation by Using Iminoquinone as a Directing Group and an Internal Oxidant or a Co-oxidant: Production of Dihydrophenanthridines, Phenanthridines, and Carbazoles. AB - A palladium-catalyzed C-H bond activation reaction, via a redox-neutral pathway, for the preparation of dihydrophenanthridine, phenanthridine, and carbazole derivatives from biaryl 2-iminoquinones is developed. The preinstalled iminoquinone was designed to act as a directing group for ortho C-H activation and an internal oxidant or a co-oxidant. This catalysis proceeded through the following sequence: C-H bond activation, coordination and insertion of activated olefins, beta-hydride elimination, H-shift, insertion, and protonation or beta hydride elimination. In addition, carbazoles can be prepared efficiently by using this method without the addition of external oxidants. PMID- 28718656 TI - Intermediate-Valence Ytterbium Compound Yb4Ga24Pt9: Synthesis, Crystal Structure, and Physical Properties. AB - The title compound was synthesized by a reaction of the elemental educts in a corundum crucible at 1200 degrees C under an Ar atmosphere. The excess of Ga used in the initial mixture served as a flux for the subsequent crystal growth at 600 degrees C. The crystal structure of Yb4Ga24Pt9 was determined from single crystal X-ray diffraction data: new prototype of crystal structure, space group C2/m, Pearson symbol mS74, a = 7.4809(1) A, b = 12.9546(2) A, c = 13.2479(2) A, beta = 100.879(1) degrees , V = 1260.82(6) A3, RF = 0.039 for 1781 observed reflections and 107 variable parameters. The structure is described as an ABABB stacking of two slabs with trigonal symmetry and compositions Yb4Ga6 (A) and Ga12Pt6 (B). The hard X-ray photoelectron spectrum (HAXPES) of Yb4Ga24Pt9 shows both Yb2+ and Yb3+ contributions as evidence of an intermediate valence state of ytterbium. The evaluated Yb valence of ~2.5 is in good agreement with the results obtained from the magnetic susceptibility measurements. The compound is a bad metallic conductor. PMID- 28718657 TI - Bitter taste of Brassica vegetables: The role of genetic factors, receptors, isothiocyanates, glucosinolates, and flavor context. AB - It is well known that consumption of Brassica vegetables has beneficial effect on human's health. The greatest interest is focused on glucosinolates and their hydrolysis products isothiocyanates, due to their potential as cancer preventing compounds. Brassica vegetables are also rich in flavor compounds belonging to many chemical groups. The main sensory sensation related to these vegetable is their characteristic sharp and bitter taste, and unique aroma. Because of these features this group of vegetables is often rejected by consumers. Interestingly, for some people unpleasant sensations are not perceived, suggesting a potential role of inter-individual variability in bitter taste perception and sensibility. Receptors responsible for bitter sensation with the emphasis on Brassica are reviewed, as well as genetic predisposition for bitterness perception by consumers. Also the role of glucosinolates and isothiocyanates as compounds responsible for bitter taste is discussed based on data from the field of food science and molecular biology. Isothiocyanates are shown in broaded context of flavor compounds also contributing to the aroma of Brassica vegetables. PMID- 28718658 TI - The effect of nurse-to-patient ratios on nurse-sensitive patient outcomes in acute specialist units: a systematic review and meta-analysis. AB - BACKGROUND: Nurses are pivotal in the provision of high quality care in acute hospitals. However, the optimal dosing of the number of nurses caring for patients remains elusive. In light of this, an updated review of the evidence on the effect of nurse staffing levels on patient outcomes is required. AIM: To undertake a systematic review and meta-analysis examining the association between nurse staffing levels and nurse-sensitive patient outcomes in acute specialist units. METHODS: Nine electronic databases were searched for English articles published between 2006 and 2017. The primary outcomes were nurse-sensitive patient outcomes. RESULTS: Of 3429 unique articles identified, 35 met the inclusion criteria. All were cross-sectional and the majority utilised large administrative databases. Higher staffing levels were associated with reduced mortality, medication errors, ulcers, restraint use, infections, pneumonia, higher aspirin use and a greater number of patients receiving percutaneous coronary intervention within 90 minutes. A meta-analysis involving 175,755 patients, from six studies, admitted to the intensive care unit and/or cardiac/cardiothoracic units showed that a higher nurse staffing level decreased the risk of inhospital mortality by 14% (0.86, 95% confidence interval 0.79 0.94). However, the meta-analysis also showed high heterogeneity (I2=86%). CONCLUSION: Nurse-to-patient ratios influence many patient outcomes, most markedly inhospital mortality. More studies need to be conducted on the association of nurse-to-patient ratios with nurse-sensitive patient outcomes to offset the paucity and weaknesses of research in this area. This would provide further evidence for recommendations of optimal nurse-to-patient ratios in acute specialist units. PMID- 28718659 TI - Predicting the future with echocardiography: Looking outside the heart? PMID- 28718660 TI - Out, out, damned blind spot! The problem of anxiety with dynamic psychotherapy. AB - OBJECTIVES: This article discusses Lady Macbeth's famous sleepwalking scene from the Shakespearean tragedy, and how it became used as a template for the formulation of obsessive-compulsive disorder. CONCLUSIONS: Psychoanalysis maintained its role in understanding the condition, despite the lack of evidence base and the repeated finding from many therapists of a failure to control symptomatology. It is suggested that psychodynamic psychotherapy suffered from a failure to recognise what components of its practice were aesthetically attractive concepts rather than evidence-based medicine and outcome measures, and is an important issue in considering its future directions. PMID- 28718661 TI - Anxiety and self-care behaviour in patients with chronic systolic heart failure: A multivariate model. AB - BACKGROUND: While comprehensive evidence exists regarding negative effects of depression on self-care behaviours in patients with chronic heart failure (CHF), the relation between anxiety and self-care behaviours in patients with CHF is not clear. The aim of this study was to analyse the interactions between anxiety, depression and self-care behaviours in patients with CHF. METHODS: The self-care behaviour of CHF outpatients was measured using the European Heart Failure Self care Behaviour Scale (EHFScBS). The Patient Health Questionnaire (PHQ) was used to assess anxiety, the PHQ-9 was used to measure depression severity. Differences between patients with and without anxiety were assessed with the respective tests. Associations between anxiety, self-care and other predictors were analysed using linear regressions. RESULTS: Of the 308 participating patients, 35 (11.4%) fulfilled the PHQ criteria for an anxiety disorder. These patients took antidepressants more frequently (11.8% versus 2.3%, p = .02), had had more contacts with their general practitioner within the last year (11.8 +/- 16.1 versus 6.7 +/- 8.6, p = .02), and had a higher PHQ-9 depression score (12.9 +/- 5.7 versus 6.5 +/- 4.7, p < .01) than patients without anxiety disorder. Anxiety and self-care were negatively associated (beta = -0.144, r2 = 0.021, p = 0.015). The explanation of variance was augmented in a multivariate regression with the predictors age, sex, education, living with a partner, and New York Heart Association (NYHA) class ( r2 = 0.098) when anxiety was added ( r2 = 0.112). Depression further increased the explanation of variance (beta = -0.161, r2 = 0.131, p = 0.019). CONCLUSIONS: Anxiety is negatively associated with self-care behaviour in patients with CHF. However, this effect disappears behind the stronger influence of depression on self-care. The consideration of mental comorbidities in patients with CHF is important. PMID- 28718662 TI - Prediction of porosity of food materials during drying: Current challenges and directions. AB - Pore formation in food samples is a common physical phenomenon observed during dehydration processes. The pore evolution during drying significantly affects the physical properties and quality of dried foods. Therefore, it should be taken into consideration when predicting transport processes in the drying sample. Characteristics of pore formation depend on the drying process parameters, product properties and processing time. Understanding the physics of pore formation and evolution during drying will assist in accurately predicting the drying kinetics and quality of food materials. Researchers have been trying to develop mathematical models to describe the pore formation and evolution during drying. In this study, existing porosity models are critically analysed and limitations are identified. Better insight into the factors affecting porosity is provided, and suggestions are proposed to overcome the limitations. These include considerations of process parameters such as glass transition temperature, sample temperature, and variable material properties in the porosity models. Several researchers have proposed models for porosity prediction of food materials during drying. However, these models are either very simplistic or empirical in nature and failed to consider relevant significant factors that influence porosity. In depth understanding of characteristics of the pore is required for developing a generic model of porosity. A micro-level analysis of pore formation is presented for better understanding, which will help in developing an accurate and generic porosity model. PMID- 28718663 TI - Time trends and socioeconomic differences in blood pressure levels: The Northern Sweden MONICA study 1994-2014. AB - Background People with low socioeconomic status have higher blood pressure (BP), increasing their risk of myocardial infarction and stroke. We hypothesized that the gap in systolic (SBP) and diastolic (DBP) BP, according to educational level, has decreased over time but, that economical vulnerability would confer higher BP. Methods A total of 4564 women and 4363 men aged 25-74 years participated in five population-based surveys in the Northern Sweden MONICA study between 1994 and 2014 (participation rate 76.8-62.5%). Results SBP decreased by 10 mmHg in women and 4 mmHg in men, while DBP was unchanged. Treatment with antihypertensives increased in all but the youngest men. The prevalence of BP control in the population (<140/90 mmHg) increased and in 2014 reached 75% among women and 70% among men. The decrease in SBP was more pronounced in people without university education than in people with university education and DBP showed the same pattern, regardless of education. After adjustment for confounding factors, age, male sex, higher body mass index, and being born in a Nordic country were related to higher SBP and DBP. University education was related to lower SBP, while variables mirroring economic vulnerability were not associated with BP levels. Conclusions BP levels as well as the socioeconomic gap in BP has decreased in Sweden but people with a lower level of education still have higher SBP. Lacking economic resources is not associated with high BP. PMID- 28718664 TI - Short-term complications for percutaneous ultrasound-guided biopsy of renal masses in adult outpatients. AB - Background Ultrasound-guided percutaneous kidney tumor biopsy (UGPKB) plays an important role in the diagnosis of renal tumor but there are no consensuses with respect to the length and the extend of the post-biopsy observation period. Purpose To assess the short-term complication rate after UGPKB and to evaluate whether the onset of complications allows for the procedure to be performed in an outpatient setting with same-day discharge. Material and Methods Between March 2012 and March 2014, a total of 287 UGPKB were performed in an outpatient setting at a Danish university referral center. All patient records were retrospectively reviewed and post-biopsy complications as well as biochemical parameters were registered. Results The overall complication rate was 3.8% (11 patients). Major complications occurred in 1.0% of all cases (three patients); one patient with ongoing bleeding that required intervention and two patients with septicemia. Minor complications occurred in 2.8% of cases (eight patients); six patients with self-limiting gross hematuria, one patient with small asymptomatic subcapsular hematoma, and one patient with vasovagal syncope. The timing of both minor and major complication onset ranged from the time of biopsy and up to four days after discharge. Conclusion UGPKB of indeterminate renal masses in adult patients in an outpatient setting appears to be a safe procedure with a very low rate of major complications. Same-day discharge after renal mass biopsy seems feasible. PMID- 28718665 TI - Prevalence of Low Vitamin D in Patients with Breast Cancer in a Predominantly Hispanic Population at the American-Mexican Border. AB - INTRODUCTION: Low level of vitamin D (VD) has been linked with a higher risk of cancers. The aim of this study was to assess the prevalence of low VD in patients with breast cancer in a predominantly Mexican Hispanic/Latino patient population, a fast growing and relatively understudied population. MATERIALS/METHODS: We sought to evaluate the serum VD levels in breast cancer patients diagnosed at the Texas Tech University Breast Cancer Center in El Paso, TX, between May 2013 and May2014 via a retrospective chart review of the Electronic Medical Records. RESULTS: We identified a total of 83 consecutive breast cancer patients with available VD levels. Mean age 57 yr, 94% were Hispanics. VD was insufficient (<30 ng/ml) in 86% of patients (95% CI: 0.76-0.92) and it was deficient (<20 ng/ml) in 39% (95% CI: 0.28-0.50). CONCLUSION: VD deficiency is widely prevalent in Hispanic/Latino patients with breast cancer. This is quite alarming in view of possible increased risk of cancer with low VD and potentially worse cancer outcomes. This calls for increased efforts to screen for, diagnose, and treat VD deficiency in this patient population. Further pharmacogenomics studies are warranted to explore the underlying etiology of VD deficiency in this paradoxically sunny region. PMID- 28718666 TI - Atrial cardiopathy: a mechanism of cryptogenic stroke. AB - INTRODUCTION: Cryptogenic stroke accounts for approximately 30% of all ischemic strokes. Recently, atrial cardiopathy diagnosed by the presence of one of its serum, imaging, or electrocardiogram biomarkers has been shown to be associated with ischemic stroke, particularly of embolic subtypes. Areas covered: This paper aims to summarize data on occult atrial fibrillation and stroke, provide an overview on mechanisms, such as inflammation and fibrosis, of stroke in atrial cardiopathy, critically review data on biomarkers of atrial cardiopathy and their association with stroke, and suggest therapeutic implications, including directions for future research. Expert commentary: Atrial cardiopathy may constitute one of the mechanisms in cryptogenic stroke, and patients with evidence of atrial cardiopathy constitute a group of patients in whom clinical trials are warranted to test anticoagulation versus antiplatelet therapy to reduce stroke recurrence risk. In addition, more studies are needed to determine the degree of overlap between these atrial cardiopathy biomarkers and which one is more useful in predicting the risk of stroke and response to anticoagulation therapy. PMID- 28718668 TI - Olea europaea Leaf Extract Improves the Efficacy of Temozolomide Therapy by Inducing MGMT Methylation and Reducing P53 Expression in Glioblastoma. AB - Unmethylated O6-methylguanine-DNA-methyltransferase (MGMT) promoter leads to Temozolomide (TMZ) resistance in most of the glioblastoma multiforme (GBM) patients. We previously investigated the synergistic effect of Olea europaea leaf extract (OLE) on TMZ cytotoxicity through modulating microRNA expression. To date, knowledge about the effect of OLE on MGMT methylation is insufficient. The aim of the current study was to evaluate the potential modulating effect of OLE on the TMZ response of GBM tumors through MGMT methylation. Exposure to 1 mg/mL OLE caused a significant induction of CpG island methylation in the MGMT gene using Methyl quantitative PCR assay (P < 0.001). In WST-1 analysis, the use of 350 uM TMZ plus 1 mg/mL OLE significantly increased the TMZ response of MGMT unmethylated cells (P = 0.003). Using the comet assay, the impact of 1 mg/mL OLE plus 350 uM TMZ on the formation of DNA strand breaks was significantly higher than that of 450 uM TMZ alone (P < 0.001) and Western blot analysis revealed that, when cells are treated with 1-mg/mL OLE, the total p53 protein levels tended to decrease. The results presented in this study uniquely demonstrated that OLE synergistically increased the TMZ response of GBM tumors by regulating MGMT gene methylation and p53 expression. However, further studies to validate our findings are required. PMID- 28718667 TI - Hydroxytyrosol Induces Apoptosis and Cell Cycle Arrest and Suppresses Multiple Oncogenic Signaling Pathways in Prostate Cancer Cells. AB - SCOPE: Hydroxytyrosol (HT), a polyphenol from olives, is a potential anticancer agent. This study was designed to evaluate the anticancer activity of HT against prostate cancer cells, and the mechanism thereof. METHODS AND RESULTS: Treatment of LNCaP and C4-2 prostate cancer cells with HT resulted in a dose-dependent inhibition of proliferation. This was in contrast to HT's ineffectiveness against normal prostate epithelial cells RWPE1 and PWLE2, suggesting cancer-cell-specific effect. HT induced G1/S cell cycle arrest, with inhibition of cyclins D1/E and cdk2/4 and induction of inhibitory p21/p27. HT also induced apoptosis, as confirmed by flow cytometry, caspase activation, PARP cleavage, and BAX/Bcl-2 ratio. It inhibited the phosphorylation of Akt/STAT3, and induced cytoplasmic retention of NF-kappaB, which may explain its observed effects. Finally, HT inhibited androgen receptor (AR) expression and the secretion of AR-responsive prostate-specific antigen. CONCLUSION: Castration-resistant prostate cancers retain AR signaling and are often marked by activated Akt, NF-kappaB, and STAT3 signaling. Our results establish a pleiotropic activity of HT against these oncogenic signaling pathways. Combined with its nontoxic effects against normal cells, our results support further testing of HT for prostate cancer therapy. PMID- 28718669 TI - Fruit Peel Polyphenolic Extract-Induced Apoptosis in Human Breast Cancer Cells Is Associated with ROS Production and Modulation of p38MAPK/Erk1/2 and the Akt Signaling Pathway. AB - Polyphenols represent a large group of natural substances with different biological properties. Currently, polyphenols are well studied due to their free radicals' scavenging and antioxidant activities. However, some studies indicate that polyphenols also exhibit pro-oxidant properties. In this study, the possible involvement of the pro-oxidant activities of fruit polyphenols was investigated in relation to apoptosis induction. To determine the type of cell death induced by fruit polyphenols (Flavine; F7), we assessed a series of assays, including measurements of caspase-7 activation, membrane mitochondrial potential changes, reactive oxygen (ROS) and nitrogen species production, lipid peroxidation, antioxidant enzymes activities, and PARP cleavage. Moreover, the effect of F7 on selected pro- and antisurvival signaling pathways was determined. We demonstrated that fruit polyphenols induced caspase-dependent cell death associated with increased oxidative stress. We also showed fruit polyphenol-mediated release of mitochondrial pro- and antiapoptotic proteins of the Bcl-2 family and modulation activity of the Akt, p38 MAPK, and Erk 1/2 pathways as well as the signaling of ROS-mediated DNA damage. Our data demonstrated that fruit peel polyphenols suppressed breast cancer cell growth through increased intracellular oxidative stress and the activation of p38 MAPK and de-activation of the Erk 1/2 and Akt signaling pathways. PMID- 28718671 TI - Freeze-dried and irradiated allograft bone combined with fresh autologous coagula promotes angiogenesis in an ectopic bone allograft implantation model. AB - BACKGROUND: Freeze-dried and irradiated allograft bone (FIAB) is more easily impacted than fresh-frozen allograft bone (FAB), but has weaker incorporation efficiency. We combined FIAB with fresh autologous coagula to enhance donor-host incorporation after impaction during hip revision. METHODS: Thirty adult male Sprague-Dawley (SD) rats were sacrificed for bone allograft harvesting, and nine male rats were subjected to ectopic bone allograft implantation. For each rat, the container on the left (study) side was filled with freeze-dried allograft bone powder and fresh autologous blood coagula, whereas the right (control) side was filled with freeze-dried allograft bone powder and physiological saline. The extent of angiogenesis (VEGFalpha) was investigated at postoperative weeks 1, 4, and 8. The deformability of the material was evaluated by performing a confined impaction mechanical test. RESULTS: At postoperative weeks 4 and 8, angiogenesis within FIAB on the left side was more pronounced than that on the right side. At postoperative week 1, the left side showed significantly higher VEGFalpha expression than that on the right side. The delta ratios of compression of the allografts were found to be influenced by bone height and impaction frequency, but not by stiffness or elastic modulus (EM). CONCLUSION: Supplementation with fresh autologous coagula promoted angiogenesis within the FIABs. Moreover, FIABs were equivalent to FABs in terms of deformability. PMID- 28718670 TI - Dietary Inflammatory Index and Renal Cell Carcinoma Risk in an Italian Case Control Study. AB - BACKGROUND: The relation between diet-related inflammation and renal cell carcinoma (RCC) has not been investigated. METHODS: In this study, we explored the association between the dietary inflammatory index (DII) and RCC in an Italian case-control study conducted between 1992 and 2004. Cases were 767 patients with incident, histologically confirmed RCC. Controls were 1534 subjects admitted to the same hospitals as cases for various acute, nonneoplastic conditions. The DII was computed based on dietary intake assessed using a reproducible and valid 78-item food frequency questionnaire. Odds ratios (ORs) were estimated through logistic regression models conditioned on age, sex, and center, and adjusted for recognized confounding factors, including total energy intake. RESULTS: Subjects in the highest quartile of DII scores (i.e., with the most proinflammatory diets) had a higher risk of RCC compared to subjects in the lowest quartile [OR 1.41, 95% confidence interval (CI) 1.02, 1.97; p-trend = 0.04)]. Apparently stronger associations were observed among females (OR 1.68, 95% CI 0.93, 3.03), subjects aged <60 yr (OR 1.77, 95% CI 1.05, 2.98), body mass index >=25 kg/m2 (OR 1.64, 95% CI 1.07, 2.51), and ever smokers (OR 1.66, 95% CI 1.08, 2.57), in the absence of significant heterogeneity. CONCLUSION: A proinflammatory diet is associated with increased RCC risk. PMID- 28718672 TI - Synthesis, anticancer and apoptosis-inducing activities of quinazoline-isatin conjugates: epidermal growth factor receptor-tyrosine kinase assay and molecular docking studies. AB - A new series of quinazolinone compounds 16-34 incorporating isatin moieties was synthesized. The antitumor efficacy of the compounds against MDA-MB-231, a breast cancer cell line, and LOVO, a colon cancer cell line, was assessed. Compounds 20, 21, 22, 23, 25, 27, 28, 29, 30, 31, 32, 33, and 34 displayed potent antitumor activity against MDA-MB-231 and LOVO cells (IC50: 10.38-38.67 MUM and 9.91-15.77 MUM, respectively); the comparative IC50 values for 5-fluorouracil and erlotinib in these cells lines were 70.28 MUM, 22.24 MUM and 15.23 MUM, 25.31 MUM respectively. The EGFR-TK assay and induction of apoptosis for compound 31 were investigated to assess its potential cytotoxic activity as a representative example of the novel synthesized compounds. At a concentration of 10 MUM, compound 31 exhibited efficient inhibitory effect against EGFR-TK and induced apoptosis in MDA-MB-231 cells. Furthermore, a molecular docking study for compound 31 and erlotinib was performed to verify the binding mode toward the EGFR kinase enzyme, and showed a similar interaction as that with erlotinib alone. Graphical Abstract: Compound 31 showed potent antitumor activity and efficient inhibitory effect against EGFR-TK and induced apoptosis of MDA-MB-231 cells at a concentration of 10 MUM. PMID- 28718673 TI - Ameliorative Effect of Gallic Acid in Doxorubicin-Induced Hepatotoxicity in Wistar Rats Through Antioxidant Defense System. AB - Hepatotoxicity has been found to be one of the main side effects associated with doxorubicin (Dox) administration in cancer therapy. The aim of the present study was to examine the ameliorative effect of gallic acid (GA) in Dox-induced hepatotoxicity. Sixty male Wistar rats of 10 rats per group were used in this study and were randomly divided into 6 experimental groups (A-F). Rats in Group A served as the control group and received distilled water orally for 7 days; Group B was given Dox at 15 mg/kg body weight intraperitoneally (IP) on Day 8. Group C was given GA at 60 mg/kg body weight orally for 7 days + Dox at 15 mg/kg IP on Day 8. Group D was given GA at 120 mg/kg body weight orally for 7 days + Dox at 15 mg/kg IP on day 8. Rats in Groups E and F were administered GA alone at 60 and 120 mg/kg body weight orally for 7 days, respectively. Dox administration led to a significant reduction in hepatic reduced glutathione and nonprotein thiol (NPT) together with significant increase in hepatic malondialdehyde, hydrogen peroxide generation, superoxide dismutase, and catalase activity; hepatic glutathione peroxidase and glutathione-S-transferase activity were significantly inhibited in Dox-treated rats. The serum alanine aminotransferase (ALT), alkaline phosphatase, and total bilirubin concentrations were significantly elevated following Dox administration. Pretreatment with GA ameliorated Dox-induced hepatotoxicity and oxidative stress. The results suggest that GA may offer protection against hepatic damage in Dox cancer chemotherapy. PMID- 28718674 TI - Design and synthesis of a novel photoaffinity probe for labelling EGF receptor tyrosine kinases. AB - The epidermal growth factor receptor (EGFR) and HER2 are two important tyrosine kinases that play crucial roles in signal transduction pathways that regulate numerous cellular functions including proliferation, differentiation, migration, and angiogenesis. In the past 20 years, many proteomic methods have emerged as powerful methods to evaluate proteins in biological processes and human disease states. Among them, activity-based protein profiling (ABPP) is one useful approach for the functional analysis of proteins. In this study, a novel photoaffinity probe 11 was designed and synthesised to assess the target profiling of the reactive group in the photoaffinity probe 11. Biological evaluation was performed, and the results showed that the novel photoaffinity probe binds to EGFR and HER2 proteins and it hits targets by the reactive group. PMID- 28718675 TI - The evolving model of care for familial hypercholesterolaemia. PMID- 28718676 TI - Selenium, zinc, copper, Cu/Zn ratio and total antioxidant status in the serum of vitiligo patients treated by narrow-band ultraviolet-B phototherapy. AB - BACKGROUND: Vitiligo is a chronic, depigmenting skin disorder, whose pathogenesis is still unknown. Narrow band ultraviolet-B (NB-UVB) is now one of the most widely used treatment of vitiligo. It was suggested that trace elements may play a role in pathogenesis of vitiligo. AIM: The aim of this study was to estimate the concentration of selenium (Se), zinc (Zn), copper (Cu) and Cu/Zn ratio as well as total antioxidant status (TAS) in the serum of patients with vitiligo. METHODS: We assessed 50 patients with vitiligo and 58 healthy controls. Serum levels of Se, Zn and Cu were determined by the atomic absorption spectrometry method, and the Cu/Zn ratio was also calculated. TAS in serum was measured spectrophotometrically. RESULT: Serum concentration of Se in patients with vitiligo before and after phototherapy was significantly lower as compared to the control group. Zn level in the serum of patients decreased significantly after phototherapy. We observed higher Cu/Zn ratio (p < .05) in examined patients than in the control group and after NB-UVB. We have found decrease in TAS in the serum of vitiligo patients after NB-UVB. CONCLUSIONS: The current study showed some disturbances in the serum levels of trace elements and total antioxidant status in vitiligo patients. PMID- 28718677 TI - Evaluation of the Cytotoxic Activity of Crocin and Safranal, Constituents of Saffron, in Oral Squamous Cell Carcinoma (KB Cell Line). AB - Crocin and safranal are active ingredients in the saffron. Some studies have demonstrated antitumor activities of saffron ingredients. The aim of this study was to evaluate cytotoxic effects of crocin and safranal in oral squamous cell carcinoma (KB cells) and NIH 3T3 cell line as nonmalignant cells. The cells were incubated with crocin and safranal at 37 degrees C for 24, 48, and 72 h, and cell viability was quantitated by MTT assay. Apoptotic cells, cell cycle distribution, and sub-G1 fraction were determined using propidium iodide staining of DNA fragmentation by flow cytometry. Crocin (0.05-4 mM) and safranal (0.2-3.2 mM) significantly inhibited the growth of KB cells (the inhibitory growth effects of all concentrations for both were >50% after 72 h), while they had less inhibitory effects on NIH 3T3 cells viability. The IC50 values of crocin and safranal against NIH 3T3 cells after 72 h were determined as 2.8 and 0.3 mM, respectively. Crocin and safranal induced a sub-G1 peak in the flow cytometry histogram of treated cells compared to control cells indicating that apoptotic cell death is involved in the toxicity of crocin and safranal. Apoptotic effects of crocin and safranal in tumor cells were more than normal cells. Neither crocin nor safranal affected the cell cycle progression. Crocin and safranal exerted apoptotic effects in KB cell line. PMID- 28718678 TI - Discovery of novel isoflavone derivatives as AChE/BuChE dual-targeted inhibitors: synthesis, biological evaluation and molecular modelling. AB - AChE and BuChE are druggable targets for the discovery of anti-Alzheimer's disease drugs, while dual-inhibition of these two targets seems to be more effective. In this study, we synthesised a series of novel isoflavone derivatives based on our hit compound G from in silico high-throughput screening and then tested their activities by in vitro AChE and BuChE bioassays. Most of the isoflavone derivatives displayed moderate inhibition against both AChE and BuChE. Among them, compound 16 was identified as a potent AChE/BuChE dual-targeted inhibitor (IC50: 4.60 MUM for AChE; 5.92 MUM for BuChE). Molecular modelling study indicated compound 16 may possess better pharmacokinetic properties, e.g. absorption, blood-brain barrier penetration and CYP2D6 binding. Taken together, our study has identified compound 16 as an excellent lead compound for the treatment of Alzheimer's disease. PMID- 28718679 TI - Salvia fruticosa Modulates mRNA Expressions and Activity Levels of Xenobiotic Metabolizing CYP1A2, CYP2E1, NQO1, GPx, and GST Enzymes in Human Colorectal Adenocarcinoma HT-29 Cells. AB - Natural products have gained considerable interests because of their use in some industrial areas including nutrition, cosmetic, pharmacy, and medicine. Salvia fruticosa M. (Lamiaceae) is known for its antioxidant, antimicrobial, and antiproliferative activities. Phase I xenobiotic metabolizing enzymes, CYP1A2 and CYP2E1, produce reactive metabolites which are eliminated by the action of phase II enzymes, NQO1, GPx, and glutathione S-transferases (GSTs). In this study, in vitro modulatory effects of S. fruticosa and its major phenolic compound rosmarinic acid (RA) on CYP1A2, CYP2E1, NQO1, GPx, and GSTm1 mRNA expressions and enzyme activities of GPx and GSTs were investigated in HT-29 cells. An mRNA expression analysis revealed that CYP1A2 and CYP2E1 levels were decreased while those of NQO1, GPx, and GSTm1 increased after S. fruticosa and RA treatments. In parallel to gene expressions, enzyme activities of GPx and GSTs by S. fruticosa increased 1.68- and 1.48-fold, respectively. Moreover, RA increased GPx and GSTs activities 1.67- and 1.94-fold, respectively. The results of this preliminary study show that metabolism of xenobiotics may be altered due to changes in the expression and activity of the investigated enzymes by S. fruticosa. PMID- 28718680 TI - Development of Emu oil-loaded PCL/collagen bioactive nanofibers for proliferation and stemness preservation of human adipose-derived stem cells: possible application in regenerative medicine. AB - Adipose tissue-derived stem cells (ASCs) are promising candidate in stem cell therapies, and maintaining their stemness potential is vital to achieve effective treatment. Natural-based scaffolds have been recently attracted increasing attention in nanomedicine and drug delivery. In the present study, a polymeric nanofibrous scaffold was developed based on the polycaprolactone/Collagen (PCL/Coll) containing Emu oil as a bioactive material to induce the proliferation of ASCs, while simultaneously preserving the stemness property of those cells. Fabrication of the electrospun Emu oil-loaded PCL/Coll nanofibers was confirmed by using FE-SEM, FTIR, and tensile test. ASCs were seeded on two types of nanofibers (PCL/Coll and Emu oil-loaded PCL/Coll) and their proliferation, cell cycle progression, and stemness gene expressions were evaluated using MTT, propidium iodide staining, and qPCR during 14 days, respectively. The results indicated that ASCs displayed improved adhesion capacity with the higher rates of bioactivity and proliferation on the Emu oil-loaded nanofibers than the other groups. The proliferation capacity of ASCs on Emu oil-loaded PCL/Coll nanofibers was further confirmed by the cell cycle progression analysis. It was also found that Emu oil-loaded nanofibers significantly up-regulated the expression of stemness markers including sox-2, nanog, oct4, klf4, and c-Myc. The results demonstrated that the nanofibers containing Emu oil can reinforce the cell adhesion and enhance ASCs proliferation while preserving their stemness; therefore, using scaffolds containing natural products may have a great potential to enhance the in vitro expansion capacity of ASCs in the field of stem cell therapy and regenerative medicine. PMID- 28718681 TI - Partial Substitution of Glucose with Xylitol Suppressed the Glycolysis and Selectively Inhibited the Proliferation of Oral Cancer Cells. AB - Suitable diet for cancer survivors remains an unresolved challenge. Increased glucose utilization is a hallmark of various cancers. Therefore, alternative carbohydrate supplying normal tissue but retarding cancer growth is needed. This study investigated the effect of sugar alcohols on the proliferation of oral cancer cells compared to nontransformed cells and explored the mechanism. Six oral squamous cell carcinoma (CAL-27, FaDu, SCC4, SCC9, SCC15, and SCC25) and one nontransformed oral keratinocyte (OKF6/TERT2) lines were cultured in media containing 1 mg/ml glucose and 5.8 mg/ml xylitol or sorbitol, yielding equal energy input to control group (4.5 mg/ml glucose). Partial substitution of glucose with sugar alcohols especially xylitol significantly suppressed proliferation of oral cancer but not nontransformed cells. Despite the addition of isocaloric quantities of the sugars, cancer cells exposed to low glucose plus xylitol had retarded ATP generation and decreased activity of phosphofructokinase (PFK), the rate-limiting enzyme in glycolysis. Furthermore, D-xylulose, its key metabolic intermediate, enhanced the anticancer effect of xylitol. These findings suggested a selective anticancer activity of xylitol and the potential mechanism involving inhibition of glucose utilization. Partial substitution of glucose with xylitol may be a proper nutrient for oral cancer survivors, deserving further investigation in animal and clinical settings. PMID- 28718682 TI - Genetic screening of SCNN1B and SCNN1G genes in early-onset hypertensive patients helps to identify Liddle syndrome. AB - BACKGROUND: Liddle syndrome is an autosomal dominant form of monogenic hypertension. Phenotypic variability makes it difficult to identify patients with Liddle syndrome, resulting in misdiagnosis and severe complications at early age. OBJECTIVES: To identify mutation in SCNN1B and SCNN1G genes in an adolescent with suspicious Liddle syndrome and his family members and to explore the screening target subjects of Liddle syndrome. METHODS: Genetic analysis of the C-terminus of SCNN1B and SCNN1G genes was conducted in an adolescent, with treatment resistant hypertension and hypokalemia, who was suspected of having Liddle syndrome, and his family members. A Medline research of the reported cases with Liddle syndrome was also performed. RESULTS: A recurrent SCNN1B mutation, c.1853C>A (p.P618H), was detected in the 19-year-old male patient, and family screening identified five additional members who were heterozygous for the mutation. The diagnosis of Liddle syndrome was made in all affected individuals. Despite the phenotypic variability, a systematic review of 54 reported index cases revealed the early-onset hypertension, aged no more than 30 years, as a common feature. CONCLUSIONS: Genetic screening for Liddle syndrome should be considered in hypertensive subjects with early penetrance, maybe no more than 30 years, after exclusion of common secondary causes of hypertension. PMID- 28718683 TI - The measurement of cough response to bronchoconstriction induced by methacholine inhalation in healthy subjects: An examination using the Astograph method. AB - BACKGROUND: We demonstrated that heightened cough response to bronchoconstriction is a fundamental feature of cough variant asthma (CVA). To evaluate this physiological feature of CVA in daily clinical practice, it is necessary to clarify the cough response to bronchoconstriction in healthy subjects. We evaluated cough response to methacholine (MCh)-induced bronchoconstriction in healthy subjects. A forced oscillometry technique was used to measure airway resistance changes with Mch. METHODS: Healthy never-smokers (21 men, 20 women; mean 22.3 +/- 3.7 years) participated. None had a >3-week cough history, clinically significant respiratory or cardiovascular disorders, or disorders that might put subjects at risk or influence the study results or the subjects' ability to participate. Twofold increasing concentrations of Mch chloride diluted in phosphate-buffered saline (0.039 to 160 mg/mL) were inhaled from nebulizers at 1-minute intervals during subjects' tidal breathing after the baseline respiratory resistance (Rrs) was recorded. Mch inhalation continued until Rrs reached twice the baseline value and forced expiratory volume in 1 second (FEV1) decreased to <90% of baseline value. Spirometry was measured before Mch inhalation and immediately after Rrs had increased twofold. Coughs were counted during and for 30 minutes after Mch inhalation. The cough reflex sensitivity to capsaicin was also examined. RESULTS: The number of coughs was 11.1 +/- 14.3 (median, 7.0; range, 0 to 71; reference range, 0 to 39.7). There was no significant difference in the cough response between the sexes. The reproducibility of the cough response to bronchoconstriction was sufficient. No correlation existed between the bronchoconstriction-induced cough response and capsaicin cough-reflex sensitivity. CONCLUSIONS: Using the Astograph method, cough response to bronchoconstriction could be measured easily, safely and highly reproducibly in healthy subjects. PMID- 28718684 TI - Role of GSK-3beta in Regulation of Canonical Wnt/beta-catenin Signaling and PI3 K/Akt Oncogenic Pathway in Colon Cancer. AB - Non-steroidal anti-inflammatory drugs (NSAIDs) are emerging as novel chemopreventive agents because of their ability in blocking cellular proliferation, and thereby tumor development, and also by promoting apoptosis. GSK-3beta, a serine threonine kinase and a negative regulator of the oncogenic Wnt/beta-catenin signaling pathway, plays a critical role in the regulation of oncogenesis. Celecoxib and etoricoxib, the two cyclooxygenase-2 (COX-2) selective NSAIDs, and Diclofenac, a preferential COX-2 inhibitory NSAID, had shown uniformly the chemopreventive and anti-neoplastic effects in the early stage of colon cancer by promoting apoptosis as well as an over-expression of GSK-3beta while down-regulating the PI3-K/Akt oncogenic pathway. PMID- 28718685 TI - Comparison of patient outcomes with and without stenting tube in pancreaticoduodenectomy. AB - Objective To evaluate the clinical effect of different pancreaticojejunostomy techniques in the treatment of pancreaticoduodenectomy and investigate the applicability of pancreaticojejunostomy without pancreatic duct stenting. Methods From January 2012 to December 2015, 87 patients who underwent pancreaticoduodenectomy were randomly assigned to either Group A (duct-to-mucosa anastomosis with pancreatic duct stenting, n = 43) or Group B (pancreas-jejunum end-to-side anastomosis without stenting (n = 44). The operative duration of pancreaticojejunostomy, postoperative hospital stay, and incidence of postoperative complications were compared between the two methods. Results The operative duration of pancreaticojejunostomy without use of the pancreatic duct stent was significantly shorter in Group B than in Group A (t = 7.137). The postoperative hospital stay was significantly shorter in Group B than in Group A (t = 2.408). The differences in the incidence of postoperative complications such as pancreatic fistula, abdominal bleeding, abdominal infection and delayed gastric emptying were not significantly different between the two groups (chi2 = 0.181, 0.322, 0.603, and 0.001, respectively). Conclusion Pancreaticoduodenectomy without pancreatic duct stenting is safe and reliable and can reduce the operative time and hospital stay. No significant differences were observed in the incidence of postoperative complications. PMID- 28718686 TI - Kinetic study on the inhibition of xanthine oxidase by acylated derivatives of flavonoids synthesised enzymatically. AB - Studies have reported that flavonoids inhibit xanthine oxidase (XO) activity; however, poor solubility and stability in lipophilic media limit their bioavailability and applications. This study evaluated the kinetic parameters of XO inhibition and partition coefficients of flavonoid esters biosynthesised from hesperidin, naringin, and rutin via enzymatic acylation with hexanoic, octanoic, decanoic, lauric, and oleic acids catalysed by Candida antarctica lipase B (CALB). Quantitative determination by ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS) showed higher conversion yields (%) for naringin and rutin esters using acyl donors with 8C and 10C. Rutin decanoate had higher partition coefficients (0.95), and naringin octanoate and naringin decanoate showed greater inhibitory effects on XO (IC50 of 110.35 and 117.51 MUM, respectively). Kinetic analysis showed significant differences (p < .05) between the flavonoids before and after acylation regarding Km values, whereas the values for Vmax were the same, implying the competitive nature of XO inhibition. PMID- 28718687 TI - Do sodium channel proteolytic fragments regulate sodium channel expression? AB - The cardiac voltage-gated sodium channel (gene: SCN5A, protein: NaV1.5) is responsible for the sodium current that initiates the cardiomyocyte action potential. Research into the mechanisms of SCN5A gene expression has gained momentum over the last few years. We have recently described the transcriptional regulation of SCN5A by GATA4 transcription factor. In this addendum to our study, we report our observations that 1) the linker between domains I and II (LDI-DII) of NaV1.5 contains a nuclear localization signal (residues 474-481) that is necessary to localize LDI-DII into the nucleus, and 2) nuclear LDI-DII activates the SCN5A promoter in gene reporter assays using cardiac-like H9c2 cells. Given that voltage-gated sodium channels are known targets of proteases such as calpain, we speculate that NaV1.5 degradation is signaled to the cell transcriptional machinery via nuclear localization of LDI-DII and subsequent stimulation of the SCN5A promoter. PMID- 28718688 TI - Effect of adjunctive ranitidine for antipsychotic-induced weight gain: A systematic review of randomized placebo-controlled trials. AB - This study was a meta-analysis of randomized controlled trials (RCTs) of ranitidine as an adjunct for antipsychotic-induced weight gain in patients with schizophrenia. RCTs reporting weight gain or metabolic side effects in patients with schizophrenia were included. Case reports/series, non-randomized or observational studies, reviews, and meta-analyses were excluded. The primary outcome measures were body mass index (BMI) (kg/m2) and body weight (kg). Four RCTs with five study arms were identified and analyzed. Compared with the control group, adjunctive ranitidine was associated with marginally significant reductions in BMI and body weight. After removing an outlier study for BMI, the effect of ranitidine remained significant. Adjunctive ranitidine outperformed the placebo in the negative symptom score of the Positive and Negative Syndrome Scale. Although ranitidine was associated with less frequent drowsiness, other adverse events were similar between the two groups. Adjunctive ranitidine appears to be an effective and safe option for reducing antipsychotic-induced weight gain and improving negative symptoms in patients with schizophrenia. Larger RCTs are warranted to confirm these findings. Trial registration PROSPERO: CRD42016039735. PMID- 28718689 TI - Orbital diffuse large B-cell lymphoma with combined variable immunodeficiency. AB - Common variable immunodeficiency (CVID) is a primary immunodeficiency manifesting as a reduction in the level of total immunoglobulin (Ig) G, a reduction in the level of either IgA or IgM, poor response to polysaccharide vaccine, and usually frequent infections. The association of CVID with an increased risk of malignancy, specifically lymphoma, is well known. A 63-year-old female with a past medical history significant for CVID presented with a 1-month history of dull, left eye pain with proptosis, hypoglobus, and left upper lid fullness without a discrete palpable mass. Magnetic resonance imaging (MRI) of the orbits revealed a diffuse infiltrating orbital mass superonasally with extension into the superior rectus muscle, medial rectus muscle, and optic nerve up to the orbital apex and ethmoid sinus. A superonasal orbital biopsy with a caruncular approach was performed and demonstrated a sparse lymphoid infiltrate that was suggestive for a large B-cell neoplasm. Positron emission tomography (PET) scan demonstrated a hypermetabolic right lymph node, anterior to the right submandibular gland, which was biopsied and histopathology confirmed diffuse large B-cell lymphoma (DLBCL). Our patient achieved a very good response to chemotherapy with minimal residual disease on PET scan at the end of treatment. She attained a complete remission after radiation therapy. In conclusion, patients with new orbital and adnexa masses in the setting of a primary immunodeficiency can have an aggressive malignancy such as DLBCL and early diagnosis and systemic treatment carries a good prognosis. PMID- 28718690 TI - Predictors of short-term and long-term incontinence after robot-assisted radical prostatectomy. AB - Purpose To determine retrospectively the prognostic factors for urinary incontinence following robot-assisted radical prostatectomy (RARP). Methods Altogether, 180 patients with localized prostate cancer underwent RARP (same surgeon). Preoperative physical status, disease characteristics, laboratory findings, and surgical technique were recorded and the patients checked 1, 6, 12, and 24 months after RARP regarding their contribution to predicting post prostatectomy urinary incontinence (PPI). Results Overall, 114 (63.3%) patients had PPI 1 month after RARP and 19 patients (16.0%) at 24 months. Univariate analysis showed that age was a significant factor for predicting PPI at 1 month. PPI predictors at 24 months were age, body mass index, preoperative serum albumin level, previous transurethral resection of the prostate, total operative time, and bladder neck sparing. Multivariate analysis indicated that age and total operative time were significant predictors. Conclusion Older age and longer operative time were highly relevant to short- and long-term PPI occurrence after RARP. PMID- 28718691 TI - Permanently open stomata of aquatic angiosperms display modified cellulose crystallinity patterns. AB - Most floating aquatic plants have stomata on their upper leaf surfaces, and usually their stomata are permanently open. We previously identified 3 distinct crystallinity patterns in stomatal cell walls, with angiosperm kidney-shaped stomata having the highest crystallinity in the polar end walls as well as the adjacent polar regions of the guard cells. A numerical bio-mechanical model suggested that the high crystallinity areas are localized to regions where the highest stress is imposed. Here, stomatal cell wall crystallinity was examined in 4 floating plants from 2 different taxa: basal angiosperms from the ANITA grade and monocots. It appears that the non-functional stomata of floating plants display reduced crystallinity in the polar regions as compared with high crystallinity of the ventral (inner) walls. Thus their guard cells are both less flexible and less stress resistant. Our findings suggest that the pattern of cellulose crystallinity in stomata of floating plants from different families was altered as a consequence of similar evolutionary pressures. PMID- 28718692 TI - Comprehensive public health action for our aging world: the quintessence of public health policy. AB - The number of elderly people is increasing rapidly because of decreasing mortality rates and increasing lifespans throughout the world. Policies and programs for elderly people are limited, and existing programs/policies are not implemented effectively towards the goal of healthier aging. Unlike other public health issues and actions, there is an urgent need to build an evidence-based comprehensive public health action policy for healthy aging. PMID- 28718693 TI - Effects of sedation with dexmedetomidine and buprenorphine on echocardiographic variables, blood pressure and heart rate in healthy cats. AB - Objectives Sedative agents are occasionally used to enable echocardiographic examination when screening cats for heart disease, such as hypertrophic cardiomyopathy (HCM). Owing to their haemodynamic effects, sedative agents may alter echocardiographic measurements. The aim of the study was to evaluate the effects of the sedative combination dexmedetomidine and buprenorphine on echocardiographic variables, blood pressure (BP) and heart rate (HR) in healthy cats. Methods Fifty healthy, client-owned cats were prospectively recruited and included after physical examination. Cats were sedated intramuscularly with dexmedetomidine and buprenorphine, according to body weight. Blood pressure and HR measurements, echocardiographic and Doppler examinations were performed prior to sedation and repeated once cats had achieved acceptable sedation. Results Left ventricular internal diameter at end-diastole and systole, right ventricular internal diameter at end-diastole, left atrium (LA), pulmonary artery (PA) deceleration time, and systolic, diastolic and mean arterial blood pressure increased after sedation ( P ?0.022). Aortic and PA maximum velocity, fractional shortening, PA acceleration/deceleration time and HR decreased after sedation ( P <0.0001). Interventricular septum at end-diastole and systole, left ventricular posterior wall at end-diastole and systole, aortic diameter (Ao), left atrial/aortic diameter (LA/Ao) and pulmonic acceleration time did not change. Conclusions and relevance Blood pressure increased and HR decreased post sedation. While wall thickness and LA/Ao were not affected by sedation, indices of LA and left ventricular size increased. Further studies are needed using cats with HCM to assess the effect of this sedative combination on HCM screening results. PMID- 28718694 TI - Updating survival estimates in patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) based on treatment-free interval length. AB - We hypothesized that the length of treatment-free survival following (a) initial diagnosis and (b) first-line treatment would be associated with improved subsequent five-year relative survival (RS5) in patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL). 19,879 patients incident CLL/SLL cases (median age = 76 years) were identified from SEER-Medicare. RS5 improved from 0.73 (95% CI: 0.72, 0.74) at diagnosis to 0.81 (95% CI: 0.80, 0.82) at year 1 and 0.89 (95% CI: 0.83, 0.96) at year 10 among those who had not received treatment. In our analysis of survival patterns following first-line treatment, RS5 improved from 0.55 (95% CI: 0.53, 0.57) at initiation of first line treatment to 0.84 (95% CI: 0.75, 0.92) among patients who had not been retreated at year 5 following first-line therapy. Longer periods of treatment free survival following initial diagnosis and first-line treatment were both predictive of meaningfully improved prognosis in CLL/SLL patients. PMID- 28718695 TI - Enhanced procoagulant activity of platelets after chemotherapy in non-small cell lung cancer. AB - The procoagulant status of patients with non-small cell lung cancer (NSCLC) after chemotherapy is poorly characterized and the role of platelets in hypercoagulative state of NSCLC is unknown. The aim of this study was to evaluate the procoagulant activity (PCA) of platelets in NSCLC before and after chemotherapy. The subjects were 52 patients newly diagnosed with NSCLC. The patients had decreased clotting time compared with healthy subjects, and the thrombin-antithrombin complex increased 2.5-fold after chemotherapy. Platelets in the patients after chemotherapy had enhanced phosphatidylserine (PS) exposure, and shortened coagulation time as well as increased thrombin and fibrin formation of platelets compared with those before chemotherapy. Platelet-derived microparticles increased 2-fold at day 1 and peaked at day 2 post-chemotherapy. Treatment of cisplatin in vitro also resulted in upregulated intrinsic FXa and thrombin formation on platelets with a dose-dependent manner. Platelets treated with aspirin significantly decreased PCA. However, lactadherin blocked PS and inhibited the PCA approximately by 70%. Seven days after chemotherapy, PCA of platelets restored to the baseline as that before chemotherapy, indicating that within a week of chemotherapy patient platelets are highly procoagulant and effective intervention should be taken in case of thrombosis. Our results suggested that platelets after chemotherapy had elevated PCA and may contribute to the hypercoagulative state of NSCLC. Prophylactic anti-coagulant combined with anti-platelet therapy may play an inhibitory role in thrombotic complications in NSCLC. PMID- 28718696 TI - Tumor-induced disorder of iron metabolism in major organs: a new insight from chemical speciation of iron. AB - Objective To investigate the evolution of iron speciation in major organs of tumor-bearing mice and its role in cancer formation and cancer-associated complications. Methods The concentration and chemical speciation of iron in the spleen, liver, lung, kidney, heart, blood, muscle, and tumor tissue of healthy mice and tumor-bearing mice were studied by synchrotron radiation-based total reflection X-ray fluorescence spectrometry (SR-TXRF) coupled with X-ray absorption spectroscopy (XAS). Results The TXRF and XAS results showed that the iron content, especially the ferritin content, significantly decreased in the blood and spleen but significantly increased in the liver, lung, and muscle of mice after tumor implantation. The chemical speciation of iron in the tumor mainly comprised ferrous-sulfide-like iron and ferritin. Conclusion The tumors disturbed the iron metabolism in major organs, and the evolution of iron may be involved in iron deficiency anemia, cancer growth, and immunity. Additionally, iron speciation-based markers may be further developed as clinical indicators for cancer and cancer-associated complications. PMID- 28718697 TI - Pain drawings predict outcome of surgical treatment for degenerative disc disease in the cervical spine. AB - INTRODUCTION: Pain drawings have been frequently used in the preoperative evaluation of spine patients. For lumbar conditions comprehensive research has established both the reliability and predictive value, but for the cervical spine most of this knowledge is lacking. The aims of this study were to validate pain drawings for the cervical spine, and to investigate the predictive value for treatment outcome of four different evaluation methods. METHODS: We carried out a post hoc analysis of a randomized controlled trial, comparing cervical disc replacement to fusion for radiculopathy related to degenerative disc disease. A pain drawing together with Neck Disability Index (NDI) was completed preoperatively, after 2 and 5 years. The inter- and intraobserver reliability of four evaluation methods was tested using kappa statistics, and its predictive value investigated by correlation to change in NDI. RESULTS: Included were 151 patients, mean age of 47 years, female/male: 78/73. The interobserver reliability was fair for the modified Ransford and Uden methods, good for the Gatchel method, and very good for the modified Ohnmeiss method. Markings in the shoulder and upper arm region on the pain drawing were positive predictors of outcome after 2 years of follow-up, and markings in the upper arm region remained a positive predictor of outcome even after 5 years of follow-up. CONCLUSIONS: Pain drawings were a reliable tool to interpret patients' pain prior to cervical spine surgery and were also to some extent predictive for treatment outcome. PMID- 28718698 TI - PEGging down risk factors for peg-asparaginase hepatotoxicity in patients with acute lymphoblastic leukemia ?. AB - Asparaginase is commonly de-emphasized/omitted in adult acute lymphoblastic leukemia regimens due to poor tolerability, including hepatotoxicity (HTX). Adult patients (n = 100) given induction therapy containing pegylated asparaginase (PEG) from January 2008 to February 2016 were evaluated for HTX. Sixteen patients met criteria for HTX (direct bilirubin >3 g/dL). A multivariable model identified body surface area >2m2 (OR 7.40; 95% CI: 1.73-31.61, p = .007), albumin <3 mg/dL (OR 4.62; 95% CI: 1.09-19.68, p = .038), and platelet count <50 K/mm3 (OR 9.36; 95% CI: 2.13-41.17, p = .003) as risk factors for HTX. More patients with HTX missed >=1 dose of intended chemotherapy (75% vs. 8%, p < .001). In patients with HTX, complete response and 30-day mortality rates were 40% and 9% versus 73% and 1% in patients without HTX (p = .02 and p < .001). A risk scoring tool was created to predict risk of toxicity, which should be validated through a prospective evaluation. PMID- 28718699 TI - Multiple facets of laticifer cells. AB - In the latex-bearing plants, the laticiferous system is the tubing structure that contains the latex and is constituted of living cells (laticifers). While laticifers are present only in a small percentage of the flowering plant species, they represent a type of specialized tissue within the plant where a myriad of metabolites are synthesized, some of them of considerable commercial importance. In this mini-review we synopsize the present knowledge about laticifer cells and discuss about their particular features as well as some evolutionary and ecophysiological cues and the potential exploitation of the knowledge generated around this peculiar type of plant cell. We illustrate some of these questions with the experience in Euphorbia lathyris laticifers and latex. PMID- 28718700 TI - Use of single-dose oral gabapentin to attenuate fear responses in cage-trap confined community cats: a double-blind, placebo-controlled field trial. AB - Objectives This double-blind, placebo-controlled study evaluated the safety and efficacy of single-dose oral gabapentin administered for the attenuation of fear responses in cage-trap confined community cats. Methods Community cats presented in cage traps for trap-neuter-return (TNR) were recruited and screened for inclusion. Each enrolled cat was randomly assigned and administered one of three equal-volume, single-dose treatments: placebo, low-dose gabapentin (50 mg) or high-dose gabapentin (100 mg). At baseline, 1, 2, 3 and 12 h post-administration, a single, blinded observer scored each cat for signs of fear and sedation using published paradigms, calculated the respiratory rate and documented any observable facial injuries. Results Fifty-three cats met the inclusion criteria and completed the study. Cat stress score (a measure of fear) was lower in cats that received gabapentin (50 or 100 mg) than in cats that received placebo (50 mg: P = 0.027; 100 mg: P = 0.029), with the greatest reduction at 2 h post treatment ( P = 0.0007). Respiratory rates did not differ between treatment groups. There was no difference in sedation scores between the groups ( P = 0.86) at any time point ( P = 0.09). Cat facial injuries did not vary by treatment group or over time. No adverse effects were detected specific to gabapentin administration. At 1 h, hypersalivation was observed in four cats across all treatment groups. All cats recovered from surgery and anesthesia uneventfully. Conclusions and relevance This study supports the hypothesis that 50 mg or 100 mg gabapentin (9.2-47.6 mg/kg per cat) reduces fear responses in confined community cats without measurable sedation over 3 h post-administration vs placebo. Gabapentin treatment was well tolerated in this population of cats. Further studies are recommended to investigate the use of oral gabapentin earlier in the TNR process, such as immediately after trapping or prior to transport for the prevention of confinement-related injuries. PMID- 28718702 TI - A novel t(3;9)(q21.2; p24.3) associated with SMARCA2 and ZNF148 genes rearrangement in myelodysplastic syndrome. PMID- 28718701 TI - Occludin regulates glucose uptake and ATP production in pericytes by influencing AMP-activated protein kinase activity. AB - Energetic regulation at the blood-brain barrier is critical for maintaining its integrity, transport capabilities, and brain demands for glucose. However, the underlying mechanisms that regulate these processes are still poorly explored. We recently characterized the protein occludin as a NADH oxidase and demonstrated its influence on the expression and activation of the histone deacetylase SIRT-1. Because SIRT-1 works in concert with AMP-activated protein kinase (AMPK) (AMPK), we investigated the impact of occludin on this metabolic switch. Here we show that in blood-brain barrier pericytes, occludin promotes AMPK expression and activation, influencing the expression of glucose transporters GLUT-1 and GLUT-4, glucose uptake, and ATP content. Furthermore, occludin expression, AMP-dependent protein kinase activity, and glucose uptake were altered under inflammatory (TNFalpha) and infectious (HIV) conditions. We also show that pericytes share glucose and mitochondria with astrocytes, and that occludin levels modify the ability of pericytes to share those energetic resources. In addition, we demonstrate that murine mitochondria can be transferred from live brain microvessels to energetically impaired human astrocytes, promoting their survival. Our findings demonstrate that occludin plays an important role in blood brain barrier pericyte metabolism by influencing AMPK protein kinase activity, glucose uptake, ATP production, and by regulating the ability of pericytes to interact metabolically with astrocytes. PMID- 28718703 TI - Nanoliposome improves inhibitory effects of naringenin on nonalcoholic fatty liver disease in mice. AB - AIM: To prepare naringenin nanoliposome (NRG-Nanolipo) and investigate its inhibitory effects on nonalcoholic fatty liver disease (NAFLD). MATERIALS & METHODS: NRG-Nanolipo was prepared by thin-film rehydration method. Its characterizations and effects on NAFLD in mice induced by methionine choline deficient diet were investigated. RESULTS: NRG-Nanolipo had high-drug loading percentage and showed a sustained release profile. The nanoliposome formulation significantly increased oral absorption of naringenin (NRG). NRG-Nanolipo showed comparable inhibitory effects as NRG crude drug at a dose fourfold lower than the crude drug on NAFLD. CONCLUSION: It is the first study to report the inhibitory effects of NRG on NAFLD, and the NRG-Nanolipo significantly improved oral absorption of NRG, thus improved liver protective effects of NRG on NAFLD. PMID- 28718704 TI - A study of sports-related orbital fractures in Singapore. AB - With an increased popularity of sport and active living worldwide, our study aims to explore the incidence and features of sports-related orbital fractures in Singapore. 1421 computer tomography (CT) imaging scans of the face and orbits done at the National University Hospital over a 24-month period from January 2013 and December 2014 were reviewed retrospectively for orbital fractures. We identified 483 orbital fractures of which sports injury was the fourth most common etiology (n = 65; 13.5%) after road traffic accident (n = 131; 27.1%), geriatric fall (n = 81; 16.8%) and workplace injury (n = 67; 13.9%). The three most common sport in orbital fractures were soccer (n = 20; 30.8%), bicycling (n = 11; 16.9%) and jogging (n = 8; 12.3%). The three most common fracture patterns were zygomatico-maxillary complex fractures (n = 24; 36.9%), isolated one wall blowout fractures (n = 19; 29.2%) and naso-orbito-ethmoid fractures (n = 7; 10.8%). Sports-related orbital fractures were associated with a low mean age of patients (45.9 years, range, 14-79 years), a higher proportion of males (n = 58; 89.2%) than that from geriatric falls (n = 37, 45.6%) (P < 0.01), a higher likelihood of unilaterality (n = 62; 95.4%) than that from traffic accidents (n = 99; 75.6%) (P < 0.01) and a lower likelihood of pan-facial involvement (n = 4; 6.15%) than that from traffic accident (n = 60; 45.8%) (P < 0.01). Sports-related orbital fractures are the fourth most common cause of orbital fractures. Though commonly seen in young male adults, in view of the aging population and people exercising more regularly, education of safety measures among sports users is paramount to preventing sports-related orbital fractures. PMID- 28718705 TI - Power curves. PMID- 28718706 TI - Public Policy and the Next Generation of Farmers, Ranchers, Producers, and Agribusiness Leaders. AB - The emerging, next generation of people engaged as managers in agriculture differs from the "baby boomer" farm generation that relishes certain traditions and an agrarian lifestyle. These futuristic producers and managers have been raised in a society that promulgates safety environment rules. They have witnessed lives saved by automobile seatbelts and lives improved from clean air and water. They know the basic cost of effective safety compliance is relatively fixed, regardless of the number of employees, and they are willing to invest resources that ensure a culture of safety, because it is economically beneficial, socially responsible, and probably required by the companies to whom they need to market their products. These same millennials understand that society and their customers will not continue to tolerate the high rate of agricultural injuries and deaths indefinitely. Public policy as a means to improve agricultural workers' safety and health is likely to be less resisted by the next generation of farmers, ranchers, producers, and agribusiness leaders who, regardless of legal or regulatory pressure, will implement internal business policies emphasizing safety, health, sustainability, and social justness as they understand it. PMID- 28718708 TI - Enhanced bone repair induced by human adipose-derived stem cells on osteogenic extracellular matrix ornamented small intestinal submucosa. AB - AIM: Our aim was to design an osteogenic extracellular matrix (ECM) coated bioscaffold and to apply it to critical bone defect repair with adipose-derived stem cells (ADSCs). MATERIALS & METHODS: Morphology of scaffolds was scanned by scanning electron microscope. Cell adhesion, proliferation and osteogenic differentiation of ADSCs on ECM-small intestinal submucosa (SIS) were evaluated by immunofluorescences staining, cell counting kit-8 and real-time qPCR, respectively. A mouse calvarial defect model was used to assess effects on bone regeneration in vivo. RESULTS: Abundant ECM was coated on SIS, which facilitated cell adhesion and proliferation of ADSCs. ECM-SIS induced osteogenic differentiation of ADSCs even without osteogenic inductive factors. Bone regeneration in vivo was enhanced by ECM-SIS + ADSCs via BMP/SMAD pathway. CONCLUSION: This work suggested a biofabricated SIS scaffold coated with osteogenic ECM-facilitated bone regeneration with ADSCs synergistically. PMID- 28718709 TI - Bioaerosols concentrations in working areas in biomethanization facilities. AB - : This study sought to fill the gap in information about the type and the concentration of bioaerosols present in the air of biomethanization facilities (BF). Evaluation of bioaerosol composition and concentration was achieved in two biomethanization facilities located in Eastern Canada, during summer and winter. In order to have a thorough understanding of the studied environment, the methodology combined culture of bacteria and molds, qualitiative polymerase chain reaction (qPCR) for specific microorganisms, endotoxin quantification, and next generation sequencing (NGS) for bacterial diversity. Results revealed that workers in biomethanization facilities are exposed to bioaerosols and pathogenic microorganisms similar to those found in composting plants. However, human exposure levels to bioaerosols are lower in BF than in composting plants. Despite these differences, use of personal protective equipment is recommended to lower the risks of health problems. IMPLICATIONS: Biomethanization is a new technology used in eastern Canada for waste management. In the next few years, it is expected that there will be an expansion of facilities in response of tight governmental regulations. Workers in biomethanization facilities are exposed to various amounts of bioaerosols composed of some harmful microorganisms. Therefore, monitoring this occupational exposure could be an interesting tool for improving worker's health. PMID- 28718707 TI - Child Sexual Abuse and Adult Mental Health, Sexual Risk Behaviors, and Drinking Patterns Among Latino Men Who Have Sex With Men. AB - One in five Latino men who have sex with men has experienced child sexual abuse. Although concerning in itself, child sexual abuse may increase an individuals' likelihood of depression and risk-taking in adult life, including engagement in HIV risk behaviors and alcohol and substance use. It is therefore urgent that researchers and practitioners better understand the long-term effects of child sexual abuse. We utilized logistic and linear regression to assess associations between child sexual abuse (operationalized as forced or coerced sexual activity before age 17) and depression, sexual behaviors, and drinking patterns in a sample of 176 adult Latino men who have sex with men from New York City. Over one fifth (22%) of participants reported child sexual abuse. In multivariable models, participants with histories of child sexual abuse were significantly more likely than participants without such histories to screen for clinically significant depressive symptoms and heavy drinking and reported more anal sex acts, male sexual partners, and incidents of condomless anal intercourse in the previous three months. These findings confirm a high prevalence of child sexual abuse among Latino men who have sex with men and associations between child sexual abuse and adulthood depressive symptoms, high-risk alcohol consumption, and sexual risk behaviors. We recommend that providers who serve Latino men who have sex with men incorporate child sexual abuse screenings into mental health, HIV prevention, and substance use treatment programs, utilizing approaches that are inclusive of resilience. PMID- 28718710 TI - Compressed air noise reductions from using advanced air gun nozzles in research and development environments. AB - The aims of this study were to evaluate sound levels produced by compressed air guns in research and development (R&D) environments, replace conventional air gun models with advanced noise-reducing air nozzles, and measure changes in sound levels to assess the effectiveness of the advanced nozzles as engineering controls for noise. Ten different R&D manufacturing areas that used compressed air guns were identified and included in the study. A-weighted sound level and Z weighted octave band measurements were taken simultaneously using a single instrument. In each area, three sets of measurements, each lasting for 20 sec, were taken 1 m away and perpendicular to the air stream of the conventional air gun while a worker simulated typical air gun work use. Two different advanced noise-reducing air nozzles were then installed. Sound level and octave band data were collected for each of these nozzles using the same methods as for the original air guns. Both of the advanced nozzles provided sound level reductions of about 7 dBA, on average. The highest noise reductions measured were 17.2 dBA for one model and 17.7 dBA for the other. In two areas, the advanced nozzles yielded no sound level reduction, or they produced small increases in sound level. The octave band data showed strong similarities in sound level among all air gun nozzles within the 10-1,000 Hz frequency range. However, the advanced air nozzles generally had lower noise contributions in the 1,000-20,000 Hz range. The observed decreases at these higher frequencies caused the overall sound level reductions that were measured. Installing new advanced noise-reducing air nozzles can provide large sound level reductions in comparison to existing conventional nozzles, which has direct benefit for hearing conservation efforts. PMID- 28718712 TI - Comparison of domains of self-reported physical activity between Kenyan adult urban-slum dwellers and national estimates. AB - BACKGROUND: Non-communicable diseases (NCDs) - largely the result of modifiable behavioral risks such as physical inactivity that gradually develop into physiological risks - are a main cause of morbidity and mortality worldwide. In Kenya, a nationally representative STEPwise survey of risk factors for NCDs established that 10.8% of Kenyans accumulated low levels of total physical activity. OBJECTIVES: The goal of our analyses was to compare domains of self reported physical activity in two Nairobi slums to national estimates. METHODS: Levels and time of self-reported activity in three domains (work, transport, and recreation), collected as part of a SCALE-UP study conducted in Korogocho and Viwandani slums in Nairobi, were compared to STEPwise findings. RESULTS: The samples included a total of 10,128 participants (5,628 slum, 4,500 national). Only 7.1% and 4.0% of slum dwellers reported low levels of work and transport physical activity, respectively, but 95.9% reported low levels of recreation related activity. Slum residents reported higher mean daily minutes of total activity than the national estimate (499 minutes versus 291 minutes), however, both samples spent similar proportions of total activity on work (79.0% slum, 78.3% national), transport (20.4% slum, 18.1% national), and recreation (0.6% slum, 3.6% national) activities. CONCLUSIONS: While the total amount of time spent in different domains of self-reported activity differs between urban slum residents and the national Kenyan population, proportions of time in each of the three domains are similar. It is important that such differences or similarities be considered when addressing NCD risk factors in these populations. PMID- 28718711 TI - Association Between a Dietary Inflammatory Index and Prostate Cancer Risk in Ontario, Canada. AB - BACKGROUND: Evidence exists showing that various aspects of diet are implicated in the etiology of prostate cancer, although results across studies remain inconsistent. METHODS: We examined the ability of the dietary inflammatory index (DII) to predict prostate cancer in a case-control study conducted in Kingston, Ontario, Canada, between 1997 and 1999. The study included 72 cases of incident primary prostate cancer patients and 302 controls of urology clinic patients who had prostate conditions other than prostate cancer. The DII was computed based on intake of 18 nutrients assessed using a 67-item food frequency questionnaire. Univariate and multivariate logistic regression models were used to estimate odds ratios (ORs). RESULTS: Men with higher DII scores were at increased risk of prostate cancer using DII score fit both as a continuous [OR = 1.58, 95% confidence interval (CI) 1.05-2.38] and categorical variable [compared to men in the lowest DII quartile, men in the highest quartile were at elevated risk (OR = 3.50, 95% CI 1.25-9.80; ptrend = 0.02)]. There was no significant heterogeneity by weight status, but stronger association was observed in men with body mass index >25 kg/m2 versus <25 kg/m2. CONCLUSION: These findings suggest that a proinflammatory diet, as indicated by increasing DII score, is a risk factor for prostate cancer. PMID- 28718713 TI - Psychiatry education programs in Australia. PMID- 28718714 TI - Imagining schizophrenia without relapses. PMID- 28718715 TI - Should the recently reported increase in Australian suicide rates alarm us? PMID- 28718716 TI - Estimating the number of adults with severe and persistent mental illness who have complex, multi-agency needs. AB - OBJECTIVE: A population health approach to mental health service planning requires estimates that align interventions with the needs of people with mental illness. The primary objective was to estimate the number of people in Australia living with severe and persistent mental illness who have complex, multi-agency needs. The secondary objective was to describe the possible service needs of individuals with severe mental illness. METHODS: We disaggregated the estimated 12-month prevalence of adults with severe mental illness into needs-based sub groups, using multiple data sources. Possible service needs of 1825 adults with psychotic disorders and 334 adults with severe past-year affective and/or anxiety disorders were described using data from the 2010 Survey of High Impact Psychosis and 2007 National Survey of Mental Health and Wellbeing, respectively. RESULTS: Using best available data, we estimated that 3.3% of adults experience a severe mental illness each year, of whom one-third (1.1% of adults) experience a persistent mental illness that requires ongoing services to address residual disability. Among those with severe and persistent mental illness, one-third of adults (0.4% or 59,000 adults in 2015) have complex needs requiring multi-agency support to maximise their health, housing, social participation and personal functioning. Survey of High Impact Psychosis data indicated that among adults with psychotic disorders, use of accommodation (40%), non-government (30%) services and receipt of income support (85%) services were common, as were possible needs for support with socialising, personal care and employment. National Survey of Mental Health and Wellbeing data indicated that among individuals with severe affective and anxiety disorders, receipt of income support (37%) was common (information on accommodation and non-government support services was not available), as were possible needs for financial management and employment support. CONCLUSION: Agreed indicators of complex, multi-agency needs are required to refine these estimates. Closer alignment of information collected about possible service needs across epidemiological surveys is needed. PMID- 28718717 TI - Movies in mind: Dr. Strange-'I think (I am a receptor) ... therefore I am'. PMID- 28718718 TI - The ANZJP and child psychiatry. PMID- 28718719 TI - Something old and something blue - Something for everyone, me and you? PMID- 28718720 TI - Phenomenal insights: Catatonia - a matter of positioning ideas? PMID- 28718721 TI - Mapping the developmental trajectory of bipolar disorder: Importance of prerequisite groundwork. PMID- 28718722 TI - Anticarcinogenic Effects of Dried Citrus Peel in Colon Carcinogenesis Due to Inhibition of Oxidative Stress. AB - Colorectal cancer is one of the leading causes of death worldwide. Reactive oxygen species produce oxidative stress and contribute to colorectal carcinogenesis. Because dietary citrus has been shown to reduce oxidative stress, we investigated the effects of citrus peel extract at dilutions of 1/200-1/500 on the activity of oxidative-stress-related transcription factors, including AP-1, NF-kappaB, NRF2, p53, and STAT3, in human colon cancer cell line HCT116 cells using a luciferase reporter gene assay. NRF2 transcriptional activities were 1.8- to 2.0-fold higher than the untreated control value. In addition, NF-kappaB, p53, and STAT3 transcriptional activities were 12-26% lower than the untreated control value. Administration of dried citrus peel in the diet of F344 rats at a dose of 1,000 ppm prevented the formation of azoxymethane-induced precancerous aberrant crypt foci (ACF) in the colon. The total number of ACF in rats fed with dried citrus peel was reduced to 75% of the control value. Moreover, the levels of oxidative-stress-related markers, reactive carbonyl species, in the serum of F344 rats were significantly reduced following the administration of dried citrus peel. These data suggest that citrus peel possesses an ability to suppress cellular oxidative stress through induction of NRF2, thereby preventing azoxymethane-induced colon carcinogenesis. PMID- 28718723 TI - Core addiction medicine competencies for doctors: An international consultation on training. AB - BACKGROUND: Despite the high prevalence of substance use disorders, associated comorbidities, and the evidence base upon which to base clinical practice, most health systems have not invested in standardized training of health care providers in addiction medicine. As a result, people with substance use disorders often receive inadequate care, at the cost of quality of life and enormous direct health care costs and indirect societal costs. Therefore, this study was undertaken to assess the views of international scholars, representing different countries, on the core set of addiction medicine competencies that need to be covered in medical education. METHODS: A total of 13 members of the International Society of 20 Addiction Medicine (ISAM), from 12 different countries (37% response rate), were interviewed over Skype, e-mail survey, or in person at the annual conference. Content analysis was used to analyze interview transcripts, using constant comparison methodology. RESULTS: We identified recommendations related to the core set of the addiction medicine competencies at 3 educational levels: (i) undergraduate, (ii) postgraduate, and (iii) continued medical education (CME). The participants described broad ideas, such as knowledge/skills/attitudes towards addiction to be obtained at undergraduate level, or knowledge of addiction treatment to be acquired at graduate level, as well as specific recommendations, including the need to tailor curriculum to national settings and different specialties. CONCLUSIONS: Although it is unclear whether a global curriculum is needed, a consensus on a core set of principles for progression of knowledge, attitudes, and skills in addiction medicine to be developed at each educational level amongst medical graduates would likely have substantial value. PMID- 28718724 TI - Black Raspberries and Their Anthocyanin and Fiber Fractions Alter the Composition and Diversity of Gut Microbiota in F-344 Rats. AB - Natural compounds can alter the diversity and composition of the gut microbiome, potentially benefiting our health. We previously demonstrated chemopreventive effects of black raspberries (BRBs) in colorectal cancer, which is associated with gut dysbiosis. To investigate the effects of whole BRBs and their fractions on gut microbiota, we fed F-344 rats a control diet, 5% BRBs, the BRB anthocyanin fraction, or the BRB residue fraction for 6 weeks. Feces were collected at baseline and at weeks 3 and 6, and bacterial sequence counts were analyzed. We observed distinct patterns of microbiota from different diet groups. Beta diversity analysis suggested that all diet groups exerted time-dependent changes in the bacterial diversity. Hierarchical clustering analysis revealed that post diet fecal microbiota was segregated from baseline fecal microbiota within each diet. It is interesting to note that fractions of BRBs induced different changes in gut bacteria compared to whole BRBs. The abundance of specific microbial species known to have anti-inflammatory effects, such as Akkermansia and Desulfovibrio, was increased by whole BRBs and their residue. Further, butyrate producing bacteria, e.g., Anaerostipes, were increased by whole BRBs. Our results suggest that whole BRBs and their fractions alter the gut microbiota in ways that could significantly influence human health. PMID- 28718725 TI - Ellagic Acid Enhances Apoptotic Sensitivity of Breast Cancer Cells to gamma Radiation. AB - Herbal polyphenols have gained increased significance because of the promises they hold in the prevention and treatment of cancer. There exists an enormous opportunity for the screening and valuation of natural dietary compounds in the development of an effective chemopreventive drug and radiosensitizer that may be of practical use for patients undergoing cancer therapy. This study describes the effect of the flavonoid ellagic acid (EA) on gamma-irradiated human breast cancer MCF-7 cells in vitro when administered alone or in combination with radiation. It was interesting to find the radioprotective effect of EA on NIH3T3, which is a normal cell line. Irradiation of breast tumor cells in the presence of EA (10 MUM) to doses of 2 and 4-Gy gamma radiation produced a marked synergistic tumor cytotoxicity while it was found to aid recovery from the radiation damage to NIH3T3 cells. When cells were given a combined treatment of EA and radiation, the cell death increased to 21.7% and 20.7% in the 2 and 4-Gy-treated cells respectively, significantly (P < 0.05) reducing the capacity of MCF-7 cells to form colonies. Even at 24 h, 38 foci/cell were observed in samples that were given the combined treatment, suggesting the cells' inability in repairing the damage. Also, increased apoptosis in EA+ 2Gy (50%) and EA+ 4 Gy (62%)-treated cells was observed in the the sub-G1 phase of the cell cycle. A 6.2-fold decrease in the mitochondrial membrane potential was observed in the combined treatment of EA and IR that facilitated the upregulation of pro-apopttotic Bax and downregulation of Bcl-2, pushing the MCF-7 cells to undergo an apoptotic cell death. It is suggested that EA may be a potential drug adjuvant for improving cancer radiotherapy by increasing tumor toxicity and reducing the normal cell damage caused by irradiation. PMID- 28718726 TI - Effects of the Notch1 signaling pathway on human lung cancer A549 cells. AB - PURPOSE: To evaluate the effects of the Notch1 signaling pathway on human lung cancer A549 cells. MATERIALS AND METHODS: A549 cells were transfected with recombinant plasmids. Cell proliferation was detected by MTT assay. A tumor bearing mouse model was established for intratumoral gene injection. Apoptosis related factors were detected by immunohistochemical assay. Caspase-8, caspase-3, caspase-9, PI3K, pAkt and pSTAT3 expressions were detected by Western blotting. RESULTS: Compared with A549-GFP and A549 cells, A549-ICN cell growth in mice decelerated, tumor volume significantly reduced (p < 0.01), and survival time significantly increased (p < 0.05). Cyclin E and phosphorylated Rb protein expressions were significantly down-regulated. Compared with control, apoptosis related protein Bcl-2 expression in tumors injected with Notch1 gene was significantly inhibited. After Deltex1 transfection, A549 cell proliferation decelerated, growth was significantly inhibited (p < 0.05), and survival time was significantly extended (p < 0.05). Cyclin E and mutant p53 protein expressions in tumors were down-regulated, phosphorylated Rb expression was almost completely inhibited, and Bcl-2 expression was significantly inhibited. TNF-alpha-related apoptosis-inducing ligand (TRAIL) inhibited A549-ICN cell growth time- and dose dependently. After treatment for 24 h or longer, TRAIL induced apoptosis of more A549-ICN cells. Cleaved caspase-3 and cleaved caspase-9 were detected only in A549-ICN cells after 6 h of 40 ng/mL TRAIL treatment, but cleaved caspase-8 was not detected. Combining Notch1 signal with TRAIL inhibited PI3K, phosphorylated Akt and phosphorylated STAT3 expressions. CONCLUSION: The Notch1 signaling pathway may inhibit A549 cell growth in vitro and in vivo by regulating cell cycle-related and anti-apoptotic protein expressions. Notch1 activation also suppressed A549 cell apoptosis by inhibiting the PI3K/pAkt pathway and activating the caspase-3 pathway in cooperation with TRAIL. PMID- 28718727 TI - Effects of palonosetron and ondansetron on preventing nausea and vomiting after laparoscopic surgery. AB - Background This meta-analysis was performed to evaluate the efficacy and safety of palonosetron and ondansetron in preventing postoperative nausea and vomiting (PONV) in patients undergoing laparoscopic surgery with general anesthesia. Methods We searched for randomized controlled clinical trials in PubMed, Embase, and The Cochrane Library. Results Nine studies were enrolled in this meta analysis and showed no statistically significant difference between palonosetron and ondansetron in the prevention of PONV in the first 24 hours after surgery (relative risk [RR], 0.62; 95% confidence interval [CI], 0.35-1.10). Palonosetron more effectively prevented vomiting at various time intervals during the first 24 hours postoperatively than did ondansetron: 0-2 hours (RR, 0.45; 95% CI, 0.26 0.78), 2-6 hours (RR, 0.74; 95% CI, 0.39-1.40), and 6-24 hours (RR, 1.20; 95% CI, 0.55-2.64). No significant differences in side effects were found between palonosetron and ondansetron (RR, 0.67; 95% CI, 0.40-1.14). Conclusion This meta analysis demonstrated that palonosetron is not more efficacious than ondansetron in the prevention of early PONV. However, palonosetron was more efficacious than ondansetron in the prevention of vomiting after laparoscopic surgery. PMID- 28718728 TI - A phase I/II randomized trial of clofarabine or fludarabine added to idarubicin and cytarabine for adults with relapsed or refractory acute myeloid leukemia. AB - The purine nucleoside analogues clofarabine and fludarabine are active in acute myeloid leukemia (AML). We conducted a phase I/II randomized study of idarubicin and cytarabine with either clofarabine (CIA) or fludarabine (FIA) for relapsed or refractory AML. Clofarabine 15 mg/m2 was identified as the recommended phase II dose. Eighty-one patients were assigned using adaptive randomization to CIA (n = 48) or FIA (n = 33). The complete response (CR)/CR without platelet recovery rate did not differ between CIA and FIA (38% versus 30%, respectively; p = .50). In both arms, more than half of patients who had received only one prior line of therapy achieved remission. The median event-free survival for CIA and FIA was 2.0 and 1.9 months (p = .48), and the median overall survival was 6.3 and 4.7 months, respectively (p = .28). No significant differences in adverse events or early mortality rates were observed. Overall, CIA and FIA resulted in similar response rates and survival in patients with relapsed/refractory AML. PMID- 28718731 TI - Top-rated AMEE MedEdPublish Papers - April 2017. PMID- 28718729 TI - The novel autophagy inhibitor elaiophylin exerts antitumor activity against multiple myeloma with mutant TP53 in part through endoplasmic reticulum stress induced apoptosis. AB - Elaiophylin is a natural compound and a novel and potent inhibitor of late stage autophagy with outstanding antitumor activity in human ovarian cancer cells. However, the possible biologic effects and functional linkage between elaiophylin and multiple myeloma (MM) have not been explored. This study aimed to assess the effect of elaiophylin on MM cells with mutant TP53 and the possible molecular mechanism. The results suggested that elaiophylin exerted anti-myeloma activity by inducing apoptosis and proliferation arrest. As expected, elaiophylin blocked autophagy flux in MM cells. Subsequently, persistent activation of endoplasmic reticulum (ER) stress was induced. Moreover, the apoptotic effect was to some extent attenuated by the ER stress inhibitor tauroursodeoxycholic acid (TUDCA). Further studies indicated that elaiophylin effectively suppressed MM cell growth without obvious side effects in zebrafish embryo and mouse xenograft models. Taken together, our data are the first to demonstrate that exposure of human MM cells with mutant TP53 to elaiophylin blocked autophagy flux and thus induced cell death, which partially involved ER stress-associated apoptosis. Targeted disruption of the cellular protein handling system by elaiophylin is therefore a promising therapeutic strategy for overcoming incurable MM, even when TP53 mutations are present. PMID- 28718730 TI - Medical Teacher in Ten Minutes. PMID- 28718732 TI - Molecular Imaging - a way forward in translating disease behaviour in an era of personalized medicine. PMID- 28718733 TI - Diagnostic utility of renal fine-needle aspirate cytology and ultrasound in the cat. AB - Objectives The primary objective of this study was to retrospectively assess the diagnostic utility of feline renal fine-needle aspiration cytology by assessing diagnostic yield, cytologic characteristics and diagnostic accuracy. The secondary objective was to characterize ultrasonographic features of sampled kidneys to determine if they influenced diagnostic yield. Methods Slides, images and patient data were collected from the University of Minnesota Veterinary Medical Center database. Slides were designated as diagnostic or non-diagnostic. Non-diagnostic slides were used in calculating diagnostic yield and excluded from other analysis. Slides were evaluated for cytologic characteristics and assigned a single primary diagnosis. Ultrasound still images were evaluated for descriptive characteristics and characteristics of specific lesions were described. Cases with confirmatory testing were used to determine diagnostic sensitivity, specificity and positive and negative predictive values for detecting neoplasia. Results Of 96 cytologic submissions available for review, diagnostic yield was 68%; 48% of samples were at least moderately cellular. Of 87 cases with ultrasound data, kidneys showing subcapsular renal infiltrate, diffuse renal enlargement without pelvic dilation and infiltrative/nodular change were more likely to yield diagnostic samples. Of 12 confirmed cases, cytology was 100% sensitive and specific for the detection of neoplasia (four round-cell tumors and two carcinomas). Three cases with non-neoplastic histologic diagnoses were considered cytologically normal, two incorrectly diagnosed the pathology present, and one correctly diagnosed the pathology. While some imaging characteristics were more commonly seen in neoplastic vs non-neoplastic lesions, the sample size was insufficient for definitive correlation. Conclusions and relevance This is the first major analysis of feline ultrasound-guided renal fine-needle aspiration cytology. This technique generates adequate samples for interpretation at rates comparable to other soft tissues and is most useful in the diagnosis of neoplasia. Some imaging characteristics are indicative of the likelihood of obtaining an adequate sample for cytologic interpretation. PMID- 28718734 TI - Pullulan production from synthetic medium by a new mutant of Aureobasidium pullulans. AB - Pullulan with different molecular-weight could be applied in various fields. A UV induced mutagenesis Aureobasidium pullulans UVMU6-1 was obtained from the strain A. pullulans CGMCC3.933 for the production of low-molecular-weight pullulan. First, the obtained polysaccharide from A. pullulans UVMU6-1 was purified and identified to be pullulan with thin-layer chromatography, Fourier transform infrared, and nuclear magnetic resonance. Then, culture medium and conditions for this strain were optimized by flask fermentation. Based on the optimized medium and culture conditions (pH 4, addition of 4 g/L Tween 80 for 96 hr of cultivation), continuously fermentation was performed. The highest pullulan production and dry biomass was 109 and 125 g/L after fermentation for 114 hr, respectively. The average productivity was about 1 g/L/hr, which was intensively higher than the previous reported. This study would lay foundations for the industrial production of pullulan. PMID- 28718736 TI - Critical health psychology Critical health psychology Michael Murray Palgrave No of pages: 270 L17.99 033399034X 033399034X [Formula: see text]. AB - This edited book provides a very useful introduction to contemporary ideas in health psychology theory and practice. 'Critical' is a term with many meanings. For this book the writers use it to mean a theoretically informed practice in the wake of Foucault's analysis of power. PMID- 28718735 TI - Correction Re: Tissue Engineering, Part C, 2017;23(5):251-261. PMID- 28718737 TI - Quality of life research: a critical introduction Quality of life research: a critical introduction Rapley Mark Sage 286 L24.99 0761954570 0761954570 [Formula: see text]. AB - Many books have been published on quality of life research in recent years, but few are as thought provoking or original as this one. It is essential reading for anyone who has a serious and critical interest in this topic. PMID- 28718738 TI - Understanding emotion at work Stephen Fineman Understanding emotion at work Sage 204 L70 (cloth) 0761947892 0761947892 [Formula: see text]. AB - The book has many positive features though it does rely very much on UK and US illustrations for the points that it is attempting to convey. Emotions are rightly seen as part and parcel of everyday life in the work place. Anger, joy, sorrow, jealousy, anxiety... and all the other emotions are always simmering away under the surface and are the very things that make an organisation seem alive. The management of emotions in. PMID- 28718739 TI - Stretching exercises for qualitative researchers Stretching exercises for qualitative researchers Janesick Valerie J Sage 0761928154 0761928154 [Formula: see text]. AB - The title of this text relates to the metaphor of art - specifically, dance and yoga. This is significant because it is a metaphor which is used throughout to emphasise the artistry of qualitative research. The author argues that qualitative researchers need to develop and refine observational, interview and journal techniques much as a dancer or yoga practitioner has to 'train the mind, eye and soul together'. PMID- 28718740 TI - Doing counselling research John McLeod Doing Counselling Research Sage No of pages: 227 L18.99 0761941088 0761941088 [Formula: see text]. AB - While this book focuses primarily on conducting research in counselling and psychotherapy, it provides sound information that will be useful to researchers from a range of disciplines. It is particularly suited to the needs of novice researchers studying health and social care in general or those attempting to plan and implement their work in counselling disciplines. PMID- 28718743 TI - The landscape of qualitative research: theories and issues Sage The landscape of qualitative research: theories and issues 480 L24.95 0761926941 0761926941 [Formula: see text]. AB - This wide-reaching book sets out to describe the origin, practice and diversity of qualitative research. It is split into three parts: locating the field; paradigms and perspectives in transition; and the future of qualitative research. The chapters are by a variety of authors representing the 'quiet revolution' that 'has been taking place in the social sciences'. PMID- 28718744 TI - Social research methodology Social research methodology Gomm Roger Palgrave 360 L19.99 0333637283 0333637283 [Formula: see text]. AB - The book begins with a very thorough overview of the topics discussed. These include controlled and natural experimental methods, survey techniques, interviews, observing naturally occurring events and analysing written documents. PMID- 28718745 TI - Research design: qualitative, quantitative and mixed methods approaches Research design: qualitative, quantitative and mixed methods approaches Creswell John W Sage 320 L29 0761924426 0761924426 [Formula: see text]. AB - The second edition of Creswell's book has been significantly revised and updated. The author clearly sets out three approaches to research: quantitative, qualitative and mixed methods. As someone who has used mixed methods in my research, it is refreshing to read a textbook that addresses this. The differences between the approaches are clearly identified and a rationale for using each methodological stance provided. PMID- 28718748 TI - Motion Capture Depends Upon the Common Fate Factor Among Elements. AB - When observers move the head backwards and forwards while fixating on the center of the concentric circles that consist of oblique lines, they see illusory rotation of those circles. If several dots are superimposed on the proximity to the inner concentric circles, observers see the illusory rotation not only for the circles but also for the superimposed dots. This illusory rotation of the dots is based on motion capture. In this study, in order to understand the basis of the motion capture, we examined how motion signal with different directions (rotation, expansion/contraction, and horizontal translation) in terms of motion on a display, as well as illusory motion signal from the oblique components, affects the motion capture. If the stimulus presented rotation with expansion/contraction, or rotation with horizontal translation for the entire stimulus, then observers tended to perceive motion capture for the superimposed dots. However, if the stimulus presented only rotation of the circles, then observers tended to perceive induced motion for the superimposed dots. These results suggest that the existences of the common fate factor for the entire stimulus determine the means of allocating and integrating the motion signal in each element in the stimulus to generate motion capture. PMID- 28718747 TI - The Role of Temporal Disparity on Audiovisual Integration in Low-Vision Individuals. AB - Recent findings have shown that sounds improve visual detection in low vision individuals when the audiovisual stimuli pairs of stimuli are presented simultaneously and from the same spatial position. The present study purports to investigate the temporal aspects of the audiovisual enhancement effect previously reported. Low vision participants were asked to detect the presence of a visual stimulus (yes/no task) presented either alone or together with an auditory stimulus at different stimulus onset asynchronies (SOAs). In the first experiment, the sound was presented either simultaneously or before the visual stimulus (i.e., SOAs 0, 100, 250, 400 ms). The results show that the presence of a task-irrelevant auditory stimulus produced a significant visual detection enhancement in all the conditions. In the second experiment, the sound was either synchronized with, or randomly preceded/lagged behind the visual stimulus (i.e., SOAs 0, +/- 250, +/- 400 ms). The visual detection enhancement was reduced in magnitude and limited only to the synchronous condition and to the condition in which the sound stimulus was presented 250 ms before the visual stimulus. Taken together, the evidence of the present study seems to suggest that audiovisual interaction in low vision individuals is highly modulated by top-down mechanisms. PMID- 28718750 TI - Corrigendum. PMID- 28718749 TI - Glycinol enhances osteogenic differentiation and attenuates the effects of age on mesenchymal stem cells. AB - AIM: Phytoestrogens, such as glycinol, have recently gained significant attention as an alternative therapy for osteoporosis due to their structural similarity to estradiol and their bone-generating potential. METHODS: The osteogenic effects of glycinol were investigated in human bone marrow mesenchymal stem cells (BMSCs) derived from older (>50 years old) and younger subjects (<25 years old). RESULTS: BMSCs isolated from older donors demonstrated reduced osteogenesis. 17beta estradiol and glycinol exposure rescued the age-related reduction in osteogenic differentiation of BMSCs. These results correlated with the induction of osteogenic genes and estrogen receptor-alpha (ER-alpha) following glycinol treatment. ER antagonist studies further support that glycinol promotes osteogenesis through ER signaling. CONCLUSION: The results from these studies support investigating glycinol as a potential preventive or treatment for osteoporosis. PMID- 28718751 TI - Aging Strikes the Self-Face Advantage in Featural Processing. AB - : Background/Study Context: The face is the most distinctive physical feature of a person. Previous work has shown that one's own face (self-face) is advantageous in perception. Here the authors investigate how aging influences the configural and featural processing of self-face. METHODS: Older and young adults searched for their own faces and faces of strangers (Experiment 1) or acquaintances (Experiment 2) among distractor faces. The configural and featural processing of faces was assessed with face inversion in Experiment 1 and with changes in point of view in Experiment 2. RESULTS: Experiment 1 revealed a robust self-face advantage for upright faces in both young and older adults. A similar advantage was observed for inverted faces in young but not in older adults. Experiment 2 revealed a self-face advantage in older adults regardless of the point of view; in young adults, however, the self-face advantage only emerged for frontal view faces. CONCLUSION: The present study shows that older adults have a self-face advantage in configural but not in featural processing. The authors suggest that the impairment in featural processing in older adults is likely the result of age related changes in perceptual experience. PMID- 28718752 TI - The Impact of Presentation Format on Younger and Older Adults' Self-Regulated Learning. AB - : Background/Study Context: Self-regulated learning involves deciding what to study and for how long. Debate surrounds whether individuals' selections are influenced more by item complexity, point values, or if instead people select in a left-to-right reading order, ignoring item complexity and value. The present study manipulated whether point values and presentation format favored selection of simple or complex Chinese-English pairs to assess the impact on younger and older adults' selection behaviors. METHODS: One hundred and five younger (Mage = 20.26, SD = 2.38) and 102 older adults (Mage = 70.28, SD = 6.37) participated in the experiment. Participants studied four different 3 * 3 grids (two per trial), each containing three simple, three medium, and three complex Chinese-English vocabulary pairs presented in either a simple-first or complex-first order, depending on condition. Point values were assigned in either a 2-4-8 or 8-4-2 order so that either simple or complex items were favored. RESULTS: Points did not influence the order in which either age group selected items, whereas presentation format did. Younger and older adults selected more simple or complex items when they appeared in the first column. However, older adults selected and allocated more time to simpler items but recalled less overall than did younger adults. Memory beliefs and working memory capacity predicted study time allocation, but not item selection, behaviors. CONCLUSION: Presentation format must be considered when evaluating which theory of self-regulated learning best accounts for younger and older adults' study behaviors and whether there are age related differences in self-regulated learning. The results of the present study combine with others to support the importance of also considering the role of external factors (e.g., working memory capacity and memory beliefs) in each age group's self-regulated learning decisions. PMID- 28718753 TI - Aging and List-Wide Modulations of Strategy Execution:A Study in Arithmetic. AB - : Background/Study Context: This study aimed at further our understanding of the cognitive processes involved during strategy execution, and how the processes involved change with age. More specifically, the main goal was to investigate whether poorer-strategy effects (i.e., poorer performance when a cued strategy is not the best) and sequential modulations of poorer-strategy effects (i.e., decreased poorer-strategy effects on current problems following poorer-strategy problems compared with after better-strategy problems) are influenced by proportions of poorer-strategy problems. METHODS: We used a computational estimation task (i.e., providing approximate products to two-digit multiplication problems such as 38 * 74) with problems sets including 75%, 50%, or 25% of poorer strategy problems (i.e., participants have to estimate products with another strategy than the better strategy). The remaining problems were cued with the better strategy. Age-related differences were also investigated. RESULTS: We found that proportions of poorer-strategy problems influenced sequential modulations of poorer-strategy effects. Indeed, sequential modulations of poorer strategy effects were larger when proportions of poorer-strategy problems were equal than unequal. Moreover, proportion effects were different for young and older adults, as older adults benefited more from low proportions of poorer strategy problems compared with young adults. CONCLUSION: These findings have important implications regarding cognitive control mechanisms underlying both list-wide and trial-to-trial modulations of strategy execution, and how these processes change during aging. PMID- 28718754 TI - Rhythmic Interlimb Coordination Impairments Are Associated With Mobility Limitations Among Older Adults. AB - : Background/Study Context: Mobility limitations affect more than 25% of adults aged 70 years or older. This study tested the hypothesis that impairments in ankle and shoulder coordination are associated with mobility limitations among older adults. METHODS: his study consisted of conducted a cross-sectional analysis from a sample of community-dwelling older adults (N = 130) aged >=67 years. Motion capture equipment was used to collect kinematic data during rhythmic antiphase coordination of the right and left: (a) ankles moving in dorsi plantarflexion; and (b) glenohumeral ("shoulder") moving in flexion-extension while paced by an auditory metronome. Coordination variability was measured as the standard deviation of the relative phase between right and left body segments. Mobility limitations were defined as a score of <=9 on the Short Physical Performance Battery (SPPB). Odds ratios for mobility limitations as a function of coordination variability quartiles were determined using multivariable logistic regression. RESULTS: Adjusting for age, gender, body mass index, number of chronic conditions and Mini-Mental State Examination score, the odds ratios for mobility limitation (SPPB score <=9) were 7.38 (95% confidence interval [CI]: 2.20-24.78) and 15.40 (95% CI: 4.31-55.07) for the 3rd and 4th (the poorest) ankle coordination quartiles, respectively, and 6.73 (95% CI: 2.11 21.51) for the 4th shoulder coordination quartile, compared with the best (the 1st) coordination quartiles. CONCLUSION: The results supported the hypothesis that impaired interlimb ankle and shoulder coordination are associated with the manifestation of mobility limitations. These findings indicate the need for further study of the role of coordination impairments as potential contributors to poor mobility among older adults. PMID- 28718755 TI - Preliminary Evidence For The Effects Of Aging And Multiple Sclerosis On Cognitive Performance: An Analysis Based On Effect Size Estimates. AB - : Background/Study Context: Although cognitive impairment is common in persons with multiple sclerosis (MS), there are limited data on older adults with MS. The current pilot study involved a preliminary examination of cognitive impairments across a comprehensive neuropsychological assessment in older adults with MS compared with older adults without MS. METHODS: Twenty older adults with MS and 20 older adults without MS (>=60 years of age) underwent cognitive assessments, including the Trail Making Test (TMT) and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). The primary analytical model involved independent-samples t tests on the TMT and RBANS scores. The analysis focused on 1/2 SD (i.e., Cohen's d of 0.5) for judging the differences as meaningful. RESULTS: Overall, the study hypotheses were supported such that older adults with MS demonstrated decreased cognitive performance that exceeded 1/2 SD compared with the older adults without MS. CONCLUSION: This preliminary study demonstrated moderate and meaningful differences in cognitive performance in older adults with MS compared with older adults without MS. This suggests a clear need for identifying strategies for alleviating cognitive impairment in older adults with MS. PMID- 28718756 TI - Stereotypes Influence Destination Memory In Normal Aging. AB - : Background/Study Context: A substantial body of literature suggests that stereotypes can play a determining role in making judgments about the source of information. This study investigated this issue for destination memory or remembering to whom information has been previously told. METHODS: Younger adults and older adults told six medical and six mechanical facts to a picture depicting a physician, and also told six different medical and six different mechanical facts to a picture depicting a mechanic. On a subsequent recognition task, participants had to decide to whom each fact had been previously told. RESULTS: Analysis showed better destination memory for destination-consistent facts than for inconsistent facts, a stereotypical tendency that was more apparent in older adults than in younger adults. Difficulties in attributing facts to their fact inconsistent destination were reliably correlated with executive functions in younger adults and older adults. CONCLUSION: Executive functions are likely to be required to monitor discrepancies between facts and their inconsistent destination, whereas no such monitoring is required when statements are consistent with their destination. PMID- 28718757 TI - The Impact Of Dispositional Variables Of Elders, Relatives, And Paid Caregivers On Elders' Empowerment And Life Satisfaction. AB - : Background/Study Context: The impact of dispositional characteristic of elders' closest network members on elders' life satisfaction and empowerment has remained largely unexplored. This innovative study aimed to assess the impact of dispositional variables of elders, relatives, and paid caregivers on life satisfaction and empowerment of elders. METHODS: One hundred forty-three triads (one elder, one paid caregiver, and one relative) completed six scales measuring modifiable personality characteristics (loneliness, optimism, regulation of positive and negative emotions), life satisfaction, and sense of empowerment. RESULTS: Two dispositional variables of relatives (positivity and ability to set goals) and one dispositional variable of care workers (self-satisfaction) were significantly related to life satisfaction of elders. Positivity of elders and the capacity to set objectives of the family members affected empowerment of elders. CONCLUSION: Future interventions aiming to improve life satisfaction and empowerment of elders should focus on these modifiable dispositional variables. PMID- 28718758 TI - Resignation Syndrome: Is it a New Phenomenon or is it Catatonia? PMID- 28718759 TI - Qualitative Investigation of the Wellness Recovery Action Plan in a UK NHS Crisis Care Setting. AB - Crisis theory suggests that in addition to presenting a threat to mental well being, crises are also opportunities where successful interventions can lead to successful outcomes. UK mental health crisis teams aim to reduce hospital admission by treating people at home and by building resilience and supporting learning from crisis, yet data on repeat crisis episodes suggest this could be improved. This qualitative study sought to explore the Wellness Recovery Action Plan (WRAP) as a means of supporting resilience-building and maximising the opportunity potential of crisis. The following themes emerged: The meaning of crisis; Engaging with the WRAP process; WRAP and self-management; and Changes and transformations. This research suggests that WRAP has potential in supporting recovery from crisis, revealing insights into the nature of crisis which can inform the further development of crisis services. PMID- 28718760 TI - CD25 expression and outcomes in older patients with acute myelogenous leukemia treated with plerixafor and decitabine. AB - We investigated CD25 expression in older (>=60 years) patients with new acute myelogenous leukemia treated with decitabine and plerixafor. Patients resistant to therapy or survival <=1 year had significantly higher percentages of CD25pos myeloid blasts in baseline bone marrow. CD25pos patients had an increased odds of resistance compared to CD25neg patients (p = .015). In univariate analysis, we found CD25pos patients had inferior survival compared to CD25neg (p = .002). In patients with intermediate risk cytogenetics, CD25pos status stratified patients associating with inferior survival (p = .002). In multivariable analysis, CD25 and TP53 mutations trended towards predicting remission to therapy but were not predictive of survival. Only remission status, ASXL1 and TET2 mutations were found to independently predict overall survival (OS). We conclude CD25 expression identifies patients at risk for resistance to hypomethylating chemotherapy but does not independently predict OS in an older AML population treated with decitabine and plerixafor. PMID- 28718761 TI - The human cytoplasmic dynein interactome reveals novel activators of motility. AB - In human cells, cytoplasmic dynein-1 is essential for long-distance transport of many cargos, including organelles, RNAs, proteins, and viruses, towards microtubule minus ends. To understand how a single motor achieves cargo specificity, we identified the human dynein interactome by attaching a promiscuous biotin ligase ('BioID') to seven components of the dynein machinery, including a subunit of the essential cofactor dynactin. This method reported spatial information about the large cytosolic dynein/dynactin complex in living cells. To achieve maximal motile activity and to bind its cargos, human dynein/dynactin requires 'activators', of which only five have been described. We developed methods to identify new activators in our BioID data, and discovered that ninein and ninein-like are a new family of dynein activators. Analysis of the protein interactomes for six activators, including ninein and ninein-like, suggests that each dynein activator has multiple cargos. PMID- 28718762 TI - Sec17/Sec18 act twice, enhancing membrane fusion and then disassembling cis-SNARE complexes. AB - At physiological protein levels, the slow HOPS- and SNARE-dependent fusion which occurs upon complete SNARE zippering is stimulated by Sec17 and Sec18:ATP without requiring ATP hydrolysis. To stimulate, Sec17 needs its central residues which bind the 0-layer of the SNARE complex and its N-terminal apolar loop. Adding a transmembrane anchor to the N-terminus of Sec17 bypasses this requirement for apolarity of the Sec17 loop, suggesting that the loop functions for membrane binding rather than to trigger bilayer rearrangement. In contrast, when complete C-terminal SNARE zippering is prevented, fusion strictly requires Sec18 and Sec17, and the Sec17 apolar loop has functions beyond membrane anchoring. Thus Sec17 and Sec18 act twice in the fusion cycle, binding to trans-SNARE complexes to accelerate fusion, then hydrolyzing ATP to disassemble cis-SNARE complexes. PMID- 28718763 TI - A theory of working memory without consciousness or sustained activity. AB - Working memory and conscious perception are thought to share similar brain mechanisms, yet recent reports of non-conscious working memory challenge this view. Combining visual masking with magnetoencephalography, we investigate the reality of non-conscious working memory and dissect its neural mechanisms. In a spatial delayed-response task, participants reported the location of a subjectively unseen target above chance-level after several seconds. Conscious perception and conscious working memory were characterized by similar signatures: a sustained desynchronization in the alpha/beta band over frontal cortex, and a decodable representation of target location in posterior sensors. During non conscious working memory, such activity vanished. Our findings contradict models that identify working memory with sustained neural firing, but are compatible with recent proposals of 'activity-silent' working memory. We present a theoretical framework and simulations showing how slowly decaying synaptic changes allow cell assemblies to go dormant during the delay, yet be retrieved above chance-level after several seconds. PMID- 28718764 TI - CRISPR-mediated genetic interaction profiling identifies RNA binding proteins controlling metazoan fitness. AB - Genetic interaction screens have aided our understanding of complex genetic traits, diseases, and biological pathways. However, approaches for synthetic genetic analysis with null-alleles in metazoans have not been feasible. Here, we present a CRISPR/Cas9-based Synthetic Genetic Interaction (CRISPR-SGI) approach enabling systematic double-mutant generation. Applying this technique in Caenorhabditis elegans, we comprehensively screened interactions within a set of 14 conserved RNA binding protein genes, generating all possible single and double mutants. Many double mutants displayed fitness defects, revealing synthetic interactions. For one interaction between the MBNL1/2 ortholog mbl-1 and the ELAVL ortholog exc-7, double mutants displayed a severely shortened lifespan. Both genes are required for regulating hundreds of transcripts and isoforms, and both may play a critical role in lifespan extension through insulin signaling. Thus, CRISPR-SGI reveals a rich genetic interaction landscape between RNA binding proteins in maintaining organismal health, and will serve as a paradigm applicable to other biological questions. PMID- 28718766 TI - Structural insights into the light-driven auto-assembly process of the water oxidizing Mn4CaO5-cluster in photosystem II. AB - In plants, algae and cyanobacteria, Photosystem II (PSII) catalyzes the light driven splitting of water at a protein-bound Mn4CaO5-cluster, the water-oxidizing complex (WOC). In the photosynthetic organisms, the light-driven formation of the WOC from dissolved metal ions is a key process because it is essential in both initial activation and continuous repair of PSII. Structural information is required for understanding of this chaperone-free metal-cluster assembly. For the first time, we obtained a structure of PSII from Thermosynechococcus elongatus without the Mn4CaO5-cluster. Surprisingly, cluster-removal leaves the positions of all coordinating amino acid residues and most nearby water molecules largely unaffected, resulting in a pre-organized ligand shell for kinetically competent and error-free photo-assembly of the Mn4CaO5-cluster. First experiments initiating (i) partial disassembly and (ii) partial re-assembly after complete depletion of the Mn4CaO5-cluster agree with a specific bi-manganese cluster, likely a di-u-oxo bridged pair of Mn(III) ions, as an assembly intermediate. PMID- 28718765 TI - A connectome of a learning and memory center in the adult Drosophila brain. AB - Understanding memory formation, storage and retrieval requires knowledge of the underlying neuronal circuits. In Drosophila, the mushroom body (MB) is the major site of associative learning. We reconstructed the morphologies and synaptic connections of all 983 neurons within the three functional units, or compartments, that compose the adult MB's alpha lobe, using a dataset of isotropic 8 nm voxels collected by focused ion-beam milling scanning electron microscopy. We found that Kenyon cells (KCs), whose sparse activity encodes sensory information, each make multiple en passant synapses to MB output neurons (MBONs) in each compartment. Some MBONs have inputs from all KCs, while others differentially sample sensory modalities. Only 6% of KC>MBON synapses receive a direct synapse from a dopaminergic neuron (DAN). We identified two unanticipated classes of synapses, KC>DAN and DAN>MBON. DAN activation produces a slow depolarization of the MBON in these DAN>MBON synapses and can weaken memory recall. PMID- 28718767 TI - In vitro analysis of RQC activities provides insights into the mechanism and function of CAT tailing. AB - Ribosomes can stall during translation due to defects in the mRNA template or translation machinery, leading to the production of incomplete proteins. The Ribosome-associated Quality control Complex (RQC) engages stalled ribosomes and targets nascent polypeptides for proteasomal degradation. However, how each RQC component contributes to this process remains unclear. Here we demonstrate that key RQC activities-Ltn1p-dependent ubiquitination and Rqc2p-mediated Carboxy terminal Alanine and Threonine (CAT) tail elongation-can be recapitulated in vitro with a yeast cell-free system. Using this approach, we determined that CAT tailing is mechanistically distinct from canonical translation, that Ltn1p mediated ubiquitination depends on the poorly characterized RQC component Rqc1p, and that the process of CAT tailing enables robust ubiquitination of the nascent polypeptide. These findings establish a novel system to study the RQC and provide a framework for understanding how RQC factors coordinate their activities to facilitate clearance of incompletely synthesized proteins. PMID- 28718768 TI - Selective and regulated trapping of nicotinic receptor weak base ligands and relevance to smoking cessation. AB - To better understand smoking cessation, we examined the actions of varenicline (Chantix) during long-term nicotine exposure. Varenicline reduced nicotine upregulation of alpha4beta2-type nicotinic receptors (alpha4beta2Rs) in live cells and neurons, but not for membrane preparations. Effects on upregulation depended on intracellular pH homeostasis and were not observed if acidic pH in intracellular compartments was neutralized. Varenicline was trapped as a weak base in acidic compartments and slowly released, blocking 125I-epibatidine binding and desensitizing alpha4beta2Rs. Epibatidine itself was trapped; 125I epibatidine slow release from acidic vesicles was directly measured and required the presence of alpha4beta2Rs. Nicotine exposure increased epibatidine trapping by increasing the numbers of acidic vesicles containing alpha4beta2Rs. We conclude that varenicline as a smoking cessation agent differs from nicotine through trapping in alpha4beta2R-containing acidic vesicles that is selective and nicotine-regulated. Our results provide a new paradigm for how smoking cessation occurs and suggest how more effective smoking cessation reagents can be designed. PMID- 28718770 TI - Benchmarking GATE/Geant4 for 16O ion beam therapy. AB - Oxygen ([Formula: see text]) ions are a potential alternative to carbon ions in ion beam therapy. Their enhanced linear energy transfer indicates a higher relative biological effectiveness and a reduced oxygen enhancement ratio. Due to the limited availability of [Formula: see text] ion beams, Monte Carlo (MC) transport codes are important research tools for investigating their potential. The purpose of this study was to validate GATE/Geant4 for [Formula: see text] ion beam therapy using experimental data from literature. Five hadron physics lists and two electromagnetic options were benchmarked against measured depth dose distributions (DDDs) and charge-changing cross sections. The simulated beam ranges deviated by less than 0.5% for all physics configurations and only a few points exceeded the gamma index criterion (2%/1 mm). However, the simulated partial charge-changing cross sections deviated considerably for some hadron physics configurations. Best agreement with the experimental values was obtained with the quantum molecular dynamics model (QMD), and we therefore suggest using this model in Geant4 to accurately describe the fragmentation of [Formula: see text] ion beams into lighter fragments ([Formula: see text]). PMID- 28718769 TI - Pesticide Exposure and Risk of Rheumatoid Arthritis among Licensed Male Pesticide Applicators in the Agricultural Health Study. AB - BACKGROUND: The occupation of farming has been associated with rheumatoid arthritis (RA); pesticides may account for this association, but there are few studies. OBJECTIVES: We investigated associations between RA and use of pesticides in the Agricultural Health Study. METHODS: The study sample was drawn from male pesticide applicators enrolled in 1993-1997 who provided questionnaire data at baseline and at least once during follow-up (over a median 18 y; interquartile range 16-19). Incident RA cases (n=220), confirmed by physicians or by self-reported use of disease-modifying antirheumatic drugs, were compared with noncases (n=26,134) who did not report RA. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression, adjusting for enrollment age, state, smoking pack-years, and education. We evaluated the association of RA with the use of 46 pesticides and across 4 levels (never use and tertiles) of lifetime days of use for 16 pesticides with OR>=1.2 for ever use. RESULTS: Incident RA was associated with ever use of fonofos (OR = 1.70; 95% CI: 1.22, 2.37), carbaryl (OR = 1.51; 95% CI: 1.03, 2.23), and chlorimuron ethyl (OR = 1.45; 95% CI: 1.01, 2.07) compared with never use. Statistically significant exposure-response trends in association with RA were observed for lifetime days of use of atrazine [ORtertile3= 1.62 (95% CI: 1.09, 2.40); ptrend=0.01] and toxaphene [ORtertile3= 2.42 (95% CI: 1.03, 5.68); ptrend=0.02]. Exposure-response was nonlinear for fonofos [ORtertile1= 2.27 (95% CI: 1.44, 3.57); ORtertile2= 0.98 (95% CI: 0.54, 1.80); ORtertile3= 2.10 (95% CI: 1.32, 3.36); ptrend=0.005] and suggestive for carbaryl (ptrend=0.053). CONCLUSIONS: Our results provide novel evidence of associations between exposure to some pesticides and RA in male farmers. https://doi.org/10.1289/EHP1013. PMID- 28718771 TI - Substitutional carbon doping of free-standing and Ru-supported BN sheets: a first principles study. AB - The development of spatially homogeneous mixed structures with boron (B), nitrogen (N) and carbon (C) atoms arranged in a honeycomb lattice is highly desirable, as they open the possibility of creating stable two-dimensional materials with tunable band gaps. However, at least in the free-standing form, the mixed BCN system is energetically driven towards phase segregation to graphene and hexagonal BN. It is possible to overcome the segregation when BCN material is grown on a particular metal substrate, for example Ru(0 0 0 1), but the stabilization mechanism is still unknown. With the use of density-functional theory we study the energetics of BN/Ru slabs, with different types of configurations of C substitutional defects introduced to the h-BN overlayer. The results are compared to the energetics of free-standing BCN materials. We found that the substrate facilitates the C substitution process in the h-BN overlayer. Thus, more homogeneous BCN material can be grown, overcoming the segregation into graphene and h-BN. In addition, we investigate the electronic and transport gaps in free-standing BCN structures, and assess their mechanical properties and stability. The band gap in mixed BCN free-standing material depends on the concentration of the constituent elements and ranges from zero in pristine graphene to nearly 5 eV in free-standing h-BN. This makes BCN attractive for application in modern electronics. PMID- 28718772 TI - Performance evaluation of MACACO: a multilayer Compton camera. AB - Compton imaging devices have been proposed and studied for a wide range of applications. We have developed a Compton camera prototype which can be operated with two or three detector layers based on monolithic lanthanum bromide ([Formula: see text]) crystals coupled to silicon photomultipliers (SiPMs), to be used for proton range verification in hadron therapy. In this work, we present the results obtained with our prototype in laboratory tests with radioactive sources and in simulation studies. Images of a [Formula: see text]Na and an [Formula: see text]Y radioactive sources have been successfully reconstructed. The full width half maximum of the reconstructed images is below 4 mm for a [Formula: see text]Na source at a distance of 5 cm. PMID- 28718773 TI - Mouse epileptic seizure detection with multiple EEG features and simple thresholding technique. AB - OBJECTIVE: Epilepsy is a common neurological disorder characterized by recurrent, unprovoked seizures. The search for new treatments for seizures and epilepsy relies upon studies in animal models of epilepsy. To capture data on seizures, many applications require prolonged electroencephalography (EEG) with recordings that generate voluminous data. The desire for efficient evaluation of these recordings motivates the development of automated seizure detection algorithms. APPROACH: A new seizure detection method is proposed, based on multiple features and a simple thresholding technique. The features are derived from chaos theory, information theory and the power spectrum of EEG recordings and optimally exploit both linear and nonlinear characteristics of EEG data. MAIN RESULT: The proposed method was tested with real EEG data from an experimental mouse model of epilepsy and distinguished seizures from other patterns with high sensitivity and specificity. SIGNIFICANCE: The proposed approach introduces two new features: negative logarithm of adaptive correlation integral and power spectral coherence ratio. The combination of these new features with two previously described features, entropy and phase coherence, improved seizure detection accuracy significantly. Negative logarithm of adaptive correlation integral can also be used to compute the duration of automatically detected seizures. PMID- 28718774 TI - Effects of microchannel confinement on acoustic vaporisation of ultrasound phase change contrast agents. AB - The sub-micron phase change contrast agent (PCCA) composed of a perfluorocarbon liquid core can be activated into gaseous state and form stable echogenic microbubbles for contrast-enhanced ultrasound imaging. It has shown great promise in imaging microvasculature, tumour microenvironment, and cancer cells. Although PCCAs have been extensively studied for different diagnostic and therapeutic applications, the effect of biologically geometrical confinement on the acoustic vaporisation of PCCAs is still not clear. We have investigated the difference in PCCA-produced ultrasound contrast enhancement after acoustic activation with and without a microvessel confinement on a microchannel phantom. The experimental results indicated more than one-order of magnitude less acoustic vaporisation in a microchannel than that in a free environment taking into account the attenuation effect of the vessel on the microbubble scattering. This may provide an improved understanding in the applications of PCCAs in vivo. PMID- 28718775 TI - High performance top-gated multilayer WSe2 field effect transistors. AB - In this paper, high performance top-gated WSe2 field effect transistor (FET) devices are demonstrated via a two-step remote plasma assisted ALD process. High quality, low-leakage aluminum oxide (Al2O3) gate dielectric layers are deposited onto the WSe2 channel using a remote plasma assisted ALD process with an ultrathin (~1 nm) titanium buffer layer. The first few nanometers (~2 nm) of the Al2O3 dielectric film is deposited at relatively low temperature (i.e. 50 degrees C) and remainder of the film is deposited at 150 degrees C to ensure the conformal coating of Al2O3 on the WSe2 surface. Additionally, an ultra-thin titanium buffer layer is introduced at the WSe2 channel surface prior to ALD process to mitigate oxygen plasma induced doping effects. Excellent device characteristics with current on-off ratio in excess of 106 and a field effect mobility as high as 70.1 cm2 V-1 s-1 are achieved in a few-layer WSe2 FET device with a 30 nm Al2O3 top-gate dielectric. With further investigation and careful optimization, this method can play an important role for the realization of high performance top gated FETs for future optoelectronic device applications. PMID- 28718776 TI - Coil geometry effects on scanning single-coil magnetic induction tomography. AB - Alternative coil designs for single coil magnetic induction tomography are considered in this work, with the intention of improving upon the standard design used previously. In particular, we note that the blind spot associated with this coil type, a portion of space along its axis where eddy current generation can be very weak, has an important effect on performance. The seven designs tested here vary considerably in the size of their blind spot. To provide the most discerning test possible, we use laboratory phantoms containing feature dimensions similar to blind spot size. Furthermore, conductivity contrasts are set higher than what would occur naturally in biological systems, which has the effect of weakening eddy current generation at coil locations that straddle the border between high and low conductivity features. Image reconstruction results for the various coils show that coils with smaller blind spots give markedly better performance, though improvements in signal-to-noise ratio could alter that conclusion. PMID- 28718777 TI - An assembly and interaction of upconversion and plasmonic nanoparticles on organometallic nanofibers: enhanced multicolor upconversion, downshifting emission and the plasmonic effect. AB - We present novel inorganic-organic hybrid nanoparticles (HNPs) constituting inorganic NPs, NaY0.78Er0.02Yb0.2F4, and organometallic nanofiber, Tb(ASA)3Phen (TAP). X-ray diffraction, Fourier transform infrared absorption and transmission electron microscopy analyses reveal that prepared ultrafine upconversion NPs (UCNPs (5-8 nm)) are dispersed on the surface of the TAP nanofibers. We observe that the addition of TAP in UCNPs effectively limits the surface quenching to boost the upconversion (UC) intensity and enables tuning of UC emission from the green to the red region by controlling the phonon frequency around the Er3+ ion. On the other hand, TAP is an excellent source of green emission under ultraviolet exposure. Therefore prepared HNPs not only give enhanced and tunable UC but also emit a strong green color in the downshifting (DS) process. To further enhance the dual-mode emission of HNPs, silver NPs (AgNPs) are introduced. The emission intensity of UC as well as DS emission is found to be strongly modulated in the presence of AgNPs. It is found that AgNPs enhance red UC emission. The possible mechanism involved in enhanced emission intensity and color output is investigated in detail. The important optical properties of these nano-hybrid materials provide a great opportunity in the fields of biological imaging, drug delivery and energy devices. PMID- 28718778 TI - Tailoring of magnetic orderings in Fe substituted GdMnO3 bulk samples towards room temperature. AB - The evolution of various magnetic ordering has been studied for the orthorhombic perovskite GdMn1-x Fe x O3 (0 ? x ? 0.7) system to obtain its comprehensive magnetic phase diagram. We observed that the substitution of Fe in GdMnO3 increases the antiferromagnetic Neel temperature (T N) from 40 K to above 400 K and importantly induces a spin-reorientation transition (T SR) for x ? 0.4. These transitions are close to room temperature at x = 0.5 and then gradually separated at a higher x value. The static orbital ordering induced by the Jahn Teller distortion seems to play an important role in changing the T N. The variations of spin-reorientation ordering along with the competition between the magnetic orderings as a function of the composition were discussed with respect to antisymmetric exchange interactions and Mn3+ single-ion anisotropy in detail. In addition, the correlation between structural and magnetic properties suggests that the subtle structural change at composition x = 0.4 may affect the magnetic ordering. The observed tunable T SR and T N in GdMn1-x Fe x O3 could add a practical value for these compositions in fields like spintronics and sensors. PMID- 28718779 TI - A review and experimental study on the application of classifiers and evolutionary algorithms in EEG-based brain-machine interface systems. AB - OBJECTIVE: Considering the importance and the near-future development of noninvasive brain-machine interface (BMI) systems, this paper presents a comprehensive theoretical-experimental survey on the classification and evolutionary methods for BMI-based systems in which EEG signals are used. APPROACH: The paper is divided into two main parts. In the first part, a wide range of different types of the base and combinatorial classifiers including boosting and bagging classifiers and evolutionary algorithms are reviewed and investigated. In the second part, these classifiers and evolutionary algorithms are assessed and compared based on two types of relatively widely used BMI systems, sensory motor rhythm-BMI and event-related potentials-BMI. Moreover, in the second part, some of the improved evolutionary algorithms as well as bi objective algorithms are experimentally assessed and compared. MAIN RESULTS: In this study two databases are used, and cross-validation accuracy (CVA) and stability to data volume (SDV) are considered as the evaluation criteria for the classifiers. According to the experimental results on both databases, regarding the base classifiers, linear discriminant analysis and support vector machines with respect to CVA evaluation metric, and naive Bayes with respect to SDV demonstrated the best performances. Among the combinatorial classifiers, four classifiers, Bagg-DT (bagging decision tree), LogitBoost, and GentleBoost with respect to CVA, and Bagging-LR (bagging logistic regression) and AdaBoost (adaptive boosting) with respect to SDV had the best performances. Finally, regarding the evolutionary algorithms, single-objective invasive weed optimization (IWO) and bi-objective nondominated sorting IWO algorithms demonstrated the best performances. SIGNIFICANCE: We present a general survey on the base and the combinatorial classification methods for EEG signals (sensory motor rhythm and event-related potentials) as well as their optimization methods through the evolutionary algorithms. In addition, experimental and statistical significance tests are carried out to study the applicability and effectiveness of the reviewed methods. PMID- 28718780 TI - Biarticular elements as a contributor to energy efficiency: biomechanical review and application in bio-inspired robotics. AB - Despite the increased interest in exoskeleton research in the last decades, not much progress has been made on the successful reduction of user effort. In humans, biarticular elements have been identified as one of the reasons for the energy economy of locomotion. This document gives an extensive literature overview concerning the function of biarticular muscles in human beings. The exact role of these muscles in the efficiency of human locomotion is reduced to three elementary functions: energy transfer towards distal joints, efficient control of output force direction and double joint actuation. This information is used to give an insight in the application of biarticular elements in bio inspired robotics, i.e. bipedal robots, exoskeletons, robotic manipulators and prostheses. Additionally, an attempt is made to find an answer on the question whether the biarticular property leads to a unique contribution to energy efficiency of locomotion, unachievable by mono-articular alternatives. This knowledge is then further utilised to indicate how biarticular actuation of exoskeletons can contribute to an increased performance in reducing user effort. PMID- 28718781 TI - Latent variable method for automatic adaptation to background states in motor imagery BCI. AB - OBJECTIVE: Brain-computer interface (BCI) systems are known to be vulnerable to variabilities in background states of a user. Usually, no detailed information on these states is available even during the training stage. Thus there is a need in a method which is capable of taking background states into account in an unsupervised way. APPROACH: We propose a latent variable method that is based on a probabilistic model with a discrete latent variable. In order to estimate the model's parameters, we suggest to use the expectation maximization algorithm. The proposed method is aimed at assessing characteristics of background states without any corresponding data labeling. In the context of asynchronous motor imagery paradigm, we applied this method to the real data from twelve able-bodied subjects with open/closed eyes serving as background states. MAIN RESULTS: We found that the latent variable method improved classification of target states compared to the baseline method (in seven of twelve subjects). In addition, we found that our method was also capable of background states recognition (in six of twelve subjects). SIGNIFICANCE: Without any supervised information on background states, the latent variable method provides a way to improve classification in BCI by taking background states into account at the training stage and then by making decisions on target states weighted by posterior probabilities of background states at the prediction stage. PMID- 28718782 TI - Prediction of Protein Hotspots from Whole Protein Sequences by a Random Projection Ensemble System. AB - Hotspot residues are important in the determination of protein-protein interactions, and they always perform specific functions in biological processes. The determination of hotspot residues is by the commonly-used method of alanine scanning mutagenesis experiments, which is always costly and time consuming. To address this issue, computational methods have been developed. Most of them are structure based, i.e., using the information of solved protein structures. However, the number of solved protein structures is extremely less than that of sequences. Moreover, almost all of the predictors identified hotspots from the interfaces of protein complexes, seldom from the whole protein sequences. Therefore, determining hotspots from whole protein sequences by sequence information alone is urgent. To address the issue of hotspot predictions from the whole sequences of proteins, we proposed an ensemble system with random projections using statistical physicochemical properties of amino acids. First, an encoding scheme involving sequence profiles of residues and physicochemical properties from the AAindex1 dataset is developed. Then, the random projection technique was adopted to project the encoding instances into a reduced space. Then, several better random projections were obtained by training an IBk classifier based on the training dataset, which were thus applied to the test dataset. The ensemble of random projection classifiers is therefore obtained. Experimental results showed that although the performance of our method is not good enough for real applications of hotspots, it is very promising in the determination of hotspot residues from whole sequences. PMID- 28718784 TI - Investigation of the Effect of the Degree of Processing of Radix Rehmanniae Preparata (Shu Dihuang) on Shu Dihuangtan Carbonization Preparation Technology. AB - Carbonization of Radix Rehmanniae Preparata (Shu Dihuangtan) via stir-frying could increase its homeostasis maintaining and antidiarrheal effects. To ensure these pharmacological functions, the quality of the raw material (processed Rehmanniae Radix) must be well controlled. Therefore, we analyzed the effects of different degrees of processing and adjuvants on processed Rehmanniae Radix (Shu Dihuang) by High Performance Liquid Chromatography (HPLC) chromatographic fingerprints, thermal gravimetric analysis and Fourier transform infrared spectroscopy (FTIR). Based on the results from HPLC fingerprints combined with similarity analysis (SA) and hierarchical cluster analysis (HCA) the optimum processing method for Shu Dihuang was five cycles of steaming and polishing, which follows the ancient processing theory. The intensity of thermal weight loss rate peaked near 210.33 +/- 4.32 degrees C or 211.33 +/- 2.62 degrees C, which was an important indicator for the degree of processing of Shu Dihuang. A temperature near 290.89 +/- 2.51 degrees C was the upper limit for carbonizing Shu Dihuangtan. FTIR spectroscopy analysis showed that the overall chemical composition of Shu Dihuangtan was affected by both the degree of processing and adjuvant, which are very important for its quality. PMID- 28718783 TI - Metallothionein from Wild Populations of the African Catfish Clarias gariepinus: From Sequence, Protein Expression and Metal Binding Properties to Transcriptional Biomarker of Metal Pollution. AB - Anthropogenic pollution with heavy metals is an on-going concern throughout the world, and methods to monitor release and impact of heavy metals are of high importance. With a view to probe its suitability as molecular biomarker of metal pollution, this study has determined a coding sequence for metallothionein of the African sharptooth catfish Clarias gariepinus. The gene product was recombinantly expressed in Escherichia coli in presence of Zn(II), Cd(II), or Cu, and characterised by Electrospray Ionisation Mass Spectrometry and elemental analysis. C. gariepinus MT displays typical features of fish MTs, including 20 conserved cysteines, and seven bound divalent cations (Zn(II) or Cd(II)) when saturated. Livers from wild C. gariepinus fish collected in all three seasons from four different sites on the Kafue River of Zambia were analysed for their metal contents and for MT expression levels by quantitative PCR. Significant correlations were found between Zn and Cu levels and MT expression in livers, with MT expression clearly highest at the most polluted site, Chililabombwe, which is situated in the Copperbelt region. Based on our findings, hepatic expression of MT from C. gariepinus may be further developed as a major molecular biomarker of heavy metal pollution resulting from mining activities in this region. PMID- 28718785 TI - UV-Surface Treatment of Fungal Resistant Polyether Polyurethane Film-Induced Growth of Entomopathogenic Fungi. AB - Synthetic polymers are the cause of some major environmental impacts due to their low degradation rates. Polyurethanes (PU) are widely used synthetic polymers, and their growing use in industry has produced an increase in plastic waste. A commercial polyether-based thermoplastic PU with hydrolytic stability and fungus resistance was only attacked by an entomopathogenic fungus, Metarhiziumanisopliae, when the films were pre-treated with Ultraviolet (UV) irradiation in the presence of reactive atmospheres. Water contact angle, Fourier transform infrared spectroscopy in attenuated total reflection mode (FTIR-ATR), scanning electron microscopy (SEM), and profilometer measurements were mainly used for analysis. Permanent hydrophilic PU films were produced by the UV assisted treatments. Pristine polyether PU films incubated for 10, 30, and 60 days did not show any indication of fungal growth. On the contrary, when using oxygen in the UV pre-treatment a layer of fungi spores covered the sample, indicating a great adherence of the microorganisms to the polymer. However, if acrylic acid vapors were used during the UV pre-treatment, a visible attack by the entomopathogenic fungi was observed. SEM and FTIR-ATR data showed clear evidence of fungal development: growth and ramifications of hyphae on the polymer surface with the increase in UV pre-treatment time and fungus incubation time. The results indicated that the simple UV surface activation process has proven to be a promising alternative for polyether PU waste management. PMID- 28718786 TI - Egg-Independent Influenza Vaccines and Vaccine Candidates. AB - Vaccination remains the principal way to control seasonal infections and is the most effective method of reducing influenza-associated morbidity and mortality. Since the 1940s, the main method of producing influenza vaccines has been an egg based production process. However, in the event of a pandemic, this method has a significant limitation, as the time lag from strain isolation to final dose formulation and validation is six months. Indeed, production in eggs is a relatively slow process and production yields are both unpredictable and highly variable from strain to strain. In particular, if the next influenza pandemic were to arise from an avian influenza virus, and thus reduce the egg-laying hen population, there would be a shortage of embryonated eggs available for vaccine manufacturing. Although the production of egg-derived vaccines will continue, new technological developments have generated a cell-culture-based influenza vaccine and other more recent platforms, such as synthetic influenza vaccines. PMID- 28718787 TI - A Note on Suckling Behavior and Laterality in Nursing Humpback Whale Calves from Underwater Observations. AB - We investigated nursing behavior on the Hawaiian breeding grounds for first year humpback whale (Megaptera novaeangliae) calves. We observed and video-documented underwater events with nursing behavior from five different whale groups. The observed nursing events include behaviors where a calf positions itself at a 30 45 degrees angle to the midline of the mother's body, with its mouth touching her mammary slit (i.e., suckling position). On two occasions, milk in the water column was recorded in close proximity to a mother/calf pair, and on one occasion, milk was recorded 2.5 min after suckling observed. Nursing events, where the calf was located in the suckling position, were found to be short in duration with a mean of 30.6 s (range 15.0-55.0, standard deviation (SD) = 16.9). All observations of the calf in the suckling position (n = 5, 100%) were with the calf located on the right side of the mother, suggesting a potential for right side laterality preference in the context of nursing behavior. Our study provides insight into mother/calf behaviors from a unique underwater vantage. Results supplement previous accounts of humpback whale nursing in Hawaiian waters, validate mother/calf positioning, document milk in the water column, and introduce the potential for laterality in nursing behavior for humpback whale calves. PMID- 28718788 TI - Implementation of an IMU Aided Image Stacking Algorithm in a Digital Camera for Unmanned Aerial Vehicles. AB - Images acquired with a long exposure time using a camera embedded on UAVs (Unmanned Aerial Vehicles) exhibit motion blur due to the erratic movements of the UAV. The aim of the present work is to be able to acquire several images with a short exposure time and use an image processing algorithm to produce a stacked image with an equivalent long exposure time. Our method is based on the feature point image registration technique. The algorithm is implemented on the light weight IGN (Institut national de l'information geographique) camera, which has an IMU (Inertial Measurement Unit) sensor and an SoC (System on Chip)/FPGA (Field Programmable Gate Array). To obtain the correct parameters for the resampling of the images, the proposed method accurately estimates the geometrical transformation between the first and the N-th images. Feature points are detected in the first image using the FAST (Features from Accelerated Segment Test) detector, then homologous points on other images are obtained by template matching using an initial position benefiting greatly from the presence of the IMU sensor. The SoC/FPGA in the camera is used to speed up some parts of the algorithm in order to achieve real-time performance as our ultimate objective is to exclusively write the resulting image to save bandwidth on the storage device. The paper includes a detailed description of the implemented algorithm, resource usage summary, resulting processing time, resulting images and block diagrams of the described architecture. The resulting stacked image obtained for real surveys does not seem visually impaired. An interesting by-product of this algorithm is the 3D rotation estimated by a photogrammetric method between poses, which can be used to recalibrate in real time the gyrometers of the IMU. Timing results demonstrate that the image resampling part of this algorithm is the most demanding processing task and should also be accelerated in the FPGA in future work. PMID- 28718789 TI - Flavonoid and Antioxidant Capacity of Propolis Prediction Using Near Infrared Spectroscopy. AB - The use of propolis as a dietary supplement or as an ingredient in different food products is increasing, due to its antioxidant and bactericidal properties. These nutritional properties directly depend on its phenolic composition. For this reason, this study analysed the total contents of flavones and flavonols, flavanones and dihydroflavonols, and the antioxidant capacity by using the methods of ABTS and linoleic acid/beta-carotene in 99 samples of propolis from Spain and Chile. A rapid method was developed for quantifying these parameters in raw propolis using near infrared (NIR) spectroscopy with a remote reflectance fibre-optic probe applied directly to the ground-up sample. The models developed allow for the determination of the total flavones and flavonols (0-183 mg quercetin/g propolis and 0-72 mg rutin/g propolis), of the total flavanones and dihydroflavonols (9-109 mg pinocembrin/g propolis extract), and of its antioxidant capacity by the ABTS method based on the reduction of the 2.2 azinobis(3-ethylbenzothiazoline-6-sulfonic acid) radical cation(0-3212.6 nmol Trolox/mg of propolis) and of linoleic acid/beta-carotene (22-86% inhibition). The NIR spectroscopy models were applied in external validation to different samples of the calibration group, which led to the conclusion that the methods developed provide significantly identical data to the initial chemical data of reference. PMID- 28718790 TI - Preliminary Study of UAS Equipped with Thermal Camera for Volcanic Geothermal Monitoring in Taiwan. AB - Thermal infrared cameras sense the temperature information of sensed scenes. With the development of UASs (Unmanned Aircraft Systems), thermal infrared cameras can now be carried on a quadcopter UAV (Unmanned Aircraft Vehicle) to appropriately collect high-resolution thermal images for volcanic geothermal monitoring in a local area. Therefore, the quadcopter UAS used to acquire thermal images for volcanic geothermal monitoring has been developed in Taiwan as part of this study to overcome the difficult terrain with highly variable topography and extreme environmental conditions. An XM6 thermal infrared camera was employed in this thermal image collection system. The Trimble BD970 GNSS (Global Navigation Satellite System) OEM (Original Equipment Manufacturer) board was also carried on the quadcopter UAV to gather dual-frequency GNSS observations in order to determine the flying trajectory data by using the Post-Processed Kinematic (PPK) technique; this will be used to establish the position and orientation of collected thermal images with less ground control points (GCPs). The digital surface model (DSM) and thermal orthoimages were then produced from collected thermal images. Tests conducted in the Hsiaoyukeng area of Taiwan's Yangmingshan National Park show that the difference between produced DSM and airborne LIDAR (Light Detection and Ranging) data are about 37% between -1 m and 1 m, and 66% between -2 m and 2 m in the area surrounded by GCPs. As the accuracy of thermal orthoimages is about 1.78 m, it is deemed sufficient for volcanic geothermal monitoring. In addition, the thermal orthoimages show some phenomena not only more globally than do the traditional methods for volcanic geothermal monitoring, but they also show that the developed system can be further employed in Taiwan in the future. PMID- 28718791 TI - Relationship between Aging-Related Skin Dryness and Aquaporins. AB - Skin function deteriorates with aging, and the dermal water content decreases. In this study, we have analyzed the mechanism of aging-related skin dryness focusing on aquaporins (AQPs), which are the water channels. Mice aged 3 and 20 months were designated as young and aged mice, respectively, to be used in the experiments. No differences were observed in transepidermal water loss between the young mice and aged mice. However, the dermal water content in aged mice was significantly lower than that in young mice, thus showing skin dryness. The expression of AQP1, AQP3, AQP4, AQP7, and AQP9 was observed in the skin. All the mRNA expression levels of these AQPs were significantly lower in aged mice. For AQP3, which was expressed dominantly in the skin, the protein level was lower in aged mice than in young mice. The results of the study showed that the expression level of AQPs in the skin decreased with aging, suggesting the possibility that this was one of the causes of skin dryness. New targets for the prevention and treatment of aging-related skin dryness are expected to be proposed when the substance that increases the expression of AQP3 is found. PMID- 28718792 TI - Recombinant Lipase from Gibberella zeae Exhibits Broad Substrate Specificity: A Comparative Study on Emulsified and Monomolecular Substrate. AB - Using the classical emulsified system and the monomolecular film technique, the substrate specificity of recombinant Gibberella zeae lipase (rGZEL) that originates from Gibberella zeae was characterized in detail. Under the emulsified reaction system, both phospholipase and glycolipid hydrolytic activities were observed, except for the predominant lipase activity. The optimum conditions for different activity exhibition were also determined. Compared with its lipase activity, a little higher ratio of glycolipid hydrolytic activity (0.06) than phospholipase activity (0.02) was found. rGZEL preferred medium chain-length triglycerides, while lower activity was found for the longer-chain triglyceride. Using the monomolecular film technique, we found that the preference order of rGZEL to different phospholipids was 1,2-diacyl-sn-glycero-3-phospho-l-serine (PS) > 1,2-dioleoyl-sn-glycero-3-phospho-rac-(1-glycerol) sodium salt (PG) > 1,2 dioleoyl-sn-glycero-3-phosphocholine (DOPC) > l-alpha-phosphatidylinositol (PI) > cardiolipin (CL) > 3-sn-phosphatidic acid sodium salt (PA) > l-alpha phosphatidylethanolamine (PE), while no hydrolytic activity was detected for sphingomyelin (SM). Moreover, rGZEL showed higher galactolipase activity on 1,2 distearoyimonoglactosylglyceride (MGDG). A kinetic study on the stereo- and regioselectivity of rGZEL was also performed by using three pairs of pseudodiglyceride enantiomers (DDGs). rGZEL presented higher preference for distal DDG enantiomers than adjacent ester groups, however, no hydrolytic activity to the sn-2 position of diglyceride analogs was found. Furthermore, rGZEL preferred the R configuration of DDG enantiomers. Molecular docking results were in concordance with in vitro tests. PMID- 28718793 TI - Detection of Guanine and Adenine Using an Aminated Reduced Graphene Oxide Functional Membrane-Modified Glassy Carbon Electrode. AB - A new electrochemical sensor based on a Nafion, aminated reduced graphene oxide and chitosan functional membrane-modified glassy carbon electrode was proposed for the simultaneous detection of adenine and guanine. Fourier transform-infrared spectrometry (FTIR), transmission electron microscopy (TEM), and electrochemical methods were utilized for the additional characterization of the membrane materials. The prepared electrode was utilized for the detection of guanine (G) and adenine (A). The anodic peak currents to G and A were linear in the concentrations ranging from 0.1 to 120 MUM and 0.2 to 110 MUM, respectively. The detection limits were found to be 0.1 MUM and 0.2 MUM, respectively. Moreover, the modified electrode could also be used to determine G and A in calf thymus DNA. PMID- 28718794 TI - BRS1 Function in Facilitating Lateral Root Emergence in Arabidopsis. AB - The BRS1 (BRI1 Suppressor 1) gene encodes a serine carboxypeptidase that plays a critical role in the brassinosteroid signaling pathway. However, its specific biological function remains unclear. In this study, the developmental role of BRS1 was investigated in Arabidopsis thaliana. We found that overexpressing BRS1 resulted in significantly more lateral roots in different Arabidopsis ecotypes (WS2 and Col-0) and in brassinosteroid mutants (bri1-5 and det2-28). Further research showed that BRS1 facilitates the process whereby lateral root primordia break through the endodermis, cortex, and epidermis. Consistent with this, BRS1 was found to be highly expressed in the root endodermis and accumulated in the extracellular space around the dome of the lateral root primordia. Taken together, these results highlight the role of BRS1 in the process of lateral root emergence and provide new insight into the role of serine carboxypeptidases in plant root development. PMID- 28718796 TI - Hydrostatic Pressure and Temperature Measurements Using an In-Line Mach-Zehnder Interferometer Based on a Two-Mode Highly Birefringent Microstructured Fiber. AB - We present a comprehensive study of an in-line Mach-Zehnder intermodal interferometer fabricated in a boron-doped two-mode highly birefringent microstructured fiber. We observed different interference signals at the output of the interferometer, related to the intermodal interference of the fundamental and the first order modes of the orthogonal polarizations and a beating of the polarimetric signal related to the difference in the group modal birefringence between the fundamental and the first order modes, respectively. The proposed interferometer was tested for measurements of hydrostatic pressure and temperature for different alignments of the input polarizer with no analyzer at the output. The sensitivities to hydrostatic pressure of the intermodal interference signals for x- and y-polarizations had an opposite sign and were equal to 0.229 nm/MPa and -0.179 nm/MPa, respectively, while the temperature sensitivities for both polarizations were similar and equal 0.020 nm/ degrees C and 0.019 nm/ degrees C. In the case of pressure, for the simultaneous excitation of both polarization modes, we observed a displacement of intermodal fringes with a sensitivity depending on the azimuth of the input polarization state, as well as on the displacement of their envelope with a sensitivity of 2.14 nm/MPa, accompanied by a change in the fringes visibility. Such properties of the proposed interferometer allow for convenient adjustments to the pressure sensitivity of the intermodal fringes and possible applications for the simultaneous interrogation of temperature and pressure. PMID- 28718795 TI - Novel Molecular Insights about Lactobacillar Sortase-Dependent Piliation. AB - One of the more conspicuous structural features that punctuate the outer cell surface of certain bacterial Gram-positive genera and species is the sortase dependent pilus. As these adhesive and variable-length protrusions jut outward from the cell, they provide a physically expedient and useful means for the initial contact between a bacterium and its ecological milieu. The sortase dependent pilus displays an elongated macromolecular architecture consisting of two to three types of monomeric protein subunits (pilins), each with their own specific function and location, and that are joined together covalently by the transpeptidyl activity of a pilus-specific C-type sortase enzyme. Sortase dependent pili were first detected among the Gram-positive pathogens and subsequently categorized as an essential virulence factor for host colonization and tissue invasion by these harmful bacteria. However, the sortase-dependent pilus was rebranded as also a niche-adaptation factor after it was revealed that "friendly" Gram-positive commensals exhibit the same kind of pilus structures, which includes two contrasting gut-adapted species from the Lactobacillus genus, allochthonous Lactobacillus rhamnosus and autochthonous Lactobacillus ruminis. This review will highlight and discuss what has been learned from the latest research carried out and published on these lactobacillar pilus types. PMID- 28718797 TI - Socioeconomic Differences in and Predictors of Home-Based Palliative Care Health Service Use in Ontario, Canada. AB - The use of health services may vary across people with different socioeconomic statuses, and may be determined by many factors. The purposes of this study were (i) to examine the socioeconomic differences in the propensity and intensity of use for three main home-based health services, that is, home-based palliative care physician visits, nurse visits and personal support worker (PSW) hours; and (ii) to explore the determinants of the use of home-based palliative care services. A prospective cohort study was employed. A total of 181 caregivers were interviewed biweekly over the course of the palliative care trajectory, yielding a total of 994 interviews. The propensity and intensity of health service use were examined using logistic regression and negative binomial regression, respectively. The results demonstrated that both the propensity and intensity of home-based nurse and PSW visits fell with socioeconomic status. The use of home based palliative care services was not concentrated in high socioeconomic status groups. The common predictors of health service use in the three service categories were patient age, the Palliative Performance Scale (PPS) score and place of death. These findings may assist health service planners in the appropriate allocation of resources and service packages to meet the complex needs of palliative care populations. PMID- 28718798 TI - Co-Expression Network and Pathway Analyses Reveal Important Modules of miRNAs Regulating Milk Yield and Component Traits. AB - Co-expression network analyses provide insights into the molecular interactions underlying complex traits and diseases. In this study, co-expression network analysis was performed to detect expression patterns (modules or clusters) of microRNAs (miRNAs) during lactation, and to identify miRNA regulatory mechanisms for milk yield and component traits (fat, protein, somatic cell count (SCC), lactose, and milk urea nitrogen (MUN)) via miRNA target gene enrichment analysis. miRNA expression (713 miRNAs), and milk yield and components (Fat%, Protein%, lactose, SCC, MUN) data of nine cows at each of six different time points (day 30 (D30), D70, D130, D170, D230 and D290) of an entire lactation curve were used. Four modules or clusters (GREEN, BLUE, RED and TURQUOISE) of miRNAs were identified as important for milk yield and component traits. The GREEN and BLUE modules were significantly correlated (|r| > 0.5) with milk yield and lactose, respectively. The RED and TURQUOISE modules were significantly correlated (|r| > 0.5) with both SCC and lactose. In the GREEN module, three abundantly expressed miRNAs (miR-148a, miR-186 and miR-200a) were most significantly correlated to milk yield, and are probably the most important miRNAs for this trait. DDR1 and DDHX1 are hub genes for miRNA regulatory networks controlling milk yield, while HHEX is an important transcription regulator for these networks. miR-18a, miR 221/222 cluster, and transcription factors HOXA7, and NOTCH 3 and 4, are important for the regulation of lactose. miR-142, miR-146a, and miR-EIA17-14144 (a novel miRNA), and transcription factors in the SMAD family and MYB, are important for the regulation of SCC. Important signaling pathways enriched for target genes of miRNAs of significant modules, included protein kinase A and PTEN signaling for milk yield, eNOS and Noth signaling for lactose, and TGF beta, HIPPO, Wnt/beta-catenin and cell cycle signaling for SCC. Relevant enriched gene ontology (GO)-terms related to milk and mammary gland traits included cell differentiation, G-protein coupled receptor activity, and intracellular signaling transduction. Overall, this study uncovered regulatory networks in which miRNAs interacted with each other to regulate lactation traits. PMID- 28718799 TI - Zebrafish as a Model Organism for the Development of Drugs for Skin Cancer. AB - Skin cancer, which includes melanoma and squamous cell carcinoma, represents the most common type of cutaneous malignancy worldwide, and its incidence is expected to rise in the near future. This condition derives from acquired genetic dysregulation of signaling pathways involved in the proliferation and apoptosis of skin cells. The development of animal models has allowed a better understanding of these pathomechanisms, with the possibility of carrying out toxicological screening and drug development. In particular, the zebrafish (Danio rerio) has been established as one of the most important model organisms for cancer research. This model is particularly suitable for live cell imaging and high-throughput drug screening in a large-scale fashion. Thanks to the recent advances in genome editing, such as the clustered regularly-interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) methodologies, the mechanisms associated with cancer development and progression, as well as drug resistance can be investigated and comprehended. With these unique tools, the zebrafish represents a powerful platform for skin cancer research in the development of target therapies. Here, we will review the advantages of using the zebrafish model for drug discovery and toxicological and phenotypical screening. We will focus in detail on the most recent progress in the field of zebrafish model generation for the study of melanoma and squamous cell carcinoma (SCC), including cancer cell injection and transgenic animal development. Moreover, we will report the latest compounds and small molecules under investigation in melanoma zebrafish models. PMID- 28718800 TI - Enriching Diet with n-3 PUFAs to Help Prevent Cardiovascular Diseases in Healthy Adults: Results from Clinical Trials. AB - Omega-3 polyunsaturated fatty acids (n-3 PUFAs) are believed to be important for cardiovascular health. Many investigations have been carried out in an attempt to examine the effect of n-3 PUFAs intake, in the form of supplementation or fortified foods, for the management of cardiovascular disease (CVD) and risk factors for CVD, whereas less is known about the effect on healthy individuals. The present study reviews the available literature in order to examine the relationship between n-3 PUFAs intake, either via supplementation or enriched food, and the prevention of CVD among healthy adults. Interventional clinical trials on subjects aged >18 years old with none of the established risk factors for CVD have been considered for review. n-3 PUFAs supplementation or enriched food may positively regulate triglycerides and some lipoprotein subsets, as well as several vascular and coagulation parameters, even in healthy patients, presenting no risk factors for CVD, suggesting a protective effect. Diet enrichment with omega-3 is likely to be useful in helping to lower the risk of developing CVD in healthy individuals, but still offers no strong evidence of a tangible benefit on a population level. Additional studies are needed to determine the optimal daily intake, especially to prevent the unfavorable effects of PUFAs over-consumption. PMID- 28718801 TI - From Variation of Influenza Viral Proteins to Vaccine Development. AB - Recurrent influenza epidemics and occasional pandemics are one of the most important global public health concerns and are major causes of human morbidity and mortality. Influenza viruses can evolve through antigen drift and shift to overcome the barriers of human immunity, leading to host adaption and transmission. Mechanisms underlying this viral evolution are gradually being elucidated. Vaccination is an effective method for the prevention of influenza virus infection. However, the emergence of novel viruses, including the 2009 pandemic influenza A (H1N1), the avian influenza A virus (H7N9), and the highly pathogenic avian influenza A virus (HPAI H5N1), that have infected human populations frequently in recent years reveals the tremendous challenges to the current influenza vaccine strategy. A better vaccine that provides protection against a wide spectrum of various influenza viruses and long-lasting immunity is urgently required. Here, we review the evolutionary changes of several important influenza proteins and the influence of these changes on viral antigenicity, host adaption, and viral pathogenicity. Furthermore, we discuss the development of a potent universal influenza vaccine based on this knowledge. PMID- 28718802 TI - Ouabain Protects Human Renal Cells against the Cytotoxic Effects of Shiga Toxin Type 2 and Subtilase Cytotoxin. AB - Hemolytic uremic syndrome (HUS) is one of the most common causes of acute renal failure in children. The majority of cases are associated with Shiga toxin (Stx) producing Escherichia coli (STEC). In Argentina, HUS is endemic and presents the highest incidence rate in the world. STEC strains expressing Stx type 2 (Stx2) are responsible for the most severe cases of this pathology. Subtilase cytotoxin (SubAB) is another STEC virulence factor that may contribute to HUS pathogenesis. To date, neither a licensed vaccine nor effective therapy for HUS is available for humans. Considering that Ouabain (OUA) may prevent the apoptosis process, in this study we evaluated if OUA is able to avoid the damage caused by Stx2 and SubAB on human glomerular endothelial cells (HGEC) and the human proximal tubule epithelial cell (HK-2) line. HGEC and HK-2 were pretreated with OUA and then incubated with the toxins. OUA protected the HGEC viability from Stx2 and SubAB cytotoxic effects, and also prevented the HK-2 viability from Stx2 effects. The protective action of OUA on HGEC and HK-2 was associated with a decrease in apoptosis and an increase in cell proliferation. Our data provide evidence that OUA could be considered as a therapeutic strategy to avoid the renal damage that precedes HUS. PMID- 28718804 TI - Electromagnetic Differential Measuring Method: Application in Microstrip Sensors Developing. AB - Electromagnetic radiation is energy that interacts with matter. The interaction process is of great importance to the sensing applications that characterize material media. Parameters like constant dielectric represent matter characteristics and they are identified using emission, interaction and reception of electromagnetic radiation in adapted environmental conditions. How the electromagnetic wave responds when it interacts with the material media depends on the range of frequency used and the medium parameters. Different disciplines use this interaction and provides non-intrusive applications with clear benefits, remote sensing, earth sciences (geology, atmosphere, hydrosphere), biological or medical disciplines use this interaction and provides non-intrusive applications with clear benefits. Electromagnetic waves are transmitted and analyzed in the receiver to determine the interaction produced. In this work a method based in differential measurement technique is proposed as a novel way of detecting and characterizing electromagnetic matter characteristics using sensors based on a microstrip patch. The experimental results, based on simulations, show that it is possible to obtain benefits from the behavior of the wave-medium interaction using differential measurement on reception of electromagnetic waves at different frequencies or environmental conditions. Differential method introduce advantages in measure processes and promote new sensors development. A new microstrip sensor that uses differential time measures is proposed to show the possibilities of this method. PMID- 28718803 TI - Serum Albumin Binding and Esterase Activity: Mechanistic Interactions with Organophosphates. AB - The albumin molecule, in contrast to many other plasma proteins, is not covered with a carbohydrate moiety and can bind and transport various molecules of endogenous and exogenous origin. The enzymatic activity of albumin, the existence of which many scientists perceive skeptically, is much less studied. In toxicology, understanding the mechanistic interactions of organophosphates with albumin is a special problem, and its solution could help in the development of new types of antidotes. In the present work, the history of the issue is briefly examined, then our in silico data on the interaction of human serum albumin with soman, as well as comparative in silico data of human and bovine serum albumin activities in relation to paraoxon, are presented. Information is given on the substrate specificity of albumin and we consider the possibility of its affiliation to certain classes in the nomenclature of enzymes. PMID- 28718805 TI - Emerging Fusarium and Alternaria Mycotoxins: Occurrence, Toxicity and Toxicokinetics. AB - Emerging Fusarium and Alternaria mycotoxins gain more and more interest due to their frequent contamination of food and feed, although in vivo toxicity and toxicokinetic data are limited. Whereas the Fusarium mycotoxins beauvericin, moniliformin and enniatins particularly contaminate grain and grain-based products, Alternaria mycotoxins are also detected in fruits, vegetables and wines. Although contamination levels are usually low (ug/kg range), higher contamination levels of enniatins and tenuazonic acid may occasionally occur. In vitro studies suggest genotoxic effects of enniatins A, A1 and B1, beauvericin, moniliformin, alternariol, alternariol monomethyl ether, altertoxins and stemphyltoxin-III. Furthermore, in vitro studies suggest immunomodulating effects of most emerging toxins and a reproductive health hazard of alternariol, beauvericin and enniatin B. More in vivo toxicity data on the individual and combined effects of these contaminants on reproductive and immune system in both humans and animals is needed to update the risk evaluation by the European Food Safety Authority. Taking into account new occurrence data for tenuazonic acid, the complete oral bioavailability, the low total body clearance in pigs and broiler chickens and the limited toxicity data, a health risk cannot be completely excluded. Besides, some less known Alternaria toxins, especially the genotoxic altertoxins and stemphyltoxin III, should be incorporated in risk evaluation as well. PMID- 28718806 TI - The Inhibitory Activity of Luzonicosides from the Starfish Echinaster luzonicus against Human Melanoma Cells. AB - Malignant melanoma is the most dangerous form of skin cancer, with a rapidly increasing incidence rate. Despite recent advances in melanoma research following the approval of several novel targeted and immuno-therapies, the majority of oncological patients will ultimately perish from the disease. Thus, new effective drugs are still required. Starfish steroid glycosides possess different biological activities, including antitumor activity. The current study focused on the determination of the in vitro inhibitory activity and the mechanism of action of cyclic steroid glycosides isolated from the starfish Echinaster luzonicus luzonicoside A (LuzA) and luzonicoside D (LuzD)-in human melanoma RPMI-7951 and SK-Mel-28 cell lines. LuzA inhibited proliferation, the formation of colonies, and the migration of SK-Mel-28 cells significantly more than LuzD. Anti-cancer activity has been ascribed to cell cycle regulation and apoptosis induction. The molecular mechanism of action appears to be related to the regulation of the activity of cleaved caspase-3 and poly(ADP-ribose) polymerase (PARP), along with Survivin, Bcl-2, p21 and cyclin D1 level. Overall, our findings support a potential anti-cancer efficacy of luzonicosides A and D on human melanoma cells. PMID- 28718807 TI - Melanin and Melanin-Related Polymers as Materials with Biomedical and Biotechnological Applications-Cuttlefish Ink and Mussel Foot Proteins as Inspired Biomolecules. AB - The huge development of bioengineering during the last years has boosted the search for new bioinspired materials, with tunable chemical, mechanical, and optoelectronic properties for the design of semiconductors, batteries, biosensors, imaging and therapy probes, adhesive hydrogels, tissue restoration, photoprotectors, etc. These new materials should complement or replace metallic or organic polymers that cause cytotoxicity and some adverse health effects. One of the most interesting biomaterials is melanin and synthetic melanin-related molecules. Melanin has a controversial molecular structure, dependent on the conditions of polymerization, and therefore tunable. It is found in animal hair and skin, although one of the common sources is cuttlefish (Sepia officinalis) ink. On the other hand, mussels synthesize adhesive proteins to anchor these marine animals to wet surfaces. Both melanin and mussel foot proteins contain a high number of catecholic residues, and their properties are related to these groups. Dopamine (DA) can easily polymerize to get polydopamine melanin (PDAM), that somehow shares properties with melanin and mussel proteins. Furthermore, PDAM can easily be conjugated with other components. This review accounts for the main aspects of melanin, as well as DA-based melanin-like materials, related to their biomedical and biotechnological applications. PMID- 28718808 TI - Beta Palmitate Improves Bone Length and Quality during Catch-Up Growth in Young Rats. AB - Palmitic acid (PA) is the most abundant saturated fatty acid in human milk, where it is heavily concentrated in the sn-2-position (termed beta palmitate, BPA) and as such is conserved in all women, regardless of their diet or ethnicity, indicating its physiological and metabolic importance. We hypothesized that BPA improves the efficiency of nutrition-induced catch up growth as compared to sn 1,3 PA, which is present in vegetable oil. Pre-pubertal male rats were subjected to a 17 days food restriction followed by re-feeding for nine days with 1,3 PA or BPA-containing diets. We measured bone length, epiphyseal growth plate height (EGP, histology), bone quality (micro-CT and 3-point bending assay), and gene expression (Affymetrix). The BPA-containing diet improved most growth parameters: humeri length and EGP height were greater in the BPA-fed animals. Further analysis of the EGP revealed that the hypertrophic zone was significantly higher in the BPA group. In addition, Affymetrix analysis revealed that the diet affected the expression of several genes in the liver and EGP. Despite the very subtle difference between the diets and the short re-feeding period, we found a small but significant improvement in most growth parameters in the BPA-fed rats. This pre-clinical study may have important implications, especially for children with growth disorders and children with special nutritional needs. PMID- 28718809 TI - Maternal Choline Supplementation Alters Fetal Growth Patterns in a Mouse Model of Placental Insufficiency. AB - Impairments in placental development can adversely affect pregnancy outcomes. The bioactive nutrient choline may mitigate some of these impairments, as suggested by data in humans, animals, and human trophoblasts. Herein, we investigated the effects of maternal choline supplementation (MCS) on parameters of fetal growth in a Dlx3+/- (distal-less homeobox 3) mouse model of placental insufficiency. Dlx3+/- female mice were assigned to 1X (control), 2X, or 4X choline intake levels during gestation. Dams were sacrificed at embryonic days E10.5, 12.5, 15.5, and 18.5. At E10.5, placental weight, embryo weight, and placental efficiency were higher in 4X versus 1X choline. Higher concentrations of hepatic and placental betaine were detected in 4X versus 1X choline, and placental betaine was positively associated with embryo weight. Placental mRNA expression of Igf1 was downregulated by 4X (versus 1X) choline at E10.5. No differences in fetal growth parameters were detected at E12.5 and 15.5, whereas a small but significant reduction in fetal weight was detected at E18.5 in 4X versus 1X choline. MCS improved fetal growth during early pregnancy in the Dlx3+/- mice with the compensatory downregulation of Igf1 to slow growth as gestation progressed. Placental betaine may be responsible for the growth-promoting effects of choline. PMID- 28718810 TI - DNA2-An Important Player in DNA Damage Response or Just Another DNA Maintenance Protein? AB - The human DNA2 (DNA replication helicase/nuclease 2) protein is expressed in both the nucleus and mitochondria, where it displays ATPase-dependent nuclease and helicase activities. DNA2 plays an important role in the removing of long flaps in DNA replication and long-patch base excision repair (LP-BER), interacting with the replication protein A (RPA) and the flap endonuclease 1 (FEN1). DNA2 can promote the restart of arrested replication fork along with Werner syndrome ATP dependent helicase (WRN) and Bloom syndrome protein (BLM). In mitochondria, DNA2 can facilitate primer removal during strand-displacement replication. DNA2 is involved in DNA double strand (DSB) repair, in which it is complexed with BLM, RPA and MRN for DNA strand resection required for homologous recombination repair. DNA2 can be a major protein involved in the repair of complex DNA damage containing a DSB and a 5' adduct resulting from a chemical group bound to DNA 5' ends, created by ionizing radiation and several anticancer drugs, including etoposide, mitoxantrone and some anthracyclines. The role of DNA2 in telomere end maintenance and cell cycle regulation suggests its more general role in keeping genomic stability, which is impaired in cancer. Therefore DNA2 can be an attractive target in cancer therapy. This is supported by enhanced expression of DNA2 in many cancer cell lines with oncogene activation and premalignant cells. Therefore, DNA2 can be considered as a potential marker, useful in cancer therapy. DNA2, along with PARP1 inhibition, may be considered as a potential target for inducing synthetic lethality, a concept of killing tumor cells by targeting two essential genes. PMID- 28718811 TI - Tissue Specific Labeling in Proteomics. AB - Mass spectrometry-based proteomics is a powerful tool for identifying and quantifying proteins in biological samples. While it is routinely used for the characterization of simple cell line systems, the analysis of the cell specific proteome in multicellular organisms and tissues poses a significant challenge. Isolating a subset of cells from tissues requires mechanical and biochemical separation or sorting, a process which can alter cellular signaling, and thus, the composition of the proteome. Recently, several approaches for cell selective labeling of proteins, that include bioorthogonal amino acids, biotinylating enzymes, and genetic tools, have been developed. These tools facilitate the selective labeling of proteins, their interactome, or of specific cell types within a tissue or an organism, while avoiding the difficult and contamination prone biochemical separation of cells from the tissue. In this review, we give an overview of existing techniques and their application in cell culture models and whole animals. PMID- 28718812 TI - Therapeutic Efficacy of the Novel Stimuli-Sensitive Nano-Ferritins Containing Doxorubicin in a Head and Neck Cancer Model. AB - Doxorubicin is employed alone or in combination for the treatment of several hematological and solid malignancies; despite its efficacy, there are associated cardiotoxicity limits both in its application in patients with heart disease risk factors and also in its long-term use. HFt-MP-PAS40 is a genetically engineered human ferritin heavy chain (HFt)-based construct able to efficiently entrap and deliver doxorubicin to cancer cells. HF-MP-PAS contains a short motif sequence (defined as MP) responsive to proteolytic cleavage by tumor matrix metalloproteases (MMPs), located between each HFt subunit and a masking polypeptide sequence rich in proline (P), alanine (A), and serine (S) residues (PAS). This carrier displayed excellent therapeutic efficacy in a xenogenic pancreatic cancer model in vivo, leading to a significant increase in overall animal survival in treated mice. Herein, we describe the HFt-MP-PAS40-Dox efficacy against squamous cell carcinomas of the head and neck (HNSCC) with the goal of validating the application of our nano-drug for the treatment of different solid tumors. In addition, a tolerability study in healthy mice was also performed. The results indicate that HFt-MP-PAS40-Dox produced increased anti-tumor effects both in vitro and in vivo in comparison to the free drug in several HNSCC cell lines. In the acute toxicity studies, the maximum tolerated dose (MTD) of HFt-MP-PAS40-Dox was about 3.5 higher than the free drug: 25 mg/kg versus 7 mg/kg doxorubicin equivalents. Importantly, evaluation of heart tissues provided evidence that doxorubicin is less cardio-toxic when encapsulated inside the ferritin carrier. In conclusion, HFt-MP-PAS40-Dox may be administered safely at higher doses compared with the free drug, resulting in superior efficacy to control HNSCC malignancies. PMID- 28718813 TI - Suppression of Nrf2 Activity by Chestnut Leaf Extract Increases Chemosensitivity of Breast Cancer Stem Cells to Paclitaxel. AB - Due to metastatic potential and drug resistance, cancer stem cells (CSCs) have become a critical target for the development of chemotherapeutic agents. Recent studies showed that CSCs highly express NF-E2-related factor 2 (Nrf2)-mediated antioxidant enzymes and thereby retain relatively low levels of reactive oxygen species (ROS). Since anticancer agents usually utilize ROS as an arsenal for killing cancer cells, we hypothesized that inhibition of Nrf2 activity could increase the sensitivity of CSCs to anticancer drugs, and thus enhancing their therapeutic efficacy. We found that MCF-7-derived CSCs with a CD44high/CD24low phenotype formed mammospheres and highly expressed Nrf2 compared to the adherent parental MCF-7 cells. In a separate experiment, we screened 89 different edible plant extracts for inhibitory activity against the Nrf2 signaling pathway by using an antioxidant response element (ARE)-luciferase assay system. Among those extracts, Castanea crenata (chestnut) leaf extract significantly decreased the nuclear translocation of Nrf2 and protein expression of antioxidant enzymes in MCF-7-derived CSCs. The combined treatment of the CSCs with chestnut leaf extract and paclitaxel resulted in more effective cell death than the treatment with paclitaxel alone. These findings suggest that the chestnut leaf extract or its constituents could increase the susceptibility of breast CSCs to an anticancer drug, paclitaxel, through inhibition of the Nrf2 signaling pathway, and could be utilized as an adjuvant for chemotherapy. PMID- 28718814 TI - Physiological Effects of Touching Wood. AB - This study aimed to clarify the physiological effects of touching wood with the palm, in comparison with touching other materials on brain activity and autonomic nervous activity. Eighteen female university students (mean age, 21.7 +/- 1.6 years) participated in the study. As an indicator of brain activity, oxyhemoglobin (oxy-Hb) concentrations were measured in the left/right prefrontal cortex using near-infrared time-resolved spectroscopy. Heart rate variability (HRV) was used as an indicator of autonomic nervous activity. The high-frequency (HF) component of HRV, which reflected parasympathetic nervous activity, and the low-frequency (LF)/HF ratio, which reflected sympathetic nervous activity, were measured. Plates of uncoated white oak, marble, tile, and stainless steel were used as tactile stimuli. After sitting at rest with their eyes closed, participants touched the materials for 90 s. As a result, tactile stimulation with white oak significantly (1) decreased the oxy-Hb concentration in the left/right prefrontal cortex relative to marble, tile, and stainless steel and (2) increased ln(HF)-reflected parasympathetic nervous activity relative to marble and stainless steel. In conclusion, our study revealed that touching wood with the palm calms prefrontal cortex activity and induces parasympathetic nervous activity more than other materials, thereby inducing physiological relaxation. PMID- 28718815 TI - Regional Delivery of Chimeric Antigen Receptor (CAR) T-Cells for Cancer Therapy. AB - Chimeric Antigen Receptor (CAR) T-cells are T-cells with recombinant receptors targeted to tumor antigens. CAR-T cell therapy has emerged as a mode of immunotherapy and is now being extensively explored in hematologic cancer. In contrast, CAR-T cell use in solid tumors has been hampered by multiple obstacles. Several approaches have been taken to circumvent these obstacles, including the regional delivery of CAR-T cells. Regional CAR-T cell delivery can theoretically compensate for poor T-cell trafficking and tumor antigen specificity while avoiding systemic toxicity associated with intravenous delivery. We reviewed completed clinical trials for the treatment of glioblastoma and metastatic colorectal cancer and examined the data in these studies for safety, efficacy, and potential advantages that regional delivery may confer over systemic delivery. Our appraisal of the available literature revealed that regional delivery of CAR-T cells in both glioblastoma and hepatic colorectal metastases was generally well tolerated and efficacious in select instances. We propose that the regional delivery of CAR-T cells is an area of potential growth in the solid tumor immunotherapy, and look towards future clinical trials in head and neck cancer, mesothelioma, and peritoneal carcinomatosis as the use of this technique expands. PMID- 28718816 TI - Complex DNA Damage: A Route to Radiation-Induced Genomic Instability and Carcinogenesis. AB - Cellular effects of ionizing radiation (IR) are of great variety and level, but they are mainly damaging since radiation can perturb all important components of the cell, from the membrane to the nucleus, due to alteration of different biological molecules ranging from lipids to proteins or DNA. Regarding DNA damage, which is the main focus of this review, as well as its repair, all current knowledge indicates that IR-induced DNA damage is always more complex than the corresponding endogenous damage resulting from endogenous oxidative stress. Specifically, it is expected that IR will create clusters of damage comprised of a diversity of DNA lesions like double strand breaks (DSBs), single strand breaks (SSBs) and base lesions within a short DNA region of up to 15-20 bp. Recent data from our groups and others support two main notions, that these damaged clusters are: (1) repair resistant, increasing genomic instability (GI) and malignant transformation and (2) can be considered as persistent "danger" signals promoting chronic inflammation and immune response, causing detrimental effects to the organism (like radiation toxicity). Last but not least, the paradigm shift for the role of radiation-induced systemic effects is also incorporated in this picture of IR-effects and consequences of complex DNA damage induction and its erroneous repair. PMID- 28718818 TI - Correction: Zielinski, W., et al. Ionic Liquids as Solvents for Rhodium and Platinum Catalysts Used in Hydrosilylation Reaction. Molecules 2016, 21, 1115. AB - The authors are sorry to report that the yield of the hydrosilylation reaction in [P44414][NTf2] (1) IL with [RhCl(PPh3)3] was replaced with the yield reported for [P44414][NTf2] (1) IL with K2PtCl4 in their published paper [1]. [...]. PMID- 28718817 TI - Time to Spread Your Wings: A Review of the Avian Ancient DNA Field. AB - Ancient DNA (aDNA) has the ability to inform the evolutionary history of both extant and extinct taxa; however, the use of aDNA in the study of avian evolution is lacking in comparison to other vertebrates, despite birds being one of the most species-rich vertebrate classes. Here, we review the field of "avian ancient DNA" by summarising the past three decades of literature on this topic. Most studies over this time have used avian aDNA to reconstruct phylogenetic relationships and clarify taxonomy based on the sequencing of a few mitochondrial loci, but recent studies are moving toward using a comparative genomics approach to address developmental and functional questions. Applying aDNA analysis with more practical outcomes in mind (such as managing conservation) is another increasingly popular trend among studies that utilise avian aDNA, but the majority of these have yet to influence management policy. We find that while there have been advances in extracting aDNA from a variety of avian substrates including eggshell, feathers, and coprolites, there is a bias in the temporal focus; the majority of the ca. 150 studies reviewed here obtained aDNA from late Holocene (100-1000 yBP) material, with few studies investigating Pleistocene-aged material. In addition, we identify and discuss several other issues within the field that require future attention. With more than one quarter of Holocene bird extinctions occurring in the last several hundred years, it is more important than ever to understand the mechanisms driving the evolution and extinction of bird species through the use of aDNA. PMID- 28718819 TI - Akanthopyrones A-D, alpha-Pyrones Bearing a 4-O-Methyl-beta-d-glucopyranose Moiety from the Spider-Associated Ascomycete Akanthomyces novoguineensis. AB - Hypocrealean fungi have proved to be prolific bioactive metabolite producers; they have caught the attention of mycologists throughout the world. However, only a few studies on the insect and spider parasitic genus Akanthomyces have so far been carried out. In this study, we report the isolation, structural elucidation and biological activities of four unprecedented glycosylated alpha-pyrone derivatives, akanthopyrones A-D (1-4), from a culture of Akanthomyces novoguineensis collected in Thailand. The chemical structures of the akanthopyrones were determined by extensive 1D- and 2D-NMR, and HRMS spectroscopic analysis. Their absolute configurations were determined. Akanthopyrone A (1) exhibited weak antimicrobial activity against Bacillus subtilis DSM10 and cytotoxicity against the HeLa cell line KB-3-1, while akanthopyrone D (4) showed weak activity against Candida tenuis MUCL 29892. PMID- 28718820 TI - A Transcriptomic Survey of Ion Channel-Based Conotoxins in the Chinese Tubular Cone Snail (Conus betulinus). AB - Conotoxins in the venom of cone snails (Conus spp.) are a mixture of active peptides that work as blockers, agonists, antagonists, or inactivators of various ion channels. Recently we reported a high-throughput method to identify 215 conotoxin transcripts from the Chinese tubular cone snail, C. betulinus. Here, based on the previous datasets of four transcriptomes from three venom ducts and one venom bulb, we explored ion channel-based conotoxins and predicted their related ion channel receptors. Homologous analysis was also performed for the most abundant ion channel protein, voltage-gated potassium (Kv; with Kv1.1 as the representative), and the most studied ion channel receptor, nicotinic acetylcholine receptor (nAChR; with alpha2-nAChR as the representative), in different animals. Our transcriptomic survey demonstrated that ion channel-based conotoxins and related ion channel proteins/receptors transcribe differentially between the venom duct and the venom bulb. In addition, we observed that putative kappa-conotoxins were the most common conotoxins with the highest transcription levels in the examined C. betulinus. Furthermore, Kv1.1 and alpha2-nAChR were conserved in their functional domains of deduced protein sequences, suggesting similar effects of conotoxins via the ion channels in various species, including human beings. In a word, our present work suggests a high-throughput way to develop conotoxins as potential drugs for treatment of ion channel-associated human diseases. PMID- 28718821 TI - Tick Haller's Organ, a New Paradigm for Arthropod Olfaction: How Ticks Differ from Insects. AB - Ticks are the vector of many human and animal diseases; and host detection is critical to this process. Ticks have a unique sensory structure located exclusively on the 1st pairs of legs; the fore-tarsal Haller's organ, not found in any other animals, presumed to function like the insect antennae in chemosensation but morphologically very different. The mechanism of tick chemoreception is unknown. Utilizing next-generation sequencing and comparative transcriptomics between the 1st and 4th legs (the latter without the Haller's organ), we characterized 1st leg specific and putative Haller's organ specific transcripts from adult American dog ticks, Dermacentor variabilis. The analysis suggested that the Haller's organ is involved in olfaction, not gustation. No known odorant binding proteins like those found in insects, chemosensory lipocalins or typical insect olfactory mechanisms were identified; with the transcriptomic data only supporting a possible olfactory G-protein coupled receptor (GPCR) signal cascade unique to the Haller's organ. Each component of the olfactory GPCR signal cascade was identified and characterized. The expression of GPCR, Galphao and beta-arrestin transcripts identified exclusively in the 1st leg transcriptome, and putatively Haller's organ specific, were examined in unfed and blood-fed adult female and male D. variabilis. Blood feeding to repletion in adult females down-regulated the expression of all three chemosensory transcripts in females but not in males; consistent with differences in post-feeding tick behavior between sexes and an expected reduced chemosensory function in females as they leave the host. Data are presented for the first time of the potential hormonal regulation of tick chemosensation; behavioral assays confirmed the role of the Haller's organ in N,N-diethyl-meta-toluamide (DEET) repellency but showed no role for the Haller's organ in host attachment. Further research is needed to understand the potential role of the GPCR cascade in olfaction. PMID- 28718822 TI - A Bacterial Toxin with Analgesic Properties: Hyperpolarization of DRG Neurons by Mycolactone. AB - Mycolactone, a polyketide molecule produced by Mycobacterium ulcerans, is the etiological agent of Buruli ulcer. This lipid toxin is endowed with pleiotropic effects, presents cytotoxic effects at high doses, and notably plays a pivotal role in host response upon colonization by the bacillus. Most remarkably, mycolactone displays intriguing analgesic capabilities: the toxin suppresses or alleviates the pain of the skin lesions it inflicts. We demonstrated that the analgesic capability of mycolactone was not attributable to nerve damage, but instead resulted from the triggering of a cellular pathway targeting AT2 receptors (angiotensin II type 2 receptors; AT2R), and leading to potassium dependent hyperpolarization. This demonstration paves the way to new nature inspired analgesic protocols. In this direction, we assess here the hyperpolarizing properties of mycolactone on nociceptive neurons. We developed a dedicated medium-throughput assay based on membrane potential changes, and visualized by confocal microscopy of bis-oxonol-loaded Dorsal Root Ganglion (DRG) neurons. We demonstrate that mycolactone at non-cytotoxic doses triggers the hyperpolarization of DRG neurons through AT2R, with this action being not affected by known ligands of AT2R. This result points towards novel AT2R dependent signaling pathways in DRG neurons underlying the analgesic effect of mycolactone, with the perspective for the development of new types of nature inspired analgesics. PMID- 28718823 TI - Surface Chemistry Interactions of Cationorm with Films by Human Meibum and Tear Film Compounds. AB - Cationorm(r) (CN) cationic nanoemulsion was demonstrated to enhance tear film (TF) stability in vivo possibly via effects on tear film lipid layer (TFLL). Therefore the interactions of CN with human meibum (MGS) and TFLL in vitro and in vivo deserve special study. MGS and CN were spread at the air/water interface of a Langmuir surface balance to ensure a range of MGS/CN oil phase ratios: 20/1, 10/1, 5/1, 3/1, 2/1 and 1/1. The films capability to reorganize during dynamic area changes was evaluated via the surface pressure-area compression isotherms and step/relaxation dilatational rheology studies. Films structure was monitored with Brewster angle microscopy. CN/TFLL interactions at the ocular surface were monitored with non-contact specular microscopy. The in vitro studies of MGS/CN layers showed that (i) CN inclusion (at fixed MGS content) increased film elasticity and thickness and that (ii) CN can compensate for moderate meibum deficiency in MGS/CN films. In vivo CN mixed with TFLL in a manner similar to CN/MGS interactions in vitro, and resulted in enhanced thickness of TFLL. In vitro and in vivo data complement each other and facilitated the study of the composition-structure-function relationship that determines the impact of cationic nanoemulsions on TF. PMID- 28718824 TI - Associations between Red Meat Intakes and the Micronutrient Intake and Status of UK Females: A Secondary Analysis of the UK National Diet and Nutrition Survey. AB - Blanket health messages to lower red meat intakes are being communicated at present. These could have adverse implications on the micronutrient quality of women's diets. The current paper evaluates the nutritional impact of lower red meat intakes on British women's micronutrient intakes and status. A secondary analysis of the UK National Diet and Nutrition Survey was undertaken using data from years 2008/2009 to 2011/2012. This was comprised of dietary and blood analyte data from 1384 and 641 females aged 11 to 64 years. Females consuming less than 40 g total red meat daily were more likely to have micronutrient intakes below the Lower Reference Nutrient Intake (LRNI) for zinc, iron, vitamin B12 and potassium and have lower habitual vitamin D intakes than females consuming between 40 and 69 g daily. After adjusting data for energy intake, zinc (% below the LRNI) and vitamin D (MUg/day) remained statistically significant (p < 0.001). No significant differences were observed for blood biomarkers. Females consuming diets lower in red meat, i.e., <40 g daily, appear to have reduced micronutrient intakes, especially in the case of zinc and vitamin D. This should be considered when giving blanket advice for whole populations to reduce red meat intakes. PMID- 28718826 TI - Enhanced Strain Measurement Range of an FBG Sensor Embedded in Seven-Wire Steel Strands. AB - FBG sensors offer many advantages, such as a lack of sensitivity to electromagnetic waves, small size, high durability, and high sensitivity. However, their maximum strain measurement range is lower than the yield strain range (about 1.0%) of steel strands when embedded in steel strands. This study proposes a new FBG sensing technique in which an FBG sensor is recoated with polyimide and protected by a polyimide tube in an effort to enhance the maximum strain measurement range of FBG sensors embedded in strands. The validation test results showed that the proposed FBG sensing technique has a maximum strain measurement range of 1.73% on average, which is 1.73 times higher than the yield strain of the strands. It was confirmed that recoating the FBG sensor with polyimide and protecting the FBG sensor using a polyimide tube could effectively enhance the maximum strain measurement range of FBG sensors embedded in strands. PMID- 28718825 TI - Olive Mill Waste Enhances alpha-Glucan Content in the Edible Mushroom Pleurotus eryngii. AB - Mushroom polysaccharides are edible polymers that have numerous reported biological functions; the most common effects are attributed to beta-glucans. In recent years, it became apparent that the less abundant alpha-glucans also possess potent effects in various health conditions. Here we explore several Pleurotus species for their total, beta and alpha-glucan content. Pleurotus eryngii was found to have the highest total glucan concentrations and the highest alpha-glucans proportion. We also found that the stalks (stipe) of the fruit body contained higher glucan content then the caps (pileus). Since mushrooms respond markedly to changes in environmental and growth conditions, we developed cultivation methods aiming to increase the levels of alpha and beta-glucans. Using olive mill solid waste (OMSW) from three-phase olive mills in the cultivation substrate. We were able to enrich the levels mainly of alpha-glucans. Maximal total glucan concentrations were enhanced up to twice when the growth substrate contained 80% of OMSW compared to no OMSW. Taking together this study demonstrate that Pleurotus eryngii can serve as a potential rich source of glucans for nutritional and medicinal applications and that glucan content in mushroom fruiting bodies can be further enriched by applying OMSW into the cultivation substrate. PMID- 28718827 TI - Synthesis of 2H-Chromenones from Salicylaldehydes and Arylacetonitriles. AB - An efficient and convenient protocol for the synthesis of 2H-chromenones has been developed. In the presence of tBuOK in DMF, good to excellent yields of various chromenones were obtained from the corresponding salicylaldehydes and arylacetonitriles. No protection of inert gas atmosphere is required here. PMID- 28718828 TI - Tobacco Harm Reduction with Vaporised Nicotine (THRiVe): The Study Protocol of an Uncontrolled Feasibility Study of Novel Nicotine Replacement Products among People Living with HIV Who Smoke. AB - Smoking is a leading cause of morbidity and premature mortality among people living with HIV (PLHIV), who have high rates of tobacco smoking. Vaporised nicotine products (VNPs) are growing in popularity as a quit aid and harm reduction tool. However, little is known about their acceptability and use among PLHIV. Using a pragmatic, uncontrolled, mixed methods design this exploratory clinical trial aims to examine the feasibility of conducting a powered randomised clinical trial of VNPs as a smoking cessation and harm reduction intervention among vulnerable populations, such as PLHIV who smoke tobacco. Convenience sampling and snowball methods will be used to recruit participants (N = 30) who will receive two VNPs and up to 12 weeks' supply of nicotine e-liquid to use in a quit attempt. Surveys will be completed at weeks 0 (baseline), 4, 8, 12 (end of treatment) and 24 (end of the study) and qualitative interviews at weeks 0 and 12. As far as we are aware, this feasibility study is the first to trial VNPs among PLHIV for smoking cessation. If feasible and effective, this intervention could offer a new approach to reducing the high burden of tobacco-related disease among PLHIV and other vulnerable populations. PMID- 28718830 TI - Exploring Relationships between Recurrent Binge Eating and Illicit Substance Use in a Non-Clinical Sample of Women over Two Years. AB - (1) Background: With the new edition of the Diagnostic and Statistical Manual of Mental disorders, 5th Edition (DSM-5), numerous parallels have been drawn between recurrent binge eating (RBE) and substance use disorders, with many authors examining RBE or binge eating disorder (BED) as a "food addiction". The present study aims to clarify the relationship between recurrent binge eating (RBE) and illicit substance use (ISU) through investigating the temporal association between the two problems. (2) Methods: This study was embedded within a larger longitudinal study of non-clinical adult women recruited from Australian tertiary institutions. Participants responded at year 2 and year 4 of follow-up to the Eating Disorder Examination-Questionnaire. ISU was measured using a modified questionnaire taken from the Australian Longitudinal Study on Women's Health. (3) Results: RBE and ISU co-morbidity was 5.88% in this non-clinical sample, and having one condition increased the likelihood of the other. The two conditions had a different trajectory over two years whereby ISU participants had significant risk of developing RBE in addition to or in place of their ISU but the reverse was not found for RBE participants. (4) Conclusion: This unidirectional relationship suggests that in spite of the similarities of RBE and ISU they may be distinct with respect to their co-morbidity over time. PMID- 28718829 TI - Aspirin Prevention of Colorectal Cancer: Focus on NF-kappaB Signalling and the Nucleolus. AB - Overwhelming evidence indicates that aspirin and related non-steroidal anti inflammatory drugs (NSAIDs) have anti-tumour activity and the potential to prevent cancer, particularly colorectal cancer. However, the mechanisms underlying this effect remain hypothetical. Dysregulation of the nuclear factor kappaB (NF-kappaB) transcription factor is a common event in many cancer types which contributes to tumour initiation and progression by driving expression of pro-proliferative/anti-apoptotic genes. In this review, we will focus on the current knowledge regarding NSAID effects on the NF-kappaB signalling pathway in pre-cancerous and cancerous lesions, and the evidence that these effects contribute to the anti-tumour activity of the agents. The nuclear organelle, the nucleolus, is emerging as a central regulator of transcription factor activity and cell growth and death. Nucleolar function is dysregulated in the majority of cancers which promotes cancer growth through direct and indirect mechanisms. Hence, this organelle is emerging as a promising target for novel therapeutic agents. Here, we will also discuss evidence for crosstalk between the NF-kappaB pathway and nucleoli, the role that this cross-talk has in the anti-tumour effects of NSAIDs and ways forward to exploit this crosstalk for therapeutic purpose. PMID- 28718831 TI - Management Effectiveness of a Secondary Coniferous Forest for Landscape Appreciation and Psychological Restoration. AB - We investigated the influence of forest management on landscape appreciation and psychological restoration in on-site settings by exposing respondents to an unmanaged, dense coniferous (crowding) forest and a managed (thinned) coniferous forest; we set the two experimental settings in the forests of the Fuji Iyashinomoroi Woodland Study Center. The respondents were individually exposed to both settings while sitting for 15 min and were required to answer three questionnaires to analyze the psychological restorative effects before and after the experiment (feeling (the Profile of Mood States), affect (the Positive and Negative Affect Schedule), and subjective restorativeness (the Restorative Outcome Scale). To compare landscape appreciation, they were required to answer another two questionnaires only after the experiment, for scene appreciation (the semantic differential scale) and for the restorative properties of each environment (the Perceived Restorativeness Scale). Finally, we obtained these findings: (1) the respondents evaluated each forest environment highly differently and evaluated the thinned forest setting more positively; (2) the respondents' impressions of the two physical environments did not appear to be accurately reflected in their evaluations; (3) forest environments have potential restorative effects whether or not they are managed, but these effects can be partially enhanced by managing the forests. PMID- 28718832 TI - Application of Carbon Nanotubes in Chiral and Achiral Separations of Pharmaceuticals, Biologics and Chemicals. AB - Carbon nanotubes (CNTs) possess unique mechanical, physical, electrical and absorbability properties coupled with their nanometer dimensional scale that renders them extremely valuable for applications in many fields including nanotechnology and chromatographic separation. The aim of this review is to provide an updated overview about the applications of CNTs in chiral and achiral separations of pharmaceuticals, biologics and chemicals. Chiral single-walled carbon nanotubes (SWCNTs) and multi-walled carbon nanotubes (MWCNTs) have been directly applied for the enantioseparation of pharmaceuticals and biologicals by using them as stationary or pseudostationary phases in chromatographic separation techniques such as high-performance liquid chromatography (HPLC), capillary electrophoresis (CE) and gas chromatography (GC). Achiral MWCNTs have been used for achiral separations as efficient sorbent objects in solid-phase extraction techniques of biochemicals and drugs. Achiral SWCNTs have been applied in achiral separation of biological samples. Achiral SWCNTs and MWCNTs have been also successfully used to separate achiral mixtures of pharmaceuticals and chemicals. Collectively, functionalized CNTs have been indirectly applied in separation science by enhancing the enantioseparation of different chiral selectors whereas non-functionalized CNTs have shown efficient capabilities for chiral separations by using techniques such as encapsulation or immobilization in polymer monolithic columns. PMID- 28718833 TI - Coconut Oil Aggravates Pressure Overload-Induced Cardiomyopathy without Inducing Obesity, Systemic Insulin Resistance, or Cardiac Steatosis. AB - Studies evaluating the effects of high-saturated fat diets on cardiac function are most often confounded by diet-induced obesity and by systemic insulin resistance. We evaluated whether coconut oil, containing C12:0 and C14:0 as main fatty acids, aggravates pressure overload-induced cardiomyopathy induced by transverse aortic constriction (TAC) in C57BL/6 mice. Mortality rate after TAC was higher (p < 0.05) in 0.2% cholesterol 10% coconut oil diet-fed mice than in standard chow-fed mice (hazard ratio 2.32, 95% confidence interval 1.16 to 4.64) during eight weeks of follow-up. The effects of coconut oil on cardiac remodeling occurred in the absence of weight gain and of systemic insulin resistance. Wet lung weight was 1.76-fold (p < 0.01) higher in coconut oil mice than in standard chow mice. Myocardial capillary density (p < 0.001) was decreased, interstitial fibrosis was 1.88-fold (p < 0.001) higher, and systolic and diastolic function was worse in coconut oil mice than in standard chow mice. Myocardial glucose uptake was 1.86-fold (p < 0.001) higher in coconut oil mice and was accompanied by higher myocardial pyruvate dehydrogenase levels and higher acetyl-CoA carboxylase levels. The coconut oil diet increased oxidative stress. Myocardial triglycerides and free fatty acids were lower (p < 0.05) in coconut oil mice. In conclusion, coconut oil aggravates pressure overload-induced cardiomyopathy. PMID- 28718834 TI - DNA-Interacting Characteristics of the Archaeal Rudiviral Protein SIRV2_Gp1. AB - Whereas the infection cycles of many bacterial and eukaryotic viruses have been characterized in detail, those of archaeal viruses remain largely unexplored. Recently, studies on a few model archaeal viruses such as SIRV2 (Sulfolobus islandicus rod-shaped virus) have revealed an unusual lysis mechanism that involves the formation of pyramidal egress structures on the host cell surface. To expand understanding of the infection cycle of SIRV2, we aimed to functionally characterize gp1, which is a SIRV2 gene with unknown function. The SIRV2_Gp1 protein is highly expressed during early stages of infection and it is the only protein that is encoded twice on the viral genome. It harbours a helix-turn-helix motif and was therefore hypothesized to bind DNA. The DNA-binding behavior of SIRV2_Gp1 was characterized with electrophoretic mobility shift assays and atomic force microscopy. We provide evidence that the protein interacts with DNA and that it forms large aggregates, thereby causing extreme condensation of the DNA. Furthermore, the N-terminal domain of the protein mediates toxicity to the viral host Sulfolobus. Our findings may lead to biotechnological applications, such as the development of a toxic peptide for the containment of pathogenic bacteria, and add to our understanding of the Rudiviral infection cycle. PMID- 28718835 TI - Do Refuge Plants Favour Natural Pest Control in Maize Crops? AB - The use of non-crop plants to provide the resources that herbivorous crop pests' natural enemies need is being increasingly incorporated into integrated pest management programs. We evaluated insect functional groups found on three refuges consisting of five different plant species each, planted next to a maize crop in Lima, Peru, to investigate which refuge favoured natural control of herbivores considered as pests of maize in Peru, and which refuge plant traits were more attractive to those desirable enemies. Insects occurring in all the plants, including the maize crop itself, were sampled weekly during the crop growing cycle, from February to June 2011. All individuals collected were identified and classified into three functional groups: herbivores, parasitoids, and predators. Refuges were compared based on their effectiveness in enhancing the populations of predator and parasitoid insects of the crop enemies. Refuges A and B were the most effective, showing the highest richness and abundance of both predators and parasitoids, including several insect species that are reported to attack the main insect pests of maize (Spodoptera frugiperda and Rhopalosiphum maidis), as well as other species that serve as alternative hosts of these natural enemies. PMID- 28718837 TI - Interactivity and Trust as Antecedents of E-Training Use Intention in Nigeria: A Structural Equation Modelling Approach. AB - BACKGROUND: The last few decades saw an intense development in information technology (IT) and it has affected the ways organisations achieve their goals. Training, in every organisation is an ongoing process that aims to update employees' knowledge and skills towards goals attainment. Through adequate deployment of IT, organisations can effectively meet their training needs. However, for successful IT integration in training, the employees who will use the system should be positively disposed towards it. This study predicts employees' intention to use the e-training system by extending the technology acceptance model (TAM) using interactivity and trust. METHODS: Two hundred and fourteen employees participated in the study and structural equation modelling was used in the analysis. RESULTS: The findings of the structural equation modelling reveal that interactivity, trust, perceived usefulness and perceived ease of use have direct and positive effects on employees' intention to use e training. It was also shown that perceived ease of use had no effects on perceived usefulness, while trust has the strongest indirect effects on employees' intention. In addition, the results of Importance-Performance Map Analysis (IPMA), which compares the contributions of each construct to the importance and performance of the model, indicate that to predict intention to use e-training, priorities should be accorded to trust and perceived usefulness. PMID- 28718836 TI - The Biological Activities of Sesterterpenoid-Type Ophiobolins. AB - Ophiobolins (Ophs) are a group of tricarbocyclic sesterterpenoids whose structures contain a tricyclic 5-8-5 carbotricyclic skeleton. Thus far, 49 natural Ophs have been reported and assigned into A-W subgroups in order of discovery. While these sesterterpenoids were first characterized as highly effective phytotoxins, later investigations demonstrated that they display a broad spectrum of biological and pharmacological characteristics such as phytotoxic, antimicrobial, nematocidal, cytotoxic, anti-influenza and inflammation-promoting activities. These bioactive molecules are promising drug candidates due to the developments of their anti-proliferative activities against a vast number of cancer cell lines, multidrug resistance (MDR) cells and cancer stem cells (CSCs). Despite numerous studies on the biological functions of Ophs, their pharmacological mechanism still requires further research. This review summarizes the chemical structures, sources, and biological activities of the oph family and discusses its mechanisms and structure-activity relationship to lay the foundation for the future developments and applications of these promising molecules. PMID- 28718838 TI - Phyllanthus Niruri Standardized Extract Alleviates the Progression of Non Alcoholic Fatty Liver Disease and Decreases Atherosclerotic Risk in Sprague Dawley Rats. AB - Non-alcoholic fatty liver disease (NAFLD) is one of the major global health issues, strongly correlated with insulin resistance, obesity and oxidative stress. The current study aimed to evaluate anti-NAFLD effects of three different extracts of Phyllanthus niruri (P. niruri). NAFLD was induced in male Sprague Dawley rats using a special high-fat diet (HFD). A 50% methanolic extract (50% ME) exhibited the highest inhibitory effect against NAFLD progression. It significantly reduced hepatomegaly (16%) and visceral fat weight (22%), decreased NAFLD score, prevented fibrosis, and reduced serum total cholesterol (TC) (48%), low-density lipoprotein (LDL) (65%), free fatty acids (FFAs) (25%), alanine aminotransferase (ALT) (45%), alkaline phosphatase (ALP) (38%), insulin concentration (67%), homeostatic model assessment of insulin resistance (HOMA-IR) (73%), serum atherogenic ratios TC/high-density lipoprotein (HDL) (29%), LDL/HDL (66%) and (TC-HDL)/HDL (64%), hepatic content of cholesterol (43%), triglyceride (29%) and malondialdehyde (MDA) (40%) compared to a non-treated HFD group. In vitro, 50% ME of P. niruri inhibited alpha-glucosidase, pancreatic lipase enzymes and cholesterol micellization. It also had higher total phenolic and total flavonoid contents compared to other extracts. Ellagic acid and phyllanthin were identified as major compounds. These results suggest that P. niruri could be further developed as a novel natural hepatoprotective agent against NAFLD and atherosclerosis. PMID- 28718840 TI - Bilinguals' Working Memory (WM) Advantage and Their Dual Language Practices. AB - The present study investigates a possible working memory (WM) difference between monolingual and bilingual groups and explores the relationship between their WM advantage and language practices. A mixed methods design was employed for the study. To measure participants' WM, auditory and visual digit span tasks were conducted on the different language groups: 20 Korean near-monolinguals, and 40 Korean-English bilinguals with two different levels of second language (L2) proficiency. Bilinguals' daily language practices were explored through semi structured interviews with eight bilinguals. The convergence of the findings from both tests and interview data suggests that knowing two languages does not guarantee bilingual WM advantages over monolinguals, but the advantage might be linked to bilinguals' unique L2 use environment where they need to hold incoming L2 information while decoding it. PMID- 28718839 TI - Dose-Dependent Prebiotic Effect of Lactulose in a Computer-Controlled In Vitro Model of the Human Large Intestine. AB - Lactulose, a disaccharide of galactose and fructose, used as a laxative or ammonia-lowering drug and as a functional food ingredient, enhances growth of Bifidobacterium and Lactobacillus at clinically relevant dosages. The prebiotic effect of subclinical dosages of Lactulose, however, remains to be elucidated. This study analyses changes in the microbiota and their metabolites after a 5 days Lactulose treatment using the TIM-2 system, a computer-controlled model of the proximal large intestine representing a complex, high density, metabolically active, anaerobic microbiota of human origin. Subclinical dosages of 2-5 g Lactulose were used. While 2 g Lactulose already increased the short-chain fatty acid levels of the intestinal content, 5 g Lactulose were required daily for 5 days in this study to exert the full beneficial prebiotic effect consisting of higher bacterial counts of Bifidobacterium, Lactobacillus, and Anaerostipes, a rise in acetate, butyrate and lactate, as well as a decrease in branched-chain fatty acids, pH (suggested by an increase in NaOH usage), and ammonia. PMID- 28718843 TI - Cascade reaction of alkynols with 1-(2-aminophenyl)prop-2-ynols to form a fused 5,5,6-tricyclic system: formation of four bonds in a single reaction. AB - A novel cascade reaction of internal alkynols with 1-(2-aminophenyl)prop-2-ynols has been developed to form a new N,O-containing fused 5,5,6-tricyclic skeleton. Mechanistic studies indicate that this reaction proceeds via alkynol cycloisomerization, intermolecular substitution with 1-(2-aminophenyl)prop-2 ynols, and intermolecular addition with alkynols and consequent cyclizations. In this way, two C-C bonds, one C-O bond and one C-N bond form to give a tricyclic skeleton in a single reaction. PMID- 28718841 TI - Development of an Immunosensor for PfHRP 2 as a Biomarker for Malaria Detection. AB - Plasmodium falciparum histidine-rich protein 2 (PfHRP 2) was selected in this work as the biomarker for the detection and diagnosis of malaria. An enzyme linked immunosorbent assay (ELISA) was first developed to evaluate the immunoreagent's suitability for the sensor's development. A gold-based sensor with an integrated counter and an Ag/AgCl reference electrode was first selected and characterised and then used to develop the immunosensor for PfHRP 2, which enables a low cost, easy to use, and sensitive biosensor for malaria diagnosis. The sensor was applied to immobilise the anti-PfHRP 2 monoclonal antibody as the capture receptor. A sandwich ELISA assay format was constructed using horseradish peroxidase (HRP) as the enzyme label, and the electrochemical signal was generated using a 3, 3', 5, 5'tetramethyl-benzidine dihydrochloride (TMB)/H2O2 system. The performance of the assay and the sensor were optimised and characterised, achieving a PfHRP 2 limit of detection (LOD) of 2.14 ng.mL-1 in buffer samples and 2.95 ng?mL-1 in 100% spiked serum samples. The assay signal was then amplified using gold nanoparticles conjugated detection antibody-enzyme and a detection limit of 36 pg?mL-1 was achieved in buffer samples and 40 pg?mL-1 in serum samples. This sensor format is ideal for malaria detection and on-site analysis as a point-of-care device (POC) in resource-limited settings where the implementation of malaria diagnostics is essential in control and elimination efforts. PMID- 28718842 TI - Secreted Protein Acidic and Rich in Cysteine (SPARC) Enhances Cell Proliferation, Migration, and Epithelial Mesenchymal Transition, and SPARC Expression is Associated with Tumor Grade in Head and Neck Cancer. AB - Secreted protein acidic and rich in cysteine (SPARC) is a secreted protein which is involved in various biological processes. SPARC expression is associated with tumor metastasis and poor prognosis in several types of cancer. However, the SPARC-induced signaling pathway was not fully understood in head and neck cancer. In this study, our results showed that SPARC treatment promoted cell proliferation and migration in head and neck cancer cell lines FaDu and Detroit 562. In addition, SPARC induced expression of epithelial mesenchymal transition (EMT) regulators, including Slug, Snail, and Twist in Detroit 562. The results of phospho-kinase array analysis showed that SPARC treatment increased phosphorylation of some molecules including protein kinase B (PKB/AKT), ribosomal S6 kinase (RSK), and extracellular signal-regulated kinases (ERK). The expression of SPARC-induced EMT regulator Slug was suppressed by AKT inhibitor, but not ERK and RSK inhibitors. The SPARC expression in grade IV tumor samples is higher when compared to that in grade I-III tumor samples. Our results suggest that SPARC treatment enhances the EMT signaling pathway via activation of AKT, and exogenous SPARC and tumor expressing SPARC might be associated with tumor progression in head and neck cancers. PMID- 28718844 TI - Solvent gradient electrospray for laser ablation electrospray ionization mass spectrometry. AB - Most electrospray based ambient ionization techniques, e.g., laser ablation electrospray ionization (LAESI), utilize a fixed spray solution composition. Complex samples often contain compounds of different polarity that exhibit a wide range of solubilities in the electrospray solvent. Thus, the fixed spray solution composition limits the molecular coverage of these approaches. Two-barrel theta glass capillaries have been used for the rapid mixing of two solutions for manipulating fast reactions including protein folding, unfolding, and charge state distributions. Here, we present a new variant of LAESI mass spectrometry (MS) by scanning the high voltages applied to the two barrels of a theta glass capillary containing two different solvents. In the resulting gradient LAESI (g LAESI), the composition of the spray solution is ramped between the two solvents in the barrels to facilitate the detection of compounds of diverse polarity and solubility. Dynamic ranges and limits of detection achieved for g-LAESI-MS were comparable to conventional LAESI-MS. We have demonstrated simultaneous detection of different types of chemical standards, and polar and less polar compounds from Escherichia coli cell pellets using g-LAESI-MS. Varying the spray solution composition in a gradient electrospray can benefit from the enhanced solubilities of different analytes in polar and less polar solvents, ultimately improving the molecular coverage in the direct analysis of biological samples. PMID- 28718847 TI - Effect of pretreatment severity on the cellulose and lignin isolated from Salix using ionoSolv pretreatment. AB - The ionoSolv pretreatment is a new technique employing protic low-cost ionic liquids and has previously been applied to successfully fractionate switchgrass and the grass Miscanthus giganteus. This study investigates the effect of using the protic ionic liquid solution [N2220][HSO4]80% with two different acid/base ratios (1.02 and 0.98) at 120, 150 and 170 degrees C on the pretreatment outcome of the hardwood willow. The ionic liquid solution was able to fractionate willow, and a pulp and lignin fraction were recovered after treatment. The pretreatment success was determined via enzymatic hydrolysis of the pulp, which showed that the ionoSolv pretreatment was able to increase enzymatic glucose yields compared to untreated willow biomass. The pretreatment produced a cellulose-rich pulp with high hemicellulose and lignin removal. The pulp composition and glucose yield after saccharification were greatly influenced by the acidity of the ionic liquid solution, temperature and pretreatment time. The extracted lignin was analysed via 2-D HSQC NMR spectroscopy and GPC to investigate the changes in the lignin structure induced by the pretreatment severity. The lignin structure (in terms of inter-unit linkages and S/G ratio) and molecular weight varied significantly depending on the pretreatment conditions used. PMID- 28718848 TI - Label-free, high-throughput holographic screening and enumeration of tumor cells in blood. AB - We introduce inline digital holographic microscopy (in-line DHM) as a label-free technique for detecting tumor cells in blood. The optimized DHM platform fingerprints every cell flowing through a microchannel at 10 000 cells per second, based on three features - size, maximum intensity and mean intensity. To identify tumor cells in a background of blood cells, we developed robust gating criteria using machine-learning approaches. We established classifiers from the features extracted from 100 000-cell training sets consisting of red blood cells, peripheral blood mononuclear cells and tumor cell lines. The optimized classifier was then applied to targeted features of a single cell in a mixed cell population to make quantitative cell-type predictions. We tested our classification system with tumor cells spiked at different levels into a background of lysed blood that contained predominantly peripheral blood mononuclear cells. Results show that our holographic screening method can readily detect as few as 10 tumor cells per mL, and can identify tumor cells at a false positive rate of at most 0.001%. This purely optical approach obviates the need for antibody labeling and allows large volumes of sample to be quickly processed. Moreover, our in-line DHM approach can be combined with existing circulation tumor cell enrichment strategies, making it a promising tool for label-free analysis of liquid-biopsy samples. PMID- 28718849 TI - An efficient method to transcription factor binding sites imputation via simultaneous completion of multiple matrices with positional consistency. AB - Transcription factors (TFs) are DNA-binding proteins that have a central role in regulating gene expression. Identification of DNA-binding sites of TFs is a key task in understanding transcriptional regulation, cellular processes and disease. Chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) enables genome-wide identification of in vivo TF binding sites. However, it is still difficult to map every TF in every cell line owing to cost and biological material availability, which poses an enormous obstacle for integrated analysis of gene regulation. To address this problem, we propose a novel computational approach, TFBSImpute, for predicting additional TF binding profiles by leveraging information from available ChIP-seq TF binding data. TFBSImpute fuses the dataset to a 3-mode tensor and imputes missing TF binding signals via simultaneous completion of multiple TF binding matrices with positional consistency. We show that signals predicted by our method achieve overall similarity with experimental data and that TFBSImpute significantly outperforms baseline approaches, by assessing the performance of imputation methods against observed ChIP-seq TF binding profiles. Besides, motif analysis shows that TFBSImpute preforms better in capturing binding motifs enriched in observed data compared with baselines, indicating that the higher performance of TFBSImpute is not simply due to averaging related samples. We anticipate that our approach will constitute a useful complement to experimental mapping of TF binding, which is beneficial for further study of regulation mechanisms and disease. PMID- 28718858 TI - ? AB - Swedish white paper on donation can give more donors without compromising ethics The White Paper on organ donation (SOU 2015:84) proposes new regulations for organ donation. In particular it spells out that it is permissible to take medical steps to preserve organs while the patient is still alive. It is proposed that this should be allowed after the medical team has declared that the continuation of life sustaining treatment is futile. The white paper opens up for donation after cardiac death. There has been some critique of the white paper for lack of deeper ethical discussions. The ethical issues pertaining to the proposals are discussed in this paper. It is concluded that the proposals are ethically acceptable. The human dignity principle will however demand that the decision to end life sustaining treatment is taken regardless of whether the patient is a possible organ donor or not. PMID- 28718859 TI - [Introduce generic prescription - now]. PMID- 28718860 TI - [Poor indoor air quality may be behind the high rate of sick leave in preschool]. PMID- 28718861 TI - ? PMID- 28718862 TI - ? PMID- 28718863 TI - ? AB - New regulations concerning EHEC/VTEC Hemolytic Uremic Syndrome (HUS) is the most severe complication to an infection with EHEC (enterohemorrhagic E. coli), also called VTEC (verocytotoxin-producing E. coli). Risk of severe complications such as HUS is an important reason why the Swedish Communicable Diseases Act (Smittskyddslag. 2004:168) includes infection with EHEC. With very few exceptions, only EHEC with the stx2 gene is associated with HUS. According to the law, persons working with unpackaged foods, infants or severely immunocompromised patients, and children attending preschool can be suspended awaiting negative test results for EHEC. Symptom free carriers of EHEC-infection only harbouring the stx1 gene and without an epidemiological association to HUS need not be suspended from work or preschool. PMID- 28718864 TI - [Cognitive-Behavioral Group Therapy Addressing Fear of Progression in Cancer Out Patients]. AB - Fear of progression (FoP) is an appropriate, rational response to the real threat of cancer and its treatments. However, patients experiencing elevated, dysfunctional levels of FoP often feel severely distressed and are in need of treatment. We previously conducted a (partly-)randomized controlled study with cancer patients undergoing in-patient rehabilitation and showed that a brief, four-session cognitive-behavioral group therapy significantly reduced dysfunctional FoP. In this report, we describe the adaption of the cognitive behavioral group therapy program for use with cancer out-patients. This group therapy program was conducted in the psycho-oncological out-patient department of a large university hospital. It comprises 6 group sessions lasting 90 min each. Because of the larger number of sessions there is more room for the use of exposure-based techniques. Imaginal exposure is used to confront the patient's cancer-related fears and worries. Patients are asked to vividly recount their worries and to think of what would be the worst that can happen (worst-case scenario exercise). In addition, interventions that focus the patient's ressources are applied. The completion of 3 group therapies in the pilot phase supported the feasibility of the program. Pre-post evaluation (n=10) revealed a significant decline of FoP (Fear of Progression Questionnaire, FoP-Q) from M=12,0 (SD=2,0) to M=10,3 (SD=1,7), p=0.029. This represents a large effect (Cohen's d=0.9). Three out of 14 participants (21%) quit treatment after 2 sessions. In sum, the results and our experiences show that this out-patient group therapy program is feasible and probably effective. However, it also shows that some patients regard confronting their cancer-related fears and worries as too stressful. High ambivalence with regard to exposure seems to increase the risk for premature termination. Thus, cancer patients should be thoroughly educated before starting exposure-based treatment of dysfunctional FoP. PMID- 28718865 TI - [Low-Intensity Cognitive Behavioral Therapy (LI-CBT) - An Introduction in Concepts and Framework]. AB - Low-intensity cognitive behavioural therapy (LI-CBT) depicts interventions that aim at increasing access to evidence-based psychological therapies. This is achieved by (1) reducing the amount of time in which the practitioner is in contact with individual patients, (2) using practitioners that have been specifically trained to deliver low intensity interventions and without any prior formal health professional qualifications and (3) use of interventions with varying intensity. Stepped care and collaborative care constitute the organizational frame to deliver low-intensity interventions. Whereas large-scale research and health service projects abroad are focussing on LI-CBT, research in German is lagging far behind. Particularly in the light of the growing demands and utilization of mental health care as well as governmental claims to develop and evaluate new forms of providing mental health services, LI-CBT represents a promising approach. PMID- 28718866 TI - [Assessing Change of Depressive Symptoms and Severity of Depression in an Inpatient Setting : Performance of the HoNOS (Health of the Nation Outcome Scales)]. AB - Objectives This study investigates the assessment of change of depressive symptoms and severity of depression with the "Health of the Nation Outcome Scales" (HoNOS) in an inpatient setting. Method Participants were 132 adults diagnosed with depressive disorder (F32: n=102; F33: n=30). Bivariate correlations were used to determine the correlation of the HoNOS with self reported (BDI) and observer-rated depressive symptoms (HAMD). The predictive validity of the HoNOS was analysed with linear regression models. Results The HoNOS differentiated significantly between patients with moderate versus severe depression at baseline (p<0,05). It correlated with the HAMD change score (r=0,25, p<0,008), but not with the BDI change score (r=0,19, p>0,008).The HoNOS was not a significant predictor of observer-rated depression at discharge (beta=0,03, p>0,05). Conclusion As the HoNOS only partially seems to assess the change and severity of depressive symptoms, it should only be used in combination with depression-specific instruments. PMID- 28718867 TI - ["Defeated by Life" - Validation of a German Version of the Defeat Scale (DS-d)]. AB - INTRODUCTION: Defeat and entrapment are transdiagnostic constructs that play an important role in the development of depression, anxiety, suicidality and trauma associated mental disorders. The present study aimed at presenting and validating a first German version of the Defeat-Scale (DS-d). MATERIAL AND METHODS: Through a web-based survey, N=480 participants were recruited (74% female; MAge=28.5, SDAge=11.1, Range: 18-80 years); 14.2% reported to currently suffer from a mental disorder, 8.5% reported at least one lifetime suicide attempt. All participants filled in the DS-d, the Entrapment Scale, the Rasch-based Depression Screening, the Depressive Symptoms Inventory - Suicidality Subscale, the Suicidal Behavior Questionnaire-Revised, the Childhood Trauma Screener, and the questionnaire Generalized Anxiety Disorders 2. Factorial validity was investigated through a unidimensional confirmatory factor analysis (CFA). Moreover, internal consistency, convergent validity (correlations with the other measured constructs) and criterion validity (suicidality) were examined. RESULTS: One residual correlation between 2 items that are inversely coded had to be allowed to reach a satisfying fit to the unidimensional model (RMSEA=0.077, TLI=0.94, NFI=0.93, CFI=0.95; item loadings>0.56). The DS-d-sumscore correlated highly with depression (r=0.87), Entrapment (r=0.83) and suicidality (r=0.70), and moderately with the other constructs. Participants with suicidal thoughts or behavior in the past showed higher DS-d-scores than participants without suicidality. DISCUSSION: The unidimensional structure of the English version could be confirmed in the DS d - after allowing for a residual correlation between two inversely coded items. Correlations with the other measured constructs give support for the validity of the DS-d. Criterion validity of the instrument is supported by its relations to suicidality. It remains open whether defeat and entrapment are 2 distinct constructs. In the current study - in accordance with the literature - both showed a very high intercorrelation. CONCLUSION: This study reports on the validation of a German version of the Defeat-Scale (DS-d) for the first time that shows good psychometric characteristics in terms of internal consistency and validity. PMID- 28718868 TI - [Implicit Associations with Death: First Validation of the German Version of the Suicide Implicit Association Test (Suicide IAT)]. AB - Nock, Park, Finn, et al. 1 developed an implicit association test for suicide (suicide IAT) measuring the implicit association between 'death' and 'self'. They demonstrated that psychiatric patients, who already attempted suicide, showed stronger implicit associations with 'death' than with 'life' compared to patients without suicide attempt history. The present study had 2 aims: (1) to present a new German version of the suicide IAT and provide its first validation and (2) to investigate how implicit associations (suicide IAT) relate to suicidal ideation and behaviour, well-known risk factors such as depressiveness and hopelessness, and central concepts of the Interpersonal Theory of Suicide 2, Thwarted Belongingness and Perceived Burdensomeness. The sample consisted of 16 patients with a current Major Depression and suicidal ideation as well as 16 non depressive, non-suicidal controls. Patients showed stronger associations between 'death' and 'self' than controls. We further found positive correlations between implicit associations with death and explicitly self-reported suicidal behaviour controlled for depressiveness, hopelessness, and suicidal ideation. Our results confirm the validity of the German version of the suicide IAT and are discussed in the light of the Interpersonal Theory of Suicidal Behaviour 2 and recent suicide research. PMID- 28718869 TI - [The (Refugee) Crisis in the Psychotherapeutic Treatment Room]. AB - OBJECTIVE: Aim of the study was to examine how discourses of refugees in the media influence the perspective of independent psychotherapists working with refugees. METHODS: 20 problem-centered interviews were carried out across Germany with independent psychotherapists, and were analyzed using the principles of Grounded Theory. RESULTS: 4 portrayals of refugees were identified: 'The problematic Other' (1), 'No Other' (2), 'The advantageous Other' (3) and 'The excluded subject' (4). CONCLUSION: The impact of discourses about refugees in the media can contribute to understand the findings in this study. Further explanations for the findings could be the differing access to knowledge about the situation of refugees, difficult living conditions of refugees in Germany and a psychotherapeutic approach focusing mainly on mental disorders. PMID- 28718870 TI - [Motivational Goals and Couple Relationship Quality in a Sample of Individuals with Infertility]. AB - 3,5-16,6% of couples worldwide with childwish suffer from infertility, and about 20% thereof show clinically relevant psychological symptoms. Until now it remained unclear, up to which extent motivational factors are associated with psychological distress when suffering from infertility. The goal of this study was to assess individual motivational factors in a sample of infertile people, and to explore their effect on psychological distress. Additionally, the role of couple relationship quality as a dyadic predictor was to be examined. We assessed psychological distress, specificity of motivational goals and their achievement, and couple relationship quality in a sample of 123 infertile subjects by online survey. About half of the subjects indicated significant levels of psychological distress. Compared to psychopathologically distressed samples (without explicit infertility problems), infertile subjects specified less approach motivation. Furthermore, low levels of approach motivation were associated with low levels of distress. This applied specifically to the need for control and self-worth. Motivational factors explained 30% of variance in distress, whereas couple relationship quality, specifically the prevalence of arguing, explained merely 4%. These findings show that infertility is associated with distinct motivational patterns, and that these may be suitable to predict psychological distress. PMID- 28718871 TI - [Brief Instruments in German for the Assessment of Disordered Eating]. AB - The development of brief instruments is an important area in the clinical and psychological assessment in the past years. Brief instruments reveal many advantages due to their efficiency and shortness for the users. However, the psychometric standards of development and validation were often neglected during the construction of short forms. The current overview presents 6 brief instruments for the assessment of disordered eating and eating disorders in German: Eating Attitudes Test 8 (EAT-8), Eating Disorder Examination Questionnaire 8 (EDE-Q8) and the child version (ChEDE-Q8), ICD-10-Symptom-Rating subscale eating disorders (ISR-E), SCOFF questionnaire, and Short Evaluation of Eating Disorders (SEED). Furthermore, recent validation studies were summarized. Users should be aware about the fact that every brief instrument is validated for specific purpose and population. Therefore, aim of the present overview is to help the reader choosing the appropriate brief instrument for the intended purpose and population. PMID- 28718872 TI - Multiple distant painful subcutaneous nodules in a healthy young non-smoker. PMID- 28718873 TI - Clinical features of drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome: a study of 25 patients in Korea. AB - BACKGROUND: Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare adverse drug reaction. This study aimed to evaluate the incidence of association with individual drugs, clinical manifestations, disease course, and outcomes of DRESS. METHODS: Using the criteria of the European Registry of Severe Cutaneous Adverse Reactions (RegiSCAR), the medical records of 25 patients diagnosed with DRESS between 2006 and 2015 were retrospectively reviewed. Demographic data, culprit drugs, latency periods, clinical and laboratory findings, and outcomes were investigated. RESULTS: The study group comprised 11 men (44%) and 14 women (56%) with an age range of 13-93 years (mean, 58 +/- 19.86 years). The drugs most commonly implicated were carbamazepine (28%), allopurinol (16%), and antituberculosis drugs (12%). Individual latency periods ranged from 4 to 40 days (mean, 17.6 +/- 9.95 days). Latency periods for anticonvulsants were significantly longer than those for other drugs (P < 0.05). However, no statistical differences were found between the RegiSCAR scores for anticonvulsants and those for other drugs. Disease severity, based on RegiSCAR score, was correlated with blood count abnormalities (P < 0.05). CONCLUSIONS: The results of our study revealed that anticonvulsants were the leading culprit drugs for DRESS, and carbamazepine was the individual drug most commonly associated with DRESS in Korea. Further studies of the mechanisms of action of these drugs are required in order to facilitate prompt diagnosis and effective management, which can affect prognosis and clinical outcome, of DRESS. PMID- 28718874 TI - Everyday territories: homelessness, outreach work and city space. AB - This article develops a situational approach to understanding urban public life and, in particular, the production of urban territories. Our aim is to examine the ways in which city space might be understood as comprising multiple, shifting, mobile and rhythmed territories. We argue that such territories are best understood through attending to their everyday production and negotiation, rather than handling territory as an a priori construct. We develop this argument from the particular case of the street-level politics of homelessness and street care. The experience of street homelessness and the provision of care in the public spaces of the city is characterised by precarious territorial claims made and lost. We describe some of the ways in which care work with rough sleepers is itself precarious; 'homeless', in lacking a distinct setting in which it might get done. Indeed, outreach work takes place within and affirms homeless territories. The affirmation of territory is shown to be central to the relationship developed between the workers and their rough sleeping clients. We also show, however, the ways in which outreach workers operate on territory not their own, twice over. Outreach work is precarious in that it is practised within, and can run counter to, other territorial productions in which the experience of urban need and the work and politics of care are entangled. In sum, this article aims to move beyond static and binary understandings by developing a mobile and situational approach to city space which recognises the intensive yet overlooked work of territorial production. PMID- 28718875 TI - Dermoscopy in terra firma-forme dermatosis and dermatosis neglecta. PMID- 28718876 TI - Is there a revision needed of the current FIGO staging system? AB - The FIGO staging system has undergone many modifications since it first appeared in about the middle of the previous century. Due to the use of modern diagnostic tools, namely computed tomography, magnetic resonance imaging, positron emission tomography, sentinel lymph node biopsy and neoadjuvant chemotherapy, certain gynecological cancer cases cannot be allocated to a specific stage if one wishes to adhere strictly to FIGO requirements. In these circumstances such cases actually remain unstaged. This should prompt appropriate modifications of the current FIGO staging system so that it fulfills its aims. PMID- 28718877 TI - Takotsubo syndrome in hemodynamically unstable patients admitted to the intensive care unit - a retrospective study. AB - INTRODUCTION: Takotsubo syndrome (TS) is an acute cardiac condition that is often triggered by critical illness but that has rarely been studied in the intensive care unit (ICU) setting. The aim of this study was to (i) estimate the incidence of TS in a hemodynamically unstable ICU-population; (ii) identify predictors of TS in this population; (iii) study the impact of TS on prognosis and course of hospitalization. METHODS: Medical records from all patients admitted to our general ICU from 2012 to 2015 were analyzed. TS was defined as having transient regional wall motion abnormalities (RWMA) with a typical pattern not attributable to a history of coronary artery disease or acute coronary syndromes. RESULTS: Out of 6470 patients admitted to the ICU, echocardiography due to hemodynamic instability was performed in 1051 patients; 467 had LV dysfunction and 59 fulfilled TS criteria. Patients with TS had higher SAPS 3 scores on admission than patients with normal LV function. Septic shock, cardiac arrest, cerebral mass lesion, female sex and low pH were independently associated with TS on admission. Patients with TS needed more ICU resources measured by higher NEMS scores and longer ICU-stay. Crude mortality was higher in TS patients (32%) vs the ICU-population (20%, P = 0.020), but there were no differences in a SAPS 3 adjusted analysis. CONCLUSION: TS was not an uncommon cause of LV dysfunction in hemodynamically unstable ICU-patients. Furthermore, TS was associated with a more complex disease. TS is a complication to take in consideration in the critically ill. PMID- 28718878 TI - Deep brain and cortical stimulation for epilepsy. AB - BACKGROUND: Despite optimal medical treatment, including epilepsy surgery, many epilepsy patients have uncontrolled seizures. Since the 1970s interest has grown in invasive intracranial neurostimulation as a treatment for these patients. Intracranial stimulation includes both deep brain stimulation (DBS) (stimulation through depth electrodes) and cortical stimulation (subdural electrodes). This is an updated version of a previous Cochrane review published in 2014. OBJECTIVES: To assess the efficacy, safety and tolerability of DBS and cortical stimulation for refractory epilepsy based on randomized controlled trials (RCTs). SEARCH METHODS: We searched the Cochrane Epilepsy Group Specialized Register on 29 September 2015, but it was not necessary to update this search, because records in the Specialized Register are included in CENTRAL. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library 2016, Issue 11, 5 November 2016), PubMed (5 November 2016), ClinicalTrials.gov (5 November 2016), the WHO International Clinical Trials Registry Platform ICTRP (5 November 2016) and reference lists of retrieved articles. We also contacted device manufacturers and other researchers in the field. No language restrictions were imposed. SELECTION CRITERIA: RCTs comparing deep brain or cortical stimulation versus sham stimulation, resective surgery, further treatment with antiepileptic drugs or other neurostimulation treatments (including vagus nerve stimulation). DATA COLLECTION AND ANALYSIS: Four review authors independently selected trials for inclusion. Two review authors independently extracted the relevant data and assessed trial quality and overall quality of evidence. The outcomes investigated were seizure freedom, responder rate, percentage seizure frequency reduction, adverse events, neuropsychological outcome and quality of life. If additional data were needed, the study investigators were contacted. Results were analysed and reported separately for different intracranial targets for reasons of clinical heterogeneity. MAIN RESULTS: Twelve RCTs were identified, eleven of these compared one to three months of intracranial neurostimulation with sham stimulation. One trial was on anterior thalamic DBS (n = 109; 109 treatment periods); two trials on centromedian thalamic DBS (n = 20; 40 treatment periods), but only one of the trials (n = 7; 14 treatment periods) reported sufficient information for inclusion in the quantitative meta-analysis; three trials on cerebellar stimulation (n = 22; 39 treatment periods); three trials on hippocampal DBS (n = 15; 21 treatment periods); one trial on nucleus accumbens DBS (n = 4; 8 treatment periods); and one trial on responsive ictal onset zone stimulation (n = 191; 191 treatment periods). In addition, one small RCT (n = 6) compared six months of hippocampal DBS versus sham stimulation. Evidence of selective reporting was present in four trials and the possibility of a carryover effect complicating interpretation of the results could not be excluded in five cross-over trials without any or a sufficient washout period. Moderate-quality evidence could not demonstrate statistically or clinically significant changes in the proportion of patients who were seizure-free or experienced a 50% or greater reduction in seizure frequency (primary outcome measures) after one to three months of anterior thalamic DBS in (multi)focal epilepsy, responsive ictal onset zone stimulation in (multi)focal epilepsy patients and hippocampal DBS in (medial) temporal lobe epilepsy. However, a statistically significant reduction in seizure frequency was found for anterior thalamic DBS (mean difference (MD), 17.4% compared to sham stimulation; 95% confidence interval (CI) -31.2 to -1.0; high-quality evidence), responsive ictal onset zone stimulation (MD -24.9%; 95% CI -40.1 to -6.0; high-quality evidence) and hippocampal DBS (MD -28.1%; 95% CI 34.1 to -22.2; moderate-quality evidence). Both anterior thalamic DBS and responsive ictal onset zone stimulation do not have a clinically meaningful impact on quality life after three months of stimulation (high-quality evidence). Electrode implantation resulted in postoperative asymptomatic intracranial haemorrhage in 1.6% to 3.7% of the patients included in the two largest trials and 2.0% to 4.5% had postoperative soft tissue infections (9.4% to 12.7% after five years); no patient reported permanent symptomatic sequelae. Anterior thalamic DBS was associated with fewer epilepsy-associated injuries (7.4 versus 25.5%; P = 0.01) but higher rates of self-reported depression (14.8 versus 1.8%; P = 0.02) and subjective memory impairment (13.8 versus 1.8%; P = 0.03); there were no significant differences in formal neuropsychological testing results between the groups. Responsive ictal-onset zone stimulation seemed to be well tolerated with few side effects.The limited number of patients preclude firm statements on safety and tolerability of hippocampal DBS. With regards to centromedian thalamic DBS, nucleus accumbens DBS and cerebellar stimulation, no statistically significant effects could be demonstrated but evidence is of only low to very low quality. AUTHORS' CONCLUSIONS: Except for one very small RCT, only short-term RCTs on intracranial neurostimulation for epilepsy are available. Compared to sham stimulation, one to three months of anterior thalamic DBS ((multi)focal epilepsy), responsive ictal onset zone stimulation ((multi)focal epilepsy) and hippocampal DBS (temporal lobe epilepsy) moderately reduce seizure frequency in refractory epilepsy patients. Anterior thalamic DBS is associated with higher rates of self-reported depression and subjective memory impairment. There is insufficient evidence to make firm conclusive statements on the efficacy and safety of hippocampal DBS, centromedian thalamic DBS, nucleus accumbens DBS and cerebellar stimulation. There is a need for more, large and well-designed RCTs to validate and optimize the efficacy and safety of invasive intracranial neurostimulation treatments. PMID- 28718879 TI - Streptococcal-induced Kawasaki disease of the psoriasiform phenotype in a young adult. PMID- 28718880 TI - 'I just don't want to connect my life with this occupation': working-class young men, manual labour, and social mobility in contemporary Russia. AB - A key strand in the Western literature on working-class masculinities focuses on whether young men are capable of the feminized performances apparently required of them in new service economies. However, the wider literature on processes of neoliberalization - emphasizing the 'hollowing out' of labour markets, the cultural devaluation of lower-skilled forms of employment, and the pathologization of working-class lives - would suggest that it is as much a classed as a gendered transformation that is demanded of young men leaving school with few qualifications. This dimension of neoliberalization is highlighted by ethnographic data exploring the experiences and subjectivities of young workers in St Petersburg, Russia, where traditional forms of manual labour have not given way to 'feminized' work, but have become materially and symbolically impoverished, and are perceived as incapable of supporting the wider transition into adult independence. In this context, young workers attempt to emulate new forms of 'successful masculinity' connected with novel service sector professions and the emergent higher education system, despite the unlikelihood of overcoming a range of structural and cultural barriers. These acquiescent, individualized responses indicate that, while ways of being a man are apparently being liberated from old constraints amongst the more privileged, neoliberalization narrows the range of subject positions available to working-class young men. PMID- 28718881 TI - Identification of Bodies by Unique Serial Numbers on Implanted Medical Devices. AB - Visual identification is the most common identification method used by medical examiners but is not always possible. Alternative methods include X-ray, fingerprint, or DNA comparison, but these methods require additional resources. Comparison of serial numbers on implanted medical devices is a rapid and definitive method of identification. To assess the practicality of using this method, we reviewed 608 consecutive forensic autopsies performed at a regional medical examiner office. Of these, 56 cases required an alternative method of identification due to decomposition (n = 35), gunshot wound (n = 9), blunt trauma (n = 6), or charring (n = 6). Of these 56 cases, eight (14.3%) were known to have an implanted medical device. Of these eight cases, five (63%) could be positively identified by comparing serial numbers. If an implanted medical device is known to be present, and medical records are available, identification by medical device serial number should be a first-line method. PMID- 28718882 TI - An Analysis on the Choice of Alpha Level in the Osteometric Pair-matching of the Os Coxa, Scapula, and Clavicle. AB - This study compares the use of 0.05 and 0.10 alpha levels with the updated osteometric pair-matching model on two samples of the os coxa, scapula, and clavicle. The samples include the Forensic Data Bank, and the osteometric sorting reference used within the Defense POW/MIA Accounting Agency. Mixed-effects two way analyses of variance were used to analyze bilateral asymmetry in the standard measurements. In total, 3,793,566 t-tests were conducted for osteometric pair matching analysis. The results indicate high levels of exclusion power, and accuracy can be obtained with the os coxa and scapula. The clavicle standard measurements capture too much asymmetry causing a lower exclusion to accuracy ratio for osteometric pair-matching relative to other elements. Both 0.05 and 0.10 alpha levels provide acceptable levels of performance. A lower alpha level will result in higher accuracy with less exclusion, and a higher alpha level will result in lower accuracy with more exclusions. PMID- 28718883 TI - Gelation kinetics and characterization of enzymatically enhanced fish scale gelatin-pectin coacervate. AB - BACKGROUND: Protein-polysaccharide complex coacervations have been considered extensively for the development of functional foods. The main problem of the complex coacervates is that they are highly unstable under different conditions and that cross-linking is necessary to stabilize them. In this study, the effects of pectin at different concentrations on the gel and structural properties of fish scale gelatin (FSG)-high methoxyl citrus pectin (HMP) coacervate enhanced by microbial transglutaminase (MTGase) were studied. RESULTS: The gelation rates and gel strength of the MTGase-enhanced FSG-HMP coacervate gels decreased with increasing HMP concentration. However, the enhanced coacervate gels exhibited better thermal behavior and mechanical properties compared with the original gels. Also, TG-P8 exhibited the highest melting point (27.15 +/- 0.12 degrees C), gelation point (15.65 +/- 0.01 degrees C) and stress (15.36 +/- 0.48 kPa) as HMP was 8 g kg-1 . Particle size distribution, fluorescence emission and UV absorbance spectra indicated that MTGase and HMP could make FSG form large aggregates. Moreover, confocal laser scanning microscopy of treated coacervate gels showed a continuous protein phase at low HMP concentrations. CONCLUSION: FSG and HMP could form soluble coacervate, and MTGase could improve the thermal and mechanical properties of coacervate gels. (c) 2017 Society of Chemical Industry. PMID- 28718884 TI - Dispersal, host genotype and environment shape the spatial dynamics of a parasite in the wild. AB - Dispersal, environment and genetic variation may all play a role in shaping host parasite dynamics. Yet, in natural systems, their relative importance remains unresolved. Here, we do so for the epidemiology of a specialist parasite (Erysiphe alphitoides) on the pedunculate oak (Quercus robur). For this purpose, we combine evidence from a multi-year field survey and two dispersal experiments, all conducted at the landscape scale. Patterns detected in the field survey suggest that the parasite is structured as a metapopulation, with trees in denser oak stands characterized by higher parasite occupancy, higher colonization rates and lower extinction rates. The dispersal experiments revealed a major impact of the environment and of host genotype on the presence and abundance of the parasite, with a weaker but detectable imprint of dispersal limitation. Overall, our findings emphasize that dispersal, host genotype and the environment jointly shape the spatial dynamics of a parasite in the wild. PMID- 28718886 TI - Brainstem auditory evoked responses in 37 dogs with otitis media before and after topical therapy. AB - OBJECTIVES: The objective of this study was to determine whether intra-aural administration of aqueous solutions of marbofloxacin, gentamicin, tobramycin and ticarcillin (used off-licence) was associated with changes in hearing as measured by brainstem auditory evoked responses. MATERIALS AND METHODS: Dogs diagnosed with otitis media (n=37) underwent brainstem auditory evoked response testing and then were treated for their ear disease. First, the external ear canal and middle ear were flushed with sterile saline followed by EDTA tris with 0.15% chlorhexidine. Then, a combination of aqueous antibiotic mixed with an aqueous solution of EDTA tris was instilled into the middle ear. Follow-up examinations were undertaken for each dog, and treatment was continued until there were no detected infectious organisms or inflammatory infiltrate. Brainstem auditory evoked response testing was repeated after resolution of the infection and discontinuation of therapy. RESULTS: Brainstem auditory evoked responses in dogs treated with aqueous solutions of marbofloxacin or gentamicin remained unchanged or improved after therapy of otitis media but were impaired in dogs treated with ticarcillin or tobramycin. CLINICAL SIGNIFICANCE: If off-licence use of topical antibiotics is deemed necessary in cases of otitis media, aqueous solutions of marbofloxacin and gentamicin appear to be less ototoxic than aqueous solutions of ticarcillin or tobramycin. PMID- 28718885 TI - Virulence determines beneficial trade-offs in the response of virus-infected plants to drought via induction of salicylic acid. AB - It has been hypothesized that plants can get beneficial trade-offs from viral infections when grown under drought conditions. However, experimental support for a positive correlation between virus-induced drought tolerance and increased host fitness is scarce. We investigated whether increased virulence exhibited by the synergistic interaction involving Potato virus X (PVX) and Plum pox virus (PPV) improves tolerance to drought and host fitness in Nicotiana benthamiana and Arabidopsis thaliana. Infection by the pair PPV/PVX and by PPV expressing the virulence protein P25 of PVX conferred an enhanced drought-tolerant phenotype compared with single infections with either PPV or PVX. Decreased transpiration rates in virus-infected plants were correlated with drought tolerance in N. benthamiana but not in Arabidopsis. Metabolite and hormonal profiles of Arabidopsis plants infected with the different viruses showed a range of changes that positively correlated with a greater impact on drought tolerance. Virus infection enhanced drought tolerance in both species by increasing salicylic acid accumulation in an abscisic acid-independent manner. Viable offspring derived from Arabidopsis plants infected with PPV increased relative to non-infected plants, when exposed to drought. By contrast, the detrimental effect caused by the more virulent viruses overcame potential benefits associated with increased drought tolerance on host fitness. PMID- 28718887 TI - Operative learning curve trajectory in a cohort of surgical trainees. AB - BACKGROUND: Certification of completion of training in general surgery in the UK requires demonstration of competence in index operations by means of three level 4 competence consultant-validated procedure-based assessments (PBAs). The aim of this study was to evaluate the trajectory of operative learning curves related to PBA performance levels for curriculum-defined indicative operations with respect to numbers performed and training time. METHODS: Logbook data from consecutive higher general surgical trainees were compared with PBA evaluations to determine the relationship between PBA performance level, operative experience, training time and indicative numbers. Learning curve gradients were calculated using the inverse trigonometric function of tan related to operative experience and training time. RESULTS: Eighty-four surgical trainees participated. Median caseload to achieve three level 4 competence assessments was 64 (range 18-110) for inguinal hernia, 83 (15-177) for emergency laparotomy, 87 (23-192) for laparoscopic cholecystectomy, 95 (22-209) for appendicectomy, 45 (17-111) for segmental colectomy and 16 (6-28) for Hartmann's procedure. Median learning curve gradients to achieve level 4 competence for emergency laparotomy were 15.3 degrees and 33.7 degrees by caseload and training time respectively, compared with 73.3 degrees and 59.9 degrees for Hartmann's procedure. Significant variance was observed in the gradients of all learning curves related to both the caseload between the first level 3 and the first level 4 PBA (P = 0.001), and between the first and third level 4 PBAs (P < 0.001). CONCLUSION: Significant learning curve gradient variance was observed, with discrepancies between expected indicative operative numbers and the point at which competence was judged to have been achieved. Numbers of index operations to achieve certification of completion of training warrant further examination. PMID- 28718888 TI - Assessing lung function using contrast-enhanced dual-energy computed tomography for potential applications in radiation therapy. AB - PURPOSE: There is an increasing interest in the evaluation of lung function from physiological images in radiation therapy treatment planning to reduce the extent of postradiation toxicities. The purpose of this work was to retrieve reliable functional information from contrast-enhanced dual-energy computed tomography (DECT) for new applications in radiation therapy. The functional information obtained by DECT is also compared with other methods using single-energy CT (SECT) and single-photon emission computed tomography (SPECT) with CT. The differential function between left and right lung, as well as between lobes is computed for all methods. METHODS: Five lung cancer patients were retrospectively selected for this study; each underwent a SPECT/CT scan and a contrast-injected DECT scan, using 100 and 140 Sn kVp. The DECT images are postprocessed into iodine concentration maps, which are further used to determine the perfused blood volume. These maps are calculated in two steps: (a) a DECT stoichiometric calibration adapted to the presence of iodine and followed by (b) a two-material decomposition technique. The functional information from SECT is assumed proportional to the HU numbers from a mixed CT image. The functional data from SPECT/CT are considered proportional to the number of counts. A radiation oncologist segmented the entire lung volume into five lobes on both mixed CT images and low-dose CT images from SPECT/CT to allow a regional comparison. The differential function for each subvolume is computed relative to the entire lung volume. RESULTS: The differential function per lobe derived from SPECT/CT correlates strongly with DECT (Pearson's coefficient r = 0.91) and moderately with SECT (r = 0.46). The differential function for the left lung shows a mean difference of 7% between SPECT/CT and DECT; and 17% between SPECT/CT and SECT. The presence of nonfunctional areas, such as localized emphysema or a lung tumor, is reflected by an intensity drop in the iodine concentration maps. Functional dose volume histograms (fDVH) are also generated for two patients as a proof of concept. CONCLUSION: The extraction of iodine concentration maps from a contrast enhanced DECT scan is achieved to compute the differential function for each lung subvolume and good agreement is found in respect to SPECT/CT. One promising avenue in radiation therapy is to include such functional information during treatment planning dose optimization to spare functional lung tissues. PMID- 28718889 TI - Veno-Arterial Extracorporeal Membrane Oxygenation Support in Patients Undergoing Aortic Surgery. AB - Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is an option for mechanical support for patients with postcardiotomy cardiogenic shock (PCS). However, the use of VA-ECMO in patients suffering from aortic disease with PCS has not been greatly reported. This is a retrospective review of adult patients undergoing aortic surgery who received VA-ECMO support to treat refractory PCS from August 2009 to May 2016. A total of 36 patients who underwent aortic surgery with VA-ECMO support for refractory PCS were included. Preoperative, perioperative, and postoperative variables were assessed and analyzed for possible correlation with in-hospital mortality. After a mean duration of 3.6 +/- 2.9 days, 24 patients (67%) were weaned off VA-ECMO, and 18 patients (50%) were discharged from the hospital. The overall in-hospital mortality was 50%. The main cause of death was multiple organ dysfunction. The survivors had a lower level of preoperative creatine kinase-MB (CK-MB), a higher rate of antegrade cannulation, and a lower lactate level at 12 h, respectively. Relevant factors for in-hospital mortality were retrograde-flow cannulation (odds ratio [OR], 2.49), peak lactate levels greater than 20 mmol/L (OR, 5.0), and preoperative CK-MB greater than 100 IU/L (OR, 6.40). Antegrade cannulation may provide better perfusion and should be emphasized to improve outcomes. Additionally, levels of peak serum lactate and preoperative CK-MB may be relevant factors for in-hospital mortality in aortic patients with PCS. PMID- 28718890 TI - In vivo veritas: Finding novel genes involved in liver cancer through in vivo genetic screens. PMID- 28718891 TI - Montelukast reduces inhaled chlorine triggered airway hyperresponsiveness and airway inflammation in the mouse. AB - BACKGROUND AND PURPOSE: Cysteinyl leukotrienes (CysLTs) are pro-inflammatory lipid mediators that exacerbate disease state in several asthma phenotypes including asthma induced by allergen, virus and exercise. However, the role of CysLTs in irritant-induced airway disease is not well characterized. The purpose of the current study was to investigate the effect of montelukast, a CysLT1 receptor antagonist, on parameters of irritant-induced asthma induced by inhalation of chlorine in the mouse. EXPERIMENTAL APPROACH: BALB/c mice were exposed to chlorine in air (100 ppm, for 5 min). Montelukast (3 mg.kg-1 ) or the vehicle (1% methylcellulose) was administered 24 and 1 h prior to chlorine exposure and 1 h prior to outcome measurements. Twenty-four hours after exposure, responses to inhaled aerosolized methacholine, cell composition and an array of cytokines/chemokines in bronchoalveolar lavage (BAL) fluid were measured. Neutralizing antibodies against IL-6 and VEGF were administered prior to exposures. KEY RESULTS: Montelukast reduced chlorine -induced airway hyperresponsiveness (AHR) to methacholine in the peripheral lung compartment as estimated from dynamic elastance, but not in large conducting airways. Montelukast treatment attenuated chlorine-induced macrophage influx, neutrophilia and eosinophilia in BAL fluid. Chlorine exposure increased VEGF, IL-6, the chemokines KC and CCL3 in BAL fluid. Montelukast treatment prevented chlorine induced increases in VEGF and IL-6. Anti-IL-6 antibody inhibited chlorine-induced neutrophilia and reduced AHR. CONCLUSIONS AND IMPLICATIONS: Pre-treatment with montelukast attenuated chlorine-induced neutrophilia and AHR in mice. These effects are mediated, in part, via IL-6. PMID- 28718893 TI - Association between maternal vascular murmur and the small-for-gestational-age fetus with abnormal umbilical artery Doppler flow. AB - OBJECTIVE: To investigate the association between maternal vascular murmurs (MVMs) and fetal growth restriction (defined as small-for-gestational-age [SGA] fetus) and abnormal Doppler pulsatility index (PI) of the uterine and/or umbilical arteries. METHODS: A cross-sectional study of women aged 18 years or older with a singleton pregnancy at 28-34 weeks was conducted at Regional Hospital Viborg, Denmark, between May 1 and August 1, 2013. Ultrasound fetal biometry was performed and the Doppler PI of the umbilical and uterine arteries was determined. An estimated fetal weight (EFW) at or below the 10th percentile was defined as SGA. Microphone recordings from the lower abdomen were divided into heart valve sounds and MVMs. RESULTS: The final analysis included 63 participants, with 25 classified as SGA and 38 as non-SGA. The mean pregnancy duration was 32.4 +/- 1.4 weeks. In total, 17 participants had MVMs. There was a clear association between MVMs and a composite of SGA and an abnormal PI of the uterine and/or the umbilical artery (P<0.001), but not between MVMs and SGA only (P=0.154). CONCLUSION: Maternal vascular murmurs are significantly associated with fetal growth restriction, but not with SGA per se. PMID- 28718892 TI - Methoxetamine affects brain processing involved in emotional response in rats. AB - BACKGROUND AND PURPOSE: Methoxetamine (MXE) is a novel psychoactive substance that is emerging on the Internet and induces dissociative effects and acute toxicity. Its pharmacological effects have not yet been adequately investigated. EXPERIMENTAL APPROACH: We examined a range of behavioural effects induced by acute administration of MXE (0.5-5 mg.kg-1 ; i.p.) in rats and whether it causes rapid neuroadaptive molecular changes. KEY RESULTS: MXE (0.5-5 mg.kg-1 ) affected motor activity in a dose- and time-dependent manner, inducing hypermotility and hypomotility at low and high doses respectively. At low and intermediate doses (0.5 and 1 mg.kg-1 ), MXE induced anxious and/or obsessive-compulsive traits (marble burying test), did not significantly increase sociability (social interaction test) or induce spatial anxiety (elevated plus maze test). At a high dose (5 mg.kg-1 ), MXE induced transient analgesia (tail-flick and hot-plate test), decreased social interaction time (social interaction test) and reduced immobility time while increasing swimming activity (forced swim test), suggesting an antidepressant effect. Acute MXE administration did not affect self-grooming behaviour at any dose tested. Immunohistochemical analysis showed that behaviourally active doses of MXE (1 and 5 mg.kg-1 ) increased phosphorylation of ribosomal protein S6 in the medial prefrontal cortex and hippocampus. CONCLUSIONS AND IMPLICATIONS: MXE differentially affected motor activity, behaviour and emotional states in rats, depending on the dose tested. As reported for ketamine, phosphorylation of the ribosomal protein S6 was increased in MXE-treated animals, thus providing a 'molecular snapshot' of rapid neuroadaptive molecular changes induced by behaviourally active doses of MXE. PMID- 28718894 TI - Sperm cryopreservation and assisted reproductive technology outcome in patients with spinal cord injury. AB - This study aimed to describe spinal cord injured patients' semen characteristics before and after cryopreservation, and assisted reproductive technology cycles outcome compared to the infertile population. Data about sperm analysis and assisted reproductive technology (ART) cycles outcomes for 78 men with spinal cord injury referred for sperm cryopreservation between 1998 and 2013 were retrospectively analysed and compared with a reference group consisting of every Intra Cytoplasmic Sperm Injection (ICSI) cycle performed in our in vitro fertilization unit over the 2009-2014 period. Semen was collected by penile vibratory stimulation (PVS), electroejaculation or via testis biopsies. Fresh and frozen semen parameters and ART outcomes with frozen-thawed sperm were measured. Patients were divided into three groups according to the sperm retrieval methods: 37 electroejaculations, 37 PVSs and four surgical sperm retrievals. Low ejaculate volume was observed in 33% of the patients, and oligozoospermia in 37% of the patients. Specimens from 77 of the patients contained motile sperm and were therefore frozen for future use. There was no statistical difference for any of the fresh semen parameters between all groups. Twenty of them underwent ICSI leading to five live births, while four underwent intrauterine insemination. ART with frozen-thawed spermatozoa can provide men with SCI with comparable results as in the infertile population. PMID- 28718895 TI - Considering the impact of pregnancy on the natural history of hidradenitis suppurativa. PMID- 28718897 TI - Cyproterone acetate in the treatment of oestrogen hypersensitivity vulvovaginitis. AB - Oestrogen hypersensitivity vulvovaginitis is a rare chronic cyclical vulvovaginitis responsive to oestrogen suppression or antagonism. We present a case series of 16 patients with refractory cyclical vulvovaginitis, all of whom responded to oestrogen suppression with cyproterone acetate. PMID- 28718896 TI - Nomograms for preoperative prediction of axillary nodal status in breast cancer. AB - BACKGROUND: Axillary staging in patients with breast cancer and clinically node negative disease is performed by sentinel node biopsy (SLNB). The aim of this study was to integrate feasible preoperative variables into nomograms to guide clinicians in stratifying treatment options into no axillary staging for patients with non-metastatic disease (N0), SLNB for those with one or two metastases, and axillary lymph node dissection (ALND) for patients with three or more metastases. METHODS: Patients presenting to Skane University Hospital, Lund, with breast cancer were included in a prospectively maintained registry between January 2009 and December 2012. Those with a preoperative diagnosis of nodal metastases were excluded. Patients with data on hormone receptor status, human epidermal growth factor receptor 2 and Ki-67 expression were included to allow grouping into surrogate molecular subtypes. Based on logistic regression analyses, nomograms summarizing the strength of the associations between the predictors and each nodal status endpoint were developed. Predictive performance was assessed using the area under the receiver operating characteristic (ROC) curve. Bootstrap resampling was performed for internal validation. RESULTS: Of the 692 patients eligible for analysis, 248 were diagnosed with node-positive disease. Molecular subtype, age, mode of detection, tumour size, multifocality and vascular invasion were identified as predictors of any nodal disease. Nomograms that included these predictors demonstrated good predictive abilities, and comparable performances in the internal validation; the area under the ROC curve was 0.74 for N0 versus any lymph node metastasis, 0.70 for one or two involved nodes versus N0, and 0.81 for at least three nodes versus two or fewer metastatic nodes. CONCLUSION: The nomograms presented facilitate preoperative decision-making regarding the extent of axillary surgery. PMID- 28718898 TI - Exposure to biological therapies during conception and pregnancy: a systematic review. AB - BACKGROUND: Biological therapies are effective treatments for psoriasis and are often prescribed to women of child-bearing age. OBJECTIVES: To evaluate the safety of biological therapy in conception and/or pregnancy. METHODS: We performed a systematic review of PubMed, MEDLINE, Embase and Cochrane databases for multivariate-adjusted studies of women exposed to biologics relevant to the treatment of psoriasis during conception and/or pregnancy. RESULTS: We identified four population-based cohort studies involving 1300 women exposed to tumour necrosis factor (TNF)-alpha inhibitors (TNFi) 3 months prior to or during the first 3 months of pregnancy. These studies showed a trend towards drug-specific harm with TNFi exposure in women with different inflammatory diseases, with an increased risk of congenital malformations [three studies; odds ratio (OR) range 1.32-1.64] and preterm birth (one study; OR 1.69, 95% confidence interval 1.10 2.60). This trend did not reach statistical significance in all studies; study heterogeneity, variation across comparator cohorts, inadequate adjustment for important confounding variables such as co-therapy, and an absence of a common constellation of malformations means there is uncertainty about the causal role of TNFi. No studies specifically addressed the effect of TNFi exposure in psoriasis during conception and/or pregnancy, or of interleukin (IL)-17 and IL 12/23 antagonists in any indication. CONCLUSIONS: When counselling women these findings must be balanced against the potential impact of untreated severe psoriasis on conception and/or pregnancy and maternal wellbeing; ongoing pharmacovigilance via registries remains essential to address this evidence gap. PMID- 28718902 TI - Pluripotent Stem Cell-Based Platforms in Cardiac Disease Modeling and Drug Testing. AB - The ability to generate patient/disease-specific human pluripotent stem cell (hPSC)-derived cardiomyocytes (hPSC-CMs) brings a unique value to the fields of cardiac disease modeling, drug testing, drug discovery, and precision medicine. Further integration of emerging innovative technologies such as developmental biology inspired differentiation into chamber-specific cardiomyocyte subtypes, genome-editing, tissue-engineering, and novel functional phenotyping methodologies should facilitate even more advanced investigations. Here, we review cornerstone concepts and recent highlights of hPSC-based cardiac disease modeling and drug testing. PMID- 28718903 TI - Affairs of the Heart: Innovation in Cardiovascular Research and Development. AB - Cardiovascular disease represents the single largest contributor to morbidity and mortality, yet the flow of therapeutic innovation is lagging. Globally, academia, industry, and regulatory agencies must work together to address this gap, and ensure new disruptive therapeutic modalities to address growing needs of patients and society. PMID- 28718904 TI - Autologous serum eye-drops and enhanced epithelial healing time after photorefractive keratectomy. AB - BACKGROUND: The aim of the study is to test whether use of autologous serum eye drops can provide earlier epithelial healing following the application of photorefractive keratectomy. METHOD: Sixty patients (60 eyes) underwent photorefractive keratectomy for myopia. Thirty eyes received autologous serum drops (Study group) while 30 eyes received conventional artificial tears (Control group) after photorefractive keratectomy. An 8 mm epithelial opening was prepared with the application of 18 per cent alcohol for 20 seconds. Photorefractive keratectomy was performed using ESIRIS excimer laser (SCHWIND, Kleinostheim, Germany) with an optic zone of 6.5 mm. Total duration of epithelial healing was monitored as the main outcome measure. The comparisons were done with chi-square test and independent samples t-test. Statistical significance was considered at p < 0.05. RESULTS: Preoperative myopic spherical refraction and ablation depths were similar in the study and control groups. The mean duration for epithelial healing was about one day shorter in the eyes receiving autologous serum compared to the eyes receiving conventional treatment (2.2 +/- 0.25 days versus 3 +/- 0 days, p = 0.001). All eyes achieved 6/7.5 or better uncorrected visual acuity in six months. In both groups, more than 90 per cent of eyes were within +/-0.50 D of emmetropia in 12 months. No significant difference was noted for the incidence of +1 haze. CONCLUSION: Use of autologous serum drops reduces epithelial healing duration following surface ablation for two days. PMID- 28718905 TI - A novel cell-cell communication mechanism in the nervous system: exosomes. AB - Exosomes are small extracellular membrane-based vesicles with a variety of cargoes that are involved in numerous physiological and pathological processes in the nervous system. Accumulating evidence has implicated that exosomes are emerging as a novel form of intercellular communication within the nervous system. In this review, we first illustrate exosome metabolism including its formation, secretion, transport, and uptake. Second, we compare exosomes to synaptic vesicles in terms of intercellular messengers and communicators. Third, we discuss the roles and prospects of exosomes in the diagnosis and treatment of neurodegenerative diseases. PMID- 28718906 TI - A retrospective analysis of the effectiveness of anterior pelvic organ prolapse repair with Prolift versus Elevate vaginal mesh. AB - OBJECTIVE: To compare the effectiveness of anterior pelvic organ prolapse (POP) repair using Prolift (Ethicon, Somerville, NJ, USA) or Elevate (American Medical Systems, Minnetonka, MN, USA) vaginal mesh at 12 months of follow-up. METHODS: A retrospective study was undertaken using the records for the first 50 Prolift procedures in 2007-2009 and the first 50 Elevate procedures in 2013-2015 performed at a tertiary urogynecology unit in Lisbon, Portugal. Postoperative follow-up occurred at 3, 6, and 12 months. The primary outcome was surgical efficacy using subjective and objective measures (vaginal bulge symptoms and POP quantification system according to the Weber criteria, respectively) at 12 months. RESULTS: Improvement according to the Weber criteria was noted for 10 (25%) of 40 women in the Prolift group and 21 (48%) of 44 in the Elevate group at 12 months (P=0.032). Additionally, the Ba point was higher with Elevate than with Prolift (-2.2 +/- 1.1 vs -1.5 +/- 1.5; P=0.031). Vaginal bulge symptoms were reported at 12 months by 7 (18%) women in the Prolift group and 3 (7%) in the Elevate group (P=0.021). CONCLUSION: Differences in anatomic results were apparent between the two vaginal mesh groups 12 months after surgery. PMID- 28718907 TI - USB Storage Device Forensics for Windows 10. AB - Significantly increased use of USB devices due to their user-friendliness and large storage capacities poses various threats for many users/companies in terms of data theft that becomes easier due to their efficient mobility. Investigations for such data theft activities would require gathering critical digital information capable of recovering digital forensics artifacts like date, time, and device information. This research gathers three sets of registry and logs data: first, before insertion; second, during insertion; and the third, after removal of a USB device. These sets are analyzed to gather evidentiary information from Registry and Windows Event log that helps in tracking a USB device. This research furthers the prior research on earlier versions of Microsoft Windows and compares it with latest Windows 10 system. Comparison of Windows 8 and Windows 10 does not show much difference except for new subkey under USB Key in registry. However, comparison of Windows 7 with latest version indicates significant variances. PMID- 28718908 TI - Death From Butane Inhalation Abuse in Teenagers: Two New Case Studies and Review of the Literature. AB - The ready availability of butane makes butane abuse frequent. Fatalities are rare. This study presents two cases of death by butane overdose. The postmortem analyses were carried out using headspace gas chromatography-mass spectrometry. It revealed femoral blood butane concentrations of 18 and 22 mg/L, respectively, as well as specific combinations of adjuvants in each victim. In one of the victims, brain and fatty tissue also contained butane, pointing to chronic consumption. The originality of this study is to show that the identification of specific combinations of adjuvants can be helpful for identifying the brand of deodorant used. Also, sampling the skin and mucosa can help identify the method of drug delivery. The histological examination documented both the direct toxic effect of the gas on the respiratory mucosa and signs of chronic abuse. Volatile substance intoxications should be systematically considered in case of sudden death in a teenager. PMID- 28718909 TI - Maturation-related changes of carrot lignins. AB - BACKGROUND: Lignified cell walls are important factors for textural and physiological properties of plant-based foods. However, carrot lignins and their modifications during maturation are poorly described. The objective of this study was to describe carrot lignins in detail and to study lignin structural alterations at later stages of maturity. RESULTS: Klason and acetyl bromide soluble lignin contents of insoluble fibers of carrots harvested at different times (26, 29 and 35 weeks after seeding) ranged between 46.38 and 62.68 g kg-1 and between 19.79 and 28.08 g kg-1 , respectively. As determined by both 2D nuclear magnetic resonance and the derivatization followed by reductive cleavage method, coniferyl alcohol heavily dominated the traditional monolignol composition in carrot lignins, independently of harvest times. By using 2D nuclear magnetic resonance experiments on isolated lignins, p-hydroxybenzoate was identified as a less common lignin constituent, attached to lignin gamma-hydroxyl groups and being increasingly incorporated with maturation. beta-Aryl ethers, phenylcoumaran, resinol and dibenzodioxocin structures were identified as lignin interunit linkages, largely independent of harvest times and with beta-aryl ethers being expectedly dominant. CONCLUSION: Carrots contain guaiacyl-rich lignins that incorporate increasing amounts of p-hydroxybenzoate with maturation. All other lignin characteristics appear to be widely independent of harvest times. (c) 2017 Society of Chemical Industry. PMID- 28718910 TI - Permanent Housing for Child Welfare-Involved Families: Impact on Child Maltreatment Overview. AB - A longitudinal randomized controlled trial tested whether access to permanent housing reduces child maltreatment among inadequately housed families under investigation for child abuse and neglect. The study followed homeless and child welfare-involved families randomly assigned to receive a referral for housing subsidies plus housing case management (n = 75, 196 children) or housing case management alone (n = 75, 186 children). Latent growth models examined change in caregiver-reported frequencies of psychological aggression, physical abuse, and neglect toward children at five time points across 2.5 years. Intent-to-treat analyses suggested treatment differences for minor assault and neglect that approached significance; families randomly assigned to permanent housing plus case management exhibited marginally greater declines compared to families referred for housing case management only. Caregiver psychological aggression remained high over time, regardless of treatment condition. No evidence indicated higher risk families benefitted more from permanent housing. Results show some promise of permanent housing and highlight the complex needs of homeless families under investigation for child maltreatment. Findings emphasize the importance of continued involvement from the child welfare system to connect families with important resources. PMID- 28718911 TI - Clear cell renal cell carcinoma: validation of World Health Organization/International Society of Urological Pathology grading. AB - AIMS: In 2012, the International Society of Urological Pathology (ISUP) introduced a novel grading system for clear cell renal cell carcinoma (ccRCC) and papillary renal cell carcinoma. This system is incorporated into the latest World Health Organization renal tumour classification, being designated WHO/ISUP grading. This study was undertaken to compare WHO/ISUP and Fuhrman grading and to validate WHO/ISUP grading as a prognostic parameter in a series of clear cell RCC. METHODS AND RESULTS: Analysis of 681 cases of ccRCC showed that 144 tumours could not be assigned a Fuhrman grade on the basis of ambiguous grading features. The application of WHO/ISUP grading resulted in a general down-grading of cases when compared with Fuhrman grading. In a sub-group of 374 cases, for which outcome data were available, 9.3% were WHO/ISUP grade 1, 50.3% were grade 2, 24.1% grade 3 and 16.3% grade 4, while the distribution of Fuhrman grades was 0.4% grade 1, 48.7% grade 2, 29.4% grade 3 and 21.5% grade 4. There were no recurrence/metastases amongst patients with WHO/ISUP grade 1 tumours and there was a significant difference in outcome for WHO/ISUP grades 2, 3 and 4. For Fuhrman grading the cancer-free survival was not significantly different for grade 2 and grade 3 tumours. On multivariate analysis WHO/ISUP grade and pT staging category were found to retain prognostic significance. CONCLUSIONS: The study demonstrates that FG cannot be applied in >20% of cases of ccRCC and the WHO/ISUP provides superior prognostic information. PMID- 28718912 TI - Survival of Atherosclerotic Calcifications in Skeletonized Material: Forensic and Pathological Implications. AB - Atherosclerosis is a chronic inflammatory disease creating calcifying plaques in the arterial walls. Because its paleopathological diagnosis remains little studied on skeletal remains, its impact on forensic and archeological data is completely underestimated. Here, 24 skeletal remains from the Milano Cemetery Skeletal Collection have been studied to evaluate the chance of atherosclerotic calcification survival, retrieval, and identification. Through direct comparison with a known autopsy collection and literature, the identification and categorization of several types of calcifications were performed. Clothing elements such as tights or socks played a definitive role in the preservation of the calcifications; hence they are more likely to be found in forensic cases than in archeological ones. Therefore, vascular calcifications are possible to collect and identify in skeletal remains if sufficient care is given to their recovery. Consequently and as markers of the disease, such identification can provide valuable pathological information for forensic and archeological cases. PMID- 28718914 TI - Reduced numbers of circulating group 2 innate lymphoid cells in patients with common variable immunodeficiency. AB - Recent studies identified an emerging role of group 2 and 3 innate lymphoid cells (ILCs) as key players in the generation of T-dependent and T-independent antibody production. In this retrospective case-control study, CD117+ ILCs (including the majority of ILC2 and ILC3) were reduced in patients with common variable immunodeficiency (CVID). The reduction in CD117+ ILCs was distinctive to CVID and could not be observed in patients with X-linked agammaglobulinemia. Patients with a more pronounced reduction in CD117+ ILC numbers showed significantly lower numbers of peripheral MZ-like B cells and an increased prevalence of chronic, non infectious enteropathy. Subsequent phenotyping of ILC subsets in CVID revealed that the reduction in CD117+ ILC numbers is due to a reduction in ILC2 numbers. In vitro expansion of CVID ILC2 in response to IL-2, IL-7, IL-25 and IL-33 was impaired. Furthermore, upregulation of MHCII and IL-2RA in response to IL-2, IL 7, IL-25 and IL-33 was impaired in CVID ILC2. Thus, our results indicate a dysregulation of ILC subsets with a reduction in ILC2 numbers in CVID, however, further studies are needed to explore whether ILC abnormalities are a primary finding or secondary to disease complications encountered in CVID. PMID- 28718913 TI - Alcohol consumption and gastric cancer risk-A pooled analysis within the StoP project consortium. AB - An association between heavy alcohol drinking and gastric cancer risk has been recently reported, but the issue is still open to discussion and quantification. We investigated the role of alcohol drinking on gastric cancer risk in the "Stomach cancer Pooling (StoP) Project," a consortium of epidemiological studies. A total of 9,669 cases and 25,336 controls from 20 studies from Europe, Asia and North America were included. We estimated summary odds-ratios (ORs) and the corresponding 95% confidence intervals (CIs) by pooling study-specific ORs using random-effects meta-regression models. Compared with abstainers, drinkers of up to 4 drinks/day of alcohol had no increase in gastric cancer risk, while the ORs were 1.26 (95% CI, 1.08-1.48) for heavy (>4 to 6 drinks/day) and 1.48 (95% CI 1.29-1.70) for very heavy (>6 drinks/day) drinkers. The risk for drinkers of >4 drinks/day was higher in never smokers (OR 1.87, 95% CI 1.35-2.58) as compared with current smokers (OR 1.14, 95% CI 0.93-1.40). Somewhat stronger associations emerged with heavy drinking in cardia (OR 1.61, 95% CI 1.11-2.34) than in non cardia (OR 1.28, 95% CI 1.13-1.45) gastric cancers, and in intestinal-type (OR 1.54, 95% CI 1.20-1.97) than in diffuse-type (OR 1.29, 95% CI 1.05-1.58) cancers. The association was similar in strata of H. pylori infected (OR = 1.52, 95% CI 1.16-2.00) and noninfected subjects (OR = 1.69, 95% CI 0.95-3.01). Our collaborative pooled-analysis provides definite, more precise quantitative evidence than previously available of an association between heavy alcohol drinking and gastric cancer risk. PMID- 28718915 TI - Temperature responses of photosynthetic capacity parameters were not affected by foliar nitrogen content in mature Pinus sylvestris. AB - A key weakness in current Earth System Models is the representation of thermal acclimation of photosynthesis in response to changes in growth temperatures. Previous studies in boreal and temperate ecosystems have shown leaf-scale photosynthetic capacity parameters, the maximum rates of carboxylation (Vcmax ) and electron transport (Jmax ), to be positively correlated with foliar nitrogen (N) content at a given reference temperature. It is also known that Vcmax and Jmax exhibit temperature optima that are affected by various environmental factors and, further, that N partitioning among the foliar photosynthetic pools is affected by N availability. However, despite the strong recent anthropogenic influence on atmospheric temperatures and N deposition to forests, little is known about the role of foliar N contents in controlling the photosynthetic temperature responses. In this study, we investigated the temperature dependencies of Vcmax and Jmax in 1-year-old needles of mature boreal Pinus sylvestris (Scots pine) trees growing under low and high N availabilities in northern Sweden. We found that needle N status did not significantly affect the temperature responses of Vcmax or Jmax when the responses were fitted to a peaked function. If such N insensitivity is a common tree trait it will simplify the interpretation of the results from gradient and multi-species studies, which commonly use sites with differing N availabilities, on temperature acclimation of photosynthetic capacity. Moreover, it will simplify modeling efforts aimed at understanding future carbon uptake by precluding the need to adjust the shape of the temperature response curves to variation in N availability. PMID- 28718917 TI - Proliferation of elastic fibres in idiopathic pulmonary fibrosis: a whole-slide image analysis and comparison with pleuroparenchymal fibroelastosis. AB - AIMS: We occasionally encounter patients with idiopathic pulmonary fibrosis (IPF) who have similar imaging patterns to those of pleuroparenchymal fibroelastosis (PPFE) in the upper lung fields but are not diagnosed as having PPFE clinically. The aim of this study is to identify the clinicopathological features and intrapulmonary distribution of elastic fibres and collagen fibres in these patients. METHODS AND RESULTS: We retrospectively reviewed the medical records of patients with a clinical diagnosis of IPF, and selected consecutive patients who underwent autopsy or pneumonectomy for lung transplantation. Patients with histologically confirmed PPFE were also reviewed for comparison. We quantified the collagen fibres and elastic fibres in each lobe as a percentage of the non aerated lung area (collagen fibre score and elastic fibre score, respectively) in histological specimens by using whole-slide image analysis, and compared these scores between IPF and PPFE patients. In a total of 55 patients (IPF, 48; PPFE, 7), there were no significant differences in the collagen fibre scores between IPF and PPFE patients. The elastic fibre scores in the upper lobe in PPFE patients were significantly higher than those in IPF patients (23.5 versus 10.3, P = 0.005). However, it is of note that, in 12 of 48 IPF patients, the elastic fibre scores of the upper lobes were above the first quartile of those in PPFE patients. CONCLUSIONS: IPF occasionally shows intense elastosis in the upper lobes, and such cases are histologically indistinguishable from PPFE. There seem to be histologically borderline cases between PPFE and IPF. PMID- 28718918 TI - A Rapid, Confirmatory Test for Body Fluid Identification. AB - We have developed a technique that allows investigators to confirm the presence of blood, semen, and/or saliva in a crime scene sample. It is a confirmatory test where multiple samples can be processed in less than an hour, and it is potentially portable, permitting samples to be processed at the crime scene. Samples at a scene giving a positive result can be further processed while those failing to do so may be ignored. There is a large and growing backlog of DNA evidence in the USA, slowing down the criminal justice system. This backlog has continued to grow despite an increase in the ability to process evidence faster. This technique uses quantum dot molecular beacons to test for tissue-specific RNA species, identifying particular body fluids. We have demonstrated the tissue specificity of molecular beacons for blood, semen, and saliva. PMID- 28718919 TI - Putting Rings around Carbon Nanotubes. AB - In the last five years, we have developed synthetic methods towards encapsulation of single-walled carbon nanotubes (SWNTs) into organic macrocycles, to form rotaxane-type molecules. These are the first examples of mechanically interlocked SWNT derivatives (MINTs). In this article, the motivation to continue developing the chemistry of SWNTs at a time well past their hype is discussed and our synthetic strategy and characterization methodology is explained in detail, stressing the general aspects. In particular, special emphasis is placed on the importance of adequate control experiments and bulk spectroscopic and analytical data to determine the structure of SWNT derivatives, as opposed to relying only (or mostly) on microscopy. Also our experimental results are used as pretext to reflect on more general/conceptual issues pertaining to the chemistry of SWNTs and mechanically interlocked molecules. PMID- 28718916 TI - The genetic landscape of endometrial clear cell carcinomas. AB - Clear cell carcinoma of the endometrium is a rare type of endometrial cancer that is generally associated with an aggressive clinical behaviour. Here, we sought to define the repertoire of somatic genetic alterations in endometrial clear cell carcinomas (ECCs), and whether ECCs could be classified into the molecular subtypes described for endometrial endometrioid and serous carcinomas. We performed a rigorous histopathological review, immunohistochemical analysis and massively parallel sequencing targeting 300 cancer-related genes of 32 pure ECCs. Eleven (34%), seven (22%) and six (19%) ECCs showed abnormal expression patterns for p53, ARID1A, and at least one DNA mismatch repair (MMR) protein, respectively. Targeted sequencing data were obtained from 30 of the 32 ECCs included in this study, and these revealed that two ECCs (7%) were ultramutated and harboured mutations affecting the exonuclease domain of POLE. In POLE wild type ECCs, TP53 (46%), PIK3CA (36%), PPP2R1A (36%), FBXW7 (25%), ARID1A (21%), PIK3R1 (18%) and SPOP (18%) were the genes most commonly affected by mutations; 18% and 11% harboured CCNE1 and ERBB2 amplifications, respectively, and 11% showed DAXX homozygous deletions. ECCs less frequently harboured mutations affecting CTNNB1 and PTEN but more frequently harboured PPP2R1A and TP53 mutations than non-POLE endometrioid carcinomas from The Cancer Genome Atlas (TCGA). Compared to endometrial serous carcinomas (TCGA), ECCs less frequently harboured TP53 mutations. When a surrogate model for the molecular-based TCGA classification was used, all molecular subtypes previously identified in endometrial endometrioid and serous carcinomas were present in the ECCs studied, including POLE, MMR-deficient, copy-number high (serous-like)/p53 abnormal, and copy-number low (endometrioid)/p53 wild-type, which were significantly associated with disease-free survival in univariate analysis. These findings demonstrate that ECCs constitute a histologically and genetically heterogeneous group of tumours with varying outcomes. Furthermore, our data suggest that the classification of ECCs as being generally 'high-grade' or 'type II' tumours may not be warranted. Copyright (c) 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 28718920 TI - Microcapsules biologically prepared using Perilla frutescens (L.) Britt. essential oil and their use for extension of fruit shelf life. AB - BACKGROUND: Perilla essential oil (EO) possesses high antioxidant, antimicrobial and insecticidal activities, and has proven to be more reliable than chemically synthesized food preservatives. Nevertheless, EOs have disadvantages of facile photo-degradation and oxidation, which limit their use in agriculture and food industries. Microencapsulation technology that generates a polymeric coating surrounding EOs could overcome these disadvantages. RESULTS: The EO concentration had a significant effect on encapsulation efficiency (EE) and loading capacity (LC). The best encapsulation conditions were obtained with 2% v/v EO, for which EE and LC were 57% and 36%, respectively. EO-loaded microspheres exhibited a crimped surface with phanic lumps by scanning electron microscopy. Thermal stability experiments revealed droplets that began to decompose sharply at 108 degrees C, with a 61% weight, loss, which was much lower than EOs of 98%. EO loaded microcapsules demonstrated good antibacterial activity. Strawberry preservation studies showed that EO-loaded microcapsules could significantly inhibit strawberry decay, maintain the quality of strawberries and prolong shelf life. CONCLUSION: Perilla EO-loaded microcapsules were successfully prepared by ionic gelation and were effective at inhibiting several bacterial strains. EO alginate microcapsules could effectively delay the volatilization of EO. Perilla EO-loaded microcapsules therefore have potential for use as an antimicrobial and preservative agent in the food industry. (c) 2017 Society of Chemical Industry. PMID- 28718921 TI - Homology, homoplasy and cusp variability at the enamel-dentine junction of hominoid molars. AB - Evolutionary studies of mammalian teeth have generally concentrated on the adaptive and functional significance of dental features, whereas the role of development on phenotypic generation and as a source of variation has received comparatively little attention. The present study combines an evolutionary biological framework with state-of-the-art imaging techniques to examine the developmental basis of variation of accessory cusps. Scholars have long used the position and relatedness of cusps to other crown structures as a criterion for differentiating between developmentally homologous and homoplastic features, which can be evaluated with greater accuracy at the enamel-dentine junction (EDJ). Following this approach, we collected digital models of the EDJ and outer enamel surface of more than 1000 hominoid teeth to examine whether cusp 5 of the upper molars (UM C5) and cusps 6 and 7 of the lower molars (LM C6 and LM C7) were associated each with a common developmental origin across species. Results revealed that each of these cusps can develop in a variety of ways, in association with different dental tissues (i.e. oral epithelium, enamel matrix) and dental structures (i.e. from different cusps, crests and cingula). Both within and between species variability in cusp origin was highest in UM C5, followed by LM C7, and finally LM C6. The lack of any species-specific patterns suggests that accessory cusps in hominoids are developmentally homoplastic and that they may not be useful for identifying phylogenetic homology. An important and unanticipated finding of this study was the identification of a new taxonomically informative feature at the EDJ of the upper molars, namely the post paracone tubercle (PPT). We found that the PPT was nearly ubiquitous in H. neanderthalensis and the small sample of Middle Pleistocene African and European humans (MPAE) examined, differing significantly from the low frequencies observed in all other hominoids, including Pleistocene and recent H. sapiens. We emphasize the utility of the EDJ for human evolutionary studies and demonstrate how features that look similar at the external surface may be the product of different developmental patterns. This study also highlights the importance of incorporating both developmental and morphological data into evolutionary studies in order to gain a better understanding of the evolutionary significance of dental and skeletal features. PMID- 28718922 TI - Physical compatibility between wax esters and triglycerides in hybrid shortenings and margarines prepared in rice bran oil. AB - BACKGROUND: Wax esters contribute to the transformation of liquid oils into solid like oleogel systems, which can act as alternatives for trans- and/or saturated fats in food products. The use of solely waxes reduces the solid content, consistency and sensory quality in the final products. Therefore, a combination of sunflower wax and palm fat in rice bran oil was created to accomplish the hybrid low-saturated shortenings and margarines with a compatible structure and lower amounts of saturated fats. RESULTS: During cooling of the hybrid shortenings, sunflower wax crystallized first and acted as nucleation sites for the crystallisation of palm fat. At 5 degrees C, a mixture of different crystal morphologies (alpha, beta', and beta crystals) existed in the hybrid shortening. In margarine processing, the hybrid samples were subjected to a simultaneous cooling-emulsification, in which sunflower wax crystallised first at the interface and adsorbed onto the water droplets. Based on the hardness measurements, the maximum amount of palm fat replaceable by 1.0%wt sunflower wax was up to 40% in shortenings and 25% in margarines. A higher amount of sunflower wax (2.5%wt) reduced up to 40% of saturated fats in the hybrid emulsions. CONCLUSION: The addition of 1.0%wt sunflower wax enhanced the solid content and network strength of hybrid palm-based shortenings. Sunflower wax helped to stabilise the water droplets inside the wax-based crystalline network without flocculation during shear-cooling. This research provides fundamental insight into the structuring of hybrid systems containing waxes, which could be interesting for the production of low-saturated fat products in the food industry. (c) 2017 Society of Chemical Industry. PMID- 28718924 TI - Preliminary Study of a Novel Puborectalis-Like Artificial Anal Sphincter. AB - Artificial anal sphincter (AAS) is an in situ implanted device that acts as a treatment for fecal incontinence regardless of etiology by augmenting the incompetent sphincteric structures. However, AAS is impeded from becoming a valid therapy by its high rate of ischemic complication and malfunction. This article presents an original puborectalis-like artificial anal sphincter (PAAS) that features a low risk of ischemia necrosis and rectal perception remodeling. The device retains continence by reproducing the action, including the pulling and angulating the rectum, of the puborectalis muscle, which forms the anorectal angle and reduces the required clamping pressure. Three rectal pressure sensors were embedded to maintain the pressure exerted on the rectal wall in a safe range and to monitor the distention of the rectum. A series of in vitro studies were conducted with a porcine rectum, and this PAAS prototype manifested the ability of maintaining continence with a clamping pressure considerably lower than that required by other AAS devices. The pressure sensors exhibit good linearity, and the function of rectal perception remodeling has also revealed high reliability with a success rate of 93.3%. PMID- 28718923 TI - Using homology modeling to interrogate binding affinity in neutralization of ricin toxin by a family of single domain antibodies. AB - In this report we investigated, within a group of closely related single domain camelid antibodies (VH Hs), the relationship between binding affinity and neutralizing activity as it pertains to ricin, a fast-acting toxin and biothreat agent. The V1C7-like VH Hs (V1C7, V2B9, V2E8, and V5C1) are similar in amino acid sequence, but differ in their binding affinities and toxin-neutralizing activities. Using the X-ray crystal structure of V1C7 in complex with ricin's enzymatic subunit (RTA) as a template, Rosetta-based homology modeling coupled with energetic decomposition led us to predict that a single pairwise interaction between Arg29 on V5C1 and Glu67 on RTA was responsible for the difference in ricin toxin binding affinity between V1C7, a weak neutralizer, and V5C1, a moderate neutralizer. This prediction was borne out experimentally: substitution of Arg for Gly at position 29 enhanced V1C7's binding affinity for ricin, whereas the reverse (ie, Gly for Arg at position 29) diminished V5C1's binding affinity by >10 fold. As expected, the V5C1R29G mutant was largely devoid of toxin neutralizing activity (TNA). However, the TNA of the V1C7G29R mutant was not correspondingly improved, indicating that in the V1C7 family binding affinity alone does not account for differences in antibody function. V1C7 and V5C1, as well as their respective point mutants, recognized indistinguishable epitopes on RTA, at least at the level of sensitivity afforded by hydrogen-deuterium mass spectrometry. The results of this study have implications for engineering therapeutic antibodies because they demonstrate that even subtle differences in epitope specificity can account for important differences in antibody function. PMID- 28718925 TI - A historical review of the key bacterial and viral pathogens of Scottish wild fish. AB - Thousands of Scottish wild fish were screened for pathogens by Marine Scotland Science. A systematic review of published and unpublished data on six key pathogens (Renibacterium salmoninarum, Aeromonas salmonicida, IPNV, ISAV, SAV and VHSV) found in Scottish wild and farmed fish was undertaken. Despite many reported cases in farmed fish, there was a limited number of positive samples from Scottish wild fish, however, there was evidence for interactions between wild and farmed fish. A slightly elevated IPNV prevalence was reported in wild marine fish caught close to Atlantic salmon, Salmo salar L., farms that had undergone clinical IPN. Salmonid alphavirus was isolated from wild marine fish caught near Atlantic salmon farms with a SAV infection history. Isolations of VHSV were made from cleaner wrasse (Labridae) used on Scottish Atlantic salmon farms and VHSV was detected in local wild marine fish. However, these pathogens have been detected in wild marine fish caught remotely from aquaculture sites. These data suggest that despite the large number of samples taken, there is limited evidence for clinical disease in wild fish due to these pathogens (although BKD and furunculosis historically occurred) and they are likely to have had a minimal impact on Scottish wild fish. PMID- 28718926 TI - ETS-NOCV Decomposition of the Reaction Force: The HCN/CNH Isomerization Reaction Assisted by Water. AB - The partitioning of the reaction force based on the extended-transition-state natural orbital for chemical valence (ETS-NOCV) scheme has been proposed. This approach, together with the analysis of reaction electronic flux (REF), has been applied in a description of the changes in the electronic structure along the IRC pathway for the HCN/CNH isomerization reaction assisted by water. Two complementary ways of partitioning the system into molecular fragments have been considered ("reactant perspective" and "product perspective"). The results show that the ETS-NOCV picture is fully consistent with REF and bond-order changes. In addition, proposed ETS-NOCV decomposition of the reaction force allows for the quantitative assessment of the influence of the observed bond-breaking and bond formation processes, providing detailed information about the reaction-driving and reaction-retarding force components within the assumed partitioning scheme. (c) 2017 Wiley Periodicals, Inc. PMID- 28718927 TI - A new nonempirical tuning scheme with single self-consistent field calculation: Comparison with global and IP-tuned range-separated functional. AB - System-dependent nonempirical tuning of range-separated functional provides a way to minimize the delocalization error of the system. However, existing nonempirical tuning method requires the computation of several DeltaSCF calculations to determine the optimal MU value. In this article, we have defined a scheme to evaluate the optimal MU value with single self-consistent field calculation. Our method is based on the evaluation of the spherically symmetric average Electron localization function (ELF) region. According to this scheme, the radius of the spherically symmetric average ELF region gives is a measure of the distance at which the long-range part of the range-separated functional becomes dominant. Numerical results indicate that our method improves the reproduction of HOMO energies and HOMO-LUMO gap in comparison to global and IP tuned range-separated functional. Moreover, in case of HOMO energies, maximum error of the ELF-tuned functional is considerably smaller than the global and IP tuned functional. Furthermore, our method gives considerably smaller deviation of HOMO energies from DeltaSCF IP than global range-separated functional. (c) 2017 Wiley Periodicals, Inc. PMID- 28718928 TI - Accessing support and empowerment online: The experiences of individuals with diabetes. AB - CONTEXT: The use of the internet for health information by those with long-term conditions is growing. It has been argued that this represents a form of empowerment by patients, as it enables them to control the content and flow of the information available to them. To explore this, the use of online discussion groups by those with diabetes was examined. METHOD: Semi-structured interviews were conducted with 21 participants with type 1 and 2 diabetes and analysed using thematic analysis. Participants were recruited via online and offline routes, namely discussion boards, newsletters, and research networks related to diabetes. RESULTS: By drawing on the advice, information, and support shared online, participants were empowered to position themselves as active participants in their own health care and to further engage with health-care professionals. CONCLUSION: The findings indicate that forums can play a valuable role in aiding and motivating individuals in the daily management diabetes and highlight how this support is used to complement formal health services. However, more work needs to be carried out to determine to explore when and under what circumstances online support may be particularly beneficial to those with long-term conditions. PMID- 28718929 TI - Commitment, Forgiveness, and Relationship Self-Regulation: An Actor Partner Interdependence Model of Relationship Virtues and Relationship Effort in Couple Relationships. AB - Dyadic data from 679 committed couples were used to examine associations between commitment, forgiveness, and perceptions of partner's relationship self regulation (RSR) behaviors-that is effort and strategies that partners exert to maintain the relationship. We found that for both partners, higher self-reports of commitment and forgiveness were associated with higher perceptions of their partner's RSR. For females, higher commitment and forgiveness were associated with higher male perceptions of her RSR, and higher male forgiveness was associated with higher female perceptions of his RSR. These findings demonstrate the importance of marital virtues and relationship work and give credence to the marital competence model of "other-centeredness" by Carroll et al. (2006, Journal of Family Issues, 27(7), 1001). Clinical implications are discussed. PMID- 28718930 TI - GENESIS 1.1: A hybrid-parallel molecular dynamics simulator with enhanced sampling algorithms on multiple computational platforms. AB - GENeralized-Ensemble SImulation System (GENESIS) is a software package for molecular dynamics (MD) simulation of biological systems. It is designed to extend limitations in system size and accessible time scale by adopting highly parallelized schemes and enhanced conformational sampling algorithms. In this new version, GENESIS 1.1, new functions and advanced algorithms have been added. The all-atom and coarse-grained potential energy functions used in AMBER and GROMACS packages now become available in addition to CHARMM energy functions. The performance of MD simulations has been greatly improved by further optimization, multiple time-step integration, and hybrid (CPU + GPU) computing. The string method and replica-exchange umbrella sampling with flexible collective variable choice are used for finding the minimum free-energy pathway and obtaining free energy profiles for conformational changes of a macromolecule. These new features increase the usefulness and power of GENESIS for modeling and simulation in biological research. (c) 2017 Wiley Periodicals, Inc. PMID- 28718931 TI - Army Soldiers and Suicidal Thoughts: The Impact of Negative Relationship Dynamics Moderated by the Dissolution of Romantic Relationships. AB - Suicide among United States active-duty Army soldiers rapidly increased over the past two decades. Using a sample of 322 soldiers from the Army STARRS study, the researchers examined if romantic relationship factors (i.e., hostile disagreements and relationship distress) were linked with suicidal thoughts in Army soldiers, and if these associations were moderated by a recent separation or divorce. Hostile disagreements and relational distress were both significantly associated with higher rates of suicidal ideation. These associations were significantly amplified in magnitude when in the context of a recent separation or divorce. Implications include novel assessment, prevention, and treatment efforts focused on romantic relationships that may reduce the likelihood of soldiers experiencing thoughts of suicide. PMID- 28718932 TI - Checking transfer efficiency and equal loading via qualitative optical way in western blotting. AB - The ability to determine that successful transfer and equal loading occur prior to using primary antibodies is important. And total protein staining is commonly used to check transfer efficiency and normalization, which play a crucial role in western blotting. Ponceau S and coomassie blue are commonly used, but there are disadvantages reported in recent years. Therefore, we are interested in finding another method, which is cheap, easy and fast. As we know, protein binding region of PVDF membrane is still hydrophilic when carbinol volatilizes, however, the non protein binding region of PVDF membrane became hydrophobic again. And this different wettability between non-protein binding region and protein binding region of Polyvinylidene difluoride membrane may be used to check transfer efficiency and equal loading in western blotting. Based on the principle above, we describe an optical approach where an experimenter can observe that the proteins have been transferred to the membrane without any staining within minutes. PMID- 28718933 TI - Treatment of hidradenitis suppurativa with rifampicin: have we forgotten tuberculosis? PMID- 28718934 TI - NAD+ : A key metabolic regulator with great therapeutic potential. AB - Nicotinamide adenine dinucleotide (NAD+ ) is a ubiquitous metabolite that serves an essential role in the catabolism of nutrients. Recently, there has been a surge of interest in NAD+ biology, with the recognition that NAD+ influences many biological processes beyond metabolism, including transcription, signalling and cell survival. There are a multitude of pathways involved in the synthesis and breakdown of NAD+ , and alterations in NAD+ homeostasis have emerged as a common feature of a range of disease states. Here, we provide an overview of NAD+ metabolism and summarise progress on the development of NAD+ -related therapeutics. PMID- 28718935 TI - Correlation functional in screened-exchange density functional theory procedures. AB - In the present study, we have explored several prospects for the further development of screened-exchange density functional theory (SX-DFT) procedures. Using the performance of HSE06 as our measure, we find that the use of alternative correlation functionals (as oppose to PBEc in HSE06) also yields adequate results for a diverse set of thermochemical properties. We have further examined the performance of new SX-DFT procedures (termed HSEB-type methods) that comprise the HSEx exchange and a (near-optimal) reparametrized B97c (cOS,0 = cSS,0 = 1, cOS,1 = -1.5, cOS,2 = -0.644, cSS,1 = -0.5, and cSS,2 = 1.10) correlation functionals. The different variants of HSEB all perform comparably to or slightly better than the original HSE-type procedures. These results, together with our fundamental analysis of correlation functionals, point toward various directions for advancing SX-DFT methods. (c) 2017 Wiley Periodicals, Inc. PMID- 28718936 TI - Heparan sulfate promotes recovery from acute liver injury: Inhibition of progressive cell death or enhanced regeneration? PMID- 28718937 TI - Wound healing in epidermolysis bullosa. PMID- 28718939 TI - Is fat tasty for the brain?: An Editorial Comment for 'Developmental regulation and localization of Carnitine Palmitoyltransferases (CPTs) in rat brain'. AB - Read the commented article 'Developmental regulation and localization of Carnitine Palmitoyltransferases (CPTs) in rat brain' on page 407. PMID- 28718938 TI - Quality control of ultrasound for fetal biometry: results from the INTERGROWTH 21st Project. AB - OBJECTIVE: To assess a comprehensive package of ultrasound quality control in the Fetal Growth Longitudinal Study of the INTERGROWTH-21st Project, a large multicenter study of fetal growth. METHODS: Quality control (QC) measures were performed for 20 313 ultrasound scan images obtained prospectively from 4321 fetuses at 14-41 weeks' gestation in eight geographical locations. At the time of each ultrasound examination, three fetal biometric variables (head circumference (HC), abdominal circumference (AC) and femur length (FL)) were measured in triplicate on separately generated images. All measurements were taken in a blinded fashion. QC had two elements: (1) qualitative QC: visual assessment by sonographers at each study site of their images based on specific criteria, with 10% of images being re-assessed at the Oxford-based Ultrasound Quality Unit (compared using an adjusted kappa statistic); and (2) quantitative QC: assessment of measurement data by comparing the first, second and third measurements (intraobserver variability), remeasurement of caliper replacement in 10% (interobserver variability), both by Bland-Altman plots and plotting frequency histograms of the SD of triplicate measurements and assessing how many were above or below 2 SD of the expected distribution. The system allowed the sonographers' performances to be monitored regularly. RESULTS: A high level of agreement between self- and external scoring was demonstrated for all measurements (kappa = 0.99 (95% CI, 0.98-0.99) for HC, 0.98 (95% CI, 0.97-0.99) for AC and 0.96 (95% CI, 0.95-0.98) for FL). Intraobserver 95% limits of agreement (LoA) of ultrasound measures for HC, AC and FL were +/- 3.3%, +/- 5.6% and +/- 6.2%, respectively; the corresponding values for interobserver LoA were +/- 4.4%, +/- 6.0% and +/- 5.6%. The SD distribution of triplicate measurements for all biometric variables showed excessive variability for three of 31 sonographers, allowing prompt identification and retraining. CONCLUSIONS: Qualitative and quantitative QC monitoring was feasible and highly reproducible in a large multicenter research study, which facilitated the production of high-quality ultrasound images. We recommend that the QC system we developed is implemented in future research studies and clinical practice. Copyright (c) 2017 ISUOG. Published by John Wiley & Sons Ltd. PMID- 28718940 TI - Changes in treatment and outcome of oesophageal cancer in Denmark between 2004 and 2013. AB - BACKGROUND: Since 2003, care for patients with oesophageal cancer has been centralized in a few dedicated centres in Denmark. The aim of this study was to assess changes in the treatment and outcome of patients registered in a nationwide database. METHODS: All patients diagnosed with oesophageal cancer or cancer of the gastro-oesophageal junction who underwent oesophagectomy in Denmark between 2004 and 2013, and who were registered in the Danish clinical database of carcinomas in the oesophagus, gastro-oesophageal junction and stomach (DECV database) were included. Quality-of-care indicators, including number of lymph nodes removed, anastomotic leak rate, 30- and 90-day mortality, and 2- and 5-year overall survival, were assessed. To compare quality-of-care indicators over time, the relative risk (RR) was calculated using a multivariable log binomial regression model. RESULTS: Some 6178 patients were included, of whom 1728 underwent oesophagectomy. The overall number of patients with 15 or more lymph nodes in the resection specimen increased from 38.1 per cent in 2004 to 88.7 per cent in 2013. The anastomotic leak rate decreased from 14.8 to 7.6 per cent (RR 0.66, 95 per cent c.i. 0.43 to 1.01). The 30-day mortality rate decreased from 4.5 to 1.7 per cent (RR 0.51, 0.22 to 1.15) and the 90-day mortality rate from 11.0 to 2.9 per cent (RR 0.46, 0.26 to 0.82). There were no statistically significant changes in 2- or 5-year survival rates over time. CONCLUSION: Indicators of quality of care have improved since the centralization of oesophageal cancer treatment in Denmark. PMID- 28718941 TI - Child understandings of the causation of childhood burn injuries: Child activity, parental domestic demands, and impoverished settings. AB - BACKGROUND: Burns are a global public health problem. In South Africa, the rate of paediatric burn deaths is 5 times higher than other upper middle-income countries, with concentrations in impoverished settings. Globally, the majority of research focuses on expert and caregiver descriptions of burn occurrence, causation, and prevention, with limited consideration of children's perspectives. This study investigated children's understanding of the causation and prevention of childhood burns. METHODS: Data were collected from eighteen 10- to 11-year-old children living in selected impoverished, fire-affected neighbourhoods in Cape Town, through 3 isiXhosa focus groups. All focus groups were transcribed, coded, and analysed for emerging themes through thematic analysis. RESULTS: Themes regarding burn causation and risks centred around 4 themes: (a) developmental limits in context; (b) domestic chores, child capacity, and inability to say "no"; (c) inadequate supervision and compromised caregiving; and (d) unsafe structures. Child accounts of prevention pertained to (e) burn injury prevention activities in comprised environments and emphasized child agency, and upgrading the physical environment. CONCLUSION: The children in this study ascribed burn injuries as the consequence of their developmental limits in the context of poverty, constraints on parental supervision, and unsafe environments. The children recommended safety education and upgrading their physical environments as part of burns injury prevention. The child accounts offer useful insights to inform safety interventions in impoverished settings. PMID- 28718942 TI - The shift toward neo-adjuvant chemotherapy and interval debulking surgery for management of advanced ovarian and related cancers in a population-based setting: Impact on clinical outcomes. AB - OBJECTIVES: The aim of this study was to determine the proportion of patients with advanced ovarian and related cancers (EOC+RC), treated with neoadjuvant chemotherapy and interval debulking surgery (NACT - IDS), and to determine if there was any relationship with optimal cytoreduction rates and overall survival (OS) in a state-wide gynaecologic oncology service over time. METHODS: A retrospective review was undertaken using a population-based database of patients with stages 3 and 4 EOC+RC treated from 1982 till 2013 at the Queensland Centre for Gynaecological Cancer (QCGC). The proportion of patients treated with NACT - IDS compared with primary debulking surgery (PDS) was determined and compared with debulking rates and with the moving five-year OS probability. RESULTS: From 1982-2013, 2601 patients with advanced EOC+RC were managed at QCGC. No patients received NACT - IDS till 1995 when the first two patients received this treatment, rising to 55% of patients in 2013. Surgical cytoreduction rates to no macroscopic residual (R0) were achieved 32% of the time by 2006, rising to 48% in 2009, and 62% in 2013. Despite the increase in utilisation of NACT - IDS, our unit has noted a continued rise in the OS probability at five years to 45%. CONCLUSIONS: The increasing utilisation of NACT - IDS in the setting of a large centralised clinical service has been associated with increasing rates of optimal cytoreduction and survival rates have continued to rise in excess of those achieved in the trials reported to date. PMID- 28718943 TI - Hepatitis E virus ORF 1 induces proliferative and functional T-cell responses in patients with ongoing and resolved hepatitis E. AB - BACKGROUND AND AIMS: Hepatitis E virus (HEV) is a major cause of acute viral hepatitis with >3 million symptomatic cases per year accounting for 70 000 HEV related deaths. HEV-specific T-cell responses have been investigated against structural proteins expressed by open reading frames (ORF) 2 and 3. T-cell responses against non-structural HEV proteins encoded by ORF1 are hardly studied. The aim of this study was to determine HEV ORF1-specific T-cell responses in comparison to ORF2/3 in patients exposed to HEV. METHODS: HEV-specific CD4+ and CD8+ T-cell responses against HEV genotype 3 were investigated in patients with acute and chronic hepatitis E as well as in HEV seropositive and seronegative individuals. HEV-specific T-cell responses were determined by proliferation and intracellular cytokine assay upon stimulation of PBMCs with HEV-specific overlapping peptide pools spanning the entire HEV genome. HEV-antigen was measured using an anti-HEV antigen-specific ELISA. RESULTS: Broad HEV ORF1 specific T-cell responses were detected in patients with acute, resolved and chronic hepatitis E without distinct dominant regions. The magnitude and frequency in recognition of ORF1-specific T-cell responses were similar compared to responses against HEV ORF2/3. Longitudinal studies of HEV-specific T-cell responses displayed similar behaviour against structural and non-structural proteins. HEV-antigen levels were inversely correlated with HEV-specific T-cell responses. CONCLUSIONS: HEV-specific T-cell responses are detectable against the entire HEV genome including the non-structural proteins. HEV-specific T-cell responses are associated with control of HEV infection. These findings have implications for the design of HEV vaccines. PMID- 28718944 TI - The effect of routine radiological reporting of thyroid incidentalomas on rates of thyroid needle biopsy, thyroid surgery and detection of thyroid malignancy. AB - OBJECTIVE: This study looked at the effect of a changing radiology reporting policy to routinely review the thyroid gland where visible and report on any thyroid lesion, recommending further investigation as appropriate. CONTEXT: Incidentaloma is a term used to describe a lesion found on imaging unrelated to the clinical issue under investigation. There is variability in the radiological reporting of thyroid incidentalomas and conflicting recommendations as to how these lesions should be managed. DESIGN: Data were collected retrospectively during a two-year period, including 12 months before and 12 months after the change in reporting policy and categorized according to whether the lesion under investigation was a thyroid incidentaloma or a symptomatic thyroid lesion. PATIENTS: All patients undergoing ultrasound-guided fine-needle aspiration cytology or core biopsy were included. MEASUREMENTS: The effects of the change in policy were analysed including rates of needle biopsy, rates of malignancy and subsequent surgical intervention. RESULTS: There was a 122% increase in thyroid incidentalomas undergoing needle biopsy, the majority of these were detected on computed tomography. The number of malignancies increased from 1 to 4 from year 1 to year 2. All patients were >35 years old. One patient had a positron emission tomography (PET)-detected cancer, two of four of the non-PET-detected malignancies were <1.5 cm. CONCLUSION: This study posits that routine radiological reporting of thyroid incidentalomas, with further investigation when clinically appropriate, is warranted. The results suggest that lesion size and CT characteristics are not reliable criteria to triage patients for investigation/biopsy. PMID- 28718945 TI - Efficient PAW-based bond strength analysis for understanding the In/Si(111)(8 * 2) - (4 * 1) phase transition. AB - A numerically efficient yet highly accurate implementation of the crystal orbital Hamilton population (COHP) scheme for plane-wave calculations is presented. It is based on the projector-augmented wave (PAW) formalism in combination with norm conserving pseudopotentials and allows to extract chemical interactions between atoms from band-structure calculations even for large and complex systems. The potential of the present COHP implementation is demonstrated by an in-depth analysis of the intensively investigated metal-insulator transition in atomic scale indium wires self-assembled on the Si(111) surface. Thereby bond formation between In atoms of adjacent zigzag chains is found to be instrumental for the phase change. (c) 2017 Wiley Periodicals, Inc. PMID- 28718946 TI - Evidence for plical support of the patella. AB - There is a consensus that there is no overt anterior joint capsule in the knee. However, other anterior structures act in lieu of a joint capsule: the quadriceps tendon and patellar retinacular fibres. In the absence of a capsule, the synovium forms the suprapatellar pouch. Other synovial structures, the plicae, are more controversial. They are often described as embryonic remnants with no function, despite surrounding the patella. We aimed to identify plical anatomy and histology on cadaveric dissection and to examine their embryology using the human virtual embryo website. Plicae were identified by two independent observers. Plical histology was examined using a panel of stains: H&E, Ab H&E, EVG and MSB trichrome. Embryonic knees were examined from Carnegie stages 20-23. Each knee had a suprapatellar plica and mediopatellar plica (MPP). The lateropatellar plica (LPP) appeared as a band in 5/10 cadavers, and as a ridge in the remainder. The overall impression, consistent across all specimens, was that the plicae formed a continuous band of synovial tissue around the proximal three-quarters of the patella. The infrapatellar fat pad (IFP) surrounded the remainder. Histologically, the plicae and IFP consisted of three layers (in order): a synovial layer, an undulated collagenous layer, and an adipose or areoloadipose layer. The subsynovial collagenisation is normally associated with the synovio capsular boundary. Embryologically, plicae were not seen in either knee at any level for any given Carnegie stage. We suggest that plicae, along with the dynamic IFP, provide internal support to the patella mirroring the external support of retinacular fibres. Thus, the plicae complete the tissue complex acting in lieu of an anterior joint capsule. Evidence of plical functionality lends credence to the theory that the plicae are anatomical structures not functionless embryonic remnants. PMID- 28718947 TI - Relevance of bioreactors and whole tissue cultures for the translation of new therapies to humans. AB - The purpose of this review is to provide a brief overview of bioreactor-based culture systems as alternatives to conventional two- and three-dimensional counterparts. The role, challenges, and future aspirations of bioreactors in the musculoskeletal field (e.g., cartilage, intervertebral disc, tendon, and bone) are discussed. Bioreactors, by recapitulating physiological processes, can be used effectively as part of the initial in vitro screening, reducing that way the number of animal required for preclinical assessment, complying with the 3R principles and, in most cases, allowing working with human tissues. The clinical significance of bioreactors is that, by providing more physiologically relevant conditions to customarily used two- and three-dimensional cultures, they hold the potential to provide a testing platform that is more predictable of a whole tissue response, thereby facilitating the screening of treatments before the initiation of clinical trials. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:10-21, 2018. PMID- 28718948 TI - Effects of short-term heat stress at the grain formation stage on physicochemical properties of waxy maize starch. AB - BACKGROUND: Waxy maize (Zea mays L. sinensis Kulesh) suffers short-term exposure to high temperature during grain filling in southern China. The effects of such exposure are poorly understood. RESULTS: Starch granule size was increased by 5 days' short-term heat stress (35.0 degrees C) and the increase was higher when the stress was introduced early. Heat stress increased the iodine binding capacity of starches and no difference was observed among the three stages. Starch relative crystallinity was increased and swelling power was decreased only when heat stress was introduced early. Heat stress also increased the pasting viscosity, and this effect became more pronounced with later applications of stress. Heat stress reduced starch gelatinization enthalpy, and the reduction gradually increased with later exposures. Heat stress increased the gelatinization temperature and retrogradation enthalpy and percentage of the samples, with the increases being largest with earlier introduction of high temperature. CONCLUSION: Heat stress increased the pasting viscosities and retrogradation percentage of starch by causing change in granule size, amylopectin chain length distribution and crystallinity, and the effects observed were more severe with earlier introduction of heat stress after pollination. (c) 2017 Society of Chemical Industry. PMID- 28718949 TI - High Dosage of Vitamin D Regulates the Energy Metabolism and Increases Insulin Sensitivity, but are Associated with High Levels of Kidney Damage. AB - Preclinical Research Metabolic disorders are responsible for more than 60% of all deaths worldwide. Calcitriol or vitamin D (vitD) deficiency is associated with a large proportion of these diseases is an important therapeutic target for exploration. This study evaluated the administration of high doses of vitD (3000 IU/kg) in obese and insulin-resistant C57BL/6J mice. Our results demonstrated that although high doses of vitD provided metabolic benefits such as increased insulin sensitivity and decreased body mass, this was associated with significant damage in the kidneys of obese mice. These findings support the role of vitD as a therapeutic strategy against metabolic disorders. However, caution is required with the dose administrated, and the renal damage associated still needs to be investigated. Drug Dev Res 78 : 203-209, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28718950 TI - Radiofrequency ablation for the management of thyroid nodules: A critical appraisal of the literature. AB - The majority of benign thyroid nodules are asymptomatic, remain stable in size and do not require treatment. However, a minority of patients with growing nodules may have local symptoms or cosmetic concerns, and thus demand surgical therapy. The timely use of ultrasound-guided, minimally invasive thermal therapies has changed the natural history of benign, enlarging thyroid nodules (TNs). These procedures produce persistent shrinkage of TNs and an improvement of local symptoms. Among the various procedures, percutaneous ethanol injection represents the first-line treatment for thyroid cysts, while in solid cold nodules, laser and radiofrequency ablation (RFA) have proven to be very effective and safe techniques in producing significant volume reduction that remains stable over several years. In particular, RFA seems to be suited for the management of small and medium nodules, while larger nodules may require repeated RFA treatments, and could be difficult to treat if they extend into the chest. RFA is performed in outpatient clinics and has a lower risk of complications compared to surgery. However, to date, there is still no unanimous consensus on the percutaneous treatment of benign nodules using such minimally invasive thermal techniques. In this review, we critically revise the literature to identify patients who are more likely to benefit from RFA treatment as an alternative to surgery. PMID- 28718952 TI - Facets of Clinical Appearance and Aetiology in an Unusual Bovine Amorphus Globosus. AB - Amorphus globosus is a rare entity, more common in the cow but also reported in mares, buffaloes and goats. In respect of both development and clinical presentation, this abnormity can be evolved very variably. Previously, it has been discussed whether it is a form of twin pregnancy or placental teratoma. This case report deals with morphology and genetic observations in an unusual bovine amorphus globosus exhibiting a rudimentary clitoris and vulva, gut-like structures and rudimentary bones. The amorphus globosus was shown to be dizygotic to the normal male twin using the BovineSNP50 v2 BeadChip and had a genetical female sex. Aspects of aetiology and pathogenesis as well as the possible impact of amorphus globosus in the emergence of freemartinism are discussed. PMID- 28718951 TI - Response to therapy of papillary thyroid cancer of known BRAF status. AB - OBJECTIVE: A dynamic risk stratification with modified initial estimated risk based on response to therapy and disease course is one of the crucial changes adopted recently by the American Thyroid Association (ATA). This approach focuses on an individualized risk-adapted approach to the management of differentiated thyroid cancer. The BRAF V600E mutation is the most common genetic alteration in papillary thyroid cancer (PTC). However, the prognostic value of this mutation remains unclear. The aim of this study was to examine the relation between the BRAF V600E status in PTC and all ATA response-to-therapy categories, as well as the recurrence and persistence of both biochemical disease and structural disease. PATIENTS: Unselected PTC cases with known BRAF status diagnosed from 2000 to 2013 and actively monitored at one institution (n=723) were reviewed retrospectively. The association between the BRAF V600E mutation and clinicopathological characteristics, ATA 2015 response-to-therapy category, recurrence after a period of no evidence of disease (NED) and persistent biochemical or structural disease, was analysed. RESULTS: BRAF V600E was found in 65.7% (475/723) of PTC cases. Although BRAF mutation status correlated significantly with certain clinicopathological prognostic factors, there was no correlation with any of the response-to-therapy categories. Recurrences and persistent biochemical or structural disease were not associated with BRAF status. CONCLUSIONS: Our data are consistent with those of other studies reporting a positive relation between BRAF V600E mutation and poor prognostic factors in PTC; however, the BRAF status did not significantly correlate with a response to therapy. PMID- 28718953 TI - Computational validation of the recently proposed pollen season definition criteria. PMID- 28718954 TI - Power profiles in multifocal contact lenses with variable multifocal zone. AB - BACKGROUND: The power profile of multifocal contact lenses has been demonstrated to report important information that could be used during the fitting process. The aim of this work is to describe the power profile of a recent set of gas permeable multifocal contact lenses as a function of the pupil radius. METHODS: The measured multifocal contact lenses have a centre-distance design, and are available with five distance-vision diameters (XS, S, M, L and XL) and two different additions: Type A (up to +2.00 D) and Type B (up to +2.50 D). The optical device NIMO TR1504 (Lambda-X, Nivelles, Belgium) was used to obtain the power profile measurements. The optical lens power distribution as a function of the aperture radius was described in terms of radial computed colour maps, radial averaged power profiles, addition, and lens portion used for near vision. RESULTS: The amount of total addition achieved depends on the diameter of the distance-vision area. That is, the bigger the distance vision area, the bigger the radius of the lens in order to get the same level of addition. In other words, the XS lens provides higher addition values compared to the XL lens design for a given aperture. CONCLUSIONS: The XS and S designs seem to be aimed to favour near vision, whereas the L and XL designs seem to favour distance vision. For this reason, patients who demand good distance vision might benefit from the L or XL designs, and those with high demand on near-vision tasks might benefit from the XS or S designs. The M design could be the best option for those patients who have the same needs for distance and near vision. PMID- 28718955 TI - An electrochemiluminescent method for glutamate measurement in small microdialysate samples in asphyxiated young rats. AB - Glutamate (Glu) quantification has been performed by a combination of intracerebral microdialysis through which the samples are obtained and analyzed by high performance liquid chromatography (HPLC); its measurement requires a large expenditure of time (15-30 min per sample) and special training. Therefore, an alternative method is presented here, based on the electrochemiluminescence produced by the use of an enzymatic reactor, containing glutamate-oxidase, mixed and incubated with microdialysate from dorsal striatum (DS) and prefrontal cortex (PFC) of young rats asphyxiated during the neonatal period, under a global asphyxia model in order to test this method. Using this approach, we found high extracellular Glu concentration in the DS of asphyxiated animals, but only during K+ stimulation, while in the PFC, only a delay in the rise of Glu after K+ stimulation was observed, without any difference in extracellular Glu content when compared with controls. This new method permitted a fast measurement of Glu in brain dialysate samples, it significantly reduces the cost of the analysis per sample, since only a single device and pump are needed without using columns and high pressure inside the system or complex hardware and software to control pumps, detector, fraction collector or any other peripheral used in HPLC. PMID- 28718956 TI - Somatic mutations identified at diagnosis by exome sequencing can predict response to imatinib in chronic phase chronic myeloid leukemia (CML) patients. PMID- 28718957 TI - Large numbers of interleukins-22- and -17A-producing T helper cells in cholangiocarcinoma related to liver fluke infection. AB - Cholangiocarcinoma (CCA) associated with liver fluke infection involves inflammatory and immune processes; however, whether these involve the proinflammatory cytokine IL-17A and proliferative cytokine IL-22 remains unclear. Here, numbers of IL-22- and IL-17A-producing Th cells and cytokine concentrations in 30 patients with CCA and long-term liver fluke infection, 40 patients with liver-fluke infection but not CCA, and 16 healthy controls were compared. Analyses were performed using immunohistochemistry, flow cytometry, ELISA and RT PCR. Immunohistochemical staining showed weaker expression of IL-22 and IL-17A in patients with CCA with than in those without liver fluke infection (P < 0.01). Flow cytometry revealed significantly greater median proportions of IL-22 producing T helper cells in patients with CCA (2.2%) than in those without it (0.69%) or controls (0.4%, P < 0.001). Similar results were obtained for IL-17A producing T helper cells. ELISA revealed plasma concentrations of IL-22 were 1.3 fold higher in patients with CCA than in those without it and 4.6-fold higher than in controls (P < 0.001). Plasma concentrations of IL-17A were 2.5-fold higher in patients with CCA than in those without it, and 21-fold higher than in controls (P < 0.001). Amounts of IL-22 and IL-17A mRNAs in blood were significantly higher in patients with CCA than in the other two groups. Proportions of CD4+ CD45RO+ T cells producing IL-22 correlated with proportions producing IL-17A (r = 0.759; P < 0.001), and plasma concentrations of IL-22 correlated with those of IL-17A (r = 0.726; P < 0.001). These results suggest that both IL-17A and IL-22 affect development of CCA related to liver fluke infection. PMID- 28718958 TI - Multiplex PCR scheme for variant plasmid mediated class C beta-lactamase typing. AB - BACKGROUND: An increasing of prevalence and diversification of plasmid-mediated AmpC (pAmpC) has been emerged worldwide. The incidence of pAmpC resulted in increasing beta-lactamase production and conferred resistance to almost all beta lactam antibiotics excluding carbapenems. The lack of standard method for pAmpC identification and classification exert a challenge in epidemiological surveillance and infection control practices. METHODS: A robust, single tube multiplex PCR has been developed to classify six different pAmpC groups including CIT (CMY-2 like, LAT and CFE), ECB (ACT, MIR), MOX & CMY-1 like, DHA, ACC, and FOX. The developed method was optimized and validated by testing of sensitivity and specificity. RESULTS: Developed method can detect crude extracted DNA template at nano-scale (2.5 etag) and has high discriminatory power as compared to phenotypic and commercial genotypic method. CONCLUSION: The developed method can be utilized for tracking the changes of clinically important resistance patterns and further investigation of occurrence and distribution of plasmid mediated AmpC types. PMID- 28718959 TI - Characterization of a highly Al3+ -selective fluorescence probe based on naphthalimide-Schiff base and its application to practical water samples. AB - A new fluorescent Al3+ -probe, N-allyl-4-[3,3'-((2-aminoethyl)azanediyl)-bis(N' (2-hydroxybenzylidene)propanehy-drazide)]-1,8-naphthalimide (L), was designed and synthesized based on 1,8-naphthalimide. The probe L contains 1,8-naphthalimide moiety as the fluorophore and a Schiff base as the recognition group. The structure of L was determined by single crystal X-ray. L emission at 526 nm increased on addition of Al3+ under excitation wavelength at 350 nm. L exhibited high selectivity and sensitivity fluorescence emission towards to Al3+ in ethanol/Tris-HCl buffer solution (1:1, v/v, pH = 7.2) as compared with other tested metal ions. A good linearity with a correlation coefficient (R2 ) of 0.99 was observed in the concentration range 2-10 MUM. The binding constant and the detection limit of L for Al3+ were calculated to 2.6 * 104 M-1 and 0.34 MUM, respectively. The results of experiments that including Job plot, ultraviolet visible (UV-Vis) light titration, fluorescence titration, ESI-MS and 1 H NMR titration, indicated a 1:1 stoichiometric complex between L and Al3+ . L was highly effective in monitoring Al3+ in real-life Yellow River and tap water samples. PMID- 28718960 TI - Chemical UPLC-ESI-MS/MS profiling of aconitum alkaloids and their metabolites in rat plasma and urine after oral administration of Aconitum carmichaelii Debx. Root extract. AB - In this paper, an ultra high performance liquid chromatography tandem mass spectrometric (UPLC-ESI-MS/MS) method in positive ion mode was established to systematically identify and to compare the major aconitum alkaloids and their metabolites in rat plasma and urine after oral administration of Fuzi extract. A total twenty-nine components including twenty-five C19-diterpenoid alkaloids and four C20-diterpenoid alkaloids were identified in Fuzi extract. Thirteen of the parent components and five metabolites were detected in rat plasma and sixteen parent compounds and six metabolites in urine. These parent components found in rat plasma and urine were mainly C19-diterpenoid alkaloids. All of the metabolites in vivo were demethylated metabolites (phase I metabolites), which suggested that demethylation was the major metabolic pathway of aconitum alkaloids in vivo. A comparison of the parent components in rat plasma and urine revealed that 3-deoxyacontine was found in plasma but not in urine, while kalacolidine, senbusine and 16-beta-hydroxycardiopetaline existed in urine but not in plasma, which indicated that most alkaloids components were disposed and excreted in prototype form. This research provides some important information for further metabolic investigations of Fuzi in vivo. PMID- 28718961 TI - Photodegradation kinetics, transformation, and toxicity prediction of ketoprofen, carprofen, and diclofenac acid in aqueous solutions. AB - Photodegradation of 3 commonly used nonsteroidal anti-inflammatory drugs, ketoprofen, carprofen, and diclofenac acid, was conducted under ultraviolet (UV) irradiation. The kinetic results showed that the 3 pharmaceuticals obeyed the first-order reaction with decreasing rate constants of 1.54 * 10-4 , 5.91 * 10-5 , and 7.78 * 10-6 s-1 for carprofen, ketoprofen, and diclofenac acid, respectively. Moreover, the main transformation products were identified by ion pair liquid-liquid extraction combined with injection port derivatization-gas chromatography-mass spectrometry and high-performance liquid chromatography quadrupole-time of flight mass spectrometric analysis. There were 8, 3, and 6 transformation products identified for ketoprofen, carprofen, and diclofenac acid, respectively. Decarboxylation, dechlorination, oxidation, demethylation, esterification, and cyclization were proposed to be associated with the transformation of the 3 pharmaceuticals. Toxicity prediction of the transformation products was conducted on the EPI Suite software based on ECOSAR model, and the results indicate that some of the transformation products were more toxic than the parent compounds. The present study provides the foundation to understand the transformation behavior of the studied pharmaceuticals under UV irradiation. Environ Toxicol Chem 2017;36:3232-3239. (c) 2017 SETAC. PMID- 28718962 TI - Nerve ultrasound showing Martin-Gruber anastomosis. PMID- 28718963 TI - Peer support for families of children with complex needs: Development and dissemination of a best practice toolkit. AB - BACKGROUND: Benefits of peer support interventions for families of children with disabilities and complex medical needs have been described in the literature. An opportunity to create an evidence-informed resource to synthesize best practices in peer support for program providers was identified. The objective of this paper is to describe the key activities used to develop and disseminate the Peer Support Best Practice Toolkit. METHODS: This project was led by a team of knowledge translation experts at a large pediatric rehabilitation hospital using a knowledge exchange framework. An integrated knowledge translation approach was used to engage stakeholders in the development process through focus groups and a working group. To capture best practices in peer support, a rapid evidence review and review of related resources were completed. Case studies were also included to showcase practice-based evidence. RESULTS: The toolkit is freely available online for download and is structured into four sections: (a) background and models of peer support, (b) case studies of programs, (c) resources, and (d) rapid evidence review. A communications plan was developed to disseminate the resource and generate awareness through presentations, social media, and champion engagement. Eight months postlaunch, the peer support website received more than 2,400 webpage hits. Early indicators suggest high relevance of this resource among stakeholders. CONCLUSIONS: The toolkit format was valuable to synthesize and share best practices in peer support. Strengths of the work include the integrated approach used to develop the toolkit and the inclusion of both the published research literature and experiential evidence. PMID- 28718964 TI - Antiangiogenic Effects of Ziyuglycoside II, a Major Active Compound of Sanguisorba officinalis L. AB - Ziyuglycoside II, a major bioactive compound of Sanguisorba officinalis L., displays anticancer potential against several human cancer cells. However, little information concerning its antiangiogenic properties and possible mechanisms is available. The aim of this study was to investigate the inhibitory effects of ziyuglycoside II on angiogenesis. Ziyuglycoside II inhibited the proliferation, migration, and tubule formation of human umbilical vein endothelial cells, as well as the number of microvessels growing from the aortic rings. The underlying antiangiogenic mechanism of ziyuglycoside II correlated with blocking vascular endothelial growth factor receptor-2 and the fibroblast growth factor receptor-1 mediated signaling pathway. Moreover, an in vivo Matrigel plug assay in mice showed a significant decrease in vascularization and hemoglobin content in the plugs from ziyuglycoside II-treated mice compared with control mice. Overall, these results suggest that ziyuglycoside II inhibits various attributes of angiogenesis, which might contribute to its reported antitumor effects. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28718966 TI - DFT studies on the mechanism of Ag2 CO3 -catalyzed hydroazidation of unactivated terminal alkynes with TMS-N3 : An insight into the silver(I) activation mode. AB - Silver-mediated hydroazidation of unactivated alkynes has been developed as a new method for the synthesis of vinyl azides. Density functional theory calculations toward this reaction reveal that terminal alkynes with TMS-N3 participated hydroazidation proceed through HN3 formation, deprotonation and silver acetylides formation, nucleophilic addition, and protonation of terminal carbon by AgHCO3 . It is also found that water molecules and activation modes of Ag (I) have a significant influence on the title reaction mechanism. Initially, catalyst Ag2 CO3 coordinates preferentially with internal N atom of TMS-N3 to assist water as hydrogen source and proton-shuttle in facilitating HN3 formation. Then, the regioselective anti-addition of HN3 to triple bond of active silver-acetylide or ethynyl carbinols affords product vinyl azide via Ag-C sigma-bond activation or Ag...C pi-coordination activation modes, and the former one is more favorable. The origin of the difference regioselectivity is ascribed to the electronic and orbital effects of the reactive sites. Moreover, Ag2 CO3 is the critical catalyst, acting as activator, base, and stabilizer to promote the HN3 and vinyl azide formation. Water molecule plays an important role as proton shuttle to promote HN3 and key active silver acetylides formation, thus improving the yield of product. (c) 2017 Wiley Periodicals, Inc. PMID- 28718965 TI - Long-term effects: Galectin-1 and specific immunotherapy for allergic responses in the intestine. AB - BACKGROUND AND AIMS: Mast cell activation interferes with the effects of allergen specific immunotherapy (SIT). Galectin-1 (Gal-1) is capable of regulating immune cells' functions. This study tests the hypothesis that administration of Gal-1 promotes and prolongs the efficacy of SIT via suppressing mast cell activation. METHODS: An intestinal allergy mouse model was developed. The coadministration of SIT and Gal-1 on suppression of the allergic responses, prevention of mast cell activation, and generation of antigen-specific regulatory T cells (Treg) in the intestine was observed in sensitized mice. RESULTS: The coadministration of Gal-1 and SIT markedly suppressed the allergic responses in the mouse intestine vs the use of either SIT alone or Gal-1 alone. The Gal-1 binds to the IgE/FcERI complexes on the surface of mast cells to prevent mast cell activation during SIT. Gal-1 promoted the SIT-generated allergen-specific Tregs in the intestine of sensitized mice. Coadministration of Gal-1 and SIT significantly enhanced the efficacy of immunotherapy in suppressing allergic responses in the intestine, which lasted for at least for 12 months. CONCLUSIONS: Long-term effects of specific immunotherapy on intestinal allergy can be achieved with Gal-1/SIT therapy by inhibiting mast cell activation and facilitating Treg development. PMID- 28718967 TI - Seeing the big picture: Broadening attention relieves sadness and depressed mood. AB - We examined whether the broadened attentional scope would affect people's sad or depressed mood with two experiments, enlightened by the meaning of "seeing the big picture" and the broaden-and-build model. Experiment 1 (n = 164) is a laboratory-based experiment, in which we manipulated the attentional scope by showing participants zoomed-out or zoomed-in scenes. In Experiment 2 (n = 44), we studied how depressed mood and positive and negative emotions were affected when participants watched distant versus proximal scenes for eight weeks in real life. Healthy participants in Experiment 1, who were induced to feel sad, could return to the baseline mood after having the broadened attention task but not after having the narrowed attention task, which indicated that immediate attention broadening manipulation could function as antidotes for the lingering effects of induced negative emotions. Participants with depressed mood in Experiment 2 showed reduced depressed mood, increased positive affect, and decreased negative affect after receiving attention broadening training compared to those receiving attention narrowing training. Our findings suggest a robust role of broadened attentional scope in relieving negative emotions and even mildly depressed mood in the long run. PMID- 28718968 TI - The design of the MBT-G adherence and quality scale. AB - Few group psychotherapy studies focus on therapists' interventions, and instruments that can measure group psychotherapy treatment fidelity are scarce. The aim of the present study was to evaluate the reliability of the Mentalization based Group Therapy Adherence and Quality Scale (MBT-G-AQS), which is a 19-item scale developed to measure adherence and quality in mentalization-based group therapy (MBT-G). Eight MBT groups and eight psychodynamic groups (a total of 16 videotaped therapy sessions) were rated independently by five raters. All groups were long-term, outpatient psychotherapy groups with 1.5 hours weekly sessions. Data were analysed by a Generalizability Study (G-study and D-study). The generalizability models included analyses of reliability for different numbers of raters. The global (overall) ratings for adherence and quality showed high to excellent reliability for all numbers of raters (the reliability by use of five raters was 0.97 for adherence and 0.96 for quality). The mean reliability for all 19 items for a single rater was 0.57 (item range 0.26-0.86) for adherence, and 0.62 (item range 0.26-0.83) for quality. The reliability for two raters obtained mean absolute G-coefficients on 0.71 (item range 0.41-0.92 for the different items) for adherence and 0.76 (item range 0.42-0.91) for quality. With all five raters the mean absolute G-coefficient for adherence was 0.86 (item range 0.63 0.97) and 0.88 for quality (item range 0.64-0.96). The study demonstrates high reliability of ratings of MBT-G-AQS. In models differentiating between different numbers of raters, reliability was particularly high when including several raters, but was also acceptable for two raters. For practical purposes, the MBT-G AQS can be used for training, supervision and psychotherapy research. PMID- 28718969 TI - Child and family-related predictors of psychological outcomes in children adopted from abroad; what is the role of caregiver time? AB - International adoptees need to cope with stressful transitions and to develop secure attachment with their caregivers at the same time. Although most children adopted from abroad adjust fine, they are at increased risk of psychological problems. We investigated whether both child and family-related factors are associated with later psychological problems and whether the length of time spent at home after adoption before daycare moderates these associations among internationally adopted children in Finland (FinAdo, Finnish Adoption Study). The sample consisted of 1,265 children (708 girls, 557 boys) who arrived in Finland before they started school (mean age 2 years at arrival). Later behavioral problems were measured using the Child Behavior Check List (CBCL). According to our results, male gender, older age, child's early clinical symptoms (problems of sensory processing) and single parenthood were associated with later behavioral problems measured by CBCL scores. Longer stay at home before the start of daycare or school modified these results. Longer stay at home was associated with less later behavioral externalizing problems in girls but not in boys compared to those who spent a shorter time at home. PMID- 28718970 TI - Activation of semantic information at the sublexical level during handwriting production: Evidence from inhibition effects of Chinese semantic radicals in the picture-word interference paradigm. AB - Using a non-alphabetic language (e.g., Chinese), the present study tested a novel view that semantic information at the sublexical level should be activated during handwriting production. Over 80% of Chinese characters are phonograms, in which semantic radicals represent category information (e.g., 'chair,' 'peach,' 'orange' are related to plants) while phonetic radicals represent phonetic information (e.g., 'wolf,' 'brightness,' 'male,' are all pronounced /lang/). Under different semantic category conditions at the lexical level (semantically related in Experiment 1; semantically unrelated in Experiment 2), the orthographic relatedness and semantic relatedness of semantic radicals in the picture name and its distractor were manipulated under different SOAs (i.e., stimulus onset asynchrony, the interval between the onset of the picture and the onset of the interference word). Two questions were addressed: (1) Is it possible that semantic information could be activated in the sublexical level conditions? (2) How are semantic and orthographic information dynamically accessed in word production? Results showed that both orthographic and semantic information were activated under the present picture-word interference paradigm, dynamically under different SOAs, which supported our view that discussions on semantic processes in the writing modality should be extended to the sublexical level. The current findings provide possibility for building new orthography-phonology-semantics models in writing. PMID- 28718971 TI - Influence of WHO versus ELN advanced phase chronic myeloid leukemia definitions on overall survival. PMID- 28718973 TI - Constructing a multidimensional free energy surface like a spider weaving a web. AB - Complete free energy surface in the collective variable space provides important information of the reaction mechanisms of the molecules. But, sufficient sampling in the collective variable space is not easy. The space expands quickly with the number of the collective variables. To solve the problem, many methods utilize artificial biasing potentials to flatten out the original free energy surface of the molecule in the simulation. Their performances are sensitive to the definitions of the biasing potentials. Fast-growing biasing potential accelerates the sampling speed but decreases the accuracy of the free energy result. Slow growing biasing potential gives an optimized result but needs more simulation time. In this article, we propose an alternative method. It adds the biasing potential to a representative point of the molecule in the collective variable space to improve the conformational sampling. And the free energy surface is calculated from the free energy gradient in the constrained simulation, not given by the negative of the biasing potential as previous methods. So the presented method does not require the biasing potential to remove all the barriers and basins on the free energy surface exactly. Practical applications show that the method in this work is able to produce the accurate free energy surfaces for different molecules in a short time period. The free energy errors are small in the cases of various biasing potentials. (c) 2017 Wiley Periodicals, Inc. PMID- 28718972 TI - Enhancement of mTOR signaling contributes to acquired X-ray and C-ion resistance in mouse squamous carcinoma cell line. AB - Our aim was to evaluate whether repetition of C-ion (carbon ion beam) irradiation induces radioresistance as well as repeated X-ray irradiation in cancer cell lines, and to find the key molecular pathway for radioresistance by comparing radioresistant cancer cells with their parental cells. A mouse squamous cell carcinoma cell line, NR-S1, and radioresistant cancer cells, NR-S1-C30 (C30) and NR-S1-X60 (X60), established by repetition of C-ion and X-ray irradiation, respectively, were used. X-ray and C-ion sensitivity, changes in lysosome, mitochondria, intracellular ATP and reactive oxygen species (ROS) level, and mechanistic target of rapamycin (mTOR) signaling were evaluated. Moreover, the effect of rapamycin on radioresistance was also assessed. X-ray and C-ion resistance of C30 cells was moderate, and the resistance of X60 cells was the highest in this study. In X60 cells, the amount of lysosome, mitochondria, intracellular ATP and ROS level were significantly increased, and mTOR and p70S6K (ribosomal protein S6 kinase p70) phosphorylation were enhanced compared with C30 and NR-S1 cells. The inhibition of mTOR signaling was effective for X-ray and C ion radiosensitization in both cell lines, especially in X60 cells in which X-ray and C-ion resistance was decreased to the same level as that in NR-S1 cells. Our results indicated that the contribution to generate X-ray and C-ion resistance was less for repeated C-ion irradiations compared with repeated X-ray irradiation. Moreover, we found that activated mTOR signaling contributes to X ray and C-ion resistance in the X60 cancer cells. PMID- 28718974 TI - Pre-pubertal diet restriction reduces reactive oxygen species and restores fertility in male WNIN/Obese rat. AB - Obesity is a multifactorial disorder associated with increased body adiposity, chronic oxidative stress which contributes to impaired fertility in males. Diet restriction and anti-oxidant supplementations are known to protect obese subjects from oxidative stress and improves fertility. However, the role of oxidative stress and the age of intervention in restoring male fertility are poorly understood. This study was aimed to assess the effect of diet restriction on fertility with respect to the age of intervention, body composition and oxidative stress using WNIN/Ob obese mutant rat strain. Unlike lean and carrier phenotypes, obese rats are hyperphagic, hyperlipaemic and infertile. Male obese rats aged for 35, 60 and 90 days were fed either ad libitum or diet restricted for 6 weeks. Upon diet restriction mean body weight, total body fat percentage, circulatory lipids and oxidative stress markers were significantly reduced and it follows the order as 35 < 60 < 90 days. Diet-restricted males of the three age groups were allowed to mate with female carrier rats, and fertility was restored only in 35 day group. Diet restriction in male obese WNIN/Ob rats lowered the rate of body weight gain, with reduced oxidative stress overall and fertility restoration in groups intervened at pre-pubertal stages. PMID- 28718975 TI - Pyrene Molecular Orbital Shuffle-Controlling Excited State and Redox Properties by Changing the Nature of the Frontier Orbitals. AB - We show that by judicious choice of substituents at the 2- and 7-positions of pyrene, the frontier orbital order of pyrene can be modified, giving enhanced control over the nature and properties of the photoexcited states and the redox potentials. Specifically, we introduced a julolidine-like moiety and Bmes2 (mes=2,4,6-Me3 C6 H2 ) as very strong donor (D) and acceptor (A), respectively, giving 2,7-D-pi-D- and unsymmetric 2,7-D-pi-A-pyrene derivatives, in which the donor destabilizes the HOMO-1 and the acceptor stabilizes the LUMO+1 of the pyrene core. Consequently, for 2,7-substituted pyrene derivatives, unusual properties are obtained. For example, very large bathochromic shifts were observed for all of our compounds, and unprecedented green light emission occurs for the D/D system. In addition, very high radiative rate constants in solution and in the solid state were recorded for the D-pi-D- and D-pi-A-substituted compounds. All compounds show reversible one-electron oxidations, and Jul2 Pyr exhibits a second oxidation, with the largest potential splitting (DeltaE=440 mV) thus far reported for 2,7-substituted pyrenes. Spectroelectrochemical measurements confirm an unexpectedly strong coupling between the 2,7-substituents in our pyrene derivatives. PMID- 28718976 TI - Low density lipopolyprotein inhibits flavivirus acquisition in Aedes aegypti. AB - Aedes aegypti is the primary vector of a number of human pathogens including dengue virus (DENV) and Zika virus (ZIKV). Ae. aegypti acquires these viruses during the processing of bloodmeals obtained from an infected vertebrate host. Vertebrate blood contains a number of factors that have the potential to modify virus acquisition in the mosquito. Interestingly, low density lipopolyprotein (LDL) levels are decreased during severe DENV infection. Accordingly, we hypothesized that LDL is a modifiable factor that can influence flavivirus acquisition in the mosquito. We found that LDL is endocytosed by Ae. aegypti cells in a dynamin-dependent manner. LDL is also endocytosed by midgut epithelial cells and accumulates at the luminal midgut epithelium during bloodmeal digestion. Importantly, pretreatment with LDL, but not high density lipopolyprotein (HDL), significantly inhibited both DENV and ZIKV infection in vitro, and LDL inhibited ZIKV infection in vivo. This study identifies human LDL or 'bad cholesterol' as a modifiable factor that can inhibit flavivirus acquisition in Ae. aegypti. Identification of modifiable blood factors and critical cellular interactions that mediate pathogen acquisition may lead to novel strategies to disrupt the transmission cycle of vector-borne diseases. PMID- 28718978 TI - Effective charges of ionic liquid determined self-consistently through combination of molecular dynamics simulation and density-functional theory. AB - A self-consistent scheme combining the molecular dynamics (MD) simulation and density functional theory (DFT) was recently proposed to incorporate the effects of the charge transfer and polarization of ions into non-poralizable force fields of ionic liquids for improved description of energetics and dynamics. The purpose of the present work is to analyze the detailed setups of the MD/DFT scheme by focusing on how the basis set, exchange-correlation (XC) functional, charge fitting method or force field for the intramolecular and Lennard-Jones interactions affects the MD/DFT results of 1,3-dimethylimidazolium bis(trifluoromethylsulfonyl) imide ( [C1mim][NTf2]) and 1-ethyl-3 methylimidazolium glycinate ( [C2mim][Gly]). It was found that the double-zeta valence polarized or larger size of basis set is required for the convergence of the effective charge of the ion. The choice of the XC functional was further not influential as far as the generalized gradient approximation is used. The charge fitting method and force field govern the accuracy of the MD/DFT scheme, on the other hand. We examined the charge-fitting methods of Blochl, the iterative Hirshfeld (Hirshfeld-I), and REPEAT in combination with Lopes et al.'s force field and general AMBER force field. There is no single combination of charge fitting and force field that provides good agreements with the experiments, while the MD/DFT scheme reduces the effective charges of the ions and leads to better description of energetics and dynamics compared to the original force field with unit charges. (c) 2017 Wiley Periodicals, Inc. PMID- 28718977 TI - Effect of simulated gastrointestinal digestion and fermentation on polyphenolic content and bioactivity of brown seaweed phlorotannin-rich extracts. AB - SCOPE: Unlike other classes of polyphenols, there is a lack of knowledge regarding brown seaweed phlorotannins and their bioactivity. We investigated the impact of in vitro gastrointestinal digestion and colonic fermentation on the bioactivity of a seaweed phlorotannin extract from Ascophyllum nodosum and its high molecular weight (HMW) and low molecular weight (LMW) fractions. METHODS AND RESULTS: The highest phlorotannin and total polyphenol (TP) concentration was observed in the HMW fraction. Antioxidant capacity broadly followed phlorotannin and TP levels, with HMW having the highest activity. Both gastrointestinal digestion (GID) and colonic fermentation (CF) significantly affected phlorotannin and TP levels, and antioxidant capacity of the extract and fractions. Despite this, in HT-29 cells, all GID extracts significantly inhibit cell growth, whereas CF extracts effectively counteracted H2 O2 induced DNA damage. CONCLUSION: Although phlorotannins, TP levels and antioxidant power of the extracts were strongly reduced after in vitro digestion and fermentation, their anti-genotoxic activity and cell growth inhibitory effect in colon HT-29 cells was maintained and enhanced. HMW was the most effective fraction, indicating that the high molecular weight phlorotannins potentially exert a stronger beneficial effect in the colon. PMID- 28718979 TI - In Situ Two-Step Photoreduced SERS Materials for On-Chip Single-Molecule Spectroscopy with High Reproducibility. AB - A method is developed to synthesize surface-enhanced Raman scattering (SERS) materials capable of single-molecule detection, integrated with a microfluidic system. Using a focused laser, silver nanoparticle aggregates as SERS monitors are fabricated in a microfluidic channel through photochemical reduction. After washing out the monitor, the aggregates are irradiated again by the same laser. This key step leads to full reduction of the residual reactants, which generates numerous small silver nanoparticles on the former nanoaggregates. Consequently, the enhancement ability of the SERS monitor is greatly boosted due to the emergence of new "hot spots." At the same time, the influence of the notorious "memory effect" in microfluidics is substantially suppressed due to the depletion of surface residues. Taking these advantages, two-step photoreduced SERS materials are able to detect different types of molecules with the concentration down to 10-13 m. Based on a well-accepted bianalyte approach, it is proved that the detection limit reaches the single-molecule level. From a practical point of view, the detection reproducibility at different probing concentrations is also investigated. It is found that the effective single-molecule SERS measurements can be raised up to ~50%. This microfluidic SERS with high reproducibility and ultrasensitivity will find promising applications in on-chip single-molecule spectroscopy. PMID- 28718981 TI - Health economic analysis of allergen immunotherapy for the management of allergic rhinitis, asthma, food allergy and venom allergy: A systematic overview. AB - BACKGROUND: The European Academy of Allergy and Clinical Immunology (EAACI) is developing guidelines for allergen immunotherapy (AIT) for the management of allergic rhinitis, allergic asthma, IgE-mediated food allergy and venom allergy. To inform the development of clinical recommendations, we undertook systematic reviews to critically assess evidence on the effectiveness, safety and cost effectiveness of AIT for these conditions. This study focusses on synthesizing data and gaps in the evidence on the cost-effectiveness of AIT for these conditions. METHODS: We produced summaries of evidence in each domain, and then, synthesized findings on health economic data identified from four recent systematic reviews on allergic rhinitis, asthma, food allergy and venom allergy, respectively. The quality of these studies was independently assessed using the Critical Appraisal Skills Programme tool for health economic evaluations. RESULTS: Twenty-three studies satisfied our inclusion criteria. Of these, 19 studies investigated the cost-effectiveness of AIT in allergic rhinitis, of which seven were based on data from randomized controlled trials with economic evaluations conducted from a health system perspective. This body of evidence suggested that sublingual immunotherapy (SLIT) and subcutaneous immunotherapy (SCIT) would be considered cost-effective using the (English) National Institute for Health and Clinical Excellence (NICE) cost-effectiveness threshold of L20 000/quality-adjusted life year (QALY). However, the quality of the studies and the general lack of attention to characterizing uncertainty and handling missing data should be taken into account when interpreting these results. For asthma, there were three eligible studies, all of which had significant methodological limitations; these suggested that SLIT, when used in patients with both asthma and allergic rhinitis, may be cost-effective with an incremental cost effectiveness ratio (ICER) of L10 726 per QALY. We found one economic modelling study for venom allergy which, despite being based largely on expert opinion and plausible assumptions, suggested that AIT for bee and wasp venom allergy is only likely to be cost-effective for very high-risk groups who may be exposed to multiple exposures to venom/year (eg bee keepers). We found no eligible studies investigating the cost-effectiveness of AIT for food allergy. CONCLUSIONS: Overall, the evidence to support the cost-effectiveness of AIT is limited and of low methodological quality, but suggests that AIT may be cost-effective for people with allergic rhinitis with or without asthma and in high-risk subgroups for venom allergy. We were unable to draw any conclusions on the cost effectiveness of AIT for food allergy. PMID- 28718980 TI - An endogenous DNA adduct as a prognostic biomarker for hepatocarcinogenesis and its prevention by Theaphenon E in mice. AB - : Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide, mainly because of its poor prognosis. A valid mechanism-based prognostic biomarker is urgently needed. gamma-hydroxy-1,N2 propanodeoxyguanosine (gamma-OHPdG) is an endogenously formed mutagenic DNA adduct derived from lipid peroxidation. We examined the relationship of gamma OHPdG with hepatocarcinogenesis in two animal models and its potential role as a prognostic biomarker for recurrence in HCC patients. Bioassays were conducted in xeroderma pigmentosum group A knockout mice and diethylnitrosamine-injected mice, both prone to HCC development. gamma-OHPdG levels in the livers of these animals were determined. The effects of antioxidant treatments on gamma-OHPdG and hepatocarcinogenesis were examined. Using two independent sets of HCC specimens from patients, we examined the relationship between gamma-OHPdG and survival or recurrence-free survival. gamma-OHPdG levels in liver DNA showed an age-dependent increase and consistently correlated with HCC development in all three animal models. Theaphenon E treatment significantly decreased gamma-OHPdG levels in the liver DNA of xeroderma pigmentosum group A knockout mice and remarkably reduced HCC incidence in these mice to 14% from 100% in the controls. It also effectively inhibited HCC development in the diethylnitrosamine-injected mice. Using clinical samples from two groups of patients, our study revealed that higher levels of gamma-OHPdG are strongly associated with low survival (P < 0.0001) and low recurrence-free survival (P = 0.007). CONCLUSION: These results support gamma OHPdG as a mechanism-based, biologically relevant biomarker for predicting the risk of HCC and its recurrence. (Hepatology 2018;67:159-170). PMID- 28718982 TI - Design and Solution-Phase Synthesis of Membrane-Targeting Lipopeptides with Selective Antibacterial Activity. AB - Designing selective antibacterial molecules remains an unmet goal in the field of membrane-targeting agents. Herein, we report the rational design and synthesis of a new class of lipopeptides, which possess highly selective bacterial killing over mammalian cells. The selective interaction with bacterial over mammalian membranes was established through various spectroscopic, as well as microscopic experiments, including biophysical studies with the model membranes. A detailed antibacterial structure-activity relationship was delineated after preparing a series of molecules consisting of the peptide moieties with varied sequence of amino acids, such as d-phenylalanine, d-leucine, and d-lysine. Antibacterial activity was found to vary with the nature and positioning of hydrophobicity in the molecules, as well as number of positive charges. Optimized lipopeptide 9 did not show any hemolytic activity even at 1000 MUg mL-1 and displayed >200-fold and >100-fold selectivity towards S. aureus and E. coli, respectively. More importantly, compound 9 was found to display good antibacterial activity (MIC 6.3 12.5 MUg mL-1 ) against the five top most critical bacteria according to World Health Organization (WHO) priority pathogens list. Therefore, the results suggested that this new class of lipopeptides bear real promises for the development as future antibacterial agents. PMID- 28718983 TI - Multimodality Image-Guided Cryoablation for Inoperable Tumor-Induced Osteomalacia. AB - Tumor-induced osteomalacia (TIO) is a debilitating paraneoplastic condition caused by small phosphaturic mesenchymal tumors (PMTs) that secrete large amounts of the phosphate-regulating and vitamin D-regulating hormone, FGF23. Tumor removal results in cure. However, because of high perioperative comorbidity, either from tumor location or host factors, surgery is sometimes not an option. Tumor destruction via cryoablation may be an effective option for inoperable PMTs. Three subjects with a confirmed diagnosis of TIO were studied. All three underwent cryoablation of suspected PMTs rather than surgery due to significant medical comorbidities or challenging anatomical location. Subject 3 had tumor embolization 24 hours prior to cryoablation because of the size and hypervascularity of the tumor. The success of the tumor cryoablation was defined by normalization of serum phosphate and FGF23. Cryoablation resulted in a rapid decrease in plasma intact FGF23 by 24 hours postprocedure in all three subjects (0, 2, and 9 pg/mL, respectively) with normalization of blood phosphate by postprocedure day 3. Three-day renal tubular reabsorption of phosphate increased to 76%, 94%, and 95.2%, respectively; 1, 25(OH)2 vitamin D increased to 84, 138, and 196 pg/ml, respectively. All three had dramatic clinical improvement in pain and weakness. Two subjects tolerated the procedure well with no complications; one had significant prolonged procedure-related localized pain. Although surgery remains the treatment of choice, cryoablation may be an effective, less invasive, and safe treatment for patients with difficult to remove tumors or who are poor surgical candidates. (c) 2017 American Society for Bone and Mineral Research. PMID- 28718984 TI - Effect of PNPLA3 I148M polymorphism on histologically proven non-alcoholic fatty liver disease in liver transplant recipients. AB - AIM: PNPLA3 I148M polymorphism (rs738409 C>G) is the most important and best known polymorphism for non-alcoholic fatty liver disease (NAFLD). However, little is known about the effect of this polymorphism on NAFLD after liver transplantation (LT). We aimed to evaluate the association between this polymorphism and post-LT NAFLD. METHODS: We designed a prospective case-control study. Among adult recipients who underwent LT between April 2014 and October 2015, those whose whole blood was preoperatively collected for genotyping in both recipients and coupled donors and those who underwent protocol biopsy at 1 year post-LT were enrolled. RESULTS: A total of 32 recipients were enrolled. Histologically proven steatosis (>=5%) was present in 28.1% of patients at a mean time of 12.7 +/- 2.0 months after LT. Moderate and more severe steatosis (>=33%) was present in 9.4%. One year after LT, steatosis was present in 50.0% of homozygous recipients with the rs738409-G allele. It was present in 27.3% of heterozygous recipients with the rs738409-G allele, and in 9.1% (P = 0.041) of recipients with rs738409-CC. The genotype of the donor was not significantly (P = 0.647) associated with post-LT NAFLD. When both recipient and coupled donor showed heterogeneous or homozygous genotype of the rs738409-G allele, there was significantly more post-LT NAFLD compared to that in others (47.1% vs. 6.7%; P = 0.018). In univariate and multivariate analyses, only the presence of the rs738409-G risk allele in both donor and recipient was a significant risk factor for post-LT NALFD (relative risk, 26.95; P = 0.048). CONCLUSIONS: PNPLA3 I148M polymorphism can significantly affect histologically proven NAFLD at 1 year post LT. PMID- 28718985 TI - Relationships between the frequency and severity of non-suicidal self-injury and suicide attempts in youth with borderline personality disorder. AB - AIM: Non-suicidal self-injury (NSSI) is a recognized indicator of suicide risk. Yet, the ubiquity of this behaviour in borderline personality disorder (BPD) limits its utility as a predictor of risk. Consequently, this study aimed to elucidate the relationship between other features of NSSI, including frequency and severity, and suicide attempts. METHOD: Participants included 107 youth (15 to 25 year olds) with BPD who were assessed for BPD severity, depressive symptoms, 12-month frequency of NSSI and suicide attempts, as well as the levels of treatment sought following each self-harm event. RESULTS: Three-quarters (75.7%) of youth with BPD reported NSSI and two-thirds (66.4%) reported a suicide attempt over the previous 12 months. The frequency of NSSI over the previous 12 months did not show a linear or quadratic relationship with the number of suicide attempts when adjusting for severity of depression, impulsivity and interpersonal problems. NSSI severity was not associated with more frequent suicide attempts. Only impulsivity and depression were uniquely predictive of suicide attempt frequency. A relative increase in the frequency and severity of NSSI occurred in the months prior to a suicide attempt. CONCLUSION: The prevalence of NSSI and suicide attempts among youth presenting for their first treatment of BPD appear to be perilously high, considerably higher than rates reported by adults with BPD. Findings suggest that clinicians should give more weight to average levels of impulsivity and depression, rather than the absolute frequency and severity of NSSI, when assessing for risk of suicide attempts. Notwithstanding this, a relative increase in the frequency and severity of NSSI appears to be predictive of a forthcoming suicide attempt. PMID- 28718986 TI - The effect of selection history on extinction risk during severe environmental change. AB - Environments rarely remain the same over time, and populations are therefore frequently at risk of going extinct when changes are significant enough to reduce fitness. Although many studies have investigated what attributes of the new environments and of the populations experiencing these changes will affect their probability of going extinct, limited work has been directed towards determining the role of population history on the probability of going extinct during severe environmental change. Here, we compare the extinction risk of populations with a history of selection in a benign environment, to populations with a history of selection in one or two stressful environments. We exposed spores and lines of the green alga Chlamydomonas reinhardtii from these three different histories to a range of severe environmental changes. We found that the extinction risk was higher for populations with a history of selection in stressful environments compared to populations with a history of selection in a benign environment. This effect was not due to differences in initial population sizes. Finally, the rates of extinction were highly repeatable within histories, indicating strong historical contingency of extinction risk. Hence, information on the selection history of a population can be used to predict their probability of going extinct during environmental change. PMID- 28718987 TI - The effect of exercise on sleep in adults with type 1 diabetes. AB - The aim of this pilot study was to investigate the effect of exercise on sleep and nocturnal hypoglycaemia in adults with type 1 diabetes (T1D). In a 3-week crossover trial, 10 adults with T1D were randomized to perform aerobic, resistance or no exercise. During each exercise week, participants completed 2 separate 45-minutes exercise sessions at an academic medical center. Participants returned home and wore a continuous glucose monitor and a wrist-based activity monitor to estimate sleep duration. Participants on average lost 70 (+/-49) minutes of sleep (P = .0015) on nights following aerobic exercise and 27 (+/-78) minutes (P = .3) following resistance exercise relative to control nights. The odds ratio with confidence intervals of nocturnal hypoglycaemia occurring on nights following aerobic and resistance exercise was 5.4 (1.3, 27.2) and 7.0 (1.7, 37.3), respectively. Aerobic exercise can cause sleep loss in T1D possibly from increased hypoglycaemia. PMID- 28718988 TI - Hydrogels with Dual Thermoresponsive Mechanical Performance. AB - Dual thermoresponsive chemical hydrogels, combining poly(N-isopropylacrylamide) side-chains within a poly(N-acryloylglycinamide) network, are designed following a simple and versatile procedure. These hydrogels exhibit two phase transitions both at low (upper critical solution temperature) and high (lower critical solution temperature) temperatures, thereby modifying their swelling, rheological, and mechanical properties. These novel thermo-schizophrenic hydrogels pave the way for the development of thermotoughening wet materials in a broad range of temperatures. PMID- 28718989 TI - Formation of Stone-Wales edge: Multistep reconstruction and growth mechanisms of zigzag nanographene. AB - Although the existence of Stone-Wales (5-7) defect at graphene edge has been clarified experimentally, theoretical study on the formation mechanism is still imperfect. In particular, the regioselectivity of multistep reactions at edge (self-reconstruction and growth with foreign carbon feedstock) is essential to understand the kinetic behavior of reactive boundaries but investigations are still lacking. Herein, by using finite-sized models, multistep reconstructions and carbon dimer additions of a bared zigzag edge are introduced using density functional theory calculations. The zigzag to 5-7 transformation is proved as a site-selective process to generate alternating 5-7 pairs sequentially and the first step with largest barrier is suggested as the rate-determining step. Conversely, successive C2 insertions on the active edge are calculated to elucidate the formation of 5-7 edge during graphene growth. A metastable intermediate with a triple sequentially fused pentagon fragment is proved as the key structure for 5-7 edge formation. (c) 2017 Wiley Periodicals, Inc. PMID- 28718990 TI - Fungitoxicity of organic extracts of Ocimum basilicum on growth and morphogenesis of Bipolaris species (teleomorph Cochliobolus). AB - AIMS: This study aimed at evaluating the inhibitory effects of various organic extracts of Ocimum basilicum against some species of Bipolaris and Cochliobolus with GC-MS and HPLC analysis. METHODS AND RESULTS: The ethyl acetate extract consisted of methyl cinnamate as the most abundant component, while butylated hydroxytoluene was the major component in the methanol extract. Pyrogallol and chlorogenic acid were major phenolic compounds in the ethyl acetate and methanol extracts, respectively. Complete growth inhibition of all fungi except Cochliobolus australiensis was observed by ethyl acetate extract, and on Bipolaris hawaiensis, Bipolaris spicifera and Cochliobolus cynodontis by methanol extract. Spore germination was completely inhibited for Bipolaris hawaiensis by ethyl acetate extract. Scanning electron microscopic observations revealed that the organic extracts cause considerable morphological changes of the fungal hyphae such as mycelial asymmetry, hyphal swelling, sunken, curling, distorted and broken hyphae. CONCLUSIONS: The ethyl acetate and methanol extracts of O. basilicum can result in an effective suppression of mycelial growth, spore germination and germ tube elongation of Bipolaris and Cochliobolus species. SIGNIFICANCE AND IMPACT OF THE STUDY: The organic extracts of O. basilicum are potential and promising natural tools for controlling Bipolaris and Cochliobolus species, economically important plant and human fungal pathogens. PMID- 28718991 TI - Learning curve for the thoracoscopic repair of esophageal atresia with tracheoesophageal fistula. AB - AIM: Thoracoscopic repair (TR) of esophageal atresia with tracheoesophageal fistula (EA/TEF) remains a considerable challenge, even for the most experienced pediatric surgeons. The aim of this study is to report the outcomes of our experience with TR of EA/TEF and to determine the learning curve for this procedure. METHODS: Eleven consecutive cases that had undergone TR of EA/TEF at our institutes were included in this study. The medical charts were reviewed retrospectively. To determine the learning curve for TR of EA/TEF, a logarithmic curve-fitting analysis was performed. The data were expressed as medians with ranges. RESULTS: The median age and birth weight were 1 day (range, 1-3 days) and 2.8 kg (range, 2.5-3.7 kg), respectively. TR was completed in all cases without any complications. The median operative time was 230 min (range, 164-383 min). There were no cases of anastomotic leakage. One patient with a long gap required repeated balloon dilatation for refractory anastomotic stricture. No mortality or recurrence of tracheoesophageal fistula occurred. The operative time was significantly longer in patients with a long gap (>20 mm) than in those with a shorter gap. Once the three cases with a long gap had been excluded, the operative time decreased as the number of treated cases increased. The relationship between the operative time and case number fit a logarithmic function curve well (operative time in minutes = 300 - 62 * log (case number), R2 = 0.8359, P = 0.0015). CONCLUSIONS: Our results suggest that TR of EA/TEF is a safe procedure. It has a considerable learning curve, but requires advanced endoscopic surgical skills. PMID- 28718992 TI - Melatonin impedes Tet1-dependent mGluR5 promoter demethylation to relieve pain. AB - Melatonin (N-acetyl-5-methoxytryptamine)/MT2 receptor-dependent epigenetic modification represents a novel pathway in the treatment of neuropathic pain. Because spinal ten-eleven translocation methylcytosine dioxygenase 1 (Tet1) dependent epigenetic demethylation has recently been linked to pain hypersensitivity, we hypothesized that melatonin/MT2-dependent analgesia involves spinal Tet1-dependent demethylation. Here, we showed that spinal Tet1 gene transfer by intrathecal delivery of Tet1-encoding vectors to naive rats produced profound and long-lasting nociceptive hypersensitivity. In addition, enhanced Tet1 expression, Tet1-metabotropic glutamate receptor subtype 5 (mGluR5) promoter coupling, demethylation at the mGluR5 promoter, and mGluR5 expression in dorsal horn neurons were observed. Rats subjected to spinal nerve ligation and intraplantar complete Freund's adjuvant injection displayed tactile allodynia and behavioral hyperalgesia associated with similar changes in the dorsal horn. Notably, intrathecal melatonin injection reversed the protein expression, protein promoter coupling, promoter demethylation, and pain hypersensitivity induced by Tet1 gene transfer, spinal nerve ligation, and intraplantar complete Freund's adjuvant injection. All the effects caused by melatonin were blocked by pretreatment with a MT2 receptor-selective antagonist. In conclusion, melatonin relieves pain by impeding Tet1-dependent demethylation of mGluR5 in dorsal horn neurons through the MT2 receptor. Our findings link melatonin/MT2 signaling to Tet1-dependent epigenetic demethylation of nociceptive genes for the first time and suggest melatonin as a promising therapy for the treatment of pain. PMID- 28718993 TI - Role of FDG-PET/MRI, FDG-PET/CT, and Dynamic Susceptibility Contrast Perfusion MRI in Differentiating Radiation Necrosis from Tumor Recurrence in Glioblastomas. AB - BACKGROUND AND PURPOSE: To compare the utility of quantitative PET/MRI, dynamic susceptibility contrast (DSC) perfusion MRI (pMRI), and PET/CT in differentiating radiation necrosis (RN) from tumor recurrence (TR) in patients with treated glioblastoma multiforme (GBM). METHODS: The study included 24 patients with GBM treated with surgery, radiotherapy, and temozolomide who presented with progression on imaging follow-up. All patients underwent PET/MRI and pMRI during a single examination. Additionally, 19 of 24 patients underwent PET/CT on the same day. Diagnosis was established by pathology in 17 of 24 and by clinical/radiologic consensus in 7 of 24. For the quantitative PET/MRI and PET/CT analysis, a region of interest (ROI) was drawn around each lesion and within the contralateral white matter. Lesion to contralateral white matter ratios for relative maximum, mean, and median were calculated. For pMRI, lesion ROI was drawn on the cerebral blood volume (CBV) maps and histogram metrics were calculated. Diagnostic performance for each metric was assessed using receiver operating characteristic curve analysis and area under curve (AUC) was calculated. RESULTS: In 24 patients, 28 lesions were identified. For PET/MRI, relative mean >= 1.31 resulted in AUC of .94 with both sensitivity and negative predictive values (NPVs) of 100%. For pMRI, CBV max >=3.32 yielded an AUC of .94 with both sensitivity and NPV measuring 100%. The joint model utilizing r-mean (PET/MRI) and CBV mode (pMRI) resulted in AUC of 1.0. CONCLUSION: Our study demonstrates that quantitative PET/MRI parameters in combination with DSC pMRI provide the best diagnostic utility in distinguishing RN from TR in treated GBMs. PMID- 28718994 TI - Hemifacial Microsomia in a Cat. AB - A 7-month-old domestic medium hair cat presented with facial asymmetry affecting the bony and soft tissue structures of the right side of the head including the maxilla, nose, eye and pinna of the ear. Additionally, neurological dysfunction of the facial and vestibulocochlear nerves on the affected side was present. A congenital malformation affecting the first and second embryologic pharyngeal arches was suspected. This is the first case of hemifacial microsomia of likely congenital origin reported in a cat. PMID- 28718995 TI - A systematic review of the prevalence and impact of urinary incontinence in cystic fibrosis. AB - This systematic review synthesizes published articles investigating the prevalence, severity and impact of urinary incontinence (UI), a condition associated with cystic fibrosis (CF). References were identified through searching Medline, Embase and PubMed using the medical subject headings 'cystic fibrosis' AND 'urinary incontinence'. Articles were included if UI prevalence was investigated as an outcome. Twelve studies met selection criteria. The prevalence of UI ranged from 5% to 76%. Age and gender contributed to this variability. When assessed, UI commonly limited airway clearance, exercise and/or spirometry, and had a variable impact on patients' lives. Worry and embarrassment were features for many; others were less affected. In CF, UI is common and can interfere with respiratory care and social well-being. The prevalence, characteristics and impact are poorly understood, which is made worse by inconsistent definitions across studies. Future research is needed to improve approaches to prevention, identification, management and education. PMID- 28718996 TI - Production of ligninolytic enzymes and some diffusible antifungal compounds by white-rot fungi using potato solid wastes as the sole nutrient source. AB - AIMS: The aim of this study was to evaluate the synthesis of ligninolytic enzymes and some diffusible antifungal compounds by white-rot fungi (WRF) using peels or discarded potato as the sole nutrient source. METHODS AND RESULTS: The strain Trametes hirsuta Ru-513 highlighted for its laccase activity (595 +/- 33 U l-1 ), which is able to decolourize 87% of an anthraquinone dye using potato peels as the sole nutritional support. A native polyacrylamide gel of laccase proteins showed the presence of two isoenzymes, corresponding to proteins of 56 and 67 kDa, which were detected by SDS-PAGE. The antifungal activity of ethyl acetate extracts was evaluated by the agar diffusion method, where Anthracophyllum discolor Sp4 and Inonotus sp. Sp2 showed the highest inhibition zones of Mucor miehei. The fungal extracts also inhibited Fusarium oxysporum and Botrytis cinerea growth, with inhibition zones of up to 18 mm. The extract with the highest antifungal activity, from A. discolor Sp4 grown in discarded potato medium, was analysed using a gas chromatograph coupled to a mass spectrometer. Among the identified compounds, chlorinated aromatic compounds and veratryl alcohol were the most abundant compounds. CONCLUSIONS: The results revealed the relevance of potato waste valorization for the sustainable production of ligninolytic enzymes and antifungal compounds. SIGNIFICANCE AND IMPACT OF THE STUDY: This study reports the synthesis of ligninolytic enzymes and diffusible antifungal compounds by WRF using potato wastes as the sole nutrient source and suggests a relationship between the enzymatic activity and the synthesis of antifungal compounds. These compounds and the synthesis of halogen compounds by WRF using agro-industrial wastes have been poorly studied before. PMID- 28718997 TI - Mesenchymal stem cell-derived factors: Immuno-modulatory effects and therapeutic potential. AB - Stem cell-based therapy is considered to be a new hope in transplantation medicine. Among stem cells, mesenchymal stem cells (MSCs) are, due to their differentiation and immuno-modulatory characteristics, the most commonly used as therapeutic agents in the treatment of immune-mediated diseases. MSCs migrate to the site of inflammation and modulate immune response. The capacity of MSC to alter phenotype and function of immune cells are largely due to the production of soluble factors which expression varies depending on the pathologic condition to which MSCs are exposed. Under inflammatory conditions, MSCs-derived factors suppress both innate and adaptive immunity by attenuating maturation and capacity for antigen presentation of dendritic cells, by inducing polarization of macrophages towards alternative phenotype, by inhibiting activation and proliferation of T and B lymphocytes and by reducing cytotoxicity of NK and NKT cells. In this review, we emphasized current findings regarding immuno-modulatory effects of MSC-derived factors and emphasize their potential in the therapy of immune-mediated diseases. (c) 2017 BioFactors, 43(5):633-644, 2017. PMID- 28718998 TI - Disconnected lives: Women with intellectual disabilities in conflict with the law. AB - BACKGROUND: Women with intellectual/developmental disabilities in conflict with the law experience childhood trauma, substance abuse and intimate partner violence but continue to have difficulty accessing appropriate therapeutic services, both within correctional settings and upon discharge. The aim of this study is to explore women's service needs and to critically assess whether the available services are meeting their identified needs. METHOD: Semi-structured interviews were conducted with 16 women with intellectual/developmental disabilities who were in the Special Needs Unit of a women's correctional centre from December 2014 to March 2015. RESULTS: Women with intellectual/developmental disabilities struggle to manage the impact of intergenerational trauma, exacerbated by issues of substance abuse and addiction, poor coping skills and minimal education, all of which impact their sense of well-being. CONCLUSIONS: This study highlights the need for increasing trauma treatment for women with intellectual/developmental disabilities, and emphasizes the need for accessible intervention to facilitate coping, trauma processing and community integration. PMID- 28719000 TI - ZC3H12A/MCPIP1/Regnase-1-related endonucleases: An evolutionary perspective on molecular mechanisms and biological functions. AB - The mammalian Zc3h12a/MCPIP1/Regnase-1, an extensively studied regulator of inflammatory response, is the founding member of a ribonuclease family, which includes proteins related by the presence of the so-called Zc3h12a-like NYN domain. Recently, several related proteins have been described in Caenorhabditis elegans, allowing comparative evaluation of molecular functions and biological roles of these ribonucleases. We discuss the structural features of these proteins, which endow some members with ribonuclease (RNase) activity while others with auxiliary or RNA-independent functions. We also consider their RNA specificity and highlight a common role for these proteins in cellular defense, which is remarkable considering the evolutionary distance and fundamental differences in cellular defense mechanisms between mammals and nematodes. PMID- 28718999 TI - Resilience is decreased in irritable bowel syndrome and associated with symptoms and cortisol response. AB - BACKGROUND: Irritable bowel syndrome (IBS) is a stress-sensitive disorder associated with early adverse life events (EALs) and a dysregulated hypothalamic pituitary-adrenal (HPA) axis. Resilience is the ability to recover and adapt positively to stress but has not been well studied in IBS. The aims of this study are to compare resilience in IBS and healthy controls (HCs) and to assess its relationships with IBS symptom severity, quality of life (QOL), EALs, and HPA axis response. METHODS: Two hundred fifty-six subjects (154 IBS, 102 HCs) completed questionnaires for resilience (Connor-Davidson Resilience Scale [CD RISC] and Brief Resilience Scale [BRS]), IBS symptoms, IBS-QOL, and EALs. Ninety six of these subjects had serial serum adrenocorticotropic hormone (ACTH) and cortisol levels to exogenous corticotrophin-releasing hormone (CRH) and ACTH measured. The relationship between IBS status, resilience, and other variables of interest was assessed by regression analysis after adjusting for demographics and neuroticism, a predictor of resilience. KEY RESULTS: Resilience was significantly lower in IBS compared to HCs (CD-RISC: 72.16+/-14.97 vs 77.32+/-12.73, P=.003; BRS: 3.29+/-0.87 vs 3.93+/-0.69, P<.001); however, only BRS was significant after controlling for neuroticism (P=.001). Lower BRS scores were associated with greater IBS symptom severity (P=.002), poorer IBS-QOL (P<.001), and a higher number of EALs (P=.01). There was a significant interaction between BRS resilience and IBS status for ACTH-stimulated cortisol response (P=.031); more resilient IBS subjects had lower cortisol response, and more resilient HCs had higher cortisol response. CONCLUSIONS AND INFERENCES: Lower resilience is associated with IBS status, worse IBS symptom severity, lower IBS-QOL, greater EALs, and stress hyperresponsiveness. PMID- 28719001 TI - Arthur C. Cope Scholar Awards. PMID- 28719002 TI - EyeSLAM: Real-time simultaneous localization and mapping of retinal vessels during intraocular microsurgery. AB - BACKGROUND: Fast and accurate mapping and localization of the retinal vasculature is critical to increasing the effectiveness and clinical utility of robot assisted intraocular microsurgery such as laser photocoagulation and retinal vessel cannulation. METHODS: The proposed EyeSLAM algorithm delivers 30 Hz real time simultaneous localization and mapping of the human retina and vasculature during intraocular surgery, combining fast vessel detection with 2D scan-matching techniques to build and localize a probabilistic map of the vasculature. RESULTS: In the harsh imaging environment of retinal surgery with high magnification, quick shaky motions, textureless retina background, variable lighting and tool occlusion, EyeSLAM can map 75% of the vessels within two seconds of initialization and localize the retina in real time with a root mean squared (RMS) error of under 5.0 pixels (translation) and 1 degrees (rotation). CONCLUSIONS: EyeSLAM robustly provides retinal maps and registration that enable intelligent surgical micromanipulators to aid surgeons in simulated retinal vessel tracing and photocoagulation tasks. PMID- 28719004 TI - Development of New Supramolecular Lyotropic Liquid Crystals and Their Application as Alignment Media for Organic Compounds. AB - Most alignment media for the residual dipolar coupling (RDC) based molecular structure determination of small organic compounds consist of rod-like polymers dissolved in organic solvents or of swollen cross-linked polymer gels. Thus far, the synthesis of polymer-based alignment media has been a challenging process, which is often followed by a time-consuming sample preparation. We herein propose the use of non-polymeric alignment media based on benzenetricarboxamides (BTAs), which self-assemble into rod-like supramolecules. Our newly found supramolecular lyotropic liquid crystals (LLCs) are studied in terms of their LLC properties and their suitability as alignment media in NMR spectroscopy. Scalable enantiodifferentiating properties are introduced through a sergeant-and-soldier principle by blending achiral with chiral substituted BTAs. PMID- 28719005 TI - Quantitative structure-reactivity relationships of hydroxyl radical rate constants for linear and cyclic volatile methylsiloxanes. AB - An accurate understanding of the fate of volatile methylsiloxanes (VMS) in air is crucial for determining their persistence and concentrations in the environment. Although oxidation by atmospheric hydroxyl radicals (*OH) is considered as a major degradation mechanism for airborne VMS, the existing bimolecular rate constants with *OH measured and modeled for any given VMS compound varied greatly, depending on the approaches used to generate the data. The objectives of the present study were to measure *OH reaction rate constants for 4 cyclic and 4 linear VMS based on a relative rate method using a newly designed atmospheric chamber and to establish structure-reactivity relationships for the kinetics. In the past, the reaction rate constants for VMS were generally recognized to increase with the number of the methyl groups per molecule, the only differential factor in the existing models. However, the new measurements indicated that molecular structure should also be considered in the prediction of the reaction rates. Better empirical models were developed by simple and multiple linear regressions of the measured values from the present study and the literature. A high correlation existed for the reaction rates with the number of the methyl group attached at 2 distinct siloxane structures (i.e., linear and cyclic VMS). Even better correlations were obtained with one or 2 molecular descriptors that are directly related to the size of VMS, which, in turn, not only depend on the number of methyl groups, but the linear/cyclic structures as well for permethylsiloxanes. Environ Toxicol Chem 2017;36:3240-3245. (c) 2017 SETAC. PMID- 28719006 TI - Relative exchangeable copper: A valuable tool for the diagnosis of Wilson disease. AB - BACKGROUND & AIMS: Measuring of the relative exchangeable copper seems to be a promising tool for the diagnosis of Wilson disease. The aim of our study is to determine the performance of REC for the diagnosis of Wilson disease in a population of patients with chronic liver diseases. METHODS: Measuring of exchangeable serum copper levels and relative exchangeable copper was performed in a group of Wilson disease patients at diagnosis or at clinical deterioration because of non-compliance (group 1, n=9), a group of stable WD patients (group 2, n=40), and two groups of patients (adult and paediatric) followed for non Wilsonian liver diseases (group 3, n=103 and group 4, n=49 respectively). RESULTS: Exchangeable serum copper (N: 0.6-1.1 MUmol/L) was significantly higher in group 1 (mean 2.2+/-0.7 MUmol/L) compared to the other three groups: group 2=0.9+/-0.4 MUmol/L, group 3=1.2+/-0.4 MUmol/L, group 4=1.1+/-0.3 MUmol/L (P<0.05). Relative exchangeable copper was significantly higher in Wilson disease patients group 1 and 2 (mean 52.6% and 43.8%) compared to patients suffering from other liver diseases (mean 7.1% and 5.9%) (P<0.05). CONCLUSIONS: Our study confirms that the determination of relative exchangeable copper is a highly valuable tool for the diagnosis of Wilson disease. PMID- 28719003 TI - Mutation intolerant genes and targets of FMRP are enriched for nonsynonymous alleles in schizophrenia. AB - Risk of schizophrenia is conferred by alleles occurring across the full spectrum of frequencies from common SNPs of weak effect through to ultra rare alleles, some of which may be moderately to highly penetrant. Previous studies have suggested that some of the risk of schizophrenia is attributable to uncommon alleles represented on Illumina exome arrays. Here, we present the largest study of exomic variation in schizophrenia to date, using samples from the United Kingdom and Sweden (10,011 schizophrenia cases and 13,791 controls). Single variants, genes, and gene sets were analyzed for association with schizophrenia. No single variant or gene reached genome-wide significance. Among candidate gene sets, we found significant enrichment for rare alleles (minor allele frequency [MAF] < 0.001) in genes intolerant of loss-of-function (LoF) variation and in genes whose messenger RNAs bind to fragile X mental retardation protein (FMRP). We further delineate the genetic architecture of schizophrenia by excluding a role for uncommon exomic variants (0.01 <= MAF >= 0.001) that confer a relatively large effect (odds ratio [OR] > 4). We also show risk alleles within this frequency range exist, but confer smaller effects and should be identified by larger studies. PMID- 28719007 TI - Validating activity indices from camera traps for commensal rodents and other wildlife in and around farm buildings. AB - BACKGROUND: Indices of rodent activity are used as indicators of population change during field evaluation of rodenticides. We investigated the potential for using camera traps to determine activity indices for commensal rodents living in and around farm buildings, and sought to compare these indices against previously calibrated survey methods. RESULTS: We recorded 41 263 images of 23 species, including Norway rats (Rattus norvegicus Berk.) and house mice (Mus musculus L.). We found a positive correlation between activity indices from camera traps and activity indices from a method (footprint tracking) previously shown to have a linear relationship with population size for Norway rats. Filtering the camera trap data to simulate a 30-s delay between camera trigger events removed 59.9% of data and did not adversely affect the correlation between activity indices from camera traps and footprint tracking. The relationship between activity indices from footprint tracking and Norway rat population size is known from a previous study; from this, we determined the relationship between activity indices from camera traps and population size for Norway rats living in and around farm buildings. CONCLUSION: Systematic use of camera traps was used to determine activity indices for Norway rats living in and around farm buildings; the activity indices were positively correlated with those derived from a method previously calibrated against known population size for this species in this context. (c) 2017 Crown copyright. Pest Management Science (c) 2017 Society of Chemical Industry. PMID- 28719008 TI - Comparative efficacy and safety of gemigliptin versus linagliptin in type 2 diabetes patients with renal impairment: A 40-week extension of the GUARD randomized study. AB - AIMS: The long-term safety and efficacy of gemigliptin was evaluated in the present extension study after a 12-week study during a 40-week follow-up period. METHODS: The main study was a randomized, placebo-controlled, double-blinded, phase IIIb study in which 50 mg of gemigliptin (N = 66) or placebo (N = 66) was administered to patients with type 2 diabetes mellitus (T2DM) and moderate or severe renal impairment over a 12-week period. Patients with a glycated haemoglobin (HbA1c) level of 7% to 11% and an estimated glomerular filtration rate (eGFR) of 15 to 59 mL/min/1.73 m2 were enrolled in the main study. After 12 weeks, patients in the gemigliptin group continued to receive gemigliptin (N = 50), whereas patients in the placebo group were transitioned from placebo to linagliptin (N = 52). Each group received the indicated treatment over the subsequent 40-week period. A total of 102 patients consented to participate in the extension study, and 79 patients ultimately completed the study. RESULTS: The HbA1c levels of both groups were significantly reduced at week 52 compared with baseline. Specifically, the adjusted mean change +/- standard error in HbA1c level in the gemigliptin and placebo/linagliptin groups was 1.00% +/- 0.21% and 0.65% +/- 0.22% lower at week 52 than at baseline (P < .001 and P = .003), respectively. No significant difference in the change in HbA1c level was found between the 2 groups (P = .148). Trends in fasting plasma glucose, fructosamine and glycated albumin levels in the 2 groups were similar to trends in HbA1c levels. The eGFR of both groups was also significantly lower at week 52 than at baseline, and no significant difference in change in eGFR was found between the 2 groups. In contrast, both drugs had little effect on urinary albumin excretion, although both drugs significantly reduced the urinary type IV collagen level. The overall rates of adverse events were similar between the 2 groups. CONCLUSIONS: Gemigliptin and linagliptin did not differ with respect to safety and efficacy in patients with T2DM and renal impairment. The 2 drugs had similar glucose-lowering effects, and the changes in eGFR and albuminuria were also similar. Additionally, the risk of side effects, including hypoglycaemia, was similar between the 2 groups. PMID- 28719009 TI - Diagnosis of chronic heart failure by the soluble suppression of tumorigenicity 2 and N-terminal pro-brain natriuretic peptide. AB - OBJECTIVE: Our study was to explore the roles between serum soluble suppression of tumorigenicity 2 (sST2) and N-terminal pro-brain natriuretic peptide (NT proBNP) while evaluating ventricular function to properly diagnose chronic heart failure (CHF). METHODS: In total, 197 CHF patients were recruited and classified into ventricular function's II, III, and IV groups, and 106 healthy people into normal control group. To detect concentrations of Sst2 and NT-proBNP, ELISA and electro-chemiluminescence immuno assay were implemented. An automatic biochemical analyzer was used to determine the levels of the following: blood urea nitrogen (BUN), creatinine (Cr), alanine aminotransferase (ALT), triglyceride (TG), high density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL C), and uric acid (UA). A receiver operating characteristic (ROC) curve was adopted to detect the diagnostic value sST2 and NT-ProBNP in CHF and the logistic regression analysis involving the risk factors of CHF. RESULTS: Serum sST2 and NT proBNP concentrations were increased significantly in the ventricular function's II, III, and IV groups in a manner dependent on concentration as opposed to the manner the normal control group occupied. The area under the curve (AUC) of sST2, found NT-proBNP and sST2+NT-proBNP to be 0.942 (95% CI: 0.917-0.966), 0.920 (95% CI: 0.891-0.948), and 0.968 (95% CI: 0.953-0.984), respectively. sST2, NT-proBNP, UA, and Cr were verified as important risk factors of CHF. CONCLUSION: Serum sST2 and NT-ProBNP could act as diagnostic indicators for CHF. PMID- 28719011 TI - From the Editors. PMID- 28719012 TI - The impact of immunoglobulin in acute HIV infection on the HIV reservoir: a randomized controlled trial. AB - OBJECTIVES: Antiretroviral therapy (ART) during acute HIV infection (AHI) restricts the HIV reservoir, but additional interventions are necessary to induce a cure. Intravenous immunoglobulin (IVIG) is not HIV-specific but is safe and temporarily reduces the HIV reservoir in chronic HIV infection. We present a randomized controlled trial to investigate whether IVIG plus ART in AHI reduces the HIV reservoir and immune activation compared with ART alone. METHODS: Ten men with AHI (Fiebig II-IV) initiated ART (tenofovir, entricitabine, ritonavir boosted darunavir and raltegravir) at HIV-1 diagnosis and were randomized to ART alone or ART plus 5 days of IVIG, once virally suppressed (week 19). Blood samples were evaluated for viral reservoir, immune activation, immune exhaustion and microbial translocation. Flexible sigmoidoscopy was performed at weeks 19, 24 and 48, and gut proviral DNA and cell numbers determined. RESULTS: IVIG was well tolerated and no viral blips (> 50 HIV-1 RNA copies/mL) occurred during IVIG therapy. From baseline to week 48, total HIV DNA in peripheral blood mononuclear cells (PBMCs) (cases: -3.7 log10 copies/106 CD4 cells; controls: -3.87 log10 copies/106 CD4 cells) declined with no differences observed between the groups (P = 0.49). Declines were observed in both groups from week 19 to week 48 in total HIV DNA in PBMCs (P = 0.38), serum low copy RNA (P = 0.57) and gut total HIV DNA (P = 0.55), but again there were no significant differences between arms. Biomarkers of immune activation, immune exhaustion and microbial translocation and the CD4:CD8 ratio were similar between arms for all comparisons. CONCLUSIONS: Although safe, IVIG in AHI did not impact total HIV DNA, immune function or microbial translocation in peripheral blood or gut tissue. PMID- 28719013 TI - In an era of highly effective treatment, hepatitis C screening of the United States general population should be considered. AB - BACKGROUND & AIMS: Hepatitis C virus (HCV) treatment with all oral direct acting antiviral agents (DAA's) achieve sustained virologic response (SVR) rates of 98%. Re-assessment of general US population screening for HCV is imperative. This study compared the cost-effectiveness (CE) of three HCV screening strategies: screen all (SA), screen Birth Cohort (BCS), and screen high risks (HRS). METHODS: Using a previous designed decision-analytic Markov model, estimations of the natural history of HCV and CE evaluation of the three HCV screening strategies over a lifetime horizon in the US population was undertaken. Based on age and risk status, 16 cohorts were modelled. Health states included: Fibrosis stages 0 to 4, decompensated cirrhosis, hepatocellular carcinoma, LT, post-LT, and death. The probability of liver disease progression was based on the presence or absence of virus. Treatment was with approved all-oral DAAs; 86% were assumed to be seen annually by a primary care provider; SVR rates, transition probabilities, utilities, and costs were from the literature. One-way sensitivity analyses tested the impact of key model drivers. RESULTS: SA cost $272.0 billion [$135 279 per patient] and led to 12.19 QALYs per patient. BCS and HRS cost $274.5 billion ($136 568 per patient) and $284.5 billion ($141 502 per patient) with 11.65 and 11.25 QALYs per patient respectively. Compared to BCS, SA led to an additional 0.54 QALYs per patient and saved $2.59 billion; compared to HRS, SA led to 0.95 additional QALYs per patient and saved $12.5 billion. CONCLUSIONS: Screening the entire US population and treating active viraemia was projected as cost-saving. PMID- 28719014 TI - Bioavailability and tolerability of nebulised dexamethasone sodium phosphate in adult horses. AB - BACKGROUND: Nebulisation of the injectable dexamethasone sodium phosphate (DSP) would offer an inexpensive way of delivering a potent corticosteroid directly to the lungs of horses with asthma. However, this approach would be advantageous only if systemic absorption is minimal and if the preservatives present in the formulation do not induce airway inflammation. OBJECTIVE: To investigate the bioavailability of nebulised DSP and determine whether it induces airway inflammation or hypothalamic-pituitary-adrenal (HPA) axis suppression in healthy adult horses. STUDY DESIGN: Randomised crossover experiment. METHODS: Dexamethasone sodium phosphate was administered to six healthy adult horses at a dose of 5 mg q. 24 h for 5 days via nebulised, or intravenous (i.v.) routes. Plasma dexamethasone concentrations were measured by UPLC/MS-MS to calculate bioavailability. Cytological examination of bronchoalveolar fluid was performed at baseline and after the last dose of DSP. A validated chemiluminescent immunoassay was used to measure basal serum cortisol concentrations. RESULTS: After nebulisation to adult horses, dexamethasone had a mean (+/-s.d.) maximum plasma concentration of 0.774 +/- 0.215 ng/mL and systemic bioavailability of 4.3 +/- 1.2%. Regardless of route of administration, there was a significant decrease in the percentage of neutrophils in bronchoalveolar lavage fluid over time. During i.v. administration, basal serum cortisol concentration decreased significantly from baseline to Day 3 and remained low on Day 5. In contrast, basal serum cortisol concentration did not change significantly during administration via nebulisation. MAIN LIMITATIONS: Small sample size and short period of drug administration. CONCLUSIONS: Dexamethasone sodium phosphate administered via nebulisation had minimal systemic bioavailability and did not induce lower airway inflammation or HPA axis suppression in healthy horses. PMID- 28719015 TI - Bisphenol A induced oxidative stress and apoptosis in mice testes: Modulation by selenium. AB - Spermatogenesis, a highly coordinated process, is prone to environmental insults which may lead to impaired spermatogenesis or, at worst, infertility. Bisphenol A (BPA) is a well-known global environmental toxicant and a ubiquitous oestrogenic chemical. This study evaluated the role of selenium (0.5 ppm sodium selenite/kg diet) on spermatogenesis after BPA treatment in different groups of male BALB/c mice: control, selenium, BPA and selenium+BPA. Markers of oxidative stress and apoptosis were evaluated in testis after BPA treatment. Significant decrease in sperm concentration and motility and increased reactive oxygen species(ROS) and LPO levels were seen in BPA group. Histopathological changes revealed extensive vacuolisation, lumen devoid of spermatozoa and decreased germ cell count, confirmed by testicular germ cell count studies. TUNEL assay for apoptosis showed increased number of TUNEL-positive germ cells in BPA group with increased percentage apoptotic index. However, in Se+BPA group, histopathological studies revealed systematic array of all germ cells, preserved basement membrane with relatively less vacuolisation, improved sperm parameters and ROS and LPO levels and decreased number of TUNEL-positive germ cells. These results clearly demonstrate the role of selenium in ameliorating oxidative stress and apoptosis induced upon BPA treatment in mice and can be further used as therapeutic target in male infertility. PMID- 28719016 TI - Insecticide resistance of adults and nymphs of Asian citrus psyllid populations from Apatzingan Valley, Mexico. AB - BACKGROUND: Control of the Asian citrus psyllid Diaphorina citri Kuwayama, the most important pest of citrus worldwide, is based on the use of insecticides, though unsatisfactory results have recently been reported. In this study, insecticide resistance of D. citri to three insecticides (bifenthrin, malathion, and chlorpyrifos) was examined. RESULTS: Three populations (designated Dci CParacuaro, Dci-El Junco, and Dci-Antunez) of both adults and fourth-instar D. citri individuals were collected in 2014 at two different times and on one occasion, respectively, from three locations (Crucero de Paracuaro, El Junco, and Antunez). These locations represent the major commercial Mexican lemon production areas in the Apatzingan Valley in the state of Michoacan, Mexico. The three populations of D. citri adults and fourth-instar nymphs at the different collection times showed low levels of resistance (<=7-fold) to bifenthrin, but were very resistant to malathion (<=345- and <=432-fold for adults and fourth instars, respectively) and chlorpyrifos (<=2435- and <=1424-fold for adults and fourth instars, respectively). CONCLUSION: Resistance levels to the tested insecticides were highly variable but homogeneous among seasons and localities. Resistance management programmes that include crop sanitation, use of biological and cultural control practices, and rotation of insecticide classes should be established, particularly in areas where D. citri has developed resistance to malathion and chlorpyrifos. (c) 2017 Society of Chemical Industry. PMID- 28719017 TI - Contrasting sirtuin and poly(ADP-ribose)polymerase activities of selected 2,4,6 trisubstituted benzimidazoles. AB - Both sirtuin and poly(ADP-ribose)polymerase (PARP) family of enzymes utilize NAD+ as co-substrate. Inhibitors of sirtuins and PARPs are important tools in drug discovery as they are reported to be linked to multiple diseases such as cancer. New potent sirtuin inhibitors (2,4,6-trisubstituted benzimidazole) were discovered from reported PARP inhibitor scaffold. Interestingly, the synthesized compounds have contrasting sirtuin and PARP-1 inhibitory activities. We showed that modification on benzimidazoles may alter their selectivity toward sirtuin or PARP-1 enzymes. This offers an opportunity for further discovery and development of new promising sirtuin inhibitors. Molecular docking studies were carried out to aid the rationalization of these observations. Preliminary antiproliferative studies of selected compounds against nasopharyngeal cancer cells also showed relatively promising results. PMID- 28719018 TI - Ante mortem cerebrospinal fluid tau levels correlate with postmortem tau pathology in frontotemporal lobar degeneration. AB - OBJECTIVE: To test the hypotheses that (1) antemortem cerebrospinal fluid (CSF) tau levels correlate with postmortem tau pathology in frontotemporal lobar degeneration (FTLD) and (2) tauopathy patients have higher phosphorylated-tau levels compared to transactivation response element DNA-binding protein 43 (TDP 43) proteinopathy patients while accounting for Alzheimer's disease (AD) copathology. METHODS: Patients had autopsy-confirmed FTLD with tauopathy (n = 31), TDP-43 proteinopathy (n = 49), or AD (n = 26) with antemortem CSF. CSF tau levels were compared between groups and correlated with digital histology measurement of postmortem tau pathology averaged from three cerebral regions (angular gyrus, mid-frontal cortex, and anterior cingulate gyrus). Multivariate linear regression tested the association of ante mortem CSF tau levels with postmortem tau pathology adjusting for demographics. RESULTS: Multivariate regression found an independent association of ante mortem CSF phosphorylated tau levels with postmortem cerebral tau pathology in FTLD (Beta = 1.3; 95% confidence interval = 0.2-2.4; p < 0.02). After excluding patients with coincident AD associated tau pathology accompanying sporadic FTLD, we found lower CSF phosphorylated tau levels in the TDP-43 group (median = 7.4pg/ml; interquartile range [IQR] = 6.0, 12.3; n = 26) compared to the tauopathy group (median = 12.5pg/ml; IQR = 10.7, 15.0; n = 23; Z = 2.6; p < 0.01). INTERPRETATION: CSF phosphorylated-tau levels are positively associated with cerebral tau burden in FTLD. In vivo detection of AD copathology in sporadic FTLD patients may help stratify clinical cohorts with pure neuropathology in which low CSF phosphorylated-tau levels may have diagnostic utility to distinguish TDP-43 proteinopathy from tauopathy. Autopsy-confirmed samples are critical for FTLD biomarker development and validation. Ann Neurol 2017;82:247-258. PMID- 28719019 TI - Initial testing of a pixelated silicon detector prototype in proton therapy. AB - As technology continues to develop, external beam radiation therapy is being employed, with increased conformity, to treat smaller targets. As this occurs, the dosimetry methods and tools employed to quantify these fields for treatment also have to evolve to provide increased spatial resolution. The team at the University of Wollongong has developed a pixelated silicon detector prototype known as the dose magnifying glass (DMG) for real-time small-field metrology. This device has been tested in photon fields and IMRT. The purpose of this work was to conduct the initial performance tests with proton radiation, using beam energies and modulations typically associated with proton radiosurgery. Depth dose and lateral beam profiles were measured and compared with those collected using a PTW parallel-plate ionization chamber, a PTW proton-specific dosimetry diode, EBT3 Gafchromic film, and Monte Carlo simulations. Measurements of the depth dose profile yielded good agreement when compared with Monte Carlo, diode and ionization chamber. Bragg peak location was measured accurately by the DMG by scanning along the depth dose profile, and the relative response of the DMG at the center of modulation was within 2.5% of that for the PTW dosimetry diode for all energy and modulation combinations tested. Real-time beam profile measurements of a 5 mm 127 MeV proton beam also yielded FWHM and FW90 within +/-1 channel (0.1 mm) of the Monte Carlo and EBT3 film data across all depths tested. The DMG tested here proved to be a useful device at measuring depth dose profiles in proton therapy with a stable response across the entire proton spread-out Bragg peak. In addition, the linear array of small sensitive volumes allowed for accurate point and high spatial resolution one-dimensional profile measurements of small radiation fields in real time to be completed with minimal impact from partial volume averaging. PMID- 28719020 TI - Fibrin(ogen) and neurodegeneration in the progressive multiple sclerosis cortex. AB - OBJECTIVE: Neuronal loss, a key substrate of irreversible disability in multiple sclerosis (MS), is a recognized feature of MS cortical pathology of which the cause remains unknown. Fibrin(ogen) deposition is neurotoxic in animal models of MS, but has not been evaluated in human progressive MS cortex. The aim of this study was to investigate the extent and distribution of fibrin(ogen) in progressive MS cortex and elucidate its relationship with neurodegeneration. METHODS: A postmortem cohort of pathologically confirmed MS (n = 47) and control (n = 10) cases was used. The extent and distribution of fibrin(ogen) was assessed and related to measures of demyelination, inflammation, and neuronal density. In a subset of cases (MS, n = 20; control, n = 10), expression of plasminogen activator inhibitor 1 (PAI-1), a key enzyme in the fibrinolytic cascade, was assessed and related to the extent of fibrin(ogen). RESULTS: Motor cortical fibrin(ogen) deposition was significantly over-represented in MS compared to control cases in all compartments studied (ie, extracellular [p = 0.001], cell body [p = 0.003], and neuritic/glial-processes [p = 0.004]). MS cases with high levels of extracellular fibrin(ogen) had significantly upregulated PAI-1 expression in all cortical layers assessed (p < 0.05) and reduced neuronal density (p = 0.017), including in the functionally-relevant layer 5 (p = 0.001). INTERPRETATION: For the first time, we provide unequivocal evidence that fibrin(ogen) is extensively deposited in progressive MS motor cortex, where regulation of fibrinolysis appears perturbed. Progressive MS cases with severe fibrin(ogen) deposition have significantly reduced neuronal density. Future studies are needed to elucidate the provenance and putative neurotoxicity of fibrin(ogen), and its potential impact on clinical disability. Ann Neurol 2017;82:259-270. PMID- 28719021 TI - High-Temperature Ionic Epitaxy of Halide Perovskite Thin Film and the Hidden Carrier Dynamics. AB - High-temperature vapor phase epitaxy (VPE) has been proved ubiquitously powerful in enabling high-performance electro-optic devices in III-V semiconductor field. A typical example is the successful growth of p-type GaN by VPE for blue light emitting diodes. VPE excels as it controls film defects such as point/interface defects and grain boundary, thanks to its high-temperature processing condition and controllable deposition rate. For the first time, single-crystalline high temperature VPE halide perovskite thin film has been demonstrated-a unique platform on unveiling previously uncovered carrier dynamics in inorganic halide perovskites. Toward wafer-scale epitaxial and grain boundary-free film is grown with alkali halides as substrates. It is shown the metal alkali halides could be used as universal substrates for VPE growth of perovskite due to their similar material chemistry and lattice constant. With VPE, hot photoluminescence and nanosecond photo-Dember effect are revealed in inorganic halide perovskite. These two phenomena suggest that inorganic halide perovskite could be as compelling as its organic-inorganic counterpart regarding optoelectronic properties and help explain the long carrier lifetime in halide perovskite. The findings suggest a new avenue on developing high-quality large-scale single-crystalline halide perovskite films requiring precise control of defects and morphology. PMID- 28719022 TI - Engineering the Surface of Smart Nanocarriers Using a pH-/Thermal-/GSH-Responsive Polymer Zipper for Precise Tumor Targeting Therapy In Vivo. AB - Nanocarrier surface chemistry plays a vital role in mediating cell internalization and enhancing delivery efficiency during in vivo chemotherapy. Inspired by the ability of proteins to alter their conformation to mediate functions, a pH-/thermal-/glutathione-responsive polymer zipper consisting of cell-penetrating poly(disulfide)s and thermosensitive polymers bearing guanidinium/phosphate (Gu+ /pY- ) motifs to spatiotemporally tune the surface composition of nanocarriers for precise tumor targeting and efficient drug delivery is developed. Surface engineering allows the nanocarriers to remain undetected during blood circulation and favors passive accumulation at tumor sites, where the acidic microenvironment and photothermal heating break the pY- /Gu+ binding and rupture the zipper, thereby exposing the penetrating shell and causing enhanced cellular uptake via counterion-/thiol-/receptor-mediated endocytosis. The in vivo study demonstrates that by manipulating the surface states on command, the nanocarriers show longer blood circulation time, minimized uptake and drug leakage in normal organs, and enhanced accumulation and efficient drug release at tumor sites, greatly inhibiting tumor growth with only slight damage to normal tissues. If integrated with a photothermal dye approved by the U.S. Food and Drug Administration (FDA), polymer zipper would provide a versatile protocol for engineering nanomedicines with high selectivity and efficiency for clinical cancer treatment. PMID- 28719023 TI - Identification of odorant-binding and chemosensory protein genes and the ligand affinity of two of the encoded proteins suggest a complex olfactory perception system in Periplaneta americana. AB - The American cockroach (Periplaneta americana) is an urban pest with a precise chemosensory system that helps it achieve complex physiological behaviours, including locating food and mating. However, its chemosensory mechanisms have not been well studied. Here, we identified 71 putative odorant carrier protein genes in P. americana, including 57 new odorant-binding proteins (OBPs) and 11 chemosensory proteins (CSPs). To identify their physiological functions, we investigated their tissue expression patterns in antennae, mouthparts, legs, and the remainder of the body of both sexes, and determined that most of these genes were expressed in chemosensory organs. A phylogenetic tree showed that the putative pheromone-binding proteins of P. americana were in different clades from those of moths. Two genes, PameOBP24 and PameCSP7, were expressed equally in antennae of both sexes and highly expressed amongst the OBPs and CSPs. These genes were expressed in Escherichia coli and the resultant proteins were purified. The binding affinities of 74 common odorant compounds were tested with recombinant PameOBP24 and PameCSP7. Both proteins bound a variety of ligands. Our findings provide a foundation for future research into the chemosensory mechanisms of P. americana and help in identifying potential target genes for managing this pest. PMID- 28719024 TI - The immunoproteasome: An old player with a novel and emerging role in alloimmunity. AB - Modern treatment strategies for the maintenance of allograft acceptance frequently target ubiquitously-expressed pathways, leading to significant side effects and poor long-term allograft outcomes. Constitutive proteasome inhibitors, which have recently been introduced for the treatment of antibody mediated rejection, target the ubiquitously-expressed proteasome. To limit off target effects and serious mechanism-based toxicity, however, these inhibitors are administered intermittently and suboptimally. Immunoproteasomes, which are an inducible subset of proteasomes enriched in immune cells, replace constitutive proteasomes after cell exposure to proinflammatory cytokines such as interferon gamma. While immunoproteasomes were first described as processors of antigen for presentation by major histocompatibility complex molecules, recent findings point to its broader biological roles. These vary from activating different subsets of the immune system, by controlling transcriptional activators and downstream cytokines, to affecting their differentiation and survival. These emerging roles of the immunoproteasome in activated immune cells have made it a rational candidate for the targeted treatment of immune-mediated diseases. Preclinical studies have established its role in maintaining allograft acceptance without significant short- or long-term toxicity. This review provides a brief background of the immunoproteasome and outlines its role in immunological pathways and its potential in alloimmunity. PMID- 28719025 TI - Frequency, risk factors, and outcomes of central nervous system relapse in lymphoma patients treated with dose-adjusted EPOCH plus rituximab. AB - BACKGROUND: Central nervous system (CNS) relapse in non-Hodgkin lymphoma (NHL) is a rare but serious complication that carries a poor prognosis. The use of infusional etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (EPOCH-R) for frontline treatment of diffuse large B cell lymphoma (DLBCL) is increasing, though little is known about incidence of and risk factors for CNS relapse with this regimen PATIENTS AND METHODS: We completed a chart review of patients with NHL who received EPOCH-R as front line therapy. Data obtained included baseline and treatment characteristics including if patients received CNS directed therapy. We measured overall survival (OS), progression free survival (PFS), and progression to CNS involvement. RESULTS: We identified 223 patients who met the inclusion criteria, 72% had DLBCL. Of all the patients, 5.8% experienced CNS relapse, and 38.6% were treated with CNS prophylaxis. There was no difference in rate of CNS relapse, OS, or PFS between patients who had and had not received CNS prophylaxis. Patients whose serum lactate dehydrogenase was greater than twice the upper limit of normal at diagnosis and those with extranodal disease were significantly more likely to have CNS relapse (P = .0247 and 0.022, respectively) than their counterparts. CONCLUSIONS: The rate of CNS relapse in this patient population approaches 6%, not significantly different from reports on those receiving R-CHOP. The results of this study suggest that CNS prophylaxis might be more selectively used among patients treated with EPOCH R with certain high-risk features. PMID- 28719026 TI - In vitro Antiproliferative and Antibacterial Activities of Essential Oils from Four Species of Guatteria. AB - The essential oils (EOs) extracted from four species of the genus Guatteria, G. australis, G. ferruginea, G. latifolia, and G. sellowiana were analyzed. A total of 24, 22, 25, and 19 constituents of the oils from four species, respectively, were identified by GC/MS. These oils showed qualitative and quantitative differences. All the oils contained the oxygenated sesquiterpenes spathulenol (11.04 - 40.29%) and caryophyllene oxide (7.74 - 40.13%) as predominant constituents. Evaluation of antiproliferative activity of the EOs showed strong selectivity (1.1 - 4.1 MUg/ml) against the tumor cell line OVCAR-03 (ovarian cancer), i.e., more active than the positive control doxorubicin (11.7 MUg/ml). All EOs showed strong antibacterial activity (minimum inhibitory concentrations of 0.062 - 0.25 mg/ml) against strains of Rhodococcus equi. PMID- 28719027 TI - Marker of coxsackievirus-B4 infection in saliva of patients with type 1 diabetes. AB - BACKGROUND: Coxsackieviruses B (CV-B) are enteroviruses that have been reported to play a role in the pathogenesis of type 1 diabetes. Enteroviral RNA was detected in the gut mucosa of patients. The mucosal immunity is an interconnected network; therefore, the response to enteroviruses possibly present in the gastrointestinal mucosa can be reflected by specific antibodies in the saliva. In the present study, the anti-CV-B neutralizing activity of saliva samples from patients with type 1 diabetes was investigated. METHODS: Saliva samples were collected from patients and controls of 3 countries, and plasma was obtained from some of them. The anti-CV-B activity of clinical samples was determined by neutralization of the cytopathic effect induced by challenging viruses in vitro and expressed as titre value. RESULTS: Overall prevalence and levels of anti-CV B4 activity of saliva were higher in patients (n = 181) than in controls (n = 135; P = .0002; titre values >= 16: odds ratio = 4.22 95% CI: 1.90-9.38 P = .0002). It has been shown that IgA1 played a role in this activity. There was no correlation between the saliva and the plasma anti-CV-B4 neutralizing activity. The neutralizing activity of saliva against CV-B1, CV-B2, CV-B3, and CV-B5 existed rarely, if at all. Increased levels of anti-CV-B4 activity were observed all along a 4 year follow-up period in patients but not in matched controls (P = .01). CONCLUSION: There is an anti-CV-B4 activity in saliva of patients with type 1 diabetes that may be a useful marker to study the role of CV-B in the pathogenesis of the disease. PMID- 28719028 TI - Sales performance and athletic outcome in young Thoroughbreds with pericarditis. AB - BACKGROUND: Pericarditis is a sporadic, but important cause of critical illness in horses of all ages. There is limited information on whether Thoroughbred horses that survive pericarditis are able to reach athletic potential. OBJECTIVES: To determine how pericarditis affected horses that had the disease as young animals with regard to selling price in public sales and the ability to race successfully. STUDY DESIGN: Retrospective case series. METHODS: Medical records were searched to identify pericarditis cases. Signalment and month of diagnosis were noted and Thoroughbreds with ultrasonographically confirmed pericarditis that presented from 2 months to 3 years old were identified. For this subgroup data on sales and racing performed were obtained from publicly available databases to determine long-term survival and post-treatment outcomes from these horses and their unaffected half-siblings. RESULTS: Horses that survived pericarditis as young animals may recover growth and maturation rates quickly enough to reach expected sales prices at public sales for horses of racing age and recovered horses can have successful racing careers. MAIN LIMITATIONS: The number of horses in this case series was not sufficient to enable statistical comparisons between affected horses and unaffected half siblings, but description of sales prices and race earnings nevertheless yields information about the chances for affected young horses to achieve their intended purposes. CONCLUSIONS: Young Thoroughbreds with pericarditis warrant treatment and can sell and have successful racing careers. PMID- 28719029 TI - Directly observed therapy of sofosbuvir/ribavirin +/- peginterferon with minimal monitoring for the treatment of chronic hepatitis C in people with a history of drug use in Chennai, India (C-DOT). AB - We assessed the feasibility of field-based directly observed therapy (DOT) with minimal monitoring to deliver HCV treatment to people with a history of drug use in Chennai, India. Fifty participants were randomized 1:1 to sofosbuvir+peginterferon alfa 2a+ribavirin (SOF+PR) for 12 weeks (Arm 1) vs sofosbuvir+ribavirin (SOF+R) for 24 weeks (Arm 2). SOF+R was delivered daily at participant chosen venues and weekly peginterferon injections at the study clinic. HCV RNA testing was performed to confirm active HCV infection and sustained virologic response 12 weeks after treatment completion (SVR12). No baseline genotyping or on-treatment viral loads were performed. Median age was 46 years. All were male and 20% had significant fibrosis/cirrhosis. All self reported history of injection drug use, 18% recent noninjection drug use and 38% alcohol dependence. Six discontinued treatment (88% completed treatment in each arm). Of 22 who completed SOF+PR, all achieved SVR12 (22/25=88%); 15 of 22 who completed SOF+R achieved SVR12 (15/25=60%; P=.05). Among those completing SOF+R, SVR12 was significantly less common in participants reporting ongoing substance use (36% vs 100%) and missed doses. Active substance use and missed doses did not impact SVR with SOF+PR. Field-based DOT of HCV therapy without real-time HCV RNA monitoring was feasible; however, achieving 100% adherence was challenging. SOF+PR appeared superior to SOF+R in achieving SVR12, even when doses were missed with no discontinuations due to side effects. Further exploration of short duration treatment with peginterferon plus direct-acting antivirals is warranted. PMID- 28719031 TI - Desert Beetle-Inspired Superwettable Patterned Surfaces for Water Harvesting. AB - With the impacts of climate change and impending crisis of clean drinking water, designing functional materials for water harvesting from fog with large water capacity has received much attention in recent years. Nature has evolved different strategies for surviving dry, arid, and xeric conditions. Nature is a school for human beings. In this contribution, inspired by the Stenocara beetle, superhydrophilic/superhydrophobic patterned surfaces are fabricated on the silica poly(dimethylsiloxane) (PDMS)-coated superhydrophobic surfaces using a pulsed laser deposition approach with masks. The resultant samples with patterned wettability demonstrate water-harvesting efficiency in comparison with the silica PDMS-coated superhydrophobic surface and the Pt nanoparticles-coated superhydrophilic surface. The maximum water-harvesting efficiency can reach about 5.3 g cm-2 h-1 . Both the size and the percentage of the Pt-coated superhydrophilic square regions on the patterned surface affect the condensation and coalescence of the water droplet, as well as the final water-harvesting efficiency. The present water-harvesting strategy should provide an avenue to alleviate the water crisis facing mankind in certain arid regions of the world. PMID- 28719030 TI - Polygenic risk for schizophrenia and neurocognitive performance in patients with schizophrenia. AB - Both neurocognitive deficits and schizophrenia are highly heritable. Genetic overlap between neurocognitive deficits and schizophrenia has been observed in both the general population and in the clinical samples. This study aimed to examine if the polygenic architecture of susceptibility to schizophrenia modified neurocognitive performance in schizophrenia patients. Schizophrenia polygenic risk scores (PRSs) were first derived from the Psychiatric Genomics Consortium (PGC) on schizophrenia, and then the scores were calculated in our independent sample of 1130 schizophrenia trios, who had PsychChip data and were part of the Schizophrenia Families from Taiwan project. Pseudocontrols generated from the nontransmitted parental alleles of the parents in these trios were compared with alleles in schizophrenia patients in assessing the replicability of PGC-derived susceptibility variants. Schizophrenia PRS at the P-value threshold (PT) of 0.1 explained 0.2% in the variance of disease status in this Han-Taiwanese samples, and the score itself had a P-value 0.05 for the association test with the disorder. Each patient underwent neurocognitive evaluation on sustained attention using the continuous performance test and executive function using the Wisconsin Card Sorting Test. We applied a structural equation model to construct the neurocognitive latent variable estimated from multiple measured indices in these 2 tests, and then tested the association between the PRS and the neurocognitive latent variable. Higher schizophrenia PRS generated at the PT of 0.1 was significantly associated with poorer neurocognitive performance with explained variance 0.5%. Our findings indicated that schizophrenia susceptibility variants modify the neurocognitive performance in schizophrenia patients. PMID- 28719032 TI - The effect of experimental diabetes and glycaemic control on guided bone regeneration: histology and gene expression analyses. AB - OBJECTIVES: To investigate the effect of experimental diabetes and metabolic control on intramembranous bone healing following guided bone regeneration (GBR). MATERIAL AND METHODS: Ninety-three Wistar rats were allocated to three experimental groups, healthy (H), uncontrolled diabetes (D) and controlled diabetes (CD). Twenty one days following diabetes induction, a standardised 5-mm defect was created at the mid-portion of each parietal bone. In 75 animals (25H, 25D, 25CD), one defect was treated with an intracranial and extracranial membrane according to the GBR principle, and one defect was left empty (control); five animals per group were then randomly sacrificed at 3, 7, 15, 30 and 60 days and processed for decalcified histology. In 18 animals (6H, 6D, 6CD), both defects were treated according to the GBR principle; three animals from each group were then randomly sacrificed at 7 and 15 days of healing and employed for gene expression analysis. RESULTS: Application of the GBR therapeutic principle led to significant bone regeneration even in the D group. However, at 15 and 30 days, the osteogenesis process was impaired by uncontrolled diabetes, as shown by the significant reduction in terms of defect closure (38-42%) and newly formed bone (54-61%) compared to the healthy group. The comparison of the D vs. H group at 15 days of healing yielded the largest number of genes with significantly differential expression, among which various genes associated with the ossification process (bmp4, ltbp4, thra and cd276) were identified. CONCLUSIONS: Uncontrolled diabetes seems to affect early phases of the bone regeneration following GBR. A misregulation of genes and pathways related to cell division, energy production, inflammation and osteogenesis may account for the impaired regeneration process in D rats. Further studies are warranted to optimise the GBR process in this medically compromised patient population. PMID- 28719034 TI - Ultrathin Vein-Like Iridium-Tin Nanowires with Abundant Oxidized Tin as High Performance Ethanol Oxidation Electrocatalysts. AB - Iridium (Ir) holds great promise for ethanol oxidation reaction (EOR), while its practical applications suffer from the limited shape-controlled synthesis due to its low-energy barrier for nucleation. To overcome this limitation, the preparation of a new class of ultrathin vein-like Ir-tin nanowires (Ir?Sn NWs) with abundant oxidized Sn is reported. By tuning the ratio of Ir to Sn, the optimized Ir67 Sn33 /C exhibits the highest mass density of 95.6 mA mg-1 Ir for EOR at low potential (0.04 V), which is 4.1-fold and 20-fold higher than that of Ir/C and the commercial Pt/C, respectively. It also exhibits the smallest Tafel slope of 153 mV dec-1 and superior stability after 2 h chronoamperometric measurement. Electrochemical measurements and X-ray photoelectron spectra results confirm that the abundant oxidized Sn promotes a complete oxidization of ethanol into CO2 at low potential. This work highlights the importance of non-noble metal on enhancing the EOR performance. PMID- 28719033 TI - Identification of driver copy number alterations in diverse cancer types and application in drug repositioning. AB - Results from numerous studies suggest an important role for somatic copy number alterations (SCNAs) in cancer progression. Our work aimed to identify the drivers (oncogenes or tumor suppressor genes) that reside in recurrently aberrant genomic regions, including a large number of genes or non-coding genes, which remain a challenge for decoding the SCNAs involved in carcinogenesis. Here, we propose a new approach to comprehensively identify drivers, using 8740 cancer samples involving 18 cancer types from The Cancer Genome Atlas (TCGA). On average, 84 drivers were revealed for each cancer type, including protein-coding genes, long non-coding RNAs (lncRNA) and microRNAs (miRNAs). We demonstrated that the drivers showed significant attributes of cancer genes, and significantly overlapped with known cancer genes, including MYC, CCND1 and ERBB2 in breast cancer, and the lncRNA PVT1 in multiple cancer types. Pan-cancer analyses of drivers revealed specificity and commonality across cancer types, and the non-coding drivers showed a higher cancer-type specificity than that of coding drivers. Some cancer types from different tissue origins were found to converge to a high similarity because of the significant overlap of drivers, such as head and neck squamous cell carcinoma (HNSC) and lung squamous cell carcinoma (LUSC). The lncRNA SOX2 OT, a common driver of HNSC and LUSC, showed significant expression correlation with the oncogene SOX2. In addition, because some drivers are common in multiple cancer types and have been targeted by known drugs, we found that some drugs could be successfully repositioned, as validated by the datasets of drug response assays in cell lines. Our work reported a new method to comprehensively identify drivers in SCNAs across diverse cancer types, providing a feasible strategy for cancer drug repositioning as well as novel findings regarding cancer-associated non-coding RNA discovery. PMID- 28719036 TI - A novel method for achieving optimal neck extension. PMID- 28719035 TI - Melatonin inhibits nucleus pulposus (NP) cell proliferation and extracellular matrix (ECM) remodeling via the melatonin membrane receptors mediated PI3K-Akt pathway. AB - Pinealectomy in vertebrates accelerated intervertebral disk degeneration (IDD). However, the potential mechanisms, particularly melatonin's role, are still to be clarified. In this study, for first time, melatonin membrane receptors of MT1 and MT2 were found to be present in the human intervertebral disk tissues and nucleus pulposus (NP) cells, respectively. Melatonin treatment significantly inhibited NP cell proliferation in dose-dependent manner. Accordingly, melatonin down regulated gene expression of cyclin D1, PCNA, matrix metallopeptidase-3, and matrix metallopeptidase-9 and upregulated gene expression of collagen type II alpha 1 chain and aggrecan in NP cells. These effects of melatonin were blocked by luzindole, a nonspecific melatonin membrane receptor antagonist. Signaling pathway analysis indicated that in the intervertebral disk tissues and NP cells, melatonin acted on MT1/2 and subsequently reduced phosphorylation of phosphoinositide 3-kinase p85 regulatory subunit, phosphoinositide-dependent kinase-1, and Akt. The results indicate that melatonin is a crucial regulator of NP cell function and plays a vital role in prevention of IDD. PMID- 28719037 TI - Efficient separation of high-purity compounds from Oxytropis falcata using two dimensional preparative chromatography. AB - The separation of high-purity compounds from traditional Tibetan medicines plays an important role in investigating their bioactivity. Nevertheless, it is often quite difficult to isolate compounds with high purity because of the complexity of traditional Tibetan medicines. In this work, an offline two-dimensional reversed-phase preparative method was successfully developed for the separation of high-purity compounds from Oxytropis falcata. Based on the analysis results, an ODS C18 prep column was used for first-dimensional preparation, and 14.8 g of the crude sample was separated into five fractions with a recovery of 74.6%. Then, an XAqua C18 prep column was used to isolate high-purity compounds in the second-dimensional preparation because its separation selectivity is different with the ODS C18 stationary phase. As a result, eight compounds in the crude sample were isolated in more than 98% purity. This is the first report of trans cinnamic acid (1) and trifolirhizin (2) from Oxytropis falcata. This method has the potential to be an efficient separation method of high-purity compounds from Oxytropis falcata and it shows great promise for the separation of high-purity compounds from complex samples. PMID- 28719038 TI - Static cerebrovascular pressure autoregulation remains intact during deep hypothermia. AB - BACKGROUND: Clinical studies measuring cerebral blood flow in infants during deep hypothermia have demonstrated diminished cerebrovascular pressure autoregulation. The coexistence of hypotension in these cohorts confounds the conclusion that deep hypothermia impairs cerebrovascular pressure autoregulation. AIM: We sought to compare the lower limit of autoregulation and the static rate of autoregulation between normothermic and hypothermic piglets. METHODS: Twenty anesthetized neonatal piglets (5-7 days old; 10 normothermic and 10 hypothermic to 20 degrees C) had continuous measurements of cortical red cell flux using laser Doppler flowmetry, while hemorrhagic hypotension was induced without cardiopulmonary bypass. Lower limit of autoregulation was determined for each subject using piecewise regression and SRoR was determined above and below each lower limit of autoregulation as (%change cerebrovascular resistance/%change cerebral perfusion pressure). RESULTS: The estimated difference in lower limit of autoregulation was 1.4 mm Hg (lower in the hypothermic piglets; 95% C.I. -10 to 14 mm Hg; P=0.6). The median lower limit of autoregulation in the normothermic group was 39 mm Hg [IQR 38-51] vs 35 mm Hg [31-50] in the hypothermic group. Intact steady-state pressure autoregulation was defined as static rate of autoregulation >0.5 and was demonstrated in all normothermic subjects (static rate of autoregulation=0.72 [0.65-0.87]) and in 9/10 of the hypothermic subjects (static rate of autoregulation=0.65 [0.52-0.87]). This difference in static rate of autoregulation of 0.06 (95% C.I. -0.3 to 0.1) was not significant (P=0.4). CONCLUSION: Intact steady-state cerebrovascular pressure autoregulation is demonstrated in a swine model of profound hypothermia. Lower limit of autoregulation and static rate of autoregulation were similar in hypothermic and normothermic subjects. PMID- 28719039 TI - Differences in clinical characteristics and prognosis of sudden low- and high frequency hearing loss. AB - OBJECTIVES/HYPOTHESIS: We compared the clinical characteristics between acute low and high-frequency hearing loss (LF and HF, respectively) patients, and the efficacy of three different treatment protocols (systemic steroids, intratympanic steroid injection, and combination therapy). STUDY DESIGN: Prospective, randomized controlled study. METHODS: A total of 111 patients diagnosed with LF or HF were treated on an outpatient basis. Each group was randomly divided into three equal subgroups based on therapy: oral steroid, intratympanic dexamethasone injection (IT), and combination therapy. Hearing gain was estimated by comparing pre- and post-treatment pure-tone averages. Recovery rate was assessed by Clinical Practice Guideline: Sudden Hearing Loss from the American Academy of Otolaryngology-Head and Neck Surgery. RESULTS: In comparison of chief complaints, ear fullness and hearing loss were more common in the LF and HF group, respectively (P = .033 and P = .001, respectively). Hearing recovery rates were significantly different between the two groups (i.e., 74.1% [40/54] in the LF group and 45.6% [26/57] in the HF group; P < .001). Oral steroid therapy was most effective in the LF group (P = .017). In the HF group, all three modalities showed similar results, although IT tended to be the most effective (P = .390). CONCLUSIONS: There were differences in chief complaints and treatment responses between LF and HF patients. Although they showed similar partial damage in the cochlea, the pathophysiology of LF and HF may be quite different. LEVEL OF EVIDENCE: 1b. Laryngoscope, 127:1878-1884, 2017. PMID- 28719040 TI - Discovering long-term potentiation (LTP) - recollections and reflections on what came after. AB - Chance events led me to a lifelong career in scientific research. They paved the way for being the first to see long-term potentiation of synaptic efficiency (LTP) in Per Andersen's laboratory in Oslo in 1966. Here I describe my way to this discovery and the experiments with Tim Bliss in 1968-1969 that led to Bliss and Lomo, 1973. Surprisingly, we later failed to reproduce these results. I discuss possible reasons for this failure, which made us both leave LTP research, in my case for good, in Tim's case for several years. After 30 years of work in a different field, I renewed my interest in the hippocampus and LTP in the early 2000s and published, for the first time, results that I had obtained 40 years earlier. Here I present my take on how interest in and research on LTP evolved after the early years. This includes a discussion of the functions of hippocampus as seen in those early days, the case of patient H.M., Donald Hebb's place in the story, the search for 'memory molecules' such as PKMzeta, and the primary site for LTP expression (pre- and/or post-synaptic?). Throughout, I reflect on my life in science, how science is done and what drives it. The reflections are quite personal and I admit to mixed feelings about broadcasting them. PMID- 28719041 TI - Prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis is more than just suppositories and stents. PMID- 28719043 TI - Implementation rates of uro-oncology multidisciplinary meeting decisions. AB - OBJECTIVES: To assess implementation rates of the consensus plans made at the uro oncology multidisciplinary meeting (MDM) of an Australian tertiary centre, and analyse obstacles to implementation. METHODS: A retrospective review was performed of all patients discussed at the uro-oncology MDM at our institution between 1 January and 30 June 2015. Rates of referral for MDM discussion after a new histological diagnosis of malignancy, categorised by tumour type, were assessed. Patient records were interrogated to confirm MDM plan implementation, with the outcomes examined being completion of MDM plan within 3 months and factors preventing implementation. RESULTS: During the enrolment period, from 291 uro-oncological procedures, 240 yielded malignant histology of which 160 (67%) were discussed at the MDM. Overall, 202 patients, including 32 females, were discussed at the uro-oncology MDM. MDM consensus plans were implemented in 184 (91.1%) patients. Reasons for deviation from the MDM plan included delay in care, patient deterioration or comorbidities, patient preference, consultant decision, loss to follow-up, and change in patient scenario due to additional new information. CONCLUSION: The MDM is increasingly important in the care of uro oncology patients, with about two-thirds of new diagnoses currently captured. There appear to be few barriers to the implementation of consensus plans, with nearly all patients undergoing the recommended management. PMID- 28719042 TI - Serotonergic paraneurones in the female mouse urethral epithelium and their potential role in peripheral sensory information processing. AB - AIM: The mechanisms underlying detection and transmission of sensory signals arising from visceral organs, such as the urethra, are poorly understood. Recently, specialized ACh-expressing cells embedded in the urethral epithelium have been proposed as chemosensory sentinels for detection of bacterial infection. Here, we examined the morphology and potential role in sensory signalling of a different class of specialized cells that express serotonin (5 HT), termed paraneurones. METHODS: Urethrae, dorsal root ganglia neurones and spinal cords were isolated from adult female mice and used for immunohistochemistry and calcium imaging. Visceromotor reflexes (VMRs) were recorded in vivo. RESULTS: We identified two morphologically distinct groups of 5 HT+ cells with distinct regional locations: bipolar-like cells predominant in the mid-urethra and multipolar-like cells predominant in the proximal and distal urethra. Sensory nerve fibres positive for calcitonin gene-related peptide, substance P, and TRPV1 were found in close proximity to 5-HT+ paraneurones. In vitro 5-HT (1 MUm) stimulation of urethral primary afferent neurones, mimicking 5 HT release from paraneurones, elicited changes in the intracellular calcium concentration ([Ca2+ ]i ) mediated by 5-HT2 and 5-HT3 receptors. Approximately 50% of 5-HT responding cells also responded to capsaicin with changes in the [Ca2+ ]i . In vivo intra-urethral 5-HT application increased VMRs induced by urethral distention and activated pERK in lumbosacral spinal cord neurones. CONCLUSION: These morphological and functional findings provide insights into a putative paraneurone-neural network within the urethra that utilizes 5-HT signalling, presumably from paraneurones, to modulate primary sensory pathways carrying nociceptive and non-nociceptive (mechano-sensitive) information to the central nervous system. PMID- 28719044 TI - Symmetry breaking in development and stochastic gene expression. AB - The prevailing emphasis in developmental biology since the expansion of the molecular biology age has been that developmental decisions are instructive. A cell differentiates to become a specific cell type because it receives a signal, whereas its neighbor that does not receive the signal adopts a different fate. This emphasis has been generally accepted, largely because of the success of this view in tractable invertebrate model organisms, and the widespread similarities in molecular regulation to the development of more complex species. An alternative emphasis, that cells make their own decisions, has until the past decade been conspicuously silent. Here I trace the re-emergence of our appreciation of single cell decision-making in development, and how widespread this phenomenon is likely to be. I will focus the discussion on the potential role of stochastic gene expression in generating differences between cells in the absence of simple instructive signals and highlight the complexity of systems proposed to involve this type of regulation. Finally, I will discuss the approaches required to fully test hypotheses that noisy gene regulation can be extrapolated through developmental time to accurately specify cell fate. WIREs Dev Biol 2017, 6:e284. doi: 10.1002/wdev.284 For further resources related to this article, please visit the WIREs website. PMID- 28719045 TI - MICAL2 promotes breast cancer cell migration by maintaining epidermal growth factor receptor (EGFR) stability and EGFR/P38 signalling activation. AB - AIM: MICAL2, a cytoskeleton dynamics regulator, is identified associated with survival and metastasis of several types of cancers recently. This study was designed to investigate the role of MICAL2 in breast cancer cell migration as well as its underlying mechanisms. METHODS: The relationship between MICAL2 and EGF/EGFR signalling was analysed by gene overexpression and knock-down techniques. Cell migration was measured by wound-healing assays. Activation of EGF/EGFR signalling pathways were evaluated by immunofluorescence, qPCR, Western blotting and zymography techniques. Rac1 activity was assessed by pull-down assay. Correlation of MICAL2 and EGFR in breast cancer specimens was examined by immunohistochemical analysis. RESULTS: Ectopic expression of MICAL2 in MCF-7 cells augmented EGFR protein level, accompanied by the promotion of cell migration. Silencing MICAL2 in MDA-MB-231 cells destabilized EGFR and inhibited cell migration. In mechanism, the maintaining effect of MICAL2 on EGFR protein content was due to a delay in EGFR degradation. Expression of MICAL2 was also shown positively correlated with the activation of P38/HSP27 and P38/MMP9 signallings, which are the main downstream signalling cascades of EGF/EGFR involved in cell migration. Further analysis indicated that Rac1 activation contributed to the maintaining effect of MICAL2 on EGFR stability. In addition, analysis of breast cancer specimens revealed a positive correlation between MICAL2 and EGFR levels and an association between MICAL2 expression and worse prognosis. CONCLUSION: MICAL2 is a major regulator of breast cancer cell migration, maintaining EGFR stability and subsequent EGFR/P38 signalling activation through inhibiting EGFR degradation in a Rac1-dependent manner. PMID- 28719046 TI - Retinal pigment epithelium adenoma in vitreous fluid cytology. AB - Ocular cytology specimens are relatively uncommon, adding to the difficulty of their evaluation by cytopathologists. While melanomas account for a majority of primary intraocular pigmented lesions, other diagnostic considerations must be included in the differential. This brief report highlights a case of a pigmented ocular lesion in a 24-year-old man and key morphologic, immunohistochemical, and clinical differences between melanoma, melanocytoma, choroidal nevus, and retinal pigment epithelium (RPE) adenoma. PMID- 28719047 TI - Effect of Typha capensis (Rohrb.)N.E.Br. rhizome extract F1 fraction on cell viability, apoptosis induction and testosterone production in TM3-Leydig cells. AB - Typha capensis (Rohrb.)N.E.Br. (bulrush) is used by traditional healers in Southern Africa to treat male reproductive problems. This study aimed at investigating the effects of T. capensis on TM3-Leydig cells. T. capensis rhizome crude extract obtained from autumn, winter, spring and summer harvest was fractionated using HPLC into four fractions, and TM3-Leydig cells were incubated with different concentrations of the F1 fraction (0.01, 0.02, 0.1, 1, 10 and 100 MUg/ml) for 24, 48 and 96 hr respectively. The following parameters were evaluated: cell morphology, viability (MTT assay), testosterone production (testosterone ELISA test), apoptosis (Annexin V-Cy3 binding) and DNA fragmentation (TUNEL assay). Results revealed that the summer harvest obtained the highest amount of extract. The F1 fraction of all harvests was the most effective. This fraction significantly enhanced testosterone production in TM3 cells in a dose-dependent manner with maximum effect at 0.1 MUg/ml. At higher concentrations, lower testosterone production was observed. Cell viability including apoptosis was not affected at concentrations used by the traditional healers to treat patients. This study shows that T. capensis enhanced testosterone production and might be useful to treat male infertility and ageing male problems. PMID- 28719048 TI - Developmental mechanisms of intervertebral disc and vertebral column formation. AB - The vertebral column consists of repeating units of ossified vertebrae that are adjoined by fibrocartilagenous intervertebral discs. These structures form from the embryonic notochord and somitic mesoderm. In humans, congenital malformations of the vertebral column include scoliosis, kyphosis, spina bifida, and Klippel Feil syndrome. In adulthood, a common malady affecting the vertebral column includes disc degeneration and associated back pain. Indeed, recent reports estimate that low back pain is the number one cause of disability worldwide. Our review provides an overview of the molecular mechanisms underlying vertebral column morphogenesis and intervertebral disc development and maintenance, with an emphasis on what has been gleaned from recent genetic studies in mice. The aim of this review is to provide a developmental framework through which vertebral column formation can be understood so that ultimately, research scientists and clinicians alike can restore disc health with appropriately designed gene and cell-based therapies. WIREs Dev Biol 2017, 6:e283. doi: 10.1002/wdev.283 For further resources related to this article, please visit the WIREs website. PMID- 28719050 TI - Thai people living with tuberculosis and how they adhere to treatment: A grounded theory study. AB - To develop a conceptual framework of adherence to treatment among Thai people living with tuberculosis, a grounded theory approach was used. A purposive sample of 20 Thai people living with tuberculosis, aged from 23 to 85 years, was interviewed. From the participants' perspective, a core category of social belonging was highlighted, with three categories of conditions connected: personal barriers, personal resilience, and social facilitation. Personal barriers encompassed fear of stigma, concealing the illness, and lack of knowledge and motivation to complete the treatment regime. Personal resilience encompassed positive thinking and self-awareness. Social facilitation encompassed the ease of access to health services, continuity in the health service's ability to choose a directly-observed therapy observer, and social support. This study contributes a deeper understanding of the perspective of Thai people living with tuberculosis with regards to adherence to tuberculosis treatment. It might improve how local healthcare workers provide tuberculosis care, and inspire them to tailor care to people living with tuberculosis in a local community to increase personal resilience and reduce stigma. PMID- 28719051 TI - The binding mechanism between azoles and FgCYP51B, sterol 14alpha-demethylase of Fusarium graminearum. AB - BACKGROUND: Fusarium graminearum is the main pathogen of Fusarium head blight (FHB), a worldwide plant disease and a major disease of wheat in China. Control of FHB is mainly dependent on the application of demethylase inhibitor (DMI) fungicides. Fungal sterol 14alpha-demethylase enzymes (CYP51) are the main target for DMI fungicides. A molecular modeling study and biological evaluation were performed to investigate the binding mechanism between azoles and CYP51B in F. graminearum. RESULTS: A homology model based on the crystal structure of Aspergillus fumigatus was built. Molecular docking and molecular dynamics (MD) simulations were then used to identify the optimum binding mode of propiconazole (PRP), diniconazole (DIN), triadimenol (TRL), tebuconazole (TEC) and triadimefon (TRN) with FgCYP51B. Furthermore, the binding free energy of the five protein inhibitor complexes was calculated using molecular mechanics generalized Born surface area and Poisson-Boltzmann surface area (MM-GB/PBSA) methods. Key residues in the selective binding of azoles to FgCYP51B were recognized by per residue free energy decomposition analysis. The five ligands have a similar binding mode in the active pocket. The binding free energy to the enzyme for inhibitors PRP and TEC is more favorable than that of TRN, TRL and DIN. Furthermore, the amino acid residues Phe511, Val136, Ile374, Ala308, Ser312 and Try137 of FgCYP51B are key residues interacting with azoles fungicides. From the experimental evaluation, the 50% effective concentration (EC50 ) values for PRP, TEC, DIN, TRL and TRN are 0.024, 0.047, 0.148, 0.154 and 0.474 mg L-1 , respectively. These five molecules exhibit potential inhibitory activity against CYP51B protein from F. graminearum. CONCLUSION: Azole fungicides for FgCYP51B should possess more hydrophobic groups interacting with residues Phe511, Val136, Ile374, Ala308, Ser312 and Tyr137. PRP and TEC are preferable for the control of FHB than DIN, TRL and TRN. (c) 2017 Society of Chemical Industry. PMID- 28719049 TI - Pulmonary vein stenosis in patients with Smith-Lemli-Opitz syndrome. AB - OBJECTIVE: To describe a group of children with co-incident pulmonary vein stenosis and Smith-Lemli-Opitz syndrome and to generate hypotheses as to the shared pathogenesis of these disorders. DESIGN: Retrospective case series. PATIENTS: Five subjects in a pulmonary vein stenosis cohort of 170 subjects were diagnosed with Smith-Lemli-Opitz syndrome soon after birth. RESULTS: All five cases were diagnosed with Smith-Lemli-Opitz syndrome within 6 weeks of life, with no family history of either disorder. All cases had pathologically elevated 7 dehydrocholesterol levels and two of the five cases had previously reported pathogenic 7-dehydrocholesterol reductase mutations. Smith-Lemli-Opitz syndrome severity scores ranged from mild to classical (2-7). Gestational age at birth ranged from 35 to 39 weeks. Four of the cases were male by karyotype. Pulmonary vein stenosis was diagnosed in all cases within 2 months of life, earlier than most published cohorts. All cases progressed to bilateral disease and three cases developed atresia of at least one vein. Despite catheter and surgical interventions, all subjects' pulmonary vein stenosis rapidly recurred and progressed. Three of the subjects died, at 2 months, 3 months, and 11 months. Survival at 16 months after diagnosis was 43%. CONCLUSIONS: Patients with pulmonary vein stenosis who have a suggestive syndromic presentation should be screened for Smith-Lemli-Opitz syndrome with easily obtainable serum sterol tests. Echocardiograms should be obtained in all newly diagnosed patients with Smith-Lemli-Opitz syndrome, with a low threshold for repeating the study if new respiratory symptoms of uncertain etiology arise. Further studies into the pathophysiology of pulmonary vein stenosis should consider the role of cholesterol-based signaling pathways in the promotion of intimal proliferation. PMID- 28719052 TI - Identification of the HLA-DQB1*06:123 allele in an unrelated stem cell donor from the Saudi Registry. AB - HLA-DQB1*06:123 differs from HLA-DQB1*06:29 by six nucleotide substitutions resulting in five amino acid changes. PMID- 28719053 TI - Microwave assisted synthesis of metal-organic framework MIL-101 nanocrystals as sorbent and pseudostationary phase in capillary electrophoresis for the separation of anthraquinones in environmental water samples. AB - In this work, a CE method was developed to separate five anthraquinones: aloe emodin, rhein, emodin, chrysophanol, and physcion. The CE method used a nano sized metal organic framework MIL-101 (nMIL-101) as pseudostationary phase (PSP) and sorbent for dispersed particle extraction (DPE). The nMIL-101 was synthesized by microwave technique and was characterized by UV-vis, TEM, Zeta potential, X ray diffraction spectrometry and micropore physisorption. In this method, anthraquinones were adsorbed by nMIL-101 of a fast kinetics within 10 min and then separated by CE. The CE conditions were optimized considering time, pH, buffer ionic strength, and nanoparticles concentration. The optimal CE condition is using 20 mM sodium borate buffer (pH 9.1) containing 15% methanol (v/v) and 400 mg/L nMIL-101 as additives within 8 min. The LODs varied from 24 to 57 MUg/L, which were lower than those previously reported. Our method has been successfully applied to determine trace anthraquinones in environmental water samples. PMID- 28719054 TI - Evolutionary Cell Biology of Proteins from Protists to Humans and Plants. AB - During evolution, the cell as a fine-tuned machine had to undergo permanent adjustments to match changes in its environment, while "closed for repair work" was not possible. Evolution from protists (protozoa and unicellular algae) to multicellular organisms may have occurred in basically two lineages, Unikonta and Bikonta, culminating in mammals and angiosperms (flowering plants), respectively. Unicellular models for unikont evolution are myxamoebae (Dictyostelium) and increasingly also choanoflagellates, whereas for bikonts, ciliates are preferred models. Information accumulating from combined molecular database search and experimental verification allows new insights into evolutionary diversification and maintenance of genes/proteins from protozoa on, eventually with orthologs in bacteria. However, proteins have rarely been followed up systematically for maintenance or change of function or intracellular localization, acquirement of new domains, partial deletion (e.g. of subunits), and refunctionalization, etc. These aspects are discussed in this review, envisaging "evolutionary cell biology." Protozoan heritage is found for most important cellular structures and functions up to humans and flowering plants. Examples discussed include refunctionalization of voltage-dependent Ca2+ channels in cilia and replacement by other types during evolution. Altogether components serving Ca2+ signaling are very flexible throughout evolution, calmodulin being a most conservative example, in contrast to calcineurin whose catalytic subunit is lost in plants, whereas both subunits are maintained up to mammals for complex functions (immune defense and learning). Domain structure of R-type SNAREs differs in mono- and bikonta, as do Ca2+ -dependent protein kinases. Unprecedented selective expansion of the subunit a which connects multimeric base piece and head parts (V0, V1) of H+ ATPase/pump may well reflect the intriguing vesicle trafficking system in ciliates, specifically in Paramecium. One of the most flexible proteins is centrin when its intracellular localization and function throughout evolution is traced. There are many more examples documenting evolutionary flexibility of translation products depending on requirements and potential for implantation within the actual cellular context at different levels of evolution. From estimates of gene and protein numbers per organism, it appears that much of the basic inventory of protozoan precursors could be transmitted to highest eukaryotic levels, with some losses and also with important additional "inventions." PMID- 28719056 TI - Tracking salience in young people: A psychometric field test of the Aberrant Salience Inventory (ASI). AB - AIM: To explore the prevalence of Aberrant Salience (AS, an alleged experiential feature of psychosis-proneness) in Italian young people and corroborate the transcultural validity of the Aberrant Salience Inventory (ASI). METHODS: Young adults attending an Italian university (n = 649) underwent serial evaluations with the ASI together with psychometric proxies for help seeking General Health Questionnaire and attenuated positive and negative symptoms Schizotypal Personality Questionnaire (SPQ). The distribution of ASI scores was explored with latent class analysis (LCA). RESULTS: Reliability of the Italian version of the ASI (I-ASI) was acceptable for all subscales (ordinal alpha >.70). Concurrent validity was in the expected direction, with higher correlations with measures of attenuated positive symptoms vs negative symptoms of psychosis (Steigers' z test, P < .005 in all comparisons). LCA identified three classes, with 217 (33.4%) participants in the "high aberrant salience" class. Gender and age were not related to class membership. Compared to the baseline class, SPQ scores in the schizotypy range were more likely in the "high aberrant salience" class (OR = 39.1; 95%confidence interval: 5.30-288.1). CONCLUSION: AS is a relatively common experience among Italian young people. The study also confirmed the validity of field-testing ASI as a tool for the real-world characterization of people with vulnerability to psychosis, such as symptomatic help seekers with clinical high risk states. PMID- 28719055 TI - Endocrine toxicity of immune checkpoint inhibitors: essential crosstalk between endocrinologists and oncologists. AB - Two types of immune checkpoint inhibitors, both antibodies that target cytotoxic T-lymphocyte antigen-4 and those that target programmed cell death-protein 1, have been approved for use in melanoma, non-small-cell lung cancer, and renal cell carcinoma as first-line or second-line therapy. Their adverse events are primarily regarded as immune-related adverse events. We felt it was important to pinpoint and discuss certain preconceptions or misconceptions regarding thyroid dysfunction, hypophysitis, and diabetes induced by immune checkpoint inhibitors. We have identified areas of uncertainty and unmet requirements, including essential interaction between endocrinologists and oncologists. Five issues have been identified for discussion: (1) diagnosis of endocrine toxicity, (2) assessment of toxicity severity, (3) treatment of toxicity, (4) withdrawal or continuation of immunotherapy, (5) preventive action. PMID- 28719057 TI - The full-length sequence of HLA-B*59:01:01:01 confirmed by cloning and sequencing. AB - The full-length sequence of HLA-B*59:01:01:01. PMID- 28719058 TI - Corrigendum: Click-Chemistry-Mediated Rapid Microbubble Capture for Acute Thrombus Ultrasound Molecular Imaging. PMID- 28719059 TI - Pancreatic allograft thrombosis: Suggestion for a CT grading system and management algorithm. AB - Pancreatic allograft thrombosis (PAT) remains the leading cause of nonimmunologic graft failure. Here, we propose a new computed tomography (CT) grading system of PAT to identify risk factors for allograft loss and outline a management algorithm by retrospective review of consecutive pancreatic transplantations between 2009 and 2014. Triple-phase CT scans were graded independently by 2 radiologists as grade 0, no thrombosis; grade 1, peripheral thrombosis; grade 2, intermediate non-occlusive thrombosis; and grade 3, central occlusive thrombosis. Twenty-four (23.3%) of 103 recipients were diagnosed with PAT (including grade 1). Three (2.9%) grafts were lost due to portal vein thrombosis. On multivariate analysis, pancreas after simultaneous pancreas-kidney transplantation/solitary pancreatic transplantation, acute rejection, and CT findings of peripancreatic edema and/or inflammatory change were significant risk factors for PAT. Retrospective review of CT scans revealed more grade 1 and 2 thromboses than were initially reported. There was no significant difference in graft or patient survival, postoperative stay, or morbidity of recipients with grade 1 or 2 thrombosis who were or were not anticoagulated. Our data suggest that therapeutic anticoagulation is not necessary for grade 1 and 2 arterial and grade 1 venous thrombosis. The proposed grading system can assist clinicians in decision-making and provide standardized reporting for future studies. PMID- 28719061 TI - Tailored Engineering of an Unusual (C4 H9 NH3 )2 (CH3 NH3 )2 Pb3 Br10 Two Dimensional Multilayered Perovskite Ferroelectric for a High-Performance Photodetector. AB - Two-dimensional (2D) layered hybrid perovskites have shown great potential in optoelectronics, owing to their unique physical attributes. However, 2D hybrid perovskite ferroelectrics remain rare. The first hybrid ferroelectric with unusual 2D multilayered perovskite framework, (C4 H9 NH3 )2 (CH3 NH3 )2 Pb3 Br10 (1), has been constructed by tailored alloying of the mixed organic cations into 3D prototype of CH3 NH3 PbBr3 . Ferroelectricity is created through molecular reorientation and synergic ordering of organic moieties, which are unprecedented for the known 2D multilayered hybrid perovskites. Single-crystal photodetectors of 1 exhibit fascinating performances, including extremely low dark currents (ca. 10-12 A), large on/off current ratios (ca. 2.5*103 ), and very fast response rate (ca. 150 MUs). These merits are superior to integrated detectors of other 2D perovskites, and compete with the most active CH3 NH3 PbI3 . PMID- 28719062 TI - Immersive virtual reality as a teaching tool for neuroanatomy. AB - BACKGROUND: Three-dimensional (3D) computer modeling and interactive virtual reality (VR) simulation are validated teaching techniques used throughout medical disciplines. Little objective data exists supporting its use in teaching clinical anatomy. Learner motivation is thought to limit the rate of utilization of such novel technologies. The purpose of this study is to evaluate the effectiveness, satisfaction, and motivation associated with immersive VR simulation in teaching medical students neuroanatomy. METHODS: Images of normal cerebral anatomy were reconstructed from human Digital Imaging and Communications in Medicine (DICOM) computed tomography (CT) imaging and magnetic resonance imaging (MRI) into 3D VR formats compatible with the Oculus Rift VR System, a head-mounted display with tracking capabilities allowing for an immersive VR experience. The ventricular system and cerebral vasculature were highlighted and labeled to create a focused interactive model. We conducted a randomized controlled study with 66 medical students (33 in both the control and experimental groups). Pertinent neuroanatomical structures were studied using either online textbooks or the VR interactive model, respectively. We then evaluated the students' anatomy knowledge, educational experience, and motivation (using the Instructional Materials Motivation Survey [IMMS], a previously validated assessment). RESULTS: There was no significant difference in anatomy knowledge between the 2 groups on preintervention, postintervention, or retention quizzes. The VR group found the learning experience to be significantly more engaging, enjoyable, and useful (all p < 0.01) and scored significantly higher on the motivation assessment (p < 0.01). CONCLUSION: Immersive VR educational tools awarded a more positive learner experience and enhanced student motivation. However, the technology was equally as effective as the traditional text books in teaching neuroanatomy. PMID- 28719060 TI - Drug use and phylogenetic clustering of hepatitis C virus infection among people who use drugs in Vancouver, Canada: A latent class analysis approach. AB - This study estimated latent classes (ie, unobserved subgroups in a population) of people who use drugs in Vancouver, Canada, and examined how these classes relate to phylogenetic clustering of hepatitis C virus (HCV) infection. HCV antibody positive people who use drugs from two cohorts in Vancouver, Canada (1996-2012), with a Core-E2 sequence were included. Time-stamped phylogenetic trees were inferred, and phylogenetic clustering was determined by time to most common recent ancestor. Latent classes were estimated, and the association with the phylogenetic clustering outcome was assessed using an inclusive classify/analyse approach. Among 699 HCV RNA-positive participants (26% female, 24% HIV+), recent drug use included injecting cocaine (80%), injecting heroin (70%), injecting cocaine/heroin (ie, speedball, 38%) and crack cocaine smoking (28%). Latent class analysis identified four distinct subgroups of drug use typologies: (i) cocaine injecting, (ii) opioid and cocaine injecting, (iii) crack cocaine smoking and (iv) heroin injecting and currently receiving opioid substitution therapy. After adjusting for age and HIV infection, compared to the group defined by heroin injecting and currently receiving opioid substitution therapy, the odds of phylogenetic cluster membership was greater in the cocaine injecting group (adjusted OR [aOR]: 3.06; 95% CI: 1.73, 5.42) and lower in the crack cocaine smoking group (aOR: 0.06; 95% CI: 0.01, 0.48). Combining latent class and phylogenetic clustering analyses provides novel insights into the complex dynamics of HCV transmission. Incorporating differing risk profiles associated with drug use may provide opportunities to further optimize and target HCV treatment and prevention strategies. PMID- 28719063 TI - Enhanced Fibrinolysis with Magnetically Powered Colloidal Microwheels. AB - Thrombi that occlude blood vessels can be resolved with fibrinolytic agents that degrade fibrin, the polymer that forms between and around platelets to provide mechanical stability. Fibrinolysis rates however are often constrained by transport-limited delivery to and penetration of fibrinolytics into the thrombus. Here, these limitations are overcome with colloidal microwheel (uwheel) assemblies functionalized with the fibrinolytic tissue-type plasminogen activator (tPA) that assemble, rotate, translate, and eventually disassemble via applied magnetic fields. These microwheels lead to rapid fibrinolysis by delivering a high local concentration of tPA to induce surface lysis and, by taking advantage of corkscrew motion, mechanically penetrating into fibrin gels and platelet-rich thrombi to initiate bulk degradation. Fibrinolysis of plasma-derived fibrin gels by tPA-microwheels is fivefold faster than with 1 ug mL-1 tPA. uWheels following corkscrew trajectories can also penetrate through 100 um sized platelet-rich thrombi formed in a microfluidic model of hemostasis in ~5 min. This unique combination of surface and bulk dissolution mechanisms with mechanical action yields a targeted fibrinolysis strategy that could be significantly faster than approaches relying on diffusion alone, making it well-suited for occlusions in small or penetrating vessels not accessible to catheter-based removal. PMID- 28719064 TI - The association between dental, general, and mental health status among underserved and vulnerable populations served at health centers in the US. AB - OBJECTIVES: Vulnerable populations in underserved communities are disproportionately at high risk for multiple medical, dental, and behavioral health conditions. This study aims to: a) examine the occurrence of acute dental needs and b) investigate the association of acute dental needs and self-rated general and mental health status among the adult dentate health center population. METHODS: This cross-sectional study analyzed data on adult patients (n = 5,035) from the 2014 Health Center Patient Survey, a nationally representative survey of health center patients. Multivariate logistic regression was used to assess the association of acute dental needs and a) self-rated general health status and b) mental health status. RESULTS: Approximately, two thirds of adult dentate heath center patients reported having an acute dental need. After adjusting for confounding factors, not having or having had health insurance that pays for dental care, general health status of fair or poor, and ever having a mental illness were associated with higher odds of having an acute dental need. CONCLUSIONS: The results highlight the role of health centers in addressing oral health disparities among vulnerable populations and the importance of a team-based multidisciplinary approach to ensuring the integration and coordination of oral health services within a comprehensive primary care delivery system. PMID- 28719065 TI - Unconventional Route to Uniform Hollow Semiconducting Nanoparticles with Tailorable Dimensions, Compositions, Surface Chemistry, and Near-Infrared Absorption. AB - Despite impressive recent advances in the synthesis of lead chalcogenide solid nanoparticles, there are no examples of lead chalcogenide hollow nanoparticles (HNPs) with controlled diameter and shell thickness as current synthetic approaches for HNPs have inherent limitations associated with their complexity, inability to precisely control the dimensions, and limited possibilities with regard to applicable materials. Herein, we report on an unconventional strategy for crafting uniform lead chalcogenide (PbS and PbTe) HNPs with tailorable size, surface chemistry, and near-IR absorption. Amphiphilic star-like triblock copolymers [polystyrene-block-poly(acrylic acid)-block-polystyrene and polystyrene-block-poly(acrylic acid)-block-poly(3,4-ethylenedioxythiophene)] were rationally synthesized and exploited as nanoreactors for the formation of uniform PbS and PbTe HNPs. Compared to their solid counterparts, the near-IR absorption of the HNPs is blue-shifted owing to the hollow interior. This strategy can be readily extended to other types of intriguing low-band-gap HNPs for diverse applications. PMID- 28719066 TI - Insights into optimal basal insulin titration in type 2 diabetes: Results of a quantitative survey. AB - AIMS: Basal insulin (BI) treatment initiation and dose titration in type 2 diabetes (T2DM) are often delayed. Such "clinical inertia" results in poor glycaemic control and high risk of long-term complications. This survey aimed to determine healthcare professional (HCP) and patient attitudes to BI initiation and titration. METHODS: An online survey (July-August 2015) including HCPs and patients with T2DM in the USA, France and Germany. Patients were >=18 years old and had been on BI for 6 to 36 months, or discontinued BI within the previous 12 months. RESULTS: Participants comprised 386 HCPs and 318 people with T2DM. While >75% of HCPs reported discussing titration at the initiation visit, only 16% to 28% of patients remembered such discussions, many (32%-42%) were unaware of the need to titrate BI, and only 28% to 39% recalled mention of the time needed to reach glycaemic goals. Most HCPs and patients agreed that more effective support tools to assist BI initiation/titration are needed; patients indicated that provision of such tools would increase confidence in self-titration. HCPs identified fear of hypoglycaemia, failure to titrate in the absence of symptoms, and low patient motivation as important titration barriers. In contrast, patients identified weight gain, the perception that titration meant worsening disease, frustration over the time to reach HbA1c goals and fear of hypoglycaemia as major factors. CONCLUSION: A disconnect exists between HCP- and patient-perceived barriers to effective BI titration. To optimize titration, strategies should be targeted to improve HCP-patient communication, and provide support and educational tools. PMID- 28719067 TI - One-Pot Synthesis of Cu-Nanocluster-Decorated Brookite TiO2 Quasi-Nanocubes for Enhanced Activity and Selectivity of CO2 Photoreduction to CH4. AB - A new kind of metallic Cu-loaded brookite TiO2 composite, in which Cu nanoclusters with a small size of 1-3 nm are decorated on brookite TiO2 quasi nanocube (BTN) surfaces (hereafter referred to as Cu-BTN), is synthesized via a one-pot hydrothermal process and then used as photocatalyst for CO2 reduction. It was found that the decoration of Cu nanoclusters on BTN surfaces can improve the activity and selectivity of CO2 photoreduction to CH4 , and 1.5 % Cu-BTN gives a maximum overall photocatalytic activity (150.9 MUmol g-1 h-1 ) for CO/CH4 production, which is ~11.4 and ~3.3 times higher than those of pristine BTN (13.2 MUmol g-1 h-1 ) and Ag-BTN (45.2 MUmol g-1 h-1 ). Moreover, the resultant Cu BTN products can promote the selective generation of CH4 as compared to CO due to the number of surface oxygen vacancies and the CO2 /H2 O adsorption behavior, which differs from that of the pristine BTN. The present results demonstrate that brookite TiO2 would be a potential effective photocatalyst for CO2 photoreduction, and that Cu nanoclusters can act as an inexpensive and efficient co-catalyst alternative to the commonly used noble metals to improve the photoactivity and selectivity for CO2 reduction to CH4 . PMID- 28719068 TI - Correlation between the proportion of stained eggs and the number of mites (Dermanyssus gallinae) monitored using a 'non-parallel board trap'. AB - The poultry red mite (Dermanyssus gallinae) is a serious problem for the poultry industry worldwide. However, the relationship between the mite population and the damage that they cause is still unclear. In this study, the mite population in poultry houses was examined using an established trap method, and the risk of blood-stained eggs caused by the mites was assessed. Traps were placed once a week outside the egg channels and/or on the floor in two poultry farms in Fukuoka Prefecture, Japan, from April 2012 to July 2014. The numbers of blood-stained eggs and total eggs were counted at weekly intervals. The results showed that the number of mites increased from April to May, and reached a peak around the beginning of June when the average temperature and humidity were >24 degrees C and 70-90%, respectively. In the segmented model, the correlation between the proportion of blood-stained eggs and the number of mites or temperature was positive over a threshold. In conclusion, our established trap method is useful for monitoring mites and can be used to predict when poultry farms should be treated to prevent appearance of blood-stained eggs. PMID- 28719069 TI - Inaccuracy of a continuous arterial pressure waveform monitor when used for congenital cardiac catheterization. AB - OBJECTIVE: To determine the accuracy of a continuous cardiac output monitor (FloTrac sensor) for measuring cardiac index in children with congenital heart disease undergoing cardiac catheterization. Cardiac index is a critical hemodynamic parameter measured during catheterizations in children with congenital heart disease. This has been challenging to measure accurately and many clinicians rely on predictive equations for calculating cardiac index. DESIGN: Prospective, nonrandomized trial. SETTING: Tertiary care congenital heart center. PATIENTS: Consecutive participants <=18 years old undergoing clinically indicated cardiac catheterizations from September 2014 through August 2015. INTERVENTIONS: Oxygen consumption was measured using the Vmax Encore 229 monitor attached to the ventilator circuit. The FloTrac transducer with third generation software was connected to a pigtail catheter in the descending aorta and cardiac index was obtained. OUTCOME MEASURES: Cardiac index by the Fick equation using measured oxygen consumption was compared to cardiac index from the FloTrac sensor using paired t-test and Bland-Altman analysis. RESULTS: 39 participants (median age 5.1 years, 1.5-18.3, 64% female) were studied. Cardiac index by FloTrac was higher than cardiac index by Fick (6.4 +/- 3.4 vs 3.7 +/- 1.2 L/min/m2 , P < .001). Bland-Altman analysis showed a consistent overestimation of cardiac index by FloTrac which worsened as cardiac index increased (mean bias 2.7 L/min/m2 , 95% limits of agreement -4.2, 9.5). CONCLUSIONS: The results of this study show that the FloTrac sensor provides cardiac index measures which are not accurate enough to justify use in children with congenital heart disease undergoing catheterization. Further studies may allow for modifications of the algorithms to obtain more accurate cardiac index in this population. PMID- 28719071 TI - Mesoporous Silica Thin Membranes with Large Vertical Mesochannels for Nanosize Based Separation. AB - Membrane separation technologies are of great interest in industrial processes such as water purification, gas separation, and materials synthesis. However, commercial filtration membranes have broad pore size distributions, leading to poor size cutoff properties. In this work, mesoporous silica thin membranes with uniform and large vertical mesochannels are synthesized via a simple biphase stratification growth method, which possess an intact structure over centimeter size, ultrathin thickness (<=50 nm), high surface areas (up to 1420 m2 g-1 ), and tunable pore sizes from ~2.8 to 11.8 nm by adjusting the micelle parameters. The nanofilter devices based on the free-standing mesoporous silica thin membranes show excellent performances in separating differently sized gold nanoparticles (>91.8%) and proteins (>93.1%) due to the uniform pore channels. This work paves a promising way to develop new membranes with well-defined pore diameters for highly efficient nanosize-based separation at the macroscale. PMID- 28719070 TI - Sirtuin 1 attenuates inflammation and hepatocellular damage in liver transplant ischemia/Reperfusion: From mouse to human. AB - Hepatic ischemia/reperfusion injury (IRI), an inevitable antigen-independent inflammation response in cadaveric liver transplantation, correlates with poor early graft function, rejection episodes, and contributes to donor organ shortage. Sirtuin 1 (SIRT1) is a histone deacetylase that may regulate inflammatory cell activity and manage liver function in IRI, though its functional role and clinical relevance remains to be elucidated. We investigated the efficacy of SIRT1 activation in a murine liver IRI model and verified the concept of putative SIRT1-mediated hepatoprotection in clinical liver transplantation. In the experimental arm, mice were subjected to 90 minutes of liver partial warm ischemia followed by 6 hours of reperfusion with or without adjunctive SIRT1 activation in vivo (resveratrol [Res]). In parallel, bone marrow derived macrophage (BMDM) or spleen lymphocyte cultures were treated with Res. In the clinical arm, liver biopsies from 21 adult primary liver transplant patients (2 hours after reperfusion) were divided into "low" (n = 11) versus "high" (n = 10) SIRT1 expression groups, assessed by Western blots. Treatment with Res attenuated murine liver IRI while up-regulating SIRT1, suppressing leukocyte infiltration, and decreasing proinflammatory cytokine programs. SIRT1 silencing (small interfering RNA) in BMDM cultures enhanced inflammatory cytokine programs, whereas addition of Res decreased proinflammatory response in a SIRT1-dependent manner. In addition, Res decreased interferon gamma production in liver infiltrating and spleen lymphocyte cultures. Human liver transplants with high SIRT1 levels showed improved hepatocellular function and superior survival (P = 0.04), accompanied by lower proinflammatory cytokine profile. In conclusion, our translational study is the first to identify SIRT1 as a regulator of hepatocellular function in human liver transplant recipients under ischemia/reperfusion stress. By targeting innate and adaptive immune activation, manipulation of SIRT1 signaling should be considered as a novel means to combat inflammation in liver transplantation. Liver Transplantation 23 1282-1293 2017 AASLD. PMID- 28719072 TI - Living donor liver transplantation in high Model for End-Stage Liver Disease score patients. PMID- 28719073 TI - Our Contributions in Nanochemistry for Antibiosis, Electrocatalyst and Energy Storage Materials. AB - This account mainly introduces and reviews our recent progress in three projects: antibacterial nanomaterial, electrocatalyst for detecting and electrode nanomaterial of energy storage device, especially the supercapacitor. Besides, our thought and idea about the design, fabrication and application of corresponding nanomaterials are sketched throughout the whole article in order to reveal the structure-function relationship and corresponding mechanism. In the end, we tend to attach importance to the bottleneck of nanomaterial's development and put forward our understanding in this field. PMID- 28719074 TI - Influence diagnostics in meta-regression model. AB - This paper studies the influence diagnostics in meta-regression model including case deletion diagnostic and local influence analysis. We derive the subset deletion formulae for the estimation of regression coefficient and heterogeneity variance and obtain the corresponding influence measures. The DerSimonian and Laird estimation and maximum likelihood estimation methods in meta-regression are considered, respectively, to derive the results. Internal and external residual and leverage measure are defined. The local influence analysis based on case weights perturbation scheme, responses perturbation scheme, covariate perturbation scheme, and within-variance perturbation scheme are explored. We introduce a method by simultaneous perturbing responses, covariate, and within variance to obtain the local influence measure, which has an advantage of capable to compare the influence magnitude of influential studies from different perturbations. An example is used to illustrate the proposed methodology. PMID- 28719075 TI - Fibrosis in small syngeneic rat liver grafts because of damaged bone marrow stem cells from chronic alcohol consumption. AB - A patient with liver failure due to chronic and acute alcohol abuse under consideration for an urgent liver transplant shortly after stopping alcohol may have residual abnormalities that threaten transplant success, particularly for a small graft. To address this, we studied a model in which reduced-size (50%) Lewis rat livers are transplanted into green fluorescence protein transgenic Lewis recipients after they are fed alcohol or a control diet for 5 weeks. Here we show that normal small Lewis grafts transplanted to alcohol-fed Lewis hosts developed fibrosis, whereas no fibrosis was observed in control-fed recipients. Host-derived CD133 + 8-hydroxy-2'-deoxyguanosine (8-OHdG) cells were significantly increased in livers recovered from both alcohol-fed and control recipients, but only alcohol-fed recipients demonstrated co-staining (a marker of oxidative DNA damage). alpha smooth muscle actin (alpha-SMA) staining, a marker for myofibroblasts, also co-localized with CD133 + cells only in the livers of alcohol-fed recipients. Immunostaining and polymerase chain reaction analysis confirmed that chronic alcohol consumption decreased the proportion of bone marrow stem cells (BMSCs) expressing CD133, c-Kit, and chemokine (C-X-C motif) receptor 4 markers and caused oxidative mitochondria DNA (mtDNA) damage. Culture of CD133 + cells from normal rats with medium containing 3% ethanol for 48 hours resulted in elevated mitochondrial 8-OHdG and mtDNA deletion, and ethanol exposure diminished CD133 expression but dramatically increased alpha-SMA expression. In conclusion, oxidative mtDNA damage and deletions occur in BMSCs of chronic alcohol-fed recipients, and these damaged cells mobilize to the small liver grafts and become myofibroblasts where they play a key role in the subsequent development of fibrosis. Liver Transplantation 23 1564-1576 2017 AASLD. PMID- 28719076 TI - Multimodal image analysis of clinical influences on preterm brain development. AB - OBJECTIVE: Premature birth is associated with numerous complex abnormalities of white and gray matter and a high incidence of long-term neurocognitive impairment. An integrated understanding of these abnormalities and their association with clinical events is lacking. The aim of this study was to identify specific patterns of abnormal cerebral development and their antenatal and postnatal antecedents. METHODS: In a prospective cohort of 449 infants (226 male), we performed a multivariate and data-driven analysis combining multiple imaging modalities. Using canonical correlation analysis, we sought separable multimodal imaging markers associated with specific clinical and environmental factors and correlated to neurodevelopmental outcome at 2 years. RESULTS: We found five independent patterns of neuroanatomical variation that related to clinical factors including age, prematurity, sex, intrauterine complications, and postnatal adversity. We also confirmed the association between imaging markers of neuroanatomical abnormality and poor cognitive and motor outcomes at 2 years. INTERPRETATION: This data-driven approach defined novel and clinically relevant imaging markers of cerebral maldevelopment, which offer new insights into the nature of preterm brain injury. Ann Neurol 2017;82:233-246. PMID- 28719078 TI - Luseogliflozin improves liver fat deposition compared to metformin in type 2 diabetes patients with non-alcoholic fatty liver disease: A prospective randomized controlled pilot study. AB - This study aimed to assess the effect of luseogliflozin on liver fat deposition and compare luseogliflozin to metformin in type 2 diabetes (T2D) patients with non-alcoholic fatty liver disease (NAFLD). Thirty-two T2D patients with NAFLD diagnosed by computed tomography or abdominal sonography were recruited. Participants were randomly assigned to receive either luseogliflozin (2.5 mg, newly administered) or metformin (1500 mg, newly or additionally administrated). Data on the liver-to-spleen attenuation ratio (L/S), visceral fat area, body mass index, glycated hemoglobin (HbA1c), alanine aminotransferase (ALT), fasting plasma glucose, C-peptide immunoreactivity (CPR), and CPR index were collected at baseline and after 6 months. The change in L/S was significantly greater in the luseogliflozin group than in the metformin group. Similarly, the changes in the visceral fat area, HbA1c, and body mass index were significantly greater in the luseogliflozin group than in the metformin group. The changes in ALT, fasting glucose, CPR, and CPR index were not significant in both groups. In conclusion, luseogliflozin significantly reduced liver fat deposition as compared to metformin, which may indicate clinical relevant benefits for NAFLD. PMID- 28719077 TI - Metformin synergistic pemetrexed suppresses non-small-cell lung cancer cell proliferation and invasion in vitro. AB - The aim of this study was to investigate whether metformin in combination with pemetrexed has an effect on the treatment of non-small-cell lung cancer (NSCLC) models and to explore the related molecular mechanism. The half maximal inhibitory concentration (IC50) and combination index (CI) of metformin and pemetrexed were detected by the CCK8 assay to assess the antiproliferative and therapeutic effects of the two-drug combination. Flow cytometry (FCM) and invasion assays were used to estimate the variation in apoptosis rate and invasion ability of the differently treated NSCLC cell lines. Apoptotic markers were detected by western blotting to validate the data related to the antiproliferation and proapoptosis effects. Metformin monotherapy inhibited the growth of NSCLC cell lines and reduced the invasion ability to different degrees compared with the control groups (P < 0.05). Metformin in combination with pemetrexed produced a synergistic effect (CI < 0.90) compared with the two drugs in monotherapy in the three tested NSCLC cell lines. Metformin in combination with pemetrexed significantly increased the cell numbers of HCC827 cells at S phase (P < 0.001), and the combination therapy had no influence on the A549 and H1975 cell lines. We found that combining metformin with pemetrexed induced more cell apoptosis than metformin or pemetrexed used alone (P < 0.05), which was validated by the apoptotic markers. These results demonstrate that the combination of metformin and pemetrexed has a synergistic effect on the treatment of NSCLC cell lines by inducing apoptosis or blocking the cell cycle. Our data indicate that the combination of metformin and pemetrexed could have beneficial antitumor effects on NSCLC cells in vitro. PMID- 28719079 TI - Associations between drugs and small-bowel mucosal bleeding: Multicenter capsule endoscopy study. AB - BACKGROUND AND AIM: Although several drugs may induce small-bowel mucosal injuries, it is unclear whether these injuries contribute to overt small-bowel bleeding. This study was designed to evaluate the associations between drug use and small-bowel mucosal injury and between these mucosal injuries and overt bleeding in a disease-relevant population. METHODS: We retrospectively studied patients with suspected small-bowel diseases who underwent capsule endoscopy between 2010 and 2013. Drug exposure, Charlson Comorbidity Index, smoking, and alcohol consumption were assessed before capsule endoscopy. Adjusted odds ratios (AOR) and confidence intervals (CI) were estimated for small-bowel mucosal injury and small-bowel overt bleeding. RESULTS: In total, 850 patients were analyzed during the study period. Median age was 64 years, and 544 patients (64.0%) were men. Among the patients with small-bowel mucosal injury (n = 60) and without mucosal injury (n = 705), use of non-steroidal anti-inflammatory drugs (NSAIDs) (AOR 1.8, 95% CI 1.01-3.31) was significantly associated with an increased risk of small-bowel mucosal injury compared with non-use. Patients with small-bowel mucosal injury with overt bleeding (n = 85) and without overt bleeding (n = 60) were compared, and no significant difference between the groups in the usage rates for NSAIDs, thienopyridine, other antiplatelets, anticoagulants, acetaminophen, tramadol hydrochloride, or steroids was revealed, even after adjusting for confounders. CONCLUSION: Although the use of NSAIDs was significantly associated with an increased risk of small-bowel mucosal injury, no significant associations were observed between the use of such drugs and small bowel overt bleeding. PMID- 28719080 TI - Near infrared quantum dots in biomedical applications: current status and future perspective. AB - To address the requirements of biomedical applications including biosensing, bioimaging, and drug delivery, fluorescent nanomaterials served as efficient tools in many cases. Among them, near-infrared quantum dots (NIR QDs) have been used as novel fluorescent labels for their binary advantages of both QDs and NIR light. In this review, through collecting references in recent 10 years, we have introduced basic structures and properties of NIR QDs and summarized the classification and the related synthetic methods. This review also highlights the functionalization and surface bioconjugation of NIR QDs, and their biomedical applications in biosensing, bioimaging, and drug delivery. This article is categorized under: Diagnostic Tools > Diagnostic Nanodevices Diagnostic Tools > In Vitro Nanoparticle-Based Sensing Diagnostic Tools > In Vivo Nanodiagnostics and Imaging. PMID- 28719081 TI - Drought-induced mortality patterns and rapid biomass recovery in a terra firme forest in the Colombian Amazon. AB - Extreme climatic events affecting the Amazon region are expected to become more frequent under ongoing climate change. In this study, we assessed the responses to the 2010 drought of over 14,000 trees >=10 cm dbh in a 25 ha lowland forest plot in the Colombian Amazon and how these responses varied among topographically defined habitats, with tree size, and with species wood density. Tree mortality was significantly higher during the 2010-2013 period immediately after the drought than in 2007-2010. The post-drought increase in mortality was stronger for trees located in valleys (+243%) than for those located on slopes (+67%) and ridges (+57%). Tree-based generalized linear mixed models showed a significant negative effect of species wood density on mortality and no effect of tree size. Despite the elevated post-drought mortality, aboveground biomass increased from 2007 to 2013 by 1.62 Mg ha-1 yr-1 (95% CI 0.80-2.43 Mg ha-1 yr-1 ). Biomass change varied among habitats, with no significant increase on the slopes (1.05, 95% CI -0.76 to 2.85 Mg ha-1 yr-1 ), a significant increase in the valleys (1.33, 95% CI 0.37-2.34 Mg ha-1 yr-1 ), and a strong increase on the ridges (2.79, 95% CI 1.20-4.21 Mg ha-1 yr-1 ). These results indicate a high carbon resilience of this forest to the 2010 drought due to habitat-associated and interspecific heterogeneity in responses including directional changes in functional composition driven by enhanced performance of drought-tolerant species that inhabit the drier ridges. PMID- 28719082 TI - Determination of seven drugs of abuse and their metabolites in surface and wastewater using solid-phase extraction coupled to liquid chromatography with high-resolution mass spectrometry. AB - A method based on liquid chromatography with electrospray ionization high resolution mass spectrometry (Exactive Orbitrap) combined with solid-phase extraction using a strong cationic exchange mixed-mode sorbent has been developed for the determination of seven drugs of abuse, including two synthetic cathinones, as well as some of their metabolites in environmental water samples. The method provides low detection limits and a high confirmation power thanks to the diagnostic and two fragment ions monitored for each compound in high resolution mass spectrometry, providing six identification points for each analyte. The clean-up step based on methanol in the extraction step adequately decreased the matrix effect, mainly for river and effluent water, and provided suitable process efficiency. Method detection and quantitation limits for environmental waters were at low nanogram per liter. The method was applied to analyze the samples of influent and effluent wastewater, as well as surface water. Codeine, methadone, and its metabolite were determined in all samples of wastewater and the metabolite of cocaine, benzoylecgonine, was found at the highest concentration. PMID- 28719083 TI - Subtypes of Personality and 'Locus of Control' in Bariatric Patients and their Effect on Weight Loss, Eating Disorder and Depressive Symptoms, and Quality of Life. AB - The present study subdivided personality types in a bariatric sample and investigated their impact on weight loss and psychopathology 6 and 12 months after surgery. One hundred thirty participants answered questionnaires on personality (NEO-FFI), 'locus of control' (IPC), depression severity (BDI-II), eating disorder psychopathology (EDE-Q), and health-related quality of life (HRQoL; SF-12). K-means cluster analyses were used to identify subtypes. Two subtypes emerged: an 'emotionally dysregulated/undercontrolled' cluster defined by high neuroticism and external orientation and a 'resilient/high functioning' cluster with the reverse pattern. Prior to surgery, the first subtype reported more eating disorder and depressive symptoms and less HRQoL. Differences persisted regarding depression and mental HRQoL until 12 months after surgery, except in the areas weight loss and eating disorders. Personality seems to influence the improvement or maintenance of psychiatric symptoms after bariatric surgery. Future research could elucidate whether adapted treatment programmes could have an influence on the improvement of procedure outcomes. Copyright (c) 2017 John Wiley & Sons, Ltd and Eating Disorders Association. PMID- 28719084 TI - Defending a "Never Event". AB - There are medical mishaps that have been deemed "Never Events" by the Centers for Medicare & Medicaid Services (CMS). This term refers generally to preventable occurrences so egregious that they should never occur. But they do occur. And when they do, litigation often follows. This article focuses on one such Never Event-the operating room fire-with strategies on how to defend it. Information provided in this article was derived from a review of the relevant literature and from the author's personal experience defending lawsuits arising from Never Events, including a jury trial involving a surgeon who was sued for a patient's injuries after a fire erupted in the operating room. PMID- 28719086 TI - Thought leadership. PMID- 28719085 TI - Case law update. PMID- 28719087 TI - MRI-guided stereotactic neurosurgical procedures in a diagnostic MRI suite: Background and safe practice recommendations. AB - The development of navigation technology facilitating MRI-guided stereotactic neurosurgery has enabled neurosurgeons to perform a variety of procedures ranging from deep brain stimulation to laser ablation entirely within an intraoperative or diagnostic MRI suite while having real-time visualization of brain anatomy. Prior to this technology, some of these procedures required multisite workflow patterns that presented significant risk to the patient during transport. For those facilities with access to this technology, safe practice guidelines exist only for procedures performed within an intraoperative MRI. There are currently no safe practice guidelines or parameters available for facilities looking to integrate this technology into practice in conventional MRI suites. Performing neurosurgical procedures in a diagnostic MRI suite does require precautionary measures. The relative novelty of technology and workflows for direct MRI-guided procedures requires consideration of safe practice recommendations, including those pertaining to infection control and magnet safety issues. This article proposes a framework of safe practice recommendations designed for assessing readiness and optimization of MRI-guided neurosurgical interventions in the diagnostic MRI suite in an effort to mitigate patient risk. The framework is based on existing clinical evidence, recommendations, and guidelines related to infection control and prevention, health care-associated infections, and magnet safety, as well as the clinical and practical experience of neurosurgeons utilizing this technology. PMID- 28719088 TI - Understanding and managing the risk of "head impact" from in-hospital falls: A cross-sectional analysis of data from 166 public hospitals. AB - BACKGROUND: Falls are a leading cause of preventable harm in the hospitalized elderly, and head impacts (HIs) can be a precursor to serious injury. The aim of this study was to examine if the risk of fall-related HI can be explained by incident characteristics. METHODS: All reported falls across public hospital facilities in the state of Queensland, Australia, over a 2-year period were analyzed using univariate and multiple logistic regression. RESULTS: In all, 650 instances of HI were reported across 24 218 falls. Falls due to fainting were associated with elevated HI odds (odds ratio [OR] = 2.00, 95% confidence interval [CI] = 1.30, 3.08). Similarly, falls while walking (OR = 1.48, 95% CI = 1.20, 1.81) and falls during certain time periods, namely, from 11:00 pm to midnight (OR = 1.79, 95% CI = 1.24, 2.59) and between 5:00 am and 6:00 am (OR = 1.50, 95% CI = 1.01, 2.22) were linked to increased HI odds. Falls among males were associated with lowered odds of HI (adjusted odds ratio [AOR] = 0.78, 95% CI = 0.64, 0.74). CONCLUSIONS: Results confirm links between characteristics of inpatient falls and the likelihood of HI, and these data can assist risk managers to better target fall prevention strategies. Assisted mobility in high-risk patients and improved environmental lighting are advanced as foci for future research. PMID- 28719090 TI - Learning: New avenues and new topics. PMID- 28719089 TI - Development and implementation of an emergency department telephone follow-up system. AB - Implementing a telephone follow-up system after a patient's emergency department (ED) visit is challenging, but it may improve patient safety and care. This study's objective was to describe the development and implementation of a comprehensive ED telephone follow-up system over a 9-year period. Discharged patients who received a follow-up telephone call within 48 hours of their ED visit included all pediatric patients, those who left without being seen by a provider, and any adult patient with a "high-risk chief complaint," which was defined as a headache, visual problem, chest pain, dyspnea, abdominal pain, syncope, trauma, and neurological-related problems. There were 127 524 cases that met criteria to receive a follow-up call, with 138 331 attempted calls being made and 46 114 (36.2%) cases successfully followed up. Forty-two percent of pediatric cases and 16% of patients who left without being seen were successfully contacted with a follow-up call; 1.6% of cases were referred to the CQI Committee. In the 9 years prior and after implementation of this follow-up system, there were 3.5 (95% confidence interval [CI] = 2.1-5.9) and 2.5 (95% CI = 1.3-4.5) medical malpractice lawsuits per 100 000 ED patient visits, respectively; this represented a 28.6% reduction. A comprehensive telephone follow-up program can be developed and implemented utilizing available resources. PMID- 28719091 TI - Multimodal analgesia as an alternative to the risks of opioid monotherapy in surgical pain management. AB - Clinicians have long been aware of the danger of overreliance on opioids to manage acute pain, such as the pain accompanying surgery. The risk of adverse drug events is higher with opioids than with any other common class of drugs. Overreliance on opioids increases length of stay and hospital costs, while decreasing patient satisfaction. Opioids can lead to problems that continue well after discharge, including chronic pain, abuse and addiction, and even death. Increasingly, prescribed opioids have proved to lead to heroin addiction. Studies show that the same professionals who prescribe, administer, and monitor opioids lack basic knowledge about their safe and effective use. The alternative to opioid monotherapy in controlling acute pain is multimodal analgesia, an approach that relies on a nonopioid foundation with addition of adjunctive opioids as needed. An increasing number of nonopioid analgesics have proved effective in this role, with fewer side effects and a higher degree of safety than opioids. Accordingly, multimodal analgesia is recommended as best practice by most recognized authorities. Increasingly, governmental authorities hold prescribing clinicians and institutions legally liable for the downstream negative effects of opioids, including abuse and addiction. Addressing this issue should be a top priority for hospital risk managers. PMID- 28719092 TI - What is targeted proteomics? A concise revision of targeted acquisition and targeted data analysis in mass spectrometry. AB - Targeted proteomics has gained significant popularity in mass spectrometry-based protein quantification as a method to detect proteins of interest with high sensitivity, quantitative accuracy and reproducibility. However, with the emergence of a wide variety of targeted proteomics methods, some of them with high-throughput capabilities, it is easy to overlook the essence of each method and to determine what makes each of them a targeted proteomics method. In this viewpoint, we revisit the main targeted proteomics methods and classify them in four categories differentiating those methods that perform targeted data acquisition from targeted data analysis, and those methods that are based on peptide ion data (MS1 targeted methods) from those that rely on the peptide fragments (MS2 targeted methods). PMID- 28719093 TI - Bone marrow harvest from unrelated donors-up-to-date methodology. AB - OBJECTIVES: Bone marrow harvesting is one of the essential sources of stem cells for hematopoietic stem cell transplantation. We describe here the current "up-to date" standard of the bone marrow harvest in unrelated stem cell donors. METHODS: We analyzed medical data of 187 unrelated hematopoietic stem cell donors who underwent bone marrow harvest without previous peripheral blood stem collection at the center between 2011 and 2015. The methodology of marrow collection includes multiple cells aimed at safety of the procedure, for example, educational movie, modified skin disinfection protocol, cell enumeration during the procedure, reduction of the contamination surfaces, and ongoing monitoring of the quality of work of the doctors. RESULTS: The total nucleated cell count over 2*108 per kg of recipient has been reached in 93.6% of harvests. All of the donors harvested more than 1*108 per kg of the recipient. There were no donors who required transfusions or had serious adverse events during and after the harvest. CONCLUSION: We describe here the current up-to-date standard of bone marrow harvest, which leads to excellent results in majority of donors without causing significant complications during the donation. PMID- 28719094 TI - Discovery and characterization of a novel tryptophan hydroxylase 1 inhibitor as a prodrug. AB - Serotonin (5-HT) is an important neurotransmitter and paracrine signaling molecule in the gastrointestinal tract. Two distinct tryptophan hydroxylases (TPH), TPH1 and TPH2, are the rate-limiting enzymes in the 5-HT biosynthesis process. TPH1 expression is mainly limited in the enterochromaffin cells and distributed in peripheries such as the skin and gut, while TPH2 is the predominant isoform in the CNS. In this study, mol002291 was screened as a drug like compound from the TCM database for the inhibitor of TPH. After the enzymological analysis of mol002291, the analgesic effect of mol002291 was also further investigated in a PI-IBS visceral hyperalgesia rat model. Results from kinetic analysis showed that mol002291 specifically inhibited the TPH1 but did not act on TPH2, and the inhibitory action displayed characteristics of competitive inhibition. In addition, the results from abdominal withdrawal reflex (AWR) tests and electromyography (EMG) recordings showed that mol002291 significantly (p < .05) alleviated the visceral hyperalgesia. This result is entirely consistent with the fact that mol002291 significantly decreased the 5-HT content. These data demonstrated that mol002291 can attenuate visceral hyperalgesia mediated via reducing colonic 5-HT content. More important is that mol002291 could be developed as a novel prodrug and offer therapeutic avenues for the diseases where there is dysregulation of peripheral serotonergic pathways. PMID- 28719095 TI - Lignin-Retaining Transparent Wood. AB - Optically transparent wood, combining optical and mechanical performance, is an emerging new material for light-transmitting structures in buildings with the aim of reducing energy consumption. One of the main obstacles for transparent wood fabrication is delignification, where around 30 wt % of wood tissue is removed to reduce light absorption and refractive index mismatch. This step is time consuming and not environmentally benign. Moreover, lignin removal weakens the wood structure, limiting the fabrication of large structures. A green and industrially feasible method has now been developed to prepare transparent wood. Up to 80 wt % of lignin is preserved, leading to a stronger wood template compared to the delignified alternative. After polymer infiltration, a high lignin-content transparent wood with transmittance of 83 %, haze of 75 %, thermal conductivity of 0.23 W mK-1 , and work-tofracture of 1.2 MJ m-3 (a magnitude higher than glass) was obtained. This transparent wood preparation method is efficient and applicable to various wood species. The transparent wood obtained shows potential for application in energy-saving buildings. PMID- 28719096 TI - The effect of state laws designed to prevent nonmedical prescription opioid use on overdose deaths and treatment. AB - Nonmedical use of prescription opioids has reached epidemic levels in the United States and globally. In response, federal, state, and local governments are taking actions to address substantial increases in prescription opioid addiction and its associated harms. This study examines the effect of two state laws specifically designed to curtail access to prescription opioids to nonmedical users: pain management clinic and doctor shopping laws. We use administrative data on overdose deaths and admissions to specialty substance use disorder treatment coupled with a differences-in-differences design. Our findings suggest that both pain management clinic and doctor shopping laws have the potential to reduce prescription opioid overdose deaths. Moreover, doctor shopping laws appear to reduce prescription opioid treatment admissions. As many states have adopted these laws in recent years, the full effects of the laws may not yet be realized. Future research using more postlaw passage data should reevaluate the effectiveness of these laws. PMID- 28719097 TI - Mitochondrial proteostasis as a shared characteristic of slowed aging: the importance of considering cell proliferation. AB - Proteostasis is one of the seven "pillars of aging research" identified by the Trans-NIH Geroscience Initiative and loss of proteostasis is associated with aging and age-related chronic disease. Accumulated protein damage and resultant cellular dysfunction are consequences of limited protein repair systems and slowed protein turnover. When relatively high rates of protein turnover are maintained despite advancing age, damaged proteins are more quickly degraded and replaced, maintaining proteome fidelity. Therefore, maintenance of protein turnover represents an important proteostatic mechanism. However, measurement of protein synthesis without consideration for cell proliferation can result in an incomplete picture, devoid of information about how new proteins are being allocated. Simultaneous measurement of protein and DNA synthesis provides necessary mechanistic insight about proteins apportioned for newly proliferating cells versus for somatic maintenance. Using this approach with a number of murine models of slowed aging shows that, compared to controls, energetic resources are directed more toward somatic maintenance and proteostasis, and away from cell growth and proliferation. In particular, slowed aging models are associated with heightened mechanisms of mitochondrial proteostatic maintenance. Taking cell proliferation into account may explain the paradoxical findings that aging itself and slowed aging interventions can both be characterized by slower rates of protein synthesis. PMID- 28719098 TI - A Pyridoindole-Based Multifunctional Bioprobe: pH-Induced Fluorescence Switching and Specific Targeting of Lipid Droplets. AB - A versatile fluorescent probe, PITE, based on alkyl-substituted pyridoindole (PI) and tetraphenylethylene (TE), which exhibits facile pH-induced fluorescence switching in solution, as nanoparticles, and in the solid state, is presented. Strong fluorescence in the solid state, as well as in solution and the aggregated state, allow sensing of toxic acid vapors. Fluorescence "off-on" switching of PITE through exposure to trifluoroacetic acid and triethylamine vapor is visualized by the naked eye. A unified picture of the switchable fluorescence of PITE is obtained by comprehensive spectroscopic investigations coupled with quantum mechanical calculations. Strong fluorescence, a large Stokes shift, high photostability, and biocompatibility of PITE make it a viable probe for subcellular imaging. Extensive fluorescence microscopic studies by employing organisms including lower and higher eukaryotes reveal specific localization of PITE to lipid droplets (LDs). LDs are dynamic subcellular organelles linked to various physiological processes and human diseases. Hence, the specific detection of LDs in diverse organisms is important to biomedical research and healthcare. Isolation of LDs and subsequent colocalization studies ascertain selective targeting of LDs by the easily affordable, lipophilic bioprobe, PITE. Thus, PITE is a promising multifunctional probe for chemosensing and the selective tracking of LDs. PMID- 28719099 TI - Spontaneous Keto-Enol Tautomerization in the Crystal Lattice Visualized with the Help of Water Encapsulated in Hydrophilic Reservoirs. AB - Keto-enol tautomerism in the solid phase is a process that is particularly difficult to follow. In this work we demonstrate how it can be done by introducing deuterium into the crystal lattice of organic compounds which tend to form hydrates. In our studies we explored H-D exchange in the crystals stored in contact with deuterium oxide vapors. Employing barbituric acid (BA) and (+) catechin (CAT) as model samples and by using advanced solid-state NMR spectroscopy and mass spectrometry, we revealed that not only OH and NH protons of these chemicals undergo exchange to deuterium in a crystal lattice, but also usually immobile protons, that is, (Ar)CH (in CAT) and CH2 (in BA) are exchanged as a result of keto-enol tautomerism. PMID- 28719100 TI - Deuteration of Hyperpolarized 13 C-Labeled Zymonic Acid Enables Sensitivity Enhanced Dynamic MRI of pH. AB - Aberrant pH is characteristic of many pathologies such as ischemia, inflammation or cancer. Therefore, a non-invasive and spatially resolved pH determination is valuable for disease diagnosis, characterization of response to treatment and the design of pH-sensitive drug-delivery systems. We recently introduced hyperpolarized [1,5-13 C2 ]zymonic acid (ZA) as a novel MRI probe of extracellular pH utilizing dissolution dynamic polarization (DNP) for a more than 10000-fold signal enhancement of the MRI signal. Here we present a strategy to enhance the sensitivity of this approach by deuteration of ZA yielding [1,5-13 C2 , 3,6,6,6-D4 ]zymonic acid (ZAd ), which prolongs the liquid state spin lattice relaxation time (T1 ) by up to 39 % in vitro. Measurements with ZA and ZAd on subcutaneous MAT B III adenocarcinoma in rats show that deuteration increases the signal-to-noise ratio (SNR) by up to 46 % in vivo. Furthermore, we demonstrate a proof of concept for real-time imaging of dynamic pH changes in vitro using ZAd , potentially allowing for the characterization of rapid acidification/basification processes in vivo. PMID- 28719101 TI - Neuronal degeneration and regeneration induced by axotomy in the olfactory epithelium of Xenopus laevis. AB - The olfactory epithelium (OE) has the remarkable capability to constantly replace olfactory receptor neurons (ORNs) due to the presence of neural stem cells (NSCs). For this reason, the OE provides an excellent model to study neurogenesis and neuronal differentiation. In the present work, we induced neuronal degeneration in the OE of Xenopus laevis larvae by bilateral axotomy of the olfactory nerves. We found that axotomy induces specific- neuronal death through apoptosis between 24 and 48h post-injury. In concordance, there was a progressive decrease of the mature-ORN marker OMP until it was completely absent 72h post injury. On the other hand, neurogenesis was evident 48h post-injury by an increase in the number of proliferating basal cells as well as NCAM-180- GAP-43+ immature neurons. Mature ORNs were replenished 21 days post-injury and the olfactory function was partially recovered, indicating that new ORNs were integrated into the olfactory bulb glomeruli. Throughout the regenerative process no changes in the expression pattern of the neurotrophin Brain Derivate Neurotrophic Factor were observed. Taken together, this work provides a sequential analysis of the neurodegenerative and subsequent regenerative processes that take place in the OE following axotomy. (c) 2017 Wiley Periodicals, Inc. Develop Neurobiol 77: 1308-1320, 2017. PMID- 28719102 TI - Plant viral and bacteriophage delivery of nucleic acid therapeutics. AB - Nucleic acid therapeutics have emerged as a powerful method for treatment of many diseases. However, the challenge lies in safe and efficient delivery of nucleic acids to their target site, as they need to cross various extracellular and intracellular barriers. Mammalian viruses have initially been favored for delivery of nucleic acid therapeutics, but safety concerns regarding their immunogenicity and potential of integration have fueled the search for alternative delivery strategies. For example, chemistry and bioengineering have led to advances in the use of nonviral vectors composed of lipids and other polymers; nevertheless, the synthetic systems often do not match the efficiency achieved using the biological systems. More recently, researchers have turned toward the development of plant viruses and bacteriophages and virus-like particles as an alternative or complementary approach. These systems unite the properties of both the viral and nonviral systems and as such are a new exciting avenue toward nucleic acid delivery. This review highlights the benefits of plant viral and bacteriophage delivery of nucleic acids and provides a summary of the current progress in research in this field. WIREs Nanomed Nanobiotechnol 2018, 10:e1487. doi: 10.1002/wnan.1487 This article is categorized under: Biology Inspired Nanomaterials > Protein and Virus-Based Structures. PMID- 28719103 TI - Associations between neighborhood food environments and deficient protein intake among elderly people in a metropolitan suburb: A case study in Kisarazu city, Japan. AB - OBJECTIVES: Living in a poor food environment and its association with an increased risk of inadequate nutrient intake are increasingly important issues in Japan due to an increase in the elderly population. METHODS: The present study examined the relationships between neighborhood food environment and the protein and fat intakes of elderly Japanese individuals (n = 181) living in the metropolitan Tokyo suburb of Kisarazu. RESULTS: A logistic regression analysis adjusted for sociodemographic and shopping behavior variables revealed associations between subjectively evaluated poor neighborhood food environment and deficient protein intake. However, there was no significant association between excessive fat intake and neighborhood food environments. CONCLUSION: The findings demonstrate that living in a poor neighborhood food environment, which is becoming increasingly prevalent in Japan and other developed countries, has the potential to result in malnutrition, or at least in a low-quality diet, in elderly populations. PMID- 28719104 TI - Modeling Solvation in Supercritical CO2. AB - In recent decades, a microscopic understanding of solute-solvent intermolecular interactions has been key to advances in technologies based on supercritical carbon dioxide. In many cases, computational work has provided the impetus for new discoveries, shedding new light on important concepts such as the local structure around the solute in the supercritical medium, the influence of the peculiar properties of the latter on the molecular behavior of dissolved substances and, importantly, CO2 -philicity. In this Review, the theoretical work that has been relevant to these developments is surveyed and, by presenting some crucial open questions, the possible routes to achieving further progress based on the interplay between theory and experiments is discussed. PMID- 28719105 TI - Screening for Hazardous Drinking in Nursing Home Residents: Evaluating the Validity of the Current Cutoffs of the Alcohol Use Disorder Identification Test Consumption Questions by Using Ethyl Glucuronide in Hair. AB - BACKGROUND: Because of physiological changes, elderly people are much more exposed to the adverse effects of alcohol. Therefore, hazardous drinking is defined at lower levels as compared to younger adults. This work aimed to evaluate the validity of the current cutoff levels of the Alcohol Use Disorder Identification Test-Consumption (AUDIT-C) questions to detect hazardous drinking in the elderly by using ethyl glucuronide in hair (HEtG). METHODS: In a border region between Austria and Germany, 344 nursing home residents were included from 33 of the 107 nursing homes. Residents were asked to answer the AUDIT-C questions, hair samples were obtained, and nursing staff members were asked for their assessments of the residents' alcohol consumption. Hair samples were analyzed for HEtG using gas chromatography-mass spectrometry. Receiver-operating characteristic (ROC) curve analysis was performed to determine the validity of cutoff values for the AUDIT-C to detect an alcohol consumption of >=10 g of alcohol/d. RESULTS: A total of 11.3% of the nursing home residents (n = 344) drank >=10 g of alcohol/d (4.9% >60 g of alcohol/d, 6.4% 10 to 60 g of alcohol/d, 88.7% <10 g of alcohol/d)). For the drinking limit of >=10 g of alcohol/d, ROC curve analysis showed a balanced sensitivity and specificity, with an AUDIT-C cutoff of >=4 for men (sensitivity: 70%, specificity: 83.6%; AUC = 0.823, CI = 0.718 to 0.928, p < 0.001) and >=2 for women (sensitivity: 73.7%, specificity: 81.9%; AUC = 0.783, CI = 0.653 to 0.914, p < 0.001). Nursing staff (n = 274) underestimated alcohol consumption and evaluated 40% of the chronic-excessive alcohol consumers (>60 g of alcohol/d) as being abstinent. CONCLUSIONS: Our data suggest that an AUDIT-C cutoff of >=4 for men and >=2 for women can be recommended to detect the consumption of >=10 g of alcohol/d in the elderly. Because the nursing staff to a large extent underestimates the alcohol consumption among nursing home residents, further teaching of the staff, improvement of screening instruments for the elderly, and the use of objective biomarkers might be helpful for recognizing hazardous drinking and can thus help improve the quality of life of the elderly. PMID- 28719106 TI - Altered pulmonary gas transfer capacity and capillary blood volume in pediatric Crohn's disease. AB - OBJECTIVES: To describe diffusing capacity for carbon monoxide (DLCO) and its components, that is, membrane diffusing capacity (DmCO) and pulmonary capillary blood volume (Vc) in children with Crohn's disease (CD), and to investigate the correlation between these parameters and disease activity. WORKING HYPOTHESIS: The most common lung function abnormalities are a reduced pulmonary DLCO and small airways disorders which are in many instances, clinically silent. No valid explanations have been proposed regarding the modifications in gas transfer capacity in active CD. METHODS: DLCO, DmCO, and Vc were measured in 25 CD children by the simultaneous single breath lung diffusing capacity method using nitric oxide (NO) and carbon monoxide (CO) transfer. These parameters were analyzed in relation to the CD disease activity index. RESULTS: DLCO (90.7 +/- 4.5% vs 128.5 +/- 4.7%; P < 0.001), Dm (92.4 +/- 5.9% vs 125.6 +/- 6.3%; P < 0.001), and Vc (72.6 +/- 3.7% vs 104.4 +/- 4.0%; P < 0.001) were significantly decreased in the active CD group in comparison with the inactive CD group. DLCO (r = -0.60; P < 0.01), DmCO (r = -0.45; P < 0.01), and Vc (r = -0.60; P < 0.01) were inversely correlated to the PCDAI. In 8 patients who participated to the study at initial diagnosis then during remission, DmCO and Vc increased significantly between the active and the inactive period of the disease. CONCLUSION: Pulmonary diffusing capacity is impaired in children with active CD, mainly because of a decrease of the pulmonary capillary volume. PMID- 28719108 TI - Isothermal Chirality Switching in Liquid-Crystalline Azobenzene Compounds with Non-Polarized Light. AB - Spontaneous mirror-symmetry breaking is a fundamental process for development of chirality in natural and in artificial self-assembled systems. A series of triple chain azobenzene based rod-like compounds is investigated that show mirror symmetry breaking in an isotropic liquid occurring adjacent to a lamellar LC phase. The transition between the lamellar phase and the symmetry-broken liquid is affected by trans-cis photoisomerization, which allows a fast and reversible photoinduced switching between chiral and achiral states with non-polarized light. PMID- 28719109 TI - Insights into Magnetic Interactions in a Monodisperse Gd12 Fe14 Metal Cluster. AB - The largest Ln-Fe metal cluster [Gd12 Fe14 (MU3 -OH)12 (MU4 -OH)6 (MU4 -O)12 (TEOA)6 (CH3 COO)16 (H2 O)8 ]?(CH3 COO)2 (CH3 CN)2 ?(H2 O)20 (1) and the core shell monodisperse metal cluster of 1 a@SiO2 (1 a=[Gd12 Fe14 (MU3 -OH)12 (MU4 OH)6 (MU4 -O)12 (TEOA)6 (CH3 COO)16 (H2 O)8 ]2+ ) were prepared. Experimental and theoretical studies on the magnetic properties of 1 and 1 a@SiO2 reveal that encapsulation of one cluster into one silica nanosphere not only effectively decreases intermolecular magnetic interactions but also significantly increases the zero-field splitting effect of the outer layer Fe3+ ions. PMID- 28719110 TI - Benefits of Attending a Weekend Childhood Cancer Survivor Family Retreat. AB - PURPOSE: To explore the long-term benefits to families of childhood cancer survivors who attended a weekend childhood cancer survivor family retreat. DESIGN: Descriptive-qualitative study including families who had attended the weekend retreat at least once but not in the past 12 months, and who attend a large pediatric hematology and oncology cancer survivorship program in Texas. METHODS: A semistructured interview guide was used during three audio-taped focus groups to explore the benefits of having attended a weekend retreat. Descriptive qualitative analysis was used to analyze the focus groups' transcripts. FINDINGS: Seven families participated in the focus groups, and the themes identified were reconnecting (with others or family), putting life in perspective, and changing outlook on life. CONCLUSIONS: Retreats offer families of cancer survivors opportunities to reconnect with others and their own family members in a therapeutic environment. These reconnections in a therapeutic environment enriched the families' positive outlooks on life and changed their perspectives. CLINICAL RELEVANCE: Families of childhood cancer survivors report a lack of support following the completion of therapy. Retreats in a nonclinical therapeutic setting optimize family-perceived support, relationship building, and reconnecting survivor families. PMID- 28719111 TI - Speeding up recovery from radical cystectomy: how low can we go? PMID- 28719112 TI - Defining the clinical utility of PSMA-targeted PET imaging of prostate cancer. PMID- 28719113 TI - Nocturia and depressive symptoms in older men. PMID- 28719114 TI - Enzalutamide for treating metastatic hormone-relapsed prostate cancer before chemotherapy is indicated: (c) NICE (2016) Enzalutamide for treating metastatic hormone-relapsed prostate cancer before chemotherapy is indicated. PMID- 28719116 TI - Medical Oncology Group of Australia Incorporated Annual Scientific Meeting, Real World Oncology: Translating Discovery in to Practice, Pullman Melbourne Albert Park, Victoria, Australia, 2-4 August 2017. PMID- 28719115 TI - Sentinel nodes in prostate cancer- are we chasing a ghost? PMID- 28719120 TI - National Speakers. PMID- 28719125 TI - Convenor's Welcome. PMID- 28719132 TI - Endometrial Biopsy: American College of Nurse-Midwives. AB - Endometrial biopsy can be used to diagnose endometrial hyperplasia, endometrial cancer, and uterine infections. This cost-effective procedure has minimal side effects, and complications are rare. The purpose of this clinical bulletin is to provide clinicians with guidance about endometrial biopsy including the procedure's advantages and disadvantages, indications and contraindications, and side effects. In addition, step-by-step instructions for performing endometrial biopsy, the equipment required, selection of sampling devices, and care before and after the procedure are discussed. PMID- 28719133 TI - Critical elements in pediatric allograft selection. PMID- 28719134 TI - Development and implementation of a clinical pathway for cardiac surgery in the intensive care unit: Effects on protocol adherence. AB - RATIONALE, AIMS AND OBJECTIVES: Cardiac surgery (CS) is facilitated by multiple perioperative guidelines and protocols. Use of a clinical pathway (CP) may facilitate the care of these patients. METHODS: This is a pre-post design study in the ICU of a tertiary referral centre. A CP for CS patients in the ICU was developed by ICU-nurses and enabled them to execute proactively predefined actions in accordance with and within the preset boundaries which were part of a variance report. A tailored implementation strategy was used. Primary outcome measure was protocol adherence above 80% on the domains of blood pressure control, action on chest tube blood loss and electrolyte control within the CP. RESULTS: In a 4-month period, 84 consecutive CP patients were included and compared with 162 matched control patients admitted in the year before implementation; 3 patients were excluded. Propensity score was used as matching parameter. CP patients were more likely to receive early adequate treatment for derangements in electrolytes (96% vs 47%, P < .001), blood pressure (90% vs 49%, P < .001) and adequate treatment for chest tube blood loss (90% vs 10%, P < .001). We found no differences in hospital and ICU LOS, ICU readmission or mortality. CONCLUSION: Use of the CP improved postoperative ICU treatment for cardiac surgical patients. Implementation of a CP and the use of a special variance report could be a blueprint for the implementation and use of a CP in low-volume high complex surgery. PMID- 28719135 TI - Multiple breath washout in pediatric patients after lung transplantation. AB - Forced expiratory volume in 1 second (FEV1 ) from spirometry is the most commonly used parameter to detect early allograft dysfunction after lung transplantation (LTx). There are concerns regarding its sensitivity. Nitrogen-multiple breath washout (N2 -MBW) is sensitive at detecting early global (lung clearance index [LCI]) and acinar (Sacin ) airway inhomogeneity. We investigated whether N2 -MBW indices indicate small airways pathology after LTx in children with stable spirometry. Thirty-seven children without bronchiolitis obliterans syndrome [BOS] at a median of 1.6 (0.6-3.0) years after LTx underwent N2 -MBW and spirometry, 28 of those on 2 occasions (<=6 months apart) during clinically stable periods. Additional longitudinal data (11 and 8 measurements, respectively) are provided from 2 patients with BOS. In patients without BOS, LCI and Sacin were significantly elevated compared with healthy controls. LCI was abnormal at the 2 test occasions in 81% and 71% of patients, respectively, compared with 30% and 39% of patients with abnormal FEV1 /forced vital capacity (FVC). Correlations of LCI with FEV1 /FVC (r = 0.1, P = .4) and FEV1 (r = -0.1, P = .6) were poor. N2 MBW represents a sensitive and reproducible tool for the early detection of airways pathology in stable transplant recipients. Moreover, indices were highly elevated in both patients with BOS. Spirometry and LCI showed poor correlation, indicating distinct and complementary physiologic measures. PMID- 28719136 TI - Comparing alternative and traditional dissemination metrics in medical education. AB - CONTEXT: The impact of academic scholarship has traditionally been measured using citation-based metrics. However, citations may not be the only measure of impact. In recent years, other platforms (e.g. Twitter) have provided new tools for promoting scholarship to both academic and non-academic audiences. Alternative metrics (altmetrics) can capture non-traditional dissemination data such as attention generated on social media platforms. OBJECTIVES: The aims of this exploratory study were to characterise the relationships among altmetrics, access counts and citations in an international and pre-eminent medical education journal, and to clarify the roles of these metrics in assessing the impact of medical education academic scholarship. METHODS: A database study was performed (September 2015) for all papers published in Medical Education in 2012 (n = 236) and 2013 (n = 246). Citation, altmetric and access (HTML views and PDF downloads) data were obtained from Scopus, the Altmetric Bookmarklet tool and the journal Medical Education, respectively. Pearson coefficients (r-values) between metrics of interest were then determined. RESULTS: Twitter and Mendeley (an academic bibliography tool) were the only altmetric-tracked platforms frequently (> 50%) utilised in the dissemination of articles. Altmetric scores (composite measures of all online attention) were driven by Twitter mentions. For short and full length articles in 2012 and 2013, both access counts and citation counts were most strongly correlated with one another, as well as with Mendeley downloads. By comparison, Twitter metrics and altmetric scores demonstrated weak to moderate correlations with both access and citation counts. CONCLUSIONS: Whereas most altmetrics showed limited correlations with readership (access counts) and impact (citations), Mendeley downloads correlated strongly with both readership and impact indices for articles published in the journal Medical Education and may therefore have potential use that is complementary to that of citations in assessment of the impact of medical education scholarship. PMID- 28719137 TI - Neocortical developmental analysis of vasculature and their growth factors offer new insight into fragile X syndrome abnormalities. AB - Fragile X Syndrome (FXS) is the most common single gene cause for Autism Spectrum Disorder and the most prevalent form of inherited mental retardation. Our prior studies have demonstrated that adult FXS mice have abnormal blood vessel density (BVD) and elevated Vascular Endothelial Growth Factor A expression (VEGF-A). VEGF A is one of the most prominent regulators of BVD, and its abnormal expression is the most likely cause for FXS BVD abnormalities. We have demonstrated that attenuating elevated VEGF-A expression can ameliorate many non-vascular FXS abnormalities (Belagodu, Zendeli Slater and Galvez: Dev Neurobiol 77 (2017) 14 25), suggesting that abnormal VEGF-A expression is an underlying cause for some FXS abnormalities. However, FXS is a developmental disorder and VEGF-A's potential role in mediating FXS abnormalities during development have never been explored. Furthermore, VEGF-A is one protein in a family of proteins (VEGF-A, VEGF-B, VEGF-C, VEGF-D, & PLGF) that activate one of three primary receptors (VEGFR1, VEGFR2, & VEGFR3). Abnormal expression of any of these proteins could hinder proper development. The current study demonstrated that FXS mice do not exhibit normal BVD developmental patterns, resulting in elevated adult expression, most likely due to observed elevated VEGF-A adult expression. Interestingly, all five VEGF family of proteins exhibited altered developmental expression patterns that could cause abnormal development. However, none of the receptors exhibited abnormal adult expression, but did exhibit altered developmental expression. Expanding upon our prior analyses, the current study provides additional interesting insight towards potential developmental mechanisms mediating FXS abnormalities, while offering further sites for age specific therapeutic interventions. (c) 2017 Wiley Periodicals, Inc. Develop Neurobiol 77: 1321-1333, 2017. PMID- 28719138 TI - Chevrel Phase Mo6 T8 (T = S, Se) as Electrodes for Advanced Energy Storage. AB - With the large-scale applications of electric vehicles in recent years, future batteries are required to be higher in power and possess higher energy densities, be more environmental friendly, and have longer cycling life, lower cost, and greater safety than current batteries. Therefore, to develop alternative electrode materials for advanced batteries is an important research direction. Recently, the Chevrel phase Mo6 T8 (T = S, Se) has attracted increasing attention as electrode candidate for advanced batteries, including monovalent (e.g., lithium and sodium) and multivalent (e.g., magnesium, zinc and aluminum) ion batteries. Benefiting from its unique open crystal structure, the Chevrel phase Mo6 T8 cannot only ensure rapid ion transport, but also retain the structure stability during electrochemical reactions. Although the history of the research on Mo6 T8 as electrodes for advanced batteries is short, there has been significant progress on the design and fabrication of Mo6 T8 for various advanced batteries as above mentioned. An overview of the recent progress on Mo6 T8 electrodes applied in advanced batteries is provided, including synthesis methods and diverse structures for Mo6 T8 , and electrochemical mechanism and performance of Mo6 T8 . Additionally, a briefly conclusion on the significant progress, obvious drawbacks, emerging challenges and some perspectives on the research of Mo6 T8 for advanced batteries in the near future is provided. PMID- 28719139 TI - Identification of metabolites in human and rat urine after oral administration of Xiao-Qing-Long-Tang granule using ultra high performance liquid chromatography combined with quadrupole time-of-flight mass spectrometry. AB - Xiao-Qing-Long-Tang is a traditional Chinese formula used for the treatment of cold syndrome, bronchitis, and nasal allergies for thousands of years. However, the in vivo integrated metabolism of its multiple components and the active chemical constituents of Xiao-Qing-Long-Tang remain unknown. In this study, a method using ultra high performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry was established for the detection and identification of the metabolites in human and rat urine after oral administration of Xiao-Qing-Long-Tang. A total of 19 compounds were detected or tentatively identified in human urine samples, including eight prototypes and 11 metabolites. Also, a total of 50 compounds were detected or tentatively identified in rat urine samples, including 15 prototypes and 35 metabolites detected with either a highly sensitive extracted ion chromatogram method or the MSE determination using Mass Fragment software. Our results indicated that phase II reactions (e.g. glucuronidation and sulfation) were the main metabolic pathways of flavones, while phase I reactions (e.g. demethylation and hydroxylation) were the major metabolic reaction for alkaloids, lignans, and ginger essential oil. This investigation provided important structural information on the metabolism of Xiao-Qing-Long-Tang and provided evidence to obtain a more comprehensive metabolic profile. PMID- 28719140 TI - Do English mental health services know whether they followed N.I.C.E. guidelines with patients who killed themselves? AB - : Freedom of Information Act requests sent to 51 NHS mental health providers in England showed an average of 20.5 suicides per organization. Only one provider, however, could report how many people that had killed themselves had been offered N.I.C.E. recommended psychological therapy. Information that might prevent suicides is being ignored. PRACTITIONER POINTS: Mental health services need, urgently, to develop data systems that can inform clinical team leaders about gaps in their services to suicidal people in their care Clinical psychologists have a particular responsibility to pressure managers to effectively monitor the provision of evidence-based treatments to suicidal people Trusts and commissioners must be aware of, and rectify, any failings of their services in relation to the prevention of suicide. PMID- 28719141 TI - Neonatal infection produces significant changes in immune function with no associated learning deficits in juvenile rats. AB - The current experiments examined the impact of early-life immune activation and a subsequent mild immune challenge with lipopolysaccharide (LPS; 25ug/kg) on hippocampal-dependent learning, proinflammatory cytokine expression in the brain, and peripheral immune function in juvenile male and female rats at P24, an age when hippocampal-dependent learning and memory first emerges. Our results indicate that neonatal infection did not produce learning deficits in the hippocampal-dependent context pre-exposure facilitation effect paradigm in juvenile males and females, contrary to what has been observed in adults. Neonatal infection produced an increase in baseline IL-1beta expression in the hippocampus (HP) and medial prefrontal cortex (mPFC) of juvenile rats. Furthermore, neonatally infected rats showed exaggerated IL-1beta expression in the HP following LPS treatment as juveniles; and juvenile females, but not males, showed exaggerated IL-1beta expression in the mPFC following LPS treatment. Neonatal infection attenuated the production of IL-6 expression following LPS treatment in both the brain and the spleen, and neonatal infection decreased the numbers of circulating white blood cells in juvenile males and females, an effect that was further exacerbated by subsequent LPS treatment. Together, our data indicate that the consequences of neonatal infection are detectable even early in juvenile development, though we found no concomitant hippocampal-dependent learning deficits at this young age. These findings underscore the need to consider age and associated on-going neurodevelopmental processes as important factors contributing to the emergence of cognitive and behavioral disorders linked to early-life immune activation. (c) 2017 Wiley Periodicals, Inc. Develop Neurobiol 77: 1221-1236, 2017. PMID- 28719142 TI - Changing prevalence of severe congenital heart disease: Results from the National Register for Congenital Heart Defects in Germany. AB - OBJECTIVE: To assess the prevalence of congenital heart disease (CHD) in Germany in relation to phenotypes, severity and gender. DESIGN: Cross-sectional registry study. SETTING: We analyzed data from patients with CHD born between 1996 and 2015. PATIENTS: A total of 26 630 patients, registered with the NRCHD, were born between 1996 and 2015. 10 927 patients were excluded from the current analysis due to prior registration with the NRCHD under the German PAN Prevalence Study, which showed a potential bias in the inclusion of this patient population (proportion of mild cardiac lesions was comparatively high due to improved diagnostic capability for earlier identifying minor lesions). At least 15 703 patients with demographic data and detailed medical information were included in the current study. INTERVENTIONS: None. OUTCOME MEASURES: Prevalence of CHD in Germany differentiated into gender, severity, and phenotype. RESULTS: In total, 15 703 patients with CHD (47.1% female) were included in this study. The five most common phenotypes were found to be ventricular septal defect (19.2%), atrial septal defect (13.0%), Tetralogy of Fallot (9.3%), univentricular heart (9.4%), and coractation of the aortae (7.0%). The prevalence of CHD in regard to severity changed over the duration of the observation period. From 1996 to 2007, the number of simple CHD rose steadily (P < .001), whereas the number of severe CHD has grown significantly since 2008/2009 (P < .001). In regard to gender, the prevalence of simple CHD was higher in females, whereas complex lesions were more common in males (P < .001). CONCLUSIONS: Our study shows a growing number of registered severe CHD in the recent decade in Germany. This development is noteworthy as it implicates a growing demand for first intensive hospital care, expert pediatric cardiologic aftercare, and consequently higher economic impact for this patient population. PMID- 28719143 TI - Osteoporotic Vertebral Fracture Prevalence Varies Widely Between Qualitative and Quantitative Radiological Assessment Methods: The Rotterdam Study. AB - Accurate diagnosis of vertebral osteoporotic fractures is crucial for the identification of individuals at high risk of future fractures. Different methods for radiological assessment of vertebral fractures exist, but a gold standard is lacking. The aim of our study was to estimate statistical measures of agreement and prevalence of osteoporotic vertebral fractures in the population-based Rotterdam Study, across two assessment methods. The quantitative morphometry assisted by SpineAnalyzer(r) (QM SA) method evaluates vertebral height loss that affects vertebral shape whereas the algorithm-based qualitative (ABQ) method judges endplate integrity and includes guidelines for the differentiation of vertebral fracture and nonfracture deformities. Cross-sectional radiographs were assessed for 7582 participants aged 45 to 95 years. With QM SA, the prevalence was 14.2% (95% CI, 13.4% to 15.0%), compared to 4.0% (95% CI, 3.6% to 4.5%) with ABQ. Inter-method agreement according to kappa (kappa) was 0.24. The highest agreement between methods was among females (kappa = 0.31), participants age >80 years (kappa = 0.40), and at the L1 level (kappa = 0.40). With ABQ, most fractures were found at the thoracolumbar junction (T12 -L1 ) followed by the T7 T8 level, whereas with QM SA, most deformities were in the mid thoracic (T7 -T8 ) and lower thoracic spine (T11 -T12 ), with similar number of fractures in both peaks. Excluding mild QM SA deformities (grade 1 with QM) from the analysis increased, the agreement between the methods from kappa = 0.24 to 0.40, whereas reexamining mild deformities based on endplate depression increased agreement from kappa = 0.24 to 0.50 (p <0.001). Vertebral fracture prevalence differs significantly between QM SA and ABQ; reexamining QM mild deformities based on endplate depression would increase the agreement between methods. More widespread and consistent application of an optimal method may improve clinical care. (c) 2017 American Society for Bone and Mineral Research. PMID- 28719144 TI - Maximizing the stability of metabolic engineering-derived whole-cell biocatalysts. AB - A systematic and powerful knowledge-based framework exists for improving the activity and stability of chemical catalysts and for empowering the commercialization of respective processes. In contrast, corresponding biotechnological processes are still scarce and characterized by case-by-case development strategies. A systematic understanding of parameters affecting biocatalyst efficiency, that is, biocatalyst activity and stability, is essential for a rational generation of improved biocatalysts. Today, systematic approaches only exist for increasing the activity of whole-cell biocatalysts. They are still largely missing for whole-cell biocatalyst stability. In this review, we structure factors affecting biocatalyst stability and summarize existing, yet not completely exploited strategies to overcome respective limitations. The factors and mechanisms related to biocatalyst destabilization are discussed and demonstrated inter alia based on two case studies. The factors are similar for processes with different objectives regarding target molecule or metabolic pathway complexity and process scale, but are in turn highly interdependent. This review provides a systematic for the stabilization of whole-cell biocatalysts. In combination with our knowledge on strategies to improve biocatalyst activity, this paves the way for the rational design of superior recombinant whole-cell biocatalysts, which can then be employed in economically and ecologically competitive and sustainable bioprocesses. PMID- 28719145 TI - Preparation of carbon dot-based ratiometric fluorescent probes for cellular imaging from Curcuma longa. AB - This work derived biocompatible and stable probes based on fluorescent nanoparticles (FNPs) from a natural source, Curcuma longa. The multi-color fluorescence emissions from carbonized Curcuma longa (C-FNPs) obtained through defined dehydration conditions are soluble in water and have a small particle size (~17 nm). The surface passivation with polyethylene glycol (PEG) capped with amine groups in FNPs (P-FNPs) generated a probe with a higher quantum yield and longer fluorescence lifetime than obtained with C-FNPs. The X-ray photoelectron spectroscopy and X-ray diffraction spectra confirmed the associated chemical moieties of C-FNPs and P-FNPs. Furthermore, the prepared material showed non toxic effects with almost 100% cell viability, even at high concentrations. In conclusion, fluorescence sensors from natural sources may be useful for numerous biomedical research applications. PMID- 28719146 TI - Natural Compounds in Cancer Prevention: Effects of Coffee Extracts and Their Main Polyphenolic Component, 5-O-Caffeoylquinic Acid, on Oncogenic Ras Proteins. AB - Recent epidemiological studies have demonstrated that the consumption of healthy foods that are particularly rich in polyphenols might reduce the incidence of cancer and neurodegenerative diseases. In particular, chlorogenic acids (CGAs) occur ubiquitously in food and represent the most abundant polyphenols in the human diet. A number of beneficial biological effects of CGAs, such as anti inflammatory activity, anti-carcinogenic activity, and protection against neurodegenerative diseases, have been reported. However, the molecular mechanisms at the base of these biological activities have not yet been investigated in depth. By combining NMR spectroscopy, molecular docking, surface plasmon resonance and ex vivo assays of the Ras-dependent breast cancer cell line MDA-MB 231, we contribute to the elucidation of the molecular basis of the activity of CGAs and natural extracts from green and roasted coffee beans as chemoprotective dietary supplements. PMID- 28719147 TI - Human immunology studies using organ donors: Impact of clinical variations on immune parameters in tissues and circulation. AB - Organ donors are sources of physiologically healthy organs and tissues for life saving transplantation, and have been recently used for human immunology studies which are typically confined to the sampling of peripheral blood. Donors comprise a diverse population with different causes of death and clinical outcomes during hospitalization, and the effects of such variations on immune parameters in blood and tissues are not known. We present here a coordinate analysis of innate and adaptive immune components in blood, lymphoid (bone marrow, spleen, lymph nodes), and mucosal (lungs, intestines) sites from a population of brain-dead organ donors (2 months-93 years; n = 291) across eight clinical parameters. Overall, the blood of donors exhibited similar monocyte and lymphocyte content and low serum levels of pro-inflammatory cytokines as healthy controls; however, donor blood had increased neutrophils and serum levels of IL-8, IL-6, and MCP-1 which varied with cause of death. In tissues, the frequency and composition of monocytes, neutrophils, B lymphocytes and T cell subsets in lymphoid or mucosal sites did not vary with clinical state, and was similar in donors independent of the extent of clinical complications. Our results reveal that organ donors maintain tissue homeostasis, and are a valuable resource for fundamental studies in human immunology. PMID- 28719149 TI - Cadmium-induced toxicity is rescued by curcumin: A review. AB - Cadmium (Cd) is one of the most common environmental and occupational heavy metals with extended distribution. Exposure to Cd may be associated with several deleterious consequences on the liver, bones, kidneys, lungs, testes, brain, immunological, and cardiovascular systems. Overproduction of reactive oxygen species (ROS) as the main mechanism behind its toxicity causes oxidative stress and subsequent damages to lipids, proteins, and DNA. Therefore, antioxidants along with chelating agents have shown promising outcomes against Cd-induced toxicity. Curcumin with various beneficial effects and medical efficacy has been evaluated for its inhibitory activities against biological impairments caused by Cd. Thus, this article is intended to address the effectiveness of curcumin against toxicity following Cd entry. Curcumin can afford to attenuate lipid peroxidation, glutathione depletion, alterations in antioxidant enzyme, and so forth through scavenging and chelating activities or Nrf2/Keap1/ARE pathway induction. (c) 2017 BioFactors, 43(5):645-661, 2017. PMID- 28719148 TI - High expression of FUNDC1 predicts poor prognostic outcomes and is a promising target to improve chemoradiotherapy effects in patients with cervical cancer. AB - FUN14 domain containing 1 (FUNDC1) is an important molecule in receptor-dependent mitophagy. However, the roles of FUNDC1 in human cancer biology remain unknown. The aim of this study was to explore the expression and roles of FUNDC1 in cervical cancer. Immunohistochemistry and Western blotting were applied to detect the expression of FUNDC1, and small-hairpin RNA was applied to inhibit the expression of endogenous FUNDC1 in cervical cancer cells. MTT assays and Flow cytometric analysis were applied to examine cell proliferation and apoptosis. Immunofluorescence was used to detect the formation of gammaH2AX foci and evaluate the extent of DNA damage. Compared with corresponding adjacent noncancerous cervical tissues, the expression of FUNDC1 in cervical cancer cells was significantly increased. High expression of FUNDC1 and the prognosis of patients with cervical cancer were correlated negatively, which could be used as an independent prognostic factor for overall survival and disease-free survival. Depletion of FUNDC1 significantly inhibited the proliferation of tumor cells, induced apoptosis, and enhanced cell sensitivity to cisplatin and ionizing radiation (IR). Our data suggested that FUNDC1 can be used as a prognostic biomarker in patients with cervical cancer, and may be a new therapeutic target to improve the antitumor effects of chemoradiotherapy. PMID- 28719150 TI - Can principles of the surface potential be combined with knowledge of natural products to reduce atrial rhythm disturbances? PMID- 28719153 TI - In-source collision-induced dissociation (IS-CID): Applications, issues and structure elucidation with single-stage mass analyzers. AB - A discussion of the definition, advantages, and issues with the formation of ions in the transition region between an electrospray ionization (ESI) source and the ion optics of a mass analyzer is presented. The various types of ions formed in the so-called in-source collision-induced dissociation (IS-CID) process are illustrated. Applications of IS-CID with single-stage mass analyzers, such as structure elucidation and quantitation, are demonstrated. The discussion is illustrated by examples of the in-source fragmentation of ginkgolides, which are marker compounds found only in Ginkgo biloba. Supercritical fluid chromatography (SFC) with non-aqueous eluents was used to achieve a fast resolution of the ginkgolides without the hydrolysis reactions possible with aqueous high performance liquid chromatography (HPLC) eluents. In-source ion generation occurs at relatively high pressures (ca. 1-3 torr) compared to the low pressure normally observed in collision chambers of tandem mass spectrometry (MS/MS). As a result, the fragmentation process is complex and often generates ions other than the fragments observed with classic CID or the same ions at different intensities. The objective of the current tutorial is to illustrate the conditions under which single-stage, quadrupole or time-of-flight mass analyzers with electrospray or in air (direct analysis in real time; DART) ionization can be used for quantitation and structure elucidation in a manner similar to that observed with MS/MS. While the low m/z (<= [M+/-H]+/- ) ions formed in-source often duplicate the ions observed in MS/MS systems, it is the focus of this discussion to illustrate the utility of in-source generated fragment ions that may not be observed or observed at different intensities than in the collision cells of MS/MS instruments. PMID- 28719151 TI - Staged Treatment in Early Psychosis: A sequential multiple assignment randomised trial of interventions for ultra high risk of psychosis patients. AB - AIM: Previous research indicates that preventive intervention is likely to benefit patients "at risk" of psychosis, in terms of functional improvement, symptom reduction and delay or prevention of onset of threshold psychotic disorder. The primary aim of the current study is to test outcomes of ultra high risk (UHR) patients, primarily functional outcome, in response to a sequential intervention strategy consisting of support and problem solving (SPS), cognitive behavioural case management and antidepressant medication. A secondary aim is to test biological and psychological variables that moderate and mediate response to this sequential treatment strategy. METHODS: This is a sequential multiple assignment randomised trial (SMART) consisting of three steps: Step 1: SPS (1.5 months); Step 2: SPS vs Cognitive Behavioural Case Management (4.5 months); Step 3: Cognitive Behavioural Case Management + Antidepressant Medication vs Cognitive Behavioural Case Management + Placebo (6 months). The intervention is of 12 months duration in total and participants will be followed up at 18 months and 24 months post baseline. CONCLUSION: This paper reports on the rationale and protocol of the Staged Treatment in Early Psychosis (STEP) study. With a large sample of 500 UHR participants this study will investigate the most effective type and sequence of treatments for improving functioning and reducing the risk of developing psychotic disorder in this clinical population. PMID- 28719152 TI - A first-in-human phase I, multicenter, open-label, dose-escalation study of the oral RAF/VEGFR-2 inhibitor (RAF265) in locally advanced or metastatic melanoma independent from BRAF mutation status. AB - To establish the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), safety profile, and anti-tumor efficacy of RAF265. We conducted a multicenter, open-label, phase-I, dose-escalation trial of RAF265, an orally available RAF kinase/VEGFR-2 inhibitor, in patients with advanced or metastatic melanoma. Pharmacokinetic (PK) analysis, pharmacodynamics (PD) and tumor response assessment were conducted. We evaluated metabolic tumor response by 18[F] fluorodeoxyglucose-positron-emission tomography (FDG-PET), tissue biomarkers using immunohistochemistry (IHC), and modulators of angiogenesis. RAF265 has a serum half-life of approximately 200 h. The MTD was 48 mg once daily given continuously. Among 77 patients, most common treatment-related adverse effects were fatigue (52%), diarrhea (34%), weight loss (31%) and vitreous floaters (27%). Eight of 66 evaluable patients (12.1%) had an objective response, including seven partial and one complete response. Responses occurred in BRAF mutant and BRAF wild-type (WT) patients. Twelve of 58 (20.7%) evaluable patients had a partial metabolic response. On-treatment versus pretreatment IHC staining in 23 patients showed dose-dependent p-ERK inhibition. We observed a significant temporal increase in placental growth factor levels and decrease in soluble vascular endothelial growth factor receptor 2 (sVEGFR-2) levels in all dose levels. RAF265 is an oral RAF/VEGFR-2 inhibitor that produced antitumor responses, metabolic responses, and modulated angiogenic growth factor levels. Antitumor activity occurred in patients with BRAF-mutant and BRAF-WT disease. Despite low activity at tolerable doses, this study provides a framework for the development of pan-RAF inhibitors and modulators of angiogenesis for the treatment of melanoma. PMID- 28719154 TI - Progression of skin autofluorescence of AGEs over 4 years in patients with type 1 diabetes. AB - BACKGROUND: The deposit of advanced glycation end-products is involved in diabetic complications. It can be evaluated by measuring the skin autofluorescence (sAF). We searched whether sAF progressed over 4 years in type 1 diabetes and analysed its relationship with the development of nephropathy. METHODS: Two measurements of skin autofluorescence (sAF) were completed on 154 patients during years 2009 and 2013. Baseline factors associated with the progression of sAF were analysed by multivariate regression analysis. The relations among sAF progression, microalbuminuria, and impaired estimated glomerular filtration rate (eGFR) were analysed by logistic regression analysis. RESULTS: The patients were 51 +/- 16 years old, with duration of diabetes of 23 +/- 13 years, HbA1c: 7.7 +/- 1.0%, 20.7% were treated by continuous subcutaneous insulin infusion (CSII). The sAF progressed by +18.1% over 4 years. Two interacting (P = .04) variables were associated with the later progression of sAF: mildly impaired eGFR and treatment by CSII. The patients with mildly impaired eGFR had the highest progression of sAF (+11.5% P = .01). Continuous subcutaneous insulin infusion was associated with a reduced progression of sAF in patients without kidney impairment (beta = -7.2%, P = .01). A +10% progression of sAF during the follow-up was associated with more microalbuminuria: OR = 1.45, P = .02, and more mildly impaired eGFR (<90 mL/min/1.73 m2 ): OR 1.22, P = .03 at 4 years of follow-up. CONCLUSIONS: The skin autofluorescence of advanced glycation end-products progresses in patients with type 1 diabetes, more if they have diabetic nephropathy, less if they are treated by continuous subcutaneous insulin infusion. This progression is associated with the development of nephropathy. PMID- 28719155 TI - Antipsychotic treatment is associated with inflammatory and metabolic biomarkers alterations among first-episode psychosis patients: A 7-month follow-up study. AB - AIM: Second-generation antipsychotics are commonly used to treat schizophrenia, but may cause metabolic syndrome (MetS) in a subset of patients. The mechanisms of antipsychotic-related metabolic changes remain to be established, especially in first-episode psychosis (FEP) patients. METHODS: In the present study, we used a chip technology to measure metabolic (C-peptide, insulin, leptin, adiponectin and resistin) and inflammatory biomarkers (ferritin, interleukin-6, interleukin 1alpha, tumour necrosis factor-alpha and plasminogen activator inhibitor-1) in the serum samples of a population of FEP patients before and after 7 months of antipsychotic drug treatment, compared to control subjects (CS). RESULTS: The comparison of these markers in antipsychotic-naive FEP patients (N = 38) and CS (N = 37) revealed significantly higher levels of ferritin (P = .004), and resistin (P = .03) and lower level of leptin (P = .03) among FEP patients group. Seven months of antipsychotic drug treatment in patients (N = 36) ameliorated clinical symptoms, but increased significantly body mass index (BMI; P = .002) and these changes were accompanied by increased levels of C-peptide (P = .03) and leptin (P = .02), as well as decreased level of adiponectin (P = .01). CONCLUSIONS: Seven months of antipsychotic drug treatment suppressed the clinical symptoms of psychosis whereas caused imbalance in metabolic biomarkers and increased BMI. These findings provide insight into antipsychotic-induced MetS and refer to problems in insulin processing already present in the early stage of the chronic psychotic disorder. PMID- 28719174 TI - Adsorption and Biodegradation of Aromatic Chemicals by Bacteria Encapsulated in a Hydrophobic Silica Gel. AB - An adsorbent silica biogel material was developed via silica gel encapsulation of Pseudomonas sp. NCIB 9816-4, a bacterium that degrades a broad spectrum of aromatic pollutants. The adsorbent matrix was synthesized using silica precursors methyltrimethoxysilane and tetramethoxysilane to maximize the adsorption capacity of the matrix while maintaining a highly networked and porous microstructure. The encapsulated bacteria enhanced the removal rate and capacity of the matrix for an aromatic chemical mixture. Repeated use of the material over four cycles was conducted to demonstrate that the removal capacity could be maintained with combined adsorption and biodegradation. The silica biogel can thus be used extensively without the need for disposal, as a result of continuous biodegradation by the encapsulated bacteria. However, an inverse trend was observed with the ratio of biodegradation to adsorption as a function of log Kow, suggesting increasing mass-transport limitation for the most hydrophobic chemicals used (log Kow > 4). PMID- 28719175 TI - A Simple, Cleated DNA Walker That Hangs on to Surfaces. AB - We designed and demonstrated a single-legged or unipedal walker that has a "cleat" that allows it to persistently associate with a track and make autonomous decisions about movement. The walker is highly processive over long periods of time, as shown by its movement over a microparticle surface suffused with substrate. The simple design can be readily optimized on the basis of simple energetic considerations. The walker can be used for signal amplification and should prove especially valuable for programming amorphous computations within chemical reaction networks. PMID- 28719176 TI - Investigation on the Electrocatalytic Determination and Photocatalytic Degradation of Neurotoxicity Drug Clioquinol by Sn(MoO4)2 Nanoplates. AB - Transition-metal molybdates have concerned enormous curiosity as supercapacitors, photocatalysts, and electrocatalysts. These materials are the best alternatives to noble-metal-based catalysts, which are generally show a limited photocatalytic and electrocatalytic activity. In addition, the antiprotozoal drug can usually pollute the environment through improper disposable and incomplete metabolism, and it is very dangerous to humans as well as aquatic animals. Therefore, here, we have studied the electrochemical determination and photodegradation of neurotoxicity clioquinol (CQL) by nanoplate-like tin molybdate (Sn(MoO4)2, denoted as SnM), which is used as both an electro- and a photocatalyst. The as prepared catalyst delivered a highly efficient activity toward the detection and degradation of CQL. The proposed nanoplate-like SnM was prepared through a simple wet-chemical route, and its physicochemical properties were characterized by various spectroscopic and analytical techniques. As an electrochemical sensor, the SnM electrocatalyst exhibited tremendous activity for the detection of CQL in terms of lower potential and enhanced anodic peak current. In addition, it showed high selectivity, a wide linear concentration range, a lower detection limit, and good sensitivity. From the UV-vis spectroscopy study, the SnM photocatalyst delivered an excellent photocatalytic activity toward the degradation of CQL in terms of increasing contact time and reducing CQL concentration, resulting in the increasing of the degradation efficiency about 98% within 70 min under visible light irradiation and showing an appreciable stability by observation of the reusability of the catalyst. PMID- 28719177 TI - Classics in Neuroimaging: Imaging the Dopaminergic Pathway with PET. AB - The success of positron emission tomography (PET) for observing molecular processes underlying brain function and disease is underpinned by radiotracer chemistry. From the earliest applications of PET to measure dopamine synthesis capacity and the abundance of neuroreceptors and transporters, to the more recent topic of dynamic neurochemical imaging, interrogation of brain dopamine in conditions such as neurodegenerative diseases, schizophrenia, mood disorders, and addictions has been a driving force that challenges the ingenuity of radiopharmaceutical scientists. In fact, the pursuit of new ligands and reaction methods to address longstanding challenges has often been pioneered in the context of dopamine imaging. From this viewpoint, we highlight the unique history of imaging the dopaminergic pathway with PET, and present our interpretation of how this worldwide effort shaped and continues to drive the field of molecular imaging. PMID- 28719178 TI - Therapeutic Role and Drug Delivery Potential of Neuroinflammation as a Target in Neurodegenerative Disorders. AB - Neuroinflammation, the condition associated with the hyperactivity of immune cells within the CNS (central nervous system), has recently been linked to a host range of neurodegenerative disorders. Targeting neuroinflammation could be of prime importance as recent research highlights the beneficial aspects associated with modulating the inflammatory mediators associated with the CNS. One of the main obstructions in neuroinflammatory treatments is the hindrance posed by the blood-brain barrier for the delivery of drugs. Hence, research has focused on novel modes of transport for drugs to cross the barrier through drug delivery and nanotechnology approaches. In this Review, we highlight the therapeutic advancement made in the field of neurodegenerative disorders by focusing on the effect neuroinflammation treatment has on these conditions. PMID- 28719179 TI - Inhibition of Human Class I vs Class III Phosphatidylinositol 3'-Kinases. AB - Most investigations of phosphatidylinositol 3'-kinase (PI3K) drug inhibition have been via assays based on ADP appearance or ATP consumption (e.g., Liu, Q., et al. ( 2011 ) J. Med. Chem. 54 , 1473 - 1480 ). However, at least some PI3K isoforms show basal ATPase activity in the absence of PI lipid substrate(s), which may complicate quantification of drug potency, isoform specificity of some drugs, and synergy for drug combinations. In this study, we probe the class I vs class III isoform specificity of a selected set of PI3K inhibitors using a simple, inexpensive, semi high-throughput assay that quantifies production of phosphatidylinositol 3'-phosphate (PI3P) from phosphatidylinositol. Results are compared to previous data largely generated using ATPase activity assays. Good agreement between EC50 values computed via ATPase assays vs the reported PI3P formation assay is found for most drugs, but with a few exceptions. Furthermore, for the first time, drug inhibition of class I vs class III enzymes is compared side-by-side with the same assay for the important class I-specific inhibitors GSK2126458 ("Omipalisib") and NVP-BGT226 ("BGT226") currently in clinical development for advanced solid tumors. PMID- 28719180 TI - Heterologous Expression, Purification, and Functional Analysis of Plasmodium falciparum Phosphatidylinositol 3'-Kinase. AB - The Plasmodium falciparum malarial parasite genome appears to encode one and only one phosphatidylinositol 3'-kinase (PI3K), and sequence analysis suggests that the enzyme is a "class III"- or "Vps34"-type PI3K. PfVps34 has generated excitement as a possible druggable target and potentially a key target of artemisinin-based antimalarials. In this study, we optimize the PfVps34 gene for heterologous expression in yeast, purify the protein to homogeneity, use a recently validated quantitative assay for phosphatidylinositol 3'-phosphate production from phosphatidylinositol ( Hassett et al., companion paper; DOI 10.1021/acs.biochem.7b00416 ) to quantify activity and drug inhibition of that activity, and investigate the importance of key residues in the enzyme's catalytic and "N-lobe" domains. Data suggest that PfVps34 is indeed inhibited by artemisinin and related drugs but only under conditions that cleave the drugs' endoperoxide bridge to generate reactive alkylating agents. PMID- 28719181 TI - Differential Ligand Binding Specificities of the Pulmonary Collectins Are Determined by the Conformational Freedom of a Surface Loop. AB - Lung surfactant proteins (SPs) play critical roles in surfactant function and innate immunity. SP-A and SP-D, members of the collectin family of C-type lectins, exhibit distinct ligand specificities, effects on surfactant structure, and host defense functions despite extensive structural homology. SP-A binds to dipalmitoylphosphatidylcholine (DPPC), the major surfactant lipid component, but not phosphatidylinositol (PI), whereas SP-D shows the opposite preference. Additionally, SP-A and SP-D recognize widely divergent pathogen-associated molecular patterns. Previous studies suggested that a ligand-induced surface loop conformational change unique to SP-A contributes to lipid binding affinity. To test this hypothesis and define the structural features of SP-A and SP-D that determine their ligand binding specificities, a structure-guided approach was used to introduce key features of SP-D into SP-A. A quadruple mutant (E171D/P175E/R197N/K203D) that introduced an SP-D-like loop-stabilizing calcium binding site into the carbohydrate recognition domain was found to interconvert SP-A ligand binding preferences to an SP-D phenotype, exchanging DPPC for PI specificity, and resulting in the loss of lipid A binding and the acquisition of more avid mannan binding properties. Mutants with constituent single or triple mutations showed alterations in their lipid and sugar binding properties that were intermediate between those of SP-A and SP-D. Structures of mutant complexes with inositol or methyl-mannose revealed an attenuation of the ligand-induced conformational change relative to wild-type SP-A. These studies suggest that flexibility in a key surface loop supports the distinctive lipid binding functions of SP-A, thus contributing to its multiple functions in surfactant structure and regulation, and host defense. PMID- 28719182 TI - Atomic White-Out: Enabling Atomic Circuitry through Mechanically Induced Bonding of Single Hydrogen Atoms to a Silicon Surface. AB - We report the mechanically induced formation of a silicon-hydrogen covalent bond and its application in engineering nanoelectronic devices. We show that using the tip of a noncontact atomic force microscope (NC-AFM), a single hydrogen atom could be vertically manipulated. When applying a localized electronic excitation, a single hydrogen atom is desorbed from the hydrogen-passivated surface and can be transferred to the tip apex, as evidenced from a unique signature in frequency shift curves. In the absence of tunnel electrons and electric field in the scanning probe microscope junction at 0 V, the hydrogen atom at the tip apex is brought very close to a silicon dangling bond, inducing the mechanical formation of a silicon-hydrogen covalent bond and the passivation of the dangling bond. The functionalized tip was used to characterize silicon dangling bonds on the hydrogen-silicon surface, which was shown to enhance the scanning tunneling microscope contrast, and allowed NC-AFM imaging with atomic and chemical bond contrasts. Through examples, we show the importance of this atomic-scale mechanical manipulation technique in the engineering of the emerging technology of on-surface dangling bond based nanoelectronic devices. PMID- 28719183 TI - Streptomyces virginiae PPDC Is a New Type of Phenylpyruvate Decarboxylase Composed of Two Subunits. AB - Streptomyces virginiae phenylpyruvate decarboxylase (PPDC) has not been identified before. Two putative branched-chain alpha-keto acid dehydrogenase subunit genes bkdC and bkdD from S. virginiae are similar to halves of other PPDC coding sequences. We cloned and characterized them biochemically in this work. The two proteins formed a stable complex attested by pull-down assay, consistent with the finding that their soluble expression was obtained only when they were coexpressed in Escherichia coli. The subunits were redesignated as SvPPDCalpha and SvPPDCbeta, because the SvPPDCalpha/beta complex catalyzed the conversion of phenylpyruvate to phenylacetaldehyde, reflecting the nature of the enzyme. Moreover, mutations of conserved residues in either of the two subunits led to inactivation or decreased specific activity of the enzymatic reaction. All previously identified PPDCs are encoded by a single gene. Here, we identified a new type of PPDC that contains two subunits, which gives new insights into the PPDC family. PMID- 28719184 TI - Nanoparticle-Mediated Mechanical Destruction of Cell Membranes: A Coarse-Grained Molecular Dynamics Study. AB - The effects of binding mode, shape, binding strength, and rotational speed of actively rotating nanoparticles on the integrity of cell membranes have been systematically studied using dissipative particle dynamics simulations. With theoretical analyses of lipid density, surface tension, stress distribution, and water permeation, we demonstrate that the rotation of nanoparticles can provide a strong driving force for membrane rupture. The results show that nanoparticles embedded inside a cell membrane via endocytosis are more capable of producing large membrane deformations under active rotation than nanoparticles attached on the cell membrane surface. Nanoparticles with anisotropic shapes produce larger deformation and have a higher rupture efficiency than those with symmetric shapes. Our findings provide useful design guidelines for a general strategy based on utilizing mechanical forces to rupture cell membranes and therefore destroy the integrity of cells. PMID- 28719186 TI - Elastomer Reinforced with Regenerated Chitin from Alkaline/Urea Aqueous System. AB - Novel hybrid elastomer/regenerated chitin (R-chitin) composites were developed, for the first time, by introducing chitin solution (dissolved in alkaline/urea aqueous solution at low temperature) into rubber latex, and then cocoagulating using ethanol as the cocoagulant. During the rapid coprecipitation process, the chitin solution showed rapid coagulant-induced gelation and a porous chitin phase was generated, and the rubber latex particles were synchronously demulsificated to form the rubbery phase. The two phases interlaced and interpenetrated simultaneously to form an interpenetrating polymer network (IPN) structure, which was evidenced by SEM observation. The ensuing compound was also characterized by thermogravimetric analysis (TGA), X-ray diffraction (XRD), and swelling experiments. The unique porous structure of R-chitin could result in strong physical entanglements and interlocks between filler and matrix, thus a highly efficient load transfer between the filler and the matrix was achieved. Accordingly, R-chitin endows the elastomer with a remarkable reinforcement. We envisage that this work may contribute new insights on novel design of chitin based elastomer hybrids with IPN structure. PMID- 28719185 TI - Small Molecule Enhancement of 20S Proteasome Activity Targets Intrinsically Disordered Proteins. AB - The 20S proteasome is the main protease for the degradation of oxidatively damaged and intrinsically disordered proteins. When accumulation of disordered or oxidatively damaged proteins exceeds proper clearance in neurons, imbalanced pathway signaling or aggregation occurs, which have been implicated in the pathogenesis of several neurological disorders. Screening of the NIH Clinical Collection and Prestwick libraries identified the neuroleptic agent chlorpromazine as a lead agent capable of enhancing 20S proteasome activity. Chemical manipulation of chlorpromazine abrogated its D2R receptor binding affinity while retaining its ability to enhance 20S mediated proteolysis at low micromolar concentrations. The resulting small molecule enhancers of 20S proteasome activity induced the degradation of intrinsically disordered proteins, alpha-synuclein, and tau but not structured proteins. These small molecule 20S agonists can serve as leads to explore the therapeutic potential of 20S activation or as new tools to provide insight into the yet unclear mechanics of 20S-gate regulation. PMID- 28719187 TI - Exploring the Role of Habitat on the Wettability of Cicada Wings. AB - Evolutionary pressure has pushed many extant species to develop micro/nanostructures that can significantly affect wettability and enable functionalities such as droplet jumping, self-cleaning, antifogging, antimicrobial, and antireflectivity. In particular, significant effort is underway to understand the insect wing surface structure to establish rational design tools for the development of novel engineered materials. Most studies, however, have focused on superhydrophobic wings obtained from a single insect species, in particular, the Psaltoda claripennis cicada. Here, we investigate the relationship between the spatially dependent wing wettability, topology, and droplet jumping behavior of multiple cicada species and their habitat, lifecycle, and interspecies relatedness. We focus on cicada wings of four different species: Neotibicen pruinosus, N. tibicen, Megatibicen dorsatus, and Magicicada septendecim and take a comparative approach. Using spatially resolved microgoniometry, scanning electron microscopy, atomic force microscopy, and high speed optical microscopy, we show that within cicada species, the wettability of wings is spatially homogeneous across wing cells. All four species were shown to have truncated conical pillars with widely varying length scales ranging from 50 to 400 nm in height. Comparison of the wettability revealed three cicada species with wings that are superhydrophobic (>150 degrees ) with low contact angle hysteresis (<5 degrees ), resulting in stable droplet jumping behavior. The fourth, more distantly related species (Ma. septendecim) showed only moderate hydrophobic behavior, eliminating some of the beneficial surface functional aspects for this cicada. Correlation between cicada habitat and wing wettability yielded little connection as wetter, swampy environments do not necessarily equate to higher measured wing hydrophobicity. The results, however, do point to species relatedness and reproductive strategy as a closer proxy for predicting wettability and surface structure and resultant enhanced wing surface functionality. This work not only elucidates the differences between inter- and intraspecies cicada wing topology, wettability, and water shedding behavior but also enables the development of rational design tools for the manufacture of artificial surfaces for energy and water applications. PMID- 28719188 TI - Phage Selection of Cyclic Peptides for Application in Research and Drug Development. AB - Cyclic peptides can bind to protein targets with high affinities and selectivities, which makes them an attractive modality for the development of research reagents and therapeutics. Additional properties, including low inherent toxicity, efficient chemical synthesis, and facile modification with labels or immobilization reagents, increase their attractiveness. Cyclic peptide ligands against a wide range of protein targets have been isolated from natural sources such as bacteria, fungi, plants, and animals. Many of them are currently used as research tools, and several have found application as therapeutics, such as the peptide hormones oxytocin and vasopressin and the antibiotics vancomycin and daptomycin, proving the utility of cyclic peptides in research and medicine. With the advent of phage display and other in vitro evolution techniques, it has become possible to generate cyclic peptide binders to diverse protein targets for which no natural peptides have been discovered. A highly robust and widely applied approach is based on the cyclization of peptides displayed on phage via a disulfide bridge. Disulfide-cyclized peptide ligands to more than a hundred different proteins have been reported in the literature. Technology advances achieved over the last three decades, including methods for generating larger phage display libraries, improved phage panning protocols, new cyclic peptide formats, and high-throughput sequencing, have enabled the generation of cyclic peptides with ever better binding affinities to more challenging targets. A relatively new cyclic peptide format developed using phage display involves bicyclic peptides. These molecules consist of two macrocyclic peptide rings cyclized through a chemical linker. Compared to monocyclic peptides of comparable molecular mass, bicyclic peptides are more constrained in their conformation. As a result, they can bind to their targets with a higher affinity and are more resistant to proteolytic degradation. Phage-encoded bicyclic peptides are generated by chemically cyclizing random peptide libraries on phage. Binders are identified by conventional phage panning and DNA sequencing. Next-generation sequencing and new sequence alignment tools have enabled the rapid identification of bicyclic peptides. Bicyclic peptide ligands were developed against a range of diverse target classes including enzymes, receptors, and cytokines. Most ligands bind with nanomolar affinities, with some reaching the picomolar range. To date, several bicyclic peptides have been positively evaluated in preclinical studies, and the first clinical tests are in sight. While bicyclic peptide phage display was developed with therapeutic applications in mind, these peptides are increasingly used as research tools for target evaluation or as basic research probes as well. Given the efficient development method, the ease of synthesis and handling, and the favorable binding and biophysical properties, bicyclic peptides are being developed against more and more targets, ever increasing their potential applications in research and medicine. PMID- 28719189 TI - Determination of Double Bond Positions in Polyunsaturated Fatty Acids Using the Photochemical Paterno-Buchi Reaction with Acetone and Tandem Mass Spectrometry. AB - The positions of double bonds along the carbon chain of methylene interrupted polyunsaturated fatty acids are unique identifiers of specific fatty acids derived from biochemical reactions that occur in cells. It is possible to obtain direct structural information as to these double bond positions using tandem mass spectrometry after collisional activation of the carboxylate anions of an acetone adduct at each of the double bond positions formed by the photochemical Paterno Buchi reaction with acetone. This reaction can be carried out by exposing a small portion of an inline fused silica capillary to UV photons from a mercury vapor lamp as the sample is infused into the electrospray ion source of a mass spectrometer. Collisional activation of [M - H]- yields a series of reverse Paterno-Buchi reaction product ions that essentially are derived from cleavage of the original carbon-carbon double bonds that yield an isopropenyl carboxylate anion corresponding to each double bond location. Aldehydic reverse Paterno-Buchi product ions are much less abundant as the carbon chain length and number of double bonds increase. The use of a mixture of D0/D6-acetone facilitates identification of these double bonds indicating product ions as shown for arachidonic acid. If oxygen is present in the solvent stream undergoing UV photoactivation, ozone cleavage ions are also observed without prior collisional activation. This reaction was used to determine the double bond positions in a 20:3 fatty acid that accumulated in phospholipids of RAW 264.7 cells cultured for 3 days. PMID- 28719190 TI - Chiral [Mo8O26]4- Polyoxoanion-Induced Three-Dimensional Architectures With Homochiral Eight-Fold Interpenetrated Metal-Organic Frameworks. AB - A pair of novel chiral compounds based on homochiral 8-fold interpenetrated metal organic frameworks (MOFs) and chiral polyoxometalates (POMs), formulated as d [Cu(4,4'-bipy)1.5]4[Mo8O26] (d-1) and l-[Cu(4,4'-bipy)1.5]4[Mo8O26] (l-1) (4,4' bipy = 4,4'-bipyridine), have been successfully synthesized and characterized by single crystal X-ray diffraction, infrared, thermogravimetric analysis, elemental analysis, and solid circular dichroism spectra. Structural analysis indicates that two compounds are enantiomers. The connection of copper cations and 4,4' bipy ligands generates helical infinite chains, while adjacent chains are further linked by Cu-N bonds to form a three-dimensional interpenetrating framework with a (10,3)-a topology. Interestingly, the chiral [Mo8O26]4- polyanions are encapsulated in the chiral MOFs via sharing the oxygen atoms. Both d- and l [Cu(4,4'-bipy)1.5]4[Mo8O26] crystallize in chiral space group C2221. Additionally, two compounds represent new examples of chiral self-assembly. PMID- 28719191 TI - Relationships Between Dissolved Organic Matter Composition and Photochemistry in Lakes of Diverse Trophic Status. AB - The North Temperate Lakes Long-Term Ecological Research site includes seven lakes in northern Wisconsin that vary in hydrology, trophic status, and landscape position. We examine the molecular composition of dissolved organic matter (DOM) within these lakes using Fourier transform-ion cyclotron resonance mass spectrometry (FT-ICR MS) and quantify DOM photochemical activity using probe compounds. Correlations between the relative intensity of individual molecular formulas and reactive species production demonstrate the influence of DOM composition on photochemistry. For example, highly aromatic, tannin-like formulas correlate positively with triplet formation rates, but negatively with triplet quantum yields, as waters enriched in highly aromatic formulas exhibit much higher rates of light absorption, but only slightly higher rates of triplet production. While commonly utilized optical properties also correlate with DOM composition, the ability of FT-ICR MS to characterize DOM subpopulations provides unique insight into the mechanisms through which DOM source and environmental processing determine composition and photochemical activity. PMID- 28719192 TI - Precise Molecular Design of High-Tc 3D Organic-Inorganic Perovskite Ferroelectric: [MeHdabco]RbI3 (MeHdabco = N-Methyl-1,4 diazoniabicyclo[2.2.2]octane). AB - With the flourishing development of (CH3NH3)PbI3, three-dimensional (3D) organic inorganic perovskites with unique structure-property flexibility have become a worldwide focus. However, they still face great challenges in effectively inducing ferroelectricity. Despite the typical 3D perovskite structure and the ability of dabco (1,4-diazabicyclo[2.2.2]octane) to trigger phase transition, unfortunately [H2dabco]RbCl3 adopts a nonpolar crystal structure without ferroelectricity. Within the larger RbI3 framework, we assemble N-methyl-1,4 diazoniabicyclo[2.2.2]octane (MeHdabco) obtained by reducing the molecular symmetry of dabco into a new 3D organic-inorganic perovskite. As expected, MeHdabco bearing a molecular dipole moment turns out to be vital in the generation of polar crystal structure and ferroelectric phase transition occurring at 430 K. It is the first time that the dabco component has been successfully wrapped into a 3D cage to achieve ferroelectricity even through there is intensive research on dabco. This precise molecular design strategy based on the modification of molecular symmetry provides an efficient route to enrich the family of 3D organic-inorganic perovskite ferroelectrics. Intriguingly, the iodine-doped crystal can exhibit intense saffron yellow luminescence with a high quantum yield of 17.17% under UV excitation, extending its application in the field of ferroelectric luminescence and/or multifunctional devices. PMID- 28719193 TI - Relationships between Atmospheric Transport Regimes and PCB Concentrations in the Air at Zeppelin, Spitsbergen. AB - Polychlorinated biphenyls (PCBs) are persistent hazardous chemicals that are still detected in the atmosphere and other environmental media, although their production has been banned for several decades. At the long-term monitoring site, Zeppelin at Spitsbergen, different PCB congeners have been continuously measured for more than a decade. However, it is not clear what factors determine the seasonal and interannual variability of different (lighter versus heavier) PCB congeners. To investigate the influence of atmospheric transport patterns on PCB 28 and PCB-101 concentrations at Zeppelin, we applied the Lagrangian Particle Dispersion Model FLEXPART and calculated "footprints" that indicate the potential source regions of air arriving at Zeppelin. By means of a cluster analysis, we assigned groups of similar footprints to different transport regimes and analyzed the PCB concentrations according to the transport regimes. The concentrations of both PCB congeners are affected by the different transport regimes. For PCB-101, the origin of air masses from the European continent is primarily related to high concentrations; elevated PCB-101 concentrations in winter can be explained by the high frequency of this transport regime in winter, whereas PCB-101 concentrations are low when air is arriving from the oceans. For PCB-28, in contrast, concentrations are high during summer when air is mainly arriving from the oceans but low when air is arriving from the continents. The most likely explanation of this finding is that local emissions of PCB-28 mask the effect of long-range transport and determine the concentrations measured at Zeppelin. PMID- 28719194 TI - Molecular Modeling of the Major DNA Adduct Formed from Food Mutagen Ochratoxin A in NarI Two-Base Deletion Duplexes: Impact of Sequence Context and Adduct Ionization on Conformational Preference and Mutagenicity. AB - Exposure to ochratoxin A (OTA), a possible human carcinogen, leads to many different DNA mutations. As a first step toward understanding the structural basis of OTA-induced mutagenicity, the present work uses a robust computational approach and a slipped mutagenic intermediate model previously studied for C8-dG aromatic amine adducts to analyze the conformational features of postreplication two-base deletion DNA duplexes containing OT-dG, the major OTA lesion at the C8 position of guanine. Specifically, a total of 960 ns of molecular dynamics simulations (excluding trial simulations) were carried out on four OT-dG ionization states in three sequence contexts within oligomers containing the NarI recognition sequence, a known hotspot for deletion mutations induced by related adducts formed from known carcinogens. Our results indicate that the structural properties and relative stability of the competing "major groove" and "stacked" conformations of OTA adducted two-base deletion duplexes depend on both the OTA ionization state and the sequence context, mainly due to conformation-dependent deviations in discrete local (hydrogen-bonding and stacking) interactions at the lesion site, as well as DNA bending. When the structural characteristics of the OT-dG adducted two-base deletion duplexes are compared to those associated with previously studied C8-dG adducts, a greater understanding of the effects of the nucleobase-carcinogen linkage, and size of the carcinogenic moiety on the conformational preferences of damaged DNA is obtained. Most importantly, our work predicts key structural features for OT-dG-adducted deletion DNA duplexes, which in turn allow us to develop hypotheses regarding OT-dG replication outcomes. Thus, our computational results are valuable for the design and interpretation of future biochemical studies on the potentially carcinogenic OT-dG lesion. PMID- 28719195 TI - Fluorinated Boronic Acid-Appended Pyridinium Salts and 19F NMR Spectroscopy for Diol Sensing. AB - The identification and discrimination of diols is of fundamental importance in medical diagnostics, such as measuring the contents of glucose in the urine of diabetes patients. Diol sensors are often based on fluorophore-appended boronic acids, but these severely lack discriminatory power and their response is one dimensional. As an alternative strategy, we present the use of fluorinated boronic acid-appended pyridinium salts in combination with 19F NMR spectroscopy. A pool of 59 (bio)analytes was screened, containing monosaccharides, phosphorylated and N-acetylated sugars, polyols, carboxylic acids, nucleotides, and amines. The majority of analytes could be clearly detected and discriminated. In addition, glucose and fructose could be distinguished up to 1:9 molar ratio in mixtures. Crucially, the receptors feature high sensitivity and selectivity and are water-soluble, and their 19F-NMR analyte fingerprint is pH-robust, thereby making them particularly well-suited for medical application. Finally, to demonstrate this applicability, glucose could be detected in synthetic urine samples down to 1 mM using merely a 188 MHz NMR spectrometer. PMID- 28719197 TI - Enabling the Cross-Coupling of Tertiary Organoboron Nucleophiles through Radical Mediated Alkyl Transfer. AB - The construction of quaternary centers is a common challenge in the synthesis of complex materials and natural products. Current cross-coupling strategies that can be generalized for setting these centers are sparse and, when known, are typically predicated on the use of reactive organometallic reagents. To address this shortcoming a new, photoredox-Ni dual catalytic strategy for the cross coupling of tertiary organoboron reagents with aryl halides is reported. In addition to details on the cross-coupling scope and limitations, full screening efforts and mechanistic experiments are communicated. PMID- 28719198 TI - Biomimetic Platinum-Promoted Polyene Polycyclizations: Influence of Alkene Substitution and Pre-cyclization Conformations. AB - Results of kinetic experiments and quantum chemical computations on a series of platinum-promoted polycyclization reactions are described. Analyses of these results reveal a reactivity model that reaches beyond the energetics of the cascade itself, incorporating an ensemble of pre-cyclization conformations of the platinum-alkene reactant complex, only a subset of which are productive for bi- (or larger) cyclization and lead to products. Similarities and differences between this scenario, including reaction coordinates for polycyclization, for platinum- and enzyme-promoted polycyclization reactions are highlighted. PMID- 28719196 TI - Thermoresponsive Elastin-b-Collagen-Like Peptide Bioconjugate Nanovesicles for Targeted Drug Delivery to Collagen-Containing Matrices. AB - Over the past few decades, (poly)peptide block copolymers have been widely employed in generating well-defined nanostructures as vehicles for targeted drug delivery applications. We previously reported the assembly of thermoresponsive nanoscale vesicles from an elastin-b-collagen-like peptide (ELP-CLP). The vesicles were observed to dissociate at elevated temperatures, despite the LCST like behavior of the tethered ELP domain, which is suggested to be triggered by the unfolding of the CLP domain. Here, the potential of using the vesicles as drug delivery vehicles for targeting collagen-containing matrices is evaluated. The sustained release of an encapsulated model drug was achieved over a period of 3 weeks, following which complete release could be triggered via heating. The ELP CLP vesicles show strong retention on a collagen substrate, presumably through collagen triple helix interactions. Cell viability and proliferation studies using fibroblasts and chondrocytes suggest that the vesicles are highly cytocompatible. Additionally, essentially no activation of a macrophage-like cell line is observed, suggesting that the vesicles do not initiate an inflammatory response. Endowed with thermally controlled delivery, the ability to bind collagen, and excellent cytocompatibility, these ELP-CLP nanovesicles are suggested to have significant potential in the controlled delivery of drugs to collagen-containing matrices and tissues. PMID- 28719199 TI - Giant PbSe/CdSe/CdSe Quantum Dots: Crystal-Structure-Defined Ultrastable Near Infrared Photoluminescence from Single Nanocrystals. AB - Toward a truly photostable PbSe quantum dot (QD), we apply the thick-shell or "giant" QD structural motif to this notoriously environmentally sensitive nanocrystal system. Namely, using a sequential application of two shell-growth techniques-partial-cation exchange and successive ionic layer adsorption and reaction (SILAR)-we are able to overcoat the PbSe QDs with sufficiently thick CdSe shells to impart new single-QD-level photostability, as evidenced by suppression of both photobleaching and blinking behavior. We further reveal that the crystal structure of the CdSe shell (cubic zinc-blende or hexagonal wurtzite) plays a key role in determining the photoluminescence properties of these giant QDs, with only cubic nanocrystals sufficiently bright and stable to be observed as single emitters. Moreover, we demonstrate that crystal structure and particle shape (cubic, spherical, or tetrapodal) and, thereby, emission properties can be synthetically tuned by either withholding or including the coordinating ligand, trioctylphosphine, in the SILAR component of the shell-growth process. PMID- 28719200 TI - cis-Pinonic Acid Oxidation by Hydroxyl Radicals in the Aqueous Phase under Acidic and Basic Conditions: Kinetics and Mechanism. AB - Aqueous-phase oxidation of cis-pinonic acid (CPA) by hydroxyl radicals (OH) was studied using a relative rate technique under acidic and basic conditions. Liquid chromatography (LC) coupled to the negative electrospray ionization (ESI) quadrupole tandem mass spectrometry (MS/MS) was used to monitor the concentrations of CPA and reference compounds. The measured second order reaction rate coefficients of CPA with OH were: 3.6 +/- 0.3 * 109 M-1 s-1 (pH 2) and 3.0 +/- 0.3 * 109 M-1 s-1 (pH 10) - combined uncertainties are 2sigma. These results indicated that the lifetimes of CPA in the atmosphere are most likely independent from the aqueous-phase pH. LC-ESI/MS/MS was also used to tentatively identify the CPA oxidation products. Formation of carboxylic acids with molecular weight (MW) 216 Da (most likely C10H16O5) and MW 214 Da (C10H14O5) was confirmed with LC ESI/MS/MS. When the initial CPA concentration was increased from 0.3 to 10 mM, formation of additional products was observed with MW 188, 200, 204, and 232 Da. Hydroperoxy, hydroxyl and carbonyl-substituted CPA derivatives were tentatively identified among the products. Similar products were formed by the CPA oxidation by OH in the gas-phase, at the air-water interface as well as in the solid phase (dry film). Formation of the stable adduct of CPA and H2O2 was also observed when the reaction mixture was evaporated to dryness and redissolved in water. Acquired mass spectrometric data argues against formation of oligomers. PMID- 28719201 TI - Silver-Catalyzed Cascade 1,6-Addition/Cyclization of para-Quinone Methides with Propargyl Malonates: An Approach to Spiro[4.5]deca-6,9-dien-8-ones. AB - An unprecedented silver-catalyzed cascade 1,6-addition/5-exo-dig cyclization reaction between para-quinone methides and propargyl malonates under mild reaction conditions has been described. This reaction provides an efficient method to construct versatile spiro[4.5]cyclohexadienones in moderate to excellent yields with high atom economy and scalability. PMID- 28719202 TI - Quadrupolar NMR Relaxation from ab Initio Molecular Dynamics: Improved Sampling and Cluster Models versus Periodic Calculations. AB - Quadrupolar NMR relaxation rates are computed for 17O and 2H nuclei of liquid water, and of 23Na+, and 35Cl- in aqueous solution via Kohn-Sham (KS) density functional theory ab initio molecular dynamics (aiMD) and subsequent KS electric field gradient (EFG) calculations along the trajectories. The calculated relaxation rates are within about a factor of 2 of experimental results and improved over previous aiMD simulations. The relaxation rates are assessed with regard to the lengths of the simulations as well as configurational sampling. The latter is found to be the more limiting factor in obtaining good statistical sampling and is improved by averaging over many equivalent nuclei of a system or over several independent trajectories. Further, full periodic plane-wave basis calculations of the EFGs are compared with molecular-cluster atomic-orbital basis calculations. The two methods deliver comparable results with nonhybrid functionals. With the molecular-cluster approach, a larger variety of electronic structure methods is available. For chloride, the EFG computations benefit from using a hybrid KS functional. PMID- 28719203 TI - Singlet La and Lb Bands for N-Acenes (N = 2-7): A CASSCF/CASPT2 Study. AB - In this work CASPT2 calculations of polyacenes (from naphthalene to heptacene) were performed to find a methodology suitable for calculations of the absorption spectra, in particular of the La (B2u state) and Lb (B3u state) bands, of more extended systems. The effect of the extension of the active space and of freezing sigma orbitals was investigated. The MCSCF excitation energy of the B2u state is not sensitive to the size of the active space used. However, the CASPT2 results depend strongly on the amount of sigma orbitals frozen reflecting the ionic character of the B2u state. On the other hand, the excitation energies of the B3u state are much more sensitive to the size of the active space used in the calculations reflecting its multiconfigurational character. We found a good agreement with experimental data for both bands by including 14 electrons in 14 pi orbitals in the active space followed by the CASPT2(14,14) perturbation scheme in which both sigma and pi orbitals are included. PMID- 28719204 TI - Norditerpenoids and Dinorditerpenoids from the Seeds of Podocarpus nagi as Cytotoxic Agents and Autophagy Inducers. AB - Nine new norditerpenoids and dinorditerpenoids, 2-oxonagilactone A (1), 7beta hydroxynagilactone D (2), nagilactones K and L (3 and 4), 3beta hydroxynagilactone L (5), 2beta-hydroxynagilactone L (6), 3-epi-15 hydroxynagilactone D (7), 1alpha-chloro-2beta,3beta,15-trihydroxynagilactone L (8), and 15-hydroxynagilactone L (9), were isolated from the seeds of Podocarpus nagi, along with eight known analogues. The structures of the new compounds were established based on detailed NMR and HRESIMS analysis, as well as from their ECD spectra. The absolute configuration of the known compound 1-deoxy-2alpha hydroxynagilactone A (16) was confirmed by single-crystal X-ray diffraction. All of the isolates were tested for their cytotoxic activities against cancer cells. The results indicated that compounds 4 and 6, as well as several known compounds, displayed cytotoxicity against A2780 and HEY cancer cells. Among the new compounds, 2beta-hydroxynagilactone L (6) showed IC50 values of less than 2.5 MUM against the two cell lines used. Furthermore, compound 6 induced autophagic flux in A2780 cells, as evidenced by an enhanced expression level of the autophagy marker phosphatidylethanolamine-modified microtubule-associated protein light chain 3 (LC3-II) and increased mRFP-GFP-LC3 puncta. Also, compound 6 activated the c-Jun N-terminal kinase (JNK) pathway, while pretreatment with the JNK inhibitor SP600125 decreased compound 6-induced autophagy. PMID- 28719205 TI - Theoretical Investigations on the Mechanism and Kinetics of OH Radical Initiated Reactions of Monochloroacetic Acid. AB - The oxidation mechanism of monochloroacetic acid (CH2ClCOOH) by OH radical has been systematically investigated employing quantum mechanical methods coupled with kinetic calculation using canonical variational transition state theory. Three distinct transition states were identified for the titled reaction, two corresponding to the hydrogen atom abstraction and one corresponding to the chlorine atom abstraction. The rate constants of the titled reactions are computed over the temperature range 278-350 K, and the branching ratios calculated for the hydrogen atom abstraction from the -C(O)OH site and the -CH2Cl site are 25 and 75%, respectively, at 298 K. The computed branching ratio indicates that the kinetically favorable reaction is the hydrogen atom abstraction from the -CH2Cl site resulting in the formation of CHClC(O)OH radical, which further undergoes secondary reaction with O2 and other atmospheric species. The calculated overall rate constant for the hydrogen atom abstraction reactions is in consistent with the reported experimental rate constant. The atmospheric lifetime of CH2ClCOOH is found to be around 18 days. PMID- 28719206 TI - Direct Quantum Dynamics Using Grid-Based Wave Function Propagation and Machine Learned Potential Energy Surfaces. AB - We describe a method for performing nuclear quantum dynamics calculations using standard, grid-based algorithms, including the multiconfiguration time-dependent Hartree (MCTDH) method, where the potential energy surface (PES) is calculated "on-the-fly". The method of Gaussian process regression (GPR) is used to construct a global representation of the PES using values of the energy at points distributed in molecular configuration space during the course of the wavepacket propagation. We demonstrate this direct dynamics approach for both an analytical PES function describing 3-dimensional proton transfer dynamics in malonaldehyde and for 2- and 6-dimensional quantum dynamics simulations of proton transfer in salicylaldimine. In the case of salicylaldimine we also perform calculations in which the PES is constructed using Hartree-Fock calculations through an interface to an ab initio electronic structure code. In all cases, the results of the quantum dynamics simulations are in excellent agreement with previous simulations of both systems yet do not require prior fitting of a PES at any stage. Our approach (implemented in a development version of the Quantics package) opens a route to performing accurate quantum dynamics simulations via wave function propagation of many-dimensional molecular systems in a direct and efficient manner. PMID- 28719207 TI - Elevation of the Energy Threshold for Isomerization of 5-Hydroxyindole-(tert butyl alcohol)1 Cluster Cations. AB - Isomerization between two hydrogen-bonded (H-bonded) isomers of 5-hydroxyindole (tert-butyl alcohol)1 cluster cations ([5HI-(t-BuOH)1]+) was investigated in the gas phase. In the S0 state, jet-cooled 5HI-(t-BuOH)1 has two structural isomers, 5HI(OH)-(t-BuOH)1 and 5HI(NH)-(t-BuOH)1, in which the t-BuOH molecule is bound to the OH or the NH group of 5HI. The IR photodissociation spectrum of [5HI-(t BuOH)1]+ generated by two-color resonant two-photon ionization (2C-R2PI) via the S1-S0 origin of 5HI(NH)-(t-BuOH)1 provided evidence of both [5HI(OH)-(t-BuOH)1]+ and [5HI(NH)-(t-BuOH)1]+ coexisting in the D0 state, indicating that [5HI(NH)-(t BuOH)1]+ isomerizes to [5HI(OH)-(t-BuOH)1]+ after 2C-R2PI of 5HI(NH)-(t-BuOH)1. The lower limit of the energy threshold for the isomerization of [5HI(NH)-(t BuOH)1]+ to [5HI(OH)-(t-BuOH)1]+ was experimentally determined to be 3362 +/- 30 cm-1, and the corresponding energy threshold for the isomerization of [5HI(NH) (H2O)1]+ to [5HI(OH)-(H2O)1]+ has been reported to be 2127 +/- 30 cm-1. Thus, the energy threshold for the isomerization is elevated by at least 1200 cm-1 when the solvent molecule changes from H2O to t-BuOH. The elevation of the energy threshold is explained by the difference in the stabilization energies of [5HI-(t BuOH)1]+ and [5HI-(H2O)1]+ in the initial and transition states owing to the larger proton affinity of t-BuOH than H2O. PMID- 28719208 TI - Quantification of Hydrogen Bond Strength Based on Interaction Coordinates: A New Approach. AB - A new approach to quantify hydrogen bond strengths based on interaction coordinates (HBSBIC) is proposed and is very promising. In this research, it is assumed that the projected force field of the fictitious three atoms fragment (DHA) where D is the proton donor and A is the proton acceptor from the full molecular force field of the H-bonded complex characterizes the hydrogen bond. The "interaction coordinate (IC)" derived from the internal compliance matrix elements of this three-atom fragment measures how the DH covalent bond (its electron density) responds to constrained optimization when the HA hydrogen bond is stretched by a known amount (its electron density is perturbed by a specified amount). This response of the DH bond, based on how the IC depends on the electron density along the HA bond, is a measure of the hydrogen bond strength. The inter- and intramolecular hydrogen bond strengths for a variety of chemical and biological systems are reported. When defined and evaluated using the IC approach, the HBSBIC index leads to satisfactory results. Because this involves only a three-atom fragment for each hydrogen bond, the approach should open up new directions in the study of "appropriate small fragments" in large biomolecules. PMID- 28719209 TI - Cycloaddition Reactions of Cobalt-Complexed Macrocyclic Alkynes: The Transannular Pauson-Khand Reaction. AB - The Pauson-Khand reaction is a powerful tool for the synthesis of cyclopentenones through the efficient [2 + 2 + 1] cycloaddition of dicobalt alkyne complexes with alkenes. While intermolecular and intramolecular variants are widely known, transannular versions of this reaction are unknown and the basis of this study. Macrocyclic enyne and dienyne complexes were readily synthesized by palladium(II) catalyzed oxidative macrocyclizations of bis(vinyl boronate esters) or ring closing metathesis reactions followed by complexation with dicobalt octacarbonyl. Several reaction modalities of these macrocyclic complexes were uncovered. In addition to the first successful transannular Pauson-Khand reactions, other intermolecular and transannular cycloaddition reactions included intermolecular Pauson-Khand reactions, transannular [4 + 2] cycloaddition reactions, intermolecular [2 + 2 + 2] cycloaddition reactions, and intermolecular [2 + 2 + 1 + 1] cycloaddition reactions. The structural and reaction requirements for each process are presented. PMID- 28719210 TI - Thermally Regulated Reversible Formation of Vesicle-Like Assemblies by Hexaproline Amphiphiles. AB - Peptides composed of hexaproline and glutamic acid (P6E) or lysine (P6K) as C terminal units show thermally promoted aggregation, affording vesicle-like assemblies upon heating to 80 degrees C. The aggregation is analyzed by dynamic light scattering (DLS), with number-averaged diameters of ca. 600 and 300 nm, respectively, for P6E and P6K. NMR studies reveal that upon heating the amount of NMR-visible species is reduced to ca. 50% and that an important conformational change is experienced by the molecules in solution. Circular dichroism (CD) shows that at 20 degrees C the peptides present a polyproline II (PP-II) conformation which is disorganized upon heating. Scanning electron microscopy for samples which were fast frozen at 80 degrees C reveals vesicle-like assemblies. Using pyrene as a fluorescence probe, a critical aggregation concentration of ca. 30 MUM was estimated for P6E, while that of P6K was above 0.6 mM. The aggregation process is found to be fully reversible and could serve as a basis for development of stimuli responsive carriers. PMID- 28719211 TI - Real Space Demonstration of Induced Crystalline 3D Nanostructuration of Organic Layers. AB - The controlled 3D nanostructuration of molecular layers of the semiconducting molecules C22H14 (pentacene) and N,N'-dioctyl-3,4,9,10-perylene tetracarboxylic diimide (PTCDI-C8) is addressed. A tip-assisted method using atomic force microscopy (AFM) is developed for removing part of the organic material and relocating it in up to six layer thick nanostructures. Moreover, unconventional molecular scale imaging combining diverse friction force microscopy modes reveals the stacking sequence of the piled layers. In particular, we unambiguously achieve epitaxial growth, an issue of fundamental importance in thin film strategies for the nanostructuration of more efficient organic nanodevices. PMID- 28719212 TI - Proteochemometrics-Based Prediction of Peptide Binding to HLA-DP Proteins. AB - Human leukocyte antigens (HLA) class II proteins are involved in the antigen processing in the antigen presenting cells. They form complexes with antigen peptide fragments. The peptide-HLA protein complexes are presented on the cell surface where they are recognized by helper T cells (Th cells). HLA-DP is one of the three HLA class II loci. The HLA-DP proteins are associated with a significant number of autoimmune diseases, as well as with a susceptibility or resistance to a number of infectious agents. In the present study, we apply proteochemometrics-a method for bioactivity modeling of multiple ligands binding to multiple target proteins-to derive and validate a robust model for peptide binding prediction to the 7 most frequent HLA-DP proteins. The model is able to identify 86% of the binders in the top 10% of the best predicted nonamers generated from one protein. PMID- 28719213 TI - Full-Dimensional Excited-State Intramolecular Proton Transfer Dynamics of Salicylic Acid. AB - Salicylic acid (SAc) and its excited-state intramolecular proton transfer (ESIPT) capabilities have been studied both experimentally and theoretically by static calculations. However, to our knowledge, no radiationless pathway has been proposed so far. Instead, excited-state deactivation was only investigated via fluorescence. Therefore, we will present full-dimensional photodynamics of SAc using the floating-occupation configuration-interaction (FOCI) treatment with single and paired double excitations based on the semiempirical RM1 Hamiltonian. To further clarify mechanistic details, the potential energy surface (PES) is scanned along the proton transfer coordinates in one and two dimensions. The time evolution of relevant degrees of freedom (DOF), quantum yields and isomer populations are evaluated from 200 surface-hopping trajectories. It was found that a deactivation pathway from the excited state to the ground state is indeed accessible through a conical intersection, via rotation of the carboxyl group. Together with the ESIPT process, this rotation can also interchange the protons of the two (formal) OH groups, which makes the overall dynamics still more complex. Our full-dimensional photodynamics study provides a comprehensive overview of all these entangled steps. PMID- 28719214 TI - Tunable, Liquid Resistant Tip Enhanced Raman Spectroscopy Probes: Toward Label Free Nano-Resolved Imaging of Biological Systems. AB - Tip enhanced Raman spectroscopy (TERS) has been established as a powerful, noninvasive technique for chemical identification at the nanoscale. However, difficulties, including the degradation of probes, limit its use in liquid systems. Here TERS probes for studies in aqueous environments have been demonstrated using titanium nitride coatings with an alumina protective layer. The probes show enhancement in signal intensity as high as 380% in liquid measurements, and the probe resonance can be tuned by varying deposition conditions to optimize performance for different laser sources and types of samples. This development of inexpensively produced probes suited for studies in aqueous environments enables its wider use for fields such as biology and biomedicine in which aqueous environments are the norm. PMID- 28719215 TI - Origin of the S* Excited State Feature of Carotenoids in Light-Harvesting Complex 1 from Purple Photosynthetic Bacteria. AB - This spectroscopic study investigates the origin of the transient feature of the S* excited state of carotenoids bound in LH1 complexes from purple bacteria. The studies were performed on two RC-LH1 complexes from Rba. sphaeroides strains that bound carotenoids with different carbon-carbon double bond conjugation N, neurosporene (N = 9) and spirilloxanthin (N = 13). The S* transient spectral feature, originally associated with an elusive and optically silent excited state of spirilloxanthin in the LH1 complex, may be successfully explained and mimicked without involving any unknown electronic state. The spectral and temporal characteristics of the S* feature suggest that it is associated with triplet triplet annihilation of carotenoid triplets formed after direct excitation of the molecule via a singlet fission mechanism. Depending on pigment homogeneity and carotenoid assembly in the LH1 complex, the spectro-temporal component associated with triplet-triplet annihilation may simply resolve a pure T-S spectrum of a carotenoid. In some cases (like spirilloxanthin), the T-S feature will also be accompanied by a carotenoid Stark spectrum and/or residual transient absorption of minor carotenoid species bound into LH1 antenna complex. PMID- 28719216 TI - Exploring Ultimate Water Capillary Evaporation in Nanoscale Conduits. AB - Capillary evaporation in nanoscale conduits is an efficient heat/mass transfer strategy that has been widely utilized by both nature and mankind. Despite its broad impact, the ultimate transport limits of capillary evaporation in nanoscale conduits, governed by the evaporation/condensation kinetics at the liquid-vapor interface, have remained poorly understood. Here we report experimental study of the kinetic limits of water capillary evaporation in two dimensional nanochannels using a novel hybrid channel design. Our results show that the kinetic-limited evaporation fluxes break down the limits predicated by the classical Hertz Knudsen equation by an order of magnitude, reaching values up to 37.5 mm/s with corresponding heat fluxes up to 8500 W/cm2. The measured evaporation flux increases with decreasing channel height and relative humidity but decreases as the channel temperature decreases. Our findings have implications for further understanding evaporation at the nanoscale and developing capillary evaporation based technologies for both energy- and bio-related applications. PMID- 28719217 TI - Single Molecule Study on Polymer-Nanoparticle Interactions: The Particle Shape Matters. AB - The study on the nanoparticle-polymer interactions is very important for the design/preparation of high performance polymer nanocomposite. Here we present a method to quantify the polymer-particle interaction at single molecule level by using AFM-based single molecule force spectroscopy (SMFS). As a proof-of-concept study, we choose poly-l-lysine (PLL) as the polymer and several different types of polyoxometalates (POM) as the model particles to construct several different polymer nanocomposites and to reveal the binding mode and quantify the binding strength in these systems. Our results reveal that the shape of the nanoparticle and the binding geometry in the composite have significantly influenced the binding strength of the PLL/POM complexes. Our dynamic force spectroscopy studies indicate that the disk-like geometry facilitate the unbinding of PLL/AlMo6 complexes in shearing mode, while the unzipping mode becomes dominate in spherical PLL-P8W48 system. We have also systematically investigated the effects of charge numbers, particle size, and ionic strength on the binding strength and binding mode of PLL/POM, respectively. Our results show that electrostatic interactions dominate the stability of PLL/POM complexes. These findings provide a way for tuning the mechanical properties of polyelectrolyte-nanoparticle composites. PMID- 28719218 TI - Palladium/Copper-Catalyzed Oxidative Coupling of Arylboronic Acids with Isocyanides: Selective Routes to Amides and Diaryl Ketones. AB - An efficient and alternative oxidative cross-coupling strategy starting from arylboronic acids and isocyanides for the selective synthesis of amides and diaryl ketones with palladium/copper catalysis is developed. Various substituted benzamides and benzophenones could be obtained in good yields. The reaction represents an efficient and alternative strategy for the synthesis of carbonyl compounds. PMID- 28719219 TI - Microsecond Structural Rheology. AB - The relationship between the local structure of complex liquids and their response to shear is generally not well understood. This concerns, in particular, the formation of particle strings in the flow direction or hydroclusters, both important for the understanding of shear thinning and thickening phenomena. Here, we present results of a microfocus X-ray scattering experiment on spherical silica colloids in a liquid jet at high shear rates. Along and across the jet, we observe direction-dependent modifications of the structure factor of the suspension, suggesting the formation of differently ordered clusters in compression lines and as particle strings. With increasing distance from the orifice, the structure relaxes to the unsheared case with a typical relaxation 10 times larger as the time scale of Brownian motion. These results provide the first experimental flow characterization of a complex fluid at high shear rates detecting cluster formation and relaxation with micrometer and microsecond resolution. PMID- 28719220 TI - EGFR-Targeted Cationic Polymeric Mixed Micelles for Codelivery of Gemcitabine and miR-205 for Treating Advanced Pancreatic Cancer. AB - Gemcitabine (GEM), a first-line chemotherapy for pancreatic cancer undergoes rapid metabolism and develops chemoresistance after repeated administration. We previously demonstrated that the combination of GEM and miR-205 provides an effective therapeutic strategy to sensitize GEM-resistant pancreatic cancer cells. Since epidermal growth factor receptor (EGFR) is overexpressed in pancreatic cancer cells, in this study, we aimed to deliver mixed micelles containing GEM and miR-205 decorated with EGFR-targeting cetuximab (C225) monoclonal antibody for targeted therapy. Cetuximab C225 was conjugated to malemido-poly(ethylene glycol)-block-poly(2-methyl-2-carboxyl-propylene carbonate graft-dodecanol (C225-PEG-PCD) to prepare mixed micelles with mPEG-b-PCC-g-GEM-g DC-g-TEPA for targeted codelivery of GEM and miR-205. This mixed micelle formulation showed a significant enhancement in EGFR-mediated cellular uptake in GEM-resistant MIA PaCa-2R cells. Further, an enhanced tumor accumulation of C225 micelles conjugated with near-infrared fluorescent Cy7.5 dye and Dy677-labeled miR-205 in orthotopic pancreatic tumor bearing NSG mice was evident after systemic administration. In addition, inhibition of tumor growth was also observed with increased apoptosis and reduced EMT after treatment with C225 micelles containing GEM and miR-205. Therefore, we believe that the targeted delivery of GEM and miR-205 in combination could be a novel strategy for treating advanced pancreatic cancer. PMID- 28719221 TI - Biosimilars: biologics that meet patients' needs and healthcare economics. AB - Biologics have revolutionized medical care, yet uniform access to these effective medicines remains difficult due to the increasing costs of healthcare. As patent exclusivity on the early biologics wanes, regulatory and legal systems are adapting to bring competition to the field in the form of biosimilars. Biosimilars are biologics that offer the same clinical benefit in one or more of the same indications as the reference biologic drug and bring competition to the biologics space. Legislation creating a pathway resulting in the first US approvals of biosimilars has been in place since 2010, but the regulatory methodology and science of evaluating the sameness of two biologics has been in use for decades. The demonstration of biosimilarity is based on the "totality of the evidence" concept, in which all structural, functional, nonclinical, and clinical data for a biosimilar product are evaluated to show high similarity to the reference product. Clinical trials for biosimilars, therefore, are designed to confirm similarity, or discover clinically relevant differences between the reference product and the biosimilar, should differences exist. It is hoped that competition from biosimilars will drive biologic innovation and increase patient access to biologics. PMID- 28719222 TI - How drug life-cycle management patent strategies may impact formulary management. AB - Drug manufacturers may employ various life-cycle management patent strategies, which may impact managed care decision making regarding formulary planning and management strategies when single-source, branded oral pharmaceutical products move to generic status. Passage of the Hatch-Waxman Act enabled more rapid access to generic medications through the abbreviated new drug application process. Patent expirations of small-molecule medications and approvals of generic versions have led to substantial cost savings for health plans, government programs, insurers, pharmacy benefits managers, and their customers. However, considering that the cost of developing a single medication is estimated at $2.6 billion (2013 dollars), pharmaceutical patent protection enables companies to recoup investments, creating an incentive for innovation. Under current law, patent protection holds for 20 years from time of patent filing, although much of this time is spent in product development and regulatory review, leaving an effective remaining patent life of 7 to 10 years at the time of approval. To extend the product life cycle, drug manufacturers may develop variations of originator products and file for patents on isomers, metabolites, prodrugs, new drug formulations (eg, extended-release versions), and fixed-dose combinations. These additional patents and the complexities surrounding the timing of generic availability create challenges for managed care stakeholders attempting to gauge when generics may enter the market. An understanding of pharmaceutical patents and how intellectual property protection may be extended would benefit managed care stakeholders and help inform decisions regarding benefit management. PMID- 28719223 TI - From Bench to Bedside: Converting Placebo Research into Belief Activation. AB - Research on the placebo effect contains important elements that can be harnessed to improve clinical care. This paper proposes a new term, "Belief Activation," to describe the deliberate use of placebo effect tools by both patients and clinicians to catalyze healing. Belief Activation includes, but is not limited to, maximizing patient and practitioner expectations, classical and social conditioning, spirituality and prayer/intention, therapeutic relationship, healing environments, and minimizing the nocebo effect. This paper demonstrates ways in which Belief Activation is a form of evidence-based medicine and seeks to translate knowledge from placebo research into medical practice. PMID- 28719224 TI - Cardiometabolic Risk Factors and Health-Related Quality of Life in Adolescents with Obesity. AB - BACKGROUND: A number of research studies have demonstrated a decrease in health related quality of life (HRQL) measures among obese children. Moreover, the causes of HRQL impairments are not completely clear. Adolescent obesity is oftentimes associated with other cardiometabolic risk factors (CRFs); hence, the aim of our research was to estimate the frequency of CRFs and to determine whether there is an association between CRFs and HRQL scores among obese adolescents. METHODS: Our research included 92 treatment-seeking obese adolescents (11-17 years), 34 males. We looked at medical records and performed physical examinations, including anthropometry and laboratory evaluations. PedsQLTM 4.0 was used to assess the HRQL score. Logistic regression models were used to identify CRFs associated with worse HRQL scores, both in total and in each domain. RESULTS: The vast majority (70.6%) of adolescents had at least one CRF in addition to obesity. A cluster of three to four CRFs was found in 23.3% and was associated with males more than with the degree of obesity [odds ratio (OR) 4; confidence interval (95% CI) 1.3-11.6, p = 0.01]. HRQL scores in emotional functioning domain and scores of HRQL total were directly associated with waist circumference Z-score (OR 4.1; 95% CI 1.1-14.9, p = 0.03 and OR 3.4; 95% CI 1-11.6, p = 0.049). Hypertension was associated with worsening HRQL scores in school functioning domain (OR 3.3; 95% CI 1-10.9, p = 0.049). CONCLUSION: Obesity in adolescents is associated with a high frequency of associated CRFs and decreased HRQL scores. Although CRFs have an influence on reducing adolescents' HRQL, they are not a determining factor. PMID- 28719225 TI - Association between Social Support and Self-Care Behaviors in Adults with Chronic Obstructive Pulmonary Disease. AB - RATIONALE: Higher social support is associated with a better quality of life and functioning in adults with chronic obstructive pulmonary disease (COPD). OBJECTIVES: To determine the association between structural and functional social support and self-care behaviors in adults with COPD. METHODS: This was a longitudinal study using data from the CASCADE (COPD Activity: Serotonin Transporter, Cytokines, and Depression) study, which was focused on depression and functioning in COPD. Physical activity was measured with a validated accelerometer at baseline, year 1, and year 2. Additional self-care behaviors included pulmonary rehabilitation attendance, smoking status, receipt of influenza and/or pneumococcal vaccinations, and medication adherence. Structural social support indicators included living status, being partnered, number of close friends/relatives, and presence of a family caregiver. Functional social support was measured with the Medical Outcomes Social Support Survey (MOSSS). Mixed-effects and logistic regression models were used. RESULTS: A total of 282 participants with Global Initiative for Chronic Obstructive Lung Disease stage II to IV COPD were included (age, 68 +/- 9 yr; 80% men; FEV1% predicted, 45 +/- 16). For physical activity, participants who lived with others accrued 903 more steps per day than those who lived alone (95% confidence interval [CI], 373-1,433; P = 0.001); increases in the MOSSS total score were associated with more steps per day (beta = 10; 95% CI, 2-18; P = 0.02). The odds of pulmonary rehabilitation participation were more than 11 times higher if an individual had a spouse or partner caregiver compared with not having a caregiver (odds ratio [OR], 11.03; 95% CI, 1.93-62.97; P < 0.01). Higher functional social support (MOSSS total score) was associated with marginally lower odds of smoking (OR, 0.99; 95% CI, 0.98-1.00; P = 0.03) and higher odds of pneumococcal vaccination (OR, 1.02; 95% CI, 1.00-1.03; P = 0.02). Social support was not associated with influenza vaccination or medication adherence. CONCLUSIONS: Structural social support, which was measured by reports of living with others and having a caregiver, was respectively associated with higher levels of physical activity and greater participation in pulmonary rehabilitation in adults with COPD. Our findings reinforce the critical importance of the social environment in shaping patients' success with self-care. Clinical Trial registered with clinicaltrials.gov (NCT01074515). PMID- 28719226 TI - Learned Helplessness and Sexual Risk Taking in Adolescent and Young Adult African American Females. AB - Research involving adolescent and young African American (AA) females has demonstrated that they face uncontrollable obstacles which can interfere with the negotiation of safer sexual behaviors. If these obstacles are perceived as uncontrollable, then these females may be at risk for the development of Learned Helplessness (LH). As the LH model predicts, if these obstacles are believed not to be in their control, it may lead to deficits in motivational or cognitive decision-making, deficits that could certainly influence their sexual risk taking behaviors. Therefore, the primary objective for this pilot study was to trial the Learned Helplessness Scale (LHS) to examine the perceptions of LH in this population. A convenience sample of 50 adolescent and young AA females between the ages of 16 and 21 were recruited from two clinics in Southeast Michigan. Scores on the LHS ranged from 20 to 57, with a mean score of 39.1 (standard deviation = 10.49). The higher range of scores in the sample demonstrates a continuum of LH among the participants in the study. PMID- 28719227 TI - Simvastatin as an Adjunctive Therapy to Risperidone in Treatment of Autism: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial. AB - OBJECTIVES: Providing novel treatments for autism has been a subject of long standing research. Based on etiopathological findings, we aim at assessing potential therapeutic effects of statins, here simvastatin, on autism symptoms for the first time. METHODS: In this randomized, double-blind, placebo controlled, parallel-group 10-week clinical trial, 70 drug-free children aged 4 to 12 years old with diagnosis of autistic disorder based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, who had an Aberrant Behavior Checklist-Community (ABC-C) scale irritability subscale score of >=12, were equally randomized to receive either simvastatin (20-40 mg/day) or placebo as an adjunct to risperidone (1-2 mg/day) whereas administration of both drugs was started simultaneously from baseline. Patients with comorbid psychiatric disorders, active medical conditions, severe intellectual disability, seizure disorders, history of any treatments for autism in the past 6 months, or history of current anti-inflammatory drug consumption were excluded. Primary outcome was defined as the difference in mean change of the ABC-C scale irritability subscale score from baseline to the endpoint ( www.irct.ir ; IRCT201602041556N86). RESULTS: Significant differences in change of the ABC-C scale irritability (mean difference [95% confidence interval (CI)] = -3.45 [-5.37 to -1.54], p = 0.001; Cohen's d = 0.89) and hyperactivity/noncompliance (mean difference [95% CI] = -4.27 [-6.69 to -1.86], p = 0.001; Cohen's d = 0.87) subscales scores were detected between the two arms. No significant difference was detected in case of the other three subscales. CONCLUSIONS: This study provides preliminary evidence for potential therapeutic effects of simvastatin in the treatment of autism that warrants further investigations. PMID- 28719228 TI - Successful Use of Noninvasive Ventilation in Chronic Obstructive Pulmonary Disease. How Do High-Performing Hospitals Do It? AB - RATIONALE: Noninvasive ventilation (NIV) is a cornerstone of treatment for patients with severe exacerbations of chronic obstructive pulmonary disease (COPD), where it has been shown to reduce the need for intubation, hospital length of stay, and mortality. Despite high-quality evidence and strong recommendations in clinical guidelines, use of NIV varies widely across hospitals. OBJECTIVES: To identify approaches used by hospitals that have been successful in implementing NIV to treat patients with severe exacerbations of COPD. METHODS: Adopting a positive deviance approach, in-depth interviews were conducted with key stakeholders from a sample of high-performing hospitals selected from a large and representative network of 386 U.S. hospitals. High performers were defined as hospitals in which a high proportion of patients with COPD requiring mechanical ventilation were treated with NIV, and that also achieved low risk-adjusted mortality for all patients with COPD. Interviews were audio-recorded and transcribed verbatim. Themes and subthemes were identified through iterative readings of the transcripts and discussion until the team agreed that all important themes and subthemes had been identified. All transcripts were coded by three or four researchers. Differences in coding were discussed to negotiate consensus, resulting in a single agreed-on set of coded transcripts. RESULTS: Interviews were conducted with 32 participants from seven hospitals. Hospitals were diverse regarding size, teaching status, and geographic location. Participants included respiratory therapists (n = 15), physicians (n = 10), and nurses (n = 7). The qualitative analyses revealed three interrelated domains that characterized effective NIV use: processes, structural elements, and contextual factors. Several themes comprised each domain. Key processes included timely identification of appropriate patients, early initiation of NIV, frequent reassessment of patients, and attention to patient comfort. Necessary structural elements included adequate equipment, sufficient numbers of qualified respiratory therapists, and flexibility in staffing. Important contextual factors included provider buy-in, respiratory therapist autonomy, interdisciplinary teamwork, and staff education. Hospital leaders, policies, and protocols were identified as playing a supporting role in promoting essential elements. CONCLUSIONS: We identified factors, such as respiratory therapist autonomy, that facilitated essential processes (e.g., timely initiation) of NIV use at high-performing hospitals. These findings may be useful to hospitals seeking to optimize their use of NIV among patients with COPD. PMID- 28719230 TI - Help seeking for mental health problems in an adolescent population: the effect of gender. AB - BACKGROUND: While the onset of many mental health problems occurs in adolescence, these problems are severely undertreated in this age group. To inform early intervention for adolescents, we investigated the effect of gender and education type on perception of barriers to help seeking, mental health literacy, and the awareness and use of mental health services. METHOD: A web-based survey using vignettes, open-ended and multiple choice items was administered to upper secondary school students in two counties in Norway. RESULTS: The survey was completed by 1249 students (88% response rate) with an average age of 17.6 years and 56% were female. Compared to males, the females were better in identifying psychological problems of anxiety and trauma, awareness of mental health services (p < 0.001) and perceived more barriers for seeking help (cost and waiting time; p < 0.001). For use of all mental health services, the effect of education type was greater than the effect of gender. CONCLUSION: For adolescents, gender appears to play a significant, but not exclusive, role in the inclination to seek professional help for mental health problems. We hypothesise that the observed gender difference in use of services is related to the gender difference in awareness of referral pathway services and the influence of parents in help seeking process. PMID- 28719229 TI - Experiences Using Pre-Exposure Prophylaxis for Safer Conception Among HIV Serodiscordant Heterosexual Couples in the United States. AB - Antiretroviral pre-exposure prophylaxis (PrEP) is a promising HIV prevention strategy for HIV serodiscordant couples (HIV-infected male, uninfected female) seeking safer conception. However, most research on PrEP for safer conception has focused on couples in sub-Saharan Africa; little is known about the perspectives or experiences of heterosexual couples in the United States. We conducted qualitative interviews with six couples (six women and five of their male partners) receiving PrEP for conception services at an urban safety net hospital in the US Northeast. In-depth interview guides explored couple relationships and contextual factors and attitudes, perceptions, and decision-making processes surrounding PrEP for safer conception. Thematic analyses focused on identifying the following emergent themes. We found that couple relationships were situated within broader social and cultural contexts of immigration, family, and community that shaped their experiences with HIV and serodiscordant relationship status. Despite strong partner support within relationships, HIV stigma and disapproval of serodiscordant relationships contributed to couples' feelings of social isolation and subsequent aspirations to have "normal" families. By enabling "natural" conception through condomless sex, PrEP for safer conception provided a sense of enhanced relationship intimacy. Couples called for increasing public awareness of PrEP through positive messaging as a way to combat HIV stigma. Findings suggest that relationship dynamics and broader social contexts appear to shape HIV serodiscordant couples' fertility desires and motivations to use PrEP. However, increased public awareness of PrEP for safer conception may be needed to combat HIV stigma at the community level. PMID- 28719231 TI - Biologic injections for osteoarthritis and articular cartilage damage: can we modify disease? AB - OBJECTIVE: The purpose of the present investigation is to conduct a systematic review of the literature to review the clinical results of platelet rich plasma (PRP) and mesenchymal stem cell treatments (MSC) (biologics) for articular cartilage lesions and osteoarthritis of the knee. METHODS: A search of the PubMed, EMBASE, and Cochrane databases was performed to identify studies involving biologic therapy for osteoarthritis or osteochondral defects. Only Level I-III clinical trials with at least 3-month follow-up were included. Outcome data was gathered on any patient-completed surveys, 2nd look arthroscopy, follow-up imaging, biopsy/histology results, and any adverse effects of treatment. RESULTS: Thirty-three articles met our inclusion criteria. There was a total of 21 PRP studies in the study. All PRP studies showed clinical improvement with PRP therapies in outcomes surveys measuring patient satisfaction, pain, and function. Two studies reported no significant difference in improvement compared to hyaluronic acid (HA). Similarly, the 7/9 MSC studies showed improvement. One study found BM-MSC implantation was not significantly superior to matrix assisted chondrocyte implantation (MACI), while one reported peripheral blood stem cells (PBSC) did not significantly improve outcomes over HA. Of the three studies looking at a combination of MSC/PRP, two found MSC/PRP combination did not improve outcomes compared to MSC or PRP therapy alone. The one PRP study that had a 2nd look arthroscopy reported increases cartilage regeneration with PRP. All 8 MSC studies with follow-up MRI and all 7 MSC studies with 2nd look arthroscopy showed improvement in cartilage regeneration in terms of coverage, fill of the defect, and/or firmness of the new cartilage. CONCLUSION: Current data suggests that, of the two treatments, MSC provides more significant disease modifying effect; however, further research needs to be done to compare these two treatments and determine if there is a synergetic effect when combined. PMID- 28719232 TI - Long-Term Outcomes of a Multidisciplinary Weight Management Intervention for Youth with Disabilities. AB - BACKGROUND: Youth with disabilities are at increased risk for obesity compared with their typically developing peers and face unique barriers to healthy lifestyles. A limited number of weight management programs have been specifically tailored to accommodate youth with disabilities, and outcomes research in this population is scarce. We investigated the effectiveness of a specialized multidisciplinary weight management program for children with disabilities. METHODS: Youth (N = 115) ages 2-18 years (mean age = 10.46) and their families receiving care in the Special Needs Weight Management Clinic (SNWMC) were followed over a period of 12 months. Child height and weight were measured by trained clinicians and used to calculate Body Mass Index z-scores (BMIz). A two level multilevel model was estimated with repeated measurements of BMIz nested within patients. RESULTS: Significant BMIz reductions of 0.02 per month were observed over the course of treatment when controlling for child age and baseline BMIz. A significant interaction between child age and time revealed that younger (vs. older) children exhibited greater decreases in BMIz over the course of treatment. Sex, ethnicity, disability diagnosis, and insurance moderated change in BMIz over the course of treatment. CONCLUSIONS: Outcomes of the SNWMC revealed significant decreases in BMIz with <5 sessions on average over 12 months and indicated the increased efficacy of early intervention in youth with disabilities. Future research should continue to modify interventions for families with adolescent children with disabilities as well as investigate additional variables that may impact success in treatment. PMID- 28719233 TI - Bronchoscopic Management of Airway Compression due to Fibrosing Mediastinitis. PMID- 28719235 TI - Artificial neural network modelling of ATTR amyloidosis: is now the time? PMID- 28719236 TI - Applying an artificial neural network model for developing a severity score for patients with hereditary amyloid polyneuropathy. AB - Hereditary (familial) amyloid polyneuropathy (FAP) is a systemic disease that includes a sensorimotor polyneuropathy related to transthyretin (TTR) mutations. So far, a scale designed to classify the severity of this disease has not yet been validated. This work proposes the implementation of an artificial neural network (ANN) in order to develop a severity scale for monitoring the disease progression in FAP patients. In order to achieve this goal, relevant symptoms and laboratory findings were collected from 98 Brazilian patients included in THAOS - the Transthyretin Amyloidosis Outcomes Survey. Ninety-three percent of them bore Val30Met, the most prevalent variant of TTR worldwide; 63 were symptomatic and 35 were asymptomatic. These data were numerically codified for the purpose of constructing a Self-Organizing Map (SOM), which maps data onto a grid of artificial neurons. Mapped data could be clustered by similarity into five groups, based on increasing FAP severity (from Groups 1 to 5). Most symptoms were virtually absent from patients who mapped to Group 1, which also includes the asymptomatic patients. Group 2 encompasses the patients bearing symptoms considered to be initial markers of FAP, such as first signs of walking disabilities and lack of sensitivity to temperature and pain. Interestingly, the patients with cardiac symptoms, which also carry cardiac-associated mutations of the TTR gene (such as Val112Ile and Ala19Asp), were concentrated in Group 3. Symptoms such as urinary and fecal incontinence and diarrhea characterized particularly Groups 4 and 5. Renal impairment was found almost exclusively in Group 5. Model validation was accomplished by considering the symptoms from a sample with 48 additional Brazilian patients. The severity scores proposed here not only identify the current stage of a patient's disease but also offer to the physician an easy-to-read, 2D map that makes it possible to track disease progression. PMID- 28719237 TI - Ask and Tell: The Importance of the Collection of Sexual Orientation and Gender Identity Data to Improve the Quality of Cancer Care for Sexual and Gender Minorities. PMID- 28719234 TI - The In Vivo Effects of the CB1-Positive Allosteric Modulator GAT229 on Intraocular Pressure in Ocular Normotensive and Hypertensive Mice. AB - PURPOSE: Orthosteric cannabinoid receptor 1 (CB1) activation leads to decreases in intraocular pressure (IOP). However, use of orthosteric CB1 agonists chronically has several disadvantages, limiting their usefulness as clinically relevant drugs. Allosteric modulators interact with topographically distinct sites to orthosteric ligands and may be useful to circumvent some of these disadvantages. The purpose of this study was to investigate the effects of the novel CB1-positive allosteric modulator (PAM) GAT229 on IOP. METHODS: IOP was measured using rebound tonometry in anesthetized normotensive C57Bl/6 mice and in a genetic model of ocular hypertension [nose, eyes, ears (nee) mice] before drug administration, and at 1, 6, and 12 h thereafter. RESULTS: In normotensive mice, topical administration of 5 MUL GAT229 alone at either 0.2% or 2% did not reduce IOP. However, a subthreshold dose (0.25%) of the nonselective orthosteric CB1 agonist WIN 55,212-2, when combined with 0.2% GAT229, significantly reduced IOP compared with vehicle at 6 and 12 h. Similarly, combination of subthreshold Delta9-tetrahydrocannabinol (a nonselective orthosteric CB1 agonist; 1 mg/kg) with topical 0.2% GAT229 produced IOP lowering at 6 h. In nee mice, administration of topical 0.2% GAT229 or 10 mg/kg GAT229 alone was sufficient to lower IOP at 6 and 12 h, and 12 h, respectively. CONCLUSIONS: The CB1 PAM GAT229 reduces IOP in ocular hypertensive mice and enhanced CB1-mediated IOP reduction when combined with subthreshold CB1 orthosteric ligands in normotensive mice. Administration of CB1 PAMs may provide a novel approach to reduce IOP with fewer of the disadvantages associated with orthosteric CB1 activation. PMID- 28719238 TI - Mining databases for protein aggregation: a review. AB - Protein aggregation is an active area of research in recent decades, since it is the most common and troubling indication of protein instability. Understanding the mechanisms governing protein aggregation and amyloidogenesis is a key component to the aetiology and pathogenesis of many devastating disorders, including Alzheimer's disease or type 2 diabetes. Protein aggregation data are currently found "scattered" in an increasing number of repositories, since advances in computational biology greatly influence this field of research. This review exploits the various resources of aggregation data and attempts to distinguish and analyze the biological knowledge they contain, by introducing protein-based, fragment-based and disease-based repositories, related to aggregation. In order to gain a broad overview of the available repositories, a novel comprehensive network maps and visualizes the current association between aggregation databases and other important databases and/or tools and discusses the beneficial role of community annotation. The need for unification of aggregation databases in a common platform is also addressed. PMID- 28719239 TI - Explaining Consumer Safe Food Handling Through Behavior-Change Theories: A Systematic Review. AB - Consumers often engage in unsafe food handling behaviors at home. Previous studies have investigated the ability of behavior-change theories to explain and predict these behaviors. The purpose of this review was to determine which theories are most consistently associated with consumers' safe food handling behaviors across the published literature. A standardized systematic review methodology was used, consisting of the following steps: comprehensive search strategy; relevance screening of identified references; confirmation of relevance and characterization of relevant articles; risk-of-bias assessment; data extraction; and descriptive analysis of study results. A total of 20 relevant studies were identified; they were mostly conducted in Australia (40%) and the United States (35%) and used a cross-sectional design (65%). Most studies targeted young adults (65%), and none focused on high-risk consumer groups. The outcomes of 70% of studies received high overall risk-of-bias ratings, largely due to a lack of control for confounding variables. The most commonly applied theory was the Theory of Planned Behavior (45% of studies), which, along with other investigated theories of behavior change, was frequently associated with consumer safe food handling behavioral intentions and behaviors. However, overall, there was wide variation in the specific constructs found to be significantly associated and in the percentage of variance explained in each outcome across studies. The results suggest that multiple theories of behavior change can help to explain consumer safe food handling behaviors and could be adopted to guide the development of future behavior-change interventions. In these contexts, theories should be appropriately selected and adapted to meet the needs of the specific target population and context of interest. PMID- 28719240 TI - Cytoprotective effects of essential oil of Pinus halepensis L. against aspirin induced toxicity in IEC-6 cells. AB - CONTEXT: Essential oils from Pinus species have been reported to have various therapeutic properties. OBJECTIVE: This study was undertaken to identify the chemical composition and cytoprotective effects of the essential oil of Pinus halepensis L. against aspirin-induced damage in cells in vitro. MATERIAL AND METHODS: The cytoprotection of the oil against toxicity of aspirin on the small intestine epithelial cells IEC-6 was tested. RESULTS: The obtained results have shown that 35 different compounds were identified. Aspirin induced a decrease in cell viability, and exhibited significant damage to their morphology and an increase in superoxide dismutase (SOD) and catalase (CAT) activities. However, the co-treatment of aspirin with the essential oil of Pinus induced a significant increase in cell viability and a decrease in SOD and CAT activities. CONCLUSION: Overall, these finding suggest that the essential oil of Pinus halepensis L. has potent cytoprotective effect against aspirin-induced toxicity in IEC-6 cells. PMID- 28719241 TI - Pressure and Time: A Recipe for Legislative Change. PMID- 28719242 TI - Rapid Radiation Therapy for Advanced Cancer of the Head and Neck #336. PMID- 28719244 TI - Evaluation of the Use of Zero-Augmented Regression Techniques to Model Incidence of Campylobacter Infections in FoodNet. AB - The Foodborne Diseases Active Surveillance Network (FoodNet) is currently using a negative binomial (NB) regression model to estimate temporal changes in the incidence of Campylobacter infection. FoodNet active surveillance in 483 counties collected data on 40,212 Campylobacter cases between years 2004 and 2011. We explored models that disaggregated these data to allow us to account for demographic, geographic, and seasonal factors when examining changes in incidence of Campylobacter infection. We hypothesized that modeling structural zeros and including demographic variables would increase the fit of FoodNet's Campylobacter incidence regression models. Five different models were compared: NB without demographic covariates, NB with demographic covariates, hurdle NB with covariates in the count component only, hurdle NB with covariates in both zero and count components, and zero-inflated NB with covariates in the count component only. Of the models evaluated, the nonzero-augmented NB model with demographic variables provided the best fit. Results suggest that even though zero inflation was not present at this level, individualizing the level of aggregation and using different model structures and predictors per site might be required to correctly distinguish between structural and observational zeros and account for risk factors that vary geographically. PMID- 28719245 TI - Production of a Mouse Monoclonal Antibody Against Mortalin by Whole Cell Immunization. AB - Pancreatic carcinoma is the fourth leading cause of cancer death and is characterized by early invasion and metastasis. Advances in molecular biology directed new strategies in targeted therapy using monoclonal antibodies. To identify new biomarkers, we generated a panel of monoclonal antibodies against the newly established cell line, Faraz-ICR, from a patient with acinar cell carcinoma. After immunization of BALB/c female mice with Faraz-ICR cell line and fusion of splenocytes with SP2/0 myeloma cell line, high reactive hybridoma producing antibodies to Faraz-ICR were detected using enzyme-linked immunosorbent assay, immunofluorescence staining and flow cytometry. Western blot and two dimensional immunoblot were used for further characterization of the targets antibodies. Among high reactive clones, the reactivity of 1C11 clone was assessed with other epithelial tumors. The isotype of the antibody was revealed to be IgM, and the antibody reacted to a protein with a molecular weight of about 70 kDa in Western blot analysis. To further characterization of the target antigen, immunoproteome of the Faraz-ICR cell line was performed. By liquid chromatography mass spectrometry (LC-MS) analysis, we identified that the target of 1C11 clone was HSP70. In conclusion, pancreatic cancer is a fatal malignancy with no reliable biomarker for early screening and diagnosis. In this study, by establishing a pancreatic cell line, a panel of monoclonal antibodies was generated aiming to explore specific or associated cancer targets. We then introduced 1C11 monoclonal antibody that can specifically recognize mortalin as a main tumor marker and may serve as a new tool for diagnostic kit and therapeutic strategies targeting this molecule. PMID- 28719243 TI - Genotyping-by-Sequencing-Based Genetic Analysis of African Rice Cultivars and Association Mapping of Blast Resistance Genes Against Magnaporthe oryzae Populations in Africa. AB - Understanding the genetic diversity of rice germplasm is important for the sustainable use of genetic materials in rice breeding and production. Africa is rich in rice genetic resources that can be utilized to boost rice productivity on the continent. A major constraint to rice production in Africa is rice blast, caused by the hemibiotrophic fungal pathogen Magnaporthe oryzae. In this report, we present the results of a genotyping-by-sequencing (GBS)-based diversity analysis of 190 African rice cultivars and an association mapping of blast resistance (R) genes and quantitative trait loci (QTLs). The 190 African cultivars were clustered into three groups based on the 184K single nucleotide polymorphisms generated by GBS. We inoculated the rice cultivars with six African M. oryzae isolates. Association mapping identified 25 genomic regions associated with blast resistance (RABRs) in the rice genome. Moreover, PCR analysis indicated that RABR_23 is associated with the Pi-ta gene on chromosome 12. Our study demonstrates that the combination of GBS-based genetic diversity population analysis and association mapping is effective in identifying rice blast R genes/QTLs that contribute to resistance against African populations of M. oryzae. The identified markers linked to the RABRs and 14 highly resistant cultivars in this study will be useful for rice breeding in Africa. PMID- 28719246 TI - Disparities in Exposure to Intimate Partner Violence Among Transgender/Gender Nonconforming and Sexual Minority Primary Care Patients. AB - PURPOSE: We investigated the odds of intimate partner violence (IPV) among primary care patients across subgroups of transgender and gender nonconforming (TGNC) individuals relative to cisgender women, and cisgender sexual minority men and women relative to cisgender heterosexual men and women. METHODS: Participants completed an IPV screener as part of routine primary care visits at an urban community health center (N = 7572). Electronic medical record data were pooled for all patients who received the IPV screener January 1 to December 31, 2014. RESULTS: Overall, 3.6% of the sample reported experiencing physical or sexual IPV in the past year. Compared to cisgender women (past-year prevalence 2.7%), all TGNC subgroups reported elevated odds of physical or sexual IPV, including transgender women (past-year prevalence 12.1%; adjusted odds ratio [AOR] = 5.0, 95% confidence interval [CI] = 2.9-8.6), transgender men (6.6%; AOR = 2.4, 95% CI: 1.2-4.6), gender non-binary individuals (8.2%, AOR = 3.1, 95% CI = 1.7-5.4), and TGNC individuals who did not report their gender identity (9.1%; AOR = 3.7, 95% CI = 2.2-6.3). The prevalence of isolation-related IPV and controlling behaviors was also high in some TGNC groups. CONCLUSION: Our findings support that IPV is prevalent across genders and sexual orientations. Clinical guidelines for IPV screening should be expanded to include TGNC individuals and not just cisgender women. Future research could explore the complex patterns by which individuals of different genders are at increased risk for different types of IPV, and investigate the best ways to screen TGNC patients and support TGNC survivors. PMID- 28719248 TI - The Efficacy of Dignity Therapy on the Psychological Well-Being in Loved Ones of Terminally Ill Patients. PMID- 28719247 TI - Telehealth in Schools Using a Systematic Educational Model Based on Fiction Screenplays, Interactive Documentaries, and Three-Dimensional Computer Graphics. AB - BACKGROUND: Preliminary studies suggest the need of a global vision in academic reform, leading to education re-invention. This would include problem-based education using transversal topics, developing of thinking skills, social interaction, and information-processing skills. We aimed to develop a new educational model in health with modular components to be broadcast and applied as a tele-education course. MATERIALS AND METHODS: We developed a systematic model based on a "Skills and Goals Matrix" to adapt scientific contents on fictional screenplays, three-dimensional (3D) computer graphics of the human body, and interactive documentaries. We selected 13 topics based on youth vulnerabilities in Brazil to be disseminated through a television show with 15 episodes. We developed scientific content for each theme, naturally inserting it into screenplays, together with 3D sequences and interactive documentaries. The modular structure was then adapted to a distance-learning course. RESULTS: The television show was broadcast on national television for two consecutive years to an estimated audience of 30 million homes, and ever since on an Internet Protocol Television (IPTV) channel. It was also reorganized as a tele-education course for 2 years, reaching 1,180 subscriptions from all 27 Brazilian states, resulting in 240 graduates. CONCLUSION: Positive results indicate the feasibility, acceptability, and effectiveness of a model of modular entertainment audio-visual productions using health and education integrated concepts. This structure also allowed the model to be interconnected with other sources and applied as tele education course, educating, informing, and stimulating the behavior change. Future works should reinforce this joint structure of telehealth, communication, and education. PMID- 28719249 TI - Applying sensory modulation to mental health inpatient care to reduce seclusion and restraint: a case control study. AB - BACKGROUND: Clinical training in managing conflicts and preventing violence seldom contains sensory modulation (SM) as a method to de-escalate and prevent restraint and seclusion. Sensory-based interventions promote adaptive regulation of arousal and emotion. SM is a complementary approach that is associated with reduced rates of seclusion and restraint in mental healthcare, but there is need for more research in this area. AIMS: Using SM to reduce restraint and seclusion in inpatient mental health care. METHODS: The study included two similar psychiatric units where one unit implemented SM and one unit served as the control group. In the very beginning of the study, a staff-training program in the use of SM including assessment tools and intervention strategies was established. Data on restraint and forced medicine were sampled post the course of the year of implementation and compared with the control group. RESULTS: The use of belts decreased with 38% compared to the control group. The use of forced medication decreased with 46% compared to the control group. Altogether the use of physical restraint and forced medication decreased significantly with 42% (p < .05). CONCLUSIONS: Implementing a SM approach in mental healthcare facilities has a significant effect on the reduction of restraint and seclusion. As a part of the implementation, staff training and education in SM are crucial. PMID- 28719251 TI - Erratum: IJSNEM 27(3). AB - The International Journal of Sport Nutrition and Exercise Metabolism 27(3), http://journals.humankinetics.com/toc/ijsnem/27/3 , was incorrectly paginated. The correct page range for this issue is 197-292. The online versions of these articles have been corrected. PMID- 28719250 TI - Sleeping Beauty Awakens New Interest. PMID- 28719252 TI - Severe Fever with Thrombocytopenia Syndrome Virus in Humans, Domesticated Animals, Ticks, and Mosquitoes, Shaanxi Province, China. AB - AbstractThe first human infection with severe fever with thrombocytopenia syndrome virus (SFTSV) was detected in Shaanxi Province, China, in 2013, although the virus had been reported in 13 other provinces of China since 2010. We collected and analyzed a total of 4,011 samples, including 936 human serum samples, 155 animal serum samples, 895 ticks, 1,950 mosquitoes, 30 midges, and 20 sandflies. SFTSV antibodies were found in 44 human samples (4.7%) with no significant differences between males and females or across counties. The incidence rate of severe fever with thrombocytopenia syndrome was significantly higher among individuals 20-60 years of age. Moreover, SFTSV-specific antibodies were detected in goats (66.7%), cattle (13.2%), and dogs (15.0%), but not in pigs (0%). We detected the virus in Haemaphysalis concinna ticks with a prevalence rate of 21.3% (17/80 pools). All mosquito, midge, and sandfly samples were negative for SFTSV. These results support wide circulation of the virus in western China. Haemaphysalis concinna ticks may serve as a novel SFTSV vector, and the role of these ticks requires further investigation. PMID- 28719253 TI - Cost-Effectiveness Evaluation of a Novel Integrated Bite Case Management Program for the Control of Human Rabies, Haiti 2014-2015. AB - AbstractHaiti has the highest burden of rabies in the Western hemisphere, with 130 estimated annual deaths. We present the cost-effectiveness evaluation of an integrated bite case management program combining community bite investigations and passive animal rabies surveillance, using a governmental perspective. The Haiti Animal Rabies Surveillance Program (HARSP) was first implemented in three communes of the West Department, Haiti. Our evaluation encompassed all individuals exposed to rabies in the study area (N = 2,289) in 2014-2015. Costs (2014 U.S. dollars) included diagnostic laboratory development, training of surveillance officers, operational costs, and postexposure prophylaxis (PEP). We used estimated deaths averted and years of life gained (YLG) from prevented rabies as health outcomes. HARSP had higher overall costs (range: $39,568 $80,290) than the no-bite-case-management (NBCM) scenario ($15,988-$26,976), partly from an increased number of bite victims receiving PEP. But HARSP had better health outcomes than NBCM, with estimated 11 additional annual averted deaths in 2014 and nine in 2015, and 654 additional YLG in 2014 and 535 in 2015. Overall, HARSP was more cost-effective (US$ per death averted) than NBCM (2014, HARSP: $2,891-$4,735, NBCM: $5,980-$8,453; 2015, HARSP: $3,534-$7,171, NBCM: $7,298-$12,284). HARSP offers an effective human rabies prevention solution for countries transitioning from reactive to preventive strategies, such as comprehensive dog vaccination. PMID- 28719254 TI - Prevalence and Risk Factors for Human Cystic Echinococcosis in the Cusco Region of the Peruvian Highlands Diagnosed Using Focused Abdominal Ultrasound. AB - AbstractLatin America is among the highly endemic regions for cystic echinococcosis (CE). In Peru, an estimated 1,139 disability-adjusted life years are lost annually from surgical treatment of CE. This is comparable with the combined total for Argentina, Brazil, Uruguay, and Chile. The prevalence of human infection has been investigated in the central Peruvian Andes, but there are no community-based screening data from other regions of Peru. We carried out a population survey in January 2015 using abdominal ultrasound to estimate the prevalence of abdominal CE in the Canas and Canchis provinces, in the Cusco region of Peru. Among 1,351 subjects screened, 41 (3%) had CE. There was significant variation between communities with similar socioeconomic features in a small geographical area. A history of CE was reported by 4.1% of the screened subjects, among whom 30.3% still had CE on ultrasound. Among patients reporting previous CE treatment, 14.9% had CE in active stages. Limited education, community of residence, and knowing people with CE in the community were associated with CE. These results demonstrate a significant burden of CE in the region and suggest the need for further investigations, control activities, and optimization of clinical management for CE in this area. PMID- 28719255 TI - Patient-Reported Adverse Effects Associated with Combination Antiretroviral Therapy and Coadministered Enzyme-Inducing Antiepileptic Drugs. AB - AbstractConcurrent treatment with combination antiretroviral therapy (cART) and an enzyme-inducing antiepileptic drug (EI-AED) is common in resource-limited settings; however, the incidence and impact of adverse effects in cotreated patients is largely unknown. Symptoms of adverse effects were assessed by both spontaneous report and checklist for 145 human immunodeficiency virus (HIV) infected Zambian adults initiating various treatment combinations, such as cART with an EI-AED (N = 20), cART only (N = 43), or neither drug (untreated; N = 82). At study baseline, the cART + EI-AED group reported more headache, generalized fatigue, problems with concentration, and depression than the untreated group (P < 0.01 for all). At 2 weeks, a greater proportion of cART + EI-AED participants reported increased nausea or vomiting compared with baseline (P < 0.05). Adverse effects did not appear to impact self-reported adherence at 2 weeks as 100% cART adherence was reported in 19 of 20 (95%) and 42 of 43 (98%) cART + EI-AED and cART-only participants, respectively; 100% EI-AED adherence was reported in 19 of 20 (95%) participants. However, adherence at 6 months was suboptimal in both groups with 18 of 33 (56%) participants on cART experiencing greater than 1-week lapse in pharmacy-reported medication supply. Our results highlight the need to educate patients about the increased potential for nausea and vomiting with cART + EI-AED cotreatment. Although adherence was high early during treatment, adherence should be reinforced overtime to minimize the potential for HIV and/or epilepsy treatment failure. PMID- 28719256 TI - Therapeutic Dilemma of Refractory Erythema Nodosum Leprosum. AB - AbstractErythema nodosum leprosum (ENL), also known as type II leprosy reaction, is a severe immune-mediated complication of multibacillary leprosy. For ENL, corticosteroids and thalidomide are the mainstays of treatment. Other immunosuppressants, such as clofazimine, cyclosporine, and azathioprine have also been used. Although most patients with ENL respond well to conventional treatments, a small number are refractory to these therapies and have severe morbidity or mortality. We report the case of a 24-year-old man with refractory ENL treated with high-dose corticosteroids for 15 months. The patient developed steroid-dependence and serious adverse effects, and died of an intracranial infection. PMID- 28719257 TI - No Serologic Evidence of Middle East Respiratory Syndrome Coronavirus Infection Among Camel Farmers Exposed to Highly Seropositive Camel Herds: A Household Linked Study, Kenya, 2013. AB - AbstractHigh seroprevalence of Middle East respiratory syndrome coronavirus (MERS CoV) among camels has been reported in Kenya and other countries in Africa. To date, the only report of MERS-CoV seropositivity among humans in Kenya is of two livestock keepers with no known contact with camels. We assessed whether persons exposed to seropositive camels at household level had serological evidence of infection. In 2013, 760 human and 879 camel sera were collected from 275 and 85 households respectively in Marsabit County. Data on human and animal demographics and type of contact with camels were collected. Human and camel sera were tested for anti-MERS-CoV IgG using a commercial enzyme-linked immunosorbent assay (ELISA) test. Human samples were confirmed by plaque reduction neutralization test (PRNT). Logistic regression was used to identify factors associated with seropositivity. The median age of persons sampled was 30 years (range: 5-90) and 50% were males. A quarter (197/760) of the participants reported having had contact with camels defined as milking, feeding, watering, slaughtering, or herding. Of the human sera, 18 (2.4%) were positive on ELISA but negative by PRNT. Of the camel sera, 791 (90%) were positive on ELISA. On univariate analysis, higher prevalence was observed in female and older camels over 4 years of age (P < 0.05). On multivariate analysis, only age remained significantly associated with increased odds of seropositivity. Despite high seroprevalence among camels, there was no serological confirmation of MERS-CoV infection among camel pastoralists in Marsabit County. The high seropositivity suggests that MERS CoV or other closely related virus continues to circulate in camels and highlights ongoing potential for animal-to-human transmission. PMID- 28719258 TI - Impact of a Food Safety Campaign on Streptococcus suis Infection in Humans in Thailand. AB - AbstractStreptococcus suis is an important zoonotic pathogen in swine and humans that causes sepsis and meningitis. Our previous study in Thailand showed that the prevalence of S. suis infection in humans, especially in northern areas of Thailand, and the transmission of the pathogen occurred mainly through the consumption of traditional raw pork products. Considering the high incidence proportion and mortality rate of the disease as an important public health problem, we implemented a food safety campaign in the Phayao Province in northern Thailand in 2011. We evaluated the effects of a food safety campaign by comparing the sociodemographic, clinical, and bacteriological characteristics of cases before and after the campaign. The follow-up study showed a marked decrease of the incidence proportion in the first 2 years, indicating the effectiveness of the campaign. In the third year, however, the incidence proportion slightly increased again, indicating the existence of deep-rooted cultural behaviors and the necessity of continuous public health intervention. Furthermore, epidemiological analysis of the cases made it possible to estimate the infectivity of the pathogen via the oral route of infection. In the present study, we showed the effectiveness of the food safety campaign for controlling the S. suis infection, and we present a role model public health intervention for prevalent areas affected by S. suis infection in humans. PMID- 28719260 TI - Symptomatic Falciparum Malaria After Living in a Nonendemic Area for 10 Years: Recrudescence or Indigenous Transmission? AB - AbstractWe report the case of a patient from Mali who, after 10 years of living in Spain, presented with symptomatic Plasmodium falciparum malaria without having visited an endemic area during that time. We cannot completely rule out the possibility of indigenous transmission, but this case most likely represents recrudescence of an infection acquired over 10 years earlier. PMID- 28719259 TI - Serosurvey of Crimean-Congo Hemorrhagic Fever Virus in Cattle, Mali, West Africa. AB - AbstractCrimean-Congo hemorrhagic fever is a tick-borne disease caused by the arbovirus Crimean-Congo hemorrhagic fever virus (CCHFV, family Bunyaviridae, genus Nairovirus). CCHFV can cause a severe hemorrhagic fever with high-case fatality rates in humans. CCHFV has a wide geographic range and has been described in around 30 countries in the Middle East, Asia, Europe, and Africa including Mali and neighboring countries. To date, little is known about the prevalence rates of CCHFV in Mali. Here, using banked bovine serum samples from across the country, we describe the results of a seroepidemiological study for CCHFV aimed at identifying regions of circulation in Mali. In total, 1,074 serum samples were tested by a modified in-house CCHFV-IgG-enzyme-linked immunosorbent assay (ELISA) with confirmatory testing by commercial ELISA and immunofluorescence assay. Overall, 66% of samples tested were positive for CCHFV specific IgG antibodies. Regional seroprevalence rates ranged from 15% to 95% and seemed to correlate with cattle density. Our results demonstrate that CCHFV prevalence is high in many regions in Mali and suggest that CCHFV surveillance should be established. PMID- 28719261 TI - More Evidence on the Effects of Deworming: What Lessons Can We Learn? PMID- 28719262 TI - Evaluation of a Mobile Phone-Based Microscope for Screening of Schistosoma haematobium Infection in Rural Ghana. AB - AbstractSchistosomiasis affects over 170 million people in Africa. Here we compare a novel, low-cost mobile phone microscope to a conventional light microscope for the label-free diagnosis of Schistosoma haematobium infections in a rural Ghanaian school setting. We tested the performance of our handheld microscope using 60 slides that were randomly chosen from an ongoing epidemiologic study in school-aged children. The mobile phone microscope had a sensitivity of 72.1% (95% confidence interval [CI]: 56.1-84.2), specificity of 100% (95% CI: 75.9-100), positive predictive value of 100% (95% CI: 86.3-100), and a negative predictive value of 57.1% (95% CI: 37.4-75.0). With its modest sensitivity and high specificity, this handheld and cost-effective mobile phone based microscope is a stepping-stone toward developing a powerful tool in clinical and public health settings where there is limited access to conventional laboratory diagnostic support. PMID- 28719263 TI - Burden of Disease Attributed to Waterborne Transmission of Selected Enteric Pathogens, Australia, 2010. AB - AbstractUniversal access to safe drinking water is a global priority. To estimate the annual disease burden of campylobacteriosis, nontyphoidal salmonellosis, cryptosporidiosis, giardiasis, and norovirus attributable to waterborne transmission in Australia, we multiplied regional World Health Organization (WHO) estimates of the proportion of cases attributable to waterborne transmission by estimates of all-source disease burden for each study pathogen. Norovirus was attributed as causing the most waterborne disease cases (479,632; 95% uncertainty interval [UI]: 0-1,111,874) followed by giardiasis and campylobacteriosis. The estimated waterborne disability-adjusted life year (DALY) burden for campylobacteriosis (2,004; 95% UI: 0-5,831) was 7-fold greater than other study pathogens and exceeded the WHO guidelines for drinking water quality (1 * 10-6 DALY per person per year) by 90-fold. However, these estimates include disease transmitted via either drinking or recreational water exposure. More precise country-specific and drinking water-specific attribution estimates would better define the health burden from drinking water and inform changes to treatment requirements. PMID- 28719264 TI - The Human Microbiome in the Fight Against Tuberculosis. AB - AbstractThe human microbiome is an intriguing potentially modifiable risk factor in our arsenal against Mycobacterium tuberculosis, the leading infectious disease killer globally. Previous studies have shown associations between the human microbiome and pulmonary disease states; however, etiological links between the microbiome and tuberculosis (TB) infection or disease remain unclear. Immunomodulatory roles of the microbiome may prove to be a critical asset in the host response against TB, including in preventing TB infection, reducing progression from latency, mitigating disease severity, and lowering the incidence of drug resistance and coinfections. This review examined the associations between TB and the gut and lung microbiome. Eight studies were identified through a PubMed database search, including one animal study (N = 1), case report (N = 1), and case-control studies (N = 6). TB infection and disease were associated with reduced gastrointestinal microbial diversity in a murine model and human case report. Sputum microbial diversity differed by TB status in case-control studies, although some reported heterogeneous findings. Current evidence suggests that the gut and lung microbiome are associated with TB infection and disease. However, as studies are limited, etiological and longitudinal research is needed to determine clinical relevance. PMID- 28719265 TI - Differences in Inflammation Patterns Induced by African and Asian Burkholderia pseudomallei Isolates in Mice. AB - AbstractBurkholderia pseudomallei is the causative agent of melioidosis, an emerging tropical disease of high mortality. Sub-Saharan Africa represents potential melioidosis "hotspots"; however, to date, only a few cases have been reported. Here in, we compared the inflammatory patterns induced by a B. pseudomallei strain recently isolated from a fatal Gabonese case with the Thai reference strain B. pseudomallei-1026b and Burkholderia thailandensis-E264. Ex vivo, no differences were observed in terms of cellular responsiveness between strains. However, when compared with the B. pseudomallei-1026b strain, the Gabonese isolate was significantly less virulent in terms of bacterial dissemination, inflammatory response, and organ damage in mice. Genomic comparison between strains showed differences in regions containing a fimbriae/adhesion virulence protein. In addition to a lack of microbiology facilities, differences in virulence of Burkholderia strains might contribute to the diverse global clinical occurrence of melioidosis. PMID- 28719266 TI - Serological and Molecular Analysis of Leishmania Infection in Healthy Individuals from Two Districts of West Bengal, India, Endemic for Visceral Leishmaniasis. AB - AbstractSeveral epidemiological studies have indicated the presence of asymptomatic infections with Leishmania donovani in the Indian subcontinent, where parasite transmission is considered anthroponotic. In India, such asymptomatic Leishmania cases have been identified in the state of Bihar. We explored here, the presence of asymptomatic Leishmania infection among healthy individuals living in two districts in the state of West Bengal, India, using serological and molecular tests. Blood samples of 246 healthy individuals were collected from nine villages of Malda and Murshidabad districts in West Bengal, considered endemic for visceral leishmaniasis (VL). Real-time quantitative polymerase chain reaction (qPCR) was performed for the quantification of parasite load in the blood. In addition, two serological tests were carried out to demonstrate anti-Leishmania antibodies: rK39 strip test and anti-total soluble Leishmania antigen IgG using enzyme-linked immunosorbent assay method. Nearly one fifth (53/246) of the screened population was positive in qPCR as against 10.97% (27/246) positive in rK39 strip test. A range of parasite load was observed in the blood of identified asymptomatic Leishmania cases with a median value of 7.7 parasites/mL (range = 1-65). There was poor agreement between qPCR and serological tests (kappa = 0.089, P = 0.13), and 29.62% and 20.54% of the population were qPCR positive in seropositive and seronegative groups, respectively. Combined molecular and serological tests enhanced the capacity to detect asymptomatic Leishmania infection in healthy individuals residing in the endemic areas of VL. A significant proportion of asymptomatic Leishmania individuals was detected in the examined endemic regions of West Bengal that might play a role in promoting VL transmission. PMID- 28719267 TI - Comparison of Cytokine Responses in Ecuadorian Children Infected with Giardia, Ascaris, or Both Parasites. AB - AbstractMore than 2 billion people are infected with parasites globally, and the majority have coinfections. Intestinal protozoa and helminths induce polarizing CD4+ T-helper cell 1 (Th1) mediated cytokine responses within the host. Such immune polarization may inhibit the ability of the host to mount an adequate immune response for pathogen clearance to concurrent pathogens. The current study evaluated the plasma cytokine profile in Ascaris and Giardia coinfected children compared with Giardia- and Ascaris-only infected children. Fecal samples and blood samples were collected from asymptomatic 3-year-old children living in the district of Quininde, Ecuador. Stool samples that tested positive for Giardia lamblia-only, Ascaris lumbricoides-only, or G. lamblia and A. lumbricoides coinfections were confirmed by quantitative real-time polymerase chain reaction. Plasma samples from the study subjects were used to quantitate cytokines. A total of 39 patients were evaluated. Children with coinfection had a significant decrease in Th1 cytokine production, interleukin 2 (IL-2) (P < 0.05), IL-12 (P < 0.05), and tumor necrosis factor alpha (P < 0.05) compared with Giardia-only infected children. Coinfected children had an increase in IL-10/interferon gamma (IFN-gamma) ratio compared with uninfected (P < 0.05) and Ascaris alone (P < 0.05). The increased IL-10/IFN-gamma ratio in the setting of decreased Th1 cytokine response indicates Th2 polarization in the coinfected group. Reduced Th1 cytokines in children coinfected with Ascaris and Giardia may impair the host's ability to eradicate Giardia infection leading to chronic giardiasis. PMID- 28719268 TI - The Cuba-United States Thaw: Building Bridges Through Science and Global Health. AB - AbstractBeginning in 2014, there has been significant progress in normalization of relations between Cuba and the United States. Herein, we discuss the history and recent progress in scientific collaboration between the two countries as well as the continued challenges. Science and global health diplomacy can be key tools in reestablishing a trusting and productive relationship of mutual and global benefit, bringing about better and healthier lives for people in both Cuba and the United States. PMID- 28719269 TI - The Influence of Household- and Community-Level Sanitation and Fecal Sludge Management on Urban Fecal Contamination in Households and Drains and Enteric Infection in Children. AB - AbstractUrban sanitation necessitates management of fecal sludge inside and outside the household. This study examined associations between household sanitation, fecal contamination, and enteric infection in two low-income neighborhoods in Vellore, India. Surveys and spatial analysis assessed the presence and clustering of toilets and fecal sludge management (FSM) practices in 200 households. Fecal contamination was measured in environmental samples from 50 households and household drains. Enteric infection was assessed from stool specimens from children under 5 years of age in these households. The two neighborhoods differed significantly in toilet coverage (78% versus 33%) and spatial clustering. Overall, 49% of toilets discharged directly into open drains ("poor FSM"). Children in households with poor FSM had 3.78 times higher prevalence of enteric infection when compared with children in other households, even those without toilets. In the neighborhood with high coverage of household toilets, children in households with poor FSM had 10 times higher prevalence of enteric infection than other children in the neighborhood and drains in poor FSM clusters who had significantly higher concentrations of genogroup II norovirus. Conversely, children in households with a toilet that contained excreta in a tank onsite had 55% lower prevalence of enteric infection compared with the rest of the study area. Notably, households with a toilet in the neighborhood with low toilet coverage had more fecal contamination on floors where children played compared with those without a toilet. Overall, both toilet coverage levels and FSM were associated with environmental fecal contamination and, subsequently, enteric infection prevalence in this urban setting. PMID- 28719270 TI - Mycetoma (Madura Foot) in Israel: Recent Cases and a Systematic Review of the Literature. AB - AbstractMycetoma is a chronic soft tissue infection caused by fungal or bacterial pathogens, and is endemic in tropical and subtropical regions. Cases in developed countries outside the mycetoma belt are rare and usually imported by immigrants. Sporadic cases have been reported in Israel. Unpublished cases in the participating medical centers are reported. In addition, a systematic review of the literature was performed. All published mycetoma cases diagnosed in Israel were included with relevant variables collected. Twenty-one cases of mycetoma were diagnosed in Israel between 1942 and 2015, including four unpublished cases and 17 published cases. The mean age at diagnosis was 42 years (range 23-73), and 16 of the patients were male. The foot was the primary involved organ. Fifteen patients were immigrants from Yemen, Ethiopia, and Sudan. Five cases were autochthonous. One case was travel related. Among patients who developed symptoms after immigration, the mean time from exposure to symptom onset was 5.6 years (range 1-10 years). The mean time from symptom onset to diagnosis was 6.6 years (range 0.2-35 years). The autochthonous cases demonstrate that Israel is endemic of mycetoma. The immigrant population represents two distinct waves of immigration to Israel in the past century. Two unpublished cases of Ethiopian immigrants are the first reported cases of mycetoma acquired in Ethiopia. The diagnostic and therapeutic challenges along with the epidemiological data emphasize the need of raising the awareness of physicians to this devastating condition even in developed countries. PMID- 28719271 TI - Trachomatous Scar Ranking: A Novel Outcome for Trachoma Studies. AB - AbstractWe evaluated a new trachoma scarring ranking system with potential use in clinical research. The upper right tarsal conjunctivas of 427 individuals from Ethiopian villages with hyperendemic trachoma were photographed. An expert grader first assigned a scar grade to each photograph using the 1981 World Health Organization (WHO) grading system. Then, all photographs were ranked from least (rank = 1) to most scarring (rank = 427). Photographic grading found 79 (18.5%) conjunctivae without scarring (C0), 191 (44.7%) with minimal scarring (C1), 105 (24.6%) with moderate scarring (C2), and 52 (12.2%) with severe scarring (C3). The ranking method demonstrated good internal validity, exhibiting a monotonic increase in the median rank across the levels of the 1981 WHO grading system. Intrarater repeatability was better for the ranking method (intraclass correlation coefficient = 0.84, 95% CI = 0.74-0.94). Exhibiting better internal and external validity, this ranking method may be useful for evaluating the difference in scarring between groups of individuals. PMID- 28719272 TI - Mycobacterial Arthritis at 19 Months After a Bacille Calmette-Guerin Vaccination. PMID- 28719273 TI - Bungarus multicinctus multicinctus Snakebite in Taiwan. AB - AbstractAlthough specific antivenom is available in Taiwan, respiratory failure and general pain frequently accompany Bungarus multicinctus envenomation and there have been few reports on the management of B. multicinctus envenomation. We retrospectively analyzed 44 cases of B. multicinctus bite admitted to Taichung Veterans General Hospital (VGH) or to Taipei VGH. Demographic data, treatment, and outcome of patients with and without respiratory failure were compared. In this study, 20.5% patients had bites without noticeable signs or symptoms of significant envenoming, 27.3% developed respiratory failure, and 27.3% experienced general pain. Bivalent specific antivenom for B. multicinctus and N. atra was administered in all envenomed cases. Respiratory failure occurred 1.5 6.5 hours post-bite and general pain occurred 1-12 hours post-bite. Specific antivenom for B. multicinctus and N. atra at the recommended dose (i.e., 2-4 vials) might not effectively prevent respiratory failure and pain. Respiratory failure, general pain, and autonomic effects after B. multicinctus bite were probably caused, at least partly, by beta-bungarotoxin. Although general weakness, ptosis, dysarthria, and dilated pupils were significantly associated with respiratory failure, their predictive value could not be accurately determined in such a retrospective study. Due to the rapid onset of respiratory failure, every suspected envenomed case thus should be closely monitored in the first few hours. We recommend the initial administration of four vials of antivenom in all envenomation cases, and a subsequent four vials be considered if the patient's condition is deteriorating. Prospective evaluation of the antivenom dosing regimen is urgently needed to improve B. multicinctus envenomation treatment. PMID- 28719274 TI - Risk Factors for Podoconiosis: Kamwenge District, Western Uganda, September 2015. AB - AbstractPodoconiosis, a noninfectious elephantiasis, is a disabling neglected tropical disease. In August 2015, an elephantiasis case-cluster was reported in Kamwenge District, western Uganda. We investigated to identify the disease's nature and risk factors. We defined a suspected podoconiosis case as onset in a Kamwenge resident of bilateral asymmetrical lower limb swelling lasting >= 1 month, plus >= 1 of the following associated symptoms: skin itching, burning sensation, plantar edema, lymph ooze, prominent skin markings, rigid toes, or mossy papillomata. A probable case was a suspected case with negative microfilaria antigen immunochromatographic card test (ruling out filarial elephantiasis). We conducted active case-finding. In a case-control investigation, we tested the hypothesis that the disease was caused by prolonged foot skin exposure to irritant soils, using 40 probable case-persons and 80 asymptomatic village control-persons, individually matched by age and sex. We collected soil samples to characterize irritants. We identified 52 suspected (including 40 probable) cases with onset from 1980 to 2015. Prevalence rates increased with age; annual incidence (by reported onset of disease) was stable over time at 2.9/100,000. We found that 93% (37/40) of cases and 68% (54/80) of controls never wore shoes at work (Mantel-Haenszel odds ratio [ORMH] = 7.7; 95% [confidence interval] CI = 2.0-30); 80% (32/40) of cases and 49% (39/80) of controls never wore shoes at home (ORMH = 5.2; 95% CI = 1.8-15); and 70% (27/39) of cases and 44% (35/79) of controls washed feet at day end (versus immediately after work) (OR = 11; 95% CI = 2.1-56). Soil samples were characterized as rich black-red volcanic clays. In conclusion, this reported elephantiasis is podoconiosis associated with prolonged foot exposure to volcanic soil. We recommended foot hygiene and universal use of protective shoes. PMID- 28719275 TI - High Triatoma brasiliensis Densities and Trypanosoma cruzi Prevalence in Domestic and Peridomestic Habitats in the State of Rio Grande do Norte, Brazil: The Source for Chagas Disease Outbreaks? AB - AbstractA total of 2,431 Triatoma brasiliensis were collected from 39 populations of Paraiba (PB) and Rio Grande do Norte (RN) states, Brazil. In PB, Trypanosoma cruzi infection was not detected in either peridomestic or domestic vector populations. In contrast, in RN, T. brasiliensis was detected with high parasite prevalence in these ecotopes (30.7-40.0%). Moreover, peridomicile insect population densities were more than double the average densities of all other settings evaluated (19.17 versus < 8.94 triatomine/man-hour). Genotyped parasites evidenced a mix of T. cruzi lineages circulating in both peridomestic and sylvatic populations. Although vector control efforts have dramatically decreased Chagas disease transmission to humans, recent outbreaks have been detected in four municipalities of RN state. Our results clearly evidence a worrisome proximity between infected vectors and humans in RN. Indeed, finding of infected T. brasiliensis inside homes is routinely recorded by local vector control surveillance staff around the outbreak area, challenging the current and conventional view that vector transmissions are controlled in northeastern Brazil. This scenario calls for strengthening vector control surveillance and interventions to prevent further Chagas transmission, especially in RN State. PMID- 28719276 TI - High Hepatitis E Seroprevalence Among Displaced Persons in South Sudan. AB - AbstractLarge protracted outbreaks of hepatitis E virus (HEV) have been documented in displaced populations in Africa over the past decade though data are limited outside these exceptional settings. Serological studies can provide insights useful for improving surveillance and disease control. We conducted an age-stratified serological survey using samples previously collected for another research study from 206 residents of an internally displaced person camp in Juba, South Sudan. We tested serum for anti-HEV antibodies (IgM and IgG) and estimated the prevalence of recent and historical exposure to the virus. Using data on individuals' serostatus, camp arrival date, and state of origin, we used catalytic transmission models to estimate the relative risk of HEV infection in the camp compared with that in the participants' home states. The age-adjusted seroprevalence of anti-HEV IgG was 71% (95% confidence interval = 63-78), and 4% had evidence of recent exposure (IgM). We estimated HEV exposure rates to be more than 2-fold (hazard ratio = 2.3, 95% credible interval = 0.3-5.8) higher in the camp than in the participants' home states, although this difference was not statistically significant. HEV transmission may be higher than previously appreciated, even in the absence of reported cases. Improved surveillance in similar settings is needed to understand the burden of disease and minimize epidemic impact through early detection and response. PMID- 28719278 TI - Evaluation of the Field Performance of ImmunoCard STAT!(r) Rapid Diagnostic Test for Rotavirus in Dadaab Refugee Camp and at the Kenya-Somalia Border. AB - AbstractRotavirus commonly causes diarrhea in children, leading to hospitalization and even death. Rapid diagnostic tests are feasible alternatives for determining rotavirus outbreaks in refugee camps that have inadequate laboratory capacity. We evaluated the field performance of ImmunoCard STAT!(r) Rotavirus (ICS-RV) in Dadaab Refugee Camp and at the Kenya-Somalia border. From May to December 2014, we prospectively enrolled children aged < 5 years hospitalized with acute diarrhea, defined as >= 3 episodes of loose stool in 24 hours for < 7 days. Stool samples were collected and tested by trained surveillance clerks using ICS-RV per manufacturer's instructions. The field performance characteristics of ICS-RV were evaluated against the gold standard test, PremierTM Rotaclone(r) enzyme immunoassay. The operational characteristics were evaluated using World Health Organization (WHO) ASSURED criteria to determine whether ICS-RV is appropriate as a point-of-care test by administering a standard questionnaire and observing surveillance clerks performing the test. We enrolled 213 patients with a median age of 10 months (range = 1-48); 58.2% were male. A total of 71 (33.3%) and 60 (28.2%) patients tested positive for rotavirus infection by immunoassay and ICS-RV, respectively. The sensitivity, specificity, and positive and negative predictive values of ICS-RV compared with the immunoassay were 83.1% (95% confidence interval [CI] = 72.3-91.0), 99.3% (95% CI = 96.1-100), 98.3% (95% CI = 91.1-100), and 92.1% (95% CI = 86.6-95.5), respectively. The ICS-RV fulfilled the WHO ASSURED criteria for point-of-care testing. ICS-RV is a field-ready point-of-care test with good field performance and operational characteristics. It can be useful in determining rotavirus outbreaks in resource-limited settings. PMID- 28719277 TI - Reducing Uncertainty for Acute Febrile Illness in Resource-Limited Settings: The Current Diagnostic Landscape. AB - AbstractDiagnosing the cause of acute febrile illness in resource-limited settings is important-to give the correct antimicrobials to patients who need them, to prevent unnecessary antimicrobial use, to detect emerging infectious diseases early, and to guide vaccine deployment. A variety of approaches are yielding more rapid and accurate tests that can detect more pathogens in a wider variety of settings. After decades of slow progress in diagnostics for acute febrile illness in resource-limited settings, a wave of converging advancements will enable clinicians in resource-limited settings to reduce uncertainty for the diagnosis of acute febrile illness. PMID- 28719279 TI - Clinical Characteristics and Prognosis of Penicilliosis Among Human Immunodeficiency Virus-Infected Patients in Eastern China. AB - AbstractTalaromyces marneffei infection is increasingly observed in people living with human immunodeficiency virus (HIV) in eastern China, a nonendemic area. This study aimed to draw the clinician's attention to this disease by presenting the clinical characteristics and prognosis of penicilliosis among HIV-infected patients from this region. We retrospectively analyzed HIV-infected patients with culture-proven T. marneffei infection admitted during January 1, 2014-December 31, 2015, at the Shanghai Public Health Clinical Center. A total of 48 patients with confirmed HIV infection and penicilliosis were enrolled, which accounted for a mean of 3.2% (95% confidence interval: 2.4-4.2%) of yearly HIV infection admissions among patients from eastern China. Symptoms included fever, cough, and gastrointestinal complaints, whereas the most common sign was skin lesions. Anemia occurred in 87.5% (42/48) of the patients. The overall mortality rate was 16.7%. Low CD4 T-cell count and hemoglobin level were correlated with mortality. Based on these results, we concluded that penicilliosis should be considered in HIV-infected patients from eastern China who present with fever, cutaneous lesions, and anemia. The clinical characters and the prognosis of patients with penicilliosis are similar to those in endemic areas. More attention should be paid to penicilliosis patients with low CD4 T-cell count and/or low hemoglobin level. PMID- 28719280 TI - Multiplex Serologic Assessment of Schistosomiasis in Western Kenya: Antibody Responses in Preschool Aged Children as a Measure of Reduced Transmission. AB - AbstractCurrently, impact of schistosomiasis control programs in Schistosoma mansoni-endemic areas is monitored primarily by assessment of parasitologic indicators only. Our study was conducted to evaluate the use of antibody responses as a way to measure the impact of schistosomiasis control programs. A total of 3,612 serum samples collected at three time points from children 1-5 years of age were tested for antibody responses to two schistosome antigens (soluble egg antigen [SEA] and Sm25) by multiplex bead assay. The overall prevalence of antibody responses to SEA was high at baseline (50.0%). After one round of mass drug administration (MDA), there was minimal change in odds of SEA positivity (odds ratio [OR] = 1.02, confidence interval [CI] = 0.79-1.32, P = 0.89). However, after two rounds of treatment, there was a slight decrease in odds of SEA positivity (OR = 0.80, CI = 0.63-1.02, P = 0.08). In contrast to the SEA results, prevalence of antibody responses to Sm25 was lowest at baseline (14.1%) and higher in years 2 (19.8%) and 3 (18.4%). After one round of MDA, odds of Sm25 positivity increased significantly (OR = 1.51, CI = 1.14-2.02, P = 0.005) and remained significantly higher than baseline after two rounds of MDA (OR = 1.37, CI = 1.07-1.76, P = 0.01). There was a significant decrease in the proportion of 1-year-olds with positive SEA responses from 33.1% in year 1 to 13.2% in year 3 and a corresponding decrease in the odds (OR = 3.25, CI = 1.75 6.08, P < 0.001). These results provide preliminary evidence that schistosomiasis program impact can be monitored using serologic responses. PMID- 28719281 TI - Risk Factors for Household Transmission of Vibrio cholerae in Dhaka, Bangladesh (CHoBI7 Trial). AB - AbstractHousehold contacts of cholera patients are at a 100 times higher risk of a Vibrio cholerae infection than the general population. To examine risk factors for V. cholerae infections and investigate intervention strategies among this population, we followed household contacts of cholera patients for the 1-week high-risk period after the index patient obtained care. This study was nested within a randomized controlled trial of the Cholera-Hospital-Based-Intervention for-7-days (CHoBI7), a handwashing with soap and water treatment intervention in Dhaka, Bangladesh. Rectal swab results were available from 320 household contacts of cholera patients at five time points over a 1-week period. Fecal and water samples were analyzed for V. cholerae by bacterial culture. All analyses were stratified by study arm. Within the intervention arm, stored household drinking water with a median free chlorine concentration below 0.5 mg/L was associated with a three times higher odds of a cholera infection (odds ratio [OR]: 3.0; 95% confidence interval [CI]: 1.32, 6.63). In the control arm, having V. cholerae in stored water was associated with a significantly higher odds of a symptomatic cholera infection (OR: 8.66; 95% CI: 2.11, 35.48). No association was found between observed handwashing with soap at food and stool-related events and V. cholerae infections. Stored household drinking water with detectable V. cholerae and chlorine concentrations below the World Health Organization guideline were found to be important risk factors for cholera infection among household contacts of cholera patients. These findings emphasize the need for water treatment interventions targeting this high risk population. PMID- 28719282 TI - Travelers' Diarrhea and Other Gastrointestinal Symptoms Among Boston-Area International Travelers. AB - AbstractThis prospective cohort study describes travelers' diarrhea (TD) and non TD gastrointestinal (GI) symptoms among international travelers from the Boston area, the association of TD with traveler characteristics and dietary practices, use of prescribed antidiarrheal medications, and the impact of TD and non-TD GI symptoms on planned activities during and after travel. We included adults who received a pre-travel consultation at three Boston-area travel clinics and who completed a three-part survey: pre-travel, during travel, and post-travel (2-4 weeks after return). TD was defined as self-reported diarrhea with or without nausea/vomiting, abdominal pain, or fever. Demographic and travel characteristics were evaluated by chi2 test for categorical and Wilcoxon rank-sum test for continuous variables. Analysis of dietary practices used logistic generalized estimating equation models or logistic regression models. Of 628 travelers, 208 (33%) experienced TD and 45 (7%) experienced non-TD GI symptoms. Of 208 with TD, 128 (64%), 71 (36%), and 123 (62%) were prescribed ciprofloxacin, azithromycin, and/or loperamide before travel, respectively. Thirty-nine (36%) of 108 took ciprofloxacin, 20 (38%) of 55 took azithromycin, and 28 (28%) of 99 took loperamide during travel. Of 172 with TD during travel, 24% stopped planned activities, and 2% were hospitalized. Of 31 with non-TD GI symptoms during travel, six (13%) stopped planned activities. International travelers continue to experience diarrhea and other GI symptoms, resulting in disruption of planned activities and healthcare visits for some. Although these illnesses resulted in interruption of travel plans, a relatively small proportion took prescribed antibiotics. PMID- 28719283 TI - American Aedes vexans Mosquitoes are Competent Vectors of Zika Virus. AB - AbstractStarting in 2013-2014, the Americas have experienced a massive outbreak of Zika virus (ZIKV) which has now reached at least 49 countries. Although most cases have occurred in South America and the Caribbean, imported and autochthonous cases have occurred in the United States. Aedes aegypti and Aedes albopictus mosquitoes are known vectors of ZIKV. Little is known about the potential for temperate Aedes mosquitoes to transmit ZIKV. Aedes vexans has a worldwide distribution, is highly abundant in particular localities, aggressively bites humans, and is a competent vector of several arboviruses. However, it is not clear whether Ae. vexans mosquitoes are competent to transmit ZIKV. To determine the vector competence of Ae. vexans for ZIKV, wild-caught mosquitoes were exposed to an infectious bloodmeal containing a ZIKV strain isolated during the current outbreak. Approximately 80% of 148 mosquitoes tested became infected by ZIKV, and approximately 5% transmitted infectious virus after 14 days of extrinsic incubation. These results establish that Ae. vexans are competent ZIKV vectors. Their relative importance as vectors (i.e., their vectorial capacity) depends on feeding behavior, longevity, and other factors that are likely to vary in ecologically distinct environments. PMID- 28719284 TI - Nonacademic Attributes Predict Medical and Nursing Student Intentions to Emigrate or to Work Rurally: An Eight-Country Survey in Asia and Africa. AB - AbstractWe sought to identify independent, nonacademic predictors of medical and nursing student intent to migrate abroad or from rural to urban areas after graduation in low- and middle-income countries (LMIC). This was a cross-sectional survey of 3,199 first- and final-year medical and nursing students at 16 training institutions in eight LMIC. Questionnaires assessed demographics, career intentions, and preferences regarding selected career, location, and work-related attributes. Using principal component analysis, student preferences were reduced into four discrete categories of priorities: 1) work environment resources, 2) location livability, 3) altruistic job values, and 4) individualistic job values. Students' preferences were scored in each category. Using students' characteristics and priority scores, multivariable proportional odds models were used to derive independent predictors of intentions to emigrate for work outside the country, or to work in a rural area in their native country. Students prioritizing individualistic values more often planned international careers (adjusted odds ratio [aOR] = 1.44, 95% confidence interval [CI] = 1.16-1.78), whereas those prioritizing altruistic values preferred rural careers (aOR = 1.82, 95% CI = 1.50-2.21). Trainees prioritizing high-resource environments preferentially planned careers abroad (aOR = 1.38, 95% CI = 1.12-1.69) and were unlikely to seek rural work (aOR = 0.60, 95% CI = 0.49-0.73). Independent of their priorities, students with prolonged prior rural residence were unlikely to plan emigration (aOR = 0.67, 95% CI = 0.50-0.90) and were more likely to plan a rural career (aOR = 1.53, 95% CI = 1.16-2.03). We conclude that use of nonacademic attributes in medical and nursing admissions processes would likely increase retention in high-need rural areas and reduce emigration "brain drain" in LMIC. PMID- 28719285 TI - Trial of a Novel Intervention to Improve Multiple Food Hygiene Behaviors in Nepal. AB - AbstractIn this study, we report on the results of a trial of an intervention to improve five food hygiene behaviors among mothers of young children in rural Nepal. This novel intervention targeted five behaviors; cleanliness of serving utensils, handwashing with soap before feeding, proper storage of cooked food, and thorough reheating and water treatment. Based on formative research and a creative process using the Behavior-Centered Design approach, an innovative intervention package was designed and delivered over a period of 3 months. The intervention activities included local rallies, games, rewards, storytelling, drama, competitions linking with emotional drivers of behavior, and "kitchen makeovers" to disrupt behavior settings. The effect of the package on behavior was evaluated via a cluster-randomized before-after study in four villages with four villages serving as controls. The primary outcome was the difference in the mean cluster level proportions of mothers directly observed practicing all five food hygiene behaviors. The five targeted food hygiene behaviors were rare at baseline (composite performance of all five behaviors in intervention 1% [standard deviation (SD) = 2%] and in control groups 2% [SD = 2%]). Six weeks after the intervention, the target behaviors were more common in the intervention than in the control group (43% [SD = 14%] versus 2% [SD = 2%], P = 0.02) during follow-up. The intervention appeared to be equally effective in improving all five behaviors in all intervention clusters. This study shows that a theory driven, systematic approach employing emotional motivators and modifying behavior settings was capable of substantially improving multiple food hygiene behaviors in Nepal. PMID- 28719286 TI - The Economic Value of Long-Lasting Insecticidal Nets and Indoor Residual Spraying Implementation in Mozambique. AB - AbstractMalaria-endemic countries have to decide how much of their limited resources for vector control to allocate toward implementing long-lasting insecticidal nets (LLINs) versus indoor residual spraying (IRS). To help the Mozambique Ministry of Health use an evidence-based approach to determine funding allocation toward various malaria control strategies, the Global Fund convened the Mozambique Modeling Working Group which then used JANUS, a software platform that includes integrated computational economic, operational, and clinical outcome models that can link with different transmission models (in this case, OpenMalaria) to determine the economic value of vector control strategies. Any increase in LLINs (from 80% baseline coverage) or IRS (from 80% baseline coverage) would be cost-effective (incremental cost-effectiveness ratios <= $114/disability-adjusted life year averted). However, LLIN coverage increases tend to be more cost-effective than similar IRS coverage increases, except where both pyrethroid resistance is high and LLIN usage is low. In high-transmission northern regions, increasing LLIN coverage would be more cost-effective than increasing IRS coverage. In medium-transmission central regions, changing from LLINs to IRS would be more costly and less effective. In low-transmission southern regions, LLINs were more costly and less effective than IRS, due to low LLIN usage. In regions where LLINs are more cost-effective than IRS, it is worth considering prioritizing LLIN coverage and use. However, IRS may have an important role in insecticide resistance management and epidemic control. Malaria intervention campaigns are not a one-size-fits-all solution, and tailored approaches are necessary to account for the heterogeneity of malaria epidemiology. PMID- 28719287 TI - Phase 1 Randomized Study of a Tetravalent Dengue Purified Inactivated Vaccine in Healthy Adults in the United States. AB - AbstractThe safety and immunogenicity of four formulations of an investigational tetravalent dengue purified inactivated vaccine (DPIV), formulated at 1 or 4 MUg with aluminum hydroxide (alum) or at 1 MUg with an adjuvant system (AS01E or AS03B), were evaluated in a first-time-in-human, placebo-controlled, randomized, observer-blind, phase 1 trial in the continental United States. Two doses of vaccine or placebo were administered intramuscularly 4 weeks apart to 100 healthy adults 18-39 years of age, randomized 1:1:1:1:1 to receive one of four DPIV formulations or saline placebo. The response to a third dose was evaluated in a subset of nine participants remote from primary vaccination. Humoral immunogenicity was assessed using a 50% microneutralization assay. All DPIV formulations were well tolerated. No vaccine-related serious adverse events were observed through 12 months after the second vaccine dose. In all DPIV groups, geometric mean antibody titers peaked at Day 56, waned through 6 months after the second vaccine dose, and then stabilized. In the nine subjects where boosting was evaluated, a strong anamnestic response was observed. These results support continuation of the clinical development of this dengue vaccine candidate (clinicaltrials.gov: NCT01666652). PMID- 28719288 TI - Evaluation of the Protective Effect of Deoxyribonucleic Acid Vaccines Encoding Granule Antigen 2 and 5 Against Acute Toxoplasmosis in BALB/c Mice. AB - AbstractToxoplasma gondii infects a broad range of warm-blooded hosts, including humans. Important clinical manifestations include encephalitis in immunocompromised patients as well as miscarriage and fetal damage during early pregnancy. Toxoplasma gondii dense granule antigen 2 and 5 (GRA2 and GRA5) are essential for parasitophorous vacuole development of the parasite. To evaluate the potential of GRA2 and GRA5 as recombinant DNA vaccine candidates, these antigens were cloned into eukaryotic expression vector (pcDNA 3.1C) and evaluated in vaccination experiments. Recombinant DNA vaccines constructed with genes encoding GRAs were validated in Chinese hamster ovary cells before evaluation using lethal challenge of the virulent T. gondii RH strain in BALB/c mice. The DNA vaccines of pcGRA2 and pcGRA5 elicited cellular-mediated immune response with significantly higher levels of interferon-gamma, interleukin-2 (IL-2), IL-4, and IL-10 (P < 0.05) compared with controls. A mixed T-helper cell 1 (Th1)/Th2 response was associated with slightly prolonged survival. These findings provide evidence that DNA vaccination with GRA2 and GRA5 is associated with Th1-like cell mediated immune responses. It will be worthwhile to construct recombinant multiantigen combining full-length GRA2 or/and GRA5 with various antigenic proteins such as the surface antigens and rhoptry antigens to improve vaccination efficacy. PMID- 28719289 TI - What is a Hotspot Anyway? AB - AbstractThe importance of spatial clusters, or "hotspots," in infectious disease epidemiology has been increasingly recognized, and targeting hotspots is often seen as an important component of disease-control strategies. However, the precise meaning of "hotspot" varies widely in current research and policy documents. Hotspots have been variously described as areas of elevated incidence or prevalence, higher transmission efficiency or risk, or higher probability of disease emergence. This ambiguity has led to confusion and may result in mistaken inferences regarding the best way to target interventions. We surveyed the literature on epidemiologic hotspots, examining the multitude of ways in which the term is used; and highlight the difference in the geographic scale of hotspots and the properties they are supposed to have. In response to the diversity in the term's usage, we advocate the use of more precise terms, such as "burden hotspot," "transmission hotspot," and "emergence hotspot," as well as explicit specification of the spatiotemporal scale of interest. Increased precision in terminology is needed to ensure clear and effective policies for disease control. PMID- 28719290 TI - Performance of Real-Time Polymerase Chain Reaction Assays for the Detection of 20 Gastrointestinal Parasites in Clinical Samples from Senegal. AB - Gastrointestinal parasite infections represent one of the biggest public health problems in the world. Therefore, appropriate innovative tools are needed for assessing interventions to control these infections. This study aims to compare the performance of real-time polymerase chain reaction (PCR) assays to microscopic examination for detection of intestinal parasites. A direct microscopic examination and stool concentration was performed on 98 stool samples from patients attending Senegalese hospitals. Negative microscopic control samples were also collected in Nice and Marseille (France). Species-specific primers/probes were used to detect 20 common gastrointestinal protozoans and helminths. Positive frequency and the sensitivity of each real-time PCR assay were compared with conventional microscopic examination. Real-time PCR was positive in 72 of 98 samples (73.5%), whereas microscopic examination was positive in 37 (37.7%) samples (P < 0.001). The real-time PCR assays were more sensitive than microscopy, with 57.4% (31/54) versus 18.5% (10/54), respectively, in the detection of parasites in asymptomatic patients (P < 0.05). In terms of polyparasitism, there were more coinfections detected by real-time PCR assays compared with microscopic methods (25.5% versus 3.06%). In comparison to parasite prevalence on individual samples, the results showed a perfect agreement (100%) between the two techniques for seven species, whereas discrepancies were observed for the others (agreement percentage varying from 64.2% to 98.9%). Real-time PCR appeared to be superior to microscopic examination for the detection of parasites in stool samples. This assay will be useful in diagnostic laboratories and in the field for evaluating the efficacy of mass drug administration programs. PMID- 28719291 TI - Knowledge and Prevention Practices among U.S. Pregnant Immigrants from Zika Virus Outbreak Areas. AB - We administered an anonymous survey to assess knowledge, attitudes, and prevention practices related to the Zika virus among pregnant women residing in Texas. Multivariate logistic regression models controlling for age, race/ethnicity, education, and number of years in the United States assessed differences between women born in outbreak areas (N = 390) versus those born in the United States (N = 249). Results demonstrated that most women wanted more information on the Zika virus and desired to obtain it from their physician. The majority did not know that the Zika virus could be spread through sex with an asymptomatic partner or how often those infected were symptomatic. Few women took precautions to avoid mosquito bites. Only 40% reported frequently using repellent; 21% stated that cost was problematic and almost half were concerned about use during pregnancy. Three-fourths stated they would agree to vaccination, if available. Compared with U.S.-born women, those born in outbreak areas were more likely to have already discussed the Zika virus with their doctor (adjusted odds ratio [aOR] = 1.86, 95% confidence interval [CI] = 1.27, 2.71) and identify microcephaly as the most common birth defect (aOR = 2.59, 95% CI = 1.78, 3.76). Moreover, women born in outbreak areas were less likely to desire to keep it a secret if they became infected (aOR = 0.47, 95% CI = 0.31, 0.71). This study found that, regardless of birthplace, pregnant women need more education on the Zika virus disease and assurance regarding the safety of using repellent during pregnancy. They also need financial assistance for repellent, especially if living in states where transmission by mosquitos has been reported. PMID- 28719292 TI - Malaria Infection and Gametocyte Carriage Rates in Preparation for Transmission Blocking Vaccine Trials in Bancoumana, Mali. AB - The epidemiological characterization of transmission reservoirs is a critical step in preparation for interventional trials for malaria elimination/eradication. Using cluster sampling and households/compounds as units of sampling, we recruited and followed monthly, from June 2011 to June 2012, 250 volunteers 3 months to 50 years of age in Bancoumana, Mali. In July 2012, only participants 5-35 years of age (N = 121) were reenrolled and followed for an additional year. Malaria infection prevalence was highest in October in both 2011 (21.5%, 50/233) and 2012 (38.2%, 26/68). During both years, malaria infection prevalence was highest in children 5-14 years of age (P = 0.01 and P = 0.02, respectively). The gametocyte carriage prevalence was highest in November 2011 (7.6%, 17/225) and in October 2012 (16.2%, 11/68). Gametocyte carriage rates by age did not significantly differ in 2011 and 2012. In Bancoumana, the asexual and sexual parasite carriage rates are relatively high and highly seasonal. Seasonal variation and age differences in parasite and gametocyte carriage provide essential knowledge for the design of transmission blocking assay and vaccine studies in the field. PMID- 28719293 TI - Case Report: Clinical Features of a Case of Suspected Borrelia miyamotoi Disease in Hokkaido, Japan. AB - We herein report a case of suspected Borrelia miyamotoi disease in Hokkaido, Japan. The patient complained of lassitude, arthralgia, and high fever after a tick bite. Furthermore, at the time of consultation, the patient exhibited momentary loss of consciousness and low blood pressure. Laboratory tests revealed elevation of liver enzymes, thrombocytopenia, and increased C-reactive protein. Seroconversion to B. miyamotoi glycerophosphoryl diester phosphodiesterase antigen suggested the patient was infected with a relapsing fever group Borrelia species. PMID- 28719294 TI - Molecular Markers for Sensitive Detection of Plasmodium falciparum Asexual Stage Parasites and their Application in a Malaria Clinical Trial. AB - Plasmodium falciparum parasite life stages respond differently to antimalarial drugs. Sensitive stage-specific molecular assays may help to examine parasite dynamics at microscopically detectable and submicroscopic parasite densities in epidemiological and clinical studies. In this study, we compared the performance of skeleton-binding protein 1 (SBP1), ring-infected erythrocyte surface antigen, Hyp8, ring-exported protein 1 (REX1), and PHISTb mRNA for detecting ring-stage trophozoite-specific transcripts using quantitative reverse transcriptase polymerase chain reaction. Markers were tested on tightly synchronized in vitro parasites and clinical trial samples alongside established markers of parasite density (18S DNA and rRNA) and gametocyte density (Pfs25 mRNA). SBP1 was the most sensitive marker but showed low-level expression in mature gametocytes. Novel markers REX1 and PHISTb showed lower sensitivity but higher specificity for ring stage trophozoites. Using in vivo clinical trial samples from gametocyte-negative patients, we observed evidence of persisting trophozoite transcripts for at least 14 days postinitiation of treatment. It is currently not clear if these transcripts represent viable parasites that may have implications for clinical treatment outcome or transmission potential. PMID- 28719295 TI - Regional Differences in the Prevalence of Major Opportunistic Infections among Antiretroviral-Naive Human Immunodeficiency Virus Patients in Japan, Northern Thailand, Northern Vietnam, and the Philippines. AB - To identify regional differences in the distribution of opportunistic infections (OIs) among human immunodeficiency virus (HIV)-infected patients in Asia, the medical records of antiretroviral therapy (ART)-naive patients who attended the following tertiary hospitals from 2003 to 2011 were reviewed: Nagoya Medical Center (NMC, Nagoya, Japan), Lampang Hospital (LPH, Lampang, northern Thailand), Bach Mai Hospital (BMH, Hanoi, northern Vietnam), and Philippine General Hospital (PGH, Manila, Philippines). Logistic regression analyses were performed to identify associations between country of origin and risk of major OIs. In total, 1,505 patients were included: NMC, N = 365; LPH, N = 442; BMH, N = 384; and PGH, N = 314. The median age was 32 years, and 73.3% of all patients were male. The median CD4 count was 200 cells/MUL. Most patients at NMC and PGH were men who have sex with men. Injection drug users were most common at BMH (35.7%). Mycobacterium tuberculosis (TB) was most common at PGH (N = 75) but was rare at NMC (N = 4). Pneumocystis pneumonia (PCP) prevalence was highest at NMC (N = 74) and lowest at BMH (N = 13). Multivariable logistic regression showed increased odds of TB at PGH (adjusted odds ratio [aOR] = 42.2, 95% confidence interval [CI] = 14.6-122.1), BMH (aOR = 12.6, CI = 3.9-40.3), and LPH (aOR = 6.6, CI = 2.1 21.1) but decreased odds of PCP at BMH (aOR = 0.1, CI = 0.04-0.2) and LPH (aOR = 0.2, CI = 0.1-0.4) compared with those at NMC. The cryptococcosis risk was increased at LPH (aOR = 6.2, CI = 0.9-41.0) compared with that at NMC. Cytomegalovirus (CMV) retinitis prevalences were similar in all countries. OI prevalence remained high among ART-naive patients in our cohort. The risks of TB, PCP, and cryptococcosis, but not CMV retinitis, differed between countries. Improved early HIV detection is warranted. PMID- 28719296 TI - Analysis of Dengue Serotype 4 in Sri Lanka during the 2012-2013 Dengue Epidemic. AB - The four serotypes of dengue virus (DENV-1, -2, -3, and -4) have had a rapidly expanding geographic range and are now endemic in over 100 tropical and subtropical countries. Sri Lanka has experienced periodic dengue outbreaks since the 1960s, but since 1989 epidemics have become progressively larger and associated with more severe disease. The dominant virus in the 2012 epidemic was DENV-1, but DENV-4 infections were also commonly observed. DENV-4 transmission was first documented in Sri Lanka when it was isolated from a traveler in 1978, but has been comparatively uncommon since dengue surveillance began in the early 1980s. To better understand the molecular epidemiology of DENV-4 infections in Sri Lanka, we conducted whole-genome sequencing on dengue patient samples from two different geographic locations. Phylogenetic analysis indicates that all sequenced DENV-4 strains belong to genotype 1 and are most closely related to DENV-4 viruses previously found in Sri Lanka and those recently found to be circulating in India and Pakistan. PMID- 28719297 TI - Rickettsia australis and Queensland Tick Typhus: A Rickettsial Spotted Fever Group Infection in Australia. AB - Rickettsia australis, the etiologic agent of Queensland tick typhus (QTT), is increasingly being recognized as a cause of community-acquired acute febrile illness in eastern Australia. Changing human population demographics, climate change, and increased understanding of expanding vector distribution indicate QTT is an emerging public health threat. This review summarizes the epidemiology, pathogenesis, clinical features, treatment principles, and future directions of this disease. Increased recognition of QTT will enable consideration of and prompt treatment of R. australis infection by clinicians in Australia. PMID- 28719298 TI - Cognitive Outcomes and Psychiatric Symptoms of Retinopathy-Positive Cerebral Malaria: Cohort Description and Baseline Results. AB - Cerebral malaria (CM) is a common cause of death and disability among children in sub-Saharan Africa. Many prior studies of neuropsychiatric morbidity have been limited by a cross-sectional design or a short duration of follow-up. Most have included subjects who may have presented with coma due to a disease process other than CM. No studies have assessed the relationship between magnetic resonance imaging (MRI) findings and long-term outcomes. The Cognitive Outcomes and Psychiatric symptoms of retinopathy-positive CM (COPS) cohort is the first large (N = 221) prospectively recruited cohort of stringently defined cases of CM and hospital-based, age-matched, non-CM controls in whom cognitive and psychiatric outcomes are assessed with standardized measures semi-annually for up to 5 years. We report baseline characteristics of the cohort and outcomes at 1 month. At enrollment, CM cases were more likely to come from families with fewer socioeconomic resources and to have health characteristics that increase risk for malaria. In children younger than 5 years, cases were delayed in motor, language, and social development by approximately 6 months, compared with controls. More significant delays occurred in those with MRI abnormalities at the 1-month follow up visit. There were no differences between cases and controls in inhibitory self control, nor in cognitive function in children >= 5 years of age. The latter finding may be related to the smaller sample size, case-control imbalance in socioeconomic status, or the use of cognitive and behavioral assessments that are less culturally appropriate to this population. Continued follow-up will help determine predictors of long-term outcomes. PMID- 28719299 TI - Conventional Wisdom versus Actual Outcomes: Challenges in the Conduct of an Ebola Vaccine Trial in Liberia during the International Public Health Emergency. AB - Clinical trials are challenging endeavors. Planning and implementing an investigational vaccine trial in Liberia, in the midst of an Ebola virus disease (EVD) epidemic that World Health Organization classified a public health emergency of international concern, presented extraordinary challenges. Normally, years of preparation and a litany of tasks lay the groundwork for a successful, randomized, blinded, placebo-controlled trial focused on safety and efficacy. Difficult research settings, unpredictable events, and other unique circumstances can add complexity. The setting in Liberia was especially problematic due to an infrastructure still badly damaged following a lengthy civil war and a very fragile health-care system that was further devastated by the EVD outbreak. The Partnership for Research on Vaccines in Liberia I EVD vaccine trial was planned and implemented in less than 3 months by a Liberian and U.S. research partnership, and its Phase II substudy was fully enrolled 3 months later. Contrasting conventional wisdom with trial outcomes offers an opportunity to compare early assumptions, barriers encountered, and adaptive strategies used, with end results. Understanding what was learned can inform future trial responses when disease outbreaks, especially in resource-poor locations with minimal infrastructure, pose a significant threat to public health. PMID- 28719300 TI - Chikungunya and Zika Virus Cases Detected against a Backdrop of Endemic Dengue Transmission in Vietnam. AB - Between 2010 and 2014, four chikungunya and two Zika virus infections were identified among 8,105 febrile children in southern Vietnam. Zika viruses were linked to French Polynesian strains, chikungunya to Cambodian strains. Against a backdrop of endemic dengue transmission, chikungunya and Zika present an additional arboviral disease burden in Vietnam. PMID- 28719301 TI - Development of a Real-Time Reverse Transcription Polymerase Chain Reaction for O'nyong-nyong Virus and Evaluation with Clinical and Mosquito Specimens from Kenya. AB - O'nyong-nyong virus (ONNV), an alphavirus closely related to chikungunya virus (CHIKV), has been the documented cause of two large outbreaks in east Africa; however, little is known about the contribution of ONNV to cases of acute febrile illness during interepidemic periods. An ONNV real-time reverse transcription polymerase chain reaction (rRT-PCR) was developed and evaluated using clinical and mosquito pool samples. The ONNV rRT-PCR linear range extended from 8.0 to 2.0 log10 copies/MUL, and the lower limit of 95% detection was 22.4 copies/MUL. No cases of ONNV infection were identified in serum from 385 Kenyan children who presented with an acute febrile illness. Additionally, ONNV was not detected in 120 mosquito pools collected in coastal and western Kenya. The ONNV rRT-PCR demonstrated good analytical sensitivity when performed in monoplex or as a component of an ONNV-CHIKV duplex assay. This assay should provide a useful diagnostic for the detection of ONNV in surveillance studies. PMID- 28719302 TI - A Fatal Hantavirus Pulmonary Syndrome Misdiagnosed as Dengue: An Investigation into the First Reported Case in Rio de Janeiro State, Brazil. AB - We report the results of an investigation into a fatal case of hantavirus pulmonary syndrome (HPS) in Rio de Janeiro State, Brazil, where the disease had not been reported previous to 2015. Following the notification of an HPS case, serum samples were collected from the household members and work contacts of the HPS patient and tested for antibody to hantaviruses. Seroprevalence of 22% (10/45) was indicated for hantavirus out of 45 human samples tested. Blood and tissue samples were collected from 72 rodents during fieldwork to evaluate the prevalence of hantavirus infection, by using enzyme-linked immunosorbent assay IgG, and to characterize the rodent hantavirus reservoir(s), by reverse transcription polymerase chain reaction and sequencing. Antibody prevalence was 6.9%. The circulation of a single genotype, the Juquitiba hantavirus, carried by two rodent species, black-footed pigmy rice rat (Oligoryzomys nigripes) and cursor grass mouse (Akodon cursor), was shown by analysis of the nucleotide sequences of the S segment. Juquitiba hantavirus circulates in rodents of various species, but mainly in the black-footed pigmy rice rat. HPS is a newly recognized clinical entity in Rio de Janeiro State and should be considered in patients with febrile illness and acute respiratory distress. PMID- 28719303 TI - Case Report: Endemic Amebiasis in Australia: Implications for Residents, Travelers, and Clinicians. AB - Entamoeba histolytica is considered endemic in Australia; however, cases are rare, occurring almost exclusively in high-risk individuals. We describe a series of locally acquired, complicated cases in low-risk individuals from Far North Queensland in whom the diagnosis was delayed. Amebiasis may pose a greater local threat than is currently recognized. PMID- 28719304 TI - Misclassification and Bias in Military Studies of Mefloquine. PMID- 28719305 TI - Optimizing Household Chlorination Marketing Strategies: A Randomized Controlled Trial on the Effect of Price and Promotion on Adoption in Haiti. AB - Household water treatment can reduce diarrheal morbidity and mortality in developing countries, but adoption remains low and supply is often unreliable. To test effects of marketing strategies on consumers and suppliers, we randomized 1,798 households in rural Haiti and collected data on purchases of a household chlorination product for 4 months. Households received randomly selected prices ($0.11-$0.56 per chlorine bottle), and half received monthly visits from sales agents. Each $0.22 drop in price increased purchases by 0.10 bottles per household per month (P < 0.001). At the mean price, each 1% drop in price increased purchases by 0.45% (elasticity = 0.45). There is suggestive evidence that household visits by some sales agents increased purchases at mid-range prices; however, the additional revenue did not offset visit cost. Choosing the lowest price and conducting visits maximizes chlorine purchase, whereas slightly raising the retail price and not conducting visits maximizes cost recovery. For the equivalent cost, price discounts increase purchases 4.2 times as much as adding visits at the current retail price. In this context, price subsidies may be a more cost-effective use of resources than household visits, though all marketing strategies tested offer cost-effective ways to achieve incremental health impact. Decisions about pricing and promotion for health products in developing countries affect health impact, cost recovery, and cost-effectiveness, and tradeoffs between these goals should be made explicit in program design. PMID- 28719306 TI - Seasonal Variation in the Epidemiology of Asymptomatic Plasmodium falciparum Infections across Two Catchment Areas in Bongo District, Ghana. AB - Understanding the epidemiology of asymptomatic Plasmodium falciparum infections is critical for countries to move toward malaria elimination. Using different methods for parasite detection, we evaluated how seasonality, spatial location, and other factors affect the age-specific epidemiology of asymptomatic malaria in Bongo District, Ghana. Asymptomatic prevalence by microscopy decreased significantly from 42.5% at the end of the wet to 27.5% at the end of the dry season (P < 0.001). Using the 18S rRNA polymerase chain reactions (PCRs), all microscopy-negative samples were screened and prevalence of submicroscopic infections also decreased significantly from the wet (55.4%) to the dry (20.7%) season (P < 0.001). Combining detection methods, 74.4% and 42.5% of the population in the wet and dry seasons, respectively, had evidence of a P. falciparum infection. Interestingly in those > 20 years of age, we found evidence of infection in 64.3% of the population in the wet and 27.0% in the dry season. Using both microscopy and PCR, the asymptomatic P. falciparum reservoir peaks at the end of the wet season and infections in all age groups constitute the reservoir of malaria infection. At the end of the wet season, spatial heterogeneity in the prevalence and density of P. falciparum infections was observed between the two catchment areas surveyed in Bongo District. These results indicate that if elimination is to succeed, interventions will need to target not just P. falciparum infections in children but also in adults, and be implemented toward the end of the dry season in this area of West Africa. PMID- 28719307 TI - First Report on Natural Infection of Phlebotomus sergenti with Leishmania tropica in a Classical Focus of Leishmania major in Tunisia. AB - In Tunisia, chronic cutaneous leishmaniasis due to Leishmania tropica is an important health problem. Its spreading has not been fully elucidated. Information on sandfly vectors, as well as their associated Leishmania species, is of paramount importance since vector dispersion is one of the major factors responsible for pathogen dissemination. Ninety-seven unfed females belonging to the genera Sergentomyia and Phlebotomus were collected between June and August 2015 using sticky paper traps. Polymerase chain reaction-restriction fragment length polymorphism analysis of the internal transcribed spacer 1and sequencing were used for Leishmania detection and identification. In total, 650 sandflies were captured and identified (380 males and 270 females). Ninety-seven unfed females were tested for the presence of Leishmania parasite DNA. Six Phlebotomus sergenti were found positive for L. tropica. This novel finding enhances the understanding of the cycle extension of L. tropica outside its original focus of Tataouine. PMID- 28719309 TI - Seroprevalence of Toxoplasma gondii Infection in Refugee and Migrant Pregnant Women along the Thailand-Myanmar Border. AB - Toxoplasma gondii primary infection in pregnancy is associated with poor obstetric outcomes. This study aimed to determine the seroprevalence of Toxoplasma infection in pregnant migrant and refugee women from Myanmar attending antenatal care in Thailand. A random selection of 199 residual blood samples from first antenatal screen in 2014-2015 was tested for Toxoplasma IgG and IgM antibodies. Seroprevalence of Toxoplasma infection was 31.7% (95% confidence interval = 25.6-38.4). Avidity testing in the three positive IgM cases indicated all were past infections. Multiparity (>= 3 children) was significantly associated with higher Toxoplasma seropositivity rates. Seroprevalence of T. gondii infection in this pregnant population is similar to the only other report from Myanmar, where multiparity was also identified as a significant association. Toxoplasma infection is important in pregnant women. Nevertheless, in this marginalized population, this infection may be given less priority, due to resource constraints in providing the most basic components of safe motherhood programs. PMID- 28719308 TI - A Recombinant 47-kDa Outer Membrane Protein Induces an Immune Response against Orientia tsutsugamushi Strain Boryong. AB - We investigated the 47-kDa outer membrane protein (OMP), which is a periplasmic serine protease and an antigenic major surface protein of Orientia tsutsugamushi, as a vaccine candidate. We developed a conventional subunit vaccine expressing recombinant 47-kDa OMP (rec47) and a DNA vaccine (p47). In mouse immunization experiments, intranasal immunization with rec47 alone or with rec47 plus heat labile enterotoxin B subunit from Escherichia coli or plus cholera toxin (CT) as adjuvants induced a higher amount of rec47-specific antibodies than intramuscular immunization with p47 alone or with p47 plus pBOOST2-samIRF7/3 (pB) as adjuvant. Moreover, the combination of rec47 and CT induced a strong cellular immune response to 47-kDa OMP, as demonstrated by a spleen cell proliferation assay, and also induced Th1- and Th2-type cytokine production, as demonstrated by a cytokine enzyme-linked immunosorbent assay. Intranasal immunization with rec47 plus CT was the most effective method for the induction of humoral and cell-mediated immune responses. Furthermore, relatively strong protection against homologous O. tsutsugamushi strain Boryong challenge was observed in mice immunized with rec47 plus CT. Therefore, 47-kDa OMP is an attractive candidate for developing a prophylactic vaccine against scrub typhus by O. tsutsugamushi infection. PMID- 28719310 TI - Severity of Pneumonia in Under 5-Year-Old Children from Developing Countries: A Multicenter, Prospective, Observational Study. AB - Pneumonia is the leading cause of death in children. The objectives were to evaluate the microbiological agents linked with hypoxemia in hospitalized children with pneumonia from developing countries, to identify predictors of hypoxemia, and to characterize factors associated with in-hospital mortality. A multicenter, observational study was conducted in five hospitals, from India (Lucknow, Vadu), Madagascar (Antananarivo), Mali (Bamako), and Paraguay (San Lorenzo). Children aged 2-60 months with radiologically confirmed pneumonia were enrolled prospectively. Respiratory and whole blood specimens were collected, identifying viruses and bacteria by real-time multiplex polymerase chain reaction (PCR). Microbiological agents linked with hypoxemia at admission (oxygen saturation < 90%) were analyzed by multivariate logistic regression, and factors associated with 14-day in-hospital mortality were assessed by bivariate Cox regression. Overall, 405 pneumonia cases (3,338 hospitalization days) were analyzed; 13 patients died within 14 days of hospitalization. Hypoxemia prevalence was 17.3%. Detection of human metapneumovirus (hMPV) and respiratory syncytial virus (RSV) in respiratory samples was independently associated with increased risk of hypoxemia (adjusted odds ratio [aOR] = 2.4, 95% confidence interval [95% CI] = 1.0-5.8 and aOR = 2.5, 95% CI = 1.1-5.3, respectively). Lower chest indrawing and cyanosis were predictive of hypoxemia (positive likelihood ratios = 2.3 and 2.4, respectively). Predictors of death were Streptococcus pneumoniae detection by blood PCR (crude hazard ratio [cHR] = 4.6, 95% CI = 1.5 14.0), procalcitonin >= 50 ng/mL (cHR = 22.4, 95% CI = 7.3-68.5) and hypoxemia (cHR = 4.8, 95% CI = 1.6-14.4). These findings were consistent on bivariate analysis. hMPV and RSV in respiratory samples were linked with hypoxemia, and S. pneumoniae in blood was associated with increased risk of death among hospitalized children with pneumonia in developing countries. PMID- 28719311 TI - Infective Endocarditis in French West Indies: A 13-Year Observational Study. AB - We conducted an observational study to describe the characteristics of infective endocarditis (IE) in French West Indies (FWI) and to identify variables associated with in-hospital case fatality. The records of the patients admitted for IE to the University Hospital of Martinique between 2000 and 2012 were collected using an electronic case report form. Only Duke-Li definite cases were considered for this analysis. Variables associated with in-hospital mortality were tested using univariate logistic regression analysis. The analysis included 201 patients (median age 58 years, sex ratio: two males to one female). There was no previously known heart disease in 45.8%, a prosthetic valve in 21.4%, and previously known native valve disease in 32.8% of the cases. Community-acquired IE represented 59.7% of all cases, health-care-associated IE represented 38.3% and injection-drug-use-acquired IE represented 1.5%. Locations of IE were distributed as follows: 42.3% were mitral valve IE, 34.8% were aortic valve IE, and 7% were right-sided IE. Microorganisms recovered from blood cultures included 30.4% streptococci, 28.9% staphylococci, and 5% enterococci. Blood cultures were negative in 20.9% of the cases. Surgical treatment was performed in 53% of the patients. In-hospital case fatality rate was 19%. Advanced age, Staphylococcus aureus IE, and health-care-associated IE were associated with in-hospital case fatality. The epidemiological and microbiological profile of IE in FWI is in between those observed in developed countries and developing countries: patients were younger, blood cultures were more frequently negative, and IE due to group D streptococci and enterococci were less common than in industrialized countries. PMID- 28719312 TI - Molecular Epidemiology of Malaria in Cameroon and Cote d'Ivoire. XXXI. Kelch 13 Propeller Sequences in Plasmodium falciparum Isolates before and after Implementation of Artemisinin-Based Combination Therapy. AB - Artemisinin-resistant malaria has not been reported from Africa, but resistance can possibly spread from Asia or arise independently in Africa. The emergence of artemisinin resistance in Africa can be monitored by molecular assay of Kelch 13 (K13) propeller sequences. A total of 251 archived DNA samples of Plasmodium falciparum isolates collected in 2002, 2003, and 2006 in Yaounde, Cameroon, and 47 samples collected in 2006 and 2013 in Abidjan, Cote d'Ivoire, were analyzed for K13-propeller sequence polymorphism. Only one isolate carried a mutant K13 propeller allele (E602D). None of the isolates carried the key mutant alleles (Y493H, R539T, I543T, and C580Y) associated with artemisinin resistance in Cambodia. The presence of the mutant allele was not correlated with in vitro response to dihydroartemisinin determined by the classical hypoxanthine incorporation assay. There was no evidence of K13 mutations associated with artemisinin resistance before and soon after the introduction of artemisinin based combination therapies in Cameroon and Cote d'Ivoire. PMID- 28719313 TI - Keynote Address (November 2016): Zika Virus Disease in the Americas: A Storm in the Making. AB - More than 700,000 cases of Zika virus (ZIKAV) disease have been officially reported to the Pan American Health Organization (PAHO) from 48 countries and territories of the Americas. The response led by the PAHO and partners suggests major lessons of this outbreak. A seemingly innocuous pathogen became the new villain, causing fear, economic losses and, most importantly, debilitating birth defects and neurological problems, reaffirming the well-known war principle of never to underestimate one's opponent. The ZIKAV tested public health capacities under the International Health Regulations, highlighting the need for continued investment in health security. Last but not least, the lack of appropriate tools was another reminder of the pressing need for innovative solutions to persistent problems. Latin America and the Caribbean have approximately 500 million persons living in areas at risk for transmission of ZIKAV. The fight against ZIKAV is not a 100-m race, but rather a marathon in which science and public health need to work hand in hand for the benefit of our peoples. PMID- 28719314 TI - Consistency of Use and Effectiveness of Household Water Treatment among Indian Households Claiming to Treat Their Water. AB - Household water treatment (HWT) can improve drinking water quality and prevent disease if used correctly and consistently by populations at risk. Current international monitoring estimates by the Joint Monitoring Programme for water and sanitation suggest that at least 1.1 billion people practice HWT. These estimates, however, are based on surveys that may overstate the level of consistent use and do not address microbial effectiveness. We sought to assess how HWT is practiced among households identified as HWT users according to these monitoring standards. After a baseline survey (urban: 189 households, rural: 210 households) to identify HWT users, 83 urban and 90 rural households were followed up for 6 weeks. Consistency of reported HWT practices was high in both urban (100%) and rural (93.3%) settings, as was availability of treated water (based on self-report) in all three sampling points (urban: 98.8%, rural: 76.0%). Nevertheless, only 13.7% of urban and 25.8% of rural households identified at baseline as users of adequate HWT had water free of thermotolerant coliforms at all three water sampling points. Our findings raise questions about the value of the data gathered through the international monitoring of HWT as predictors of water quality in the home, as well as questioning the ability of HWT, as actually practiced by vulnerable populations, to reduce exposure to waterborne diseases. PMID- 28719315 TI - Analysis of Clinical and Laboratory Alterations Related to Dengue Case Severity: Comparison between Serotypes 2 and 4 in Brazil. AB - The increase in severe dengue (SD) cases has caused great impact on public health and has concerned authorities of countries where the disease is endemic and epidemics reach high proportions. The recognition of progression signs of this severe disease during the initial febrile phase can be difficult, since the symptoms are often indistinguishable from other febrile diseases. The aim of this study was to evaluate the clinical manifestations and laboratory findings in patients from two dengue outbreaks and their association with the disease. The study was conducted in patients (n = 153) with signs and symptoms consistent with dengue occurred during two distinct epidemics, 2010 and 2013, in the city of Campos dos Goytacazes, Rio de Janeiro, Brazil. According to the 2009 World Health Organization criteria, patients were classified as dengue without warning signs ([DwoWS] 60.6%, 57/94), dengue with warning signs ([DwWS] 30.9%, 29/94), and SD (4.25%, 4/94). Patients with DwWS/SD presented lower platelet and leukocyte counts and higher transaminase levels when compared with the DwoWS ones. Interestingly, patients from the epidemic of 2010 caused by dengue virus 2 (DENV 2) had lower platelet counts than patients of the 2013 epidemic caused by DENV-4. Furthermore, plasma leakage, gastrointestinal bleeding, and pleural effusion, hallmarks for a more severe disease, were also more frequently observed in those cases. Although previous studies may have extensively reported the wide range of the clinical aspects of dengue, the characterization of DENV-4 is desirable considering the burden of the disease during epidemics, especially for the health units and hospitals performing patient's management. PMID- 28719316 TI - High Mortality and Coinfection in a Prospective Cohort of Human Immunodeficiency Virus/Acquired Immune Deficiency Syndrome Patients with Histoplasmosis in Guatemala. AB - Histoplasmosis is one of the most common and deadly opportunistic infections among persons living with human immunodeficiency virus (HIV)/acquired immune deficiency syndrome in Latin America, but due to limited diagnostic capacity in this region, few data on the burden and clinical characteristics of this disease exist. Between 2005 and 2009, we enrolled patients >= 18 years of age with suspected histoplasmosis at a hospital-based HIV clinic in Guatemala City. A case of suspected histoplasmosis was defined as a person presenting with at least three of five clinical or radiologic criteria. A confirmed case of histoplasmosis was defined as a person with a positive culture or urine antigen test for Histoplasma capsulatum. Demographic and clinical data were also collected and analyzed. Of 263 enrolled as suspected cases of histoplasmosis, 101 (38.4%) were confirmed cases. Median time to diagnosis was 15 days after presentation (interquartile range [IQR] = 5-23). Crude overall mortality was 43.6%; median survival time was 19 days (IQR = 4-69). Mycobacterial infection was diagnosed in 70 (26.6%) cases; 26 (25.7%) histoplasmosis cases were coinfected with mycobacteria. High mortality and short survival time after initial symptoms were observed in patients with histoplasmosis. Mycobacterial coinfection diagnoses were frequent, highlighting the importance of pursuing diagnoses for both diseases. PMID- 28719317 TI - Climate Influence on Emerging Risk Areas for Rift Valley Fever Epidemics in Tanzania. AB - Rift Valley Fever (RVF) is a climate-related arboviral infection of animals and humans. Climate is thought to represent a threat toward emerging risk areas for RVF epidemics globally. The objective of this study was to evaluate influence of climate on distribution of suitable breeding habitats for Culex pipiens complex, potential mosquito vector responsible for transmission and distribution of disease epidemics risk areas in Tanzania. We used ecological niche models to estimate potential distribution of disease risk areas based on vectors and disease co-occurrence data approach. Climatic variables for the current and future scenarios were used as model inputs. Changes in mosquito vectors' habitat suitability in relation to disease risk areas were estimated. We used partial receiver operating characteristic and the area under the curves approach to evaluate model predictive performance and significance. Habitat suitability for Cx. pipiens complex indicated broad-scale potential for change and shift in the distribution of the vectors and disease for both 2020 and 2050 climatic scenarios. Risk areas indicated more intensification in the areas surrounding Lake Victoria and northeastern part of the country through 2050 climate scenario. Models show higher probability of emerging risk areas spreading toward the western parts of Tanzania from northeastern areas and decrease in the southern part of the country. Results presented here identified sites for consideration to guide surveillance and control interventions to reduce risk of RVF disease epidemics in Tanzania. A collaborative approach is recommended to develop and adapt climate-related disease control and prevention strategies. PMID- 28719318 TI - Experience with a Multinational, Secondary School Education Module with a Focus on Prevention of Virus Infections. AB - Worldwide, virus infections are responsible for many diseases in terms of morbidity and mortality. Vaccinations and therapies are only available for relatively few virus infections and not always where they are needed. However, knowledge of transmission routes can prevent virus infection. In the context of this study, we measured the effects of a secondary school education module, named Viruskenner, on knowledge, attitude, and risk behavior as these relate to virus infections. A nonrandomized intervention study was conducted between April and August 2015 to assess the effect of this 2-month education module on knowledge, attitude, and behavior of 684 secondary school students in the Netherlands, Suriname, and Indonesia. For the Netherlands, a control group of a further 184 students was added. Factor analysis was performed on questions pertaining to attitude and behavior. Comparative analyses between pre- and posttest per country were done using multiple linear regression, independent sample T-tests, and one way analysis of variance. These showed a significant increase in knowledge about virus infections and the prevention of infectious diseases among the Dutch and Surinamese groups, whereas a trend of increased knowledge was evident among the Indonesian participants. The Dutch control group showed an overall decrease in knowledge. Regression analyses showed that there was a significant interaction effect between participation and time on knowledge, attitude, and awareness and behavior and risk infection. Attitudes improved significantly in the intervention group. Pearson correlation coefficients between knowledge, attitude, and behavior were found to be positive. PMID- 28719320 TI - Skin Manifestations of Primary Vibrio vulnificus Septicemia. PMID- 28719319 TI - Phosphoproteome of Toxoplasma gondii Infected Host Cells Reveals Specific Cellular Processes Predominating in Different Phases of Infection. AB - The invasion of Toxoplasma gondii tachyzoites into the host cell results in extensive host cell signaling activation/deactivation that is usually regulated by the phosphorylation/dephosphorylation. To elucidate how T. gondii regulates host cell signal transduction, the comparative phosphoproteome of stable isotope labeling with amino acids in cell culture-labeled human foreskin fibroblast cells was analyzed. The cells were grouped (Light [L], Medium [M], and Heavy [H] groups) based on the labeling isotope weight and were infected with T. gondii for different lengths of time (L: 0 hour; M: 2 hours; and H: 6 hours). A total of 892 phosphoproteins were identified with 1,872 phosphopeptides and 1,619 phosphorylation sites. The M versus L comparison revealed 694 significantly regulated phosphopeptides (436 upregulated and 258 downregulated). The H versus L comparison revealed 592 significantly regulated phosphopeptides (146 upregulated and 446 downregulated). The H versus M comparison revealed 794 significantly regulated phosphopeptides (149 upregulated and 645 downregulated). At 2 and 6 hours post-T. gondii infection, the most predominant host cell reactions were cell cycle regulation and cytoskeletal reorganization, which might be required for the efficient invasion and multiplication of T. gondii. Similar biological process profiles but different molecular function categories of host cells infected with T. gondii for 2 and 6 hours, which suggested that the host cell processes were not affected significantly by T. gondii infection but emphasized some differences in specific cellular processes at this two time points. Western blotting verification of some significantly regulated phosphoprotein phosphorylation sites was consistent with the mass spectra data. This study provided new insights into and further understanding of pathogen-host interactions from the host cell perspective. PMID- 28719321 TI - Association of Interferon-gamma Receptor-1 Gene Polymorphism with Nontuberculous Mycobacterial Lung Infection among Iranian Patients with Pulmonary Disease. AB - Nontuberculous mycobacteria (NTM) cause significant pulmonary infections in humans. Researchers have reported an association between interferon-gamma receptor-1 (IFN-gammaR1 or IFNGR1) deficiency and susceptibility to NTM, but the relevance of polymorphism within these genes is not yet clear. In this study, a single nucleotide polymorphism (SNP), T to C, at position-56 in NTM patients with pulmonary disease was investigated. Molecular identification of Mycobacterium isolates was performed with hsp65 genes using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). Then, the host genomic DNA from confirmed NTM patients (N = 80) and control subjects (N = 80) were screened for SNPs of IFNGR1 (T-56C) by PCR-RFLP. The results indicated that NTM patients had higher TC (26/80; 32.5%) or CC (46/80; 57.5%) genotypes in comparison with control groups (TC genotypes [22/80, 27.5%]; CC genotypes [6/80, 7.5%]) (P < 0.05). In this regard, all the patients infected with rapid-growing Mycobacterium (RGM, i.e., Mycobacterium chelonae and Mycobacterium fortuitum) had CC genotypes (100%). In contrary, only 50.7% (35/69) of infected patients with slow-growing Mycobacterium (i.e., Mycobacterium simiae, Mycobacterium kansasii, and Mycobacterium avium-intracellulare) had CC genotypes. Thus, patients with CC mutation in IFNGR1 at position-56 are more likely to develop RGM infection. In overall, there is a significant association between SNP of IFNGR1 at position-56 and susceptibility to NTM infection. Based on these data, we propose SNP of IFNGR1 at position-56 as a suitable "biomarker" for identifying populations at higher risk of infection. PMID- 28719322 TI - Case Report: Disseminated Talaromyces (Penicillium) marneffei and Mycobacterium tuberculosis Coinfection in a Japanese Patient with Acquired Immunodeficiency Syndrome. AB - Talaromyces marneffei is a dimorphic fungus endemic mainly in southeast and south Asia. It causes severe mycosis, usually in immunocompromised individuals, such as those with human immunodeficiency virus (HIV) infection. Concomitant infection with T. marneffei and other opportunistic pathogens is plausible because the majority of T. marneffei infections occur in patients with advanced HIV infection. Nonetheless, coinfection in the same site has rarely been reported, and poses a considerable diagnostic and therapeutic challenge. We report the case of an HIV-infected Japanese patient who had lived in Thailand for 6 years. The patient developed T. marneffei and Mycobacterium tuberculosis coinfection, and both pathogens were isolated from the same sites: a blood specimen and a lymph node aspirate. Clinicians should be aware of concomitant infection with T. marneffei and other pathogens in patients with advanced HIV disease who are living in or who have visited endemic areas. PMID- 28719323 TI - Burden and Seasonality of Viral Acute Respiratory Tract Infections among Outpatients in Southern Sri Lanka. AB - In tropical and subtropical settings, the epidemiology of viral acute respiratory tract infections varies widely between countries. We determined the etiology, seasonality, and clinical presentation of viral acute respiratory tract infections among outpatients in southern Sri Lanka. From March 2013 to January 2015, we enrolled outpatients presenting with influenza-like illness (ILI). Nasal/nasopharyngeal samples were tested in duplicate using antigen-based rapid influenza testing and multiplex polymerase chain reaction (PCR) for respiratory viruses. Monthly proportion positive was calculated for each virus. Bivariable and multivariable logistic regression were used to identify associations between sociodemographic/clinical information and viral detection. Of 571 subjects, most (470, 82.3%) were >= 5 years of age and 53.1% were male. A respiratory virus was detected by PCR in 63.6% (N = 363). Common viral etiologies included influenza (223, 39%), human enterovirus/rhinovirus (HEV/HRV, 14.5%), respiratory syncytial virus (RSV, 4.2%), and human metapneumovirus (hMPV, 3.9%). Both ILI and influenza showed clear seasonal variation, with peaks from March to June each year. RSV and hMPV activity peaked from May to July, whereas HEV/HRV was seen year-round. Patients with respiratory viruses detected were more likely to report pain with breathing (odds ratio [OR] = 2.60, P = 0.003), anorexia (OR = 2.29, P < 0.001), and fatigue (OR = 2.00, P = 0.002) compared with patients with no respiratory viruses detected. ILI showed clear seasonal variation in southern Sri Lanka, with most activity during March to June; peak activity was largely due to influenza. Targeted infection prevention activities such as influenza vaccination in January February may have a large public health impact in this region. PMID- 28719324 TI - Susceptibility of Clinical Isolates of Burkholderia pseudomallei to a Lipid A Biosynthesis Inhibitor. AB - Burkholderia pseudomallei is the causative agent of melioidosis, a serious infection associated with high mortality and relapse. Current antimicrobial therapy using ceftazidime (CAZ) is often ineffective. Inhibitors of LpxC, the enzyme responsible for lipid A biosynthesis, have potential antimicrobial activity against several Gram-negative bacteria in vivo, but their activity against B. pseudomallei is unclear. Herein, we investigated the susceptibility of B. pseudomallei clinical isolates to LpxC-4, an LpxC inhibitor, and LpxC-4 in combination with CAZ. Time-kill assays for bactericidal activity were conducted for B. pseudomallei K96243, revealing growth inhibition and bactericidal effect at LpxC-4 concentrations of 2 MUg/mL and 4 MUg/mL, respectively. No significant synergistic effect was observed with the combination of LpxC-4 and CAZ. LpxC-4 susceptibility was tested on three groups of clinical isolates:1) CAZ- and trimethoprim-sulfamethoxazole (SXT)-susceptible (N = 71), 2) CAZ-resistant (N = 14), and 3) SXT-resistant (N = 23) isolates, by broth microdilution. The minimum concentration of LpxC-4 required to inhibit the growth of 90% of organisms was 2 MUg/mL for all isolates. The median minimum inhibitory concentration of both the CAZ/SXT-susceptible and CAZ-resistant groups was 1 MUg/mL (interquartile range [IQR] = 1-2 MUg/mL), compared with 2 MUg/mL (IQR = 2-4 MUg/mL) for the SXT resistant group. Cell morphology was observed after drug exposure by immunofluorescent staining, and a change from rod-shaped to cell wall-defective spherical cells was observed in surviving bacteria. LpxC-4 is a potent bactericidal agent against B. pseudomallei and warrants further testing as a new antibiotic to treat melioidosis. PMID- 28719325 TI - Serologic Monitoring of Public Health Interventions against Strongyloides stercoralis. AB - Northwestern Argentina is endemic for soil-transmitted helminths, and annual deworming programs are carried out in prioritized areas. High prevalence of Strongyloides stercoralis was reported in this area; therefore, control programs including ivermectin are being evaluated. The NIE-enzyme linked immunosorbent assay (ELISA) was used for this purpose. In this community trial, two groups of patients, classified according to housing and living conditions were evaluated. Simultaneous with baseline survey, Group 1 was moved to new households with access to improved water and sanitation facilities (W and S), where deworming (MDA, massive drug administration) took place within 1 month; whereas Group 2 received MDA but remained living with unimproved W and S. The mean time interval between baseline and the follow-up was 331 days for Group 1 and 508 for Group 2. Anti-NIE levels were measured for each individual before and after interventions and follow-up optical density (OD) ratios were calculated to quantify the variation. A significant decrease of the anti-NIE levels between baseline and follow-up was observed in both groups. Nonetheless, the number of patients that achieved the cure criteria (OD ratio < 0.6) was higher in Group 1 than Group 2 with values of 72.7% (24/33) and 45.0% (18/40), respectively (P = 0.0197). Our results support the conclusion that a combined intervention including deworming and improvements in life conditions is more effective, in terms of the proportion of subjects cured than deworming alone. Furthermore, we found that NIE-ELISA is a useful test for assessing the response to treatment and to evaluate the outcome of control intervention programs. PMID- 28719326 TI - Malaria-Related Hospitalizations in the United States, 2000-2014. AB - Few data are available on the burden of malaria hospitalization in the United States. Study of malaria using hospital-based data can better define the impact of malaria and help inform prevention efforts. U.S. malaria cases identified from hospitalization discharge records in the 2000-2014 Nationwide Inpatient Sample were examined. Frequencies and population rates were reported by demographics, infecting species, clinical, financial, institutional, geographic, and seasonal characteristics, and disparities were identified. Time trends in malaria cases were assessed using negative binomial regression. From 2000 to 2014, there were an estimated 22,029 malaria-related hospitalizations (4.88 per 1 million population) in the United States, including 182 in-hospital deaths and 4,823 severe malaria cases. The rate of malaria-related hospitalizations did not change significantly over the study period. The largest number of malaria-related hospitalizations occurred in August. Malaria-related hospitalizations occurred disproportionately among patients who were male, black, or 25-44 years of age. Plasmodium falciparum accounted for the majority of malaria-related hospitalizations. On average, malaria patients were hospitalized for 4.36 days with charges of $25,789. Patients with a malaria diagnosis were more often hospitalized in the Middle Atlantic and South Atlantic census divisions, urban teaching, private not-for-profit, and large-bed-size hospitals. Malaria imposes a substantial disease burden in the United States. Enhanced primary and secondary prevention measures, including strategies to increase the use of pretravel consultations and prompt diagnosis and treatment are needed. PMID- 28719327 TI - Extensive Resistance of Anopheles sinensis to Insecticides in Malaria-Endemic Areas of Hainan Province, China. AB - Anopheles sinensis is one of the major malaria vectors and among the dominant species in Hainan Province, China. The resistance of An. sinensis to insecticides is an important threat to malaria control. However, few reports on insecticide resistance of An. sinensis were reported in this area. Eight districts in Hainan Province were selected as the study areas. Insecticide susceptibility bioassays were tested on wild-caught female mosquitoes of An. sinensis to 4% dichlorodiphenyltrichloroethane (DDT), 0.05% deltamethrin, and 5% malathion by using the World Health Organization standard resistance tube assay procedure. All the tested An. sinensis mosquitoes demonstrated resistance to 4% DDT, with less than 72% mortality in the standard assay. The populations from Baisha and Qiongzhong demonstrated possible resistance to 0.05% deltamethrin, with 94-95% mortality, whereas the populations from other districts demonstrated resistance to 0.05% deltamethrin in the standard assay. The populations from Baisha, Qiongzhong, and Dongfang demonstrated susceptibility to 5% malathion, but the populations from other districts demonstrated resistance. These results facilitate the improvement of effective control strategies for malaria vector mosquitoes in Hainan. PMID- 28719328 TI - President's Address (November 2016): American Society of Tropical Medicine and Hygiene. PMID- 28719329 TI - Rift Valley Fever Seroprevalence in Coastal Kenya. AB - Rift Valley fever virus (RVFV) causes severe disease in both animals and humans, resulting in significant economic and public health damages. The objective of this study was to measure RVFV seroprevalence in six coastal Kenyan villages between 2009 and 2011, and characterize individual-, household-, and community level risk factors for prior RVFV exposure. Sera were tested for anti-RVFV IgG via enzyme-linked immunosorbent assay. Overall, 51 (1.8%; confidence interval [CI95] 1.3-2.3) of 2,871 samples were seropositive for RVFV. Seroprevalence differed significantly among villages, and was highest in Jego Village (18/300; 6.0%; CI95 3.6-9.3) and lowest in Magodzoni (0/248). Adults were more likely to be seropositive than children (P < 0.001). Seropositive subjects were less likely to own land or a motor vehicle (P < 0.01), suggesting exposure is associated with lower socioeconomic standing (P = 0.03). RVFV exposure appears to be low in coastal Kenya, although with some variability among villages. PMID- 28719330 TI - Case Report: Microcephaly in Twins due to the Zika Virus. AB - Recent studies have demonstrated an association between congenital Zika virus (ZIKV) infection and microcephaly; however, to date, there have been no reports on the consequences of ZIKV infection on fetuses in twin pregnancies. Herein, we reported on the first case of a monochorionic diamniotic (MCDA) twin pregnancy having ZIKV-related microcephaly. Our findings suggested that, in an MCDA twin pregnancy, the ZIKV may cause infection in both fetuses, resulting in severe abnormalities in the central nervous system due to neural cell destruction and the disruption of the normal development processes of the brain. This case report and other similar twin cases may help to understand the pathogenesis and to confirm the etiology of ZIKV as a teratogenic microorganism. PMID- 28719331 TI - Factors Associated with the Duration of Moderate-to-Severe Diarrhea among Children in Rural Western Kenya Enrolled in the Global Enteric Multicenter Study, 2008-2012. AB - Diarrheal disease is a leading cause of death among young children worldwide. As rates of acute diarrhea (AD; 1-6 days duration) have decreased, persistent diarrhea (PD; > 14 days duration) accounts for a greater proportion of the diarrheal disease burden. We describe factors associated with the duration of moderate-to-severe diarrhea in Kenyan children < 5 years old enrolled in the Global Enteric Multicenter Study. We found 587 (58%) children experienced AD, 360 (35%) had prolonged acute diarrhea (ProAD; 7-13 days duration), and 73 (7%) had PD. We constructed a Cox proportional hazards model to identify factors associated with diarrheal duration. Risk factors independently associated with longer diarrheal duration included infection with Cryptosporidium (hazard ratio [HR]: 0.868, P = 0.035), using an unimproved drinking water source (HR: 0.87, P = 0.035), and being stunted at enrollment (HR: 0.026, P < 0.0001). Diarrheal illness of extended duration appears to be multifactorial; given its association with adverse health and development outcomes, effective strategies should be implemented to reduce the duration and severity of diarrheal illness. Effective treatments for Cryptosporidium should be identified, interventions to improve drinking water are imperative, and nutrition should be improved through exclusive breastfeeding in infants <= 6 months and appropriate continued feeding practices for ill children. PMID- 28719332 TI - Case Report: A Symptomatic Case of Hymenolepis diminuta Infection in an Urban Dwelling Adult in Malaysia. AB - A case of Hymenolepis diminuta infection in a 43-year-old Malaysian male with persistent abdominal colicky pain is reported. Endoscopy revealed whitish worms in the lumen of the small intestine, which were identified as H. diminuta after microscopy. Patient was successfully treated with a single dose of praziquantel (25 mg/kg). PMID- 28719333 TI - Bidirectional Exchange in Global Health: Moving Toward True Global Health Partnership. AB - Although there has been rapid growth in global health educational experiences over the last two decades, the flow of learners remains overwhelmingly one directional; providers from high-resourced settings travel to limited-resourced environments to participate in clinical care, education, and/or research. Increasingly, there has been a call to promote parity in partnerships, including the development of bidirectional exchanges, where trainees from each institution travel to the partner's setting to learn from and teach each other. As global health educators and steering committee members of the Association of Pediatric Program Directors Global Health Pediatric Education Group, we endorse the belief that we must move away from merely sending learners to international partner sites and instead become true global health partners offering equitable educational experiences. In this article, we summarize the benefits, review common challenges, and highlight solutions to hosting and providing meaningful global health experiences for learners from limited-resourced partner institutions to academic health centers in the United States. PMID- 28719334 TI - Precisely Tracking Childhood Death. AB - Little is known about the specific causes of neonatal and under-five childhood death in high-mortality geographic regions due to a lack of primary data and dependence on inaccurate tools, such as verbal autopsy. To meet the ambitious new Sustainable Development Goal 3.2 to eliminate preventable child mortality in every country, better approaches are needed to precisely determine specific causes of death so that prevention and treatment interventions can be strengthened and focused. Minimally invasive tissue sampling (MITS) is a technique that uses needle-based postmortem sampling, followed by advanced histopathology and microbiology to definitely determine cause of death. The Bill & Melinda Gates Foundation is supporting a new surveillance system called the Child Health and Mortality Prevention Surveillance network, which will determine cause of death using MITS in combination with other information, and yield cause specific population-based mortality rates, eventually in up to 12-15 sites in sub Saharan Africa and south Asia. However, the Gates Foundation funding alone is not enough. We call on governments, other funders, and international stakeholders to expand the use of pathology-based cause of death determination to provide the information needed to end preventable childhood mortality. PMID- 28719335 TI - Experimental Infection with and Maintenance of Cell Fusing Agent Virus (Flavivirus) in Aedes aegypti. AB - During the past two decades, there has been a dramatic increase in the recognition and characterization of novel insect-specific flaviviruses (ISFVs). Some of these agents are closely related to important mosquito-borne flavivirus pathogens. Results of experimental studies suggest that mosquitoes and mosquito cell cultures infected with some ISFVs are refractory to superinfection with related flavivirus pathogens; and it has been proposed that ISFVs potentially could be used to alter the vector competence of mosquitoes and reduce transmission of specific flavivirus pathogens, such as dengue, West Nile, or Zika viruses. In order for an ISFV to be used in such a control strategy, the virus would have to be vertically transmitted at a high rate in the target vector population to insure its continued maintenance. This study compared the vertical transmission rates of an ISFV, cell fusing agent virus (CFAV), in two Aedes aegypti colonies: one naturally infected with CFAV and the other experimentally infected but previously free of the virus. CFAV filial infection rates in progeny of female mosquitoes from both colonies were > 90% after two generations of selection, indicating the feasibility of introducing an ISFV into a mosquito population. This and other considerations for evaluating the feasibility of using ISFVs as an arbovirus control strategy are discussed. PMID- 28719337 TI - Determination of some heavy metals in Mastacembelus mastacembelus (Banks & Solander, 1794) in terms of public health. AB - In this study, the accumulation of some heavy metals in spiny eel (Mastacembelus mastacembelus Banks and Solander, 1794) living in Karakaya Dam Lake was determined and human health risk of this fish when consumed as food was examined. For this purpose, the amounts of copper (Cu), chromium (Cr), cadmium(Cd), iron (Fe), zinc (Zn) in water samples and in the muscle tissues of the fishes were determined. The amounts of heavy metals showed differences in the muscle tissues of Mastacembelus mastacembelus according to weight, length, sex and age groups of fish. In conclusion the amounts of heavy metals in the flesh of spiny eels were found lower than that recommended by EPA, WHO, FAO and TFC. PMID- 28719336 TI - Infant Nutritional Status, Feeding Practices, Enteropathogen Exposure, Socioeconomic Status, and Illness Are Associated with Gut Barrier Function As Assessed by the Lactulose Mannitol Test in the MAL-ED Birth Cohort. AB - The lactulose mannitol (LM) dual sugar permeability test is the most commonly used test of environmental enteropathy in developing countries. However, there is a large but conflicting literature on its association with enteric infection and host nutritional status. We conducted a longitudinal cohort using a single field protocol and comparable laboratory procedures to examine intestinal permeability in multiple, geographically diverse pediatric populations. Using a previously published systematic review to guide the selection of factors potentially associated with LM test results, we examined the relationships between these factors and mucosal breach, represented by percent lactulose excretion; absorptive area, represented by percent mannitol excretion; and gut barrier function, represented by the L/M ratio. A total of 6,602 LM tests were conducted in 1,980 children at 3, 6, 9, and 15 months old; percent lactulose excretion, percent mannitol excretion, and the L/M ratio were expressed as age- and sex specific normalized values using the Brazil cohort as the reference population. Among the factors considered, recent severe diarrhea, lower socioeconomic status, and recent asymptomatic enteropathogen infections were associated with decreased percent mannitol excretion and higher L/M ratios. Poorer concurrent weight-for age, infection, and recent breastfeeding were associated with increased percent lactulose excretion and increased L/M ratios. Our results support previously reported associations between the L/M ratio and factors related to child nutritional status and enteropathogen exposure. These results were remarkably consistent across sites and support the hypothesis that the frequency of these exposures in communities living in poverty leads to alterations in gut barrier function. PMID- 28719338 TI - miR-675 promotes disease progression of non-small cell lung cancer via activating NF-kappaB signaling pathway. AB - Non-small cell lung cancer (NSCLC) is a major type of lung cancer significantly affected human life. Current studies have revealed potential role of miR-675 in the etiology of lung cancer. Therefore, in this study, we aimed to investigate the role of miR-675 in NSCLC cell line. We recruited 92 cases of NSCLC patients from July 2009 to February 2011 in the oncology department. Tumor and peripheral tissue was collected for miR-675 expression. NSCLC cell lines with either miR-675 over-expression or low-expression were established. Western blotting and immunofluorescence staining were used for detecting P65 and pP65 expression and translocation in the nuclei. MiR-675 expression was significantly higher in the lung cancer tissue than the peripheral normal tissue (P < 0.001). The gene expression of pP65 was also increased and decreased in cells with over-expression or low-expression of miR-675, respectively (both P < 0.05). Whereas the trend of P65 expression was on the opposite (both P < 0.05), indicating the NF-kappaB signaling pathway was activated when miR-675 was expressed and vice versa. Immunofluorescence staining showed that more pP65 expression was clustered in the nuclei in miR-675 over-expressed cells, which further demonstrated NF-kappaB signaling pathway activation. Increased miR-675 expression is associated with NSCLC progression through activation of NF-kappaB signaling pathway. PMID- 28719339 TI - Modulation of oxidative and glycolytic skeletal muscle fibers Na+/H+ exchanger1 (NHE1) and Na+/HCO3- co-transporter1 (NBC1) genes and proteins expression in type 2 diabetic rat (Streptozotocin + high fat diet) following long term endurance training. AB - Diabetes is known to alter both oxidative and glycolytic pathways in a fiber type dependent manner. The aim of present study was to investigate the effects of endurance training on muscle NHE1 and NBC1 genes and proteins expression in type 2 diabetic rats. Male wistar rats (n=30), 4 weeks old and 95.7+/-10.8g, were randomly selected and divided into control, diabetic without training and diabetic with training groups. Diabetes was induced by injection of low dose of streptotozin and feeding with high-fat diet. The Endurance training was performed for 7 weeks that started with relatively low speed and duration of 20 m min-1 for 20 min in the first week and gradually reached to 30 m min-1 for 35min in the last week. NHE1 and NBC1 genes and proteins expression were determined by Real time-PCR and western blotting techniques, respectively, in Soleus as an oxidative and EDL (Extensor digitorum longus) as a glycolytic muscle preparation. NHE1 mRNA and protein expression reduced significantly in EDL and Soleus in the diabetic without training group compared with the control group. However, reduction in the expression of NBC1 gene and protein in the diabetic without training group compared to controls did not significant. Endurance training increased NHE1 and NBC1 genes and proteins expression in both EDL and Soleus in the diabetic training group compared to control groups. In conclusion, endurance training may improve the capacity of pHi regulation in muscles by lactate-independent pathway. PMID- 28719340 TI - Sequence comparison of phoR, gyrB, groEL, and cheA genes as phylogenetic markers for distinguishing Bacillus amyloliquefaciens and B. subtilis and for identifying Bacillus strain B29. AB - Given the close genetic relationship between Bacillus amyloliquefaciens and B. subtilis, distinguishing the two solely based on their physiological and biochemical characteristics and 16S rRNA sequences is difficult. Molecular identification was used to discover suitable genes for distinguishing the two bacteria, and to identify the bio-controlling strain B29, due to molecular identification has been paid more and more attention. The similarity of four genes, cheA, gyrB, groEL and phoR, of the two species was compared by the software BLASTN and MAGA, and phylogenetic tree was constructed. The B29 strain was re-identified by using the screened genes. The similarities of the four genes, gyrB, groEL, cheA and phoR, of the two species were 93-95%, 82-84%, 76-78% and 76-77%, respectively. The homologies of the four genes of the strain B29 and the strains of B. amyloliquefaciens strains were more than 95%. We determined how well the phoR and cheA genes could be used to differentiate B. amyloliquefacien and B. subtilis. The previously isolated biological control strain B29, initially classified as B. subtilis, was re-classified as B. amyloliquefaciens. Our data indicate that other than the phoR gene, the cheA gene might be a useful phylogenetic marker for differentiating B. subtilis and B. amyloliquefaciens. PMID- 28719341 TI - Label free quantitative proteomics analysis on the cisplatin resistance in ovarian cancer cells. AB - Quantitative proteomics has been made great progress in recent years. Label free quantitative proteomics analysis based on the mass spectrometry is widely used. Using this technique, we determined the differentially expressed proteins in the cisplatin-sensitive ovarian cancer cells COC1 and cisplatin-resistant cells COC1/DDP before and after the application of cisplatin. Using the GO analysis, we classified those proteins into different subgroups bases on their cellular component, biological process, and molecular function. We also used KEGG pathway analysis to determine the key signal pathways that those proteins were involved in. There are 710 differential proteins between COC1 and COC1/DDP cells, 783 between COC1 and COC1/DDP cells treated with cisplatin, 917 between the COC1/DDP cells and COC1/DDP cells treated with LaCl3, 775 between COC1/DDP cells treated with cisplatin and COC1/DDP cells treated with cisplatin and LaCl3. Among the same 411 differentially expressed proteins in cisplatin-sensitive COC1 cells and cisplain-resistant COC1/DDP cells before and after cisplatin treatment, 14% of them were localized on the cell membrane. According to the KEGG results, differentially expressed proteins were classified into 21 groups. The most abundant proteins were involved in spliceosome. This study lays a foundation for deciphering the mechanism for drug resistance in ovarian tumor. PMID- 28719342 TI - A pilot study for determination of anxiety related SLC6A4 promoter "S" and "L" alleles in healthy Turkish athletes. AB - We aimed to analyze the allelic distribution of solute carrier family-6 member-4 promoter region in Turkish athletes. Recent studies showed the association of lesser expressing "S" allele with anxiety. Genotype percentages for LL, LS and SS genotypes were found as 46, 35 and 19, respectively. 38% of the males had LL, %38 had LS and 24% had SS genotypes. Percentages of LL, LS and SS genotypes were 54, 31 and 15 in females, respectively. 15 (58%) male and 18 (69%) females had L, 11 (42%) male and 8 (31%) females had S alleles. Variations in the association of the SLC6A4 alleles with neuropsychiatric disorders according to different nationalities have been reported. This is the first report showing that LL genotype and L allele in Turkish athletes was more frequent than SS genotype and S allele. PMID- 28719343 TI - Preparation and properties of polyvinyl alcohol (PVA) and hydroxylapatite (HA) hydrogels for cartilage tissue engineering. AB - A novel bioactive hydrogel for cartilage tissue based on polyvinyl alcohol (PVA) and hydroxylapatite (HA) were prepared, the effects of its component contents on the mechanical properties and microstructure of the hydrogel were investigated. The important properties of the scaffold composites, such as density, porosity, compressive modulus and microstructure were studied and analyzed through various measurements and methods. The biodegradability of hydrogel was evaluated by soaking the samples into artificial degradation solution at body temperature (36 37 oC) in vitro. Experimental results showed that the PVA/HA hydrogels had a density of 0.572 - 0.683 g/cm3, a porosity of 63.25 - 96.14% and a compressive modulus of 5.62 - 8.24 MP. The HA compound in the hydrogels enhanced the biodegradation significantly and linearly increased the rate of biodegradation by 2.3 - 8.5 %. The compressive modulus of PVA/HA exhibited a linear reduce to 0.86 1.53 MP with the time of degradation. The scaffold composites PVA/HA possess a high porosity, decent compressive modulus and good biodegradability. After further optimizing the structure and properties, this composite might be considered as novel hydrogel biomaterials to be applied in the field of cartilage tissue engineering. PMID- 28719344 TI - Protective Effect of Edaravone Against Abeta25-35-Induced Mitochondrial Oxidative Damage in SH-SY5Y Cells. AB - Amyloid-beta (Abeta)-induced oxidative stress plays an important role in the pathogenesis of Alzheimer's disease (AD). Recent studies show that Abeta accumulation may lead to mitochondrial oxidative damage. In the present study, we investigated the protective effect of edaravone on mitochondrial damage in SH SY5Y cells treated with Abeta25-35. SH-SY5Y cells were pre-treated with 20, 40 or 80 MUM edaravone before treatment with 25 MUM Abeta25-35. After 24h cell culture, cellular apoptosis, intracellular reactive oxygen species (ROS), mitochondrial membrane potential (DeltaPsim), ATP levels and mitochondrial morphology were evaluated. SH-SY5Y cells exposed to Abeta25-35 had high levels of apoptosis and ROS; loss of DeltaPsim, decreased ATP levels and presence of mitochondrial swelling. However, these effects were significantly inhibited by edaravone pre treatment. These results indicate that edaravone prevents mitochondria oxidative damage caused by Abeta in SH-SY5Y cells, which suggests that it may have potential clinical application in AD therapy. PMID- 28719345 TI - H2O2-induced mild stress in relation with in vitro ovine oocyte developmental competence: implications for blastocyst apoptosis and related genes expression. AB - In this study, in vitro maturation was performed in presence of various concentrations (0, 10, 100, or 1000 uM) of H2O2. The intracellular glutathione (GSH) level, fertilization, cleavage, and blastocyst rates, total cell number, and apoptotic cell number and expression of Bax, Bcl-2, and p53 genes in blastocyst-stage embryos were studied. At 10 MUM H2O2 concentration, a higher GSH level was detected in comparison to the other groups while oocytes exposed to 1000 MUM H2O2 had the lowest GSH level. Treatment of oocytes with 1000 MUM H2O2 decreased the rate of two pronuclei formation as compared with other groups. A higher rate of blastocyst formation was seen in 100 MUM H2O2 group as compared with the control group. However, exogenous H2O2 in maturation medium did not affect total cell numbers and apoptotic cell ratio at the blastocyst stage. Moreover, mRNA transcript abundance of Bax, Bcl-2, and p53 genes was similar between blastocysts derived from H2O2-induced oocytes and control blastocysts. Treatment of oocytes with H2O2 at mild level during in vitro maturation had a positive effect on GSH level and this, in turn, may lead to improvement in preimplantation embryonic development. PMID- 28719346 TI - Virulence genes in biofilm producer Enterococcus faecalis isolates from root canal infections. AB - Enterococcus faecalis is occurring in opportunistic infections involving the oral cavity. This study aimed to evaluate the presence of E. faecalis virulence genes in dental root canal isolates recovered from advanced chronic periodontitis patients. One hundred E. faecalis isolated from dental root canal during July 2015 to Oct 2016. After analysis of biofilm formation by the semi-quantitative determination in 96-well flat bottom polystyrene plates, the presence of asa, esp, efaA, ace, ebpR, gel and hyl gene were studied by PCR. Gelatinase and hemolytic activity were detected by phenotypic methods. Ninety-one percent of isolates had ebpR gene, 85% ace, 82% efaA, 81% gel, 56% esp, 33% asa1, 2% hyl and 0% cyl gene. Evaluation of biofilm formation by microtiter plate method presented 49% of the isolates as strong biofilm producer, 42% displayed moderate biofilm formation, and 10 % weak or no biofilm was observed. asa1, efaA, esp, and ebpR positive isolates had significantly higher biofilm formation than negative isolates, while no significant differences were found when comparing ace-positive and - negative isolates. Present study showed that the ace genes do not seem to be necessary nor sufficient for the production of biofilm in Enterococcus faecalis but the presence of asa1, efaA, esp, and ebpR correlates with increased biofilm formation of dental root canal isolates. PMID- 28719347 TI - Regulatory effects of the novel synthesized Indole-3-carbaldehyde on expression of cell cycle genes: A study on Cyclin D and P21 expression by acute promylocytic leukemia cell line (NB4) AB - This article has been withdrawn. The Publisher and the editor apologize for any inconvenience this may cause. PMID- 28719348 TI - TRIM59 is a key regulator of growth and migration inrenal cell carcinoma. AB - Renal cell carcinoma (RCC) is the most common renal neoplasms and metastatic is common. Previous data have shown that the tripartite motif (TRIM) family proteinswere implicated in human tumoriogenesis. In this study, we aimed to investigate the role of TRIM59 in the cell growth and migration in RCC. The expression of TRIM59 in human RCC tissues was initially examined by qRT-PCR. Alentivirus-based shRNA against TRIM59 (Lv-shTRIM59) was constructed. The effects of TRIM59 knockdown on cell proliferation were examined by in vitro MTT assay, colony formation assay and in vivo a mouse xenograft model of RCC. Cell migration and invasion after knockdown of TRIM59 were also examined by transwell assay. Our data showed that the mRNA level of TRIM59 in cancerous tissues was 2-fold increased as compared with non-cancerous tissues. Knockdown of TRIM59 in a RCC cell line 786-O significantly slowed down cell proliferative rate and decreased both the colony number and sizes. In the mouse model, knockdown of TRIM59 consistently inhibited tumor growth in vivo. Moreover, it was shown that cell migration and invasion were suppressed by 68% and 50%, respectively in TRIM59 depleted 786-O cells. Our data suggest that TRIM59 may serve as a pro-oncogenic protein in promoting the progression of RCC. Knockdown of TRIM59 may be a promising strategy concerning the early detection and treatment of RCC. PMID- 28719349 TI - Identification of G2607A mutation in EGFR gene with a significative rate in Moroccan patients with Bladder Cancer. AB - The epidermal growth factor receptor (EGFR) is involved in the regulation of several cellular processes and in the development of many human cancers. Somatic mutations of EGFR at tyrosine kinase domain have been associated with clinical response to tyrosine kinase inhibitors (TKIs) in lung cancer patients. In this study, we evaluated the frequency of point mutations in EGFR for future use of TKI in clinical treatment of bladder cancer. A total, 50 Moroccan patient specimens with bladder cancer and 48 healthy controls were analysed for EGFR mutations in the region delimiting exons 18-21 by PCR amplification and direct sequencing. Our results showed the absence of mutations in the EGFR kinase domain in these exons in all analysed specimens. However, sequence analysis of the EGFR TK domain, revealed the presence of (G2607A) polymorphism at exon 20. Statistical analysis showed significant difference in the frequencies of G2607A polymorphism between cancer cases and healthy controls (p=0.0001) and the frequencies of the GG and GA/AA genotypes among the cancer cases were 28% and 72%, respectively. Moreover, allelic frequencies of G2607A polymorphism showed significant difference between cancer cases and healthy controls (p=0.0025). Data analysis showed no significant association between G2607A polymorphism and patients' age, clinical stage and tumor grade (p > 0.05). However, a significant difference was found between this polymorphism and patients' sex that could be a sampling bias due to the very limited number of women with bladder cancer. Our findings highlight that, mutations in EGFR kinase domain is a rare event in bladder cancer, suggesting, that treatment of bladder cancer patients with TKI may not be effective. However, the EGFR G2607A polymorphism in exon 20 is frequent in bladder cancer cases and must be further explored for its relevance in the treatment of this disease. PMID- 28719350 TI - Characterization of Candidate probionts isolated from human breast milk. AB - This study was designed to isolate and identify the potential probionts present in 32 healthy mothers' breast milk. Microbial culture media and 16SrRNA sequencing were used to isolate and identify the bacteria and all isolates were analyzed for their antagonistic potential, resistance to acidic pH, bile salts and survival under simulated gastric and intestinal conditions. The colonization potential was further assessed based on adherence to human enterocyte-like Caco-2 cell lines. The breast milk samples harbored significant numbers of Gram positive and catalase negative (85%) bacteria. Based on 16SrRNA sequencing, these isolates were identified as Lactobacillus casei, L.gasseri, L.fermentum, L.plantarum, Pediococcus acidilactici, and Enterococcus facieum. Among the isolates, P. acidilactici was the most frequent species (71%) present in these samples. Few Gram and catalase positive isolates, Staphylococcus aureus and S.hominiis were also observed. The isolates were viable and unviable in pH 3 and 1.5, respectively, while all isolates survived in 1.0% bile salt. As putative probionts, P.acidilactici 1C showed a significantly higher percentage of adhesion to Caco-2 cells (p< 0.05)than the other two isolates L.plantarum 7A and E.facieum 2C. Bacterial strains isolated from human breast milk were shown to have probiotic properties including anti-infective protection and may be considered as future therapeutics for infants. PMID- 28719351 TI - CCAT1 expressed in malignant and pre-malignant human gastric tissues. AB - CCAT1 has been reported to implicate in various human malignancies. However, its expression in the oncogenesis of gastric cancer (GC) remains unknown. Quantitative reverse transcription (RT)-qPCR assay was performed to detect the expression of CCAT1 in 68cases of GC tissues,paired tumor-proximal gastric mucosa and normal gastric mucosa, 19 cases of gastric intraepithelial neoplasia (GIN), and the sera of these 68 GC patients and 22 healthy volunteers. And the relationship between CCAT1 and clinicopathologic features of GC patients were analyzed. Inthe present study, we found that CCAT1 expression was significantly abnormally deregulated in GC tissues (185.43 +/- 21.37), GIN tissues (121.30 +/- 43.61), tumor-proximal mucosa (8.9 +/- 1.21), and normal mucosa (1.5 +/- 0.55). CCAT1 wasalso overexpressed in the sera of GC patients (47.40 +/- 6.60) compared with healthy controls (0.62 +/- 0.06; p < 0.001). And high CCAT1 expression in GC tissues was associated with high tumor burden, including larger tumor size, lymphatic metastasis and advanced TNM stage (all p < 0.05). These results reveal that CCAT1 is a detectable biomarkerforgastric cancertumorigenesis and may be utilized as adiagnosticand prognosticindicator. PMID- 28719352 TI - Determination of IL-6, TNF-alpha and VEGF levels in the serums of patients with colorectal cancer. AB - Cytokines are multifunctional polypeptides synthesized by different body cells. They have clinical significance in terms of disease diagnosis, treatment and prevention. Cytokines TNF-alpha and IL-6 play an important role in the growth and differentiation of cells.Vascular Endothelial Growth Factor (VEGF) is excessively produced in epithelial, mesenchymal, and particularly in tumor cells. Studies have shown that the increased serum concentrations of IL-6, TNF-alpha, VEGF are strongly associated with colorectal cancer and directly with the clinical stage of the disease. This can be used to diagnose cancer and to identify patients with a bad prognosis who can avail themselves of a more aggressive treatment. The present study investigated the role of cytokines in the development of cancer by comparing preoperative serum cytokine levels of patients suffering from colorectal cancer with those of the healthy control group. The prognostic significance of the data obtained has also been evaluated. For this purpose, IL 6, TNF-alpha and VEGF levels in 60 serums, 30 preoperatively taken from patients with colorectal cancer and 30 from a healthy control group at Canakkale Onsekiz Mart University General Surgery Clinic, were determined by ELISA kits. The statistical analyses of the obtained data were evaluated on SPSS, a statistical package program. In this study, no significant difference was obtained between the mean scores concerning the IL-6 and VEGF serums of the colorectal cancer and healthy group (p>.05). But a statistically significant decrease was observed in the TNF-alpha serum level of the colorectal cancer group in comparison with the control group (p= .016; p < .05). PMID- 28719353 TI - Effect of Triptolide on retinal ganglion cell survival in an optic nerve crush model. AB - Optic nerve crush model could be used to investigate the mechanism of neuronal survival and axonal regeneration in central nervous system. Triptolide, a Chinese herb extract with anti-inflammatory and immunosuppressive activities, has shown neuron protective functions in nervous system. In this study, we investigated the changes in retinal ganglion cell survival and axonal regeneration after administration of triptolide in optic nerve crush model. Triptolide treatment tended to promote retinal ganglion cell survival rather than optic nerve regeneration as well as inhibit the expression of tumor necrosis factor-alpha and activation of nuclear factor-kappa B. These findings suggested that intraperitoneal injection of triptolide may be an effective treatment for optic nerve injury and this effect was attributed at least in part to its anti inflammatory actions. PMID- 28719354 TI - Thymol and carvacrol strongly inhibit biofilm formation and growth of carbapenemase-producing Gram negative bacilli. AB - Discovery of novel drugs with new mechanisms of action and without cross-reaction with current therapeutic agents is crucial in the management of infections caused by multi-drug resistant (MDR) bacteria. The aim of the present study was to investigate effects of carvacrol and thymol on biofilm formation and antimicrobial activity against different carbapenemase-producing Gram negative bacilli. The antimicrobial and antibiofilm effect of thymol and carvacrol was investigated against strains harboring different genes related to carbapenemase resistance. Antimicrobial resistance was examined by an agar dilution method and antibiofilm effect was evaluated by microtiter plate assay and staining by crystal violet. Thymol and carvacrol had antibacterial effects ranging from 200 1600 MUg/mL and 62-250 MUg/mL respectively, and antibiofilm effect from 125-500 and 400-1600 MUg/mL respectively. Seoul imipenemase- (SIM) producing isolates had the highest sensitivity, and NDM (New Delhi metallo-beta-lactamase) producing isolates had the lowest sensitivity to these components. Findings of the present study indicated a potential role of carvacrol and thymol in controlling carbapenemase-producing gram negative bacterial infections. These findings helped to develop herbal drugs for replacing antibiotics. In addition, their antibiofilm effects showed that carvacrol and thymol inhibit biofilm formation of carbapenemase-producing strains. PMID- 28719355 TI - miRNA-223 suppresses FOXO1 and functions as a potential tumor marker in breast cancer. AB - Breast cancer is the most commonly diagnosed cancer in women and a leading cause of cancer mortality. MicroRNAs (miRNAs) have been found to play a key role in proliferation, metastasis and invasion of cancer. In previous study, we found that miRNA-223 was significant expression inexosome derived from peripheral blood serum of breast cancer patients than in samples from control subjects, Therefor,the role ofmiRNA-223willbe researched in MCF-7 breast cancer cells.In this study, to explore the role of miRNA-223in influencing cell proliferation, metastasis and invasion of breast cancer, TargetScan tools (http://www.targetscan.org/vert_71/) was used to scan target genes of miRNA-223, and thenmiRNA expression, real time PCR, Western blotting andluciferase report assay were used to test regulates relationship of miRNA-223and its targets,cell viability and BrdU analysiswere used to test cell proliferation of MCF-7 breast cancer cells after expression miRNA-223inhibitor. Scanning targets of miRNA 223found FOXO1 was listed in targets content, and luciferase reporter assay was used to assess and confirm the binding sequence of 3'untranslated region between FOXO1 and miRNA-223. Results showedthat miRNA-223inhibitorexpression increased protein expression level of FOXO1 in MCF-7 breast cancer cells,meanwhile, cell viability and BrdU analysis showed MCF-7 breast cancer cells were suppressed proliferation after up-regulation of FOXO1.In conclusion, we demonstrated that the miRNA-223can maintain cell proliferation of breast cancer cell through targeting FOXO 1, these results provide a new insight in tumor marker and potential therapeutic targets for breast cancer. PMID- 28719356 TI - Co-incubation of PMN and CaCo-2 cells modulates inflammatory potential. AB - Polymorphonuclear granulocytes (PMN) are activated in inflammatory reactions. Intestinal epithelial cells are relevant for maintaining the intestinal barrier. We examined interactions of PMN and intestinal epithelial cell-like CaCo-2 cells to elucidate their regulation of inflammatory signalling and the impact of cyclooxygenase (COX), nitric oxide (NO) and platelet-activating factor (PAF). Human PMN and CaCo-2 cells, separately and in co-incubation, were stimulated with the calcium ionophore A23187 or with N-Formyl-methionyl-leucyl-phenylalanin (fMLP) that activates PMN only. Human neutrophil elastase (HNE) and respiratory Burst were measured. To evaluate the modulation of inflammatory crosstalk we applied inhibitors of COX (acetyl salicylic acid; ASA), NO-synthase (N-monomethyl L-arginin; L-NMMA), and the PAF-receptor (WEB2086). Unstimulated, co-incubation of CaCo-2 cells and PMN led to significantly reduced Burst and elevated HNE as compared to PMN. After stimulation with A23187, co-incubation resulted in an inhibition of Burst and HNE. Using fMLP co-incubation failed to modulate Burst but increased HNE. Without stimulation, all three inhibitors abolished the effect of co-incubation on Burst but did not change HNE. ASA partly prevented modulation of Burst L-NMMA and WEB2086 did not change Burst but abolished mitigation of HNE. Without stimulation, co-incubation reduced Burst and elevated HNE. Activation of PMN and CaCo-2 cells by fMLP as compared to A23187 resulted in a completely different pattern of Burst and HNE, possibly due to single vs. dual cell activation. Anti-inflammatory effect of co-incubation might in part be due to due to COX-signalling governing Burst whereas NO- and PAF-dependent signalling seemed to control HNE release. PMID- 28719357 TI - Vitamin D receptor BsmI polymorphism may be associated with an decreased osteoporosis risk in South China. AB - Although many epidemiology studies have evaluated the correlation between vitamin D receptor (VDR) BsmI polymorphism and osteoporosis, the current results remain inconclusive. This meta-analysis updated and reevaluated the possible association between VDR BsmI polymorphism and osteoporosis in Chinese populations. Studies were identified using PubMed and Chinese databases through December 2016. The associations were assessed with pooled odds ratios (ORs) and 95% confidence intervals (CIs). A total of nine studies with 688 osteoporosis cases and 730 controls were included in this meta-analysis. Overall, no significant association was found between VDR BsmI polymorphism and osteoporosis when all studies in Chinese populations were pooled into this meta-analysis. In subgroup analyses, significantly decreased risk was found in South China (bb vs. BB: OR = 0.22, 95% CI = 0.06-0.76; bb+Bb vs.BB: OR = 0.27, 95% CI = 0.09-0.81). This meta-analysis suggests that VDR BsmI polymorphism may have a protective role against the development of osteoporosis in South China. PMID- 28719358 TI - The association between the UBQLN1 polymorphism and Alzheimer's disease risk: A systematic review. AB - Recently, some studies suggested that UBQLN1 variant was associated with AD risk. However, the results were inconsistent. This meta-analysis aimed to determine the association between UBQLN1 variant and AD risk. We searched the electronic databases PubMed, Embase, and CNKI databases. Random-effects model was used. All statistical tests were performed using the STATA 11.0 software (StataCorp, College Station, TX, USA). UBQLN1 variant was not associated with the risk of AD (OR=1.05; 95%CI, 0.92-1.19; I2=35%). The corresponding pooled ORs were not materially altered in sensitivity analysis. The Galbraith plot was used to find the source of the heterogeneity and no study was the outlier. The shape of the funnel plot showed symmetry. Egger's test found no evidence of publication bias (P=0.8). These results suggest that the UBQ-8i polymorphism was not associated with AD risk. PMID- 28719359 TI - Levodopa in Parkinson's Disease: A Review of Population Pharmacokinetics/Pharmacodynamics Analysis. AB - BACKGROUND: Parkinson's disease is the second most common neurodegenerative disorder after Alzheimer's disease. Although levodopa remains the single effective agent in the management of Parkinson's disease, the accurate determination of this optimal dosage is complicated by marked between-subject and between-occasion variability in this population. This review presents a synthesis of the population pharmacokinetic and pharmacodynamic models of levodopa described in Parkinson's disease. METHODS: A literature search was conducted from the PubMed database, from their inception through April 2016, using the following terms: levodopa, pharmacokinetic(s), pharmacodynamic(s) population, model(ling) and nonlinear mixed effect. Articles were excluded if they were not pertinent. References of all selected articles were also evaluated. RESULTS: A total of 12 articles were finally retained. The following covariates were selected as interindividual variability factors: body weight, age, sex, creatinine clearance and levodopa dose. The clinical response versus effect site concentration relationship was described with different sigmoidal Emax models. Different pharmacodynamic effects were described: UPDRS, Tapping, Dyskinesia, CURSSigma and treatment response scale. DISCUSSION: This review allows us to realize interpretation of a patient's clinical picture and confirmed the appropriateness of the pharmacokinetic-pharmacodynamic modeling for levodopa. External evaluation of previous published models should be also continued to evaluate these previous studies. New pharmacokinetic and/or pharmacodynamic population modelling studies could be consider to improve future models and decrease variability, to better understand the evolution of patients with Parkinson's disease treated by levodopa. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page. PMID- 28719360 TI - Alzheimer's Disease: Dawn of a New Era? AB - Alzheimer's disease (AD) is an irreversible neurodegenerative disease characterized by a progressive decline in cognition and memory, leading to significant impairment in daily activities and ultimately death. It is the most common cause of dementia, the prevalence of which increases with age; however, age is not the only predisposing factor. The pathology of this cognitive impairing disease is still not completely understood, which has limited the development of valid therapeutic options. Recent years have witnessed a wide range of novel approaches to combat this disease, so that they greatly increased our understanding of the disease and of the unique drug development issues associated with this disease. In this paper, we provide a brief overview of the history, the clinical presentation and diagnosis, and we undertake a comprehensive review of the various approaches that have been brought to clinical trials in recent years, including immunotherapeutic approaches, tau-targeted strategies, neurotransmitter-based therapies, neurotropic and hematopoietic growth factors, and antioxidant therapies, trying to highlight the lessons learned from these approaches. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page. PMID- 28719361 TI - Effectiveness of Valganciclovir 900mg Versus 450mg for Cytomegalovirus Prophylaxis in Renal Transplantation: A Systematic Review and Meta-Analysis. AB - OBJECTIVES: Valganciclovir 900 mg/day is approved for cytomegalovirus (CMV) prophylaxis, but 450 mg/day is seems also effective. We systematically reviewed the efficacy and safety of low-dose versus high-dose valganciclovir prophylaxis in renal transplantation recipients. METHODS: An electronic search was conducted up to November 29, 2016. The primary outcomes were incidences of CMV, CMV disease, mortality and opportunistic infection. The second outcomes were acute rejection, allograft loss, adverse drug reaction (ADR). RESULTS: 7 cohort studies, all with high quality involving (1431 patients) were included. There was no significant difference of the incidence of following CMV disease (1271 patients, odds ratio [OR] 0.74, 95% confidence interval [CI], 0.38-1.43, p=0.36), acute rejection (1343 patients, OR 0.77, 95%CI 0.53-1.14, p=0.19), allograft loss (1271 patients, OR 0.64, 95%CI 0.31-1.35, p=0.24), mortality (1271 patients, OR 0.55, 95%CI 0.20-1.47, p=0.23) and opportunistic infections (OI) (985 patients, OR 0.76, 95%CI 0.52-1.10, p=0.14) between the low-dose and the high-dose valganciclovir prophylaxis. And no significant difference was observed for premature valganciclovir discontinuation (1010 patients, OR 0.81, 95%CI 0.52 1.25, p=0.33) and the incidence of leukopenia (1082 patients, OR 0.65, 95%CI 0.34 1.22, p=0.18) between the two regimens. CONCLUSION: 450 mg and 900 mg doses of valganciclovir are equipotent for CMV universal prophylaxis. CMV 450 mg prophylaxis should be used for renal transplant recipients. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page. PMID- 28719362 TI - Association Between Vancomycin Blood Brain Barrier Penetration and Clinical Response in Postsurgical Meningitis. AB - PURPOSE: This study investigated the association between vancomycin blood brain barrier penetration and clinical response in patients with postsurgical meningitis. METHODS: Adult patients with postsurgical meningitis were recruited. Eligible patients received vancomycin 500 mg every 6 h for at least 5 days. On day 3 or 4, cerebrospinal fluid (CSF) and simultaneous serum samples were obtained to determine CSF minimum concentrations (Cmin), serum Cmin and CSF to serum Cmin ratio. RESULTS: Twenty-two patients (14 men and 8 women; mean age of 52.6+/- 12.1 years) were recruited. The vancomycin Cmin was 3.63 +/- 1.64 mg/L in CSF and 13.38 +/- 5.36 mg/L in serum, with the CSF to serum Cmin ratio of 0.291 +/- 0.118. The Cmin in serum and in CSF showed a significant correlation (p=0.005, r =0.575). The vancomycin CSF Cmin had a significant correlation with the decline of white blood cell counts (WBCs) in CSF (p=0.003, r =0.609). CSF Cmin, serum Cmin and CSF to serum Cmin ratio all showed no significant correlation with clinical response (p=0.335, 0.100, 0.679, respectively). CONCLUSIONS: There was a positive correlation between serum Cmin and CSF Cmin. However, only CSF Cmin is positively correlated with WBCs improvement in CSF. All other parameters such as serum Cmin, CSF Cmin and CSF to serum Cmin ratio had no correlation with clinical response. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page. PMID- 28719363 TI - Vitamin D metabolism in human adipose tissue: could it explain low vitamin D status in obesity? AB - Obesity and a low vitamin D (VD) status, as well as a positive association between them, are prevalent worldwide. Additionally, a low VD status has been positively correlated with metabolic dysfunction (although not so convincingly as for obesity). The VD receptor (VDR) mediates VD biological actions in adipose tissue (AT), where VD can be activated or inactivated/degraded through specific hydroxylation steps. Additionally, AT can also store and release VD when needed. A lower VD activation/VD inactivation ratio and an impaired VDR signaling in AT could contribute to metabolic dysfunction besides the aforementioned association between obesity and VD status. However, subcutaneous (SAT) and visceral AT (VAT) are not expected to be similarly accountable as these two fat depots play differential roles in metabolic regulation/dysfunction. To our knowledge, only three articles disclose the evaluation of the expression of VDR and/or VD hydroxylating enzymes in human SAT and VAT. A clear dependence on the subcutaneous and/or the visceral fat depot is missing for the relationships of a) obesity and/or metabolic dysfunction with VD status and b) adipose VDR signaling and adipose VD activation/VD inactivation ratio with VD status, obesity and/or metabolic dysfunction. Further studies are warranted to unravel the influence of adipose VD metabolism on VD status. PMID- 28719364 TI - Is there a link between self-perceived stress and physical activity levels in Scottish adolescents? AB - Purpose Accumulating life stress is a driving factor underlying the most pervasive, incapacitating health conditions in 21st century, First World societies. The most widely supported strategy, for remediating the negative health consequences of elevated life stress, is physical activity (PA). Evidence also suggests accumulating life stress impedes PA uptake. Thus, ironically, persistently elevated life stress not only negatively impacts multiple dimensions of health, simultaneously it may also reduce likelihood of participation in the most effective remediating strategy, PA. This study sought to compare patterns of PA uptake in adolescents of low socioeconomic status (SES) backgrounds, a significant risk factor for elevated biopsychosocial stress, with more affluent age-matched peers. Related health behaviours such as smoking and alcohol consumption were also analysed. Methods PA patterns were determined using the Physical Activity Questionnaire for High School (PAQA). Stress scores were assessed using the 10-item perceived stress scale (PSS-10). Results PA scores were significantly different between groups (p < 0.05). Low SES participants were significantly less active every day (p < 0.05), excepting Saturdays (U = 31.0, Z = -1.594, p = < 0.05). Spearman's correlation demonstrated an inverse relationship between total stress and PA during spare time (rs = -0.61, n = 10, p = < 0.05). Conclusion These findings add to mounting evidence suggesting excessively accumulating life stress, not only diminishes health, but simultaneously reduces PA uptake in vulnerable populations. Thereby highlighting the bidirectional relationship between stress and PA. These findings support proposals that conventional Physical Education practice should be re-framed to not only provide PA during school years, but to promote lifelong interest in PA. PMID- 28719365 TI - Proposed model for the cultural adaptation of an Internet-based depression prevention intervention (CATCH-IT) for Arab adolescents. AB - Background Evidence-based Internet depression prevention intervention programs are not readily available for Arab youth, but may be effective in this group. Cultural adaptation of evidence-based Western psychotherapy is an important step toward better prevention and treatment of depressive illness in the Arab community. Project CATCH-IT is an Internet-based depression prevention intervention tool that is tailored for adolescents and young adults. Methods The PEN-3 theoretical framework was used for the cultural adaptation of Project CATCH IT for Arab adolescents. First, a narrative review of existing research about depression in Arab nations was performed. Next, expert opinions about applicability and societal values were obtained. This model was then used to suggest relevant changes to the CATCH-IT modules. These modifications were applied to create sample webpages from the culturally adapted version of CATCH-IT for Arab youth. Results The narrative review, expert opinions and resultant PEN-3 analysis suggest that Internet-based depression interventions are effective, private and confidential. To be most effective, religious leaders and fathers should be the stakeholders approached for dissemination and adequate usage of the service. Arab themes, quotes, language and relevant stories must be incorporated. Conclusion This study sets the background for future studies and research for implementation of the Arabic version of CATCH-IT for the prevention of depression. Using the contextual information provided in this paper to make the necessary changes, huge strides can be made in providing cost-effective and accessible Internet-based interventions to Arab youth. PMID- 28719366 TI - A web-based anger management program for parent-female adolescents' conflicts: a cluster randomized controlled trial. AB - Objective This cluster randomized control trial was performed to evaluate the effectiveness of a web-based anger management program for mother-female adolescents' conflicts. Methods Eight out of 23 high-schools in District Two of Shiraz, Iran were chosen using random cluster sampling and randomly assigned to an intervention and a control group (each group consisted of four schools). The conflict tactics scale was filled out by all eligible third grade high school students in both groups and 140 students who had the scores higher than 30 were randomly selected; 70 adolescents in the intervention group participated in an 8 week intervention, while 70 adolescents in the control group did not undergo any intervention. Data collection was performed at the end of the intervention and 1 month later. Results The results of the t-test revealed no statistically significant differences between the study groups regarding the total conflict tactics scores (p = 0.935) or any of the three subscales before the intervention (p > 0.05). However, a significant difference was observed between the two groups in this regard immediately and 1 month after the intervention (p < 0.05). The results of repeated measure analysis of variance (ANOVA) demonstrated a significant difference between the intervention and control groups regarding the conflict scores and its subscales during the three study periods and groups (F = 79.43, p < 0.001). Conclusion This study highlighted the importance of applying a web-based anger management program in decreasing mother-female adolescents' conflicts. Similar studies are recommended to be conducted on the issue. PMID- 28719368 TI - Change Is In the Air: What You Need to Know About Pharmacy Ventilation Under United States Pharmacopeia <800>. AB - On July 1, 2018, United States Pharmacopeia <800> takes effect in those states that adopt it, and the discussion within this article may be applicable to those states that develop their own standards. United States Pharmacopeia <800> changes requirements for storage and compounding of hazardous drugs. The new requirements have important implications for air management and ventilation in some pharmacies. This article discusses how United States Pharmacopeia <800> compares to United States Pharmacopeia <797>, how the changes impact room ventilation and pressurization requirements, and how high-performance airflow control systems that ensure compliance and safety are impacted. PMID- 28719369 TI - Component Selection for Sterile Compounding. AB - This article describes the factors to consider, as well as the process of proper component selection, for use in preparing compounded sterile preparations. Special emphasis is placed on individual chemical factors that may impact a preparation's accuracy and potency. Values reported in a typical certificate of analysis are discussed, including methods of identifying any required adjustments to a master formulation or compounding record during the compounding of sterile preparations. Proper screening of the certificate of analysis, the Safety Data Sheet, procedural documentation, and the filing of all certificates of conformance are crucial to the operation of a sterile compounding facility. PMID- 28719371 TI - The International Academy of Compounding Pharmacists Applauds the Leadership of Congressmen Griffith and Cuellar in Introducing Bill HR 2871. PMID- 28719370 TI - Simple Preparation of Timolol 0.5% Gel from Eye Drop Solution for Superficial Infantile Hemangiomas. AB - The discovery of beta-adrenergic blocker effects on infantile hemangiomas has affected the choice of treatment in recent years. Oral propranolol is effective in treating infantile hemangiomas, but the risk of systemic side effects remains a concern. Data from literature review reported positive clinical outcomes with no major adverse effects observed in children using topical beta-blocker such as timolol maleate. Topical application of timolol eye drop has been mentioned in few studies, most of which reported that the solution cannot stay on the site of application due to its fluidity. Adding hydroxyethyl cellulose into a timolol solution increased its viscosity by forming a hydrogel and thus changed the rheology property. The compounded timolol gel exhibited thixotropy property allowing better and longer contact at sites of application. Experimental data from literature review showed desirable characteristics and measurable flux of timolol across human stratum corneum. Gel dosage form allows easy and precise application and maximizes timolol's therapeutic efficacy at the sites of application. PMID- 28719372 TI - Basics of Compounding: 3D Printing: Pharmacy Applications, Part 3: Compounding, Formulation Considerations, and the Future. AB - 3D printing is a standard tool in the automotive, aerospace, and consumer goods in industry and is gaining traction in pharmaceutical manufacturing, which has introduced a new element into dosage form development. This article, which represents part 3 of a 3-part article on the topic of 3D printing, discusses the compounding, formulation considerations, and the future of 3D printing. PMID- 28719373 TI - Basics of Sterile Compounding: Excipients Used in Injections. AB - This article focuses on the majority of different excipients (all formulation components. PMID- 28719374 TI - Physical and Chemical Stability of Budesonide Mucoadhesive Oral Suspensions (MucoLox). AB - Budesonide is a corticosteroid that has been shown effective in the treatment of eosinophilic esophagitis, but there are currently no commercial medicines to treat this chronic allergic/immune condition, despite its prevalence in the U.S. Therefore, pharmaceutical compounding is the alternative choice to meet the therapeutic need of eosinophilic esophagitis patients. Two budesonide mucoadhesive oral suspensions (1 mg/10 mL and 2 mg/10 mL) were developed using the compounding vehicle MucoLox, a proprietary mucoadhesive polymer blend that promotes mucosal adhesion. The physical and chemical stability of the oral suspensions was tested over a period of 182 days, at room temperature and refrigerated conditions, in order to determine the corresponding beyond-use date. The physical characterization consisted in observing all samples for color/appearance and odor, and testing for pH and density, whereas the chemical characterization consisted in ultra-performance liquid chromatography assay testing. Both oral suspensions were proven physically and chemically stable, and the ultra-performance liquid chromatography method was proven stability indicating. As a result, the beyond-use date of the budesonide 1-mg/10-mL and 2 mg/10-mL mucoadhesive oral suspensions (MucoLox), in amber plastic bottles, is six months at both room temperature and refrigerated conditions. PMID- 28719375 TI - Compounded Levofloxacin Triple Therapy is Safe and Effective for Refractory Helicobacter pylori. AB - Failure of first line and subsequent Helicobacter pylori therapy is a significant problem, as alternate treatments are cumbersome and difficult to access. The purpose of this study was to evaluate the efficacy and safety of a compounded levofloxacin triple therapy in clinical practice as a second or third-line salvage regimen for Helicobacter pylori. Patients referred after first or subsequent treatment failures were prescribed compounded levofloxacin 500 mg, amoxicillin 1 g, and esomeprazole 40 mg, all twice daily for 10 days. Eradication success was determined by 14C-urea breath test or histology at least 4 weeks after completion of therapy. The study included 93 patients, the majority of whom were female (57%) with a mean age of 44. The most common indication for treatment was dyspepsia/risk reduction (84%). Median number of previous treatments was 1 (range: 1 through 6) with treatment used as second line in 83%. Helicobacter pylori eradication was achieved in 89.2% (74/83) per protocol and 79.6% (74/93) on an intention-to-treat basis. Outcome was independent of gender, ethnicity, treatment indication, or number. Treatment was well tolerated, with minor adverse events in 8.4% and only one patient discontinuing therapy. Compounded levofloxacin triple therapy is an effective and safe second line treatment for Helicobacter pylori, with eradication rates comparable to standard levofloxacin based regimens. PMID- 28719376 TI - Stability of Spironolactone Oral Suspension in PCCA Base, SuspendIt. AB - Spironolactone (Aldactone) is a potassium-sparing diuretic used to treat hypertension and heart failure and may also be used to treat edema resulting from kidney disease, low potassium levels, or excess aldosterone. No commercial liquid dosage form of spironolactone exists. An extemporaneously compounded suspension from pure drug powder or commercial tablets would provide an alternative option to meet unique patient needs. The purpose of this study was to determine the physicochemical stability of spironolactone in the PCCA base SuspendIt. This base is a sugar-free, paraben-free, dye-free, and gluten-free thixotropic vehicle containing a natural sweetener obtained from the monk fruit. It thickens upon standing to minimize settling of any insoluble drug particles and becomes fluid upon shaking to allow convenient pouring during administration to the patient. A robust stability-indicating highperformance liquid chromatographic assay for the determination of spironolactone in PCCA base SuspendIt was developed and validated. This assay was used to determine the chemical stability of the drug in SuspendIt. Samples were prepared and stored under three different temperature conditions (5 degrees C, 25 degrees C, 40 degrees C) and assayed using the high performance liquid chromatographic assay at pre-determined intervals over an extended period of time as follows: 0, 7, 14, 29, 46, 60, 90, 120, and 180 days at each designated temperature. Physical data such as pH, viscosity, and appearance were also monitored. The study showed that drug concentration did not go below 90% of the label claim (initial drug concentration) at all three temperatures studied. Viscosity and pH values also did not change significantly. This study demonstrates that spironolactone is physically and chemically stable in SuspendIt for 180 days in the refrigerator and at room temperature, thus providing a viable, compounded alternative for spironolactone in a liquid dosage form, with an extended beyond-use date to meet patient needs. PMID- 28719377 TI - Stability of Acetazolamide, Baclofen, Dipyridamole, Mebeverine Hydrochloride, Propylthiouracil, Quinidine Sulfate, and Topiramate Oral Suspensions in SyrSpend SF PH4. AB - The objective of this study was to evaluate the stability of 7 commonly used active pharmaceutical ingredients compounded in oral suspensions using an internationally used suspending vehicle (SyrSpend SF PH4): acetazolamide 25.0 mg/mL, baclofen 10.0 mg/mL, dipyridamole 10.0 mg/mL, mebeverine hydrochloride 10.0 mg/mL, propylthiouracil 5.0 mg/mL, quinidine sulfate 10.0 mg/mL, and topiramate 5.0 mg/mL. All suspensions were stored both at controlled refrigerated (2 degrees C to 8 degrees C) and room temperature (20 degrees C to 25 degrees C). Stability was assessed by measuring the percentage recovery at varying time points throughout a 90-day period. Active pharmaceutical ingredient quantification was performed by ultraviolet (UV) high-performance liquid chromatography, via a stability-indicating method. Given the percentage of recovery of the active pharmaceutical ingredients within the suspensions, the beyond-use date of the final products (active pharmaceutical ingredient + vehicle) was at least 90 days for all suspensions with regards to both temperatures. This suggests that SyrSpend SF PH4 is suitable for compounding active pharmaceutical ingredients from different pharmacological classes. PMID- 28719378 TI - Chemical Stability of Morphine, Ropivacaine, and Ziconotide in Combination for Intrathecal Analgesia. AB - Pain is the most feared symptom amongst individuals living with cancer. In 15% to 20% of patients, conventional analgesic therapy either fails to relieve pain or induces adverse effects. Intrathecal drug delivery systems may present an effective alternative for pain management. The Cancerology Center Paul Papin protocol includes an admixture of morphine, ropivacaine, and ziconotide in intrathecal preparations. These drugs are administered by a fully implantable or an external pump. Syringes or polyolefin infusion bags are prepared for refill just before use. Few centers in France use the method of intrathecal analgesia. Therefore, for those patients receiving intrathecal preparations, each filling requires that the patients be transported from their local hospital (or their home) to a referral center where the patients are monitored. They sometimes must travel up to a hundred kilometers to have a pump filled. The preparation and the analytical control of the mixture are carried out only by those centers meeting the proper criteria, which includes the proper equipment. To spare the patient this travel, a peripheral center may be subcontracted to manage the patient's pump refill. No data are available concerning the chemical stability of admixtures in syringes or polyolefin infusion bags. The aim of this study was to evaluate, with a new analytical method using ultra high-performance liquid chromatography, the chemical stability of these admixtures in syringes or in polyolefin infusion bags. Ziconotide 1 ug/mL was combined with ropivacaine (7.5 mg/mL) and morphine (3.5 mg/mL) in syringes at 5 degrees C, 21 degrees C, and 31 degrees C, and in polyolefin infusion bags at 21 degrees C. Assays were performed using ultra high-pressure liquid chromatography. In syringes stored at 21 degrees C and 31 degrees C, concentrations after 6 hours were not in the acceptable criterion of 10% variability. When syringes were stored at 5 degrees C, the residual concentration of ziconotide after 3 days was 100.5% +/- 2.6% [92.7% to 108.4%]. In polyolefin infusion bags, the residual concentration of ziconotide after 14 days was 96.9% +/- 2.2% [90.1% to 103.6%]. This study demonstrates the chemical stability of this admixture in syringes stored at 5 degrees C for 3 days and in polyolefin plastibags stored at 21 degrees C for 14 days. PMID- 28719379 TI - Critical Evaluation of Metallization in Electric Injury. AB - The article presents 3 forensic medicine cases in the field of electric injury. In addition to traditional findings in electric injury (electric mark and histological findings), the forensic medicine experts in Lithuania also perform an atomic absorption spectrometry analysis. This method confirms the effects of electric current to the body through the electric conductor. Typical macroscopic finding in the skin is electric mark. Histologically, the damaged skin possesses characteristic features of thermal burns. The atomic absorption spectroscopy analysis identifies traces of metal particles devolved from the electrical conductor, which confirms a premortal contact with it. In one of our presented cases, the metallization was negative, although there were obvious data of electric current effect. This shows that it is not always worth to rely on the method of atomic absorption spectrometry analysis recognized worldwide in forensic medicine. The determination of electrical injury diagnosis requires a critical and comprehensive assessment of all the available data and laboratory tests. PMID- 28719381 TI - Detection of Putative Stem-cell Markers in Invasive Ductal Carcinoma of the Breast by Immunohistochemistry: Does It Improve Prognostic/Predictive Assessments? AB - INTRODUCTION: Experimental evidences from the last 2 decades supports the existence of a special type of neoplastic cell with stem-like features [cancer stem cell (CSC)] and their role in the pathophysiology and therapeutic resistance of breast cancer. However, their clinical value in human breast cancer has not been fully determined. MATERIALS AND METHODS: An immunohistochemistry panel of 10 putative CSC markers (CD34, C-KIT, CD10, SOX-2, OCT 3/4, p63, CD24, CD44, CD133, and ESA/EPCAM) was applied to 74 cases of breast cancer, followed in a Regional Cancer Center of Minas Gerais State, Brazil, from 2004 to 2006. Possible associations between CSC markers and classic variables of clinicopathologic relevance were investigated. RESULTS: The most frequently positive CSC markers were CD44, CD24, CD133, and ESA (the others were present in <15% of the cases). Two CSC profiles were defined: CD24/CD44 (CSC-1) and CD133/ESA (CSC-2). CSC-1 was significantly associated to patients older than 40 years, tumors of <2.0 cm in diameter, early clinical stages (P<0.05), and increased death risk of 4 times (P=0.03; 95% confidence interval, 1.09-14.41). CSC-2 was related to increased relapse risk of 3.75 times (P=0.04; 95% confidence interval, 1.02-13.69). CONCLUSION: The detection of the most frequently positive CSC markers by immunohistochemistry is of clinicopathologic and prognostic relevance. PMID- 28719382 TI - In Response. PMID- 28719380 TI - Comparison of Different Antibody Clones for Immunohistochemistry Detection of Programmed Cell Death Ligand 1 (PD-L1) on Non-Small Cell Lung Carcinoma. AB - Programmed cell death ligand 1 (PD-L1) is a major immune checkpoint protein that mediates antitumor immune suppression and response. Preliminary data suggest that its detection using immunohistochemistry (IHC) in formalin-fixed and paraffin embedded tissues may predict clinical response to PD-1/PD-L1 therapy. In diagnostic pathology, it is essential to count with a validated IHC that can reliably detect PD-L1-positive cases. The present study was conducted to compare and validate different PD-L1 commercial clones and identify which ones can be reliably used by surgical pathologist to detect PD-L1 expression in human cancer tissues. Eight commercial available PD-L1 clones were tested and compared with a noncommercial PD-L1 antibody clone 5H1. Western blot and IHC using cell lines and human tissues were used to validate these clones. From all PD-L1 antibodies, only the clones E1L3N, E1J2J, SP142, 28-8, 22C3, and SP263 passed the Western blot and IHC validation, providing similar pattern than the clone 5H1 and then they were tested in 259 non-small cell lung cancer cases placed in 9 tissue microarrays. Among all cases, only those with >=2 cores were included (185 cases). Positive and significant correlation was found between the median PD-L1 H-score in tumor and stroma compartments, for all selected antibodies. Overall, 56 of 185 cases were detected as positive cases in malignant cells expressing membranous PD-L1 by all the clones. However, the clone SP263 identified more PD-L1-positive cases compared with the other clones. Our results show that clones E1L3N, E1J2J, SP142, 28-8, 22C3, and SP263 provide positive membrane staining pattern comparable with clone 5H1. These commercial clones are comparable, but a careful evaluation by the pathologist is necessary to minimize error of positive misinterpretations. PMID- 28719383 TI - Closed-Loop Control of Total Intravenous Anesthesia During Significant Intraoperative Blood Loss: A Case Report. AB - Closed-loop control of anesthesia based on continuous feedback from processed electroencephalography adjusts drug dosing to target a desired depth of hypnosis during dynamic clinical circumstances, freeing the anesthesiologist to focus on more complex tasks. We describe a case of closed-loop control of total intravenous anesthesia in which a sudden loss of blood required immediate intervention. This case illustrates that closed-loop control of drug delivery maintained an appropriate depth of hypnosis during a rapidly changing surgical situation, and that processed electroencephalography may be a useful adjunct indicator for cerebral hypoperfusion. PMID- 28719384 TI - Anesthetic Management of an Infant With Postnatally Diagnosed Tracheal Agenesis Undergoing Tracheal Reconstruction: A Case Report. AB - A term infant born cyanotic failed multiple intubation attempts and tracheostomy placement. After esophageal intubation resulted in the ability to ventilate, he was presumed to have tracheal agenesis and distal bronchoesophageal fistula. He was transferred to our institution where he was diagnosed with Floyd Type II tracheal agenesis. He underwent staged tracheal reconstruction. He was discharged to home at 4 months of age with a tracheostomy collar, cervical spit fistula, and gastrostomy tube. He represents the sole survivor-to-discharge of tracheal agenesis in the United States. We describe the anesthetic considerations for a patient with tracheal agenesis undergoing reconstruction. PMID- 28719385 TI - Prevention of hemolytic disease of the fetus and newborn: what have we learned from animal models? AB - PURPOSE OF REVIEW: This review aims to highlight recent advances in our understanding of how anti-red blood cell (RBC) antibodies prevent erythrocyte immunization with an emphasis on new murine models. RECENT FINDINGS: New murine models with clinically relevant human erythrocyte antigens have been used to understand the alloimmunization process and its inhibition. The search to elucidate the mechanism of action of IgG-mediated inhibition of erythrocyte alloimmunization has provided new evidence in support of a potential role for epitope masking, immune deviation and/or antigen modulation in this process. In addition, recent evidence suggests that blends of monoclonal antibodies targeting nonoverlapping epitopes on the RBC surface can improve the efficacy of monoclonal antibodies approaching that of polyclonal IgG. SUMMARY: Animal models with defined alloantigens have helped to identify important mechanistic components that lead to alloimmunization and its inhibition by IgG. A better understanding of the underlying mechanisms leading to hemolytic disease of the fetus and newborn is required to develop the most effective prevention strategies for future patients. PMID- 28719386 TI - Is there a standard-of-care for transfusion therapy in thalassemia? AB - PURPOSE OF REVIEW: Thalassemia is the most common form of inherited anemia, characterized by variable clinical phenotypes. The purpose of this review is to summarize the transfusion support in thalassemia patients and the management of transfusion-related iron overload. RECENT FINDINGS: The most recent evidence on transfusion strategy and iron chelation therapy in thalassemia arising from clinical trials as well as from recommendation guidelines are critically discussed. SUMMARY: Enhancements in the global care of thalassemia, resulting from the combination of an appropriate transfusion approach and iron chelation therapy, have produced a significant improvement in the quality of life and, finally, in the prognosis of patients affected by this inherited hematologic disorder. PMID- 28719387 TI - Pediatric mitochondrial diseases and the heart. AB - PURPOSE OF REVIEW: Mitochondrial disorders are an increasingly recognized cause of heart dysfunction, with the primary manifestations being cardiomyopathy and conduction defects. This review focuses on the complex genetics of mitochondrial disease and recently discovered conditions that affect mitochondrial function. RECENT FINDINGS: Next-generation sequencing techniques, especially whole-exome sequencing, have led to the discovery of a number of conditions that cause mitochondrial dysfunction and subsequent cardiac abnormalities. Nuclear DNA defects are the main cause of mitochondrial disease in children, with disease pathogenesis being related to either abnormalities in specific mitochondrial electron transport chain subunits or in proteins related to subunit or mitochondrial DNA maintenance, mitochondrial protein translation, lipid bilayer structure, or other aspects of mitochondrial function. SUMMARY: Currently, symptomatic therapy using standard medications targeting relief of complications is the primary approach to treatment. There are no US Food and Drug Administration-approved therapies for the specific treatment of mitochondrial disease. However, on the basis of recent advances in understanding of the pathophysiology of these complex disorders, various novel approaches are either in clinical trials or in development. PMID- 28719388 TI - What is new in managing patients with food allergy? Almost everything. AB - PURPOSE OF REVIEW: This review aims to describe current concepts in managing patients with food allergy. There have been many recent advances in the management of patients with IgE-mediated reactions to food, including diagnosis, prevention, management, and ongoing research in the field. Food allergy is increasing in prevalence and may be life threatening. This review aims to highlight changes in recommended practice when diagnosing and managing patients with food allergy. RECENT FINDINGS: Early introduction of highly allergenic foods, particularly peanut, has been shown to decrease the risk for development of food allergy in patients who are at elevated risk. Avoidance of foods without a clinical history of food allergy may increase the risk of subsequent allergy. Epinephrine remains the first line therapy for anaphylaxis, and patients and families need to be instructed on indications and technique for use. Promising research is ongoing in areas of immunotherapy to food allergens. SUMMARY: Food allergy is a potentially life-threatening condition that may persist throughout adulthood. Practitioners should be aware of changes to recommendations for the diagnosis, prevention, and management of patients with food allergy. PMID- 28719390 TI - Total pancreatectomy with islet autotransplantation: recent updates and outcomes. AB - PURPOSE OF REVIEW: Total pancreatectomy with islet autotransplantation (TPIAT) is a reliable therapy to retain endocrine function, to alleviate pain and improve quality of life in adult and pediatric patients suffering from refractory chronic pancreatitis and recurrent acute pancreatitis. Recently, an expansion of indications to include benign and malignant pancreatic disease has been suggested. Improved methods for evaluating the functional quality of islets and predicting transplant outcome have been discussed. Furthermore, this review will discuss the recent advances in the procedure, anti-inflammatory strategies and outcomes of TPIAT. RECENT FINDINGS: New assays to measure posttransplant islet damage and improved methods to assess islet quality by monitoring the oxygen consumption rate have shown great promise. Anti-inflammatory strategies such as an interleukin-1 receptor antagonist, alpha-1 antitrypsin, tumor necrosis factor alpha inhibitor and an inhibitor of CXCR1/2 have been widely investigated under clinical trials. SUMMARY: The primary objective of TPIAT, which is to relieve pain and reduce narcotic usage, has been shown to have long-term success. However, achieving long-term insulin independence is still a challenge that needs to be addressed. The mechanism that leads to chronic graft failure in TPIAT needs to be delineated. PMID- 28719389 TI - Genetic contribution to neurodevelopmental outcomes in congenital heart disease: are some patients predetermined to have developmental delay? AB - PURPOSE OF REVIEW: Neurodevelopmental impairment is common in children with moderate to severe congenital heart disease (CHD). As children live longer and healthier lives, research has focused on identifying causes of neurodevelopmental morbidity that significantly impact long-term quality of life. This review will address the role of genetic factors in predicting neurodevelopmental outcome in CHD. RECENT FINDINGS: A robust literature suggests that among children with various forms of CHD, those with known genetic/extracardiac anomalies are at highest risk of neurodevelopmental impairment. Advances in genetic technology have identified genetic causes of CHD in an increasing percentage of patients. Further, emerging data suggest substantial overlap between mutations in children with CHD and those that have previously been associated with neurodevelopmental disorders. SUMMARY: Innate and patient factors appear to be more important in predicting neurodevelopmental outcome than medical/surgical variables. Future research is needed to establish a broader understanding of the mutations that contribute to neurodevelopmental disorders and the variations in expressivity and penetrance. PMID- 28719391 TI - Pediatric and congenital hand transplantation. AB - PURPOSE OF REVIEW: We review the approach and challenges associated with pediatric hand transplantation, including new knowledge gleaned from our recent case of bilateral hand-forearm transplantation in an 8-year old child. RECENT FINDINGS: Bilateral heterologous hand-forearm transplantation was performed in a child with a prior kidney transplant in July 2015. The initial surgery necessitated a large team of experts in microvascular surgery, transplant surgery, orthopedics and plastic surgery as well as pediatric anesthesia. Medical management has highlighted the need for extensive multidisciplinary support with pediatric expertise in transplant medicine, occupational therapy and rehabilitation, neurology, and neuroradiology. The clinical course has been complicated by the need for robust immunosuppression to control ongoing, even though low-grade, and intermittent rejection. Neurological findings have demonstrated cortical neuroplasticity with reorganization of the somatosensory cortex. SUMMARY: Heterologous hand-forearm transplantation in a child is feasible and has the potential for functional benefit to improve quality of life; however, immunological and ethical concerns warrant proceeding with caution. More data are needed to inform patient and family selection to achieve optimal functional and quality of life outcomes. PMID- 28719392 TI - Intestinal microbiome in scleroderma: recent progress. AB - PURPOSE OF REVIEW: Our evolving understanding of how gut microbiota affects immune function and homeostasis has led many investigators to explore the potentially pathologic role of gut microbiota in autoimmune diseases. This review will discuss the rapidly advancing field of microbiome research in systemic sclerosis (SSc), an incurable autoimmune disease with significant gastrointestinal morbidity and mortality. RECENT FINDINGS: Recent reports have identified common perturbations in gut microbiota across different SSc cohorts. Compared with healthy controls, patients with SSc have decreased abundance of beneficial commensal genera (e.g. Faecalibacterium, Clostridium and Bacteroides) and increased abundance of pathbiont genera (e.g. Fusobacterium, Prevotella and Erwinia). Certain genera may protect against (e.g. Bacteroides, Clostridium, and Lactobacillus), or conversely exacerbate (e.g. Fusobacterium and Prevotella) gastrointestinal symptoms in SSc. These genera represent potential targets to avert or treat gastrointestinal dysfunction in SSc. SUMMARY: Emerging evidence suggests that alterations in gut microbiota exist in the SSc disease state; however, future basic and clinical studies are needed to ascertain the mechanism by which these alterations perpetuate inflammation and fibrosis in SSc. Therapeutic trials are also needed to investigate whether dietary interventions or fecal transplantation can restore the gut microbial balance and improve health outcomes in SSc. VIDEO ABSTRACT: http://links.lww.com/COR/A38. PMID- 28719393 TI - Restrictions and limitations after pelvic floor surgery: what's the evidence? AB - PURPOSE OF REVIEW: A common concern regarding pelvic floor surgery is the relatively high risk of recurrence. In an effort to minimize this risk, many surgeons instruct their patients to avoid certain activities during the healing process so as not to damage the repair before proper healing has occurred. However, many of these restrictions have been historically based on little to no hard evidence. The purpose of this review is to present the latest evidence-based recommendations regarding restrictions and limitations after pelvic floor surgery. RECENT FINDINGS: The current review covers postoperative activities that could impact proper healing of a vaginal incision and of the strength of the reconstruction itself. It also looks at safety of the patient and those around her as she heals. Topics include pelvic rest, swimming, lifting exercising, working, and driving. Observational research suggests that many unavoidable activities of daily living may have as great, if not an even greater, risk of impacting the healing process than many of the modifiable activity restrictions that are commonly imposed on patients. This may explain why recent clinical trials show no greater problem with healing in patients randomized to less strict postoperative restrictions than the standard. SUMMARY: Although further research is necessary, it appears that patients are more satisfied with less strict postoperative limitations, and this less restrictive activity may not have any significant negative impact on the healing process. PMID- 28719394 TI - Cochlear implantation in children under 12 months of age. AB - PURPOSE OF REVIEW: Children with congenital hearing loss are being identified earlier, leading to earlier intervention. Current US Food and Drug Administration (FDA) criteria states a child must be 12 months or older for cochlear implantation. The purpose of this article is to review recent publications regarding the benefits of implanting infants under 12 months of age. Topics include: safety and efficacy of surgery, speech and language acquisition outcomes, audiologic components, and limitations. RECENT FINDINGS: Since the early 1990s, the candidacy criteria evolved drastically. However, the FDA criteria for cochlear implantation in children has remained at 12 months of age or older since 2000. Recent research indicates implanting below 12 months of age a safe and effective procedure. Speech and language outcomes showed better speech and language advantages. In addition, infants implanted earlier showed normal auditory skills as early as 3 months post cochlear implant activation. This article will also address recent findings on the limitations of earlier implantation. SUMMARY: Recent research demonstrates positive outcomes in children implanted under 12 months of age. Developing research on earlier implantation could lead to a change in the current FDA criteria allowing infants to reach their speech and hearing potential faster. PMID- 28719395 TI - Closing the gap in cochlear implant access for African-Americans: a story of outreach and collaboration by our cochlear implant program. AB - PURPOSE OF REVIEW: Minorities often lag behind in hearing loss evaluation and treatment. Our cochlear implant program aimed to identify the socioeconomic and cultural barriers that prevented our African-American cochlear implant candidates from seeking help for their hearing loss, specifically cochlear implant surgery. RECENT FINDINGS: Our pilot study surveyed 11 African-Americans with cochlear implants and identified obstacles that included patient-physician mistrust, social stigma, financial cost, and lack of education about the devices and procedures. Our experienced cochlear implant team then addressed these issues in its weekly meetings to review cases and potential cochlear implant candidates, and we partnered with community organizations to improve awareness about cochlear implants among healthcare professionals and the public. SUMMARY: During our cochlear implant team's community outreach to African-Americans with hearing loss, we initiated several actions to address the various disparities in access to care and use of services: development of patient education, patient-run support group, tracking of clinical outcomes, and opportunities for involvement in health policy making for cochlear implants. Cochlear implant teams should deepen their involvement with African-Americans and other minorities with hearing loss to better support and ultimately improve cochlear implant access, performance, and function. PMID- 28719397 TI - Obesity and pancreatitis. AB - PURPOSE OF REVIEW: The obesity pandemic poses a unique set of problems for acute pancreatitis - both by increasing acute pancreatitis incidence, and worsening acute pancreatitis severity. This review explores these associations, underlying mechanisms, and potential therapies. RECENT FINDINGS: We review how the obesity associated increase in gallstones, surgical, and endoscopic interventions for obesity management, diabetes, and related medications such as incretin-based therapies and hypertriglyceridemia may increase the incidence of acute pancreatitis. The mechanism of how obesity may increase acute pancreatitis severity are discussed with a focus on cytokines, adipokines, damage-associated molecular patterns and unsaturated fatty acid-mediated lipotoxicity. The role of obesity in exacerbating pancreatic necrosis is discussed; focusing on obesity associated pancreatic steatosis. We also discuss how peripancreatic fat necrosis worsens organ failure independent of pancreatic necrosis. Last, we discuss emerging therapies including choice of intravenous fluids and the use of lipase inhibitors which have shown promise during severe acute pancreatitis. SUMMARY: We discuss how obesity may contribute to increasing acute pancreatitis incidence, the role of lipolytic unsaturated fatty acid release in worsening acute pancreatitis, and potential approaches, including appropriate fluid management and lipase inhibition in improving acute pancreatitis outcomes. PMID- 28719398 TI - Interventional approaches to deep venous thrombosis. AB - PURPOSE OF REVIEW: Catheter-directed therapy in deep vein thrombosis (DVT) is a beneficial adjunct treatment when anticoagulation alone does not provide an adequate therapeutic response. This review aims to deliver an up-to-date discussion behind the rationale, safety profile, and clinical outcomes in endovascular management of DVT. RECENT FINDINGS: Early studies have shown that the use of catheter-directed thrombolysis (CDT) to be successful in rapid thrombus removal, carry a lower incidence of postthrombotic syndrome (PTS), and improved quality of life. To date, the most robust study evaluating the use of CDT is the Catheter-Directed Venous Thrombolysis in Acute Iliofemoral Vein Thrombosis trial published in 2012, which demonstrated a relative risk reduction in PTS of 26% in the patients who received CDT at 2-year follow-up. The 5-year follow-up results from the trial has recently been published, which revealed persistent clinical benefit of CDT. Since, additional small randomized trials confer the efficacy and safety profile of CDT. Short-term results from pharmacomechanical catheter-directed thrombolysis are promising; however, the long-term efficacy has yet to be established. The recently completed Acute Venous Thrombosis: Thrombus Removal with Adjunctive Catheter-Directed Thrombolysis trial will be a pivotal study in defining the future role of pharmacomechanical catheter-directed thrombolysis in prevention of PTS. SUMMARY: CDT is a reasonable and well tolerated treatment option in selected patients with acute proximal DVT. PMID- 28719396 TI - Preclinical Models of Ovarian Cancer: Pathogenesis, Problems, and Implications for Prevention. AB - Preclinical models are relatively underutilized and underfunded resources for modeling the pathogenesis and prevention of ovarian cancers. Several reviews have detailed the numerous published models of ovarian cancer. In this review, we will provide an overview of experimental model systems, their strengths and limitations, and use selected models to illustrate how they can be used to address specific issues about ovarian cancer pathogenesis. We will then highlight some of the preclinical prevention studies performed to date and discuss experiments needed to address important unanswered questions about ovarian cancer prevention strategies. PMID- 28719399 TI - Impact of rotavirus vaccines in low and middle-income countries. AB - PURPOSE OF REVIEW: Rotavirus vaccines are playing a pivotal role in improving lives of infants and young children in low and middle-income countries (LMICs). Many of these countries have adopted the vaccine into their routine immunization, whereas others are considering introduction. This article provides an update on the impact of rotavirus vaccines in LMICs on morbidity and mortality in children aged less than 5 years, and their cost-effectiveness. RECENT FINDINGS: The WHO, in 2013, updated its recommendation to prioritize introduction of rotavirus vaccines in the routine immunization schedule, without age restrictions. Despite the decreased efficacy of the vaccines in LMICs, data from Sub-Saharan Africa have demonstrated a decrease in rotavirus-related morbidity, with some sites reporting an indirect protective effect on children age ineligible to receive the vaccine. Even with improvements in sanitation, nutritional status in children, and other health-related indices in LMICs, the use of rotavirus vaccines will play an important role in preventing rotavirus-related gastroenteritis. Economic models predict a reduction in economic burden because of rotavirus-related health costs, making vaccine introduction cost-effective in resource-constrained settings. SUMMARY: Increasing evidence from impact studies shows the significant impact of rotavirus vaccination on hospitalizations and economic burden because of rotavirus gastroenteritis in LMICs. Universal rotavirus vaccination is recommended, and introductions should be monitored by robust surveillance systems to measure effectiveness and impact. PMID- 28719400 TI - Dengue vaccines: implications for dengue control. AB - PURPOSE OF REVIEW: Dengue, the most common arbovirus, is an increasingly significant cause of morbidity worldwide. After decades of research, an approved tetravalent dengue vaccine is finally available. Models constructed using recently available vaccine efficacy data allow for a data-driven discussion of the potential impact of dengue vaccine deployment on global control. RECENT FINDINGS: Phase 3 efficacy trials demonstrated that the approved dengue vaccine, chimeric yellow fever-dengue-tetravalent dengue vaccine, has an efficacy of 60% against dengue illness of any severity. However, among dengue unexposed recipients, vaccination offers limited efficacy and may increase dengue severity. The WHO consequently recommends dengue vaccination for populations in which 70% of intended recipients are dengue seropositive. Models predict that routine childhood dengue vaccine may reduce dengue burden, but over time, population level impact may be limited. Additional vaccine candidates in late-stage development may not suffer from the same limitations as chimeric yellow fever dengue-tetravalent dengue vaccine. SUMMARY: The efficacy and safety profile of the recently approved dengue vaccine is favorable only in previously dengue exposed recipients, which limits its potential for global control. Future work must evaluate the approved vaccine's long-term durability, efficacy of other late phase vaccine candidates, and potential for vector control efforts to work synergistically with vaccine deployment. PMID- 28719401 TI - Antibiotic-Coated Interlocking Intramedullary Nail for the Treatment of Long-Bone Osteomyelitis. PMID- 28719402 TI - Current Treatment Options for Glenohumeral Instability and Bone Loss: A Critical Analysis Review. PMID- 28719403 TI - Passive Transcutaneous Bone Conduction Hearing Implants: A Systematic Review. AB - OBJECTIVE: To systematically review the literature on currently available passive transcutaneous bone conduction hearing implants (pTCBI) with regard to complications, audiological outcomes, and quality-of-life scores. DATA SOURCES: MEDLINE, EMBASE, Scopus, and Cochrane Library. STUDY SELECTION: All identified English-language articles reporting on the implantation of currently available pTCBI's and their complications. Both pediatric and adult patients were included. No limitation was placed on study design or level of evidence. DATA EXTRACTION: Complications, audiological outcomes including mean pure-tone average gain and mean speech reception threshold gain, and quality-of-life outcomes. DATA SYNTHESIS: Twenty-six articles were included in the review. Four hundred eighty two pTCBIs have been reported in the literature. Major complications including skin breakdown, wound dehiscence, hematoma, seroma, and inability to use the device occurred in 5.2% of patients. Minor complications including pain and self resolving erythema at the implant site occurred in 13.1% of the patients. The weighted mean pure-tone average gain of the two included devices was 28.4 +/- 2.1 dB and the mean speech reception threshold gain was 32.9 +/- 3.9 dB. Favorable quality-of-life scores have been demonstrated with pTCBIs. CONCLUSION: pTCBIs are a viable alternative to percutaneous devices in a carefully selected group of patients. These devices have demonstrated good audiological outcomes, low morbidity, and high patient satisfaction. PMID- 28719404 TI - Predictive Factors for Hearing Outcomes After Canaloplasty in Patients With Congenital Aural Atresia. AB - OBJECTIVE: The aim of this study was to determine the most important factors in preoperative imaging, including components of Jahrsdoefer score (J score), and favorable prognostic factors for postoperative hearing results after canaloplasty for congenital aural atresia. STUDY DESIGN: Retrospective review of medical records. SETTING, PATIENTS, INTERVENTION, MAIN OUTCOME MEASURE: One hundred eight patients who underwent canaloplasty by a single surgeon between January 2011 and July 2014 were included. The influence of the following factors on the success for restoring of hearing was evaluated by univariable and multivariable logistic regression analyses: sex, atretic side, total J score, each component of Jahrsdoerfer grading scale, incudostapedial joint angle, inferior displacement of the tegmen, middle ear height, and inner ear anomaly. RESULTS: Successful hearing outcome was defined as postoperative air conduction <=40 dB at 3 months after surgery, and it was achieved in 74 of 108 ears (70.5%). Univariable analysis revealed that the total J score, course of the facial nerve, presence of the malleus-incus complex, pneumatization of the mastoid, and middle ear height were significant as favorable predictive factors. Multivariable analysis revealed that middle ear height and inferior displacement of the tegmen were significant as favorable predictive factors. Inferior displacement of the tegmen was the most significant factor by the stepwise selection method in the final model. CONCLUSION: Middle ear height and inferior displacement of the tegmen are useful factors in predicting favorable hearing results after canaloplasty for congenital aural atresia. These factors might have a useful prognostic value supplementary to the J score. PMID- 28719405 TI - Clinical outcomes 1 year after empiric 131I therapy for hyperthyroid disorders: real life experience and predictive factors of functional response. AB - : Radioiodine is a therapeutic option in Europe for Graves' disease (GD) and toxic multinodular goiter (MNG). PURPOSE: To compare empiric and calculated I activities using 2013 EANM recommendations. To look for predictive factors of therapeutic response to an empiric activity of I. To assess clinical situations favoring calculated treatment modalities. PATIENTS AND METHODS: Prospective monocentric study of clinical outcomes at 1 year follow-up in 86 patients with GD and MNG who received empiric I therapeutic activities (348-939 MBq). Differences between empiric and calculated activities were confronted to clinical outcomes. Physicians were not aware of the calculated activity at the time of prescription. RESULTS: One year after treatment, 9% (5/57) of GD patients and 7% (2/29) of MNG patients were still in a hyperthyroid state. Thyroid volume was reduced by 67% for GD and by 50% for MNG. In GD, empiric I activities were higher than calculated ones (564+/-131 vs. 316+/-319 MBq, P<0.001) in 93% (53/57) of patients. Pretherapeutic thyroid volume (>26 ml for GD; >40 ml for MNG) was associated with persistent hyperthyroidism. CONCLUSION: Empirically administered I for GD and MNG was associated with very high efficacy in thyroid function control and no side effects. Thyroid volume reduction did not preclude treatment efficacy. Activity calculation could be a useful method for treating patients with GD and thyroid volumes higher than 26 ml or patients with MNG and thyroid volumes higher than 40 ml. A selective approach based on pretherapeutic thyroid volume and radioiodine biokinetics might improve treatment success. PMID- 28719407 TI - The International Council of Nurses Congress 2017. PMID- 28719406 TI - Toward a Biopsychosocial Ecology of the Human Microbiome, Brain-Gut Axis, and Health. AB - OBJECTIVE: Rapidly expanding insights into the human microbiome and health suggest that Western medicine is poised for significant evolution, or perhaps revolution-this while medicine continues on a trajectory from reductionism to a biopsychosocial (BPS) paradigm recognizing biological, psychological, and social influences on health. The apparent sensitivity of the microbiota to perturbations across BPS domains suggests that a broad and inclusive framework is needed to develop applicable knowledge in this emerging area. We outline an ecological framework of the human microbiome by extending the BPS concept to better incorporate environmental and human factors as members of a global, dynamic set of systems that interact over time. METHODS: We conducted a selective literature review across disciplines to integrate microbiome research into a BPS framework. RESULTS: The microbiome can be understood in terms of ecological systems encompassing BPS domains at four levels: (a) immediate (molecular, genetic, and neural processes), (b) proximal (physiology, emotion, social integration), (c) intermediate (built environments, behaviors, societal practices), and (d) distal (physical environments, attitudes, and broad cultural, economic, and political factors). The microbiota and host are thus understood in terms of their immediate interactions and the more distal physical and social arenas in which they participate. CONCLUSIONS: A BPS ecological paradigm encourages replicable, generalizable, and interdisciplinary/transdisciplinary research and practices that take into account the vast influences on the human microbiome that may otherwise be overlooked or understood out of context. It also underscores the importance of sustainable bioenvironmental, psychological, and social systems that broadly support microbial, neural, and general health. PMID- 28719408 TI - Glucocorticoid-induced hyperglycemia. PMID- 28719409 TI - Shared decisions: The art of healthcare. PMID- 28719411 TI - An update on type 2 diabetes management in primary care. PMID- 28719410 TI - Assessment and management of wrist pain. PMID- 28719412 TI - New oral antiplatelet medications. PMID- 28719413 TI - Evaluation of a new genetic family history screening questionnaire for identifying Lynch syndrome. AB - Family history is essential when screening for hereditary cancer syndromes. This article explores if a detailed genetic family history questionnaire is more effective in identifying at-risk individuals for Lynch syndrome than a basic family health questionnaire. PMID- 28719415 TI - Heart Failure: Self-care to Success: Development and evaluation of a program toolkit. AB - The Heart Failure: Self-care to Success toolkit was developed to assist NPs in empowering patients with heart failure (HF) to improve individual self-care behaviors. This article details the evolution of this toolkit for NPs, its effectiveness with patients with HF, and recommendations for future research and dissemination strategies. PMID- 28719416 TI - The Ophthalmology Surgical Competency Assessment Rubric for Trabeculectomy. AB - PURPOSE: To produce an internationally valid tool to assess skill in performing trabeculectomy surgery. METHODS: A panel of 5 experts developed a tool for assessing trabeculectomy surgery by using a modified Dreyfus scale of skill acquisition and providing descriptors for each level of skill for each category. The tool was then reviewed by a panel of 10 international content experts for their constructive comments, which were incorporated into the final rubric tool. RESULTS: A final rubric, incorporating the suggestions of the international panel, published here as the ICO-OSCAR: Trabeculectomy. CONCLUSIONS: The tool ICO OSCAR: Trabeculectomy has content and face validity. It can be used internationally to assess trabeculectomy surgery skill. Predictive and construct validity, and reliability are yet to be determined. PMID- 28719417 TI - Anterior Chamber Angle and Trabecular Meshwork Measurements Made by Fourier domain Optical Coherence Tomography in Healthy White Children. AB - PURPOSE: To obtain anterior chamber angle and trabecular meshwork (TM) measurements by Fourier-domain optical coherence tomography (FD-OCT) in a population of healthy white children. MATERIALS AND METHODS: This was a cross sectional study examining 409 right eyes of 409 children. Trabecular-iris angle (TIA) and TM length and area were measured by FD-OCT (RTVue 100) in the nasal and temporal quadrants to analyze correlations between angle or TM measurements and age, sex, and refractive error. RESULTS: Mean participant age was 10.5+/-3.4 years (range, 3 to 18 y); 51% were boys. Mean spherical error was 0.56+/-2.4 D (range, -9 to +7.5 D). TIA could be measured in 99%, whereas TM measurements could only be made in 83%. Mean TIA was 43.1+/-10.0 degrees (range, 16 to 76 degrees). No differences were observed in angle width according to sex (P=0.299; t test). TIA was correlated with age (R=0.204; P<0.001) and with spherical error (R=-0.457; P<0.001). Mean TM length was 530+/-106 MUm (range, 299 to 891 MUm) and mean TM area was 0.065+/-0.021 mm (range, 0.030 to 0.180 mm). No correlation was observed between TM metrics and age, sex or refractive error (R<0.08; P>=0.172). CONCLUSIONS: FD-OCT proved useful for the noninvasive measurement of TIA and TM metrics in children. Spherical error was the main determinant of TIA. PMID- 28719418 TI - Comparison of Glaucoma Progression Between Unilateral and Bilateral Disc Hemorrhage Eyes and Associated Risk Factors for Progression. AB - PURPOSE: To compare glaucoma progression between unilateral and bilateral disc hemorrhage (DH) eyes and to determine the associated risk factors. METHODS: A total of 78 bilateral primary open-angle glaucoma (POAG) patients who had shown one or more occurrences of DH (48 eyes of 38 unilateral DH patients and 30 eyes of 30 bilateral DH patients) were included. Glaucoma progression was defined by visual field (VF) deterioration. The mean VF global indices progression rates in the pre-DH, post-DH and total follow-up periods were compared between the unilateral and bilateral DH groups. The cumulative probability of glaucoma progression between the 2 groups was compared by the Kaplan-Meier survival analysis. Univariate and multivariate Cox proportional hazard models were used to identify the risk factors for glaucoma progression. RESULTS: Among the mean VF global indices progression rates, only the mean pattern standard deviation progression rate showed a statistically significant difference between the groups (unilateral DH group: 0.30+/-0.38 dB/y; bilateral DH group: 0.13+/-0.27 dB/y) (P=0.042). The Kaplan-Meier analysis revealed a greater cumulative probability of progression in the unilateral than in the bilateral DH group (P=0.008). The multivariate Cox's proportional hazard model indicated unilaterality of DH to be a factor associated with glaucoma progression (hazard ratio, 2.587; P=0.030). CONCLUSIONS: In bilateral POAG patients with DH, unilaterality of DH is associated with glaucoma progression. Therefore, clinicians need to perform careful and frequent follow-up on bilateral POAG patients showing DH in only 1 eye during the follow-up period. PMID- 28719419 TI - In Reply. PMID- 28719420 TI - The bidirectional relationship between vasomotor symptoms and depression across the menopausal transition: a systematic review of longitudinal studies. AB - OBJECTIVE: To explore the nature of the bidirectional relationship between vasomotor symptoms (VMS) and depression, and to determine whether hot flashes and night sweats differentially affect the association between VMS and depression through their effect on sleep disruption. METHODS: Multiple databases were searched from 1961 until July 31, 2016, and a manual search of reference lists of identified articles was conducted. Sixteen articles that involved 10,008 participants were identified and analyzed. RESULTS: The methods of analyses and measurement of VMS and depression varied across the studies. Two studies explored the bidirectional association, but only one was significant in both directions (odds ratio [OR] depression to VMS 3.06, 95% confidence interval [CI] 1.43-6.58; OR VMS to depression 8.88, 95% CI 2.57-30.68). In both cases, the association between VMS leading to depressive symptoms was stronger than the opposite. Eleven studies examined VMS leading to depression, but only five showed a significant effect (OR 1.57-1.81, P <= 0.02). Treating VMS and depressive symptoms as continuous variables (n = 3) diminished the relationship. Three studies showed a significant association of depression leading to VMS (OR 1.62-1.94, P <= 0.01). We found little evidence for a specific effect of night sweats on the association between VMS and depressive symptoms. The effect might not be related to sleep disruption. CONCLUSIONS: There is a bidirectional association between VMS and depressive symptoms. The menopausal transition appears to increase the risk of recurrent episodes of depression that might not be explained only by VMS. Further investigation is needed to explain the differential effect of night sweats and hot flashes on depression. PMID- 28719422 TI - Polarity-independent effects of transcranial direct current stimulation over the bilateral opercular somatosensory region: a magnetoencephalography study. AB - The opercular somatosensory region (OP) plays an indispensable role in pain perception. In the present study, we investigated the neurophysiological effects of transcranial direct current stimulation (tDCS) over the OP. Somatosensory evoked magnetic fields following noxious intraepidermal electrical stimulation to the left index finger (pain-SEFs) were recorded before and after tDCS with a single-blind, sham-controlled, cross-over trial design. Three tDCS conditions of left anodal/right cathodal tDCS, left cathodal/right anodal tDCS (each, 2 mA, 12 min), and sham tDCS (2 mA, 15 s) were applied. Despite the subjective pain sensation being unaltered, the two anodal (real) interventions significantly decreased OP activity associated with pain-SEFs. In conclusion, tDCS over the OP with the present parameters did not have a significant impact on pain sensation, but modulated its cortical processing. PMID- 28719421 TI - Lifelong estradiol exposure and risk of depressive symptoms during the transition to menopause and postmenopause. AB - OBJECTIVE: Depression risk increases during the menopausal transition (MT) and initial postmenopausal years-both times of significant fluctuations of estrogen. Research to date provides limited support for the hypothesis that estrogen fluctuations play a role in the greater susceptibility to midlife depression. Importantly, not all women report depressive symptoms during the MT, and recent reports suggest that duration of exposure to estradiol throughout the adult years may also play a role in vulnerability to depression. This study examines patterns of estrogen exposure during the reproductive years and risk of depression during the MT and early postmenopausal years. METHODS: A longitudinal, US community based, multiethnic study of menopause. Data were collected at baseline and annually for 10 years, and included 1,306 regularly menstruating premenopausal women, aged 42 to 52 years at study entry. The main outcome was incidence of high level of depressive symptoms, Center for Epidemiological Studies Depression Scale (CES-D) score at least 16, in the MT and initial postmenopausal years, independent of premenopausal depression symptoms. Risk factors examined were duration of estrogen exposure (menarche to MT), duration of hormonal birth control use, pregnancies, and lactation. RESULTS: In a multivariate adjusted model, longer duration of estrogen exposure from menarche to MT onset was significantly associated with a reduced risk of depression (CES-D >=16) during the MT and 10 years or less postmenopause (odds ratio 0.85, 95% confidence interval 0.78-0.92). Longer duration of birth control use was associated with a decreased risk of CES-D at least 16 (odds ratio 0.90, 95% confidence interval 0.83-0.98), but number of pregnancies or breastfeeding was not. CONCLUSIONS: Patterns of reproductive lifetime exposure to estrogen are associated with risk of high depressive symptoms during the MT and initial postmenopausal years; longer exposure to estrogen seemed protective. PMID- 28719423 TI - Sleepwalking Is Associated With Coadministration of Olanzapine and Propranolol: A Case Report. PMID- 28719424 TI - Excessive and Frequent Menstrual Bleeding With Methylphenidate in an Adolescent Girl With Attention-Deficit Hyperactivity Disorder. PMID- 28719426 TI - Blunt Traumatic Injury to the Aortic Root and Aortic Valve. PMID- 28719425 TI - Organizational Contributors to the Variation in Red Blood Cell Transfusion Practices in Cardiac Surgery: Survey Results From the State of Michigan. AB - BACKGROUND: While large volumes of red blood cell transfusions are given to preserve life for cardiac surgical patients, indications for lower volume transfusions (1-2 units) are less well understood. We evaluated the relationship between center-level organizational blood management practices and center-level variability in low volume transfusion rates. METHODS: All 33 nonfederal, Michigan cardiac surgical programs were surveyed about their blood management practices for isolated, nonemergent coronary bypass procedures, including: (1) presence and structure of a patient blood management program, (2) policies and procedures, and (3) audit and feedback practices. Practices were compared across low (N = 14, rate: 0.8%-10.1%) and high (N = 18, rate: 11.0%-26.3%) transfusion rate centers. RESULTS: Thirty-two (97.0%) of 33 institutions participated in this study. No statistical differences in organizational practices were identified between low- and high-rate groups, including: (1) the membership composition of patient blood management programs among those reporting having a blood management committee (P= .27-1.0), (2) the presence of available red blood cell units within the operating room (4 of 14 low-rate versus 2 of 18 high-rate centers report that they store no units per surgical case, P= .36), and (3) the frequency of internal benchmarking reporting about blood management audit and feedback practices (low rate: 8 of 14 versus high rate: 9 of 18; P= .43). CONCLUSIONS: We did not identify meaningful differences in organizational practices between low- and high-rate intraoperative transfusion centers. While a larger sample size may have been able to identify differences in organizational practices, efforts to reduce variation in 1- to 2 unit, intraoperative transfusions may benefit from evaluating other determinants, including organizational culture and provider transfusion practices. PMID- 28719427 TI - Opioid Reduction Following Interventional Procedures for Chronic Pain: A Synthesis of the Evidence. AB - The past decade has witnessed the tremendous growth of procedures to treat chronic pain, which has resulted in increased third-party scrutiny. Although most of these procedures appear to be associated with significant pain relief, at least in the short and intermediate term, their ability to improve secondary outcome measures, including function and work status is less clear-cut. One of these secondary outcome measures that has garnered substantial interest in the pain and general medical communities is whether interventions can reduce opioid intake, which is associated with significant risks that in most cases outweigh the benefits in the long term. In the article, we examine whether procedural interventions for chronic pain can reduce opioid intake. Most studies that have examined analgesic reduction as a secondary outcome measure have not separated opioid and nonopioid analgesics, and, among those studies that have, few have demonstrated between-group differences. Reasons for failure to demonstrate opioid reduction can be broadly classified into procedural, design-related, clinical, psychosocial, biological, and pharmacological categories, all of which are discussed. In the future, clinical trials in which this outcome is examined should be designed to evaluate this, at least on a preliminary basis. PMID- 28719428 TI - Blood Product Utilization Among Trauma and Nontrauma Massive Transfusion Protocols at an Urban Academic Medical Center. AB - BACKGROUND: Hospital-wide massive transfusion protocols (MTPs) primarily designed for trauma patients may lead to excess blood products being prepared for nontrauma patients. This study characterized blood product utilization among distinct trauma and nontrauma MTPs at a large, urban academic medical center. METHODS: A retrospective study of blood product utilization was conducted in patients who required an MTP activation between January 2011 and December 2015 at an urban academic medical center. Trauma MTP containers included 6 red blood cell (RBC) units, 5 plasma units, and 1 unit of apheresis platelets. Nontrauma MTP containers included 6 RBC and 3 plasma units. RESULTS: There were 334 trauma MTP activations, 233 nontrauma MTP activations, and 77 nontrauma MTP activations that subsequently switched to a trauma MTP ("switched activations"). All nontrauma MTP activations were among bleeding patients who did not have a traumatic injury (100% [233/233]). Few patients with a nontrauma activation required ad hoc transfusion of RBC units (1.3% [95% confidence interval {CI}, 0.3%-3.7%]) or plasma (3.4% [95% CI, 1.5%-6.7%]), and only 45.5% (95% CI, 39.0%-52.1%) required ad hoc transfusion of apheresis platelets. Compared to trauma and switched activations, nontrauma activations transfused a lower median number of RBC, plasma, and apheresis platelet units (P < .001 for all comparisons). There was also a lower median number of prepared but unused plasma units for nontrauma activations (3; [interquartile range {IQR}, 3-5]) compared to trauma (7; [IQR, 5 10]; P < .001) and switched activations (8; [IQR, 5-11]; P < .001). The median number of unused apheresis platelet units was 1 (IQR, 1-2) for trauma activations and 0 (IQR, 0-1) for switched activations. There was a high proportion of trauma and switched activations in which all of the prepared apheresis platelet units were unused (28.1% [95% CI, 23.4%-33.3%] and 9.1% [95% CI, 3.7%-17.8%], respectively). CONCLUSIONS: The majority of initial nontrauma MTP activations did not require a switch to a trauma MTP. Patients remaining under a nontrauma MTP activation were associated with a lower number of transfused and unused plasma and apheresis platelet units. Future studies evaluating the use of hospital-wide nontrauma MTPs are warranted since an MTP designed for nontrauma patient populations may yield a key strategy to optimize blood product utilization in comparison to a universal MTP for both trauma and nontrauma patients. PMID- 28719429 TI - Maternal Salvage With Extracorporeal Life Support: Lessons Learned in a Single Center. AB - The American Heart Association scientific statement on cardiac arrest in pregnancy did not endorse extracorporeal life support for lack of cohort data. We studied all pregnancy and peripartum cases of extracorporeal life support in 1 medical center (n = 11), including collapse due to infection (n = 6, 55%), thromboembolism (n = 3, 27%), and cardiac disease (n = 2, 18%). Half of the cases (n = 5, 45%) involved extracorporeal cardiopulmonary resuscitation. Most mothers survived (n = 7, 64% [95% confidence interval, 32%-88%]). Deaths were attributable to oxygenator blockage (n = 1) and late sepsis (n = 3). The 2 unique clinical challenges were maintenance of high peripartum cardiac outputs and balancing anticoagulation with hemostasis. PMID- 28719430 TI - High-Sensitivity Cardiac Troponin T Improves the Diagnosis of Perioperative MI. AB - BACKGROUND: The diagnosis of myocardial infarction (MI) after noncardiac surgery has traditionally relied on using relatively insensitive contemporary cardiac troponin (cTn) assays. We hypothesized that using a recently introduced novel high-sensitivity cTnT (hscTnT) assay would increase the detection rate of perioperative MI. METHODS: In this ancillary study of the Vitamins in Nitrous Oxide trial, readjudicated incidence rates of myocardial injury (new isolated cTn elevation) and MI were compared when diagnosed by contemporary cTnI versus hscTnT. We probed various relative (eg, >50%) or absolute (eg, +5 ng/L) hscTnT change metrics. Inclusion criteria for this ancillary study were the presence of a baseline and at least 1 postoperative hscTnT value. RESULTS: Among 605 patients, 70 patients (12%) had electrocardiogram changes consistent with myocardial ischemia; 82 patients (14%) had myocardial injury diagnosed by contemporary cTnI, 31 (5.1%) of which had an adjudicated MI. After readjudication, 67 patients (11%) were diagnosed with MI when using hscTnT, a 2 fold increase. Incidence rates of postoperative myocardial injury ranged from 12% (n = 73) to 65% (n = 393) depending on the hscTnT metric used. Incidence rates of MI using various hscTnT change metrics and the presence of ischemic electrocardiogram changes, but without event adjudication, ranged from 3.6% (n = 22) to 12% (n = 74), a >3-fold difference. New postoperative hscTnT elevation, either by absolute or relative hscTnT change metric, was associated with an up to 5-fold increase in 6-month mortality. CONCLUSIONS: The use of hscTnT compared to contemporary cTnI increases the detection rate of perioperative MI by a factor of 2. Using different absolute or relative hscTnT change metrics may lead to under- or overdiagnosis of perioperative MI. PMID- 28719431 TI - Bispectral Index Measurements Are Not Degraded During Aeromedical Evacuations. AB - For a decade, depth of anesthesia monitoring has become a reality in the operating room. It provides valuable help for managing anesthesia, especially for unstable patients. This might be particularly relevant during aeromedical evacuation. In this study, we aimed to assess the validity of the bispectral index (BIS) during long-range patient transportation aboard fixed-wing aircraft. BIS was recorded in 30 patients, 25 under anesthesia and 5 awake, during aeromedical evacuations performed by the French Air Force. BIS index was available and analyzable (signal quality index above 50%) more than 90% of time. Despite potential pitfalls related to mechanical or electrical interference, BIS monitor can be reliably used to monitor depth of anesthesia during individual strategic aeromedical evacuations. PMID- 28719433 TI - Cutaneous Atypical Neurofibroma: A Case Report and Review of Literature. PMID- 28719434 TI - Primary Cutaneous Small/Medium CD4+ T-CELL Lymphoproliferative Disorder Occurring in a Patient With Metastatic Melanoma. AB - Therapeutic agents designed to stimulate the immune system are now cornerstones in the treatment of metastatic melanoma. These drugs promote lymphocyte growth and survival, which could plausibly result in clinical lymphoproliferative disorders. We report the case of a 62-year-old female with metastatic melanoma who developed primary cutaneous small/medium CD4 T-cell lymphoproliferative disorder (PC-SMTCL) after treatment with vemurafenib and recombinant high-dose interleukin-2 (IL-2). The patient developed a painless red papule behind the ear. A biopsy showed a dense population of CD4 lymphocytes with a T-follicular helper cell phenotype. Molecular studies confirmed the presence of a clonal population of T cells, and the process was classified as PC-SMTCL. The patient was diagnosed with metastatic melanoma approximately 3 years before the development of the cutaneous lymphoma and had been treated with vemurafenib followed by 2 courses of IL-2. The patient's last course of IL-2 was completed in April of 2013. She developed the cutaneous lymphoma behind her ear in December of 2015. An association between PC-SMTCL and vemurafenib treatment for advanced melanoma has been reported previously in one patient; however, an association between PC-SMTCL and IL-2 treatment has not been documented. The immunostimulatory properties of IL-2 or vemurafenib may be responsible for the development of PC-SMTCL in our patient. Additionally, antigenic stimulation of the immune system by melanoma itself could contribute to clonal selection of lymphocytes. PMID- 28719435 TI - Leukocytoclastic Vasculitis and Dermal Perivascular Hemophagocytosis Associated With Adalimumab Therapy for Rheumatoid Arthritis. AB - Tumor necrosis factor (TNF)-alpha inhibitors target TNF-alpha to effectively treat autoimmune inflammatory conditions, such as rheumatoid arthritis. However, many cases of cutaneous and systemic vasculitis related to TNF-alpha inhibitors have been reported in the literature. Here, the authors report the first case of a 61-year-old Japanese woman who developed leukocytoclastic vasculitis with cutaneous perivascular hemophagocytosis, which was related to elevated cytokines and immune complexes after initiating adalimumab for rheumatoid arthritis without evidence of hemophagocytic syndrome and rarely encountered in the skin. The patient was successfully treated by discontinuing adalimumab and initiating corticosteroid therapy, which should be considered as the treatment of choice. We believe that our case confirms and adds to the evidence pertaining to the involvement of TNF-alpha in dermal perivascular hemophagocytosis, a histologic finding rarely observed in the skin. PMID- 28719436 TI - Melanocytic Nevus Does Not Metastasize! PMID- 28719437 TI - A 12-Day-Old Male With a "Skin Tag" on the Chin. PMID- 28719438 TI - Comparative Analysis of Chilblain Lupus Erythematosus and Idiopathic Perniosis: Histopathologic Features and Immunohistochemistry for CD123 and CD30. AB - Distinction of chilblain lupus erythematosus (CLE) from idiopathic perniosis (IP) could predict an underlying connective tissue disease; however, histopathologic discrimination of the two is difficult. Increased CD123 plasmacytoid dendritic cells and CD30 lymphocytes have been demonstrated in various forms of cutaneous lupus erythematosus and IP, respectively. To our knowledge, CD123 and CD30 have not been examined in CLE. Our objective was to identify helpful histopathologic and immunohistochemical features in distinguishing CLE and IP. Skin biopsies classified as CLE (n = 20) and IP (n = 39) based on clinicopathologic correlation were collected from 2000 to 2015. Various histopathologic features were examined on hematoxylin and eosin and alcian blue stains. CD123 and CD30 immunostains were performed and characterized. We identified dermal interstitial fibrin exudate (P = 0.0352) and increased dermal mucin (P = 0.0002) as features significantly associated with CLE. Other histopathologic features and CD123 failed to distinguish between groups. CD30 lymphocytes were sparse in all cases. Despite being the largest series of CLE and IP to date, the number of CLE cases in this study remained relatively limited, and some patients in the IP group may have yet to develop diagnostic features of systemic lupus erythematosus. In conclusion, histopathologic distinction between CLE and IP remains challenging. Interstitial fibrin and abundant dermal mucin help favor CLE. The number and distribution of CD123 plasmacytoid dendritic cells and CD30 lymphocytes have no discriminatory role. PMID- 28719439 TI - Papulonodular Eruption on the Hands in a Patient With Arthritis: Challenge. PMID- 28719440 TI - Onychomatricoma in a Patient With Extensive Vitiligo. PMID- 28719442 TI - Social Media and Pathology: Where Are We Now and Why Does it Matter? AB - Social media has exploded in popularity in recent years. It is a powerful new tool for networking, collaborating, and for the communication and evolution of ideas. It has been increasingly used for business purposes and is now being embraced by physicians including pathologists. Pathology professional organizations and even peer-reviewed pathology journals are now beginning to use social media, as well. There are multiple social media platforms, including Twitter, Facebook, Instagram, LinkedIn, and others. Each platform has different audiences and different ways to share content and interact with other users. This paper discusses the different social media platforms and how they are being used in pathology currently. PMID- 28719441 TI - Fourteen Day In Vivo Testing of a Compliant Thoracic Artificial Lung. AB - The compliant thoracic artificial lung (cTAL) has been studied in acute in vivo and in vitro experiments. The cTAL's long-term function and potential use as a bridge to lung transplantation are assessed presently. The cTAL without anticoagulant coatings was attached to sheep (n = 5) via the pulmonary artery and left atrium for 14 days. Systemic heparin anticoagulation was used. Compliant thoracic artificial lung resistance, cTAL gas exchange, hematologic parameters, and organ function were recorded. Two sheep were euthanized for nondevice-related issues. The cTAL's resistance averaged 1.04 +/- 0.05 mmHg/(L/min) with no statistically significant increases. The cTAL transferred 180 +/- 8 ml/min of oxygen with 3.18 +/- 0.05 L/min of blood flow. Except for transient surgical effects, organ function markers were largely unchanged. Necropsies revealed pulmonary edema and atelectasis but no other derangements. Hemoglobin levels dropped with device attachment but remained steady at 9.0 +/- 0.1 g/dl thereafter. In a 14 day experiment, the cTAL without anticoagulant coatings exhibited minimal clot formation. Sheep physiology was largely unchanged except for device attachment-related hemodilution. This suggests that patients treated with the cTAL should not require multiple blood transfusions. Once tested with anticoagulant coatings and plasma resistant gas exchange fiber, the cTAL could serve as a bridge to transplantation. PMID- 28719443 TI - 18F-FDG PET/CT Scan Can Predate Clinical Presentation in Acute Appendicitis. AB - Acute appendicitis is a clinical diagnosis typically presenting with right lower quadrant pain. We describe the case of an asymptomatic 53-year-old man with stage 2A diffuse large B-cell lymphoma, who underwent F-FDG PET/CT at the completion of chemotherapy. The scan showed complete lymphomatous disease remission. Incidentally, there was increased FDG uptake in a tubular structure adjacent to the cecum. Clinical examination was negative. Subsequently, the patient presented 6 days later with typical acute appendicitis symptoms. This case is interesting wherein increased FDG uptake in the appendix predated the appearance of clinical symptoms. PMID- 28719444 TI - Oligometastatic Stomach Carcinoma From Lung Squamous Cell Carcinoma Detected by 18F-FDG PET/CT. AB - Metastasis from squamous cell carcinoma of the lung to the stomach is extremely rare. F-FDG PET/CT demonstrated intense F-FDG uptake in the lower lobe of the left lung, stomach, and mediastinal lymph node in a 61-year-old man. Lower lobe of the left lung resection, mediastinal lymphadenectomy, partial gastrectomy, and esophagogastric anastomosis was performed. Immunohistochemical studies revealed squamous cell lung carcinoma in the left lung and metastatic carcinoma of gastric and lymph nodes. The present case further demonstrated the value of F-FDG PET/CT in the staging of malignant disease. PMID- 28719445 TI - Adefovir-Induced Hypophosphatemic Osteomalacia Mimicking Bone Metastases From Primary Hepatocarcinoma. AB - Adefovir-induced hypophosphatemic osteomalacia in the context of hepatocarcinoma is rare and needs to be differentiated from metastatic hepatocarcinoma. We here report a case of severe osteomalacia whose focal uptakes of radiotracer on the Tc MDP SPECT/CT images mimicked that of metastatic hepatocarcinoma. PMID- 28719446 TI - Tophaceous Gout of the Lumbar Spine Mimicking Malignancy on FDG PET/CT. AB - A 46-year-old man with over a 10-year history of gout complained of progressive bilateral buttock pain with numbness of legs for 4 months. Serum uric acid level was elevated. Lumbar radiographs showed decreased density of the bilateral L4-L5 facet joints. CT showed lytic lesions of the facet joints with hyperdense periarticular lesions. Enhanced MRI showed marked enhancement of these lesions. FDG PET/CT showed avid FDG uptake of the bony and periarticular lesions with SUVmax of 16.8. A decompressive posterior lumbar laminectomy with periarticular lesion resection was performed. Histopathologic findings of the periarticular lesions were consistent with tophaceous gout. PMID- 28719447 TI - Diffuse Increased Sodium Fluoride Gastric Activity in a Patient With Hypercalcemia. AB - Increased extraosseous uptake of sodium fluoride can be visualized because of many different etiologies. A 62-year-old man with a history of osteoporosis had an F-sodium fluoride PET/CT scan for accessing chest pain caused by an accident. The images showed multiple fractures. Unexpectedly, diffuse activity was noted in the gastric wall, which was suggestive of possible hypercalcemia. The serum calcium level confirmed the patient had hypercalcemia. PMID- 28719448 TI - Biopsy-Proven Diffuse Mediastinal Prostate Cancer Metastases Negative on 18F Fluorocholine, Diagnosed on 68Ga-PSMA and 18F-PSMA PET/CT. AB - A 72-year-old man with prostate cancer (stage T3b, Gleason score 7) treated by radical prostatectomy was found to have biochemical failure (prostate-specific antigen 8.5 ng/mL) and a suspicious growing nodularity at the left prostate bed on MRI. F-fluorocholine PET/CT failed to demonstrate any site of uptake suggestive of malignancy. A bone scan did exclude bone metastases. Ga-PSMA PET/CT revealed various positive lymph nodes in the supraclavicular, mediastinal, and hilar regions. This was confirmed on F-DCFPyl PET/CT, with the addition of a suspicious right axillary lymph node. Mediastinal biopsy confirmed metastatic prostate cancer. PMID- 28719449 TI - 68Ga-DOTATATE Uptake in Solitary Pancreatic Metastasis From Clear Cell Renal Cancer. AB - A 64-year-old man with a lesion of the pancreatic tail was referred for Ga DOTATATE PET/CT imaging. His medical history included previous metastatic clear cell renal cell cancer. Ga-DOTATATE PET/CT demonstrated increased DOTATATE uptake (SUVmax 10.5) in a pancreatic tail lesion. Histopathology of the resected lesion confirmed clear renal cell cancer metastasis. This case illustrates that clear cell renal cancer metastasis can demonstrate Ga-DOTATATE accumulation. PMID- 28719450 TI - Combination of 177Lu-PSMA-617 and External Radiotherapy for the Treatment of Cerebral Metastases in Patients With Castration-Resistant Metastatic Prostate Cancer. AB - Two castration-resistant prostate cancer patients, both with cerebral and visceral and lymphatic metastases, received multiple cycles of Lu-PSMA-617 treatments. The prognosis of both cases is dependent on brain metastases. Between Lu-PSMA-617 treatment cycles, local radiotherapy was also applied to the brain metastases. Prior to the combined therapy, all systemic metastases, including cerebral lesions, showed PSMA expression using Ga-PSMA PET/CT. Under the combined therapy, all the metastases, particularly the cerebral lesions, showed significant regression in size and PSMA expression over time. PMID- 28719452 TI - Treatment of Spinal Tumors in a High Volume Center has Direct Impact on Local Recurrence, Morbidity, and Mortality. AB - OBJECTIVE OF THE STUDY: En bloc resections of spine tumors aim at locally controlling the disease for both improving the patient's quality of life as well as improving mortality. The purpose of this study was to compare the outcome between patients who were initially treated in a high volume specialized center, and patients who initially underwent either invasive diagnostic procedure or an initial surgical attempt to treat the disease in a different center. MATERIALS AND METHODS: A retrospective study of 1681 patients affected by spine tumors treated from 1990 to 2015 by the same team. RESULTS: A total of 220 en bloc resections that were performed on 216 patients during that period. Most of the tumors were primary-165 cases (43 benign and 122 malignant), metastases occurred in 55 cases. One hundred sixty-eight patients (77.8%) were solely treated in the institute and were considered noncontaminated cases (NCCs) and 48 (22.2%) were previously treated elsewhere and were considered contaminated cases (CCs). Median follow-up was 45 months (0-371).Thirty-three local recurrences (15.28%) were recorded. Fourteen patients (29.17%) from the CC and 19 (11.31%) from the NCC group.A total of 153 complications were observed in 100 out of 216 patients (46.2%). Sixty-four of these patients (30%) suffered 1 complication, while the rest had 2 or more. Twenty-eight (58%) of the CC group and 72 (42.85%) of the NCC group, had at least 1 complication.Sixty patients died as a result of the disease during the follow-up period. Twenty-one (43.75%) and 39 (23.21%) patients died in the CC and NCC cohorts, respectively.CC, surgical margins of the resected tumor intralesional, marginal, and malignant tumors, were statistically significant independent risk factors for local recurrence of the tumor. Contamination, local recurrence, neoadjuvant radiotherapy, the number of level resected, and metastatic tumors compared with primary malignant tumor, were shown to be independent risk factors for patient's death. CONCLUSIONS: It is apparent that there is a substantial added risk in performing either invasive diagnostic procedures or attempting a surgical resection of the tumor in a nonspecialized center. This risk includes both higher recurrences of the tumor as well as increased mortality. It is therefore reasonable to conclude that the whole treatment, from biopsy to resection, should be performed in the same center, and this center should be a high volume, specialized in treating these type of spine pathologies.The surgeon who treats the patient first has a great responsibility, as it is the first treatment that most affects prognosis. To reduce the chance of local recurrence, morbidity, and mortality, all invasive diagnosis and treatment, should be performed by an experienced team, as the consequences are dramatic. PMID- 28719453 TI - Reliability and Clinical Utility of the CARDS Classification for Degenerative Spondylolisthesis. AB - STUDY DESIGN: Retrospective cohort study. OBJECTIVE: The objective of this study is to determine the reliability and clinical utility of the of the proposed CARDS classification for degenerative spondylolisthesis. BACKGROUND: The Clinical and Radiographic Degenerative Spondylolisthesis (CARDS) classification system was recently proposed as an alternative to the Meyerding system for classifying degenerative spondylolisthesis (DS). Unlike Meyerding, CARDS considers other relevant radiographic findings such as disk space collapse and segmental kyphosis to stratify DS into 4 radiographically discreet types. Currently, no studies have been conducted to assess the clinical utility of the CARDS system. METHODS: A total of 78 consecutive surgical patients with L4-L5 DS were rated as CARDS types A through D and Fleiss' kappa for interobserver agreement was calculated. Then, demographics as well as preoperative and postoperative outcome scores (ODI, SF-12 mental and physical, VAS) were collected. The Kruskal-Wallis test was used to detect significant differences amongst CARDS types. An unpaired t test was used to compare individual CARDS types with all other subtypes combined. RESULTS: Grading showed: 4 type A, 19 type B, 45 type C, and 8 type D (k=0.63). There was a statistically significant difference in preoperative back pain (P=0.046) between groups. CARDS type D had the highest mean back pain scores (8.8) of all subtypes which was significantly higher than mean back pain for all other subtypes combined (P=0.016). CARDS D showed the largest degree of improvement in all outcome measures. There was a trend towards an increased improvement in ODI (P=0.074) and SF-12 MCS (P=0.095) in the CARDS D subtype relative to the rest of the cohort. CONCLUSIONS: The CARDS classification system represents a reliable method for classifying cases of DS. Our results indicate that kyphotic segmental alignment (CARDS D) may be a less common, yet clinically distinct subset of DS characterized by worse preoperative back pain. CARDS type D cases may also show a greater degree of improvement in multiple outcome measures following surgical intervention. PMID- 28719454 TI - The Difference in Clinical Outcomes After Anterior Cervical Fusion, Disk Replacement, and Foraminotomy in Professional Athletes. AB - STUDY DESIGN: Retrospective case series. OBJECT: To compare postoperative outcomes of professional athletes treated for cervical disk herniation after anterior cervical discectomy and fusion (ACDF) and posterior foraminotomy (PF), or total disk replacement (TDR). SUMMARY OF BACKGROUND DATA: ACDF, PF, and TDR have all led to excellent outcomes in the general population but the unique demands in the professional athlete necessitate specific study. METHODS: Athletes of 4 major American professional sports leagues-National Football League, Major League Baseball, National Hockey League and National Basketball Association diagnosed with cervical disk herniation and managed operatively were identified. Athletes were grouped into cohorts based on operation type. Athlete performance outcome measures were calculated based on sport-specific statistics and assessed as a percentage change after surgery to standardize comparison across sports. RESULTS: A total of 101 professional athletes were identified (ACDF=86, PF=13, and TDR=2). The PF cohort had a significantly greater return to play rate and shortest time to return after surgery (P=0.03 and P=0.04, respectively). However, the reoperation rate at the index level was significantly higher in PF athletes compared with ACDF (46.2% vs. 5.8%; P<0.001) over the study follow-up period (average, 13.5 y). There was no significant difference in performance score after surgery for all surgical cohorts (P=0.41) and among cohorts (P=0.41). When analyzed by sport only baseball athletes experienced a significant decrease in performance after surgery (P=0.049). CONCLUSIONS: ACDF and PF are both viable options with excellent outcomes in professional athletes. PF allows a significantly higher rate and quicker return to play but portends a higher risk for reoperation compared with ACDF. TDR results are limited in our cohort and require further study to determine professional athlete outcomes. LEVEL OF EVIDENCE: Level IV. PMID- 28719455 TI - Microscope and Fiberscope-assisted Subarachnoid-Subarachnoid (S-S) Bypass: A Novel Surgical Technique to Reestablish Cerebrospinal Fluid Flow in Treating Dorsal Spinal Arachnoid Webs, Diagnosed by Cine-MRI. AB - A "dorsal spinal arachnoid web" is the thickened arachnoid band on the surface of the spinal cord which disturbs the cerebrospinal fluid (CSF) flow, known as a rare cause of thoracic myelopathy. The ideal treatment is controversial because of the risk of readhesion after simple resection of the web. A subarachnoid subarachnoid bypass is a method to reestablish CSF flow through a silicon tube between the cranial and caudal subarachnoid space. This method is reported to be useful for traumatic syringomyelia, adhesive arachnoiditis, etc. We applied this technique for arachnoid webs with the assistance of a microscope and fiberscope. After a dura incision, the thickened arachnoid web can be seen fluttering within the CSF flow inside the arachnoid space, which partitions the subarachnoid space into cranial and caudal parts. After opening the subarachnoid space and resection of the web under a microscope, the fiberscope is inserted toward the cranial and caudal directions to check for the presence of another arachnoid web. If another web is found, it is penetrated using a guiding wire. Then, a silicone tube is inserted into the cranial and caudal normal subarachnoid space. In this paper, we would like to introduce this technique. PMID- 28719456 TI - Warning criteria for intraoperative neurophysiologic monitoring. AB - PURPOSE OF REVIEW: Intraoperative changes in somatosensory (SEP) and motor evoked potentials (MEPs) may indicate potential injury to the spinal cord and will require timely intervention to prevent permanent damage. This review focuses on the validity of currently recommended warning criteria for intraoperative evoked potential monitoring. RECENT FINDINGS: Current guideline recommends a decrease in SEP amplitude by 50% and MEP amplitude by 50-100% as warning signals for injury to the ascending sensory and descending motor pathway, respectively. On the basis of cohort studies, the diagnostic accuracy of SEP and MEP to predict postoperative neurologic deficits was variable. Importantly, 0.1-4.1% of monitored patients suffered postoperative neurologic deficit despite apparently normal SEP and MEP recordings (i.e. false negative events). These data suggested that the true warning criteria may be lower than previously acknowledged. A systematic review of studies that reported changes in SEP or MEP monitoring and postoperative neurological outcome showed an association between changes in monitoring signals and postoperative neurological deficits. However, the confidence intervals were wide and it is not possible to determine a threshold value in SEP or MEP amplitude beyond which may indicate neurologic deficit. SUMMARY: Current recommendations for warning criteria during intraoperative evoked potential monitoring are empirically derived. Until a threshold that predicts spinal cord injury can be accurately determined, it remains difficult to define the clinical utility of intraoperative neurophysiologic monitoring. PMID- 28719457 TI - Regional anesthesia in diabetic peripheral neuropathy. AB - PURPOSE OF REVIEW: The aim of this review is to summarize recent relevant literature regarding regional anesthesia in the diabetic neuropathic patient and formulate recommendations for clinical practice. RECENT FINDINGS: Diabetic neuropathic nerves, but not nerves of diabetic patients per se, exhibit complex functional changes. As a result, they seem more sensitive to local anesthetics, and are more difficult to stimulate. When catheters are used postoperatively, diabetes is an independent risk factor for infection. SUMMARY: The pathophysiologic mechanisms underlying diabetic polyneuropathy are complex. Several pathways are thought to contribute to the development of diabetic neuropathy, triggered most importantly by chronic hyperglycemia. The latter induces inflammation and oxidative stress, causing microvascular changes, local ischemia and decreased axonal conduction velocity. Regional anesthesia is different in patients with diabetic neuropathy in several regards. First, the electric stimulation threshold of the nerve is markedly increased whereby the risk for needle trauma in stimulator-guided nerve blocks is theoretically elevated. Second, the diabetic nerve is more sensitive to local anesthetics, which results in longer block duration. Third, local anesthetics have been conjectured to be more toxic in diabetic neuropathy but the evidence is equivocal and should not be a cause to deny regional anesthesia to patients with a valid indication. Lastly, when peripheral nerve catheters are used, diabetes is an independent predisposing factor for infection. PMID- 28719458 TI - Acupuncture for chronic pain: an update and critical overview. AB - PURPOSE OF REVIEW: Acupuncture is now recommended for several chronic pain conditions. Despite supportive evidence of its effectiveness, this ancient approach is often misunderstood, and may still be underused in mainstream practice. A critical review on its effectiveness and practice integration, and mechanisms of action is essential to the medical community that is continuing to seek nonopioid therapies for chronic pain. RECENT FINDINGS: Mounting evidence supports the effectiveness of acupuncture to treat chronic low back, neck, shoulder, and knee pain, as well as headaches. Additional data are emerging that support the use of acupuncture as an adjunct or alternative to opioids, and in perioperative settings. Findings related to its mechanisms of action include transient receptor potential cation channel vanilloid 1 activation in the periphery, microglial suppression in the cerebral cortex and spinal cord, and regulation of cytokines and other key inflammatory factors in the spinal cord. Incremental integration of acupuncture into pain medicine practices and training programmes continues to grow. SUMMARY: Acupuncture is effective, safe, and cost effective for treating several chronic pain conditions when performed by well trained healthcare professionals. Further studies on its use as an adjunct or alternative to opioids, and in perioperative settings are needed. PMID- 28719459 TI - Coagulation management in patients undergoing neurosurgical procedures. AB - PURPOSE OF REVIEW: Management of coagulation in neurosurgical procedures is challenging. In this contest, it is imperative to avoid further intracranial bleeding. Perioperative bleeding can be associated with a number of factors, including anticoagulant drugs and coagulation status but is also linked to the characteristic and the site of the intracranial disorder. The aim of this review will be to focus primarily on the new evidence regarding the management of coagulation in patients undergoing craniotomy for neurosurgical procedures. RECENT FINDINGS: Antihemostatic and anticoagulant drugs have shown to be associated with perioperative bleeding. On the other hand, an increased risk of venous thromboembolism and hypercoagulative state after elective and emergency neurosurgery, in particular after brain tumor surgery, has been described in several patients. To balance the risk between thrombosis and bleeding, it is important to be familiar with the perioperative changes in coagulation and with the recent management guidelines for anticoagulated patients undergoing neurosurgical procedures, in particular for those taking new direct anticoagulants. We have considered the current clinical trials and literature regarding both safety and efficacy of deep venous thrombosis prophylaxis in the neurosurgical population. These were mainly trials concerning both elective surgical and intensive care patients with a poor grade intracranial bleed or multiple traumas with an associated severe traumatic brain injury (TBI). SUMMARY: Coagulation management remains a major issue in patients undergoing neurosurgical procedures. However, in this field of research, literature quality is poor and further studies are necessary to identify the best strategies to minimize risks in this group of patients. PMID- 28719460 TI - The Association Between Perceived Stress and Low Back Pain Among Eldercare Workers in Japan. AB - OBJECTIVE: We investigated the association between perceived stress and low back pain (LBP) among Japanese eldercare workers. METHODS: Self-reported questionnaires were completed regarding perceived stress (Perceived Stress Scale 14), presence of memorable LBP in the preceding month, and other relevant factors (age, sex, body mass index, smoking status, job demands, job control, and social support) among 954 eldercare workers. Univariate and multivariate logistic regression analysis were performed to estimate odds ratios (OR) and 95% confidence intervals (95%CI). RESULTS: Data from 571 eldercare workers were analyzed. In the multivariate logistic regression model, higher perceived stress was significantly associated with a higher prevalence of memorable LBP (adjusted OR [95% CI] = 1.05 [1.02 to 1.08]). CONCLUSIONS: Higher perceived stress was independently associated with LBP among eldercare workers. Our study indicates the importance of considering perceived stress as one of the factors related to LBP. PMID- 28719461 TI - Serotonin, ATRX, and DAXX Expression in Pituitary Adenomas: Markers in the Differential Diagnosis of Neuroendocrine Tumors of the Sellar Region. AB - Differential diagnosis based on morphology and immunohistochemistry between a clinically nonfunctioning pituitary neuroendocrine tumor (NET)/pituitary adenoma and a primary or secondary NET of nonpituitary origin in the sellar region may be difficult. Serotonin, a frequently expressed marker in the NETs, has not been systematically evaluated in pituitary NETs. Although mutations in ATRX or DAXX have been reported in a significant proportion of pancreatic NETs, the mutational status of ATRX and DAXX and their possible pathogenetic role in pituitary NETs are unknown. Facing a difficult diagnostic case of an invasive serotonin and adrenocorticotroph hormone immunoreactive NET in the sellar region, we explored the immunohistochemical expression of serotonin, ATRX, and DAXX in a large series of pituitary endocrine tumors of different types from 246 patients and in 2 corticotroph carcinomas. None of the pituitary tumors expressed serotonin, suggesting that serotonin immunoreactive sellar tumors represent primary or secondary NETs of nonpituitary origin. Normal expression of ATRX and DAXX in pituitary tumors suggests that ATRX and DAXX do not play a role in the pathogenesis of pituitary endocrine tumors that remain localized to the sellar and perisellar region. A lack of ATRX or DAXX in a sellar NET suggests a nonpituitary NET, probably of pancreatic origin. One of the 2 examined corticotroph carcinomas, however, demonstrated negative ATRX immunolabeling due to an ATRX gene mutation. Further studies on a larger cohort of pituitary carcinomas are needed to clarify whether ATRX mutations may contribute to the metastatic potential in a subset of pituitary NETs. PMID- 28719462 TI - Spindle Cell Lipomas in Women: A Report of 53 Cases. AB - Spindle cell lipomas (SCL) are typically tumors of the upper back/neck (shawl region) of men (80% to 90%). In general, there is a frequent tendency to restrict the diagnosis to this specific clinical scenario and a hesitancy to diagnose SCL in women. We hypothesized that SCL in women have a more varied presentation. A total of 395 SCL were diagnosed at our institution over the last 11 years. The diagnosis of SCL in women was confirmed by re-review. Immunohistochemical stains for CD34, desmin, estrogen receptor, and p16 were performed. In a subset, fluorescence in situ hybridization to detect Retinoblastoma1 (RB1) gene deletion was performed. Of 395 SCLs, 331 (86%) occurred in men; 53 (14%) occurred in women (11 cases excluded). Of the 64 SCL in women, 58 had available material. In total, 53 of 58 were confirmed as SCL. Women were younger at diagnosis (median, 51 y; range, 5 to 76 y) compared with men (64 y; range, 23 to 98 y), P<0.0001, t test. SCL in women typically occurred outside the shawl distribution (36/53, 68%) compared with men (95/331, 29%) (P<0.001), including extremities (16/53, 30% vs. 32/331, 10%) and face (11/53, 21% vs. 47/331, 14%). Dermal SCL in women were also relatively common (16/53, 30%). The cases demonstrated varying proportions of bland spindled cells, ropey collagen, myxoid matrix, and adipocytes. By immunohistochemistry, 46/46 were CD34, 48 of 48 were desmin negative, 33 of 42 were estrogen receptor negative, and 29 of 42 had loss of p16 expression. In total, 12 of 14 showed RB1 loss by fluorescence in situ hybridization. SCL in women frequently occurs in unconventional locations and in at a slightly younger patient age. PMID- 28719463 TI - Do Nonseminomatous Germ Cell Tumors of the Testis With Lymphovascular Invasion of the Spermatic Cord Merit Staging as pT3? AB - The staging of testicular nonseminomatous germ cell tumors (NSGCTs) with lymphovascular invasion (LVI) of the spermatic cord in the absence of cord parenchymal involvement remains controversial. Our previous study showed that tumors with spermatic cord LVI present at a higher clinical stage than tumors with LVI confined to the testis (pT2). We compared NSGCTs with LVI of the spermatic cord without direct involvement of the spermatic cord soft tissues to pT3 tumors to help clarify the appropriate staging of this histologic finding. A retrospective, multi-institutional review was performed to identify cases of NSGCTs with LVI in the spermatic cord without soft tissue invasion of the cord. The clinical-pathologic findings were compared with NSGCTs with spermatic cord soft tissue invasion (pT3). We identified 38 pT2 NSGCTs with LVI in the spermatic cord without soft tissue invasion of the cord and 89 pT3 tumors. There were no significant differences in patient age, tumor size, or clinical stage at presentation between the 2 groups. There were no significant differences in dominant histologic subtype, rete testis invasion, hilar soft tissue invasion, or margin status. There were no significant differences in disease recurrence/progression (P=0.63), recurrence/progression after chemotherapy (P=0.35), or death (P=0.51) between patients with only spermatic cord LVI versus patients with cord soft tissue invasion. In patients with pT2 NSGCTs according to the current staging, LVI in the spermatic cord without cord soft tissue invasion is comparable with pT3 tumors in terms of clinical stage at presentation as well as disease recurrence and survival. PMID- 28719464 TI - Nuclear CRX and FOXJ1 Expression Differentiates Non-Germ Cell Pineal Region Tumors and Supports the Ependymal Differentiation of Papillary Tumor of the Pineal Region. AB - Papillary tumor of the pineal region (PTPR) is a neuroepithelial neoplasm first described in 2003. Despite the anatomic association of PTPR with the pineal gland, the features of these tumors resemble those of the ependymal circumventricular subcommissural organ (SCO) of the posterior third ventricle. Given the presumed distinct derivation of PTPR and pineal parenchymal tumors, we hypothesized that expression of lineage-specific transcription factors could distinguish these tumors and provide additional insight into the differentiation of PTPR. A broad series of pineal region samples was reviewed, including 7 benign pineal glands, 4 pineal cysts, 13 pineocytomas, 28 pineal parenchymal tumors of intermediate differentiation, 11 pineoblastomas, and 18 PTPR. All samples were evaluated by immunohistochemistry for expression of CRX, a master transcriptional regulator of photoreceptor differentiation expressed in pineal gland and retina and/or FOXJ1, a master transcriptional regulator of ciliogenesis expressed in normal ependymal cells and ependymal neoplasms. Diffuse nuclear CRX expression is present in 100% of pineal samples. FOXJ1 is negative in all pineal samples. CRX staining is present in 53% of PTPR, though expression is nearly always limited to rare cells. Diffuse nuclear FOXJ1 expression is present in 100% of PTPR. Fetal human SCO diffusely expressed FOXJ1 but was negative for CRX. Immunohistochemistry for FOXJ1 and CRX differentiates non-germ cell pineal region tumors with high sensitivity and specificity, including pineal parenchymal tumors and PTPR. Our findings support the hypothesis that PTPR have ependymal differentiation and are phenotypically more similar to SCO than pineal gland. PMID- 28719465 TI - Predictors of Outcome in Adenoid Cystic Carcinoma of Salivary Glands: A Clinicopathologic Study With Correlation Between MYB Fusion and Protein Expression. AB - Adenoid cystic carcinoma (ACC) is the second most common salivary gland malignancy and it has a high rate of recurrences and a poor long-term prognosis. Our aim was to assess the prognostic factors in ACC and study MYB-NFIB fusion and MYB protein expression in a large retrospective cohort of 135 patients with a median follow-up of 6.3 years. The 5- and 10-year local recurrence-free survival (RFS) rate of 94% and 78%, 5- and 10-year distant metastasis survival rate of 77% and 58%, and 5- and 10-year RFS of 66% and 44%. The following features were identified as adverse prognostic factors of RFS on univariate analysis: large tumor size, solid growth pattern, increased mitoses, positive margin, American Joint Committee on Cancer clinical staging, high-grade transformation, vascular invasion, nuclear atypia, open chromatin, prominent nucleoli, and tumor necrosis. However, on multivariate analysis, only increased mitoses (>=5/10 high-power fields), any solid growth pattern, and advanced American Joint Committee on Cancer TNM staging were independent adverse predictors for RFS. MYB immunoexpression and MYB-NFIB translocation were common findings in ACC, occurring in 72% and 59% of the tested ACCs, respectively. The sensitivity and specificity of MYB immunohistochemistry in detecting MYB-NFIB fusion was relatively low at 78% sensitivity and 50% specificity. The high prevalence of alterations leading to high expression of the MYB transcription factor family suggests that targeted approaches developed to suppress the expression of these oncogenic transcription factors and/or the transcriptional activity of these proteins would be a rational therapeutic approach to investigate in ACC. PMID- 28719466 TI - Dedifferentiated Liposarcoma With Epithelioid/Epithelial Features. AB - Dedifferentiated liposarcoma (DDLPS) demonstrates a variety of growth patterns, and their histologic resemblance to other spindle cell mesenchymal tumors has been widely recognized. However, epithelioid morphology in DDLPS has only rarely been documented. Here, we report 6 cases of DDLPS with striking epithelioid/epithelial features. The patients were 5 men and 1 woman with a median age of 61 years. All tumors were located in the internal trunk. During follow-up of 1 to 41 months, local recurrence, distant metastases, and tumor related death occurred in 4, 2, and 4 patients, respectively. Beside well differentiated liposarcoma component and conventional high-grade spindle cell morphology, all tumors focally exhibited growth comprising small or large epithelioid cells in diffuse or sheet-like proliferation. Rhabdoid cells were present in 2 cases. All 5 tumors tested harbored MDM2 amplification. Cytokeratin and/or epithelial membrane antigen were at least focally positive in all 5 tumors tested. One case contained a small focus of novel heterologous epithelial differentiation with acinar structures, wherein cytokeratin, MOC31, and claudin-4 were diffusely expressed and H3K27me3 expression was lost. DDLPS with epithelioid/epithelial features may lead to misdiagnosis of carcinoma or mesothelioma, and their diagnosis should be based on correlation with clinicopathologic and molecular findings. The epithelioid morphology in DDLPS may suggest an aggressive behavior based on this small series. In addition, we document 2 cases of MDM2-amplified undifferentiated neoplasm with epithelioid features in the internal trunk that lacked association with well-differentiated liposarcoma histology and showed rapid clinical course. Whether these latter tumors belong to DDLPS with epithelioid features requires further study. PMID- 28719467 TI - Pan-Trk Immunohistochemistry Is an Efficient and Reliable Screen for the Detection of NTRK Fusions. AB - Activating neurotrophic tyrosine receptor kinase (NTRK) fusions, typically detected using nucleic-acid based assays, are highly targetable and define certain tumors. Here, we explore the utility of pan-TRK immunohistochemistry (IHC) to detect NTRK fusions. NTRK rearrangements were detected prospectively using MSK-IMPACT, a DNA-based next-generation sequencing assay. Transcription of novel NTRK rearrangements into potentially functional fusion transcripts was assessed via Archer Dx fusion assay. Pan-Trk IHC testing with mAb EPR17341 was performed on all NTRK rearranged cases and 20 cases negative for NTRK fusions on Archer. Of 23 cases with NTRK rearrangements, 15 had known activating fusions. Archer detected fusion transcripts in 6 of 8 novel NTRK rearrangements of uncertain functional significance. Pan-Trk IHC was positive in 20 of 21 cases with NTRK fusion transcripts confirmed by Archer. The discordant negative case was a mismatch repair- deficient colorectal carcinoma with an ETV6-NTRK3 fusion. All 20 additional Archer-negative cases had concordant pan-TRK IHC results. Pan Trk IHC sensitivity and specificity for transcribed NTRK fusions was 95.2% and 100%, respectively. All positive IHC cases had cytoplasmic staining while the following fusion partner-specific patterns were discovered: all 5 LMNA-NTRK1 fusions displayed nuclear membrane accentuation, all 4 TPM3/4 fusions displayed cellular membrane accentuation, and half (3/6) of ETV6-NTRK3 fusions displayed nuclear staining. Pan-Trk IHC is a time-efficient and tissue-efficient screen for NTRK fusions, particularly in driver-negative advanced malignancies and potential cases of secretory carcinoma and congenital fibrosarcoma. Pan-Trk IHC can help determine whether translation occurs for novel NTRK rearrangements. PMID- 28719468 TI - ETV6 Gene Rearrangements Characterize a Morphologically Distinct Subset of Sinonasal Low-grade Non-intestinal-type Adenocarcinoma: A Novel Translocation associated Carcinoma Restricted to the Sinonasal Tract. AB - Low-grade sinonasal adenocarcinomas (low-grade SNACs) of the sinonasal tract comprise a poorly characterized and histologically heterogeneous group of tumors. We describe three cases of a histologically distinct variant of low-grade SNAC characterized by ETV6 gene rearrangements. The patients included 2 women (aged 32 and 88 y) and a man (aged 75 y); all were initially treated with surgery alone. Follow-up ranged from 9 to 170 months with one patient having 2 local recurrences and none experiencing distant or regional metastases. Tumors were composed of cytologically bland columnar and cuboidal eosinophilic tumor cells with basally located nuclei arranged in tubular and tubulotrabecular patterns. Immunohistochemically, CK7, DOG1, GCDFP-15, and SOX10 were positive in all cases, and vimentin was positive in 2 cases. Scattered single cells or small groups of tumor cells were S-100 positive. Only one case had weak, focal expression of GATA3, and mammaglobin was consistently negative. Two cases had ETV6-NTRK3 gene fusions, whereas ETV6 had an unknown fusion partner gene in one case. The highly similar morphology, immunohistochemical profile, and genetics of the presented cases are suggestive of a specific disease. Although translocation-associated adenocarcinomas in the sinonasal tract have previously been described exclusively as salivary-type carcinomas, we present the first type of carcinoma characterized by recurrent genetic rearrangements and distinct phenotype occurring exclusively in the sinonasal tract with no known major salivary gland counterpart. We provisionally designate this tumor ETV6-rearranged low-grade SNAC. Identification of additional cases is necessary to fully appreciate the morphologic and biological spectrum of this disease. PMID- 28719469 TI - INSM1 Demonstrates Superior Performance to the Individual and Combined Use of Synaptophysin, Chromogranin and CD56 for Diagnosing Neuroendocrine Tumors of the Thoracic Cavity. AB - Despite the importance of recognizing neuroendocrine differentiation when diagnosing tumors of the thoracic cavity, the sensitivity of traditional neuroendocrine markers is suboptimal, particularly for high-grade neuroendocrine carcinomas such as small cell lung carcinoma and large cell neuroendocrine carcinoma. To increase sensitivity, neuroendocrine markers are routinely ordered as panels of multiple immunostains where any single positive marker is regarded as sufficient evidence of neuroendocrine differentiation. Insulinoma-associated protein 1 (INSM1) is a well-validated transcription factor of neuroendocrine differentiation that has only recently been evaluated for diagnostic use. We performed INSM1 immunohistochemistry on a large series of thoracic neuroendocrine and non-neuroendocrine tumors and compared its performance to synaptophysin, chromogranin, and CD56. INSM1 was positive in 94.9% of small cell lung carcinomas and 91.3% of large cell neuroendocrine carcinomas, compared with 74.4% and 78.3% with the combined panel of traditional markers. INSM1 also stained all (100%) of the atypical carcinoids, typical carcinoids and mediastinal paragangliomas, but only 3.3% of adenocarcinomas and 4.2% of squamous cell carcinomas. Overall, INSM1 demonstrated a sensitivity of 96.4% across all grades of thoracic neuroendocrine tumors, significantly more than the 87.4% using the panel of traditional markers (P=0.02). INSM1 is sufficiently sensitive and specific to serve as a standalone first-line marker of neuroendocrine differentiation. A more restrained approach to immunohistochemical analysis of small thoracic biopsies is appropriate given the expanding demand on this limited material for therapeutic biomarker analysis. PMID- 28719470 TI - Diurnal variation and repeatability of arterial stiffness and cardiac output measurements in the third trimester of uncomplicated pregnancy. AB - AIM: To investigate same day repeated measures and diurnal variation of arterial stiffness, cardiac output (CO), stroke volume (SV) and total peripheral resistance (TPR) during the third trimester of normal pregnancy. METHODOLOGY: Pulse wave velocity (PWV) and augmentation index (AIx) were recorded using the Arteriograph, while CO, SV and TPR were recorded using noninvasive cardiac output monitoring. The measurements were obtained in the third trimester of pregnancy from 21 healthy pregnant women at four time points (morning, afternoon, evening and midnight) over a 24-h period. Triplicate measurements of 67 women were obtained at 5-min intervals to assess repeatability between measurements within a patient. RESULTS: Diurnal measurements of arterial stiffness for brachial AIx, aortic AIx and PWV were not statistically significantly different at any of the four time points. Estimated means (SD) for PWV at the four stated time points were 7.81 (2.05), 8.45 (1.68), 7.87 (1.74) and 7.64 m/s (1.15), respectively (P = 0.267). Estimates for AIx at those time points were 10.22 (15.62), 4.44 (10.07), 6.49 (10.92) and 8.40% (8.16), respectively (P = 0.295). Similarly, mean arterial pressure, SV, SV index and TPR did not show any evidence of diurnal variation. However, we observed that the mean CO, cardiac index (CI) and heart rate (HR) varied from morning to midnight; the mean CO, HR and CI increased significantly in the afternoon compared with the corresponding mean morning measurements in a similar fashion to HR. Mean (SD) CO estimates at the four stated time points were 5.90 (1.33), 6.38 (1.49), 6.18 (1.43) and 5.80 ml/min (1.19), respectively, (P < 0.001), whereas mean CI estimates were 3.65 (0.58), 3.93 (0.68), 3.81 (0.65), and 3.57 (0.48), respectively, (P < 0.001), and mean HR estimates were 95 (12), 98 (13), 95 (12) and 88 (12.98), respectively (P < 0.001). Triplicate measurements of 61 women in our repeatability study showed moderate-to-high correlation between observations on the same woman for all Arteriograph and noninvasive cardiac output monitoring variables (estimates of intraclass correlation ranged from 0.49 to 0.91). CONCLUSION: With the exception of CO, CI and HR which showed a diurnal variation, measurements of most haemodynamic parameters did not change significantly from morning to midnight, suggesting there was no evidence of systematic differences in the mean values of these variables at these time points. Multiple consecutive noninvasive measurements of vascular stiffness, CO, SV and TPR were highly correlated confirming repeatability of measurements in the third trimester of uncomplicated pregnancy, so these haemodynamic measurements do not need to be undertaken at a specific time period of the day. PMID- 28719472 TI - Contact Sensitization to Allergens in Nail Cosmetics. AB - Ingredients found in the nail cosmetic industry, including but not limited to methacrylate and acrylate monomers, formaldehyde, and toluene sulfonamide formaldehyde resin, can incite allergic contact dermatitis. An eczematous outbreak presents on areas surrounding the nail plate and may spread through contact transfer of the allergen, commonly to the face and neck. Even components that were originally deemed nonsensitizing, such as the ubiquitous cyanoacrylate adhesive family, have been found to be allergenic. They do not, however, cross react with methacrylates and acrylates. Alternative options for individuals with allergic contact dermatitis reactions to these ingredients can be avoidance of these procedures or use of products that are "3, 4, 5 free" in which the common allergens dibutyl phthalate, toluene, and formaldehyde are absent. In cases where strengthening of the nail is the sole purpose, nail wraps or preformed nails can be applied for non-cyanoacrylate-sensitive individuals. PMID- 28719473 TI - Delayed Patch-Test Reading After 5 Days: An Update From the Mayo Clinic Contact Dermatitis Group. AB - BACKGROUND: Patch-test readings after day 5 have previously been used to identify delayed reactions to metals and topical antibiotics. OBJECTIVE: The aims of this study were to identify allergens for which late readings (beyond day 5) would be most valuable and to compare our results with our previous study on delayed patch test readings. METHODS: This was a retrospective study of 298 patients who underwent metal and corticosteroid series patch testing from January 1, 2007, through December 31, 2013. Patch-test readings were conducted on days 3 and 5 and at least once sometime between days 7 and 14. All reactions were examined at each reading. CONCLUSIONS: These results were concordant with our previous findings that additional readings after day 7 are particularly useful for identifying reactions to metals (gold, cobalt, beryllium, palladium), specific preservatives (dodecyl gallate, propolis), and the topical antibiotic neomycin. New delayed reactions to bacitracin, p-phenylenediamine, and topical corticosteroids were not seen in this cohort. PMID- 28719474 TI - Photographic Documentation and Hand Eczema Severity Index for Severity Assessment of Hand Eczema. AB - BACKGROUND: Hand eczema (HE) is a fluctuating disease, and an objective assessment of HE severity is coveted. OBJECTIVES: This study was undertaken to test the association between Hand Eczema Severity Index (HECSI) score and panel scores of photographs taken by dermatologists. METHODS: A total of 33 patients with mild HE were included. The patients were part of an intervention study, and HECSI scores and standardized photographs were taken at baseline and at follow-up after 5 months. Actual change in HECSI score was compared with rating of change from photographs. A total of 15 dermatologists were engaged in blinded evaluation of photographs. RESULTS: The highest correlation coefficients between delta HECSI scores and delta panel scores of photographs in the first and second evaluation rounds were found for moderate improvement and moderate worsening, rs = -0.46 (P = 0.009) and 0.52 (P = 0.003), respectively, and major worsening, r = 0.41 (P = 0.021). With respect to minor changes, no statistically significant correlations were found (P > 0.05). CONCLUSIONS: In patients with mild HE, photographic assessment was found useful for major and moderate changes only. Further studies would need to be performed in patients with moderate or severe HE, to evaluate whether clinical photographs are able to capture similar changes as HECSI scores. PMID- 28719475 TI - Allergic Contact Dermatitis From Methylisothiazolinone in Residential Wall Paint. AB - A 33-year-old woman presented to our clinic for suspected photoallergic contact dermatitis with a recent episode of severe, vesicular dermatitis involving exposed skin and correlating with relocation to a new home. Biopsy results showed spongiotic and lichenoid dermatitis with eosinophils. Patch test results showed a very strong (+++) reaction to methylisothiazolinone (MI), mild (+) reaction to MI/methylchloroisothiazolinone, and no reaction to benzisothiazolinone. These allergens were found in several personal products. However, the patient was suspicious of 4 wall paints recently used in her home. Semiopen patch tests to 3 Behr interior paints showed positive results. Nine controls showed negative results. High-performance liquid chromatography demonstrated MI and benzisothiazolinone in all 4 paints at concentrations ranging from 50 to 100 ppm and 290 to 340 ppm, respectively. Although MI has been reported to cause occupational airborne contact dermatitis in European household painters, to our knowledge, this is the first documented case of paint-related MI allergy in the United States. PMID- 28719476 TI - A Rare Case of Contact Urticaria and Allergic Contact Dermatitis to Maleic and Fumaric Acids. PMID- 28719477 TI - Gait analysis on force treadmill in children: comparison with results from ground based force platforms. AB - Gait analysis (GA) typically includes surface electromyographic (sEMG) recording from several lower limb muscles, optoelectronic measurement of joint rotations, and force recordings from ground-based platforms. From the latter two variables, the muscle power acting on the lower limb joints can be estimated. Recently, gait analysis on a split-belt force treadmill (GAFT) was validated for the study of adult walking. It showed high reliability of spatiotemporal, kinematic, dynamic, and sEMG parameters, matching those obtainable with GA on the basis of ground walking. GAFT, however, still needs validation in children. Potential differences with respect to adult GAFT relate to (a) possible high signal-to-noise ratio, given the lower forces applied; (b) higher differences between treadmill and over ground walking; and (c) limited compliance with the experimental setup. This study aims at investigating whether GAFT provides results comparable with those obtainable from ground walking in children and consistent with results from GAFT in adults. GAFT was applied to three groups of healthy children aged 5-6 years (n=6), 7-8 years (n=6), and 9-13 years (n=8) walking at the same average speed spontaneously adopted overground. The results were compared with those obtained from another study applying GA to an age-matched and speed-matched sample of 47 children, and with those obtained from GAFT in adults. The reliability (as indicated by the SD) of both spatiotemporal and dynamic parameters was higher in GAFT compared with GA. In the 5-6-, 7-8-, and 9-13-year-old groups, at average speeds of 0.83, 1.08, and 1.08 m/s, step length was shorter by 9.19, 3.57, and 2.30% compared with GA in controls at comparable speeds, respectively. For the youngest group, a lower power generation from the plantar flexors (peak power: 1.35+/-0.32 vs. 2.11+/-1.02 W/kg) and a slightly more flexed posture of the hip, knee, and ankle joints were observed during GAFT compared with GA in controls. The other gait parameters were very similar between the GAFT and the GA groups. The shortening of step length during GAFT, relative to GA at superimposable speed, was on average of all children 6.8%, in line with the 8% decrease found in adults. The profiles of sEMG and joint rotations, and all of the weight standardized joint power parameters, matched those recorded in adults. The entire experimental session lasted about 1 h. All children complied with the experimental setting and easily completed the requested tests. In conclusion, GAFT seems to be a promising alternative to conventional GA in children. PMID- 28719478 TI - A Review of Nonfatal Drowning in the Pediatric-Age Group: A 10-Year Experience at a University Hospital in Saudi Arabia. AB - OBJECTIVE: The aim of this study was to evaluate the nonfatal drowning experience, risk factors, intrahospital assessment and postincidental outcomes for children admitted to King Fahd Hospital of the University, AlKhobar, Saudi Arabia, over a 10-year period. METHODS: Children up to the age of 14 years who were admitted with the diagnosis of nonfatal drowning from July 2005 to June 2015 were included. Data regarding demographics, timing, season and location of drowning, presence of an assigned lifeguard, duration of submersion and transport to hospital, cardiopulmonary resuscitation, initial Glasgow Coma Scale, temperature, pH, blood sugar level, total hospital stay, and discharge status were extrapolated, and their effects on the patient's outcome analyzed. Patients' outcomes were classified into either full recovery, moderate to severe neurological damage, or brain death. RESULTS: Fifty-one subjects were included in the study; 66.7% were males, 57% were younger than 6 years, and 80% were Saudi citizens. Of the total cases, 94% recovered fully, and 6% were diagnosed as having brain death or discharged from the intensive care unit with severe neurological injury. Submersion time of more than 5 minutes, Glasgow Coma Scale of 4 or less, pH of less than 7.1, temperature of 35 degrees C or less, and blood sugar of 180 mg/dL or greater were found to correlate with bad outcomes with great statistical significance. CONCLUSIONS: The findings of this study were in line with results of most of the international and local studies on the subject. Significant defects have been concluded in prehospital medical care and cardiopulmonary resuscitation. Adequate swimming safety regulations, assignments of lifeguards, and parental education should be taken into consideration by media and involved authorities. PMID- 28719479 TI - A Simulation-Based Quality Improvement Initiative Improves Pediatric Readiness in Community Hospitals. AB - BACKGROUND: The National Pediatric Readiness Project Pediatric Readiness Survey (PRS) measured pediatric readiness in 4149 US emergency departments (EDs) and noted an average score of 69 on a 100-point scale. This readiness score consists of 6 domains: coordination of pediatric patient care (19/100), physician/nurse staffing and training (10/100), quality improvement activities (7/100), patient safety initiatives (14/100), policies and procedures (17/100), and availability of pediatric equipment (33/100). We aimed to assess and improve pediatric emergency readiness scores across Connecticut's hospitals. OBJECTIVE: The aim of this study was to compare the National Pediatric Readiness Project readiness score before and after an in situ simulation-based assessment and quality improvement program in Connecticut hospitals. METHODS: We leveraged in situ simulations to measure the quality of resuscitative care provided by interprofessional teams to 3 simulated patients (infant septic shock, infant seizure, and child cardiac arrest) presenting to their ED resuscitation bay. Assessments of EDs were made based on a composite quality score that was measured as the sum of 4 distinct domains: (1) adherence to sepsis guidelines, (2) adherence to cardiac arrest guidelines, (3) performance on seizure resuscitation, and (4) teamwork. After the simulation, a detailed report with scores, comparisons to other EDs, and a gap analysis were provided to sites. Based on this report, a regional children's hospital team worked collaboratively with each ED to develop action items and a timeline for improvements. The National Pediatric Readiness Project PRS scores, the primary outcome of this study, were measured before and after participation. RESULTS: Twelve community EDs in Connecticut participated in this project. The PRS scores were assessed before and after the intervention (simulation-based assessment and gap analysis/report-out). The average time between PRS assessments was 21 months. The PRS scores significantly improved 12.9% from the first assessment (mean +/- SEM = 64 +/- 4.4) to the second assessment (77 +/- 4.0, P = 0.022). The PRS score domains also showed improvements in coordination of pediatric patient care (median improvement, 50%), quality improvement activities (median improvement, 79%), patient safety initiatives (mean improvement, 7%), policies and procedures (mean improvement, 17%), and availability of pediatric equipment (mean improvement, 7%). CONCLUSIONS: Participation in a simulation-based quality improvement collaborative was associated with improvements in pediatric readiness. PMID- 28719480 TI - A Rare Pediatric Case of Posttraumatic Pseudoaneurysm: Case Report and Literature Review. AB - Posttraumatic pseudoaneurysms are extremely rare in pediatric populations. In many cases, pseudoaneurysms may be confused with abscesses, epidermoid cysts, arteriovenous fistula, foreign objects, and ganglion cysts, as well as tumors. They are associated with distinguishing findings of "pulsatile mass, a palpable thrill, and an audible to-and-fro murmur" (1), which can be confirmed by various imaging techniques. In this report, we describe the case of a 4-year-old boy who presented to the pediatric emergency department 3 weeks after falling and subsequently getting cut by glass. Upon clinical examination, the patient presented with pulsatile, swollen mass in the left wrist. A Doppler ultrasound of the left wrist demonstrated that the area of clinical concern in the left wrist showed a pseudoaneurysm, and prominent arterial blood flow was seen within the pseudoaneurysm. Because pseudoaneurysms, particularly posttraumatic pseudoaneurysms, are extremely rare in the pediatric population, it may be easy to miss these cases during clinical examination. Misdiagnosis of the pseudoaneurysm can cause delayed treatment, a longer recovery period, and complications such as infection, rupture, and hemorrhage. It is important for physicians to consider this entity when evaluating patients with symptoms of asymptomatic bulges to painful pulsatile masses after trauma. PMID- 28719481 TI - Opioid Prescribing Practices in Pediatric Acute Care Settings. AB - OBJECTIVES: Deaths due to prescription opioid overdoses are at record-high levels. Limiting the amount of opioid prescribed has been suggested as a prevention strategy. The purpose of this study was to describe the opioid prescribing practices in the emergency departments and urgent care sites of a Midwestern tertiary care children's hospital system. METHODS: This retrospective medical record review examined the visits from the 2 pediatric emergency departments and 2 pediatric urgent care sites in the system from June 1, 2012, to May 31, 2013, during which an outpatient opioid prescription was written. The primary outcome was number of days of opioid prescribed. Other data collected included patient demographics, diagnosis, and prescriber information; factors associated with prescriptions written for more than 5 days were identified. RESULTS: A total of 4075 opioid prescriptions were included in the 1-year study period, and 3991 of these had complete data for analysis. The median amount prescribed was 3.3 days with an interquartile range of 2.5 days. Odds of receiving a prescription of more than 5 days' duration were higher for children younger than 1 year (odds ratio [OR], 12.3; 95% confidence interval [CI], 7.3 21.0), 1 to 4 years of age (OR, 7.7; 95% CI, 5.5-10.8), and 5 to 9 years of age (OR, 2.4; 95% CI, 1.7-3.4); for children with noninjury diagnoses (OR, 1.4; 95% CI, 1.2-1.7); or if prescribed by a resident physician (OR, 1.4; 95% CI, 1.1-1.8) or from the urgent care (OR, 1.4; 95% CI, 1.1-1.7). CONCLUSIONS: Opioid prescriptions of more than 5 days were more frequently prescribed for younger patients, noninjury diagnoses, or if prescribed by a resident physician or from the urgent care. We need to focus on medical student, resident, and provider education as well as further opioid research in order to decrease unnecessary prescribing. PMID- 28719482 TI - Teaching Incision and Drainage: Perceived Educational Value of Abscess Models. AB - OBJECTIVES: Incision and drainage (I&D) of skin abscesses is an important procedural skill for pediatric emergency medicine providers. Practical skills training using simulation provides an opportunity to learn and gain confidence with this invasive procedure. Our objective was to assess the perceived educational value of 2 versions of an abscess model as part of an educational workshop for teaching I&D. METHODS: A combined didactic and practical skills workshop was developed for use at 2 national conferences. The didactic content was created through an iterative process. To facilitate hands-on training, 2 versions of an abscess model were created: 1 constructed from a negative mold and the other using a 3-dimensional printer. Participants were surveyed regarding prior experience with I&D, procedural confidence, and perceptions of the educational utility of the models. RESULTS: Seventy physicians and 75 nurse practitioners participated in the study. Procedural confidence improved after training using each version of the model, with the greatest improvements noted among novice learners. Ninety-four percent of physicians, and 99% of nurse practitioners rated the respective models as either "educational" or "very educational," and 97% and 100%, respectively, would recommend the abscess models to others. CONCLUSIONS: A combined didactic and practical skills educational workshop using novel abscess models was effective at improving learners' confidence. Our novel models provide an effective strategy for teaching procedural skills such as I&D and demonstrate a novel use of 3-dimensional printers in medical education. Further study is needed to determine if these educational gains translate into improvement in clinical performance or patient outcomes. PMID- 28719483 TI - Difficult Intubation and Ventilation in an Infant With Retropharyngeal Abscess With Mediastinal Extension. AB - A previously healthy 7-month-old male infant presented for evaluation of fever, deceased oral intake, and intermittent noisy breathing. Physical examination revealed neck tenderness. Soft tissue neck radiographs and computed tomography (CT) scan supported a diagnosis of retropharyngeal swelling with extension to the superior mediastinum. Surgical exploration was planned, and endotracheal intubation was performed in the operating room. Significant cardiorespiratory derangements developed immediately after the tracheal tube was inserted, including hypotension, hypoxia, and bradycardia with signs of cardiac ischemia. The patient was resuscitated with intravenous fluids, vasopressors, and bronchodilators; his condition improved after resuscitation and surgical evacuation of purulent material. A combination of mediastinal mass effect, aspiration, and bronchospasm likely contributed to the patient's deterioration. The subsequent clinical course was uneventful. The patient was extubated in a delayed fashion and discharged on the fourth postoperative day. This case highlights the importance of preparing for a difficult airway in cases of retropharyngeal abscesses that necessitate tracheal intubation. A multidisciplinary approach is best suited to manage the airway, preferably in the operating room. PMID- 28719484 TI - Amitraz: A Perpetual Silent Menace Among Children in Developing Countries-A Case Report. AB - Amitraz is an acaricide and insecticide used to treat ticks, which infest domestic animals in developing countries. Because of its widespread use, it is one of the common poisons unintentionally consumed by infants and children when left unsupervised. A 3-year-old boy was brought with unintentional consumption of Amitraz. On examination, he was found to be progressively drowsy, with an irregular pulse, bradycardia, and hypotension. He was treated with atropine, intravenous fluids, and dopamine infusion; hemodynamic stability was achieved within 36 hours after ingestion. Amitraz is an unusual but deadly poison unintentionally consumed by children. It can be suspected in the setting of rural households in developing countries having pets. There is no antidote available, and treatment is mainly supportive. PMID- 28719485 TI - Does the Application of Heat Gel Pack After Eutectic Mixture of Local Anesthetic Cream Improve Venipuncture or Intravenous Cannulation Success Rate in Children? A Randomized Control Trial. AB - OBJECTIVE: Needle-related procedures are the most common sources of pain for children in the hospital setting. The most used topical anesthetic, eutectic mixture of local anesthetic (EMLA) cream, may cause transient vasoconstriction. It has been postulated that this vasoconstriction may decrease vein visualization. The application of heat gel pack after removal of EMLA cream in the site of venipuncture counteracts the vasoconstriction, improving vein visualization. We assessed using a prospective randomized controlled trial whether the application of heat gel pack increases the needle procedure success rate. The primary study outcome was procedural success rate at the first attempt. METHODS: The study enrolled 400 children, 200 of whom applied heat gel pack after removing EMLA (treatment group) and 200 did not (control group). Procedural success rate at the first attempt, vein perception before procedure, procedural pain, and adverse events were recorded in both groups. RESULTS: Eighty-eight percent of the procedures were successful at the first attempt in the treatment group and 89% in the control group (P = 0.876). Vein perception was not significantly different in the 2 groups (P = 0.081). Pain score after the procedure was similar in the 2 groups. CONCLUSIONS: This study shows that the application of heat gel pack after removal of EMLA cream does not improve venipuncture or intravenous cannulation success rate. PMID- 28719486 TI - p16 Expression and Biological Behavior of Flat Vulvar Low-grade Squamous Intraepithelial Lesions (LSIL). AB - Flat low-grade squamous intraepithelial lesion (LSIL) of the vulva [vulvar intraepithelial neoplasia (VIN) 1, flat condyloma] is an uncommon entity with poorly understood biological behavior. We aimed to determine the risk of subsequent vulvar high-grade squamous intraepithelial lesion (HSIL) or carcinoma following a diagnosis of vulvar LSIL/VIN 1, as well as the frequency and predictive value of p16 immunohistochemical expression in this setting. Of the 51 included cases, p16 positivity (diffuse block staining) was identified in 2 (4%). Follow-up data were available in 34 cases, of which 2 (5.9%) developed subsequent vulvar HSIL, including 1/2 p16-positive cases and 1/32 p16-negative cases. The difference in HSIL frequency between p16-positive and p16-negative cases was not statistically significant (P=0.116 for VIN 2+, P=0.061 for VIN 3). For the 18 patients with treatment information available, 10 (56%) received medical or surgical treatment after biopsy. Our results indicate that flat vulvar LSIL is infrequently p16 positive, and that few patients with vulvar LSIL develop subsequent vulvar HSIL. Despite the use of destructive treatment in some cases, the data provide support for the nonpreneoplastic nature of the entity. Immunohistochemical expression of p16 may not be a predictor of HSIL risk in vulvar LSIL, although this result may also be related to the very low rates of both p16 positivity and subsequent vulvar HSIL in our sample. It is clear that vulvar LSIL is distinct from LSIL in other lower anogenital sites in terms of its behavior and p16 expression frequency. PMID- 28719487 TI - GOOGLE CARDBOARD INDIRECT OPHTHALMOSCOPY. PMID- 28719488 TI - The Impact of the Affordable Care Act's Dependent Coverage Mandate on Use of Dental Treatments and Preventive Services. AB - BACKGROUND: Oral health problems are the leading chronic conditions among children and younger adults. Lack of dental coverage is thought to be an important barrier to care but little empirical evidence exists on the causal effect of private dental coverage on use of dental services. We explore the relationship between dental coverage and dental services utilization with an analysis of a natural experiment of increasing private dental coverage stemming from the Affordable Care Act's (ACA)-dependent coverage mandate. OBJECTIVES: To evaluate whether increased private dental insurance due to the spillover effect of the ACA-dependent coverage health insurance mandate affected utilization of dental services among a group of affected young adults. DATA: 2006-2013 Medical Expenditure Panel Surveys. STUDY DESIGN: We used a difference-in-difference regression approach comparing changes in dental care utilization for 25-year olds affected by the policy to unaffected 27-year olds. We evaluate effects on dental treatments and preventive services RESULTS:: Compared to 27-year olds, 25-year olds were 8 percentage points more likely to have private dental coverage in the 3 years following the mandate. We do not find compelling evidence that young adults increased their use of preventive dental services in response to gaining insurance. We do find a nearly 5 percentage point increase in the likelihood of dental treatments among 25-year olds following the mandate, an effect that appears concentrated among women. CONCLUSIONS: Increases in private dental coverage due to the ACA's-dependent coverage mandate do not appear to be driving significant changes in overall preventive dental services utilization but there is evidence of an increase in restorative care. PMID- 28719489 TI - Antithrombin III Attenuates AKI Following Acute Severe Pancreatitis. AB - BACKGROUND: Antithrombin III (ATIII), the predominant coagulation factor inhibitor, possesses anti-inflammatory properties and exerts renoprotective effects on renal ischemia-reperfusion injury in animal models. However, the ATIII's protective effects of ATIII on acute kidney injury (AKI) following severe acute pancreatitis (SAP) need to be confirmed. METHODS: We assessed the association between ATIII activities and the incidence of AKI in patients with SAP, and explored therapeutic effects and potential mechanisms of ATIII on kidney injury in sodium taurocholate induced SAP rat model. Rats were intravenously injected with ATIII (500 MUg/kg) before or after the induction of SAP. RESULTS: The results demonstrated ATIII did not attenuate pancreatic injury, but significantly ameliorate renal dysfunction and renal histological injury. ATIII administration alleviated renal inflammation response, oxidative stress, and cell apoptosis. Moreover, ATIII attenuated tumor necrosis factor alpha (TNFalpha) stimulated intercellular cell adhesion molecule 1(ICAM-1) and monocyte chemotactic protein 1 (MCP-1) upregulation in cultured renal tubular epithelial cells. CONCLUSION: ATIII appears to ameliorate SAP-induced kidney injury by inhibiting inflammation, oxidative stress, and apoptosis. ATIII supplementation may have a potential prophylactic and therapeutic effect on SAP induced AKI. PMID- 28719490 TI - Identification of Hypotensive Emergency Department Patients with Cardiogenic Etiologies. AB - OBJECTIVE: Identify predictors of cardiogenic etiology among emergency department (ED) patients with hypotension, and use these predictors to create a clinical tool to discern cardiogenic etiology of hypotension. METHODS: This secondary analysis evaluated a prospective cohort of consecutive patients with hypotension in an urban, academic, tertiary care ED from November 2012 to September 2013. We included adults with hypotension, defined as a new vasopressor requirement, systolic blood pressure (SBP) < 90 mm Hg after at least 1 L of crystalloid or 2 units packed red blood cells, or SBP < 90 mm Hg and fluids withheld due to concern for fluid overload. The primary outcome was cardiogenic etiology, adjudicated by two physician chart review, with 25% paired chart review (kappa = 0.92). We used multivariable logistic regression to predict cardiogenic etiology, utilizing clinical data abstracted from the electronic medical record. We created a prediction score from significant covariates and calculated its test characteristics for cardiogenic hypotension. RESULTS: Of 700 patients with hypotension, 107 (15.3%, 95% CI: 12.6%-18.0%) had cardiogenic etiology. Independent predictors of cardiogenic etiology were shortness of breath (OR 4.1, 95% CI: 2.5-6.7), troponin > 0.1 ng/mL (37.5, 7.1-198.2), electrocardiographic ischemia (8.9, 4.0-19.8), history of heart failure (2.0, 1.1-3.3), and absence of fever (4.5, 2.3-8.7) (area under the curve [AUC] = 0.83). The prediction score created from these predictors yielded 78% sensitivity and 77% specificity for cardiogenic etiology (AUC = 0.827). CONCLUSIONS: Clinical predictors offer reasonable ED screening sensitivity for cardiogenic hypotension, while demonstrating sufficient specificity to facilitate early cardiac interventions. PMID- 28719491 TI - Greater Effect of East versus West Travel on Jet Lag, Sleep, and Team Sport Performance. AB - PURPOSE: This study aimed to determine the recovery timeline of sleep, subjective jet lag and fatigue, and team sport physical performance after east and west long haul travel. METHODS: Ten physically trained men underwent testing at 0900 h and 1700 h local time on four consecutive days 2 wk before outbound travel (BASE), and the first 4 d after 21 h of outbound (WEST) and return (EAST) air travel across eight time zones between Australia and Qatar. Data collection included performance (countermovement jump, 20-m sprint, and Yo-Yo intermittent recovery level 1 [YYIR1] test) and perceptual (jet lag, motivation, perceived exertion, and physical feeling) measures. In addition, sleep was measured via wrist activity monitors and self-report diaries throughout the aforementioned data collection periods. RESULTS: Compared with the corresponding day at BASE, the reduction in YYIR1 distance after EAST was significantly different from the increase in WEST on day 1 after travel (P < 0.001). On day 2, significantly slower 20-m sprint times were detected in EAST compared with WEST (P = 0.03), with large effect sizes (ES) also indicating a greater reduction in YYIR1 distance in EAST compared with WEST (d = 1.06). Mean sleep onset and offset were significantly later and mean time in bed and sleep duration were significantly reduced across the 4 d in EAST compared with BASE and WEST (P < 0.05). Lastly, mean jet lag, fatigue, and motivation ratings across the 4 d were significantly worse in EAST compared with BASE and WEST (P < 0.05) and WEST compared with BASE (P < 0.05). CONCLUSIONS: Long-haul transmeridian travel can impede team sport physical performance. Specifically, east travel has a greater detrimental effect on sleep, subjective jet lag, fatigue, and motivation. Consequently, maximal and intermittent sprint performance is also reduced after east travel, particularly within 72 h after arrival. PMID- 28719492 TI - Fifty Men, 3510 Marathons, Cardiac Risk Factors, and Coronary Artery Calcium Scores. AB - INTRODUCTION/PURPOSE: Many male marathon runners have elevated coronary artery calcium (CAC) scores despite high physical activity. We examined the association between CAC scores, cardiovascular risk factors, and lifestyle habits in long term marathoners. METHODS: We recruited men who had run one or more marathons annually for 25 consecutive years. CAC was assessed using coronary computed tomography angiography. Atherosclerotic cardiovascular disease risk factors were measured with a 12-lead ECG, serum lipid panel, height, weight, resting blood pressure and heart rate, and a risk factor questionnaire. RESULTS: Fifty males, mean age 59 +/- 0.9 yr with a combined total of 3510 marathons (median = 58.5, range = 27-171), had a mean BMI of 22.44 +/- 0.4 kg.m, HDL and LDL cholesterols of 58 +/- 1.6 and 112 +/- 3.7 mg.dL, and CAC scores from 0 to 3153. CAC scores varied from 0 in 16 runners to 1-100 in 12, 101-400 in 12, and >400 in 10. There was no statistical difference in the number of marathons run between the four groups. Compared with marathoners with no CAC, marathoners with moderate and extensive CAC were older (P = 0.002), started running at an older age (P = 0.003), were older when they ran their first marathon (P = 0.006), and had more CAD risk factors (P = 0.005), and marathoners with more CAC had higher rates of previous tobacco use (P = 0.002) and prevalence of hyperlipidemia (P = 0.01). CONCLUSION: Among experienced males who have run marathons for 26-34 yr and completed between 27 and 171 marathons, CAC score is related to CAD risk factors and not the number of marathons run or years of running. This suggests that among long-term marathoners, more endurance exercise is not associated with an increased risk of CAC. PMID- 28719493 TI - Validity and Reliability of Assessing Body Composition Using a Mobile Application. AB - PURPOSE: The purpose of this study was to determine the validity and reliability of the LeanScreen (LS) mobile application that estimates percent body fat (%BF) using estimates of circumferences from photographs. METHODS: The %BF of 148 weight-stable adults was estimated once using dual-energy x-ray absorptiometry (DXA). Each of two administrators assessed the %BF of each subject twice using the LS app and manually measured circumferences. A mixed-model ANOVA and Bland Altman analyses were used to compare the estimates of %BF obtained from each method. Interrater and intrarater reliabilities values were determined using multiple measurements taken by each of the two administrators. RESULTS: The LS app and manually measured circumferences significantly underestimated (P < 0.05) the %BF determined using DXA by an average of -3.26 and -4.82 %BF, respectively. The LS app (6.99 %BF) and manually measured circumferences (6.76 %BF) had large limits of agreement. All interrater and intrarater reliability coefficients of estimates of %BF using the LS app and manually measured circumferences exceeded 0.99. CONCLUSIONS: The estimates of %BF from manually measured circumferences and the LS app were highly reliable. However, these field measures are not currently recommended for the assessment of body composition because of significant bias and large limits of agreements. PMID- 28719494 TI - Hockey Fans in Training: A Pilot Pragmatic Randomized Controlled Trial. AB - INTRODUCTION: Hockey Fans in Training (Hockey FIT) is a gender-sensitized weight loss and healthy lifestyle program. We investigated 1) feasibility of recruiting and retaining overweight and obese men into a pilot pragmatic randomized controlled trial and 2) potential for Hockey FIT to lead to weight loss and improvements in other outcomes at 12 wk and 12 months. METHODS: Male fans of two ice hockey teams (35-65 yr; body mass index >=28 kg.m) located in Ontario (Canada) were randomized to intervention (Hockey FIT) or comparator (wait-list control). Hockey FIT includes a 12-wk active phase (weekly, coach-led group meetings including provision of dietary information, practice of behavior change techniques, and safe exercise sessions plus incremental pedometer walking) and a 40-wk minimally supported phase (smartphone app for sustaining physical activity, private online social network, standardized e-mails, booster session/reunion). Measurement at baseline and 12 wk (both groups) and 12 months (intervention group only) included clinical outcomes (e.g., weight) and self-reported physical activity, diet, and self-rated health. RESULTS: Eighty men were recruited in 4 wk; trial retention was >80% at 12 wk and >75% at 12 months. At 12 wk, the intervention group lost 3.6 kg (95% confidence interval, -5.26 to -1.90 kg) more than the comparator group (P < 0.001) and maintained this weight loss to 12 months. The intervention group also demonstrated greater improvements in other clinical measures, physical activity, diet, and self-rated health at 12 wk; most sustained to 12 months. CONCLUSIONS: Results suggest feasible recruitment/retention of overweight and obese men in the Hockey FIT program. Results provide evidence for the potential effectiveness of Hockey FIT for weight loss and improved health in at-risk men and, thus, evidence to proceed with a definitive trial. PMID- 28719495 TI - Late-Onset Hiv Encephalopathy In Children With Long-Standing Virologic Suppression Followed By Slow Spontaneous Recovery Despite no Change In Antiretroviral Therapy: 4 Case Reports. AB - We describe 4 Children with HIV Early Antiretroviral Therapy trial participants with late-onset HIV encephalopathy despite long-standing viral suppression in blood and undetectable HIV DNA and RNA polymerase chain reaction in cerebrospinal fluid. Extensive investigations revealed no alternative etiology. Reassuringly, all 4 experienced slow spontaneous recovery despite no change in antiretroviral therapy. Virally suppressed HIV-infected children remain at risk for fluctuating neurologic signs and symptoms. PMID- 28719496 TI - Safety and Immunogenicity of 13-Valent Pneumococcal Conjugate Vaccine in Children 6-17 Years of Age in India: An Open-label Trial. AB - In an open-label study in India, 200 healthy participants 6-17 years of age received 13-valent pneumococcal conjugate vaccine (PCV13). PCV13 elicited robust functional antibody immune responses. No adverse events were reported by caregivers at the 1-month follow-up visit. The immunogenicity results together with the known favorable risk-benefit profile of PCV13 support extension of the indication to this age group in India. PMID- 28719498 TI - Incidence of Active Tuberculosis and Cohort Retention Among Adolescents in Western Kenya. AB - SETTING: Siaya County, with the highest tuberculosis notification rates in Kenya. OBJECTIVES: To determine the incidence of active tuberculosis and 1-year cohort retention in 12-18-year-old adolescents, in preparation for phase III tuberculosis vaccine trials. METHODS: Adolescents were enrolled and followed up for 1-2 years to determine tuberculosis incidence. Adolescents with a positive tuberculin skin test, history of cohabitation with a tuberculosis case or at least 1 tuberculosis symptom received clinical and sputum examination and a chest radiograph. Definite tuberculosis cases were bacteriologically confirmed and clinical cases diagnosed by a clinician based on a suggestive chest radiograph and having clinical symptoms. Risk factors were explored using Poisson regression. RESULTS: Among 4934 adolescents without tuberculosis at baseline, 26 tuberculosis cases were identified during follow-up with a corresponding incidence density of 4.4 [95% confidence interval (CI): 3.0-6.4] events per 1000 person-years of observation, 12 definite tuberculosis cases; incidence density of 2.0 (95% CI: 0.9-3.1). Having previous tuberculosis (rate ratio: 12.5; CI: 1.8 100) and presence of tuberculin skin test conversion (rate ratio: 3.4; CI: 1.5 7.7) were significantly associated with higher risk of tuberculosis. Overall (4086/4925), 83.0% of adolescents were retained in the study after 1 year of follow-up. Being female, older, out of school and being orphaned were significant risk factors for loss to follow-up. CONCLUSION: The tuberculosis incidence in adolescents will help inform future tuberculosis vaccine trial sample size calculations for this setting. The predictive factors for tuberculosis and retention can be further explored in future trials. PMID- 28719497 TI - Serologic Responses in Childhood Pulmonary Tuberculosis. AB - BACKGROUND: Identification of the Mycobacterium tuberculosis immunoproteome and antigens associated with serologic responses in adults has renewed interest in developing a serologic test for childhood tuberculosis (TB). We investigated IgG antibody responses against M. tuberculosis antigens in children with well characterized TB. METHODS: We studied archived sera obtained from hospitalized children with suspected pulmonary TB, and classified as having confirmed TB (culture-confirmed), unlikely TB (clinical improvement without TB treatment), or unconfirmed TB (all others). A multiplexed bead-based assay for IgG antibodies against 119 M. tuberculosis antigens was developed, validated and used to test sera. The area under the curves (AUCs) of the empiric receiver-operator characteristic curves were generated as measures of predictive ability. A cross validated generalized linear model was used to select the most predictive combinations of antigens. RESULTS: For the confirmed TB versus unlikely TB comparison, the maximal single antigen AUC was 0.63, corresponding to sensitivity 0.60 and specificity 0.60. Older (age: 60+ months old) children's responses were better predictive of TB status than younger (age: 12-59 months old) children's, with a maximal single antigen AUC of -0.76. For the confirmed TB versus unlikely TB groups, the most predictive combinations of antigens assigned TB risk probabilities of 0.33 and 0.33, respectively, when all ages were considered, and 0.57 (interquartile range: 0.48-0.64) and 0.35 (interquartile range: 0.32-0.40) when only older children were considered. CONCLUSION: An antigen-based IgG test is unlikely to meet the performance characteristics required of a TB detection test applicable to all age groups. PMID- 28719499 TI - A Retrospective Cohort Study of the Incidence, Healthcare Resource Utilization, and Costs of ICD-9 Diagnosed Influenza and Related Complications in US Children. AB - BACKGROUND: There is a paucity of data on the clinical and economic impact of seasonal influenza in children. This study estimated the incidence of diagnosed influenza and related complications, and associated healthcare resource utilization (HRU) and costs in US children. METHODS: Children >=6 months and <18 years old diagnosed with influenza using ICD-9 codes and enrolled in a health plan during at least one influenza season between 2010-2014 were matched to similar patients without diagnosed influenza (GSK study identifier: HO-15-15728). Outcomes included incidence of influenza and complications, HRU frequency, and healthcare costs during 21 days of follow-up. Adjusted costs were estimated using generalized linear models. RESULTS: Incidence (per 1,000) of influenza was 20.3 (commercially-insured) and 32.6 (Medicaid), with the highest incidence among 6 to 35-month olds (Commercial: 26.8; Medicaid: 47.9). Approximately 12-17% of influenza patients experienced complications, with the 6-35 months group having the highest percentage (25-30%). The 6-35-month-old influenza patients with complications had the highest proportion with hospitalizations (5-6%) and emergency room visits (Commercial: 19%; Medicaid: 36%). Influenza patients with (vs. without) complications had greater adjusted mean influenza-specific costs (Commercial: $1,161 vs. $337; Medicaid: $1,199 vs. $354; p<0.05), and influenza cases (vs. controls) had greater adjusted mean all-cause costs (Commercial: $688 vs. $470; Medicaid: $818 vs. $453; p<0.05). CONCLUSIONS: Pediatric patients with influenza incurred higher healthcare costs compared with matched controls, and influenza-specific costs were greater among those with complications. PMID- 28719500 TI - A Randomized Controlled Study of a Fully Liquid DTaP-IPV-HB-PRP-T Hexavalent Vaccine for Primary and Booster Vaccinations of Healthy Infants and Toddlers in Latin America. AB - BACKGROUND: Hexavalent diphtheria-tetanus-acellular pertussis-inactivated poliovirus-hepatitis B-Haemophilus influenzae type b (DTaP-IPV-HB-PRP-T) containing vaccines are increasingly the standard of care. This study evaluated the primary series (NCT01177722) and booster (NCT01444781) of a fully liquid DTaP IPV-HB-PRP-T vaccine in Latin America. METHODS: Infants (N = 1375) received hepatitis B vaccine at birth and were randomized to one of 3 batches of the investigational DTaP-IPV-HB-PRP-T or licensed control vaccine (DTaP-HB-IPV//PRP T) at 2-4 to 6 months of age, coadministered with 7-valent pneumococcal conjugate vaccine (PCV7) (2-4-6 months) and rotavirus vaccine (2-4 months). A booster of either DTaP-IPV-HB-PRP-T or control was given at 12-24 months, coadministered with PCV7. Immunogenicity was assessed by validated assays and safety from parental reports. RESULTS: Primary series seroprotection and vaccine response rates were equivalent for DTaP-IPV-HB-PRP-T batches. For pooled batches, noninferiority to the control vaccine was demonstrated for each antigen. There were no descriptive differences in antibody persistence or booster response between DTaP-IPV-HB-PRP-T and the control. The booster responses to either vaccine following DTaP-IPV-HB-PRP-T primary series or to DTaP-IPV-HB-PRP-T following a control vaccine primary series were similar. The anti-aP component (filamentous hemagglutinin [FHA] and pertussis toxin [PT]) vaccine response and anti-Haemophilus influenzae type b (PRP) series seroprotection (>=0.15 ug/mL) rates were >=73.0% after 2 primary series doses. Antipyretics had no effect on the immune response, and an extra (oral) polio vaccination had no effect on the antipolio booster response. Responses to PCV7 and rotavirus vaccine were similar for each coadministration. There were no safety concerns observed with any vaccine. CONCLUSIONS: These results confirm the suitability of the fully liquid DTaP-IPV-HB-PRP-T vaccine for primary and booster vaccination of infants. PMID- 28719502 TI - Safety of Quadrivalent Meningococcal Conjugate Vaccine in Children 2-10 Years. AB - BACKGROUND: Quadrivalent meningococcal conjugate vaccine is recommended for children, adolescents and adults at increased risk of meningococcal disease. In 2011, MenACWY-CRM (Menveo, GSK, Siena, Italy) was approved for children 2-10 years of age in the United States. Although no safety concerns arose from clinical trials, it remains important to monitor its safety in routine clinical settings. METHODS: Kaiser Permanente Southern California members 2-10 years old who received MenACWY-CRM between September 2011 and September 2014 were included. Electronic health records were searched using a validated algorithm to identify 26 prespecified events of interests (EOIs) and serious medically attended events (SMAEs) from inpatient or emergency settings up to 1 year after MenACWY-CRM vaccination. SMAEs were categorized by International Classification of Diseases, 9th revision diagnostic categories. All events were reviewed to confirm the diagnosis and symptom onset date. The study was descriptive (NCT01452438); no statistical tests were performed. RESULTS: Among 387 vaccinated children, 327 with >=6 months membership before vaccination were analyzed. Among EOIs, 9 asthma cases and 1 myasthenia gravis case underwent chart review which confirmed 1 incident asthma case occurring 237 days after concomitant vaccination with MenACWY-CRM and typhoid vaccine. Thirty-one children experienced SMAEs, most commonly because of unrelated injury and poisoning. The remaining events occurred sporadically after vaccination and most were unlikely related to vaccination based on medical record review. CONCLUSIONS: One incident EOI of asthma late in the 1-year observation period and sporadic distribution of SMAEs were observed. These data do not suggest safety concerns associated with MenACWY-CRM vaccination in children 2-10 years old. PMID- 28719501 TI - Evaluation of the Adequacy of the 2010 Revised World Health Organization Recommended Dosages of the First-line Antituberculosis Drugs for Children: Adequacy of Revised Dosages of TB Drugs for Children. AB - BACKGROUND: The World Health Organization recommended increased dosages of the first-line antituberculosis (anti-TB) drugs for children in 2010. We examined the frequency of and factors associated with low plasma maximum concentration (Cmax) of each drug in children treated with the revised dosages. METHODS: Children on anti-TB therapy for at least 4 weeks underwent pharmacokinetic testing. Plasma Cmax below the lower limit of proposed reference range was considered low. Bivariate and multivariate analyses were used to examine the factors associated with low Cmax of each drug. RESULTS: Of the 100 children, 58% were male, 50% HIV infected and 49% younger than 5 years old. The median (interquartile range) Cmax was 5.9 (4.5-7.7) ug/mL for isoniazid, 6.5 (4.9-8.8) ug/mL for rifampin, 26.0 (21.2-33.4) ug/mL for pyrazinamide and 1.7 (0.9-2.7) ug/mL for ethambutol. There was a strong correlation between Cmax and AUC0-8h for all drugs. Low Cmax occurred in 9/100 (9.0%), 61/100 (61.0%), 17/97 (17.5%) and 60/97 (61.9%) for isoniazid, rifampin, pyrazinamide and ethambutol, respectively. In addition, 75/97 (77.3%) children had pyrazinamide Cmax < 35 ug/mL. Factors associated with low Cmax were NAT2 metabolizer phenotype status for isoniazid; height, dosage and HIV coinfection status for rifampin; height for pyrazinamide; and age, dosage and HIV coinfection status for ethambutol. CONCLUSIONS: The high frequency of low rifampin and ethambutol Cmax in our study is consistent with emerging pharmacokinetic data in children treated according to the new WHO recommendations. Higher dosages than currently recommended especially for rifampin may be necessary in children. PMID- 28719503 TI - Central-peripheral Temperature Monitoring as a Marker for Diagnosing Late-onset Neonatal Sepsis. AB - BACKGROUND: The prognosis for late-onset sepsis depends largely on a timely diagnosis. We assess central-peripheral temperature difference monitoring as a marker for late-onset neonatal sepsis diagnosis. METHODS: We performed a prospective, observational study focusing on a cohort of 129 very low-birth weight infants. Thermal gradient alteration was defined as a difference of > 2 degrees C maintained during 4 hours. We then determined its association with the late-onset sepsis variable through logistic regression. RESULTS: We enrolled 129 preterm babies in 52 months. Thermal gradient alterations showed an adjusted odds ratio for late-onset sepsis of 23.60 (95% confidence interval [CI], 6.80-81.88), with a sensitivity of 83% and negative predictive value of 94%. In 71% of cases, thermal gradient alteration was the first clinical sign of sepsis, while C reactive protein was < 1.5 mg/dL in 64% of cases and procalcitonin < 2 ng/mL in 36%. These figures indicate potential for early diagnosis. CONCLUSIONS: Sustained increases of central-peripheral temperature differences are an early sign of evolving late-onset sepsis. PMID- 28719504 TI - Severe Lower Respiratory Tract Infection Caused by Human Bocavirus 1 in an Infant. AB - We report a case of human bocavirus 1 (HBoV1) bronchiolitis that led to life threatening respiratory failure in a 9-month-old boy with no other pathogens detected. The virus-specific diagnosis was confirmed with the detection of HBoV1 DNA in respiratory samples and both DNA and IgM and IgG to HBoV1 in serum samples. PMID- 28719505 TI - Prevalence of Persistent Renal Dysfunction in Perinatally HIV-infected Thai Adolescents. AB - BACKGROUND: Persistent renal dysfunction (PRD) has been reported in up to 22% of perinatally HIV-infected adolescents (PHAs) in the United States and Europe. There are limited data available on PRD among PHAs in resource-limited settings regarding access to antiretroviral therapy (ART) at more advanced HIV stages. METHODS: We retrospectively described the prevalence of PRD and associated factors in a Thai PHA cohort. Inclusion criteria were current age >=10 years old and at least 2 serum creatinine (Cr) measurements after ART initiation. Cr and urine examination were performed every 6-12 months. PRD was defined as having >=2 measurements of low estimated glomerular filtration rate (eGFR); either <60 mL/min/1.73 m2 or elevated Cr for age and eGFR 60-89 mL/min/1.73 m2, or proteinuria (dipstick proteinuria >=1+). Factors associated with PRD were analyzed using a multivariate logistic regression analysis. RESULTS: This study included 255 PHAs with median (interquartile range) age of 16.7 (14.5-18.8) and ART duration of 10.3 (7.1-12.4) years. Fifty-six percentage used boosted protease inhibitor (bPI)-based regimens, and 63% used tenofovir disoproxil fumarate (TDF). The overall PRD prevalence was 14.1% [95% confidence interval (CI): 10.1-19.0]; low eGFR 6.7%, proteinuria 3.5% and both 3.9%. Among 109 users of TDF with bPI, 22.9% had PRD and 2.8% discontinued/adjusted dosing of TDF because of nephrotoxicity. Factors associated with PRD were age 10-15 years old (adjusted odd ratio (aOR): 10.1, 95% CI: 4.1-25.2), male (aOR: 3.2, 95% CI: 1.4-7.7), CD4 nadir <150 cells/mm (aOR: 2.6, 95% CI: 1.1-6.1) and use of TDF with bPI (aOR: 9.6, 95% CI: 3.2-28.9). CONCLUSIONS: PRD is common among PHAs. Almost one-fifth of adolescents using TDF with bPI had PRD. These adolescents should be a priority group for renal monitoring. PMID- 28719506 TI - Zika Virus-associated Ocular and Neurologic Disorders: The Emergence of New Evidence. AB - BACKGROUND: It has been approximately 70 years since the discovery of the Zika virus (ZIKV). It had been established that the virus causes mild infections and is confined to Africa and Asia; however, major changes in the clinical and epidemiologic patterns of ZIKV infection have occurred in recent years. The virus has attracted intense interest because of the possible association of several autoimmune and neurodevelopmental disorders. METHODS: We present a summary of the articles that attempt to explain the ZIKV unknowns and strengthen the association with some disorders that are thought to be related to ZIKV, by describing the discovery milestones from the initial identification of the virus to the present day. RESULTS: New evidence strengthens the association between ZIKV infections and Guillain-Barre syndrome (GBS), microcephaly and various neurodevelopmental and ophthalmologic disorders as a result of numerous new clinical and experimental studies. CONCLUSIONS: The World Health Organization declared the end of the "Public Health Emergency of International Concern" in December 2016, but ZIKV and associated consequences remain a significant enduring public health challenge. PMID- 28719508 TI - Is the Organization of the Primary Motor Cortex in Low Back Pain Related to Pain, Movement, and/or Sensation? AB - AIM/BACKGROUND: Primary motor cortex (M1) organization differs between individuals with and without chronic low back pain (CLBP), in parallel with motor and sensory impairments. This study investigated whether movement behaviour and tactile/pain sensation are related to M1 organisation in CLBP. METHODS: Transcranial magnetic stimulation (TMS) was used to map the M1 representation of the erector spinae and multifidus muscles in 20 participants with and without CLBP. Cortical organisation was quantified by: map volume; center of gravity (CoG); number of peaks; and primary and secondary peak location. Movement behaviour was assessed as the ability to dissociate lumbar from thorax motion and sensory function as two-point discrimination, pressure pain thresholds, and pain intensity (visual analogue scale). RESULTS: People with CLBP showed more anterior location of the CoG than controls. Map peaks were more numerous in CLBP participants who performed the movement task good than those with poor performance. In CLBP, smaller map volume correlated with greater pain during the movement task. Movement behaviour was not linearly correlated with M1 features. CONCLUSIONS: This study confirms that M1 maps differ between people with and without CLBP, but these changes are variable within the CLBP group and are not related to motor and sensory features in a simple manner. PMID- 28719507 TI - The Relationship Between Chronic Pain and Neurocognitive Function: A Systematic Review. AB - OBJECTIVE: Understanding the relationship between chronic pain and neurocognition has important implications for the assessment and treatment of patient experiencing pain. This paper provides an overview of the current literature examining the neurocognition-chronic pain relationship and suggests future avenues of research, along with a discussion of clinical implications of the literature findings. Consideration of potential moderators and mediators of this relationship, as well as a brief discussion of the importance of future research in special populations at particular risk for these problems, are also a focus of this paper. METHODS: This systematic review summarizes the findings of clinical studies in which neurocognitive performance was measured in chronic pain samples. A literature search led to the inclusion of 53 articles in the review. RESULTS: Studies of neurocognitive performance in clinical chronic pain samples support a relationship between chronic pain and neurocognitive abnormalities, particularly on tests of memory, attention, and processing speed, with mixed data regarding executive functioning. DISCUSSION: Several factors may moderate or mediate the relationship between chronic pain and neurocognitive functioning, including mood symptoms, medication side effects, and intensity and/or chronicity of pain. Limitations in the literature include a paucity of methodologically rigorous studies controlling for confounding variables (eg, opioid analgesia) and a limited number of studies examining the relationship between chronic pain and traumatic brain injury (a potential precipitant of both pain and neurocognitive impairment). Nonetheless, findings from the existing literature have significant clinical implications, including for populations with heightened risk of both pain and neurocognitive disorders. PMID- 28719509 TI - The Relationship Between Structural and Functional Brain Changes and Altered Emotion and Cognition in Chronic Low Back Pain Brain Changes: A Systematic Review of MRI and fMRI Studies. AB - OBJECTIVES: Chronic low back pain (CLBP) is a major health issue, yet its underlying mechanisms remain unknown. Studies have demonstrated the importance of emotion and cognition in chronic pain; however, the relevant brain physiology in magnetic resonance imaging (MRI) studies are unclear in CLBP populations. Therefore, this review aimed to identify MRI brain changes and examine their potential relationship with emotional and cognitive processes in CLBP. METHODS: A systematic search was conducted in 5 databases. Studies that recruited adult, CLBP populations, and used brain MRI protocols were included. RESULTS: In total, 55 studies met the inclusion criteria. Of the structural MRI studies, 10 of 15 studies found decreased gray matter and 7 of 8 studies found white matter changes in CLBP groups compared with controls. Fourteen resting-state functional MRI studies all reported differences between CLBP and control groups in the default mode network. Interestingly, only 3 of 10 functional MRI studies observed significant differences during noxious stimulation between CLBP and control groups, whereas 13 of 16 studies observed significant brain activation differences in CLBP groups during various external tasks. Finally, there were 3 studies that observed a degree of recovery in functional connectivity following intervention. DISCUSSION: The brain changes in CLBP groups were mainly observed in areas and networks important in emotion and cognition, rather than those typically associated with nociception. This supports the understanding that emotional and cognitive processes may be the core contributor to the CLBP experience; however, future studies need to explore these processes further. PMID- 28719511 TI - Plasma Cell Myeloma in Children and Young Adults: A Report of 4 Cases From a Single Institution and a Review of the Literature. AB - Plasma cell myeloma (PCM) is rare in children and young adults and therefore may be difficult to diagnose. Here we report the clinicopathologic findings of 4 patients under the age of 30 diagnosed with PCM at our institution and summarize the literature about 48 other cases of PCM in this age group. The male:female ratio was 1.2:1 and the number of cases increased with age. Children and young adults with PCM often present with a plasmacytoma and are less likely to have asymptomatic PCM than their adult counterparts. From the cases that reported ethnicity, the majority (55%) were non-white suggesting a possible ethnic predisposition to PCM in this age group. PCM should be included in the differential diagnosis of mass lesions, especially a destructive bony lesion, after more common causes have been ruled out in this age group. The optimal treatment for PCM in this patient population is unclear and conclusions into this are hampered by the paucity of cases and the lack of standardized follow-up. PMID- 28719510 TI - Evaluation of the Clinical and Laboratory Characteristics of Previously Followed up Thalassemia Intermedia Patients to Provide Them Better Care in the Future. AB - The increased awareness about the severity of complications in thalassemia intermedia patients led authorities to develop strategies for better management and follow-up of these patients. In this study, we aimed to define the clinical and laboratory characteristics in previously followed-up beta-thalassemia intermedia patients and wanted to gain an insight about the follow-up of this patient population in a developing country to provide them better care in the future. The mean age at diagnosis was 4 years, and the mean hemoglobin was 7.13 g/dL. The mean age at the beginning of regular transfusion was 4.8 years. An overall 74% of patients were on a regular transfusion program. The mean ferritin values at diagnosis and the last follow-up were 487 and 1225 ng/mL, respectively. The most common mutations detected in patients were IVS-I-110, IVS-I-6, IVS-II-1, and FCS 8/9 in order of frequency. Complications were seen in 48% of patients. The most common complications were osteopenia/osteoporosis (34%), growth retardation (24%), hypogonadism (18%), and cardiomyopathy (13%). In conclusion, the relatively higher complication rate in our patients who were previously treated highlights once again the need for an increased effort for optimal management and follow-up of this specific group of patients. PMID- 28719512 TI - A Pediatric Case of Persistent Thrombocytopenia in a Patient Who Developed All. AB - Inherited thrombocytopenia is a topic that was expanded greatly over the last decade and many new genes are being identified. However, inheritance patterns are not always easy to identify because sporadic cases from de novo mutations may in fact be more common. Few studies have assessed the relationship between thrombocytopenia and malignancies, specifically acute lymphoblastic leukemia (ALL). Here we present a pediatric case of persistent thrombocytopenia associated with T-cell ALL. Our patient was initially diagnosed with immune thrombocytopenic purpura with no evidence of malignancy on bone marrow biopsy but presented shortly after with ALL. PMID- 28719513 TI - Dihydrofolate Reductase Genetic Polymorphisms Affect Methotrexate Dose Requirements in Pediatric Patients With Acute Lymphoblastic Leukemia on Maintenance Therapy. AB - We have aimed to determine the effect of polymorphisms in regulatory regions of the DHFR gene in relation to methotrexate (MTX) dose adjustments and drug-induced toxicity in children on maintenance therapy for acute lymphoblastic leukemia (ALL). In total, 41 children diagnosed with ALL were screened for 3 tag-single nucleotide polymorphisms in the DHFR promoter (C-1610G, C-680G/T, A-317G) and an intronic 19-bp insertion/deletion. Genotypes were analyzed in relation to dose requirements and toxicity. The percentage of MTX dose administered (with respect to protocol-recommended values) was affected by DHFR polymorphisms. Carriers of the -680AA genotype displayed a median percentage of 44.08 (interquartile range=34.69), compared with 77.98 (interquartile range=33.90) for CC and CA carriers (P=0.01). The number of counts within white blood cell therapeutic range (2.0 to 3.0*10/L) was higher for -680AA carriers than for CC/CA carriers (P=0.003). With regard to toxicity, carriers of the -680AA genotype displayed more treatment interruptions than CC/CG carriers (P=0.03), as well as more episodes of severe neutropenia (P=0.04) and higher number of blood counts with elevated levels (>400 mg/dL) of lactate dehidrogenase (P=0.04). Overall, our findings suggest that the identification of DHFR polymorphisms in the promoter region of the gene may be helpful in tailoring MTX doses for ALL pediatric patients on maintenance therapy. PMID- 28719514 TI - Mature Ovarian Teratoma After Treatment for Unilateral Retinoblastoma With Nonmutated RB1. PMID- 28719515 TI - Anaesthetic management of patients with myopathies. AB - : The anaesthetic management of patients with myopathies is challenging. Considering the low incidence and heterogeneity of these disorders, most anaesthetists are unfamiliar with key symptoms, associated co-morbidities and implications for anaesthesia. The pre-anaesthetic assessment aims at the detection of potentially undiagnosed myopathic patients and, in case of known or suspected muscular disease, on the quantification of disease progression. Ancillary testing (e.g. echocardiography, ECG, lung function testing etc.) is frequently indicated, even at a young patient age. One must differentiate between myopathies associated with malignant hyperthermia (MH) and those that are not, as this has significant impact on preoperative preparation of the anaesthesia workstation and pharmacologic management. Only few myopathies are clearly associated with MH. If a regional anaesthetic technique is not possible, total intravenous anaesthesia is considered the safest approach for most patients with myopathies to avoid anaesthesia-associated rhabdomyolysis. However, the use of propofol in patients with mitochondrial myopathies may be problematic, considering the risk for propofol-infusion syndrome. Succinylcholine is contra indicated in all patients with myopathies. Following an individual risk/benefit evaluation, the use of volatile anaesthetics in several non-MH-linked myopathies (e.g. myotonic syndromes, mitochondrial myopathies) is considered to be well tolerated. Perioperative monitoring should specifically focus on the cardiopulmonary system, the level of muscular paralysis and core temperature. Given the high risk of respiratory compromise and other postoperative complications, patients need to be closely monitored postoperatively. PMID- 28719516 TI - Echocardiography and passive leg raising in the postoperative period: A prospective observational study. AB - BACKGROUND: Signs of hypovolaemia are frequent in the postoperative period, but not all patients need or respond to fluid administration. An increase in cardiac output (CO) after passive leg raising (PLR) has been demonstrated to be useful as a volume response predictor in non-surgical, spontaneously breathing patients. OBJECTIVE: The objective of this study was to evaluate the accuracy of transthoracic echocardiography after PLR to predict fluid responsiveness in post surgical patients. DESIGN: A prospective observational study. SETTING: A tertiary hospital between January and July 2015. PATIENTS: Fifty-one spontaneously breathing postoperative patients with suspected hypovolaemia (arterial hypotension, oliguria, tachycardia or delayed capillary refill) were considered for the study. INTERVENTION: Demographic and personal data were collected, as well as heart rate variations, mean arterial pressure during PLR and after administering 500 ml of Ringer's lactate solution. CO was measured by transthoracic echocardiography. MAIN OUTCOME MEASURES: The primary outcome was measurement of CO before and after PLR and Ringer's lactate administration. RESULTS: Forty-one patients were included in the study (six patients were excluded because of a poor echocardiographic window and four because of misalignment of the Doppler and outflow tract of the left ventricle). Twenty-two patients (54%) were considered responders to fluid therapy, with an increase of stroke volume greater than or equal to 15% after 500 ml lactated Ringer's infusion. The highest area under the curve was found for an increase in CO (0.91 +/- 0.05; 95% confidence interval 0.78 to 0.97). An increase in CO greater than 11% after the PLR manoeuvre predicts a volume response with 68% sensitivity and 100% specificity. CONCLUSION: This is the first study showing that measurement of CO after PLR can predict volume response in spontaneously breathing postoperative patients. PMID- 28719524 TI - Establishing Obstetric Anesthesiology Practice Guidelines in the Republic of Armenia: A Global Health Collaboration. AB - BACKGROUND: Disparity exists in anesthesia practices between high- and low-to middle income countries, and awareness has been raised within the global health community to improve the standards of anesthesia care and patient safety. The establishment of international collaborations and appropriate practice guidelines may help address clinical care deficiencies. This report's aim was to assess the impact of a multiyear collaboration on obstetric anesthesia practices in the Republic of Armenia. METHODS: An invited multinational team of physicians conducted six visits to Armenia between 2006 and 2015 to observe current practice and establish standards of obstetric anesthesia care. The Armenian Society of Anaesthesiologists and Intensive Care specialists collected data on the numbers of vaginal delivery, cesarean delivery, and neuraxial anesthesia use in maternity units during the period. Data were analyzed with the Fisher exact or chi-square test, as appropriate. RESULTS: Neuraxial anesthesia use for cesarean delivery increased significantly (P < 0.0001) in all 10 maternity hospitals within the capital city of Yerevan. For epidural labor analgesia, there was sustained or increased use in only two hospitals. For hospitals located outside the capital city, there was a similar increase in the use of neuraxial anesthesia for cesarean delivery that was greater in hospitals that were visited by an external team (P < 0.0001); however, use of epidural labor analgesia was not increased significantly. Over the course of the collaboration, guidelines for obstetric anesthesia were drafted and approved by the Armenian Ministry of Health. CONCLUSIONS: Collaboration between Armenian anesthesiologists and dedicated visiting physicians to update and standardize obstetric anesthesia practices led to national practice guidelines and sustained improvements in clinical care in the Republic of Armenia. PMID- 28719527 TI - Pupillometry-guided Intraoperative Remifentanil Administration versus Standard Practice Influences Opioid Use: A Randomized Study. AB - BACKGROUND: Pupillometry has shown promising results for assessing nociception in anesthetized patients. However, its benefits in clinical practice are not demonstrated. The aim of this prospective randomized study was to evaluate the impact of intraoperative pupillometry monitoring on perioperative opioid consumption in major gynecologic surgery. METHODS: After receiving ethics committee approval and written consent of patients, American Society of Anesthesiologists status I to II women undergoing gynecologic surgery were included in this single-blinded, prospective, parallel-arm randomized study. General anesthesia was standardized with propofol-remifentanil target-controlled infusion. Patients were randomly assigned into two groups. In the pupillometry group, remifentanil administration was guided by pupillary diameter changes. In the standard group, remifentanil administration was left to the discretion of the anesthesiologist. The primary outcome was intraoperative remifentanil consumption. RESULTS: Fifty-five patients were analyzed. Remifentanil consumption was markedly decreased in the pupillometry group (3.8 [3.4 to 4.8 ug . kg . h] vs. 7.9 ug . kg . h [6.5 to 9.0 ug . kg . h] in the standard group; difference = 4.2 ug . kg . h [95% CI, 3.0 to 5.3 ug . kg . h]; P < 0.001). Cumulative 0- to 12 h morphine consumption was reduced in the pupillometry group (two-way repeated measures ANOVA 0.3 +/- 0.1 vs. 0.4 +/- 0.2 mg/kg; P = 0.048). A telephone survey 3 months after surgery revealed that 15 of 29 patients in the standard group still experienced procedure-related pain versus 3 of 23 in the pupillometry group (chi-square P = 0.037). No adverse events associated with pupillometry were observed during the study. CONCLUSIONS: The use of pupillometry to guide intraoperative analgesia reduced intraoperative remifentanil consumption and postoperative morphine requirements. The possible consequences of decreasing intraoperative remifentanil in terms of chronic pain require further investigation. PMID- 28719530 TI - Images in Anesthesiology: Congenital Pulmonary Airway Malformation. PMID- 28719531 TI - Nocturnal Dexmedetomidine in Nonintubated, Critically Ill Patients: Sleep or Sedation? PMID- 28719532 TI - Low-dose, Nontitrated Dexmedetomidine Trials: Clarifying Possible Coenrollment. PMID- 28719533 TI - In Reply. PMID- 28719534 TI - Is the PeriOperative ISchemic Evaluation-2 Trial Equipoised? PMID- 28719535 TI - Venous Thromboembolism Prevention: The Evidence for Aspirin? PMID- 28719536 TI - In Reply. PMID- 28719537 TI - The Effect of SLT Laser Application on Iris to Treat Sectorial Heterochromia: A Promising Technique. AB - The purpose of this study is to report a new and promising method for changing iris color in a sectorial heterochromia iridis patient. A 22-year-old man with a complaint of innate color disparity between his eyes presented to our clinic to seek medical advice. He underwent a comprehensive ophthalmic examination, including visual acuity, biomicroscopy, fundoscopy, intraocular pressure measurements, endothelial cell count, and evaluation of iridocorneal angle. The causes of acquired heterochromia were excluded. After a detailed explanation of the procedure and probable side effects, the patient underwent an application with a laser device that produces a frequency-doubled 532 nm wavelength Nd:YAG laser beam with a spot size of 400 MUm (selective laser trabeculoplasty laser device). The heterochromic areas (brown) were divided into zones and a gradual treatment pattern was performed to avoid inflammation and flare. The patient showed no side effects such as increased intraocular pressure, pain, corneal edema, hypopyon formation, decrease in visual acuity, synechia, or iris defect. After two complete sessions, the color difference disappeared and a solid eye color was achieved. PMID- 28719538 TI - MiSight Assessment Study Spain: A Comparison of Vision-Related Quality-of-Life Measures Between MiSight Contact Lenses and Single-Vision Spectacles. AB - OBJECTIVES: Recent research has shown that concentric contact lenses (CLs) can be a way to control the progression of myopia. The purpose of the current study was to compare vision-related quality-of-life measures in children wearing distance single-vision (SV) spectacles versus MiSight CLs, a specific concentric design for myopia control. METHODS: Subjects aged 8 to 12 with myopia from -0.75 to 4.00 diopters (D) of sphere and astigmatism less than 1.00 D of cylinder were allocated to the lenses study group (MiSight) or control group (SV). A Pediatric Refractive Error Profile (PREP) questionnaire was administered at 12- and 24 month intervals to evaluate children's perceptions in overall vision, near vision, far distance vision, symptoms, appearance, satisfaction, activities, academic performance, handling, and peer perceptions. The mean score of all items was calculated as the overall score. RESULTS: In total, 74 children completed the study: n=41 in the MiSight group and n=33 in the SV group. In the MiSight group, the ratings at 12 and 24 months for appearance, satisfaction, effect on activities, handling, and peer perceptions were significantly better than those given by children in the SV group (P<0.001), as was the overall score. However, near vision was significantly better in the SV group at both 12 and 24 months (P<0.001). CONCLUSIONS: MiSight CL wear for controlling myopia improves vision related quality of life in children when compared with spectacle wear. PMID- 28719539 TI - Inflammatory Bowel Disease Pharmacist Adherence Counseling Improves Medication Adherence in Crohn's Disease and Ulcerative Colitis. AB - BACKGROUND: While inflammatory bowel diseases (IBD) require long-term medication usage to maintain remission, nonadherence is common and adversely associated with poorer clinical outcomes. Personalized IBD Pharmacist Adherence Counselling, based on the Health Beliefs Model of medication perception, may increase medication adherence. METHODS: This prospective multi-center longitudinal parallel study recruited consecutive IBD subjects that were classified as baseline medication non-adherers and adherers. Non-adherers received a single IBD Pharmacist Adherence Counselling intervention at baseline, while adherers served as controls. Medication Adherence Report Scale and Beliefs about Medicines Questionnaire were administered up to 24 months. Medication acceptance was defined as high perception of medication necessity with low concerns. The primary endpoint was medication adherence at 24 months. RESULTS: Of 114 subjects approached, 100 completed follow-up, with 36 being baseline nonadherers (median Medication Adherence Report Scale = 15.0) and 64 baseline adherers (median Medication Adherence Report Scale = 19.0; P < 0.001). At 24 months, nonadherence in the IBD Pharmacist Adherence Counselling group decreased from 100% to 44.4% (P = 0.001), whereas nonadherence in controls remained unchanged (P = 0.38). Individually, Beliefs about Medicines Questionnaire Necessity and Concern scores showed no significant changes in both groups, but medication acceptance significantly improved in baseline nonadherers at 12 months (P = 0.031) with a trend toward durable improvement at 24 months (P = 0.063). CONCLUSIONS: Medication nonadherence in IBD can be improved through a single personalized counseling session by an IBD pharmacist, and the benefit was durable for 2 years. This benefit was through improving the acceptance of medication. PMID- 28719540 TI - Clinical Predictors of the Risk of Early Colectomy in Ulcerative Colitis: A Population-based Study. AB - BACKGROUND: A subset of patients with ulcerative colitis (UC) will require colectomy within a few years of diagnosis. Thus, our aim was to determine the clinical predictors of early colectomy among patients with UC who are hospitalized with an acute flare. METHODS: Using population-based surveillance (1996-2009), all adults (>=18 years) hospitalized for UC within 3 years of diagnosis (n = 489) were identified. The primary outcome was a colectomy within 3 years of diagnosis. All medical charts were reviewed. A logistic regression model evaluated clinical variables that predicted colectomy within 3 years of diagnosis, and adjusted odds ratios (ORs) with 95% confidence intervals (CIs) were reported. RESULTS: Among patients admitted to hospital with UC within 3 years of diagnosis, 57.7% underwent colectomy, with the odds of colectomy decreasing by 12% per year. Early colectomy was more likely among patients aged 35 to 64 years versus 18 to 34 years (OR 2.18 [95% CI, 1.27-3.74]), males (OR 2.03 [95% CI, 1.24-3.34]), those with pancolitis (OR 5.38 [95% CI, 3.20-9.06]), and living in rural areas (OR 2.81 [95% CI, 1.49-5.29]). Prescription of infliximab before hospitalization increased odds of surgery (OR 5.12 [95% CI, 1.36-19.30]). CONCLUSIONS: Patients hospitalized for UC have a high risk of early colectomy. This is particularly true in middle-aged men, those living in rural areas, and those without response to infliximab. PMID- 28719541 TI - Systematic Review and Meta-analysis: Adalimumab Monotherapy Versus Combination Therapy with Immunomodulators for Induction and Maintenance of Remission and Response in Patients with Crohn's Disease. AB - BACKGROUND: It is unclear whether the combination of adalimumab (ADA) and immunomodulators is superior to ADA monotherapy in patients with Crohn's disease. METHODS: PubMed, Medline, Embase, Web of Science, and other databases were searched. Randomized controlled trials, open-label, prospective cohort, and retrospective studies, and pooled analyses were included. Primary outcomes were induction (<=12 wk) and maintenance (up to 56 wk) of remission and response. Secondary outcomes were severe adverse events, opportunistic infections, and development of antibodies to adalimumab. RESULTS: Twenty-four of 1194 articles were eligible for inclusion. No significant difference was noted between regimens for induction of remission (odds ratio [OR] 0.86; 95% confidence interval [CI]: 0.70-1.06; P = 0.19) and response (OR 1.01; 95% CI: 0.62-1.65; P = 0.96). Similarly, no difference was noted for maintenance of remission (OR 0.97; 95% CI: 0.79-1.14; P = 0.75) or response (OR 0.91; 95% CI: 0.54-1.54; P = 0.74). Severe adverse events and opportunistic infections were not different between arms. Patients on combination therapy had lower odds of developing antibodies to adalimumab (OR 0.24; 95% CI: 0.07-0.82; P = 0.02). Subgroup and sensitivity analyses showed significantly higher odds of successful induction (OR 1.26; 95% CI: 1.06-1.49, P = 0.008) and opportunistic infections (OR 2.44; 95% CI: 1.07 5.54, P = 0.03) in anti-TNF-experienced patients. CONCLUSIONS: The combination of ADA and immunomodulators does not seem superior to ADA monotherapy for induction and maintenance of remission and response in Crohn's disease. Combination therapy is associated with lower immunogenicity. Analyses associating combination therapy with better induction of remission in anti-TNF-experienced patients and a higher rate of opportunistic infections deserve further evaluation. PMID- 28719542 TI - Cideb Deficiency Aggravates Dextran Sulfate Sodium-induced Ulcerative Colitis in Mice by Exacerbating the Oxidative Burden in Colonic Mucosa. AB - BACKGROUND: Abnormal lipid metabolism is one of many factors that contribute to the development of ulcerative colitis (UC). As a lipid droplet-associated protein, Cideb facilitated the export of lipids from enterocytes and promoted intestinal lipid absorption. We found that Cideb was upregulated in the colonic mucosa of both UC patients and dextran sodium sulfate (DSS)-induced mouse colitis, but its roles in the pathogenesis of UC are still ill-defined. METHODS: Acute colitis was induced with DSS in Cideb-null and wild-type mice, and the inflammation and oxidative stress were evaluated in the colonic mucosa. Moreover, triglyceride accumulation and oxidative stress were further analyzed in polarized Caco-2 cells with overexpression of Cideb. RESULTS: Our present data indicated that Cideb-null mice were more susceptible to DSS-induced colitis, and consumption of a high-fat diet exacerbated the deterioration of DSS-induced colitis in Cideb-null mice. Moreover, Cideb deficiency increased the colonic oxidative stress in DSS-treated mice and more significant under a high-fat diet condition. In exploring the mechanism, we found that Cideb deficiency elevated the lipid content in both feces and the colonic mucosa of DSS-treated mice, especially those fed with a high-fat diet. The in vitro evidence proved that Cideb expression reduced triglyceride accumulation and oxidative stress in polarized Caco-2 cells in the presence of oleic acid. CONCLUSIONS: Our data suggest that Cideb plays a protective role against the development of UC by reducing the lipid accumulation and oxidative damage in the colonic mucosa. Therefore, Cideb could be a potential therapeutic target for UC. PMID- 28719543 TI - The Association Between Maternal Chronic Inflammatory Bowel Disease and Long-term Health Outcomes in Children-A Nationwide Cohort Study. AB - BACKGROUND: Very little is known about the long-term impact of maternal inflammatory bowel disease (IBD) on the offspring's future health. We aimed to examine whether children born to mothers with IBD had an increased risk of long term morbidities. METHODS: In this nationwide register-based cohort study, including all children born alive in Denmark between 1989 and 2013, we investigated the association between maternal IBD and 15 selected disease categories of physical and mental conditions in the offspring. We used multivariate regression models estimating the hazard ratio (HR) of long-term child morbidities. RESULTS: The cohort comprised 9238 children born to women with IBD (exposed), and 1,371,407 born to women without IBD (unexposed). Median follow up time among the exposed was 9.7 years (interquartile range [IQR] 4.9-15.7) and 13.8 (interquartile range 7.4-19.9) among the unexposed. In children, who in utero had been exposed to maternal ulcerative colitis, the HR of IBD in the offspring was 4.63 (95% confidence interval, 3.49-6.16). For maternal Crohn's disease, the HR of IBD in the offspring was 7.70 (95% confidence interval, 5.66 10.47). For all other diseases in the offspring, we did not find a significantly increased risk associated with maternal IBD. CONCLUSIONS: Children born to mothers with IBD are more likely to be diagnosed with IBD themselves, compared with children born to women without IBD. Our data otherwise do not provide evidence for an increased risk of any of the other examined diseases in the offspring. PMID- 28719544 TI - Postoperative Pyoderma Gangrenosum in Children: The Case Report of a 13-Year-Old Boy With Pyoderma Gangrenosum After Hip Reconstruction Surgery and a Review of the Literature. AB - BACKGROUND: Postoperative pyoderma gangrenosum (PG) is a neutrophilic dermatosis and pathergic reaction at surgical sites. Reports of children with postoperative PG are rare in the literature. METHODS: We report the case of a 13-year-old boy without any known preexisting illnesses, who developed severe systemic response and wound deterioration after elective hip reconstruction surgery. The working diagnosis of necrotizing fasciitis was later determined to be postoperative PG. RESULTS: The patient was successfully treated by the systemic application of corticosteroids. CONCLUSIONS: Postoperative PG is a very rare complication after surgery, especially in children. If mistaken for necrotizing fasciitis, it can substantially mutilate a patient because PG is worsened by surgical debridement. It can be treated successfully only by corticosteroids and other immunosuppressive drugs. LEVEL OF EVIDENCE: Level IV-this is a case report. PMID- 28719545 TI - Social Media in Pediatric Orthopaedics. AB - BACKGROUND: Internet searches and social media utilization in health care has exploded over the past 5 years, and patients utilize it to gain information on their health conditions and physicians. Social media has the potential to serve as a means for education, communication, and marketing in all health care specialties. Physicians are sometimes reluctant to engage because of concerns of privacy, litigation, and lack of experience with this modality. Many surgical subspecialties have capitalized on social media but no study to date has examined the specific footprint of pediatric orthopaedic surgeons in this realm. We aim to quantify the utilization of individual social media platforms by pediatric orthopaedic surgeons, and identify any differences between private and hospital based physicians, but also regional differences. METHODS: Using the Pediatric Orthopaedic Society of North America Member Directory, each active member's social media presence was reviewed through an Internet search. Members were stratified on the basis of practice model and geographic location. Individual Internet searches, social media sites, and number of publications were reviewed for social media presence. RESULTS: Of 987 Pediatric Orthopaedic Society of North America members, 95% had a professional webpage, 14.8% a professional Facebook page, 2.2% a professional Twitter page, 36.8% a LinkedIn profile, 25.8% a ResearchGate profile, 33% at least 1 YouTube. Hospital-based physicians had a lower mean level of utilization of social media compared with their private practice peers, and a higher incidence of Pubmed publications. Private practice physicians had double the social media utilization. Regional differences reveal that practicing Pediatric Orthopaedists in the Northeast had increased utilization of ResearchGate and LinkedIn and the West had the lowest mean social media utilization levels. CONCLUSIONS: The rapid expansion of social media usage by patients and their family members is an undeniable force affecting the health care industry. The Internet and social media platforms provide all physicians with a means to educate patients, collaborate with colleagues, and promote their practice and areas of interest. Our survey indicates that pediatric orthopaedic surgeons may be underutilizing their potential social media presence. LEVELS OF EVIDENCE: Level IV. PMID- 28719546 TI - Fracture Table Application for Pediatric Femur Fractures: Incidence and Risk Factors Associated With Adverse Outcomes. AB - BACKGROUND: Flexible elastic nails, submuscular plating, and rigid locked intramedullary nails are common methods of fixation for pediatric femur fractures (PFF) in which the fracture table is used to aid reduction. Little is known about complications associated with fracture table application in PFF. The purpose of this study was to determine the incidence and risk factors associated with adverse outcomes related to fracture table application for the treatment of PFF. METHODS: A retrospective chart review of all children (younger than 18 y) treated for a femur fracture with the use of the fracture table between 2004 and 2015 at a single tertiary pediatric hospital was performed. Data on demographics, mechanism of injury, treatment modality, radiographic characteristics, and fracture table-related complications were gathered. Complications of interest included nerve palsy, skin breakdown/ulceration, vascular injury, and compartment syndrome. Penalized likelihood logistic regression was used to determine risk factors associated with adverse outcomes. RESULTS: In total, 260 patients were included. There were 8 patients with nerve palsies related to positioning and traction on the fracture table (1 bilateral and 6 ipsilateral peroneal nerve palsies, 1 contralateral tibial nerve palsy; incidence of 3.1%). No other fracture table-related complications were recorded. Patients who developed a nerve palsy were significantly heavier (78.7 vs. 44.3 kg, P<0.001) and had a significantly longer mean surgical time (188.6 vs. 117.0 min, P<0.001). Multivariate analysis demonstrated weight to be the only significant risk factor for complications, with a 5% increase in odds of complication with each additional kilogram (odds ratio, 1.05; confidence interval, 1.03-1.08; P<0.001). CONCLUSIONS: Nerve palsy related to the use of the fracture table during the fixation of PFF occurred in 3.1% of patients in our series. Patients who developed nerve palsies were significantly heavier and had significantly longer surgical times. Although the use of the fracture table for fixation of PFF is safe, every effort should be made to minimize time in traction to avoid iatrogenic nerve palsy, particularly in heavier children (>80 kg). LEVEL OF EVIDENCE: Level III. PMID- 28719547 TI - Growth Modulation in Achondroplasia. AB - INTRODUCTION: Achondroplasia is the most common skeletal dysplasia with a rate of nearly 1/10,000. The development of lower extremity deformity is well documented, and various modes of correction have been reported. There are no reports on the use of growth modulation to correct angular deformity in achondroplasia. METHODS: Medical Records from 1985 to 2015 were reviewed for the diagnosis of achondroplasia and growth modulation procedures. Patients who had been treated for angular deformity of the legs by growth modulation were identified. A detailed analysis of their medical record and preoperative and final lower extremity radiographs was completed. RESULTS: Four patients underwent growth modulation procedures, all to correct existing varus deformity of the legs. Three of the 4 patients underwent bilateral distal femoral and proximal tibial growth modulation. The remaining patient underwent tibial correction only. Two of the 4 patients had a combined proximal fibular epiphysiodesis. All limbs had some improvement of alignment; however, 1 patient went on to bilateral osteotomies. Only 1 limb corrected to a neutral axis with growth modulation alone at last follow-up, initial implantation was done before 5 years of age. CONCLUSIONS: Growth modulation is an effective means for deformity correction in the setting of achondroplasia. However implantation may need to be done earlier than would be typical for patients without achondroplasia. Osteotomy may still be required after growth modulation for incomplete correction. PMID- 28719548 TI - Forearm Pronation Osteotomy for Supination Contracture Secondary to Obstetrical Brachial Plexus Palsy: A Retrospective Cohort Study. AB - BACKGROUND: Obstetrical brachial plexus palsy can lead to fixed forearm supination contracture. Fixed supination may lead to functional deficits as the affected hand cannot be positioned optimally for activities on a desk such as writing and typing, or for using tools including utensils, which require a neutral or pronated forearm. Forearm pronation osteotomy has been used to address this problem, although the functional benefit over nonoperative management has not been clearly defined. Potentially deleterious consequences on hand function that requires supination or fine motor skills are also uncertain. METHODS: Patients with fixed forearm supination contracture were selected from our institutional brachial plexus database. Those who underwent both bone forearm rotational osteotomy were analyzed for age at time of surgery, preoperative forearm resting position, active and passive supination and pronation, and preoperative function assessed by the brachial plexus outcome measure (BPOM) and active movement scale (AMS). Preoperative results were compared with values obtained at follow-up at least 12 months postoperatively. A matched cohort of children with fixed forearm supination contracture that were treated nonoperatively and followed for at least 12 months, was also selected. For this group, forearm resting position, movement, AMS, and BPOM scores were analyzed at a baseline clinic visit and the most recent follow-up. Changes in forearm resting position, AMS, and BPOM activity scale scores were then compared between groups. RESULTS: Records were obtained for 14 cases and 10 controls. Study groups were similar with respect to resting forearm position, hand function, and time from initial to final evaluation. Groups differed with respect to age and active supination. We observed a statistically significant change in resting position among operative patients compared with their preoperative status and compared with controls. Hand-specific AMS score did not change significantly in the operative group as compared with controls. The BPOM score for drums, reflective of function in neutral rotation to mild pronation, improved in the operated patients as compared with controls. There was no loss of plate holding ability (reflective of supination function, putty (grasp), or bead placement (fine motor) among the operated patients as compared with controls. CONCLUSIONS: By pronating resting forearm position by about 90 degrees to near neutral, osteotomy resulted in improved neutral to mild pronation-dependent function without loss of supination-dependent function or hand motor skills. LEVEL OF EVIDENCE: Level III retrospective cohort study. PMID- 28719549 TI - Long-term Follow-up of Neonatal Brachial Plexopathy: Psychological and Physical Function in Adolescents and Young Adults. AB - PURPOSE: The prevalence of neonatal brachial plexus palsy (NBPP) has been increasing since the early 1980s. No known studies have examined long-term psychological health and quality of life (QOL) in young adults. The purpose of this study was to investigate the psychosocial and intellectual aspects of NBPP during adolescence into young adulthood. METHODS: A total of 31 patients were enrolled in the adolescent group (16 to 18 y) and 25 in the young adult group (23 to 28 y). Clinical assessment included functional ability, range of motion and strength, weight and body mass index, and education level. Patients were administered measures of psychiatric symptomatology, self-concept, QOL, and cognitive function. RESULTS: Narakas injury level for the adolescent group included 11 level I, 6 level II, 8 level III, and 6 level IV. The young adult group had 10 level I, 2 level II, 9 level III, and 4 level IV. The degree of physical impairment determined by the Modified Mallet Classification showed persistent impairment in both groups. The average DASH scores were higher than the normal range for the adolescent and young adult groups. Forty-five percent of the adolescents and 68% of the young adults were either overweight or obese. All received high school diplomas with 20 of the young adults pursuing higher education.Scores on measures of psychiatric symptomatology and self-concept showed that both groups fell within the normal range. QOL for both groups was also within the normal range. All participants scored average to above average on the cognitive assessment. All measurements were patient reported. CONCLUSIONS: Patients with NBPP can adapt and participate in most activities. This patient sample demonstrated persistent functional limitations and a higher rate of comorbid obesity. However, these patients function psychologically and cognitively within the normal range and many have pursued higher education. LEVEL OF EVIDENCE: Level IV. PMID- 28719550 TI - Does an Annular Puncture Influence the Herniation Path?: An In Vitro Mechanical and Structural Investigation. AB - STUDY DESIGN: A study of mechanically induced herniation in punctured ovine discs followed by structural analysis. OBJECTIVE: To investigate whether an annular puncture influences the path that herniation takes by providing direct passage for nucleus through the annulus and therefore whether it increases the risk of acute herniation from overload at the site of damage independent of any longer term degeneration. SUMMARY OF BACKGROUND DATA: Ten years after treatment with discography both degenerative changes and frequency of herniation have been shown to increase compared to untreated discs. Although the effect of an annular puncture over time has been widely investigated the question of whether it increases the risk of acute herniation has not been resolved. METHODS: The posterolateral annuli of healthy ovine lumbar discs were punctured with either a 25-gauge (n = 8) or a larger 18-gauge (n = 8) needle and then compressed in a flexed posture of 10 degrees until initial indications of failure. The entire volume of the disc was visually assessed for structural damage by obtaining progressive, full transverse cross-sections of its entire height thus exposing all regions of the disc. RESULTS: There was no association between the 25-gauge puncture and disc disruption and herniation. In contrast, nuclear material was observed to migrate through the 18-gauge needle puncture. Disruption of the lateral inner annulus was observed in 12 out of the 16 discs tested. CONCLUSION: The risk of acute herniation through the puncture site is dependent on the needle diameter used. Under the conditions employed the lateral inner annulus remains the site most vulnerable to disruption independent of the presence of a posterolateral puncture. LEVEL OF EVIDENCE: N /A. PMID- 28719551 TI - Annulus Fibrosus Repair Using High-Density Collagen Gel: An In Vivo Ovine Model. AB - STUDY DESIGN: Ovine in vivo study. OBJECTIVE: To perform lateral approach lumbar surgery in an ovine model to administer an injectable riboflavin cross-linked high-density collagen (HDC) gel and to assess its ability to mitigate intervertebral disc (IVD) degeneration after induced annulus fibrosus (AF) injury. SUMMARY OF BACKGROUND DATA: Biological-based injectable gels have shown efficacy in restoring biomechanical, radiographic, and histological parameters in IVD-injured animal models. Riboflavin cross-linked HDC gel has previously demonstrated retention of nucleus pulposus (NP) tissue, reduced loss of disc height, and prevention of terminal cellular degenerative changes in rat-tail spines. However, this biological therapy has never been tested in large animal models. METHODS: Forty lumbar IVDs were accessed from eight sheep via lateral approach surgery. IVDs were randomly assigned to healthy control, injury and HDC treatment, or negative control with injury and no treatment. IVD injury was carried out using a drill-bit through the AF followed by needle puncture of the NP. Sheep were followed for 16 weeks and underwent qualitative/quantitative magnetic resonance imaging, x-ray, and histological analyses of collagen and proteoglycan content. RESULTS: The lateral approach to the ovine lumbar spine to deliver HDC gel proved to be safe and reproducible. IVDs treated with the HDC gel revealed less degenerative changes at the microscopic level based on AF and NP histology. However, mean Pfirrmann grade, T2 relaxation time, NP voxel size, and disc height index were not significantly different between the two injury groups. CONCLUSION: Injectable HDC gel can be administered safely via lateral approach surgery in an ovine AF injury model. IVDs treated with HDC gel demonstrated less degeneration at the microscopic level though radiographic changes were slight when comparing treated to untreated IVDs. Future studies will need to elucidate the role of injury technique and time frame for follow-up in correlating histological and radiographical outcomes. LEVEL OF EVIDENCE: N /A. PMID- 28719552 TI - Immune Checkpoint Inhibitors in Organ Transplant Patients. AB - Modulation of T-cell activity through blockade of coinhibitory molecules has revolutionized the treatment of various malignancies. Several immune checkpoint inhibitors are currently Food and Drug Administration approved which target various coinhibitory pathways including cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed death 1 receptor (PD-1), and programmed cell death ligand 1. Clinical trials that lead to the Food and Drug Administration approval of these agents often excluded patients with an organ transplant. Excluding these patients was deliberate due to concern that immune checkpoint inhibitor therapy could lead to graft rejection. The PD-1 and CTLA-4 pathways are essential to downregulate our immune system in the setting of T-cell activation to prevent autoimmunity. Furthermore, both pathways are implicated in transplanted organ tolerance and modulation of the pathways may inadvertently lead to peripheral transplant rejection. Currently, there are no guidelines for the treatment of patients with immune checkpoint inhibitors in the setting of a prior organ transplant. Thus far, there are only 10 reported cases of patients in the literature who were treated in this setting. Two additional cases are reported herein, including 1 patient with a prior cardiac transplant receiving nivolumab for non-small cell lung cancer. Of the 12 cases, 4 patients experienced organ rejection. From these observations, the authors hypothesize factors that affect safety and of this treatment modality in this patient population. These factors include the integral role of the PD-1 pathway compared with the CTLA-4 pathway in organ acceptance, sequential implementation of different immune checkpoint inhibitor classes, length of time with a transplant before therapy, strength of immunosuppressive agents to prevent organ transplant rejection, and immunogenicity of the particular organ grafted. Although limited cases have been reported, there are circumstances in which immune checkpoint inhibitors have been used in the setting of organ transplantation without resulting in organ rejection. A thorough discussion with the patient of the potential risks, including graft rejection, and benefits of this therapy is necessary before beginning this treatment. More research is needed to explore the safety and efficacy of immune checkpoint inhibitors in the setting of organ transplantation. PMID- 28719554 TI - Treatment of Displaced Midshaft Clavicle Fractures: Figure-of-Eight Harness Versus Anterior Plate Osteosynthesis: A Randomized Controlled Trial. AB - BACKGROUND: Most midshaft clavicle fractures affect the economically active population, which is negatively impacted by transient limb impairment during the treatment. There is still debate about the advantages and disadvantages of surgical treatment for these fractures. METHODS: In this prospective randomized controlled trial, 117 patients were allocated to 1 of 2 groups: nonsurgical treatment with a figure-of-eight harness or surgical treatment with anteroinferior plate osteosynthesis. The primary outcome was upper-limb limitation measured with the Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire at 6 months. Other outcomes included pain, radiographic findings, satisfaction with the cosmetic result, complications, and time to return to previous work and activities. Participants were assessed at 6 weeks, 6 months, and 1 year after the intervention. RESULTS: No difference between the 2 groups was detected in the DASH score at any time point (p = 0.398, 0.403, and 0.877 at 6 weeks, 6 months, and 1 year, respectively), pain levels measured with a visual analogue scale (VAS), time to return to previous activities, or dissatisfaction with the cosmetic result. Seven patients (14.9%) developed nonunion after nonsurgical treatment, a nonunion rate that was significantly higher than that in the surgical group, in which all fractures had healed (p = 0.004). The patients in the nonsurgical group had radiographic evidence of greater clavicle shortening (p < 0.001) and more of the patients in that group answered "yes" when asked if their clavicle felt short (p < 0.001) and if they felt bone prominence (p < 0.001). More patients answered "yes" when asked if they felt paresthesia in the surgical group (7; 13.7%) than in the nonsurgical group (1; 2.1%) (p = 0.036). CONCLUSIONS: This study did not demonstrate a difference in limb function between patients who underwent surgical treatment and those nonsurgically treated for a dislocated midshaft clavicle fracture. Meanwhile, surgical treatment decreased the likelihood of nonunion. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence. PMID- 28719556 TI - Inadvertent Harvest of the Median Nerve Instead of the Palmaris Longus Tendon. AB - BACKGROUND: The palmaris longus tendon is frequently used as a tendon graft or ligament replacement. In rare instances the median nerve has been inadvertently harvested instead of the palmaris longus for use as a tendon. METHODS: Nineteen cases in which the median nerve had been mistakenly harvested instead of the palmaris longus tendon were collected from members of the American Society for Surgery of the Hand (ASSH) Listserve. Surgeons involved in the subsequent care of the subject who had had an inadvertent harvest were contacted or the chart was reviewed. The reason for the initial procedure, the skill level of the primary surgeon, and when the inadvertent harvest was recognized were documented. When possible, the method of harvest and subsequent treatment were also documented. RESULTS: The most common initial procedure was a reconstruction of the elbow ulnar collateral ligament, followed by basal joint arthroplasty, tendon reconstruction, and reconstruction of the ulnar collateral ligament of the thumb metacarpophalangeal joint. Only 7 of the inadvertent harvests were recognized intraoperatively; in the remaining 12 cases the nerve was used as a tendon graft. The sensory loss was not recognized as being due to the inadvertent harvest until the first postoperative visit (2 subjects), 3 to 4 weeks (2 subjects), 2 to 3 months (2 subjects), 5 to 7 months (2 subjects), 1 year (1 subject), 3 years (1 subject), or 10 years (1 subject). Preoperative clinical identification of the presence or absence of a palmaris longus did not necessarily prevent an inadvertent harvest. CONCLUSIONS: Knowledge of the relevant anatomy is crucial to avoiding inadvertent harvest of the median nerve instead of the palmaris longus tendon. PMID- 28719555 TI - The Influence of Shortening on Clinical Outcome in Healed Displaced Midshaft Clavicular Fractures After Nonoperative Treatment. AB - BACKGROUND: We aimed to evaluate the effect of clavicular shortening, measured with 3-dimensional computed tomography (3DCT), on functional outcomes and satisfaction in patients with healed displaced midshaft clavicular fractures up to 1 year following injury. METHODS: The data used in this study were collected as part of a multicenter, prospective randomized controlled trial of open reduction and plate fixation compared with nonoperative treatment for acute, displaced midshaft clavicular factures. Patients who were randomized to nonoperative treatment and had healed by 1 year were included in the present study. Clavicular shortening relative to the uninjured, contralateral clavicle was measured on 3DCT. Outcome analysis was conducted at 6 weeks, 3 months, 6 months, and 1 year following injury and included the Disabilities of the Arm, Shoulder and Hand (DASH), Constant, and Short Form-12 (SF-12) scores and patient satisfaction. RESULTS: In the original trial, 105 patients were randomized to nonoperative treatment. Thirteen patients were lost to follow-up, leaving 92 patients, and an additional 16 (17%) developed nonunion and were excluded from the present study. Of the remaining 76 patients, 48 who had a 3DCT scan that included the whole length of both clavicles were included in the present study. The shortening of the injured clavicles, relative to the contralateral side, was a mean (and standard deviation) of 11.3 +/- 7.6 mm, with a mean proportional shortening of 8%. Proportional shortening did not significantly correlate with the DASH (p >= 0.42), Constant (p >= 0.32), or SF-12 (p >= 0.08) scores at any point during follow-up. There was no significant difference in the mean DASH or Constant scores at any follow-up time point when the cutoff for shortening was defined as 1 cm (p >= 0.11) or as 2 cm (p >= 0.35). There was no significant difference in clavicular shortening between satisfied and unsatisfied patients (p >= 0.49). CONCLUSIONS: The present study demonstrated no association between shortening and functional outcome or satisfaction in patients with healed displaced midshaft clavicular fractures up to 1 year following injury. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 28719558 TI - Recurrence of Hallux Valgus Can Be Predicted from Immediate Postoperative Non Weight-Bearing Radiographs. AB - BACKGROUND: The aims of this study were to identify risk factors for the recurrence of hallux valgus deformity and to clarify whether recurrence after surgery to treat hallux valgus can be predicted using radiographic parameters assessed on immediate postoperative non-weight-bearing radiographs. METHODS: A proximal chevron osteotomy combined with a distal soft-tissue procedure was performed by a single surgeon to treat moderate to severe hallux valgus deformity in 93 patients (117 feet). The feet were grouped according to nonrecurrence or recurrence. Changes in the hallux valgus angle, the intermetatarsal angle, and sesamoid position over time were analyzed by comparing values measured during each postoperative period. The relative risks of recurrence as indicated by preoperative and postoperative radiographic parameters were determined. RESULTS: Twenty (17.1%) of the 117 feet showed hallux valgus recurrence at the time of the last follow-up. The hallux valgus angle and the intermetatarsal angle stabilized at 6 months after surgery in the nonrecurrence group. An immediate postoperative hallux valgus angle of >=8 degrees , an immediate postoperative sesamoid position of grade 4 or greater, a preoperative metatarsus adductus angle of >=23 degrees , and a preoperative hallux valgus angle of >=40 degrees were significantly associated with recurrence. CONCLUSIONS: Recurrence of hallux valgus after a proximal chevron osteotomy can be reliably predicted from immediate postoperative non-weight-bearing radiographs. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 28719557 TI - Functional Gain and Pain Relief After Total Joint Replacement According to Obesity Status. AB - BACKGROUND: Obesity has been associated with lower function and more pain before and after total hip or knee replacement (THR or TKR). We examined the changes between preoperative and postoperative function and pain in a large representative U.S. cohort to determine if there was a relationship to obesity status. METHODS: Preoperative and 6-month postoperative data on function (Short Form-36 Physical Component Summary [PCS] score), joint pain (Hip disability and Osteoarthritis Outcome Score and Knee injury and Osteoarthritis Outcome Score), and body mass index (BMI) were collected from a national sample of 2,040 patients who had undergone THR and 2,964 who had undergone TKR from May 2011 to March 2013. Preoperative and postoperative function and pain were evaluated according to BMI status, defined as under or of normal weight, overweight, obese, severely obese, or morbidly obese. RESULTS: Patients undergoing THR were an average of 65 years of age; 59% were women, 94% were white, and 14% were severely or morbidly obese. A greater obesity level was associated with a lower (worse) PCS score at baseline and 6 months postoperatively. Severely and morbidly obese patients had less postoperative functional gain than the other BMI groups. A greater obesity level was associated with more pain at baseline but greater postoperative pain relief, so the average postoperative pain scores did not differ significantly according to BMI status. Patients undergoing TKR had an average age of 69 years; 61% were women, 93% were white, and 25% were severely or morbidly obese. A greater obesity level was associated with a lower PCS score at baseline and 6 months. The postoperative gain in PCS score did not differ by BMI level. A greater obesity level was associated with worse pain at baseline but greater pain relief at 6 months, so the average pain scores at 6 month were similar across the BMI levels. CONCLUSIONS: Six months after total joint replacement (TJR), severely or morbidly obese patients reported excellent pain relief and substantial functional gain that was similar to the findings in other patients. While obesity is associated with a greater risk of early complications, obesity in itself should not be a deterrent to undergoing TJR to relieve symptoms. LEVEL OF EVIDENCE: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence. PMID- 28719559 TI - Relationship Between Age and Rotator Cuff Retear: A Study of 1,600 Consecutive Rotator Cuff Repairs. AB - BACKGROUND: The prevalence of rotator cuff tears increases with age, and many patients undergo surgical repair. Retears are not uncommon, with rates ranging between 9% and 36% in recent studies, and are a major concern. The aim of this study was to investigate the relationship between patient age and the chance of healing following rotator cuff repair. METHODS: This was a retrospective cohort study of patients who had undergone arthroscopic rotator cuff repair performed by a single surgeon. All patients had an ultrasound performed by a musculoskeletal sonographer 6 months after rotator cuff repair to assess the repair integrity. RESULTS: The cohort of 1,600 patients was normally distributed in terms of age, with a mean age (and standard error of the mean) of 59 +/- 0.3 years and a range of 15 to 91 years. The 212 patients (13%) who had a retear at 6 months were also normally distributed in terms of age, with a mean age of 65 +/- 0.8 years and a range of 15 to 88 years. The retear rate in patients <50 years old was 5%. This increased to 10% in patients aged 50 to 59 years, 15% in those aged 60 to 69 years, 25% in those aged 70 to 79 years, and 34% in those aged >=80 years. Multiple logistic regression analysis showed that patient age was an independent factor strongly associated with retears. CONCLUSIONS: The rate of rotator cuff retears is low in patients <50 years of age. The relationship between age and rotator cuff retears is linear in patients 50 to 69 years of age, with an increase of 5% between decades, and increases substantially in patients >=70 years old. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 28719560 TI - Perioperative and Delayed Major Complications Following Surgical Treatment of Adolescent Idiopathic Scoliosis. AB - BACKGROUND: Reporting accurate surgical complication rates to patients and their families is important in the management of adolescent idiopathic scoliosis (AIS). In this study, we report the rate of major complications following the surgical treatment of AIS both in the perioperative period and among patients with a minimum of 2 years of follow-up. METHODS: We reviewed the prospectively collected data of a multicenter registry of patients who underwent surgical treatment of AIS during the period of 1995 to 2014 in order to identify all complications. A complication was defined as "major" if it resulted in reoperation or in spinal cord or nerve root injury, or was life-threatening. A total of 3,582 patients with preoperative and early postoperative data (4 to 6 weeks of follow-up) were included. A subset of 2,220 patients with a minimum of 2 years of follow-up comprised the cohort for delayed complications. Overall complication rates were calculated, as was the percentage of complications according to the year of the index surgery and type of surgical approach. RESULTS: The mean age of the 3,582 patients at the time of surgery was 14.8 +/- 2.2 years. The average major curve magnitude was 56 degrees +/- 13 degrees for thoracic curves and 51 degrees +/- 11 degrees for lumbar. In 365 patients, anterior spinal fusion (ASF) with instrumentation was performed, and in 3,217 patients, posterior spinal fusion (PSF) with instrumentation was performed; 142 patients in the PSF group underwent concomitant anterior release. There were 192 major complications, with 93 (2.6%) occurring perioperatively. Perioperative complications included wound-related (1.0% of the patients), neurologic (0.5%), pulmonary (0.4%), instrumentation related (0.4%), and gastrointestinal (0.2%) complications. One patient died. The mean annual perioperative major complication rate based on the year of surgery ranged from 0% to 10.5%. The complication rate by surgical approach was 3.0% for ASF and 2.6% for PSF (2.4% for PSF only and 5.6% for PSF with anterior release). The major complication rate for the 2,220 patients with at least 2 years of follow-up was 4.1%; all but 1 had a reoperation (4.1%). The majority of these major complications were wound and instrumentation-related (1.9% and 0.8%, respectively). CONCLUSIONS: After surgery for AIS, a 2.6% rate of perioperative major complications and a 4.1% rate of major complications at 2 or more years after surgery can be anticipated. The complication rate decreased over the period of study. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 28719561 TI - Arterial Topographic Anatomy Near the Femoral Head-Neck Perforation with Surgical Relevance. AB - BACKGROUND: Knowledge of the vascular supply of the femoral head is crucial for hip-preserving surgical procedures. The critical area for reshaping cam deformity is at the retinacular vessel penetration, an area with ill-defined topographic anatomy. We performed a cadaver study of the extension of the lateral retinaculum near the head-neck junction, distribution of the arterial vascular foramina, and initial intracapital course of these vessels. METHODS: In 16 fresh proximal parts of the femur without head-neck deformities, the deep branch of the medial femoral circumflex artery was injected with gadolinium for magnetic resonance imaging (MRI) sequences to identify arterial structures. RESULTS: We found a mean number of 4.5 arterial foramina, showing a predominance from 10 to 12 o'clock. The retinaculum extended 20 mm from 1 to 10 o'clock. The surface distance from the cartilage border to the vascular foramina under the synovial fold was 6.5 mm, and the depth from the same cartilage border to the initial intraosseous vessel pathways was 5.3 mm. CONCLUSIONS: The data add further precision to the arterial topography at the retinacular foramina, an area that is crucial for the perfusion of the femoral head. It may overlap with the area of anterolateral cam deformity and plays a role in choosing the cuts for subcapital and intracapital osteotomies. CLINICAL RELEVANCE: The information is taken from normal hips and may not be directly applicable to the deformed hip. Nevertheless, it is a prerequisite for a surgeon to understand the normal anatomy and use those boundaries to prevent mistakes during intra-articular joint-preserving hip surgical procedures. PMID- 28719562 TI - Meniscal Repair: Reconsidering Indications, Techniques, and Biologic Augmentation. PMID- 28719563 TI - What's New in Musculoskeletal Infection: Update Across Orthopaedic Subspecialties. PMID- 28719564 TI - The New APGAR SCORE: A Checklist to Enhance Quality of Life in Geriatric Patients with Hip Fracture. AB - For geriatric patients with hip fractures, the broken bone is the reason for admission, but only part of the overall disease. Indeed, it may be more helpful to consider the patient having geriatric hip fracture syndrome or sustaining a hip attack, as there are many associated medical, social, psychological, and other problems to which attention must be paid. To that end, we have identified a series of 10 steps, collected into a checklist, that can be undertaken for all patients with geriatric hip fracture. In homage to the maxim "we come into the world under the brim of the pelvis and go out through the neck of the femur," we defined our checklist by the acronym APGAR SCORE, named after the classic checklist of the same name used to assess a newborn child. The 10 elements include attending to problems of Alimentation and nutrition, Polypharmacy, and Gait; initiating a discussion about Advance care planning; correcting any Reversible cognitive impairment; maximizing Social support; checking for and remediating Cataracts or other impairments of vision; assessing for and addressing Osteoporosis; and last, ensuring that Referrals are made and that the patient has a safe Environment after discharge. For the newborn, the Apgar score has been criticized as an imperfect tool, and likewise the problem of geriatric hip fracture will not be solved with this new Apgar score either. Nonetheless, a score of 10 here,1 point for each item, may help to optimize the outcome for this difficult disease. PMID- 28719565 TI - Burnout in Orthopaedic Surgeons: A Challenge for Leaders, Learners, and Colleagues: AOA Critical Issues. AB - Burnout, depression, suicidal ideation, and dissatisfaction with work-life balance have been reported in all medical specialties and at all stages of medical education and practice experience. Burnout consists of progressive emotional, attitudinal, and physical exhaustion. Physicians with burnout may treat patients as objects and feel emotionally depleted. Burnout is characterized by a loss of enthusiasm for work (emotional exhaustion), feelings of cynicism (depersonalization), and a low sense of personal accomplishment. The most complete study of emotional burnout among different medical specialties demonstrated that orthopaedic surgery is one of the specialties with the highest burnout rate. Qualitative descriptive studies are available. There was a 45.8% burnout rate among physicians in the U.S. in 2012, and a 2014 update suggested even higher rates. Burnout has a correlation with medical education. Burnout rates are similar to those in the general population when medical students enter school, and increase steadily through medical education prior to residency. Burnout rates in residents are high, reported to be between 41% and 74% across multiple specialties. This impacts our young physician workforce in orthopaedics. The purpose of this review is to provide the available information that characterizes burnout and addresses the issues inherent to preventing burnout, and to build awareness in orthopaedic surgeons. Wellness "goes beyond merely the absence of distress and includes being challenged, thriving, and achieving success in various aspects of personal and professional life." The challenge for the orthopaedic community is to develop interventions and strategies that are personalized to the individuals in this specialty. PMID- 28719566 TI - Midshaft Clavicle Fractures: The Saga Continues: Commentary on articles by Marcel Jun Sugawara Tamaoki, MD, PhD, et al.: "Treatment of Displaced Midshaft Clavicle Fractures: Figure-of-Eight Harness Versus Anterior Plate Osteosynthesis. A Randomized Controlled Trial" and E.B. Goudie, MRCSEd, et al.: "The Influence of Shortening on Clinical Outcome in Healed Displaced Midshaft Clavicular Fractures After Nonoperative Treatment". PMID- 28719567 TI - Bunion Surgery: Check These Radiographic Parameters Intraoperatively to Avoid Recurrence: Commentary on an article by Chul Hyun Park, MD, PhD, and Woo-Chun Lee, MD, PhD: "Recurrence of Hallux Valgus Can Be Predicted from Immediate Postoperative Non-Weight-Bearing Radiographs". PMID- 28719568 TI - Effect of Serial Use of Bone Morphogenetic Protein 2 and Fibroblast Growth Factor 2 on Periodontal Tissue Regeneration. AB - PURPOSE: This study evaluates the synergistic effect of serial application of bone morphogenetic protein 2 (BMP2) and fibroblast growth factor 2 (FGF2) on both new bone formation and periodontal tissue regeneration using 1-wall intrabony defect in mongrel dogs. MATERIALS AND METHODS: One-wall defects were created at the mesial aspect of the mandibular first molars of 6 male mongrel dogs. Each mandibular defect received 1 of the 2 experimental treatments randomly (BMP2 or BMP2 + FGF2), and it was allowed to heal for either 4 or 8 weeks postoperatively. Histologic and histomorphometric analyses were performed for the evaluation of the overall healing patterns of new bone formation and periodontal tissue regeneration. RESULTS: The results showed that after 8 weeks, serial application of BMP2 and FGF2 significantly improved the periodontal tissue regeneration, whereas application of BMP2 only showed greater new bone formation after 4 weeks. CONCLUSIONS: The serial application of BMP2 and FGF2 may have synergistic effects on periodontal tissue regeneration over time. PMID- 28719569 TI - Stress Analysis of Zygomatic Implants on the Augmented Maxillary Sinus: Is It Necessary to Graft? AB - PURPOSE: Zygomatic implants are becoming an ideal therapy with advanced implant supported prosthetic treatment for the posterior atrophic maxilla. The purpose of this study is to examine the quantity and distribution of stress, which was caused by zygomatic implants placed using intrasinus method with or without augmentation to the atrophic posterior maxilla. MATERIALS & METHODS: In this study, 3-dimensional atrophic edentulous maxilla models with and without sinus augmentation are designed with computer-aided programs. Stress analysis was carried out on the created computer models for maxillary alveolar cortical bone, for cortical bone in the zygomaticomaxillary suture, and for zygomatic spongy bone at the apex of the zygomatic implant and for metal substructure of Von Misses stress data. RESULTS: Having augmented the maxillary sinus with graft, it was observed that after the loading especially in the posterior region, the tensile and compressive stresses on the alveolar crest was distributed more homogeneously and the stress generated on the cortical bone was reduced through the graft. CONCLUSION: Although zygomatic implants are graftless solutions for athrophic maxilla, sinus augmentation will be useful for bearing stress around the implants. PMID- 28719570 TI - Immediate Versus Delayed Loading of Postextraction Implants: A Long-Term Retrospective Cohort Study. AB - PURPOSE: To compare the long-term clinical and radiographic outcomes between immediate loading (IL) and conventional loading of implants placed immediately in fresh extraction sockets. MATERIALS AND METHODS: Demographic data, implant details, and periapical radiographs of patients were collected. The long-term marginal bone level remodeling and implant survival rate were calculated. RESULTS: Twenty-one patients (mean age 52.55 +/- 14.61 years) with 35 implants immediately inserted into postextraction sites (22 immediate loaded and 13 delayed loaded) were analyzed. The mean follow-up duration was 6 years (range 2 11 years). The implant cumulative survival rate was 96.5%. At the longest follow up, the mean crestal bone level averaged 0.144 +/- 0.705 for IL and 0.161 +/- 0.877 for delayed loading, respectively. The mean implant aesthetic score was 7. CONCLUSIONS: IL does not negatively influence the long-term prognosis of implants inserted into fresh extraction sockets. PMID- 28719571 TI - miR-27b-3p Suppressed Osteogenic Differentiation of Maxillary Sinus Membrane Stem Cells by Targeting Sp7. AB - OBJECTIVE: To explore the critical role and function of miRNAs in the regulation of development and physiology of maxillary sinus membrane stem cell (MSMSC) osteogenesis. METHODS: Microarray analysis was performed to screen the miRNAs expression profiles during the process of MSMSC osteogenic differentiation. Quantitative real-time polymerase chain reaction was applied to verify the miRNAs expression profiles. Gain- and loss-of-function experiments were used to demonstrate that miR-27b-3p inhibited MSMSC osteoblastic differentiation. Bioinformatic analysis was performed to predict the potential target of miR-27b 3p and then demonstrated by luciferase reporter assay and western blot. The negative regulation between miR-27b-3p and Sp7 was further confirmed using mimic and inhibitor of miR-27b-3p in vitro. Xenograft mice model was generated to confirm the relationship between miR-27b-3p and Sp7 using recombinant adenoviruses in vivo. RESULTS: MiR-27b-3p was downregulated during osteogenic differentiation of MSMSCs. The expression of Sp7, alkaline phosphatase, and osteocalcin decreased when transfected with miR-27b-3p-mimic in MSMSCs after osteogenic differentiation. MiR-27b-3p directly targeted Sp7 and inhibited the MSMSC osteogenesis in vivo. CONCLUSION: MiR-27b-3p suppressed the osteogenic differentiation of MSMSCs by directly inhibiting Sp7. PMID- 28719572 TI - Neuroimaging Correlates of Post-Stroke Aphasia Rehabilitation in a Pilot Randomized Trial of Constraint-Induced Aphasia Therapy. AB - BACKGROUND Recovery from post-stroke aphasia is a long and complex process with an uncertain outcome. Various interventions have been proposed to augment the recovery, including constraint-induced aphasia therapy (CIAT). CIAT has been applied to patients suffering from post-stroke aphasia in several unblinded studies to show mild-to-moderate linguistic gains. The aim of the present study was to evaluate the neuroimaging correlates of CIAT in patients with chronic aphasia related to left middle cerebral artery stroke. MATERIAL AND METHODS Out of 24 patients recruited in a pilot randomized blinded trial of CIAT, 19 patients received fMRI of language. Eleven of them received CIAT (trained) and eight served as a control group (untrained). Each patient participated in three fMRI sessions (before training, after training, and 3 months later) that included semantic decision and verb generation fMRI tasks, and a battery of language tests. Matching healthy control participants were also included (N=38; matching based on age, handedness, and sex). RESULTS Language testing showed significantly improved performance on Boston Naming Test (BNT; p<0.001) in both stroke groups over time and fMRI showed differences in the distribution of the areas involved in language production between groups that were not present at baseline. Further, regression analysis with BNT indicated changes in brain regions correlated with behavioral performance (temporal gyrus, postcentral gyrus, precentral gyrus, thalamus, left middle and superior frontal gyri). CONCLUSIONS Overall, our results suggest the possibility of language-related cortical plasticity following stroke-induced aphasia with no specific effect from CIAT training. PMID- 28719573 TI - Crystalline metamaterials for topological properties at subwavelength scales. AB - The exciting discovery of topological condensed matter systems has lately triggered a search for their photonic analogues, motivated by the possibility of robust backscattering-immune light transport. However, topological photonic phases have so far only been observed in photonic crystals and waveguide arrays, which are inherently physically wavelength scaled, hindering their application in compact subwavelength systems. In this letter, we tackle this problem by patterning the deep subwavelength resonant elements of metamaterials onto specific lattices, and create crystalline metamaterials that can develop complex nonlocal properties due to multiple scattering, despite their very subwavelength spatial scale that usually implies to disregard their structure. These spatially dispersive systems can support subwavelength topological phases, as we demonstrate at microwaves by direct field mapping. Our approach gives a straightforward tabletop platform for the study of photonic topological phases, and allows to envision applications benefiting the compactness of metamaterials and the amazing potential of topological insulators. PMID- 28719574 TI - Ancient European dog genomes reveal continuity since the Early Neolithic. AB - Europe has played a major role in dog evolution, harbouring the oldest uncontested Palaeolithic remains and having been the centre of modern dog breed creation. Here we sequence the genomes of an Early and End Neolithic dog from Germany, including a sample associated with an early European farming community. Both dogs demonstrate continuity with each other and predominantly share ancestry with modern European dogs, contradicting a previously suggested Late Neolithic population replacement. We find no genetic evidence to support the recent hypothesis proposing dual origins of dog domestication. By calibrating the mutation rate using our oldest dog, we narrow the timing of dog domestication to 20,000-40,000 years ago. Interestingly, we do not observe the extreme copy number expansion of the AMY2B gene characteristic of modern dogs that has previously been proposed as an adaptation to a starch-rich diet driven by the widespread adoption of agriculture in the Neolithic. PMID- 28719575 TI - Non-canonical NOTCH3 signalling limits tumour angiogenesis. AB - Notch signalling is a causal determinant of cancer and efforts have been made to develop targeted therapies to inhibit the so-called canonical pathway. Here we describe an unexpected pro-apoptotic role of Notch3 in regulating tumour angiogenesis independently of the Notch canonical pathway. The Notch3 ligand Jagged-1 is upregulated in a fraction of human cancer and our data support the view that Jagged-1, produced by cancer cells, is inhibiting the apoptosis induced by the aberrant Notch3 expression in tumour vasculature. We thus present Notch3 as a dependence receptor inducing endothelial cell death while this pro-apoptotic activity is blocked by Jagged-1. Along this line, using Notch3 mutant mice, we demonstrate that tumour growth and angiogenesis are increased when Notch3 is silenced in the stroma. Consequently, we show that the well-documented anti tumour effect mediated by gamma-secretase inhibition is at least in part dependent on the apoptosis triggered by Notch3 in endothelial cells. PMID- 28719576 TI - Laser-induced plasmonic colours on metals. AB - Plasmonic resonances in metallic nanoparticles have been used since antiquity to colour glasses. The use of metal nanostructures for surface colourization has attracted considerable interest following recent developments in plasmonics. However, current top-down colourization methods are not ideally suited to large scale industrial applications. Here we use a bottom-up approach where picosecond laser pulses can produce a full palette of non-iridescent colours on silver, gold, copper and aluminium. We demonstrate the process on silver coins weighing up to 5 kg and bearing large topographic variations (~1.5 cm). We find that colours are related to a single parameter, the total accumulated fluence, making the process suitable for high-throughput industrial applications. Statistical image analyses of laser-irradiated surfaces reveal various nanoparticle size distributions. Large-scale finite-difference time-domain computations based on these nanoparticle distributions reproduce trends seen in reflectance measurements, and demonstrate the key role of plasmonic resonances in colour formation. PMID- 28719577 TI - Physical limits to biomechanical sensing in disordered fibre networks. AB - Cells actively probe and respond to the stiffness of their surroundings. Since mechanosensory cells in connective tissue are surrounded by a disordered network of biopolymers, their in vivo mechanical environment can be extremely heterogeneous. Here we investigate how this heterogeneity impacts mechanosensing by modelling the cell as an idealized local stiffness sensor inside a disordered fibre network. For all types of networks we study, including experimentally imaged collagen and fibrin architectures, we find that measurements applied at different points yield a strikingly broad range of local stiffnesses, spanning roughly two decades. We verify via simulations and scaling arguments that this broad range of local stiffnesses is a generic property of disordered fibre networks. Finally, we show that to obtain optimal, reliable estimates of global tissue stiffness, a cell must adjust its size, shape, and position to integrate multiple stiffness measurements over extended regions of space. PMID- 28719579 TI - Using primate neural stem cells cultured in self-assembling peptide nanofiber scaffolds to repair injured spinal cords in rats. AB - This corrects the article DOI: 10.1038/sc.2016.36. PMID- 28719578 TI - De novo active sites for resurrected Precambrian enzymes. AB - Protein engineering studies often suggest the emergence of completely new enzyme functionalities to be highly improbable. However, enzymes likely catalysed many different reactions already in the last universal common ancestor. Mechanisms for the emergence of completely new active sites must therefore either plausibly exist or at least have existed at the primordial protein stage. Here, we use resurrected Precambrian proteins as scaffolds for protein engineering and demonstrate that a new active site can be generated through a single hydrophobic to-ionizable amino acid replacement that generates a partially buried group with perturbed physico-chemical properties. We provide experimental and computational evidence that conformational flexibility can assist the emergence and subsequent evolution of new active sites by improving substrate and transition-state binding, through the sampling of many potentially productive conformations. Our results suggest a mechanism for the emergence of primordial enzymes and highlight the potential of ancestral reconstruction as a tool for protein engineering. PMID- 28719580 TI - Central insulin modulates food valuation via mesolimbic pathways. AB - Central insulin is thought to act at the neural interface between metabolic and hedonic drives to eat. Here, using pharmacological fMRI, we show that intranasal insulin (INI) changes the value of food cues through modulation of mesolimbic pathways. Overnight fasted participants rated the palatability of food pictures and attractiveness of non-food items (control) after receiving INI or placebo. We report that INI reduces ratings of food palatability and value signals in mesolimbic regions in individuals with normal insulin sensitivity. Connectivity analyses reveal insulinergic inhibition of forward projections from the ventral tegmentum to the nucleus accumbens. Importantly, the strength of this modulation predicts decrease of palatability ratings, directly linking neural findings to behaviour. In insulin-resistant participants however, we observe reduced food values and aberrant central insulin action. These data demonstrate how central insulin modulates the cross-talk between homeostatic and non-homeostatic feeding systems, suggesting that dysfunctions of these neural interactions may promote metabolic disorders. PMID- 28719583 TI - Prevention: Low-fat diet linked to decline in breast cancer mortality. PMID- 28719581 TI - Phosphorylated HBO1 at UV irradiated sites is essential for nucleotide excision repair. AB - HBO1, a histone acetyl transferase, is a co-activator of DNA pre-replication complex formation. We recently reported that HBO1 is phosphorylated by ATM and/or ATR and binds to DDB2 after ultraviolet irradiation. Here, we show that phosphorylated HBO1 at cyclobutane pyrimidine dimer (CPD) sites mediates histone acetylation to facilitate recruitment of XPC at the damaged DNA sites. Furthermore, HBO1 facilitates accumulation of SNF2H and ACF1, an ATP-dependent chromatin remodelling complex, to CPD sites. Depletion of HBO1 inhibited repair of CPDs and sensitized cells to ultraviolet irradiation. However, depletion of HBO1 in cells derived from xeroderma pigmentosum patient complementation groups, XPE, XPC and XPA, did not lead to additional sensitivity towards ultraviolet irradiation. Our findings suggest that HBO1 acts in concert with SNF2H-ACF1 to make the chromosome structure more accessible to canonical nucleotide excision repair factors. PMID- 28719582 TI - Prostate cancer: Mutations in ctDNA reflect features of metastatic disease. PMID- 28719584 TI - Health policy: Me-too drugs with limited benefits - the tale of regorafenib for HCC. PMID- 28719585 TI - Immunotherapy: Reality check for nivolumab in advanced-stage melanoma. PMID- 28719586 TI - Breast cancer: Profiling of ultra-low-risk disease. PMID- 28719587 TI - Outcomes research: Integrating PROs into the clinic - overall survival benefit or not, it's worth the trouble. PMID- 28719589 TI - An excited state underlies gene regulation of a transcriptional riboswitch. AB - Riboswitches control gene expression through ligand-dependent structural rearrangements of the sensing aptamer domain. However, we found that the Bacillus cereus fluoride riboswitch aptamer adopts identical tertiary structures in solution with and without ligand. Using chemical-exchange saturation transfer (CEST) NMR spectroscopy, we revealed that the structured ligand-free aptamer transiently accesses a low-populated (~1%) and short-lived (~3 ms) excited conformational state that unravels a conserved 'linchpin' base pair to signal transcription termination. Upon fluoride binding, this highly localized, fleeting process is allosterically suppressed, which activates transcription. We demonstrated that this mechanism confers effective fluoride-dependent gene activation over a wide range of transcription rates, which is essential for robust toxicity responses across diverse cellular conditions. These results unveil a novel switching mechanism that employs ligand-dependent suppression of an aptamer excited state to coordinate regulatory conformational transitions rather than adopting distinct aptamer ground-state tertiary architectures, exemplifying a new mode of ligand-dependent RNA regulation. PMID- 28719588 TI - Structures of carboxylic acid reductase reveal domain dynamics underlying catalysis. AB - Carboxylic acid reductase (CAR) catalyzes the ATP- and NADPH-dependent reduction of carboxylic acids to the corresponding aldehydes. The enzyme is related to the nonribosomal peptide synthetases, consisting of an adenylation domain fused via a peptidyl carrier protein (PCP) to a reductase termination domain. Crystal structures of the CAR adenylation-PCP didomain demonstrate that large-scale domain motions occur between the adenylation and thiolation states. Crystal structures of the PCP-reductase didomain reveal that phosphopantetheine binding alters the orientation of a key Asp, resulting in a productive orientation of the bound nicotinamide. This ensures that further reduction of the aldehyde product does not occur. Combining crystallography with small-angle X-ray scattering (SAXS), we propose that molecular interactions between initiation and termination domains are limited to competing PCP docking sites. This theory is supported by the fact that (R)-pantetheine can support CAR activity for mixtures of the isolated domains. Our model suggests directions for further development of CAR as a biocatalyst. PMID- 28719590 TI - Pericyte-expressed Tie2 controls angiogenesis and vessel maturation. AB - The Tie receptors with their Angiopoietin ligands act as regulators of angiogenesis and vessel maturation. Tie2 exerts its functions through its supposed endothelial-specific expression. Yet, Tie2 is also expressed at lower levels by pericytes and it has not been unravelled through which mechanisms pericyte Angiopoietin/Tie signalling affects angiogenesis. Here we show that human and murine pericytes express functional Tie2 receptor. Silencing of Tie2 in pericytes results in a pro-migratory phenotype. Pericyte Tie2 controls sprouting angiogenesis in in vitro sprouting and in vivo spheroid assays. Tie2 downstream signalling in pericytes involves Calpain, Akt and FOXO3A. Ng2-Cre-driven deletion of pericyte-expressed Tie2 in mice transiently delays postnatal retinal angiogenesis. Yet, Tie2 deletion in pericytes results in a pronounced pro angiogenic effect leading to enhanced tumour growth. Together, the data expand and revise the current concepts on vascular Angiopoietin/Tie signalling and propose a bidirectional, reciprocal EC-pericyte model of Tie2 signalling. PMID- 28719591 TI - Non-equilibrium dissipative supramolecular materials with a tunable lifetime. AB - Many biological materials exist in non-equilibrium states driven by the irreversible consumption of high-energy molecules like ATP or GTP. These energy dissipating structures are governed by kinetics and are thus endowed with unique properties including spatiotemporal control over their presence. Here we show man made equivalents of materials driven by the consumption of high-energy molecules and explore their unique properties. A chemical reaction network converts dicarboxylates into metastable anhydrides driven by the irreversible consumption of carbodiimide fuels. The anhydrides hydrolyse rapidly to the original dicarboxylates and are designed to assemble into hydrophobic colloids, hydrogels or inks. The spatiotemporal control over the formation and degradation of materials allows for the development of colloids that release hydrophobic contents in a predictable fashion, temporary self-erasing inks and transient hydrogels. Moreover, we show that each material can be re-used for several cycles. PMID- 28719592 TI - Ten-Day Quadruple Therapy Comprising Proton Pump Inhibitor, Bismuth, Tetracycline, and Levofloxacin is More Effective than Standard Levofloxacin Triple Therapy in the Second-Line Treatment of Helicobacter pylori Infection: A Randomized Controlled Trial. AB - OBJECTIVES: Proton pump inhibitor (PPI)-amoxicillin-fluoroquinolone triple therapy is recommended as a second-line treatment of Helicobacter pylori infection in the Maastricht V/Florence Consensus Report. However, the eradication rate of this standard salvage treatment is suboptimal. The objective of this study is to compare the efficacy of esomeprazole-bismuth-tetracycline levofloxacin therapy (TL quadruple therapy) and esomeprazole-amoxicillin levofloxacin triple therapy (AL triple therapy) in rescue treatment for H. pylori infection. METHODS: Consecutive H. pylori-infected subjects after failure of first-line therapies were randomly allocated to receive either TL quadruple therapy (esomeprazole 40 mg b.d., bismuth 120 mg q.d.s., tetracycline 500 mg q.d.s., and levofloxacin 500 mg o.d.) or AL triple therapy (esomeprazole 40 mg b.d., amoxicillin 500 mg q.d.s., and levofloxacin 500 mg o.d.) for 10 days. H. pylori status was assessed 6 weeks after the end of treatment. RESULTS: The study was stopped after an interim analysis. Of 50 patients in the TL quadruple therapy, 49 (98.0%) had successful eradication of H. pylori infection. Cure of H. pylori infection was achieved in 36 of 52 patients (69.2%) receiving AL triple therapy. Intention-to-treat analysis demonstrated that TL quadruple therapy achieved a markedly higher eradication rate than AL triple therapy (difference: 28.8%; 95% confidence interval: 15.7% to 41.9%; P<0.001). Per-protocol analysis yielded a similar result (97.8% vs. 68.6%; P<0.001). The two treatment groups exhibited comparable frequencies of overall adverse events (22.0% vs. 11.5%) and drug compliance (90.0% vs. 98.1%). The subgroup analysis showed that TL quadruple therapy was superior to AL triple therapy in patients with failure of either standard triple therapy (100% vs. 75.0%; P=0.010) or non-bismuth quadruple therapy (95.0% vs. 52.6%; P=0.003). CONCLUSIONS: Ten-day PPI-bismuth-tetracycline levofloxacin quadruple therapy is a good option for rescue treatment of H. pylori infection following failure of standard triple or non-bismuth quadruple therapy. PMID- 28719593 TI - Long-Term Treatment of Eosinophilic Esophagitis With Swallowed Topical Corticosteroids: Development and Evaluation of a Therapeutic Concept. AB - OBJECTIVES: Swallowed topical corticosteroids (STCs) are efficacious in inducing and presumably maintaining remission in patients with active eosinophilic esophagitis (EoE). Hitherto, it has not been evaluated whether long-lasting remission can be achieved, and whether treatment can be stopped once patients have achieved this remission. METHODS: Since 2007, EoE patients included into a large database at the Swiss EoE Clinics were put on STCs as induction/maintenance therapy. Disease activity was assessed on an annual basis. In patients who achieved long-lasting (>=6 months) clinical, endoscopic, and histological (=deep) remission, treatment was stopped. Data on all patients treated using this therapeutic strategy were analyzed retrospectively. RESULTS: Of the 351 patients, 33 (9.4%) who were treated with STCs achieved deep remission. Median age of remitters at disease onset was 32.6 years (interquartile range (IQR) 19.1-49.3), and diagnostic delay was 5.4 years (IQR 1.2-11.4). Deep remission was achieved after 89.0 weeks (IQR 64.6-173.8). Female gender was the only independent prognostic factor for achieving deep remission (odds ratio (OR) 2.518, 95% confidence interval (CI) 1.203-5.269). Overall, STCs were stopped after 104.7 weeks (IQR 65.5-176.6). No mucosal damage was observed upon histological examination. In 27 of the 33 remitters (81.8%), a clinical relapse occurred after a median of 22.4 weeks (95% CI 5.1-39.7). Six remitters (18.2%) did not experience a clinical relapse during a follow-up of 35.1 weeks (IQR 18.3-44.9). Hence, a total of 1.7% (6/351) patients were able to discontinue STCs in the long term. CONCLUSIONS: Long-term EoE treatment with STCs was well tolerated, but only a minority achieved deep remission. Female gender is the only prognostic factor for attainment of such remission. After treatment cessation, the majority experienced a clinical relapse. PMID- 28719594 TI - Prophylactic Therapy of Cyclic Vomiting Syndrome in Children: Comparison of Amitriptyline and Cyproheptadine: A Randomized Clinical Trial. AB - OBJECTIVES: Cyclic vomiting syndrome (CVS) is a common functional gastrointestinal disorder characterized by recurrent episodes of nausea and vomiting. There is no definite treatment for the condition, although some medications are recommended. We aimed to compare the efficacy of amitriptyline and cyproheptadine in prophylactic therapy of CVS. METHODS: This is a single blinded randomized clinical trial conducted during 2015-2016 in Isfahan, Iran. Sixty-four children who were 3-15 years old, with a diagnosis of CVS (based on Rome III criteria), were included in the study and were randomly divided into two groups of amitriptyline and cyproheptadine. They were followed for 6 months, looking for frequency and duration of attacks as the primary outcome. RESULTS: The mean monthly frequency of attacks in the last 2 months of the study in the amitriptyline and cyproheptadine group were 0.38+/-0.55 and 0.59+/-0.71, respectively (P-value=0.197), after intervention. The mean duration of attacks between amitriptyline and cyproheptadine group were 1.41+/-2.86 and 1.81+/-2.22 h, respectively (P-value=0.212). In the amitriptyline group 65.6% of patients reported 100% remission, whereas in the cyproheptadine group 50% reported full remission (P-value=0.206). CONCLUSIONS: There was no superiority of one of the medications over the other. We did not find any age-related effect on the efficacy of these medications as well. PMID- 28719595 TI - Risk of Postoperative Complications Among Inflammatory Bowel Disease Patients Treated Preoperatively With Vedolizumab. AB - OBJECTIVES: Vedolizumab is increasingly used to treat patients with ulcerative colitis (UC) and Crohn's disease (CD), however, its safety during the perioperative period remains unclear. We compared the 30-day postoperative complications among patients treated preoperatively with vedolizumab, anti-tumor necrosis factor (TNF)-alpha agents or non-biological therapy. METHODS: The retrospective study cohort was comprised of patients receiving vedolizumab, anti TNF-alpha agents or non-biological therapy within 4 weeks of surgery. The rates of 30-day postoperative complications were compared between groups using univariate and multivariate analysis. Propensity score-matched analysis was performed to compare the outcome between groups. RESULTS: Among 443 patients (64 vedolizumab, 129 anti-TNF-alpha agents, and 250 non-biological therapy), a total of 144 patients experienced postoperative complications (32%). In multivariate analysis, age >65 (odds ratio (OR) 3.56, 95% confidence interval (CI) 1.30-9.76) and low-albumin (OR 2.26, 95% CI 1.28-4.00) were associated with increased risk of 30-day postoperative complications. For infectious complications, steroid use (OR 3.67, 95% CI 1.57-8.57, P=0.003) and low hemoglobin (OR 3.03, 95% CI 1.32 6.96, P=0.009) were associated with increased risk in multivariate analysis. Propensity score matched analysis demonstrated that the risks of postoperative complications were not different among patients preoperatively receiving vedolizumab, anti-TNF-alpha agents or non-biological therapy (UC, P=0.40; CD, P=0.35). CONCLUSIONS: In the present study, preoperative vedolizumab exposure did not affect the risk of 30-day postoperative complications in UC and CD. Further, larger studies are required to confirm our findings. PMID- 28719596 TI - The influence of FCGR2A and FCGR3A polymorphisms on the survival of patients with recurrent or metastatic squamous cell head and neck cancer treated with cetuximab. AB - FCGR2A-H131R and FCGR3A-V157F are single-nucleotide polymorphisms known to influence the outcome of patients treated with rituximab, cetuximab and trastuzumab. We investigated the impact of these polymorphisms on the clinical outcome of 103 patients with recurrent or metastatic squamous cell carcinoma of the head and neck treated with a platinum compound, fluorouracil and cetuximab as palliative first-line therapy. The survival of patients with FCGR2A-131H/H and/or FCGR3A-157V/V genotypes was significantly longer compared with patients carrying 131R and 157F alleles (median progression-free survival (PFS): 5.5 vs 4.1 months, P=0.02; median overall survival: 10.2 vs 7.2 months, P=0.04). In multivariate analysis, the FCGR2A and 3A genotypes as well as the time between initial diagnosis and relapse of disease not amenable to curative therapy remained the only independent prognostic factors for PFS. The results are in line with previous reports in colorectal cancer patients and confirm the possible value of genetic polymorphisms of immunocompetent cells for the success of cetuximab treatment. PMID- 28719599 TI - The smectic order of wrinkles. AB - A thin elastic sheet lying on a soft substrate develops wrinkled patterns when subject to an external forcing or as a result of geometric incompatibility. Thin sheet elasticity and substrate response equip such wrinkles with a global preferred wrinkle spacing length and with resistance to wrinkle curvature. These features are responsible for the liquid crystalline smectic-like behaviour of such systems at intermediate length scales. This insight allows better understanding of the wrinkling patterns seen in such systems, with which we explain pattern breaking into domains, the properties of domain walls and wrinkle undulation. We compare our predictions with numerical simulations and with experimental observations. PMID- 28719598 TI - The predictive value of ABCB1, ABCG2, CYP3A4/5 and CYP2D6 polymorphisms for risperidone and aripiprazole plasma concentrations and the occurrence of adverse drug reactions. AB - We investigated in ninety Caucasian pediatric patients the impact of the main polymorphisms occurring in CYP3A, CYP2D6, ABCB1 and ABCG2 genes on second generation antipsychotics plasma concentrations, and their association with the occurrence of adverse drug reactions. Patients with the CA/AA ABCG2 genotype had a statistically significant lower risperidone plasma concentration/dose ratio (Ct/ds) (P-value: 0.007) and an higher estimated marginal probability of developing metabolism and nutrition disorders as compared to the ABCG2 c.421 non CA/AA genotypes (P-value: 0.008). Multivariate analysis revealed that the ABCG2 c.421 CA/AA genotype was found associated to a higher hazard (P-value: 0.004) of developing adverse drug reactions classified as metabolism and nutrition disorders. The ABCB1 2677TT/3435TT genotype had a statistically significant lower aripiprazole Ct/ds if compared with patients with others ABCB1 genotypes (P value: 0.026). Information obtained on ABCB1 and ABCG2 gene variants may result useful to tailor treatments with these drugs in Caucasian pediatric patients. PMID- 28719600 TI - Lupus nephritis: Mesenchymal stromal cells in lupus nephritis. PMID- 28719597 TI - Pharmacogenomics study of thiazide diuretics and QT interval in multi-ethnic populations: the cohorts for heart and aging research in genomic epidemiology. AB - Thiazide diuretics, commonly used antihypertensives, may cause QT interval (QT) prolongation, a risk factor for highly fatal and difficult to predict ventricular arrhythmias. We examined whether common single-nucleotide polymorphisms (SNPs) modified the association between thiazide use and QT or its component parts (QRS interval, JT interval) by performing ancestry-specific, trans-ethnic and cross phenotype genome-wide analyses of European (66%), African American (15%) and Hispanic (19%) populations (N=78 199), leveraging longitudinal data, incorporating corrected standard errors to account for underestimation of interaction estimate variances and evaluating evidence for pathway enrichment. Although no loci achieved genome-wide significance (P<5 * 10-8), we found suggestive evidence (P<5 * 10-6) for SNPs modifying the thiazide-QT association at 22 loci, including ion transport loci (for example, NELL1, KCNQ3). The biologic plausibility of our suggestive results and simulations demonstrating modest power to detect interaction effects at genome-wide significant levels indicate that larger studies and innovative statistical methods are warranted in future efforts evaluating thiazide-SNP interactions. PMID- 28719601 TI - CLIC, a tool for expanding biological pathways based on co-expression across thousands of datasets. AB - In recent years, there has been a huge rise in the number of publicly available transcriptional profiling datasets. These massive compendia comprise billions of measurements and provide a special opportunity to predict the function of unstudied genes based on co-expression to well-studied pathways. Such analyses can be very challenging, however, since biological pathways are modular and may exhibit co-expression only in specific contexts. To overcome these challenges we introduce CLIC, CLustering by Inferred Co-expression. CLIC accepts as input a pathway consisting of two or more genes. It then uses a Bayesian partition model to simultaneously partition the input gene set into coherent co-expressed modules (CEMs), while assigning the posterior probability for each dataset in support of each CEM. CLIC then expands each CEM by scanning the transcriptome for additional co-expressed genes, quantified by an integrated log-likelihood ratio (LLR) score weighted for each dataset. As a byproduct, CLIC automatically learns the conditions (datasets) within which a CEM is operative. We implemented CLIC using a compendium of 1774 mouse microarray datasets (28628 microarrays) or 1887 human microarray datasets (45158 microarrays). CLIC analysis reveals that of 910 canonical biological pathways, 30% consist of strongly co-expressed gene modules for which new members are predicted. For example, CLIC predicts a functional connection between protein C7orf55 (FMC1) and the mitochondrial ATP synthase complex that we have experimentally validated. CLIC is freely available at www.gene-clic.org. We anticipate that CLIC will be valuable both for revealing new components of biological pathways as well as the conditions in which they are active. PMID- 28719602 TI - Prehospital immune responses and development of multiple organ dysfunction syndrome following traumatic injury: A prospective cohort study. AB - BACKGROUND: Almost all studies that have investigated the immune response to trauma have analysed blood samples acquired post-hospital admission. Thus, we know little of the immune status of patients in the immediate postinjury phase and how this might influence patient outcomes. The objective of this study was therefore to comprehensively assess the ultra-early, within 1-hour, immune response to trauma and perform an exploratory analysis of its relationship with the development of multiple organ dysfunction syndrome (MODS). METHODS AND FINDINGS: The immune and inflammatory response to trauma was analysed in 89 adult trauma patients (mean age 41 years, range 18-90 years, 75 males) with a mean injury severity score (ISS) of 24 (range 9-66), from whom blood samples were acquired within 1 hour of injury (mean time to sample 42 minutes, range 17-60 minutes). Within minutes of trauma, a comprehensive leukocytosis, elevated serum pro- and anti-inflammatory cytokines, and evidence of innate cell activation that included neutrophil extracellular trap generation and elevated surface expression of toll-like receptor 2 and CD11b on monocytes and neutrophils, respectively, were observed. Features consistent with immune compromise were also detected, notably elevated numbers of immune suppressive CD16BRIGHT CD62LDIM neutrophils (82.07 x 106/l +/- 18.94 control versus 1,092 x 106/l +/- 165 trauma, p < 0.0005) and CD14+HLA-DRlow/- monocytes (34.96 x 106/l +/- 4.48 control versus 95.72 x 106/l +/- 8.0 trauma, p < 0.05) and reduced leukocyte cytokine secretion in response to lipopolysaccharide stimulation. Exploratory analysis via binary logistic regression found a potential association between absolute natural killer T (NKT) cell numbers and the subsequent development of MODS. Study limitations include the relatively small sample size and the absence of data relating to adaptive immune cell function. CONCLUSIONS: Our study highlighted the dynamic and complex nature of the immune response to trauma, with immune alterations consistent with both activation and suppression evident within 1 hour of injury. The relationship of these changes, especially in NKT cell numbers, to patient outcomes such as MODS warrants further investigation. PMID- 28719603 TI - The ?100 lab: A 3D-printable open-source platform for fluorescence microscopy, optogenetics, and accurate temperature control during behaviour of zebrafish, Drosophila, and Caenorhabditis elegans. AB - Small, genetically tractable species such as larval zebrafish, Drosophila, or Caenorhabditis elegans have become key model organisms in modern neuroscience. In addition to their low maintenance costs and easy sharing of strains across labs, one key appeal is the possibility to monitor single or groups of animals in a behavioural arena while controlling the activity of select neurons using optogenetic or thermogenetic tools. However, the purchase of a commercial solution for these types of experiments, including an appropriate camera system as well as a controlled behavioural arena, can be costly. Here, we present a low cost and modular open-source alternative called 'FlyPi'. Our design is based on a 3D-printed mainframe, a Raspberry Pi computer, and high-definition camera system as well as Arduino-based optical and thermal control circuits. Depending on the configuration, FlyPi can be assembled for well under ?100 and features optional modules for light-emitting diode (LED)-based fluorescence microscopy and optogenetic stimulation as well as a Peltier-based temperature stimulator for thermogenetics. The complete version with all modules costs approximately ?200 or substantially less if the user is prepared to 'shop around'. All functions of FlyPi can be controlled through a custom-written graphical user interface. To demonstrate FlyPi's capabilities, we present its use in a series of state-of-the art neurogenetics experiments. In addition, we demonstrate FlyPi's utility as a medical diagnostic tool as well as a teaching aid at Neurogenetics courses held at several African universities. Taken together, the low cost and modular nature as well as fully open design of FlyPi make it a highly versatile tool in a range of applications, including the classroom, diagnostic centres, and research labs. PMID- 28719604 TI - Research questions in pre-hospital trauma care. AB - Noting that a variety of pre-hospital interventions can now be applied to treat traumatic injury, David J Lockey calls for research to determine which of these actually improve survival and reduce morbidity. PMID- 28719605 TI - Extracellular phosphorylation of a receptor tyrosine kinase controls synaptic localization of NMDA receptors and regulates pathological pain. AB - Extracellular phosphorylation of proteins was suggested in the late 1800s when it was demonstrated that casein contains phosphate. More recently, extracellular kinases that phosphorylate extracellular serine, threonine, and tyrosine residues of numerous proteins have been identified. However, the functional significance of extracellular phosphorylation of specific residues in the nervous system is poorly understood. Here we show that synaptic accumulation of GluN2B-containing N methyl-D-aspartate receptors (NMDARs) and pathological pain are controlled by ephrin-B-induced extracellular phosphorylation of a single tyrosine (p*Y504) in a highly conserved region of the fibronectin type III (FN3) domain of the receptor tyrosine kinase EphB2. Ligand-dependent Y504 phosphorylation modulates the EphB NMDAR interaction in cortical and spinal cord neurons. Furthermore, Y504 phosphorylation enhances NMDAR localization and injury-induced pain behavior. By mediating inducible extracellular interactions that are capable of modulating animal behavior, extracellular tyrosine phosphorylation of EphBs may represent a previously unknown class of mechanism mediating protein interaction and function. PMID- 28719606 TI - Prescription medicine use by pedestrians and the risk of injurious road traffic crashes: A case-crossover study. AB - BACKGROUND: While some medicinal drugs have been found to affect driving ability, no study has investigated whether a relationship exists between these medicines and crashes involving pedestrians. The aim of this study was to explore the association between the use of medicinal drugs and the risk of being involved in a road traffic crash as a pedestrian. METHODS AND FINDINGS: Data from 3 French nationwide databases were matched. We used the case-crossover design to control for time-invariant factors by using each case as its own control. To perform multivariable analysis and limit false-positive results, we implemented a bootstrap version of Lasso. To avoid the effect of unmeasured time-varying factors, we varied the length of the washout period from 30 to 119 days before the crash. The matching procedure led to the inclusion of 16,458 pedestrians involved in an injurious road traffic crash from 1 July 2005 to 31 December 2011. We found 48 medicine classes with a positive association with the risk of crash, with median odds ratios ranging from 1.12 to 2.98. Among these, benzodiazepines and benzodiazepine-related drugs, antihistamines, and anti-inflammatory and antirheumatic drugs were among the 10 medicines most consumed by the 16,458 pedestrians. Study limitations included slight overrepresentation of pedestrians injured in more severe crashes, lack of information about self-medication and the use of over-the-counter drugs, and lack of data on amount of walking. CONCLUSIONS: Therapeutic classes already identified as impacting the ability to drive, such as benzodiazepines and antihistamines, are also associated with an increased risk of pedestrians being involved in a road traffic crash. This study on pedestrians highlights the necessity of improving awareness of the effect of these medicines on this category of road user. PMID- 28719607 TI - Stress-induced mutagenesis: Stress diversity facilitates the persistence of mutator genes. AB - Mutator strains are expected to evolve when the availability and effect of beneficial mutations are high enough to counteract the disadvantage from deleterious mutations that will inevitably accumulate. As the population becomes more adapted to its environment, both availability and effect of beneficial mutations necessarily decrease and mutation rates are predicted to decrease. It has been shown that certain molecular mechanisms can lead to increased mutation rates when the organism finds itself in a stressful environment. While this may be a correlated response to other functions, it could also be an adaptive mechanism, raising mutation rates only when it is most advantageous. Here, we use a mathematical model to investigate the plausibility of the adaptive hypothesis. We show that such a mechanism can be mantained if the population is subjected to diverse stresses. By simulating various antibiotic treatment schemes, we find that combination treatments can reduce the effectiveness of second-order selection on stress-induced mutagenesis. We discuss the implications of our results to strategies of antibiotic therapy. PMID- 28719608 TI - Cholesterol esterification inhibition and imatinib treatment synergistically inhibit growth of BCR-ABL mutation-independent resistant chronic myelogenous leukemia. AB - Since the advent of tyrosine kinase inhibitors (TKIs) such as imatinib, nilotinib, and dasatinib, chronic myelogenous leukemia (CML) prognosis has improved greatly. However, ~30-40% of patients develop resistance to imatinib therapy. Although most resistance is caused by mutations in the BCR-ABL kinase domain, 50-85% of these patients develop resistance in the absence of new mutations. In these cases, targeting other pathways may be needed to regain clinical response. Using label-free Raman spectromicroscopy, we evaluated a number of leukemia cell lines and discovered an aberrant accumulation of cholesteryl ester (CE) in CML, which was found to be a result of BCR-ABL kinase activity. CE accumulation in CML was found to be a cancer-specific phenomenon as untransformed cells did not accumulate CE. Blocking cholesterol esterification with avasimibe, a potent inhibitor of acyl-CoA cholesterol acyltransferase 1 (ACAT-1), significantly suppressed CML cell proliferation in Ba/F3 cells with the BCR-ABLT315I mutation and in K562 cells rendered imatinib resistant without mutations in the BCR-ABL kinase domain (K562R cells). Furthermore, the combination of avasimibe and imatinib caused a profound synergistic inhibition of cell proliferation in K562R cells, but not in Ba/F3T315I. This synergistic effect was confirmed in a K562R xenograft mouse model. Analysis of primary cells from a BCR-ABL mutation-independent imatinib resistant patient by mass cytometry suggested that the synergy may be due to downregulation of the MAPK pathway by avasimibe, which sensitized the CML cells to imatinib treatment. Collectively, these data demonstrate a novel strategy for overcoming BCR-ABL mutation independent TKI resistance in CML. PMID- 28719609 TI - Renal function following xenon anesthesia for partial nephrectomy-An explorative analysis of a randomized controlled study. AB - BACKGROUND: Perioperative preservation of renal function has a significant impact on morbidity and mortality in kidney surgery. Nephroprotective effects of the anesthetic xenon on ischemia-reperfusion injury were found in several experimental studies. OBJECTIVE: We aimed to explore whether xenon anesthesia can reduce renal damage in humans undergoing partial nephrectomy and to gather pilot data of possible nephroprotection in these patients. DESIGN: A prospective randomized, single-blinded, controlled study. SETTING: Single-center, University Hospital of Aachen, Germany between July 2013-October 2015. PATIENTS: Forty-six patients with regular renal function undergoing partial nephrectomy. INTERVENTIONS: Patients were randomly assigned to receive xenon- (n = 23) or isoflurane (n = 23) anesthesia. MAIN OUTCOME MEASURES: Primary outcome was the maximum postoperative glomerular filtration rate (GFR) decline within seven days after surgery. Secondary outcomes included intraoperative and tumor-related data, assessment of further kidney injury markers, adverse events and optional determination of renal function after 3-6 months. RESULTS: Unexpected radical nephrectomy was performed in 5 patients, thus they were excluded from the per protocol analysis, but included in the intention-to-treat analysis. The maximum postoperative GFR decline was attenuated by 45% in the xenon-group (10.9 ml min-1 1.73 cm-2 versus 19.7 ml min-1 1.73 cm-2 in the isoflurane group), but without significance (P = 0.084). Occurrence of adverse events was reduced (P = 0.003) in the xenon group. Renal function was similar among the groups after 3-6 months. CONCLUSION: Xenon anesthesia was feasible and safe in patients undergoing partial nephrectomy with regard to postoperative renal function. We found no significant effect on early renal function but less adverse events in the xenon group. Larger randomized controlled studies in more heterogeneous collectives are required, to confirm or refute the possible clinical benefit on renal function by xenon. TRIAL REGISTRATION: ClinicalTrials.gov NCT01839084 and EudraCT 2012-005698-30. PMID- 28719610 TI - A decade of HIV care in rural Tanzania: Trends in clinical outcomes and impact of clinic optimisation in an open, prospective cohort. AB - OBJECTIVES: Our objectives were to describe trends in enrolment and clinical outcomes in the open, prospective Kilombero and Ulanga Antiretroviral Cohort (KIULARCO) in the Morogoro region of southern Tanzania, and identify strengths and areas for improvement in the care of HIV-positive individuals in rural Tanzania. METHODS: We included adults (>=15 years) and children (<15 years) enrolled in the cohort in 2005-2014. The cohort underwent significant changes from autumn 2012 to optimise care. We evaluated mortality and loss to follow-up (LTFU) using competing risks methods, ART usage, opportunistic infections (OI), co-infections and laboratory abnormalities. RESULTS: Overall, 7010 adults and 680 children were enrolled; enrolment peaked in 2008 but has increased steadily since 2011. Among adults (65% female; median age 37 [interquartile range 31-45] years), the proportion referred from hospital wards quadrupled in 2013-14 versus earlier years. 653 (9%) adults died and 2648 (38%) were LTFU; the five-year cumulative probabilities of death and LTFU were 10.3% and 44.0%, respectively. Among children, 69 (10%) died and 225 (33%) were LTFU. The corresponding five-year probabilities were 12.1% and 39.6%. Adult ART use (regardless of eligibility) increased from 5% in 2005 to 89% in 2014 (similarly among children), with 9% on second-line therapy in 2014 (17% of children). OI diagnoses increased over time; tuberculosis prevalence at enrolment quadrupled from 6% in 2011 to 26% in 2014. The proportion of newly-enrolled participants assessed for laboratory abnormalities peaked at nearly 100% in 2014 (from a minimum of 24%), yet abnormality prevalences remained fairly constant. CONCLUSIONS: In this cohort, ART usage improved dramatically and is approaching targets of 90%. Improved screening led to increases in detection of OIs and laboratory abnormalities, suggesting that a large number of these co-morbidities previously went undetected and untreated. Further work will address the high LTFU rates and implications for mortality estimates, and the management and outcomes of co-morbidities. PMID- 28719611 TI - RNA sequencing to determine the contribution of kinase receptor transactivation to G protein coupled receptor signalling in vascular smooth muscle cells. AB - G protein coupled receptor (GPCR) signalling covers three major mechanisms. GPCR agonist engagement allows for the G proteins to bind to the receptor leading to a classical downstream signalling cascade. The second mechanism is via the utilization of the beta-arrestin signalling molecule and thirdly via transactivation dependent signalling. GPCRs can transactivate protein tyrosine kinase receptors (PTKR) to activate respective downstream signalling intermediates. In the past decade GPCR transactivation dependent signalling was expanded to show transactivation of serine/threonine kinase receptors (S/TKR). Kinase receptor transactivation enormously broadens the GPCR signalling paradigm. This work utilizes next generation RNA-sequencing to study the contribution of transactivation dependent signalling to total protease activated receptor (PAR)-1 signalling. Transactivation, assessed as gene expression, accounted for 50 percent of the total genes regulated by thrombin acting through PAR-1 in human coronary artery smooth muscle cells. GPCR transactivation of PTKRs is approximately equally important as the transactivation of the S/TKR with 209 and 177 genes regulated respectively, via either signalling pathway. This work shows that genome wide studies can provide powerful insights into GPCR mediated signalling pathways. PMID- 28719612 TI - Renal osteodystrophy in the obesity era: Is metabolic syndrome relevant? AB - BACKGROUND: Observational studies have shown a beneficial effect of obesity on bone health; however, most of those studies were not based on bone biopsies. Metabolic syndrome (MetS) could have an effect on bone remodeling. However, there are no data on the effects of MetS in the presence of renal osteodystrophy. OBJECTIVE: The aim of this study was to investigate associations between MetS and renal osteodystrophy using the bone histomorphometric turnover-mineralization volume (TMV) classification. DESIGN, SETTING, PARTICIPANTS & MEASUREMENTS: This observational cross-sectional study included 55 hemodialysis patients (28 women/27 men) who were evaluated for MetS and bone histomorphometry. Biochemical parameters included calcium, phosphorus, alkaline phosphatase, intact parathyroid hormone (iPTH), 25-hydroxyvitamin D, free serum leptin, fibroblast growth factor 23 (FGF23), intact osteocalcin, sclerostin (Scl), glucose, insulin, and thyroid hormones. Robust models of multivariate linear regressions were used for the statistical analyses. RESULTS: Females had higher iPTH levels (1,143 vs. 358, p = 0.02). Patients with normal bone volume (BV/TV) had a higher prevalence of MetS (73.6% vs. 41.7%, p = 0.02) and higher serum phosphorus, C-terminal FGF23 and insulin levels. The multivariate regression analysis showed that low-density lipoprotein cholesterol (LDL) was positively correlated with bone formation rate (BFR/BS) and negatively associated with mineralization lag time. Bone volume was negatively associated with age but positively associated with MetS. Body mass index (BMI) was not correlated with any of the bone histomorphometric parameters. CONCLUSION: Our results suggest that MetS is not a risk factor for low bone volume in hemodialysis patients. Furthermore, BMI alone was not related to bone volume in this population. PMID- 28719613 TI - Visual detection of Brucella in bovine biological samples using DNA-activated gold nanoparticles. AB - Brucellosis is a bacterial disease, which, although affecting cattle primarily, has been associated with human infections, making its detection an important challenge. The existing gold standard diagnosis relies on the culture of bacteria which is a lengthy and costly process, taking up to 45 days. New technologies based on molecular diagnosis have been proposed, either through dip-stick, immunological assays, which have limited specificity, or using nucleic acid tests, which enable to identify the pathogen, but are impractical for use in the field, where most of the reservoir cases are located. Here we demonstrate a new test based on hybridization assays with metal nanoparticles, which, upon detection of a specific pathogen-derived DNA sequence, yield a visual colour change. We characterise the components used in the assay with a range of analytical techniques and show sensitivities down to 1000 cfu/ml for the detection of Brucella. Finally, we demonstrate that the assay works in a range of bovine samples including semen, milk and urine, opening up the potential for its use in the field, in low-resource settings. PMID- 28719614 TI - Beat-ID: Towards a computationally low-cost single heartbeat biometric identity check system based on electrocardiogram wave morphology. AB - In recent years, safer and more reliable biometric methods have been developed. Apart from the need for enhanced security, the media and entertainment sectors have also been applying biometrics in the emerging market of user-adaptable objects/systems to make these systems more user-friendly. However, the complexity of some state-of-the-art biometric systems (e.g., iris recognition) or their high false rejection rate (e.g., fingerprint recognition) is neither compatible with the simple hardware architecture required by reduced-size devices nor the new trend of implementing smart objects within the dynamic market of the Internet of Things (IoT). It was recently shown that an individual can be recognized by extracting features from their electrocardiogram (ECG). However, most current ECG based biometric algorithms are computationally demanding and/or rely on relatively large (several seconds) ECG samples, which are incompatible with the aforementioned application fields. Here, we present a computationally low-cost method (patent pending), including simple mathematical operations, for identifying a person using only three ECG morphology-based characteristics from a single heartbeat. The algorithm was trained/tested using ECG signals of different duration from the Physionet database on more than 60 different training/test datasets. The proposed method achieved maximal averaged accuracy of 97.450% in distinguishing each subject from a ten-subject set and false acceptance and rejection rates (FAR and FRR) of 5.710+/-1.900% and 3.440+/-1.980%, respectively, placing Beat-ID in a very competitive position in terms of the FRR/FAR among state-of-the-art methods. Furthermore, the proposed method can identify a person using an average of 1.020 heartbeats. It therefore has FRR/FAR behavior similar to obtaining a fingerprint, yet it is simpler and requires less expensive hardware. This method targets low-computational/energy-cost scenarios, such as tiny wearable devices (e.g., a smart object that automatically adapts its configuration to the user). A hardware proof-of-concept implementation is presented as an annex to this paper. PMID- 28719616 TI - Analytical network process based optimum cluster head selection in wireless sensor network. AB - Wireless Sensor Networks (WSNs) are becoming ubiquitous in everyday life due to their applications in weather forecasting, surveillance, implantable sensors for health monitoring and other plethora of applications. WSN is equipped with hundreds and thousands of small sensor nodes. As the size of a sensor node decreases, critical issues such as limited energy, computation time and limited memory become even more highlighted. In such a case, network lifetime mainly depends on efficient use of available resources. Organizing nearby nodes into clusters make it convenient to efficiently manage each cluster as well as the overall network. In this paper, we extend our previous work of grid-based hybrid network deployment approach, in which merge and split technique has been proposed to construct network topology. Constructing topology through our proposed technique, in this paper we have used analytical network process (ANP) model for cluster head selection in WSN. Five distinct parameters: distance from nodes (DistNode), residual energy level (REL), distance from centroid (DistCent), number of times the node has been selected as cluster head (TCH) and merged node (MN) are considered for CH selection. The problem of CH selection based on these parameters is tackled as a multi criteria decision system, for which ANP method is used for optimum cluster head selection. Main contribution of this work is to check the applicability of ANP model for cluster head selection in WSN. In addition, sensitivity analysis is carried out to check the stability of alternatives (available candidate nodes) and their ranking for different scenarios. The simulation results show that the proposed method outperforms existing energy efficient clustering protocols in terms of optimum CH selection and minimizing CH reselection process that results in extending overall network lifetime. This paper analyzes that ANP method used for CH selection with better understanding of the dependencies of different components involved in the evaluation process. PMID- 28719615 TI - A human tissue-based functional assay platform to evaluate the immune function impact of small molecule inhibitors that target the immune system. AB - While the immune system is essential for the maintenance of the homeostasis, health and survival of humans, aberrant immune responses can lead to chronic inflammatory and autoimmune disorders. Pharmacological modulation of drug targets in the immune system to ameliorate disease also carry a risk of immunosuppression that could lead to adverse outcomes. Therefore, it is important to understand the 'immune fingerprint' of novel therapeutics as they relate to current and, clinically used immunological therapies to better understand their potential therapeutic benefit as well as immunosuppressive ability that might lead to adverse events such as infection risks and cancer. Since the mechanistic investigation of pharmacological modulators in a drug discovery setting is largely compound- and mechanism-centric but not comprehensive in terms of immune system impact, we developed a human tissue based functional assay platform to evaluate the impact of pharmacological modulators on a range of innate and adaptive immune functions. Here, we demonstrate that it is possible to generate a qualitative and quantitative immune system impact of pharmacological modulators, which might help better understand and predict the benefit-risk profiles of these compounds in the treatment of immune disorders. PMID- 28719617 TI - MicroRNA 155-deficiency leads to decreased autoantibody levels and reduced severity of nephritis and pneumonitis in pristane-induced lupus. AB - OBJECTIVE: We herein examine the role of endogenous miR155 in the development of systemic manifestations in pristane induced lupus. MATERIALS AND METHODS: Systemic lupus in miR155-deficient and wild type mice was induced upon injection of pristane and analyzed after 8 months, PBS-injected mice served as controls. Glomerulonephritis and pneumonitis were quantified using the kidney biopsy score and a newly adapted histomorphometric image analysis system; lung tissue was further analyzed by tissue cytometry. Serum levels of anti-dsDNA, anti-histone and anti-chromatin antibodies were measured by ELISA. Frequencies of B cells, activated and regulatory CD4+ T cells as well as Th1, Th2, Th17 cells were measured by flow cytometry. RT-qPCR was used to measure expression levels of interferon-signature and T-cell subset related as well as miR155-associated genes. RESULTS: After induction of lupus, miR155-deficient mice had significant less pulmonary involvement (perivascular inflammatory area in mm2/mm2 lung area 0.00092+/-0.00015 vs. 0.0027+/-0.00075, p = 0.0347) and renal disease (glomerular activity score 1.95+/-0.19 vs 3+/-0.26, p = 0.0029) compared to wild types. MiR155-deficient mice had significantly lower serum levels of disease-associated auto-antibodies and decreased frequencies of activated CD4+CD25+ (Foxp3-) cells. Upon restimulation, CD4+ cells showed a less pronounced Th2 and Th17 and a slightly decreased Th1 response in mir155-deficient mice. Pristane-treated wild types showed significantly up-regulated expression of genes related to the INF signature (MX1, IP10, IRF7, ISG15). CONCLUSIONS: MiR155-deficient mice had less severe organ involvement, lower serum auto-antibody levels, a less prominent T cell response and lower expressions of genes jointly responsible for disease development. Thus, antagonizing miR155 might be a future approach in treating SLE. PMID- 28719618 TI - An update on psoriasis and metabolic syndrome: A meta-analysis of observational studies. AB - The relationship between psoriasis and metabolic syndrome is not well understood. Though multiple epidemiologic studies have suggested a link between psoriasis and metabolic syndrome, there is a lack of a comprehensive meta-analysis synthesizing the results of all available observational studies to date. In this meta analysis, we examined global data on the relationship between psoriasis and odds of metabolic syndrome by searching for studies published between 1946-2016. Specifically, we analyzed the results from 35 observational studies from 20 countries with 1,450,188 total participants, of which 46,714 were psoriasis patients. The pooled odds ratio based on random effects analysis was 2.14 (95% CI 1.84-2.48). Publication bias was present, as evidenced by an Egger test and graphical visualization through a funnel plot (p = 0.001). Based on this comprehensive meta-analysis, psoriasis patients have higher odds of having metabolic syndrome when compared with the general population. PMID- 28719619 TI - Diagnostic utility of corneal confocal microscopy and intra-epidermal nerve fibre density in diabetic neuropathy. AB - OBJECTIVES: Corneal confocal microscopy (CCM) is a rapid, non-invasive, reproducible technique that quantifies small nerve fibres. We have compared the diagnostic capability of CCM against a range of established measures of nerve damage in patients with diabetic neuropathy. METHODS: In this cross sectional study, thirty subjects with Type 1 diabetes without neuropathy (T1DM), thirty one T1DM subjects with neuropathy (DSPN) and twenty seven non-diabetic healthy control subjects underwent detailed assessment of neuropathic symptoms and neurologic deficits, quantitative sensory testing (QST), electrophysiology, skin biopsy and corneal confocal microscopy (CCM). RESULTS: Subjects with DSPN were older (C vs T1DM vs DSPN: 41.0+/-14.9 vs 38.8+/-12.5 vs 53.3+/-11.9, P = 0.0002), had a longer duration of diabetes (P<0.0001), lower eGFR (P = 0.006) and higher albumin-creatinine ratio (P = 0.03) with no significant difference for HbA1c, BMI, lipids and blood pressure. Patients with DSPN were representative of subjects with diabetic neuropathy with clinical signs and symptoms of neuropathy and greater neuropathy deficits quantified by QST, electrophysiology, intra epidermal nerve fibre density and CCM. Corneal nerve fibre density (CNFD) (Spearman's Rho = 0.60 P<0.0001) and IENFD (Spearman's Rho = 0.56 P<0.0001) were comparable when correlated with peroneal nerve conduction velocity. For the diagnosis of diabetic neuropathy the sensitivity for CNFD was 0.77 and specificity was 0.79 with an area under the ROC curve of 0.81. IENFD had a diagnostic sensitivity of 0.61, specificity of 0.80 and area under the ROC curve of 0.73. CONCLUSIONS: CCM is a valid accurate non-invasive method to identify small nerve fibre pathology and is able to diagnose DPN. PMID- 28719620 TI - Endurance performance and energy metabolism during exercise in mice with a muscle specific defect in the control of branched-chain amino acid catabolism. AB - It is known that the catabolism of branched-chain amino acids (BCAAs) in skeletal muscle is suppressed under normal and sedentary conditions but is promoted by exercise. BCAA catabolism in muscle tissues is regulated by the branched-chain alpha-keto acid (BCKA) dehydrogenase complex, which is inactivated by phosphorylation by BCKA dehydrogenase kinase (BDK). In the present study, we used muscle-specific BDK deficient mice (BDK-mKO mice) to examine the effect of uncontrolled BCAA catabolism on endurance exercise performance and skeletal muscle energy metabolism. Untrained control and BDK-mKO mice showed the same performance; however, the endurance performance enhanced by 2 weeks of running training was somewhat, but significantly less in BDK-mKO mice than in control mice. Skeletal muscle of BDK-mKO mice had low levels of glycogen. Metabolome analysis showed that BCAA catabolism was greatly enhanced in the muscle of BDK mKO mice and produced branched-chain acyl-carnitine, which induced perturbation of energy metabolism in the muscle. These results suggest that the tight regulation of BCAA catabolism in muscles is important for homeostasis of muscle energy metabolism and, at least in part, for adaptation to exercise training. PMID- 28719621 TI - Security analysis and enhanced user authentication in proxy mobile IPv6 networks. AB - The Proxy Mobile IPv6 (PMIPv6) is a network-based mobility management protocol that allows a Mobile Node(MN) connected to the PMIPv6 domain to move from one network to another without changing the assigned IPv6 address. The user authentication procedure in this protocol is not standardized, but many smartcard based authentication schemes have been proposed. Recently, Alizadeh et al. proposed an authentication scheme for the PMIPv6. However, it could allow an attacker to derive an encryption key that must be securely shared between MN and the Mobile Access Gate(MAG). As a result, outsider adversary can derive MN's identity, password and session key. In this paper, we analyze Alizadeh et al.'s scheme regarding security and propose an enhanced authentication scheme that uses a dynamic identity to satisfy anonymity. Furthermore, we use BAN logic to show that our scheme can successfully generate and communicate with the inter-entity session key. PMID- 28719622 TI - Characterization of plasma metal profiles in Alzheimer's disease using multivariate statistical analysis. AB - The exact cause of Alzheimer's disease (AD) and the role of metals in its etiology remain unclear. We have used an analytical approach, based on inductively coupled plasma mass spectrometry coupled with multivariate statistical analysis, to study the profiles of a wide range of metals in AD patients and healthy controls. AD cannot be cured and the lack of sensitive biomarkers that can be used in the early stages of the disease may contribute to this treatment failure. In the present study, we measured plasma levels of amyloid-beta1-42(0.142+/-0.029MUg/L)and furin(2.292+/-1.54MUg/L), together with those of the metalloproteinases, insulin-degrading enzyme(1.459+/-1.14MUg/L) and neprilysin(0.073+/-0.015MUg/L), in order to develop biomarkers for AD. Partial least squares discriminant analysis models were used to refine intergroup differences and we discovered that four metals(Mn, Al, Li, Cu) in peripheral blood were strongly associated with AD. Aberration in homeostasis of these metals may alter levels of proteinases, such as furin, which are associated with neurodegeneration in AD and can be a used as plasma-based biomarkers. PMID- 28719623 TI - Moderate irrigation intervals facilitate establishment of two desert shrubs in the Taklimakan Desert Highway Shelterbelt in China. AB - BACKGROUND: Water influences various physiological and ecological processes of plants in different ecosystems, especially in desert ecosystems. The purpose of this study is to investigate the response of physiological and morphological acclimation of two shrubs Haloxylon ammodendron and Calligonum mongolicunl to variations in irrigation intervals. METHODOLOGY/PRINCIPAL FINDINGS: The irrigation frequency was set as 1-, 2-, 4-, 8- and 12-week intervals respectively from March to October during 2012-2014 to investigate the response of physiological and morphological acclimation of two desert shrubs Haloxylon ammodendron and Calligonum mongolicunl to variations in the irrigation system. The irrigation interval significantly affected the individual-scale carbon acquisition and biomass allocation pattern of both species. Under good water conditions (1- and 2-week intervals), carbon assimilation was significantly higher than other treatments; while, under water shortage conditions (8- and 12 week intervals), there was much defoliation; and under moderate irrigation intervals (4 weeks), the assimilative organs grew gently with almost no defoliation occurring. CONCLUSION/SIGNIFICANCE: Both studied species maintained similar ecophysiologically adaptive strategies, while C. mongolicunl was more sensitive to drought stress because of its shallow root system and preferential belowground allocation of resources. A moderate irrigation interval of 4 weeks was a suitable pattern for both plants since it not only saved water but also met the water demands of the plants. PMID- 28719624 TI - Sequence-specific DNA binding by MYC/MAX to low-affinity non-E-box motifs. AB - The MYC oncoprotein regulates transcription of a large fraction of the genome as an obligatory heterodimer with the transcription factor MAX. The MYC:MAX heterodimer and MAX:MAX homodimer (hereafter MYC/MAX) bind Enhancer box (E-box) DNA elements (CANNTG) and have the greatest affinity for the canonical MYC E-box (CME) CACGTG. However, MYC:MAX also recognizes E-box variants and was reported to bind DNA in a "non-specific" fashion in vitro and in vivo. Here, in order to identify potential additional non-canonical binding sites for MYC/MAX, we employed high throughput in vitro protein-binding microarrays, along with electrophoretic mobility-shift assays and bioinformatic analyses of MYC-bound genomic loci in vivo. We identified all hexameric motifs preferentially bound by MYC/MAX in vitro, which include the low-affinity non-E-box sequence AACGTT, and found that the vast majority (87%) of MYC-bound genomic sites in a human B cell line contain at least one of the top 21 motifs bound by MYC:MAX in vitro. We further show that high MYC/MAX concentrations are needed for specific binding to the low-affinity sequence AACGTT in vitro and that elevated MYC levels in vivo more markedly increase the occupancy of AACGTT sites relative to CME sites, especially at distal intergenic and intragenic loci. Hence, MYC binds diverse DNA motifs with a broad range of affinities in a sequence-specific and dose-dependent manner, suggesting that MYC overexpression has more selective effects on the tumor transcriptome than previously thought. PMID- 28719625 TI - Differences of immune disorders between Alzheimer's disease and breast cancer based on transcriptional regulation. AB - Although chronic inflammation and immune disorders are of great importance to the pathogenesis of both dementia and cancer, the pathophysiological mechanisms are not clearly understood. In recent years, growing epidemiological evidence and meta-analysis data suggest an inverse association between Alzheimer's disease (AD), which is the most common form of dementia, and cancer. It has been revealed that some common genes and biological processes play opposite roles in AD and cancer; however, the biological immune mechanism for the inverse association is not clearly defined. An unsupervised matrix decomposition two-stage bioinformatics procedure was adopted to investigate the opposite behaviors of the immune response in AD and breast cancer (BC) and to discover the underlying transcriptional regulatory mechanisms. Fast independent component analysis (FastICA) was applied to extract significant genes from AD and BC microarray gene expression data. Based on the extracted data, the shared transcription factors (TFs) from AD and BC were captured. Second, the network component analysis (NCA) algorithm in this study was presented to quantitatively deduce the TF activities and regulatory influences because quantitative dynamic regulatory information for TFs is not available via microarray techniques. Based on the NCA results and reconstructed transcriptional regulatory networks, inverse regulatory processes and some known innate immune responses were described in detail. Many of the shared TFs and their regulatory processes were found to be closely related to the adaptive immune response from dramatically different directions and to play crucial roles in both AD and BC pathogenesis. From the above findings, the opposing cellular behaviors demonstrate an invaluable opportunity to gain insights into the pathogenesis of these two types of diseases and to aid in developing new treatments. PMID- 28719626 TI - Impact of respiratory infections, outdoor pollen, and socioeconomic status on associations between air pollutants and pediatric asthma hospital admissions. AB - BACKGROUND: Epidemiology studies have shown that ambient concentrations of ozone and fine particulate matter (PM2.5) are associated with increased emergency department (ED) visits and hospital admissions (HAs) for asthma. OBJECTIVE: Evaluate the impact of outdoor pollen, respiratory infections, and socioeconomic status (SES) on the associations between ambient ozone and PM2.5 and asthma HAs in New York City. METHODS: Daily ozone, PM2.5, meteorological factors, pollen, and hospitalization records during 1999 to 2009 were obtained for New York City residents. Daily counts of HAs for asthma and respiratory infections were calculated for all-age and specific age groups, and for high- and low-SES communities. Generalized additive models were used to examine ambient concentrations of ozone and PM2.5 and asthma HAs, potential confounding effects of outdoor pollen and HAs for respiratory infections, and potential effect modification by neighborhood SES. RESULTS: Both ozone and PM2.5 were statistically significantly associated with increased asthma HAs in children aged 6-18 years (per 10 ppb increase in ozone: RR = 1.0203, 95% CI: 1.0028-1.0382; per 10 MUg/m3 increase in PM2.5: RR = 1.0218, 95% CI: 1.0007-1.0434), but not with total asthma HAs, or asthma HAs in other age groups. These associations were stronger for children living in the high-SES areas. Adjustment for respiratory infection HAs at various lags did not result in changes greater than 10% in the risk estimates for either ozone or PM2.5. In contrast, adjustment for outdoor pollen generally attenuated the estimated RRs for both ozone and PM2.5. CONCLUSIONS: Ambient ozone and PM2.5 are associated with asthma HAs in school-age children, and these associations are not modified by SES. HAs for respiratory infections do not appear to be a confounder for observed ozone- and PM2.5-asthma HAs associations, but pollen may be a weak confounder. PMID- 28719627 TI - The role of gender in the association between self-rated health and mortality among older adults in Santiago, Chile: A cohort study. AB - BACKGROUND: Previous studies on the role of gender in the association between self-rated health and mortality have shown contrasting results. This study was aimed to determine the importance of gender in the association between self-rated health and mortality among older people in Santiago, Chile. METHODS: A 10 year follow-up of 1066 people aged 60 or more, from the Chilean cohort of the Study of Health, Ageing and Well-Being. Self-rated health was assessed in face to face interviews through a single general question, along with socio-demographic and health status information. Cox proportional hazards and flexible parametric models for survival analyses were employed. RESULTS: By the end of follow-up, 30.7% of women and 39.4% of men died. Adjusted hazard ratio of poor self-rated health, compared to good self-rated health, was 1.92(95% CI 1.29-2.86). In models stratified by gender, an increased risk of mortality was observed among women who rated their health as poor (HR = 2.21, 95% CI 1.43-3.40), but not among men (HR = 1.04, 95% CI 0.58-1.86). Age was associated with mortality in both groups; for men, functional limitation and underweight were also risk factors and obesity was a protective factor. CONCLUSIONS: Compared to older women who rated their health as good, older women who rated their health as poor had a 2 fold increased risk of mortality over the subsequent 10 years. These findings stress the importance of considering a gender perspective into health programmes, including those focused on older people, in order to address the different elements that increase, on the long run, the risk of dying among older women and men. PMID- 28719628 TI - Salt-tolerant and -sensitive alfalfa (Medicago sativa) cultivars have large variations in defense responses to the lepidopteran insect Spodoptera litura under normal and salt stress condition. AB - In nature, plants are often exposed to multiple stress factors at the same time. Yet, little is known about how plants modulate their physiology to counteract simultaneous abiotic and biotic stresses, such as soil salinity and insect herbivory. In this study, insect performance bioassays, phytohormone measurements, quantification of transcripts, and protein determination were employed to study the phenotypic variations of two alfalfa (Medicago sativa) cultivars in response to insect Spodoptera litura feeding under normal and salt stress condition. When being cultivated in normal soil, the salt-tolerant alfalfa cultivar Zhongmu-1 exhibited lower insect resistance than did the salt-sensitive cultivar Xinjiang Daye. Under salinity stress, the defense responses of Xinjiang Daye were repressed, whereas Zhongmu-1 did not show changes in resistance levels. It is likely that salinity influenced the resistance of Xinjiang Daye through suppressing the accumulation of jasmonic acid-isoleucine (JA-Ile), which is the bioactive hormone inducing herbivore defense responses, leading to attenuated trypsin proteinase inhibitor (TPI) activity. Furthermore, exogenous ABA supplementation suppressed the insect herbivory-induced JA/JA-Ile accumulation and levels of JAR1 (jasmonate resistant 1) and TPI, and further decreased the resistance of Xinjiang Daye, whereas Zhongmu-1 showed very little response to the increased ABA level. We propose a mechanism, in which high levels of abscisic acid induced by salt treatment may affect the expression levels of JAR1 and consequently decrease JA-Ile accumulation and thus partly suppress the defense of Xinjiang Daye against insects under salt stress. This study provides new insight into the mechanism by which alfalfa responds to concurrent abiotic and biotic stresses. PMID- 28719629 TI - Multiparametric [11C]Acetate positron emission tomography-magnetic resonance imaging in the assessment and staging of prostate cancer. AB - BACKGROUND: The aim of this study was to evaluate whether MP [11C]Acetate PET-MRI enables an accurate differentiation of benign and malignant prostate tumors as well as local and distant staging. MATERIALS AND METHODS: Fifty-six consecutive patients fulfilling the following criteria were included in this IRB-approved prospective study: elevated PSA levels or suspicious findings at digital rectal examination or TRUS; and histopathological verification. All patients underwent MP [11C]Acetate PET-MRI of the prostate performed on separate scanners with PET/CT using [11C]Acetate and 3T MP MR imaging. Appropriate statistical tests were used to determine diagnostic accuracy, local and distant staging. RESULTS: MP imaging with two MRI parameters (T2w and DWI) achieved the highest sensitivity, specificity, and diagnostic accuracy of 95%, 68.8%, and 88%, with an AUC of 0.82 for primary PCa detection. Neither assessments with a single parameter (AUC, 0.54-0.79), nor different combinations with up to five parameters (AUC, 0.67-0.79) achieved equally good results. MP [11C]Acetate PET-MRI improved local staging with a sensitivity, specificity, and diagnostic accuracy of 100%, 96%, and 97% compared to MRI alone with 72.2%, 100%, and 95.5%. MP [11C]Acetate PET-MRI correctly detected osseous and liver metastases in five patients. CONCLUSIONS: MP [11C]Acetate PET-MRI merges morphologic with functional information, and allows insights into tumor biology. MP [11C]Acetate PET-MRI with two MRI-derived parameters (T2 and DWI) yields the highest diagnostic accuracy. The addition of more parameters does not improve diagnostic accuracy of primary PCa detection. MP [11C]Acetate PET-MRI facilitates improved local and distant staging, providing "one-stop" staging in patients with primary PCa, and therefore has the potential to improve therapy. PATIENT SUMMARY: In this report we investigated MP [11C]Acetate PET-MRI for detection, local and distant staging of prostate cancer. We demonstrate that MP [11C]Acetate PET-MRI with two MRI-derived parameters (T2 and DWI) achieves the best diagnostic accuracy for primary prostate cancer detection and that MP [11C]Acetate PET-MRI enables an improved local and distant staging. PMID- 28719631 TI - The distribution and host range of the banana Fusarium wilt fungus, Fusarium oxysporum f. sp. cubense, in Asia. AB - Fusarium oxysporum formae specialis cubense (Foc) is a soil-borne fungus that causes Fusarium wilt, which is considered to be the most destructive disease of bananas. The fungus is believed to have evolved with its host in the Indo-Malayan region, and from there it was spread to other banana-growing areas with infected planting material. The diversity and distribution of Foc in Asia was investigated. A total of 594 F. oxysporum isolates collected in ten Asian countries were identified by vegetative compatibility groups (VCGs) analysis. To simplify the identification process, the isolates were first divided into DNA lineages using PCR-RFLP analysis. Six lineages and 14 VCGs, representing three Foc races, were identified in this study. The VCG complex 0124/5 was most common in the Indian subcontinent, Vietnam and Cambodia; whereas the VCG complex 01213/16 dominated in the rest of Asia. Sixty-nine F. oxysporum isolates in this study did not match any of the known VCG tester strains. In this study, Foc VCG diversity in Bangladesh, Cambodia and Sri Lanka was determined for the first time and VCGs 01221 and 01222 were first reported from Cambodia and Vietnam. New associations of Foc VCGs and banana cultivars were recorded in all the countries where the fungus was collected. Information obtained in this study could help Asian countries to develop and implement regulatory measures to prevent the incursion of Foc into areas where it does not yet occur. It could also facilitate the deployment of disease resistant banana varieties in infested areas. PMID- 28719630 TI - Oligo- and dsDNA-mediated genome editing using a tetA dual selection system in Escherichia coli. AB - The ability to precisely and seamlessly modify a target genome is needed for metabolic engineering and synthetic biology techniques aimed at creating potent biosystems. Herein, we report on a promising method in Escherichia coli that relies on the insertion of an optimized tetA dual selection cassette followed by replacement of the same cassette with short, single-stranded DNA (oligos) or long, double-stranded DNA and the isolation of recombinant strains by negative selection using NiCl2. This method could be rapidly and successfully used for genome engineering, including deletions, insertions, replacements, and point mutations, without inactivation of the methyl-directed mismatch repair (MMR) system and plasmid cloning. The method we describe here facilitates positive genome-edited recombinants with selection efficiencies ranging from 57 to 92%. Using our method, we increased lycopene production (3.4-fold) by replacing the ribosome binding site (RBS) of the rate-limiting gene (dxs) in the 1-deoxy-D xylulose-5-phosphate (DXP) biosynthesis pathway with a strong RBS. Thus, this method could be used to achieve scarless, proficient, and targeted genome editing for engineering E. coli strains. PMID- 28719632 TI - Viscum album neutralizes tumor-induced immunosuppression in a human in vitro cell model. AB - Tumor cells have the capacity to secrete immunosuppressive substances in order to diminish dendritic cell (DC) activity and thereby escape from immune responses. The impact of mistletoe (Viscum album) extracts (VAE), which are frequently used as an additive anti-cancer therapy to stimulate the immune response, is still unknown. Using a human cellular system, the impact of two different VAE (VAEA + VAEI) on the maturation of human dendritic cells and on T cell function has been investigated using flow cytometry, automated fluorescence microscopy and cytokine bead array assays. Furthermore, we examined whether VAEI was able to counteract tumor-induced immunosuppression within this cellular system using a renal cancer cell model. The role of mistletoe lectin (ML) was analyzed using ML-specific antibodies and ML-depleted VAEI. VAEI and VAEA augmented the maturation of dendritic cells. VAEI abrogated tumor-induced immunosuppression of dendritic cells and both processes were partially mediated by ML since ML-depleted VAEI and ML-specific antibodies almost neutralized the rehabilitative effects of VAEI on DC maturation. Using these settings, co-culture experiments with purified CD4+ T cells had no influence on T cell proliferation and activation but did have an impact on IFN-gamma secretion. The study provides a potential mode-of-action of VAE as an additive cancer therapy based on immunomodulatory effects. However, the impact on the in vivo situation has to be evaluated in further studies. PMID- 28719633 TI - Trauma care: Finding a better way. AB - In a Perspective, Hasan Alam discusses emerging treatment approaches in trauma care. PMID- 28719634 TI - Taxa-area relationship of aquatic fungi on deciduous leaves. AB - One of the fundamental patterns in macroecology is the increase in the number of observed taxa with size of sampled area. For microbes, the shape of this relationship remains less clear. The current study assessed the diversity of aquatic fungi, by the traditional approach based on conidial morphology (captures reproducing aquatic hyphomycetes) and next generation sequencing (NGS; captures other fungi as well), on graded sizes of alder leaves (0.6 to 13.6 cm2). Leaves were submerged in two streams in geographically distant locations: the Oliveira Stream in Portugal and the Boss Brook in Canada. Decay rates of alder leaves and fungal sporulation rates did not differ between streams. Fungal biomass was higher in Boss Brook than in Oliveira Stream, and in both streams almost 100% of the reads belonged to active fungal taxa. In general, larger leaf areas tended to harbour more fungi, but these findings were not consistent between techniques. Morphospecies-based diversity increased with leaf area in Boss Brook, but not in Oliveira Stream; metabarcoding data showed an opposite trend. The higher resolution of metabarcoding resulted in steeper taxa-accumulation curves than morphospecies-based assessments (fungal conidia morphology). Fungal communities assessed by metabarcoding were spatially structured by leaf area in both streams. Metabarcoding promises greater resolution to assess biodiversity patterns in aquatic fungi and may be more accurate for assessing taxa-area relationships and local to global diversity ratios. PMID- 28719636 TI - The non-diuretic hypotensive effects of thiazides are enhanced during volume depletion states. AB - Thiazide derivatives including Hydrochlorothiazide (HCTZ) represent the most common treatment of mild to moderate hypertension. Thiazides initially enhance diuresis via inhibition of the kidney Na+-Cl- Cotransporter (NCC). However, chronic volume depletion and diuresis are minimal while lowered blood pressure (BP) is maintained on thiazides. Thus, a vasodilator action of thiazides is proposed, likely via Ca2+-activated K+ (BK) channels in vascular smooth muscles. This study ascertains the role of volume depletion induced by salt restriction or salt wasting in NCC KO mice on the non-diuretic hypotensive action of HCTZ. HCTZ (20mg/kg s.c.) lowered BP in 1) NCC KO on a salt restricted diet but not with normal diet; 2) in volume depleted but not in volume resuscitated pendrin/NCC dKO mice; the BP reduction occurs without any enhancement in salt excretion or reduction in cardiac output. HCTZ still lowered BP following treatment of NCC KO on salt restricted diet with paxilline (8 mg/kg, i.p.), a BK channel blocker, and in BK KO and BK/NCC dKO mice on salt restricted diet. In aortic rings from NCC KO mice on normal and low salt diet, HCTZ did not alter and minimally decreased maximal phenylephrine contraction, respectively, while contractile sensitivity remained unchanged. These results demonstrate 1) the non-diuretic hypotensive effects of thiazides are augmented with volume depletion and 2) that the BP reduction is likely the result of HCTZ inhibition of vasoconstriction through a pathway dependent on factors present in vivo, is unrelated to BK channel activation, and involves processes associated with intravascular volume depletion. PMID- 28719637 TI - Microbiome overview in swine lungs. AB - Mycoplasma hyopneumoniae is the etiologic agent of swine enzootic pneumonia. However other mycoplasma species and secondary bacteria are found as inhabitants of the swine respiratory tract, which can be also related to disease. In the present study we have performed a total DNA metagenomic analysis from the lungs of pigs kept in a field condition, with suggestive signals of enzootic pneumonia and without any infection signals to evaluate the bacteria variability of the lungs microbiota. Libraries from metagenomic DNA were prepared and sequenced using total DNA shotgun metagenomic pyrosequencing. The metagenomic distribution showed a great abundance of bacteria. The most common microbial families identified from pneumonic swine's lungs were Mycoplasmataceae, Flavobacteriaceae and Pasteurellaceae, whereas in the carrier swine's lungs the most common families were Mycoplasmataceae, Bradyrhizobiaceae and Flavobacteriaceae. Analysis of community composition in both samples confirmed the high prevalence of M. hyopneumoniae. Moreover, the carrier lungs had more diverse family population, which should be related to the lungs normal flora. In summary, we provide a wide view of the bacterial population from lungs with signals of enzootic pneumonia and lungs without signals of enzootic pneumonia in a field situation. These bacteria patterns provide information that may be important for the establishment of disease control measures and to give insights for further studies. PMID- 28719638 TI - Combination of twelve alleles at six quantitative trait loci determines grain weight in rice. AB - Grain weight, which is controlled by quantitative trait loci (QTLs), is one of the most important determinants of rice yield. Although many QTLs for grain weight have been identified, little is known about how different alleles in different QTLs coordinate to determine grain weight. In the present study, six grain-weight-QTLs were detected in seven mapping populations (two F2, one F3, and four recombinant inbred lines) developed by crossing 'Lemont', a United States japonica variety, with 'Yangdao 4', a Chinese indica variety. In each of the six loci, one allele from one parent increased grain weight and one allele from another parent decreased it. Thus, the 12 alleles at the six QTLs were subjected to regression analysis to examine whether they acted additively across loci leading to a linear relationship between the predicted breeding value of QTL and phenotype. Results suggested that a combination of the 12 alleles determined grain weight. In addition, plants carrying more grain-weight-increasing alleles had heavier grains than those carrying more grain-weight-decreasing alleles. This trend was consistent in the seven mapping populations. Thus, these six QTLs might be used in marker-assisted selection of grain weight, by stacking different grain weight-increasing or -decreasing alleles. PMID- 28719635 TI - Differential protein expression profile in the hypothalamic GT1-7 cell line after exposure to anabolic androgenic steroids. AB - The abuse of anabolic androgenic steroids (AAS) has been considered a major public health problem during decades. Supraphysiological doses of AAS may lead to a variety of neuroendocrine problems. Precisely, the hypothalamic-pituitary gonadal (HPG) axis is one of the body systems that is mainly influenced by steroidal hormones. Fluctuations of the hormonal milieu result in alterations of reproductive function, which are made through changes in hypothalamic neurons expressing gonadotropin-releasing hormone (GnRH). In fact, previous studies have shown that AAS modulate the activity of these neurons through steroid-sensitive afferents. To increase knowledge about the cellular mechanisms induced by AAS in GnRH neurons, we performed proteomic analyses of the murine hypothalamic GT1-7 cell line after exposure to 17alpha-methyltestosterone (17alpha-meT; 1 MUM). These cells represent a good model for studying regulatory processes because they exhibit the typical characteristics of GnRH neurons, and respond to compounds that modulate GnRH in vivo. Two-dimensional difference in gel electrophoresis (2D DIGE) and mass spectrometry analyses identified a total of 17 different proteins that were significantly affected by supraphysiological levels of AAS. Furthermore, pathway analyses showed that modulated proteins were mainly associated to glucose metabolism, drug detoxification, stress response and cell cycle. Validation of many of these proteins, such as GSTM1, ERH, GAPDH, PEBP1 and PDIA6, were confirmed by western blotting. We further demonstrated that AAS exposure decreased expression of estrogen receptors and GnRH, while two important signaling pathway proteins p-ERK, and p-p38, were modulated. Our results suggest that steroids have the capacity to directly affect the neuroendocrine system by modulating key cellular processes for the control of reproductive function. PMID- 28719639 TI - Oral administration of Chinese herbal medicine during gestation period for preventing hemolytic disease of the newborn due to ABO incompatibility: A systematic review of randomized controlled trials. AB - BACKGROUND: About 85.3% of hemolytic disease of the newborn (HDN) is caused by maternal-fetal ABO blood group incompatibility. However, there is currently no recommended "best" therapy for ABO incompatibility during pregnancy. OBJECTIVES: To systematically assess the safety and effectiveness of oral Chinese herbal medicine (CHM) for preventing HDN due to ABO incompatibility. METHODS: The protocol of this review was registered on the PROSPERO website (No. CRD42016038637).Six databases were searched from inception to April 2016. Randomized controlled trials (RCTs) of CHM for maternal-fetal ABO incompatibility were included. The primary outcome was incidence of HDN. The Cochrane risk of bias tool was used to assess the methodological quality of included trials. Risk ratios (RR) and mean differences with 95% confidence interval were used as effect measures. Meta-analyses using Revman 5.3 software were conducted if there were sufficient trials without obvious clinical or statistical heterogeneity available. RESULTS: Totally 28 RCTs involving3413 women were included in the review. The majority of the trials had unclear or high risk of bias. Our study found that the rate of HDN and the incidence of neonatal jaundice might be 70% lower in the herbal medicine group compared with the usual care group (RR from 0.25 to 0.30).After treatment with herbal medicine, women were twice as likely to have antibody titers lower than 1:64 compared with women who received usual care(RR from 2.15 to 3.14) and the umbilical cord blood bilirubin level in the herbal medicine group was 4umol/L lower than in those receiving usual care. There was no difference in Apgar scores or birthweights between the two groups. CONCLUSIONS: This review found very low-quality evidence that CHM prevented HDN caused by maternal-fetal ABO incompatibility. No firm conclusions can be drawn regarding the effectiveness or safety of CHM for this condition. PMID- 28719640 TI - Short-lived long non-coding RNAs as surrogate indicators for chemical exposure and LINC00152 and MALAT1 modulate their neighboring genes. AB - Whole transcriptome analyses have revealed a large number of novel long non coding RNAs (lncRNAs). Although accumulating evidence demonstrates that lncRNAs play important roles in regulating gene expression, the detailed mechanisms of action of most lncRNAs remain unclear. We previously reported that a novel class of lncRNAs with a short half-life (t1/2 < 4 h) in HeLa cells, termed short-lived non-coding transcripts (SLiTs), are closely associated with physiological and pathological functions. In this study, we focused on 26 SLiTs and nuclear enriched abundant lncRNA, MALAT1(t1/2 of 7.6 h in HeLa cells) in neural stem cells (NSCs) derived from human induced pluripotent stem cells, and identified four SLiTs (TUG1, GAS5, FAM222-AS1, and SNHG15) that were affected by the following typical chemical stresses (oxidative stress, heavy metal stress and protein synthesis stress). We also found the expression levels of LINC00152 (t1/2 of 2.1 h in NSCs), MALAT1 (t1/2 of 1.8 h in NSCs), and their neighboring genes were elevated proportionally to the chemical doses. Moreover, we confirmed that the overexpression of LINC00152 or MALAT1 upregulated the expressions of their neighboring genes even in the absence of chemical stress. These results reveal that LINC00152 and MALAT1 modulate their neighboring genes, and thus provide a deeper understanding of the functions of lncRNAs. PMID- 28719641 TI - Inversion of the imprinting control region of the Peg3 domain. AB - The imprinting of the mouse Peg3 domain is controlled through a 4-kb genomic region encompassing the bidirectional promoter and 1st exons of Peg3 and Usp29. In the current study, this ICR was inverted to test its orientation dependency for the transcriptional and imprinting control of the Peg3 domain. The inversion resulted in the exchange of promoters and 1st exons between Peg3 and Usp29. Paternal transmission of this inversion caused 10-fold down-regulation of Peg3 and 2-fold up-regulation of Usp29 in neonatal heads, consistent with its original promoter strength in each direction. The paternal transmission also resulted in reduced body size among the animals, which was likely contributed by the dramatic down-regulation of Peg3. Transmission through either allele caused no changes in the DNA methylation and imprinting status of the Peg3 domain except that Zfp264 became bi-allelic through the maternal transmission. Overall, the current study suggests that the orientation of the Peg3-ICR may play no role in its allele specific DNA methylation, but very critical for the transcriptional regulation of the entire imprinted domain. PMID- 28719643 TI - Retraction: A Novel Image Recuperation Approach for Diagnosing and Ranking Retinopathy Disease Level Using Diabetic Fundus Image. PMID- 28719642 TI - Infections with Schistosoma mansoni and geohelminths among school children dwelling along the shore of the Lake Hawassa, southern Ethiopia. AB - BACKGROUND: Infections with Schistosoma mansoni and soil-transmitted helminthes (STHs) are major public health problems in Ethiopia. However, information was scarce on the current status of these infections to guide an intervention in the study area. Therefore, this study was conducted to assess the prevalence of infections with S. mansoni and STHs and associated factors among school children in southern Ethiopia. METHODS: This cross-sectional study investigated children who were attending the Finchawa and Tullo junior elementary schools and were residing along the shore of the lake Hawassa in January and February, 2015. A total of 374 students were selected using systematic random sampling technique. Data on socio-demography and related factors was collected using structured questionnaires. A single stool sample was collected from each child and processed using formol-ether concentration technique and examined microscopically for parasites' ova/larva. RESULTS: The prevalence of parasitic infection with one or more than one helminthiasis was found to be 67.9%. Seven different types of helminths were identified and the most prevalent parasites were Ascaris lumbricoides (44.4%), followed by S. mansoni (31%), Trichuris trichiura (11%), and hookworms (7.7%). The rate of infection with STHs was 52.4%. Single, double, triple and quadruple infections were 42.2, 22.5, 2.4, and 0.8%, respectively. Children who practiced open-field defecation (AOR, 3.6; 95% CI 1.6-8.0; p = 0.001) and had not always washed their hands before eating a meal (AOR, 5.0; 95%CI 2.15-11.7; p <0.001) were more infected with STHs. Moreover, the rate of S. mansoni infection was significantly higher among children who were attending the Finchawa school (AOR, 2.13; 95% CI 1.31-3.46; p = 0.002), aged 11-15 years (AOR, 1.97; 95% CI 1.22-3.19; p = 0.006), had swum in the lake Hawassa (AOR, 2.73; 95%CI 1.20-6.17; p = 0.016), and had involved in irrigation-related activities (AOR, 1.68; 95%CI 1.04-2.71; p = 0.034). CONCLUSION: The study showed high prevalence of STHs and moderate rate of schisotosomiasis. Mass deworming twice a year for STHs and once every two years for S. mansoni, further to strengthening other prevention measures, is critically needed to reduce these infections to inconsequential level. PMID- 28719644 TI - Isolation of putative stem cells present in human adult olfactory mucosa. AB - The olfactory mucosa (OM) has the unique characteristic of performing an almost continuous and lifelong neurogenesis in response to external injuries, due to the presence of olfactory stem cells that guarantee the maintenance of the olfactory function. The easy accessibility of the OM in humans makes these stem cells feasible candidates for the development of regenerative therapies. In this report we present a detailed characterization of a patient-derived OM, together with a description of cell cultures obtained from the OM. In addition, we present a method for the enrichment and isolation of OM stem cells that might be used for future translational studies dealing with neuronal plasticity, neuro-regeneration or disease modeling. PMID- 28719645 TI - Comment on "The GalNAc-T Activation Pathway (GALA) is not a general mechanism for regulating mucin-type O-glycosylation". PMID- 28719646 TI - A synergistic negative effect of gestational smoke-exposure and small litter size on rat placental efficiency, vascularisation and angiogenic factors mRNA expression. AB - Smoking increases the risk of pregnancy complications such as spontaneous abortion and low birth weight (LBW). By cigarette smoke exposure (gestational day, GD3-17), normal-litter-size pregnancy with low birth weight (NP-LBW) and small-litter-size pregnancy with normal birth weight (SP-NBW) in rats were induced. The placental weight in SP-NBW was twice the weight of the normal in contrast with the smaller placenta in NP-LBW. Compared with the normal, placental efficiency (expressed as fetus-to-placenta weight ratio) and placental vascularisation were significantly decreased in smoke exposed placentas with more obvious decrease in SP-NBW. For NP-LBW, decreased placental vascularisation was due to decreased labyrinth vascularisation which was caused by both decreased number density and diameter of fetal capillary. For SP-NBW, decreased placental vascularisation was due to reduced proportion of labyrinth in placenta and decreased labyrinth vascularisation which was caused by decreased fetal capillary number density. Real time RT-PCR analysis showed a tendency for decreased placental mRNA level of vascular endothelial growth factor (VEGF), angiopoietin-1 (Ang1) and tyrosine kinase receptor-2 (Tie2) in NP-LBW(P<0.1), and the tendency became obvious in SP-NBW(P<0.05). A tendency for decreased placental mRNA level of fms-like tyrosine kinase-1(Flt1) and angiopoietin-2 (Ang2) was also observed in SP-LBW(P<0.1). Our data demonstrated the synergistic negative effect of gestational smoke-exposure and small litter size on placental efficiency, placental vascularisation and placental angiogenic growth factor mRNA expression in rat. PMID- 28719647 TI - Morbidity, outcomes and cost-benefit analysis of wildlife rehabilitation in Catalonia (Spain). AB - BACKGROUND: There are few studies of careful examination of wildlife casualties in Wildlife Rehabilitation Centers. These studies are essential for detecting menaces to wild species and providing objective criteria about cost-benefit of treatments in those centers. The release rate is considered the main outcome indicator, but other parameters such as length of stay at the center and a cost benefit index expressed as number of released animals per euro and day, could be used as reliable estimators of the rehabilitation costs. METHODOLOGY: A retrospective study based on 54772 admissions recorded from 1995-2013 in the database of the Wildlife Rehabilitation Center of Torreferrussa (Catalonia, NW Spain) assessed the morbidity, outcomes and cost-benefits of the rehabilitation practices. RESULTS: Three hundred and two species were included: 232 birds (n = 48633), 37 mammals (n = 3293), 20 reptiles (n = 2705) and 13 amphibians (n = 141). The most frequent causes of admission were: 39.8% confiscation of protected species (89.4% passerines), 31.8% orphaned young animals (35.3% swifts, 21.7% diurnal raptors and owls) and 17.4% trauma casualties (46.7% raptors and owls). The highest proportion of releases was found in the captivity confiscation category [87.4% passerines (median time of stay: 12 days)], followed by the orphaned category [78% owls (66 days), 76.5% diurnal birds of prey (43 days), 75.6% hedgehogs (49 days), 52.7% swifts (19 days) and 52% bats (55 days)]. For the trauma group, 46.8% of releases were hedgehogs (44 days) and 25.6% owls (103 days). As regards the cost-benefit index, the trauma casualties and infectious diseases had the worse values with 1.3 and 1.4 released animals/euro/day respectively, and were particularly low in raptors, waders, marine birds and chiroptera. On the contrary, captivity (4.6) and misplacement (4.1) had the best index, particulary in amphibian, reptiles and passerines. CONCLUSIONS/SIGNIFICANCE: Cost-benefit studies including the release rate, the time of stay at the center and the cost-benefit index should be implemented for improving management efficiency of the Wildlife Rehabilitation Centers. PMID- 28719648 TI - Oligo(ethylene glycol)-sidechain microgels prepared in absence of cross-linking agent: Polymerization, characterization and variation of particle deformability. AB - We present a systematic study of self-cross-linked microgels formed by precipitation polymerization of oligo ethylene glycol methacrylates. The cross linking density of these microgels and, thus, the network flexibility can be easily tuned through the modulation of the reaction temperature during polymerization. Microgels prepared in absence of any difunctional monomer, i.e. cross-linker, show enhanced deformability and particle spreading on solid surfaces as compared to microgels cross-linked with varying amounts of poly(ethylene glycol diacrylate) (PEG-DA) in addition to self-crosslinking. Particles prepared at low reaction temperatures exhibit the highest degree of spreading due to the lightly cross-linked and flexible polymer network. Moreover, AFM force spectroscopy studies suggest that cross-linker-free microgels constitute of a more homogeneous polymer network than PEG-DA cross-linked particles and have elastic moduli at the particle apex that are ~5 times smaller than the moduli of 5 mol-% PEG-DA cross-linked microgels. Resistive pulse sensing experiments demonstrate that microgels prepared at 75 and 80 degrees C without PEG-DA are able to deform significantly to pass through nanopores that are smaller than the microgel size. Additionally, we found that polymer network flexibility of microgels is a useful tool to control the formation of particle dewetting patterns. This offers a promising new avenue for build-up of 2D self assembled particle structures with patterned chemical and mechanical properties. PMID- 28719649 TI - Differential expression of small RNA pathway genes associated with the Biomphalaria glabrata/Schistosoma mansoni interaction. AB - The World Health Organization (WHO) estimates that approximately 240 million people in 78 countries require treatment for schistosomiasis, an endemic disease caused by trematodes of the genus Schistosoma. In Brazil, Schistosoma mansoni is the only species representative of the genus whose passage through an invertebrate host, snails of the genus Biomphalaria, is obligatory before infecting a mammalian host, including humans. The availability of the genome and transcriptome of B. glabrata makes studying the regulation of gene expression, particularly the regulation of miRNA and piRNA processing pathway genes, possible. This might assist in better understanding the biology of B. glabrata as well as its relationship to the parasite S. mansoni. Some aspects of this interaction are still poorly explored, including the participation of non-coding small RNAs, such as miRNAs and piRNAs, with lengths varying from 18 to 30 nucleotides in mature form, which are potent regulators of gene expression. Using bioinformatics tools and quantitative PCR, we characterized and validated the miRNA and piRNA processing pathway genes in B. glabrata. In silico analyses showed that genes involved in miRNA and piRNA pathways were highly conserved in protein domain distribution, catalytic site residue conservation and phylogenetic analysis. Our study showed differential expression of putative Argonaute, Drosha, Piwi, Exportin-5 and Tudor genes at different snail developmental stages and during infection with S. mansoni, suggesting that the machinery is required for miRNA and piRNA processing in B. glabrata at all stages. These data suggested that the silencing pathway mediated by miRNAs and piRNAs can interfere in snail biology throughout the life cycle of the snail, thereby influencing the B. glabrata/S. mansoni interaction. Further studies are needed to confirm the participation of the small RNA processing pathway proteins in the parasite/host relationship, mainly the effective participation of small RNAs in regulating their target genes. PMID- 28719650 TI - Heat-stimuli-enhanced osteogenesis using clinically available biomaterials. AB - A recent study reported that heat stress stimulates osteogenesis in an in vivo rat model using alginate gel and magnetite cationic liposomes. However, for clinical use, the efficacy for promoting osteogenesis needs to be investigated using clinically approved materials, and preferably with animals larger than rats. The aim of this study was to evaluate multiple heat stimuli-triggered osteogenesis in rat tibial defect models using already clinically applicable materials (Resovist(r) and REGENOS(r)) and determine the efficacy also in the rabbit. Fifty-eight rats and 10 rabbits were divided into two groups, respectively, with or without hyperthermia treatment at 45 degrees C for 15 min. (hyperthermia; 20 rats once a week, 8 rats three times a week, 5 rabbits once a week, control; 30 rats and 5 rabbits). Micro-CT assessment at 4 weeks revealed that a significantly stimulated osteogenesis was observed in the once a week group of both rats and rabbits as compared to the control group (p = 0.018 and 0.036, respectively). In contrast, the three times a week group did not show enhanced osteogenesis. Histological examination and image analysis showed consistent results in which the area of mineralized bone formation in the once a week hyperthermia group was significantly increased compared with that in the control group at four weeks (rat; p = 0.026, rabbit; p = 0.031). Newly formed bone was observed in the grafted materials from the periphery toward the center, and more osteoclasts were found in the once a week group. Heat stress also induced enhanced alkaline phosphatase expression in cultured osteoblastic cells, MC3T3, in vitro (p = 0.03). On the other hand, heat stress had no obvious effects on chondrogenic differentiation using ATDC5 cells. Our study demonstrates that heat-stimuli with clinically applicable novel heating materials can promote significant osteogenesis, and may thus be a promising treatment option for diseases associated with bone defects. PMID- 28719651 TI - Link prediction on Twitter. AB - With over 300 million active users, Twitter is among the largest online news and social networking services in existence today. Open access to information on Twitter makes it a valuable source of data for research on social interactions, sentiment analysis, content diffusion, link prediction, and the dynamics behind human collective behaviour in general. Here we use Twitter data to construct co occurrence language networks based on hashtags and based on all the words in tweets, and we use these networks to study link prediction by means of different methods and evaluation metrics. In addition to using five known methods, we propose two effective weighted similarity measures, and we compare the obtained outcomes in dependence on the selected semantic context of topics on Twitter. We find that hashtag networks yield to a large degree equal results as all-word networks, thus supporting the claim that hashtags alone robustly capture the semantic context of tweets, and as such are useful and suitable for studying the content and categorization. We also introduce ranking diagrams as an efficient tool for the comparison of the performance of different link prediction algorithms across multiple datasets. Our research indicates that successful link prediction algorithms work well in correctly foretelling highly probable links even if the information about a network structure is incomplete, and they do so even if the semantic context is rationalized to hashtags. PMID- 28719652 TI - Long-term follow up of human T-cell responses to conserved HIV-1 regions elicited by DNA/simian adenovirus/MVA vaccine regimens. AB - BACKGROUND: Durability of vaccine-elicited immune responses is one of the key determinants for vaccine success. Our aim is to develop a vaccination strategy against the human immunodeficiency virus type 1 (HIV-1), which induces protective and durable CD8+ T-cell responses. The central theorem of our approach is to focus T cells on highly conserved regions of the HIV-1 proteome and this is achieved through the use of the first-generation conserved vaccine immunogen HIVconsv. This immunogen vectored by plasmid DNA, simian adenovirus and poxvirus MVA was tested in healthy, HIV-1-negative adults in UK and induced high magnitudes of HIVconsv-specific plurifunctional CD8+ T cells capable of in vitro HIV-1 inhibition. Here, we assessed the durability of these responses. METHODS: Vaccine recipients in trial HIV-CORE 002 were invited to provide a blood sample at 1 and 2 years after vaccination. Their PBMCs were tested in IFN-gamma ELISPOT, 25-analyte Luminex, CFSE proliferation and intracellular cytokine staining assays, the last enhanced by HLA-peptide dextramer analysis. RESULTS: 12/12 (1 year) and 8/8 (2 years) returning subjects had median (range) of 990 (150-2495) and 763 (70-1745) IFN-gamma SFU/106 PBMC specific for HIVconsv, respectively, and recognized 5 (1-6) out of 6 peptide pools at 2 years. Over one-half of the HIVconsv-specific cells expressed at least 3 functions IFN-gamma, TNF-alpha and CD107a, and were capable of proliferation. Among dextramer-reactive cells, naive, transitional, effector and terminally differentiated memory subsets were similarly represented. CONCLUSIONS: First generation HIVconsv vaccine induced human T cells, which were plurifunctional and persisted for at least 2 years. TRIAL REGISTRATION: ClinicalTrials.gov NCT01151319. PMID- 28719654 TI - Vibrio vulnificus induces mTOR activation and inflammatory responses in macrophages. AB - Vibrio vulnificus (V. vulnificus), a Gram-negative marine bacterium, can cause life-threatening primary septicemia, especially in patients with liver diseases. How V. vulnificus affects the liver and how it acts on macrophages are not well understood. In this report, we demonstrated that V. vulnificus infection causes a strong inflammatory response, marked expansion of liver-resident macrophages, and liver damage in mice. We demonstrated further that V. vulnificus activates mTOR in macrophages and inhibition of mTOR differentially regulates V. vulnificus induced inflammatory responses, suggesting the possibility of targeting mTOR as a strategy to modulate V. vulnificus induced inflammatory responses. PMID- 28719653 TI - Isolation of a monoclonal antibody from a phage display library binding the rhesus macaque MHC class I allomorph Mamu-A1*001. AB - Monoclonal antibodies that bind to human leukocyte antigen (HLA) are useful tools for HLA-typing, tracking donor-recipient chimerisms after bone marrow transplants, and characterizing specific major histocompatibility complexes (MHC) on cell surfaces. Unfortunately, equivalent reagents are not available for rhesus macaques, which are commonly used animal as models in organ transplant and infectious disease research. To address this deficiency, we isolated an antibody that recognizes the common Indian rhesus macaque MHC class I molecule, Mamu A1*001. We induced Mamu-A1*001-binding antibodies by alloimmunizing a female Mamu A1*001-negative rhesus macaque with peripheral blood mononuclear cells (PBMC) from a male Mamu-A1*001-positive donor. A Fab phage display library was constructed with PBMC from the alloimmunized macaque and panned to isolate an antibody that binds to Mamu-A1*001 but not to other common rhesus macaque MHC class I molecules. The isolated antibody distinguishes PBMC from Mamu-A1*001 positive and -negative macaques. Additionally, the Mamu-A1*001-specific antibody binds the cynomolgus macaque MHC class I ortholog Mafa-A1*001:01 but not variants Mafa-A1*001:02/03, indicating a high degree of binding specificity. The Mamu A1*001-specific antibody will be useful for identifying Mamu-A1*001-positive rhesus macaques, for detecting Mamu-A1*001-positive cells in populations of Mamu A1*001-negative cells, and for examining disease processes that alter expression of Mamu-A1*001 on cell surfaces. Moreover, the alloimmunization process we describe will be useful for isolating additional MHC allomorph-specific monoclonal antibodies or antibodies against other polymorphic host proteins which are difficult to isolate with traditional technologies. PMID- 28719655 TI - Protein analysis and gene expression indicate differential vulnerability of Iberian fish species under a climate change scenario. AB - Current knowledge on the biological responses of freshwater fish under projected scenarios of climate change remains limited. Here, we examine differences in the protein configuration of two endemic Iberian freshwater fish species, Squalius carolitertii and the critically endangered S. torgalensis that inhabit in the Atlantic-type northern and in the Mediterranean-type southwestern regions, respectively. We performed protein structure modeling of fourteen genes linked to protein folding, energy metabolism, circadian rhythms and immune responses. Structural differences in proteins between the two species were found for HSC70, FKBP52, HIF1alpha and GPB1. For S. torgalensis, besides structural differences, we found higher thermostability for two proteins (HSP90 and GBP1), which can be advantageous in a warmer environment. Additionally, we investigated how these species might respond to projected scenarios of 3 degrees climate change warming, acidification (DeltapH = -0.4), and their combined effects. Significant changes in gene expression were observed in response to all treatments, particularly under the combined warming and acidification. While S. carolitertii presented changes in gene expression for multiple proteins related to folding (hsp90aa1, hsc70, fkbp4 and stip1), only one such gene was altered in S. torgalensis (stip1). However, S. torgalensis showed a greater capacity for energy production under both the acidification and combined scenarios by increasing cs gene expression and maintaining ldha gene expression in muscle. Overall, these findings suggest that S. torgalensis is better prepared to cope with projected climate change. Worryingly, under the simulated scenarios, disturbances to circadian rhythm and immune system genes (cry1aa, per1a and gbp1) raise concerns for the persistence of both species, highlighting the need to consider multi stressor effects when evaluating climate change impacts upon fish. This work also highlights that assessments of the potential of endangered freshwater species to cope with environmental change are crucial to help decision-makers adopt future conservation strategies. PMID- 28719656 TI - Phenotypic characterization of circulating tumor cells in the peripheral blood of patients with small cell lung cancer. AB - BACKGROUND: To evaluate the phenotypic heterogeneity of circulating tumor cells (CTCs) based on the expression of proliferative, apoptotic and Epithelial-to Mesenchymal Transmission (EMT) markers during front-line treatment in patients with small cell lung cancer (SCLC) and to evaluate their clinical relevance. METHODS: CTCs from 108 chemotherapy-naive patients with SCLC were analyzed by double immunofluorescence staining using anti-Ki67, anti-M30, anti-Vimentin along with anti-CKs antibodies. In 83 patients CTCs were also enumerated using the CellSearch. RESULTS: Sequential samples were available from 76 and 48 patients after one-treatment cycle and on disease progression (PD), respectively, for immunofluorescence and from 50 and 36 patients after one-cycle and on PD, respectively, for CellSearch. At baseline, 60.2% of the patients had detectable CTCs by either method. Both proliferative (CK67+) and non-proliferative (Ki67-), apoptotic (M30+) and non-apoptotic (M30-) as well as EMT (Vim+) CTCs were present in the same patient. Among 22 patients without detectable CTCs by CellSearch, CK+/Ki67+ and CK+/Vim+ CTCs could be detected in 6 (27.3%) and 6 (27.3%) patients, respectively. One-chemotherapy cycle reduced both the incidence of detection (p<0.001) and the absolute number (p<0.001) of CTCs; conversely, on PD both the incidence of detection and the number of CTCs were significantly increased (p = 0.002 and p = 0.04, respectively). Multivariate analysis revealed that the increased number of Vim+ CTCs at baseline and of non-apoptotic CTCs on PD could be emerged as independent prognostic factors associated with decreased OS(p = 0.009 and p = 0.023, respectively). CONCLUSIONS: CK+/Ki67+, CK+/M30+ and CK+/Vim+ CTCs represent distinct subpopulations of CTCs in patients with SCLC, can be detected even in the absence of detectable CTCs by CellSearch; CK+/Ki67+ and CK+/Vim+ CTCs are associated with unfavorable clinical outcome. PMID- 28719657 TI - Isolation and in vitro evaluation of bacteriophages against MDR-bacterial isolates from septic wound infections. AB - Multi-drug resistance has become a major problem for the treatment of pathogenic bacterial infections. The use of bacteriophages is an attractive approach to overcome the problem of drug resistance in several pathogens that cause fatal diseases. Our study aimed to isolate multi drug resistant bacteria from patients with septic wounds and then isolate and apply bacteriophages in vitro as alternative therapeutic agents. Pus samples were aseptically collected from Rajiv Gandhi Institute of Medical Science (RIMS), Kadapa, A.P., and samples were analyzed by gram staining, evaluating morphological characteristics, and biochemical methods. MDR-bacterial strains were collected using the Kirby-Bauer disk diffusion method against a variety of antibiotics. Bacteriophages were collected and tested in vitro for lytic activity against MDR-bacterial isolates. Analysis of the pus swab samples revealed that the most of the isolates detected had Pseudomonas aeruginosa as the predominant bacterium, followed by Staphylococcus aureus, Klebsiella pneumoniae and Escherichia coli. Our results suggested that gram-negative bacteria were more predominant than gram-positive bacteria in septic wounds; most of these isolates were resistant to ampicillin, amoxicillin, penicillin, vancomycin and tetracycline. All the gram-positive isolates (100%) were multi-drug resistant, whereas 86% of the gram-negative isolates had a drug resistant nature. Further bacteriophages isolated from sewage demonstrated perfect lytic activity against the multi-drug resistant bacteria causing septic wounds. In vitro analysis of the isolated bacteriophages demonstrated perfect lysis against the corresponding MDR-bacteria, and these isolated phages may be promising as a first choice for prophylaxis against wound sepsis, Moreover, phage therapy does not enhance multi-drug resistance in bacteria and could work simultaneously on a wide variety of MDR-bacteria when used in a bacteriophage cocktail. Hence, our results suggest that these bacteriophages could be potential therapeutic options for treating septic wounds caused by P. aeruginosa, S. aureus, K. pneumoniae and E. coli. PMID- 28719658 TI - OptisampleTM: Open web-based application to optimize sampling strategies for active surveillance activities at the herd level illustrated using Porcine Respiratory Reproductive Syndrome (PRRS). AB - Porcine reproductive and respiratory syndrome virus (PRRSv) infection causes a devastating economic impact to the swine industry. Active surveillance is routinely conducted in many swine herds to demonstrate freedom from PRRSv infection. The design of efficient active surveillance sampling schemes is challenging because optimum surveillance strategies may differ depending on infection status, herd structure, management, or resources for conducting sampling. Here, we present an open web-based application, named 'OptisampleTM', designed to optimize herd sampling strategies to substantiate freedom of infection considering also costs of testing. In addition to herd size, expected prevalence, test sensitivity, and desired level of confidence, the model takes into account the presumed risk of pathogen introduction between samples, the structure of the herd, and the process to select the samples over time. We illustrate the functionality and capacity of 'OptisampleTM' through its application to active surveillance of PRRSv in hypothetical swine herds under disparate epidemiological situations. Diverse sampling schemes were simulated and compared for each herd to identify effective strategies at low costs. The model results show that to demonstrate freedom from disease, it is important to consider both the epidemiological situation of the herd and the sample selected. The approach illustrated here for PRRSv may be easily extended to other animal disease surveillance systems using the web-based application available at http://stemma.ahc.umn.edu/optisample. PMID- 28719659 TI - Dengue prediction by the web: Tweets are a useful tool for estimating and forecasting Dengue at country and city level. AB - BACKGROUND: Infectious diseases are a leading threat to public health. Accurate and timely monitoring of disease risk and progress can reduce their impact. Mentioning a disease in social networks is correlated with physician visits by patients, and can be used to estimate disease activity. Dengue is the fastest growing mosquito-borne viral disease, with an estimated annual incidence of 390 million infections, of which 96 million manifest clinically. Dengue burden is likely to increase in the future owing to trends toward increased urbanization, scarce water supplies and, possibly, environmental change. The epidemiological dynamic of Dengue is complex and difficult to predict, partly due to costly and slow surveillance systems. METHODOLOGY / PRINCIPAL FINDINGS: In this study, we aimed to quantitatively assess the usefulness of data acquired by Twitter for the early detection and monitoring of Dengue epidemics, both at country and city level at a weekly basis. Here, we evaluated and demonstrated the potential of tweets modeling for Dengue estimation and forecast, in comparison with other available web-based data, Google Trends and Wikipedia access logs. Also, we studied the factors that might influence the goodness-of-fit of the model. We built a simple model based on tweets that was able to 'nowcast', i.e. estimate disease numbers in the same week, but also 'forecast' disease in future weeks. At the country level, tweets are strongly associated with Dengue cases, and can estimate present and future Dengue cases until 8 weeks in advance. At city level, tweets are also useful for estimating Dengue activity. Our model can be applied successfully to small and less developed cities, suggesting a robust construction, even though it may be influenced by the incidence of the disease, the activity of Twitter locally, and social factors, including human development index and internet access. CONCLUSIONS: Tweets association with Dengue cases is valuable to assist traditional Dengue surveillance at real-time and low-cost. Tweets are able to successfully nowcast, i.e. estimate Dengue in the present week, but also forecast, i.e. predict Dengue at until 8 weeks in the future, both at country and city level with high estimation capacity. PMID- 28719660 TI - Factors associated with life-sustaining treatment restriction in a general intensive care unit. AB - PURPOSE: Few previous studies have investigated associations between clinical variables available after 24 hours in the intensive care unit (ICU), including the Charlson Comorbidity Index (CCI), and decisions to restrict life-sustaining treatment. The aim of this study was to identify factors associated with the life sustaining treatment restriction and to explore if CCI contributes to explaining decisions to restrict life-sustaining treatment in the ICU at a university hospital in Norway from 2007 to 2009. METHODS: Patients' Simplified Acute Physiology Score II (SAPS II), age, sex, type of admission, and length of hospital stay prior to being admitted to the unit were recorded. We retrospectively registered the CCI for all patients based on the medical records prior to the index stay. A multivariable logistic regression analysis was used to assess factors associated with treatment restriction during the ICU stay. RESULTS: We included 936 patients, comprising 685 (73%) medical, 204 (22%) unscheduled and 47 (5%) scheduled surgical patients. Treatment restriction was experienced by 241 (26%) patients during their ICU stay. The variables that were significantly associated with treatment restriction in multivariable analysis were older age (odds ratio [OR] = 1.48 per 10 years, 95% confidence interval [CI] = 1.28-1.72 per 10 years), higher SAPS II (OR = 1.05, 95% CI = 1.04-1.07) and CCI values relative to the reference of CCI = 0: CCI = 2 (OR = 2.08, 95% CI = 1.20 3.61) and CCI>=3 (OR = 2.72, 95% CI = 1.65-4.47). CONCLUSIONS: In multivariable analysis, older age, greater illness severity after 24 h in the ICU and greater comorbidity at hospital admission were independently associated with subsequent life-sustaining treatment restriction. The CCI score contributed additional information independent of the SAPS II illness severity rating. PMID- 28719661 TI - Minimizing endpoint variability through reinforcement learning during reaching movements involving shoulder, elbow and wrist. AB - Reaching movements are comprised of the coordinated action across multiple joints. The human skeleton is redundant for this task because different joint configurations can lead to the same endpoint in space. How do people learn to use combinations of joints that maximize success in goal-directed motor tasks? To answer this question, we used a 3-degree-of-freedom manipulandum to measure shoulder, elbow and wrist joint movements during reaching in a plane. We tested whether a shift in the relative contribution of the wrist and elbow joints to a reaching movement could be learned by an implicit reinforcement regime. Unknown to the participants, we decreased the task success for certain joint configurations (wrist flexion or extension, respectively) by adding random variability to the endpoint feedback. In return, the opposite wrist postures were rewarded in the two experimental groups (flexion and extension group). We found that the joint configuration slowly shifted towards movements that provided more control over the endpoint and hence higher task success. While the overall learning was significant, only the group that was guided to extend the wrist joint more during the movement showed substantial learning. Importantly, all changes in movement pattern occurred independent of conscious awareness of the experimental manipulation. These findings suggest that the motor system is generally sensitive to its output variability and can optimize joint-space solutions that minimize task-relevant output variability. We discuss biomechanical biases (e.g. joint's range of movement) that could impose hurdles to the learning process. PMID- 28719662 TI - The GalNAc-T Activation Pathway (GALA) is not a general mechanism for regulating mucin-type O-glycosylation. AB - Mucin-type O-glycosylation is initiated by the UDP-GalNAc polypeptide:N acetylgalactosaminyltransferase (GalNAc-T) family of enzymes. Their activity results in the GalNAc alpha1-O-Thr/Ser structure, termed the Tn antigen, which is further decorated with additional sugars. In neoplastic cells, the Tn antigen is often overexpressed. Because O-glycosylation is controlled by the activity of GalNAc-Ts, their regulation is of great interest. Previous reports suggest that growth factors, EGF or PDGF, induce Golgi complex-to-endoplasmic reticulum (ER) relocation of both GalNAc-Ts and Tn antigen in HeLa cells, offering a mechanism for Tn antigen overexpression termed "GALA". However, we were unable to reproduce these findings. Upon treatment of HeLa cells with either EGF or PDGF we observed no change in the co-localization of endogenous GalNAc-T1, GalNAc-T2 or Tn antigen with the Golgi complex marker TGN46. There was also no enhancement of localization with the ER marker calnexin. We conclude that growth factors do not cause redistribution of GalNAc-Ts from the Golgi complex to the ER in HeLa cells. PMID- 28719663 TI - The prevalence of familial hypercholesterolemia in the West Siberian region of the Russian Federation: A substudy of the ESSE-RF. AB - BACKGROUND: The prevalence of familial hypercholesterolemia (FH) in Russia has not previously been evaluated. The aim of our study was to investigate the prevalence of FH in the population of the West Siberian region of Russia, and then estimate the frequency of coronary artery disease (CAD) and treatment with cholesterol-lowering medication in FH patients. METHODS: The sample of our study consisted of participants from the population-based cohort of The Epidemiology of Cardiovascular Risk Factors and Diseases in Regions of the Russian Federation Study (ESSE-RF), conducted in the Tyumen and Kemerovo regions (1,630 and 1,622 people, respectively, aged 25-64). All participants who had LDL-cholesterol higher than 4.9 mmol/l and who had LDL-cholesterol less than or equal to 4.9 mmol/l but had statin therapy were examined and interviewed by experts in FH. RESULTS: The prevalence of patients with definite FH was 0.24% (one in 407) (95% confidence interval [CI]: 0.06%-0.42%), with probable FH was 0.68% (one in 148) (95% CI: 0.38%-0.98%), and with definite or probable FH combined was 0.92% (one in 108) (95% CI: 0.58%-1.26%). 40% (95% CI: 20.8%-59.2%) of patients with definite or probable FH had CAD. However, only 23% (95% CI: 6.3%-39.7%) of patients with definite or probable FH were on statins. The odds ratios for CAD and myocardial infarction (MI), adjusted for age, gender, region, smoking, hypertension, and diabetes mellitus, were 3.71 (95% CI: 1.58-8.72) (p = 0.003) and 4.06 (95% CI: 0.89-18.55) (r = 0.070) respectively for individuals with definite or probable FH relative to those who were unlikely to have FH. CONCLUSIONS: The prevalence of FH in Russia may be significantly higher than previously estimated. There is underdiagnosis and undertreatment of FH in Russia. PMID- 28719664 TI - Predicting the protein half-life in tissue from its cellular properties. AB - Protein half-life is an important feature of protein homeostasis (proteostasis). The increasing number of in vivo and in vitro studies using high throughput proteomics provide estimates of the protein half-lives in tissues and cells. However, protein half-lives in cells and tissues are different. Due to the resource requirements for researching tissues, more data is available from cellular studies than tissues. We have designed a multivariate linear model for predicting protein half-life in tissue from its cellular properties. Inputs to the model are cellular half-life, abundance, intrinsically disordered sequences, and transcriptional and translational rates. Before the modeling, we determined substructures in the data using the relative distance from the regression line of the protein half-lives in tissues and cells, identifying three separate clusters. The model was trained on and applied to predict protein half-lives from murine liver, brain and heart tissues. In each tissue type we observed similar prediction patterns of protein half-lives. We found that the model provides the best results when there is a strong correlation between tissue and cell culture protein half-lives. Additionally, we clustered the protein half-lives to determine variations in correlation coefficients between the protein half-lives in the tissue versus in cell culture. The clusters identify strongly and weakly correlated protein half-lives, further improves the overall prediction and identifies sub groupings which exhibit specific characteristics. The model described herein, is generalizable to other data sets and has been implemented in a freely available R code. PMID- 28719665 TI - Risk factors for hospital-acquired infections in teaching hospitals of Amhara regional state, Ethiopia: A matched-case control study. AB - BACKGROUND: Hospital-acquired infection affects hundreds of millions of people worldwide. It is a major global issue for patient safety. Understanding the potential risk factors is important to appreciate the local context. A matched case control study design, which is the first of its kind in the study region, was undertaken to identify risk factors in teaching hospitals of Amhara regional state, Ethiopia. METHOD: A matched case control study design matched with age and hospital type was used. The study was conducted in University of Gondar and Felege-Hiwot medical teaching hospital. Cases were patients who fulfilled the criteria based on CDC definition of hospital-acquired infection and controls were patients admitted to the hospital that stayed for more than 48 hours in the ward in the study period, but who did not develop infection. For one case, four controls were selected. Of 545 patients, 109 were cases and 436 were controls. Conditional logistic regression using STATA 13 was used for data analysis. RESULT: The median length of stay for cases and controls was 7 and 8 days, respectively. Patients admitted in wards with the presence of medical waste container in the room had 82% less chance of developing hospital-acquired infection (AOR 0.18; 95% CI, 0.03-0.98). The odds of developing hospital-acquired infection among immune deficient patients were 2.34 times higher than their counterparts (95% CI; 1.17-4.69). Patients received antimicrobials, central vascular catheter and surgery since admission had 8.63, 6.91 and 2.35 higher odds of developing hospital-acquired infection, respectively. CONCLUSION: Health providers and mangers should consider the provision and availability of healthcare materials and facilities in all of the ward rooms, follow appropriate safe medical procedures for use of external devices on patients, and give attention to the immunocompromised patients for the prevention and control of hospital-acquired infections. PMID- 28719666 TI - Effects of prey, pitcher age, and microbes on acid phosphatase activity in fluid from pitchers of Sarracenia purpurea (Sarraceniaceae). AB - Carnivory in pitcher plants generally involves digestion of prey, by the plant itself, by symbionts, or both. While symbionts appear to be important in the digestion of prey in Sarracenia purpurea, the importance of pitcher-derived enzymes is less well documented. Our goal was to reduce microbial numbers in pitcher fluid in order to measure the acid phosphatase activity attributable to the pitchers themselves. Preliminary experiments indicated that various antibiotics were minimally effective at reducing microbial populations and that antibiotic-resistant microbes were easily cultured from pitcher fluid. Consequently, we measured the abundance of culturable microbes in every sample taken for the measurement of acid phosphatase activity. Pitchers fed with one sterilized ant had higher levels of acid phosphatase activity than unfed pitchers. Older pitchers were more responsive to feeding than young pitchers. Pitchers with high levels of microbes (on Day 5) had higher acid phosphatase activity than pitchers with low levels of microbes. However, fed pitchers were not more likely to have higher microbe levels and microbe levels were not related to pitcher age. When fluid samples from inside the pitcher were compared to appropriate controls incubated outside the pitcher, acid phosphatase activity was higher inside the pitcher. Results from the feeding experiments are consistent with a primary role of microbes in the digestion of prey in pitchers of S. purpurea. However, the relationship between pitcher age and enzyme activity is not a function of microbes in the pitcher fluid and may depend on enzymes produced by the plant. Our methods would not detect microbes embedded on the inner surface of the pitcher; and if they survived the alcohol rinse and antibiotics, we cannot rule out microbes as the source of the relationship between pitcher age and acid phosphatase activity. PMID- 28719667 TI - Assessing intragenomic variation of the internal transcribed spacer two: Adapting the Illumina metagenomics protocol. AB - Primary and secondary structural data from the internal transcribed spacer two (ITS2) have been used extensively for diversity studies of many different eukaryotic organisms, including the green algae. Ease of amplification is due, at least in part, to the fact that ITS2 is part of the tandemly-repeated rRNA array. The potential confounding influence of intragenomic variability has yet to be addressed except in a few organisms. Moreover, few of the assessments of intragenomic variation have taken advantage of the deep sequencing capacity of sequence-by-synthesis protocols. We present results from our adaptation of the 16S Metagenomics Sequencing Library Preparation/Illumina protocol for deep sequencing of the ITS2 genes in selected isolates of the green algal genus, Haematococcus. Deep sequencing yielded from just under 20,000 to more than 500,000 merged reads, outpacing results from recent pyrosequencing efforts. Furthermore, a conservative evaluation of these data revealed a range of three to six ITS2 sequence haplotypes (defined as unique sets of nucleotide polymorphisms) across the taxon sampling. The frequency of the dominant haplotype ranged from 0.35 to 0.98. In all but two cases, the haplotype with the greatest frequency corresponded to a sequence obtained by the Sanger method using PCR templates. Our data also show that results from the sequencing-by-synthesis approach are reproducible. In addition to advancing our understanding of ribosomal RNA variation, the results of this investigation will allow us to begin testing hypotheses regarding the maintenance of homogeneity across multi-copy genes. PMID- 28719668 TI - Epidemiology and distribution of 10 superantigens among invasive Streptococcus pyogenes disease in Germany from 2009 to 2014. AB - A nationwide laboratory-based surveillance study of invasive S. pyogenes infections was conducted in Germany. Invasive isolates (n = 719) were obtained between 2009 and 2014. Most isolates were obtained from blood (92.1%). The proportions of isolates from cerebrospinal fluid, pleural fluid, synovial fluid and peritoneal fluid were 3.9%, 1.8%, 1.7% and 0.6%, respectively. The most common emm types were emm 1 (31.8%), emm 28 (15.4%) and emm 89 (14.5%). The most common superantigen genes (speA, speC, speG, speH, speI, speJ, speK, speL, speM, ssa) identified from S. pyogenes were speG (92.1%), speJ (50.9%), and speC (42.0%). Significant associations of superantigen genes with underlying conditions or risks were observed in speG, speH, speJ, and speK. Significant associations between emm types or superantigen genes with clinical complications were observed in emm type 3 and in superantigen gene speA 1-3. Most frequent clinical manifestations included sepsis 59.4%, STSS 6.3%, meningitis 5.4%, and necrotizing fasciitis 5.0% (significantly associated with emm1). PMID- 28719671 TI - Environmentally benign dry-gel conversions of Zr-based UiO metal-organic frameworks with high yield and the possibility of solvent re-use. AB - Herein we report an alternative synthesis method for Zr-based UiO metal-organic frameworks (MOFs), namely dry-gel conversion (DGC). It was possible to synthesize nano- to microsized UiO-66, UiO-66-NH2 and UiO-67 with high crystallinity, high surface area and increased yield using only one-sixth or less of the solvent volume compared to the solution synthesis on the same scale. Additionally, it is shown that solvent re-use is possible over at least five synthesis runs making the DGC method an ecological and extremely solvent-economical route to obtain Zr based UiO-MOFs with reproducible results. PMID- 28719672 TI - The effects of ice on methane hydrate nucleation: a microcanonical molecular dynamics study. AB - Although ice powders are widely used in gas hydrate formation experiments, the effects of ice on hydrate nucleation and what happens in the quasi-liquid layer of ice are still not well understood. Here, we used high-precision constant energy molecular dynamics simulations to study methane hydrate nucleation from vapor-liquid mixtures exposed to the basal, prismatic, and secondary prismatic planes of hexagonal ice (ice Ih). Although no significant difference is observed in hydrate nucleation processes for these different crystal planes, it is found, more interestingly, that methane hydrate can nucleate either on the ice surface heterogeneously or in the bulk solution phase homogeneously. Several factors are mentioned to be able to promote the heterogeneous nucleation of hydrates, including the adsorption of methane molecules at the solid-liquid interface, hydrogen bonding between hydrate cages and the ice structure, the stronger ability of ice to transfer heat than that of the aqueous solution, and the higher occurrence probability of hydrate cages in the vicinity of the ice surface than in the bulk solution. Meanwhile, however, the other factors including the hydrophilicity of ice and the ice lattice mismatch with clathrate hydrates can inhibit heterogeneous nucleation on the ice surface and virtually promote homogeneous nucleation in the bulk solution. Certainly, the efficiency of ice as a promoter and as an inhibitor for heterogeneous nucleation is different. We estimate that the former is larger than the latter under the working conditions. Additionally, utilizing the benefit of ice to absorb heat, the NVE simulation of hydrate formation with ice can mimic the phenomenon of ice shrinking during the heterogeneous nucleation of hydrates and lower the overly large temperature increase during homogeneous nucleation. These results are helpful in understanding the nucleation mechanism of methane hydrate in the presence of ice. PMID- 28719670 TI - Suppressive effect of AMP-activated protein kinase on the epithelial-mesenchymal transition in retinal pigment epithelial cells. AB - The epithelial-mesenchymal transition (EMT) in retinal pigment epithelial (RPE) cells plays a central role in the development of proliferative vitreoretinopathy (PVR). The purpose of this study was to investigate the effect of AMP-activated protein kinase (AMPK), a key regulator of energy homeostasis, on the EMT in RPE cells. In this study, EMT-associated formation of cellular aggregates was induced by co-stimulation of cultured ARPE-19 cells with tumor necrosis factor (TNF) alpha (10 ng/ml) and transforming growth factor (TGF)-beta2 (5 ng/ml). 5 Aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR), a potent activator of AMPK, significantly suppressed TNF-alpha and TGF-beta2-induced cellular aggregate formation (p < 0.01). Dipyridamole almost completely reversed the suppressive effect of AICAR, whereas 5'-amino-5'-deoxyadenosine restored aggregate formation by approximately 50%. AICAR suppressed the downregulation of E-cadherin and the upregulation of fibronectin and alpha-smooth muscle actin by TNF-alpha and TGF-beta2. The levels of matrix metalloproteinase (MMP)-2, MMP-9, interleukin-6, and vascular endothelial growth factor were significantly decreased by AICAR. Activation of the mitogen-activated protein kinase and mammalian target of rapamycin pathways, but not the Smad pathway, was inhibited by AICAR. These findings indicate that AICAR suppresses the EMT in RPE cells at least partially via activation of AMPK. AMPK is a potential target molecule for the prevention and treatment of PVR, so AICAR may be a promising candidate for PVR therapy. PMID- 28719669 TI - A whey protein-based multi-ingredient nutritional supplement stimulates gains in lean body mass and strength in healthy older men: A randomized controlled trial. AB - : Protein and other compounds can exert anabolic effects on skeletal muscle, particularly in conjunction with exercise. The objective of this study was to evaluate the efficacy of twice daily consumption of a protein-based, multi ingredient nutritional supplement to increase strength and lean mass independent of, and in combination with, exercise in healthy older men. Forty-nine healthy older men (age: 73 +/- 1 years [mean +/- SEM]; BMI: 28.5 +/- 1.5 kg/m2) were randomly allocated to 20 weeks of twice daily consumption of either a nutritional supplement (SUPP; n = 25; 30 g whey protein, 2.5 g creatine, 500 IU vitamin D, 400 mg calcium, and 1500 mg n-3 PUFA with 700 mg as eicosapentanoic acid and 445 mg as docosahexanoic acid); or a control (n = 24; CON; 22 g of maltodextrin). The study had two phases. Phase 1 was 6 weeks of SUPP or CON alone. Phase 2 was a 12 week continuation of the SUPP/CON but in combination with exercise: SUPP + EX or CON + EX. Isotonic strength (one repetition maximum [1RM]) and lean body mass (LBM) were the primary outcomes. In Phase 1 only the SUPP group gained strength (Sigma1RM, SUPP: +14 +/- 4 kg, CON: +3 +/- 2 kg, P < 0.001) and lean mass (LBM, +1.2 +/- 0.3 kg, CON: -0.1 +/- 0.2 kg, P < 0.001). Although both groups gained strength during Phase 2, upon completion of the study upper body strength was greater in the SUPP group compared to the CON group (Sigma upper body 1RM: 119 +/ 4 vs. 109 +/- 5 kg, P = 0.039). We conclude that twice daily consumption of a multi-ingredient nutritional supplement increased muscle strength and lean mass in older men. Increases in strength were enhanced further with exercise training. TRIAL REGISTRATION: ClinicalTrials.gov NCT02281331. PMID- 28719673 TI - A Bleeding Oral Mass in a Pregnant Woman. PMID- 28719674 TI - Obesity and Excessive Weight Gain in Young Adults: New Targets for Prevention. PMID- 28719675 TI - Readmissions Have Declined, and Mortality Has Not Increased: The Importance of Evaluating Unintended Consequences. PMID- 28719676 TI - Opioid Should Come Off the Market. PMID- 28719677 TI - Expanded Use for Heart Valve. PMID- 28719678 TI - Generic ADHD Drug. PMID- 28719679 TI - Management of Acute Diverticulitis. PMID- 28719681 TI - Revisiting Medicaid. PMID- 28719682 TI - The Crucial Test of Therapeutic Evidence: Torald Sollmann, M.D., Cleveland. PMID- 28719683 TI - Association Between Structured Physical Activity and Sedentary Time in Older Adults. PMID- 28719684 TI - For-Profit Medical Education. PMID- 28719685 TI - Screening Pelvic Examinations. PMID- 28719686 TI - For-Profit Medical Education. PMID- 28719687 TI - Vitamin D Supplementation and Cancer Risk. PMID- 28719688 TI - Screening Pelvic Examinations-Reply. PMID- 28719689 TI - Vitamin D Supplementation and Cancer Risk. PMID- 28719690 TI - For-Profit Medical Education-Reply. PMID- 28719691 TI - Associations of Weight Gain From Early to Middle Adulthood With Major Health Outcomes Later in Life. AB - Importance: Data describing the effects of weight gain across adulthood on overall health are important for weight control. Objective: To examine the association of weight gain from early to middle adulthood with health outcomes later in life. Design, Setting, and Participants: Cohort analysis of US women from the Nurses' Health Study (1976-June 30, 2012) and US men from the Health Professionals Follow-Up Study (1986-January 31, 2012) who recalled weight during early adulthood (at age of 18 years in women; 21 years in men), and reported current weight during middle adulthood (at age of 55 years). Exposures: Weight change from early to middle adulthood (age of 18 or 21 years to age of 55 years). Main Outcomes and Measures: Beginning at the age of 55 years, participants were followed up to the incident disease outcomes. Cardiovascular disease, cancer, and death were confirmed by medical records or the National Death Index. A composite healthy aging outcome was defined as being free of 11 chronic diseases and major cognitive or physical impairment. Results: A total of 92 837 women (97% white; mean [SD] weight gain: 12.6 kg [12.3 kg] over 37 years) and 25 303 men (97% white; mean [SD] weight gain: 9.7 kg [9.7 kg] over 34 years) were included in the analysis. For type 2 diabetes, the adjusted incidence per 100 000 person-years was 207 among women who gained a moderate amount of weight (>=2.5 kg to <10 kg) vs 110 among women who maintained a stable weight (weight loss <=2.5 kg or gain <2.5 kg) (absolute rate difference [ARD] per 100 000 person-years, 98; 95% CI, 72 to 127) and 258 vs 147, respectively, among men (ARD, 111; 95% CI, 58 to 179); hypertension: 3415 vs 2754 among women (ARD, 662; 95% CI, 545 to 782) and 2861 vs 2366 among men (ARD, 495; 95% CI, 281 to 726); cardiovascular disease: 309 vs 248 among women (ARD, 61; 95% CI, 38 to 87) and 383 vs 340 among men (ARD, 43; 95% CI, -14 to 109); obesity-related cancer: 452 vs 415 among women (ARD, 37; 95% CI, 4 to 73) and 208 vs 165 among men (ARD, 42; 95% CI, 0.5 to 94). Among those who gained a moderate amount of weight, 3651 women (24%) and 2405 men (37%) achieved the composite healthy aging outcome. Among those who maintained a stable weight, 1528 women (27%) and 989 men (39%) achieved the composite healthy aging outcome. The multivariable-adjusted odds ratio for the composite healthy aging outcome associated with moderate weight gain was 0.78 (95% CI, 0.72 to 0.84) in women and 0.88 (95% CI, 0.79 to 0.97) in men. Higher amounts of weight gain were associated with greater risks of major chronic diseases and lower likelihood of healthy aging. Conclusions and Relevance: In these cohorts of health professionals, weight gain during adulthood was associated with significantly increased risk of major chronic diseases and decreased odds of healthy aging. These findings may help counsel patients regarding the risks of weight gain. PMID- 28719694 TI - Checking Blood Pressure at Home. PMID- 28719692 TI - Association of Changing Hospital Readmission Rates With Mortality Rates After Hospital Discharge. AB - Importance: The Affordable Care Act has led to US national reductions in hospital 30-day readmission rates for heart failure (HF), acute myocardial infarction (AMI), and pneumonia. Whether readmission reductions have had the unintended consequence of increasing mortality after hospitalization is unknown. Objective: To examine the correlation of paired trends in hospital 30-day readmission rates and hospital 30-day mortality rates after discharge. Design, Setting, and Participants: Retrospective study of Medicare fee-for-service beneficiaries aged 65 years or older hospitalized with HF, AMI, or pneumonia from January 1, 2008, through December 31, 2014. Exposure: Thirty-day risk-adjusted readmission rate (RARR). Main Outcomes and Measures: Thirty-day RARRs and 30-day risk-adjusted mortality rates (RAMRs) after discharge were calculated for each condition in each month at each hospital in 2008 through 2014. Monthly trends in each hospital's 30-day RARRs and 30-day RAMRs after discharge were examined for each condition. The weighted Pearson correlation coefficient was calculated for hospitals' paired monthly trends in 30-day RARRs and 30-day RAMRs after discharge for each condition. Results: In 2008 through 2014, 2 962 554 hospitalizations for HF, 1 229 939 for AMI, and 2 544 530 for pneumonia were identified at 5016, 4772, and 5057 hospitals, respectively. In January 2008, mean hospital 30-day RARRs and 30-day RAMRs after discharge were 24.6% and 8.4% for HF, 19.3% and 7.6% for AMI, and 18.3% and 8.5% for pneumonia. Hospital 30-day RARRs declined in the aggregate across hospitals from 2008 through 2014; monthly changes in RARRs were -0.053% (95% CI, -0.055% to -0.051%) for HF, -0.044% (95% CI, -0.047% to -0.041%) for AMI, and -0.033% (95% CI, -0.035% to -0.031%) for pneumonia. In contrast, monthly aggregate changes across hospitals in hospital 30-day RAMRs after discharge varied by condition: HF, 0.008% (95% CI, 0.007% to 0.010%); AMI, -0.003% (95% CI, -0.005% to -0.001%); and pneumonia, 0.001% (95% CI, -0.001% to 0.003%). However, correlation coefficients in hospitals' paired monthly changes in 30-day RARRs and 30-day RAMRs after discharge were weakly positive: HF, 0.066 (95% CI, 0.036 to 0.096); AMI, 0.067 (95% CI, 0.027 to 0.106); and pneumonia, 0.108 (95% CI, 0.079 to 0.137). Findings were similar in secondary analyses, including with alternate definitions of hospital mortality. Conclusions and Relevance: Among Medicare fee for-service beneficiaries hospitalized for heart failure, acute myocardial infarction, or pneumonia, reductions in hospital 30-day readmission rates were weakly but significantly correlated with reductions in hospital 30-day mortality rates after discharge. These findings do not support increasing postdischarge mortality related to reducing hospital readmissions. PMID- 28719693 TI - Effect of High-Dose vs Standard-Dose Wintertime Vitamin D Supplementation on Viral Upper Respiratory Tract Infections in Young Healthy Children. AB - Importance: Epidemiological studies support a link between low 25-hydroxyvitamin D levels and a higher risk of viral upper respiratory tract infections. However, whether winter supplementation of vitamin D reduces the risk among children is unknown. Objective: To determine whether high-dose vs standard-dose vitamin D supplementation reduces the incidence of wintertime upper respiratory tract infections in young children. Design, Setting, and Participants: A randomized clinical trial was conducted during the winter months between September 13, 2011, and June 30, 2015, among children aged 1 through 5 years enrolled in TARGet Kids!, a multisite primary care practice-based research network in Toronto, Ontario, Canada. Interventions: Three hundred forty-nine participants were randomized to receive 2000 IU/d of vitamin D oral supplementation (high-dose group) vs 354 participants who were randomized to receive 400 IU/d (standard-dose group) for a minimum of 4 months between September and May. Main Outcome Measures: The primary outcome was the number of laboratory-confirmed viral upper respiratory tract infections based on parent-collected nasal swabs over the winter months. Secondary outcomes included the number of influenza infections, noninfluenza infections, parent-reported upper respiratory tract illnesses, time to first upper respiratory tract infection, and serum 25-hydroxyvitamin D levels at study termination. Results: Among 703 participants who were randomized (mean age, 2.7 years, 57.7% boys), 699 (99.4%) completed the trial. The mean number of laboratory-confirmed upper respiratory tract infections per child was 1.05 (95% CI, 0.91-1.19) for the high-dose group and 1.03 (95% CI, 0.90-1.16) for the standard-dose group, for a between-group difference of 0.02 (95% CI, -0.17 to 0.21) per child. There was no statistically significant difference in number of laboratory-confirmed infections between groups (incidence rate ratio [RR], 0.97; 95% CI, 0.80-1.16). There was also no significant difference in the median time to the first laboratory-confirmed infection: 3.95 months (95% CI, 3.02-5.95 months) for the high-dose group vs 3.29 months (95% CI, 2.66-4.14 months) for the standard-dose group, or number of parent-reported upper respiratory tract illnesses between groups (625 for high-dose vs 600 for standard-dose groups, incidence RR, 1.01; 95% CI, 0.88-1.16). At study termination, serum 25 hydroxyvitamin D levels were 48.7 ng/mL (95% CI, 46.9-50.5 ng/mL) in the high dose group and 36.8 ng/mL (95% CI, 35.4-38.2 ng/mL) in the standard-dose group. Conclusions and Relevance: Among healthy children aged 1 to 5 years, daily administration of 2000 IU compared with 400 IU of vitamin D supplementation did not reduce overall wintertime upper respiratory tract infections. These findings do not support the routine use of high-dose vitamin D supplementation in children for the prevention of viral upper respiratory tract infections. Trial Registration: clinicaltrials.gov Identifier: NCT01419262. PMID- 28719696 TI - The Absurd. PMID- 28719700 TI - Drug-Resistant Tuberculosis Predicted to Increase in High-Burden Countries. PMID- 28719699 TI - Health Care Attacks Continue in 23 Countries Around the World. PMID- 28719701 TI - Vaginal Microbiome Affects Efficacy of HIV Microbicide. PMID- 28719697 TI - Diagnosis and Management of Asthma in Adults: A Review. AB - Importance: Asthma affects about 7.5% of the adult population. Evidence-based diagnosis, monitoring, and treatment can improve functioning and quality of life in adult patients with asthma. Observations: Asthma is a heterogeneous clinical syndrome primarily affecting the lower respiratory tract, characterized by episodic or persistent symptoms of wheezing, dyspnea, and cough. The diagnosis of asthma requires these symptoms and demonstration of reversible airway obstruction using spirometry. Identifying clinically important allergen sensitivities is useful. Inhaled short-acting beta2-agonists provide rapid relief of acute symptoms, but maintenance with daily inhaled corticosteroids is the standard of care for persistent asthma. Combination therapy, including inhaled corticosteroids and long-acting beta2-agonists, is effective in patients for whom inhaled corticosteroids alone are insufficient. The use of inhaled long-acting beta2-agonists alone is not appropriate. Other controller approaches include long acting muscarinic antagonists (eg, tiotropium), and biological agents directed against proteins involved in the pathogenesis of asthma (eg, omalizumab, mepolizumab, reslizumab). Conclusions and Relevance: Asthma is characterized by variable airway obstruction, airway hyperresponsiveness, and airway inflammation. Management of persistent asthma requires avoidance of aggravating environmental factors, use of short-acting beta2-agonists for rapid relief of symptoms, and daily use of inhaled corticosteroids. Other controller medications, such as long acting bronchodilators and biologics, may be required in moderate and severe asthma. Patients with severe asthma generally benefit from consultation with an asthma specialist for consideration of additional treatment, including injectable biologic agents. PMID- 28719702 TI - Evidence-based medicine: Yet more concerns [Editorial]. PMID- 28719703 TI - An embedded earring backing in the tragus. PMID- 28719704 TI - Thyrocervical trunk pseudoaneurysm presenting as a neck mass. PMID- 28719705 TI - Lobular capillary hemangioma (pyogenic granuloma) of the oral cavity. PMID- 28719706 TI - Bilateral second branchial cleft fistulae in a boy with congenital heart disease. PMID- 28719707 TI - Community triage of otology patients using a store-and-forward telemedicine device: A feasibility study. AB - Chronic otitis media is a major contributor to acquired hearing loss in developing countries. Developing countries such as India, with huge populations and poor health infrastructures, have always felt the shortage of trained specialists who can provide quality care to meet the enormous demand for treatment of this disease. This pilot study assessed the feasibility of empowering trained health workers equipped with ENTraview, a store-and-forward telemedicine device that integrates a camera- enabled smart phone with an otoscope. This device allows the screening of otology patients within the community. Three months of extensive training was provided to five community health workers on primary ear and hearing care, including training on the use of the ENTraview device. Community otology screenings were conducted to triage otology patients and provide them with specialized ENT care at a tertiary hospital. In the initial 6 months of the project, 45 screening camps were organized, which screened 3,000 patients free of cost. Of these 3,000 screened patients, 54% (1,619) were referred for ENT consultation and 215 patients reported. Nearly 50% (103) of the 215 reporting patients required surgical intervention, and 29 patients underwent surgery. Reaching out to the community by remote screening of ear diseases by trained technicians with a telemedicine device seems to be an effective and cost-effective way to triage patients with otologic pathologies. PMID- 28719708 TI - PlasmaBlade vs. cold dissection tonsillectomy: A prospective, randomized, double blind, controlled study in adults. AB - We conducted a prospective, randomized, double-blind, controlled clinical study to compare the efficacy and safety of the PlasmaBlade device and cold dissection for adult tonsillectomy. Our study group was made up of 20 patients-12 men and 8 women, aged 18 to 50 years (mean: 27.1)-who were undergoing a bilateral tonsillectomy. Each patient had one randomly chosen tonsil removed by the PlasmaBlade and the other by cold instrumentation. We compared the duration of surgery, the amount of intraoperative blood loss, the number of sutures required, the status of tonsillar fossa wound healing at 7 and 14 days postoperatively, the amount of postoperative pain, and postoperative complications. We found statistically significant differences in the amount of blood loss and the number of sutures in favor of the PlasmaBlade technique. No significant differences were observed in any of the other outcomes. PMID- 28719709 TI - Prospective, randomized, controlled trial using best-selling smoking-cessation book. AB - Our prospective, randomized, controlled trial aimed to evaluate the efficacy of the self-help book, The Easy Way to Stop Smoking, by Allen Carr, in promoting smoking cessation in patients with head and neck cancer. We assessed active smokers for their willingness to read a smoking cessation book. Participants were randomized to either receive the book from our department or recommended to purchase the book. All patients received smoking cessation counseling at recruitment. Phone surveys were conducted at short- and long-term intervals to determine if the patients had purchased and/or read the book and whether they were still smoking. One hundred twelve patients were recruited, 52 of whom completed follow-up surveys. Those who received the book for free were more likely to read the book (p = 0.05). Reading the book did not correlate with successful smoking cessation (p = 0.81). Some 26% of the 27 patients who received the book quit smoking compared with 32% of the 25 patients who were recommended the book (p = 0.76). Patients who indicated motivation to quit smoking were more likely to succeed. In our study, smoking cessation did not appear to be influenced by reading The Easy Way to Stop Smoking. Despite 80.8% of the cohort indicating at least a readiness to quit smoking at recruitment, only 28.8% of patients managed to achieve successful smoking cessation at long-term follow-up. Patient motivation remains an important factor in achieving long-term smoking abstinence. Quitting smoking remains a daunting challenge for patients, with multiple interventions likely needed to achieve cessation. PMID- 28719710 TI - Conservative management of postoperative chylous fistula with octreotide and peripheral total parenteral nutrition. AB - Postoperative chylous fistula after neck dissection is an uncommon complication associated with significant patient morbidity. Octreotide acetate is a somatostatin analogue established in the treatment of chylothorax; however, its utility in the management of cervical chylous fistulae has not been fully evaluated. The investigators hypothesized that chylous fistula can be managed by a combination of octreotide and peripheral total parenteral nutrition (TPN). A retrospective review of cases compiled at our institution from 2009 to 2015 was conducted. Ten patients, all men, were identified as having a postoperative chylous fistula after a neck dissection. All patients were treated with peripheral TPN and intravenous octreotide. Mean age of the patients was 63.0 years (range 49 to 82). Five (50.0%) had a neck dissection for the management of metastatic nasopharyngeal carcinoma and had previous neck irradiation. In 8 (80%) patients, chylous fistula occurred in the left neck. Seven (70.0%) of the leaks occurred within the first 2 postoperative days. Eight (80%) leaks were controlled using TPN and octreotide, with 2 (20%) patients requiring surgical intervention. No factors were significant in the successful conservative management of chylous fistulae. One patient with a chylous fistula of 1,800 ml/day was managed successfully without surgical intervention. The results of this case series suggest that chylous fistulae may be managed conservatively with octreotide and TPN. However, long-term evaluation is needed to define if and when surgical intervention is required for control. PMID- 28719711 TI - CT and MRI features in adult patients with orbital subperiosteal abscess secondary to paranasal sinus mucocele. AB - Orbital subperiosteal abscess (OSPA) secondary to paranasal sinus mucocele (PSM) is rare, and it may be misdiagnosed as PSM with orbital invasion or even as a malignant neoplasm. The present study explored the computed tomography (CT) and magnetic resonance imaging (MRI) features of OSPA. The cases of 13 patients with OSPA secondary to PSM were retrospectively reviewed. CT had been performed in 12, MRI in 7, and postcontrast MRI in 4. OSPA was revealed as a well-demarcated, spindle-shaped mass that was broad-based and located beneath the superior orbital wall (orbital roof) in 11 and at the medial wall in 2. PSM appeared as an expansile cystic lesion in the ethmofrontal sinus in 7, frontal sinus in 5, and ethmoidal sinus in 1. Because the OSPA was connected to the PSM, it looked like a single lesion involving both the orbit and the sinus. All 12 OSPAs examined on CT were low-density; 9 of the 12 PSMs were low-density and 3 were iso-density. Densities of the OSPAs and PSMs were equal in 4 and slightly different in 8. Five of the 10 OSPAs occurring beneath the orbital roof had unclear boundaries with the PSMs on CT. On MRI, although both OSPAs and PSMs mainly demonstrated hypointensity on T1-weighted images and hyperintensity on T2-weighted images, the signal intensities were slightly different, and linear-shaped hypointensity could be found between them. Postcontrast MRI revealed arch- and ring-shaped enhancement, respectively, at the edge of the OSPA and the PSM. Septal enhancement separated them more clearly. PSM is an important cause of OSPA in adults. CT and MRI can accurately display these entities' characteristic findings and their anatomic relationship, as well as playing an important role in the differential diagnosis. PMID- 28719712 TI - Post-tonsillectomy hemorrhage rates in children compared by surgical technique. AB - Despite the sheer number of pediatric tonsillectomies performed in the United States annually, there is no clear consensus as to which surgical technique is superior. One way to compare surgical techniques is to study the morbidity associated with each. We report postoperative hemorrhage rates, one of the frequently encountered major adverse events, as part of a retrospective chart review across four different surgical techniques. These surgeries involved either (1) Coblation, (2) Co-blation with partial suture closure of the tonsillar fossa, (3) diathermy, or (4) partial intracapsular tonsillectomy (PIT). Of the 7,024 children we evaluated, 99 (1.4%) experienced a postoperative hemorrhage that required a second surgery; hemorrhage occurred after 33 of the 3,177 Coblation alone procedures (1.04%), 28 of the 1,633 Coblation with partial suture closure procedures (1.71%), 29 of the 1,850 diathermies (1.57%), and 9 of the 364 PIT procedures (2.47%). Statistical analysis of hemorrhage rates with each surgical technique yielded p values >0.05 in each case (Coblation alone and Coblation with partial suture closure: p = 0.29; diathermy: p = 0.47; PIT, p = 0.20). Based on these data, we conclude that none of these techniques is significantly superior in terms of decreasing the risk of post-tonsillectomy hemorrhage in children. Therefore, surgeons should continue to use the surgical procedure they are most familiar with to optimize recovery in the postoperative period. PMID- 28719713 TI - Lymph-node-positive cutaneous nonmelanoma skin cancer: A poor-prognosis disease in need of treatment intensification. AB - Locoregionally advanced nonmelanoma skin cancer (NMSC) has an aggressive clinical course characterized by high rates of treatment failure and poor survival compared with localized skin cancers. Our goal was to investigate multimodal therapy for lymph-node-positive NMSC. Data from patients with lymph-node-positive NMSC who underwent surgery and adjuvant therapy at a single tertiary center from 2002 to 2012 were retrospectively reviewed. Median follow-up was 1.8 years (range: 0.5 to 8.5). Overall survival (OS) and progression-free survival (PFS) were calculated using the Kaplan-Meier method. The chi-square test and logistic regression were used to determine the association between locoregional control (LRC) and the following variables: evidence of extracapsular extension, number of lymph nodes positive, largest involved lymph node, presence of a positive margin, and use of concurrent chemoradiation (CRT). Forty-six patients were evaluated, 13 (28%) of whom received adjuvant CRT. CRT patients were younger (p < 0.001) and had a significantly greater number of positive lymph nodes (p = 0.016) than patients who received adjuvant radiation alone. At 5 years, LRC was 76%, PFS was 65%, and OS was 49%. Univariate analysis demonstrated that CRT (p = 0.006), largest lymph node measurement (p = 0.039), and >=3 involved lymph nodes (p = 0.001) predicted local recurrence. CRT (p = 0.035, odds ratio [OR] 0.20 [95% confidence interval 0.05 to 0.90]) and >=3 involved lymph nodes (p = 0.017, OR 0.07 [95% confidence interval 0.01 to 0.62]) remained significant on multivariate analysis. CRT was well tolerated. No grade >=3 toxicities were observed except for 1 asymptomatic grade-4 thrombocytopenia. Patients with lymph-node-positive NMSC do poorly. Patient selection for intensification of adjuvant therapy needs clarification. PMID- 28719714 TI - Myiasis in patients with head and neck cancer: Seldom described but commonly seen. AB - Human myiasis is a parasitosis usually found in tropical and underdeveloped countries. It usually affects ulcerated lesions or devitalized tissues, developing after deposition of dipterous eggs. Patients with head and neck cancer are at risk to develop secondary myiasis. A representative percentage of those patients manifest with neglected and advanced tumors, usually in exposed areas and with necrotic tissues. Few case reports and small series constitute the available information about this parasitosis. Most studies have been conducted in patients with skin carcinomas, although myiasis has already been described in association with other head and neck malignancies. The authors present a series of 12 cases of myiasis secondary to head and neck cancer in addition to a literature review. PMID- 28719715 TI - Long-term recurrence-free survival after an unplanned reduction in radiotherapy for HPV-positive oropharyngeal SCC: Two cases and a review of the literature. AB - There is currently no clear distinction between the treatment of HPV-positive and HPV-negative oropharyngeal squamous cell carcinoma (OPSCC). HPV-positive OPSCC has been demonstrated to be more radiosensitive than its HPV-negative counterpart. Despite this, patients with HPV-positive OPSCC continue to receive a full dose of radiation (70 Gy) outside clinical trials. However, this high dose comes with considerable morbidities, including severe mucositis, dysphagia, and xerostomia. We describe the cases of 2 patients with HPV-positive OPSCC who received two cycles of high-dose cisplatin at 100 mg/m2 on 3 separate days, along with concurrent radiotherapy at 50 Gy in 25 fractions for one and 46 Gy in 23 fractions for the other. During treatment, both patients experienced significant acute-phase toxicities-including grade 3 mucositis, grade 3 nausea, and grade 2 dermatitis-and their treatment regimen was stopped before its planned completion. Nevertheless, after a follow-up of 75 and 78 months, respectively, neither patient exhibited any evidence of disease. Late toxicities included grade 1 xerostomia, grade 1 pharyngeal-phase dysphagia, and grade 1 dysgeusia with some foods. We conclude that de-escalating the dose of radiation for HPV-positive patients by 30% and identifying which patients can safely be treated with this level of dose reduction warrants further study. PMID- 28719716 TI - The Sophono bone-conduction system: Surgical, audiologic, and quality-of-life outcomes. AB - We prospectively evaluated the surgical, audiologic, and quality-of-life outcomes in 5 patients-2 men and 3 women, aged 22 to 64 years (mean: 41.8)-who were implanted with the Sophono Alpha 2 MPO Processor. The indications for implantation of this bone-conduction device included recurrent ear canal infections with hearing aids (n = 3), single-sided deafness (n = 1), and patient preference in view of difficulty using a conventional hearing aid (n = 1). In addition to the patient with single-sided deafness, 3 patients had a bilateral mixed hearing loss and 1 had a bilateral conductive hearing loss. Outcomes measures included surgical complications, functional gain (FG), speech discrimination in quiet and noise, and patient satisfaction as determined by the Glasgow Benefit Inventory (GBI) and the Entific Medical Systems bone-anchored hearing aid questionnaire (BAQ). The only postsurgical complication noted was a minor skin reaction and pain in 1 patient that resolved with conservative management. In the 3 patients with the mixed hearing loss, the mean FG was 13.3, 20.0, 11.7, and 11.7 dB at 0.5, 1, 2, and 4 kHz, respectively; in the patient with the bilateral conductive hearing loss, the FG was 10, 25, 10, and 15 dB at the same frequencies. Speech discrimination scores with the Sophono device were comparable to those seen with conventional hearing aids. After implantation, all 5 patients experienced a positive quality-of-life outcome according to the GBI, although 1 of them had only a marginal improvement. On follow-up, all patients reported that they remained satisfied with their implant and that they used their device all day long. We conclude that the Sophono bone-conduction system is a safe and effective option that should be considered for patients with a mixed or conductive hearing loss who are unable to use a conventional hearing aid, as well as for those with single-sided deafness. PMID- 28719717 TI - Audiometry results and TEOAE and DPOAE amplitudes in men taking a phosphodiesterase type 5 inhibitor for erectile dysfunction. AB - We conducted a prospective study of transient evoked otoacoustic emissions (TEOAEs) and distortion-product otoacoustic emissions (DPOAEs) in men who were taking an oral phosphodiesterase type 5 (PDE5) inhibitor for erectile dysfunction. Our study group was made up of 30 men (60 ears), aged 34 to 60 years (mean: 50.9). They were randomly divided into three groups; 10 men were given sildenafil (Viagra) at 50 mg twice a week, 10 were given tadalafil (Cialis) at 20 mg twice a week, and 10 were given vardenafil (Levitra) at 20 mg twice a week. All patients took their drug for 3 weeks, for a total of 6 tablets for each patient. Audiometric tests and TEOAE and DPOAE measurements were performed before and after treatment. Post-treatment audiometry demonstrated improvement in hearing in all three groups. However, post-treatment TEOAE amplitudes and DPOAE amplitudes differed among the three groups; they were significantly higher in the sildenafil group at 1.0 kHz and the same in the tadalafil group; in the vardenafil group, the DPOAE amplitude was significantly lower at 3.0 kHz while there was no change in the TEOAE amplitude. We speculate that the possible mechanism for these findings is that PDE5 inhibitors block degradation of cyclic guanosine monophosphate (cGMP) and induce dilation of the cochlear microcirculation, resulting in an increase in cochlear blood flow. We also believe that the decrease in DPOAE amplitudes at 3.0 kHz seen in the vardenafil group may be related to an accumulation of nitric oxide/cGMP complex, which is toxic to the cochlea; however, since there was no change in TEOAE amplitude in the vardenafil group, this influence may be minimal. Further studies are needed to obtain a more comprehensive assessment of the effects of PDE5 inhibitors on hearing with the use of higher doses and longer durations of therapy. PMID- 28719718 TI - Cochlear implant electrode array exposure: A delayed complication. AB - Exposure of the cochlear implant electrode array as a late complication has been reported rarely in the literature. A retrospective analysis revealed 4 patients presenting with exposure of their cochlear implant electrode arrays from 2 to 17 years after implantation. Data collected from these 4 patients were surgical implantation approach, type of implant, age at implant, interval between implant and complication, surgical correction of the problem, pathology at the time of correction, and length of follow-up after intervention. All 4 patients presented with otitis or mastoiditis. Each had undergone a transmastoid approach with facial recess and cochleostomy and full implant insertion. In 3 cases, the tympanic membrane had retracted to expose the electrode array. In 1 patient, the electrode array had eroded through the external canal, lateral to the facial recess. The exposed arrays were addressed surgically, including explantation/reimplantation for 1 patient. Cochlear implant electrode arrays can become exposed by relative migration of the array and the tympanic membrane. Implant surgeons and audiologists need to be aware of the possibility of this complication. Closure of the ear canal appears to be the most effective surgical intervention. PMID- 28719719 TI - Choanal polyp originating from the superior meatus: An endoscopic view. PMID- 28719720 TI - A severe case of Reinke edema. PMID- 28719721 TI - Effect of Hepatic Impairment on Eluxadoline Pharmacokinetics. PMID- 28719722 TI - Learning anatomy through Thiel- vs. formalin-embalmed cadavers: Student perceptions of embalming methods and effect on functional anatomy knowledge. AB - Thiel-embalmed cadavers, which have been adopted for use in anatomy teaching in relatively few universities, show greater flexibility and color retention compared to formalin-embalmed cadavers, properties which might be considered advantageous for anatomy teaching. This study aimed to investigate student attitudes toward the dissection experience with Thiel- compared to formalin/ethanol-embalmed cadavers. It also aimed to determine if one embalming method is more advantageous in terms of learning functional anatomy through the comparison of student anterior forearm functional anatomy knowledge. Student opinions and functional anatomy knowledge were obtained through use of a questionnaire from students at two medical schools, one using Thiel-, and one using more traditional formalin/ethanol-embalmed cadavers. Both the Thiel group and the formalin group of students were surveyed shortly after completing an anterior forearm dissection session. Significant differences (P-values <0.01) in some attitudes were found toward the dissection experience between cohorts using Thiel- vs. formalin-embalmed cadavers. The Thiel group of students felt more confident about recognizing anatomy in the living individual, found it easier to identify and dissect anatomical structures, and indicated more active exploration of functional anatomy due to the retained flexibility of the cadaver. However, on testing, no significant difference in functional anatomy knowledge was found between the two cohorts. Overall, although Thiel embalming may provide an advantageous learning experience in some investigated areas, more research needs to be carried out, especially to establish whether student perception is based on reality, at least in terms of structure identification. Anat Sci Educ 11: 166 174. (c) 2017 American Association of Anatomists. PMID- 28719723 TI - De Novo Human Herpesvirus 8 Tumors Induced by Rituximab in Autoimmune or Inflammatory Systemic Diseases. AB - OBJECTIVE: Human herpesvirus 8 (HHV-8), also known as Kaposi's sarcoma (KS) associated herpesvirus, is involved in KS and other tumors, including multicentric Castleman's disease and primary effusion lymphoma. Rituximab (RTX) is currently used for the treatment of several autoimmune or inflammatory diseases and humoral organ transplant rejection. De novo HHV-8 tumors induced by RTX used for these indications have not been reported previously. This study was undertaken to evaluate de novo HHV-8 tumors induced by RTX. METHODS: In this retrospective study, we investigated the clinical, virologic, and pathologic features of 5 HIV-negative male patients with HHV-8 tumors induced by RTX therapy. RESULTS: Patients were all immunocompromised by previous treatments, which consisted of steroids and/or immunosuppressive agents, and received RTX for insufficient response, disease progression, or transplant rejection. They developed HHV-8 tumors a median of 4 months after beginning treatment with RTX (range 3-13 months). Four patients had at least 1 risk factor for HHV-8, including a high Fitzpatrick skin phototype (of >3) (n = 3) and homosexuality (n = 1). Four patients developed KS (all 4 had skin lesions and 2 had visceral involvement), and 1 patient developed a solid primary effusion lymphoma. RTX was discontinued in all patients, and immunosuppressants were reduced when feasible. After a median follow-up of 20 months, 2 patients died. Remission of KS was complete in 1 patient and partial in 1 patient, and 1 patient had progression. CONCLUSION: Our findings indicate that patients who have a high skin phototype and are at risk of HHV-8 should be carefully screened for HHV-8 before RTX therapy. The safety of RTX, especially in nonlymphomatous disorders, should be carefully evaluated in patients at risk of HHV-8 tumors. PMID- 28719724 TI - Synthesis and Properties of New N-Heteroheptacenes for Solution-Based Organic Field Effect Transistors. AB - A series of N-heteroheptacenes was synthesized from ortho-thiophene-substituted aryl azides using a Rh2II -catalyzed C-H bond amination reaction to construct the thienoindole moieties. This reaction tolerated the presence of electron-donating or withdrawing groups on the aryl azide without adversely affecting the yield of the amination reaction. The central thiophene ring was created from two thienoindole pieces through a Pd-catalyzed Stille reaction to install the thioether followed by a Cu-mediated Ullman reaction to trigger the cyclization. The photophysical and electrochemical properties of the resulting focused library of N-heteroheptacenes revealed that the electronic nature is controlled by the arene substituent while single crystals grown reveal that the packing motif is influenced by the N-substituent. Solution-processed thin-film OFET devices were fabricated with the N-heteroheptacenes, and one exhibited a hole-mobility of 0.02 cm2 V-1 s-1 . PMID- 28719725 TI - Effects of eupatilin on the contractility of corpus cavernosal smooth muscle through nitric oxide-independent pathways. AB - Eupatilin (5,7-dihydroxy-3,4,6-trimethoxyflavone) is one of the main compounds present in Artemisia species. Eupatilin has both antioxidative and anti inflammatory properties and a relaxation effect on vascular contraction regardless of endothelial function. We evaluated the relaxant effects of eupatilin on the corpus cavernosum (CC) of rabbits and the underlying mechanisms of its activity in human corpus cavernosum smooth muscle (CCSM) cells. Isolated rabbit CC strips were mounted in an organ bath system. A conventional whole-cell patch clamp technique was used to measure activation of calcium-sensitive K+ channel currents in human CCSM cells. The relaxation effect of eupatilin was evaluated by cumulative addition (10-5 m ~ 3 * 10-4 m) to CC strips precontracted with 10-5 m phenylephrine. Western blotting analysis was performed to measure myosin phosphatase targeting subunit 1 (MYPT1) and protein kinase C potentiated inhibitory protein for heterotrimeric myosin light chain phosphatase of 17-kDa (CPI-17) expression and to evaluate the effect of eupatilin on the RhoA/Rho-kinase pathway. Eupatilin effectively relaxed the phenylephrine-induced tone in the rabbit CC strips in a concentration-dependent manner with an estimated EC50 value of 1.2 +/- 1.6 * 10-4 m (n = 8, p < 0.05). Iberiotoxin and tetraethylammonium significantly reduced the relaxation effect (n = 8, p < 0.001 and p = 0.003, respectively). Removal of the endothelium or the presence of L NAME or indomethacin did not affect the relaxation effect of eupatilin. In CCSM cells, the extracellular application of eupatilin 10-4 m significantly increased the outward currents, and the eupatilin-stimulated currents were significantly attenuated by treatment with 10-7 m iberiotoxin (n = 13, p < 0.05). Eupatilin reduced the phosphorylation level of MYPT1 at Thr853 of MLCP and CPI-17 at Thr38. Eupatilin-induced relaxation of the CCSM cells via NO-independent pathways. The relaxation effects of eupatilin on CCSM cells were partially due to activation of BKCa channels and inhibition of RhoA/Rho-kinase. PMID- 28719726 TI - How can we pay the piper? Inclusion body myositis and the high price of a longer life. PMID- 28719727 TI - The Ability of a Single BMD and Fracture History Assessment to Predict Fracture Over 25 Years in Postmenopausal Women: The Study of Osteoporotic Fractures. AB - The ability of bone mineral density (BMD) and other risk factors to predict fracture risk is well-established for as long as 5 to 10 years. However, their value to predict risk over a longer term has not been directly studied. We investigated whether a single assessment of femoral neck BMD and fracture history can predict fracture risk over 20 to 25 years. We used data from the Study of Osteoporotic Fractures (SOF) that assessed BMD and risk factors in 7959 women age >=67 (mean = 73.4) in 1988-1990. Follow-up for fractures continued for 25 years for hip fracture, and for 20 years for any nonvertebral fracture. Using age adjusted proportional hazards models, we analyzed the relationships between a single baseline assessment of femoral neck BMD, fracture history and age, and 20 25-year fracture incidence. The 25-year cumulative incidence of hip fracture was 17.9%; 20-year incidence of any nonvertebral fracture was 46.2%. The 25-year hip fracture incidence was highest in those >=80 years old (22.6%) compared to 13.9% in women aged <70 years. A single femoral neck BMD measurement strongly predicted long-term hip fracture risk to 25 years: 29.6% risk in the lowest BMD quartile versus 7.6% with the highest relative hazard (RH) = 4.9 (95% CI, 4.1 to 6.0). Femoral neck BMD predicted hip fracture with little degradation over time from RH/SD = 2.6 (2.2 to 3.0) for 0 to 5 years to RH/SD = 1.8 (1.4 to 2.4) for 20 to 25 years. Lifetime hip fracture risk was similar (~30%) regardless of age from 67 to >80 years. History of hip fracture predicted hip fractures only slightly better than history of nonvertebral fracture (RH = 1.6 [95% CI, 1.1 to 2.2] versus RH = 1.4 [95% CI, 1.2 to 1.5], respectively). Fracture history remained strongly predictive up to 25 years. We conclude that a single BMD and fracture history assessment can predict fracture risk over 20 to 25 years. Long-term risk of hip fracture remains extremely high in the oldest age groups, supporting risk assessment and consideration of treatment even in the oldest, highest-risk women.(c) 2017 American Society for Bone and Mineral Research. PMID- 28719728 TI - Robust Acenaphthoimidazolylidene Palladacycles: Highly Efficient Catalysts for the Amination of N-Heteroaryl Chlorides. AB - A series of robust N-heterocyclic carbene palladacycles have been successfully developed. These showed high catalytic activity and selectivity toward the challenging amination of N-heteroaryl chlorides. Different primary and secondary amines were fully compatible with this catalytic system. Remarkably, no double amination products could be detected when primary amines were utilized in our catalytic transformation. Furthermore, the protocol has been successfully extended to synthesize rosiglitazone, a clinical drug for diabetes mellitus, highlighting its potential pharmaceutical feasibility. PMID- 28719729 TI - Synthesis of C-Glucosylated Octaketide Anthraquinones in Nicotiana benthamiana by Using a Multispecies-Based Biosynthetic Pathway. AB - Carminic acid is a C-glucosylated octaketide anthraquinone and the main constituent of the natural dye carmine (E120), possessing unique coloring, stability, and solubility properties. Despite being used since ancient times, longstanding efforts to elucidate its route of biosynthesis have been unsuccessful. Herein, a novel combination of enzymes derived from a plant (Aloe arborescens, Aa), a bacterium (Streptomyces sp. R1128, St), and an insect (Dactylopius coccus, Dc) that allows for the biosynthesis of the C-glucosylated anthraquinone, dcII, a precursor for carminic acid, is reported. The pathway, which consists of AaOKS, StZhuI, StZhuJ, and DcUGT2, presents an alternative biosynthetic approach for the production of polyketides by using a type III polyketide synthase (PKS) and tailoring enzymes originating from a type II PKS system. The current study showcases the power of using transient expression in Nicotiana benthamiana for efficient and rapid identification of functional biosynthetic pathways, including both soluble and membrane-bound enzymes. PMID- 28719730 TI - Single Cell Analysis of Human Tissues and Solid Tumors with Mass Cytometry. PMID- 28719731 TI - Anatomical versus functional motor points of selected upper body muscles. AB - INTRODUCTION: In this study we aimed to identify nerve entry points (NEPs) of superficial skeletal muscles obtained by dissection of 20 human cadavers and compared them with motor points (MP) obtained previously by electrical stimulation. METHODS: The biceps brachii (BB), trapezius (TZ), latissimus dorsi (LD), pectoralis major (Pmaj), and pectoralis minor (Pmin) muscles were dissected from human cadavers. NEP data (mean +/- standard deviation) from each muscle were calculated. F-tests with Bonferroni corrections were used to compare NEPs and MPs. RESULTS: The number of NEPs was 2 in BB, 1 in Pmin, 4 in TZ, and 3 in LD, whereas the total number in Pmaj varied from 3 to 5. NEPs and MPs were statistically equal only in Pmin and in the descending part of TZ. DISCUSSION: The findings show crucial differences between NEPs and MPs, possibly impacting the effectiveness of several medical treatment strategies. Muscle Nerve 57: 460 465, 2018. PMID- 28719733 TI - Characterizing a mouse model for evaluation of countermeasures against hydrogen sulfide-induced neurotoxicity and neurological sequelae. AB - Hydrogen sulfide (H2 S) is a highly neurotoxic gas. It is the second most common cause of gas-induced deaths. Beyond mortality, surviving victims of acute exposure may suffer long-term neurological sequelae. There is a need to develop countermeasures against H2 S poisoning. However, no translational animal model of H2 S-induced neurological sequelae exists. Here, we describe a novel mouse model of H2 S-induced neurotoxicity for translational research. In paradigm I, C57/BL6 mice were exposed to 765 ppm H2 S for 40 min on day 1, followed by 15-min daily exposures for periods ranging from 1 to 6 days. In paradigm II, mice were exposed once to 1000 ppm H2 S for 60 minutes. Mice were assessed for behavioral, neurochemical, biochemical, and histopathological changes. H2 S intoxication caused seizures, dyspnea, respiratory depression, knockdowns, and death. H2 S exposed mice showed significant impairment in locomotor and coordinated motor movement activity compared with controls. Histopathology revealed neurodegenerative lesions in the collicular, thalamic, and cortical brain regions. H2 S significantly increased dopamine and serotonin concentration in several brain regions and caused time-dependent decreases in GABA and glutamate concentrations. Furthermore, H2 S significantly suppressed cytochrome c oxidase activity and caused significant loss in body weight. Overall, male mice were more sensitive than females. This novel translational mouse model of H2 S-induced neurotoxicity is reliable, reproducible, and recapitulates acute H2 S poisoning in humans. PMID- 28719732 TI - Genome-Wide Association Meta-Analysis Reveals Novel Juvenile Idiopathic Arthritis Susceptibility Loci. AB - OBJECTIVE: Juvenile idiopathic arthritis (JIA) is the most common childhood rheumatic disease and has a strong genomic component. To date, JIA genetic association studies have had limited sample sizes, used heterogeneous patient populations, or included only candidate regions. The aim of this study was to identify new associations between JIA patients with oligoarticular disease and those with IgM rheumatoid factor (RF)-negative polyarticular disease, which are clinically similar and the most prevalent JIA disease subtypes. METHODS: Three cohorts comprising 2,751 patients with oligoarticular or RF-negative polyarticular JIA were genotyped using the Affymetrix Genome-Wide SNP Array 6.0 or the Illumina HumanCoreExome-12+ Array. Overall, 15,886 local and out-of-study controls, typed on these platforms or the Illumina HumanOmni2.5, were used for association analyses. High-quality single-nucleotide polymorphisms (SNPs) were used for imputation to 1000 Genomes prior to SNP association analysis. RESULTS: Meta-analysis showed evidence of association (P < 1 * 10-6 ) at 9 regions: PRR9_LOR (P = 5.12 * 10-8 ), ILDR1_CD86 (P = 6.73 * 10-8 ), WDFY4 (P = 1.79 * 10 7 ), PTH1R (P = 1.87 * 10-7 ), RNF215 (P = 3.09 * 10-7 ), AHI1_LINC00271 (P = 3.48 * 10-7 ), JAK1 (P = 4.18 * 10-7 ), LINC00951 (P = 5.80 * 10-7 ), and HBP1 (P = 7.29 * 10-7 ). Of these, PRR9_LOR, ILDR1_CD86, RNF215, LINC00951, and HBP1 were shown, for the first time, to be autoimmune disease susceptibility loci. Furthermore, associated SNPs included cis expression quantitative trait loci for WDFY4, CCDC12, MTP18, SF3A1, AHI1, COG5, HBP1, and GPR22. CONCLUSION: This study provides evidence of both unique JIA risk loci and risk loci overlapping between JIA and other autoimmune diseases. These newly associated SNPs are shown to influence gene expression, and their bounding regions tie into molecular pathways of immunologic relevance. Thus, they likely represent regions that contribute to the pathology of oligoarticular JIA and RF-negative polyarticular JIA. PMID- 28719734 TI - Tissue engineering of a composite trachea construct using autologous rabbit chondrocytes. AB - The repair of large tracheal segmental defects remains an unsolved problem. The goal of this study is to apply tissue engineering principles for the fabrication of large segmental trachea replacements. Engineered tracheal replacements composed of autologous cells (neotracheas) were tested in a New Zealand White rabbit model. Neotracheas were formed in the rabbit neck by wrapping a silicone tube with consecutive layers of skin epithelium, platysma muscle, and an engineered cartilage sheet and allowing the construct to mature for 8-12 weeks. In total, 28 rabbits were implanted and the neotracheas assessed for tissue morphology. In 11 cases, neotracheas deemed sufficiently strong were used to repair segmental tracheal defects. Initially, the success rate of producing structurally sound neotracheas was impeded by physical disruption of the cartilage sheets during animal handling, but by the end of the study, 15 of 18 neotracheas (83.3%) were structurally sound. Of the 15 structurally sound neotracheas, 11 were used for segmental reconstruction and were left in place for up to 21 days. Histological examination showed the presence of variable amounts of viable epithelium, a vascularized platysma flap, and a layer of safranin O positive cartilage along with evidence of endochondral ossification. Rabbits that had undergone segmental reconstruction showed good tracheal integration, had a viable epithelium with vascular support, and the cartilage was sufficiently strong to maintain a lumen when palpated. The results demonstrated that viable, trilayered, scaffold-free neotracheas could be constructed from autologous cells and could be integrated into native trachea to repair a segmental defect. PMID- 28719735 TI - Rare-Earth- and Uranium-Mesoionic Carbenes: A New Class of f-Block Carbene Complex Derived from an N-Heterocyclic Olefin. AB - Neutral mesoionic carbenes (MICs) have emerged as an important class of carbene, however they are found in the free form or ligated to only a few d-block ions. Unprecedented f-block MIC complexes [M(N'')3 {CN(Me)C(Me)N(Me)CH}] (M=U, Y, La, Nd; N''=N(SiMe3 )2 ) are reported. These complexes were prepared by a formal 1,4 proton migration reaction when the metal triamides [M(N'')3 ] were treated with the N-heterocyclic olefin H2 C=C(NMeCH)2 , which constitutes a new, general way to prepare MIC complexes. Quantum chemical calculations on the 5f3 uranium(III) complex suggest the presence of a U=C donor-acceptor bond, composed of a MIC->U sigma-component and a U(5f)->MIC(2p) pi-back-bond, but for the d0 f0 Y and La and 4f3 Nd congeners only MIC->M sigma-bonding is found. Considering the generally negligible pi-acidity of MICs, this is surprising and highlights that greater consideration should possibly be given to recognizing MICs as potential pi-acid ligands when coordinated to strongly reducing metals. PMID- 28719736 TI - CD326 (EpCAM) testing by flow cytometric BerEP4 antibody is a useful and rapid adjunct to histopathology. AB - Flow cytometry has been traditionally used to diagnose leukaemia and lymphoma in peripheral blood, bone marrow, body fluids, and tissue samples. The diagnosis of a malignant epithelial tumour is usually made by correlation between histopathologic appearance and the use of immunohistochemical staining. A CE approved BerEP4 antibody (anti-EpCAM, CD326) is available for flow cytometric testing, but has been evaluated predominantly in body fluids in the current literature. In this study, we have evaluated the performance of this antibody in detecting the presence of epithelial cells in tissue samples which have traditionally been reported as CD45 negative cells by flow cytometry. Among the 42 cases studied, 21 (50%) were found to be positive for CD326, thereby suggesting epithelial differentiation. The results had good concordance rates (97.6%) with final histopathological diagnosis. The results clearly show that flow cytometric testing for BerEP4 (CD326) can be a useful method for diagnosing nonhaematological malignancies that are poorly differentiated. As this is a rapid method for identifying epithelial differentiation, it can help the histopathologists tailor and rationalise the immunohistochemical panel, with the potential benefits of improving reporting times and work-flow in the laboratory. (c) 2017 International Clinical Cytometry Society. PMID- 28719738 TI - An Activator-Blocker Pair Provides a Controllable On-Off Switch for a Ketosteroid Isomerase Active Site Mutant. AB - Control of enzyme activity is fundamental to biology and represents a long-term goal in bioengineering and precision therapeutics. While several powerful molecular strategies have been developed, limitations remain in their generalizability and dynamic range. We demonstrate a control mechanism via separate small molecules that turn on the enzyme (activator) and turn off the activation (blocker). We show that a pocket created near the active site base of the enzyme ketosteriod isomerase (KSI) allows efficient and saturable base rescue when the enzyme's natural general base is removed. Binding a small molecule with similar properties but lacking general-base capability in this pocket shuts off rescue. The ability of small molecules to directly participate in and directly block catalysis may afford a broad controllable dynamic range. This approach may be amenable to numerous enzymes and to engineering and screening approaches to identify activators and blockers with strong, specific binding for engineering and therapeutic applications. PMID- 28719737 TI - A novel framework for analyzing conservation impacts: evaluation, theory, and marine protected areas. AB - Environmental conservation initiatives, including marine protected areas (MPAs), have proliferated in recent decades. Designed to conserve marine biodiversity, many MPAs also seek to foster sustainable development. As is the case for many other environmental policies and programs, the impacts of MPAs are poorly understood. Social-ecological systems, impact evaluation, and common-pool resource governance are three complementary scientific frameworks for documenting and explaining the ecological and social impacts of conservation interventions. We review key components of these three frameworks and their implications for the study of conservation policy, program, and project outcomes. Using MPAs as an illustrative example, we then draw upon these three frameworks to describe an integrated approach for rigorous empirical documentation and causal explanation of conservation impacts. This integrated three-framework approach for impact evaluation of governance in social-ecological systems (3FIGS) accounts for alternative explanations, builds upon and advances social theory, and provides novel policy insights in ways that no single approach affords. Despite the inherent complexity of social-ecological systems and the difficulty of causal inference, the 3FIGS approach can dramatically advance our understanding of, and the evidentiary basis for, effective MPAs and other conservation initiatives. PMID- 28719739 TI - Graphene Electronic Tattoo Sensors. AB - Tattoo-like epidermal sensors are an emerging class of truly wearable electronics, owing to their thinness and softness. While most of them are based on thin metal films, a silicon membrane, or nanoparticle-based printable inks, we report sub-micrometer thick, multimodal electronic tattoo sensors that are made of graphene. The graphene electronic tattoo (GET) is designed as filamentary serpentines and fabricated by a cost- and time-effective "wet transfer, dry patterning" method. It has a total thickness of 463 +/- 30 nm, an optical transparency of ~85%, and a stretchability of more than 40%. The GET can be directly laminated on human skin just like a temporary tattoo and can fully conform to the microscopic morphology of the surface of skin via just van der Waals forces. The open-mesh structure of the GET makes it breathable and its stiffness negligible. A bare GET is able to stay attached to skin for several hours without fracture or delamination. With liquid bandage coverage, a GET may stay functional on the skin for up to several days. As a dry electrode, GET-skin interface impedance is on par with medically used silver/silver-chloride (Ag/AgCl) gel electrodes, while offering superior comfort, mobility, and reliability. GET has been successfully applied to measure electrocardiogram (ECG), electromyogram (EMG), electroencephalogram (EEG), skin temperature, and skin hydration. PMID- 28719740 TI - Tuning Superhydrophobic Nanostructures To Enhance Jumping-Droplet Condensation. AB - It was recently discovered that condensation growing on a nanostructured superhydrophobic surface can spontaneously jump off the surface, triggered by naturally occurring coalescence events. Many reports have observed that droplets must grow to a size of order 10 MUm before jumping is enabled upon coalescence; however, it remains unknown how the critical jumping size relates to the topography of the underlying nanostructure. Here, we characterize the dynamic behavior of condensation growing on six different superhydrophobic nanostructures, where the topography of the nanopillars was systematically varied. The critical jumping diameter was observed to be highly dependent upon the height, diameter, and pitch of the nanopillars: tall and slender nanopillars promoted 2 MUm jumping droplets, whereas short and stout nanopillars increased the critical size to over 20 MUm. The topology of each surface is successfully correlated to the critical jumping diameter by constructing an energetic model that predicts how large a nucleating embryo needs to grow before it can inflate into the air with an apparent contact angle large enough for jumping. By extending our model to consider any possible surface, it is revealed that properly designed nanostructures should enable nanometric jumping droplets, which would further enhance jumping-droplet condensers for heat transfer, antifogging, and antifrosting applications. PMID- 28719741 TI - Macroscopic Strain-Induced Transition from Quasi-infinite Gold Nanoparticle Chains to Defined Plasmonic Oligomers. AB - We investigate the formation of chains of few plasmonic nanoparticles-so-called plasmonic oligomers-by strain-induced fragmentation of linear particle assemblies. Detailed investigations of the fragmentation process are conducted by in situ atomic force microscopy and UV-vis-NIR spectroscopy. Based on these experimental results and mechanical simulations computed by the lattice spring model, we propose a formation mechanism that explains the observed decrease of chain polydispersity upon increasing strain and provides experimental guidelines for tailoring chain length distribution. By evaluation of the strain-dependent optical properties, we find a reversible, nonlinear shift of the dominant plasmonic resonance. We could quantitatively explain this feature based on simulations using generalized multiparticle Mie theory (GMMT). Both optical and morphological characterization show that the unstrained sample is dominated by chains with a length above the so-called infinite chain limit-above which optical properties show no dependency on chain length-while during deformation, the average chain length decrease below this limit and chain length distribution becomes more narrow. Since the formation mechanism results in a well-defined, parallel orientation of the oligomers on macroscopic areas, the effect of finite chain length can be studied even using conventional UV-vis-NIR spectroscopy. The scalable fabrication of oriented, linear plasmonic oligomers opens up additional opportunities for strain-dependent optical devices and mechanoplasmonic sensing. PMID- 28719742 TI - Integrated Smartphone-App-Chip System for On-Site Parts-Per-Billion-Level Colorimetric Quantitation of Aflatoxins. AB - We demonstrate herein an integrated, smartphone-app-chip (SPAC) system for on site quantitation of food toxins, as demonstrated with aflatoxin B1 (AFB1), at parts-per-billion (ppb) level in food products. The detection is based on an indirect competitive immunoassay fabricated on a transparent plastic chip with the assistance of a microfluidic channel plate. A 3D-printed optical accessory attached to a smartphone is adapted to align the assay chip and to provide uniform illumination for imaging, with which high-quality images of the assay chip are captured by the smartphone camera and directly processed using a custom developed Android app. The performance of this smartphone-based detection system was tested using both spiked and moldy corn samples; consistent results with conventional enzyme-linked immunosorbent assay (ELISA) kits were obtained. The achieved detection limit (3 +/- 1 ppb, equivalent to MUg/kg) and dynamic response range (0.5-250 ppb) meet the requested testing standards set by authorities in China and North America. We envision that the integrated SPAC system promises to be a simple and accurate method of food toxin quantitation, bringing much benefit for rapid on-site screening. PMID- 28719743 TI - Machine Learning on Signal-to-Noise Ratios Improves Peptide Array Design in SAMDI Mass Spectrometry. AB - Emerging peptide array technologies are able to profile molecular activities within cell lysates. However, the structural diversity of peptides leads to inherent differences in peptide signal-to-noise ratios (S/N). These complex effects can lead to potentially unrepresentative signal intensities and can bias subsequent analyses. Within mass spectrometry-based peptide technologies, the relation between a peptide's amino acid sequence and S/N remains largely nonquantitative. To address this challenge, we present a method to quantify and analyze mass spectrometry S/N of two peptide arrays, and we use this analysis to portray quality of data and to design future arrays for SAMDI mass spectrometry. Our study demonstrates that S/N varies significantly across peptides within peptide arrays, and variation in S/N is attributable to differences of single amino acids. We apply supervised machine learning to predict peptide S/N based on amino acid sequence, and identify specific physical properties of the amino acids that govern variation of this metric. We find low peptide-S/N concordance between arrays, demonstrating that different arrays require individual characterization and that global peptide-S/N relationships are difficult to identify. However, with proper peptide sampling, this study illustrates how machine learning can accurately predict the S/N of a peptide in an array, allowing for the efficient design of arrays through selection of high S/N peptides. PMID- 28719744 TI - High-Resolution Insights into the Stepwise Self-Assembly of Nanofiber from Bioactive Peptides. AB - Peptide self-assembly has a profound biological significance since self-assembled bioactive peptides are gifted with improved bioactivity as well as life-span. In this study, peptide self-assembly was investigated using a therapeutic peptide, PTP-7S (EENFLGALFKALSKLL). Combining experiments of atomic force microscopy (AFM), circular dichroism (CD), and 8-anilino-1-naphthalenesulfonic acid (ANS) fluorescence spectra, PTP-7S showed the alpha-helical structure and was found self-assembling into nanofibers in solution. Relying on the coarse-grained (CG) dynamic simulations, the self-assembling of PTP-7S was revealed as a stepwise process that peptide monomers first clustered into peptide-assembling units (PUs) with charged surface, and then the PUs integrated together to construct nanofibril aggregates. Different roles of the nonbonded driving forces did play in the two phases: the hydrophobic force and electrostatic interaction acted as the predominant motivations in the formation of PUs and nanofiber, respectively. Moreover, the electrostatic interaction helped to guide the longitudinal growth of peptide nanofibers. A sequence principle is proposed for peptide self assembling in aqueous solution: a balance of the counter charges and sufficient hydrophobicity degree. The self-assembled PTP-7S displayed good anticancer activity, proteases resistance, and sustained drug-release, showing a great potential for clinical application. This study reveals the molecular mechanism in explaining PTP-7S self-assembly and it is beneficial for future innovation of the self-assembled bioactive peptides. PMID- 28719745 TI - Highly Efficient Water Decontamination by Using Sub-10 nm FeOOH Confined within Millimeter-Sized Mesoporous Polystyrene Beads. AB - Millimeter-sized polymer-based FeOOH nanoparticles (NPs) provide a promising option to overcome the bottlenecks of direct use of NPs in scaled-up water purification, and decreasing the NP size below 10 nm is expected to improve the decontamination efficiency of the polymeric nanocomposites due to the size and surface effect. However, it is still challenging to control the dwelled FeOOH NP sizes to sub-10 nm, mainly due to the wide pore size distribution of the currently available polymeric hosts. Herein, we synthesized mesoporous polystyrene beads (MesoPS) via flash freezing to assemble FeOOH NPs. The embedded NPs feature with alpha-crystal form, tunable size ranging from 7.3 to 2.0 nm and narrow size distribution. Adsorption of As(III/V) by the resultant nanocomposites was greatly enhanced over the alpha-FeOOH NPs of 18 * 60 nm, with the iron mass normalized capacity of As(V) increasing to 10.3 to 14.8 fold over the bulky NPs. Higher density of the surface hydroxyl groups of the embedded NPs as well as their stronger affinity toward As(V) was proved to contribute to such favorable effect. Additionally, the as-obtained nanocomposites could be efficiently regenerated for cyclic runs. We believe this study will shed new light on how to fabricate highly efficient nanocomposites for water decontamination. PMID- 28719746 TI - Structure-Activity Study of Ghrelin(1-8) Resulting in High Affinity Fluorine Bearing Ligands for the Ghrelin Receptor. AB - The ghrelin receptor, also known as the growth hormone secretagogue receptor 1a (GHS-R1a), is a G-protein-coupled receptor that is differentially expressed in healthy tissue and several cancers, including prostate, testicular, and ovarian. Selectively targeting the ghrelin receptor using fluorine-18 tagged entities would allow localization and visualization of ghrelin receptor expressing carcinomas using PET imaging. The endogenous ligand ghrelin, a 28 amino acid peptide with 3.1 nM affinity, has poor in vivo stability. Here we report on ghrelin(1-8) analogues bearing modifications at residues 1, 3, 4, and 8. The lead analogue, [Inp1,Dpr3(6-fluoro-2-naphthoate),1-Nal4,Thr8]ghrelin(1-8), possessed an IC50 value of 0.11 nM that is a 28-fold improvement compared to the natural ligand. A novel 6-fluoro-2-pentafluorophenyl naphthoate (PFPN) prosthetic group was synthesized to incorporate fluorine-18 for PET imaging. This is not only the highest affinity ghrelin analogue reported but also the shortest ghrelin analogue capable of binding GHS-R1a with better affinity than ghrelin(1-28). PMID- 28719747 TI - Detection of Fumonisins in Fresh and Dehydrated Commercial Garlic. AB - An epidemic fungal disease caused by Fusarium proliferatum, responsible for fumonisin production (FB1, FB2, and FB3), has been reported in the main garlic producing countries in recent years. Fumonisins are a group of structurally related toxic metabolites produced by this pathogen. The aim of this work was to establish an enzyme-linked immunosorbent assay (ELISA) procedure, mostly applied to cereals, that is suitable for fumonisin detection in garlic and compare these results to those obtained by high-performance liquid chromatography (HPLC) and screening of fresh and dehydrated garlic for toxicological risk. The results show good correlation between the two analytical methods. In fresh symptomatic garlic, fumonisin levels were higher in the basal plates than those in the portions with necrotic spots. Among the 56 commercially dehydrated garlic samples screened, three were positive by ELISA test and only one was above the limit of quantitation. The same samples analyzed by HPLC showed the presence of FB1 in trace amounts that was below the limit of quantitation; FB2 and FB3 were absent. The results are reassuring, because no substantial contamination by fumonisins was found in commercial garlic. PMID- 28719748 TI - Low-Temperature Fusible Silver Micro/Nanodendrites-Based Electrically Conductive Composites for Next-Generation Printed Fuse-Links. AB - We systematically investigate the long-neglected low-temperature fusing behavior of silver micro/nanodendrites and demonstrate the feasibility of employing this intriguing property for the printed electronics application, i.e., printed fuse links. Fuse-links have experienced insignificant changes since they were invented in the 1890s. By introducing silver micro/nanodendrites-based electrically conductive composites (ECCs) as a printed fusible element, coupled with the state of-the-art printed electronics technology, key performance characteristics of a fuse-link are dramatically improved as compared with the commercially available counterparts, including an expedient fabrication process, lower available rated current (40% of the minimum value of Littelfuse 467 series fuses), shorter response time (only 3.35% of the Littelfuse 2920L030 at 1.5 times of the rated current), milder surface temperature rise (16.89 degrees C lower than FGMB) and voltage drop (only 24.26% of FGMB) in normal operations, easier to mass produce, and more flexible in product design. This technology may inspire the development of future printed electronic components. PMID- 28719749 TI - Transformation of Unsaturated Fatty Acids/Esters to Corresponding Keto Fatty Acids/Esters by Aerobic Oxidation with Pd(II)/Lewis Acid Catalyst. AB - Utilization of renewable biomass to partly replace the fossil resources in industrial applications has attracted attention due to the limited fossil feedstock with the increased environmental concerns. This work introduced a modified Wacker-type oxidation for transformation of unsaturated fatty acids/esters to the corresponding keto fatty acids/esters, in which Cu2+ cation was replaced with common nonredox metal ions, that is, a novel Pd(II)/Lewis acid (LA) catalyst. It was found that adding nonredox metal ions can effectively promote Pd(II)-catalyzed oxidation of unsaturated fatty acids/esters to the corresponding keto fatty acids/esters, even much better than Cu2+, and the promotional effect is highly dependent on the Lewis acidity of added nonredox metal ions. The improved catalytic efficiency is attributed to the formation of heterobimetallic Pd(II)/LA species, and the oxidation mechanism of this Pd(II)/LA catalyst is also briefly discussed. PMID- 28719750 TI - Electrostatic-Interaction-Assisted Construction of 3D Networks of Manganese Dioxide Nanosheets for Flexible High-Performance Solid-State Asymmetric Supercapacitors. AB - A three-dimensional (3D) macroscopic network of manganese oxide (MnO2) sheets was synthesized by an easily scalable solution approach, grafting the negatively charged surfaces of the MnO2 sheets with an aniline monomer by electrostatic interactions followed by a quick chemical oxidizing polymerization reaction. The obtained structure possessed MnO2 sheets interconnected with polyaniline chains, producing a 3D monolith rich in mesopores. The MnO2 sheets had almost all their reactive centers exposed on the electrode surface, and combined with the electron transport highways provided by polyaniline and the shortened diffusion paths provided by the porous structure, the deliberately designed electrode achieved an excellent capacitance of 762 F g-1 at a current of 1 A g-1 and cycling performance with a capacity retention of 90% over 8000 cycles. Furthermore, a flexible asymmetric supercapacitor based on the constructed electrode and activated carbon serving as the positive and negative electrodes, respectively, was successfully fabricated, delivering a maximum energy density of 40.2 Wh kg-1 (0.113 Wh cm-2) and power density of 6227.0 W kg-1 (17.44 W cm-2) in a potential window of 0-1.7 V in a PVA/Na2SO4 gel electrolyte. PMID- 28719751 TI - Determining the Mechanism and Efficiency of Industrial Dye Adsorption through Facile Structural Control of Organo-montmorillonite Adsorbents. AB - The structural evolution of cost-effective organo-clays (montmorillonite modified with different loadings of CTAB (cetyltrimethylammonium bromide)) is investigated and linked to the adsorption uptake and mechanism of an important industrial dye (hydrolyzed Remazol Black B). Key organo-clay characteristics, such as the intergallery spacing and the average number of well-stacked layers per clay stack, are determined by low-angle X-ray diffraction, while differential thermogravimetric analysis is used to differentiate between surface-bound and intercalated CTAB. Insights into the dye adsorption mechanism are gained through the study of the adsorption kinetics and through the characterization of the organo-clay structure and surface charge after dye adsorption. It is shown that efficient adsorption of anionic industrial dyes is driven by three key parameters: (i) sufficiently large intergallery spacing to enable accommodation of the relatively large dye molecules, (ii) crystalline disorder in the stacking direction of the clay platelets to facilitate dye access, (iii) and positive surface charge to promote interaction with the anionic dyes. Specifically, it is shown that, at low modifier loadings (0.5 cation exchange capacity (0.5CEC)), CTAB molecules exclusively intercalate as a monolayer into the clay intergallery spaces, while, with increasing modifier loadings, the CTAB molecules adopt a bilayer arrangement and adsorb onto the exterior clay surface. Bilayer intercalation results in sufficiently large expansion of the intergallery spaces and significant disordering along the (001) stacking direction to enable high and relatively fast dye uptake via intraparticle diffusion. Poor and slow dye uptake is observed for the organo-clays with a monolayer structure, suggesting relatively inefficient dye adsorption at the clay edges. The optimized bilayer organo-clays (montmorillonite modified with 3CEC of CTAB) also show enhanced adsorption efficiencies for other important industrial dyes, highlighting the importance of structural control in organo-clays while also showing the adsorbents' great potential for use in industry where dye mixtures are encountered. PMID- 28719752 TI - Return to Sport After Shoulder Arthroplasty in Recreational Athletes: A Systematic Review and Meta-analysis. AB - BACKGROUND: One of the most frequent demands from patients after shoulder replacement surgery is to return to sport. PURPOSE: To determine the rate of return to sport after shoulder arthroplasty (total shoulder arthroplasty, reverse shoulder arthroplasty, hemiarthroplasty) in recreational athletes. STUDY DESIGN: Meta-analysis and systematic review. METHODS: The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines were followed to perform this systematic review and meta-analysis of the results in the literature as well as the presentation of results. A search of the literature was performed in the electronic databases MEDLINE, Scopus, Embase, and the Cochrane Library. The quality of the included studies was evaluated according to the MINORS (Methodological Index for Nonrandomized Studies) score. Inclusion criteria were studies in English evaluating return to sport after shoulder replacement surgery and on patients practicing a sport regularly, whatever the level, with all ages and sports included. The main criterion was the rate of patients who returned to a sport activity. RESULTS: Nine studies were selected among the 35 identified, including a total of 613 patients (39% male and 61% female) with a mean age of 71.7 years (range, 22.6-92.6 years). All the included patients practiced sports before surgery. The most common reported sports were golf (n = 140), swimming (n = 128), and tennis (n = 54). The mean rate of return to sport was 80.7% (range, 57.1%-97.3%). All patients who returned to sport were practicing in the 3 months before surgery. No radiological data were reported in the literature. The subgroup analysis for resuming golf after shoulder arthroplasty revealed a rate of return to sport of 79.2% (95% CI, 62.9%-89.5%). In the swimming subgroup, the rate was 75.6% (95% CI, 61.3%-85.8%) and in the tennis subgroup was 63.5% (95% CI, 34.1%-85.5%). The subgroup analysis for reverse shoulder arthroplasty reported a lower rate of return to sport than for all types of shoulder arthroplasty combined: 76.5% (95% CI, 60%-87%) versus 80.7% (95% CI, 70.9% 87.8%), respectively. CONCLUSION: Most patients returned to sport after surgery, and all who returned to sport were practicing their sport in the 3 months before surgery. No radiological data were reported in the literature. PMID- 28719753 TI - Exercise Prescriptions for Training and Rehabilitation in Patients with Heart and Lung Disease. AB - Rehabilitation in patients with advanced cardiac and pulmonary disease has been shown to increase survival and improve quality of life, among many other benefits. Exercise training is the fundamental ingredient in these rehabilitation programs. However, determining the amount of exercise is not straightforward or uniform. Most rehabilitation and training programs fix the time of exercise and set the exercise intensity to the goals of the rehabilitation program and the exercise-related hurdles of the individual. The exercise training intensity prescription must balance the desired gain in conditioning with safety. Symptom limited cardiopulmonary exercise testing is the fundamental tool to identify the exercise intensity and define the appropriate training. In addition, cardiopulmonary exercise testing provides an understanding of the systems involved in oxygen transport and utilization, making it possible to identify the factors limiting exercise capacity in individual patients. PMID- 28719754 TI - Influence of community satisfaction with individual happiness: comparative study in semi-urban and rural areas of Tikapur, Nepal. AB - Happiness is a subjective indicator of overall living conditions and quality of life. Recently, community- and national-level investigations connecting happiness and community satisfaction were conducted. This study investigated the effects of community satisfaction on happiness in Nepal. A factor analysis was employed to examine 24 items that are used to measure community satisfaction, and a multiple regression analysis was conducted to investigate the effects of these factors on happiness. In semi-urban areas, sanitation showed a positive relationship with happiness. In rural areas, edu-medical services were negatively related to happiness, while agriculture was positively related. Gender and perceived health were closely associated with happiness in rural areas. Both happiness and satisfaction are subjective concepts, and are perceived differently depending on the socio-physical environment and personal needs. Sanitation, agriculture (food) and edu-medical services were critical factors that affected happiness; however, the results of this study cannot be generalized to high-income countries. PMID- 28719756 TI - Medialization Laryngoplasty in the Elderly: Outcomes and Expectations. AB - Objective To describe the profile and outcomes of elderly patients undergoing medialization laryngoplasty for vocal cord paralysis. Study Design Case series with retrospective review. Setting Tertiary care hospital. Subjects and Methods Patients were included in the study if they were >65 years old at the time of medialization laryngoplasty between 2008 and 2015. Patient comorbidities, anticoagulation status, disease etiology, and physical examination findings were recorded with postoperative length of stay, complications, pre- and posttreatment voice outcomes with the Voice Handicap Index (at 6 weeks, 4 months, 8 months, and 1 year), and postprocedural interventions (revision injections, surgery, therapy). Results A total of 112 patients met the eligibility criteria. Iatrogenic injury to the recurrent laryngeal nerve (50%) was the most common etiology, followed by idiopathic (31%) causes. Sixty percent of patients were receiving long-term antiplatelet and/or anticoagulation therapy. All but 14 patients on aspirin therapy stopped their antiplatelet/anticoagulation therapy prior to surgery. Most patients were discharged on the day of surgery. Postprocedure Voice Handicap Index scores significantly improved ( P < .001) by 47%, 53%, 64%, and 57% at each of the 4 measured postprocedure dates, respectively. Two patients had major nonsurgical complications postoperatively requiring inpatient hospitalization. Chi-square analysis revealed no differences between intraoperative aspirin use, sex, or comorbidities and the incidence of complications ( P > .05). Conclusion The clinical profile and outcomes of our patients undergoing medialization laryngoplasty are comparable to those seen in younger cohorts. Medialization laryngoplasty is a safe and successful option for elderly patients with vocal cord paralysis and vocal handicap. PMID- 28719755 TI - Clinical Risk Factors and Prognostic Model for Primary Graft Dysfunction after Lung Transplantation in Patients with Pulmonary Hypertension. AB - RATIONALE: Pulmonary hypertension from pulmonary arterial hypertension or parenchymal lung disease is associated with an increased risk for primary graft dysfunction after lung transplantation. OBJECTIVE: We evaluated the clinical determinants of severe primary graft dysfunction in pulmonary hypertension and developed and validated a prognostic model. METHODS: We conducted a retrospective cohort study of patients in the multicenter Lung Transplant Outcomes Group with pulmonary hypertension at transplant listing. Severe primary graft dysfunction was defined as PaO2/FiO2 <=200 with allograft infiltrates at 48 or 72 hours after transplantation. Donor, recipient, and operative characteristics were evaluated in a multivariable explanatory model. A prognostic model derived using donor and recipient characteristics was then validated in a separate cohort. RESULTS: In the explanatory model of 826 patients with pulmonary hypertension, donor tobacco smoke exposure, higher recipient body mass index, female sex, listing mean pulmonary artery pressure, right atrial pressure and creatinine at transplant, cardiopulmonary bypass use, transfusion volume, and reperfusion fraction of inspired oxygen were associated with primary graft dysfunction. Donor obesity was associated with a lower risk for primary graft dysfunction. Using a 20% threshold for elevated risk, the prognostic model had good negative predictive value in both derivation and validation cohorts (89.1% [95% confidence interval, 85.3 92.8] and 83.3% [95% confidence interval, 78.5-88.2], respectively), but low positive predictive value. CONCLUSIONS: Several recipient, donor, and operative characteristics were associated with severe primary graft dysfunction in patients with pulmonary hypertension, including several risk factors not identified in the overall transplant population. A prognostic model with donor and recipient clinical risk factors alone had low positive predictive value, but high negative predictive value, to rule out high risk for primary graft dysfunction. PMID- 28719757 TI - The Plasma Concentration of MUC5B Is Associated with Clinical Outcomes in Paraquat-poisoned Patients. PMID- 28719758 TI - Reflections on Patient-Centered Care: From the Perspective of a Young Otolaryngologist. AB - It is now well recognized that patient engagement in health care is a key factor in improving satisfaction; however, it is also critical if we are to improve the health outcomes of our patients, as well as the economic and quality outcomes of our health system. Medicine, though, has traditionally resisted a culture of patient-centered or patient-controlled care. What follow are the reflections of one otolaryngologist on the importance and challenges of making the transition to patient-centered care. PMID- 28719759 TI - Airway Closure Could Be Confirmed by Electrical Impedance Tomography. PMID- 28719760 TI - For Whom the Mind Wanders, and When, Varies Across Laboratory and Daily-Life Settings. AB - Undergraduates ( N = 274) participated in a weeklong daily-life experience sampling study of mind wandering after being assessed in the lab for executive control abilities (working memory capacity; attention-restraint ability; attention-constraint ability; and propensity for task-unrelated thoughts, or TUTs) and personality traits. Eight times a day, electronic devices prompted subjects to report on their current thoughts and context. Working memory capacity and attention abilities predicted subjects' TUT rates in the lab, but predicted the frequency of daily-life mind wandering only as a function of subjects' momentary attempts to concentrate. This pattern replicates prior daily-life findings but conflicts with laboratory findings. Results for personality factors also revealed different associations in the lab and daily life: Only neuroticism predicted TUT rate in the lab, but only openness predicted mind-wandering rate in daily life (both predicted the content of daily-life mind wandering). Cognitive and personality factors also predicted dimensions of everyday thought other than mind wandering, such as subjective judgments of controllability of thought. Mind wandering in people's daily environments and TUTs during controlled and artificial laboratory tasks have different correlates (and perhaps causes). Thus, mind-wandering theories based solely on lab phenomena may be incomplete. PMID- 28719762 TI - A Million Steps: Developing a Health Promotion Program at the Workplace to Enhance Physical Activity. AB - The workplace is a key setting for the prevention of occupational risks and for promoting healthy activities such as physical activity. Developing a physically active lifestyle results in many health benefits, improving both well-being and quality of life. This article details the experience of two Spanish companies that implemented a program to promote physical exercise in the workplace, called "A Million Steps." This program aimed to increase the physical activity of participants, challenging them to reach at least a million steps in a month through group walks. Participant workers reached the set goal and highlighted the motivational and interpersonal functions of the program. PMID- 28719761 TI - Rehabilitation and Postoperative Management Practices After Osteochondral Allograft Transplants to the Distal Femur: A Report From the Metrics of Osteochondral Allografts (MOCA) Study Group 2016 Survey. AB - CONTEXT: We present the current spectrum of postoperative management practices for patients receiving distal femur osteochondral allograft (OCA) transplants. EVIDENCE ACQUISITION: The Joint Restoration Foundation database was examined in cooperation with the Metrics of Osteochondral Allografts study group to identify 121 surgeons who had performed at least 1 OCA transplant in the past year; 63% of surgeons responded. STUDY DESIGN: Clinical survey. LEVEL OF EVIDENCE: Level 3. RESULTS: Postoperative weightbearing restrictions ranged from immediate nonweightbearing with full weightbearing by 12 weeks to immediate weightbearing as tolerated. Most surgeons who performed fewer (<10) OCA transplants per year followed the most restrictive protocol, while surgeons who performed more (>20) OCA transplants per year followed the least restrictive protocol. One-third of surgeons with the most restrictive protocol were more likely to change their protocol to be less restrictive over time, while none of those with the least restrictive protocol changed their protocol over time. Fifty-five percent of surgeons permitted return to full activity at 26 weeks, while 27% of surgeons lifted restrictions at 16 weeks. CONCLUSION: Characterization of the spectrum of postoperative management practices after OCA transplantation provides a foundation for future investigations regarding patient outcomes and associated cost to establish best practice guidelines. Fundamentally, surgeons with more experience with this procedure tended to be more aggressive with their postoperative rehabilitation guidelines. Most commonly, rehabilitation provided for some degree of limited weightbearing; however, the spectrum also included immediate full weightbearing practices. PMID- 28719763 TI - Two Equals One: Two Human Actions During Social Interaction Are Grouped as One Unit in Working Memory. AB - Every day, people perceive other people performing interactive actions. Retaining these actions of human agents in working memory (WM) plays a pivotal role in a normal social life. However, whether the semantic knowledge embedded in the interactive actions has a pervasive impact on the storage of the actions in WM remains unknown. In the current study, we investigated two opposing hypotheses: (a) that WM stores the interactions individually (the individual-storage hypothesis) and (b) that WM stores the interactions as chunks (the chunk-storage hypothesis). We required participants to memorize a set of individual actions while ignoring the underlying social interactions. We found that although the social-interaction aspect was task irrelevant, the interactive actions were stored in WM as chunks that were not affected by memory load (Experiments 1 and 2); however, inverting the human actions vertically abolished this chunking effect (Experiment 3). These results suggest that WM automatically and efficiently used semantic knowledge about interactive actions to store them and support the chunk-storage hypothesis. PMID- 28719764 TI - Surgical Anatomy Does Not Affect the Progression of Intestinal Failure-Associated Liver Disease in Neonatal Piglets. AB - BACKGROUND: Intestinal failure-associated liver disease (IFALD) causes significant morbidity in neonates with short bowel syndrome (SBS) dependent on parenteral nutrition (PN). Resected ileum, with loss of the ileocecal valve (ICV), is the most common anatomy in SBS, yet its impact on IFALD has not been adequately studied. METHODS: Neonatal piglets were randomized to 75% intestinal resection with jejunocolic anastomosis (JC, n = 12), 75% resection with jejunoileal anastomosis and intact ICV (JI, n = 13), PN-fed sham (sham, n = 14), or sow-fed control (SF, n = 8). Surgical and sham piglets received 100% PN for 14 days before bile flow was measured and blood chemistry, liver pathology, jejunal permeability, and bacterial translocation were assessed. RESULTS: Bile flow was lower for PN-fed compared with SF (P = .002) but not different between the PN-fed groups. Total bilirubin (P = .03) and liver pathology (P < .001) were greater in PN-fed than SF groups but not different between PN-fed groups. Serum bile acids were increased in sham (P = .01) but not different between SBS groups. PN-fed piglets with sepsis had lower bile flow (P = .001) and increased bilirubin (P = .04). Neither jejunal permeability nor bacterial translocation were different between JC, JI, or sham groups. CONCLUSION: Contrary to our hypothesis, the remnant anatomy does not appear to worsen the progression of IFALD. However, the role of sepsis in IFALD should be further explored, in addition to other mechanisms, including PN factors, host immune responses, and intestinal bacterial dysbiosis. PMID- 28719766 TI - Energy Expenditure of Standing Compared to Sitting While Conducting Office Tasks. AB - Objectives This study aimed to investigate the energy expenditure of common office-based tasks. The objectives were to: (a) test the classification of tasks as sedentary or light-intensity physical activity and (b) compare the energy expenditure of tasks under two postural conditions (sitting and standing). Background The sedentary nature of office work has been highlighted as a health risk, and strategies to reduce sedentary behavior at work have been developed. However, there is limited evidence to guide the utilization of sit-stand workstations in the workplace for metabolic health benefits. Method A repeated measures laboratory-based study compared the energy expenditure of common office tasks in sitting and standing using indirect calorimetry ( n = 22). Four standardized tasks (sitting/standing quietly, reading, typing, sorting paper) under two postural conditions (sitting, standing) were performed in a randomized order. Results The mean energy expenditure for all tasks in sitting and standing was <1.5 METs. There were no significant differences in the energy expenditure of doing the same task in sitting compared to standing. In a repeated measures ANOVA, task ( p < .001) had a greater influence on METs expended than posture ( p = .030). Conclusion The study confirmed that the difference in energy expenditure of tasks carried out in sitting compared to standing is negligible. Application The ubiquitous use and utility of sit-stand workstations in the workplace needs to be reviewed. Notwithstanding the potential benefits of movement that may occur naturally, this study confirmed that standing as opposed to sitting does not produce a clinically important increase in energy expenditure. PMID- 28719765 TI - Beetroot juice is more beneficial than sodium nitrate for attenuating muscle pain after strenuous eccentric-bias exercise. AB - The aim of this study was to compare the effects of beetroot juice (BTJ) and a nitrate only drink (sodium nitrate; SN) on indices of exercise-induced muscle damage (EIMD). Thirty recreationally active males consumed either BTJ (n = 10), a nitrate-matched SN drink (n = 10), or an isocaloric placebo (PLA; n = 10) immediately and at 24 and 48 h after performing 100 drop jumps. To assess muscle damage, maximal isometric voluntary contractions (MIVCs), countermovement jumps (CMJs), pressure-pain threshold (PPT), creatine kinase (CK), and high-sensitivity C-reactive protein (hs-CRP) were measured before, immediately after and at 24, 48, and 72 h following the drop jumps. BTJ and SN increased serum nitric oxide, which peaked at 2 h post-ingestion (136 +/- 78 and 189 +/- 79 MUmol.L-1, respectively). PPT decreased in all groups postexercise (P = 0.001), but was attenuated with BTJ compared with SN and PLA (P = 0.043). PPT was 104% +/- 26% of baseline values at 72 h after BTJ, 94% +/- 16% after SN, and 91% +/- 19% after PLA. MIVC and CMJ were reduced following exercise (-15% to 25%) and did not recover to baseline by 72 h in all groups; however, no group differences were observed (P > 0.05). Serum CK increased after exercise but no group differences were present (P > 0.05). hsCRP levels were unaltered by the exercise protocol (P > 0.05). These data suggest that BTJ supplementation is more effective than SN for attenuating muscle pain associated with EIMD, and that any analgesic effects are likely due to phytonutrients in BTJ other than nitrate, or interactions between them. PMID- 28719767 TI - Capacity of Commune Health Stations in Chi Linh District, Hai Duong Province, for Prevention and Control of Noncommunicable Diseases. AB - The primary health care system in Vietnam has been playing an important role in prevention and control of diseases. This study aimed to describe the capacity of commune health stations in Chi Linh district, Hai Duong province for prevention and control of noncommunicable diseases (NCDs). A mixed-methods (quantitative and qualitative approaches) approach was applied to collect data in 20 commune health stations. The participants, including health workers, stakeholders, and patients with NCDs, were selected for the study. The findings reported that the main activities of prevention and control of NCDs at commune health stations (CHSs) still focused on information-education-community (IECs), unqualified for providing screening, diagnosis, and treatments of NCDs. The capacity for prevention and control of NCDs in CHSs was inadequate to provide health care services related to prevention and control of NCDs and unmet with the community's demands. In order to ensure the role and implementation of primary care level, there is an urgent need to improve the capacity of CHSs for prevention and control of NCDs, particularly a national budget for NCDs prevention and control, the essential equipment and medicines recommended by the World Health Organization should be provided and available at the CHSs. PMID- 28719768 TI - Public Health in Vietnam: Findings From the 2016 Chi Linh Health and Demographic Surveillance System (CHILILAB HDSS). PMID- 28719769 TI - Prevalence of Smoking and Associated Factors: Evidence From the CHILILAB Demographic Surveillance System in Vietnam. AB - This study analyzed secondary data from Chi Linh Health and Demographic Surveillance System (CHILILAB) database to identify smoking prevalence and associated demographic factors. Data were extracted from the database of the CHILILAB 2016, which included information on individual smoking behaviors, as well as individual and household demographic data. Descriptive and binary logistic regression analyses were performed with significance level of 0.05. The smoking prevalences were 34.7%, 0.9%, and 16.1% for men, women, and both genders, respectively. A total of 78.2% of current smokers smoked daily inside their houses. Lower smoking status was associated with younger age, being student, rich, and/or single. Future efforts should not only spend on further reduction of smoking rate in Chi Linh Town but should also pay special attention on reducing the prevalence of in-home smoking. This will help to decrease the risk of nonsmokers being exposed to secondhand smoke in their home environment. PMID- 28719770 TI - Household Exposure to Livestock and Health in the CHILILAB HDSS Cohort, Vietnam. AB - In Vietnam, pigs and poultry are predominantly produced by small-scale farmers, creating challenges for zoonotic disease management. The objective of this study was to characterize practices related to livestock and manure management and to measure association with 3 self-reported health symptoms (coughing, fever, and diarrhea/nausea/vomiting) in a region currently undergoing health transitions. We analyzed cross-sectional survey data collected from a subset (N = 5520) of the Chi Linh Health and Demographic Surveillance System cohort in Chi Linh district, Vietnam. Bivariate analyses indicated that female gender was a significant risk factor for all 3 health symptoms, whereas age (>=60 years), suburban living, low education level, and household wealth were risk factors for 2 symptoms. Overall, we found no indication that biogas production or exposure to livestock and manure adversely affected human health. Efforts to control zoonotic disease transmission should prioritize utilization of veterinarians, enhanced farm biosecurity, and improvements to commune drinking water/wastewater infrastructure. PMID- 28719771 TI - Prevalence of Self-Treatment Practice and Related Factors Among Workers Aged 15 to 60 Years in Chi Linh Town, Hai Duong Province, Vietnam. AB - Self-treatment is particularly prevalent in Vietnam. However, the prevalence of this practice among the working population is unclear. This study aims to describe the prevalence of self-treatment and related factors among workers aged 15 to 60 years in the suburban area of Chi Linh, Hai Duong, Vietnam. Secondary data of 3128 respondents was retrieved from the CHILILAB HDSS 2016 survey for analysis using logistic regression with a significance level of .05. Results show that 47.5% of respondents treated themselves at least once during one previous year. While rural residence and the presence of acute health symptoms and chronic diseases significantly associate with the choice of self-treatment among all investigated workers, lower education level and health insurance status only significantly relate to this practice among the formally employed workers. The findings imply the need for specific measures to manage self-treatment practices among different groups of workers. PMID- 28719772 TI - Inequalities in Household Catastrophic Health Expenditure and Impoverishment Associated With Noncommunicable Diseases in Chi Linh, Hai Duong, Vietnam. AB - A costly modern-day double burden, the expenses of noncommunicable diseases (NCDs) are becoming a devastating epidemic. The World Health Organization estimates $7 trillion in economic losses from NCDs in 2011-2025. Although regarded as affluent diseases, the burden of NCDs is shifting into poorer groups. In this study, we assessed the socioeconomic inequalities in catastrophic health expenditure and impoverishment associated with NCDs in Northern Vietnam. We also identified associated factors for catastrophic health expenditure and impoverishment. Households self-reporting NCD diagnoses had the highest association with both catastrophic health expenditure and impoverishment, followed by those in urban areas. Such households were likely poorer according to our calculations estimating socioeconomic inequalities. Households with at least 1 member older than 60 years were also more likely to suffer catastrophic health expenditures. These findings suggest that targeted policy to prevent or subsidize care for NCDs could prevent catastrophic health expenditure and impoverishment among those already most disadvantaged. PMID- 28719773 TI - Methods for the 2016 Socioeconomic and Health Survey in Chi Linh Health and Demographic Surveillance System (CHILILAB HDSS). AB - The Chi Linh Health and Demographic Surveillance System (CHILILAB HDSS) was established in 2004 in Chi Linh District, Hai Duong Province (Northern Vietnam). Up to 2013, 22 rounds of data collection at CHILILAB HDSS had been completed. This article reports the methods and key sociodemographic characteristics of households and individuals captured by the survey conducted among the subsamples of CHILILAB HDSS in 2016. We observed and compared them to the previous HDSS survey rounds and found no significant differences for household size and gender compositions in CHILILAB HDSS. The educational level and economic status of CHILILAB people in 2016 have improved. However, it can be seen that the Chi Linh population is undergoing a strong "aging" trend. PMID- 28719774 TI - A Secular Trend in Birth Weight and Delivery Practices in Periurban Vietnam During 2005-2012. AB - The remarkable increase in Vietnamese economic conditions can increase the birth weight in neonates and better delivery practices among women. The Chi Linh Health and Demographic Surveillance System started in 2004. An open cohort of data consisting of about 57 561 people from 17 993 households has been followed primarily with respect to demography, economy, and education. The aim of this research is to study secular trends in delivery practice and birth weight in the past decade (2005-2012) in Chi Linh. We found a significant change in delivery rates at hospitals and cesarean section rates, but the birth weights over a decade of drastic economic development were stable. Furthermore, the findings show significant associations of birth weight and delivery practices with the child's sex, mother's age, and household income. Our results might be considered as representative for other similar periurban settings in Vietnam. We suggest that appropriate policies should be developed given the reduction in the use of delivery services in commune health centers in urban areas. PMID- 28719775 TI - Health and Health Care Transitions in Vietnam: Evidence From the CHILILAB Health and Demographic Surveillance System (CHILILAB HDSS). PMID- 28719777 TI - Sex Ratio at Birth in Vietnam: Results From Data in CHILILAB HDSS, 2004 to 2013. AB - This study aimed to explore the association of demographic and socioeconomic characteristics and imbalanced sex ratio at birth (SRB) in Chi Linh district, Hai Duong. The data were collected from a longitudinal study using a community-based periodic, referred as Chi Linh Health and Demographic Surveillance System (CHILILAB HDSS) during 2004 to 2013. A total of 7568 children were analyzed. Results showed that SRB in Chi Linh dramatically increased to the imbalanced sex ratio (114.6 boys to 100 girls) by 2013. SRB was associated with birth order and sex of preceding siblings. SRB was extremely high among families without any sons (136/100). SRB was highest among families having third or more children (175/100). Imbalanced SRB was more likely to occur among women working in small business/homemakers and others, women who attained high education level, and women in wealthy households. We suggested further efforts to tackle imbalanced SRB in periurban areas in Vietnam. PMID- 28719776 TI - Blood Glucose Disorders and Access to Health Care Services Among Adults Aged 30 to 69 Years in Chi Linh, Hai Duong, Vietnam. AB - Planning for control of diabetes in Vietnam needs valid information about the burden of diseases in general population. This study employed a cross-sectional design among population aged 30 to 69 years to measure the burden of type 2 diabetes and gaps in access to health care to explore the negative effects of rapid economic growth and urbanization in Chi Linh in recent years. A total of 594 adults were interviewed and had their fasting blood glucose tested. Results indicated that the prevalence of impaired fasting glycaemia was 11.8% and of diabetes was 12.1%. Only 16.8% diabetes cases detected in this study were diagnosed before, indicating a high level of unmet needs for detecting/managing diabetes in Chi Linh population. Significant associated factors with abnormal blood glucose included age and body mass index level. Without effective intervention programs for diabetes control and management, its burden will continue raising in the coming years. Chi Linh need to strengthen the diagnostic/treatment services at primary health care levels to ensure that people at early stage of raised blood pressure, raised blood glucose can be detected and provided with proper management to avoid serious complications, and to reduce hospital overload at central level. PMID- 28719778 TI - Medial Malleoli Fractures: Clinical Comparison Between Newly Designed Sled Device and Conventional Screws. AB - BACKGROUND: The Trimed Medial Malleolar Sled is a newer device designed to treat medial malleolus fracture. The purpose of this study was to compare the outcome of medial malleolar fractures treated with the sled and conventional malleolar screws. METHODS: After obtaining an institutional review board approval, we conducted a retrospective study to identify all skeletally mature patients who sustained an ankle fracture with medial malleolar involvement treated with the sled and we identified a matched cohort treated with conventional malleolar screws. The patients were divided into 2 groups: group A included patients treated with malleolar screws and group B included patients treated with the sled device. The outcomes measured included rate of union, implant removal, and pain over the implant site. RESULTS: Eighty-five medial malleolar ankle fractures were divided into 2 groups: group A included patients (n = 64) treated with malleolar screws and group B included patients (n = 21) treated with the sled device. In group A (n = 64), 62 patients (96.8%) achieved radiological union with a mean union rate of 11 weeks and 10 (15%) patients underwent repeat surgery for implant removal of which 3 patients (4.6%) had pain specifically over the medial implant. In group B (n = 21), all of the patients (100%) achieved radiological union with a mean union rate of 10.8 weeks and 3 patients (14.2%) underwent repeat surgery of which 1 (4.7%) was related to the medial pain. There is no significant difference between the groups for the outcomes measured, including rate of union ( P = .93), visual analog scale score for pain ( P = .07), implant removal ( P = .41), and pain over the implant site ( P = .88). CONCLUSION: Based on the data from our study, we conclude that there are no major differences between the sled devices and conventional screws relating to union rate and complications. LEVELS OF EVIDENCE: Level III: Observational study. PMID- 28719779 TI - Cement Casting to Optimize Reconstruction of Chronic Osteochondral Lesions of the Talus. AB - : Few surgical techniques have been described for reconstruction in massive osteochondral lesions of the talus, and there is limited evidence of techniques for accurately reproducing native talar anatomy with bone auto/allograft techniques. In this article, we present a novel technique, which is highly reproducible, using bone cement to restore the congruence and anatomy of the ankle joint. LEVELS OF EVIDENCE: Level V: Technical tip. PMID- 28719780 TI - Venous Thromboembolic Prophylaxis in Foot and Ankle Surgery: A Review of Current Literature and Practice. AB - : Venous thromboembolism (VTE) is a well-known and feared complication following foot and ankle surgery, as it is a source of morbidity and mortality in the perioperative phase. The most recent CHEST guidelines recommended against the use of chemoprophylaxis and the majority of the literature has found a low incidence of VTE following foot and ankle surgery. Some authors prefer screening patients for risk factors and recommend the use of chemoprophylaxis on a case-by-case basis. Interestingly, studies that found high incidence of VTE were unable to determine a statistically significant difference between the prophylaxis and placebo groups. Major limitations of retrospective reviews is they are only able to study symptomatic VTE because no routine screening is typically performed. In a survey study, up to 98% of foot and ankle surgeons responded that they use prophylaxis in high-risk patients. Despite evidence-based recommendations, a significant number of foot and ankle surgeons are routinely using some form of VTE prophylaxis without taking risk factors into account. LEVELS OF EVIDENCE: Clinical, Level IV: Review Article. PMID- 28719782 TI - Sports Injuries of the Foot and Ankle: How Do Treatments Differ From the General Patient Population. PMID- 28719783 TI - Making Sense of Studies That Claim Benefits of Frenotomy in the Absence of Classic Tongue-Tie. AB - By performing an in-depth analysis of one high profile example, this article aims to help breastfeeding support professionals understand the methodological flaws that characterize recent studies claiming to show the efficacy of frenotomy for the diagnoses of posterior tongue-tie and upper lip-tie. The example study does not address definitional confusion or control for the effects of the passage of time. It does not consider the effects of caring attention, validation, and lactation consultant support. It also does not consider the extensive research over the past three decades that has established that reflux in the first 6 months of life is benign, even though increased reflux frequency may correlate with unsettled infant behavior. The study authors relied on the hypothesis that reflux is caused by excessive air swallowing in infants with poor latch due to posterior tongue-tie and upper lip-tie, which lacks credible physiological mechanisms or supporting evidence. The authors' claim that conducting a randomized controlled trial to investigate the efficacy of frenotomy would be unethical contradicts the basic principles of good science. This article argues that our breastfeeding women and their babies deserve the most rigorous scientific methods available, and acknowledgment of the biases inherent in less rigorous research, if we are to make appropriate decisions concerning intervention with frenotomy and to prevent unnecessary oral surgery. PMID- 28719785 TI - 2017 International Lactation Consultant Association(r) Conference: Knowledge, Diversity, Equity. PMID- 28719786 TI - JHL News. PMID- 28719788 TI - Asthma Control and Care Among Malaysian Primary School Children: A Cross Sectional Study. AB - Children with uncontrolled asthma have high risk of poor health outcomes. The aim of this study was to assess asthma control and care in primary school children with reported asthma. A total of 6441 primary school children were first screened for parent-reported physician-diagnosed asthma and 448 (8.9%) children were reported to have asthma. Of these, 311 (69.4%) parents agreed to participate in assessment of asthma control study using Global Initiative for Asthma 2009 guidelines. Only 161 (51.8%) children were found to have good asthma control, 99 (31.8%) had partly controlled asthma, and 51 (16.4%) had uncontrolled asthma in the past one week. In the past 1 year, 157 (50.5%) children had asthma exacerbations, 21 (6.8%) had hospitalizations, and 104 (33.4%) had received emergency asthma care. Only 108 (34.7%) asthmatic children received regular follow-up care. Controller medications were underutilized (12.2%) compared to reliever medications (35.0%). Asthma control among primary school children was poor indicating suboptimal care. PMID- 28719787 TI - In Vivo Performance of a Novel, Anatomically Shaped, Total Meniscal Prosthesis Made of Polycarbonate Urethane: A 12-Month Evaluation in Goats. AB - BACKGROUND: Injury or loss of the meniscus generally leads to degenerative osteoarthritic changes in the knee joint. However, the treatment options for symptomatic patients with total meniscectomy are limited. Therefore, we developed a novel, anatomically shaped, total meniscal implant made of polycarbonate urethane. PURPOSE: To evaluate the in vivo performance of this novel total meniscal implant. The assessment particularly focused on the implant's response to long-term physiological loading in a goat model and its chondroprotective capacity in comparison to clinically relevant controls. STUDY DESIGN: Controlled laboratory study. METHODS: Surgery was performed to the stifle joint of 26 female Saanen goats, subdivided into 4 groups: implant, allograft, total meniscectomy, and sham surgery. The sham group's contralateral joints served as nonoperated controls. After 12 months of follow-up, investigators evaluated implant wear, deformation, and the histopathological condition of the synovium and cartilage. RESULTS: Wear of the implant's articulating surfaces was minimal, which was confirmed by the absence of wear particles in the synovial fluid. Implant deformation was limited. However, one implant failed by complete tearing of the posterior horn extension. No differences in cartilage histopathological condition were observed for the implant, allograft, and meniscectomy groups. However, locally, the cartilage scores for these groups were significantly worse than those of the nonoperated controls. CONCLUSION: Whereas this study demonstrated that the novel implant is resistant to wear and that deformation after 12 months of physiological loading is acceptable, reinforcement of the implant horns is necessary to prevent horn failure. Although the implant could not protect the cartilage from developing degenerative changes, the progression of damage was similar in the allograft group. CLINICAL RELEVANCE: This novel polycarbonate urethane implant may have the potential to become an alternative treatment for symptomatic patients with total meniscectomy. PMID- 28719789 TI - Waist-to-Height Ratio in Indian Women: Comparison With Traditional Indices of Obesity, Association With Inflammatory Biomarkers and Lipid Profile. AB - We compared waist-to-height ratio (WHtR) with traditional anthropometric indices in healthy women aged 21 to 45 years from urban slums of Mumbai city, India. Lipid profile and inflammatory markers were measured in a subsample of 200 women, and their relationship with WHtR was examined. Mean WHtR was 0.50 +/- 0.1, but a little more than half (51.9%) of the women had WHtR >=0.50. WHtR could correctly identify centrally obese adult women, even when they were categorized as healthy or normal according to body mass index, waist circumference, waist to hip ratio, and percentage body fat. Also, in centrally obese women, inflammatory markers namely, high-sensitivity C-reactive protein, interleukin-6, and interleukin-10 were significantly and positively correlated with WHtR. Thus, results of this study indicate that WHtR is a simple and effective anthropometric variable that has the potential to identify central obesity and the associated inflammation even in women with normal BMI. PMID- 28719790 TI - Disease Burden, Characteristics, and Outcomes of Methicillin-Resistant Staphylococcus aureus Bloodstream Infection in Hong Kong. AB - We aimed to describe disease burden, characteristics, and outcomes of methicillin resistant Staphylococcus aureus (MRSA) bloodstream infection (BSI) in Hong Kong. A retrospective, observational study was conducted in 26 Hong Kong public hospitals between January 2010 and December 2012. The primary outcome measures were 30-day mortality rate and infection-related hospital cost. Of 1133 patients reviewed, 727 (64.17%) were male, 1075 (94.88%) had health care-associated community-onset and 44 (3.88%) had hospital-onset MRSA infection. The mean age of patients was 76 (SD = 15) years, including 172 (15.18%) aged 20 to 59 years and 961 (84.8%) aged >=60 years. The annual incidence rates in age groups of 20 to 59 years and >=60 years were 0.96 to 1.148 per 100 000 and 22.7 to 24.8 per 100 000, respectively. The 30-day mortality was 367 (32.39%). Older patients (>79 years), chronic lung disease, and prior hospitalization were associated with increased mortality. The mean cost was US$10 565 (SD = 11 649; US$1 = HK$7.8). MRSA BSI was a significant burden in Hong Kong. PMID- 28719791 TI - Effectiveness of Psychosocial and Educational Prenatal and Postnatal Care Interventions for Married Immigrant Women in Korea: Systematic Review and Meta analysis. AB - The rapid influx of married immigrant women from low-income Asian countries is a concern in South Korea, Japan, and Taiwan. In South Korea, 1 in 10 couples includes a Korean man and a migrant woman, increasing the need for prenatal and postnatal care interventions. Studies published in English or Korean after 2000 were retrieved from 8 databases and reviewed via a systematic review and meta analysis of the effectiveness of prenatal and postnatal psychosocial and educational interventions in Korea. Of 3583 records, 10 studies (1 randomized controlled trial [RCT] and 9 non-RCTs) involving 408 married immigrant women fulfilled the inclusion criteria. A meta-analysis of the non-RCTs showed that prenatal and postnatal care interventions were effective in improving family support, knowledge regarding self-care management and infant rearing, and self efficacy regarding self-care management and infant rearing. Subgroup analysis showed that interventions involving husbands and individualized care were most effective. This study illustrated the extent to which strategies are needed for developing prenatal and postnatal care interventions for married immigrant women. Further studies should explore other factors and identify the most important factor for improving the effectiveness of such interventions. Robust study designs published in peer-reviewed journals are required for examining the effectiveness of these interventions. PMID- 28719792 TI - Hepatitis Requires Public Health Action. PMID- 28719793 TI - Twenty Years of Progress on Maternal and Child Health in the Philippines: An Equity Lens. AB - This article assesses trends and inequalities in maternal and child health in the Philippines between 1993 and 2013, using 6 national household surveys, and also compares the Philippines' performance to 15 other Asia-Pacific countries. Thirteen indicators of child health outcomes and maternal and child health interventions are examined. Two measures of inequality are used: the absolute difference between the poorest and wealthiest quintile, and the concentration index. Coverage of all indicators has improved, both on average and among the poorest quintile; however, increases are very small for child health interventions (especially immunization coverage). By the first measure of inequality, all indicators show narrowing inequalities. By the second measure, inequality has fallen only for maternal health interventions. Compared with other 15 other developing Asia-Pacific countries, the Philippines performs among the best on the child health outcomes examined and above average on maternal health interventions (except family planning), but only at or below average on child health interventions. PMID- 28719794 TI - Associations of Breast Density With Demographic, Reproductive, and Lifestyle Factors in a Developing Southeast Asian Population. AB - The aim of this study was to investigate how breast density interacted with demographic, reproductive, and lifestyle features among Vietnamese women. Mammographic density and established risk factors for breast cancer were collected from 1651 women (345 cancer cases and 1306 normal cases) in Vietnam. The association of breast density categories with potential risk factors was investigated using Spearman's test for continuous variables and chi2 tests for categorical variables. Independent factors associated with high breast density and breast cancer in specific density groupings were assessed using logistic regression. Results showed that high breast density was significantly associated with young age, low body mass index, low number of children, early age at having the last child, premenopausal status, and increased vegetable consumption. Reproductive factors were key agents associated with breast cancer for women with high breast density, which was not so evident for women with low breast density. PMID- 28719795 TI - Estimating the Direct Medical Economic Burden of Health Care-Associated Infections in Public Tertiary Hospitals in Hubei Province, China. AB - This study estimated the attributable direct medical economic burden of health care-associated infections (HAIs) in China. Data were extracted from hospitals' information systems. Inpatient cases with HAIs and non-HAIs were grouped by the propensity score matching (PSM) method. Attributable hospitalization expenditures and length of hospital stay were measured to estimate the direct medical economic burden of HAIs. STATA 12.0 was used to conduct descriptive analysis, bivariate chi2 test, paired Z test, PSM ( r = 0.25sigma, nearest neighbor 1:1 matching), and logistic regress analysis. The statistically significant level was set at .05. The HAIs group had statistically significant higher expenditures and longer hospitalization stay than the non-HAIs group during 2013 to 2015 ( P < .001). The annual average HAI attributable total expenditure, medicines expenditure, out-of pocket expenditure, and number of hospitalization days per inpatient were (2015 US$) 6173.02, 2257.98, and 1958.25 and 25 days during 2013 to 2015. The direct medical cost savings was estimated at more than 2015 US$12 billion per year in Chinese tertiary hospitals across the country. The significant attributable direct medical economic burden of HAIs calls for more effective HAI surveillance and better control with appropriate incentives. PMID- 28719797 TI - Welcome to the Digital World of Quantitative Biology. PMID- 28719798 TI - Chimeric antigen receptor T-cells for B-cell malignancies. AB - The adoptive transfer of T-lymphocytes modified to express chimeric antigen receptors (CAR-Ts) has produced impressive clinical responses among patients with B-cell malignancies. This has led to a rapid expansion in the number of clinical trials over the past several years. Although CD19-specific CAR-Ts are the most extensively evaluated, CAR-Ts specific for other B-cell-associated targets have also shown promise. However, despite this success, toxicities associated with CAR T administration remain a significant concern. There continues to be substantial heterogeneity among CAR-T products, and differences in both CAR designs and CAR-T production strategies can substantially affect clinical outcomes. Ongoing clinical studies will further elucidate these differences and many other innovative approaches are being evaluated at the preclinical level. In this review, we will discuss the background and rationale for the use of CAR-Ts, provide an overview of advances in the field, and examine the application of CAR Ts to the treatment of B-cell malignancies, including a summary of clinical trials published to date. PMID- 28719799 TI - Mesencephalic astrocyte-derived neurotrophic factor (MANF), a new player in endoplasmic reticulum diseases: structure, biology, and therapeutic roles. AB - Mesencephalic astrocyte-derived neurotrophic factor (MANF), a newly identified 18 kDa soluble protein, localizes to the luminal endoplasmic reticulum (ER), whose stress can stimulate MANF expression and secretion. In Drosophila and zebrafish, MANF regulates dopaminergic neuron development. In contrast, in mice, MANF deficiency leads to diabetes and activation of the unfolded protein response. Recent studies in rodent models have demonstrated that MANF mitigates diabetes, exerts neurotrophic function in neurodegenerative disease, protects cardiomyocytes and neurons in myocardial infarction and cerebral ischemia, respectively, and promotes immune cell phenotype switch from proinflammatory macrophages to prorepair anti-inflammatory macrophages. The cytoprotective mechanisms of MANF on ER stress are currently under active investigation. In addition, for the first time, we have discovered that MANF can potentially serve as a urinary ER stress biomarker in ER stress-mediated kidney disease. These studies have underscored the diagnostic and therapeutic importance of MANF in ER diseases. PMID- 28719800 TI - Variants in the interleukin 8 gene and the response to inhaled bronchodilators in cystic fibrosis. AB - OBJECTIVE: Interleukin 8 protein promotes inflammatory responses, even in airways. The presence of interleukin 8 gene variants causes altered inflammatory responses and possibly varied responses to inhaled bronchodilators. Thus, this study analyzed the interleukin 8 variants (rs4073, rs2227306, and rs2227307) and their association with the response to inhaled bronchodilators in cystic fibrosis patients. METHODS: Analysis of interleukin 8 gene variants was performed by restriction fragment length polymorphism of polymerase chain reaction. The association between spirometry markers and the response to inhaled bronchodilators was evaluated by Mann-Whitney and Kruskal-Wallis tests. The analysis included all cystic fibrosis patients, and subsequently patients with two mutations in the cystic fibrosis transmembrane conductance regulator gene belonging to classes I to III. RESULTS: This study included 186 cystic fibrosis patients. There was no association of the rs2227307 variant with the response to inhaled bronchodilators. The rs2227306 variant was associated with FEF50% in the dominant group and in the group with two identified mutations in the cystic fibrosis transmembrane conductance regulator gene. The rs4073 variant was associated with spirometry markers in four genetic models: co-dominant (FEF25-75% and FEF75%), dominant (FEV1, FEF50%, FEF75%, and FEF25-75%), recessive (FEF75% and FEF25-75%), and over-dominant (FEV1/FVC). CONCLUSIONS: This study highlighted the importance of the rs4073 variant of the interleukin 8 gene, regarding response to inhaled bronchodilators, and of the assessment of mutations in the cystic fibrosis transmembrane conductance regulator gene. PMID- 28719801 TI - Biology-oriented drug synthesis (BIODS) of 2-(2-methyl-5-nitro-1H-imidazol-1 yl)ethyl aryl ether derivatives, in vitro alpha-amylase inhibitory activity and in silico studies. AB - A new library of 2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl aryl ether derivatives (1-23) were synthesized and characterized by EI-MS and 1H NMR, and screened for their alpha-amylase inhibitory activity. Out of twenty-three derivatives, two molecules 19 (IC50=0.38+/-0.82uM) and 23 (IC50=1.66+/-0.14uM), showed excellent activity whereas the remaining compounds, except 10 and 17, showed good to moderate inhibition in the range of IC50=1.77-2.98uM when compared with the standard acarbose (IC50=1.66+/-0.1uM). A plausible structure-activity relationship has also been presented. In addition, in silico studies was carried out in order to rationalize the binding interaction of compounds with the active site of enzyme. PMID- 28719802 TI - Cerebral hypoperfusion is not associated with an increase in amyloid beta pathology in middle-aged or elderly people. AB - INTRODUCTION: It is hypothesized that cerebral hypoperfusion promotes the development of Alzheimer pathology. We therefore studied whether longstanding cerebral hypoperfusion is associated with Alzheimer pathology in nondemented humans. METHODS: Cerebral blood flow and amyloid beta (18F-Flutemetamol) positron emission tomography retention were assessed in eleven patients with unilateral occlusion of precerebral arteries resulting in chronic and uneven hypoperfusion. A subset of patients underwent tau (18F-AV-1451) positron emission tomography. RESULTS: The blood flow was significantly reduced on the affected side of the brain in patients with unilateral occlusion of the internal carotid artery or stenosis of the middle cerebral artery. However, the cortical uptake of 18F Flutemetamol or 18F-AV-1451 was not altered. DISCUSSION: Our results suggest that longstanding cerebral hypoperfusion in humans does not result in accumulation of amyloid beta fibrils or tau aggregates. PMID- 28719803 TI - Elevated sterol regulatory elementary binding protein 1 and GluA2 levels in the hippocampal nuclear fraction of Genetic Absence Epilepsy Rats from Strasbourg. AB - Studies in animal models and human tissues show that nuclear translocation of sterol regulatory element binding protein 1 (SREBP1) and glutamate A2 subunit (GluA2) of cell-surface AMPA receptor (AMPAR) trigger neuronal excitotoxicity induced apoptosis in stroke. However, it is not known whether a similar type of underlying pathophysiology occurs in absence epilepsy. To explore this issue, we examined the levels of mature SREBP1, GluA2, glyceraldehyde 3-phosphate dehydrogenase (GAPDH), p53, and activated to total caspase 3 ratio in nuclear fractions (NF) of hippocampal homogenate from 8 to 10 week old male Genetic Absence Epilepsy Rats from Strasbourg (GAERS) and non-epileptic control (NEC) strains. Mature SREBP1 and GluA2 levels were elevated approximately two-fold in NFs of GAERS hippocampal homogenates compared to NEC animals. Significant increases in GAPDH (~15-fold) and total caspase 3 (~10-fold) levels were also found in NFs of GAERS hippocampal homogenates in comparison to the non-epileptic strain. Data from the current study suggest that absence epilepsy in GAERS is associated with nuclear translocation of mature SREBP1, GluA2 subunit of AMPARs, and recruitment of pro-cell death signaling proteins such as GAPDH and caspase 3. These changes may contribute to hippocampal neuronal/glial cell death in GAERS. Therefore, inhibiting the nuclear accumulation of mature SREBP1 and GluA2 translocation may reduce the pathophysiology of absence epilepsy. PMID- 28719804 TI - Maternal obesity attenuates predelivery inflammatory reaction in C57BL/6N mice. AB - Inflammation and oxidative stress are known to increase before labour. Whether gonadal white adipose tissue (gWAT) participates in this process and whether labour-related processes in placental and adipose tissue are altered in obese women is unknown. In our mouse model, lean mice display elevated placental inflammation and oxidative stress towards the end of pregnancy, accompanied by an increased expression of pro-inflammatory factors in gWAT. Obese mice also display elevated levels of pro-inflammatory factors and oxidative stress in placentas shortly before birth. However, placental infiltration with leukocytes and an increase in gWAT pro-inflammatory factor expression in obese dams are lacking. PMID- 28719805 TI - Seizure detection from EEG signals using Multivariate Empirical Mode Decomposition. AB - We present a data driven approach to classify ictal (epileptic seizure) and non ictal EEG signals using the multivariate empirical mode decomposition (MEMD) algorithm. MEMD is a multivariate extension of empirical mode decomposition (EMD), which is an established method to perform the decomposition and time frequency (T-F) analysis of non-stationary data sets. We select suitable feature sets based on the multiscale T-F representation of the EEG data via MEMD for the classification purposes. The classification is achieved using the artificial neural networks. The efficacy of the proposed method is verified on extensive publicly available EEG datasets. PMID- 28719806 TI - Effect of cage design, supplemental posterior instrumentation and approach on primary stability of a lumbar interbody fusion - A biomechanical in vitro study. AB - BACKGROUND: There are various techniques and approaches for lumbar interbody fusion differing in access, cage type and type of supplemental posterior instrumentation. While a transforaminal access usually includes a hemifacetectomy, the facet joint can be preserved with a more lateral extraforaminal access. The supplemental posterior instrumentation required for both fusion techniques is still debated. The purpose of the present study was to compare primary stability of the two accesses for two different cage types with none, unilateral and bilateral supplemental posterior instrumentation. METHODS: Six monosegmental lumbar functional spinal units (FSUs) were included in each of the two groups, and subjected to a flexibility test. As cages, a newly designed cage was compared to a standard cage in the following states: (a) native, (b) stand-alone cage, (c) bilateral internal fixator, (d) unilateral internal fixator, (e) unilateral facetectomy+bilateral internal fixator, (f) unilateral facetectomy+unilateral internal fixator and (g) unilateral facetectomy with stand alone cage. For comparison the range of motion was normalized to the native state and the effects of the facetectomy, cage type, and supplemental instrumentation was compared. FINDINGS: Within the subject comparison showed a significantly higher flexibility for the unilateral facetectomy in all motion directions (p<0.001). In between subject comparison showed a significant effect of cage type on flexibility in flexion/extension (p=0.002) and lateral bending (p=0.028) but not in axial rotation (p=0.322). The type of supplemental posterior fixation had a significant effect on the flexibility in all motion directions (stand alone>unilateral fixator>bilateral fixator). INTERPRETATION: Cage design and approach type are affecting the primary stability of lumbar interbody fusion procedures while the type of posterior instrumentation is the most influencing factor. PMID- 28719807 TI - Evaluation of a novel radiotracer for positron emission tomography imaging of reactive oxygen species in the central nervous system. AB - INTRODUCTION: Few, if any, radiotracers are available for the in vivo imaging of reactive oxygen species (ROS) in the central nervous system. ROS play a critical role in normal cell processes such as signaling and homeostasis but overproduction of ROS is implicated in several disorders. We describe here the radiosynthesis and initial ex vivo and in vivo evaluation of [11C]hydromethidine ([11C]HM) as a radiotracer to image ROS using positron emission tomography (PET). METHODS: [11C]HM and its deuterated isotopologue [11C](4) were produced using [11C]methyl triflate in a one-pot, two-step reaction and purified by high performance liquid chromatography. Ex vivo biodistribution studies were performed after tail vein injections of both radiotracers. To demonstrate sensitivity of uptake to ROS, [11C]HM was administered to rats treated systemically with lipopolysaccharide (LPS). In addition, ex vivo autoradiography and in vivo PET imaging were performed using [11C]HM on rats which had been microinjected with sodium nitroprusside (SNP) to induce ROS. RESULTS: [11C]HM and [11C](4) radiosyntheses were reliable and produced the radiotracers at high specific activities and radiochemical purities. Both radiotracers demonstrated good brain uptake and fast washout of radioactivity, but [11C](4) washout was faster. Pretreatment with LPS resulted in a significant increase in brain retention of radioactivity. Ex vivo autoradiography and PET imaging of rats unilaterally treated with microinjections of SNP demonstrated increased retention of radioactivity in the treated side of the brain. CONCLUSIONS: [11C]HM has the attributes of a radiotracer for PET imaging of ROS in the brain including good brain penetration and increased retention of radioactivity in animal models of oxidative stress. PMID- 28719808 TI - Activated neuro-oxidative and neuro-nitrosative pathways at the end of term are associated with inflammation and physio-somatic and depression symptoms, while predicting outcome characteristics in mother and baby. AB - OBJECTIVES: To examine oxidative & nitrosative stress (O&NS) biomarkers at the end of term in relation to perinatal affective symptoms, neuro-immune biomarkers and pregnancy-related outcome variables. METHODS: We measured plasma advanced oxidation protein products (AOPP), nitric oxide metabolites (NOx), total radical trapping antioxidant parameter (TRAP), -sulfhydryl (-SH), peroxides (LOOH) and paraoxonase (PON)1 activity in pregnant women with and without prenatal depression and non-pregnant controls. RESULTS: Pregnancy is accompanied by significantly increased AOPP and NOx, and lowered TRAP, -SH and LOOH. Increased O&NS and lowered LOOH and -SH levels are associated with prenatal depressive and physio-somatic symptoms (fatigue, pain, dyspepsia, gastro-intestinal symptoms). Increased AOPP and NOx are significantly associated with lowered -SH, TRAP and zinc, and with increased haptoglobin and C-reactive protein levels. Increased O&NS and lowered TRAP and PON 1 activity, at the end of term predict mother (e.g. hyperpigmentation, labor duration, caesarian section, cord length, breast milk flow) and baby (e.g. sleep and feeding problems) outcome characteristics. CONCLUSIONS: Pregnancy is accompanied by interrelated signs of O&NS, lowered antioxidant defenses and activated neuro-immune pathways. Increased O&NS at the end of term is associated with perinatal depressive and physio-somatic symptoms and may predict obstetric and behavioral complications in mother and baby. PMID- 28719809 TI - Assessing participants' perceptions on group-based principles for action in community-based health enhancing physical activity programmes: The APEF tool. AB - In community-based health enhancing physical activity (CBHEPA) programmes, group based principles for action such as active participation, enjoyment, and fostering group processes are widely advocated. However, not much is known about participants' perceptions of these principles as there are no assessment tools available. Therefore, this article describes the development of the APEF (Active Participation, Enjoyment, and Fostering group processes) tool and reports on its implementation in a Dutch CBHEPA programme. Indicators for the principles have been identified from literature research, interviews with professionals, and secondary analysis of three group interviews with 11 practitioners. To address the identified indicators, the APEF tool was developed, pretested, and used in 10 focus groups with 76 participants. The APEF tool consists of eight statements about group-based principles for action, on which CBHEPA participants vote, followed by in-depth discussion. The voting procedure engages participants. Spider diagrams visualise participants' perceptions of group-based principles. The APEF tool addresses the challenge of relating group level outcomes to individual outcomes such as physical activity behaviour. The tool facilitates as well as evaluates group-based principles for action, it stimulates dialogue and is culturally sensitive, but it needs strong facilitating skills to manage group dynamics. PMID- 28719810 TI - Social impacts evaluation and insider-outsider paradigm: Floodwater spreading project on the Gareh-Bygone plain as an illustrative case. AB - Selection of the appropriate social impact evaluation approach has become an important issue in agricultural and rural development projects in developing countries. The aim of this research was to use the lens of insider-outsider or mutual social impact assessment approach to assess the social impacts of floodwater spreading project (FWSP) on the Gareh-Bygone plain, Iran. A survey methodology with systematic sampling techniques was used to select 138 households as insider group in four villages' of the Gareh-Bygone plain which is covered by FWSP. Furthermore, key person interview was used to assess the viewpoints of experts (outsider group) who had close, ongoing involvement with the project. Result indicated that the experts' viewpoints were more positive towards social impacts of the project. Whereas, the project had some negative and positive social impacts from the local people point of view. PMID- 28719811 TI - Risk of secondary malignancies after radiation therapy for breast cancer: Comprehensive results. AB - GOALS: To assess risks of secondary malignancies in breast cancer patients who received radiation therapy compared to patients who did not. METHODS: The SEER database was used to identify females with a primary diagnosis of breast cancer as their first malignancy, during 1973-2008. We excluded patients with metastatic disease, age <18 years, no definitive surgical intervention, ipsilateral breast cancer recurrence, or who developed a secondary malignancy within 1 year of diagnosis. Standardized incidence ratios and absolute excess risk were calculated using SEER*Stat, version 8.2.1 and SAS, version 9.4. PRINCIPLE RESULTS: There were 374,993 patients meeting the inclusion criteria, with 154,697 who received radiation therapy. With a median follow-up of 8.9 years, 13% of patients (49,867) developed a secondary malignancy. The rate of secondary malignancies was significantly greater than the endemic rate in breast cancer patients treated without radiation therapy, (O/E 1.2, 95% CI 1.19-1.22) and with radiation therapy (O/E 1.33, 95% CI 1.31-1.35). Approximately 3.4% of secondary malignancies were attributable to radiation therapy. The increased risk of secondary malignancies in breast cancer patients treated with radiation therapy compared to those without was significant regardless of age at breast cancer diagnosis (p < 0.01) and more pronounced with longer latency periods. CONCLUSION: There was an increased risk of secondary malignancies for breast cancer patients both with and without radiation therapy compared to the general population. There was an increased risk in specific sites for patients treated with radiation therapy. This risk was most evident in young patients and who had longer latency periods. PMID- 28719812 TI - The impact of ZnO and TiO2 on the stability of clotrimazole under UVA irradiation: Identification of photocatalytic degradation products and in vitro cytotoxicity assessment. AB - In order to ensure the safe and effective use of pharmaceutical products especially for topical administration photostability testing is necessary. The current paper presents an in-depth analysis of the stability of one of the most common antifungal agents, namely clotrimazole. Clotrimazole has proven to be stable under UVA irradiation in applied experimental conditions, but the presence of catalysts such as ZnO and TiO2 has contributed significantly to the degradation of this compound. The findings indicate that its photocatalytic degradation reactions followed the pseudo first-order kinetics with rate constant depending on the pH and the used solvent. Using LC-MS/MS, 14 presumable degradation products of clotrimazole were identified and the plausible transformation pathways were proposed. The in vitro cytotoxicity risk evaluation based on photostability of clotrimazole was also performed using the Human skin fibroblast cell line (BJ) ATCCTM CRL-2522. There was no statistically significant difference between cells viability in all analyzed combinations of clotrimazole, TiO2/ZnO, and UVA irradiation (p<0.05). PMID- 28719813 TI - Comparative stability-indicating chromatographic methods for determination of 4 hexylresorcinol in pharmaceutical formulation and shrimps. AB - Three chromatographic stability-indicating methods were developed for determination of 4-hexylresorcinol in pure form and in a pharmaceutical formulation. Method A was based on a gradient elution liquid chromatographic HPLC determination of 4-hexylresorcinol, its related impurities and in presence of its degradation products. UPLC-MS/MS (Method B) was described for determination of the cited drug in presence of its degradation products. Method C was a thin- layer chromatography (TLC)-densitometry method for the separation and determination of the active ingredient, one of its related impurities and in presence of its degradation products. The mechanism of alkali, oxidative and photodegradation of 4-hexylresorcinol was studied according to ICH guidelines. The degradation products were characterized by the LC-MS/MS method. Methods A and B were applicable for determination of 4-hexylresorcinol residues in shrimp meat. The studied drug was easily degraded in alkali medium giving toxic compounds. The results obtained by the proposed methods were statistically analyzed and compared with those obtained by applying a reported method. PMID- 28719814 TI - Enantiomeric separation of seven beta-agonists by NACE-Study of chiral selectivity with diacetone-d-mannitol-boric acid complex. AB - A rapid and effective nonaqueous capillary electrophoresis (NACE)-ultraviolet (UV) method was developed for the enantiomeric separation of seven beta-agonists. Diacetone-d-mannitol-boric acid complex was used as a new chiral selector. It was in situ synthesized by the reaction of diacetone-d-mannitol and boric acid in methanol medium containing triethylamine. The effects of diacetone-d-mannitol, boric acid, and triethylamine concentrations on the enantioseparation were carefully investigated. Under the optimized conditions, baseline enantioseparation could be obtained for six of the tested beta-agonists within 12min. These results were better than that obtained with d-mannitol-boric acid complex in previous work. 11B nuclear magnetic resonance (11B NMR) was applied to determine the fraction of boron species and confirm the formation of diacetone-d mannitol-boric acid complex. Validation of the established NACE method was also carried out according to ICH guidelines. Calibration curves showed good linearity with correlation coefficients (r)>=0.9992 over a certain concentration range for each enantiomer of the tested five beta-agonists. The relative standard deviations (RSDs) of intra-day precisions and inter-day precisions of migration times were <=1.4% (n=6), and <=6.3% (n=10), respectively. That of peak areas were <=3.7% (n=6), and <=5.6% (n=10), respectively. The limits of detection (LODs) and the limits of quantitation (LOQs) based on the signal-to-noise ratios of 3 and 10 were found below 1.25MUgmL-1 and 5.00MUgmL-1, respectively. The proposed method was successfully applied to the determination of clenbuterol enantiomers in a multi-component pharmaceutical dosage form called "Ambroxol Hydrochloride and Clenbuterol Hydrochloride Oral Solution". PMID- 28719815 TI - Receptiveness to participation in genetic research: A pilot study comparing views of people with depression, diabetes, or no illness. AB - BACKGROUND: Genetic research in human health relies on the participation of individuals with or at-risk for different types of diseases, including health conditions that may be stigmatized, such as mental illnesses. This preliminary study examines the differences in attitudes toward participation in genetic research among individuals with a psychiatric disorder, individuals with a physical disorder, and individuals with no known illness. METHODS: Seventy-nine individuals with a history of diabetes or depression, or no known illness, underwent a simulated consent process for a hypothetical genetic research study. They were then surveyed about their willingness to participate in the hypothetical study and their attitudes about future and family participation in genetic research. RESULTS: Participants with and without a history of depression ranked participating in genetic and medical research as very important and indicated that they were likely to participate in the hypothetical genetics study. Expressed willingness to participate was generally stable and consistent with future willingness. Individuals less strongly endorsed willingness to ask family members to participate in genetic research. CONCLUSION: Individuals with and without a history of mental illness viewed genetic and medical research favorably and expressed willingness to participate in real-time and in the future. Informed consent processes ideally include an exploration of influences upon volunteers' enrollment decisions. Additional empirical study of influences upon genetic research participation is important to ensure that volunteers' rights are respected and that conditions that greatly affect the health of the public are not neglected scientifically. PMID- 28719816 TI - Sulfate radical induced degradation of beta2-adrenoceptor agonists salbutamol and terbutaline: Phenoxyl radical dependent mechanisms. AB - The present study investigated the reactivity and oxidation mechanisms of salbutamol (SAL) and terbutaline (TBL), two typical beta2-adrenoceptor agonists, towards sulfate radical (SO4-) by using photo-activated persulfate (PS). The reaction pathways and mechanisms were proposed based on products identification using high resolution HPLC-ESI-MS, laser flash photolysis (LFP) and molecular orbital calculations. The results indicated that SO4- was the dominant reactive species in the UV/PS process. The second-order rate constants of sulfate radical reaction with SAL and TBL were measured as (3.7 +/- 0.3) * 109 and (4.2 +/- 0.3) * 109 M-1 s-1 by LFP, respectively. For both SAL and TBL, phenoxyl radicals were found to play key roles in the orientation of the primary pathways. For SAL, a benzophenone derivative was generated by oxidation of the phenoxyl radical. However, in the case of TBL, the transformation of the phenoxyl radical into benzoquinone was impossible. Instead, the addition of OSO3H on the aromatic ring was the major pathway. The same reactivity pattern was observed in the case of TBL structural analogs resorcinol and 3,5-dihydroxybenzyl alcohol. Our results revealed that basic conditions inhibited the decomposition of SAL and TBL, while, increasing PS dose enhanced the degradation. The present work could help for a better understanding of the difference in oxidation reactivity of substituted phenols widely present in natural waters. PMID- 28719817 TI - Aged refuse enhances anaerobic digestion of waste activated sludge. AB - In this work, a low-cost alternative approach (i.e., adding aged refuse (AR) into waste activated sludge) to significantly enhance anaerobic digestion of sludge was reported. Experimental results showed that with the addition dosage of AR increasing from 0 to 400 mg/g dry sludge soluble chemical oxygen demand (COD) increased from 1150 to 5240 mg/L at the digestion time of 5 d, while the maximal production of volatile fatty acids (VFA) increased from 82.6 to 183.9 mg COD/g volatile suspended solids. Although further increase of AR addition decreased the concentrations of both soluble COD and VFA, their contents in these systems with AR addition at any concentration investigated were still higher than those in the blank, which resulted in higher methane yields in these systems. Mechanism studies revealed that pertinent addition of AR promoted solubilization, hydrolysis, and acidogenesis processes and did not affect methanogenesis significantly. It was found that varieties of enzymes and anaerobes in AR were primary reason for the enhancement of anaerobic digestion. Humic substances in AR benefited hydrolysis and acidogenesis but inhibited methanogenesis. The effect of heavy metals in AR on sludge anaerobic digestion was dosage dependent. Sludge anaerobic digestion was enhanced by appropriate amounts of heavy metals but inhibited by excessive amounts of heavy metals. The relative abundances of microorganisms responsible for sludge hydrolysis and acidogenesis were also observed to be improved in the system with AR addition, which was consistent with the performance of anaerobic digestion. PMID- 28719818 TI - Insights into the unique functionality of inorganic micro/nanoparticles for versatile ultrasound theranostics. AB - The clinical ultrasound (US)-based theranostic biomedicine suffers from the critical issue that traditional microbubbles (MBs) have lots of drawbacks such as low stability, large particle size, difficult structural control, etc. The unique composition, structure and functionality of inorganic micro/nanoplatforms have shown their great prospect for solving these critical issues and drawbacks of traditional organic MBs. This review summarizes and discusses the state-of-art development on exploring inorganic micro/nanoparticles for versatile US-based biomedical applications, ranging from US imaging, photoacoustic imaging, sonodynamic therapy, high intensity-focused US ablation and US-triggered chemotherapy. These inorganic micro/nanoplatforms include silica-based particles, Au, carbon nanotubes, TiO2, manganese oxide, iron oxide, Prussian blue, inorganic gas-generating nanoparticles and their versatile composite micro/nanosystems. Especially, their unique structure/composition-functionality relationships and biocompatibility/biosafety in US-based theranostics have been discussed and revealed in detail. Their facing challenges and future developments are finally discussed to promote their further clinical translations. It is highly expected that these inorganic micro/nanoplatforms will enter the clinical stage to benefit the personalized theranostics biomedicine based on their unique functionalities and high performance as necessarily required in US-based theranostics. PMID- 28719820 TI - Intrarater reliability and agreement of linear encoder derived heel-rise endurance test outcome measures in healthy adults. AB - A linear encoder measuring vertical displacement during the heel-rise endurance test (HRET) enables the assessment of work and maximum height in addition to the traditional repetitions measure. We aimed to compare the test-retest reliability and agreement of these three outcome measures. Thirty-eight healthy participants (20 females, 18 males) performed the HRET on two occasions separated by a minimum of seven days. Reliability was assessed by the intraclass correlation coefficient (ICC) and agreement by a range of measures including the standard error of measurement (SEM), coefficient of variation (CV), and 95% limits of agreement (LoA). Reliability for repetitions (ICC=0.77 (0.66, 0.85)) was equivalent to work (ICC=0.84 (95% CI 0.76, 0.89)) and maximum height (ICC=0.85 (0.77, 0.90)). Agreement for repetitions (SEM=6.7 (5.8, 7.9); CV=13.9% (11.9, 16.8%); LoA=-1.9+/ 37.2%) was equivalent to work (SEM=419J (361, 499J); CV=13.1% (11.2, 15.8%); LoA=0.1+/-34.8%) with maximum height superior (SEM=0.8cm (0.6, 1.0cm); CV=6.6% (5.7, 7.9%); LoA=1.3+/-17.1%). Work and maximum height demonstrated acceptable reliability and agreement that was at least equivalent to the traditional repetitions measure. PMID- 28719819 TI - Electrical preconditioning of stem cells with a conductive polymer scaffold enhances stroke recovery. AB - Exogenous human neural progenitor cells (hNPCs) are promising stroke therapeutics, but optimal delivery conditions and exact recovery mechanisms remain elusive. To further elucidate repair processes and improve stroke outcomes, we developed an electrically conductive, polymer scaffold for hNPC delivery. Electrical stimulation of hNPCs alters their transcriptome including changes to the VEGF-A pathway and genes involved in cell survival, inflammatory response, and synaptic remodeling. In our experiments, exogenous hNPCs were electrically stimulated (electrically preconditioned) via the scaffold 1 day prior to implantation. After in vitro stimulation, hNPCs on the scaffold are transplanted intracranially in a distal middle cerebral artery occlusion rat model. Electrically preconditioned hNPCs improved functional outcomes compared to unstimulated hNPCs or hNPCs where VEGF-A was blocked during in vitro electrical preconditioning. The ability to manipulate hNPCs via a conductive scaffold creates a new approach to optimize stem cell-based therapy and determine which factors (such as VEGF-A) are essential for stroke recovery. PMID- 28719821 TI - BCG - old workhorse, new skills. AB - Bacille Calmette-Guerin (BCG), the only tuberculosis (TB) vaccine in clinical practice, has limitations in efficacy, immunogenicity and safety. Much current TB vaccine research focuses on engineering live mycobacteria to interfere with phagosome biology and host intracellular pathways including apoptosis and autophagy, with candidates such as BCG Deltazmp1, BCG DeltaureC::hly, BCG::ESX 1Mmar, Mtb DeltaphoP DeltafadD26, Mtb DeltaRD1 DeltapanCD and M. smegmatis Deltaesx-3::esx-3(Mtb) in the development pipeline. Correlates of protection in preclinical studies include increased central memory CD4+ T cells and recruitment of antigen-specific T cells to the lungs, with mucosal vaccination found to be superior to parenteral vaccination. Finally, recent studies suggest beneficial non-specific effects of BCG on immunity, which should be taken into account when considering these vaccines for BCG replacement. PMID- 28719822 TI - Heavy truck restrictions and air quality implications in Sao Paulo, Brazil. AB - This study quantified the effects of traffic restrictions on diesel fuel heavy vehicles (HVs) on the air quality of the Bandeirantes corridor using hourly data obtained by continuous monitoring of traffic and air quality at sites located on this avenue. The study addressed the air quality of a city impacted by vehicular emissions and that PM10 and NOX concentrations are mainly due to diesel burning. Data collection was split into two time periods, a period of no traffic constraint on HVs (Nov 2008 and 2009) and a period of constraint (Nov 2010, 2011 and 2012). We found that pollutants on this corridor, mainly PM10 and NOX, decreased significantly during the period from 2008 to 2012 (28 and 43%, 15.8 and 86.9 ppb) as a direct consequence of HV traffic restrictions (a 72% reduction). Rebound effects in the form of increased traffic of light vehicles (LVs) during this time had impacts on the concentration levels, explaining the differences between rates of reduction in HV traffic and pollutants. Reductions in the number of trucks resulted in longer travel times and increased traffic congestion as a consequence of the modal shift towards LVs. We found that a 51% decrease in PM10 (28.8 MUg m-3) was due to a reduction in HV traffic (vehicle emissions were estimated to be 71% of total sources, 40.1 MUg m-3). This percentage was partially offset by 10% more PM10 emissions related to an increase in LV traffic, while other causes, such as climatic conditions, contributed to a 13% increase in PM10 concentrations. The relationships analyzed in this research served to highlight the need to apply urban transport policies aimed at decreasing pollutant concentrations in Sao Paulo, especially in heavily congested urban corridors on working days. PMID- 28719823 TI - Supplementation with dietary linseed oil during peri-puberty stimulates steroidogenesis and testis development in rams. AB - Omega-3 polyunsaturated fatty acids (omega-3 PUFAs), such as alpha-linolenic acid (ALA), eicosapentaenoic acid, and docosahexaenoic acid, are involved in male reproductive function. In this study, we investigated the effects of linseed oil (LO) as a source of ALA on the steroidogenesis and changes of testicular histology in rams. Sixteen 3-month old rams during peri-puberty were randomly assigned into two groups. Eight rams were assigned as the control group, and the other received LO (4% dry matter of total diet) as the LO treatment group. After an 81-day feeding trial, the rams were slaughtered and investigated. Results revealed that compared with control group, diet containing LO did not affect body weight (36.87 +/- 0.53 kg vs. 37.65 +/- 0.64 kg, respectively; P = 0.361), average daily gain (227.47 +/- 5.82 g vs. 237.95 +/- 9.22 g, respectively; P = 0.353) and epididymis weight (40.77 +/- 4.41 g vs. 45.53 +/- 4.01 g, respectively; P = 0.398), however, it up-regulated PUFAs metabolism and steroidogenesis-related genes mRNA expression (P < 0.05), and increased plasma estradiol concentration (14.88 +/- 0.67 pg/mL vs. 19.50 +/- 1.27 pg/mL, respectively; P < 0.05). Therefore, LO stimulated seminiferous tubule development and increased the number of Sertoli cells (19.17 +/- 2.14 vs. 27.2 +/- 2.39, respectively; P < 0.01), germ-cell layers, as well as testis weight (148.65 +/- 22.66 g vs. 249.96 +/- 30.63 g, respectively; P < 0.05). All these results suggested that LO can improve testis development during peri-puberty by regulating steroidogenesis in rams' testes. PMID- 28719824 TI - Supplementation of l-carnitine during in vitro maturation improves embryo development from less competent bovine oocytes. AB - The present study was designed to define the impact of l-carnitine, supplemented during maturation, on bovine oocytes with different meiotic competence in terms of their IVF outcomes. Meiotically more competent (MMC) and less competent (MLC) oocytes were obtained separately from differently sized follicles at selected phases of folliculogenesis. The oocytes were matured with or without l-carnitine, fertilized and cultured to the blastocyst stage. The oocytes were examined for nuclear maturation, mitochondrial cluster formation, lipid consumption, fertilization and embryo development. The proportion of oocytes at metaphase II was significantly higher in the l-carnitine-treated MMC than that in the l carnitine-treated MLC oocytes. However in comparison with the untreated controls, the proportion of MII oocytes with mitochondrial clusters was significantly higher only in the l-carnitine-treated MLC oocytes, which also showed a significantly lower mean lipid content. The l-carnitine-treated MLC oocytes showed significantly higher fertilization and syngamy rates than the untreated MLC oocytes. On the other hand, in the l-carnitine-treated MMC oocytes, the fertilization rate was similar to that of the untreated controls and the syngamy rate was significantly delayed. Although no significant differences in cleavage on Day 2 were found among all oocyte categories, l-carnitine treatment resulted in a significantly higher blastocyst yield in the MLC oocytes on Day 7 and Day 8 and a significantly higher proportion of expanded blastocysts in relation to the total number of blastocysts in MMC oocytes on Day 8. It can be concluded that l carnitine supplementation during maturation improves the development of bovine embryos from meiotically less competent oocytes and accelerates blastocyst formation from more competent oocytes. PMID- 28719825 TI - Degeneration of the vestibular nerve in unilateral Meniere's disease evaluated by galvanic vestibular-evoked myogenic potentials. AB - OBJECTIVE: The staging system of Meniere's disease utilizes audiograms to probe cochlear dysfunction. We explored the addition of galvanic vestibular-evoked myogenic potentials (VEMP) to further explore vestibular function. METHODS: Seventy patients with unilateral Meniere's disease were enrolled in this study. Within 2weeks of diagnosis, all subjects underwent pure tone audiometry, cervical and ocular VEMP, and caloric test. The prevalence of abnormal tests and the VEMP characteristic parameters such as latencies and amplitudes were analyzed. RESULTS: In affected ears, the abnormal rate of acoustic cVEMPs, galvanic cVEMPs, vibratory oVEMPs and galvanic oVEMPs was 37%, 17%, 20%, and 9%, respectively. No significant differences existed in VEMP latencies and amplitudes between affected ears and unaffected ears. CONCLUSIONS: The impairment of otolithic organs was found to be more than that of vestibular afferents. The deterioration of the saccule was more than that of the utricle, whereas retrolabyrinthine degeneration of sacculo-collic reflex and vestibulo-ocular reflex was similar. SIGNIFICANCE: This study is the first to use an electrophysiological test to evaluate the retrolabyrinthine function of patients with unilateral Meniere's disease. PMID- 28719826 TI - The terminal latency of the phrenic nerve correlates with respiratory symptoms in amyotrophic lateral sclerosis. AB - OBJECTIVE: The aim of the study was to investigate the electrophysiological parameters in phrenic nerve conduction studies (NCS) that sensitively reflect latent respiratory insufficiency present in amyotrophic lateral sclerosis (ALS). METHOD: Forty-nine patients with ALS were examined, and after exclusion, 21 patients with ALS and their phrenic NCS results were reviewed. The patients were divided into two groups according to their respiratory sub-score in the ALS functional rating scale - revised (Group A, sub-score 12vs. Group B, sub-score 11). We compared the parameters of phrenic NCS between the two groups. RESULTS: There were no significant differences in the clinical characteristics between the two groups. Using a multivariate model, we found that the terminal latency of the phrenic nerve was the only parameter that was associated with early symptoms of respiratory insufficiency (p<0.05). The optimal cutoff value for the terminal latency of the phrenic nerve was 7.65ms (sensitivity 80%, specificity 68.2%). CONCLUSION: The significantly prolonged terminal latency of the phrenic nerve in our study may reflect a profound distal motor axonal dysfunction of the phrenic nerve in patients with ALS in the early stage of respiratory insufficiency that can be used as a sensitive electrophysiological marker reflecting respiratory symptoms in ALS. SIGNIFICANCE: The terminal latency of the phrenic nerve is useful for early detection of respiratory insufficiency in patients with ALS. PMID- 28719827 TI - Mixed evidence for the potential of non-invasive transcutaneous vagal nerve stimulation to improve the extinction and retention of fear. AB - Extinction memories are fragile and their formation has been proposed to partially rely on vagus nerve activity. We tested whether stimulating the auricular branch of the vagus (transcutaneous VNS; tVNS) accelerates extinction and reduces spontaneous recovery of fear. Forty-two healthy students participated in a 3-day fear conditioning study, where we tested fear acquisition (day 1), fear extinction (day 2) and the retention of the extinction memory (day 3). During extinction, participants were randomly allocated to receive tVNS or sham stimulation concurrently with each CS presentation. During the acquisition and retention phases, all participants received sham stimulation. Indexes of fear included US-expectancy, startle blink EMG and skin conductance responses. Results showed successful acquisition and extinction of fear in all measures. tVNS facilitated the extinction of declarative fear (US expectancy ratings), but did not promote a stronger retention of the declarative extinction memory. No clear effects of tVNS on extinction and retention of extinction were found for the psychophysiological indexes. The present findings provide tentative indications that tVNS could be a promising tool to improve fear extinction and call for larger scale studies to replicate these effects. PMID- 28719828 TI - Functional analysis of PCSK2 coding variants: A founder effect in the Old Order Amish population. AB - AIMS: In humans, noncoding variants of PCSK2, the gene encoding prohormone convertase 2 (PC2), have been previously associated with risk for and age of onset of type 2 diabetes (T2D). The aims of this study were to identify coding variants in PCSK2; to determine their possible association with glucose handling; and to determine functional outcomes for coding variants in biochemical studies. METHODS: Exome-wide genotyping was performed on 1725 Old Order Amish (OOA) subjects. PCSK2 coding variants were tested for association with diabetes-related phenotypes. In vitro analyses using transfected human PC2-encoding constructs were performed to determine the impact of each mutation on PC2 activity. RESULTS: We identified 10 rare missense coding variants in PCSK2 in various genomic databases. R430W (rs200711626) is greatly enriched in the OOA population (MAF 4.3%). This variant is almost twice as common (MAF 7.4%) in OOA individuals with T2D as in OOA individuals with normal or with normal/impaired glucose tolerance (MAF 3.9% and 2.9%, respectively; p=0.25 and p=0.10). In vitro experiments revealed a broadening of the pH optimum for the R430W variant, which may result in increased activity against PCSK2 substrates. CONCLUSIONS: Although the association of the R430W variation with T2D in the OOA population did not reach significance, based upon the broadened pH profile of R430W PC2, we speculate that the presence of this substitution may result in altered processing of PCSK2 substrates, ultimately leading to increased conversion to diabetes. PMID- 28719829 TI - Detection of driver engagement in secondary tasks from observed naturalistic driving behavior. AB - Distracted driving has long been acknowledged as one of the leading causes of death or injury in roadway crashes. The focus of past research has been mainly on the impact of different causes of distraction on driving behavior. However, only a few studies attempted to address how some driving behavior attributes could be linked to the cause of distraction. In essence, this study takes advantage of the rich SHRP 2 Naturalistic Driving Study (NDS) database to develop a model for detecting the likelihood of a driver's involvement in secondary tasks from distinctive attributes of driving behavior. Five performance attributes, namely speed, longitudinal acceleration, lateral acceleration, yaw rate, and throttle position were used to describe the driving behavior. A model was developed for each of three selected secondary tasks: calling, texting, and passenger interaction. The models were developed using a supervised feed-forward Artificial Neural Network (ANN) architecture to account for the effect of inherent nonlinearity in the relationships between driving behavior and secondary tasks. The results show that the developed ANN models were able to detect the drivers' involvement in calling, texting, and passenger interaction with an overall accuracy of 99.5%, 98.1%, and 99.8%, respectively. These results show that the selected driving performance attributes were effective in detecting the associated secondary tasks with driving behavior. The results are very promising and the developed models could potentially be applied in crash investigations to resolve legal disputes in traffic accidents. PMID- 28719830 TI - Relationship between psychological inflexibility and experiential avoidance and internet addiction: Mediating effects of mental health problems. AB - Internet addiction became a major mental health problem in college student. Our objective was to examine the relationship between psychological inflexibility and experiential avoidance (PIEA) and Internet addiction (IA) and the mediating effects of mental health problem indicators. 500 college students (238 men and 262 women) participated in this study. The level of PIEA was examined using the Acceptance and Action Questionnaire-II. The severity of IA was assessed using the Chen Internet Addiction Scale. The levels of depression, anxiety, interpersonal sensitivity, and hostility were evaluated using the Symptom Checklist-90 item Revised Scale. The relationship among PIEA, mental health problems, and IA was examined using structural equation modeling. The severity of PIEA was positively associated with the severity of IA as well as positively associated with the severity of mental health problems. In addition, the severity of mental health problem indicators was positively associated with the severity of IA. These results provide the severity of PIEA is directly related to the severity of IA and indirectly related to the severity of IA through increasing the severity of mental health problems. The PIEA should be one of the target objectives when administer cognitive-behavioral therapy to college students with IA and mental health problems. PMID- 28719831 TI - Metacognitive profiles in schizophrenia and bipolar disorder: Comparisons with healthy controls and correlations with negative symptoms. AB - While deficits in metacognition, or the ability to notice and reflect upon mental states has been observed in schizophrenia and linked with poorer concurrent and future function, it is unknown whether these deficits are unique to schizophrenia. Accordingly, this study assessed metacognition using the Metacognitive Assessment Scale-Abbreviated (MAS-A) and the Metacognitions Questionnaire- 30 (MCQ-30) among 26 adults with schizophrenia, 23 with bipolar disorder and 23 healthy controls. Symptom levels of the psychiatric groups were assessed with the Brief Psychiatric Rating Scale. ANCOVA controlling for age and education revealed that the schizophrenia group had lower scores on the MAS-A total and its subscales compared to the bipolar group and healthy controls. The bipolar disorder group also had lower MAS-A scores than the healthy control group. No group differences were found for the MCQ-30. Examination of symptom correlates revealed MAS-A scores were most commonly related to negative symptoms in both clinical groups. The total score and need for control subscale of MCQ-30 was related to total symptomatology and positive symptoms in patients with bipolar disorder. Correlations between the two measures of metacognition revealed that higher MAS-A scores were significantly related to lower scores on the Need to Control Thoughts MCQ-30 subscale. PMID- 28719832 TI - Expression of MyHC isoforms mRNA transcripts in different regions of the masseter and medial pterygoid muscles in chimpanzees. AB - OBJECTIVE: The aim of this study is to examine the expression pattern of the different myosin heavy chain (MyHC) isoforms in the masseter and medial pterygoid muscles by real time quantitative polymerase chain reaction (RT-qPCR) to obtain information at molecular level which can be related to the functional characteristics of these two muscles. DESIGN: The masseter, deep and superficial portion, and medial pterygoid muscles of five adult Pan troglodytes were dissected in order to obtain samples of the anterior and posterior regions of each portion of the masseter and of the medial pterygoid. The expression of MyHC isoforms mRNA transcripts was analyzed by RT-qPCR. RESULTS: No significant differences in expression of MyHC isoforms between the masseter and the medial pterygoid were found. In contrast, when comparing the superficial and the deep portion of the masseter, we found that the MyHC-IIM isoform was expressed at a significantly higher level in the superficial portion. CONCLUSIONS: The superficial portion of the masseter and the medial pterygoid muscle have the same expression pattern regarding the different MyHC isoforms. On the other hand, the deep portion of the masseter, which is activated mainly during lateral and repositioning movements of the mandible, has a lower MyHC-IIM isoform expression than the superficial portion. Our findings provide new data on functional aspects of the masseter and medial pterygoid that can complement results obtained by other techniques. PMID- 28719833 TI - In silico search of inhibitors of Streptococcus mutans for the control of dental plaque. AB - Biofilm is an extremely complex microbial community arranged in a matrix of polysaccharides and attached to a substrate. Its development is crucial in the pathophysiology of oral infections like dental caries, as well as in periodontal, pulp, and periapical diseases. Streptococcus mutans is one of the most effective microorganisms in lactic acid production of the dental biofilm. Identifying essential Streptococcus mutans proteins using bioinformatics methods helps to search for alternative therapies. To this end, the bacterial genomes of several Streptococcus mutans strains and representative strains of other cariogenic and non-cariogenic bacteria were analysed by identifying pathogenicity islands and alignments with other bacteria, and by detecting the exclusive genes of cariogenic species in comparison to the non-pathogenic ones. This study used tools for orthology prediction such as BLAST and OrthoMCL, as well as the server IslandViewer for the detection of pathogenicity islands. In addition, the potential interactome of Streptococcus mutans was rebuilt by comparing it to interologues of other species phylogenetically close to or associated with cariogenicity. This protocol yielded a final list of 20 proteins related to potentially virulent factors that can be used as therapeutic targets in future analyses. The EIIA and EIIC enzymatic subunits of the phosphotransferase system (PTS) were prioritized, as well as the pyruvate kinase enzyme, which are directly involved in the metabolism of carbohydrates and in obtaining the necessary energy for the microorganism's survival. These results will guide a subsequent experimental trial to develop new, safe, and effective molecules in the treatment of dental caries. PMID- 28719834 TI - The exon3-deleted growth hormone receptor gene polymorphism (d3-GHR) is associated with insulin and spontaneous growth in short SGA children (NESGAS). AB - OBJECTIVE: The effect of a common polymorphism in the Growth Hormone (GH) receptor (d3-GHR) gene on growth, metabolism and body composition was examined in short children born small for gestational age (SGA) on GH treatment. DESIGN: In 96 prepubertal, short SGA children treated with high-dose GH (67MUg/kg/day) in the NESGAS study, insulin sensitivity (IS), insulin secretion and disposition index (DI) were determined during the first year of treatment. Body composition was analysed by DXA. The d3-GHR locus was determined by simple multiplex PCR. RESULTS: At baseline, children in the d3-GHR group (d3/fl (n=37), d3/d3 (n=7)) had significantly lower IS (median (25-75 percentile)) (223.3% (154.4-304.8)) vs. (269.7% (185.1-356.7)) (p=0.03) and higher concentrations of glucose (mean (SD)) (4.4mmol/L (0.6) vs. 4.2mmol/L (0.7)) (p=0.03), C-peptide (232.1pmol/L (168.8 304.1) vs. 185.1pmol/L (137.7-253.9)) (p=0.04) and insulin (19.2pmol/L (11.8 32.2)) vs. (13.7pmol/L (9.3-20.8)) (p=0.04) compared to children homozygous for the full length allele (fl/fl-GHR (n=52)). There were no differences in DI or insulin secretion. Postnatal, spontaneous growth was significantly greater in the d3-GHR group compared to the fl/fl-GHR group (p=0.02). There were no significant differences in growth response, body composition or metabolism after one year of GH therapy. CONCLUSION: Short SGA children carrying the d3-GHR polymorphism had increased spontaneous growth, lower IS and a compensatory increase in glucose, C peptide and insulin before GH therapy compared to children homozygous for the full-length allele. PMID- 28719835 TI - Silencing the tobacco gene for RNA-dependent RNA polymerase 1 and infection by potato virus Y cause remodeling of cellular organelles. AB - RNA-dependent RNA polymerase 1 (RDR1) has been shown to be involved in DNA methylation, RNA silencing and regulating expression of other genes. RDR1 gene expression is stimulated by infection with potato virus Y degrees (PVY). Transgenic Nicotiana tabacum plants silenced for RDR1 gene expression showed morphological changes in mesophyll cells, associated with remodeling of the nuclei, chloroplasts and mitochondria. RDR1 silencing led to decreased nuclear size, increased heterochromatin content and aggregation, decreased numbers of chloroplasts, plus changes in shape, internal structures and integrity of chloroplasts and mitochondria. RDR1-silenced transgenic plants showed increased PVY accumulation and ultrastructural remodeling was intensified in both chloroplasts and mitochondria of PVY-infected, RDR1-silenced plants. By contrast, heterochromatin condensation was reduced by PVY infection, and in non-transgenic plants the nuclei were translucent and lacked morphology after PVY infection. Thus, RDR1 regulates gene expression leading to remodeling of chromosomes, and PVY infection counteracts these effects on chromosomal remodeling. PMID- 28719836 TI - Long-term management of patients with hormone receptor-positive metastatic breast cancer: Concepts for sequential and combination endocrine-based therapies. AB - Treatment options for hormone receptor-positive (HR-positive) metastatic breast cancer (MBC) continue to increase in parallel with expanding knowledge about the complex biology of breast cancer subtypes and resistance mechanisms to endocrine therapy. For patients with HR-positive MBC, there are now an unprecedented number of endocrine-based treatment options that can improve long-term outcomes, while preserving or optimizing quality of life, and that can be used before selecting more cytotoxic chemotherapeutic regimens. In addition to antiestrogens, steroidal and nonsteroidal aromatase inhibitors, the selective estrogen-receptor degrader, fulvestrant, and new endocrine-based combinations provide significant and clinically meaningful improvements in outcomes in the first line setting and beyond. Also, new clinical scenarios and indications for monotherapy endocrine and targeted therapies continue to be explored. Patients have several therapeutic options when their disease progresses or becomes resistant, although the optimal sequencing of these therapies remains unclear. Ongoing research in the resistant/refractory setting is anticipated to continue improving the outlook for these patients. This review will discuss current and investigational approaches to sequential single-agent endocrine and endocrine-based combination therapy for the long-term management of patients with HR-positive, human epidermal growth factor receptor 2-negative MBC. PMID- 28719837 TI - Prescription trends and the selection of initial oral antidiabetic agents for patients with newly diagnosed type 2 diabetes: a nationwide study. AB - OBJECTIVES: The aim of this study was to examine the characteristics of patients, physicians, and medical facilities, and their association with prescriptions that do not include metformin as the initial oral antidiabetic agent. STUDY DESIGN: Observational, cross-sectional study. METHODS: Patients with incident type 2 diabetes between January 1, 2006, and December 31, 2010, were identified from the Taiwan National Insurance Research Database. We describe trends in the initial prescription of antidiabetic medications that do not contain metformin during the study period. A multivariable logistic model and a multilevel linear model were used in the analysis of factors at a range of levels (patient, physician, and medical facility), which may be associated with the selection of oral antidiabetic drugs. RESULTS: During the study period, the proportion of prescriptions that did not include metformin declined from 43.8% to 26.2%. Male patients were more likely to obtain non-metformin prescriptions (adjusted odds ratio [OR]: 1.15; 95% confidence interval [CI]: 1.08-1.23), and the likelihood that a patient would be prescribed a non-metformin prescription increased with age. Physicians aged >=35 years and those with specialties other than endocrinology tended to prescribe non-metformin prescriptions. Metformin was less commonly prescribed in for-profit hospitals (adjusted OR: 1.34, 95% CI: 1.11 1.61) and hospitals in smaller cities (adjusted OR: 1.28, 95% CI: 1.05-1.57) and rural areas (adjusted OR: 1.83, 95% CI: 1.32-2.54). CONCLUSIONS: Disparities continue to exist in clinical practice with regard to the treatment of diabetes. These inequalities appear to be linked to a variety of factors related to patients, physicians, and medical facilities. Further study will be required to understand the effects of continuing medical education in enhancing adherence to clinical guidelines. PMID- 28719838 TI - Identification of a prototypical single-stranded uracil DNA glycosylase from Listeria innocua. AB - A recent phylogenetic study on UDG superfamily estimated a new clade of family 3 enzymes (SMUG1-like), which shares a lower homology with canonic SMUG1 enzymes. The enzymatic properties of the newly found putative DNA glycosylase are unknown. To test the potential UDG activity and evaluate phylogenetic classification, we isolated one SMUG1-like glycosylase representative from Listeria innocua (Lin). A biochemical screening of DNA glycosylase activity in vitro indicates that Lin SMUG1-like glycosylase is a single-strand selective uracil DNA glycosylase. The UDG activity on DNA bubble structures provides clue to its physiological significance in vivo. Mutagenesis and molecular modeling analyses reveal that Lin SMUG1-like glycosylase has similar functional motifs with SMUG1 enzymes; however, it contains a distinct catalytic doublet S67-S68 in motif 1 that is not found in any families in the UDG superfamily. Experimental investigation shows that the S67M-S68N double mutant is catalytically more active than either S67M or S68N single mutant. Coupled with mutual information analysis, the results indicate a high degree of correlation in the evolution of SMUG1-like enzymes. This study underscores the functional and catalytic diversity in the evolution of enzymes in UDG superfamily. PMID- 28719839 TI - The prognostic value of brain natriuretic peptide (BNP) in non-cardiac patients with sepsis, ultra-long follow-up. AB - OBJECTIVES: Sepsis is a multifactorial syndrome with increasing incidence of morbidity and mortality. Identification of outcome predictors is therefore essential. Recently, elevated brain natriuretic peptide (BNP) levels have been observed in patients with septic shock. Little information is available concerning BNP levels in patients with critical illness, especially with sepsis. Therefore, this study aims to evaluate the role of BNP as a biomarker for long term mortality in patients with sepsis. METHODS: We studied 259 patients with sepsis and absence of heart failure. BNP levels were obtained for all patients. A long-term survival follow-up was done, and survival was evaluated 90days after admission, and during the subsequent 60months of follow-up. RESULTS: Eighty-two patients died during the 90-day follow-up (31.7%), 53 died in the index hospitalization (20.5%). On multivariate analysis models, elevated values of BNP were a strong predictor of in-hospital mortality, 90-day and 60-month mortality in patients with sepsis. BNP was a better prognostic predictor than the Sepsis related Organ Failure Assessment (SOFA) score for 90-day mortality, and a better predictor for 60-month mortality in low risk groups. CONCLUSION: In the population of hospitalized patients with sepsis, BNP is a strong independent predictor of short- and long-term mortality. PMID- 28719840 TI - Environmental and human health challenges of industrial livestock and poultry farming in China and their mitigation. AB - Driven by the growing demand for food products of animal origin, industrial livestock and poultry production has become increasingly popular and is on the track of becoming an important source of environmental pollution in China. Although concentrated animal feeding operations (CAFOs) have higher production efficiency and profitability with less resource consumption compared to the traditional family-based and "free range" farming, they bring significant environmental pollution concerns and pose public health risks. Gaseous pollutants and bioaerosols are emitted directly from CAFOs, which have health implications on animal producers and neighboring communities. A range of pollutants are excreted with the animal waste, including nutrients, pathogens, natural and synthetic hormones, veterinary antimicrobials, and heavy metals, which can enter local farmland soils, surface water, and groundwater, during the storage and disposal of animal waste, and pose direct and indirect human health risks. The extensive use of antimicrobials in CAFOs also contributes to the global public health concern of antimicrobial resistance (AMR). Efforts on treating the large volumes of manure generated in CAFOs should be enhanced (e.g., by biogas digesters and integrated farm systems) to minimize their impacts on the environment and human health. Furthermore, the use of veterinary drugs and feed additives in industrial livestock and poultry farming should be controlled, which will not only make the animal food products much safer to the consumers, but also render the manure more benign for treatment and disposal on farmlands. While improving the sustainability of animal farming, China also needs to promote healthy food consumption, which not only improves public health from avoiding high-meat diets, but also slows down the expansion of industrial animal farming, and thus reduces the associated environmental and public health risks. PMID- 28719841 TI - Risk of treatment-related mortality in cancer patients treated with ipilimumab: A systematic review and meta-analysis. AB - BACKGROUND: Fatal adverse events (FAEs) have been reported in cancer patients receiving ipilimumab-a monoclonal antibody against cytotoxic T-lymphocyte antigen 4, but the risk of treatment-related mortality is unknown. We performed a systematic review and meta-analysis of randomised controlled trials (RCTs) of ipilimumab to determine the overall risk of FAEs associated with ipilimumab. METHODS: We systematically searched MEDLINE, EMBASE, Cochrane CENTRAL, ClinicalTrial.gov and conference proceedings from inception to December 2016, for prospective trials that randomly assigned patients to ipilimumab treatment (with or without concurrent therapy) or controls with available data regarding incidence of FAEs. Two reviewers extracted data independently. Incidence of FAEs was pooled using a random effects model, and the risk of FAEs associated with ipilimumab was estimated using Peto odds ratios (ORs). RESULTS: A total of 5775 patients with solid tumours included in 12 RCTs (10 from journal reports and 2 from ClinicalTrials.gov) were included in the meta-analysis. The pooled incidence of FAEs for patients treated with ipilimumab was 1.13% (95% confidence interval [CI], 0.56-1.86), compared with 0.22% in the control arms. Ipilimumab was associated with statistically significantly increased risk of FAEs, with a pooled Peto OR of 2.3 (95% CI, 1.4-3.6; P < 0.001). Analyses according to cancer type (melanoma versus other cancers); treatment mode (combination therapy or monotherapy); control type (active control versus placebo/best supportive care only); ipilimumab dose (high versus low dose [10 versus 3 mg/kg every 3 weeks]) found no statistically significantly differential effect by subgroups. Among the specific causes of FAEs, ipilimumab was associated with an increased risk of fatal gastrointestinal toxicity, with an OR of 4.5 (95% CI, 1.5-13.6). CONCLUSION: The use of ipilimumab, compared with controls, was associated with increased risk of treatment-related mortality. PMID- 28719842 TI - Spatiotemporal gait changes with use of an arm swing cueing device in people with Parkinson's disease. AB - Impaired arm swing is a common motor symptom of Parkinson's disease (PD), and correlates with other gait impairments and increased risk of falls. Studies suggest that arm swing is not merely a passive consequence of trunk rotation during walking, but an active component of gait. Thus, techniques to enhance arm swing may improve gait characteristics. There is currently no portable device to measure arm swing and deliver immediate cues for larger movement. Here we test report pilot testing of such a device, ArmSense (patented), using a crossover repeated-measures design. Twelve people with PD walked in a video-recorded gym space at self-selected comfortable and fast speeds. After baseline, cues were given either visually using taped targets on the floor to increase step length or through vibrations at the wrist using ArmSense to increase arm swing amplitude. Uncued walking then followed, to assess retention. Subjects successfully reached cueing targets on >95% of steps. At a comfortable pace, step length increased during both visual cueing and ArmSense cueing. However, we observed increased medial-lateral trunk sway with visual cueing, possibly suggesting decreased gait stability. In contrast, no statistically significant changes in trunk sway were observed with ArmSense cues compared to baseline walking. At a fast pace, changes in gait parameters were less systematic. Even though ArmSense cues only specified changes in arm swing amplitude, we observed changes in multiple gait parameters, reflecting the active role arm swing plays in gait and suggesting a new therapeutic path to improve mobility in people with PD. PMID- 28719843 TI - Atomic scale modeling of electrically doped p-i-n FET from adenine based single wall nanotube. AB - The Field Effect Transistor (FET) characteristics has been observed from a single walled Adenine nanotube device using Density Functional Theory associated with Non Equilibrium Green's Function based First Principle approach. This device is electrically doped which shows both n and p channel characteristics of a p-i-n FET. This device is designed and originated from a single-walled biomolecular nanotube structure. The p and n regions have been induced at the two ends of the device using electrical doping process. Thus both n and p channel current-voltage response can be obtained within a single nano-scale device at room temperature operation. The device is 3.35nm long and 1.4nm wide. The quasi-ballistic quantum transmission property reveals impressive and almost ideal current-voltage characteristics of the FET. Highest Occupied Molecular Orbital (HOMO) and Lowest Unoccupied Molecular Orbital (LUMO) gap reveals the possibility of quasi ballistic coherent transmission of the device. The electronic properties based on Molecular Projected Self-consistent Hamiltonian are analyzed using Hilbert space spanned basis functions. The maximum tunneling current observed for the bio molecular FET is 15.9MUA for n-channel and 13.8MUA for p-channel. The device is operated in atomic scale regime with 1000THz frequency. The present results reveal the role of quantum-ballistic tunneling phenomenon in the current-voltage characteristics and channel conductance properties of the bio nanotube structure, which is useful in future generation nano-electronics. PMID- 28719844 TI - Phosphate functionalized (4,4)-armchair CNTs as novel drug delivery systems for alendronate and etidronate anti-osteoporosis drugs. AB - The ability of (4,4)-armchair CNT and its three phosphate functionalized forms (CNT-nH2PO4, n=1-3) were evaluated as novel drug delivery systems (DDSs) for the two commercially well-known anti-osteoporosis drugs namely alendronate (AL) and etidronate (ET). For this purpose, the DFT calculations were accomplished at both B3LYP and B3PW91 levels using 6-31g(d) basis set. The binding energy was increased by increasing number of H2PO4 moieties attached on the CNT with the most negative binding energy was measured for the carrier containing three phosphate groups. The dipole moments of all phosphate containing CNTs were much greater (~2.2-4.4D) than that of pristine CNT (~0D). The contour maps proved that when the CNT was functionalized by H2PO4 groups, the symmetric distribution of electric charge was vanished with the charge distribution was the highest asymmetric for the CNT-2H2PO4 while it was the lowest asymmetric for CNT-3H2PO4 leading to the greatest dipole moment for the CNT-2H2PO4 (4.177D) while the smallest dipole moment for the CNT-3H2PO4 (1.614D). Among all compounds, those containing the CNT-3H2PO4 exhibited the smallest band gap energy, chemical potential and hardness but the greatest electronegativity and electrophilicity index which were all suitable and effective for the attachment of drugs onto the bone surface (having partial positive charge due to the presence of Ca2+ as CaCO3) and therefore inhibiting the osteoporosis. Consequently, it was established that the drug-CNT-3H2PO4 was the most appropriate drug-carrier compound for both of the AL and ET drugs and it could be used as the most effective drug vehicle. The attachment of AL, ET drugs as well as the AL-CNT 3H2PO4 and ET-CNT-3H2PO4 drug-carrier systems to the bone tissue was modelled by optimization of the structures of these compounds bonded to the hydroxyapatite (HA)-17water (w). It was found that among these four systems, the AL-CNT-3H2PO4 could be suggested as the most suitable DDS for application in the treatment of osteoporosis. PMID- 28719845 TI - The effects of ibuprofen on activated sludge: Shift in bacterial community structure and resistance to ciprofloxacin. AB - Ibuprofen (IBP) is ranked at the 4th place among 57 pharmaceutical compounds according to the number of citations in prioritization documents. The response of microbial community of activated sludge to IBP was studied at the concentrations of 50-5000mg/L. Batch incubation was performed in an OxiTop(r) device for 21days. The reduction of biological oxygen demand depended on the IBP concentration and varied in the range from 321 to 107mg O2/L. Massive DNA sequencing analysis of the activated sludge revealed that Proteobacteria became more dominant when grown in the presence of IBP. Microbial diversity was reduced in the presence of 500 1000mg/L IBP, but increased again in the presence of 5000mg/L IBP, despite the domination of Enterobacteriales (48.1%) in this sample. Incubation of activated sludge in the presence of 1000mg/L IBP led to an increased occurrence of ciprofloxacin-resistant bacteria. The use of Eosin Methylene Blue Agar for disc diffusion assay was shown to be more appropriate in order to reveal the changes in antibiotic resistance. The predominance of Enterobacteriales in the activated sludge is suggested as one of the possible explanations of the enhanced resistance to ciprofloxacin. PMID- 28719846 TI - Preparation, characterization, and application of TiO2-patterned polyimide film as a photocatalyst for oxidation of organic contaminants. AB - Photocatalytically active TiO2-patterned polyimide (PI) films (PI-TiO2) were fabricated using thermal transfer patterning (TTP). When subjected to hot pressing, the TiO2 nanoparticles electrosprayed on steel mesh templates were successfully transferred and formed checker plate patterns on PI film. FE-SEM studies confirmed that pressing at 350 degrees C and 100MPa was optimum for obtaining patterns with uniform TiO2 coverage. When the quantity of TiO2 on the template increased, the amount of it immobilized on PI film also increased from 0.3245 to 1.2378mg per 25cm2. XPS studies confirmed the presence TiO2 on the patterns, and indicated the formation of carboxylic acid and amide groups on the PI surface during TTP. When tested under UVA irradiation, PI-TiO2 with 1.2378mg/25cm2 TiO2 loading exhibited the highest photocatalytic performance for methylene blue (10MUM) degradation, with a rate constant of 0.0225min-1 and stable photocatalytic efficacy for 25 cycles of reuse. The PI-TiO2 was also successfully used to degrade amoxicillin, atrazine, and 4-chlorophenol. During photocatalysis, the toxicity of 4-chlorophenol against Vibrio fischeri and the antibiotic activity of amoxicillin against Escherichia coli were decreased. Overall, TTP was found to be a potentially scalable method for fabricating robust immobilized TiO2 photocatalyst. PMID- 28719847 TI - High photocatalytic activity of hierarchical SiO2@C-doped TiO2 hollow spheres in UV and visible light towards degradation of rhodamine B. AB - Ongoing research activities are targeted to explore high photocatalytic activity of TiO2-based photocatalysts for the degradation of environmental contaminants under UV and visible light irradiation. In this work, we devise a facile, cost effective technique to in situ synthesize hierarchical SiO2@C-doped TiO2 (SCT) hollow spheres for the first time. This strategy mainly contains the preparation of monodisperse cationic polystyrene spheres (CPS), sequential deposition of inner SiO2, the preparation of the sandwich-like CPS@SiO2@CPS particles, and formation of outer TiO2. After the one-step removal of CPS templates by calcination at 450 degrees C, hierarchical SiO2@C-doped TiO2 hollow spheres are in situ prepared. The morphology, hierarchical structure, and properties of SCT photocatalyst were characterized by TEM. SEM, STEM Mapping, BET, XRD, UV-vis spectroscopy, and XPS. Results strongly confirm the carbon doping in the outer TiO2 lattice of SCT hollow spheres. When the as-synthesized SCT hollow spheres were employed as a photocatalyst for the degradation of Rhodamine B under visible light and ultraviolet irradiation, the SCT photocatalyst exhibits a higher photocatalytic activity than commercial P25, effectively overcoming the limitations of poorer UV activity for many previous reported TiO2-based photocatalysts due to doping. PMID- 28719848 TI - Transformation of DON in reclaimed water under solar light irradiation leads to decreased haloacetamide formation potential during chloramination. AB - Reclaimed water is usually stored in rivers or lakes before subsequent use. In storage ecosystems, the natural process of solar light irradiation plays a key role in water quality, altering disinfection byproduct formation potential in later use. This study investigated changes in haloacetamide formation potential (HAcAm FP) during subsequent chloramination when reclaimed water was exposed to solar light irradiation. Significant decreases in HAcAm FP were observed for the solar light irradiated reclaimed water, with reductions of 27%-69% for different haloacetamides. Moreover, transformation of dissolved organic nitrogen (DON) to inorganic nitrogen occurred during irradiation. The application of 15N- labeled monochloramine indicated that the nitrogen source of the decreased HAcAms mainly originated from DON, rather than chloramine. Chloramination of the model compound l-asparagine after irradiation demonstrated that the decreased HAcAms could be attributed to the decrease in DON. After solar light irradiation, the brominated HAcAm FP in the presence of bromide was also reduced, while the bromine incorporation factor remained steady. Overall, this study revealed the contribution of natural processes in controlling HAcAm FP during subsequent chloramination, suggesting solar light irradiation is important to water purification during reclaimed water storage. PMID- 28719849 TI - Selective cathodic microbial biofilm retention allows a high current-to-sulfide efficiency in sulfate-reducing microbial electrolysis cells. AB - Selective microbial retention is of paramount importance for the long-term performance of cathodic sulfate reduction in microbial electrolysis cells (MECs) due to the slow growth rate of autotrophic sulfate-reducing bacteria. In this work, we investigate the biofilm retention and current-to-sulfide conversion efficiency using carbon granules (CG) or multi-wall carbon nanotubes deposited on reticulated vitreous carbon (MWCNT-RVC) as electrode materials. For ~2months, the MECs were operated at sulfate loading rates of 21 to 309gSO4 -S/m2/d. Although MWCNT-RVC achieved a current density of 57+/-11A/m2, greater than the 32+/-9A/m2 observed using CG, both materials exhibited similar sulfate reduction rates (SRR), with MWCNT-RVC reaching 104+/-16gSO4 -S/m2/d while 110+/-13gSO4 -S/m2/d were achieved with CG. Pyrosequencing analysis of the 16S rRNA at the end of experimentation revealed a core community dominated by Desulfovibrio (28%), Methanobacterium (19%) and Desulfomicrobium (14%), on the MWCNT-RVC electrodes. While a similar Desulfovibrio relative abundance of 29% was found in CG-biofilms, Desulfomicrobium was found to be significantly less abundant (4%) and Methanobacterium practically absent (0.2%) on CG electrodes. Surprisingly, our results show that CG can achieve higher current-to-sulfide efficiencies at lower power consumption than the nano-modified three-dimensional MWCNT-RVC. PMID- 28719850 TI - Tinzaparin in cancer associated thrombosis beyond 6months: TiCAT study. AB - INTRODUCTION: The safety and efficacy of low-molecular-weight heparin (LMWH) treatment in patients with cancer-associated thrombosis (CAT) beyond 6months are unknown. Our aim was to determine the safety of long-term tinzaparin use in patients with CAT. METHODS: We performed a prospective, open, single arm, multicentre study in patients with CAT receiving treatment with tinzaparin. We evaluated the rate of clinically relevant bleeding events (major and non-major clinically relevant bleeding) and venous thromboembolism (VTE) recurrence. RESULTS: A total of 247 patients were recruited, with a crude incidence of major bleeding of 4.9% (12/247). The rate of clinically relevant bleeding during months 1-6 and 7-12, was 0.9% [95% confidence interval (95% CI) 0.5 to 1.6%] and 0.6% (95% CI 0.2 to 1.4%) (p=0.5) per patient and month, respectively. Male gender showed greater risk for clinically relevant bleeding with a hazard ratio (HR) of 2.97 (95% CI 1.01 to 8.1; p=0.02). The incidence of VTE recurrence at months 1-6 and 7-12 was 4.5% (95% CI 2.2 to 7.8%) and 1.1% (95% CI 0.1 to 3.9%), respectively. One patient died due to VTE recurrence and two because of severe bleeding. CONCLUSIONS: Treatment with tinzaparin beyond 6months is safe in patients with CAT. PMID- 28719851 TI - Interaction of cholera toxin B subunit with T and B lymphocytes. AB - We have prepared 125I-labeled cholera toxin B subunit (125I-labeled CT-B, a specific activity of 98Ci/mmol) and found that its binding to T and B lymphocytes from the blood of healthy donors was high-affinity (Kd 2.8 and 3.0nM, respectively). The binding of labeled protein was completely inhibited by unlabeled thymosin-alpha1 (TM-alpha1), interferon-alpha2 (IFN-alpha2), and the synthetic peptide LKEKK that corresponds to residues 16-20 in TM-alpha1 and 131 135 in IFN-alpha2, but was not inhibited by the synthetic peptide KKEKL with inverted amino acid sequence (Ki>10MUM). Thus, TM-alpha1, IFN-alpha2, and the peptide: LKEKK bind with high affinity and specificity to CT-B receptor on donor blood T and B lymphocytes. It was found that CT-B and the peptide: LKEKK at concentrations of 10-1000nM increased in a dose-dependent manner the soluble guanylate cyclase activity in T and B lymphocytes. PMID- 28719852 TI - Rapid gamma spectrometric analysis of soil samples after radioactive fallout using a "conjugate view" technique. AB - A method for fast determination of the activity in soil samples by measuring a fresh soil core sample from both ends with an HPGe-detector is proposed. The method was tested by simulations, as well as by measurements on spiked soil samples. Both simulations and measurements showed that the geometrical mean of the count rates when the sample is measured twice, with the bottom and the top end, respectively, facing the detector closely resembles the count rate from a measurement on a homogenized sample. Therefore, an efficiency calibration for homogenized samples could be used even if the activity is highly inhomogeneous in the soil core, as is the case with fresh fallout. It was also shown that by studying the ratio between the two measurements, a rough estimation of the extent of penetration of the radionuclide in the soil can be found. This will enhance the possibility to make rapid estimations of the soil inventory by field gamma spectrometry. PMID- 28719853 TI - Determination of chemical forms of 14C in liquid discharges from nuclear power plants. AB - Developments of radioanalytical methods for determination of radiocarbon in wastewaters from nuclear power plants (NPP) with pressurized light water reactors, which would distinguish between the dissolved organic and inorganic forms have been carried out. After preliminary tests, the method was used to process pilot samples from wastewater outlets from the Temelin and Dukovany NPPs (Czech Republic). The results of analysis of pilot water samples collected in 2015 indicate that the instantaneous 14C releases into the water streams would be about 7.10-5 (Temelin) and 4.10-6 (Dukovany) of the total quantity of the 14C liberated into the environment. PMID- 28719854 TI - Clinically silent Alzheimer's and vascular pathologies influence brain networks supporting executive function in healthy older adults. AB - Aging is associated with declines in executive function. We examined how executive functional brain systems are influenced by clinically silent Alzheimer's disease (AD) pathology and cerebral white-matter hyperintensities (WMHs). Twenty-nine younger adults and 34 cognitively normal older adults completed a working memory paradigm while functional magnetic resonance imaging was performed. Older adults further underwent lumbar cerebrospinal fluid draw for the assessment of AD pathology and FLAIR imaging for the assessment of WMHs. Accurate working memory performance in both age groups was associated with high fronto-visual functional connectivity (fC). However, in older adults, higher expression of fronto-visual fC was linked with lower levels of clinically silent AD pathology. In addition, AD pathology and WMHs were each independently related to increased functional magnetic resonance imaging response in the left dorsolateral prefrontal cortex, a pattern associated with slower task performance. Our results suggest that clinically silent AD pathology is related to lower expression of a fronto-visual fC pattern supporting executive task performance. Further, our findings suggest that AD pathology and WMHs appear to be linked with ineffective increases in frontal response in CN older adults. PMID- 28719856 TI - Contribution of Kupffer cells to liposome accumulation in the liver. AB - The liver is a major barrier for site-specific delivery of systemically injected nanoparticles, as up to 90% of the dose is usually captured by this organ. Kupffer cells are thought to be the main cellular component responsible for nanoparticle accumulation in the liver. These resident macrophages form part of the mononuclear phagocyte system, which recognizes and engulfs foreign bodies in the circulatory system. In this study, we have compared two strategies for reducing nanoparticle accumulation in the liver, in order to investigate the specific contribution of Kupffer cells. Specifically, we have performed a comparison of the capability of pegylation and Kupffer cell depletion to reduce liposome accumulation in the liver. Pegylation reduces nanoparticle interactions with all types of cells and can serve as a control for elucidating the role of specific cell populations in liver accumulation. The results indicate that liposome pegylation is a more effective strategy for avoiding liver uptake compared to depletion of Kupffer cells, suggesting that nanoparticle interactions with other cells in the liver may also play a contributing role. This study highlights the need for a more complete understanding of factors that mediate nanoparticle accumulation in the liver and for the exploration of microenvironmental modulation strategies for reducing nanoparticle-cell interactions in this organ. PMID- 28719855 TI - High-fat diet and aging interact to produce neuroinflammation and impair hippocampal- and amygdalar-dependent memory. AB - More Americans are consuming diets higher in saturated fats and refined sugars than ever before, and based on increasing obesity rates, this is a growing trend among older adults as well. While high saturated fat diet (HFD) consumption has been shown to sensitize the inflammatory response to a subsequent immune challenge in young adult rats, the inflammatory effect of HFD in the already vulnerable aging brain has not yet been assessed. Here, we explored whether short term (3 days) consumption of HFD would serve as a neuroinflammatory trigger in aging animals, leading to cognitive deficits. HFD impaired long-term contextual (hippocampal dependent) and auditory-cued fear (amygdalar dependent) memory in aged, but not young adult rats. Short-term memory performance for both tasks was intact, suggesting that HFD impairs memory consolidation processes. Microglial markers of activation Iba1 and cd11b were only increased in the aged rats, while MHCII was further amplified by HFD. Furthermore, these HFD-induced long-term memory impairments were accompanied by IL-1beta protein increases in both the hippocampus and amygdala in aged rats. Central administration of IL-1RA in aged rats following conditioning mitigated both contextual and auditory-cued fear memory impairments caused by HFD, strongly suggesting that IL-1beta plays a critical role in these effects. Voluntary wheel running, known to have anti inflammatory effects in the hippocampus, rescued hippocampal-dependent but not amygdalar-dependent memory impairments caused by HFD. Together, these data suggest that short-term consumption of HFD can lead to memory deficits and significant brain inflammation in the aged animal, and strongly suggest that appropriate diet is crucial for cognitive health. PMID- 28719857 TI - In situ adjuvant therapy using a responsive doxorubicin-loaded fibrous scaffold after tumor resection. AB - As tumor microenvironment becoming more and more important in tumor study, the acid pH around or in solid tumors drew lots of attentions. And the progress of drug delivery systems made the responsive-release possible. This time, we fabricated a new-type composite electrospun poly (L-lactide) (PLLA) fibrous scaffolds, that blent with the mesoporous silica particles (MSNs). Further more, we used sodium bicarbonate (SB) as acid sensitive agent which was wrapped inside the MSNs. And doxorubicin (DOX) was also wrapped into MSNs in order to achieve a sustained release to inhibit tumors in mice, which mimicked the remnant breast cancer with surgery. In vitro experiments proved the characteristic of pH responsive release of the composite fibrous scaffold. In vivo results showed that these composite fibers could induce obvious apoptosis and necrosis over 10 weeks. Further, the cancer-kill effects were also confirmed by the decreased level of Bcl-2 and TNF-alpha, while increased Bax and caspase-3 expression levels. Altogether, the results indicated that the composite drug delivery system as a local implantable scaffold could effectively kill cancer cells in a long term with pH-sensitivity after the tumor resection. PMID- 28719858 TI - Interfacial analysis of siRNA complexes with poly-ethylenimine (PEI) or PAMAM dendrimers in gene delivery. AB - Solution and interfacial analysis has been employed to gain insight into the complexation of siRNA using either G4 PAMAM dendrimers or 25kDa branched poly ethylenimine (bPEI). The size, charge and shape/structure of the complexing agents were probed using atomic force microscopy (AFM), circular dichroism spectrometry (CD), dynamic light scattering (DLS), and gel electrophoresis (GE). The binding capability of these cationic polymers to the siRNA molecule, subsequently controls the surface/adsorption behaviour of the complexes to a negatively charged surface. G4 PAMAM dendrimers bind to the major groove of the siRNA structure, while bPEI binds to both major and minor groove. PAMAM-siRNA complexes form a thin uniform surface film with adsorption of monomeric particles, whilst bPEI-siRNA complexes adsorb as particles in random orientations at low bPEI concentration and form network structures across the surface at high charge ratio. This is due to their ability to bind to both regions within siRNA. This new understanding of the interfacial behaviour of siRNA complexes correlates with observations of cellular transfection and can be used in the design of optimal transfection agents. PMID- 28719859 TI - "Curcumin-loaded Poly (d, l-lactide-co-glycolide) nanovesicles induce antinociceptive effects and reduce pronociceptive cytokine and BDNF release in spinal cord after acute administration in mice". AB - Given the poor bioavailability of curcumin, its antinociceptive effects are produced after chronic intravenous administration of high doses, while poly (d,l lactide-co-glycolide)-loaded vesicles (PLGA) can improve drug delivery. This paper investigates the antinociceptive effects of curcumin-loaded PLGA nanovesicles (PLGA-CUR) administered via intravenous (i.v.) or intrathecal (i.t.) routes at low and high doses. The following models of pain were used: formalin test, zymosan-induced hyperalgesia and sciatic nerve ligation inducing neuropathic allodynia and hyperalgesia. PLGA-CUR administered intravenously was able to reduce the response to nociceptive stimuli in the formalin test and hyperalgesia induced by zymosan. Curcumin, instead, was inactive. Low-dose i.t. administration of PLGA-CUR significantly reduced allodynia produced by sciatic nerve ligation, whereas low doses of curcumin did not change the response to nociceptive stimuli. Long-lasting antinociceptive effects were observed when high doses of PLGA-CUR were administered intrathecally. At high doses, i.t. administration of curcumin only exerted rapid and transient antinociceptive effects. Measurement of cytokine and BDNF in the spinal cord of neuropathic mice demonstrate that the antinociceptive effects of PLGA-CUR depend on the reduction in cytokine release and BDNF in the spinal cord. The results demonstrate the effectiveness of PLGA-CUR and suggest that PLGA-CUR nanoformulation might be a new potential drug in the treatment of pain. PMID- 28719860 TI - Liposome-modified titanium surface: A strategy to locally deliver bioactive molecules. AB - Titanium and its alloys are widely employed materials for implants in orthopedic or dental surgery due to their mechanical properties, resistance to corrosion and osseointegration capability. However adverse reactions at the tissue/implant interface may occur, which limit the success of the osseointegration process. Therefore, different strategies have to be used to overcome these drawbacks. In this work, we developed two different liposome-based coatings on titanium surfaces as drug or bioactive molecule deposits for dental/orthopedic implant applications. The first one is a supported vesicular layer (SVL), obtained by liposome adhesion on passivated Ti surface, the second one is a covalently bonded vesicular layer (CBVL) grafted on properly functionalized Ti. Photoluminescence spectroscopy and atomic force microscopy investigations demonstrated the effective anchoring of intact liposomes in both systems. Cytotoxicity assays, performed after 48h, showed a MG63 cell viability higher than 75% and 70% on SVLs and CBVLs, respectively. Scanning electron microscopy investigation revealed numerous and spread MG63 cells after 48h on SVL modified Ti surface and a lower cell adhesion on samples coated with CBVL. The cellular uptake capability of liposome content was proved by fluorescence microscopy using carboxyfluorescein loaded SVLs and CBVLs. Finally, we demonstrated that these liposome-modified Ti surfaces were able to deliver a model bioactive molecule (phosphatidylserine) to adherent cells, confirming the potentiality of developed systems in bone related prosthetic applications. PMID- 28719861 TI - Stabilized cationic dipeptide capped gold/silver nanohybrids: Towards enhanced antibacterial and antifungal efficacy. AB - The nanoparticles of silver/gold and cationic peptides have been recognized as potent antimicrobials for long, but their combined effect has so far not been explored. The present study reports the green synthesis of short cationic dipeptide stabilized AuNPs/AgNPs based nanohybrid materials. It thoroughly investigates the effect of conjugation of short cationic peptides on the antimicrobial properties of metallic nanoparticles. In the context of the antimicrobial evaluation of synthesized nanoconjugates, it was observed that peptide capped AgNPs exhibited higher antimicrobial activity as compared to peptide capped AuNPs as well as native peptides and unconjugated metallic nanoparticles. Specifically, l-His-l-Arg-OMe capped AgNPs exhibited MIC of 0.50, 0.37 and 0.25MUM against E.coli, S. aureus and S. typhimurium respectively and MIC of 0.80 and 10.00MUM against C. albicans and C. glabrata respectively. These results indicate that synthetic dipeptides render AgNPs as better antimicrobial agents in comparison to the native AgNPs and positively charged dipeptides. In addition, the time kill profile of cationic peptide (l-His-l-Arg-OMe) capped AgNPs was found to be even better than the known antibiotics. The cytotoxic behavior of all synthesized nanoconjugates of cationic peptides was studied and was found to be within acceptable limits. The present study opens a completely new class of antimicrobials for combating a wide range of bacterial and fungal pathogens. Another interesting and crucial finding was that dipeptide capped AgNPs displayed maximum antimicrobial activity with observed approximate 2-10 fold reduction in nano formulation dosage against tested microbes. PMID- 28719862 TI - Green biosynthesis of silver nanoparticles using leaves extract of Artemisia vulgaris and their potential biomedical applications. AB - Biosynthesis of nanoparticles from plant extracts is receiving enormous interest due to their abundant availability and a broad spectrum of bioactive reducing metabolites. In this study, the reducing potential of Artemisia vulgaris leaves extract (AVLE) was investigated for synthesizing silver nanoparticles without the addition of any external reducing or capping agent. The appearance of blackish brown color evidenced the complete synthesis of nanoparticles. The synthesized silver nanoparticles were characterized by UV-vis spectroscopy, scanning electron microscope (SEM), energy dispersive X-ray spectroscopy (EDX), transmission electron microscope (TEM), atomic force microscopy (AFM) and Fourier transforms infrared spectroscopy (FT-IR) analysis. UV-vis absorption profile of the bio reduced sample elucidated the main peak around 420nm, which correspond to the surface plasmon resonance of silver nanoparticles. SEM and AFM analyses confirmed the morphology of the synthesized nanoparticles. Similarly, particles with a distinctive peak of silver were examined with EDX. The average diameter of silver nanoparticles was about 25nm from Transmission Electron Microscopy (TEM). FTIR spectroscopy scrutinized the involvement of various functional groups during nanoparticle synthesis. The green synthesized nanoparticles presented effective antibacterial activity against pathogenic bacteria than AVLE alone. In-vitro antioxidant assays revealed that silver nanoparticles (AV-AgNPs) exhibited promising antioxidant properties. The nanoparticles also displayed a potent cytotoxic effect against HeLa and MCF-7 cell lines. In conclusion, the results supported the advantages of employing a bio-green approach for developing silver nanoparticles with antimicrobial, antioxidant, and antiproliferative activities in a simple and cost- competitive manner. PMID- 28719863 TI - Evaluation of platelet adhesion and activation on polymers: Round-robin study to assess inter-center variability. AB - The regulatory agencies provide recommendations rather than protocols or standard operation procedures for the hemocompatibility evaluation of novel materials e.g. for cardiovascular applications. Thus, there is a lack of specifications with regard to test setups and procedures. As a consequence, laboratories worldwide perform in vitro assays under substantially different test conditions, so that inter-laboratory and inter-study comparisons are impossible. Here, we report about a prospective, randomized and double-blind multicenter trial which demonstrates that standardization of in vitro test protocols allows a reproducible assessment of platelet adhesion and activation from fresh human platelet rich plasma as possible indicators of the thrombogenicity of cardiovascular implants. Standardization of the reported static in vitro setup resulted in a laboratory independent scoring of the following materials: poly(dimethyl siloxane) (PDMS), poly(ethylene terephthalate) (PET) and poly(tetrafluoro ethylene) (PTFE). The results of this in vitro study provide evidence that inter-laboratory and inter-study comparisons can be achieved for the evaluation of the adhesion and activation of platelets on blood-contacting biomaterials by stringent standardization of test protocols. PMID- 28719864 TI - In vivo magnetic resonance imaging of pancreatic tumors using iron oxide nanoworms targeted with PTR86 peptide. AB - To cut the high mortality rate of malignant disease such as pancreatic cancer, development of newly diagnostic probes for early stage detection of tumor lesions is required. Multimodal imaging nanoprobes allowing targeted and real time functional/anatomical imaging of tumors meet the demands. For this purpose, a MRI/optical dual-modality probe based on biodegradable magnetic iron oxide nanoworms has been developed. The cross-linked surface of nanoworms were anchored to fluorescent dyes and to FITC.PTR86; a novel synthetic peptide with high affinity towards somatostatin receptors. Combination of various in vitro techniques including Prussian blue staining, fluorescent microscopy and fluorescence activated cell sorting (FACS) have been performed to explore the interaction of developed nanoprobe with pancreatic tumor cell lines. Together with in vivo studies in a xenograft mouse model of human pancreatic adenocarcinoma and ex vivo investigations, the results show the efficient imaging and targeting of pancreatic tumors by our newly developed nanosystem using both MRI and optical imaging modalities. PMID- 28719865 TI - Antioxidant effect of exercise: Exploring the role of the mitochondrial complex I superassembly. AB - Mitochondrial respiratory complexes become assembled into supercomplexes (SC) under physiological conditions. One of the functional roles of these entities is the limitation of reactive oxygen species (ROS) produced by complex I (CI) of the respiratory chain. We sought to determine whether the systemic antioxidant effect of exercise is mediated by the assembly of mitochondrial CIs into SCs in rats. Male Wistar rats were exercise trained or remained sedentary for ten weeks; then, blood samples were collected, and the gastrocnemius muscle was isolated. The assembly of mitochondrial SCs and the lipid peroxidation of the mitochondrial and plasmatic fractions were assessed. Our results demonstrate that exercise induced the assembly of CI into SCs in the gastrocnemius and induced a systemic decrease in lipid peroxidation. We also found an inverse association between the superassembly of CIs and mitochondrial lipid peroxidation (p < 0.01) and protein carbonyls (p < 0.05). We conclude that exercise induces the chronic assembly of CIs into SCs, which provide mitochondrial protection against oxidative damage, at least in the studied muscle. Given the relevant role that mitochondria play in health and disease, these findings should help to elucidate the role of exercise as a therapeutic approach for metabolic diseases. PMID- 28719866 TI - Cell competition in mammals - novel homeostatic machinery for embryonic development and cancer prevention. AB - In the multi-cellular community, cells with different properties often compete with each other for survival and space. This process is named cell competition and was originally discovered in Drosophila. Recent studies have revealed that comparable phenomena also occur in mammals under various physiological and pathological conditions. Within the epithelium, normal cells often recognize the presence of the neighboring transformed cells and actively eliminate them from the epithelium; a process termed EDAC (Epithelial Defense Against Cancer). Furthermore, physical force can play a crucial role in the intercellular recognition and elimination of loser cells during cell competition. Further studies are expected to reveal a variety of roles of cell competition in embryonic development and human diseases. PMID- 28719867 TI - Tissue homeostasis and aging: new insight from the fly intestine. AB - Adult somatic stem cells facilitate tissue homeostasis throughout the life of the organism. The mechanisms controlling stem cell activity are under intense scrutiny, with the aims of elucidating how they mediate tissue homeostasis, contribute to age-related decline of adult tissues, and promote tumorigenesis. Recently, the use of model systems such as the Drosophila intestine has enriched our understanding of how stem cells integrate local and systemic signals to maintain tissue and organs function in physiological conditions of homeostasis or after damage. Here we highlight recent advances made in this model allowing a better understanding of stem cell lineage decisions, their regulation by epithelial and intra-organ cues, and their altered activity during aging. PMID- 28719868 TI - Quantitative meta-analytic approaches for the systematic synthesis of data and hazard identification: A case study of decreased pain sensitivity due to trimethylbenzene exposure. AB - Traditionally, human health risk assessments have relied on qualitative approaches for hazard identification, which involves weight of evidence determinations that integrate evidence across multiple studies. Recently, the National Research Council has recommended the development of quantitative approaches for evidence integration, including the application of meta-analyses, to help summarize and evaluate the results of a systematic review. In the meta analytic approach, a pooled effect size is calculated after consideration of multiple potential confounding factors in order to determine whether the entire database under consideration indicates a chemical is a hazard. The following case study applies qualitative and quantitative approaches to determine whether trimethylbenzene (TMB) isomers represent a neurotoxic hazard, specifically focusing on pain sensitivity. Following a thorough literature search, the only pain sensitivity studies available for TMBs initially seem discordant in their results: effects on pain sensitivity are seen immediately after termination of exposure, appear to resolve 24h after exposure, and then reappear 50 days later following foot-shock. Qualitative consideration of toxicological and toxicokinetic characteristics of the TMB isomers suggests that the observed differences between studies are likely due to testing time and the application of external stressors. Meta-analyses and -regressions support this conclusion: when all studies are included and possible confounders (isomer, testing time, laboratory, etc.) are accounted for, the pooled effect sizes are statistically significant, thus supporting that TMBs are a possible neurotoxic hazard to human health. Ultimately, this case study demonstrates how qualitative and quantitative methods can be combined to provide a robust hazard identification analysis by incorporating more of the available information. PMID- 28719869 TI - Effectiveness of table top water pitcher filters to remove arsenic from drinking water. AB - Arsenic contamination of drinking water is a serious threat to the health of hundreds of millions of people worldwide. In the United States ~3 million individuals drink well water that contains arsenic levels above the Environmental Protection Agency (EPA) maximum contaminant level (MCL) of 10MUg/L. Several technologies are available to remove arsenic from well water including anion exchange, adsorptive media and reverse osmosis. In addition, bottled water is an alternative to drinking well water contaminated with arsenic. However, there are several drawbacks associated with these approaches including relatively high cost and, in the case of bottled water, the generation of plastic waste. In this study, we tested the ability of five tabletop water pitcher filters to remove arsenic from drinking water. We report that only one tabletop water pitcher filter tested, ZeroWater(r), reduced the arsenic concentration, both As3+ and As5+, from 1000MUg/L to < 3MUg/L, well below the MCL. Moreover, the amount of total dissolved solids or competing ions did not affect the ability of the ZeroWater(r) filter to remove arsenic below the MCL. Thus, the ZeroWater(r) pitcher filter is a cost effective and short-term solution to remove arsenic from drinking water and its use reduces plastic waste associated with bottled water. PMID- 28719870 TI - Effects of endocrine disrupting chemicals on estrogen receptor alpha and heat shock protein 60 gene expression in primary cultures of loggerhead sea turtle (Caretta caretta) erythrocytes. AB - The loggerhead turtle (Caretta caretta) can be considered a good indicator species for studying the ecological impact of endocrine disrupting chemicals (EDCs) on wildlife. However, the effect of these environmental pollutants on nuclear steroid hormone signaling has not yet been addressed in sea turtles mainly due to the legal constraints of their endangered status. Here we describe the use of primary erythrocyte cell cultures as in vitro models for evaluating the effects of different EDCs on the expression of estrogen receptor alpha (ERalpha). In addition, we evaluated erythrocyte toxicity caused by EDCs using Alamar Blue assay and heat shock proteins 60 (HSP60) expression. Primary cultures of erythrocytes were exposed to increasing concentrations of 4-nonylphenol (4NP), Diisodecyl phthalate (DiDP), Tri-m-cresyl phosphate (TMCP) and Tributyltin (TBT) for 48h. Alamar Blue demonstrated that exposure of erythrocytes to each contaminant for up to 48h led to a significant impairment of cellular metabolic activity at 100MUM, with the exception of TBT. Moreover, our data indicate that loggerhead erythrocytes constitutively express ERalpha and HSP60 at the transcript level and respond to EDCs by up-regulating their expression. In this regard, ERalpha was up-regulated in a dose-dependent manner after 48h exposure to both 4NP and TMCP. Interestingly, the dosage-dependent effects of DiDP on ERalpha expression were opposite in comparison to that obtained following exposure to the other tested compounds. This work provides the first indication regarding the potential of primary erythrocytes as study models for evaluating the effects of EDCs on sea turtles. PMID- 28719871 TI - Optic neuritis in pregnancy after Tdap vaccination: Report of two cases. AB - Two pregnant women developed one-eye blurring vision within three weeks after Tdap vaccination. Neurophtalmologic and MR examination confirmed an unilateral optic neuritis without evidence of underlying disease. Both patients had a full recovery, one after intravenous metilprednisolone. This is the first report of optic neuritis related with Tdap vaccination in pregnancy. PMID- 28719872 TI - Health-related quality of life in patients undergoing lumbar total disc replacement: A comparison with the general population. AB - OBJECTIVES: In up to half of the cases, low back pain (LBP) is thought to be related to a degeneration of the lumbar disc. Lumbar total disc replacement (LTDR) emerged as an alternative to fusion, but its use and indications are still subject to debate. The purpose of this paper was to compare Health-related Quality of life (HRQOL) in patients undergoing LTDR for one or two-level degenerative disc disease (DDD) with the paired age and gender general population values and to assess functional disability and residual pain at one year after the surgical procedure. MATERIAL AND METHODS: A series of 51 patients operated on for a one or two level DDD, were evaluated at one year after the surgical procedure. HRQOL was compared to that of paired age and gender general population using the EQ-5D-5L questionnaire. Disability, back (BP) and leg pain (LP) were compared to the preoperative values. RESULTS: ODI showed a mean improvement of 31.78 (p<0.001, 95% CI 27.39-36.17), BP-VAS of 5.29/10 (95% CI 4.56-6.02), LP-VAS of 4.03/10 (95% CI 3.15-4.92) at one year compared to the preoperative assessment. HRQOL had similar values to the general population in 32 patients and inferior in 19 patients. "Pain" was the HRQOL dimension in which most of the patients had inferior results compared to data from the general population. Patients with previous spinal surgery had lower improvements in HRQOL index, disability, and pain than those without previous surgery. CONCLUSIONS: We found that the majority of patients improved their HQOL to values similar to those of the general population. Disability and pain are significantly reduced compared to preoperative evaluations. Larger scale studies are needed to identify the best candidates for LTDR. PMID- 28719873 TI - Characteristics of electron transport chain and affecting factors for thiosulfate driven perchlorate reduction. AB - The mechanism for perchlorate reduction was investigated using thiosulfate-driven (T-driven) perchlorate reduction bacteria. The influences of various environmental conditions on perchlorate reduction, including pH, temperature and electron acceptors were examined. The maximum perchlorate removal rate was observed at pH 7.5 and 40 degrees C. Perchlorate reduction was delayed due to the coexistence of perchlorate-chlorate and perchlorate-nitrate. The mechanism of the T-driven perchlorate reduction electron transport chain (ETC) was also investigated by utilizing different inhibitors. The results were as follows: firstly, the NADH dehydrogenase was not involved in the ETC; secondly, the FAD dehydrogenase and quinone loop participated in the ETC; and thirdly, cytochrome oxidase was the main pathway in the ETC. Meanwhile, microbial consortium structure analysis indicated that Sulfurovum which can oxidize sulfur compounds coupled to the reduction of nitrate or perchlorate was the primary bacterium in the T-driven and sulfur-driven consortium. This study generates a better understanding of the mechanism of T-driven perchlorate reduction. PMID- 28719874 TI - Combined effects of temperature and clomazone (Gamit(r)) on oxidative stress responses and B-esterase activity of Physalaemus nattereri (Leiuperidae) and Rhinella schneideri (Bufonidae) tadpoles. AB - Temperature is an important factor influencing the toxicity of chemicals in aquatic environments. Neotropical tadpoles experience large temperature fluctuations in their habitats and many species are distributed in areas impacted by agriculture. This study evaluated the effects caused by the exposure to clomazone (Gamit(r)) at different temperatures (28, 32 and 36 degrees C) on biochemical stress responses and esterase activities in Physalaemus nattereri and Rhinella schneideri tadpoles. Results evidenced that temperature modulates the effects of clomazone on biochemical response of tadpoles. Antioxidant enzymes, including catalase, superoxide dismutase (SOD), and glucose-6-phosphate dehydrogenase had their activities increased by clomazone in P. nattereri treated at higher temperatures. The biotransformation enzyme glutathione-S-transferase (GST) was also induced by clomazone at 32 and 36 degrees C. In R. schneideri, clomazone failed to alter antioxidant enzymes at 28 degrees C, but SOD and GST were increased by clomazone at higher temperatures after three days. All enzymes had their activities returned to the control levels after eight days in R. schneideri. Lipid peroxidation was induced in both species exposed to clomazone at 32 and 36 degrees C, but not at 28 degrees C. Acetylcholinesterase was not sensitive to clomazone and temperature, while most treatments impaired carboxylesterase activity. Integrated biomarker response (IBR) was notably induced by temperature in both species, and a synergic effect of temperature and clomazone was mostly observed after three days of exposure. These findings imply that tadpoles from tropical areas may present differential responses in their physiological mechanism linked to antioxidant defense to deal with temperature fluctuations and agrochemicals presence in their habitats. PMID- 28719875 TI - Novel magnetic carboxyl modified hypercrosslinked resins for effective removal of typical PPCPs. AB - A series of novel magnetic carboxyl modified hypercrosslinked resins were successfully prepared via a sequence of suspension polymerization, hydrolysis and post-crosslinking reactions. The serial resins possessed both high cation exchange capacity and high specific surface area with MA-10 having the supreme specific surface area of 1238.65 m2/g and MA-70 having the largest exchange capacity of 6.45 mmol/g. The serial resins exhibited excellent adsorption capacity of typical PPCPs including chloramphenicol, atenolol, ibuprofen and tetracycline, which were neutral, cationic, anionic and zwitterionic respectively in natural water. The adsorption of chloramphenicol and ibuprofen was dominated by the hydrophobic and pi-pi Electron-Donor-Acceptor (EDA) interactions, while as to atenolol, the electrostatic interaction dominated the adsorption process. Especially, MA-50 was found to have the largest adsorption amount and the longest equilibrium time of zwitterionic tetracycline compared with other resins, the mechanism of which needed further investigation. Breakthrough tests showed that the serial resins had significant advantages over granular activated carbon F400D in contaminants removal for all of the four target pharmaceuticals. Batch experiments proved that the serial resins possessed strong anti-pollution ability and excellent regeneration property, which made it possible for the practical application in future water treatment. PMID- 28719876 TI - Photoelectrocatalytic degradation of methylene blue using F doped TiO2 photoelectrode under visible light irradiation. AB - Photoelectrocatalysis (PEC) has attracted great interest due to cost effectiveness and high efficiency in water treatment. In this study, F doped TiO2 (F-TiO2) photoelectrodes with honeycomb like morphology were prepared, and the PEC performance was investigated. F-TiO2 particles that showed enhanced absorption of visible light were synthesized via a sol-gel method. F-TiO2 particles were anchored onto the surface of F-doped SnO2 glass by a screen printing method to prepare the F-TiO2 photoelectrodes. The PEC performance of the F-TiO2 photoelectrodes was investigated via the degradation of methylene blue (MB) under visible light irradiation. The results show that the F-TiO2 photoelectrodes exhibited an excellent PEC performance that was affected by the F doping content, applied bias and solution pH. A maximum decolorization percentage of 97.8% was achieved by the FT-15 photoelectrode, with a 1.4 V bias at pH 9.94 after 4.0 h of visible light irradiation. The high PEC performance of the F-TiO2 photoelectrodes is mainly ascribed to the efficient separation of electron-hole (e--h+) pairs and the creation of active radicals such as hydroxyl radicals (OH). The PEC decolorization kinetic data were analyzed using the first-order kinetic model and the Langmuir-Hinshelwood (L-H) model. The data indicates that the PEC degradation of MB molecules mainly occurred on the surface of the F-TiO2 photoelectrodes, and the MB molecules were discolored mainly by h+ (41.5%) and OH (46.5%). In addition, 8.2% of the MB molecules were discolored by other oxidative species, and 3.8% of the MB molecules were discolored by self-sensitized oxidation. PMID- 28719877 TI - Functional genomic assessment of 2, 2-bis (bromomethyl)-1, 3-propanediol induced cytotoxicity in a single-gene knockout library of E. coli. AB - Functional gene fingerprinting of chemicals could be used to understand the direct gene-chemical interaction in the process of toxification from a genome wide scale. 2, 2-bis (bromomethyl)-1, 3-propanediol (BMP) is a brominated flame retardant with widespread production but with very limited toxicological data. Here the cytotoxicity of BMP was assessed by Escherichia coli (E. coli) functional genome-wide knockout mutants screening and the underlying molecular mechanism was investigated. The median inhibition concentration (IC50) of BMP was 1.608 +/- 0.078 mg/ml after 24 h exposure. 119 initial, including 66 sensitive and 53 resistant single gene mutants, were identified by a full library screening of BMP at the concentration of IC50. The resistant genes were significantly enriched in nucleobase-containing compound biosynthetic process (GO: 0034654) by gene ontology (GO) biological process analyses, which suggested that the pathway of DNA repair is a critical cellular process in the survival of cells exposed to BMP. Meanwhile, function annotation of all BMP responsive genes suggested the mechanism of BMP was associated with DNA damage, oxidative stress and cellular transmembrane transport process. Many genes were exclusively responsive to BMP comparing with other chemicals that has been assessed by E. coli mutant screening approach, which indicated that BMP has a distinct mode of toxic action. Overall, the functional genomic screening approach presented here provides a great tool to assess the cellular toxicological mechanism of environmental chemicals. PMID- 28719878 TI - The effects of fluoride on neuronal function occurs via cytoskeleton damage and decreased signal transmission. AB - It has been reported that fluoride exposure may cause serious public health problems, particularly neurotoxicity. However, the underlying mechanisms remain unclear. This study used Neuro-2A cells to investigate the effects of fluoride on the cytoskeleton. The Neuro-2A cells were exposed to 0, 1, 2, 4 and 6 mM sodium fluoride (NaF) for 24 h. Cell viability and lactate dehydrogenase (LDH) release were examined. It was observed that exposure to NaF reduced cell viability, disrupted cellular membrane integrity, and high levels of LDH were released. The observed changes occurred in a dose response manner. Morphologic observations showed that cell became rounded and were loosely adherent following exposure to NaF. Axon spines and normal features disappeared with high dose NaF treatment. The expression of MAP2 and synaptophysin decreased, particularly at 4 mM and 6 mM (P < 0.05) for MAP2. These results corroborate the morphologic observations. The content of glutamate and NMDAR (glutamate receptor) protein were assessed to help understand the relationship between synapses and neurotransmitter release using ELISA and Western-blot. Compared with the control, glutamate and NMDAR expression declined significantly at 4 mM and 6 mM (P < 0.05) group. Finally, the ultrastructural changes observed with increasing doses of NaF were: disappearance of synapses, mitochondrial agglutination, vacuole formation, and cellular edema. Taken together, NaF exposure disrupted cellular integrity and suppressed the release of neurotransmitters, thus effecting neuronal function. These findings provide deeper insights into roles of NaF in neuron damage, which could contribute to a better understanding of fluoride-induced neurotoxicity. PMID- 28719879 TI - Four types of attenuation of phenol and cresols in microcosms under simulated marine conditions: A kinetic study. AB - Phenol, o-cresol, m-cresol, and p-cresol were selected to conduct microcosm experiments to examine their attenuation under simulated marine conditions, aiming at estimating natural attenuation and the contribution of oxidation, photolysis, biodegradation, and volatilisation to total attenuation of phenol and three cresols in the marine environment. The development of attenuation in microcosms showed the relevance of the pseudo-first-order kinetic for all phenols. The half-lives of phenol, o-cresol, m-cresol, and p-cresol attenuation under optimal conditions were 7.9, 4.3, 5.3, and 4.4 d, respectively. Attenuation kinetics was proposed to analyse the natural attenuation of phenol and cresols. The leading attenuation type of phenol, o-cresol, and p-cresol was volatilisation, and the attenuation rate constants (Kv) were 0.0356, 0.0687, and 0.0710 d-1. Photolysis (Kp: 0.0584 d-1) was the major attenuation type for m cresol. Biodegradation of phenol (Kb: 0.0021 d-1) and m-cresol (Kb: 0.0049 d-1) were extremely inhibited. The rank between the contributions of the four types of attenuation to total attenuation differed between phenol and the three cresols. The attenuation kinetics proposed in this study possibly demonstrated the attenuation of the phenol and cresols in microcosm. This new reaction kinetics can be used in the analysis of natural attenuation of chemical substances. PMID- 28719880 TI - A scheme to scientifically and accurately assess cadmium pollution of river sediments, through consideration of bioavailability when assessing ecological risk. AB - Evaluating heavy metal pollution status and ecological risk in river sediments is a complex task, requiring consideration of contaminant pollution levels, as well as effects of biological processes within the river system. There are currently no simple or low-cost approaches to heavy metal assessment in river sediments. Here, we introduce a system of assessment for pollution status of heavy metals in river sediments, using measurements of Cd in the Shaocun River sediments as a case study. This system can be used to identify high-risk zones of the river that should be given more attention. First, we evaluated the pollution status of Cd in the river sediments based on their total Cd content, and calculated a risk assessment, using local geochemical background values at various sites along the river. Using both acetic acid and ethylenediaminetetraacetic acid to extracted the fractions of Cd in sediments, and used DGT to evaluate the bioavailability of Cd. Thus, DGT provided a measure of potentially bioavailable concentrations of Cd concentrations in the sediments. Last, we measured Cd contents in plant tissue collected at the same site to compare with our other measures. A Pearson's correlation analysis showed that Cd-Plant correlated significantly with Cd-HAc, (r = 0.788, P < 0.01), Cd-EDTA (r = 0.925, P < 0.01), Cd-DGT (r = 0.976, P < 0.01), and Cd-Total (r = 0.635, P < 0.05). We demonstrate that this system of assessment is a useful means of assessing heavy metal pollution status and ecological risk in river sediments. PMID- 28719881 TI - Perfluoroalkyl acids in surface waters and tapwater in the Qiantang River watershed-Influences from paper, textile, and leather industries. AB - Perfluoroalkyl acids (PFAAs) are widely used as multi-purpose surfactants or water/oil repellents. In order to understand the contamination level and compositional profiles of PFAAs in aqueous environment in textile, leather, and paper making industrial areas, surface waters and tap waters were collected along the watershed of the Qiantang River where China's largest textile, leather, and paper making industrial bases are located. For comparison, surface water and tapwater samples were also collected in Hangzhou and its adjacent areas. 17 PFAAs were analyzed by solid phase extraction-high performance liquid chromatography tandem mass spectrometry. The results show that the total concentrations of PFAAs (SigmaPFAAs) in the Qiantang River waters ranged from 106.1 to 322.9 ng/L, averaging 164.2 ng/L. The contamination levels have been found to be extremely high, comparable to the levels of the most serious PFAA contamination in surface waters of China. The PFAA composition profiles were characterized by the dominant PFOA (average 58.1% of the total PFAAs), and PFHxA (average 18.8%). The SigmaPFAAs in tap water ranged from 9.5 to 174.8 ng/L, showing PFAA compositional pattern similar to the surface waters. Good correlations between PFAA composition profiles in tap waters and the surface waters were observed. PMID- 28719882 TI - Antileishmanial activity and tubulin polymerization inhibition of podophyllotoxin derivatives on Leishmania infantum. AB - Leishmania microtubules play an important role not only in cell division, but also in keeping the shape of the parasite and motility of its free-living stages. Microtubules result from the self-assembly of alpha and beta tubulins, two phylogenetically conserved and very abundant eukaryotic proteins in kinetoplastids. The colchicine binding domain has inspired the discovery and development of several drugs currently in clinical use against parasites. However, this domain is less conserved in kinetoplastids and may be selectively targeted by new compounds. This report shows the antileishmanial effect of several series of compounds (53), derived from podophyllotoxin (a natural cyclolignan isolated from rhizomes of Podophyllum spp.) and podophyllic aldehyde, on a transgenic, fluorescence-emitting strain of Leishmania infantum. These compounds were tested on both promastigotes and amastigote-infected mouse splenocytes, and in mammalian - mouse non-infected splenocytes and liver HepG2 cells - in order to determine selective indexes of the drugs. Results obtained with podophyllotoxin derivatives showed that the hydroxyl group at position C 7alpha was a structural requisite to kill the parasites. On regards podophyllic aldehyde, derivatives with C9-aldehyde group integrated into a bicyclic heterostructure displayed more potent antileishmanial effects and were relatively safe for host cells. Docking studies of podophyllotoxin and podophyllic aldehyde derivatives showed that these compounds share a similar pattern of interaction at the colchicine site of Leishmania tubulin, thus pointing to a common mechanism of action. However, the results obtained suggested that despite tubulin is a remarkable target against leishmaniasis, there is a poor correlation between inhibition of tubulin polymerization and antileishmanial effect of many of the compounds tested, fact that points to alternative pathways to kill the parasites. PMID- 28719883 TI - Sublethal insecticide exposure affects reproduction, chemical phenotype as well as offspring development and antennae symmetry of a leaf beetle. AB - The area of agriculturally used land and following to that the use of pesticides are steadily increasing. Insecticides do not only reduce pest organisms on crops but can also affect non-target organisms when present in sublethal concentrations in the environment. We investigated the effects of an exposure to sublethal pyrethroid (lambda-cyhalothrin) concentrations, at doses 20 and 60 times lower than the LC50, respectively, on reproductive traits and adult cuticular hydrocarbon (CHC) profiles of a leaf beetle (Phaedon cochleariae Fabricius). Furthermore, we tested for effects on growth and antennae symmetry of the offspring generation that was not exposed to the insecticide. Sublethal insecticide concentrations decreased the egg number produced by the adults and the hatching rate. Moreover, the chemical phenotype (CHC profile) of adults was altered in dependence of the insecticide treatment, with sex-specific effects. In the unexposed offspring of insecticide-exposed parents, a prolonged development time and a fluctuating asymmetry of the females' antennae were detected, revealing transgenerational effects. The insecticide effects on the CHC profiles of the parental generation might have been caused by changes in CHC precursors, which were potentially induced by the insecticide treatment of the insect diet. Such altered CHC pattern may have implications for intraspecific communication, e.g., in mate choice, as well as in an interspecific way, e.g., in interactions with other arthropod species. The observed detrimental transgenerational effects might be explainable by a reduced investment in the offspring, maternal transfer or epigenetic processes. An asymmetry of the antennae may lead to defects in the reception of chemical signals. In conclusion, the results disclose that, besides detrimental (transgenerational) effects on reproduction and development, an exposure to sublethal insecticide concentrations can impair the chemical communication between individuals, with impacts on the sender (i.e., the CHC profile) and the receiver (i.e., caused by asymmetry of the antennae). PMID- 28719884 TI - Increases from 2002 to 2015 in prescription opioid overdose deaths in combination with other substances. AB - BACKGROUND: Prescription opioid (PO) overdose deaths increased sharply over the last decade. Changes in PO deaths in combination with other psychoactive substances may provide a partial explanation. METHODS: PO deaths from the National Multiple-Cause-of-Death Files for 2002-03 (N=15,973) and 2014-15 (N=41,491) were analyzed. We calculated (1) changes in proportions of deaths in combination with benzodiazepines, antidepressants, heroin, alcohol, cocaine between the two periods, and (2) proportions of increase in deaths attributable to each substance among PO and synthetic opioids other than methadone (SO-M) deaths, by age, gender, race/ethnicity. RESULTS: Between 2002-03 and 2014-15, PO deaths increased 2.6 times; SO-M deaths 5.6 times, especially for ages 18-34, males, African-Americans. For PO deaths, most frequent combinations at both periods were with benzodiazepines; for SO-M, benzodiazepines, antidepressants in 2002-03, heroin, benzodiazepines in 2014-15. The largest increases occurred in combination with heroin among all PO (4.6% to 15.4%, change ratio=3.3[95%CI=3.1 3.6]), but especially SO-M deaths (1.2% to 24.5%, change ratio=21.3[95%CI=15.0 30.3]). Deaths involving cocaine decreased among PO, increased among SO-M deaths. One-fifth of increased PO or SO-M deaths were attributable to any of the five substances. Increased PO deaths were equally attributable to benzodiazepines and heroin; deaths attributable to heroin were higher among ages 18-49, males, and non-Hispanic whites. Increased SO-M deaths were attributable mostly to heroin among all groups. CONCLUSIONS: Increased PO overdose deaths over the last decade may be partially explained by increased deaths in combination with other psychoactive substances. Use of other substances should be considered in efforts toward reducing prescription opioid overdoses. PMID- 28719887 TI - Anesthetic management of Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy (CRS/HIPEC): The importance of hydro-electrolytic and acid-basic control. AB - JUSTIFICATION AND OBJECTIVES: Patients affected by gynecological or gastrointestinal tract neoplasms that evolve to peritoneal carcinomatosis experience a significant drop in their quality of life, high morbidity and short survival times with currently available chemotherapeutic schemes. The surgical treatment based on cytoreduction and the employment of hyperthermic intraperitoneal chemotherapy in the intra-operative period is a true challenge to anesthesiologist. CASE REPORT: A 67 years old patient diagnosed with mucinous adenocarcinoma of the Appendix associated with mucinous carcinomatosis, was submitted to cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), under general anesthesia and epidural block. Volume replacement was performed with crystalloids, colloids and blood products to support an important ascites volume drained during the procedure. The target was the strict control of hydro-electrolytic and acid-basic equilibrium. The patient was referred to the ICU and evolved to a hospital discharge on the third postoperative day. CONCLUSION: The neoplastic compromise of the peritoneum has long been considered to be a pre-terminal state. The advent of CRS/HIPEC represent an alternative promising with numerous challenges to the anesthesiologist regarding the metabolic and hemodynamic adjustment, which once again demand training and ongoing study from the perioperative team. PMID- 28719886 TI - A longitudinal study of the reciprocal relationship between ever smoking and urgency in early adolescence. AB - BACKGROUND: Among early adolescents in the United States (U.S.), the prevalence of cigarette smoking is at its lowest level in recent decades. Nonetheless, given the risks of smoking in early development, it remains critically important to study both risk factors for smoking and risks from smoking. This longitudinal study with U.S. early adolescents examines smoking initiation and tests a model of reciprocal prediction between ever smoking and the personality trait of urgency (i.e., mood-based impulsivity), a trait that increases risk for multiple forms of dysfunction. METHODS: Participants (n=1906; 90% 10-11 years old, 50% female, 39% racial minorities at baseline) completed questionnaires 1-2 times per year starting in 5th grade and ending in 9th grade. Structural equation modeling allowed tests of bidirectional relationships between ever smoking and urgency controlling for pubertal status and negative affect at each wave. RESULTS: Incidence of ever smoking increased from 5% to 27% over time, with current smoking around 5% at the last wave. Urgency at each wave predicted ever smoking at the next wave above and beyond covariates and prior smoking (all p<0.01). Likewise, with one exception, ever smoking predicted an increase in urgency at the subsequent wave above and beyond covariates and prior urgency (all p<0.05). CONCLUSION: Results show that risk for smoking increases with higher levels of urgency and urgency increases secondary to engagement in smoking. Future work should therefore explore urgency as a point of prevention for smoking and smoking cessation as a means to mitigate mood-based impulsivity. PMID- 28719885 TI - Racial and ethnic differences in opioid agonist treatment for opioid use disorder in a U.S. national sample. AB - BACKGROUND: Opioid Agonist Treatment (OAT) is the standard of care for the treatment of opioid use disorders. However, most people in treatment do not receive OAT. This study evaluated whether there are racial and/or ethnic differences in OAT receipt among adults entering specialty treatment for opioid use disorders in publicly-funded treatment programs across the U.S. METHODS: Using data from the national Treatment: Episode Data Base, odds of OAT receipt were compared among black, Hispanic and white clients. Mediation analyses were used to explore whether any racial/ethnic differences in OAT receipt were explained by variation in clinical need or by other treatment, sociodemographic, or geographic characteristics. Interaction terms were used to assess whether this association was modified by primary opioid type. RESULTS: Only 28.7% of clients received OAT. Odds of OAT receipt were significantly higher odds among blacks (OR: 2.27(2.14-2.41)) and Hispanics (OR: 1.98(1.88-2.09)), compared to whites. Differences in clinical need accounted for a substantial portion of this difference (76.79% and 49.74%, respectively). Differences persisted after accounting for other potential explanatory variables (adjusted OR: 1.37 (1.24 1.52); 1.21(1.11-1.32)), but were only evident for primary heroin users (adjusted OR: 1.50 (1.34-1.69); 1.29 (1.17-1.42)) and not other opioid users. CONCLUSIONS: OAT receipt in treatment programs is low overall and particularly lacking among white heroin users. Differences in OAT receipt cannot be fully explained by differences in clinical need. More research is needed to understand and address barriers that underpin these differences so more patients with opioid use disorder can access evidenced-based treatment. PMID- 28719888 TI - Inhibition of Single Routes of Intracellular Signaling is Not Sufficient to Neutralize the Biphasic Disturbance of a Retinal Endothelial Cell Barrier Induced by VEGF-A165. AB - BACKGROUND/AIMS: Hallmark of diabetic macular edema is the enhanced permeability of retinal endothelial cells (REC) induced by vascular endothelial growth factor (VEGF-A165), which acts through activating specific receptors. To improve the predictability of inhibitors' potentials to block harmful effects of VEGF-A165, we investigated if its signaling pathways triggered in REC are redundant. METHODS: Immortalized bovine REC monolayers were treated with inhibitors specific for various protein kinases in combination with VEGF-A165. Permeability was monitored continuously by measurements of the cell index (CI) to reveal even subtle and transient changes. Expression of tight junction (TJ) proteins was determined as additional indicator of barrier stability. RESULTS: After a sharp but transient CI drop caused by VEGF-A165 early after its addition, further exposure resulted in a continuous CI decline over several days associated with loss of TJ protein claudin-1. Both phases were blocked by inhibition of VEGF receptor 2. Tested inhibitors of intracellular kinases had a limited or no effect, or were efficient only in certain phases of exposure to VEGF-A165, e.g. inhibiting protein kinase C only prevented the early response. High concentrations of some inhibitors even resulted in VEGF-independent barrier destabilization. CONCLUSIONS: Specific kinase inhibitors differently affect VEGF A165-triggered processes in distinct phases of its action. VEGF-A165-initiated signaling is redundant and blocking of key proteins of single pathways is not sufficient to suppress REC barrier breakdown. PMID- 28719889 TI - Combined 23-G Pars Plana Vitrectomy and Lensectomy in the Management of Glaucoma Associated with Nanophthalmos. AB - PURPOSE: To investigate the surgical results of 23-G pars plana vitrectomy (PPV) combined with lensectomy (PPL) in nanophthalmic patients with angle closure glaucoma. METHODS: This prospective nonrandomized study included consecutive patients with nanophthalmic glaucoma recruited for 23-G PPV combined with PPL. Best-corrected visual acuity (BCVA), intraocular pressure (IOP), the number of antiglaucoma medications, and surgery-associated complications were recorded. Surgical success rates were evaluated at each follow-up. Prognostic factors for success were also assessed using logistic regression analysis. RESULTS: This study enrolled 21 eyes of 21 patients. The mean follow-up was 18.6 +/- 7.0 months. At the final follow-up visit, the mean IOP was significantly reduced (from 47.4 +/- 5.7 to 18.6 +/- 3.6 mm Hg). The mean number of antiglaucoma medications dropped from 5 to 0. BCVA improved in 3 (14.3%) eyes. The complete success rate (IOP >6 and <21 mm Hg without antiglaucoma medication) was 71.4, 66.7, and 71.4% at the 6-month, 12-month, and final follow-up visit, respectively. CONCLUSIONS: Nanophthalmic glaucoma can be effectively managed with the combined surgery of 23-G PPV and PPL. IOP control was achieved with elimination of pupillary block and deepening of the anterior chamber. This surgical procedure proved to be safe in eyes with a potential risk of vision threatening complications. PMID- 28719890 TI - Effect of Neoadjuvant Nab-Paclitaxel plus Gemcitabine Therapy on Overall Survival in Patients with Borderline Resectable Pancreatic Cancer: A Prospective Multicenter Phase II Trial (NAC-GA Trial). AB - We conducted a prospective multicenter phase II trial of patients with borderline resectable pancreatic carcinoma to investigate the efficacy of neoadjuvant nab paclitaxel plus gemcitabine therapy on overall survival (OS). The clinical trial primarily evaluated OS time from the first day of protocol therapy as a primary endpoint. The secondary endpoints were recurrence-free survival from the first day of protocol therapy, safety of the protocol therapy (adverse effect), morbidity based on the Clavien Dindo classification of more than III, response rate, preoperative/postoperative tumor marker (CA 19-9, CEA), rate of normalization, reduction rate of the maximum standardized uptake value on positron emission tomography-computed tomography (limited to institutions where positron emission tomography-computed tomography was available), chemotherapeutic effect grade based on Evans' classification, resection rate, R0 resection rate, surgical data (operative time, blood loss, transfusion, postoperative hospital day), overall morbidity rates (reoperation, rate of readmission, mortality), patient rate in postoperative adjuvant therapy (entry rate, completion rate), dose intensity, quality of life regarding fatigue and malaise assessed by the questionnaire of FACIT-F (Japanese version), and peripheral sensory neuropathy assessed by the questionnaire of the FACT/GOG-NTX subscale (version 4; Japanese version). Sixty patients were included in the study, and 18 leading Japanese institutions and hospitals (all high-volume centers in pancreatic surgery) participated in this trial. PMID- 28719891 TI - Serum Interleukin-10 Levels Correlate with Cerebrospinal Fluid Amyloid Beta Deposition in Alzheimer Disease Patients. AB - BACKGROUND AND OBJECTIVE: In Alzheimer disease (AD) inflammation becomes evident throughout the course of the disease. However, the association between inflammation, cognitive impairment, and cerebrospinal biomarkers (Abeta42, t-tau, p-tau181, and Abeta42/p-tau181 ratio) is poorly understood. METHODS: A large panel of inflammatory cytokines (interleukin [IL]-1beta, IL-1ra, IL-2, IL-4, IL 6, IL-10, IL-17, interferon-gamma, tumor necrosis factor-alpha, and vascular endothelial growth factor) was analyzed using a multiplex immunoassay in 27 patients with a diagnosis of AD dementia and in 18 control subjects. In a subgroup with available cerebrospinal fluid (CSF) samples, cytokines in serum were correlated with the levels of neurodegenerative CSF biomarkers (Abeta42, t tau, p-tau181, and Abeta42/p-tau181 ratio). RESULTS: Compared to control subjects, AD patients showed a significant upregulation of IL-10, IL-1beta, and IL-17 serum levels. Several cytokines appeared intercorrelated, and IL-10 in particular presented a significant inverse correlation with CFS levels of Abeta42 and the Abeta42/p-tau ratio. CONCLUSION: Our findings indicate that serum levels of IL-10 may represent a possible peripheral expression of amyloid beta deposition in AD patients. PMID- 28719892 TI - Cinnamaldehyde Ameliorates Diet-Induced Obesity in Mice by Inducing Browning of White Adipose Tissue. AB - BACKGROUND/AIMS: Obesity has become a major health concern with few effective medications. Cinnamaldehyde (CA) has been reported to exhibit anti-diabetic and anti-inflammatory properties. However, whether CA shows anti-obesity activity remains unknown. Therefore, the present study aimed to investigate the potential anti-obesity effects of CA on mice fed a high-fat diet (HFD) and to explore the possible mechanisms involved. METHODS: Male C57BL/6J mice fed an HFD for 12 weeks were supplemented with CA (40 mg/kg/day) via gavage for an additional 8 weeks. Mice fed a standard diet were used as normal controls. RESULTS: The results revealed that CA treatment decreased body weight, fat mass, food intake, and serum lipid, free fatty acid and leptin levels. CA administration also improved insulin sensitivity in HFD-induced obese mice. Additionally, CA inhibited the hypertrophy of adipose tissue and induced browning of white adipose tissue. Uncoupling protein 1 (UCP1) was expressed in white adipose tissue after the oral administration of CA. Furthermore, CA enhanced the expression of the peroxisome proliferator-activated receptor gamma (PPARgamma), PR domain-containing 16 (PRDM16) and PPARgamma coactivator 1alpha (PGC-1alpha) proteins in both brown and white adipose tissues. CONCLUSIONS: The results suggest that CA exhibits therapeutic potency against obesity by inducing the browning of white adipose tissue in HFD-fed mice. PMID- 28719893 TI - Treatment of COPD Exacerbation in Switzerland: Results and Recommendations of the European COPD Audit. AB - BACKGROUND: The European COPD Audit initiated by the European Respiratory Society (ERS) evaluated the management of hospital admissions due to exacerbation of chronic obstructive pulmonary disease (COPD) in several European countries. Data on the treatment of severe acute exacerbations of COPD (AECOPDs) in Switzerland are scarce. OBJECTIVES: In light of the GOLD 2010 guidelines, this work aims to examine the quality of care for AECOPD and to provide specific recommendations for the management of severe AECOPD in Switzerland. METHODS: A total of 295 patients requiring hospital admission to 19 Swiss hospitals due to exacerbation of COPD during a predefined 60 days in 2011 were included in the study. We compared the Swiss data to the official GOLD 2010 recommendations and to the results of the other European countries. RESULTS: Approximately 43% of the Swiss patients with severe AECOPD were current smokers at hospital admission, compared to 33% of the patients in other European countries (p < 0.001). In Switzerland and in Europe, spirometry data were not available for most patients at hospital admission (65 and 60%, respectively; p = 0.08). In comparison to other European countries, antibiotics were prescribed 14% less often in Switzerland (p < 0.001). Only 79% of the patients in the Swiss cohort received treatment with a short acting bronchodilator at admission. CONCLUSIONS: Considering the overall high standard of health care in Switzerland, in light of the GOLD 2010 guidelines we are able to make 7 recommendations to improve and standardize the management of severe AECOPD for patients treated in Switzerland. PMID- 28719894 TI - Karyotype Evolution and Phylogenetic Relationships of Cricetulus sokolovi Orlov et Malygin 1988 (Cricetidae, Rodentia) Inferred from Chromosomal Painting and Molecular Data. AB - Sokolov's dwarf hamster (Cricetulus sokolovi) is the least studied representative of the striped hamsters (Cricetulus barabensis species group), the taxonomy of which remains controversial. The species was described based on chromosome morphology, but neither the details of the karyotype nor the phylogenetic relationships with other Cricetulus are known. In the present study, the karyotype of C. sokolovi was examined using cross-species chromosome painting. Molecular and cytogenetic data were employed to determine the phylogenetic position of Sokolov's hamster and to analyze the potential pathways of chromosome evolution in Cricetulus. Both the chromosome and molecular data support the species status of Sokolov's hamster. Phylogenetic analysis of the CYTB data placed C. sokolovi as sister to all other striped hamsters (sequence divergence of 8.1%). FISH data revealed that the karyotype of C. sokolovi is highly rearranged, with the most parsimonious scenario of its origin implying at least 4 robertsonian events and a centromere shift. Comparative cytogenetic data on Cricetinae suggest that their evolutionary history includes both periods of chromosomal conservatism and episodes of rapid chromosomal change. PMID- 28719895 TI - Update on the Pathophysiology and Risk Factors for the Development of Malignant Testicular Germ Cell Tumors in Complete Androgen Insensitivity Syndrome. AB - Prophylactic gonadectomy in young adult women with complete androgen insensitivity syndrome (CAIS) to avoid development of an invasive testicular germ cell tumor (TGCT) is currently advised in most centers. However, women with CAIS increasingly question the need of this procedure. In order to provide optimal counseling and follow-up of these women, insight in the mechanisms underlying TGCT development in androgen insensitivity syndrome (AIS), data regarding the incidence of TGCT in AIS adults specifically, and an overview of existing and novel screening tools for in situ and invasive neoplastic lesions are crucial. The current knowledge regarding these topics is revised in this paper. PMID- 28719896 TI - Update on the Diagnosis and Prognosis of Preeclampsia with the Aid of the sFlt-1/ PlGF Ratio in Singleton Pregnancies. AB - Preeclampsia (PE) is involved in a group of obstetrical conditions closely related by the presence of placental dysfunction (PD), which also includes intrauterine growth restriction and placental abruption. The timely and accurate recognition and management of PE are often challenging because diagnostic criteria are still based on nonspecific signs and symptoms and because common severity criteria correlate poorly with adverse maternal and fetal outcomes. The discovery of the role of angiogenesis-related factors - soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) - in the underlying pathophysiology of PD has marked an important step for improving its early diagnosis and prognosis assessment before gestational week 34. Nowadays, an sFlt 1/PlGF ratio cutoff level of <=38 is widely accepted for ruling out PE in patients with suspicion of the disease, and its use is cost-effective. However, the evidence is more limited regarding the management and prognosis of women with an abnormally high sFlt-1/PlGF ratio. This review summarizes the current evidence of the clinical application of the sFlt-1/PlGF ratio for the diagnosis and prognosis assessment of PE and points out the next challenges for these biomarkers, including their role as target for the development and monitoring of new therapies. PMID- 28719897 TI - Clinical Manifestations and Prognostic Factors of Pneumocystis jirovecii Pneumonia without HIV. AB - INTRODUCTION: Pneumocystis jirovecii pneumonia (PCP) can occur in HIV patients but also in those without HIV (non-HIV PCP) but with other causes of immunodeficiency including malignancy or rheumatic diseases. OBJECTIVE AND METHODS: To evaluate the clinical presentation and prognostic factors of non-HIV PCP, we retrospectively reviewed all patients diagnosed as having PCP without HIV at Kameda Medical Center, Chiba, Japan, from January 2005 until June 2012. For the purpose of examining a prognostic factor for non-HIV PCP with 30-day mortality, we compared the characteristics of patients, clinical symptoms, radiological images, Eastern Cooperative Oncology Group performance status (PS), and the time from the onset of respiratory symptoms to the start of therapy, in both survival and fatality groups. RESULTS: A total of 38 patients were eligible in this study. Twenty-five survived and 13 had died. The non-HIV PCP patients in the survivor group had a better PS and received anti-PCP therapy earlier than those in the nonsurvivor group. Rales upon auscultation and respiratory failure at initial visits were seen more frequently in the nonsurvivor group than in the survivor group. Lactate dehydrogenase and C-reactive protein values tended to be higher in the nonsurvivor group, but this was not statistically significant. Multivariate analyses using 5 variables showed that a poor PS of 2-4 was an independent risk factor for non-HIV PCP patients and resulted in death (odds ratio 15.24; 95% confidence interval 1.72-135.21). CONCLUSION: We suggest that poor PS is an independent risk factor in non-HIV PCP, and a patient's PS and disease activity may correlate with outcome. PMID- 28719898 TI - Role of MiR-155 Signal Pathway in Regulating Podocyte Injury Induced by TGF beta1. AB - BACKGROUND/AIMS: Transforming growth factor beta 1 (TGF-beta1) plays a critical role in the pathogenesis of glomerulosclerosis. The purpose of this study was to examine the effects of inhibition of miR-155 on podocyte injury induced by TGF beta1 and to determine further molecular mediators involved in the effects of miR 155. METHODS: Conditionally immortalized podocytes were cultured in vitro and they were divided into four groups: control; TGF-beta1 treatment; TGF-beta1 with miR-155 knockdown [using antisense oligonucleotides against miR-155 (ASO-miR 155)] and TGF-beta1 with negative control antisense oligonucleotides (ASO-NC). Real time RT-PCR and Western blot analysis were employed to determine the mRNA and protein expression of nephrin, desmin and caspase-9, respectively. Flow cytometry was used to examine the apoptotic rate of podocytes and DAPI fluorescent staining was used to determine apoptotic morphology. In addition, we examined the levels of miR-155, TGF-beta1, nephrin, desmin and caspase-9 in glomerular tissues of nephropathy induced by intravenous injections of adriamycin in rats. RESULTS: mRNA and protein expression of desmin and caspase-9 was increased in cultured TGF-beta1-treated podocytes, whereas nephrin was decreased as compared with the control group. Importantly, miR-155 knockdown significantly attenuated upregulation of desmin and caspase-9, and alleviated impairment of nephrin induced by TGF-beta1. Moreover, the number of apoptotic podocytes was increased after exposure to TGF-beta1 and this was alleviated after miR-155 knockdown. Knocking down miR-155 also decreased an apoptosis rate of TGF-beta1 treated podocytes. Note that negative control antisense oligonucleotides failed to alter an increase of the apoptosis rate in TGF-beta1-treated podocytes. Consistent with in vitro results, expression of miR-155, TGF-beta1, desmin and caspase-9 was increased and nephrin was decreased in glomerular tissues with nephropathy in vivo experiments. CONCLUSIONS: TGF-beta1 impairs the protein expression of nephrin and amplifies the protein expression of desmin and caspase 9 via miR-155 signal pathway. Inhibition of miR-155 alleviates these changes in podocytes-treated with TGF-beta1 and attenuated apoptosis of podocytes. Our data suggest that miR-155 plays a role in mediating TGF-beta1-induced podocyte injury via nephrin, desmin and caspase-9. Results of the current study also indicate that blocking miR-155 signal has a protective effect on podocyte injury. Targeting one or more of these signaling molecules may present new opportunities for treatment and management of podocyte injury observed in glomerulosclerosis. PMID- 28719899 TI - The Relationship Between MMP-2 -1306C>T and MMP-9 -1562C>T Polymorphisms and the Risk and Prognosis of T-Cell Acute Lymphoblastic Leukemia in a Chinese Population: A Case-Control Study. AB - BACKGROUND: T-cell acute lymphoblastic leukemia (T-ALL) is a malignant hematological disease and is often accompanied by a variety of genetic abnormalities. Hence, our study aims to investigate the relationship between MMP 2 -1306C>T and MMP-9 -1562C>T polymorphisms and the risk and prognosis of T-ALL. METHODS: From April 2009 to February 2011, a total of 376 T-ALL patients were chosen as the case group. Meanwhile, 352 healthy people who passed routine health examinations were selected as the control group. A polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) assay was used to detect the frequency of MMP-2 -1306C>T (rs243865) and MMP-9 -1562C>T (rs3918242) polymorphisms in the study subjects. The serum levels of MMP-2 and MMP-9 were detected using enzyme-linked immunosorbent assay (ELISA). A Kaplan-Meier analysis was employed to analyze the event-free survival (EFS) rates of the T-All patients with different MMP-2 and MMP-9 genotypes. A multivariate COX model was applied to analyze the relationship between MMP-2 and MMP-9 polymorphisms and the prognosis of T-ALL patients. A C-statistic and net reclassification index (NRI) was carried out to evaluate the predictive value of MMP-2 and MMP-9 gene polymorphisms using the Cox model. RESULTS: Compared to the control group, the genotypic frequency of MMP-2 -1306C>T (CT + TT) and MMP-9 -1562C>T (CT + TT) in the case group was significantly higher. The serum level of MMP-9 was markedly elevated in T-ALL patients with the CT + TT genotype compared to patients with the CC genotype. The results of the Kaplan-Meier analysis showed that the median EFS was lower in T ALL patients with the CT + TT genotype of MMP-9 -1562C>T compared to patients with the CC genotype. The results of a multivariate analysis using the Cox proportional hazard model indicated that the MMP-9 -1562C>T polymorphism was associated with the prognosis of T-ALL patients. CONCLUSION: These results indicated that MMP-2 -1306C/T and MMP-9 -1562C/T polymorphisms might be associated with an increased risk of T-ALL. The MMP-9 -1562C>T polymorphism may also be related to the prognosis of T-ALL patients. PMID- 28719900 TI - Second- to Third-Trimester Longitudinal Growth Assessment for the Prediction of Largeness for Gestational Age and Macrosomia in an Unselected Population. AB - BACKGROUND: Prenatal detection of excessive growth remains inaccurate. Most strategies rely on a single cross-sectional evaluation of fetal size during the third trimester. OBJECTIVES: To compare second- to third-trimester longitudinal growth assessment with cross-sectional evaluation at the third trimester in the prediction of largeness for gestational age (LGA) and macrosomia. METHODS: A cohort of 2,696 unselected singleton pregnancies scanned at 21 +/- 2 and 32 +/- 2 weeks was created. Abdominal circumference (AC) measurements were transformed to z values according to the INTERGROWTH-21st standards. Longitudinal growth assessment was performed by calculation of z velocity and conditional growth. Both methods were compared to cross-sectional assessment at 32 +/- 2 weeks. Predictive performance for LGA and macrosomia was determined by receiver operating characteristic curve analysis. RESULT: A total of 188 (7%) newborns qualified for LGA and 182 (6.8%) for macrosomia. The areas under the curve (AUCs) for 32-week AC z score, AC z velocity, and conditional AC were 0.78, 0.61, and 0.55, respectively, for the prediction of LGA, and 0.75, 0.61, and 0.55, respectively, for the prediction of macrosomia. Both AUCs of AC z velocity and conditional AC were significantly lower (p < 0.001) than the AUC of cross sectional AC z scores. CONCLUSIONS: In the general population, second- to third trimester longitudinal assessment of fetal growth is inferior to third-trimester cross-sectional evaluation of size in the prediction of LGA and macrosomia. PMID- 28719901 TI - Patient-Related Benefits for Adults with Cochlear Implantation: A Multicultural Longitudinal Observational Study. AB - OBJECTIVES: To assess subjectively perceived, real-world benefits longitudinally for unilateral cochlear implant (CI) recipients in a multinational population treated routinely. To identify possible predictors of self-reported benefits. DESIGN: This was a prospective, multicenter, repeated-measures study. Self assessment of performance at preimplantation and postimplantation at 1, 2, and 3 years using standardized, validated, local language versions of the Speech, Spatial, and Qualities of Hearing Scale (SSQ), and the Health Utilities Index Mark 3 (HUI3) was performed. Outcomes were analyzed using a longitudinal mixed effects model incorporating country effect. Patient demographics were explored for associations with change over time. SUBJECTS: Two hundred ninety-one routinely treated, unilateral CI recipients, aged 13-81 years, from 9 clinics across 4 countries. RESULTS: Highly significant improvements were observed for all outcome measures (p < 0.0001). Postimplantation, mean outcome scores remained stable beyond 1 year, with notable individual variability. A significant association for one or more outcomes with preimplantation contralateral hearing aid use, telephone use, age at implantation, implantation side, preimplantation comorbidities, dizziness, and tinnitus was observed (p < 0.004). CONCLUSIONS: Longitudinal benefits of CI treatment can be measured using clinically standardized self-assessment tools to provide a holistic view of patient-related benefits in routine clinical practice for aggregated data from multinational populations. Self-reported outcomes can provide medical-based evidence regarding CI treatment to support decision-making by health service providers. PMID- 28719902 TI - Serum Hyaluronic Acid Levels Are Altered in Acute Leukemia Patients: Potential Prognostic Implications. AB - BACKGROUND: Studies on the serum concentration of hyaluronic acid (HA) in newly diagnosed patients with acute myeloid leukemia (AML), B-acute lymphoblastic leukemia (B-ALL), and mantle-cell lymphoma (MCL) are scarce. In this study, we focused on investigating whether HA could serve as a possible prognostic marker in patients with AML, B-ALL, and MCL. METHODS: The serum concentration of HA was measured in a total of 51 patients with newly diagnosed AML, B-ALL, and MCL. Venous blood was collected 1 day before the initiation of chemotherapy (D0), on day 16 of the first cycle of chemotherapy (D16), and on D30. RESULTS: The serum HA concentration on D0 in patients with AML, B-ALL, and MCL was higher than in the control group. For all types of hematological malignancy, on D0, serum HA values of nonsurvivors were higher than in survivors. Moreover, patients in relapse had higher levels of serum HA than patients in remission. A strong positive correlation between serum HA and ferritin, beta2-microglobulin, and lactate dehydrogenase was found. CONCLUSION: Serum HA may serve as a possible prognostic marker for AML, B-ALL, and MCL patients, especially on D0. Prospective case-control studies on larger populations may provide further information. PMID- 28719903 TI - Thinning of Inner Retinal Layers after Vitrectomy with Silicone Oil versus Gas Endotamponade in Eyes with Macula-Off Retinal Detachment. AB - PURPOSE: To evaluate retinal layer thickness with optical coherence tomography (OCT) in eyes with macula-off retinal detachment after silicone oil (SiO) or gas endotamponade. PROCEDURES: Cross-sectional study of 40 eyes with macula-off rhegmatogenous retinal detachment that underwent vitrectomy. 20 eyes received SiO tamponade and 20 matched eyes received gas. 33 healthy fellow eyes served as controls. Macular spectral domain OCT was performed with automated layer detection in the 5 inner subfields of the Early Treatment Diabetic Retinopathy Study (ETDRS) map. RESULTS: Comparing the SiO group with the gas group, the ganglion cell layer showed a significant thinning in all fields of the inner ring of the ETDRS map, the inner plexiform layer in the nasal, superior and temporal quadrants, and the outer plexiform layer in the nasal quadrant. CONCLUSIONS: Inner retinal layers in the fovea/parafovea were significantly thinner in the SiO group. Prospective studies are warranted to further elucidate possible retinal adverse effects of SiO tamponade. PMID- 28719904 TI - Gonadectomy in Complete Androgen Insensitivity Syndrome: Why and When? AB - Prophylactic gonadectomy has been recommended in complete androgen insensitivity syndrome (CAIS) because of an increased risk for the development of malignant germ cell tumors in the intra-abdominal gonads. No reliable screening parameters are available to detect early (pre-)malignant changes. Because the tumor risk before puberty is very low, the timing of gonadectomy has been postponed to allow spontaneous puberty and involvement of the patients in important decisions affecting their body and health. Gonadectomy after puberty is still discussed controversially. There are difficulties in determining the absolute malignancy risk for individuals with CAIS, difficulties with hormone therapy, and lack of studies supporting different protocols. In contrast, endogenous hormone profiles show very specific features that influence bone health, psychosocial well-being, and many other aspects which still have to be investigated. For women with CAIS who wish to keep their gonads, we propose a biannual screening program which has to be evaluated in a prospective multi-center trial. PMID- 28719905 TI - Childhood-Onset Adult Growth Hormone Deficiency: Clinical, Hormonal, and Radiological Assessment in a Single Center in China. AB - BACKGROUND: Although growth hormone deficiency (GHD) is an important issue in pediatric patients, adult GHD (AGHD) is a neglected field of endocrinology in China. The aim of this study is to characterize the clinical, hormonal, and radiological features in childhood-onset AGHD (CO AGHD) in a single center in China and to compare them with counterparts from Japan. METHODS: The medical records of 78 Chinese patients with CO AGHD were reviewed and compared with data from the HypoCCS database study from Japan (N = 69). RESULTS: The majority of our patients had pituitary stalk interruption, while hypothalamo-pituitary tumors were the most common cause of CO AGHD in Japan. Chinese patients had a lag of 6 years for diagnosis. The majority of both groups had multiple pituitary hormone deficiencies. Body mass index and lipid profiles were similar between the 2 patient groups. Dyslipidemia and hyperuricemia were the most common metabolic disturbances in Chinese patients. CONCLUSIONS: Our findings confirm that there are possible regional differences in the etiology, metabolic characteristics, and hormonal status in CO AGHD patients in different countries in Asia. PMID- 28719906 TI - A Common Ancestral Asn242Ser Mutation in TMEM67 Identified in Multiple Iranian Families with Joubert Syndrome. AB - BACKGROUND: Joubert syndrome (JS) is a clinically and genetically heterogeneous group of rare neurodevelopmental disorder characterised by peculiar midbrain hindbrain malformation, known as the "molar tooth" sign. JS can manifest a broad range of signs and symptoms. The most common features of JS are hypotonia, ataxia, developmental delay/intellectual disability, abnormal eye movements, and neonatal breathing abnormalities. To date, 29 genes have been shown to cause JS. METHODS: We employed whole-genome single nucleotide polymorphism genotyping in a group of Iranian families with JS and Sanger sequencing of a known mutation associated with JS located in a single homozygous regions shared by affected members of the families. RESULTS: Homozygosity mapping uncovered a shared ~2.2-Mb run of homozygosity on chromosome 8q21.3-q22.1 encompassing the known JS-causing TMEM67 gene. Sanger sequencing of a known mutation (NM_153704.5: c.725A>G; p.Asn242Ser) in TMEM67 identified from studying another Iranian family using whole-exome sequencing confirmed the presence of the homozygous mutation in 22 affected members of 12 nuclear families. "Molar tooth" sign of brain magnetic resonance imaging, moderate-to-severe neurodevelopmental delay, and abnormal eye movements were the most common features of affected individuals. In addition, liver disease, seizure, behavioural abnormalities, failure to thrive, and kidney disease were observed variably in some of the patients. CONCLUSION: We propose that Asn242Ser is a founder mutation in the Iranian population, which might explain a significant proportion of JS cases from eastern Iran. Therefore, screening for this variant should be considered for genetic testing in Iranian patients with JS. In addition, this finding is important for developing population-specific genetic testing in Iran. PMID- 28719907 TI - Tumor Heterogeneity in Lymphomas: A Different Breed. AB - The facts that cancer represents tissues consisting of heterogeneous neoplastic, as well as reactive, cell populations and that cancers of the same histotype may show profound differences in clinical behavior have long been recognized. With the advent of new technologies and the demands of precision medicine, the investigation of tumor heterogeneity has gained much interest. An understanding of intertumoral heterogeneity in patients with the same disease entity is necessary to optimally guide personalized treatment. In addition, increasing evidence indicates that different tumor areas or primary tumors and metastases in an individual patient can show significant intratumoral heterogeneity on different levels. This phenomenon can be driven by genomic instability, epigenetic events, the tumor microenvironment, and stochastic variations in cellular function and antitumoral therapies. These mechanisms may lead to branched subclonal evolution from a common progenitor clone, resulting in spatial variation between different tumor sites, disease progression, and treatment resistance. This review addresses tumor heterogeneity in lymphomas from a pathologist's viewpoint. The relationship between morphologic, immunophenotypic, and genetic heterogeneity is exemplified in different lymphoma entities and reviewed in the context of high-grade transformation and transdifferentiation. In addition, factors driving heterogeneity, as well as clinical and therapeutic implications of lymphoma heterogeneity, will be discussed. PMID- 28719909 TI - Francoise-Kyou Jouffroy (1931-2016). PMID- 28719908 TI - Ultrasound-Guided Intrauterine Labeling of Rat Fetuses. AB - AIM: To compare intra-amniotic versus fetal subcutaneous injections for selective fetal labeling in multifetal rat pregnancies. METHODS: A total of 14 pregnant rats were randomized to receive intra-amniotic injections of dyes (including Fluorescein, Indigo Carmine, or Evans Blue) or fetal subcutaneous injections (of commercial tattoo ink) both guided by ultrasound at 15-17 days of gestation. Survival, injection, and labeling success rates of both techniques were compared. RESULTS: Survival rates (84.4% for intra-amniotic injections vs. 90.9% for fetal subcutaneous injections) and injection success rates (94% for intra-amniotic injections vs. 100% for fetal subcutaneous injections) were similar among both groups. None of the neonates from the intra-amniotic injections group were labeled at birth, while 93% of the neonates from fetal subcutaneous injections group were tagged, showing a visible spot in the skin at birth. CONCLUSION: Our results suggest that ultrasound-guided fetal subcutaneous injections might be an adequate strategy for selectively labeling fetuses in multifetal pregnant animals. PMID- 28719910 TI - Correlating the Genetic and Physical Map of Barley Chromosome 3H Revealed Limitations of the FISH-Based Mapping of Nearby Single-Copy Probes Caused by the Dynamic Structure of Metaphase Chromosomes. AB - Genetic maps are based on the recombination frequency of molecular markers which often show different positions in comparison to the corresponding physical maps. To decipher the position and order of DNA sequences genetically mapped to terminal and interstitial regions of barley (Hordeum vulgare) chromosome 3H, fluorescence in situ hybridization (FISH) on mitotic metaphase chromosomes was performed with 16 genomic single-copy probes derived from fingerprinted BAC contigs. Long genetic distances at subterminal regions translated into short physical distances, confirming that recombination events occur more often at distal regions of chromosome 3H. Nonoverlapping FISH signals were frequently obtained for probes with a physical distance of at least 30-60 kb. Only 8% of the analyzed chromosomes showed a symmetric order of FISH signals on both sister chromatids. Due to the dynamic packing of metaphase chromatin, the order of 2 adjacent single-copy signals along the chromosome arms outside the (peri)centromeric region can only reliably be determined if the cytological distance is approximately 3%, corresponding to 21.6 Mb. PMID- 28719911 TI - Dissecting Survival Pathways in Lung Cancer, Fibrosis and Emphysema: "The Four Horses of the Apocalypse". PMID- 28719913 TI - Texture density adaptation can be bidirectional. AB - Texture density has previously been thought of as a scalar attribute on the assumption that texture density adaptation only reduces, not enhances, perceived density (Durgin & Huk, 1997). This "unidirectional" property of density adaptation is in contradistinction to the finding that simultaneous density contrast (SDC) is "bidirectional"; that is, not only do denser surrounds reduce the perceived density of a lower density region, but sparser surrounds enhance it (Sun, Baker, & Kingdom, 2016). Here we reexamine the directionality of density adaptation using random dot patterns and a two-alternative forced choice task in which observers compare the perceived density of adapted test patches with unadapted match stimuli. In the first experiment, we observed a unidirectional density aftereffect when test and match were presented simultaneously as in previous studies. However, when they were presented sequentially, bidirectionality was obtained. This bidirectional aftereffect remained when the presentation order of test and match was reversed (second experiment). In the third experiment, we used sequential presentation to measure the density aftereffect for a wide range of adaptor densities (0-73 dots/deg2) and test densities (1.6, 6.4, and 25.6 dots/deg2). We found bidirectionality for all combinations of adaptor and test densities, consistent with our previous SDC results. This evidence supports the idea that there are multiple channels selective to texture density in human vision. PMID- 28719912 TI - Crocin Protects Podocytes Against Oxidative Stress and Inflammation Induced by High Glucose Through Inhibition of NF-kappaB. AB - BACKGROUND/AIMS: Diabetic nephropathy (DN) is a microangiopathic disease characterized by excessive urinary albumin excretion, which occurs in 30% of patients with diabetes mellitus. It is the second leading cause of end-stage renal diseases in China. Nuclear factor-kappa B (NF-kappaB) is reported to be closely correlated with the inflammation underlying diabetes-associated renal damage. Crocin, a plant-derived compound, has antioxidant properties that may inhibit NF-kappaB. METHODS: In the present study, we used a conditionally immortalized mouse podocyte cell line to explore whether crocin could effectively block albuminuria. Cells were incubated with 15 or 25 mM D-glucose to mimic diabetic conditions. The expression of Wilms tumor 1 (WT-1) and synaptopodin was evaluated to identify differentiated podocytes, and the expression of nephrin, podocin, and CD2ap was measured as markers of slit diaphragms, the main structures within the glomerular filtration barrier. RESULTS: The high-glucose conditions led to reduced nephrin, podocin, and CD2ap expression, which was prevented by pretreatment with crocin. The oxidative stress and pro-inflammatory response of podocytes associated with DN induced by high glucose were also reduced by crocin pretreatment. Phosphorylated IkappaBalpha (p-IkappaBalpha) expression induced by high glucose was also significantly decreased by crocin pretreatment. Moreover, pyrrolidine dithiocarbamate, a NF-kappaB inhibitor, pyrrolidine dithio carbamate, augmented the protective effects of crocin. CONCLUSION: Our results demonstrate a protective role of crocin against damage to podocytes and slit diaphragms under high-glucose conditions via inhibition of NF kappaB. This study presents a potential therapy for DN and contributes to the understanding of the mechanism underlying DN. PMID- 28719914 TI - The Significance of Antibodies against Domain I of Beta-2 Glycoprotein I in Antiphospholipid Syndrome. AB - The antiphospholipid syndrome (APS) is characterized by vascular thrombosis and/or pregnancy morbidity with the persistent presence of antiphospholipid antibodies (aPLs). Progress is being made in understanding the pathogenesis of the syndrome, but difficulties persist in the identification of patients at risk for thrombosis and/or pregnancy morbidity. Beta-2 glycoprotein I (beta2GPI), a plasma protein consisting of five sushi domains, is thought to be the main antigenic target of aPLs. Antibodies recognizing domain I of beta2GPI are predominantly present in patients with an elevated risk of thrombosis, whereas antidomain IV/V antibodies are found in nonthrombotic autoimmune diseases. Indeed, domain I antibodies proved to be pathogenic in multiple studies. Retrospective studies have provided evidence for an added clinical value of antidomain I antibodies in the risk stratification of patients with APS. Still, wide ranges of odds ratio exist between studies, probably due to differences in the study and control population, and detection methods used. Despite the proven pathogenicity of antidomain I antibodies and their correlations with clinical manifestations of APS, heterogeneity of the current studies has prohibited their acceptance in the official diagnostic criteria. Well-designed large longitudinal prospective studies with available and new, preferentially functional, assays for the risk stratification of patients with APS are required. PMID- 28719915 TI - Predictive Value of Whole Blood and Plasma Coagulation Tests for Intra- and Postoperative Bleeding Risk: A Systematic Review. PMID- 28719916 TI - Pediatric Short Bowel Syndrome: Predicting Four-Year Outcome after Massive Neonatal Resection. AB - OBJECTIVES: The aim of this study was to ascertain predictors of survival, liver disease (LD), and enteral autonomy 48 months after resection in neonatal short bowel syndrome (SBS) patients with residual small bowel length (SBL) <=40 cm. PATIENTS AND METHODS: Medical records of all SBS patients followed up between 1996 and 2016 were retrospectively reviewed. Survival rate, prevalence of LD, and of enteral autonomy were evaluated. RESULTS: Forty-seven patients were included, and 43 were still alive at the end of the study period, with cumulative 48-month survival of 91.5%. Twenty-one (45%) patients developed LD, all within the first 6 months. On the final follow-up visit, three (6%) patients were still jaundiced and progressed toward end-stage LD. LD prevalence was higher in patients with recurrent bloodstream infections (odds ratio [OR] 5.4, 95% confidence interval [CI] 1.5-19.3). Of the 43 surviving patients, 22 (51%) had enteral autonomy 48 months after resection. The probability of weaning off parenteral nutrition (PN) was strongly correlated with the remaining SBL. CONCLUSION: Survival of patients who have undergone neonatal massive small bowel resection has improved in recent years. Multidisciplinary strategies can improve the course of LD, but not the probability of weaning off PN, which seems to be strongly dependent on the anatomical profile of residual bowel. Therefore, the primary surgical approach should be as conservative as possible to gain even small amounts of intestinal length, which may be crucial in promoting intestinal adaptation. PMID- 28719917 TI - Surgical Health Needs of Minor Refugees in Germany: A Cross-Sectional Study. AB - INTRODUCTION: There has been a substantial rise in refugees entering Germany over the past years, of which approximately one-third are underaged. Many end up in pediatric surgical care, and little is known about the health of these individuals. Our study was designed to assess the surgical-related health status of underage refugees based on a large sample cohort. MATERIALS AND METHODS: After ethics board approval, we used a structured questionnaire to collect demographic information and surgical health-related elements in three large refugee accommodation centers. RESULTS: A total of 461 minor refugees were included. The majority were boys (54.5%) with an average age of 8 years. Out of the eight recorded countries of origin, most children came from Syria (33.6%) followed by Afghanistan (23.2%). Previous operative interventions were recorded in 42.2% of participants. Among girls, 11% suffered genital mutilation. Trauma was common and the most common mechanism was a fall from bicycle (38%) followed by burn injuries (7.4%). Up to 20% of them experienced physical violence during the flight or in the accommodation facility. Vaccination rates varied widely according to origin. Of the participants, only 63% were vaccinated according to schedule. Chronic diseases were found in only 13% of the study cohort, anemia being most prevalent at 4%. CONCLUSION: Minor refugees have specific health related problems that must be considered to ensure appropriate medical care. Many refugee children were victims of physical violence and many girls suffered genital mutilation. Vaccination status is unreliable; therefore, tetanus vaccination should always be considered when these patients seek pediatric surgical care. Tailored anticipatory guidance should be provided to this patient population. PMID- 28719918 TI - [The Wish for a Child in the Case of (Permanent) Infertility: Development of the "German Questionnaire on Attitudes Toward Motherhood"]. AB - Study 1 Development of the questionnaire Most questionnaires on attitudes toward motherhood presume that the subject is fertile and positive and negative attitudes are represented on a one-dimensional scale. Moreover, the questionnaires often do not provide German versions and German norms. The aim of this study is to examine whether the German Questionnaire on Attitudes toward Motherhood ("FEMu") can be used to describe attitudes toward motherhood multi dimensionally and whether it is applicable independent of a person's fertility status. The FEMu was developed based on a female sample (n=932) using principal factor analysis (oblique rotation) which yielded 2 independent main factors ("pro child", "contra child") with 5 subfactors (privation/conformation, attractiveness/balance, incompleteness, relation, affiliation) and 4 prototypes (idealization, rejection, ambivalence, indifference). Study 2Evaluation of clinical Samples of people with Complete Androgen Insensitivity Syndrome (CAIS, n=12), Mayer-Rokitansky-Kuster-Hauser Syndrome (MRKHS, n=49) and Polycystic Ovary Syndrome (PCOS, n=55) were included for testing. The first 2 suffer from permanent infertility, in the latter fertility is compromised. The intensity of their wish for a child, the FEMu main factors and the prototypes were analyzed. The independence of pro and contra child scores and the prototypes were emipirically confirmed. Participants with CAIS had a low wish for a child and an indifferent attitude toward motherhood, women with MRKHS had a moderate wish for a child and were ambivalent, women with PCOS had a maximum wish for a child and idealized motherhood. Conclusion The FEMu represents attitudes toward motherhood in a multi-dimensional way. It is appropriate for use in fertile and infertile individuals and can be applied in research and single-case settings. The FEMu results can be useful in individual counseling, e. g. within the scope of fertility treatmernt, at gynecological consultations, in pregnancy counseling or psychological counseling. In psychotherapy the results can help to develop suited interventions. The FEMu could also bring about valuable insights outside of the clinical setting, e. g., in the realms of family planning and women's conflict between family and career. PMID- 28719919 TI - [Not Available]. PMID- 28719920 TI - [Parenting Concerns and Psychological Burden in Cancer Patients with Minor and Young Adult Children]. AB - Background Aim of the study was to analyze parenting concerns in cancer survivors and to identify covariats for parenting concerns. Method In a cross-sectional epidemiological sample of cancer survivors with minor children (n=1416) demographic and disease-related variables and psychological distress (HADS) were assessed. Parenting concerns were assessed using the Parenting Concerns Questionnaire (PCQ). The instrument covers the 3 subscales concerns about the 'practical impact' of the disease on the children, about the 'emotional impact' and concerns about the 'co-parent'. Results 73% of survivors were female; mean age was 47.5 years (SD 5.9). 24% to 71% of patients reporting parenting concerns showed normal levels of anxiety and depression. We identified living alone, younger age of the youngest child, higher tumor stage and suffering from a comorbidity as significantly associated with parenting concerns in all subscales of the PCQ. Low socio-economic status was found to be significantly associated with parenting concerns regarding the emotional and practical impact of the disease. Being a mother was associated with concerns in the subscale co-parent. Discussion Parents with cancer not only suffer from psychological distress but also from parenting concerns about the impact of their disease on their children. Psychological support services should broach the issue of parenting concerns. Families at risk should be identified to allocate tailored support. PMID- 28719921 TI - [Patient's Autonomy and Information in Psycho-Oncology: Computer Based Distress Screening for an Interactive Treatment Planning (ePOS-react)]. AB - To identify distressed patients in oncology using screening questionnaires is quite challenging in clinical routine. Up to now there is no evidence based recommendation which instrument is most suitable and how to put a screening to practice. Using computer based screening tools offers the possibility to automatically analyse patient's data, inform psycho-oncological and medical staff about the results, and use reactive questionnaires. Studies on how to empower patients in decision making in psycho-oncology are rare.Methods Women with breast and gynaecological cancer have been consecutively included in this study (n=103) at time of inpatient surgical treatment in a gynaecological clinic. They answered the computer based screening questionnaire (ePOS-react) for routine distress screening at time of admission. At the end of the tool an individual recommendation concerning psycho-oncological treatment is given ( i) psycho oncological counselling, ii) brief psycho-oncological contact, iii) no treatment suggestion). The informed patients could choose autonomously either the recommended treatment or an individually more favoured alternative possibility. Additionally, a clinical interview (approx. 30 min) based on the "Psychoonkologische Basisdiagnostik (PO-Bado)" has been carried out for a third party assessment of patients' need for treatment.Results 68.9% followed the treatment recommendation. 22.3% asked for a more "intense" (e. g. counselling instead of recommended brief contact) and 8,7% for a "less intense" intervention than recommended. The accordance of third-party assessment (clinical interview "PO-Bado") and treatment recommendation is about 72.8%. The accordance of third party assessment and patient's choice (ePOS-react) is about 58.3%. The latter is smaller because 29.1% asked for a brief psycho-oncological contact for whom from the third-party assessment's perspective no indication for treatment has been existent.Discussion A direct response of the screening result (treatment recommendation) during the computer based screening and asking for a patient's choice leads to an increase of brief psycho-oncological contacts for personal information about psycho-oncological interventions. Compared with a third-party assessment (clinical interview) there is no improvement of the accuracy of the indications. But it improves the transparency for the access to psycho oncological interventions which may strengthen patient's autonomy and adherence. PMID- 28719922 TI - [Stigmatization in Employed Patients with Breast, Intestinal, Prostate and Lung Cancer]. AB - Background The stigma of cancer patients can lead to far-reaching consequences, both for the individual and for the society. Quantitative studies on the stigmatization of cancer patients are scarce. The present study assessed the stigma of cancer patients in relation to their status of employment, and analyzes sociodemographic, disease and occupational predictors. Methods In a bicentric study, 858 patients with breast, bowel, lung or prostate cancer were included. Of these, n=305 were employed and entered into the analyses (age average 55 years, 43% female, 47% breast cancer). As a comparison group, a matched sample of non employed persons (n=213) is used from our data set. In addition to questions on work and health aspects, stigmatization was measured using the SIS-D (Social Impact Scale). The data are evaluated uni- and multivariable. Results Employed persons with prostate or breast cancer are less stigmatized (p<0.01) than non employed persons, with effects between d=0.35-0.97. The strongest influence on perceived stigma is the lack of support from the employer, further predictors are poor health, low mental workability and diagnosis of breast cancer (R2 of the final model=0.35). Conclusion The employment of cancer patients is associated with lesser perceived stigmatization. Occupational stigmatization depends above all on the work environment or the employer's supportive attitude. PMID- 28719923 TI - [Breaking Bad News to Cancer Patients: Content, Communication Preferences and Psychological Distress]. AB - Objectives Breaking bad news can be a very distressing situation for both patients and physicians. Physician communication behavior should therefore match patients' communication preferences. The aim of this study was to characterize the content of bad news from the patients' perspective. Patients' preferences for communication of bad news as well as the fit to communication behavior displayed by physicians were also investigated. Finally, consequences of a mismatch between patients' preferences and physician communication were investigated in relation to psychological distress in patients. Methods The sample consisted of N=270 cancer patients (mean age=56.8 years, 48% female) with various cancer entities and different stages of disease (n=115 patients with early stage of cancer, n=155 patients with advanced cancer). The content of bad news was assessed with a specifically developed list of questions. The Measure of Patients' Preferences Scale (MPP) was used to assess patients' preferences for communication of bad news. Patients further completed the NCCN Distress Thermometer (cancer specific distress), the Hospital Anxiety and Depression Scale (HADS- anxiety and depression) and the Demoralization Scale (DS-Scale) to gain information about psychological distress. Results Patients with early stage breast cancer received bad news M=1.6 times (SD=1.1, range: 1-5), patients with advanced cancers M=2.1 times (SD=1.6, range: 1-12). For 77% of early stage cancer patients and 70% of advanced cancer patients, the subjectively worst consultation was receiving the diagnosis and discussing treatment options. Patients' most important communication preferences were physicians' clinical competence and patient centered communication, clear and direct communication and asking about patients information preferences. Patients in advanced stages report significantly more (29%) unmet communication needs than patients' in early stages (20%; p<0.01). Breaking bad news without considering patients' preferences was associated with higher psychological distress in patients. Conclusion Physicians should communicate in a patient-centered way to reduce mismatch with patients' preferences and thereby potentially reduce patients' psychological distress. PMID- 28719924 TI - Erratum: Decontamination of Mikania glomerata Leaves by Gamma Irradiation: Coumarin Determination by HPLC-DAD, Microbiological Control and Genotoxicological Studies. PMID- 28719925 TI - Acetylated Furostene Glycosides from Solanum gilo Fruits. AB - In continuation of our work on a traditional mixture of spices called "Nkui", used in Cameroon for its influence on women's reproductive health, we investigated the chemical composition of Solanum gilo, one component of "Nkui". A methanolic extract was studied in detail. After dereplication of several known compounds, two furo-5-stene-derived saponin glycosides with acetylated sugar moieties were isolated. By extensive 1- and 2D NMR experiments and HR-MS and GC MS methods, the structures were elucidated as 26-[(3''',4''',6'''-tri-O-acetyl) beta-D-glucopyranosyloxy]-22-hydroxyfurost-5-en-3beta-yl-O-alpha-L rhamnopyranosyl-(1"->2')-beta-D-glucopyranoside (A) and 26-[(3''',4''',6'''-tri-O acetyl)-beta-D-glucopyranosyloxy]-22-hydroxyfurost-5-en-3beta-yl-[O-alpha-L rhamnopyranosyl-(1''''->4')-O-alpha-L-rhamnopyranosyl-(1"->2')]-beta-D glucopyranoside (B), both new natural compounds. PMID- 28719926 TI - Cholangioscopy-directed lithotripsy for a large bile duct stone: the "donut technique". PMID- 28719927 TI - Endoscopic submucosal dissection of a huge esophageal atypical lipomatous tumor (well-differentiated liposarcoma) with a 4-year recurrence-free survival. PMID- 28719928 TI - Endoscopy-guided surgery of an atrio-esophageal fistula after failure of self expandable metal stents. PMID- 28719929 TI - Percutaneous endoscopic necrosectomy. PMID- 28719930 TI - Successful two-sided sponge pull-through treatment of anastomotic leakage following pancreaticoduodenectomy with pancreaticogastrostomy. PMID- 28719931 TI - Management of a rare cause of significant acute upper gastrointestinal bleeding: gastric lipoma resected by hybrid endoscopic submucosal dissection. PMID- 28719932 TI - Endoscopic removal of migrated colonic self-expandable metallic stent using a sliding tube. PMID- 28719933 TI - New endoscopic technique for uncontrollable bilious vomiting after gastrojejunal surgical bypass. PMID- 28719934 TI - Endoscopic ultrasound-guided pancreaticogastrostomy in a pediatric patient. PMID- 28719935 TI - A case of endoscopic hemostasis using double-balloon endoscopy for an intestinal hemorrhage in a giant incisional hernia. PMID- 28719936 TI - Using NOTES to salvage a misdeployed lumen-apposing metal stent during an endoscopic ultrasound-guided gastroenterostomy. PMID- 28719937 TI - A challenging case of giant biliary stones in a patient with situs inversus totalis: conventional ERCP combined with intraductal cholangioscopy and laser lithotripsy. PMID- 28719938 TI - Terminal Condylar Facets of the Femur: Implications for Knee Arthroplasty. AB - In wake of changing lifestyle and increasing surgical expertise, knee replacement surgeries have become common. Attempts at improving the postoperative range of motion have prompted high-flexion knee arthroplasties. Consequently, there is a need to study the anatomy of knee joint in high flexion. This study focused on a holistic description of terminal condylar articular facet (TCAF; part of the femoral articular area in contact with the tibia in high flexion) of medial and lateral condyles and their quantification. In total, 104 dry femora and 16 dissected cadaveric knee joints (10 adult and 6 fetal) were studied. In most cases, the medial TCAF showed a tongue- or wedge-shaped extension in its lateral half, which has been referred to as extended condylar facet (ECF). The surface area of the ECF was approximately 0.5 cm2. In adult cadaveric dissections, the fibrous capsule showed the lax attachment beyond the ECF, thus creating a cave in the medial tibiofemoral compartment. These features were absent in fetal dissection. The presence of an ECF has not been documented in dry bones and has not been quantified. The variability of the size of this extension supports the hypothesis of this being an acquired trait. This study is expected to provide factual data for implant design improvement and a new anthropological data on Indian femora. PMID- 28719939 TI - Biomechanics and Microstructural Analysis of the Mouse Knee and Ligaments. AB - The purpose of this study is to determine the feasibility of using murine models for translational study of knee ligament injury, repair, and reconstruction. To achieve this aim, we provide objective, quantitative data detailing the gross anatomy, biomechanical characteristics, and microscopic structure of knee ligaments of 44 male mice (C57BL6, 12 weeks of age). Biomechanical testing determined the load-to-failure force, stiffness, and the site of ligament failure for the anterior cruciate ligament (ACL), posterior cruciate ligament (PCL), and the medial and lateral collateral ligaments (MCL and LCL). These data are complemented by histological characterization of each of the knee ligaments. In addition, the osseous morphology of the mouse knee was examined using high resolution nanofocus computed tomography (CT), while standard micro-CT was employed to measure bone morphometrics of the distal femur and proximal tibia. Collectively, our findings suggest that the gross anatomy of the mouse knee is similar to the human knee despite some minor differences and features unique to the murine knee. The ACL had the highest load to failure (5.60 +/- 0.75 N), the MCL (3.33 +/- 1.45 N), and the PCL (3.45 +/- 0.84 N) were similar, and the LCL (1.44 +/- 0.37 N) had the lowest load to failure and stiffness. Murine models provide a unique opportunity to focus on biological processes that impact ligament pathology and healing due to the availability of transgenic strains. Our data support their use as a translational platform for the in vivo study of ligament injury, repair, and reconstruction. PMID- 28719940 TI - Surgical Repair of Neglected Bucket-Handle Meniscal Tears Displaced into the Intercondylar Notch: Clinical and Radiological Results. AB - The literature contains very limited articles wherein the treatment results of bucket-handle meniscal tears according to various types are evaluated and wherein results for repair of chronic tears are discussed. The objective of this study is a clinical and radiologic evaluation of arthroscopic repair for patients suffering flipped, neglected chronic bucket-handle meniscal tear in the intercondylar notch. A total of 26 patients were evaluated retrospectively. The mean age at the time of surgery was 27 years (range, 16-44). Mean period from meniscal injury to surgery was 28 months (range, 4-96). The mean follow-up period was 31 months (range, 11-67). During the follow-up, the patients were evaluated clinically, functional scores from the International Knee Documentation Committee (IKDC), Lysholm, and Tegner as well as magnetic resonance imaging (MRI). The mean preoperative Lysholm score of 24 increased to 85 postoperatively. Mean IKDC score was 56.3 preoperatively and 84.5 postoperatively. The mean Tegner score of 3.4 increased to 5.6 postoperatively. Mean Lysholm, IKDC, and Tegner scores in the first group were 84, 74, and 5.1, respectively, and in the anterior cruciate ligament (ACL) reconstruction group; 86, 85.9, and 5.8. While 20 (77%) out of 26 patients had none of the clinical findings, 6 patients (23%) presented with these findings. Postoperative MRI assessment revealed meniscal healing in 21 patients (27% complete, 54% partial healing) and no healing in 5 patients (19%). A clinical healing rate of 77% and a radiological healing rate of 81% along with statistically significant increases in Lysholm, IKDC, and Tegner scores prove that the repair option is effective for neglected, chronic bucket-handle meniscal tears flipping to the intercondylar notch. This study showed that good results could be achieved with the repair of neglected, chronic period bucket-handle meniscal tears flipping to the intercondylar notch, whether with an accompanying ACL tear or not. PMID- 28719941 TI - Pain Control in Total Knee Arthroplasty. AB - As surgical techniques and pharmacology advance, the management of postoperative pain in patients undergoing total knee arthroplasty (TKA) continues to evolve. The current standards of care are composed of multimodal pain management including opioids, nonsteroidal anti-inflammatory drugs and gabapentinoids, peripheral nerve blocks, and periarticular injections. Newer modalities are composed of delayed release local anesthetics and cryoneurolysis. To summarize the current evidence-based treatment modalities and forecast changes in the management of patients having TKAs, we reviewed available data on: (1) oral analgesics; (2) periarticular injections; (3) peripheral nerve blocks; (4) multimodal regimens; and (5) newer modalities in post-TKA pain management. Multimodal analgesic regimens that target numerous pain pathways may provide the best pain management, rehabilitation, patient satisfaction, and reduce opioid use and related side effects. Periarticular injections of delayed-release local anesthetics may further enhance pain management. PMID- 28719942 TI - Factors Contributing to Patient Satisfaction and Expectations following Computer Assisted Total Knee Arthroplasty. AB - The purpose of this study was to determine which factors contribute to patient satisfaction and expectations after total knee arthroplasty (TKA). A total of 109 patients (130 knees) with knee osteoarthritis who underwent primary TKA with navigation were studied. Intraoperative mediolateral laxity was measured. The factors including mediolateral laxity that affected patient satisfaction and expectations were evaluated using the 2011 Knee Society Score. Patient satisfaction after TKA correlated positively with symptoms and functional activities, and negatively with old age in univariate analysis. Multivariate analysis showed that symptoms and functional activities remained statistically significant; however, old age showed no difference. Patient expectations after TKA correlated positively with symptoms and functional activities, and negatively with mediolateral laxity at 60 degrees in univariate analysis. Multivariate analysis showed that symptoms, functional activities, and mediolateral laxity at 60 degrees remained statistically significant. In conclusion, midflexion instability was associated with worse expectations. PMID- 28719943 TI - Treatment with Circular External Fixation of Bicondylar Tibial Fractures: Potential in Accurate Reduction and Efficacy on Functional Results. AB - Surgical reconstruction of bicondylar tibial fractures with external fixation relies on indirect fracture reduction that could affect anatomical restoration. The aim of the present study is to evaluate the radiographic and clinical outcomes of tibial bicondylar fractures treated with circular external fixation. A total of 20 bicondylar fractures of the proximal tibia in 20 patients treated with circular external fixation were included in the study. Two fractures were open. Mean clinical and radiographic follow-up was 37.3 months after frame removal. Angular, translation, and length deformities were assessed on nonweight bearing anteroposterior, lateral, and two 45 degrees oblique views. The medial proximal tibia (MPTA) and posterior proximal tibia angles (PPTA) were calculated in all cases. The condylar widening was calculated in relation to the width of the femoral condyles. Joint depressions or gaps of the articular surface were identified on the four views of the knee. The modified Hospital for Special Surgery (HSS) knee scoring system was used for clinical evaluation. The MPTA was good in 18 (90%) and fair in 2 patients (10%). The PPTA was good in 13 (65%), fair in 6 (30%), and poor in 1 patient (5%). The articular reduction was good in 12 (60%) and fair in 8 patients (40%). The condylar widening was good in 15 (75%) and fair in 5 patients (25%). Mechanical axis deviation was within the normal range in 11/12 patients (91.7%). All fractures consolidated. One deep infection was successfully treated with local debridement, the mean modified HSS knee score at the latest follow-up was 90.5 (range: 67-100). Articular reconstruction and tibia alignment based on radiographic evaluation in the present study, along with functional results compare favorably with those of external and internal fixation presented in the literature. PMID- 28719944 TI - Radiographic and Functional Outcomes following Knee Arthrodesis Using the Wichita Fusion Nail. AB - The purpose of this study was to report both the radiographic and functional outcomes of patients undergoing knee arthrodesis with the Wichita Fusion Nail (WFN) within the Republic of Ireland and compare the results to existing literature. Patient charts and radiographs were reviewed on all patients who had a WFN implanted in Ireland to date. Patients were invited to complete a Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score as a functional assessment. Twenty-three patients were identified. Patients had an average of 8 (range: 0-26) knee surgeries prior to arthrodesis. The most common indication was failed arthroplasty due to recalcitrant infection (69.5%). Successful fusion occurred in 60.8% of patients. The mean time to fusion was 9.21 months. The mean WOMAC score was 58.55 with a range of 31 to 96. We found a rate of arthrodesis lower than that reported in other published series. However, the rate of major complications was comparable to those published previously, reflecting the often-challenging patient cohort. Our study shows that the WFN should not be viewed as a near-universally successful option to salvage an unreconstructable knee. PMID- 28719945 TI - Management of Injuries to the Medial Patellofemoral Ligament: A Review. AB - The medial patellofemoral ligament (MPFL) is thought to be the most important medial structure providing restraint to lateral subluxation of the patella. After an initial patellar dislocation, the MPFL is frequently injured and can usually be treated with conservative measures. However, these patients often suffer from recurrent dislocations, which thereby necessitate operative intervention. In the setting of normal anatomy and kinematics, isolated reconstruction of the MPFL is an effective treatment for preventing recurrent dislocations. Various surgical techniques have been described, with differences in fixation and graft selection. The treatment of MPFL injuries should aim to provide patellar stabilization and restore normal kinematics throughout the joint. This review will discuss the following: (1) anatomy of the MPFL, (2) presentation and assessment of MPFL injuries, (3) management of patients with MPFL injuries, and (4) complications following MPFL reconstruction. PMID- 28719946 TI - Cell-assisted lipotransfer: Friend or foe in fat grafting? Systematic review and meta-analysis. AB - Autologous fat grafting is a common procedure for soft-tissue reconstruction but is associated with a graft resorption rate ranging from 20% to 80%. To improve the fat graft survival rate, a new technique, called cell-assisted lipotransfer (CAL), was developed. With CAL, fat is injected along with adipose-derived stromal cells that are assumed to improve fat survival rate. We conducted an evidence-based meta-analysis to evaluate the efficacy and safety of CAL as compared with conventional autologous fat grafting (non-CAL). The databases MEDLINE (via PubMed), Cochrane Library, EBSCO, Web of Science, and EMBASE were searched for reports of clinical trials, case series, and cohorts available from 2008 to 2016. We conducted a meta-analysis of the efficacy of CAL with data analysis concerning fat survival rate. The incidence of complications and the need for multiple procedures were evaluated to determine the safety of CAL. We identified 25 studies (696 patients) that were included in the systematic review; 16 studies were included in the meta-analysis to evaluate the efficacy of CAL. The fat survival rate was significantly higher with CAL than non-CAL (64% vs. 44%, p < .0001) independent of injection site (breast and face). This benefit of CAL was significant for only injection volumes <100 ml (p = .03). The two groups did not differ in frequency of multiple procedures after fat grafting, but the incidence of complications was greater with CAL than non-CAL (8.4% vs. 1.5%, p = .0019). The CAL method is associated with better fat survival rate than with conventional fat grafting but only for small volumes of fat grafting (<100 ml). Nonetheless, the new technique is associated with more complications and did not reduce the number of surgical procedures needed after the first fat grafting. More prospective studies are required to draw clinical conclusions and to demonstrate the real benefit of CAL as compared with common autologous fat grafting. PMID- 28719947 TI - Efficient Liquid Media for Encystation of Pathogenic Free-Living Amoebae. AB - Pathogenic Naegleria fowleri, Acanthamoeba castellanii, and Acanthamoeba polyphaga, are distributed worldwide. They are causative agents of primary amoebic meningoencephalitis or acanthamoebic keratitis in humans, respectively. Trophozoites encyst in unfavorable environments, such as exhausted food supply and desiccation. Until recently, the method of N. fowleri encystation used solid non-nutrient agar medium supplemented with heat-inactivated Escherichia coli; however, for the amoebic encystment of Acanthamoeba spp., a defined, slightly modified liquid media is used. In this study, in order to generate pure N. fowleri cysts, a liquid encystment medium (buffer 1) modified from Page's amoeba saline was applied for encystation of N. fowleri. N. fowleri cysts were well induced after 24 hr with the above defined liquid encystment medium (buffer 1). This was confirmed by observation of a high expression of differential mRNA of nfa1 and actin genes in trophozoites. Thus, this liquid medium can replace the earlier non-nutrient agar medium for obtaining pure N. fowleri cysts. In addition, for cyst formation of Acanthamoeba spp., buffer 2 (adjusted to pH 9.0) was the more efficient medium. To summarize, these liquid encystment media may be useful for further studies which require axenic and pure amoebic cysts. PMID- 28719948 TI - Isolation and Genotyping of Toxoplasma gondii in Brazilian Dogs. AB - Strains of Toxoplasma gondii in Brazil are highly genetically diverse compared to strains from North America and Europe. Dogs are epidemiologically important because they act as sentinels for T. gondii infections in humans and are good indicators of environmental contamination. The aim of this study was to isolate and genetically characterize T. gondii strains from tissues of naturally infected Brazilian dogs. For this study, 21 blood samples were collected from dogs at the Zoonosis Control Centers of Ilheus and Itabuna cities, Bahia, Brazil. The sera were examined for T. gondii antibodies using the indirect hemagglutination test. Brains and hearts of seropositive dogs were bioassayed in mice to isolate and characterize T. gondii parasites by PCR-RFLP using 10 genetic markers (SAG1, newSAG2, SAG3, BTUB, c22-8, c29-2, GRA6, PK1, APICO, and L358). However, T. gondii was isolated from only 4 (57.1%) dogs, designated TgDgBr6, 13, 17, and 21. All strains were virulent, causing clinical changes (rough hair coat, lethargy, and abdominal distention) and the death of all mice within 8-20 days after inoculation. Genetic analysis of these 4 T. gondii isolates revealed 4 distinct genotypes with different clonal lineage combinations (types I, II, and III) and 2 atypical alleles. Using PCR-RFLP with several markers, this study contributes to evaluations of the genetic diversity of strains circulating in Brazil. PMID- 28719949 TI - Seroprevalence of Toxoplasmosis with ELISA and Rapid Diagnostic Test among Residents in Gyodong-do, Inchon city, Korea: A Four-Year Follow-up. AB - ELISA has been used for the diagnosis of toxoplasmosis, but it is being gradually replaced by a rapid diagnostic test (RDT). We compared and analyzed ELISA and RDT results using the sera collected during 4 consecutive years from residents of Gyodong-do (Island), Incheon-city, Korea. Sera from 921, 993, 940, and 838 adult residents were collected on a yearly basis (2010-2013). ELISA was performed by using a crude extract of T. gondii RH strain antigen and IgG/IgM RDT mounted with recombinant fragment of major surface antigen (SAG1), GST-linker-SAG1A, were applied to the sera. Comparison between groups was analyzed by the Student's t test. The positive seroprevalence surged from 14.7% (135/921, 2010), 23.1% (231/993, 2011), 23.6% (222/940, 2012), and 32.1% (269/838, 2013) by ELISA. In contrast, RDT showed a more moderate increasing trend from 21.7% (200/921, 2010), 25.5% (253/993, 2011), 28.9% (272/940, 2012) and 33.1% (277/838, 2013). Discrepancies between ELISA and RDT were noted near the cut-off value. At the OD 0.15-0.24 range, RDT could detect 16.1% (169/1051) more positives, which suggests an early or acute toxoplasmosis, but at the OD 0.25-0.34 range, ELISA could detect 35.9% (92/256) more positives of possible chronic infections. Over the OD > 0.35 ELISA and RDT agreed in the majority of the cases. This surge in seroprevalence may be caused by the organic agriculture in addition to eating behavior or increase in pets among Koreans. These facts may be applied on a full scale national survey using RDT to supplement ELISA to define the characteristics of the infection. PMID- 28719950 TI - Isolation and Characterization of Vaccine Candidate Genes Including CSP and MSP1 in Plasmodium yoelii. AB - Malaria is an infectious disease affecting humans, which is transmitted by the bite of Anopheles mosquitoes harboring sporozoites of parasitic protozoans belonging to the genus Plasmodium. Despite past achievements to control the protozoan disease, malaria still remains a significant health threat up to now. In this study, we cloned and characterized the full-unit Plasmodium yoelii genes encoding merozoite surface protein 1 (MSP1), circumsporozoite protein (CSP), and Duffy-binding protein (DBP), each of which can be applied for investigations to obtain potent protective vaccines in the rodent malaria model, due to their specific expression patterns during the parasite life cycle. Recombinant fragments corresponding to the middle and C-terminal regions of PyMSP1 and PyCSP, respectively, displayed strong reactivity against P. yoelii-infected mice sera. Specific native antigens invoking strong humoral immune response during the primary and secondary infections of P. yoelii were also abundantly detected in experimental ICR mice. The low or negligible parasitemia observed in the secondary infected mice was likely to result from the neutralizing action of the protective antibodies. Identification of these antigenic proteins might provide the necessary information and means to characterize additional vaccine candidate antigens, selected solely on their ability to produce the protective antibodies. PMID- 28719952 TI - Molecular Phylogenetics of Trichostrongylus Species (Nematoda: Trichostrongylidae) from Humans of Mazandaran Province, Iran. AB - The present study was performed to analyze molecularly the phylogenetic positions of human-infecting Trichostrongylus species in Mazandaran Province, Iran, which is an endemic area for trichostrongyliasis. DNA from 7 Trichostrongylus infected stool samples were extracted by using in-house (IH) method. PCR amplification of ITS2-rDNA region was performed, and products were sequenced. Phylogenetic analysis of the nucleotide sequence data was performed using MEGA 5.0 software. Six out of 7 isolates had high similarity with Trichostrongylus colubriformis, while the other one showed high homology with Trichostrongylus axei registered in GenBank reference sequences. Intra-specific variations within isolates of T. colubriformis and T. axei amounted to 0-1.8% and 0-0.6%, respectively. Trichostrongylus species obtained in the present study were in a cluster with the relevant reference sequences from previous studies. BLAST analysis indicated that there was 100% homology among all 6 ITS2 sequences of T. colubriformis in the present study and most previously registered sequences of T. colubriformis from human, sheep, and goat isolates from Iran and also human isolates from Laos, Thailand, and France. The ITS2 sequence of T. axei exhibited 99.4% homology with the human isolate of T. axei from Thailand, sheep isolates from New Zealand and Iran, and cattle isolate from USA. PMID- 28719951 TI - Neuronal Apoptosis: Pathological Basis of Behavioral Dysfunctions Induced by Angiostrongylus cantonensis in Rodents Model. AB - Angiostrongylus cantonensis invades the central nervous system (CNS) of humans to induce eosinophilic meningitis and meningoencephalitis and leads to persistent headache, cognitive dysfunction, and ataxic gait. Infected mice (nonpermissive host), admittedly, suffer more serious pathological injuries than rats (permissive host). However, the pathological basis of these manifestations is incompletely elucidated. In this study, the behavioral test, histological and immunohistochemical techniques, and analysis of apoptotic gene expression, especially caspase-3, were conducted. The movement and motor coordination were investigated at week 2 post infection (PI) and week 3 PI in mice and rats, respectively. The cognitive impairs could be found in mice at week 2 PI but not in rats. The plaque-like lesion, perivascular cuffing of inflammatory cells, and dilated vessels within the cerebral cortex and hippocampus were more serious in mice than in rats at week 3 PI. Transcriptomic analysis showed activated extrinsic apoptotic pathway through increased expression of TNFR1 and caspase-8 in mice CNS. Immunohistochemical and double-labeling for NeuN and caspase-3 indicated the dramatically increased expression of caspase-3 in neuron of the cerebral cortex and hippocampus in mice but not in rats. Furthermore, western blotting results showed high expression of cleaved caspase-3 proteins in mice but relatively low expression in rats. Thus, extrinsic apoptotic pathway participated in neuronal apoptosis might be the pathological basis of distinct behavioral dysfunctions in rodents with A. cantonensis infection. It provides the evidences of a primary molecular mechanism for the behavioral dysfunction and paves the ways to clinical diagnosis and therapy for A. cantonensis infection. PMID- 28719953 TI - New Definitive Hosts and Differential Body Indices of Isthmiophora hortensis (Digenea: Echinostomatidae). AB - The present study was performed to record new definitive hosts of Isthmiophora hortensis, and to describe morphological characteristics derived from a variety of worm samples for clarification of its taxonomic validity. Morphological characteristics with dimensions were observed in worm samples (n=21) from naturally infected wild animals, including a raccoon dog Nyctereutes procyonoides from Gimhae-si (City), Gyeongsangnam-do, stray cats and a striped field mouse from several localities, and a wild boar Sus scrofa, from Gurye-gun (County), Jeollanam-do. In addition, adult flukes (n=45) recovered in albino rats experimentally infected with the metacercariae from a freshwater fish species were also subjected to morphological studies. The mean ratios of the body length (BL) to body width (BW) were 5.86 and 5.76 in worms from wild animals and experimental rats, respectively. Those of the ventral sucker to oral sucker were 2.92 and 3.01 in worms from 2 groups. The mean percentages of the hindbody length (HBL) to BL were 42.1 and 41.2 in 2 groups. Those of uterine fields to BL were 9.8 and 12.2 in the 2 worm groups. By the present study, the 2 species of wild animals, the raccoon dog and wild boar, have been added as new definitive hosts for I. hortensis. The morphological characteristics of adult flukes derived from a variety of host source were redescribed to support the taxonomic validity of this echinostome species. PMID- 28719954 TI - Subsets of Inflammatory Cytokine Gene Polymorphisms are Associated with Risk of Carcinogenic Liver Fluke Opisthorchis viverrini-Associated Advanced Periductal Fibrosis and Cholangiocarcinoma. AB - Opisthorchis viverrini infection induces chronic inflammation, and a minor proportion of infected individuals develop advanced periductal fibrosis (APF) and cholangiocarcinoma (CCA). Inflammatory cytokines and/or their gene polymorphisms may link to these biliary pathologies. We therefore investigated associations among cytokine gene polymorphisms and cytokine production in 510 Thai cases infected with O. viverrini who presented with APF+ or APF-, as established by abdominal ultrasonography as well as in patients diagnosed with CCA. Levels of pro-inflammatory and anti-inflammatory cytokines were determined in culture supernatants after stimulation of peripheral blood mononuclear cells (PBMCs) with O. viverrini excretory-secretory (ES) products. Pro-inflammatory cytokines, IL 1beta, IL-6, IFN-gamma, LT-alpha, and TNF-alpha were significantly increased in CCA patients compared with non-CCA (APF- and APF+) cases. Polymorphisms in genes encoding IL-1beta-511C/T, IL-6-174G/C, IFN-gamma +874T/A, LT-alpha +252A/G, and TNF-alpha -308G/A were then investigated by using PCR-RFLP or allele specific-PCR (AS-PCR) analyses. In the CCA cases, LT-alpha +252A/G and TNF-alpha -308G/A heterozygous and homozygous variants showed significantly higher levels of these cytokines than the wild type. By contrast, levels of cytokines in wild type of IFN-gamma +874T/A were significantly higher than the variants in CCA cases. IFN gamma +874T/A polymorphisms were associated with advanced periductal fibrosis, whereas IL-6 -174G/C polymorphisms were associated with CCA. To our knowledge, these findings provide the first demonstration that O. viverrini infected individuals carrying several specific cytokine gene polymorphisms are susceptible to develop fibrosis and CCA. PMID- 28719955 TI - Prevalence of Clonorchis sinensis Metacercariae in Fish from Water Systems of Seomjin-gang (River). AB - The prevalence of Clonorchis sinensis metacercariae (CsMc) was examined in freshwater fish from the water systems of Seomjin-gang (River), the Republic of Korea. Total 1,604 fish from 7 local sites of Seomjin-gang were examined by artificial digestion methods. The metacercariae of C. sinensis were detected in 102 (39.8%) out of 256 fish (14 species) from the upper reaches of Seomjin-gang, i.e., Osucheon (22.3% in 6 fish species) in Imsil-gun, and Seomjin-gang (63.9% in 9 fish species) in Sunchang-gun, Jeollabuk-do. Their average density was 9.0 per infected fish. They were also found in 132 (48.0%) out of 275 fish (12 spp.) from the middle reaches of Seomjin-gang, i.e., Songdaecheon (58.9% in 4 fish species) in Namwon-si, Jeollabuk-do, and Seomjin-gang (45.2% in 10 fish species) in Gokseong-gun, Jeollanam-do. Their average density was 21.0 per infected fish. CsMc were detected in 77 (56.6%) out of 136 fish (11 species) from the lower reaches of Seomjin-gang, i.e., Seomjin-gang (73.3% in 11 fish species) in Gurye gun, Jeollanam-do, and Namsancheon (8.6% in 1 fish species) in Hadong-gun, Gyeongsangnam-do. Their average density was 64.9 per infected fish. The metacercariae of Metorchis orientalis were also detected in 6 fish species from 4 sites of Seomjin-gang. Conclusively, it has been confirmed that CsMc are more or less prevalent in fish from some water systems of Seomjin-gang in Korea. PMID- 28719956 TI - A Case of Ectopic Peritoneal Paragonimiasis Mimicking Diverticulitis or Abdominal Abscess. AB - Paragonimiasis is a parasitic disease caused by Paragnonimus species. The primary site of infection is the lung, and extrapulmonary involvement is also reported. When infected with Paragonimus westermani, which is the dominant species in Korea, the central nervous system is frequently involved along with the liver, intestine, peritoneal cavity, retroperitoneum, and abdominal wall. Ectopic paragonimiasis raises diagnostic challenge since it is uncommon and may be confused with malignancy or other inflammatory diseases. Here, we report an ectopic paragonimiasis case initially presented with recurrent abdominal pain. The patient developed abdominal pain 3 times for the previous 3 years and the computed tomography (CT) of the abdomen revealed fluid collection with wall enhancement. Recurrent diverticulitis was initially suspected and part of the ascending colon was resected. However, the specimen showed intact colon wall without evidence of diverticulitis and multiple parasite eggs and granulomas were found instead. The size of about 70 MUm, the presence of an operculum and relatively thick egg shell suggested eggs of Paragonimus species. With appropriate exposure history and a positive antibody test, the definitive diagnosis was made as peritoneal paragonimiasis. PMID- 28719957 TI - Four Human Cases of Diphyllobothrium nihonkaiense (Eucestoda: Diphyllobothriidae) in China with a Brief Review of Chinese Cases. AB - We described 4 human infection cases of zoonotic fish-tapeworm, Diphyllobothrium nihonkaiense, identified with morphological and molecular characters and briefly reviewed Chinese cases in consideration of it as an emerging parasitic disease in China. The scolex and mature and gravid proglottids of some cases were seen, a rosette-shaped uterus was observed in the middle of the mature and gravid proglottids, and the diphyllobothriid eggs were yellowish-brown in color and displayed a small knob or abopercular protuberance on the opposite end of a lid like opening. The average size of the eggs was recorded as 62-67*42-45 MUm. The parasitic materials gathered from 4 human cases were morphologically identified as belonging to the genera Diphyllobothrium and Adenocephalus. The phylogenetic analysis based on the nucleotide sequences of cytochrome c oxidase subunit 1 gene of the etiologic agents confirmed that the 4 cases were D. nihonkaiense infection. The finding of 4 additional D. nihonkaiense cases suggests that D. nihonkaiense might be a major causative species of human diphyllobothriasis in China. A combined morphological and molecular analysis is the main method to confirm D. nihonkaiense infection. PMID- 28719958 TI - A Case of Furuncular Myiasis Due to Cordylobia anthropophaga in a Korean Traveler Returning from Uganda. AB - A fly larva was recovered from a boil-like lesion on the left leg of a 33-year old male on 21 November 2016. He has worked in an endemic area of myiasis, Uganda, for 8 months and returned to Korea on 11 November 2016. The larva was identified as Cordylobia anthropophaga by morphological features, including the body shape, size, anterior end, posterior spiracles, and pattern of spines on the body. Subsequent 28S rRNA gene sequencing showed 99.9% similarity (916/917 bp) with the partial 28S rRNA gene of C. anthropophaga. This is the first imported case of furuncular myiasis caused by C. anthropophaga in a Korean overseas traveler. PMID- 28719959 TI - PCR Identification and Phylogenetic Analysis of Trichomonas gallinae from Domestic Pigeons in Guangzhou, China. AB - Avian trichomoniasis caused by Trichomonas gallinae is a serious protozoan disease worldwide. The domestic pigeon (Columba livia domestica) is the main host for T. gallinae and plays an important role in the spread of the disease. Based on the internal transcribed spacers of nuclear ribosomal DNA of this parasite, a pair of primers (TgF2/TgR2) was designed and used to develop a PCR assay for the diagnosis of T. gallinae infection in domestic pigeons. This approach allowed the identification of T. gallinae, and no amplicons were produced when using DNA from other common avian pathogens. The minimum amount of DNA detectable by the specific PCR assay developed in this study was 15 pg. Clinical samples from Guangzhou, China, were examined using this PCR assay and a standard microscopy method, and their molecular characteristics were determined by phylogenetic analysis. All of the T. gallinae-positive samples detected by microscopic examination were also detected as positive by the PCR assay. Most of the samples identified as negative by microscopic examination were detected as T. gallinae positive by the PCR assay and were confirmed by sequencing. The positive samples of T. gallinae collected from Guangzhou, China, were identified as T. gallinae genotype B by sequencing and phylogenetic analyses, providing relevant data for studying the ecology and population genetic structures of trichomonads and for the prevention and control of the diseases they cause. PMID- 28719960 TI - Evaluation of Boldine Activity against Intracellular Amastigotes of Leishmania amazonensis. AB - Leishmaniasis is a neglected and endemic disease that affects poorest population mainly in developing countries. A lack of adequate and definitive chemotherapeutic agents to fight against this infection has led to the investigation of numerous compounds. The aim of this study was to investigate in vitro activity of boldine against Leishmania amazonensis murine cell infection. Boldine ((S)-2,9-dihydroxy-1,10-dimethoxy-aporphine) is an aporphine alkaloid found abundantly in the leaves/bark of boldo (Peumus boldus Molina), a widely distributed tree native to Chile. The in vitro system consisted of murine macrophage infection with amastigotes of L. amazonensis treated with different concentrations from 50 to 600 MUg/ml of boldine for 24 hr. Intracellular parasite destruction was assessed by morphological examination and boldine cytotoxicity to macrophages was tested by the MTT viability assay. When cells were treated with 100 MUg/ml of boldine the reduction of parasite infection was 81% compared with untreated cultures cells. Interestingly, boldine-treatment caused a concentration dependent decrease of macrophage infection that culminated with 96% of reduction when cells were submitted to 600 MUg/ml of boldine. Cell cultures exposed to 100 MUg/ml of boldine and 300 MUg/ml of Glucantime(r) during 24 hr showed a significant reduction of 50% in parasitized cells compared with cell cultures exposed just to Glucantime(r). The study showed that treatment with boldine produces a better effect than treatment with the reference antimonial drug, glucantime, in L. amazonensis infected macrophage. Our results suggest that boldine is a potentially useful agent for the treatment of leishmaniasis. PMID- 28719961 TI - Artyfechinostomum malayanum: Metacercariae Encysted in Pila sp. Snails Purchased from Phnom Penh, Cambodia. AB - The metacercariae of Artyfechinostomum malayanum (Leiper, 1911) Mendheim, 1943 were discovered in Pila sp. snails purchased from a market in Phnom Penh, Cambodia. They were isolated from the snails using the artificial digestion technique and were orally fed to 2 hamsters, 1 rat, and 2 mice to obtain the adult flukes. The metacercariae were round, 145-165 MUm in diameter, having a cyst wall of 6-10 MUm in thickness, a head collar and collar spines, and characteristic features of excretory granules. Adult flukes were recovered in the small intestines of the animals at days 14 and 32 post infection and were morphologically observed using a light microscope and a scanning electron microscope. They were plump or elongated, ventrally curved, 6.0-8.1*1.6-2.0 mm in size, and characterized by the head collar bearing 43 collar spines, including 5 end group ones on each side, a long cirrus sac extending beyond the posterior margin of the ventral sucker, a submedian ovary, and 2 deeply lobed testes. Eggs in uteri were operculate, ovoid to ellipsoid, and 120-135*68-75 MUm in size. In scanning electron microscopy, the head collar was prominent with collar spines looking like horns. Scale-like tegumental spines were densely distributed on the ventral surface between the head collar and ventral sucker. Sensory papillae were distributed mainly on the tegument around suckers. By this study, it has been first confirmed that the life cycle of A. malayanum exists in Cambodia. PMID- 28719962 TI - Recent Incidence of Paragonimus westermani Metacercariae in Freshwater Crayfish, Cambaroides similis, from Two Enzootic Sites in Jeollanam-do, Korea. AB - An epidemiological study was performed to know the recent infection status of Paragonimus westermani metacercariae (PwMc) in freshwater crayfish, Cambaroides similis, from 2 streams in Jeollanam-do, Republic of Korea. Crayfish were collected from creeks in Bogil-do (Island), Wando-gun, and in a creek near Daeheung Temple in Haenam-gun. The infection rate of crayfish with PwMc in Bogil do was 89.8%, and the metacercarial burden was 37 PwMc per the infected crayfish. Crayfish in a creek near Daeheung Temple were larger and twice heavier than those in Bogil-do. Of them, 96.5% were infected with PwMc. An average of 140 metacercariae was found in the infected crayfish, almost quadruple to those of Bogil-do. There was a strong correlation between the number of PwMc and body weight of the crayfish. These results suggest that P. westermani metacercariae are still prevalent in crayfish of the 2 regions in Jeollanam-do, Korea. PMID- 28719963 TI - Prevalence of Hymenolepis nana and H. diminuta from Brown Rats (Rattus norvegicus) in Heilongjiang Province, China. AB - Hymenolepis nana and Hymenolepis diminuta are globally widespread zoonotic cestodes. Rodents are the main reservoir host of these cestodes. Brown rats (Rattus norvegicus) are the best known and most common rats, and usually live wherever humans live, especially in less than desirable hygiene conditions. Due to the little information of the 2 hymenolepidid species in brown rats in China, the aim of this study was to understand the prevalence and genetic characterization of H. nana and H. diminuta in brown rats in Heilongjiang Province, China. Total 114 fecal samples were collected from brown rats in Heilongjiang Province. All the samples were subjected to morphological examinations by microscopy and genetic analysis by PCR amplification of the mitochondrial cytochrome c oxidase subunit 1 (COX1) gene and the internal transcribed spacer 2 (ITS2) region of the nuclear ribosomal RNA gene. In total, 6.1% (7/114) and 14.9% (17/114) of samples were positive for H. nana and H. diminuta, respectively. Among them, 7 and 3 H. nana isolates were successfully amplified and sequenced at the COX1 and ITS2 loci, respectively. No nucleotide variations were found among H. nana isolates at either of the 2 loci. Seventeen H. diminuta isolates produced 2 different COX1 sequences while 7 ITS2 sequences obtained were identical to each other. The present results of H. nana and H. diminuta infections in brown rats implied the risk of zoonotic transmission of hymenolepiasis in China. These molecular data will be helpful to deeply study intra-specific variations within Hymenolepis cestodes in the future. PMID- 28719964 TI - Discovery of Parasite Eggs in Archeological Residence during the 15th Century in Seoul, Korea. AB - During civil engineering construction near Sejong-ro, Jongro-ku, Seoul, cultural sites were found that are thought to have been built in the 15th century. This area was home to many different people as well as the leaders of the Yi dynasty. To gain further insight into the life styles of the inhabitants of the old capital, soil samples were collected from various areas such as toilets, water foundations, and drainage ways. Parasite eggs were examined by microscopy after 5 g soil samples were rehydrated in 0.5% trisodium phosphate solution. A total of 662 parasite eggs from 7 species were found. Species with the highest number of eggs found were Ascaris lumbricoides (n=483), followed by Trichuris trichiura (138), Trichuris vulpis (21), Fasciola hepatica (8), Clonorchis sinensis (6), Paragonimus westermani (4), and Metagonimus yokogawai (2). These findings indirectly indicate the food habits of the people in Yi dynasty. PMID- 28719965 TI - Living-donor liver transplantation for giant hepatic hemangioma with diffuse hemangiomatosis in an adult: a case report. AB - Hepatic hemangioma represents the most common benign primary hepatic neoplasm. Although most such tumors are small and asymptomatic, giant hepatic hemangioma is frequently symptomatic, and requires intervention. Moreover, diffuse multiple hepatic hemangiomatosis occupying almost the entire liver is extremely rare in adults, and the optimal management for this condition is unclear. We report a case of a rapidly growing, symptomatic giant hepatic hemangioma with diffuse hepatic hemangiomatosis in a 50-year-old female patient who was treated by living donor liver transplantation. This case shows malignant behavior of a benign hemangioma that required liver transplantation. Although this case could not meet the criteria for transplantation according to the MELD (model for end-stage liver disease) score system, it should be considered as an exceptional indication for deceased-donor liver allocation. Further studies of the mechanism underlying hemangioma growth are warranted. PMID- 28719966 TI - Safety and Complications of Interventional Endoscopic Ultrasound. AB - Endoscopic ultrasound (EUS) has become an essential tool for the diagnostic and therapeutic intervention of gastrointestinal diseases. Beyond the drainage of fluid collections, it enables decompression of inaccessible bile and pancreatic ducts, the gallbladder, and the creation of anastomosis within the gastrointestinal tract using fully lumen-apposing stents. This review explored the safety and efficacy of these novel procedures and discussed the training pathway that is necessary to perform them efficiently and safely. PMID- 28719967 TI - Is a Cytopathologist Always Needed during Endoscopic Ultrasonography-Guided Tissue Acquisition? PMID- 28719968 TI - Training in Endoscopy: Endoscopic Retrograde Cholangiopancreatography. AB - Endoscopic retrograde cholangiopancreatography (ERCP) is a key endoscopy skill used to diagnose and treat pancreatobiliary diseases. However, its diagnostic use is decreasing in favor of other less invasive methods such as magnetic resonance cholangiopancreatography and endoscopic ultrasound. Alternatively, its use has become more important in the therapeutic area. ERCP trainees must know the anatomy and physiology of the pancreatobiliary system, several key basic skills, and complications of a successful procedure. This article briefly introduces basic ERCP knowledge, techniques, numbers necessary to achieve competency, and complications for new ERCP operators. PMID- 28719969 TI - DMF as an Additive in a Two-Step Spin-Coating Method for 20% Conversion Efficiency in Perovskite Solar Cells. AB - DMF as an additive has been employed in FAI/MAI/IPA (FA= CH2(NH2)2, MA = CH3NH3, IPA = isopropanol) solution for a two-step multicycle spin-coating method in order to prepare high-quality FAxMA1-xPbI2.55Br0.45 perovskite films. Further investigation reveals that the existence of DMF in the FAI/MAI/IPA solution can facilitate perovskite conversion, improve the film morphology, and reduce crystal defects, thus enhancing charge-transfer efficiency. By optimization of the DMF amount and spin-coating cycles, compact, pinhole-free perovskite films are obtained. The nucleation mechanisms of perovskite films in our multicycle spin coating process are suggested; that is, the introduction of DMF in the spin coating FAI/MAI/IPA solution can lead to the formation of an amorphous phase PbX2 AI-DMSO-DMF (X = I, Br; A = FA, MA) instead of intermediate phase (MA)2Pb3I8.2DMSO. This amorphous phase, similar to that in the one-step method, can help FAI/MAI penetrate into the PbI2 framework to completely convert into the perovskite. As high as 20.1% power conversion efficiency (PCE) has been achieved with a steady-state PCE of 19.1%. Our work offers a simple repeatable method to prepare high-quality perovskite films for high-performance PSCs and also help further understand the perovskite-crystallization process. PMID- 28719971 TI - Is the Microbiome the Fifth Horseman of the Apocalypse in Drug Discovery? Implications for the Gut-Brain Axis. PMID- 28719972 TI - Risk Stratification of Thyroid Nodules With Atypia of Undetermined Significance/Follicular Lesion of Undetermined Significance (AUS/FLUS) Cytology Using Ultrasonography Patterns Defined by the 2015 ATA Guidelines. AB - PURPOSE: The purpose of this study was to evaluate the predictive value of ultrasonography (US) patterns based on the 2015 American Thyroid Association (ATA) guidelines for malignancy in atypia of undetermined significance or follicular lesion of undetermined significance (AUS/FLUS) nodules. METHODS: From January 2014 to August 2015, 133 thyroid nodules that were initially diagnosed as AUS/FLUS on fine needle aspiration (FNA) were included in this study. Each nodule was assigned a category with US patterns defined by the ATA guidelines. Clinical characteristics and US patterns were compared between the benign and malignant nodules, and malignancy rates were calculated according to the ATA guidelines. RESULTS: The malignancy rate in the very low suspicion group was 0.0% in AUS/FLUS nodules. When applying the ATA guidelines, significant differences existed for US patterns between the benign and malignant nodules in the AUS group ( P = .032) but not the FLUS group ( P = .168). CONCLUSIONS: Ultrasonography patterns by the 2015 ATA guidelines can provide risk stratification for nodules with AUS cytology but not for ones with FLUS cytology. For nodules with AUS/FLUS cytology with the very low suspicion pattern of the ATA guidelines, follow-up US might be recommended instead of repeat FNA. PMID- 28719973 TI - An Exploratory Study of Autonomic Function Investigations in Hemophiliacs on Homoeopathy Medications Using Impedance Plethysmography. AB - BACKGROUND: Status of autonomic homoeostasis in hemostasic disturbances due to hemophilia needs to be studied. OBJECTIVES: To compare autonomic nervous system markers measured by heart rate variability (HRV) and blood flow variability (BFV) in hemophiliacs and healthy age-matched control population using medical analyzer system. DESIGN: Cross-sectional study. SETTINGS: Motiwala Homoeopathy Medical College, and Hemophilia Clinics, Nashik. SUBJECTS: Eighty subjects. INTERVENTIONS: Nil. OUTCOME MEASURES: Autonomic function markers for HRV and BFV. RESULTS: Among 80 subjects, BFV time domain measure, root mean square of successive NN (normal-to-normal) interval differences (RMSSD), was significantly higher among hemophiliacs than nonhemophiliacs. Frequency domain analysis parameter, low frequency for both HRV and BFV was significantly higher among hemophiliacs as compared with nonhemophiliacs. CONCLUSIONS: Hemophiliacs were shown to have higher autonomic activity as compared with healthy controls. Homoeopathic medicines used as an adjunct was associated with decrease in parasympathetic modulations. PMID- 28719974 TI - The Accuracy of Common Hand Injections With and Without Ultrasound: An Anatomical Study. AB - BACKGROUND: The aim of the study is to determine the accuracy of hand injections with and without the aid of ultrasound (U/S) into the carpal tunnel, thumb carpometacarpal (CMC) joint, first dorsal compartment (DC) and the radiocarpal (RC) joint. METHODS: Four participants of various level of experience injected the carpal tunnel, thumb CMC, first DC, and RC joint into 40 fresh frozen cadaver specimens with blue dye and radiographic contrast. Participants 1 and 2 were injected without U/S guidance, and participants 3 and 4 were injected with U/S guidance. A successful injection was determined by both fluoroscopy and dissection/direct observation. Additional information was recorded for each injection such as median nerve infiltration and evidence of thumb CMC arthrosis. RESULTS: The overall accuracy for carpal tunnel, thumb CMC, first DC, and RC injections were 95%, 63%, 90%, and 90%, respectively. Success was compared with and without U/S guidance. Success rates were similar for each injection site, except the thumb CMC joint, where U/S participants had 25% higher accuracy. In the setting of thumb CMC arthrosis, the incidence of success was 38% for participants with no U/S aid and 72% for participants with U/S aid. There was a significant difference between participants who used U/S with the participant with more U/S experience being more successful. CONCLUSION: Carpal tunnel, first DC, and RC injections had an accuracy of greater than 90%. Thumb CMC injections have a lower accuracy (63%) and one can improve accuracy with U/S. The accuracy of U/S-guided injections is dependent on the user and their experience. PMID- 28719975 TI - Toxicological Effects of Aqueous Extract From African Walnut ( Tetracarpidium conophorum) Leaves in Rats. AB - Tetracarpidium conophorum leaves are used in traditional medicine for the treatment of male infertility, without considering its toxicity and side effects. In this study, we investigated the effects of T conophorum leaves on some biochemical parameters such as alanine aminotransferase, aspartate aminotransferase, bilirubin, albumin, creatinine, and uric acid. Histology of the liver and kidney were also assessed. The result revealed that the alanine aminotransferase and aspartate aminotransferase levels of the control group were not significantly different from the experimental groups. There was no significant difference in the albumin and bilirubin levels of the control and experimental groups. Similarly, the uric acid and creatinine levels of the experimental rats were not significantly different from the control. The examination of liver and kidney sections did not show any morphological changes and inflammatory cell infiltrations. These findings suggest that the leaves did not induce any pathological changes at the doses tested. PMID- 28719976 TI - Radiographic Analysis of Simulated First Dorsal Interosseous and Opponens Pollicis Loading Upon Thumb CMC Joint Subluxation: A Cadaver Study. AB - BACKGROUND: Therapy programs to treat thumb carpometacarpal (CMC) arthritis may engage selective activation and reeducation of thenar muscles, particularly the first dorsal interosseous (FDI) and opponens pollicis (OP) to reduce subluxation of the joint. We describe the effect of simulated selective activation of the FDI and OP muscles upon radiographic subluxation of the thumb CMC joint. METHODS: In a cadaver model of CMC subluxation, loads were applied to the FDI, the OP, and then concomitantly at 0%, 25%, 50%, 75%, and 100% maximal loads and radial subluxation of the joint and reduction in subluxation was measured. RESULTS: Selective activation of the OP, alone, improved the subluxation ratio (SR) in a dose-dependent manner. Selective activation of FDI, alone, demonstrated minimal effects on SR. Concomitant activation of OP and FDI improved the SR across all loading states, and activation of 75% and greater, when compared with FDI activation alone, resulted in a statistically significant improvement in SR to within 10% of the presubluxed joint. CONCLUSIONS: Concomitant activation of the FDI and OP acts to reduce subluxation of the thumb CMC joint in a dose-dependent fashion. The OP is likely the predominant reducing force. Hand therapy programs that focus on selective strengthening programs likely function in part to encourage patients to activate the easily palpable and easily understood FDI. Concomitant coactivation of the OP may be the major reducing force to elicit clinical and radiographic reduction of subluxation, improved thumb positioning, and reduction of pain and arthritic symptoms. PMID- 28719977 TI - The efficacy of interactive, motion capture-based rehabilitation on functional outcomes in an inpatient stroke population: a randomized controlled trial. AB - OBJECTIVE: To compare the efficacy of novel interactive, motion capture rehabilitation software to usual care stroke rehabilitation on physical function. DESIGN: Randomized controlled clinical trial. SETTING: Two subacute hospital rehabilitation units in Australia. PARTICIPANTS: In all, 73 people less than six months after stroke with reduced mobility and clinician determined capacity to improve. INTERVENTIONS: Both groups received functional retraining and individualized programs for up to an hour, on weekdays for 8-40 sessions (dose matched). For the intervention group, this individualized program used motivating virtual reality rehabilitation and novel gesture controlled interactive motion capture software. For usual care, the individualized program was delivered in a group class on one unit and by rehabilitation assistant 1:1 on the other. MAIN MEASURES: Primary outcome was standing balance (functional reach). Secondary outcomes were lateral reach, step test, sitting balance, arm function, and walking. RESULTS: Participants (mean 22 days post-stroke) attended mean 14 sessions. Both groups improved (mean (95% confidence interval)) on primary outcome functional reach (usual care 3.3 (0.6 to 5.9), intervention 4.1 (-3.0 to 5.0) cm) with no difference between groups ( P = 0.69) on this or any secondary measures. No differences between the rehabilitation units were seen except in lateral reach (less affected side) ( P = 0.04). No adverse events were recorded during therapy. CONCLUSION: Interactive, motion capture rehabilitation for inpatients post stroke produced functional improvements that were similar to those achieved by usual care stroke rehabilitation, safely delivered by either a physical therapist or a rehabilitation assistant. PMID- 28719978 TI - Optimizing RNA Extraction of Renal Papilla Biopsy Tissue in Kidney Stone Formers: A New Methodology for Genomic Study. AB - INTRODUCTION: Endoscopic tools have provided versatile examination and treatment for kidney stone procedures. Despite endourologists researching urinary stone disease using endoscopes to collect tissue, this tissue collection method is limited. Endoscopically removed tissues are small in size, restricting the types of genome-based examination possible. We investigated a new method of renal papilla biopsy and RNA extraction to establish a genomic research methodology for kidney stone disease. PATIENTS AND METHODS: We conducted a prospective multi institutional study and collected renal papilla specimens from consecutive percutaneous nephrolithotomy and ureteroscopy (URS) cases performed for removal of upper urinary tract stones. Renal papilla tissue was extracted using ureteroscopic biopsy forceps after stone removal. RNA was extracted using two different extraction kits, and their quantity and quality were examined. Additionally, the impact of biopsy on surgical complications was compared between cases performed with and without biopsy by matched case-control analysis adjusted for age, gender, body mass index, bilaterality, and stone burden. RESULTS: A total of 90 biopsies from 49 patients were performed, and the median duration between specimen collection and RNA extraction was 61 days. Both univariate and multivariate analyses showed BIGopsy(r) forceps usage significantly increased the total yield (p = 0.004) and quality (p = 0.001 for A260/280, p = 0.004 for A260/A230) of extracted RNA. Extraction using the RNeasy Micro Kit(r) also improved A260/A230, whereas reduced RNA integrity number of extracted RNA by univariate and multivariate analyses (p = 0.002 and p < 0.001, respectively). Moreover, matched case-control study demonstrated that endoscopic renal papilla biopsy caused no significant surgical complications, including bleeding, decreased stone clearance and hematocrit, and renal dysfunction. Biopsies during URS imparted an average of 20 minutes of procedure time over nonbiopsy cases. CONCLUSIONS: We demonstrate a safe methodology for optimal RNA extraction of renal papilla tissue. This technique will accelerate advanced genomic studies for kidney stone formers by facilitating larger tissue yields. PMID- 28719980 TI - Distinguishing Epidermolysis Bullosa Acquisita From Bullous Pemphigoid Without Direct Immunofluorescence. AB - BACKGROUND: It has been postulated that periodic acid-Schiff staining of basement membrane can predict direct immunofluorescence patterns seen in epidermolysis bullosa acquisita and bullous pemphigoid. It has also been suggested that the type of inflammatory infiltrate or presence of fraying of basal keratinocytes may differentiate these two conditions. OBJECTIVE: In this study, we aimed to confirm these observations. METHODS: We reviewed 13 cases of direct immunofluorescence confirmed epidermolysis bullosa acquisita and 19 cases of direct immunofluorescence-confirmed bullous pemphigoid, all with a subepidermal blister in the routinely processed specimen. The gold standard for diagnosis of epidermolysis bullosa acquisita vs bullous pemphigoid was taken to be identification of immune deposits on the dermal side ('floor' for epidermolysis bullosa acquisita) or the epidermal side ('roof' for bullous pemphigoid) of the salt-split direct immunofluorescence specimen. Our tests to distinguish epidermolysis bullosa acquisita from bullous pemphigoid on the routinely processed biopsy included periodic acid-Schiff basement membrane on the blister roof, neutrophilic infiltrate, lack of eosinophilic infiltrate, and absence of keratinocyte fraying. RESULTS: Sensitivity and specificity for each test were as follows: periodic acid-Schiff staining of roof (sensitivity 25%, specificity 95%), neutrophilic infiltrate (sensitivity 54%, specificity 74%), lack of eosinophilic infiltrate (sensitivity 92%, specificity 68%), and absence of keratinocyte fraying (sensitivity 62%, specificity 58%). CONCLUSIONS: Features in the routinely processed biopsy were unable to reliably distinguish between epidermolysis bullosa acquisita and bullous pemphigoid. Direct immunofluorescence on salt-split skin remains the standard for differentiation. PMID- 28719979 TI - Prevalence of Protective Shielding Utilization for Radiation Dose Reduction in Adult Patients Undergoing Body Scanning Using Computed Tomography. AB - PURPOSE: Ionizing radiation is implicated in nearly 2% of malignancies in the United States; radiation shields prevent unnecessary radiation exposure during medical imaging. Contemporary radiation shield utilization for adult patients in the United States is poorly defined. Therefore, we evaluated the prevalence of protective shielding utilization in adult patients undergoing CT scans in United States' hospitals. MATERIALS AND METHODS: An online survey was sent to established radiology departments randomly selected from the 2015 American Hospital Association Guide. Radiology departments conducting adult CT imaging were eligible; among 370 eligible departments, 215 departments accepted the study participation request. Questions focused on shielding practices during CT imaging of the eyes, thyroid, breasts, and gonads. Prevalence data were stratified per hospital location, size, and type. Main outcomes included overall protective shielding utilization, respondents' belief and knowledge regarding radiation safety, and organ-specific shielding prevalence. RESULTS: Sixty-seven of 215 (31%) hospitals completed the survey; 66 (99%) reported familiarity with the ALARA (as low as reasonably achievable) principle and 56 (84%) affirmed their belief that shielding is beneficial. Only 60% of hospitals employed shielding during CT imaging; among these institutions, shielding varied based on CT study: abdominopelvic CT (13, 33%), head CT (33, 83%), or chest CT (30, 75%). CONCLUSIONS: Among surveyed hospitals, 40% do not utilize CT shielding despite the majority acknowledging the ALARA principle and agreeing that shielding is a beneficial practice. Failure to address the low prevalence of protective shielding may lead to poor community health due to increased risk of radiation related cancers. PMID- 28719981 TI - The mental representation of the human gait in patients with severe knee osteoarthrosis: a clinical study to aid understanding of impairment and disability. AB - OBJECTIVE: Objectives were (1) to explore differences in gait-specific long-term memory structures and gait performance between knee osteoarthrosis patients and healthy subjects and (2) to identify the extent to which the gait-specific mental representation is associated with gait performance. DESIGN: Cross-sectional study. SUBJECTS: In total, 18 knee osteoarthrosis patients and 18 control subjects. METHODS: Spatio-temporal (gait speed, step length) and temporophasic (stance time, swing time, single support time, total double support time) gait parameters and gait variability were measured with an electronic walkway (OptoGait). The mental representation was assessed using the structural dimensional analysis of mental representations (SDA-M). RESULTS: (1) Patients showed significantly longer stance times ( P < 0.002) and total double support times, shorter swing times and single support times, a decreased gait speed ( P values < 0.001) and structural differences in the gait-specific mental representation as compared with the healthy controls. (2) Correlation analyses revealed the mental representation of the human gait to be associated with actual gait performance in osteoarthrosis patients. Double support times were positively associated with the structural quality of the mental representation and step length variability was positively associated with the number of sequencing errors in the representation. CONCLUSION: The gait-specific mental representation and actual gait performance differ between patients with severe knee osteoarthrosis and healthy controls, and both are linked to one another. This finding suggests that musculoskeletal disorders can lead to changes in the mental representation of the gait, and as such the SDA-M could provide useful information to improve the rehabilitation following osteoarthrosis. PMID- 28719983 TI - Neonatal Lemierre Syndrome: Youngest Reported Case and Literature Review. AB - A previously healthy 5-week-old female was admitted for sepsis secondary to methicillin-resistant Staphylococcus aureus (MRSA) bacteremia. After several days of hospitalization, she experienced acute decompensation in mental status despite having received targeted antibiotic therapy. Imaging revealed left peritonsillar/parapharyngeal space abscess, left venous thrombophlebitis of the internal jugular vein, and septic emboli of the lungs and brain consistent with Lemierre syndrome. Bedside needle aspiration of the parapharyngeal abscess confirmed MRSA involvement. Unfortunately, the patient continued to deteriorate over the next several days and life support was withdrawn on hospital day 16. We present the youngest reported case of Lemierre syndrome and review the literature. PMID- 28719982 TI - Deep Friction Massage Versus Steroid Injection in the Treatment of Lateral Epicondylitis. AB - BACKGROUND: The aim of the study was to determine the efficacy of deep friction massage in the treatment of lateral epicondylitis by comparing outcomes with a control group treated with splinting and therapy and with an experimental group receiving a local steroid injection. METHODS: A randomized clinical trial was conducted to compare outcomes after recruitment of consecutive patients presenting with lateral epicondylitis. Patients were randomized to receive one of 3 treatments: group 1: splinting and stretching, group 2: a cortisone injection, or group 3: a lidocaine injection with deep friction massage. Pretreatment and posttreatment parameters of visual analog scale (VAS) pain ratings, Disabilities of the Arm, Shoulder and Hand (DASH) scores, and grip strength were measured. RESULTS: Outcomes were measured at early follow-up (6-12 weeks) and at 6-month follow-up. There was a significant improvement in VAS pain score in all treatment groups at early follow-up. DASH score and grip strength improved in the cortisone injection group and the deep friction massage group at early follow-up; these parameters did not improve in the splinting and stretching group. At 6-month follow-up, only patients in the deep friction massage group demonstrated a significant improvement in all outcome measures, including VAS pain score, DASH score, and grip strength. CONCLUSIONS: Deep friction massage is an effective treatment for lateral epicondylitis and can be used in patients who have failed other nonoperative treatments, including cortisone injection. PMID- 28719985 TI - A Focus on Behavior Management of Avoidant/Restrictive Food Intake Disorder (ARFID): A Case Series. PMID- 28719984 TI - Cytotoxic and Immunomodulatory Potential Activity of Physalis peruviana Fruit Extracts on Cervical Cancer (HeLa) and Fibroblast (L929) Cells. AB - It was purposed to evaluate the biological potential of ethanol and isopropanol crude extracts of ripe Physalis peruviana fruits. Cytotoxic and immunomodulatory effects of the expression of interleukin-6, interleukin-8, and monocyte chemoattractant protein-1 (MCP-1) were evaluated on human cervical cancer (HeLa) and murine fibroblast (L929) cells. The composition was evaluated by high performance liquid chromatography diode-array detection and high-performance liquid chromatography ultraviolet/visible detection. The presence of ursolic acid and rosmarinic acid was found in both solvents. However, gallic acid, quercetin, and epicatechin were higher in isopropanol extracts ( P < .05). The results indicated a relationship among the total polyphenol content, antioxidant activity, and cytotoxic activity that was dependent on the solvent used. Isopropanol extracts presented a half-maximal inhibition concentration value (IC50) of 60.48 +/- 3.8 MUg/mL for HeLa cells and 66.62 +/- 2.67 MUg/mL for L929 fibroblasts. The extracts reduced the release of interleukin-6, interleukin-8, and MCP-1 in a dose-dependent manner. Extracts showed anticancer and immunomodulatory potential for new complementary pharmaceutical products development. PMID- 28719986 TI - Three-Dimensional Printing of Surgical Clips: An In Vitro Pilot Study and Trial of Efficacy. AB - INTRODUCTION AND OBJECTIVE: Three-dimensional (3D) printing applications have increased over the past decade. Our objective was to test rapid prototyping of a 3D printed surgical clip for intraoperative use. MATERIALS AND METHODS: Our prototype was modeled after the 10 mm Weck(r) Hem-o-lok(r) polymer clip (Teleflex, Inc., Wayne, PA). A 3D computer-aided design model of the Hem-o-lok clip was reverse engineered using commercial microscopy and printing was done using an Objet Connex500 multijetting system (Stratasys, Eden Prairie, MN). The initial polymer was Objet VeroWhitePlus RGD835; the addition of Objet TangoBlackPlus FLX980 during the design process improved hinge flexibility. The 3D printed clips were then pressure tested on rubber Penrose tubing and compared in vitro versus commercial Hem-o-lok clips. RESULTS: Initial 3D printed clips were not functional as they split at the hinge upon closure of the clip jaws. Design changes were made to add Objet TangoBlackPlus FLX980 at the hinge to improve flexibility. Additional modifications were made to allow for clips to be compatible with the Hem-o-lok endoscopic clip applier. A total of 50 clips were tested. Fracture rate for the printed clips using a clip applier was 54% (n = 27), whereas none of the commercial Hem-o-lok clips broke upon closure. Of the 23 printed clips that closed, mean leak was at 20.7 kappaPa (range 4.8-42.7). In contrast, none of the commercial clips leaked, and fill continued until Penrose rupture at mean 46.2 kappaPa (44.8-47.6). CONCLUSIONS: This pilot study demonstrates feasibility of 3D printing functional surgical clips. However, the performance of our first generation clips is poor compared with commercial grade product. Refinement in printers and materials available may allow for customization of such printed surgical instruments that could be economically competitive to purchasing and stocking product. PMID- 28719987 TI - Corrective Osteotomy of Malunited Diaphyseal Fractures of the Forearm Simplified Using 3-Dimensional CT Data: Proposal of Our Simple Strategy Through Case Presentation. AB - BACKGROUND: Reconstruction of malunited diaphyseal fractures of the forearm is one of the most difficult treatments due to its complicated structure. Widespread usage of Digital Imaging and Communications in Medicine (DICOM) data of 3 dimensional (3D) computed tomography (CT) and 3D printing can make estimating the true plane of the deformity easy. METHODS: A 21-year-old man with limited supination due to left forearm nonunion deformity initially treated by locking plate fixation was referred to our hospital. We evaluated the deformity by superimposing the mirror image bone model of the contralateral normal bone onto a model of the affected bone and 3D real full-scale bone model. RESULTS: The patient underwent a manual corrective osteotomy according to our planning. He had satisfactory improvement of his symptoms with no complications. CONCLUSIONS: We postulated that our simple preoperative simulation and manual osteotomy with the aid of 3D CT reconstruction and 3D real full-scale bone model fit in the clinical practice as a recent trend. PMID- 28719988 TI - Experiences of Integrated Care for dementia from family and carer perspectives: A framework analysis of massive open online course discussion board posts. AB - Background Integrated Care for dementia is an increasingly popular approach to supporting people with dementia, bringing services together to form a single cohesive provision for service users. This approach is still in its infancy but has the potential to improve the management of dementia, social care and to enhance the patient experience. Aims To understand views and experiences of integrated health and social care for dementia from the perspective of carers, families, healthcare professionals and researchers. Methods Crowdsourcing views and experiences from 'Bridging the Dementia Divide', a massive open online course at the University of Derby, provide a rich source of qualitative data from carers, families and healthcare professionals. We analysed 847 massive open online course discussion board posts using a Framework Analysis approach. Results Participants described how Integrated Care for dementia should be person-centred and holistic, involving a multidisciplinary team of health and social care practitioners, as well as the patient, the family and the wider community. The establishment of Integrated Care for dementia was viewed positively. PMID- 28719989 TI - Table Saw Injuries: Are Our Safety Features Really Keeping Us Safe? AB - BACKGROUND: Currently, table saws sold in the United States have 3 safety features (riving knife, blade guard, and antikickback device) designed to prevent personal injury; however, these features can hinder the user's movements and are often disabled or removed. Despite the frequency of table saw injuries, there is relatively limited literature regarding them. METHODS: We performed a retrospective, observational study of characteristics associated with injuries incurred while using a table saw. Electronic medical records from Bassett Medical Center were reviewed from 2002 to 2014 to identify patients who sustained table saw injury, and surveys were sent to the patients. Tests of association between survey variables (eg, presence/absence of safety device vs severity of injury) were carried out using chi-square or Fisher exact test. RESULTS: Seventy-three percent of those injured had disabled their safety features or had no safety features present; 27% of those injured had one or more safety features enabled when they sustained the injury. Of those injured, 18% sustained a "mild" injury (skin laceration), 39% sustained a "moderate" injury (nerve or tendon injury), and 43% sustained a "severe" injury (partial or complete amputation). There was no statistically significant association between severity of the injury and presence/absence of safety features. CONCLUSIONS: This study highlights 2 major problems with the current safety features: People are dissatisfied with current safety features, disabling them and sustaining injuries, and even when they are enabled, people are still getting injured-suggesting inadequacy of the current features. PMID- 28719990 TI - Radiographic and Clinical Assessment of Intramedullary Nail Fixation for the Treatment of Unstable Metacarpal Fractures. AB - BACKGROUND: The purpose of the article was to evaluate clinical and radiographic outcomes in a case series of unstable metacarpal fractures treated with flexible intramedullary nail (IMN) fixation. METHODS: A total of 55 patients with unstable metacarpal fractures between 2003 and 2010 were treated with IMN fixation and followed for a minimum of 1 year. The outcomes were assessed via a radiological study of longitudinal and angular collapse, Disabilities of the Arm, Shoulder, and Hand (DASH) score, total active range of motion (ROM) of the wrist, and grip strength testing. RESULTS: In the 55 patients, metacarpal fractures were healed by clinical and radiographic assessment at an average of 12.7 weeks. IMNs were removed in all cases at an average of 13.9 weeks. Patients regained full finger ROM at the final follow-up and were capable of 72.4% of motion at 2 weeks postoperatively. The mean DASH score at the final follow-up was 6.5. Complications included 3 cases of extensor tendon irritation that resolved without functional impairment and 2 cases of "backing out" that required reoperation to replace the pin. In one case, a bony exostosis formed on the affected metacarpal that led to tendon irritation and required operative excision. CONCLUSIONS: We found that this technique allowed for the stabilization of fractures, early ROM, resumption of usual activities, reduced immobilization, and minimal complications. A removable orthosis, instead of a cast, allowed for earlier mobilization of the wrist, metacarpophalangeal, and proximal interphalangeal joints. PMID- 28719991 TI - The Diagnostic Utility and Clinical Implications of Wrist MRI in the Pediatric Population. AB - BACKGROUND: Unexplained wrist pain is a common presentation in children. To our knowledge, no studies have explored the clinical utility of magnetic resonance imaging (MRI) in the diagnostic workup of pediatric patients. METHODS: We retrospectively reviewed 307 consecutive wrist MRIs ordered at a tertiary-care pediatric hospital. Demographic data and the indication for imaging were recorded and grouped into admitting categories. The final impression of each MRI was scored with regard to potential impact on future treatment (0 = normal, 1 = minimal, 2 = moderate, 3 = high). Patients who went on to wrist surgery within 1 year were noted. RESULTS: In our cohort, 27% of all studies were normal, including 34% of those with pain. Although pain was the most common category, MRI was most useful in the delineation of a mass/cyst, evaluating for infection and evaluating arthropathy. Compared with all other categories, patients with pain were 3.6 times more likely to have a normal study and 4.6 times more likely to have a clinical score less than or equal to 1. Given an admitting diagnosis of pain, females were 1.7 times more likely to present for an MRI and 2.4 times more likely to have a normal MRI. The Spearman correlation revealed no linear relationship between age and MRI outcome. In all, 13% of patients went on to have surgery within 1 year of MRI. CONCLUSIONS: At our pediatric institution, the majority of wrist MRIs were ordered for wrist pain. Given our data, wrist MRI is not an ideal screening tool in children, particularly in those with wrist pain, and should only be used to exclude or confirm a specific diagnosis. PMID- 28719992 TI - Does Mindfulness Correlate With Physical Function and Pain Intensity in Patients With Upper Extremity Illness? AB - BACKGROUND: Mindfulness skills training interventions seem efficacious in increasing physical function and decreasing pain intensity in patients with chronic pain. The relationship of mindfulness and upper extremity complaints in patients presenting to orthopedic surgical practices is not known. The aim of this study was to assess if mindfulness has a relationship to physical function and pain intensity in patients with upper extremity illness. METHODS: In this cross-sectional study, a total of 126 patients with a nontraumatic upper extremity condition were asked to fill out questionnaires assessing the 5 facets of mindfulness, pain intensity, and upper extremity physical function, along with clinical and demographic variables prior to their visit with the surgeon. RESULTS: Nonreactivity to inner experiences was the only facet of mindfulness that was correlated with upper extremity physical function and pain intensity. The overall mindfulness score was correlated with pain intensity only. In multivariable analyses, mindfulness was not associated with either physical function or with pain intensity. Pain interference was the most important predictor of both pain intensity and physical function. CONCLUSIONS: Greater overall mindfulness was associated with lower pain intensity, and greater ability to be nonreactive to inner experiences was associated with both pain intensity and upper extremity physical function in bivariate but not multivariable analyses. Pain interference was the most important predictor of both pain intensity and upper extremity physical function. Psychosocial interventions focused on improving physical function and decreasing pain intensity in this population should focus primarily on reducing pain interference, and secondarily on teaching patients mindfulness skills. PMID- 28719993 TI - Comparison of Treatment Results for Mallet Finger Fractures in Children Between Low-Intensity Pulsed Ultrasound Stimulation and Ishiguro's Method. AB - BACKGROUND: We compared the treatment results for displaced mallet finger fractures in children between low-intensity pulsed ultrasound (LIPUS) stimulation and Ishiguro's method, which involves extension block and arthrodesis of the distal interphalangeal (DIP) joint with pinning. METHODS: Eleven cases (5 females and 6 males; average age, 13.5 years) of mallet finger were operated with Ishiguro's method, and 8 cases (3 females and 5 males; average age, 13.0 years) were treated with LIPUS stimulation. Lateral radiographs were used to determine the distance of fragment displacement and the percentage of the articular surface involved in the fragments. Functional outcomes in flexion and extension and those estimated using Crawford's evaluation criteria at the final visits were assessed in each group. RESULTS: The duration needed for fracture healing was longer, however, active extension and flexion of the DIP joint were significantly larger in the LIPUS group compared with those in the pinning group. Functional recovery was excellent in all cases in the LIPUS group; however, recovery was good in 3 cases and excellent in 8 cases in the pinning group. Extension of the DIP joint was significantly larger when pins were removed in 35 or lesser days postoperatively compared with cases in which pin fixation was continued for more than 35 days. CONCLUSIONS: LIPUS therapy may be recommended as an option to treat type I mallet finger in children for whom initiation of treatment was delayed up to 8 weeks. When Ishiguro's method is applied to the displaced mallet fracture in children, arthrodesis of the DIP joint for more than 5 weeks should be avoided to prevent flexion contracture. PMID- 28719994 TI - Giant Cell Tumor of the Metacarpal: Case Report. AB - BACKGROUND: Giant cell tumor (GCT) of bone is a benign, though locally aggressive tumor, classically described as an eccentric lytic lesion, often with cortical expansion and destruction. It typically involves the metaphysis or epiphysis of long bones in skeletally mature patients, with a slight female predominance. The incidence in the small bones of the hand has been reported to be 2% to 5%. METHODS: Treatment options have evolved in recent years, and currently include intralesional curettage with or without adjuvant therapy, wide resection, and occasionally amputation. RESULTS: In this report, we present a long-term follow up (10 years) of a patient with GCT involving a metacarpal, who was initially reconstructed with a metacarpal head allograft, which was eventually revised to a metacarpophalangeal (MCP) total joint arthroplasty. CONCLUSIONS: To our knowledge, this is the only report of pyrocarbon being used for tumor reconstruction and the only report of late MCP allograft salvage. PMID- 28719995 TI - Biomechanics of the Proximal Radius Following Drilling of the Bicipital Tuberosity to Mimic Cortical Button Distal Biceps Repair Technique. AB - BACKGROUND: A fracture through the proximal radius is a theoretical concern after cortical button distal biceps fixation in an active patient. The permanent, nonossified cortical defect and medullary tunnel is at risk during a fall eliciting rotational and compressive forces. We hypothesized that during simulated torsion and compression, in comparison with unaltered specimens, the cortical button distal biceps repair model would have decreased torsional and compressive strength and would fracture in the vicinity of the bicipital tuberosity bone tunnel. METHODS: Sixteen fourth-generation composite radius Sawbones models were used in this controlled laboratory study. A bone tunnel was created through the bicipital tuberosity to mimic the exact bone tunnel, 8 mm near cortex and 3.2 mm far cortex, made for the BicepsButton distal biceps tendon repair. The radius was then prepared and mounted on either a torsional or compression testing device and compared with undrilled control specimens. RESULTS: Compression tests resulted in average failure loads of 9015.2 N in controls versus 8253.25 N in drilled specimens ( P = .074). Torsional testing resulted in an average failure torque of 27.3 Nm in controls and 19.3 Nm in drilled specimens ( P = .024). Average fracture angle was 35.1 degrees in controls versus 21.1 degrees in drilled. Gross fracture patterns were similar in compression testing; however, in torsional testing all fractures occurred through the bone tunnel in the drilled group. CONCLUSION: There are weaknesses in the vicinity of the bone tunnel in the proximal radius during biomechanical stress testing which may not be clinically relevant in nature. CLINICAL RELEVANCE: In cortical button fixation, distal biceps repairs creates a permanent, nonossified cortical defect with tendon interposed in the bone tunnel, which can alter the biomechanical properties of the proximal radius during compressive and torsional loading. PMID- 28719996 TI - Efficacy of Short-Term Robot-Assisted Rehabilitation in Patients With Hand Paralysis After Stroke: A Randomized Clinical Trial. AB - BACKGROUND: We evaluated the effectiveness of robot-assisted motion and activity in additional to physiotherapy (PT) and occupational therapy (OT) on stroke patients with hand paralysis. METHODS: A randomized controlled trial was conducted. Thirty-two patients, 34.4% female (mean +/- SD age: 68.9 +/- 11.6 years), with hand paralysis after stroke participated. The experimental group received 30 minutes of passive mobilization of the hand through the robotic device Gloreha (Brescia, Italy) , and the control group received an additional 30 minutes of PT and OT for 3 consecutive weeks (3 d/wk) in addition to traditional rehabilitation. Outcomes included the National Institutes of Health Stroke Scale (NIHSS), Modified Ashworth Scale, Barthel Index (BI), Motricity Index (MI), short version of the Disabilities of the Arm, Shoulder and Hand (QuickDASH), and the visual analog scale (VAS) measurements. All measures were collected at baseline and end of the intervention (3 weeks). RESULTS: A significant effect of time interaction existed for NIHSS, BI, MI, and QuickDASH, after stroke immediately after the interventions (all, P < .001). The experimental group had a greater reduction in pain compared with the control group at the end of the intervention, a reduction of 11.3 mm compared with 3.7 mm, using the 100-mm VAS scale. CONCLUSIONS: In the treatment of pain and spasticity in hand paralysis after stroke, robot-assisted mobilization performed in conjunction with traditional PT and OT is as effective as traditional rehabilitation. PMID- 28719997 TI - The benefit of evolving multidisciplinary care in ALS: a diagnostic cohort survival comparison. AB - BACKGROUND: Care for people with amyotrophic lateral sclerosis (ALS) has altered at King's College Hospital over the last 20 years. The clinic has been a multidisciplinary, specialist, tertiary referral centre since 1995 with a large team with integrated palliative and respiratory care since 2006. We hypothesised that these changes would improve survival. METHODS: In this retrospective observational study, patients diagnosed with El Escorial definite, probable and possible ALS between 1995-1998 and 2008-2011 were followed up. The primary outcome measure was a chi-square test for the proportion of each cohort surviving. Kaplan-Meier survival analysis and Cox multivariate regression were secondary analyses. RESULTS: There was low reporting of some interventions. Five hundred and forty-seven people were included. Survival between the cohorts was significantly different (p = 0.022) with a higher proportion surviving during 2008-2011. Survival time was 21.6 (95% CI 19.2-24.0) months in the 2008-2011 cohort compared to 19.2 years (15.6-21.6) in the 1995-1998 cohort (log rank p = 0.018). Four hundred and ninety-three cases were included in the Cox regression. Diagnostic cohort was a significant predictor variable (HR 0.79 (0.64-0.97) p = 0.023). CONCLUSIONS: These results support the hypothesis that integrated specialist clinics with multidisciplinary input improve survival in ALS. PMID- 28719998 TI - Beta-lactamase database (BLDB) - structure and function. AB - Beta-Lactamase Database (BLDB) is a comprehensive, manually curated public resource providing up-to-date structural and functional information focused on this superfamily of enzymes with a great impact on antibiotic resistance. All the enzymes reported and characterised in the literature are presented according to the class (A, B, C and D), family and subfamily to which they belong. All three dimensional structures of beta-lactamases present in the Protein Data Bank are also shown. The characterisation of representative mutants and hydrolytic profiles (kinetics) completes the picture and altogether these four elements constitute the essential foundation for a better understanding of the structure function relationship within this enzymes family. BLDB can be queried using different protein- and nucleotide-based BLAST searches, which represents a key feature of particular importance in the context of the surveillance of the evolution of the antibiotic resistance. BLDB is available online at http://bldb.eu without any registration and supports all modern browsers. PMID- 28719999 TI - Comparison of anticancer activity of biocompatible ZnO nanoparticles prepared by solution combustion synthesis using aqueous leaf extracts of Abutilon indicum, Melia azedarach and Indigofera tinctoria as biofuels. AB - Recently, there has been an upsurge in the use of naturally available fuels for solution combustion synthesis (SCS) of nanoparticles. Although many reports suggest that these biofuels pose less harm to the environment, their strategic advantages and reliability for making NPs has not been discussed. In the present work, we try to address this issue using plant extracts as biofuels for the SCS of zinc oxide nanoparticles as a model system. In the present work, combustion synthesis of ZnO NPs using lactose and aqueous leaf extracts of Abutilon indicum, Melia azedarach, Indigofera tinctoria as biofuels has been carried out. A comparative analysis of the obtained powders has been conducted to understand the strategic advantages of using plant extracts over a chemical as combustion fuel for the synthesis of zinc oxide nanoparticles. The X-ray diffractograms of the samples revealed the presence of Wurtzite hexagonal structure with varying crystallite sizes. Morphological studies indicated that samples prepared using biofuels had smaller diameter than those prepared using lactose as fuel. Surface characteristics of the samples were measured by X-ray photoelectron spectroscopy. Qualitative phytochemical screening of aqueous leaf extracts revealed the presence of many phytochemicals in them, which might be responsible for combustion. Gas chromatography mass spectrum was carried out to detect the phytochemicals present in the aqueous extracts of the leaves. Further, anticancer evaluation carried out against DU-145 and Calu-6 cancer cells indicated higher anticancer activity of zinc oxide nanoparticles prepared using biofuels. The results of blood haemolysis revealed the biocompatibility of zinc oxide nanoparticles at lower concentrations. In conclusion, we propose that multiple other studies would be required in order to vindicate the potential advantages of using naturally available fuels in SCS. PMID- 28720000 TI - Differentiation Between Pyogenic Flexor Tenosynovitis and Other Finger Infections. AB - BACKGROUND: Hospital transfer decisions regarding pyogenic flexor tenosynovitis (PFT) are made difficult by emergency department presentations similar to other finger infections, with pain, redness, and functional limitation. Our objectives were to: (1) determine diagnostic sensitivity and specificity of Kanavel signs; and (2) identify existing factors most predictive of PFT during initial presentation. METHODS: Adult patients who underwent surgical consultation for concern of PFT over a 5-year period were identified retrospectively. Bivariate screening identified clinical criteria for differentiation, and multivariate logistic regression was performed to control for confounding. We then created a prediction algorithm for diagnosis of PFT. Receiver operating characteristic (ROC) curve analysis was used to evaluate diagnostic accuracy. RESULTS: Patients with PFT differed significantly from those with non-PFT finger infections in regard to the 4 Kanavel signs, duration of symptoms less than 5 days, and erythrocyte sedimentation rate. Sensitivity of the Kanavel signs ranged from 91.4% to 97.1%. Specificity ranged from 51.3% to 69.2%. Logistic regression identified independent predictors for PFT as tenderness along the flexor tendon sheath, pain with passive extension, and duration of symptoms less than 5 days. A prediction algorithm incorporating these 3 factors showed an area under the ROC curve of 0.91 (95% confidence interval, 0.840-0.979). CONCLUSIONS: Kanavel signs have high sensitivity for detecting PFT but have poor specificity on an individual basis. Clinical prediction algorithms that combine the relevant factors may be helpful in the development of clinical prediction tools and educational materials for optimization of emergency hand care systems. Further prospective study is needed. PMID- 28720001 TI - Differential effects of heat stress on fibre capillarisation in tenotomised soleus and plantaris muscles. AB - PURPOSE: Capillary regression is commonly observed in response to disuse muscle atrophy. Heat stress is known to alleviate muscle atrophy, while effect of heat exposure on capillary adaptation following disuse atrophy is not defined. Here, we examined the effect of heat treatment on capillarisation and the associated signalling in slow-oxidative soleus and fast-glycolytic plantaris muscles following Achilles tendon ablation (tenotomy). MATERIALS AND METHODS: Male Wistar rats were assigned into control (CON), control with heat stress (CON + HEAT), tenotomy (TEN) and tenotomy with heat stress (TEN + HEAT) groups. Tenotomy was induced for 8 days in TEN and TEN + HEAT groups. Heat stress was maintained at 40.5-41.5 degrees C, 30 min for 7 days. RESULTS: Tenotomy resulted in reduction of capillary-to-fibre ratio, decreased VEGFR-2 and increased TSP-1 in soleus muscle, whereas VEGF protein expression remained unaffected. Tenotomy had no effect on capillary distribution and angiogenic signalling in plantaris muscle. These results were concomitant with larger reduction of cross-sectional area (CSA) in MHC type I and II myofibres of soleus compared to plantaris muscles. Interestingly, heat stress increased VEGFR-2 and attenuated TSP-1 protein expression in tenotomised soleus, but not plantaris muscles. Additionally, CSA of both type I and type II myofibres was greater in tenotomised soleus than plantaris muscles after heat treatment. CONCLUSIONS: Heat stress mitigated effect of tenotomy-induced capillary regression in a fibre-type-specific response, in part, by shifting the balance between angiogenic and angiostatic regulators. These results suggest beneficial effect of heat treatment for maintaining microcirculation in disuse muscle atrophy. PMID- 28720002 TI - Green synthesis of silver nanoparticles using Prosopis juliflora bark extract: reaction optimization, antimicrobial and catalytic activities. AB - In the present study, silver nanoparticles (PJB-AgNPs) have been biosynthesized employing Prosopis juliflora bark extract. The biosynthesis of silver nanoparticles was monitored on UV-vis spectrophotometer. The size, charge and polydispersity index (PDI) of PJB-AgNPs were determined using dynamic light scattering (DLS). Different parameters dictating the size of PJB-AgNPs were explored. Nanoparticles biosynthesis optimization studies suggested efficient synthesis of highly dispersed PJB-AgNPs at 25 degrees C when 9.5 ml of 1 mM AgNO3 was reduced with 0.5 ml of bark extract for 40 min. Characterization of PJB AgNPs by SEM showed spherical-shaped nanoparticles with a size range ~10-50 nm along with a hydrodynamic diameter of ~55 nm as evaluated by DLS. Further, characterizations were done by FTIR and EDS to evaluate the functional groups and purity of PJB-AgNPs. The antibacterial potential of PJB-AgNPs was tested against E. coli and P. aeruginosa. The PJB-AgNPs remarkably exhibited anticancer activity against A549 cell line as evidenced by Alamar blue assay. The dye degradation activity was also evaluated against 4-nitrophenol that has carcinogenic effect. The results thus obtained suggest application of PJB-AgNPs as antimicrobial, anticancer and catalytic agents. PMID- 28720003 TI - Current Trends in the Management of Ballistic Fractures of the Hand and Wrist: Experiences of a High-Volume Level I Trauma Center. AB - BACKGROUND: Ballistic fractures of the carpus and hand are routinely treated in large urban centers. These injuries can be challenging due to many factors. Various treatment options exist for these complicated injuries, but there are limited data available. This report analyzes patient demographics, treatments, and outcomes at a large urban trauma center. METHODS: All ballistic fractures of the hand and wrist of the patients who presented to a single center from 2011 to 2014 were retrospectively reviewed. Patient demographics, injury mechanism, treatment modalities, and outcomes were analyzed. RESULTS: Seventy-seven patients were identified; 70 were male, and 7 were female. Average age of the patients was 29.6 years. Seventy-five injuries were low velocity, whereas 2 were high velocity. Sixty-seven patients had fractures of a metacarpal or phalanx, whereas 4 had isolated carpal injuries. Six had combined carpal and metacarpal or phalanx fractures. Thirty-six patients had concomitant tendon, nerve, or vascular injuries requiring repair. Sixty-three patients underwent operative intervention, with the most common intervention being percutaneous fixation. Sixteen patients required secondary surgery. Eighteen complications were reported. CONCLUSIONS: The majority of patients in this report underwent early operative intervention with percutaneous fixation. Antibiotics were administered in almost all cases and can usually be discontinued within 24 hours after surgery. It is important to consider concomitant nerve, vascular, or tendon injuries requiring repair. We recommend early treatment of these injuries with debridement and stabilization. Due to lack of follow-up and patient noncompliance, early definitive treatment with primary bone grafting should be considered. PMID- 28720004 TI - Antinociceptive synergistic interaction between Achillea millefolium and Origanum vulgare L. extract encapsulated in liposome in rat. AB - AIM: This study aims to evaluate the antinociceptive effect of combined Achillea millefolium and Origanum extract encapsulated in liposome. METHODS: The effect of Achillea millefolium and Origanum vulgare L. extract, and their liposome incorporated form was assessed using 3% formalin test in rat. 12 male Wistar rats, 4 in each group, were used in this study, and increasing doses of Achillea millefolium (31.6, 100, 178, and 316 mg/kg) and Origanum vulgare L. extract (5.6, 10, 17.8, and 31.6 mg/kg), and co-administered extract were i.p. administered 10 min before 3% formalin. The mechanisms of action were evaluated for the liposomal encapsulated co-administered extract using N(G)-nitro-l-arginine methyl ester (L NAME) (3 mg/kg) and naloxone (1 mg/kg). RESULTS: The interaction index and isobolographic analysis revealed a synergistic effect of the extracts. We observed a lower experimental ED30 as compared to the theoretical ED30. Naloxone also reduced the antinociceptive effect of the liposome encapsulated co administered extract. CONCLUSION: These data suggest that the Achillea millefolium and Origanum vulgare L. extract encapsulated in liposome gave a synergistic effect. PMID- 28720005 TI - ALSUntangled 41: "Eric Is Winning". PMID- 28720006 TI - Correction to: Vitale, Bianchi, Rapetti, Pepe, Giacco, Giacco and Riccardi, A nutritional intervention programme at a worksite canteen to promote a healthful inspired by the traditional Mediterranean diet. PMID- 28720007 TI - Extensor Pollicis Brevis Spiral Tenodesis for Combined Metacarpophalangeal Instability and Trapeziometacarpal Arthritis. AB - BACKGROUND: In more advanced stages of trapeziometacarpal arthritis, the thumb metacarpal may develop an adduction contracture, leading to secondary hyperextension instability of the metacarpophalangeal joint. Following trapeziometacarpal arthroplasty, uncorrected substantial metacarpophalangeal hyperextension may contribute to ongoing Z-collapse deformity, weakness of pinch and grip, and patient perception of diminished function. METHODS: We prospectively analyzed a consecutive case series of 55 trapeziometacarpal arthroplasty patients (mean age, 60 years; 7 males) who received simultaneous extensor pollicis brevis spiral tenodesis for thumb metacarpophalangeal hyperextension of at least 50 degrees . Preoperative/postoperative (mean, 24 weeks) objective measurements and Disabilities of the Arm, Shoulder and Hand (DASH) scores were compared using paired t tests with P < .05. RESULTS: Mean preoperative/postoperative measurements were as follows: metacarpophalangeal hyperextension, 62.0 degrees /-1.7 degrees ; metacarpophalangeal flexion, 52.1 degrees /50.1 degrees ; interphalangeal arc of motion, 66.4 degrees /65.5 degrees ; key pinch, 3.6/5.4 kg; grip strength, 14.1/20.1 kg; DASH score, 56.6/8.4. Differences were statistically significant for metacarpophalangeal hyperextension, key pinch, grip strength, and DASH score. Differences were not significant for metacarpophalangeal flexion or interphalangeal arc of motion. No patient demonstrated paresthesias or hypersensitivity of the digital nerves. All patients achieved stability at the metacarpophalangeal joint. One Kirschner wire was removed earlier than planned after migration and penetration through the skin. CONCLUSIONS: Performed in conjunction with trapeziometacarpal arthroplasty, spiral tenodesis effectively stabilizes the metacarpophalangeal joint without compromising metacarpophalangeal flexion, interphalangeal motion, or the digital nerves. Postoperatively, patients demonstrate significant improvements in key pinch, grip strength, and DASH scores. PMID- 28720008 TI - A Cadaveric Study of the Thread Trigger Finger Release: The First Annular Pulley Transection Through Thread Transecting Technique. AB - BACKGROUND: After the thread transecting technique was successfully applied for the thread carpal tunnel release, we researched using the same technique in the thread trigger finger release (TTFR). This study was designed to test the operational feasibility of the TTFR on cadavers and verify the limits of division on the first annular (A1) pulley to ensure a complete trigger finger release with minimal iatrogenic injuries. METHODS: The procedure of TTFR was performed on 14 fingers and 4 thumbs of 4 unembalmed cadaveric hands. After the procedures, all fingers and thumbs were dissected and visually assessed. RESULTS: All of the digits and thumbs demonstrated a complete A1 pulley release. There was no injury to the neurovascular bundle (radial digital nerve in case of thumb), flexor tendon, or A2 pulley for each case. CONCLUSIONS: The cadaveric study showed that the technique of TTFR was safe and effective, and the future clinical study is necessary to verify the findings of this study. PMID- 28720009 TI - The Effect of Isolated Finger Stiffness on Adjacent Digit Function. AB - BACKGROUND: Isolated stiffness in a single finger can affect the function of adjacent digits and decrease overall hand function due to the quadriga phenomenon. This study objectively quantifies the dysfunctional impact of each individual stiff finger upon the remaining digits. METHODS: Twenty-five individuals (10 men and 15 women) with a mean age of 31 years (range, 18-58 years) without any upper limb pathology, neuropathy, or systemic illness were recruited. Volar-based finger splints were used to hold individual digits of the dominant hand (24 right and 1 left) sequentially in full extension at the metacarpophalangeal (MCP), proximal interphalangeal (PIP), and distal interphalangeal (DIP) joints. Motion of the remaining 3 nonsplinted digits was assessed using a finger goniometer and linear scale to measure the total active range of motion (TAM) and fingertip-to-distal palmar crease (DPC) distance. TAM before and after splinting for each digit was compared using 1-way analysis of variance (ANOVA). RESULTS: Splinting of any individual finger resulted in a significant reduction in the TAM of all adjacent fingers, regardless of which finger was splinted ( P < .001). Digits immediately adjacent to the splinted finger were more heavily impacted compared with nonadjacent digits. Splinting of the ring finger produced the greatest detriment, with a 26% to 47% reduction in the TAM and a DPC distance greater than 40 mm in a third of participants. The index finger caused the least disturbance to remaining digital motion. CONCLUSIONS: Isolated finger stiffness causes a variable degree of dysfunction on adjacent normal digits. This emphasizes the need for a focused and proactive approach to restore full active motion following isolated finger injuries to prevent persistent functional sequelae of the hand. PMID- 28720011 TI - Facial Emotion Recognition and Empathy in Employees at a Juvenile Detention Center. AB - Numerous studies have shown that emotion recognition is impaired in individuals with a history of violent offenses, especially in those diagnosed with psychopathy. However, in criminological contexts, there is insufficient research regarding the role of empathy and facial emotion recognition abilities of personnel employed in correction centers. Accordingly, we sought to explore facial emotion recognition abilities and empathy in administrative officers and security guards at a center for institutionalized juvenile offenders. One hundred twenty-two Mexican subjects, including both men and women, were recruited for the study. Sixty-three subjects were administrative officers, and 59 subjects were security guards at a juvenile detention center. Tasks included "Pictures of Facial Affect" and the "Cambridge Behavior Scale." The results showed that group and gender had an independent effect on emotion recognition abilities, with no significant interaction between the two variables. Specifically, administrative officers showed higher empathy than security guards. Moreover, women in general exhibited more empathy than men. This study provides initial evidence of the need to study emotion recognition and empathy among professionals working in forensic settings or criminological contexts. PMID- 28720010 TI - Determinants and Predictors of Grief Severity and Persistence: The Rotterdam Study. AB - OBJECTIVE: We aimed to explore correlates and predictors of bereavement severity and persistence (triggered by "loss of a loved one"; referent group partner loss) in the Rotterdam cohort. METHOD: We used linear regression to examine factors associated with grief severity using a cross-sectional analysis and logistic regression to determine prospective associations. RESULTS: Cross-sectionaly, females, child-lost, higher depressive symptoms, lower education, and difficulties in daily activities were independently associated with a higher bereavement severity. Prospectively (6 years; response rate 71%), the baseline value of the grief severity was the single predictor significantly associated with grief persistence. DISCUSSION: Our results suggest that only grief severity is independently associated with grief persistence. Further studies are needed to confirm our findings. PMID- 28720012 TI - Maturity of hospital information systems: Most important influencing factors. AB - Maturity models facilitate organizational management, including information systems management, with hospital organizations no exception. This article puts forth a study carried out with a group of experts in the field of hospital information systems management with a view to identifying the main influencing factors to be included in an encompassing maturity model for hospital information systems management. This study is based on the results of a literature review, which identified maturity models in the health field and relevant influencing factors. The development of this model is justified to the extent that the available maturity models for the hospital information systems management field reveal multiple limitations, including lack of detail, absence of tools to determine their maturity and lack of characterization for stages of maturity structured by different influencing factors. PMID- 28720013 TI - The 5-HT1B serotonin receptor regulates methylphenidate-induced gene expression in the striatum: Differential effects on immediate-early genes. AB - Drug combinations that include a psychostimulant such as methylphenidate (Ritalin) and a selective serotonin reuptake inhibitor such as fluoxetine are indicated in several medical conditions. Co-exposure to these drugs also occurs with "cognitive enhancer" use by individuals treated with selective serotonin reuptake inhibitors. Methylphenidate, a dopamine reuptake inhibitor, by itself produces some addiction-related gene regulation in the striatum. We have demonstrated that co-administration of selective serotonin reuptake inhibitors potentiates these methylphenidate-induced molecular effects, thus producing a more "cocaine-like" profile. There is evidence that the 5-HT1B serotonin receptor subtype mediates some of the cocaine-induced gene regulation. We thus investigated whether the 5-HT1B receptor also modifies methylphenidate-induced gene regulation, by assessing effects of a selective 5-HT1B receptor agonist (CP94253) on immediate-early gene markers ( Zif268, c- Fos, Homer1a) in adolescent male rats. Gene expression was measured by in situ hybridization histochemistry. Our results show that CP94253 (3, 10 mg/kg) produced a dose dependent potentiation of methylphenidate (5 mg/kg)-induced expression of Zif268 and c- Fos. This potentiation was widespread in the striatum and was maximal in lateral (sensorimotor) sectors, thus mimicking the effects seen after cocaine alone, or co-administration of fluoxetine. However, in contrast to fluoxetine, this 5-HT1B agonist did not influence methylphenidate-induced expression of Homer1a. CP94253 also potentiated methylphenidate-induced locomotor activity. These findings indicate that stimulation of the 5-HT1B receptor can enhance methylphenidate (dopamine)-induced gene regulation. This receptor may thus participate in the potentiation induced by fluoxetine (serotonin) and may serve as a pharmacological target to attenuate methylphenidate + selective serotonin reuptake inhibitor-induced "cocaine-like" effects. PMID- 28720014 TI - The impact of intrauterine treatment on fetal tachycardia: a nationwide survey in Japan. AB - OBJECTIVES: To investigate the clinical course of fetal tachycardia and analyze the impact of intrauterine treatment on the postnatal treatment and patient outcomes. STUDY DESIGN: This was a retrospective review of cases of fetal tachycardia that occurred from 2004 to 2006. Data were collected from questionnaires that were sent to all 750 secondary or tertiary perinatal care centers in Japan. RESULTS: Eighty-two cases (14 with fetal hydrops) were analyzed (supraventricular tachycardia [SVT], n = 52; atrial flutter [AFL], n = 23; and ventricular tachycardia, n = 7). The overall mortality was 3.7%. Intrauterine treatment was performed for 41 fetuses (50.0%). Digoxin, flecainide and sotalol were mainly used for SVT and AFL. Fetal tachycardia resolved in 90.0% (27/30) of the cases without fetal hydrops and 90.9% (10/11) of the cases with fetal hydrops. Intrauterine treatment significantly reduced the incidence of cesarean delivery (29.3 vs. 70.7%, p < .01), preterm birth (12.2 vs. 41.5%, p = .02) and neonatal arrhythmias (48.8 vs. 78.0%, p = .01) in comparison to untreated fetuses. CONCLUSIONS: This nationwide survey revealed that intrauterine treatment was performed for approximately half of the cases of fetal tachycardia and was associated with lower rates of cesarean delivery, premature birth and neonatal arrhythmias in comparison to untreated fetuses. PMID- 28720015 TI - Sexual Violence by Juveniles in Institutions: A Descriptive Study on Prevalence and Circumstances. AB - Adolescents in institutionalized care are at a particularly high risk of exhibiting sexually aggressive behavior including sexual harassment. So far, however, studies about the prevalence of sexually aggressive behavior in institutions are lacking. In this survey, 322 adolescents (43% female, average age 16.7 years) from 32 residential care facilities and boarding schools across Germany were asked about sexually aggressive behavior via a standardized questionnaire. Overall, 23.5% of the participants engaged in some form of sexually aggressive behavior in their lives, and 4.6% reported having committed a sexual assault with (actual or attempted) penetration. A closer look at the circumstances of those offenses shows that the victims were in most cases acquainted with and of the same age as the offenders, that threats and violence were used in some cases, and especially in the case of actual or attempted penetration, and that only a minority of offenders suffered any consequences for their acts. The implementation of protective measures for institutions and the treatment of adolescents in institutions will be discussed. PMID- 28720016 TI - First-Grade Cognitive Predictors of Writing Disabilities in Grades 2 Through 4 Elementary School Students. AB - The primary aim of this study was determining Grade 1 cognitive predictors of students at risk for writing disabilities in Grades 2 through 4. Applying cognitive measures selected to align with theoretical and empirical models of writing, tasks were administered to Grade 1 students assessing fine-motor, linguistic, and executive functions: 84 at risk (bottom quartile for age-base expectations) and 54 typically developing. A model with individual predictors was compared to a previously developed latent trait model to determine the relative predictive worth of each approach. Data analysis primarily involved stepwise logistic regression. Results revealed that the individual measures of orthographic choice, working memory, inhibitory control, visual memory recognition, and planning all were significant predictors of at risk status in Grades 2 through 4. The latent trait model also fared well but did not account for the same amount of variance as any of the individual measurement models for any of the grades. The findings lay the foundation for an empirically based approach to cognitive assessment in Grade 1 for identifying potential at-risk students in later elementary grades and suggest potential underlying neurocognitive abilities that could be employed with educational interventions for students with later-emerging writing disabilities. PMID- 28720017 TI - Obesity and ovarian cancer risk: A systematic review. AB - The association between obesity and ovarian cancer risk has been extensively investigated, but studies have yielded inconsistent findings. This review aims to summarise and discuss the evidence generated to date. Articles published in English prior to August 2016 were retrieved from PubMed. Keywords included obesity, overweight, body size, body mass index, waist-hip ratio, waist circumference, body weight, ovarian cancer, ovarian carcinoma, ovarian neoplasm, and ovarian tumour. Eligible studies compared two or more groups of women, with at least one group in the overweight or obese category and one comprising normal weight controls. Summary data in the form of relative risk, hazard ratio, or odds ratio for each comparison group from individual studies were collated and reviewed. Forty-three studies were included in the final analysis, with a total of 3,491,943 participants. All studies included body mass index as an exposure measure, and a majority relied on self-reported measures from participants; 14 studies found a statistically significant positive association between ovarian cancer risk and higher body mass index, 26 studies found no significant association, and 3 studies found a negative association between ovarian cancer risk and higher body mass index. This review concludes that there is limited, inconsistent evidence of a positive association between obesity and ovarian cancer risk. PMID- 28720018 TI - Structural risk and limits on agency among exotic dancers: HIV risk practices in the exotic dance club. AB - This paper provides longitudinal examination of women's health and sexual risk trajectories in US exotic dance clubs, which represent an important commercial setting for the economic mainstreaming of sexual services and an important target for public health programmes. Between July 2014 and May 2015, two semi-structured interviews (at baseline and at three months) were conducted with 24 female exotic dancers who had recently started working in in Baltimore City, USA. Results from a constant comparative analysis point to the interrelationship between the structures of the club setting, including the social context, and women's agentic practices concerning their sexual health. Study findings highlight the centrality of the interrelationship between individual- and structural-level experiences in influencing dancers' risk behavior. Findings point to the need for interventions to empower women both individually and collectively so as to provide the foundation for longer-term structural change. PMID- 28720021 TI - Ricky and Lucy: gender stereotyping among young Black men who have sex with men in the US Deep South and the implications for HIV risk in a severely affected population. AB - HIV disproportionately affects young Black men who have sex with men in the USA, with especially high rates in the Deep South. In this Alabama study, we interviewed 24 pairs of young Black men who have sex with men aged 19-24 and their close friends (n = 48) about sexual scripts, dating men and condom use. Three main themes emerged from the study: the power dynamics of 'top' and 'bottom' sexual positions for condom use; gender stereotyping in the iconic style of the 'I Love Lucy' show of the 1950s; and the sexual dominance of 'trade' men. Gender stereotyping was attributed to the cultural mores of Black families in the South, to the preferences of 'trade' men who exerted sexual and financial control and to internalised stigma relating to being Black, gay and marginalised. The findings suggest that HIV prevention education for young Black men who have sex with men is misguided if gendered power dynamics are ignored, and that funded access to self-protective strategies such as pre-exposure prophylaxis and post exposure prophylaxis could reduce HIV risk for this severely affected population. PMID- 28720022 TI - Good work ability among unemployed individuals: Association of sociodemographic, work-related and well-being factors. AB - AIMS: The aims of this study were to describe the perceived work ability of unemployed individuals and to explore the association between perceived good work ability and sociodemographic, work-related and well-being factors. METHODS: The data were derived from the Finnish Regional Health and Well-being Study (ATH) collected by postal and Internet-based questionnaires in 2014-2015. The random sample was selected from the Finnish National Population Register. The present study includes data from unemployed or laid-off respondents ( n=1975) aged 20-65 years. Logistic regression was used in the statistical analysis. Perceived work ability was measured with the Work Ability Score. RESULTS: Factors significantly associated with good work ability were having young children living in the household, short-term unemployment, low or moderate physical strain in most recent job, moderate mental strain in most recent job, satisfaction with most recent job, good self-rated health and good quality of life. Good self-rated health (odds ratio=10.53, 95% confidence interval 5.90-18.80) was the most substantial factor in the multivariate model. CONCLUSIONS: The findings provide further evidence on the factors related to good work ability of the unemployed. These factors should be considered when designing interventions for promoting work ability and to minimise the harmful effects of long-term unemployment. PMID- 28720023 TI - Early motor development and cognitive abilities among Mexican preschoolers. AB - Psychomotricity plays a very important role in children's development, especially for learning involving reading-writing and mathematical calculations. Evaluate motor development in children 3 years old and its relationship with their cognitive abilities at the age of 5 years. Based on a cohort study, we analyzed the information about motor performance evaluated at 3 years old by Peabody Motor Scale and cognitive abilities at 5 years old. The association was estimated using linear regression models adjusted by mother's intelligence quotient, sex, Bayley mental development index at 18 months, and quality of the environment at home (HOME scale). 148 children whose motor performance was determined at age 3 and was evaluated later at age 5 to determine their cognitive abilities. Cognitive abilities (verbal, quantitative, and memory) measured by McCarthy Scales. Significant positive associations were observed between stationary balance at age 3 with verbal abilities (beta = 0.67, p = .04) and memory (beta = 0.81, p = .02) at 5 years. Grasping and visual-motor integration were significant and positively associated with quantitative abilities (beta = 0.74, p = .005; beta = 0.61, p = .01) and memory (beta = 2.11, p = .001; beta = 1.74, p = .004). The results suggest that early motor performance contributes to the establishment of cognitive abilities at 5 years. Evaluation and early motor stimulation before the child is faced with formal learning likely helps to create neuronal networks that facilitate the acquisition of academic knowledge. PMID- 28720024 TI - The Wayfinding Questionnaire: A clinically useful self-report instrument to identify navigation complaints in stroke patients. AB - Post-stroke navigation complaints are frequent (about 30%) and intervention is possible, but there is no assessment instrument to identify patients with navigation complaints. We therefore studied the clinical validity of the Wayfinding Questionnaire (WQ) in a cross-sectional study with 158 chronic stroke patients and 131 healthy controls. Patients with low (more navigation complaints) versus normal WQ scores were compared for demographics, stroke characteristics, emotional and cognitive complaints, and health-related quality of life (HRQoL). Actual navigation performance of 78 patients was assessed in a virtual reality setting. Effect sizes (d) were calculated. WQ responses (22 items) of stroke patients were compared with those of controls (discriminant validity). Results showed that patients with a low WQ score (n = 49, 32%) were more often women (p = 0.013) and less educated (p = 0.004), reported more cognitive complaints (d = 0.69), more emotional problems (d = 0.38 and 0.52), and lower HRQoL (d = 0.40 and 0.45) and, last but not least, performed worse on the navigation ability tasks (d = 0.23-0.80). Patients scored lower than controls on 21/22 WQ items, predominantly with small to medium effect sizes (d = 0.20-0.51). We conclude that the WQ is valid as a measure of navigation complaints in stroke patients, and thus strongly advocate its use in stroke care. PMID- 28720025 TI - Perspectives on induced abortion among Palestinian women: religion, culture and access in the occupied Palestinian territories. AB - Induced abortion is an important public health issue in the occupied Palestinian territories (OPT), where it is illegal in most cases. This study was designed to elicit the views of Palestinian women on induced abortion given the unique religious, ethical and social challenges in the OPT. Sixty Palestinian women were interviewed on their perceptions of the religious implications, social consequences and accessibility of induced abortions in the OPT at Al-Makassed Islamic Charitable Hospital in East Jerusalem. Themes arising from the interviews included: the centrality of religion in affecting women's choices and views on abortion; the importance of community norms in regulating perspectives on elective abortion; and the impact of the unique medico-legal situation of the OPT on access to abortion under occupation. Limitations to safe abortion access included: legal restrictions; significant social consequences from the discovery of an abortion by one's community or family; and different levels of access to abortion depending on whether a woman lived in East Jerusalem, the West Bank, or Gaza. This knowledge should be incorporated to work towards a legal and medical framework in Palestine that would allow for safe abortions for women in need. PMID- 28720026 TI - Models of Reading in Different Orthographies: An Introduction. AB - The authors provide a summary of the articles in the special series on reading development in different orthographies from various writing systems and scripts. PMID- 28720027 TI - Long-term alteration of the hypothalamic-pituitary-adrenal axis in children undergoing cardiac surgery in the first 6 months of life. AB - Children with congenital heart disease (CHD) have poorer neurodevelopmental and psychological outcomes. The mechanisms underlying this remain unclear. One mechanism could be that the stressful experience of cardiac surgery early in life influences long-term hypothalamic-pituitary-adrenal (HPA) axis regulation. Dysregulation of the HPA axis has been linked to poorer neurocognitive and psychological outcomes in other study populations. This case-control study aims to compare HPA-axis regulation (circadian rhythm and reactivity) using salivary cortisol in 3- to 5-year-olds with CHD who did and did not have cardiac surgery prior to 6 months of age. Saliva samples for cortisol analysis were collected from preschoolers with CHD (N = 28, Males = 18, Females = 10) over two weekend days, and before and after an echocardiogram. Caregiver education, child age, sex, and cardiac disease severity score were included as confounders. Multilevel analysis (hierarchical linear modeling) was used to analyze the data. The analysis for the cortisol circadian rhythm shows that the early surgery group has a flatter diurnal slope secondary to lower mean weekend morning waking cortisol levels than controls but similar mean bed time values. Multilevel analysis of the stress response to an echocardiogram indicates that the early surgery group has an increased response when compared to the control group. This is the first study to show that cardiac surgery prior to 6 months of age is associated with a different pattern of HPA-axis regulation at 3-5 years of age. PMID- 28720028 TI - Growth of Word and Pseudoword Reading Efficiency in Alphabetic Orthographies: Impact of Consistency. AB - Word and pseudoword reading are related abilities fundamental to reading development in alphabetic orthographies. They are respectively assumed to index children's orthographic representations of words, which are in turn acquired through the underlying "self-teaching mechanism" of alphabetic pseudoword decoding. Little is known about concurrent growth trajectories of these skills in the early grades among children learning different alphabetic orthographies. In the present study, between- and within-group latent growth models of word and pseudoword reading efficiency were tested on data spanning Grades 1 and 2 from learners of the inconsistent English and consistent Czech and Slovak orthographies. Several language-general patterns emerged. Significant growth was observed for both skills in all languages. Growth was faster for word than pseudoword reading efficiency, and strong lexicality effects that increased over time were obtained across languages. Language-specific patterns were also found. In line with predictions about the costs of learning lower-consistency orthographies, readers of English experienced relatively slower growth on both reading skills. However, their lag was smaller, and evident only at the latter two time points for word reading. In contrast, on pseudoword reading, the English group performed considerably less well than their Czech and Slovak peers at every time point. Thus, weaker decoding skills were the main contributor to the larger lexicality effects of the English group. These findings are considered within the frame of recent theorizing about the effect of orthographic consistency on decoding as a self-teaching mechanism in alphabetic reading acquisition. PMID- 28720029 TI - The Effects of the Relaxation Response on Nurses' Level of Anxiety, Depression, Well-Being, Work-Related Stress, and Confidence to Teach Patients. AB - PURPOSE: The purpose of this pilot study was threefold: to teach nurses the Relaxation Response ( RR), a relaxation technique created by Benson; to measure the effects of the RR on nurses' levels of anxiety, depression, well-being, and work-related stress; and to explore nurses' confidence in teaching their patients the RR. DESIGN: A wait-list, randomized-control quantitative study design was used. METHOD: Nurses in the intervention group were trained on the benefits and the technique of the RR and were then asked to practice the RR over an 8-week period. FINDINGS: No statistical significance was found in nurses' reported level of anxiety, depression, well-being, and work-related stress. However, the nurses reported greater confidence in teaching this technique to patients ( p < .001). CONCLUSION: As a strategy for self-care in the workplace, nurses were receptive to learning the RR and reported confidence in using this strategy for their patients. Larger studies may reveal more significant reductions in workplace stress and anxiety for nurses. PMID- 28720030 TI - Rose Spots Following Oral Typhoid Vaccine. PMID- 28720031 TI - Knee Pain in a Boy With Hyper IgE Type 1 Syndrome (Job Variant). PMID- 28720033 TI - Inattention and Poor Eye Contact Is Not All Autism. PMID- 28720034 TI - Rheumatic Fever Presenting as Recurrent Pericarditis and Cardiac Tamponade. PMID- 28720032 TI - Electronic Immunization Alerts and Spillover Effects on Other Preventive Care. AB - The impact of electronic health record (EHR) immunization clinical alert systems on the delivery of other preventive services remains unknown. We assessed for spillover effects of an EHR immunization alert on delivery of 6 other preventive services, in children 18 to 30 months of age needing immunizations. We conducted a secondary data analysis, with additional primary data collection, of a randomized, historically controlled trial to improve immunization rates with EHR alerts, in an urban, primary care clinic. No significant differences were found in screening for anemia, lead, development, nutrition, and injury prevention counseling in children prompting EHR immunization alerts (n = 129), compared with controls (n = 135). Significant increases in oral health screening in patients prompting EHR alerts (odds ratio = 4.8, 95% CI = 1.8-13.0) were likely due to practice changes over time. An EHR clinical alert system targeting immunizations did not have a spillover effect on the delivery of other preventive services. PMID- 28720035 TI - Home Visiting and the Health of Preterm Infants. AB - The results of home visiting programs which target medically fragile low-birth weight preterm infants (LBWPT) have been inconsistent. We provided nurse/social worker home visits to families of LBWPT infants on a regular schedule. Teams were trained in approaches to improve the health and development of the infants. The completion of immunization series was sigmificantly higher and the infant mortality rates of the home visits childen were significanly lower compared to national and state rates. We used state Medicaid data and examined frequency of hospitalization, emergency department visits, routine and nonscheduled visits to primary care physician, and pharmacy use of the home-visited subjects compared with a propensity-matched group. The home-visited group had more routine and nonscheduled visits but no more hospitalizations or E.D. visits. Home visiting teams improved important markers of child health, including completed immunizations and mortality rate, perhaps by the careful monitoring of health status and assuring health care when needed. PMID- 28720036 TI - Procalcitonin to Detect Bacterial Infections in Critically Ill Pediatric Patients. AB - The diagnostic power of procalcitonin (PCT) in the pediatric intensive care unit (PICU) is uncertain. This study aimed to determine the diagnostic ability of PCT to detect serious bacterial infections (SBI) in a heterogeneous PICU population. This was a retrospective cohort study of patients on whom a PCT level was obtained within 48 hours of admission to a PICU from 2013 to 2015. Discriminatory ability of PCT to predict SBI was examined by test and receiver operating characteristics (AUC [area under the curve]-ROC). Seventy-five patients were included and 28 (37%) had an SBI (median PCT = 6.48 ng/mL) compared with 47 (63%) in the noninfection group (median PCT = 0.23 ng/mL, P < .0001). PCT was able to adequately predict SBI (AUC-ROC = 0.83, 95% CI 0.74-0.93; P < .0001), and a PCT >=1.28 ng/mL was the optimal threshold to detect SBI with a positive predictive value of 76.7% and negative predictive value of 88.9%. PCT adequately predicted SBI in a heterogeneous PICU population and may be useful for minimizing antibiotic consumption. PMID- 28720037 TI - Emergency department visits of Syrian refugees and the cost of their healthcare. AB - The aim of this study was to evaluate the demographic and clinical characteristics of Emergency Department (ED) visits made by Syrian refugees and to assess the cost of their healthcare. This retrospective study was conducted in adult Syrians who visited the ED of Adiyaman University Training and Research Hospital, Adiyaman Province, Turkey, between 01 January and 31 December 2015. We evaluated 10,529 Syrian refugees who visited the ED, of whom 9,842 were included in the study. The number of ED visits significantly increased in 2015 compared with 2010; the increase in the proportion of total ED visits was 8% (n = 11,275, dif: 8%, CI 95%: 7.9- 8.2, p < 0.001). Of this 8%, 6.5% were visits made by Syria refugees and the remaining 1.5% accounted for the visits made by other individuals. Upper respiratory tract infections (URTI) were the diseases most frequently presented (n = 4,656; 47.3%), and 68.5% of ED visits were inappropriate (n = 6,749). The median ED length of stay (LOS) of the Syrian refugees was significantly longer than that of the other individuals visiting the ED (p < 0.001). The total cost of the healthcare of the Syrian refugees who visited the ED was calculated as US$ 773,374.63. This study showed that Syrian refugees have increased the proportion of ED visits and the financial healthcare burden. The majority of ED visits made by Syrian refugees were inappropriate. In addition, their ED LOS was longer than that of other individuals making ED visits. PMID- 28720038 TI - Neuroprotective effect of G14-humanin on global cerebral ischemia/reperfusion by activation of SOCS3 - STAT3 - MCL-1 signal transduction pathway in rats. AB - OBJECTIVE: Humanin (HN) has been identified to suppress neuron death. Gly14-HN (HNG), as a variant of HN, can decrease infarct volume after ischemia/reperfusion (I/R) injury. This study aimed to investigate the neuroprotective mechanism of HNG on global cerebral I/R (GI) in rats. METHODS: Rats were randomly divided into 13 groups: Sham group, GI groups and HNG groups. Both GI group and HNG groups included six time points (1, 3, 6, 12, 24, and 72 h). At 24 h after reperfusion, Nissl staining was used to observe positive neurons, and p-STAT3, MCL-1, SOCS3, Bax and Caspase-3 in different groups were detected by immunohistochemistry. qRT PCR and western blot were used to evaluate the expression of STAT3, p-STAT3, MCL 1, and SOCS3. RESULTS: The immunohistochemistry also showed a significant increase in Bax (0.29 +/- 0.007 vs. 0.22 +/- 0.007, P < 0.01) and Caspase-3 (0.24 +/- 0.02 vs. 0.18 +/- 0.006, P < 0.01) in GI group compared with Sham group, while Bax (0.26 +/- 0.01 vs. 0.29 +/- 0.008, P < 0.01) and Caspase-3 (0.20 +/- 0.008 vs. 0.24 +/- 0.02, P < 0.01) were significantly decreased by HNG-treatment compared with GI group. Along with immunohistochemistry, western blot and qRT-PCR indicated that the protein and mRNA levels of STAT3, MCL-1, and SOCS3 were up regulated after administration of HNG at six time points after global cerebral I/R in rat. CONCLUSION: HNG might exert neuroprotective effects through alleviating apoptosis and activating of SOCS3 - STAT3 - MCL-1 signal transduction pathway. Highlights (1) Cerebral ischemia led to neuronal loss in hippocampal CA1 region of rats. (2) HNG had neuroprotective effects on ischemia/reperfusion rats. (3) The protective effect of HNG might be related to the SOCS3 - STAT3 - MCL-1 pathway. PMID- 28720040 TI - Distal Radius Fractures: AAOS Appropriate Use Criteria Versus Actual Management at a Level I Trauma Center. AB - BACKGROUND: The aim of this study is to determine whether the American Academy of Orthopaedic Surgeons' (AAOS) Appropriate Use Criteria (AUC) for distal radius fractures correlates with actual treatment by orthopedic hand surgeons at a level I trauma center. METHODS: ICD-9 codes were used to retrospectively identify patients who presented with wrist fractures over 1 year. Patients with isolated distal radius fractures were evaluated using the AAOS AUC application for distal radius fractures. Actual treatment was then compared with treatment recommended by the AUC. RESULTS: Of the 112 patients, 64 (57%) received treatment that matched the AAOS AUC recommendation as an "appropriate treatment." Actual management matched the AUC recommendation 100%, 7%, and 50% of the time, for Arbeitsgemeinschaft fur Osteosynthesefragen/Orthopaedic Trauma Association (AO/OTA) type A, B, and C fractures, respectively. Surgery was performed for type A, B, and C fractures 30%, 7%, and 50% of the time, respectively. For type B fractures, only the 2 cases that were managed operatively were in agreement with the AUC. For type C fractures, increased patient age (57 years and older) was significantly associated with nonoperative treatment decisions. Surgeon decisions for nonoperative treatment were in agreement with the AUC recommendations 40% of the time, whereas surgeon decisions for surgery matched the AUC recommendations 97% of the time. CONCLUSIONS: We found low agreement between actual treatment decisions and the AUC-recommended "appropriate" treatments, especially for the type B and C fractures that were managed nonoperatively. The AUC favors surgery for all intra-articular fractures, while we emphasized age and fracture displacement in our decision-making process. PMID- 28720039 TI - The REVAMP trial to evaluate HIV resistance testing in sub-Saharan Africa: a case study in clinical trial design in resource limited settings to optimize effectiveness and cost effectiveness estimates. AB - BACKGROUND: In sub-Saharan Africa, rates of sustained HIV virologic suppression remain below international goals. HIV resistance testing, while common in resource-rich settings, has not gained traction due to concerns about cost and sustainability. OBJECTIVE: We designed a randomized clinical trial to determine the feasibility, effectiveness, and cost-effectiveness of routine HIV resistance testing in sub-Saharan Africa. APPROACH: We describe challenges common to intervention studies in resource-limited settings, and strategies used to address them, including: (1) optimizing generalizability and cost-effectiveness estimates to promote transition from study results to policy; (2) minimizing bias due to patient attrition; and (3) addressing ethical issues related to enrollment of pregnant women. METHODS: The study randomizes people in Uganda and South Africa with virologic failure on first-line therapy to standard of care virologic monitoring or immediate resistance testing. To strengthen external validity, study procedures are conducted within publicly supported laboratory and clinical facilities using local staff. To optimize cost estimates, we collect primary data on quality of life and medical resource utilization. To minimize losses from observation, we collect locally relevant contact information, including Whatsapp account details, for field-based tracking of missing participants. Finally, pregnant women are followed with an adapted protocol which includes an increased visit frequency to minimize risk to them and their fetuses. CONCLUSIONS: REVAMP is a pragammatic randomized clinical trial designed to test the effectiveness and cost-effectiveness of HIV resistance testing versus standard of care in sub Saharan Africa. We anticipate the results will directly inform HIV policy in sub Saharan Africa to optimize care for HIV-infected patients. PMID- 28720041 TI - Burden of Hand Maladies in US Emergency Departments. AB - BACKGROUND: Hand conditions commonly present to the emergency department (ED), yet data are lacking regarding the magnitude of hand-related conditions in the emergency setting. The purpose of this study is to describe the burden and quantify the health care resource utilization of hand conditions seen in EDs across the United States. METHODS: Using the National Emergency Department Sample, we identified all ED encounters by patients at least 18 years of age that were associated with a hand condition in 2009 to 2012. The primary outcomes were prevalence, etiology, and associated health care charges for specific categories of hand conditions. RESULTS: The final sample included 34.4 million ED encounters associated with a common hand condition generating $180.4 billion in health care charges. The volume of hand-related presentations varied in a predictable and cyclical manner, peaking in July and waning in December of each year. Trauma was the most common etiology (77.5%) predominantly due to falls (26.2%) and lacerations (19.7%). Over 4 years, the volume of ED encounters rose (5% increase, P < .001) and as did the resulting health care charges (24.6% increase, P < .001). CONCLUSIONS: Our study confirms that hand-related conditions contribute significantly to ED volume and consume a growing quantity of health care resources in the United States. The volume of patients presenting to EDs with hand-related conditions fluctuates cyclically throughout the year. Open wounds are the most common cause of presentation and mostly occur in young adults, followed by joint pain, contusions, and fractures. PMID- 28720042 TI - Exotic dancing and relationship violence: exploring Indigeneity, gender and agency. AB - How should we begin to explore the complex considerations influencing young Indigenous New Zealand Maori women's sexuality? Centring a Maori woman's analysis through a Mana Wahine methodology, and utilising an Indigenous form of storying, purakau, I explore this question by attending to my autobiographical memory of experiences of exotic dancing and moments of violence in heterosexual relationships. The analysis provides critical reflection on the interchanges between individual experience and the social and cultural conditions of a reality, informed by colonisation and historical trauma. Attending to the rawness and detail of lived experience highlights how complicated the workings of sexual(ised) agency and power, as well as pleasure and risk, can be in the lives of Maori teenage girls. It has also provided an impetus to consider how complex vectors of oppression are brought to bear on us as individuals, and how Indigenous cultural forms can provide the basis for knowing beyond imposed colonising racist and sexist cultural forms. PMID- 28720043 TI - Open, Arthroscopic, and Percutaneous Surgical Treatment of Lateral Epicondylitis: A Systematic Review. AB - BACKGROUND: Approximately 10% of patients with lateral epicondylitis go on to have surgical treatment; however, multiple surgical treatment options exist. The purpose of this study was to review the literature for the clinical outcomes of open, arthroscopic, and percutaneous treatment of lateral epicondylitis. The authors hypothesized that the clinical outcome of all 3 analyzed surgical treatments would be equivalent. METHODS: A systematic review was performed using PubMed, Cochrane Central Register of Controlled Trials, and Google Scholar in July 2016 to compare the functional outcome, pain, grip strength, patient satisfaction, and return to work at 1-year follow-up for open, arthroscopic, and percutaneous treatment of lateral epicondylitis. RESULTS: Six studies (2 Level I and 4 Level II) including 179 elbows (83 treated open, 14 arthroscopic, 82 percutaneous) were analyzed. Three outcome measures (Disabilities of the Arm, Shoulder, and Hand [DASH] score, visual analog scale [VAS], and patient satisfaction) were reported for more than one category of surgical technique. Of these, the authors noted no clinically significant differences between the techniques. CONCLUSIONS: This is the first systematic review looking at high level evidence to compare open, percutaneous, and arthroscopic techniques for treating lateral epicondylitis. There are no clinically significant differences between the 3 surgical techniques (open, arthroscopic, and percutaneous) in terms of functional outcome (DASH), pain intensity (VAS), and patient satisfaction at 1 year follow-up. PMID- 28720044 TI - Ulnar Artery Aneurysm in a 6-Month-Old: A Case Report. AB - BACKGROUND: Pediatric ulnar aneurysms are rare and, unlike their adult counterparts, cannot be explained by repetitive trauma to the palm. A small number of case reports describe diagnostic difficulty with these lesions and different treatments. METHODS: We present the case of a 6-month-old with an ulnar artery aneurysm of unknown cause. The diagnosis was supported with magnetic resonance imaging, and the lesion was resected. RESULTS: Because the hand remained well perfused, the ulnar artery was not reconstructed. CONCLUSIONS: Although the early result was good, the long-term outcome of this approach is unknown. PMID- 28720045 TI - Neonatal Acute Paronychia. AB - BACKGROUND: Paronychia is defined as infection afflicting the eponychial nail folds of the hand or foot. Such infections are rarely reported in the perinatal age group, and not previously described in a neonate younger than 2 weeks. Trauma resulting in inoculation of the nail fold is the most common predisposing factor to paronychia. Oral trauma in the pediatric population from finger sucking predisposes this population to a different set of bacterial pathogens than adults. Contamination can progress to infection and abscess formation within the nail fold with the most prevalent vector in adult infections being Staphylococcus aureus. Comparatively, mixed anaerobic and aerobic infections tend to afflict children with oral soothing habits. METHODS: This is a case report will present the rare occurrence of a paronychia in a neonate caused by methicillin-resistant Staphylococcus aureus. RESULTS: The management and treatment strategies for paronychia in this atypical neonatal patient consisted of incision and drainage and antibiotic therapy. CONCLUSION: Neonates with oral self-soothing behaviors may be more at risk for developing paronychia of mixed anaerobic and aerobic infections. Initial therapy with broad-spectrum antibiotics amoxicillin/clavulanate or clindamycin is suggested. Incision and drainage in the perinatal setting coupled with antibiotics is curative. PMID- 28720046 TI - Strain as a Function of Time in Extrinsic Wrist Ligaments Tensioned Through External Fixation. AB - BACKGROUND: The objective of this study is to determine the time-dependent dissipation of extrinsic wrist ligament tension following the application external fixation with axial distraction of the wrist in a cadaveric model. METHODS: Six paired fresh-frozen cadaveric specimens underwent mechanical testing simulating external fixation with 1 arm of each pair osteotomized to simulate a distal radius fracture. The change in tension was then recorded over 24 hours. RESULTS: The rate of stress relaxation decreased with time. The average loss in tension in the control arms and osteotomized arms was 55% and 59%, respectively, over a 24-hour period. There was no statistically significant difference in the stress relaxation behavior between the 2 groups. CONCLUSION: This study further supports the recommendation that comminuted distal radius fractures treated with an external fixator should have Kirschner wire augmentation or other additional means of fixation to help maintain fracture length and alignment. The results of this study call in to question the efficacy of ligamentotaxis alone through external fixation as the sole means of maintaining reduction of displaced, unstable distal radius fractures. PMID- 28720047 TI - Ring Avulsion Injuries: A Systematic Review. AB - BACKGROUND: Ring avulsion injuries can range from soft tissue injury to complete amputation. Grading systems have been developed to guide treatment, but there is controversy with high-grade injuries. Traditionally, advanced ring injuries have been treated with completion amputation, but there is evidence that severe ring injuries can be salvaged. The purpose of this systematic review was to pool the current published data on ring injuries. METHODS: A systematic review of the English literature published from 1980 to 2015 in PubMed and MEDLINE databases was conducted to identify patients who underwent treatment for ring avulsion injuries. RESULTS: Twenty studies of ring avulsion injuries met the inclusion criteria. There were a total of 572 patients reported with ring avulsion injuries. The Urbaniak class breakdown was class I (54 patients), class II (204 patients), and class III (314 patients). The average total arc of motion (TAM) for patients with a class I injury was 201.25 (n = 40). The average 2-point discrimination was 5.6 (n = 10). The average TAM for patients with a class II injury undergoing microsurgical revascularization was 187.0 (n = 114), and the average 2-point discrimination was 8.3 (n = 40). The average TAM for patients with a class III injury undergoing microsurgical revascularization was 168.2 (n = 170), and the average 2-point discrimination was 10.5 (n = 97). CONCLUSIONS: Ring avulsion injuries are commonly classified with the Urbaniak class system. Outcomes are superior for class I and II injuries, and there are select class III injuries that can be treated with replantation. Shared decision making with patients is imperative to determine whether replantation is appropriate. PMID- 28720048 TI - Mesangial proliferative lupus nephritis with podocytopathy: a special entity of lupus nephritis. AB - Mesangial proliferative lupus nephritis may coexist with podocytopathy, but its clinical-morphological features, treatment response and outcomes have not been compared with mesangial proliferative lupus nephritis without podocytopathy. In this study, 125 biopsies of lupus nephritis patients showing mesangial proliferation with mesangial immune deposits were collected and divided into podocytopathy group (defined as podocyte foot process effacement (FPE) >50% with nephrotic syndrome (NS)) and mesangial group (FPE <=50%, or FPE >50% without NS). Mesangial proliferation and tubular- interstitial lesions were semi quantitatively analyzed. We found that the incidence of renal involvement as the onset symptoms ( P < .001), nephrotic syndrome ( P < .001), acute kidney injury ( P < .001), the degree of acute tubular- interstitial lesions ( P < .001), and renal relapse (51.6% vs. 23.7%, P = .005) were significantly higher in the podocytopathy group than in the mesangial group. In contrast, the incidence of arthritis ( P < .001), fever ( P = .042), low serum C4 ( P = .008) and hematuria ( P = .033) was significantly lower in the podocytopathy group than in the mesangial group. No patients developed end stage renal disease or death during a median follow-up of 64 (interquartile range (IQR) 37-103) months in the podocytopathy group and 53 (IQR 30-83) months in the mesangial group. In conclusion, mesangial proliferative lupus nephritis with and without podocytopathy should be subdivided into two separate classes of lupus nephritis. PMID- 28720049 TI - Outcomes Following Isolated Posterior Interosseous Nerve Neurectomy: A Systematic Review. AB - BACKGROUND: Posterior interosseous nerve neurectomies (PINN) are an option in the treatment of chronic dorsal wrist pain. However, the literature describing PINN consists primarily of small case series, and the procedure is typically done as an adjunct treatment; therefore, the outcomes of the PINN itself are not well known. We performed a systematic review of the literature to provide characteristics of patients following a PINN. METHODS: A systematic review of the literature was performed. Papers published in the PubMed database in English on isolated PINN were included. Articles in which a PINN was performed as an adjunct were excluded. Primary outcomes were return to work, patient satisfaction, pain/function scores, wrist range of motion, complications, and pain recurrence. Weighted averages were used to calculate continuous data, whereas categorical data were noted in percentages. RESULTS: The search yielded 427 articles including 6 studies and 135 patients (136 cases). The average age was 43.6 years (range, 17-75), and most patients were female (54.1%). At an average final follow up of 51 months, 88.9% of patients were able to return to work. After initial improvement, a recurrence of pain occurred in 25.5% of patients at an average of 12.3 months. Excluding recurrence of pain, the complication rate was 0.9%, including 1 reflex sympathetic dystrophy. Overall, 88.4% of patients experienced a subjective improvement and were satisfied with the procedure. CONCLUSIONS: Isolated PINN have shown excellent clinical outcomes, with few patients experiencing recurrent pain at long-term follow-up. PINN can provide relief in patient's chronic wrist pain. PMID- 28720050 TI - Localized prostate cancer and robot-assisted laparoscopic radical prostatectomy: a retrospective, comparative study between pre- and post-operative Gleason scores. AB - INTRODUCTION: To compare the pre- and post-operative Gleason scores (GS) in patients with localized prostate cancer treated with robot-assisted laparoscopic radical prostatectomy. MATERIALS AND METHODS: A single center, retrospective comparison between pre- and post-operative GS. Age, prostate volume, PSA, number of biopsies, number of positive cores, biopsy GS, cTNM, final pathology GS and pTNM of 286 patients were retrieved. They were divided into risk groups. RESULTS: A total of 286 patients with a mean age at surgery of 64.64 +/- 7.81 y and mean PSA-value of 9.35 +/- 8.38 ng/mL. Mean prostate volume was 55.09 +/- 24.93 mL, mean number of biopsies was 11.90 +/- 4.63. Mean percentage of positive cores was 36.90 +/- 22.42%. A GS of <7 was seen in 23.4%, 66.8% had a GS of 7 and 9.7% of >7 in final pathology. Of the total, 38.1% were pre-operative low risk, 58.7% of them had an upgrade in GS on final pathology, 45.1% were in the intermediate risk group, 5.4% showed a downgrade, 64.3% remained stable and 30.2% had an upgrade in GS. Also, 16.8% were high risk patients of which 35.4% had a downgrade, 39.6% remained stable and 25% showed an upgrade of the GS. CONCLUSIONS: We found a substantial underestimation of the GS in the pre-operative setting when compared to the GS in final pathology. PMID- 28720051 TI - Plasma and amniotic fluid PPARgamma is involved in the lipid metabolism of maternal-fetal interface cells. AB - OBJECTIVES: The aim of this study was at detecting the expression of peroxisome proliferator-activated receptor gamma (PPARgamma) in patients with gestational diabetes mellitus (GDM) and to investigate whether PPARgamma regulates the lipid metabolism of maternal-fetal interface cells. METHODS: We detected the expression of PPARgamma in the maternal plasma, fetal plasma and amniotic fluid of two groups of women with GDM or normal pregnancy using ELISA and western blot. Establish the cell models of the indirect coculture model and the separate culture model using BeWo cells and endometrial stromal cells (ESCs). Oil red O staining was used to detect the lipid uptake, and the mRNA levels of the rate limiting enzyme stearoyl CoA desaturase (SCD) and glucose transporter 1 (GLUT1) were detected by RT-PCR. RESULTS: PPARgamma is detectable in maternal plasma, fetal plasma and amniotic fluid. Levels of PPARgamma in GDM maternal plasma were significant higher than other groups in vitro, with increasing PPARgamma, the cytoplasmic lipid uptake levels of BeWo cells and ESCs were both increased in coculture conditions. GLUT1 and SCD mRNA rose significantly with increasing PPARgamma in indirect coculture conditions, but both did not respond to PPARgamma in ESC-absent culture conditions. CONCLUSIONS: The extracellular concentration of PPARgamma may be involved in the lipid transport of maternal-fetal interface cells and may play a role in the abnormal lipid metabolism of GDM patients. PMID- 28720052 TI - The effectiveness of various interventions versus standard stripping in patients with varicose veins in terms of quality of life. AB - Purpose Lower limb varicose veins have a significant effect upon the quality of life and a considerable socioeconomic impact despite their relatively benign nature. The aim of this study is to compare the effects of various therapeutic strategies among patients with varicose veins to surgical ligation and vein stripping on the basis of quality of life. Methods PubMed/Medline and Scopus databases were systemically searched from 1 January 2000 until 23 December 2015 for studies reporting outcome on the quality of life of different treatment techniques for varicose veins. We used Cohen's d to make the outcomes of the reported scales comparable. Heterogeneity was calculated with the use of the Q statistic and the I2. Results A total of 1047 participants were randomized across all analyzed trials. The number of participants in a single trial ranged from 30 to 308. The majority of participants in any trial were C2 on the CEAP scores. Overall, the quality of evidence was low. For the meta-analysis performed at 12 months postintervention (seven studies, n = 1047 patients) and after random effects meta-analyses due to high heterogeneity, no differences are observed between intervention and surgical ligation and vein stripping. The pooled estimate is -0.001 and the 95% confidence interval is -0.069 to 0.067 with a p = 0.98. In the case of the 24 months, postintervention analysis (six studies, n = 840 patients) the inference is almost identical. The effect of various interventional modes of treatment compared to surgical ligation and vein stripping is negligible in terms of clinical outcomes and quality of life so that surgical ligation and vein stripping versus the other interventional procedures were equally effective approaches to treat great saphenous vein incompetence in terms of quality of life measurements. Conclusion The procedures were at least equally efficient in treating patients with varicose vein disease in terms of quality of life assessment tools at 12 and 24 months compared to surgical ligation and vein stripping. PMID- 28720053 TI - Paracetamol versus ibuprofen for the treatment of patent ductus arteriosus in preterm neonates: a meta-analysis of randomized controlled trials. AB - BACKGROUND: Paracetamol has been suggested as an effective treatment for patent ductus arteriosus (PDA). However, the comparative efficacy and safety between paracetamol and ibuprofen were not determined. METHODS: A meta-analysis of randomized controlled trials (RCTs) was performed. Relevant studies were identified via database searching. A fixed or random effect model was applied depending on the extent of heterogeneity. RESULTS: Five RCTs with 677 neonates were included. The efficacies for the primary (risk ratio [RR]: 1.03, p = .56) and overall PDA closure were comparable between the two medications (RR: 1.02, p = .62). Neonates of the two groups were comparable for the incidence of PDA complications, including necrotizing enterocolitis (RR: 0.86, p = .70), intraventricular hemorrhage (RR: 0.84, p = .55), bronchopulmonary dysplasia (RR: 0.69, p = .16), and retinopathy of prematurity (RR: 0.58, p = .15), and the risks of sepsis (RR = 0.88, p = .48) and death (RR: 1.45, p = .45) within hospitalization. However, treatment with paracetamol was associated with a trend of reduced risk of renal failure (RR: 0.20, p = .07), and a significantly reduced risk of gastrointestinal bleeding (RR: 0.28, p = .009). CONCLUSIONS: Paracetamol may confer comparable treatment efficacy for the closure of PDA as ibuprofen, although paracetamol is associated with lower risk of adverse events. PMID- 28720054 TI - Impact of novel agents on patient-relevant outcomes in patients with previously untreated chronic lymphocytic leukemia who are not eligible for fludarabine-based therapy. AB - BACKGROUND: Chronic lymphocytic leukemia (CLL) is an orphan disease that primarily affects the elderly. The majority of symptomatic patients eligible for frontline treatment are unfit for fludarabine based chemoimmunotherapy. Historical treatment includes chlorambucil (Chl), bendamustine/rituximab (BR), and chlorambucil/rituximab/ChlR combination. Clinical guidelines now recommend the use of novel agents, such as ibrutinib (Ibr), in both frontline and relapse settings and other novel agents, such as idelalisib (with rituximab), in relapse settings. Despite compelling clinical results for novel agents, follow-up in clinical trials is relatively short and, thus, the comparative long-term benefits are still unknown. MATERIALS AND METHODS: The authors developed a simulation model to generate treatment specific lifetime estimates of Overall Survival (OS) and Quality Adjusted Life Years (QALYs) for treatment with BR, Chl, ChlR, and Ibr. Two potential clinical scenarios were modelled: with and without novel agents for treating CLL. The model was based on health states relating to first- and second-line progression-free survival (PFS), post-progression survival, and death. RESULTS: Where novel agents were assumed unavailable, mean OS ranged from 5.4-8.5 years and QALYs from 3.5-6.1. Where novel agents were available, the mean OS increased to 10.0 years, with a corresponding increase in QALYs to 7.6. Frontline Ibr use followed by Physician's Choice, including novel agents at relapse, resulted in projected increase in OS of between 18% (1.5 years) and 85% (4.6 years), corresponding to a 25-117% increase in QALYs, compared with currently available traditional therapies. LIMITATIONS: The limitations of this analysis include immature OS data and the assumption of equivalent efficacy across all novel agents in terms of their impact on PFS and OS. CONCLUSIONS: The use of novel agents is predicted to yield substantive gains in predicted lifetime OS and QALY improvements compared to traditional therapies in CLL patients who are ineligible for fludarabine-based chemoimmunotherapy. PMID- 28720055 TI - Review for textiles and human thermophysiological comfort in the indoor environment. PMID- 28720056 TI - Influence of Tissue Microstructure on Shear Wave Speed Measurements in Plane Shear Wave Elastography: A Computational Study in Lossless Fibrotic Liver Media. AB - Shear wave elastography (SWE) has been used to measure viscoelastic properties for characterization of fibrotic livers. In this technique, external mechanical vibrations or acoustic radiation forces are first transmitted to the tissue being imaged to induce shear waves. Ultrasonically measured displacement/velocity is then utilized to obtain elastographic measurements related to shear wave propagation. Using an open-source wave simulator, k-Wave, we conducted a case study of the relationship between plane shear wave measurements and the microstructure of fibrotic liver tissues. Particularly, three different virtual tissue models (i.e., a histology-based model, a statistics-based model, and a simple inclusion model) were used to represent underlying microstructures of fibrotic liver tissues. We found underlying microstructures affected the estimated mean group shear wave speed (SWS) under the plane shear wave assumption by as much as 56%. Also, the elastic shear wave scattering resulted in frequency dependent attenuation coefficients and introduced changes in the estimated group SWS. Similarly, the slope of group SWS changes with respect to the excitation frequency differed as much as 78% among three models investigated. This new finding may motivate further studies examining how elastic scattering may contribute to frequency-dependent shear wave dispersion and attenuation in biological tissues. PMID- 28720057 TI - Use of Integra in the Management of Complex Hand Wounds From Cancer Resection and Nonburn Trauma. AB - BACKGROUND: Despite extensive use of Integra in burn reconstruction, little has been published regarding its utility in complex hand wounds from nonburn trauma or cancer resection. This study aimed to review outcomes following Integra use for hand reconstruction following cancer resection or nonburn trauma with exposed bone, joints, and/or tendons. METHODS: Retrospective review was performed of patients undergoing hand reconstruction with Integra for exposed bones, joints, or tendons over a 6-year period at a single institution. RESULTS: Fourteen patients underwent hand reconstruction using Integra, 8 following cancer resection and 6 following acute nonburn trauma. The mean defect size was 19 cm2, 79% had exposed tendon without peritenon, 43% had exposed bone without periosteum, and 28% had exposed joint capsule. Mean time from Integra to skin graft was 11.3 days, and negative-pressure wound therapy did not significantly decrease the mean time from Integra to skin graft placement ( P = .76). Overall, 13 patients achieved successful reconstruction with mean skin graft take of 97%, and 1 required revision amputation at the proximal interphalangeal (PIP) joint. Six months postoperative, 92% patients had return of preoperative hand function. Without any surgical revision, 85% of patients were extremely satisfied with the aesthetic result and 15% were fairly satisfied. CONCLUSIONS: Integra is an effective method to treat complex hand wounds with exposed bone, joints, and/or tendons. This technique can be used in the office, lessens the need for local or free flap coverage, and provides an excellent aesthetic outcome. Integra should be considered a viable option in hand reconstruction algorithm. PMID- 28720058 TI - Long form of thymic stromal lymphopoietin of keratinocytes is induced by protein allergens. AB - A growing body of evidence suggests that epicutaneous sensitization of protein allergens induces immediate-type hypersensitivity (IHS) following induction of Type 2 immune responses in animals and humans. Thymic stromal lymphopoietin (TSLP) derived from keratinocytes is a cytokine that can activate dendritic cells and has been implicated in development of inflammatory Type 2 helper T-cells. However, there is no direct evidence that allergens directly regulate TSLP expression in keratinocytes. This study aimed to evaluate the response of TSLP to protein allergens in cultured human keratinocytes and to identify appropriate endpoints for IHS. The transcription of long-form TSLP (loTSLP) was strongly induced by ovalbumin, wheat gluten (WG), acid-hydrolyzed WG (acid-HWG), and extracts from feces of Dermatophagoides pteronyssinus and D. farina, and trypsin, but not by rare allergens, human serum albumin (HSA), or extracts of mite bodies. In acid-HWG, loTSLP mRNA was significantly augmented by acid hydrolysis of WG for 0.5 h compared to WG. However, prolonged acid hydrolysis attenuated this induction similarly to that reported in previous animal studies. These results suggested that intense loTSLP transcriptional induction was a characteristic of a high-allergenic protein. Additionally, TSLP production was induced by exposure to ovalbumin, WG, and acid-HWG in combination with a trio of cytokines, i.e. interleukin (IL)-4, IL-13, and tumor necrosis factor (TNF)-alpha. However, no TSLP protein was detected following exposure to HSA, even in the presence of these cytokines. With acid-HWG, TSLP protein release was consistent with loTSLP transcription. Thus, intense loTSLP transcriptional induction and TSLP protein expression are each effective indicators that can be used for in vitro screening of IHS. PMID- 28720059 TI - Cervical cancer cell-derived angiopoietins promote tumor progression. AB - Metastatic or recurrent cervical cancer has limited treatment options and a high rate of mortality. Although anti-vascular endothelial growth factor drugs have shown great promise as a therapeutic target for treatment of advanced cervical cancer, drug resistance and class-specific side effects negate long-term benefits. The identification of alternative anti-angiogenic factors will be critical for future drug development for advanced or recurrent cervical cancer. In this study, we found that angiopoietins and Tie receptors were highly expressed in cervical cancer cells. Tie-2 expression in tumor cells predicted poorer prognosis. Wound closure assay and Transwell assay showed that upregulated or downregulated Ang-1 and Ang-2 expression promoted or reduced cervical cancer cell lines migration and invasion, respectively. In subcutaneous xenograft models of cervical cancer, downregulation of Ang-1 and Ang-2 attenuated tumor growth. The expression of vimentin and endomucin and microvessel density were all significantly decreased in the siAng-1 group and siAng-2 group relative to the infection control group. Our data support that dual inhibition of Ang-1 and Ang-2 may be an alternative target for anti-angiogenic adjuvant therapy in advanced or recurrent cervical squamous cell cancer. PMID- 28720060 TI - PPFIA1 is upregulated in liver metastasis of breast cancer and is a potential poor prognostic indicator of metastatic relapse. AB - Although the oncogenic role of PPFIA1 (liprin-alpha1) in breast cancer has been reported, whether its dysregulation is associated with metastasis risk or survival outcomes in breast cancer patients is not clear. Our primary data showed that PPFIA1 expression was significantly higher in liver metastatic breast tumors than in the primary tumors. Then, we tried to pool previous annotated genomic data to assess the prognostic value of PPFIA1 in distant metastasis-free survival, the risk of metastatic relapse, and metastatic relapse-free survival in breast cancer patients by data mining in two large databases, Kaplan-Meier plotter and bc-GenExMiner 4.0. Results from Kaplan-Meier plotter showed that although high PPFIA1 expression was generally associated with decreased distant metastasis-free survival in estrogen receptor+ patients, subgroup analysis only confirmed significant association in estrogen receptor+/N- (nodal negative) group (median survival, high PPFIA1 group vs low PPFIA1 cohort: 191.21 vs 236.22 months; hazard ratio: 2.23, 95% confidence interval: 1.42-3.5, p < 0.001), but not in estrogen receptor+/N+ (nodal positive) group (hazard ratio: 1.63, 95% confidence interval: 0.88-3.03, p = 0.12). In estrogen receptor- patients, there was no association between PPFIA1 expression and distant metastasis-free survival, no matter in Nm (nodal status mixed), N-, or N+ subgroups. In bc GenExMiner 4.0, Nottingham Prognostic Index- and Adjuvant! Online-adjusted analysis validated the independent prognostic value of PPFIA1 in metastatic risks in estrogen receptor+/N- patients. Based on these findings, we infer that high PPFIA1 expression might be an independent prognostic indicator of increased metastatic relapse risk in patients with estrogen receptor+/N- breast cancer, but not in estrogen receptor+/N+ or estrogen receptor- patients. PMID- 28720061 TI - The long non-coding RNA MALAT1 promotes the migration and invasion of hepatocellular carcinoma by sponging miR-204 and releasing SIRT1. AB - Increasing evidence supports the significance of long non-coding RNA in cancer development. Several recent studies suggest the oncogenic activity of long non coding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) in hepatocellular carcinoma. In this study, we explored the molecular mechanisms by which MALAT1 modulates hepatocellular carcinoma biological behaviors. We found that microRNA-204 was significantly downregulated in sh-MALAT1 HepG2 cell and 15 hepatocellular carcinoma tissues by quantitative real-time polymerase chain reaction analysis. Through bioinformatic screening, luciferase reporter assay, RNA-binding protein immunoprecipitation, and RNA pull-down assay, we identified microRNA-204 as a potential interacting partner for MALAT1. Functionally, wound healing and transwell assays revealed that microRNA-204 significantly inhibited the migration and invasion of hepatocellular carcinoma cells. Notably, sirtuin 1 was recognized as a direct downstream target of microRNA-204 in HepG2 cells. Moreover, si-SIRT1 significantly inhibited cell invasion and migration process. These data elucidated, by sponging and competitive binding to microRNA-204, MALAT1 releases the suppression on sirtuin 1, which in turn promotes hepatocellular carcinoma migration and invasion. This study reveals a novel mechanism by which MALAT1 stimulates hepatocellular carcinoma progression and justifies targeting metastasis-associated lung adenocarcinoma transcript 1 as a potential therapy for hepatocellular carcinoma. PMID- 28720063 TI - STYK1 promotes Warburg effect through PI3K/AKT signaling and predicts a poor prognosis in nasopharyngeal carcinoma. AB - STYK1 (Serine/threonine/tyrosine kinase 1), a member of the receptor tyrosine kinase family, exhibits tumorigenicity in many types of cancers. Our study reveals the important role played by STYK1 in nasopharyngeal carcinoma. STYK1 is upregulated in nasopharyngeal carcinoma tissues compared with para-carcinoma. Knockdown of STYK1 inhibits nasopharyngeal carcinoma cell proliferation, migration, and invasion, while ectopic STYK1 expression significantly promoted cell proliferation, migration, and invasion abilities. In addition, we provided lines of evidence supporting the critical role of STYK1 in the regulation of glycolysis via activation of phosphoinositide 3-kinase/AKT pathway. Survival analysis reveals that STYK1 level is an independent prognostic factor for nasopharyngeal carcinoma patients. Our results indicate that STYK1 is a promising therapeutic target in nasopharyngeal carcinoma. PMID- 28720064 TI - Evaluation of the antitumor activity of platinum nanoparticles in the treatment of hepatocellular carcinoma induced in rats. AB - This study aimed to evaluate the antitumor activity of platinum nanoparticles compared with cis-platin both in vitro and in vivo in the treatment of hepatocellular carcinoma induced in rats. The treatment efficacy of platinum nanoparticles was evaluated by measuring antioxidant activities against oxidative stress caused by diethylnitrosamine in liver tissue. The measurements included reduced glutathione content and superoxide dismutase activity, as well as malondialdehyde level. Liver function tests were also determined, in addition to the evaluation of serum alpha-fetoprotein, caspase-3, and cytochrome c in liver tissue. Total RNA extraction from liver tissue samples was also done for the relative quantification of B-cell lymphoma 2, matrix metallopeptidase 9, and tumor protein p53 genes. Histopathological examination was also performed for liver tissue. Results showed that platinum nanoparticles are more potent than cis platin in treatment of hepatocellular carcinoma induced by diethylnitrosamine in rats as it ameliorated the investigated parameters toward normal control animals. These findings were well appreciated with histopathological studies of diethylnitrosamine group treated with platinum nanoparticles, suggesting that platinum nanoparticles can serve as a good therapeutic agent for the treatment of hepatocellular carcinoma which should attract further studies. PMID- 28720065 TI - MicroRNA-139-5p inhibits bladder cancer proliferation and self-renewal by targeting the Bmi1 oncogene. AB - MiR-139-5p has been reported to be overexpressed in many types of cancers, but its role in bladder cancer has not been elucidated yet. Here, we report that miR 139-5p functions as a tumor suppressor in bladder cancer and inhibits the cancer stem cell self-renewal by targeting Bmi1 directly. We found that miR-139-5p expression was significantly downregulated in the bladder cancer specimens compared with that in adjacent normal tissues. In vitro, restoration of miR-139 5p expression significantly inhibited the proliferation of bladder cancer cells. Mechanism analysis revealed that miR-139-5p could decrease Bmi1 protein levels by binding to the 3' untranslated region of Bmi1 messenger RNA. Stem cell-related proteins such as c-MYC, NANOG, OCT4, and KLF4 and signaling pathways such as Wnt signaling were suppressed by restoration of miR-139-5p in bladder cancer cells. In addition, miR-139-5p expression also blocked self-renewal of bladder cancer stem cells by inhibiting Bmi1. In summary, our study supports that miR-139-5p acts as a tumor suppressor in bladder cancer development and suppresses cancer stem cell property of bladder cancer. Our study also suggests that miR-139-5p has the potential to be used as a therapeutic molecule for bladder cancer treatment. PMID- 28720066 TI - High expression of SLC34A2 is a favorable prognostic marker in lung adenocarcinoma patients. AB - Dysregulation of SLC34A2 (NaPi2b) in tumors has attracted wide attention, but its expression and function in non-small cell lung cancer remains unclear. By examining its expression in lung adenocarcinoma and correlation to patient outcome, we aimed to explore its prognostic and therapeutic values in this deadly disease. Overall, 175 cases of lung adenocarcinoma sample were included in this study. Histological subtyping of them was diagnosed according to standards of the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society in 2011. Protein expression of SLC34A2 and anaplastic lymphoma kinase in these samples was determined by immunohistochemistry. Epidermal growth factor receptor mutations were examined using amplification refractory mutation system. Statistical analysis was performed using software of Pearson's correlation coefficient. High expression of SLC34A2 was identified in about 2/3 patients and correlated with significantly better patient's overall survival. Epidermal growth factor receptor mutations were detected in about 53% of patients with no statistically significant difference to patient's overall survival. Anaplastic lymphoma kinase rearrangement was found in 8 out of 175 patients, harboring this abnormality leads to shorter overall survival. No correlation has been found between SLC34A2 expression and epidermal growth factor receptor mutation or anaplastic lymphoma kinase rearrangements in lung adenocarcinoma. High expression of SLC34A2 is present in about 3/4 lung adenocarcinoma samples and predicts better outcome. Since it is a membrane protein, antibody-based drugs targeting this marker might bring new resolution to this deadly disease. PMID- 28720067 TI - HPV16 E6/E7 upregulates HIF-2alpha and VEGF by inhibiting LKB1 in lung cancer cells. AB - Long-term persistent infection of HPV16 E6/E7 is frequently associated with lung cancers, especially in non-smokers and in Asians. However, molecular mechanisms of HPV16 E6/E7 induction of lung cancer are not fully understood. Using bi directional genetic manipulation and four well-established lung cancer cell lines, we showed HPV16 E6/E7 downregulated expression of liver kinase B1 at both protein and messenger RNA levels; liver kinase B1 downregulated hypoxia-inducible factor 2alpha at protein level but not at messenger RNA level, and hypoxia inducible factor 2alpha upregulated vascular endothelial growth factor at both protein and messenger RNA levels. This is the first study to show hypoxia inducible factor 2alpha as a downstream effector of liver kinase B1 in lung cancer cells. Our results indicate that HPV16 E6/E7 indirectly upregulated the expression of vascular endothelial growth factor by inhibition of liver kinase B1 expression and upregulation of hypoxia-inducible factor 2alpha expression, thus propose a human papillomavirus-liver kinase B1-hypoxia-inducible factor 2alpha vascular endothelial growth factor axis for the tumorigenesis of lung cancer. Our study also provides new evidence to support the critical role of liver kinase B1 in the pathogenesis of human papillomavirus-related lung cancer and suggests novel therapeutic targets. PMID- 28720068 TI - Inhibitory effect of Par-4 combined with cisplatin on human Wilms' tumor cells. AB - Wilms' tumor is associated with a high treatment success rate, but there is still a risk of recurrence. Cisplatin, which is one of the chemotherapeutic agents used for its treatment, is associated with a very high rate of resistance. Par-4 (prostate apoptosis response 4) is a tumor suppressor, which is capable of sensitizing tumor cells to chemotherapy. Therefore, the aim of this study was to determine whether combined treatment with Par-4 and cisplatin is effective for inhibiting growth of Wilms' tumor. Wilms' tumor and control cell samples were collected and analyzed by immunofluorescence assay and immunohistochemistry. Total proteins extracted from cultured cells were analyzed using western blotting and flow cytometry. In addition, a mouse xenograft model was established. We discovered significantly low expression of Par-4 in the tumor tissue, which was positively correlated with high expression of GRP78 (glucose-regulated protein 78). In addition, we found that ectopic Par-4 co-localized with cell surface GRP78 and induced high expression of the endoplasmic reticulum proteins ATF4 and BAX, which activated the endoplasmic reticulum apoptosis pathway. Moreover, treatment with ectopic Par-4 and cisplatin suppressed xenograft growth in nude mice. In conclusion, our results showed that Par-4 overexpression and cisplatin had a synergistic effect on SK-NEP-1 cells, as a result of which cell growth was inhibited and cellular apoptosis was induced. Thus, in vitro and in vivo upregulation of Par-4 expression is indispensable for the trafficking of GRP78 to the cell membrane and subsequent apoptosis of cancer cells. PMID- 28720069 TI - Long non-coding RNA SPRY4-IT1 promotes proliferation and invasion by acting as a ceRNA of miR-101-3p in colorectal cancer cells. AB - Long non-coding RNAs are associated with a spectrum of biological processes such as gene regulation on transcriptional and post-transcriptional levels. Increasing evidence indicates that SPRY4-IT1 plays an important role in carcinogenesis, and the mechanisms whereby SPRY4-IT1 induces colorectal carcinoma progression remain largely unknown. The aim of this study is to evaluate the expression and function of SPRY4-IT1 in colorectal carcinoma. In this study, we analyzed SPRY4-IT1 expression levels in a series of colorectal carcinoma patients by quantitative reverse transcription polymerase chain reaction. Knockdown of SPRY4-IT1 by RNA interference was performed to explore its roles in cell proliferation, migration, and invasion. Our results found that SPRY4-IT1 was upregulated in human primary colorectal carcinoma tissues. Knockdown of SPRY4-IT1 inhibited colorectal carcinoma cell proliferation, migration, and invasion. Moreover, we confirmed that the expression of epithelial-mesenchymal transition-related genes was modulated through alteration of SPRY4-IT1 expression. SPRY4-IT1 could negatively regulate the expression of miR-101-3p in colorectal carcinoma cells. The bioinformatics prediction revealed putative miR-101-3p binding sites within SPRY4 IT1 transcripts. Above all, knockdown of SPRY4-IT1 could represent a rational therapeutic strategy for colorectal carcinoma. PMID- 28720070 TI - Anammox biomass carrying efficiency of polyethylene non-woven sheets as a carrier material. AB - To access the effects of the surface modification and fabric structure of polyethylene (PE) non-woven fabric sheets on retaining the attachment efficiency of anammox biomass, three different non-woven sheets were prepared and inserted in an anammox reactor. The hydrophobic surface modification with 10% KMnO4 and gelatin did not improve the attachment efficiency of the anammox biomass on the surface of the PE non-woven fibers. Densely packed PE-755 having the highest specific surface area to volume ratio (SA/V) (755) retained 221.4 mg biomass per unit sheet, whereas PE-181 having the lowest SA/V (181) retained only 66.4 mg biomass per unit. Accordingly, the volumetric anammox activity of non-woven sheet PE-755 was the highest among the three PE non-woven sheets because of the strong positive relationship between the specific anammox activity and biomass amount (R = 0.835, P < .01). The specific surface area to volume ratio (cm2 cm-3) as well as the bulk density should be considered as important parameters for the selection of non-woven biocarriers for anammox biomass. PMID- 28720071 TI - Developmental Expression and Dysregulation of miR-146a and miR-155 in Down's Syndrome and Mouse Models of Down's Syndrome and Alzheimer's Disease. AB - BACKGROUND: miR-146a and miR-155 are key regulators of the innate immune response. We hypothesized that an inflammation-mediated dysregulation of these miRNAs may occur in patients with Down syndrome (DS) and Alzheimer's disease (AD). METHODS: The miRNA expression patterns were investigated by in situ hybridization in developing hippocampus from controls, patients with DS and in adults with AD pathology (DS and sporadic AD; sAD). Quantitative real-time PCR was employed to evaluate the miRNA levels in the hippocampus of sAD and in mouse models of DS and AD. Both miRNAs were expressed in prenatal human hippocampus. In DS we detected increased miR-146a expression in reactive astrocytes. Increased expression of miR-146a was found in the hippocampus of sAD and negatively correlated with its target IRAK-1. APP/PS1 mice showed a significant increase in the expression of both miRNAs at 11-13 months of age as compared to WT and mice at 3 months. A negative correlation between miR-146a levels and its target TRAF6 was observed in both Ts65Dn and APP/PS1 mice. CONCLUSION: These findings suggest a possible involvement of miR-146a and miR-155 in brain development and neurodegeneration. In particular, we provide evidence of a dysregulation of these two immunomodulatory miRNAs in AD with a potential therapeutical implication, deserving further investigation. PMID- 28720072 TI - Tissue and cell-specific transcriptomes in cotton reveal the subtleties of gene regulation underlying the diversity of plant secondary cell walls. AB - BACKGROUND: Knowledge of plant secondary cell wall (SCW) regulation and deposition is mainly based on the Arabidopsis model of a 'typical' lignocellulosic SCW. However, SCWs in other plants can vary from this. The SCW of mature cotton seed fibres is highly cellulosic and lacks lignification whereas xylem SCWs are lignocellulosic. We used cotton as a model to study different SCWs and the expression of the genes involved in their formation via RNA deep sequencing and chemical analysis of stem and seed fibre. RESULTS: Transcriptome comparisons from cotton xylem and pith as well as from a developmental series of seed fibres revealed tissue-specific and developmentally regulated expression of several NAC transcription factors some of which are likely to be important as top tier regulators of SCW formation in xylem and/or seed fibre. A so far undescribed hierarchy was identified between the top tier NAC transcription factors SND1-like and NST1/2 in cotton. Key SCW MYB transcription factors, homologs of Arabidopsis MYB46/83, were practically absent in cotton stem xylem. Lack of expression of other lignin-specific MYBs in seed fibre relative to xylem could account for the lack of lignin deposition in seed fibre. Expression of a MYB103 homolog correlated with temporal expression of SCW CesAs and cellulose synthesis in seed fibres. FLAs were highly expressed and may be important structural components of seed fibre SCWs. Finally, we made the unexpected observation that cell walls in the pith of cotton stems contained lignin and had a higher S:G ratio than in xylem, despite that tissue's lacking many of the gene transcripts normally associated with lignin biosynthesis. CONCLUSIONS: Our study in cotton confirmed some features of the currently accepted gene regulatory cascade for 'typical' plant SCWs, but also revealed substantial differences, especially with key downstream NACs and MYBs. The lignocellulosic SCW of cotton xylem appears to be achieved differently from that in Arabidopsis. Pith cell walls in cotton stems are compositionally very different from that reported for other plant species, including Arabidopsis. The current definition of a 'typical' primary or secondary cell wall might not be applicable to all cell types in all plant species. PMID- 28720073 TI - Heterogeneity in national U.S. mortality trends within heart disease subgroups, 2000-2015. AB - BACKGROUND: The long-term downward national U.S. trend in heart disease-related mortality slowed substantially during 2011-2014 before turning upward in 2015. Examining mortality trends in the major subgroups of heart disease may provide insight into potentially more targeted and effective prevention and treatment approaches to promote favorable trajectories. We examined national trends between 2000 and 2015 in mortality attributed to major heart disease subgroups including ischemic heart disease, heart failure, and all other types of heart disease. METHODS: Using the Centers for Disease Control and Prevention Wide-ranging Online Data for Epidemiologic Research (WONDER) data system, we determined national trends in age-standardized mortality rates attributed to ischemic heart disease, heart failure, and other heart diseases from January 1, 2000, to December 31, 2011, and from January 1, 2011, to December 31, 2015. Annual rate of changes in mortality attributed to ischemic heart disease, heart failure, and other heart diseases for 2000-2011 and 2011-2015 were compared. RESULTS: Death attributed to ischemic heart disease declined from 2000 to 2015, but the rate of decline slowed from 4.96% (95% confidence interval 4.77%-5.15%) for 2000-2011 to 2.66% (2.00% 3.31%) for 2011-2015. In contrast, death attributed to heart failure and all other causes of heart disease declined from 2000 to 2011 at annual rates of 1.94% (1.77%-2.11%) and 0.64% (0.44%-0.82%) respectively, but increased from 2011 to 2015 at annual rates of 3.73% (3.21% 4.26%) and 1.89% (1.33-2.46%). Differences in 2000-2011 and 2011-2015 decline rates were statistically significant for all 3 endpoints overall, by sex, and all race/ethnicity groups except Asian/Pacific Islanders (heart failure only significant) and American Indian/Alaskan Natives. CONCLUSIONS: While the long-term decline in death attributed to heart disease slowed between 2011 and 2014 nationally before turning upward in 2015, heterogeneity existed in the trajectories attributed to heart disease subgroups, with ischemic heart disease mortality continuing to decline while death attributed to heart failure and other heart diseases switched from a downward to upward trend. While systematic efforts to prevent and treat ischemic heart disease continue to be effective, urgent attention is needed to address the challenge of heart failure. PMID- 28720074 TI - Regeneration of long-distance peripheral nerve defects after delayed reconstruction in healthy and diabetic rats is supported by immunomodulatory chitosan nerve guides. AB - BACKGROUND: Delayed reconstruction of transection or laceration injuries of peripheral nerves is inflicted by a reduced regeneration capacity. Diabetic conditions, more frequently encountered in clinical practice, are known to further impair regeneration in peripheral nerves. Chitosan nerve guides (CNGs) have recently been introduced as a new generation of medical devices for immediate peripheral nerve reconstruction. Here, CNGs were used for 45 days delayed reconstruction of critical length 15 mm rat sciatic nerve defects in either healthy Wistar rats or diabetic Goto-Kakizaki rats; the latter resembling type 2 diabetes. In short and long-term investigations, we comprehensively analyzed the performance of one-chambered hollow CNGs (hCNGs) and two-chambered CNGs (CFeCNGs) in which a chitosan film has been longitudinally introduced. Additionally, we investigated in vitro the immunomodulatory effect provided by the chitosan film. RESULTS: Both types of nerve guides, i.e. hCNGs and CFeCNGs, enabled moderate morphological and functional nerve regeneration after reconstruction that was delayed for 45 days. These positive findings were detectable in generally healthy as well as in diabetic Goto-Kakizaki rats (for the latter only in short-term studies). The regenerative outcome did not reach the degree as recently demonstrated after immediate reconstruction using hCNGs and CFeCNGs. CFeCNG-treatment, however, enabled tissue regrowth in all animals (hCNGs: only in 80% of animals). CFeCNGs did further support with an increased vascularization of the regenerated tissue and an enhanced regrowth of motor axons. One mechanism by which the CFeCNGs potentially support successful regeneration is an immunomodulatory effect induced by the chitosan film itself. Our in vitro results suggest that the pro-regenerative effect of chitosan is related to the differentiation of chitosan-adherent monocytes into pro-healing M2 macrophages. CONCLUSIONS: No considerable differences appear for the delayed nerve regeneration process related to healthy and diabetic conditions. Currently available chitosan nerve grafts do not support delayed nerve regeneration to the same extent as they do after immediate nerve reconstruction. The immunomodulatory characteristics of the biomaterial may, however, be crucial for their regeneration supportive effects. PMID- 28720076 TI - Prevalence and risk factors of intracranial and extracranial artery stenosis in asymptomatic rural residents of 13 villages in China. AB - BACKGROUND: The present study aimed to investigate the prevalence and risk factors for extracranial carotid artery stenosis (ECAS) and intracranial carotid artery stenosis (ICAS) simultaneously in asymptomatic Chinese pure rural population. METHODS: We analyzed 2589 asymptomatic subjects aged over 30 yr. by ultrasonography and transcranial Doppler simultaneously in 13 isolated villages by door-to-door investigation. Both ECAS and ICAS were defined as more than 50% stenosis. Demographics, medical history documentation, and investigation of biochemical results were performed for each subject. Univariate and multivariate logistic regression analyses were employed to assess the risk factors associated with ECAS and ICAS, respectively. RESULTS: One hundred twenty-two (4.7%) residents with ICAS and 56 (2.2%) with ECAS were found in 2589 subjects. Three factors emerged as independent risk factors for ICAS: age (95% confidence interval [CI] = 1.01-1.04, odds ratio [OR] = 1.07), hypertension (95% CI = 1.98 4.37, OR = 2.94), and diabetes mellitus (95% CI = 1.72-4.38, OR = 2.75). As for ECAS, five factors presented as independent risk factors: age (95% CI = 1.09 1.11, OR = 1.10), male sex (95% CI = 1.01-1.02, OR = 1.01), diabetes mellitus (95% CI = 1.10-2.12, OR = 1.53), systolic blood pressure (95% CI = 1.95-2.88, OR = 2.37), and total cholesterol (95% CI = 1.00-1.13, OR = 1.06). CONCLUSIONS: ICAS and ECAS were relatively common among asymptomatic rural Chinese subjects. Although they shared similar risk factors, differences still existed between them. PMID- 28720075 TI - Physical activity, body functions and disability among middle-aged and older Spanish adults. AB - BACKGROUND: Physical activity (PA) is a health determinant among middle-aged and older adults. In contrast, poor health is expected to have a negative impact on PA. This study sought to assess to what extent specific International Classification of Functioning, Disability and Health (ICF) health components were associated with PA among older adults. METHODS: We used a sample of 864 persons aged >=50 years, positively screened for disability or cognition in a cross sectional community survey in Spain. Weekly energy expenditure during PA was measured with the Yale Physical Activity Survey (YPAS) scale. The associations between body function impairment, health conditions or World Health Organization Disability Assessment Schedule (WHODAS 2.0) disability scores and energy expenditure were quantified using negative-binomial regression, and expressed in terms of adjusted mean ratios (aMRs). RESULTS: Mean energy expenditure was 4542 Kcal/week. A lower weekly energy expenditure was associated with: severe/extreme impairment of mental functions, aMR 0.38, 95% confidence interval, CI (0.21 0.68), and neuromusculoskeletal and movement functions, aMR 0.50 (0.35-0.72); WHODAS 2.0 disability, aMR 0.55 (0.34-0.91); dementia, aMR 0.45 (0.31-0.66); and heart failure, aMR 0.54 (0.34-0.87). In contrast, people with arthritis/osteoarthritis had a higher energy expenditure, aMR 1.27 (1.07-1.51). CONCLUSION: Our results suggest that there is a strong relationship between selected body function impairments, mainly mental, and PA. Although more research is needed to fully understand causal relationships, strategies to improve PA among the elderly may require targeting mental, neuromusculoskeletal and movement functions, disability determinants (including barriers), and specific approaches for persons with dementia or heart failure. PMID- 28720077 TI - Hemolytic uremic syndrome as the presenting manifestation of WT1 mutation and Denys-Drash syndrome: a case report. AB - BACKGROUND: Hemolytic uremic syndrome (HUS) can occur as a primary process due to mutations in complement genes or secondary to another underlying disease. HUS sometimes occurs in the setting of glomerular diseases, and it has been described in association with Denys-Drash syndrome (DDS), which is characterized by the triad of abnormal genitourinary development; a pathognomonic glomerulopathy, diffuse mesangial sclerosis; and the development of Wilms tumor. CASE PRESENTATION: We report the case of a 46, XX female infant who presented with HUS and biopsy-proven thrombotic microangiopathy. Next generation sequencing of genes with known mutations causative of atypical HUS found that she was homozygous for the Complement Factor H H3 haplotype and heterozygous for a variant of unknown significance in the DGKE gene. Whole exome sequencing identified a de novo heterozygous WT1 c.1384C > T; p.R394W mutation, which is classically associated with Denys-Drash syndrome (DDS). At the time of bilateral nephrectomy five months after her initial biopsy, she had diffuse mesangial sclerosis, typical of Denys Drash syndrome, without evidence of thrombotic microangiopathy. CONCLUSION: This unique case highlights HUS as a rare but important manifestation of WT1 mutation and provides new insight into the genetics underlying this association. PMID- 28720078 TI - Characteristics of cardio-Cerebrovascular modulation in patients with generalized anxiety disorder: an observational study. AB - BACKGROUND: Generalized anxiety disorder (GAD) has been shown in previous studies to display abnormal cerebral blood flow velocity (CBFV); however, the characteristics of cardio-cerebrovascular modulation are unknown. We aimed to analyze cardio-cerebrovascular modulation using parameters from a supine-to standing test. METHODS: There are 2 parts to this study; in Part 1, 125 participants with Hamilton Anxiety scale scores >=14 were enrolled, and 33 age- and sex-matched medically and psychiatrically healthy volunteers were recruited as control participants. Patients were divided by score into mild, moderate, and severe anxiety groups. The cardio-cerebrovascular modulation using the parameters of dynamic changes of CBFV and heart rate in response to an orthostatic challenge were investigated. In Part 2, we followed up the severe GAD patients for 6 months and repeated the supine-to-standing test, and severe GAD patients were divided into recovery and non-recovery groups. RESULTS: In part 1, the GAD group displayed more marked CBFV and heart rate changes than the healthy group, but there was no difference in the CBFV and heart rate changes from the supine to upright position in mild, moderate, and severe anxiety groups. In part 2, The recovery group demonstrated significant improvement in changes in the CBFV and heart rate values from the supine to the upright position after treatment compared with before treatment. In the non-recovery group, the CBFV and heart rate changes were significantly higher than the healthy group regardless of treatment. CONCLUSIONS: Cardio-cerebrovascular modulation is compromised in patients with GAD, however, this impairment can be restored to normal after the disappearance of anxiety. PMID- 28720079 TI - Implementation-effectiveness trial of an ecological intervention for physical activity in ethnically diverse low income senior centers. AB - BACKGROUND: As the US population ages, there is an increasing need for evidence based, peer-led physical activity programs, particularly in ethnically diverse, low income senior centers where access is limited. METHODS/DESIGN: The Peer Empowerment Program 4 Physical Activity' (PEP4PA) is a hybrid Type II implementation-effectiveness trial that is a peer-led physical activity (PA) intervention based on the ecological model of behavior change. The initial phase is a cluster randomized control trial randomized to either a peer-led PA intervention or usual center programming. After 18 months, the intervention sites are further randomized to continued support or no support for another 6 months. This study will be conducted at twelve senior centers in San Diego County in low income, diverse communities. In the intervention sites, 24 peer health coaches and 408 adults, aged 50 years and older, are invited to participate. Peer health coaches receive training and support and utilize a tablet computer for delivery and tracking. There are several levels of intervention. Individual components include pedometers, step goals, counseling, and feedback charts. Interpersonal components include group walks, group sharing and health tips, and monthly celebrations. Community components include review of PA resources, walkability audit, sustainability plan, and streetscape improvements. The primary outcome of interest is intensity and location of PA minutes per day, measured every 6 months by wrist and hip accelerometers and GPS devices. Secondary outcomes include blood pressure, physical, cognitive, and emotional functioning. Implementation measures include appropriateness & acceptability (perceived and actual fit), adoption & penetration (reach), fidelity (quantity & quality of intervention delivered), acceptability (satisfaction), costs, and sustainability. DISCUSSION: Using a peer led implementation strategy to deliver a multi-level community based PA program can enhance program adoption, implementation, and sustainment. TRIAL REGISTRATION: ClinicalTrials.gov, USA ( NCT02405325 ). Date of registration, March 20, 2015. This website also contains all items from the World Health Organization Trial Registration Data Set. PMID- 28720080 TI - Long-term effectiveness of mailed nicotine replacement therapy: study protocol of a randomized controlled trial 5-year follow-up. AB - BACKGROUND: Our group recently completed a randomized controlled trial, evaluating the efficacy of providing 5 weeks of free nicotine replacement therapy (NRT; in the form of the nicotine patch) by expedited postal mail without behavioral assistance to regular adult smokers interested in receiving it. The findings revealed that mailed provision of nicotine patches resulted in more than a doubling of quit rates at a six-month follow-up compared to a no intervention control group. While this trial provided evidence for the effectiveness of mailed nicotine patches in promoting cessation, the findings speak only to the short term effectiveness of this approach. As relapse to smoking is known to occur beyond the 6 month period, it is important to evaluate whether the net benefit of NRT in naturalistic settings can be maintained long-term. The present study aims to perform a 5-year follow-up survey of participants in the original trial to evaluate the long-term effectiveness of mailed NRT. METHODS/DESIGN: Trained interviewers will contact participants in the randomized controlled trial 5 years post-enrollment. A total of 924 participants will be eligible to be contacted. Interviewers will first assess participants' smoking status and their level of nicotine dependence. Participants reporting not currently smoking will be asked whether they have smoked tobacco, even a puff, in the last 30 days (primary outcome measure: 30-day point prevalence abstinence), past 6 months (secondary outcome measure: prolonged 6-month abstinence), and since the 8-week follow-up survey (secondary outcome measure: > 4 year continuous abstinence). Interviewers will be blind to experimental condition at the time the primary outcome measure will be assessed. It is hypothesized that participants who received nicotine patches at baseline will display significantly higher quit rates at the 5-year follow-up as compared to participants who did not receive nicotine patches at baseline. DISCUSSION: If the study finds that the mailed distribution of free NRT is effective at promoting long-term cessation, it would provide further evidence to move forward with policies designed to make NRT treatment readily and freely available to smokers who request it. TRIAL REGISTRATION: ClinicalTrials.gov : NCT01429129 , Registered 2 September 2011; NCT03097445 , Registered 25 March 2017. PMID- 28720081 TI - Identification of an easy to use 3D culture model to investigate invasion and anticancer drug response in chondrosarcomas. AB - BACKGROUND: Cytotoxic efficacy of anticancer drugs has been widely studied with monolayer-cultured cancer cells. However, the efficacy of drugs under two dimensional (2D) culture condition usually differs from that of three-dimensional (3D) one. In the present study, an in vitro tumor tissue model was constructed using alginate hydrogel, and in vitro cytotoxic efficacy of two anticancer drugs (cisplatin and DZNep) was investigated in chondrosarcomas, and compared to in vivo response. METHODS: Three cell lines derived from human chondrosarcomas, CH2879, JJ012 and SW1353, were embedded in alginate hydrogel. Proliferation and survival were assayed by ATP measurement using Cell Titer-Glo luminescent cell viability assay kit, and by counting viable cells in beads. Collagen and COMP expression was determined by RT-PCR. Invasion/migration was estimated by counting cells leaving alginate beads and adhering to culture dish. Then, chondrosarcoma response to cisplatin and DZNep was compared between cells cultured in monolayer or embedded in alginate, and using chondrosarcoma xenografts in nude mice. RESULTS: Chondrosarcomas survived at least for 8 weeks, after embedment in alginate. However, only CH2879 cells could proliferate. Also, this cell line is more invasive than SW1353 and JJ012, which was coherent with the grade of their respective primary tumors. Furthermore, the expression of type II collagen was higher in chondrosarcomas cultured in 3D than in 2D. Interestingly, this 3D culture system allows to validate the absence of response of chondrosarcomas to cisplatin, and to predict the efficiency of DZNep to reduce chondrosarcoma growth in vivo. CONCLUSIONS: This study validates alginate beads as a relevant 3D model to study cancer biology and tumor responses to biological treatments. PMID- 28720083 TI - A prolonged, community-wide cholera outbreak associated with drinking water contaminated by sewage in Kasese District, western Uganda. AB - BACKGROUND: In May 2015, a cholera outbreak that had lasted 3 months and infected over 100 people was reported in Kasese District, Uganda, where multiple cholera outbreaks had occurred previously. We conducted an investigation to identify the mode of transmission to guide control measures. METHODS: We defined a suspected case as onset of acute watery diarrhoea from 1 February 2015 onwards in a Kasese resident. A confirmed case was a suspected case with Vibrio cholerae O1 El Tor, serotype Inaba cultured from a stool sample. We reviewed medical records to find cases. We conducted a case-control study to compare exposures among confirmed case-persons and asymptomatic controls, matched by village and age-group. We conducted environmental assessments. We tested water samples from the most affected area for total coliforms using the Most Probable Number (MPN) method. RESULTS: We identified 183 suspected cases including 61 confirmed cases of Vibrio cholerae 01; serotype Inaba, with onset between February and July 2015. 2 case persons died of cholera. The outbreak occurred in 80 villages and affected all age groups; the highest attack rate occurred in the 5-14 year age group (4.1/10,000). The outbreak started in Bwera Sub-County bordering the Democratic Republic of Congo and spread eastward through sustained community transmission. The first case-persons were involved in cross-border trading. The case-control study, which involved 49 confirmed cases and 201 controls, showed that 94% (46/49) of case-persons compared with 79% (160/201) of control-persons drank water without boiling or treatment (ORM-H=4.8, 95% CI: 1.3-18). Water collected from the two main sources, i.e., public pipes (consumed by 39% of case-persons and 38% of control-persons) or streams (consumed by 29% of case-persons and 24% control-persons) had high coliform counts, a marker of faecal contamination. Environmental assessment revealed evidence of open defecation along the streams. No food items were significantly associated with illness. CONCLUSIONS: This prolonged, community-wide cholera outbreak was associated with drinking water contaminated by faecal matter and cross-border trading. We recommended rigorous disposal of patients' faeces, chlorination of piped water, and boiling or treatment of drinking water. The outbreak stopped 6 weeks after these recommendations were implemented. PMID- 28720082 TI - Cost-effectiveness analysis of different types of human papillomavirus vaccination combined with a cervical cancer screening program in mainland China. AB - BACKGROUND: China has a high prevalence of human papillomavirus (HPV) and a consequently high burden ofdisease with respect to cervical cancer. The HPV vaccine has proved to be effective in preventing cervical cancer and is now a part of routine immunization programs worldwide. It has also proved to be cost effective. This study aimed to assess the cost-effectiveness of 2-, 4-, and 9 valent HPV vaccines (hereafter, HPV2, 4 or 9) combined with current screening strategies in China. METHODS: A Markov model was developed for a cohort of 100,000 HPV-free girls to simulate the natural history toHPV infection. Three recommended screening methods (1. liquid-based cytology test + HPV DNA test; 2. pap smear cytology test + HPV DNA test; 3. visual inspection with acetic acid) and three types of HPV vaccination program (HPV2/4/9) were incorporated into 15 intervention options, and the incremental cost-effectiveness ratio (ICER) was calculated to determine the dominant strategies. Costs, transition probabilities and utilities were obtained from a review of the literature and national databases. One-way sensitivity analyses and threshold analyses were performed for key variables in different vaccination scenarios. RESULTS: HPV9 combined with screening showed the highest health impact in terms of reducing HPV relateddiseases and increasing the number of quality-adjusted life years (QALYs). Under the current thresholds ofwillingness to pay (WTP, 3 times the per capita GDP or USD$ 23,880), HPV4/9 proved highly cost effective, while HPV2 combined with screening cost more and was less cost effective. Only when screening coverage increased to 60% ~ 70% did the HPV2 and screening combination strategy become economically feasible. CONCLUSIONS: The combination of the HPV4/9 vaccine with current screening strategies for adolescent girls was highlycost-effective and had a significant impact on reducing the HPV infection-related disease burden in Mainland China. PMID- 28720084 TI - Sequence-based identification of inositol monophosphatase-like histidinol phosphate phosphatases (HisN) in Corynebacterium glutamicum, Actinobacteria, and beyond. AB - BACKGROUND: The eighth step of L-histidine biosynthesis is carried out by an enzyme called histidinol-phosphate phosphatase (HolPase). Three unrelated HolPase families are known so far. Two of them are well studied: HAD-type HolPases known from Gammaproteobacteria like Escherichia coli or Salmonella enterica and PHP type HolPases known from yeast and Firmicutes like Bacillus subtilis. However, the third family of HolPases, the inositol monophosphatase (IMPase)-like HolPases, present in Actinobacteria like Corynebacterium glutamicum (HisN) and plants, are poorly characterized. Moreover, there exist several IMPase-like proteins in bacteria (e.g. CysQ, ImpA, and SuhB) which are very similar to HisN but most likely do not participate in L-histidine biosynthesis. RESULTS: Deletion of hisN, the gene encoding the IMPase-like HolPase in C. glutamicum, does not result in complete L-histidine auxotrophy. Out of four hisN homologs present in the genome of C. glutamicum (impA, suhB, cysQ, and cg0911), only cg0911 encodes an enzyme with HolPase activity. The enzymatic properties of HisN and Cg0911 were determined, delivering the first available kinetic data for IMPase-like HolPases. Additionally, we analyzed the amino acid sequences of potential HisN, ImpA, SuhB, CysQ and Cg0911 orthologs from bacteria and identified six conserved sequence motifs for each group of orthologs. Mutational studies confirmed the importance of a highly conserved aspartate residue accompanied by several aromatic amino acid residues present in motif 5 for HolPase activity. Several bacterial proteins containing all identified HolPase motifs, but showing only moderate sequence similarity to HisN from C. glutamicum, were experimentally confirmed as IMPase like HolPases, demonstrating the value of the identified motifs. Based on the confirmed IMPase-like HolPases two profile Hidden Markov Models (HMMs) were build using an iterative approach. These HMMs allow the fast, reliable detection and differentiation of the two paralog groups from each other and other IMPases. CONCLUSION: The kinetic data obtained for HisN from C. glutamicum, as an example for an IMPase-like HolPases, shows remarkable differences in enzyme properties as compared to HAD- or PHP-type HolPases. The six sequence motifs and the HMMs presented in this study can be used to reliably differentiate between IMPase-like HolPases and IMPase-like proteins with no such activity, with the potential to enhance current and future genome annotations. A phylogenetic analysis reveals that IMPase-like HolPases are not only present in Actinobacteria and plant but can be found in further bacterial phyla, including, among others, Proteobacteria, Chlorobi and Planctomycetes. PMID- 28720085 TI - My child cannot breathe while sleeping: a report of three cases and review. AB - BACKGROUND: Sudden breath-holding episodes during sleep in young children are potentially related to sudden infant death syndrome and other life-threatening events. Additionally, these episodes can negatively affect child's growth and development. CASE PRESENTATION: Here, we present 3 cases of preschool children with similar paroxysmal nocturnal waking events associated with choking that had different etiologies (nocturnal frontal lobe epilepsy, nocturnal gastroesophageal reflux disease, and parasomnia, respectively). CONCLUSIONS: It is important to take into consideration the fact that breath spells during sleep can occur as a rare manifestation of parasomnia due to gastroesophageal reflux or as a symptom of nocturnal frontal lobe epilepsy. Full video electroencephalography, polysomnography, and simultaneous gastric pH monitoring should be used for the differential diagnosis of sleep-related disorders, such as breath spells, in children. PMID- 28720086 TI - Pregnancy outcomes in patients with acute kidney injury during pregnancy: a systematic review and meta-analysis. AB - BACKGROUND: Presently, the matter of pregnancy outcomes of patients with pregnancy related AKI (PR-AKI) were disputed. Thus, we conducted a meta-analysis to evaluate the impact of PR-AKI on pregnancy outcomes. METHOD: We systematically searched MEDLINE, Embase, VIP, CNKI and Wanfang Databases for cohort or case control studies in women with PR-AKI and those without AKI as a control group to assess the influence of PR-AKI on pregnancy outcomes and kidney outcome. Reduction of odd ratio (OR) was calculated by a random-effects model. RESULTS: One thousand one hundred fifty two articles were systematically reviewed, of those 11 studies were included, providing data of 845 pregnancies in 834 women with PR-AKI and 5387 pregnancies in 5334 women without AKI. In terms of maternal outcomes, women with PR-AKI had a greater likelihood of cesarean delivery (OR, 1.49; 95% confidence interval [CI], 1.37 to 1.61), hemorrhage (1.26; 1.02 to 1.56), HELLP syndrome (1.86; 1.41 to 2.46), placental abruption (3.13; 1.96 to 5.02), DIC (3.41; 2.00 to 5.84), maternal death (4.50; 2.73 to 7.43), but had a lower risk of eclampsia (0.53; 0.34 to 0.83). Women with PR-AKI also had a longer stay in ICU (weighted mean difference, 2.13 day [95% CI 1.43 to 2.83 day]) compared with those without PR-AKI. As for fetal outcomes, higher incidence of stillbirth/perinatal death (3.39, 2.76 to 4.18), lower mean gestational age at delivery (-0.70 week [95% CI -1.21 to -0.19 week]) and lower birth weight (-740 g [95% CI -1180 to 310 g]) were observed in women with PR-AKI. The occurrence of kidney outcome, defined as ESRD requiring dialysis, in women with PR-AKI was 2.4% (95% CI 1.3% to 4.2%). CONCLUSIONS: PR-AKI remains a grave complication and has been associated with increased maternal and fetal mortality. PMID- 28720087 TI - Resident perceptions of the impact of duty hour restrictions on resident attending interactions: an exploratory study. AB - BACKGROUND: The institution of duty hour reforms by the Accreditation Council for Graduate Medical Education in 2003 has created a learning environment where residents are consistently looking for input from attending physicians with regards to balancing duty hour regulations and providing quality patient care. There is a paucity of literature regarding resident perceptions of attending physician actions or attitudes towards work hour restrictions. The purpose of this study was to identify attending physician behaviors that residents perceived as supportive or unsupportive of their compliance with duty hour regulations. METHODS: Focus group interviews were conducted with residents exploring their perceptions of how duty hour regulations impact their interactions with attending physicians. Qualitative analysis identified key themes in residents' experiences interacting with faculty in regard to duty hour regulations. Forty residents from five departments in two hospital systems participated. RESULTS: Discussion of these interactions highlighted that attending physicians demonstrate behaviors that explicitly or implicitly either lend their support and understanding of residents' need to comply with these regulations or imply a lack of support and understanding. Three major themes that contributed to the ease or difficulty in addressing duty hour regulations included attending physicians' explicit communication of expectations, implicit non-verbal and verbal cues and the program's organizational culture. CONCLUSIONS: Resident physicians' perception of attending physicians' explicit and implicit communication and residency programs organization culture has an impact on residents' experience with duty hour restrictions. Residency faculty and programs could benefit from explicitly addressing and supporting the challenges that residents perceive in complying with duty hour restrictions. PMID- 28720088 TI - Sex is a moderator of the association between NOS1AP sequence variants and QTc in two long QT syndrome founder populations: a pedigree-based measured genotype association analysis. AB - BACKGROUND: Sequence variants in the NOS1AP gene have repeatedly been reported to influence QTc, albeit with moderate effect sizes. In the long QT syndrome (LQTS), this may contribute to the substantial QTc variance seen among carriers of identical pathogenic sequence variants. Here we assess three non-coding NOS1AP sequence variants, chosen for their previously reported strong association with QTc in normal and LQTS populations, for association with QTc in two Swedish LQT1 founder populations. METHODS: This study included 312 individuals (58% females) from two LQT1 founder populations, whereof 227 genotype positive segregating either Y111C (n = 148) or R518* (n = 79) pathogenic sequence variants in the KCNQ1 gene, and 85 genotype negatives. All were genotyped for NOS1AP sequence variants rs12143842, rs16847548 and rs4657139, and tested for association with QTc length (effect size presented as mean difference between derived and wildtype, in ms), using a pedigree-based measured genotype association analysis. Mean QTc was obtained by repeated manual measurement (preferably in lead II) by one observer using coded 50 mm/s standard 12-lead ECGs. RESULTS: A substantial variance in mean QTc was seen in genotype positives 476 +/- 36 ms (Y111C 483 +/- 34 ms; R518* 462 +/- 34 ms) and genotype negatives 433 +/- 24 ms. Female sex was significantly associated with QTc prolongation in all genotype groups (p < 0.001). In a multivariable analysis including the entire study population and adjusted for KCNQ1 genotype, sex and age, NOS1AP sequence variants rs12143842 and rs16847548 (but not rs4657139) were significantly associated with QT prolongation, +18 ms (p = 0.0007) and +17 ms (p = 0.006), respectively. Significant sex-interactions were detected for both sequent variants (interaction term r = 0.892, p < 0.001 and r = 0.944, p < 0.001, respectively). Notably, across the genotype groups, when stratified by sex neither rs12143842 nor rs16847548 were significantly associated with QTc in females (both p = 0.16) while in males, a prolongation of +19 ms and +8 ms (p = 0.002 and p = 0.02) was seen in multivariable analysis, explaining up to 23% of QTc variance in all males. CONCLUSIONS: Sex was identified as a moderator of the association between NOS1AP sequence variants and QTc in two LQT1 founder populations. This finding may contribute to QTc sex differences and affect the usefulness of NOS1AP as a marker for clinical risk stratification in LQTS. PMID- 28720089 TI - Analysis of the association between millennium development goals 4 & 5 and the physician workforce across international economic strata. AB - BACKGROUND: The Millennium Development Goals (MDGs) are 8 international development goals voluntarily adopted by 189 nations. The goals included health related aims to reduce the under-five child mortality rate by two-thirds (MDG4), and to reduce the maternal mortality ratio by three-quarters (MDG5). To assess the relationship between the healthcare workforce and MDGs 4-5, we examined the physician workforces of countries around the globe, in terms of the Physician Density Level (PDL, or number of physicians per 1000 population), and compared this rate across a number of years to several indicator variables specified as markers of progress towards MDG4 and MDG5. METHODS: Data for each variable of interest were obtained from the World Bank's Millennium Development Goals and World Development Indicators databases for 208 countries and territories from 2004 to 2014, representing a ten-year period for which the most information is available. We analyzed the relationships between MDG outcomes and PDL, controlling for national income levels and other covariates, using linear mixed model regression. Dependent variables were logarithmically transformed to meet assumptions necessary for multivariate analysis. RESULTS: In unadjusted models, an increase of every one physician per 1000 population (one unit change in PDL) lowered the risk of not being vaccinated for measles-mumps-rubella (MMR) to 29.3% (p < 0.001, 95% CI: 22.2%-38.7%) and for not receiving diphtheria-tetanus pertussis (DTaP) vaccination rate decreased to 38.5% (p < 0.001, 95% CI: 28.7% - 51.7%). Maternal mortality rate decreased to 76.6% (p < 0.001, 95% CI: 74.3% - 79.0%), neonatal mortality decreased to 58.8% (p < 0.001, 95% CI: 54.8% - 63.2%) and under-5 mortality rate decreased to 52.1% (p < 0.001, 95% CI: 48.0% - 56.4%), with every one-unit change in PDL. Adjusted models tended to reflect unadjusted risk assessments. CONCLUSION: The maintenance and improvement of the health workforce is a vital consideration when assessing how to achieve global development goals related to health outcomes. PMID- 28720090 TI - "We and the nurses are now working with one voice": How community leaders and health committee members describe their role in Sierra Leone's Ebola response. AB - BACKGROUND: Across low-income settings, community volunteers and health committee members support the formal health system - both routinely and amid emergencies - by engaging in health services such as referrals and health education. During the 2014-2015 Ebola epidemic, emerging reports suggest that community engagement was instrumental in interrupting transmission. Nevertheless, literature regarding community volunteers' roles during emergencies generally, and Ebola specifically, is scarce. This research outlines what this cadre of the workforce did, how they coped, and the facilitators and barriers they faced to providing care in Sierra Leone. METHODS: Thirteen focus group discussions (FGD) were conducted with community members (including members of Health Management Committees (HMC)) near the height of the Ebola epidemic in two districts of Sierra Leone: Bo and Kenema. Conducted in either Krio or Mende, each FGD lasted an average of two hours and was led by a trained moderator who was accompanied by a note taker. All FGDs were audio recorded, transcribed, and translated into English by the data collection team. Analysis followed a modified framework approach, which entailed coding (both inductive and deductive), arrangement of codes into themes, and drafting, distribution and discussion of analytic summaries across the study team. RESULTS: Community volunteers and HMC members described engaging in labor-related tasks (e.g. building isolation structures, digging graves) and administrative/community outreach tasks (e.g. screening, contact tracing, and encouraging care seeking within facilities). Through their dual orientation as community members and as individuals linked to the health system, respondents described building community trust and support for Ebola prevention and treatment, while also enabling formal health workers to better understand and address people's fears and needs. Community volunteers' main concerns included inadequate communication with - and a sense of being forgotten by - the health system, negative perceptions of their role within their communities, and concerns regarding the amount and nature of their compensation. DISCUSSION & CONCLUSION: Respondents described commitment to supporting their health system and their communities during the Ebola crisis. The health system could more effectively harness the potential of local responders by recognizing community strengths and weaknesses, as well as community volunteers' motivations and limitations. Clarifying the roles, responsibilities, and remuneration of health volunteers to the recipients themselves, facility-based staff, and the wider community will enable organizations that partner with health committees to bolster trust, manage expectations, and reinforce collaboration. PMID- 28720091 TI - Clinical and imaging outcome of osteochondral lesions of the talus treated using autologous matrix-induced chondrogenesis technique with a biomimetic scaffold. AB - BACKGROUND: The purpose of our study was to assess the clinical and imaging outcome of autologous matrix-induced chondrogenesis (AMIC) technique consisting of microfractures followed by the filling of osteochondral lesions of the talus (OLTs) with a cell-free biphasic collagen-hydroxyapatite osteochondral scaffold (MaioRegen). METHODS: Sixteen patients (eight males, age: 42.6 +/- 18.4, range 14 74) with OLT repaired using AMIC technique, with implantation of MaioRegen, were clinically evaluated through the American Orthopedic Foot and Ankle Society Score (AOFAS) and a 10-point Visual Analogue Scale (VAS) pain score after a mean follow up of 30 +/- 16.9 months. The MRI examinations were performed 12 and 24 months after surgery. A paired t-test was applied to compare pre- and post-operative clinical findings (VAS and AOFAS) and Magnetic resonance observation of cartilage repair tissue (MOCART) score changes in the follow-up. To assess the correlation between variation of AOFAS and MOCART scores, the Pearson's correlation coefficient was calculated. RESULTS: No complications after surgery were encountered. From pre-operative to post-operative values, there was a significant (P < 0.001) reduction of mean VAS pain score (6.3 +/- 0.9,range: 4-8 and 2.9 +/- 1.8,range: 0-6, respectively) and increase of AOFAS score (60.2 +/- 7.8,range: 50 74 and 77.4 +/- 16.2,range: 50-100, respectively). Among 16 patients, six (37%) were not satisfied at the end of follow-up, six (37%) were moderately satisfied and four (25%) were highly satisfied. The treatment was considered failed in five out of 16 patients (31%). Among them, four (25%) required re-interventions with implantation of ankle prostheses, whereas one patient was treated with a further AMIC technique combined with autologous bone graft and platelet-rich plasma. The mean MOCART score was 41.9 +/- 14.6 (25-70) 12 months after surgery and 51.9 +/- 11.6 (30-70) after 24 months, with a statistically significant increase (P = 0.012). However, no correlation was seen between AOFAS and MOCART changes (r = 0.215, p = 0.609). CONCLUSION: The high rates of treatment failure encountered in our study using MaioRegen need to be confirmed by larger studies and should induce the scientific community questioning the reliability of this biomimetic scaffold for the treatment of OLTs. PMID- 28720092 TI - A qualitative study of clinic and community member perspectives on intervention toolkits: "Unless the toolkit is used it won't help solve the problem". AB - BACKGROUND: Intervention toolkits are common products of grant-funded research in public health and primary care settings. Toolkits are designed to address the knowledge translation gap by speeding implementation and dissemination of research into practice. However, few studies describe characteristics of effective intervention toolkits and their implementation. Therefore, we conducted this study to explore what clinic and community-based users want in intervention toolkits and to identify the factors that support application in practice. METHODS: In this qualitative descriptive study we conducted focus groups and interviews with a purposive sample of community health coalition members, public health experts, and primary care professionals between November 2010 and January 2012. The transdisciplinary research team used thematic analysis to identify themes and a cross-case comparative analysis to explore variation by participant role and toolkit experience. RESULTS: Ninety six participants representing primary care (n = 54, 56%) and community settings (n = 42, 44%) participated in 18 sessions (13 focus groups, five key informant interviews). Participants ranged from those naive through expert in toolkit development; many reported limited application of toolkits in actual practice. Participants wanted toolkits targeted at the right audience and demonstrated to be effective. Well organized toolkits, often with a quick start guide, with tools that were easy to tailor and apply were desired. Irrespective of perceived quality, participants experienced with practice change emphasized that leadership, staff buy-in, and facilitative support was essential for intervention toolkits to be translated into changes in clinic or public -health practice. CONCLUSIONS: Given the emphasis on toolkits in supporting implementation and dissemination of research and clinical guidelines, studies are warranted to determine when and how toolkits are used. Funders, policy makers, researchers, and leaders in primary care and public health are encouraged to allocate resources to foster both toolkit development and implementation. Support, through practice facilitation and organizational leadership, are critical for translating knowledge from intervention toolkits into practice. PMID- 28720094 TI - A literature review of applied adaptive design methodology within the field of oncology in randomised controlled trials and a proposed extension to the CONSORT guidelines. AB - BACKGROUND: The application of adaptive design methodology within a clinical trial setting is becoming increasingly popular. However the application of these methods within trials is not being reported as adaptive designs hence making it more difficult to capture the emerging use of these designs. Within this review, we aim to understand how adaptive design methodology is being reported, whether these methods are explicitly stated as an 'adaptive design' or if it has to be inferred and to identify whether these methods are applied prospectively or concurrently. METHODS: Three databases; Embase, Ovid and PubMed were chosen to conduct the literature search. The inclusion criteria for the review were phase II, phase III and phase II/III randomised controlled trials within the field of Oncology that published trial results in 2015. A variety of search terms related to adaptive designs were used. RESULTS: A total of 734 results were identified, after screening 54 were eligible. Adaptive designs were more commonly applied in phase III confirmatory trials. The majority of the papers performed an interim analysis, which included some sort of stopping criteria. Additionally only two papers explicitly stated the term 'adaptive design' and therefore for most of the papers, it had to be inferred that adaptive methods was applied. Sixty-five applications of adaptive design methods were applied, from which the most common method was an adaptation using group sequential methods. CONCLUSIONS: This review indicated that the reporting of adaptive design methodology within clinical trials needs improving. The proposed extension to the current CONSORT 2010 guidelines could help capture adaptive design methods. Furthermore provide an essential aid to those involved with clinical trials. PMID- 28720093 TI - Solanum nigrum Unripe fruit fraction attenuates Adriamycin resistance by down regulating multi-drug resistance protein (Mdr)-1 through Jak-STAT pathway. AB - BACKGROUND: Solanum nigrum, herbal plant that commonly grows in temperate climate zone, has been used as a traditional folk medicine whose ripen fruits were proven to exhibit anti-tumor properties. In traditional Chinese medicine, it has been used for centuries to cure inflammation, edema, mastitis and hepatic cancer and in the Ayurvedic system of traditional medicine in India, S. nigrum is applied against enteric diseases, ulcer, diarrhea and skin diseases. A methanolic glycosidic extract fraction of unripe fruit of S. nigrum (SNME) was investigated for its anticancer property and possible mechanism to surmount adriamycin resistance in NCI/ADR-RES cells. METHODS: The NCI/ADR-RES cells were treated with 7.8125, 15.625, 31.25, 62.5, 125 and 250 MUg/ml of methanolic extract of S. nigrum (SNME) for 12, 24 and 48 h, to check the cell viability and proliferation. The cells were also exposed to adriamycin alone or in combination with SNME and the effects on cell growth were determined by MTT. Cell cycle analysis, Ethidium bromide and Acridine orange staining, Annexin-binding efficiency, nuclear condensation and DNA fragmentation of the apoptotic NCI/ADR-RES cells were also determined. To elucidate the relationship between SNME and multi drug resistance, we analyzed the expression levels of Mdr-1, JAK1, STAT3, and pSTAT3 in NCI/ADR RES cells after treatment with SNME. RESULTS: Results from the cytotoxicity assay showed a direct correlation between the concentration of methanolic glycosidic extract fraction of S. nigrum (SNME) and the surviving cell population. Combination with Adriamycin, SNME exhibits a synergistic action on NCI/ADR-RES cells, giving the first line of evidence to overcoming Adriamycin resistance. The SNME mediated cell growth suppression was proven to be apoptotic, based on results obtained from DNA fragmentation, annexin V apoptosis assaay and PARP cleavage analysis. Looking into the molecular insight SNME surpasses the chemoresistance of NCI/ADR-RES cells by inhibiting the JAK-STAT3 signaling pathway through the down regulation of JAK1, STAT3, pSTAT3, and Mdr1 expression. CONCLUSIONS: Collectively our findings suggest that unripe fruit of Solanum nigrum could possibly be used as a chemosensitizing agent against Adriamycin resistant cancers. PMID- 28720095 TI - Fibrocyte measurement in peripheral blood correlates with number of cultured mature fibrocytes in vitro and is a potential biomarker for interstitial lung disease in Rheumatoid Arthritis. AB - BACKGROUND: Interstitial lung disease (ILD) can be a severe extra-articular disease manifestation in Rheumatoid Arthritis (RA). A potential role of fibrocytes in RA associated ILD (RA-ILD) has not previously been described. We present a modified faster method for measuring circulating fibrocytes, without intracellular staining. The results are compared to the traditional culture method, where the number of monocytes that differentiate into mature fibrocytes in vitro are counted. The results are following compared to disease activity in patients with severe asthma, ILD, RA (without diagnosed ILD) and RA with verified ILD (RA-ILD). METHOD: CD45+ CD34+ CD11b+ (7-AAD- CD3- CD19- CD294-) cells were isolated by cell sorting and stained for pro-collagen type 1. Thirty-nine patients (10 RA, 9 ILD and 10 with severe asthma, 10 with RA-ILD) and 10 healthy controls (HC) were included. Current medication, disease activity, pulmonary function test and radiographic data were collected. Circulating fibrocytes were quantified by flow cytometry. Peripheral blood mononuclear cells were isolated and cultured for 5 days and the numbers of mature fibrocytes were counted. RESULTS: 90.2% (mean, SD = 1.5%) of the sorted cells were pro-collagen type 1 positive and thereby fulfilled the criteria for being circulating fibrocytes. The ILD and RA-ILD groups had increased levels of circulating fibrocytes compared to HC (p < 0.05). Levels of circulating fibrocytes correlated overall to number of monocytes that subsequently in vitro differentiated to mature fibrocytes (r = 0.81, p < 0.001). RA patients with pathologically reduced diffusion capacity for carbon monoxide adjusted for hemoglobin (DLCOc) in both the RA and in the combined RA + RA-ILD group, had significantly higher levels of both circulating and number of cultured mature fibrocytes (both p < 0.05). In both groups, the level of circulating fibrocytes and number of mature fibrocytes in culture also correlated to a reduction in DLCOc (r = -0.61 an r = -0.58 both p < 0.05). CONCLUSIONS: We presented a fast and valid method for measuring circulating fibrocytes using flow cytometry on lysed peripheral blood. Further, we showed for the first time, that the level of circulating fibrocytes correlated with the number of peripheral blood mononuclear cells, that differentiated into mature fibrocytes in vitro. Reduced DLCOc was correlated with high levels of circulating and mature fibrocytes in RA, which have not been reported previously. In such, this study suggests that fibrocytes may exhibit an important role in the pathogenesis of RA-ILD, which requires further clarification in future studies. TRIAL REGISTRATION: ClinicalTrials.gov : NCT02711657 , registered 13/3-2016, retrospectively registered. PMID- 28720096 TI - Clinical and radiographic predictors of acute compartment syndrome in the treatment of tibial plateau fractures: a retrospective cohort study. AB - BACKGROUND: The aim of the study was to evaluate the relation between demographic, injury-related, clinical and radiological factors of patients with tibial plateau fractures and the development of acute compartment syndrome. METHODS: All consecutive adult patients with intra-articular tibial plateau fractures admitted in our urban academic medical centre between January 2005 and December 2009 were included in this retrospective cohort study. The main outcome measurement was the development of acute compartment syndrome. RESULTS: The charts of 265 patients (mean age 48.6 years) sustaining 269 intra-articular tibial plateau fractures were retrospectively reviewed. Acute compartment syndrome occurred in 28 fractures (10.4%). Four patients presented bilateral tibial plateau fractures; of them, 2 had unilateral, but none had bilateral acute compartment syndrome. Non-contiguous tibia fracture or knee dislocation and higher AO/OTA classification (type 41-C) were statistically significantly associated with the development of acute compartment syndrome in multivariable regression analysis, while younger age (<45 years), male sex, higher Schatzker grade (IV-V-VI), higher tibial widening ratio (>=1.05) and higher femoral displacement ratio (>=0.08) were significantly associated in the analysis adjusted for age and sex. CONCLUSIONS: Two parameters related to the occurrence of ACS in tibial plateau fractures were highlighted in this study: the presence of a non-contiguous tibia fracture or knee dislocation, and higher AO/OTA classification. They may be especially useful when clinical findings are difficult to assess (doubtful clinical signs, obtunded, sedated or intubated patients), and should rise the suspicion level of the treating surgeon. In these cases, regular clinical examinations and/or intra-compartmental pressure measurements should be performed before and after surgery, even if acute compartment syndrome seemed unlikely during initial assessment. However, larger studies are mandatory to confirm and refine both factors in predicting the occurrence of acute compartment syndrome. PMID- 28720097 TI - A versatile papaya mosaic virus (PapMV) vaccine platform based on sortase mediated antigen coupling. AB - BACKGROUND: Flexuous rod-shaped nanoparticles made of the coat protein (CP) of papaya mosaic virus (PapMV) have been shown to trigger innate immunity through engagement of toll-like receptor 7 (TLR7). PapMV nanoparticles can also serve as a vaccine platform as they can increase the immune response to fused peptide antigens. Although this approach shows great potential, fusion of antigens directly to the CP open reading frame (ORF) is challenging because the fused peptides can alter the structure of the CP and its capacity to self assemble into nanoparticles-a property essential for triggering an efficient immune response to the peptide. This represents a serious limitation to the utility of this approach as fusion of small peptides only is tolerated. RESULTS: We have developed a novel approach in which peptides are fused directly to pre-formed PapMV nanoparticles. This approach is based on the use of a bacterial transpeptidase (sortase A; SrtA) that can attach the peptide directly to the nanoparticle. An engineered PapMV CP harbouring the SrtA recognition motif allows efficient coupling. To refine our engineering, and to predict the efficacy of coupling with SrtA, we modeled the PapMV structure based on the known structure of PapMV CP and on recent reports revealing the structure of two closely related potexviruses: pepino mosaic virus (PepMV) and bamboo mosaic virus (BaMV). We show that SrtA can allow the attachment of long peptides [Influenza M2e peptide (26 amino acids) and the HIV-1 T20 peptide (39 amino acids)] to PapMV nanoparticles. Consistent with our PapMV structural model, we show that around 30% of PapMV CP subunits in each nanoparticle can be fused to the peptide antigen. As predicted, engineered nanoparticles were capable of inducing a strong antibody response to the fused antigen. Finally, in a challenge study with influenza virus, we show that mice vaccinated with PapMV-M2e are protected from infection. CONCLUSIONS: This technology will allow the development of vaccines harbouring long peptides containing several B and/or T cell epitopes that can contribute to a broad and robust protection from infection. The design can be fast, versatile and can be adapted to the development of vaccines for many infectious diseases as well as cancer vaccines. PMID- 28720098 TI - Arcyriaflavin a, a cyclin D1-cyclin-dependent kinase4 inhibitor, induces apoptosis and inhibits proliferation of human endometriotic stromal cells: a potential therapeutic agent in endometriosis. AB - BACKGROUND: We previously showed that microRNA-503 (miR-503) transfection into endometriotic cyst stromal cells (ECSCs) induced cell cycle arrest at the G0/G1 phase by suppressing cyclin D1. This finding prompted us to evaluate the potential therapeutic effects of cyclin D1 inhibitors in endometriotic cells. This study aimed to determine whether arcyriaflavin A, a representative inhibitor of cyclin D1-cyclin-dependent kinase 4 (CDK4), is beneficial in the treatment of endometriosis. METHODS: ECSCs were isolated from the ovarian endometriotic tissues of 32 women. The effects of arcyriaflavin A on cell viability and proliferation, vascular endothelial growth factor A expression, apoptosis, and cell cycle progression were evaluated using a modified methylthiazoletetrazolium assay, enzyme-linked immunosorbent assay (ELISA), Caspase-Glo(r) 3/7 assay, and flow cytometry. RESULTS: Arcyriaflavin A significantly inhibited cell viability, proliferation, and angiogenesis of ECSCs as assessed using the 5-bromo-2 deoxyuridine (BrdU) and methylthiazoletetrazolium bromide (MTT) assays, and vascular endothelial growth factor (VEGF) ELISA. Arcyriaflavin A induced apoptosis as shown in the Caspase-Glo(r) 3/7 assay and cell death detection ELISA whilethe cell cycle was arrested at the G0/G1 phase. CONCLUSION: The findings indicate that cyclin D1-CDK4 inhibitors may be promising candidates for the treatment of endometriosis. This is the first study to demonstrate the potential usefulness of arcyriaflavin A as a therapeutic agent for endometriosis. Further studies of the effects of cyclin D1-CDK4 inhibitors on endometriosis may provide useful information on pathogenesis and treatment. PMID- 28720099 TI - Association between genome-wide copy number variation and arsenic-induced skin lesions: a prospective study. AB - BACKGROUND: Exposure to arsenic in drinking water is a global health problem and arsenic-induced skin lesions are hallmark of chronic arsenic toxicity. We and others have reported germline genetic variations as risk factors for such skin lesions. The role of copy number variation (CNV) in the germline DNA in this regard is unknown. METHODS: From a large prospectively followed-up cohort, exposed to arsenic, we randomly selected 2171 subjects without arsenic-induced skin lesions at enrollment and genotyped their whole blood DNA samples on Illumina Cyto12v2.1 SNP chips to generate DNA copy number. Participants were followed up every 2 years for a total of 8 years, especially for the development of skin lesions. In Cox regression models, each CNV segment was used as a predictor, accounting for other potential covariates, for incidence of skin lesions. RESULT: The presence of genomic deletion(s) in a number of genes (OR5J2, GOLGA6L7P, APBA2, GALNTL5, VN1R31P, PHKG1P2, SGCZ, ZNF658) and lincRNA genes (RP11-76I14.1, CTC-535 M15.2, RP11-73B2.2) were associated with higher risk [HR between 1.67 (CI 1.3-2.1) and 2.15 (CI 1.5-2.9) for different CNVs] for development of skin lesions independent of gender, age, and arsenic exposure. Some deletions had stronger effect in a specific gender (ZNF658 in males, SGCZ in females) and some had stronger effect in higher arsenic exposure (lincRNA CTD 3179P9.1) suggesting a possible gene-environment interaction. CONCLUSION: This first genome-wide CNV study in a prospectively followed-up large cohort, exposed to arsenic, suggests that DNA deletion in several genes and lincRNA genes may predispose an individual to a higher risk of development of arsenic-induced skin lesions. PMID- 28720100 TI - Effect of seasonal malaria chemoprevention on the acquisition of antibodies to Plasmodium falciparum antigens in Ouelessebougou, Mali. AB - BACKGROUND: Seasonal malaria chemoprevention (SMC) is a new strategy to reduce malaria burden in young children in Sahelian countries. It consists of the administration of full treatment courses of sulfadoxine-pyrimethamine plus amodiaquine to children at monthly intervals during the malaria season. However, it is not clear if there is a cumulative effect of SMC over time on acquisition of antibodies to malaria antigens. METHODS: A cross-sectional serosurvey was carried out 1 month after the last dose of SMC in 2016. Children aged 3-4 years were randomly selected from areas where SMC was given for 1, 2 or 3 years during the malaria season. Children in the areas where SMC had been implemented for 1 year but who failed to receive SMC were used as comparison group. Antibody extracted from dry blood spots was used to measure IgG levels to CSP, MSP-142 and AMA1. RESULTS: The prevalence of antibodies to AMA-1 were high and similar in children who received SMC for 1, 2 or 3 years and also when compared to those who never received SMC (96.3 vs 97.5%, adjusted OR = 0.99, 95% CI 0.33-2.97, p = 0.99). The prevalence of antibodies to MSP-142 and to CSP were similar in children that received SMC for 1, 2 or 3 years, but were lower in these children compared to those who did not receive SMC (87.1 vs 91.2%, adjusted OR = 0.55, 95% CI 0.29-1.01, p = 0.05 for MSP-142; 79.8 vs 89.2%, adjusted OR = 0.52, 95% CI 0.30-0.90, p = 0.019 for CSP). CONCLUSIONS: SMC reduced seropositivity to MSP-142 and CSP, but the duration of SMC did not further reduce seropositivity. Exposure to SMC did not reduce the seropositivity to AMA1. PMID- 28720101 TI - Drug candidates in clinical trials for Alzheimer's disease. AB - Alzheimer's disease (AD) is a major form of senile dementia, characterized by progressive memory and neuronal loss combined with cognitive impairment. AD is the most common neurodegenerative disease worldwide, affecting one-fifth of those aged over 85 years. Recent therapeutic approaches have been strongly influenced by five neuropathological hallmarks of AD: acetylcholine deficiency, glutamate excitotoxicity, extracellular deposition of amyloid-beta (Abeta plague), formation of intraneuronal neurofibrillary tangles (NTFs), and neuroinflammation. The lowered concentrations of acetylcholine (ACh) in AD result in a progressive and significant loss of cognitive and behavioral function. Current AD medications, memantine and acetylcholinesterase inhibitors (AChEIs) alleviate some of these symptoms by enhancing cholinergic signaling, but they are not curative. Since 2003, no new drugs have been approved for the treatment of AD. This article focuses on the current research in clinical trials targeting the neuropathological findings of AD including acetylcholine response, glutamate transmission, Abeta clearance, tau protein deposits, and neuroinflammation. These investigations include acetylcholinesterase inhibitors, agonists and antagonists of neurotransmitter receptors, beta-secretase (BACE) or gamma-secretase inhibitors, vaccines or antibodies targeting Abeta clearance or tau protein, as well as anti-inflammation compounds. Ongoing Phase III clinical trials via passive immunotherapy against Abeta peptides (crenezumab, gantenerumab, and aducanumab) seem to be promising. Using small molecules blocking 5-HT6 serotonin receptor (intepirdine), inhibiting BACE activity (E2609, AZD3293, and verubecestat), or reducing tau aggregation (TRx0237) are also currently in Phase III clinical trials. We here systemically review the findings from recent clinical trials to provide a comprehensive review of novel therapeutic compounds in the treatment and prevention of AD. PMID- 28720104 TI - Erratum to: Altered neuroendocrine control and association to clinical symptoms in adolescent chronic fatigue syndrome: a cross-sectional study. PMID- 28720103 TI - An information and communication technology-based centralized clinical trial to determine the efficacy and safety of insulin dose adjustment education based on a smartphone personal health record application: a randomized controlled trial. AB - BACKGROUND: A Personal Health Record (PHR) is an online application that allows patients to access, manage, and share their health data. PHRs not only enhance shared decision making with healthcare providers, but also enable remote monitoring and at-home-collection of detailed data. The benefits of PHRs can be maximized in insulin dose adjustment for patients starting or intensifying insulin regimens, as frequent self-monitoring of glucose, self-adjustment of insulin dose, and precise at-home data collection during the visit-to-visit period are important for glycemic control. The aim of this study is to examine the efficacy and safety of insulin dose adjustment based on a smartphone PHR application in patients with diabetes mellitus (DM) and to confirm the validity and stability of an information and communication technology (ICT)-based centralized clinical trial monitoring system. METHODS: This is a 24-week, open label, randomized, multi-center trial. There are three follow-up measures: baseline, post-intervention at week 12, and at week 24. Subjects diagnosed with type 1 DM, type 2 DM, and/or post-transplant DM who initiate basal insulin or intensify their insulin regimen to a basal-bolus regimen are included. After education on insulin dose titration and prevention for hypoglycemia and a 1-week acclimation period, subjects are randomized in a 1:1 ratio to either an ICT-based intervention group or a conventional intervention group. Subjects in the conventional intervention group will save and send their health information to the server via a PHR application, whereas those in ICT-based intervention group will receive additional algorithm-based feedback messages. The health information includes level of blood glucose, insulin dose, details on hypoglycemia, food diary, and step count. The primary outcome will be the proportion of patients who reach an optimal insulin dose within 12 weeks of study enrollment, without severe hypoglycemia or unscheduled clinic visits. DISCUSSION: This clinical trial will reveal whether insulin dose adjustment based on a smartphone PHR application can facilitate the optimization of insulin doses in patients with DM. In addition, the process evaluation will provide information about the validity and stability of the ICT-based centralized clinical trial monitoring system in this research field. TRIAL REGISTRATION: Clinicaltrials.gov NCT 03112343 . Registered on 12 April 2017. PMID- 28720102 TI - Environmental/lifestyle factors in the pathogenesis and prevention of type 2 diabetes. AB - BACKGROUND: Environmental and lifestyle changes, in addition to the ageing of populations, are generally believed to account for the rapid global increase in type 2 diabetes prevalence and incidence in recent decades. DISCUSSION: In this review, we present a comprehensive overview of factors contributing to diabetes risk, including aspects of diet quality and quantity, little physical activity, increased monitor viewing time or sitting in general, exposure to noise or fine dust, short or disturbed sleep, smoking, stress and depression, and a low socioeconomic status. In general, these factors promote an increase in body mass index. Since loss of beta-cell function is the ultimate cause of developing overt type 2 diabetes, environmental and lifestyle changes must have resulted in a higher risk of beta-cell damage in those at genetic risk. Multiple mechanistic pathways may come into play. CONCLUSIONS: Strategies of diabetes prevention should aim at promoting a 'diabetes-protective lifestyle' whilst simultaneously enhancing the resistance of the human organism to pro-diabetic environmental and lifestyle factors. More research on diabetes-protective mechanisms seems warranted. PMID- 28720105 TI - Decomposing the causes of socioeconomic-related health inequality among urban and rural populations in China: a new decomposition approach. AB - BACKGROUND: In recent decades, China has experienced tremendous economic growth and also witnessed growing socioeconomic-related health inequality. The study aims to explore the potential causes of socioeconomic-related health inequality in urban and rural areas of China over the past two decades. METHODS: This study used six waves of the China Health and Nutrition Survey (CHNS) from 1991 to 2006. The recentered influence function (RIF) regression decomposition method was employed to decompose socioeconomic-related health inequality in China. Health status was derived from self-rated health (SRH) scores. The analyses were conducted on urban and rural samples separately. RESULTS: We found that the average level of health status declined from 1989 to 2006 for both urban and rural populations. Average health scores were greater for the rural population compared with those for the urban population. We also found that there exists pro rich health inequality in China. While income and secondary education were the main factors to reduce health inequality, older people, unhealthy lifestyles and a poor home environment increased inequality. Health insurance had the opposite effects on health inequality for urban and rural populations, resulting in lower inequality for urban populations and higher inequality for their rural counterparts. CONCLUSION: These findings suggest that an effective way to reduce socioeconomic-related health inequality is not only to increase income and improve access to health care services, but also to focus on improvements in the lifestyles and the home environment. Specifically, for rural populations, it is particularly important to improve the design of health insurance and implement a more comprehensive insurance package that can effectively target the rural poor. Moreover, it is necessary to comprehensively promote the flush toilets and tap water in rural areas. For urban populations, in addition to promoting universal secondary education, healthy lifestyles should be promoted, including measures such as alcohol control. PMID- 28720106 TI - Caretaker-adolescent communication on sexual and reproductive health: a cross sectional study in Unguja-Tanzania Zanzibar. AB - BACKGROUND: Caretakers/parents/caregivers/guardians play important roles in improving Sexual and Reproductive Health (SRH) of adolescents. Caretaker adolescent sexual communication suggested to influence young people's sexual behaviours. Despite this significance, the communication is believed to be low in Unguja due to the increase of risky sexual behaviours among adolescents. This study assessed the pattern of such communication using IMB model as a framework. METHODS: This is a cross-sectional study targeted caretakers of adolescents aged 15-19. One thousand caretakers of adolescents were interviewed using structured questionnaire. Comparison between male and female caretakers on discussing different SRH topics to both sexes of adolescents was made. The mean-score difference of overall communication was examined using Univariate analysis of variance (ANOVA). Bivariate correlation and simple path analysis via regression was conducted to determine the association of IMB variables in relation to communication practice. RESULTS: This study finds 40.7% of caretakers had ever communicated with their adolescents on SRH matters and 9.2% reported to have had communicated in the past 30 days. The weighted topic measure revealed only 26.5% of caretakers communicated with their adolescents. Both caretakers communicated more with their female adolescents. The communication was more common between same sex and between caretakers and their biological adolescents (p < 0.000). Both male and female caretakers mostly discussed sexual abstinence to female adolescents while to male adolescents, HIV/STIs was mostly discussed by female caretakers and pregnancy by male caretakers. The least discussed topics to both sexes are safer sex and other contraceptives use. The bivariate correlations suggested that IMB constructs were inter-related and associated with communication practice. CONCLUSION: Caretakers-adolescents communication on SRH in Unguja is low and it is not comprehensive. Caretakers fail to communicate with their adolescents on sensitive issues but do so on less sensitive ones. The pattern of communication found to vary across gender of caretaker and that of adolescent and depends on the nature of relationship between caretaker and adolescent. There is gender differences in selecting SRH topics of discussion. Interventions programmes have to include strategies that enhance caretaker's information, motivation and skills so as to improve SRH communication between caretakers and adolescent. PMID- 28720107 TI - Reversible bacterial immobilization based on the salt-dependent adhesion of the bacterionanofiber protein AtaA. AB - BACKGROUND: Immobilization of microbial cells is an important strategy for the efficient use of whole-cell catalysts because it simplifies product separation, enables the cell concentration to be increased, stabilizes enzymatic activity, and permits repeated or continuous biocatalyst use. However, conventional immobilization methods have practical limitations, such as limited mass transfer in the inner part of a gel, gel fragility, cell leakage from the support matrix, and adverse effects on cell viability and catalytic activity. We previously showed a new method for bacterial cell immobilization using AtaA, a member of the trimeric autotransporter adhesin family found in Acinetobacter sp. Tol 5. This approach is expected to solve the drawbacks of conventional immobilization methods. However, similar to all other immobilization methods, the use of support materials increases the cost of bioprocesses and subsequent waste materials. RESULTS: We found that the stickiness of the AtaA molecule isolated from Tol 5 cells is drastically diminished at ionic strengths lower than 10 mM and that it cannot adhere in deionized water, which also inhibits cell adhesion mediated by AtaA. Cells immobilized on well plates and polyurethane foam in a salt solution were detached in deionized water by rinsing and shaking, respectively. The detached cells regained their adhesiveness in a salt solution and could rapidly be re-immobilized. The cells expressing the ataA gene maintained their adhesiveness throughout four repeated immobilization and detachment cycles and could be repeatedly immobilized to polyurethane foam by a 10-min shake in a flask. We also demonstrated that both bacterial cells and a support used in a reaction could be reused for a different type of reaction after detachment of the initially immobilized cells from the support and a subsequent immobilization step. CONCLUSIONS: We invented a unique reversible immobilization method based on the salt-dependent adhesion of the AtaA molecule that allows us to reuse bacterial cells and supports by a simple manipulation involving a deionized water wash. This mitigates problems caused by the use of support materials and greatly helps to enhance the efficiency and productivity of microbial production processes. PMID- 28720108 TI - Early pregnancy sex steroids during primiparous pregnancies and maternal breast cancer: a nested case-control study in the Northern Sweden Maternity Cohort. AB - BACKGROUND: Pregnancy and parity are associated with subsequent breast cancer risk. Experimental and epidemiologic data suggest a role for pregnancy sex steroid hormones. METHODS: We conducted a nested case-control study in the Northern Sweden Maternity Cohort (1975-2007). Eligible women had provided a blood sample in the first 20 weeks of gestation during a primiparous pregnancy leading to a term delivery. The current study includes 223 cases and 417 matched controls (matching factors: age at and date of blood collection). Estrogen receptor (ER) and progesterone receptor (PR) status was available for all cases; androgen receptor (AR) data were available for 41% of cases (n = 92). Sex steroids were quantified by high-performance liquid chromatography tandem mass spectrometry. Odds ratios (ORs) and 95% confidence intervals were estimated using conditional logistic regression. RESULTS: Higher concentrations of circulating progesterone in early pregnancy were inversely associated with ER+/PR+ breast cancer risk (ORlog2: 0.64 (0.41-1.00)). Higher testosterone was positively associated with ER+/PR+ disease risk (ORlog2: 1.57 (1.13-2.18)). Early pregnancy estrogens were not associated with risk, except for relatively high estradiol in the context of low progesterone (split at median, relative to low concentrations of both; OR: 1.87 (1.11-3.16)). None of the investigated hormones were associated with ER-/PR- disease, or with AR+ or AR+/ER+/PR+ disease. CONCLUSIONS: Consistent with experimental models, high progesterone in early pregnancy was associated with lower risk of ER+/PR+ breast cancer in the mother. High circulating testosterone in early pregnancy, which likely reflects nonpregnant premenopausal exposure, was associated with higher risk of ER+/PR+ disease. PMID- 28720109 TI - Cancer related fatigue: implementing guidelines for optimal management. AB - BACKGROUND: Cancer-related fatigue (CRF) is a key concern for people living with cancer and can impair physical functioning and activities of daily living. Evidence-based guidelines for CRF are available, yet inconsistently implemented globally. This study aimed to identify barriers and enablers to applying a cancer fatigue guideline and to derive implementation strategies. METHODS: A mixed method study explored the feasibility of implementing the CRF guideline developed by the Canadian Association for Psychosocial Oncology (CAPO). Health professionals, managers and consumers from different practice settings participated in a modified Delphi study with two survey rounds. A reference group informed the design of the study including the surveys. The first round focused on guideline characteristics, compatibility with current practice and experience, and behaviour change. The second survey built upon and triangulated the first round. RESULTS: Forty-five health practitioners and managers, and 68 cancer survivors completed the surveys. More than 75% of participants endorsed the CAPO cancer related fatigue guidelines. Some respondents perceived a lack of resources for accessible and expert fatigue management services. Further barriers to guideline implementation included complexity, limited practical details for some elements, and lack of clinical tools such as assessment tools or patient education materials. Recommendations to enhance guideline applicability centred around four main themes: (1) balancing the level of detail in the CAPO guideline with ease of use, (2) defining roles of different professional disciplines in CRF management, (3) how best to integrate CRF management into policy and practice, (4) how best to ensure a consumer-focused approach to CRF management. CONCLUSIONS: Translating current knowledge on optimal management of CRF into clinical practice can be enhanced by the adoption of valid guidelines. This study indicates that it is feasible to adopt the CAPO guidelines. Clinical application may be further enhanced with guideline adaptation, professional education and integration with existing practices. PMID- 28720110 TI - Molecular characterisation of protist parasites in human-habituated mountain gorillas (Gorilla beringei beringei), humans and livestock, from Bwindi impenetrable National Park, Uganda. AB - BACKGROUND: Over 60 % of human emerging infectious diseases are zoonotic, and there is growing evidence of the zooanthroponotic transmission of diseases from humans to livestock and wildlife species, with major implications for public health, economics, and conservation. Zooanthroponoses are of relevance to critically endangered species; amongst these is the mountain gorilla (Gorilla beringei beringei) of Uganda. Here, we assess the occurrence of Cryptosporidium, Cyclospora, Giardia, and Entamoeba infecting mountain gorillas in the Bwindi Impenetrable National Park (BINP), Uganda, using molecular methods. We also assess the occurrence of these parasites in humans and livestock species living in overlapping/adjacent geographical regions. RESULTS: Diagnostic PCR detected Cryptosporidium parvum in one sample from a mountain gorilla (IIdA23G2) and one from a goat (based on SSU). Cryptosporidium was not detected in humans or cattle. Cyclospora was not detected in any of the samples analysed. Giardia was identified in three human and two cattle samples, which were linked to assemblage A, B and E of G. duodenalis. Sequences defined as belonging to the genus Entamoeba were identified in all host groups. Of the 86 sequence types characterised, one, seven and two have been recorded previously to represent genotypes of Cryptosporidium, Giardia, and Entamoeba, respectively, from humans, other mammals, and water sources globally. CONCLUSIONS: This study provides a snapshot of the occurrence and genetic make-up of selected protists in mammals in and around BINP. The genetic analyses indicated that 54.6% of the 203 samples analysed contained parasites that matched species, genotypes, or genetic assemblages found globally. Seventy-six new sequence records were identified here for the first time. As nothing is known about the zoonotic/zooanthroponotic potential of the corresponding parasites, future work should focus on wider epidemiological investigations together with continued surveillance of all parasites in humans, other mammals, the environment, and water in this highly impoverished area. PMID- 28720111 TI - LncRNA SNHG15 contributes to proliferation, invasion and autophagy in osteosarcoma cells by sponging miR-141. AB - BACKGROUND: LncRNA small nucleolar RNA host gene 15 (SNHG15) was reported to play an oncogenic role in tumors. However, the role of SNHG15 and its molecular mechanism in osteosarcoma (OS) cells are largely unknown. METHODS: qRT-PCR was performed to evaluate the expression levels of SNHG15 and miR-141 in OS tissues and cells. Cell transfection with different siRNAs, miRNAs or pcDNAs into U2OS and MG63 cells were carried out by Lipofectamine 2000. The effects of SNHG15 and miR-141 on OS cell proliferation, invasion and the levels of autophagy-related proteins were analyzed by MTT assay, Transwell invasion/migration assay and western blot, respectively. Luciferase reporter assay was used to confirm whether SNHG15 could directly interact with miR-141. RESULTS: We found that up-regulation of SNHG15 was inversely correlated with miR-141 expression in OS tissues. SNHG15 knockdown and miR-141 overexpression significantly suppressed cell proliferation, invasion, migration and autophagy while SNHG15 overexpression and miR-141 repression exhibited the opposite effects on OS cells. Besides, SNHG15 could directly interact with miR-141 and regulate its expression. Furthermore, miR-141 suppressing significantly overturned the inhibition on proliferation, invasion, migration and autophagy mediated by SNHG15 knockdown while miR-141 overexpression remarkably attenuated SNHG15 overexpression-induced proliferation, invasion, migration and autophagy in OS cells. CONCLUSION: Our data showed that SNHG15 contributes to proliferation, invasion, migration and autophagy in OS by negatively regulating miR-141, providing a new potential target and prognostic biomarker for the treatment of OS. PMID- 28720112 TI - Association of the FDA Amendment Act with trial registration, publication, and outcome reporting. AB - BACKGROUND: Selective clinical trial publication and outcome reporting has the potential to bias the medical literature. The 2007 Food and Drug Administration (FDA) Amendment Act (FDAAA) mandated clinical trial registration and outcome reporting on ClinicalTrials.gov, a publicly accessible trial registry. METHODS: Using publicly available data from ClinicalTrials.gov, FDA documents, and PubMed, we determined registration, publication, and reporting of findings for all efficacy trials supporting FDA approval of new drugs for cardiovascular disease and diabetes between 2005 and 2014, before and after the FDAAA. For published trials, we compared the published interpretation of the findings (positive, equivocal, or negative) with the FDA reviewer's interpretation. RESULTS: Between 2005 and 2014, the FDA approved 30 drugs for 32 indications of cardiovascular disease (n = 17) and diabetes (n = 15) on the basis of 183 trials (median per indication 5.7 (IQR, 3-8)). Compared with pre FDAAA, post-FDAAA studies were more likely to be registered (78 of 78 (100%) vs 73 of 105 (70%); p < 0.001), to be published (76 of 78 (97%) vs 93 of 105 (89%); p = 0.03), and to present findings concordant with the FDA reviewer's interpretation (74 of 76 (97%) vs 78 of 93 (84%); p = 0.004). Pre FDAAA, the FDA reviewer interpreted 80 (76%) trials as positive and 91 (98%) were published as positive. Post FDAAA, the FDA reviewer interpreted 71 (91%) trials as positive and 71 (93%) were published as positive. CONCLUSIONS: FDAAA was associated with increased registration, publication, and FDA-concordant outcome reporting for trials supporting FDA approval of new drugs for cardiovascular disease and diabetes. PMID- 28720113 TI - Evaluation of electric nets as means to sample mosquito vectors host-seeking on humans and primates. AB - BACKGROUND: Plasmodium knowlesi is found in macaques and is the only major zoonotic malaria to affect humans. Transmission of P. knowlesi between people and macaques depends on the host species preferences and feeding behavior of mosquito vectors. However, these behaviours are difficult to measure due to the lack of standardized methods for sampling potential vectors attracted to different host species. This study evaluated electrocuting net traps as a safe, standardised method for sampling P. knowlesi vectors attracted to human and macaque hosts. Field experiments were conducted within a major focus on P. knowlesi transmission in Malaysian Borneo to compare the performance of human (HENET) or macaque (MENET) odour-baited electrocuting nets, human landing catches (HLC) and monkey baited traps (MBT) for sampling mosquitoes. The abundance and diversity of Anopheles sampled by different methods were compared over 40 nights, with a focus on the P. knowlesi vector Anopheles balabancensis. RESULTS: HLC caught more An. balabacensis than any other method (3.6 per night). In contrast, no An. balabacensis were collected in MBT collections, which generally performed poorly for all mosquito taxa. Anopheles vector species including An. balabacensis were sampled in both HENET and MENET collections, but at a mean abundance of less than 1 per night. There was no difference between HENET and MENET in the overall abundance (P = 0.05) or proportion (P = 0.7) of An. balabacensis. The estimated diversity of Anopheles species was marginally higher in electrocuting net than HLC collections, and similar in collections made with humans or monkey hosts. CONCLUSIONS: Host-baited electrocuting nets had moderate success for sampling known zoonotic malaria vectors. The primary vector An. balabacensis was collected with electrocuting nets baited both with humans and macaques, but at a considerably lower density than the HLC standard. However, electrocuting nets were considerably more successful than monkey-baited traps and representatively characterised anopheline species diversity. Consequently, their use allows inferences about relative mosquito attraction to be meaningfully interpreted while eliminating confounding factors due to trapping method. On this basis, electrocuting net traps should be considered as a useful standardised method for investigating vector contact with humans and wildlife reservoirs. PMID- 28720114 TI - Effects of the EQUIP quasi-experimental study testing a collaborative quality improvement approach for maternal and newborn health care in Tanzania and Uganda. AB - BACKGROUND: Quality improvement is a recommended strategy to improve implementation levels for evidence-based essential interventions, but experience of and evidence for its effects in low-resource settings are limited. We hypothesised that a systemic and collaborative quality improvement approach covering district, facility and community levels, supported by report cards generated through continuous household and health facility surveys, could improve the implementation levels and have a measurable population-level impact on coverage and quality of essential services. METHODS: Collaborative quality improvement teams tested self-identified strategies (change ideas) to support the implementation of essential maternal and newborn interventions recommended by the World Health Organization. In Tanzania and Uganda, we used a plausibility design to compare the changes over time in one intervention district with those in a comparison district in each country. Evaluation included indicators of process, coverage and implementation practice analysed with a difference-of-differences and a time-series approach, using data from independent continuous household and health facility surveys from 2011 to 2014. Primary outcomes for both countries were birth in health facilities, breastfeeding within 1 h after birth, oxytocin administration after birth and knowledge of danger signs for mothers and babies. Interpretation of the results considered contextual factors. RESULTS: The intervention was associated with improvements on one of four primary outcomes. We observed a 26-percentage-point increase (95% CI 25-28%) in the proportion of live births where mothers received uterotonics within 1 min after birth in the intervention compared to the comparison district in Tanzania and an 8-percentage point increase (95% CI 6-9%) in Uganda. The other primary indicators showed no evidence of improvement. In Tanzania, we saw positive changes for two other outcomes reflecting locally identified improvement topics. The intervention was associated with an increase in preparation of clean birth kits for home deliveries (31 percentage points, 95% CI 2-60%) and an increase in health facility supervision by district staff (14 percentage points, 95% CI 0-28%). CONCLUSIONS: The systemic quality improvement approach was associated with improvements of only one of four primary outcomes, as well as two Tanzania specific secondary outcomes. Reasons for the lack of effects included limited implementation strength as well a relatively short follow-up period in combination with a 1-year recall period for population-based estimates and a limited power of the study to detect changes smaller than 10 percentage points. TRIAL REGISTRATION: Pan African Clinical Trials Registry: PACTR201311000681314. PMID- 28720116 TI - Retraction Note: The microRNA-1246 promotes metastasis in non-small cell lung cancer by targeting cytoplasmic polyadenylation element-binding protein. PMID- 28720115 TI - Expression pattern of CD11c on lung immune cells after disseminated murine cytomegalovirus infection. AB - BACKGROUND: Cytomegalovirus (CMV) infection occurs frequently and is widespread globally. Numerous studies have shown that various types of immune cells play roles in mediating the response to CMV infection. CD11c, a commonly used dendritic cell (DC) marker, is expressed by other immune cells as well, such as T cells. This study analyzed the immune cells that express CD11c and monitored the expression level of their specific cell surface markers in the lung following a disseminated murine (M)CMV infection. METHODS: Mouse models of disseminated MCMV infection were used; uninfected and lipopolysaccharide (LPS)-treated mice were used as controls. At 1, 3 and 7 days following infection, single cell suspensions prepared from freshly digested lung tissue were stained for CD11c, CD86 and MHC II. Stained cells were analyzed using flow cytometry. Peripheral blood and single cell suspensions from spleen were sorted as well. Then these cells were subjected to analyze the CD11c expression pattern on natural killer (NK) cells and T cells. RESULTS: This assay showed that after MCMV infection, the expression of CD86 on pulmonary CD11chiMHC-IIhi cells (encompassing conventional DCs) was higher at 3 days post-infection than at 1 or 7 days post-infection, accompanied by a downregulation of MHC II. In addition, expression of CD11c was greatly increased in the MCMV infection group at 7 days post infection. This study also detected a large population of cells displaying an intermediate level of expression of CD11c (CD11cint); these cells were in the MCMV groups exclusively, and were subsequently identified as CD8+ T cells. In lung, spleen and blood, different proportions of CD11cint cells among the NK cell and T cell populations were observed between the BALB/c and C57BL/6 mice with or without MCMV infection. The expression level of NKp46 in NK cells dropped to a lower level after MCMV infection. CONCLUSIONS: The findings collectively indicate that CD11cintCD8+ T cells might play a key role in anti-MCMV adaptive immune response in lungs, as well as in spleen and blood. B220+CD11cint NK cells might be a more effective type of NK cell, participating in anti-MCMV infection. The downregulation of NKp46, in particular, might be linked with the immune evasion of MCMV. PMID- 28720117 TI - Systematic review adherence to methodological or reporting quality. AB - BACKGROUND: Guidelines for assessing methodological and reporting quality of systematic reviews (SRs) were developed to contribute to implementing evidence based health care and the reduction of research waste. As SRs assessing a cohort of SRs is becoming more prevalent in the literature and with the increased uptake of SR evidence for decision-making, methodological quality and standard of reporting of SRs is of interest. The objective of this study is to evaluate SR adherence to the Quality of Reporting of Meta-analyses (QUOROM) and PRISMA reporting guidelines and the A Measurement Tool to Assess Systematic Reviews (AMSTAR) and Overview Quality Assessment Questionnaire (OQAQ) quality assessment tools as evaluated in methodological overviews. METHODS: The Cochrane Library, MEDLINE(r), and EMBASE(r) databases were searched from January 1990 to October 2014. Title and abstract screening and full-text screening were conducted independently by two reviewers. Reports assessing the quality or reporting of a cohort of SRs of interventions using PRISMA, QUOROM, OQAQ, or AMSTAR were included. All results are reported as frequencies and percentages of reports and SRs respectively. RESULTS: Of the 20,765 independent records retrieved from electronic searching, 1189 reports were reviewed for eligibility at full text, of which 56 reports (5371 SRs in total) evaluating the PRISMA, QUOROM, AMSTAR, and/or OQAQ tools were included. Notable items include the following: of the SRs using PRISMA, over 85% (1532/1741) provided a rationale for the review and less than 6% (102/1741) provided protocol information. For reports using QUOROM, only 9% (40/449) of SRs provided a trial flow diagram. However, 90% (402/449) described the explicit clinical problem and review rationale in the introduction section. Of reports using AMSTAR, 30% (534/1794) used duplicate study selection and data extraction. Conversely, 80% (1439/1794) of SRs provided study characteristics of included studies. In terms of OQAQ, 37% (499/1367) of the SRs assessed risk of bias (validity) in the included studies, while 80% (1112/1387) reported the criteria for study selection. CONCLUSIONS: Although reporting guidelines and quality assessment tools exist, reporting and methodological quality of SRs are inconsistent. Mechanisms to improve adherence to established reporting guidelines and methodological assessment tools are needed to improve the quality of SRs. PMID- 28720118 TI - Inhibiting function of human fetal dermal mesenchymal stem cells on bioactivities of keloid fibroblasts. AB - BACKGROUND: Keloid is one kind of benign skin disease caused by hyperplasia of fibroblasts and collagen fibrils. It is refractory due to the lack of an effective treatment at present, which puts pressure on seeking a new therapeutic regimen. Mesenchymal stem cells (MSCs) from fetal skin are considered to play a crucial role in scarless healing. Nevertheless, the efficacy of them in keloid disorders remains poorly understood. METHODS: Keloid fibroblasts (KFs), human adult dermal fibroblasts (ADFs), and human fetal dermal mesenchymal stem cells (FDMSCs) were isolated to single cells and cultured in Dulbecco's modified Eagle's medium (DMEM). ADFs and FDMSCs were used to generate ADF-conditioned medium (A-CM) and FDMSC-conditioned medium (F-CM). The effects of A-CM and F-CM on KFs were tested using MTT assay, BrdU assay, TUNEL assay, quantitative polymerase chain reaction, Western blot, and annexin V-FITC/PI binding assay,. RESULTS: FDMSCs inhibited the bioactivity of KFs, downregulated the expression of the antiapoptotic protein BCL-2, and upregulated the expression of the proapoptotic protein BAX of KFs by secreting some soluble substances, thus accelerating the apoptosis of KFs. CONCLUSION: F-CM induces apoptosis of KFs, providing a novel treatment strategy for keloid disorders. PMID- 28720119 TI - Calcified amorphous tumor of the heart with mitral annular calcification: a case report. AB - BACKGROUND: Calcified amorphous tumor of the heart is a rare, non-neoplastic cardiac mass characterized by nodular calcium in the background of amorphous degenerating fibrinous material. Clinical diagnosis of calcified amorphous tumor can be difficult, and current single imaging techniques do not specifically differentiate calcified amorphous tumor from other cardiac tumors such as calcified atrial myxoma, calcified thrombi, or vegetation. Complete surgical resection is the treatment of choice for both symptom improvement and prevention of embolization, as well as for pathological diagnosis. CASE PRESENTATION: A 70 year-old Asian man with end-stage renal disease complained of chest discomfort during exercise. He had no history of thromboembolism or endocarditis. A transthoracic echocardiogram revealed mitral annular calcification as well as a highly mobile mass (8 * 6 mm) attached to the ventricular side of the posterior mitral valve leaflet. As the mass was highly mobile, suggesting a high risk of embolization, he underwent surgical resection. A histopathological examination revealed multiple nodular amorphous calcifications, along with fibrous connective tissue. There were no identifiable myxoma or malignancy cells. Consequently, the diagnosis of calcified amorphous tumor was confirmed. CONCLUSIONS: In the present case, a calcified amorphous tumor arose from mitral annular calcification. A characteristic of mitral annular calcification-related calcified amorphous tumor is its highly mobile nature, with a high risk of stroke or other systemic embolism. Therefore, surgical therapy should be considered for treatment of calcified amorphous tumors. PMID- 28720120 TI - Interrogating the "unsequenceable" genomic trinucleotide repeat disorders by long read sequencing. AB - Microsatellite expansion, such as trinucleotide repeat expansion (TRE), is known to cause a number of genetic diseases. Sanger sequencing and next-generation short-read sequencing are unable to interrogate TRE reliably. We developed a novel algorithm called RepeatHMM to estimate repeat counts from long-read sequencing data. Evaluation on simulation data, real amplicon sequencing data on two repeat expansion disorders, and whole-genome sequencing data generated by PacBio and Oxford Nanopore technologies showed superior performance over competing approaches. We concluded that long-read sequencing coupled with RepeatHMM can estimate repeat counts on microsatellites and can interrogate the "unsequenceable" genomic trinucleotide repeat disorders. PMID- 28720121 TI - The effectiveness of daily SMS reminders in pharmaceutical care of older adults on improving patients' adherence to antihypertensive medication (SPPA): study protocol for a randomized controlled trial. AB - BACKGROUND: Despite a variety of efficient and cost-effective antihypertensive medication, hypertension remains a serious health and economic burden. High consumption of cardiovascular drugs in the Slovak Republic does result neither in better hypertension control nor in significant decrease in cardiovascular mortality. At the same time, Slovakia has alarmingly low patients' adherence to medication intake. Studies have shown the efficiency of short messaging service (SMS) reminders to improve patients' adherence and health outcomes at low costs. Since SMS is popular among Slovaks, this approach may be feasible also in Slovakia. The primary objective is to assess if daily SMS reminders of antihypertensive medication intake provided by pharmacists in addition to the standard pharmaceutical care increase the proportion of adherent older hypertensive ambulatory patients. METHODS: The SPPA trial is a pragmatic randomized parallel group (1:1) trial in 300 older hypertensive patients carried out in community pharmacies in Slovakia. Trial pharmacies will be selected from all main regions of Slovakia. Trial intervention comprises daily personalized SMS reminders of medication intake embedded into usual pharmaceutical practice. The primary outcome is a combined adherence endpoint consisting of subjective self reported medication adherence via the eight-item Morisky Medication Adherence Scale (MMAS-8) and objective pill count rate. Secondary outcomes include: change in the MMAS-8; comparison of adherence rates using pill count; change in systolic blood pressure; and patient satisfaction. Also, direct treatment costs will be evaluated and a cost-effectiveness analysis will be carried out. DISCUSSION: The SPPA trial engages community pharmacists and mobile health (mHealth) technologies via evidence-based pharmaceutical care to efficiently and cost-effectively addresses current main healthcare challenges: high prevalence of hypertension; overconsumption of cardiovascular medicines; low adherence to medication treatment; and resulting uncontrolled blood pressure. The results may identify new possibilities and capacities in healthcare with low additional costs and high value to patients. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03105687 . Registered on 07 March 2017. PMID- 28720122 TI - Enhance the performance of current scoring functions with the aid of 3D protein ligand interaction fingerprints. AB - BACKGROUND: In structure-based drug design, binding affinity prediction remains as a challenging goal for current scoring functions. Development of target-biased scoring functions provides a new possibility for tackling this problem, but this approach is also associated with certain technical difficulties. We previously reported the Knowledge-Guided Scoring (KGS) method as an alternative approach (BMC Bioinformatics, 2010, 11, 193-208). The key idea is to compute the binding affinity of a given protein-ligand complex based on the known binding data of an appropriate reference complex, so the error in binding affinity prediction can be reduced effectively. RESULTS: In this study, we have developed an upgraded version, i.e. KGS2, by employing 3D protein-ligand interaction fingerprints in reference selection. KGS2 was evaluated in combination with four scoring functions (X-Score, ChemPLP, ASP, and GoldScore) on five drug targets (HIV-1 protease, carbonic anhydrase 2, beta-secretase 1, beta-trypsin, and checkpoint kinase 1). In the in situ scoring test, considerable improvements were observed in most cases after application of KGS2. Besides, the performance of KGS2 was always better than KGS in all cases. In the more challenging molecular docking test, application of KGS2 also led to improved structure-activity relationship in some cases. CONCLUSIONS: KGS2 can be applied as a convenient "add-on" to current scoring functions without the need to re-engineer them, and its application is not limited to certain target proteins as customized scoring functions. As an interpolation method, its accuracy in principle can be improved further with the increasing knowledge of protein-ligand complex structures and binding affinity data. We expect that KGS2 will become a practical tool for enhancing the performance of current scoring functions in binding affinity prediction. The KGS2 software is available upon contacting the authors. PMID- 28720124 TI - Defining the role of Lgr5+ stem cells in colorectal cancer: from basic research to clinical applications. AB - Intestinal epithelium is structured by two distinct components: the villi and the crypts. The crypts harbor stem cells expressing Lgr5 and thus have been a representative model to study tissue stem cell functions. Recent advances in organoid technology and analytical modalities have enabled precise characterization of Lgr5+ intestinal stem cells, providing insights into their roles in homeostasis and cancer. PMID- 28720123 TI - Cardiovascular magnetic resonance in an adult human population: serial observations from the multi-ethnic study of atherosclerosis. AB - The Multi-Ethnic Study of Atherosclerosis (MESA) is the first large-scale multi ethnic population study in the U.S. to use advanced cardiovascular magnetic resonance (CMR) imaging. MESA participants were free of cardiovascular disease at baseline between 2000 and 2002, and were followed up between 2009 and 2011 with repeated CMR examinations as part of MESA. CMR allows the clinician to visualize and accurately quantify volume and dimensions of all four cardiac chambers; measure systolic and diastolic ventricular function; assess myocardial fibrosis; assess vessel lumen size, vessel wall morphology, and vessel stiffness. CMR has a number of advantages over other imaging modalities such as echocardiography, computed tomography, and invasive angiography, and has been proposed as a diagnostic strategy for high-risk populations. MESA has been extensively evaluating CMR imaging biomarkers, as markers of subclinical disease, in the last 15 years for low-risk populations. On a more practical level, some of the imaging biomarkers developed and studied are translatable to at-risk populations. In this review, we discuss the progression of subclinical cardiovascular disease and the mechanisms responsible for the transition to symptomatic clinical outcomes based on our findings from MESA. PMID- 28720125 TI - Profiling of the perturbed metabolomic state of mouse spleen during acute and chronic toxoplasmosis. AB - BACKGROUND: Toxoplasma gondii, a common opportunistic protozoan, is a leading cause of illness and mortality among immunosuppressed individuals and during congenital infections. Current therapeutic strategies for toxoplasmosis are not fully effective at curtailing disease progression in these cases. Given the parasite ability to influence host immunity and metabolism, understanding of the metabolic alterations in the host's immune organs during T. gondii infection may enhance the understanding of the molecular mechanisms that define the pathophysiology of T. gondii infection. METHODS: We investigated the global metabolic changes in the spleen of BALB/c mice at early and late stage of infection with T. gondii using LC-MS/MS-based metabolomics. Multivariate data analysis methods, principal components analysis (PCA) and partial least squares discriminant analysis (PLS-DA), were used to identify metabolites that are influenced by T. gondii infection. RESULTS: Multivariate analyses clearly separated the metabolites of spleen of infected and control mice. A total of 132 differential metabolites were identified, 23 metabolites from acutely infected versus control mice and 109 metabolites from chronically infected versus control mice. Lipids, hormones, lactones, acids, peptides, antibiotics, alkaloids and natural toxins were the most influenced chemical groups. There were 12 shared differential metabolites between acutely infected versus control mice and chronically infected versus control mice, of which 4,4-Dimethyl-5alpha-cholesta 8,14,24-trien-3beta-ol was significantly upregulated and ubiquinone-8 was significantly downregulated. Major perturbed metabolic pathways included primary bile acid biosynthesis, steroid hormone biosynthesis, biotin metabolism, and steroid biosynthesis, with arachidonic acid metabolism being the most significantly impacted pathway. These metabolic changes suggest a multifactorial nature of the immunometabolic responses of mouse spleen to T. gondii infection. CONCLUSIONS: This study demonstrated that T. gondii infection can cause significant metabolomic alterations in the spleen of infected mice. These findings provide new insights into the molecular mechanisms that underpin the pathogenesis of T. gondii infection. PMID- 28720127 TI - Parasomnia overlap disorder, Parkinson's disease and subthalamic deep brain stimulation: three case reports. AB - BACKGROUND: Parasomnia overlap disorder (POD) is a distinct parasomnia and characterized by concomitant manifestation of rapid-eye-movement (REM)- and non REM (NREM)-parasomnias. Although not uncommon among patients with Parkinson's disease, POD is often under-investigated. CASE PRESENTATION: This is the first report of patients with PD and features of POD that underwent deep brain stimulation. Our patients exhibited different outcomes of POD features after subthalamic deep brain stimulation. CONCLUSIONS: We expect that the reporting of these first patients will open the discussion about the need for more detailed and broad-spectrum assessments regarding parasomnias in PD patients that undergo deep brain stimulation. The implications of our observations are both clinical and neurobiological. PMID- 28720126 TI - A small-molecule/cytokine combination enhances hematopoietic stem cell proliferation via inhibition of cell differentiation. AB - BACKGROUND: Accumulated evidence supports the potent stimulating effects of multiple small molecules on the expansion of hematopoietic stem cells (HSCs) which are important for the therapy of various hematological disorders. Here, we report a novel, optimized formula, named the SC cocktail, which contains a combination of three such small molecules and four cytokines. METHODS: Small molecule candidates were individually screened and then combined at their optimal concentration with the presence of cytokines to achieve maximum capacity for stimulating the human CD34+ cell expansion ex vivo. The extent of cell expansion and the immunophenotype of expanded cells were assessed through flow cytometry. The functional preservation of HSC stemness was confirmed by additional cell and molecular assays in vitro. Subsequently, the expanded cells were transplanted into sublethally irradiated NOD/SCID mice for the assessment of human cell viability and engraftment potential in vivo. Furthermore, the expression of several genes in the cell proliferation and differentiation pathways was analyzed through quantitative polymerase chain reaction (qPCR) during the process of CD34+ cell expansion. RESULTS: The SC cocktail supported the retention of the immunophenotype of hematopoietic stem/progenitor cells remarkably well, by yielding purities of 86.6 +/- 11.2% for CD34+ cells and 76.2 +/- 10.5% for CD34+CD38- cells, respectively, for a 7-day culture. On day 7, the enhancement of expansion of CD34+ cells and CD34+CD38- cells reached a maxima of 28.0 +/- 5.5 fold and 27.9 +/- 4.3-fold, respectively. The SC cocktail-expanded CD34+ cells preserved the characteristics of HSCs by effectively inhibiting their differentiation in vitro and retained the multilineage differentiation potential in primary and secondary in vivo murine xenotransplantation trials. Further gene expression analysis suggested that the small-molecule combination strengthened the ability of the cytokines to enhance the Notch pathway for the preservation of HSC stemness, and inhibited the ability of the cytokines to activate the Wnt pathway for HSC differentiation. CONCLUSIONS: We developed an optimal small molecule/cytokine combination for the enhancement of HSC expansion via inhibition of differentiation. This approach indicates promising application for preparation of both the HSCs and the mature, functional hematopoietic cells for clinical transplantation. PMID- 28720128 TI - The utility of mini-Clinical Evaluation Exercise (mini-CEX) in undergraduate and postgraduate medical education: protocol for a systematic review. AB - BACKGROUND: One of the most frequently used assessment tools that measure the trainees' performance in workplace is the mini-Clinical Evaluation Exercise (mini CEX), in which an expert observes and rates the actual performance of trainees. Several primary studies have evaluated the effectiveness of mini-CEX by assessing its educational and psychometric properties. The objective of this BEME review is to explore, analyze, and synthesize the evidence considering the utility of the mini-CEX for assessing undergraduate and postgraduate medical trainees. METHODS: Studies reporting on mini-CEX performed in undergraduate and postgraduate medical education and providing some empirical data for mini-CEX in relation to one or more of the validity, reliability, educational impact, acceptability, and cost of mini-CEX will be included in the review. No restrictions on study design or publication date or language will be handled. To ensure comprehensiveness of our search, we will use different approaches and methods. In addition to electronic search in bibliographic databases, we will conduct forward and backward searching. We will also contact leading authors in the field of mini-CEX and will search for the gray literature. Data extractions will be done independently by two coders based on a form. If there is any discordance, a third author will resolve it. The quality assessment will be also done independently by two team members, based on critical appraisal checklists. In attempting to answer our original research questions, we will use meta-analysis or meta-synthesis. DISCUSSION: The findings of this study can be transferred to the medical education stakeholders such as administrators of medical schools, residency program directors, and faculty members. We also hope that publication of this review will encourage stakeholders who have already adopted the mini-CEX to evaluate and report its different characteristics. Lastly, we expect that we can identify gap of knowledge in this field and suggest areas for future research. PMID- 28720129 TI - Predictors of return to work among patients in treatment for common mental disorders: a pre-post study. AB - BACKGROUND: Effects of return to work (RTW) interventions vary, and more knowledge is needed about the factors that contribute to RTW. This study investigated changes in work participation and mental health, and predictors of RTW among patients being treated for common mental disorders (CMDs). METHODS: The study was a prospective pre-post study of 164 patients treated at an RTW outpatient clinic for CMDs. Differences between before and after treatment were analysed using paired t tests for continuous variables and marginal homogeneity test for categorical variables. Univariable and multivariable logistic regression analyses were used to identify factors associated with RTW. Baseline data (patient characteristics, clinical status, generalized self-efficacy, expectations of future work ability) and treatment variables were used as independent variables in logistic regressions. Further analysis investigated whether improvements in symptoms, work ability, expectations of future work ability and generalized self-efficacy were associated with RTW. RESULTS: Number of individuals with full work participation increased, and there were improvements in symptoms, work ability and generalized self-efficacy. In the final model for predicting RTW, baseline work ability and expectancy of future work ability, a history of psychiatric treatment and focus on RTW in the treatment predicted RTW. Improvement in expectations of future work ability at post-treatment did also predict RTW. CONCLUSIONS: Assessing work ability and expectations of RTW at the beginning of treatment is recommended to identify patients at risk of long-term sick leave. Individuals with a history of psychiatric treatment are also risking long-term work disability. It is essential that treatment focus not only on symptom-relief, but also on improving work ability and expectations of RTW. An RTW-focused approach in therapy is associated with RTW. TRAIL REGISTRATION: ClinicalTrails.gov ID NCT01181635 . Registered 08/12/2010. PMID- 28720130 TI - Psychosocial and behavioral impact of breast cancer risk assessed by testing for common risk variants: protocol of a prospective study. AB - BACKGROUND: The 'common variant, common disease' model predicts that a significant component of hereditary breast cancer unexplained by pathogenic variants in moderate or high-penetrance genes is due to the cumulative effect of common risk variants in DNA (polygenic risk). Assessing a woman's breast cancer risk by testing for common risk variants can provide useful information for women who would otherwise receive uninformative results by traditional monogenic testing. Despite increasing support for the utility of common risk variants in hereditary breast cancer, research findings have not yet been integrated into clinical practice. Translational research is therefore critical to ensure results are effectively communicated, and that women do not experience undue adverse psychological outcomes. METHODS: In this prospective study, 400 women with a personal and/or high risk family history of breast cancer will be recruited from six familial cancer centers (FCCs) in Australia. Eligible women will be invited to attend a FCC and receive their personal polygenic risk result for breast cancer. Genetic health professionals participating in the study will receive training on the return of polygenic risk information and a training manual and visual aids will be developed to facilitate patient communication. Participants will complete up to three self-administered questionnaires over a 12-months period to assess the short-and long-term psychological and behavioral outcomes of receiving or not receiving their personal polygenic risk result. DISCUSSION: This is the world's first study to assess the psychological and behavioral impact of offering polygenic risk information to women from families at high risk of breast cancer. Findings from this research will provide the basis for the development of a new service model to provide polygenic risk information in familial cancer clinics. TRIAL REGISTRATION: The study was retrospectively registered on 27th April 2017 with the Australian and New Zealand Clinical Trials Group (Registration no: ACTRN12617000594325; clinical trial URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=372743 ). PMID- 28720131 TI - Anti-arthritic activity of aqueous-methanolic extract and various fractions of Berberis orthobotrys Bien ex Aitch. AB - BACKGROUND: The roots and stem bark of Berberis orthobotrys (Berberidaceae) have long been used traditionally to treat joint pain. Though, it has not been pharmacologically assessed for rheumatoid arthritis. The current study explores anti-arthritic activity and phytochemical analysis of aqueous-methanolic extract (30:70) and fractions (ethyl acetate, n-butanol, and aqueous) of Berberis orthobotrys roots. METHODS: Anti-arthritic potential was evaluated in vitro using protein denaturation (bovine serum albumin and egg albumin) and membrane stabilization methods at 12.5-800 MUg/ml concentration and in vivo via turpentine oil, formaldehyde and Complete Freund Adjuvant (CFA) models at 50, 100 and 150 mg/kg doses. Also, in vitro antioxidant ability was appraised by reducing power assay. Moreover, total flavonoid content, Fourier transform infrared spectroscopy and High performance liquid chromatography of n-butanol fraction were performed. RESULTS: The results revealed concentration dependent inhibition of albumin denaturation and notable RBC membrane stabilization, with maximum results obtained at 800 MUg/ml. Similarly, plant exhibited dose dependent anti-arthritic effect in turpentine oil and formaldehyde models, with maximum activity observed at 150 mg/kg. The results of CFA model depicted better protection against arthritic lesions and body weight alterations. Also, B.orthobotrys remarkably ameliorated altered hematological parameters, rheumatoid factor and positively modified radiographic and histopathological changes. Additionally, plant exhibited remarkable anti-oxidant activity. Moreover, phytochemical analysis revealed polyphenols and flavonoids. CONCLUSION: Taken together, these results support traditional use of B.orthobotrys as potent anti-arthritic agent that may be proposed for rheumatoid arthritis treatment. PMID- 28720133 TI - Developing a questionnaire to determine the impact of self-management in diabetes: giving people with diabetes a voice. AB - BACKGROUND: The prevalence of diabetes mellitus (DM) is increasing dramatically, placing considerable financial burden on the healthcare budget of each country. Patient self-management is crucial for the control of blood glucose, which largely determines the chances of developing diabetes-related complications. Self management interventions vary widely, and a method is required for assessing the impact of self-management. This paper describes the development of a questionnaire intended for use to measure the impact of self-management in diabetes. METHODS: An iterative development process was undertaken to identify the attributes of self-management using 5 steps. First, a literature review was undertaken to identify and understand themes relating to self-management of DM to inform a topic guide. Second, the topic guide was further refined following consultation with a Patient and Public Involvement group. Third, the topic guide was used to inform semi-structured interviews with patients with Type 1 DM (T1DM) and Type 2 DM (T2DM) to identify how self-management of DM affects individuals. Fourth, the research team considered potential attributes alongside health attributes from an existing measure (Diabetes Health Profile, DHP) to produce an instrument reflecting both health and self-management outcomes simultaneously. Finally, a draft instrument was tested in a focus group to determine the wording and acceptability. RESULTS: Semi-structured interviews were carried out with 32 patients with T1DM and T2DM. Eight potential attributes were identified: fear/worry/anxiety, guilt, stress, stigma, hassle, control, freedom, and feeling supported. Four of these self-management attributes were selected with four health attributes (mood, worry about hypos (hypoglycaemic episodes), vitality and social limitations) to produce the Health and Self-Management in Diabetes (HASMIDv1) questionnaire. CONCLUSIONS: HASMIDv1 is a short questionnaire that contains eight items each with four response levels to measure the impact of self management in diabetes for both T1DM and T2DM. The measure was developed using a mixed-methods approach that involved semi-structured interviews with people with diabetes. The measure has high face validity. Ongoing research is being undertaken to assess the validity of this questionnaire for measuring the impact of self-management interventions in economic evaluation. PMID- 28720132 TI - Efficacy and safety of direct switch to indacaterol/glycopyrronium in patients with moderate COPD: the CRYSTAL open-label randomised trial. AB - BACKGROUND: Dual bronchodilation combining a long-acting beta2-agonist (LABA) and a long-acting muscarinic antagonist (LAMA) is the preferred choice of treatment recommended by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2017 guidelines for the management of patients with moderate-to-severe chronic obstructive pulmonary disease (COPD). The once-daily (q.d.) fixed-dose combination (FDC) of LABA, indacaterol 110 MUg and LAMA, glycopyrronium 50 MUg (IND/GLY 110/50 MUg q.d.) demonstrated superior improvements in lung function, dyspnoea and overall health status and better tolerability against LABA or LAMA monotherapies and combination of LABA and inhaled corticosteroid (ICS) in more than 11,000 patients with moderate-to-severe COPD in several randomised controlled clinical trials. METHODS: The CRYSTAL study was the first, 12-week, randomised, open-label trial that evaluated the efficacy and safety of a direct switch from previous treatments to IND/GLY 110/50 MUg q.d. on lung function and dyspnoea in patients with moderate COPD and a history of up to one exacerbation in the previous year. Patients were divided into 2 groups according to their background therapy and symptom scores and were randomised (3:1) to IND/GLY or to continue with their previous treatments. RESULTS: The study included 4389 randomised patients, of whom 2160 were in groups switched to IND/GLY (intention to-treat population). The effect of IND/GLY was superior to LABA + ICS on trough forced expiratory volume in 1 s (FEV1; treatment difference, Delta = +71 mL) and transition dyspnoea index (TDI; [Delta = 1.09 units]), and to LABA or LAMA on trough FEV1 (Delta = +101 mL) and a TDI (Delta = 1.26 units). Improvements in health status and lower rescue medication use were also observed with IND/GLY. The safety profile of the study medication was similar to that observed in previous studies. CONCLUSIONS: IND/GLY demonstrated superior improvements in lung function and dyspnoea after direct switch from previous treatments. TRIAL REGISTRATION: ClinicalTrials.gov number: NCT01985334 . PMID- 28720134 TI - In vitro antioxidant and antimalarial activities of leaves, pods and bark extracts of Acacia nilotica (L.) Del. AB - BACKGROUND: The emergence of drug resistant malaria is threatening our ability to treat and control malaria in the Southeast Asian region. There is an urgent need to develop novel and chemically diverse antimalarial drugs. This study aimed at evaluating the antimalarial and antioxidant potentials of Acacia nilotica plant extracts. METHODS: The antioxidant activities of leaves, pods and bark extracts were determined by standard antioxidant assays; reducing power capacity, % lipid peroxidation inhibition and ferric reducing antioxidant power assay. The antimalarial activities of plant extracts against Plasmodium falciparum parasites were determined by the 48 h schizont maturation inhibition assay. Further confirmation of schizonticide activity of extracts was made by extending the incubation period up to 96 h after removing the plant extract residues from parasites culture. Inhibition assays were analyzed by dose-response modelling. RESULTS: In all antioxidant assays, leaves of A. nilotica showed higher antioxidant activity than pods and bark. Antimalarial IC50 values of leaves, pods and bark extracts were 1.29, 4.16 and 4.28 MUg/ml respectively, in the 48 h maturation assay. The IC50 values determined for leaves, pods and bark extracts were 3.72, 5.41 and 5.32 MUg/ml respectively, after 96 h of incubation. All extracts inhibited the development of mature schizont, indicating schizonticide activity against P. falciparum. CONCLUSION: A. nilotica extracts showed promising antimalarial and antioxidant effects. However, further investigation is needed to isolate and identify the active components responsible for the antimalarial and antioxidant effects. PMID- 28720135 TI - Exploring anti-malarial potential of FDA approved drugs: an in silico approach. AB - BACKGROUND: The critically important issue on emergence of drug-resistant malarial parasites is compounded by cross resistance, where resistance to one drug confers resistance to other chemically similar drugs or those that share mode of action. This aspect requires discovery of new anti-malarial compounds or formulation of new combination therapy. The current study attempts to contribute towards accelerating anti-malarial drug development efforts, by exploring the potential of existing FDA-approved drugs to target proteins of Plasmodium falciparum. METHODS: Using comparative sequence and structure analyses, FDA approved drugs, originally developed against other pathogens, were identified as potential repurpose-able candidates against P. falciparum. The rationale behind the undertaken approach is the likeliness of small molecules to bind to homologous targets. Such a study of evolutionary relationships between established targets and P. falciparum proteins aided in identification of approved drug candidates that can be explored for their anti-malarial potential. RESULTS: Seventy-one FDA-approved drugs were identified that could be repurposed against P. falciparum. A total of 89 potential targets were recognized, of which about 70 are known to participate in parasite housekeeping machinery, protein biosynthesis, metabolic pathways and cell growth and differentiation, which can be prioritized for chemotherapeutic interventions. An additional aspect of prioritization of predicted repurpose-able drugs has been explored on the basis of ability of the drugs to permeate cell membranes, i.e., lipophilicity, since the parasite resides within a parasitophorous vacuole, within the erythrocyte, during the blood stages of infection. Based on this consideration, 46 of 71 FDA approved drugs have been identified as feasible repurpose-able candidates against P. falciparum, and form a first-line for laboratory investigations. At least five of the drugs identified in the current analysis correspond to existing antibacterial agents already under use as repurposed anti-malarial agents. CONCLUSIONS: The drug-target associations predicted, primarily by taking advantage of evolutionary information, provide a valuable resource of attractive and feasible candidate drugs that can be readily taken through further stages of anti-malarial drug development pipeline. PMID- 28720136 TI - Bilateral multiple pulmonary artery aneurysms associated with cavitary pulmonary tuberculosis: a case report. AB - BACKGROUND: Pulmonary artery aneurysms constitute <1% of aneurysms occurring in the thoracic cavity. Congenital cardiac defects are responsible for the majority (>50%) of cases, however, pulmonary artery aneurysm is a rare sequelae of pulmonary tuberculosis reported in about 5% of patients with chronic cavitary tuberculosis on autopsy. The natural history of this potentially fatal condition remains poorly understood and guidelines for optimal management are controversial. CASE PRESENTATION: A 24-year-old man, a nursing student of African descent, was referred to us from an up-country regional hospital with a 4-week history of recurrent episodes of breathlessness, awareness of heartbeats and coughing blood 3 weeks after completing a 6-month course of anti-tuberculosis drugs. A physical examination revealed conjuctival and palmar pallor but there were no stigmata of connective tissue disorders, systemic vasculitides or congenital heart disease. An examination of the cardiovascular system revealed accentuated second heart sound (S2) with early diastolic (grade 1/6) and holosystolic (grade 2/6) murmurs at the pulmonic and tricuspid areas respectively. Blood tests showed iron deficiency anemia, prolonged bleeding time, and mild hyponatremia. A chest radiograph revealed bilateral ovoid-shaped perihilar opacities while a computed tomography scan showed bilateral multiple pulmonary artery pseudoaneurysms with surrounding hematoma together with adjacent cystic changes, consolidations, and tree-in-bud appearance. Our patient refused to undergo surgery and died of aneurismal rupture after 9 days of hospitalization. CONCLUSIONS: The presence of intractable hemoptysis among patients with tuberculosis even after completion of anti-tuberculosis course should raise an index of suspicion for pulmonary artery aneurysm. Furthermore, despite of its rarity, early recognition and timely surgical intervention of pulmonary artery aneurysm is crucial to reducing morbidity and preventing the attributed mortality. PMID- 28720137 TI - Cortical thickness in the intertrochanteric region may be relevant to hip fracture type. AB - BACKGROUND: This study assessed the differences in femoral geometry and bone mineral density between femoral neck fragility fractures and trochanteric fractures. METHODS: One hundred and seventeen patients were divided into femoral neck and trochanteric fracture groups. There were 69 patients with femoral neck fractures, 20 men and 49 women with an average age of 75.1 +/- 9.6 years and an average body mass index (BMI) value of 21.6 +/- 4.1 kg/m2. The trochanteric group consisted of 48 patients, 16 men and 32 women with an average age of 78.1 +/- 9.1 years and an average BMI value of 21.5 +/- 4.3 kg/m2. All patients underwent dual energy X-ray absorptiometry (DXA) of the contralateral hip; hip structural analysis (HSA) software was used to analyze the femoral geometry parameters, including hip axis length (HAL), neck-shaft angle (NSA), cross-sectional area (CSA), the cross-sectional moment of inertia (CSMI), the buckling ratio (BR), and cortical thickness. RESULTS: The cortical thickness in the intertrochanteric region was reduced in the trochanteric fractures group compared to the femoral neck fracture group (P < 0.05). There were no statistically significant differences (P > 0.05) in gender, age, height, weight, or BMI between the two groups. In addition, no statistically significant differences (P > 0.05) were found in the CSA, CSMI, or BR of the femoral neck or the intertrochanteric region between the two groups. There were no statistically significant differences (P > 0.05) in femoral neck cortical thickness between the two groups. CONCLUSIONS: Cortical thickness thinning in the intertrochanteric region may be one of the relevant factors causing different types of hip fractures, especially in elderly patients. PMID- 28720138 TI - Plantar plate pathology is associated with erosive disease in the painful forefoot of patients with rheumatoid arthritis. AB - BACKGROUND: Disease-related foot pathology is recognised to have a significant impact on mobility and functional capacity in the majority of patients with rheumatoid arthritis (RA). The forefoot is widely affected and the metatarsophalangeal (MTP) joints are the most common site of symptoms. The plantar plates are the fibrocartilaginous distal attachments of the plantar fascia inserting into the five proximal phalanges. Together with the transverse metatarsal ligament they prevent splaying of the forefoot and subluxation of the MTP joints. Damage to the plantar plates is a plausible mechanism therefore, through which the forefoot presentation, commonly described as 'walking on pebbles', may develop in patients with RA. The aims of this study were to investigate the relationship between plantar plate pathology and clinical, biomechanical and plain radiography findings in the painful forefoot of patients with RA. Secondly, to compare plantar plate pathology at the symptomatic lesser (2nd-5th) MTP joints in patients with RA, with a group of healthy age and gender matched control subjects without foot pain. METHODS: In 41 patients with RA and ten control subjects the forefoot was imaged using 3T MRI. Intermediate weighted fat-suppressed sagittal and short axis sequences were acquired through the lesser MTP joints. Images were read prospectively by two radiologists and consensus reached. Plantar plate pathology in patients with RA was compared with control subjects. Multivariable multilevel modelling was used to assess the association between plantar plate pathology and the clinical, biomechanical and plain radiography findings. RESULTS: There were significant differences between control subjects and patients with RA in the presence of plantar plate pathology at the lesser MTP joints. No substantive or statistically significant associations were found between plantar plate pathology and clinical and biomechanical findings. The presence of plantar plate pathology was independently associated with an increase in the odds of erosion (OR = 52.50 [8.38-326.97], p < 0.001). CONCLUSION: The distribution of plantar plate pathology at the lesser MTP joints in healthy control subjects differs to that seen in patients with RA who have the consequence of inflammatory disease in the forefoot. Longitudinal follow-up is required to determine the mechanism and presentation of plantar plate pathology in the painful forefoot of patients with RA. PMID- 28720139 TI - The GOLMePsA study protocol: an investigator-initiated, double-blind, parallel group, randomised, controlled trial of GOLimumab and methotrexate versus methotrexate in early diagnosed psoriatic arthritis using clinical and whole body MRI outcomes. AB - BACKGROUND: Psoriatic arthritis (PsA) is a chronic inflammatory arthritis which impacts significantly on the quality of life and work capacity of affected individuals. Recent evidence has shown that early control of inflammation in PsA leads to improved long-term outcomes. It is postulated that prompt intervention after diagnosis using a remission-induction treatment strategy will lead to improved outcomes and optimal disease control of PsA. The aim of the present study was to compare the clinical efficacy of a treatment strategy in newly diagnosed, treatment naive PsA subjects, using the combination of golimumab (GOL), methotrexate (MTX) and steroids versus standard care (MTX monotherapy plus steroids). METHODS/DESIGN: GOLMePsA is an investigator initiated, phase IIIb, single-centre, randomised, double-blind, placebo-controlled, two-armed, parallel group, imaging-supplemented study. Eighty-eight PsA patients, diagnosed within 24 months prior to screening and treatment naive, will be randomised at baseline to receive: (arm 1) the combination of intramuscular/intra-articular prednisolone, MTX and GOL or (arm 2) the combination of intramuscular/intra-articular prednisolone, MTX and placebo for 24 weeks (interventional period). Primary outcome measure is clinical improvement (at least 1 unit difference) in the Psoriatic ArthritiS Disease Activity Score (PASDAS) composite index. Reflecting a "step down" therapeutic approach, all participants successfully completing the interventional period will be followed up for a further 28 weeks. During this observational period, stable maintenance MTX monotherapy will continue for both arms, unless in case of intolerance or PsA relapse. In the latter case, additional treatment will be provided. Overall, the GOLMePsA study length is planned to be 52 weeks. DISCUSSION: The hypothesis underlining this study is that very early treatment with first-line GOL reduces disease activity in PsA, in comparison to conventional therapy. TRIAL REGISTRATION: EudraCT 2013-004122-28 . 24/09/2013. PMID- 28720140 TI - A mixed methods protocol for developing and testing implementation strategies for evidence-based obesity prevention in childcare: a cluster randomized hybrid type III trial. AB - BACKGROUND: Despite the potential to reach at-risk children in childcare, there is a significant gap between current practices and evidence-based obesity prevention in this setting. There are few investigations of the impact of implementation strategies on the uptake of evidence-based practices (EBPs) for obesity prevention and nutrition promotion. This study protocol describes a three phase approach to developing and testing implementation strategies to support uptake of EBPs for obesity prevention practices in childcare (i.e., key components of the WISE intervention). METHODS: Informed by the i-PARIHS framework, we will use a stakeholder-driven evidence-based quality improvement (EBQI) process to apply information gathered in qualitative interviews on barriers and facilitators to practice to inform the design of implementation strategies. Then, a Hybrid Type III cluster randomized trial will compare a basic implementation strategy (i.e., intervention as usual) with an enhanced implementation strategy informed by stakeholders. All Head Start centers (N = 12) within one agency in an urban area in a southern state in the USA will be randomized to receive the basic or enhanced implementation with approximately 20 classrooms per group (40 educators, 400 children per group). The educators involved in the study, the data collectors, and the biostastician will be blinded to the study condition. The basic and enhanced implementation strategies will be compared on outcomes specified by the RE-AIM model (e.g., Reach to families, Effectiveness of impact on child diet and health indicators, Adoption commitment of agency, Implementation fidelity and acceptability, and Maintenance after 6 months). Principles of formative evaluation will be used throughout the hybrid trial. DISCUSSION: This study will test a stakeholder-driven approach to improve implementation, fidelity, and maintenance of EBPs for obesity prevention in childcare. Further, this study provides an example of a systematic process to develop and test a tailored, enhanced implementation strategy. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03075085. PMID- 28720141 TI - Selecting and implementing overview methods: implications from five exemplar overviews. AB - BACKGROUND: Overviews of systematic reviews are an increasingly popular method of evidence synthesis; there is a lack of clear guidance for completing overviews and a number of methodological challenges. At the UK Cochrane Symposium 2016, methodological challenges of five overviews were explored. Using data from these five overviews, practical implications to support methodological decision making of authors writing protocols for future overviews are proposed. METHODS: Methods, and their justification, from the five exemplar overviews were tabulated and compared with areas of debate identified within current literature. Key methodological challenges and implications for development of overview protocols were generated and synthesised into a list, discussed and refined until there was consensus. RESULTS: Methodological features of three Cochrane overviews, one overview of diagnostic test accuracy and one mixed methods overview have been summarised. Methods of selection of reviews and data extraction were similar. Either the AMSTAR or ROBIS tool was used to assess quality of included reviews. The GRADE approach was most commonly used to assess quality of evidence within the reviews. Eight key methodological challenges were identified from the exemplar overviews. There was good agreement between our findings and emerging areas of debate within a recent published synthesis. Implications for development of protocols for future overviews were identified. CONCLUSIONS: Overviews are a relatively new methodological innovation, and there are currently substantial variations in the methodological approaches used within different overviews. There are considerable methodological challenges for which optimal solutions are not necessarily yet known. Lessons learnt from five exemplar overviews highlight a number of methodological decisions which may be beneficial to consider during the development of an overview protocol. PMID- 28720142 TI - Comparison of serological assays to titrate Hantaan and Seoul hantavirus-specific antibodies. AB - BACKGROUND: Hantaan and Seoul viruses, in the Hantavirus genus, are known to cause hemorrhagic fever with renal syndrome (HFRS). The plaque reduction neutralization test (PRNT), as conventional neutralization test for hantaviruses, is laborious and time-consuming. Alternatives to PRNT for hantaviruses are required. METHODS: In this study, the methods for Hantaan and Seoul viruses serological typing including microneutralization test (MNT), pseudoparticle neutralization test (PPNT) and immunofluorescence assay based on viral glycoproteins (IFA-GP) were developed and compared with PRNT using a panel of 74 sera including 44 convalescent sera of laboratory confirmed HFRS patients and 30 patients sera of non-hantavirus infection. Antibody titres and serotyping obtained with different methods above were analyzed by paired-t, linear correlation, McNemar chi2 and Kappa agreement tests. RESULTS: Antibody titres obtained with MNT50, PPNT50 and IFA-GP were significantly correlated with that obtained with PRNT50 (p < 0.001). GMT determined by PPNT50 was statistically higher than that determined by PRNT50 (p < 0.001), while GMT determined by MNT50 and IFA-GP were equal with (p > 0.05) and less than (p < 0.001) that obtained with PRNT50 respectively. Serotyping obtained with MNT50 and PRNT50, PPNT50 and PRNT50 were highly consistent (p < 0.001), whereas that obtained with IFA-GP and PRNT50 were moderately consistent (p < 0.001). There were no significant differences for serotyping between PRNT50 and MNT50, as well as PRNT50 and PPNT50 (p > 0.05). IFA-GP was less sensitive than PRNT50 and MNT50 for serotyping of hantaviruses infection (p < 0.05). However, for 79.5% (35/44) samples, serotyping determined by IFA-GP and PRNT50 were consistent. CONCLUSIONS: MNT50 and PPNT50 both can be used as simple and rapid alternatives to PRNT50, and MNT50 is more specific while PPNT50 is more sensitive than other assays for neutralizing antibody determination. So far, this work has been the most comprehensive comparison of alternatives to PRNT. PMID- 28720143 TI - MHC class II expression and potential antigen-presenting cells in the retina during experimental autoimmune uveitis. AB - BACKGROUND: Controversy exists regarding which cell types are responsible for autoantigen presentation in the retina during experimental autoimmune uveitis (EAU) development. In this study, we aimed to identify and characterize the retinal resident and infiltrating cells susceptible to express major histocompatibility complex (MHC) class II during EAU. METHODS: EAU was induced in C57BL/6 mice by adoptive transfer of autoreactive lymphocytes from IRBP1-20 immunized animals. MHC class II expression was studied by immunostainings on eye cryosections. For flow cytometry (FC) analysis, retinas were dissected and enzymatically digested into single-cell suspensions. Three MHC class II+ retinal cell populations were sorted by FC, and their RNA processed for RNA-Seq. RESULTS: Immunostainings demonstrate strong induction of MHC class II expression in EAU, especially in the inner retina at the level of inflamed vessels, extending to the outer retinal layers and the subretinal space in severely inflamed eyes. Most MHC class II+ cells express the hematopoietic marker IBA1. FC quantitative analyses demonstrate that MHC class II induction significantly correlates with disease severity and is associated with upregulation of co-stimulatory molecule expression. In particular, most MHC class IIhi cells express co-stimulatory molecules during EAU. Further phenotyping identified three MHC class II+ retinal cell populations: CD45-CD11b- non-hematopoietic cells with low MHC class II expression and CD45+CD11b+ hematopoietic cells with higher MHC class II expression, which can be further separated into Ly6C+ and Ly6C- cells, possibly corresponding to infiltrating macrophages and resident microglia. Transcriptome analysis of the three sorted populations leads to a clear sample clustering with some enrichment in macrophage markers and microglial cell markers in Ly6C+ and Ly6C- cells, respectively. Functional annotation analysis reveals that both hematopoietic cell populations are more competent in MHC class II-associated antigen presentation and in T cell activation than non-hematopoietic cells. CONCLUSION: Our results highlight the potential of cells of hematopoietic origin in local antigen presentation, whatever their Ly6C expression. Our work further provides a first transcriptomic study of MHC class II-expressing retinal cells during EAU and delivers a series of new candidate genes possibly implicated in the pathogenesis of retinal autoimmunity. PMID- 28720144 TI - Identifying predictors for postoperative clinical outcome in lumbar spinal stenosis patients using smart-shoe technology. AB - BACKGROUND: Approximately 33% of the patients with lumbar spinal stenosis (LSS) who undergo surgery are not satisfied with their postoperative clinical outcomes. Therefore, identifying predictors for postoperative outcome and groups of patients who will benefit from the surgical intervention is of significant clinical benefit. However, many of the studied predictors to date suffer from subjective recall bias, lack fine digital measures, and yield poor correlation to outcomes. METHODS: This study utilized smart-shoes to capture gait parameters extracted preoperatively during a 10 m self-paced walking test, which was hypothesized to provide objective, digital measurements regarding the level of gait impairment caused by LSS symptoms, with the goal of predicting postoperative outcomes in a cohort of LSS patients who received lumbar decompression and/or fusion surgery. The Oswestry Disability Index (ODI) and predominant pain level measured via the Visual Analogue Scale (VAS) were used as the postoperative clinical outcome variables. RESULTS: The gait parameters extracted from the smart shoes made statistically significant predictions of the postoperative improvement in ODI (RMSE =0.13, r=0.93, and p<3.92*10-7) and predominant pain level (RMSE =0.19, r=0.83, and p<1.28*10-4). Additionally, the gait parameters produced greater prediction accuracy compared to the clinical variables that had been previously investigated. CONCLUSIONS: The reported results herein support the hypothesis that the measurement of gait characteristics by our smart-shoe system can provide accurate predictions of the surgical outcomes, assisting clinicians in identifying which LSS patient population can benefit from the surgical intervention and optimize treatment strategies. PMID- 28720145 TI - Slipped capital femoral epiphysis: a population-based study. AB - BACKGROUND: Slipped capital femoral epiphysis (SCFE) is the most common hip disorder in children 9-15 years old. This is a population-based study in Sweden presenting the epidemiology for SCFE. METHODS: In a prospective cohort study, we analysed pre- and postoperative radiographs, medical records for all children treated for SCFE in Sweden 2007-2013, demographic data, severity of slip and surgical procedures performed. RESULTS: We identified 379 Swedish children with primary SCFE 2007-2013; 162 girls, median age 11.7 (7.2-15.4) years, and 217 boys, median age 13 (3.8-17.7) years. The average annual incidence was 4.4/10000 for girls and 5.7/10000 for boys 9-15 years old. Obesity or overweight was found in 56% of the girls and in 76% of the boys. As an initial symptom, 66% of the children had hip/groin pain and 12% knee pain. At first presentation, 7% of the children had bilateral SCFE. Prophylactic fixation was performed in 43%. Of the remaining children, 21% later developed a contralateral slip. Fixation with implants permitting further growth was used in >90% of the children. Femoral neck osteotomy was performed for 11 hips. CONCLUSIONS: The annual average incidence 2007-2013 in Sweden showed a mild increase for girls. The male-to-female ratio was lower than previous regional data from Sweden. Overweight or obesity is one major characteristic for boys with SCFE but to a less extent for girls. Knee pain as initial symptom cause a delay in diagnosis. Most hospitals in Sweden treat <2 children annually. PMID- 28720146 TI - Analysis of long term CD4+CD25highCD127- T-reg cells kinetics in peripheral blood of lung transplant recipients. AB - BACKGROUND: The role of CD4+CD25highCD127- T-reg cells in solid-organ Transplant (Tx) acceptance has been extensively studied. In previous studies on kidney and liver recipients, peripheral T-reg cell counts were associated to graft survival, while in lung Tx, there is limited evidence for similar findings. This study aims to analyze long term peripheral kinetics of T-reg-cells in a cohort of lung recipients and tests its association to several clinical variables. METHODS: From jan 2009 to dec 2014, 137 lung Tx recipients were submitted to an immunological follow up (median: 105.9 months (6.7-310.5)). Immunological follow up consisted of a complete blood peripheral immuno-phenotype, inclusive of CD4+CD25highCD127- T and FOXP3+ cells. We tested the association between T-reg and relevant variables by linear OR regression models for repeated measures, adjusting for time from Tx. Also, by ordered logistic models for panel data, the association between Chronic Lung Allograft Dysfuncton (CLAD) onset/progression and T-reg counts in the previous 3 months was tested. RESULTS: Among all variables analyzed at multivariate analysis: Bronchiolitis Obliterans Syndrome (OR -6.51, p < 0.001), Restrictive Allograft Syndrome (OR -5.19, p = 0.04) and Extracorporeal photopheresis (OR -5.65, p < 0.001) were significantly associated to T-reg cell. T-reg cell counts progressively decreased according to the severity of CLAD. Furthermore, patients with higher mean T-reg counts in a trimester had a significantly lower risk (OR 0.97, p = 0.012) of presenting CLAD or progressing in the graft dysfunction in the following trimester. CONCLUSIONS: Our present data confirm animal observations on the possible role of T-reg in the evolution of CLAD. PMID- 28720147 TI - Safety and immunogenicity of the quadrivalent human papillomavirus (qHPV) vaccine in HIV-positive Spanish men who have sex with men (MSM). AB - BACKGROUND: Safety and immunogenicity of the quadrivalent human papillomavirus (qHPV) vaccine were evaluated in HIV-positive Spanish MSM. The prevalence of High Squamous Intraepithelial Lesions (HSIL) and genotypes of high-risk human papillomavirus (HR-HPV) were also determined, as well as risk factors associated with the presence of HR-HPV in anal mucosa. METHODS: This is a randomised, double blind, placebo-controlled trial of the quadrivalent HPV (qHPV) vaccine. The study enrolled from May 2012 to May 2014. Vaccine and placebo were administered at 0, 2 and 6 months (V1, V2, V3 clinical visits). Vaccine antibody titres were evaluated at 7 months. Cytology (Thin Prep(r) Pap Test), HPV PCR genotyping (Linear Array HPV Genotyping Test), and high-resolution anoscopy (Zeiss 150 fc(c) colposcope) were performed at V1. RESULTS: Patients (n = 162; mean age 37.9 years) were screened for inclusion; 14.2% had HSIL, 73.1% HR-HPV and 4.5% simultaneous infection with HPV16 and 18. Study participants (n = 129) were randomized to qHPV vaccine or placebo. The most common adverse event was injection-site pain predominating in the placebo group [the first dose (83.6% vs. 56.1%; p = 0.0001]; the second dose (87.8% vs. 98.4%; p = 0.0001); the third dose (67.7% vs. 91.9%; p = 0.0001). The vaccine did not influence either the viral load of HIV or the levels of CD4. Of those vaccinated, 76% had antibodies to HPV vs. 30.2% of those receiving placebo (p = 0.0001). In the multivariate analysis, Older age was associated with lower HR-HPV infection (RR 0.97; 95% CI 0.96-0.99), and risk factor were viral load of HIV >200 copies/uL (RR 1.42 95% CI 1.17-1.73) and early commencement of sexual activity (RR 1.35; 95% CI 1.001-1.811). CONCLUSIONS: This trial showed significantly higher anti-HR-HPV antibody titres in vaccinated individuals than in unvaccinated controls. There were no serious adverse events attributable to the vaccine. In our cohort, 1 of every 7 patients had HSIL and the prevalence of combined infection by genotypes 16 and 18 was low. This suggests that patients could benefit from receiving qHPV vaccine. Older age was the main protective factor against HR-HPV infection, and non-suppressed HIV viremia was a risk factor. CLINICAL TRIAL REGISTRATION: ISRCTN14732216 ( http://www.isrctn.com/ISRCTN14732216 ). PMID- 28720150 TI - Metabotyping and its application in targeted nutrition: an overview. AB - Metabolic diversity leads to differences in nutrient requirements and responses to diet and medication between individuals. Using the concept of metabotyping - that is, grouping metabolically similar individuals - tailored and more efficient recommendations may be achieved. The aim of this study was to review the current literature on metabotyping and to explore its potential for better targeted dietary intervention in subjects with and without metabolic diseases. A comprehensive literature search was performed in PubMed, Google and Google Scholar to find relevant articles on metabotyping in humans including healthy individuals, population-based samples and patients with chronic metabolic diseases. A total of thirty-four research articles on human studies were identified, which established more homogeneous subgroups of individuals using statistical methods for analysing metabolic data. Differences between studies were found with respect to the samples/populations studied, the clustering variables used, the statistical methods applied and the metabotypes defined. According to the number and type of the selected clustering variables, the definitions of metabotypes differed substantially; they ranged between general fasting metabotypes, more specific fasting parameter subgroups like plasma lipoprotein or fatty acid clusters and response groups to defined meal challenges or dietary interventions. This demonstrates that the term 'metabotype' has a subjective usage, calling for a formalised definition. In conclusion, this literature review shows that metabotyping can help identify subgroups of individuals responding differently to defined nutritional interventions. Targeted recommendations may be given at such metabotype group levels. Future studies should develop and validate definitions of generally valid metabotypes by exploiting the increasingly available metabolomics data sets. PMID- 28720149 TI - Heparanase promotes neuroinflammatory response during subarachnoid hemorrhage in rats. AB - BACKGROUND: Heparanase, a mammalian endo-beta-D-glucoronidase that specifically degrades heparan sulfate, has been implicated in inflammation and ischemic stroke. However, the role of heparanase in neuroinflammatory response in subarachnoid hemorrhage (SAH) has not yet been investigated. This study was designed to examine the association between heparanase expression and neuroinflammation during subarachnoid hemorrhage. METHODS: Rats were subjected to SAH by endovascular perforation, and the expression of heparanase was determined by Western blot analysis and immunofluorescence in the ipsilateral brain cortex at 24 h post-SAH. Pial venule leukocyte trafficking was monitored by using intravital microscopy through cranial window. RESULTS: Our results indicated that, compared to their sham-surgical controls, the rats subjected to SAH showed marked elevation of heparanase expression in the ipsilateral brain cortex. The SAH-induced elevation of heparanase was accompanied by increased leukocyte trafficking in pial venules and significant neurological deficiency. Intracerebroventricular application of a selective heparanase inhibitor, OGT2115, which was initiated at 3 h after SAH, significantly suppressed the leukocyte trafficking and improved the neurological function. CONCLUSIONS: Our findings indicate that heparanase plays an important role in mediating the neuroinflammatory response after SAH and contributes to SAH-related neurological deficits and early brain injury following SAH. PMID- 28720148 TI - Multifocal gastric adenocarcinoma in a patient with LRBA deficiency. AB - BACKGROUND: Lipopolysaccharide-responsive, beige-like anchor protein (LRBA) deficiency is characterized by primary immunodeficiency and autoimmunity. Cancer may present another feature of LRBA deficiency. We describe a case history of a young adult with LRBA deficiency and two independent malignancies. METHODS: Family-trio whole exome sequencing with unbiased phenotype ontology approach was used for identification of causative mutations of a primary immune deficiency disorder. Additionally, we sought to identify germline mutations in genes known to be associated with two independent malignancies using a targeted approach. A cytotoxic T-lymphocyte associated protein 4 (CTLA4) expression in T lymphocytes was determined by flow cytometry. RESULTS: In the patient with clinical signs of LRBA deficiency multifocal gastric carcinoma and malignant melanoma were diagnosed and surgically treated at 19 and 27 years of age, respectively. Despite refusal of any adjuvant chemotherapy or radiotherapy, the patient demonstrated disease free survival for at least 13 years after the first cancer diagnosis. A homozygous frameshift deletion in LRBA gene (p.Glu946Ter) and two common variants in TYR gene were identified. Reduced CTLA4 expression in a subset of regulatory T lymphocytes was identified in the patient and his unaffected mother carrying a heterozygous LRBA mutation as compared to control in a dose-dependent manner. CONCLUSION: This is the first description of gastric cancer and malignant melanoma in a young adult with LRBA deficiency. The role of LRBA gene knockout in cancer development and its prognosis remains to be elucidated. PMID- 28720151 TI - Supplementation with Lactobacillus paracasei or Pediococcus pentosaceus does not prevent diarrhoea in neonatal pigs infected with Escherichia coli F18. AB - Infectious diarrhoea is a worldwide problem in newborns. Optimal bacterial colonisation may enhance gut maturation and protect against pathogenic bacteria after birth. We hypothesised that lactic acid bacteria (LAB) administration prevents pathogen-induced diarrhoea in formula-fed newborns. Newborn caesarean delivered, colostrum-deprived term piglets on parenteral nutrition for the first 15 h, were used as models for sensitive newborn infants. A commercially available probiotic strain, Lactobacillus paracasei F19 (LAP, 2.6*108 colony-forming units (CFU)/kg per d) and a novel LAB isolate, Pediococcus pentosaceus (PEP, 1.3*1010 CFU/kg per d), were administered for 5 d with or without inoculation of the porcine pathogen, Escherichia coli F18 (F18, 1010 CFU/d). This resulted in six treatment groups: Controls (n 9), LAP (n 10), PEP (n 10), F18 (n 10), F18-LAP (n 10) and F18-PEP (n 10). The pathogen challenge increased diarrhoea and density of F18 in the intestinal mucosa (P<0.05). LAB supplementation further increased the diarrhoea score, relative to F18 alone (P<0.01). Intestinal structure and permeability were similar among groups, whereas brush border enzymes were affected in variable intestinal regions with decreased activities in most cases after F18 and LAB inoculation. Bacterial density in colon mucosa increased after F18 inoculation (P<0.05) but was unaffected by LAB supplementation. In colon contents, acetic and butyric acids were increased by PEP (P<0.05). The LAB used in this study failed to reduce E. coli-induced diarrhoea in sensitive newborn pigs. In vulnerable newborns there may be a delicate balance among bacterial composition and load, diet and the host. Caution may be required when administering LAB to compromised newborns suffering from enteric infections. PMID- 28720152 TI - USING COUPLES' DISCORDANT REPORTS TO ESTIMATE FEMALE COVERT USE OF MODERN CONTRACEPTION IN SUB-SAHARAN AFRICA. AB - SummarySubstantial numbers of married women use contraceptives without their partner's knowledge in sub-Saharan Africa, but studies of female covert use across time are rare. This study investigates the levels, trends and correlates of covert use in nine countries and determines which contraceptive methods are more frequently used covertly by women. Data from monogamous couples in Demographic and Health Surveys were used from nine sub-Saharan African countries that had experienced an increase of 10 percentage points in current modern contraceptive use between an earlier (1991-2004) and later (2007-2011) survey. Covert use was indirectly estimated as the percentage of women who reported a female modern method whose husband did not report a modern method. The percentage of women using covertly increased in eight of the countries studied (significantly in three of them), yet when comparing across countries cross sectionally, covert use was lower where contraceptive prevalence was higher. In general, women with more years of schooling and those with larger spousal schooling gaps had lower odds of covert use. There was no significant difference between covert and open injectable use, though more than half of both groups used this method in the later surveys. Encouraging couple communication about contraception, where the woman feels it is safe to do so, could be an important strategy to minimize covert use. Further research is needed to better identify the contraceptive prevalence and social context in which covert use declines within a country. PMID- 28720153 TI - Molecular characterization of Moniezia sichuanensis in captive musk deer (Moschus berezovskii). AB - The musk deer (Moschus berezovskii) is an economically important species from which musk is extracted and used in perfumes and medicines. Cestodes (parasitic flatworms) of the genus Moniezia are important parasites that infect this endangered species and can cause high mortality in young deer. In 1982, Moniezia (S.) sichuanensis sp. nov. was described from a specimen obtained from wild musk deer. The new species was distinct from the other described species of Moniezia by the sawtooth-shaped interproglottidal glands, the thick vagina and the absence of a cirrus spine. In the present study, 12 cestodes collected from musk deer were examined morphologically and confirmed to be M. sichuanensis. Molecular characterization was performed by amplifying and comparing the internal transcribed spacer 1 (ITS1) and 5.8S rRNA gene (ITS1-5.8S) of ribosomal DNA with available sequences from other Moniezia species. The amplified sequences ranged from 761 to 764 bp and similarity ranged from 98.7-100%, compared to 67.8-92.4% with other Moniezia spp. Construction of a phylogenetic tree using the neighbour joining method indicated that all 12 ITS1-5.8S sequences formed a single clade, confirming M. sichuanensis as a separate species. This study provides novel molecular insight into M. sichuanensis that could prove useful for future diagnosis and control of monieziasis in musk deer. PMID- 28720154 TI - Human papillomavirus tumour status is not associated with a positive depression screen for patients with oropharyngeal cancer. AB - BACKGROUND: Several risk factors for depression in patients with oropharyngeal cancer have been determined. However, it is unknown whether human papillomavirus associated oropharyngeal cancer, which has a distinct clinico-demographic profile, modulates this risk. METHODS: A retrospective analysis was conducted of patients with oropharyngeal cancer. These patients had completed a 10-item depression screening questionnaire before receiving treatment for their disease from 2011 to 2014. Associations between patient or disease characteristics and depression screening questionnaire results were investigated. RESULTS: The study comprised 69 patients, 31 (44.9 per cent) of whom screened positive for depression. There were no significant differences in distributions of clinico demographic or histopathological characteristics, including human papillomavirus tumour status, by depression screen result. CONCLUSION: This population has a high risk for depression, but no obvious risk factors, including human papillomavirus tumour status, were associated with an elevated risk. This inability to risk-stratify patients by clinico-demographic or disease characteristics emphasises the importance of regular depression screening for all patients in this population. PMID- 28720155 TI - Effect of slaughter age and feeding system on the neutral and polar lipid composition of horse meat. AB - This study was undertaken to provide a thorough analysis of the neutral lipid (NL) and polar lipid (PL) fractions of horse meat that included the content and distribution of acyl and alkenyl moieties in foals under different rearing conditions. Two groups of crossbred horses were studied; the first group was selected from suckling foals produced under grazing conditions and slaughtered at 4 months of age (n=8), and the second group was selected from concentrate finished foals and slaughtered at 12 months of age (n=7). There were significant differences related to the age and feeding practices of foals which affected the intramuscular (IM) fat content and the fatty acid (FA) composition of NL and PL fractions. Samples from suckling foals were leaner and provided the highest content of methylation products from the plasmalogenic lipids, and total and n-3 polyunsaturated fatty acid (PUFA). By contrast, the meat from concentrate finished foals had a higher IM fat level resulting in a greater accumulation of 16:0 and total monounsaturated FAs in the NL fraction, whereas the muscle PL fraction retained a similar FA composition between both groups. Linolenic acid was preferentially deposited in the NL fraction, but linoleic acid and the long chain n-3 and n-6 PUFAs were incorporated into the PL fraction where they served as cell membrane constituents and in eicosanoid formation. PMID- 28720157 TI - The influence of azaperone treatment at weaning on reproductive performance of sows: altering effects of season and parity. AB - Azaperone treatment can control aggression and decrease stress due to weaning, re grouping and hierarchical fighting of gilts and sows. However, the effects of this butyrophenone neuroleptic and sedative administered at weaning on pig reproductive function are poorly characterized. In this year-long study, a total of 619 cross-bred sows (Polish Large White*Polish Landrace) kept on a commercial farm received an i.m. injection of azaperone (Stresnil(r); 2 mg/kg BW) just before weaning and were artificially inseminated during the ensuing estrus with 3*109 spermatozoa per dose of an inseminate; 1180 sows served as untreated controls. Immediately after weaning, the sows were moved to four pens of seven to nine animals each. A teaser boar was used twice daily to check for estrus and sows were bred at heat detection. Subsequently, all sows stayed in individual stalls until pregnancy testing on day 30 post-artificial insemination and were then re-grouped until farrowing. The proportion of pigs that were in estrus within 6 days post-weaning was significantly lower in azaperone-treated groups of animals than in controls (71.4% v. 84.2%). Overall, the azaperone-treated sows had a significantly longer weaning-to-estrus interval (WEI; 8.7+/-10.1 v. 6.3+/ 8.1 days; mean+/-SD) and a significantly larger litter size (LS: 11.8+/-3.0 v.11.3+/-3.2; azaperone-treated v. control sows). Treatment of the winter farrowing sows was associated with increased LS (12.8+/-2.6 and 11.3+/-3.1 piglets/sow, respectively; P<0.05) and longer (P<0.05) weaning-to-effective service intervals (11.7+/-19.3 and 8.4+/-12.3 days, respectively) as well as farrowing intervals (155.7+/-19.7 and 152.2+/-16.1 days, respectively) compared with untreated controls. In the summer months, significantly longer WEIs (12.1+/ 21.0 v. 8.4+/-16.9 days) were accompanied by a significant decline in LS only in azaperone-treated sows that were inseminated within 6 days post-weaning (10.8+/ 2.9 v. 11.5+/-3.3 piglets/sow; azaperone-treated v. controls). Azaperone-treated second parity sows had greater LS (P<0.001) along with prolonged WEIs (P<0.05) in comparison to their respective controls, regardless of the timing of estrus. An application of azaperone at weaning increased the annual piglet productivity of winter-farrowing animals and of second parity sows but depressed it significantly in summer. The extra cost and labor due to delayed onset of estrus may cancel out any reproductive benefits of azaperone treatment. PMID- 28720156 TI - FMR1 CGG repeat expansion mutation detection and linked haplotype analysis for reliable and accurate preimplantation genetic diagnosis of fragile X syndrome. AB - Fragile X mental retardation 1 (FMR1) full-mutation expansion causes fragile X syndrome. Trans-generational fragile X syndrome transmission can be avoided by preimplantation genetic diagnosis (PGD). We describe a robust PGD strategy that can be applied to virtually any couple at risk of transmitting fragile X syndrome. This novel strategy utilises whole-genome amplification, followed by triplet-primed polymerase chain reaction (TP-PCR) for robust detection of expanded FMR1 alleles, in parallel with linked multi-marker haplotype analysis of 13 highly polymorphic microsatellite markers located within 1 Mb of the FMR1 CGG repeat, and the AMELX/Y dimorphism for gender identification. The assay was optimised and validated on single lymphoblasts isolated from fragile X reference cell lines, and applied to a simulated PGD case and a clinical in vitro fertilisation (IVF)-PGD case. In the simulated PGD case, definitive diagnosis of the expected results was achieved for all 'embryos'. In the clinical IVF-PGD case, delivery of a healthy baby girl was achieved after transfer of an expansion negative blastocyst. FMR1 TP-PCR reliably detects presence of expansion mutations and obviates reliance on informative normal alleles for determining expansion status in female embryos. Together with multi-marker haplotyping and gender determination, misdiagnosis and diagnostic ambiguity due to allele dropout is minimised, and couple-specific assay customisation can be avoided. PMID- 28720158 TI - Costs and quality of life in community-dwelling patients with Alzheimer's disease in Spain: results from the GERAS II observational study. AB - BACKGROUND: Country-specific data on resource use and costs associated with Alzheimer's disease (AD) help inform governments about the increasing need for medical and financial support as the disease increases in prevalence. METHODS: GERAS II, a prospective observational study, assessed resource use, costs, and health-related quality of life (HRQoL) among patients with AD and their caregivers in Spain. Community-dwelling patients aged >=55 years with probable AD, and their primary caregivers, were recruited by study investigators during routine clinical practice and assessed as having mild, moderate, or moderately severe/severe (MS/S) AD dementia based on patient Mini-Mental State Examination scores. Costs of AD were calculated by applying costs to resource-use data obtained in caregiver interviews using the Resource Utilization in Dementia instrument. Total societal costs included patients' health and social care costs and caregiver informal care costs. Baseline results are presented. RESULTS: Total mean monthly societal costs/patient (2013 values) were ?1514 for mild (n = 116), ?2082 for moderate (n = 118), and ?2818 for MS/S AD dementia (n = 146) (p value <0.001 between groups). Caregiver informal care costs comprised most of the total societal costs and differed significantly between groups (?1050, ?1239, ?1580, respectively; p value = 0.013), whereas patient healthcare costs did not. Across AD dementia severity groups, patient HRQoL (measured by proxy) decreased significantly (p value <0.001), caregiver subjective burden significantly increased (p value <0.001) and caregiver HRQoL was similar. CONCLUSIONS: Societal costs associated with AD in Spain were largely attributable to caregiver informal care costs and increased with increasing AD dementia severity. PMID- 28720159 TI - Carbapenem-Resistant Enterobacteriaceae: A Strategic Roadmap for Infection Control-CORRIGENDUM. PMID- 28720160 TI - The incidence of health financing in South Africa: findings from a recent data set. AB - There is an international call for countries to ensure universal health coverage. This call has been embraced in South Africa (SA) in the form of a National Health Insurance (NHI). This is expected to be financed through general tax revenue with the possibility of additional earmarked taxes including a surcharge on personal income and/or a payroll tax for employers. Currently, health services are financed in SA through allocations from general tax revenue, direct out-of-pocket payments, and contributions to medical scheme. This paper uses the most recent data set to assess the progressivity of each health financing mechanism and overall financing system in SA. Applying standard and innovative methodologies for assessing progressivity, the study finds that general taxes and medical scheme contributions remain progressive, and direct out-of-pocket payments and indirect taxes are regressive. However, private health insurance contributions, across only the insured, are regressive. The policy implications of these findings are discussed in the context of the NHI. PMID- 28720161 TI - Validity of the American College of Surgeons' National Surgical Quality Improvement Program risk calculator in South Australian glossectomy patients. AB - BACKGROUND: Appropriate selection of tongue cancer patients considering surgery is critical in ensuring optimal outcomes. The American College of Surgeons' National Surgical Quality Improvement Program ('ACS-NSQIP') risk calculator was developed to assess patients' 30-day post-operative risk, providing surgeons with information to guide decision making. METHOD: A retrospective review of 30-day actual mortality and morbidity of tongue cancer patients was undertaken to investigate the validity of this tool for South Australian patients treated from 2005 to 2015. RESULTS: One hundred and twenty patients had undergone glossectomy. Predicted length of stay using the risk calculator was significantly different from actual length of stay. Predicted mortality and other complications were found to be similar to actual outcomes. CONCLUSION: The American College of Surgeons' National Surgical Quality Improvement Program risk calculator was found to be effective in predicting post-operative complication rates in South Australian tongue cancer patients. However, significant discrepancies in predicted and actual length of stay may limit its use in this population. PMID- 28720162 TI - Maternal pregnancy C-reactive protein predicts offspring birth size and body composition in metropolitan Cebu, Philippines. AB - The gestational milieu is an important influence on fetal development and long term disease risk. Here we assess relationships between maternal pregnancy inflammation, indicated by C-reactive protein (CRP), and offspring anthropometric outcomes measured soon after birth. Data come from female participants (n=327, age 24.4-30.2 years) in a longitudinal study located in Metropolitan Cebu, Philippines. Between 2009 and 2014, pregnancy interviews (n=429) were conducted during which questionnaire and anthropometric data were obtained along with dried blood spot cards for CRP measurement. Offspring body weight, length, head circumference and five skinfold thickness measures were obtained soon after birth. Maternal pregnancy CRP was borderline (-1.11+/-0.64 days/log-mg/l; P<0.1) inversely related to gestational age at delivery, but did not increase the likelihood of preterm delivery. After adjusting for maternal pre-pregnancy body mass index, height, pregnancy adiposity, age, parity and other covariates, CRP was significantly, inversely related to offspring body weight (-0.047+/-0.017 kg/log-mg/l), length (-0.259+/-0.092 cm/log-mg/l) and sum of skinfolds (-0.520+/ 0.190 mm/log-mg/l) (all P<0.05), and borderline inversely related to offspring head circumference (-0.102+/-0.068 cm/log-mg/l; P<0.1). Notably, relationships were continuous across the full CRP range, and not limited to unusually high levels of inflammation. These findings point to an important role of maternal non specific immune activation as a predictor of offspring birth outcomes. In light of evidence that early life microbial, nutritional and stress experiences influence adult inflammatory regulation, these findings point to inflammation as a potential pathway for the intergenerational transmission of maternal experience to offspring health. PMID- 28720163 TI - Transferrin saturation concentrations associated with telomeric ageing: a population-based study. AB - There are limited data on the association between Fe overload and leucocyte telomere length (LTL), known as a useful biomarker of the replicative ageing of cells. The aim of the study was to evaluate associations between Fe-status biomarkers and LTL. A cross-sectional study included 1174 men and women aged 50 79 years who provided blood samples for assays of Fe-status biomarkers including ferritin, transferrin saturation (TSAT), total Fe-binding capacity (TIBC) and relative LTL. They were free of hepatitis, potential infection or Fe deficiency. In multiple linear regression analysis adjusted for potential confounding variables, log-transformed LTL was positively associated with TIBC (adjusted coefficient estimate for its highest quartile: 0.17 (se 0.03), P45 %) but also with high-normal concentrations (35-45 %) of TSAT had shorter LTL compared with those with low-normal concentrations (<30 %) (P<0.05). We also observed that less active or obese persons with high TSAT concentrations had shorter LTL than others. Our findings that cellular ageing is influenced not only by Fe overload but also by high-normal concentrations of TSAT support the hypothesis regarding the detrimental effects of labile Fe, which has a potent pro-oxidant activity in the body. PMID- 28720164 TI - The detection, diagnosis, and impact of cognitive impairment among inpatients aged 65 years and over in an Irish general hospital - a prospective observational study. AB - BACKGROUND: The diagnosis of dementia remains inadequate, even within clinical settings. Data on rates and degree of impairment among inpatients are vital for service planning and the provision of appropriate patient care as Ireland's population ages. METHODS: Every patient aged 65 years and over admitted over a two-week period was invited to participate. Those who met inclusion criteria were screened for delirium then underwent cognitive screening. Demographic, functional, and outcome data were obtained from medical records, participants, and family. RESULTS: Consent to participate was obtained from 68.6% of the eligible population. Data for 143 patients were obtained. Mean age 78.1 years. 27.3% met criteria for dementia and 21% had mild cognitive impairment (MCI). Only 41% of those with dementia and 10% of those with MCI had a previously documented impairment. Between-group analysis showed differences in length of stay (p = 0.003), number of readmissions in 12 months (p = 0.036), and likelihood of returning home (p = 0.039) between the dementia and normal groups. MCI outcomes were similar to the normal group. No difference was seen for one-year mortality. Effects were less pronounced on multivariate analysis but continued to show a significant effect on length of stay even after controlling for demographics, personal and family history, and anxiety and depression screening scores. Patients with dementia remained in hospital 15.3 days longer (p = 0.047). A diagnosis is the single biggest contributing factor to length of stay in our regression model. CONCLUSIONS: Cognitive impairment is pervasive and under recognized in the acute hospital and impacts negatively on patient outcomes. PMID- 28720166 TI - Trigeminal Neuralgia and Multiple Sclerosis: A Historical Perspective. AB - Trigeminal neuralgia (TN) associated with multiple sclerosis (MS) was first described in Lehrbuch der Nervenkrankheiten fur Arzte und Studirende in 1894 by Hermann Oppenheim, including a pathologic description of trigeminal root entry zone demyelination. Early English-language translations in 1900 and 1904 did not so explicitly state this association compared with the German editions. The 1911 English-language translation described a more direct association. Other later descriptions were clinical with few pathologic reports, often referencing Oppenheim but citing the 1905 German or 1911 English editions of Lehrbuch. This discrepancy in part may be due to the translation differences of the original text. PMID- 28720165 TI - BDNF Val66Met in preclinical Alzheimer's disease is associated with short-term changes in episodic memory and hippocampal volume but not serum mBDNF. AB - BACKGROUND: The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism Met allele exacerbates amyloid (Abeta) related decline in episodic memory (EM) and hippocampal volume (HV) over 36-54 months in preclinical Alzheimer's disease (AD). However, the extent to which Abeta+ and BDNF Val66Met is related to circulating markers of BDNF (e.g. serum) is unknown. We aimed to determine the effect of Abeta and the BDNF Val66Met polymorphism on levels of serum mBDNF, EM, and HV at baseline and over 18-months. METHODS: Non-demented older adults (n = 446) underwent Abeta neuroimaging and BDNF Val66Met genotyping. EM and HV were assessed at baseline and 18 months later. Fasted blood samples were obtained from each participant at baseline and at 18-month follow-up. Abeta PET neuroimaging was used to classify participants as Abeta- or Abeta+. RESULTS: At baseline, Abeta+ adults showed worse EM impairment and lower serum mBDNF levels relative to Abeta- adults. BDNF Val66Met polymorphism did not affect serum mBDNF, EM, or HV at baseline. When considered over 18-months, compared to Abeta- Val homozygotes, Abeta+ Val homozygotes showed significant decline in EM and HV but not serum mBDNF. Similarly, compared to Abeta+ Val homozygotes, Abeta+ Met carriers showed significant decline in EM and HV over 18-months but showed no change in serum mBDNF. CONCLUSION: While allelic variation in BDNF Val66Met may influence Abeta+ related neurodegeneration and memory loss over the short term, this is not related to serum mBDNF. Longer follow-up intervals may be required to further determine any relationships between serum mBDNF, EM, and HV in preclinical AD. PMID- 28720168 TI - Infant statistical-learning ability is related to real-time language processing. AB - Infants are adept at learning statistical regularities in artificial language materials, suggesting that the ability to learn statistical structure may support language development. Indeed, infants who perform better on statistical learning tasks tend to be more advanced in parental reports of infants' language skills. Work with adults suggests that one way statistical learning ability affects language proficiency is by facilitating real-time language processing. Here we tested whether 15-month-olds' ability to learn sequential statistical structure in artificial language materials is related to their ability to encode and interpret native-language speech. Specifically, we tested their ability to learn sequential structure among syllables (Experiment 1) and words (Experiment 2), as well as their ability to encode familiar English words in sentences. The results suggest that infants' ability to learn sequential structure among syllables is related to their lexical-processing efficiency, providing continuity with findings from children and adults, though effects were modest. PMID- 28720169 TI - Characteristics of Healthy Older Adults that Influence Self-rated Cognitive Function. AB - OBJECTIVES: We sought to clarify the nature of self-reported cognitive function among healthy older adults by considering the short-term, within-person association (coupling) of subjective cognitive function with objective cognitive performance. We expected this within-person coupling to differ between persons as a function of self-perceived global cognitive decline and depression, anxiety, or neuroticism. METHODS: This was an intensive measurement (short-term longitudinal) study of 29 older adult volunteers between the ages of 65 and 80 years without an existing diagnosis of dementia or mild cognitive impairment. Baseline assessment included neuropsychological testing and self-reported depression, anxiety, and neuroticism, as well as self- and informant-reported cognitive decline (relative to 10 years previously). Intensive within-person measurement occasions included subjective ratings of cognitive function paired with performance on a computerized working memory (n-back) task; each participant attended four or five assessments separated by intervals of at least one day. Statistical analysis was comprised of multilevel linear regression. RESULTS: Comparison of models suggested that both neuroticism and self-rated cognitive decline explained unique variance in the within-person, across-occasion coupling of subjective cognitive function with objective working memory performance. CONCLUSIONS: Self-ratings of cognition may accurately reflect day-to-day variations in objective cognitive performance among older adults, especially for individuals lower in neuroticism and higher in self-reported cognitive decline. Clinicians should consider these individual differences when determining the validity of complaints about perceived cognitive declines in the context of otherwise healthy aging. (JINS, 2018, 24, 57-66). PMID- 28720167 TI - Recovery from DSM-IV post-traumatic stress disorder in the WHO World Mental Health surveys. AB - BACKGROUND: Research on post-traumatic stress disorder (PTSD) course finds a substantial proportion of cases remit within 6 months, a majority within 2 years, and a substantial minority persists for many years. Results are inconsistent about pre-trauma predictors. METHODS: The WHO World Mental Health surveys assessed lifetime DSM-IV PTSD presence-course after one randomly-selected trauma, allowing retrospective estimates of PTSD duration. Prior traumas, childhood adversities (CAs), and other lifetime DSM-IV mental disorders were examined as predictors using discrete-time person-month survival analysis among the 1575 respondents with lifetime PTSD. RESULTS: 20%, 27%, and 50% of cases recovered within 3, 6, and 24 months and 77% within 10 years (the longest duration allowing stable estimates). Time-related recall bias was found largely for recoveries after 24 months. Recovery was weakly related to most trauma types other than very low [odds-ratio (OR) 0.2-0.3] early-recovery (within 24 months) associated with purposefully injuring/torturing/killing and witnessing atrocities and very low later-recovery (25+ months) associated with being kidnapped. The significant ORs for prior traumas, CAs, and mental disorders were generally inconsistent between early- and later-recovery models. Cross-validated versions of final models nonetheless discriminated significantly between the 50% of respondents with highest and lowest predicted probabilities of both early-recovery (66-55% v. 43%) and later-recovery (75-68% v. 39%). CONCLUSIONS: We found PTSD recovery trajectories similar to those in previous studies. The weak associations of pre trauma factors with recovery, also consistent with previous studies, presumably are due to stronger influences of post-trauma factors. PMID- 28720170 TI - A DECADE OF HEALTH TECHNOLOGY ASSESSMENT IN POLAND. AB - OBJECTIVES: The objective of this study is to illustrate and provide a better understanding of the role of health technology assessment (HTA) processes in decision making for drug reimbursement in Poland and how this approach could be considered by other countries of limited resources. METHODS: We analyzed the evolution of the HTA system and processes in Poland over the past decade and current developments based on publicly available information. RESULTS: The role of HTA in drug-reimbursement process in Poland has increased substantially over the recent decade, starting in 2005 with the formation the Agency for Health Technology Assessment and Tariff System (AOTMiT). The key success factors in this development were effective capacity building based on the use of international expertise, the implementation of transparent criteria into the drug reimbursement processes, and the selective approach to the adoption of innovative medicines based on the cost-effectiveness threshold among other criteria. CONCLUSIONS: While Poland is regarded as a leader in Central and Eastern Europe, there is room for improvement, especially with regard to the quality of HTA processes and the consistency of HTA guidelines with reimbursement law. In the "pragmatic" HTA model use by AOTMiT, the pharmaceutical company is responsible for the preparation of a reimbursement dossier of good quality in line with HTA guidelines while the assessment team in AOTMiT is responsible for critical review of that dossier. Adoption of this model may be considered by other countries with limited resources to balance differing priorities and ensure transparent and objective access to medicines for patients who need them. PMID- 28720172 TI - Comparative Validation of the Determination of Sofosbuvir in Pharmaceuticals by Several Inexpensive Ecofriendly Chromatographic, Electrophoretic, and Spectrophotometric Methods. AB - Sofosbuvir (SOFO) was approved by the U.S. Food and Drug Administration in 2013 for the treatment of hepatitis C virus infection with enhanced antiviral potency compared with earlier analogs. Notwithstanding, all current editions of the pharmacopeias still do not present any analytical methods for the quantification of SOFO. Thus, rapid, simple, and ecofriendly methods for the routine analysis of commercial formulations of SOFO are desirable. In this study, five accurate methods for the determination of SOFO in pharmaceutical tablets were developed and validated. These methods include HPLC, capillary zone electrophoresis, HPTLC, and UV spectrophotometric and derivative spectrometry methods. The proposed methods proved to be rapid, simple, sensitive, selective, and accurate analytical procedures that were suitable for the reliable determination of SOFO in pharmaceutical tablets. An analysis of variance test with P-value > 0.05 confirmed that there were no significant differences between the proposed assays. Thus, any of these methods can be used for the routine analysis of SOFO in commercial tablets. PMID- 28720171 TI - PacBio assembly of a Plasmodium knowlesi genome sequence with Hi-C correction and manual annotation of the SICAvar gene family. AB - Plasmodium knowlesi has risen in importance as a zoonotic parasite that has been causing regular episodes of malaria throughout South East Asia. The P. knowlesi genome sequence generated in 2008 highlighted and confirmed many similarities and differences in Plasmodium species, including a global view of several multigene families, such as the large SICAvar multigene family encoding the variant antigens known as the schizont-infected cell agglutination proteins. However, repetitive DNA sequences are the bane of any genome project, and this and other Plasmodium genome projects have not been immune to the gaps, rearrangements and other pitfalls created by these genomic features. Today, long-read PacBio and chromatin conformation technologies are overcoming such obstacles. Here, based on the use of these technologies, we present a highly refined de novo P. knowlesi genome sequence of the Pk1(A+) clone. This sequence and annotation, referred to as the 'MaHPIC Pk genome sequence', includes manual annotation of the SICAvar gene family with 136 full-length members categorized as type I or II. This sequence provides a framework that will permit a better understanding of the SICAvar repertoire, selective pressures acting on this gene family and mechanisms of antigenic variation in this species and other pathogens. PMID- 28720173 TI - Simultaneous Determination of First-Line 4-FDC Antituberculosis Drugs by UHPLC-UV and HPLC-UV: A Comparative Study. AB - Tuberculosis is the second most deadly infectious disease, surpassed only by HIV/AIDS, and has resulted in over 1 billion deaths in the last 200 years. The World Health Organization estimates that in 2014, 9.6 million people were infected by this disease and 1.5 million had died. First-choice treatment consists of fixed-dose combination tablets containing rifampicin, isoniazid, pyrazinamide, and ethambutol hydrochloride (4-FDC). There are pharmacopeial protocols available to test 4-FDC, but they are prolonged, two-step methods. One single-step method in the literature performs the simultaneous determination by HPLC, but requires a long acquisition time. In this context, an ultra-HPLC (UHPLC) method was developed based on the HPLC method with the objective of reducing analysis time. A C18 column (1.9 um particle size) was used with UV diode-array detection at 238 and 282 nm. The method was found to be selective, linear, exact, precise, and robust. Samples from two batches were analyzed and the results compared with those obtained by the HPLC method, with no statistically significant differences observed (P > 0.05). This UHPLC method reduced the analysis time from 17 to 4 min, with a more than 90% reduction in sample and reagent consumption and a financial economy of almost 50-fold. PMID- 28720174 TI - Selective Determination of Human Growth Hormone (Somatropin) in the Presence of Its Chemical Degradation Products. AB - A rapid and sensitive HPLC method was developed and validated for selective determination of the human growth hormone (hGH) somatropin in the presence of its deamidated and oxidized degradation products. Reversed-phase chromatography with an acetonitrile and ammonium bicarbonate mobile phase in gradient elution mode was used. A short run time of 15 min allowed rapid and cost-effective analysis, with an average retention time of 7.4 min for native hGH, 6.2 min for its deamidated form, and 4.3 and 6 min for its oxidized variants. The method was validated for selectivity, linearity, and intra- and interday variations according to International Conference on Harmonization guidelines. The proposed method was successfully applied for rapid evaluation of the quantity of hGH during downstream processing, formulation, and storage. PMID- 28720175 TI - Development of a Method for Determination of Buckwheat Allergens Using Liquid Chromatography with Tandem Mass Spectrometry. AB - An analysis technique using LC with tandem MS (MS/MS) has been developed for the determination of buckwheat proteins, including major allergens. A protein solution extracted from buckwheat was reduced, alkylated, and digested by trypsin. Peptide spectra were obtained using full-scan LC-MS/MS analysis, and peptide sequences were determined through a protein search. Nine peptides of the 13S globulin seed storage protein and one peptide of a 16 kDa allergen were selected as the marker peptides, and multiple reaction monitoring conditions were optimized. Using the conditions, different kinds of buckwheat noodles, powders, and other food ingredients were analyzed. As a result, buckwheat samples present all the fragment peaks, whereas other foods, including Sesamum indicum, wheat, and soybeans, are not detected at all. These findings indicate that LC-MS/MS analysis may be applied to the detection of buckwheat food allergens. PMID- 28720176 TI - Determination of Polycyclic Aromatic Hydrocarbons in Commercial Parenteral Formulations and Medications Using High-Performance Liquid Chromatography with Diode Array Detection. AB - HPLC coupled to UV diode array detection (DAD) is proposed for the determination of polycyclic aromatic hydrocarbons (PAHs) in pharmaceutical products for parenteral administration. Because rubber is a possible source of PAHs for these products, samples stored in containers with rubber parts were selected for the analysis. The basis for method optimization was EPA Method 8310, which determines 16 priority PAHs in ground water and wastewater by HPLC using both UV and fluorescence detection. Using DAD, two channels were selected for detection, with one operating at 254 nm for the detection of nine PAHs and the other at 225 nm for the detection of seven PAHs. This method allowed for the detection of PAHs using external calibration with LODs and LOQs ranging from 0.001 to 0.060 ug/mL and from 0.003 to 0.167 ug/mL, respectively. Within-day precision, expressed as RSD, varied from 1.24 to 7.76% for PAH concentrations from 0.05 to 0.50 ug/mL, and intraday precision varied from 3.10 to 9.40% for the same concentration range. Method accuracy was confirmed by recoveries of 75-120% of the spiked samples. This method was applied for the determination of PAHs in three commercial infusion solutions and in nine different medications stored in syringes prior to administration to patients. Twelve of 16 PAHs were found in these samples. Total PAH concentrations varied from 0.13 to 13.50 ug/mL. Pyrene was the most prevalent contaminant, being present in 11 of 12 samples in concentrations ranging from 0.17 to 4.80 ug/mL. This method presented good sensitivity for the measurement of PAH in the target samples, allowing for the determination of the 16 priority PAHs in one run and in 30 min. PMID- 28720177 TI - Validation of Multiresidue Method for Analysis of 31 Pesticides in Rice Using Gas Chromatography-Tandem Mass Spectrometry. AB - Five modified QuEChERS were tested for the multiresidue analysis of 31 pesticides in rice. Rice was spiked with mixture solution of pesticides at 10 ng/g. Method selection was based on the LODs (sensitivity) and recovery tests (accuracy) of the pesticides. Analysis was done in GC-tandem MS in multiple reaction monitoring mode with a total run time of approximately 37 min. The selected method was validated after spiking rice at 20 and 100 ng/g in rice. The performance characteristics of the method impacted for all selected pesticides were acceptable according to the guidelines for method validation (recovery of 70-120% with an RSD of <20% and r2 value of >=0.99). For rice, matrix effect on the signals of the compounds was corrected by using matrix-matched calibration standards. The LOQs met the requirements of the maximum residue limits for pesticides in rice. The developed method allowed for the simultaneous determination and confirmation of a large number of different groups of pesticides and was fast, simple, inexpensive, and useful for the routine analysis of rice. PMID- 28720178 TI - Creating Best Practices for the Submission of Actionable Food and Feed Testing Data Generated in State and Local Laboratories. AB - Laboratory accreditation provides a level of standardization in laboratories and confidence in generated food and feed testing results. For some laboratories, ISO/IEC 17025:2005 accreditation may not be fiscally viable, or a requested test method may be out of the scope of the laboratory's accreditation. To assist laboratories for whom accreditation is not feasible, the Association of Public Health Laboratories Data Acceptance Work Group developed a white paper entitled "Best Practices for Submission of Actionable Food and Feed Testing Data Generated in State and Local Laboratories." The basic elements of a quality management system, along with other best practices that state and local food and feed testing laboratories should follow, are included in the white paper. It also covers program-specific requirements that may need to be addressed. Communication with programs and end data users is regarded as essential for establishing the reliability and accuracy of laboratory data. Following these suggested best practices can facilitate the acceptance of laboratory data, which can result in swift regulatory action and the quick removal of contaminated product from the food supply, improving public health nationally. PMID- 28720180 TI - Synergy. PMID- 28720181 TI - Computerized Tests of Team Performance and Crew Coordination Suitable for Military/Aviation Settings. AB - INTRODUCTION: The coordination of team effort on shared tasks is an area of inquiry. A number of tests of team performance in challenging environments have been developed without comparison or standardization. This article provides a systematic review of the most accessible and usable low-to-medium fidelity computerized tests of team performance and determines which are most applicable to military- and aviation-relevant research, such as studies of group command, control, communication, and crew coordination. METHODS: A search was conducted to identify computerized measures of team performance. In addition to extensive literature searches (DTIC, Psychinfo, PubMed), the authors reached out to team performance researchers at conferences and through electronic communication. RESULTS: Identified were 57 potential tests according to 6 specific selection criteria (e.g., the requirement for automated collection of team performance and coordination processes, the use of military-relevant scenarios). The following seven tests (listed alphabetically) were considered most suitable for military needs: Agent Enabled Decision Group Environment (AEDGE), C3Conflict, the C3 (Command, Control, & Communications) Interactive Task for Identifying Emerging Situations (NeoCITIES), Distributed Dynamic Decision Making (DDD), Duo Wondrous Original Method Basic Awareness/Airmanship Test (DuoWOMBAT), the Leader Development Simulator (LDS), and the Planning Task for Teams (PLATT). Strengths and weaknesses of these tests are described and recommendations offered to help researchers identify the test most suitable for their particular needs. DISCUSSION: Adoption of a few standard computerized test batteries to study team performance would facilitate the evaluation of interventions intended to enhance group performance in multiple challenging military and aerospace operational environments.Lawson BD, Britt TW, Kelley AM, Athy JR, Legan SM. Computerized tests of team performance and crew coordination suitable for military/aviation settings. Aerosp Med Hum Perform. 2017; 88(8):722-729. PMID- 28720182 TI - Ground Reaction Forces During Reduced Gravity Running in Parabolic Flight. AB - BACKGROUND: Treadmills have been employed as both a form of exercise and a countermeasure to prevent changes in the musculoskeletal system on almost all NASA missions and many Russian missions since the early Space Shuttle flights. It is possible that treadmills may also be part of exercise programs on future Mars missions and that they may be a component of exercise facilities in lunar or Martian habitats. METHODS: In order to determine if the ambient gravity on these destinations will provide osteogenic effects while performing exercise on a treadmill, ground reactions forces (GRFs) were measured on eight subjects (six women and two men) running at 6 mph during parabolic flight in Martian and lunar gravity conditions. RESULTS: On average, stride length increased as gravity decreased. The first and second peaks of the GRFs decreased by 0.156 and 0.196 bodyweights, respectively, per 1/10 g change in ambient gravity. DISCUSSION: Based on comparisons with previously measured GRF during loaded treadmill running on the International Space Station, we conclude that unloaded treadmill running under lunar and Martian conditions during exploration missions is not likely to be an osteo-protective exercise.Cavanagh P, Rice A, Glauberman M, Sudduth A, Cherones A, Davis S, Lewis M, Hanson A, Wilt G. Ground reaction forces during reduced gravity running in parabolic flight. Aerosp Med Hum Perform. 2017; 88(8):730-736. PMID- 28720183 TI - G-LOC Warning Algorithms Based on EMG Features of the Gastrocnemius Muscle. AB - BACKGROUND: G-induced loss of consciousness (G-LOC) is mainly caused by failure to sustain an oxygenated blood supply to the pilot's brain because of the sudden acceleration in the direction of the +Gz axis, and is considered a critical safety issue. The purpose of this study was to develop G-LOC warning algorithms based on monitoring electromyograms (EMG) of the gastrocnemius muscle on the calf. METHODS: EMG data was retrieved from a total of 67 pilots and pilot trainees of the Korean Air Force during high-G training on a human centrifugal simulator. Seven EMG features were obtained from root mean square (RMS), integrated absolute value (IAV), and mean absolute value (MAV) for muscle contraction, slope sign changes (SSC), waveform length (WL), zero crossing (ZC), and median frequency (MF) for muscle contraction and fatigue. RESULTS: Out of seven EMG features, IAV and WL showed a rapid decay before G-LOC. Based on these findings, this study developed two algorithms which can detect G-LOC during flight and provide warning signals to the pilots. The probability of G-LOC occurrence was detected through monitoring the decay trend for representing muscle endurance and climb rate of the IAV and WL value during sudden acceleration above 6 G, representing muscle power. The sensitivity of the algorithms using IAV and WL features was 100% and the specificity was 66.7%. DISCUSSION: This study suggests that a G-LOC detecting and warning system may be a customized, real-time countermeasure by improving the accuracy of detecting G LOC.Kim S, Cho T, Lee Y, Koo H, Choi B, Kim D. G-LOC warning algorithms based on EMG features of the gastrocnemius muscle. Aerosp Med Hum Perform. 2017; 88(8):737 742. PMID- 28720184 TI - Human Performance Time Model of Spacecraft Control Panel Operation in Simulated Microgravity. AB - BACKGROUND: Human performance modeling plays an important role in the design and management of human spaceflight missions. Previous studies reported that manual control task time increased in microgravity conditions. The current study aimed to find a modeling method that can quantify and predict the task time of spacecraft control panel operation in the simulated microgravity condition. METHODS: We proposed the application of a predetermined elemental task method together with an information processing time model to quantify both physical motion time and cognitive time. The time increment due to microgravity was hypothesized to be proportional to physical motion time. The total task time in the microgravity condition could be calculated as the model time from the normal ground condition plus the predicted time increment. Human data were collected from an experiment asking participants to perform six emergency operating procedure tasks in both normal ground and simulated microgravity conditions. RESULTS: The proposed method resulted in good fitness to human data in both conditions, as shown by both regression fitness (R2 values = 0.99) and modeling error measures (root mean square error <= 3.3 s; mean absolute percentage error <= 16.1%). CONCLUSIONS: Although the method has its limitations, the current findings suggest that it has value in aerospace human factors and ergonomics applications.Cao S, Zhang Y, Guo Y, Chen S. Human performance time model of spacecraft control panel operation in simulated microgravity. Aerosp Med Hum Perform. 2017; 88(8):743-751. PMID- 28720185 TI - Statin Therapy in Low-Risk Air Force Aviators with Isolated Hypercholesterolemia. AB - INTRODUCTION: This study evaluated the use of statin therapy in U.S. Air Force (USAF) aviators with isolated hypercholesterolemia in terms of compliance with clinical practice guidelines (CPGs) and effectiveness in reducing low-density lipoprotein cholesterol (LDL-C) and coronary heart disease (CHD) risk. METHODS: This was a mixed design, 8-yr retrospective study that included 8185 participants with isolated hypercholesterolemia, of which 1458 (17.81%) were prescribed statin monotherapy. RESULTS: Overall agreement between CPG recommendations and patient clinician decision makers was 0.920 (95% confidence interval: 0.955, 0.959) and 0.891 (95% confidence interval: 0.843, 0.851) per 2002 and 2013 CPGs, respectively. Overall agreement was primarily driven by the negative proportion of specific agreement; positive agreement was moderate for the 2002 CPG and poor for the 2013 CPG. LDL-C levels marginally decreased for all participants except non-CPG-recommended statin users per the 2002 CPG. CHD risk was minimally reduced for all participants per the 2002 CPG with the exception of CPG-recommended statin users, for whom risk increased; CHD risk decreased for CPG-recommended statin users, but increased for non-CPG-recommended statin users per the 2013 CPG. No one statin medication was found to be more clinically effective in reducing LDL-C or CHD risk, regardless of dose intensity. CONCLUSIONS: Aerospace medicine practitioners are following CPG recommendations for statin therapy. Statins provided minimal benefit, however, and CPG recommendations proved irrelevant in reducing LDL-C and CHD risk in this population of Air Force aviators. This result is attributable, in part, to the young age of the study cohort and the short follow-up period.Tvaryanas AP, Mahaney HJ, Schroeder VM, Maupin GM. Statin therapy in low-risk air force aviators with isolated hypercholesterolemia. Aerosp Med Hum Perform. 2017; 88(8):752-759. PMID- 28720186 TI - Flight Performance During Exposure to Acute Hypobaric Hypoxia. AB - INTRODUCTION: The purpose of the present study was to examine the influence of hypobaric hypoxia (HH) on a pilot's flight performance during exposure to simulated altitudes of 91, 3048, and 4572 m (300, 10,000, and 15,000 ft) and to monitor the pilot's physiological reactions. METHOD: In a single-blinded counter balanced design, 12 male pilots were exposed to HH while flying in a flight simulator that had been placed in a hypobaric chamber. Flight performance of the pilots, pilot's alertness level, Spo2, heart rate (HR), minute ventilation (VE), and breathing frequency (BF) were measured. RESULTS: A significant difference was found in Flight Profile Accuracy (FPA) between the three altitudes. Post hoc analysis showed no significant difference in performance between 91 m and 3048 m. A trend was observed at 4572 m, suggesting a decrease in flight performance at that altitude. Significantly lower alertness levels were observed at the start of the flight at 4572 m compared to 91 m, and at the end of the flight at 4572 m compared to the start at that altitude. Spo2 and BF decreased, and HR increased significantly with altitude. DISCUSSION: The present study did not provide decisive evidence for a decrease in flight performance during exposure to simulated altitudes of 3048 and 4572 m. However, large interindividual variation in pilots' flight performance combined with a gradual decrease in alertness levels observed in the present study puts into question the ability of pilots to safely fly an aircraft while exposed to these altitudes without supplemental oxygen.Steinman Y, van den Oord MHAH, Frings-Dresen MHW, Sluiter JK. Flight performance during exposure to acute hypobaric hypoxia. Aerosp Med Hum Perform. 2017; 88(8):760-767. PMID- 28720187 TI - Experiences with Regional Anesthesia for Analgesia During Prolonged Aeromedical Evacuation. AB - INTRODUCTION: There is much debate regarding the appropriate analgesic management of patients undergoing medical evacuation following combat trauma. Our primary objective was to review the utility of regional anesthetic techniques in patients undergoing aeromedical evacuation following surgical limb amputation as treatment for combat trauma. METHODS: This study was conducted as an observational retrospective cohort whereby acutely injured amputee patients were identified via the U.S. Transportation Command's patient movement database. The Theater Medical Data Store was cross-referenced for additional patient care data including opioid consumption, duration of regional technique, pain scores, and rates of intubation. RESULTS: Eighty-four records were retrieved from the Theater Medical Data Store. All 84 patients were victims of improvised explosive device detonation requiring limb amputation and subsequent transport from Kandahar Airfield or Camp Bastion, Afghanistan, to the United States. The majority of interventions remained in place throughout the evacuation process. A significant decrease in opioid consumption in patients receiving regional anesthesia was identified at each leg of the medical evacuation process. Pain scores were sporadically reported and not statistically different. Higher rates of intubation were identified in the nonregional anesthetic group. DISCUSSION: Our analysis demonstrates the feasibility and effectiveness of applying regional anesthetic techniques for pain management to our combat wounded trauma patients throughout multiple stages of aeromedical evacuation. Benefits include the potential for less sedation and less opioid consumption while potentially foregoing the requirement for intubation during transport.Carness JM, Wilson MA, Lenart MJ, Smith DE, Dukes SF. Experiences with regional anesthesia for analgesia during prolonged aeromedical evacuation. Aerosp Med Hum Perform. 2017; 88(8):768-772. PMID- 28720188 TI - The Importance of the Study of Cognitive Performance Enhancement for U.S. National Security. AB - INTRODUCTION: The American military is embarking on the 'Third Offset'-a strategy designed to produce seismic shifts in the future of warfare. Central to the approach is the conjoining of humans, technology, and machines to deliver a decisive advantage on the battlefield. Because technology will spread rapidly and globally, tactical overmatch will occur when American operators possess a competitive edge in cognition. Investigation of cognitive enhancing therapeutics is not widely articulated as an adjunct to the Third Offset, yet failure to study promising agents could represent a strategic vulnerability. Because of its legacy of research into therapeutic agents to enhance human-machine interplay, the aerospace medical community represents a front-running candidate to perform this work. Notably, there are strong signals emanating from gambling, academic, and video-gaming enterprises that already-developed stimulants and other agents provide cognitive benefits. These agents should be studied not only for reasons of national security, but also because cognitive enhancement may be a necessary step in the evolution of humankind. To illustrate these points, this article will assert that: 1) the need to preserve and enhance physical and cognitive health will become more and more important over the next century; 2) aeromedical specialists are in a position to take the lead in the endeavor to enhance cognition; 3) signals of enhancement of the type useful to both military and medical efforts exist aplenty in today's society; and 4) the aeromedical community should approach human enhancement research deliberately but carefully.Malish RG. The importance of the study of cognitive performance enhancement for U.S. national security. Aerosp Med Hum Perform. 2017; 88(8):773 778. PMID- 28720189 TI - Enhancing the Meaningfulness of Work for Astronauts on Long Duration Space Exploration Missions. AB - INTRODUCTION: Numerous authors have identified the stressors likely to be encountered on long duration space exploration missions (e.g., to Mars), including the possibility of significant crises, separation from family, boredom/monotony, and interpersonal conflict. Although many authors have noted that meaningful work may be beneficial for astronauts on these missions, none have detailed the sources of meaningful work for astronauts and how these sources may differ between astronauts. The present article identifies how engagement in meaningful work during long duration missions may mitigate the adverse effects of demands and increase the potential for benefits resulting from the missions. METHOD: Semistructured interviews were conducted with nine NASA personnel, including astronauts, flight directors, and flight surgeons. Questions addressed sources of meaning for astronauts, characteristics of tasks that enhance vs. detract from meaning, and recommendations for enhancing meaning. RESULTS: Personnel mentioned contributing to humanity and the next generation, contributing to the mission, and exploration as the most meaningful aspects of their work. Characteristics of tasks that enhanced meaning included using a variety of skills, feeling personal control over their schedule, autonomy in the execution of tasks, and understanding the importance of the experiments conducted on the mission. Top recommendations to sustain meaning were insuring social needs were met through such activities as the strategic use of social media, giving astronauts autonomy as well as structure, and conducting training during transit. DISCUSSION: Implications are addressed for tailoring meaning-based interventions for astronauts participating on long duration missions and assessing the effectiveness of these interventions.Britt TW, Sytine A, Brady A, Wilkes R, Pittman R, Jennings K, Goguen K. Enhancing the meaningfulness of work for astronauts on long duration space exploration missions. Aerosp Med Hum Perform. 2017; 88(8):779-783. PMID- 28720190 TI - Clinical Herpes Zoster in Antarctica as a Model for Spaceflight. AB - INTRODUCTION: Antarctica is a useful analog for spaceflight, as both environments are remote, isolated, and with limited resources. While previous studies have demonstrated increased asymptomatic viral shedding in both the Antarctic and spaceflight environments, clinical manifestations of reactivated viral disease have been less frequently identified. We sought to identify the incidence of clinical herpes zoster from viral reactivation in the Antarctic winter-over population. METHODS: Medical records from the 2014 winter season were reviewed for the incidence of zoster in U.S. Antarctic personnel and then compared to the age-matched U.S. POPULATION: RESULTS: Five cases of clinical herpes zoster occurred in the Antarctic Station population of 204 persons, for an incidence of 33.3 per 1000 person-years vs. 3.2 per 1000 person-years in the general population. Four cases were in persons under age 40, yielding an incidence of 106.7 per 1000 person-years in persons ages 30-39 compared to an incidence of 2.0 per 1000 person-years in the same U.S. age group. DISCUSSION: Immune suppression due to the stressful Antarctic environment may have contributed to the increased incidence of herpes zoster in U.S. Antarctic personnel during the winter of 2014. Working and living in isolated, confined, and extreme environments can cause immune suppression, reactivating latent viruses and increasing viral shedding and symptomatic disease. Such changes have been observed in other austere environments, including spaceflight, suggesting that clinical manifestations of viral reactivation may be seen in future spaceflight.Reyes DP, Brinley AA, Blue RS, Gruschkus SK, Allen AT, Parazynski SE. Clinical herpes zoster in Antarctica as a model for spaceflight. Aerosp Med Hum Perform. 2017; 88(8):784-788. PMID- 28720191 TI - Sustained Accelerated Idioventricular Rhythm in a Centrifuge-Simulated Suborbital Spaceflight. AB - INTRODUCTION: Hypergravitational exposures during human centrifugation are known to provoke dysrhythmias, including sinus dysrhythmias/tachycardias, premature atrial/ventricular contractions, and even atrial fibrillations or flutter patterns. However, events are generally short-lived and resolve rapidly after cessation of acceleration. This case report describes a prolonged ectopic ventricular rhythm in response to high G exposure. CASE REPORT: A previously healthy 30-yr-old man voluntarily participated in centrifuge trials as a part of a larger study, experiencing a total of 7 centrifuge runs over 48 h. Day 1 consisted of two +Gz runs (peak +3.5 Gz, run 2) and two +Gx runs (peak +6.0 Gx, run 4). Day 2 consisted of three runs approximating suborbital spaceflight profiles (combined +Gx and +Gz). Hemodynamic data collected included blood pressure, heart rate, and continuous three-lead electrocardiogram. Following the final acceleration exposure of the last Day 2 run (peak +4.5 Gx and +4.0 Gz combined, resultant +6.0 G), during a period of idle resting centrifuge activity (resultant vector +1.4 G), the subject demonstrated a marked change in his three lead electrocardiogram from normal sinus rhythm to a wide-complex ectopic ventricular rhythm at a rate of 91-95 bpm, consistent with an accelerated idioventricular rhythm (AIVR). This rhythm was sustained for 2 m, 24 s before reversion to normal sinus. The subject reported no adverse symptoms during this time. DISCUSSION: While prolonged, the dysrhythmia was asymptomatic and self limited. AIVR is likely a physiological response to acceleration and can be managed conservatively. Vigilance is needed to ensure that AIVR is correctly distinguished from other, malignant rhythms to avoid inappropriate treatment and negative operational impacts.Suresh R, Blue RS, Mathers C, Castleberry TL, Vanderploeg JM. Sustained accelerated idioventricular rhythm in a centrifuge simulated suborbital spaceflight. Aerosp Med Hum Perform. 2017; 88(8):789-793. PMID- 28720192 TI - Erratum. PMID- 28720193 TI - You're the Flight Surgeon. AB - Brough B. You're the flight surgeon: subependymoma. Aerosp Med Hum Perform. 2017; 88(8):794-796. PMID- 28720194 TI - You're the Flight Surgeon. AB - Harris Graessle CL. You're the flight surgeon: coccidioidomycosis. Aerosp Med Hum Perform. 2017; 88(8):796-800. PMID- 28720195 TI - Early Ejection Seats in Germany. PMID- 28720196 TI - This Month in Aerospace Medicine History. PMID- 28720199 TI - A national survey exploring UK trainees' perceptions, core training experience, and decisions to pursue advanced training in breast radiology. AB - AIM: To investigate UK radiology trainees' perceptions of breast radiology and the factors that influenced their decision whether or not to choose breast radiology as an area of special interest. MATERIALS & METHODS: An online survey was compiled and distributed to all UK specialty trainees in clinical radiology via the Royal College of Radiologists Junior Radiologists' Forum (JRF) regional representatives. RESULTS: There were 275 respondents, representing 22% of all UK radiology trainees. Responses were received from all regions. A significant factor identified in influencing whether or not trainees decide to pursue advanced training in breast radiology is the timing and quality of their initial core training experience. Specific positive aspects of breast radiology that were repeatedly identified included the high level of patient contact and frequent use of interventional procedures. Recurring negative aspects of breast radiology included isolation from general radiology and finding the subject matter boring. CONCLUSION: Breast radiology faces a significant workforce shortfall that is predicted to worsen in the coming years. There has never been a greater need to recruit specialty trainees into this field, and action is urgently needed to help ensure the sustainability of breast services and drive further improvements to patient care. The findings from this survey should be regarded as a challenge to all breast radiologists to engage with trainees from an early stage in their training and to enthuse them with the many positive aspects of a career in breast radiology. PMID- 28720200 TI - Influence of erythrocyte aggregation on radial migration of platelet-sized spherical particles in shear flow. AB - Blood platelets when activated are involved in the mechanisms of hemostasis and thrombosis, and their migration toward injured vascular endothelium necessitates interaction with red blood cells (RBCs). Rheology co-factors such as a high hematocrit and a high shear rate are known to promote platelet mass transport toward the vessel wall. Hemodynamic conditions promoting RBC aggregation may also favor platelet migration, particularly in the venous system at low shear rates. The aim of this study was to confirm experimentally the impact of RBC aggregation on platelet-sized micro particle migration in a Couette flow apparatus. Biotin coated micro particles were mixed with saline or blood with different aggregation tendencies, at two shear rates of 2 and 10s-1 and three hematocrits ranging from 20 to 60%. Streptavidin membranes were respectively positioned on the Couette static and rotating cylinders upon which the number of adhered fluorescent particles was quantified. The platelet-sized particle adhesion on both walls was progressively enhanced by increasing the hematocrit (p<0.001), reducing the shear rate (p<0.001), and rising the aggregation of RBCs (p<0.001). Particle count was minimum on the stationary cylinder when suspended in saline at 2s-1 (57+/-33), and maximum on the rotating cylinder at 60% hematocrit, 2s-1 and the maximum dextran-induced RBC aggregation (2840+/-152). This fundamental study is confirming recent hypotheses on the role of RBC aggregation on venous thrombosis, and may guide molecular imaging protocols requiring injecting active labeled micro particles in the venous flow system to probe human diseases. PMID- 28720201 TI - Exposure to buffer solution alters tendon hydration and mechanics. AB - A buffer solution is often used to maintain tissue hydration during mechanical testing. The most commonly used buffer solution is a physiological concentration of phosphate buffered saline (PBS); however, PBS increases the tissue's water content and decreases its tensile stiffness. In addition, solutes from the buffer can diffuse into the tissue and interact with its structure and mechanics. These bathing solution effects can confound the outcome and interpretation of mechanical tests. Potential bathing solution artifacts, including solute diffusion, and their effect on mechanical properties, are not well understood. The objective of this study was to measure the effects of long-term exposure of rat tail tendon fascicles to several concentrations (0.9-25%) of NaCl, sucrose, polyethylene glycol (PEG), and SPEG (NaCl+PEG) solutions on water content, solute diffusion, and mechanical properties. We found that with an increase in solute concentration the apparent water content decreased for all solution types. Solutes diffused into the tissue for NaCl and sucrose, however, no solute diffusion was observed for PEG or SPEG. The mechanical properties changed for both NaCl solutions, in particular after long-term (8h) incubation the modulus and equilibrium stress decreased compared to short-term (15min) for 25% NaCl, and the cross sectional area increased for 0.9% NaCl. However, the mechanical properties were unchanged for both PEG and SPEG except for minor alterations in stress relaxation parameters. This study shows that NaCl and sucrose buffer solutions are not suitable for long-term mechanical tests. We therefore propose using PEG or SPEG as alternative buffer solutions that after long-term incubation can maintain tissue hydration without solute diffusion and produce a consistent mechanical response. PMID- 28720202 TI - A Novel Surgical Approach to Mechanical Circulatory Support in Univentricular Infants. AB - BACKGROUND: Historically, the options for mechanical circulatory support in infants, particularly those with single-ventricle physiology, have been limited and outcomes have generally been poor. We report a new approach implemented for long-term support in a series of such patients. METHODS: This study is a single center case series of 7 patients with single-ventricle physiology after stage 1 palliation supported with mechanical circulatory support using a novel technique, between May 2014 and September 2015. Our technique included modification and implantation of commercially available pediatric cannulae into the common atrium and the ascending aorta or reconstructed neoaorta and utilization of a centrifugal extracorporeal pump. RESULTS: Median circulatory support duration was 64 days (range, 35 to 99). One adverse neurologic event was observed in 1 patient, and bleeding requiring reoperation in 2 patients. Support to recovery, decision, or heart transplantation was accomplished in all cases. Of all patients, 43% were successfully discharged home. CONCLUSIONS: Our experience shows that long-term extracorporeal mechanical circulatory support of patients with underlying single-ventricle physiology after stage 1 palliation is feasible utilizing our technique. This approach overcomes several major challenges encountered in these patients, such as high flow requirement and stability of the cannulae, and allows extubation, rehabilitation, and at times, myocardial recovery. PMID- 28720203 TI - The personal and professional face of the Basque urologist Jose Julian Guimon Rezola (1898-1980). AB - OBJECTIVE: To understand certain outstanding aspects of the life of the Basque surgeon and urologist Julian Guimon Rezola. His personal and bibliographic documentary legacy helps reconstruct his works and personal character. MATERIAL AND METHODS: We analysed the written works of Julian Guimon Rezola and a collection of documents, letters, photographs, illustrations and objects from his personal and professional life, accessed through his family. We analysed the content of the author's main publications and related the documents to historic facts. RESULTS: Julian Guimon Rezola was an upstanding individual, a father, a family man and a nationalist before the struggle, who was dedicated to his work and particularly to teaching and health management. He started his urological career under the direction of Francisco Perez Andres in the Santo Civil Hospital of Bilbao. He endured unjust repression for participating in the creation of the Basque University in 1936. Sentenced to life imprisonment, he stated a new life as a reclusive surgeon in the prison of Puerto de Santa Maria. He was pardoned three years later but was deprived of all his offices and disqualified from civil service. He founded his clinic and maintained his training in the United States. He presided over the Medical-Surgical Insurance Group of Bilbao (Igualatorio Medico-Quirurgico) and, on 2 occasions, the Bilbao Academy of Medical Sciences. He was considerably active professionally and focused on social medicine and modern urology. He wrote 104 scientific articles, a number of which were of considerable quality and impact. We observed an evolution in the subject matter of these articles, all with exquisite professionalism and humanity. He corresponded with renowned practitioners and was admitted to the Spanish Royal National Academy of Medicine in 1970. He ended his career with an appointment as honorary professor at the University of the Basque Country 2 years before his death. CONCLUSIONS: Surgeon urologist Julian Guimon Rezola was a fundamental figure in Basque and Spanish medicine in the 20th century. He was the victim of a severe reprisal, not so much for political issues but rather for his institutional loyalty. However, he regained his professional and academic prestige. His written works reveal modern medicine with a considerable social foundation and the mind of a brilliant health manager. PMID- 28720204 TI - Research, development and innovation at gastroenterology outpatient consults. PMID- 28720205 TI - Recurrent gastrointestinal bleeding secondary to Dieulafoy's lesion successfully treated with endoscopic ultrasound-guided sclerosis. PMID- 28720206 TI - Fenestrated duodenal web treated by endoscopic dilatation. PMID- 28720207 TI - Thrombotic Microangiopathy: A Multidisciplinary Team Approach. AB - Thrombotic microangiopathy (TMA) is characterized by the presence of microangiopathic hemolytic anemia and thrombocytopenia along with organ dysfunction, and pathologically, by the presence of microthrombi in multiple microvascular beds. Delays in diagnosis and initiation of therapy are common due to the low incidence, variable presentation, and poor awareness of these diseases, underscoring the need for interdisciplinary approaches to clinical care for TMA. We describe a new approach to improve clinical management via a TMA team that originally stemmed from an Affinity Research Collaborative team focused on thrombosis and hemostasis. The TMA team consists of clinical faculty from different disciplines who together are charged with the responsibility to quickly analyze clinical presentations, guide laboratory testing, and streamline prompt institution of treatment. The TMA team also includes faculty members from a broad range of disciplines collaborating to elucidate the pathogenesis of TMA. To this end, a clinical database and biorepository have been constructed. TMA leaders educate front-line providers from other departments through presentations in various forums across multiple specialties. Facilitated by an Affinity Research Collaborative mechanism, we describe an interdisciplinary team dedicated to improving both clinical care and translational research in TMA. PMID- 28720209 TI - The influence of oxazaphosphorine agents on kidney function in rats. AB - BACKGROUND AND OBJECTIVE: The application of cytostatic oxazaphosphorines such as cyclophosphamide (CP) and ifosfamide (IF) is associated with the risk of kidney damage that, depending on the type of drug, dose and route of administration, adopts a different clinical entity and severity. The aim of our study was to assess the influence of CP and IF on the kidney histology and function in rats intraperitoneally treated with four doses of either CP or IF. MATERIALS AND METHODS: A total of 30 rats were divided into three groups (10 in each group): group 1 (control), sham treated with saline solution, group 2 (treated with 75mg/kg b.w. of CP), and group 3 (treated with 60mg/kg b.w. of IF). After the treatment rats were sacrificed, blood was collected and nephrectomy and cystectomy were performed. Qualitative and quantitative parameters (including neutrophil gelatinase-associated lipocalin-1, NGAL-1) of kidney function were assayed in urine and plasma. RESULTS: CP-treated rats were characterized by a significant polyuria, decreased urine pH and by decreased daily urinary excretion of sodium, potassium, urea and uric acid accompanied by increased NGAL-1 excretion. A significant decrease of the plasma uric acid concentration was also observed. IF-treated animals were also characterized by decreased urine pH but with normal daily urinary excretion of assessed substances (except for reduced uric acid excretion). Both CP and IF treated rats did not show any histopathological abnormalities in their kidneys. CONCLUSIONS: CP caused more advanced kidney dysfunction and some indices suggested the development of prerenal acute kidney injury. In the CP-treated group some particularly marked urinary and plasma uric acid disturbances suggested compensation of increased oxidative stress as uric acid is considered to exert also antioxidant properties. PMID- 28720208 TI - Treatment of Uremic Pruritus: A Systematic Review. AB - BACKGROUND: Uremic pruritus is a common and burdensome symptom afflicting patients with advanced chronic kidney disease (CKD) and has been declared a priority for CKD research by patients. The optimal treatments for uremic pruritus are not well defined. STUDY DESIGN: Systematic review. SETTING & POPULATION: Adult patients with advanced CKD (stage >= 3) or receiving any form of dialysis. SELECTION CRITERIA FOR STUDIES: PubMed, CINAHL, Embase, International Pharmaceutical Abstracts, Scopus, Cochrane Library, and ClinicalTrials.gov from their inception to March 6, 2017, were systematically searched for randomized controlled trials (RCTs) of uremic pruritus treatments in patients with advanced CKD (stage >= 3) or receiving any form of dialysis. 2 reviewers extracted data independently. Risk of bias was assessed using the Cochrane Collaboration risk-of bias tool. INTERVENTION: Any intervention for the treatment of uremic pruritus was included. OUTCOMES: A quantitative change in pruritus intensity on a visual analogue, verbal rating, or numerical rating scale. RESULTS: 44 RCTs examining 39 different treatments were included in the review. These treatments included gabapentin, pregabalin, mast cell stabilizers, phototherapy, hemodialysis modifications, and multiple other systemic and topical treatments. The largest body of evidence was found for the effectiveness of gabapentin. Due to the limited number of trials for the other treatments included, we are unable to comment on their efficacy. Risk of bias in most studies was high. LIMITATIONS: Heterogeneity in design, treatments, and outcome measures rendered comparisons difficult and precluded meta-analysis. CONCLUSIONS: Despite the acknowledged importance of uremic pruritus to patients, with the exception of gabapentin, the current evidence for treatments is weak. Large, simple, rigorous, multiarm RCTs of promising therapies are urgently needed. PMID- 28720210 TI - Editorial overview: Cell organelles. PMID- 28720211 TI - Implantation of Ventricular Assist Devices in Hypertrophic Cardiomyopathy. Is It a Safe Option? Response. PMID- 28720212 TI - Changing the curve in chronic lung allograft dysfunction: Implications of chronic lung allograft dysfunction phenotypes in assessing treatment interventions. PMID- 28720213 TI - Professor Christian Cabrol (1925 to 2017). PMID- 28720214 TI - [Hypophosphatasia: Clinical manifestations, diagnostic recommendations and therapeutic options]. AB - Hypophosphatasia is a very rare bone metabolism disorder caused by a deficiency in alkaline phosphatase activity, due to mutations in the ALPL gene. Its clinical hallmark is the impairment of skeletal and teeth mineralisation, although extra skeletal manifestations are frequent. Its phenotypic spectrum is widely variable from a subtype with exclusive odontological impairment (odontohypophosphatasia) to five subtypes with systemic involvement, classified according to the age at the onset of the first symptoms (four of them in the paediatric age range: perinatal lethal, perinatal benign, infant and childhood hypophosphatasia). Those subtypes of hypophosphatasia with an earliest onset usually involve a worse prognosis, due to the risk of developing potentially lethal complications, such as seizures or severe respiratory insufficiency, secondary to rib cage malformations. Due to the extremely low prevalence of the severe forms of hypophosphatasia, its clinical variability and overlapping phenotypic features with several more prevalent conditions, the diagnosis of hypophosphatasia in the clinical setting is challenging. However, its potential lethality and impact on the patient's quality of life, along with the recent availability of an enzyme replacement therapy, increases the relevance of the early and accurate identification of patients affected with hypophosphatasia. On the basis of published evidence and clinical experience, this article suggests an algorithm with practical recommendations for the differential diagnosis of childhood hypophosphatasia, as well as an updated review of current therapeutic options. PMID- 28720215 TI - Autoimmune meningitis and encephalitis in adult-onset still disease - Case report. AB - INTRODUCTION: Adult-onset Still disease (AOSD) is a rare systemic inflammatory disease of unknown cause. Its symptoms usually include persistent fever, fugitive salmon-colored rash, arthritis, sore throat (not specific), but it may also lead to internal organs' involvement, which presents with enlargement of the liver and spleen, swollen lymph nodes, carditis or pleuritis - potentially life-threatening complications. In rare cases, AOSD can cause aseptic meningitis or/and encephalitis. CASE PRESENTATION: We report a case of 31-year-old male patient, who was referred to neurological department for extending diagnostics of frontal lobes lesions with involvement of adjacent meninges. Abnormalities have been revealed in brain MRI, which was performed due to persistent headaches, visual disturbances, fever, fatigue and cognitive decline. Wide differential diagnosis was performed including laboratory findings, contrast enhanced MRI, MR spectroscopy, flow cytometry and finally brain biopsy to exclude neoplastic or infectious origin. Final diagnosis of autoimmune meningoencephalitis in adult onset Still disease has been made. CONCLUSION: Adult-onset Still disease is a rare cause of inflammatory changes in central nervous system, which if diagnosed, may be treated successfully with steroids (commonly available agent), intravenous immunoglobulins or more specific immunomodulating regiments. PMID- 28720216 TI - The effects of red cell transfusion donor age on nosocomial infection among trauma patients. AB - BACKGROUND: We hypothesized that packed red blood cell (PRBC) transfusions from older donors would be associated with fewer nosocomial infections among trauma patients. METHODS: We performed a four-year retrospective analysis of 264 consecutive adult trauma patients who received >=1 PRBC transfusion during admission. The capacity of donor age to predict nosocomial infection was assessed by logistic regression. RESULTS: Thirty-three percent of all patients developed a nosocomial infection. Donor age was significantly higher among patients with nosocomial infection (40.3 vs. 37.6 years, p = 0.035), and the incidence of infection was directly proportional to donor age. The association between donor age and infection was strongest among recipients age >=60 years, and was significant on multivariate regression for this cohort (OR 1.07 (95% CI 1.01 1.13), p = 0.024). CONCLUSIONS: Among trauma patients receiving PRBC transfusions, blood from older donors may be associated with increased risk for nosocomial infection. PMID- 28720217 TI - Body mass index mediates the prognostic significance of circulating tumor cells in inflammatory breast cancer. AB - BACKGROUND: Obesity (BMI>=30) may be an etiologic and prognostic factor in inflammatory breast cancer (IBC). We examined the relationship between BMI, pathologic complete response (pCR), and circulating-tumor-cell (CTC) levels in IBC. METHODS: Cohort included IBC patients diagnosed 2005-2015 who had neoadjuvant chemotherapy during a prospective trial on CTCs and pathologic review describing pCR. Chi-square, logistic regression, and Cox proportional hazards models were used to identify clinicopathologic associations with event-free survival (EFS). RESULTS: Of 73 patients, 61 (84%) had CTC values, 22 (30%) achieved a pCR, and 39 (53%) were obese. There was no difference between obese and non-obese patients for pCR rates (31% vs. 29%, p = 0.90) or presence of CTCs (23% vs. 26%, p = 0.80). Among non-obese patients, CTCs were associated with worse EFS (HR 11.69, p < 0.01), but among obese patients, there was no difference in EFS between those with and without CTCs. CONCLUSIONS: BMI mediates CTCs' prognostic significance in IBC. PMID- 28720218 TI - Pesticide analysis in coffee leaves using a quick, easy, cheap, effective, rugged and safe approach and liquid chromatography tandem mass spectrometry: Optimization of the clean-up step. AB - An analytical method using a quick, easy, cheap, effective, rugged and safe (QuEChERS) procedure for multi-residue determination of 52 pesticides in coffee leaf extractshas been developed and validated according to SANTE/11945/2015 guidelines. Different sorbent combinations for dispersive solid phase extraction (d-SPE) clean-up as well as dispersive liquid-liquid microextraction (DLLME) were tested. The relative standard deviations (RSDs) for the recovery of 87-94% of pesticides added to coffee leaf extracts,was <=20% for samples spiked at concentrations up to 50ng*g-1 depending on the clean-up procedures. However, samples spiked with a 100ng*g-1 pesticide mixture gave RSDs>20% for most pesticides when d-SPE was carried out adding Supelclean ENVI-Carb 120/400. To explain this fact,the secondary metabolic profile was analyzed in all the extraction and clean-up procedures. Only in the clean-up procedure with the addition of Supel QuE Z-Sep+, does caffeine show a constant adsorption between blank and spiked samples. In other clean-up procedures, the amount of caffeine was higher in those samples spiked with pesticides. This indicates competition between caffeine and pesticides for adsorption to the sorbent. Addition of Supel QuE Z-Sep+ to the procedure revealed only a 32% matrix effect, whereas using PSA+ C18 the matrix effect was close to 97%. The process efficiency is up to 54% with the addition of Supel QuE Z-Sep+ and just up to 7% for the other clean-up procedures. The method was successfully tested in coffee leaves from different types of cultivars. Pesticides were not detected in organic coffee leaf extracts, but thiametoxan was clearly detected in 50% of coffee leaf extracts harvested from coffee trees grown under traditional conditions as determined by UHPLC TOFMSLC/QqTOF-MS/MS. PMID- 28720219 TI - Monitoring leachables from single-use bioreactor bags for mammalian cell culture by dispersive liquid-liquid microextraction followed by ultra high performance liquid chromatography quadrupole time of flight mass spectrometry. AB - A method for the identification of leachables in chemically defined media for CHO cell culture using dispersive liquid-liquid microextraction (DLLME) and UHPLC-MS is described. A Box-Behnken design of experiments (DoE) approach was applied to obtain the optimum extraction conditions of the target analytes. Performance of DLLME as extraction technique was studied by comparison of two commercial chemically defined media for CHO cell culture. General extraction conditions for any group of leachables, regardless of their specific chemical functionalities can be applied and similar optimum conditions were obtained with the two media. Extraction efficiency and matrix effects were determined. The method was validated using matrix-matched standard calibration followed by recovery assays with spiked samples. Finally, cell culture media was incubated in 7 single use bioreactors (SUBs) from different vendors and analysed. TBPP was not detected in any of the samples, whereas DtBP and TBPP-ox were found in all samples, with bDtBPP detected in six SUBs. This method can be used for early identification of non-satisfactory SUB films for cultivation of CHO cell lines for biopharmaceutical production. PMID- 28720220 TI - Application of ultrahigh-performance liquid chromatography-quadrupole time-of flight mass spectrometry for the characterization of organic aerosol: Searching for naphthenic acids. AB - Naphthenic acids (NAs) are naturally occurring constituents of hydrocarbon deposits (petroleum, oil sands bitumen, and crude oils), and present in any facilities that extract, process or use crude oil or bitumen for manufacturing. In the Athabasca oil sands region (AOSR) of Alberta, Canada, this diverse group of saturated acyclic, monocyclic, and polycyclic carboxylic acids is present in bitumen and in tailing ponds. Little is known about the occurrence of residual oil sands derived organic material, including NAs, in atmospheric particulate matter (PM). This work describes the optimization of an ultrahigh-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC/QTOF-MS) method to characterize and identify classical NAs in atmospheric PM. Under the optimum conditions, analysis of the Sigma-Aldrich technical NA STD Mix showed the absence of saturated fatty acids, while branched and cyclic NAs isomers with carbon number ranged between 10 and 30, and Z families between 0 and -12 were detected. Higher molecular weight NAs representing compounds with carbon number ranging between 30 and 40 were identified in the analyzed PM samples collected in AOSR. In contrast, isomeric branched acyclic NAs were not detected in the background (PM-R) samples collected far from AOSR. Except for fatty acids (Z=0), other Z homologues were also not detectable or present at very low concentration in the analysed PM-R samples. Preliminary examination of NA profiles showed that the composition of NAs in PM collected in close proximity to surface mining operations is predominantly "refractory" high molecular weight branched NAs, differing from that collected closer to upgraders and tailings ponds. It is suspected that dust released from the mine faces and dry tailings in the AOSR are sources of NAs to atmosphere. Further samples should be examined to confirm findings. This preliminary study presents, to our knowledge, the first direct identification of branched acyclic and cyclic NAs in atmospheric PM. PMID- 28720221 TI - Evaluation of nanoflow liquid chromatography high resolution mass spectrometry for pesticide residue analysis in food. AB - This article reports on the evaluation of nanoflow liquid chromatography-mass spectrometry (LC-MS) for pesticide residue analysis in food. The approach is based on the use of reversed-phase C18nano columns with an integrated emitter, so that separation, ionization and detection are performed minimizing dead volumes. The use of nanoflow not only increases ionization efficiency and minimizes ionization suppression but also boost sensitivity compared to analytical-scale LC MS methods. The nanoflow LC system was combined with full-scan high resolution mass spectrometry using a Q-Exactive Orbitrap instrument. The analytical performance was assessed for over 60 representative pesticides in five representative commodities (tomato, baby food, orange, fruit-based jam and olive oil). The sensitivity achieved with this configuration enables the implementation of high dilution factors (eg. 1:20, 1:50 or beyond) in pesticide residue workflows without compromising sensitivity, featuring limits of quantitation in the low ng kg-1 range. Using this dilution factors, signal suppression was found negligible in most cases (<10% in most cases, especially with 1:50 dilution), so that matrix-matched standards may be skipped, thus simplifying laboratory workflows. The robustness of the nanoflow LC system and its capability to withstand long analytical runs was also evaluated. Appropriate precision in terms of peak area and retention time was obtained at different concentration levels for over 125 injections without any instrument servicing. The main benefits of the nanoflow liquid chromatography approach are the high sensitivity gain and the outstanding reduction in matrix effects thanks to the high sample dilution factors that can be implemented, along with the substantial reduction in solvent usage. PMID- 28720222 TI - Molecular insight into protein binding orientations and interaction modes on hydrophobic charge-induction resin. AB - Hydrophobic charge-induction chromatography (HCIC) with 4-mercaptoethyl-pyridine (MEP) as the functional ligand has been developed as a new technology for antibody purification. In the present work, molecular simulation methods were developed to investigate the interactions between the Fc fragment of IgG and a MEP ligand net. The MM/PBSA method was used to evaluate the binding energy for the MEP ligand net at different densities. It was found that ligand density had significant influence on the binding of Fc. Potential binding conformations were further analyzed by molecular dynamics simulation. It was found that the interaction between Fc and MEP ligand net is driven by self-adaptive conformation adjustment and multiple-site binding. Hydrophobic forces dominate the binding interaction, which appeared as the results of synergistic actions of binding sites located on CH2, CH3, and the consensus binding site (CBS) of the Fc fragment. At acidic pH, the electrostatic repulsion between the basic residues and the protonated pyridine ring group on MEP ligands is the main driving force for the detachment of the Fc fragment from the MEP net. PMID- 28720223 TI - Absorbance detector for high performance liquid chromatography based on a deep-UV light-emitting diode at 235nm. AB - In this communication, we describe a flow-through optical absorption detector for HPLC using for the first time a deep-UV light-emitting diode with an emission band at 235nm as light source. The detector is also comprised of a UV-sensitive photodiode positioned to enable measurement of radiation through a flow-through cuvette with round aperture of 1mm diameter and optical path length of 10mm, and a second one positioned as reference photodiode; a beam splitter and a power supply. The absorbance was measured and related to the analyte concentration by emulating the Lambert-Beer law with a log-ratio amplifier circuitry. This detector showed noise levels of 0.30mAU, which is comparable with our previous LED-based detectors employing LEDs at 280 and 255nm. The detector was coupled to a HPLC system and successfully evaluated for the determination of the anti diabetic drugs pioglitazone and glimepiride in an isocratic separation and the benzodiazepines flurazepam, oxazepam and clobazam in a gradient elution. Good linearities (r>0.99), a precision better than 0.85% and limits of detection at sub-ppm levels were achieved. PMID- 28720224 TI - Development of a 1.0 mm inside diameter temperature-assisted focusing precolumn for use with 2.1 mm inside diameter columns. AB - On-column solute focusing is a simple and powerful method to decrease the influence of precolumn band spreading and increase the allowable volume injected increasing sensitivity. It relies on creating conditions so that the retention factor, k', is transiently increased during the injection process. Both solvent composition and temperature control can be used to effect solute focusing. In the case of temperature, the release of the transiently delayed solute band requires increasing the temperature rapidly and with a minimum of radial thermal gradients. Thus, the focus of attention in temperature-based efforts to carry out on-column focusing has been on capillary columns. As a result, the benefits of this simple and reliable approach, temperature-assisted solute focusing or TASF, are not available to those using larger diameter columns, in particular the highly successful 2.1mm inside diameter columns. Based on considerations of thermal entrance length at the volume flow rates used with 2.1mm inside diameter columns, TASF would not be effective with such columns. However, we determined that the thermal entrance length for a 1.0mm inside diameter precolumn is sufficiently short, about 2mm, that it could work as a precolumn before a 2.1mm inside diameter analytical column. Finite element calculations demonstrate that a 1.0*20mm precolumn packed with 5MUm reversed phase particles is effective at a flow rate of 250MUL/min, suitable for the 2.1mm inside diameter column. Eight 1 cm2 Peltier devices are used to heat (and cool) the precolumn. The computed axial temperature profile shows that the center of the column heats more rapidly than the ends. Based on the changes in back pressure, the full temperature transient from 5 degrees C (focus) to 80 degrees C (release) takes about 10s. Experimental van Deemter curves indicate that the reduced velocity in the precolumn at 250MUL/min flow rate is about 50. Nonetheless, about 1000 theoretical plates are generated. When operating as a precolumn, clear advantages are seen for solutes across a range of modest k' values (2.2-23.4 at the separation conditions at 65 degrees C) using TASF alone (5 degrees C) with 50MUL injection volumes of methyl through n-butyl parabens, and with 100MUL injections that also include solvent based focusing (90:10 aqueous/acetonitrile sample, 80:20 mobile phase). PMID- 28720225 TI - [Ultrasound screening for birth defects: A medico-economic review]. AB - OBJECTIVES: The systematic use of ultrasound during pregnancy aims at birth defect detection. Our objective was to assess the economic efficiency of prenatal ultrasound screening for fetal malformations. METHODS: We carried out a literature review on Medline via PubMed between 1985 and 2015, from the economic perspective of the prenatal ultrasound screening for fetal malformations. RESULTS: The literature on this subject was sparse and we selected only twelve articles presenting relevant economic data, of which only eight were proper medico-economic studies. We found arguments for the economic effectiveness of ultrasound screening for fetal malformation detection, which is largely linked to the terminations of pregnancies and to the cost of the handicaps "avoided". However, none of the reviewed articles could reach medico-economic conclusions. Additionally, we highlighted various elements making economic analyses more complex in this field: the choice of the method, the uncertainty around two essential parameters (the efficiency of ultrasound and the costs of procedures) and the difficulties to compare or to generalize results. We also noticed important methodological heterogeneity among the studies and the absence of French study. CONCLUSIONS: Previously published data are insufficient to assess the economic efficiency of prenatal ultrasound screening for fetal malformations. PMID- 28720226 TI - A comparative review of open and endovascular abdominal aortic aneurysm repairs in the national operative quality improvement database. AB - Repair of abdominal aortic aneurysms with endovascular techniques has emerged as the first line of therapy, due to procedural ease and excellent patient outcomes. Open aneurysm repair is increasingly used as a secondary option for lesions with anatomic complexity that involve arterial branches. Understanding the impact of endovascular abdominal aortic aneurysms repair on the shift in vascular operation practice for abdominal aortic aneurysms repair, requires a comprehensive and risk adjusted review of operative outcomes between the 2 repair types. The American College of Surgeons National Surgical Quality Improvement Project is a comprehensive, outcomes-based program, which provides valuable data on operative complications with endovascular and open repair. In this review, we use the National Surgical Quality Improvement Project database to critically review complications, mortality, and morbidity associated with endovascular and open abdominal aneurysmal repair. PMID- 28720227 TI - Co-creative development of an eHealth nursing intervention: Self-management support for outpatients with cancer pain. AB - INTRODUCTION: Co-creative methods, having an iterative character and including different perspectives, allow for the development of complex nursing interventions. Information about the development process is essential in providing justification for the ultimate intervention and crucial in interpreting the outcomes of subsequent evaluations. This paper describes a co-creative method directed towards the development of an eHealth intervention delivered by registered nurses to support self-management in outpatients with cancer pain. METHODS: Intervention development was divided into three consecutive phases (exploration of context, specification of content, organisation of care). In each phase, researchers and technicians addressed five iterative steps: research, ideas, prototyping, evaluation, and documentation. Health professionals and patients were consulted during research and evaluation steps. RESULTS: Collaboration of researchers, health professionals, patients and technicians was positive and valuable in optimising outcomes. The intervention includes a mobile application for patients and a web application for nurses. Patients are requested to monitor pain, adverse effects and medication intake, while being provided with graphical feedback, education and contact possibilities. Nurses monitor data, advise patients, and collaborate with the treating physician. CONCLUSION: Integration of patient self-management and professional care by means of eHealth key into well-known barriers and seem promising in improving cancer pain follow up. Nurses are able to make substantial contributions because of their expertise, focus on daily living, and their bridging function between patients and health professionals in different care settings. Insights from the intervention development as well as the intervention content give thought for applications in different patients and care settings. PMID- 28720228 TI - Percent weight reduction required to achieve minimal clinically important improvements in health-related quality of life among African Americans: A secondary analysis of the fit body and soul study. AB - OBJECTIVE: To calculate the percent weight reduction required to achieve minimal clinically important improvement (MCII) in health-related quality of life (HRQOL). DESIGN: Secondary data analysis from the longitudinal cohort of a single blinded, cluster-randomized community trial to test the efficacy of the faith based adaptation of the Diabetes Prevention Program. SETTING: African-American churches. PARTICIPANTS: This study included 472 congregants with a body mass index of >=25 and fasting plasma glucose<126mg/dl. MAIN OUTCOME MEASURE: Percent weight reduction required to achieve the MCII in HRQOL measured by two instruments, SF-12 and EQ-5D, one year following baseline. ANALYSIS: The percent weight reduction required to achieve established MCII in SF-12 Physical Component Summary (PCS), SF-12 Mental Component Summary (MCS), and EQ-5D Health Status (HS) at one-year follow-up were calculated using fitted linear regression models. In addition to models for the total sample, we generated models, stratified by baseline BMI, PCS, and HS, to calculate the percent weight reduction required to achieve MCII in HRQOL for those most in need of weight reduction and those in need of improved HRQOL. RESULTS: The percent weight reduction was a significant predictor of improvement in the SF-12PCS and the EQ-5DHS but not SF-12MCS. To achieve a MCII in SF-12PCS and EQ-5DHS, 18% and 30% weight reductions were required, respectively. A smaller percent weight reduction was required when the baseline BMI was >=40. CONCLUSIONS AND IMPLICATIONS: Improvements in HRQOL among African-American congregants seeking weight reduction required more than the 3-5% weight reduction associated with improvements in physical health. PMID- 28720229 TI - Perioperative registered nurses knowledge, attitudes, behaviors, and barriers regarding pressure ulcer prevention in perioperative patients. AB - BACKGROUND: Hospital acquired pressure ulcers have a detrimental effect on patient quality of life, morbidity, mortality, and cost to the healthcare industry. Little is known about pressure ulcer prevention in perioperative services. OBJECTIVES: The objectives of this study were to describe perioperative registered nurses (RNs) knowledge, attitudes, behaviors, and barriers about pressure ulcer prevention and to determine if knowledge and the availability of a pressure ulcer staging tool are predictors of pressure ulcer prevention behavior. METHODS: A cross-sectional descriptive pilot study was conducted. Sixty-two perioperative RNs from 10 acute care hospitals participated. RESULTS: Perioperative nurses believed carrying out pressure ulcer prevention strategies is essential to nursing practice but only two-thirds reported conducting pressure ulcer risk assessment on all patients and daily assessment on at risk patients. Results indicated a knowledge deficit regarding assessment and prevention of pressure ulcers as performance on the PUKT (72%) fell below the recommended score of 90%. Results of binary logistic regression indicated that knowledge as measured by the PUKT and availability of a pressure ulcer staging tool were statistically significant (p=0.03) predictors of pressure ulcer prevention behavior. The initial model without the predictor variables, indicated an overall success rate of correct predictions of 64% which increase to 73% when the predictor variables were added to the initial model. CONCLUSIONS: Although perioperative nurses believe that pressure ulcer prevention is important, a knowledge deficit exists and there is a need for pressure ulcer prevention education. PMID- 28720230 TI - The effect of acupressure on fatigue among female nurses with chronic back pain. AB - AIM: To investigate the effect of acupressure on fatigue among female nurses with chronic back pain. BACKGROUND: Chronic back pain is one of the most common problems among nurses and has numerous physical and psychological effects. One of these effects is fatigue that impairs an individual's life. MATERIALS AND METHODS: This randomized single-blind clinical trial was conducted on 50 nurses with chronic back pain working at the selected hospitals in Isfahan, Iran. After convenient sampling, the subjects were randomly allocated, through lottery, to the two groups of experimental (n=25) and sham (n=25). In the experimental group, acupressure techniques were performed during 9 sessions, 3 times a week for 14min for each patient. In the sham group, points within 1cm of the main points were only touched. Data were collected using the Fatigue Severity Scale (FSS), before, and immediately, 2weeks, and 4weeks after the intervention. Data analysis was performed using SPSS software. RESULTS: The mean score of fatigue severity before the intervention was not significantly different between the two groups (P=0.990). However, it was significantly lower in the experimental group than the sham group immediately (P<0.001), 2weeks (P=0.005), and 1month after the intervention (P<0.001). CONCLUSIONS: Acupressure on specific points of the foot and back improves back pain so, reduces fatigue. Therefore, acupressure can be used as a drug-free and low-cost approach without side effects to improve fatigue in nurses with chronic back pain. PMID- 28720231 TI - Overcoming diabetes-related stigma in Iran: A participatory action research. AB - OBJECTIVE: The study aimed to overcome diabetes-related stigma in individuals living with type 1 Diabetes Mellitus (T1DM) in Iran. The study proposed that if individuals with T1DM and the community work together to develop and implement an anti-stigma program, diabetes-related stigma in individuals with T1DM can be reduced. RESEARCH DESIGN AND METHOD: This study was conducted as a participatory action research study based on Kemmis and McTaggert's (2000) Model to design and implement an anti-stigma program for T1DM. Participants were selected among individuals with T1DM, their family members, health care providers, and residents without diabetes in Isfahan, Iran. Data collection was conducted using interviews, focus groups, emails, and text messages. Content analysis was used to analyze the data to develop anti-stigma interventions. Interventions were prioritized based on the Suitability, Feasibility and Flexibility (SFF) Matrix. Anti-stigma interventions were implemented in different levels in Isfahan, Iran, from 2011 to 2014. The effect of the program was evaluated based on interviews, feedback, and focus groups at the individual level. However, interventions were implemented in different levels including community, organization, family, and individual. RESULTS: Participants with T1DM experienced significant empowerment during the project to overcome diabetes-related stigma. The three main themes indicating this feeling of empowerment are "from doubt to trust", "from shadow to light", and "from me to us". CONCLUSION: Participatory action research can be an effective way to reduce diabetes-related stigma in individuals living with T1DM. It integrates the voices of the marginalized group reducing stigma and discrimination against diabetes. PMID- 28720232 TI - Meta-analysis of the predictive factors of postpartum fatigue. AB - PURPOSE: Nearly 64% of new mothers are affected by fatigue during the postpartum period, making it the most common problem that a woman faces as she adapts to motherhood. Postpartum fatigue can lead to serious negative effects on the mother's health and the newborn's development and interfere with mother-infant interaction. The aim of this meta-analysis was to identify predictive factors of postpartum fatigue and to document the magnitude of their effects using effect sizes. METHOD: We used two search engines, PubMed and Google Scholar, to identify studies that met three inclusion criteria: (a) the article was written in English, (b) the article studied the predictive factors of postpartum fatigue, and (c) the article included information about the validity and reliability of the instruments used in the research. Nine articles met these inclusion criteria. The direction and strength of correlation coefficients between predictive factors and postpartum fatigue were examined across the studies to determine their effect sizes. RESULTS: Measurement of predictor variables occurred from 3days to 6months postpartum. Correlations reported between predictive factors and postpartum fatigue were as follows: small effect size (rrange=0.10 to 0.29) for education level, age, postpartum hemorrhage, infection, and child care difficulties; medium effect size (rrange=0.30 to 0.49) for physiological illness, low ferritin level, low hemoglobin level, sleeping problems, stress and anxiety, and breastfeeding problems; and large effect size (rrange=0.50+) for depression. CONCLUSION: Postpartum fatigue is a common condition that can lead to serious health problems for a new mother and her newborn. Therefore, increased knowledge concerning factors that influence the onset of postpartum fatigue is needed for early identification of new mothers who may be at risk. Appropriate treatments, interventions, information, and support can then be initiated to prevent or minimize the postpartum fatigue. PMID- 28720233 TI - The effect of reflexology upon spasticity and function among children with cerebral palsy who received physiotherapy: Three group randomised trial. AB - PURPOSE: To assess the effectiveness of reflexology method upon spasticity and function among children with cerebral palsy who received physiotherapy. METHODS: A three group, randomised trial with blinded evaluator. Randomization was made sealed and opaque envelopes. 45 children with cerebral palsy who were trained at a Special Education and Rehabilitation Centre. In the reflexology and placebo group; a 20min reflexology was performed twice a week in a total 24 sessions. In the control group; no intervention was done. Before and after the implementation; measurements of the participants were obtained. The data were collected using Gross Motor Function Measure, Modified Ashworth Scale (MAS), Modified Tardieu Scale, Pediatric Functional Independence Scale, Pediatric Quality of Life Scale (PedsQL) and demographic data. RESULTS: A total of 45 children completed the study. The groups were homogeneous at baseline. Between right MAS Gastrocnemius muscle was a difference and right and left Soleus muscles was significant among the groups (p<0.05). Also; there was significant difference in between right and left Tardieu value in the legs; right M. Gastrocnemius V1,V3 and M. Soleus V1, V3 values; p<0.001 and left Gastrocnemius V1 and M. Soleus V1, V3 values; p<0.001. In Gross Motor Function Measure total scores and sitting position; in Pediatric Functional Independence Scale total scores, self-care and communication subscales (p<0.05). But in terms of PedsQL was no statistically significant difference among the groups (p>0.05). CONCLUSIONS: Reflexology with physiotherapy reduced spasticity in legs, improved gross motor functions, decreased dependency but led to no change in quality of life. PMID- 28720234 TI - Effect of music therapy on the anxiety levels and pregnancy rate of women undergoing in vitro fertilization-embryo transfer: A randomized controlled trial. AB - PURPOSE: The aim of this study was to determine the effect of music therapy on the anxiety levels and pregnancy rates of women who underwent in vitro fertilization-embryo transfer. METHODS: This prospective randomized controlled trial was conducted with 186 infertile women who presented to the In Vitro Fertilization Unit at the American Hospital in Turkey between April 2015 and April 2016. The infertile women who met the inclusion criteria were assigned to the music therapy group or the standard therapy group through block randomization. The study data were collected using the Personal Information Form, and State-Trait Anxiety Inventory. Early treatment success was determined by serum beta human chorionic gonadotrophin levels seven or ten days after the luteal day zero. For the analysis, descriptive statistics, chi-square test, Fisher's exact test, independent sample t-test were used. RESULTS: After the embryo transfer, the mean state anxiety scores decreased in both groups, and the mean trait anxiety score decreased in the music therapy group; however, the difference was not statistically significant (p>0.05). Clinical pregnancy rates did not differ between the music (48.3%) and standard (46.4%) therapy groups. CONCLUSION: After the two sessions of music therapy, state and trait anxiety levels decreased and pregnancy rates increased, but the difference was not significant. Therefore, larger sample sizes and more sessions are needed to evaluate whether music therapy has an effect on clinical outcomes. PMID- 28720235 TI - Self-efficacy and self-care behaviours among adults with type 2 diabetes. AB - BACKGROUND: Type 2 Diabetes Mellitus (T2DM) has an impact on an individuals' health and is influenced by glycemic control. AIM: To examine the relationship between glycemic control, demographic and clinical factors on self-efficacy and self-care behaviours among adults with T2DM. DESIGN: A correlational, descriptive study was used. One hundred and forty Omani adults with T2DM were recruited from a public hospital. METHODS: Data on self-efficacy, self-care behaviours and glycemic control were collected between April and July 2016. The study was approved by the College Ethics Committee and Hospital Board. Bivariate and multivariate analyses were conducted. RESULTS: Most adults had a fasting blood glucose >7.2mmol/L (90.7%), with the majority demonstrating 'uncontrolled' or poor HbA1c of >8% (65%). Variance of self-care behaviour (20.6%) and 31.3% of the variance of the self-efficacy was explained by the age, duration of diabetes, medication, HbA1c and prevention of activities of living. CONCLUSIONS: Adults with T2DM with poor glycemic control were more probable to have poor self efficacy and self-care behaviours. Glycemic control has an effect on improving diet, exercise, medication, foot care efficacy and behaviours. CLINICAL RELEVANCE: The study recommends using these findings to plan self-efficacy and self-care behaviour to improve glycemic control among adults with T2DM. PMID- 28720236 TI - Leadership tenure is related to aide turnover in US assisted living facilities: Cross-sectional secondary data analysis. PMID- 28720237 TI - Work engagement, social support, and job satisfaction in Portuguese nursing staff: A winning combination. AB - BACKGROUND: Job Demands-Resources model assumes the mediator role of work engagement between social support (job resource) and job satisfaction (organizational result). However, recent studies suggest that social support can be considered as a moderator variable in the relationship between engagement and job satisfaction in nursing staff. AIM: The aim of this study is to analyze the moderator role of social support, from supervisor and from co-workers, in the relationship between work engagement and job satisfaction in a Portuguese nursing sample. METHOD: We conducted a cross-sectional and correlational study assessing a final sample of 215 participants (55.56% response rate, 77.21% women). Moderation analyses were carried out using multiple and hierarchical linear regression models. RESULTS: Job satisfaction was significantly predicted by work engagement and social support from supervisor and from co-workers. The significant interaction in predicting job satisfaction showed that social support from co-workers enhances the effects of work engagement on nurses' satisfaction. CONCLUSION: A climate of social support among co-workers and higher levels of work engagement have a positive effect on job satisfaction, improving quality care and reducing turnover intention in nursing staff. PMID- 28720238 TI - Job satisfaction, demands of immigration among international nursing staff working in the long-term care setting: A cross-sectional study. PMID- 28720239 TI - Effect of diet and exercise intervention in Chinese pregnant women on gestational weight gain and perinatal outcomes: A quasi-experimental study. AB - : Aim To determine the effect of a diet and exercise intervention in pregnant women on total gestational weight gain, weekly weight gain, 42-days postpartum weight retention, mode of delivery, and infant birth weight. METHODS: One hundred and one eligible Chinese pregnant women whose pre-pregnancy body mass index ranged from 18.5 to 24.9 were recruited between June 2013 and June 2014 from a tertiary hospital. Ninety participants, 45 in each group, completed the study. Intervention women received three face-to-face interventions and three follow-up phone calls which were developed based on the Transtheoretical Model. Gestational weight was measured at each prenatal check. Mode of delivery and infant birth weight were collected from the medical record. The 42-days postpartum weight was measured during the postpartum visits. RESULTS: (1) The total gestational weight gain and mean weight gain per week in the intervention group were significantly less than the control group (P=0.045 and P=0.008 respectively). (2) Infant birth weight was significantly lower in the intervention group (P=0.012). (3) Postpartum weight retention was significantly less in the intervention group (P=0.001). 4) There were not significant differences in mode of delivery. 5) Infant birth weight was significantly less than the control group (P=0.012). CONCLUSIONS: The lifestyle intervention significantly reduced gestational weight gain, optimized infant weight and lowered postpartum weight retention. Promotion of gestational weight management is needed and cultural health beliefs about pregnancy and postpartum practices should be considered when developing the intervention plan. PMID- 28720240 TI - Collaboration in discharge planning in relation to an implicit framework. PMID- 28720241 TI - The physician-nurse collaboration in feeding critically ill patients: A multicenter survey. AB - AIMS: Describe physician-nurse collaboration in feeding critically ill patients and explore the influence factors related to this collaboration, which can provide information for clinical practice and future studies. BACKGROUND: Appropriate nutrition support is essential and significant for critically ill patients, and the importance of physician-nurse collaboration in other fields has been confirmed, yet there are limited studies put insights into the status of physician-nurse collaboration in feeding critically ill patients. METHODS: A cross-sectional survey with a covering of 15 hospitals was conducted. A 21-item questionnaire was administered to physicians and nurses in critical care units. Descriptive statistics, univariate and multiple stepwise regression analysis were performed to evaluate the physician-nurse collaboration in feeding critically ill patients. RESULTS: A total of 331 respondents completed the questionnaire. Nurses and physicians were found to have differing perceptions of the physician-nurse collaboration in feeding critically ill patients, with nurses reporting lower levels of collaboration. Nurses consistently gave more negative responses on every survey question compared with physicians. Age, education and clinical experience significantly influenced the nurses' perceptions of cooperation, and age, education, ICU type, and seniority affected the physicians' perceptions of collaboration. CONCLUSIONS: Physicians, nurses and hospital administrators should highlight the physician-nurse collaboration in feeding critically ill patients and reinforce the cooperation based on potential influencing factors. Further research is required to establish feasible cooperative protocol and evaluate the effectiveness of the approach. PMID- 28720242 TI - Contribution of family social support to the metabolic control of people with diabetes mellitus: A randomized controlled clinical trial. AB - AIM: This randomized controlled clinical trial aimed to evaluate the contribution of family social support to the clinical/metabolic control of people with type 2 diabetes mellitus. BACKGROUND: Diabetes mellitus is a chronic disease that requires continuous care in order for individuals to reach glycemic control, the primordial goal of treatment. Family social support is essential to the development of care skills and their maintenance. However, there are few studies that investigate the contribution of family social support to diabetes control. METHODS: The study was developed between June 2011 and May 2013, and included 164 people who were randomized using simple randomization. The intervention group differed from the control group in that it included a family caregiver, who was recognized by the patient as a source of social support. The educational interventions received by people with diabetes mellitus were used as the basis of the education provided through telephone calls to patients' family members and caregivers, and their purpose was to encourage dialogue between the patients and their relatives about the topics related to diabetes. RESULTS: Regarding the clinical impact, the results showed that there was a greater reduction in blood pressure and glycated hemoglobin in the intervention group than in the control group, showing a positive effect on the control of the disease. CONCLUSIONS: Families should be incorporated into the care of people with diabetes mellitus and especially in health care programs, in particular those that can promote different forms of social support to strengthen the bond between family members. PMID- 28720243 TI - Strategies to engage older adults with behavioral and psychological symptoms of dementia in exercise: A multiple case study. PMID- 28720244 TI - CPAP nonadherence issues in a small sample of men with obstructive sleep apnea. PMID- 28720245 TI - Recruitment process of a Chinese immigrant study in Canada. AB - The objectives of this article were to provide a comprehensive overview of the recruitment experience and participant characteristics in an antihypertensive dietary educational intervention pilot trial among Chinese Canadians. The recruitment was conducted in a community centre. Two recruitment approaches, self referral and proactive recruitment, were used. Among 618 Chinese Canadians in the blood pressure screening, 105 (17.0%) individuals were eligible to participate in this trial. Of the 105 eligible individuals, 45 (42.9%) declined enrollment and 60 (57.1%) consented to participate in the trial and were recruited. The most common reason for refusal was being unable to access to the education location (n=19, 42.2%) followed by being too busy to participate (n=18, 40.0%). All participants were Chinese immigrants and the mean number of years living in Canada was 9.2. Most participants had low English proficiency, accepted Chinese culture more than Western culture, and had strong traditional health beliefs. It is concluded that both self-referral and proactive recruitment approaches were effective. Home-based interventions using Internet and telephone should be used as alternative delivery approaches to improve recruitment rate and facilitate participation. PMID- 28720246 TI - Does recovery buffer against emotional labor in terms of motivational outcomes at work? Analyzing age differences among Finnish health care professionals. PMID- 28720247 TI - Organizational culture among levels of health care services in Crete (Greece). PMID- 28720248 TI - Adaptation of the contraceptive self-efficacy scale for heterosexual Mexican men and women of reproductive age. AB - AIM: Development of a Spanish Version Contraceptive Self-efficacy Scale for use among heterosexual Mexican populations of reproductive age inclusive of 18 35years. BACKGROUND: Methods of family planning have decreased in Mexico which may lead to an increase in unintended pregnancies. Contraceptive self-efficacy is considered a predictor and precursor for use of family planning methods. METHODS: Cross-sectional, descriptive study design was used to assess contraceptive self efficacy among a heterosexual Mexican population (N=160) of reproductive age (18 35years). Adaptation of a Spanish Version Contraceptive Self-efficacy scale was conducted prior to instrument administration. RESULTS: Exploratory and confirmatory factorial analyses identified seven factors with a variance of 72.812%. The adapted scale had a Cronbach alpha of 0.771. A significant correlation between the Spanish Version Contraceptive Self-efficacy Scale and the use of family planning methods was identified. CONCLUSIONS: The Spanish Version Contraceptive Self-efficacy scale has an acceptable Cronbach alpha. Exploratory factor analysis identified 7 components. A positive correlation between self reported contraceptive self-efficacy and family planning method use was identified. This scale may be used among heterosexual Mexican men and women of reproductive age. The factor analysis (7 factors versus 4 factors for the original scale) identified a discrepancy for interpretation of the Spanish versus English language versions. Interpretation of findings obtained via the Spanish version among heterosexual Mexican men and women of reproductive age require interpretation based upon these differences identified in these analyses. PMID- 28720249 TI - Using wheel availability to shape running behavior of the rat towards improved behavioral and neurobiological outcomes. AB - BACKGROUND: Though voluntary wheel running (VWR) has been used extensively to induce changes in both behavior and biology, little attention has been given to the way in which different variables influence VWR. This lack of understanding has led to an inability to utilize this behavior to its full potential, possibly blunting its effects on the endpoints of interest. NEW METHOD: We tested how running experience, sex, gonadal hormones, and wheel apparatus influence VWR in a range of wheel access "doses". RESULTS: VWR increases over several weeks, with females eventually running 1.5 times farther and faster than males. Limiting wheel access can be used as a tool to motivate subjects to run but restricts maximal running speeds attained by the rodents. Additionally, circulating gonadal hormones regulate wheel running behavior, but are not the sole basis of sex differences in running. COMPARISON WITH EXISTING METHOD(S): Limitations from previous studies include the predominate use of males, emphasis on distance run, variable amounts of wheel availability, variable light-dark cycles, and possible food and/or water deprivation. We designed a comprehensive set of experiments to address these inconsistencies, providing data regarding the "microfeatures" of running, including distance run, time spent running, running rate, bouting behavior, and daily running patterns. CONCLUSIONS: By systematically altering wheel access, VWR behavior can be finely tuned - a feature that we hypothesize is due to its positive incentive salience. We demonstrate how to maximize VWR, which will allow investigators to optimize exercise-induced changes in their behavioral and/or biological endpoints of interest. PMID- 28720250 TI - Cardiovascular disease and perceived weight, racial, and gender discrimination in U.S. adults. AB - OBJECTIVE: To date, most research on perceived discrimination and cardiovascular disease (CVD) has examined racial discrimination although other forms of discrimination may also impact physical and mental health. The current study investigated the relationship between three forms of discrimination (weight, race, and gender) and 3-year incidence of CVD in a large national sample of U.S. adults. METHODS: 26,992 adults (55.5% women) who participated in the 2001-2002 and 2004-2005 National Epidemiologic Survey of Alcohol and Related Conditions (NESARC) were included in this study. Multiple logistic regression analyses were used to calculate odds ratios (OR) and 95% confidence intervals (CI) for three forms of perceived discrimination (simultaneously included in equations after adjusting for relevant potential confounds) for predicting CVD incidence at Wave 2. RESULTS: Perceived weight and racial discrimination were associated with significantly greater likelihood of reporting myocardial infarction (OR=2.56 [95% CI=1.31-4.98], OR=1.84 [95% CI=1.19-2.84], respectively) and minor heart conditions (OR=1.48 [95% CI=1.11-1.98], OR=1.41 [95% CI=1.18-1.70], respectively). Perceived racial discrimination was also significantly associated with greater likelihood of reporting arteriosclerosis (OR=1.61 [95% CI=1.11 2.34]). Odds ratios for diagnoses of arteriosclerosis, myocardial infarction, and other minor heart disease were largest for individuals reporting multiple forms of discrimination. CONCLUSIONS: Adults who experience weight and racial discrimination, and especially multiple forms of discrimination, may be at heightened risk for CVD. Perceived discrimination may be important to consider during assessment of life stressors by health providers. Future research should address the mechanisms that link discrimination and CVD to assist public health and policy efforts to reduce discrimination. PMID- 28720251 TI - [Advises and performs physical exercise]. PMID- 28720252 TI - The cryptochrome-photolyase protein family in diatoms. AB - The cryptochrome - photolyase family (CPF) consists of homologous flavoproteins having completely different functions involving DNA repair, circadian rhythm and/or photoreception. From the original photolyases, working either as (6-4) or cyclobutane pyrimidine dimer photolyases, the animal- and plant-type cryptochromes, respectively, evolved and also the more intermediate DASH cryptochromes. Whereas animal cryptochromes work mostly in clock-related functions, plant cryptochromes are also directly involved in developmental processes such as hypocotyl elongation or flower induction. In diatoms, all types of cryptochromes and photolyases were predicted from genome sequences. However, up to now only two proteins have been characterised in more detail, CPF1 and CryP. CPF1 is related to animal-type cryptochromes, but works as a (6-4) photolyase in addition to having photoreceptor functions. It was shown to interact with the CLOCK:Bmal1 heterodimer in a heterologous system, and thus is probably involved in clock-related processes. Moreover, CPF1 directly influences transcription. The latter was also true for CryP, which is a cryptochrome distantly related to plant-type cryptochromes. In addition, CryP influences light harvesting protein accumulation. For all diatom cryptochromes, down-stream signalling has to proceed via interaction partners different from the classical proteins involved in cryptochrome signalling in higher plants, because these candidates are missing in diatoms. PMID- 28720253 TI - Pulmonary Actinomycosis in a Patient with Chronic Eosinophilic Pneumonia treated with Omalizumab. PMID- 28720254 TI - Myxoma or Lung Cancer? PMID- 28720255 TI - Altitude-Related Illnesses. PMID- 28720257 TI - Feasibility of advanced practice nursing in lung cancer consultations during early treatment: A phase II study. AB - PURPOSE: There are limited data on the effectiveness of Advanced Practice Nurses in Lung Cancer (APNLC). Previous studies have demonstrated barriers to investigation including low recruitment and high attrition rates in lung cancer population. The primary aim of this study was to assess the feasibility of APNLC consultations and the ability to collect patient-reported outcome measures (PROMs) during first-line treatment. The secondary aim was to describe changes in self-efficacy for managing lung cancer-related symptoms, symptom intensity/burden and unmet supportive care needs of APNLC patients during first-line treatment. METHODS: An exact single-stage phase II design was applied. We recruited a consecutive sample of newly diagnosed lung cancer patients receiving systemic treatment in a Swiss oncology outpatient center. The intervention consisted of four systematic, alternating face-to-face/telephone consultations during first line-treatment. Feasibility of the study was defined by at least 55% of patients receiving all scheduled APNLC-led consultations and completing PROMs assessments at the three timepoints. RESULTS: In total, 35/46 (76%) (95% CI, 0.61 to 0.87) of patients met the feasibility criteria receiving all scheduled APNLC consultations. Fifty-six percent (26/46) (95% CI, 0.41 to 0.71) completed the PROMs at the three timepoints. Self-efficacy for managing symptoms remained stable, intensity of predominant symptoms increased. Unmet information needs decreased significantly while psychological and sexuality related needs increased over time. CONCLUSION: Results were promising for the feasibility of the APNLC consultation and the ability to collect PROMs. Further investigations are needed to increase the impact of the APNLC consultations on symptom intensity and sexual and psychological needs. PMID- 28720256 TI - Efficacy of a hydroactive colloid gel versus historical controls for the prevention of radiotherapy-induced moist desquamation in breast cancer patients. AB - PURPOSE: Radiotherapy-induced moist desquamation (RIMD) is a complication that can affect patients' quality of life and jeopardize radiotherapy outcomes. The curative use of a hydroactive colloid gel has previously been shown effective in the management of RIMD in breast cancer patients. This study aimed at investigating the efficacy of this same gel but in the prevention of RIMD. METHODS: A group of breast cancer patients who applied the hydroactive gel from start to end of post-lumpectomy radiotherapy (Preventive Hydrogel group) were compared with two groups of matched historical controls: a group applying a dexpanthenol cream throughout their therapy and a group applying first the dexpanthenol cream then, after 11-14 fractions of radiotherapy, the hydroactive gel (Curative Hydrogel group). All patients received identical fractionation regimen. The clinical outcomes were the incidence and time to onset of RIMD. KEY RESULTS: After 25 fractions of radiotherapy (50 Gy), patients in the Preventive Hydrogel group (N = 202) developed RIMD significantly less frequently and later than patients in the Dexpanthenol group (N = 131; incidence = 7% vs 35% respectively, odds ratios = 7.27; probability of RIMD-free survival after 50 Gy = 0.88 vs 0.62). There were no significant differences between the Preventive and the Curative Hydrogel group (N = 87). CONCLUSIONS: These findings confirm our previous results: applying the hydroactive colloid gel, rather than dexpanthenol, delayed the onset and reduced the incidence of RIMD in breast cancer patients. However, applying the hydrogel preventively offered no statistically significant advantages over applying it curatively. PMID- 28720258 TI - Feasibility and acceptability of the use of patient-reported outcome measures (PROMs) in the delivery of nurse-led supportive care to people with colorectal cancer. AB - PURPOSE: Logistical issues pertinent to the use of patient-reported outcome measures (PROMs) by colorectal cancer nurse specialists (CNS) to identify the needs of people with colorectal cancer (CRC) in acute care remain unknown. We explored the feasibility and acceptability of PROMs-driven, CNS-led consultations to enhance delivery of supportive care to people with CRC completing adjuvant chemotherapy. METHODS: A systematic literature review and focus groups with patients and CNS (Phase 1) were followed by a repeated-measures, exploratory study (Phase 2), whereby pre-consultation PROM data were collected during three consecutive, monthly consultations, and used by the CNS to enable delivery of personalised supportive care. RESULTS: Based on Phase 1 data, the Supportive Care Needs Survey was selected for use in Phase 2. Fourteen patients were recruited (recruitment rate: 56%); thirteen (93%) completed all study assessments. Forty in clinic patient-clinician consultations took place. At baseline, 219 unmet needs were reported in total, with a notable 21% (T2) and 32% (T3) over-time reduction. Physical/daily living and psychological domain scores declined from T1 to T3, yet not statistically significantly. In exit interviews, patients described how using the PROM helped them shortlist and prioritise their needs. CNS stressed how the PROM helped them tease out more issues with patients than they would normally. CONCLUSIONS: Nurse-led, PROMs-driven needs assessments with patients with CRC appear to be feasible and acceptable in clinical practice, possibly associated with a sizeable reduction in the frequency of unmet needs, and smaller decreases in physical/daily living and psychosocial needs in the immediate post chemotherapy period. PMID- 28720260 TI - Cancer survivorship: Advancing the concept in the context of colorectal cancer. AB - PURPOSE: Previous conceptualizations of cancer survivorship have focused on heterogeneous cancer survivors, with little consideration of the validity of conclusions for homogeneous tumour groups. This paper aims to examine the concept of cancer survivorship in the context of colorectal cancer (CRC). METHOD: Rodgers' (1989) Evolutionary Method of Concept Analysis guided this study. A systematic search of PUBMED, CINAHL, PsycINFO and The Cochrane Library was conducted in November 2016 to identify studies of CRC survivorship. The Braun and Clarke (2006) framework guided the analysis and interpretation of data extracted from eighty-five publications. RESULTS: Similar to general populations of cancer survivors, CRC survivors experience survivorship as an individual, life-changing process, punctuated by uncertainty and a duality of positive and negative outcomes affecting quality of life. However, CRC survivors experience specific concerns arising from the management of their disease. The concept of cancer survivorship has evolved over the past decade as the importance of navigating the healthcare system and its resources, and the constellation of met and unmet needs of cancer survivors are realised. CONCLUSIONS: The results highlight core similarities between survivorship in the context of CRC and other tumour groups, but underlines issues specific to CRC survivorship. Communication and support are key issues in survivorship care which may detrimentally affect CRC survivors' well-being if they are inadequately addressed. Healthcare professionals (HCP's) therefore have a duty to ensure cancer survivors' health, information and supportive care needs are met in the aftermath of treatment. PMID- 28720259 TI - Empowering survivors after colorectal and lung cancer treatment: Pilot study of a Self-Management Survivorship Care Planning intervention. AB - PURPOSE: This study evaluates the feasibility and acceptability of a Self Management Survivorship Care Planning (SM-SCP) intervention in colorectal and lung cancer survivors. METHODS: This is a single-group, pre- and post-mixed methods study of an advance practice nurse-driven survivorship care intervention that integrates a survivorship care plan with self-management skills coaching. Colorectal and lung cancer survivors with stage I-III disease were enrolled at 3 6 months after completing treatments, and the intervention was administered in one in-person or telephone session. Survivor outcome measures included depression, anxiety, self-efficacy, QOL, and satisfaction. Paired t-tests were used for exploratory evaluations of pre-to post-intervention score changes. Content analysis was conducted to analyze the qualitative data to describe survivors' experience with the intervention. RESULTS: Thirty participants (15 colorectal, 15 lung) enrolled and completed the study (73% retention). It took an average of 40 min to complete the TS/CP and 34.2 min to deliver the intervention. Exploratory analysis revealed significant differences from baseline to post intervention in depression, anxiety, self-efficacy, physical functioning, role limitations-physical, pain, general health, health transition, physical health summary, and total QOL. Three qualitative themes emerged: 1) Feeling empowered about having a plan; 2) Struggling with psychosocial concerns; and 3) Suggestions for intervention content and delivery. CONCLUSIONS: The SM-SCP intervention was feasible and acceptable for colorectal and lung cancer survivors after treatment completion. Survivorship care interventions have potential to fulfill the unmet needs of colorectal and lung cancer survivors. Their effectiveness might be greater by integrating conceptually-based models of care, such as self-management skills building. PMID- 28720261 TI - Motivation to uphold physical activity in women with breast cancer during adjuvant chemotherapy treatment. AB - PURPOSE: Physical activity (PA) is important for recovery after a breast cancer diagnosis; however, women's motivation to engage in PA can be impacted by disease and/or treatment, and can therefore be a challenge. This study explored factors associated with PA levels during chemotherapy among women with breast cancer. METHOD: The study had a cross-sectional descriptive and comparative design using a study-specific questionnaire. One hundred women with breast cancer receiving adjuvant chemotherapy were included. Data were analysed by Pearson's correlation coefficient and linear regression. The open question was subjected to manifest content analysis. RESULTS: Identified factors associated with engaging in PA during chemotherapy treatment were: being physically active before diagnosis, and the information given by the oncology nurse before the treatment start. The physically active women experienced higher psychological wellbeing, less fatigue, and faster recovery after treatment. They also experienced an overall feeling of fitness. CONCLUSION: It seems that PA is associated with less fatigue, better recovery between chemotherapy treatments, and a better mental condition leading to wellbeing. Information given by the oncology nurse may be an important factor for being physically active. Women with breast cancer need to get specific advice about and support in engaging in PA to feel better during chemotherapy treatment. Further research is required to develop guidelines for advice about and support regarding PA during chemotherapy treatment. PMID- 28720262 TI - Nothing is more important than my partner's health: Turkish men's perspectives on partner's appearance after mastectomy and alopecia. AB - PURPOSES: The aim of this study was to acquire a deeper understanding of male experiences on the emotional and social impact of their partners' mastectomy and chemotherapy-induced alopecia. METHODS: A purposive sample of 16 males whose partners had undergone mastectomy and alopecia due to chemotherapy was chosen. The data were collected through a semi-structured interview method. Interpretative Phenomenological Analysis of tape-recorded interviews was employed. RESULTS: Two main themes emerged from the data: facing the changes and my wife and I at present. Male partners were affected differently by the change in the physical appearance of their female partners. Our study participants said it was a difficult experience to see their partners for the first time after the surgery, but they emphasized that it was more important that their partners were healthy than the fact that they did not have a breast and hair. They also said they did not know how to behave towards their partners after surgery and/or chemotherapy. Nevertheless, they felt that the disease process of their partners had strengthened their bond and had not negatively influenced their relationship with others. CONCLUSIONS: The changes in the partners' physical appearance after mastectomy and chemotherapy affected males differently in psychological, emotional and social terms. Since nurses working in this field are in contact with patients during all phases of treatment and care, it would be positive and beneficial to plan nursing interventions that give emotional support for male partners of patients with breast cancer. PMID- 28720265 TI - The mediating role of resilience in the relationship between social support and posttraumatic growth among colorectal cancer survivors with permanent intestinal ostomies: A structural equation model analysis. AB - PURPOSE: Information on posttraumatic growth (PTG) among colorectal cancer (CRC) survivors with permanent intestinal ostomies is limited. The aim of this cross sectional study was to investigate the occurrence of PTG among CRC survivors with permanent intestinal ostomies and its association with perceived social support and resilience. METHODS: This study was conducted with 164 CRC survivors with permanent intestinal ostomies at least one month after surgery. Participants completed questionnaires assessing socio-demographic and clinical characteristics, perceived social support, resilience and PTG. RESULTS: The mean total score on the Post Traumatic Growth Inventory was 66.74 (SD = 13.99). Perceived social support (r = 0.450) and resilience (r = 0.545) were significantly positively correlated with PTG. Structural equation modeling analysis showed that resilience mediated the relationship between perceived social support and PTG in which the indirect effect of perceived social support on PTG through resilience was 0.203 (P < 0.001). CONCLUSIONS: Moderate to high PTG was found in CRC survivors with permanent intestinal ostomies. The most important implication of this study was that improving social support and resilience might be scientific intervention strategies for promoting PTG among CRC survivors. PMID- 28720263 TI - Aiming for a holistic integrated service for men diagnosed with prostate cancer - Definitions of standards and skill sets for nurses and allied healthcare professionals. AB - PURPOSE: To establish a comprehensive set of recommendations for the service structure and skill set of nurses and allied healthcare professionals in prostate cancer care. METHODS: Using components of formal consensus methodology, a 30 member multidisciplinary panel produced 53 items for discussion relating to the provision of care for prostate cancer patients by specialist nurses and allied healthcare professionals. Items were developed by two rounds of email correspondence in which, first, items were generated and, second, items refined to form the basis of a consensus meeting which constituted the third round of review. The fourth and final round was an email review of the consensus output. RESULTS: The panel agreed on 33 items that were appropriate for recommendations to be made. These items were grouped under categories of "Environment" and "Patient Pathway" and included comments on training, leadership, communication and quality assessment as well as specific items related to prostate diagnosis clinics, radical treatment clinics and follow-up survivor groups. CONCLUSIONS: Specialist nurses and allied healthcare professionals play a vital role alongside urologists and oncologists to provide care to men with prostate cancer and their families. We present a set of standards and consensus recommendations for the roles and skill-set required for these practitioners to provide gold-standard prostate cancer care. These recommendations could form the basis for development of comprehensive integrated prostate cancer pathways in prostate cancer centres as well as providing guidance for any units treating men with prostate cancer. PMID- 28720264 TI - Fatigue and health related quality of life in children and adolescents with cancer. AB - PURPOSE: The study examined the different dimensions of fatigue (general, sleep/rest, cognitive), health related quality of life (HRQL) (physical, emotional, cognitive, social), and the relationships between fatigue and HRQL in hospitalized children and adolescents with cancer in Brazil. METHOD: Participants were recruited from a pediatric oncology inpatient unit in a comprehensive cancer care hospital in southeast Brazil. They completed the PedsQL Multidimensional Fatigue Scale and the PedsQL Inventory of Quality of Life (Generic and Cancer module) once during hospitalization. RESULTS: The majority (66.7%) of the participants (n = 38; mean age 12.1 +/- 2.9 years) had total fatigue scores < 75 on 0 to 100 scale; with the mean total fatigue score of 63.8 +/- 18.5. The majority (72.2% generic; 83.3% cancer modules) had total PedsQL scores < 75 on 0 to 100 scale. The mean PedsQL score on generic module (61.1 +/- 17.0) was similar to the mean PedsQL score cancer module (59.1 +/- 16.7). Significant correlations were found between total fatigue and quality of life generic (r = 0.63, p = 0.000) and cancer module (r = 0.74, p = 0.000). CONCLUSIONS: The study is the first to report fatigue and health related quality of life in hospitalized children and adolescents with cancer in Brazil. Similar to experiences of other children in the world, our findings indicate that children and adolescents with cancer had problems with fatigue that were associated with low HRQL. Future studies are recommended to examine interventions (exercise, leisurely activities) that may alleviate fatigue and improve HRQL in pediatric patients with cancer. PMID- 28720266 TI - Strengths and resources used by Australian and Danish adult patients and their family caregivers during treatment for cancer. AB - PURPOSE: Family plays an essential role in supporting the patient with cancer, however, relatively little attention has been given to understanding the strengths and resources of the family unit across different settings and countries. This study aims to investigate the strengths and resources of patients and family members in Australia and Denmark. METHODS: Using a descriptive, cross sectional design, 232 patient and family participants from inpatient and outpatient oncology services in Australia and Denmark completed paper based surveys that included the Family Hardiness Index (FHI) and Family Crisis Orientated Personal Evaluation Scales (F-COPES), together with demographic and health information. RESULTS: The family's appraisal of the cancer and ways the family worked together predicted the level of external resources used to manage their circumstances. CONCLUSION: After a cancer diagnosis patients and family respond in different ways related to their family functioning. There is a need for nurses to work closely with the family to understand their strengths and resources, and tailor support and information for family to promote optimal patient outcomes. PMID- 28720267 TI - A systematic review of the supportive care needs of people living with and beyond cancer of the colon and/or rectum. AB - PURPOSE: Gaining a clear understanding of the health needs and concerns of people with cancer of the colon and/or rectum can help identify ways to offer a comprehensive care package. Our aim was to systematically assess the relevant literature and synthesise current available evidence. METHODS: A systematic review was conducted according to the PRISMA Statement guidelines. Five electronic databases were searched to identify studies employing qualitative and/or quantitative methods. Pre-specified selection criteria were applied to all retrieved records. Findings were integrated in a narrative synthesis. RESULTS: Of 3709 references initially retrieved, 54 unique studies were retained. A total of 136 individual needs were identified and classified into eight domains. Just over half of the needs (70; 51%) concerned information/education or health system/patient-clinician communication issues. Emotional support and reassurance when trying to deal with fear of cancer recurrence featured as the most prominent need regardless of clinical stage or phase of treatment. Information about diet/nutrition and about long-term self-management of symptoms and complications at home; tackling issues relating to the quality and mode of delivery of health related information; help with controlling fatigue; and on-going contact with a trustworthy health professional also featured as salient needs. Available research evidence is of moderate-to-good quality. CONCLUSIONS: Investing time to sensitively inquire about the supportive care needs of this patient population is key, whilst evaluating and re-shaping clinical interactions based on patients' priorities is equally essential. The diverse needs identified require a multi professional and multi-agency approach to ensure unmet needs are addressed or measures offered. PMID- 28720268 TI - Art in cancer care: Exploring the role of visual art-making programs within an Energy Restoration Framework. AB - PURPOSE: In contrast to art-therapy, little is known about the role of art-making for people who have been diagnosed with cancer, and even less is known about program-based art-making. This study explored the experience of participation in a visual art-making program for people during and after cancer treatment in the Northern Territory of Australia. METHOD: A longitudinal, qualitative, single cohort study was undertaken. Eight women diagnosed with breast and/or ovarian cancer participated in weekly art-making sessions over eight weeks, facilitated by two professional artists. Data were collected before, during and after the sessions by interviews and group discussions. The Energy Restoration Framework was used to document and analyse the benefits of participation in terms of the a priori themes of: Expansive, Belonging, Nurturing and Purposeful. RESULTS: The four a priori themes were retained and an additional attribute of an energy restoration activity called Stimulating was added, along with sub-themes, which broadened and deepened understanding of the art-making experience within cancer care. CONCLUSIONS: Involvement in an activity that was expansive, new, beautiful and fascinating was highly valued in addition to the appreciation for being with and belonging to a supportive and accepting group facilitated by dynamic artists. There is much scope for continued research and promotion of art-making programs as an adjunct to cancer treatment. PMID- 28720269 TI - Relationships of salivary cortisol and melatonin rhythms to sleep quality, emotion, and fatigue levels in patients with newly diagnosed lung cancer. AB - PURPOSE: After being diagnosed with lung cancer, patients often experience sleep disturbance, anxiety, depression, and fatigue. These symptoms may occur because of changes in neurotransmitter secretion caused by tumors. This study investigated the correlation of cortisol and melatonin rhythms with sleep quality, anxiety, depression, and fatigue levels in patients with newly diagnosed lung cancer. METHOD: We conducted a case-control study and recruited 40 patients with newly diagnosed lung cancer and 40 healthy adults. RESULTS: The patient group had a lower salivary melatonin level and flatter slope (p < 0.001 and p < 0.001), higher salivary cortisol level and steeper slope (p < 0.001 and p < 0.001), higher sleep disturbance level (p = 0.004), and higher depression level (p < 0.001). The multivariate linear regression analysis indicated that the cortisol slope (p = 0.005) and fatigue score (p = 0.032) predicted the sleep quality score (p = 0.011). CONCLUSION: Overall, the patients with newly diagnosed lung cancer had poorer sleep quality, higher depression levels, lower salivary melatonin levels, higher cortisol levels, and flatter melatonin and cortisol slopes than did the controls. The fatigue level and cortisol slope significantly predicted sleep quality. Therefore, the assessment of cortisol and melatonin rhythms and levels could provide crucial information that may be beneficial for managing symptoms in patients with newly diagnosed lung cancer. PMID- 28720270 TI - Cancer through black eyes - The views of UK based black men towards cancer: A constructivist grounded theory study. AB - PURPOSE: Little is known about black African (BA) and black African-Caribbean (BAC) men's views towards cancer; yet culture and acculturation can contribute to the way in which people understand, explain and develop their attitudes towards cancer. Hence, cancer prevention and early detection strategies may not be sensitive to United Kingdom (UK)-based black men's views, affecting their awareness of risk factors and early detection services. This study explored the views of UK-based BA and BAC men towards cancer. METHOD: In collaboration with black community organisations based in four major cities in the UK, 25 participants were recruited using convenience and theoretical sampling methods. Data were collected using 33 semi-structured interviews, and analysed using grounded theory analytic procedures. RESULTS: One core category (cancer through black eyes) and seven sub-categories emerged; 'cultural views', 'religious beliefs', 'avoiding Babylon', 'alienation', 'suspicious mind', 'advertisements and information influence very little', and 'gap in service provision (bridging the gap)'. Participants' views towards cancer were linked to socially constructed perspectives, linked with cultural and religious beliefs, and shaped by what being a black male means in society. Risk factors such as smoking and obesity had different meanings and symbolisation through black eyes. There were macro- and micro-level similarities and differences between BA and BAC men. CONCLUSIONS: Cancer services and related public-health campaigns aimed at black men need to understand cancer through black eyes. Public health campaigns based solely on the clinical meaning of cancer are incongruent with black men's understandings of cancer, and therefore ineffective at reducing health inequality. PMID- 28720271 TI - It's a question of endurance - Patients with head and neck cancer experiences of 18F-FDG PET/CT in a fixation mask. AB - PURPOSE: This study aimed to explore how patients with head and neck cancer experienced undergoing an 18F-fluoro-deoxy-glucose positrons emissions tomography/computed tomography (18F-FDG PET/CT) examination in a fixation mask. METHOD: Interviews were conducted with nine patients with known or suspected head and neck cancer who were scheduled for the examination for the first time. The phenomenological method according to van Manen and his four lifeworld existentials; lived space, lived body, lived time, and lived relation was used to analyse the interviews. RESULTS: The thoughts and feelings of the patients during the PET/CT examination varied, some found it very difficult, while others did not. However, for all the patients, it was an experience that required some form of coping to maintain composure for example distraction. CONCLUSIONS: PET/CT examnation in a fixation mask may be strenuous for some patients. Patients need more detailed information, including suggestions for coping behaviours, prior to the examination, as well as higher level of support during and after the examination. The results of this study may be used to improve patient care and optimize the procedure of PET/CT examination in a fixation mask. PMID- 28720272 TI - An ethnographic exploration of the delivery of psychosocial care to children with cancer in Argentina. AB - PURPOSE: The integration of psychosocial care in the routine care of cancer patients has been set as an international standard, but there are healthcare contexts where these services are lacking as psychosocial care providers are not incorporated in multidisciplinary teams and screening for psychological distress is not carried out routinely or systematically. METHOD: In this article, we discuss the findings from an ethnographic study that focused on exploring the working experiences of psychosocial care providers from one children's hospital in Buenos Aires, Argentina. The study is based on 10 in-depth interviews with hospital staff members and participant observation in selected hospital areas. The transcripts from the interviews and fieldnotes from the observations were analyzed using thematic analysis. RESULTS: We found that psychosocial care providers encounter difficulties while attempting to deliver services to children and their families, produced mainly by their lack of collaboration with other professional groups, insufficient human resources, and a growing patient population. As a result of this situation, psychosocial care providers often prioritize some patients over others, leaving a considerable number of patients and family members without psychosocial support. CONCLUSIONS: The study highlighted the barriers psychosocial care providers encounter while attempting to deliver services to children and their families. Further work needs to be carried out to fully integrate psychosocial care in national health policies and ensure this type of support is available for all patients and their families. PMID- 28720274 TI - Quality of care: A plea for patient perspectives and cost analyses. PMID- 28720273 TI - Meeting psychosocial and health information needs to ensure quality of cancer care in outpatients. AB - PURPOSE: The purpose of this study was to investigate patients' and caregivers' health needs for a re-orientation program based on principles of health promotion in an Oncology Department from an Italian University Hospital. METHOD: A Cross sectional design with qualitative and quantitative approaches was used. Participants included cancer patients and their caregivers. Information about disease concerns were collected using a survey form. Information about healthy lifestyle was obtained using motivational interviews. Information about perceived quality of oncology services was collected by a self-administered questionnaire. RESULTS: A total of 403 information requests were collected about patients' disease, 203 motivational interviews were carried out, and 219 questionnaires were collected. Overall, the results showed that patients and caregivers have healthy lifestyles even if meat consumption was high. Weak points were: poor physical space organization in the Service, long waiting times, and limited access to healthcare providers for patients. CONCLUSIONS: This study revealed the need for an approach based on health-promotion principles, with a particular focus on patient wellbeing and quality of life. The study increases awareness about the influence that an environment has on patient health, thus suggesting that changes in culture, attitude, and health services re-organization are crucial to meet total needs of the individual as a whole process. PMID- 28720275 TI - Nitrite accumulation in continuous-flow partial autotrophic denitrification reactor using sulfide as electron donor. AB - The nitrite accumulation in handling nitrate and sulfide-laden wastewater in a continuous-flow upflow anaerobic sludge blanket reactor was studied. At sulfide/nitrate-nitrogen ratio of 1:0.76 and loading rates of 1.2kg-Sm-3d-1 and 0.4kg-Nm-3d-1, the elemental sulfur and nitrite accumulation rates peaked at 90% and 70%, respectively, with Acrobacter, Azoarcus and Thauera presenting the functional strains in the studied reactor. The accumulated nitrite was proposed a promising feedstock for anaerobic ammonia oxidation process. An integrated partial autotrophic denitrification-anaerobic ammonia oxidation-aeration process for handling the ammonia and sulfide-laden wastewaters is proposed for further studies. PMID- 28720276 TI - Arsenic removal by periphytic biofilm and its application combined with biochar. AB - A biochar and periphyton-based system (BPS) comprising of a biochar column and a periphyton bioreactor was designed to avoid the toxicity issue associated with removing As(III) from wastewater. Results showed that the periphyton can grow when As(III) is less than 5.0mgL-1. The BPS obtained a high As(III) removal rate (~90.2-95.4%) at flow rate=1.0mLmin-1 and initial concentration of As(III)=2.0mgL 1. About 60% of the As(III) was pre-treated (adsorbed) in the biochar column and the removal of the remaining As(III) was attributed to the periphyton bioreactor. The As(III) removal process by periphytic biofilm in the initial stage fits a pseudo-second-kinetic model. The calcite in the periphytic biofilm surfaces and the OH and CO groups were responsible for the As(III) removal. This study indicates the feasibility of the BPS for As(III) removal in practice. PMID- 28720277 TI - Effect of feeding mode and dilution on the performance and microbial community population in anaerobic digestion of food waste. AB - The effect of feeding mode and dilution was studied in anaerobic digestion of food waste. An upflow anaerobic digester with a settler was fed at six different organic loading rates (OLRs) from 4.6 to 8.6kgCOD/m3/d for 200days. The highest methane productivity of 2.78LCH4/L/d was achieved at 8.6kgCOD/m3/d during continuous feeding of diluted FW. Continuous feeding of diluted food waste showed more stable and efficient performance than stepwise feeding of undiluted food waste. Sharp increase in propionate concentration attributed towards deterioration of the digester performances in stepwise feeding of undiluted food waste. Microbial communities at various OLRs divulged that the microbial distribution in the continuous feeding of diluted food waste was not significantly perturbed despite the increase of OLR up to 8.6kgCOD/m3/d, which was contrast to the unstable distribution in stepwise feeding of undiluted food waste at 6.1kgCOD/m3/d. PMID- 28720278 TI - [Development of a liquid fermentation system and encystment for a nitrogen-fixing bacterium strain having biofertilizer potential]. AB - The indiscriminate use of chemical fertilizers has contributed to the deterioration of the biological, physical and chemical properties of the soil, resulting in the loss of its productive capacity. For this reason, the use of biofertilizers has emerged as a technological alternative. The objective of this research was to develop a suitable liquid fermentation system and encystment for the multiplication of Azotobacter chroococcum AC1 strain, a bacterium employed in a biofertilizer formulation produced at present by CARPOICA, Colombia. Sequential statistical designs were used to determine the conditions in the fermentation system. The interaction between agitation, aeration and pH was evaluated on the viable biomass (CFU/ml) of AC1. In addition, the encystment ability of the strain was evaluated using two encystment agents and the potential plant growth promoting rhizobacteria (PGPR) activity was assessed by different techniques, such as nitrogen fixation by ARA, phosphate solubilization by the phospho molybdenum-blue reaction and indolic compound production by colorimetric reaction using the Salkowski reagent. Results showed significant effects (p<0.05) on the viable biomass in the three conditions (pH, aeration and agitation) tested individually, in one dual interaction and one tripartite interaction, were demonstrated to have a positive effect on the response variable aeration and agitation. The addition of the two encystment agents evaluated, AE01 and AE02, demonstrated the ability of AC1 to form cysts under stress conditions. Likewise, fermentation and encystment conditions did not affect the biological activities tested. PMID- 28720279 TI - Metabolomic analysis identifies altered metabolic pathways in Multiple Sclerosis. AB - Multiple sclerosis (MS) is a chronic, demyelinating disease that affects the central nervous system and is characterized by a complex pathogenesis and difficult management. The identification of new biomarkers would be clinically useful for more accurate diagnoses and disease monitoring. Metabolomics, the identification of small endogenous molecules, offers an instantaneous molecular snapshot of the MS phenotype. Here the metabolomic profiles (utilizing plasma from patients with MS) were characterized with a Gas cromatography-mass spectrometry-based platform followed by a multivariate statistical analysis and comparison with a healthy control (HC) population. The obtained partial least square discriminant analysis (PLS-DA) model identified and validated significant metabolic differences between individuals with MS and HC (R2X=0.223, R2Y=0.82, Q2=0.562; p<0.001). Among discriminant metabolites phosphate, fructose, myo inositol, pyroglutamate, threonate, l-leucine, l-asparagine, l-ornithine, l glutamine, and l-glutamate were correctly identified, and some resulted as unknown. A receiver operating characteristic (ROC) curve with AUC 0.84 (p=0.01; CI: 0.75-1) generated with the concentrations of the discriminant metabolites, supported the strength of the model. Pathway analysis indicated asparagine and citrulline biosynthesis as the main canonical pathways involved in MS. Changes in the citrulline biosynthesis pathway suggests the involvement of oxidative stress during neuronal damage. The results confirmed metabolomics as a useful approach to better understand the pathogenesis of MS and to provide new biomarkers for the disease to be used together with clinical data. PMID- 28720280 TI - Hospitalised rotavirus gastroenteritis in New Zealand: The laboratory database is a valuable tool for assessing the impact of rotavirus vaccination. AB - AIM: To assess the impact of the introduction of rotavirus vaccination in New Zealand at a regional and national level, underlining the utility of a passively collected laboratory dataset. METHOD: Retrospective laboratory data for rotavirus testing from Wellington and Hutt Hospitals from 1 January 2010 to 31 December 2016, matched with hospital admissions data of children under 5years of age with gastroenteritis primary and secondary coded admissions. The second part of the study examined the national dataset of primary coded hospital gastroenteritis admissions from the same period. RESULTS: Rotavirus testing was performed in 1054 (64.1%) of the 1645 gastroenteritis admissions to Wellington and Hutt Hospitals. Four hundred and nine of these tests (38.8%) were positive. Children who were not given a primary code of gastroenteritis accounted for 5.7% of rotavirus admissions. The estimated annual rotavirus hospitalisation rate in the Hutt and Wellington regions for children under 5years during the pre-vaccination period was 427.1 per 100,000. In the post-vaccination period (2015-2016), there was a 94.6% reduction in confirmed rotavirus gastroenteritis hospitalisations with only 8 confirmed cases. The total number of gastroenteritis admissions declined by 51.4%. On a national scale, there was a decline of 34.4% in the average annual number of gastroenteritis admissions and the number of coded rotavirus admissions was 87.1% lower than the pre-vaccination average. CONCLUSION: The non-restrictive continuous approach to rotavirus testing has provided a detailed description of the epidemiology of rotavirus gastroenteritis hospitalisations in the Wellington and Hutt regions. Rotavirus vaccination introduced on the crest of a peak in rotavirus cases has lead to a marked reduction in the number of admissions with gastroenteritis in New Zealand in the two years following vaccine introduction. The national figures likely underestimate the impact of the vaccine. PMID- 28720282 TI - Vaccinology in the 21st century-The 10th Annual Vaccine Congress. PMID- 28720281 TI - Evaluation of a primary course of H9N2 vaccine with or without AS03 adjuvant in adults: A phase I/II randomized trial. AB - BACKGROUND: Avian influenza A H9N2 strains have pandemic potential. METHODS: In this randomized, observer-blind study (ClinicalTrials.gov: NCT01659086), 420 healthy adults, 18-64years of age, received 1 of 10 H9N2 inactivated split-virus vaccination regimens (30 participants per group), or saline placebo (120 participants). H9N2 groups received 2 doses (days 0, 21) of 15ug hemagglutinin (HA) without adjuvant, or 1.9ugHA+AS03A, 1.9ugHA+AS03B, 3.75ugHA+AS03A, or 3.75ugHA+AS03B; followed by the same H9N2 formulation or placebo (day 182). AS03 is an adjuvant system containing alpha-tocopherol (AS03A: 11.86mg; AS03B: 5.93mg) and squalene in an oil-in-water emulsion. Immunogenicity (hemagglutination inhibition [HI] and microneutralization assays) and safety were assessed up to day 546. RESULTS: All adjuvanted formulations exceeded regulatory immunogenicity criteria at days 21 and 42 (HI assay), with seroprotection and seroconversion rates of >=94.9% and >=89.8% at day 21, and 100% and >=98.1% at day 42. Immunogenicity criteria were also met for unadjuvanted vaccine, with lower geometric mean titers. In groups administered a third vaccine dose (day 182), an anamnestic immune response was elicited with robust increases in HI and microneutralization titers. Injection site pain was reported more frequently with adjuvanted vaccines. No vaccine-related serious adverse events were observed. CONCLUSIONS: All H9N2 vaccine formulations were immunogenic with a clinically acceptable safety profile; adjuvanted formulations were 4-8 times dose-sparing (3.75-1.9vs 15ugHA). TRIAL REGISTRATION: Registered on ClinicalTrials.gov: NCT01659086. PMID- 28720283 TI - Addressing the Digital Divide in Contemporary Biology: Lessons from Teaching UNIX. AB - Life and medical science researchers increasingly rely on applications that lack a graphical interface. Scientists who are not trained in computer science face an enormous challenge analyzing high-throughput data. We present a training model for use of command-line tools when the learner has little to no prior knowledge of UNIX. PMID- 28720284 TI - Modeling of Plasmas for Biomedicine. AB - Studies in plasma medicine, which are currently actively expanding, are of multidisciplinary character, involving physical, chemical and biological processes. Rapid progress has been achieved in this field due to synergy between experimental and theoretical/computational methods. Joint use of diagnostic tools and computations gives a better understanding of mechanisms of interaction of plasma with bio-objects. This review focuses on recent achievements in modeling of plasma for biomedical applications. Various computational approaches used in these studies are described. We discuss some results of simulations that concern the production of reactive species by plasma and their delivery to bio-objects, and we consider the effect of electroporation at direct contact of cold plasma with cells. PMID- 28720285 TI - Ultrasound-Based Shear Wave Elastography in the Assessment of Patients with Diabetic Kidney Disease. AB - In previous studies of acoustic radiation force impulse (ARFI) elastography, using Virtual Touch tissue quantification (VTQ) (Siemens Acuson S2000), it was reported that the measurement of renal shear wave speed in patients with chronic kidney disease (CKD) is not influenced exclusively by renal fibrosis. The purpose of the present study was to analyze the role of VTQ in patients with diabetic kidney disease, considered the main cause of CKD. The study group included 164 patients: 80 patients with diabetic kidney disease (DKD) and 84 without renal disease or diabetes mellitus. In each subject in lateral decubitus, five valid VTQ measurements were performed in each kidney and a median value was calculated, the result being expressed in meters/second. The following means of the median values were obtained In DKD patients, the means of the median values were for VTQ right kidney, 2.21 +/- 0.71 m/s, and for VTQ left kidney, 2.13 +/- 0.72 m/s, whereas in the normal controls statistically significant higher values were obtained: 2.58 +/- 0.78 m/s for VTQ right kidney (p = 0.0017) and 2.46 +/- 0.81 m/s for VTQ left kidney (p = 0.006). Patients with an estimated glomerular filtration rate (eGFR) >60 mL/min (DKD stages 1 and 2 together with normal controls) had a significantly higher kidney shear wave speed compared with patients with an eGFR <60 mL/min (2.53 m/s vs. 2.09 m/s, p < 0.05). In the DKD group, there was a significant correlation between eGFR and VTQ levels for the right kidney (r = 0.28, p = 0.04). There was no correlation of VTQ values with proteinuria level, stage of diabetic retinopathy or glycated hemoglobin. Our study indicates that shear wave speed values in patients with diabetic kidney disease and eGFRs <60 mL/min are significantly lower compared with those of patients with eGFRs >60 mL/min (either normal controls or diabetic patients with DKD stages 1 and 2), and values decrease with the decrease in eGFR. However, proteinuria, diabetic retinopathy and glycated hemoglobin have no influence on VTQ. PMID- 28720286 TI - Stress Generation during Pecking Motion of Rotary Nickel-titanium Instruments with Different Pecking Depth. AB - INTRODUCTION: The aim of this study was to evaluate the effect of different pecking depth on the stress generated by the screw-in forces of a rotating endodontic file in simulated canals. METHODS: Twenty simulated resin blocks with a J-shaped curvature were used. Twenty OneG files (MicroMega, Besancon, France) were assigned for a screw-in test depending on the pecking depth in 2 groups (n = 10). The files were operated at 300 rpm, and the up and down speed was controlled at 1 mm/s stroke velocity and a 10-millisecond dwell time using a customized device. The distances (pecking depth) for the pecking motion were 2 mm or 4 mm for each group; "6 mm forward and 4 mm backward" and "6 mm forward and 2 mm backward" movements were applied, respectively, for the 2 pecking groups. During the operation, the positive and negative apical loads were recorded at a rate of 50 Hz using customized software attached to the device. The maximum negative apical load (screw-in force [SF]) was recorded, and the total energy during pecking motion until the file reached the working length (cumulative screw-in forces [CSFs]) was computed. The data were analyzed using an independent t test at a significance level of 95%. RESULTS: No significant difference in SF was found between the 2 groups of pecking depths. However, the longer pecking depth (4-mm group) showed a significantly larger CSF compared with the shorter pecking depth group (P < .05). CONCLUSIONS: The shorter pecking depth may generate lower overall stresses for the root dentin as well as the instrument. PMID- 28720287 TI - Occurrence, toxicity, bioaccessibility and mitigation strategies of beauvericin, a minor Fusarium mycotoxin. AB - Emerging Fusarium mycotoxins include the toxic secondary metabolites fusaproliferin, enniatins, beauvericin (BEA), and moniliform. BEA is produced by some entomo- and phytopathogenic Fusarium species and occurs naturally on corn and corn-based foods and feeds infected by Fusarium spp. BEA has shown various biological activities (antibacterial, antifungal, and insecticidal) and possesses toxic activity, including the induction of apoptosis, increase cytoplasmic calcium concentration and lead to DNA fragmentation in mammalian cell lines. Cereals food processing has an important effect on mycotoxin stability, leading to less-contaminated food compared to the raw materials. Different industrial processes have shown to be effective practices to reduce BEA contents due to thermal food processing applied, such as cooking, boiling, baking, frying, roasting and pasteurization. Some studies demonstrated the capacity of lactic acid bacteria to reduce the presence of the BEA in model solution and in food chain through fermentation processes, modifying this mycotoxin in a less toxic derivate. Prebiotic and probiotic ingredient can modulate the bioaccessibility of BEA reducing the risk of intake of this minor Fusarium mycotoxin. This review summarizes the existing data on occurrence, toxicity and especially on BEA reduction strategies in food and feed such as chemical reduction, biocontrol and food processing. PMID- 28720288 TI - Potential adverse effects of engineered nanomaterials commonly used in food on the miRNome. AB - The emergence of nanotechnology has greatly impacted our daily lives. Multiple products, including cosmetics, pharmaceuticals, electronics and food, are produced with incorporation of nanomaterials (NMs). Nanotechnology has yielded many promising benefits, yet, there remains much uncertainty about the hazards of NMs to humans. Hence, it is important to ensure safety of the users. Although many in vitro and in vivo studies have been carried out on the potential toxicity generated by NMs in food, its effects on the microRNA genome (miRNome) involved in the regulation of gene expression have been poorly understood. Therefore, this review focuses on the types of commonly used NMs (containing silicon dioxide, titanium dioxide, silver or zinc oxide) in food products and their potential toxic effects, including how NMs can induce epigenetic toxicity mediated via altered miRNA expression. PMID- 28720289 TI - Transcriptomics in toxicology. AB - Xenobiotics, of which many are toxic, may enter the human body through multiple routes. Excessive human exposure to xenobiotics may exceed the body's capacity to defend against the xenobiotic-induced toxicity and result in potentially fatal adverse health effects. Prevention of the adverse health effects, potentially associated with human exposure to the xenobiotics, may be achieved by detecting the toxic effects at an early, reversible and, therefore, preventable stage. Additionally, an understanding of the molecular mechanisms underlying the toxicity may be helpful in preventing and/or managing the ensuing adverse health effects. Human exposures to a large number of xenobiotics are associated with hepatotoxicity or pulmonary toxicity. Global gene expression changes taking place in biological systems, in response to exposure to xenobiotics, may represent the early and mechanistically relevant cellular events contributing to the onset and progression of xenobiotic-induced adverse health outcomes. Hepatotoxicity and pulmonary toxicity resulting from exposure to xenobiotics are discussed as specific examples to demonstrate the potential application of transcriptomics or global gene expression analysis in the prevention of adverse health effects associated with exposure to xenobiotics. PMID- 28720290 TI - How to improve sleep in a neonatal intensive care unit: A systematic review. AB - : There is increasing evidence that sleep plays a major role in the development of neural pathways in the neonatal brain. Several studies have suggested evidence based approaches to improve sleep for infants admitted to the neonatal intensive care unit (NICU); however, in many neonatal centers very few of these strategies seem to be implemented in routine care. OBJECTIVE: To systematically review the literature to determine interventions promoting neonatal sleep on the NICU, in order to develop key guidelines to improve neonatal sleep. METHODS: A systematic search was conducted according to the criteria of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement for conducting and reporting systematic reviews. The search was performed in Pubmed, CINAHL and the Cochrane Library on 19 September 2016 and again on 28 January 2017. RESULTS: In total, fourteen studies were included (10 RCT's and three quasi-experimental study designs): four studies were of high quality, eight of moderate quality and two of low quality. Two studies investigating kangaroo care reported significant effect on infant sleep behavior, two studies comparing Yakson and Gentle Human Touch (GHT) found significant effect on behavioral states and one study reported an increase in sleep behavior using different sleep surfaces. One study showed a significant effect on sleep patterns using music as an intervention and one study showed no significant effect using music. Two studies showed no significant effect on infant sleep using cycled light and different types of LED-light and one study showed significant effect of cycled lightning. There were no effects of Neonatal Individualized Developmental Care Program (NIDCAP) or massage therapy. CONCLUSION: Although many different interventions have been reported to promote sleep in infants who require intensive care, there is great heterogeneity across studies: the methods of sleep assessment, the targeted sleep behaviors, and the study populations vary significantly across published reports. Based on the results there seems to be insufficient evidence to recommend any new intervention to promote neonatal sleep on the NICU. However because of the importance of sleep for the development of the neonatal brain we do suggest some key guidelines based on moderate evidence, expert opinion and parental values to improve sleep on the NICU and to direct future neonatal sleep studies. PMID- 28720291 TI - Mesenchymal stem cells in daily veterinary practice: Are we there yet? PMID- 28720292 TI - Serotypes and Spa types of Erysipelothrix rhusiopathiae isolates from British pigs (1987 to 2015). AB - Erysipelothrix spp. cause a range of clinical signs in pigs and at least 28 different Erysipelothrix spp. serotypes have been identified. In this study, 128 isolates of Erysipelothrix spp. from pigs in Great Britain from 1987 to 2015 were characterised by serotyping and multiplex real time PCR assays targeting the surface protective antigen (Spa) and the main genotypes (Erysipelothrix rhusiopathiae, Erysipelothrix tonsillarum and Erysipelothrix spp. strain 2). All 128 British isolates were characterised as E. rhusiopathiae and were classified as serotypes 1a (n=21), 1b (n=17), 2 (n=75), 5 (n=2), 9 (n=2), 10 (n=2), 11 (n=4) and 15 (n=1), while four isolates were untypeable. All isolates were positive for the spa A gene. Serotypes 1a, 1b and 2 constituted 88.3% of the isolates; current serotype 2 based vaccines should protect against these isolates. PMID- 28720293 TI - Effect of claw horn lesion type and severity at the time of treatment on outcome of lameness in dairy cows. AB - Prompt diagnosis and treatment of claw horn lesions in cattle affects the likelihood of recovery; however, it is unknown if the type of lesion influences the likelihood of recovery. The aim of this study was to investigate whether the type, severity and frequency of claw horn lesions in newly lame cows (lame for no more than 2 weeks) at the time of corrective foot trimming affects the probability of recovery from lameness after treatment. The images of 112 feet (224 claws) from newly lame cows (n=112; lame in only one hind foot), which were treated with a standardised therapeutic hoof trim only, were used to score claw horn lesions (sole ulcer, sole haemorrhage, white line haemorrhage or white line separation). Most cows (n=107/112; 95.5%) were classified as mildly lame at the time of treatment. The proportion of cows that recovered 2 weeks after therapeutic hoof trimming was 88/112 (78.6%). Results of a multilevel logistic regression model indicated that severely lame cows were less likely to recover than those that were mildly lame (odds ratio, OR, 0.16; P=0.04). White line haemorrhage had a significant negative impact on the likelihood of recovery from lameness (OR 0.14; P>0.01); however, recovery of cows with white line haemorrhage was positively associated with the length of the lesion (OR 1.05; P=0.03). This latter finding may be associated with the severity of the lesion, since mild claw horn lesions affected a significantly larger area of the claw than more severe lesions. The length and type of claw horn lesion were associated with recovery from lameness. PMID- 28720294 TI - Papillomaviruses in dogs and cats. AB - Papillomaviruses (PVs) cause disease in both dogs and cats. In dogs, PVs are thought to cause oral papillomatosis, cutaneous papillomas and canine viral pigmented plaques, whereas PVs have been rarely associated with the development of oral and cutaneous squamous cell carcinomas in this species. In cats, PVs are currently thought to cause oral papillomas, feline viral plaques, Bowenoid in situ carcinomas and feline sarcoids. Furthermore, there is increasing evidence that PVs may also be a cause of cutaneous squamous cell carcinomas and basal cell carcinomas in cats. These diseases are discussed in this review. Additionally, there is a brief overview of PV biology, including how these viruses cause disease. Diagnostic techniques and possible methods to prevent PV infection are also discussed. PMID- 28720295 TI - Equine papillomavirus type 2: An equine equivalent to human papillomavirus 16? AB - In horses, squamous cell carcinomas (SCC) commonly affect the external genitals. There is growing evidence that equine papillomavirus type 2 (EcPV2) infection promotes disease development. To assess the possible association of EcPV2 with equine SCCs of the head (HSCC), 15 HSCC DNA samples were screened by E6/E7, E2, and LCR PCR and amplicons were analysed for sequence variations. The physical form of EcPV2 in HSCC, genital lesions, and smegma from horses with SCC was then addressed using EcPV2 immunocapture PCR (IC/PCR) for detection of virion, and E6 vs. E2 qPCR to investigate possible integration events. Four of 15 HSCC tested positive for EcPV2 DNA and harboured known or novel genetic variants of E6, E7, E2 and the LCR. Eighteen of 35 sample extracts including 3/4 smegma samples scored positive by IC/PCR, suggesting that about 51% of tested extracts harboured virions. E6/E2 qPCR from tumour DNA revealed E2/E6 copies/cell ranging between <1 (E2; E6) and 797 (E2) or 1434 (E6). IC/PCR-positive smegma samples contained higher E2 and E6 copy numbers, ranging between 1490 and 4.95*105 (E2) or 2227 and 8.54*105 (E6) copies/cell. Together with IC/PCR results, this finding suggests that smegma can serve as a rich EcPV2 reservoir. HSCCs harboured significantly lower viral DNA amounts (<1-25 copies/cell) than most genital tumour and smegma DNA isolates. The majority of samples contained more E6 than E2 DNA, with E6:E2 ratios ranging between 0.88 and 4.12. Although not statistically significant (P>0.05), this finding suggests that EcPV2 can integrate into the equine host cell genome. PMID- 28720296 TI - Urinary heat shock protein 72 as a biomarker of acute kidney injury in dogs. AB - Early recognition of acute kidney injury (AKI) is important, as therapy is potentially more efficacious if instituted early in the course of disease. Urinary heat shock protein-72 to urinary creatinine ratio (uHSP72/uCr) was assessed as a diagnostic and prognostic marker in AKI in dogs. Fifty-three dogs were enrolled in five groups: healthy controls (n=11), urinary tract infection (n=10), chronic kidney disease (CKD; n=11), AKI (n=13), and acute decompensating CKD (n=8). Urinary heat shock protein-72 to urinary creatinine ratio was highest in the AKI group (P<0.001 when compared to the control and urinary tract infection groups, individually; P>0.05 compared to each of the other two groups). The area under the curve (AUC) for the receiver operator characteristic (ROC) analysis of uHSP72/uCr to predict AKI, compared to the control group, was 0.97. A cutoff value of 0.20ng/mg corresponded to sensitivity and specificity of 100% and 82%, respectively. Urinary heat shock protein-72 to urinary creatinine ratio was significantly lower in dogs categorized as survivors vs. non-survivors of AKI; ROC AUC, 0.91 (95% confidence intervals, 0.74-1.0). Urinary heat shock protein-72 to urinary creatinine ratio is a potentially useful diagnostic and prognostic biomarker of AKI in dogs. PMID- 28720297 TI - Comparison of tibial anatomical-mechanical axis angle between predisposed dogs and dogs at low risk for cranial cruciate ligament rupture. AB - The purpose of this prospective, radiographic, descriptive study was to compare measurements of tibial anatomical-mechanical axis angle (AMA-angle), tibial plateau angle (TPA), relative tibial tuberosity width (rTTW) and Z-angle from mediolateral radiographs of the tibia between two canine breeds (72 dogs) not predisposed to cranial cruciate ligament rupture (CCLR) and those from a consecutive series of 185 large dogs and 17 West Highland white terriers (WHWT) diagnosed with unilateral, surgically confirmed CCLR. Correlations among these measurements were determined, and levels of inter- and intra-observer variability among and within three observers for each measurement were established using Kendall's coefficient of concordance. Breed had a significant effect on AMA angle. The median AMA-angle of the subject population of large dogs affected by CCLR was 2.80 degrees (range 1.09 degrees -5.21 degrees ); for the WHWT, it was 6.34 degrees (range 5.68 degrees -8.88 degrees ); and for the clinically normal dogs, it was 0.74 degrees (range 0.00 degrees -5.40 degrees ). In the CCLR group, AMA-angle and TPA were strongly correlated (r=0.745; p<0.0001). A receiver operating characteristic (ROC) curve analysis showed that an AMA-angle higher than 1.87 degrees had a sensitivity of 0.941 (95% confidence interval [CI]: 0.898-0.966) and a specificity of 0.965 (95% CI: 0.919-0.987) for predicting CCLR and was more accurate than TPA, rTTW and Z-angle at predicting CCLR (p<0.0001). Good inter- and intra-observer agreement was found for all measurements. The highly significant difference in AMA-angle found between clinically normal dogs and dogs with CCL injury suggests that AMA-angle magnitude may be a clinically relevant predisposing factor for the development of canine CCLR. PMID- 28720298 TI - Steroids, steroid precursors, and neuroactive steroids in critically ill equine neonates. AB - Hypothalamic-pituitary-adrenal axis (HPAA) dysfunction has been associated with sepsis and mortality in foals. Most studies have focused on cortisol, while other steroids have not been investigated. The objectives of this study were to characterise the adrenal steroid and steroid precursor response to disease and to determine their association with the HPAA response to illness, disease severity, and mortality in hospitalised foals. All foals (n=326) were classified by two scoring systems into three categories: based on the sepsis score (septic, sick non-septic [SNS] and healthy) and the foal survival score (Group 1: 3-18%; Group 2: 38-62%; Group 3: 82-97% likelihood of survival). Blood concentrations of adrenocorticotropic hormone (ACTH) and steroids were determined by immunoassays. ACTH-cortisol imbalance (ACI) was defined as a high ACTH/cortisol ratio. Septic foals had higher ACTH, cortisol, progesterone, 17alpha-OH-progesterone, pregnenolone, and androstenedione concentrations as well as higher ACTH/cortisol, ACTH/progesterone, ACTH/aldosterone, and ACTH/DHEAS ratios than SNS and healthy foals (P<0.01). Foals with DHEAS of 0.4-5.4ng/mL were more likely to have ACI (OR=2.5). Foals in Group 1 had higher ACTH, aldosterone, progesterone, and cortisol concentrations as well as ACTH/cortisol, ACTH/progesterone, and ACTH/DHEAS ratios than foals in Groups 2 and 3 (P<0.01). High progesterone concentrations were associated with non-survival and the cutoff value below which survival could be predicted was 23.5ng/mL, with 75% sensitivity and 72% specificity. In addition to cortisol, the response to the stress of illness in foals is characterised by the release of multiple adrenal steroids. DHEAS and progesterone were good predictors of HPAA dysfunction and outcome in hospitalised foals. PMID- 28720299 TI - Cats with diabetes mellitus have diastolic dysfunction in the absence of structural heart disease. AB - Diabetes mellitus (DM) can result in cardiovascular dysfunction and heart failure characterized by diastolic dysfunction with or without the presence of systolic dysfunction in people and laboratory animals. The objective of this prospective study was to determine if cats with newly diagnosed DM had myocardial dysfunction and, if present, whether it would progress if appropriate antidiabetic therapy was commenced. Thirty-two diabetic cats were enrolled and received baseline echocardiographic examination; of these, 15 cats were re-examined after 6 months. Ten healthy age- and weight-matched cats served as controls. Diabetic cats at diagnosis showed decreased diastolic, but not systolic function, when compared to healthy controls, with lower mitral inflow E wave (E) and E/E' than controls. After 6 months, E and E/IVRT' decreased further in diabetic cats compared to the baseline evaluation. After excluding cats whose DM was in remission at 6 months, insulin-dependent diabetic cats had lower E, E/A and E' than controls. When classifying diastolic function according to E/A and E'/A', there was shift towards impaired relaxation patterns at 6 months. All insulin-dependent diabetic cats at 6 months had abnormal diastolic function. These results indicate that DM has similar effects on diastolic function in feline and human diabetics. The dysfunction seemed to progress rather than to normalize after 6 months, despite antidiabetic therapy. In cats with pre-existing heart disease, the development of DM could represent an important additional health risk. PMID- 28720300 TI - Epidemiological study of gastric Helicobacter spp. in dogs with gastrointestinal disease in Japan and diversity of Helicobacter heilmannii sensu stricto. AB - Epidemiological and pathological studies of Helicobacter spp. in canine stomachs in Japan were performed to investigate strain specific pathogenicity. Gastric biopsies from 144 dogs with gastrointestinal diseases were evaluated for the presence of Helicobacter spp. using genus and species specific PCRs for Helicobacter felis, Helicobacter bizzozeronii, Helicobacter heilmannii sensu stricto (s.s.) and Helicobacter pylori. PCR indicated that 50/144 (34.7%) dogs were infected with Helicobacter spp. Of the genus positive samples, 21/50 could not be amplified by any of the species specific PCRs. To investigate Helicobacter at the species level, partial ureAB gene sequences from 48/50 genus positive samples were determined; 47 strains were identified. Thirty-five strains from 45 cases were closely related to H. heilmannii s.s. (89-99% sequence similarity), seven strains from seven cases were closely related to H. bizzozeronii (95-99% sequence similarity), three strains from three cases were closely related to Helicobacter felis (86%, 98% and 99% sequence similarity), one strain from one case was closely related to Helicobacter salomonis (99% sequence similarity) and one strain from one case was closely related to H. pylori (99% sequence similarity). Dogs infected with Helicobacter spp. most similar to H. heilmannii s.s. had a higher frequency of moderate to severe gastritis than dogs negative for Helicobacter spp. (P=0.044). In conclusion, the predominant Helicobacter spp. detected in canine stomachs in our study were most closely related to H. heilmannii s.s. and displayed substantial genetic diversity. Infection with Helicobacter spp. may be associated with more severe gastritis in dogs. PMID- 28720301 TI - A quantitative swab is a good non-invasive alternative to a quantitative biopsy for quantifying bacterial load in wounds healing by second intention in horses. AB - The aim of this study was to evaluate different techniques for diagnosing wound infection in wounds healing by second intention in horses and to assess the effect of a vortex and sonication protocol on quantitative bacteriology in specimens with a histologically confirmed biofilm. In 50 wounds healing by second intention, a clinical assessment, a quantitative swab, a semi-quantitative swab, and a swab for cytology were compared to a quantitative tissue biopsy (reference standard). Part of the biopsy specimen was examined histologically for evidence of a biofilm. There was a significant, high correlation (P<0.001; r=0.747) between the outcome of the quantitative swabs and the quantitative biopsies. The semi-quantitative swabs showed a significant, moderate correlation with the quantitative biopsies (P<0.001; rho=0.524). Higher white blood cell counts for cytology were significantly associated with lower log10 colony-forming units (CFU) in the wounds (P=0.02). Wounds with black granulation tissue showed significantly higher log10 CFU (P=0.003). Specimens with biofilms did not yield higher bacteriological counts after a vortex and sonication protocol was performed to release bacteria from the biofilm. Based on these findings, a quantitative swab is an acceptable non-invasive alternative to a quantitative biopsy for quantifying bacterial load in equine wounds healing by second intention. PMID- 28720302 TI - Clinical reasoning in feline epilepsy: Which combination of clinical information is useful? AB - We sought to identify the association between clinical risk factors and the diagnosis of idiopathic epilepsy (IE) or structural epilepsy (SE) in cats, using statistical models to identify combinations of discrete parameters from the patient signalment, history and neurological examination findings that could suggest the most likely diagnosis. Data for 138 cats with recurrent seizures were reviewed, of which 110 were valid for inclusion. Seizure aetiology was classified as IE in 57% and SE in 43% of cats. Binomial logistic regression analyses demonstrated that pedigree status, older age at seizure onset (particularly >7years old), abnormal neurological examinations, and ictal vocalisation were associated with a diagnosis of SE compared to IE, and that ictal salivation was more likely to be associated with a diagnosis of IE than SE. These findings support the importance of considering inter-ictal neurological deficits and seizure history in clinical reasoning. PMID- 28720303 TI - Internet gaming disorder: A sign of the times, or time for our attention? PMID- 28720304 TI - Characterization of the single-cell derived bovine induced pluripotent stem cells. AB - Single-cell derived bovine induced pluripotent stem cells (iPSCs) were generated by the introduction of piggyBac transposons with CAG promoting transcription factors (Oct3/4, Sox2, Klf4 and cMyc). In the study, the bovine iPSCs colony from single cell could passage more than 50 passages after enzymatic dissociation into single cells. These bovine iPSCs cells kept the normal karyotype and displayed dome shaped clones similar to mouse embryonic stem cells. They showed pluripotency in many ways, including their expression of pluripotency markers, such as OCT3/4, NANOG, SOX2, SSEA1, SSEA4, and AP in immunofluorescence assay, Oct4, Nanog, Sox2, Klf4 and cMyc in RT-PCR. Additionally, single-cell derived bovine iPSCs formed embryoid bodies and teratomas that all subsequently gave rise to differentiated cells from all three embryonic germ layers. The results showed that our reprogramming method could obtain high efficiency single-cell cloning bovine iPSCs, and the efficiency of single cell cloning is 40%. PMID- 28720305 TI - Ecto-5'-nucleotidase (CD73) regulates bone formation and remodeling during intramembranous bone repair in aging mice. AB - Ecto-5'-nucleotidase (CD73) generates adenosine, an osteoblast activator and key regulator of skeletal growth. It is unknown, however, if CD73 regulates osteogenic differentiation during fracture healing in adulthood, and in particular how CD73 activity regulates intramembranous bone repair in the elderly. Monocortical tibial defects were created in 46-52-week-old wild type (WT) and CD73 knock-out mice (CD73-/-) mice. Injury repair was analyzed at post operative days 5, 7, 14 and 21 by micro-computed tomography (micro-CT), histomorphometry, proliferating cell nuclear antigen (PCNA) immunostaining, alkaline phosphatase (ALP) and tartrate-resistant acid phosphatase (TRAP) histochemistry. Middle-aged CD73 knock-out mice exhibited delayed bone regeneration and significantly reduced bone matrix deposition detected by histomorphometry and micro-CT. Cell proliferation, ALP activity and osteoclast number were reduced in the CD73-/- mice, suggesting a combined defect in bone formation and resorption due the absence of CD73 activity in this model of intramembranous bone repair. Results from this study demonstrate that osteoblast activation through CD73 activity is essential during bone repair in aging mice, and it may present a drugable target for future biomimetic therapeutic approaches that aim at enhancing bone formation in the elderly patients. PMID- 28720306 TI - In response to the letter to the editor regarding: Rat model of chronic tympanic membrane perforation: Ventilation tube with mitomycin C and dexamethasone. PMID- 28720307 TI - Diagnosis of relapsing polychondritis in a patient with chronic cough and without nasal or auricular chondritis. PMID- 28720308 TI - Fibromyalgia and FacebookTM: Beyond the " likes". PMID- 28720309 TI - Chloroquine-induced oral mucosal hyperpigmentation and nail dyschromia. PMID- 28720310 TI - Epithelial membrane protein 2: Molecular interactions and clinical implications. AB - Epithelial membrane protein 2 (EMP2) is a cell surface protein that has recently emerged as an object of neuro-oncological interest due to its potential to be utilized as a biomarker and target for antibody therapies. Preclinical studies have demonstrated that EMP2 is associated with disease prognosis in a number of human cancers, including glioblastoma. The four large extracellular domains of EMP2 and its association with the extracellular matrix makes it an attractive target for future cancer therapies. Translational research suggests that EMP2 may be targeted with antibodies to improve tumor control and survival in a variety of murine models and cancer types. However, in order to translate these preclinical findings into the clinic, future research will need to focus on elucidating the role EMP2 in the normal human body by better understanding its molecular and chemical interactions. The focus of this review is to provide a comprehensive insight into current research endeavors, discuss the potential for clinically translatable applications, and predict the future directions of such research. PMID- 28720311 TI - Evaluation of changes in blood flow of the uterine artery by Doppler ultrasonography during the estrous cycle in lactating Bos indicus cows. AB - The objective of this study was to evaluate the changes in uterine blood flow (UBF) based on the resistance index (RI) and the pulsatility index (PI) by Doppler ultrasonography throughout the estrous cycle in lactating Sahiwal cows (n=9). Cows were randomly selected during their spontaneous estrus. UBF was examined on alternate days in all cows during the estrous cycle. The results revealed that the mean RI values were higher (P<0.05) on day -1 (estrus) than on day 0 (ovulation). The mean RI values followed a consistent pattern on days 2, 4, 6, and 8 (metestrus to early diestrus) and were lower (P<0.05) than on days 10, 14 16, and 18 (diestrus to early proestrus). The RI and corpus luteum (CL) size negatively correlated during its static phase (r=-0.99; P<0.05). The mean RI was greater (P<0.05) in high producers than in low producing cows. The mean PI value was higher (P<0.05) on day 10 than on day -1 and day 0. Similarly, the mean PI values were lower (P <0.05) on days 2 and 4 than on day 10. The PI value remained significantly lower (P<0.05) on day 2 than on day 8 of the estrous cycle. There was a positive correlation between RI and P4 (r=0.70; P<0.05) and PI and P4 (r=0.56; P<0.05) during the estrous cycle. It is concluded that the RI of uterine arteries, as a measure of blood flow, is considerably lower, while the PI is substantially elevated during diestrus compared to estrus and ovulation in Sahiwal cows. PMID- 28720312 TI - Differential likelihood of NSTEMI vs STEMI in patients with sleep apnea. AB - BACKGROUND: Sleep apnea (SA) is associated with intermittent hypoxemia that may lead to ischemic preconditioning in the myocardium. This potential cardioprotective effect of SA may play a role in the development of non-ST elevation myocardial infarction (NSTEMI) versus ST-elevation myocardial infarction (STEMI) during acute ischemia. However, there is limited evidence about the relative prevalence of NSTEMI versus STEMI in SA patients. We therefore prospectively investigated the prevalence of these two types of MI in patients with SA. METHODS: We prospectively studied 782 consecutive patients admitted with the diagnosis of acute MI (both NSTEMI and STEMI). All subjects underwent sleep evaluations using a portable diagnostic device after at least 48h post-admission, provided they were in stable condition. Six hundred and seven out of 782 patients had technically adequate sleep studies, and therefore were included in the final analysis. RESULTS: SA was present in 65.7% (n=399) and NSTEMI in 30% (n=182) of patients. Increasing severity of SA was associated with increasing likelihood of NSTEMI, and with decreasing likelihood of STEMI (p<0.001). Relative frequency of NSTEMI in the moderate to severe SA group (AHI>=15events/h) was 40.6% versus 29.9% for STEMI (p=0.01). CONCLUSION: The prevalence of NSTEMI increases with increasing severity of SA. This finding may suggest a cardioprotective role of SA, which may attenuate the development of STEMI, perhaps through ischemic preconditioning. PMID- 28720313 TI - Binocular diplopia in a tertiary hospital: Aetiology, diagnosis and treatment. AB - OBJECTIVE: To study the causes, diagnosis and treatment in a case series of binocular diplopia. MATERIAL AND METHOD: A retrospective chart review was performed on patients seen in the Diplopia Unit of a tertiary centre during a one year period. Diplopia was classified as: acute<=1 month since onset; subacute (1 6 months); and chronic (>6 months). Resolution of diplopia was classified as: spontaneous if it disappeared without treatment, partial if the course was intermittent, and non-spontaneous if treatment was required. It was considered a good outcome when diplopia disappeared completely (with or without treatment), or when diplopia was intermittent without significantly affecting the quality of life. RESULTS: A total of 60 cases were included. The mean age was 58.65 years (60% female). An acute or subacute presentation was observed in 60% of the patients. The mean onset of diplopia was 82.97 weeks. The most frequent aetiology was ischaemic (45%). The most frequent diagnosis was sixth nerve palsy (38.3%), followed by decompensated strabismus (30%). Neuroimaging showed structural lesions in 17.7% of the patients. There was a spontaneous resolution in 28.3% of the cases, and there was a good outcome with disappearance of the diplopia in 53.3% at the end of the study. CONCLUSIONS: The most frequent causes of binocular diplopia were cranial nerve palsies, especially the sixth cranial nerve, followed by decompensated strabismus. Structural lesions in imaging tests were more than expected. Only one third of patients had a spontaneous resolution, and half of them did not have a good outcome despite of treatment. PMID- 28720314 TI - Antibiotic susceptibility of Helicobacter pylori strains isolated from Iranian children: High frequency of A2143G point mutation associated with clarithromycin resistance. AB - OBJECTIVE: Increasing antibiotic resistance in Helicobacter pylori is a global concern and is associated with treatment failure. The aim of this study was to evaluate antibiotic resistance of H. pylori to different antibiotics including amoxicillin, erythromycin, ciprofloxacin, furazolidone, tetracycline, metronidazole and clarithromycin. In addition, detection of A2143G mutation in clarithromycin resistant isolates was performed using real-time PCR technique. METHODS: Ninety patients with upper gastrointestinal symptoms were enrolled in this study. H. pylori were isolated from 32 specimens and the resistance rate of these strains to amoxicillin, erythromycin, ciprofloxacin, furazolidone, and tetracycline was tested by disc agar diffusion method. The resistance level to metronidazole and clarithromycin was determined by agar dilution method. The presence of A2143G point mutation in clarithromycin resistant isolates was determined using real-time PCR technique. RESULTS: The resistance rates to amoxicillin, erythromycin, ciprofloxacin, furazolidone, tetracycline, metronidazole and clarithromycin were 53%, 50%, 37.5%, 62.5%, 25%, 62.5% and 22%, respectively. The A2143G point mutation was detected in 71% of clarithromycin resistant strains (5 out of 7). CONCLUSIONS: The prevalence of H. pylori resistance to metronidazole, ciprofloxacin, erythromycin, amoxicillin and furazolidone in Iran is high. Determination of antibiotic susceptibility plays an important role in selecting of the appropriate anti H. pylori regimen. PMID- 28720315 TI - [Evaluation of the antithrombotic strategy in low thrombotic risk patients who underwent aortic valve replacement with a bioprosthesis]. AB - According to current guidelines, in patients without additional risk factors who have undergone aortic valve replacement with a bioprosthesis, anticoagulation in the first 3 months after surgery is still a matter of debate. According to current evidence, aspirin in low doses is a reasonable alternative to vitamin K antagonists (VKA). A comparison is made between the incidence of thrombotic and haemorrhagic complications in patients with low thrombotic risk who underwent aortic valve replacement with a bioprosthesis in the National Institute of Cardiology of Ignacio Chavez of Mexico. The hypothesis: aspirin as monotherapy has a beneficial effect compared to VKA. The studied patients were the low thrombotic risk patients who underwent aortic valve replacement with a bioprosthesis in the National Institute of Cardiology of Ignacio Chavez of Mexico from 2011 to 2015. The groups studied were: aspirin only, VKA only, and the combination of VKA plus aspirin. The patients were retrospectively followed-up for 12 months, and the thrombotic and haemorrhagic complications were documented. Of the 231 patients included in the study, only one patient in the VKA only group presented with a haemorrhagic complication. No thrombotic complications were observed. In the present study no thrombotic complications were observed in patients who did not receive anticoagulation in the first 3 months after an aortic valve replacement with a bioprosthesis after a follow up period of 12 months. This suggests that the use of aspirin only is safe during this period. PMID- 28720316 TI - Pigeons and their droppings as reservoirs of Candida and other zoonotic yeasts. AB - BACKGROUND: The importance of pigeons as reservoirs and carriers of Cryptococcus neoformans and other species of this genus is well-known; however, less is known about their role as reservoirs and carriers of other yeasts that impact public health. AIMS: The present study was performed on Gran Canaria Island to define yeasts other than Cryptococcus spp. that have been reported to impact public health and which could be carried by pigeons. METHODS: Samples were obtained from 83 pigeon lofts (Columba livia); moreover, 331 crop samples, 331 cloacal samples and 174 dropping samples were collected. In addition, 17 dropping samples were taken from a total of 17 public squares. Samples were inoculated on Sabouraud dextrose agar with chloramphenicol. RESULTS: Different yeast species, i.e. Candida guilliermondii (24.36%), Candida kefyr (1.21%), Saccharomyces cerevisiae (2.43%), and Trichosporon asahii (1.21%) were isolated for the first time from the cloaca. The most frequently isolated yeast from the crop, cloaca and dropping samples from lofts was C. guilliermondii (30.46%, 24.36% and 49.37%, respectively). In addition, for the first time, C. kefyr (3.65%), Candida pelliculosa (2.43%), Candida rugosa (1.21%), T. asahii (3.65%), Trichosporon mucoides (3.65%) and Prototheca wickerhamii (1.21%) were obtained from crop samples; Candida pelliculosa (1.20%), T. asahii (9.63%) and T. mucoides (7.22%) were isolated from dropping samples in the lofts. Candida albicans was the most frequently isolated yeast in dropping samples collected in public squares. CONCLUSIONS: It can be assumed that pigeons and their droppings act as carriers and reservoirs of Candida spp. and other zoonotic yeasts. PMID- 28720318 TI - Immunogenicity and protective efficacy of a newly developed tri-component diphtheria, tetanus, and acellular pertussis vaccine in a murine model. AB - BACKGROUND/PURPOSE: Although assessing the immunogenicity and protective efficacy of acellular pertussis (aP) vaccines via murine model studies faces limitations, preliminary assessments have been achieved by evaluating respiratory challenge and humoral and cellular immunity. METHODS: We performed a long-term intranasal respiratory challenge with reference and clinically isolated strains of Bordetella pertussis. Simultaneously, we assessed humoral and cellular immunity for evaluating the immunogenicity of a newly developed tri-component diphtheria tetanus-aP (DTaP) vaccine. Moreover, comparative assessment was made by performing the same evaluations with a commercially available tri-component DTaP vaccine as the positive control. RESULTS: Both groups showed significantly increased levels of antibodies against pertussis toxin, filamentous hemagglutinin and pertactin, and the levels of interferon-gamma and interleukin-10 were significantly increased after two doses of vaccination. Furthermore, since cross cell-mediated immune reactivity between the two vaccines was detected, the possibility of interchangeability was indirectly suggested. Although the positive control group showed significantly higher titers in antibody responses for filamentous hemagglutinin and pertactin compared to the experimental group, anti pertussis toxin antibody titers of the two groups were not significantly different and the protective efficacy against the clinical and reference strains was maintained in both groups for 18 weeks. CONCLUSION: The results showed inferior immunogenicity of the new DTaP vaccine compared to a commercial vaccine despite comparable cellular immunity and protective efficacy. Some efforts are necessary for improving immunogenicity against filamentous hemagglutinin and pertactin before conducting human clinical trials. PMID- 28720317 TI - DCC Receptors Drive Prefrontal Cortex Maturation by Determining Dopamine Axon Targeting in Adolescence. AB - BACKGROUND: Dopaminergic input to the prefrontal cortex (PFC) increases throughout adolescence and, by establishing precisely localized synapses, calibrates cognitive function. However, why and how mesocortical dopamine axon density increases across adolescence remains unknown. METHODS: We used a developmental application of axon-initiated recombination to label and track the growth of dopamine axons across adolescence in mice. We then paired this recombination with cell-specific knockdown of the netrin-1 receptor DCC to determine its role in adolescent dopamine axon growth. We then assessed how altering adolescent PFC dopamine axon growth changes the structural and functional development of the PFC by quantifying pyramidal neuron morphology and cognitive performance. RESULTS: We show, for the first time, that dopamine axons continue to grow from the striatum to the PFC during adolescence. Importantly, we discover that DCC, a guidance cue receptor, controls the extent of this protracted growth by determining where and when dopamine axons recognize their final target. When DCC-dependent adolescent targeting events are disrupted, dopamine axons continue to grow ectopically from the nucleus accumbens to the PFC and profoundly change PFC structural and functional development. This leads to alterations in cognitive processes known to be impaired across psychiatric conditions. CONCLUSIONS: The prolonged growth of dopamine axons represents an extraordinary period for experience to influence their adolescent trajectory and predispose to or protect against psychopathology. DCC receptor signaling in dopamine neurons is a molecular link where genetic and environmental factors may interact in adolescence to influence the development and function of the prefrontal cortex. PMID- 28720319 TI - Safety and efficacy of anti-influenza drugs, intravenous peramivir against influenza virus infection in elderly patients with underlying disease. AB - We retrospectively analyzed data of 38 elderly patients, each with an underlying disease, to evaluate peramivir safety and efficacy. Six patients (15.8%) experienced adverse events, all tolerated. Median time from administration until the return to normal temperatures was 31.5 h (95% CI: 22.4-40.6). Results confirm intravenous peramivir's usefulness. PMID- 28720320 TI - Hydrogen sulfide improves diabetic wound healing in ob/ob mice via attenuating inflammation. AB - BACKGROUND: The proposed mechanisms of impaired wound healing in diabetes involve sustained inflammation, excess oxidative stress and compromised agiogenesis. Hydrogen sulfide (H2S) has been reported to have multiple biological activities. We aim to investigate the role of H2S in impaired wound healing in ob/ob mice and explore the possible mechanisms involved. PROCEDURES: Full-thickness skin dorsal wounds were created on ob/ob mice and C57BL/6 mice. Cystathionine-gamma-lyase (CSE) expression and H2S production were determined in granulation tissues of the wounds. Effects of NaHS on wound healing were evaluated. Inflammation and angiogenesis in granulation tissues of the wounds were examined. RESULTS: CSE expression, and H2S content were significantly reduced in granulation tissues of wounds in ob/ob mice compared with control mice. NaHS treatment significantly improved wound healing in ob/ob mice, which was associated with reduced neutrophil and macrophage infiltration, decreased production of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6. NaHS treatment decreased metalloproteinase (MMP)-9, whereas increased collagen deposition and vascular like structures in granulation tissues of wounds in ob/ob mice. CONCLUSION: CSE down-regulation may play a role in the pathogenesis of diabetic impaired wound healing. Exogenous H2S could be a potential agent to improve diabetic impaired wound healing by attenuating inflammation and increasing angiogenesis. PMID- 28720321 TI - No evidence for progressive deterioration in stimulated insulin secretion in renal transplant recipients after 12years tacrolimus exposure. AB - AIMS: Tacrolimus (Tac) inhibits insulin secretion in a Tac-trough blood level dependent way early post-transplant in renal transplant recipients (Rtx). It is unknown whether long-term exposure results into a progressive beta cells dysfunction. METHODS: Two independent cohorts of Tac-treated non-diabetic Rtx, previously participating in glucose metabolism studies using intravenous Glucose Tolerance Test (ivGTT) were included: Fifty-eight Rtx were tested by ivGTT cross sectional between 0.25 and 12.6years post-transplant. Factors related to glucose metabolism parameters were explored by multilinear regression analysis. Eighteen non-diabetic Rtx tested by ivGTT 6months post-transplant were retested at 12years. The glucose metabolism outcome parameters were also adjusted according to the results of the cross-sectional study. RESULTS: Multivariate analysis showed 'Age', 'BMI' and 'use of steroids' to be significantly related, in different combinations, to the glucose metabolism parameters 'insulin resistance', 'fasting insulin level' and 'stimulated insulin secretion'. However 'time on tacrolimus' wasn't related to any parameter. In the longitudinal study, none of the glucose metabolism parameters (either analyzed crude or adjusted) deteriorated clinically or statistically significant. Numerically, 'stimulated insulin secretion' even increased. CONCLUSIONS: Chronic Tac exposure does NOT lead to a progressive decrease in 'stimulated insulin secretion' between 6months and 12years post renal transplant in our population of 18 patients. PMID- 28720322 TI - Rodent, large animal and non-human primate models of spinal cord injury. AB - In this narrative review we aimed to assess the usefulness of the different animal models in identifying injury mechanisms and developing therapies for humans suffering from spinal cord injury (SCI). Results obtained from rodent studies are useful but, due to the anatomical, molecular and functional differences, confirmation of these findings in large animals or non-human primates may lead to basic discoveries that cannot be made in rodent models and that are more useful for developing treatment strategies in humans. SCI in dogs can be considered as intermediate between rodent models and human clinical trials, but the primate models could help to develop appropriate methods that might be more relevant to humans. Ideally, an animal model should meet the requirements of availability and repeatability as well as reproduce the anatomical features and the clinical pathological changing process of SCI. An animal model that completely simulates SCI in humans does not exist. The different experimental models of SCI have advantages and disadvantages for investigating the different aspects of lesion development, recovery mechanisms and potential therapeutic interventions. The potential advantages of non-human primate models include genetic similarities, similar caliber/length of the spinal cord as well as biological and physiological responses to injury which are more similar to humans. Among the potential disadvantages, high operating costs, infrastructural requirements and ethical concerns should be considered. The translation from experimental repair strategies to clinical applications needs to be investigated in future carefully designed studies. PMID- 28720323 TI - Rapid divergence of histones in Hydrozoa (Cnidaria) and evolution of a novel histone involved in DNA damage response in hydra. AB - Histones are fundamental components of chromatin in all eukaryotes. Hydra, an emerging model system belonging to the basal metazoan phylum Cnidaria, provides an ideal platform to understand the evolution of core histone components at the base of eumetazoan phyla. Hydra exhibits peculiar properties such as tremendous regenerative capacity, lack of organismal senescence and rarity of malignancy. In light of the role of histone modifications and histone variants in these processes it is important to understand the nature of histones themselves and their variants in hydra. Here, we report identification of the complete repertoire of histone-coding genes in the Hydra magnipapillata genome. Hydra histones were classified based on their copy numbers, gene structure and other characteristic features. Genomic organization of canonical histone genes revealed the presence of H2A-H2B and H3-H4 paired clusters in high frequency and also a cluster with all core histones along with H1. Phylogenetic analysis of identified members of H2A and H2B histones suggested rapid expansion of these groups in Hydrozoa resulting in the appearance of unique subtypes. Amino acid sequence level comparisons of H2A and H2B forms with bilaterian counterparts suggest the possibility of a highly mobile nature of nucleosomes in hydra. Absolute quantitation of transcripts confirmed the high copy number of histones and supported the canonical nature of H2A. Furthermore, functional characterization of H2A.X.1 and a unique variant H2A.X.2 in the gastric region suggest their role in the maintenance of genome integrity and differentiation processes. These findings provide insights into the evolution of histones and their variants in hydra. PMID- 28720324 TI - Synthesis and diabetic neuropathic pain-alleviating effects of 2N-(pyrazol-3 yl)methylbenzo[d]isothiazole-1,1-dioxide derivatives. AB - A novel series of fused-benzensulfonamide 2-N-(pyrazol-3 yl)methylbenzo[d]isothiazole-1,1-dioxide derivatives was designed and synthesized as metabolically stable T-type calcium channel inhibitors. Several compounds, 9, 10, and 17, displayed potent T-type channel inhibitory activity. Among them, compounds 10 and 17 showed good metabolic stability in human liver microsomes, and low hERG channel and CYP450 inhibition. Compound 10 exhibited diabetic neuropathic pain-alleviating effects in a streptozotocin-induced peripheral diabetic neuropathy (PDN) model. The maximum efficacy of compound 10, which was 3 fold more potent than gabapentin, was observed at 1h after administration, and co administration of compound 10 with gabapentin showed a considerable synergic effect. PMID- 28720325 TI - Therapeutic peptides: Historical perspectives, current development trends, and future directions. AB - Peptide therapeutics have played a notable role in medical practice since the advent of insulin therapy in the 1920s. Over 60 peptide drugs are approved in the United States and other major markets, and peptides continue to enter clinical development at a steady pace. Peptide drug discovery has diversified beyond its traditional focus on endogenous human peptides to include a broader range of structures identified from other natural sources or through medicinal chemistry efforts. We maintain a comprehensive dataset on peptides that have entered human clinical studies that includes over 150 peptides in active development today. Here we provide an overview of the peptide therapeutic landscape, including historical perspectives, molecular characteristics, regulatory benchmarks, and a therapeutic area breakdown. PMID- 28720326 TI - Piperidine and octahydropyrano[3,4-c] pyridine scaffolds for drug-like molecular libraries of the European Lead Factory. AB - We report short and efficient scalable syntheses of enantiomerically pure (3R,4S) 3-(hydroxymethyl4-(hydroxyethyl))-piperidine and 1-hydroxymethyl-octahydro-1H pyrano[3,4-c]pyridine scaffolds. The alkaloid core was readily synthesized from naturally occurring quinine and can serve as a valued starting point for drug discovery. Cleavage of a terminal 1,2-diol and acid catalysed epoxide opening cyclization are the key steps involved. A number of members of a projected small molecular library is synthesized for each scaffold. PMID- 28720327 TI - Asymmetric synthesis and evaluation of epoxy-alpha-acyloxycarboxamides as selective inhibitors of cathepsin L. AB - Cathepsin L plays important roles in physiological processes as well as in the development of many pathologies. Recently the attentions were turned to its association with tumor progress what makes essential the development of more potent and selective inhibitors. In this work, epoxipeptidomimetics were investigated as new cathepsin inhibitors. This class of compounds is straightforward obtained by using a green one-pot asymmetric epoxidation/Passerini 3-MCR. A small library of 17 compounds was evaluated against cathepsin L, and among them LSPN423 showed to be the most potent. Investigations of the mechanism suggested a tight binding uncompetitive inhibition. PMID- 28720328 TI - Design, synthesis, molecular modeling and anti-hyperglycemic evaluation of quinazolin-4(3H)-one derivatives as potential PPARgamma and SUR agonists. AB - Peroxisome proliferator-activated receptor gamma (PPARgamma) and sulfonylurea receptor (SUR) play crucial roles in management of type-2 diabetes mellitus. In this study, a series of novel quinazoline-4(3H)-one-sulfonylurea hybrids were designed and synthesized as dual PPARgamma and SUR agonists. The synthesized compounds were evaluated for their in vivo anti-hyperglycemic activities against STZ-induced hyperglycemic rats. Four compounds (19a, 19d, 19f and 25g) demonstrated potent activities with reduction in blood glucose levels of 40.43, 46.42, 41.23 and 42.50 %, respectively. The most active ten compounds were further evaluated in vitro for their PPARgamma binding affinities and insulin secreting abilities. Compounds 19b, 19d, 19f, 25f and 25g exhibited the highest affinities against PPARgamma with IC50 values of 0.371, 0.350, 0.369, 0.408 and 0.353uM, respectively. In addition, compounds 19d, 19f, and 25d showed the highest insulin-secreting activities with EC50 values of 0.97, 1.01 and 1.15uM, respectively. Furthermore, molecular docking and pharmacophore generation techniques were carried out to investigate binding patterns and fit values of the designed compounds with PPARgamma and SUR, respectively. Also, two QSAR models were generated to explore the structural requirements controlling the different biological activities of the synthesized compounds against PPARgamma and SUR. PMID- 28720329 TI - Recent synthetic and medicinal perspectives of tryptanthrin. AB - Tryptanthrin is a natural alkaloidal compound having basic indoloquinazoline moiety. It is obtained from various natural plant sources as well as different cell cultures including yeast etc. Trptanthrin is considered as biogenetic precursor for phaitanthrin A-C, pyrroloindoloquinazoline, (+/-)-cruciferane. Different synthetic approaches for the synthesis of tryptanthrin have been very well reported. It has broad spectrum of biological activities including anticancer activity, anti-inflammatory, antiprotozoal, antiallergic, antioxidant, and antimicrobial. In this review, our focus will be, on the various approaches for the synthesis of tryptanthrins and its derivatives along with the biological activities. PMID- 28720330 TI - Generation of hazardous methyl azide and its application to synthesis of a key intermediate of picarbutrazox, a new potent pesticide in flow. AB - Generation and reactions of methyl azide (MeN3) were successfully performed by using a flow reactor system, demonstrating that the flow method serves as a safe method for handling hazardous explosive methyl azide. The reaction of NaN3 and Me2SO4 in a flow reactor gave a MeN3 solution, which was used for Huisgen reaction with benzoyl cyanide in a flow reactor after minimal washing. The resulting 1-methyl-5-benzoyltetrazole serves as a key intermediate of picarbutrazox (IX), a new potent pesticide. PMID- 28720331 TI - A novel antihypertension agent, sargachromenol D from marine brown algae, Sargassum siliquastrum, exerts dual action as an L-type Ca2+ channel blocker and endothelin A/B2 receptor antagonist. AB - We isolated the novel vasoactive marine natural products, (5E,10E)-14-hydroxy 2,6,10-trimethylpentadeca-5,10-dien-4-one (4) and sargachromenol D (5), from Sargassum siliquastrum collected from the coast of the East Sea in South Korea by using activity-guided HPLC purification. The compounds effectively dilated depolarization (50mMK+)-induced basilar artery contraction with EC50 values of 3.52+/-0.42 and 1.62+/-0.63MUM, respectively, but only sargachromenol D (5) showed a vasodilatory effect on endothelin-1 (ET-1)-induced basilar artery contraction (EC50=9.8+/-0.6MUM). These results indicated that sargachromenol D (5) could act as a dual antagonist of l-type Ca2+ channel and endothelin A/B2 receptors. Moreover, sargachromenol D (5) lowered blood pressure in spontaneous hypertensive rats (SHRs) 2h after oral treatment at a dose of 80mg/kg dose and the effect was maintained for 24h. Based on our ex vivo and in vivo experiments, we propose that sargachromenol D (5) is a strong candidate for the treatment of hypertension that is not controlled by conventional drugs, in particular, severe , type II diabetes-, salt-sensitive, and metabolic disease-induced hypertension. PMID- 28720332 TI - Synthesis and biological evaluation of fluoro-substituted 3,4-dihydroquinazoline derivatives for cytotoxic and analgesic effects. AB - As a bioisosteric strategy to overcome the poor metabolic stability of lead compound KYS05090S, a series of new fluoro-substituted 3,4-dihydroquinazoline derivatives was prepared and evaluated for T-type calcium channel (Cav3.2) block, cytotoxic effects and liver microsomal stability. Among them, compound 8h (KCP10068F) containing 4-fluorobenzyl amide and 4-cyclohexylphenyl ring potently blocked Cav3.2 currents (>90% inhibition) at 10MUM concentration and exhibited cytotoxic effect (IC50=5.9MUM) in A549 non-small cell lung cancer cells that was comparable to KYS05090S. Furthermore, 8h showed approximately a 2-fold increase in liver metabolic stability in rat and human species compared to KYS05090S. Based on these overall results, 8h (KCP10068F) may therefore represent a good backup compound for KYS05090S for further biological investigations as novel cytotoxic agent. In addition, compound 8g (KCP10067F) was found to partially protect from inflammatory pain via a blockade of Cav3.2 channels. PMID- 28720333 TI - Bioactivity and properties of a dental adhesive functionalized with polyhedral oligomeric silsesquioxanes (POSS) and bioactive glass. AB - OBJECTIVES: This study aimed to analyze the effect of infiltrating a commercial adhesive with nanosized bioactive glass (BG-Bi) particles or methacryl functionalized polyhedral oligomeric silsesquioxanes (POSS) on material properties and bioactivity. METHODS: An acetone-based dental adhesive (Solobond Plus adhesive, VOCO GmbH, Cuxhaven, Germany) was infiltrated with nanosized bioactive glass particles (0.1 or 1wt%), or with monofunctional or multifunctional POSS particles (10 or 20wt%). Unfilled adhesive served as control. Dispersion and hydrodynamic radius of the nanoparticles were studied by dynamic light scattering. Set specimens were immersed for 28days in artificial saliva at 37 degrees C, and surfaces were mapped for the formation of calcium phospate (Ca/P) precipitates (scanning electron microscopy/energy-dispersive X ray spectroscopy). Viscosity (rheometry) and the structural characteristic of the networks were studied, such as degree of conversion (FTIR spectroscopy), sol fraction and water sorption. RESULTS: POSS particles showed a good dispersion of the particles for both types of particles being smaller than 3nm, while the bioactive glass particles had a strong tendency to agglomerate. All nanoparticles induced the formation of Ca/P precipitates. The viscosity of the adhesive was not or only slightly increased by POSS particle addition but strongly increased by the bioactive glass particles. The degree of conversion, water sorption and sol fraction showed a maintained or improved network structure and properties when filled with BG-Bi and multifunctional POSS, however, less polymerization was found when loading a monofunctional POSS. SIGNIFICANCE: Multifunctional POSS may be incorporated into dental adhesives to provide a bioactive potential without changing material properties adversely. PMID- 28720335 TI - Not infection with parasitic worms, but rather colonization with therapeutic helminths. PMID- 28720337 TI - Scurvy and Wernicke's encephalopathy: An underdiagnosed association? PMID- 28720336 TI - Baseline Symptom Score Impact on Benefits of Glycopyrrolate/Formoterol Metered Dose Inhaler in COPD. AB - BACKGROUND: The clinical severity of COPD is currently categorized by symptom burden and exacerbation risk. Previous 24-week phase III trials (NCT01854645 and NCT01854658) that demonstrated better improvement of lung function with glycopyrrolate/formoterol fumarate (GFF) metered dose inhaler (MDI) (an MDI fixed dose of GFF 18/9.6 MUg) over individual monocomponent MDIs included a cross section of patients with moderate to very severe airflow limitation and a broad range of COPD symptoms. METHODS: These post hoc analyses of pooled data investigated whether baseline symptom burden, assessed using the COPD Assessment Test (CAT) score, impacted GFF MDI-associated improvements in lung function, health status, rescue medication use, and exacerbation risk. RESULTS: In 3,699 patients, improvement in FEV1 at week 24 between the GFF MDI and monocomponent MDIs and a placebo MDI was similar in magnitude regardless of baseline CAT score. In contrast, the magnitude of mean difference in the St. George's Respiratory Questionnaire total score for GFF MDI vs monocomponent MDIs and the placebo MDI increased with increasing baseline CAT scores. Likewise, reduced rescue medication use and lower exacerbation risk were more pronounced in GFF MDI groups with a higher baseline symptom burden. CONCLUSIONS: Beneficial effects of GFF MDI on health status, rescue medication use, and exacerbation risk in symptomatic patients with COPD increased as a function of baseline symptom burden, whereas lung function benefits were independent. These data suggest a greater clinical benefit from dual bronchodilators in symptomatic patients than in patients without symptoms. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01854645 and NCT01854658; URL: www.clinicaltrials.gov. PMID- 28720334 TI - Salmonella infection: Interplay between the bacteria and host immune system. AB - Salmonella infection causes morbidity and mortality throughout the world with the host immune response varying depending on whether the infection is acute and limited, or systemic and chronic. Additionally, Salmonella bacteria have evolved multiple mechanisms to avoid or subvert immunity to its own benefit and often the anatomical location of infection plays a role in both the immune response and bacterial fate. Here, we provide an overview of the interplay between the immune system and Salmonella, while discussing how different host and bacterial factors influence the outcome of infection. PMID- 28720338 TI - Complete denture fabrication using piezography and CAD-CAM: A clinical report. AB - To provide maxillary and mandibular complete dentures for a patient with severe ridge resorption, the denture space was recorded using the piezography technique. After the piezographic space was scanned, a virtual tooth arrangement and festooning were performed within the space using computer-aided design software. The denture bases were milled from a polymethylmethacrylate resin block using computer-aided manufacturing, and commercially available denture teeth were bonded with resin adhesive. Using the piezography technique described, physiologically appropriate complete dentures were fabricated based on the neutral zone concept. PMID- 28720339 TI - In vitro fit of CAD-CAM complete arch screw-retained titanium and zirconia implant prostheses fabricated on 4 implants. AB - STATEMENT OF PROBLEM: Computer-aided designed and computer-aided manufactured (CAD-CAM) titanium and zirconia implant-supported fixed implant prostheses on 4 implants have become popular. The precision and accuracy of their interface fit has not been widely researched. PURPOSE: The purpose of this in vitro study was to compare the marginal fit of zirconia and titanium implant-supported screw retained CAD-CAM complete fixed dental prostheses (CFDP) fit with a standardized cast simulating the all-on-4 implant distribution. MATERIAL AND METHODS: Representation of an edentulous maxilla with 4 multiunit replicas embedded in sites corresponding to the positions of the maxillary first molars and canines was chosen. Multiunit abutments were digitally scanned using scan bodies and a laboratory scanner. CAD software was used to design screw-retained implant-fixed complete prostheses framework, and the file was sent to a milling machine for CAM. Titanium (n=5) and zirconia (n=5) frameworks were milled on 4 implants, and the frameworks were scanned with an industrial computed tomography (CT) scanner while applying the 1-screw test. The direct CT scans were reconstructed to generate a standard tessellation language (STL) file from the voxel data set and transported to volume graphics analysis software from which measurements were extracted. The circular mating surfaces of the corresponding framework interfaces to their representative multiunit abutment replicas on the standard were measured for implant position left maxillary canine (LMC), implant position right maxillary canine (RMC) and implant position right maxillary first molar (RMFM). In addition, color maps were generated to show the marginal discrepancy between the mating surfaces using +/-0.500 mm color scale ranges. RESULTS: The material type (zirconia or titanium) was not significant for 3D discrepancy measurements (P=.904). However, 3D discrepancy measurement values were significantly different between RMC and RMFM within each group (P<.001). The mean 3D +/-SD discrepancy measurement for LMC for titanium was 48.2 +/-2.6 MUm. The mean +/-3D discrepancy measurement for RMC for titanium was 74 +/-15 MUm and 84.4 +/-12.1 MUm for zirconia. The mean 3D discrepancy measurement for RMFM for titanium was 102 +/ 26.7 MUm and 93.8 +/-30 MUm for zirconia. All 3D discrepancy measurements showed values <135 MUm. CONCLUSIONS: Within the limitations of the present in vitro study, implant-supported CAD-CAM fabricated titanium and zirconia complete fixed dental prosthesis frameworks showed comparable marginal fit. Three-dimensional microgap measurements of frameworks showed clinically acceptable misfit values. Absolute passive fit was not achieved. PMID- 28720340 TI - Mechanical strength and fracture point of a dental implant under certification conditions: A numerical approach by finite element analysis. AB - STATEMENT OF PROBLEM: Implant prosthodontics provides high-quality outcomes thanks to recent technological developments and certification procedures such as International Organization for Standardization (ISO) 14801. However, these certification tests are costly, and the result is highly uncertain as the influence of design variables (materials and structure) is still unknown. The design process could be significantly improved if the influence of design parameters were identified. PURPOSE: The purpose of this in vitro study was to use finite element analysis (FEA) to assess the influence of design parameters on the mechanical performance of an implant in regard to testing conditions of ISO 14801 standard. MATERIAL AND METHODS: An endosseous dental implant was loaded under ISO 14801 testing conditions by numerical simulation, with 4 parameters evaluated under the following conditions: conditions of the contact surface area between the implant and the loading tool, length of the fixation screw, implant embedding depth, and material used for implant stiffness. FEA was used to compare the force that needed to reach the implant's yield and fracture strength. RESULTS: A dental implant's fracture point can be increased by 41% by improving the contact surface area, by 20% depending on the type of material, by 4% depending on the length of the fixation screw, and by 1.4% by changing the implant embedding depth. CONCLUSIONS: FEA made it possible to evaluate 4 performance parameters of a dental implant under ISO 14801 conditions. Under these conditions, the contact surface area was found to be the major parameter influencing implant performance. This observation was validated experimentally in a fatigue test under ISO 14801 conditions. PMID- 28720341 TI - Lipase or amylase for the diagnosis of acute pancreatitis? AB - Acute pancreatitis is a rapid onset of inflammation of the pancreas causing mild to severe life threatening conditions [1, 2]. In Canada, acute pancreatitis is the 5th most expensive digestive disease in Canada with a considerable economic burden on the health care system [3]. The diagnosis of acute pancreatitis is usually based on the presence of abdominal pain and elevated levels of serum amylase and/or lipase. Many health care centers use either serum amylase, lipase or both to diagnose acute pancreatitis without considering which one could provide a better diagnostic accuracy. The aim of this review is to investigate whether serum lipase alone is a sufficient biomarker for the diagnosis of acute pancreatitis. We have examined various studies looking at the utilization, sensitivity, specificity and cost associated savings of lipase and amylase in the diagnosis of acute pancreatitis. When comparing different studies, serum lipase offers a higher sensitivity than serum amylase in diagnosing acute pancreatitis. Lipase also offers a larger diagnostic window than amylase since it is elevated for a longer time, thus allowing it to be a useful diagnostic biomarker in early and late stages of acute pancreatitis. Several recent evidence-based guidelines recommend the use of lipase over amylase. Nevertheless, both lipase and amylase alone lack the ability to determine the severity and etiology of acute pancreatitis. The co-ordering of both tests has shown little to no increase in the diagnostic sensitivity and specificity. Thus, unnecessary testing and laboratory expenditures can be reduced by testing lipase alone. PMID- 28720342 TI - Severe hypoglycaemia is a major predictor of incident diabetic retinopathy in Japanese patients with type 2 diabetes. AB - AIM: Hypoglycaemia is a common complication in diabetes patients. However, its relationship with retinopathy has not been well documented in patients with type 2 diabetes (T2D). This study aimed to investigate the associations between hypoglycaemia and the incidence and progression of diabetic retinopathy (DR). METHODS: In this longitudinal cohort study, which was part of the Japan Diabetes Complications Study (JDCS), adult patients with T2D were recruited at 59 diabetes clinics across Japan. Their history of hypoglycaemia was assessed by standardized self-reported questionnaires. Severe hypoglycaemia was defined as having at least one episode with coma requiring an outpatients visit or hospitalization. Adjusted hazard ratios (HRs) for incidence and progression of DR over 8 years of follow-up were determined. RESULTS: Of 1221 patients without DR, 127 (10.4%) had experienced non-severe hypoglycaemia within the previous year, whereas 10 (0.8%) reported severe hypoglycaemia episodes. During the 8-year follow-up involving 8492 person-years, 329 patients developed DR. In 410 patients with prevalent DR, the adjusted HRs for incident DR were 4.35 (95% CI: 1.98-9.56; P<0.01) and, for progression of DR, 2.29 (95% CI: 0.45-11.78; P=0.32) with severe hypoglycaemia. CONCLUSION: Having a history of severe hypoglycaemia was one of the strongest predictors of incident DR in patients with T2D, with a fourfold increased risk. Identifying patients with greater risks of DR based on their history of hypoglycaemia may help to personalize risk evaluation in patients with diabetes. PMID- 28720344 TI - APOE genotype associates with food consumption and body composition to predict dyslipidaemia in Brazilian adults with normal-weight obesity syndrome. AB - BACKGROUND & AIM: Normal-Weight Obesity Syndrome has been characterized by a normal body mass index and high percentage of body fat. It is associated with an increased risk of cardiovascular disease development. This study aimed to evaluate whether apolipoprotein E (APOE) genotypes and food consumption are related to the lipid profiles of adults with Normal-Weight Obesity Syndrome. METHODS: Analytical cross-sectional study, including adults with Normal-Weight Obesity Syndrome. Socioeconomic, health and lifestyle questionnaires were administered. Anthropometric variables, body composition and blood pressure were evaluated. Dietary intake, lipid profile and genotyping of polymorphisms rs7412 and rs429358 in the APOE gene were evaluated. RESULTS: Only 6.0% of women and none of the men had increased waist circumference (>=80 cm for women and >=94 cm for men). No women and 6.2% of men had altered blood pressure (systolic blood pressure >=130 mmHg and/or diastolic blood pressure >=85 mmHg). When the traditional lipid profile was assessed, 52.5% of individuals presented dyslipidaemia. When the levels of apolipoproteins A1 and B were included, the prevalence was 73.0%. Regression analysis showed a positive relationship between the presence of allele epsilon2 and apolipoprotein A1 levels (95% CI = 4.2 to 38.3; p = 0.015) and between the epsilon4 allele and apolipoprotein B (epsilon4 versus epsilon2: 95% CI = 0.08 to 29.5; p = 0.049 and epsilon4 versus epsilon3: 95% CI = 0.6 to 17.6; p = 0.036). Carriers of the epsilon2 allele had a 75.0% lower probability of presenting dyslipidaemia compared with epsilon3epsilon3 individuals (95% CI = 0.04 to 0.8; p = 0.027). Relationships between body fat, food consumption and lipid profile were observed and differed among genotypes. CONCLUSIONS: APOE genotype and food consumption were associated with lipid profile. This was the first study to evaluate the APOE genotype and to analyze relationships between genetic profile, food intake and lipid profile of subjects with Normal-Weight Obesity Syndrome. PMID- 28720343 TI - Exposure to ambient dichloromethane in pregnancy and infancy from industrial sources and childhood cancers in California. AB - BACKGROUND: The incidence of childhood cancers has been increasing and environmental exposure to air toxics has been suggested as a possible risk factor. This study aims to explore ambient exposure to dichloromethane (methylene chloride). METHODS: We frequency matched by birth year approximately 20 cancer free controls identified from birth records to all childhood cancers ages 0-5 in the California Cancer Registry diagnosed from 1988 to 2012; i.e. 13,636 cases and a total of 270,673 controls. Information on industrial releases of dichloromethane within 3km of birth addresses was retrieved from mandatory industry reports to the EPA's Toxics Release Inventory (TRI). We derived exposure to dichloromethane within close vicinity of birth residences using several modeling techniques including unconditional logistic regression models with multiple buffer distances, inverse distance weighting, and quadratic decay models. RESULTS: We observed elevated risks for germ cell tumors [Odds Ratio (OR): 1.52, 95% Confidence Interval (CI) 1.11, 2.08], particularly teratomas (OR: 2.08, 95% CI 1.38-3.13), and possible increased risk for acute myeloid leukemias (AML) (OR: 1.64, 95% CI 1.15-2.32 in the quadratic decay model). Risk estimates were similar in magnitude whether releases occurred in pregnancy or the child's first year of life. CONCLUSION: Our findings suggest that exposure to industrial dichloromethane releases may be a risk factor for childhood germ cell tumors, teratomas, and possibly AML. PMID- 28720345 TI - The potential of phage therapy in cystic fibrosis: Essential human-bacterial phage interactions and delivery considerations for use in Pseudomonas aeruginosa infected airways. AB - As antimicrobial-resistant microbes become increasingly common and a significant global issue, novel approaches to treating these infections particularly in those at high risk are required. This is evident in people with cystic fibrosis (CF), who suffer from chronic airway infection caused by antibiotic resistant bacteria, typically Pseudomonas aeruginosa. One option is bacteriophage (phage) therapy, which utilises the natural predation of phage viruses upon their host bacteria. This review summarises the essential and unique aspects of the phage-microbe human lung interactions in CF that must be addressed to successfully develop and deliver phage to CF airways. The current evidence regarding phage biology, phage bacterial interactions, potential airway immune responses to phages, previous use of phages in humans and method of phage delivery to the lung are also summarised. PMID- 28720346 TI - Pharmacokinetic data reduce uncertainty in the acceptable daily intake for benzoic acid and its salts. AB - The current acceptable daily intake (ADI) for benzoic acid and its salts as food additives is 0-5 mg/kg body weight. This accounts for a total uncertainty factor (UF) of 100, which includes a default factor of 10 for interspecies differences. Based on pharmacokinetic data in rodents and humans, we derived a chemical specific adjustment factor (CSAF) of 2 for the pharmacokinetic component of the interspecies UF. Additional analyses indicate that this CSAF is conservative and interspecies differences between rats and humans are likely closer to unity. Human clinical studies indicate that the pharmacokinetics of benzoic acid and its salts are similar in children and adults, and that there is a lack of adverse events in humans at doses comparable to the no observed adverse effect level (NOAEL) in rodents; this suggests that the pharmacokinetic UF for intraspecies variability, as well as the pharmacodynamic components of the UFs, may also be reduced, although we did not calculate to what degree. In conclusion, the total UF can be reduced to 50 (2 for interspecies differences in pharmacokinetics, 2.5 for interspecies differences in pharmacodynamics, and 10 for intraspecies variability), which would increase the ADI to 0-10 mg/kg body weight. PMID- 28720347 TI - Transgenesis affects endogenous soybean allergen levels less than traditional breeding. AB - The regulatory body that oversees the safety assessment of genetically modified (GM) crops in the European Union, the European Food Safety Authority (EFSA), uniquely requires that endogenous allergen levels be quantified as part of the compositional characterization of GM versions of crops, such as soybean, that are considered to be major allergenic foods. The value of this requirement for assessing food safety has been challenged for multiple reasons including negligible risk of altering allergen levels compared with traditional non-GM breeding. Scatter plots comparing the mean endogenous allergen levels in non-GM soybean isoline grain with the respective levels in GM grain or concurrently grown non-GM commercial reference varieties clearly show that transgenesis causes less change compared with traditional breeding. This visual assessment is confirmed by the quantitative fit of the line of identity (y = x) to the datasets. The current science on allergy does not support the requirement for quantifying allergen levels in GM crops to support safety assessment. PMID- 28720348 TI - Safety evaluation of a novel muramidase for feed application. AB - Safety evaluation of a muramidase produced by a Trichoderma reesei strain (safe lineage), expressing a muramidase gene isolated from Acremonium alcalophilum is presented. Intended use in feed of this enzyme is as digestive aid in broiler chickens. Muramidase 007, was non-mutagenic and non-clastogenic in vitro, and no adverse effects were observed in 90-day subchronic toxicity studies in rats at doses up to 1132 mg TOS/kg body weight/day. The enzyme did not exhibit, in vitro, skin, nor eye irritation potential. Acute aquatic toxicity evaluated on daphnia and algae showed absence of effect of the enzyme at the standard doses tested. Muramidase 007 was fully tolerated by broiler chickens in a 6-weeks tolerance study showing no adverse effects in any of the dietary treatments (0, 1*, 5* and 10* maximum recommended dose). In conclusion, Muramidase 007 is found to be toxicologically inert, and there are no worker's safety concerns if standard precautions are instituted and a non-dusty formulation is employed. Muramidase 007 is well tolerated by the target species (broiler chickens) and cause no harm to the environment. The beneficial safety evaluation of Muramidase 007 is in line with this type of enzyme that is found ubiquitously in nature. PMID- 28720349 TI - Rejection of the synonymization of Pegosomum saginatum (Ratz, 1898) Ratz, 1903 with Pegosomum asperum (Wright, 1879) Ratz, 1903. AB - The Pegosomum Ratz, 1903 are digenean parasites of piscivorous birds. They exhibit few morphological autapomorphies and some of their identification features (number of collar spines) can be altered before or during fixation. Several re-classifications within the genus were suggested, but they have never been supported by molecular analyses. We addressed the synonymization of species within Pegosomum asperum/saginatum complex suggested by Dubinin, Dubinina and Saidov. We analyzed one nuclear (ITS2) and two mitochondrial (CO1, ND1) loci of two central European species of Pegosomum, namely Pegosomum asperum (Wright, 1879) Ratz, 1903 and Pegosomum saginatum (Ratz, 1898) Ratz, 1903. Our combined molecular and comparative morphological analyses confirmed the validity of the two Pegosomum spp. Both species had highly similar morphology and occurred sympatrically in the gall bladder and bile duct of Ardea alba (Linnaeus, 1758). P. saginatum occurred more frequently in hosts infected concurrently with P. asperum. We also provided host-, age- and sex-specific prevalence and intensity of infections, and comparative measurements of the two Pegosomum spp. based on an extensive dataset collected from 1962 to 2016. These species can be morphologically distinguished based on the extent of vitellarium, which reached anteriorly to the pharynx in P. asperum but extended anteriorly to the midline of the esophagus in P. saginatum. The species also differed in the cirrus diameter (P. asperum>=447, P. saginatum<=447). PMID- 28720350 TI - An overview of in vitro dissolution/release methods for novel mucosal drug delivery systems. AB - In vitro dissolution/release tests are an important tool in the drug product development phase as well as in its quality control and the regulatory approval process. Mucosal drug delivery systems are aimed to provide both local and systemic drug action via mucosal surfaces of the body and exhibit significant differences in formulation design, as well as in their physicochemical and release characteristics. Therefore it is not possible to devise a single test system which would be suitable for release testing of such complex dosage forms. This article is aimed to provide a comprehensive review of both compendial and noncompendial methods used for in vitro dissolution/release testing of novel mucosal drug delivery systems aimed for ocular, nasal, oromucosal, vaginal and rectal administration. PMID- 28720351 TI - The Future of Stone Research. PMID- 28720352 TI - Medical Measures for Secondary Prevention of Urolithiasis. AB - The global prevalence of nephrolithiasis has progressively increased over the past several decades. Kidney stone disease without treatment is a recurrent illness that represents a major health burden across the globe with associated economic costs. PMID- 28720353 TI - Kallikreins Panel for Prostate Cancer Aggressiveness Prediction: More Is Not Enough. PMID- 28720354 TI - Training Modalities in Robot-assisted Urologic Surgery: A Systematic Review. AB - CONTEXT: Novel surgical techniques demand that surgical training adapts to the need for technical and nontechnical skills. OBJECTIVE: To identify training methods available for robot-assisted surgical (RAS) training in urology, evaluate their effectiveness in terms of validation, educational impact, acceptability, and cost effectiveness, and assess their effect on learning curves (LCs). EVIDENCE ACQUISITION: A systematic review following Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines searched Ovid Medline, Embase, PsycINFO, and the Cochrane Library. Results were screened to include appropriate studies. Quality was evaluated. Each method was evaluated, and conclusions were drawn regarding LCs. EVIDENCE SYNTHESIS: Of 359 records, 24 were included (521 participants). Training methods included dry-lab training (n=7), wet-lab training (n=7), mentored training (n=7), and nonstructured pathways (n=5). Dry-lab training demonstrated educational impact by reducing console time and was acceptable in a study; 100% of participants confirmed face validity. Wet-lab training principally uses human cadaveric material; effectiveness is well rated, although dry-lab training and observation were rated as equally useful. Mentored programmes combine lectures, tutorials, observation, simulation, and proctoring. Minifellowships were linked to greater practice of RAS 1 yr later. LCs vary according to experience. One study found that surgeons from robot-related fellowships demonstrated fewer positive surgical margins than surgeons from laparoscopic-related fellowships (24% vs 34.6%; p=0.05) and reduced time (132 vs 152min; p=0.0003). Five studies examined nonstructured training pathways (clinical practice). Experience correlated with fewer complications (p=0.007), improved continence (p=0.049), and reduced time (p=0.002). CONCLUSIONS: RAS training methods include dry and wet lab, mentored training, and nonstructured pathways. Limited available evidence suggests that they affect LCs differently and are rarely used alone. The different methods of training appear effective when combined. Their benefits must be explored to facilitate validated acceptable training with educational impact. PATIENT SUMMARY: Robot-assisted training encompasses several methods used in combination, but more evidence is required to gain the greatest benefit and formulate future training pathways. PMID- 28720355 TI - Surgical Training in the Robotic Surgery Era: The Importance of Structured Programs. PMID- 28720357 TI - Clinical Case Discussion: Kidney Stone in a Patient with an Ileal Conduit. AB - A patient underwent robot-assisted laparoscopic cystectomy with an ileal conduit urinary diversion. Percutaneous nephrolithotomy was performed for treatment of a kidney stone. Stone analysis revealed struvite. PMID- 28720356 TI - Phosphodiesterase Type 5 Inhibitors for Premature Ejaculation: A Systematic Review and Meta-analysis. AB - CONTEXT: Phosphodiesterase type 5 inhibitors (PDE5-Is) are prescribed off-label for the treatment of premature ejaculation (PE). OBJECTIVE: To systematically review the evidence from randomised controlled trials (RCTs) for PDE5-Is in the management of PE. EVIDENCE ACQUISITION: Medline and other databases were searched through September 2015. Quality of RCTs was assessed. Intravaginal ejaculatory latency time (IELT) data were pooled in a meta-analysis. Heterogeneity was assessed. EVIDENCE SYNTHESIS: Fifteen RCTs were included. The majority were of unclear methodological quality. Pooled IELT evidence suggests that PDE5-Is are significantly more effective than placebo (231 participants, p<0.00001), that there is no difference between PDE5-Is and selective serotonin reuptake inhibitors (SSRIs; 405 participants, p=0.50), and that PDE5-Is combined with an SSRI are significantly more effective than SSRIs alone (521 participants, p=0.001); however, high levels of statistical heterogeneity are evident (I2 >= 40%). Single-RCT evidence suggests that sildenafil is significantly more effective than the squeeze technique, but both lidocaine gel and tramadol are significantly more effective than sildenafil. Sildenafil combined with behavioural therapy is significantly more effective than behavioural therapy alone. Sexual satisfaction and ejaculatory control appear to be better with PDE5 Is compared with placebo and with PDE5-Is combined with an SSRI compared with an SSRI alone. Adverse events are reported with both PDE5-Is and other agents. CONCLUSIONS: PDE5-Is are significantly more effective than placebo and PDE5-Is combined with an SSRI are significantly more effective than SSRIs alone at increasing IELT and improving other effectiveness outcomes; however, heterogeneity is evident across RCTs. The methodological quality of the majority of RCTs is unclear. PATIENT SUMMARY: We reviewed phosphodiesterase type 5 inhibitors (PDE5-Is) for treating premature ejaculation. We found evidence to suggest that PDE5-Is are effective compared with placebo and that PDE5-Is combined with an SSRI are more effective than an SSRI alone. Adverse events are reported with PDE5-Is and other agents; however, the quality of the evidence is uncertain. TRIAL REGISTRATION: PROSPERO registration number CRD42013005289. PMID- 28720358 TI - Prognostic Significance of Neutrophilic Infiltration in Benign Lymph Nodes in Patients with Muscle-invasive Bladder Cancer. AB - BACKGROUND: Preclinical studies suggest that signal transducer and activator of transcription 3 (STAT3)-mediated recruitment of neutrophils to premetastatic tissue occurs prior to metastatic progression. OBJECTIVE: We sought to determine if neutrophilic infiltration in benign nodal tissue is associated with poor clinical outcome in patients with muscle-invasive bladder cancer. DESIGN, SETTING, AND PARTICIPANTS: Formalin-fixed, paraffin-embedded tissue was secured from 55 patients with muscle-invasive bladder cancer who had undergone cystectomy at our institution. Sections of benign lymph nodes were obtained and stained with primary antibodies against 3-fucosyl-N-acetyl-lactosamine, phosphorylated STAT3, and interleukin-17, the latter being a key mediator of neutrophil infiltration and STAT3 activation. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The Kaplan Meier method was used to interrogate differences in overall survival (OS) in patients with high versus low biomarker expression. Cohorts stratified by receipt and nonreceipt of neoadjuvant chemotherapy were separately explored. RESULTS AND LIMITATIONS: Of the 55 patients examined, 19 patients (35%) had no prior neoadjuvant chemotherapy. Amongst these patients, median OS was improved in patients with low 3-fucosyl-N-acetyl-lactosamine+ cell counts (196 mo vs 37 mo; p=0.0062) and low phosphorylated STAT3+ cell counts (278 mo vs 106 mo; p=0.025). In the same cohort, a trend towards improved OS in patients with low interleukin 17+ cell count was observed (not reached vs 117 mo; p=0.18). No differences in OS were noted in biomarker-based subgroups amongst patients that had received prior neoadjuvant chemotherapy. CONCLUSIONS: The results herein support the hypothesis that bladder cancer metastasis may be driven by STAT3-mediated neutrophilic infiltration in premetastatic sites. Validation of these findings using tissues derived from a phase 3 surgical trial (Southwest Oncology Group 1011) is currently underway. PATIENT SUMMARY: Lymph node metastases occur in up to 25% of patients with muscle-invasive cancer and it represents one of the most frequent sites of bladder cancer metastasis. This report provides preliminary evidence that neutrophil levels in benign lymph nodes may predict clinical outcome. PMID- 28720359 TI - Functional Outcomes Following Radical Cystectomy in Women with Bladder Cancer: A Systematic Review. AB - CONTEXT: Gender-specific functional and health-related quality of life (HRQOL) outcomes following radical cystectomy (RC) for bladder cancer (BCa) remain unclear, with many studies excluding women from the study population. OBJECTIVE: To better characterize female-specific functional outcomes following RC and urinary diversion for BCa. EVIDENCE ACQUISITION: We performed a critical review of PubMed/Medline and Embase in August 2015 according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis statement. Outcomes of interest included urinary function (for orthotopic neobladder), sexual function, bowel function, and quality of life. Excluded were nonbladder malignancies, RCs performed for neurogenic bladder dysfunction, and patients with exposure to radiation therapy prior to surgery. Forty-five publications were selected for inclusion in this analysis. EVIDENCE SYNTHESIS: Included reports addressed urinary function (34 studies), sexual function (11 studies), and HRQOL (9 studies). All studies had a high risk of bias and ranged significantly in sample size, inclusion criteria, and follow-up time, precluding meaningful meta analysis. Daytime incontinence approximated 20%, nighttime incontinence 20%, and hypercontinence 10-20%. Sexual function appeared to be better among those patients undergoing genitalia-sparing RC, but generally poor outcomes were noted among those undergoing routine RC. Only 40% of studies assessed sexual function using standardized instruments. HRQOL differences between diversion types appeared to be minimal, whereas comparisons with the general population revealed significant differences in emotional problems, role functioning, fatigue, and appetite. CONCLUSIONS: Functional outcomes among women undergoing RC for BCa are poorly studied with limitations regarding use of validated questionnaires, heterogeneous patient populations, and small sample sizes. Collaborative efforts will be needed to better define functional outcomes among this poorly studied patient population. PATIENT SUMMARY: We reviewed functional outcomes following cystectomy among women with bladder cancer. We found that urinary, sexual, and bowel function and quality of life are poorly studied among women, with function ranging significantly across studies. PMID- 28720360 TI - Kidney Stone in a Patient with an Ileal Conduit. AB - The advantage of a retrograde over an antegrade approach in ileal conduit diversion is the lower morbidity. Furthermore, in cases in which there are bone deformities and no ureteral reflux from the reservoir into the upper tract, percutaneous access can be challenging. Thus, a retrograde approach should be considered as the first-line option for the treatment of renal stones in patients with an ileal conduit, but the urologist should keep in mind that an antegrade or combined approach may be possible in the case of failure. PMID- 28720361 TI - Grey Zones in Urolithiasis Guidelines. PMID- 28720362 TI - Case Discussion: Kidney stone in a patient with an ileal conduit. AB - Kidney stones in patients with ileal conduit and multiple sclerosis are secondary to postoperative anatomical changes and ascending urinary tract infections by urea-splitting bacteria. PNL is the preferred treatment option in patients with urinary diversion and infectious renal stones. PMID- 28720363 TI - Burden of Urolithiasis: Trends in Prevalence, Treatments, and Costs. AB - CONTEXT: The recent evolution of management options for urolithiasis has presented a unique dilemma for the modern urologist. A comprehensive understanding of epidemiological trends along with current provider preferences in treating urinary stones would be beneficial. OBJECTIVE: To review trends in the prevalence, treatments, and costs of urolithiasis worldwide. EVIDENCE ACQUISITION: A literature review was performed using the MEDLINE database, the Cochrane Library Central search facility, Web of Science, and Google Scholar between 1986 and 2016. Keywords used for the search were "urolithiasis" and "prevalence; treatment; and cost". EVIDENCE SYNTHESIS: The incidence and prevalence of urinary stones are rising around the world, including regions that have historically had low rates of urolithiasis. Common theories explaining this trend involve climate warming, dietary changes, and obesity. Shockwave lithotripsy (SWL) has been the preferred mode of treatment since its introduction in the 1980s. However, ureteroscopy (URS) has become increasingly popular for small stones regardless of location because of lower recurrence rates and costs. Developing countries have been slower to adopt URS technology and continue to use percutaneous nephrolithotomy at a steady rate. CONCLUSIONS: URS has recently challenged SWL as the treatment modality preferred for small upper urinary tract stones. In some cases it is less expensive but still highly effective. As the burden of stone disease increases worldwide, appropriate selection of stone removal therapies will continue to play an important role and will thus require further investigation. PATIENT SUMMARY: Urinary stones are becoming more prevalent. Recent advances in technology have improved the management of this disease and have decreased costs. PMID- 28720364 TI - Medical Expulsive Therapy in Urolithiasis: A Review of the Quality of the Current Evidence. AB - CONTEXT: Medical expulsive therapy (MET) is widely used to promote spontaneous passage of urinary stones. However, there is conflicting evidence on the actual role of MET. OBJECTIVE: To evaluate the conformance of published randomized controlled trials (RCTs) on MET with the Consolidated Standards for Reporting Trials (CONSORT) criteria, and to clarify the current role of MET in management of urinary stones on the basis of our findings. EVIDENCE ACQUISITION: We carried out an electronic search of the Cochrane Library, PubMed, and Embase databases for RCTs on MET. For each RCT included, we created a checklist table documenting the minimum essential items that should be included in reports of RCTs according to the CONSORT 2010 statement. EVIDENCE SYNTHESIS: Clinical heterogeneity between pooled studies in terms of the MET given, inclusion criteria, sample size, pre- and post-treatment imaging, and differential follow-up was profound. The overall methodological rigor of the pooled studies was low, as indicated by the moderate to poor conformance of the studies with the CONSORT criteria. The aforementioned reasons may explain the discrepancies found between the supporting results of several meta-analyses and those of well-designed placebo-controlled double-blind studies revealing no benefit from MET. Recent well-designed RCTs have shown no benefit from alpha-blockers versus placebo. However, on the basis of sensitivity analyses in a recently published meta-analysis, alpha-blockers may still promote spontaneous expulsion of large stones. CONCLUSIONS: Conflicting data on MET may be explained by clinical heterogeneity and methodological flaws. Urologists must decide whether to follow single, large, well-conducted RCTs or pooled data from meta-analyses. The latter still support selective use of MET for larger urinary stones. PATIENT SUMMARY: In this review we tested the accuracy of the studies published on various medications given to promote spontaneous passage of stones from the ureter. Although the majority of the studies were not designed properly, there is still some evidence to support medical expulsive therapy. PMID- 28720365 TI - The Role of Medical Expulsive Therapy for Ureteral Stones: Pro MET. AB - Medical expulsive therapy is efficacious in patients with ureteric stones who are amenable to conservative management. The greatest benefit might be among those with larger stones. Therefore, the European Association of Urology Guideline Panel has kept the recommendation to offer alpha-blockers for patients with distal ureteral stones of 5-10mm. PMID- 28720366 TI - The Evolving Role of Retrograde Intrarenal Surgery in the Treatment of Urolithiasis. AB - CONTEXT: Retrograde intrarenal surgery has gained substantial popularity worldwide thanks to continuous improvements in technology and techniques, and is now considered one of the first-line treatment options for active removal of renal stones. OBJECTIVE: To provide a comprehensive synthesis of the main evidences in literature on the current management of kidney stones by means of retrograde intrarenal surgery (RIRS). EVIDENCE ACQUISITION: A review of literature has been conducted using search string "retrograde intrarenal surgery OR flexible ureteroscop* OR ureterorenoscop*", without any language restriction; PubMed, Embase, and Scopus databases were searched in November 2016. Exclusion criteria involved manuscripts dealing with paediatric patients, and RIRS for proximal ureteric stones and for upper tract urothelial tumours. Fifty-seven papers were finally included in the analysis. EVIDENCE SYNTHESIS: Technological progress focuses on the miniaturisation of disposables and scopes, as well as on the increase of durability and improvement of the quality of image provided by these instruments. The technique has been in continuous development following the progress in technology. Currently, the main target of RIRS are renal stones 1-2cm in size, even though tertiary centres are pushing the boundaries to the treatment of larger stones. Nomograms predicting surgical outcomes and improving preoperative surgical planning have been developed. RIRS has been shown to be safe and effective in patients with specific conditions such as bleeding diathesis, anatomical malformation, or pregnancy. Cost effectiveness of the approach is still a matter of controversy when compared with other treatment modalities. CONCLUSIONS: RIRS is a well-established procedure under constant evolution with advances in technique and technology. It has gained worldwide popularity due to its minimal invasiveness and satisfactory outcomes. Future developments are needed to increase its cost effectiveness and extend its use to a wider range of indications. PATIENT SUMMARY: In this collaborative review, we have summarised the best evidence in literature with respect to current management of renal stones by means of retrograde intrarenal surgery (RIRS) with flexible ureteroscopy. RIRS has been shown to be a safe and effective treatment modality in a wide spectrum of clinical scenarios; technology and technique are continuously evolving to further push boundaries of its indications and efficacy. PMID- 28720367 TI - The Role of Medical Expulsive Therapy for Ureteral Stones: Against MET. AB - We no longer advocate the use of medical expulsive therapy in our patients. We also believe that the European Association of Urology guidelines group should believe the findings of the SUSPEND study and stop advocating the use of medical expulsive therapy. PMID- 28720368 TI - A Critical Review of Miniaturised Percutaneous Nephrolithotomy: Is Smaller Better? AB - CONTEXT: In an effort to reduce morbidity related to percutaneous nephrolithotomy (PCNL), some investigators have progressively introduced miniaturised approaches. The development of miniaturised nephroscopes facilitated widespread dissemination of these techniques and a significant expansion of the role of PCNL in endourology. OBJECTIVE: To discuss the different techniques comprising modern PCNL and identify the pros and cons of each of them. EVIDENCE ACQUISITION: Data for this review were identified through a search of PubMed, including studies published in the last 20 yr in core clinical journals in English. The search terms included "urolithiasis", "nephrolithiasis", or "urinary stones" in combination with "miniaturised PCNL", "mini-PCNL", "micro-PCNL", "minimally invasive PCNL", and "ultra-mini PCNL". Publications relevant to the subject were retrieved and critically appraised. EVIDENCE SYNTHESIS: The indications for miniaturised PCNL have not been standardised yet. Even though data in the literature reveal limitations and conflicting results, these techniques seem promising in terms of effectiveness and safety for the treatment of renal stones. The development of miniaturised scopes facilitated knowledge of the physics behind the vacuum cleaner effect generated during procedures, and greater efficacy of holmium laser generators and surgeon skill have led to progressive expansion of the indications for miniaturised techniques. Well-designed, randomised, multi-institutional studies are needed to better understand the indications for these miniaturised techniques before considering them a standard procedure for potential replacement of conventional PCNL. CONCLUSIONS: Miniaturised PCNL represents a valuable new tool in the armamentarium of modern endourologists, capable of offering good outcomes with lower complications rates compared to the standard technique and higher cost effectiveness compared to flexible ureteroscopy. PATIENT SUMMARY: Miniaturised percutaneous nephrolithotomy represents a safe and effective alternative to standard techniques for the treatment of renal stones. Each patient needs to be considered individually and tailored surgical treatment has to be offered. PMID- 28720369 TI - Metabolic Work-up of Patients with Urolithiasis: Indications and Diagnostic Algorithm. AB - CONTEXT: The incidence of urinary tract stone disease is increasing and the risk of recurrent stone formation is high. Appropriate therapeutic procedures with the aim of counteracting the progress of stone formation are highly desirable. Metabolic work-up is considered essential as a base for optimal design and follow up of effective recurrence prevention. OBJECTIVE: To scrutinize the current literature with regard to principles of metabolic work-up for this heterogeneous group of patients. EVIDENCE ACQUISITION: Relevant articles in PubMed, guideline documents, consensus reports, and the Cochrane Library published during the past 20 yr were consulted. EVIDENCE SYNTHESIS: Grades of recommendation were used according to the principles applied in the European Association of Urology and American Urological Association guidelines. Medical efforts to prevent recurrent stone formation should be part of the care of patients with urinary tract stone disease (grade of recommendation A). A careful medical history and imaging together with analysis of stone composition, blood, and urine provide the basis for appropriate measures, but the treatment has to be individualized (grade of recommendation D). Whenever possible, stone analysis should be carried out at least once for every patient or each time when a long time has elapsed between two stone episodes because the risk factors explaining stone formation may have changed (clinical principle). The medical history, including information on dietary and drinking habits as well as lifestyle, is necessary for appropriate advice (grade of recommendation C). The medical history, together with imaging and stone composition, is used to estimate the severity of the disease (clinical principle). Identification of specific medical conditions should be supported by blood and/or urine analysis (grade of recommendation B). Pharmacological agents associated with an increased risk of stone formation should be identified (grade of recommendation C). Patients who have formed noncalcium stones should always be given recurrence preventive treatment. Analysis of urine composition for these patients is optional, but might be of value in the follow-up to support decisions on appropriate dosage regimens (grade of recommendation C). For patients with idiopathic calcium stone disease information from 24-h urine samples should be used, although the number of samples to be taken is debated (grade of recommendation C). Information from 24-h urine analysis should be used for selective dietary and drinking advice as well as for selection of the most appropriate pharmacological agent (grade of recommendation B). The treatment effects on the risk of stone formation can be followed by estimates of supersaturation based on urine composition (grade of recommendation C). CONCLUSIONS: It is clear that the metabolic work-up of patients with urinary tract stone disease should be individualized according to stone type and severity of the disease, and that the different therapeutic approaches are closely associated with the availability of therapeutic tools and motivation by the patient. PATIENT SUMMARY: Effective prevention of recurrent stone formation is determined by several factors such as the current and previous stone episodes and surgical procedures, stone composition, medical history, dietary and drinking habits, lifestyle, and ongoing pharmacological therapy. Analysis of blood and urine is an important part of the metabolic evaluation, but how extensive the risk evaluation should be is determined by the type of stone and the severity of the disease. PMID- 28720370 TI - The Swiss Kidney Stone Cohort: An Observational Study to Unravel the Cause of Renal Stone Formation. AB - Its nationwide character, standardized and extensive patient work-up, long-term follow-up, and significant number of patients recruited make the Swiss Kidney Stone Cohort a valuable tool to better understand the pathophysiology of kidney stone formation. PMID- 28720371 TI - Genetic Risk Factors for Idiopathic Urolithiasis: A Systematic Review of the Literature and Causal Network Analysis. AB - CONTEXT: Urolithiasis has a high prevalence and recurrence rate. Prevention is key to patient management, but risk stratification is challenging. In particular, genetic predisposition for urinary stones is not fully understood. OBJECTIVE: To review current evidence of potential causative genes for idiopathic urolithiasis and map their relationships to one another. This evidence is essential for future establishment of molecular targeted therapy. EVIDENCE ACQUISITION: A systematic literature review from 2007 to 2017 was performed in accordance with the Preferred Reporting Items for Systematic Review and Meta-analyses guidelines. The search was restricted to human studies conducted as either case-control or genome wide association studies, and published in English. We also performed a causal network analysis of candidate genes gained from the systematic review using Ingenuity Pathway Analysis (IPA). EVIDENCE SYNTHESIS: During the systematic screening of literature, 30 papers were selected for the review. A total of 20 genes with 42 polymorphisms/variants were found to be associated with urolithiasis risk. Their functional roles were mainly categorized as stone matrix, calcium and phosphate regulation, urinary concentration and constitution, and inflammation/oxidative stress. IPA network analysis revealed that these genes connected via signaling pathways and a proinflammatory/oxidative environment. CONCLUSIONS: This systematic review provides an updated gene list and novel causal networks for idiopathic urolithiasis risk. Although some genes such as SPP1, CASR, VDR, CLDN14, and SLC34A1 were identified by several studies and recognized by prior reviews, further investigation elucidating their roles in stone formation will be essential for future studies. PATIENT SUMMARY: In this review, we summarized recent literature regarding genes responsible for kidney stone risk. Based on a detailed review of 30 articles and computational network analysis, we concluded that disorder of mineral regulation with local inflammation in the kidney may cause kidney stone disease. PMID- 28720372 TI - Comparing the Efficacy and Safety of Ultrasonic Versus Pneumatic Lithotripsy in Percutaneous Nephrolithotomy: A Randomized Clinical Trial. AB - BACKGROUND: Percutaneous nephrolitotomy (PCNL) is the preferred treatment for large renal stones. There is a need for more comparative data for different lithotripters used in PCNL. OBJECTIVE: To evaluate the comparative safety and efficacy of ultrasonic and pneumatic lithotripsy in patients undergoing PCNL. DESIGN, SETTING, AND PARTICIPANTS: This randomized clinical trial was conducted at Labbafinejad University Hospital, Tehran, Iran. A total of 180 patients were selected and divided randomly into two groups: 88 patients to pneumatic and 92 to ultrasonic lithotripsy. INTERVENTION: Standard fluoroscopy-guided PCNL was performed using pneumatic or ultrasonic lithotripsy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was the procedure success rate. We also evaluated other outcome measures including operation time, stone fragmentation and removal time (SFRT), length of hospital stay, and postoperative complications. We used SPSS software version 18.0 for data analysis. RESULTS AND LIMITATIONS: The two groups were similar in baseline characteristics. There were no significant differences between the groups in stone fragmentation and removal time (p=0.63), stone free rate (p=0.44), and hospital stay (p=0.66). SFRT for hard stones was shorter using pneumatic lithotripsy (p<0.001). By contrast, ultrasonic lithotripsy was associated with a shorter SFRT for soft stones (p<0.001). Postoperative complications were similar in the two groups. A limitation of this study might be the 3-mo follow-up period. CONCLUSIONS: In general, there were no significant differences in the success rate and complications between pneumatic and ultrasonic lithotripsy. SFRT was significantly shorter using pneumatic lithotripsy for hard stones, and ultrasonic lithotripsy for soft stones. PATIENT SUMMARY: We found no significant differences in the success rate and complications of percutaneous nephrolitotomy using pneumatic and ultrasonic lithotripsy. Ultrasonic and pneumatic lithotripsy differed in the time for stone fragmentation and removal for hard and soft stones. PMID- 28720373 TI - Incidence of Adverse Contrast Reaction Following Nonintravenous Urinary Tract Imaging. AB - : Adverse reactions (ARs) to intravenous (IV) radiographic contrast range from mild urticaria to life-threatening anaphylaxis. Intraluminal contrast dye is routinely used in the urinary tract with a minimal perceived risk of AR. We used the Healthcare Cost and Utilization Project State Inpatient Databases for California and Florida from 2007 to 2011 to identify patients who received urinary tract contrast dye for retrograde pyelography, percutaneous pyelography, retrograde/other cystogram, and ileal conduitogram. After excluding patients who had received IV contrast for other radiologic studies, ARs to contrast were identified by a composite end point of diagnoses not present on admission including shock, anaphylaxis, iatrogenic hypotension, urticaria, angioedema, laryngospasm, laryngeal edema, and/or a new diagnosis of contrast reaction. Overall, 76 174 patients were included who had undergone non-IV urinary tract imaging, 367 (0.48%) of whom developed an AR. On multivariate analysis, receipt of contrast in the lower urinary tract (odds ratio [OR]: 1.8; p=0.04) or upper urinary tract by retrograde pyelography (OR: 1.6; p=0.04) or antegrade pyelography (OR: 2.0; p=0.007) increased the risk of AR compared with control patients. The use of contrast dye in the urinary tract is associated with a low, but present risk of AR. PATIENT SUMMARY: We looked at patients who underwent a urologic procedure using radiographic contrast media in the urinary tract. Although adverse reactions (ARs) may occur with the use of contrast media in the urinary tract, these reactions are experienced by a minority of patients (approximately 1 in 200). In addition, we found that an allergy to intravenous contrast does not increase a patient's risk of an AR to contrast within the urinary tract. PMID- 28720374 TI - The 4Kscore Predicts the Grade and Stage of Prostate Cancer in the Radical Prostatectomy Specimen: Results from a Multi-institutional Prospective Trial. AB - BACKGROUND: The 4Kscore accurately predicts aggressive prostate cancer (PCa) on prostate biopsy. OBJECTIVE: We assessed how well the 4Kscore predicts pathology at radical prostatectomy (RP). DESIGN, SETTING, AND PARTICIPANTS: Among 1312 men who prospectively underwent a 4Kscore and biopsy of the prostate at 26 sites throughout the United States from October 2013 to April 2014, we selected men who were diagnosed with cancer and underwent RP. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was the presence of high-grade PCa or extracapsular extension. We assessed the association between the 4Kscore and the grade and extent of PCa at RP using the Wilcoxon rank sum test. We used logistic regression to investigate the added value of the 4Kscore in predicting a high-grade or non organ-confined tumor when added to available postbiopsy clinical predictive tools. RESULTS AND LIMITATIONS: A total of 144 men were diagnosed with PCa and underwent RP. Higher 4Kscores were associated with higher grade at RP. For men with Gleason scores >=6, 7, and 8 cancers in the surgical specimen, the median 4Kscores were 7% (interquartile range [IQR]: 4-2), 25% (IQR: 12-38), and 47% (IQR: 24-66) (p<0.0001), respectively. The median 4Kscore among men with non organ-confined cancer was significantly higher then men with organ-confined cancers (36% [IQR: 19-58] vs 19% [IQR: 9-35]; p=0.002). The 4Kscore did not significantly add to available clinical prediction tools for determining the likelihood of a high grade or non-organ-confined cancer; however, we were limited by a small sample size for this analysis. CONCLUSIONS: In a subset of men who underwent RP, the 4Kscore was significantly associated with pathologic grade and extracapsular extension in the surgical specimen, with higher scores associated with higher grade and more aggressive histology. The 4Kscore test may be helpful in selecting men who are likely to have adverse pathologic features at RP that may preclude them from being safely observed. PATIENT SUMMARY: Among men with prostate cancer who underwent removal of the prostate, the 4Kscore was associated with the final grade and extent of cancer. PMID- 28720375 TI - Protective role of antioxidant compounds against peroxynitrite-mediated modification of R54C mutant alphaA-crystallin. AB - As a highly potent reactive oxygen and nitrogen species, peroxynitrite (PON) has endogenous production in the eye ball and contributes to a variety of ocular disorders. In the current study the structural characteristics, chaperone-like activity and conformational stability of R54C mutant alphaA-crystallin (alphaA Cry) were studied upon modification with PON and in the presence of three antioxidant compounds such as ascorbic acid (ASA), glutathione (GSH) and N acetylcysteine (NAC) using gel electrophoresis and different spectroscopy methods. The results of both fluorescence analysis and gel electrophoresis suggested that PON modification leads to dityrosine-mediated intermolecular cross linking of this cataractogenic mutant protein. Also, the propensity of R54C mutant alphaA-Cry for disulfide cross-linking was increased upon PON modification. In addition, the PON-modified protein indicated structural alteration, reduced chemical stability and different pattern of proteolysis. Upon modification with PON, mutant alphaA-Cry displayed a significant increase in the chaperone-like activity against aggregation of gamma-crystallin and insulin. In addition, different antioxidant compounds indicated a prominent role in neutralizing the PON damaging effects on structural integrity and stability of this protein. The results of this study may highlight the importance of antioxidant-rich foods or potent antioxidant supplements in protection of lens crystallins against PON-mediated structural damages and cataract development. PMID- 28720376 TI - The increase in positively charged residues in cecropin D-like Galleria mellonella favors its interaction with membrane models that imitate bacterial membranes. AB - A comparative study of three synthetic peptides, namely neutral Cecropin D-like G. mellonella (WT) and two cationic peptides derived from its sequence, DeltaM1 (+5) and DeltaM2 (+9) is reported in this work. The influence of charge on the interactions between peptides and membranes and its effect on phase were studied by calorimetric assays. Differential scanning calorimetry (DSC) showed that DeltaM2 peptide showed the strongest effect when the membrane contained phosphatidylcholine (PC) and phosphatidylglycerol (PG), increasing membrane fluidization. Fourier transform infrared spectroscopy (FTIR) was used to determine lipid segregation in the presence of peptides. When WT and DeltaM1 bound to model membrane containing PG and PC (1:1 molar ratio) a separation of both lipids was observed. Meanwhile, DeltaM2 peptide also induced a demixing of PG-peptide rich domains separated from PC. FTIR experiments also suggested that the presence of DeltaM1 and DeltaM2 peptides increased lipid carbonyl group hydration in DMPG membrane fluid phase, However, hydration at the interface level in fluid phase was notably increased in the presence of WT and DeltaM1 peptides in DMPC/DMPG. Overall the increase in positively charged residues favors the interaction of the peptides with the negatively charged membrane and its perturbation. PMID- 28720377 TI - Sucrose and fat content significantly affects palatable food consumption in adolescent male and female rats. AB - Hyperpalatable foods are highly pleasurable and possess a heightened capacity to stimulate eating. Adolescents appear especially vulnerable to hyperpalatable foods. These foods are typically high in sugar, fat, or both, but the specific elements that underlie their increased consumption are still not clearly understood. Combinations of high fat and high sugar may particularly intensify overeating. Animal models allow investigation of the consumption of these foods separately from many of the environmental and psychological influences that impact eating in humans. The current study compared intakes of sucrose, fat, and a sucrose-fat combination when offered to male and female rats intermittently (2 h, three times per week for five weeks) during the vulnerable period of adolescence. Consumption of these foods, and of freely available normally nutritive lab chow was measured. Animals given the sucrose-fat food consumed significantly more than all other groups and were the only group to show significant increases in consumption during the first week. Moreover, the sucrose fat group consumed significantly less chow than any other group. In comparison with previous reports in adult rats, adolescent rats appeared to heighten consumption of the sucrose-fat food more markedly and to show less pronounced sex differences. These data highlight the unique vulnerability and increased biological susceptibility of adolescent rats to sweet-fat food rewards and demonstrate the need to similarly investigate the preference for and the consumption of different hyperpalatable foods in human adolescents. PMID- 28720378 TI - A novel technique: Carbon dioxide gas-assisted total peritonectomy, diaphragm and intestinal meso stripping in open surgery for advanced ovarian cancer (Cukurova technique). AB - OBJECTIVE: Most of the ovarian cancers are diagnosed at advanced stages. As peritoneal carcinomatosis increases, especially when it extends to the diaphragm and intestinal mesos, probability of obtaining complete cytoreduction is reduced. Complete cytoreduction (residue zero: R0) is one of the main factors affecting survival [1-3]. Here we present a novel technique of stripping the peritoneal surfaces as a part of cytoreductive surgery in such cases. METHODS: A 55year-old woman diagnosed with peritoneal carcinomatosis was considered appropriate for primary cytoreduction after assessment of her thorax-abdominopelvic tomography, which revealed resectable intra-abdominal disease. Upon laparotomy, omental cake adherent to pelvis-filling mass, disseminated implants on the diaphragm, meso of the descending colon and small intestine were observed. The mass invaded the rectosigmoid colon, uterus, adnexa and the bladder resulting in frozen pelvis. Palpable retroperitoneal pelvic and para-aortic lymph nodes were detected. On the other side, stomach, anti-mesenteric surfaces and mesentery root of the small bowel were tumor-free. Hence, upon these perioperative and preoperative imaging findings, complete cytoreduction was thought to be achievable. Therefore, primary cytoreduction was performed. Total omentectomy, hysterectomy with bilateral salpingo-oophorectomy, rectosigmoid low anterior resection and retroperitoneal lymphadenectomy were performed. With the assistance of an injector needle connected to the insufflator tube (as in laparoscopic surgery), carbon dioxide gas was blown into the right retroperitoneal area and subsequently peritoneum was rapidly stripped up to the right diaphragm. The same procedure was then applied to the diaphragm and meso of the bowels, respectively. Owing to this technique, total stripping of all involved peritoneal surfaces was clearly facilitated and R0 goal was reached. RESULTS: Gas insufflation caused convenient detachment of the peritoneal surfaces along their anatomical line which led to concluding the stripping procedures easily, rapidly and safely without bleeding. Thus, according to our experience, about 10 to 15min per procedure are saved in such cases. Potential complications of CO2 gas used here are not superior to those in transperitoneal or retroperitoneal laparoscopic procedures. During the operation, patient was followed-up for potential complications such as subcutaneous emphysema and CO2 gas embolism.Thus, hourly blood gas was monitored. Another potential complication is injury of the vessels while inserting the needle which can be avoided by cautious inserting under the peritoneal surfaces superficially and using transillumination. In case such injuries happen, tamponing is a sufficient measure. In our serial, no perioperative complications belonging to this technique were encountered. However, long term outcomes such as precise time difference, difference in blood loss, complication rates, adhesions, morbidity associated with this technique and its impact on survival of the patients with advanced ovarian cancer have yet to be investigated. Therefore, a prospective study to validate this technique's long-term usefulness has been initiated in our clinic. CONCLUSION: We believe that this practical and effective technique will offer significant improvements in efforts to achieve complete cytoreduction. PMID- 28720379 TI - Inhibition of 12/15 LOX ameliorates cognitive and cholinergic dysfunction in mouse model of hypobaric hypoxia via. attenuation of oxidative/nitrosative stress. AB - 12/15 Lipoxygenase has recently been described as potent propagator of oxidative stress and is closely associated with cognitive decline in neurodegenerative diseases. The mechanism/s behind 12/15 LOX involvement in cognitive deficits remain obscure. The current study has been designed to investigate the underlying role of 12/15LOX and effect of 12/15 LOX inhibition on hypobaric hypoxia-induced memory impairment and cholinergic deficits. Male Balb/c mice subjected to simulated hypobaric hypoxia/reoxygenation condition for 3days showed marked working memory impairment concomitant with hippocampal neuronal damage and malondialdehyde production which were significantly attenuated by baicalein, a specific inhibitor of 12/15LOX. Hypobaric hypoxia-exposed mice had consistently increased expression of 12/15LOX and elevated 12(S) HETE levels in the hippocampus as well as plasma which were significantly mitigated following baicalein treatment. 12/15LOX inhibition also reduced hypobaric hypoxia-mediated upregulation of hippocampal HIF-1alpha protein expression along with reduction in expression of inflammatory genes. The inhibition of 12/15 LOX resulted in a significant decrease in NO levels in the hippocampal homogenate associated with downregulated iNOS, nNOS transcription but not eNOS speculating that 12/15 LOX is critically involved in HIF-1alpha, mediated by nitric oxide-induced neurotoxicity. We also observed a similar effect of 12/15 LOX inhibition on hippocampal COX2 expression. 12/15LOX inhibition could effectively modulate central cholinergic indices during hypobaric hypoxia by restoring mAChR-1, alpha7NAChR expression and AChE, ChAT activity in the hippocampus comparable to normal mice. We report here the mechanistic involvement of 12/15LOX in orchestrating hypoxia-associated neuronal damage and HIF-1alpha-dependent neuroinflammation resulting in cognitive decline. PMID- 28720380 TI - [Comprehensive geriatric assessment and intervention proposal in a patient with a diffuse large B-cell lymphoma]. PMID- 28720381 TI - Tolerance to baked and fermented cow's milk in children with IgE-mediated and non IgE-mediated cow's milk allergy in patients under two years of age. AB - BACKGROUND: IgE-mediated cow's milk allergy (CMA) has been shown consistent in milder heated-milk tolerant and severe heated-milk reactant groups in patients older than two years. Little is known whether fermentation of milk gives rise to similar clinical phenotypes. We aimed to determine the influence of extensively heated and fermented cow's milk on the IgE-mediated and non-IgE-mediated CMA in children younger than two years. METHODS: Subjects followed with the diagnosis of IgE-mediated and non-IgE-mediated CMA for at least six months underwent unheated milk challenge. IgE-mediated and non-IgE-mediated groups were categorised as unheated milk-reactive and tolerant, separately. Unheated milk-reactive groups were further challenged sequentially with fermented milk (yoghurt) and baked milk, 15 days apart. Allergy evaluation with skin tests, prick-to-prick tests and atopy patch tests were performed. RESULTS: Fifty-seven children (median age: 14 months; range: 7-24 months) underwent unheated milk challenge. Eleven of 27 children with IgE-mediated CMA and 14 of 30 children with non-IgE-mediated CMA tolerated unheated milk. Among subjects who reacted to unheated milk; 15 of 16 subjects (93%) with IgE-mediated CMA also reacted to yoghurt, whereas 11 of 16 subjects (68%) with non-IgE-mediated CMA tolerated fermented milk. Thirteen subjects (81%) of the unheated milk-reactive IgE-mediated group tolerated to heated milk. None of 16 subjects of unheated milk-reactive non-IgE-mediated group reacted to baked milk. CONCLUSION: The majority of children under the age of two years with both IgE-mediated and non-IgE-mediated CMA tolerated baked-milk products. Yoghurt was tolerated in two thirds of unheated milk reactive patients suffering from non-IgE-mediated CMA. PMID- 28720382 TI - Activated leukocyte cell adhesion molecule is involved in excitatory synaptic transmission and plasticity in the rat spinal dorsal horn. AB - Activated leukocyte cell adhesion molecule (ALCAM), a member of type I transmembrane immunoglobulin superfamily of cell adhesion molecule, is expressed in the surface membrane of various cell types including neurons. In the spinal cord dorsal horn (DH), the first gate for the sensory and pain transmission to the brain, the expression and function of ALCAM have not been known yet. Therefore, we here investigate the synaptic function of ALCAM in the substantia gelatinosa (lamina II) of the spinal DH, as well as its expression in the DH. Bath-application of ALCAM/Fc or CD6/Fc, the recombinant human IgG1-Fc chimeric proteins, specifically potentiated C-fiber-mediated excitatory synaptic transmission and predominantly increased spontaneous release of glutamate. In addition, the development of long-term potentiation, a form of synaptic plasticity, at excitatory synapses was significantly inhibited in the presence of the recombinant proteins. The functional roles of ALCAM in the spinal DH were further supported by immunohistochemical analysis; it showed that ALCAM intensely expressed through laminae I/II with the exception of lateral portion of the dorsal part of inner lamina II and distinctly co-localized with molecular markers of C-fibers, such as peptidergic calcitonin gene-related protein and transient receptor potential vanilloid type 1 and non-peptidergic isolectin B4. This study, for the first time, suggests the modulatory roles of ALCAM in the excitatory synaptic transmission and plasticity in the rat spinal DH. PMID- 28720383 TI - Preliminary behavioral assessment of cagemates living with conspecifics submitted to chronic restraint stress in mice. AB - The capacity of rodents to recognize and respond to emotional signs from a conspecific is a valuable adaptive behavior, which provides essential skills for species survival. However, repeated exposure to aversive situations may elicit maladaptive behavioral responses in subjects that experience noxious episodes and their colony members. Previous findings by our group demonstrated that living with a subject in neuropathic pain induces anxiogenic-like behaviors and hypernociception in mice. Whereas chronic pain may be considered a stressful stimulus, we extended our findings on stress-induced emotional transfer. For this purpose, we investigated whether cohabitation with a partner subjected to chronic restraint stress was able to promote alterations in anxiety-like behaviors, pain sensibility and defensive responses. Male Swiss mice were housed in pairs for 14days and then separated into control, stress, and cagemate groups. The stress group was subjected to 14days of restraint stress (1h/day) in the presence of the cagemates, while the pair-housed control group was left undisturbed. A day after last stress session control, stress, and cagemate groups were evaluated using elevated plus maze test, writhing test, and rat exposure test. Results demonstrated that chronic stress attenuated weight gain in the stress group. Moreover, cohabitation with mice subjected to chronic restraint stress induced anxiogenic-like behaviors, pain hypernociception, and alterations in defensive responses in both cagemate and stress groups. These preliminary findings suggest that chronic exposure to aversive stimulus may induce behavioral alterations even in observers. PMID- 28720384 TI - Understanding the Delamination Risk of a Trilayer Tablet Using Minipiloting Tools. AB - A multilayer tablet is one of the formulation options used to mitigate chemical and physical incompatibility between different drug substances. Feasibility studies of multilayer tablets are often conducted using round flat-faced punch tooling. However, the link between different tooling designs and multilayer tablet performance is not well established. This study uses a prototype trilayer tablet and examines tooling design considerations when conducting small-scale studies to gauge the risk of interfacial defects. The impact of tablet weight and dimensions was evaluated to gain understanding of the effect of scale-up/down of tablet size. The factors in tooling selection, including tablet shape, cup depth, and size of embossing were evaluated to gain insight on the impact of tooling design on the interfacial strength of the trilayer tablet. It was found that tablet weight and dimensions can significantly affect the interfacial strength due to their impact on force transmission during compression and the retardation force from the die wall during ejection. Round flat-faced tooling generated trilayer tablets of the strongest interfacial strength compared to typical commercial tablets-oval shaped with concave surfaces. These factors should be accounted for when using round flat compacts to assess the interface risks of a multilayer tablet. PMID- 28720386 TI - Cdc42-interacting protein 4 silencing relieves pulmonary fibrosis in STZ-induced diabetic mice via the Wnt/GSK-3beta/beta-catenin pathway. AB - Cdc42-interacting protein-4 (CIP4) has been reported to be closely associated with diabetic nephropathy in rat. However, little is known about the correlation between CIP4 and diabetic pulmonary fibrosis (PF) in mice. Here, diabetes was induced by streptozotocin (STZ), and later lung tissue was collected and subjected to hematoxylin and eosin (H & E) staining for morphological examination. The distinct up-regulation of CIP4 was observed in diabetic PF mice. CIP4 silencing increased overall weight and decreased lung weight. Simultaneously, levels of TGF-beta1, collagen-1, collagen-3 and hydroxyproline were down-regulated by CIP4 silencing, accompanied by an increase in MMP-9 expression and a decrease in TIMP-1 expression. Down-regulation of CIP4 suppressed EMT by decreasing the expression of vimentin and alpha-SMA as well as augmenting E-cadherin expression. Mechanistic analysis confirmed that CIP4 silencing inhibited p-GSK-3beta and beta-catenin expression, indicating that CIP4 down-regulation attenuated the activation of Wnt/GSK-3beta/beta-catenin signaling. However, beta-catenin overexpression ameliorated the inhibitory effect of CIP4 down-regulation on lung tissue damage, fibrosis-related cytokines and EMT. These results suggest that CIP4 silencing can efficiently alleviate STZ induced PF in mice, perhaps through suppressing Wnt/GSK-3beta/beta-catenin signaling. PMID- 28720385 TI - Differences of lipid membrane modulation and oxidative stress by digoxin and 21 benzylidene digoxin. AB - Cardiotonic steroids (CTS) are compounds which bind to the Na,K-ATPase, leading to its inhibition and in some cases initiating signaling cascades. Long utilized as a treatment for congestive heart disease, CTS have more recently been observed to inhibit proliferation and cause apoptosis in several cancer cell lines. A synthetic derivative of the CTS digoxin, called 21-benzylidene digoxin (21-BD), activates the Na,K-ATPase rather than cause its inhibition, as its parent compound does. Here, the mechanism behind the unique effects of 21-BD are further explored. In HeLa cancer cells, low (5uM) and high (50uM) doses of 21-BD activated and inhibited the Na,K-ATPase, respectively, without altering the membrane expression of the Na,K-ATPase. While digoxin did not affect HeLa membrane cholesterol or phospholipid content, 50uM 21-BD increased both lipids via a mechanism reliant on an intact cell. Afterwards, the direct action of 21-BD was evaluated on erythrocyte membranes; however, no effect was observed. As CTS may generate reactive oxygen species (ROS) which can affect plasma membrane fluidity and therefore Na,K-ATPase activity, several markers involved in ROS generation were analyzed such as, lipid peroxidation (TBARS), reduced glutathione (GSH), catalase (CAT) and superoxide dismutase (SOD). GSH content and catalase activity were unaffected by digoxin or 21-BD. Surprisingly, TBARS and SOD activity was decreased with digoxin and with 50uM 21-BD. Thus, 21-BD and digoxin altered components involved in ROS generation and inhibition in a similar fashion. This study suggests alterations to the Na,K-ATPase and membrane lipids by 21-BD is not reliant on ROS generation. PMID- 28720387 TI - The Other Microeukaryotes of the Coral Reef Microbiome. AB - In marine ecosystems microbial communities are critical to ocean function, global primary productivity, and biogeochemical cycles. Both prokaryotic and eukaryotic microbes are essential symbionts and mutualists, nonpathogenic invaders, primary pathogens, have been linked to disease emergence, and can underpin broader ecosystem changes. However, in the effort to determine coral-microbial interactions, the structure and function of the eukaryotic microbes of the microbiome have been studied less. Eukaryotic microbes are important members of the microbiome, constitute entire kingdoms of life, and make important contributions to ecosystem function. Here, we outline the roles of eukaryotic microbes in marine systems and their contribution to ecosystem change, and discuss the microeukaryotic microbiome of corals and coral reefs. PMID- 28720388 TI - Strain specific effects of low level lead exposure on associative learning and memory in rats. AB - Exposure to lead (Pb) remains a significant public health concern. Lead exposure in early life impairs the normal development of numerous cognitive and neurobehavioral processes. Previous work has shown that the effects of developmental Pb exposure on gene expression patterns in the brain are modulated by various factors including the developmental timing of the exposure, level of exposure, sex, and genetic background. Using gene microarray profiling, we previously reported a significant strain-specific effect of Pb exposure on the hippocampal transcriptome, with the greatest number of differentially expressed transcripts in Long Evans (LE) rats and the fewest in Sprague Dawley (SD) rats. The present study examined the extent to which this differential effect of Pb on hippocampal gene expression might influence behavior. Animals (males and females) were tested in a trace fear conditioning paradigm to evaluate effects of Pb exposures (perinatal (PERI; gestation to postnatal day 21) or early postnatal (EPN; postnatal day 1 to day 21)) on associative learning and memory. All animals (Pb-exposed and non-Pb-exposed controls) showed normal acquisition of the conditioned stimulus (tone)-unconditioned stimulus (footshock) association. Long Evans rats showed a significant deficit in short- and long-term recall, influenced by sex and the timing of Pb exposure (PERI or EPN). In contrast, Pb exposure had no significant effect on memory consolidation or recall in any SD rats. These results further demonstrate the important influence of genetic background to the functional outcomes from developmental Pb exposure. PMID- 28720389 TI - Exposure to pesticide as a risk factor for depression: A population-based longitudinal study in Korea. AB - BACKGROUND: Exposure to pesticides is associated with mental disorders, including depression, especially among occupationally exposed populations, such as farmers. The results of experimental studies ascribed the negative effects of pesticides on mental health to their neurotoxic and endocrine-disrupting activities. PURPOSE: This study aimed to investigate the association between the risk of depression and high- or low-level exposure to pesticides in a rural population. METHODS: This longitudinal study was performed in 2005-2008 (baseline) and 2008 2012 (follow-up) to evaluate the risk of depression among 2151 Korean adults. A standardized questionnaire was used to obtain information on depression upon self reported exposure to pesticide based on the Center for Epidemiologic Studies Depression Scale. Logistic regression analysis was performed to evaluate the association between pesticide exposure and depression. We adjusted the data for age, cigarette smoking status, current alcohol use, monthly income, educational level, marriage status, and religion. RESULTS: Among the individuals who reported depression, the number of participants who used pesticides was significantly higher than that who did not (N=61 [7.2%] vs. N=54 [4.2%], P=0.003). A positive association was noted between >20-year period of pesticide use and depression (odds ratio [OR], 2.35; 95% confidence interval [CI], 1.41-3.88). Individuals who reported depression showed greater odds of being exposed to higher pesticide concentrations (OR, 2.33; 95% CI, 1.40-3.88) and experiencing pesticide poisoning (OR, 5.83; 95% CI, 1.80-18.86) than those who did not. CONCLUSION: Exposure to pesticides at a high concentration was found to be associated with depressive symptoms among Korean adults. PMID- 28720390 TI - Epigenetic regulation of epithelial to mesenchymal transition by the Lysine specific demethylase LSD1/KDM1A. AB - The Lysine-specific demethylase 1, KDM1A/LSD1, plays a central role in the regulation of Pol II transcription through the removal of the activation mark (mono- and dimethyl lysine 4 of histone H3). LSD1 is often deregulated in human cancers, and it is frequently overexpressed in human solid cancers and leukemia. LSD1 regulates the epithelial mesenchymal transition (EMT) in epithelial cells, i.e., the ability to transition into mesenchymal cells, to lose homotypic adhesion and to acquire migratory capacity. From its initial discovery as a component of the Snail complex, multiple studies highlighted the causative role of LSD1 in cell invasiveness and EMT, describing its direct involvement in different molecular processes through the interaction with specific partners. Here we present an overview of the role of LSD1 in the EMT process, summarizing recent findings on its emerging functions in cell migration and invasion in cancer. PMID- 28720392 TI - Are We Ready for Active Surveillance for Clinical Stage IS Testicular Cancer? PMID- 28720391 TI - Recommendations for the Management of Rare Kidney Cancers. AB - CONTEXT: The European Association of Urology Renal Cell Carcinoma Guideline Panel recently conducted a systematic review of treatment options for patients with advanced non-clear-cell renal cell carcinomas (RCCs), which showed a substantial lack of evidence for management recommendations. OBJECTIVE: To improve the outcomes of patients with rare kidney cancers (RKCs), we performed a subsequent unstructured review to determine current treatment strategies and druggable pathways, involving key stakeholders with a global perspective to generate recommendations. EVIDENCE ACQUISITION: Based on the systematic review, literature was queried in Pubmed, Medline, and abstracts from proceedings of European Society for Medical Oncology and American Society of Clinical Oncology, in addition to consulting key opinion leaders and stakeholders. A conventional narrative review strategy was adopted to summarize the data. EVIDENCE SYNTHESIS: The systematic review showed an absence of evidence for treating RKCs, with data only supporting sunitinib or MET inhibitors for some specific subtypes. However, a growing body of evidence implicates druggable pathways in specific RKC subtypes. To test hypotheses, the small patient numbers in each subtype require coordinated multicenter efforts. Many RKC patients are currently excluded from studies or are not analyzed using subtype-specific parameters, despite their unmet medical need. CONCLUSIONS: We recognize the need for additional multicenter studies and subtype-specific analyses; however, we present management recommendations based on the data available. Web-based tools facilitating subtype specific global registries and shared translational research resources will help generate sufficient data to formulate evidence-based recommendations for guidelines. PATIENT SUMMARY: Patients confronted with rare kidney cancers are often treated the same way as clear-cell renal cell carcinoma patients, despite little evidence from randomized trials. Molecular characterization of tumors to stratify patients may improve outcomes. Availability of potential agents and trials remain a problem. Collaboration among medical centers is important to pool scarce data. PMID- 28720393 TI - Maxillary nerve blocks in horses: an experimental comparison of surface landmark and ultrasound-guided techniques. AB - OBJECTIVE: The aim of this preliminary proof-of-concept study was to evaluate and compare the success and complication rate of infiltration of the maxillary nerve of cadaver heads using previously described surface landmarks, standard ultrasound and a novel needle guidance positioning ultrasound system (SonixGPS). STUDY DESIGN: Prospective, anatomical, method-comparison study. ANIMALS: Thirty eight equine cadaver heads. METHODS: Twenty-six veterinary students performed the three methods consecutively on cadaver heads using an 18 gauge, 8.9 cm spinal needle and 0.5 mL iodinated contrast medium. Computed tomography was used to quantify success (deposition of contrast in contact with the maxillary nerve) and complication rate (contrast identified within surrounding vasculature or periorbital structures) associated with each method. RESULTS: Perineural injection of the maxillary nerve was attempted 76 times, with an overall success rate of 65.8% (50/76) and complication rate of 53.9% (41/76). Success rates were 50% (13/26) with surface landmark, 65.4% (17/26) with standard ultrasound guidance and 83.3% (20/24) with SonixGPS guidance approaches (Fisher's exact test, p=0.046). No significant difference in complication rate was found between the three methods. CONCLUSIONS: Ultrasound-guided maxillary nerve blocks were significantly more successful than surface landmark approaches when performed by inexperienced operators, and the highest success rate was achieved with guidance positioning system (GPS) needle guidance. CLINICAL RELEVANCE: Local anaesthesia of the equine maxillary nerve in the fossa pterygopalatina is frequently used for diagnostic and surgical procedures in the standing sedated horse. Due to vague superficial landmarks with various approaches and the need for experience via ultrasound guidance, this block remains challenging. GPS guidance may improve reliability of maxillary and other nerve blocks, and allow a smaller volume of local anaesthetic solution to be used, thereby improving specificity and reducing the potential for side effects. PMID- 28720394 TI - Is myocardial bridging transient in patients with takotsubo syndrome? PMID- 28720395 TI - Acetazolamide and N-acetylcysteine in the treatment of chronic mountain sickness (Monge's disease). AB - Patients suffering from chronic mountain sickness (CMS) have excessive erythrocytosis. Low -level cobalt toxicity as a likely contributor has been demonstrated in some subjects. We performed a randomized, placebo controlled clinical trial in Cerro de Pasco, Peru (4380m), where 84 participants with a hematocrit (HCT) >=65% and CMS score>6, were assigned to four treatment groups of placebo, acetazolamide (ACZ, which stimulates respiration), N-acetylcysteine (NAC, an antioxidant that chelates cobalt) and combination of ACZ and NAC for 6 weeks. The primary outcome was change in hematocrit and secondary outcomes were changes in PaO2, PaCO2, CMS score, and serum and urine cobalt concentrations. The mean (+/-SD) hematocrit, CMS score and serum cobalt concentrations were 69+/-4%, 9.8+/-2.4 and 0.24+/-0.15MUg/l, respectively for the 66 participants. The ACZ arm had a relative reduction in HCT of 6.6% vs. 2.7% (p=0.048) and the CMS score fell by 34.9% vs. 14.8% (p=0.014) compared to placebo, while the reduction in PaCO2 was 10.5% vs. an increase of 0.6% (p=0.003), with a relative increase in PaO2 of 13.6% vs. 3.0%. NAC reduced CMS score compared to placebo (relative reduction of 34.0% vs. 14.8%, p=0.017), while changes in other parameters failed to reach statistical significance. The combination of ACZ and NAC was no better than ACZ alone. No changes in serum and urine cobalt concentrations were seen within any treatment arms. ACZ reduced polycythemia and CMS score, while NAC improved CMS score without significantly lowering hematocrit. Only a small proportion of subjects had cobalt toxicity, which may relate to the closing of contaminated water sources and several other environmental protection measures. PMID- 28720397 TI - Cardioprotective effect of nesfatin-1 against isoproterenol-induced myocardial infarction in rats: Role of the Akt/GSK-3beta pathway. AB - The present study was designed to evaluate the cardioprotective effects of nesfatin-1, a novel peptide with anorexigenic properties, in rats with isoproterenol (ISO)-induced myocardial infarction (MI), and to further investigate the role of Akt/GSK-3beta signaling pathway in the protective effect of nesfatin-1. To induce MI, ISO was subcutaneously injected into the rats for two consecutive days at a dosage of 85mg/kg/day. ISO-induced myocardial damage was indicated by elevated levels of cardiac specific troponin-T, enhanced myocardial expression of proinflammatory cytokines (interleukin-1beta, interleukin-6 and tumor necrosis factor-alpha), and increased number of cells with apoptotic and necrotic appearance in the myocardial tissue. Levels of p Akt/Akt and p-GSK-3beta/GSK-3beta significantly decreased in heart tissue after ISO-induced MI. However, intraperitoneal administration of nesfatin-1 (10MUg/kg/day) elicited a significant cardioprotective activity by lowering the levels of cardiac troponin-T and proinflammatory cytokines, indicating the protective effect of nesfatin-1 against ISO-induced MI. The biochemical findings were further confirmed by histopathological examination, which was demonstrated by reduced number of apoptotic and necrotic cells. Moreover, expressions of p Akt/Akt and p-GSK-3beta/GSK-3beta in the myocardium of MI group rats were significantly increased by nesfatin-1 administration, suggesting that nesfatin-1, which appears to possess anti-apoptotic and anti-inflammatory properties, may confer protection against ISO-induced MI via an Akt/GSK-3beta-dependent mechanism. PMID- 28720398 TI - Perinatal and neonatal use of paracetamol for pain relief. AB - Paracetamol (acetaminophen) is the most widely used drug to treat pain or fever in pregnant women or neonates, but its pharmacokinetics (PK) and pharmacodynamics (PD) warrant a focused analysis. During pregnancy, there is an important increase in paracetamol clearance. Consequently, it is reasonable to anticipate that the analgesic effect of paracetamol will decrease faster, whereas higher doses may result in even higher oxidative toxic metabolites. Therefore, most peripartal PD data relate to multimodal analgesia strategies. In neonates, weight/size is the most relevant covariate of paracetamol PK. This resulted in proposed dosing regimens containing higher doses than currently prescribed in the label for term neonates. Using adequate dosing, paracetamol is a poor procedural analgesic, is effective for mild-to-moderate pain, and has morphine-sparing effects. Short-term safety has been well documented, and there is active research investigating the potential association between paracetamol exposure and atopy, fertility, and neurobehavior. PMID- 28720396 TI - Pituitary adenylate cyclase-activating polypeptide (PACAP) protects against mitoxantrone-induced cardiac injury in mice. AB - Mitoxantrone (MXT) is an androstenedione that is used to treat cancers and progressive forms of multiple sclerosis; however, its use is limited by its cardiotoxicity. Pituitary adenylate cyclase activating polypeptide (PACAP) is a member of the secretin/growth hormone-releasing hormone/vasoactive intestinal peptide family and has many functions, including cytoprotection and immunosuppression. We tested the hypothesis that PACAP can protect against MXT induced cardiotoxicity in mice. Female BALB/c mice were treated once weekly for 4 weeks with saline (n=14) or MXT (3mg/kg, i.p.; n=14). Half of the mice in each group received PACAP (10MUg, i.p.) 1h before and 24 and 48h after MXT, while the remaining mice received injections of saline on the same schedule. Echocardiography was used to assess cardiac structure and function. In mice treated with MXT and saline, body weight was significantly reduced after the third dose of MXT. PACAP significantly attenuated the reduction in body weight; however, the weights did not return to control level. Compared to controls, MXT treated mice had significantly increased left ventricular (LV) diameter and LV volume and decreased LV posterior wall thickness. Fractional shortening (FS) and ejection fraction (EF) were also significantly decreased. Treatment with PACAP prevented MXT-induced LV dilation and significantly attenuated the reductions in FS and EF, although FS and EF did not return to control level. PACAP38 did not prevent MXT-induced decreases in LV posterior wall thickness. MXT dose dependently decreased the viability of cultured U937 (human leukemia) cells; PACAP did not protect cultured U937 cells from MXT-mediated cell death. In conclusion, PACAP can attenuate MXT-mediated LV dilation and dysfunction in mice. PMID- 28720399 TI - Prenatal and postnatal administration of prebiotics and probiotics. AB - Colonization of the neonatal gut by beneficial bacteria is important for the establishment and maintenance of the mucosal barrier, thus protecting the neonate from enteric pathogens and local and systemic inflammation. The neonatal microbiome is influenced by infant diet, environment, and the maternal microbiome. Dysbiosis in pregnancy increases the risk of pre-eclampsia, diabetes, infection, preterm labor, and later childhood atopy. Dysbiosis of the neonatal gut plays an important role in colic in the term infant, in the disease processes which plague preterm infants, including necrotizing enterocolitis and sepsis, and in the long-term outcomes of neonates. Administration of enteral prebiotics, probiotics, and synbiotics during pregnancy, lactation, and postnatal life appears to be a safe and feasible method to alter the maternal and neonatal microbiome, thus improving pregnancy and neonatal outcomes. PMID- 28720400 TI - Viewing an ultra-brief chest compression only video improves some measures of bystander CPR performance and responsiveness at a mass gathering event. AB - BACKGROUND: CPR training at mass gathering events is an important part of health initiatives to improve cardiac arrest survival. However, it is unclear whether training lay bystanders using an ultra-brief video at a mass gathering event improves CPR quality and responsiveness. OBJECTIVE: To determine if showing a chest-compression only (CCO) Ultra-Brief Video (UBV) at a mass gathering event is effective in teaching lay bystanders CCO-CPR. METHODS: Prospective control trial in adults (age >18) who attended either a women's University of Arizona or a men's Phoenix Suns basketball game. Participants were evaluated using a standardized cardiac arrest scenario with Laerdal SkillreporterTM mannequins. CPR responsiveness (calling 911, time to calling 911, starting compressions within two minutes) and quality (compression rate, depth, hands-off time) were assessed for participants and data collected at Baseline and Post-intervention. Different participants were tested before and after the exposure of the UBV. Data were analyzed via the intention to treat principle using logistic regression for binary outcomes and median regression for continuous outcomes, controlling for clustering by venue. RESULTS: A total of 96 people were consented (Baseline=45; Post intervention=51). CPR responsiveness post intervention improved with faster time to calling 911 (s) and time to starting compressions (sec). Likewise, CPR quality improved with deeper compressions and improved hands-off time. CONCLUSIONS: Showing a UBV at a mass gathering sporting event is associated with improved CPR responsiveness and performance for lay bystanders. This data provides further support for the use of mass media interventions. PMID- 28720401 TI - Multisensory integration induces body ownership of a handtool, but not any handtool. AB - Bodily boundaries are computed by integrating multisensory bodily signals and can be experimentally manipulated using bodily illusions. Research on tool use demonstrates that tools alter body representations motorically to account for changes in a user's action repertoire. The present experiment sought to unify perceptual and motoric accounts of tool embodiment using a modified Rubber Hand Illusion (RHI) that also addressed the skill and practice aspects of the tool use literature. In Experiment 1, synchronous multisensory stimulation induced perceptual embodiment of a tool, chopsticks. The embodiment of chopsticks was stronger for more skilled participants, and if the illusion was preceded by tool use. In Experiment 2, the illusion was not elicited with a different type of tool, a teacup, showing that not all objects can be incorporated. This experiment helps to clarify the role of perceptual and motoric embodiment and suggests future avenues for research into tools embodiment using this method. PMID- 28720402 TI - Comparison of different airway-management devices used by non-anaesthetist personnel: A crossover manikin study. PMID- 28720403 TI - Gradenigo's syndrome: A common infection with uncommon consequences. AB - Acute otitis media is a common diagnosis encountered by emergency medicine providers. With appropriate antibiotic treatment, patients with otitis media, in general, have minimal long-term sequela from their underlying infection (Limb et al., 2017 [1]). However, untreated cases can develop life-threatening complications that require prompt intervention. We report a case of an 8-year-old that developed Gradenigo's syndrome, a condition characterized by the triad of otitis media, facial pain in the distribution of the trigeminal nerve, and abducens nerve palsy (Yeung and Lustig, 2016; Janjua et al., 2016; Kantas et al., 2010; Motamed and Kalan, n.d.; Vita Fooken Jensen et al., 2016 [2-6]). Signs and symptoms are often subtle, so a high-level of suspicion is required in order not to miss this potentially fatal process. PMID- 28720404 TI - Role of spatial contiguity in sensory preconditioning with humans. AB - The present study demonstrates the contribution of spatial contiguity in the formation of associations between two neutral stimuli. Using human participants, we used visual conditioned stimuli (CSs) in a sensory preconditioning design in which simultaneous CS2-CS1 pairings and CS4-CS3 pairings were interspersed during Phase 1, followed by sequential CS1-US+ (i.e., CS1-pleasant US) and CS3-US-- (i.e., CS3-unpleasant US) pairings during Phase 2. The conditioned response was a shift in the gaze of the participants to the location where the US+ (i.e., short video clip) appeared. Distances between CS2 and CS1 and between CS4 and CS3 were manipulated. Our results showed a greater response to CS2 when the Phase 1 stimuli were adjacent rather than separated by 100 pixels. Implications for the role of spatial contiguity in associative learning are discussed. PMID- 28720405 TI - Persistent cognitive and morphological alterations induced by repeated exposure of adolescent rats to the abused inhalant toluene. AB - While thepsychoactive inhalant toluene causes behavioral effects similarto those produced by other drugs of abuse, the persistent behavioral and anatomical abnormalities induced by toluene exposure are not well known. To mimic human "binge-like" inhalant intoxication, adolescent, male Sprague-Dawley rats were exposed to toluene vapor (5700ppm) twice daily for five consecutive days. These rats remained in their home cages until adulthood (P60), when they were trained in operant boxes to respond to a palatable food reward and then challenged with several different cognitive tasks. Rats that experienced chronic exposure to toluene plus abstinence ("CTA") showed enhanced performance in a strategy set shifting task using a between-session, but not a within-session test design. CTA also blunted operant and classical conditioning without affecting responding during a progressive ratio task. While CTA rats displayed normal latent inhibition, previous exposure to a non-reinforced cue enhanced extinction of classically conditioned approach behavior of these animals compared to air controls. To determine whether CTA alters the structural plasticity of brain areas involved in set-shifting and appetitive behaviors, we quantified basal dendritic spine morphology in DiI-labeled pyramidal neurons in layer 5 of the medial prefrontal cortex (mPFC) and medium spiny neurons in the nucleus accumbens (NAc). There were no changes in dendritic spine density or subtype in the mPFC of CTA rats while NAc spine density was significantly increased due to an enhanced prevalence of long-thin spines. Together, these findings suggest that the persistent effects of CTA on cognition are related to learning and memory consolidation/recall, but not mPFC-dependent behavioral flexibility. PMID- 28720406 TI - MRI anatomical preoperative evaluation of distally based peroneus brevis muscle flap in reconstructive surgery of the lower limb. AB - BACKGROUND: The distally based peroneus brevis muscle flap has proved to be a simple solution for small- to moderate-sized wounds of the lower limb. The length of the muscle belly suitable for coverage is a crucial parameter. In this study, we evaluated the capability of 3D MRI of the lower limb to measure it preoperatively. METHODS: Between 2008 and 2017, 32 patients with lower limb defects underwent preoperative MRI to measure the peroneus brevis muscle length. All patients underwent reconstruction, and the muscle was measured again intraoperatively during surgical dissection. Surgical measurements were then compared to the MRI ones. RESULTS: MRI measures of the peroneus brevis muscle belly ranged from 9 to 21 cm (MU = 14.44 +/- 3.43 cm), and intraoperative measures ranged from 9 to 20 cm (MU = 14.2 +/- 2.3 cm). Thirty of 32 intraoperative measures corresponded to the MRI ones (variation = +/- 1 cm, r = 0.92, p = 0.002). One patient showed an intraoperative muscle length 3 cm shorter than the MRI measure, and another patient had intraoperative muscle length 3 cm longer than the MRI one. All flaps survived, and no secondary local flap coverage was required, with no flap-related complication, limited donor site morbidity, and acceptable patient discomfort. CONCLUSIONS: The reverse peroneus brevis muscle flap is a versatile alternative to free flap reconstruction in small- to moderate-sized defects of the lower limb. Preoperative 3D MRI is accurate to evaluate the anatomy of the muscle when performed by an expert radiologist. In our experience, it should become part of preoperative workup before performing a peroneus brevis flap procedure. PMID- 28720407 TI - Mechanical properties of the human spinal cord under the compressive loading. AB - The spinal cord as the most complex and critical part of the human body is responsible for the transmission of both motor and sensory impulses between the body and the brain. Due to its pivotal role any types of physical injury in that disrupts its function following by shortfalls, including the minor motor and sensory malfunctions as well as complicate quadriplegia and lifelong ventilator dependency. In order to shed light on the injuries to the spinal cord, the application of the computational models to simulate the trauma impact loading to that are deemed required. Nonetheless, it has not been fulfilled since there is a paucity of knowledge about the mechanical properties of the spinal cord, especially the cervical one, under the compressive loading on the grounds of the difficulty in obtaining this tissue from the human body. This study was aimed at experimentally measuring the mechanical properties of the human cervical spinal cord of 24 isolated fresh samples under the unconfined compressive loading at a relatively low strain rate. The stress-strain data revealed the elastic modulus and maximum/failure stress of 40.12+/-6.90 and 62.26+/-5.02kPa, respectively. Owing to the nonlinear response of the spinal cord, the Yeoh, Ogden, and Mooney Rivlin hyperelastic material models have also been employed. The results may have implications not only for understanding the linear elastic and nonlinear hyperelastic mechanical properties of the cervical spinal cord under the compressive loading, but also for providing a raw data for investigating the injury as a result of the trauma thru the numerical simulations. PMID- 28720408 TI - Comparative investigation of neuronal nitric oxide synthase immunoreactivity in rat and human claustrum. AB - We compared the distribution, density and morphological characteristics of nitric oxide synthase-immunoreactive (NOS-ir) neurons in the rat and human claustrum. These neurons were categorized by diameter into three main types: large, medium and small. In the human claustrum, large neurons ranged from 26 to 40MUm in diameter, medium neurons from 20 to 25MUm and small neurons from 13 to 19MUm. In the rat claustrum, large neurons ranged from 19 to 23MUm in diameter, medium neurons from 15 to 18MUm and small neurons from 10 to 14MUm. The cell bodies of large and medium neurons varied broadly in shape - multipolar, elliptical, bipolar and irregular, consistent with a projection neuron phenotype. The small neurons were most seen as being oval or elliptical in shape, resembling an interneuron phenotype. Based on a quantitative comparison of their dendritic characteristics, the NOS-ir neurons of humans and rats displayed a statistically significant difference. PMID- 28720409 TI - Role of collaboration between urologists and medical oncologists in the advanced prostate cancer space. PMID- 28720410 TI - Increased use of antihypertensive medications after partial nephrectomy vs. radical nephrectomy. AB - PURPOSE: A prospective study of partial vs. radical nephrectomy demonstrated worse overall survival in patients undergoing partial nephrectomy which appeared to be driven by cardiovascular outcomes. We sought to determine if the blood pressures or use of antihypertensive medications differed between patients who underwent partial or radical nephrectomy. MATERIALS AND METHODS: A tertiary referral institutional renal mass database was queried for patients between 2006 and 2012 undergoing partial or radical nephrectomy. Serial blood pressure follow up, clinicopathologic variables, and changes in medications were collected. Patients were excluded for inadequate data, noncurative-intent surgery, noncancer surgical indication, and absence of medication information. Time-dependent hemodynamic changes were compared by split-plot analysis of variance and addition to antihypertensive regimen was studied as time-to-event survival analyses with Kaplan-Meier curves and a Cox proportional hazards model. RESULTS: A final cohort of 264 partial nephrectomy and 130 radical nephrectomy cases were identified. Patients undergoing partial nephrectomy were younger, more likely to have T1 tumors, and had lower preoperative creatinine (P<0.001 for all). No differences were noted on postoperative hemodynamics (P>0.05). Significantly more patients who underwent partial nephrectomy added antihypertensive medications postoperatively (P<=0.001) and surgical treatment remained as a significant independent predictor on Cox regression (hazard ratio = 2.51, P = 0.002). Limitations include the retrospective nature of the study and potential for unidentified confounders. CONCLUSION: Hemodynamic parameters after radical or partial nephrectomy may be different. The etiology of this observation, is currently unexplored. Additional prospective mechanistic investigations are warranted. PMID- 28720411 TI - Modeling mechanical control of spindle orientation of intestinal crypt stem cells. AB - Tissue development requires a control over the sequence of symmetric and asymmetric stem cell divisions to obtain the specific numbers of differentiated cells populating the tissue and stem cells residing in the niche. A good experimental model to study this process is the mouse intestinal crypt development, where it has been shown that stem cells follow an optimal strategy in which asymmetric division occurs only after all symmetric divisions have taken place to reach a fixed number of cells in the niche in the shortest time. Here we introduce a model of stem cell division that is able to explain the experimentally observed stem cell population dynamics by the effect of mechanical forces acting on the spindle. We also observe that the mechanically induced strategy for development is sub-optimal and crucially depends on the stiffness of the spindle. These findings highlight the crucial importance of mechanical forces for the development and maintenance of the intestinal crypt. PMID- 28720412 TI - Vascular Compression of the Anterior Optic Pathway: A Rare Occurrence? AB - BACKGROUND: Vascular compression of the anterior optic pathway has been documented as an infrequent cause of visual impairments. Here we characterize such vascular compression using magnetic resonance imaging. METHODS: A total of 183 patients without pathologies affecting the optic pathways underwent T2 weighted or constructive interference steady-state sequence magnetic resonance imaging. Imaging data from coronal sections were analyzed. RESULTS: A vascular compression of the anterior optic pathway was identified in 20 patients (11%). They comprised 13 men and 7 women with a mean age of 60.8 years. The vascular compressions were observed at 22 sites, 15 on the optic nerve (ON) and 7 on the optic chiasm (OC). Twelve of them were on the right and 10 were on the left side. The offending vessels were the supraclinoid portion of the internal carotid artery in 86.4% and the A1 segment of the anterior cerebral artery in 13.6%. Compression sites at the ON and OC were variable, with the inferolateral surface being the most frequent (77.3% occurrences). In 2 patients (9.1%), the ON was compressed in a sandwich manner. CONCLUSIONS: Vascular compression of the ON and OC may not be an infrequent occurrence in the cranial cavity. Progressive and unexplainable visual impairment might possibly be caused by vascular-compressive neuropathy. PMID- 28720413 TI - Multiparametric Magnetic Resonance Imaging of the Prostate for Tumour Detection and Local Staging: Imaging in 1.5T and Histopathologic Correlation. AB - PURPOSE: The study sought to prospectively evaluate which technique among T2 weighted images, dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI), diffusion-weighted (DW) MRI, or a combination of the 2, is best suited for prostate cancer detection and local staging. METHODS: Twenty-seven consecutive patients with biopsy-proven adenocarcinoma of the prostate underwent MRI on a 1.5T scanner with a surface phased-array coil prior radical prostatectomy. Combined anatomical and functional imaging was performed with the use of T2 weighted sequences, DCE MRI, and DW MRI. We compared the imaging results with whole mount histopathology. RESULTS: For the multiparametric approach, significantly higher sensitivity values, that is, 53% (95% confidence interval [CI]: 41.0-64.1) were obtained as compared with each modality alone or any combination of the 3 modalities (P < .05). The specificity for this multiparametric approach, being 90.3% (95% CI: 86.3-93.3) was not significantly higher (P < .05) as compared with the values of the combination of T2+DCE MRI, DW+DCE MRI, or DCE MRI alone. Among the 3 techniques, DCE had the best performance for tumour detection in both the peripheral and the transition zone. High negative predictive value rates (>86%) were obtained for both tumour detection and local staging. CONCLUSIONS: The combination of T2-weighted sequences, DCE MRI, and DW MRI yields higher diagnostic performance for tumour detection and local staging than can any of these techniques alone or even any combination of them. PMID- 28720414 TI - Global Health Imaging in Radiology Residency: A Survey of Canadian Radiology Residents. AB - PURPOSE: The study sought to determine Canadian radiology resident perception of and interest in global health imaging (GHI) and the barriers they encounter in pursuing GHI experiences during residency training. METHODS: A peer-reviewed, online, anonymous, multiple-choice survey was distributed to Canadian radiology residents at English-language programs. RESULTS: Fifty residents responded to the survey (~16% response rate); 72% of respondents perceived an unmet need for medical imaging in the developing world. A majority of residents (60%) would have been likely to participate in a GHI experience if one had been available during their residency; 65% planned on pursuing international outreach work as future radiologists, 81% of whom with on-site collaboration in education and training of local staff. However, 82% of respondents were uncertain or believed they would not be adequately prepared to help improve access and availability of medical imaging services in developing countries upon completion of residency. Overall, residents believed a GHI program would increase their knowledge of infectious diseases, increase their exposure to diseases at advanced stage presentation, enhance their knowledge of basic imaging modalities, and improve their cultural competence. Lack of information about opportunities, lack of funding, and lack of infrastructure were ranked as the most important barriers to participating in a radiology rotation in a developing country during residency. CONCLUSION: While many Canadian radiology residents are interested in participating in GHI, their preparation to do so may be inadequate. Formalizing international GHI rotations may alleviate barriers impeding their pursuit. PMID- 28720415 TI - Assessment of Cirrhotic Liver Enhancement With Multiphasic Computed Tomography Using a Faster Injection Rate, Late Arterial Phase, and Weight-Based Contrast Dosing. AB - PURPOSE: This study aimed to update our liver computed tomography (CT) protocol according to published guidelines, and to quantitatively evaluate the effect of these modifications. METHODS: The modified liver CT protocol employed a faster injection rate (5 vs 3 mL/s), later arterial phase (20-second vs 10-second postbolus trigger), and weight-based dosing of iodinated contrast (1.7 mL/kg vs 100 mL fixed dose). Liver and vascular attenuation values were measured on CTs of patients with cirrhosis from January to September 2015 (old protocol, n = 49) and from October to December 2015 (modified protocol, n = 31). CTs were considered adequate if liver enhancement exceeded 50 Hounsfield units (HU) in portal venous phase, or when the unenhanced phase was unavailable, if a minimum iodine concentration of 500 mg I/kg was achieved. Attenuations and iodine concentrations were compared using the t test and the number of suboptimal studies was compared with Fisher's exact test. RESULTS: CTs acquired with the modified protocol demonstrated higher aortic (P = .001) and portal vein (P < .0001) attenuations in the arterial phase as well as greater hepatic attenuation on all postcontrast phases (P = .0006, .002, and .003 for arterial, venous, and equilibrium phases, respectively). Hepatic enhancement in the portal venous phase (61 +/- 15 HU vs 51 +/- 16 HU; P = .0282) and iodine concentrations (595 +/- 88 mg I/kg vs 456 +/- 112 mg I/kg; P < .0001) were improved, and the number of suboptimal studies was reduced from 57% to 23% (P = .01). CONCLUSIONS: A liver CT protocol with later arterial phase, faster injection rate, and weight-based dosing of intravenous contrast significantly improves liver enhancement and iodine concentrations in patients with cirrhosis, resulting in significantly fewer suboptimal studies. PMID- 28720416 TI - Emotional fMR auditory paradigm demonstrates normalization of limbic hyperactivity after cognitive behavior therapy for auditory hallucinations. PMID- 28720417 TI - Application of plasma levels of olanzapine and N-desmethyl-olanzapine to monitor metabolic parameters in patients with schizophrenia. AB - Metabolic disturbance is a common side effect of olanzapine (OLZ); however, the relationships between plasma OLZ concentration (COLZ) and metabolic disturbance remain unclear. Our previous study revealed that COLZ?22.77ng/mL was a positive predictor of therapeutic efficacy in patients with schizophrenia. This study aimed to investigate the roles of OLZ or N-desmethyl-olanzapine (DMO) in metabolic outcomes among OLZ-treated patients with schizophrenia. The metabolic syndrome (MS) was diagnosed based on the modified the National Cholesterol Education Program Adult Treatment Panel III criteria for Asians. HPLC-ECD analytical system was applied to determine the COLZ and DMO concentration (CDMO). The absolute drug levels and concentration-to-dose ratios (C/D ratios) were tested for their correlations to metabolic parameters. Total 151 fasting blood samples from patients with schizophrenia were collected. DMO C/D ratio negatively correlated with weight, body mass index, waist circumference, and C-peptide level. The receiver operator characteristic analysis determined a threshold CDMO>5.63ng/mL and DMO C/D ratio>0.35ng/mL/mg were negative predictors of MS. The COLZ/CDMO ratio>6.03 was identified as positive predictor of MS. Combined with previous study result, we proposed that the optimal OLZ treatment should maintain COLZ/CDMO ratio between 3 and 6 to maximize the clinical efficacy and minimize the metabolic side effects. Our findings suggested that therapeutic drug monitoring on OLZ and DMO is a valuable tool to monitor metabolic side effects in OLZ-treated patients with schizophrenia. PMID- 28720418 TI - Invasive Lobular Breast Carcinoma: Pleomorphic Versus Classical Subtype, Associations and Prognosis. AB - BACKGROUND: Invasive pleomorphic lobular carcinoma (IPLC) has been associated with a worse prognosis compared with classic invasive lobular carcinoma (cILC); however, studies are small and conflicting. We seek to examine the prognosis of women with IPLC compared with cILC. METHODS: A retrospective review of women with breast cancer at a single institution from 2003 to 2012 identified 193 women with invasive lobular carcinoma (ILC). IPLC was defined as ILC with a pathological description of primarily pleomorphic features and Nottingham histological grade score of 7, 8, or 9 or overall grade of 3 or mixed classic/pleomorphic features and overall grade of 3. All others were designated cILCs. Clinicopathologic variables, progression-free survival (PFS), per STEEP criteria, and overall survival (OS), using all-cause mortality, were examined in both groups. RESULTS: Of the 193 women, 46 (24%) had IPLC and 147 (76%) had cILC. The IPLC group had significantly higher stage at diagnosis and more Hispanic women, but there were no differences in other clinicopathologic features or treatment. Median follow-up was 57 months (0.1-155 months). In univariate analysis, IPLC was associated with worse PFS (log-rank P = .09, Wilcoxon P = .01) but no significant differences in OS (log-rank P = .20, Wilcoxon P = .16). In multivariate models adjusting for stage, IPLC was not significantly associated with PFS (hazard ratio [HR] 1.43; 95% confidence interval [CI], 0.73-2.79; P = .30) or OS (HR 1.52; 95% CI, 0.58 4.01; P = .40). CONCLUSIONS: IPLC was initially associated with worse PFS, but this was attenuated after adjustment for cancer stage, and there were no differences in OS. PMID- 28720419 TI - Isolation of two Ochrobactrum sp. strains capable of degrading the nootropic drug Piracetam. AB - Piracetam (2-oxo-1-pyrrolidine acetamide) is a popular cognitive enhancer, which has recently been detected in waste and drinking water. Nootropic drugs are designed to affect human metabolism and act on the nervous system, but their environmental effects have yet to be the subject of detailed studies. In this report, we present the efficient biodegradation of the cognitive enhancer, piracetam. Two bacterial strains capable of using this compound as the sole carbon source were isolated and later identified as Ochrobactrum anthropi strain MW6 and Ochrobactrum intermedium strain MW7. The compound's mineralization and the cleavage of the heterocyclic ring were shown in the experiments with 14C labeled piracetam. This is also the first report of a pharmaceutical's degradation by the Ochrobactrum genus. This study presents model microorganisms that can be used in further investigation of piracetam's degradation pathways as well as enzymes and genes involved in the process. PMID- 28720420 TI - Transoral robotic total laryngopharyngectomy and free jejunal flap reconstruction for hypopharyngeal cancer. AB - BACKGROUND: To report on the feasibility of total laryngopharyngectomy and free jejunal flap transfer for patient with hypopharyngeal cancer via the transoral robotic surgery (TORS) approach. MATERIAL AND METHODS: A patient with hypopharyngeal cancer involving the post-cricoid region is used for demonstration of the TORS total laryngopharyngectomy and free jejunal flap reconstruction. RESULTS: The procedure starts with a cruciate incision for terminal tracheostomy. The trachea and cervical esophagus is exposed and transected, making sure that the resection margins are adequate. This is followed by the transoral dissection using the robotic surgical system. The laryngopharyngectomy specimen is delivered and the free jejunal flap is replaced transorally. Jejuno-oesophageal suturing and the microvascular anastomosis are performed through the tracheostomy wound. The remaining pharyngo-jejunal anastomosis is performed transorally via the TORS approach. CONCLUSION: TORS total laryngopharyngectomy and free jejunal flap reconstruction is feasible and provides and alternative option to the traditional transcervical approach. PMID- 28720421 TI - Assessment of the HIV-1 reservoir in CD4+ regulatory T cells by a Droplet Digital PCR based approach. AB - The relative contribution of regulatory T cells (Treg) as reservoir of HIV-1 in patients on chronic antiretroviral therapy is unclear to date. The aim of the current study was to assess the total HIV DNA burden and replication competent viral reservoir in Treg in comparison to central and effector memory cells (Tcm and Tem). Peripheral blood mononuclear cells were obtained from 10 HIV patients treated with antiretroviral therapy. Droplet Digital PCR (ddPCR) was used to quantify total HIV DNA loads in FACS-sorted CD4+ Treg (CD25+CD127lo) as compared to Tcm (CD45RO+CCR7+) and Tem (CD45RO+CCR7-). In contrast to earlier reports, no significant difference was found in total HIV DNA burden associated with Treg when compared to Tem and Tcm cells. In a subset of patients, quantitative viral outgrowth assays were also performed, using novel ddPCR based readout to quantify frequencies of Treg harboring replication competent virus. PMID- 28720422 TI - Drug targeting to myofibroblasts: Implications for fibrosis and cancer. AB - Myofibroblasts are the key players in extracellular matrix remodeling, a core phenomenon in numerous devastating fibrotic diseases. Not only in organ fibrosis, but also the pivotal role of myofibroblasts in tumor progression, invasion and metastasis has recently been highlighted. Myofibroblast targeting has gained tremendous attention in order to inhibit the progression of incurable fibrotic diseases, or to limit the myofibroblast-induced tumor progression and metastasis. In this review, we outline the origin of myofibroblasts, their general characteristics and functions during fibrosis progression in three major organs: liver, kidneys and lungs as well as in cancer. We will then discuss the state-of the art drug targeting technologies to myofibroblasts in context of the above mentioned organs and tumor microenvironment. The overall objective of this review is therefore to advance our understanding in drug targeting to myofibroblasts, and concurrently identify opportunities and challenges for designing new strategies to develop novel diagnostics and therapeutics against fibrosis and cancer. PMID- 28720423 TI - Undergraduate Clinical Teaching in Orthopedic Surgery: A Randomized Control Trial Comparing the Effect of Case-Based Teaching and Bedside Teaching on Musculoskeletal OSCE Performance. AB - INTRODUCTION: Musculoskeletal (MSK) complaints are the second most common reason for a hospital outpatient appointment in the US, and account for 19.5% of general practice consultations. Previous studies have shown that passive teaching in medical school does not imbue students with an adequate degree of confidence in MSK evaluation. The aim of this study was to conduct a randomized control trial to compare the effect of the gold standard small group tutorial of bedside teaching against case-based teaching (CBT) in relation to orthopedic surgery in medical students. METHODS: All third-year medical students at our institution were invited to participate in a randomized control trial comparing CBT and bedside tutorials in relation to MSK. The primary outcome was student performance in an Objective Structured Clinical Examination (OSCE). Participants were randomized into 2 groups, receiving either a bedside tutorial or a case-based tutorial. Participants were then assigned self-directed learning before undergoing a final OSCE assessment. Student feedback was attained through a poststudy questionnaire. RESULTS: Complete data was acquired for 96 study participants (n = 45 CBT; n = 51 bedside tutorial). The results of a linear regression model used to assess differences in the final OSCE scores, adjusting for the baseline OSCE score, gender, age, previous problem-based learning exposure and whether English was their first language or not showed no evidence of a difference between the bedside teaching group and the CBT group (mean difference: 0.34; 95% confidence interval: -3.79 to 4.47; p = 0.872). Almost all (95%) of the study participants felt that CBT was an important component in their learning. CONCLUSION: There was no difference in OSCE performance between groups. The introduction of CBT before clinical placement in medical school could accentuate the clinical skills of students before transition into the apprenticeship model of clinical attachment. PMID- 28720424 TI - Participation of Colon and Rectal Fellows in Robotic Rectal Cancer Surgery: Effect on Surgical Outcomes. AB - OBJECTIVES: To determine whether involvement of colon and rectal fellows has an effect on short-term surgical and oncological outcomes in robotic rectal cancer surgery. PATIENTS AND METHODS: From a dataset of 263 robotic-assisted rectal cancer operations, 114 case-matched patients over a 5-year period (January 2010 December 2015) were included in the study. Patients who underwent resection with and without fellow involvement were compared. Cases were matched according to age, body mass index, neoadjuvant therapy, and tumor location. Intraoperative, postoperative, and pathological outcomes were compared between the 2 groups. RESULTS: There was no difference in tumor grade, type of surgical procedure, presence of an anastomosis, or diverting stoma between groups. In addition, there was no difference in the incidence of intraoperative or postoperative complications between the 2 groups. Estimated blood loss was higher in the fellow group compared to the consultant group (mean difference of 70mL, p = 0.007). For pathological outcomes, there was no difference in surrogate oncological quality indicators, specifically margin positivity and lymph node yield, between the 2 groups. Furthermore, fellow involvement did not adversely affect operative time. CONCLUSION: This study demonstrates that equivalent short-term surgical and oncological outcomes can be achieved with colorectal fellow participation in the field of robotic-assisted rectal cancer surgery. PMID- 28720425 TI - Toward Best Practices for Surgical Morbidity and Mortality Conferences: A Mixed Methods Study. AB - OBJECTIVE: To assess formats for surgical morbidity and mortality conferences (M&M) for strengths and challenges. DESIGN: A mixed methods approach with local observations to assess key domains of M&M practice (i.e., goals, structure, and process/content) and surveys to assess participants' expectations and experiences. SETTING: Surgical departments of two teaching hospitals (Boston, USA and Leiden, Netherlands). PARTICIPANTS: Participants of surgical M&M, including attending surgeons, residents, physician assistants, and medical students (total n = 135). RESULTS: Surgical M&M practices at both hospitals had education as its overarching goal, but varied in structure and process/content. Expectations were similar at both sites with >=80% of participants (n = 90; 67% response) expecting M&M to be focused on education as well as quality improvement (QI), blame-free, mandatory for both residents and attendings, and to lead to changes in clinical practice. However, compared to expectations, significantly fewer participants at both sites experienced: a QI focus (both p < 0.001); mandatory faculty attendance (p = 0.004; p < 0.001) and changes to practice (both p < 0.001). In comparison, at the site where an active moderator and QI committee are present, respondents seemed more positive about experiencing a QI focus (73% vs 30%) and changes to practice (44% vs 16%). CONCLUSION: Despite variation in M&M practice, the same (unmet) expectations existed at both hospitals, indicating that certain challenges may be more universal. M&M was reported to be well-focused on education, and certain aspects (e.g., active moderator and QI committee) seemed beneficial, but expectations were not met for the conference's focus and function for QI. Greater exchange of "best practices" for M&M may enhance the conference's value for improving surgical care. PMID- 28720426 TI - Langerhans Cells - The Macrophage in Dendritic Cell Clothing. AB - Our assumptions on the identity and functions of Langerhans cells (LCs) of the epidermis have undergone considerable changes. Once thought to be prototypic representatives of the dendritic cell (DC) lineage, they are now considered to be a specialized subset of tissue-resident macrophages. Despite this, LCs display a remarkable mixture of properties. Like many tissue macrophages, they self maintain locally. However, unlike tissue macrophages and similar to DCs, they homeostatically migrate to lymph nodes and present antigen to antigen-specific T cells. Current evidence indicates that the immune responses initiated by LCs are complex and dependent on antigenic properties and localization of the stimulus. This complexity is reflected in the recently demonstrated roles of LCs in type 17, regulatory, and humoral immune responses. PMID- 28720427 TI - The challenges and promise of targeting the Liver X Receptors for treatment of inflammatory disease. AB - The Liver X Receptors (LXRs) are oxysterol-activated transcription factors that upregulate a suite of genes that together promote coordinated mobilization of excess cholesterol from cells and from the body. The LXRs, like other nuclear receptors, are anti-inflammatory, inhibiting signal-dependent induction of pro inflammatory genes by nuclear factor-kappaB, activating protein-1, and other transcription factors. Synthetic LXR agonists have been shown to ameliorate atherosclerosis and a wide range of inflammatory disorders in preclinical animal models. Although this has suggested potential for application to human disease, systemic LXR activation is complicated by hepatic steatosis and hypertriglyceridemia, consequences of lipogenic gene induction in the liver by LXRalpha. The past several years have seen the development of multiple advanced LXR therapeutics aiming to avoid hepatic lipogenesis, including LXRbeta-selective agonists, tissue-selective agonists, and transrepression-selective agonists. Although several synthetic LXR agonists have made it to phase I clinical trials, none have progressed due to unforeseen adverse reactions or undisclosed reasons. Nonetheless, several sophisticated pharmacologic strategies, including structure guided drug design, cell-specific drug targeting, as well as non-systemic drug routes have been initiated and remain to be comprehensively explored. In addition, recent studies have identified potential utility for targeting the LXRs during therapy with other agents, such as glucocorticoids and rexinoids. Despite the pitfalls encountered to date in translation of LXR agonists to human disease, it appears likely that this accelerating field will ultimately yield effective and safe applications for LXR targeting in humans. PMID- 28720430 TI - Oncogenic pathways that affect antitumor immune response and immune checkpoint blockade therapy. AB - Mechanistic insights of cancer immunology have led to the development of immune checkpoint blockade therapy (ICBT), which has elicited a remarkable clinical response in some cancer patients. Increasing evidence suggests that activation of oncogenic pathways, such as RAS/RAF/MAPK and PI3K signaling, impairs the antitumor immune response. Such oncogenic signaling, in turn, activates many inhibitory factors, including expression of immune checkpoint genes-allowing active infiltration of immunosuppressive cells into the tumor environment and inducing resistance against T-cell killing. In preclinical tumor models, effective targeting of oncogenic pathways has enhanced the response to ICBT. Ongoing clinical trials are now evaluating combination therapy (i.e., the use of oncogenic pathway inhibitors in combination with ICBT). However, more translational and clinical research is needed, to optimize ICBT doses and sequence, minimize toxicity, and assess the impact on study participants of certain genetic backgrounds. Also, it is crucial to understand whether wild-type tumors with elevated oncogenic signaling will respond to combination therapy. Insights gained through current and future translational studies will provide the scientific premise and rationale to target 1 or more oncogenic pathways in ICBT resistant tumors, thus enabling more human patients to benefit from combination therapy. PMID- 28720431 TI - Biological responses to immobilized microscale and nanoscale surface topographies. AB - Cellular responses are highly influenced by biochemical and biomechanical interactions with the extracellular matrix (ECM). Due to the impact of ECM architecture on cellular responses, significant research has been dedicated towards developing biomaterials that mimic the physiological environment for design of improved medical devices and tissue engineering scaffolds. Surface topographies with microscale and nanoscale features have demonstrated an effect on numerous cellular responses, including cell adhesion, migration, proliferation, gene expression, protein production, and differentiation; however, relationships between biological responses and surface topographies are difficult to establish due to differences in cell types and biomaterial surface properties. Therefore, it is important to optimize implant surface feature characteristics to elicit desirable biological responses for specific applications. The goal of this work was to review studies investigating the effects of microstructured and nanostructured biomaterials on in vitro biological responses through fabrication of microscale and nanoscale surface topographies, physico-chemical characterization of material surface properties, investigation of protein adsorption dynamics, and evaluation of cellular responses in specific biomedical applications. PMID- 28720429 TI - Stable isotope-based flux studies in nonalcoholic fatty liver disease. AB - Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and is associated with the worldwide epidemics of obesity, diabetes and cardiovascular diseases. NAFLD ranges from benign fat accumulation in the liver (steatosis) to non-alcoholic steatohepatitis (NASH), and cirrhosis which can progress to hepatocellular carcinoma and liver failure. Mass spectrometry and magnetic resonance spectroscopy-coupled stable isotope-based flux studies provide new insights into the understanding of NAFLD pathogenesis and the disease progression. This review focuses mainly on the utilization of mass spectrometry based methods for the understanding of metabolic abnormalities in the different stages of NAFLD. For example, stable isotope-based flux studies demonstrated multi-organ insulin resistance, dysregulated glucose, lipids and lipoprotein metabolism in patients with NAFLD. We also review recent developments in the stable isotope-based technologies for the study of mitochondrial dysfunction, oxidative stress and fibrogenesis in NAFLD. We highlight the limitations of current methodologies, discuss the emerging areas of research in this field, and future directions for the applications of stable isotopes to study NAFLD and its complications. PMID- 28720432 TI - Adhesion and invasion of Clostridium perfringens type A into epithelial cells. AB - Clostridium perfringens is the causative agent for necrotic enteritis. It secretes the major virulence factors, and alpha- and NetB-toxins that are responsible for intestinal lesions. The TpeL toxin affects cell morphology by producing myonecrosis, but its role in the pathogenesis of necrotic enteritis is unclear. In this study, the presence of netB and tpeL genes in C. perfringens type A strains isolated from chickens with necrotic enteritis, their cytotoxic effects and role in adhesion and invasion of epithelial cells were evaluated. Six (27.3%) of the 22 C. perfringens type A strains were harboring the tpeL gene and produced morphological alterations in Vero cells after 6h of incubation. Strains tpeL (-) induced strong cell rounding after 6h of incubation and produced cell enlargement. None of the 22 strains harbored netB gene. All the six tpeL (+) gene strains were able to adhere to HEp-2 cells; however, only four of them (66.6%) were invasive. Thus, these results suggest that the presence of tpeL gene or TpeL toxin might be required for the adherence of bacteria to HEp-2 cells; however, it could not have any role in the invasion process. PMID- 28720433 TI - Single channel planar lipid bilayer recordings of the melittin variant MelP5. AB - MelP5 is a 26 amino acid peptide derived from melittin, the main active constituent of bee venom, with five amino acid replacements. The pore-forming activity of MelP5 in lipid membranes is attracting attention because MelP5 forms larger pores and induces dye leakage through liposome membranes at a lower concentration than melittin. Studies of MelP5 have so far focused on ensemble measurements of membrane leakage and impedance; here we extend this characterization with an electrophysiological comparison between MelP5 and melittin using planar lipid bilayer recordings. These experiments reveal that MelP5 pores in lipid membranes composed of 3:1 phosphatidylcholine:cholesterol consist of an average of 10 to 12 monomers compared to an average of 3 to 9 monomers for melittin. Both peptides form transient pores with dynamically varying conductance values similar to previous findings for melittin, but MelP5 occasionally also forms stable, well-defined pores with single channel conductance values that vary greatly and range from 50 to 3000pS in an electrolyte solution containing 100mM KCl. PMID- 28720434 TI - Incipient serous cystic neoplasia of the pancreas is a very rare phenomenon: a systematic prospective observation in pancreatectomy specimens. PMID- 28720435 TI - Incipient serous cystic neoplasia of the pancreas is a very rare phenomenon: a systematic prospective observation in pancreatectomy specimens-reply. PMID- 28720436 TI - Direct measurement of pressure-independent aqueous humour flow using iPerfusion. AB - Reduction of intraocular pressure is the sole therapeutic target for glaucoma. Intraocular pressure is determined by the dynamics of aqueous humour secretion and outflow, which comprise several pressure-dependent and pressure-independent mechanisms. Accurately quantifying the components of aqueous humour dynamics is essential in understanding the pathology of glaucoma and the development of new treatments. To better characterise aqueous humour dynamics, we propose a method to directly measure pressure-independent aqueous humour flow. Using the iPerfusion system, we directly measure the flow into the eye when the pressure drop across the pressure-dependent pathways is eliminated. Using this approach we address i) the magnitude of pressure-independent flow in ex vivo eyes, ii) whether we can accurately measure an artificially imposed pressure-independent flow, and iii) whether the presence of a pressure-independent flow affects our ability to measure outflow facility. These studies are conducted in mice, which are a common animal model for aqueous humour dynamics. In eyes perfused with a single cannula, the average pressure-independent flow was 1 [-3, 5] nl/min (mean [95% confidence interval]) (N = 6). Paired ex vivo eyes were then cannulated with two needles, connecting the eye to both iPerfusion and a syringe pump, which was used to impose a known pressure-independent flow of 120 nl/min into the experimental eye only. The measured pressure-independent flow was then 121 [117, 125] nl/min (N = 7), indicating that the method could measure pressure independent flow with high accuracy. Finally, we showed that the artificially imposed pressure-independent flow did not affect our ability to measure facility, provided that the pressure-dependence of facility and the true pressure independent flow were accounted for. The present study provides a robust method for measurement of pressure-independent flow, and demonstrates the importance of accurately quantifying this parameter when investigating pressure-dependent flow or outflow facility. PMID- 28720437 TI - Quantification of MicroRNAs in human aqueous humor by miRFLP assay. AB - MiRNAs are expressed in a tissue-specific fashion in the eyes and changes in miRNAs levels in aqueous humor (AH) may reflect the function of the eye and eye disease. Due to the low concentration of total miRNA in human aqueous humor, high volume of sample is required for RNA extraction prior to routine quantification such as RT-qPCR. However, limited volume of AH could be collected through surgery because of the characteristic of the eye. In addition, inefficiency of RNA extraction kits could affect target miRNA quantification dramatically. AH-direct miRFLP assay was developed for quantification of target miRNAs in human aqueous humor samples. For the first time, accurate miRNA quantification in human AH was achieved with microliter scale sample loading. Higher copy numbers of target miRNAs were obtained in direct detection than in RNA-extraction solution. It indicates that AH-direct miRFLP assay was able to quantify target miRNAs more accurately with no requirement for RNA-extraction to avoid sampling variability. PMID- 28720428 TI - Inhibitors of connexin and pannexin channels as potential therapeutics. AB - While gap junctions support the exchange of a number of molecules between neighboring cells, connexin hemichannels provide communication between the cytosol and the extracellular environment of an individual cell. The latter equally holds true for channels composed of pannexin proteins, which display an architecture reminiscent of connexin hemichannels. In physiological conditions, gap junctions are usually open, while connexin hemichannels and, to a lesser extent, pannexin channels are typically closed, yet they can be activated by a number of pathological triggers. Several agents are available to inhibit channels built up by connexin and pannexin proteins, including alcoholic substances, glycyrrhetinic acid, anesthetics and fatty acids. These compounds not always strictly distinguish between gap junctions, connexin hemichannels and pannexin channels, and may have effects on other targets as well. An exception lies with mimetic peptides, which reproduce specific amino acid sequences in connexin or pannexin primary protein structure. In this paper, a state-of-the-art overview is provided on inhibitors of cellular channels consisting of connexins and pannexins with specific focus on their mode-of-action and therapeutic potential. PMID- 28720438 TI - On the utility of 3D hand cursors to explore medical volume datasets with a touchless interface. AB - Analyzing medical volume datasets requires interactive visualization so that users can extract anatomo-physiological information in real-time. Conventional volume rendering systems rely on 2D input devices, such as mice and keyboards, which are known to hamper 3D analysis as users often struggle to obtain the desired orientation that is only achieved after several attempts. In this paper, we address which 3D analysis tools are better performed with 3D hand cursors operating on a touchless interface comparatively to a 2D input devices running on a conventional WIMP interface. The main goals of this paper are to explore the capabilities of (simple) hand gestures to facilitate sterile manipulation of 3D medical data on a touchless interface, without resorting on wearables, and to evaluate the surgical feasibility of the proposed interface next to senior surgeons (N=5) and interns (N=2). To this end, we developed a touchless interface controlled via hand gestures and body postures to rapidly rotate and position medical volume images in three-dimensions, where each hand acts as an interactive 3D cursor. User studies were conducted with laypeople, while informal evaluation sessions were carried with senior surgeons, radiologists and professional biomedical engineers. Results demonstrate its usability as the proposed touchless interface improves spatial awareness and a more fluent interaction with the 3D volume than with traditional 2D input devices, as it requires lesser number of attempts to achieve the desired orientation by avoiding the composition of several cumulative rotations, which is typically necessary in WIMP interfaces. However, tasks requiring precision such as clipping plane visualization and tagging are best performed with mouse-based systems due to noise, incorrect gestures detection and problems in skeleton tracking that need to be addressed before tests in real medical environments might be performed. PMID- 28720439 TI - Outcomes of Patients With Long-Term Treatment Response to Vascular Endothelial Growth Factor-Targeted Therapy for Metastatic Renal Cell Cancer. AB - BACKGROUND: Although targeted therapies with inhibitors of the vascular endothelial growth factor (VEGF) are the mainstay of treatment for metastatic renal cell carcinoma, there are limited data on the outcome of patients with long term response to this treatment. PATIENTS AND METHODS: In a retrospective, registry-based study, patients continuously treated with first-line anti-VEGF agents for at least 24 months were included. In total, 219 patients had evaluable data and were included in the outcome analysis. RESULTS: Median progression-free survival (PFS) after initiation of first-line targeted therapy was 39.7 months (95% confidence interval [CI], 35.9-43.5 months), with 5-year PFS of 34.2% (95% CI, 27.2%-41.2%). Median overall survival (OS) reached 79.1 months (95% CI, 65.2 93.0 months) with the 5-year OS of 62.1% (95% CI, 54.5%-69.7%). In this cohort, 28, 103, and 88 patients achieved complete response (CR), partial response (PR), or stable disease (SD) as the best response, respectively. Median PFS and OS were comparable in patients with PR and SD, but significantly longer in patients with CR (log rank test P value for PFS difference < .001 and .009 for OS difference). CONCLUSION: There are marked differences in PFS and OS between patients who receive long-term anti-VEGF treatment, achieving CR and non-CR as the best clinical response. Patients with non-CR experienced a relatively high progression rate shortly after the landmark time point of 2 years. PMID- 28720440 TI - First report of two complete Clostridium chauvoei genome sequences and detailed in silico genome analysis. AB - Clostridium (C.) chauvoei is a Gram-positive, spore forming, anaerobic bacterium. It causes black leg in ruminants, a typically fatal histotoxic myonecrosis. High quality circular genome sequences were generated for the C. chauvoei type strain DSM 7528T (ATCC 10092T) and a field strain 12S0467 isolated in Germany. The origin of replication (oriC) was comparable to that of Bacillus subtilis in structure with two regions containing DnaA boxes. Similar prophages were identified in the genomes of both C. chauvoei strains which also harbored hemolysin and bacterial spore formation genes. A CRISPR type I-B system with limited variations in the repeat number was identified. Sporulation and germination process related genes were homologous to that of the Clostridia cluster I group but novel variations for regulatory genes were identified indicative for strain specific control of regulatory events. Phylogenomics showed a higher relatedness to C. septicum than to other so far sequenced genomes of species belonging to the genus Clostridium. Comparative genome analysis of three C. chauvoei circular genome sequences revealed the presence of few inversions and translocations in locally collinear blocks (LCBs). The species genome also shows a large number of genes involved in proteolysis, genes for glycosyl hydrolases and metal iron transportation genes which are presumably involved in virulence and survival in the host. Three conserved flagellar genes (fliC) were identified in each of the circular genomes. In conclusion this is the first comparative analysis of circular genomes for the species C. chauvoei, enabling insights into genome composition and virulence factor variation. PMID- 28720441 TI - Increased TNF-alpha and sTNFR2 levels are associated with high-grade anal squamous intraepithelial lesions in HIV-positive patients with low CD4 level. AB - Compared with HIV-negative individuals, HIV-positive individuals have a higher prevalence of anogenital human papillomavirus (HPV) infection, the causative agent of anogenital cancer. TNF-alpha is a major proinflammatory cytokine. sTNFR2 is the soluble form of one of its receptors and is strongly expressed on stimulated lymphocytes. To further understand the role of TNF-alpha, sTNFR2 and other cytokines in the pathogenesis in HPV-related neoplasia, the profiles of serum cytokines in high-risk patients were analyzed for association with anal lesion status. Patients were categorized into 4 groups based on HIV status (HIV negative vs. HIV-positive with a CD4+ level <200/uL) and anal lesion status [no lesion, low-grade anal squamous intraepithelial lesion (LSIL) vs. high-grade squamous intraepithelial lesion (HSIL)] based on high resolution anoscopy-guided biopsy. Following adjustment for multiplicity, HIV-negative men with HSIL had lower levels of sTNFR2 than HIV-positive men with low CD4 level and HSIL (p=0.02). HIV-positive men with HSIL had higher levels of TNF-alpha than HIV negative men with HSIL (p<0.001), as well as HIV-positive men with no lesion or LSIL (p=0.03). The levels of other factors, including IL-1beta, IL-2, IL-4, IL-8, IFN-gamma, GM-CSF, sTNFR1 and DR5, were not significantly different between groups. Although the sample size was small, these results suggest that systemic activation of TNF-alpha/sTNFR2 in HIV-positive patients with a low CD4 level may promote the development of HSIL and possibly anal cancer. PMID- 28720442 TI - Impact of baseline covariates on the immunogenicity of the 9-valent HPV vaccine - A combined analysis of five phase III clinical trials. AB - BACKGROUND: The immunogenicity profile of the 9-valent HPV (9vHPV) vaccine was evaluated across five phase III clinical studies conducted in girls and boys 9-15 years of age and young women 16-26 years of age. The effect of baseline characteristics of subjects on vaccine-induced HPV antibody responses was assessed. METHODS: Immunogenicity data from 11,304 subjects who received >=1 dose of 9vHPV vaccine in five Phase III studies were analyzed. Vaccine was administered as a 3-dose regimen. HPV antibody titers were assessed 1 month after dose 3 using a competitive Luminex immunoassay and summarized as geometric mean titers (GMTs). Covariates examined were age, gender, race, region of residence, and HPV serostatus and PCR status at day 1. RESULTS: GMTs to all 9 vaccine HPV types decreased with age at vaccination initiation, and were otherwise generally similar among the demographic subgroups defined by gender, race and region of residence. For all subgroups defined by race or region of residence, GMTs were higher in girls and boys than in young women. Vaccination of subjects who were seropositive at day 1 to a vaccine HPV type resulted in higher GMTs to that type, compared with those in subjects who were seronegative for that type at day 1. CONCLUSIONS: 9vHPV vaccine immunogenicity was robust among subjects with differing baseline characteristics. It was generally comparable across subjects of different races and from different regions. Greater immunogenicity in girls and boys versus young women (the population used to establish 9vHPV vaccine efficacy in clinical studies) indicates that the anti-HPV responses generated by the vaccine in adolescents from all races or regions were sufficient to induce high-level protective efficacy. This immunogenicity profile supports a widespread 9vHPV vaccination program and early vaccination. PMID- 28720443 TI - Squamous intraepithelial lesions of the anal squamocolumnar junction: Histopathological classification and HPV genotyping. AB - BACKGROUND: Human papillomavirus (HPV)-related anal cancer lesions are often found adjacent to the squamocolumnar junction (SCJ). We have assessed the histopathology and associated HPV genotypes in anal SCJ lesions in surgically excised anal warts in HIV-negative and -positive patients. METHODS: Histopathology identified 47 squamous intraepithelial lesions (SILs) adjacent to the SCJ amongst a total of 145 cases of clinically diagnosed anal condylomata. The anal SCJ lesions were further analyzed with p16, CK7 and p63 immunohistochemistry and HPV genotyping. RESULTS: Sixteen (16/47) of the excised anal wart lesions contained HSIL; Three were HSIL and exclusively associated with oncogenic HPVs. A further thirteen (13/47) were mixed lesions. Of these eight were HSILs with LSIL and six were HSILs with papillary immature metaplasia (PIM); Ten of the mixed lesions were associated with one or more oncogenic HPVs, while three cases were exclusively associated with HPV6. CONCLUSIONS: Clinically diagnosed anal warts cannot be assumed to be limited to low-grade lesions as anal warts of the SCJ often show heterogeneous lesions, with coexistence of LSIL, PIM, and HSIL. Lesions showing PIM, however, may mimic HSIL, because they are hypercellular, but lack the nuclear atypia and conspicuous mitotic activity of HSIL; and are p16 negative. PMID- 28720444 TI - Characterization of a spray-dried candidate HPV L2-VLP vaccine stored for multiple years at room temperature. AB - HPV infections are associated with human cancers. Although three prophylactic vaccines have been approved to protect against HPV infections, the vaccines require cold-chain storage and may not be suitable for third world countries with less developed refrigeration facilities. We previously developed a bacteriophage L2 virus-like particle (VLP)-based candidate vaccine, which elicited broadly protective antibodies against diverse HPV types. Spray-drying of MS2-16L2 VLPs into a dry powder enhanced the stability of these VLPs. Building on these studies, we assessed the long-term stability and immunogenicity of the spray dried VLPs. Mice immunized with a single dose of spray-dried MS2-16L2 VLPs, which had been stored for 14 months at room temperature (RT), were partially protected from challenge with a high dose of HPV16, one year after immunization. However, immunization with two doses of MS2-16L2 VLPs stored at RT for 34 months elicited high titer anti-HPV antibodies. More importantly, this group of mice showed significant protection from HPV16, 4 months after immunization. These results suggest that spray-dried MS2-16L2 VLPs retain their effectiveness after long-term storage at RT, and may be suitable in third world countries with less developed refrigeration facilities. PMID- 28720445 TI - Moving beyond sex: Assessing the impact of gender identity on human papillomavirus vaccine recommendations and uptake among a national sample of rural-residing LGBT young adults. AB - BACKGROUND: While national human papillomavirus (HPV) vaccination estimates exist by sex, little is known about HPV vaccination rates by gender identity. METHODS: We conducted a self-administered, anonymous online cross-sectional survey, with recruitment through Facebook ads, of lesbian, gay, bisexual, and transgender individuals in rural areas of the US. We compared HPV vaccine recommendation and uptake by self-reported sex assigned at birth and current gender identity. RESULTS: Six hundred sixty respondents were age eligible for HPV vaccination: 84% reported gender identity aligned with their sex assigned at birth, while 10% reported gender identity the differed from their sex assigned at birth; an additional 6% reported non-binary gender identity. Only 14% of male sex assigned at birth and 44% of female sex assigned at birth received HPV vaccine, similar to estimates by current gender identity. Transgender respondents' HPV vaccination experience mirrored that of cisgender respondents with regard to sex assigned at birth. CONCLUSIONS: Providers may base HPV vaccine recommendations on individuals' sex assigned at birth, which may impact transgender individuals' vaccine coverage. Future HPV vaccine uptake studies should account for gender identity. With sex-specific catch-up HPV vaccination recommendations, the role of gender identity on provider recommendation and reimbursement needs to be addressed. PMID- 28720446 TI - Acceptability of multipurpose human papillomavirus vaccines among providers and mothers of adolescent girls: A mixed-methods study in five countries. AB - INTRODUCTION: Multipurpose vaccines (MPVs) could be formulated to prevent multiple sexually transmitted infections simultaneously. Little is known about acceptability of MPVs among vaccine health care providers (HCPs) or mothers of adolescent girls. METHODS: 151 adolescent vaccine providers and 118 mothers of adolescent girls aged 9-14 were recruited from five geographically-diverse countries: Argentina, Malaysia, South Africa, South Korea, and Spain. We assessed providers' preferences for single-purpose human papillomavirus (HPV) vaccine versus MPVs (including HPV+herpes simplex virus (HSV)-2, HPV+HIV, or HPV+HSV 2+HIV) via quantitative surveys. Maternal MPV attitudes were assessed in four focus group discussions (FGDs) in each country. RESULTS: Most providers preferred MPVs over single-purpose HPV vaccination, with preference ranging from 61% in Malaysia to 96% in South Africa. HPV+HSV-2+HIV was the most preferred MPV formulation (56-82%). Overall, 53% of the mothers preferred MPVs over single purpose HPV vaccines, with strongest support in South Africa (90%) and lowest support in South Korea (29%). Convenience and trust in the health care system were commonly-cited reasons for MPV acceptability. Safety and efficacy concerns were common barriers to accepting MPVs, though specific concerns differed by country. Across FGDs, additional safety and efficacy information on MPVs were requested, particularly from trusted sources like HCPs. CONCLUSIONS: Though maternal acceptability of MPVs varied by country, MPV acceptability would be enhanced by having HCPs provide parents with additional MPV vaccine safety and efficacy information. While most providers preferred MPVs, future health behavior research should identify acceptability barriers, and targeted provider interventions should equip providers to improve vaccination discussions with parents. PMID- 28720447 TI - Projected impact of HPV vaccination and primary HPV screening on cervical adenocarcinoma: Example from Australia. AB - Cytology-based cervical screening appears to have had a limited effect on the incidence of adenocarcinoma, however HPV vaccination and HPV-based screening will likely play a role in reducing future burden. Using Australia as an example, we estimated the future burden (2015-2040) of adenocarcinoma in the absence of other interventions; and the impact of HPV vaccination (introduced 2007) and HPV-based screening (commencing 2017). Future burden was estimated considering underlying trends in adenocarcinoma, using national data (1982-2010). The relative reduction in adenocarcinoma due to HPV vaccination and HPV-based screening was derived from observed clinical data. Adenocarcinoma incidence rates have been increasing since the early-mid 2000s (average annual increases from 3.0%(25-49 years) -8.1%(20-24 years)). If these trends continue, rates would increase from 1.4 to 2.4/100,000 in <50 years and from 2.2 to 4.4/100,000 in 50+ years by 2040. Taking into account coverage, HPV vaccination will reduce 2040 incidence by 36-39%, mainly in women <50 years (61% reduction). Taking into account uncertainties in trends and screening effectiveness, HPV-based screening will reduce incidence by an additional 19-43%, mainly in women 50+ years (additional 30-68% reduction). Together, these interventions will reduce incidence by 55-81%. PMID- 28720448 TI - The feminization of HPV: How science, politics, economics and gender norms shaped U.S. HPV vaccine implementation. AB - Human papillomavirus (HPV) can cause a number of anogenital cancers (i.e., cervical, penile, anal, vaginal, vulvar) and genital warts. A decade ago, the HPV vaccine was approved, and has been shown to be a public health achievement that can reduce the morbidity and mortality for HPV-associated diseases. Yet, the mistaken over-identification of HPV as a female-specific disease has resulted in the feminization of HPV and HPV vaccines. In this critical review, we trace the evolution of the intersection of science, politics, economics and gender norms during the original HPV vaccine approval, marketing era, and implementation. Given the focus on cervical cancer screening, women were identified as bearing the burden of HPV infection and its related illnesses, and the group responsible for prevention. We also describe the consequences of the feminization of HPV, which has resulted primarily in reduced protection from HPV-related illnesses for males. We propose a multilevel approach to normalizing HPV vaccines as an important aspect of overall health for both genders. This process must engage multiple stakeholders, including providers, parents, patients, professional organizations, public health agencies, policymakers, researchers, and community based organizations. PMID- 28720449 TI - Human papillomavirus in anal biopsy tissues and liquid-based cytology samples of HIV-positive and HIV-negative Thai men who have sex with men. AB - BACKGROUND: Men who have sex with men (MSM) are at high risk of developing human papillomavirus (HPV)-related anal cancer. We compared HPV genotypes in anal tissues (Bx) and anal liquid-based cytology fluid (LBC) from HIV-positive and HIV negative MSM. METHODS: Bx (32 normal, 41 low-grade squamous intraepithelial lesions (LSIL) and 22 high-grade squamous intraepithelial lesions (HSIL)), along with LBC from the same visit, were selected from 61 HIV-positive and 34 HIV negative MSM who enrolled into a prospective cohort in Bangkok, Thailand. HPV genotyping was performed on Bx and LBC. RESULTS: Any HPV and high-risk HPV (HR HPV) prevalence were 63.2% and 60.0% in Bx and 71.6% and 62.1% in LBC, respectively. HIV-positive MSM had higher rates of HR-HPV genotypes detection (70.5% vs. 47.1%, p=0.03) in LBC than HIV-negative MSM. HPV16 (27%) was the most common HR-HPV found in HSIL tissue. In HIV-positive MSM, the frequency of HR-HPV detection increased with histopathologic grading in both Bx and LBC samples. HSIL was associated with the presence of any HR-HPV(OR 7.6 (95%CI 1.8-31.9); P=0.006) in LBC and in Bx((OR 5.6 (95%CI 1.4-22.7); P=0.02). CONCLUSIONS: Our data strongly support the integration of HR-HPV screening on LBC samples, along with HPV vaccination, into an anal cancer prevention program. PMID- 28720450 TI - Detection of cervical precancerous lesions with Aptima HPV assays using SurePath preservative fluid specimens. AB - SurePath specimens from women referred to colposcopy were treated with Aptima Transfer Solution (ATS) before testing in Aptima HPV (AHPV) and Aptima HPV 16, 18/45 (AHPV-GT) assays. Untreated SurePath specimens were tested with the cobas HPV test. PreservCyt specimens were assessed for cytology and tested with AHPV. High-grade cervical intraepithelial neoplasia lesions served as the reference standard. Excellent agreement (95.5%; k=0.91) was observed for ATS-treated SurePath specimens between Tigris and Panther systems and between the PreservCyt and ATS-treated SurePath specimens (91.1%, k=0.81) with the AHPV assay on Tigris. Agreement between the AHPV and cobas assays with SurePath specimens was substantial (89.9%, k=0.80). AHPV sensitivity for CIN2+(n=147) was 91.2% for SurePath and PreservCyt. Cobas HPV sensitivity was 93.9% for SurePath specimens. AHPV testing of SurePath specimens was more specific (59.4%) than cobas (54.7%) (p<0.001). Detection and genotyping showed similar absolute and relative risks. ATS-treated SurePath specimens tested with AHPV and AHPV-GT assays showed similar performance with greater specificity than cobas HPV on SurePath specimens. Similar overall results were seen using a CIN3 disease endpoint. PMID- 28720451 TI - High diversity of alpha, beta and gamma human papillomaviruses in genital samples from HIV-negative and HIV-positive heterosexual South African men. AB - BACKGROUND: This study investigated the prevalence of HPVs in heterosexual South African men and the impact of HIV co-infection. METHODS: HPV was detected in penile swabs from 195 HIV-infected and 140 HIV-uninfected men using PCR with FAP59/64 primers and Roche Linear Array HPV genotyping (LA). Genotyping of FAP positive specimens was achieved by high-throughput sequencing of amplicons. RESULTS: HPV was detected by FAP PCR and LA in 79% (266/335) of the men. Men with HIV co-infection and men with HIV infected sexual partners had a significantly (p<0.0001) higher HPV infection risk (adjusted odds ratio 4.0 (2.1-8.2) and 3.7 (2.1-6.7), respectively). LA genotyping and 454 sequencing of 218 FAP positive specimens detected 45 known alpha-HPV types, 45 beta-HPV types (34 known, 10 putative and 1 novel putative), and 91 gamma-HPV types (26 known, 51 putative and 14 novel putative). Alpha, beta and gamma types were detected in 89.8%, 51.4% and 62.4% of the 218 men with HPV-62, HPV-5 and HPV-121 most common in each genus, respectively. CONCLUSION: A great diversity of known and novel alpha, beta and gamma HPV types were detected with higher prevalence in HIV co-infected men and unknown associations, if any, with genital lesions and cancers. PMID- 28720452 TI - Socioeconomic predictors of human papillomavirus vaccination in Danish men - A nationwide study. AB - BACKGROUND: The quadrivalent human papillomavirus vaccine was licensed in Denmark in 2006. Unlike women, men are not offered human papillomavirus vaccination free of charge but can have it at their own expense. We investigated human papillomavirus vaccine uptake by men in Denmark and the socioeconomic factors that may predict human papillomavirus vaccination. METHODS: Using the Civil Registration System, we identified all boys and men aged 9-26 years in 2006-2013 and their mothers. By linkage to Statistics Denmark and the National Prescription Registry, we obtained information on socioeconomic variables and human papillomavirus vaccination during the study period. Using Cox regression, we examined the associations between socioeconomic variables and human papillomavirus vaccination. RESULTS: Between 2006 and 2013, 6253 (0.8%) males aged 9-26 years were vaccinated against human papillomavirus. The strongest predictor identified was ethnicity. Males who were immigrants (hazard ratio, 0.12; 95% confidence interval, 0.08-0.180) or sons of immigrant parents (hazard ratio, 0.13; 95% confidence interval, 0.10-0.17) were less likely to be vaccinated than Danish males. Additionally, sons of mothers who were unemployed, unmarried, had a low income, and basic education initiated human papillomavirus vaccination less frequently. Finally, sons of mothers who were physicians or nurses were more likely to be vaccinated than sons of other highly educated mothers. CONCLUSION: We found low uptake, with social disparities in human papillomavirus vaccination of boys and young men in Denmark. PMID- 28720453 TI - Parental acceptance of human papillomavirus vaccinations and community pharmacies as vaccination settings: A qualitative study in Alabama. AB - PURPOSE: To determine parents' knowledge and attitudes regarding human papillomavirus (HPV) vaccinations in their adolescent children and to describe parents' perceptions of adolescent vaccinations in community pharmacies. METHODS: In-depth interviews were completed with parents or guardians of children ages 11 17 years from Alabama's Lee and Macon counties. One-hour long, open-ended telephonic or in-person interviews were conducted until the saturation point was reached. Using ATLAS.ti software and thematic analysis, interview transcripts were coded to identify themes. RESULTS: Twenty-six parents were interviewed, most of whom were female (80.8%) and white (50%). A total of 12 themes were identified. First, two themes emerged regarding elements facilitating children's HPV vaccination, the most common being positive perception of the HPV vaccine. Second, elements hindering children's vaccination contained seven themes, the top one being lack of correct or complete information about the HPV vaccine. The last topic involved acceptance/rejection of community pharmacies as vaccination settings, and the most frequently cited theme was concern about pharmacists' clinical training. CONCLUSIONS: Physician-to-parent vaccine education is important, and assurances of adequate pharmacy immunization training will ease parents' fears and allow pharmacists to better serve adolescents, especially those who do not see physicians regularly. PMID- 28720454 TI - Comparative accuracy of Pap smear and HPV screening in Ubon Ratchathani in Thailand. AB - We evaluate the potential for using high-risk human papillomavirus (hr-HPV) testing-based screening for cervical intraepithelial neoplasia (CIN) in routine health services in Thailand; its accuracy in comparison to that of conventional cytology (CC); and the utility of HPV16/18 positive results and liquid-based cytology (LBC) triage for HPV-positive women in the detection of high-grade CIN. Women aged 30-60 years in Ubon Ratchathani province, Thailand were screened with CC and hr-HPV testing and those abnormal on either tests were referred for colposcopy and/or directed biopsies. The final diagnosis using COBAS was based on histology or colposcopy when histology was not available. Estimation of test accuracy parameters was done using latent class analysis using Bayesian models. Of the 5004 women were enrolled, 20 (0.4%) had abnormal CC and 174 (3.5%) women were HPV-positive. Among 185 women abnormal on CC or HPV-positive, 176 (95.1%) underwent colposcopy, of whom 101 (57.4%) had abnormal colposcopy findings. Ninety-seven women with abnormal and 69 with normal colposcopy had biopsies performed. All 21 women with histological CIN2 or worse had hr-HPV and none were abnormal on CC. The estimated sensitivity, specificity and positive predictive value were respectively 71.8%, 97.0% and 13.0% of HPV testing; 53%, 98.7% and 20.3% for triage of HPV-positive women with LBC; and 70.4%, 98.2% and 16.9% when test positivity was taken as HPV16/18 irrespective of LBC result or positive for hr-HPV non 16/18 types and LBC triage. Our study findings indicate poor performance of cytology screening and demonstrate the potential and utility of using HPV testing in public health services in Thailand as well as the utility of primary HPV testing and LBC triage in screening for cervical neoplasia. PMID- 28720455 TI - Reasons for acceptance or refusal of Human Papillomavirus Vaccine in a California pediatric practice. AB - Despite the effectiveness and availability of the Human Papillomavirus (HPV) vaccine, HPV remains the most common sexually transmitted infection in the United States and has the lowest initiation rate of any routinely recommended teen vaccine. In January 2015, we surveyed parents at a Southern California pediatric private practice about reasons they accept or refuse HPV vaccine for their children. Of the 200 consecutive parents that had HPV vaccine initiation recommended for their child, 123 (61.5%) children were male and 38.5% were female. The overall age range of children was 10-17 years (median 12 years). Of the 164 (82.0%) who accepted the vaccine, a higher percentage were male (88.6% vs 71.4%, p=0.001). The most common reasons for accepting was strength of provider recommendation (84.1%) and available information (63.4%). The most common (52.8%) reason for refusing was wanting to learn more about the vaccine. These results further support the importance of both the strength of physician recommendation and improving public education about the vaccine. PMID- 28720456 TI - Mechanistic mathematical models: An underused platform for HPV research. AB - Health economic modeling has become an invaluable methodology for the design and evaluation of clinical and public health interventions against the human papillomavirus (HPV) and associated diseases. At the same time, relatively little attention has been paid to a different yet complementary class of models, namely that of mechanistic mathematical models. The primary focus of mechanistic mathematical models is to better understand the intricate biologic mechanisms and dynamics of disease. Inspired by a long and successful history of mechanistic modeling in other biomedical fields, we highlight several areas of HPV research where mechanistic models have the potential to advance the field. We argue that by building quantitative bridges between biologic mechanism and population level data, mechanistic mathematical models provide a unique platform to enable collaborations between experimentalists who collect data at different physical scales of the HPV infection process. Through such collaborations, mechanistic mathematical models can accelerate and enhance the investigation of HPV and related diseases. PMID- 28720457 TI - High-risk human papillomavirus seroprevalence in men and women of six different ethnicities in Amsterdam, the Netherlands: The HELIUS study. AB - BACKGROUND: Ethnic variations in the (sero)prevalence of Human Papillomavirus (HPV) and HPV related diseases have been observed previously. We explored if high risk HPV (hrHPV) seropositivity indeed differs among 6 ethnic groups in Amsterdam the Netherlands and assessed if hrHPV seroprevalence is higher among women than men within each ethnic group, both after adjustment for confounders. METHODS: From the multi-ethnic HEalthy Life In an Urban Setting (HELIUS) study in Amsterdam (the Netherlands) we randomly selected 4637 men and women aged 18-44 years with a Dutch, South-Asian Surinamese, African Surinamese, Ghanaian, Moroccan, or Turkish ethnicity. Blood samples were tested for HPV-16,-18,-31,-33, 45,-52, and -58 antibodies using a validated Luminex-based multiplex serology assay. We assessed the association of both ethnicity and gender with hrHPV seropositivity using logistic regression models with generalised estimating equations. RESULTS: The hrHPV seroprevalence in Dutch, South-Asian Surinamese, African Surinamese, Ghanaian, Moroccan, and Turkish participants was 18%, 12%, 23%, 19%, 17%, and 15% in men, and 30%, 22%, 34%, 31%, 14%, and 15% in women, respectively. HrHPV seroprevalence of non-Dutch men did not differ significantly from Dutch men. HrHPV seroprevalence was significantly higher among African Surinamese women, and significantly lower among Moroccan and Turkish women when compared to Dutch women. These differences were not significant anymore after adjustment for demographic, health, and sexual behavioural differences between ethnicities. HrHPV seroprevalence varied by age, age of sexual debut, and lifetime sexual partners among women but not among men. Seroprevalence of hrHPV was higher among women than among men, except in the Turkish group. CONCLUSION: Among women hrHPV seroprevalence differed by ethnicity, yet among men no pronounced differences were observed across ethnicities. PMID- 28720458 TI - Prevalence of cutaneous beta and gamma human papillomaviruses in the anal canal of men who have sex with women. AB - BACKGROUND: Data regarding anal cutaneous HPV detection among HIV-positive and HIV-negative persons largely relies on studies among men who have sex with men in limited geographical settings. Understanding the distribution, determinants, and potential human health effects of anal cutaneous HPV types among men who have sex with women (MSW) is important. METHODS: Anal canal swab samples from 415 Russian MSW (384 HIV-negative and 31 HIV-positive) were tested for 43 beta-HPVs and 29 gamma-HPVs, using a multiplex PCR combined with Luminex technology. RESULTS: beta HPV was detected in 24.4% and gamma-HPV in 15.9% of anal samples of all Russian MSW. In total, 34 beta-HPV and 19 gamma-HPV types were detected, with the most commonly detected beta-HPV types being 110, 22 and 124 and the most common gamma HPV types being 95, 132 and 50. For both genera, being HIV-positive at the time of testing was a significant determinant of detection (74.2% for beta-HPVs and 48.4% for gamma-HPVs compared to 20.1% and 12.5% in HIV-negative MSW, respectively). CONCLUSIONS: A wide spectrum and moderate prevalence of anal beta HPV and gamma-HPV types was found in our MSW study sample, suggesting that routes other than penile-anal intercourse may be important in cutaneous HPV transmission. PMID- 28720459 TI - Investigating the role of human papillomavirus in lung cancer. AB - Lung cancer is the leading cancer worldwide among men and women with morbidity reaching 1.6 million. Human Papillomavirus is the causal factor of cervical cancer while its association with others is still under investigation. The purpose of our study is to examine the presence of HPV DNA as well as high-risk E6/E7 mRNA in patients with lung cancer. Lung tissues were collected during bronchoscopy and tested for HPV DNA and E6/E7 mRNA. 67 lung tissue samples were analysed. The age range was 49-85 years old (y.o) with a mean age of 67.6 y.o. 9 patients were female and 58 were male. The study included 12 Small Cell Lung Cancers (SCLC) and 55 Non Small Cell Lung Cancer (NSCLC). HPV DNA was detected in 3.0% (2/67) of lung cancer cases, while no E6/E7 mRNA of five high-risk HPV types was found in tissue samples examined. The two positive patients had no prior history of an HPV related disease. Using the mRNA test as a gold standard for the association of HPV with malignant transformation, the present results showed no association of HPV status with lung cancer. Further investigation of more lung cancer tissues is required to reach safe conclusions. PMID- 28720460 TI - Loss of chance associated with sub-optimal HPV vaccination coverage rate in France. AB - INTRODUCTION: Since 2007, HPV vaccination programs have been implemented in Europe. Significant real-life impact has already been reported in countries where the programs have been successfully implemented. In France, HPV vaccination coverage rate (VCR) is currently one of the lowest in Europe. This represents a missed opportunity for individuals who will not be protected. The study aimed to estimate the consequences of the sub-optimal VCR. METHODS: A dynamic transmission model was calibrated to the French setting. Outcomes resulting from the vaccination of girls with quadrivalent HPV vaccine according to two theoretical VCR: 17% and 70%, reflecting the range of VCRs in Western Europe, were evaluated. RESULTS: Over 100 years, with the current low VCR, an additional 85,000 cancers, 28,000 deaths and more than 5 million avertable disease events overall would occur compared with a 70% VCR. At steady state, the 17% VCR was estimated to be associated with an additional 1700 cancers, 600 deaths and 66,000 avertable disease events each year, compared with a 'standard' EU VCR. CONCLUSION: The loss of chance associated with sub-optimal VCR is substantial for the French population and could amount to the occurrence of hundreds of avoidable deaths and thousands of disease events annually. PMID- 28720461 TI - Vaccine-preventable anal human papillomavirus in Australian gay and bisexual men. AB - OBJECTIVE: HPV causes ~90% of anal cancer and HPV16 is the type most commonly associated with anal cancer. Gay and bisexual men (GBM) are at greatly increased risk. We investigated patterns of vaccine-preventable anal HPV in older GBM. METHODS: The Study of the Prevention of Anal Cancer (SPANC) is an ongoing, prospective cohort study of HIV-positive and HIV-negative Australian GBM. Participants completed questionnaires and underwent an anal swab for HPV genotyping using Roche Linear Array. We analysed baseline data from SPANC by HPV type, mean number of types, stratified by age and HIV status. RESULTS: Anal HPV results from 606 (98.2%) of 617 participants (median age 49 years, 35.7% HIV positive) showed 525 (86.7%) had >=1 HPV type and 178 (29.4%) had HPV16. Over one third of participants (214, 35.3%) had no nonavalent vaccine-preventable types detected. Two (0.3%) participants had all quadrivalent types and none had all nonavalent vaccine types. HIV-positive participants (p<0.001) and younger participants (p=0.059) were more likely to have more vaccine-preventable HPV types detected. CONCLUSION: Anal HPV was highly prevalent in this largely community-based GBM cohort. Vaccine-preventable HPV16 was detected in approximately one third of participants. These findings suggest that the potential efficacy of HPV vaccination of older GBM should be explored. PMID- 28720462 TI - A novel trivalent HPV 16/18/58 vaccine with anti-HPV 16 and 18 neutralizing antibody responses comparable to those induced by the Gardasil quadrivalent vaccine in rhesus macaque model. AB - Persistent infection with human papillomavirus (HPV) is a key factor in the development of precancerous lesions and invasive cervical cancer. Prophylactic vaccines to immunize against HPV are an effective approach to reducing HPV related disease burden. In this study, we investigated the immunogenicity and dosage effect of a trivalent HPV 16/18/58 vaccine (3vHPV) produced in Escherichia coli (E.coli), with Gardasil quadrivalent vaccine (4vHPV, Merck & Co.) as a positive control. Sera collected from rhesus macaques vaccinated with three dosage formulations of 3vHPV (termed low-, mid-, and high-dosage formulations, respectively), and the 4vHPV vaccine were analyzed by both Pseudovirus-Based Neutralization Assay (PBNA) and Enzyme-Linked Immunosorbent Assay (ELISA). Strong immune responses against HPV 16/18/58 were successfully elicited, and dosage dependence was observed, with likely occurrence of immune interference between different L1-VLP antigens. HPV 16/18 specific neutralizing antibody (nAb) and total immunoglobulin G (IgG) antibody responses in rhesus macaques receiving 3vHPV at the three dosages tested were generally non-inferior to those observed in rhesus macaques receiving 4vHPV throughout the study period. Particularly, HPV 18 nAb titers induced by the mid-dosage formulation that contained the same amounts of HPV 16/18 L1-VLPs as Gardasil 4vHPV were between 7.3 to 12.7-fold higher compared to the positive control arm from weeks 24-64. The durability of antibody responses specific to HPV 16/18 elicited by 3vHPV vaccines was also shown to be non-inferior to that associated with Gardasil 4vHPV. PMID- 28720463 TI - Incidence rates of Guillain Barre (GBS), chronic fatigue/systemic exertion intolerance disease (CFS/SEID) and postural orthostatic tachycardia syndrome (POTS) prior to introduction of human papilloma virus (HPV) vaccination among adolescent girls in Finland, 2002-2012. AB - BACKGROUND: In Finland a vaccination programme against human papillomavirus (HPV) was introduced in November 2013 for girls aged 11-12 years with a catchup for girls 13-15 years. Allegations that HPV vaccine is causing Guillain Barre syndrome (GBS) and non-specific diagnostic entities, such as chronic fatigue syndrome/systemic exertion intolerance disease (CFS/SEID) and postural orthostatic tachycardia syndrome (POTS), continue to surface. We examined population register-based incidence rates of CFS/SEID, GBS and POTS to provide baseline data for future HPV vaccine safety evaluations. METHODS: First diagnosis of CFS/SEID, GBS and POTS in girls aged 11-15 years were obtained from the National Hospital Discharge Register during 2002-2012. We considered the following ICD-10 codes: G93.3 for CFS; G61.0 for GBS and G90.9, G90.8, G93.3, I49.8 for POTS. We calculated incidence rates per 100,000 person-years with 95% confidence intervals (CI). RESULTS: In total, 9 CFS/SEID, 19 GBS and 72 POTS cases were identified. The overall incidence rate was 0.53/100,000 (95% CI; 0.27 1.01) for CFS/SEID, 1.11 (95% CI; 0.71-1.74) for GBS and 4.21 (95%CI; 3.34-5.30) for POTS. Significant relative increase in annual incidence rate with a peak in 2012 was observed in CFS/SEID (33% (95% CI; 3.0-70.3: p=0.029) and POTS (16.5% (95% CI; 7.8-25.9: p<0.05), but not in GBS (5.4% (95% CI; -8.4-21.3: p=0.460). CONCLUSIONS: Our findings provide baseline estimates of CFS/SEID, GBS and POTS incidences in Finland. However, rates based on register data should be interpreted with caution, especially for non-specific diagnostic entities for which internationally and even nationally agreed criteria are still being discussed. To assess the associations with HPV vaccine, methods using register linkage for cohort and self-controlled case series should be explored in addition to factors contributing to patients seeking care, treating physicians setting the diagnoses, and their preference of using of codes for these clinical entities. PMID- 28720464 TI - Prospects for the new HPV Prevention and Control Board. PMID- 28720465 TI - Effect of age-difference between heterosexual partners on risk of cervical cancer and human papillomavirus infection. AB - BACKGROUND: Age difference (Adiff) within a heterosexual couple may influence a woman's risk of being HPV-positive and developing cervical cancer (CC). METHODS: We assessed the relationship between Adiff within the first and current sexual partnership and risk of CC and HPV infection in 1495 cases and 1358 control women from 6 countries included in IARC's multicentric case-control study (median age: 48 years). RESULTS: Large Adiff within the first partnerships was associated with increased CC risk (OR>=3 vs. <=2 years=1.49, CI: 1.26-1.75); this association disappeared after correction for age at first sexual intercourse (OR=1.03, 0.86 1.24). The relationship between Adiff within the current partnership and HPV positivity was opposite (OR>=3 vs. <=2 years=0.59, 0.41-0.86) and not affected by adjustment for sexual confounding. The influences of Adiff on CC risk and HPV positivity were consistent across age groups and countries. CONCLUSION: The association between CC risk and large Adiff in the first sexual partnership is mostly explained by young age at first intercourse. Conversely, the negative association between Adiff in current partnership and HPV-positivity is probably related to decreased infectiousness of the male partner with age. The study of Adiff in sexual partnerships helps elucidate HPV circulation in different populations. PMID- 28720466 TI - Antinociceptive effects of HUF-101, a fluorinated cannabidiol derivative. AB - Cannabidiol (CBD) is a phytocannabinoid with multiple pharmacological effects and several potential therapeutic properties. Its low oral bioavailability, however, can limit its clinical use. Preliminary results indicate that fluorination of the CBD molecule increases its pharmacological potency. Here, we investigated whether HUF-101 (3, 10, and 30mg/kg), a fluorinated CBD analogue, would induce antinociceptive effects. HUF-101 effects were compared to those induced by CBD (10, 30, and 90mg/kg) and the cannabinoid CB1/2 receptor agonist WIN55,212-2 (1, 3, and 5mg/kg). These drugs were tested in male Swiss mice submitted to the following models predictive to antinociceptive drugs: hot plate, acetic acid induced writhing, and carrageenan-induced inflammatory hyperalgesia. To evaluate the involvement of CB1 and CB2 receptors in HUF-101 and CBD effects, mice received the CB1 receptor antagonist AM251 (1 or 3mg/kg) or the CB2 receptor antagonist AM630 (1 or 3mg/kg) 30min before HUF-101, CBD, or WIN55,212-2. In the hot plate test, HUF-101 (30mg/kg) and WIN55,212-2 (5mg/kg) induced antinociceptive effects, which were attenuated by the pretreatment with AM251 and AM630. In the abdominal writhing test, CBD (30 and 90mg/kg), HUF-101 (30mg/kg), and WIN55,212-2 (3 and 5mg/kg) induced antinociceptive effects indicated by a reduction in the number of writhing. Whereas the pretreatment with AM630 did not mitigate the effects induced by any drug in this test, the pretreatment with AM251 attenuated the effect caused by WIN55,212-2. In the carrageenan-induced hyperalgesia test, CBD (30 and 90mg/kg), HUF-101 (3, 10 and 30mg/kg) and WIN55,212-2 (1mg/kg) decreased the intensity of mechanical hyperalgesia measured by the electronic von Frey method. The effects of all compounds were attenuated by the pretreatment with AM251 and AM630. Additionally, we evaluated whether HUF 101 would induce the classic cannabinoid CB1 receptor-mediated tetrad (hypolocomotion, catalepsy, hypothermia, and antinociception). Unlike WIN55,212 2, CBD and HUF-101 did not induce the cannabinoid tetrad. These findings show that HUF-101 produced antinociceptive effects at lower doses than CBD, indicating that the addition of fluoride improved its pharmacological profile. Furthermore, some of the antinociceptive effects of CBD and HUF-101 effects seem to involve the activation of CB1 and CB2 receptors. PMID- 28720467 TI - Intradermal Immunization with rAAV1 Vector Induces Robust Memory CD8+ T Cell Responses Independently of Transgene Expression in DCs. AB - Recombinant adeno-associated viral (rAAV) vectors exhibit interesting properties as vaccine carriers for their ability to induce long-lasting antibody responses. However, rAAV-based vaccines have been suggested to trigger functionally impaired long-term memory CD8+ T cell responses, in part due to poor dendritic cell (DC) transduction. Such results, albeit limited to intramuscular immunization, undermined the use of rAAV as vaccine vehicles against intracellular pathogens. We report here that intradermal immunization with a model rAAV2/1-based vaccine drives the development of bona fide long-term memory CD8+ T cell responses. The intradermal route of immunization and the presence of potent major histocompatibility complex (MHC) class II responses showed synergistic effects on the overall quantity and quality of systemic long-term effector memory transgene specific CD8+ T cells being generated against the transgene. Of key interest, we found that the induction of memory cytotoxic T lymphocytes (CTLs) following intradermal immunization was solely dependent on the cross-presentation of skin expressed transgene products, which appeared highly enhanced as compared to muscle-expressed transgene products. Overall our results highlight key tissue specific differences in transgene presentation pathway requirements of importance for the design of rAAV-based T cell-inducing vaccines. PMID- 28720468 TI - Production of a Chikungunya Vaccine Using a CHO Cell and Attenuated Viral-Based Platform Technology. AB - Vaccinia-based systems have been extensively explored for the development of recombinant vaccines. Herein we describe an innovative vaccinia virus (VACV) derived vaccine platform technology termed Sementis Copenhagen Vector (SCV), which was rendered multiplication-defective by targeted deletion of the essential viral assembly gene D13L. A SCV cell substrate line was developed for SCV vaccine production by engineering CHO cells to express D13 and the VACV host-range factor CP77, because CHO cells are routinely used for manufacture of biologics. To illustrate the utility of the platform technology, a SCV vaccine against chikungunya virus (SCV-CHIK) was developed and shown to be multiplication defective in a range of human cell lines and in immunocompromised mice. A single vaccination of mice with SCV-CHIK induced antibody responses specific for chikungunya virus (CHIKV) that were similar to those raised following vaccination with a replication-competent VACV-CHIK and able to neutralize CHIKV. Vaccination also provided protection against CHIKV challenge, preventing both viremia and arthritis. Moreover, SCV retained capacity as an effective mouse smallpox vaccine. In summary, SCV represents a new and safe vaccine platform technology that can be manufactured in modified CHO cells, with pre-clinical evaluation illustrating utility for CHIKV vaccine design and construction. PMID- 28720469 TI - Value of intraoperative ultrasound with conventional probes and its usefulness in surgical and therapeutic management of patients. AB - OBJECTIVE: To prove both the reliability and the applications presented by intraoperative ultrasonography (IOUS) in surgical and therapeutic management of diverse pathologies and the possibility of doing it by using conventional equipment. MATERIAL AND METHODS: Single-center retrospective study of 145 IOUS performed by using conventional equipment in 135 patients between January 2011 and June 2016. We assessed the organs studied by ultrasound, underlying conditions of patients, preoperative imaging and the degree of matching them with the histological findings. The functions of the intraoperative ultrasound were assessed in each case. RESULTS: 91,7% of the scans performed were hepatic, being other locations varied but less common. They had a high concordance with the histological results of the lesions analyzed (95.4%) and in 24% of the cases their results did not coincide with those of the preoperative imaging tests, being decisive for the management of the patients. CONCLUSION: Despite the limitations of our study, IOUS has proven to be a reliable and safe diagnostic test with advantages over conventional imaging techniques. It contributes to get a correct diagnosis in those lesions not characterized by the preoperative imaging tests, to locate and delimit the extension of a lesion within an organ and facilitate the performance of diagnostic procedures (intraoperative biopsy) even in centers where we do not have specific probes. PMID- 28720470 TI - Molecular docking prediction and in vitro studies elucidate anti-cancer activity of phytoestrogens. AB - AIM: The study is aimed at evaluating the chemosensitization and apoptotic effect of aglycone rich extracts of dietary phytoestrogens (derived from soybean and flaxseed) on estrogen receptor positive, MCF-7 and estrogen receptor negative, MDA-MB-231 cells. The extracts show potent activity on both the cell lines, hence, in silico studies have been carried out to find the possible reason for their activity. MAIN METHODS: MTT assay was carried to assess chemosensitization effect and activated caspase-3/7 activity was studied using flow-cytometry and western blotting. In silico studies were carried out using PharmMapper and the top hits were taken up for docking using the Schrodinger software. Top molecular targets were subjected to gene expression studies by qPCR and protein expression using Western blot analysis. KEY FINDINGS: This study reports the apoptotic activity and chemosensitization effect of the phytoestrogens. Molecular docking studies predict AKR1B1 (aldose reductase), HRAS (Harvey rat sarcoma) and GSTP1 (glutathione s-transferase pi) as potential molecular targets for genistein, daidzein and secoisolariciresinol, respectively. Gene and protein expression studies show down-regulation of AKR1BI, HRAS and GSTP1 by the extracts. SIGNIFICANCE: The qPCR and western blot analysis results support the computational analyses, and hence genistein, daidzein and secoisolariciresinol may be considered as good candidates for future development into potent inhibitors of the respective protein targets through medicinal chemistry optimization. PMID- 28720471 TI - Endoscopic transcecal appendectomy: the first human case report. PMID- 28720472 TI - Mantle cell lymphoma involving the esophagus evaluated by magnifying endoscopy with narrow-band imaging. PMID- 28720473 TI - EUS-guided antegrade stent placement for unresectable malignant hilar biliary strictures by use of a stent-in-stent method. PMID- 28720475 TI - A case of IgG4-related disease presenting with multiple gastric submucosal tumors. PMID- 28720474 TI - Nitrous oxide cryotherapy for treatment of esophageal squamous cell neoplasia: initial multicenter international experience with a novel portable cryoballoon ablation system (with video). AB - BACKGROUND AND AIMS: Early esophageal squamous cell neoplasia (ESCN) can be successfully treated by EMR, endoscopic submucosal dissection (ESD), or radiofrequency ablation. A new portable, battery-powered cryotherapy system using nitrous oxide (cryoballoon focal ablation system [CbFAS]) has been used for Barrett's esophagus. It consists of a small hand-held device containing liquid nitrous oxide, which converts to gas within a low-pressure-compliant through-the scope balloon and freezes targeted mucosa in contact with the balloon. This study evaluated the feasibility of endoscopic eradication of early ESCN with the CbFAS. METHODS: Patients with early ESCN (defined as low-grade intraepithelial neoplasia [LGIN], high-grade intraepithelial neoplasia [HGIN], or early T1 squamous mucosal cancer) were treated with the CbFAS. After chromoendoscopy, all Lugol's unstained lesions (USLs) were targeted with 8, 10, or 12 seconds of ice per site, and treatment was repeated until biopsy samples demonstrated eradication of ESCN. Postprocedure adverse events were recorded. RESULTS: Ten patients (4 men; median age, 69.5 years) with LGIN (n=2), HGIN (n=7), or esophageal squamous cell carcinoma (ESCC; n=1, after EMR) in 24 USLs were treated. The median maximum diameter of the largest USL was 1.5 cm (interquartile range, 1-2 cm), and median total length of all neoplastic USLs was 2 cm (range, 1-10 cm). Patients with focal disease received a median of 2 cryoablations, whereas 4 patients with large and/or multifocal circumferential neoplasia had 6 to 12 ablations per procedure. The median procedure time was 34 minutes (range, 18-57 minutes). Treatment was completed in all patients. No major adverse events occurred. Four patients developed mild self-limited chest pain requiring narcotic analgesics immediately after the procedure. Two patients who received circumferential ablation developed a stricture responding to dilation, with no recurrence. Complete endoscopic and pathologic response was achieved in all patients at 3 months. One year follow-up biopsy specimens in 7 patients showed no USL or ESCN. All patients were disease free at last visit, with a median follow-up time of 10.7 months (interquartile range, 4-14 months). CONCLUSIONS: We report the first application of nitrous cryoballoon ablation for curative treatment of early primary or recurrent ESCN. Our initial experience suggests that efficacy is high and the safety profile is reasonable. Prospective trials are needed to optimize cryogen dosimetry and assess safety and efficacy. PMID- 28720476 TI - Atypical appearance of a rectal Dieulafoy lesion. PMID- 28720477 TI - Nanoquinacrine caused apoptosis in oral cancer stem cells by disrupting the interaction between GLI1 and beta catenin through activation of GSK3beta. AB - Presences of cancer stem cells (CSCs) in a bulk of cancer cells are responsible for tumor relapse, metastasis and drug resistance in oral cancer. Due to high drug efflux, DNA repair and self-renewable capacity of CSCs, the conventional chemotherapeutic agents are unable to kill the CSCs. CSCs utilizes Hedgehog (HH GLI), WNT-beta catenin signalling for its growth and development. GSK3beta negatively regulates both the pathways in CSCs. Here, we have shown that a nano formulated bioactive small molecule inhibitor Quinacrine (NQC) caused apoptosis in oral cancer stem cells (OCSCs; isolated from different oral cancer cells and oral cancer patient derived primary cells) by down regulating WNT-beta catenin and HH-GLI components through activation of GSK3beta. NQC activates GSK3beta in transcriptional and translational level and reduces beta catenin and GLI1 as well as downstream target gene of both the pathways Cyclin D1, C-Myc. The transcription factor activity of both the pathways was also reduced by NQC treatment. GSK3beta, beta catenin and GLI1 interacts with each other and NQC disrupts the co-localization and interaction between beta catenin and GLI1 in OCSCs in a dose dependent manner through activation of GSK3beta. Thus, data suggest NQC caused OCSCs death by disrupting the crosstalk between beta catenin and GLI1 by activation of GSK3beta. PMID- 28720478 TI - Monoamine receptor interaction profiles of 4-thio-substituted phenethylamines (2C T drugs). AB - BACKGROUND: 4-Thio-substituted phenethylamines (2C-T drugs) are potent psychedelics with poorly defined pharmacological properties. Because of their psychedelic effects, 2C-T drugs are sometimes sold as new psychoactive substances (NPSs). The aim of the present study was to characterize the monoamine receptor and transporter interaction profiles of a series of 2C-T drugs. METHODS: We determined the binding affinities of 2C-T drugs at monoamine receptors and transporters in human cells that were transfected with the respective receptors or transporters. We also investigated the functional activation of serotonergic 5 hydroxytryptamine 2A (5-HT2A) and 5-HT2B receptors, activation of human trace amine-associated receptor 1 (TAAR1), and inhibition of monoamine uptake transporters. RESULTS: 2C-T drugs had high affinity for 5-HT2A and 5-HT2C receptors (1-54 nM and 40-350 nM, respectively). With activation potencies of 1 53 nM and 44-370 nM, the drugs were potent 5-HT2A receptor and 5-HT2B receptor, respectively, partial agonists. An exception to this were the benzylthiophenethylamines, which did not potently activate the 5-HT2B receptor (EC50 > 3000 nM). Furthermore, the compounds bound to serotonergic 5-HT1A and adrenergic receptors. The compounds had high affinity for the rat TAAR1 (5-68 nM) and interacted with the mouse but not human TAAR1. The 2C-T drugs did not potently interact with monoamine transporters (Ki > 4000 nM). CONCLUSION: The receptor binding profile of 2C-T drugs predicts psychedelic effects that are mediated by potent 5-HT2 receptor interactions. This article is part of the Special Issue entitled 'Designer Drugs and Legal Highs.' PMID- 28720479 TI - Interaction between prenatal risk and infant parasympathetic and sympathetic stress reactivity predicts early aggression. AB - Nonreciprocal action of the parasympathetic (PNS) and sympathetic (SNS) nervous systems, increases susceptibility to emotional and behavioral problems in children exposed to adversity. Little is known about the PNS and SNS in interaction with early adversity during infancy. Yet this is when the physiological systems involved in emotion regulation are emerging and presumably most responsive to environmental influences. We examined whether parasympathetic respiratory sinus arrhythmia (RSA) and sympathetic pre-ejection period (PEP) response and recovery at six months, moderate the association between cumulative prenatal risk and physical aggression at 20 months (N=113). Prenatal risk predicted physical aggression, but only in infants exhibiting coactivation of PNS and SNS (i.e., increase in RSA and decrease in PEP) in response to stress. These findings indicate that coactivation of the PNS and SNS in combination with prenatal risk is a biological marker for the development of aggression. PMID- 28720480 TI - Heart rate variability predicts inhibitory control in adults with autism spectrum disorders. AB - Several studies suggest that inhibition difficulties among people with ASD might be related to atypical cardiac vagal control. We examined how low versus high baseline heart rate variability (HRV) influences prepotent response inhibition in 31 males with autism spectrum disorder (ASD; mean age: 32.2; mean IQ: 107.8) compared to 39 typically developing (TD) males (mean age: 30.5; mean IQ: 102.0) by administering a stop signal task. Moreover, we examined whether adding an affective manipulation would alter findings and whether this manipulation affected HRV. Findings indicated that baseline HRV influenced inhibition in ASD males. Specifically, an ASD subgroup with low baseline HRV performed significantly worse compared to an ASD subgroup with high baseline HRV. No influence of baseline HRV was found in TD males. The affective manipulation did negatively influence performance and also altered HRV. Although replication is required, these first findings indicate that baseline cardiac vagal control seems to affect inhibitory control in males with ASD. PMID- 28720481 TI - Knee extension and flexion strength asymmetry in Human Immunodeficiency Virus positive subjects: a cross-sectional study. AB - BACKGROUND: Human Immunodeficiency Virus positive subjects present impairment in muscle function, neural activation, balance, and gait. In other populations, all of these factors have been associated with muscle strength asymmetry. OBJECTIVE: To investigate the existence of muscle strength asymmetry between dominant and non-dominant lower limbs and to determine the hamstrings-to-quadriceps strength ratio in Human Immunodeficiency Virus positive subjects. METHODS: In this cross sectional study, 48 subjects were included (22 men and 26 women; mean age 44.6 years), all of them under highly active antiretroviral therapy. They performed isokinetic strength efforts at speeds of 60 degrees /s and 180 degrees /s for knee extension and flexion in concentric-concentric mode. RESULTS: Peak torque was higher (p<0.01) at 60 degrees /s for quadriceps (193, SD=57 vs. 173, SD=55% body mass) and hamstrings (97, SD=36 vs. 90, SD=37% body mass) in dominant compared to non-dominant. Similarly, peak torque was higher at 180 degrees /s (quadriceps 128, SD=44 vs. 112, SD=42; hamstrings 64, SD=24 vs. 57, SD=26% body mass) in dominant. Average power was also higher for all muscle groups and speeds, comparing dominant with non-dominant. The hamstrings-to-quadriceps ratio at 60 degrees /s was 0.50 for dominant and 0.52 for non-dominant, and at 180 degrees /s, it was 0.51 for both limbs, with no significant difference between them. The percentage of subjects with strength asymmetry ranged from 46 to 58%, depending upon muscle group and speed analyzed. CONCLUSION: Human Immunodeficiency Virus positive subjects present muscle strength asymmetry between lower limbs, assessed through isokinetic dynamometry. PMID- 28720482 TI - Time to Go Bigger: Emerging Patterns in Macrogenetics. AB - The increasing availability of large-scale and high-resolution data sets in population genetics is moving the field toward a novel research agenda. Here, we show how this shift toward macrogenetics should generate new perspectives and theories allowing the description, understanding, and prediction of patterns of genetic diversity at broad spatial, temporal, and taxonomic scales. PMID- 28720483 TI - Left-Right Patterning: Breaking Symmetry to Asymmetric Morphogenesis. AB - Vertebrates exhibit striking left-right (L-R) asymmetries in the structure and position of the internal organs. Symmetry is broken by motile cilia-generated asymmetric fluid flow, resulting in a signaling cascade - the Nodal-Pitx2 pathway - being robustly established within mesodermal tissue on the left side only. This pathway impinges upon various organ primordia to instruct their side-specific development. Recently, progress has been made in understanding both the breaking of embryonic L-R symmetry and how the Nodal-Pitx2 pathway controls lateralized cell differentiation, migration, and other aspects of cell behavior, as well as tissue-level mechanisms, that drive asymmetries in organ formation. Proper execution of asymmetric organogenesis is critical to health, making furthering our understanding of L-R development an important concern. PMID- 28720484 TI - Long-term enzyme replacement therapy improves neurocognitive functioning and hippocampal synaptic plasticity in immune-tolerant alpha-mannosidosis mice. AB - Alpha-mannosidosis is a glycoproteinosis caused by deficiency of lysosomal acid alpha-mannosidase (LAMAN), which markedly affects neurons of the central nervous system (CNS), and causes pathognomonic intellectual dysfunction in the clinical condition. Cognitive improvement consequently remains a major therapeutic objective in research on this devastating genetic error. Immune-tolerant LAMAN knockout mice were developed to evaluate the effects of enzyme replacement therapy (ERT) by prolonged administration of recombinant human enzyme. Biochemical evidence suggested that hippocampus may be one of the brain structures that benefits most from long-term ERT. In the present functional study, ERT was initiated in 2-month-old immune-tolerant alpha-mannosidosis mice and continued for 9months. During the course of treatment, mice were trained in the Morris water maze task to assess spatial-cognitive performance, which was related to synaptic plasticity recordings and hippocampal histopathology. Long term ERT reduced primary substrate storage and neuroinflammation in hippocampus, and improved spatial learning after mid-term (10weeks+) and long-term (30weeks+) treatment. Long-term treatment substantially improved the spatial-cognitive abilities of alpha-mannosidosis mice, whereas the effects of mid-term treatment were more modest. Detailed analyses of spatial memory and spatial-cognitive performance indicated that even prolonged ERT did not restore higher cognitive abilities to the level of healthy mice. However, it did demonstrate marked therapeutic effects that coincided with increased synaptic connectivity, reflected by improvements in hippocampal CA3-CA1 long-term potentiation (LTP), expression of postsynaptic marker PSD-95 as well as postsynaptic density morphology. These experiments indicate that long-term ERT may hold promise, not only for the somatic defects of alpha-mannosidosis, but also to alleviate cognitive impairments of the disorder. PMID- 28720485 TI - Ceftaroline modulates the innate immune and host defense responses of immunocompetent cells exposed to cigarette smoke. AB - BACKGROUND: Cigarette smoke, the principal risk factor for chronic obstructive pulmonary disease (COPD), negatively influences the effectiveness of the immune system's response to a pathogen. The antibiotic ceftaroline exerts immune modulatory effects in bronchial epithelial cells exposed to cigarette smoke. AIMS AND METHODS: The present study aims to assess the effects of ceftaroline on TLR2 and TLR4 expression, LPS binding and TNF-alpha and human beta defensin (HBD2) release in an undifferentiated and PMA-differentiated human monocyte cell line (THP-1) exposed or not to cigarette smoke extracts (CSE). TLR2, TLR4, and LPS binding were assessed by flow cytometry, TNF-alpha and HBD2 release were evaluated by ELISA. RESULTS: The constitutive expression of TLR2 and TLR4 and LPS binding were higher in differentiated compared to undifferentiated THP-1 cells. In undifferentiated THP-1 cells, CSE increased TLR2 and TLR4 protein levels, LPS binding and TNF-alpha release and reduced HBD2 release and ceftaroline counteracted all these effects. In differentiated THP-1, CSE did not significantly affect TLR2 and TLR4 expression and LPS binding but reduced HBD2 release and increased TNF-alpha release. Ceftaroline counteracted the effects of CSE on HBD2 release in differentiated THP-1. CONCLUSION: Ceftaroline counteracts the effect of CSE in immune cells by increasing the effectiveness of the innate immune system. This effect may also assist in reducing pathogen activity and recurrent exacerbations in COPD patients. PMID- 28720486 TI - Loss of synaptic zinc transport in progranulin deficient mice may contribute to progranulin-associated psychopathology and chronic pain. AB - Affective and cognitive processing of nociception contributes to the development of chronic pain and vice versa, pain may precipitate psychopathologic symptoms. We hypothesized a higher risk for the latter with immanent neurologic diseases and studied this potential interrelationship in progranulin-deficient mice, which are a model for frontotemporal dementia, a disease dominated by behavioral abnormalities in humans. Young naive progranulin deficient mice behaved normal in tests of short-term memory, anxiety, depression and nociception, but after peripheral nerve injury, they showed attention-deficit and depression-like behavior, over-activity, loss of shelter-seeking, reduced impulse control and compulsive feeding behavior, which did not occur in equally injured controls. Hence, only the interaction of 'pain x progranulin deficiency' resulted in the complex phenotype at young age, but neither pain nor progranulin deficiency alone. A deep proteome analysis of the prefrontal cortex and olfactory bulb revealed progranulin-dependent alterations of proteins involved in synaptic transport, including neurotransmitter transporters of the solute carrier superfamily. In particular, progranulin deficiency was associated with a deficiency of nuclear and synaptic zinc transporters (ZnT9/Slc30a9; ZnT3/Slc30a3) with low plasma zinc. Dietary zinc supplementation partly normalized the attention deficit of progranulin-deficient mice, which was in part reminiscent of autism-like and compulsive behavior of synaptic zinc transporter Znt3-knockout mice. Hence, the molecular studies point to defective zinc transport possibly contributing to progranulin-deficiency-associated psychopathology. Translated to humans, our data suggest that neuropathic pain may precipitate cognitive and psychopathological symptoms of an inherent, still silent neurodegenerative disease. PMID- 28720487 TI - PDMS-b-PMOXA polymersomes for hepatocyte targeting and assessment of toxicity. AB - Nanoparticles, such as polymersomes, can be directed to the hepatic asialoglycoprotein receptor to achieve targeted drug delivery. In this study, we prepared asialofetuin conjugated polymersomes based on the amphiphilic di-block copolymer poly(dimethylsiloxane)-b-poly(2-methyloxazoline) (PDMS-b-PMOXA). They had an average diameter of 150nm and formed monodisperse vesicles. Drug encapsulation and sustained release was monitored using the hydrophilic model compound carboxyfluorescein. Asialoglycoprotein receptor specific uptake by HepG2 cells in vitro was energy dependent and could be competitively inhibited by the free targeting ligand. Mechanistic uptake studies revealed intracellular trafficking of asialofetuin conjugated polymersomes from early endosomes and to the lysosomal compartment. Polymersomes showed no toxicity in the MTT assay up to concentrations of 500MUg/mL. In addition, acute toxicity and tolerability of our PDMS-b-PMOXA polymersome formulations was assessed in vivo using zebrafish embryos as a vertebrate screening model. In conclusion, a hepatocyte specific drug delivery system was designed, which is safe and biocompatible and which can be used to implement liver-specific targeting strategies. PMID- 28720488 TI - Hormonal correlates of natal dispersal and rank attainment in wild male baboons. AB - In many mammals, maturational milestones such as dispersal and the attainment of adult dominance rank mark stages in the onset of reproductive activity and depend on a coordinated set of hormonal and socio-behavioral changes. Studies that focus on the link between hormones and maturational milestones are uncommon in wild mammals because of the challenges of obtaining adequate sample sizes of maturing animals and of tracking the movements of dispersing animals. We examined two maturational milestones in wild male baboons-adult dominance rank attainment and natal dispersal-and measured their association with variation in glucocorticoids (fGC) and fecal testosterone (fT). We found that rank attainment is associated with an increase in fGC levels but not fT levels: males that have achieved any adult rank have higher fGC than males that have not yet attained an adult rank. This indicates that once males have attained an adult rank they experience greater energetic and/or psychosocial demands than they did prior to attaining this milestone, most likely because of the resulting participation in both agonistic and sexual behaviors that accompany rank attainment. In contrast, natal dispersal does not produce sustained increases in either fGC or fT levels, suggesting that individuals are either well adapted to face the challenges associated with dispersal or that the effects of dispersal on hormone levels are ephemeral for male baboons. PMID- 28720489 TI - Simplified membrane feeding of bloodsucking triatomines (Hemiptera: Reduviidae). AB - Laboratory-reared hematophagous triatomines that are the main vectors of Chagas disease are generally fed on small vertebrates or on blood-filled membrane devices. Such devices allow a large-scale rearing of these vectors without sacrificing host animals but are almost always expensive, fragile, not easily purchased, and usually difficult to use because they need to be sterilized before and carefully cleaned after each feeding. We present here a simple device to feed triatomines that is composed of a circular series of alternating short pieces of stainless steel and silicon tubing connected to a pump that circulates water heated at 50 degrees C in a water bath. An unlubricated condom filled with 50ml of blood, is fixed around each steel tube section and placed onto the screened tops of containers with triatomines. Nymphs and adults access the blood source by climbing a vertical piece of folded filter paper. After feeding, each condom can be easily and safely removed and discarded. This device consists of simple, cheap, safe and robust components that can be easily purchased, assembled and used. Contamination during or after feeding is practically excluded. The technique is successfully used in our Laboratory for almost two years. PMID- 28720490 TI - First record of natural vertical transmission of dengue virus in Aedes aegypti from Cuba. AB - While horizontal transmission (human-mosquito-human) of dengue viruses largely determines the epidemiology of the disease, vertical transmission (infected female mosquito- infected offspring) has been suggested as a mechanism that ensures maintenance of the virus during adverse conditions for horizontal transmission to occur. The purpose of this study was to analyze the natural infection of larval stages of Aedes aegypti (Diptera: Culicidae) with the dengue virus (DENV) in Cuba. Here, we report vertical transmission of DENV-3 genotype III in natural populations of Ae. aegypti through RT-PCR detection and serotyping plus sequencing. Our report constitutes the first record of vertical transmission of DENV in Ae. aegypti from Cuba with details of its serotype and genotype. PMID- 28720491 TI - The immunomodulatory effects of the Enalapril in combination with Benznidazole during acute and chronic phases of the experimental infection with Trypanosoma cruzi. AB - Trypanosoma cruzi infection triggers a chronic inflammatory process responsible for the alterations in the extracellular matrix and functionality of the heart. The angiotensin converting enzyme (ACE) inhibitors affects T. cruzi in vitro surveillance and modulates in vivo some inflammatory mediators. In this study, we investigated the treatment with an ACE inhibitor (Enalapril) and the Benznidazole (Bz) in a single and combination therapies (CT) in C57BL/6 mice infected with VL 10 strain of the T. cruzi. Animals were treated during 20days with different doses of Bz (100, 80, 60mg/kg), Enalapril (25, 20, 15mg/kg) and their CT (100+25; 80+20; 60+15mg/kg) and euthanized at 30 degrees (acute) and at 120 degrees (chronic) days post infection. The plasma and heart were processed for immunopathological investigations. Our data shown that Bz and Enalapril controlled, in part, the parasite replication and reduced plasma levels of TNF, CCL2 and CCL5 in the acute and in chronic phase of infection. However, the CT doses reduced in around 20% the inflammatory parameters obtained with the Bz therapy. The CT doses of 100+25 and 80+20mg/kg increased the IL-10 levels and reduced the cardiac inflammation while Bz inhibited the collagen neogenesis in the infection. In conclusion, we assume that the CT administrated in the initial stage of infection, presents a minor immunomodulatory effect when the VL-10 strain of T. cruzi is used. In contrast, Bz and Enalapril in monotherapies persist suggesting a potential protection against cardiac damages during experimental T. cruzi infection. PMID- 28720492 TI - Prevention of congenital Chagas disease by Benznidazole treatment in reproductive age women. An observational study. AB - Since the decline in new cases of infection by insect/vector, congenital Chagas disease has become more relevant in the transmission of Chagas disease. Treatment with benznidazole significantly reduces the parasitemia, which constitutes an important factor linked to vertical transmission. The objective of this study was to evaluate whether treatment with benznidazole previously administered to women of childbearing age can prevent or reduce the incidence of new cases of congenital Chagas disease. An historical cohort study that included all women in reproductive age (15-45 years) assisted in our center was designed. We included 67 mothers with chronic Chagas disease; 35 women had not been treated prior to pregnancy, 15 had been treated prior to pregnancy and 17 gave birth prior and after treatment with benznidazole. Eight mothers gave birth to 16 children with congenital Chagas disease (8/67, 12%). The prevalence of congenital Chagas was 16/114 (14%) children born to untreated mothers and 0/42 (0%) children born to benznidazole- treated mothers, p=0.01. No significant differences were observed in clinical, serologic, epidemiological or socioeconomic baseline variables between mothers with and without children born with congenital Chagas. A 32% conversion rate to negative serology was observed in benznidazole-treated women after long-term follow up. Antiparasitic treatment administered to women in reproductive age can prevent the occurrence of congenital Chagas disease. PMID- 28720493 TI - Crystal structures of monkey and mouse nicotinamide N-methyltransferase (NNMT) bound with end product, 1-methyl nicotinamide. AB - Nicotinamide N-methyltransferase (NNMT) is a S-adenosyl-l-methionine (SAM) dependent enzyme that catalyzes N-methylation of nicotinamide (NA) and other pyridines to form N-methyl pyridinium ions. Here we report the first ternary complex X-ray crystal structures of monkey NNMT and mouse NNMT in bound form with the primary endogenous product, 1-methyl nicotinamide (MNA) and demethylated cofactor, S-adenosyl-homocysteine (SAH) determined at 2.30 A and 1.88 A respectively. The structural fold of these enzymes is identical to human NNMT. It is known that the primary endogenous product catalyzed by NNMT, MNA is a specific inhibitor of NNMT. Our data clearly indicates that the MNA binds to the active site and it would be trapped in the active site due to the formation of the bridge between the pole (long helix, alpha3) and long C-terminal loop. This might explain the mechanism of MNA acting as a feedback inhibitor of NNMT. PMID- 28720494 TI - The eukaryotic enzyme Bds1 is an alkyl but not an aryl sulfohydrolase. AB - The eukaryotic enzyme Bds1 in Saccharomyces cerevisiae is a metallo-beta lactamase-related enzyme evolutionarily originating from bacterial horizontal gene transfer that serves an unknown biological role. Previously, Bds1 was reported to be an alkyl and aryl sulfatase. However, we demonstrate here that Bds1 acts on primary alkyl sulfates (of 6-12 carbon atoms) but not the aryl sulfates p-nitrophenyl sulfate and p-nitrocatechol sulfate. The apparent catalytic rate constant for hydrolysis of the substrate 1-hexyl sulfate by Bds1 is over 100 times lower than that of the reaction catalyzed by its bacterial homolog SdsA1. We show that Bds1 shares a catalytic mechanism with SdsA1 in which the carbon atom of the sulfate ester is the subject of nucleophilic attack, rather than the sulfur atom, resulting in C-O bond lysis. In contrast to SdsA1 and another bacterial homolog with selectivity for secondary alkyl sulfates named Pisa1, Bds1 does not show any substantial activity towards secondary alkyl sulfates. Neither Bds1 nor SdsA1 have any significant activity towards a branched primary alkyl sulfate, primary and secondary steroid sulfates, or phosphate diesters. Therefore, the enzymes homologous to SdsA1 that have been identified and characterized thus far vary in their selectivity towards primary and secondary alkyl sulfates but do not exhibit aryl sulfatase activity. PMID- 28720495 TI - Crystal structure of LysK, an enzyme catalyzing the last step of lysine biosynthesis in Thermus thermophilus, in complex with lysine: Insight into the mechanism for recognition of the amino-group carrier protein, LysW. AB - LysK is an M20 peptidase family enzyme that hydrolyzes the isopeptide bond between the carrier protein LysW and lysine in order to release lysine, which is the last step of lysine biosynthesis in Thermus thermophilus. In the present study, we determined the crystal structure of LysK in complex with lysine at a resolution of 2.4 A. The alpha-amino group of the bound lysine was oriented toward the catalytic center, which was composed of the residues coordinating divalent metal ions for the hydrolysis of the isopeptide bond. An 11 A-long path was observed from the active site binding lysine to the protein surface, which may be responsible for recognizing the C-terminal extension domain of LysW with the conserved EDWGE sequence. A positively-charged surface region was detected around the exit of the path, similar to other lysine biosynthetic enzymes using LysW as the carrier protein. Mutational studies of the surface residues provided a plausible model for the electrostatic interaction with LysW. PMID- 28720496 TI - Substrate binding interferes with active site conformational dynamics in endoglucanase Cel5A from Thermobifida fusca. AB - The role of protein dynamics in enzyme catalysis is one of the most active areas in current enzymological research. Here, using endoglucanase Cel5A from Thermobifida fusca (TfCel5A) as a model, we applied molecular dynamics simulations to explore the dynamic behavior of the enzyme upon substrate binding. The collective motions of the active site revealed that the mechanism of TfCel5A substrate binding can likely be described by the conformational-selection model; however, we observed that the conformations of active site residues changed differently along with substrate binding. Although most active site residues retained their native conformational ensemble, some (Tyr163 and Glu355) generated newly induced conformations, whereas others (Phe162 and Tyr189) exhibited shifts in the equilibration of their conformational distributions. These results showed that TfCel5A substrate binding relied on a hybrid mechanism involving induced fit and conformational selection. Interestingly, we found that TfCel5A active site could only partly rebalance its conformational dynamics upon substrate dissociation within the same simulation time, which implies that the conformational rebalance upon substrate dissociation is likely more difficult than the conformational selection upon substrate binding at least in the view of the time required. Our findings offer new insight into enzyme catalysis and potential applications for future protein engineering. PMID- 28720497 TI - NRF2 overexpression in mesenchymal stem cells induces stem-cell marker expression and enhances osteoblastic differentiation. AB - Hypoxic environment has been suggested in stem cell culturing as their physiologic niche requires oxygen tension to maintain stemness. The administration of cobalt chloride (CoCl2) was widely applied in mimicking hypoxia for its economic advantages and convenience. We confirmed that CoCl2 could maintain stemness and promote the osteogenesis capacity of MSCs. However, CoCl2 could induce the apoptosis and hinder the proliferation of MSCs. To find out a potential method maintaining their stemness without threatening their survival, we analyzed the database of Gene Expression Omnibus (GEO) and proposed that NRF2 (nuclear factor erythroid-derived 2-like 2) might be the potential target. We found that knocking down NRF2 expression in MSCs impaired the expression of stem cell markers and the osteogenesis process even under hypoxic environment, but with NRF2 overexpression, the proliferation of MSCs was increased with significantly reduced rate of apoptosis. Therefore, our findings suggested that overexpressing NRF2 could be a potential method for maintaining stemness and preventing apoptosis in MSCs under oxidative stress. PMID- 28720498 TI - RNA aptamers targeted for human alphaA-crystallin do not bind alphaB-crystallin, and spare the alpha-crystallin domain. AB - The molecular chaperones, alpha-crystallins, belong to the small heat shock protein (sHSP) family and prevent the aggregation and insolubilization of client proteins. Studies in vivo have shown that the chaperone activity of the alpha crystallins is raised or lowered in various disease states. Therefore, the development of tools to control chaperone activity may provide avenues for therapeutic intervention, as well as enable a molecular understanding of chaperone function. The major human lens alpha-crystallins, alphaA- (HAA) and alphaB- (HAB), share 57% sequence identity and show similar activity towards some clients, but differing activities towards others. Notably, both crystallins contain the "alpha-crystallin domain" (ACD, the primary client binding site), like all other members of the sHSP family. Here we show that RNA aptamers selected for HAA, in vitro, exhibit specific affinity to HAA but do not bind HAB. Significantly, these aptamers also exclude the ACD. This study thus demonstrates that RNA aptamers against sHSPs can be designed that show high affinity and specificity - yet exclude the primary client binding region - thereby facilitating the development of RNA aptamer-based therapeutic intervention strategies. PMID- 28720499 TI - Coronary artery disease associated gene Phactr1 modulates severity of vascular calcification in vitro. AB - Calcification of vessels is strongly associated with atherosclerosis and leads to coronary artery disease (CAD) and myocardial infarction (MI). Genome-wide association studies (GWAS) revealed several genes that are associated with and contribute to CAD/MI as well as coronary artery calcification (CAC); however, the underlying mechanisms are unknown. PHACTR1, which encodes phosphatase and actin regulator 1, is among these risk genes. The aim of this study was to functionally test whether Phactr1 regulates calcification in vitro using murine embryonic stem cell (mESC)-derived smooth muscle cells (SMCs). Phactr1 was stably up- or down regulated in mESCs. These mESCs were differentiated into SMCs, and calcification was enhanced using osteogenic medium. Calcium phosphate deposits were detected and quantified. RT-PCR analysis demonstrated that gene expression of Phactr1 correlated with increased calcification in mESC-derived SMCs as well as primary human aortic SMCs. Down-regulation of Phactr1 decreased calcification. Decreased expression of the osteogenic marker osteopontin confirmed this finding at the molecular level. By contrast, overexpression of Phactr1 in calcifying mESC derived SMCs enhanced mineralization. Taken together, we demonstrated that PHACTR1 gene expression increases with the progression of calcification and that regulation of PHACTR1 in SMCs modulates the severity of vascular calcification. PMID- 28720500 TI - Essential slow degrees of freedom in protein-surface simulations: A metadynamics investigation. AB - Many proteins exhibit strong binding affinities to surfaces, with binding energies much greater than thermal fluctuations. When modelling these protein surface systems with classical molecular dynamics (MD) simulations, the large forces that exist at the protein/surface interface generally confine the system to a single free energy minimum. Exploring the full conformational space of the protein, especially finding other stable structures, becomes prohibitively expensive. Coupling MD simulations with metadynamics (enhanced sampling) has fast become a common method for sampling the adsorption of such proteins. In this paper, we compare three different flavors of metadynamics, specifically well tempered, parallel-bias, and parallel-tempering in the well-tempered ensemble, to exhaustively sample the conformational surface-binding landscape of model peptide GGKGG. We investigate the effect of mobile ions and ion charge, as well as the choice of collective variable (CV), on the binding free energy of the peptide. We make the case for explicitly biasing ions to sample the true binding free energy of biomolecules when the ion concentration is high and the binding free energies of the solute and ions are similar. We also make the case for choosing CVs that apply bias to all atoms of the solute to speed up calculations and obtain the maximum possible amount of information about the system. PMID- 28720501 TI - Numb positively regulates autophagic flux via regulating lysosomal function. AB - Autophagy is a lysosome-dependent catabolic process involving in the degradation and recycling of unnecessary or damaged proteins and organelles. Emerging evidence indicates that autophagy dysfunction is closely related to various human diseases including cancer, aging, myopathies and neurodegenerative disorders. Here, using genetic knockdown, we uncover the role of Numb, an endocytic adaptor protein, in regulating the late steps of autophagy. We found that Numb depletion led to the accumulation of autophagic vacuole, as verified by RFP-LC3 staining combined with transmission electron microscopy. Further investigation indicated that Numb depletion impaired autophagic degradation through inhibiting the activities of lysosomal enzymes (Cathepsin D, beta-glucuronidase and beta glucosidase). Moreover, Numb depletion induced elevation of lysosomal pH values and decrease of glycosylated lysosome-associated membrane proteins. We further observed that Rab7 activity was inhibited in Numb-depleted cells. Together, our findings revealed a novel function of Numb and its likely mechanism in regulation of autophagy events. PMID- 28720502 TI - Design, synthesis and in vitro anti-mycobacterial evaluation of gatifloxacin-1H 1,2,3-triazole-isatin hybrids. AB - A set of novel gatifloxacin-1H-1,2,3-triazole-isatin hybrids 6a-l was designed, synthesized and evaluated for their in vitro anti-mycobacterial activities against M. tuberculosis (MTB) H37Rv and MDR-TB as well as cytotoxicity. The results showed that all the targets (MIC: 0.025-3.12MUg/mL) exhibited excellent inhibitory activity against MTB H37Rv and MDR-TB, but were much more toxic (CC50: 7.8-62.5MUg/mL) than the parent gatifloxacin (GTFX) (CC50: 125MUg/mL). Among them, 61 (MIC: 0.025MUg/mL) was 2-32 times more potent in vitro than the references INH (MIC: 0.05MUg/mL), GTFX (MIC: 0.78MUg/mL) and RIF (MIC: 0.39MUg/mL) against MTB H37Rv. The most active conjugate 6k (MIC: 0.06MUg/mL) was 16->2048 times more potent than the three references (MIC: 1.0->128MUg/mL) against MDR-TB. Both of the two hybrids warrant further investigations. PMID- 28720503 TI - Discovery of 3-morpholino-imidazole[1,5-a]pyrazine BTK inhibitors for rheumatoid arthritis. AB - 8-Amino-imidazo[1,5-a]pyrazine-based Bruton's tyrosine kinase (BTK) inhibitors, such as 6, exhibited potent inhibition of BTK but required improvements in both kinase and hERG selectivity (Liu et al., 2016; Gao et al., 2017). In an effort to maintain the inhibitory activity of these analogs and improve their selectivity profiles, we carried out SAR exploration of groups at the 3-position of pyrazine compound 6. This effort led to the discovery of the morpholine group as an optimized pharmacophore. Compounds 13, 23 and 38 displayed excellent BTK potencies, kinase and hERG selectivities, and pharmacokinetic profiles. PMID- 28720504 TI - Synthesis of novel hybrids of pyrazole and coumarin as dual inhibitors of COX-2 and 5-LOX. AB - In our previous study, we designed a series of pyrazole derivatives as novel COX 2 inhibitors. In order to obtain novel dual inhibitors of COX-2 and 5-LOX, herein we designed and synthesized 20 compounds by hybridizing pyrazole with substituted coumarin who was reported to exhibit 5-LOX inhibition to select potent compounds using adequate biological trials sequentially including selective inhibition of COX-2 and 5-LOX, anti-proliferation in vitro, cells apoptosis and cell cycle. Among them, the most potent compound 11g (IC50=0.23+/-0.16MUM for COX-2, IC50=0.87+/-0.07MUM for 5-LOX, IC50=4.48+/-0.57MUM against A549) showed preliminary superiority compared with the positive controls Celecoxib (IC50=0.41+/-0.28MUM for COX-2, IC50=7.68+/-0.55MUM against A549) and Zileuton (IC50=1.35+/-0.24MUM for 5-LOX). Further investigation confirmed that 11g could induce human non-small cell lung cancer A549 cells apoptosis and arrest the cell cycle at G2 phase in a dose-dependent manner. Our study might contribute to COX 2, 5-LOX dual inhibitors thus exploit promising novel cancer prevention agents. PMID- 28720505 TI - Chemically generated IgG2 bispecific antibodies through disulfide bridging. AB - Bispecific antibodies (BsAbs) are designed to engage two antigens simultaneously, thus, effectively expanding the ability of antibody-based therapeutics to target multiple pathways within the same cell, engage two separate soluble antigens, bind the same antigen with distinct paratopes, or crosslink two different cell types. Many recombinant BsAb formats have emerged, however, expression and purification of such constructs can often be challenging. To this end, we have developed a chemical strategy for generating BsAbs using native IgG2 architecture. Full-length antibodies can be conjugated via disulfide bridging with linkers bearing orthogonal groups to produce BsAbs. We report that an alphaHER2/EGFR BsAb was successfully generated by this approach and retained the ability to bind both antigens with no significant loss of potency. PMID- 28720506 TI - Arecoline activates latent transforming growth factor beta1 via mitochondrial reactive oxygen species in buccal fibroblasts: Suppression by epigallocatechin-3 gallate. AB - BACKGROUND/PURPOSE: Oral submucous fibrosis (OSF) is a premalignant condition caused by the chewing of areca nut (AN). Transforming growth factor beta (TGFbeta) plays a central role in the pathogenesis of OSF. Connective tissue growth factor (CTGF or CCN2) and early growth response-1 (Egr-1) are important mediators in the fibrotic response to TGFbeta in several fibrotic disorders including OSF. Arecoline, a major AN alkaloid, induced the synthesis of CCN2 and Egr-1 in human buccal mucosal fibroblast (BMFs). The aims of this study were to investigate whether arecoline-induced CCN2 and Egr-1 syntheses are mediated through TGFbeta1 signaling and to inspect the detailed mechanisms involved. METHODS: Western blot and TGFbeta1 Emax(r) ImmunoAssay were used to measure the effect of arecoline on the TGFbeta signaling pathways. 2',7' dichlorodihydrofluorescein diacetate and MitoSOXTM Red were used to measure the effect of arecoline on the cellular and mitochondrial reactive oxygen species (ROS). RESULTS: Arecoline induced latent TGFbeta1 activation, Smad2 phosphorylation, and mitochondrial and total cellular ROS in BMFs. TGFbeta neutralizing antibody completely inhibited the arecoline-induced synthesis of CCN2 and Egr-1. Mito-TEMPO, a mitochondria-targeted antioxidant, completely suppressed arecoline-induced latent TGFbeta1 activation and mitochondrial and total cellular ROS. Epigallocatechin-3-gallate (EGCG) dose-dependently inhibited arecoline-induced TGFbeta1 activation and mitochondrial ROS in BMFs. CONCLUSION: Our results indicated that arecoline-induced mitochondrial ROS plays pivotal roles in the activation of latent TGFbeta1 leading to the initiation of TGFbeta1 signaling and subsequent increase in the synthesis of CCN2 and Egr-1. EGCG can be a useful agent in the chemoprevention and treatment of OSF. PMID- 28720508 TI - To swim or not to swim: A population-level model of Xenopus tadpole decision making and locomotor behaviour. AB - We present a detailed computational model of interacting neuronal populations that mimic the hatchling Xenopus tadpole nervous system. The model includes four sensory pathways, integrators of sensory information, and a central pattern generator (CPG) network. Sensory pathways of different modalities receive inputs from an "environment"; these inputs are then processed and integrated to select the most appropriate locomotor action. The CPG populations execute the selected action, generating output in motor neuron populations. Thus, the model describes a detailed and biologically plausible chain of information processing from external signals to sensors, sensory pathways, integration and decision-making, action selection and execution and finally, generation of appropriate motor activity and behaviour. We show how the model produces appropriate behaviours in response to a selected scenario, which consists of a sequence of "environmental" signals. These behaviours might be relatively complex due to noisy sensory pathways and the possibility of spontaneous actions. PMID- 28720507 TI - Formation and degradation of nitrogen mustard-induced MGMT-DNA crosslinking in 16HBE cells. AB - N-methyl-2,2-di(chloroethyl)amine (HN2) is a kind of bifunctional alkyltating agent, which can react with nucleophilic groups in DNA and/or protein to form HN2 bridged crosslinking of target molecules, such as DNA-protein crosslinkings (DPC). O6-methylguanine-DNA methyltransferase (MGMT) is a DNA damage repair enzyme which solely repairs alkyl adduct on DNA directly. However, MGMT was detected to act as a protein cross-linked with DNA via alkylation in presence of HN2, and unexpectedly turned into a DNA damage enhancer in the form of MGMT-DNA cross-link (mDPC). Present study aimed to explore the possible ways to lessen the incorporation of MGMT into DPC as well as to save it for DNA repair. To find out the influencing factors of mDPC formation and cleavage, human bronchial epithelial cell line 16HBE was exposed to HN2 and the factors related with MGMT expression and degradation were investigated. When c-Myc, a negative transcriptional factor of MGMT was inhibited by 10058-F4, MGMT expression and mDPC formation were increased, and more gamma-H2AX was also detected. Sustained treatment with O6BG, a specific exogenous substrate and depleter of MGMT, could reduce the level of MGMT and mDPC formation. In contrast, a transient 1h pre treatment of O6GB before HN2 exposure would cause a high MGMT and mDPC level. MGMT was increasingly ubiquitinated after HN2 exposure in a time-dependent manner. At the same time, MGMT was also SUMOylated with a downward time-dependent manner compared to its ubiquitination. Inhibitors of E1, E2 or E3 ligases of ubiqutination all led to the accumulation of mDPC and total-DPC (tDPC) with the difference as that mDPC was sensitive to E1 inhibitor while tDPC more sensitive to E2 and E3 inhibitor. Our results demonstrated the control of mDPC level could be realized through transcription inhibitory effect of c-Myc, O6GB application, and the acceleration of mDPC ubiquitination and subsequent degradation. PMID- 28720509 TI - The neuropeptide galanin promotes an anti-thrombotic phenotype on endocardial endothelial cells from heart failure patients. AB - Thromboembolic complications are a significant cause of mortality and re hospitalization in heart failure (HF) patients. One source of thrombi is the ventricular endocardial surface that becomes increasingly pro-thrombotic as HF progresses. Anticoagulation comes with bleeding risks so identifying therapeutic agents for improving cardiac endothelial health are of critical clinical importance. Endocardial endothelial cells are closely apposed to cardiac sympathetic nerves. In HF, cardiac sympathetic nerves are dysregulated and promote disease progression. Whether endocardial endothelial health and function is impacted by sympathetic dysregulation in HF is unknown. Also unexplored is the impact of neuropeptides, such as galanin and neuropeptide Y (NPY), co-released from sympathetic nerve terminals, on endothelial health. In this study we examined the effect of sympathetic nerve-released neurotransmitters and neuropeptides on the procoagulant phenotype of cultured human endocardial endothelial cells from HF patients. As a functional readout of procoagulant state we examined thrombin-mediated von Willebrand factor (vWF) extrusion and multimer expression. We demonstrate that vWF extrusion and multimer expression is promoted by thrombin, that isoproterenol (a beta-adrenergic receptor agonist) augments this effect, whereas co-treatment with the beta-blockers propranolol and carvedilol blocks this effect. We also show that vWF extrusion and multimer expression is attenuated by treatment with the neuropeptide galanin, but not with NPY. Our results are consistent with a protective role of beta-blockers and galanin on endocardial endothelial health in heart failure. Improving endothelial health through galanin therapy is a future clinical application of this study. PMID- 28720510 TI - AHRQ series on complex intervention systematic reviews-paper 3: adapting frameworks to develop protocols. AB - BACKGROUND: Once a proposed topic has been identified for a systematic review and has undergone a question formulation stage, a protocol must be developed that specifies the scope and research questions in detail and outlines the methodology for conducting the systematic review. RATIONALE: Framework modifications are often needed to accommodate increased complexity. We describe and give examples of adaptations and alternatives to traditional analytic frameworks. DISCUSSION: This article identifies and describes elements of frameworks and how they can be adapted to inform the protocol and conduct of systematic reviews of complex interventions. Modifications may be needed to adapt the population, intervention, comparators, and outcomes normally used in protocol development to successfully describe complex interventions; in some instances, alternative frameworks may be better suited. Possible approaches to analytic frameworks for complex interventions that illustrate causal and associative linkages are outlined, including time elements, which systematic reviews of complex interventions may need to address. The need for and specifics of the accommodations vary with details of a specific systematic review. This in turn helps determine whether traditional frameworks are sufficient, can be refined, or if alternate frameworks must be adopted. PMID- 28720511 TI - AHRQ series on complex intervention systematic reviews-paper 1: an introduction to a series of articles that provide guidance and tools for reviews of complex interventions. PMID- 28720512 TI - AHRQ series on complex intervention systematic reviews-paper 5: advanced analytic methods. AB - BACKGROUND AND OBJECTIVE: Advanced analytic methods for synthesizing evidence about complex interventions continue to be developed. In this paper, we emphasize that the specific research question posed in the review should be used as a guide for choosing the appropriate analytic method. METHODS: We present advanced analytic approaches that address four common questions that guide reviews of complex interventions: (1) How effective is the intervention? (2) For whom does the intervention work and in what contexts? (3) What happens when the intervention is implemented? and (4) What decisions are possible given the results of the synthesis? CONCLUSION: The analytic approaches presented in this paper are particularly useful when each primary study differs in components, mechanisms of action, context, implementation, timing, and many other domains. PMID- 28720513 TI - AHRQ series on complex intervention systematic reviews-paper 7: PRISMA-CI elaboration and explanation. AB - BACKGROUND: Complex interventions are widely used in health care, public health, education, criminology, social work, business, and welfare. They have increasingly become the subject of systematic reviews and are challenging to effectively report. The Complex Interventions Methods Workgroup developed an extension to the Preferred Reporting Items for Systematic Reviews and Meta Analyses for Complex Interventions (PRISMA-CI). RATIONALE: Following the EQUATOR Network guidance for Preferred Reporting Items for Systematic Reviews and Meta Analysis extensions, this Explanation and Elaboration (EE) document accompanies the PRISMA-CI checklist to promote consistency in reporting of systematic reviews of complex interventions. DISCUSSIONS: The EE document explains the meaning and rationale for each unique PRISMA-CI checklist item and provides examples to assist systematic review authors in operationalizing PRISMA-CI guidance. The Complex Interventions Workgroup developed PRISMA-CI as an important start toward increased consistency in reporting of systematic reviews of complex interventions. Because the field is rapidly expanding, the Complex Interventions Methods Workgroup plans to re-evaluate periodically for the need to add increasing specificity and examples as the field matures. PMID- 28720514 TI - AHRQ series on complex intervention systematic reviews-paper 2: defining complexity, formulating scope, and questions. AB - BACKGROUND: The early stages of a systematic review set the scope and expectations. This can be particularly challenging for complex interventions given their multidimensional and dynamic nature. RATIONALE: This paper builds on concepts introduced in paper 1 of this series. It describes the methodological, practical, and philosophical challenges and potential approaches for formulating the questions and scope of systematic reviews of complex interventions. Furthermore, it discusses the use of theory to help organize reviews of complex interventions. DISCUSSION: Many interventions in medicine, public health, education, social services, behavioral health, and community programs are complex, and they may not fit neatly within the established paradigm for reviews of straightforward interventions. This paper provides conceptual and operational guidance for these early stages of scope formulation to assist authors of systematic reviews of complex interventions. PMID- 28720515 TI - AHRQ series on complex intervention systematic reviews-paper 4: selecting analytic approaches. AB - BACKGROUND: Systematic reviews of complex interventions can vary widely in purpose, data availability and heterogeneity, and stakeholder expectations. RATIONALE: This article addresses the uncertainty that systematic reviewers face in selecting methods for reviews of complex interventions. Specifically, it lays out parameters for systematic reviewers to consider when selecting analytic approaches that best answer the questions at hand and suggests analytic techniques that may be appropriate in different circumstances. DISCUSSION: Systematic reviews of complex interventions comprising multiple questions may use multiple analytic approaches. Parameters to consider when choosing analytic methods for complex interventions include nature and timing of the decision (clinical practice guideline, policy, or other); purpose of the review; extent of existing evidence; logistic factors such as the timeline, process, and resources for deciding the scope of the review; and value of information to be obtained from choosing specific systematic review methods. Reviewers may elect to revise their analytic approach based on new or changing considerations during the course of the review but should guard against bias through transparency of reporting. PMID- 28720516 TI - AHRQ series on complex intervention systematic reviews-paper 6: PRISMA-CI extension statement and checklist. AB - BACKGROUND: Complex interventions are widely used in health systems, public health, education, and communities and are increasingly the subject of systematic reviews. Oversimplification and inconsistencies in reporting about complex interventions can limit the usability of review findings. RATIONALE: Although guidance exists to ensure that reports of individual studies and systematic reviews adhere to accepted scientific standards, their design-specific focus leaves important reporting gaps relative to complex interventions in health care. This paper provides a stand-alone extension to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting tool for complex interventions-PRISMA-CI-to help authors, publishers, and readers understand and apply to systematic reviews of complex interventions. DISCUSSION: PRISMA-CI development followed the Enhancing the QUAlity and Transparency Of health Research Network guidance for extensions and focused on adding or modifying only essential items that are truly unique to complex interventions and are not covered by broader interpretation of current PRISMA guidance. PRISMA-CI provides an important structure and guidance for systematic reviews and meta-analyses for the highly prevalent and dynamic field of complex interventions. PMID- 28720517 TI - Transient receptor potential TRPM3 channels: Pharmacology, signaling, and biological functions. AB - The transient receptor potential melastatin-3 (TRPM3) channel belongs to the family of transient receptor potential (TRP) cation channels that are expressed in a variety of tissues and cell types, including dorsal root ganglia, cardiomyocytes and pancreatic beta-cells. Although its natural ligands are currently unknown, TRPM3 channels can be activated by the neurosteroid pregnenolone sulfate, the synthetic ligand CIM0216, and by noxious heat. TRPM3 channels are regulated by phosphoinositides, and perhaps by calmodulin. Stimulation of TRPM3 induces an intracellular signaling cascade involving a rise in intracellular Ca2+, activation of the protein kinases Raf, ERK and JNK, and the activation of the stimulus-responsive transcription factors AP-1, CREB, Egr 1, and Elk-1. Functionally, stimulation of TRPM3 channels is connected with heat sensation by somatosensory neurons, insulin secretion by pancreatic beta-cells, regulation of neurotransmitter release, iris constriction, and tumor promotion. With the development of highly specific activators and inhibitors of TRPM3 channels, we expect that additional tissue-specific functions of TRPM3 channels will be discovered, establishing TRPM3 channels as a new therapeutic target. PMID- 28720518 TI - Nanoparticle-based hyperthermia, a local treatment modulating the tumor extracellular matrix. AB - The structural complexity and physical properties of the tumor microenvironment negatively affect the penetration and efficiency of conventional anticancer drugs. While previously underestimated, the tumor microenvironment now becomes a potential target for cancer treatment. This microenvironment can be modulated either systemically by pharmacological means, or locally, through physical effects mediated by certain nanoparticles. Some of them, such as magnetic, plasmonic or carbon-based nanoparticles, can generate heat on demand in a spatially and temporally controlled manner. In addition, the nanoparticles can be either activated by light or magnetic stimuli. The impact of the resulting local heating can be observed on the ultrastructural level, as it strongly affects the organization of collagen fibers, and on the macroscopic level, since the thermal damages alter the mechanical properties of the tumor. Nanoparticle-based hyperthermia thus improves the effect of conventional anticancer drugs, as it allows their better penetration through the altered extracellular matrix. Here we suggest the use of nanoparticle-generated hyperthermia, obtained after magnetic or light activation, as an adjuvant treatment to prime the tumor microenvironment and improve the efficacy of chemotherapy. PMID- 28720519 TI - Taltirelin alleviates fatigue-like behavior in mouse models of cancer-related fatigue. AB - Fatigue affects most cancer patients and has numerous potential causes, including cancer itself and cancer treatment. Cancer-related fatigue (CRF) is not relieved by rest, can decrease quality of life, and has no FDA-approved therapy. Thyrotropin-releasing hormone (TRH) has been proposed as a potential novel treatment for CRF, but its efficacy against CRF remains largely untested. Thus, we tested the TRH analog, taltirelin (TAL), in mouse models of CRF. To model fatigue, we used a mouse model of chemotherapy, a mouse model of radiation therapy, and mice bearing colon 26 carcinoma tumors. We used the treadmill fatigue test to assess fatigue-like behavior after treatment with TAL. Additionally, we used wild-type and TRH receptor knockout mice to determine which TRH receptor was necessary for the actions of TAL. Tumor-bearing mice displayed muscle wasting and all models caused fatigue-like behavior, with mice running a shorter distance in the treadmill fatigue test than controls. TAL reversed fatigue-like behavior in all three models and the mouse TRH1 receptor was necessary for the effects of TAL. These data suggest that TAL may be useful in alleviating fatigue in all cancer patients and provide further support for evaluating TAL as a potential therapy for CRF in humans. PMID- 28720521 TI - Increased entrances to side compartments indicate incubation of craving in morphine-induced rat and tree shrew CPP models. AB - In humans, cues associated with the rewarding effect of drugs of abuse induce drug craving and activate drug-associated memories after prolonged abstinence. In animal studies with the self-administration (SA) paradigm, responses to drug associated cues increase within time after extinction, a phenomenon described as incubation of craving. Conditioned place preference (CPP) is widely used to measure the rewarding effect of drugs and the reward memory thereof. However, little is known whether responses to drug associated cues progressively increase after abstinence from the drugs in the CPP paradigm. To test whether the drug associated cues could increase specific responses over the abstinence period in the CPP paradigm, we employed the high dose morphine-induced CPP paradigms in rats and tree shrews in the present study. We examined the CPP scores and the entrances to side chambers of the CPP apparatus to check whether they would progressively increase in the CPP paradigms. Twenty-one male adult Sprague-Dawley rats and eight adult male tree shrews were used to establish morphine-induced CPP and another ten rats treated with saline were controls for the rat experiments. After morphine conditioning, rats and tree shrews showed significant higher CPP scores at the first or second post tests than at baseline but then the CPP scores in the abstinence period decreased gradually. During the abstinence period, animals with morphine-conditioning experiences entered progressively more times to both side compartments, whereas the number of entrances to side chambers of the saline group in rats had no such significant differences. These findings suggest that progressively increased entrances to the side chambers in the extended abstinence period reflect the incubation of craving in high dose morphine-induced CPP paradigms. Also, our data imply that reward memory and drug craving can be distinguished in the CPP paradigm. PMID- 28720520 TI - Neural systems mediating the inhibition of cocaine-seeking behaviors. AB - Over the past decades, research has targeted the neurobiology regulating cocaine seeking behaviors, largely in the hopes of identifying potential targets for the treatment of cocaine addiction. Although much of this work has focused on those systems driving cocaine seeking, recently, studies examining the inhibition of cocaine-related behaviors have made significant progress in uncovering the neural systems that attenuate cocaine seeking. Such systems include the infralimbic cortex, nucleus accumbens shell, and hypothalamus. Research in this field has focused largely on the infralimbic cortex, as activity in this region appears to attenuate cocaine seeking during reinstatement and contribute to extinction learning. However, an overarching theory of function for this region that includes its role in other types of reward seeking and learning remains to be determined. Furthermore, the precise relationship between other regions involved in attenuating cocaine-seeking behavior and the infralimbic cortex remains unclear. Recent advances in the use of viral vectors combined with optogenetics, chemogenetics, and other approaches have greatly affected our capacity to investigate those systems inhibiting behavior dependent on cocaine-associated memories. This review will present current understanding regarding the neurobiology underlying the inhibition of such behaviors, especially focusing on the extinction of such memories, and explore how viral-vector targeting of specific brain circuits has begun to alter, and will continue to enrich, our knowledge regarding this issue. PMID- 28720522 TI - Patients with non-ambulatory cerebral palsy have higher sclerostin levels and lower bone mineral density than patients with ambulatory cerebral palsy. AB - Bone loss is a serious clinical issue in patients with cerebral palsy (CP). Sclerostin has garnered interest as a key mechanosensor in osteocytes, leading to considerations of the therapeutic utilization of anti-sclerostin medications. This study was undertaken to determine associations among mechanical unloading, sclerostin levels, and bone imbalance in patients with CP. A total of 28 patients with CP participated in this cross-sectional study. The following measurements were taken: anthropometrics, clinical diagnosis of CP subtype and ambulatory status, bone mineral density (BMD) z-scores at the lumbar spine and hip, and blood biochemical markers, including sclerostin, parathyroid hormone (PTH), osteocalcin, C-terminal telopeptide, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, creatinine, calcium, and phosphorus. In analysis according to CP subtype, patients with spastic CP showed significantly lower BMD z-scores at the lumbar spine and femur neck regions than patients with dyskinetic CP. In analysis according to ambulatory status, patients with non-ambulatory CP showed significantly lower BMD z-scores at all lumbar spine and femoral sites, lower PTH and creatinine levels, and higher plasma sclerostin levels than patients with ambulatory CP. In regression analysis, ambulatory status was a significant determinant of plasma sclerostin levels. This study is the first to report on sclerostin levels and BMD in patients with CP, based on the hypothesis that patients who lack sufficient weight-bearing activities would show increased sclerostin levels and decreased BMD scores, compared with patients who sustain relatively sufficient physical activity. Therefore, this report may provide clinical insights for clinicians considering ambulatory status, sclerostin levels, and bone loss in patients with CP. PMID- 28720523 TI - Sensory attenuation of self-initiated sounds maps onto habitual associations between motor action and sound. AB - Sensory attenuation refers to reduced brain responses to self-initiated sensations relative to those produced by the external world, a distinction that is vital for dynamic motor control and our sense of agency. Typically, willed vocalizations elicit larger N1 reduction of the auditory evoked potential compared to indirectly evoked sounds, such as tones generated by button-presses, which is attributed to the prediction and cancellation of incoming signals enabled by speech motor commands. However, physical confounds exist, including different stimuli and the increased motor artefact associated with mouth vs. finger movements. The present study investigated N1 attenuation to physically identical sounds evoked by hand, eye, and mouth-initiated movements. Twenty-eight healthy participants had their electroencephalogram (EEG) recorded as they blew into a microphone, pressed a button, or moved their eye to generate a pure tone. We found that N1 and P2 response was most reduced in the blow initiation condition, and that both blow and button-press but not saccade initiated tones elicited significantly reduced N1 and P2 amplitude compared to external initiation. This indicates that the eliciting motor action markedly influences ERP response to auditory stimuli. Given that saccades are never associated with sounds, finger movements sometimes are, and mouth movements often are, the pattern of results suggests that N1 attenuation to self-initiated sounds may depend on existing associations between the initiating action and resultant sensation. PMID- 28720524 TI - This racket is not mine: The influence of the tool-use on peripersonal space. AB - The aim of the present study was to test whether the peripersonal space (PPS), defined as the portion of the space immediately surrounding the body, is modulated by the long-term motor experience with a specific tool in a sportsmen population. To this end, we evaluated, by means of a multisensory integration paradigm, how tennis players and novices to the sport of tennis perceived the PPS while holding a tennis racket. Going deeply, in the case of the athletes, we tested the effect of their personal racket, i.e., the one they regularly use during their sport activities, compared to a common one. When handling one of these objects or nothing, participants were requested to verbally respond to a tactile stimulus administered at the right wrist while hearing a task-irrelevant sound emitted by a speaker positioned either near to the hand (Near) or far from it (Far). Reaction time to a tactile stimulus associated with the Far sound were higher than those associated with the Near sound when tennis players and novices held the common racket, whereas this difference disappeared when the athletes handled the personal tennis racket. These results suggest that the tool daily used during sport activity is stably embodied in the peripersonal space of tennis players. PMID- 28720525 TI - Motor resonance during action observation is gaze-contingent: A TMS study. AB - When we observe others performing an action, visual input to our mirror neuron system is reflected in the facilitation of primary motor cortex (M1), a phenomenon known as 'motor resonance'. However, it is unclear whether this motor resonance is contingent upon our point-of-gaze. In order to address this issue, we collected gaze data from participants as they viewed an intransitive action - thumb abduction/adduction - under four conditions: with natural gaze behaviour (free viewing) and with their gaze fixated on each of three predetermined loci at various distances from the prime mover. In a control condition, participants viewed little finger movements, also with a fixated gaze. Transcranial magnetic stimulation (TMS) was delivered to M1 and motor evoked potentials (MEPs) were recorded from the right abductor pollicis brevis (APB) and right abductor digiti minimi (ADM). Results showed that, relative to a free viewing condition, a fixated point-of-gaze which maximized transfoveal motion facilitated MEPs in APB. Moreover, during free viewing, saccade amplitudes and APB MEP amplitudes were negatively correlated. These findings indicate that motor resonance is contingent on the observer's gaze behaviour and that, for simple movements, action observation effects may be enhanced by employing a fixed point-of-gaze. PMID- 28720526 TI - Effects of musical expertise on oscillatory brain activity in response to emotional sounds. AB - Emotions can be conveyed through a variety of channels in the auditory domain, be it via music, non-linguistic vocalizations, or speech prosody. Moreover, recent studies suggest that expertise in one sound category can impact the processing of emotional sounds in other sound categories as they found that musicians process more efficiently emotional musical and vocal sounds than non-musicians. However, the neural correlates of these modulations, especially their time course, are not very well understood. Consequently, we focused here on how the neural processing of emotional information varies as a function of sound category and expertise of participants. Electroencephalogram (EEG) of 20 non-musicians and 17 musicians was recorded while they listened to vocal (speech and vocalizations) and musical sounds. The amplitude of EEG-oscillatory activity in the theta, alpha, beta, and gamma band was quantified and Independent Component Analysis (ICA) was used to identify underlying components of brain activity in each band. Category differences were found in theta and alpha bands, due to larger responses to music and speech than to vocalizations, and in posterior beta, mainly due to differential processing of speech. In addition, we observed greater activation in frontal theta and alpha for musicians than for non-musicians, as well as an interaction between expertise and emotional content of sounds in frontal alpha. The results reflect musicians' expertise in recognition of emotion-conveying music, which seems to also generalize to emotional expressions conveyed by the human voice, in line with previous accounts of effects of expertise on musical and vocal sounds processing. PMID- 28720527 TI - Usefulness of Percutaneous Endoscopic Lumbar Foraminoplasty for Lumbar Disc Herniation. AB - OBJECTIVE: Endoscopic foraminoplasty facilitates engagement of the working cannula via the intervertebral foramen, allowing cannula access near a herniated disc (HD) for successful application of percutaneous endoscopic lumbar discectomy (PELD). The purpose of this study was to evaluate the efficacy of foraminoplasty for HD and propose applicable situations for foraminoplasty in PELD. METHODS: A retrospective review of consecutive patients who underwent PELD was performed. Patients were divided into a foraminoplasty group (FG) and nonforaminoplasty group (NFG). Group differences in disc location and radiologic parameters, such as disc height (DH), foraminal width, lamina angle, facet angle, superior articular process thickness, and iliac height, were evaluated. Clinical outcomes were assessed using a visual analog scale for back and leg pain. RESULTS: There were 136 patients (36 FG and 100 NFG) were. The FG had a significantly smaller DH and higher prevalence of high-grade down migration, downward sequestration, and recurrent HD compared with the NFG. For HDs at the L5-S1 level, the FG had a significantly greater iliac crest height and smaller DH and foraminal width compared with the NFG. For central HDs, the FG had a wider lamina angle and smaller DH compared with the NFG. Improvements in back and leg pain were similar in the 2 groups. CONCLUSIONS: Percutaneous endoscopic lumbar foraminoplasty may be effective for small DH, migration, sequestration, recurrent HD, HD in L5-S1 with a high iliac crest, and central HD with a wide lamina angle. PMID- 28720528 TI - Postoperative Dilatation of Superficial Temporal Artery Associated with Transient Neurologic Symptoms After Direct Bypass Surgery for Moyamoya Angiopathy. AB - OBJECTIVE: In moyamoya angiopathy, transient neurologic symptoms (TNS) are occasionally observed after superficial temporal artery (STA)-middle cerebral artery direct bypass surgery. The purpose of this study was to investigate the correlation between TNS and postoperative magnetic resonance imaging as well as perform a perfusion study. METHODS: We reviewed 52 hemispheres in 33 consecutive patients with moyamoya angiopathy. TNS were defined as reversible neurologic dysfunction without any apparent intracranial infarction or hemorrhage. All patients underwent magnetic resonance imaging and single-photon emission computed tomography before and within 5 days after surgery. Maximum diameter of STA on time-of-flight magnetic resonance angiography and the dilatation ratio of STA were calculated. The presence of signal changes on fluid-attenuated inversion recovery images and regional cerebral blood flow were also evaluated. RESULTS: TNS were observed in 13 of 52 (25%) cases 1-16 days after surgery. The mean preoperative STA dilatation, postoperative STA dilatation, and dilatation ratio of STA were 1.33 mm +/- 0.27, 1.67 mm +/- 0.30, and 29.31% +/- 28.13%. Postoperative intraparenchymal cortical hyperintensity lesions and high-intensity signals in the cortex sulci (ivy sign) were detected in 24 (46.2%) cases and 29 (55.8%) cases, respectively. Univariate analyses demonstrated no association between TNS and postoperative signal change on fluid-attenuated inversion recovery images as well as cerebral blood flow. Only >1.5-fold dilatation of STA was significantly correlated with TNS (P < 0.0001). CONCLUSIONS: STA dilatation was correlated with TNS after direct bypass surgery for moyamoya angiopathy. PMID- 28720529 TI - Population Characteristics and Progressive Disability in Neurofibromatosis Type 2. AB - OBJECTIVE: To characterize the clinical features of patients with neurofibromatosis type 2 (NF2) and determine prognostic risk factors for progressive disabilities. METHODS: In this retrospective cohort study of the Japanese national NF2 registry between 2009 and 2013, clinical data (demographic, history, oncologic, and neurologic) of 807 patients with a diagnosis of NF2 were analyzed. The overall severity of neurologic disability was assessed using a comprehensive 25-point scoring system encompassing a wide variety of neurologic deficits. In 587 patients in whom longitudinal disability data were available, multivariate logistic regression was performed to identify risk factors for significant progression of disability. RESULTS: The clinical characteristics of the Japanese NF2 population were heterogeneous. The median age of onset was 24 years (range, 1-80 years), the male:female ratio was 1:1.29, and the initial severity score was 4 (range, 0-22) out of 25 points. A family history of NF2 was present in 33% of the patients. Most frequent clinical features were bilateral cranial nerve VIII nerve sheath tumor (NST) in 87%, spinal NST in 80%, hearing loss in 65%, spinal dysfunction in 50%, intracranial meningioma in 49%, and facial paresis in 36%. The disability score progressed by >=5 points in 6.1% of patients over the study period. Based on multivariate logistic regression analyses, the significant independent risk factors of progression (P value) included age of onset <25 years (P = 0.015), positive family history (P = 0.007), positive treatment history (P = 0.026), hearing loss (P = 0.014), facial paresis (P = 0.015), blindness (P = 0.011), and hemiparesis (P = 0.025). CONCLUSIONS: The Japanese NF2 population has heterogeneous clinical features. Risk factors for progressive disability include younger age of onset, positive family history, positive treatment history, and specific neurologic deficits. PMID- 28720530 TI - Downregulation of protein phosphatase 2A by apolipoprotein E: Implications for Alzheimer's disease. AB - The apolipoprotein E epsilon4 allele is the single most important genetic risk factor associated with Alzheimer's disease (AD). Tau phosphorylation and hyperphosphorylation is an underlying feature of AD and is regulated by specific kinases and phosphatases. Among phosphatases, protein phosphatase 2A (PP2A) is the principal tau dephosphorylating enzyme in the brain. Several abnormalities of PP2A have been reported in AD, including among others decreased protein levels of PP2A, decreased mRNA and protein levels of the catalytic subunit PP2AC and variable regulatory B subunits and reduced methylation of the catalytic subunit, all of which results in disruption of the PP2A phosphatase activity. In earlier studies we described a novel mechanism for ApoE as a transcription factor that binds regions of double-stranded DNA with high affinity, including the promoter regions of ~3000 different genes. The list of genes also included PPP2R5E (B56epsilon), a regulatory B' subunit of protein phosphatase 2A. Using a combination of A172 human glioblastoma cells, ApoE3/4 and ApoE-/- NSC and human postmortem tissue, we now demonstrate that ApoE not only binds to the PPP2R5E promoter but also triggers a significant reduction in PP2A activity by two mechanisms: 1) ApoE transcriptionally represses PPP2R5E and reduces protein expression, and 2) ApoE triggers demethylation of the catalytic subunit (PP2AC) of PP2A, resulting in the disruption of the PPP2R5E-PP2AC complex. Our results indicated a significant down-regulation of PPP2R5E gene expression and reduction in PP2A activity by ApoE4 compared with ApoE3. This may also explain an elevated Tau phosphorylation in AD human brains that featured at least one ApoE4 allele. Thus, our present work links ApoE and PPP2R5E expression to a reduction in the PP2A catalytic activity that has implications for Alzheimer's disease. PMID- 28720532 TI - Lipoid proteinosis: A clinical and molecular study in Egyptian patients. AB - Lipoid proteinosis (LP) is an autosomal recessive disorder caused by the loss of function of ECM1 gene. Clinical features include varying degrees of skin thickening, hoarseness of voice and less frequently neuropsychiatric abnormalities. Twelve patients from ten unrelated families with a clinical diagnosis of lipoid proteinosis were enrolled in this study. Extraction of DNA samples of the 12 patients and their parents from peripheral blood by standard methods was performed. Polymerase chain reaction (PCR) amplification of the ECM1 gene was conducted using eight pairs of primers spanning over the 10 exons and splice junctions. Patients exhibited a variety of clinical manifestations with skin affection and hoarseness of voice being the consistent feature. We identified five novel homozygous insertion, small deletion, missense, and splice site mutations as well as two homozygous previously published splice site mutation c.70+1G>C in intron 1 and c.1305-2A>G in intron 8. The specific mutations were: c.10_11insC in exon 1, c.690_691delAG in exon 6, c.734G>A in exon 7, c.1286_1287delAA in exon 8 and c.1393-1G>T in intron 9. The novel mutations c.1393-1G>T and c.10_11insC occurred in three (30%) and two (20%) unrelated patients of the studied families, respectively. Further studies may designate an increased frequency of these mutations among Egyptian LP patients. Identification of pathogenic ECM1 mutations is important for accurate diagnosis and proper genetic counseling. PMID- 28720531 TI - Molecular cloning and characterization of the genes encoding the proteins of Zika virus. AB - Zika virus (ZIKV) encodes a precursor protein (also called polyprotein) of about 3424 amino acids that is processed by proteases to generate 10 mature proteins and a small peptide. In the present study, we characterized the chemical features, suborganelle distribution and potential function of each protein using Flag-tagged protein expression system. Western blot analysis revealed the molecular weight of the proteins and the polymerization of E, NS1, and NS3 proteins. In addition, we performed multi-labeled fluorescent immunocytochemistry and subcellular fractionation to determine the subcellular localization of these proteins in host cells. We found that 1) the capsid protein colocalizes with 3 different cellular organelles: nucleoli, Golgi apparatus, and lipid droplet; NS2b and NS4a are associated with the Golgi apparatus; 2) the capsid and NS1proteins distribute in both cytoplasm and nucleus, NS5 is a nuclear protein; 3) NS3 protein colocalizes with tubulin and affects Lamin A; 4) Envelope, PrM, and NS2a proteins co-localize with the endoplasmic reticulum; 5) NS1 is associated with autophagosomes and NS4b is related to early endosome; 6) NS5 forms punctate structures in the nucleus that associate with splicing compartments shown by SC35, leading to reduction of SC35 protein level and trafficking of SC35 from the nucleus to the cytoplasm. These data suggest that ZIKV generates 10 functional viral proteins that exhibit distinctive subcellular distribution in host cells. PMID- 28720533 TI - Phylogenetic relationships of diurnal, phytotelm-breeding Melanophryniscus (Anura: Bufonidae) based on mitogenomic data. AB - Melanophryniscus is a bufonid frog genus with a broad geographic distribution over southeastern South America. In recent years, several new species of Melanophryniscus have been discovered in southern Brazil showing a distinctive life-history strategy for the genus - breeding in phytotelmata - as well as a strong association with high-altitude regions. In this study, we use mitogenomic data to infer the phylogenetic relationships among diurnal, phytotelm-breeding Melanophryniscus and to determine the timing of their divergence. We obtained the mitochondrial genomes (not including the control region) for eight individuals of Melanophryniscus representing all three described species (M. alipioi, M. milanoi, and M. xanthostomus), as well as some recently-discovered and potentially new species. Gene order was conserved in all species and corresponded to the general order found in bufonids. Although the phylogenetic relationships among the studied species was poorly supported, dating confirmed that they diverged during the Pleistocene, suggesting that phytotelm breeding could have arisen during drier periods in the glacial/interglacial cycles due to a decrease in the availability of permanent streams or ephemeral/temporary streams or ponds in which Melanophryniscus species commonly breed. PMID- 28720535 TI - Effect of polymer type on the surface energy of acetaminophen solid dispersions prepared by melt method. AB - Many newly developed active pharmaceutical ingredients (APIs) have very low solubility in aqueous media. The preparation of solid dispersions (SDs) is one way of avoiding this problem. However, compound wettability and thus solubility are influenced by surface energy. In this study, we used inverse gas chromatography (IGC) to evaluate the surface energies of prepared SDs, and compared them with those obtained for physical mixtures (PMs). SDs containing different weight ratios of crystalline acetaminophen and one of three polymers (Kollidon(r) 12 PF, Kollidon(r) VA 64 or Soluplus(r)) were prepared by the melt quenching of corresponding PMs. In all cases, as the polymer content increased, the surface energy decreased significantly. For the SDs and PMs containing Soluplus(r), this decrease in surface energy showed the same non-linear trend. In the cases of Kollidon(r) 12 PF and Kollidon(r) VA 64, the trend was linear, with the SDs showing a steeper decrease in surface energy than the corresponding PMs. Typically, such decreases are ascribed to the dissolution of the crystalline structure of an API. Our results suggest that in the case of the Kollidons, the steeper decrease is caused by another mechanism, namely, strong API-Kollidon interaction leading to the less wettable surface of SDs. PMID- 28720534 TI - TGF-beta signaling regulates p-Akt levels via PP2A during diapause entry in the cotton bollworm, Helicoverpa armigera. AB - Akt, which is a key kinase in the insulin signaling pathway, plays important roles in glucose metabolism, cell proliferation, transcription and cell migration. Our previous studies indicated that low insulin levels and high p-Akt levels are present in diapause-destined individuals. Here, we show that PI3K, which is upstream of Akt, is low in diapause-destined pupal brains but high in p Akt levels, implying that p-Akt is modified by factors other than the insulin signaling pathway. Protein phosphatase 2A (PP2A), which is a key regulator in the TGF-beta signaling pathway, can directly bind to and dephosphorylate Akt. Low PP2A expression and activity in diapause-destined individuals suggest that a weak Akt dephosphorylation contributes to p-Akt accumulation. In addition, transforming growth factor-beta receptor I (TbetaRI), which is upstream of PP2A, increases the activity of PP2A and decreases the p-Akt levels. These results show that TGF-beta signaling decreases p-Akt levels by increasing the activity of PP2A. This is the first report showing that TGF-beta signaling negatively regulates the insulin pathway in insect development or diapause. PMID- 28720536 TI - A diffusing wave spectroscopy study of pharmaceutical emulsions for physical stability assessment. AB - Emulsions are broadly used in pharmaceutics either as intermediate products or as final dosage forms. Such disperse systems are only kinetically stabilized and therefore early detection of physical instability is highly desirable. This work employed diffusing wave spectroscopy (DWS) to study a series of model emulsions that were categorized, based on their composition, as either "simple" or "complex". DWS data were compared with results of droplet size imaging, apparent viscosity obtained by microfluidics, and near-infrared (NIR) analytical centrifugation. A mathematical model of the droplet mean square displacement (MSD) was modified by us regarding improved fitting of experimental data. Although the emulsions showed different types of instability like creaming and sedimentation, a good rank correlation was found between the DWS parameters and results from the comparative stability methods. Our findings indicate that DWS provides a highly attractive method for stability analysis of pharmaceutical emulsions because it requires only low sample volumes, is rapid and non-invasive. The proposed data modeling provides the means for a better understanding of emulsion microstructure that in turn will help designing quality into pharmaceutical dispersions. PMID- 28720537 TI - Inhaled powder formulation of naked siRNA using spray drying technology with l leucine as dispersion enhancer. AB - Pulmonary delivery of short interfering RNA (siRNA) has been widely studied in both animal and clinical studies to treat various respiratory diseases by gene silencing through RNA interference. Some of these studies showed that the administration of naked siRNA (without the use of any delivery vectors) could achieve satisfactory gene silencing effect, a unique feature to pulmonary delivery. Liquid aerosols were mostly used with very limited studies on the use of powder aerosols for siRNA. In this study, siRNA was co-spray dried with mannitol and l-leucine, the latter being a dispersion enhancer. To the best of our knowledge, this is the first time that siRNA in its naked form was formulated into an inhalable dry powder using spray drying technology. The aerosol performance of the powder was evaluated by Next Generation Impactor (NGI). The presence of l-leucine in the formulation could improve the aerosolization of siRNA-containing powders. Results from the X-ray photoelectron spectroscopy (XPS) suggested that l-leucine was enriched on the particle surface and promote powder dispersion. Among the different siRNA formulations being examined, the one that contained 50% w/w of l-leucine exhibited the best aerodynamic performance, with a high emitted fraction (EF) of around 80% and a modest fine particle fraction (FPF) of 45%. Importantly, the integrity of siRNA was successfully retained as evaluated by gel retardation assay and high performance liquid chromatography (HPLC). PMID- 28720538 TI - Direct compaction: An update of materials, trouble-shooting, and application. AB - Direct compaction (DC) is the preferred choice for tablet manufacturing; however, only less than 20% of active pharmaceutical ingredients could be compacted via DC as its high requirement for functional properties of materials. Materials with improper functionalities could lead to serious troubles during DC manufacturing, such as content non-uniformity, sticking, and capping, all of which profoundly affect the properties of final products and, thus, severely restrict the practical application of DC. With undoubted importance, these seem to be unexpectedly ignored by reviewers but not researchers in terms of many original research articles published recently. Therefore, as an informative supplement and update, this review mainly focused on trouble-shooting and application situation of DC, together with several newly reported materials. PMID- 28720539 TI - In-depth experimental analysis of pharmaceutical twin-screw wet granulation in view of detailed process understanding. AB - Twin-screw wet granulation is gaining increasing interest within the pharmaceutical industry for the continuous manufacturing of solid oral dosage forms. However, limited prior fundamental physical understanding has been generated relating to the granule formation mechanisms and kinetics along the internal compartmental length of a twin-screw granulator barrel, and about how process settings, barrel screw configuration and formulation properties such as particle size, density and surface properties influence these mechanisms. One of the main reasons for this limited understanding is that experimental data is generally only collected at the exit of the twin-screw granulator barrel although the granule formation occurs spatially along the internal length of the barrel. The purpose of this study is to analyze the twin-screw wet granulation process using both hydrophilic and hydrophobic formulations, manufactured under different process settings such as liquid-to-solid ratio, mass throughput and screw speed, in such a way that the mechanisms occurring in the individual granulator barrel compartments (i.e., the wetting and different conveying and kneading compartments) and their impact upon granule formation are understood. To achieve this, a unique experimental setup was developed allowing granule characteristic data-collection such as size, shape, liquid and porosity distribution at the different compartments along the length of the granulator barrel. Moreover, granule characteristic information per granule size class was determined. The experimental results indicated that liquid-to-solid ratio is the most important factor dictating the formation of the granules and their corresponding properties, by regulating the degree of aggregation and breakage in the different compartments along the internal length of the twin-screw granulator barrel. Collecting appropriate and detailed experimental data about granule formation along the internal length of the granulator barrel is thus crucial for gaining fundamental physical understanding of the twin-screw wet granulation process. PMID- 28720540 TI - Formulations and toxicologic in vivo studies of aqueous cyclosporin A eye drops with cyclodextrin nanoparticles. AB - Cyclosporin A (CyA) is an immunosuppressive drug used topically to treat ocular inflammatory disorder such as dry eye disease (DES). It is a lipophilic cyclic peptide with molecular weight of 1202.6Da. The aim of this study was to develop surfactant free aqueous 0.2% (w/v) CyA eye drops where the drug is present in an aqueous vehicle containing CyA/cyclodextrin (CyA/CD) nanoparticles and then do three-month toxicological testing in rabbits. Five formulations of different CD concentrations were studied, all of them contained 12.5% (w/v) of alpha cyclodextrin (alphaCD) and various amounts of gamma-cyclodextrin (gammaCD) (ranging from 0 to 12.5% w/v). alphaCD was used to solubilize the drug and gammaCD to promote formation of complex aggregates. CyA/CD complex aggregates were formed in all the formulations tested. However, the formulation containing 12.5% (w/v) alphaCD and 12.5% (w/v) gammaCD created more CyA/CD nanoparticles of suitable size and was therefore tested in vivo. The eye drops did not cause ocular irritation or toxic side effects upon topical administration to rabbits once or twice a day for three months. PMID- 28720541 TI - Biological sources of variation of serum adiponectin among healthy individuals in comparison with related nutritional and inflammatory markers. AB - BACKGROUND: Serum adiponectin (AN) is a nutritional and inflammatory marker of various diseases. Its biological sources of variation (SVs) have been widely evaluated, but its relationships with other related markers remain to be studied comprehensibly by use of multivariate analyses including factor analysis. METHODS: Serum specimens from 752 well-defined healthy subjects (295 males; 457 females) obtained from Japan, Hong Kong, Taiwan, and Vietnam were tested for total AN (tAN) and high-molecular-weight AN (hmAN) together with 71 major analytes. We chose test results of 11 analytes known as nutritional and inflammatory markers: insulin, HDL-C, LDL-C, TG, ALT, GGT, UA, TTR, CRP, C3, and C4. Factor analysis (FA) was performed to elucidate commonality among the analytes. Multiple regression analysis (MRA) was performed analyte by analyte to evaluate its biological SVs including age, BMI, and levels of alcohol consumption, smoking, and exercise. RESULTS: Both serum ANs showed female predominance, reduction with increased BMI, and regional difference (lower in Southeast Asia). The ratio of hmAN to tAN was higher in females. MRA showed no clear associations of tAN or hmAN with the levels of drinking alcohol or cigarette smoking. FA revealed that both tAN and hmAN have a commonality in biological variations with HDL-C, TG, CRP, and insulin but not with ALT, GGT, and TTR. CONCLUSIONS: No apparent differences were observed between tAN and hmAN with regard to commonality or association with related analytes by FA or MRA. It appears not necessary to distinguish hmAN from tAN when interpreting test results among healthy individuals. PMID- 28720542 TI - One-step reverse transcription loop-mediated isothermal amplification assay for detection of Apple chlorotic leaf spot virus. AB - A reverse transcription loop-mediated isothermal amplification (RT-LAMP) assay was developed for the detection of Apple chlorotic leaf spot virus (ACLSV). In this method, a set of four primers was designed based on the conserved regions in the coat protein gene of ACLSV, and the primers were synthesized for the RT-LAMP assay using total RNA extracted from ACLSV-infected leaf tissues. The optimal reaction temperature and assay time were determined to be 64 degrees C and 75min, respectively. The sensitivity of RT-LAMP reactions was reliable up to a maximum dilution of 1:3125, which was more sensitive than the RT-PCR assay. The successful application of RT-LAMP to field-collected apple samples demonstrated its potential for broader applications in effectively diagnosing diseases and, consequently, its potential to control ACLSV from spreading further, particularly in many developing countries around the world. To our knowledge, this is the first application of RT-LAMP for the detection of ACLSV. PMID- 28720543 TI - BIK is involved in BRAF/MEK inhibitor induced apoptosis in melanoma cell lines. AB - In patients with BRAF-mutated melanoma specific inhibitors of BRAFV600E and MEK1/2 frequently induce initial tumor reduction, frequently followed by relapse. As demonstrated previously, BRAFV600E-inhibition induces apoptosis only in a fraction of treated cells, while the remaining arrest and survive providing a source or a niche for relapse. To identify factors contributing to the differential initial response towards BRAF/MEK inhibition, we established M14 melanoma cell line-derived single cell clones responding to treatment with BRAF inhibitor vemurafenib and MEK inhibitor trametinib predominantly with either cell cycle arrest (CCA-cells) or apoptosis (A-cells). Screening for differentially expressed apoptosis-related genes revealed loss of BCL2-Interacting Killer (BIK) mRNA in CCA-cells. Importantly, ectopic expression of BIK in CCA-cells resulted in increased apoptosis rates following vemurafenib/trametinib treatment, while knockdown/knockout of BIK in A-cells attenuated the apoptotic response. Furthermore, we demonstrate reversible epigenetic silencing of BIK mRNA expression in CCA-cells. Importantly, HDAC inhibitor treatment associated with re expression of BIK augmented sensitivity of CCA-cells towards vemurafenib/trametinib treatment both in vitro and in vivo. In conclusion, our results suggest that BIK can be a critical mediator of melanoma cell fate determination in response to MAPK pathway inhibition. PMID- 28720544 TI - Degalactosylation of xyloglucans modify their pro-inflammatory properties on murine peritoneal macrophages. AB - Considering the potential applications of partially degalactosylated xyloglucans as a drug delivery vehicle and reconstruction of tissues, the aim of this study was to investigate whether degalactosylated xyloglucans are immunologically active. The effects of the degalactosylated xyloglucan from seeds of Copaifera langsdorffii (XGCd), Hymenaea courbaril (XGJd), and Tamarindus indica (XGTd) on murine peritoneal macrophages in vitro were evaluated. XGCd, XGJd, and XGTd stimulated NO production in a dose-dependent manner reaching ~280% for XGTd at 50MUg/mL. Regarding cytokines production, XGJd at 50MUg/mL increased IL-1beta level by ~100% and XGCd (10MUg/mL) enhanced IL-6 level by 40%. At 10MUg/mL, XGTd increased TNF- alpha and IL-1beta levels by 104 and 2370%, respectively, as compared to the control group. For IL-6, XGTd enhanced this cytokine production by 80% at all concentrations tested. XGTd exhibited the most intensive effects on the production of pro-inflammatory mediators by peritoneal macrophages. All degalactosylated xyloglucans evaluated showed not to be biologically inert. Thus, this finding is relevant for groups that are investigating the use of degalactosylated xyloglucan from T. indica for drug delivery and reconstruction of tissues. The effects observed could contribute to potentiate the immune system against infections or toxicity to tumor cells. PMID- 28720545 TI - Identification and kinetic characterization of a novel superoxide dismutase from Avicennia marina: An antioxidant enzyme with unique features. AB - A novel Cu/Zn-superoxide dismutase was extracted from Avicennia marina and purified. The sample was collected from Khamir port located in the north shore of Persian Gulf. The purification procedure comprised of (NH4)2SO4 precipitation followed by CM-Sephadex C-50 and DEAE-Sepharose chromatography, and gel filtration chromatography (Sephadex G-75). The enzyme with a characteristic molecular weight of 31kDa, measured by SDS-page, showed its highest catalytic efficiency at pH 8.0 and 50 degrees C. Its activity was greatly inhibited by cyanide and hydrogen peroxide. The pH profile showed that the enzyme could maintain most of its activity at pH values ranging from 5 to 10. The temperature profile of this enzyme showed a broad range of activity compared with other superoxide dismutases. Catalytic hydrolysis rate followed Michaelis-Menten equation. The values of kcat and Km were obtained from Michaelis-Menten plot as 107000s-1 and 11.5MUmol respectively. The evidences from kinetic and thermodynamic parameters suggest that Avicennia marina superoxide dismutase (AmSOD) can be used as a suitable enzyme for biotechnological and pharmacological applications. PMID- 28720547 TI - Novel water soluble morpholine substituted Zn(II) phthalocyanine: Synthesis, characterization, DNA/BSA binding, DNA photocleavage and topoisomerase I inhibition. AB - In this study, novel peripherally tetra 3-morpholinophenol substituted zinc(II) phthalocyanine (4) and its water soluble form quaternized zinc(II) phthalocyanine (ZnQ) were synthesized for the first time. These novel compounds were characterized by a combination of different spectroscopic techniques such as FT IR, 1H NMR, 13C NMR, UV-vis and mass. The DNA binding of ZnQ was investigated using UV-vis absorption titration, competitive ethidium bromide, thermal denaturation and viscosity experiments that the ZnQ bound to CT-DNA via intercalation mode. ZnQ indicated photocleavage activity on supercoiled pBR322 plasmid DNA via formation of singlet oxygen under irradiation at 700nm. Besides, the topoisomerase I inhibitory effect experiments showed that ZnQ inhibited topoisomerase I enzyme in a concentration-dependent manner. The bovine serum albumin (BSA) binding experiments indicated that ZnQ bound to proteins through a static quenching mechanism. All of these results claim that ZnQ has potential agent for photodynamic therapy owing to its nucleic acid interactions and photobiological or photochemical properties. PMID- 28720546 TI - The lncRNA NEAT1 facilitates cell growth and invasion via the miR-211/HMGA2 axis in breast cancer. AB - Long non-coding RNAs play a significant role in cancer metastasis. Studies have demonstrated that LncRNA NEAT1 promotes cancer progression. We aimed to explore whether NEAT1 regulated growth and invasion in breast cancer cells. We provided evidence that lncRNA NEAT1 was up-regulated in breast cancer cell lines and tissues. NEAT1 promoted invasion through inducing Epithelial-mesenchymal transition (EMT) and NEAT1 played a role in 5-fluorouracil (5-FU) resistance. In addition, we revealed a reciprocal repression between NEAT1 and miR-211. Furthermore, the EMT-inducer HMGA2 was identified as a down-stream target of miR 211. LncRNA NEAT1 induced EMT and 5-FU resistance through the miR-211/HMGA2 axis. Our findings suggest that lncRNA NEAT1 could be a new diagnostic biomarker and therapy target for breast cancer. PMID- 28720548 TI - PxAPN5 serves as a functional receptor of Cry2Ab in Plutella xylostella (L.) and its binding domain analysis. AB - Lepidopteran midgut aminopeptidases N (APNs) are widely studied for their potential roles as one of the receptors for Bacillus thuringiensis (Bt) crystal toxins. In the present study, a loss of function analyses by RNAi (RNA interference) silencing of the Plutella xylostella APN5 (PxAPN5), a binding protein of Bt crystal toxin Cry2Ab, were performed. The knocking down of PxAPN5 in P. xylostella larvae greatly reduced their susceptibility to Cry2Ab and led to a decrease of Cry2Ab binding to P. xylostella midgut. Four truncated fragments of PxAPN5 were further constructed and expressed in Escherichia coli (E.coli) to find the binding region of PxAPN5 to Cry2Ab. The ligand blot result indicated that D1 domain (residues 1-262) and D3 domain (residues 510-620) of PxAPN5 could specially bind to Cry2Ab. PMID- 28720550 TI - Sex-linked association between cortical scene selectivity and navigational ability. AB - Spatial navigation is a crucial ability for living. Previous studies have shown that males are better at navigation than females, but little is known about the neural basis underlying the sex differences. In this study, we investigated whether cortical scene processing in three well-established scene-selective regions was sexually different, by examining sex differences in scene selectivity and its behavioral relevance to navigation. To do this, we used functional magnetic resonance imaging (fMRI) to scan the parahippocampal place area (PPA), retrosplenial complex (RSC), and occipital place area (OPA) in a large cohort of healthy young adults viewing navigationally relevant scenes (N = 202), and correlated their neural selectivity to scenes with their self-reported navigational ability. Behaviorally, we replicated the previous finding that males were better at navigation than females. Neurally, we found that the scene selectivity in the bilateral PPA, not in the RSC or OPA, was significantly higher in males than females. Such differences could not be explained by confounding factors including brain size and fMRI data quality. Importantly, males, not females, with stronger scene selectivity in the left PPA possessed better navigational ability. This brain-behavior association could not be accounted for by non-navigational abilities (i.e., intelligence and mental rotation ability). Overall, our study provides novel empirical evidence demonstrating sex differences in the brain activity, inviting further studies on sex differences in the neural network for spatial navigation. PMID- 28720549 TI - Evolutionary basis of a new gene- and immune-therapeutic approach for the treatment of malignant brain tumors: from mice to clinical trials for glioma patients. AB - Glioma cells are one of the most aggressive and malignant tumors. Following initial surgery, and radio-chemotherapy they progress rapidly, so that patients' median survival remains under two years. They invade throughout the brain, which makes them difficult to treat, and are universally lethal. Though total resection is always attempted it is not curative. Standard of care in 2016 comprises surgical resection, radiotherapy and chemotherapy (temozolomide). Median survival is currently ~14-20months post-diagnosis though it can be higher in high complexity medical university centers, or during clinical trials. Why the immune system fails to recognize the growing brain tumor is not completely understood. We believe that one reason for this failure is that the brain lacks cells that perform the role that dendritic cells serve in other organs. The lack of functional dendritic cells from the brain causes the brain to be deficient in priming systemic immune responses to glioma antigens. To overcome this drawback we reconstituted the brain immune system for it to initiate and prime anti-glioma immune responses from within the brain. To achieve brain immune reconstitution adenoviral vectors are injected into the resection cavity or remaining tumor. One adenoviral vector expresses the HSV-1 derived thymidine kinase which converts ganciclovir into phospho-ganciclovir which becomes cytotoxic to dividing cells. The second adenovirus expresses the cytokine fms-like tyrosine kinase 3 ligand (Flt3L). Flt3L differentiates precursors into dendritic cells and acts as a chemokine for dendritic cells. This results in HSV-1/ganciclovir killing of tumor cells, and the release of tumor antigens, which are then taken up by dendritic cells recruited to the brain tumor microenvironment by Flt3L. Concomitant release of HMGB1, a TLR2 agonist that activates dendritic cells, stimulates dendritic cells loaded with glioma antigens to migrate to the cervical lymph nodes to prime a systemic CD8+ T cytotoxic killing of brain tumor cells. This induced immune response causes glioma-specific cytotoxicity, induces immunological memory, and does not cause brain toxicity or autoimmunity. A Phase I Clinical Trial, to test our hypothesis in human patients, was opened in December 2013 (see: NCT01811992, Combined Cytotoxic and Immune-Stimulatory Therapy for Glioma, at ClinicalTrials.gov). This trial is a first in human trial to test whether the re engineering of the brain immune system can serve to treat malignant brain tumors. The long and winding road from the laboratory to the clinical trial follows below. PMID- 28720551 TI - Accelerating permutation testing in voxel-wise analysis through subspace tracking: A new plugin for SnPM. AB - Permutation testing is a non-parametric method for obtaining the max null distribution used to compute corrected p-values that provide strong control of false positives. In neuroimaging, however, the computational burden of running such an algorithm can be significant. We find that by viewing the permutation testing procedure as the construction of a very large permutation testing matrix, T, one can exploit structural properties derived from the data and the test statistics to reduce the runtime under certain conditions. In particular, we see that T is low-rank plus a low-variance residual. This makes T a good candidate for low-rank matrix completion, where only a very small number of entries of T (~0.35% of all entries in our experiments) have to be computed to obtain a good estimate. Based on this observation, we present RapidPT, an algorithm that efficiently recovers the max null distribution commonly obtained through regular permutation testing in voxel-wise analysis. We present an extensive validation on a synthetic dataset and four varying sized datasets against two baselines: Statistical NonParametric Mapping (SnPM13) and a standard permutation testing implementation (referred as NaivePT). We find that RapidPT achieves its best runtime performance on medium sized datasets (50<=n<=200), with speedups of 1.5* 38* (vs. SnPM13) and 20x-1000* (vs. NaivePT). For larger datasets (n>=200) RapidPT outperforms NaivePT (6* - 200*) on all datasets, and provides large speedups over SnPM13 when more than 10000 permutations (2* - 15*) are needed. The implementation is a standalone toolbox and also integrated within SnPM13, able to leverage multi-core architectures when available. PMID- 28720552 TI - Autoimmune Limbic Encephalitis Associated with Type 1 Diabetes Mellitus. PMID- 28720553 TI - Response to Growth Hormone Treatment in a Patient with Insulin-Like Growth Factor 1 Receptor Deletion. AB - We report a six-year-old boy who presented with short stature, microcephaly, dysmorphic features, and developmental delay and who was identified with a terminal deletion of 15q26.2q26.3 containing the insulin-like growth factor receptor (IGF1R) gene in addition to a terminal duplication of the 4q35.1q35.2 region. We compare our case with other reports of deletions and mutations affecting the IGF1R gene associated with pre-and postnatal growth restriction. We report the dramatic response to growth hormone therapy in this patient which highlights the importance of identifying patients with IGF1R deletion and treating them early. PMID- 28720554 TI - Is There an Association Between Cortisol and Hypertension in Overweight or Obese Children? AB - OBJECTIVE: The precise mechanisms behind the development of hypertension in overweight or obese children are not yet completely understood. Alterations in hypothalamic-pituitary-adrenal axis activity may play a role. We aimed to investigate the association between cortisol parameters and hypertension in overweight or obese children. METHODS: Random urine (n=180) and early-morning saliva samples (n=126) for assessment of cortisol and cortisone were collected from 1) hypertensive overweight children (n=50), 2) normotensive overweight children (n=145), and 3) normotensive non-overweight children (n=75). RESULTS: The age of participants was 10.4+/-3.3 years and 53% were boys. The urinary cortisol-to-cortisone ratio [beta 1.11, 95% confidence interval (CI) 1.05-1.19] as well as urinary cortisol/creatinine (beta 1.38, 95% CI 1.09-1.54), and cortisone/creatinine ratios (beta 1.26, 95% CI 1.17-1.36) were significantly higher in overweight or obese than in non-overweight children. After adjusting for body mass index-standard deviation score and urinary cortisone/creatinine ratio, but not cortisol/creatinine ratio, was significantly associated with presence of hypertension (beta 1.12, 95% CI 1.02-1.23). Salivary cortisol and cortisone levels were significantly lower in overweight or obese than in non overweight children (beta -4.67, 95% CI -8.19- -1.15, and beta 0.89, 95% CI 0.80 0.97 respectively). There were no significant differences in cortisol parameters between hypertensive and normotensive overweight or obese children. CONCLUSION: This study provided further evidence for an increased cortisol production rate with decreased renal 11beta-hydroxysteroid dehydrogenase 2 activity and flattening of early-morning peak cortisol and cortisone in overweight or obese children. However, there were no significant differences in cortisol parameters between hypertensive and normotensive overweight and obese children. PMID- 28720555 TI - Readability of Wikipedia Pages on Autoimmune Disorders: Systematic Quantitative Assessment. AB - BACKGROUND: In the era of new information and communication technologies, the Internet is being increasingly accessed for health-related information. Indeed, recently published patient surveys of people with autoimmune disorders confirmed that the Internet was reported as one of the most important health information sources. Wikipedia, a free online encyclopedia launched in 2001, is generally one of the most visited websites worldwide and is often consulted for health-related information. OBJECTIVE: The main objective of this investigation was to quantitatively assess whether the Wikipedia pages related to autoimmune disorders can be easily accessed by patients and their families, in terms of readability. METHODS: We obtained and downloaded a list of autoimmune disorders from the American Autoimmune Related Diseases Association (AARDA) website. We analyzed Wikipedia articles for their overall level of readability with 6 different quantitative readability scales: (1) the Flesch Reading Ease, (2) the Gunning Fog Index, (3) the Coleman-Liau Index, (4) the Flesch-Kincaid Grade Level, (5) the Automated Readability Index (ARI), and (6) the Simple Measure of Gobbledygook (SMOG). Further, we investigated the correlation between readability and clinical, pathological, and epidemiological parameters. Moreover, each Wikipedia analysis was assessed according to its content, breaking down the readability indices by main topic of each part (namely, pathogenesis, treatment, diagnosis, and prognosis plus a section containing paragraphs not falling into any of the previous categories). RESULTS: We retrieved 134 diseases from the AARDA website. The Flesch Reading Ease yielded a mean score of 24.34 (SD 10.73), indicating that the sites were very difficult to read and best understood by university graduates, while mean Gunning Fog Index and ARI scores were 16.87 (SD 2.03) and 14.06 (SD 2.12), respectively. The Coleman-Liau Index and the Flesch-Kincaid Grade Level yielded mean scores of 14.48 (SD 1.57) and 14.86 (1.95), respectively, while the mean SMOG score was 15.38 (SD 1.37). All the readability indices confirmed that the sites were suitable for a university graduate reading level. We found no correlation between readability and clinical, pathological, and epidemiological parameters. Differences among the different sections of the Wikipedia pages were statistically significant. CONCLUSIONS: Wikipedia pages related to autoimmune disorders are characterized by a low level of readability. The onus is, therefore, on physicians and health authorities to improve the health literacy skills of patients and their families and to create, together with patients themselves, disease-specific readable sites, disseminating highly accessible health-related online information, in terms of both clarity and conciseness. PMID- 28720556 TI - Ecological Momentary Assessment of Physical Activity: Validation Study. AB - BACKGROUND: Ecological momentary assessment (EMA) may elicit physical activity (PA) estimates that are less prone to bias than traditional self-report measures while providing context. OBJECTIVES: The objective of this study was to examine the convergent validity of EMA-assessed PA compared with accelerometry. METHODS: The participants self-reported their PA using International Physical Activity Questionnaire (IPAQ) and Behavioral Risk Factor Surveillance System (BRFSS) and wore an accelerometer while completing daily EMAs (delivered through the mobile phone) for 7 days. Weekly summary estimates included sedentary time and moderate , vigorous-, and moderate-to vigorous-intensity physical activity (MVPA). Spearman coefficients and Lin's concordance correlation coefficients (LCC) examined the linear association and agreement for EMA and the questionnaires as compared with accelerometry. RESULTS: Participants were aged 43.3 (SD 13.1) years, 51.7% (123/238) were African American, 74.8% (178/238) were overweight or obese, and 63.0% (150/238) were low income. The linear associations of EMA and traditional self-reports with accelerometer estimates were statistically significant (P<.05) for sedentary time (EMA: rho=.16), moderate-intensity PA (EMA: rho=.29; BRFSS: rho=.17; IPAQ: rho=.24), and MVPA (EMA: rho=.31; BRFSS: rho=.17; IPAQ: rho=.20). Only EMA estimates of PA were statistically significant compared with accelerometer for agreement. CONCLUSIONS: The mobile EMA showed better correlation and agreement to accelerometer estimates than traditional self report methods. These findings suggest that mobile EMA may be a practical alternative to accelerometers to assess PA in free-living settings. PMID- 28720557 TI - Comparing Mobile Health Strategies to Improve Medication Adherence for Veterans With Coronary Heart Disease (Mobile4Meds): Protocol for a Mixed-Methods Study. AB - BACKGROUND: Adherence to antiplatelet medications is critical to prevent life threatening complications (ie, stent thrombosis) after percutaneous coronary interventions (PCIs), yet rates of nonadherence range from 21-57% by 12 months. Mobile interventions delivered via text messaging or mobile apps represent a practical and inexpensive strategy to promote behavior change and enhance medication adherence. OBJECTIVE: The Mobile4Meds study seeks to determine whether text messaging or a mobile app, compared with an educational website control provided to all Veterans, can improve adherence to antiplatelet therapy among patients following acute coronary syndrome (ACS) or PCI. The three aims of the study are to: (1) determine preferences for content and frequency of text messaging to promote medication adherence through focus groups; (2) identify the most patient-centered app that promotes adherence, through a content analysis of all commercially available apps for medication adherence and focus groups centered on usability; and (3) compare adherence to antiplatelet medications in Veterans after ACS/PCI via a randomized clinical trial (RCT). METHODS: We will utilize a mixed-methods design that uses focus groups to achieve the first and second aims (N=32). Patients will be followed for 12 months after being randomly assigned to one of three arms: (1) customized text messaging, (2) mobile app, or (3) website-control groups (N=225). Medication adherence will be measured with electronic monitoring devices, pharmacy records, and self-reports. RESULTS: Enrollment for the focus groups is currently in progress. We expect to enroll patients for the RCT in the beginning of 2018. CONCLUSIONS: Determining the efficacy of mobile technology using a Veteran-designed protocol to promote medication adherence will have a significant impact on Veteran health and public health, particularly for individuals with chronic diseases that require strict medication adherence. TRIAL REGISTRATION: ClinicalTrials.gov NCT03022669. PMID- 28720559 TI - An older man with memory impairment and convulsions. PMID- 28720558 TI - My Team of Care Study: A Pilot Randomized Controlled Trial of a Web-Based Communication Tool for Collaborative Care in Patients With Advanced Cancer. AB - BACKGROUND: The management of patients with complex care needs requires the expertise of health care providers from multiple settings and specialties. As such, there is a need for cross-setting, cross-disciplinary solutions that address deficits in communication and continuity of care. We have developed a Web based tool for clinical collaboration, called Loop, which assembles the patient and care team in a virtual space for the purpose of facilitating communication around care management. OBJECTIVE: The objectives of this pilot study were to evaluate the feasibility of integrating a tool like Loop into current care practices and to capture preliminary measures of the effect of Loop on continuity of care, quality of care, symptom distress, and health care utilization. METHODS: We conducted an open-label pilot cluster randomized controlled trial allocating patients with advanced cancer (defined as stage III or IV disease) with >=3 months prognosis, their participating health care team and caregivers to receive either the Loop intervention or usual care. Outcome data were collected from patients on a monthly basis for 3 months. Trial feasibility was measured with rate of uptake, as well as recruitment and system usage. The Picker Continuity of Care subscale, Palliative care Outcomes Scale, Edmonton Symptom Assessment Scale, and Ambulatory and Home Care Record were patient self-reported measures of continuity of care, quality of care, symptom distress, and health services utilization, respectively. We conducted a content analysis of messages posted on Loop to understand how the system was used. RESULTS: Nineteen physicians (oncologists or palliative care physicians) were randomized to the intervention or control arms. One hundred twenty-seven of their patients with advanced cancer were approached and 48 patients enrolled. Of 24 patients in the intervention arm, 20 (83.3%) registered onto Loop. In the intervention and control arms, 12 and 11 patients completed three months of follow-up, respectively. A mean of 1.2 (range: 0 to 4) additional healthcare providers with an average total of 3 healthcare providers participated per team. An unadjusted between-arm increase of +11.4 was observed on the Picker scale in favor of the intervention arm. Other measures showed negligible changes. Loop was primarily used for medical care management, symptom reporting, and appointment coordination. CONCLUSIONS: The results of this study show that implementation of Loop was feasible. It provides useful information for planning future studies further examining effectiveness and team collaboration. Numerically higher scores were observed for the Loop arm relative to the control arm with respect to continuity of care. Future work is required to understand the incentives and barriers to participation so that the implementation of tools like Loop can be optimized. TRIAL REGISTRATION: ClinicalTrials.gov NCT02372994; https://clinicaltrials.gov/ct2/show/NCT02372994 (Archived by WebCite at http://www.webcitation.org/6r00L4Skb). PMID- 28720560 TI - Increase in life expectancy in England has halted, new figures show. PMID- 28720562 TI - Author's reply to Welch. PMID- 28720563 TI - Our failure to put knowledge into practice causes harm. PMID- 28720561 TI - The metabolism of lipoprotein (a): an ever-evolving story. AB - Lipoprotein (a) [Lp(a)] is characterized by apolipoprotein (a) [apo(a)] covalently bound to apolipoprotein B 100. It was described in human plasma by Berg et al. in 1963 and the gene encoding apo(a) (LPA) was cloned in 1987 by Lawn and colleagues. Epidemiologic and genetic studies demonstrate that increases in Lp(a) plasma levels increase the risk of atherosclerotic cardiovascular disease. Novel Lp(a) lowering treatments highlight the need to understand the regulation of plasma levels of this atherogenic lipoprotein. Despite years of research, significant uncertainty remains about the assembly, secretion, and clearance of Lp(a). Specifically, there is ongoing controversy about where apo(a) and apoB-100 bind to form Lp(a); which apoB-100 lipoproteins bind to apo(a) to create Lp(a); whether binding of apo(a) is reversible, allowing apo(a) to bind to more than one apoB-100 lipoprotein during its lifespan in the circulation; and how Lp(a) or apo(a) leave the circulation. In this review, we highlight past and recent data from stable isotope studies of Lp(a) metabolism, highlighting the critical metabolic uncertainties that exist. We present kinetic models to describe results of published studies using stable isotopes and suggest what future studies are required to improve our understanding of Lp(a) metabolism. PMID- 28720564 TI - UK doctors re-examine case for mandatory vaccination. PMID- 28720565 TI - Tobacco plan aims to produce England's first smoke-free generation. PMID- 28720566 TI - Junior doctor contract is making paediatric rotas more difficult to fill, finds survey. PMID- 28720567 TI - Big data's big bias: bringing noise and conflicts to US drug regulation. PMID- 28720568 TI - Serine proteases of the complement lectin pathway and their genetic variations in ischaemic stroke. AB - AIMS: The aim of the current study was to assess the proteolytic activities of collectin-bound MASP-1 and MASP-2 in the blood of patients with ischaemic stroke, as well as the association of their six genetic polymorphisms (rs3203210, rs28945070, rs28945073 in MASP1 gene and rs2273343, rs12711521, rs147270785 in MASP2 gene) with this pathology. METHODS: In total, 250 patients and 300 healthy subjects were involved in this study. MBL-associated serine protease (MASP)-1 and MASP-2 activities were measured using in-house developed immunofluorescent and enzyme-linked immunosorbent assays, respectively. Sequence specific primer PCR was used to study the association of MASP1 and MASP2 genetic polymorphisms with ischaemic stroke. RESULTS: The results obtained demonstrate that the activities of collectin-bound MASP-1 and MASP-2 in patients with ischaemic stroke are significantly higher than those in healthy subjects (p<0.001). According to the data obtained for genotyping, the rs3203210 polymorphism in the MASP1 gene and the rs147270785 polymorphism in the MASP2 gene are associated with ischaemic stroke (p<0.0001). CONCLUSIONS: In conclusion we suggest that the complement lectin pathway serine proteases, MASP-1 and MASP-2, can be associated with ischaemic stroke development risk and may participate in pathological events leading to post-ischaemic brain damage. Moreover rs3203210 and rs147270785 single nucleotide polymorphisms in the MASP1 and MASP2 genes, respectively, are strongly associated with ischaemic stroke, and the minor rs3203210*C and rs147270785*A alleles of these polymorphisms may be considered as protective factors for ischameic stroke, at least in the Armenian population. PMID- 28720570 TI - Protesters show support for assisted dying campaigner. PMID- 28720569 TI - Platelets as autonomous drones for hemostatic and immune surveillance. AB - Platelets participate in many important physiological processes, including hemostasis and immunity. However, despite their broad participation in these evolutionarily critical roles, the anucleate platelet is uniquely mammalian. In contrast with the large nucleated equivalents in lower vertebrates, we find that the design template for the evolutionary specialization of platelets shares remarkable similarities with human-engineered unmanned aerial vehicles in terms of overall autonomy, maneuverability, and expendability. Here, we review evidence illustrating how platelets are uniquely suited for surveillance and the manner in which they consequently provide various types of support to other cell types. PMID- 28720572 TI - Sixty seconds on . . . 999 calls. PMID- 28720573 TI - Margaret McCartney: Let's ditch the stuff we don't need to do. PMID- 28720571 TI - The integrated stress response in hypoxia-induced diffuse white matter injury. AB - Currently no treatments exist for preterm infants with diffuse white matter injury (DWMI) caused by hypoxia. Due to improved care of preterm neonates and increased recognition by advanced imaging techniques, the prevalence of DWMI is increasing. A better understanding of the pathophysiology of DWMI is therefore of critical importance. The integrated stress response (ISR), a conserved eukaryotic response to myriad stressors including hypoxia, may play a role in hypoxia induced DWMI and may represent a novel target for much needed therapies. In this study we utilize in vitro and in vivo hypoxic models of DWMI to investigate whether the ISR is involved in DWMI. We demonstrate that hypoxia activates the ISR in primary mouse oligodendrocyte precursor cells (OPCs) in vitro and that genetically inhibiting the ISR in differentiating OPCs increases their susceptibility to in vitro hypoxia. We also show that a well-established in vivo mild chronic hypoxia (MCH) mouse model and a new severe acute hypoxia (SAH) mouse model of DWMI activates the initial step of the ISR. Nonetheless, genetic inhibition of the ISR has no detectable effect on either MCH or SAH-induced DWMI. In addition, we demonstrate that genetic enhancement of the ISR does not ameliorate MCH or SAH-induced DWMI. These studies suggest that while the ISR protects OPCs from hypoxia in vitro, it does not appear to play a major role in either MCH or SAH-induced DWMI and is therefore not a likely target for therapies aimed at improving neurological outcome in preterm neonates with hypoxia-induced DWMI.SIGNIFICANCE STATEMENTDiffuse white matter injury (DWMI) caused by hypoxia is a leading cause of neurological deficits following premature birth. An increased understanding of the pathogenesis of this disease is critical. The integrated stress response (ISR) is activated by hypoxia and protects oligodendrocyte lineage cells in other disease models. This has led to an interest in the potential role of the ISR in DWMI. Here we examine the ISR in hypoxia-induced DWMI and show that while the ISR protects oligodendrocyte lineage cells from hypoxia in vitro, genetic inhibition or enhancement of the ISR has no effect on hypoxia-induced DWMI in vivo suggesting that the ISR does not play a major role in, and is not a likely therapeutic target for, DWMI. PMID- 28720574 TI - Fructose-1,6-bisphosphatase Inhibits ERK Activation and Bypasses Gemcitabine Resistance in Pancreatic Cancer by Blocking IQGAP1-MAPK Interaction. AB - Dysregulation of the MAPK pathway correlates with progression of pancreatic ductal adenocarcinoma (PDAC) progression. IQ motif containing GTPase-activating protein 1 (IQGAP1) is a MAPK scaffold that directly regulates the activation of RAF, MEK, and ERK. Fructose-1,6-bisphosphatase (FBP1), a key enzyme in gluconeogenesis, is transcriptionally downregulated in various cancers, including PDAC. Here, we demonstrate that FBP1 acts as a negative modulator of the IQGAP1 MAPK signaling axis in PDAC cells. FBP1 binding to the WW domain of IQGAP1 impeded IQGAP1-dependent ERK1/2 phosphorylation (pERK1/2) in a manner independent of FBP1 enzymatic activity. Conversely, decreased FBP1 expression induced pERK1/2 levels in PDAC cell lines and correlated with increased pERK1/2 levels in patient specimens. Treatment with gemcitabine caused undesirable activation of ERK1/2 in PDAC cells, but cotreatment with the FBP1-derived small peptide inhibitor FBP1 E4 overcame gemcitabine-induced ERK activation, thereby increasing the anticancer efficacy of gemcitabine in PDAC. These findings identify a primary mechanism of resistance of PDAC to standard therapy and suggest that the FBP1-IQGAP1-ERK1/2 signaling axis can be targeted for effective treatment of PDAC. Cancer Res; 77(16); 4328-41. (c)2017 AACR. PMID- 28720575 TI - Hsp72 and Nek6 Cooperate to Cluster Amplified Centrosomes in Cancer Cells. AB - Cancer cells frequently possess extra amplified centrosomes clustered into two poles whose pseudo-bipolar spindles exhibit reduced fidelity of chromosome segregation and promote genetic instability. Inhibition of centrosome clustering triggers multipolar spindle formation and mitotic catastrophe, offering an attractive therapeutic approach to selectively kill cells with amplified centrosomes. However, mechanisms of centrosome clustering remain poorly understood. Here, we identify a new pathway that acts through NIMA-related kinase 6 (Nek6) and Hsp72 to promote centrosome clustering. Nek6, as well as its upstream activators polo-like kinase 1 and Aurora-A, targeted Hsp72 to the poles of cells with amplified centrosomes. Unlike some centrosome declustering agents, blocking Hsp72 or Nek6 function did not induce formation of acentrosomal poles, meaning that multipolar spindles were observable only in cells with amplified centrosomes. Inhibition of Hsp72 in acute lymphoblastic leukemia cells resulted in increased multipolar spindle frequency that correlated with centrosome amplification, while loss of Hsp72 or Nek6 function in noncancer-derived cells disturbs neither spindle formation nor mitotic progression. Hence, the Nek6-Hsp72 module represents a novel actionable pathway for selective targeting of cancer cells with amplified centrosomes. Cancer Res; 77(18); 4785-96. (c)2017 AACR. PMID- 28720576 TI - Deubiquitinating Enzyme USP9X Suppresses Tumor Growth via LATS Kinase and Core Components of the Hippo Pathway. AB - The core LATS kinases of the Hippo tumor suppressor pathway phosphorylate and inhibit the downstream transcriptional co-activators YAP and TAZ, which are implicated in various cancers. Recent studies have identified various E3 ubiquitin ligases that negatively regulate the Hippo pathway via ubiquitination, yet few deubiquitinating enzymes (DUB) have been implicated. In this study, we report the DUB USP9X is an important regulator of the core kinases of this pathway. USP9X interacted strongly with LATS kinase and to a lesser extent with WW45, KIBRA, and Angiomotin, and LATS co-migrated exclusively with USP9X during gel filtration chromatography analysis. Knockdown of USP9X significantly downregulated and destabilized LATS and resulted in enhanced nuclear translocation of YAP and TAZ, accompanied with activation of their target genes. In the absence of USP9X, cells exhibited an epithelial-to-mesenchymal transition phenotype, acquired anchorage-independent growth in soft agar, and led to enlarged, disorganized, three-dimensional acini. YAP/TAZ target gene activation in response to USP9X knockdown was suppressed by knockdown of YAP, TAZ, and TEAD2. Deletion of USP9X in mouse embryonic fibroblasts resulted in significant downregulation of LATS. Furthermore, USP9X protein expression correlated positively with LATS but negatively with YAP/TAZ in pancreatic cancer tissues as well as pancreatic and breast cancer cell lines. Overall, these results strongly indicate that USP9X potentiates LATS kinase to suppress tumor growth. Cancer Res; 77(18); 4921-33. (c)2017 AACR. PMID- 28720577 TI - Lysyl Oxidase-like Protein LOXL2 Promotes Lung Metastasis of Breast Cancer. AB - The lysyl oxidase-like protein LOXL2 has been suggested to contribute to tumor progression and metastasis, but in vivo evidence has been lacking. Here we provide functional evidence that LOXL2 is a key driver of breast cancer metastasis in two conditional transgenic mouse models of PyMT-induced breast cancer. LOXL2 ablation in mammary tumor cells dramatically decreased lung metastasis, whereas LOXL2 overexpression promoted metastatic tumor growth. LOXL2 depletion or overexpression in tumor cells does not affect extracellular matrix stiffness or organization in primary and metastatic tumors, implying a function for LOXL2 independent of its conventional role in extracellular matrix remodeling. In support of this likelihood, cellular and molecular analyses revealed an association of LOXL2 action with elevated levels of the EMT regulatory transcription factor Snail1 and expression of several cytokines that promote premetastatic niche formation. Taken together, our findings established a pathophysiologic role and new function for LOXL2 in breast cancer metastasis. Cancer Res; 77(21); 5846-59. (c)2017 AACR. PMID- 28720578 TI - Systematic longitudinal survey of invasive Escherichia coli in England demonstrates a stable population structure only transiently disturbed by the emergence of ST131. AB - Escherichia coli associated with urinary tract infections and bacteremia has been intensively investigated, including recent work focusing on the virulent, globally disseminated, multidrug-resistant lineage ST131. To contextualize ST131 within the broader E. coli population associated with disease, we used genomics to analyze a systematic 11-yr hospital-based survey of E. coli associated with bacteremia using isolates collected from across England by the British Society for Antimicrobial Chemotherapy and from the Cambridge University Hospitals NHS Foundation Trust. Population dynamics analysis of the most successful lineages identified the emergence of ST131 and ST69 and their establishment as two of the five most common lineages along with ST73, ST95, and ST12. The most frequently identified lineage was ST73. Compared to ST131, ST73 was susceptible to most antibiotics, indicating that multidrug resistance was not the dominant reason for prevalence of E. coli lineages in this population. Temporal phylogenetic analysis of the emergence of ST69 and ST131 identified differences in the dynamics of emergence and showed that expansion of ST131 in this population was not driven by sequential emergence of increasingly resistant subclades. We showed that over time, the E. coli population was only transiently disturbed by the introduction of new lineages before a new equilibrium was rapidly achieved. Together, these findings suggest that the frequency of E. coli lineages in invasive disease is driven by negative frequency-dependent selection occurring outside of the hospital, most probably in the commensal niche, and that drug resistance is not a primary determinant of success in this niche. PMID- 28720582 TI - Three quarters of patients with diabetes in England and Wales meet blood pressure targets. PMID- 28720579 TI - Recruitment of histone modifications to assist mRNA dosage maintenance after degeneration of cytosine DNA methylation during animal evolution. AB - Following gene duplication, mRNA expression of the duplicated gene is reduced to maintain mRNA dosage. In mammals, this process is achieved with increased cytosine DNA methylation of the promoters of duplicated genes to suppress transcriptional initiation. However, not all animal species possess a full apparatus for cytosine DNA methylation. For such species, such as the roundworm (Caenorhabditis elegans, "worm" hereafter) or fruit fly (Drosophila melanogaster, "fly" hereafter), it is unclear how reduced expression of duplicated genes has been achieved evolutionarily. Here, we hypothesize that in the absence of a classical cytosine DNA methylation pathway, histone modifications play an increasing role in maintaining mRNA dosage following gene duplication. We initially verified that reduced gene expression of duplicated genes had occurred in the worm, fly, and mouse (Mus musculus). Next, several histone marks, with the capacity to control mRNA abundance in the models studied, were examined. In the worm and fly, but not in the mouse, multiple histone modifications were found to assist mRNA dosage maintenance following gene duplication events and the possible involvement of adenine DNA methylation in this process was excluded. Furthermore, the histone marks and acting regions that mediated the reduction in duplicated gene expression were found to be largely organism specific. Thus, it appears that many of the histone marks that maintain mRNA dosage were independently recruited during the evolution of worms and flies to compensate for the loss of cytosine DNA methylation machinery from their genomes. PMID- 28720580 TI - Detecting ancient positive selection in humans using extended lineage sorting. AB - Natural selection that affected modern humans early in their evolution has likely shaped some of the traits that set present-day humans apart from their closest extinct and living relatives. The ability to detect ancient natural selection in the human genome could provide insights into the molecular basis for these human specific traits. Here, we introduce a method for detecting ancient selective sweeps by scanning for extended genomic regions where our closest extinct relatives, Neandertals and Denisovans, fall outside of the present-day human variation. Regions that are unusually long indicate the presence of lineages that reached fixation in the human population faster than expected under neutral evolution. Using simulations, we show that the method is able to detect ancient events of positive selection and that it can differentiate those from background selection. Applying our method to the 1000 Genomes data set, we find evidence for ancient selective sweeps favoring regulatory changes and present a list of genomic regions that are predicted to underlie positively selected human specific traits. PMID- 28720583 TI - Central effects of insulin detemir on feeding, body weight, and metabolism in rats. AB - Insulin detemir (DET) is a basal insulin analog that, in contrast to other long acting forms of insulin, has significant weight-gain-sparing effects in diabetic patients. We hypothesized that this effect of DET may be due to its enhanced catabolic action in the central nervous system. We investigated the long-term effects of single third ventricular (3V) microinjections of equimolar doses of DET and regular insulin in normal male rats on feeding, body weight, energy expenditure (EE), and respiratory quotient (RQ). Also, in acute testing, we assessed the ability of lower doses of DET to alter feeding, EE, and RQ when microinjected directly into the paraventricular nucleus (PVN). The anabolic peptide ghrelin served as a positive control in acute testing. 3V administration of both DET (0.5-2.0 mU) and regular insulin (2.0-8.0 mU) significantly reduced feeding and body weight over 48 and 120 h, respectively, with DET yielding greater inhibitory effects. DET also stimulated greater elevations of EE and reductions of RQ over 72 and 48 h postinjection, respectively. In acute (4 h) testing, microinjections of DET (0.5 mU) into the PVN reduced feeding, increased EE, and reduced RQ, while ghrelin (100 pmol) had the opposite effects. When administered sequentially into the PVN, DET (0.25 and 0.5 mU) reversed ghrelin induced feeding, EE, and RQ effects. These data support the notion that the weight-sparing effect of DET is at least in part based on its central catabolic action and that enhanced EE and reduced RQ may participate in this effect. PMID- 28720585 TI - Evidence based medicine misses the "art" of helping humans. PMID- 28720586 TI - A MALT lymphoma prognostic index. AB - There are no widely accepted prognostic indices for extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT). This study aimed to develop and validate a specific prognostic tool to personalize and optimize treatment of patients with MALT lymphoma. A prognostic index was built by Cox regression (stepwise selection) using data from 401 patients enrolled in the international randomized International Extranodal Lymphoma Study Group 19 (IELSG-19) trial (NCT 00210353). A validation set, including 633 patients, was obtained by merging 3 independent cohorts of MALT lymphoma patients. The 3 individual features maintaining the greatest prognostic significance for event-free survival (EFS, the main endpoint of the IELSG-19 trial) were age >=70 years (hazard ratio [HR], 1.72; 95% confidence interval [CI], 1.26-2.33), Ann Arbor stage III or IV (HR, 1.79; 95% CI ,1.35-2.38), and an elevated lactate dehydrogenase level (HR, 1.87; 95% CI, 1.27-2.77). The prognostic index (MALT-IPI) constructed using these 3 parameters identified 3 groups: low, intermediate, and high risk (corresponding to the presence of 0, 1, or >=2 of these factors, respectively). The 5-year EFS rates in the low-, intermediate-, and high-risk groups were 70%, 56%, and 29%, respectively. The MALT-lymphoma International Prognostic Index (MALT-IPI) also significantly discriminated between patients with different progression-free, overall, and cause-specific survival. The prognostic utility was retained in gastric and nongastric lymphomas, in each treatment arm (chlorambucil, rituximab, and rituximab plus chlorambucil), and was confirmed in the validation set. The new index, MALT-IPI, is a simple, accessible, and effective tool to identify MALT lymphoma patients at risk of poor outcomes. It may help define appropriate treatment approaches for individual patients. PMID- 28720584 TI - Protein kinase N2 regulates AMP kinase signaling and insulin responsiveness of glucose metabolism in skeletal muscle. AB - Insulin resistance is central to the development of type 2 diabetes and related metabolic disorders. Because skeletal muscle is responsible for the majority of whole body insulin-stimulated glucose uptake, regulation of glucose metabolism in this tissue is of particular importance. Although Rho GTPases and many of their affecters influence skeletal muscle metabolism, there is a paucity of information on the protein kinase N (PKN) family of serine/threonine protein kinases. We investigated the impact of PKN2 on insulin signaling and glucose metabolism in primary human skeletal muscle cells in vitro and mouse tibialis anterior muscle in vivo. PKN2 knockdown in vitro decreased insulin-stimulated glucose uptake, incorporation into glycogen, and oxidation. PKN2 siRNA increased 5'-adenosine monophosphate-activated protein kinase (AMPK) signaling while stimulating fatty acid oxidation and incorporation into triglycerides and decreasing protein synthesis. At the transcriptional level, PKN2 knockdown increased expression of PGC-1alpha and SREBP-1c and their target genes. In mature skeletal muscle, in vivo PKN2 knockdown decreased glucose uptake and increased AMPK phosphorylation. Thus, PKN2 alters key signaling pathways and transcriptional networks to regulate glucose and lipid metabolism. Identification of PKN2 as a novel regulator of insulin and AMPK signaling may provide an avenue for manipulation of skeletal muscle metabolism. PMID- 28720587 TI - Platelet soluble CD40-ligand level is associated with transfusion adverse reactions in a mixed threshold-and-hit model. PMID- 28720588 TI - EWS/FLI is a Master Regulator of Metabolic Reprogramming in Ewing Sarcoma. AB - Ewing sarcoma is a bone malignancy driven by a translocation event resulting in the fusion protein EWS/FLI1 (EF). EF functions as an aberrant and oncogenic transcription factor that misregulates the expression of thousands of genes. Previous work has focused principally on determining important transcriptional targets of EF, as well as characterizing important regulatory partnerships in EF dependent transcriptional programs. Less is known, however, about EF-dependent metabolic changes or their role in Ewing sarcoma biology. Therefore, the metabolic effects of silencing EF in Ewing sarcoma cells were determined. Metabolomic analyses revealed distinct separation of metabolic profiles in EF knockdown versus control-knockdown cells. Mitochondrial stress tests demonstrated that knockdown of EF increased respiratory as well as glycolytic functions. Enzymes and metabolites in several metabolic pathways were altered, including de novo serine synthesis and elements of one-carbon metabolism. Furthermore, phosphoglycerate dehydrogenase (PHGDH) was found to be highly expressed in Ewing sarcoma and correlated with worse patient survival. PHGDH knockdown or pharmacologic inhibition in vitro caused impaired proliferation and cell death. Interestingly, PHGDH modulation also led to elevated histone expression and methylation. These studies demonstrate that the translocation-derived fusion protein EF is a master regulator of metabolic reprogramming in Ewing sarcoma, diverting metabolites toward biosynthesis. As such, these data suggest that the metabolic aberrations induced by EF are important contributors to the oncogenic biology of these tumors.Implications: This previously unexplored role of EWS/FLI1 driven metabolic changes expands the understanding of Ewing sarcoma biology, and has potential to significantly inform development of therapeutic strategies. Mol Cancer Res; 15(11); 1517-30. (c)2017 AACR. PMID- 28720591 TI - Using fluorescence to understand beta subunit-NaV channel interactions. PMID- 28720590 TI - Mechanisms of noncovalent beta subunit regulation of NaV channel gating. AB - Voltage-gated Na+ (NaV) channels comprise a macromolecular complex whose components tailor channel function. Key components are the non-covalently bound beta1 and beta3 subunits that regulate channel gating, expression, and pharmacology. Here, we probe the molecular basis of this regulation by applying voltage clamp fluorometry to measure how the beta subunits affect the conformational dynamics of the cardiac NaV channel (NaV1.5) voltage-sensing domains (VSDs). The pore-forming NaV1.5 alpha subunit contains four domains (DI DIV), each with a VSD. Our results show that beta1 regulates NaV1.5 by modulating the DIV-VSD, whereas beta3 alters channel kinetics mainly through DIII-VSD interaction. Introduction of a quenching tryptophan into the extracellular region of the beta3 transmembrane segment inverted the DIII-VSD fluorescence. Additionally, a fluorophore tethered to beta3 at the same position produced voltage-dependent fluorescence dynamics strongly resembling those of the DIII VSD. Together, these results provide compelling evidence that beta3 binds proximally to the DIII-VSD. Molecular-level differences in beta1 and beta3 interaction with the alpha subunit lead to distinct activation and inactivation recovery kinetics, significantly affecting NaV channel regulation of cell excitability. PMID- 28720589 TI - Dynamic role of the tether helix in PIP2-dependent gating of a G protein-gated potassium channel. AB - G protein-gated inwardly rectifying potassium (GIRK) channels control neuronal excitability in the brain and are implicated in several different neurological diseases. The anionic phospholipid phosphatidylinositol 4,5 bisphosphate (PIP2) is an essential cofactor for GIRK channel gating, but the precise mechanism by which PIP2 opens GIRK channels remains poorly understood. Previous structural studies have revealed several highly conserved, positively charged residues in the "tether helix" (C-linker) that interact with the negatively charged PIP2 However, these crystal structures of neuronal GIRK channels in complex with PIP2 provide only snapshots of PIP2's interaction with the channel and thus lack details about the gating transitions triggered by PIP2 binding. Here, our functional studies reveal that one of these conserved basic residues in GIRK2, Lys200 (6'K), supports a complex and dynamic interaction with PIP2 When Lys200 is mutated to an uncharged amino acid, it activates the channel by enhancing the interaction with PIP2 Atomistic molecular dynamic simulations of neuronal GIRK2 with the same 6' substitution reveal an open GIRK2 channel with PIP2 molecules adopting novel positions. This dynamic interaction with PIP2 may explain the intrinsic low open probability of GIRK channels and the mechanism underlying activation by G protein Gbetagamma subunits and ethanol. PMID- 28720592 TI - Exercise Training Improves but Does Not Normalize Left Ventricular Systolic and Diastolic Function in Adolescents With Type 1 Diabetes. AB - OBJECTIVE: To determine the impact of 20 weeks of exercise training in aerobic capacity on left ventricular function and glycemic control in adolescents with and without type 1 diabetes. RESEARCH DESIGN AND METHODS: Fifty-three adolescents with type 1 diabetes (aged 15.6 years) were divided into two groups: exercise training (n = 38) and nontraining (n = 15). Twenty-two healthy adolescents without diabetes (aged 16.7 years) were included and, with the 38 participants with type 1 diabetes, participated in a 20-week exercise-training intervention. Assessments included VO2max and body composition. Left ventricular parameters were obtained at rest and during acute exercise using MRI. RESULTS: Exercise training improved aerobic capacity (10%) and stroke volume (6%) in both trained groups, but the increase in the group with type 1 diabetes remained lower than trained control subjects. Increased stroke volume in adolescents with type 1 diabetes resulted from greater left ventricular contractility (9% increase in ejection fraction and an 11% reduction in end-systolic volumes) and, to a lesser extent, improved left ventricular filling (6%), suggesting that impaired diastolic function can be affected by exercise training in adolescents with type 1 diabetes. Insulin use decreased by ~10%, but no change in glycemic status was observed. CONCLUSIONS: These data demonstrate that in adolescents, the impairment in left ventricular function seen with type 1 diabetes can be improved, although not normalized, with regular intense physical activity. Importantly, diastolic dysfunction, a common mechanism causing heart failure in older subjects with diabetes, appears to be partially reversible in this age group. PMID- 28720594 TI - Impact of transition on quality of life in patients with congenital adrenal hyperplasia diagnosed during childhood. AB - BACKGROUND: Health-related quality of life (QoL) in adult patients with congenital adrenal hyperplasia (CAH) has been variously reported. However, there is no study evaluating the impact of transition on quality of life. METHODS: Adult patients with classic or non-classic CAH diagnosed during childhood CAH, born between 1970 and 1990, were recruited from the registers of Pediatric departments belonging to the French reference center for endocrine rare disease. Primary end point was the quality of life (WHOQoL -BREF). RESULTS: Seventy three patients were included in the study, among them 59/73 (81%) were transferred to adult endocrinologist by their pediatricians for transition. WHOQoL -BREF scores were similar between patients with or without transition to specialist adult services, except for environment dimension score, which was slightly higher in CAH patients without transition. However, CAH patients with a regular follow-up had a better physical health, psychological health and environment score and item global quality of life than the group without regular follow-up after transition. CONCLUSION: Regular medical follow-up in adulthood is associated with the transition between pediatric and adult care and with better QoL in adults with CAH. PMID- 28720593 TI - Vitamin A, endocrine tissues and hormones: interplay and interactions. AB - Vitamin A (retinol) is a micronutrient critical for cell proliferation and differentiation. In adults, vitamin A and metabolites such as retinoic acid (RA) play major roles in vision, immune and brain functions, and tissue remodelling and metabolism. This review presents the physiological interactions of retinoids and endocrine tissues and hormonal systems. Two endocrine systems have been particularly studied. In the pituitary, retinoids targets the corticotrophs with a possible therapeutic use in corticotropinomas. In the thyroid, retinoids interfere with iodine metabolism and vitamin A deficiency aggravates thyroid dysfunction caused by iodine-deficient diets. Retinoids use in thyroid cancer appears less promising than expected. Recent and still controversial studies investigated the relations between retinoids and metabolic syndrome. Indeed, retinoids contribute to pancreatic development and modify fat and glucose metabolism. However, more detailed studies are needed before planning any therapeutic use. Finally, retinoids probably play more minor roles in adrenal and gonads development and function apart from their major effects on spermatogenesis. PMID- 28720596 TI - The Elongator complex regulates hypocotyl growth in darkness and during photomorphogenesis. AB - The Elongator complex (hereafter Elongator) promotes RNA polymerase II-mediated transcript elongation through epigenetic activities such as histone acetylation. Elongator regulates growth, development, immune response and sensitivity to drought and abscisic acid. We demonstrate that elo mutants exhibit defective hypocotyl elongation but have a normal apical hook in darkness and are hyposensitive to light during photomorphogenesis. These elo phenotypes are supported by transcriptome changes, including downregulation of circadian clock components, positive regulators of skoto- or photomorphogenesis, hormonal pathways and cell wall biogenesis-related factors. The downregulated genes LHY, HFR1 and HYH are selectively targeted by Elongator for histone H3K14 acetylation in darkness. The role of Elongator in early seedling development in darkness and light is supported by hypocotyl phenotypes of mutants defective in components of the gene network regulated by Elongator, and by double mutants between elo and mutants in light or darkness signaling components. A model is proposed in which Elongator represses the plant immune response and promotes hypocotyl elongation and photomorphogenesis via transcriptional control of positive photomorphogenesis regulators and a growth-regulatory network that converges on genes involved in cell wall biogenesis and hormone signaling.This article has an associated First Person interview with the first author of the paper. PMID- 28720595 TI - Transcription controls growth, cell kinetics and cholesterol supply to sustain ACTH responses. AB - Chronic ACTH exposure is associated with adrenal hypertrophy and steroidogenesis. The underlying molecular processes in mice have been analysed by microarray, histological and immunohistochemical techniques. Synacthen infused for 2 weeks markedly increased adrenal mass and plasma corticosterone levels. Microarray analysis found greater than 2-fold changes in expression of 928 genes (P < 0.001; 397 up, 531 down). These clustered in pathways involved in signalling, sterol/lipid metabolism, cell proliferation/hypertrophy and apoptosis. Signalling genes included some implicated in adrenal adenomas but also upregulated genes associated with cyclic AMP and downregulated genes associated with aldosterone synthesis. Sterol metabolism genes were those promoting cholesterol supply (Scarb1, Sqle, Apoa1) and disposal (Cyp27a1, Cyp7b1). Oil red O staining showed lipid depletion consistent with reduced expression of genes involved in lipid synthesis. Genes involved in steroidogenesis (Star, Cyp11a1, Cyp11b1) were modestly affected (P < 0.05; <1.3-fold). Increased Ki67, Ccna2, Ccnb2 and Tk1 expression complemented immunohistochemical evidence of a 3-fold change in cell proliferation. Growth arrest genes, Cdkn1a and Cdkn1c, which are known to be active in hypertrophied cells, were increased >4-fold and cross-sectional area of fasciculata cells was 2-fold greater. In contrast, genes associated with apoptosis (eg Casp12, Clu,) were downregulated and apoptotic cells (Tunel staining) were fewer (P < 0.001) and more widely distributed throughout the cortex. In summary, long-term steroidogenesis with ACTH excess is sustained by genes controlling cholesterol supply and adrenal mass. ACTH effects on adrenal morphology and genes controlling cell hypertrophy, proliferation and apoptosis suggest the involvement of different cell types and separate molecular pathways. PMID- 28720597 TI - Accuracy of administrative claims data for cerebral palsy diagnosis: a retrospective cohort study. AB - BACKGROUND: Cerebral palsy is the most common cause of childhood physical disability, with multiple associated comorbidities. Administrative claims data provide population-level prevalence estimates for cerebral palsy surveillance; however, their diagnostic accuracy has never been validated in Quebec. This study aimed to assess the accuracy of administrative claims data for the diagnosis of cerebral palsy. METHODS: We conducted a retrospective cohort study of children with cerebral palsy born between 1999 and 2002 within 6 health administrative regions of Quebec. Provincial cerebral palsy registry data (reference standard) and administrative physician claims were linked. We explored differences between true-positive and false-negative cases using subgroup sensitivity analysis. RESULTS: A total of 301 children were identified with confirmed cerebral palsy from the provincial registry, for an estimated prevalence of 1.8 (95% confidence interval [CI] 1.6-2.1) per 1000 children 5 years of age. The sensitivity and specificity of administrative claims data for cerebral palsy were 65.5% (95% CI 59.8%-70.8%) and 99.9% (95% CI 99.9%-99.9%), respectively, yielding a prevalence of 2.0 (95% CI 1.9-2.3) per 1000 children 5 years of age. The positive and negative predictive values were 58.8% (95% CI 53.3%-64.1%) and 99.9% (95% CI 99.9%-99.9%), respectively. The kappa value was 0.62 (95% CI 0.57-0.67). Administrative claims data were more sensitive for children from rural regions, born preterm, with spastic quadriparesis and with higher levels of motor impairment. INTERPRETATION: Administrative claims data do not capture the full spectrum of children with cerebral palsy. This suggests the need for a more sensitive case definition and caution when using such data without validation. PMID- 28720598 TI - Giant schwannomas of the sciatic nerve. AB - We report a very rare case of giant schwannomas of the sciatic nerve in a 39-year old woman who presented with increasing swelling and discomfort in the posterior aspect of her right thigh. We demonstrate that even with such large tumours, surgical excision could be successfully carried out to resolve all symptoms while causing no permanent nerve damage. It remains paramount that large soft tissue tumours get referred to a sarcoma centre and be managed by a specialist multidisciplinary team. PMID- 28720599 TI - Hyperacute muscle weakness in an unusual coexistence of antisignal recognition particle and anti-Mi-2 antibodies. AB - Idiopathic inflammatory myopathies are a heterogeneous group of systemic diseases characterised by variable phenotypes of chronic progressive muscle weakness. Myositis-specific antibodies (MSAs) include antibodies to cytoplasmic signal recognition particle (SRP) and various tRNA synthetases as well as the nuclear helicase protein Mi-2. These antibodies are typically found only in a fraction of true myositis cases and they tend to be mutually exclusive. Few cases of coexistence of two MSAs in the same patient have been reported and these cases all involve an antisynthetase antibody coexisting with either anti-SRP or anti-Mi 2 antibody. Peculiar clinical manifestations may be associated with different combinations of MSAs but the rarity of these cases makes their characterisation difficult. We report the first ever case of anti-SRP and anti-Mi-2 copositive polymyositis in a 19-year-old boy who presented with a week history of profound muscle weakness that attained its peak within 24a?0/00hours of onset. PMID- 28720600 TI - Is the mechanism of re-expansion pulmonary oedema in a heart-lung interaction? AB - The mechanism of re-expansion pulmonary oedema (Re-PE) is unclear. There are multiple variables in play when evaluating the response to evacuation of pleural fluid. We present an educational case of a critically ill patient admitted for respiratory failure who was fully dependent on ventricular pacing set at a constant rate throughout the episode of Re-PE. The transthoracic echocardiography (TTE) showed an ejection fraction of 38%, moderate mitral regurgitation (MR), mildly dilated right ventricle and moderate pulmonary hypertension. A pleural tap evacuated 850 mL of transudate, which was followed by tachypnoea and deteriorating oxygenation. Another repeat TTE revealed a Re-PE with elevated left ventricular end-diastolic pressure, severe MR, increased pulmonary hypertension and a decrease in stroke volume. There were no parallel changes in ventilation modality, heart rate, fluid therapy and vasopressor dosage. The treatment was initiated with dobutamine. The patient was extubated the next day and was later discharged to the cardiology department. PMID- 28720601 TI - A case of progressive orthopnoea and shoulder pain secondary to bilateral diaphragmatic paralysis. AB - A 45-year-old man with a raised body mass index presented with an acute history of right lower chest pain and increasing breathlessness. C reactive protein, D dimer and cardiac echocardiography were negative, with mild bibasal atelectasis the only positive reported finding from erect chest X-ray and CT pulmonary angiogram. He was discharged with antibiotics for a chest infection. He remained severely breathless and was referred to the sleep-related breathing disorders clinic. He described shoulder pain, daytime tiredness and sleeping upright due to a Aca'!EoesuffocatingAca'!a"c sensation. The video demonstrates the clinical findings. The CT topogram confirmed bilateral diaphragmatic paralysis. Spirometry demonstrated an 80% reduction in forced vital capacity in the supine position, when compared with erect. Consultation with a neurologist yielded the diagnosis of neuralgic amyotrophy, leading to bilateral diaphragmatic paralysis. The respiratory symptoms have been controlled with night-time non-invasive ventilation, allowing him to sleep supine. PMID- 28720602 TI - A reminder of Escherichia coli sepsis-induced reversible cardiomyopathy. AB - Cardiomyopathy is a progressive disease of myocardium causing either mechanical or electrical disturbances. Sepsis-induced cardiomyopathy (SICM) is an entity of cardiomyopathy which is reversible in 1a?"2 weeks after recovery from sepsis or septic shock. SICM is thought to have unpredictable cumulative mortality towards sepsis but its exact mechanism remains elusive. We report a case of Escherichia coli SICM in a 63-year-old woman presented with sudden onset of dyspnoea on exertion and orthopnoea following nausea, vomiting and diarrhoea after consuming Chinese foods. Transthoracic echocardiogram revealed severely reduced global left ventricular ejection fraction (LVEF) of <20%a?0/00which returned back to normal LVEF of 57% after 10 days. Subsequent cardiac catheterisation showed non obstructive coronaries. No specific therapy intended for reversal of SICM presents to date despite current sepsis survival guideline available for haemodynamic support. Initiation of beta blockers after recovery from septic shock has been beneficial. PMID- 28720603 TI - A rare case of spontaneous tracheal perforation. PMID- 28720604 TI - Intracardiac mass from Burkitt's lymphoma in an immunocompromised patient: a very rare form of presentation. PMID- 28720605 TI - Persistent fever and right hypochondrium pain. PMID- 28720606 TI - Re-using blood products as an alternative supplement in the optimisation of clinical-grade adipose-derived mesenchymal stem cell culture. AB - OBJECTIVES: Adipose-derived mesenchymal stem cells (ADMSCs) are a promising strategy for orthopaedic applications, particularly in bone repair. Ex vivo expansion of ADMSCs is required to obtain sufficient cell numbers. Xenogenic supplements should be avoided in order to minimise the risk of infections and immunological reactions. Human platelet lysate and human plasma may be an excellent material source for ADMSC expansion. In the present study, use of blood products after their recommended transfusion date to prepare human platelet lysate (HPL) and human plasma (Hplasma) was evaluated for in vitro culture expansion and osteogenesis of ADMSCs. METHODS: Human ADMSCs were cultured in medium supplemented with HPL, Hplasma and a combination of HPL and Hplasma (HPL+Hplasma). Characteristics of these ADMSCs, including osteogenesis, were evaluated in comparison with those cultured in fetal bovine serum (FBS). RESULTS: HPL and HPL+Hplasma had a significantly greater growth-promoting effect than FBS, while Hplasma exhibited a similar growth-promoting effect to that of FBS. ADMSCs cultured in HPL and/or Hplasma generated more colony-forming unit fibroblasts (CFU-F) than those cultured in FBS. After long-term culture, ADMSCs cultured in HPL and/or Hplasma showed reduced cellular senescence, retained typical cell phenotypes, and retained differentiation capacities into osteogenic and adipogenic lineages. CONCLUSION: HPL and Hplasma prepared from blood products after their recommended transfusion date can be used as an alternative and effective source for large-scale ex vivo expansion of ADMSCs.Cite this article: J. Phetfong, T. Tawonsawatruk, K. Seenprachawong, A. Srisarin, C. Isarankura-Na Ayudhya, A. Supokawej. Re-using blood products as an alternative supplement in the optimisation of clinical-grade adipose-derived mesenchymal stem cell culture. Bone Joint Res 2017;6:414-422. DOI: 10.1302/2046-3758.67.BJR-2016-0342.R1. PMID- 28720607 TI - New diagnostic tests: more harm than good. PMID- 28720609 TI - Doctors are being denied time off for non-clinical work. PMID- 28720608 TI - Shining Light on the Function of NPH3/RPT2-Like Proteins in Phototropin Signaling. PMID- 28720610 TI - Follow-up of patients with metal-on-metal hip replacements. PMID- 28720611 TI - Prevalence and risk factors of latent tuberculosis infection in Africa: a systematic review and meta-analysis protocol. AB - INTRODUCTION: Latent tuberculosis infection (LTBI) remains a major public health problem and one of the major contributors to the pool of active tuberculosis cases. The true burden of LTBI in Africa is not known. Early modelling studies estimate that over 33% of the world's population is infected with latent tuberculosis. We propose conducting a systematic review and a meta-analysis to evaluate the burden and risk factors of LTBI in Africa reported in studies from 2000 to 2017. METHODS AND ANALYSIS: We will include cross-sectional studies, cohort studies and case-control studies estimating either tuberculin skin test (TST) or interferon-gamma release assay (IGRA) confirmed prevalence of LTBI and associated risk factors among people in African countries. A comprehensive search of relevant literature will be conducted on electronic databases using common and medical subject heading (MeSH) terms for LTBI, and an African search filter. Risk of bias will be evaluated by assessing all qualifying full-text articles for quality and eligibility using a quality score assessment tool. Standardised data extraction will be carried out after which prevalence estimates will be pooled using random-effects models in Stata V.13. Where there is sufficient data , subgroup meta-analyses will be conducted by risk factors including participant's age group, occupation, location and HIV status. This systematic review will be reported according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses Protocols 2015 Statement. ETHICS AND DISSEMINATION: No ethical issues were foreseen given that this was a protocol for a systematic review of published studies. The results of this study will be published in a peer-reviewed journal and presented at conferences. TRIAL REGISTRATION NUMBER: Systematic review registration: PROSPERO CRD42016037997. PMID- 28720612 TI - Translating staff experience into organisational improvement: the HEADS-UP stepped wedge, cluster controlled, non-randomised trial. AB - OBJECTIVES: Frontline insights into care delivery correlate with patients' clinical outcomes. These outcomes might be improved through near-real time identification and mitigation of staff concerns. We evaluated the effects of a prospective frontline surveillance system on patient and team outcomes. DESIGN: Prospective, stepped wedge, non-randomised, cluster controlled trial; prespecified per protocol analysis for high-fidelity intervention delivery. PARTICIPANTS: Seven interdisciplinary medical ward teams from two hospitals in the UK. INTERVENTION: Prospective clinical team surveillance (PCTS): structured daily interdisciplinary briefings to capture staff concerns, with organisational facilitation and feedback. MAIN MEASURES: The primary outcome was excess length of stay (eLOS): an admission more than 24 hours above the local average for comparable patients. Secondary outcomes included safety and teamwork climates, and incident reporting. Mixed-effects models adjusted for time effects, age, comorbidity, palliation status and ward admissions. Safety and teamwork climates were measured with the Safety Attitudes Questionnaire. High-fidelity PCTS delivery comprised high engagement and high briefing frequency. RESULTS: Implementation fidelity was variable, both in briefing frequency (median 80% working days/month, IQR 65%-90%) and engagement (median 70 issues/ward/month, IQR 34-113). 1714/6518 (26.3%) intervention admissions had eLOS versus 1279/4927 (26.0%) control admissions, an absolute risk increase of 0.3%. PCTS increased eLOS in the adjusted intention-to-treat model (OR 1.32, 95% CI 1.10 to 1.58, p=0.003). Conversely, high-fidelity PCTS reduced eLOS (OR 0.79, 95% CI 0.67 to 0.94, p=0.006). High-fidelity PCTS also increased total, high-yield and non-nurse incident reports (incidence rate ratios 1.28-1.79, all p<0.002). Sustained PCTS significantly improved safety and teamwork climates over time. CONCLUSIONS: This study highlighted the potential benefits and pitfalls of ward-level interdisciplinary interventions. While these interventions can improve care delivery in complex, fluid environments, the manner of their implementation is paramount. Suboptimal implementation may have an unexpectedly negative impact on performance. TRIAL REGISTRATION NUMBER: ISRCTN 34806867 (http://www.isrctn.com/ISRCTN34806867). PMID- 28720614 TI - Effect of occupational safety and health education received during schooling on the incidence of workplace injuries in the first 2 years of occupational life: a prospective study. AB - OBJECTIVES: This study aimed to determine the effect of occupational safety and health (OSH) education during formal schooling on the incidence of workplace injuries (WIs) in young people starting their careers. We hypothesised that young people who had received OSH education during their schooling would have fewer WIs than those who received no OSH education. Secondary objectives focused on the effect of 'first aid at work' training during schooling and the conditions encountered on arrival in the company (occupational hazard information, safety training and job task training) on WI occurrence. DESIGN: Prospective cohort study. PARTICIPANTS: From 2009 to 2012, French apprentices and students at the end of their schooling and starting their careers were included. OUTCOMES: Occurrence of WIs. METHODS: At the time of inclusion, information about school courses and personal characteristics were collected, and subsequent half-yearly contacts gathered information relating to work and personal data. During the 2 year follow-up, WIs were directly reported by participants and were identified by searching the French National Health Insurance Funds' databases listing compulsory WI declarations. RESULTS: 755 participants reported holding 1290 jobs. During follow-up, 158 WIs were identified, corresponding to an incident rate of 0.12 (0.10 to 0.14) WIs per full-time worker. Subjects who reported having received OSH education at school had two times less WIs than those declaring not having received OSH education (incidence rate ratio (IRR) 0.51, 0.00 to 0.98). A lower WI risk was observed for participants who received the 'first aid at work' training (IRR=0.68, 0.00 to 0.98). The conditions on arrival in company were not associated with WIs occurrence. CONCLUSION: In France, the OSH education provided to apprentices and students is mostly broader than the specific risks related to future jobs. Our results highlight the advantages of reinforcing this approach. PMID- 28720613 TI - Retrospective analysis of newly recorded certifications of visual impairment due to diabetic retinopathy in Wales during 2007-2015. AB - OBJECTIVE: The aim of this study was to analyse the changes in new certifications for both sight impairment (SI) and severe sight impairment (SSI, blindness) in Wales due to diabetic retinopathy (DR)/maculopathy between 2007 and 2015. RESEARCH DESIGN AND METHODS: This is a retrospective analysis of annual data of new certifications for visual impairment and blindness (Certificate of Vision Impairment) for England and Wales derived from the national database provided by the Certifications Office, Moorfields Eye Hospital, over a period of 8 years from 2007. RESULTS: In Wales there were 339 less new certifications for both SI and severe SSI from any cause combined from 2007-2008 to 2014-2015. The number SI and SSI combined specifically due to DR was reduced by 22 in people with known diabetes. This was a reduction in new certifications over the observation period from 82.4 to 46.9 per 100 000 (-43.1%) with a fall in SSI from 31.3 to 15.8 per 100 000 (-49.4%), respectively. During this observation period however, there was a parallel increase in 52 229 (39.8%) persons with diabetes in Wales. CONCLUSIONS: While acknowledging the limitations of the certification process and the increasing numbers of persons with diabetes, the incidence of SI and SSI per 100 000 population of persons with diabetes in Wales has almost halved over an 8 year period up to 2015. This may reflect the earlier diagnosis of DR and sight threatening DR since the introduction of screening and/or improved diabetes management with timely onward referral and newer treatments. PMID- 28720615 TI - Assessment of the effectiveness and safety of ethosuximide in the treatment of abdominal pain related to irritable bowel syndrome - IBSET: protocol of a randomised, parallel, controlled, double-blind and multicentre trial. AB - INTRODUCTION: Irritable bowel syndrome (IBS) is characterised by the association of abdominal chronic pain with bowel habit disorders in the absence of identifiable organic disease. This is the first reason for consultation in gastroenterology, with an estimated prevalence of 10%-15% in industrialised countries. Although this is a benign gastrointestinal disease, its chronicity profoundly impacts the patient's quality of life and causes considerable health spending. Actual medical treatments are poorly efficient on IBS-related abdominal pain, making it a major public health concern. The mechanisms causing IBS symptoms are unknown. Recent studies have shown the involvement of T-type channel in abdominal pain. We aim to evaluate the therapeutic potential of ethosuximide, a T-type channel blocker, on the abdominal pain of patients presenting an IBS. METHODS AND ANALYSIS: The IBSET trial is a randomised, controlled, parallel, double-blind and multicentre study. It is the first clinical trial evaluating the efficacy and safety of ethosuximide on abdominal pain related to IBS. Adults with IBS that report significant abdominal pain (>=4/10) at least for 3 months will be included. 290 patients will be randomly assigned to receive either ethosuximide or placebo over 12 weeks after 1 week of run-in period. The primary endpoint is the rate of responders (pain reduction >=30% and Subject Global Assessment of Relief score >=4). The intensity of abdominal pain will be assessed by an 11 point Numerical Rating Scale before and after 12 weeks of treatment and the score of the Subject Global Assessment of Relief scale at the end of treatment. The secondary endpoints are the safety of ethosuximide, the intensity and features of IBS and quality of life. ETHICS AND DISSEMINATION: The study was approved by an independent medical ethics committee (CPP Sud-Est VI, Clermont-Ferrand, France). The results will be published in a peer-review journal and presented at international congresses. TRIAL REGISTRATION NUMBER: NCT02973542; Pre-results. PMID- 28720616 TI - Concomitant preterm birth and severe small-for-gestational age birth weight among infants of immigrant mothers in Ontario originating from the Philippines and East Asia: a population-based study. AB - OBJECTIVES: Women from the Philippines form one of the largest immigrant groups to North America. Their newborns experience higher rates of preterm birth (PTB), and separately, small-for-gestational age (SGA) birth weight, compared with other East Asians. It is not known if Filipino women are at elevated risk of concomitant PTB and severe SGA (PTB-SGA), a pathological state likely reflective of placental dysfunction and neonatal morbidity. METHODS: We conducted a population-based study of all singleton or twin live births in Ontario, from 2002 to 2011, among immigrant mothers from the Philippines (n=27 946), Vietnam (n=15 297), Hong Kong (n=5618), South Korea (n=5148) and China (n=42 517). We used modified Poisson regression to generate relative risks (RR) of PTB-SGA, defined as a birth <37 weeks' gestation and a birth weight <5th percentile. RRs were adjusted for maternal age, parity, marital status, income quintile, infant sex and twin births. RESULTS: Relative to mothers from China (2.3 per 1000), the rate of PTB-SGA was significantly higher among infants of mothers from the Philippines (6.5 per 1000; RR 2.91, 95% CI 2.27 to 3.73), and those from Vietnam (3.7 per 1000; RR 1.68, 95% CI 1.21 to 2.34). The RR of PTB-SGA was not higher for infants of mothers from Hong Kong or South Korea. INTERPRETATION: Among infants born to immigrant women from five East Asian birthplaces, the risk of PTB-SGA was highest among those from the Philippines. These women and their fetuses may require additional monitoring and interventions. PMID- 28720617 TI - Protocol for an online randomised controlled trial to evaluate the clinical and cost-effectiveness of a peer-supported self-management intervention for relatives of people with psychosis or bipolar disorder: Relatives Education And Coping Toolkit (REACT). AB - INTRODUCTION: Despite clinical guidelines recommendations, many relatives of people with psychosis or bipolar disorder do not currently receive the support they need. Online information and support may offer a solution. METHODS AND ANALYSIS: This single-blind, parallel, online randomised controlled trial will determine clinical and cost-effectiveness of the Relatives Education And Coping Toolkit (REACT) (including an online resource directory (RD)), compared with RD only, for relatives of people with psychosis or bipolar disorder. Both groups continue to receive treatment as usual. Independent, web-based variable, block, individual randomisation will be used across 666 relatives. Primary outcome is distress at 24 weeks (measured by General Health Questionnaire; GHQ-28) compared between groups using analysis of covariance, adjusting for baseline score. Secondary clinical outcomes are carer well-being and support. Cost-effectiveness analysis will determine cost of a significant unit change (three-point reduction) in the GHQ-28. Costs include offering and supporting the intervention in the REACT arm, relevant healthcare care costs including health professional contacts, medications prescribed and time off (or ability to) work for the relative. Cost utility analysis will be calculated as the marginal cost of changes in quality adjusted life years, based on EuroQol. We will explore relatives' beliefs, perceived coping and amount of REACT toolkit use as possible outcome mediators. We have embedded two methodological substudies in the protocol to determine the relative effectiveness of a low-value (L10) versus higher value (L20) incentive, and an unconditional versus conditional incentive, on improving follow-up rates. ETHICS AND DISSEMINATION: The trial has ethical approval from Lancaster National Research Ethics Service (NRES)Committee (15/NW/0732) and is overseen by an independent Data Monitoring and Ethics Committee and Trial Steering Committee. Protocol version 1.5 was approved on 9 January 2017. All updates to protocols are uploaded to the National Institute for Health Research (NIHR) Journals Library. A full statistical analysis plan is available at https://figshare.com/account/home#/projects/19975. Publications will be in peer reviewed journals (open access wherever possible). Requests for access to the data at the end of the study will be reviewed and granted where appropriate by the Trial Management Group. TRIAL REGISTRATION NUMBER: ISRCTN72019945, pre results. PMID- 28720618 TI - Interpretation of CIs in clinical trials with non-significant results: systematic review and recommendations. AB - OBJECTIVES: Interpretation of CIs in randomised clinical trials (RCTs) with treatment effects that are not statistically significant can distinguish between results that are 'negative' (the data are not consistent with a clinically meaningful treatment effect) or 'inconclusive' (the data remain consistent with the possibility of a clinically meaningful treatment effect). This interpretation is important to ensure that potentially beneficial treatments are not prematurely abandoned in future research or clinical practice based on invalid conclusions. DESIGN: Systematic review of RCT reports published in 2014 in Annals of Internal Medicine, New England Journal of Medicine, JAMA, JAMA Internal Medicine and The Lancet (n=247). RESULTS: 85 of 99 articles with statistically non-significant results reported CIs for the treatment effect. Only 17 of those 99 articles interpreted the CI. Of the 22 articles in which CIs indicated an inconclusive result, only four acknowledged that the study could not rule out a clinically meaningful treatment effect. CONCLUSIONS: Interpretation of CIs is important but occurs infrequently in study reports of trials with treatment effects that are not statistically significant. Increased author interpretation of CIs could improve application of RCT results. Reporting recommendations are provided. PMID- 28720619 TI - Predictors of emergency department use by adolescents and adults with autism spectrum disorder: a prospective cohort study. AB - OBJECTIVES: To determine predictors of emergency department (ED) visits in a cohort of adolescents and adults with autism spectrum disorder (ASD). DESIGN: Prospective cohort study. SETTING: Community-based study from Ontario, Canada. PARTICIPANTS: Parents reported on their adult sons and daughters with ASD living in the community (n=284). MAIN OUTCOME MEASURES: ED visits for any reason, ED visits for medical reasons and ED visits for psychiatric reasons over 1 year. RESULTS: Among individuals with ASD, those with ED visits for any reason were reported to have greater family distress at baseline (p<0.01), a history of visiting the ED during the year prior (p<0.01) and experienced two or more negative life events at baseline (p<0.05) as compared with those who did not visit the ED. Unique predictors of medical versus psychiatric ED visits emerged. Low neighbourhood income (p<0.01) and living in a rural neighbourhood (p<0.05) were associated with medical but not psychiatric ED visits, whereas a history of aggression (p<0.05) as well as being from an immigrant family (p<0.05) predicted psychiatric but not medical emergencies. CONCLUSIONS: A combination of individual and contextual variables may be important for targeting preventative community based supports for individuals with ASD and their families. In particular, attention should be paid to how caregiver supports, integrative crisis planning and community-based services may assist in preventing or minimising ED use for this vulnerable population. PMID- 28720620 TI - In This Issue: Opiates, Tobacco, Social Determinants of Health, Social Accountability for Non-Profit Hospitals, More on PCMH, and Clinical Topics. AB - This issue contains several articles about the factors contributing to the complex and deadly interplay between social determinants of health, pain, mental illness, and addictive substances such as opioids and tobacco. One article clearly is a call to action: more than half of opioid prescriptions in the United States are given to patients with mental health problems. Two articles report work on the next steps for social determinants of health in health care settings. Social accountability based on community health needs assessments required of community hospitals should lead to the creation of more family medicine residency positions. Patient-centered medical home (PCMH) recognition can be costly. A new typology for PCMHs is proposed. Other topics include group advance care planning visits, the interaction of dental and primary care, free clinics, a fix for a squeaking wrist, adherence to latent tuberculosis treatment, and more. PMID- 28720621 TI - Who Will Deliver the Babies? Identifying and Addressing Barriers. PMID- 28720622 TI - Intention Versus Reality: Family Medicine Residency Graduates' Intention to Practice Obstetrics. AB - Although 21% of new family medicine graduates in 2016 reported an intention to include obstetric delivery in their scope of practice, only 7% of family physicians currently do so. The reasons for this stark difference must be identified in order to address potential barriers leading to family medicine graduates ultimately not including obstetric delivery despite intent. PMID- 28720623 TI - Prescription Opioid Use among Adults with Mental Health Disorders in the United States. AB - BACKGROUND: The extent to which adults with mental health disorders in the United States receive opioids has not been adequately reported. METHODS: We performed a cross-sectional study of a nationally representative sample of the noninstitutionalized U.S. adult population from the Medical Expenditure Panel Survey. We examined the relationship between mental health (mood and anxiety) disorders and prescription opioid use (defined as receiving at least 2 prescriptions in a calendar year). RESULTS: We estimate that among the 38.6 million Americans with mental health disorders, 18.7% (7.2 million of 38.6 million) use prescription opioids. Adults with mental health conditions receive 51.4% (60 million of 115 million prescriptions) of the total opioid prescriptions distributed in the United States each year. Compared with adults without mental health disorders, adults with mental health disorders were significantly more likely to use opioids (18.7% vs 5.0%; P < .001). In adjusted analyses, having a mental health disorder was associated with prescription opioid use overall (odds ratio, 2.08; 95% confidence interval, 1.83-2.35). CONCLUSIONS: The 16% of Americans who have mental health disorders receive over half of all opioids prescribed in the United States. Improving pain management among this population is critical to reduce national dependency on opioids. PMID- 28720624 TI - Screening for Social Determinants of Health in Michigan Health Centers. AB - OBJECTIVE: Through an academic-community partnership with a statewide consortium of health centers (HCs) in Michigan, we characterize the current scope of screening for social determinants of health (SDH). METHODS: We requested copies of forms used to screen for SDH at the 39 HC organizations in Michigan. Using content analysis, we examined variation in screening domains and processes. We present descriptive analyses of HC characteristics and patient demographics. RESULTS: We received screening documentation from 23 of the 39 HCs (59%), representing 167 delivery sites. We found broad empiric consensus regarding a core set of 13 SDH screening domains that align with nationally recommended screening guidelines. Two additional domains, Culture and Functional Status, were screened for by <40% of HCs. While patient self-report is the most frequent mode of SDH screening (41%), many HCs use staff members to administer the screening documents. CONCLUSIONS: HCs across a large and diverse state are screening for SDH and largely agree on core SDH screening domains. Using existing empiric data from frontline providers can inform potential best practices in SDH screening. PMID- 28720625 TI - Developing Electronic Health Record (EHR) Strategies Related to Health Center Patients' Social Determinants of Health. AB - BACKGROUND: "Social determinants of heath" (SDHs) are nonclinical factors that profoundly affect health. Helping community health centers (CHCs) document patients' SDH data in electronic health records (EHRs) could yield substantial health benefits, but little has been reported about CHCs' development of EHR based tools for SDH data collection and presentation. METHODS: We worked with 27 diverse CHC stakeholders to develop strategies for optimizing SDH data collection and presentation in their EHR, and approaches for integrating SDH data collection and the use of those data (eg, through referrals to community resources) into CHC workflows. RESULTS: We iteratively developed a set of EHR-based SDH data collection, summary, and referral tools for CHCs. We describe considerations that arose while developing the tools and present some preliminary lessons learned. CONCLUSION: Standardizing SDH data collection and presentation in EHRs could lead to improved patient and population health outcomes in CHCs and other care settings. We know of no previous reports of processes used to develop similar tools. This article provides an example of 1 such process. Lessons from our process may be useful to health care organizations interested in using EHRs to collect and act on SDH data. Research is needed to empirically test the generalizability of these lessons. PMID- 28720626 TI - Family Physicians' Perceptions of Electronic Cigarettes in Tobacco Use Counseling. AB - BACKGROUND: Recent support has been shown for physicians to recommend e cigarettes to patients who are trying to quit smoking. Supporters of this recommendation argue that e-cigarettes are not combustible products and are less harmful and more effective cessation products than regular cigarettes, with less inherent risk. Those who oppose this idea argue that little reliable evidence suggests that e-cigarettes are better cigarette cessation devices than currently available nicotine replacement therapies, and that they pose as much risk as cigarettes. This study was conducted to explore family physicians' perceptions of recommending e-cigarettes as smoking cessation aids to patients who smoke cigarettes. METHODS: The study used a mixed-methods approach whereby a 12-item survey was sent to 154 family physicians throughout the state of Kansas. Data were collected from 117, a 76% response rate. A multidisciplinary team used an immersion-crystallization approach to analyze the content of respondents' qualitative data; contingency table analysis was used to evaluate the quantitative data. RESULTS: The results showed that family physicians have negative perceptions of e-cigarettes and do not recommend them for smoking cessation. Family physicians are concerned about the effectiveness of e cigarettes and the uncertainty regarding safety. CONCLUSIONS: The results suggest that most family physicians do not recommend e-cigarettes for smoking cessation, citing lack of evidence on effectiveness and uncertainty regarding short- and long-term safety. PMID- 28720627 TI - Costs of Transforming Established Primary Care Practices to Patient-Centered Medical Homes (PCMHs). AB - BACKGROUND: The patient-centered medical home (PCMH) shows promise for improving care and reducing costs. We sought to reduce the uncertainty regarding the time and cost of PCMH transformation by quantifying the direct costs of transforming 57 practices in a medical group to National Committee for Quality Assurance (NCQA)-recognized Level III PCMHs. METHODS: We conducted structured interviews with corporate leaders, and with physicians, practice administrators, and office managers from a representative sample of practices regarding time spent on PCMH transformation and NCQA application, and related purchases. We then developed and sent a survey to all primary care practices (practice-level response rate: initial recognition-44.6%, renewal-35.7%). Direct costs were estimated as time spent multiplied by average hourly wage for the relevant job category, plus observed expenditures. RESULTS: We estimated HealthTexas' corporate costs for initial NCQA recognition (2010-2012) at $1,508,503; for renewal (2014-2016), $346,617; the Care Coordination resource costs an additional ongoing $390,790/year. A hypothetical 5-physician HealthTexas practice spent another estimated 239.5 hours ($10,669) obtaining, and 110.5 hours ($4,957) renewing, recognition. CONCLUSION: Centralized PCMH support reduces the burden on practices; however, overall time and cost remains substantial, and should be weighed against the mixed evidence regarding PCMH's impact on quality and costs of care. PMID- 28720628 TI - The Patient-Centered Medical Home (PCMH) Framing Typology for Understanding the Structure, Function, and Outcomes of PCMHs. AB - INTRODUCTION: Patient-centered medical homes (PCHMs) aspire to transform today's challenged primary care services. However, it is unclear which PCMH characteristics produce specific outcomes of interest for care delivery. This study tested a novel typology of PCMH practice transformation, the PCMH framing typology, and evaluated measurable outcomes by each type. METHODS: Using the Patient-Centered Primary Care Collaborative 2012 to 2013 Annual Review, this secondary analysis of the published PCMH literature extracted data from publications of 59 PCMHs. Each of the 59 sites was categorized as 1 of 4 PCMH types: add-on, renovated, hybrid, or integrated. Six outcome measures (cost reductions, decreased emergency department/hospital utilization, improved quality, improved access, increased preventive services, and improved patient satisfaction) were independently coded for each site. Practices were combined based on type, and mean outcomes scores for each measure were displayed on radar graphs for comparison. RESULTS: While each type showed a characteristic pattern of success, only the integrated type improved in all 6 outcomes. No type achieved high success in all measures. DISCUSSION: There seem to be 4 types of PCMH, each of which shows a distinctive outcomes profile. Within the PCMH framing typology, direction is emerging for how best to transform primary care to achieve the greatest success. PMID- 28720629 TI - A Group Visit Initiative Improves Advance Care Planning Documentation among Older Adults in Primary Care. AB - INTRODUCTION: Group visits for advance care planning (ACP) may help patients document preferences for decision makers and future care. We assessed the impact of a primary care-based ACP group visit (ACP-GV) intervention on older adults' ACP documentation and why patients participated. METHODS: Older adults (>65 years) in primary care participated in a 2-session ACP-GV intervention that promotes group dynamics, peer-based learning, and goal setting. Charts were reviewed at baseline, 3 months, and 12 months for documentation of decision makers and ACP forms. We described patients' reasons for participating through analysis of transcripts. RESULTS: 118 patients (mean age 76 years; 62% female and 82% white) participated in 16 ACP-GV cohorts. From baseline to 3-month follow-up, documentation of decision maker preferences increased from 39% to 81%, and was 89% at 12-month follow-up. Patients with completed ACP forms increased from 20% to 57% at 3 months, and was 67% at 12 months. Reasons for participating included recognizing the importance of ACP, curiosity, participation recommended by primary care provider, desire to talk with family/friends, and desire to complete advance directives. CONCLUSIONS: This ACP-GV intervention increased ACP documentation among patients with diverse reasons for participating. This is a patient-centered approach to ACP in primary care. PMID- 28720630 TI - Primary Care Physician Roles in Health Centers with Oral Health Care Units. AB - INTRODUCTION: Integrating oral health care and primary care is a priority for improving population health. Primary care physicians (PCP) are filling expanded roles within oral health care to secure strong overall health for their patients. METHODS: This comparative case study examines the roles of PCPs at 5 federally qualified health centers that have integrated oral health care and primary care. Administrative data were obtained directly from the Health Resources and Services Administration. Key informant interviews were performed with administrators and clinical care team members at each of the health centers. Data were reviewed by 2 experts in oral health to identify emerging roles for physicians. RESULTS: PPCPs' roles in health centers' integration models vary, but 3 distinct roles emerged: (1) the physician as a champion, (2) the physician as a collaborator, and (3) the physician as a member of an interprofessional team. In addition, providing physicians with the necessary training to identify oral health issues was critical to preparing physicians to take on expanded roles in integrated health care delivery models. CONCLUSIONS: Regardless of the roles that they play, family physicians can contribute a great deal to the success of integration models. PMID- 28720631 TI - Accrued Cost Savings of a Free Clinic Using Quality-Adjusted Life Years Saved and Return on Investment. AB - INTRODUCTION: Savings garnered through the provision of preventive services is a form of profit for health systems. Free clinics have been using this logic to demonstrate their cost-savings. The Community-Based Chronic Disease Management (CCDM) clinic treats hypertension using nurse-led teams, clinical protocols, and community-based settings. METHODS: We calculated CCDM's cost-effectiveness from 2007 to 2013 using 2 metrics: Quality-adjusted life years (QALYs) saved and return on investment (ROI). QALYs were calculated using the Clinical Preventive Burden (CPB) score for hypertension care. ROI was calculated by tallying the savings from prevented heart attacks, strokes, and emergency department visits against the total operating costs. RESULTS: Using conservative assumptions for cost estimates, hypertension care resulted in a value of QALYs saved of $711,000 to $2,133,000 and an ROI ratio range of 0.35 to 1.20. Our study shows that when using conservative assumptions to calculate cost-savings, our free clinic did not save money. Cost-savings did occur, but the amount was modest, was less than that of cost-inputs, and was not likely captured by any single health entity. CONCLUSION: Although free clinics remain a vital health care access point for many Americans, it has yet to be demonstrated that they generate a net savings. PMID- 28720632 TI - Improving Efficiency While Improving Patient Care in a Student-Run Free Clinic. AB - INTRODUCTION: Student-run free clinics (SRFCs) have the capacity to decrease health care inequity in underserved populations. These facilities can benefit from improved patient experience and outcomes. We implemented a series of quality improvement interventions with the objectives to decrease patient wait times and to increase the variety of services provided. METHODS: A needs assessment was performed. Problems related to time management, communication between staff and providers, clinic resources, and methods for assessing clinic performance were identified as targets to reduce wait times and improve the variety of services provided. Seventeen interventions were designed and implemented over a 2-month period. RESULTS: The interventions resulted in improved efficiency for clinic operations and reduced patient wait times. The number of specialty providers, patient visits for specialty care, lifestyle education visits for disease prevention and treatment, free medications, and free laboratory investigations increased to achieve the goal of improving the availability and the variety of services provided. CONCLUSIONS: We demonstrated that it is feasible to implement successful quality improvement interventions in SRFCs to decrease patient wait times and to increase the variety of services provided. We believe that the changes we implemented can serve as a model for other SRFCs to improve their performance. PMID- 28720633 TI - Factors That Influence Treatment Completion for Latent Tuberculosis Infection. AB - INTRODUCTION: The aim of this study is to describe factors associated with noncompletion of latent tuberculosis infection (LTBI) therapy. METHODS: We conducted a retrospective cohort study of adults who initiated LTBI treatment with isoniazid, rifampin, or isoniazid-rifapentine at 5 clinics. Demographic, treatment, and monitoring characteristics were abstracted. We estimated descriptive statistics and compared differences between completers and noncompleters using t tests and chi2 tests. RESULTS: The rate of completion across LTBI regimens was 66% (n = 393). A greater proportion of noncompleters were unmarried, used tobacco and/or alcohol, and had more medical problems than completers (all P < .05). A larger proportion of noncompleters received charity care compared with completers (P < .001). The most common reason for treatment discontinuation was loss to follow-up; the majority of these participants were treated with the longest isoniazid-only regimen. CONCLUSIONS: Patients at risk of progression to active tuberculosis with factors associated with noncompletion may benefit from interventions that enhance adherence to LTBI therapy. These interventions could include enhanced outreach, incentive programs, or home visits. PMID- 28720634 TI - Physician Factors Associated with Polypharmacy and Potentially Inappropriate Medication Use. AB - BACKGROUND: Despite accumulating evidence about the harm of polypharmacy in family medicine, few studies have investigated factors related to polypharmacy. The objective of this study was to explore factors related to physicians' prescribing behavior. METHODS: We conducted a survey of physicians at 5 family medicine residency practices and a linked health record review of their patients >=65 years old. The determinants of physicians' mean number of prescriptions and potentially inappropriate medications (PIMs) were examined using a generalized linear model. RESULTS: A total of 61 physicians (38 residents, 23 fellows/faculty) completed the survey, and 2103 visits by 932 patients seen by these physicians were analyzed. The mean numbers of prescriptions and PIMs per visit per physician were 9.50 and 0.46, respectively. After controlling for patient race and age, low prescribers were more likely to consider the number of medications (P = .007) and benefit/risk information for deprescribing (P = .017) when making prescribing decisions. Use of the Beers List was marginally significant in lower PIM prescribing (P = .05). Physicians' sex, duration of experience, and perceived confidence were not associated with prescribing patterns. CONCLUSIONS: Conscious consideration concerning the number of medications and benefit/risk information, as well as using the Beers List, were associated with less polypharmacy and fewer PIMs. PMID- 28720635 TI - Increased Public Accountability for Hospital Nonprofit Status: Potential Impacts on Residency Positions. AB - BACKGROUND: The Institute of Medicine recently called for greater graduate medical education (GME) accountability for meeting the workforce needs of the nation. The Affordable Care Act expanded community health needs assessment (CHNA) requirements for nonprofit and tax-exempt hospitals to include community assessment, intervention, and evaluation every 3 years but did not specify details about workforce. Texas receives relatively little federal GME funding but has used Medicaid waivers to support GME expansion. The objective of this article was to examine Texas CHNAs and regional health partnership (RHP) plans to determine to what extent they identify community workforce need or include targeted GME changes or expansion since the enactment of the Affordable Care Act and the revised Internal Revenue Service requirements for CHNAs. METHODS: Texas hospitals (n = 61) received federal GME dollars during the study period. Most of these hospitals completed a CHNA; nearly all hospitals receiving federal GME dollars but not mandated to complete a CHNA participated in similar state-based RHP plans. The 20 RHPs included assessments and intervention proposals under a 1115 Medicaid waiver. Every CHNA and RHP was reviewed for any mention of GME related needs or interventions. The latest available CHNAs and RHPs were reviewed in 2015. All CHNA and RHP plans were dated 2011 to 2015. RESULTS: Of the 38 hospital CHNAs, 26 identified a workforce need in primary care, 34 in mental health, and 17 in subspecialty care. A total of 36 CHNAs included implementation plans, of which 3 planned to address the primary care workforce need through an increase in GME funding, 1 planned to do so for psychiatry training, and 1 for subspecialty training. Of the 20 RHPs, 18 identified workforce needs in primary care, 20 in mental health, and 15 in subspecialty training. Five RHPs proposed to increase GME funding for primary care, 3 for psychiatry, and 1 for subspecialty care. CONCLUSIONS: Hospital CHNAs and other regional health assessments could be potentially strategic mechanisms to assess community needs as well as GME accountability in light of community needs and to guide GME expansion more strategically. Internal Revenue Service guidance regarding CHNAs could include workforce needs assessment and intervention requirements. Preference for future Medicaid or Medicare GME funding expansion could potentially favor states that use CHNAs or RHPs to identify workforce needs and track outcomes of related interventions. PMID- 28720636 TI - A Listening Tour: Conversations about Obamacare across America's Heartland. AB - During my sabbatical, I rode my bike 3300 miles from Washington, DC, to Seattle, WA, in order to engage in dialog with people along the northern tier of America's heartland. Through informal and candid conversations with >100 people, I gained insights into attitudes and opinions about the Patient Protection and Affordable Care Act (Obamacare). The comments were overwhelmingly negative. In this reflective essay, I share some of the conversations I had and the insights I gained from this remarkable journey across our beautiful country. PMID- 28720637 TI - Intersection Syndrome: The Subtle Squeak of an Overused Wrist. AB - Patient histories that include wrist pain can be pivotal in the distinction between intersection syndrome (IS) and the more common de Quervain's tenosynovitis (DQT). Presented here is a 26-year-old pregnant woman with a history of rowing who developed left radial/dorsal wrist pain and a rubbing/squeaking sensation. Nine months of conservative DQT therapy and a landmark-guided corticosteroid injection failed to relieve her symptoms. An in clinic ultrasound showed tenosynovitis at the intersection of the first and second compartments, confirming a diagnosis of IS. She found immediate relief with ultrasound-guided saline hydrodissection, the injection of saline into the intercompartmental space to reduce adhesions. Both DQT and IS are overuse injuries caused by repetitive wrist extension, as occurs in rowing, and either condition can worsen after pregnancy. Distinguishing the subtleties between DQT and IS can be challenging. Close attention to the patient's description of the pain can guide treatment, potentially expediting recovery. In addition, saline hydrodissection can be both a diagnostic tool and a potentially therapeutic alternative to steroid injections for such tendinopathies. PMID- 28720638 TI - A Case of Shingles Following Auricular Acupuncture. AB - This is a case report of an occurrence of shingles (herpes zoster [HZ]) following auricular acupuncture. The patient developed acute reactivation HZ in the V1 distribution of the right trigeminal nerve involving the forehead, scalp, and medial upper eyelid 13 days after being treated with auricular acupuncture for chronic low-back pain. The lesions were initially painless, but they clustered and became painful within 2 days. The patient was treated with oral valacyclovir 1000 mg, 3 times daily for 7 days, and ibuprofen as needed. The lesions resolved without sequelae. PMID- 28720639 TI - Angioedema Spotlight: A Closer Examination of Sacubitril/Valsartan Safety Results. AB - Incorporation of neprilysin inhibition into heart failure pharmacotherapy regimens has recently been recommended by U.S. guidelines, based on results from the PARADIGM-HF trial comparing sacubitril/valsartan to enalapril. While most of the discussion has focused on efficacy, a closer examination of the safety results, particularly the incidence of angioedema during the run-in and double blind periods, is also warranted. Although no major safety concerns were identified, an angioedema risk comparable to enalapril was found, primarily in the black population. Therefore, despite combination with an angiotensin receptor blocker, which historically has a lower incidence of angioedema, the addition of neprilysin inhibition yields an angioedema risk profile comparable to angiotensin converting enzyme (ACE) inhibitors. Clinicians should recognize this safety risk when prescribing sacubitril/valsartan and remain vigilant in counseling patients regarding the signs and symptoms of angioedema. As recommended by the guidelines, avoiding sacubitril/valsartan use concurrently or within 36 hours of the last dose of an ACE inhibitor or in patients with a history of angioedema is also crucial to minimize angioedema risk and prevent patient harm. PMID- 28720640 TI - Correction to "FitwitsTM Leads to Improved Parental Recognition of Childhood Obesity and Plans to Encourage Change". AB - In the above-mentioned article,1 the electronic version differs from the print version due to a numeric error in Table 4. While the nearby text above the table does use the correct number (23) [proportionate hand-based portion sizes (n = 23)]; Table 4 reads "3" rather than "23" in the third row, first column under Eat healthier portion sizes The electronic version on the Journal of the American Board of Family Medicine website has been corrected. We apologize for the error, and we regret any confusion or inconvenience it may have caused. PMID- 28720641 TI - Correction to "Implementation of Technology-based Patient Engagement Strategies within Practice-Based Research Networks". AB - In the above-mentioned article,1 the electronic version differs from the print version due to the placement of the figures. While the figure headings for Figure 1 and 2 are correct, the figures themselves were flipped during the processing of the article. The electronic version on the Journal of the American Board of Family Medicine website has been corrected. We apologize for the error, and we regret any confusion or inconvenience it may have caused. PMID- 28720642 TI - Evidence based medicine manifesto for better healthcare: A response to systematic bias, wastage, error and fraud in research underpinning patient care. PMID- 28720643 TI - Authors' reply to Spiegel and colleagues. PMID- 28720644 TI - Effects of Non-Vitamin K Antagonist Oral Anticoagulants Versus Warfarin in Patients With Atrial Fibrillation and Valvular Heart Disease: A Systematic Review and Meta-Analysis. AB - BACKGROUND: The original non-vitamin K antagonist oral anticoagulant (NOAC) trials in nonvalvular atrial fibrillation (AF) enrolled patients with native valve pathologies. The object of this study was to quantify the benefit-risk profiles of NOACs versus warfarin in AF patients with native valvular heart disease (VHD). METHODS AND RESULTS: Trials were identified by exhaustive literature search. Trial data were combined using inverse variance weighting to produce a meta-analytic summary hazard ratio (HR) and 95% confidence interval (CI) of efficacy and safety of NOACs versus warfarin. Our final analysis included 4 randomized controlled trials that enrolled 71 526 participants, including 13 574 with VHD. Pooling results from included trials showed that NOACs versus warfarin reduced stroke or systemic embolism (HR: 0.70; 95% CI, 0.60-0.82) and intracranial hemorrhage (HR: 0.47; 95% CI, 0.24-0.92) in AF patients with VHD. However, risk reduction of major bleeding and intracranial hemorrhage was driven by apixaban, edoxaban, and dabigatran (HR for major bleeding: 0.79 [95% CI, 0.69 0.91]; HR for intracranial hemorrhage: 0.33 [95% CI, 0.25-0.45]) but not rivaroxaban (HR for major bleeding: 1.56 [95% CI, 1.20-2.04]; HR for intracranial hemorrhage: 1.27 [95% CI, 0.77-2.10]). CONCLUSIONS: Among patients with AF and native VHD, NOACs reduce stroke and systemic embolism compared with warfarin. Evidence shows that apixaban, dabigatran, and edoxaban also reduce bleeding in this patient subgroup, whereas major bleeding (but not intracranial hemorrhage or mortality rate) is significantly increased in VHD patients treated with rivaroxaban. NOACs are a reasonable alternative to warfarin in AF patients with VHD. PMID- 28720646 TI - Senate committee inquiry into drug price hikes will continue despite arrest of hedge fund manager Shkreli. PMID- 28720645 TI - Influences of manganese on pubertal development. AB - The onset of puberty is the result of complex neuroendocrine interactions within hypothalamic region of the brain, as well as from genetic and environmental influences. These interactions ultimately result in the increased synthesis and release of luteinizing hormone-releasing hormone (LHRH). Manganese (Mn) is an essential environmental element known for years to be involved in numerous mammalian physiological processes, including growth and reproductive function. Studies in recent years have shown the ability of Mn to cross the blood-brain barrier and act within the hypothalamus to influence the timing of puberty. This review will depict research showing the molecular and physiological actions of Mn in the control of prepubertal LHRH and discuss the potential for the element to cause either helpful or harmful outcomes on the developmental process depending upon the age and accumulation of Mn within the hypothalamus. PMID- 28720647 TI - In situ targeting of dendritic cells sets tolerogenic environment and ameliorates CD4+ T-cell response in the postischemic liver. AB - CD4+ T cells recruited to the liver play a key role in the pathogenesis of ischemia/reperfusion (I/R) injury. The mechanism of their activation during alloantigen-independent I/R is not completely understood. We hypothesized that liver-resident dendritic cells (DCs) interact with CD4+ T cells in the postischemic liver and that modulation of DCs or T-cell-DC interactions attenuates liver inflammation. In mice, warm hepatic I/R (90/120-240 min) was induced. Tolerogenic DCs were generated in situ by pretreatment of animals with the vitamin D analog paricalcitol. A mAb-CD44 was used for blockade of CD4+ T cell-DC interactions. As shown by 2-photon in vivo microscopy as well as confocal microscopy, CD4+ T cells were closely colocalized with DCs in the postischemic liver. Pretreatment with paricalcitol attenuated I/R-induced maturation of DCs (flow cytometry), CD4+ T-cell recruitment into the liver (intravital microscopy), and hepatocellular/microvascular damage (intravital microscopy, alanine aminotransferase/aspartate aminotransferase, histology). However, interruption of T-cell-DC interaction increased proinflammatory DC maturation and even enhanced tissue damage. Simultaneous treatment with an anti-CD44mAb completely abolished the beneficial effect of paricalcitol on T-cell migration and tissue injury. Our study demonstrates for the first time that hepatic DCs interact with CD4+ T cells in the postischemic liver in vivo; modulation of DCs and/or generation of tolerogenic DCs attenuates intrahepatic CD4+ T-cell recruitment and reduces I/R injury; and interruption of CD44-dependent CD4+ T-cell-DC interactions enhances tissue injury by preventing the modulatory effect of hepatic DCs on T cells, especially type 1 T helper effector cells. Thus, hepatic DCs are strongly involved in the promotion of CD4+ T-cell-dependent postischemic liver inflammation.-Funken, D., Ishikawa-Ankerhold, H., Uhl, B., Lerchenberger, M., Rentsch, M., Mayr, D., Massberg, S., Werner, J., Khandoga, A. In situ targeting of dendritic cells sets tolerogenic environment and ameliorates CD4+ T-cell response in the postischemic liver. PMID- 28720648 TI - Neutrophil extracellular traps induced by cigarette smoke activate plasmacytoid dendritic cells. AB - BACKGROUND: Neutrophil extracellular traps (NETs) represent a distinct strategy by which neutrophils trap, confine and eliminate invading microorganisms. Emerging evidence suggests that NETs exert a deleterious effect to the host in the absence of microbial stimuli. However, the role of NETs in smoking-related lung diseases remains to be elucidated. OBJECTIVES: To evaluate the formation of NETs in the context of chronic inflammation induced by cigarette smoking and explore its potential role in an experimental mouse model of emphysema. METHODS: The formation and degradation of NETs in cigarette smoke exposed mice was assessed with a fluorescence microscope. The potential influences of NETs on plasmacytoiddendritic cells were also investigated. RESULTS: NETs were more prone to formation by polymorphonuclearneutrophils but defective in degradation in cigarette smoke exposed mice. Cigarette smoke extract (CSE) served as an important facilitator that triggered neutrophils to undergo NETosis in vitro. Furthermore, CSE-induced NETs were capable of driving plasmacytoiddendritic cell maturation and activation, thereby initiating a T-cell-mediated immune response. CONCLUSIONS: NETs may represent a critical connection between innate and adaptive immune responses under conditions of chronic inflammation induced by cigarette smoke exposure. PMID- 28720649 TI - The greatest kinetochore show on earth. PMID- 28720650 TI - The status of the human embryo in various religions. AB - Research into human development involves the use of human embryos and their derivative cells and tissues. How religions view the human embryo depends on beliefs about ensoulment and the inception of personhood, and science can neither prove nor refute the teaching of those religions that consider the zygote to be a human person with an immortal soul. This Spotlight article discusses some of the dominant themes that have emerged with regard to how different religions view the human embryo, with a focus on the Christian faith as well as Buddhist, Hindu, Jewish and Islamic perspectives. PMID- 28720651 TI - Interspecies chimeras for human stem cell research. AB - Interspecies chimeric assays are a valuable tool for investigating the potential of human stem and progenitor cells, as well as their differentiated progeny. This Spotlight article discusses the different factors that affect interspecies chimera generation, such as evolutionary distance, developmental timing, and apoptosis of the transplanted cells, and suggests some possible strategies to address them. A refined approach to generating interspecies chimeras could contribute not only to a better understanding of cellular potential, but also to understanding the nature of xenogeneic barriers and mechanisms of heterochronicity, to modeling human development, and to the creation of human transplantable organs. PMID- 28720652 TI - A framework for understanding the roles of miRNAs in animal development. AB - MicroRNAs (miRNAs) contribute to the progressive changes in gene expression that occur during development. The combined loss of all miRNAs results in embryonic lethality in all animals analyzed, illustrating the crucial role that miRNAs play collectively. However, although the loss of some individual miRNAs also results in severe developmental defects, the roles of many other miRNAs have been challenging to uncover. This has been mostly attributed to their proposed function as tuners of gene expression or providers of robustness. Here, we present a view of miRNAs in the context of development as a hierarchical and canalized series of gene regulatory networks. In this scheme, only a fraction of embryonic miRNAs act at the top of this hierarchy, with their loss resulting in broad developmental defects, whereas most other miRNAs are expressed with high cellular specificity and play roles at the periphery of development, affecting the terminal features of specialized cells. This view could help to shed new light on our understanding of miRNA function in development, disease and evolution. PMID- 28720656 TI - Letter by Archer Regarding Article, "Sugar- and Artificially Sweetened Beverages and the Risks of Incident Stroke and Dementia: A Prospective Cohort Study". PMID- 28720654 TI - Letter by Chiu Regarding Article, "Sugar- and Artificially Sweetened Beverages and the Risks of Incident Stroke and Dementia. A Prospective Cohort Study". PMID- 28720653 TI - Three-dimensional structural analysis reveals a Cdk5-mediated kinase cascade regulating hepatic biliary network branching in zebrafish. AB - The intrahepatic biliary network is a highly branched three-dimensional network lined by biliary epithelial cells, but how its branching patterns are precisely established is not clear. We designed a new computer-based algorithm that quantitatively computes the structural differences of the three-dimensional networks. Utilizing the algorithm, we showed that inhibition of Cyclin-dependent kinase 5 (Cdk5) led to reduced branching in the intrahepatic biliary network in zebrafish. Further, we identified a previously unappreciated downstream kinase cascade regulated by Cdk5. Pharmacological manipulations of this downstream kinase cascade produced a crowded branching defect in the intrahepatic biliary network and influenced actin dynamics in biliary epithelial cells. We generated larvae carrying a mutation in cdk5 regulatory subunit 1a (cdk5r1a), an essential activator of Cdk5. cdk5r1a mutant larvae show similar branching defects as those observed in Cdk5 inhibitor-treated larvae. A small-molecule compound that interferes with the downstream kinase cascade rescued the mutant phenotype. These results provide new insights into branching morphogenesis of the intrahepatic biliary network. PMID- 28720657 TI - Response by Pase et al to Letters Regarding Article, "Sugar- and Artificially Sweetened Beverages and the Risks of Incident Stroke and Dementia. A Prospective Cohort Study". PMID- 28720658 TI - Ticagrelor Versus Aspirin in Acute Embolic Stroke of Undetermined Source. AB - BACKGROUND AND PURPOSE: Ticagrelor is an effective antiplatelet therapy among patients with atherosclerotic disease and, therefore, could be more effective than aspirin in preventing recurrent stroke and cardiovascular events among patients with embolic stroke of unknown source (ESUS), which includes patients with ipsilateral stenosis <50% and aortic arch atherosclerosis. METHODS: We randomized 13 199 patients with a noncardioembolic, nonsevere ischemic stroke or high-risk transient ischemic attack to ticagrelor (180 mg loading dose on day 1 followed by 90 mg twice daily for days 2-90) or aspirin (300 mg on day 1 followed by 100 mg daily for days 2-90) within 24 hours of symptom onset. In all patients, investigators informed on the presence of ipsilateral stenosis >=50%, small deep infarct <15 mm, and on cardiac source of embolism detected after enrollment or rare causes, which allowed to construct an ESUS category in all other patients with documented brain infarction. The primary end point was the time to the occurrence of stroke, myocardial infarction, or death within 90 days. RESULTS: ESUS was identified in 4329 (32.8%) patients. There was no treatment-by-ESUS category interaction (P=0.83). Hazard ratio in ESUS patients was 0.87 (95% confidence interval, 0.68-1.10; P=0.24). However, hazard ratio was 0.51 (95% confidence interval, 0.29-0.90; P=0.02) in ESUS patients with ipsilateral stenosis <50% or aortic arch atherosclerosis (n=961) and 0.98 (95% confidence interval, 0.76-1.27; P=0.89) in the remaining ESUS patients (n=3368; P for heterogeneity =0.04). CONCLUSIONS: In this post hoc, exploratory analysis, we found no treatment-by-ESUS category interaction. ESUS subgroups have heterogeneous response to treatment (Funded by AstraZeneca). CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01994720. PMID- 28720659 TI - Microbleeds, Cerebral Hemorrhage, and Functional Outcome After Stroke Thrombolysis: Individual Patient Data Meta-Analysis. AB - BACKGROUND AND PURPOSE: We assessed whether the presence, number, and distribution of cerebral microbleeds (CMBs) on pre-intravenous thrombolysis MRI scans of acute ischemic stroke patients are associated with an increased risk of intracerebral hemorrhage (ICH) or poor functional outcome. METHODS: We performed an individual patient data meta-analysis, including prospective and retrospective studies of acute ischemic stroke treated with intravenous tissue-type plasminogen activator. Using multilevel mixed-effects logistic regression, we investigated associations of pre-treatment CMB presence, burden (1, 2-4, >=5, and >10), and presumed pathogenesis (cerebral amyloid angiopathy defined as strictly lobar CMBs and noncerebral amyloid angiopathy) with symptomatic ICH, parenchymal hematoma (within [parenchymal hemorrhage, PH] and remote from the ischemic area [remote parenchymal hemorrhage, PHr]), and poor 3- to 6-month functional outcome (modified Rankin score >2). RESULTS: In 1973 patients from 8 centers, the crude prevalence of CMBs was 526 of 1973 (26.7%). A total of 77 of 1973 (3.9%) patients experienced symptomatic ICH, 210 of 1806 (11.6%) experienced PH, and 56 of 1720 (3.3%) experienced PHr. In adjusted analyses, patients with CMBs (compared with those without CMBs) had increased risk of PH (odds ratio: 1.50; 95% confidence interval: 1.09-2.07; P=0.013) and PHr (odds ratio: 3.04; 95% confidence interval: 1.73-5.35; P<0.001) but not symptomatic ICH. Both cerebral amyloid angiopathy and noncerebral amyloid angiopathy patterns of CMBs were associated with PH and PHr. Increasing CMB burden category was associated with the risk of symptomatic ICH (P=0.014), PH (P=0.013), and PHr (P<0.00001). Five or more and >10 CMBs independently predicted poor 3- to 6-month outcome (odds ratio: 1.85; 95% confidence interval: 1.10-3.12; P=0.020; and odds ratio: 3.99; 95% confidence interval: 1.55-10.22; P=0.004, respectively). CONCLUSIONS: Increasing CMB burden is associated with increased risk of ICH (including PHr) and poor 3- to 6-month functional outcome after intravenous thrombolysis for acute ischemic stroke. PMID- 28720660 TI - An Amish founder mutation disrupts a PI(3)P-WHAMM-Arp2/3 complex-driven autophagosomal remodeling pathway. AB - Actin nucleation factors function to organize, shape, and move membrane-bound organelles, yet they remain poorly defined in relation to disease. Galloway-Mowat syndrome (GMS) is an inherited disorder characterized by microcephaly and nephrosis resulting from mutations in the WDR73 gene. This core clinical phenotype appears frequently in the Amish, where virtually all affected individuals harbor homozygous founder mutations in WDR73 as well as the closely linked WHAMM gene, which encodes a nucleation factor. Here we show that patient cells with both mutations exhibit cytoskeletal irregularities and severe defects in autophagy. Reintroduction of wild-type WHAMM restored autophagosomal biogenesis to patient cells, while inactivation of WHAMM in healthy cell lines inhibited lipidation of the autophagosomal protein LC3 and clearance of ubiquitinated protein aggregates. Normal WHAMM function involved binding to the phospholipid PI(3)P and promoting actin nucleation at nascent autophagosomes. These results reveal a cytoskeletal pathway controlling autophagosomal remodeling and illustrate several molecular processes that are perturbed in Amish GMS patients. PMID- 28720661 TI - Stabilization of F-actin by tropomyosin isoforms regulates the morphology and mechanical behavior of red blood cells. AB - The short F-actins in the red blood cell (RBC) membrane skeleton are coated along their lengths by an equimolar combination of two tropomyosin isoforms, Tpm1.9 and Tpm3.1. We hypothesized that tropomyosin's ability to stabilize F-actin regulates RBC morphology and mechanical properties. To test this, we examined mice with a targeted deletion in alternatively spliced exon 9d of Tpm3 (Tpm3/9d-/- ), which leads to absence of Tpm3.1 in RBCs along with a compensatory increase in Tpm1.9 of sufficient magnitude to maintain normal total tropomyosin content. The isoform switch from Tpm1.9/Tpm3.1 to exclusively Tpm1.9 does not affect membrane skeleton composition but causes RBC F-actins to become hyperstable, based on decreased vulnerability to latrunculin-A-induced depolymerization. Unexpectedly, this isoform switch also leads to decreased association of Band 3 and glycophorin A with the membrane skeleton, suggesting that tropomyosin isoforms regulate the strength of F-actin-to-membrane linkages. Tpm3/9d-/- mice display a mild compensated anemia, in which RBCs have spherocytic morphology with increased osmotic fragility, reduced membrane deformability, and increased membrane stability. We conclude that RBC tropomyosin isoforms directly influence RBC physiology by regulating 1) the stability of the short F-actins in the membrane skeleton and 2) the strength of linkages between the membrane skeleton and transmembrane glycoproteins. PMID- 28720662 TI - Proximal tubule apical endocytosis is modulated by fluid shear stress via an mTOR dependent pathway. AB - Cells lining the proximal tubule (PT) have unique membrane specializations that are required to maintain the high-capacity ion transport and endocytic functions of this nephron segment. PT cells in vivo acutely regulate ion transport in response to changes in glomerular filtration rate (GFR) to maintain glomerulotubular balance. PT cells in culture up-regulate endocytic capacity in response to acute changes in fluid shear stress (FSS); however, it is not known whether GFR modulates PT endocytosis to enable maximally efficient uptake of filtered proteins in vivo. Here, we show that cells cultured under continuous FSS develop an expanded apical endocytic pathway and increased endocytic capacity and lysosomal biogenesis. Furthermore, endocytic capacity in fully differentiated cells is rapidly modulated by changes in FSS. PT cells exposed to continuous FSS also acquired an extensive brush border and basolateral membrane invaginations resembling those observed in vivo. Culture under suboptimal levels of FSS led to intermediate phenotypes, suggesting a threshold effect. Cells exposed to FSS expressed higher levels of key proteins necessary for PT function, including ion transporters, receptors, and membrane-trafficking machinery, and increased adenine nucleotide levels. Inhibition of the mechanistic target of rapamycin (mTOR) using rapamycin prevented the increase in cellular energy levels, lysosomal biogenesis, and endocytic uptake, suggesting that these represent a coordinated differentiation program. In contrast, rapamycin did not prevent the FSS-induced increase in Na+/K+-ATPase levels. Our data suggest that rapid tuning of the endocytic response by changes in FSS may contribute to glomerulotubular balance in vivo. Moreover, FSS provides an essential stimulus in the differentiation of PT cells via separate pathways that up-regulate endocytosis and ion transport capacity. Variations in FSS may also contribute to the maturation of PT cells during kidney development and during repair after kidney injury. PMID- 28720663 TI - Direct interaction of the Golgi V-ATPase a-subunit isoform with PI(4)P drives localization of Golgi V-ATPases in yeast. AB - Luminal pH and phosphoinositide content are fundamental features of organelle identity. Vacuolar H+-ATPases (V-ATPases) drive organelle acidification in all eukaryotes, and membrane-bound a-subunit isoforms of the V-ATPase are implicated in organelle-specific targeting and regulation. Earlier work demonstrated that the endolysosomal lipid PI(3,5)P2 activates V-ATPases containing the vacuolar a subunit isoform in Saccharomyces cerevisiae Here we demonstrate that PI(4)P, the predominant Golgi phosphatidylinositol (PI) species, directly interacts with the cytosolic amino terminal (NT) domain of the yeast Golgi V-ATPase a-isoform Stv1. Lysine-84 of Stv1NT is essential for interaction with PI(4)P in vitro and in vivo, and interaction with PI(4)P is required for efficient localization of Stv1 containing V-ATPases. The cytosolic NT domain of the human V-ATPase a2 isoform specifically interacts with PI(4)P in vitro, consistent with its Golgi localization and function. We propose that NT domains of Vo a-subunit isoforms interact specifically with PI lipids in their organelles of residence. These interactions can transmit organelle-specific targeting or regulation information to V-ATPases. PMID- 28720664 TI - Dynein efficiently navigates the dendritic cytoskeleton to drive the retrograde trafficking of BDNF/TrkB signaling endosomes. AB - The efficient transport of cargoes within axons and dendrites is critical for neuronal function. Although we have a basic understanding of axonal transport, much less is known about transport in dendrites. We used an optogenetic approach to recruit motor proteins to cargo in real time within axons or dendrites in hippocampal neurons. Kinesin-1, a robust axonal motor, moves cargo less efficiently in dendrites. In contrast, cytoplasmic dynein efficiently navigates both axons and dendrites; in both compartments, dynamic microtubule plus ends enhance dynein-dependent transport. To test the predictions of the optogenetic assay, we examined the contribution of dynein to the motility of an endogenous dendritic cargo and found that dynein inhibition eliminates the retrograde bias of BDNF/TrkB trafficking. However, inhibition of microtubule dynamics has no effect on BDNF/TrkB motility, suggesting that dendritic kinesin motors may cooperate with dynein to drive the transport of signaling endosomes into the soma. Collectively our data highlight compartment-specific differences in kinesin activity that likely reflect specialized tuning for localized cytoskeletal determinants, whereas dynein activity is less compartment specific but is more responsive to changes in microtubule dynamics. PMID- 28720665 TI - Targeted Exome Sequencing of Krebs Cycle Genes Reveals Candidate Cancer Predisposing Mutations in Pheochromocytomas and Paragangliomas. AB - Purpose: Mutations in Krebs cycle genes are frequently found in patients with pheochromocytomas/paragangliomas. Disruption of SDH, FH or MDH2 enzymatic activities lead to accumulation of specific metabolites, which give rise to epigenetic changes in the genome that cause a characteristic hypermethylated phenotype. Tumors showing this phenotype, but no alterations in the known predisposing genes, could harbor mutations in other Krebs cycle genes.Experimental Design: We used downregulation and methylation of RBP1, as a marker of a hypermethylation phenotype, to select eleven pheochromocytomas and paragangliomas for targeted exome sequencing of a panel of Krebs cycle-related genes. Methylation profiling, metabolite assessment and additional analyses were also performed in selected cases.Results: One of the 11 tumors was found to carry a known cancer-predisposing somatic mutation in IDH1 A variant in GOT2, c.357A>T, found in a patient with multiple tumors, was associated with higher tumor mRNA and protein expression levels, increased GOT2 enzymatic activity in lymphoblastic cells, and altered metabolite ratios both in tumors and in GOT2 knockdown HeLa cells transfected with the variant. Array methylation-based analysis uncovered a somatic epigenetic mutation in SDHC in a patient with multiple pheochromocytomas and a gastrointestinal stromal tumor. Finally, a truncating germline IDH3B mutation was found in a patient with a single paraganglioma showing an altered alpha-ketoglutarate/isocitrate ratio.Conclusions: This study further attests to the relevance of the Krebs cycle in the development of PCC and PGL, and points to a potential role of other metabolic enzymes involved in metabolite exchange between mitochondria and cytosol. Clin Cancer Res; 23(20); 6315-24. (c)2017 AACR. PMID- 28720667 TI - MAPK Pathway and TERT Promoter Gene Mutation Pattern and Its Prognostic Value in Melanoma Patients: A Retrospective Study of 2,793 Cases. AB - Purpose: Ethnic differences are conspicuous in melanoma. This study is to obtain a comprehensive view of a genomic landscape and a better understanding of the correlations of gene mutation status with clinicopathologic characteristics and disease prognosis in the Asian population.Experimental Design: A total of 2,793 melanoma patient samples were retrospectively collected and analyzed for mutations in C-KIT, BRAF, NRAS, and PDGFRA coding regions and telomerase reverse transcriptase (TERT) promoter region by Sanger sequencing. Mutations were correlated to clinicopathologic features and overall survival.Results: The incidences of somatic mutations within the BRAF, NRAS, C-KIT, TERT-228, TERT-250, and PDGFRA genes were 23.7%, 10.4%, 8.0%, 5.9%, 5.5%, and 1.4%, respectively. Hotspot mutations accounted for 95.8% and 87.2% of BRAF and NRAS mutations, respectively; meanwhile, C-KIT and PDGFRA mutations showed more heterogeneity. BRAF, C-KIT, and NRAS mutations were mutually exclusive. BRAF, C-KIT, NRAS, and numbers of gene mutations of the MAPK pathway were all independent negative prognostic factors (P = 0.007, other P < 0.001, respectively). In acral melanoma, BRAF, C-KIT, and NRAS mutations were all independent prognostic factors of worse overall survival (all P < 0.001), whereas in mucosal melanoma, only C-KIT was (P = 0.006). Although correlated with BRAF mutations (P = 0.001 and P < 0.001 for C228T and C250T, respectively), TERT promoter gene mutations were not correlated with overall survival (P = 0.406 and 0.256, respectively).Conclusions: The MAPK pathway and TERT promoter gene mutations are differentially represented in the Asian population. Mutations in BRAF, C-KIT, and NRAS have prognostic values that vary by melanoma subtypes. Clinical treatment targeting these critical pathways should be aimed directly at these poor-prognosis subpopulations for maximum potential impact. Clin Cancer Res; 23(20); 6120-7. (c)2017 AACR. PMID- 28720666 TI - Inactivation of Receptor Tyrosine Kinases Reverts Aberrant DNA Methylation in Acute Myeloid Leukemia. AB - Purpose: Receptor tyrosine kinases (RTKs) are frequently deregulated in leukemia, yet the biological consequences of this deregulation remain elusive. The mechanisms underlying aberrant methylation, a hallmark of leukemia, are not fully understood. Here we investigated the role of RTKs in methylation abnormalities and characterized the hypomethylating activities of RTK inhibitors.Experimental Design: Whether and how RTKs regulate expression of DNA methyltransferases (DNMTs), tumor suppressor genes (TSGs) as well as global and gene-specific DNA methylation were examined. The pharmacologic activities and mechanisms of actions of RTK inhibitors in vitro, ex vivo, in mice, and in nilotinib-treated leukemia patients were determined.Results: Upregulation of RTKs paralleled DNMT overexpression in leukemia cell lines and patient blasts. Knockdown of RTKs disrupted, whereas enforced expression increased DNMT expression and DNA methylation. Treatment with the RTK inhibitor, nilotinib, resulted in a reduction of Sp1-dependent DNMT1 expression, the diminution of global DNA methylation, and the upregulation of the p15INK4B gene through promoter hypomethylation in AML cell lines and patient blasts. This led to disruption of AML cell clonogenicity and promotion of cellular apoptosis without obvious changes in cell cycle. Importantly, nilotinib administration in mice and human patients with AML impaired expression of DNMTs followed by DNA hypomethylation, TSG re-expression, and leukemia regression.Conclusions: Our findings demonstrate RTKs as novel regulators of DNMT-dependent DNA methylation and define DNA methylation status in AML cells as a pharmacodynamic marker for their response to RTK-based therapy, providing new therapeutic avenues for RTK inhibitors in overcoming epigenetic abnormalities in leukemia. Clin Cancer Res; 23(20); 6254-66. (c)2017 AACR. PMID- 28720668 TI - Efficient Mitochondrial Glutamine Targeting Prevails Over Glioblastoma Metabolic Plasticity. AB - Purpose: Glioblastoma (GBM) is the most common and malignant form of primary human brain tumor in adults, with an average survival at diagnosis of 18 months. Metabolism is a new attractive therapeutic target in cancer; however, little is known about metabolic heterogeneity and plasticity within GBM tumors. We therefore aimed to investigate metabolic phenotyping of primary cultures in the context of molecular tumor heterogeneity to provide a proof of concept for personalized metabolic targeting of GBM.Experimental Design: We have analyzed extensively several primary GBM cultures using transcriptomics, metabolic phenotyping assays, and mitochondrial respirometry.Results: We found that metabolic phenotyping clearly identifies 2 clusters, GLNHigh and GLNLow, mainly based on metabolic plasticity and glutamine (GLN) utilization. Inhibition of glutamine metabolism slows the in vitro and in vivo growth of GLNHigh GBM cultures despite metabolic adaptation to nutrient availability, in particular by increasing pyruvate shuttling into mitochondria. Furthermore, phenotypic and molecular analyses show that highly proliferative GLNHigh cultures are CD133neg and display a mesenchymal signature in contrast to CD133pos GLNLow GBM cells.Conclusions: Our results show that metabolic phenotyping identified an essential metabolic pathway in a GBM cell subtype, and provide a proof of concept for theranostic metabolic targeting. Clin Cancer Res; 23(20); 6292-304. (c)2017 AACR. PMID- 28720669 TI - MUC1-Mediated Metabolic Alterations Regulate Response to Radiotherapy in Pancreatic Cancer. AB - Purpose:MUC1, an oncogene overexpressed in multiple solid tumors, including pancreatic cancer, reduces overall survival and imparts resistance to radiation and chemotherapies. We previously identified that MUC1 facilitates growth promoting metabolic alterations in pancreatic cancer cells. The present study investigates the role of MUC1-mediated metabolism in radiation resistance of pancreatic cancer by utilizing cell lines and in vivo models.Experimental Design: We used MUC1-knockdown and -overexpressed cell line models for evaluating the role of MUC1-mediated metabolism in radiation resistance through in vitro cytotoxicity, clonogenicity, DNA damage response, and metabolomic evaluations. We also investigated whether inhibition of glycolysis could revert MUC1-mediated metabolic alterations and radiation resistance by using in vitro and in vivo models.Results: MUC1 expression diminished radiation-induced cytotoxicity and DNA damage in pancreatic cancer cells by enhancing glycolysis, pentose phosphate pathway, and nucleotide biosynthesis. Such metabolic reprogramming resulted in high nucleotide pools and radiation resistance in in vitro models. Pretreatment with the glycolysis inhibitor 3-bromopyruvate abrogated MUC1-mediated radiation resistance both in vitro and in vivo, by reducing glucose flux into nucleotide biosynthetic pathways and enhancing DNA damage, which could again be reversed by pretreatment with nucleoside pools.Conclusions: MUC1-mediated nucleotide metabolism plays a key role in facilitating radiation resistance in pancreatic cancer and targeted effectively through glycolytic inhibition. Clin Cancer Res; 23(19); 5881-91. (c)2017 AACR. PMID- 28720670 TI - Symptom Clusters and Quality of Life in Subjects With COPD. AB - BACKGROUND: COPD is one of the most common respiratory diseases. Patients with COPD experience and suffer from various physical and psychological symptoms. We performed this study to identify symptom clusters and the effects on quality of life (QOL) in patients with COPD. METHODS: A total of 130 COPD subjects were recruited from a university hospital in South Korea. Dyspnea, fatigue, depression, anxiety, sleep disturbance, dry mouth, and physical functional status were assessed with structured questionnaires. QOL was measured with the Clinical COPD Questionnaire. Factor analysis and cluster analysis were used to identify symptom clusters based on severity of symptom experiences. RESULTS: Three distinct clusters were identified: a respiratory-functional cluster (symptom cluster 1), a mood cluster (symptom cluster 2), and a fatigue-sleep cluster (symptom cluster 3). Symptom cluster 1 consisted of dyspnea, physical functional status, and dry mouth; symptom cluster 2 consisted of anxiety and depression; and symptom cluster 3 consisted of sleep disturbance and fatigue. Subgroup cluster analysis showed that COPD subjects with higher-scoring symptoms in symptom clusters 1, 2, and 3 had significantly poorer QOL. The symptom clusters were significantly different depending on age, educational level, and monthly income. CONCLUSIONS: COPD subjects may have specific patterns of symptom clusters. The symptom clusters are related with clinical characteristics and had a negative impact on QOL. To enhance symptom management and QOL, approaches and interventions based on symptom clusters, rather than independent intervention for each symptom, may be more effective. Understanding COPD symptom clusters may help successful symptom management, which can improve QOL for COPD patients. PMID- 28720671 TI - The Impact of Ventilator-Associated Events in Critically Ill Subjects With Prolonged Mechanical Ventilation. AB - BACKGROUND: The Centers for Disease Control and Prevention recently released a surveillance definition for respiratory complications in ventilated patients, ventilator-associated events (VAEs), to replace ventilator-associated pneumonia (VAP). VAEs consist of ventilator-associated conditions (VAC), infection-related ventilator-associated complications (IVAC), and possible VAP. A duration of mechanical ventilation of at least 4 d is required to diagnose VAE. However, the observed duration of mechanical ventilation was < 4 d in many previous studies. We evaluated the impact of VAEs on clinical outcomes in critically ill subjects who required mechanical ventilation for >= 4 d. METHODS: This single-center retrospective cohort study was conducted in the general ICU of an academic hospital. We included 407 adult subjects who were admitted to the ICU and required mechanical ventilation for at least 4 d. VAC and IVAC were identified from the electronic medical records. VAP was defined according to the Centers for Disease Control and Prevention 2008 criteria and was identified from the surveillance data of the infection control team of our hospital. Clinical outcomes were studied in the VAC, IVAC, and VAP groups. Possible VAP was not investigated. RESULTS: Higher mortality was seen in VAC and IVAC subjects, but not in VAP subjects, compared with those without VAEs and VAP. By multivariable hazard analysis for hospital mortality, IVAC was independently associated with hospital mortality (hazard ratio 2.42, 95% CI 1.39-4.20, P = .002). VAC also tended to show a similar association with hospital mortality (hazard ratio 1.45, 95% CI 0.97-2.18, P = .07). On the other hand, VAP did not increase a hazard of hospital death (hazard ratio 1.08, 95% CI 0.44-2.66, P = .87). CONCLUSIONS: We found that a VAE was related to hospital mortality in critically ill subjects with prolonged mechanical ventilation, and that VAP was not. PMID- 28720672 TI - 1-Year Survival of Subjects Discharged From a Long-Term Chronic Ventilator Unit. AB - INTRODUCTION: Among survivors of intensive care, many remain dependent on mechanical ventilation and are discharged to long-term chronic ventilator units or to skilled nursing facilities. Few long-term outcome data are available on patients transferred from long-term chronic ventilator units. METHODS: We retrospectively followed subjects discharged from a long-term chronic ventilator unit from 2010-2012. We determined where these subjects went, evaluating whether location of discharge had an effect on mortality. RESULTS: We followed 79 subjects who were 64.9 +/- 15.9 y old. Average stay in the long-term chronic ventilator unit was 38.5 +/- 20.1 d. Within the first year after discharge, 24 (30.3%) subjects died: 17 in a skilled nursing facility, 7 at home. Of those who survived the first year, 28 had been discharged to a skilled nursing facility and 27 to home. Survivors were younger (62.6 +/- 12.4 vs 70.4 +/- 13.1 y, P = .03), had shorter intensive care unit lengths of stay (10.4 +/- 5.0 vs 16.4 +/- 11.5 d, P = .03), and were more likely discharged home from long-term chronic ventilator unit (49.0% vs 29.1%, P = .040). CONCLUSIONS: Subjects discharged from an long term chronic ventilator unit and were alive at 1 y had shorter stays in the ICU and were more likely to be discharged home. Further attention is warranted to assure the survival of critical care patients once they are discharged from intensive care units. PMID- 28720673 TI - Challenges With Implementation of a Respiratory Therapist-Driven Protocol of Spontaneous Breathing Trials in the Pediatric ICU. AB - BACKGROUND: Timely ventilator liberation is crucial in the pediatric ICU. In many pediatric ICUs, the decision to initiate weaning is driven by the physician, which may lead to delays in ventilator liberation. The objectives of this quality improvement project were to develop and implement a respiratory therapist (RT) led protocol for screening for spontaneous breathing trial (SBT) readiness, to test protocol feasibility, and to evaluate its impact on SBT timing. METHODS: A retrospective chart review was performed on all intubated patients in the pediatric ICU for 18 months prior to protocol institution. An RT-driven protocol was developed and implemented, enabling consistent screening for SBT readiness. When criteria were met, an SBT was initiated after order placement. The difference in the timing of the first SBT between physician-directed screening and the RT-driven protocol was evaluated. RESULTS: A total of 219 subjects were included in this project (128 pre-intervention; 91 intervention). Baseline demographic data, including mortality risk and endotracheal tube size, were similar in both groups. The time of the first SBT (median [25th, 75th percentile]) was not significantly different between the intervention and preintervention groups (39.5 [25.3, 85.2] vs 42.6 [26.4, 81.3], respectively). There was no difference in mechanical ventilation duration, or length of hospital and ICU stay. The odds of being placed on noninvasive respiratory support were higher in the intervention group at 1 h (odds ratio [95% CI]: 2.29 [1.10, 4.78], P = .03) and 12 h (odds ratio 2.53 [1.23, 5.20], P = .01) postextubation, but the odds of re-intubation did not reach statistical significance (odds ratio 2.60 [0.73, 9.27], P = .14). RT adherence with patient screening was 56.4%. CONCLUSIONS: An RT-driven protocol was successfully introduced in an academic pediatric ICU. However, it did not impact time of SBT initiation, potentially due to the difficulty in maintaining adherence over time. RT-driven protocols require further study. PMID- 28720674 TI - Tracheal Tube Design and Ventilator-Associated Pneumonia. AB - Microaspiration of contaminated oropharyngeal and gastric secretions is the main mechanism for ventilator-associated pneumonia (VAP) in critically ill patients. Improving the performance of tracheal tubes in reducing microaspiration is one potential means to prevent VAP. The aim of this narrative review is to discuss recent findings on the impact of tracheal tube design on VAP prevention. Several randomized controlled studies have reported that subglottic secretion drainage (SSD) is efficient in VAP prevention. Meta-analyses have reported conflicting results regarding the impact of SSD on duration of mechanical ventilation, and one animal study raised concern about SSD-related tracheal lesions. However, this measure appears to be cost-effective. Therefore, SSD should probably be used in all patients with expected duration of mechanical ventilation > 48 h. Three randomized controlled trials have shown that tapered-cuff tracheal tubes are not useful to prevent VAP and should probably not be used in critically ill patients. Further studies are required to confirm the promising effects of continuous control of cuff pressure, polyurethane-cuffed, silver-coated, and low-volume low pressure tracheal tubes. There is moderate evidence for the use of SSD and strong evidence against the use of tapered-cuff tracheal tubes in critically ill patients for VAP prevention. However, more data on the safety and cost effectiveness of these measures are needed. Other tracheal tube-related preventive measures require further investigation. PMID- 28720675 TI - The Effect of Nebulizer Position on Aerosolized Epoprostenol Delivery in an Adult Lung Model. AB - BACKGROUND: Aerosolized epoprostenol is an alternative for inhaled nitric oxide in the management of pulmonary arterial hypertension and possibly acute hypoxemia. Our objective was to determine differences in drug deposition based on different nebulizer positions in the ventilator circuit, using a vibrating mesh nebulizer. METHODS: An 8.0-mm inner diameter endotracheal tube (ETT) was connected to a training test lung, compliance of 30 mL/cm H2O, with a collecting filter placed at the ETT-test lung junction. A mechanical ventilator, heated wire circuit, and pass-over humidifier were utilized. A syringe pump continuously instilled a 15,000-ng/mL epoprostenol solution at 30, 50, and 70 ng/kg/min into the vibrating mesh nebulizer at all 4 positions. Tidal volumes (VT) were set at 4, 6, and 8 mL/kg for a 70-kg patient with breathing frequencies of 25, 16, and 12 breaths/min, respectively. Epoprostenol was eluted from the filters (no. = 180) and analyzed with ultraviolet-visible spectrophotometry at 205 nm to estimate drug deposition. RESULTS: Epoprostenol deposition increased significantly (P = .02) as the dosage increased from 30 ng/kg/min (median 4,520.0 ng, interquartile range [IQR] 2,285.0-6,712.2 ng) to 50 ng/kg/min (median 6,065.0 ng, IQR 3,220.0-13,002.5 ng) and 70 ng/kg/min (median 9,890.0 ng, IQR 6,270.0 16,140.0 ng). No significant difference was found between variations in ventilator settings. No difference in deposition was found between the humidifier inlet and outlet, but these positions resulted in greater deposition compared with the inspiratory limb and between the ETT and Y-piece. CONCLUSIONS: The greatest amount of mean epoprostenol deposition resulted with the nebulizer placed at the humidifier inlet or outlet in a ventilator with bias flow. PMID- 28720676 TI - Inhaler Training Delivered by Internet-Based Home Videoconferencing Improves Technique and Quality of Life. AB - BACKGROUND: COPD is common, and inhaled medications can reduce the risk of exacerbations. Incorrect inhaler use is also common and may lead to worse symptoms and increased exacerbations. We examined whether inhaler training could be delivered using Internet-based home videoconferencing and its effect on inhaler technique, self-efficacy, quality of life, and adherence. METHODS: In this pre-post pilot study, participants with COPD had 3 monthly Internet-based home videoconference visits with a pharmacist who provided inhaler training using teach-to-goal methodology. Participants completed mailed questionnaires to ascertain COPD severity, self-efficacy, health literacy, quality of life, adherence, and satisfaction with the intervention. RESULTS: A total of 41 participants completed at least one, and 38 completed all 3 home videoconference visits. During each visit, technique improved for all inhalers, with significant improvements for the albuterol metered-dose inhaler, budesonide/formoterol metered-dose inhaler, and tiotropium dry powder inhaler. Improved technique was sustained for nearly all inhalers at 1 and 2 months. Quality of life measured with the Chronic Respiratory Questionnaire improved following the training: dyspnea (+0.3 points, P = .01), fatigue (+0.6 points, P < .001), emotional function (+0.5 points, P = .001), and mastery (+0.7 points, P < .001). Coping skills measured with the Seattle Obstructive Lung Disease Questionnaire improved (+9.9 points, P = .003). Participants reported increased confidence in inhaler use; for example, mean self-efficacy for using albuterol increased 3 points (P < .001). Inhaler adherence improved significantly after the intervention from 1.6 at the initial visit to 1.1 at month 2 (P = .045). The pharmacist reported technical issues in 64% of visits. CONCLUSIONS: Inhaler training using teach-to goal methodology delivered by home videoconference is a promising means to provide training to patients with COPD that can improve technique, quality of life, self-efficacy, and adherence. PMID- 28720677 TI - Synthetic Circulating Cell-free DNA as Quality Control Materials for Somatic Mutation Detection in Liquid Biopsy for Cancer. AB - BACKGROUND: Detection of somatic genomic alterations in tumor-derived cell-free DNA (cfDNA) in the plasma is challenging owing to the low concentrations of cfDNA, variable detection methods, and complex workflows. Moreover, no proper quality control materials are available currently. METHODS: We developed a set of synthetic cfDNA quality control materials (SCQCMs) containing spike-in cfDNA on the basis of micrococcal nuclease digestion carrying somatic mutations as simulated cfDNA and matched genomic DNA as genetic background to emulate paired tumor-normal samples in real clinical tests. Site-directed mutagenesis DNA that contained 1500-2000 bases with single-nucleotide variants or indels and genomic DNA from CRISPR/Cas9 edited cells with EML4-ALK rearrangements was fragmented, quantified, and added into micrococcal nuclease-digested DNA derived from HEK293T cells. To prove their suitability, the SCQCMs were compared with patient-derived plasma samples and validated in a collaborative study that encompassed 11 laboratories. RESULTS: The results of SCQCM analysis by next-generation sequencing showed strong agreement with those of patient-derived plasma samples, including the size profile of cfDNA and the quality control metrics of the sequencing data. More than 95% of laboratories correctly detected the SCQCMs with EGFR T790M, L858R, KRAS G12D, and a deletion in exon 19, as well as with EML4-ALK variant 2. CONCLUSIONS: The SCQCMs were successfully applied in a broad range of settings, methodologies, and informatics techniques. We conclude that SCQCMs can be used as optimal quality controls in test performance assessments for circulating tumor DNA somatic mutation detection. PMID- 28720680 TI - Quality Materials for Quality Assurance in the Analysis of Liquid Biopsy Samples. PMID- 28720678 TI - Standardization of Free Thyroxine Measurements Allows the Adoption of a More Uniform Reference Interval. AB - BACKGROUND: The IFCC Committee for Standardization of Thyroid Function Tests intended to standardize free thyroxine (FT4) immunoassays. We developed a Systeme International d'Unites traceable conventional reference measurement procedure (RMP) based on equilibrium dialysis and mass spectrometry. We describe here the latest studies intended to recalibrate against the RMP and supply a proof of concept, which should allow continued standardization efforts. METHODS: We used the RMP to target the standardization and reference interval (RI) panels, which were also measured by 13 manufacturers. We validated the suitability of the recalibrated results to meet specifications for bias (3.3%) and total error (8.0%) determined from biological variation. However, because these specifications were stringent, we expanded them to 10% and 13%, respectively. The results for the RI panel were reported as if the assays were recalibrated. We estimated all but 1 RI using parametric statistical procedures and hypothesized that the RI determined by the RMP was suitable for use by the recalibrated assays. RESULTS: Twelve of 13 recalibrated assays had a bias, meeting the 10% specification with 95% confidence; for 7 assays, this applied even for the 3.3% specification. Only 1 assay met the 13% total error specification. Recalibration reduced the CV of the assay means for the standardization panel from 13% to 5%. The proof-of-concept study confirmed our hypothesis regarding the RI but within constraints. CONCLUSIONS: Recalibration to the RMP significantly reduced the FT4 immunoassays' bias, so that the RI determined by the RMP was suitable for common use within a margin of 12.5%. PMID- 28720679 TI - Potential for Monitoring Gut Microbiota for Diagnosing Infections and Graft versus-Host Disease in Cancer and Stem Cell Transplant Patients. AB - BACKGROUND: Gut microbiota, the collective community of microorganisms inhabiting the intestine, have been shown to provide many beneficial functions for the host. Recent advances in next-generation sequencing and advanced molecular biology approaches have allowed researchers to identify gut microbiota signatures associated with disease processes and, in some cases, establish causality and elucidate underlying mechanisms. CONTENT: This report reviews 3 commonly used methods for studying the gut microbiota and microbiome (the collective genomes of the gut microorganisms): 16S rRNA gene sequencing, bacterial group or species specific quantitative polymerase chain reaction (qPCR), and metagenomic shotgun sequencing (MSS). The technical approaches and resources needed for each approach are outlined, and advantages and disadvantages for each approach are summarized. The findings regarding the role of the gut microbiota in the health of patients with cancer and stem cell transplant (SCT) patients (specifically in modulating the development of gut-derived bacterial infections and a posttransplant immune mediated complication known as graft-vs-host-disease) are reviewed. Finally, there is discussion of the potential viability of these approaches in the actual clinical treatment of cancer and SCT patients. SUMMARY: Advances in next generation sequencing have revolutionized our understanding of the importance of the gut microbiome to human health. Both 16S rRNA gene sequencing and MSS are currently too labor-intensive or computationally burdensome to incorporate into real-time clinical monitoring of gut microbiomes. Yet, the lessons learned from these technologies could be adapted to currently used methods (e.g., qPCR) that could then be rigorously tested in the clinical care of these patients. PMID- 28720681 TI - The EuBIVAS Project: Within- and Between-Subject Biological Variation Data for Serum Creatinine Using Enzymatic and Alkaline Picrate Methods and Implications for Monitoring. AB - BACKGROUND: The European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) European Biological Variation Study (EuBIVAS) has been established to deliver rigorously determined biological variation (BV) indices. EuBIVAS determined BV for serum creatinine using the enzymatic and alkaline picrate measurement methods. METHOD: In total, 91 healthy individuals (38 males, 53 females; age range, 21-69 years) were bled for 10 consecutive weeks at 6 European laboratories. An equivalent protocol was followed at each center. Sera were stored at -80 degrees C before analysis. Analyses for each patient were performed in duplicate within a single run on an ADVIA 2400 system (San Raffaele Hospital, Milan). The data were subjected to outlier and homogeneity analysis before performing CV-ANOVA to determine BV and analytical variation (CVA) estimates with confidence intervals (CI). RESULTS: The within-subject BV estimates [CVI (95% CI)] were similar for enzymatic [4.4% (4.2-4.7)] and alkaline picrate [4.7% (4.4-4.9)] methods and lower than the estimate presently available online (CVI = 5.9%). No significant male/female BV differences were found. Significant differences were observed in mean creatinine values between men and women and between Turkish individuals and those of other nationalities. Between subject BV (CVG) estimates, stratified accordingly, produced CVG values similar to historical BV data. CVA was 1.1% for the enzymatic and 4.4% for alkaline picrate methods, indicating that alkaline picrate methods fail to fulfill analytical performance specifications for imprecision (CVAPS). CONCLUSIONS: The serum creatinine CVI obtained by EuBIVAS specifies a more stringent CVAPS than previously identified. The alkaline picrate method failed to meet this CVAPS, raising questions regarding its future use. PMID- 28720682 TI - Reducing Artifactual EGFR T790M Mutations in DNA from Formalin-Fixed Paraffin Embedded Tissue by Use of Thymine-DNA Glycosylase. AB - BACKGROUND: False-positive EGFR T790M mutations have been reported in formalin fixed lung tumors, but the cause of the false positives has not been identified. The T790M mutation results from a C>T change at the cytosine of a CpG dinucleotide. The presence or absence of methylation at this cytosine has different consequences following deamination, resulting in a thymine or uracil, respectively, both of which however result in an artifactual change. Uracil-DNA glycosylase (UDG) can be used to eliminate DNA templates with uracil residues but is not active against artifactual thymines. We therefore investigated the use of thymine-DNA glycosylase (TDG) to reduce artifactual T790M mutations. METHODS: Formalin-fixed normal lung tissues and lung squamous cell carcinomas were tested to measure the frequency of false-positive EGFR mutations by use of droplet digital PCR before and after treatment with either UDG or TDG. Methylation at the cytosine at EGFR T790 was assessed by pyrosequencing and by analysis of public databases. RESULTS: Artifactual EGFR T790M mutations were detected in all of the archival formalin-fixed normal lung and lung squamous cell carcinomas at mutant allele frequencies of 1% or lower. The cytosine at EGFR T790 showed high levels of methylation in all lung cancer samples and normal tissues. Pretreatment of the formalin-fixed DNA with either UDG or TDG reduced the false EGFR T790M mutations, but a greater reduction was seen with the TDG treatment. CONCLUSIONS: Both U:G and T:G lesions in formalin-fixed tissue are sources of false-positive EGFR T790M mutations. This is the first report of the use of TDG to reduce sequence artifacts in formalin-fixed DNA and is applicable to the accurate detection of mutations arising at methylated cytosines. PMID- 28720683 TI - MicroRNA as Novel Exercise Mimetic for Muscle Wasting in CKD. PMID- 28720684 TI - FSGS as an Adaptive Response to Growth-Induced Podocyte Stress. AB - Glomerular sclerotic lesions develop when the glomerular filtration surface area exceeds the availability of podocyte foot process coverage, but the mechanisms involved are incompletely characterized. We evaluated potential mechanisms using a transgenic (podocin promoter-AA-4E-BP1) rat in which podocyte capacity for hypertrophy in response to growth factor/nutrient signaling is impaired. FSGS lesions resembling human FSGS developed spontaneously by 7 months of age, and could be induced earlier by accelerating kidney hypertrophy by nephrectomy. Early segmental glomerular lesions occurred in the absence of a detectable reduction in average podocyte number per glomerulus and resulted from the loss of podocytes in individual glomerular capillary loops. Parietal epithelial cell division, accumulation on Bowman's capsule, and tuft invasion occurred at these sites. Three different interventions that prevented kidney growth and glomerular enlargement (calorie intake reduction, inhibition of mammalian target of rapamycin complex, and inhibition of angiotensin-converting enzyme) protected against FSGS lesion development, even when initiated late in the process. Ki67 nuclear staining and unbiased transcriptomic analysis identified increased glomerular (but not podocyte) cell cycling as necessary for FSGS lesion development. The rat FSGS-associated transcriptomic signature correlated with human glomerular transcriptomes associated with disease progression, compatible with similar processes occurring in man. We conclude that FSGS lesion development resulted from glomerular growth that exceeded the capacity of podocytes to adapt and adequately cover some parts of the filtration surface. Modest modulation of the growth side of this equation significantly ameliorated FSGS progression, suggesting that glomerular growth is an underappreciated therapeutic target for preservation of renal function. PMID- 28720686 TI - Oncolytic virus-induced cell death and immunity: a match made in heaven? AB - Our understanding of the mechanisms responsible for cancer development has increased enormously over the last decades. However, for many cancers, this has not been translated into a significant improvement in overall survival, and overall mortality remains high. Treatment for many malignancies remains based on surgery, chemotherapy, and radiotherapy. Significant progress has been made toward the development of more specific, more potent, and less invasive treatment modalities, but such targeted therapies remain the exception for most cancers. Thus, cancer therapies based on a different mechanism of action should be explored. The immune system plays an important role in keeping tumor growth at bay. However, in many cases, these responses are not strong enough to keep tumor growth under control. Thus, immunotherapy aims to boost the immune system to suppress tumor growth efficiently. This has been demonstrated by the recent successes of immune checkpoint therapy in several cancers. Oncolytic viruses (OVs) are another exciting class of immunotherapy agent. As well as replicating selectively within and killing tumor cells, OVs are able to elicit potent anti tumor immune responses. Therapeutic vaccination with OVs, also referred to as cancer virotherapy, can thus be tailored to elicit vigorous cellular immune responses and even target individual malignancies in a personalized manner. In this review, we will describe the intricate link among oncolytic virotherapy, tumor immunology, and immunogenic cell death (ICD) and discuss ways to harness optimally their potential for future cancer therapy. PMID- 28720685 TI - The Loss of GSTM1 Associates with Kidney Failure and Heart Failure. AB - Glutathione S-transferase mu 1 (GSTM1) encodes an enzyme that catalyzes the conjugation of electrophilic compounds with glutathione to facilitate their degradation or excretion. The loss of one or both copies of GSTM1 is common in many populations and has been associated with CKD progression. With the hypothesis that the loss of GSTM1 is also associated with incident kidney failure and heart failure, we estimated GSTM1 copy number using exome sequencing reads in the Atherosclerosis Risk in Communities (ARIC) Study, a community-based prospective cohort of white and black participants. Overall, 51.2% and 39.8% of white participants and 25.6% and 48.5% of black participants had zero or one copy of GSTM1, respectively. Over a median follow-up of 24.6 years, 256 kidney failure events occurred in 5715 participants without prevalent kidney failure, and 1028 heart failure events occurred in 5368 participants without prevalent heart failure. In analysis adjusted for demographics, diabetes, and hypertension, having zero or one copy of GSTM1 associated with higher risk of kidney failure and heart failure (adjusted hazard ratio [95% confidence interval] for zero or one versus two copies of GSTM1: kidney failure, 1.66 [1.27 to 2.17]; heart failure, 1.16 [1.04 to 1.29]). Risk did not differ significantly between participants with zero and one copy of GSTM1 (P>0.10). In summary, the loss of GSTM1 was significantly associated with incident kidney and heart failure, independent of traditional risk factors. These results suggest GSTM1 function is a potential treatment target for the prevention of kidney and heart failure. PMID- 28720688 TI - Primary immune thrombocytopenia in adults: clinical practice versus management guidelines. PMID- 28720687 TI - Transcriptional profiling reveals functional dichotomy between human slan+ non classical monocytes and myeloid dendritic cells. AB - Human 6-sulfo LacNac-positive (slan+) cells have been subject to a paradigm debate. They have previously been classified as a distinct dendritic cell (DC) subset. However, evidence has emerged that they may be more related to monocytes than to DCs. To gain deeper insight into the functional specialization of slan+ cells, we have compared them with both conventional myeloid DC subsets (CD1c+ and CD141+) in human peripheral blood (PB). With the use of genome-wide transcriptional profiling, as well as functional tests, we clearly show that slan+ cells form a distinct, non-DC-like population. They cluster away from both DC subsets, and their gene-expression profile evidently suggests involvement in distinct inflammatory processes. An extensive transcriptional meta-analysis confirmed the relationship of slan+ cells with the monocytic compartment rather than with DCs. From a functional perspective, their ability to prime CD4+ and CD8+ T cells is relatively low. Combined with the finding that "antigen presentation by MHC class II" is at the top of under-represented pathways in slan+ cells, this points to a minimal role in directing adaptive T cell immunity. Rather, the higher expression levels of complement receptors on their cell surface, together with their high secretion of IL-1beta and IL-6, imply a specific role in innate inflammatory processes, which is consistent with their recent identification as non-classical monocytes. This study extends our knowledge on DC/monocyte subset biology under steady-state conditions and contributes to our understanding of their role in immune-mediated diseases and their potential use in immunotherapeutic strategies. PMID- 28720689 TI - Cost of achieving WHO sustainable development goals by 2030 is $58 a head. PMID- 28720690 TI - David Oliver: NHS doctors' licence to challenge. PMID- 28720691 TI - Disseminated cryptococcosis in an immunocompetent patient. AB - Cryptococcosis is a fungal infection which is commonly associated with immune compromised state. Disseminated infection in immunocompetent individuals is extremely rare. We present a case of a 56-year-old African American patient who presented with unilateral knee pain and swelling and was subsequently diagnosed with cryptococcal bone mass with dissemination of infection. PMID- 28720692 TI - Primary greater omental GIST presenting with acute intra-abdominal haemorrhage. AB - Primary omental gastrointestinal stromal tumours (GISTs) are classified as extra GISTs with a reported incidence of <1% of all GISTs. There are only a few cases in the English literature reporting omental GIST with none reporting acute intra abdominal haemorrhage as a presenting feature. We report a case of a 67-year-old man who presented with haemorrhage from a primary omental GIST requiring emergency laparotomy. PMID- 28720693 TI - Catastrophic cervical spinal injury in an amateur college wrestler. AB - A young amateur wrestler presented with a burst fracture of the seventh cervical vertebra with complete paraplegia. He was treated with surgery for spine stabilisation and was actively rehabilitated. Adolescents and teenagers are indulging in high-contact sports like wrestling, without proper training and technical know-how, which can lead to severe injuries and possibly, permanent handicap or death. Trainers, assistants and institutions should be well equipped to diagnose and provide initial care of people with a spinal injury to prevent a partial injury from progressing to complete injury. Athletes, coaches and the public should be aware of methods of first aid and how to transport a patient with a cervical spine injury. Authorities should take steps to improve infrastructures in training institutions and ambulance services. Specialised spinal centres should be established throughout the country for management and rehabilitation of patients with paraplegia. PMID- 28720694 TI - Myocardial infarction masquerading as myocarditis in a patient with factor V Leiden: unmasked with MR. AB - We present a case of a 21-year-old man presenting with sharp left-sided chest pain. A CT pulmonary angiogram was negative, ECG was unremarkable and a mild troponin rise was observed. Myocarditis was suspected as the most likely diagnosis, particularly in view of the patient's previous diagnosis of myocarditis 3 years prior. A cardiac MRI was indicative of an acute mid-anterior myocardial infarction (MI) and an old inferior MI with an associated aneurysm. A subsequent angiogram revealed a subtotal occlusion in the second diagonal artery, likely precipitated by homozygous factor V Leiden.This case illustrates the value of MRI in differentiating acute MI from myocarditis when clinical suspicion is low, as in this young patient with atypical chest pain. Further, it demonstrates the value of MRI in detecting previous MIs and reinforces the importance of searching for precipitants of MI in young patients. PMID- 28720695 TI - Adult Wilms' tumour: an illustration of multimodality imaging characteristics. PMID- 28720696 TI - Low-Dose Persistent Organic Pollutants Impair Insulin Secretory Function of Pancreatic beta-Cells: Human and In Vitro Evidence. AB - Low-dose persistent organic pollutants (POPs), especially organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs), have emerged as a new risk factor for type 2 diabetes. We evaluated whether chronic exposure to low dose POPs affects insulin secretory function of beta-cells in humans and in vitro cells. Serum concentrations of OCPs and PCBs were measured in 200 adults without diabetes. Mathematical model-based insulin secretion indices were estimated by using a 2-h seven-sample oral glucose tolerance test. Insulin secretion by INS-1E beta-cells was measured after 48 h of treatment with three OCPs or one PCB mixture. Static second-phase insulin secretion significantly decreased with increasing serum concentrations of OCPs. Adjusted means were 63.2, 39.3, 44.1, 39.3, 39.7, and 22.3 across six categories of a summary measure of OCPs (Ptrend = 0.02). Dynamic first-phase insulin secretion remarkably decreased with increasing concentrations of OCPs among only insulin-sensitive individuals (Ptrend = 0.02); the insulin levels among individuals with high OCPs were ~30% of those with low OCPs. Compared with OCPs, PCBs showed weaker associations. The decreased insulin secretion by INS-1E beta-cells was observed for even 1 pmol/L OCP. The data from human and in vitro cell experiments suggest that chronic exposure to low-dose POPs, especially OCPs, can induce pancreatic beta-cell dysfunction. PMID- 28720697 TI - Inhibition of complement C5 protects against organ failure and reduces mortality in a baboon model of Escherichia coli sepsis. AB - Bacterial sepsis triggers robust activation of the complement system with subsequent generation of anaphylatoxins (C3a, C5a) and the terminal complement complex (TCC) that together contribute to organ failure and death. Here we tested the effect of RA101295, a 2-kDa macrocyclic peptide inhibitor of C5 cleavage, using in vitro whole-blood assays and an in vivo baboon model of Escherichia coli sepsis. RA101295 strongly inhibited E. coli-induced complement activation both in vitro and in vivo by blocking the generation of C5a and the soluble form of TCC, sC5b-9. RA101295 reduced the E. coli-induced "oxidative burst," as well as leukocyte activation, without affecting host phagocytosis of E. coli RA101295 treatment reduced plasma LPS content in E. coli-challenged baboons, implying reduced complement-mediated bacteriolysis, whereas treated animals showed slightly improved bacterial clearance during the bacteremic stage compared with controls. Treatment with RA101295 also improved consumptive coagulopathy and preserved endothelial anticoagulant and vascular barrier functions. RA101295 abolished sepsis-induced surges in proinflammatory cytokines and attenuated systemic circulatory and febrile responses, likely reflecting decreased systemic levels of LPS and C5a. Overall, RA101295 treatment was associated with significant organ protection and markedly reduced mortality compared with nontreated controls (four of five animals survived in a 100% lethal model). We therefore conclude that inhibition of C5 cleavage during the bacteremic stage of sepsis could be an important therapeutic approach to prevent sepsis-induced inflammation, consumptive coagulopathy, and subsequent organ failure and death. PMID- 28720698 TI - Catalysis and chemical mechanisms of calcite dissolution in seawater. AB - Near-equilibrium calcite dissolution in seawater contributes significantly to the regulation of atmospheric [Formula: see text] on 1,000-y timescales. Despite many studies on far-from-equilibrium dissolution, little is known about the detailed mechanisms responsible for calcite dissolution in seawater. In this paper, we dissolve 13C-labeled calcites in natural seawater. We show that the time-evolving enrichment of [Formula: see text] in solution is a direct measure of both dissolution and precipitation reactions across a large range of saturation states. Secondary Ion Mass Spectrometer profiles into the 13C-labeled solids confirm the presence of precipitated material even in undersaturated conditions. The close balance of precipitation and dissolution near equilibrium can alter the chemical composition of calcite deeper than one monolayer into the crystal. This balance of dissolution-precipitation shifts significantly toward a dissolution dominated mechanism below about [Formula: see text] Finally, we show that the enzyme carbonic anhydrase (CA) increases the dissolution rate across all saturation states, and the effect is most pronounced close to equilibrium. This finding suggests that the rate of hydration of [Formula: see text] is a rate limiting step for calcite dissolution in seawater. We then interpret our dissolution data in a framework that incorporates both solution chemistry and geometric constraints on the calcite solid. Near equilibrium, this framework demonstrates a lowered free energy barrier at the solid-solution interface in the presence of CA. This framework also indicates a significant change in dissolution mechanism at [Formula: see text], which we interpret as the onset of homogeneous etch pit nucleation. PMID- 28720699 TI - Cellular trade-offs and optimal resource allocation during cyanobacterial diurnal growth. AB - Cyanobacteria are an integral part of Earth's biogeochemical cycles and a promising resource for the synthesis of renewable bioproducts from atmospheric CO2 Growth and metabolism of cyanobacteria are inherently tied to the diurnal rhythm of light availability. As yet, however, insight into the stoichiometric and energetic constraints of cyanobacterial diurnal growth is limited. Here, we develop a computational framework to investigate the optimal allocation of cellular resources during diurnal phototrophic growth using a genome-scale metabolic reconstruction of the cyanobacterium Synechococcus elongatus PCC 7942. We formulate phototrophic growth as an autocatalytic process and solve the resulting time-dependent resource allocation problem using constraint-based analysis. Based on a narrow and well-defined set of parameters, our approach results in an ab initio prediction of growth properties over a full diurnal cycle. The computational model allows us to study the optimality of metabolite partitioning during diurnal growth. The cyclic pattern of glycogen accumulation, an emergent property of the model, has timing characteristics that are in qualitative agreement with experimental findings. The approach presented here provides insight into the time-dependent resource allocation problem of phototrophic diurnal growth and may serve as a general framework to assess the optimality of metabolic strategies that evolved in phototrophic organisms under diurnal conditions. PMID- 28720700 TI - Hitchhiking and epistasis give rise to cohort dynamics in adapting populations. AB - Beneficial mutations are the driving force of adaptive evolution. In asexual populations, the identification of beneficial alleles is confounded by the presence of genetically linked hitchhiker mutations. Parallel evolution experiments enable the recognition of common targets of selection; yet these targets are inherently enriched for genes of large target size and mutations of large effect. A comprehensive study of individual mutations is necessary to create a realistic picture of the evolutionarily significant spectrum of beneficial mutations. Here we use a bulk-segregant approach to identify the beneficial mutations across 11 lineages of experimentally evolved yeast populations. We report that nearly 80% of detected mutations have no discernible effects on fitness and less than 1% are deleterious. We determine the distribution of driver and hitchhiker mutations in 31 mutational cohorts, groups of mutations that arise synchronously from low frequency and track tightly with one another. Surprisingly, we find that one-third of cohorts lack identifiable driver mutations. In addition, we identify intracohort synergistic epistasis between alleles of hsl7 and kel1, which arose together in a low-frequency lineage. PMID- 28720701 TI - De novo peptide sequencing by deep learning. AB - De novo peptide sequencing from tandem MS data is the key technology in proteomics for the characterization of proteins, especially for new sequences, such as mAbs. In this study, we propose a deep neural network model, DeepNovo, for de novo peptide sequencing. DeepNovo architecture combines recent advances in convolutional neural networks and recurrent neural networks to learn features of tandem mass spectra, fragment ions, and sequence patterns of peptides. The networks are further integrated with local dynamic programming to solve the complex optimization task of de novo sequencing. We evaluated the method on a wide variety of species and found that DeepNovo considerably outperformed state of the art methods, achieving 7.7-22.9% higher accuracy at the amino acid level and 38.1-64.0% higher accuracy at the peptide level. We further used DeepNovo to automatically reconstruct the complete sequences of antibody light and heavy chains of mouse, achieving 97.5-100% coverage and 97.2-99.5% accuracy, without assisting databases. Moreover, DeepNovo is retrainable to adapt to any sources of data and provides a complete end-to-end training and prediction solution to the de novo sequencing problem. Not only does our study extend the deep learning revolution to a new field, but it also shows an innovative approach in solving optimization problems by using deep learning and dynamic programming. PMID- 28720702 TI - Identification of a vesicular ATP release inhibitor for the treatment of neuropathic and inflammatory pain. AB - Despite the high incidence of neuropathic and inflammatory pain worldwide, effective drugs with few side effects are currently unavailable for the treatment of chronic pain. Recently, researchers have proposed that inhibitors of purinergic chemical transmission, which plays a key role in the pathological pain response, may allow for targeted treatment of pathological neuropathic and inflammatory pain. However, such therapeutic analgesic agents have yet to be developed. In the present study, we demonstrated that clodronate, a first generation bisphosphonate with comparatively fewer side effects than traditional treatments, significantly attenuates neuropathic and inflammatory pain unrelated to bone abnormalities via inhibition of vesicular nucleotide transporter (VNUT), a key molecule for the initiation of purinergic chemical transmission. In vitro analyses indicated that clodronate inhibits VNUT at a half-maximal inhibitory concentration of 15.6 nM without affecting other vesicular neurotransmitter transporters, acting as an allosteric modulator through competition with Cl- A low concentration of clodronate impaired vesicular ATP release from neurons, microglia, and immune cells. In vivo analyses revealed that clodronate is more effective than other therapeutic agents in attenuating neuropathic and inflammatory pain, as well as the accompanying inflammation, in wild-type but not VNUT-/- mice, without affecting basal nociception. These findings indicate that clodronate may represent a unique treatment strategy for chronic neuropathic and inflammatory pain via inhibition of vesicular ATP release. PMID- 28720703 TI - Canopy structure drives orangutan habitat selection in disturbed Bornean forests. AB - The conservation of charismatic and functionally important large species is becoming increasingly difficult. Anthropogenic pressures continue to squeeze available habitat and force animals into degraded and disturbed areas. Ensuring the long-term survival of these species requires a well-developed understanding of how animals use these new landscapes to inform conservation and habitat restoration efforts. We combined 3 y of highly detailed visual observations of Bornean orangutans with high-resolution airborne remote sensing (Light Detection and Ranging) to understand orangutan movement in disturbed and fragmented forests of Malaysian Borneo. Structural attributes of the upper forest canopy were the dominant determinant of orangutan movement among all age and sex classes, with orangutans more likely to move in directions of increased canopy closure, tall trees, and uniform height, as well as avoiding canopy gaps and moving toward emergent crowns. In contrast, canopy vertical complexity (canopy layering and shape) did not affect movement. Our results suggest that although orangutans do make use of disturbed forest, they select certain canopy attributes within these forests, indicating that not all disturbed or degraded forest is of equal value for the long-term sustainability of orangutan populations. Although the value of disturbed habitats needs to be recognized in conservation plans for wide-ranging, large-bodied species, minimal ecological requirements within these habitats also need to be understood and considered if long-term population viability is to be realized. PMID- 28720704 TI - Cytosolic interaction of type III human CD38 with CIB1 modulates cellular cyclic ADP-ribose levels. AB - CD38 catalyzes the synthesis of the Ca2+ messenger, cyclic ADP-ribose (cADPR). It is generally considered to be a type II protein with the catalytic domain facing outside. How it can catalyze the synthesis of intracellular cADPR that targets the endoplasmic Ca2+ stores has not been resolved. We have proposed that CD38 can also exist in an opposite type III orientation with its catalytic domain facing the cytosol. Here, we developed a method using specific nanobodies to immunotarget two different epitopes simultaneously on the catalytic domain of the type III CD38 and firmly established that it is naturally occurring in human multiple myeloma cells. Because type III CD38 is topologically amenable to cytosolic regulation, we used yeast-two-hybrid screening to identify cytosolic Ca2+ and integrin-binding protein 1 (CIB1), as its interacting partner. The results from immunoprecipitation, ELISA, and bimolecular fluorescence complementation confirmed that CIB1 binds specifically to the catalytic domain of CD38, in vivo and in vitro. Mutational studies established that the N terminus of CIB1 is the interacting domain. Using shRNA to knock down and Cas9/guide RNA to knock out CIB1, a direct correlation between the cellular cADPR and CIB1 levels was demonstrated. The results indicate that the type III CD38 is functionally active in producing cellular cADPR and that the activity is specifically modulated through interaction with cytosolic CIB1. PMID- 28720705 TI - Conceptual framework of the eco-physiological phases of insect diapause development justified by transcriptomic profiling. AB - Insects often overcome unfavorable seasons in a hormonally regulated state of diapause during which their activity ceases, development is arrested, metabolic rate is suppressed, and tolerance of environmental stress is bolstered. Diapausing insects pass through a stereotypic succession of eco-physiological phases termed "diapause development." The phasing is varied in the literature, and the whole concept is sometimes criticized as being too artificial. Here we present the results of transcriptional profiling using custom microarrays representing 1,042 genes in the drosophilid fly, Chymomyza costata Fully grown, third-instar larvae programmed for diapause by a photoperiodic (short-day) signal were assayed as they traversed the diapause developmental program. When analyzing the gradual dynamics in the transcriptomic profile, we could readily distinguish distinct diapause developmental phases associated with induction/initiation, maintenance, cold acclimation, and termination by cold or by photoperiodic signal. Accordingly, each phase is characterized by a specific pattern of gene expression, supporting the physiological relevance of the concept of diapause phasing. Further, we have dissected in greater detail the changes in transcript levels of elements of several signaling pathways considered critical for diapause regulation. The phase of diapause termination is associated with enhanced transcript levels in several positive elements stimulating direct development (the 20-hydroxyecdysone pathway: Ecr, Shd, Broad; the Wnt pathway: basket, c-jun) that are countered by up-regulation in some negative elements (the insulin signaling pathway: Ilp8, PI3k, Akt; the target of rapamycin pathway: Tsc2 and 4EBP; the Wnt pathway: shaggy). We speculate such up-regulations may represent the early steps linked to termination of diapause programming. PMID- 28720706 TI - Broadly expressed repressors integrate patterning across orthogonal axes in embryos. AB - The role of spatially localized repressors in supporting embryonic patterning is well appreciated, but, alternatively, the role ubiquitously expressed repressors play in this process is not well understood. We investigated the function of two broadly expressed repressors, Runt (Run) and Suppressor of Hairless [Su(H)], in patterning the Drosophila embryo. Previous studies have shown that Run and Su(H) regulate gene expression along anterior-posterior (AP) or dorsal-ventral (DV) axes, respectively, by spatially limiting activator action, but here we characterize a different role. Our data show that broadly expressed repressors silence particular enhancers within cis-regulatory systems, blocking their expression throughout the embryo fully but transiently, and, in this manner, regulate spatiotemporal outputs along both axes. Our results suggest that Run and Su(H) regulate the temporal action of enhancers and are not dedicated regulators of one axis but, instead, act coordinately to pattern both axes, AP and DV. PMID- 28720708 TI - Reply to Le Pape et al.: Management is key to preventing marine extinctions. PMID- 28720707 TI - Intrinsically disordered chromatin protein NUPR1 binds to the C-terminal region of Polycomb RING1B. AB - Intrinsically disordered proteins (IDPs) are ubiquitous in eukaryotes, and they are often associated with diseases in humans. The protein NUPR1 is a multifunctional IDP involved in chromatin remodeling and in the development and progression of pancreatic cancer; however, the details of such functions are unknown. Polycomb proteins are involved in specific transcriptional cascades and gene silencing. One of the proteins of the Polycomb complex is the Ring finger protein 1 (RING1). RING1 is related to aggressive tumor features in multiple cancer types. In this work we characterized the interaction between NUPR1 and the paralogue RING1B in vitro, in silico, and in cellulo. The interaction occurred through the C-terminal region of RING1B (C-RING1B), with an affinity in the low micromolar range (~10 MUM). The binding region of NUPR1, mapped by NMR, was a hydrophobic polypeptide patch at the 30s region of its sequence, as pinpointed by computational results and site-directed mutagenesis at Ala33. The association between C-RING1B and wild-type NUPR1 also occurred in cellulo as tested by protein ligation assays; this interaction is inhibited by trifluoperazine, a drug known to hamper binding of wild-type NUPR1 with other proteins. Furthermore, the Thr68Gln and Ala33Gln/Thr68Gln mutants had a reduction in the binding toward C RING1B as shown by in vitro, in silico, and in cellulo studies. This is an example of a well-folded partner of NUPR1, because its other interacting proteins are also unfolded. We hypothesize that NUPR1 plays an active role in chromatin remodeling and carcinogenesis, together with Polycomb proteins. PMID- 28720709 TI - Overfishing causes frequent fish population collapses but rare extinctions. PMID- 28720710 TI - Application of Response Surface Methods To Determine Conditions for Optimal Genomic Prediction. AB - An epistatic genetic architecture can have a significant impact on prediction accuracies of genomic prediction (GP) methods. Machine learning methods predict traits comprised of epistatic genetic architectures more accurately than statistical methods based on additive mixed linear models. The differences between these types of GP methods suggest a diagnostic for revealing genetic architectures underlying traits of interest. In addition to genetic architecture, the performance of GP methods may be influenced by the sample size of the training population, the number of QTL, and the proportion of phenotypic variability due to genotypic variability (heritability). Possible values for these factors and the number of combinations of the factor levels that influence the performance of GP methods can be large. Thus, efficient methods for identifying combinations of factor levels that produce most accurate GPs is needed. Herein, we employ response surface methods (RSMs) to find the experimental conditions that produce the most accurate GPs. We illustrate RSM with an example of simulated doubled haploid populations and identify the combination of factors that maximize the difference between prediction accuracies of best linear unbiased prediction (BLUP) and support vector machine (SVM) GP methods. The greatest impact on the response is due to the genetic architecture of the population, heritability of the trait, and the sample size. When epistasis is responsible for all of the genotypic variance and heritability is equal to one and the sample size of the training population is large, the advantage of using the SVM method vs. the BLUP method is greatest. However, except for values close to the maximum, most of the response surface shows little difference between the methods. We also determined that the conditions resulting in the greatest prediction accuracy for BLUP occurred when genetic architecture consists solely of additive effects, and heritability is equal to one. PMID- 28720712 TI - Regulation of the autophagy system during chronic contractile activity-induced muscle adaptations. AB - Skeletal muscle is adaptable to exercise stimuli via the upregulation of mitochondrial biogenesis, and recent studies have suggested that autophagy also plays a role in exercise-induced muscle adaptations. However, it is still obscure how muscle regulates autophagy over the time course of training adaptations. This study examined the expression of autophagic proteins in skeletal muscle of rats exposed to chronic contractile activity (CCA; 6 h/day, 9V, 10 Hz continuous, 0.1 msec pulse duration) for 1, 3, and 7 days (n = 8/group). CCA-induced mitochondrial adaptations were observed by day 7, as shown by the increase in mitochondrial proteins (PGC-1alpha, COX I, and COX IV), as well as COX activity. Notably, the ratio of LC3 II/LC3 I, an indicator of autophagy, decreased by day 7 largely due to a significant increase in LC3 I. The autophagic induction marker p62 was elevated on day 3 and returned to basal levels by day 7, suggesting a time-dependent increase in autophagic flux. The lysosomal system was upregulated early, prior to changes in mitochondrial proteins, as represented by increases in lysosomal system markers LAMP1, LAMP2A, and MCOLN1 as early as by day 1, as well as TFEB, a primary regulator of lysosomal biogenesis and autophagy flux. Our findings suggest that, in response to chronic exercise, autophagy is upregulated concomitant with mitochondrial adaptations. Notably, our data reveal the surprising adaptive plasticity of the lysosome in response to chronic contractile activity which enhances muscle health by providing cells with a greater capacity for macromolecular and organelle turnover. PMID- 28720713 TI - Sensory processing of deep tissue nociception in the rat spinal cord and thalamic ventrobasal complex. AB - Sensory processing of deep somatic tissue constitutes an important component of the nociceptive system, yet associated central processing pathways remain poorly understood. Here, we provide a novel electrophysiological characterization and immunohistochemical analysis of neural activation in the lateral spinal nucleus (LSN). These neurons show evoked activity to deep, but not cutaneous, stimulation. The evoked responses of neurons in the LSN can be sensitized to somatosensory stimulation following intramuscular hypertonic saline, an acute model of muscle pain, suggesting this is an important spinal relay site for the processing of deep tissue nociceptive inputs. Neurons of the thalamic ventrobasal complex (VBC) mediate both cutaneous and deep tissue sensory processing, but in contrast to the lateral spinal nucleus our electrophysiological studies do not suggest the existence of a subgroup of cells that selectively process deep tissue inputs. The sensitization of polymodal and thermospecific VBC neurons to mechanical somatosensory stimulation following acute muscle stimulation with hypertonic saline suggests differential roles of thalamic subpopulations in mediating cutaneous and deep tissue nociception in pathological states. Overall, our studies at both the spinal (lateral spinal nucleus) and supraspinal (thalamic ventrobasal complex) levels suggest a convergence of cutaneous and deep somatosensory inputs onto spinothalamic pathways, which are unmasked by activation of muscle nociceptive afferents to produce consequent phenotypic alterations in spinal and thalamic neural coding of somatosensory stimulation. A better understanding of the sensory pathways involved in deep tissue nociception, as well as the degree of labeled line and convergent pathways for cutaneous and deep somatosensory inputs, is fundamental to developing targeted analgesic therapies for deep pain syndromes. PMID- 28720711 TI - Gene Expression Networks in the Murine Pulmonary Myocardium Provide Insight into the Pathobiology of Atrial Fibrillation. AB - The pulmonary myocardium is a muscular coat surrounding the pulmonary and caval veins. Although its definitive physiological function is unknown, it may have a pathological role as the source of ectopic beats initiating atrial fibrillation. How the pulmonary myocardium gains pacemaker function is not clearly defined, although recent evidence indicates that changed transcriptional gene expression networks are at fault. The gene expression profile of this distinct cell type in situ was examined to investigate underlying molecular events that might contribute to atrial fibrillation. Via systems genetics, a whole-lung transcriptome data set from the BXD recombinant inbred mouse resource was analyzed, uncovering a pulmonary cardiomyocyte gene network of 24 transcripts, coordinately regulated by chromosome 1 and 2 loci. Promoter enrichment analysis and interrogation of publicly available ChIP-seq data suggested that transcription of this gene network may be regulated by the concerted activity of NKX2-5, serum response factor, myocyte enhancer factor 2, and also, at a post transcriptional level, by RNA binding protein motif 20. Gene ontology terms indicate that this gene network overlaps with molecular markers of the stressed heart. Therefore, we propose that perturbed regulation of this gene network might lead to altered calcium handling, myocyte growth, and contractile force contributing to the aberrant electrophysiological properties observed in atrial fibrillation. We reveal novel molecular interactions and pathways representing possible therapeutic targets for atrial fibrillation. In addition, we highlight the utility of recombinant inbred mouse resources in detecting and characterizing gene expression networks of relatively small populations of cells that have a pathological significance. PMID- 28720714 TI - Maxi-K channel (BKCa) activity veils the myogenic tone of mesenteric artery in rats. AB - Arterioles and small arteries change their tone in response to transmural pressure changes, called myogenic tone (MT). In comparison to the branches of cerebral arteries (CA) showing prominent MT, the third branches of mesenteric arteries (MA) with similar diameters show weaker MT Here, we aimed to analyze the electrophysiological differences responsible for the weaker MT in MA (MTMA) than MT in CA (MTCA). We measured ionic current using patch clamp in isolated MA smooth muscle cells (MASMCs) and CA smooth muscle cells (CASMCs) of rats. MT was analyzed using video analysis of pressurized small arteries. Quantitative-PCR (q PCR) and immunofluorescence confocal microscopy were used to compare the mRNA and protein expression level of big-conductance Ca2+-activated K+ channel (BKCa) subunits (Slo1alpha and Slobeta1). Whole-cell patch clamp study revealed higher density of voltage-operated Ca2+ channel current (ICaV) in the MASMCs than in CASMCs. Although voltage-gated K+ channel current (IKv) was also higher in MASMCs, treatment with Kv inhibitor (4-aminopyridine) did not affect MTMA Interestingly, BKCa current density and the frequency of spontaneous transient outward currents (STOCs) were consistently higher in MASMCs than in CASMCs. Inside-out patch clamp showed that the Ca2+-sensitivity of BKCa is higher in MASMCs than in CASMCs. Iberiotoxin, a selective BKCa inhibitor, augmented MTMA by a larger extent than MTCA Although q-PCR analysis did not reveal a significant difference of mRNAs for Slo1alpha and Slobeta1, immunofluorescence image suggested higher expression of Slo1alpha in MASMCs than in CASMCs. Despite the large ICaV density, the high activities of BKCa including the more frequent STOCs in MASMCs veils the potentially strong MTMA. PMID- 28720715 TI - Ischemic preconditioning does not alter muscle sympathetic responses to static handgrip and metaboreflex activation in young healthy men. AB - Ischemic preconditioning (IPC) has been hypothesized to elicit ergogenic effects by reducing feedback from metabolically sensitive group III/IV muscle afferents during exercise. If so, reflex efferent neural outflow should be attenuated. We investigated the effects of IPC on muscle sympathetic nerve activity (MSNA) during static handgrip (SHG) and used post-exercise circulatory occlusion (PECO) to isolate for the muscle metaboreflex. Thirty-seven healthy men (age: 24 +/- 5 years [mean +/- SD]) were randomized to receive sham (n = 16) or IPC (n = 21) interventions. Blood pressure, heart rate, and MSNA (microneurography; sham n = 11 and IPC n = 18) were collected at rest and during 2 min of SHG (30% maximal voluntary contraction) and 3 min of PECO before (PRE) and after (POST) sham or IPC treatment (3 * 5 min 20 mmHg or 200 mmHg unilateral upper arm cuff inflation). Resting mean arterial pressure was higher following sham (79 +/- 7 vs. 83 +/- 6 mmHg, P < 0.01) but not IPC (81 +/- 6 vs. 82 +/- 6 mmHg, P > 0.05), while resting MSNA burst frequency was unchanged (P > 0.05) with sham (18 +/- 7 vs. 19 +/- 9 bursts/min) or IPC (17 +/- 7 vs. 19 +/- 7 bursts/min). Mean arterial pressure, heart rate, stroke volume, cardiac output, and total vascular conductance responses during SHG and PECO were comparable PRE and POST following sham and IPC (All P > 0.05). Similarly, MSNA burst frequency, burst incidence, and total MSNA responses during SHG and PECO were comparable PRE and POST with sham and IPC (All P > 0.05). These findings demonstrate that IPC does not reduce hemodynamic responses or central sympathetic outflow directed toward the skeletal muscle during activation of the muscle metaboreflex using static exercise or subsequent PECO. PMID- 28720716 TI - PI3Kgamma activity in leukocytes promotes adipose tissue inflammation and early onset insulin resistance during obesity. AB - The phosphoinositide 3-kinase gamma (PI3Kgamma) plays a major role in leukocyte recruitment during acute inflammation and has been proposed to inhibit classical macrophage activation by driving immunosuppressive gene expression. PI3Kgamma plays an important role in diet-induced obesity and insulin resistance. In seeking to determine the underlying molecular mechanisms, we showed that PI3Kgamma action in high-fat diet-induced inflammation and insulin resistance depended largely on its role in the control of adiposity, which was due to PI3Kgamma activity in a nonhematopoietic cell type. However, PI3Kgamma activity in leukocytes was required for efficient neutrophil recruitment to adipose tissue. Neutrophil recruitment was correlated with proinflammatory gene expression in macrophages in adipose tissue, which triggered insulin resistance early during the development of obesity. Our data challenge the concept that PI3Kgamma is a general suppressor of classical macrophage activation and indicate that PI3Kgamma controls macrophage gene expression by non-cell-autonomous mechanisms, the outcome of which is context-dependent. PMID- 28720717 TI - STING is an essential mediator of the Ku70-mediated production of IFN-lambda1 in response to exogenous DNA. AB - We previously identified Ku70, a subunit of a DNA repair protein complex, as a cytosolic DNA sensor that induces the production of interferon-lambda1 (IFN lambda1) by human primary cells and cell lines. IFN-lambda1 is a type III IFN and has similar antiviral activity to that of the type I IFNs (IFN-alpha and IFN beta). We observed that human embryonic kidney (HEK) 293T cells, which are deficient in the innate immune adaptor protein STING (stimulator of IFN genes), did not produce IFN-lambda1 in response to DNA unless they were reconstituted with STING. Conversely, parental HEK 293 cells produced IFN-lambda1 after they were exposed to exogenous DNA; however, when STING was knocked out in the HEK 293 cells through the CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 genome editing system, they lost this response. Through confocal microscopy, we demonstrated that endogenous Ku70 was located in the nucleus and then translocated to the cytoplasm upon DNA exposure to form a complex with STING. Additionally, the DNA binding domain of Ku70 was essential for formation of the Ku70-STING complex. Knocking down STING in primary human macrophages inhibited their ability to produce IFN-lambda1 in response to transfection with DNA or infection with the DNA virus HSV-2 (herpes simplex virus-2). Together, these data suggest that STING mediates the Ku70-mediated IFN-lambda1 innate immune response to exogenous DNA or DNA virus infection. PMID- 28720718 TI - Phosphorylation of amyloid precursor protein by mutant LRRK2 promotes AICD activity and neurotoxicity in Parkinson's disease. AB - Mutations in LRRK2, which encodes leucine-rich repeat kinase 2, are the most common genetic cause of familial and sporadic Parkinson's disease (PD), a degenerative disease of the central nervous system that causes impaired motor function and, in advanced stages, dementia. Dementia is a common symptom of another neurodegenerative disease, Alzheimer's disease, and research suggests that there may be pathophysiological and genetic links between the two diseases. Aggregates of beta amyloid [a protein produced through cleavage of amyloid precursor protein (APP)] are seen in both diseases and in PD patients carrying G2019S-mutant LRRK2. Using patient-derived cells, brain tissue, and PD model mice, we found that LRRK2 interacted with and phosphorylated APP at Thr668 within its intracellular domain (AICD). Phosphorylation of APP at Thr668 promoted AICD transcriptional activity and correlated with increased nuclear abundance of AICD and decreased abundance of a dopaminergic neuron marker in cultures and brain tissue. The AICD regulates the transcription of genes involved in cytoskeletal dynamics and apoptosis. Overexpression of AICD, but not a phosphodeficient mutant (AICDT668A), increased the loss of dopaminergic neurons in older mice expressing LRRK2G2019S Moreover, the amount of Thr668-phosphorylated APP was substantially greater in postmortem brain tissue and dopaminergic neurons (generated by reprogramming skin cells) from LRRK2G2019S patients than in those from healthy individuals. LRRK2 inhibitors reduced the phosphorylation of APP at Thr668 in the patient-derived dopaminergic neurons and in the midbrains of LRRK2G2019S mice. Thus, APP is a substrate of LRRK2, and its phosphorylation promotes AICD function and neurotoxicity in PD. PMID- 28720719 TI - Introduction of a new imaging guideline for suspected renal colic in the ED reduces CT urography utilisation. AB - BACKGROUND: Patients presenting to the ED with suspected renal colic are frequently imaged with CT urography (CTU), which rarely alters diagnosis or management. To reduce use of CTU in this population, we instigated a new imaging and management guideline in our ED. METHODS: This was a quasi-experimental prospective study, whereby a new guideline was commenced at the intervention site (Monash Medical Centre) and the existing guideline continued at the control site (Dandenong Hospital). The new guideline promotes focused ultrasound for diagnosing renal colic and restricts CT to those with poor response to analgesia or 'red flags'. A consecutive series of patients with suspected renal colic were prospectively enrolled and outcomes compared between the sites. The primary outcome was CTU utilisation and secondary outcomes were radiation exposure, stone rate on CTU, admission, ED length of stay and rates of urological intervention and returns to ED at 4-week follow-up. RESULTS: Preintervention CTU rates were 76.7% at Monash and 72.1% at Dandenong. 324 patients were enrolled; 148 at Monash and 176 at Dandenong. Median age 47 years vs 49 years, males 76.4% vs 66.5% and medianSex, Timing, Origin, Nausea, Erythrocytes (STONE) score 10 vs 10 for Monash and Dandenong, respectively. CTU was performed in 54.1% vs 75.0% (p<0.001), median radiation exposure 2.8 vs 4.0 mSv (p<0.001) and urological intervention occurred in 16.4% vs 15.7% for Monash and Dandenong, respectively. CONCLUSIONS: We found that use of CTU for renal colic was significantly reduced by introduction of a guideline promoting ultrasound and encouraging selective CTU. Although intervention rates were similar between the two sites, further prospective study is needed to ensure other patient-centred outcomes do not differ. PMID- 28720720 TI - Comparison of prehospital triage and five-level triage system at the emergency department. AB - OBJECTIVE: There is lack of scientific evidence regarding the effectiveness of prehospital triage systems. This study compared the two-level Taiwan Prehospital Triage System (TPTS) with the five-level Taiwan Triage and Acuity Scale (TTAS) at ED arrival regarding the prediction of patient outcomes and the utilisation of medical resources. DESIGN: This was a retrospective cohort study. Adult patients transported via the emergency medical service (EMS), who arrived at the ED of a medical centre in northern Taiwan during the study period were enrolled. TTAS acuity levels 1-2 were considered comparable to the designation of 'emergent' by the prehospital TPTS system. The outcomes were analysed by comparing TPTS and TTAS by acuity levels. RESULTS: Among 4430 enrolled patients, 25.2% and 74.8% were classified as emergent and non-emergent by TPTS; 44.1% and 55.9% were classified as levels 1-2 and levels 3-5 by TTAS. Of the TPTS emergent patients, 15.2% were classified as TTAS levels 3-5, whereas 30.4% of TPTS non-emergent transports were classified as TTAS levels 1-2 at the ED. TTAS levels 1-2 showed better predictability than TPTS emergent level for hospitalisation rate with a sensitivity of 70.3% (95% CI 68.3% to 72.2%) versus 41.1% (95% CI 39.0% to 43.2%), and a negative predictive value of 74.8% (95% CI 73.4% to 76.0%) versus 62.6% (95% CI 61.7% to 63.5%). CONCLUSION: The current prehospital triage system is insufficient and inappropriate in classifying patients transported to the ED. The present study offers supporting evidence for the introduction of a five-level triage system to prehospital EMS systems. PMID- 28720721 TI - Predictors of repeat visits to hospital psychiatric emergency departments in Malaga (Spain) and in Lisbon (Portugal). AB - OBJECTIVE: This study describes the profile of people with mental disorders attending emergency departments (EDs) in two countries and to identify specific mental disorders associated with repeat emergency visits. METHODS: Retrospective analyses of 1 year of EDs data from two hospitals with psychiatric departments, one in Amadora/Sintra (Lisbon, Portugal, 2008) and the other in Malaga (Spain, 2009), were carried out. To determine which mental disorders were associated with repeat visits in each setting, negative binomial models were calculated. RESULTS: There were 5141 visits for a mental disorder made by 3667 patients. Patients with affective disorder were the most frequent (32.2%). Among all mental health patients, 19.9% had at least one repeat visit during the year. For the two EDs setting combined, patients with personality disorders (incidence rate ratio (IRR)=3.79, 95% CI: 2.39 to 6.02) and psychotic disorders (IRR=1.46, 95% CI: 1.13 to 1.89) were more likely to have repeat visits compared with patients with affective disorders, whereas mental disorders due to psychoactive substance use (IRR=0.52, 95% CI: 0.37 to 0.73) was associated with lower likelihood of repeat visits. Nearly all significant differences were attributable to the Malaga sample, where patients with personality disorders were four times more likely to have repeat EDs visits compared with patients with affective disorders. However, at both sites, patients with mental disorders due to psychoactive substance use were less likely to have repeat visits. CONCLUSIONS: Certain mental disorders may be predictive of more frequent ED visits. The different results for each country suggest that further studies might focus not only on the characteristics of patients, but also on local healthcare organisation. PMID- 28720722 TI - Emergency department diagnostic codes: useful data? PMID- 28720723 TI - Profile and outcomes of critically ill children in a lower middle-income country. AB - OBJECTIVE: To determine the clinical profile and outcome of critically ill children presenting to a paediatric ED in a lower middle-income country. METHODS: We performed a retrospective analysis of children (<14 years) presenting to the ED of the National Institute of Child Health, Karachi, between January and December 2014 who were assigned to acuity 1 (requiring immediate life-saving interventions) according to the Emergency Severity Index. Data included demographic variables, presenting complaints, interventions and outcomes in the ED. RESULTS: There were 172 162 visits during the year. Of these, 13 551 (8%) were level 1. 64% of level 1 patients were transported to the ED without ambulance service. Neonates (0-28 days) constituted 48% of level 1 children; their most frequent presenting complaints were respiratory symptoms, followed by fever and reluctance to feed. Above the neonatal age group, the most common presenting complaints were gastrointestinal symptoms (with signs of hypoperfusion), followed by seizures, reluctance to feed and respiratory symptoms. 64% of children of >28 days presenting were malnourished. Interventions included cardiopulmonary resuscitation, application of bubble continuous positive airway pressure and endotracheal intubation. Overall mortality was 13%; 63% of all deaths were in the neonatal age group. CONCLUSION: Children with the highest triage acuity represent 8% of all visits to a paediatric ED. In this group, neonates account for nearly half of all the children, and more than half of all the deaths among critically ill children came in ED. A large proportion of high acuity children are malnourished. PMID- 28720724 TI - Aortic Wall Inflammation Predicts Abdominal Aortic Aneurysm Expansion, Rupture, and Need for Surgical Repair. AB - BACKGROUND: Ultrasmall superparamagnetic particles of iron oxide (USPIO) detect cellular inflammation on magnetic resonance imaging (MRI). In patients with abdominal aortic aneurysm, we assessed whether USPIO-enhanced MRI can predict aneurysm growth rates and clinical outcomes. METHODS: In a prospective multicenter open-label cohort study, 342 patients with abdominal aortic aneurysm (diameter >=40 mm) were classified by the presence of USPIO enhancement and were monitored with serial ultrasound and clinical follow-up for >=2 years. The primary end point was the composite of aneurysm rupture or repair. RESULTS: Participants (85% male, 73.1+/-7.2 years) had a baseline aneurysm diameter of 49.6+/-7.7 mm, and USPIO enhancement was identified in 146 (42.7%) participants, absent in 191 (55.8%), and indeterminant in 5 (1.5%). During follow-up (1005+/ 280 days), 17 (5.0%) abdominal aortic aneurysm ruptures, 126 (36.8%) abdominal aortic aneurysm repairs, and 48 (14.0%) deaths occurred. Compared with those without uptake, patients with USPIO enhancement have increased rates of aneurysm expansion (3.1+/-2.5 versus 2.5+/-2.4 mm/year, P=0.0424), although this was not independent of current smoking habit (P=0.1993). Patients with USPIO enhancement had higher rates of aneurysm rupture or repair (47.3% versus 35.6%; 95% confidence intervals, 1.1-22.2; P=0.0308). This finding was similar for each component of rupture (6.8% versus 3.7%, P=0.1857) or repair (41.8% versus 32.5%, P=0.0782). USPIO enhancement was associated with reduced event-free survival for aneurysm rupture or repair (P=0.0275), all-cause mortality (P=0.0635), and aneurysm-related mortality (P=0.0590). Baseline abdominal aortic aneurysm diameter (P<0.0001) and current smoking habit (P=0.0446) also predicted the primary outcome, and the addition of USPIO enhancement to the multivariate model did not improve event prediction (c-statistic, 0.7935-0.7936). CONCLUSIONS: USPIO enhanced MRI is a novel approach to the identification of aortic wall cellular inflammation in patients with abdominal aortic aneurysms and predicts the rate of aneurysm growth and clinical outcome. However, it does not provide independent prediction of aneurysm expansion or clinical outcomes in a model incorporating known clinical risk factors. CLINICAL TRIAL REGISTRATION: URL: http://www.isrctn.com. Unique identifier: ISRCTN76413758. PMID- 28720725 TI - Optical Coherence Tomography Findings in Patients With Coronary Stent Thrombosis: A Report of the PRESTIGE Consortium (Prevention of Late Stent Thrombosis by an Interdisciplinary Global European Effort). AB - BACKGROUND: Stent thrombosis (ST) is a serious complication following coronary stenting. Intravascular optical coherence tomography (OCT) may provide insights into mechanistic processes leading to ST. We performed a prospective, multicenter study to evaluate OCT findings in patients with ST. METHODS: Consecutive patients presenting with ST were prospectively enrolled in a registry by using a centralized telephone registration system. After angiographic confirmation of ST, OCT imaging of the culprit vessel was performed with frequency domain OCT. Clinical data were collected according to a standardized protocol. OCT acquisitions were analyzed at a core laboratory. Dominant and contributing findings were adjudicated by an imaging adjudication committee. RESULTS: Two hundred thirty-one patients presenting with ST underwent OCT imaging; 14 (6.1%) had image quality precluding further analysis. Of the remaining patients, 62 (28.6%) and 155 (71.4%) presented with early and late/very late ST, respectively. The underlying stent type was a new-generation drug-eluting stent in 50.3%. Mean reference vessel diameter was 2.9+/-0.6 mm and mean reference vessel area was 6.8+/-2.6 mm2. Stent underexpansion (stent expansion index <0.8) was observed in 44.4% of patients. The predicted average probability (95% confidence interval) that any frame had uncovered (or thrombus-covered) struts was 99.3% (96.1-99.9), 96.6% (92.4-98.5), 34.3% (15.0-60.7), and 9.6% (6.2-14.5) and malapposed struts was 21.8% (8.4-45.6), 8.5% (4.6-15.3), 6.7% (2.5-16.3), and 2.0% (1.2-3.3) for acute, subacute, late, and very late ST, respectively. The most common dominant finding adjudicated for acute ST was uncovered struts (66.7% of cases); for subacute ST, the most common dominant finding was uncovered struts (61.7%) and underexpansion (25.5%); for late ST, the most common dominant finding was uncovered struts (33.3%) and severe restenosis (19.1%); and for very late ST, the most common dominant finding was neoatherosclerosis (31.3%) and uncovered struts (20.2%). In patients presenting very late ST, uncovered stent struts were a common dominant finding in drug-eluting stents, and neoatherosclerosis was a common dominant finding in bare metal stents. CONCLUSIONS: In patients with ST, uncovered and malapposed struts were frequently observed with the incidence of both decreasing with longer time intervals between stent implantation and presentation. The most frequent dominant observation varied according to time intervals from index stenting: uncovered struts and underexpansion in acute/subacute ST and neoatherosclerosis and uncovered struts in late/very late ST. PMID- 28720728 TI - Disguised as a Sulfate Reducer: Growth of the Deltaproteobacterium Desulfurivibrio alkaliphilus by Sulfide Oxidation with Nitrate. AB - This study demonstrates that the deltaproteobacterium Desulfurivibrio alkaliphilus can grow chemolithotrophically by coupling sulfide oxidation to the dissimilatory reduction of nitrate and nitrite to ammonium. Key genes of known sulfide oxidation pathways are absent from the genome of D. alkaliphilus Instead, the genome contains all of the genes necessary for sulfate reduction, including a gene for a reductive-type dissimilatory bisulfite reductase (DSR). Despite this, growth by sulfate reduction was not observed. Transcriptomic analysis revealed a very high expression level of sulfate-reduction genes during growth by sulfide oxidation, while inhibition experiments with molybdate pointed to elemental sulfur/polysulfides as intermediates. Consequently, we propose that D. alkaliphilus initially oxidizes sulfide to elemental sulfur, which is then either disproportionated, or oxidized by a reversal of the sulfate reduction pathway. This is the first study providing evidence that a reductive-type DSR is involved in a sulfide oxidation pathway. Transcriptome sequencing further suggests that nitrate reduction to ammonium is performed by a novel type of periplasmic nitrate reductase and an unusual membrane-anchored nitrite reductase.IMPORTANCE Sulfide oxidation and sulfate reduction, the two major branches of the sulfur cycle, are usually ascribed to distinct sets of microbes with distinct diagnostic genes. Here we show a more complex picture, as D. alkaliphilus, with the genomic setup of a sulfate reducer, grows by sulfide oxidation. The high expression of genes typically involved in the sulfate reduction pathway suggests that these genes, including the reductive-type dissimilatory bisulfite reductases, are also involved in as-yet-unresolved sulfide oxidation pathways. Finally, D. alkaliphilus is closely related to cable bacteria, which grow by electrogenic sulfide oxidation. Since there are no pure cultures of cable bacteria, D. alkaliphilus may represent an exciting model organism in which to study the physiology of this process. PMID- 28720726 TI - Mitochondrial Cochaperone Mge1 Is Involved in Regulating Susceptibility to Fluconazole in Saccharomyces cerevisiae and Candida Species. AB - MGE1 encodes a yeast chaperone involved in Fe-S cluster metabolism and protein import into the mitochondria. In this study, we identified MGE1 as a multicopy suppressor of susceptibility to the antifungal fluconazole in the model yeast Saccharomyces cerevisiae We demonstrate that this phenomenon is not exclusively dependent on the integrity of the mitochondrial DNA or on the presence of the drug efflux pump Pdr5. Instead, we show that the increased dosage of Mge1 plays a protective role by retaining increased amounts of ergosterol upon fluconazole treatment. Iron metabolism and, more particularly, Fe-S cluster formation are involved in regulating this process, since the responsible Hsp70 chaperone, Ssq1, is required. Additionally, we show the necessity but, by itself, insufficiency of activating the iron regulon in establishing the Mge1-related effect on drug susceptibility. Finally, we confirm a similar role for Mge1 in fluconazole susceptibility in the pathogenic fungi Candida glabrata and Candida albicansIMPORTANCE Although they are mostly neglected compared to bacterial infections, fungal infections pose a serious threat to the human population. While some of them remain relatively harmless, infections that reach the bloodstream often become lethal. Only a few therapies are available, and resistance of the pathogen to these drugs is a frequently encountered problem. It is thus essential that more research is performed on how these pathogens cope with the treatment and cause recurrent infections. Baker's yeast is often used as a model to study pathogenic fungi. We show here, by using this model, that iron metabolism and the formation of the important iron-sulfur clusters are involved in regulating susceptibility to fluconazole, the most commonly used antifungal drug. We show that the same process likely also occurs in two of the most regularly isolated pathogenic fungi, Candida glabrata and Candida albicans. PMID- 28720727 TI - Impact of Paracoccin Gene Silencing on Paracoccidioides brasiliensis Virulence. AB - Among the endemic deep mycoses in Latin America, paracoccidioidomycosis (PCM), caused by thermodimorphic fungi of the Paracoccidioides genus, is a major cause of morbidity. Disease development and its manifestations are associated with both host and fungal factors. Concerning the latter, several recent studies have employed the methodology of gene modulation in P. brasiliensis using antisense RNA (AsRNA) and Agrobacterium tumefaciens-mediated transformation (ATMT) to identify proteins that influence fungus virulence. Our previous observations suggested that paracoccin (PCN), a multidomain fungal protein with both lectin and enzymatic activities, may be a potential P. brasiliensis virulence factor. To explore this, we used AsRNA and ATMT methodology to obtain three independent PCN silenced P. brasiliensis yeast strains (AsPCN1, AsPCN2, and AsPCN3) and characterized them with regard to P. brasiliensis biology and pathogenicity. AsPCN1, AsPCN2, and AsPCN3 showed relative PCN expression levels that were 60%, 40%, and 60% of that of the wild-type (WT) strain, respectively. PCN silencing led to the aggregation of fungal cells, blocked the morphological yeast-to mycelium transition, and rendered the yeast less resistant to macrophage fungicidal activity. In addition, mice infected with AsPCN1, AsPCN2, and AsPCN3 showed a reduction in fungal burden of approximately 96% compared with those inoculated with the WT strain, which displayed a more extensive destruction of lung tissue. Finally, mice infected with the PCN-silenced yeast strains had lower mortality than those infected with the WT strain. These data demonstrate that PCN acts as a P. brasiliensis contributory virulence factor directly affecting fungal pathogenesis.IMPORTANCE The nonexistence of efficient genetic transformation systems has hampered studies in the dimorphic fungus Paracoccidioides brasiliensis, the etiological agent of the most frequent systemic mycosis in Latin America. The recent development of a method for gene expression knockdown by antisense RNA technology, associated with an Agrobacterium tumefaciens mediated transformation system, provides new strategies for studying P. brasiliensis Through this technology, we generated yeasts that were silenced for paracoccin (PCN), a P. brasiliensis component that has lectin and enzymatic properties. By comparing the phenotypes of PCN-silenced and wild-type strains of P. brasiliensis, we identified PCN as a virulence factor whose absence renders the yeasts unable to undergo the transition to mycelium and causes a milder pulmonary disease in mice, with a lower mortality rate. Our report highlights the importance of the technology used for P. brasiliensis transformation and demonstrates that paracoccin is a virulence factor acting on fungal biology and pathogenesis. PMID- 28720729 TI - Inhibition of Inflammasome-Dependent Interleukin 1beta Production by Streptococcal NAD+-Glycohydrolase: Evidence for Extracellular Activity. AB - Group A Streptococcus (GAS) is a common human pathogen and the etiologic agent of a large number of diseases ranging from mild, self-limiting infections to invasive life-threatening conditions. Two prominent virulence factors of this bacterium are the genetically and functionally linked pore-forming toxin streptolysin O (SLO) and its cotoxin NAD+-glycohydrolase (NADase). Overexpression of these toxins has been linked to increased bacterial virulence and is correlated with invasive GAS disease. NADase can be translocated into host cells by a SLO-dependent mechanism, and cytosolic NADase has been assigned multiple properties such as protection of intracellularly located GAS bacteria and induction of host cell death through energy depletion. Here, we used a set of isogenic GAS mutants and a macrophage infection model and report that streptococcal NADase inhibits the innate immune response by decreasing inflammasome-dependent interleukin 1beta (IL-1beta) release from infected macrophages. Regulation of IL-1beta was independent of phagocytosis and ensued also under conditions not allowing SLO-dependent translocation of NADase into the host cell cytosol. Thus, our data indicate that NADase not only acts intracellularly but also has an immune regulatory function in the extracellular niche.IMPORTANCE In the mid-1980s, the incidence and severity of invasive infections caused by serotype M1 GAS suddenly increased. The results of genomic analyses suggested that this increase was due to the spread of clonal bacterial strains and identified a recombination event leading to enhanced production of the SLO and NADase toxins in these strains. However, despite its apparent importance in GAS pathogenesis, the function of NADase remains poorly understood. In this study, we demonstrate that NADase inhibits inflammasome-dependent IL 1beta release from infected macrophages. While previously described functions of NADase pertain to its role upon SLO-mediated translocation into the host cell cytosol, our data suggest that the immune regulatory function of NADase is exerted by nontranslocated enzyme, identifying a previously unrecognized extracellular niche for NADase functionality. This immune regulatory property of extracellular NADase adds another possible explanation to how increased secretion of NADase correlates with bacterial virulence. PMID- 28720730 TI - Drought Stress Results in a Compartment-Specific Restructuring of the Rice Root Associated Microbiomes. AB - Plant roots support complex microbial communities that can influence plant growth, nutrition, and health. While extensive characterizations of the composition and spatial compartmentalization of these communities have been performed in different plant species, there is relatively little known about the impact of abiotic stresses on the root microbiota. Here, we have used rice as a model to explore the responses of root microbiomes to drought stress. Using four distinct genotypes, grown in soils from three different fields, we tracked the drought-induced changes in microbial composition in the rhizosphere (the soil immediately surrounding the root), the endosphere (the root interior), and unplanted soils. Drought significantly altered the overall bacterial and fungal compositions of all three communities, with the endosphere and rhizosphere compartments showing the greatest divergence from well-watered controls. The overall response of the bacterial microbiota to drought stress was taxonomically consistent across soils and cultivars and was primarily driven by an enrichment of multiple Actinobacteria and Chloroflexi, as well as a depletion of several Acidobacteria and Deltaproteobacteria While there was some overlap in the changes observed in the rhizosphere and endosphere communities, several drought responsive taxa were compartment specific, a pattern likely arising from preexisting compositional differences, as well as plant-mediated processes affecting individual compartments. These results reveal that drought stress, in addition to its well-characterized effects on plant physiology, also results in restructuring of root microbial communities and suggest the possibility that constituents of the altered plant microbiota might contribute to plant survival under extreme environmental conditions.IMPORTANCE With the likelihood that changes in global climate will adversely affect crop yields, the potential role of microbial communities in enhancing plant performance makes it important to elucidate the responses of plant microbiomes to environmental variation. By detailed characterization of the effect of drought stress on the root-associated microbiota of the crop plant rice, we show that the rhizosphere and endosphere communities undergo major compositional changes that involve shifts in the relative abundances of a taxonomically diverse set of bacteria in response to drought. These drought-responsive microbes, in particular those enriched under water deficit conditions, could potentially benefit the plant as they could contribute to tolerance to drought and other abiotic stresses, as well as provide protection from opportunistic infection by pathogenic microbes. The identification and future isolation of microbes that promote plant tolerance to drought could potentially be used to mitigate crop losses arising from adverse shifts in climate. PMID- 28720731 TI - An In Vitro Chicken Gut Model Demonstrates Transfer of a Multidrug Resistance Plasmid from Salmonella to Commensal Escherichia coli. AB - The chicken gastrointestinal tract is richly populated by commensal bacteria that fulfill various beneficial roles for the host, including helping to resist colonization by pathogens. It can also facilitate the conjugative transfer of multidrug resistance (MDR) plasmids between commensal and pathogenic bacteria which is a significant public and animal health concern as it may affect our ability to treat bacterial infections. We used an in vitro chemostat system to approximate the chicken cecal microbiota, simulate colonization by an MDR Salmonella pathogen, and examine the dynamics of transfer of its MDR plasmid harboring several genes, including the extended-spectrum beta-lactamase blaCTX-M1 We also evaluated the impact of cefotaxime administration on plasmid transfer and microbial diversity. Bacterial community profiles obtained by culture-independent methods showed that Salmonella inoculation resulted in no significant changes to bacterial community alpha diversity and beta diversity, whereas administration of cefotaxime caused significant alterations to both measures of diversity, which largely recovered. MDR plasmid transfer from Salmonella to commensal Escherichia coli was demonstrated by PCR and whole-genome sequencing of isolates purified from agar plates containing cefotaxime. Transfer occurred to seven E. coli sequence types at high rates, even in the absence of cefotaxime, with resistant strains isolated within 3 days. Our chemostat system provides a good representation of bacterial interactions, including antibiotic resistance transfer in vivo It can be used as an ethical and relatively inexpensive approach to model dissemination of antibiotic resistance within the gut of any animal or human and refine interventions that mitigate its spread before employing in vivo studies.IMPORTANCE The spread of antimicrobial resistance presents a grave threat to public health and animal health and is affecting our ability to respond to bacterial infections. Transfer of antimicrobial resistance via plasmid exchange is of particular concern as it enables unrelated bacteria to acquire resistance. The gastrointestinal tract is replete with bacteria and provides an environment for plasmid transfer between commensals and pathogens. Here we use the chicken gut microbiota as an exemplar to model the effects of bacterial infection, antibiotic administration, and plasmid transfer. We show that transfer of a multidrug-resistant plasmid from the zoonotic pathogen Salmonella to commensal Escherichia coli occurs at a high rate, even in the absence of antibiotic administration. Our work demonstrates that the in vitro gut model provides a powerful screening tool that can be used to assess and refine interventions that mitigate the spread of antibiotic resistance in the gut before undertaking animal studies. PMID- 28720732 TI - Pseudomonas aeruginosa Alters Staphylococcus aureus Sensitivity to Vancomycin in a Biofilm Model of Cystic Fibrosis Infection. AB - The airways of cystic fibrosis (CF) patients have thick mucus, which fosters chronic, polymicrobial infections. Pseudomonas aeruginosa and Staphylococcus aureus are two of the most prevalent respiratory pathogens in CF patients. In this study, we tested whether P. aeruginosa influences the susceptibility of S. aureus to frontline antibiotics used to treat CF lung infections. Using our in vitro coculture model, we observed that addition of P. aeruginosa supernatants to S. aureus biofilms grown either on epithelial cells or on plastic significantly decreased the susceptibility of S. aureus to vancomycin. Mutant analyses showed that 2-n-heptyl-4-hydroxyquinoline N-oxide (HQNO), a component of the P. aeruginosa Pseudomonas quinolone signal (PQS) system, protects S. aureus from the antimicrobial activity of vancomycin. Similarly, the siderophores pyoverdine and pyochelin also contribute to the ability of P. aeruginosa to protect S. aureus from vancomycin, as did growth under anoxia. Under our experimental conditions, HQNO, P. aeruginosa supernatant, and growth under anoxia decreased S. aureus growth, likely explaining why this cell wall-targeting antibiotic is less effective. P. aeruginosa supernatant did not confer additional protection to slow growing S. aureus small colony variants. Importantly, P. aeruginosa supernatant protects S. aureus from other inhibitors of cell wall synthesis as well as protein synthesis-targeting antibiotics in an HQNO- and siderophore-dependent manner. We propose a model whereby P. aeruginosa causes S. aureus to shift to fermentative growth when these organisms are grown in coculture, leading to reduction in S. aureus growth and decreased susceptibility to antibiotics targeting cell wall and protein synthesis.IMPORTANCE Cystic fibrosis (CF) lung infections are chronic and difficult to eradicate. Pseudomonas aeruginosa and Staphylococcus aureus are two of the most prevalent respiratory pathogens in CF patients and are associated with poor patient outcomes. Both organisms adopt a biofilm mode of growth, which contributes to high tolerance to antibiotic treatment and the recalcitrant nature of these infections. Here, we show that P. aeruginosa exoproducts decrease the sensitivity of S. aureus biofilm and planktonic populations to vancomycin, a frontline antibiotic used to treat methicillin-resistant S. aureus in CF patients. P. aeruginosa also protects S. aureus from other cell wall-active antibiotics as well as various classes of protein synthesis inhibitors. Thus, interspecies interactions can have dramatic and unexpected consequences on antibiotic sensitivity. This study underscores the potential impact of interspecies interactions on antibiotic efficacy in the context of complex, polymicrobial infections. PMID- 28720733 TI - Dengue Virus Hijacks a Noncanonical Oxidoreductase Function of a Cellular Oligosaccharyltransferase Complex. AB - Dengue virus (DENV) is the most common arboviral infection globally, infecting an estimated 390 million people each year. We employed a genome-wide clustered regularly interspaced short palindromic repeat (CRISPR) screen to identify host dependency factors required for DENV propagation and identified the oligosaccharyltransferase (OST) complex as an essential host factor for DENV infection. Mammalian cells express two OSTs containing either STT3A or STT3B. We found that the canonical catalytic function of the OSTs as oligosaccharyltransferases is not necessary for DENV infection, as cells expressing catalytically inactive STT3A or STT3B are able to support DENV propagation. However, the OST subunit MAGT1, which associates with STT3B, is also required for DENV propagation. MAGT1 expression requires STT3B, and a catalytically inactive STT3B also rescues MAGT1 expression, supporting the hypothesis that STT3B serves to stabilize MAGT1 in the context of DENV infection. We found that the oxidoreductase CXXC active site motif of MAGT1 was necessary for DENV propagation, as cells expressing an AXXA MAGT1 mutant were unable to support DENV infection. Interestingly, cells expressing single-cysteine CXXA or AXXC mutants of MAGT1 were able to support DENV propagation. Utilizing the engineered peroxidase APEX2, we demonstrate the close proximity between MAGT1 and NS1 or NS4B during DENV infection. These results reveal that the oxidoreductase activity of the STT3B-containing OST is necessary for DENV infection, which may guide the development of antiviral agents targeting DENV.IMPORTANCE The host oligosaccharyltransferase (OST) complexes have been identified as essential host factors for dengue virus (DENV) replication; however, their functions during DENV infection are unclear. A previous study showed that the canonical OST activity was dispensable for DENV replication, suggesting that the OST complexes serve as scaffolds for DENV replication. However, our work demonstrates that one function of the OST complex during DENV infection is to provide oxidoreductase activity via the OST subunit MAGT1. We also show that MAGT1 associates with DENV NS1 and NS4B during viral infection, suggesting that these nonstructural proteins may be targets of MAGT1 oxidoreductase activity. These results provide insight into the cell biology of DENV infection, which may guide the development of antivirals against DENV. PMID- 28720736 TI - Inner Workings: Networks of cameras are tracking meteorites with unprecedented precision. PMID- 28720734 TI - Lack of AcrB Efflux Function Confers Loss of Virulence on Salmonella enterica Serovar Typhimurium. AB - AcrAB-TolC is the paradigm resistance-nodulation-division (RND) multidrug resistance efflux system in Gram-negative bacteria, with AcrB being the pump protein in this complex. We constructed a nonfunctional AcrB mutant by replacing D408, a highly conserved residue essential for proton translocation. Western blotting confirmed that the AcrB D408A mutant had the same native level of expression of AcrB as the parental strain. The mutant had no growth deficiencies in rich or minimal medium. However, compared with wild-type SL1344, the mutant had increased accumulation of Hoechst 33342 dye and decreased efflux of ethidium bromide and was multidrug hypersusceptible. The D408A mutant was attenuated in vivo in mouse and Galleria mellonella models and showed significantly reduced invasion into intestinal epithelial cells and macrophages in vitro A dose dependent inhibition of invasion was also observed when two different efflux pump inhibitors were added to the wild-type strain during infection of epithelial cells. RNA sequencing (RNA-seq) revealed downregulation of bacterial factors necessary for infection, including those in the Salmonella pathogenicity islands 1, 2, and 4; quorum sensing genes; and phoPQ Several general stress response genes were upregulated, probably due to retention of noxious molecules inside the bacterium. Unlike loss of AcrB protein, loss of efflux function did not induce overexpression of other RND efflux pumps. Our data suggest that gene deletion mutants are unsuitable for studying membrane transporters and, importantly, that inhibitors of AcrB efflux function will not induce expression of other RND pumps.IMPORTANCE Antibiotic resistance is a major public health concern. In Gram negative bacteria, overexpression of the AcrAB-TolC multidrug efflux system confers resistance to clinically useful drugs. Here, we show that loss of AcrB efflux function causes loss of virulence in Salmonella enterica serovar Typhimurium. This is due to the reduction of bacterial factors necessary for infection, which is likely to be caused by the retention of noxious molecules inside the bacterium. We also show that, in contrast to loss of AcrB protein, loss of efflux does not induce overexpression of other efflux pumps from the same family. This indicates that there are differences between loss of efflux protein and loss of efflux that make gene deletion mutants unsuitable for studying the biological function of membrane transporters. Understanding the biological role of AcrB will help to assess the risks of targeting efflux pumps as a strategy to combat antibiotic resistance. PMID- 28720737 TI - Core Concept: Phytoremediation advances in the lab but lags in the field. PMID- 28720739 TI - [Disorder of Gastric Myoelectric Activity in Patients with Cerebral Infarction:Electrogastrographic Assessment]. AB - In this study, gastric myoelectric activity in patients with acute cerebral infarction was investigated using electrogastrography. The patients were divided into four groups; those with mild brainstem infarction(group A, n=13, men:8, women:5, 75+/-2 years old), severe brainstem infarction(group B, n=6, men:4, women:2, 79+/-4 years old), mild non-brainstem infarction(group C, n=14, men:7, women:7, 76+/-3 years old), and severe non-brainstem infarction(group D, n=9, men:3, women:6, 87+/-2 years old). In group B, the% ratio of normogastria(2.4-3.6 cycles per minute)was significantly lower in the fasting period. The dominant power(DP)significantly increased after the meal in group C, but did not in group A, compared to before the meal. The DP increased in all patients in group C after the meal, whereas it increased in only five of ten patients in group A. The possibility of gastric dysfunction should be considered in patients with brainstem infarction. PMID- 28720735 TI - A Nonredundant Phosphopantetheinyl Transferase, PptA, Is a Novel Antifungal Target That Directs Secondary Metabolite, Siderophore, and Lysine Biosynthesis in Aspergillus fumigatus and Is Critical for Pathogenicity. AB - Secondary metabolites are key mediators of virulence for many pathogens. Aspergillus fumigatus produces a vast array of these bioactive molecules, the biosynthesis of which is catalyzed by nonribosomal peptide synthetases (NRPSs) or polyketide synthases (PKSs). Both NRPSs and PKSs harbor carrier domains that are primed for acceptance of secondary metabolic building blocks by a phosphopantetheinyl transferase (P-pant). The A. fumigatus P-pant PptA has been shown to prime the putative NRPS Pes1 in vitro and has an independent role in lysine biosynthesis; however, its role in global secondary metabolism and its impact on virulence has not been described. Here, we demonstrate that PptA has a nonredundant role in the generation of the vast majority of detectable secondary metabolites in A. fumigatus, including the immunomodulator gliotoxin, the siderophores triacetylfusarinine C (TAFC) and ferricrocin (FC), and dihydroxy naphthalene (DHN)-melanin. We show that both the lysine and iron requirements of a pptA null strain exceed those freely available in mammalian tissues and that loss of PptA renders A. fumigatus avirulent in both insect and murine infection models. Since PptA lacks similarity to its mammalian orthologue, we assert that the combined role of this enzyme in both primary and secondary metabolism, encompassing multiple virulence determinants makes it a very promising antifungal drug target candidate. We further exemplify this point with a high-throughput fluorescence polarization assay that we developed to identify chemical inhibitors of PptA function that have antifungal activity.IMPORTANCE Fungal diseases are estimated to kill between 1.5 and 2 million people each year, which exceeds the global mortality estimates for either tuberculosis or malaria. Only four classes of antifungal agents are available to treat invasive fungal infections, and all suffer pharmacological shortcomings, including toxicity, drug-drug interactions, and poor bioavailability. There is an urgent need to develop a new class of drugs that operate via a novel mechanism of action. We have identified a potential drug target, PptA, in the fungal pathogen Aspergillus fumigatus PptA is required to synthesize the immunotoxic compound gliotoxin, DHN-melanin, which A. fumigatus employs to evade detection by host cells, the amino acid lysine, and the siderophores TAFC and FC, which A. fumigatus uses to scavenge iron. We show that strains lacking the PptA enzyme are unable to establish an infection, and we present a method which we use to identify novel antifungal drugs that inactivate PptA. PMID- 28720740 TI - [Tentorial Dural Arteriovenous Fistula Successfully Treated with Transvenous Embolization Using a Double Catheterization Technique through Venous Drainage:A Case Report]. AB - BACKGROUND: Tentorial dural arteriovenous fistulas(dAVFs)are a rare clinical entity accounting for less than 10% of all intracranial dAVFs. Because these lesions are characterized by high hemorrhagic risk, aggressive treatment should be considered. Although the number of reported cases treated with endovascular transarterial embolization(TAE)using glue has been increasing, little is known about the transvenous approach. Here, we report the case of a patient with a tentorial dAVF who was successfully treated with transvenous embolization(TVE)through venous drainage using a double catheterization technique. CASE PRESENTATION: A 68-year-old male patient who had a history of left putaminal hemorrhage treated with a craniotomy was diagnosed with a tentorial dAVF on a magnetic resonance angiogram. Because the patient refused another craniotomy for surgical interruption of the dAVF, an endovascular approach was considered. We first attempted to perform TAE with glue, but catheterization into the tortuous meningohypophyseal trunk failed. We then performed a TVE of the venous drainage near the shunt with detachable coils and achieved complete obliteration of the fistula. During coil embolization of the venous drainage, insertion of small coils near the shunt was supported by another anchor coil that was delivered using a double catheterization technique. CONCLUSIONS: The method of TVE through venous drainage using a double catheterization technique, which involved placing coils in the fragile drainage vein, was safe and effective in a case of tentorial dAVF. This technique should be considered as another option for the management of complex tentorial dAVFs. PMID- 28720741 TI - [Transvenous Embolization by Direct Puncture of the Superior Sagittal Sinus Using Indocyanine Green(ICG)Videoangiography for Treatment of Dural Arteriovenous Fistula of the Transverse-Sigmoid Sinus:A Case Report]. AB - We report a case of dural arteriovenous fistula at the left transverse sinus and sigmoid sinus(TS-dAVF), which was treated with transvenous embolization(TVE)by direct puncture of the superior sagittal sinus(SSS)under indocyanine green(ICG)fluoroscopic guidance. A 71-year-old woman presented with pulsatile tinnitus and progressive dementia. A left TS-dAVF with retrograde SSS and cortical venous reflux(Cognard type IIb)was demonstrated on cerebral angiography. The left internal jugular vein and distal portion of the right transverse sinus were occluded. We considered that TVE via the femoral vein would be difficult for complete cure. We performed trepanation of the frontal portion of the SSS. The SSS was directly punctured with an 18-G needle under ICG fluoroscopic guidance. We inserted a 4-Fr sheath into the SSS. A microcatheter was navigated into the affected sinus. Coils were placed through the microcatheter. The dAVF was completely diminished. No complications occurred. The patient's pulsatile tinnitus disappeared and dementia improved. Transvenous approach with direct puncture of the SSS under ICG fluoroscopic guidance was a useful approach for the treatment of dAVF when other approaches were difficult. PMID- 28720742 TI - [Two Cases of Ruptured Blood Blister-like Aneurysm Treated with X-ray Angiography Perfusion(XAP)Analysis]. AB - Two cases of ruptured blood blister-like internal carotid artery aneurysms for which low flow bypass was sufficient to attain successful treatment of trapping are reported. In the acute stage of rupture, it is troublesome to perform accurate examinations of tolerance to ischemia like balloon occlusion test(BOT)for estimating the required amount of bypass flow. In our cases, X-ray angiography perfusion(XAP)analysis was introduced, which could be performed in a couple dozen seconds without room-to-room transfer of patients, following the ordinary examination of diagnostic digital subtraction angiography. The perfusion index(PI)ratio measured in this analysis is equivalent to the laterality of cerebral blood flow between the right and left hemispheres. The PI ratio of 0.85 approximately corresponds to the mean stump pressure(MSTP)of 40mmHg, on the basis of the correlation diagram between the PI ratio and MSTP(approximate straight line:PI ratio%=0.6*MSTP+60). Even though the PI ratio of the cases was superior to this threshold of tolerance for parent artery occlusion, complementary low flow bypass was added in the acute case for the overwhelming succeeding vasospasm and for securing the flow to peripheral perforators, which resulted in a successful treatment without any ischemic events. PMID- 28720743 TI - [Usefulness of Edoxaban for Deep Cerebral Venous Sinus Thrombosis with Hemorrhagic Infarction:A Case Report]. AB - We describe a case of deep cerebral venous sinus thrombosis(DCVST)that was successfully treated by oral administration of the Xa inhibitor edoxaban. A 53 year-old man was admitted to our hospital because of a headache and undifferentiated dizziness. Computed tomography(CT)demonstrated a low-density area in the bilateral thalamus and high-density lesions in the internal cerebral veins(ICVs)and vein of Galen. Magnetic resonance imaging with diffusion-weighted images detected areas of hyperintensity in the bilateral thalamus. Additionally, the inferior sagittal sinus, ICV, and vein of Galen were not detected by CT venography or cerebral angiography. We therefore diagnosed DCVST and started anticoagulation therapy with heparin(IV)and warfarin. A week after admission, lesions that showed hypointensity on T2* images and high density on CT scans were detected in the bilateral thalamus. We thought that hemorrhagic infarction had occurred in association with DCVST, and changed the anticoagulation therapy to oral administration of edoxaban on day 9. The patient's symptoms gradually diminished, and CT venography indicated partial recanalization of the DCV from the ICV to the vein of Galen on day 72. We report our experience, and discuss the safety and usefulness of the Xa inhibitor for treating DCVST with hemorrhagic infarction. PMID- 28720744 TI - [Preoperative Embolization for Solid Cerebellar Hemangioblastoma on the Day of Surgery:Two Case Reports]. AB - Surgical resection of solid cerebellar hemangioblastomas can be challenging because of the profuse blood supply and tight space. We report two cases of solid cerebellar hemangioblastomas treated via surgical resection with the aid of preoperative endovascular embolization on the day of surgery. Case 1: A 36-year old woman presented with a two-month history of headache and vomiting. Magnetic resonance imaging(MRI)revealed a right cerebellar solid mass, mild hydrocephalus, and apparent peritumoral edema. Angiogram showed a highly vascularized mass, three feeding arteries from the superior cerebellar artery(SCA), and a dilated vein draining into the confluence. We performed preoperative embolization of the three feeders with 15% n-butyl-2-cyanoacrylate(NBCA). Final angiogram showed an absence of tumor staining. Tumor resection was performed on the same day, and gross total resection was achieved with no complications. Case 2: A 36-year-old man presented with a four-month history of headache and numbness in the left upper extremity. MRI revealed a right cerebellar solid mass with peritumoral edema. Angiogram showed a highly vascularized mass with two feeding arteries from the right SCA, one from the left posterior inferior cerebellar artery(PICA), and a dilated vein draining into the confluence. Preoperative embolization was performed with 15% NBCA, and complete devascularization was achieved. Tumor resection was performed on the same day, and gross total resection was achieved with no complications. In conclusion, preoperative embolization with NBCA on the day of surgery is a safe and effective adjunctive treatment for solid cerebellar hemangioblastoma. PMID- 28720745 TI - [A Case of Intradural Retroclival Chordoma]. AB - A 67-year-old woman was referred to our department with a retroclival lesion including a cyst on MRI. MRI revealed a lesion appearing as an isointense region on a diffusion-weighted image(DWI). Gadolinium(Gd)-DTPA T1-WI showed heterogeneous enhancement of the lesion in the prepontine cistern. Computed tomography(CT)revealed an isodense lesion with no invasion into the clival bone. Based on a preoperative diagnosis of retroclival chordoma, extended trans sphenoidal surgery(TSS)was performed by a direct endoscopic endonasal approach via the left nostril. We found a round dural defect with a diameter of 5 mm, through which the tumor was incarcerated. However, the tumor had no connection to the clival bone. The lesion was totally removed and histologically diagnosed as a chordoma. Furthermore, the clival bone included no tumor cells. Based on those radiological and histological findings, we diagnosed the lesion as an intradural retroclival chordoma. We should consider intradural retroclival chordoma as a candidate for the differential diagnosis of a retroclival lesion without clival bone invasion. PMID- 28720747 TI - [Importance of Determining the True Etiology of Bleeding:A Case of Left VA-PICA Aneurysm with Subarachnoid Hemorrhage Caused by Another Etiology Confirmed during Craniotomy]. PMID- 28720746 TI - [A Rare Case of Ruptured Internal Carotid-Posterior Communicating Artery Aneurysm Associated with Contralateral Delayed Oculomotor Nerve Palsy]. AB - A 55-year-old man presented with difficulty breathing, chest pain, and disturbance of consciousness, and was transferred to our hospital. Initial whole body CT revealed a diffuse subarachnoid hemorrhage(SAH)with severe pulmonary edema that was considered neurogenic in origin. He received controlled ventilation under sedation and conservative care for the SAH. One day after the onset of the SAH, his left pupil suddenly became dilated to 6mm, with no reaction to light. Head CT showed no new bleeding. Subsequent CT angiogram revealed a right internal carotid-posterior communicating artery aneurysm(IC-PC AN)with a posterior-lateral projection; however, no vessel abnormality was observed in the left anterior or posterior circulations. The aneurysm was successfully treated with coil embolization. We reviewed reported cases of isolated oculomotor nerve palsy(ONP), without direct compression by ruptured aneurysms, and found that only 11 cases exist, including our case. Interestingly, six of them were associated with anterior communicating artery aneurysms. A mass effect, chemical stimulation, and a jet stream of blood were proposed as the mechanisms of this rare type of ONP, in addition to the specific neurovascular relationships between the oculomotor nerve and the posterior cerebral/posterior communicating/superior cerebellar arteries, with abnormal nerve contact or compression. Though rare, ruptured IC-PC ANs could cause contralateral ONP; other types of ruptured aneurysms may also lead to indirect effects on nervous structures without direct compression. This type of rare presentation of ruptured aneurysms should be considered, especially in cases of multiple aneurysms, such as IC-PC ANs. PMID- 28720748 TI - [Pre- and Intra-Operative Supporting Technology for Brain Tumors(9)Surgery for Foramen Magnum Tumors]. PMID- 28720749 TI - Effects of Intrinsic and Extrinsic Factors on the Level of Hope and Psychological Health Status of Patients with Cervical Cancer During Radiotherapy. AB - BACKGROUND This study aimed to explore the factors affecting the level of hope and psychological health status of patients with cervical cancer (CC) during radiotherapy. MATERIAL AND METHODS A total of 480 CC patients were recruited. Psychological distress scale, Herth hope index, functional assessment cancer therapy-cervix, and Jolowiec coping scale were used to conduct surveys on psychological distress, level of hope, quality of life (QOL), and coping style to analyze the factors affecting the level of hope and psychological health status of CC patients. RESULTS The morbidity of significant psychological distress in 480 CC patients during radiotherapy was 68%, and the main factors causing psychological distress were emotional problems and physical problems. During radiotherapy, most patients had middle and high levels of hope, and the psychological distress index of patients was negatively correlated with the level of hope. The QOL of CC patients during radiotherapy were at middle and high levels, and the QOL was positively correlated with confrontment, optimism, appeasement, and self-reliance, but it was negatively correlated with predestination and emotional expression. CONCLUSIONS For CC patients during radiotherapy, the morbidity of psychological distress was high, but they were at middle and high levels of hope. PMID- 28720750 TI - Tuberculous Psoas Abscess and Worsening Vascular Aneurysm; All from Bacillus Calmette-Guerin (BCG) Therapy? AB - BACKGROUND Intravesical bacillus Calmette-Guerin (BCG) is used in the treatment and prophylaxis of carcinoma in situ of the urinary bladder and for the prophylaxis of primary or recurrent stage Ta and T1 papillary tumors following transurethral resection. Significant systemic complications are rare but have been reported. CASE REPORT We describe this case of Mycobacterium bovis psoas abscess and worsening abdominal aortic aneurysm following BCG therapy for bladder cancer. A 76-year-old male presented with a fever of a few days. He had a computed tomography (CT) scan of abdomen and pelvis that showed left iliopsoas fluid collection measuring 6.7*3.8 cm and an abdominal aortic aneurysm that had almost doubled in size from 4.9 cm to 8.5 cm. The patient underwent CT-guided aspiration of the iliopsoas collection. Mycobacterium bovis was isolated from the aspirate cultures. He had received intravesical BCG therapy for bladder cancer a few years prior. CONCLUSIONS The rapid increase in the size of the abdominal aortic aneurysm (mycotic aneurysm) in our patient was most likely due to BCG therapy. The risk-benefit assessment of this treatment should be carefully considered especially in patients with a pre-existing vascular aneurysm. PMID- 28720751 TI - Exploring the perspectives of clinical professionals and support staff on implementing supported self-management for asthma in UK general practice: an IMP2ART qualitative study. AB - Despite an overwhelming evidence base, supported self-management of asthma is poorly implemented into routine practice. Strategies for implementation must address organisational routines, as well as provide resources for patients and training to improve professionals' skills. We aimed to explore the priority that primary care practices attach to asthma self-management, to describe their existing asthma management routines, and to generate innovative implementation strategies. We recruited 33 participants (23 general practitioners; seven nurses; three administrative staff) from 14 general practices. The 12 interviews and three focus groups were transcribed, coded and analysed thematically. Supported self-management was largely a nurse-led task within clinic-based annual reviews. Barriers included poor attendance at asthma clinics, lack of time, demarcation of roles, limited access to a range of tailored resources, and competing agendas in consultation, often due to multimorbidity. Suggestions for initiatives to improve the provision of supported self-management included emphasising the evidence for benefit (to influence prioritisation), improving teamwork (including team-based education), organisational strategies (including remote consulting) which need to fit within existing practice routines. Technology offers some potential solutions (e.g., improved templates, 'app'-based plans), but must be integrated with the practice information technology systems. Building on these insights, we will now develop a theoretically-based implementation strategy that will address patient, professional, and organisational buy-in, provide team-based education and offer a range of practical options and tools, which can be adapted and integrated within existing routines of individual practices.OVERCOMING THE ORGANISATIONAL BARRIERS TO IMPLEMENTING ASTHMA SELF-MANAGEMENT: Understanding the routines of primary care practices can suggest strategies to implement supported self-management in general practice. Supported self-management of asthma including provision of individual action plans improves patient health and reduces the burden on healthcare services, but is not well implemented in routine practice. As part of a large-scale programme to implement self-management into UK general practice, Hilary Pinnock at the University of Edinburgh and co-workers conducted interviews and focus groups with 33 participants from 14 general practices to explore the organisational routines that hinder or enable professionals to provide support asthma self-management. Poor attendance at asthma clinics, demarcation of roles, lack of time and limited access to tailored resources were identified as specific barriers. Improvements suggested included improved teamwork between doctors and other medical healthcare professionals, comprehensive training, and improvements to IT systems. PMID- 28720753 TI - Ferromagnetic Resonance Revised - Electrodynamic Approach. AB - Resonance in a ferromagnetic sphere, known in the body of literature as the mode of uniform precession, has recently been proven to be magnetic plasmon resonance (MPR). This finding has prompted research which is presented in this paper on the relation between the Q-factor at the MPR and the ferromagnetic resonance (FMR) linewidth DeltaH, which is a parameter of magnetized gyromagnetic materials. It is proven in this paper that DeltaH can be unequivocally determined from the Q factor measured at the MPR, if all losses in the resonance system are properly accounted for. It can be undertaken through a rigorous but simple electrodynamic study involving the transcendental equation, as proposed in this paper. The present study also reveals that electric losses have a substantially reduced impact on DeltaH due to the large magnetic to electric energy storage ratio at the MPR. Theoretical results are supported by measurements of the Q-factors on a monocrystalline yttrium iron garnet (YIG) sphere. PMID- 28720752 TI - A Quasi-direct LC-MS/MS-based Targeted Proteomics Approach for miRNA Quantification via a Covalently Immobilized DNA-peptide Probe. AB - MicroRNAs (miRNAs) play a vital role in regulating gene expression and are associated with a variety of cancers, including breast cancer. Their distorted and unique expression is a potential marker in clinical diagnoses and prognoses. Thus, accurate determination of miRNA expression levels is a prerequisite for their applications. However, the assays currently available for miRNA detection typically require pre-enrichment, amplification and labeling steps, and most of the assays are only semi-quantitative. Therefore, we developed a quasi-direct liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based targeted proteomics approach to quantify target miRNA by innovatively converting the miRNA signal into the mass response of a reporter peptide via a covalently immobilized DNA-peptide probe. Specifically, the probe containing the targeted proteomics selected substrate/reporter peptide, GDRAVQLGVDPFR/AVQLGVDPFR, and the DNA sequence complementary to the target miRNA (i.e., miR-21) was first immobilized on APMTS modified silica nanoparticles using PDITC. After the immobilized probe was recognized and hybridized with the target miRNA, the excess probe was degraded using MBN and followed by a trypsin digestion of the hybrids. The reporter peptide was released and quantified using LC-MS/MS. The obtained LOQ was 5 pM. Finally, the developed assay was used for the quantitative analysis of miR 21 in breast cells and tissue samples. PMID- 28720754 TI - Analysis of the Conduction Mechanism and Copper Vacancy Density in p-type Cu2O Thin Films. AB - A quantitative and analytical investigation on the conduction mechanism in p-type cuprous oxide (Cu2O) thin films is performed based on analysis of the relative dominance of trap-limited and grain-boundary-limited conduction. It is found that carrier transport in as-deposited Cu2O is governed by grain-boundary-limited conduction (GLC), while after high-temperature annealing, GLC becomes insignificant and trap-limited conduction (TLC) dominates. This suggests that the very low Hall mobility of as-deposited Cu2O is due to significant GLC, and the Hall mobility enhancement by high-temperature annealing is determined by TLC. Evaluation of the grain size and the energy barrier height at the grain boundary shows an increase in the grain size and a considerable decrease in the energy barrier height after high-temperature annealing, which is considered to be the cause of the significant reduction in the GLC effect. Additionally, the density of copper vacancies was extracted; this quantitatively shows that an increase in annealing temperature leads to a reduction in copper vacancies. PMID- 28720755 TI - Functional variants of the melanocortin-4 receptor associated with the Odontoceti and Mysticeti suborders of cetaceans. AB - Cetaceans, a group of mammals adapted to the aquatic environment that descended from terrestrial artiodactyls, exhibit tremendous interspecific differences in a number of phenotypes, including feeding behavior, such as filter feeding in the Mysticeti vs prey-hunting Odontoceti, and size, with the smallest cetacean, the vaquita, at 1.4 meters and the largest, the blue whale, reaching 33 meters. The Melanocortin-4 receptor (MC4R) regulates food intake, energy balance, and somatic growth in both mammals and teleosts. In this study, we examined allelic variants of the MC4R in cetaceans. We sequenced the MC4R from 20 cetaceans, and pharmacologically characterized 17 of these protein products. Results identified a single variation at amino acid 156 in the MC4R from representative species of major cetacean lineages uniquely associated with the toothed whales or Odontoceti (arginine at 156) and baleen whales or Mysticeti (glutamine at 156). The Q156 receptor variant found in the larger baleen whales was functionally less responsive to its endogenous anorexigenic ligand, alpha-MSH. Furthermore, the R156 receptor variant showed greater constitutive activity and a higher affinity for ligand. These data suggest that the MC4R may be one gene involved in the evolution of feeding ecology, energy balance, and body size in cetaceans. PMID- 28720756 TI - Pixuna virus modifies host cell cytoskeleton to secure infection. AB - Pixuna virus (PIXV) is an enzootic member of the Venezuelan Equine Encephalitis Virus complex and belongs to the New World cluster of alphaviruses. Herein we explore the role of the cellular cytoskeleton during PIXV replication. We first identified that PIXV undergoes an eclipse phase consisting of 4 h followed by 20 h of an exponential phase in Vero cells. The infected cells showed morphological changes due to structural modifications in actin microfilaments (MFs) and microtubules (MTs). Cytoskeleton-binding agents, that alter the architecture and dynamics of MFs and MTs, were used to study the role of cytoskeleton on PIXV replication. The virus production was significantly affected (p < 0.05) after treatment with paclitaxel or nocodazole due to changes in the MTs network. Interestingly, disassembly of MFs with cytochalasin D, at early stage of PIXV replication cycle, significantly increased the virus yields in the extracellular medium (p < 0.005). Furthermore, the stabilization of actin network with jasplakinolide had no effect on virus yields. Our results demonstrate that PIXV relies not only on intact MTs for the efficient production of virus, but also on a dynamic actin network during the early steps of viral replication. PMID- 28720757 TI - Integrative analyses of translatome and transcriptome reveal important translational controls in brown and white adipose regulated by microRNAs. AB - The epidemic of obesity and diabetes has markedly spurred the research interest in adipocyte biology. Brown adipocytes are specialized for energy expenditure and of therapeutic interest for treatment of metabolic diseases, but how brown adipocytes are distinguished from white adipocytes at the level of translational regulation remains poorly understood. To systemically determine the translational control of gene expression in adipose tissue, we performed ribosome profiling and RNA-seq in parallel to depict the translatome and transcriptome changes during primary brown and white adipogenesis, and between brown and white adipose tissue. The most prominent layer of translational regulation was the increased translation efficiency of genes encoding mitochondria components in brown adipocytes relative to white. Systemic analysis of the regulatory interactions between microRNAs and their targets revealed that microRNAs were more active in repressing targets' mRNA abundance and translation in brown fat. Together, our data comprehensively delineated a landscape integrating transcriptome and translatome in adipose tissue. PMID- 28720758 TI - Multi-pinhole fluorescent x-ray computed tomography for molecular imaging. AB - We propose a multi-pinhole fluorescent x-ray computed tomography (mp-FXCT) technique for preclinical molecular imaging that can provide the complete data necessary to produce 3-D tomographic images during anaesthesia. In this method, multiple projections are simultaneously acquired through a multi-pinhole collimator with a 2-D detector and full-field volumetric beam to accelerate the data acquisition process and enhance the signal-to-noise ratios of the projections. We constructed a 15-pinhole mp-FXCT imaging system at beamline ARNE 7A at KEK and performed preliminary experiments to investigate its imaging properties using physical phantoms and a non-radioactive I imaging agent. The mp FXCT system could detect an I concentration of 0.038 mg/ml, the minimum required for in-vivo imaging, at a spatial resolution of about 0.3 mm during a data acquisition time of 90 min, which is less than the time for which anaesthesia is effective and suggests that preclinical molecular imaging is feasible with mp FXCT. PMID- 28720760 TI - Exploring spatial and temporal trends in the soundscape of an ecologically significant embayment. AB - The Hauraki Gulf, a shallow embayment in north-eastern New Zealand, provides an interesting environment for ecological soundscape research. It is situated on a tectonic plate boundary, contains one of the busiest ports in the southern hemisphere and is home to a diverse range of soniferous animals. The underwater soundscape was monitored for spatial and temporal trends at six different listening stations using passive acoustic recorders. The RMS sound pressure level of ambient sound (50-24,000 Hz) at the six listening stations was similar, ranging from 90-110 dB re 1 MUPa throughout the recording period. Biophony had distinct temporal patterns and biological choruses of urchins were significantly correlated to temperature. Geophony and biophony followed the acoustic niche hypothesis, where each sound exhibited both temporal and frequency partitioning. Vessel passage sound were identified in 1.9-35.2% of recordings from the different listening stations. Vessel sound recorded in the Hauraki Gulf has the potential to mask concurrent geophony and biophony, sounds that may be important to marine life. This study provides a baseline of ambient sound, useful for future management strategies in shallow embayments where anthropogenic pressure is likewise increasing. PMID- 28720759 TI - Depleted tumor suppressor miR-107 in plasma relates to tumor progression and is a novel therapeutic target in pancreatic cancer. AB - This study explored decreased tumor suppressor microRNA (miRNA) plasma levels in pancreatic cancer (PCa) patients to clarify their potential as novel biomarkers and therapeutic targets. We used the microRNA array-based approach to select candidates by comparing plasma levels between PCa patients and healthy volunteers. Six down-regulated miRNAs (miR-107, miR-126, miR-451, miR-145, miR 491-5p, and miR-146b-5p) were selected. Small- and large-scale analyses using samples from 100 PCa patients and 80 healthy volunteers revealed that miR-107 was the most down-regulated miRNA in PCa patients compared with healthy volunteers (P < 0.0001; area under the receiver-operating characteristic curve, 0.851). A low miR-107 plasma level was significantly associated with advanced T stage, N stage, and liver metastasis and was an independent factor predicting poor prognosis in PCa patients (P = 0.0424; hazard ratio, 2.95). miR-107 overexpression in PCa cells induced G1/S arrest with the production of p21 and inhibited cell proliferation through the transcriptional regulation of Notch2. In vivo, the restoration and maintenance of the miR-107 plasma level significantly inhibited tumor progression in mice. Depletion of the tumor suppressor miR-107 in plasma relates to tumor progression and poor outcomes. The restoration of the plasma miR 107 level might be a novel anticancer treatment strategy for PCa. PMID- 28720761 TI - Parylene C topographic micropattern as a template for patterning PDMS and Polyacrylamide hydrogel. AB - Parylene C is a well-known polymer and it has been mainly employed as a protective layer for implantable electronics. In this paper, we propose a new approach to use Parylene C as a versatile template for patterning soft materials potentially applicable as scaffolds in cardiac tissue engineering (TE). Parylene C substrates were anisotropically patterned through standard lithographic process with hydrophilic channels separating raised hydrophobic strips. Ridges and grooves of the template are 10 um width and depth ranging from 1 to 17 um. Polydimethylsiloxane (PDMS) and Polyacrylamide (PAm) hydrogel have been chosen as soft polymers to be moulded. Thanks to their chemical and physical properties PDMS and PAm hydrogel mimic the extracellular matrix (ECM). PDMS was spin coated on micropatterned Parylene C obtaining composite substrates with 460 nm and 1.15 um high grooves. The Young's modulus of the composite Parylene C/PDMS was evaluated and it was found to be almost half when compared to PDMS. PAm hydrogel was also printed using collagen coated micro-grooved Parylene C. Optical micrographs and fluorescence analysis show the successful topographic and protein pattern transfer on the hydrogel. PMID- 28720762 TI - Quantitative Measurement of the Thyroid Uptake Function of Mouse by Cerenkov Luminescence Imaging. AB - Cerenkov luminescence imaging (CLI) has been an evolutional and alternative approach of nuclear imaging in basic research. This study aimed to measure the 131I thyroid uptake of mouse using CLI for assessment of thyroid function. Quantification of 131I thyroid uptake of mice in euthyroid, hypothyroid and hyperthyroid status was performed by CLI and gamma-scintigraphy at 24 hours after injection of 131I. The 131I thyroid uptake was calculated using the equation: (thyroid counts - background counts)/(counts of injected dose of 131I) * 100%. Serum T4 concentration was determined to evaluate the thyroid function. The radioactivity of 131I was linearly correlated with the CL signals in both in vitro and in vivo measurements. CLI showed a significant decrease and increase of 131I thyroid uptake in the mice in hypo- and hyperfunctioning status, respectively, and highly correlated with that measured by gamma-scintigraphy. However, the percent thyroid uptake measured by CLI were one-fifth of those measured by gamma-scintigraphy due to insufficient tissue penetration of CL. These results indicate that CLI, in addition to nuclear imaging, is able to image and evaluate the 131I thyroid uptake function in mice in preclinical and research settings. PMID- 28720763 TI - High frequency of RUNX1 mutation in myelodysplastic syndrome patients with whole arm translocation of der(1;7)(q10;p10). PMID- 28720764 TI - High expression of ABCG2 induced by EZH2 disruption has pivotal roles in MDS pathogenesis. AB - Both proto-oncogenic and tumor-suppressive functions have been reported for enhancer of zeste homolog 2 (EZH2). To investigate the effects of its inactivation, a mutant EZH2 lacking its catalytic domain was prepared (EZH2 dSET). In a mouse bone marrow transplant model, EZH2-dSET expression in bone marrow cells induced a myelodysplastic syndrome (MDS)-like disease in transplanted mice. Analysis of these mice identified Abcg2 as a direct target of EZH2. Intriguingly, Abcg2 expression alone induced the same disease in the transplanted mice, where stemness genes were enriched. Interestingly, ABCG2 expression is specifically high in MDS patients. The present results indicate that ABCG2 de-repression induced by EZH2 mutations have crucial roles in MDS pathogenesis. PMID- 28720765 TI - C/EBPalpha deregulation as a paradigm for leukemogenesis. AB - Myeloid master regulator CCAAT enhancer-binding protein alpha (C/EBPalpha) is deregulated by multiple mechanisms in leukemia. Inhibition of C/EBPalpha function plays pivotal roles in leukemogenesis. While much is known about how C/EBPalpha orchestrates granulopoiesis, our understanding of molecular transformation events, the role(s) of cooperating mutations and clonal evolution during C/EBPalpha deregulation in leukemia remains elusive. In this review, we will summarize the latest research addressing these topics with special emphasis on CEBPA mutations. We conclude by describing emerging therapeutic strategies to restore C/EBPalpha function. PMID- 28720767 TI - Assessment of the occurrence, spatiotemporal variations and geoaccumulation of fifty-two inorganic elements in sewage sludge: A sludge management revisit. AB - The limited information about the sludge quality has made its management a top environmental challenge. In the present study, occurrence and the spatiotemporal variations of 52 inorganic elements were investigated in the sludge samples from three wastewater treatment plants (WWTPs) in Xiamen city, China. The results showed, the occurrence of 49 elements with the concentrations in the range of >125-53500 mg kg-1 dry sludge (DS) for commonly used industrial metals, 1.22-14.0 mg kg-1 DS for precious metals, and 1.12-439.0 mg kg-1 DS for rare earth elements. The geo-accumulation studies indicated a moderate to high levels of buildup of some elements in the sewage sludge. Principal components analysis (PCA) indicated strong spatial and weak temporal variations in the concentrations of the elements. Therefore, the sludge disposal operations, based on the element concentrations, geoaccumulation and economic potential are suggested for each WWTP. Sludge from W1 and W2 were found suitable for agricultural usage, while that from W3 showed a higher economic potential for the recovery of precious metals. This study concludes that a comprehensive analysis of the elements in the sewage sludge could provide critical information for the disposal and management of the sludge. PMID- 28720766 TI - Predicting susceptibility to tuberculosis based on gene expression profiling in dendritic cells. AB - Tuberculosis (TB) is a deadly infectious disease, which kills millions of people every year. The causative pathogen, Mycobacterium tuberculosis (MTB), is estimated to have infected up to a third of the world's population; however, only approximately 10% of infected healthy individuals progress to active TB. Despite evidence for heritability, it is not currently possible to predict who may develop TB. To explore approaches to classify susceptibility to TB, we infected with MTB dendritic cells (DCs) from putatively resistant individuals diagnosed with latent TB, and from susceptible individuals that had recovered from active TB. We measured gene expression levels in infected and non-infected cells and found hundreds of differentially expressed genes between susceptible and resistant individuals in the non-infected cells. We further found that genetic polymorphisms nearby the differentially expressed genes between susceptible and resistant individuals are more likely to be associated with TB susceptibility in published GWAS data. Lastly, we trained a classifier based on the gene expression levels in the non-infected cells, and demonstrated reasonable performance on our data and an independent data set. Overall, our promising results from this small study suggest that training a classifier on a larger cohort may enable us to accurately predict TB susceptibility. PMID- 28720769 TI - Concentration-Dependent Binding of Small Ligands to Multiple Saturable Sites in Membrane Proteins. AB - Membrane proteins are primary targets for most therapeutic indications in cancer and neurological diseases, binding over 50% of all known small molecule drugs. Understanding how such ligands impact membrane proteins requires knowledge on the molecular structure of ligand binding, a reasoning that has driven relentless efforts in drug discovery and translational research. Binding of small ligands appears however highly complex involving interaction to multiple transmembrane protein sites featuring single or multiple occupancy states. Within this scenario, looking for new developments in the field, we investigate the concentration-dependent binding of ligands to multiple saturable sites in membrane proteins. The study relying on docking and free-energy perturbation provides us with an extensive description of the probability density of protein ligand states that allows for computation of thermodynamic properties of interest. It also provides one- and three-dimensional spatial descriptions for the ligand density across the protein-membrane system which can be of interest for structural purposes. Illustration and discussion of the results are shown for binding of the general anesthetic sevoflurane against Kv1.2, a mammalian ion channel for which experimental data are available. PMID- 28720768 TI - Gilgamesh is required for the maintenance of germline stem cells in Drosophila testis. AB - Emerging evidence supports that stem cells are regulated by both intrinsic and extrinsic mechanisms. However, factors that determine the fate of stem cells remain incompletely understood. The Drosophila testis provides an exclusive powerful model in searching for potential important regulatory factors and their underlying mechanisms for controlling the fate of germline stem cells (GSCs). In this study, we have found that Drosophila gilgamesh (gish), which encodes a homologue of human CK1-gamma (casein kinase 1-gamma), is required intrinsically for GSC maintenance. Our genetic analyses indicate gish is not required for Dpp/Gbb signaling silencing of bam and is dispensable for Dpp/Gbb signaling dependent Dad expression. Finally, we show that overexpression of gish fail to dramatically increase the number of GSCs. These findings demonstrate that gish controls the fate of GSCs in Drosophila testis by a novel Dpp/Gbb signaling independent pathway. PMID- 28720770 TI - Multivariate time series analysis on the dynamic relationship between Class B notifiable diseases and gross domestic product (GDP) in China. AB - The surveillance of infectious diseases is of great importance for disease control and prevention, and more attention should be paid to the Class B notifiable diseases in China. Meanwhile, according to the International Monetary Fund (IMF), the annual growth of Chinese gross domestic product (GDP) would decelerate below 7% after many years of soaring. Under such circumstances, this study aimed to answer what will happen to the incidence rates of infectious diseases in China if Chinese GDP growth remained below 7% in the next five years. Firstly, time plots and cross-correlation matrices were presented to illustrate the characteristics of data. Then, the multivariate time series (MTS) models were proposed to explore the dynamic relationship between incidence rates and GDP. Three kinds of MTS models, i.e., vector auto-regressive (VAR) model for original series, VAR model for differenced series and error-correction model (ECM), were considered in this study. The rank of error-correction term was taken as an indicator for model selection. Finally, our results suggested that four kinds of infectious diseases (epidemic hemorrhagic fever, pertussis, scarlet fever and syphilis) might need attention in China because their incidence rates have increased since the year 2010. PMID- 28720771 TI - Plasmonically Enhanced Reflectance of Heat Radiation from Low-Bandgap Semiconductor Microinclusions. AB - Increased reflectance from the inclusion of highly scattering particles at low volume fractions in an insulating dielectric offers a promising way to reduce radiative thermal losses at high temperatures. Here, we investigate plasmonic resonance driven enhanced scattering from microinclusions of low-bandgap semiconductors (InP, Si, Ge, PbS, InAs and Te) in an insulating composite to tailor its infrared reflectance for minimizing thermal losses from radiative transfer. To this end, we compute the spectral properties of the microcomposites using Monte Carlo modeling and compare them with results from Fresnel equations. The role of particle size-dependent Mie scattering and absorption efficiencies, and, scattering anisotropy are studied to identify the optimal microinclusion size and material parameters for maximizing the reflectance of the thermal radiation. For composites with Si and Ge microinclusions we obtain reflectance efficiencies of 57-65% for the incident blackbody radiation from sources at temperatures in the range 400-1600 degrees C. Furthermore, we observe a broadbanding of the reflectance spectra from the plasmonic resonances due to charge carriers generated from defect states within the semiconductor bandgap. Our results thus open up the possibility of developing efficient high-temperature thermal insulators through use of the low-bandgap semiconductor microinclusions in insulating dielectrics. PMID- 28720772 TI - Blockade of Axl signaling ameliorates HPV16E6-mediated tumorigenecity of cervical cancer. AB - Axl receptor tyrosine kinase is involved in the tumorigenesis and metastasis of many cancers. Axl expression was markedly higher in human papilloma virus type 16E6 (HPV16E6)-overexpressing HeLa (HE6F) cells and lower in HPV16E6-suppressing CaSki (CE6R) cells than in the controls. SiRNA-mediated knockdown of E6 expression led to increased phosphatase and tensin homolog (PTEN) phosphorylation at Ser380 and attenuated AKT phosphorylation. Expression of membrane-associated guanylate kinase inverted-2 (MAGI-2), an E6-induced degradation target, was induced in E6-siRNA-transfected cells. Moreover, myeloid zinc finger protein 1 (MZF1) binds directly to the Axl promoter in HE6F cells. Axl expression was regulated by HPV16E6-mediated PTEN/AKT signalling pathway, and Axl promoter activity was regulated through MZF1 activation in cervical cancer, which promoted malignancy. Axl silencing suppressed the metastasis of Caski cells and enhanced the susceptibility to NK cell-mediated killing of HE6F cells. In addition, the expression of Axl and MZF1 was highly correlated with clinical stage of cervical cancer and HPV16/18 infection. Taken together, Axl expression was induced by HPV16E6 in cervical cancer cells, suggesting that blockade of Axl signalling might be an effective way to reduce the progression of cervical cancer. PMID- 28720773 TI - Local structure of liquid gallium under pressure. AB - In situ high energy X-ray pair distribution function (PDF) measurements, microtomography and reverse Monte Carlo simulations were used to characterize the local structure of liquid gallium up to 1.9 GPa. This pressure range includes the well-known solid-solid phase transition from Ga-I to Ga-II at low temperature. In term of previous research, the local structure of liquid gallium within this domain was suggested a mixture of two local structures, Ga I and Ga II, based on fitting experimental PDF to known crystal structure, with a controversy. However, our result shows a distinctly different result that the local structure of liquid gallium resembles the atomic arrangement of both gallium phase II and III (the high pressure crystalline phase). A melting mechanism is proposed for Ga, in which the atomic structure of phase Iota breaks up at the onset of melting, providing sufficient free volume for atoms to rearrange, to form the melt. PMID- 28720774 TI - A novel fluorescent probe-based flow cytometric assay for mineral-containing nanoparticles in serum. AB - Calciprotein particles, nanoscale aggregates of insoluble mineral and binding proteins, have emerged as potential mediators of phosphate toxicity in patients with Chronic Kidney Disease. Although existing immunochemical methods for their detection have provided compelling data, these approaches are indirect, lack specificity and are subject to a number of other technical and theoretical shortcomings. Here we have developed a rapid homogeneous fluorescent probe-based flow cytometric method for the detection and quantitation of individual mineral containing nanoparticles in human and animal serum. This method allows the discrimination of membrane-bound from membrane-free particles and different mineral phases (amorphous vs. crystalline). Critically, the method has been optimised for use on a conventional instrument, without the need for manual hardware adjustments. Using this method, we demonstrate a consistency in findings across studies of Chronic Kidney Disease patients and commonly used uraemic animal models. These studies demonstrate that renal dysfunction is associated with the ripening of calciprotein particles to the crystalline state and reveal bone metabolism and dietary mineral as important modulators of circulating levels. Flow cytometric analysis of calciprotein particles may enhance our understanding of mineral handling in kidney disease and provide a novel indicator of therapeutic efficacy for interventions targeting Chronic Kidney Disease Mineral Bone Disorder. PMID- 28720775 TI - Metformin ameliorates the Phenotype Transition of Peritoneal Mesothelial Cells and Peritoneal Fibrosis via a modulation of Oxidative Stress. AB - Phenotype transition of peritoneum is an early mechanism of peritoneal fibrosis. Metformin, 5'-adenosine monophosphate-activated protein kinase (AMPK) activator, has recently received a new attention due to its preventive effect on organ fibrosis and cancer metastasis by inhibiting epithelial-to-mesenchymal transition (EMT). We investigated the effect of metformin on EMT of human peritoneal mesothelial cells (HPMC) and animal model of peritoneal dialysis (PD). TGF-beta1 induced EMT in HPMC was ameliorated by metformin. Metformin alleviated NAPDH oxidase- and mitochondria-mediated ROS production with an increase in superoxide dismutase (SOD) activity and SOD2 expression. Metformin inhibited the activation of Smad2/3 and MAPK, GSK-3beta phosphorylation, nuclear translocalization of beta catenin and Snail in HPMCs. Effect of metformin on TGF-beta1-induced EMT was ameliorated by either AMPK inhibitor or AMPK gene silencing. Another AMPK agonist, 5-amino-1-beta-D-ribofuranosyl-imidazole-4-carboxamide partially blocked TGF-beta1-induced EMT. In animal model of PD, intraperitoneal metformin decreased the peritoneal thickness and EMT with an increase in ratio of reduced to oxidized glutathione and the expression of SOD whereas it decreased the expression of nitrotyrosine and 8-hydroxy-2'-deoxyguanosine. Therefore, a modulation of AMPK in peritoneum can be a novel tool to prevent peritoneal fibrosis by providing a favorable oxidant/anti-oxidant milieu in peritoneal cavity and ameliorating phenotype transition of peritoneal mesothelial cells. PMID- 28720776 TI - Dissonance encoding in human inferior colliculus covaries with individual differences in dislike of dissonant music. AB - Harmony is one of the most fundamental elements of music that evokes emotional response. The inferior colliculus (IC) has been known to detect poor agreement of harmonics of sound, that is, dissonance. Electrophysiological evidence has implicated a relationship between a sustained auditory response mainly from the brainstem and unpleasant emotion induced by dissonant harmony. Interestingly, an individual's dislike of dissonant harmony of an individual correlated with a reduced sustained auditory response. In the current paper, we report novel evidence based on functional magnetic resonance imaging (fMRI) for such a relationship between individual variability in dislike of dissonance and the IC activation. Furthermore, for the first time, we show how dissonant harmony modulates functional connectivity of the IC and its association with behaviourally reported unpleasantness. The current findings support important contributions of low level auditory processing and corticofugal interaction in musical harmony preference. PMID- 28720777 TI - Aging and rejuvenation of active matter under topological constraints. AB - The coupling of active, self-motile particles to topological constraints can give rise to novel non-equilibrium dynamical patterns that lack any passive counterpart. Here we study the behavior of self-propelled rods confined to a compact spherical manifold by means of Brownian dynamics simulations. We establish the state diagram and find that short active rods at sufficiently high density exhibit a glass transition toward a disordered state characterized by persistent self-spinning motion. By periodically melting and revitrifying the spherical spinning glass, we observe clear signatures of time-dependent aging and rejuvenation physics. We quantify the crucial role of activity in these non equilibrium processes, and rationalize the aging dynamics in terms of an absorbing-state transition toward a more stable active glassy state. Our results demonstrate both how concepts of passive glass phenomenology can carry over into the realm of active matter, and how topology can enrich the collective spatiotemporal dynamics in inherently non-equilibrium systems. PMID- 28720778 TI - Visualization of kidney fibrosis in diabetic nephropathy by long diffusion tensor imaging MRI with spin-echo sequence. AB - Renal fibrosis (RF) is an indicator for progression of chronic kidney disease (CKD). Although diabetic nephropathy (DN) is the leading cause of CKD and end stage renal disease in Western populations, the ability of MRI to evaluate RF in DN patients has not been determined. As a first step to identify possible MRI methods for RF evaluation, we examined the use of diffusion tensor imaging (DTI) MRI to evaluate RF in a rat model of DN (SHR/NDmcr-cp(cp/cp): SHR/ND). The signal to-noise ratio in DTI MRI was enhanced using a spin-echo sequence, and a special kidney attachment was developed for long-term stabilization. The changes in renal temperature and blood flow during measurement were minimal, suggesting the feasibility of this method. At 38 weeks of age, RF had aggressively accumulated in the outer stripe (OS) of the outer medulla. FA maps showed that this method was successful in visualizing and evaluating fibrosis in the OS of the SHR/ND rat kidney (r = 0.7697, P = 0.0126). Interestingly, in the FA color maps, the directions of water molecule diffusion in RF were random, but distinct from conventional water diffusion in brain neuron fibers. These findings indicate that DTI MRI may be able to evaluate RF in CKD by DN. PMID- 28720780 TI - Parameter determination and transformation for the focusing of dielectric microspheres illuminated by optical needle. AB - By eliminating the spherical aberrations of microsphere we derived a simple but useful formula on the focusing of dielectric microsphere. On basis of this formula, not only can researchers determine the parameters of an optical microsphere system with super-resolution, but they can also perform parameter transformation. In order to facilitate the application, the principle of parameter transformation was summarized into three kinds of case listed in Table 1, which were all demonstrated numerically with concrete examples by finite difference time-domain method. This formula will be conducive to the development of applications based on microsphere, such as photonic nano-jet lithography, microsphere nano-scope. PMID- 28720779 TI - Mimicking Paracrine TGFbeta1 Signals during Myofibroblast Differentiation in 3D Collagen Networks. AB - TGFbeta1 is a key regulator for induction of tissue remodeling after dermal wounding. We present a model of paracrine delivery of TGFbeta1 for differentiation of dermal fibroblasts based on a fibrillar 3D collagen matrix and embedded TGFbeta1 releasing microparticles. We found differentiation into myofibroblasts was achieved in a TGFbeta1 dependent manner at much lower doses than systemic delivery. This effect is accounted to the slow and sustained TGFbeta1 release mimicking paracrine cell signals. PMID- 28720781 TI - Distinct Top-down and Bottom-up Brain Connectivity During Visual Perception and Imagery. AB - Research suggests that perception and imagination engage neuronal representations in the same visual areas. However, the underlying mechanisms that differentiate sensory perception from imagination remain unclear. Here, we examine the directed coupling (effective connectivity) between fronto-parietal and visual areas during perception and imagery. We found an increase in bottom-up coupling during perception relative to baseline and an increase in top-down coupling during both perception and imagery, with a much stronger increase during imagery. Modulation of the coupling from frontal to early visual areas was common to both perception and imagery. Furthermore, we show that the experienced vividness during imagery was selectively associated with increases in top-down connectivity to early visual cortex. These results highlight the importance of top-down processing in internally as well as externally driven visual experience. PMID- 28720782 TI - Dysregulated miRNAs and their pathogenic implications for the neurometabolic disease propionic acidemia. AB - miRNome expression profiling was performed in a mouse model of propionic acidemia (PA) and in patients' plasma samples to investigate the role of miRNAs in the pathophysiology of the disease and to identify novel biomarkers and therapeutic targets. PA is a potentially lethal neurometabolic disease with patients developing neurological deficits and cardiomyopathy in the long-term, among other complications. In the PA mouse liver we identified 14 significantly dysregulated miRNAs. Three selected miRNAs, miR-34a-5p, miR-338-3p and miR-350, were found upregulated in brain and heart tissues. Predicted targets involved in apoptosis, stress-signaling and mitochondrial function, were inversely found down-regulated. Functional analysis with miRNA mimics in cellular models confirmed these findings. miRNA profiling in plasma samples from neonatal PA patients and age matched control individuals identified a set of differentially expressed miRNAs, several were coincident with those identified in the PA mouse, among them miR-34a 5p and miR-338-3p. These two miRNAs were also found dysregulated in childhood and adult PA patients' cohorts. Taken together, the results reveal miRNA signatures in PA useful to identify potential biomarkers, to refine the understanding of the molecular mechanisms of this rare disease and, eventually, to improve the management of patients. PMID- 28720783 TI - A Simple, Robust and Efficient Computational Method for n-Octanol/Water Partition Coefficients of Substituted Aromatic Drugs. AB - In this paper, multiple linear regression (MLR) was used to build quantitative structure property relationship (QSPR) of n-octanol-water partition coefficient (logPo/w) of 195 substituted aromatic drugs. The molecular descriptors were calculated for each compound by the VLifeMDS. By applying genetic algorithm/multiple linear regressions (GA/MLR) the most relevant descriptors were selected to build a QSPR model. The robustness of the model was characterized by the statistical validation and applicability domain (AD). The prediction results from MLR are in good agreement with the experimental values. The R2 and Q2LOO for MLR are 0.9433, 0.9341. The AD of the model was analyzed based on the Williams plot. The effects of different selected descriptors are described. PMID- 28720784 TI - SNAP-tagged Chikungunya Virus Replicons Improve Visualisation of Non-Structural Protein 3 by Fluorescence Microscopy. AB - Chikungunya virus (CHIKV), a mosquito-borne alphavirus, causes febrile disease, muscle and joint pain, which can become chronic in some individuals. The non structural protein 3 (nsP3) plays essential roles during infection, but a complete understanding of its function is lacking. Here we used a microscopy based approach to image CHIKV nsP3 inside human cells. The SNAP system consists of a self-labelling enzyme tag, which catalyses the covalent linking of exogenously supplemented synthetic ligands. Genetic insertion of this tag resulted in viable replicons and specific labelling while preserving the effect of nsP3 on stress granule responses and co-localisation with GTPase Activating Protein (SH3 domain) Binding Proteins (G3BPs). With sub-diffraction, three dimensional, optical imaging, we visualised nsP3-positive structures with variable density and morphology, including high-density rod-like structures, large spherical granules, and small, low-density structures. Next, we confirmed the utility of the SNAP-tag for studying protein turnover by pulse-chase labelling. We also revealed an association of nsP3 with cellular lipid droplets and examined the spatial relationships between nsP3 and the non-structural protein 1 (nsP1). Together, our study provides a sensitive, specific, and versatile system for fundamental research into the individual functions of a viral non-structural protein during infection with a medically important arthropod-borne virus (arbovirus). PMID- 28720785 TI - Evidence of Multi-Domain Morphological Structures in Living Escherichia coli. AB - A combination of light-microscopy and image processing was used to elaborate on the fluctuation in the width of the cylindrical part of Escherichia coli at sub pixel-resolution, and under in vivo conditions. The mean-squared-width-difference along the axial direction of the cylindrical part of a number of bacteria was measured. The results reveal that the cylindrical part of Escherichia coli is composed of multi-domain morphological structures. The length of the domains starts at 150 nm in newborn cells, and linearly increases in length up to 300 nm in aged cells. The fluctuation in the local-cell-widths in each domain is less than the fluctuation of local-cell-widths between different domains. Local cell width correlations along the cell body occur on a length scale of less than 50 nm. This finding could be associated with the flexibility of the cell envelope in the radial versus longitudinal directions. PMID- 28720786 TI - A few enlarged chloroplasts are less efficient in photosynthesis than a large population of small chloroplasts in Arabidopsis thaliana. AB - The photosynthetic, biochemical, and anatomical traits of accumulation and replication of chloroplasts (arc) mutants of Arabidopsis thaliana were investigated to study the effects of chloroplast size and number on photosynthesis. Chloroplasts were found to be significantly larger, and the chloroplast surface area exposed to intercellular air spaces (S c) significantly lower in the mutants than in their wild-types. The decreased S c and increase cytoplasm thickness in the mutants resulted in a lower mesophyll conductance (g m) and a consequently lower chloroplast CO2 concentration (C c). There were no significant differences between the mutants and their wild-types in maximal carboxylation rate (V cmax), maximal electron transport (J cmax), and leaf soluble proteins. Leaf nitrogen (N) and Rubisco content were similar in both Wassilewskija (Ws) wild-type (Ws-WT) and the Ws mutant (arc 8), whereas they were slightly higher in Columbia (Col) wild-type (Col-WT) than the Col mutant (arc 12). The photosynthetic rate (A) and photosynthetic N use efficiency (PNUE) were significantly lower in the mutants than their wild-types. The mutants showed similar A/C c responses as their wild-type counterparts, but A at given C c was higher in Col and its mutant than in Ws and its mutant. From these results, we conclude that decreases in g m and C c are crucial to the reduction in A in arc mutants. PMID- 28720787 TI - Comparison between an African town and a neighbouring village shows delayed, but not decreased, sleep during the early stages of urbanisation. AB - The well-established negative health outcomes of sleep deprivation, and the suggestion that availability of electricity may enable later bed times without compensating sleep extension in the morning, have stimulated interest in studying communities whose sleep pattern may resemble a pre-industrial state. Here, we describe sleep and activity in two neighbouring communities, one urban (Milange) and one rural (Tengua), in a region of Mozambique where urbanisation is an ongoing process. The two communities differ in the amount and timing of daily activity and of light exposure, with later bedtimes (~1 h) associated with more evening and less daytime light exposure seen in the town of Milange. In contrast to previous reports comparing communities with and without electricity, sleep duration did not differ between Milange (7.28 h) and Tengua (7.23 h). Notably, calculated sleep quality was significantly poorer in rural Tengua than in Milange, and poor sleep quality was associated with a number of attributes more characteristic of rural areas, including more intense physical labour and less comfortable sleeping arrangements. Thus, whilst our data support the hypothesis that access to electricity delays sleep timing, the higher sleep quality in the urban population also suggests that some aspects of industrialisation are beneficial to sleep. PMID- 28720788 TI - Preservative solution that stabilizes erythrocyte morphology and leukocyte viability under ambient conditions. AB - The deterioration of whole blood ex vivo represents a logistical hurdle in clinical and research settings. Here, a cocktail preservative is described that stabilizes leukocyte viability and erythrocyte morphology in whole blood under ambient storage. Neutrophil biostabilization was explored using a sophisticated microfluidic assay to examine the effectiveness of caspase inhibition to stabilize purified neutrophils. Following 72 h ambient storage, neutrophils remained fully functional to migrate towards chemical cues and maintained their ability to undergo NETosis after stimulation. Furthermore, stored neutrophils exhibited improved CD45 biomarker retention and reduced apoptosis and mortality compared to untreated controls. To stabilize erythrocyte morphology, a preservative solution was formulated using Taguchi methods of experimental design, and combined with the caspase inhibitor to form a whole blood cocktail solution, CSWB. CSWB was evaluated in blood from healthy donors and from women with metastatic breast cancer stored under ambient conditions for 72 h. CSWB treated samples showed a significant improvement in erythrocyte morphology compared to untreated controls. Leukocytes in CSWB-treated blood exhibited significantly higher viability and CD45 biomarker retention compared to untreated controls. This 72 h shelf life under ambient conditions represents an opportunity to transport isolates or simply ease experimental timelines where blood degradation is problematic. PMID- 28720789 TI - Evolutionarily conserved BIL4 suppresses the degradation of brassinosteroid receptor BRI1 and regulates cell elongation. AB - Brassinosteroids (BRs), plant steroid hormones, play important roles in plant cell elongation and differentiation. To investigate the mechanisms of BR signaling, we previously used the BR biosynthesis inhibitor Brz as a chemical biology tool and identified the Brz-insensitive-long hypocotyl4 mutant (bil4). Although the BIL4 gene encodes a seven-transmembrane-domain protein that is evolutionarily conserved in plants and animals, the molecular function of BIL4 in BR signaling has not been elucidated. Here, we demonstrate that BIL4 is expressed in early elongating cells and regulates cell elongation in Arabidopsis. BIL4 also activates BR signaling and interacts with the BR receptor brassinosteroid insensitive 1 (BRI1) in endosomes. BIL4 deficiency increases the localization of BRI1 in the vacuoles. Our results demonstrate that BIL4 regulates cell elongation and BR signaling via the regulation of BRI1 localization. PMID- 28720790 TI - Neural oscillations associated with auditory duration maintenance in working memory. AB - The neural representation of auditory duration remains unknown. Here, we used electroencephalogram (EEG) recordings to investigate neural oscillations during the maintenance of auditory duration in working memory (WM). EEG analyses indicated that the auditory duration length was not associated with changes in the theta band amplitude, whereas the alpha band amplitudes during 3-s and 4-s auditory duration conditions were lower than during the 1-s and 2-s conditions. Moreover, the alpha band amplitude and accuracy were positively correlated in the 2-s duration condition. We also found that the neural representation of auditory duration is segmented, with a critical threshold point of approximately 2 s, which is shorter than that for visual duration (3 s). The results emphasised the involvement of the alpha band in auditory duration maintenance in WM. Our study's findings indicate that different internal representations of auditory durations are maintained in WM below and above 2 s from the perspective of electrophysiology. Additionally, the critical threshold point is related to the sensory modality of duration. PMID- 28720791 TI - In vivo analysis of protein crowding within the nuclear pore complex in interphase and mitosis. AB - The central channel of the nuclear pore complex (NPC) is occupied by non structured polypeptides with a high content of Phe-Gly (FG) motifs. This protein rich environment functions as an entropic barrier that prevents the passage of molecules, as well as the binding sites for karyopherins, to regulate macromolecular traffic between the nucleoplasm and the cytoplasm. In this study, we expressed individual Nups fused with a crowding-sensitive probe (GimRET) to determine the spatial distribution of protein-rich domains within the central channel in vivo, and characterize the properties of the entropic barrier. Analyses of the probe signal revealed that the central channel contains two protein-rich domains at both the nucleoplasmic and cytoplasmic peripheries, and a less-crowded central cavity. Karyopherins and other soluble proteins are not the constituents of the protein-rich domains. The time-lapse observation of the post mitotic reassembly process also revealed how individual protein-rich domains are constructed by a sequential assembly of nucleoporins. PMID- 28720792 TI - Optical Read-out of Neural Activity in Mammalian Peripheral Axons: Calcium Signaling at Nodes of Ranvier. AB - Current neural interface technologies have serious limitations for advanced prosthetic and therapeutic applications due primarily to their lack of specificity in neural communication. An optogenetic approach has the potential to provide single cell/axon resolution in a minimally invasive manner by optical interrogation of light-sensitive reporters and actuators. Given the aim of reading neural activity in the peripheral nervous system, this work has investigated an activity-dependent signaling mechanism in the peripheral nerve. We demonstrate action potential evoked calcium signals in mammalian tibial nerve axons using an in vitro mouse model with a dextran-conjugated fluorescent calcium indicator. Spatial and temporal dynamics of the signal are presented, including characterization of frequency-modulated amplitude. Pharmacological experiments implicate T-type CaV channels and sodium-calcium exchanger (NCX) as predominant mechanisms of calcium influx. This work shows the potential of using calcium associated optical signals for neural activity read-out in peripheral nerve axons. PMID- 28720794 TI - Percolation-theoretic bounds on the cache size of nodes in mobile opportunistic networks. AB - The node buffer size has a large influence on the performance of Mobile Opportunistic Networks (MONs). This is mainly because each node should temporarily cache packets to deal with the intermittently connected links. In this paper, we study fundamental bounds on node buffer size below which the network system can not achieve the expected performance such as the transmission delay and packet delivery ratio. Given the condition that each link has the same probability p to be active in the next time slot when the link is inactive and q to be inactive when the link is active, there exists a critical value p c from a percolation perspective. If p > p c , the network is in the supercritical case, where we found that there is an achievable upper bound on the buffer size of nodes, independent of the inactive probability q. When p < p c , the network is in the subcritical case, and there exists a closed-form solution for buffer occupation, which is independent of the size of the network. PMID- 28720793 TI - Genome-wide Identification and Characterization of Natural Antisense Transcripts by Strand-specific RNA Sequencing in Ganoderma lucidum. AB - Ganoderma lucidum is a white-rot fungus best-known for its medicinal and ligninolytic activities. To discover the underlying genes responsible for these activities, we identified and characterized the natural antisense transcripts (NATs) using strand-specific (ss) RNA-seq data obtained from the mycelia, primordia and fruiting bodies. NATs were identified using a custom pipeline and then subjected to functional enrichment and differential expression analyses. A total of 1613 cis- and 244 trans- sense and antisense transcripts were identified. Mapping to GO terms and KEGG pathways revealed that NATs were frequently associated with genes of particular functional categories in particular stages. ssRT-qPCR experiments showed that the expression profiles of 30 of 50 (60%) transcripts were highly correlated with those of the RNA-seq results (r >= 0.9). Expression profiles of 22 of 25 (88%) pairs of NATs and STs were highly correlated (p <= 0.01), with 15 having r >= 0.8 and 4 having r <= 0.8. Six lignin-modifying genes and their NATs were analyzed in detail. Diverse patterns of differential expression among different stages and positive and negative correlations were observed. These results suggested that NATs were implicated in gene expression regulation in a function-group and developmental stage specific manner through complex mechanisms. PMID- 28720795 TI - Symmetry of learning rate in synaptic plasticity modulates formation of flexible and stable memories. AB - Spike-timing-dependent plasticity (STDP) is considered critical to learning and memory functions in the human brain. Across various types of synapse, STDP is observed as different profiles of Hebbian and anti-Hebbian learning rules. However, the specific roles of diverse STDP profiles in memory formation still remain elusive. Here, we show that the symmetry of the learning rate profile in STDP is crucial to determining the character of stored memory. Using computer simulations, we found that an asymmetric learning rate generates flexible memory that is volatile and easily overwritten by newly appended information. Moreover, a symmetric learning rate generates stable memory that can coexist with newly appended information. In addition, by combining these two conditions, we could realize a hybrid memory type that operates in a way intermediate between stable and flexible memory. Our results demonstrate that various attributes of memory functions may originate from differences in the synaptic stability. PMID- 28720796 TI - EEG machine learning for accurate detection of cholinergic intervention and Alzheimer's disease. AB - Monitoring effects of disease or therapeutic intervention on brain function is increasingly important for clinical trials, albeit hampered by inter-individual variability and subtle effects. Here, we apply complementary biomarker algorithms to electroencephalography (EEG) recordings to capture the brain's multi-faceted signature of disease or pharmacological intervention and use machine learning to improve classification performance. Using data from healthy subjects receiving scopolamine we developed an index of the muscarinic acetylcholine receptor antagonist (mAChR) consisting of 14 EEG biomarkers. This mAChR index yielded higher classification performance than any single EEG biomarker with cross validated accuracy, sensitivity, specificity and precision ranging from 88-92%. The mAChR index also discriminated healthy elderly from patients with Alzheimer's disease (AD); however, an index optimized for AD pathophysiology provided a better classification. We conclude that integrating multiple EEG biomarkers can enhance the accuracy of identifying disease or drug interventions, which is essential for clinical trials. PMID- 28720797 TI - Commensal Gut Microbiota Immunomodulatory Actions in Bone Marrow and Liver have Catabolic Effects on Skeletal Homeostasis in Health. AB - Despite knowledge the gut microbiota regulates bone mass, mechanisms governing the normal gut microbiota's osteoimmunomodulatory effects on skeletal remodeling and homeostasis are unclear in the healthy adult skeleton. Young adult specific pathogen-free and germ-free mice were used to delineate the commensal microbiota's immunoregulatory effects on osteoblastogenesis, osteoclastogenesis, marrow T-cell hematopoiesis, and extra-skeletal endocrine organ function. We report the commensal microbiota has anti-anabolic effects suppressing osteoblastogenesis and pro-catabolic effects enhancing osteoclastogenesis, which drive bone loss in health. Suppression of Sp7(Osterix) and Igf1 in bone, and serum IGF1, in specific-pathogen-free mice suggest the commensal microbiota's anti-osteoblastic actions are mediated via local disruption of IGF1-signaling. Differences in the RANKL/OPG Axis in vivo, and RANKL-induced maturation of osteoclast-precursors in vitro, indicate the commensal microbiota induces sustained changes in RANKL-mediated osteoclastogenesis. Candidate mechanisms mediating commensal microbiota's pro-osteoclastic actions include altered marrow effector CD4+T-cells and a novel Gut-Liver-Bone Axis. The previously unidentified Gut-Liver-Bone Axis intriguingly implies the normal gut microbiota's osteoimmunomodulatory actions are partly mediated via immunostimulatory effects in the liver. The molecular underpinnings defining commensal gut microbiota immunomodulatory actions on physiologic bone remodeling are highly relevant in advancing the understanding of normal osteoimmunological processes, having implications for the prevention of skeletal deterioration in health and disease. PMID- 28720798 TI - Neuroprotective effect of 5-aminolevulinic acid against low inorganic phosphate in neuroblastoma SH-SY5Y cells. AB - PiT-1 (encoded by SLC20A1) and PiT-2 (encoded by SLC20A2) are type-III sodium dependent phosphate cotransporters (NaPiTs). Recently, SLC20A2 mutations have been found in patients with idiopathic basal ganglia calcification (IBGC), and were predicted to bring about an inability to transport Pi from the extracellular environment. Here we investigated the effect of low Pi loading on the human neuroblastoma SH-SY5Y and the human glioblastoma A172 cell lines. The results show a different sensitivity to low Pi loading and differential regulation of type-III NaPiTs in these cells. We also examined whether 5-aminolevulinic acid (5 ALA) inhibited low Pi loading-induced neurotoxicity in SH-SY5Y cells. Concomitant application of 5-ALA with low Pi loading markedly attenuated low Pi-induced cell death and mitochondrial dysfunction via the induction of HO-1 by p38 MAPK. The findings provide us with novel viewpoints to understand the pathophysiology of IBGC, and give a new insight into the clinical prevention and treatment of IBGC. PMID- 28720799 TI - Reduced ultrafine particle levels in Sao Paulo's atmosphere during shifts from gasoline to ethanol use. AB - Despite ethanol's penetration into urban transportation, observational evidence quantifying the consequence for the atmospheric particulate burden during actual, not hypothetical, fuel-fleet shifts, has been lacking. Here we analyze aerosol, meteorological, traffic, and consumer behavior data and find, empirically, that ambient number concentrations of 7-100-nm diameter particles rise by one-third during the morning commute when higher ethanol prices induce 2 million drivers in the real-world megacity of Sao Paulo to substitute to gasoline use (95% confidence intervals: +4,154 to +13,272 cm-3). Similarly, concentrations fall when consumers return to ethanol. Changes in larger particle concentrations, including US-regulated PM2.5, are statistically indistinguishable from zero. The prospect of increased biofuel use and mounting evidence on ultrafines' health effects make our result acutely policy relevant, to be weighed against possible ozone increases. The finding motivates further studies in real-world environments. We innovate in using econometrics to quantify a key source of urban ultrafine particles.The biofuel ethanol has been introduced into urban transportation in many countries. Here, by measuring aerosols in Sao Paulo, the authors find that high ethanol prices coincided with an increase in harmful nanoparticles by a third, as drivers switched from ethanol to cheaper gasoline, showing a benefit of ethanol. PMID- 28720800 TI - iTRAQ-based quantitative proteomic analysis reveals alterations in the metabolism of Actinidia arguta. AB - Actinidia arguta 'Tianyuanhong' is a new kiwifruit variety with an all-red pericarp and pulp, in contrast to the all-green pulp of A. arguta 'Yongfengyihao'. Transcriptome profile analysis of fruit color has been reported, however, the metabolic mechanisms producing red flesh remain unknown, and it is unclear why the pulp of 'Tianyuanhong' is red rather than green. Herein, we identified differences between the proteomes of two A. arguta cultivars with different fruit color by using iTRAQ-based quantitative proteomic methods during the stage of color change. In total, 2310 differentially abundant proteins were detected between the two cultivars at 70 and 100 days after flowering, and the protein functions were analyzed based on KEGG and GO. The largest group of differentially expressed proteins were related to photosynthesis, glyoxylate metabolism, N metabolism, and anthocyanin biosynthesis. Finally, to verify the iTRAQ data, 12 representative genes encoding differentially expressed proteins were analyzed via quantitative real-time PCR, and these genes differed in transcriptional and translational expression levels. Our proteomic study contributes to understanding the metabolic pathways and biological processes involved in fruit color changes in different cultivars of A. arguta. These data and analyses will provide new insight into the development of kiwifruit flesh color. PMID- 28720801 TI - Mapping and characterization of G-quadruplexes in Mycobacterium tuberculosis gene promoter regions. AB - Mycobacterium tuberculosis is the causative agent of tuberculosis (TB), one of the top 10 causes of death worldwide in 2015. The recent emergence of strains resistant to all current drugs urges the development of compounds with new mechanisms of action. G-quadruplexes are nucleic acids secondary structures that may form in G-rich regions to epigenetically regulate cellular functions. Here we implemented a computational tool to scan the presence of putative G-quadruplex forming sequences in the genome of Mycobacterium tuberculosis and analyse their association to transcription start sites. We found that the most stable G quadruplexes were in the promoter region of genes belonging to definite functional categories. Actual G-quadruplex folding of four selected sequences was assessed by biophysical and biomolecular techniques: all molecules formed stable G-quadruplexes, which were further stabilized by two G-quadruplex ligands. These compounds inhibited Mycobacterium tuberculosis growth with minimal inhibitory concentrations in the low micromolar range. These data support formation of Mycobacterium tuberculosis G-quadruplexes in vivo and their potential regulation of gene transcription, and prompt the use of G4 ligands to develop original antitubercular agents. PMID- 28720802 TI - A novel ADOA-associated OPA1 mutation alters the mitochondrial function, membrane potential, ROS production and apoptosis. AB - Autosomal dominant optic atrophy (ADOA) is a dominantly inherited optic neuropathy, affecting the specific loss of retinal ganglion cells (RGCs). The majority of affected cases of ADOA are associated with mutations in OPA1 gene. Our previous investigation identified the c.1198C > G (p.P400A) mutation in the OPA1 in a large Han Chinese family with ADOA. In this report, we performed a functional characterization using lymphoblostoid cell lines derived from affected members of this family and control subjects. Mutant cell lines exhibited the aberrant mitochondrial morphology. A ~24.6% decrease in the mitochondrial DNA (mtDNA) copy number was observed in mutant cell lines, as compared with controls. Western blotting analysis revealed the variable reductions (~45.7%) in four mtDNA encoded polypeptides in mutant cell lines. The impaired mitochondrial translation caused defects in respiratory capacity. Furthermore, defects in mitochondrial ATP synthesis and mitochondrial membrane potential (DeltaPsim) were observed in mutant cell lines. These abnormalities resulted in the accumulation of oxidative damage and increasing of apoptosis in the mutant cell lines, as compared with controls. All those alterations may cause the primary degeneration of RGCs and subsequent visual loss. These data provided the direct evidence for c.1198C > G mutation leading to ADOA. Our findings may provide new insights into the understanding of pathophysiology of ADOA. PMID- 28720803 TI - Contingent sounds change the mental representation of one's finger length. AB - Mental body-representations are highly plastic and can be modified after brief exposure to unexpected sensory feedback. While the role of vision, touch and proprioception in shaping body-representations has been highlighted by many studies, the auditory influences on mental body-representations remain poorly understood. Changes in body-representations by the manipulation of natural sounds produced when one's body impacts on surfaces have recently been evidenced. But will these changes also occur with non-naturalistic sounds, which provide no information about the impact produced by or on the body? Drawing on the well documented capacity of dynamic changes in pitch to elicit impressions of motion along the vertical plane and of changes in object size, we asked participants to pull on their right index fingertip with their left hand while they were presented with brief sounds of rising, falling or constant pitches, and in the absence of visual information of their hands. Results show an "auditory Pinocchio" effect, with participants feeling and estimating their finger to be longer after the rising pitch condition. These results provide the first evidence that sounds that are not indicative of veridical movement, such as non naturalistic sounds, can induce a Pinocchio-like change in body-representation when arbitrarily paired with a bodily action. PMID- 28720804 TI - The lower pT limit of deep hydrocarbon synthesis by CaCO3 aqueous reduction. AB - The deep abiogenic synthesis of hydrocarbons is possible under the conditions of the asthenosphere. We have found that this process can also occur under the mineral and thermobaric conditions of subducting slabs. We have investigated the abiogenic synthesis of hydrocarbon systems at pressures of 2.0-6.6 GPa and temperatures of 250-600 degrees C. The determined lower thermobaric limit of the reaction at 280-300 degrees C and 2-3 GPa corresponds to a depth of 70-80 km during cold subduction. The hydrocarbon fluid formed in the slab can migrate upwards through the network of faults and fractures to form petroleum deposits. PMID- 28720805 TI - A portable system for rapid bacterial composition analysis using a nanopore-based sequencer and laptop computer. AB - We developed a portable system for 16S rDNA analyses consisting of a nanopore technology-based sequencer, the MinION, and laptop computers, and assessed its potential ability to determine bacterial compositions rapidly. We tested our protocols using a mock bacterial community that contained equimolar 16S rDNA and a pleural effusion from a patient with empyema, for time effectiveness and accuracy. MinION sequencing targeting 16S rDNA detected all 20 of the bacterial species present in the mock bacterial community. Time course analysis indicated that the sequence data obtained during the first 5 minutes of sequencing (1,379 bacterial reads) were enough to detect all 20 bacteria in the mock sample and to determine species composition, consistent with results of those obtained from 4 hours of sequencing (24,202 reads). Additionally, using a clinical sample extracted from the empyema patient's pleural effusion, we could identify major bacterial pathogens in that effusion using our rapid sequencing and analysis protocol. All results are comparable to conventional 16S rDNA sequencing results using an IonPGM sequencer. Our results suggest that rapid sequencing and bacterial composition determination are possible within 2 hours after obtaining a DNA sample. PMID- 28720806 TI - Heteroborospherene clusters Nin ? B40 (n = 1-4) and heteroborophene monolayers Ni2 ? B14 with planar heptacoordinate transition-metal centers in eta7-B7 heptagons. AB - With inspirations from recent discoveries of the cage-like borospherene B40 and perfectly planar Co ? B18- and based on extensive global minimum searches and first-principles theory calculations, we present herein the possibility of the novel planar Ni ? B18 (1), cage-like heteroborospherenes Nin ? B40 (n = 1-4) (2 5), and planar heteroborophenes Ni2 ? B14 (6, 7) which all contain planar or quasi-planar heptacoordinate transition-metal (phTM) centers in eta7-B7 heptagons. The nearly degenerate Ni2 ? B14 (6) and Ni2 ? B14 (7) monolayers are predicted to be metallic in nature, with Ni2 ? B14 (6) composed of interwoven boron double chains with two phNi centers per unit cell being the precursor of cage-like Nin ? B40 (n = 1-4) (2-5). Detailed bonding analyses indicate that Nin ? B40 (n = 1-4) (2-5) and Ni2 ? B14 (6, 7) possess the universal bonding pattern of sigma + pi double delocalization on the boron frameworks, with each phNi forming three lone pairs in radial direction (3dz22, 3dzx2, and 3dyz2) and two effective nearly in-plane 8c-2e sigma-coordination bonds between the remaining tangential Ni 3d orbitals (3dx2-y2 and 3dxy) and the eta7-B7 heptagon around it. The IR, Raman, and UV-vis absorption spectra of 1-5 are computationally simulated to facilitate their experimental characterizations. PMID- 28720807 TI - Fast atom transport and launching in a nonrigid trap. AB - We study the shuttling of an atom in a trap with controllable position and frequency. Using invariant-based inverse engineering, protocols in which the trap is simultaneously displaced and expanded are proposed to speed up transport between stationary trap locations as well as launching processes with narrow final-velocity distributions. Depending on the physical constraints imposed, either simultaneous or sequential approaches may be faster. We consider first a perfectly harmonic trap, and then extend the treatment to generic traps. Finally, we apply this general framework to a double-well potential to separate different motional states with different launching velocities. PMID- 28720808 TI - Preparation of polydopamine-coated graphene oxide/Fe3O4 imprinted nanoparticles for selective removal of fluoroquinolone antibiotics in water. AB - Antibiotics in water have recently caused increasing concerns for public health and ecological environments. In this work, we demonstrated polydopamine-coated graphene oxide/Fe3O4 (PDA@GO/Fe3O4) imprinted nanoparticles coupled with magnetic separation for fast and selective removal of fluoroquinolone antibiotics in water. The nanoparticles were prepared by the self-polymerization of dopamine using sarafloxacin as a template. The imprinted PDA film of 10~20 nm uniformly covered the surface of GO/Fe3O4 providing selective binding sites. The nanoparticles showed rapid binding and a large capacity (70.9 mg/g). The adsorption data fitted well the Langmuir and pseudo-second order kinetic equations. The nanoparticles could be easily separated by a magnet following the adsorption and then regenerated by simple washing for repetitive adsorptions. The nanoparticles were successfully used for the removal of fluoroquinolone antibiotics in seawater, with removal efficiencies of more than 95%. The proposed strategy has potentials for efficient removal of antibiotics in environmental water. PMID- 28720810 TI - Biofilm formation in enterococci: genotype-phenotype correlations and inhibition by vancomycin. AB - Enterococci are nosocomial pathogens that can form biofilms, which contribute to their virulence and antibiotic resistance. Although many genes involved in biofilm formation have been defined, their distribution among enterococci has not been comprehensively studied on a genome scale, and their diagnostic ability to predict biofilm phenotypes is not fully established. Here, we assessed the biofilm-forming ability of 90 enterococcal clinical isolates. Major patterns of virulence gene distribution in enterococcal genomes were identified, and the differentiating virulence genes were screened by polymerase chain reaction (PCR) in 31 of the clinical isolates. We found that detection of gelE in Enterococcus faecalis is not sufficient to predict gelatinase activity unless fsrAB, or fsrB alone, is PCR-positive (P = 0.0026 and 0.0012, respectively). We also found that agg is significantly enriched in isolates with medium and strong biofilm formation ability (P = 0.0026). Additionally, vancomycin, applied at sub minimal inhibitory concentrations, inhibited biofilm in four out of five strong biofilm forming isolates. In conclusion, we suggest using agg and fsrB genes, together with the previously established gelE, for better prediction of biofilm strength and gelatinase activity, respectively. Future studies should explore the mechanism of biofilm inhibition by vancomycin and its possible use for antivirulence therapy. PMID- 28720809 TI - Microbial turnover times in the deep seabed studied by amino acid racemization modelling. AB - The study of active microbial populations in deep, energy-limited marine sediments has extended our knowledge of the limits of life on Earth. Typically, microbial activity in the deep biosphere is calculated by transport-reaction modelling of pore water solutes or from experimental measurements involving radiotracers. Here we modelled microbial activity from the degree of D:L-aspartic acid racemization in microbial necromass (remains of dead microbial biomass) in sediments up to ten million years old. This recently developed approach (D:L amino acid modelling) does not require incubation experiments and is highly sensitive in stable, low-activity environments. We applied for the first time newly established constraints on several important input parameters of the D:L amino acid model, such as a higher aspartic acid racemization rate constant and a lower cell-specific carbon content of sub-seafloor microorganisms. Our model results show that the pool of necromass amino acids is turned over by microbial activity every few thousand years, while the turnover times of vegetative cells are in the order of years to decades. Notably, microbial turnover times in million-year-old sediment from the Peru Margin are up to 100-fold shorter than previous estimates, highlighting the influence of microbial activities on element cycling over geologic time scales. PMID- 28720811 TI - Some coral diseases track climate oscillations in the Caribbean. AB - Disease outbreaks continue to reduce coral populations worldwide. Understanding coral diseases and their relationships with environmental drivers is necessary to forecast disease outbreaks, and to predict future changes in coral populations. Yet, the temporal dynamics of coral diseases are rarely reported. Here we evaluate trends and periodicities in the records of three common coral diseases (white-band disease, yellow-band disease, and dark-spot syndrome) that were surveyed between 1997 and 2014 at 2082 sites throughout the Caribbean. The relationship between the periodicities of disease prevalence and El Nino Southern Oscillation (ENSO) cycles was examined using cross-wavelet analyses and convergent cross mapping (CCM). The prevalence of the diseases peaked every two to four years, and matched periodicities in ENSO conditions. CCM models suggested that environmental conditions associated with recent ENSO cycles may have influenced the patterns in disease prevalence. We also found no increasing trends in disease prevalence through time. Instead, our work suggests that the prevalence of coral diseases is dynamic and complex. The gradual increase in sea surface temperature, a consequence of increasing greenhouse gas emissions, progressively raises the modal temperature threshold of each ENSO cycle. These dynamic cycles and the increasing modal temperatures appear to influence the dynamics of coral diseases. PMID- 28720812 TI - Silicon nanocrystal-based photonic crystal slabs with broadband and efficient directional light emission. AB - Light extraction from a thin planar layer can be increased by introducing a two dimensional periodic pattern on its surface. This structure, the so-called photonic crystal (PhC) slab, then not only enhances the extraction efficiency of light but can direct the extracted emission into desired angles. Careful design of the structures is important in order to have a spectral overlap of the emission with extraction (leaky) modes. We show that by fabricating PhC slabs with optimized dimensions from silicon nanocrystals (SiNCs) active layers, the extraction efficiency of vertical light emission from SiNCs at a particular wavelength can be enhanced ~ 11 times compared to that of uncorrugated SiNCs-rich layer. More importantly, increased light emission can be obtained in a broad spectral range and, simultaneously, the extracted light can stay confined within relatively narrow angle around the normal to the sample plane. We demonstrate experimentally and theoretically that the physical origin of the enhancement is such that light originating from SiNCs first couples to leaky modes of the PhCs and is then efficiently extracted into the surrounding. PMID- 28720813 TI - A new Prenylated Flavonoid induces G0/G1 arrest and apoptosis through p38/JNK MAPK pathways in Human Hepatocellular Carcinoma cells. AB - Prenylated flavonoids have been demonstrated to possess diverse bioactivities including antitumor effects. One new, daphnegiravone D (1), and four known (2-5) prenylated flavonoids were isolated from Daphne giraldii. Their cytotoxic activities revealed that daphnegiravone D markedly inhibited the proliferation of cancer cells, but had no apparent cytotoxicity on human normal cells. Mechanistically, daphnegiravone D induced G0/G1 arrest and apoptosis, reduced the expression of cyclin E1, CDK2 and CDK4, and promoted the cleavage of caspase 3 and PARP in Hep3B and HepG2 cells. Meanwhile, daphnegiravone D increased the level of phosphorylated p38 and attenuated phosphorylated JNK. Further studies indicated that SB203580 partially reversed daphnegiravone D-induced G0/G1 arrest and apoptosis. The addition of SP600125 to both cell lines increased the cleavage of caspase 3 and PARP, but did not affect the G0/G1 arrest. Besides, in vivo studies demonstrated that daphnegiravone D obviously inhibited tumor growth in a nude mouse xenograft model through suppressing the proliferation of tumor cells, without significant effect on body weight or pathology characteristics. Taken together, the new compound selectively inhibited the proliferation of hepatoma cells via p38 and JNK MAPK pathways, suggesting its potential as a novel natural anti-hepatocellular carcinoma agent. PMID- 28720814 TI - Small RNA mediated repression of subtilisin production in Bacillus licheniformis. AB - The species Bacillus licheniformis includes important strains that are used in industrial production processes. Currently the physiological model used to adapt these processes is based on the closely related model organism B. subtilis. In this study we found that both organisms reveal significant differences in the regulation of subtilisin, their main natural protease and a product of industrial fermentation processes. We identified and characterized a novel antisense sRNA AprAs, which represents an RNA based repressor of apr, the gene encoding for the industrial relevant subtilisin protease. Reduction of the AprAs level leads to an enhanced proteolytic activity and an increase of Apr protein expression in the mutant strain. A vector based complementation of the AprAs deficient mutant confirmed this effect and demonstrated the necessity of cis transcription for full efficiency. A comparative analysis of the corresponding genome loci from B. licheniformis and B. subtilis revealed the absence of an aprAs promoter in B. subtilis and indicates that AprAs is a B. licheniformis species specific phenomenon. The discovery of AprAs is of great biotechnological interest since subtilisin Carlsberg is one of the main products of industrial fermentation by B. licheniformis. PMID- 28720815 TI - Generation of spin waves by a train of fs-laser pulses: a novel approach for tuning magnon wavelength. AB - Currently spin waves are considered for computation and data processing as an alternative to charge currents. Generation of spin waves by ultrashort laser pulses provides several important advances with respect to conventional approaches using microwaves. In particular, focused laser spot works as a point source for spin waves and allows for directional control of spin waves and switching between their different types. For further progress in this direction it is important to manipulate with the spectrum of the optically generated spin waves. Here we tackle this problem by launching spin waves by a sequence of femtosecond laser pulses with pulse interval much shorter than the relaxation time of the magnetization oscillations. This leads to the cumulative phenomenon and allows us to generate magnons in a specific narrow range of wavenumbers. The wavelength of spin waves can be tuned from 15 MUm to hundreds of microns by sweeping the external magnetic field by only 10 Oe or by slight variation of the pulse repetition rate. Our findings expand the capabilities of the optical spin pump-probe technique and provide a new method for the spin wave generation and control. PMID- 28720816 TI - Functional divergence and origin of the DAG-like gene family in plants. AB - The nuclear-encoded DAG-like (DAL) gene family plays critical roles in organelle C-to-U RNA editing in Arabidopsis thaliana. However, the origin, diversification and functional divergence of DAL genes remain unclear. Here, we analyzed the genomes of diverse plant species and found that: DAL genes are specific to spermatophytes, all DAL genes share a conserved gene structure and protein similarity with the inhibitor I9 domain of subtilisin genes found in ferns and mosses, suggesting that DAL genes likely arose from I9-containing proproteases via exon shuffling. Based on phylogenetic inference, DAL genes can be divided into five subfamilies, each composed of putatively orthologous and paralogous genes from different species, suggesting that all DAL genes originated from a common ancestor in early seed plants. Significant type I functional divergence was observed in 6 of 10 pairwise comparisons, indicating that shifting functional constraints have contributed to the evolution of DAL genes. This inference is supported by the finding that functionally divergent amino acids between subfamilies are predominantly located in the DAL domain, a critical part of the RNA editosome. Overall, these findings shed light on the origin of DAL genes in spermatophytes and outline functionally important residues involved in the complexity of the RNA editosome. PMID- 28720817 TI - Facile Synthesis of MgO-Modified Carbon Adsorbents with Microwave- Assisted Methods: Effect of MgO Particles and Porosities on CO2 Capture. AB - In this study, magnesium oxide (MgO)-modified carbon adsorbents were fabricated using a nitrogen-enriched carbon precursor by microwave-assisted irradiation for CO2 capture. The X-ray diffraction (XRD) patterns showed the characteristic diffraction peaks of MgO at 43 degrees and 62.5 degrees , and no impurities were apparent. By changing the microwave reaction time, the spherical structure of the parent material was transformed to a hybrid structure with MgO crystalline particles in a carbon matrix. The morphology evolution and properties of the prepared materials were also investigated using transmission electron microscopy and N2 adsorption, respectively. On optimising the conditions, the prepared sample attained a high CO2 uptake of 1.22 mmol/g (5.3 wt.%) under flue gas conditions (15% CO2 in N2). It was found that MgO affected the CO2 capture behaviour by enhancing the fundamental characteristics of the carbon surfaces. PMID- 28720819 TI - Neurodegenerative disorders: Amyloid clearance. PMID- 28720818 TI - Structural and rheological properties conferring fertilization competence to Xenopus egg-coating envelope. AB - The extracellular egg-coating envelope that comprises a meshwork of filaments polymerized by glycoproteins plays a pivotal role in species-selective sperm recognition and subsequent fertilization; however, the structural and rheological properties conferring fertilization competence to the egg-coating envelope remain poorly unveiled. Here we show several nanoscale-structural and viscoelastic properties of the egg-coat using the transmission electron microscopy and the quartz crystal microbalance experiments, following clamp of the egg-coat at either fertilization-competent or -incompetent statuses by short-term pretreatment with synthetic peptides. Individual filament of approximately 4.8 nm diameter crossed one another, forming several types of intersections. Higher competence-inducing treatment changed the proportion of V-, Y-, and T-type intersections, and induced more randomly deflected angles at intersections. Incompetence-inducing treatment increased the median of a Gaussian distribution of filament lengths that had a peak of 10-20 nm under control conditions; furthermore, this treatment created bumps in the 30-40 and 50-60 nm windows. Quartz crystal microbalance study revealed that viscoelasticity of the competent VE suspension was lower than that of incompetent VE, indicating that viscoelastic property required for successful fertilization resides within a specific range. These findings indicated that the architecture of the egg-coat is capable of rapid and dynamic remodeling, which determines fertilization efficiency. PMID- 28720820 TI - Gut-brain communication: Making contact. PMID- 28720821 TI - Neural circuits: Hanging in the balance. PMID- 28720822 TI - Neural development: Regional influence. PMID- 28720823 TI - Learning and memory: Catching fear memories. PMID- 28720824 TI - Pain: A painful loss of inhibition. PMID- 28720825 TI - Non-motor features of Parkinson disease. AB - This corrects the article DOI: 10.1038/nrn.2017.62. PMID- 28720826 TI - Neural circuits: The influence of hunger. PMID- 28720827 TI - Small chaperons and autophagy protected neurons from necrotic cell death. AB - Neuronal necrosis occurs during early phase of ischemic insult. However, our knowledge of neuronal necrosis is still inadequate. To study the mechanism of neuronal necrosis, we previously established a Drosophila genetic model of neuronal necrosis by calcium overloading through expression of a constitutively opened cation channel mutant. Here, we performed further genetic screens and identified a suppressor of neuronal necrosis, CG17259, which encodes a seryl-tRNA synthetase. We found that loss-of-function (LOF) CG17259 activated eIF2alpha phosphorylation and subsequent up-regulation of chaperons (Hsp26 and Hsp27) and autophagy. Genetically, down-regulation of eIF2alpha phosphorylation, Hsp26/Hsp27 or autophagy reduced the protective effect of LOF CG17259, indicating they function downstream of CG17259. The protective effect of these protein degradation pathways indicated activation of a toxic protein during neuronal necrosis. Our data indicated that p53 was likely one such protein, because p53 was accumulated in the necrotic neurons and down-regulation of p53 rescued necrosis. In the SH-SY5Y human cells, tunicamycin (TM), a PERK activator, promoted transcription of hsp27; and necrosis induced by glutamate could be rescued by TM, associated with reduced p53 accumulation. In an ischemic stroke model in rats, p53 protein was also increased, and TM treatment could reduce the p53 accumulation and brain damage. PMID- 28720828 TI - Universal mechanism for hybrid percolation transitions. AB - Hybrid percolation transitions (HPTs) induced by cascading processes have been observed in diverse complex systems such as k-core percolation, breakdown on interdependent networks and cooperative epidemic spreading models. Here we present the microscopic universal mechanism underlying those HPTs. We show that the discontinuity in the order parameter results from two steps: a durable critical branching (CB) and an explosive, supercritical (SC) process, the latter resulting from large loops inevitably present in finite size samples. In a random network of N nodes at the transition the CB process persists for O(N 1/3) time and the remaining nodes become vulnerable, which are then activated in the short SC process. This crossover mechanism and scaling behavior are universal for different HPT systems. Our result implies that the crossover time O(N 1/3) is a golden time, during which one needs to take actions to control and prevent the formation of a macroscopic cascade, e.g., a pandemic outbreak. PMID- 28720829 TI - Betulinic acid is a PPARgamma antagonist that improves glucose uptake, promotes osteogenesis and inhibits adipogenesis. AB - PPAR antagonists are ligands that bind their receptor with high affinity without transactivation activity. Recently, they have been demonstrated to maintain insulin-sensitizing and antidiabetic properties, and they serve as an alternative treatment for metabolic diseases. In this work, an affinity-based bioassay was found to be effective for selecting PPAR ligands from the dried extract of an African plant (Diospyros bipindensis). Among the ligands, we identified betulinic acid (BA), a compound already known for its anti-inflammatory, anti-tumour and antidiabetic properties, as a PPARgamma and PPARalpha antagonist. Cell differentiation assays showed that BA inhibits adipogenesis and promotes osteogenesis; either down-regulates or does not affect the expression of a series of adipogenic markers; and up-regulates the expression of osteogenic markers. Moreover, BA increases basal glucose uptake in 3T3-L1 adipocytes. The crystal structure of the complex of BA with PPARgamma sheds light, at the molecular level, on the mechanism by which BA antagonizes PPARgamma, and indicates a unique binding mode of this antagonist type. The results of this study show that the natural compound BA could be an interesting and safe candidate for the treatment of type 2 diabetes and bone diseases. PMID- 28720830 TI - Effect of CXCL12/CXCR4 signaling on neuropathic pain after chronic compression of dorsal root ganglion. AB - Neuropathic pain is a complex, chronic pain state that often accompanies tissue damage, inflammation or injury of the nervous system. However the underlying molecular mechanisms still remain unclear. Here, we showed that CXCL12 and CXCR4 were upregulated in the dorsal root ganglion (DRG) after chronic compression of DRG (CCD), and some CXCR4 immunopositive neurons were also immunopositive for the nociceptive neuronal markers IB4, TRPV1, CGRP, and substance P. The incidence and amplitude of CXCL12-induced Ca2+ response in primary sensory neurons from CCD mice was significantly increased compared to those from control animals. CXCL12 depolarized the resting membrane potential, decreased the rheobase, and increased the number of action potentials evoked by a depolarizing current at 2X rheobase in neurons from CCD mice. The mechanical and thermal hypernociception after CCD was attenuated by administration of a CXCR4 antagonist AMD3100. These findings suggest that CXCL12/CXCR4 signaling contributes to hypernociception after CCD, and targeting CXCL12/CXCR4 signaling pathway may alleviate neuropathic pain. PMID- 28720831 TI - Minimum Winfree loop determines self-sustained oscillations in excitable Erdos Renyi random networks. AB - The investigation of self-sustained oscillations in excitable complex networks is very important in understanding various activities in brain systems, among which the exploration of the key determinants of oscillations is a challenging task. In this paper, by investigating the influence of system parameters on self-sustained oscillations in excitable Erdos-Renyi random networks (EERRNs), the minimum Winfree loop (MWL) is revealed to be the key factor in determining the emergence of collective oscillations. Specifically, the one-to-one correspondence between the optimal connection probability (OCP) and the MWL length is exposed. Moreover, many important quantities such as the lower critical connection probability (LCCP), the OCP, and the upper critical connection probability (UCCP) are determined by the MWL. Most importantly, they can be approximately predicted by the network structure analysis, which have been verified in numerical simulations. Our results will be of great importance to help us in understanding the key factors in determining persistent activities in biological systems. PMID- 28720832 TI - Deep-ocean dissolved organic matter reactivity along the Mediterranean Sea: does size matter? AB - Despite of the major role ascribed to marine dissolved organic matter (DOM) in the global carbon cycle, the reactivity of this pool in the dark ocean is still poorly understood. Present hypotheses, posed within the size-reactivity continuum (SRC) and the microbial carbon pump (MCP) conceptual frameworks, need further empirical support. Here, we provide field evidence of the soundness of the SRC model. We sampled the high salinity core-of-flow of the Levantine Intermediate Water along its westward route through the entire Mediterranean Sea. At selected sites, DOM was size-fractionated in apparent high (aHMW) and low (aLMW) molecular weight fractions using an efficient ultrafiltration cell. A percentage decline of the aHMW DOM from 68-76% to 40-55% was observed from the Levantine Sea to the Strait of Gibraltar in parallel with increasing apparent oxygen utilization (AOU). DOM mineralization accounted for 30 +/- 3% of the AOU, being the aHMW fraction solely responsible for this consumption, verifying the SRC model in the field. We also demonstrate that, in parallel to this aHMW DOM consumption, fluorescent humic-like substances accumulate in both fractions and protein-like substances decline in the aLMW fraction, thus indicating that not only size matters and providing field support to the MCP model. PMID- 28720833 TI - Competition between Superconductor - Ferromagnetic stray magnetic fields in YBa2Cu3O7-x films pierced with Co nano-rods. AB - Superconductivity and ferromagnetism are two antagonistic phenomena that combined can lead to a rich phenomenology of interactions, resulting in novel physical properties and unique functionalities. Here we propose an original hybrid system formed by a high-temperature superconducting film, patterned with antidots, and with ferromagnetic nano-rods grown inside them. This particular structure exhibits the synergic influence of superconductor (SC) - ferromagnetic (FM) stray fields, in both the superconducting behaviour of the film and the three dimensional (3D) magnetic structure of nano-rods. We show that FM stray fields directly influence the critical current density of the superconducting film. Additional functionalities appear due to the interaction of SC stray fields, associated to supercurrent loops, with the non-trivial 3D remanent magnetic structure of FM nano-rods. This work unravels the importance of addressing quantitatively the effect of stray magnetic fields from both, the superconductor and the ferromagnet in hybrid magnetic nano-devices based on high temperature superconductors. PMID- 28720834 TI - Chemical inhibitors of Candida albicans hyphal morphogenesis target endocytosis. AB - Candida albicans is an opportunistic pathogen, typically found as a benign commensal yeast living on skin and mucosa, but poised to invade injured tissue to cause local infections. In debilitated and immunocompromised individuals, C. albicans may spread to cause life-threatening systemic infections. Upon contact with serum and at body temperature, C. albicans performs a regulated switch to filamentous morphology, characterized by emergence of a germ tube from the yeast cell followed by mold-like growth of branching hyphae. The ability to switch between growth morphologies is an important virulence factor of C. albicans. To identify compounds able to inhibit hyphal morphogenesis, we screened libraries of existing drugs for inhibition of the hyphal switch under stringent conditions. Several compounds that specifically inhibited hyphal morphogenesis were identified. Chemogenomic analysis suggested an interaction with the endocytic pathway, which was confirmed by direct measurement of fluid-phase endocytosis in the presence of these compounds. These results suggest that the activity of the endocytic pathway, which is known to be particularly important for hyphal growth, represents an effective target for hyphae-inhibiting drugs. PMID- 28720835 TI - Exophagy of annexin A2 via RAB11, RAB8A and RAB27A in IFN-gamma-stimulated lung epithelial cells. AB - Annexin A2 (ANXA2), a phospholipid-binding protein, has multiple biological functions depending on its cellular localization. We previously demonstrated that IFN-gamma-triggered ANXA2 secretion is associated with exosomal release. Here, we show that IFN-gamma-induced autophagy is essential for the extracellular secretion of ANXA2 in lung epithelial cells. We observed colocalization of ANXA2 containing autophagosomes with multivesicular bodies (MVBs) after IFN-gamma stimulation, followed by exosomal release. IFN-gamma-induced exophagic release of ANXA2 could not be observed in ATG5-silenced or mutant RAB11-expressing cells. Furthermore, knockdown of RAB8A and RAB27A, but not RAB27B, reduced IFN-gamma triggered ANXA2 secretion. Surface translocation of ANXA2 enhanced efferocytosis by epithelial cells, and inhibition of different exophagic steps, including autophagosome formation, fusion of autophagosomes with MVBs, and fusion of amphisomes with plasma membrane, reduced ANXA2-mediated efferocytosis. Our data reveal a novel route of IFN-gamma-induced exophagy of ANXA2. PMID- 28720836 TI - Calcifying algae maintain settlement cues to larval abalone following algal exposure to extreme ocean acidification. AB - Ocean acidification (OA) increasingly threatens marine systems, and is especially harmful to calcifying organisms. One important question is whether OA will alter species interactions. Crustose coralline algae (CCA) provide space and chemical cues for larval settlement. CCA have shown strongly negative responses to OA in previous studies, including disruption of settlement cues to corals. In California, CCA provide cues for seven species of harvested, threatened, and endangered abalone. We exposed four common CCA genera and a crustose calcifying red algae, Peyssonnelia (collectively CCRA) from California to three pCO2 levels ranging from 419-2,013 uatm for four months. We then evaluated abalone (Haliotis rufescens) settlement under ambient conditions among the CCRA and non-algal controls that had been previously exposed to the pCO2 treatments. Abalone settlement and metamorphosis increased from 11% in the absence of CCRA to 45-69% when CCRA were present, with minor variation among CCRA genera. Though all CCRA genera reduced growth during exposure to increased pCO2, abalone settlement was unaffected by prior CCRA exposure to increased pCO2. Thus, we find no impacts of OA exposure history on CCRA provision of settlement cues. Additionally, there appears to be functional redundancy in genera of CCRA providing cues to abalone, which may further buffer OA effects. PMID- 28720837 TI - Morphological and functional maturity of the oral jaws covary with offspring size in Trinidadian guppies. AB - Large size of individual offspring is routinely selected for in highly competitive environments, such as in low-predation populations of the Trinidadian guppy (Poecilia reticulata). Large guppy offspring outcompete their smaller conspecifics, but the functional mechanisms underlying this advantage are unknown. We measured jaw kinematics during benthic feeding and cranial musculoskeletal morphologies in neonates and juveniles from five populations of Trinidadian guppy and found that both kinematics and morphologies vary substantially with neonatal size. Rotation at the intramandibular joint (IMJ), but not the quadratomandibular joint (QMJ), increases with size among guppy offspring, from 11.7 degrees in the smallest neonates to 22.9 degrees in the largest neonates. Ossification of the cranial skeleton varies from 20% in the smallest neonates to 90% in the largest. Relative to standard length (SL; jaw tip to caudal fin base distance), the surface area of jaw-closing musculature scales with positive allometry (SL2.72) indicating that muscle growth outpaces body growth. Maximum gape also scales with positive allometry (SL1.20), indicating that larger neonates are capable of greater jaw excursions. These findings indicate that size is not the sole adaptive benefit to producing larger offspring; maturation provides a potential functional mechanism underlying the competitive advantage of large offspring size among Trinidadian guppies. PMID- 28720838 TI - The efficacy and safety of sugammadex for reversing postoperative residual neuromuscular blockade in pediatric patients: A systematic review. AB - The aim of this study is to evaluate the efficacy and safety of sugammadex for reversing neuromuscular blockade in pediatric patients. MEDLINE and other three Databases were searched. Randomized clinical trials were included if they compared sugammadex with neostigmine or placebo in pediatric patients undergoing surgery involving the use of rocuronium or vecuronium. The primary outcome was the time interval from administration of reversal agents to train-of-four ratio (TOFr, T4/T1) > 0.9. Incidences of any drug-related adverse events were secondary outcomes. Trial inclusion, data extraction, and risk of bias assessment were performed independently. Mean difference and relative risk were used as summary statistics with random effects models. Statistical heterogeneity was assessed by the I2 statistic. Funnel plot was used to detect publication bias. Ten studies with 580 participants were included. Although considerable heterogeneity (I2 = 98.5%) was detected in primary outcome, the results suggested that, compared with placebo or neostigmine, sugammadex can reverse rocuronium-induced neuromuscular blockade more rapidly with lower incidence of bradycardia. No significant differences were found in the incidences of other adverse events. Compared with neostigmine or placebo, sugammadex may reverse rocuronium-induced neuromuscular blockade in pediatric patients rapidly and safely. PMID- 28720839 TI - Effect of head group and lipid tail oxidation in the cell membrane revealed through integrated simulations and experiments. AB - We report on multi-level atomistic simulations for the interaction of reactive oxygen species (ROS) with the head groups of the phospholipid bilayer, and the subsequent effect of head group and lipid tail oxidation on the structural and dynamic properties of the cell membrane. Our simulations are validated by experiments using a cold atmospheric plasma as external ROS source. We found that plasma treatment leads to a slight initial rise in membrane rigidity, followed by a strong and persistent increase in fluidity, indicating a drop in lipid order. The latter is also revealed by our simulations. This study is important for cancer treatment by therapies producing (extracellular) ROS, such as plasma treatment. These ROS will interact with the cell membrane, first oxidizing the head groups, followed by the lipid tails. A drop in lipid order might allow them to penetrate into the cell interior (e.g., through pores created due to oxidation of the lipid tails) and cause intracellular oxidative damage, eventually leading to cell death. This work in general elucidates the underlying mechanisms of ROS interaction with the cell membrane at the atomic level. PMID- 28720840 TI - Positioning of the SCRAMBLED receptor requires UDP-Glc:sterol glucosyltransferase 80B1 in Arabidopsis roots. AB - The biological function of sterol glucosides (SGs), the most abundant sterol derivatives in higher plants, remains uncertain. In an effort to improve our understanding of these membrane lipids we examined phenotypes exhibited by the roots of Arabidopsis (Arabidopsis thaliana) lines carrying insertions in the UDP Glc:sterol glucosyltransferase genes, UGT80A2 and UGT80B1. We show that although ugt80A2 mutants exhibit significantly lower levels of total SGs they are morphologically indistinguishable from wild-type plants. In contrast, the roots of ugt80B1 mutants are only deficient in stigmasteryl glucosides but exhibit a significant reduction in root hairs. Sub-cellular investigations reveal that the plasma membrane cell fate regulator, SCRAMBLED (SCM), is mislocalized in ugt80B1 mutants, underscoring the aberrant root epidermal cell patterning. Live imaging of roots indicates that SCM:GFP is localized to the cytoplasm in a non cell type dependent manner instead of the hair (H) cell plasma membrane in these mutants. In addition, we provide evidence for the localization of the UGT80B1 enzyme in the plasma membrane. These data lend further support to the notion that deficiencies in specific SGs are sufficient to disrupt normal cell function and point to a possible role for SGs in cargo transport and/or protein targeting to the plasma membrane. PMID- 28720841 TI - Novel immunohistochemistry-based signatures to predict metastatic site of triple negative breast cancers. AB - BACKGROUND: Although distant metastasis (DM) in breast cancer (BC) is the most lethal form of recurrence and the most common underlying cause of cancer related deaths, the outcome following the development of DM is related to the site of metastasis. Triple negative BC (TNBC) is an aggressive form of BC characterised by early recurrences and high mortality. Athough multiple variables can be used to predict the risk of metastasis, few markers can predict the specific site of metastasis. This study aimed at identifying a biomarker signature to predict particular sites of DM in TNBC. METHODS: A clinically annotated series of 322 TNBC were immunohistochemically stained with 133 biomarkers relevant to BC, to develop multibiomarker models for predicting metastasis to the bone, liver, lung and brain. Patients who experienced metastasis to each site were compared with those who did not, by gradually filtering the biomarker set via a two-tailed t test and Cox univariate analyses. Biomarker combinations were finally ranked based on statistical significance, and evaluated in multivariable analyses. RESULTS: Our final models were able to stratify TNBC patients into high risk groups that showed over 5, 6, 7 and 8 times higher risk of developing metastasis to the bone, liver, lung and brain, respectively, than low-risk subgroups. These models for predicting site-specific metastasis retained significance following adjustment for tumour size, patient age and chemotherapy status. CONCLUSIONS: Our novel IHC-based biomarkers signatures, when assessed in primary TNBC tumours, enable prediction of specific sites of metastasis, and potentially unravel biomarkers previously unknown in site tropism. PMID- 28720842 TI - Pre-diagnostic statin use, lymph node status and mortality in women with stages I III breast cancer. AB - BACKGROUND: Recent meta-analyses suggest that pre-diagnostic statin use is associated with reduced breast cancer-specific mortality. Studies have shown that high breast tumour expression of the statin target (3-hydroxy-3-methylglutaryl coenzyme-A reductase) is associated with lymph-node negative cancer. Therefore, we examined the association between pre-diagnostic statin use and; lymph node status, breast cancer-specific and all-cause mortality. METHODS: Women with stages I-III breast cancer were identified from the National Cancer Registry of Ireland (N=6314). Pre-diagnostic statin users were identified from linked prescription claims data (N=2082). Relative risks were estimated for associations between pre-diagnostic statin use and lymph node status. Hazard ratios (HR) were estimated for associations between pre-diagnostic statin use and breast cancer specific and all-cause mortality. RESULTS: Pre-diagnostic statin use was not associated with lymph node negative status at diagnosis. In multivariate analyses, pre-diagnostic statin use was associated with reduced all-cause (HR 0.78 95% confidence interval (CI) 0.69, 0.89) and breast cancer-specific mortality (HR 0.81 95% CI 0.68, 0.96). This reduction in cancer-specific mortality was greatest in statin-users with oestrogen (ER) receptor-positive tumours (HR 0.69 95% CI 0.55, 0.85). CONCLUSION: Patients with pre-diagnostic statin exposure had a significant reduction in breast cancer-specific mortality, which was even more pronounced in women with ER+ tumours. PMID- 28720843 TI - Clinical study of genomic drivers in pancreatic ductal adenocarcinoma. AB - BACKGROUND: Pancreatic ductal adenocarcinoma (PDA) is a lethal cancer with complex genomes and dense fibrotic stroma. This study was designed to identify clinically relevant somatic aberrations in pancreatic cancer genomes of patients with primary and metastatic disease enrolled and treated in two clinical trials. METHODS: Tumour nuclei were flow sorted prior to whole genome copy number variant (CNV) analysis. Targeted or whole exome sequencing was performed on most samples. We profiled biopsies from 68 patients enrolled in two Stand Up to Cancer (SU2C) sponsored clinical trials. These included 38 resected chemoradiation naive tumours (SU2C 20206-003) and metastases from 30 patients who progressed on prior therapies (SU2C 20206-001). Patient outcomes including progression-free survival (PFS) and overall survival (OS) were observed. RESULTS: We defined: (a) CDKN2A homozygous deletions that included the adjacent MTAP gene, only its' 3' region, or excluded MTAP; (b) SMAD4 homozygous deletions that included ME2; (c) a pancreas-specific MYC super-enhancer region; (d) DNA repair-deficient genomes; and (e) copy number aberrations present in PDA patients with long-term (? 40 months) and short-term (? 12 months) survival after surgical resection. CONCLUSIONS: We provide a clinically relevant framework for genomic drivers of PDA and for advancing novel treatments. PMID- 28720844 TI - Highly Efficient Non-Enzymatic Glucose Sensor Based on CuO Modified Vertically Grown ZnO Nanorods on Electrode. AB - There is a major challenge to attach nanostructures on to the electrode surface while retaining their engineered morphology, high surface area, physiochemical features for promising sensing applications. In this study, we have grown vertically-aligned ZnO nanorods (NRs) on fluorine doped tin oxide (FTO) electrodes and decorated with CuO to achieve high-performance non-enzymatic glucose sensor. This unique CuO-ZnO NRs hybrid provides large surface area and an easy substrate penetrable structure facilitating enhanced electrochemical features towards glucose oxidation. As a result, fabricated electrodes exhibit high sensitivity (2961.7 MUA mM-1 cm-2), linear range up to 8.45 mM, low limit of detection (0.40 MUM), and short response time (<2 s), along with excellent reproducibility, repeatability, stability, selectivity, and applicability for glucose detection in human serum samples. Circumventing, the outstanding performance originating from CuO modified ZnO NRs acts as an efficient electrocatalyst for glucose detection and as well, provides new prospects to biomolecules detecting device fabrication. PMID- 28720845 TI - Pulsation of electrified jet in capillary microfluidics. AB - In this work, we investigate the pulsation of an electrically charged jet surrounded by an immiscible dielectric liquid in flow-focusing capillary microfluidics. We have characterized a low-frequency large-amplitude pulsation and a high-frequency small-amplitude pulsation, respectively. The former, due to the unbalanced charge and fluid transportation is responsible for generating droplets with a broad size distribution. The latter is intrinsic and produces droplets with a relatively narrow size distribution. Moreover, the average size of the final droplets can be tuned via the intrinsic pulsating frequency through changing the diameter of the emitted liquid jet. Our results provide degree of control over the emulsion droplets with submicron sizes generated in microfluidic electrospray platform. PMID- 28720846 TI - Physiological stress-induced corticosterone increases heme uptake via KLF4-HCP1 signaling pathway in hippocampus neurons. AB - Iron overload has attracted much attention because of its adverse effect in increasing the risk of developing several neurodegenerative disorders. Under various pathologic conditions, a lot of heme are released. The aggregation of heme is more neurotoxic than that of iron released from the heme breakdown. Our previous studies demonstrated that psychological stress (PS) is a risk factor of cerebral iron metabolism disorders, thus causing iron accumulation in rat brains. In the present study, we found PS could increase heme uptake via heme carrier protein 1 (HCP1) in rat brains. We demonstrated that Glucocorticoid (GC), which is largely secreted under stress, could up-regulate HCP1 expression, thus promoting heme uptake in neurons. We also ascertained that HCP1 expression can be induced by GC through a transcription factor, Kruppel-like factor 4 (KLF4). These results may gain new insights into the etiology of heme uptake and iron accumulation in PS rats, and find new therapeutic targets of iron accumulation in Parkinson's disease or Alzheimer's disease. PMID- 28720847 TI - The glycointeractome of serogroup B Neisseria meningitidis strain MC58. AB - Neisseria meningitidis express numerous virulence factors that enable it to interact with diverse microenvironments within the host, during both asymptomatic nasopharyngeal colonization and invasive disease. Many of these interactions involve bacterial or host glycans. In order to characterise the meningococcal glycointeractome, glycan arrays representative of structures found on human cells, were used as a screening tool to investigate host glycans bound by N. meningitidis. Arrays probed with fluorescently labelled wild-type MC58 revealed binding to 223 glycans, including blood group antigens, mucins, gangliosides and glycosaminoglycans. Mutant strains lacking surface components, including capsule, lipooligosaccharide (LOS), Opc and pili, were investigated to identify the factors responsible for glycan binding. Surface plasmon resonance and isothermal calorimetry were used to confirm binding and determine affinities between surface components and host glycans. We observed that the L3 LOS immunotype (whole cells and purified LOS) bound 26 structures, while L8 only bound 5 structures. We further demonstrated a direct glycan-glycan interaction between purified L3 LOS and Thomsen-Friedenreich (TF) antigen, with a KD of 13 nM. This is the highest affinity glycan-glycan interaction reported to date. These findings highlight the diverse glycointeractions that may occur during different stages of meningococcal disease, which could be exploited for development of novel preventative and therapeutic strategies. PMID- 28720848 TI - The natural Disc1-deletion present in several inbred mouse strains does not affect sleep. AB - The gene Disrupted in Schizophrenia-1 (DISC1) is linked to a range of psychiatric disorders. Two recent transgenic studies suggest DISC1 is also involved in homeostatic sleep regulation. Several strains of inbred mice commonly used for genome manipulation experiments, including several Swiss and likely all 129 substrains, carry a natural deletion mutation of Disc1. This constitutes a potential confound for studying sleep in genetically modified mice. Since disturbed sleep can also influence psychiatric and neurodegenerative disease models, this putative confound might affect a wide range of studies in several fields. Therefore, we asked to what extent the natural Disc1 deletion affects sleep. To this end, we first compared sleep and electroencephalogram (EEG) phenotypes of 129S4 mice carrying the Disc1 deletion and C57BL/6N mice carrying the full-length version. We then bred Disc1 from C57BL/6N into the 129S4 background, resulting in S4-Disc1 mice. The differences between 129S4 and C57BL/6N were not detected in the 129S4 to S4-Disc1 comparison. We conclude that the mutation has no effect on the measured sleep and EEG characteristics. Thus, it is unlikely the widespread Disc1 deletion has led to spurious results in previous sleep studies or that it alters sleep in mouse models of psychiatric or neurodegenerative diseases. PMID- 28720849 TI - Melatonin promotes osteoblast differentiation by regulating Osterix protein stability and expression. AB - Although the biological role of melatonin in osteogenic differentiation has been suggested, the mechanism of osteoblast differentiation remains unclear. Thus, the present study investigated the underlying molecular mechanisms based on osteoblast-specific transcription factors. We found that melatonin enhanced BMP-4 induced osteogenic differentiation and increased the expression of osteogenic markers, especially Osterix, which is an essential transcription factor for the differentiation of preosteoblasts into mature osteoblasts in the late stage of osteoblast differentiation. Melatonin treatment increased the expression of Osterix during osteoblast differentiation and stabilized its expression by the inhibition of ubiquitin-proteasome-mediated degradation of Osterix, leading to up regulated Osterix transcriptional activity on the osteogenic promoter and promoting alkaline phosphatase activity and bone mineralization. Furthermore, treatment with protein kinase A (PKA) inhibitor H89 and protein kinase C (PKC) inhibitor Go6976 blocked the melatonin-induced transcriptional activity and phosphorylation of Osterix, indicating that melatonin regulates Osterix expression via the PKA and PKC signaling pathways. Overall, these findings suggest that melatonin directly regulates the late stage of osteoblast differentiation by enhancing Osterix expression; this provides further evidence of melatonin as a potent agent for treating osteoporosis. PMID- 28720850 TI - Energy Dissipation Pathways in Few-Layer MoS2 Nanoelectromechanical Systems. AB - Free standing, atomically thin transition metal dichalcogenides are a new class of ultralightweight nanoelectromechanical systems with potentially game-changing electro- and opto-mechanical properties, however, the energy dissipation pathways that fundamentally limit the performance of these systems is still poorly understood. Here, we identify the dominant energy dissipation pathways in few layer MoS2 nanoelectromechanical systems. The low temperature quality factors and resonant frequencies are shown to significantly decrease upon heating to 293 K, and we find the temperature dependence of the energy dissipation can be explained when accounting for both intrinsic and extrinsic damping sources. A transition in the dominant dissipation pathways occurs at T ~ 110 K with relatively larger contributions from phonon-phonon and electrostatic interactions for T > 110 K and larger contributions from clamping losses for T < 110 K. We further demonstrate a room temperature thermomechanical-noise-limited force sensitivity of ~8 fN/Hz1/2 that, despite multiple dissipation pathways, remains effectively constant over the course of more than four years. Our results provide insight into the mechanisms limiting the performance of nanoelectromechanical systems derived from few-layer materials, which is vital to the development of next-generation force and mass sensors. PMID- 28720851 TI - Microneedle patch delivery of influenza vaccine during pregnancy enhances maternal immune responses promoting survival and long-lasting passive immunity to offspring. AB - Influenza virus causes life-threatening infections in pregnant women and their newborns. Immunization during pregnancy is the most effective means of preventing maternal and infant mortality/morbidity; however, influenza vaccination rates of pregnant women remain under 50%. Furthermore, the availability of vaccines in low resource populations is limited. Skin immunization with microneedle patches (MN) is a novel and safe vaccination platform featuring thermostable vaccine formulations. Cold-chain independence and the potential for self-administration can expand influenza vaccination coverage in developing countries. In this study of pregnant BALB/c mice immunized with subunit H1N1 influenza vaccine, we demonstrate the advantage of skin vaccination over intramuscular delivery of a two-fold higher vaccine dose. MN vaccine induced superior humoral immune responses and conferred protective immunity against a lethal challenge dose of homologous influenza virus. Importantly, MN vaccination of mice at mid-gestation resulted in enhanced and long-lasting passive immunity of the offspring, measured by neutralizing antibody titers and survival rates after virus challenge. We conclude that skin vaccination using MN is a superior immunization approach with the potential to overcome immune tolerance observed in pregnancy, and lower vaccination costs through antigen dose-sparing, which is especially relevant in underserved countries. PMID- 28720852 TI - Quantum Critical Scaling under Periodic Driving. AB - Universality is key to the theory of phase transitions, stating that the equilibrium properties of observables near a phase transition can be classified according to few critical exponents. These exponents rule an universal scaling behaviour that witnesses the irrelevance of the model's microscopic details at criticality. Here we discuss the persistence of such a scaling in a one dimensional quantum Ising model under sinusoidal modulation in time of its transverse magnetic field. We show that scaling of various quantities (concurrence, entanglement entropy, magnetic and fidelity susceptibility) endures up to a stroboscopic time tau bd , proportional to the size of the system. This behaviour is explained by noticing that the low-energy modes, responsible for the scaling properties, are resilient to the absorption of energy. Our results suggest that relevant features of the universality do hold also when the system is brought out-of-equilibrium by a periodic driving. PMID- 28720853 TI - Complete chloroplast genome sequences of Lilium: insights into evolutionary dynamics and phylogenetic analyses. AB - Lilium is a large genus that includes approximately 110 species distributed throughout cold and temperate regions of the Northern Hemisphere. The species level phylogeny of Lilium remains unclear; previous studies have found universal markers but insufficient phylogenetic signals. In this study, we present the use of complete chloroplast genomes to explore the phylogeny of this genus. We sequenced nine Lilium chloroplast genomes and retrieved seven published chloroplast genomes for comparative and phylogenetic analyses. The genomes ranged from 151,655 bp to 153,235 bp in length and had a typical quadripartite structure with a conserved genome arrangement and moderate divergence. A comparison of sixteen Lilium chloroplast genomes revealed ten mutation hotspots. Single nucleotide polymorphisms (SNPs) for any two Lilium chloroplast genomes ranged from 8 to 1,178 and provided robust data for phylogeny. Except for some of the shortest internodes, phylogenetic relationships of the Lilium species inferred from the chloroplast genome obtained high support, indicating that chloroplast genome data will be useful to help resolve the deeper branches of phylogeny. PMID- 28720854 TI - Laser-pulse-shape control of seeded QED cascades. AB - QED cascades are complex avalanche processes of hard photon emission and electron positron pair creation driven by ultrastrong electromagnetic fields. They play a fundamental role in astrophysical environments such as a pulsars' magnetosphere, rendering an earth-based implementation with intense lasers attractive. In the literature, QED cascades were also predicted to limit the attainable intensity in a set-up of colliding laser beams in a tenuous gas such as the residual gas of a vacuum chamber, therefore severely hindering experiments at extreme field intensities. Here, we demonstrate that the onset of QED cascades may be either prevented even at intensities around 1026 W/cm2 with tightly focused laser pulses and low-Z gases, or facilitated at intensities below 1024 W/cm2 with enlarged laser focal areas or high-Z gases. These findings pave the way for the control of novel experiments such as the generation of pure electron-positron-photon plasmas from laser energy, and for probing QED in the extreme-intensity regime where the quantum vacuum becomes unstable. PMID- 28720855 TI - Influence of Cu on modifying the beta phase and enhancing the mechanical properties of recycled Al-Si-Fe cast alloys. AB - High iron impurity affects the castability and the tensile properties of the recycled Al-Si alloys due to the presence of the Fe containing intermetallic beta Al9Fe2Si2 phase. To date only Mn addition is known to transform the beta Al9Fe2Si2 phase in the Al-Si-Fe system. However, for the first time, as reported here, it is shown that beta-phase transforms to the omega-Al7Cu2Fe phase in the presence of Cu, after solutionization at 793 K. The omega-phase decomposes below 673 K resulting into the formation of theta-Al2Cu phase. However, the present thermodynamic description of the Al-Si-Fe-Cu system needs finer tuning to accurately predict the stability of the omega-phase in these alloys. In the present study, an attempt was made to enhance the strength of Al-6wt%Si-2wt%Fe model recycled cast alloy with different amount of Cu addition. Microstructural and XRD analysis were carried out in detail to show the influence of Cu and the stability range of the omega-phase. Tensile properties and micro-hardness values are also reported for both as-cast and solutionized alloys with different amount of Cu without and with ageing treatment at 473 K. The increase in strength due to addition of Cu, in Fe-rich Al-Si alloys is promising from the alloy recyclability point of view. PMID- 28720856 TI - Optimization of microfluidic biosensor efficiency by means of fluid flow engineering. AB - Binding reaction kinetics of analyte-ligand at the level of a sensitive membrane into a microchannel of a biosensor has been limited by the formation of the boundary diffusion layer. Therefore, the response time increases and affects the overall performance of a biosensor. In the present work, we develop an approach to engineer fluid streams into a complex configuration in order to improve the binding efficiency. We investigate numerically the flow deformations around a parallelepiped with square cross-section inside the microfluidic channel and exploit these deformations to simulate the analyte transport to the sensitive membrane and enhance both association and dissociation processes. The effect of several parameters on the binding reaction is provided such as: the obstacle location from the inlet of the microchannel, the average flow velocity, and the inlet analyte concentration. The optimal position of the obstacle is determined. An appropriate choice of the inlet flow velocity and inlet analyte concentration may reduce significantly the response time. PMID- 28720857 TI - Population variation in the trophic niche of the Trinidadian guppy from different predation regimes. AB - Population variation in trophic niche is widespread among organisms and is of increasing interest given its role in both speciation and adaptation to changing environments. Trinidadian guppies (Poecilia reticulata) inhabiting stream reaches with different predation regimes have rapidly evolved divergent life history traits. Here, we investigated the effects of both predation and resource availability on guppy trophic niches by evaluating their gut contents, resource standing stocks, and delta15N and delta13C stable isotopes across five streams during the wet season. We found that guppies from low predation (LP) sites had a consistently higher trophic position and proportion of invertebrates in their guts and assimilate less epilithon than guppies from high predation (HP) sites. Higher trophic position was also associated with lower benthic invertebrate availability. Our results suggest that LP guppies could be more efficient invertebrate consumers, possibly as an evolutionary response to greater intraspecific competition for higher quality food. This may be intensified by seasonality, as wet season conditions can alter resource availability, feeding rates, and the intensity of intraspecific competition. Understanding how guppy diets vary among communities is critical to elucidating the role of niche shifts in mediating the link between environmental change and the evolution of life histories. PMID- 28720858 TI - GSK-3beta deletion in dentate gyrus excitatory neuron impairs synaptic plasticity and memory. AB - Increasing evidence suggests that glycogen synthase kinase-3beta (GSK-3beta) plays a crucial role in neurodegenerative/psychiatric disorders, while pan-neural knockout of GSK-3beta also shows detrimental effects. Currently, the function of GSK-3beta in specific type of neurons is elusive. Here, we infused AAV-CaMKII-Cre 2A-eGFP into GSK-3betalox/lox mice to selectively delete the kinase in excitatory neurons of hippocampal dentate gyrus (DG), and studied the effects on cognitive/psychiatric behaviors and the molecular mechanisms. We found that mice with GSK-3beta deletion in DG excitatory neurons displayed spatial and fear memory defects with an anti-anxiety behavior. Further studies demonstrated that GSK-3beta deletion in DG subset inhibited hippocampal synaptic transmission and reduced levels of GluN1, GluN2A and GluN2B (NMDAR subunits), GluA1 (AMPAR subunit), PSD93 and drebrin (postsynaptic structural proteins), and synaptophysin (presynaptic protein). GSK-3beta deletion also suppressed the activity-dependent neural activation and calcium/calmodulin-dependent protein kinase II (CaMKII)/CaMKIV-cAMP response element binding protein (CREB) signaling. Our data suggest that GSK-3beta in hippocampal DG excitatory neurons is essential for maintaining synaptic plasticity and memory. PMID- 28720859 TI - Increased Male-Male Mounting Behaviour in Desert Locusts during Infection with an Entomopathogenic Fungus. AB - Same-sex sexual behaviour occurs across diverse animal taxa, but adaptive explanations can be difficult to determine. Here we investigate male-male mounting (MMM) behaviour in female-deprived desert locust males infected with the entomopathogenic fungus Metarhizium acridum. Over a four-week period, infected locusts performed more MMM behaviours than healthy controls. Among infected locusts, the probability of MMM, and the duration of time spent MMM, significantly increased with the mounting locust's proximity to death. In experimental trials, infected locusts were also significantly more likely than controls to attempt to mount healthy males. Therefore, we demonstrate that MMM is more frequent among infected than healthy male locusts, and propose that this may be explained by terminal reproductive effort and a lowered mate acceptance threshold in infected males. However, during experimental trials mounting attempts were more likely to be successful if the mounted locusts were experimentally manipulated to have a reduced capacity to escape. Thus, reduced escape capability resulting from infection may also contribute to the higher frequency of MMM among infected male locusts. Our data demonstrate that pathogen infection can affect same-sex sexual behaviour, and suggest that the impact of such behaviours on host and pathogen fitness will be a novel focus for future research. PMID- 28720861 TI - Prostate cancer: STAMPEDE, LATITUDE and Fernand Labrie's legacy. PMID- 28720862 TI - TRACERx Renal: tracking renal cancer evolution through therapy. PMID- 28720860 TI - Altered hippocampal volume and functional connectivity in males with Internet gaming disorder comparing to those with alcohol use disorder. AB - Internet gaming disorder (IGD) has been conceptualized as a behavioral addiction and shares clinical, neuropsychological, and personality characteristics with alcohol use disorder (AUD), but IGD dose not entail brain exposure to toxic agents, which renders it different from AUD. To achieve a clear understanding of the neurobiological features of IGD, we aimed to identify morphological and functional changes in IGD and compare them with those in AUD. Individuals with IGD showed larger volume in the hippocampus/amygdala and precuneus than healthy controls (HCs). The volume in the hippocampus positively correlated with the symptom severity of IGD. Moreover, functional connectivity analysis with the hippocampus/amygdala cluster revealed that the left ventromedial prefrontal cortex showed stronger functional connectivity in individuals with IGD compared to those with AUD. In contrast, individuals with AUD exhibited the smaller cerebellar volume and thinner medial frontal cortex than HCs. The volume in the cerebellum correlated with impaired working memory function as well as duration of illness in AUD group. Findings suggested that altered volume and functional connectivity in the hippocampus/amygdala in IGD might be associated with abnormally enhanced memory process of gaming-related cues, while abnormal cortical changes and cognitive impairments in AUD might be associated with neurotoxic effects of alcohol. PMID- 28720863 TI - Prostate cancer: Mutations in ctDNA reflect features of metastatic disease. PMID- 28720864 TI - Sexuality as a health-promoting factor - theoretical and clinical considerations. PMID- 28720865 TI - Immunology: PD-1 and PD-L1 prognostic in UTUC. PMID- 28720866 TI - Surges in trematode prevalence linked to centennial-scale flooding events in the Adriatic. AB - The forecasts of increasing global temperature and sea level rise have led to concern about the response of parasites to anthropogenic climate change. Whereas ecological studies of parasite response to environmental shifts are necessarily limited to short time scales, the fossil record can potentially provide a quantitative archive of long-term ecological responses to past climate transitions. Here, we document multi-centennial scale changes in prevalence of trematodes infesting the bivalve host Abra segmentum through multiple sea-level fluctuations preserved in brackish Holocene deposits of the Po Plain, Italy. Prevalence values were significantly elevated (p < 0.01) in samples associated with flooding surfaces, yet the temporal trends of parasite prevalence and host shell length, cannot be explained by Waltherian facies change, host availability, salinity, diversity, turnover, or community structure. The observed surges in parasite prevalence during past flooding events indicate that the ongoing global warming and sea-level rise will lead to significant intensification of trematode parasitism, suppressed fecundity of common benthic organisms, and negative impacts on marine ecosystems, ecosystem services, and, eventually, to human well being. PMID- 28720867 TI - Graphene microfiber as a scaffold for regulation of neural stem cells differentiation. AB - We report the cytocompatibility and regulating effects of the nanostructured reduced graphene oxide (rGO) microfibers, which are synthesized through a capillary hydrothermal method, on neural differentiation of neural stem cells (NSCs). Our findings indicate that the flexible, mechanically strong, surface nanoporous, biodegradable, and cytocompatible nanostructured rGO microfibers not only offer a more powerful substrate for NSCs adhesion and proliferation compared with 2D graphene film and tissue cluture plate but also regulate the NSCs differentiation into neurons and form a dense neural network surrounding the microfiber. These results illustrate the great potential of nanostructured rGO microfibers as an artificial neural tissue engineering (NTE) scaffold for nerve regeneration. PMID- 28720868 TI - Adhesion of Toxoplasma gondii tachyzoite-infected vehicle leukocytes to capillary endothelial cells triggers timely parasite egression. AB - Intracellular pathogens have numerous strategies for effective dissemination within the host. Many intracellular pathogens first infect leukocytes, which they use as a vehicle to transport them to target organs. Once at the target organ, intracellular parasite Toxoplasma gondii can cross the capillary wall in extracellular form by infecting endothelial cells. However, after egression from leukocytes, extracellular parasites face the risk of host immune attack. In this study, observation of infected mouse organs, using a method that renders tissue transparent, revealed that adhesion of tachyzoite-infected leukocytes to endothelial cells triggers immediate egression of the parasite. This signal enables the parasite to time egression from its vehicle leukocyte to coincide with arrival at a target organ, minimizing the opportunity for immune attack during the transition from a vehicle leukocyte to capillary endothelial cells. PMID- 28720869 TI - Rapid Bayesian optimisation for synthesis of short polymer fiber materials. AB - The discovery of processes for the synthesis of new materials involves many decisions about process design, operation, and material properties. Experimentation is crucial but as complexity increases, exploration of variables can become impractical using traditional combinatorial approaches. We describe an iterative method which uses machine learning to optimise process development, incorporating multiple qualitative and quantitative objectives. We demonstrate the method with a novel fluid processing platform for synthesis of short polymer fibers, and show how the synthesis process can be efficiently directed to achieve material and process objectives. PMID- 28720870 TI - Monocyte adhesion to atherosclerotic matrix proteins is enhanced by Asn-Gly-Arg deamidation. AB - Atherosclerosis arises from leukocyte infiltration and thickening of the artery walls and constitutes a major component of vascular disease pathology, but the molecular events underpinning this process are not fully understood. Proteins containing an Asn-Gly-Arg (NGR) motif readily undergo deamidation of asparagine to generate isoDGR structures that bind to integrin alphavbeta3 on circulating leukocytes. Here we report the identification of isoDGR motifs in human atherosclerotic plaque components including extracellular matrix (ECM) proteins fibronectin and tenascin C, which have been strongly implicated in human atherosclerosis. We further demonstrate that deamidation of NGR motifs in fibronectin and tenascin C leads to increased adhesion of the monocytic cell line U937 and enhanced binding of primary human monocytes, except in the presence of a alphavbeta3-blocking antibody or the alphav-selective inhibitor cilengitide. In contrast, under the same deamidating conditions monocyte-macrophages displayed only weak binding to the alternative ECM component vitronectin which lacks NGR motifs. Together, these findings confirm a critical role for isoDGR motifs in mediating leukocyte adhesion to the ECM via integrin alphavbeta3 and suggest that protein deamidation may promote the pathological progression of human atherosclerosis by enhancing monocyte recruitment to developing plaques. PMID- 28720871 TI - Localization of damage in the human leg muscles induced by downhill running. AB - We investigated localization of damage within the knee extensors (KEs) and plantar flexors (PFs) induced by downhill running (DR) by using transverse relaxation time (T2)-weighted magnetic resonance imaging (MRI). Fourteen young adults performed 45-min DR (-15% slope) at their maximal tolerable velocity. At pre- and 24, 48, and 72 h post-exercise, T2-MRI was scanned and T2 values for each muscle composing KEs and PFs at proximal, middle, and distal sites were calculated. Maximal isometric torque and rate of torque development (RTD: 0-30, 0 50, 0-100, 0-200 ms) were also measured. Maximal torque significantly decreased in KEs (14-17%) and PFs (6-8%) at 24-48 h post-exercise, with greater reductions for KEs. RTD in all phases, except for 0-200 ms in PFs, significantly decreased in KEs (11-42%) and PFs (13-23%) at least at one time point post-exercise. T2 significantly increased at several sites (3-5%) in both muscle groups at 24 and/or 48 h post-exercise. Among the T2-increased sites, the peak effect size (Cohen's d) regarding T2 change was pronounced at proximal (1.05) and middle (1.64) vastus intermedius compared to the other sites (0.72-0.77). These results suggest that DR induces damage in both KEs and PFs, and especially affects proximal-middle sites of the vastus intermedius. PMID- 28720872 TI - Associating transcription factors and conserved RNA structures with gene regulation in the human brain. AB - Anatomical subdivisions of the human brain can be associated with different neuronal functions. This functional diversification is reflected by differences in gene expression. By analyzing post-mortem gene expression data from the Allen Brain Atlas, we investigated the impact of transcription factors (TF) and RNA secondary structures on the regulation of gene expression in the human brain. First, we modeled the expression of a gene as a linear combination of the expression of TFs. We devised an approach to select robust TF-gene interactions and to determine localized contributions to gene expression of TFs. Among the TFs with the most localized contributions, we identified EZH2 in the cerebellum, NR3C1 in the cerebral cortex and SRF in the basal forebrain. Our results suggest that EZH2 is involved in regulating ZIC2 and SHANK1 which have been linked to neurological diseases such as autism spectrum disorder. Second, we associated enriched regulatory elements inside differentially expressed mRNAs with RNA secondary structure motifs. We found a group of purine-uracil repeat RNA secondary structure motifs plus other motifs in neuron related genes such as ACSL4 and ERLIN2. PMID- 28720873 TI - Bulk vs. Surface Structure of 3d Metal Impurities in Topological Insulator Bi2Te3. AB - Topological insulators have become one of the most prominent research topics in materials science in recent years. Specifically, Bi2Te3 is one of the most promising for technological applications due to its conductive surface states and insulating bulk properties. Herein, we contrast the bulk and surface structural environments of dopant ions Cr, Mn, Fe, Co, Ni, and Cu in Bi2Te3 thin films in order to further elucidate this compound. Our measurements show the preferred oxidation state and surrounding crystal environment of each 3d-metal atomic species, and how they are incorporated into Bi2Te3. We show that in each case there is a unique interplay between structural environments, and that it is highly dependant on the dopant atom. Mn impurities in Bi2Te3 purely substitute into Bi sites in a 2+ oxidation state. Cr atoms seem only to reside on the surface and are effectively not able to be absorbed into the bulk. Whereas for Co and Ni, an array of substitutional, interstitial, and metallic configurations occur. Considering the relatively heavy Cu atoms, metallic clusters are highly favourable. The situation with Fe is even more complex, displaying a mix of oxidation states that differ greatly between the surface and bulk environments. PMID- 28720874 TI - Knowledge-transfer learning for prediction of matrix metalloprotease substrate cleavage sites. AB - Matrix Metalloproteases (MMPs) are an important family of proteases that play crucial roles in key cellular and disease processes. Therefore, MMPs constitute important targets for drug design, development and delivery. Advanced proteomic technologies have identified type-specific target substrates; however, the complete repertoire of MMP substrates remains uncharacterized. Indeed, computational prediction of substrate-cleavage sites associated with MMPs is a challenging problem. This holds especially true when considering MMPs with few experimentally verified cleavage sites, such as for MMP-2, -3, -7, and -8. To fill this gap, we propose a new knowledge-transfer computational framework which effectively utilizes the hidden shared knowledge from some MMP types to enhance predictions of other, distinct target substrate-cleavage sites. Our computational framework uses support vector machines combined with transfer machine learning and feature selection. To demonstrate the value of the model, we extracted a variety of substrate sequence-derived features and compared the performance of our method using both 5-fold cross-validation and independent tests. The results show that our transfer-learning-based method provides a robust performance, which is at least comparable to traditional feature-selection methods for prediction of MMP-2, -3, -7, -8, -9 and -12 substrate-cleavage sites on independent tests. The results also demonstrate that our proposed computational framework provides a useful alternative for the characterization of sequence-level determinants of MMP substrate specificity. PMID- 28720875 TI - Ruthenium-conjugated chrysin analogues modulate platelet activity, thrombus formation and haemostasis with enhanced efficacy. AB - The constant increase in cardiovascular disease rate coupled with significant drawbacks of existing therapies emphasise the necessity to improve therapeutic strategies. Natural flavonoids exert innumerable pharmacological effects in humans. Here, we demonstrate the effects of chrysin, a natural flavonoid found largely in honey and passionflower on the modulation of platelet function, haemostasis and thrombosis. Chrysin displayed significant inhibitory effects on isolated platelets, however, its activity was substantially reduced under physiological conditions. In order to increase the efficacy of chrysin, a sulfur derivative (thio-chrysin), and ruthenium-complexes (Ru-chrysin and Ru-thio chrysin) were synthesised and their effects on the modulation of platelet function were evaluated. Indeed, Ru-thio-chrysin displayed a 4-fold greater inhibition of platelet function and thrombus formation in vitro than chrysin under physiologically relevant conditions such as in platelet-rich plasma and whole blood. Notably, Ru-thio-chrysin exhibited similar efficacy to chrysin in the modulation of haemostasis in mice. Increased bioavailability and cell permeability of Ru-thio-chrysin compared to chrysin were found to be the basis for its enhanced activity. Together, these results demonstrate that Ru-thio coupled natural compounds such as chrysin may serve as promising templates for the development of novel anti-thrombotic agents. PMID- 28720876 TI - Not performing an OGTT results in significant underdiagnosis of (pre)diabetes in a high risk adult Caucasian population. AB - OBJECTIVE: Type 2 diabetes (T2DM) is known to be underdiagnosed. Tests for diagnosis include fasting plasma glucose (FPG), oral glucose tolerance test (OGTT) and HbA1c. HbA1c can be tested in non-fasting conditions. Therefore, general practitioners almost no longer execute OGTT's. We evaluated the performance of OGTT versus HbA1c in a population consisting of overweight and obese subjects, which can be considered a 'high risk' population. RESEARCH DESIGN AND METHODS: A total of, 1241 overweight and obese subjects without a history of diabetes (male/female: 375/866, age 44+/-13 years, body mass index 38.0+/-6.1 kg m-2) were tested for glucose tolerance status using FPG, OGTT and HbA1c. RESULTS: Exactly, 46.8% were found to have prediabetes and 11.9% were newly diagnosed with T2DM (male/female=18.9/8.9%) using ADA criteria. Testing only HbA1c would have resulted in 78 subjects being diagnosed with T2DM, but 47.3% of newly diagnosed patients would have been missed if OGTT would not have been done. Exactly 581 subjects were diagnosed with prediabetes, 1.4% subjects had impaired fasting glucose (IFG) 30.5% had impaired glucose tolerance (IGT), 5.1% subjects had a combined IFG+IGT, and 9.8% had an isolated elevated HbA1c (5.7-6.4%). Of the 581 subjects with prediabetes, 257 had an HbA1c <5.7%. Therefore, 44.2% subjects would have been missed when OGTT would not have been done. CONCLUSION: In a population with only overweight and obese adult subjects, 46.8% were diagnosed with prediabetes and 11.9% were newly diagnosed with diabetes. Exactly, 5.6 and 20.7% of total population met the diagnostic criteria of the OGTT for diabetes and prediabetes, respectively, but did not meet the diagnostic criteria of the HbA1c. These data suggest that not performing an OGTT results in significant underdiagnose of T2DM in an overweight and obese adult population. PMID- 28720877 TI - Role of the histone deacetylase inhibitor valproic acid in high-fat diet-induced hypertension via inhibition of HDAC1/angiotensin II axis. AB - BACKGROUND: Obesity is known as an epidemic worldwide because of consumption of westernized high-fat diets and one of the major risk factors of hypertension. Histone deacetylases (HDACs) control gene expression by regulating histone/non histone protein deacetylation. HDAC inhibitors exert anti-cancer and anti inflammatory effects and play a protective role in cardiovascular diseases. In the present study, we tested the effect of an FDA-approved pan-HDAC inhibitor valproic acid (VPA) on high-fat diet (HFD)-induced hypertension in mice. Furthermore, we examined the mechanism of VPA-induced prevention of hypertension. METHODS: Nine-week-old male C57BL/6 mice were fed either a normal diet (ND) or HFD. When the HFD group reached a pre-hypertensive phase (130-140 mm Hg systolic blood pressure), VPA was administered for 6 days (300 mg kg-1 per day). Body weights and blood pressure (BP), expression of renin-angiotensin system (RAS) components and HDAC1 were determined. The direct role of HDAC1 in the expression of RAS components was investigated using gene silencing. RESULTS: HFD accelerated the increase in body weight from 22.4+/-1.3 to 31.9+/-3.0 compared to in the ND group from 22.7+/-0.9 to 26.0+/-1.7 (P=0.0134 ND vs HFD), systolic BP from 118.5+/-5.7 to 145.0+/-3.0 (P<0.001), and diastolic BP from 91.0+/-13.6 to 121.0+/-5.0 (P=0.006); BP was not altered in the ND group. HFD increased RAS components and HDAC1 in the kidneys as well as leptin in the plasma. VPA administration prevented the progression of hypertension and inhibited the increase in expression of HDAC1 and RAS components. VPA did not affect plasma leptin level. Knockdown of HDAC1 in MDCK cells decreased the expression of angiotensinogen and type 1 angiotensin II receptor. CONCLUSIONS: VPA prevented HFD-induced hypertension by downregulating angiotensin II and its receptor via inhibition of HDAC1, offering a novel therapeutic option for HFD-induced hypertension. PMID- 28720878 TI - Comparison of DNA-, PMA-, and RNA-based 16S rRNA Illumina sequencing for detection of live bacteria in water. AB - The limitation of 16S rRNA gene sequencing (DNA-based) for microbial community analyses in water is the inability to differentiate live (dormant cells as well as growing or non-growing metabolically active cells) and dead cells, which can lead to false positive results in the absence of live microbes. Propidium monoazide (PMA) has been used to selectively remove DNA from dead cells during downstream sequencing process. In comparison, 16S rRNA sequencing (RNA-based) can target live microbial cells in water as both dormant and metabolically active cells produce rRNA. The objective of this study was to compare the efficiency and sensitivity of DNA-based, PMA-based and RNA-based 16S rRNA Illumina sequencing methodologies for live bacteria detection in water samples experimentally spiked with different combination of bacteria (2 gram-negative and 2 gram-positive/acid fast species either all live, all dead, or combinations of live and dead species) or obtained from different sources (First Nation community drinking water; city of Winnipeg tap water; water from Red River, Manitoba, Canada). The RNA-based method, while was superior for detection of live bacterial cells still identified a number of 16S rRNA targets in samples spiked with dead cells. In environmental water samples, the DNA- and PMA-based approaches perhaps overestimated the richness of microbial community compared to RNA-based method. Our results suggest that the RNA-based sequencing was superior to DNA- and PMA-based methods in detecting live bacterial cells in water. PMID- 28720879 TI - Microwave Tunable Metamaterial Based on Semiconductor-to-Metal Phase Transition. AB - A microwave tunable metamaterial utilizing the semiconductor-to-metal transition of vanadium dioxide (VO2) is proposed, experimentally demonstrated and theoretically scrutinized. Basic concept of the design involves the combination of temperature-dependent hysteresis in VO2 with resonance induced heating, resulting in a nonlinear response to power input. A lithographically prepared gold split-rings resonator (SRR) array deposited with VO2 thin film is fabricated. Transmission spectra analysis shows a clear manifestation of nonlinearity, involving power-dependence of resonant frequency as well as transmitted intensity at both elevated and room temperature. Simulation performed with CST Microwave Studio conforms with the findings. The concept may find applications in transmission modulation and frequency tuning devices working under microwave frequency bands. PMID- 28720880 TI - Pattern of retinal morphological and functional decay in a light-inducible, rhodopsin mutant mouse. AB - Hallmarks of Retinitis Pigmentosa (RP), a family of genetic diseases, are a typical rod-cone-degeneration with initial night blindness and loss of peripheral vision, followed by decreased daylight sight and progressive visual acuity loss up to legal blindness. Great heterogeneity in nature and function of mutated genes, variety of mutations for each of them, variability in phenotypic appearance and transmission modality contribute to make RP a still incurable disease. Translational research relies on appropriate animal models mimicking the genetic and phenotypic diversity of the human pathology. Here, we provide a systematic, morphological and functional analysis of RhoTvrm4/Rho+ rhodopsin mutant mice, originally described in 2010 and portraying several features of common forms of autosomal dominant RP caused by gain-of-function mutations. These mice undergo photoreceptor degeneration only when exposed briefly to strong, white light and allow controlled timing of induction of rod and cone death, which therefore can be elicited in adult animals, as observed in human RP. The option to control severity and retinal extent of the phenotype by regulating intensity and duration of the inducing light opens possibilities to exploit this model for multiple experimental purposes. Altogether, the unique features of this mutant make it an excellent resource for retinal degeneration research. PMID- 28720881 TI - Patients with Orthostatic Intolerance: Relationship to Autonomic Function Tests results and Reproducibility of Symptoms on Tilt. AB - This study was designed to investigate the frequency and pattern of orthostatic symptoms during head-up tilt (HUT) in patients with orthostatic intolerance during daily life, and to identify the relationship between the orthostatic symptoms during HUT and autonomic parameters. We prospectively collected autonomic data from 464 patients with orthostatic symptoms. Adrenergic and cardiovagal function tests including HUT were performed. Based on HUT results, we divided patients into orthostatic hypotension (OH), postural tachycardia syndrome (POTS), or normal HUT groups. We also investigated orthostatic symptoms during HUT. Only 25% of the patients reported orthostatic symptoms during HUT and 75% were asymptomatic. Typical orthostatic symptoms such as orthostatic dizziness and blurred vision, and atypical symptoms like chest tightness and headache occurred in 86% and 66%, respectively. Patients with POTS had symptoms more frequently than patients with OH during HUT. There were no differences in degrees of BP or HR changes between symptomatic and asymptomatic groups within the OH and POTS groups. HUT fails to reproduce symptoms of orthostatic intolerance in the majority of patients. Clinicians need to be aware that most patients with OH are asymptomatic during HUT and patients with POTS are more likely to be symptomatic than patients with OH. PMID- 28720882 TI - Cell-type specific differences in promoter activity of the ALS-linked C9orf72 mouse ortholog. AB - A hexanucleotide repeat expansion in the C9orf72 gene is the most common cause of inherited forms of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Both loss-of-function and gain-of-function mechanisms have been proposed to underlie this disease, but the pathogenic pathways are not fully understood. To better understand the involvement of different cell types in the pathogenesis of ALS, we systematically analyzed the distribution of promoter activity of the mouse ortholog of C9orf72 in the central nervous system. We demonstrate that C9orf72 promoter activity is widespread in both excitatory and inhibitory neurons as well as in oligodendrocytes and oligodendrocyte precursor cells. In contrast, few microglia and astrocytes exhibit detectable C9orf72 promoter activity. Although at a gross level, the distribution of C9orf72 promoter activity largely follows overall cellular density, we found that it is selectively enriched in subsets of neurons and glial cells that degenerate in ALS. Specifically, we show that C9orf72 promoter activity is enriched in corticospinal and spinal motor neurons as well as in oligodendrocytes in brain regions that are affected in ALS. These results suggest that cell autonomous changes in both neurons and glia may contribute to C9orf72-mediated disease, as has been shown for mutations in superoxide dismutase-1 (SOD1). PMID- 28720883 TI - Chronic high-sodium diet intake after weaning lead to neurogenic hypertension in adult Wistar rats. AB - In this study, we investigated some mechanisms involved in sodium-dependent hypertension of rats exposed to chronic salt (NaCl) intake from weaning until adult age. Weaned male Wistar rats were placed under high (0.90% w/w, HS) or regular (0.27% w/w, Cont) sodium diets for 12 weeks. Water consumption, urine output and sodium excretion were higher in HS rats compared to control. Blood pressure (BP) was directly measured by the arterial catheter and found 13.8% higher in HS vs Cont rats. Ganglionic blockade with hexamethonium caused greater fall in the BP of HS rats (33%), and central antagonism of AT1 receptors (losartan) microinjected into the lateral ventricle reduced BP level of HS, but not of Cont group. Heart rate variability analysis revealed sympathetic prevalence on modulation of the systolic interval. HS diet did not affect creatinine clearance. Kidney histological analysis revealed no significant change in renal corpuscle structure. Sodium and potassium concentrations in CSF were found higher in HS rats despite no change in plasma concentration of these ions. Taken together, data suggest that animals exposed to chronic salt intake to a level close to that reported for human' diet since weaning lead to hypertension, which appears to rely on sodium-driven neurogenic mechanisms. PMID- 28720885 TI - Two-photon interference of polarization-entangled photons in a Franson interferometer. AB - We present two-photon interference experiments with polarization-entangled photon pairs in a polarization-based Franson-type interferometer. Although the two photons do not meet at a common beamsplitter, a phase-insensitive Hong-Ou-Mandel type two-photon interference peak and dip fringes are observed, resulting from the two-photon interference effect between two indistinguishable two-photon probability amplitudes leading to a coincidence detection. A spatial quantum beating fringe is also measured for nondegenerate photon pairs in the same interferometer, although the two-photon states have no frequency entanglement. When unentangled polarization-correlated photons are used as an input state, the polarization entanglement is successfully recovered through the interferometer via delayed compensation. PMID- 28720884 TI - Molecular tools for GABAA receptors: High affinity ligands for beta1-containing subtypes. AB - gamma-Aminobutyric acid type A (GABAA) receptors are pentameric GABA-gated chloride channels that are, in mammalians, drawn from a repertoire of 19 different genes, namely alpha1-6, beta1-3, gamma1-3, delta, epsilon, theta, pi and rho1-3. The existence of this wide variety of subunits as well as their diverse assembly into different subunit compositions result in miscellaneous receptor subtypes. In combination with the large number of known and putative allosteric binding sites, this leads to a highly complex pharmacology. Recently, a novel binding site at extracellular alpha+/beta- interfaces was described as the site of modulatory action of several pyrazoloquinolinones. In this study we report a highly potent ligand from this class of compounds with pronounced beta1 selectivity that mainly lacks alpha-subunit selectivity. It constitutes the most potent beta1-selective positive allosteric modulatory ligand with known binding site. In addition, a proof of concept pyrazoloquinolinone ligand lacking the additional high affinity interaction with the benzodiazepine binding site is presented. Ultimately, such ligands can be used as invaluable molecular tools for the detection of beta1-containing receptor subtypes and the investigation of their abundance and distribution. PMID- 28720886 TI - Spatio-temporal variations of typhoid and paratyphoid fevers in Zhejiang Province, China from 2005 to 2015. AB - Typhoid and paratyphoid are two common enteric infectious diseases with serious gastrointestinal symptoms. Data was collected of the registered cases in Zhejiang Province from 2005 to 2015. The epidemiological characteristics were investigated and high-risk regions were detected with descriptive epidemiological methods and in-depth spatio-temporal statistics. A sharp decline in the incidences of both diseases was observed. The seasonal patterns were identified with typhoid and paratyphoid, one in summer from May to September was observed from 2005 to 2010 and the other lesser one in spring from January to March only observed from 2005 to 2007. The men were more susceptible and the adults aged 20 to 60 constituted the major infected population. The farmers were more likely to get infected, especially to typhoid. The Wilcoxon sum rank test proved that the incidences in the coastal counties were significantly higher than the inland. Besides, a positive autocorrelation was obtained with typhoid fever in global autocorrelation analysis but not with paratyphoid fever. Local autocorrelation analysis and spatio-temporal scan statistics revealed that high-risk clusters were located mainly in the coastal regions with typhoid fever but scattered across the province with paratyphoid fever. The spatial risks were evaluated quantitatively with hierarchical Bayesian models. PMID- 28720887 TI - Olfactory bulb plasticity ensures proper olfaction after severe impairment in postnatal neurogenesis. AB - The olfactory bulb (OB) neurons establish a complex network that ensures the correct processing of the olfactory inputs. Moreover, the OB presents a lifelong addition of new neurons into its existing circuitry. This neurogenesis is considered essential for the OB function. However, its functional impact on physiology and behavior is still unclear. Here, we investigate the mechanisms of OB plasticity that underlie bulbar physiology in relation to severe damage of neurogenesis. The neurogenesis of young mice was altered by ionizing radiation. Afterwards, both multi-channel olfactometry and electrophysiological studies were performed. Furthermore, neurogenesis and differentiation of the newly formed cells were assessed using bromodeoxyuridine labeling combined with a wide battery of neuronal markers. Our results demonstrate a reduction in both neurogenesis and volume of the OB in irradiated animals. The number of neuroblasts reaching the OB was reduced and their differentiation rate into interneurons selectively changed; some populations were noticeably affected whereas others remained preserved. Surprisingly, both olfactory detection and discrimination as well as electrophysiology presented almost no alterations in irradiated mice. Our findings suggest that after damaging postnatal neurogenesis, the neurochemical fate of some interneurons changes within a new biological scenario, while maintaining homeostasis and olfaction. PMID- 28720888 TI - Bivalent DNA vaccine induces significant immune responses against infectious hematopoietic necrosis virus and infectious pancreatic necrosis virus in rainbow trout. AB - Infectious hematopoietic necrosis virus (IHNV) and infectious pancreatic necrosis virus (IPNV) are important pathogens of salmon and trout. An active bivalent DNA vaccine was constructed with the glycoprotein gene of Chinese IHNV isolate Sn1203 and VP2-VP3 gene of Chinese IPNV isolate ChRtm213. Rainbow trout (5 g) were vaccinated by intramuscular injection with 1.0 ug of the bivalent DNA vaccine and then challenged with an intraperitoneal injection of IHNV, IPNV, or both, at 30 and 60 days post-vaccination (d.p.v.). High protection rates against IHNV were observed, with 6% and 10% cumulative mortality, respectively, compared with 90 94% in the mock-vaccinated groups. IPNV loads (531-fold and 135-fold, respectively) were significantly reduced in the anterior kidneys of the vaccinated trout. Significant protection against co-infection with IHNV and IPNV was observed, with cumulative mortality rates of 6.67% and 3.33%, respectively, compared with 50.0% and 43.3%, respectively, in the mock-vaccinated groups. No detectable infective IHNV or IPNV was recovered from vaccinated trout co-infected with IHNV and IPNV. The bivalent DNA vaccine increased the expression of Mx-1 and IFN-gamma at 4, 7, and 15 d.p.v, and IgM at 21 d.p.v., and induced high titres (>=160) of IHNV and IPNV neutralizing antibodies at 30 and 60 d.p.v. PMID- 28720889 TI - Acquisition of terrestrial life by human ancestors influenced by forest microclimate. AB - Bipedalism, terrestriality and open habitat were thought to be linked to each other in the course of human evolution. However, recent paleontological evidence has revealed that early hominins evolved in a wooded, humid environment. Did the evolutionary process from arboreal to terrestrial life actually require open habitat? Here I report the seasonal change in forest utilization height of West African chimpanzees (Pan troglodytes) and central African bonobos (Pan paniscus), and show that the difference in terrestriality between these two species was mainly caused by ambient temperature differences between the two study sites. The key factor was the vertical structure of the microclimate in forests and its seasonality. The results suggest the possibility that human terrestrial life began inside a forest rather than in the savannah. Increasing seasonality and prolongation of the dry months throughout the late Miocene epoch alone could have promoted terrestrial life of our human ancestors. PMID- 28720890 TI - Iron overload exacerbates age-associated cardiac hypertrophy in a mouse model of hemochromatosis. AB - Cardiac damage associated with iron overload is the most common cause of morbidity and mortality in patients with hereditary hemochromatosis, but the precise mechanisms leading to disease progression are largely unexplored. Here we investigated the effects of iron overload and age on cardiac hypertrophy using 1 , 5- and 12-month old Hfe-deficient mice, an animal model of hemochromatosis in humans. Cardiac iron levels increased progressively with age, which was exacerbated in Hfe-deficient mice. The heart/body weight ratios were greater in Hfe-deficient mice at 5- and 12-month old, compared with their age-matched wild type controls. Cardiac hypertrophy in 12-month old Hfe-deficient mice was consistent with decreased alpha myosin and increased beta myosin heavy chains, suggesting an alpha-to-beta conversion with age. This was accompanied by cardiac fibrosis and up-regulation of NFAT-c2, reflecting increased calcineurin/NFAT signaling in myocyte hypertrophy. Moreover, there was an age-dependent increase in the cardiac isoprostane levels in Hfe-deficient mice, indicating elevated oxidative stress. Also, rats fed high-iron diet demonstrated increased heart-to body weight ratios, alpha myosin heavy chain and cardiac isoprostane levels, suggesting that iron overload promotes oxidative stress and cardiac hypertrophy. Our findings provide a molecular basis for the progression of age-dependent cardiac stress exacerbated by iron overload hemochromatosis. PMID- 28720892 TI - Dual-band wide-angle metamaterial perfect absorber based on the combination of localized surface plasmon resonance and Helmholtz resonance. AB - In this article, a dual-band wide-angle metamaterial perfect absorber is proposed to achieve absorption at the wavelength where laser radar operates. It is composed of gold ring array and a Helmholtz resonance cavity spaced by a Si dielectric layer. Numerical simulation results reveal that the designed absorber displays two absorption peaks at the target wavelength of 10.6 MUm and 1.064 MUm with the large frequency ratio and near-unity absorptivity under the normal incidence. The wide-angle absorbing property and the polarization-insensitive feature are also demonstrated. Localized surface plasmons resonance and Helmholtz resonance are introduced to analyze and interpret the absorbing mechanism. The designed perfect absorber can be developed for potential applications in infrared stealth field. PMID- 28720891 TI - Whole exome sequencing reveals inherited and de novo variants in autism spectrum disorder: a trio study from Saudi families. AB - Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with genetic and clinical heterogeneity. The interplay of de novo and inherited rare variants has been suspected in the development of ASD. Here, we applied whole exome sequencing (WES) on 19 trios from singleton Saudi families with ASD. We developed an analysis pipeline that allows capturing both de novo and inherited rare variants predicted to be deleterious. A total of 47 unique rare variants were detected in 17 trios including 38 which are newly discovered. The majority were either autosomal recessive or X-linked. Our pipeline uncovered variants in 15 ASD-candidate genes, including 5 (GLT8D1, HTATSF1, OR6C65, ITIH6 and DDX26B) that have not been reported in any human condition. The remaining variants occurred in genes formerly associated with ASD or other neurological disorders. Examples include SUMF1, KDM5B and MXRA5 (Known-ASD genes), PRODH2 and KCTD21 (implicated in schizophrenia), as well as USP9X and SMS (implicated in intellectual disability). Consistent with expectation and previous studies, most of the genes implicated herein are enriched for biological processes pertaining to neuronal function. Our findings underscore the private and heterogeneous nature of the genetic architecture of ASD even in a population with high consanguinity rates. PMID- 28720893 TI - Nanoplasmonic fiber tip probe detects significant reduction of intracellular Alzheimer's disease-related oligomers by curcumin. AB - Considerable evidence shows critical roles of intracellular pathogenic events of Alzheimer's disease (AD). In particular, intracellular amyloid-beta accumulation and oligomerization are early AD pathologic processes, which may lead to changes in inflammatory molecules and other AD-related pathological components. Curcumin and its analogs have been identified as potential drug candidates for AD. However, the effects of curcumin on intracellular AD pathologic processes remain largely unknown. Here we utilized a recently developed nanoplasmonic fiber tip probe (nFTP) technology and investigated whether curcumin leads to intracellular AD pathologic changes. We showed that our nFTP technology could robustly detect intracellular AD-related protein changes caused by a well-known inflammation inducer and a familial AD mutation. Intriguingly, curcumin remarkably reduced the level of intracellular oligomers while modestly reduced the level of an inflammatory cytokine. Thus, our results provided evidence that curcumin's mechanism of action in attenuating AD pathology is through a major role of decreasing oligomerization. PMID- 28720894 TI - Coronavirus nucleocapsid proteins assemble constitutively in high molecular oligomers. AB - Coronaviruses (CoV) are enveloped viruses and rely on their nucleocapsid N protein to incorporate the positive-stranded genomic RNA into the virions. CoV N proteins form oligomers but the mechanism and relevance underlying their multimerization remain to be fully understood. Using in vitro pull-down experiments and density glycerol gradients, we found that at least 3 regions distributed over its entire length mediate the self-interaction of mouse hepatitis virus (MHV) and severe acute respiratory syndrome coronavirus (SARS CoV) N protein. The fact that these regions can bind reciprocally between themselves provides a possible molecular basis for N protein oligomerization. Interestingly, cytoplasmic N molecules of MHV-infected cells constitutively assemble into oligomers through a process that does not require binding to genomic RNA. Based on our data, we propose a model where constitutive N protein oligomerization allows the optimal loading of the genomic viral RNA into a ribonucleoprotein complex via the presentation of multiple viral RNA binding motifs. PMID- 28720895 TI - Rapid Response of Eastern Mediterranean Deep Sea Microbial Communities to Oil. AB - Deep marine oil spills like the Deepwater Horizon (DWH) in the Gulf of Mexico have the potential to drastically impact marine systems. Crude oil contamination in marine systems remains a concern, especially for countries around the Mediterranean Sea with off shore oil production. The goal of this study was to investigate the response of indigenous microbial communities to crude oil in the deep Eastern Mediterranean Sea (E. Med.) water column and to minimize potential bias associated with storage and shifts in microbial community structure from sample storage. 16S rRNA amplicon sequencing was combined with GeoChip metagenomic analysis to monitor the microbial community changes to the crude oil and dispersant in on-ship microcosms set up immediately after water collection. After 3 days of incubation at 14 degrees C, the microbial communities from two different water depths: 824 m and 1210 m became dominated by well-known oil degrading bacteria. The archaeal population and the overall microbial community diversity drastically decreased. Similarly, GeoChip metagenomic analysis revealed a tremendous enrichment of genes related to oil biodegradation, which was consistent with the results from the DWH oil spill. These results highlight a rapid microbial adaption to oil contamination in the deep E. Med., and indicate strong oil biodegradation potential. PMID- 28720896 TI - Nanoscale Control of Amyloid Self-Assembly Using Protein Phase Transfer by Host Guest Chemistry. AB - Amyloid fibrils have recently been highlighted for their diverse applications as functional nanomaterials in modern chemistry. However, tight control to obtain a targeted fibril length with low heterogeneity has not been achieved because of the complicated nature of amyloid fibrillation. Herein, we demonstrate that fibril assemblies can be homogeneously manipulated with desired lengths from ~40 nm to ~10 MUm by a phase transfer of amyloid proteins based on host-guest chemistry. We suggest that host-guest interactions with cucurbit[6]uril induce a phase transfer of amyloid proteins (human insulin, human islet amyloid polypeptide, hen egg lysozyme, and amyloid-beta 1-40 & 1-42) from the soluble state to insoluble state when the amount of cucurbit[6]uril exceeds its solubility limit in solution. The phase transfer of the proteins kinetically delays the nucleation of amyloid proteins, while the nuclei formed in the early stage are homogeneously assembled to fibrils. Consequently, supramolecular assemblies of amyloid proteins with heterogeneous kinetics can be controlled by protein phase transfer based on host-guest interactions. PMID- 28720897 TI - A Predictive Mathematical Modeling Approach for the Study of Doxorubicin Treatment in Triple Negative Breast Cancer. AB - Doxorubicin forms the basis of chemotherapy regimens for several malignancies, including triple negative breast cancer (TNBC). Here, we present a coupled experimental/modeling approach to establish an in vitro pharmacokinetic/pharmacodynamic model to describe how the concentration and duration of doxorubicin therapy shape subsequent cell population dynamics. This work features a series of longitudinal fluorescence microscopy experiments that characterize (1) doxorubicin uptake dynamics in a panel of TNBC cell lines, and (2) cell population response to doxorubicin over 30 days. We propose a treatment response model, fully parameterized with experimental imaging data, to describe doxorubicin uptake and predict subsequent population dynamics. We found that a three compartment model can describe doxorubicin pharmacokinetics, and pharmacokinetic parameters vary significantly among the cell lines investigated. The proposed model effectively captures population dynamics and translates well to a predictive framework. In a representative cell line (SUM-149PT) treated for 12 hours with doxorubicin, the mean percent errors of the best-fit and predicted models were 14% (+/-10%) and 16% (+/-12%), which are notable considering these statistics represent errors over 30 days following treatment. More generally, this work provides both a template for studies quantitatively investigating treatment response and a scalable approach toward predictions of tumor response in vivo. PMID- 28720898 TI - Balance training improves memory and spatial cognition in healthy adults. AB - Physical exercise has been shown to improve cognitive functions. However, it is still unknown which type of exercise affects cognition. In the present study, we tested the hypothesis that a demanding balance training program improves memory and spatial cognition. Forty healthy participants aged 19-65 years were randomly assigned to either a balance or relaxation training intervention. Each group exercised twice a week for a total of 12 weeks. Pre- and posttests assessed balance performance, cardiorespiratory fitness, memory, spatial cognition, and executive functions. Only the balance group significantly increased in balance performance from pre- to posttest, while cardiorespiratory fitness remained unchanged in both groups. Moreover, the balance group significantly improved in memory and spatial cognition. Effects on executive functions were not observed. These results suggest that balance training is capable of improving particularly memory and spatial cognition. Therefore, an increase in cardiorespiratory fitness does not seem to be necessary to induce beneficial effects of physical exercise on cognition. It might be speculated that stimulating the vestibular system during balance training induces changes of the hippocampus and parietal cortex possibly via direct pathways between the vestibular system and these brain regions. PMID- 28720899 TI - p32 heterozygosity protects against age- and diet-induced obesity by increasing energy expenditure. AB - Obesity is increasing in prevalence and has become a global public health problem. The main cause of obesity is a perturbation in energy homeostasis, whereby energy intake exceeds energy expenditure. Although mitochondrial dysfunction has been linked to the deregulation of energy homeostasis, the precise mechanism is poorly understood. Here, we identify mitochondrial p32 (also known as C1QBP) as an important regulator of lipid homeostasis that regulates both aerobic and anaerobic energy metabolism. We show that while whole-body deletion of the p32 results in an embryonic lethal phenotype, mice heterozygous for p32 are resistant to age- and high-fat diet-induced ailments, including obesity, hyperglycemia, and hepatosteatosis. Notably, p32 +/- mice are apparently healthy, demonstrate an increased lean-to-fat ratio, and show dramatically improved insulin sensitivity despite prolonged high-fat diet feeding. The p32 +/- mice show increased oxygen consumption and heat production, indicating that they expend more energy. Our analysis revealed that haploinsufficiency for p32 impairs glucose oxidation, which results in a compensatory increase in fatty acid oxidation and glycolysis. These metabolic alterations increase both aerobic and anaerobic energy expenditure. Collectively, our data show that p32 plays a critical role in energy homeostasis and represents a potential novel target for the development of anti-obesity drugs. PMID- 28720900 TI - Low-frequency ultrasound-induced VEGF suppression and synergy with dendritic cell mediated anti-tumor immunity in murine prostate cancer cells in vitro. AB - High tumor vascular endothelial growth factor (VEGF) levels are associated with poor treatment outcomes in prostate cancer (PCa), and immune deficiency in the PCa microenvironment, especially suppression of dendritic cell (DC) proliferation, has been confirmed. In this study, we (1) investigated whether VEGF participates in DC suppression in murine PCa cells (RM-1), (2) down regulated VEGF expression using low-frequency ultrasound and microbubbles (UM), and (3) further explored any synergistic effect on immunological activation. DCs from the bone marrow of BALB/c mice were stimulated by the addition of cytokines (granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL 4)), and we analyzed their proliferation status via flow cytometric recognition of the surface antigen markers CD11c and CD83. The results demonstrated that co culture with RM-1 cells markedly inhibited expression of the general marker CD11c and the mature marker CD83; UM weakened this inhibition by down-regulating VEGF expression. T lymphocytes were extracted from murine spleens, and CD4 and CD8a were identified as the biomarkers of activated cells participating in the anti tumor immune response. When DCs, T lymphocytes and RM-1 cells were co-cultured, cell migration and invasion assays and cytoactive detection showed that UM could not only directly suppress PCa cell evolution but also promote activation of anti tumor immunocytes in the VEGF-inhibited microenvironment. PMID- 28720901 TI - A novel connection between the Cell Wall Integrity and the PKA pathways regulates cell wall stress response in yeast. AB - Fungal cells trigger adaptive mechanisms to survive in situations that compromise cell wall integrity. We show here that the global transcriptional response elicited by inhibition of the synthesis of beta-1,3-glucan by caspofungin, encompasses a set of genes that are dependent on Slt2, the MAPK of the Cell Wall Integrity (CWI) pathway, and a broad group of genes regulated independently of Slt2. Genes negatively regulated by the cyclic AMP/Protein Kinase A (PKA) signaling pathway were overrepresented in the latter group. Moreover, cell wall stress mediated by inhibition of beta-1,3-glucan synthesis, but not by other cell wall interfering compounds, negatively regulated PKA signaling as indicated by the nuclear localisation of Msn2, cellular glycogen accumulation, a decrease of intracellular cAMP levels and a severe decrease in both the activation of the small GTPase Ras2 and the phosphorylation of known substrates of PKA. All these effects relied on the plasma membrane-spanning sensor of the CWI pathway Wsc1. In addition, caspofungin induced a reduction in the cytosolic pH, which was dependent on the extracellular region of Wsc1. Therefore, alterations of the beta 1,3-glucan network in the fungal cell wall, induce, through Wsc1, the activation of the CWI pathway and parallel inhibition of PKA signaling. PMID- 28720902 TI - Comparative genomic analysis of Paenibacillus sp. SSG-1 and its closely related strains reveals the effect of glycometabolism on environmental adaptation. AB - The extensive environmental adaptability of the genus Paenibacillus is related to the enormous diversity of its gene repertoires. Paenibacillus sp. SSG-1 has previously been reported, and its agar-degradation trait has attracted our attention. Here, the genome sequence of Paenibacillus sp. SSG-1, together with 76 previously sequenced strains, was comparatively studied. The results show that the pan-genome of Paenibacillus is open and indicate that the current taxonomy of this genus is incorrect. The incessant flux of gene repertoires resulting from the processes of gain and loss largely contributed to the difference in genomic content and genome size in Paenibacillus. Furthermore, a large number of genes gained are associated with carbohydrate transport and metabolism. It indicates that the evolution of glycometabolism is a key factor for the environmental adaptability of Paenibacillus species. Interestingly, through horizontal gene transfer, Paenibacillus sp. SSG-1 acquired an approximately 150 kb DNA fragment and shows an agar-degrading characteristic distinct from most other non-marine bacteria. This region may be transported in bacteria as a complete unit responsible for agar degradation. Taken together, these results provide insights into the evolutionary pattern of Paenibacillus and have implications for studies on the taxonomy and functional genomics of this genus. PMID- 28720903 TI - Pharmacological Modulation of 5-HT2C Receptor Activity Produces Bidirectional Changes in Locomotor Activity, Responding for a Conditioned Reinforcer, and Mesolimbic DA Release in C57BL/6 Mice. AB - Converging lines of behavioral, electrophysiological, and biochemical evidence suggest that 5-HT2C receptor signaling may bidirectionally influence reward related behavior through an interaction with the mesolimbic dopamine (DA) system. Here we directly test this hypothesis by examining how modulating 5-HT2C receptor activity affects DA-dependent behaviors and relate these effects to changes in nucleus accumbens (NAc) DA release. In C57BL/6 mice, locomotor activity and responding for a conditioned reinforcer (CRf), a measure of incentive motivation, were examined following treatment with three 5-HT2C receptor ligands: the agonist CP809101 (0.25-3 mg/kg), the antagonist SB242084 (0.25-1 mg/kg), or the antagonist/inverse agonist SB206553 (1-5 mg/kg). We further tested whether doses of these compounds that changed locomotor activity and responding for a CRf (1 mg/kg CP809101, 0.5 mg/kg SB242084, or 2.5 mg/kg SB206553) also altered NAc DA release using in vivo microdialysis in anesthetized mice. CP809101 reduced locomotor activity, responding for a CRf, and NAc DA release. In contrast, both SB242084 and SB206553 enhanced locomotor activity, responding for a CRf, and NAc DA release, although higher doses of SB206553 produced opposite behavioral effects. Pretreatment with the non-selective DA receptor antagonist alpha flupenthixol prevented SB242084 from enhancing responding for a CRf. Thus blocking tonic 5-HT2C receptor signaling can release serotonergic inhibition of mesolimbic DA activity and enhance reward-related behavior. The observed bidirectional effects of 5-HT2C receptor ligands may have important implications when considering the 5-HT2C receptor as a therapeutic target for psychiatric disorders, particularly those presenting with motivational dysfunctions. PMID- 28720904 TI - Interaction between trait and housing condition produces differential decision making toward risk choice in a rat gambling task. AB - Poor decision-making is a core problem in psychiatric disorders such as pathological gambling and substance abuse. Both trait and environmental factors are considerably important to affect decision-making. However, it has not yet been systematically shown how they interact to affect risk preference in animal models evaluating decision-making. Here, we trained rats, housed in pairs or in isolation, in a touch screen chamber to detect the association between four different light signals on the screen and accompanied reward and punishment outcomes arranged with different schedules. Then, the rats were allowed to freely choose from 4 different light signals. Once animals showed a stabilized pattern of preference (risk-averse or risk-seeking), they were injected with saline or cocaine (a single injection per day for 7 days) followed by 2 weeks of withdrawal. Then, their preference of choice was re-tested in the touch screen chamber while they were cocaine challenged. All rats significantly changed their preference toward more risky choices when they were exposed to and challenged with cocaine, except those in the risk-averse/isolated housing group. These results indicate that the pre-existing trait toward risk and the housing condition interact to affect the quality of decision-making, and cocaine may help to aggravate this process. PMID- 28720905 TI - Antiplasmodial Ealapasamines A-C,'Mixed' Naphthylisoquinoline Dimers from the Central African Liana Ancistrocladus ealaensis. AB - Three unusual heterodimeric naphthylisoquinoline alkaloids, named ealapasamines A C (1-3), were isolated from the leaves of the tropical plant Ancistrocladus ealaensis J. Leonard. These 'mixed', constitutionally unsymmetric dimers are the first stereochemically fully assigned cross-coupling products of a 5,8'- and a 7,8'-coupled naphthylisoquinoline linked via C-6' in both naphthalene portions. So far, only two other West and Central Ancistrocladus species were known to produce dimers with a central 6,6"-axis, yet, in contrast to the ealapasamines, usually consisting of two 5,8'-coupled monomers, like e.g., in michellamine B. The new dimers 1-3 contain six elements of chirality, four stereogenic centers and the two outer axes, while the central biaryl axis is configurationally unstable. The elucidation of the complete stereostructures of the ealapasamines was achieved by the interplay of spectroscopic methods including HRESIMS, 1D and 2D NMR (in particular ROESY measurements), in combination with chemical (oxidative degradation) and chiroptical (electronic circular dichroism) investigations. The ealapasamines A-C display high antiplasmodial activities with excellent half-maximum inhibition concentration values in the low nanomolar range. PMID- 28720906 TI - Trail (TNF-related apoptosis-inducing ligand) induces an inflammatory response in human adipocytes. AB - High serum concentrations of TNF-related apoptosis-inducing ligand (TRAIL), a member of the tumor necrosis factor protein family, are found in patients with increased BMI and serum lipid levels. In a model of murine obesity, both the expression of TRAIL and its receptor (TRAIL-R) is elevated in adipose tissue. Accordingly, TRAIL has been proposed as an important mediator of adipose tissue inflammation and obesity-associated diseases. The aim of this study was to investigate if TRAIL regulates inflammatory processes at the level of the adipocyte. Using human Simpson-Golabi-Behmel syndrome (SGBS) cells as a model system, we found that TRAIL induces an inflammatory response in both preadipocytes and adipocytes. It stimulates the expression of interleukin 6 (IL 6), interleukin 8 (IL-8) as well as the chemokines monocyte chemoattractant protein-1 (MCP-1) and chemokine C-C motif ligand 20 (CCL-20) in a time- and dose dependent manner. By using small molecule inhibitors, we found that both the NFkappaB and the ERK1/2 pathway are crucial for mediating the effect of TRAIL. Taken together, we identified a novel pro-inflammatory function of TRAIL in human adipocytes. Our findings suggest that targeting the TRAIL/TRAIL-R system might be a useful strategy to tackle obesity-associated adipose tissue inflammation. PMID- 28720907 TI - Top-down Fabrication and Enhanced Active Area Electronic Characteristics of Amorphous Oxide Nanoribbons for Flexible Electronics. AB - Inorganic amorphous oxide semiconductor (AOS) materials such as amorphous InGaZnO (a-IGZO) possess mechanical flexibility and outstanding electrical properties, and have generated great interest for use in flexible and transparent electronic devices. In the past, however, AOS devices required higher activation energies, and hence higher processing temperatures, than organic ones to neutralize defects. It is well known that one-dimensional nanowires tend to have better carrier mobility and mechanical strength along with fewer defects than the corresponding two-dimensional films, but until now it has been difficult, costly, and impractical to fabricate such nanowires in proper alignments by either "bottom-up" growth techniques or by "top-down" e-beam lithography. Here we show a top-down, cost-effective, and scalable approach for the fabrication of parallel, laterally oriented AOS nanoribbons based on lift-off and nano-imprinting. High mobility (132 cm2/Vs), electrical stability, and transparency are obtained in a IGZO nanoribbons, compared to the planar films of the same a-IGZO semiconductor. PMID- 28720909 TI - Lessons Learned on the Other Side of Campus. PMID- 28720908 TI - Negative Reflecting Meta-Mirrors. AB - Using the gradient phase discontinuities that meta-mirrors provide, we show that the incident wave can be reflected anomalously with a broad angle range of negative reflections. Such reversed behaviors promote the immediate applications for the planar meta-mirrors to steer the signals more arbitrarily and the convex meta-mirrors to focus and collimate electromagnetic fields. We practically implement these negative reflecting meta-mirrors through an arrangement of subwavelength ring patches and generate the desired phase distribution by also considering the incident angle. Finally, the experiments are carried out to verify the functionality of the convex meta-mirror firstly, and the performances of the planar meta-mirror are also tested by further building up a dual reflector system with the demonstration of obtaining the plane wave from the convex meta mirror and then having the well collimated beam negative reflected by the planar meta-mirror. The proposed design should be readily applicable to a wide range of electromagnetic problems, especially for devising smart planar illusion devices, and highly directive antennas mounting on convex surfaces of various platforms. PMID- 28720910 TI - Understanding Business Models in Pharmacy Schools. AB - The objectives of this article are to define business models, contrast the business models in pharmacy schools, and discuss issues that can arise from misunderstandings about whom pharmacy schools serve and how they do so. PMID- 28720911 TI - Is Lecturing Obsolete? Advocating for High Value Transformative Lecturing. PMID- 28720912 TI - Professional Stereotypes of Interprofessional Education Naive Pharmacy and Nursing Students. AB - Objective. To assess and compare interprofessional education (IPE) naive pharmacy and nursing student stereotypes prior to completion of an IPE activity. Methods. Three hundred and twenty-three pharmacy students and 275 nursing students at Mercer University completed the Student Stereotypes Rating Questionnaire. Responses from pharmacy and nursing students were compared, and responses from different level learners within the same profession also were compared. Results. Three hundred and fifty-six (59.5%) students completed the survey. Pharmacy students viewed pharmacists more favorably than nursing students viewed pharmacists for all attributes except the ability to work independently. Additionally, nursing students viewed nurses less favorably than pharmacy students viewed nurses for academic ability and practical skills. There was some variability in stereotypes between professional years. Conclusion. This study confirms the existence of professional stereotypes, although overall student perceptions of their own profession and the other were generally positive. PMID- 28720913 TI - Should Torsion Balance Technique Continue to be Taught to Pharmacy Students? AB - Objective. To determine the types of balances used in compounding pharmacies: torsion or digital. Methods. A survey was mailed to the pharmacist-in-charge at 698 pharmacies, representing 47% of the pharmacies in Missouri as of July 2013. The pharmacies were randomly selected and stratified by region into eight regions to ensure a representative sample. Information was gathered regarding the type and use of balances and pharmacists' perspectives on the need to teach torsion balance technique to pharmacy students. Results. The response rate for the survey was 53.3%. Out of the total responses received, those pharmacies having a torsion balance, digital balance or both were 46.8%, 27.4% and 11.8%, respectively. About 68.3% of respondents compound prescriptions. The study showed that 52% of compounding pharmacies use torsion balances in their practice. Of those with a balance in their pharmacy, 65.6% favored continuation of torsion balance instruction. Conclusions. Digital balances have become increasingly popular and have replaced torsion balances in some pharmacies, especially those that compound a significant number of prescriptions. The results of this study indicate that torsion balances remain integral to compounding practice. Therefore, students should continue being taught torsion balance technique at the college. PMID- 28720914 TI - Examining the Association Between the NAPLEX, Pre-NAPLEX, and Pre- and Post admission Factors. AB - Objective. To examine the relationship between the NAPLEX and Pre-NAPLEX among pharmacy graduates, as well as determine effects of pre-pharmacy, pharmacy school, and demographic variables on NAPLEX performance. Methods. A retrospective review of pharmacy graduates' NAPLEX scores, Pre-NAPLEX scores, demographics, pre pharmacy academic performance factors, and pharmacy school academic performance factors was performed. Bivariate (eg, ANOVA, independent samples t-test) and correlational analyses were conducted, as was stepwise linear regression to examine the significance of Pre-NAPLEX score and other factors as related to NAPLEX score. Results. One hundred fifty graduates were included, with the majority being female (60.7%) and white (72%). Mean NAPLEX score was 104.7. Mean Pre-NAPLEX score was 68.6. White students had significantly higher NAPLEX scores compared to Black/African American students. NAPLEX score was correlated to Pre NAPLEX score, race/ethnicity, PCAT composite and section scores, undergraduate overall and science GPAs, pharmacy GPA, and on-time graduation. The regression model included pharmacy GPA and Pre-NAPLEX score. Conclusion. The findings provide evidence that, although pharmacy GPA is the most critical determinant, the Pre-NAPLEX score is also a significant predictor of NAPLEX score. PMID- 28720915 TI - Evaluation of the Use of a Virtual Patient on Student Competence and Confidence in Performing Simulated Clinic Visits. AB - Objective. To assess the effect of incorporating virtual patient activities in a pharmacy skills lab on student competence and confidence when conducting real time comprehensive clinic visits with mock patients. Methods. Students were randomly assigned to a control or intervention group. The control group completed the clinic visit prior to completing virtual patient activities. The intervention group completed the virtual patient activities prior to the clinic visit. Student proficiency was evaluated in the mock lab. All students completed additional exercises with the virtual patient and were subsequently assessed. Student impressions were assessed via a pre- and post-experience survey. Results. Student performance conducting clinic visits was higher in the intervention group compared to the control group. Overall student performance continued to improve in the subsequent module. There was no change in student confidence from pre- to post-experience. Student rating of the ease of use and realistic simulation of the virtual patient increased; however, student rating of the helpfulness of the virtual patient decreased. Despite student rating of the helpfulness of the virtual patient program, student performance improved. Conclusion. Virtual patient activities enhanced student performance during mock clinic visits. Students felt the virtual patient realistically simulated a real patient. Virtual patients may provide additional learning opportunities for students. PMID- 28720916 TI - Assessing Faculty and Student Interpretations of AACP Survey Items with Cognitive Interviewing. AB - Objective. To use cognitive interviewing techniques to determine faculty and student interpretation of a subset of items from the AACP faculty and graduating student surveys. Methods. Students and faculty were interviewed individually in a private room. The interviewer asked each respondent for his/her interpretation of 15 randomly selected items from the graduating student survey or 20 items from the faculty survey. Results. While many items were interpreted consistently by respondents, the researchers identified several items that were either difficult to interpret or produced differing interpretations. Conclusion. Several interpretational inconsistencies and ambiguities were discovered that could compromise the usefulness of certain survey items. PMID- 28720917 TI - Exploring Electronic Communication Modes Between Iraqi Faculty and Students of Pharmacy Schools Using the Technology Acceptance Model. AB - Objective. To explore for the first time the extent to which Iraqi pharmacy students and faculty use Facebook and university email for academic communications, and to examine factors influencing utilization within the framework of the Technology Acceptance Model (TAM). Methods. An electronic survey was administered to convenience samples of students and faculty of six Iraqi public schools and colleges of pharmacy in 2015. Results. Responses included 489 student and 128 faculty usable surveys. Both students and faculty use Facebook more than university email for academic communications. Less than a third of the faculty used university email. Students used Facebook for academic purposes twice as much as faculty. Conclusion. Absence of university email in Iraqi schools and colleges of pharmacy makes Facebook essential for faculty-student communications. The majority (71.1% to 82%) of respondents perceived that Facebook was easy to use. Three TAM variables (intention to use, attitude toward use and perceived usefulness) had significant positive associations with actual use of both Facebook messaging and university email. PMID- 28720918 TI - Perceived Motivating Factors and Barriers for the Completion of Postgraduate Training Among American Pharmacy Students Prior to Beginning Advanced Pharmacy Practice Experiences. AB - Objective. To examine perceived motivating factors and barriers (MFB) to postgraduate training (PGT) pursuit among pharmacy students. Methods. Third-year pharmacy students at 13 schools of pharmacy provided demographics and their plan and perceived MFBs for pursuing PGT. Responses were characterized using descriptive statistics. Kruskal-Wallis equality-of-proportions rank tests determined if differences in perceived MFBs existed between students based on plan to pursue PGT. Results. Among 1218 (69.5%) respondents, 37.1% planned to pursue PGT (32.9% did not, 30% were undecided). Students introduced to PGT prior to beginning pharmacy school more frequently planned to pursue PGT. More students who planned to pursue PGT had hospital work experience. The primary PGT rationale was, "I desire to gain more knowledge and experience." Student debt was the most commonly cited barrier. Conclusion. Introducing pharmacy students early to PGT options and establishing work experiences in the hospital setting may increase students' desire to pursue PGT. PMID- 28720919 TI - Delivering Tobacco Cessation Content in the Middle East Through Interprofessional Learning. AB - Objective. To explore the attitudes of pharmacy, pharmacy technician, medical, and public health students before and after an IPE activity that focused on smoking cessation in the Middle East. Methods. A pre-post intervention research design using the Readiness for Interprofessional Learning Scale (RIPLS) was used for this study. The tool contained 20 items, categorized under the following subscales: teamwork and collaboration, professional identity, and patient centeredness. Results. A total of 47 out of 50 students from four different health disciplines in Qatar (medicine, pharmacy, pharmacy technician, and public health) who participated in the activity completed a pre- and post-intervention pre-validated questionnaire (94% response rate). Total attitude scores were calculated for all the 20 items along with attitudinal scores of the three domains. Most of the students reported having a positive attitude toward IPE; the number of students having a positive attitude toward IPE increased after the IPE session. The overall median (IQR) score increased from 82 (16) before the session to 84 (15) after the session. Students from different disciplines did not vary in their attitude scores. Conclusion. Health care professional students in Qatar perceived IPE positively, believing that it enhanced their communication skills, collaboration and appreciation of professional roles. This study has implication on developing effective methods to implement IPE in various health professional education curricula. PMID- 28720920 TI - Dietary Supplement Use, Knowledge, and Perceptions Among Student Pharmacists. AB - Objective. To compare dietary supplement use between student pharmacists and the general population, and assess knowledge, attitudes toward use, and dietary supplement effectiveness; and to explore how student pharmacists view their education on dietary supplements. Methods. Paper questionnaires administered to student pharmacists collected data about their use, knowledge, and attitudes of dietary supplements. Use was compared to the 2007 National Health Interview survey findings. Results. Of 179 students who responded, 52% had used at least one dietary supplement in their lifetime versus 25% in the general population. Students perceived supplement label information as unhelpful, research into supplements inadequate, and supplements non-essential to health. Students thought supplement knowledge was important but their education was inadequate. Conclusion. Dietary supplement use was higher in this sample of student pharmacists than the general population. Student pharmacists had limited knowledge and need more education on dietary supplements. PMID- 28720921 TI - A Team-based Assignment to Integrate Basic Science and Pharmacotherapeutic Principles for Anticancer Agents. AB - Objective. To implement and evaluate an active-learning, team-based assignment centered on anticancer agents for the integration of basic science and pharmacotherapeutic principles. Methods. Student teams were assigned a specific anticancer agent and were expected to answer a series of questions on the written section of the assignment, followed by a presentation to the class. Each assignment was assessed using a grading rubric that was mapped to the 2013 CAPE educational outcomes. Student perceptions of the assignment were assessed using a short survey. Results. Student cohort performance on the assignment was in the B range (83%) with a mean of 33.2 out of 40. Using the grading rubric, the 12 student cohorts performed particularly well under professionalism (Domain 4.4) that focuses on personal and professional development from CAPE 2013 with means >4 on a 1-5 scale. Student impressions of the assignment suggested that students believed the assignment had a positive effect on their learning and should be continued. Conclusion. The assignment provided a focused review of basic science and pharmacotherapeutic principles and enabled integration of concepts relating to the therapeutic application of anticancer agents, and management of anticancer agent mediated adverse effects. The assignment could contribute toward preparing students for the evolving role of the pharmacist in the management of cancer. PMID- 28720922 TI - Transformation of an Online Multidisciplinary Course into a Live Interprofessional Experience. AB - Objective. To design, implement, and assess an interprofessional education (IPE) course in the first professional year of students enrolled in eight different health professions programs. Design. An interprofessional faculty committee created a 1-credit hour required IPE course to not only teach students about the roles and responsibilities of each discipline and how they may contribute to an interprofessional team, but to also improve collaboration and team-based communication skills among health care professions students. Students were placed in interprofessional groups and met weekly to participate in didactic lectures, discussion sessions, and a standardized patient encounter. Assessment. Seven hundred and eighty-three health professions students were enrolled in the course, of which 130 students completed questionnaires at all three time points. Students were neutral about the course and found it moderately valuable (Mean 6.23 [on a scale from 1 to 10], interesting (Mean 5.61), and enjoyable (Mean 5.57). Written feedback from the course indicated that the majority of students enjoyed the standardized patient encounter and thought the course provided a valuable opportunity to interact with other students in other health professions programs. Conclusion. This required course served as an introductory interprofessional approach in preparing health professions students to learn from each other about their various roles and responsibilities and how each can contribute to the health care team. PMID- 28720923 TI - A Narrative Review of Medication Adherence Educational Interventions for Health Professions Students. AB - Objective. To review published educational interventions focusing on medication non-adherence. Methods. A literature search was performed of educational articles on the topic of medication adherence. Data on interventions and learning assessments were abstracted for relevant studies meeting search criteria. Results. Twenty studies met inclusion criteria. Sixteen included pill-taking experiences with regimens of candies or placebos and varied in their inclusion of novel elements to highlight issues such as stigma, regimen complexity, and adherence measurement. Three studies involved interacting with the public. Qualitative and quantitative methods were used to assess a variety of learning outcomes. Conclusion. Pill-taking experiences can help future providers appreciate the complex logistics of medication-taking, but are less capable of addressing the psychosocial aspects of adherence. A promising area for learning is to interact with actual medication users to understand their experiences and perspectives. PMID- 28720924 TI - Overview of Faculty Development Programs for Interprofessional Education. AB - Objectives. To describe characteristics of faculty development programs designed to facilitate interprofessional education, and to compile recommendations for development, delivery, and assessment of such faculty development programs. Methods. MEDLINE, CINAHL, ERIC, and Web of Science databases were searched using three keywords: faculty development, interprofessional education, and health professions. Articles meeting inclusion criteria were analyzed for emergent themes, including program design, delivery, participants, resources, and assessment. Results. Seventeen articles were identified for inclusion, yielding five characteristics of a successful program: institutional support; objectives and outcomes based on interprofessional competencies; focus on consensus-building and group facilitation skills; flexibility based on institution- and participant specific characteristics; and incorporation of an assessment strategy. Conclusion. The themes and characteristics identified in this literature overview may support development of faculty development programs for interprofessional education. An advanced evidence base for interprofessional education faculty development programs is needed. PMID- 28720925 TI - Considerations in Determining the Ideal Pharmacy Residency Candidate. PMID- 28720926 TI - RE: Considerations in Determining the Ideal Pharmacy Residency Candidate. PMID- 28720927 TI - Report of the 2016-17 Academic Affairs Standing Committee: Entrustable Professional Activities Implementation Roadmap. AB - The purpose of this report is to: 1) Identify linkages across the EPA statements, Center for the Advancement of Pharmacy Education 2013 Educational Outcomes (CAPE 2013) and the Joint Commission of Pharmacy Practitioners' Pharmacist Patient Care Process (PPCP); 2) Provide ways EPA statements can be used to communicate core skills that are part of the entry-level pharmacist identity; 3) Suggest a potential roadmap for AACP members on how to implement EPA statements. PMID- 28720929 TI - Antioxidant characteristics of extracts of Hibiscus sabdariffa calyces encapsulated with mesquite gum. AB - This study compared the stability of extracts of H. sabdariffa calyces microencapsulated with different concentrations of mesquite gum during storage. Dry Roselle calyces were mixed with 50:50 (v/v) ethanol:water solution to obtain 18 degrees Bx concentrate. This Roselle extract concentrate was mixed with purified mesquite gum (100:1-100:5 v/w). The Roselle extract concentrate-gum (RECG) was spray dried at inlet and outlet temperatures of 180 +/- 2 and 104 +/- 2.3 degrees C, respectively, at an air flow rate of 38 m3/h. Encapsulated Roselle powders (ERP) were analyzed for moisture content, total monomeric anthocyanins (differential pH), phenolic compounds (Folin and Ciocalteu method), antioxidant capacity (ABTS), and color parameters ([Formula: see text], and [Formula: see text]) after 5 weeks and 1 year of storage. Sorption properties (isotherms) and micrographs of powders were also obtained. The average yield of RECG powders was 15.27 +/- 0.81 g/100 mL. During storage, ERP showed average values of phenolic compounds, antioxidant capacity, and anthocyanins of 3.43 +/- 0.25 g gallic acid equivalents/100 g, 9.34 +/- 1.4 g Trolox equivalents/100 g, and 318.7 +/- 20.6 mg cyanidin-O-glycoside/100 g, respectively. Color parameters remained constant along the storage time. PMID- 28720930 TI - Changes in oxidation indices and minor components of low free fatty acid and freshly extracted crude palm oils under two different storage conditions. AB - This article reports on the changes of oxidation indices and minor components of low free fatty acid (FFA) and freshly extracted crude palm oils after storage at ambient (28 +/- 1 C) and 60 C for 77 days. The changes in peroxide value (PV), FFA, extinction coefficient at 233 and 269 nm (K233 and K269), bleachability index (DOBI), carotene and vitamin E contents were monitored. PV, FFA, K233 and K269 of both oil samples increased as storage progressed while the values of carotene and vitamin E contents decreased. At the end of storage period at 60 degrees C, the carotene content of low FFA crude palm oil was 4.24 ppm. The storage conditions used led to the loss of entire vitamin E fractions of both oil samples as well as a reduction in DOBI values except for freshly extracted crude palm oil stored at ambient temperature. PMID- 28720931 TI - Quality attributes of dahi prepared from milk fortified with omega-3 fatty acids, phytosterols and polydetxrose. AB - In the present study, dahi prepared using milk fortified with omega-3 fatty acids (flaxseed oil), phytosterols and soluble fibre (polydextrose) through an oil-in water emulsion was evaluated for the physico-chemical and sensory quality. The levels of fortificants in fortified dahi were also estimated. Fortification process did not affect the degree of fermentation in terms of pH and acidity. Sensory scores of fortified and control dahi did not differ significantly. Fortified dahi had lower viscosity, firmness and consistency, and higher water holding capacity (WHC) compared to control; however, significant differences were not observed in firmness and consistency values. Storage study indicated that pH, acidity, %WHC, firmness and consistency values and lactic acid bacterial counts did not differ significantly throughout storage period in both the dahi samples and recorded good sensory acceptability during storage. Fortified dahi provides 282.53 mg, 415.92 mg and 1.019 g of alpha-linolenic acid, total phytosterols and polydextrose, respectively per 100 g of product. Moreover, no loss in the initial content of ALA, phytosterols and polydextrose had occurred after 8 days of storage period. The present study suggests the feasibility of adding flaxseed oil, phytosterols and polydextrose as functional ingredients in the form of water soluble emulsion to milk, which could be converted to dahi with acceptable properties and enhanced nutritional and therapeutic potency. PMID- 28720932 TI - Investigating the amount of TFAs, CLAs and omega6/omega3 of various brands of corn oil heated at different time-temperature treatments. AB - A qualitative and quantitative analysis of trans fatty acids (TFAs), conjugated linoleic acids (CLAs) and linoleic acid/alpha-linolenic acid (omega6/omega3) in eleven different brands of fresh and heated corn oil was investigated. Corn oil was subjected to thermal treatment at 180, 210 and 230 degrees C for 4, 8 and 12 h. The kinds of fatty acids were almost the same in all eleven brands of corn oil, but there were differences in the quantities of TFAs, CLAs and omega6/omega3 among the brands. The formation of TFAs in different brands of corn oil increased slowly at 180 degrees C and rapidly at 230 degrees C with the maximum increase of 28 and 374%, respectively. The formation of CLAs also increased during the heating with the amount of 0.00-0.32 g/100 g in fresh corn oil and 0.71-1.12 g/100 g in corn oil heated at 230 degrees C for 12 h. The value of omega6/omega3 was high in corn oil and increased with heating temperature and time. The largest rise of omega6/omega3 can reach upwards of 239:1. The results showed that temperature control was essential for maintaining the quality and nutritional value of corn oil. PMID- 28720933 TI - Bioaccessibility of hydroxytyrosol and n-3 fatty acids as affected by the delivery system: simple, double and gelled double emulsions. AB - This study examines the influence of different food-grade n-3 PUFA-enriched simple emulsion (SE), double emulsion (DE) and gelled double emulsion (GDE) delivery systems on the extent of lipolysis, antioxidant capacity and the bioaccessibility of hydroxytyrosol (HTy). GDE emulsion offered better protection for HTy (89%) than the other systems (79% in SE and DE). The reducing capacity of the emulsions containing HTy were not altered during oral digestion. However, "in vitro" gastric and intestinal phases significantly reduced the antioxidant activity of all systems. The structural and physical state of GDE entailed a slowing-down of triacylglyceride hydrolysis (36.4%) in comparison with that of SE and DE (22.7 and 24.8% for SE and DE, respectively). PMID- 28720934 TI - Evaluation of antioxidant properties of Za'atar (Thymbra spicata) essential oils as natural antioxidant for stability of palm olein during deep-fat frying process. AB - The yield of Za'atar (Thymbra spicata) essential oils were found to be 2.5-3.4% at extraction process temperatures of 100-175 degrees C. The essential oils contained 79.5-86.2% carvacrol. Effects of BHT and Za'atar essential oil on stability of palm olein during deep-fat frying of potato slices were studied at 180 degrees C. Changes in peroxide, para-anisidine, iodine values, free fatty acid and color were determined. Za'atar essential oil and BHT reduced free fatty acid content of olein from 0.27 to 0.21% (oleic acid) after 50 frying cycles. Antioxidant addition did not change the peroxide value of oil. Frying decreased Hunter L value and increased a, b, and total color difference values of used oils. The P-anisidine value changed from 15 to 33 for control oil during frying. BHT and Za'atar essential oil reduced this value to 28. The iodine values of olein reduced from an initial value of 54.5 to 45, 49 and 49 for control, BHT and Za'atar essential oil added frying oils, respectively. Za'atar essential oils could be used for preserving palm olein during deep-fat frying process. PMID- 28720935 TI - Technological options to control quality of fish burgers. AB - This research was focused on preservation strategies applied to develop fish burgers enriched with tomato flour and extra-virgin olive oil. The effects of three different gas mixtures (5:95 O2/CO2; 10:60:30 O2/CO2/N2 and 5:50:45 O2/CO2/N2) on burger quality were analyzed by monitoring microbial cell load of main spoilage microorganisms, pH and sensory properties. As expected, modified atmosphere packaging significantly affected mesophilic bacteria with a reduction of about 2 log cycles for samples under 5% O2 and 95% CO2. Afterward, the best gas mixture was used in combination with various natural antimicrobial compounds (thymol, grape fruit seed extract and biocitrus). The biocitrus showed the strike balance between microbial and sensory quality, thus suggesting to be adopted for dipping treatment of the entire fish fillet before the mincing process. Later all the strategies tested individually were combined and samples were monitored for microbiological and sensory quality. Results obtained showed that dipping treatment of fillet in biocitrus solution (20,000 ppm) under modified conditions extended the shelf life by 8 days compared to the control sample, without affecting the sensory acceptability. PMID- 28720936 TI - The effects of superchilling with modified atmosphere packaging on the physicochemical properties and shelf life of swimming crab. AB - The objective of the present study was to investigate the effects of superchilling with modified atmosphere packaging on the physicochemical properties and shelf life of swimming crab. As the storage time increased, the rates at which the total aerobic plate count, total volatile basic nitrogen, pH, peroxide value and thiobarbituric acid-reactive substances value increase were significantly lower for the superchilling with modified atmosphere packaging (SCS + MAP) treatment compared to superchilling storage (SCS) and chilling storage (CS). With increasing storage time, the carbonyl content of the proteins increased from 1.21 nmol/mg of protein (0 day) to 2.03, 1.87, 1.66 nmol carbonyl/mg protein on the 6th day for CS, SCS and SCS + MAP, respectively. The disulfide bonds increased in a similar manner, and the total sulfhydryl content, salt extractable protein and Ca-ATPase stability decreased. Sodium dodecyl sulphate polyacrylamide gel elcetrophoresis (SDS-PAGE) and microstructure analysis also indicated that SCS + MAP could reduce the degree of protein degradation. These results suggested that superchilling with modified atmosphere packaging offers an effective approach to slowdown protein and lipid oxidation, and extends the shelf life of swimming crab. However, superchilling with high-CO2 packaging had a negative effect on the surface hydrophobicity and drip loss of swimming crab. PMID- 28720937 TI - Quality characteristics of broiler chicken meat from free-range and industrial poultry system for the consumers. AB - ABSTRACT: The aim of this study was to determine and compare the quality parameters of broiler chicken meat from free-range and industrial poultry system. Proximate composition, color, pH, shear force, microbial quality and sensory characteristics were evaluated. Both free-range and industrial chicken meat presented PSE (pale, soft and exudative) anomaly (L* > 53). An inverse correlation between lightness, pH and shear force was observed. The free range broiler meat had higher yellow color (b* 11.56) and shear force (2.75 kgf) and lower red color (a* 1.65) and pH (5.75) in comparison to the industrial broiler meat, due intensive physical activity on growing phase and influence of the pre slaughter stress on the rigor mortis. The thigh cut from free range broiler meat showed higher protein levels (18.00%), while to the thigh and drumstick cuts of industrial broiler meat showed higher total fat levels (3.4 and 5.0%, respectively). In general, each strain and chickens producing methods gave the peculiar characteristics to meat (chemical, physical, microbiological and sensorial). GRAPHICAL ABSTRACT: PMID- 28720938 TI - Effect of green coffee extract on rheological, physico-sensory and antioxidant properties of bread. AB - Green coffee extract, GCE (Coffee canephora) was used at 1.0, 1.5 and 2.0% levels for making bioactive rich bread. The processed GCE from the green coffee beans had 21.42% gallic acid equivalents (GAE) total polyphenols (TPP), 37.28% chlorogenic acid (CGA) and 92.73% radical scavenging activity (RSA), at 100 ppm concentration of GCE and caffeine content (1.75%). Rheological, physico-sensory and antioxidant properties of GCE incorporated breads were analysed and compared with control bread. The results revealed not much significant change in the rheological characteristics of dough up to 1.5% level; an increase in bread volume; greenness of bread crumb and mostly unchanged textural characteristics of the bread with increased addition of GCE from 0 to 2.0%. Sensory evaluation showed that maximum level of incorporation of GCE without adverse effect on the overall quality of bread (especially taste) was at 1.5% level. The contents of TPP, RSA and CGA increased by 12, 6 and 42 times when compared to control bread and had the highest amount of 4-5 caffeoylquinic acid. PMID- 28720939 TI - Cholesterol analysis of Korean eat-out foods for national food composition database. AB - Information on cholesterol intake through restaurant meal is of high concern because of increasing eat-out population. Since nutrient labeling is not mandatory for restaurant food in Korea, cholesterol database on restaurant menu is unavailable. This study was performed to construct regional and national cholesterol database on primary Korean restaurant foods including 30 soup/stew, 24 rice dishes, and 27 noodles. From 2009 to 2012, Korea Ministry of Food and Drug Safety collected total 5832 foods (81 food types *6 regions *12 restaurants) nationwide and then 486 composites representing food types and regions were prepared for cholesterol analysis. Cholesterol contents of 486 composite samples were highly affected by recipe, food type, seasonality of ingredients, and geographical location, showing the range of 1.1-143.0, 1.5-85.1, and 0.4-62.2 mg/100 g for soup/stew, rice dishes, and noodles, respectively. The highest cholesterol value was observed in Al-tang (spicy fish roe soup) while Maemil guksu (buckwheat noodle in beef stock) showed the lowest among all samples. Most foods contain relatively low cholesterol content, but the serving size and consumption frequency of dishes should be considered in order not to exceed the recommended daily intake limit (300 mg cholesterol). Saponification coupled with gas chromatography applied for cholesterol analysis was reliable based on accuracy (95% > recovery) and precision (repeatability <4% and reproducibility <8%). Quality control chart monitored for 4 years showed that all analyses were under the control. This study provides reliable and representative cholesterol contents of Korean restaurant key foods, which can be utilized for assessments of cholesterol intake in the current Korean diet. PMID- 28720940 TI - Recovery of protein hydrolysate and chitosan from black tiger shrimp (Penaeus monodon) heads: approaching a zero waste process. AB - Shrimp heads are considered as a potential source for the recovery of many valuable components such as chitin, protein and carotenoids. In the present study, both protein hydrolysate and chitin/chitosan were recovered using combination of physical, biological and chemical treatments. Shrimp heads were separated from liquid phase by a facile and efficient physical pretreatment. The liquid fraction was then hydrolyzed using formic acid and vacuum concentrated to obtain an astaxanthin-rich protein hydrolysate. The solid fraction was used to produce chitin by deproteination and demineralization. The hydrolysate consisted of a high astaxanthin (192 ppm) and protein (26.3 wt%) content. Chitosan prepared from chitin showed a high degree of deacetylation (85.4%) with low protein (0.25 wt%) and mineral (0.22 wt%) contents. The relative crystalline structure of the chitin and chitosan were 54.7 and 10.4%, respectively. The deacetylation of chitin was confirmed by Fourier Transform Infrared Spectroscopy. The present procedure approached to produce maximum valuable components including astaxanthin rich protein hydrolysate and chitin/chitosan from shrimp head waste. PMID- 28720941 TI - Chemical composition and bioactivity of essential oils from flower and fruit of Thymbra capitata and Thymus species. AB - Thymbra capitata and Thymus species are commonly known as thyme in Spain and they are currently used as culinary herbs, as well as for ornamental, aromatizing and traditional medicinal purposes. Given the economic importance of thyme oils, many thyme species have been studied, and their essential oils (EOs) and other volatile-containing extracts have been chemically characterized. The aim of this study was to evaluate the antioxidant, antimicrobial and cytotoxic activities as well as the phytochemical composition of the EOs from fruits and flowers of T. capitata and Thymus species. High antioxidant capacity has been observed and related to the relative amounts of terpenoid and phenolic with good antioxidant properties. The antioxidant activities decreased as follows: TAC > TZ > TC > TM. The results of antimicrobial activity showed that all tested EOs were active against all tested microbial species, including Gram-positive and negative bacteria. The minimum inhibition concentration values obtained ranged from 0.1 to 0.01 MUL/mL. Furthermore, all EOs assayed induced cell death in both human epitheloid cervix carcinoma and histiocytic leukemia cell lines. Overall, the results of this study indicates that the EOs from fruits and flowers of T. capitata and Thymus species posses interesting antioxidant properties and represent a potential source of medicine for the treatment of infectious diseases and cancer. PMID- 28720942 TI - Nutritional quality of flours from guar bean (Cyamopsis tetragonoloba) varieties as affected by different processing methods. AB - In present study, three varieties (G 80, Ageta 112 and HG 365) of guar bean (Cyamopsis tetragonoloba) were analysed for proximate analysis and were processed by different methods (dehusking, soaking, autoclaving, extrusion and germination) to reduce its antinutritional factors. Processed guar flours were studied for antinutritional factors (tannins, phytic acid and polyphenols) and protein fractions. The highest protein, ash and polyphenols contents were observed in Ageta 112. G 80 contained the lowest tannin and phytic acid content. High temperature treatments (i.e. autoclaving at 110 degrees C/10 min, 120 psi and extrusion-Clextral, Twin screw extruder) were found to be most effective in reducing the tannin and polyphenol content. More than 90% reduction in tannins was observed with high temperature treatments in HG 365. Phytic acid fraction increased slightly on soaking, however, extensive reduction was observed with other treatments. Globulins formed the major protein fraction in guar bean and various processing treatments significantly affected the protein fractions. Autoclaving was observed to be the best treatment to reduce antinutritional factors in guar bean and thereafter, its utilization in food. PMID- 28720943 TI - Non-enzymatic browning due to storage is reduced by using clarified lemon juice as acidifier in industrial-scale production of canned peach halves. AB - Non-enzymatic browning (NEB) in canned peach halves in syrup during storage was investigated. Absorbance at 420 nm (A420), colorimetric parameters (CIELab, TCD and La/b), fructose, glucose and sucrose, total sugar, organic acids, ascorbic acid (AA), dehydroascorbic acid, and 2,3-diketogulonic acid were used to estimate the extent of NEB during 1 year of storage at 30 degrees C and the relationships between each of these parameters and A420 were established. The investigation was carried out to explore the possibility of replacing the E330 commonly used as acidifier by turbid or clarified lemon juice (TLJ or CLJ) to obtain a product having good nutrition with better retention of quality. The a, La/b, glucose and fructose were positively correlated with A420 and all proved to be good indicators of browning development. Overall results showed that replacement of acidifier E330 with CLJ for controlling pH in canned peach halves in syrup had some advantages. PMID- 28720945 TI - Cold pressed versus solvent extracted lemon (Citrus limon L.) seed oils: yield and properties. AB - During the processing of lemon fruit, a large quantity of seeds is produced as a by-product. These seeds contain valuable components; therefore, required to be evaluated. This study aimed to compare the cold pressed with hexane-extracted lemon seed oils and determine their physicochemical and thermal properties. Cold pressing yielded significantly lower oil (36.84%) than hexane extraction (71.29%). In addition, the concentrations of free fatty acids, peroxides, and p anisidine were lower in the cold pressed oil. Cold pressed oil showed higher total phenolics, alpha-tocopherol and antioxidant capacity. The major fatty acids found in the cold pressed oil were linoleic and palmitic acids, whereas beta sitosterol and campesterol were the dominant sterols. The crystallization and melting temperatures and enthalpies were also elucidated. In conclusion, this study proved that high quality of lemon seed oils can be produced by the cold pressing technique; this oil can be used in industries such as the food, cosmetic or chemical industries. PMID- 28720944 TI - Evaluation of the chemical composition, antioxidant and anti-inflammatory activities of distillate and residue fractions of sweet basil essential oil. AB - In this study, the chemical composition and antioxidant and anti-inflammatory activities of sweet basil (Ocimum basilicum L. Lamiaceae family) were evaluated. Sweet basil is a food-related plant that is widely used in traditional Chinese medicine. Sweet basil crude oil was processed via molecular distillation and further characterized using gas chromatography-mass spectrometry (GC-MS) to screen for new compounds. The GC-MS analysis identified thirty-eight compounds. The major constituents of the residue fraction were estragole (17.06%), methyl eugenol (11.35%) and linoleic acid (11.40%), while the distillate fraction primarily contained methyl eugenol (16.96%), alpha-cadinol (16.24%) and alpha bergamotene (11.92%). The antioxidant (DPPH and ABTS assays) and anti inflammatory (in Raw264.7 cells) activities were evaluated. The residue fraction markedly scavenged the DPPH (IC50 = 1.092 +/- 0.066 mg/mL) and ABTS (IC50 = 0.707 +/- 0.042 mg/mL) radicals. Meanwhile, the distillate fraction distinctly suppressed the production of cytokines (TNF-alpha, IL-beta, IL-6) and their gene expression in LPS-induced Raw264.7 cells and suppressed NO and iNOS in an in vitro model when compared with the crude oil. In conclusion, the fractions obtained from sweet basil crude oil showed different antioxidant and anti inflammatory properties, and they could be used as an effective source of natural antioxidant and anti-inflammatory agents after molecular distillation. Thus, the properties of essential oils in natural herbal medicines may be maximized to provide a valuable therapeutic strategy for treating various disorders caused by extreme oxidative stress. PMID- 28720946 TI - Effect of partial replacement of porcine fat with pre-emulsified soybean oil using fish protein isolate as emulsifier on characteristic of sausage. AB - Partial replacement of animal fats with n-3 rich oils is a promising way to improve nutritive value of meat products. In the present work, the effects of porcine fat substitution with soybean oil (SBO) on characteristics of sausages were studied at the oil substitution levels of 25, 35, and 45% by weight of porcine fat. SBO was introduced to the sausages alternatively in native or pre emulsified forms, the latter with fish protein isolate (FPI) or Na-caseinate (Nc) as emulsifier. Characteristics of the sausages, including cooking loss, water holding capacity, texture attributes, microstructure, and color, were then determined. The sausages added with pre-emulsified SBO stabilized by FPI showed better stability than the control (without added SBO), as indicated by lower cooking loss and higher hardness. Microstructure with better homogeneity was also evident in the sausages added with pre-emulsified SBO stabilized by FPI. However, the sausages added with pre-emulsified SBO stabilized by Nc showed poorer stability than the control, and possessed sponge-like microstructure. Generally, increased oil substitution level led to inferior stability of the product, especially in the sausages formulated with pre-emulsified SBO stabilized by Nc. The results suggested that FPI might be used in comminuted meat products with desirable effects, in the pre-emulsification, on replacement level up to 35% of porcine fat. PMID- 28720947 TI - Reduction of whey protein concentrate antigenicity by using a combined enzymatic digestion and ultrafiltration approach. AB - The global interest in saving food resources is leading to recycle wasted-food materials to extract useful nutrients. In dairy industry, the recycling of whey proteins determines their utilization in the healthy-addressed foods, which, however, can cause immunological responses in allergic subjects. In this work, a whey protein concentrate (WPC) was alternatively hydrolyzed with pepsin, papain, trypsin and rennin in order to attenuate or abolish the beta-lactoglobulin (BLG) antigenicity. The electrophoretic profiles of both pepsin and papain WPC hydrolysates proved the disappearance of the BLG band, even though a slight antigenicity was still found by ELISA. Pepsin hydrolysates, filtered through a 10 kDa cut-off membrane, did not produce immunological response. A deeper investigation carried out on pepsin digested and ultrafiltered samples by LC MS/MS showed the disappearance of the immunoreactive BLG-fragment IVTQMKGLDIQKVAGTW. The remaining peptides, partially overlapped to major IgE binding epitopes, were not able to give immunoreactivity response. The combined WPC pepsin digestion with ultrafiltration confirmed to be a user-friendly strategy to reduce markedly the WPC antigenicity. The improvement of this two steps process could be used to produce novel hypoallergenic infant food formulas. PMID- 28720948 TI - Extracts of Mauritian Carica papaya (var. solo) protect SW872 and HepG2 cells against hydrogen peroxide induced oxidative stress. AB - In line with literature documenting the pluripotent activities of tropical fruits, this study evaluated the antioxidant effects of Carica papaya fruit extracts at cellular level. Investigations using cellular models of oxidative stress provided complementary evidence of the antioxidant activities of papaya fruit. At 2 mg dry weight ml-1, extracts of seed from ripe and unripe fruit significantly reduced oxidative stress levels within human pre-adipocytes (SW872) and hepatocellular carcinoma cells (HepG2) exposed to hydrogen peroxide (H2O2). Maintenance of mitochondrial viability, reduction of intracellular reactive oxygen species levels and mediation of pro-inflammatory cytokine secretory levels (tumour necrosis factor-alpha, interleukin-6, monocyte chemoattractant protein-1) were all indicative of its cytoprotective effects against oxidative-inflammation. This work demonstrates that the Mauritian Solo papaya is an important source of natural antioxidants that could be used for the dietary modulation of oxidative stress and inflammation. PMID- 28720949 TI - Rheological properties and microstructure of xylanase containing whole wheat bread dough. AB - The present research work was undertaken to investigate the effect of xylanase, produced by Penicillium citrinum, on rheological behavior of whole wheat bread dough at large and small deformation respectively. Dough attributes including textural properties (penetration) and structure related characteristics (oscillatory tests) were evaluated. Change in visco-elastic properties of xylanase containing dough was evaluated by oscillatory and creep measurements. The flow experiments were conducted under steady-state condition with shear rate ranging from 0.01 to 100 s-1. Frequency sweep experiments were performed between 0.01 and 10 Hz. It revealed that in both control and xylanase containing dough formulation, the elastic modulus was higher than viscous modulus in the entire range of frequency. Our results represent the adequacy of fitting of dynamic moduli in Power law model and week gel model. Peleg model as well as six element Kelvin model described well the creep behaviour of control and xylanase containing dough. Uniaxial extensibility was assessed by Kieffer dough and gluten extensibility rig. Lyophilized powder of untreated and xylanase treated doughs were tested under scanning electron microscope. FTIR spectra of lyophilized powder of untreated and xylanase treated dough were recorded in the range of 600 4000 cm-1. PMID- 28720950 TI - Importance of the higher retention of tocopherols and sterols for the oxidative stability of soybean and rapeseed oils. AB - Tocopherols and sterols were lost considerably during the refining process of vegetable oils, resulting in a dramatic decrease in the oxidation stability. However, the oxidation stability of vegetable oils was not directly proportional to tocopherol content, not mention to its synergistic interaction with sterol. Based on the peroxide values of oils with different content of tocopherols and sterols during storage at 65 degrees C, it was found that soybean oil (SO) had the best stability when the content of tocopherols and sterols was 0.14 and 1.09%, respectively, whereas the value in rapeseed oil (RO) was 0.06% and 1.14 2.90%. The optimal content of tocopherol in RO was lower than that in SO was due to the different tocopherol isoforms. Furthermore, it was found that the storage stability decreased significantly when adding a same content of alpha-tocopherol, compared with that by retaining more tocopherol isoforms existed in SO. It was suggested that retaining more tocopherol and sterol during vegetable oils refining improved the oxidation stability, however, it did not mean the more the better. The oxidation stability was dependent on both the content and the isoform. This study helps to define the effective contents of tocopherol and sterol under the moderate refining technology. PMID- 28720951 TI - Isolation and characterization of lactic acid bacteria from traditional pickles of Himachal Pradesh, India. AB - A total of 15 isolates of lactic acid bacteria (LAB) were isolated from traditional pickles of rural and urban areas of Himachal Pradesh. These isolates were identified as Enterococcus faecalis (7), Lactobacillus plantarum (3), Pediococcus pentosaceus (2), Leuconostoc mesenteroides (1), Lactococcus lactis (1) and Enterococcus sp. (1) on the basis of morphological, biochemical and 16S rDNA sequence analysis. All the LABs produced exopolysaccharides, have antibiotic susceptibility, and possess activity of beta-galactosidase, beta-glucosidase, protease and amylase, while none of the isolates showed haemolytic activity. Out of 15 isolates tested, only 6 isolates showed the phytase activity. These LAB exhibited antimicrobial activity against food borne pathogenic bacteria i.e. Bacillus cereus, Escherichia coli, Staphylococcus aureus and Shigella dysenteriae. These results suggested that LAB isolates from traditional pickles of Himachal Pradesh have very good potential to be used as probiotics. PMID- 28720953 TI - Physico-chemical changes during progressive ripening of mango (Mangifera indica L.) cv. Dashehari under different temperature regimes. AB - The effect of different temperature regimes on ripening quality of mango cv. Dashehari was investigated. Fruits were kept at 20, 25 degrees C in temperature controlled chambers and at room temperature. Fruits were analyzed periodically for physico-chemical characteristics after every 24 h interval up to 168 h of ripening period. Development of soluble solid contents (SSC), flesh softening and physiological loss of weight of fruits occurred progressively during ripening. Progression of ripening changes in fruit were found to be less at 20 and 25 degrees C than at room temperature. beta-carotene content of pulp improved with ripening but declined after 144 h. Sensory quality (SQ) of mangoes ripened at lower temperature maintained for longer duration and were more acceptable than fruits ripened at room temperature. Pearson's correlation matrix studies showed the inverse relationship of quality parameters SSC, beta-carotene and SQ with firmness and titratable acidity during progressive ripening of fruits. Further, principal component analysis for extensive view of changes in quality parameters and their contribution to overall variability revealed that sensory quality (F1) contributed to maximum variation in ripening indices of fruit. PMID- 28720952 TI - Anthocyanins enriched purple tea exhibits antioxidant, immunostimulatory and anticancer activities. AB - Purple coloured tea shoot clones have gained interest due to high content of anthocyanins in addition to catechins. Transcript expression of genes encoding anthocyanidin reductase (ANR), dihydroflavonol-4-reductase (DFR), anthocyanidin synthase (ANS), flavonol synthase (FLS) and leucoantho cyanidin reductase (LAR) enzymes in three new purple shoot tea clones compared with normal tea clone showed higher expression of CsDFR, CsANR, CsANS and lower expression of CsFLS and CsLAR in purple shoot clones compared to normal clone. Expression pattern supported high content of anthocyanins in purple tea. Four anthocyanins (AN1-4) were isolated and characterized by UPLC-ESI-QToF-MS/MS from IHBT 269 clone which recorded highest total anthocyanins content. Cyanidin-3-O-beta-d-(6-(E) coumaroyl) glucopyranoside (AN2) showed highest in vitro antioxidant activity (IC50 DPPH = 25.27 +/- 0.02 MUg/mL and IC50 ABTS = 10.71 +/- 0.01 MUg/mL). Anticancer and immunostimulatory activities of cyanidin-3-glucoside (AN1), cyanidin-3-O-beta-d-(6-(E)-coumaroyl) glucopyranoside (AN2), delphinidin-3-O-beta d-(6-(E)-coumaroyl) glucopyranoside (AN3), cyanidin-3-O-(2-O-beta-xylopyranosyl-6 O-acetyl)-beta-glucopyranoside (AN4) and crude anthocyanin extract (AN5) showed high therapeutic perspective. Anthocyanins AN1-4 and crude extract AN5 showed cytotoxicity on C-6 cancer cells and high relative fluorescence units (RFU) at 200 MUg/mL suggesting promising apoptosis induction activity as well as influential immunostimulatory potential. Observations demonstrate potential of purple anthocyanins enriched tea clone for exploitation as a nutraceutical product. PMID- 28720954 TI - Effect of partial substitution of gluten-free flour mixtures with chia (Salvia hispanica L.) flour on quality of gluten-free noodles. AB - In this study, chia seed flour (CSF) was used in gluten-free noodle formulation at different levels (0, 10, 20 and 30%, w/w) with and without diacetyl tartaric esters of mono (and di) glycerides (DATEM). Chemical, nutritional, sensory properties and cooking quality of gluten-free noodle samples were investigated. Protein, fat, antioxidant activity and total phenolic content of gluten-free noodles increased by 1.7, 5.5, 2.6 and 2.0 times at 30% usage level of CSF as compared to control sample. Phytic acid and phytate phosphorus content increased from 168.30 mg/100 g and 47.46 mg/100 g to 1057.69 mg/100 g and 298.27 mg/100 g, respectively with CSF usage. Increase of CSF level in gluten-free noodle samples caused an expected increase in the amounts of Ca, P, K, Mg, Fe and Zn. Noodle samples containing CSF showed darker colour than control. Significant increase was observed in volume increase and weight increase values with CSF addition. DATEM reduced cooking loss values of noodle samples. The use of CSF improved the gluten-free noodles taste and odor score. As a result, 20% of CSF with DATEM can be used in gluten-free noodle formulation with acceptable sensory attributes of raw and cooked samples. The present results showed that CSF had a good potential to improve the nutritional quality of noodle. PMID- 28720955 TI - Crystallinity properties and crystallization behavior of chocolate fat blends. AB - Cocoa butter (CB) provides unique crystallization characteristics to chocolates and confectionary products; hence, it is an important value-add product. However, other alternative fats that minimally affect the crystallization behaviour of chocolates and confectionary products are now being increasingly used. This study analyzed the crystallization behaviour of CB, cocoa butter substitutes (CBSs), and their blends. Blends were prepared using CBS concentrations: 5, 10, 15, 20 and 37.5%. CB, CBS, and their blends were evaluated by following analysis: solid fat content, isothermal analysis, polarized light microscopic, thermal behaviour, X-ray diffraction and consistency. Crystallization analysis showed an incompatibility between the 2 fats, with a reduction in the crystallinity and increase in liquid content in all the blends. Eutectic crystallization at 20 degrees C was only observed for the blend containing 20% CBSs. This was considered as a positive result because previous studies have indicated that CBS concentration in CB blends should not be more than 5%. PMID- 28720956 TI - Influence of sodium chloride and vacuum impregnation on the quality and bioactive compounds of parboiled glutinous rice. AB - This study investigated the effect of NaCl (2 and 4% (w/v)) and vacuum impregnation (VI) (150, 200, 250, and 300 Pa) on the quality parameters (water uptake, elongation ratio, visual color, and texture), tocols, gamma-oryzanol and phenolic compounds of parboiled rice. Parboiling with NaCl and VI resulted in increased lightness and higher concentrations of bioactive compounds than rice parboiled by the traditional method. The highest concentration of tocopherols, gamma-oryzanol, and phenolic acids (syringic, and ferulic acids) were obtained from parboiled rice with NaCl concentration at 2% (w/v) and VI at 250 and 300 Pa. As the NaCl concentration and VI levels increased the hardness L*, b* and DeltaE values also increased, but the a* value and water uptake decreased. Results suggested that NaCl-VI soaking was observed to be an effective method for parboiling which promoted the visual color and enhanced the concentration of bioactive compounds in the parboiled rice. PMID- 28720957 TI - Bioactive compounds and antioxidant activity in scalded Jalapeno pepper industrial byproduct (Capsicum annuum). AB - Bioactive compounds and antioxidant activity were evaluated from industrial Jalapeno pepper byproducts and simulated non processed byproducts from two Mexican states (Chihuahua and Sinaloa) to determine their value added potential as commercial food ingredients. Aqueous 80% ethanol produced about 13% of dry extract of polar compounds. Total phenolic content increased and capsaicin and dihydrocapsaicin decreased on scalding samples (80 degrees C, 2 min) without affecting ascorbic acid. The major phenolic compounds, rutin, epicatechin and catechin comprised 90% of the total compounds detected by HPLC of each Jalapeno pepper byproducts. ORAC analysis showed that the origin and scalding process affected the antioxidant activity which correlated strongly with capsaicin content. Although scalding decreased capsaicinoids (up to 42%), phenolic content by (up to 16%), and the antioxidant activity (variable). Jalapeno pepper byproduct is a good source of compounds with antioxidant activity, and still an attractive ingredient to develop useful innovative products with potential food/non-food applications simultaneously reducing food loss and waste. PMID- 28720958 TI - Aroma composition of shalgam: a traditional Turkish lactic acid fermented beverage. AB - Shalgam, a traditional red, cloudy and sour soft beverage, is produced by lactic acid fermentation of black carrot, sourdough, salt, bulgur flour, turnip and adequate water. The present study was designed to characterize the volatile compounds of shalgam obtained from different methods. The aroma compounds of shalgams produced by traditional and direct methods, and addition of Lactic acid bateria (LAB) cultures were examined. Volatile components of shalgam samples were extracted by liquid-liquid extraction technique with pentane/dichloromethane and analyzed by gas chromatography-mass spectrometry (GC-MS). Sixty aroma compounds were identified in shalgam samples including 20 terpenes, 9 esters, 9 alcohols, 5 volatile acids, 6 volatile phenols, 5 lactones, 3 naphthalenes, 2 carbonyl compounds and 1 C13-norisoprenoids. It was found that the aroma profiles of shalgams were quite similar. However, the total volatile content of the shalgam samples increased with addition of Lb. plantarum. PMID- 28720959 TI - Fortification of the whey protein isolate antioxidant and antidiabetic activity with fraction rich in phenolic compounds obtained from Stevia rebaudiana (Bert.). Bertoni leaves. AB - A stevia fraction (ASF) free of steviol glycosides was extracted from Stevia rebaudiana leaves (Stevia UEM-13). ASF essentially constitutes phenolic compounds (52.42%), which were identified by liquid chromatography tandem mass spectrometry (LC-MS/MS) as caffeic acid, quercetin-3-o-glycoside, cyanidin-3-glucoside, kaempferol, quercetin, apigenin, rozmarinic acid, chlorogenic acid and dicaffeoylquinic acid. ASF was used as a multi-functional source of phenolic compounds to fortify the whey protein isolate (WPI) obtained by membrane separation. WPI fortified with 0.2% ASF showed an 80% increase in its antioxidant activity and more pronounced antidiabetic effects than the unfortified WPI, mainly in the glycemic control of diabetic animals induced by streptozotocin. The in vitro and in vivo antioxidant effects of ASF may enhance the effects of WPI. Indeed, this pioneering study revealed that ASF can be used to enrich the antioxidant and antidiabetic properties of WPI. PMID- 28720961 TI - Valorizing guava (Psidium guajava L.) seeds through germination-induced carbohydrate changes. AB - Guava seeds are produced as a waste product by the guava processing industry. Their high carbohydrate contents may suit the carbohydrate needs of the feed sector but their high dietary fiber content limits their feed value. The feed values of fruit seeds can be improved through germination, which involves the mobilization of nutrients through seed enzymes and alters the seed carbohydrate composition. The changes of selected carbohydrates in guava (Psidium guajava L.) seeds brought by germination to those in red bean (Vigna angularis) and winter wheat (Triticum aestivum L.) were compared. The contents of soluble carbohydrates, digestible starch, resistant starch and cellulose in the seeds were determined. The radial diffusion method was used to detect carbohydrate degrading enzymes in the seed extracts. Guava seeds were rich in cellulose (402.2 mg/g), which decreased progressively during germination, probably through the action of cellulase. Winter wheat contained the highest starch content (412.2 mg/g) and also distinct quantities of alpha-amylase and cellulase. The starch contents of all the seeds decreased, but the soluble carbohydrate contents in red beans and guava seeds increased significantly by the end of germination, suggesting the transient oversupply of reserve metabolites. The content of hydrolyzed polysaccharides increased in the germinated seeds with detectable amounts of cellulose-degrading enzymes present, indicating improved value as feed. Further research is warranted to explore the potential of guava seeds as a source of low-cost animal feed supplements. PMID- 28720960 TI - Levels and formation of alpha-dicarbonyl compounds in beverages and the preventive effects of flavonoids. AB - ABSTRACT: Methylglyoxal (MGO) and glyoxal (GO), alpha-dicarbonyl compounds found in the Maillard reaction, progressively and irreversibly modify proteins. Beverages are an exogenous source of alpha-dicarbonyl compounds and may potentially increase MGO and GO levels in vivo. Using GC-FID method, we detected the MGO and GO contents of 86 beverages in Chinese supermarkets. The highest MGO and GO 587.5 ug/100 mL and 716.7 ug/100 mL respectively found in soyamilk and coffee. Herbal beverages, which contained bioactive components, had lower average levels of MGO (48.1 ug/100 mL) and GO (25.9 ug/100 mL). A box-and-whisker plot was used to display variation of the same group drinks, and comparing distributions between six different groups. It was further discovered that fat, protein and flavonoids, in addition to sweeteners, had notable effects on the formation of MGO and GO in soybean milk. The result of LC/MS indicated that quercetin could prevent the formation of MGO by trapping MGO to form the mono-MGO and di-MGO adducts during soybean milk manufacturing. GRAPHICAL ABSTRACT: PMID- 28720962 TI - Minimally processed beetroot waste as an alternative source to obtain functional ingredients. AB - Large amounts of waste are generated by the minimally processed vegetables industry, such as those from beetroot processing. The aim of this study was to determine the best method to obtain flour from minimally processed beetroot waste dried at different temperatures, besides producing a colorant from such waste and assessing its stability along 45 days. Beetroot waste dried at 70 degrees C originates flour with significant antioxidant activity and higher betalain content than flour produced from waste dried at 60 and 80 degrees C, while chlorination had no impact on the process since microbiological results were consistent for its application. The colorant obtained from beetroot waste showed color stability for 20 days and potential antioxidant activity over the analysis period, thus it can be used as a functional additive to improve nutritional characteristics and appearance of food products. These results are promising since minimally processed beetroot waste can be used as an alternative source of natural and functional ingredients with high antioxidant activity and betalain content. PMID- 28720963 TI - Releasing characteristics of anthocyanins extract in pectin-whey protein complex microcapsules coated with zein. AB - This study investigated pectin-based capsules as delivery systems for purple rice bran anthocyanin extract (AE) during exposure to simulated gastrointestinal conditions. Four different capsules loaded with AE were prepared by ionotropic gelation/extrusion, including (1) pectin capsules (PE), (2) pectin capsules coated with zein (PE/ZE), (3) pectin-whey protein isolate complex capsules (PE + WP), and (4) pectin-whey protein isolate complex capsules coated with zein (PE + WP/ZE). CaCl2 in an ethanol solution with or without zein was used as a crosslinking solution. Swelling and release characteristics of all capsules under simulated gastric fluid at pH 1.2 (SGF) and simulated intestinal fluid at pH 6.8 (SIF) for 120 and 180 min, respectively, were examined. PE + WP, PE + WP/ZE, and PE/ZE capsules had higher encapsulation efficiency than PE capsules. After incubation, PE + WP/ZE and PE capsules had the lowest swelling ratio in SGF and SIF, respectively. PE + WP/ZE capsules had the lowest AE release in SGF, while PE capsules had the highest. Both PE + WP and PE + WP/ZE capsules had significantly lower AE release in SIF than PE and PE/ZE capsules. The study demonstrated that PE + WP and PE + WP/ZE capsules have potential to function as a slow release delivery system for AE. PMID- 28720964 TI - Antimicrobial effect of black pepper petroleum ether extract for the morphology of Listeria monocytogenes and Salmonella typhimurium. AB - This study aimed to evaluate the effects of black pepper petroleum extract (BPPE) on pathogenic bacteria. The extraction from black pepper showed intense antimicrobial activity against the Gram-positive Listeria monocytogenes ATCC 19115 and the Gram-negative bacteria Salmonella typhimurium ATCC 14028. The minimum inhibitory concentrations of BPPE against L. monocytogenes and S. typhimurium were 0.625 and 1.25 mg/ml, respectively. Detection of Alkaline phosphatase outside the cell revealed that BPPE treatment destroyed the cell wall integrity. BPPE also altered the membrane integrity, thereby causing leaching of 260 and 280 nm UV-absorbing materials into the medium, particularly, nucleic acids and proteins. Propidium iodide infiltration experiments also indicated that BPPE treatment altered the permeability of bacterial cell membrane. Moreover, Na+/K+-ATPase activity was inhibited by BPPE. And the results of scanning electron microscopy showed that BPPE treatment damaged the morphology of the tested bacteria. These results indicated that BPPE could destroy cell wall integrity, alter the permeability of cell membrane, and inhibit the activity of intracellular enzyme, which could kill bacteria. PMID- 28720965 TI - Antioxidant efficacy of soybean cake extracts in soy oil protection. AB - The aim of this study was to evaluate the presence and possibility of extracting compounds with antioxidant properties of soybean cake to extend the storage stability of soybean oil. Results showed that the highest DPPH radical scavenging activity was observed for sample to solvent ratio 1:25 while extracting by 70% ethanol for 3 h). The most phenolic compounds equivalents (Gallic acid) was observed for sample to solvent ratio 1:25 while extracting by 70% methanol for 14 h. In addition, the soybean cake extract at concentrations of 50, 100, 150 and 200 ppm in soybean oil could significantly lower the peroxide, diene and p anisidine values of soy oil during storage at 65 degrees C. PMID- 28720966 TI - Biochemical characterization and thermal inactivation of polyphenol oxidase from elephant foot yam (Amorphophallus paeoniifolius). AB - Polyphenol oxidase from Amorphophallus corm was purified (5.54 fold) by acetone precipitation and ion exchange chromatography. Electrophoretic-blot analysis revealed that the molecular weight of enzyme is 40 kDa. Enzyme preferred catechol as substrate and showed optimum activity at pH 6 and 35 degrees C with Km of 17.56 mM and Vmax 0.023 U/ml/min. Thermal inactivation kinetics study showed that 5.68% inactivation was achieved at 75 degrees C within 40 min. The half-life time of PPO is between 126.00 and 32.54 min. The activation energy (Ea) and Z values are 64.22 kJ/mol and 34.01 degrees C, respectively. The inhibitory action of L-ascorbic acid, sodium azide, NaCl, CaCl2, ZnSO4 and EDTA were studied. Thermodynamic studies indicated a non-spontaneous (DeltaG > 0) and endothermic reaction process. Other thermodynamic activation parameters, such as Ea, DeltaH#, DeltaG# and DeltaS#, were also studied. Amorphophallus paeoniifolius polyphenol oxidase can find application in baking industry. PMID- 28720967 TI - Degree of roasting of carob flour affecting the properties of gluten-free cakes and cookies. AB - Carob flour is a product rich in fibre obtained from by-products of the locust bean gum extraction processing. The flour is commercialised with different degrees of roasting in order to improve its organoleptic characteristics. In this study, carob flour with three different roasting degrees was used to replace rice flour (15%) in gluten-free cakes and cookies. The influence of this replacement was studied on the psychochemical characteristics and acceptability of the final products. The incorporation of carob flour increased the viscosity of cake batters and increased the solid elastic-like behaviour of the cookie doughs, indicating a stronger interaction among the formula ingredients. The inclusion of carob flour, with a low time of roasting, did not lead to any significant differences in the specific volume and hardness of the cakes, but reduced cake staling and the thickness and width of the cookies. Darker colours were obtained when carob flour was incorporated into the product. The acceptability of cakes was only reduced with the addition of highly roasted carob flour, while in the case of cookies there was a decline in the acceptability of all carob flour cookies, which was mostly perceived with the highest roasting degree, something mainly attributed to the bitter taste of the products. PMID- 28720968 TI - Technological quality of dough and breads from commercial algarroba-wheat flour blends. AB - Algarroba flour is used to supplement lysine-limiting systems such as wheat flour due to its amino acidic composition. The effects of adding up to 30% of this flour to wheat flour (W-A30) on dough characteristics and breadmaking performance were studied. Dough rheology was tested by farinograph, oscillatory rheometry and texture profile analyses. Molecular mobility was evaluated by nuclear magnetic resonance, and thermal properties were analyzed by differential scanning calorimetry and viscoamylograph studies. Besides, different bread quality parameters were evaluated. Incorporation of algarroba flour resulted into increase in water absorption, development time and degree of softening, and decrease in stability of wheat flour, leading to softer, less adhesive and elastic dough, although at intermediate replacement levels cohesiveness improved. At the molecular level, a reduction of water activity and limited proton motion were observed in W-A30 samples, suggesting that protons were highly bound to the dough matrix. Dough samples with algarroba flour showed lower G' and G" values than the control, although with the formation of a more elastic structure for W A30. In addition, algarroba flour produced a protective effect on starch granule disruption and interfered with amylose-amylose association during cooling. The specific volume of breads decreased with the increase in algarroba level, W-A30 reaching the highest decrease (15%). Bread crumbs with algarroba flour exhibited higher values of hardness and resilience. The use of algarroba flour resulted in lower quality when compared to the control. However, algarroba flour at 20% level can be added to wheat flour to obtain bakery products of similar technological quality and with improved nutritional components. PMID- 28720969 TI - Quantification of phenolics in Syzygium cumini seed and their modulatory role on tertiary butyl-hydrogen peroxide-induced oxidative stress in H9c2 cell lines and key enzymes in cardioprotection. AB - The study quantified the major phenolics in different fractions of Syzygium cumini seeds and evaluated their cardioprotective efficacy. Gallic acid, ellagic acid, cinnamic acid, quercetin, syringic acid and ferulic acid were the major polyphenols present in different fractions of Syzygium cumini seeds. The cardioprotective effect of Syzygium cumini seed fractions in modulating angiotensin converting enzyme (ACE), HMG-CoA reductase, LDL oxidation and tertiary butyl hydrogen peroxide (TBHP) induced oxidative stress in H9c2 cardiac cell lines were investigated. Syzygium cumini effectively attenuated the cellular oxidative stress in H9c2 cardiomyoblasts. These fractions possessed inhibitory potential against ACE, HMG-CoA reductase and LDL oxidation. Molecular docking studies of the predominant polyphenols with ACE and HMG-CoA proteins revealed the binding interactions of these compounds, thus confirming their modulation of activity. The present study demonstrated the cardioprotective efficacy of Syzygium cumini seed fractions which can be attributed to the presence of phenolic acids and flavonoids. PMID- 28720970 TI - Effect of rice bran oil spread on the physical, sensory and fatty acid profile of cake. AB - Studies were carried out to replace hydrogenated fat (HF) with rice bran oil (RBO) and two varieties of rice bran oil spread RBOS1 and RBOS2 in the preparation of cake. Physico-chemical properties, sensory properties, scanning electronic microscopic (SEM) study and fatty acid estimation with reference to trans fatty acids of cake made with control and experimental samples were studied. The best acceptable cake among the four i.e., RBOS2 cake was selected for consumer evaluation along with control (HF) cake. Results revealed that there was no significant difference in overall acceptability of cake made with HF and RBOS2. The internal structure and pore structure of RBOS2 cake was finer and smoother than the control cake as per SEM imaging. The pores within the core varied in diameter between 13.9 and 29.6 um in control cake and between 16.9 and 58.6 um in RBOS2 cake at 500 * magnification indicating good textural properties compared to HF cake. The fatty acids analysis results showed that the amount of total trans fatty acids (TFA) was 15.46% in HF cake, 3.56% in RBO cake, 4.54% in RBOS1 cake, and 3.78% in RBOS2 cake. The major trans fatty acids observed in all samples were elaidic acid (C18:1 trans-9) and Linolelidic acid (C18:2, trans-6). Elaidic acid was the highest in HF cake (6.64%) and the least in RBO cake (2.62%). Linolelidic acid was the highest in HF cake (8.48%) and the least in RBOS2 cake (0.91%). Trans Vaccenic acid was detected only in HF cake (0.34%). TFA content assumes significance in terms of its ill effects on the health of consumers, only if fat content is also high. Hence, consumption of the HF products might prove to be harmful, if consumed in large amounts and at higher frequencies. Therefore RBOS can be promoted as healthy fat for production of baked products. PMID- 28720971 TI - Determination of anthocyanins and non-anthocyanin polyphenols by ultra performance liquid chromatography/electrospray ionization mass spectrometry (UPLC/ESI-MS) in jussara (Euterpe edulis) extracts. AB - This work aimed to propose two analytical methods for the quantitative and qualitative analysis of major anthocyanins and non-anthocyanin phenolic compounds in jussara (Euterpe edulis) extracts, using ultra performance liquid chromatography-mass spectrometry. These methods were evaluated for selectivity, precision, linearity, detection and quantification limits. The complete separation of 5 anthocyanins and 22 non-anthocyanins polyphenols was achieved in 4.5 and 7 min, respectively. Limits of detection ranged from 0.55 to 9.24 ug/L, with relative standard deviation for concentration up to 7.0%. In jussara extract, 13 of the 27 analytes were characterized. The dominant compound was cyanidin-3-O-rutinoside, representing about 73% of the total phenolic compounds content (approximately 23 mg/g of extract in dry weight). Other phenolic compounds found in the extract were: cyanidin-3-O-glucoside, pelargonidin-3-O glucoside, quercetin, rutin, myricetin, kaempferol, kaempferol-3-O-rutinoside, luteolin, apigenin, catechin, ellagic acid and 4,5-dicaffeoylquinic acid. PMID- 28720972 TI - Optimization of microwave roasting of peanuts and evaluation of its physicochemical and sensory attributes. AB - In this study, the microwave (MW) roasting (MWR) of peanuts (Arachis hypogaea L.) is attempted, optimized and compared with conventional drum roasting. A two factor/three level face centered composite design based MWR experiments was conducted at different roasting time (60, 180 and 300 s) and MW power levels (180, 540 and 900 W). The roasting quality was analyzed by physicochemical and sensory attributes of roasted peanuts and extracted oil viz., moisture loss, hardness, browning index (BI), induction period (IP) based on Rancimat, peroxide value (PV) and overall acceptability (OA), respectively. A roasting time and MW power dependent improvement in the desired quality of roasted peanuts and extracted oil was observed attributable to the formation of antioxidant Maillard reaction compounds. A second order polynomial model adequately described the roasting experimental data (p < 0.0001, R2 > 0.90) with an insignificant lack of fit (p > 0.05). Using response surface methodology, the MWR was optimized at roasting time of 201 s and MW power level of 900 W which yielded favorable values of quality attributes (moisture loss, 3.06%; hardness, 4528.34 g; BI, 58.89; IP, 8.12 h; PV, 8.80 milliequivalents O2/kg; OA, 6.40). Furthermore, the quality assessment of ground peanuts for selected time-power combinations (low, optimum and high roasts) was attempted using scanning electron microscopy, electronic nose and Fourier transform infrared spectroscopy which revealed better quality of optimized MWR peanuts. PMID- 28720973 TI - Functional and physicochemical characteristics of cookies prepared from Amorphophallus paeoniifolius flour. AB - This study was undertaken to prepare novelly formulated cookies from elephant foot yam flour (EFYF) with refined wheat flour (RWF) and evaluate their proximate composition, quality characteristics, texture, pasting and organoleptic properties. The formulated cookies prepared from EFYF, substituting RWF up to 70% had sensory properties similar to that of refined flour cookies (control). EFYF and RWF blend revealed reduced water and oil absorption capacity with increased peak and final viscosities when compared with RWF. Reduced lightness, increased redness and hardness were observed for formulated cookies with increase in storage time. Irrespective of the decreasing trend in their texture, overall acceptance of the EFYF cookies by the consumers was increased. Sensory scores revealed the preference of consumers towards formulated cookies. Overall analysis disclosed that the cookies prepared from A. paeoniifolius flour proved acceptable not only in quality characteristics but also fulfil the demand of functional foods in preparation of cookies. PMID- 28720974 TI - Effect of electric field on the characteristics of crude avocado oil and virgin olive. AB - The objective of this study was to analyze the effect of an electric field treatment (voltage 9 kV cm-1, frequency 720 Hz and time of 5 and 25 min) as method of preservation on two edible oils. Unsaturated fatty acid oxidation in the crude avocado oil and virgin olive oil was analyzed by Fourier transform infrared spectroscopy in the mid infrared region and by quality parameters (acidity, peroxide and iodine). The electric field is a suitable method to preserve the crude oils composition with minimal modifications without the synthetic antioxidant addition. PMID- 28720975 TI - Active starch biopolymeric packaging film for sausages embedded with essential oil of Syzygium aromaticum. AB - Starch polymer matrices were developed with the incorporation of 1% clove essential oil (EO) (Syzygium aromaticum) aiming for use as active packaging for sausages. At the concentration of 1% EO in the polymer matrix, it showed exponential behavior with respect to oil release over 30 days, with faster release in the beginning and a tendency towards a reduction in release velocity over time. The presence of OE in the biofilm led to significant differences versus the control in terms of aroma and flavor parameters. It was found that EO had an antioxidant effect in sausages with a significant difference between treatments with respect to TBA (thiobarbituric acid) values at the end of a 15 day period of refrigerated storage. There were no significant variations in pH and Aw among treatments during the evaluated period. A significant negative correlation (-0.78) between brightness (L*) and the lipid oxidation of the products was observed. PMID- 28720976 TI - Effect of enzymatic treatment on the rheological behavior and vitamin C content of Spondias tuberosa (umbu) pulp. AB - Umbu is a native fruit of the semi-arid Northeastern region of Brazil, which presents an exotic and differentiated flavor. Containing vitamin C and presenting a high potential of consumption, no appropriated technology has been developed to process this fruit and expand its commercialization to other markets. The enzymatic treatment of fruit pulps leads to viscosity reduction, which makes possible an efficient processing for obtaining high quality umbu juices. In order to contribute to the valorization of this underexploited culture, two commercial pectinolytic enzymes, Pectinex Ultra SP-L(r) and Rapidase TF(r), were used to promote viscosity reduction of umbu pulp. The effect of reaction temperature (35, 45 and 55 degrees C) and enzyme concentration (100, 200 and 300 ppm) on the rheological properties of the fruit pulp was evaluated. In relation to the viscosity of the original pulp (84.8 mPa s at 100 s-1 shear rate), a significant, four times lower, viscosity reduction of 18.9 mPa s was observed. Under optimum process condition (35 degrees C and Rapidase at 100 ppm concentration), the lowest viscosity was achieved after 40 min of reaction. Under these reaction conditions, no significant change was found in the vitamin C content, indicating the preservation of functional and nutritional properties of umbu pulp. PMID- 28720977 TI - Effect of integration of oxalic acid and hot water treatments on postharvest quality of rambutan (Nephelium lappaceum L. cv. Anak Sekolah) under modified atmosphere packaging. AB - The shelf life of rambutan is often limited due to rapid water loss from the spinterns and browning of the pericarp. An integrated approach, which combined hot water treatment (HWT) (56 degrees C for 1 min), oxalic acid (OA) dip (10% for 10 min) and modified atmosphere packaging (MAP), was used to study their effectiveness on the quality of rambutan during storage (10 degrees C, 90-95% relative humidity). Significant differences were observed in rambutan quality with the combination of MAP + HWT + OA after 20 days of storage. This treatment combination resulted into better retention of firmness and colour (L and a* values) than in the control. Change in the total soluble solid content was significantly delayed however the titratable acidity showed no significant change in comparison to the control at the end of storage. PMID- 28720978 TI - Extraction and preparation of high-aroma and low-caffeine instant green teas by the novel column chromatographic extraction method with gradient elution. AB - The lack of aroma and natural taste is a critical problem in production and consumption of instant green teas. A method to prepare instant green teas high in natural-aroma and low-caffeine by the novel column chromatographic extraction with gradient elution is reported. This method simultaneously extracted aroma (or volatile) and non-aroma compounds from green tea. Green tea was loaded into columns with 2.0-fold of petroleum ether (PE): ethanol (8:2). After standing for 3 h until the aroma compounds dissolved, the column was sequentially eluted with 3.0-fold 40% ethanol and 3.5-fold water. The eluant was collected together and automatically separated into PE and ethanol aqueous phases. The aroma extracts was obtained by vacuum-evaporation of PE phase at 45 degrees C. The ethanol aqueous phase was vacuum-concentrated to aqueous and partially or fully decaffeinated with 4% or 9% charcoal at 70 degrees C. A regular instant green tea with epigallocatechin-3-gallate: caffeine of 3.5:1 and a low-caffeine instant green tea (less than 1% caffeine) with excellent aroma and taste were prepared, by combining the aroma and non-aroma extracts at a 1:10 ratio. This work provides a practical approach to solve the low-aroma and low-taste problems in the production of high quality instant green teas. PMID- 28720979 TI - First report of Phyllosticta citricarpa and description of two new species, P. paracapitalensis and P. paracitricarpa, from citrus in Europe. AB - The genus Phyllosticta occurs worldwide, and contains numerous plant pathogenic, endophytic and saprobic species. Phyllosticta citricarpa is the causal agent of Citrus Black Spot disease (CBS), affecting fruits and leaves of several citrus hosts (Rutaceae), and can also be isolated from asymptomatic citrus tissues. Citrus Black Spot occurs in citrus-growing regions with warm summer rainfall climates, but is absent in countries of the European Union (EU). Phyllosticta capitalensis is morphologically similar to P. citricarpa, but is a non-pathogenic endophyte, commonly isolated from citrus leaves and fruits and a wide range of other hosts, and is known to occur in Europe. To determine which Phyllosticta spp. occur within citrus growing regions of EU countries, several surveys were conducted (2015-2017) in the major citrus production areas of Greece, Italy, Malta, Portugal and Spain to collect both living plant material and leaf litter in commercial nurseries, orchards, gardens, backyards and plant collections. A total of 64 Phyllosticta isolates were obtained from citrus in Europe, of which 52 were included in a multi-locus (ITS, actA, tef1, gapdh, LSU and rpb2 genes) DNA dataset. Two isolates from Florida (USA), three isolates from China, and several reference strains from Australia, South Africa and South America were included in the overall 99 isolate dataset. Based on the data obtained, two known species were identified, namely P. capitalensis (from asymptomatic living leaves of Citrus spp.) in Greece, Italy, Malta, Portugal and Spain, and P. citricarpa (from leaf litter of C. sinensis and C. limon) in Italy, Malta and Portugal. Moreover, two new species were described, namely P. paracapitalensis (from asymptomatic living leaves of Citrus spp.) in Italy and Spain, and P. paracitricarpa (from leaf litter of C. limon) in Greece. On a genotypic level, isolates of P. citricarpa populations from Italy and Malta (MAT1-2-1) represented a single clone, and those from Portugal (MAT1-1-1) another. Isolates of P. citricarpa and P. paracitricarpa were able to induce atypical lesions (necrosis) in artificially inoculated mature sweet orange fruit, while P. capitalensis and P. paracapitalensis induced no lesions. The Phyllosticta species recovered were not found to be widespread, and were not associated with disease symptoms, indicating that the fungi persisted over time, but did not cause disease. PMID- 28720980 TI - Efficacy of Cognitive Rehabilitation Therapy on Poststroke Depression among Survivors of First Stroke Attack in Ibadan, Nigeria. AB - BACKGROUND AND PURPOSE: Poststroke depression (PSD) is a common complication after stroke. There is no adequate treatment for PSD. This study examined efficacy of cognitive rehabilitation therapy (CRT) in the treatment of PSD among stroke survivors. METHODS: An experimental design, 30 participants with poststroke depression were randomly assigned into 3 groups of cognitive rehabilitation therapy (CRT), psychoeducation (PE), and the control group (CG). CRT consisted of nine sessions with three-phased sessions focusing on activity stimulation, negative thoughts, and people contacts, PE consisted of nine sessions focusing on knowledge on stroke and poststroke depression, and the CG group was on the waiting list. The BDI scale was used for assessing PSD at posttest. RESULTS: There was a significant difference in the efficacy of CRT, PE, and the CG on PSD, with CRT-CG mean difference of -9.4 +/- 3.11 and PE-CG 1.0 +/- 3.83. Furthermore, stress was not a confounding variable on the efficacy of CRT. The type of therapy significantly influenced PSD at posttest, with the CRT having greater mean reduction to CG (-11.1 +/- 3.1) than PE to the CG (3.0 +/- 3.8). CONCLUSIONS: Cognitive rehabilitation therapy significantly reduced poststroke depression. Hence, it should be integrated as an adjunct treatment of poststroke depression. PMID- 28720982 TI - Single incision pediatric flexible intramedullary tibial nailing. AB - BACKGROUND: There has been a trend towards flexible intramedullary nailing for unstable tibial shaft fractures in the pediatric population, traditionally, utilizing a 2-incision technique with passage of one nail medially and one nail laterally. Our study aims to compare a single incision approach for flexible nailing of unstable tibial shaft fractures in pediatric patients to the traditional 2-incision approach. METHODS: Patients were selected for operative fixation if they had a length unstable tibial shaft fracture confirmed by fluoroscopy. Exclusion criteria included length stable tibial fractures that could undergo nonoperative treatment. Single incision technique utilized the medial incision only. Patients were monitored in the hospital for one postoperative day and followed up at 4 week, 8 week, and 12 week marks. Radiographic analysis was performed to evaluate for malunion or nonunion. Operative times, infection rates and complications were recorded and analyzed. RESULTS: All patients achieved complete fracture healing at the 12-week follow up. There were no delayed unions, nonunions or malunions in either treatment group. CONCLUSIONS: Single medial incision for tibial flexible nails had equivalent outcomes with no difference in primary healing rate, malunion or nonunion rate when compared to the dual incision technique. PMID- 28720983 TI - Spinal trauma. PMID- 28720981 TI - Cerebral Reorganization in Subacute Stroke Survivors after Virtual Reality-Based Training: A Preliminary Study. AB - BACKGROUND: Functional magnetic resonance imaging (fMRI) is a promising method for quantifying brain recovery and investigating the intervention-induced changes in corticomotor excitability after stroke. This study aimed to evaluate cortical reorganization subsequent to virtual reality-enhanced treadmill (VRET) training in subacute stroke survivors. METHODS: Eight participants with ischemic stroke underwent VRET for 5 sections per week and for 3 weeks. fMRI was conducted to quantify the activity of selected brain regions when the subject performed ankle dorsiflexion. Gait speed and clinical scales were also measured before and after intervention. RESULTS: Increased activation in the primary sensorimotor cortex of the lesioned hemisphere and supplementary motor areas of both sides for the paretic foot (p < 0.01) was observed postintervention. Statistically significant improvements were observed in gait velocity (p < 0.05). The change in voxel counts in the primary sensorimotor cortex of the lesioned hemisphere is significantly correlated with improvement of 10 m walk time after VRET (r = 0.719). CONCLUSIONS: We observed improved walking and increased activation in cortical regions of stroke survivors after VRET training. Moreover, the cortical recruitment was associated with better walking function. Our study suggests that cortical networks could be a site of plasticity, and their recruitment may be one mechanism of training-induced recovery of gait function in stroke. This trial is registered with ChiCTR-IOC-15006064. PMID- 28720984 TI - Spinal cord injury-The role of surgical treatment for neurological improvement. AB - Acute spinal cord injury (ASCI) is common and no consensuses have been reached regarding timing of surgical decompression. This article highlights the main issues regarding surgical management of ASCI patients. The importance of timing of surgery along with physiological stability of the cord, and indications for surgery has been discussed to facilitate better understanding of the condition. The importance of the type of injury to the spinal column, besides the cord injury, is also discussed. A brief review of relevant literature has been done to try and answer the question whether early or late surgical treatment for ASCI is better than conservative management, reflecting the ethos of treatment for these problems in Robert Jones And Agnes Hunt Orthopaedic Hospital in Oswestry. PMID- 28720985 TI - Conservative Management of Odontoid Peg Fractures, long term follow up. AB - OBJECTIVE: The aim of the study was to look at the long-term effects of conservative management of odontoid peg fractures. METHODS: We reviewed 48 consecutive patients with type II (32) and 16 type III, odontoid peg fractures. The clinical & radiological outcomes were assessed over an average period of follow up of 8 years. Union rate was determined and we discussed several factors that may affect it. Patients were treated conservatively with an average period of bed rest of 4 weeks followed by bracing for an average of 9 weeks. RESULTS: Bony union was established in 25 of 32 (78%) type II fractures. Of 7 cases of no bony union 4 were stable probably with fibrous union. 3 remained unstable. In 13 of 16(83%) type III fractures bony union was established. 2 of the 3 with no bony union were considered stable. CONCLUSION: Osseous non-union was higher in patients with displacement of >5 mm, but there is no correlation between union and age, gender or angulation of the fracture in both types. PMID- 28720987 TI - Management of post-traumatic neglected cervical facet dislocation. AB - BACKGROUND: Post-traumatic unilateral or bilateral sub-axial cervical spine dislocations with locked facets are quite common. In developing countries like India, many patients with cervical injuries report late due to many reasons like rural backgrounds, lack of infrastructures and skilled surgeons, unawareness, poor socioeconomic status, lack of transportation to the specialized center with proper facility, etc. Early management is essential to maximize better neurological outcome. Delayed or neglected presentation makes treatment more challenging. Very few literatures are currently available regarding management of neglected cervical facet dislocation but no one offers clear cut management. Purpose of our study is to evaluate treatment outcome of 15 patients with post traumatic neglected cervical facet dislocation. Here we have reviewed 15 patients with post-traumatic neglected presentation of cervical facet dislocations and evaluated their treatment outcome. MATERIALS AND METHODS: This is a retrospective type of study done in spine care unit of VMMC and Safdarjung Hospital, New Delhi from July 2013 to June 2016. Record of 15 patients with neglected cervical dislocation who were undergone anterior cervical discectomy and fusion along with posterior lateral mass screw fixation depending upon close reduction and integrity of disco-ligamentous complex. RESULTS: 15 patients were included in this study. 4 patients underwent only anterior cervical discectomy and fusion (ACDF) after complete close reduction with intact disco-ligamentous complex. Remaining 11 patients who failed to achieve complete reduction or had posterior disco-ligamentous injuries underwent posterior partial facetectomy and lateral mass screw fixation with anterior discectomy and fusion concomitantly. Mean follow up period was 14 months. All patients achieved pain relief and sufficient neck movements. 1 patient with only nerve root injuries recovered completely. 6 out of 11 patients with incomplete spinal cord injuries, improved by one Frankel grade and remaining 5 patients by two grades. 3 patients with complete quadriplegia showed no clinical and neurological improvement. CONCLUSION: Proper decompression, reduction and fixation should be done in neglected cervical dislocation as it provides mechanical stability and alignment, facilitates rehabilitation, prevent kyphotic deformity as well as offers a fair chance of neurological recovery. PMID- 28720986 TI - Imaging investigations in Spine Trauma: The value of commonly used imaging modalities and emerging imaging modalities. AB - Traumatic spine injuries can be devastating for patients affected and for health care professionals if preventable neurological deterioration occurs. This review discusses the imaging options for the diagnosis of spinal trauma. It lays out when imaging is appropriate and when it is not. It discusses strength and weakness of available imaging modalities. Advanced techniques for spinal injury imaging will be explored. The review concludes with a review of imaging protocols adjusted to clinical circumstances. PMID- 28720988 TI - Non-surgical management of acute osteoporotic vertebral compression fracture: A review. AB - Osteoporosis is a major public health problem. Last decade has seen rise in osteoporotic vertebral fractures. Pragmatic management of osteoporotic VCF is challenging to the surgeons. In clinical settings, the situation becomes more complex when it comes to managing painful osteoporotic vertebral compression fractures (VCFs) due to various co-morbid factors that may limit aggressive interventions. Patients with Osteoporotic vertebral fractures are often characterized by general/relative immobility and physical frailty. Osteoporotic VCF not only affects the quality of life (e.g. pain) but also decreases the lifespan of the individual. The present review critically evaluates the currently prevailing non-surgical management modalities (conservative) offered in acute symptomatic osteoporotic VCFs that occur either within (0-5 days) of any incident event or present with the onset of symptoms such as pain. PMID- 28720989 TI - Trapezius perforator flap for reconstruction of a posterior cervical defect. AB - The use of free flaps is considered the "gold standard" for reconstruction of head and neck defects. Locoregional flaps allows a better aesthetic result compared to free flaps, whenever there's an external skin defect. However the use of free flaps is not always adequate in the presence of preoperative comorbidities or previous surgeries. Since the description of the trapezius myocutaneous flap in the 1980's, many authors have published the results of the applicability of this flap in head and neck salvage reconstructive surgery. Nonetheless, the concern with trapezius muscle function remains an important issue. The onset of free-style dissection perforator flaps has attenuated this problem. The authors present a case of a 68 year old man with a posterior cervical wound after a cervical spine trauma, who underwent multiple spine surgeries, successfully treated with an island muscle-sparing trapezius flap. All the details of the dissection technique are outlined. The authors found the trapezius perforator flap to be a reliable and accessible to raise flap with a negligible donor-site morbidity. This flap can be used for occiput, nuchal and spinal areas injuries without the local morbidity related to other flap options. PMID- 28720990 TI - Selective nerve root blocks vs. caudal epidural injection for single level prolapsed lumbar intervertebral disc - A prospective randomized study. AB - BACKGROUND: Chronic lumbar radiculopathy has a lifetime prevalence of 5.3% in men and 3.7% in women. It usually resolves spontaneously, but up to 30% cases will have pronounced symptoms even after one year. AIMS: A prospective randomized single-blind study was conducted to compare the efficacy of caudal epidural steroid injection and selective nerve root block in management of pain and disability in cases of lumbar disc herniation. METHODS: Eighty patients with confirmed single-level lumbar disc herniation were equally divided in two groups: (a) caudal epidural and (b) selective nerve root block group, by a computer generated random allocation method. The caudal group received three injections of steroid mixed with local anesthetics while selective nerve root block group received single injection of steroid mixed with local anesthetic agent. Patients were assessed for pain relief and reduction in disability. RESULTS: In SNRB group, pain reduced by more than 50% up till 6 months, while in caudal group more than 50% reduction of pain was maintained till 1 year. The reduction in ODI in SNRB group was 52.8% till 3 months, 48.6% till 6 months, and 46.7% at 1 year, while in caudal group the improvement was 59.6%, 64.6%, 65.1%, and 65.4% at corresponding follow-up periods, respectively. CONCLUSIONS: Caudal epidural block is an easy and safe method with better pain relief and improvement in functional disability than selective nerve root block. Selective nerve root block injection is technically more demanding and has to be given by a skilled anesthetist. PMID- 28720991 TI - Transforaminal epidural Etanercept for the treatment of prolapsed lumbar intervertebral disc induced sciatica. AB - STUDY DESIGN: Hospital based prospective study. OBJECTIVE: To study clinical response of transforaminal epidural Etanercept for lumbar prolapsed intervertebral disc induced sciatica. METHOD: Patients presenting to O.P.D and Emergency services of our hospital were screened for inclusion and exclusion criteria & suitable candidates were enrolled in study. Patients received 2 transforaminal epidural injections of Etanercept 2 mg, 2 weeks apart, and were assessed for efficacy at 2 week, 1 month and 3 months after the second injection. Primary outcome was based on Visual Analog Scale for leg (VASL) and back pain (VASB) and secondary outcome was based on Modified Oswestry back related disability index (ODI). RESULTS: 31 of 33 enrolled patients completed study. Patients showed clinically and statistically significant (p < 0.001) reduction in VASL, VASB and ODI. There was no incidence of adverse events. CONCLUSION: Epidural Etanercept is promising and effective non-operative treatment for patients with sciatica. But these results need to be confirmed by a randomized controlled trial. PMID- 28720992 TI - Ganglion cyst of the hip mimicking lumbar disk herniation - A case report. AB - Sciatic nerve compression due to a ganglion cyst around the posterior aspect of the hip joint is not commonly described in literature. We report a rare case of a 63-year-old man with a ganglion cyst around his hip joint, who presented with symptoms of sciatica. After excision of the cyst, the patient was symptom free. A high index of clinical doubt and detailed clinical examination is required for non-palpable cystic lesions in close proximity to the sciatic nerve in patients presenting with symptoms of sciatica and in patients with concomitant of lumbar disk herniation. PMID- 28720993 TI - Inserting pedicle screws in lumbar spondylolisthesis - The easy bone conserving way. AB - BACKGROUND: Pedicle screw fixation in high grade lumbar listhetic vertebral body has been nightmare for Orthopaedic and spine surgeons. This is because of abnormally positioned listhetic pedicles and non-visualization of pedicle in conventional image intensifier (C-Arm). This results into increased surgical time, more blood loss, radiation exposure and more chances of infection. To overcome this problem, we have devised a new Technique of putting of pedicle screw fixation in listhetic vertebrae. METHODS: Total 20 patients of average age of 42 (25-56) were included during 2010 to 2015. Listhesis was classified according to etiology, Meyerding grading and DeWald modification of Newman criteria used for assessment of severity for spondylolisthesis on standing X-ray lumbosacral spine. Patients satisfying following criteria were considered for surgery. Age more than 20 years, with single involvement of either L4-5/L5-S1, high grade spondylolisthesis (>= 50% Meyerding grade), unresolving radiculopathy, cauda equina syndrome or pain with and without instability not relieved by 6 months of conservative treatment. According to Meyerding radiographic grading system,10 patients were of type II and 8 of type III and 2 of type IV. Treatment given was pedicle screw fixation, reduction of listhesis vertebra and spinal fusion with our technique. PLT was done in 10 cases and transforaminal lumbar interbody fusion (TLIF) in the other 10 cases. RESULTS: Mean follow up duration was 2 years (range 1.3-3.3 year). The average preoperative LBP VAS of low back pain were 6.7 and average LP VAS for leg pain 5.7. Postoperatively at final follow up there was reduction of LBP VAS to 2.2 and LP VAS to 0.5. There was rapid reduction in their LBP VAS in first two visits at 4 weeks and in LP VAS in first three visits at 8 weeks. The pain-free walking distance improved significantly. The average pre-operative ODI score was 51.4, improved to 18.6 postoperatively. There was no difference in above scores between PLT and TLIF. CONCLUSION: Our surgical technique used for high grade spondylolisthesis is safe, cost-effective, bone-preserving, reliable, and reproducible for high grade Lumber spondylolisthesis. PMID- 28720994 TI - Early migration of bone graft causing sigmoid colon perforation after trans foraminal lumbar interbody fusion. AB - BACKGROUND: Tran foraminal lumbar interbody fusion (TLIF) is a well accepted and standard technique of achieving spinal fusion using pedicle screws, cage and bone graft. We are presenting here a case of L4-L5 lumbar canal stenosis managed with TLIF that presented with sigmoid colon perforation due to bone graft migration 4 days after surgery. CASE REPORT: A 35 years old female underwent open TLIF (from right side) with decompression for L4-L5 lumbar canal stenosis. On 4th post op day she started having abdominal pain and distension. After radiograph reveled gas under diaphragm emergency laparotomy was done and 1 by 1 cm sigmoid colon perforation seen near recto-sigmoid junction. Bony spicules with sharp edges were seen embedded inside the perforation. DISCUSSION: The purpose of this case report is to present a rare complication and to raise awareness and high index of suspicion among spine surgeons for prevention, early detection and treatment. PMID- 28720995 TI - Tuberculosis - 'The great masquerader' presenting as a dumb-bell-shaped intradural extramedullary tumor in a 20-year-old female. AB - Tuberculosis has been known as the great masquerader for its varied presentations. We present an extraordinary case of a 20-year-old female who presented with paraparesis of two months. MRI showed an intradural, extramedullary dumb-bell-shaped, spinal cord tumor. With a provisional clinicoradiological diagnosis of benign nerve sheath tumor (schwannoma/neurofibroma), laminectomy was done. But after durotomy, frank pus was drained from the site of lesion and the laboratory investigations of the tissue and pus obtained proved it to be tubercular. This is a rare case reported in the literature where tuberculosis is mimicking as a dumb-bell-shaped, spinal cord tumor. PMID- 28720996 TI - Horner's syndrome in cervico-dorsal tuberculosis: A rare case report. AB - Tuberculosis is a disease that affects any part of body and presents with varied complications. A case of cervico-dorsal tuberculosis is described here presenting with quadriparesis and Horner's syndrome. Horner's syndrome as a complication of cervico-dorsal tuberculosis has not been reported yet in literature. PMID- 28720997 TI - Ossified ligamentum flavum causing neurological deficit above the level of post tuberculous kyphotic deformity. AB - Late onset paraplegia is a rare complication of spinal tuberculosis. Disease reactivation and cord compression by internal gibbus are the common causes for neurological deficit. We report a patient with post-tubercular kyphotic deformity in whom the late onset paraplegia is caused by ossified ligamentum flavum above the level of kyphotic deformity. The deficit was attributable to the ossified ligamentum flavum and she recovered completely following posterior decompression and instrumented posterolateral fusion. To the best of our knowledge, this is the first report of this unusual cause of late onset paraplegia. PMID- 28720998 TI - Spontaneous spinal epidural abscess in a normoglycemic diabetic patient - Keep it as a differential. AB - Spinal epidural abscess (SEA) is a rare and serious condition which can lead to permanent neurological deficit. Spontaneous SEA is even rarer condition with an incidence of less than 1 per 10,000 person-year. Being spontaneous, it has high chances of being misdiagnosed, more so when the risk factors are not clearly explainable for the condition. This is a case report of such a case in a middle aged normoglycemic recently diagnosed diabetic man with atypical presentation. The diagnosis was made after magnetic resonance imaging and confirmed after surgical intervention in form of spinal decompression and patient recovered after appropriate antibiotics. This article also sums up the risk factors of spontaneous SEA. PMID- 28720999 TI - India contribution to Spine Surgery: 15 most influential articles. AB - OBJECTIVE: To determine the number of articles published by Indian authors related to spine surgery and to enumerate the 15 most influential articles from India published in the field of spine surgery in national & international journals based on the citations they have received both in pubmed and google scholar. MATERIAL AND METHODS: A retrospective study using Pubmed database was performed for the years between 1960 and 2015, for the articles published from India in the field of spine surgery in various national and international journals. A total of 3181 citations were received for top 15 most influential articles in the field of spine surgery from India. RESULTS: A total of 885 papers from India were identified which were published by Indian authors related to spine surgery between year 1960 to 2015. The largest numbers of papers were published in International journals such as Spine (82) and in European Spine Journal (47). CONCLUSION: There are an increasing number of papers from India in the field of spine surgery literature. Most of the highly cited papers were related to tuberculosis. We expect further contributions from our country to the medical literature in the future. PMID- 28721000 TI - Roentgenographic and computerized tomography based morphometric analysis of cervical spinal canal diameters to establish normative measurements in an Indian population. AB - Compressive cervical myelopathy secondary to degenerative changes in the cervical spine is a common cause of neurologic morbidity in the elderly. Identification of canal stenosis and addressing it surgically in addition to the obvious compressive lesions is essential to obtain satisfactory results. We attempt to define the saggital and transverse diameters in a normal adult population presenting at our centre with head injuries. We found that the values were lower than those reported in comparable studies for a western population, and also that the dimensions in women are significantly lower than in men. PMID- 28721002 TI - Mobile Schwannomas of lumbar spine: A diagnostic dilemma. AB - Mobile Schwannoma is a very rare entity and is reported sparsely in literature, with most of them occurring in lumbar spine region. We present a case of seventy year-old male patient who had pain in lower back radiating to ipsilateral thigh. A diagnosis of migratory tumour was made based on findings of plain and contrast MRI preoperatively. We did a two level laminectomy and tumour excision. In this report, we intend to discuss various likely causes of tumour migration and various diagnostic methods to tackle this surgical dilemma, we have also attempted to review the sparse literature available till date on migratory lumber schwannoma. PMID- 28721001 TI - Diffuse idiopathic skeletal hyperostosis (DISH) - A common but less known cause of back pain. AB - Diffuse idiopathic skeletal hyperostosis (DISH) is a systemic non-inflammatory disease of an unknown aetiology. It is characterized by ossification of the enthesis and may significantly affect the quality of life of the affected individuals. Despite the fact that this disease was first described more than 60 years ago and is a relatively common condition in the society, its awareness among clinician is still limited. An awareness of this entity and its mimicking conditions is essential so as to reach to an early diagnosis and avoid unnecessary investigations and treatment. PMID- 28721003 TI - Patient compliance with venous thromboembolism prophylaxis (VTE). AB - Venous thromboembolic disease (VTE) comprises pulmonary embolism (PE) and deep vein thrombosis (DVT), and causes morbidity and mortality, particularly in trauma and orthopaedic patients. Prevalence of 0.9% and 1.2% respectively are reported, with mortality rates up to 13.8%. Chemical thromboprophylactic agents including low molecular weight heparin (LMWH) are considered cost effective in reducing VTE risk. Evidence for anti-platelets including Aspirin for VTE prophylaxis is less compelling and is not supported as monotherapy. There has been no published data on patient compliance with LMWH in trauma outpatients. We aimed to determine whether trauma outpatients accept LMWH after discussing their VTE risk and the evidence for prophylaxis. For those accepting prophylaxis, we also investigated their compliance for the duration of immobilisation. Lower limb injured patients treated with external immobilisation over a 6 month period at our major trauma centre were included. On completion of immobilisation, they were requested to complete a 17-point questionnaire. Patients declining injectable subcutaneous LMWH as prophylaxis were offered Aspirin 75 mg as a second line agent. Seventy five questionnaires were completed and five were excluded. Nineteen patients required surgical intervention for their injury, 51 were managed non-operatively. Thirty-one patients accepted LMWH and 30 chose Aspirin as an alternative. Nine patients declined or were not commenced on prophylaxis. Nineteen reported no missed Aspirin doses and 25 reported no missed LMWH doses. No patients reported missed doses due to pain, side effects or cessation of treatment for another reason. The mean average pain score recorded on the VAS was 3.8. No patients in the study were diagnosed with a VTE. LMWH is a recognised chemical thromboprophylactic and is well tolerated by patients for VTE risk reduction in lower limb immobilised outpatients. With poor evidence supporting Aspirin as a solo prophylactic agent, our local policy has withdrawn Aspirin for this purpose. PMID- 28721004 TI - Epithelium-on photorefractive intrastromal cross-linking (PiXL) for reduction of low myopia. AB - PURPOSE: To report the 9-12-month outcomes of a novel procedure for reduction of low myopia through epithelium-on photorefractive intrastromal cross-linking (PiXL) with customized control of topographic distribution of ultraviolet (UV) fluence. METHOD: Myopic patients with normal (non-ectatic) corneas underwent the PiXL procedure for reduction of low myopia. PiXL treatments were delivered through selective application of UVA light based on the refractive error of each patient. Clinical evaluation included safety (corrected distance visual acuity, endothelial cell count, central corneal thickness, anterior ocular health) and efficacy (uncorrected distance visual acuity, manifest refraction, K-mean) examinations. In addition, a patient satisfaction survey was conducted at 9 months post-procedure to evaluate patients' subjective experience with the procedure. RESULTS: Fourteen myopic eyes (mean manifest refraction spherical equivalent -1.62+/-0.6D; range -0.75 to -2.65D) of 8 subjects (mean age 30 years old; range 24-51 years old) were enrolled in the study. At 12 months post procedure, a mean manifest refraction spherical equivalent reduction of 0.72+/ 0.43D (P<0.001) was observed, with a corresponding gain in uncorrected visual acuity of 0.25 logMAR and mean K-mean flattening of 0.47+/-0.46D. All patients achieved best corrected visual acuity of 20/20 or better from 1 month onward. There were no cases of ocular infection or secondary changes to the crystalline lens and retina due to UV exposure, while transient corneal haze subsided gradually. CONCLUSION: The epithelium-on PiXL procedure was safe and effective in reducing myopic refractive error in this study with up to 12 months follow-up. Early results of this novel application of collagen cross-linking are encouraging but longer-term data in larger studies are required. PRECIS: This paper serves to introduce and report the early clinical results of epithelium-on PiXL, a novel application of cornea cross-linking, in reducing low myopia in Asian eyes, which are under-represented in studies of similar design. PMID- 28721005 TI - Evaluation of a paper-based visual acuity questionnaire. AB - PURPOSE: To validate a paper-based visual acuity (PBVA) questionnaire. METHODS: In 2015, a cross-sectional survey was conducted among 301 young and middle-aged, mostly male, Japanese subjects. The participants were asked to self-rate their visual acuity (VA) on a scale from 1 to 5. Self-ratings of VA were categorized into three groups: good (1 and 2), normal (3), and poor (4 and 5). For objective validation, we performed a functional VA (FVA) assessment in the same subjects. RESULTS: A total of 301 subjects answered the PBVA and completed the FVA test including initial VA. We found out that the result of PBVA was significantly correlated with FVA test and initial VA (r=0.33, P<0.0001, r=0.273, P<0.0001). The trend test analysis between PBVA and FVA also showed statistically significant (P<0.0001). CONCLUSION: There was a significant statistical correlation between the PBVA and the FVA, as well as the initial VA. This short questionnaire on VA might be a sensitive tool that is easy to implement and utilized in large epidemiological and clinical researches. PMID- 28721007 TI - Comparative electrophysiological responses in anisometropic and strabismic amblyopic children. AB - PURPOSE: To compare anisometropic hypermetropic amblyopic and strabismic amblyopic responses to pattern electroretinogram (PERG) and pattern visual evocated potential (PVEP). MATERIALS AND METHODS: Fifty-six patients - 18 hypermetropic anisometropic amblyopic children (mean age 9.70+/-2.5 years), 19 strabismic amblyopic children (mean age 10.30+/-2.6 years) and 19 normal emetropic subjects (mean age 10.10+/-2.2 years) - were enrolled in this study. After routine ophthalmic examination, PERG and PVEP were recorded in response to checks reversed at the rate of two reversals/second stimulating macular area. RESULTS: The difference between hypermetropic anisometropic amblyopia and strabismus amblyopia with respect to P100/P50/N95 wave latencies (P=0.055/0.855/0.132) and P100/P50/N95 amplitudes (P=0.980/0.095/0.045) was not statistically significant. However, there was a significant statistical difference between strabismic amblyopia group and controls for P100/P50/N95 latencies (P=0.000/0.006/0.004). CONCLUSION: Our findings indicated that despite clinical differences between anisometropic amblyopic and strabismic amblyopic patients, no differences were found in the responses of PVEP and PERG. The abnormal components of the PVEP and PERG in amblyopic subjects could reflect a retinal dysfunction in the visual pathway. PMID- 28721006 TI - Incidence of outer retinal tubulation in eyes with choroidal neovascularization under intravitreal anti-vascular endothelial growth factor therapy in a Japanese population. AB - PURPOSE: The purpose of this study was to investigate the occurrence of outer retinal tubulation (ORT) among patients with different types of choroidal neovascularization (CNV) over time. MATERIALS AND METHODS: In this retrospective chart review, disease type was classified as typical age-related macular degeneration (t-AMD), polypoidal choroidal vasculopathy (PCV), retinal angiomatous proliferation (RAP), or myopic CNV (mCNV). Spectral domain-optical coherence tomography (SD-OCT) images were evaluated for the appearance of ORT and subretinal fibrosis and fluid. Furthermore, the association of the presence of ORT with clinical data and OCT findings was investigated. RESULTS: Among the 136 eyes studied, the overall rates of occurrence of ORT were 7.8%, 18.8%, and 31.6% after 12, 24, and 36 months from baseline, respectively. Among patients with t AMD, RAP, and mCNV, the occurrence of ORT increased soon after the initial visit. In contrast, among patients with PCV, the occurrence of ORT increased slowly over time. Patients with and without ORT - ORT(+) and ORT(-) groups, respectively - differed significantly in terms of sex ratio and presence of intraretinal fluid at the initial visit and presence of subretinal fibrosis at 3 years from baseline. The ORT(+) group exhibited lower visual acuity (VA; 0.67+/-0.43) than that of the ORT(-) group (0.41+/-0.36; P<0.001). CONCLUSION: The occurrence of ORT tended to increase more slowly among eyes diagnosed with PCV than among eyes with other types of CNV. PMID- 28721008 TI - Effect of age, sex, and refractive errors on central corneal thickness measured by Oculus Pentacam(r). AB - BACKGROUND: Central corneal thickness (CCT) can be used to assess the corneal physiological condition as well as the pathological changes associated with ocular diseases. It has an influence on the measurement of intraocular pressure and is being used as a screening tool for refractive surgery candidates. The aim of this study was to determine the median CCT among normal Pakistani population and to correlate CCT with age, sex, and refractive errors. METHODS: We conducted a retrospective analysis of 5,171 healthy eyes in 2,598 patients who came to Hashmanis Hospital, Karachi, Pakistan. The age of the patients ranged from 6 to 70 years. The refractive error was gauged by an auto-refractometer, and CCT was measured using Oculus Pentacam(r). RESULTS: The median CCT of our study was 541.0 MUm with an interquartile range (IQR) of 44.0 MUm. The median age was 26.0 years (IQR: 8.0). Median spherical equivalent (SE) of the patients was -4.3 D (IQR: 3.3) with the median sphere value as -4.0 D (IQR: 3.8). Lastly, the median cylinder was -1.0 D (IQR: 1.3). Age has a weak negative correlation with CCT (r= 0.058) and shows statistical significance (P<0.001). Additionally, males had thinner CCT readings than females (P=0.001). The cylinder values, on the other hand, had a significant (P=0.004) and positive correlation (r=0.154). Three values showed no significant correlation: sphere (P=0.100), SE (P=0.782), and the left or right eye (P=0.151). CONCLUSION: Among the Pakistani population, CCT was significantly affected by three variables: sex, age, and cylinder. No relationship of CCT was observed with the left or right eye, sphere, and SE. PMID- 28721009 TI - Patient profiles and clinical utility of mepolizumab in severe eosinophilic asthma. AB - Mepolizumab (Nucala(r)) is an effective and specific anti-eosinophil molecular therapy that has recently been approved as add-on therapy for the management of severe eosinophilic asthma by the US Food and Drug Administration (FDA), European Medicines Agency (EMA; European Union) and more recently National Institute for Health and Care Excellence (NICE; UK). It is one of several molecular therapies in development for this indication and is illustrative of the strategic trajectory for pharmaceutical drug development taken over the past decade in several disease areas. Molecular therapies offer the prospect of improved specificity and effectiveness of biological effect. However, this necessitates a clear understanding of the underlying mechanistic pathways underpinning pathological processes, to inform drug development that yields novel more efficacious treatment options with a better clinical profile than existing agents. For the first time, utilization of molecular therapies in clinical trials is providing a novel in vivo model to characterize the association between specific pathways and clinical disease expression. It is increasingly recognized that asthma exhibits both clinical and pathological heterogeneity. It follows that a one-size-fits-all approach will not be appropriate and cost-effectiveness may only be achieved by identifying responder subgroups. This so-called personalized approach to therapy is being supported by the parallel development of companion biomarkers for clinical application. In this review, the author summarizes the clinical studies, their interpretation and the lessons learnt with mepolizumab that have informed our understanding of the approach to personalized molecular therapy in asthma. PMID- 28721010 TI - Antiglioma effects of cytarabine on leptomeningeal metastasis of high-grade glioma by targeting the PI3K/Akt/mTOR pathway. AB - Leptomeningeal metastasis (LM) of high-grade glioma is a highly lethal disease requiring new effective therapeutic measures. For both de novo or relapsed glioma with LM, intrathecal cytarabine chemotherapy is not frequently used for first line and relapse protocols. We encountered a clinical case demonstrating effective application of cytarabine in high-grade glioma with LM, prompting us to explore the effects of cytarabine on malignant glioma and molecular mechanisms of such effects through in vivo and in vitro experiments. The U87 cell line was selected to represent human glioma for studies. Cell viability was measured by MTT assay, plate colony formation assay, and trypan-blue dye exclusion test. Apoptosis was assessed by flow cytometry. Protein expression levels were detected by Western blot assay and immunohistochemistry. mRNA expression was examined by quantitative real-time reverse transcription polymerase chain reaction. Cytarabine inhibited tumor growth during the in vivo experiment. The present study confirmed that cytarabine inhibits proliferation and promotes apoptosis of U87 cells, and molecular analysis of this effect showed that cytarabine significantly reduces expression of phosphatidylinositol 3 kinase/serine/threonine kinase also known as the protein kinase B/mechanistic target of rapamycin (PI3K/Akt/mTOR) pathway, Ki-67, BCL2, and 4-1BB, and upregulates Bax and cleaved caspase-3. Our findings indicated that intrathecal administration of cytarabine manifests potential in prophylaxis and treatment of malignant glioma with LM. Effective medications for high-grade glioma with LM should contain cytarabine. PMID- 28721011 TI - Effect of picroside II on hind limb ischemia reperfusion injury in rats. AB - INTRODUCTION: Many structural and functional damages are observed in cells and tissues after reperfusion of previously viable ischemic tissues. Acute ischemia reperfusion (I/R) injury of lower extremities occurs especially when a temporary cross-clamp is applied to the abdominal aorta during aortic surgery. Research regarding the treatment of I/R injury has been increasing day-by-day. In this study, we aimed to investigate the effect of picroside II on skeletal muscle of rats experiencing simulated I/R. MATERIALS AND METHODS: Twenty-four male Wistar albino rats weighing between 210 and 300 g were used in this study. Rats were randomly divided into 4 groups of 6 rats each (control, I/R, control + picroside II, and I/R + picroside II). The infrarenal section of the abdominal aorta was occluded with an atraumatic microvascular clamp in I/R group. The clamp was removed after 120 minutes and reperfusion was provided for a further 120 minutes. Picroside II (10 mg kg-1) was administered intraperitoneally to the animals in control + picroside II and I/R + picroside II groups. At the end of the study, skeletal muscle tissue was obtained for the determination of total oxidant status (TOS) and total antioxidant status (TAS) levels. Apoptosis was evaluated by TUNEL experiment. RESULTS: TOS levels were significantly higher in I/R group than that of control and I/R + picroside II groups (P=0.014, P=0.005, respectively). TAS levels were significantly higher in I/R group than that of control and I/R + picroside II groups (P=0.007 P=0.005, respectively). TUNEL assay revealed that picroside II reduced cell necrosis. CONCLUSION: The results of this study demonstrated that picroside II plays a critical role to prevent I/R injury. Even though our results were found to be satisfactory, it should be encouraging to those who want to conduct future research on this topic. PMID- 28721012 TI - Comparison of neurotoxic potency between a novel chinbotulinumtoxinA with onabotulinumtoxinA, incobotulinumtoxinA and lanbotulinumtoxinA in rats. AB - Four botulinumtoxin type A (BoNT/A) products, onabotulinumtoxinA (A/Ona), incobotulinumtoxinA (A/Inco), lanbotulinumtoxinA (A/Lan) and chinbotulinumtoxinA (A/Chin), are applied in the present study, among which A/Chin is newly produced. We aimed to compare the neurotoxic potency of these toxins by the gauge of muscle strength reduction. Furthermore, potential molecular and cellular mechanisms were also explored. According to our data, muscle strengths in the four toxin groups were all significantly decreased after injection for 1 week. A/Chin achieved the most obvious reduction in muscle strength as compared to the other three products at the dose of 0.5 U. However, there was no difference between the four toxins when increased to 2 U. As the toxins wore off, muscle strength recovered to basal level 12 weeks postinjection. We further measured the expression levels of key factors involved in neuromuscular junction stabilization and muscle genesis. Our results showed that nicotinic acetylcholine receptor, myogenic regulatory factors and muscle-specific receptor tyrosine kinase were all significantly upregulated upon BoNT/A treatment. Consistent with the result of muscle strength, A/Chin had the most obvious induction of gene expression. Moreover, we also found local inflammation response following BoNT/A injection. Owing to lack of complexing proteins, both A/Inco and A/Chin stimulated relatively lighter inflammation compared to that of A/Ona and A/Lan groups. In conclusion, our study provided evidence for the efficacy of the novel A/Chin and its similar functional mode to that of A/Ona, A/Inco and A/Lan. In addition, A/Chin has superiority in inducing muscle paralysis and inflammation stimulation, which may indicate faster onset and longer duration of this novel A/Chin. PMID- 28721013 TI - A novel local anesthetic system: transcriptional transactivator peptide-decorated nanocarriers for skin delivery of ropivacaine. AB - PURPOSE: Barrier properties of the skin and physicochemical properties of drugs are the main factors for the delivery of local anesthetic molecules. The present work evaluates the anesthetic efficacy of drug-loaded nanocarrier (NC) systems for the delivery of local anesthetic drug, ropivacaine (RVC). METHODS: In this study, transcriptional transactivator peptide (TAT)-decorated RVC-loaded NCs (TAT RVC/NCs) were successfully fabricated. Physicochemical properties of NCs were determined in terms of particle size, zeta potential, drug encapsulation efficiency, drug-loading capacity, stability, and in vitro drug release. The skin permeation of NCs was examined using a Franz diffusion cell mounted with depilated mouse skin in vitro, and in vivo anesthetic effect was evaluated in mice. RESULTS: The results showed that TAT-RVC/NCs have a mean diameter of 133.2 nm and high drug-loading capacity of 81.7%. From the in vitro skin permeation results, it was observed that transdermal flux of TAT-RVC/NCs was higher than that of RVC-loaded NCs (RVC/NCs) and RVC injection. The evaluation of in vivo anesthetic effect illustrated that TAT-RVC/NCs can enhance the transdermal delivery of RVC by reducing the pain threshold in mice. CONCLUSION: These results indicate that TAT-decorated NCs systems are useful for overcoming the barrier function of the skin, decreasing the dosage of RVC and enhancing the anesthetic effect. Therefore, TAT-decorated NCs can be used as an effective transdermal delivery system for local anesthesia. PMID- 28721014 TI - Determining optimal dosing regimen of oral administration of dicloxacillin using Monte Carlo simulation. AB - BACKGROUND: Dicloxacillin, a semisynthetic isoxazolyl penicillin, exhibits antimicrobial activity against a wide variety of Gram-positive bacteria, as well as stability against penicillinases and low level of toxicity. The objective of this study was to obtain optimal dosing regimen of oral administration of dicloxacillin by analyzing the pharmacokinetic (PK) index in healthy volunteers and in vitro antibacterial activity by using Monte Carlo simulation. MATERIALS AND METHODS: A total of 867 clinical isolates from community-onset infections were collected from 31 secondary hospitals in People's Republic of China. The minimum inhibitory concentration (MIC) values of dicloxacillin were determined by the agar dilution method. Based on the MICs and the PK parameters of different dosage regimens, Monte Carlo simulation was performed to simulate the PK/pharmacodynamic indices of 250 mg once-daily (qd), 500 mg qd, 1,000 mg qd, 2,000 mg qd, 250 mg every 6 hours (q6h), and 500 mg q6h, respectively. The probability of target attainment was estimated at each MIC value, and the cumulative fraction of response (CFR) was calculated to evaluate the efficacy of these regimens. RESULTS: Dicloxacillin showed poor antibacterial activity against Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae. Resistance to dicloxacillin was observed in 7.5% of coagulase-negative Staphylococcus (CNS) isolates and 9.2% of other Streptococcus isolates, whereas 1.5% of methicillin-sensitive Staphylococcus aureus (MSSA) was resistant to dicloxacillin. Multiple-dose regimens could obtain higher CFR than single-dose regimens against H. influenza and S. pneumoniae. However, all dosing regimens against MSSA achieved CFR >=$90%. Meanwhile, dosing regimen of 2,000 mg qd, 250 mg q6h, and 500 mg q6h could achieve >90% of CFR for CNS. For other Streptococcus isolates, multiple-dose regimens achieved CFR >=90%. CONCLUSION: Dicloxacillin has a significant antibacterial activity against MSSA, CNS, and other Streptococcus isolates. The simulation results suggest that dicloxacillin 250 mg q6h and 500 mg q6h dosing regimens may be recommended for clinical applications, especially for community-onset infections. PMID- 28721015 TI - Cell and small animal models for phenotypic drug discovery. AB - The phenotype-based drug discovery (PDD) approach is re-emerging as an alternative platform for drug discovery. This review provides an overview of the various model systems and technical advances in imaging and image analyses that strengthen the PDD platform. In PDD screens, compounds of therapeutic value are identified based on the phenotypic perturbations produced irrespective of target(s) or mechanism of action. In this article, examples of phenotypic changes that can be detected and quantified with relative ease in a cell-based setup are discussed. In addition, a higher order of PDD screening setup using small animal models is also explored. As PDD screens integrate physiology and multiple signaling mechanisms during the screening process, the identified hits have higher biomedical applicability. Taken together, this review highlights the advantages gained by adopting a PDD approach in drug discovery. Such a PDD platform can complement target-based systems that are currently in practice to accelerate drug discovery. PMID- 28721016 TI - A review of the literature analyzing benefits and concerns of infliximab biosimilar CT-P13 for the treatment of rheumatologic diseases: focus on interchangeability. AB - The introduction of biological agents drastically changed the treatment paradigm of inflammatory arthritides, ameliorating the natural history of the diseases but concomitantly increasing the drug costs due to the manufacturing process. On this concern, biosimilar drugs may represent a valid option for reducing this elevated cost and increasing the availability of these highly effective treatments. Recently, CT-P13, the first biosimilar of infliximab, has been approved with the same indications established for the reference product (RP), and its daily use is progressively increasing. However, the experience with biosimilar drugs in the field of rheumatology is still limited, raising potential doubts and concerns on their correct management in real-life settings. Comparability analysis between CT P13 and its RP was evaluated in equivalence randomized controlled trials (RCTs) - PLANETRA and PLANETAS - performed on patients with rheumatoid arthritis and axial spondylitis, respectively. CT-P13 and RP showed similar profile in terms of quality, biological activity, safety, immunogenicity, and efficacy. However, the interchangeability between infliximab RP and its biosimilar still represents the most challenging issue because of a lack of a long-lasting experience. To date, reassuring preliminary data on this topic were reported in open-label extensions of PLANETRA and PLANETAS RCTs and in ongoing real-life observational studies. These findings, taken all together, significantly affect the landscape of biosimilar regulatory pathways and strongly support CT-P13 introduction as a great opportunity for expanding the accessibility to these very effective and high-cost therapies. PMID- 28721017 TI - Targeted therapy in severe asthma today: focus on immunoglobulin E. AB - Asthma is a complex chronic inflammatory disease of multifactorial etiology. International guidelines increasingly recognize that a standard "one size fits all" approach is no longer an effective approach to achieve optimal treatment outcomes, and a number of disease phenotypes have been proposed for asthma, which has the potential to guide treatment decisions. Among the many asthma phenotypes, allergic asthma represents the widest and most easily recognized asthma phenotype, present in up to two-thirds of adults with asthma. Immunoglobulin E (IgE) production is the primary and key cause of allergic asthma leading to persistent symptoms, exacerbations and a poor quality of life. Therefore, limiting IgE activity upstream could stop the entire allergic inflammation cascade in IgE-mediated allergic asthma. The anti-IgE treatment omalizumab has an accepted place in the management of severe asthma (Global Initiative for Asthma [GINA] step 5) and represents the first (and, currently, only) targeted therapy with a specific target in severe allergic asthma. This review summarizes current knowledge of the mechanisms and pathogenesis of severe asthma, examines the actual role of IgE in asthma and the biological rationale for targeting IgE in allergic asthma and reviews the data for the efficacy and safety of omalizumab in the treatment of severe asthma. Current knowledge of the role of IgE in asthma, extensive clinical trial data and a decade of use in clinical practice has established omalizumab as a safe and effective targeted therapy for the treatment of patients with severe persistent IgE-mediated allergic asthma. PMID- 28721018 TI - Salidroside pretreatment attenuates apoptosis and autophagy during hepatic ischemia-reperfusion injury by inhibiting the mitogen-activated protein kinase pathway in mice. AB - Ischemia-reperfusion injury (IRI) contributes to liver damage in many clinical situations, such as liver resection and liver transplantation. In the present study, we investigated the effects of the antioxidant, anti-inflammatory, and anticancer agent salidroside (Sal) on hepatic IRI in mice. The mice were randomly divided into six groups: normal control, Sham, Sal (20 mg/kg), IRI, IRI + Sal (10 mg/kg), and IRI + Sal (20 mg/kg). We measured liver enzymes, proinflammatory cytokines, TNF-alpha and interleukin-6, and apoptosis- and autophagy-related marker proteins at 2, 8, and 24 hours after reperfusion. Components of mitogen activated protein kinase (MAPK) signaling, including P-38, jun N-terminal kinase (JNK), and extracellular signal-regulated kinase (ERK), were also measured using an MAPK activator anisomycin to deduce their roles in hepatic IRI. Our results show that Sal safely protects hepatocytes from IRI by reducing levels of liver enzymes in the serum. These findings were confirmed by histopathology. We concluded that Sal protects hepatocytes from IRI partly by inhibiting the activation of MAPK signaling, including the phosphorylation of P38, JNK, and ERK. This ameliorates inflammatory reactions, apoptosis, and autophagy in the mouse liver. PMID- 28721019 TI - Inhibitors of the PD-1/PD-L1 axis for the treatment of head and neck cancer: current status and future perspectives. AB - Head and neck cancer (HNC) is a common malignant tumor, but traditional therapeutic methods have unsatisfactory curative effects and many complications occur. Hence, there is an urgent need to develop therapeutic methods that can elicit curative effects as well as low toxic and few side effects. With the development of cancer molecular biology and immunology, targeted therapy for immune checkpoints of programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) has shown enormous development prospects for HNC treatment. Groundbreaking progress has been achieved in the treatment of recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). This review describes current treatment by PD-1- and PD-L1-targeted drugs for HNC. PMID- 28721020 TI - Access to credible information on schizophrenia patients' medication adherence by prescribers can change their treatment strategies: evidence from an online survey of providers. AB - OBJECTIVE: Overestimating patients' medication adherence diminishes the ability of psychiatric care providers to prescribe the most effective treatment and to identify the root causes of treatment resistance in schizophrenia. This study was conducted to determine how credible patient drug adherence information (PDAI) might change prescribers' treatment decisions. METHODS: In an online survey containing 8 clinical case vignettes describing patients with schizophrenia, health care practitioners who prescribe antipsychotics to patients with schizophrenia were instructed to choose a preferred treatment recommendation from a set of predefined pharmacologic and non-pharmacologic options. The prescribers were randomly assigned to an experimental or a control group, with only the experimental group receiving PDAI. The primary outcome was the prescribers' treatment choice for each case. Between-group differences were analyzed using multinomial logistic regression. RESULTS: A convenience sample (n=219) of prescribers completed the survey. For 3 nonadherent patient vignettes, respondents in the experimental group were more likely to choose a long-acting injectable antipsychotic compared with those in the control group (77.7% experimental vs 25.8% control; P<0.001). For 2 adherent but poorly controlled patient vignettes, prescribers who received PDAI were more likely to increase the antipsychotic dose compared with the control group (49.1% vs 39.1%; P<0.001). For the adherent and well-controlled patient vignette, respondents in both groups made similar treatment recommendations across all choices (P=0.099), but respondents in the experimental arm were more likely to recommend monitoring clinical stability (87.2% experimental vs 75.5% control, reference group). CONCLUSION: The results illustrate how credible PDAI can facilitate more appropriate clinical decisions for patients with schizophrenia. PMID- 28721021 TI - Addressing the elephant in the room: a possible new way to increase patient adherence to medical advice. AB - Lack of patient adherence to medical advice (PAMA) is recognized as an area of interest. None of the previous initiatives to improve PAMA, such as patient centered care and shared decision making, have proved to be successful in terms of improving patient adherence. The aim of the present study is to assess beliefs about priorities in public health care, and adherence to medical advice, to establish a novel approach to increase PAMA. The present study is based on responses to two questions in an experimental survey from the Norwegian Citizen Panel, addressing people's attitudes to priorities in public health care and adherence to medical advice. The questions on priorities in the health care sector are organized into six groups. The questions on adherence are organized into three groups. All questions are answered on a 7-point Likert scale. This study is the first to use experimental surveys to assess PAMA. The results indicate that if health care providers refer to national expertise and patient organizations' recommendations on a given treatment, PAMA could improve. Although technical and methodological interventions in health care have, to some extent, improved PAMA, medical adherence is still low. In the present study, it is shown that integrating either national expertise or collaborated messages with other health professions and patient organizations' recommendations in everyday care may help improve patients adherence to medical advice. A minor change in how treatment suggestions are presented could improve PAMA. PMID- 28721022 TI - Physicians' attitude, belief and practice of complementary alternative medication use. PMID- 28721023 TI - Persistence to disease-modifying therapies for multiple sclerosis in a Canadian cohort. AB - PURPOSE: To examine the long-term persistence to the first-line injectable disease-modifying therapies (DMTs) for multiple sclerosis (MS) and to identify the factors associated with nonpersistence. PATIENTS AND METHODS: We used population-based administrative data from Manitoba, Canada. All adult subjects who were diagnosed with MS and dispensed a first-line injectable DMT (beta interferon-1b, beta-interferon-1a, and glatiramer acetate) between 1996 and 2011 and had a minimum of 1 year of follow-up were included. The primary outcome was the median time to discontinuation of any DMT. The associations between potential predictors and persistence were estimated using multivariable Cox-proportional hazard models. RESULTS: Overall, 721 subjects were followed for a median of 7.8 years (interquartile range 6.1). The median time to discontinuation of all first line DMTs was 4.2 years (25th and 75th percentile: 1.7, 10.6 years). Of the 451 (62.6%) subjects who discontinued their DMT during the study period, 259 (57.4%) eventually resumed or restarted a DMT. Subjects who were younger when starting a DMT, had prior MS-related hospitalizations, were more recently diagnosed with MS, or had a greater lag time between their MS diagnosis and DMT initiation were more likely to discontinue therapy. CONCLUSION: Over half of the individuals receiving a DMT for MS in Manitoba remained on therapy for at least 4 years. DMT discontinuation occurred in 60% of the cohort, but most restarted a DMT within 1 year. While not all of the factors identified with discontinuing DMT are modifiable, they may help practitioners enhance MS care by identifying individuals who may be at particular risk for DMT discontinuation. PMID- 28721024 TI - Cost of medication adherence and persistence in type 2 diabetes mellitus: a literature review. AB - PURPOSE: To explore published evidence on health care costs associated with adherence or persistence to antidiabetes medications in adults with type 2 diabetes mellitus (T2DM). METHODS: Primary research studies published between January 2006 and December 2015 on compliance, adherence, or persistence and treatment in patients with T2DM that document a link with health care costs were identified through literature searches in bibliographic databases and 2015 abstract books for relevant DM congresses. Results were assessed for relevance by two reviewers. The review was part of a larger overview evaluating the impact of adherence and persistence on a range of clinical and economic outcomes; only findings from the cost element are reported herein. RESULTS: A total of 4,662 de duplicated abstracts were identified and 110 studies included in the wider review. Of these, 19 reported an association between adherence (n=13), persistence (n=5), or adherence and persistence (n=1), and health care costs. All studies were retrospective, with sample sizes ranging from 301 to 740,195. Medication possession ratio was the most commonly employed adherence measure (n=11). The majority of adherence studies (n=9) reported that medication adherence was associated with lower total health care costs. Pharmacy costs were often increased in adherent patients but this was offset by beneficial effects on other costs. Findings were more variable in persistence studies; three reported that higher pharmacy costs in persistent patients were not sufficiently offset by savings in other areas to result in a reduction in total health care costs. CONCLUSIONS: Few studies have evaluated the relationship between adherence, persistence, and health care costs in T2DM. However, it has been consistently shown that medication nonadherence increases health care costs, suggesting that cost savings from better adherence could be substantial. Available data support the economic case for identification of strategies that facilitate improved medication adherence in patients with T2DM. PMID- 28721025 TI - Antibacterial effect of silver nanoparticles in Pseudomonas aeruginosa. AB - Pseudomonas aeruginosa has great intrinsic antimicrobial resistance limiting the number of effective antibiotics. Thus, other antimicrobial agents such as silver nanoparticles (AgNPs) are considered potential agents to help manage and prevent infections. AgNPs can be used in several applications against bacteria resistant to common antibiotics or even multi-resistant bacteria such as P. aeruginosa. This study assessed the antimicrobial activity of commercial 10 nm AgNPs on two hospital strains of P. aeruginosa resistant to a large number of antibiotics and a reference strain from a culture collection. All strains were susceptible to 5 ug/mL nanoparticles solution. Reference strains INCQS 0230 and P.a.1 were sensitive to AgNPs at concentrations of 1.25 and 0.156 ug/mL, respectively; however, this was not observed for hospital strain P.a.2, which was more resistant to all antibiotics and AgNPs tested. Cytotoxicity evaluation indicated that AgNPs, up to a concentration of 2.5 ug/mL, are very safe for all cell lines tested. At 5.0 ug/mL, AgNPs had a discrete cytotoxic effect on tumor cells HeLa and HepG2. Results showed the potential of using AgNPs as an alternative to conventional antimicrobial agents that are currently used, and a perspective for application of nanosilver with antibiotics to enhance antimicrobial activity. PMID- 28721026 TI - A community virtual ward model to support older persons with complex health care and social care needs. AB - BACKGROUND: Globally the older population is increasing rapidly. As a result there is an increase in frail older persons living within the community, with increased risks of a hospital admission and higher mortality and morbidity rates. Due to complexity of care, health care professionals face challenges in providing effective case management and avoiding unplanned admissions to hospital. A community virtual ward (CVW) model was developed to assist health care professionals to support older persons at home during periods of illness and/or functional decline. METHODS: A quantitative observational study was conducted to examine if a CVW model of care reduced unplanned hospital admissions and emergency department (ED) presentations in 54 patients over a 12-month period. The sign-rank test examined matched data on bed days, ED presentations, and unplanned hospital admissions pre- and post-CVW implementation. Other risk factors for admission to hospital were examined using the Mann-Whitney test pre and post-CVW admission, including falls, living alone, and cognition. Correlations between hospital admission avoidances and unplanned hospital admissions and ED presentations were tested using Spearman's rho test. RESULTS: There was a reduction in ED presentations post-CVW admission (P<0.001), and median unscheduled admissions were reduced (P=0.001). Those living alone had a lower number of ED presentations (median 0.5, interquartile range 0-1) prior to admission in comparison to those living with a caregiver, with no differences observed during admission to CVW. For those who experienced a fall during CVW admission, the odds ratio (OR) of requiring long-term care doubled for each extra fall (OR =2.24, 95% CI 1.11 to 4.52, P=0.025). Reduced cognition was associated with an increased risk of ED presentations (rho=0.292, P<0.05) but not associated with increased risks of unplanned hospital admissions (rho=0.09, P=0.546). There were no significant correlations seen between admission avoidance and the number of unplanned hospital admissions or ED presentations. CONCLUSION: Through an integrated approach to care, a CVW model in the care of older persons can reduce ED presentations and unplanned hospital admissions. PMID- 28721027 TI - Frequency of frailty and its association with cognitive status and survival in older Chileans. AB - BACKGROUND: Age-associated brain physiologic decline and reduced mobility are key elements of increased age-associated vulnerability. OBJECTIVE: To study the frequency of frailty phenotype and its association with mental health and survival in older Chileans. METHODS: Follow-up of ALEXANDROS cohorts designed to study disability associated with obesity in community-dwelling people 60 years and older living in Santiago, Chile. At baseline, 2,098 (67% women) of 2,372 participants had the necessary measurements for the identification of the frailty phenotype: weak handgrip dynamometry, unintentional weight loss, fatigue/exhaustion, five chair-stands/slow walking speed and difficulty walking (low physical activity). After 10-15 years, 1,298 people were evaluated and 373 had died. Information regarding deaths was available for the whole sample. RESULTS: The prevalence of frailty at baseline (>=3 criteria) in the whole sample was 13.9% (women 16.4%; men 8.7%) and the pre-frailty prevalence (1-2 criteria) was 63.8% (65.0% vs 61.4%), respectively. Frailty was associated with cognitive impairment (frail 48.1%; pre-frail 21.7%; nonfrail 20.5%, P<0.001) and depression (frail 55.1%; pre-frail 27.3%; nonfrail 18.8%, P<0.001). Logistic regression models for frailty adjusted for sex and age showed a strong association between frailty and mild cognitive impairment (MCI) (odds ratio [OR] =3.93; 95% CI: 1.41 10.92). Furthermore, an important association was found for depression and frailty (OR =2.36; 95% CI 1.82-3.06). Age- and sex-adjusted hazard ratios (HRs) for death showed an increased risk with increasing frailty: pre-frail HR =1.56 (95% CI: 1.07-2.29), frail HR =1.91 (95% CI: 1.15-3.19); after adjustment by age and sex, a higher risk of death was observed for people identified as frail (HR =1.56, P=0.014) and pre-frail (HR =1.30, P=0.065). MCI and dementia were also risk factors for death (MCI: HR =1.69, P<0.027; dementia: HR =1.66, P=0.016). CONCLUSION: Frailty is highly prevalent and strongly associated with cognitive impairment and depression in older Chileans. The risk for death was higher for frail people, but underlying cognitive impairment is a key component of the lower survival rate. PMID- 28721028 TI - Frailty in community-dwelling older adults: association with adverse outcomes. AB - BACKGROUND: The study of frailty is important to identify the additional needs of medical long-term care and prevent adverse outcomes in community dwelling older adults. This study aimed to determine the prevalence of frailty and its association with adverse outcomes in community dwelling older adults. METHODS: A cross-sectional study was carried out from April to September 2014. The population sample was 1,252 older adults (>=60 years) who were beneficiaries of the Mexican Institute of Social Security (IMSS) in Mexico City. Data were derived from the database of the "Cohort of Obesity, Sarcopenia and Frailty of Older Mexican Adults" (COSFOMA). Operationalization of the phenotype of frailty was performed using the criteria of Fried et al (weight loss, self-report of exhaustion, low physical activity, slow gait, and weakness). Adverse outcomes studied were limitation in basic activities of daily living (ADLs), falls and admission to emergency services in the previous year, and low quality of life (WHOQOL-OLD). RESULTS: Frailty was identified in 20.6% (n=258), pre-frailty in 57.6% (n=721), and not frail in 21.8% (n=273). The association between frailty and limitations in ADL was odds ratio (OR) =2.3 (95% confidence interval [CI] 1.7 3.2) and adjusted OR =1.7 (95% CI 1.2-2.4); falls OR =1.6 (95% CI 1.2-2.1) and adjusted OR =1.4 (95% CI 1.0-1.9); admission to emergency services OR =1.9 (95% CI 1.1-3.1) and adjusted OR =1.9 (95% CI 1.1-3.4); low quality of life OR =3.4 (95% CI 2.6-4.6) and adjusted OR =2.1 (95% CI 1.5-2.9). CONCLUSION: Approximately 2 out of 10 older adults demonstrate frailty. This is associated with limitations in ADL, falls, and admission to emergency rooms during the previous year as well as low quality of life. PMID- 28721029 TI - The impact of transient and persistent acute kidney injury on short-term outcomes in very elderly patients. AB - OBJECTIVES: Acute kidney injury (AKI) is a common complication in elderly patients and is associated with poor outcomes. However, the effect of transient and persistent geriatric AKI on short-term mortality is unclear. We aimed to study the incidence, clinical characteristics, and prognostic impact of transient and persistent AKI in such patients. METHODS: We retrospectively enrolled very elderly patients (>=75 years) from the geriatric department of the Chinese PLA General Hospital between 2007 and 2015. AKI was defined according to the 2012 Kidney Disease: Improving Global Outcomes criteria. AKI patients were divided into transient or persistent AKI groups based on their renal function at 3 days post-AKI. Renal function recovery was defined as a return to the baseline serum creatinine (SCr) levels. RESULTS: In total, 668 geriatric patients (39.0%) experienced AKI, and 652 satisfied the inclusion criteria. Of these 652 patients, 270 (41.4%) had transient AKI, and 382 (58.6%) had persistent AKI. The 90-day mortality was 5.9% in patients with transient AKI and 53.1% in patients with persistent AKI. Multivariate analysis revealed that low hemoglobin levels (odds ratio [OR] =0.989; 95% CI: 0.980-0.999; P=0.025), low mean aortic pressure (OR =0.985; 95% CI: 0.971-1.000; P=0.043), peak SCr (OR =1.020; 95% CI: 1.015-1.026; P<0.001) levels, high uric acid (OR =1.002; 95% CI: 1.000-1.003; P=0.040) levels, high blood urea nitrogen (OR =1.028; 95% CI: 1.000-1.056; P=0.047) levels, and mechanical ventilation requirements (OR =1.610; 95% CI: 1.012-2.562; P=0.044) were associated with persistent AKI. Persistent AKI (hazard ratio [HR] =5.741; 95% CI: 3.356-9.822; P<0.001) and more severe AKI stages (stage 2: HR =3.363; 95% CI: 1.973-5.732; P<0.001 and stage 3: HR =4.741; 95% CI: 2.807-8.008; P<0.001) were associated with 90-day mortality. CONCLUSION: AKI is common in very elderly patients, with transient renal injury representing close to 42% of all cases of geriatric AKI. More frequent SCr measurements may be helpful for the early diagnosis of transient geriatric AKI. Persistent geriatric AKI is independently associated with a significantly higher risk of 90-day mortality. PMID- 28721030 TI - Regular physical exercise improves cardiac autonomic and muscle vasodilatory responses to isometric exercise in healthy elderly. AB - The objective of this study was to evaluate cardiac autonomic control and muscle vasodilation response during isometric exercise in sedentary and physically active older adults. Twenty healthy participants, 10 sedentary and 10 physically active older adults, were evaluated and paired by gender, age, and body mass index. Sympathetic and parasympathetic cardiac activity (spectral and symbolic heart rate analysis) and muscle blood flow (venous occlusion plethysmography) were measured for 10 minutes at rest (baseline) and during 3 minutes of isometric handgrip exercise at 30% of the maximum voluntary contraction (sympathetic excitatory maneuver). Variables were analyzed at baseline and during 3 minutes of isometric exercise. Cardiac autonomic parameters were analyzed by Wilcoxon and Mann-Whitney tests. Muscle vasodilatory response was analyzed by repeated measures analysis of variance followed by Tukey's post hoc test. Sedentary older adults had higher cardiac sympathetic activity compared to physically active older adult subjects at baseline (63.13+/-3.31 vs 50.45+/-3.55 nu, P=0.02). The variance (heart rate variability index) was increased in active older adults (1,438.64+/-448.90 vs 1,402.92+/-385.14 ms, P=0.02), and cardiac sympathetic activity (symbolic analysis) was increased in sedentary older adults (5,660.91+/ 1,626.72 vs 4,381.35+/-1,852.87, P=0.03) during isometric handgrip exercise. Sedentary older adults showed higher cardiac sympathetic activity (spectral analysis) (71.29+/-4.40 vs 58.30+/-3.50 nu, P=0.03) and lower parasympathetic modulation (28.79+/-4.37 vs 41.77+/-3.47 nu, P=0.03) compared to physically active older adult subjects during isometric handgrip exercise. Regarding muscle vasodilation response, there was an increase in the skeletal muscle blood flow in the second (4.1+/-0.5 vs 3.7+/-0.4 mL/min per 100 mL, P=0.01) and third minute (4.4+/-0.4 vs 3.9+/-0.3 mL/min per 100 mL, P=0.03) of handgrip exercise in active older adults. The results indicate that regular physical activity improves neurovascular control of muscle blood flow and cardiac autonomic response during isometric handgrip exercise in healthy older adult subjects. PMID- 28721031 TI - Operationalizing a frailty index using routine blood and urine tests. AB - BACKGROUND: Uncomplicated frailty instruments are desirable for use in a busy clinical setting. The aim of this study was to operationalize a frailty index (FI) from routine blood and urine tests, and to evaluate the properties of this FI compared to other frailty instruments. MATERIALS AND METHODS: We conducted a secondary analysis of a prospective cohort study on 306 patients aged >=65 years hospitalized on geriatric wards. An FI comprising 22 routine blood parameters and one standard urine parameter (FI-Lab), a 50-item FI based on a comprehensive geriatric assessment (FI-CGA), a combined FI (FI-combined [items from the FI-Lab + others from the FI-CGA]), the Clinical Frailty Scale, rule-based frailty definition, and frailty phenotype were operationalized from data obtained during patients' hospital stays (ie, before discharge [baseline examination]). Follow-up data were obtained up to 1 year after the baseline examination. RESULTS: The mean FI-Lab score was 0.34+/-15, with an upper limit of 0.74. The FI-Lab was correlated with all the other frailty instruments (all P<0.001). The FI-Lab revealed an area under the receiver-operating characteristic curve (AUC) for 6 month and 1-year mortality of 0.765 (0.694-0.836) and 0.769 (0.706-0.833), respectively (all P<0.001). Each 0.01 increment in FI-Lab increased the risk (adjusted for age and sex) for 6-month and 1-year mortality by 7.2% and 7.1%, respectively (all adjusted P<0.001). When any of the other FIs (except the FI combined) were also included in the models, each 0.01 increment in FI-Lab score was associated with an increase in the risk of 6-month and 1-year mortality by 4.1%-5.4% (all adjusted P<0.001). CONCLUSION: The FI-Lab showed key characteristics of an FI. The FI-Lab can be applied as a single frailty measure or in combination with/in addition to other frailty instruments. PMID- 28721032 TI - 11C-PIB PET imaging reveals that amyloid deposition in cases with early-onset Alzheimer's disease in the absence of known mutations retains higher levels of PIB in the basal ganglia. AB - PURPOSE: Early-onset Alzheimer's disease (EOAD) has a different pathologic burden and clinical features compared with late-onset Alzheimer's disease (LOAD). We examined the effects of age at onset on the burden and distribution of beta amyloid in patients with EOAD, in whom well-characterized mutations associated with Alzheimer's disease were absent. METHODS: We genotyped ApoE, APP, PSEN1 and PSEN2 in the patients with Alzheimer's disease: 9 patients with EOAD (age <65), 11 with LOAD (age >70) and 8 normal controls (NCs), all of whom had undergone 11C labeled Pittsburgh compound B-positron emission tomography imaging. RESULTS: Patients with EOAD exhibited higher z scores and larger cluster sizes, and retained higher levels of Pittsburgh compound B in the bilateral thalamus and in some parts of the globus pallidus (P<0.05, false discovery rate). CONCLUSION: Distribution of amyloid deposition in EOAD outside the context of genetic mutations topographically showed some differences from that in LOAD. PMID- 28721033 TI - Interfaces and ventilator settings for long-term noninvasive ventilation in COPD patients. AB - INTRODUCTION: The establishment of high-intensity (HI) noninvasive ventilation (NIV) that targets elevated PaCO2 has led to an increase in the use of long-term NIV to treat patients with chronic hypercapnic COPD. However, the role of the ventilation interface, especially in more aggressive ventilation strategies, has not been systematically assessed. METHODS: Ventilator settings and NIV compliance were assessed in this prospective cross-sectional monocentric cohort study of COPD patients with pre-existing NIV. Daytime arterialized blood gas analyses and lung function testing were also performed. The primary end point was the distribution among study patients of interfaces (full-face masks [FFMs] vs nasal masks [NMs]) in a real-life setting. RESULTS: The majority of the 123 patients studied used an FFM (77%), while 23% used an NM. Ventilation settings were as follows: mean +/- standard deviation (SD) inspiratory positive airway pressure (IPAP) was 23.2+/-4.6 mbar and mean +/- SD breathing rate was 16.7+/-2.4/minute. Pressure support ventilation (PSV) mode was used in 52.8% of patients, while assisted pressure-controlled ventilation (aPCV) was used in 47.2% of patients. Higher IPAP levels were associated with an increased use of FFMs (IPAP <21 mbar: 73% vs IPAP >25 mbar: 84%). Mean compliance was 6.5 hours/day, with no differences between FFM (6.4 hours/day) and NM (6.7 hours/day) users. PaCO2 assessment of ventilation quality revealed comparable results among patients with FFMs or NMs. CONCLUSION: This real-life trial identified the FFM as the predominantly used interface in COPD patients undergoing long-term NIV. The increased application of FFMs is, therefore, likely to be influenced by higher IPAP levels, which form part of the basis for successful application of HI-NIV in clinical practice. PMID- 28721034 TI - Readmission After COPD Exacerbation Scale: determining 30-day readmission risk for COPD patients. AB - BACKGROUND: COPD affects over 13 million Americans, and accounts for over half a million hospitalizations annually. The Hospital Readmission Reduction Program, established by the Affordable Care Act requires the Centers for Medicare and Medicaid Services to reduce payments to hospitals with excess readmissions for COPD as of 2015. This study sought to develop a predictive readmission scale to identify COPD patients at higher readmission risk. METHODS: Demographic and clinical data on 339,389 patients from New York and California (derivation cohort) and 258,113 patients from Washington and Florida (validation cohort) were abstracted from the State Inpatient Database (2006-2011), and the Readmission After COPD Exacerbation (RACE) Scale was developed to predict 30-day readmission risk. RESULTS: Thirty-day COPD readmission rates were 7.54% for the derivation cohort and 6.70% for the validation cohort. Factors including age 40-65 years (odds ratio [OR] 1.17; 95% CI, 1.12-1.21), male gender (OR 1.16; 95% CI, 1.13 1.19), African American (OR 1.11; 95% CI, 1.06-1.16), 1st income quartile (OR 1.10; 95% CI, 1.06-1.15), 2nd income quartile (OR 1.06; 95% CI, 1.02-1.10), Medicaid insured (OR 1.83; 95% CI, 1.73-1.93), Medicare insured (OR 1.45; 95% CI, 1.38-1.52), anemia (OR 1.05; 95% CI, 1.02-1.09), congestive heart failure (OR 1.06; 95% CI, 1.02-1.09), depression (OR 1.18; 95% CI, 1.14-1.23), drug abuse (OR 1.17; 95% CI, 1.09-1.25), and psychoses (OR 1.19; 95% CI, 1.13-1.25) were independently associated with increased readmission rates, P<0.01. When the devised RACE scale was applied to both cohorts together, it explained 92.3% of readmission variability. CONCLUSION: The RACE Scale reliably predicts an individual patient's 30-day COPD readmission risk based on specific factors present at initial admission. By identifying these patients at high risk of readmission with the RACE Scale, patient-specific readmission-reduction strategies can be implemented to improve patient care as well as reduce readmissions and health care expenditures. PMID- 28721035 TI - Intracellular interactions of umeclidinium and vilanterol in human airway smooth muscle. AB - BACKGROUND: Intracellular mechanisms of action of umeclidinium (UMEC), a long acting muscarinic receptor antagonist, and vilanterol (VI), a long-acting beta2 adrenoceptor (beta2R) agonist, were investigated in target cells: human airway smooth-muscle cells (ASMCs). MATERIALS AND METHODS: ASMCs from tracheas of healthy lung-transplant donors were treated with VI, UMEC, UMEC and VI combined, or control compounds (salmeterol, propranolol, ICI 118.551, or methacholine [MCh]). Cyclic adenosine monophosphate (cAMP) was measured using an enzyme-linked immunosorbent assay, intracellular free calcium ([Ca2+]i) using a fluorescence assay, and regulator of G-protein signaling 2 (RGS2) messenger RNA using real time quantitative polymerase chain reaction. RESULTS: VI and salmeterol (10-12-10 6 M) induced cAMP production from ASMCs in a concentration-dependent manner, which was greater for VI at all concentrations. beta2R antagonism by propranolol or ICI 118.551 (10-12-10-4 M) resulted in concentration-dependent inhibition of VI-induced cAMP production, and ICI 118.551 was more potent. MCh (5*10-6 M, 30 minutes) attenuated VI-induced cAMP production (P<0.05), whereas pretreatment with UMEC (10-8 M, 1 hour) restored the magnitude of VI-induced cAMP production. ASMC stimulation with MCh (10-11-5*10-6 M) resulted in a concentration-dependent increase in [Ca2+]i, which was attenuated with UMEC pretreatment. Reduction of MCh-induced [Ca2+]i release was greater with UMEC + VI versus UMEC. UMEC enhanced VI-induced RGS2 messenger RNA expression. CONCLUSION: These data indicate that UMEC reverses cholinergic inhibition of VI-induced cAMP production, and is a more potent muscarinic receptor antagonist when in combination with VI versus either alone. PMID- 28721036 TI - Prevalence and associated factors of COPD among Aboriginal peoples in Canada: a cross-sectional study. AB - BACKGROUND: COPD among Aboriginal peoples in Canada is a major public health concern. This study was conducted in order to determine the prevalence and association between certain risk factors and COPD among the 35-year-old or older Aboriginal peoples in Canada. METHODS: This is a cross-sectional study. It uses data from Statistics Canada's Aboriginal Peoples Survey (APS), 2012. It consists of 8,117 self-identified Aboriginal peoples, aged 35 years old or older from all Canadian provinces and territories. The study outcomes centered on evaluating the prevalence and associated factors of COPD. RESULTS: This study found that 6.80% of the participants self-reported having COPD. Results of the logistic regression analysis show that COPD was significantly higher among daily smokers (odds ratio [OR], 2.28; 95% confidence interval [95% CI], 1.65-3.14), aged 55 years or older (OR, 3.04; 95% CI, 2.14-4.30), who earned $5,000-$9,999 per annum (OR, 4.21; 95% CI, 2.39-7.41) and needed health care over the past 12 months and did not receive it (OR, 1.83; 95% CI, 1.27-2.65). CONCLUSION: The findings of our study show that COPD is strongly associated with Aboriginal peoples, who are older, smoke, have a low socioeconomic status (SES) and do not have access to health care when needed. Clinicians, health care professionals, medical/public health organizations, researchers and patients will greatly benefit from additional research in this common, serious and often overlooked disease among Aboriginal peoples in Canada. PMID- 28721038 TI - Toxicity-based toxicokinetic/toxicodynamic assessment of bioaccumulation and nanotoxicity of zerovalent iron nanoparticles in Caenorhabditis elegans. AB - Elucidating the relationships between the toxicity-based-toxicokinetic (TBTK)/toxicodynamic (TD) properties of engineered nanomaterials and their nanotoxicity is crucial for human health-risk analysis. Zerovalent iron (Fe0) nanoparticles (NPs) are one of the most prominent NPs applied in remediating contaminated soils and groundwater. However, there are concerns that Fe0NP application contributes to long-term environmental and human health impacts. The nematode Caenorhabditis elegans is a surrogate in vivo model that has been successfully applied to assess the potential nanotoxicity of these nanomaterials. Here we present a TBTK/TD approach to appraise bioaccumulation and nanotoxicity of Fe0NPs in C. elegans. Built on a present C. elegans bioassay with estimated TBTK/TD parameters, we found that average bioconcentration factors in C. elegans exposed to waterborne and food-borne Fe0NPs were ~50 and ~5*10-3, respectively, whereas 10% inhibition concentrations for fertility, locomotion, and development, were 1.26 (95% CI 0.19-5.2), 3.84 (0.38-42), and 6.78 (2.58-21) MUg.g-1, respectively, implicating that fertility is the most sensitive endpoint in C. elegans. Our results also showed that biomagnification effects were not observed in waterborne or food-borne Fe0NP-exposed worms. We suggest that the TBTK/TD assessment for predicting NP-induced toxicity at different concentrations and conditions in C. elegans could enable rapid selection of nanomaterials that are more likely to be nontoxic in larger animals. We conclude that the use of the TBTK/TD scheme manipulating C. elegans could be used for rapid evaluation of in vivo toxicity of NPs or for drug screening in the field of nanomedicine. PMID- 28721037 TI - Future trends and emerging issues for nanodelivery systems in oral and oropharyngeal cancer. AB - Oral cancer is a prevalent cancer type on a global scale, whose traditional treatment strategies have several drawbacks that could in the near future be overcome through the development of novel therapeutic and prognostic strategies. Nanotechnology provides an alternative to traditional therapy that leads to enhanced efficiency and less toxicity. Various nanosystems have been developed for the treatment of oral cancer, including polymeric, metallic, and lipid-based formulations that incorporate chemotherapeutics, natural compounds, siRNA, or other molecules. This review summarizes the main benefits of using these nanosystems, in parallel with a particular focus on the issues encountered in medical practice. These novel strategies have provided encouraging results in both in vitro and in vivo studies, but few have entered clinical trials. The use of nanosystems in oral cancer has the potential of becoming a valid therapeutic option for patients suffering from this malignancy, considering that clinical trials have already been completed and others are currently being developed. PMID- 28721039 TI - Top-down nanofabrication of silicon nanoribbon field effect transistor (Si-NR FET) for carcinoembryonic antigen detection. AB - Sensitive and quantitative detection of tumor markers is highly required in the clinic for cancer diagnosis and consequent treatment. A field-effect transistor based (FET-based) nanobiosensor emerges with characteristics of being label-free, real-time, having high sensitivity, and providing direct electrical readout for detection of biomarkers. In this paper, a top-down approach is proposed and implemented to fulfill a novel silicon nano-ribbon FET, which acts as biomarker sensor for future clinical application. Compared with the bottom-up approach, a top-down fabrication approach can confine width and length of the silicon FET precisely to control its electrical properties. The silicon nanoribbon (Si-NR) transistor is fabricated on a Silicon-on-Insulator (SOI) substrate by a top-down approach with complementary metal oxide semiconductor (CMOS)-compatible technology. After the preparation, the surface of Si-NR is functionalized with 3 aminopropyltriethoxysilane (APTES). Glutaraldehyde is utilized to bind the amino terminals of APTES and antibody on the surface. Finally, a microfluidic channel is integrated on the top of the device, acting as a flowing channel for the carcinoembryonic antigen (CEA) solution. The Si-NR FET is 120 nm in width and 25 nm in height, with ambipolar electrical characteristics. A logarithmic relationship between the changing ratio of the current and the CEA concentration is measured in the range of 0.1-100 ng/mL. The sensitivity of detection is measured as 10 pg/mL. The top-down fabricated biochip shows feasibility in direct detecting of CEA with the benefits of real-time, low cost, and high sensitivity as a promising biosensor for tumor early diagnosis. PMID- 28721042 TI - Erratum: Preparation of bufalin-loaded pluronic polyetherimide nanoparticles, cellular uptake, distribution, and effect on colorectal cancer [Corrigendum]. AB - [This corrects the article on p. 4035 in vol. 9, PMID: 25187707.]. PMID- 28721040 TI - Effect of ultraviolet treatment on bacterial attachment and osteogenic activity to alkali-treated titanium with nanonetwork structures. AB - PURPOSE: Alkali-treated titanium with nanonetwork structures (TNS) possesses good osteogenic activity; however, the resistance of this material to bacterial contamination remains inadequate. As such, TNS implants are prone to postoperative infection. In this work, we attempted to alter the biological properties of TNS by treatment with short-duration high-intensity ultraviolet (UV) irradiation. METHODS: TNS discs were treated with UV light (wavelength =254 nm, strength =100 mW/cm2) for 15 minutes using a UV-irradiation machine. We carried out a surface characterization and evaluated the discs for bacterial film formation, protein adsorption, and osteogenic features. RESULTS: The superhydrophilicity and surface hydrocarbon elimination exhibited by the treated material (UV-treated titanium with a nanonetwork structure [UV-TNS]) revealed that this treatment effectively changed the surface characteristics of TNS. Notably, UV-TNS also showed reduced colonization by Actinomyces oris during an initial attachment period and inhibition of biofilm formation for up to 6 hours. Moreover, compared to conventional TNS, UV-TNS showed superior osteogenic activity as indicated by increased levels of adhesion, proliferation, alkaline phosphatase activity, osteogenic factor production, and osteogenesis-related gene expression by rat bone marrow mesenchymal stem cells (rBMMSCs). This inverse relationship between bacterial attachment and cell adhesion could be due to the presence of electron-hole pairs induced by high-intensity UV treatment. CONCLUSION: We suggest that simple UV treatment has great clinical potential for TNS implants, as it promotes the osseointegration of the TNS while reducing bacterial contamination, and can be conducted chair-side immediately prior to implantation. PMID- 28721041 TI - High-intensity focused ultrasound-triggered nanoscale bubble-generating liposomes for efficient and safe tumor ablation under photoacoustic imaging monitoring. AB - High-intensity focused ultrasound (HIFU) is widely applied to tumors in clinical practice due to its minimally invasive approach. However, several issues lower therapeutic efficiency in some cases. Many synergists such as microbubbles and perfluorocarbon nanoparticles have recently been used to improve HIFU treatment efficiency, but none were determined to be effective and safe in vivo. In this study, nanoscale bubble-generating liposomes (liposomes containing ammonium bicarbonate [Lip-ABC]) were prepared by film hydration followed by sequential extrusion. Their stable nanoscale particle diameter was confirmed, and their bubble-generating capacity after HIFU triggering was demonstrated with ultrasound imaging. Lip-ABC had good stability in vivo and accumulated in the tumor interstitial space based on the enhanced permeability and retention effect evaluated by photoacoustic imaging. When used to synergize HIFU ablation to bovine liver in vitro and implanted breast tumors of BALB/c nude mice, Lip-ABC outperformed the control. Importantly, all mice survived HIFU treatment, suggesting that Lip-ABC is a safe HIFU synergist. PMID- 28721043 TI - Preparation of exenatide-loaded linear poly(ethylene glycol)-brush poly(l-lysine) block copolymer: potential implications on diabetic nephropathy. AB - The poly(ethylene glycol)-b-brush poly(l-lysine) polymer (PEG-b-(PELG50-g-PLL3)) was synthesized and evaluated as a nanocarrier for prolonging delivery of exenatide through the abdominal subcutaneous injection route. The isoelectric point of exenatide was 4.86, and exenatide could combine with PEG-b-(PELG50-g PLL3) polymers via electrostatic interactions at pH 7.4. This polymer was a good candidate for achieving prolonged drug delivery for exenatide, considering its high molecular weight. Besides the physicochemical characterization of the polymer, in vitro and in vivo applications were researched as a sustained exenatide delivery system. In the in vitro release research, 20.16%-76.88% of total exenatide was released from the PEG-b-(PELG50-g-PLL3) polymer within 7 days. The synthesized block-brush polymers and exenatide-block-brush polymers were analyzed by nuclear magnetic resonance spectroscopy, gel permeation chromatography, transmission electron microscopy, nanoparticle size instrument, and scanning electron microscopy. The best formulation was selected for in vivo experimentation to achieve blood glucose control in diabetic rat models using free exenatide as the control. The hypoglycemic action of the formulation following subcutaneous injection in diabetic rats lasted 7 days, and the results indicated that exenatide-block-brush polymers demonstrate enhanced long-acting hypoglycemic action. Besides the hypoglycemic action, exenatide-block-brush polymers significantly alleviated diabetic nephropathy via improving renal function, decreasing oxidative stress injury, decreasing urinary albumin excretion rate, mitigating albumin/creatinine ratio, reducing blood lipids, abating kidney index, weakening apoptosis, and downregulating expression of connective tissue growth factor. All of the results suggested that PEG-b-(PELG50 g-PLL3) polymers could be used as potential exenatide nanocarriers, with efficient encapsulation and sustained release. PMID- 28721044 TI - Stimulated phase-shift acoustic nanodroplets enhance vancomycin efficacy against methicillin-resistant Staphylococcus aureus biofilms. AB - PURPOSE: Bacterial biofilms on the surface of prostheses are becoming a rising concern in managing prosthetic joint infections. The inherent resistant features of biofilms render traditional antimicrobial therapy unproductive and revision surgery outcomes uncertain. This situation has prompted the exploration of novel antimicrobial strategies. The synergy of ultrasound microbubbles and vancomycin has been proposed as an efficient alternative for biofilm eradication. The purpose of this study was to evaluate the anti-biofilm effect of stimulated phase shift acoustic nanodroplets (NDs) combined with vancomycin. MATERIALS AND METHODS: We fabricated lipid phase-shift NDs with a core of liquid perfluoropentane. A new phase change mode for NDs incorporating an initial unfocused low-intensity pulsed ultrasound for 5 minutes and a subsequent incubation at 37 degrees C into a 24-hour duration was developed. Methicillin resistant Staphylococcus aureus (MRSA) biofilms were incubated with vancomycin and NDs under the hybrid stimulation. Biofilm morphology following treatment was determined using confocal laser scanning microscopy and scanning electron microscopy. Resazurin assay was used to quantify bactericidal efficacy against MRSA biofilm bacteria. RESULTS: NDs treated sequentially with ultrasound and heating at 37 degrees C achieved gradual and substantial ND vaporization and cavitation in a successive process. NDs after stimulation were capable of generating stronger destruction on biofilm structure which was best characterized by residual circular arc margins and more dead bacteria. Furthermore, NDs combined with vancomycin contributed to significantly decreasing the metabolic activity of bacteria in MRSA biofilms (P<0.05). CONCLUSION: Phase-shift acoustic NDs could exert a significant bactericidal effect against MRSA biofilms through a new stimulation mode. Acoustic NDs present advantages over microbubbles for biofilm damage. This anti-biofilm strategy could be used either alone or as an enhancer of traditional antibiotics in the control of prosthetic joint infections. PMID- 28721045 TI - Synthesis, construction, and evaluation of self-assembled nano-bacitracin A as an efficient antibacterial agent in vitro and in vivo. AB - Bacitracin A (BA) is an excellent polypeptide antibiotic that is active against gram-positive bacteria without triggering multidrug resistance. However, BA is inactive against gram-negative bacteria because of its inability to cross the outer membrane of these cells, and it has strong nephrotoxicity, thus limiting its clinical applications. Nanoantibiotics can effectively localize antibiotics to the periplasmic space of bacteria while decreasing the adverse effects of antibiotics. In this study, biodegradable hydrophobic copolymers of poly (d,l lactide-co-glycolide) (PLGA) were attached to the N-termini of BA to design a novel class of self-assembled nano-bacitracin A (nano-BAs), and their potential as antibacterial agents was evaluated in vitro and in vivo. Nano-BAs had a core shell structure with a mean diameter <150 nm. Impressively, nano-BAs had strong antibacterial properties against both gram-positive and gram-negative bacteria, and the distribution of antibacterial activity as a function of PLGA block length was skewed toward longer PLGA chains. No cytotoxicity against HK-2 cells or human red blood cells (hRBCs) was observed in vitro, suggesting good biocompatibility. A high local density of BA mass on the surface promoted endocytotic cellular uptake, and hydrophobic interactions between the PLGA block and lipopolysaccharide (LPS) facilitated the uptake of nano-BAs, thereby leading to greater antibacterial activities. In addition, Nano-BA5K was found to be effective in vivo, and it served as an anti-infective agent for wound healing. Collectively, this study provides a cost-effective means of developing self assembling nano-polypeptide antibiotic candidates with a broader antibacterial spectrum and a lower toxicity than commercially available peptide antibiotics, owing to their modification with biodegradable copolymers. PMID- 28721046 TI - Brain metabolite values in children with breath-holding spells. AB - Breath-holding spells are benign, paroxysmal events with apnea and postural tone changes after a crying episode in infants. The objective of this study was to investigate the pathologies in brain metabolite values in the absence of seizure in children with breath-holding spells by using magnetic resonance spectroscopy (MRS). Brain MRS examination was performed on 18 children with breath-holding spells and 13 neurologically normal children who were included as the control group. There was no significant difference in terms of N-acetyl aspartate (NAA), choline (Cho), creatine (Cr), and myoinositol (mI) levels and also in terms of NAA/Cr, Cho/Cr, and mI/Cr ratios between the patients and the control group (all P>0.05). Our study suggested that there is no permanent neuronal damage in patients with breath-holding spells. This result confirms the previous studies, which reported no permanent neuronal damage in patients with breath-holding spells. PMID- 28721047 TI - The role of microglia in multiple sclerosis. AB - Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS). Microglia are the resident innate immune cells in the CNS; they play an important role in the processes of demyelination and remyelination in MS. Microglia can function as antigen-presenting cells and phagocytes. In the past, microglia were considered to be the same cell type as macrophages, and researchers have different opinions about the role of microglia in MS. This review focuses on the original classification of microglia and their role in the pathogenesis of MS. Moreover, we present a hypothetical model for the role of microglia in the pathogenesis of MS based on recent findings. PMID- 28721048 TI - Adapting the short form of the Coping Inventory for Stressful Situations into Chinese. AB - OBJECTIVES: The Coping Inventory for Stressful Situations (CISS) is a measurement tool for evaluating stress that has good psychometric properties. We investigated the applicability of a short-form version of the CISS in a large sample of Chinese university students. METHODS: Nine hundred and seventy-two Chinese university students aged 18-30 years (mean =20.15, standard deviation =3.26) were chosen as subjects, of whom 101 were randomly selected to be retested after a 2 week interval. RESULTS: The results of a confirmatory factor analysis revealed that the root mean square error of approximation of a four-factor model was 0.06, while the comparative fit index was 0.91, the incremental fit index was 0.93, the non-normed fit index was 0.91, and the root mean residual was 0.07. The Cronbach's alpha coefficients for the task-oriented, emotion-oriented, distraction, and social diversion coping subscales were 0.81, 0.74, 0.7, and 0.66, respectively. The 2-week test-retest reliability was 0.78, 0.74, 0.7, and 0.65 for the task-oriented, emotion-oriented, distraction, and social diversion coping subscales, respectively. In the Chinese version of the CISS short form, task-oriented coping was positively correlated with positive affect and extraversion and negatively correlated with neuroticism; emotion-oriented coping was negatively correlated with extraversion and positively correlated with negative affect, anxiety, and neuroticism; distraction coping was positively correlated with neuroticism, extroversion, anxiety, positive affect, and negative affect and negatively correlated with psychoticism; and social diversion coping was positively correlated with extroversion and positive affect and negatively correlated with psychoticism. CONCLUSION: The Chinese version of the CISS short form is satisfactorily valid and reliable among Chinese university students. PMID- 28721049 TI - The potential role of vagus-nerve stimulation in the treatment of HIV-associated depression: a review of literature. AB - Depression is the most common comorbidity and neuropsychiatric complication in HIV. Estimates suggest that the prevalence rate for depression among HIV-infected individuals is three times that of the general population. The association between HIV and clinical depression is complex; however, chronic activation of inflammatory mechanisms, which disrupt central nervous system (CNS) function, may contribute to this association. Disruptions in CNS function can result in cognitive disorders, social withdrawal, fatigue, apathy, psychomotor impairment, and sleep disturbances, which are common manifestations in depression and HIV alike. Interestingly, the parasympathetic system-associated vagus nerve (VN) has primary homeostatic properties that restore CNS function following a stress or inflammatory response. Unfortunately, about 30% of adults with HIV are resistant to standard psychotherapeutic and psychopharmacological treatments for depression, thus suggesting the need for alternative treatment approaches. VN stimulation (VNS) and its benefits as a treatment for depression have been well documented, but remain unexplored in the HIV population. Historically, VNS has been delivered using a surgically implanted device; however, transcutanous VNS (tVNS) with nonsurgical auricular technology is now available. Although it currently lacks Food and Drug Administration approval in the US, evidence suggests several advantages of tVNS, including a reduced side-effect profile when compared to standard treatments and comparable results to implantable VNS in treating depression. Therefore, tVNS could offer an alternative for managing depression in HIV via regulating CNS function; moreover, tVNS may be useful for treatment of other symptoms common in HIV. From this, implications for nursing research and practice are provided. PMID- 28721051 TI - Effectiveness of amisulpride in Chinese patients with predominantly negative symptoms of schizophrenia: a subanalysis of the ESCAPE study. AB - BACKGROUND: Effective management strategies for the negative symptoms of schizophrenia remain an unmet need, and data on the use of antipsychotics in this population are scarce, particularly in Chinese patients. Therefore, we investigated amisulpride for the treatment of Chinese patients with predominantly negative symptoms of schizophrenia. METHODS: This post hoc subanalysis of the prospective Effectiveness and Safety of Amisulpride in Chinese Patients with Schizophrenia (ESCAPE) study included adult Chinese patients with an International Classification of Diseases-10 diagnosis of schizophrenia and predominantly negative symptoms, who received amisulpride for 8 weeks. Effectiveness outcomes included >=50% decrease in Positive and Negative Syndrome Scale (PANSS) negative score, and a reduction in PANSS negative symptom score and Clinical Global Impression Severity Scale (CGI-S). The study was registered at ClinicalTrials.gov (NCT01795183). RESULTS: In total, 26 patients were included in the analysis. A >=50% decrease in PANSS negative score from baseline to week 8 was achieved by 34.6% of patients. From baseline to week 8, the mean PANSS negative symptom score decreased by 45.2% (31.9 to 20.7) and CGI-S decreased 1.9 points (5.2 to 3.3). The mean week 8 dose of amisulpride was lower for patients who achieved a >=50% decrease in PANSS negative score at week 8 versus those who did not (481.2 vs 704.1 mg/day). The most common treatment-related adverse events included blood prolactin increase (19.2%) and extrapyramidal disorder (19.2%). Weight gain was reported by one patient. CONCLUSION: Amisulpride effectively reduced PANSS negative symptom score and CGI-S for Chinese patients with predominantly negative symptoms of schizophrenia. No unexpected adverse events were reported. PMID- 28721050 TI - The use of natalizumab for multiple sclerosis. AB - Natalizumab is a monoclonal antibody that acts as an alpha4 integrin antagonist to prevent leukocyte trafficking into the central nervous system. It is US Food and Drug Administration (FDA) approved for the treatment of relapsing-remitting multiple sclerosis (RRMS). Natalizumab demonstrated high efficacy in Phase III trials by reducing the annualized relapse rate, preventing multiple sclerosis (MS) lesion accumulation on magnetic resonance imaging, and decreasing the probability of sustained progression of disability. The leading safety concern with natalizumab is its association with progressive multifocal leukoencephalopathy (PML), a rare brain infection typically seen only in severely immunocompromised patients caused by reactivation of the John Cunningham virus (JCV). Careful analysis of risk factors for PML in natalizumab-treated MS patients, specifi-cally the presence of anti-JCV antibodies, has led to risk mitigation strategies to improve safety. Additional biomarkers are under investigation to further aid risk stratification. Natalizumab's high efficacy and favorable tolerability profile have led to a broad use by MS physicians, as both first-and second-line treatments. This review discusses the natalizumab efficacy, safety, and tolerability and finishes with pragmatic considerations regarding its use in clinical practice. PMID- 28721052 TI - Study of the combinatorial impact of empathy and emotion on the processing of conflicts of interest with the event-related potential technique. AB - OBJECTIVES: Studies have found that empathy is important in moral development and violence suppression, and emotion also affects empathy. However, the combinatorial effect of emotion and empathy on the processing of conflicts is not known. MATERIALS AND METHODS: A total of 44 undergraduate students (23 in low empathy group and 21 in high-empathy group) were enrolled in this study. They were subjected to positive, negative, and neutral emotion evoking, as well as conflicting or nonconflicting proposals. Event-related potential technology was used to study the combinatorial effects of empathy and emotion on the processing of conflict of interest. RESULTS: We found that under the influence of a positive emotion, both low- and high-empathy groups exhibited lower rejection rates. In the context of conflict, individuals in the high-empathy group showed fewer refusals under positive emotion. In the low-empathy group, there was no significant difference between responses to different emotions, but conflicting proposals induced more negative medial frontal negativity than nonconflicting proposals. Individuals in the low-empathy group showed different late positive potentials when responding to different types of proposals under both neutral and negative emotions, whereas those in the high-empathy group only showed different late positive potentials responding to different types of proposals under negative emotion. CONCLUSION: Our results indicate that under positive emotion, individuals with low empathy show less difference in processing either conflicting or nonconflicting proposals, whereas under negative emotion, individuals with high empathy show enhanced motivation toward nonconflicting proposals. PMID- 28721053 TI - Reduced prefrontal activation during verbal fluency task in chronic insomnia disorder: a multichannel near-infrared spectroscopy study. AB - PURPOSE: Daytime complaints such as memory and attention deficits and failure to accomplish daily tasks are common in insomnia patients. However, objective psychological tests to detect cognitive impairment are equivocal. Neural function associated with cognitive performance may explain the discrepancy. The aim of this study was to investigate the hemodynamic response patterns of patients with chronic insomnia disorder (CID) using the noninvasive and low-cost functional neuroimaging technique of multichannel near-infrared spectroscopy (NIRS) in order to identify changes of neural function associated with cognitive performance. PATIENTS AND METHODS: Twenty-four CID patients and twenty-five healthy controls matched for age, right-hand dominance, educational level, and gender were examined during verbal fluency tasks (VFT) using NIRS. A covariance analysis was conducted to analyze differences of oxygenated hemoglobin (oxy-Hb) changes in prefrontal cortex (PFC) between the two groups and reduce the influence of the severity of depression. Pearson correlation coeffcients were calculated to examine the relationship between the oxy-Hb changes, with the severity of insomnia and depressive symptoms assessed by the Pittsburgh Sleep Quality Index (PSQI) and the Hamilton Rating Scale for Depression (HAMD). RESULTS: The number of words generated during the VFT in CID groups showed no statistical differences with healthy controls. CID patients showed hypoactivation in the PFC during the cognitive task. In addition, we found that the function of left orbitofrontal cortex (OFC) during the VFT was significantly negatively correlated with the PSQI scores and the function of right dorsolateral PFC (DLPFC) was significantly negatively correlated with the HAMD scores. CONCLUSION: The present study detected dysfunctions in PFC in spite of intact performance which indicates the role of PFC in the neurophysiological underpinnings. Left OFC function is associated with insomnia symptoms and right DLPFC function is associated with depressive symptoms. PMID- 28721054 TI - Neuroprotective effects of curdione against focal cerebral ischemia reperfusion injury in rats. AB - BACKGROUND: Curdione is one of the most highly concentrated component of the active constituents in E-zhu, which has been reported to possess a variety of activities. However, the pharmacologic neuroprotective activity of curdione has not been evaluated. The present study aimed to investigate the protective effect of curdione on focal cerebral ischemia reperfusion-induced injury in rats and further exploring the underlying mechanisms. MATERIALS AND METHODS: Adult male Sprague Dawley rats were subjected to middle cerebral artery occlusion (MCAO) surgery for 2 h, followed by reperfusion stage. All animals received treatment once a day for 7 days before surgery and 14 days from 4 h after the reperfusion started. The neurological deficit test and Morris water maze test were performed at 1, 4, 7 and 14 days after MCAO. The infarct size of animals was determined by the 2,3,5-triphenyltetrazolium chloride staining, and pathological brain damage was estimated by hematoxylin-eosin staining. The malonaldehyde (MDA) levels and the activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-PX) were detected by enzyme-linked immunosorbent assay. Expression of apoptotic proteins was measured by Western blot. RESULTS: Our results showed that curdione could significantly reduce the infarct size and neurological deficits, promote cognitive function recovery and recover neuronal morphologic damages in MCAO rats. It also blocked the increase of MDA content and elevated the activities of SOD, CAT and GSH-PX. Moreover, curdione attenuated the expression of Cyt-C, c-caspase-3 and c-caspase-9 increased the Bcl-2/Bax ratio and hence decreased the cellular apoptosis. CONCLUSION: Curdione possessed potential neuroprotective effect on rats in the MCAO model. The anti-oxidative and anti-apoptotic properties may be involved in the underlying mechanisms. PMID- 28721055 TI - Chitosan oligosaccharide improves the therapeutic efficacy of sitagliptin for the therapy of Chinese elderly patients with type 2 diabetes mellitus. AB - Sitagliptin improves glycemic control in type 2 diabetes mellitus (T2DM) patients but its side effects are undesirable. Chitosan oligosaccharide (COS) is expected to improve the therapeutic result as a natural product. A total of 200 elderly T2DM patients were evenly assigned into four groups: sitagliptin group (SG), receiving sitagliptin 100 mg/day; COS group (CG), receiving COS 100 mg/day; combination therapy of sitagliptin and COS group (SCG), receiving both sitagliptin and COS 100 mg/day; and placebo group (PG), receiving placebo 100 mg/day. After 42-week therapy, biochemical indices and clinical parameters for the alterations from start points were analyzed. The related molecular mechanism was tested by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot at cell level. Lower risk of hypoglycemia was found in the SCG group when compared with SG and other groups (P<0.05). More patients from the SCG group than other groups attained hemoglobin A1c (HbA1c) reduction >2.5% (P<0.05). Weight reduction of 1.2+/-0.9, 2.6+/-0.8, 4.7+/-1.3, and 0.9+/-0.6 kg was observed in the patients from SG, CG, SCG, and PG groups, respectively (P<0.05). The combined treatment of COS and sitagliptin presented better therapeutic results by improving insulin sensitivity, lipid profile, adiponectin levels, and glucagon-like peptide 1 and reducing side effects, insulin resistance, HbA1c, body mass index, resistin, tumor necrosis factor (TNF)-alpha, and C-reactive protein (CRP) (P<0.05). qRT-PCR and Western blot analysis also showed that COS treatment reduced the levels of resistin, TNF-alpha, and CRP, and increased the level of adiponectin. The combination of COS and sitagliptin provided better glycemic control with fewer side effects and with more weight reduction in the elderly participants with T2DM. PMID- 28721056 TI - Onset of chronic myeloid leukemia with complex karyotype in a pregnant patient: case report and revision of literature. AB - Approximately 10%-12% of patients in chronic-phase chronic myeloid leukemia (CP CML) have additional chromosomal aberrations at diagnosis; moreover, CML occurs in up to 10% of pregnancy-associated leukemias, with an annual incidence of 1 per 100,000 pregnancies. In this report we describe the case of a 36-year-old female with CP-CML diagnosed in the 18th week of pregnancy and with a new complex variant translocation t(4;9;22;21)(q24;q34;q11;q22) and an additional chromosomal aberration t(1;20)(p36;p11). In consideration of her pregnancy, the patient strictly monitored her blood cell count without any specific treatment. At 32 weeks of pregnancy, the patient delivered via cesarean section a healthy baby girl. After 10 days from childbirth, dasatinib was started at a standard dosage of 100 mg/day and 3 months later complete cytogenetic response and major molecular response were obtained, with the achievement of an optimal response according to European Leukemia Net recommendations and showing efficacy of this tyrosine kinase inhibitor (TKI) in the presence of a complex karyotype. PMID- 28721058 TI - Clinical patterns and outcomes of status epilepticus in patients with tuberous sclerosis complex. AB - INTRODUCTION: Refractory epilepsy is a common clinical manifestation in patients with tuberous sclerosis complex (TSC), which can be complicated by many life threatening conditions, such as status epilepticus (SE). However, very few reports mention the patterns and semiology of SE in those patients. OBJECTIVE: To study the clinical characteristics and outcomes of SE in TSC patients. MATERIALS AND METHODS: This observational, prospective study was carried out on 36 Egyptian children with definite TSC. Clinical history, general and neurological examination and psychometric evaluation by standard questionnaires were used to explore characteristics of epileptic manifestations and clinical patterns of SE. All included patients were required to have long-term video electroencephalograms (EEGs) and brain MRI performed. RESULTS: A total of 32 attacks of SE were recorded in 21 patients (58.3%) in our cohort during a follow-up period of 2.8+/ 1.1 years; of those patients, 15 had convulsive status, 7 had non-convulsive SE, 6 had refractory/super-refractory SE and 14 patients had a history of infantile spasms (epileptic spasms). The duration of status ranged from 40 to 150 min (mean +/- standard deviation: 90+/-15). Fourteen patients with SE had severe mental retardation, 9 had autistic spectrum disorder and 22 had severe epileptogenic EEG findings. Patients with SE had higher tuber numbers (mean: 9.6), 5 patients had subependymal giant cell astrocytomas and 2 patients had their SE after receiving everolimus. CONCLUSIONS: The incidence of SE in our patient sample is high (>50%); severe mental retardation, autistic features, history of infantile spasm (epileptic spasms) and high tuber burden are risk factors for developing SE. PMID- 28721059 TI - Cost-effectiveness analysis of dolutegravir plus backbone compared with raltegravir plus backbone, darunavir+ritonavir plus backbone and efavirenz/tenofovir/emtricitabine in treatment naive and experienced HIV-positive patients. AB - BACKGROUND: In January 2014, the European Medicines Agency issued a marketing authorization for dolutegravir (DTG), a second-generation integrase strand transfer inhibitor for HIV treatment. The study aimed at determining the incremental cost-effectiveness ratio (ICER) of the use of DTG+backbone compared with raltegravir (RAL)+backbone, darunavir (DRV)+ritonavir(r)+backbone and efavirenz/tenofovir/emtricitabine (EFV/TDF/FTC) in HIV-positive treatment-naive patients and compared with RAL+backbone in treatment-experienced patients, from the Italian National Health Service's point of view. MATERIALS AND METHODS: A published Monte Carlo Individual Simulation Model (ARAMIS-DTG model) was used to perform the analysis. Patients pass through mutually exclusive health states (defined in terms of diagnosis of HIV with or without opportunistic infections [OIs] and cardiovascular disease [CVD]) and successive lines of therapy. The model considers costs (2014) and quality of life per monthly cycle in a lifetime horizon. Costs and quality-adjusted life years (QALYs) are dependent on OI, CVD, AIDS events, adverse events and antiretroviral therapies. RESULTS: In treatment naive patients, DTG dominates RAL; compared with DRV/r, the ICER obtained is of 38,586 ?/QALY (6,170 ?/QALY in patients with high viral load) and over EFV/TDF/FTC, DTG generates an ICER of 33,664 ?/QALY. In treatment-experienced patients, DTG compared to RAL leads to an ICER of 12,074 ?/QALY. CONCLUSION: The use of DTG+backbone may be cost effective in treatment-naive and treatment experienced patients compared with RAL+backbone and in treatment-naive patients compared with DRV/r+backbone and EFV/TDF/FTC considering a threshold of 40,000 ?/QALY. PMID- 28721060 TI - Clinical use of lenvatinib in combination with everolimus for the treatment of advanced renal cell carcinoma. AB - INTRODUCTION: Renal cell carcinoma (RCC) represents 2%-3% of all cancers in adults, and its pathogenesis is mainly related to altered cellular response to hypoxia. Lenvatinib, a novel multitarget tyrosine kinase inhibitor (TKI), represents a therapeutic option, in combination with mammalian target of rapamycin (mTOR) inhibitor everolimus, for the treatment of metastatic RCC (mRCC). AIM: The objective of this article is to review the evidence about the treatment of mRCC with combination of lenvatinib plus everolimus. EVIDENCE REVIEW: Phase I studies supported clinical activity of lenvatinib in mRCC. A randomized, Phase II, open-label, multicenter trial demonstrated the clinical efficacy of combination treatment with lenvatinib plus everolimus in patients with progressive mRCC after prior therapy with TKI. Median progression-free survival was improved by 9 months with the combination therapy compared to the single-agent everolimus, with an overall response rate of 43% for the experimental regimen. Lenvatinib plus everolimus appeared to be slightly less toxic than single-agent lenvatinib and more toxic than single-agent everolimus; grade 3-4 adverse events occurred in 71% of patients. Currently, lenvatinib plus everolimus has US Food and Drug Administration approval for its use in mRCC after failure of previous treatment with TKI. CONCLUSION: The combination therapy with lenvatinib plus everolimus might be a promising choice for second-line treatment of mRCC patients. Based on the results of the Phase II trial, it is possible to speculate that the combination therapy could be appropriate for patients with high disease burden or strongly symptomatic patients. PMID- 28721061 TI - Clinical and ultrasound parameters in prediction of excessive hemorrhage during management of cesarean scar pregnancy. AB - PRECIS: During the management of cesarean scar pregnancy, gestational mass size >6 cm, uterine scar thickness <0.2 cm, peak systolic velocity >70 cm/s, and resistance index <0.35 are independent risk factors for excessive hemorrhage. OBJECTIVE: The objective of this study was to investigate risk factors associated with excessive hemorrhage during the management of cesarean scar pregnancy (CSP). PATIENTS AND METHODS: A retrospective case-control study was conducted, including 40 patients who experienced excessive bleeding and 80 controls without severe hemorrhage. RESULTS: Six parameters (two clinical and four ultrasound parameters) potentially related to excessive hemorrhage were analyzed. Single-variable statistical analyses showed that the case group had higher gestational age (74.1+/-23.6 days), higher pretreatment serum beta-human chorionic gonadotropin (HCG) level (46,201+/-32,294 mIU/mL), larger gestational mass size (6.5+/-2.2 cm), thinner uterine scar thickness (0.17+/-0.12 cm), and richer peritrophoblastic perfusion (peak systolic velocity [PSV] 72.8+/-33.7 cm/s, resistance index [RI] 0.35+/-0.12), showing statistical significance compared with the control group. Further multivariable logistic regression analysis of the association between each of the risk factors and hemorrhage confirmed that increased gestational mass size and PSV were risk factors for hemorrhage (odds ratio [OR] 3.624, 95% confidence interval [CI] [1.179-11.138] and OR 1.062, 95% CI [1.007-1.121]) and increased uterine scar thickness and RI were protective factors against hemorrhage (OR 0.181, 95% CI [0.034-0.957] and OR 0.851, 95% CI [0.729-0.994]); however, there was no statistical significance between the two clinical parameters. CONCLUSION: Gestational mass size >6 cm, uterine scar thickness <0.2 cm, PSV >70 cm/s, and RI <0.35 are independent risk factors for excessive hemorrhage during the management of CSP. PMID- 28721057 TI - Safety, tolerability, and risks associated with first- and second-generation antipsychotics: a state-of-the-art clinical review. AB - Since the discovery of chlorpromazine (CPZ) in 1952, first-generation antipsychotics (FGAs) have revolutionized psychiatric care in terms of facilitating discharge from hospital and enabling large numbers of patients with severe mental illness (SMI) to be treated in the community. Second-generation antipsychotics (SGAs) ushered in a progressive shift from the paternalistic management of SMI symptoms to a patient-centered approach, which emphasized targets important to patients - psychosocial functioning, quality of life, and recovery. These drugs are no longer limited to specific Diagnostic and Statistical Manual of Mental Disorders (DSM) categories. Evidence indicates that SGAs show an improved safety and tolerability profile compared with FGAs. The incidence of treatment-emergent extrapyramidal side effects is lower, and there is less impairment of cognitive function and treatment-related negative symptoms. However, treatment with SGAs has been associated with a wide range of untoward effects, among which treatment-emergent weight gain and metabolic abnormalities are of notable concern. The present clinical review aims to summarize the safety and tolerability profile of selected FGAs and SGAs and to link treatment-related adverse effects to the pharmacodynamic profile of each drug. Evidence, predominantly derived from systematic reviews, meta-analyses, and clinical trials of the drugs amisulpride, aripiprazole, asenapine, brexpiprazole, cariprazine, clozapine, iloperidone, lurasidone, olanzapine, paliperidone, quetiapine, risperidone, sertindole, ziprasidone, CPZ, haloperidol, loxapine, and perphenazine, is summarized. In addition, the safety and tolerability profiles of antipsychotics are discussed in the context of the "behavioral toxicity" conceptual framework, which considers the longitudinal course and the clinical and therapeutic consequences of treatment-emergent side effects. In SMI, SGAs with safer metabolic profiles should ideally be prescribed first. However, alongside with safety, efficacy should also be considered on a patient-tailored basis. PMID- 28721062 TI - The association of ADAM12 polymorphism with osteoarthritis susceptibility: a meta analysis. AB - BACKGROUND: The pathology of osteoarthritis (OA) is partly attributed to genetic factors; however, the role of ADAM12 polymorphism is still controversial. It is necessary to perform a meta-analysis to investigate this possible correlation. METHODS: Case-control studies on the association between OA susceptibility and ADAM12 polymorphism were comprehensively collected by searching PubMed, Embase, and Web of Science. Odds ratios (ORs) and 95% confidence intervals (CIs) were pooled to evaluate OA risk that was possibly conferred by ADAM12 variant. The analyses were performed not only among general population but also in male and female groups. RESULTS: A total of 8 studies with 10 populations were finally included in this meta-analysis. In the general population, 4 comparisons were carried out (C allele vs G allele, CC vs GG, GC + CC vs GG, and CC vs GC + GG) and found that ADAM12 rs3740199 polymorphism was not associated with increased OA vulnerability. On the other hand, the analyses stratified by gender made 5 comparisons (C allele vs G allele, CC vs GG, GC vs GG, GC + CC vs GG, and CC vs GC + GG). It was shown that rs3740199 polymorphism (GC + CC vs GG) was a risk factor for OA among male patients (OR =1.45, 95% CI =1.04-2.01). Sensitivity analysis indicated that it was an unstable outcome. No correlation was identified in women. Neither heterogeneity nor publication bias was detected in the analyses mentioned above. CONCLUSION: ADAM12 rs3740199 polymorphism is likely to be associated with OA susceptibility among male patients, other than the general population. More studies are needed to confirm this observation. The mechanism by which ADAM12 variant plays a role in OA pathogenesis is also warranted and important for interpreting this possible correlation. PMID- 28721063 TI - Annual deterioration of renal function in hypertensive patients with and without diabetes. AB - BACKGROUND: Chronic kidney disease (CKD) complicates hypertension and diabetes. Knowledge of the deterioration rate of CKD may anticipate adjustment of therapies with renal elimination. This study evaluates the rate of annual deterioration of renal function in hypertensive patients either with type 2 diabetes (DM2) or without it (non-DM) followed for 5 years and relates it with blood pressure (BP) and glycemic control. MATERIALS AND METHODS: Out of a total of 1924 patients, 1023 patients (594 non-DM and 429 DM2, 53% female, aged 62.1+/-10.2 years) were evaluated over 5 years for the annual evolution of renal function (estimated glomerular filtration rate [eGFR], Modification of Diet in Renal Disease) ambulatory 24-hour blood pressure and metabolic parameters, corresponding to the analysis of 2378 patient-years. RESULTS: DM2 and non-DM did not differ for age, mean 24-hour BP levels, nighttime BP, albuminuria, and body mass index. DM2 versus non-DM showed a higher (p<0.02) prevalence of stage 3 CKD (24.0% vs 18.0%, eGFR 30-59), stage 4 (5.4% vs 2.7%, eGFR 15-29), and stage 5 (0.8% vs 0.5%, eGFR <15). Average annual decline of eGFR was 3.3+/-8.2 in DM2 versus 2.4+/-7.7 in non DM (p=0.12, nonsignificant). Annual changes of eGFR and of albuminuria correlated (r=0.578, p<0.001). In multivariate analysis, age, nighttime BP, double inhibition of renin angiotensin system, albuminuria, and HbA1c >8.0% in DM2 predicted the decline in eGFR. On average, 16.2% of DM2 and 13.1% of non-DM moved each year toward a more severe stage of CKD. For initial eGFR <90 mL/min/1.73 m2, 26.4% of DM2 and 18.1% of non-DM patients showed a reduction per year >10% from the previous eGFR value (p=0.042). CONCLUSION: Progressive deterioration of renal function each year is frequent in hypertensive diabetic and non-diabetic patients. Beyond aging, this is particularly dependent on BP control particularly at nighttime, on drug therapy, and on highly abnormal glucose control. PMID- 28721064 TI - Lived experiences of Iranian parents of beta-thalassemia children. AB - INTRODUCTION: Thalassemia is a chronic blood disease, which imposes adverse effects on patients and their families. Parents of such patients, given that they had the thalassemia trait, hold themselves responsible for their children's disease in addition to other difficulties, bear the burden of guilt and hopelessness and worry about the health and future of their children. This study aimed to explore the lived experiences of parents of children with thalassemia. METHODS: The present research was conducted using a descriptive phenomenological approach. A purposive sampling was carried out until data saturation. Participants included 15 parents of children with thalassemia who were referred to the Thalassemia Center of Zabol to perform therapeutic procedures for their child in 2016. RESULTS: Extracted interviews were analyzed employing Colaizzi's method, and four main themes were obtained, including "Gray marriage consanguinity", "Burdened with increased number of thalassemia children", "Socio familial worries" and "Inexpressible wishes for having an ideal society". CONCLUSION: The results revealed that parents of children with thalassemia experience a wide range of problems in different aspects, such as physical, emotional, mental, social, economic and familial dimensions. Their experiences are valuable and can help in achieving a better understanding of their problems, which in turn can enable the members of the treatment team to play a more active role and the society to have a better understanding of this disease. PMID- 28721065 TI - Optimizing the treatment of bevacizumab as first-line therapy for human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer: an updated meta analysis of published randomized trials. AB - BACKGROUND: Manifold data have demonstrated that the addition of bevacizumab to chemotherapy improved progression-free survival (PFS), while few trials have revealed its significant overall survival (OS) benefit. Furthermore, it still remains suspended how to maximize the benefits of bevacizumab as first-line therapy for human epidermal growth factor receptor 2 (HER2)-negative breast cancer. We sought to conduct a meta-analysis to assess the benefits of bevacizumab with chemotherapy and to identify the ideal chemotherapy partner of bevacizumab in the first-line setting for HER2-negative advanced breast cancer patients. METHODS: Computerized and manual searches were performed to identify randomized clinical trials evaluating the efficacy of bevacizumab plus chemotherapy versus chemotherapy alone or bevacizumab with different chemotherapy regimens as first-line therapy for HER2-negative locally recurrent or metastatic breast cancer patients. Risk ratios or odds ratios with their 95% CIs were used to estimate the association between multiple combinations of bevacizumab with chemotherapy and various clinical outcomes. RESULTS: With 7 trials identified, this analysis included 3,984 eligible patients. The addition of bevacizumab to chemotherapy resulted in a statistically significant improvement in PFS (P=0.019) and objective response rate (ORR; P<0.001) rather than in OS (P=0.783) when compared with chemotherapy alone. The greater benefits in PFS and ORR were achieved from bevacizumab plus taxane-based regimens compared with bevacizumab plus capecitabine-based regimens, while bevacizumab plus capecitabine had comparable OS with bevacizumab plus paclitaxel. Additionally, bevacizumab-based triplet therapy failed to improve the clinical outcomes when compared with doublet therapy. CONCLUSION: This meta-analysis reveals that the addition of bevacizumab to chemotherapy yielded PFS and ORR benefits in HER2-negative advanced breast cancer. Additional studies are still prompted to further optimize the first-line treatment of bevacizumab. PMID- 28721066 TI - Clinical importance of serum HE4 and MMP2 levels in endometrial cancer patients. AB - INTRODUCTION: Endometrial cancer is the one of the most common cancers of the genital organ. HE4 and MMP2 are both proteins whose serum levels increase in endometrial cancer. AIM: To explore the diagnostic potential of the serum levels of HE4 and MMP2 in patients with endometrial cancer and benign endometrial diseases. To assess the relationship between the serum levels of HE4 and MMP2 and the typical prognostic factors in patients with endometrial cancer. MATERIALS AND METHODS: Included in the study was a group of 112 patients presenting with bleeding abnormalities at the Pomeranian Medical University in years 2012-2016. Serum HE4 concentrations were measured using the Elecsys Electrochemiluminescence Immunoassay (ECLIA). MMP2 concentrations were quantified in the serum using multiplex immunoassays. RESULTS: We observed statistically significant differences in mean serum levels of HE4 and MMP2 between the group of endometrial cancer patients and the group of patients with no changes in the endometrium (P=0.002/0.003). The diagnostic potential of HE4 and MMP2 in differentiation of high (International Federation of Gynecology and Obstetrics [FIGO] III and IV) vs low (FIGO I and II) clinical stage of tumor and prediction of cellular differentiation grade (G1 vs G3) on the basis of the analysis of the area under the curve is, respectively, 0.86 and 0.82 for HE4 and 0.82 and 0.74 for MMP2. The HE4 marker was significantly more specific than MMP2 in every study group and amounted to 93% vs 86% in all patients included in the analysis, 94% vs 84% in pre-menopausal patients and 84% vs 79% in post-menopausal patients. CONCLUSION: HE4 and MMP2 are characterized by high specificity and may be useful as biomarkers in the diagnostics of endometrial cancer. When determined preoperatively, HE4 is correlated with the prognostic factors of endometrial cancer and may be helpful in the planning of individual treatment of endometrial cancer patients. PMID- 28721067 TI - Phase I dose-escalation study of long-acting pasireotide in patients with neuroendocrine tumors. AB - This phase I study aimed at determining the maximum tolerated dose (MTD) and characterizing the safety, tolerability, pharmacokinetics (PKs), and efficacy of pasireotide in patients with advanced neuroendocrine tumors (NETs). Patients were enrolled in two phases: dose-escalation phase (to determine the MTD) at a starting dose of 80 mg pasireotide long-acting release (LAR) i.m. followed by a dose-expansion phase (to evaluate safety and prelimi-nary efficacy). Associations between PK/pharmacodynamic parameters and clinical outcomes were evaluated using linear regression analysis. A total of 29 patients were treated with 80 mg (n=13) and 120 mg (n=16) doses. Most common primary tumor sites included small intestine (44.8%), pancreas (24.1%), and lung (17.2%). No protocol-defined dose-limiting toxicities were observed in the study; however, in post hoc analysis, a higher incidence of bradycardia (heart rate [HR] <40 beats per minute [bpm]) was observed with 120 mg (31.3%) vs 80 mg (0%). Two partial responses (PRs) were observed, both in the 120 mg dose cohort. Pasireotide concentrations correlated with tumor shrinkage, although the association was not statistically significant (P=0.08). Among the biomarkers analyzed, insulin-like growth factor 1 (IGF-1) showed a decreasing trend with increasing pasireotide concentration, while chromogranin A (CgA) and neuron-specific enolase (NSE) levels did not show any dose-response relationship. The most common adverse events in any dose group were hyperglycemia, fatigue, and nausea. MTD was defined at 120 mg for pasireotide LAR in patients with advanced NETs. Although objective radiographic responses were rarely observed with somatostatin analogs, two PRs were observed among 16 patients in the 120 mg cohort. Bradycardia (HR <40 bpm) appears to be a dose limiting effect; however, the mechanism and clinical significance are uncertain. This study was registered with clinicaltrials.gov (NCT01364415). PMID- 28721068 TI - Patients harboring ALK rearrangement adenocarcinoma after acquired resistance to crizotinib and transformation to small-cell lung cancer: a case report. AB - Anaplastic lymphoma kinase (ALK) rearrangement responds to ALK tyrosine kinase inhibitors (TKIs) in lung cancer. Many cases ultimately acquire resistance to crizotinib. Resistance, including ALK-dominant or ALK non-dominant, mechanisms have been described. Transformation to small-cell lung cancer is rare. Herein, we report a 49-year-old man diagnosed with adenocarcinoma, who was negative for EGFR and ALK genes as detected by reverse transcription polymerase chain reaction, and was treated with crizotinib. A new biopsy showed a small-cell lung cancer after disease progression. Then, next-generation sequencing (NGS) was carried out and detected a TP53 gene mutation, an ALK rearrangement, and no loss of the retinoblastoma gene (RB). Although a regimen for small-cell lung cancer may be one treatment option, a heterogeneous tumor may exist at the time of diagnosis and manifest during the course of disease. PMID- 28721069 TI - The effect of circulating miR-223 on surveillance of different cancers: a meta analysis. AB - PURPOSE: Abnormal expression of miR-223 in cancerous tissue has confirmed it as an important player in tumorigenesis of cancers, such as hepatocellular carcinoma, colorectal carcinoma, osteosarcoma, gastric cancer, and chronic lymphocytic leukemia. The present meta-analysis aimed to explore the association between circulating miR-223 and prognosis of cancers. METHODS: The studies were accessed by an electronic search of multiple databases. RevMan5.3 and STATA14.0 were used to estimate the heterogeneity among studies, pooled effects, and publication bias. RESULTS: Ten studies with data of 1,002 patients with cancer were included in this meta-analysis. The risk of metastasis from stages 3 to 4 of TNM did not decrease when high versus low circulating expression of miR-223 were compared (pooled odds ratio =0.50, 95% CI: 0.24-1.03). In case of prognosis, the overall survival time was not significantly longer with high circulating miR-223 expression (pooled hazard ratio [HR] =0.64, 95% CI: 0.38-1.11) in all cancer types. However, the overall survival time of chronic lymphocytic leukemia (pooled HR =0.19, 95% CI: 0.07-0.54) increased in subgroup analysis. Moreover, the treatment-free survival of chronic lymphocytic leukemia was significantly increased with high circulating miR-223 expression (pooled HR =0.38, 95% CI: 0.23 0.64). CONCLUSION: Circulating miR-223 was not an effective biomarker in prognosis surveillance in all cancers but in chronic lymphocytic leukemia. PMID- 28721070 TI - Association of estrogen receptor alpha PvuII and XbaI polymorphisms with prostate cancer susceptibility and risk stratification: a meta-analysis from case-control studies. AB - BACKGROUND: Studies on the association between two single nucleotide polymorphisms (SNPs) in estrogen receptor alpha (ERalpha), PvuII (rs2234693 T>C) and XbaI (rs9340799 A>G), and the prostate cancer risk are inconsistent. Therefore, we performed a meta-analysis to derive a more accurate estimation of this relationship. METHODS: A literature search of PubMed, Embase, Web of Science databases until October 1, 2016, was conducted. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to assess the strength of this association. RESULTS: Eighteen case-control studies, with a total of 3,317 prostate cancer patients and 8,324 controls, were included. Results showed that both PvuII and XbaI polymorphisms were significantly associated with a higher prostate cancer risk in overall populations. To derive a more accurate estimation, subgroup analysis stratified by ethnicity revealed that this relation ship existed only in Caucasians, but not in Asians. Furthermore, PvuII polymorphism was significantly associated with high Gleason grade (Gleason score >=7) cancers. CONCLUSION: The current meta-analysis demonstrates that ERalpha PvuII and XbaI polymorphisms are associated with a higher prostate cancer risk in Caucasians, but not in Asians, and PvuII polymorphism is significantly associated with high Gleason grade tumors, indicating the probability of inherited susceptibility to prostate cancer arising from different genomic ERalpha SNPs, which may help us understand the pathogenesis of prostate cancer in Caucasians. PMID- 28721071 TI - Adverse renal effects of anaplastic lymphoma kinase inhibitors and the response to alectinib of an ALK+ lung cancer patient with renal dysfunction. AB - A 62-year-old female patient with renal dysfunction and pulmonary adenocarcinoma developed postoperative recurrence and received carboplatin/pemetrexed and maintenance pemetrexed. As an anaplastic lymphoma kinase (ALK) gene translocation was identified, the therapy was changed to crizotinib. However, the patient's blood creatinine level increased, and her physical status worsened. Alectinib also induced exacerbation of renal dysfunction but was controlled by dose reduction of 140 mg twice daily for 2 weeks treatment and 2 weeks break were repeated, and exhibited a partial response for 16 months. Here, we describe the case in which alectinib treatment had beneficial clinical effects on ALK-positive lung adenocarcinoma, which controlled the adverse renal effects by dose reduction and drug breaks. PMID- 28721072 TI - CXCL12 suppresses cisplatin-induced apoptosis through activation of JAK2/STAT3 signaling in human non-small-cell lung cancer cells. AB - AIMS: Poor efficacy of chemotherapy drugs in non-small-cell lung cancer (NSCLC) is the key reason for the failure of treatment, but the mechanism of this remains largely unknown. Stromal cell-derived factor 1-alpha (SDF-1alpha/CXCL12) is a small chemotactic cytokine protein that plays an important role in tumor progression. In this study, we investigated the anti-apoptotic mechanism of the CXCL12/CXCR4 axis in response to cisplatin, a commonly used chemotherapeutic drug, in human lung adenocarcinoma A549 cells. METHODS: CXCL12 blocks cisplatin induced apoptosis in A549, and the results were shown by propidium iodide/annexin V staining in vitro. The mechanism of CXCL12 stimulating phosphorylation of STAT3 through CXCR4/JAK2 was demonstrated by immunofluorescence and Western blotting. The expression of CXCL12 and p-STAT3 in clinical specimens was examined by immunohistochemistry. RESULTS: CXCL12 significantly decreased the ratio of apoptotic cells and stimulation of phospho-signal transducer and activator of transcription (p-STAT)-3 in a time-dependent manner through interaction with CXCR4. Among the signaling molecules downstream of CXCR4, the JAK2/STAT3 pathway plays a predominant role in the anti-apoptotic effect of CXCL12. Analysis of clinical specimens revealed that increased CXCL12 and p-STAT3 expression correlates with enhanced lung cancer progression. CONCLUSION: These data suggest that CXCR4 contributes to CXCL12-mediated anti-apoptosis by activating JAK2/STAT3 pathway in NSCLC cells. Therefore, targeting CXCL12/CXCR4 signaling pathway reveals a potential therapeutic approach for NSCLC. PMID- 28721073 TI - Exploration of the molecular mechanism of prostate cancer based on mRNA and miRNA expression profiles. AB - Prostate cancer, the second most common cancer in men, has been rarely explored by integrating mRNA and miRNA expression profiles. In this study, we combined two mRNA expression datasets and six documented miRNAs to uncover the comprehensive molecular mechanism of prostate cancer. Results showed that a total of 30 genes were significantly differentially expressed in 49 tumor samples by comparing with 22 normal samples. Importantly, all samples from the two datasets can be clearly classified into two groups, tumor group and normal group, based on the selected differentially expressed genes (DEGs). The miRNA-mRNA regulation network indicated that 4 out of 30 DEGs can be regulated by three miRNAs. In addition, prognostic performance validation using in silico databases showed that the DEGs can significantly differentiate between low-risk and high-risk prostate cancer. In summary, multiple biological processes are probably involved in the development and progression of prostate cancer. First, dysregulation of SV2 can regulate transporter and transmembrane transporter activity and then provide the necessary nutrients for tumor cell proliferation. Second, HOXD10 can induce cell proliferation via TCF-4. Finally, dysregulation of CACNA1D can further suppress tumor apoptosis in prostate cancer. The identification of critical genes and valuable biological processes can be useful for the understanding of the molecular mechanism of prostate cancer. PMID- 28721074 TI - Targeted regulation of MiR-98 on E2F1 increases chemosensitivity of leukemia cells K562/A02. AB - BACKGROUND: miRNA is a microRNA that negatively regulates protein expression at post-transcriptional or translational level. It is widely involved in the pathogenesis of tumors. miR-98 belongs to the let-7 family, and its overexpression can increase the sensitivity to drugs in solid cancer cells. However, the function of miR-98 in leukemia is still unclear. In this study, the effect of miR-98 on drug resistance and proliferation of leukemia cells were investigated. METHODS: Real-time quantitative polymerase chain reaction analyzed the expression difference between miR-98 and E2F1 in leukemia cell lines, K562 and K562/A02. The downstream target gene of miR-98 was predicted by TargetScan; K562/A02 was transiently transfected with miR-98 mimic to upregulate the expression of miR-98; real-time quantitative polymerase chain reaction and Western blot were used to analyze the expression alterations of E2F1; cell counting kit-8 was used to evaluate the influence on K562/A02 proliferation and sensitivity to chemotherapeutic drugs; meanwhile, Western blot was used to analyze the expression of p21, Bax, matrix metalloproteinase 9 and ABCG2 proteins. RESULTS: E2F1 is one of the target genes of miR-98 proved by bioinformatics. Compared with the K562, the level of miRNA-98 expression was decreased in K562/A02, but the level of E2F1 expression was upregulated. Leukemia cell line K562/A02 was transfected with miR-98 mimic to upregulate the expression of miR-98, the expression of E2F1 was significantly decreased. After upregulating the miR-98 expression in K562/A02, the proliferation was weakened, and the sensitivity to chemotherapy was increased. Western blot showed that upregulated miR-98 expression increased the levels of p21 and BAX proteins in K562/A02 cells, and decreased the levels of matrix metalloprotease 9 and ABCG2 proteins, which were significantly different compared with those before miR-98 mimic transfection. CONCLUSION: In the leukemia drug-resistant cell line K562/A02, the targeted upregulated expression of miR-98 could decrease the proliferation of leukemia cells and improve the sensitivity to chemotherapeutics by inhibiting E2F1 expression. miR-98 might be a potential target for overcoming leukemia multidrug resistance. PMID- 28721075 TI - LincRNA-p21 inhibits invasion and metastasis of hepatocellular carcinoma through miR-9/E-cadherin cascade signaling pathway molecular mechanism. AB - In the previous study, it was found that long intergenic noncoding RNA-p21 (lincRNA-p21) was downregulated in hepatocellular carcinoma (HCC) and lincRNA-p21 overexpression inhibited tumor invasion through inducing epithelial-mesenchymal transition. However, the underlying mechanism was not fully elaborated. In this study, lincRNA-p21 expression was measured in 12 paired HCC and nontumor adjacent normal tissues by quantitative real-time polymerase chain reaction. The effects of lincRNA-p21 on HCC cells were studied using lentivirus expressing lincRNA-p21 vector in vitro. The association between lincRNA-p21 level and miR-9 level was tested with the Spearman rank correlation. The effects of miR-9 on HCC cells were studied by using miR-9 inhibitor in vitro. Luciferase assay was used to validate the target of miR-9. The results showed that lincRNA-p21 was downregulated in human HCC tissues and cell lines. LincRNA-p21 overexpression significantly inhibited HCC cell migration and invasion in vitro. Besides, lincRNA-p21 negatively regulated miR-9 expression level, and miR-9 was upregulated in human HCC tissues and cells. MiR-9 knockdown inhibited HCC cell migration and invasion in vitro. Finally, the luciferase assay results showed that E-cadherin was a direct target of miR-9. The expression level of E-cadherin was found to be regulated by lincRNA-p21 and miR-9. Altogether, the results suggested that lincRNA-p21 inhibits migration and invasion of HCC cells through regulating miR-9 mediated E-cadherin cascade signaling pathway. PMID- 28721077 TI - Food protein-induced enterocolitis syndrome - a review of the literature with focus on clinical management. AB - Food protein-induced enterocolitis syndrome (FPIES) is a potentially severe presentation of non-IgE-mediated gastrointestinal food allergy (non-IgE-GI-FA) with heterogeneous clinical manifestations. Acute FPIES is typically characterized by profuse vomiting and lethargy, occurring classically 1-4 hours after ingestion of the offending food. When continuously exposed to the incriminated food, a chronic form has been described with persistent vomiting, diarrhea, and/or failure to thrive. Although affecting mainly infants, FPIES has also been described in adults. Although FPIES is actually one of the most actively studied non-IgE-GI-FAs, epidemiologic data are lacking, and estimation of the prevalence is based on a limited number of prospective studies. The exact pathomechanisms of FPIES remain not well defined, but recent data suggest involvement of neutrophils and mast cells, in addition to T cells. There is a wide range of food allergens that can cause FPIES with some geographical variations. The most frequently incriminated foods are cow milk, soy, and grains in Europe and USA. Furthermore, FPIES can be induced by foods usually considered as hypoallergenic, such as chicken, potatoes or rice. The diagnosis relies currently on typical clinical manifestations, resolving after the elimination of the offending food from the infant's/child's diet and/or an oral food challenge (OFC). The prognosis is usually favorable, with the vast majority of the case resolving before 5 years of age. Usually, assessment of tolerance acquisition by OFC is proposed every 12-18 months. Of note, a switch to an IgE-mediated FA is possible and has been suggested to be associated with a more severe phenotype. Avoiding the offending food requires education of the family of the affected child. A multidisciplinary approach including ideally allergists, gastroenterologists, dieticians, specialized nurses, and caregivers is often useful to optimize the management of these patients, that might be difficult. PMID- 28721076 TI - Hedgehog signaling pathway in colorectal cancer: function, mechanism, and therapy. AB - Colorectal cancer (CRC) is one of the most common gastrointestinal cancers worldwide. It is a complicated and often fatal cancer, and is related to a high disease-related mortality. Around 90% of mortalities are caused by the metastasis of CRC. Current treatment statistics shows a less than 5% 5-year survival for patients with metastatic disease. The development and metastasis of CRC involve multiple factors and mechanisms. The Hedgehog (Hh) signaling plays an important role in embryogenesis and somatic development. Abnormal activation of the Hh pathway has been proven to be related to several types of human cancers. The role of Hh signaling in CRC, however, remains controversial. In this review, we will go through previous literature on the Hh signaling and its functions in the formation, proliferation, and metastasis of CRC. We will also discuss the potential of targeting Hh signaling pathway in the treatment, prognosis, and prevention of CRC. PMID- 28721078 TI - Incomplete recovery of the fecal flora of hematological patients with neutropenia and repeated fluoroquinolone prophylaxis. AB - BACKGROUND: Routine fluoroquinolone prophylaxis in neutropenic patients with hematological malignancies is still controversial, because of antibiotic resistance concerns. The recovery of the fecal microbiota to the initial composition in patients receiving multiple courses of quinolone prophylaxis and repeated chemotherapy has not been evaluated. METHODS: We prospectively examined the changes in the fecal bacterial composition before and after levofloxacin prophylaxis. A sequential observation of bacterial resistance in patients receiving multiple prophylactic courses was also conducted. RESULTS: In this trial, 68 cases, including (35 with the first course and 33 with the second and subsequent courses) were registered. The disappearance of quinolone-susceptible (QS) Entero-bacteriaceae and dominant emergence of quinolone-resistant (QR) coagulase negative staphylococci (CNS) and QR Enterococci were observed after the first prophylaxis. The detection of QS Enterobacteriaceae was recovered before the second and subsequent courses to a level of the initial composition (28/35 samples, 80.0% before the first course vs 23/33 samples, 69.7% before the second and subsequent courses, P=0.41). In contrast, the detection rate of QR CNS and Enterococci significantly increased at the second and subsequent courses, even before prophylaxis (8/35 samples, 22.9% before the first course vs 20/33 samples, 60.6% before the second and subsequent courses, P=0.003). The incomplete recovery of the initial bacterial composition was associated with a prophylactic interval of within 30 days. Of the patients receiving multiple prophylactic courses, six had QR Escherichia coli, including extended-spectrum beta-lactamase (ESBL) producers, at the first course, and four (66.3%) of the six patients had persistent detection of QR E. coli at the second course. CONCLUSION: In patients receiving multiple courses of prophylactic quinolone, along with a common chemotherapy schedule, newly emergent resistant bacteria could be frequently persistent in their fecal flora. PMID- 28721079 TI - Burden of air leak complications in thoracic surgery estimated using a national hospital billing database. AB - BACKGROUND: One of the most common outcomes of lung resections are parenchymal air leaks. These air leaks are most often self-limited and spontaneously resolve several days after surgery. Historically, only prolonged air leaks have been considered to have a significant effect on patient outcomes. This study aims to evaluate the impact of any air leak complications (aALCs) on resource utilization and mortality. METHODS: The Premier Perspective(r) database was used to identify all elective primary lobectomy, segmentectomy, and wedge resections performed from 2012 to 2014; aALC was defined as a composite of air leak and pneumothorax. Generalized estimating equation models were used to estimate the impact of aALCs on length of stay (LOS), operating room time (ORT), hospital costs, and mortality during index hospitalization. RESULTS: A total of 21,150 patients undergoing lung resection surgery were included in the analysis: lobectomy (n=10,946), segmentectomy (n=1,788), and wedge resection (n=8,416). The overall incidence of aALCs was 24.26% (95% CI [23.68, 24.83]). Identified risk factors included resection type, surgical approach, male gender, and presence of COPD. Patients with aALCs had a significantly higher economic burden (adjusted mean [standard error of mean, SE]: LOS=7.24 [SE=0.12] days; ORT=214.9 [SE=6.4] min; and hospital costs=$26,070 [SE=$1404]) compared to those without aALCs (adjusted mean [SE]: LOS=4.75 [SE=0.07] days; ORT=201.7 [SE=3.9] min; and hospital costs=$19,558 [SE=$399]). aALC was also associated with increased overall index hospitalization mortality (odds ratio=1.90, 95% CI [1.42, 2.55]). CONCLUSION: This analysis showed that aALCs are not only frequent but also associated with significantly higher resource utilization and mortality. PMID- 28721080 TI - A cost analysis of a broad-spectrum antibiotic therapy in the empirical treatment of health care-associated infections in cirrhotic patients. AB - BACKGROUND: Early diagnosis and appropriate treatment of infections in cirrhosis are crucial. As new guidelines in this context, particularly for health care associated (HCA) infections, would be needed, we performed a trial documenting whether an empirical broad-spectrum antibiotic therapy is more effective than the standard one for these infections. Because of the higher daily cost of broad spectrum than standard antibiotics, we performed a cost analysis to compare: 1) total drug costs, 2) profitability of hospital admissions. METHODS: This retrospective observational analysis was performed on patients enrolled in the trial NCT01820026, in which consecutive cirrhotic patients with HCA infections were randomly assigned to a standard vs a broad-spectrum treatment. Antibiotic daily doses, days of treatment, length of hospital stay, and DRG (diagnosis related group) were recorded from the clinical trial medical records. The profitability of hospitalizations was calculated considering DRG tariffs divided by length of hospital stay. RESULTS: We considered 84 patients (42 for each group). The standard therapy allowed to obtain a first-line treatment cost lower than in the broad-spectrum therapy. Anyway, the latter, being related to a lower failure rate (19% vs 57.1%), resulted in cost saving in terms of cumulative antibiotic costs (first- and second-line treatments). The mean cost saving per patient for the broad-spectrum arm was ?44.18 (-37.6%), with a total cost saving of about ?2,000. Compared to standard group, we observed a statistically significant reduction in hospital stay from 17.8 to 11.8 days (p<0.002) for patients treated with broad-spectrum antibiotics. The distribution of DRG tariffs was similar in the two groups. According to DRG, the shorter length of hospital stay of the broad-spectrum group involved a higher mean profitable daily cost than standard group (?345.61 vs ?252.23; +37%). CONCLUSION: Our study supports the idea that the use of a broad-spectrum empirical treatment for HCA infections in cirrhosis would be cost-saving and that hospitals need to be aware of the clinical and economic consequences of a wrong antibiotic treatment in this setting. PMID- 28721081 TI - Insulin glargine 300 U/mL for basal insulin therapy in type 1 and type 2 diabetes mellitus. AB - OBJECTIVE: To review published clinical studies on the efficacy and safety of new insulin glargine 300 units/mL (Gla-300), a new long-acting insulin analog, for the treatment of type 1 and type 2 diabetes mellitus (T1DM, T2DM). MATERIALS AND METHODS: Data sources comprised primary research articles on Gla-300, including pharmacodynamic, pharmacokinetic, and clinical studies. RESULTS: In pharmacodynamic and pharmacokinetic studies, Gla-300 showed a flatter time-action profile and longer duration of action than Gla-100. Noninferiority of Gla-300 versus Gla-100 for lowering of glycated hemoglobin was demonstrated in Phase III clinical studies covering a range of T1DM and T2DM patient populations. Over 6-12 months of follow-up, Gla-300 consistently showed comparable glycemic efficacy with less hypoglycemia vs Gla-100, even during the first 8 weeks of treatment. Although titrated insulin doses were 11%-17% higher with Gla-300 vs Gla-100, changes in body weight were similar or favored Gla-300. CONCLUSION: Clinical studies provide evidence that the pharmacodynamic and pharmacokinetic properties of Gla-300 may translate into clinical benefits in both T1DM and T2DM. Gla-300 may provide a new option for people initiating basal insulin, those requiring higher basal insulin doses, those with T1DM, and those who may be at increased risk for hypoglycemia, such as people with chronic kidney disease, the elderly, and those with cardiovascular comorbidities. PMID- 28721082 TI - Effectiveness evaluation of two volumizing hyaluronic acid dermal fillers in a controlled, randomized, double-blind, split-face clinical study. AB - BACKGROUND: Enhancement of the midface can be achieved with volumizing hyaluronic acid (HA) fillers. OBJECTIVE: The objective of this study was to compare the safety and effectiveness of Cohesive Polydensified Matrix(r) 26 mg/mL HA gel (CPM 26) and Vycross(r) 20 mg/ml HA gel (VYC-20) in a controlled, randomized, evaluator-blind, split-face clinical study. PATIENTS AND METHODS: Subjects with moderate-to-severe malar volume loss on the Merz Aesthetics Scale (MAS) received CPM-26 on one side and VYC-20 on the contralateral side of the face. Effectiveness assessments were performed by blinded evaluators including photographic and live MAS ratings and live Global Aesthetic Improvement Scale (GAIS) ratings. Calculations of anatomical volume variations at month 3 (M3), month 6 (M6), month 12 (M12) and month 18 (M18) were also performed. RESULTS: Non inferiority of CPM-26 versus VYC-20 was demonstrated at M3 (primary end point) based on MAS. GAIS rating showed that significantly more subjects had better improvement with CPM-26 than with VYC-20 at month 1, M3, M12 and M18 (p=0.0032, p=0.0074, p=0.0384 and p=0.0110, respectively). Standardized evaluation of volume variations from baseline to M3, M12 and M18 showed that CPM-26 created more volume augmentation at all time points, and the difference was significant at M3. CONCLUSION: CPM-26 was non-inferior to VYC-20 based on MAS ratings at M3 and demonstrated a favorable safety and effectiveness profile for midfacial volume enhancement with results lasting up to M18. PMID- 28721083 TI - Effect of a lotion containing the heat-treated probiotic strain Lactobacillus johnsonii NCC 533 on Staphylococcus aureus colonization in atopic dermatitis. AB - OBJECTIVE: Staphylococcus aureus dominates the skin microbiota in patients with atopic dermatitis (AD), with bacterial loads correlating with disease severity. The aim of this exploratory study was to investigate the effect of a cosmetic lotion containing heat-treated Lactobacillus johnsonii NCC 533 (HT La1) on S. aureus colonization in AD patients. METHODS: This open-label, multicenter study was performed in AD patients in Germany. First, detection of S. aureus was performed in all patients using the swab or scrub-wash method of sampling, followed by quantitative culture or quantitative polymerase chain reaction. Repeatability and reproducibility of all method combinations were evaluated to select the best combination of sampling and quantification. Second, a lotion containing HT La1 was applied to lesional skin twice daily for 3 weeks. Scoring using local objective SCORing Atopic Dermatitis (SCORAD), measurement of S. aureus load, and lesional microbiome analysis were performed before and after the 3-week treatment period. RESULTS: Thirty-one patients with AD were included in the study. All sampling and quantification methods were found to be robust, reproducible, and repeatable for assessing S. aureus load. For simplicity, a combination of swab and quantitative polymerase chain reaction was chosen to assess the efficacy of HT La1. Following application of a lotion containing HT La1 to AD lesions for 3 weeks, a reduction in S. aureus load was observed in patients, which correlated with a decrease in local objective SCORAD. Interestingly, high baseline skin concentrations of S. aureus were associated with good responses to the lotion. CONCLUSION: This study demonstrated that the application of a lotion containing HT La1 to the lesional skin of patients with AD for 3 weeks controlled S. aureus colonization and was associated with local clinical improvement (SCORAD). These findings support further development of topical treatments containing heat-treated nonreplicating beneficial bacteria for patients with AD. PMID- 28721084 TI - Urinary TIMP2?IGFBP7 for the prediction of platinum-induced acute renal injury. AB - INTRODUCTION: Platinum-based chemotherapy (PBC) is a potent antineoplastic treatment, but cisplatin nephrotoxicity is often the limiting factor. Identifying the patients who are at risk for developing platinum-induced renal injury is an important issue. We tested urinary TIMP2.IGFBP7, a new US Food and Drug Administration (FDA)-cleared test to assess the risk of acute kidney injury (AKI), in a cohort of patients with malignant neoplastic disease receiving PBC. PATIENTS AND METHODS: A total of 58 patients with malignant neoplastic disease were enrolled in this study, of whom 32 patients had both urine samples and subsequent serum creatinine values available for detecting AKI within 72 hours. Urine samples were collected within 6 hours prior to PBC application and within 12 hours after the end of chemotherapy administration. We examined the predictive ability of TIMP2.IGFBP7 for the development of AKI as defined by KDIGO (Kidney Disease: Improving Global Outcomes) criteria within 72 hours after the administration of chemotherapy. Operating characteristics were determined for the previously validated TIMP2.IGFBP7 cutoff of 0.3 (ng/mL)2/1000. RESULTS: Four (12.5%) patients developed AKI within 72 hours. Primary disease was lymphoma in 13 patients (40.6%) and solid tumors in 19 patients (59.4%). Eight patients (25.0%) received carboplatin and 24 (75.0%) cisplatin. TIMP2.IGFBP7 after PBC administration discriminated for the risk of AKI with an area under the receiver operating characteristic curve (AUC; 95% confidence interval) of 0.92 (0.80 1.00). At the cutoff of 0.3 for TIMP2.IGFBP7, sensitivity was 50%, specificity was 87%, negative predictive value was 95% and positive predictive value was 25% for the prediction of AKI within 72 hours. CONCLUSION: Urinary TIMP2.IGFBP7 measured in specimens gathered after PBC may be a useful tool to early identify patients who are at risk for developing platinum-induced AKI. PMID- 28721085 TI - Ambulatory and home blood pressure monitoring: gaps between clinical guidelines and clinical practice in Singapore. AB - PURPOSE: Out-of-office blood pressure (BP) measurements (home blood pressure monitoring [HBPM] and ambulatory blood pressure monitoring [ABPM]) provide important additional information for effective hypertension detection and management decisions. Therefore, out-of-office BP measurement is now recommended by several international guidelines. This study evaluated the practice and uptake of HBPM and ABPM among physicians from Singapore. MATERIALS AND METHODS: A sample of physicians from Singapore was surveyed between 8 September and 5 October 2016. Those included were in public or private practice had been practicing for >=3 years, directly cared for patients >=70% of the time, and treated >=30 patients for hypertension per month. The questionnaire covered six main categories: general BP management, BP variability (BPV) awareness/diagnosis, HBPM, ABPM, BPV management, and associated training needs. RESULTS: Sixty physicians (30 general practitioners, 20 cardiologists, and 10 nephrologists) were included (77% male, 85% aged 31-60 years, and mean 22-year practice). Physicians recommended HBPM and ABPM to 81% and 27% of hypertensive patients, respectively. HBPM was most often used to monitor antihypertensive therapy (88% of physicians) and 97% thought that ABPM was useful for providing information on BPV. HBPM instructions often differed from current guideline recommendations in terms of frequency, number of measurements, and timing. The proportion of consultation time devoted to discussing HBPM and BPV was one-quarter or less for 73% of physicians, and only 55% said that they had the ability to provide education on HBPM and BPV. Patient inertia, poor patient compliance, lack of medical consultation time, and poor patient access to a BP machine were the most common challenges for implementing out-of-office BP monitoring. CONCLUSION: Although physicians from Singapore do recommend out-of-office BP measurement to patients with hypertension, this survey identified several important gaps in knowledge and clinical practice. PMID- 28721086 TI - Adaptation to illness in relation to pain perceived by patients after surgery. AB - BACKGROUND: Pain is one of the factors that decrease quality of life. Undergoing surgery is inevitably associated with the sensation of pain, which can affect a patient's level of acceptance of an illness. The aim of the study was to evaluate the level of acceptance of illness in patients undergoing surgical treatment with relation to the pain perceived by them during surgical treatment and to determine other factors that affect adaptation to illness among patients subjected to invasive treatment. MATERIAL AND METHODS: The study was conducted on a group of 100 patients with mean age of 51.27 (SD=18.98) hospitalized in surgery departments in the Provincial Specialist Hospital in Wroclaw, Poland, in April 2016. The Acceptance of Illness Scale (AIS) and the Visual Analog Scale (VAS) for pain were used. RESULTS: The mean score of VAS was 3.86 (SD =2.02). The mean score of AIS was 24.42 (SD =7.35). The level of acceptance of illness was significantly negatively correlated with the intensity of pain (p<0.001; r= 0.498), the number of coexisting diseases (p=0.002; r=-0.31), age (p<0.001; r= 0.391), and the period of time since the operation (p=0.007; r=-0.266). Patients taking analgesics showed a significantly lower acceptance of illness than those who did not (p=0.009). A patient's place of living, education, and sex had no significant impact on their acceptance of illness. CONCLUSION: A higher level of pain translates into a lower adaptation to illness despite the use of analgesics, which may indicate that inadequate pain control leads to a decrease in the acceptance of illness. Further research on monitoring postoperative pain, as well as the development of postoperative prevention programs, is required. PMID- 28721087 TI - Epicrania fugax combining forward and backward paroxysms in the same patient: the first four cases. AB - BACKGROUND: The first description of epicrania fugax (EF) reported brief painful paroxysms that start in posterior regions of the scalp and move forward to reach the ipsilateral forehead, eye, or nose. A backward variation, wherein pain stems from frontal areas and radiates to the posterior scalp, has also been acknowledged. We report four patients with features reminiscent of EF and the coexistence of forward and backward pain paroxysms. METHODS: We considered all patients attending the headache outpatient office at two tertiary hospitals from March 2008 to March 2016. We enrolled four patients with paroxysms fulfilling criteria for EF and a combination of forward and backward radiations. RESULTS: In all cases, pain paroxysms moved both in forward and backward directions with either a zigzag (n=2) or linear (n=2) trajectory. Three patients presented two stemming points, in the occipital scalp and forehead (n=2) or in the parietal area and eye (n=1), whereas the fourth patient only had a stemming point located in the parietal region. Pain quality was mainly stabbing, and its intensity was moderate (n=1) or severe (n=3). The duration of the paroxysms was highly variable (3-30 seconds), and two patients reported autonomic symptoms. CONCLUSION: The clinical picture presented by our patients does not fit with other types of known headache or neuralgia syndromes; we propose it corresponds to a bidirectional variant of EF. PMID- 28721089 TI - Combination treatment of neuropathic pain: Danish expert recommendations based on a Delphi process. AB - BACKGROUND: Current Danish treatment algorithms for pharmacological treatment of neuropathic pain (NeP) are tricyclic antidepressants (TCA), gabapentin and pregabalin as first-line treatment for the most common NeP conditions. Many patients have insufficient pain relief on monotherapy, but combination therapy had not been included in guidelines until recently. Based on clinical empiricism and scientific evidence, a Delphi consensus process provided a consolidated guidance on pharmacological combination treatment of NeP. METHODS: A two-round virtual internet-based Delphi process with 6 Danish pain specialists was undertaken. In the first round, questions were answered individually and anonymously, whereas in the second round, the panel openly discussed first round's summary of outcomes. Combinations of pharmacological pain treatments, that is, pregabalin/gabapentin, TCAs, serotonin-norepinephrine reuptake inhibitors (SNRIs), selective serotonin reuptake inhibitors, opioids, other antiepileptics and cutaneous patches, were assessed based on both scientific and clinical practice experiences. The Centers for Disease Control and Prevention (CDC) grading system was used for evidence rating. RESULTS: Combination of pregabalin/gabapentin with TCA is useful in patients who do not gain sufficient pain relief or tolerate either drug in high doses, or to improve sleep disturbance. Also, combination of pregabalin/gabapentin and SNRIs is reasonably well documented and experienced by some experts to result in sufficient pain relief and fewer side effects than monotherapy. Good evidence on efficacy was found for the combination of pregabalin/gabapentin or TCAs and opioids, which was also frequently used in clinical practice. The evidence for combining TCAs and SNRIs is insufficient, although sometimes used in clinical practice despite the risk of serotonin syndrome. For localized NeP, combination therapy with cutaneous patches should be considered. There was insufficient scientific evidence for any pharmacologic combination therapies with selective serotonin reuptake inhibitors as well as for other potential combinations. CONCLUSIONS: The study revealed that combination therapy is widely used in clinical practice and supported by some scientific evidence. However, further studies are needed. PMID- 28721088 TI - Forced exercise attenuates neuropathic pain in chronic constriction injury of male rat: an investigation of oxidative stress and inflammation. AB - BACKGROUND AND OBJECTIVE: Initial peripheral/central nerve injuries, such as chronic constriction injury (CCI)/spinal cord injury, are often compounded by secondary mechanisms, including inflammation and oxidative stress, which may lead to chronic neuropathic pain characterized by hyperalgesia or allodynia. On the other hand, exercise as a behavioral and non-pharmacological treatment has been shown to alleviate chronic neuropathic pain. Therefore, this study was conducted to examine whether or not exercise reduces neuropathic pain through modifying oxidative stress and inflammation in chronic constriction injury of the sciatic nerve. MATERIALS AND METHODS: Wistar male rats weighing 200+/-20 g were randomly divided into five groups (normal, sham, CCI, pre-CCI exercise, and post-CCI exercise group). Sciatic nerve of anesthetized rats was loosely ligated to induce CCI, and they were then housed in separate cages. The rats ran on treadmill at a moderate speed for 3 weeks. Mechanical allodynia and thermal hyperalgesia were determined using von Frey filament and plantar test, respectively. Tumor necrosis factor-alpha (TNF-alpha) assayed in the cerebrospinal fluid, malondialdehyde, and total antioxidant capacity were measured in the serum using Western blot test, thiobarbituric acid, and ferric reducing ability of plasma (FRAP), respectively. RESULTS: The mechanical allodynia (P=0.024) and thermal hyperalgesia (P=0.002) in the CCI group were higher than those in the sham group. Exercise after CCI reduced (P=0.004) mechanical allodynia and thermal hyperalgesia (P=0.025) compared with the CCI group. Moreover, the level of FRAP in the CCI group was (P=0.001) lower than that in the sham group, and post-CCI exercise reversed FRAP amount toward the control level (P=0.019). The amount of malondialdehyde did not differ between groups. Level of TNF-alpha increased in the CCI group (P=0.0002) compared with sham group and post-CCI exercise could reverse it toward the level of control (P=0.005). CONCLUSION: Post CCI-exercise but not pre CCI-exercise reduces CCI-induced neuropathic pain. One of the possible involved mechanisms is increasing the total antioxidant capacity and reducing the amount of TNF-alpha. PMID- 28721090 TI - Muscle injections with lidocaine improve resting fatigue and pain in patients with chronic fatigue syndrome. AB - OBJECTIVE: Patients with chronic fatigue syndrome (CFS) complain of long-lasting fatigue and pain which are not relieved by rest and worsened by physical exertion. Previous research has implicated metaboreceptors of muscles to play an important role for chronic fatigue and pain. Therefore, we hypothesized that blocking impulse input from deep tissues with intramuscular lidocaine injections would improve not only the pain but also fatigue of CFS patients. METHODS: In a double-blind, placebo-controlled study, 58 CFS patients received 20 mL of 1% lidocaine (200 mg) or normal saline once into both trapezius and gluteal muscles. Study outcomes included clinical fatigue and pain, depression, and anxiety. In addition, mechanical and heat hyperalgesia were assessed and serum levels of lidocaine were obtained after the injections. RESULTS: Fatigue ratings of CFS patients decreased significantly more after lidocaine compared to saline injections (p = 0.03). In contrast, muscle injections reduced pain, depression, and anxiety (p < 0.001), but these changes were not statistically different between lidocaine and saline (p > 0.05). Lidocaine injections increased mechanical pain thresholds of CFS patients (p = 0.04) but did not affect their heat hyperalgesia. Importantly, mood changes or lidocaine serum levels did not significantly predict fatigue reductions. CONCLUSION: These results demonstrate that lidocaine injections reduce clinical fatigue of CFS patients significantly more than placebo, suggesting an important role of peripheral tissues for chronic fatigue. Future investigations will be necessary to evaluate the clinical benefits of such interventions. PMID- 28721091 TI - Comparison of single-injection ultrasound-guided approach versus multilevel landmark-based approach for thoracic paravertebral blockade for breast tumor resection: a retrospective analysis at a tertiary care teaching institution. AB - BACKGROUND: The role of thoracic paravertebral blockade (TPVB) in decreasing opioid requirements in breast cancer surgery is well documented, and there is mounting evidence that this may improve survival and reduce the rate of malignancy recurrence following cancer-related mastectomy. We compared the two techniques currently in use at our institution, the anatomic landmark-guided (ALG) multilevel versus an ultrasound-guided (USG) single injection, to determine an optimal technique. METHODS: We retrospectively reviewed records of patients who received TPVB from January 2013 to December 2014. Perioperative opioid use, post anesthesia care unit (PACU) pain scores and length of stay, block performance, and complications were compared between the two groups. RESULTS: We found no statistical difference between the two approaches in the studied outcomes. We did find that the number of times attending physicians in the ALG group took over the blocks from residents was significantly greater than that of the USG group (p=0.006) and more local anesthetic was used in the USG group (p=0.04). CONCLUSION: This study compared the ALG approach with the USG approach for patients undergoing mastectomy for breast cancer. Based on our observations, an attending physician is more likely to take over an ALG injection, and more local anesthetic is administered during USG single injection. PMID- 28721093 TI - Gout mimicking spondyloarthritis: case report and literature review. AB - Gout is clinically characterized by episodes of monoarthritis, which not only typically affects the peripheral joints but also occasionally affect the axial joint, such as the sacroiliac joint (SIJ), and often mimics spondyloarthritis (SpA). Two cases of gout mimicking SpA are presented in the current paper. One patient was a 32-year-old man with a history of asymmetrical oligoarthritis of ankle and metatarsophalangeal joints (MTPJ). He had left gluteal pain for 2 weeks. Computed tomography (CT) and magnetic resonance imaging (MRI) revealed the bone erosion of the left SIJ. T1-weighted MRI showed hypointense T1 and hyperintense T2 signals of the left SIJ. The other patient was a 24-year-old man with left back pain and hip pain for 4 months and intermittent fever for 3 months. He had a history of gout for 3 years. Both patients underwent CT-guided sacroiliac biopsy, and monosodium urate (MSU) crystals were shown by polarized microscopy. Gout can often mimic SpA and seldomly affects the SIJ. Thus, its correct diagnosis and adequate therapy can halt the development of such damaging complications. PMID- 28721094 TI - Spinal anesthesia: the Holy Grail? PMID- 28721092 TI - Hemicrania continua: clinical review, diagnosis and management. AB - Hemicrania continua (HC) is an indomethacin-responsive primary headache disorder which is currently classified under the heading of trigeminal autonomic cephalalgias (TACs). It is a highly misdiagnosed and underreported primary headache. The pooled mean delay of diagnosis of HC is 8.0 +/- 7.2 years. It is not rare. We noted more than 1000 cases in the literature. It represents 1.7% of total headache patients attending headache or neurology clinic. Just like other TACs, it is characterized by strictly unilateral pain in the trigeminal distribution, cranial autonomic features in the same area and agitation during exacerbations/attacks. It is different from other TACs in one aspect. While all other TACs are episodic, HC patients have continuous headaches with superimposed severe exacerbations. The central feature of HC is continuous background headache. However, the patients may be worried only for superimposed exacerbations. Focusing only on exacerbations and ignoring continuous background headache are the most important factors for the misdiagnosis of HC. A large number of patients may have migrainous features during exacerbation phase. Up to 70% patients may fulfill the diagnostic criteria for migraine during exacerbations. Besides migraine, its exacerbations can mimic a large number of other primary and secondary headaches. The other specific feature of HC is a remarkable response to indomethacin. However, a large number of patients develop side effects because of the long-term use of indomethacin. A few other medications may also be effective in a subset of patients with HC. Various surgical interventions have been suggested for patients who are intolerant to indomethacin. Several aspects of HC are still not defined. There is a great heterogeneity in types of patients or articles on the HC in the literature. Diagnostic criteria have been modified several times over the years. The current diagnostic criteria are too restrictive in some aspects. We suggest a more accommodating type of criteria for the appendix of International Classification of Headache Disorder (ICHD). PMID- 28721095 TI - Chemotherapy-associated paronychia treated with 2% povidone-iodine: a series of cases. AB - BACKGROUND: Nail changes are known to occur during the use of chemotherapy for a variety of malignancies, particularly those treated with taxanes and EGFR inhibitors. There are currently no actively recruiting prospective clinical trials investigating potential treatments. There are also no US Food and Drug Administration-approved medical treatments for chemotherapy-associated paronychia and no consensus on the best way to treat these common chemotherapy-induced events. METHODS: A retrospective review of all cases presenting to a single dermatology private practice from June 2016 to January 2017 identified nine patients with chemotherapy-associated paronychia seeking treatment. Each patient was prescribed a topical solution comprised of 2% povidone-iodine in a dimethylsulfoxide vehicle that was prepared by a licensed compounding pharmacy. Patients were seen at 3 week and 6 week follow-up visits. RESULTS: All 9/9 patients demonstrated complete or partial resolution. The number of nails involved for each patient ranged from 4-12. There were a total of 58 nails affected in the case series, and 44/58 (76%) resolved overall. The treatment was well tolerated. CONCLUSION: The topical povidone-iodine/dimethylsufoxide solution described is very effective in alleviating the signs and symptoms of paronychia associated with chemotherapy. This novel combination warrants further investigation in randomized, controlled trials to further elucidate its clinical utility. PMID- 28721096 TI - Comparison of gefitinib as first- and second-line therapy for advanced lung adenocarcinoma patients with positive exon 21 or 19 del epidermal growth factor receptor mutation. AB - OBJECTIVES: Gefitinib, a tyrosine kinase inhibitor (TKI) targeting epidermal growth factor receptor (EGFR), shows excellent clinical benefit in treating advanced non-small-cell lung cancer (NSCLC). The aim of this study was to compare the efficacy and toxicity of gefitinib as first-line therapy and second-line therapy for advanced lung adenocarcinoma patients with positive exon 21 (L858R) or exon 19 deletion of EGFR mutation. METHODS: We retrospectively analyzed the clinical data of 60 EGFR-mutated advanced lung adenocarcinoma patients from July 2011 to November 2015 who have received oral gefitinib 250 mg once daily. Gefitinib was taken until disease progression, intolerable toxicity or death. RESULTS: After a median follow-up of 792 days, one death had occurred. Among the 59 patients who survived, 17 patients progressed. Overall, the median progression free survival (mPFS) was 10 months (95% confidence interval [CI]: 7.53-12.46 months, p<0.05). The response rate (RR) and disease control rate (DCR) were 33.33% and 71.66%, respectively. However, there was longer mPFS in the first line therapy than that in the second-line therapy: in the first-line gefitinib therapy, mPFS was 12 months among 41 patients (95% CI: 9.58-14.41 months, p<0.05), and in the second-line therapy, mPFS was 7 months among 19 patients (95% CI: 1.31-12.68 months, p<0.05). Furthermore, in subgroup analyses examining different EGFR mutation types, we noted that mPFS was significantly longer for patients with exon 19 deletion than for those with positive exon 21in both the first-line therapy and second-line therapy. CONCLUSION: Patients with advance lung adenocarcinoma who were selected by positive exon 21 or 19 deletion mutations had significantly longer mPFS in the first-line therapy than that in the second-line therapy when treated with gefitinib. EGFR mutation types may influence the response to gefitinib therapy. PMID- 28721097 TI - Tumor cell PD-L1 predicts poor local control for rectal cancer patients following neoadjuvant radiotherapy. AB - The tumor cell (TC) PD-L1 expression has been reported by several studies in various types of cancer, and it reduces the cytotoxicity of T-cells toward cancer and evades the anticancer immune response. Herein, our study focuses on the impact of PD-L1 expression in prognosis and the correlation with clinical prognostic factors for local advanced rectal cancer with neoadjuvant radiotherapy (RT). A total of 68 rectal cancer patients treated with neoadjuvant RT were retrospectively enrolled in the present study. PD-L1 expression was investigated using immunohistochemistry. A regression model was used to identify prognostic factors associated with the disease-free survival, the local recurrence-free survival (LRFS), and the overall survival rates. The median follow-up was 32.5 months. Seven patients presented TC PD-L1 positive (TC PD-L1+), while the others were TC PD-L1 negative (TC PD-L1-). TC PD-L1+ patients showed frequent tumor recurrence than TC PD-L1- patients. Several patients with TC PD-L1- underwent long-course RT. TC PD-L1 expression was similar to interstitial cell (IC) PD-L1 expression, and the relationship between IC PD-L1 and pathological T stage was observed. TC PD-L1+ was related to poor LRFS. The multivariate analysis showed TC PD-L1+ as an independent negative prognostic factor for LRFS. In conclusion, TC PD-L1 expression putatively predicts the LRFS for patients with rectal cancer following neoadjuvant RT. The patients with TC PD-L1+ are susceptible to high local recurrent rate, thereby proposing a novel immunotherapeutic strategy for PD L1 inhibition-mediated control. PMID- 28721098 TI - Patient selection for cytoreductive surgery and HIPEC for the treatment of peritoneal metastases from colorectal cancer. AB - Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is a viable option for selected patients with peritoneal metastases (PM) from colorectal origin, resulting in long-term survival and even cure in some cases. However, adequate patient selection for this treatment is currently one of the major challenges. The aim of this review is to provide a comprehensive overview of clinically relevant factors associated with overall survival. This may help to guide clinicians through the complex interplay of patient, tumor, and treatment characteristics to adequately select patients who benefit the most from this extensive surgical treatment. First, basic principles of colorectal PM and the CRS and HIPEC treatment will be discussed. According to available literature, especially extent of peritoneal disease, completeness of cytoreduction, and signet ring cell histology have great influence on the outcome after CRS and HIPEC. Other factors that seem to have a negative prognostic value are the presence of liver metastases and the absence of treatment with neo-adjuvant systemic therapy. Prognostic models combining the above-mentioned factors, such as the Colorectal Peritoneal Metastases Prognostic Surgical Score nomogram, may provide clinically relevant tools to use in everyday practice. PMID- 28721100 TI - Shear bond strength of different surface treatments in bulk fill, microhybrid, and nanoparticle repair resins. AB - OBJECTIVES: The purpose of this study was to evaluate the influence of surface treatment and different types of composite resin on the microshear bond strength of repairs. MATERIALS AND METHODS: Seventy-two specimens (n=72) were prepared using a nanoparticle resin and stored in artificial saliva at 37 +/- 1 degrees C for 24 h. After this period, the specimens (n=24) were restored with microhybrid resin P60 (3M ESPE), nanoparticle resin Filtek Z350 (3M ESPE), and Bulk Fill Surefil SDR Flow (Dentsply) composite resins. Previously, the surfaces of the samples were treated, forming the following subgroups (n=12): (A) conditioned with 37% phosphoric acid for 30 s, and (B) abrasioned with a diamond tip for 3 s and conditioned with 37% phosphoric acid. In all groups, before insertion of the composite resin, the adhesive system Adper Single Bond 2 was actively applied and photopolymerized for 20 s. RESULTS: The microshear test was executed to assess bond strength. Kruskal-Wallis (p<0.05) and Mann-Whitney statistical tests showed significant statistical difference considering that the bulk-fill resin turned out to have a lower bond strength than the conventional nanoparticle and microhybrid composites. With regard to the technique, the roughening with diamond bur followed by the application of phosphoric acid exhibited values higher than the exclusive use of acid. CONCLUSION: The microshear bond strength of the composite resin repairs varies in accordance with the type of composite resin utilized, and roughening the surface increased the bond strength of these materials. PMID- 28721099 TI - Sociodemographic characteristics of nonparticipants in the Danish colorectal cancer screening program: a nationwide cross-sectional study. AB - INTRODUCTION: Fecal occult blood tests are recommended for colorectal cancer (CRC) screening in Europe. Recently, the fecal immunochemical test (FIT) has come into use. Sociodemographic differences between participants and nonparticipants may be less pronounced when using FIT as there are no preceding dietary restrictions and only one specimen is required. The aim of this study was to examine the associations between sociodemographic characteristics and nonparticipation for both genders, with special emphasis on those who actively unsubscribe from the program. METHODS: The study was a national, register-based, cross-sectional study among men and women randomized to be invited to participate in the prevalence round of the Danish CRC screening program between March 1 and December 31, 2014. Prevalence ratios (PRs) were used to quantify the association between sociodemographic characteristics and nonparticipation (including active nonparticipation). PRs were assessed using Poisson regression with robust error variance. RESULTS: The likelihood of being a nonparticipant was highest in the younger part of the population; however, for women, the association across age groups was U-shaped. Female immigrants were more likely to be nonparticipants. Living alone, being on social welfare, and having lower income were factors that were associated with nonparticipation among both men and women. For both men and women, there was a U-shaped association between education and nonparticipation. For both men and women, the likelihood of active nonparticipation rose with age; it was lowest among non-western immigrants and highest among social welfare recipients. CONCLUSION: Social inequality in screening uptake was evident among both men and women in the Danish CRC screening program, even though the program is free of charge and the screening kit is based on FIT and mailed directly to the individuals. Interventions are needed to bridge this gap if CRC screening is to avoid aggravating existing inequalities in CRC-related morbidity and mortality. PMID- 28721101 TI - Survey of malaria and anti-dengue virus IgG among febrile HIV-infected patients attending a tertiary hospital in Abuja, Nigeria. AB - BACKGROUND: Dengue and malaria are infections, of great public health concern, especially in sub-Saharan Africa where the burden of HIV infection is high. This study was conducted to determine the seroprevalence of dengue virus IgG antibodies and dengue/malaria coinfection among febrile HIV-infected patients attending the University of Abuja Teaching Hospital, Gwagwalada, Abuja. METHODS: In this cross-sectional study, blood samples from 178 consenting HIV-infected patients receiving antiretroviral therapy were collected and tested for plasmodiasis and anti-Dengue virus IgG using malaria microscopy and ELISA, respectively. Interviewer-based questionnaires were used to assess subjects' sociodemographic variables and dengue risk factors. RESULTS: Of the 178 screened participants, 44.4% were seropositive for dengue virus IgG antibody, whereas 29.2% were positive for Plasmodium falciparum. About 44.2% were positive for both dengue virus and P. falciparum. There was a statistical association between anti dengue IgG and occupation (p=0.03) but not with age, residential area, educational level and patients' gender (p>0.05). Seroprevalence of anti-dengue specific IgG was relatively higher in participants who adopted protective measures. There was a statistical association between seroprevalence of anti dengue IgG and adoption of preventive measures (p<0.05). CONCLUSION: The high prevalence of malaria and dengue virus IgG indicates the need to strengthen vector control and dengue surveillance programs. PMID- 28721102 TI - Vulvar varicosities: diagnosis, treatment, and prevention. AB - OBJECTIVE: Vulvar varicosity is a relatively common venous disorder in women with varicose veins of the pelvis and lower extremities and in pregnant women, but there is little information in the medical literature concerning its diagnosis and management. The aim of this study was to describe our experience with 101 women with vulvar varicosities who were examined and treated at our center during 2000-2014. PATIENTS AND METHODS: Patients were divided into two groups: group 1 with 61 women with varicose veins of the pelvis and enlarged vulvar veins, and group 2 with 40 pregnant women (11-38 weeks of pregnancy) with vulvar varicosities. RESULTS: In most cases, vulvar varicosities were able to be diagnosed at clinical examination. In both groups, duplex ultrasound of the veins of the pelvis and lower extremities was used to confirm the presence of varicose veins, identify any retrograde flow, accurately determine vein diameter, and to reveal any anatomical feature of the intrapelvic veins. Treatment approaches varied significantly between the two groups from purely conservative measures during pregnancy to surgical procedures on the ovarian and vulvar veins in group 1. The venoactive agent, micronized purified flavonoid fraction, was effective at reducing the symptoms of vulvar varicosities in both groups. CONCLUSION: A tailored approach to the diagnosis and treatment of vulvar varicosities can significantly improve the quality of care of women with this disorder. PMID- 28721103 TI - Identifying features of primary fallopian tube carcinoma using magnetic resonance imaging. AB - Definitively diagnosing primary fallopian tube carcinoma (PFTC) prior to surgery is difficult. In the first working diagnosis, PFTC is often misdiagnosed as ovarian cancer. Preoperative workups using magnetic resonance imaging (MRI) are capable of differentiating PFTC from epithelial ovarian carcinomas (EOCs). Both the sensitivity and the specificity of MRI for identifying PFTC are high. The presence of a hydrosalpinx is a hallmark of PFTC. On MRI, hydrosalpinges have characteristic sausage-shaped appearances due to intrauterine fluid accumulation and fallopian tube distention. Additionally, MRI scans are superior to computed tomography (CT) scans or ultrasound images in detecting tumor infiltration into surrounding organs. Here, we report a case in which PFTC was pre-operatively misdiagnosed as EOC. PMID- 28721104 TI - Case report of a computerized tomography sign in Strongyloides stercoralis infection. AB - This is a case of strongyloidiasis showing colon enhancement on a computerized tomography (CT) scan. The patient presented with chief complaints of diarrhea and abdominal pain. She gave a history of recent travel to El Salvador and her stool was positive for Strongyloides stercoralis. A CT scan revealed a circumferential enhancement of the sigmoid colon. This CT sign was unusual in strongyloidiasis and when combined with the symptoms, caused us to rule out inflammatory bowel disease and shock bowel. Stool examination revealed ova and parasites of Strongyloides stercoralis. She was then treated with ivermectin which resulted in resolution of her symptoms. PMID- 28721105 TI - Prediction of efficacy for conversion from adjunctive therapy to monotherapy with eslicarbazepine acetate 800 mg once daily for partial-onset epilepsy. AB - PURPOSE: Eslicarbazepine acetate (ESL) is a once-daily (QD) oral antiepileptic drug (AED) indicated for partial-onset seizures (POS). Clinical studies of gradual conversion to ESL 1,200 and 1,600 mg QD monotherapies were previously conducted in patients with POS who were not well-controlled by 1 or 2 AEDs. This report describes modeling and simulation of plasma eslicarbazepine (primary active metabolite of ESL) concentrations and time to monotherapy study exit to predict efficacy for conversion to ESL monotherapy at a lower dose of 800 mg, as an option for patients requiring or not tolerating higher doses since this regimen is effective in adjunctive therapy for POS. PATIENTS AND METHODS: A previously developed population pharmacokinetic model for ESL monotherapy was used to predict minimum plasma eslicarbazepine concentration (Cmin) in 1,500 virtual patients taking 1 (n=1,000) or 2 (n=500) AEDs at baseline, treated with ESL 400 mg QD for 1 week, followed by 800 mg QD for 17 weeks (similar to ESL monotherapy trials where the other AEDs were withdrawn during the first 6 weeks following titration to the randomized ESL dose). Model-predicted Cmin as a time varying covariate and number of baseline AEDs were used to determine the weekly probability of each patient meeting exit criteria (65.3% threshold) indicative of worsening seizure control in 500 simulated ESL monotherapy trials. A previously developed extended Cox proportional hazards exposure-response model was used to relate time-varying eslicarbazepine exposure to the time to study exit. RESULTS: For virtual patients receiving ESL monotherapy (800 mg QD), the 95% upper prediction limit for exit rate at 112 days of 34.9% in patients taking 1 AED at baseline was well below the 65.3% threshold from historical control trials, while the estimate for patients taking 2 AEDs (70.6%) was slightly above the historical control threshold. CONCLUSION: This model-based assessment supports conversion to ESL 800 mg QD monotherapy for POS in adults taking 1 AED. For patients taking 2 concomitant AEDs, however, prescribers should consider maintenance doses of 1,200 or 1,600 mg ESL QD to reduce the likelihood of seizure worsening if conversion to ESL monotherapy is contemplated. PMID- 28721106 TI - Adverse reactions in leprosy patients who underwent dapsone multidrug therapy: a retrospective study. AB - OBJECTIVE: To investigate the occurrence and clinical characteristics of dapsone related adverse drug reactions (ADRs) among leprosy patients who underwent multidrug therapy (MDT) from 2010 to 2013 in the western region of Nepal. METHODS: A retrospective review was carried out in the rehabilitation center. Data were collected from the record files of the hospital. RESULTS: From 2010 to 2013, there were 18 patients reported to have dapsone ADRs, with an occurrence rate of 0.82% in the 4-year duration. The maximum incidence of ADRs (1.043%) was in 2010 and the minimum incidence of ADRs (0.26%) was in 2013. Among two types of bacterial infections, 94.44% were of multibacillary and 5.56% were of paucibacillary type. The age range of patients with dapsone ADRs was 11-68 years. The male-to-female ratio was 1.25. The onset of dapsone ADRs after taking MDT was within a minimum of 3 weeks and a maximum of 21 weeks. There were 14 (77.77%) patients who presented with jaundice, 8 (44.44%) with exfoliative dermatitis, 5 (27.77%) with hemolytic anemia and 4 (22.22%) with fever and headache. The rare side effects (5.5%) found were agranulocytosis or toxic epidermal necrolysis. Three patients were cured; some were still on the treatment. Four patients died with dapsone ADRs. CONCLUSION: The common dapsone ADRs present in leprosy patients were jaundice, exfoliative dermatitis and hemolytic anemia in MDT treated patients. Patients could be cured by managing the dapsone ADRs effectively on time. Some patients may die of dapsone ADRs if clinicians fail to manage the side effects on time. PMID- 28721107 TI - Bite force and dental implant treatment: a short review. AB - Dental implants are placed endosseously, and the bone is the ultimate bearer of the occlusal load. Patients are not uniform in the maximum bite force they can generate. The occlusal biting load in the posterior jaw is usually about three times of that found in the anterior. It is possible for supporting implants to be overloaded by the patients' biting force, resulting in bone loss and failure of the fixture. Bite force measurement may be an important parameter when planning dental implant treatment. Some patients can generate extreme biting loads that may cause a luxation of the fixture and subsequent loss of osseointegration. A patient with low biting force may be able to have a successful long-term outcome even with poor anatomical bone qualities. Patients with a high bite force capability may have an increased risk for late component fracture or implant failure. There is no correlation of any bite force value that would indicate any overload of a given implant in a given osseous site. Nonetheless, after bite force measurement, a qualitative judgement may be made by the clinician for the selection of an implant diameter and length and prosthetic design. PMID- 28721108 TI - Effect of self-paced active recovery and passive recovery on blood lactate removal following a 200 m freestyle swimming trial. AB - PURPOSE: The aim of this study was to investigate the effect of self-paced active recovery (AR) and passive recovery (PR) on blood lactate removal following a 200 m freestyle swimming trial. PATIENTS AND METHODS: Fourteen young swimmers (with a training frequency of 6-8 sessions per week) performed two maximal 200 m freestyle trials followed by 15 minutes of different recovery methods, on separate days. Recovery was performed with 15 minutes of passive rest or 5 minutes of passive rest and 10 minutes of self-paced AR. Performance variables (trial velocity and time), recovery variables (distance covered and AR velocity), and physiological variables (blood lactate production, blood lactate removal, and removal velocity) were assessed and compared. RESULTS: There was no difference between trial times in both conditions (PR: 125.86+/-7.92 s; AR: 125.71+/-8.21 s; p=0.752). AR velocity was 69.10+/-3.02% of 200 m freestyle trial velocity in AR. Blood lactate production was not different between conditions (PR: 8.82+/-2.47 mmol L-1; AR: 7.85+/-2.05 mmol L-1; p=0.069). However, blood lactate removal was higher in AR (PR: 1.76+/-1.70 mmol L-1; AR: 4.30+/-1.74 mmol L-1; p<0.001). The velocity of blood lactate removal was significantly higher in AR (PR: 0.18+/-0.17 mmol L-1 min-1; AR: 0.43+/-0.17 mmol L-1 min-1; p<0.001). CONCLUSION: Self-paced AR shows a higher velocity of blood lactate removal than PR. These data suggest that athletes may be able to choose the best recovery intensity themselves. PMID- 28721109 TI - Association of social support with gratitude and sense of coherence in Japanese young women: a cross-sectional study. AB - PURPOSE: Recent studies have shown that perceived social support is associated with gratitude and sense of coherence, but evidence for this concept remains scarce. In the present study, we investigated relationships between social support, gratitude, and sense of coherence, focusing on the construct of and source of social support among young women. METHODS: The study was conducted in 2014 in Japan. Participants comprised 208 female university students (aged 19.9 +/- 1.1 years), who completed a self-administered anonymous questionnaire regarding perceived social support, gratitude, and sense of coherence. RESULTS: Emotional and instrumental social support from acquaintances were found to be lower than those from family and friends. Gratitude was positively correlated with all forms of social support except instrumental social support from acquaintances. However, sense of coherence was positively correlated with both emotional and instrumental social support from family and only emotional social support from acquaintances. Multiple regression analysis showed that emotional support from family and emotional support from acquaintances were positively associated with gratitude whereas emotional support from family was associated with sense of coherence. CONCLUSION: These results indicate that emotional social support from family was related to both gratitude and sense of coherence. PMID- 28721110 TI - Total sleep time, alcohol consumption, and the duration and severity of alcohol hangover. AB - INTRODUCTION: An evening of alcohol consumption often occurs at the expense of sleep time. The aim of this study was to determine the relationship between total sleep time and the duration and severity of the alcohol hangover. METHODS: A survey was conducted among Dutch University students to collect data on their latest alcohol hangover. Data on alcohol consumption, total sleep time, hangover severity, and duration were collected. Alcohol consumption and hangover severity and duration were compared for participants who (a) slept <5 hours, (b) slept between 5 and 7 hours, or (c) slept >7 hours. RESULTS: Data from N=578 students (40.1% men and 59.9% women) were included in the statistical analyses. Significant correlations were found between total sleep time and alcohol consumption (r=0.117, p=0.005), hangover severity (r= -0.178, p=0.0001) and hangover duration (r=0.168, p=0.0001). In contrast, total alcohol consumption did not correlate significantly with overall hangover severity or duration. Those who slept longer than 7 hours consumed significantly more alcohol (p=0.016) and reported extended hangover duration (p=0.004). However, they also reported significantly less severe hangovers (p=0.001) than students who slept <7 hours. CONCLUSION: Reduced total sleep time is associated with more severe alcohol hangovers. PMID- 28721111 TI - Visual consequences of medications for multiple sclerosis: the good, the bad, the ugly, and the unknown. AB - Multiple sclerosis (MS) is associated with vision changes both due to MS effects on visual pathways and due to medication effects on the visual pathways. Distinguishing the causes of vision change are critical to appropriate diagnosis and management. The incidence, presentation, and treatment of fingolimod associated macular edema, alemtuzumab-associated thyroid orbitopathy, and progressive multifocal leukoencephalopathy in MS patients are reviewed. Evidence for beneficial effects of acute, chronic, and symptomatic MS medications on vision is presented. PMID- 28721112 TI - Current perspectives in the USA on the diagnosis and treatment of pelvic inflammatory disease in adolescents. AB - In this review, the epidemiology, diagnosis, and treatment of pelvic inflammatory disease (PID) are discussed from a USA perspective and the difficulties that USA adolescents face in recognizing and seeking care for PID and other sexually transmitted infections (STIs) are emphasized. Females aged 15-24 years have the highest incidence of cervical infection with Chlamydia trachomatis and Neisseria gonorrheae, the principal causes of PID. PID is common in this age group. However, the incidence of PID in the USA is not known, because it is not a reportable disease, and because clinicians vary in the criteria used for the diagnosis. The Centers for Disease Control and Prevention (CDC) recommended the following diagnostic criteria that include lower abdominal or pelvic pain and at least one of the following: adnexal tenderness or cervical motion tenderness or uterine tenderness. Because PID can have serious sequelae, the criteria emphasize sensitivity (few false-negatives) at the expense of specificity (some false positives). Patients who have PID are usually treated in the outpatient setting, following the CDC's Guidelines for the Treatment of Sexually Transmitted Diseases 2015. They receive one dose of an intramuscular cephalosporin, together with 2 weeks of oral doxy cycline, and sometimes oral metronidazole. Improvement should usually be evident in 3 days. The USA does not offer comprehensive sex education for adolescents in public or private schools. Adolescents are unlikely to recognize the symptoms of PID and seek medical treatment. Confidentiality is important to adolescents, and low cost or free sources of confidential care are uncommon, making it unlikely that an adolescent would seek care even if she suspected an STI. The CDC has concluded that screening programs for chlamydia and gonorrhea infection help prevent PID; however, the lack of appropriate sources of care makes adolescents' participation in screening programs unlikely. PMID- 28721113 TI - Telehealth and eHealth in nurse practitioner training: current perspectives. AB - Telehealth is becoming a vital process for providing access to cost-effective quality care to patients at a distance. As such, it is important for nurse practitioners, often the primary providers for rural and disadvantaged populations, to develop the knowledge, skills, and attitudes needed to utilize telehealth technologies in practice. In reviewing the literature, very little information was found on programs that addressed nurse practitioner training in telehealth. This article provides an overview of both the topics and the techniques that have been utilized for training nurse practitioners and nurse practitioner students in the delivery of care utilizing telehealth. Specifically, this article focuses on topics including 1) defining telehealth, 2) telehealth etiquette, 3) interprofessional collaboration, 4) regulations, 5) reimbursement, 6) security/Health Insurance Portability and Accountability Act (HIPAA), 7) ethical practice in telehealth, and 8) satisfaction of patients and providers. A multimodal approach based on a review of the literature is presented for providing the training: 1) didactics, 2) simulations including standardized patient encounters, 3) practice immersions, and 4) telehealth projects. Studies found that training using the multimodal approach allowed the students to develop comfort, knowledge, and skills needed to embrace the utilization of telehealth in health care. PMID- 28721114 TI - The use of distractors in multiple-choice questions: a medical student perspective. PMID- 28721115 TI - Online nutrition and T2DM continuing medical education course launched on state level medical association. AB - OBJECTIVE: The purpose of this research study was to determine whether a 1-hour online continuing medical education (CME) course focused on nutrition for type 2 diabetes would result in a gain in nutrition knowledge by practicing physicians. METHODS: A practicing physician and dietitian collaborated to develop an online CME course (both webinar and self-study versions) on type 2 diabetes. This 1-hour accredited course was launched through the state-level medical association's education library, available to all physicians. RESULTS: Physicians (n=43) registered for the course, and of those, 31 completed the course in its entirety. A gain in knowledge was found when comparing pre- versus post-test scores related to the online nutrition CME (P<0.0001). CONCLUSIONS: Online CME courses launched via state-level medical associations offer convenient continuing education to assist practicing physicians in addressing patient nutrition and lifestyle concerns related to chronic disease. The present diabetes CME one-credit course allowed physicians to develop basic nutrition care concepts on this topic to assist patients in a better way. PMID- 28721116 TI - What factors facilitate the engagement with flipped classrooms used in the preparation for postgraduate medical membership examinations? AB - BACKGROUND: The "flipped classroom," a pedagogical model where typical lecture and homework elements are reversed, is being advocated in medical education to support the teaching of a large curriculum. However, research into the use of this model in postgraduate medical education, which requires the application of acquired knowledge, is limited. The aim of this study was to explore the barriers and facilitators to engagement with the flipped classroom model in preparation for the written element of postgraduate membership examinations. METHODS: Three focus groups (n=14) were held between February and June 2016. Participants were drawn from a membership examination preparation course, run by the University of Shef-field. Two of the groups (n=10) involved "students" (public health registrars) while the other focus group (n=4) was held with "tutors" (experienced registrars and consultants). The focus groups were audiorecorded and transcribed verbatim. Transcripts were thematically analyzed by using both predetermined and emergent themes. RESULTS: Key themes that emerged from the data included variation in learning and teaching styles of individuals as well as the feasibility and flexibility of the overall course design. However, management of students' expectations was found to be the fundamental factor, which underpinned the engagement. CONCLUSION: The complex interaction of factors affecting engagement in this study highlights the need to consider the appropriateness of the flipped classroom model. However, this must be balanced by the potential benefits of the approach for delivering a large curriculum. Recognizing the central importance of managing expectations at the outset would be useful when considering this model in postgraduate medical education. PMID- 28721117 TI - Experiential learning in physical therapy education. AB - BACKGROUND AND PURPOSE: Experiential learning can provide students in entry-level physical therapy (PT) education programs the opportunity to practice skills and techniques, learned in the classroom, in a real-world setting. Experiential learning is currently being utilized in all entry-level PT programs in the form of professional practice experiences but may be integrated throughout the curriculum to enhance student engagement and knowledge application and retention. The purpose of this paper is to express the need for increased integration of experiential learning into entry-level PT education curricula. POSITION AND RATIONALE: Experiential learning can effectively replace a portion of in-class laboratory time in entry-level PT education programs. Several methods of experiential learning exist, including simulation, integrated clinical experiences, service learning, community patient resource groups, and professional practice opportunities. Students benefit from the ability to practice hands-on skills in a safe, nonjudgmental environment. Students can still experience consequences of poor decisions but can have multiple opportunities to master the skill without the fear of negative outcomes. Incorporation of high risk age ranges and diagnoses can be achieved through simulation. DISCUSSION AND CONCLUSION: Experiential learning can be integrated into any PT curriculum if faculties are committed and flexible. Experiential learning may be particularly useful in specialty practice areas where there are fewer opportunities for students to practice skills. The practice of reflection upon experiences that is commonly performed in conjunction with experiential learning will help prepare students for the type of reflective practice that is essential to transition from novice to expert practitioners. PMID- 28721119 TI - Educational challenges faced by international medical graduates in the UK. AB - INTRODUCTION: International medical graduates (IMGs) in the UK constitute approximately one-quarter of the total number of doctors registered in the General Medical Council (GMC). The transition of IMGs into the health care system in the UK is accompanied by significant sociocultural and educational challenges. This study aims to explore the views of IMGs in medical training on the educational challenges they face. METHODS: This study was conducted in the Kent, Surrey and Sussex region in 2015. All IMGs who work in medical (physicianly) training programs were included. Data were collected through a questionnaire and semi-structured interviews. Thematic approach was used to analyze the qualitative data. RESULTS: Of the total 61 IMGs included, 17 responded to the survey and 3 were interviewed. The common educational barriers faced by IMGs were related to lack of appreciation of the values and structure of the National Health Service (NHS), ethical and medicolegal issues, receiving feedback from colleagues and the different learning strategies in the UK. IMGs suggested introduction of a mandatory dedicated induction program in the form of formal teaching sessions. They also believed that a supervised shadowing period prior in the first job in the UK would be beneficial. Further assessment areas should be incorporated into the prequalifying examinations to address specific educational needs such as NHS structure and hospital policies. Other measures such as buddying schemes with senior IMGs and educating NHS staff on different needs of IMGs should also be considered. CONCLUSION: This study highlighted important educational challenges faced by IMGs and generated relevant solutions. However, the opinions of the supervisors and other health care professionals need to be explored. PMID- 28721118 TI - Ophthalmoscopy simulation: advances in training and practice for medical students and young ophthalmologists. AB - OBJECTIVE: To describe and appraise the latest simulation models for direct and indirect ophthalmoscopy as a learning tool in the medical field. METHODS: The present review was conducted using four national and international databases - PubMed, Scielo, Medline and Cochrane. Initial set of articles was screened based on title and abstracts, followed by full text analysis. It comprises of articles that were published in the past fifteen years (2002-2017). RESULTS: Eighty-three articles concerning simulation models for medical education were found in national and international databases, with only a few describing important aspects of ophthalmoscopy training and current application of simulation in medical education. After secondary analysis, 38 articles were included. CONCLUSION: Different ophthalmoscopy simulation models have been described, but only very few studies appraise the effectiveness of each individual model. Comparison studies are still required to determine best approaches for medical education and skill enhancement through simulation models, applied to both medical students as well as young ophthalmologists in training. PMID- 28721120 TI - Effective learning environments - the process of creating and maintaining an online continuing education tool. AB - Continuing medical education (CME) is an indispensable part of maintaining physicians' competency. Since attending conferences requires clinical absenteeism and is not universally available, online learning has become popular. The purpose of this study is to conduct a retrospective analysis examining the creation process of an anesthesia website for adherence to the published guidelines and, in turn, provide an illustration of developing accredited online CME. Using Kern's guide to curriculum development, our website analysis confirmed each of the six steps was met. As well, the technical design features are consistent with the published literature on efficient online educational courses. Analysis of the database from 3937 modules and 1628 site evaluations reveals the site is being used extensively and is effective as demonstrated by the participants' examination results, content evaluations and reports of improvements in patient management. Utilizing technology to enable distant learning has become a priority for many educators. When creating accredited online CME programs, course developers should understand the educational principles and technical design characteristics that foster effective online programs. This study provides an illustration of incorporating these features. It also demonstrates significant participation in online CME by anesthesiologists and highlights the need for more accredited programs. PMID- 28721121 TI - Does the injection of platelet-rich plasma induce changes in the gene expression and morphology of intact Thoroughbred skeletal muscle? AB - Platelet-rich plasma (PRP) therapy is promising for treating skeletal muscle injuries in human athletes by promoting muscle regeneration. It might also be useful for treating muscle injuries in equine athletes. In the present study, muscle regeneration induced by injection of PRP into intact muscle of Thoroughbred was investigated. Autologous PRP and saline were injected twice into intact left and right gluteus medius muscles of seven clinically healthy Thoroughbreds. Muscle samples were collected from the injection sites by needle biopsy at 2 and 7 days after PRP injection. Immunohistochemical staining to identify the types of myosin heavy chains (MHCs) and satellite cells was performed to compare morphological changes among intact (pre-injection), saline-, and PRP-injected muscles. The expression of marker genes related to muscle regeneration (MHC-I, MHC-II, and embryonic MHC [MHC-e]), satellite cell activity (CK, Pax7, MyoD, and myogenin), and proinflammatory and promyogenic cytokines (IL 6, IGF-1, and HGF) was analyzed and compared between saline- and PRP-injected muscles. There were no obvious morphological differences among the three treatments. There were no significant differences in gene expression associated with satellite cell activity between saline and PRP injection at 7 days after injection. MHC genes showed significantly higher expression levels with PRP than with saline, including MHC-e at 2 days and MHC-I at 7 days after injection. It is suggested that injection of PRP into intact skeletal muscle does not induce specific morphological changes, but upregulate the expression of genes related to muscle regeneration. PMID- 28721122 TI - Hypoxic training increases maximal oxygen consumption in Thoroughbred horses well trained in normoxia. AB - Hypoxic training is effective for improving athletic performance in humans. It increases maximal oxygen consumption (VO2max) more than normoxic training in untrained horses. However, the effects of hypoxic training on well-trained horses are unclear. We measured the effects of hypoxic training on VO2max of 5 well trained horses in which VO2max had not increased over 3 consecutive weeks of supramaximal treadmill training in normoxia which was performed twice a week. The horses trained with hypoxia (15% inspired O2) twice a week. Cardiorespiratory valuables were analyzed with analysis of variance between before and after 3 weeks of hypoxic training. Mass-specific VO2max increased after 3 weeks of hypoxic training (178 +/- 10 vs. 194 +/- 12.3 ml O2 (STPD)/(kg * min), P<0.05) even though all-out training in normoxia had not increased VO2max. Absolute VO2max also increased after hypoxic training (86.6 +/- 6.2 vs. 93.6 +/- 6.6 l O2 (STPD)/min, P<0.05). Total running distance after hypoxic training increased 12% compared to that before hypoxic training; however, the difference was not significant. There were no significant differences between pre- and post-hypoxic training for end-run plasma lactate concentrations or packed cell volumes. Hypoxic training may increase VO2max even though it is not increased by normoxic training in well-trained horses, at least for the durations of time evaluated in this study. Training while breathing hypoxic gas may have the potential to enhance normoxic performance of Thoroughbred horses. PMID- 28721123 TI - Aborted fetal sizes of Thoroughbred horses in Hidaka, Japan, between 2005 and 2015. AB - The degree of fetal growth restriction has been unclear in equine reproduction. In this study, 2,195 fetuses from 2,137 abortions during 11 seasons were examined to determine the causes of abortion, and fetal size dimensions (crown rump length and body weight) were measured. In total, 900 cases (42.1%) of abortion were identified as caused by viral infection (215, 10.1%), bacterial infection (156, 7.3%), fungal infection (25, 1.2%), circulation failure (406, 19.0%), multiple causes (66, 3.1%), deformity (13, 0.6%), placental abnormality (12, 0.6%), and other causes (7, 0.3%). All viral infections originated from equine herpes virus. Of all abortions, 94.3% occurred between 181-360 days of pregnancy, and the gestational ages at abortion were different based on the causes. Fetal sizes in viral abortions were considerably larger than those due to other reasons. Compared with viral infection, the crown rump length size dimension of fetuses aborted from multiple and fungal infection was affected. In addition, bacterial infection, circulation failure, and unknown causes of abortions also contributed to growth restriction in terms of body weight. In conclusion, the present study showed details of equine abortion and the relationships between causes of abortion and fetal size. Most of the aborted fetuses showed restrictions in their growth. The manifestations of growth restriction were more related to weight than skeletal length. PMID- 28721124 TI - Association between exercise-induced pulmonary hemorrhage and inflammatory airway disease in polo ponies. AB - The respiratory system is essential for health and high athletic performance in horses. Respiratory diseases have been recognized as having a major impact on training equine animals and are commonly cited as the second most common cause of wasted training time. Inflammatory airway disease (IAD) is an important cause of poor performance in young racehorses. Exercise-induced pulmonary hemorrhage (EIPH) is considered a major issue for the equine industry because of its high prevalence and association with reduced athletic performance. In Brazil, polo is a growing equestrian sport, but studies on it are still scarce. The aim of this study was to evaluate the occurrence of EIPH, the association between EIPH and IAD, and EIPH influence on the tracheal cytological profile of polo ponies. Thirty-seven horses regularly used for polo were included in this study. Endoscopic examination was performed every 30 to 90 min after practice, and tracheal lavage was performed after 18 to 24 hr. Sixteen animals (43.2%) presented a score of 0 for mucus in endoscopy; twelve animals (32.4%) presented a score for 1 and nine animals (24.3%) presented score 2 of mucus. IAD was characterized by tracheal cytology in 12 animals (32.4%). The occurrence of EIPH in this study was 29.7% (11/37). No significant difference was found in the cell types in tracheal cytology when EIPH-positive and EIPH-negative horses were compared. Polo ponies are affected by IAD and EIPH in relevant proportions, but there was no association between EIPH and tracheal cytological profile. PMID- 28721125 TI - Evaluating the potential roles of the Gray and Extension loci in the coat coloration of Thoroughbred racing horses. AB - Horses have substantial variation in coat color, and the genetic loci responsible for the coat color variations have been well investigated. It has been believed that some color variations should follow a single-locus Mendelian law. Examples include the Gray locus that causes the gray phenotype and the Extension locus that specifies the chestnut phenotype. We reevaluated the roles of the Gray and Extension loci by using a large number of mating records of Thoroughbred racing horses. We showed that the data indeed fits the Mendelian law extremely well for the two loci. Furthermore, we demonstrated that the Extension and Agouti loci might have an additional role in determining the degree of melanin that should distinguish bay, dark bay, and brown. PMID- 28721126 TI - The thyroid gland in postmenopausal women: physiology and diseases. AB - The incidence of most thyroid diseases: hypothyroidism, nodular goitre, and cancer is highest among postmenopausal and elderly women. The diagnosis of thyroid dysfunction in this group of patients is difficult because the symptoms can be nonspecific or common with menopausal and ageing complaints. In the interpretation of thyroid function tests the physiological changes in secretion and metabolism of thyrotropin (TSH) and thyroid hormones must be considered, as well as the influence of comorbidities. Unrecognised thyroid dysfunction leads to increased: cardiovascular risk, bone fractures, cognitive impairment, depression, and mortality. Therapy of thyroid dysfunction is different in postmenopausal and elderly women than in young people; hypothyroidism should be treated with caution, because high doses of L-thyroxine can lead to cardiac arrhythmias and increased bone turnover, and hyperthyroidism should be preferentially treated with radioiodine. Thyroid status beneficially influencing longevity relates to low thyroid function. Thyroid nodules and cancer often affect women over 50 years old; the diagnostic and therapeutic approach is the same as in the general population, but the surgical risk and cancer prognosis is worse than in young patients. PMID- 28721127 TI - Diabetes in the elderly. AB - The prevalence of both type 2 diabetes and prediabetes increases with advancing age. The most important factors leading to hyperglycaemia are as follows: deficiency of insulin secretion developing with age, and growing insulin resistance caused by a change in body composition and sarcopaenia. Clinical features of diabetes in the elderly could be different. Diabetes in elderly people is often diagnosed with delay due to atypical symptoms (dementia, urinary incontinence) and occurrence of mainly postprandial hyperglycaemia. Elderly people are more exposed to diabetes complications, have more risk of myocardial infarction and end-stage renal disease, and are hospitalised more often due to hypoglycaemia than are younger patients. Elderly people with diabetes are a heterogeneous group with different life expectancy, concomitant of chronic diseases, and the ability to self-control blood glucose or give themselves an injection. The therapy should be individualised. Older people with long-term diabetes and numerous chronic complications need a more liberal approach to reach specific goals of therapy. Additional goals should be avoiding hypoglycaemia, safety of the therapy, and its acceptance by the patient. PMID- 28721128 TI - Insulin and brain aging. AB - The world's population is living much longer than in the past. It is crucial to find as many pathological factors that deteriorate the health condition and well being of elderly people as possible. Loss of activity and functions over time is typical for elderly people. Aging affects brain function, metabolism and structure in different ways, and these effects have multiple etiologies. Cognitive impairment, impaired neurotransmitter activity and reduction of brain volume are observed in the elderly population. The process of brain aging is associated with a decrease of central insulin concentration as well as impairment of insulin receptor binding ability, resulting in deterioration of glucose homeostasis in the brain. Peripheral insulin resistance is a typical feature of older age. Data from the literature suggest that high circulating insulin and insulin resistance are important contributors to progressive cognitive impairment and neurodegenerative processes. The maintenance of insulin sensitivity and proper insulin signaling may lead to preserved cognition that results in well being of elderly people. PMID- 28721129 TI - Anti-Mullerian hormone (AMH) as a good predictor of time of menopause. AB - Anti-Mullerian hormone (AMH) in women is secreted by granulosa cells in late preantral and small antral follicles. AMH seems to be a very stable marker having some advantages over other biochemical and biophysical markers and is very useful in the assessment of ovarian reserve. AMH measurement may be used in cases of premature ovarian failure, including iatrogenic, due to treatment for cancer, hypogonadotropic hypogonadism, and lastly, in polycystic ovary syndrome (PCOS). It is also a very specific marker of ovarian tumors - folliculomas. According to outcomes of some studies, AMH seems to be highly predictive for the timing of menopause. There are mathematical models in which a single AMH measurement is used to predict the time of menopause even in very young women, many years before the last period. PMID- 28721130 TI - Premature ovarian failure. AB - Premature ovarian failure (POF) is the term usually used to describe women aged younger than 40 years, who present with amenorrhoea, hypergonadotropic hypogonadism, and infertility. POF is a devastating diagnosis for reproductive aged women. The clinical presentation is diverse, and several different disorders can lead to premature ovarian failure. POF has serious health consequences, including psychological distress, infertility, osteoporosis, autoimmune disorders, ischaemic heart disease, and increased risk of mortality. Hashimoto's disease is the most frequent autoimmune disorder associated with premature ovarian failure. Management should be initiated immediately to prevent long-term consequences. Oestrogen therapy is the mainstay of management. Hormone therapy should be provided to eliminate symptoms of oestrogen deficiency. PMID- 28721131 TI - Adrenopause - does it really exist? AB - In ageing human adrenal glands there occur some morphological changes which result in alterations of their cortex endocrine function. Glucocorticoid excreting cells in the zona glomerulosa live longer than androgen-producing cells in the zona reticularis, which undergo significant apoptosis. Therefore, in elderly humans cortisol levels are normal (significantly higher than at young age), while adrenal androgen concentrations decline with ageing. Function of the zona glomerulosa is affected by the adrenal status, circulatory system condition, efficiency of the kidneys and liver and medication. An important problem of ageing is the rising incidence of non-secreting, incidentally detected, benign adrenal tumors, called incidentalomas. They necessitate clear-sighted radiological and hormonal diagnosis. PMID- 28721132 TI - Obesity in menopause - our negligence or an unfortunate inevitability? AB - Numerous concerns about menopause exist among women, and fear of an increase in body weight is one of the most important of them. This paper presents an overview of current knowledge concerning the etiology of obesity related to menopause and about the mechanisms of its development, with particular regard to the hormonal changes that occur during this period of life. The role of estrogens in the regulation of energy balance and the effect of sex hormones on metabolism of adipose tissue and other organs are presented. The consequence of the sharp decline in the secretion of estrogens with subsequent relative hyperandrogenemia is briefly discussed. The main intention of this review is to clarify what is inevitable and what perhaps results from negligence and unhealthy lifestyles. In the last part of the paper the possibilities of counteracting the progress of adverse changes in body composition, by promoting beneficial lifestyle modifications and the use of hormonal substitution treatment, in cases where it is reasonable and possible, are described. PMID- 28721133 TI - Late-onset hypogonadism. AB - In Poland, the number of men over the age of 50 years exceeds 6 million. It is estimated that about 2-6% of this population develops symptoms of late-onset hypogonadism (LOH). In men, testosterone deficiency increases slightly with age. LOH is a clinically and biochemically defined disease of older men with serum testosterone level below the reference parameters of younger healthy men and with symptoms of testosterone deficiency, manifested by pronounced disturbances of quality of life and harmful effects on multiple organ systems. Testosterone replacement therapy may give several benefits regarding body composition, metabolic control, and psychological and sexual parameters. PMID- 28721134 TI - Osteoporosis in men. AB - Osteoporotic fractures are the leading cause of morbidity and mortality among aging men. 30% of all hip fractures occur in men, and mortality resulting from not only the hip fracture, but also the spine and other major osteoporotic fractures, is significantly higher in men than in women. As in women, hypogonadism is the best documented risk factor for developing osteoporosis in men. In older men, testosterone levels are negatively correlated with the risk of fractures, and it seems that this age-related testosterone deficiency should not be considered as one of the many causes of secondary osteoporosis, rather one of the major and most important mechanisms of senile osteoporosis. Acute hypogonadism induced by ablation treatment for prostate cancer (surgical or pharmacological castration, antiandrogen therapy) is associated with an extremely high risk of fracture. Other documented causes of bone loss in men are cigarette smoking and alcohol abuse, and a number of diseases that require corticosteroid treatment. Pharmacotherapy of osteoporosis should be recommended to all men with a diagnosed osteoporotic fracture and all men with a high 10-year absolute fracture risk (FRAXTM). Not all drugs registered for the treatment of postmenopausal osteoporosis have been registered for the treatment of osteoporosis in men, and others have not been the subject of long-term and costly clinical trials required for such registration. The risk reduction of new fractures was documented only for treatment with zoledronic acid. Risedronate, strontium ranelate, teriparatide, and denosumab in men increase in bone mineral density comparable to that seen in postmenopausal women. PMID- 28721135 TI - A comprehensive guidelines-based approach reduces cardiovascular risk in everyday practice: the VARO study. AB - INTRODUCTION: The aim of study was to investigate the possibility of cardiovascular risk improvement through systematic identification of high-risk individuals and treatment in accordance with current guidelines using modern therapy in daily clinical practice. MATERIAL AND METHODS: Two hundred and sixty three physicians participated in the study. The physicians were asked to screen for cardiovascular risk factors in patients presenting with unrelated problems and to re-evaluate the attainment of treatment goals in those with already known risk factors. Each physician enrolled up to 20 consecutive patients with hypertension and/or hyperlipidemia. A total of 3015 patients were included. Cardiovascular risk was assessed using the SCORE system. Risk factors were treated in accordance with current national guidelines. The therapy of hyperlipidemia and hypertension was preferentially based on rosuvastatin, amlodipine and valsartan. Further medication was at the discretion of the attending physician. Patients were examined at baseline and after 3 and 6 months. RESULTS: The principal result is that global cardiovascular risk decreased by 35% (from 8.9 +/-6.4 to 5.9 +/-4.4, p < 0.001). Systolic and diastolic blood pressure decreased by 12.5% (from 152 +/-18 to 133 +/-11, p < 0.001) and 11.4% (from 88 +/ 11 to 78 +/-7, p < 0.001). The level of total cholesterol decreased 21% (from 6.3 +/-1.2 to 5.0 +/-0.9, p < 0.001) and the concentration of LDL-C decreased 28% (from 3.9 +/-1.1 to 2.8 +/-0.8, p < 0.001). HDL-C increased by 7% (from 1.43 +/ 0.58 to 1.53 +/-0.56, p < 0.001) and triglycerides decreased by 25% (from 2.4 +/ 1.3 to 1.8 +/-0.9, p < 0.001). Blood pressure and LDL-C target values were reached in 68% and 34%of patients, respectively. CONCLUSIONS: The VARO study demonstrates that in daily practice settings, both individual risk factors and global cardiovascular risk are significantly improved through the systematic identification of high-risk individuals and their treatment in accordance with current guidelines using modern pharmacotherapy. PMID- 28721136 TI - Mean platelet volume changes before and after glycated hemoglobin (HbA1c) improvement in a large study population. AB - INTRODUCTION: Diabetes mellitus (DM) is a metabolic disorder associated with both microvascular and macrovascular complications. Mean platelet volume (MPV) is a marker of platelet activity, which plays a major role in the development of vascular complications of DM. The aim of this study is to compare the MPV levels before and after the decrease of glycated hemoglobin (HbA1c) levels in a large diabetic population. MATERIAL AND METHODS: This was a retrospective study conducted on type 2 diabetic patients from the outpatient clinic for 1 year between 2014 and 2015 with the participation of 595 diabetic patients. RESULTS: When we compared the basal and post-treatment values, a significant decrease of MPV and HbA1c levels was found (HbA1c: 9.41 +/-1.98% vs. 7.43 +/-1.29%, p < 0.001; MPV: 9.11 +/-1.42 vs. 8.17 +/-1.04, p < 0.001). There was also a positive correlation between the mean changes of MPV and HbA1c levels after the treatment (DeltaMPV: 0.93 +/-0.96 vs. DeltaHbA1c: 1.96 +/-1.43; p = 0.005, r = 0.115). When the participants were divided into two groups according to their basal HbA1c levels (group A: HbA1c <= 6.5% and group B: HbA1c > 6.5%), it was clearly seen that improvement of glucose levels led to a significant decrease in MPV levels in both groups. CONCLUSIONS: The results of this study show that better glycemic control is associated with a significant decrease of MPV levels, regardless of whether the treatment modality is insulin or oral antidiabetic. PMID- 28721137 TI - Beneficial effects of n-3 polyunsaturated fatty acids on adiponectin levels and AdipoR gene expression in patients with type 2 diabetes mellitus: a randomized, placebo-controlled, double-blind clinical trial. AB - INTRODUCTION: There is evidence that n-3 polyunsaturated fatty acids (n-3 PUFAs) exert beneficial effects to improve type 2 diabetes mellitus (T2DM), but its complications remain poorly understood. Hypoadiponectinemia is one of the important mechanisms responsible for T2DM which necessitates developing novel therapeutic strategies. We aimed to determine the effect of n-3 PUFA supplementation on circulating adiponectin and mRNA expression of adiponectin receptors (AdipoR1, AdipoR2) and Sirt-1 in T2DM patients. MATERIAL AND METHODS: A randomized, double-blind, placebo-controlled trial of 10-week follow-up of n-3 PUFAs (2.7 g/day) vs. placebo in T2DM patients (n = 88) was conducted. In detail, T2DM patients (n = 44) were treated with n-3 PUFAs and the remainder received placebo. Anthropometric and metabolic characteristics were assessed in all participants. Circulating level of adiponectin and mRNA expression of AdipoR1, AdipoR2 and Sirt-1 were measured in peripheral blood mononuclear cells (PBMC) using real-time polymerase chain reaction before and after the intervention. RESULTS: It was found that n-3 PUFAs increased AdipoR1 gene expression (fold change = 1.321 in n-3 PUFAs vs. 1.037 in placebo) and AdipoR2 mRNA (fold change = 1.338 in n-3 PUFAs vs. 1.034 in placebo). No significant changes were observed for Sirt-1 expression. The serum level of adiponectin significantly (p = 0.035) increased in n-3 PUFAs (5.09 to 5.58 MUg/ml) but remained unchanged in the placebo group. CONCLUSIONS: Daily supplementation with n-3 PUFAs (2.7 g) was effective to significantly improve gene expression of AdipoR1 and AdipoR2 and the serum level of adiponectin in T2DM patients. Therefore, n-3 PUFAs might emerge as an adjuvant for current antidiabetic therapies. However, confirmatory long-term studies are required. PMID- 28721138 TI - The effect of orlistat versus metformin on body composition and insulin resistance in obese premenopausal women: 3-month randomized prospective open label study. AB - INTRODUCTION: Our aim was to evaluate the effects of metformin and orlistat on body composition and glucose-insulin homeostasis in obese premenopausal women. MATERIAL AND METHODS: Seventy-three obese premenopausal Caucasian women aged 32.4 +/-8.3 years were treated with either metformin (1000 mg/day; n = 37) or orlistat (360 mg/day; n = 36). Anthropometric parameters were measured using dual-energy X ray absorptiometry. Glucose tolerance, using the oral glucose tolerance test; insulin resistance, using the homeostasis model assessment (HOMA-IR); and insulin sensitivity, using the Matsuda insulin sensitivity index (ISI Matsuda), were assessed at the commencement of the study and after 3 months. RESULTS: Those treated with orlistat showed greater weight loss (-9.4 +/-2.3 vs. -4.9 +/-1.3 kg, p < 0.05) and decrease of fat mass (-5.4 +/-3.0 vs. -3.5 +/-0.7 kg, p < 0.05) than those treated with metformin. The percentage of android and gynoid fat deposits was reduced in both groups; however, a greater decrease in android fat was observed in those treated with metformin. Improvement in ISI Matsuda and post load insulin were similar in both groups. High initial post-load insulin and low ISI Matsuda corresponded with reductions in total fat, trunk fat, and waist circumference in both groups, and a decrease in android fat in those treated with metformin. CONCLUSIONS: Orlistat treatment resulted in greater weight loss and improvement in body composition; metformin treatment resulted in a reduction of android fat. Both drugs produced a comparable improvement in insulin/glucose homeostasis. Overall, insulin-resistant women showed improvement with treatment, irrespective of which drug was used. PMID- 28721139 TI - Vitamin D deficiency and non-lipid biomarkers of cardiovascular risk. AB - INTRODUCTION: Deficient 25-hydroxyvitamin D (25(OH)D) levels have been associated with dyslipidemia and cardiovascular diseases, though the underlying mechanism of these associations is uncertain. We analyzed associations between vitamin D and other non-lipid biomarkers of cardiovascular risk to better elucidate possible relationships between deficient 25(OH)D and cardiovascular disease. MATERIAL AND METHODS: We performed a cross-sectional analysis of 4,591 adults included in a clinical laboratory database from 2009 to 2011 with available measurements for 25(OH)D and the following biomarkers: homocysteine (Hcy), high-sensitivity C reactive protein (hs-CRP), cystatin-C, creatinine, gamma-glutamyltransferase (GGT), uric acid, and hemoglobin A1c (HbA1c). We calculated odds ratios (OR) of having high levels of each biomarker associated with 25(OH)D deficiency (< 20 ng/ml) compared to optimal levels (>= 30 ng/ml) using logistic regression adjusted for age, sex, and lipids. RESULTS: The mean +/- SD age was 60 +/-14 years and 46% of patients were women. In multivariable-adjusted models, adults with deficient 25(OH)D compared to those with optimal levels had increased odds of elevated biomarkers as follows: Hcy (OR = 2.53, 95% CI: 1.92-3.34), hs-CRP (1.62, 1.36-1.93), cystatin-C (2.02, 1.52-2.68), creatinine (2.06, 1.35-3.14), GGT (1.39, 1.07-1.80), uric acid (1.60, 1.31-1.95), and HbA1c (2.47, 1.95-3.13). In analyses evaluating women and men separately, 25(OH)D deficient women but not men had increased odds of elevated levels of all biomarkers studied. There were significant interactions based on sex between 25(OH)D and Hcy (p = 0.003), creatinine (p = 0.004), uric acid (p = 0.040), and HbA1c (p = 0.037). CONCLUSIONS: Deficient 25(OH)D is associated with elevated levels of many biomarkers of cardiovascular risk, particularly among women, in a United States population. PMID- 28721140 TI - Serum adipokines and vitamin D levels in patients with type 1 diabetes mellitus. AB - INTRODUCTION: Adiponectin, leptin and resistin are adipokines that play important roles in the regulation of lipid and carbohydrate metabolism in type 2 diabetes (T2DM). However, their influence in type 1 diabetes mellitus is still unknown. The aim of this study was to measure serum adiponectin, leptin and resistin levels and to investigate their relationships with vitamin D and other clinical and laboratory parameters in patients with type 1 diabetes. MATERIAL AND METHODS: Fifty subjects with type 1 diabetes and 50 healthy age- and sex-matched subjects were selected from the Endocrinology Outpatient Clinic of Cairo University Pediatrics Hospital. Enzyme-linked immunosorbent assay was used to measure the levels of leptin, adiponectin and resistin. Vitamin D levels were measured using electro-chemiluminescence immunoassay. RESULTS: There were no significant differences in adiponectin and leptin levels between diabetic and control subjects (p = 0.6 and p = 0.5 respectively). Resistin levels were significantly higher in the diabetic group compared to controls (p < 0.001) and in postpubertal patients compared to prepubertal patients (p < 0.04). Serum resistin in type 1 diabetes showed a negative correlation with vitamin D (p < 0.001) and a positive correlation with glycated hemoglobin (HbA1c) (p = 0.006), while other adipokines were not interrelated. CONCLUSIONS: These results strongly support a role of resistin and vitamin D deficiency in the pathophysiology of type 1 diabetes. Vitamin D may be involved in resistin regulation through an unknown mechanism. Further studies are recommended to understand resistin regulation in type 1 diabetes. PMID- 28721141 TI - Impact of 25-hydroxyvitamin D, free and bioavailable fractions of vitamin D, and vitamin D binding protein levels on metabolic syndrome components. AB - INTRODUCTION: Various forms of vitamin D and factors involved in their metabolism can play a role in the etiopathogenesis of metabolic disorders. This paper aims to define the relationship between concentration of the hydroxylated form of vitamin D (25(OH)D), the fraction of free and bioavailable vitamin D, and of vitamin D binding protein (VDBP) levels on the one hand and the prevalence of metabolic syndrome components on the other. MATERIAL AND METHODS: The studies were conducted on 79 people, including 52 with metabolic syndrome (MetS+) and 27 without it (MetS-). Biochemical measurements (lipid profile, glycemia, 25(OH)D, VDBP, albumin, calcium, parathyroid hormone) were performed, concentration of free and bioavailable vitamin D was mathematically calculated, and anthropometric and blood pressure measurements were taken. RESULTS: The mean +/- SD concentration of 25(OH)D among MetS+ individuals (41.90 +/-13.12 nmol/l) was lower (p < 0.0001) than among the MetS- group (66.09 +/-18.02 nmol/l). Differences between groups were observed in relation to medians/means of concentrations of free and bioavailable vitamin D (p < 0.0001) but not in the case of VDBP. In the entire study population, 25(OH)D correlated with all metabolic syndrome components, whereas its free and bioavailable fraction correlated with particular components of the syndrome. In the MetS+ group, VDBP concentration negatively correlated with body mass index (p = 0.037) and levels of diastolic pressure (p = 0.022). In the case of the MetS- group, the free fraction of vitamin D negatively correlated with triglyceridemia (p = 0.049). CONCLUSIONS: The evaluation of various forms of vitamin D and VDBP in different population groups seems to have significant clinical value in evaluating the prevalence of metabolic disorders. PMID- 28721142 TI - Maternal lipids associated with large-for-gestational-age birth weight in women with type 1 diabetes: results from a prospective single-center study. AB - INTRODUCTION: Despite improvement in diabetes care over the years, the incidence of macrosomia in type 1 diabetic mothers is still very high and even shows an increasing tendency. It is suggested that other factors that maternal hyperglycemia might be associated with excessive fetal growth in diabetic mothers. The aim of this study was to determine whether maternal lipids might contribute to high rates of large-for-gestational-age (LGA) newborns in women with type 1 diabetes (T1DM). MATERIAL AND METHODS: This prospective, single center study was performed in a population of women with T1DM admitted to the perinatal center for women with diabetes. Data were collected in the first trimester (< 12th week), in mid-pregnancy (20th-24th weeks), and before delivery (34th-39th weeks). RESULTS: Among 114 women included in the analysis, 30 (26.3%) delivered LGA newborns. The remaining 84 (73.7%) newborns were appropriate for gestational age (AGA). Lower high-density lipoprotein (HDL) HDL concentration in the first trimester was significantly associated with LGA (p = 0.01). Similar associations were observed for the HDL concentrations in mid-pregnancy (p = 0.04) and before delivery (p = 0.03). Higher triglyceride concentrations in the first trimester (p = 0.02) and before delivery (p = 0.008) were associated with LGA. Higher glycated haemoglobin (HbA1c) levels in mid-pregnancy and before delivery were associated with LGA. The associations between maternal lipids and LGA were independent of maternal body mass index at onset of the study, gestational weight gain and HbA1c concentrations. CONCLUSIONS: Decreased HDL and increased triglycerides during pregnancy might contribute to the development of LGA in women with type 1 diabetes. PMID- 28721143 TI - The effect of antihypertensive treatment on arterial stiffness and serum concentration of selected matrix metalloproteinases. AB - INTRODUCTION: The aim of the study was to assess the arterial stiffness and serum levels of selected metalloproteinases (MMPs) in hypertensive patients and their changes following antihypertensive therapy. MATERIAL AND METHODS: The study group consisted of 95 patients with essential arterial hypertension (HT) stage 1 or 2 (mean age: 53.1 +/-13.0 years). The control group consisted of 31 normotensives of the same age range. Hypertension patients were randomized to one of the following monotherapies for 6 months: quinapril, losartan, amlodipine, hydrochlorothiazide or bisoprolol. Carotid-femoral pulse wave velocity (PWV) was measured using a Complior device. Serum concentrations of MMPs (proMMP-1, MMP-2, MMP-3, MMP-9) and plasma concentration of tissue inhibitor of MMPs (TIMP-1) were measured using ELISA. RESULTS: Pulse wave velocity and serum concentrations of MMP-2 and MMP-9 were higher in HT patients than in the control group. In HT patients PWV was significantly associated (R2 = 0.41) with age (B = 0.408, p = 0.00027), systolic blood pressure (SBP) (B = 0.441, p = 0.0011), and MMP-3 (B = 0.204, p = 0.0459). After 6 months of treatment, regardless of the agent used, we observed a significant decrease of PWV, SBP, MMP-2 and MMP-3 and an increase of TIMP-1 plasma concentration. The decrease of PWV was significantly associated with a decrease of SBP (R2 = 0.07, B = 0.260, p = 0.015) only. CONCLUSIONS: In patients with arterial hypertension, beside age and systolic blood pressure, the determinants of arterial stiffness include serum MMP-3 concentration. For drugs compared in the study with the same hypotensive effect obtained, the arterial stiffness reduction effect is not dependent on the drug used. Systolic blood pressure is one of the independent factors responsible for the reduction of arterial stiffness in the course of antihypertensive treatment. PMID- 28721144 TI - Clinical implications of plasma Nogo-A levels in patients with coronary heart disease. AB - INTRODUCTION: Nogo-A is an important neurite growth-regulatory protein in the adult and developing nervous system. Recently, increasing evidence has shown that Nogo-A plays important roles in cardiac development and may act as a potential indicator for heart failure. In addition, increased oxidative stress has been found in individuals with cardiovascular diseases. However, not much is known regarding the expression levels of Nogo-A and reactive oxygen species (ROS) in patients with coronary heart disease (CHD). Therefore, we sought to investigate the relationship between Nogo-A, ROS levels and CHD. MATERIAL AND METHODS: The plasma Nogo-A and ROS concentrations of 122 acute coronary syndrome (ACS), 101 unstable angina pectoris (UAP), and 21 acute myocardial infarction (AMI) patients and 56 healthy controls were measured by enzyme-linked immunosorbent assay (ELISA). We further generated a receiver operating characteristic (ROC) curve to assess the diagnostic accuracy of Nogo-A and ROS in CHD. RESULTS: The Nogo-A and ROS levels were significantly higher in patients with CHD than those in healthy controls. In addition, multivariate logistic regression analysis revealed that the level of Nogo-A (odds ratio (OR) = 1.624, 95% confidence interval: 1.125 2.293, p = 0.009) is a risk factor for prediction of CHD. Nogo-A has diagnostic value, with an optimal threshold of 5.466 ng/ml for maximized diagnostic performance (59% sensitivity and 78.6% specificity, area under curve, p < 0.05). However, ROS concentration is not a risk factor for prediction of CHD (OR = 0.999, 95% confidence interval: 0.997-1.001, p = 0.320). CONCLUSIONS: Increased plasma Nogo-A level may be associated with CHD. PMID- 28721145 TI - Increased plasma concentrations of interleukin 35 in patients with coronary artery disease. AB - INTRODUCTION: Atherosclerosis leading to coronary artery disease (CAD) is a chronic inflammatory condition. Interleukin 35 (IL-35) released by regulatory T cells (Tregs) has been found to be associated with CAD in the Chinese population. However, nothing is known about the relation between IL-35 concentrations and cholesterol levels. The aim of the study was to assess the levels of IL-35 in CAD patients and healthy subjects from a Caucasian population, and to analyze the relationship between IL-35 and the levels of total cholesterol, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol, left ventricular ejection fraction (LVEF), sex and postmenopausal status. MATERIAL AND METHODS: Thirty-one patients with CAD and 30 healthy controls were included in the study. Levels of plasma IL-35 were analyzed by ELISA. The LVEF was assessed by transthoracic echocardiographic examination. Plasma levels of cholesterol fractions and C-reactive protein (CRP) were assessed by immunoenzymatic methods. RESULTS: The CAD patients had higher levels of IL-35 as compared to healthy controls (58.1 +/-16.6 pg/ml vs. 5.35 +/-3.35 pg/ml; p < 0.001). IL-35 levels negatively correlated with total and LDL cholesterol concentrations (R = -0.31, p < 0.01) and positively correlated with HDL cholesterol in men (R = 0.53, p < 0.01). In women, IL-35 levels negatively correlated with LVEF (R = -0.29, p < 0.05) and positively with the duration of postmenopausal status (R = 0.55, p < 0.01). CONCLUSIONS: These results suggest a possible association between high levels of IL-35 and CAD. PMID- 28721146 TI - The role of selected adipokines and ghrelin in the prognosis after myocardial infarction in a 12-month follow-up in the presence of metabolic syndrome. AB - INTRODUCTION: The aim of this study was to evaluate the predictive value of selected adipokines in the improvement in the ejection fraction and in the development of adverse cardiac remodeling during 12 months of follow-up among patients with an ST-segment elevation acute myocardial infarction (STEMI) in the presence of metabolic syndrome (MeS). MATERIAL AND METHODS: The study population consisted of 69 patients (49 male; mean age: 59 +/-10 years) with a first STEMI that was treated with a primary percutaneous coronary intervention (pPCI). In this group, 36 patients (18 male; mean age: 60 +/-15 years) had MeS according to the definition of the International Diabetes Federation. The baseline clinical evaluation included a clinical examination and evaluation of the blood levels of C-reactive protein, ghrelin, resistin, and fasting glucose. Within 72 h after the STEMI, an echocardiographic examination was performed. A complete clinical evaluation was repeated after 12 months. Adverse cardiac remodeling was defined as an increase in the left ventricular end-diastolic volume of >= 8%. An improvement of the ejection fraction (EF) was defined as an increase of more than 5% in the EF. RESULTS: A concentration of ghrelin <= 160.46 pg/ml (AUC = 0.71, p = 0.032) had a good predictive value for the occurrence of adverse left ventricular remodeling but only in the patients without MeS. Among the patients with MeS, a concentration of resistin <= 5196 pg/ml (AUC = 0.073, p = 0.024) had a good predictive value for the occurrence of left ventricular remodeling. A concentration of leptin > 52.18 pg/ml (AUC = 0.81, p < 0.0001) and resistin > 4419.27 ng/ml (AUC = 0.67, p = 0.049) had a good predictive value for improvement of the LVEF in the patients without MeS. CONCLUSIONS: The selected adipokines had a good predictive value for the development of adverse cardiac remodeling and for improvement of the ejection fraction among patients after a STEMI in the presence of metabolic syndrome. PMID- 28721147 TI - The importance of two metabolic syndrome diagnostic criteria and body fat distribution in predicting clinical severity and prognosis of acute myocardial infarction. AB - INTRODUCTION: The interrelation between metabolic syndrome (MetS) (the revised National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATP III) and International Diabetes Federation (IDF)) and obesity indices in predicting clinical severity and prognosis of acute ST-elevation myocardial infarction (STEMI) is insufficiently known. MATERIAL AND METHODS: This prospective study included 250 acute STEMI patients treated with primary percutaneous coronary intervention. The patients with/without MetS were analyzed by baseline (medical history, demography and obesity indices: overall - body mass index (BMI) vs.central - body adiposity index (BAI), conicity index (Cindex), visceral adiposity index (VAI), waist circumference (WC), waist-to-hip (WHR) and waist-to height ratio (WHtR)), severity (clinical presentation, laboratory, echocardiography, coronary angiography and in-hospital complications) and prognostic parameters (major adverse cardiovascular events and sick leave duration during 12-month follow-up). RESULTS: There were 136 (54.4%) and 147 (58.8%) patients with MetS (NCEP-ATP III) and MetS (IDF), respectively. MetS (NCEP-ATP III) increased the risk of > 1 significantly stenosed coronary artery (CA), very high BAI increased the risk of dyspnea, Cindex > 1.25/1.18 increased the risk of total in-hospital complications, increased VAI increased the risk of coronary segment 3 significant stenosis, WHR >= 0.90/0.85 increased the risk of proximal/middle coronary segments (especially of segment 1) significant stenosis, WHtR >= 63/58 increased the risk of heart failure, and the number of significantly stenosed CAs increased the risk of total MACE (p < 0.05). CONCLUSIONS: MetS (NCEP-ATP III) and several central obesity indices are superior to BMI in predicting acute STEMI severity (clinical presentation, in-hospital complications, severity of coronary disease), while WC and MetS (IDF) have no influence on it. They all have no influence on prognosis. PMID- 28721148 TI - Association of moderate aerobic exercise and rho-associated kinase 2 concentration in subjects with dyslipidemia. AB - INTRODUCTION: Dyslipidemia is associated with increased rho-associated kinase 2 (ROCK2) concentration. Whether moderate aerobic exercise could attenuate leukocyte ROCK2 concentration is unknown. MATERIAL AND METHODS: One hundred subjects with dyslipidemia and without statin treatment were enrolled and assigned to exercise and control groups. In the exercise group, at least 30 min of moderate aerobic exercise per day 5 times weekly was recommended. In the control group, participants were recommended to undertake exercise of the same intensity as the exercise group but not mandatorily. At baseline and 3 months later, between-group differences were compared. RESULTS: At baseline, dyslipidemia in both groups was characterized by increased serum levels of total cholesterol and low density lipoprotein cholesterol (LDL-C). Serum high sensitivity C-reactive protein (hs-CRP) level was comparably increased too, and the average daily exercise time was extremely low: 5.8 +/-2.7 min and 6.2 +/-3.1 min respectively. Leukocyte ROCK2 concentration in the two groups was 38.4 +/-7.5 mg/ml and 40.2 +/-8.2 mg/ml respectively. Three months later, compared with the control group, average daily exercise time was significantly longer in the exercise group (37.4 +/-4.3 min vs. 16.5 +/-7.5 min, p < 0.05). Leukocyte ROCK2 concentration was also significantly reduced (27.6 +/-4.3 mg/ml vs. 34.6 +/-5.2 mg/ml, p < 0.05). Serum nitric oxide (NO) concentration in the exercise group was significantly higher than the control group (p < 0.05). Multivariate linear regression analysis revealed that NO and exercise time were significantly associated with leukocyte ROCK2 concentration after adjusting for traditional risk factors. CONCLUSIONS: Moderate aerobic exercise could effectively attenuate leukocyte ROCK2 concentration in subjects with dyslipidemia. PMID- 28721149 TI - Apolipoprotein A1 polymorphisms and risk of coronary artery disease: a meta analysis. AB - INTRODUCTION: It has been reported that APOA1 -75G/A polymorphism might be associated with susceptibility to coronary artery disease (CAD). Owing to mixed and inconclusive results, we conducted a meta-analysis to systematically summarize and clarify the association between APOA1-75G/A polymorphism and the risk of CAD. MATERIAL AND METHODS: A systematic search of studies on the association of single nucleotide polymorphisms (SNP) with susceptibility to CAD was conducted. A total of 9 case-control studies (1864 cases and 1196 controls) on the APOA1-75G/A polymorphism were included. RESULTS: We observed no statistically significant association between APOA1 -75G/A polymorphism and risk of CAD under the dominant genetic model (AA + AG vs. GG: OR = 1.03, 95% CI: 0.65 1.66), allelic contrast (A vs. G: OR = 0.88, 95% CI: 0.58-1.32), heterozygote model (AG vs. GG: OR = 1.24, 95% CI: 0.81-1.89) or homozygote model (AA vs. GG: OR = 0.52, 95% CI: 0.26-1.05). Significant heterogeneity between individual studies appears in all five models, but a strong association under the recessive genetic model (AA vs. AG + GG: OR = 0.51, 95% CI: 0.28-0.92). In the subgroup analysis by Hardy-Weinberg equilibrium (HWE; the presence or absence of HWE in controls), significantly decreased CAD risk and no significant heterogeneity were observed among controls consistent with HWE. Overall, the APOA1 A allele is one of the protective factors of CAD. A stronger association between APOA1-75G/A polymorphisms and CAD risk was present in the studies consistent with HWE. CONCLUSIONS: The minor allele of the APOA1-75G/A polymorphism is a protective factor for CAD, especially in the studies consistent with HWE. PMID- 28721150 TI - Phenotype distribution of the paraoxonase gene in patients with cardiac disease. AB - INTRODUCTION: Paraoxonase (PON1) is an enigmatic enzyme with multiple enzymatic properties including arylesterase and lactonase activities besides its ability to hydrolyze the toxic metabolite of parathion, paraoxon. The aim of this study was to determine the phenotype distribution of PON1 in patients with cardiac disease who were classified in coronary artery bypass grafting (CABG), heart valve disease (HVD), heart failure (HF) and ST elevation myocardial infarction (STEMI) groups and healthy subjects as a control group. MATERIAL AND METHODS: A total of 300 people (100 cardiac surgery (70 CABG and 30 HVD), 70 HF, 30 STEMI patients and 100 healthy controls) were admitted to this study. Individual variations in PON1 were determined using the dual substrate (paraoxon and phenylacetate) method. RESULTS: The following phenotype distributions were found in the cardiac disease and control groups: cardiac disease group (n = 200): 48.5% (QQ), 42.5% (QR), 9% (RR) and control group (n = 100): 58% (QQ), 39% (QR), 3% (RR). RR (high activity) phenotypic distribution was more common in the cardiac disease group than in controls (p = 0.04). In particular, the frequency of the RR phenotype was two- to three-fold higher in the STEMI and HF patients compared to the controls as well as CABG and HVD groups. CONCLUSIONS: We found a higher percentage of RR phenotype in STEMI and HF patients compared to a large control group as well as compared to two other groups of cardiac disease patients. PMID- 28721151 TI - Moderate-dose atorvastatin improves arterial endothelial function in patients with angina pectoris and normal coronary angiogram: a pilot study. AB - INTRODUCTION: Endothelial dysfunction could contribute to the pathophysiology of angina pectoris (AP) in patients with normal coronary angiograms. Besides lipid lowering effects, statins exert pleiotropic effects including improving endothelial function. MATERIAL AND METHODS: Our double-blind study included 58 patients with AP, noninvasively confirmed myocardial ischemia and a normal coronary angiogram. The effect of once-daily 20 mg atorvastatin (A) was compared with placebo (P) for 6 months. Endothelial function was evaluated by flow mediated dilation (FMD) of the brachial artery, and microcirculation by peripheral arterial tonometry (EndoPAT) measuring the reactive hyperemia index (RHI), indicating microcirculatory endothelial function, and the augmentation index (AI), an indicator of arterial stiffness. The impact of AP on the quality of life was monitored using the Seattle Angina Questionnaire (SAQ). RESULTS: Brachial artery endothelial dysfunction was found in 91.4% of patients at study entry, and subnormal RHI in 41%. Group A showed an improvement of FMD compared with group P, both at 3 and 6 months (+120.8% vs. -21.2%, and +70.8% vs. -1.9%, respectively, p < 0.001). No difference was detected in the RHI. Rate-normalized AI showed an improvement (-114.49% group A vs. -30.77% group P, p = 0.077), although the differences between the groups were not significant. According to the SAQ, an improvement was found in almost all observed variables with the exception of the issue of quality of life (QoL), where patients in both groups assessed their QoL at the control study visits as poorer compared with baseline. CONCLUSIONS: Moderate-dose atorvastatin therapy improves endothelial function of large conduit arteries in patients with AP and a normal coronary angiogram, which probably reflects positive effects on coronary artery endothelial function. No effect was found with vascular effects at the level of the peripheral microcirculation. PMID- 28721152 TI - Clinical SYNTAX Score - a good predictor for renal artery stenosis in acute myocardial infarction patients: analysis from the REN-ACS trial. AB - INTRODUCTION: In ST-elevation myocardial infarction (STEMI) patients, multisite artery disease represents a serious issue influencing evolution, outcomes and prognosis. We evaluated for the first time the power of the Myocardial Infarction SYNTAX Score (MI SS) and Clinical SYNTAX Score (MI CSS) as predictors for renal artery stenosis (RAS) in STEMI. We also stratified the study population according to the two scores, and identified the variables correlated with the higher score. MATERIAL AND METHODS: We used data from the REN-ACS study, which included 181 consecutive patients prospectively investigated for presence of RAS (through renal angiography), arterial stiffness (carotid-femoral pulse wave velocity, cf PWV) and hydration status (bioimpedance). MI SS and CSS were computed. RESULTS: Multivariate regressions indicated that the independent variables correlated with MI SS were left ventricular ejection fraction < 40%, significant RAS (> 50%, defined as RAS+), history of heart failure, and multivascular coronary disease (CAD, p < 0.03 for each), while those correlated with MI CSS were RAS+, cf-PWV, history of CAD, multivascular CAD, cholesterol, and total body water (p < 0.02 for each). In order to evaluate the ability to predict RAS+ we generated receiver operating characteristics and areas under curves, and the Youden index for MI SS and CSS. CONCLUSIONS: Both scores correlated with extensive atherosclerotic disease and presence of RAS+. A lower CSS proved to be a good predictor for exclusion of RAS+, with high specificity (85%) and negative predictive value (92%), and fair sensitivity (60%). We aim to further pursue this line of research and design a better predictor for RAS, with the inclusion of a novel biomarker in order to increase sensitivity. PMID- 28721153 TI - Fibroblast growth factor 23, iron and inflammation - are they related in early stages of chronic kidney disease? AB - INTRODUCTION: Fibroblast growth factor 23 (FGF-23) levels are elevated in impaired renal function. Inflammation and iron are potential regulators of FGF 23. The aim of the study was to evaluate the association between FGF-23 concentration, novel iron status biomarkers and inflammatory parameters among patients with early stages of chronic kidney disease (CKD). MATERIAL AND METHODS: The study population included 84 patients with CKD in the early stage. Serum hemoglobin, fibrinogen, creatinine, iron, transferrin saturation and ferritin levels were measured using standard laboratory methods. Commercially available kits were used to measure: intact FGF-23, hepcidin, soluble transferrin receptor (sTfR), interleukin 6 (IL-6) and high-sensitivity C-reactive protein (hsCRP). RESULTS: In patients with CKD no differences in FGF-23 concentration according to iron status were observed. Lower iron concentration was associated with higher concentrations of hsCRP, IL-6 and fibrinogen. In univariate and multivariate analysis FGF-23 correlated with fibrinogen (r = -0.23, p < 0.05) and eGFR (r = 0.36, p < 0.05). CONCLUSIONS: FGF-23 is affected by kidney function and fibrinogen but not iron status parameters in the early stages of CKD. Our data are paving the way for further studies on the role of FGF-23 in iron metabolism, especially in early stages of CKD. PMID- 28721154 TI - Obesity and inflammation: the linking mechanism and the complications. AB - Obesity is the accumulation of abnormal or excessive fat that may interfere with the maintenance of an optimal state of health. The excess of macronutrients in the adipose tissues stimulates them to release inflammatory mediators such as tumor necrosis factor alpha and interleukin 6, and reduces production of adiponectin, predisposing to a pro-inflammatory state and oxidative stress. The increased level of interleukin 6 stimulates the liver to synthesize and secrete C reactive protein. As a risk factor, inflammation is an imbedded mechanism of developed cardiovascular diseases including coagulation, atherosclerosis, metabolic syndrome, insulin resistance, and diabetes mellitus. It is also associated with development of non-cardiovascular diseases such as psoriasis, depression, cancer, and renal diseases. On the other hand, a reduced level of adiponectin, a significant predictor of cardiovascular mortality, is associated with impaired fasting glucose, leading to type-2 diabetes development, metabolic abnormalities, coronary artery calcification, and stroke. Finally, managing obesity can help reduce the risks of cardiovascular diseases and poor outcome via inhibiting inflammatory mechanisms. PMID- 28721155 TI - Clinical importance of epicardial adipose tissue. AB - Different visceral fat compartments have several systemic effects and may play a role in the development of both insulin resistance and cardiovascular diseases. In the last couple of years special attention has been paid to the epicardial adipose tissue (EAT), which can be quantified by non-invasive cardiac imaging techniques. The epicardial fat is a unique fat compartment between the myocardium and the visceral pericardium sharing a common embryologic origin with the visceral fat depot. Epicardial adipose tissue has several specific roles, and its local effects on cardiac function are incorporated in the complex pathomechanism of coronary artery disease. Importantly, EAT may produce several adipocytokines and chemokines that may influence - through paracrine and vasocrine effects - the development and progression of coronary atherosclerosis. Epicardial adipose tissue volume has a relatively strong genetic dependence, similarly to other visceral fat depots. In this article, the anatomical and physiological as well as pathophysiological characteristics of the epicardial fat compartment are reviewed. PMID- 28721156 TI - Obstructive sleep apnea and hormones - a novel insight. AB - Obstructive sleep apnea (OSA), a disorder characterized by repetitive collapse of the upper respiratory tract during sleep, occurs in about 4% of middle-aged men and 2% of women. The incidence of the disorder is rising due to an increase in obesity and ageing of the population. Patients with obstructive sleep apnea are at elevated risk of some endocrinal and metabolic disorders, which may lead to serious consequences including shortening of life expectancy. The recognition and understanding of interactions between local upper airway dysfunction and its endocrinal consequences is therefore vital. In this review we will focus on the influence of OSA on bone metabolism and endocrine homeostasis. PMID- 28721157 TI - MicroRNAs and metabolic disorders - where are we heading? AB - MicroRNAs (miRNAs, miRs) are short, non-coding molecules engaged in normal functioning of eukaryotic cells, as negative regulators of gene expression. Since the first discovery of miRNA in the early 1990s, hundreds of different miRNAs and their targets have been identified. A growing number of studies have aimed to search for microRNAs which have a key role in the regulation of insulin signaling and metabolic homeostasis. Recent evidence indicates that dysregulation of miRNA expression is involved in the development of various diseases, including type 2 diabetes mellitus (T2DM), obesity and cardiovascular diseases. This review summarizes the biogenesis of miRNAs and their role in pancreatic beta cell biology, insulin signaling and metabolism. We also discuss recent findings of miRNAs associated with metabolic disorders and vascular diabetic complications, their diagnosis and therapeutic value. The PubMed database and published reference lists were searched for articles published between 1990 and 2016 using the following keywords: miRNA, miRNA and pancreas; miRNA and insulin; miRNA and type 2 diabetes mellitus, miRNA and obesity, and miRNA and microvascular or macrovascular diabetic complication. This review indicates that miRNA functioning is significantly different in metabolic diseases than in the normal condition. PMID- 28721158 TI - Potential novel biomarkers of cardiovascular dysfunction and disease: cardiotrophin-1, adipokines and galectin-3. AB - Cardiovascular disease is one of the main burdens of healthcare systems worldwide. Nevertheless, assessing cardiovascular risk in both apparently healthy individuals and low/high-risk patients remains a difficult issue. Already established biomarkers (e.g. brain natriuretic peptide, troponin) have significantly improved the assessment of major cardiovascular events and diseases but cannot be applied to all patients and in some cases do not provide sufficiently accurate information. In this context, new potential biomarkers that reflect various underlying pathophysiological cardiac and vascular modifications are needed. Also, a multiple biomarker evaluation that shows changes in the cardiovascular state is of interest. This review describes the role of selected markers of vascular inflammation, atherosclerosis, atherothrombosis, endothelial dysfunction and cardiovascular fibrosis in the pathogenesis and prognosis of cardiovascular disease: the potential use of cardiotrophin-1, leptin, adiponectin, resistin and galectin-3 as biomarkers for various cardiovascular conditions is discussed. PMID- 28721159 TI - PCSK9 inhibitors - from discovery of a single mutation to a groundbreaking therapy of lipid disorders in one decade. AB - Hypercholesterolemia is one of the main risk factors for coronary heart disease and significantly contributes to the high mortality associated with cardiovascular diseases. Statin therapy represents the gold standard in the reduction of low-density lipoprotein cholesterol concentration. Nevertheless, many patients still cannot achieve the recommended target levels, due to either inadequate effectiveness or intolerance of these drugs. Monoclonal antibodies that inhibit proprotein convertase subtilisin/kexin type 9 (PCSK9) have emerged as a promising option in lipid-lowering treatment. After confirmation of their efficacy and safety in clinical trials, evolocumab and alirocumab received approval from the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) for introduction into clinical practice. In this review, we present a history of the development and mechanisms of action, as well as the results of the most important studies concerning PCSK9 inhibitors. PMID- 28721160 TI - Genetic disruption of multidrug resistance-associated protein 1 improves endothelial function and attenuates atherosclerosis in MRP1-/- LDLr-/- double knockout mice. AB - INTRODUCTION: Multidrug resistance-associated protein 1 (MRP1) is an anion transporter which is implicated in the efflux of the intracellular antioxidant anion glutathione as well as leukotrienes. Pharmacological inhibition of MRP1 exhibits antioxidative and anti-atherosclerotic effects both in vitro and in vivo. However, pharmacological inhibitors of MRP1 lack selectivity, which prompted us to study the in vivo impact of a genetic disruption of MRP1 on endothelial dysfunction, reactive oxygen species formation and atherogenesis in an atherosclerotic mouse model. MATERIAL AND METHODS: MRP1-/- LDLr-/- double knockout mice. were fed a high-fat and cholesterol-rich diet for 7 weeks. Thereafter, endothelial function was assessed in isolated aortic rings. Reactive oxygen species were quantified by L-012 chemiluminescence, and the atherosclerotic plaque burden was measured following oil red O staining. RESULTS: Endothelium-dependent vasodilation of MRP1-/- LDLr-/- double knockout mice was significantly improved compared to MRP1-competent LDLr-/- single knockout mice (0.56 +/-0.06 vs. 0.78 +/-0.08; n = 10; p = 0.048). This improvement was accompanied by a significant reduction in reactive oxygen species formation within the aortic tissue (102 +/-27 RLU/s/mg vs. 315 +/-78 RLU/s/mg, n = 9-11, p = 0.03). Moreover, the atherosclerotic plaque burden of MRP1-/- LDLr-/- double knockout mice was significantly reduced (0.06 +/-0.01 vs. 0.12 +/-0.02; n = 6; p = 0.047). Finally, arterial blood pressure was significantly reduced in MRP1-/- LDLr-/- double knockout mice (93 +/-5 mm Hg vs. 128 +/-4 mm Hg; n = 8-12; p < 0.001). CONCLUSIONS: Genetic disruption of MRP1 appears to reduce blood pressure and vascular oxidative stress in vivo, which leads to improved endothelial function and a reduced plaque burden in atherosclerotic mice. Therefore, MRP1 might represent a promising therapeutic target to improve endothelial function in patients suffering from atherosclerosis. PMID- 28721161 TI - Repeated positive acceleration exposure exacerbates endothelial dysfunction in high-fat-diet-induced hyperlipidemic rats. AB - INTRODUCTION: It remains unclear whether exposure to repeated positive acceleration (+Gz) can exacerbate endothelial dysfunction on the basis of hyperlipidemia. The aim of this study was to investigate the effect of repeated +Gz exposure on endothelial function in high-fat-diet-induced hyperlipidemic rats. MATERIAL AND METHODS: Male Sprague-Dawley rats were randomly divided into control, repeat +Gz exposure, high-fat diet (HFD), and +Gz + HFD groups. The rats in the +Gz group were exposed to +Gz and the rats in the HFD group were fed a diet with 2% cholesterol. The rats in the +Gz + HFD group received both the +Gz exposure and HFD. Eight weeks later, the endothelium-dependent relaxation of the aorta was tested and the ultrastructure of the endothelial cells was observed using transmission electron microscopy. Quantitative real-time polymerase chain reaction and Western blot were used to detect the mRNA and protein expression of endothelial function-associated proteins. RESULTS: Repeated +Gz exposure elevated the serum level of LDL-C in HFD rats. In the +Gz + HFD rats, the ACh-induced relaxation in the aorta rings was significantly attenuated and the endothelial cells of the aorta were dramatically damaged compared with HFD rats. Nitric oxide content and eNOS expression in the aortic tissue were markedly decreased and the oxidative stress was more serious in the +Gz + HFD rats compared with HFD rats. In addition, repeated +Gz exposure significantly increased serum ox-LDL level and LOX-1 expression in the aorta of HFD rats, thereby activating NF-kappaB p65 and upregulating the expression of interleukin 6, ICAM-1 and VAP-1. CONCLUSIONS: Repeated +Gz exposure promotes endothelial dysfunction in HFD-induced hyperlipidemic rats. PMID- 28721162 TI - The influence of rapamycin on the early cardioprotective effect of hypoxic preconditioning on cardiomyocytes. AB - INTRODUCTION: The purpose of this study was to examine the effects of rapamycin on the cardioprotective effect of hypoxic preconditioning (HPC) and on the mammalian target of rapamycin (mTOR)-mediated hypoxia-inducible factor 1 (HIF-1) signaling pathway. MATERIAL AND METHODS: Primary cardiomyocytes were isolated from rat pups and underwent rapamycin and/or HPC, followed by hypoxia/re oxygenation (H/R) injury. Cell viability and cell injury were determined by 3 (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays, and qRT-PCR was used to measure HIF-1alpha and mTOR mRNA expression. A Langendorff heart perfusion model was conducted to observe the effect of rapamycin. RESULTS: Rapamycin treatment nearly abolished the cardioprotective effect of HPC in cardiomyocytes, reduced cell viability (p = 0.007) and increased cell damage (p = 0.032). HIF-1alpha and mTOR mRNA expression increased in cardiomyocytes undergoing I/R injury within 2 h after HPC. After rapamycin treatment, mTOR mRNA expression and HPC-induced HIF-1alpha mRNA expression were both reduced (p < 0.001). A Langendorff heart perfusion model in rat hearts showed that rapamycin greatly attenuated the cardioprotective effect of HPC in terms of heart rate, LVDP, and dp/dtmax (all, p < 0.029). CONCLUSIONS: Rapamycin, through inhibition of mTOR, reduces the elevated HIF-1alpha expression at an early stage of HPC, and attenuates the early cardioprotective effect of HPC. PMID- 28721163 TI - Additive effects of atorvastatin combined with sitagliptin on rats with myocardial infarction: a pilot study. AB - INTRODUCTION: Atorvastatin and sitagliptin are able to exert cardio-protective effects. However, whether atorvastatin plus sitagliptin could confer additive benefits for rats with myocardial infarction (MI) is unknown. MATERIAL AND METHODS: Forty rats with MI were produced and 37 surviving rats were randomly divided into atorvastatin (10 mg/kg daily, n = 9), sitagliptin (10 mg/kg daily, n = 9), combined (10 mg/kg daily atorvastatin plus 10 mg/kg daily sitagliptin, n = 9), and control groups (3 ml normal saline daily, n = 10). Fourteen days later, cardiac function was detected and fasting venous blood was sampled for lipid profiles and glucose evaluation. Cardiac tissues were used for hematoxylin-eosin staining, for interleukin-6 (IL-6) and tumor necrotic factor-alpha (TNF-alpha) evaluation, and for rho-associated kinase 2 (ROCK2) assessment. RESULTS: Fourteen days after MI, the inflammatory reaction regarding the degree of leukocyte infiltration and IL-6 and TNF-alpha expression in cardiac tissues was ameliorated in atorvastatin and sitagliptin groups compared to the control group (p < 0.05). In addition, ROCK2 was attenuated by either atorvastatin or sitagliptin (p < 0.05). Echocardiography showed that cardiac function was significantly improved with atorvastatin and sitagliptin therapy (p < 0.05). Overall, all these benefits were further enhanced by combined therapy, suggesting that atorvastatin combined with sitagliptin therapy has additive effects on reducing cardiac inflammation and improving cardiac function. No significant changes in lipid profiles or glucose were observed, suggesting that the benefits derived from atorvastatin and sitagliptin therapy might not depend on cholesterol and glucose modulation. CONCLUSIONS: In rats with MI, atorvastatin plus sitagliptin therapy provides additive effects for cardio-protection, and mechanisms operating in these processes may be due to ROCK2 diminishment. PMID- 28721164 TI - Influence of half marathon race on aortic stiffness in amateur runners. PMID- 28721165 TI - Case studies in applied epidemiology. PMID- 28721166 TI - Overview of the design and development of public health case studies. PMID- 28721168 TI - Cholera outbreak in Homa Bay County, Kenya, 2015. AB - Cholera is among the re-emerging diseases in Kenya. Beginning in December 2014, a persistent outbreak occurred involving 29 out of the 47 countries. Homa Bay County in Western Kenya was among the first counties to report cholera cases from January to April 2015. This case study is based on an outbreak investigation conducted by FELTP residents in Homa Bay County in February 2015. It simulates an outbreak investigation including laboratory confirmation, active case finding, descriptive epidemiology and implementation of control measures. This case study is designed for the training of basic level field epidemiology trainees or any other health care workers working in public health-related fields. It can be administered in 2-3 hours. Used as adjunct training material, the case study provides the trainees with competencies in investigating an outbreak in preparation for the actual real-life experience of such outbreaks. PMID- 28721167 TI - Unexplained haemorrhagic fever in Rural Ethiopia. AB - This case study was written based on events of an outbreak investigation of an unfamiliar disease in Ethiopia during October-December 2012. Ethiopia did not have reports of similar cases in the 50 years prior to this outbreak. In this case study, we recapitulate and analyse this outbreak investigation based on data gathered from the community, health facility, and laboratory systems. It can be used to teach: 1) the outbreak investigation process; 2) selection of appropriate epidemiological design for the investigation process, 3) basic statistical analysis of surveillance data, and 4) principals of disease control. The target audiences for this case study are officials working in public health and public health trainees. It will take at most 3.5 hours to complete this case study. At the end of the case study, participants should be able to apply the principals of outbreak investigation and use surveillance data to respond to an outbreak in their country-specific context. PMID- 28721169 TI - Investigating an outbreak of measles in Margibi County, Liberia, October 2015. AB - The emergence and re-emergence of infectious diseases highlights the need to have well-trained field epidemiologists who will be at the forefront in the fight against these diseases, especially during an outbreak. Training for outbreak investigation is most effective when participants can develop their competencies in a practical exercise. To that end, this case study was based on a measles outbreak investigation conducted in Liberia during October 2015 by Liberia Frontline Field Epidemiology Training Program (FETP) residents, simulating steps to perform outbreak investigation in a real-life situation as a field epidemiologist. This case study is ideally suited to reinforce principles and skills already covered in a classroom lecture or in background reading by providing a practical training beyond the scope of theoretical learning. It is primarily intended for training novice public health practitioners who should be able to complete the exercises in approximately 3 hours. PMID- 28721170 TI - An epidemic of spastic paraparesis of unknown aetiology in Northern Mozambique. AB - This case study is based on a real-life outbreak investigation undertaken in Mozambique in 1981. This case study describes and promotes one particular approach to unknown disease outbreak investigation. Investigational procedures, however, may vary depending on location and outbreak. It is anticipated that the epidemiologist investigating an unknown disease outbreak will work within the framework of a "multidisciplinary investigation team". It is through the collaborative efforts of this team, with each member playing a critical role, that outbreak investigations are successfully completed. Some aspects of the original outbreak and investigation have, however, been altered to assist in meeting the desired teaching objectives and to allow completion of the case study in less than 3 hours. PMID- 28721171 TI - Response to an unusual outbreak in a high-risk situation. AB - In 2010, a series of lead poisoning outbreaks linked to artisanal gold processing killed at least 400 young children in Zamfara State in northwestern Nigeria. There were several efforts to respond to the outbreaks as they occurred. Subsequent recurrence of lead poisoning outbreaks within Zamfara and beyond suggested that there were no efforts to mitigate the outbreaks as recommended for disaster management. This case study, to be completed within 3 hours, is suitable for senior level public health officials and those training for such positions. It enables participants to review and apply epidemiological principles for managing disasters and suggest steps toward development of policy recommendations based on the context of environmental lead exposure. It will serve as a generic training module for managers/responders of other natural (floods, heat stroke) and man-made disasters (civil strife, conflict, insurgency) based on the general/standard principle of the complete disaster management cycle. PMID- 28721172 TI - Contact tracing following outbreak of Ebola virus disease in urban settings in Nigeria. AB - An outbreak of Ebola virus disease occurred in Nigeria between July and September 2014. Contact tracing commenced in Lagos, and extended to Port Harcourt and Enugu as the outbreak continued to spread. A total of 899 contacts were traced. Contact tracing enhanced immediate identification of symptomatic contacts, some of whom eventually became cases. Contact tracing could be challenging in urban cities. However, use of electronic technology, adequate logistics, and highly skilled personnel enhanced the tracing of contacts to facilitate the successful containment of the outbreak. Nigeria was certified to be Ebola free on 21st October 2014. Ebola virus surveillance needs to be maintained to ensure the disease has been contained and to prevent future outbreaks. This case study aims to help trainees to review concepts, apply skills, and address challenges for contact tracing based on the experience of the Nigerian Field Epidemiology Training Network during the 2014 Ebola virus disease outbreak. PMID- 28721173 TI - Detecting, reporting, and analysis of priority diseases for routine public health surveillance in Liberia. AB - An essential component of a public health surveillance system is its ability to detect priority diseases which fall within the mandate of public health officials at all levels. Early detection, reporting and response to public health events help to reduce the burden of mortality and morbidity on communities. Analysis of reliable surveillance data provides relevant information which can enable implementation of timely and appropriate public health interventions. To ensure that a resilient system is in place, the World Health Organization (WHO) has provided guidelines for detection, reporting and response to public health events in the Integrated Disease Surveillance and Response (IDSR) strategy. This case study provides training on detection, reporting and analysis of priority diseases for routine public health surveillance in Liberia and highlights potential errors and challenges which can hinder effective surveillance. Table-top exercises and group discussion lead participants through a simulated verification and analyses of summary case reports in the role of the District Surveillance Officer. This case study is intended for public health training in a classroom setting and can be accomplished within 2 hours 30 minutes. The target audience include residents in Frontline Epidemiology Training Programs (FETP-Frontline), Field Epidemiology and Laboratory Training Programs (FELTPs), and others who are interested in this topic. PMID- 28721174 TI - Detecting, reporting, and analysis of priority diseases for routine public health surveillance in Liberia. AB - Public health officials depend on timely, complete, and accurate surveillance data for decision making. The quality of data generated from surveillance is highly dependent on external and internal factors which may either impede or enhance surveillance activities. One way of identifying challenges affecting the quality of data generated is to conduct a data quality audit. This case study, based on an audit conducted by residents of the Liberia Frontline Field Epidemiology Training Program, was designed to be a classroom simulation of a data quality audit in a health facility. It is suited to enforce theoretical lectures in surveillance data quality and auditing. The target group is public health trainees, who should be able to complete this exercise in approximately 2 hours and 30 minutes. PMID- 28721175 TI - Conducting a surveillance problem analysis on poor feedback from Reference Laboratory, Liberia, February 2016. AB - The laboratory plays a major role in surveillance, including confirming the start and end of an outbreak. Knowing the causative agent for an outbreak informs the development of response strategies and management plans for a public health event. However, issues and challenges may arise that limit the effectiveness or efficiency of laboratories in surveillance. This case study applies a systematic approach to analyse gaps in laboratory surveillance, thereby improving the ability to mitigate these gaps. Although this case study concentrates on factors resulting in poor feedback from the laboratory, practise of this general approach to problem analysis will confer skills required in analysing most public health issues. This case study was developed based on a report submitted by the district surveillance officer in Grand Bassa County, Liberia, as a resident of the Liberian Frontline Field Epidemiology Training Program in 2016. This case study will serve as a training tool to reinforce lectures on surveillance problem analysis using the fishbone approach. It is designed for public health training in a classroom setting and can be completed within 2 hours 30 minutes. PMID- 28721176 TI - From one to the other: responding to Ebola cases on either side of the line. AB - This case study is adapted from events that occurred along the Sierra Leone and Guinea land border during the 2014-2016 Ebola epidemic in West Africa. The response activities involved Sierra Leone and Guinea officials, along with assistance from U.S. Centers for Disease Control and Prevention (CDC) and the World Health Organisation (WHO). This case study builds upon an understanding of basic surveillance systems and outbreak response activities. Through this exercise, students will understand how to incorporate communication and coordination into surveillance and response efforts with counterparts across the border in neighbouring countries. This integration is important to reduce the spread of communicable diseases between neighbouring countries. The time required to complete this case study is 2-3 hours. PMID- 28721177 TI - Antiretroviral therapy outcomes among HIV infected clients in Gweru City, Zimbabwe 2006 - 2011: a cohort analysis. AB - The government of Zimbabwe began providing antiretroviral therapy (ART) to People Living with HIV/AIDS (PLHIV) in public institutions in 2004. In Midlands province two clinics constituted the most active HIV care service points, with patients being followed up through a comprehensive patient monitoring and tracking system which captured specific patient variables and outcomes over time. The data from 2006 to 2011 were subjected to analysis to answer specific research questions and this case study is based on that analysis. The goal of this case study is to build participants' capacity to undertake secondary data analysis and interpretation using a dataset for HIV antiretroviral therapy in Zimbabwe and to draw conclusions which inform recommendations. Case studies in applied epidemiology allow students to practice applying epidemiologic skills in the classroom to address real-world public health problems. Case studies as a vital component of an applied epidemiology curriculum are instrumental in reinforcing principles and skills covered in lectures or in background reading. The target audience includes Field Epidemiology and Laboratory Training Programs (FELTPs), university students, district health executives, and health information officers. PMID- 28721178 TI - Global reproductive health - Why do we persist in neglecting the undeniable problem of childlessness in resource-poor countries? AB - The consequences of involuntary childlessness in developing countries create more wide-ranging societal problems compared to Western societies, particularly for women. Negative psychosocial and economical consequences for childless couples are often severe and underestimated by the local and international society. Infertility treatment is often limited to certain procedures and certain costumers. Most common arguments against supporting infertility care in resource poor countries are the "overpopulation" and the "limited resources" argument, but they totally neglect the reproductive rights and systematic exclusion of millions of women from the right to reproduce. Because ART procedures are very expensive, governments and international aid-organisations are currently not investing in this technique. But the scene has changed recently: inexpensive ovarian stimulation protocols for IVF have proven their value and simplified but high quality low cost IVF techniques are available nowadays. From an ethical point of view it is our belief that the community can no longer justify the systematic exclusion of one tenth of couples from the right to reproduce in resource-poor countries. PMID- 28721179 TI - Early and late onset complications of gynaecologic surgery: a multimodality imaging approach. AB - The role of imaging after surgery is pivotal to drive clinical management of early and/or late onset complications. Most frequently used imaging technique after pelvic surgery is Ultrasound (US), Magnetic Resonance Imaging (MRI) and Computed Tomography (CT). While Ultrasound is a standard procedure, using grey scale and/or colour Doppler evaluation, MRI and CT scan protocols should be derived on the basis of the specific indication of the exam. Correct evaluation of female pelvis after gynaecologic surgery, having in mind the most frequent complications, is based on the correct use of the instruments and on the experience of the examiner, who should be aware of the history of the patient, type of surgery and clinical symptoms for which the exam is required; the clinician should be aware of the possibilities and limits of the different techniques, in order to choose the most appropriate imaging modality and promptly make a correct diagnosis. PMID- 28721180 TI - Adenomyosis: Back to the future? AB - Adenomyosis is a benign invasion of endometrium into the myometrium. It produces a diffusely enlarged uterus and predominantly affects women in the late reproductive age. It has recently been associated with a negative impact on female fertility. Diagnosis is challenging because nonspecific symptoms can be present. However, it is asymptomatic in the majority of women. Medical treatment with GnRH agonist seems to be promising, particularly in subfertile women. A retrospective study was performed (182 patients) by examination of histopathological results with "adenomyosis" between January/2013 and September/2016. The patients ranged in age from 34 to 78 years and the majority (94.5%) were over 40 years old. Most (90.6%) were multiparous. All women underwent a sonographic evaluation. More than a half had a heterogeneous myometrium (75.7%) and concomitant presence of myoma (65.4%). The majority of women were asymptomatic, nevertheless, when symptoms were present, menorrhagia and metrorrhagia were the most important complaints. About one third of women had had prior uterine surgery, 67.6% had had previous caesarean section(s). Medical treatment with progestatives was used by 61.3% of women and 23% tried more than one type of hormone therapy. Endometrial cancer was present in 5.5% of cases, all of which were lowgrade endometrioid adenocarcinoma. Adenomyosis is an important challenge in gynaecology and often remains a post-operative diagnosis after hysterectomy. Clinicians should be on the watch for ultrasound features suggesting its presence to allow an early diagnosis. Future investments in the creation of diagnostic algorithms and alternative treatments are warranted. PMID- 28721181 TI - Adding sildenafil vaginal gel to clomiphene citrate in infertile women with prior clomiphene citrate failure due to thin endometrium: a prospective self-controlled clinical trial. AB - : We aimed to investigate the effect of adding sildenafil vaginal gel to clomiphene citrate (CC) in infertile women with prior CC failure. METHODS: This is a self- controlled clinical trial. Women with CC failure (in prior 5 cycles) and thin endometrium were recruited (N = 42). In their 6th (CC only) cycle, women continued on CC 100 mg/ day for 5 days, and had measurement of endometrial thickness and Doppler assessment of uterine arteries on day of HCG administration. In the 7th cycle, women (N = 36) were given usual dose of CC supplemented with sildenafil vaginal gel (5 gm, containing 50 mg sildenafil) twice daily from cycle day 8 to day of HCG administration. Endometrial thickness and uterine artery Doppler were measured on the day of HCG injection. RESULTS: In the 7th (CC + sildenafil vaginal gel) cycle, endometrial thickness was significantly higher than in the 6th (CC only) cycle (9.3 mm +/- 3.1mm versus 6.6 mm +/- 1.4 mm, respectively, P = < 0.001). Uterine artery pulsatility index dropped from 2.4 +/- 0.8 in 6th cycle to 1.6 +/- 1.3 in 7th cycle (P = 0.002). Clinical pregnancy rate increased but numbers were too small (only 3 pregnancies). CONCLUSION: Sildenafil vaginal gel significantly increased endometrial thickness and uterine blood flow, and may improve pregnancy rate in patients with CC failure due to thin endometrium. Mucoadhesive vaginal gel formulation allowed shorter duration of sildenafil application, and less frequent daily dosing. PMID- 28721183 TI - Infertility in the Global South: Raising awareness and generating insights for policy and practice. AB - Infertility is a highly prevalent reproductive health condition in the global South, which often has a devastating impact on the people concerned. Yet, thus far it hardly received any attention from policy makers, Non-Governmental Organizations (NGOs) or donors working in the field of Sexual and Reproductive Health and Rights (SRHR). For this reason we have set up a project to increase knowledge and awareness about infertility and childlessness among those stakeholders and organizations and to generate insight into (possible) interventions in this field. The project received a grant by Share-Net International (the Knowledge Platform in the field of SRHR, funded by the Dutch Ministry of Foreign Affairs) and is a unique collaboration between universities, fertility clinics, fertility support groups and the Walking Egg Foundation. The project consists of multimethods studies in Ghana and Kenya as well as dissemination workshops and meetings in these countries and the Netherlands. The first workshops in Kenya have already taken place with successful feedback from stakeholders. In this commentary we provide insight into the project and the main points and recommendations discussed in the Workshops in Kenya. PMID- 28721182 TI - Mitochondria in oocyte aging: current understanding. AB - The oocyte is the largest cell found in multicellular organisms. Mitochondria, as the energy factories for cells, are found in high numbers in oocytes, as they provide the energy for oocyte maturation, fertilization, and embryo formation via oxidative phosphorylation. Failure of assisted reproduction is mainly attributed to oocyte aging and increased aneuploidy. As the most numerous organelle in the oocyte, the mitochondrion has been confirmed as a crucial player in the process of oocyte aging, which is highly influenced by mitochondrion dysfunction. Every mitochondrion contains one or more mitochondrial DNA (mtDNA) molecule, which, at about 16.5 KD in length, encodes 13 proteins. In this review, we discuss the function of mitochondria and the relationship between mtDNA and oocyte aging. We also discuss technologies that aim to enhance oocyte developmental potential and delay ovarian aging. PMID- 28721184 TI - Axillary lymph node dissection on the run? AB - The standard approach of performing a completion axillary lymph node dissection (cALND) after a positive sentinel node for breast cancer patients is no longer generally accepted. This study applied the criterion of a 27% risk of having residual positive lymph nodes calculated by the MD Anderson nomogram to perform a cALND. This 27% cut-off is based on the number of positive non-sentinels in the Z0011 trial. A cohort of 166 cN0, sentinel positive breast cancer patients was used to validate the MD Anderson nomogram. ROC (Receiver Operating Characteristic) analysis shows an AUC (Area Under the Curve) of 0.76 and an optimal cut-off at 34% risk of positive non- SLNs (sensitivity 86%, specificity 57%). The 27% cut-off has a sensitivity of 88% and a specificity of 41% to detect positive non-sentinels. In a second cohort (N= 114) the 27% cut-off criterion was prospectively applied and appeared to be practice changing. Although we take minimal risk to leave disease behind (2/166 patients >3 positive nodes), 30.7 % in the first cohort and 54.4 % of the patients in the second cohort could be spared a cALND. The Z0011 criteria would have had more impact, omitting 90% of the cALND, but leaves more disease behind. The impact of leaving disease behind on survival remains unanswered but is awaited by long term follow up of large prospective cohort studies. PMID- 28721185 TI - The smooth and bumpy road of trastuzumab administration: from intravenous (IV) in a hospital to subcutaneous (SC) at home. AB - Trastuzumab has become standard of care in the treatment of early and metastatic HER2-positive breast cancer. Initially trastuzumab could only be administered intravenously (IV), however since a few years there is also a subcutaneous (SC) formulation. The efficacy and the safety profile of both formulations is the comparable. The administration logistics however have an impact on the patients, the health care professionals (HCPs), the hospital and the government. The preference for the patients (89%) and the HCPs (77%) is in favour of the SC formulation. The patient chair time per cycle, as defined by the time between entry and exit of infusion chair, is between 53 and 122 minutes shorter for SC administration. Also, the time actively dedicated by the HCP on preparation and administration SC, is between 17 and 50 minutes shorter per cycle. These time savings may increase the capacity of an oncological day clinic and reduce waiting lists. An additional benefit is that the use of SC formulation reduces the consumables and the waste. When the SC form was given at home instead of in the hospital the safety profile remained the same, but the satisfaction rate improved further for both the patients and the HCPs. The next and final step will be potentially to invest in teaching the patients to self-administer the medication. The home administration and the education of the patients and the HCPs will have a cost price and it will be interesting to see how the hospital financial authorities and the government will deal with this situation in the time of budgetary restrictions. PMID- 28721186 TI - Factors driving the global decline of cycad diversity. AB - Mounting evidence indicates that we are witnessing the sixth mass extinction period. Given the important goods and services biodiversity delivers to humans, there is a need for a continued commitment to investigate what pre-disposes some taxa to greater risk of extinction. Here, we investigate this question using a phylogenetic comparative method and fitting a cumulative link mixed effect model on biological, ecological and evolutionary data of cycads, the most threatened lineage in the plant kingdom. We identified nine groups of threats to cycads, with habitat loss, over-collection, fire and reproduction failure being the most prominent, but only four of these threats (habitat loss, over-collection, medicinal uses and reproduction failure) clustered on the cycad tree of life. This clustering suggests that closely related species may be exposed to similar threats, perhaps because of geographic regionalization of cycad genera. Nonetheless, the diversity of threats and several variables linked to the biology and ecology of cycads correlate with extinction risk (e.g. altitude, height, diameter, geographic range), and different variables seem to be linked to different IUCN status of cycads. Although their predictive power is generally < 50 %, geographic range and maximum diameter stood out as the best predictors particularly for the Vulnerable (VU) category, with a predictive power of 87 % and 69 %, respectively. Using our best model for VU, we predicted all five Data Deficient (DD) species of cycads to be in the VU category. Collectively, our results elucidate the pattern of extinction risk in cycads and, since most threats that we identified as drivers of extinction risk of cycads are anthropogenically mediated, we recommend stronger legislation to regulate human cycad interactions and the commitment of all governments globally to implement this regulation. PMID- 28721187 TI - Individual and interactive effects of white-tailed deer and an exotic shrub on artificial and natural regeneration in mixed hardwood forests. AB - Underplanting tree seedlings in areas where natural regeneration is limited may offer a tool by which desired overstory composition can be maintained or restored in forests. However, invasive plant species and ungulate browsing may limit the effectiveness of underplanting, and in-turn, the successful restoration of forest ecosystems. Individually, the invasive shrub Lonicera maackii and browsing by white-tailed deer (Odocoileus virginianus) have been found to negatively affect the regeneration of native tree species in the Midwestern United States, but few studies have examined their interactive or cumulative effects. Using exclosures and shrub removal at five sites, we examined the effects of white-tailed deer and L. maackii both on underplanted seedlings of Castanea dentata and Quercus rubra and on the composition, species richness and diversity of naturally regenerated native tree seedlings. Individually, both deer and L. maackii had negative effects on the survival of underplanted seedlings, but we identified no interactive effects. The presence of L. maackii or deer alone resulted in similar declines in the survivorship of Q. rubra seedlings, but the presence of deer alone resulted in lower survival of C. dentata seedlings than the presence of L. maackii alone. Lonicera maackii reduced light levels, increased seedling moisture stress and decreased relative basal diameter growth for Q. rubra seedlings. Deer reduced the relative growth in height of underplanted C. dentata and Q. rubra seedlings and increased moisture stress of C. dentata seedlings. No effects of L. maackii or deer were found on soil or foliar nitrogen or the overall abundance, species richness and diversity of naturally regenerated seedlings. However, L. maackii and white-tailed deer did affect the abundance of individual tree species, shifting composition of the regeneration layer towards shade tolerant and unpalatable and/or browse tolerant species. PMID- 28721188 TI - Trait variation along elevation gradients in a dominant woody shrub is population specific and driven by plasticity. AB - Elevation gradients are frequently used as space-for-time substitutions to infer species' trait responses to climate change. However, studies rarely investigate whether trait responses to elevation are widespread or population-specific within a species, and the relative genetic and plastic contributions to such trait responses may not be well understood. Here, we examine plant trait variation in the dominant woody shrub, Rhododendron maximum, along elevation gradients in three populations in the South Central Appalachian Mountains, USA, in both field and common garden environments. We ask the following: (i) do plant traits vary along elevation? (ii) do trait responses to elevation differ across populations, and if so, why? and (iii) does genetic differentiation or phenotypic plasticity drive trait variation within and among populations? We found that internode length, shoot length, leaf dry mass, and leaf area varied along elevation, but that these responses were generally unique to one population, suggesting that trait responses to environmental gradients are population-specific. A common garden experiment identified no genetic basis to variation along elevation or among populations in any trait, suggesting that plasticity drives local and regional trait variation and may play a key role in the persistence of plant species such as R. maximum with contemporary climate change. Overall, our findings highlight the importance of examining multiple locations in future elevation studies and indicate that, for a given plant species, the magnitude of trait responses to global climate change may vary by location. PMID- 28721189 TI - Strangulated gallbladder caused by a tip of the omentum attached to the abdominal wall: a case report. AB - Strangulation of the gallbladder associated with the omentum is extremely rare and, to our knowledge, only two cases have been previously reported. The patient was a 91-year-old female who presented to our emergency room with a chief complaint of upper abdominal pain. Computed tomography imaging revealed a gourd shaped gallbladder with biphasic appearance divided clearly at the body. In the fundus side, the wall of the gallbladder was oedematous and thickened, while the neck side was intact. On the second day after onset, a laparoscopic cholecystectomy was performed. A tip of the omentum encircling the gallbladder was adhered to the abdominal wall and was strangling the gallbladder. By cutting the omentum at the attachment site, the strangulation was released. Laparoscopic cholecystectomy was performed, and the patient was discharged with an uneventful course. We experienced an extremely rare case of strangulated gallbladder caused by a tip of the omentum attached to the abdominal wall. PMID- 28721190 TI - A case of fatal internal jugular vein perforation during nasogastric tube insertion. AB - Nasogastric tube (NGT) insertion is a routine procedure in the management of surgical patients. We report the second case of internal jugular vein perforation during NGT insertion. A 79-year-old man presented with diffuse abdominal pain secondary to a perforated viscus. Abdominal CT revealed pneumoperitoneum, necessitating emergent exploratory laparotomy. On post-operative Day 7, the patient developed mild abdominal distension and subjective nausea for which NGT placement was ordered for decompression. Tube placement was confirmed by insufflation of air without aspiration of gastric contents. Output from the NGT upon placement revealed frank blood. The patient then developed respiratory distress requiring intubation, followed by a fatal arrhythmia. Post-mortem exam revealed the trajectory of the NGT through the pharyngeal wall into the right internal jugular vein. This case illustrates the importance of systematic evaluation of all procedures, as the outcome resulted from failure to recognize the initial error in tube placement. PMID- 28721191 TI - Small bowel obstruction due to mesenteric abscess caused by Mycobacterium avium complex in an HIV patient: a case report and literature review. AB - Small bowel obstruction in HIV patients is reportedly caused by inflammatory pseudotumor, Kaposi's sarcoma, cryptococcal lymphadenopathy and intestinal tuberculosis. The incidence of Mycobacterium avium complex (MAC) infection in HIV patients is 3% for CD4 cell count of 100-199 /mm3. MAC causing small bowel obstruction is rarely reported in the literature. We report a rare case of MAC causing mesenteric abscess with small bowel obstruction in a HIV patient with a CD4 cell count of 144 /mm3. Patient was a 35-year-old HIV-positive male on highly active antiretroviral therapy who presented with partial small bowel obstruction secondary to mesenteric abscess. He underwent operative intervention for drainage with cultures growing MAC. PMID- 28721192 TI - A case report on a rare anatomic variant of cystic duct insertion. AB - We report a case a 70-year-old female presenting with abdominal pain who has a cystic duct coursing medial to the common bile duct before anastomosing just proximal to the ampulla. Low medial insertion of the cystic duct is a rare anatomic variant that is easily misidentified on imaging studies and may complicate surgical and percutaneous intervention. It can be identified by pre operative imaging modalities such as magnetic resonance cholangiopancreatography. PMID- 28721193 TI - Giant spontaneous herniation of the post-pneumonectomy cavity. AB - Following a pneumonectomy, excessive mediastinal shift can cause rare complications involving the post-pneumonectomy cavity, which can become the seat of herniation of the residual lung and of the heart. We herein report an even more rare event, entailing an impressive herniation of the actual entire post pneumonectomy cavity through an intercostal space, which developed spontaneously nearly 3 years after surgery. Surgical excision of the hernia sac and repair of the defect with polypropylene mesh provided adequate treatment and good cosmetic results. Postoperative recovery was uneventful and no signs of recurrence have been observed. PMID- 28721194 TI - Successful laparoscopic repair of gastro-gastric fistula following Roux-en-Y gastric bypass at Harlem Community Hospital. AB - Gastro-gastric fistula is a communication between the gastric remnant and gastric pouch. It is a rare complication of Roux-en-Y gastric bypass. It is caused by anastomotic leak, marginal ulcers, distal obstruction or erosion from foreign body. In this case report, we are presenting a successful laparoscopic repair of gastro-gastric fistula in a patient who presented with weight gain after initial loss. PMID- 28713543 TI - GeneBreak: detection of recurrent DNA copy number aberration-associated chromosomal breakpoints within genes. AB - Development of cancer is driven by somatic alterations, including numerical and structural chromosomal aberrations. Currently, several computational methods are available and are widely applied to detect numerical copy number aberrations (CNAs) of chromosomal segments in tumor genomes. However, there is lack of computational methods that systematically detect structural chromosomal aberrations by virtue of the genomic location of CNA-associated chromosomal breaks and identify genes that appear non-randomly affected by chromosomal breakpoints across (large) series of tumor samples. 'GeneBreak' is developed to systematically identify genes recurrently affected by the genomic location of chromosomal CNA-associated breaks by a genome-wide approach, which can be applied to DNA copy number data obtained by array-Comparative Genomic Hybridization (CGH) or by (low-pass) whole genome sequencing (WGS). First, 'GeneBreak' collects the genomic locations of chromosomal CNA-associated breaks that were previously pinpointed by the segmentation algorithm that was applied to obtain CNA profiles. Next, a tailored annotation approach for breakpoint-to-gene mapping is implemented. Finally, dedicated cohort-based statistics is incorporated with correction for covariates that influence the probability to be a breakpoint gene. In addition, multiple testing correction is integrated to reveal recurrent breakpoint events. This easy-to-use algorithm, 'GeneBreak', is implemented in R ( www.cran.r-project.org) and is available from Bioconductor ( www.bioconductor.org/packages/release/bioc/html/GeneBreak.html). PMID- 28713544 TI - Heterogeneous ensembles for predicting survival of metastatic, castrate-resistant prostate cancer patients. AB - Ensemble methods have been successfully applied in a wide range of scenarios, including survival analysis. However, most ensemble models for survival analysis consist of models that all optimize the same loss function and do not fully utilize the diversity in available models. We propose heterogeneous survival ensembles that combine several survival models, each optimizing a different loss during training. We evaluated our proposed technique in the context of the Prostate Cancer DREAM Challenge, where the objective was to predict survival of patients with metastatic, castrate-resistant prostate cancer from patient records of four phase III clinical trials. Results demonstrate that a diverse set of survival models were preferred over a single model and that our heterogeneous ensemble of survival models outperformed all competing methods with respect to predicting the exact time of death in the Prostate Cancer DREAM Challenge. PMID- 28713544 TI - Heterogeneous ensembles for predicting survival of metastatic, castrate-resistant prostate cancer patients. AB - Ensemble methods have been successfully applied in a wide range of scenarios, including survival analysis. However, most ensemble models for survival analysis consist of models that all optimize the same loss function and do not fully utilize the diversity in available models. We propose heterogeneous survival ensembles that combine several survival models, each optimizing a different loss during training. We evaluated our proposed technique in the context of the Prostate Cancer DREAM Challenge, where the objective was to predict survival of patients with metastatic, castrate-resistant prostate cancer from patient records of four phase III clinical trials. Results demonstrate that a diverse set of survival models were preferred over a single model and that our heterogeneous ensemble of survival models outperformed all competing methods with respect to predicting the exact time of death in the Prostate Cancer DREAM Challenge. PMID- 28721198 TI - BRD4 inhibition for the treatment of pathological organ fibrosis. AB - Fibrosis is defined as excess deposition of extracellular matrix, resulting in tissue scarring and organ dysfunction. It is estimated that 45% of deaths in the developed world are due to fibrosis-induced organ failure. Despite the well accepted role of fibrosis in the pathogenesis of numerous diseases, there are only two US Food and Drug Administration-approved anti-fibrotic therapies, both of which are currently restricted to the treatment of pulmonary fibrosis. Thus, organ fibrosis represents a massive unmet medical need. Here, we review recent findings suggesting that an epigenetic regulatory protein, BRD4, is a nodal effector of organ fibrosis, and we highlight the potential of small-molecule BRD4 inhibitors for the treatment of diverse fibrotic diseases. PMID- 28721199 TI - Evidence-informed capacity building for setting health priorities in low- and middle-income countries: A framework and recommendations for further research. AB - Priority-setting in health is risky and challenging, particularly in resource constrained settings. It is not simply a narrow technical exercise, and involves the mobilisation of a wide range of capacities among stakeholders - not only the technical capacity to "do" research in economic evaluations. Using the Individuals, Nodes, Networks and Environment (INNE) framework, we identify those stakeholders, whose capacity needs will vary along the evidence-to-policy continuum. Policymakers and healthcare managers require the capacity to commission and use relevant evidence (including evidence of clinical and cost effectiveness, and of social values); academics need to understand and respond to decision-makers' needs to produce relevant research. The health system at all levels will need institutional capacity building to incentivise routine generation and use of evidence. Knowledge brokers, including priority-setting agencies (such as England's National Institute for Health and Care Excellence, and Health Interventions and Technology Assessment Program, Thailand) and the media can play an important role in facilitating engagement and knowledge transfer between the various actors. Especially at the outset but at every step, it is critical that patients and the public understand that trade-offs are inherent in priority-setting, and careful efforts should be made to engage them, and to hear their views throughout the process. There is thus no single approach to capacity building; rather a spectrum of activities that recognises the roles and skills of all stakeholders. A range of methods, including formal and informal training, networking and engagement, and support through collaboration on projects, should be flexibly employed (and tailored to specific needs of each country) to support institutionalisation of evidence-informed priority-setting. Finally, capacity building should be a two-way process; those who build capacity should also attend to their own capacity development in order to sustain and improve impact. PMID- 28721200 TI - Protein-bound polyphenols create "ghost" band artifacts during chemiluminescence based antigen detection. AB - Antigen detection during Western blotting commonly utilizes a horseradish peroxidase-coupled secondary antibody and enhanced chemiluminescent substrate. We utilized this technique to examine the impact of green tea-derived polyphenols on the binding of egg white protein-specific IgE antibodies from allergic human plasma to their cognate antigens. Our experiments unexpectedly showed that green tea-derived polyphenols, when stably complexed with egg white proteins, caused hyperactivation of horseradish peroxidase resulting in the appearance of white "ghost" bands. This study suggests that caution should be taken when evaluating polyphenol-bound proteins by enhanced chemiluminescence Western blotting using horseradish peroxidase and demonstrates that protein-bound polyphenols can be a source of "ghost" band artifacts on Western blots. PMID- 28713552 TI - Case Report: Diagnosis of hypogeusia after oral exposure to commercial cleaning agent and considerations for clinical taste testing. AB - Few reports in the literature document acute taste disturbance following exposure to toxic chemicals. We describe the case of a 54-year-old man who presented with primary complaint of tongue numbness and persistent problems with taste 1.5 years following oral exposure to a commercial cleaning agent. A test of olfaction revealed normosmia for age and gender. Lingual tactile two-point discrimination testing showed reduced somatosensation. Taste threshold testing using a 3-drop method demonstrated severe hypogeusia, though the patient was able to discriminate tastants at lower concentrations with a whole mouth swish and spit test. We conclude that clinical evaluation of dysgeusia can be performed using a number of previously published testing methods, however, determining causative factors may be confounded by duration since exposure, lack of knowledge of baseline taste function, and medications. Although many testing options exist, basic taste testing can be performed with minimal expertise or specialized equipment, depending on the patient history and goals of evaluation. PMID- 28721202 TI - Defining the inflammatory signature of human lung explant tissue in the presence and absence of glucocorticoid. AB - BACKGROUND: Airway inflammation is a feature of many respiratory diseases and there is a need for newer, more effective anti-inflammatory compounds. The aim of this study was to develop an ex vivo human lung explant model which can be used to help study the mechanisms underlying inflammatory responses and which can provide a tool to aid drug discovery for inflammatory respiratory diseases such as asthma and COPD. METHOD: Parenchymal lung tissue from 6 individual donors was dissected and cultured with two pro-inflammatory stimuli, lipopolysaccharide (LPS) (1 ug/ml) and interleukin-1 beta (IL-1beta) (10 ng/ml) in the presence or absence of dexamethasone (1 uM). Inflammatory responses were assessed using Luminex analysis of tissue culture supernatants to measure levels of 21 chemokines, growth factors and cytokines. RESULTS: A robust and reproducible inflammatory signal was detected across all donors for 12 of the analytes measured following LPS stimulation with a modest fold increase (<2-fold) in levels of CCL22, IL-4, and IL-2; increases of 2-4-fold in levels of CXCL8, VEGF and IL-6 and increases >4-fold in CCL3, CCL4, GM-CSF, IL-10, TNF-alpha and IL 1beta. The inflammatory signal induced by IL-1beta stimulation was less than that observed with LPS but resulted in elevated levels of 7 analytes (CXCL8, CCL3, CCL4, GM-CSF, IL-6, IL-10 and TNF-alpha). The inflammatory responses induced by both stimulations was supressed by dexamethasone for the majority of analytes. CONCLUSIONS: These data provide proof of concept that this ex vivo human lung explant model is responsive to inflammatory signals and could be used to investigate the anti-inflammatory effects of existing and novel compounds. In addition this model could be used to help define the mechanisms and pathways involved in development of inflammatory airway disease. ABBREVIATIONS: COPD: Chronic Obstructive Pulmonary Disease; ICS: inhaled corticosteroids; LPS: lipopolysaccharide; IL-1beta: interleukin-1 beta; PSF: penicillin, streptomycin and fungizone. PMID- 28721203 TI - Evaluation of mineral oil saturated hydrocarbons (MOSH) and mineral oil aromatic hydrocarbons (MOAH) in pure mineral hydrocarbon-based cosmetics and cosmetic raw materials using 1H NMR spectroscopy. AB - Mineral hydrocarbons consist of two fractions, mineral oil saturated hydrocarbons (MOSH) and mineral oil aromatic hydrocarbons (MOAH). MOAH is a potential public health hazard because it may include carcinogenic polycyclic compounds. In the present study, 400 MHz nuclear magnetic resonance (NMR) spectroscopy was introduced, in the context of official controls, to measure MOSH and MOAH in raw materials or pure mineral hydrocarbon final products (cosmetics and medicinal products). Quantitative determination (qNMR) has been established using the ERETIC methodology (electronic reference to access in vivo concentrations) based on the PULCON principle (pulse length based concentration determination). Various mineral hydrocarbons (e.g., white oils, paraffins or petroleum jelly) were dissolved in deuterated chloroform. The ERETIC factor was established using a quantification reference sample containing ethylbenzene and tetrachloronitrobenzene. The following spectral regions were integrated: MOSH delta 3.0 - 0.2 ppm and MOAH delta 9.2 - 6.5, excluding solvent signals. Validation showed a sufficient precision of the method with a coefficient of variation <6% and a limit of detection <0.1 g/100 g. The applicability of the method was proven by analysing 27 authentic samples with MOSH and MOAH contents in the range of 90-109 g/100 g and 0.02-1.10 g/100 g, respectively. It is important to distinguish this new NMR-approach from the hyphenated liquid chromatography-gas chromatography methodology previously used to characterize MOSH/MOAH amounts in cosmetic products. For mineral hydrocarbon raw materials or pure mineral hydrocarbon-based cosmetic products, NMR delivers higher specificity without any sample preparation besides dilution. Our sample survey shows that previous methods may have overestimated the MOAH amount in mineral oil products and opens new paths to characterize this fraction. Therefore, the developed method can be applied for routine monitoring of consumer products aiming to minimize public health risks. PMID- 28713559 TI - Draft genome sequencing of the sugarcane hybrid SP80-3280. AB - Sugarcane commercial cultivar SP80-3280 has been used as a model for genomic analyses in Brazil. Here we present a draft genome sequence employing Illumina TruSeq Synthetic Long reads. The dataset is available from NCBI BioProject with accession PRJNA272769. PMID- 28721204 TI - Initial genome sequencing of the sugarcane CP 96-1252 complex hybrid. AB - The CP 96-1252 cultivar of sugarcane is a complex hybrid of commercial importance. DNA was extracted from lab-grown leaf tissue and sequenced. The raw Illumina DNA sequencing results provide 101 Gbp of genome sequence reads. The dataset is available from https://www.ncbi.nlm.nih.gov/bioproject/PRJNA345486/. PMID- 28721206 TI - A bipedal mammalian model for spinal cord injury research: The tammar wallaby. AB - Background: Most animal studies of spinal cord injury are conducted in quadrupeds, usually rodents. It is unclear to what extent functional results from such studies can be translated to bipedal species such as humans because bipedal and quadrupedal locomotion involve very different patterns of spinal control of muscle coordination. Bipedalism requires upright trunk stability and coordinated postural muscle control; it has been suggested that peripheral sensory input is less important in humans than quadrupeds for recovery of locomotion following spinal injury. Methods: We used an Australian macropod marsupial, the tammar wallaby (Macropuseugenii), because tammars exhibit an upright trunk posture, human-like alternating hindlimb movement when swimming and bipedal over-ground locomotion. Regulation of their muscle movements is more similar to humans than quadrupeds. At different postnatal (P) days (P7-60) tammars received a complete mid-thoracic spinal cord transection. Morphological repair, as well as functional use of hind limbs, was studied up to the time of their pouch exit. Results: Growth of axons across the lesion restored supraspinal innervation in animals injured up to 3 weeks of age but not in animals injured after 6 weeks of age. At initial pouch exit (P180), the young injured at P7-21 were able to hop on their hind limbs similar to age-matched controls and to swim albeit with a different stroke. Those animals injured at P40-45 appeared to be incapable of normal use of hind limbs even while still in the pouch. Conclusions: Data indicate that the characteristic over-ground locomotion of tammars provides a model in which regrowth of supraspinal connections across the site of injury can be studied in a bipedal animal. Forelimb weight-bearing motion and peripheral sensory input appear not to compensate for lack of hindlimb control, as occurs in quadrupeds. Tammars may be a more appropriate model for studies of therapeutic interventions relevant to humans. PMID- 28721207 TI - Heterocellular cadherin connections: coordinating adhesive cues in homeostasis and cancer. AB - This short insight covers some of the recent topics relevant to the field of cadherin-catenin adhesion in mediating connections between different cell types, so-called heterotypic or heterocellular connections, in both homeostasis and cancer. These scientific discoveries are increasing our understanding of how multiple cells residing in complex tissues can be instructed by cadherin adhesion receptors to regulate tissue architecture and function and how these cadherin mediated heterocellular connections spur tumor growth and the acquisition of malignant characteristics in tumor cells. Overall, the findings that have emerged over the past few years are elucidating the complexity of the functional roles of the cadherin-catenin complexes. Future exciting research lies ahead in order to understand the physical basis of these heterotypic interactions and their influence on the behavior of heterogeneous cellular populations as well as their roles in mediating phenotypic and genetic changes as cells evolve through complex environments during morphogenesis and cancer. PMID- 28721209 TI - Recent advances in preventing stroke recurrence. AB - Recent advances in secondary stroke prevention include new evidence in hypertension, nutrition, anticoagulation, antiplatelet therapy, intracranial stenosis, percutaneous closure of patent foramen ovale, and lipid-lowering therapy. Individualized therapy for hypertension based on phenotyping with plasma renin and aldosterone markedly improves blood pressure control in patients with resistant hypertension. A Mediterranean diet can reduce the risk of stroke by nearly half. The diagnosis and treatment of metabolic vitamin B12 deficiency, and B vitamins to lower homocysteine, can reduce the risk of stroke by approximately 30%. There are problems with clopidogrel that can be overcome by using ticagrelor, and new anticoagulant drugs markedly improve anticoagulation for stroke prevention, particularly in atrial fibrillation. There are pharmacokinetic problems with dabigatran that deserve attention. Intensive medical therapy is better than stenting for intracranial stenosis, and new therapies directed at proprotein convertase subtilisin-kexin type 9 (PCSK9) will revolutionize lipid lowering therapy. In the past, it was estimated that rational therapy could reduce recurrent stroke by about 80%. With recent advances, we should be able to do even better. PMID- 28721211 TI - Microbial metal resistance and metabolism across dynamic landscapes: high throughput environmental microbiology. AB - Multidimensional gradients of inorganic compounds influence microbial activity in diverse pristine and anthropogenically perturbed environments. Here, we suggest that high-throughput cultivation and genetics can be systematically applied to generate quantitative models linking gene function, microbial community activity, and geochemical parameters. Metal resistance determinants represent a uniquely universal set of parameters around which to study and evaluate microbial fitness because they represent a record of the environment in which all microbial life evolved. By cultivating microbial isolates and enrichments in laboratory gradients of inorganic ions, we can generate quantitative predictions of limits on microbial range in the environment, obtain more accurate gene annotations, and identify useful strategies for predicting and engineering the trajectory of natural ecosystems. PMID- 28721210 TI - Current progress and future perspectives in the development of anti-polo-like kinase 1 therapeutic agents. AB - Although significant levels of side effects are often associated with their use, microtubule-directed agents that primarily target fast-growing mitotic cells have been considered to be some of the most effective anti-cancer therapeutics. With the hope of developing new-generation anti-mitotic agents with reduced side effects and enhanced tumor specificity, researchers have targeted various proteins whose functions are critically required for mitotic progression. As one of the highly attractive mitotic targets, polo-like kinase 1 (Plk1) has been the subject of an extensive effort for anti-cancer drug discovery. To date, a variety of anti-Plk1 agents have been developed, and several of them are presently in clinical trials. Here, we will discuss the current status of generating anti-Plk1 agents as well as future strategies for designing and developing more efficacious anti-Plk1 therapeutics. PMID- 28721208 TI - New perspectives on the regulation of type II inflammation in asthma. AB - Asthma is a chronic inflammatory disease of the lungs which has been thought to arise as a result of inappropriately directed T helper type-2 (Th2) immune responses of the lungs to otherwise innocuous inhaled antigens. Current asthma therapeutics are directed towards the amelioration of downstream consequences of type-2 immune responses (i.e. beta-agonists) or broad-spectrum immunosuppression (i.e. corticosteroids). However, few approaches to date have been focused on the primary prevention of immune deviation. Advances in molecular phenotyping reveal heterogeneity within the asthmatic population with multiple endotypes whose varying expression depends on the interplay between numerous environmental factors and the inheritance of a broad range of susceptibility genes. The most common endotype is one described as "type-2-high" (i.e. high levels of interleukin [IL]-13, eosinophilia, and periostin). The identification of multiple endotypes has provided a potential explanation for the observations that therapies directed at typical Th2 cytokines (IL-4, IL-5, and IL-13) and their receptors have often fallen short when they were tested in a diverse group of asthmatic patients without first stratifying based on disease endotype or severity. However, despite the incorporation of endotype-dependent stratification schemes into clinical trial designs, variation in drug responses are still apparent, suggesting that additional genetic/environmental factors may be contributing to the diversity in drug efficacy. Herein, we will review recent advances in our understanding of the complex pathways involved in the initiation and regulation of type-2-mediated immune responses and their modulation by host factors (genetics, metabolic status, and the microbiome). Particular consideration will be given to how this knowledge could pave the way for further refinement of disease endotypes and/or the development of novel therapeutic strategies for the treatment of asthma . PMID- 28721213 TI - Diagnostic approaches and treatment of eosinophilic esophagitis. A review article. AB - Eosinophilic Esophagitis (EoE) is a condition that involves eosinophilic influx into the esophageal epithelium. It affects both children and adults; Adults present with dysphagia whereas children with vague abdominal complaints. The clinical symptoms as well as pathologic features of EoE and gastro esophageal reflux disease (GERD) are similar. Since eosinophilia in the esophagus is a non specific finding, the clinical presentation in conjunction with endoscopic findings and pathology, is crucial in determining a differential diagnosis. Infections such as parasites, allergic phenomenon, Crohn's disease, malignancies, medication, and chemotherapy are all associated with eosinophilia. A primary endoscopic difference to note between EoE and GERD is that EoE often involves long segments of the esophagus, could be patchy or focal and frequently involves the proximal esophagus. GERD, however, typically involves the distal much more frequently than the proximal esophagus. Because of the similarity between them, GERD should be excluded by using high dose proton pump inhibitor (PPI) treatment or through evidence of a normal pH by esophageal testing, prior to treatment with an elimination diet or steroids. Until further research establishes different diagnostic tests and criteria, clinical and pathological response to therapy is considered to be the absolute confirmation of this diagnosis. The following is a more detailed discussion of this entity. PMID- 28721212 TI - Recent advances in the management of ventricular tachyarrhythmias. AB - Ventricular arrhythmias are an important cause of cardiovascular morbidity and mortality, particularly in those with structural heart disease, inherited cardiomyopathies, and channelopathies. The goals of ventricular arrhythmia management include symptom relief, improving quality of life, reducing implantable cardioverter defibrillator shocks, preventing deterioration of left ventricular function, reducing risk of arrhythmic death, and potentially improving overall survival. Guideline-directed medical therapy and implantable cardioverter defibrillator implantation remain the mainstay of therapy to prevent sudden cardiac death in patients with ventricular arrhythmias in the setting of structural heart disease. Recent advances in imaging modalities and commercial availability of genetic testing panels have enhanced our mechanistic understanding of the disease processes and, along with significant progress in catheter-based ablative therapies, have enabled a tailored and more effective management of drug-refractory ventricular arrhythmias. Several gaps in our knowledge remain and require further research. In this article, we review the recent advances in the diagnosis and management of ventricular arrhythmias. PMID- 28721214 TI - Porocarcinoma; presentation and management, a meta-analysis of 453 cases. AB - BACKGROUND: porocarcinoma is a rare sort of skin cancer developing from sweat glands. Its clinical course and management are not well understood. OBJECTIVES: the current meta-analysis is to address the presentation and management of porocarcinoma. DATA SOURCES: Web of Science, PubMed, MEDLINE on OVID and Google scholar were searched for English-language studies published before December 1, 2016. RESULTS: The review of literature revealed 453 cases. From which 222 (49%) cases were male and female were 231 (51%). The mean age was 67.57 years. The mean duration of presentation was 5.57 years ranging from 4 days to 60 years of age. The most common site of affection is the head and neck (39.9%) followed by lower extremity (33.9%). Mass and nodule are the most common modes of presentation. Metastasis occurred at presentation in 110 (31%) cases. The most common organ to which porocarcinoma metastizes is the nearby lymph node (57.7%). CONCLUSIONS: Porocarcinoma is an aggressive skin cancer. Surgery is the main modality of treatment. SYSTEMATIC REVIEW REGISTRATION NUMBER: reviewregistry233. PMID- 28721216 TI - Switch to restoration therapy in a testosterone treated central hypogonadism with erythrocytosis. AB - : We describe a case of severe erythrocytosis caused by testosterone replacement therapy in a 66-year-old man affected with hypogonadotropic hypogonadism (HH) determining osteoporosis, resolved by switching to restoration therapy with clomiphene citrate. The patient complained fatigue, loss of libido and defective erections and a spontaneous vertebral fracture despite bisphosphonate therapy and vitamin D supplementation. The examinations proved isolated HH and he was therefore treated with testosterone gel with regression of specific manifestations but elevated hemoglobin and hematocrit values. Therefore, it was decided to switch to a restoration therapy with clomiphene citrate 25 mg/die, which resulted in the resolution of symptoms without evident side effects. In a couple of months, the patient showed normalization of testosterone levels and increment of testicular volume. Since secondary hypogonadism is the consequence of an insufficient stimulation of the gonads by hypothalamic-pituitary axis, therapeutic approaches aimed to restore endogenous testosterone production should be considered in alternative to testosterone replacement, particularly if side effects intervene. Among these strategies, clomiphene citrate seems to have a high efficacy and safety profile also in the elderly with isolated HH and no evident pituitary lesion. LEARNING POINTS: Hypogonadism should always be assessed in patients with severe loss in BMD and undergo appropriate medical treatment.In hypogonadotropic hypogonadism, more approaches are available other than testosterone replacement therapy alone.In patients with severe late-onset central hypogonadism presenting with erythrocytosis even at low doses of replacement therapy, restoration therapy with clomiphene could prove to be an effective solution, particularly in patients with a reversible disruption of GNRH/gonadotropin functions.Clomiphene citrate increases gonadotropin levels and testicular volume and should therefore be considered in hypogonadal men who wish to remain fertile. PMID- 28721215 TI - Assessment of season-dependent body condition scores in relation to faecal glucocorticoid metabolites in free-ranging Asian elephants. AB - We studied seasonal and annual changes in visual body condition scores (BCSs), and assessed how these scores were related to levels of faecal glucocorticoid metabolites (fGCMs) in free-ranging Asian elephants (Elephas maximus) in the seasonally dry tropical forests of the Mysore and Nilgiri Elephant Reserves in southern India. We assessed the animals' BCS visually on a scale of 1 to 5; where 1 represents a very thin and 5 represents a very fat elephant. To understand the influence of seasonality on BCS, we sampled the population during dry (n = 398) and wet seasons (n = 255) of 2013 and 2015 while, for annual changes in BCS, we sampled nine free-ranging adult females from different family groups that had been repeatedly sighted over seven years. To evaluate the influence of body condition on fGCM, 307 faecal samples were collected from 261 different elephants and were analysed. As a parameter of adrenocortical activity, and thus stress, fGCM was measured (MUg/g) in the ethanol-extracted samples using a group-specific 11-oxoaetiocholanolone EIA (antibody raised against 11-oxoaetiocholanolone-17 CMO:BSA and biotinylated-11-oxoaetiocholanolone as a label). Effect of age and season on BCS in relation to fGCM was also studied. A seasonal shift in BCS was observed as expected, i.e. individuals with low BCS were more frequent during the dry season when compared with the wet season. Concentrations of fGCM were highest in individuals with lowest BCS (BCS 1) and then significantly declined till BCS 3. fGCM levels were almost comparable for BCS 3, 4 and 5. This pattern was more conspicuous in female than in male elephants. Season-dependent BCS, hence, reflect the stress status as measured by fGCM, especially in female Asian elephants. This could be used as an important non-invasive approach to monitor the physiological health of free-ranging elephant populations. PMID- 28721217 TI - An FSH and TSH pituitary adenoma, presenting with precocious puberty and central hyperthyroidism. AB - : A 19-year-old woman with a history of isosexual precocious puberty and bilateral oophorectomy at age 10 years because of giant ovarian cysts, presents with headaches and mild symptoms and signs of hyperthyroidism. Hormonal evaluation revealed elevated FSH and LH levels in the postmenopausal range and free hyperthyroxinemia with an inappropriately normal TSH. Pituitary MRI showed a 2-cm macroadenoma with suprasellar extension. She underwent successful surgical resection of the pituitary tumor, which proved to be composed of two distinct populations of cells, each of them strongly immunoreactive for FSH and TSH, respectively. This mixed adenoma resulted in two different hormonal hypersecretion syndromes: the first one during childhood and consisting of central precocious puberty and ovarian hyperstimulation due to the excessive secretion of biologically active FSH and which was not investigated in detail and 10 years later, central hyperthyroidism due to inappropriate secretion of biologically active TSH. Although infrequent, two cases of isosexual central precocious puberty in girls due to biologically active FSH secreted by a pituitary adenoma have been previously reported in the literature. However, this is the first reported case of a mixed adenoma capable of secreting both, biologically active FSH and TSH. LEARNING POINTS: Although functioning gonadotrophinomas are infrequent, they should be included in the differential diagnosis of isosexual central precocious puberty.Some functioning gonadotrophinomas are mixed adenomas, secreting other biologically active hormones besides FSH, such as TSH.Early recognition and appropriate treatment of these tumors by transsphenoidal surgery is crucial in order to avoid unnecessary therapeutic interventions that may irreversibly compromise gonadal function. PMID- 28721218 TI - Spontaneous reossification of the sella in transsphenoidal reoperation associated with strontium ranelate. AB - : Spontaneous reossification of the sellar floor after transsphenoidal surgery has been rarely reported. Strontium ranelate, a divalent strontium salt, has been shown to increase bone formation, increasing osteoblast activity. We describe an unusual case of a young patient with Cushing's disease who was treated with strontium ranelate for low bone mass who experienced spontaneous sellar reossification after transsphenoidal surgery. A 21-year-old male presented with Cushing's features. His past medical history included delayed puberty diagnosed at 16 years, treated with testosterone for 3 years without further work-up. He was diagnosed with Cushing's disease initially treated with transsphenoidal surgery, which was not curative. The patient did not come to follow-up visits for more than 1 year. He was prescribed strontium ranelate 2 g orally once daily for low bone mass by an outside endocrinologist, which he received for more than 1 year. Two years after first surgery he was reevaluated and persisted with active Cushing's disease. Magnetic resonance image revealed a left 4 mm hypointense mass, with sphenoid sinus occupation by a hyperintense material. At repeated transsphenoidal surgery, sellar bone had a very hard consistency; surgery was complicated and the patient died. Sellar reossification negatively impacted surgery outcomes in this patient. While this entity is possible after transsphenoidal surgery, it remains unclear whether strontium ranelate could have affected sellar ossification. LEARNING POINTS: Delayed puberty can be a manifestation of Cushing's syndrome. A complete history, physical examination and appropriate work-up should be performed before initiating any treatment.Sellar reossification should always be taken into account when considering repeated transsphenoidal surgery. Detailed preoperative evaluation of bony structures by computed tomography ought to be performed in all cases of reoperation.We speculate if strontium ranelate may have affected bone mineralization at the sellar floor. We strongly recommend that indications for prescribing this drug should be carefully followed. PMID- 28721219 TI - Two rare manifestations of primary hyperparathyroidism: paralysis and peptic ulcer bleeding. AB - : Primary hyperparathyroidism revealed by thoracic spine brown tumor and peptic ulcer bleeding is rare. We presented a case of 33-year-old male patient who was admitted with paraplegia. Thoracic spine magnetic resonance imaging (MRI) showed extradural lesion at T4 level. He underwent surgical decompression in T4. According to histopathologic finding and elevated serum parathormone (PTH) and hypercalcemia (total serum calcium 12.1 mg/dL), the diagnosis of brown tumor was down. Ultrasonography of his neck showed a well-defined lesion of 26 * 14 * 6 mm. The day after surgery, he experienced 2 episodes of melena. Bedside upper gastrointestinal endoscopy showed gastric peptic ulcer with visible vessel. Treatment with intragastric local instillation of epinephrine and argon plasma coagulation was done to stop bleeding. After stabilization of the patient, parathyroidectomy was performed. Histologic study showed the parathyroid adenoma without any manifestation of malignancy. At discharge, serum calcium was normal (8.6 mg/dL). On 40th day of discharge, standing and walking status was normal. LEARNING POINTS: Thoracic spine involvement is a very rare presentation of primary hyperparathyroidism.The issue of whether primary hyperparathyroidism increases the risk of peptic ulcer disease remains controversial. However, gastrointestinal involvement has been reported in association with classic severe primary hyperparathyroidism.The treatment of brown tumor varies from case to case. PMID- 28721220 TI - Severe diabetic ketoacidosis complicated by hypocapnic seizure. AB - : In clinical practice, seizures independent of hypoglycemia are observed in patients with type 1 diabetes mellitus (T1DM) more frequently than expected by chance, suggesting a link. However, seizures during management of diabetic ketoacidosis (DKA) have generally been considered a bad prognostic factor, and usually associated with well-known biochemical or neurological complications. We present the case of a 17-year-old girl with known T1DM managed for severe DKA complicated by hypocapnic seizure. We review the literature on this rare occurrence as well as outline other possible differentials to consider when faced with the alarming combination of DKA and seizure. LEARNING POINTS: Seizures during DKA treatment require immediate management as well as evaluation to determine their underlying cause.Their etiology is varied, but a lowered seizure threshold, electrolyte disturbances and serious neurological complications of DKA such as cerebral edema must all be considered.Sudden severe hypocapnia may represent a rare contributor to seizure during the treatment of DKA. PMID- 28721221 TI - Pasireotide: successful treatment of a sparsely granulated tumour in a resistant case of acromegaly. AB - : The granulation pattern of somatotroph adenomas is well known to be associated with differing clinical and biochemical characteristics, and it has been shown that sparsely granulated tumours respond poorly to commonly used somatostatin receptor ligands (SRLs). We report a challenging case of acromegaly with a sparsely granulated tumour resistant to multiple modalities of treatment, ultimately achieving biochemical control with pasireotide. A 26-year-old lady presented with classical features of acromegaly, which was confirmed by an oral glucose tolerance test. Insulin-like growth factor 1 (IGF1) was 1710 ug/L (103 310 ug/L) and mean growth hormone (GH) was >600 U/L. MRI scan showed a 4 cm pituitary macroadenoma with suprasellar extension and right-sided cavernous sinus invasion. She underwent trans-sphenoidal pituitary surgery. Histology displayed moderate amounts of sparsely granular eosinophilic cytoplasm, staining only for GH. Postoperative investigations showed uncontrolled disease (IGF1:1474 ug/L, mean GH:228 U/L) and residual tumour in the cavernous sinus. She received external beam fractionated radiation. Over the years, she received octreotide LAR (up to 30 mg), lanreotide (up to 120 mg) two weekly, cabergoline, pegvisomant and stereotactic radiosurgery to no avail. Only pegvisomant resulted in an element of disease control; however, this had to be stopped due to abnormal liver function tests. Fifteen years after the diagnosis, she was started on pasireotide 40 mg monthly. Within a month, her IGF1 dropped and has remained within the normal range (103-310 ug/L). Pasireotide has been well tolerated, and there has been significant clinical improvement. Somatostatin receptor subtyping revealed a positivity score of two for both sst5 and sst2a subtypes. LEARNING POINTS: Age, size of the tumour, GH levels on presentation, histopathological type and the somatostatin receptor status of the tumour in acromegaly should be reviewed in patients who poorly respond to first-generation somatostatin receptor ligands.Tumours that respond poorly to first-generation somatostatin receptor ligands, especially sparsely granulated somatotroph adenomas, can respond to pasireotide and treatment should be considered early in the management of resistant tumours.Patients with membranous expression of sst5 are likely to be more responsive to pasireotide. PMID- 28721222 TI - Serological evidence of Francisella tularensis in febrile patients seeking treatment at remote hospitals, northeastern Kenya, 2014-2015. AB - Tularaemia is a highly contagious infectious zoonosis caused by the bacterial agent Francisella tularensis. The aim of this study was to investigate the presence of antibodies to F. tularensis in febrile patients in northeastern Kenya. During 2014-2015, 730 patients were screened for anti-F. tularensis antibodies using a combination of ELISA and Western blot. Twenty-seven (3.7%) individuals were positive for F. tularensis. Tularaemia was not suspected by the treating clinicians in any of them. Our results suggest that tularaemia may be present in Kenya but remain unreported, and emphasizes the need for local clinicians to broaden their diagnostic repertoire when evaluating patients with undifferentiated febrile illness. PMID- 28721223 TI - Atrial fibrillation in a preterm newborn with structurally normal heart. AB - Atrial fibrillation (AF) is a really uncommon arrhythmia in newborns. Here, we report the case of a 1-day-old infant who was recovered in Neonatal Intensive Care Unit for a twin-to-twin transfusion. The appearance of an unexpected AF was registered at his continuous electrocardiographic monitoring. Both chest X-ray and echocardiographic examination revealed the anomalous insertion of the tip of a central venous catheter (CVC) into the heart ('umbilical artery -> inferior vena cava -> right atrium -> patent foramen ovale -> left atrium'). AF ceased as soon as the CVC was extracted from the heart. The mechanical irritation of both atria caused by the malposition of the CVC might be the underlying mechanism responsible for the triggering of AF in this unique case report. PMID- 28721224 TI - Erratum: Intense, flu-like symptoms in women using menstrual devices: always think of staphylococcal Toxic Shock Syndrome. AB - [This corrects the article DOI: 10.1093/omcr/omx020.]. PMID- 28721225 TI - The technological side of the microbiome. PMID- 28721226 TI - Chartering new waters of biofilm ecology and evolution. PMID- 28721227 TI - A personal perspective on the nature of npj Biofilms and Microbiomes. PMID- 28721228 TI - Introducing npj Biofilms and Microbiomes. PMID- 28721229 TI - Microbial biofilms and the human intestinal microbiome. AB - Since early life we are colonised by a myriad of microbes that make up our microbiome. This colonisation process starts at birth or even before, when the virtually sterile baby encounters new microbial environments. It is likely that at this time or at later moments in life, microbial communities are met that have high-level structures with a temporal and spatial organisation, termed biofilms. This perspective will focus on these biofilms and the microbes in the intestinal tract as these are the most numerous in the human body, are found in luminal and mucosal locations, and have a great impact on human health and disease. PMID- 28721230 TI - Community quorum sensing signalling and quenching: microbial granular biofilm assembly. AB - BACKGROUND: Recent reports exploring the role of gradients of quorum sensing (QS) signals in functional activated sludge have raised the question of whether shared systems of signalling synthesis and degradation, or quorum quenching (QQ), across the community inform of the means by which QS biology regulate floccular and granular biofilm assembly. AIMS: In this study, we aimed to explore the species origin and interactive role of QS and QQ activities in such highly diverse microbial biofilm communities. METHODS: Here, such aims were addressed systematically by a comprehensive multi-pronged RNA-sequencing, microbiological and analytical chemistry experimental approach, using two related but independently evolved floccular and granular sludge communities. RESULTS: Our data revealed a distinct difference between the QS and QQ potentials of the two communities, with different species largely displaying either QS or QQ functions. The floccular sludge community showed a high rate of QQ activity, and this rate was dependent on the acyl chain length demonstrating specificity of degradation. When the floccular biomass was transformed into the granular sludge, the QQ activity of the community was reduced by 30%. N-acyl homoserine lactones with four to eight carbons on the acyl chain accumulated at the granular stage, and their concentrations were at least threefold higher than those of the floccular stage. These findings corroborated meta-community analysis where a major shift in the dominant species from potential signal quenchers to producers was observed during the transition from flocs to granules, indicating the role of species composition and associated signalling activities in coordinating community behaviours. CONCLUSIONS: This study suggests that QQ has an important function in regulating community level QS signalling, and provides a mechanistic insight into the role of QS biology in complex community assembly. PMID- 28721231 TI - Comparative integrated omics: identification of key functionalities in microbial community-wide metabolic networks. AB - BACKGROUND: Mixed microbial communities underpin important biotechnological processes such as biological wastewater treatment (BWWT). A detailed knowledge of community structure and function relationships is essential for ultimately driving these systems towards desired outcomes, e.g., the enrichment in organisms capable of accumulating valuable resources during BWWT. METHODS: A comparative integrated omic analysis including metagenomics, metatranscriptomics and metaproteomics was carried out to elucidate functional differences between seasonally distinct oleaginous mixed microbial communities (OMMCs) sampled from an anoxic BWWT tank. A computational framework for the reconstruction of community-wide metabolic networks from multi-omic data was developed. These provide an overview of the functional capabilities by incorporating gene copy, transcript and protein abundances. To identify functional genes, which have a disproportionately important role in community function, we define a high relative gene expression and a high betweenness centrality relative to node degree as gene-centric and network topological features, respectively. RESULTS: Genes exhibiting high expression relative to gene copy abundance include genes involved in glycerolipid metabolism, particularly triacylglycerol lipase, encoded by known lipid accumulating populations, e.g., CandidatusMicrothrix parvicella. Genes with a high relative gene expression and topologically important positions in the network include genes involved in nitrogen metabolism and fatty acid biosynthesis, encoded by Nitrosomonas spp. and Rhodococcus spp. Such genes may be regarded as 'keystone genes' as they are likely to be encoded by keystone species. CONCLUSION: The linking of key functionalities to community members through integrated omics opens up exciting possibilities for devising prediction and control strategies for microbial communities in the future. PMID- 28721232 TI - Estimation of a biofilm-specific reaction rate: kinetics of bacterial urea hydrolysis in a biofilm. AB - BACKGROUND/OBJECTIVES: Biofilms and specifically urea-hydrolysing biofilms are of interest to the medical community (for example, urinary tract infections), scientists and engineers (for example, microbially induced carbonate precipitation). To appropriately model these systems, biofilm-specific reaction rates are required. A simple method for determining biofilm-specific reaction rates is described and applied to a urea-hydrolysing biofilm. METHODS: Biofilms were grown in small silicon tubes and influent and effluent urea concentrations were determined. Immediately after sampling, the tubes were thin sectioned to estimate the biofilm thickness profile along the length of the tube. Urea concentration and biofilm thickness data were used to construct an inverse model for the estimation of the urea hydrolysis rate. RESULTS/CONCLUSIONS: It was found that urea hydrolysis in Escherichia coli MJK2 biofilms is well approximated by first-order kinetics between urea concentrations of 0.003 and 0.221 mol/l (0.186 and 13.3 g/l). The first-order rate coefficient (k1) was estimated to be 23.2+/ 6.2 h-1. It was also determined that advection dominated the experimental system rather than diffusion, and that urea hydrolysis within the biofilms was not limited by diffusive transport. Beyond the specific urea-hydrolysing biofilm discussed in this work, the method has the potential for wide application in cases where biofilm-specific rates must be determined. PMID- 28721233 TI - Effect of electrical energy on the efficacy of biofilm treatment using the bioelectric effect. AB - BACKGROUND/OBJECTIVES: The use of electric fields in combination with small doses of antibiotics for enhanced treatment of biofilms is termed the 'bioelectric effect' (BE). Different mechanisms of action for the AC and DC fields have been reported in the literature over the last two decades. In this work, we conduct the first study on the correlation between the electrical energy and the treatment efficacy of the bioelectric effect on Escherichia coli K-12 W3110 biofilms. METHODS: A thorough study was performed through the application of alternating (AC), direct (DC) and superimposed (SP) potentials of different amplitudes on mature E. coli biofilms. The electric fields were applied in combination with the antibiotic gentamicin (10 MUg/ml) over a course of 24 h, after the biofilms had matured for 24 h. The biofilms were analysed using the crystal violet assay, the colony-forming unit method and fluorescence microscopy. RESULTS: Results show that there is no statistical difference in treatment efficacy between the DC-, AC- and SP-based BE treatment of equivalent energies (analysis of variance (ANOVA) P>0.05) for voltages <1 V. We also demonstrate that the efficacy of the BE treatment as measured by the crystal violet staining method and colony-forming unit assay is proportional to the electrical energy applied (ANOVA P<0.05). We further verify that the treatment efficacy varies linearly with the energy of the BE treatment (r2 =0.984). Our results thus suggest that the energy of the electrical signal is the primary factor in determining the efficacy of the BE treatment, at potentials less than the media electrolysis voltage. CONCLUSIONS: Our results demonstrate that the energy of the electrical signal, and not the type of electrical signal (AC or DC or SP), is the key to determine the efficacy of the BE treatment. We anticipate that this observation will pave the way for further understanding of the mechanism of action of the BE treatment method and may open new doors to the use of electric fields in the treatment of bacterial biofilms. PMID- 28721234 TI - Functional biomarkers for chronic periodontitis and insights into the roles of Prevotella nigrescens and Fusobacterium nucleatum; a metatranscriptome analysis. AB - BACKGROUND/OBJECTIVES: Periodontitis is the most prevalent inflammatory disease worldwide and is caused by a dysbiotic subgingival biofilm. Here we used metatranscriptomics to determine the functional shift from health to periodontitis, the response of individual species to dysbiosis and to discover biomarkers. METHODS: Sixteen individuals were studied, from which six were diagnosed with chronic periodontitis. Illumina sequencing of the total messenger RNA (mRNA) yielded ~42 million reads per sample. A total of 324 human oral taxon phylotypes and 366,055 open reading frames from the HOMD database reference genomes were detected. RESULTS: The transcriptionally active community shifted from Bacilli and Actinobacteria in health to Bacteroidia, Deltaproteobacteria, Spirochaetes and Synergistetes in periodontitis. Clusters of orthologous groups (COGs) related to carbohydrate transport and catabolism dominated in health, whereas protein degradation and amino acid catabolism dominated in disease. The LEfSe, random forest and support vector machine methods were applied to the 2,000 most highly expressed genes and discovered the three best functional biomarkers, namely haem binding protein HmuY from Porphyromonas gingivalis, flagellar filament core protein FlaB3 from Treponema denticola, and repeat protein of unknown function from Filifactor alocis. They predicted the diagnosis correctly for 14 from 16 individuals, and when applied to an independent study misclassified one out of six subjects only. Prevotella nigrescens shifted from commensalism to virulence by upregulating the expression of metalloproteases and the haem transporter. Expression of genes for the synthesis of the cytotoxic short-chain fatty acid butyrate was observed by Fusobacterium nucleatum under all conditions. Four additional species contributed to butyrate synthesis in periodontitis and they used an additional pathway. CONCLUSION: Gene biomarkers of periodontitis are highly predictive. The pro-inflammatory role of F. nucelatum is not related to butyrate synthesis. PMID- 28721235 TI - Enhancement in hydrogen evolution using Au-TiO2 hollow spheres with microbial devices modified with conjugated oligoelectrolytes. AB - OBJECTIVE: Although photoelectrochemical (PEC) water splitting heralds the emergence of the hydrogen economy, the need for external bias and low efficiency stymies the widespread application of this technology. By coupling water splitting (in a PEC cell) to a microbial fuel cell (MFC) using Escherichia coli as the biocatalyst, this work aims to successfully demonstrate a sustainable hybrid PEC-MFC platform functioning solely by biocatalysis and solar energy, at zero bias. Through further chemical modification of the photo-anode (in the PEC cell) and biofilm (in the MFC), the performance of the hybrid system is expected to improve in terms of the photocurrent generated and hydrogen evolved. METHODS: The hybrid system constitutes the interconnected PEC cell with the MFC. Both PEC cell and MFC are typical two-chambered systems housing the anode and cathode. Au TiO2 hollow spheres and conjugated oligoelectrolytes were synthesised chemically and introduced to the PEC cell and MFC, respectively. Hydrogen evolution measurements were performed in triplicates. RESULTS: The hybrid PEC-MFC platform generated a photocurrent density of 0.35 mA/cm2 (~70* enhancement) as compared with the stand-alone P25 standard PEC cell (0.005 mA/cm2) under one-sun illumination (100 mW/cm2) at zero bias (0 V vs. Pt). This increase in photocurrent density was accompanied by continuous H2 production. No H2 was observed in the P25 standard PEC cell whereas H2 evolution rate was ~3.4 MUmol/h in the hybrid system. The remarkable performance is attributed to the chemical modification of E. coli through the incorporation of novel conjugated oligoelectrolytes in the MFC as well as the lower recombination rate and higher photoabsorption capabilities in the Au-TiO2 hollow spheres electrode. CONCLUSIONS: The combined strategy of photo-anode modification in PEC cells and chemically modified MFCs shows great promise for future exploitation of such synergistic effects between MFCs and semiconductor-based PEC water splitting. PMID- 28721236 TI - Bacterial attachment and biofilm formation on surfaces are reduced by small diameter nanoscale pores: how small is small enough? AB - BACKGROUND/OBJECTIVES: Prevention of biofilm formation by bacteria is of critical importance to areas that directly affect human health and life including medicine, dentistry, food processing and water treatment. This work showcases an effective and affordable solution for reducing attachment and biofilm formation by several pathogenic bacteria commonly associated with foodborne illnesses and medical infections. METHODS: Our approach exploits anodisation to create alumina surfaces with cylindrical nanopores with diameters ranging from 15 to 100 nm, perpendicular to the surface. The anodic surfaces were evaluated for attachment by Escherichia coli, Listeria monocytogenes, Staphylococcus aureus and Staphylococcus epidermidis. Cell-surface interaction forces were calculated and related to attachment. RESULTS: We found that anodic alumina surfaces with pore diameters of 15 and 25 nm were able to effectively minimise bacterial attachment or biofilm formation by all the microorganisms tested. Using a predictive physicochemical approach on the basis of the extended Derjaguin and Landau, Verwey and Overbeek (XDLVO) theory, we attributed the observed effects largely to the repulsive forces, primarily electrostatic and acid-base forces, which were greatly enhanced by the large surface area originating from the high density, small-diameter pores. We also demonstrate how this predictive approach could be used to optimise different elements of surface topography, particularly pore diameter and density, for further enhancing the observed bacteria-repelling effects. CONCLUSIONS: We demonstrate that anodic nanoporous surfaces can effectively reduce bacterial attachment. These findings are expected to have immediate, far-reaching implications and commercial applications, primarily in health care and the food industry. PMID- 28721237 TI - Micromanagement in the gut: microenvironmental factors govern colon mucosal biofilm structure and functionality. AB - The human gut microbiome provides us with functional features that we did not have to evolve ourselves and can be viewed as a structured microbial community that operates like a microbial organ within the human host. A minor but important part of this microbiome is the ability to colonise and thrive within the mucous layer that covers the colon epithelium. These mucosal microbes intimately interact with the intestinal tissue and seem to be important modulators of human health. Embedded in the host-secreted mucous matrix, they form a 'mucosal biofilm' with a distinct composition and functionality. In this review, we provide evidence that six specific (micro)environmental factors near the colon mucosa shape and determine mucosal biofilm formation and stability, that is, (1) mucous rigidity, (2) gradients of fluid shear, (3) radial oxygen gradients, (4) secretions of host defense molecules, (5) the presence of a rich but challenging nutrient platform and (6) the presence of niches at the colon epithelial surface. In addition, it appears that microbes actively participate in shaping their mucosal environment. Current insights into the interaction between mucosal microbes and their environment are rather limited, and many questions regarding the contribution of mucosal biofilm functionality and stability to human health remain to be answered. Yet, given the higher potency of mucosal microbes than their luminal counterparts to interact with the host, new insights can accelerate the development of novel disease-preventive or therapeutic strategies. PMID- 28721238 TI - Not so simple, not so subtle: the interspecies competition between Bacillus simplex and Bacillus subtilis and its impact on the evolution of biofilms. AB - Bacillus subtilis biofilms have a fundamental role in shaping the soil ecosystem. During this process, they unavoidably interact with neighbour bacterial species. We studied the interspecies interactions between biofilms of the soil-residing bacteria B. subtilis and related Bacillus species. We found that proximity between the biofilms triggered recruitment of motile B. subtilis cells, which engulfed the competing Bacillus simplex colony. Upon interaction, B. subtilis secreted surfactin and cannibalism toxins, at concentrations that were inert to B. subtilis itself, which eliminated the B. simplex colony, as well as colonies of Bacillus toyonensis. Surfactin toxicity was correlated with the presence of short carbon-tail length isomers, and synergistic with the cannibalism toxins. Importantly, during biofilm development and interspecies interactions a subpopulation in B. subtilis biofilm lost its native plasmid, leading to increased virulence against the competing Bacillus species. Overall, these findings indicate that genetic programs and traits that have little effect on biofilm development when each species is grown in isolation have a dramatic impact when different bacterial species interact. PMID- 28721239 TI - Bacteria differently deploy type-IV pili on surfaces to adapt to nutrient availability. AB - The structure of bacterial biofilms depends on environmental conditions, such as availability of nutrients, during biofilm formation. In turn, variations in biofilm structure in part reflect differences in bacterial motility during early biofilm formation. Pseudomonas aeruginosa deprived of nutrients remain dispersed on a surface, whereas cells supplemented with additional nutrients cluster and form microcolonies. At the single-cell scale, how bacteria modify their motility to favour distinct life cycle outcomes remains poorly understood. High-throughput algorithms were used to track thousands of P. aeruginosa moving using type-IV pili (TFP) on surfaces in varying nutrient conditions and hence identify four distinct motility types. A minimal stochastic model was used to reproduce the TFP driven motility types. We report that P. aeruginosa cells differently deploy TFP to alter the distribution of motility types under different nutrient conditions. Bacteria preferentially crawl unidirectionally under nutrient-limited conditions, but preferentially stall under nutrient-supplemented conditions. Motility types correlate with subcellular localisation of FimX, a protein required for TFP assembly and implicated in environmental response. The subcellular distribution of FimX is asymmetric for unidirectional crawling, consistent with TFP assembled primarily at the leading pole, whereas for non-translational types FimX expression is symmetric or non-existent. These results are consistent with a minimal stochastic model that reproduces the motility types from the subcellular average concentration and asymmetry of FimX. These findings reveal that P. aeruginosa deploy TFP symmetrically or asymmetrically to modulate motility behaviours in different nutrient conditions and thereby form biofilms only where nutrients are sufficient, which greatly enhances their competitive capacity in diverse environments. PMID- 28721240 TI - Spatio-temporal assembly of functional mineral scaffolds within microbial biofilms. AB - Historically, multicellular bacterial communities, known as biofilms, have been thought to be held together solely by a self-produced extracellular matrix. Our study identified a novel mechanism maintaining Bacillus subtilis and Mycobacterium smegmatis biofilms-active production of calcite minerals. We studied, for the first time, the effects of mutants defective in biomineralization and calcite formation on biofilm development, resilience and morphology. We demonstrated that an intrinsic rise in carbon dioxide levels within the biofilm is a strong trigger for the initiation of calcite-dependent patterning. The calcite-dependent patterns provide resistance to environmental insults and increase the overall fitness of the microbial community. Our results suggest that it is highly feasible that the formation of mineral scaffolds plays a cardinal and conserved role in bacterial multicellularity. PMID- 28721241 TI - Degradation intermediates of polyhydroxy butyrate inhibits phenotypic expression of virulence factors and biofilm formation in luminescent Vibrio sp. PUGSK8. AB - Luminescent vibrios are ubiquitous in the marine environment and are the causative agents of vibriosis and mass mortality in many aquatic animals. In aquatic environments, treatments cannot be limited to the diseased population alone, therefore treatment of the entire aquatic system is the only possible approach. Thus, the use of antibiotics to treat part of the infected animals requires a dose based on the entire biomass, which results in the treatment of uninfected animals as well as non-target normal microbial flora. A treatment method based on anti-virulence or quorum quenching has recently been proposed as an effective treatment strategy for aquatic animals. Polyhydroxy butyrates (PHB) are bacterial storage molecules, which accumulate in cells under nutritional stress. The degradation of PHB releases short-chain beta-hydroxy butyric acid, which may act as anti-infective molecule. To date, there is very limited information on the potential anti-infective and anti-virulence mechanisms involving PHB. In this study, we aim to examine the effect of PHB on inhibition of the virulence cascade of Vibrio such as biofilm formation, luminescence, motility behaviour, haemolysin and quorum sensing. A luminescent Vibrio PUGSK8, tentatively identified as Vibrio campbellii PUGSK8 was tested in vitro for production of extracellular virulence factors and then established as a potential shrimp pathogen based on in vivo challenge experiments. The ability of Vibrio PUGSK8 to form biofilms and the effect of PHB on biofilm formation was tested in a 96-well microtitre-plate assay system. The motility behaviour of Vibrio PUGSK8 was evaluated using twitching, swimming and swarming plate assays. Reporter strains such as Chromobacterium violaceum CV026 and Agrobacterium tumefaciens were used to detect quorum-sensing molecules. Gas chromatography-mass spectrometry spectral analysis was performed to elucidate the fragmentation pattern and structure of N-hexanoyl homoserine lactone. PHB depolymerase activity in Vibrio PUGSK8 was quantified as the amount of the enzyme solution to hydrolyse 1 MUg of PHB per min. An in vivo challenge experiment was performed using a gnotobiotic Artemia assay. Of the 27 isolates tested, the Vibrio PUGSK8 strain was selected for target-specific assays based on the high intensity of luminescence and production of virulence factors. The virulence cascade detected in Vibrio PUGSK8 include luminescence, motility behaviour, biofilm formation, quorum sensing and haemolysin production. Thus inhibition/degradation of the virulence cascade would be an effective approach to contain Vibrio infections in aquatic animals. In this report, we demonstrate that the degradation intermediate of PHB effectively inhibits biofilm formation, luminescence, motility behaviour, haemolysin production and the N-acyl-homoserine lactone (AHL)-mediated quorum sensing pathway in PUGSK8. Interestingly, the growth of Vibrio PUGSK8 remains unaffected in the presence of PHB, with PHB degradation being detected in the media. PHB depolymerase activity in Vibrio PUGSK8 results in the release of degradation intermediates include a short-chain beta-hydroxy butyric acid, which inhibits the virulence cascade in Vibrio PUGSK8. Thus, a molecule that targets quorum sensing and the virulence cascade and which is species/strain-specific could prove to be an effective alternative to antimicrobial agents to control the pathogenesis of Vibrio, and thereby help to contain Vibrio outbreaks in aquatic systems. PMID- 28721243 TI - A perspective on 16S rRNA operational taxonomic unit clustering using sequence similarity. AB - The standard pipeline for 16S amplicon analysis starts by clustering sequences within a percent sequence similarity threshold (typically 97%) into 'Operational Taxonomic Units' (OTUs). From each OTU, a single sequence is selected as a representative. This representative sequence is annotated, and that annotation is applied to all remaining sequences within that OTU. This perspective paper will discuss the known shortcomings of this standard approach using results obtained from the Human Microbiome Project. In particular, we will show that the traditional approach of using pairwise sequence alignments to compute sequence similarity can result in poorly clustered OTUs. As OTUs are typically annotated based upon a single representative sequence, poorly clustered OTUs can have significant impact on downstream analyses. These results suggest that we need to move beyond simple clustering techniques for 16S analysis. PMID- 28721242 TI - The gut microbiota: a major player in the toxicity of environmental pollutants? AB - Exposure to environmental chemicals has been linked to various health disorders, including obesity, type 2 diabetes, cancer and dysregulation of the immune and reproductive systems, whereas the gastrointestinal microbiota critically contributes to a variety of host metabolic and immune functions. We aimed to evaluate the bidirectional relationship between gut bacteria and environmental pollutants and to assess the toxicological relevance of the bacteria-xenobiotic interplay for the host. We examined studies using isolated bacteria, faecal or caecal suspensions-germ-free or antibiotic-treated animals-as well as animals reassociated with a microbiota exposed to environmental chemicals. The literature indicates that gut microbes have an extensive capacity to metabolise environmental chemicals that can be classified in five core enzymatic families (azoreductases, nitroreductases, beta-glucuronidases, sulfatases and beta-lyases) unequivocally involved in the metabolism of >30 environmental contaminants. There is clear evidence that bacteria-dependent metabolism of pollutants modulates the toxicity for the host. Conversely, environmental contaminants from various chemical families have been shown to alter the composition and/or the metabolic activity of the gastrointestinal bacteria, which may be an important factor contributing to shape an individual's microbiotype. The physiological consequences of these alterations have not been studied in details but pollutant induced alterations of the gut bacteria are likely to contribute to their toxicity. In conclusion, there is a body of evidence suggesting that gut microbiota are a major, yet underestimated element that must be considered to fully evaluate the toxicity of environmental contaminants. PMID- 28721244 TI - Tobramycin and bicarbonate synergise to kill planktonic Pseudomonas aeruginosa, but antagonise to promote biofilm survival. AB - Increasing antibiotic resistance and the declining rate at which new antibiotics come into use create a need to increase the efficacy of existing antibiotics. The aminoglycoside tobramycin is standard-of-care for many types of Pseudomonas aeruginosa infections, including those in the lungs of cystic fibrosis (CF) patients. P. aeruginosa is a nosocomial and opportunistic pathogen that, in planktonic form, causes acute infections and, in biofilm form, causes chronic infections. Inhaled bicarbonate has recently been proposed as a therapy to improve antimicrobial properties of the CF airway surface liquid and viscosity of CF mucus. Here we measure the effect of combining tobramycin and bicarbonate against P. aeruginosa, both lab strains and CF clinical isolates. Bicarbonate synergises with tobramycin to enhance killing of planktonic bacteria. In contrast, bicarbonate antagonises with tobramycin to promote better biofilm growth. This suggests caution when evaluating bicarbonate as a therapy for CF lungs infected with P. aeruginosa biofilms. We analyse tobramycin and bicarbonate interactions using an interpolated surface methodology to measure the dose response function. These surfaces allow more accurate estimation of combinations yielding synergy and antagonism than do standard isobolograms. By incorporating predictions based on Loewe additivity theory, we can consolidate information on a wide range of combinations that produce a complex dose-response surface, into a single number that measures the net effect. This tool thus allows rapid initial estimation of the potential benefit or harm of a therapeutic combination. Software code is freely made available as a resource for the community. PMID- 28721245 TI - Biofilms on glacial surfaces: hotspots for biological activity. AB - Glaciers are important constituents in the Earth's hydrological and carbon cycles, with predicted warming leading to increases in glacial melt and the transport of nutrients to adjacent and downstream aquatic ecosystems. Microbial activity on glacial surfaces has been linked to the biological darkening of cryoconite particles, affecting albedo and increased melt. This phenomenon, however, has only been demonstrated for alpine glaciers and the Greenland Ice Sheet, excluding Antarctica. In this study, we show via confocal laser scanning microscopy that microbial communities on glacial surfaces in Antarctica persist in biofilms. Overall, ~35% of the cryoconite sediment surfaces were covered by biofilm. Nanoscale scale secondary ion mass spectrometry measured significant enrichment of 13C and 15N above background in both Bacteroidetes and filamentous cyanobacteria (i.e., Oscillatoria) when incubated in the presence of 13C-NaHCO3 and 15NH4. This transfer of newly synthesised organic compounds was dependent on the distance of heterotrophic Bacteroidetes from filamentous Oscillatoria. We conclude that the spatial organisation within these biofilms promotes efficient transfer and cycling of nutrients. Further, these results support the hypothesis that biofilm formation leads to the accumulation of organic matter on cryoconite minerals, which could influence the surface albedo of glaciers. PMID- 28721246 TI - Oral treatment with Eubacterium hallii improves insulin sensitivity in db/db mice. AB - An altered intestinal microbiota composition is associated with insulin resistance and type 2 diabetes mellitus. We previously identified increased intestinal levels of Eubacterium hallii, an anaerobic bacterium belonging to the butyrate-producing Lachnospiraceae family, in metabolic syndrome subjects who received a faecal transplant from a lean donor. To further assess the effects of E. hallii on insulin sensitivity, we orally treated obese and diabetic db/db mice with alive E. hallii and glycerol or heat-inactive E. hallii as control. Insulin tolerance tests and hyperinsulinemic-euglycemic clamp experiments revealed that alive E. hallii treatment improved insulin sensitivity compared control treatment. In addition, E. hallii treatment increased energy expenditure in db/db mice. Active E. hallii treatment was found to increase faecal butyrate concentrations and to modify bile acid metabolism compared with heat-inactivated controls. Our data suggest that E. hallii administration potentially alters the function of the intestinal microbiome and that microbial metabolites may contribute to the improved metabolic phenotype. PMID- 28721247 TI - Piggyback-the-Winner in host-associated microbial communities. AB - Phages can exploit their bacterial hosts by lytic infection, when many viral particles are released at cell lysis, or by lysogeny, when phages integrate into the host's genome. We recently proposed a new dynamic model of bacteria-phage interactions in which lysogeny predominates at high microbial abundance and growth rates. This model, named Piggyback-the-Winner (PtW), contrasts to current accepted models on the frequency of lysis and lysogeny and predicts that phages integrate into their hosts' genomes as prophages when microbial abundances and growth rates are high. According to PtW, switching to the temperate life cycle reduces phage predation control on bacterial abundance and confers superinfection exclusion, preventing that a closely-related phage infects the same bacterial cell. Here we examine how PtW is important for metazoans. Specifically, we postulate that PtW and the recently described bacteriophage adherence to mucus (BAM) model are strongly interrelated and have an important role in the development of the microbiome. In BAM, phage produced by the microbiome attach to mucins and protect underlying epithelial cells from invading bacteria. Spatial structuring of the mucus creates a gradient of phage replication strategies consistent with PtW. We predict that lysogeny is favored at the top mucosal layer and lytic predation predominates in the bacteria-sparse intermediary layers. The lysogeny confers competitive advantage to commensals against niche invasion and the lytic infection eliminates potential pathogens from deeper mucus layers. PMID- 28721248 TI - Reaction-diffusion theory explains hypoxia and heterogeneous growth within microbial biofilms associated with chronic infections. AB - Reaction-diffusion models were applied to gain insight into the aspects of biofilm infection and persistence by comparing mathematical simulations with the experimental data from varied bacterial biofilms. These comparisons, including three in vitro systems and two clinical investigations of specimens examined ex vivo, underscored the central importance of concentration gradients of metabolic substrates and the resulting physiological heterogeneity of the microorganisms. Relatively simple one-dimensional and two-dimensional (2D) models captured the: (1) experimentally determined distribution of specific growth rates measured in Pseudomonas aeruginosa cells within sputum from cystic fibrosis patients; (2) pattern of relative growth rate within aggregates of streptococcal biofilm harboured in an endocarditis vegetation; (3) incomplete penetration of oxygen into a Pseudomonas aeruginosa biofilm under conditions of exposure to ambient air and also pure oxygen; (4) localisation of anabolic activity around the periphery of P. aeruginosa cell clusters formed in a flow cell and attribution of this pattern to iron limitation; (5) very low specific growth rates, as small as 0.025 h-1, in the interior of cell clusters within a Klebsiella pneumoniae biofilm in a complex 2D domain of variable cell density. PMID- 28721249 TI - Bidirectional communication between the Aryl hydrocarbon Receptor (AhR) and the microbiome tunes host metabolism. AB - The ligand-induced transcription factor, aryl hydrocarbon receptor (AhR) is known for its capacity to tune adaptive immunity and xenobiotic metabolism-biological properties subject to regulation by the indigenous microbiome. The objective of this study was to probe the postulated microbiome-AhR crosstalk and whether such an axis could influence metabolic homeostasis of the host. Utilising a systems biology approach combining in-depth 1H-NMR-based metabonomics (plasma, liver and skeletal muscle) with microbiome profiling (small intestine, colon and faeces) of AhR knockout (AhR-/-) and wild-type (AhR+/+) mice, we assessed AhR function in host metabolism. Microbiome metabolites such as short-chain fatty acids were found to regulate AhR and its target genes in liver and intestine. The AhR signalling pathway, in turn, was able to influence microbiome composition in the small intestine as evident from microbiota profiling of the AhR+/+ and AhR-/- mice fed with diet enriched with a specific AhR ligand or diet depleted of any known AhR ligands. The AhR-/- mice also displayed increased levels of corticosterol and alanine in serum. In addition, activation of gluconeogenic genes in the AhR-/- mice was indicative of on-going metabolic stress. Reduced levels of ketone bodies and reduced expression of genes involved in fatty acid metabolism in the liver further underscored this observation. Interestingly, exposing AhR-/- mice to a high-fat diet showed resilience to glucose intolerance. Our data suggest the existence of a bidirectional AhR-microbiome axis, which influences host metabolic pathways. PMID- 28721250 TI - Arabinoxylans, inulin and Lactobacillus reuteri 1063 repress the adherent invasive Escherichia coli from mucus in a mucosa-comprising gut model. AB - The microbiota that colonises the intestinal mucus may particularly affect human health given its proximity to the epithelium. For instance, the presence of the adherent-invasive Escherichia coli (AIEC) in this mucosal microbiota has been correlated with Crohn's disease. Using short-term screening assays and a novel long-term dynamic gut model, which comprises a simulated mucosal environment (M SHIME), we investigated how (potential) pro- and prebiotics may repress colonisation of AIEC from mucus. Despite that during the short-term screening assays, some of the investigated Lactobacillus strains adhered strongly to mucins, none of them competed with AIEC for mucin-adhesion. In contrast, AIEC survival and growth during co-culture batch incubations was decreased by Lactobacillus rhamnosus GG and L. reuteri 1063, which correlated with (undissociated) lactic acid and reuterin levels. Regarding the prebiotics, long chain arabinoxylans (LC-AX) lowered the initial mucin-adhesion of AIEC, while both inulin (IN) and galacto-oligosaccharides (GOS) limited AIEC survival and growth during batch incubations. L. reuteri 1063, LC-AX and IN were thus retained for a long-term study with the M-SHIME. All treatments repressed AIEC from mucus without affecting AIEC numbers in the luminal content. As a possible explanation, L. reuteri 1063 treatment increased lactobacilli levels in mucus, while LC-AX and IN additionally increased mucosal bifidobacteria levels, thus leading to antimicrobial effects against AIEC in mucus. Overall, this study shows that pro- and prebiotics can beneficially modulate the in vitro mucosal microbiota, thus limiting occurrence of opportunistic pathogens among those mucosal microbes which may directly interact with the host given their proximity to the epithelium. PMID- 28721251 TI - Temporal dynamics of bacterial microbiota in the human oral cavity determined using an in situ model of dental biofilms. AB - Numerous studies on oral biofilms have been performed in vitro, although it is difficult to mimic the oral environment. Here we used an in situ model to conduct a quantitative analysis and comprehensive identification of bacterial communities over time by performing deep sequencing of 16S rRNA genes. We show here that the number of viable bacteria in supragingival biofilms increased in two steps. Using scanning and transmission electron microscopy, as well as confocal laser scanning microscopy, we detected gram-positive cocci during the first 8 h. The biofilm was subsequently covered with a thick matrix-like structure composed of different bacterial morphotypes that diversified as the number of bacteria increased. Streptococcus accounted for >20% of the population until 16 h, and obligate anaerobes such as Fusobacterium, Prevotella and Porphyromonas predominated after 48 h, and this increase was statistically significant after 96 h (P<0.05). Together, our data demonstrate that an initial population of facultative anaerobic bacteria was replaced with a population of gram-negative anaerobic bacteria during oral biofilm formation. This study, therefore, contributes to a comprehensive understanding of the composition of the bacterial microbiota involved in the health of the human oral cavity. PMID- 28721252 TI - Biofilm development of an opportunistic model bacterium analysed at high spatiotemporal resolution in the framework of a precise flow cell. AB - Life of bacteria is governed by the physical dimensions of life in microscales, which is dominated by fast diffusion and flow at low Reynolds numbers. Microbial biofilms are structurally and functionally heterogeneous and their development is suggested to be interactively related to their microenvironments. In this study, we were guided by the challenging requirements of precise tools and engineered procedures to achieve reproducible experiments at high spatial and temporal resolutions. Here, we developed a robust precise engineering approach allowing for the quantification of real-time, high-content imaging of biofilm behaviour under well-controlled flow conditions. Through the merging of engineering and microbial ecology, we present a rigorous methodology to quantify biofilm development at resolutions of single micrometre and single minute, using a newly developed flow cell. We designed and fabricated a high-precision flow cell to create defined and reproducible flow conditions. We applied high-content confocal laser scanning microscopy and developed image quantification using a model biofilm of a defined opportunistic strain, Pseudomonas putida OUS82. We observed complex patterns in the early events of biofilm formation, which were followed by total dispersal. These patterns were closely related to the flow conditions. These biofilm behavioural phenomena were found to be highly reproducible, despite the heterogeneous nature of biofilm. PMID- 28721253 TI - Real-time optotracing of curli and cellulose in live Salmonella biofilms using luminescent oligothiophenes. AB - Extracellular matrix (ECM) is the protein- and polysaccharide-rich backbone of bacterial biofilms that provides a defensive barrier in clinical, environmental and industrial settings. Understanding the dynamics of biofilm formation in native environments has been hindered by a lack of research tools. Here we report a method for simultaneous, real-time, in situ detection and differentiation of the Salmonella ECM components curli and cellulose, using non-toxic, luminescent conjugated oligothiophenes (LCOs). These flexible conjugated polymers emit a conformation-dependent fluorescence spectrum, which we use to kinetically define extracellular appearance of curli fibres and cellulose polysaccharides during bacterial growth. The scope of this technique is demonstrated by defining biofilm morphotypes of Salmonella enterica serovars Enteritidis and Typhimurium, and their isogenic mutants in liquid culture and on solid media, and by visualising the ECM components in native biofilms. Our reported use of LCOs across a number of platforms, including intracellular cellulose production in eukaryotic cells and in infected tissues, demonstrates the versatility of this optotracing technology, and its ability to redefine biofilm research. PMID- 28721254 TI - Markers of T-cell senescence and physical frailty: insights from Singapore Longitudinal Ageing Studies. AB - BACKGROUND: Elderly individuals have an eroded immune system but whether immune senescence is implicated with the development of frailty is unknown. The underlying immune mechanisms and the link between markers of senescence and physical frailty is not well established. METHODS: We explored the association of specific T-cell subset markers of immune differentiation and senescence on CD4+ and CD8+ cells (CD28-, CD27- and CD57+) and the immune risk profile (inverted CD4/CD8 ratio <1) with physical frailty among 421 participants who were frail (N=32), prefrail (N=187) and robust (N=202) in the Singapore Longitudinal Ageing Study cohort. RESULTS: In ordinal logistic regression models relating tertile category rank scores of immune biomarker with frailty status (robust, prefrail and frail), CD8+CD28-CD27+ (odds ratio (OR)=1.35, P=0.013), CD4+CD28-CD27+ (OR=1.29, P=0.025), CD8+CD28- (OR=1.31, P=0.022), and CD4/CD8 ratio (OR=1.27, P=0.026) were positively associated with frailty, controlling for age, sex and multimorbidity. CD4/CD8 ratio less than one was not associated with frailty (OR=0.84, P=0.64). In stepwise multinomial logistic regression controlling for age, sex and comorbidity, only CD8+CD28-CD27+ was the independent predictor of prefrailty: highest tertile of the immune marker significantly predicted prefrailty (versus low tertile, OR=1.72, P=0.037) and frailty (OR=2.56, P=0.06). CONCLUSION: The study supports the hypothetical role of immune senescence in physical frailty, particularly in regard to the observed loss of CD28 expression from both CD8+ cells and CD4+ cells, but not for CD27 or CD4/CD8 ratio as a marker of senescence. The potential of CD8+CD28-CD27+ as a biological marker of frailty should be further investigated in prospective studies. PMID- 28721255 TI - 'Purpose in Life' as a psychosocial resource in healthy aging: an examination of cortisol baseline levels and response to the Trier Social Stress Test. AB - 'Purpose in Life' (Purpose) is associated with healthy aging, but it is unknown whether this association is causal. Conceptualizing Purpose as a form of psychosocial resource, one mechanism promoting health could be the regulation of stress hormones. To test this hypothesis, we recruited 44 older community dwelling adults to examine the association between Purpose and cortisol at baseline, in response to, and recovery from, an acute social laboratory stressor. Purpose did not predict cortisol baseline or reactivity, but did predict a faster recovery to pre-stress baseline levels. The health benefits of Purpose in aging may therefore reflect the combination of a normal stress response, which serves an adaptive benefit of allostasis, with an accelerated stress recovery, which reduces the burden of allostatic load. This model should be tested in future studies using larger samples, multiple related constructs, and longitudinal designs that include participants' health records. PMID- 28721256 TI - Aging science comes of age. PMID- 28721257 TI - The mammalian target of rapamycin at the crossroad between cognitive aging and Alzheimer's disease. AB - Age-dependent cognitive decline is a major debilitating event affecting even individuals who are otherwise healthy. Understanding the molecular basis underlying these changes may increase the healthspan of the elderly population. It may also reveal insights into the pathogenesis of numerous neurodegenerative disorders characterized by cognitive deficits, as aging is the major risk factor for most of these disorders. Alzheimer's disease (AD), the most common neurodegenerative disorder, first manifests itself as deficits in encoding new memories. As AD progresses, these deficits spread to other cognitive domains that further debilitate the person before contributing to their demise. Suppression of the mammalian target of rapamycin (mTOR) increases healthspan and lifespan in several organisms. Numerous reports have linked alterations in mTOR signaling to age-dependent cognitive decline and the pathogenesis of AD. This review will discuss recent work highlighting the complex role of mTOR in cognitive aging and in the pathogenesis of AD. PMID- 28721258 TI - Role of the central nervous system and adipose tissue BDNF/TrkB axes in metabolic regulation. AB - BACKGROUND/OBJECTIVES: Brain-derived neurotrophic factor (BDNF) and its receptor (tropomyosin-related kinase B: TrkB, also known as Ntrk2) have a key role in central regulation of the energy balance. BDNF and TrkB are also expressed in the peripheral tissues, including adipose tissue, but their peripheral role has been unclear. Here we report on the functional significance of the adipose tissue BDNF/TrkB axis in metabolic homeostasis. MATERIALS AND METHODS: To examine the role of the BDNF/TrkB axis in the central nervous system and in adipose tissue, we generated adipocyte-specific or neuron-specific BDNF/TrkB conditional knockout (CKO) mice. Then we compared the feeding behavior and metabolic profile between each type of CKO mouse and their littermates. RESULTS: Bdnf expression was significantly increased in the adipose tissue of mice receiving a high-calorie diet, whereas Ntrk2 expression was decreased. The Bdnf/Ntrk2 expression ratio of adipose tissue was higher in female mice than male mice. Fabp4-Cre mice are widely used to establish adipocyte-specific CKO mice. However, we found that Fabp4-Cre-induced deletion of Bdnf or Ntrk2 led to hyperphagia, obesity, and aggressiveness, presumably due to ectopic Fabp4-Cre mediated gene recombination in the brain. Next, we attempted to more specifically delete Bdnf or Ntrk2 in adipocytes using Adipoq-Cre mice. Expression of Ntrk2, but not Bdnf, in the adipose tissue was reduced by Adipoq-Cre mediated gene recombination, indicating that adipocytes only expressed TrkB. No phenotypic changes were detected when Adipoq-Cre TrkB CKO mice were fed a normal diet, whereas female CKO mice receiving a high-calorie diet showed a decrease in food intake and resistance to obesity. CONCLUSIONS: The adipose tissue BDNF/TrkB axis has a substantial influence on the feeding behavior and obesity in female mice. PMID- 28721261 TI - Heterochronic microRNAs in temporal specification of neural stem cells: application toward rejuvenation. AB - Plasticity is a critical factor enabling stem cells to contribute to the development and regeneration of tissues. In the mammalian central nervous system (CNS), neural stem cells (NSCs) that are defined by their capability for self renewal and differentiation into neurons and glia, are present in the ventricular neuroaxis throughout life. However, the differentiation potential of NSCs changes in a spatiotemporally regulated manner and these cells progressively lose plasticity during development. One of the major alterations in this process is the switch from neurogenesis to gliogenesis. NSCs initiate neurogenesis immediately after neural tube closure and then turn to gliogenesis from midgestation, which requires an irreversible competence transition that enforces a progressive reduction of neuropotency. A growing body of evidence indicates that the neurogenesis-to-gliogenesis transition is governed by multiple layers of regulatory networks consisting of multiple factors, including epigenetic regulators, transcription factors, and non-coding RNA (ncRNA). In this review, we focus on critical roles of microRNAs (miRNAs), a class of small ncRNA that regulate gene expression at the post-transcriptional level, in the regulation of the switch from neurogenesis to gliogenesis in NSCs in the developing CNS. Unraveling the regulatory interactions of miRNAs and target genes will provide insights into the regulation of plasticity of NSCs, and the development of new strategies for the regeneration of damaged CNS. PMID- 28721259 TI - Fine mapping the CETP region reveals a common intronic insertion associated to HDL-C. AB - BACKGROUND: Individuals with exceptional longevity and their offspring have significantly larger high-density lipoprotein concentrations (HDL-C) particle sizes due to the increased homozygosity for the I405V variant in the cholesteryl ester transfer protein (CETP) gene. In this study, we investigate the association of CETP and HDL-C further to identify novel, independent CETP variants associated with HDL-C in humans. METHODS: We performed a meta-analysis of HDL-C within the CETP region using 59,432 individuals imputed with 1000 Genomes data. We performed replication in an independent sample of 47,866 individuals and validation was done by Sanger sequencing. RESULTS: The meta-analysis of HDL-C within the CETP region identified five independent variants, including an exonic variant and a common intronic insertion. We replicated these 5 variants significantly in an independent sample of 47,866 individuals. Sanger sequencing of the insertion within a single family confirmed segregation of this variant. The strongest reported association between HDL-C and CETP variants, was rs3764261; however, after conditioning on the five novel variants we identified the support for rs3764261 was highly reduced (betaunadjusted=3.179 mg/dl (P value=5.25*10-509), betaadjusted=0.859 mg/dl (P value=9.51*10-25)), and this finding suggests that these five novel variants may partly explain the association of CETP with HDL-C. Indeed, three of the five novel variants (rs34065661, rs5817082, rs7499892) are independent of rs3764261. CONCLUSIONS: The causal variants in CETP that account for the association with HDL-C remain unknown. We used studies imputed to the 1000 Genomes reference panel for fine mapping of the CETP region. We identified and validated five variants within this region that may partly account for the association of the known variant (rs3764261), as well as other sources of genetic contribution to HDL-C. PMID- 28721260 TI - Adiponectin/adiponectin receptor in disease and aging. AB - Adipocytes are not merely organs for energy conservation but endocrine organs secreting a wide array of physiologically active substances, i.e., adipokines. Of these adipokines, adiponectin is known to exert anti-diabetic and anti atherosclerotic effects via adiponectin receptors (AdipoR)s, AdipoR1 and AdipoR2. Adiponectin has also recently been shown to regulate longevity signaling thus prolonging lifespan. Therefore, the strategy for activating adiponectin/AdipoR signaling pathways are expected to provide a solid basis for the prevention and treatment of obesity-related diseases such as the metabolic syndrome, type 2 diabetes and cardiovascular disease, as well as for ensuring healthy longevity in humans. PMID- 28721262 TI - A glimpse at the aging eye. AB - Extensive investigations have demonstrated that organismal aging is associated with tissue dysfunction in many organs. The eye is no exception to this rule. Under healthy conditions, the eye is designed like an advanced camera with the central role of translating light from the external world into a coherent neural signal that can be transmitted to the brain for processing into a precise visual image. This complex process requires precisely maintained machinery. At the front of the eye, the transparency of both the cornea and the lens are crucial to allow passage of photons to the light-sensitive portion of the eye. Similarly, the highly organized structure of the retina located at the back of the eye is indispensable to allow for effective signal transduction and efficient signal transmission. Aging affects ocular structures in various ways, and these sequelae have been well defined as distinct clinical entities. In many instances, aging leads to ocular tissue dysfunction and disease. Nonetheless, despite clear evidence that age-associated visual impairment has significant psychosocial consequences, current treatment paradigms for many of these conditions are inadequate. In addition, strategies to decelerate or reverse age-associated deterioration in ocular function are still in their infancy. This review focuses on the cellular and molecular pathophysiology of the aging eye. Ultimately, we hope that a refined understanding of the aging eye can guide targeted therapies against cellular aging and disease. PMID- 28721263 TI - Yeast longevity promoted by reversing aging-associated decline in heavy isotope content. AB - Dysregulation of metabolism develops with organismal aging. Both genetic and environmental manipulations promote longevity by effectively diverting various metabolic processes against aging. How these processes converge on the metabolome is not clear. Here we report that the heavy isotopic forms of common elements, a universal feature of metabolites, decline in yeast cells undergoing chronological aging. Supplementation of deuterium, a heavy hydrogen isotope, through heavy water (D2O) uptake extends yeast chronological lifespan (CLS) by up to 85% with minimal effects on growth. The CLS extension by D2O bypasses several known genetic regulators, but is abrogated by calorie restriction and mitochondrial deficiency. Heavy water substantially suppresses endogenous generation of reactive oxygen species (ROS) and slows the pace of metabolic consumption and disposal. Protection from aging by heavy isotopes might result from kinetic modulation of biochemical reactions. Altogether, our findings reveal a novel perspective of aging and new means for promoting longevity. PMID- 28721265 TI - Molecular hydrogen stimulates the gene expression of transcriptional coactivator PGC-1alpha to enhance fatty acid metabolism. AB - We previously reported that molecular hydrogen (H2) acts as a novel antioxidant to exhibit multiple functions. Moreover, long-term drinking of H2-water (water infused with H2) enhanced energy expenditure to improve obesity and diabetes in db/db mice accompanied by the increased expression of fibroblast growth factor 21 (FGF21) by an unknown mechanism. H2 was ingested by drinking of H2-water or by oral administration of an H2-producing material, MgH2. The comprehensive gene expression profile in the liver of db/db mice was analyzed by DNA microarray. The molecular mechanisms underlying the gene expression profile was investigated using cultured HepG2 cells. Moreover, the effects on lifespan of drinking H2 water were examined using wild-type mice that were fed a fatty diet. Pathway analyses based on comprehensive gene expression revealed the increased expression of various genes involved in fatty acid and steroid metabolism. As a transcription pathway, the PPARalpha signaling pathway was identified to upregulate their genes by ingesting H2. As an early event, the gene expression of PGC-1alpha was transiently increased, followed by increased expression of FGF21. The expression of PGC-1alpha might be regulated indirectly through sequential regulation by H2, 4-hydroxy-2-nonenal, and Akt/FoxO1 signaling, as suggested in cultured cell experiments. In wild-type mice fed the fatty diet, H2-water improved the level of plasma triglycerides and extended their average of lifespan. H2 induces expression of the PGC-1alpha gene, followed by stimulation of the PPARalpha pathway that regulates FGF21, and the fatty acid and steroid metabolism. PMID- 28721264 TI - Cytochrome b5 reductase and the control of lipid metabolism and healthspan. AB - Cytochrome b5 reductases (CYB5R) are required for the elongation and desaturation of fatty acids, cholesterol synthesis and mono-oxygenation of cytochrome P450 enzymes, all of which are associated with protection against metabolic disorders. However, the physiological role of CYB5R in the context of metabolism, healthspan and aging remains ill-defined. We generated CYB5R-overexpressing flies (CYB5R-OE) and created a transgenic mouse line overexpressing CYB5R3 (CYB5R3-Tg) in the C57BL/6J background to investigate the function of this class of enzymes as regulators of metabolism and age-associated pathologies. Gender- and/or stage specific induction of CYB5R, and pharmacological activation of CYB5R with tetrahydroindenoindole extended fly lifespan. Increased expression of CYB5R3 was associated with significant improvements in several metabolic parameters that resulted in modest lifespan extension in mice. Diethylnitrosamine-induced liver carcinogenesis was reduced in CYB5R3-Tg mice. Accumulation of high levels of long chain polyunsaturated fatty acids, improvement in mitochondrial function, decrease in oxidative damage and inhibition of chronic pro-inflammatory pathways occurred in the transgenic animals. These results indicate that CYB5R represents a new target in the study of genes that regulate lipid metabolism and healthspan. PMID- 28721268 TI - The Keio Medical Science Prize for 2015. PMID- 28721267 TI - Amyloid proteotoxicity initiates an inflammatory response blocked by cannabinoids. AB - The beta amyloid (Abeta) and other aggregating proteins in the brain increase with age and are frequently found within neurons. The mechanistic relationship between intracellular amyloid, aging and neurodegeneration is not, however, well understood. We use a proteotoxicity model based upon the inducible expression of Abeta in a human central nervous system nerve cell line to characterize a distinct form of nerve cell death caused by intracellular Abeta. It is shown that intracellular Abeta initiates a toxic inflammatory response leading to the cell's demise. Abeta induces the expression of multiple proinflammatory genes and an increase in both arachidonic acid and eicosanoids, including prostaglandins that are neuroprotective and leukotrienes that potentiate death. Cannabinoids such as tetrahydrocannabinol stimulate the removal of intraneuronal Abeta, block the inflammatory response, and are protective. Altogether these data show that there is a complex and likely autocatalytic inflammatory response within nerve cells caused by the accumulation of intracellular Abeta, and that this early form of proteotoxicity can be blocked by the activation of cannabinoid receptors. PMID- 28721266 TI - Lifespan-regulating genes in C. elegans. AB - The molecular mechanisms underlying the aging process have garnered much attention in recent decades because aging is the most significant risk factor for many chronic diseases such as type 2 diabetes and cancer. Until recently, the aging process was not considered to be an actively regulated process; therefore, discovering that the insulin/insulin-like growth factor-1 signaling pathway is a lifespan-regulating genetic pathway in Caenorhabditis elegans was a major breakthrough that changed our understanding of the aging process. Currently, it is thought that animal lifespans are influenced by genetic and environmental factors. The genes involved in lifespan regulation are often associated with major signaling pathways that link the rate of aging to environmental factors. Although many of the major mechanisms governing the aging process have been identified from studies in short-lived model organisms such as yeasts, worms and flies, the same mechanisms are frequently observed in mammals, indicating that the genes and signaling pathways that regulate lifespan are highly conserved among different species. This review summarizes the lifespan-regulating genes, with a specific focus on studies in C. elegans. PMID- 28721269 TI - Gene expression signatures of human cell and tissue longevity. AB - Different cell types within the body exhibit substantial variation in the average time they live, ranging from days to the lifetime of the organism. The underlying mechanisms governing the diverse lifespan of different cell types are not well understood. To examine gene expression strategies that support the lifespan of different cell types within the human body, we obtained publicly available RNA seq data sets and interrogated transcriptomes of 21 somatic cell types and tissues with reported cellular turnover, a bona fide estimate of lifespan, ranging from 2 days (monocytes) to a lifetime (neurons). Exceptionally long-lived neurons presented a gene expression profile of reduced protein metabolism, consistent with neuronal survival and similar to expression patterns induced by longevity interventions such as dietary restriction. Across different cell lineages, we identified a gene expression signature of human cell and tissue turnover. In particular, turnover showed a negative correlation with the energetically costly cell cycle and factors supporting genome stability, concomitant risk factors for aging-associated pathologies. In addition, the expression of p53 was negatively correlated with cellular turnover, suggesting that low p53 activity supports the longevity of post-mitotic cells with inherently low risk of developing cancer. Our results demonstrate the utility of comparative approaches in unveiling gene expression differences among cell lineages with diverse cell turnover within the same organism, providing insights into mechanisms that could regulate cell longevity. PMID- 28721270 TI - Time distortions in Alzheimer's disease: a systematic review and theoretical integration. AB - Time perception is an essential function of the human brain, which is compromised in Alzheimer's disease (AD). Here, we review empirical findings on time distortions in AD and provide a theoretical framework that integrates time and memory distortions in AD and explains their bidirectional modulation. The review was based on a literature survey performed on the PubMed and PsycInfo databases. According to our theoretical framework, time distortions may induce decline in the ability to mentally project oneself in time (i.e., mental time travel), and consequently may contribute to an episodic memory compromise in AD. Conversely, episodic memory compromise in AD may result in a loss of the ability to retrieve information about time and/or the ability to project oneself in subjective time. The relationship between time distortions and memory decline in AD can be jointly attributed to hippocampus involvement, as this brain area supports both time perception and memory and is preferentially targeted by the neuropathological processes of AD. Clinical implications of time distortions are discussed and directions for future research are suggested. PMID- 28721271 TI - It takes two to tango: NAD+ and sirtuins in aging/longevity control. AB - The coupling of nicotinamide adenine dinucleotide (NAD+) breakdown and protein deacylation is a unique feature of the family of proteins called 'sirtuins.' This intimate connection between NAD+ and sirtuins has an ancient origin and provides a mechanistic foundation that translates the regulation of energy metabolism into aging and longevity control in diverse organisms. Although the field of sirtuin research went through intensive controversies, an increasing number of recent studies have put those controversies to rest and fully established the significance of sirtuins as an evolutionarily conserved aging/longevity regulator. The tight connection between NAD+ and sirtuins is regulated at several different levels, adding further complexity to their coordination in metabolic and aging/longevity control. Interestingly, it has been demonstrated that NAD+ availability decreases over age, reducing sirtuin activities and affecting the communication between the nucleus and mitochondria at a cellular level and also between the hypothalamus and adipose tissue at a systemic level. These dynamic cellular and systemic processes likely contribute to the development of age associated functional decline and the pathogenesis of diseases of aging. To mitigate these age-associated problems, supplementation of key NAD+ intermediates is currently drawing significant attention. In this review article, we will summarize these important aspects of the intimate connection between NAD+ and sirtuins in aging/longevity control. PMID- 28721273 TI - The first human clinical study for NMN has started in Japan. PMID- 28721272 TI - Macrophages in age-related chronic inflammatory diseases. AB - Chronic inflammation is the common pathological basis for such age-associated diseases as cardiovascular disease, diabetes, cancer and Alzheimer's disease. A multitude of bodily changes occur with aging that contribute to the initiation and development of inflammation. In particular, the immune system of elderly individuals often exhibits diminished efficiency and fidelity, termed immunosenescence. But, although immune responses to new pathogens and vaccines are impaired, immunosenescence is also characterized by a basal systemic inflammatory state. This alteration in immune system function likely promotes chronic inflammation. Changes in the tissue microenvironment, such as the accumulation of cell debris, and systemic changes in metabolic and hormonal signals, also likely contribute to the development of chronic inflammation. Monocyte/macrophage lineage cells are crucial to these age-associated changes, which culminate in the development of chronic inflammatory diseases. In this review, we will summarize the diverse physiological and pathological roles of macrophages in the chronic inflammation underlying age-associated diseases. PMID- 28721274 TI - Increased oxidative phosphorylation in response to acute and chronic DNA damage. AB - Accumulation of DNA damage is intricately linked to aging, aging-related diseases and progeroid syndromes such as Cockayne syndrome (CS). Free radicals from endogenous oxidative energy metabolism can damage DNA, however the potential of acute or chronic DNA damage to modulate cellular and/or organismal energy metabolism remains largely unexplored. We modeled chronic endogenous genotoxic stress using a DNA repair-deficient Csa-/-|Xpa-/- mouse model of CS. Exogenous genotoxic stress was modeled in mice in vivo and primary cells in vitro treated with different genotoxins giving rise to diverse spectrums of lesions, including ultraviolet radiation, intrastrand crosslinking agents and ionizing radiation. Both chronic endogenous and acute exogenous genotoxic stress increased mitochondrial fatty acid oxidation (FAO) on the organismal level, manifested by increased oxygen consumption, reduced respiratory exchange ratio, progressive adipose loss and increased FAO in tissues ex vivo. In multiple primary cell types, the metabolic response to different genotoxins manifested as a cell autonomous increase in oxidative phosphorylation (OXPHOS) subsequent to a transient decline in steady-state NAD+ and ATP levels, and required the DNA damage sensor PARP-1 and energy-sensing kinase AMPK. We conclude that increased FAO/OXPHOS is a general, beneficial, adaptive response to DNA damage on cellular and organismal levels, illustrating a fundamental link between genotoxic stress and energy metabolism driven by the energetic cost of DNA damage. Our study points to therapeutic opportunities to mitigate detrimental effects of DNA damage on primary cells in the context of radio/chemotherapy or progeroid syndromes. PMID- 28721275 TI - Deficiency of angiotensin-converting enzyme 2 causes deterioration of cognitive function. AB - The classical renin-angiotensin system (RAS), known as the angiotensin (Ang) converting enzyme (ACE)/Ang II/Ang II type 1 (AT1) receptor axis, induces various organ damages including cognitive decline. On the other hand, the ACE2/Ang-(1 7)/Mas receptor axis has been highlighted as exerting antagonistic actions against the classical RAS axis in the cardiovascular system. However, the roles of the ACE2/Ang-(1-7)/Mas axis in cognitive function largely remain to be elucidated, and we therefore examined possible roles of ACE2 in cognitive function. Male, 10-week-old C57BL6 (wild type, WT) mice and ACE2 knockout (KO) mice were subjected to the Morris water maze task and Y maze test to evaluate cognitive function. ACE2KO mice exhibited significant impairment of cognitive function, compared with that in WT mice. Superoxide anion production increased in ACE2KO mice, with increased mRNA levels of NADPH oxidase subunit, p22phox, p40phox, p67phox, and gp91phox in the hippocampus of ACE2KO mice compared with WT mice. The protein level of SOD3 decreased in ACE2KO mice compared with WT mice. The AT1 receptor mRNA level in the hippocampus was higher in ACE2KO mice compared with WT mice. In contrast, the AT2 receptor mRNA level in the hippocampus did not differ between the two strains. Mas receptor mRNA was highly expressed in the hippocampus compared with the cortex. Brain-derived neurotrophic factor (BDNF) mRNA and protein levels were lower in the hippocampus in ACE2KO mice compared with WT mice. Taken together, ACE2 deficiency resulted in impaired cognitive function, probably at least in part because of enhanced oxidative stress and a decrease in BDNF. PMID- 28721276 TI - Metformin decreases progerin expression and alleviates pathological defects of Hutchinson-Gilford progeria syndrome cells. AB - Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder that causes systemic accelerated aging in children. This syndrome is due to a mutation in the LMNA gene that leads to the production of a truncated and toxic form of lamin A called progerin. Because the balance between the A-type lamins is controlled by the RNA-binding protein SRSF1, we have hypothesized that its inhibition may have therapeutic effects for HGPS. For this purpose, we evaluated the antidiabetic drug metformin and demonstrated that 48 h treatment with 5 mmol/l metformin decreases SRSF1 and progerin expression in mesenchymal stem cells derived from HGPS induced pluripotent stem cells (HGPS MSCs). The effect of metformin on progerin was then confirmed in several in vitro models of HGPS, i.e., human primary HGPS fibroblasts, LmnaG609G/G609G mouse fibroblasts and healthy MSCs previously treated with a PMO (phosphorodiamidate morpholino oligonucleotide) that induces progerin. This was accompanied by an improvement in two in vitro phenotypes associated with the disease: nuclear shape abnormalities and premature osteoblastic differentiation of HGPS MSCs. Overall, these results suggest a novel approach towards therapeutics for HGPS that can be added to the currently assayed treatments that target other molecular defects associated with the disease. PMID- 28721277 TI - The oxidation state of the cytoplasmic glutathione redox system does not correlate with replicative lifespan in yeast. AB - What is cause and what is consequence of aging and whether reactive oxygen species (ROS) contribute to this phenomenon is debated since more than 50 years. Notwithstanding, little is known about the cellular buffer and redox systems in aging Saccharomyces cerevisiae, which is a model for aging stem cells. Using genetically encoded fluorescent sensors, we measured pH, H2O2 levels and the glutathione redox potential compartment-specific in the cytosol of living, replicatively aging yeast cells, growing under fermenting and respiratory conditions until the end of their lifespan. We found that the pH decreases under both conditions at later stages of the replicative lifespan. H2O2 levels increase in fermenting cells in the post-replicative stage, but increase continuously with age in respiring cells. The glutathione redox couple becomes also more oxidizing in respiring cells but surprisingly more reducing under fermenting conditions. In strains deleted for the gene encoding glutathione reductase Glr1, such a reduction of the glutathione redox couple with age is not observed. We demonstrate that in vivo Glr1 is activated at lower pH explaining the reduced glutathione potential. The deletion of glr1 dramatically increases the glutathione redox potential especially under respiratory conditions but does not reduce lifespan. Our data demonstrate that pH and the glutathione redox couple is linked through Glr1 and that yeast cells can cope with a high glutathione redox potential without impact on longevity. Our data further suggest that a breakdown of cellular energy metabolism marks the end of replicative lifespan in yeast. PMID- 28721278 TI - Hsa-miR-520d-5p promotes survival in human dermal fibroblasts exposed to a lethal dose of UV irradiation. AB - We previously reported that hsa-miR-520d-5p is functionally involved in the induction of the epithelial-mesenchymal transition and stemness-mediated processes in normal cells and cancer cells, respectively. On the basis of the synergistic effect of p53 upregulation and demethylation induced by 520d-5p, the current study investigated the effect of this miRNA on apoptotic induction by ultraviolet B (UVB) light in normal human dermal fibroblast (NHDF) cells. 520d-5p was lentivirally transfected into NHDF cells either before or after a lethal dose of UVB irradiation (302 nm) to assess its preventive or therapeutic effects, respectively. The methylation level, gene expression, production of type I collagen and cell cycle distribution were estimated in UV-irradiated cells. NHDF cells transfected with 520d-5p prior to UVB irradiation had apoptotic characteristics, and the transfection exerted no preventive effects. However, transfection with 520d-5p into NHDF cells after UVB exposure resulted in the induction of reprogramming in damaged fibroblasts, the survival of CD105-positive cells, an extended cell lifespan and prevention of cellular damage or malfunction; these outcomes were similar to the effects observed in 520d-5p transfected NHDF cells (520d/NHDF). The gene expression of c-Abl (Abelson murine leukemia viral oncogene homolog 1), ATR (ataxia telangiectasia and Rad3-related protein), and BRCA1 (breast cancer susceptibility gene I) in transfectants was transcriptionally upregulated in order. These mechanistic findings indicate that ATR-dependent DNA damage repair was activated under this stressor. In conclusion, 520d-5p exerted a therapeutic effect on cells damaged by UVB and restored them to a normal senescent state following functional restoration via survival of CD105 positive cells through c-Abl-ATR-BRCA1 pathway activation, p53 upregulation, and demethylation. PMID- 28721279 TI - Age-related circadian disorganization caused by sympathetic dysfunction in peripheral clock regulation. AB - The ability of the circadian clock to adapt to environmental changes is critical for maintaining homeostasis, preventing disease, and limiting the detrimental effects of aging. To date, little is known about age-related changes in the entrainment of peripheral clocks to external cues. We therefore evaluated the ability of the peripheral clocks of the kidney, liver, and submandibular gland to be entrained by external stimuli including light, food, stress, and exercise in young versus aged mice using in vivo bioluminescence monitoring. Despite a decline in locomotor activity, peripheral clocks in aged mice exhibited normal oscillation amplitudes under light-dark, constant darkness, and simulated jet lag conditions, with some abnormal phase alterations. However, age-related impairments were observed in peripheral clock entrainment to stress and exercise stimuli. Conversely, age-related enhancements were observed in peripheral clock entrainment to food stimuli and in the display of food anticipatory behaviors. Finally, we evaluated the hypothesis that deficits in sympathetic input from the central clock located in the suprachiasmatic nucleus of the hypothalamus were in part responsible for age-related differences in the entrainment. Aged animals showed an attenuated entrainment response to noradrenergic stimulation as well as decreased adrenergic receptor mRNA expression in target peripheral organs. Taken together, the present findings indicate that age-related circadian disorganization in entrainment to light, stress, and exercise is due to sympathetic dysfunctions in peripheral organs, while meal timing produces effective entrainment of aged peripheral circadian clocks. PMID- 28721280 TI - Increasing detection of significant prostate cancer in younger men - ten year trends in prostate cancer risk profile in the Mid-West of Ireland. AB - INTRODUCTION: Although PSA (prostate specific antigen) based screening for prostate cancer (PCa) is controversial, an increasing number of men are undergoing Transrectal Ultrasound Guided prostate biopsy (TRUSPB) through primary care-based PSA testing and referral to hospitals. The aim of our study was to investigate presenting risk profiles of PCa over the last decade in a cohort of men in Ireland and to examine any change in the same over this time period. MATERIAL AND METHODS: The hospital patient administration system was analysed for patients who underwent TRUSPB from January 2005 to December 2015. Clinically significant PCa was defined as Gleason score of 7 or above. RESULTS: Complete data was available on 2391 TRUSPB patients: number of biopsies increased by 53%, median age decreased by 0.9%, median PSA decreased by 6% (p = 0.001, ANOVA) and abnormal DRE increased by 9% (p = 0.001, chi square). Overall positive biopsy was 44% and significant cancer rate was 21%. There was a significant change in trend of detection (p = 0.02) with average annual increase in significant cancer of 3%. The median age of the significant cancer cohort reduced by 1% and the PSA at diagnosis reduced by 9%. In younger men (<50 years), the rate of significant cancer detection increased by 18%. CONCLUSIONS: Significant PCa detection increased across all age groups but recently, a younger patient profile was diagnosed with high-grade disease. This paves the way for future research on early-onset PCa. Younger patients with significant disease would result in increasing number of patients being eligible for radical treatment with implications on health resource planning and provision. PMID- 28721281 TI - Safety and efficacy of tamsulosin, alfuzosin or silodosin as monotherapy for LUTS in BPH - a double-blind randomized trial. AB - INTRODUCTION: Currently alpha1-adrenoceptor blockers (AB) are widely used as first-line therapy to improve lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH). We compared the efficacy and safety profile of tamsulosin, alfuzosin and silodosin in LUTS due to BPH. MATERIAL AND METHODS: Consecutive consenting male patients (N = 269) undergoing medical management of BPH with AB from February 2012 to October 2015 were enrolled. Patients were randomized to a 0.4 mg tamsulosin (group T), 10 mg alfuzosin (group A) or a 8 mg silodosin (group S) by double-blind randomization. All patients were assessed for improvements and post-void residual urine (PVR) and for adverse drug events (ADE). RESULTS: IPSS showed significant improvement in Group S at the first week (11.7 +/-4.18, p = 0.027) and at 3 months (7.97 +/-3.84, p = 0.020). QOL showed significant improvement at 1 (2.2 +/-0.76, p = 0.020), 4 (1.47 +/-0.63, p <0.001) and 12 (1.2 +/-0.66, p <0.001) weeks in Group S. The mean Qmax improvement was the maximum (13.76 +/-2.44, p = 0.028) in Group S at 1 week. Reduction in PVR was the maximum in Group S, but it was not statistically significant. Adverse drug events (ADE) were observed in 20.07% (54/269) patients and distribution was similar in the three groups with decreasing incidence with progression of time. CONCLUSIONS: Silodosin is the most efficacious AB with rapid onset of action. Silodosin also improves the quality of life in patients with LUTS due to BPH and objectively improves maximum flow rate. However, silodosin has more adverse events when compared to tamsulosin and alfuzosin. PMID- 28721282 TI - Structural differences and architectural features of two different polypropylene slings (TVT-O and I-STOP) have no impact on biocompatibility and tissue reactions. AB - INTRODUCTION: To evaluate the impact of design features of the synthetic mid urethral slings on tissue integrity and inflammatory responses. MATERIAL AND METHODS: In total 30 female Sprague-Dawley rats were implanted with type I monofilamentous, macroporous polypropylene meshes: Gynecare TVT-Obturator tape(r) (Ethicon Inc., Johnson & Johnson, Somerville, NJ, USA) and I-STOP(r) (CL Medical Inc., Lyon, France). All animal groups were sacrificed at set time intervals - 6 weeks, 3 months, 6 months, 9 months and 12 months - and the abdominal wall was harvested with mesh strips for histological evaluation. RESULTS: All mesh strips appeared to be well incorporated into the abdominal wall, and no signs of shrinkage was noticed. All specimens showed a thin/delicate, loose, fibrous interface between the synthetic graft plate and abdominal wall, along with mild inflammatory reactions from 6 weeks to 12 months. CONCLUSIONS: Both mesh brands induced comparable, minimal foreign body reactions and integrated well into the host tissues despite differences in architectural features. TVT-O(r) and I STOP(r) evoked similar low-grade inflammatory responses up to 12 months in this animal model. Structural differences and architectural features of polypropylene slings used in this study have had no impact on tissue integrity and inflammatory responses. PMID- 28721283 TI - Stereological comparison of intraprostatic injection of alcohol and bleomycin with finasteride gavages in rats. AB - INTRODUCTION: Resection of the prostate is one of the standard surgical treatments for symptomatic Benign Prostatic Hyperplasia (BPH). To evaluate minimally invasive treatments, intraprostatic injections of ethanol and bleomycin were compared with oral finasteride administration in rats with BPH. MATERIAL AND METHODS: The rats were divided into six groups. The control rats received no BPH/no treatment. BPH was induced using injections of testosterone (2 mg/day/rat for 4 weeks) in groups II-VI. After 4 weeks, Group II received no treatment while Group III received oral finasteride (10 mg/kg/day). Moreover, Groups IV-VI received a single injection of ethanol (95%), bleomycin (5 mg/kg) and normal saline 25 mm3 in each ventral lobe of the prostate respectively. Two weeks after the injections, the ventral lobes underwent a quantitative stereological study. RESULTS: The volume of the ventral lobes, glandular epithelium, fibromuscular tissue and microvessles increased by 1.7, 3.1, 2.4 and 1.6 times in BPH rats respectively (P <0.01). Alcohol or bleomycin injection in PBH rats induced drastic recession of the increased volume of the ventral lobe, glandular epithelium and fibromuscular tissue (P <0.01). Regarding the BPH+alcohol group, the glandular epithelium volume restored to the normal values of the control rats (P <0.01). BPH+finasteride also incited an atrophic change in the volume of the whole prostate and glandular epithelium, but not the fibromuscular tissue and microvessels (P <0.01). CONCLUSIONS: Injection of alcohol and bleomycin (approximately 10% of the volume of ventral prostatic) as well as consuming finasteride can induce a reduction of 1/3, 1/4 and 1/5 in the hypertrophied gland respectively. PMID- 28721284 TI - Performing easy prone punction. AB - INTRODUCTION: Percutaneous renal surgery has been considered one of the most important advances in urology. There are several possibilities to perform a kidney puncture such as using fluoroscopy, ultrasound or both. The aim of this article is to describe our puncture technique. MATERIAL AND METHODS: Correct puncture is one of the most critical and challenging steps during percutaneous surgery. Bull's eye technique and other similar techniques supported by fluoroscopy try to make triangulations and provide different views. On the other hand, many urologists prefer the usage of ultrasound to help reach the calyx. The perfect puncture could also be a scanner guided puncture. RESULTS: Under general anesthesia, cystoscopy is performed for ureteral catheter placement. The excretory system is opacified by administering contrast to the ureteral catheter. Perpendicular puncture on the selected calyx is done; this is a 90 degrees puncture with a fine spinal needle 20G into the selected calyx under fluoroscopy control to visualize the correct penetration into the calyx. Moving forward to the next step, an 18G needle is used to follow the correct calyx - infundibulum - renal pelvis path. The goal is to put together both tips of the 2 needles (needle Kiss technique). CONCLUSIONS: After several years of performing percutaneous surgery, we conclude that our technique can facilitate the prone position puncture thanks to the information given from the thin needle while simultaneously minimizing the use of fluoroscopy for triangulation maneuvers and avoiding the use of ultrasound to determine the depth of the target calyx. PMID- 28721285 TI - Ureteroscopy for stone disease: expanding roles in the modern era. AB - INTRODUCTION: The prevalence of urolithiasis is increasing worldwide and is causing significant morbidity and cost to the healthcare systems. While ureteroscopy (URS) has been established as a treatment option, our review highlights the expanding role of URS for the management of more complex stones and patients in the modern era. MATERIAL AND METHODS: Ureteroscopy has shown to have good outcomes with stone free rates (SFR) comparable to other treatment modalities. Relevant publications have been identified. Their findings were critically appraised and used to formulate clinically oriented conclusions. RESULTS: The use of URS has increased and now includes URS management for large stones, bilateral stone disease, obesity, pregnancy, pediatrics, solitary kidney, horseshoe kidney and patients with a bleeding diathesis. CONCLUSIONS: With advances in URS technique and technology, its role has expanded to offer treatment in difficult clinical scenarios with good outcomes. PMID- 28721286 TI - Open stone surgery: a still-in-use approach for complex stone burden. AB - INTRODUCTION: Urinary stone disease is a major urological condition. Endourologic techniques have influenced the clinical approach and outcomes. Open surgery holds a historic importance in the management of most conditions. However, complex kidney stone burden may be amenable to successful results with open stone surgery. In this article, we report our eighteen cases of complex urinary stone disease who underwent open stone removal. MATERIAL AND METHODS: A total of 1701 patients have undergone surgical treatment for urinary stone disease in our clinic between July 2012 and July 2016, comprising eighteen patients who underwent open stone surgery. Patients' demographic data, stone analysis results, postoperative clinical data, and stone status were evaluated retrospectively. The choice of surgical approach is mostly dependent on the surgeon's preference. In two patients, open surgery was undertaken because of perioperative complications. RESULTS: We did not observe any Clavien-Dindo grade 4 or 5 complications. Three patients were managed with a course of antibiotics due to postoperative fever. One patient had postoperative pleurisy, one patient had urinoma, and two patients had postoperative ileus. Mean operation time was 84 (57-124) minutes and mean hospitalization time was 5.5 (3-8) days. Stone-free status was achieved in 15 patients (83.3%). CONCLUSIONS: Endourologic approaches are the first options for treatment of urinary stone disease. However, open stone surgery holds its indispensable position in complicated cases and in complex stone burden. Open stone surgery is also a valid alternative to endourologic techniques in all situations. PMID- 28721287 TI - Mediterranean diet and erectile dysfunction: a current perspective. AB - INTRODUCTION: In this current perspective we analyzed the role of Mediterranean diet (MedDiet) in sexual function and particularly in erectile dysfunction (ED), according to the latest scientific evidence. MATERIAL AND METHODS: We conducted a systematic search of relevant full-length papers identified during the time period from 1 January 2010 to the present. RESULTS: Published studies showed that adherence to a MedDiet contributes to preventing ED through an improved lipid and glucose metabolism, increased antioxidant defenses, and increased arginine levels which could raise nitric oxide activity. CONCLUSIONS: Our findings suggest that the encouragement of a healthy lifestyle, such as MedDiet promotion, could be an attractive dietary approach to prevent ED and preserve sexual function. PMID- 28721288 TI - Extended Boari-flap technique as a reconstruction method of total ureteric avulsion. AB - Indication has led ureteroscopy to be a worldwide technique, with the expected appearance of multiple complications. The ureteral avulsion is an uncommon severe urological complication of ureteroscopy (URS). Surgery in patients with a total ureteral loss is a demanding challenge for urologist. It requires usually immediate open or laparoscopic intervention. This case report was to present the treatment modality after ureteral avulsion. We have presented a case of 58-year old male patient who underwent a successful repair of an upper ureteral injury. We have comprehensively described the effectiveness of an extended Boari-flap procedure for reconstruction after iatrogenic ureteral trauma. Particularly in an unexpected and casual situations, the presented extended Boari flap modification can be a great alternative for reconstructing a total ureteral loss. In conclusion we have recommend useful tips, how to counteract such unwanted events. PMID- 28721289 TI - Fluoroquinolone-resistant Escherichia coli in intestinal flora of patients undergoing transrectal ultrasound-guided prostate biopsy - possible shift in biopsy prophylaxis. AB - INTRODUCTION: Infection of prostate gland following biopsy is common complication. Most common pathogen is E.coli. Since fluorochinolones are commonly prescribed as prophylaxis, infection caused by E.coli leads to complicated infections, especially due to fluoroquinolone-resistant species. The aim of this study was to evaluate the incidence of fluoroquinolone-resistant E.coli species in rectal swabs of patients undergoing prostate biopsy and to define appropriate antimicrobial agent as prostate biopsy prophylaxis. MATERIAL AND METHODS: Rectal swabs were collected in 159 patients undergoing prostate biopsy. The identification of E.coli was performed using the BBL Crystal E/NF identification (ID) System. RESULTS: In the rectal swab of 112/159 patients E.coli was found. In 47/159 cases after incubation, the microbiological evaluation showed no E.coli in these swabs. Defining the specific resistance to microbiological agents, we obtained that E.coli resistant to ciprofloxacin was found in 40 out of 112 patients (50.9%). Resistance to I and II generation of cephalosporin were found in 7%, and 5%, respectively. In 40 out of 112 (35.7%) E.coli resistant to trimetoprim/sulfametoksazol was reported. E.coli resistant to amoxicillin with clavulonian acid and ampicillin was found in 16 out of 112 (14.28%), and in 67 out of 112 patients (59.8%), respectively. CONCLUSIONS: In all cases with fluoroquinolone-resistant E.coli species positive rectal swabs I generation of cephalosporin seems to be a best choice for prostate biopsy prophylaxis. Moreover, II generation of cephalosporin should be considered for treatment of the eventual subsequent infection. The evaluation of rectal swabs before prostate biopsy is crucial in determining targeted antimicrobial prophylaxis. PMID- 28721290 TI - Frailty and elderly in urology: Is there an impact on post-operative complications? AB - INTRODUCTION: Frailty used as predictive tool is still not carried out in daily practice, although many studies confirm the great clinical importance of the frailty syndrome in surgical outcomes. There is no standardized method of measuring the physiological reserves of older surgical patients. The aim of this study was to analyze a cohort of older urological patients according to various frailty indices, in order to evaluate whether they are predictors of post operative complications after urological procedures. MATERIAL AND METHODS: This is a prospective observational study on 78 consecutive older (>=70 years) patients, subjected to major urological (both endoscopic and 'open surgical') procedures. Frailty was defined according to the Edmonton Frail Scale. Several risk models and biochemical parameters were evaluated. Post-operative outcomes were surgical and medical complications, mortality and rehospitalisation within 3 months. RESULTS: An overall prevalence of frailty of 21.8% was found. Patients with complications were frailer than those without complications (univariate analysis), considering both total patients (p = 0.002) and endoscopic (p = 0.04) and 'open surgical' patients (p = 0.013). However, in multivariate analysis, a significant correlation was not found between all frailty indices tested and the risk of major complications. Limitation of the study: the small sample size (lack of statistical power), although this is a prospective study focused on older urological patients. CONCLUSIONS: New urology-tailored pre-operative assessment tools may prove beneficial when calculating the risks/benefits of urological procedures, so that objective data can guide surgical decision- making and patient counselling. Further large clinical studies specifically focusing on elderly in urology will be needed. PMID- 28721292 TI - A prospective evaluation of surgical outcomes of laparoscopic transperitoneal radical prostatectomy in obese patients: our experience. PMID- 28721291 TI - Basic issues concerning health-related quality of life. AB - INTRODUCTION: Chronic diseases such as cancer have a strong influence on both physical health and quality of life, which together comprise the concept of health-related quality of life (HRQoL) - in other words, the complete state of physical, social, and psychological functioning. Herein, we review the literature on the theory of HRQoL in relation to oncological diseases. MATERIAL AND METHODS: A literature search of English-language publications that included an analysis of the conceptual models of HRQoL was performed using PubMed. The data were screened and synthesized by all authors and relevant papers were selected. RESULTS: We outline the theoretical models most often used to conceptualize HRQoL, including the Centre for Health Promotion model from the University of Toronto, the conceptual model of Wilson and Cleary and the contextual model of Ashing-Giwa formulated specifically for cancer patients. CONCLUSIONS: Understanding the theoretical basis of HRQoL is indispensable for valid research in this area. PMID- 28721293 TI - Laparoscopic transperitoneal partial nephrectomy for clinical T1b renal tumors: A prospective evaluation. PMID- 28721294 TI - A prospective evaluation of surgical outcomes of laparoscopic transperitoneal radical cystectomy/anterior pelvic exenteration: our surgical technique and experience. PMID- 28721295 TI - Different treatment approaches after failure of laparascopic treatment of calyceal diverticulum confused with communicating-type renal cyst: Case report. PMID- 28721296 TI - Mithridates VI Eupator king of Pontus and the venomous snakes. PMID- 28721298 TI - Hydrocortisone relieves the immediate post-operative scrotal edema after inguinal varicocelectomy: A prospective clinical trial. AB - This study aimed to assess the effect of a single IM injection of hydrocortisone succinate in relieving the immediate post-varicocelectomy scrotal edema. In all, 117 patients with grades II and III varicocele who developed post-varicocelectomy scrotal edema were randomly classified into group A (n = 59) that received a single IM hydrocortisone sodium succinate injection plus ordinary post-operative treatment and Group B (n = 58), which received the post-operative treatment alone. All patients were followed up to assess; changes in scrotal edema, the day of return to work and emergence of complications. Post-operative scrotal edema was assessed using a scrotal edema rating grades (SERG = 0-3) score. In group A, scrotal edema disappeared 1 day after steroid injection in 33 patients (55.9%), and after 2 days in the remaining 26 patients (44.1%), and all patients were returned to work within 5-7 days. In group B, the edema remained large in 36 patients (62.1%), moderate in 22 patients (37.9%), and disappeared after 9-12 days; and those patients returned to work within 11-13 days. It is concluded that a single IM hydrocortisone injection could be effective to reduce the immediate post-operative scrotal edema after inguinal varicocelectomy without obvious side effects. PMID- 28721297 TI - Potential application of Bacillus subtilis SPB1 lipopeptides in toothpaste formulation. AB - Toothpaste is a gel dentifrice used with a toothbrush as an accessory to clean, keep and promote oral hygiene. The literature review suggests that there are many different formulations of toothpastes and that each of their individual components present specific functions. The concentration of the toothpaste ingredients must be appropriately chosen taking into account the purposes of the toothpaste. Biosurfactants are considered as suitable molecules for application in many formulations such as in toothpaste one. In the present work, two dentifrice formulations were investigated and their efficiencies were tested using chemical surfactant agent and lipopeptide biosurfactant isolated from Bacillus subtilis SPB1. The physicochemical properties were analyzed considering several tests mainly spreading ability, water activity, pH, foaming and cleaning tests. The obtained results indicated that the SPB1 biosurfactant was as efficient as the chemical surfactant confirming its potential utilization in toothpaste formulation compared to the commercial one. The evaluation of the antimicrobial activity of the formulated dentifrice was carried out against eight bacteria. The results demonstrated that the biosurfactant-based product exhibited an important antimicrobial activity, which was very effective against Enterobacter sp and Salmonella typhinirium. PMID- 28721299 TI - Development of ionophore-based nanosphere emulsion incorporating ion-exchanger for complexometric titration of thiocyanate anion. AB - Ionophore-based ion-exchange nanosphere emulsion was prepared and tested for the determination of thiocyanate. The emulsified nanosphere contained the cationic additive tridodecylmethyl ammonium chloride (TDMAC), the plasticizer, and the ionophore Mn(III)-salophen or Mn(III)-salen. This emulsion was used as titrating agent for thiocyanate complexation with ionophores, which could be transduced using an ion-selective electrode (ISE) as an indicator electrode for the end point detection. The method showed no need for pH control and reliable selectivity, as thiocyanate could be determined in presence of other interfering ions with high accuracy. As well, the emulsion was stable and could be used for approximately couple of weeks. The developed emulsion could be used for the determination of thiocyanate in human saliva with standard deviation <4%. In sum, the proposed method could be used as an alternative for the argentometric titration and would open new avenues for the determination of neutral, anionic, and cationic species without necessity for water soluble ligands or pH control. PMID- 28721300 TI - Extracellular matrix alterations in the Peyronie's disease. AB - Peyronie's disease is characterized by fibrous plaque formation of the tunica albuginea, causing penile deformity and fertility problems. The aim of the present study was to investigate alterations in the extracellular matrix in Peyronie's disease. The study used tissues collected by surgical procedure from individuals that presented a well-established disease, while control samples were obtained by biopsies of fresh cadavers. Immunohistochemistry analysis followed by digital quantification was performed to evaluate TGF-beta, heparanases and metalloproteinases (MMPs). The profile of sulfated glycosaminoglycans, chondroitin sulfate and dermatan sulfate was determined by agarose gel electrophoresis, while hyaluronic acid quantification was obtained by an ELISA like assay. The expression of mRNA was investigated for syndecan-1 proteoglycan (Syn-1), interleukine-6 (IL-6), hyaluronic acid synthases, and hyaluronidases. Pathologic features showed decreased apoptosis and blood vessel number in Peyronie's tissues. TGF-beta and IL-6 were significantly enhanced in Peyronie's disease. There was an increased expression of heparanases, though no alteration was observed for MMPs. Hyaluronic acid as well as hyaluronic acid synthases, hyaluronidases, and dermatan sulfate were not changed, while the level of chondroitin sulfate was significantly (P = 0.008, Mann-Whitney test) increased in Peyronie's samples. Heparanases and sulfated glycosaminoglycans seem to be involved in extracellular matrix alterations in Peyronie's disease. PMID- 28721301 TI - Synthesis and characterization of N-Mannich based prodrugs of ciprofloxacin and norfloxacin: In vitro anthelmintic and cytotoxic evaluation. AB - Prodrugs, the inert derivatives of existing drugs have successfully contributed to the modification of their physicochemical properties. The improved antimicrobial potential due to enhanced lipophilicity of some of the synthesized prodrugs of antibacterial agents by various schemes has already been reported. In the current study, synthesis, characterization, and biological evaluation of some more lipid based prodrugs/compounds of ciprofloxacin and norfloxacin has been carried out. The synthesized prodrugs/compounds have been screened for anthelmintic activity using Indian earthworms and cytotoxic activity against human lung cancer cell lines A-549 employing sulforhodamine B (SRB) assay method. The prodrugs FQF1, 6b, 6c, and 6k were found to possess promising anthelmintic activity due to improved partition coefficient. Growth of selected cells lines was found to decrease with increase in concentration of prodrugs as compared to parent drug. Prodrug, 6k having GI50 value 28.8, has been proved to be the most active among all the synthesized prodrugs. Results of present investigation reveal that some of the synthesized prodrugs/compounds were found to possess promising biological activity. PMID- 28721302 TI - Correlation between two methods of florbetapir PET quantitative analysis. AB - This study evaluated performance of a commercially available standardized software program for calculation of florbetapir PET standard uptake value ratios (SUVr) in comparison with an established research method. Florbetapir PET images for 183 subjects clinically diagnosed as cognitively normal (CN), mild cognitive impairment (MCI) or probable Alzheimer's disease (AD) (45 AD, 60 MCI, and 78 CN) were evaluated using two software processing algorithms. The research method uses a single florbetapir PET template generated by averaging both amyloid positive and amyloid negative registered brains together. The commercial software simultaneously optimizes the registration between the florbetapir PET images and three templates: amyloid negative, amyloid positive, and an average. Cortical average SUVr values were calculated across six predefined anatomic regions with respect to the whole cerebellum reference region. SUVr values were well correlated between the two methods (r2 = 0.98). The relationship between the methods computed from the regression analysis is: Commercial method SUVr = (0.9757*Research SUVr) + 0.0299. A previously defined cutoff SUVr of 1.1 for distinguishing amyloid positivity by the research method corresponded to 1.1 (95% CI = 1.098, 1.11) for the commercial method. This study suggests that the commercial method is comparable to the published research method of SUVr analysis for florbetapir PET images, thus facilitating the potential use of standardized quantitative approaches to PET amyloid imaging. PMID- 28721303 TI - Value of 99mTc-MDP SPECT/CT and 18F-FDG PET/CT scanning in the evaluation of malignantly transformed fibrous dysplasia. AB - Although fibrous dysplasia is not considered a potentially premalignant disorder, malignant transformation occurs. Because of its rarity, radiographic features of malignantly transformed fibrous dysplasia on cross-sectional imaging modalities are less recognized, making diagnosis and differential diagnosis of the disease quite difficult in clinical practice. In this study, we analyzed the clinical characteristics, imaging features, pathology findings and surgery strategies of 19 malignantly transformed fibrous dysplasia. We found that there was significant male predominance in this specific cohort (13/6). While osteosarcoma (63.2%) was the most frequently occurring neoplasm secondary to fibrous dysplasia, other less commonly malignantly changed types included fasciculated sarcoma, malignant fibrous histiocytoma, fibrosarcoma and chondrosarcoma. We found that the diagnostic value of single modality imaging method, like conventional X-ray, computed tomography or non-contrast magnetic resonance imaging, was limited mainly because of a lack of whole-body metabolic information. In contrast, we highlighted that 99mTc-MDP SPECT/CT and/or 18F-FDG PET/CT scanning could exert a pivotal role in the management of malignantly transformed fibrous dysplasia by guiding precise biopsy and optimizing surgery options. PMID- 28721304 TI - Imaging features of Paget's disease on 11C choline PET/CT. AB - The purpose of this study was to investigate the appearance of Paget's disease (PD) on 11C choline PET/CT and correlate these findings to serum alkaline phosphatase (ALP) level and skeletal scintigraphy. With IRB approval, our institutional 11C choline PET/CT database (9/2005-6/2015) was searched for patients with PD. Site of osseous involvement, CT appearance, and multiple semi quantitative measures were measured and correlated with ALP and degree of uptake on bone scan. Our search identified 10 males (mean age 79.6 +/- 7.8 years). Four had polyostotic disease and seven had more than one 11C choline PET/CT. In total, 58 affected bones were evaluated on 25 PET/CTs. Mean lesion SUVmax was 2.6 +/- 0.89 (range 1.0-4.4), SUVmax/Liver SUVmean 0.33 +/- 0.13 (0.12-0.61), SUVmax/Liver SUVmax 0.29 +/- 0.11 (0.10-0.52), SUVmax/BP SUVmean 2.47 +/- 0.86 (0.91-4.22), and SUVmax/BP SUVmax 1.92 +/- 0.71 (0.68-3.45). There was no correlation between ALP and any semiquantitative measure. Bone scan uptake was marked in 41 bones, moderate in nine, and mild in six. There was no correlation between lesion SUVmax and bone scan uptake (P = 0.26). Paget's disease on 11C choline PET/CT demonstrates mild to moderate activity, which does not correlate with bone scan uptake or ALP level. It is important to recognize Paget's disease as a potential pitfall on 11C choline PET/CT. However, the characteristic appearance on the CT portion of PET/CT examinations should allow confident diagnosis and differentiation from prostate cancer osseous metastases. PMID- 28721305 TI - Fully automated GMP production of [68Ga]Ga-DO3A-VS-Cys40-Exendin-4 for clinical use. AB - [68Ga]Ga-DO3A-VS-Cys40-Exendin-4/PET-CT targeting glucagon like peptide-1 receptor (GLP-1R) has previously demonstrated its potential clinical value for the detection of insulinomas. The production and accessibility of this radiopharmaceutical is one of the critical factors in realization of clinical trials and routine clinical examinations. Previously, the radiopharmaceutical was prepared manually, however larger scale of clinical trials and healthcare requires automation of the production process in order to limit the operator radiation dose as well as improve tracer manufacturing robustness and on-line documentation for enhanced good manufacturing practice (GMP) compliance. A method for 68Ga-labelling of DO3A-VS-Cys40-Exendin-4 on a commercially available synthesis platform was developed. Equipment such as 68Ge/68Ga generator, synthesis platform, and disposable cassettes for 68Ga-labelling used in the study was purchased from Eckert & Ziegler. DO3A-VS-Cys40-Exendin-4 was synthesized in house. The parameters such as time, temperature, precursor concentration, radical scavenger, buffer concentration, pH, product purification step were investigated and optimised. Reproducible and GMP compliant automated production of [68Ga]Ga DO3A-VS-Cys40-Exendin-4 was developed. Exendin-4 comprising methionine amino acid residue was prone to oxidation which was strongly influenced by the elevated temperature, radioactivity amount, and precursor concentration. The suppression of the oxidative radiolysis was achieved by addition of ethanol, dihydroxybenzoic acid and ascorbic acid to the reaction buffer as well as by optimizing heating temperature. The non-decay corrected radiochemical yield was 43+/-2% with radiochemical purity of over 90% wherein the individual impurity signals in HPLC chromatogram did not exceed 5%. Automated production and quality control methods were established for paving the pathway for broader clinical use of [68Ga]Ga-DO3A VS-Cys40-Exendin-4. PMID- 28721306 TI - Role of conventional magnetic resonance imaging in the screening of epilepsy with structural abnormalities: a pictorial essay. AB - Epilepsy is a chronic neurological disease with serious impact on patients and society. The causes of epilepsy comprise a heterogeneous group of disorders, rendering epilepsy diagnoses rather difficult and challenging. The primary role of MRI is to locate and define the probable anatomic epileptogenic lesions. In the developing countries, where functional MRI (fMRI) is not popular, conventional MRI (cMRI) becomes especially important in epilepsy diagnoses. Apart from that, an experienced radiologist can increase the diagnostic yield of MRI to epileptogenic lesions. Thus, we present a pictorial review focusing on the role of cMRI in the screening of epilepsy with structural abnormalities and highlighting the key findings on cMRI to help radiologists to be familiar with the characteristic findings. Considering the complexity and diversity of the structural abnormalities, we propse a mnemonic "MAGIC TVs" approach to reduce false negative diagnosis and improve the diagnosis rate. PMID- 28721307 TI - Multispectral fluorescence guided surgery; a feasibility study in a phantom using a clinical-grade laparoscopic camera system. AB - Although the possibilities in image guided surgery are advancing rapidly, complex surgical procedures such as nerve sparing prostatectomy still lack precision regarding differentiation between diseased and delicate anatomical structures. Here, the use of complementary fluorescent tracers in combination with a dedicated multispectral fluorescence camera system could support differentiation between healthy and diseased tissue. In this study, we provide proof of concept data indicating how a modified clinical-grade fluorescence laparoscope can be used to sensitively detect white light and three fluorescent dyes (fluorescein, Cy5, and ICG) in a sequential fashion. Following detailed analysis of the system properties and detection capabilities, the potential of laparoscopic three-color multispectral imaging in combination with white light imaging is demonstrated in a phantom set-up for prostate cancer. PMID- 28721308 TI - Eliciting Disease Data from Wikipedia Articles. AB - Traditional disease surveillance systems suffer from several disadvantages, including reporting lags and antiquated technology, that have caused a movement towards internet-based disease surveillance systems. Internet systems are particularly attractive for disease outbreaks because they can provide data in near real-time and can be verified by individuals around the globe. However, most existing systems have focused on disease monitoring and do not provide a data repository for policy makers or researchers. In order to fill this gap, we analyzed Wikipedia article content. We demonstrate how a named-entity recognizer can be trained to tag case counts, death counts, and hospitalization counts in the article narrative that achieves an F1 score of 0.753. We also show, using the 2014 West African Ebola virus disease epidemic article as a case study, that there are detailed time series data that are consistently updated that closely align with ground truth data. We argue that Wikipedia can be used to create the first community-driven open-source emerging disease detection, monitoring, and repository system. PMID- 28721310 TI - A Pilot Study to Determine the Effect of an Educational DVD in Philippine Languages on Cancer Clinical Trial Participation among Filipinos in Hawai'i. AB - We conducted an experimental pilot study in an oncology clinic in Honolulu, Hawai'i to determine the effect of a culturally-tailored educational DVD on cancer clinical trial participation among Filipino cancer patients. Thirty-seven patients participated in the study, with 17 randomized into the control group (ie, usual education) and 20 into the intervention group (ie, usual education plus educational DVD). Participants completed pre- and post-educational questionnaires with items asking about understanding of several cancer topics, behavioral outcomes, and attitudes regarding several treatment and physician related topics. A Fisher's exact test was conducted to explore the association between enrollment into a clinical trial and group assignment. General linear models were created to determine significant differences between study groups in post-education response scores for each questionnaire item after controlling for age, gender, education, and pre-education response scores. Two participants from the control group and three participants from the intervention group enrolled into clinical trials. Results showed no significant association between clinical trial enrollment and study group assignment (P > .99). A significant difference was found between study groups on surety of joining the clinical trial suggested to them (P = .013). A multilingual educational DVD to supplement clinical trial education may positively influence Filipino cancer patients to move forward with the decision to join a cancer clinical trial. However, health literacy may serve as a major barrier to actual enrollment into the particular clinical trial available to a patient. PMID- 28721309 TI - Retinal Pigment Epithelial Cells are a Potential Reservoir for Ebola Virus in the Human Eye. AB - PURPOSE: Success of Ebola virus (EBOV) as a human pathogen relates at the molecular level primarily to blockade the host cell type I interferon (IFN) antiviral response. Most individuals who survive Ebola virus disease (EVD) develop a chronic disease syndrome: approximately one-quarter of survivors suffer from uveitis, which has been associated with presence of EBOV within the eye. Clinical observations of post-Ebola uveitis indicate involvement of retinal pigment epithelial cells. METHODS: We inoculated ARPE-19 human retinal pigment epithelial cells with EBOV, and followed course of infection by immunocytochemistry and measurement of titer in culture supernatant. To interrogate transcriptional responses of infected cells, we combined RNA sequencing with in silico pathway, gene ontology, transcription factor binding site, and network analyses. We measured infection-induced changes of selected transcripts by reverse transcription-quantitative polymerase chain reaction. RESULTS: Human retinal pigment epithelial cells were permissive to infection with EBOV, and supported viral replication and release of virus in high titer. Unexpectedly, 28% of 560 upregulated transcripts in EBOV-infected cells were type I IFN responsive, indicating a robust type I IFN response. Following EBOV infection, cells continued to express multiple immunomodulatory molecules linked to ocular immune privilege. CONCLUSIONS: Human retinal pigment epithelial cells may serve as an intraocular reservoir for EBOV, and the molecular response of infected cells may contribute to the persistence of live EBOV within the human eye. TRANSLATIONAL RELEVANCE: This bedside-to-bench research links ophthalmic findings in survivors of EVD who suffer from uveitis with interactions between retinal pigment epithelial cells and EBOV. PMID- 28721311 TI - From Kaua'i to Hawai'i Island: Interisland Differences in Emergency Contraceptive Pill Availability. AB - Emergency contraceptive pills (ECPs) are medications used after unprotected intercourse, underprotected intercourse, or sexual assault to decrease the risk of pregnancy. Availability of ECPs in Hawai'i's retail pharmacies was last assessed in 2007, following over-the-counter access to levonorgestrel ECPs (LNG ECP) for women age 18 years or older and prior to U.S. Food and Drug Administration (FDA) approval of prescription-only ulipristal acetate (UPA). We conducted a county-by-county subanalysis from a larger observational population based study on statewide availability of ECPs in Hawai'i's pharmacies. In the original study, researchers called all 198 unique retail pharmacies in Hawai'i between December 2013 and June 2014. Only 3% of pharmacies had UPA immediately available on-site in the state, with UPA available on Kaua'i and O'ahu only. At least one form of LNG-ECPs was available in 82% of pharmacies in 2013-2014, roughly the same as 2007 (81%) (P=0.9) when Lana'i and Moloka'i lacked access. Currently, only Moloka'i lacks retail pharmacy access to ECPs. When controlling for general inflation, the 2013-2014 mean price for name brand LNG-ECP fell within the reported range of 2007 prices. Generic LNG-ECPs were substantially lower in price than name brand LNG-ECPs in 2007 and 2013-2014. Availability of UPA is limited and significantly lower compared to LNG-ECPs. Availability of LNG ECPs statewide has remained stable and the arrival of generics has decreased prices. PMID- 28721312 TI - 2016 Writing Contest Undergraduate Winner: The Relationship Between Medication Adherence and Total Healthcare Expenditures by Race/Ethnicity in Patients with Diabetes in Hawai'i. AB - Diabetes is a costly, chronic disease that is becoming increasingly prevalent worldwide. Studies show that Native Hawaiians suffer from higher rates of diabetes and lower rates of medication adherence compared to Caucasians and Japanese. This study compared total annual healthcare expenditures of patients with diabetes in Hawai'i by race and ethnicity and determined whether any existing differences persisted after controlling for medication adherence and demographic factors. The study population consisted of 30,445 individuals, using administrative claims data from a large health plan in Hawai'i. Filipinos, Native Hawaiians, and Other Pacific Islanders had significantly lower medication adherence rates compared to other groups. These ethnic groups also had the lowest median healthcare costs. In contrast, Caucasians had one of the highest medication adherence rates coupled with the highest median annual healthcare expenditures at $5,132. Generalized linear regression models showed that after controlling for demographic factors and medication adherence, Japanese (RR=0.86, 95%CI [0.78, 0.94]), Chinese (RR=0.83, 95%CI [0.73, 0.95]), Filipinos (RR=0.74, 95%CI [0.67, 0.82]), and Native Hawaiians (RR=0.74, 95%CI [0.67, 0.82]) had significantly lower total healthcare costs compared to Caucasians. Costs for Other Pacific Islanders were not significantly different from those of Caucasians. This study provides evidence that total health-related cost is associated with a multitude of factors that further research may reveal. PMID- 28721314 TI - Medical School Hotline: John A. Burns School of Medicine University of Hawai'i at Manoa, Convocation Ceremony Keynote Address, May 14, 2017. PMID- 28721313 TI - 2016 Writing Contest graduate Winner: Cardiovascular Disease Training for Community Health Workers Serving Native Hawaiians and Other Pacific Peoples. AB - To help community health workers (CHW) meet increased demand for their services, it is essential to have data supported strategies for approaches to their training and capacity development. The objective of this paper is to report on the development, implementation, and evaluation of "Heart 101," a cardiovascular disease (CVD) training program, conducted among CHW in Hawai'i who serve Native Hawaiians and other Pacific Peoples (NHPP). Principles from Community-Based Participatory Research provided a framework to develop and implement the 5-hour training curriculum. Developers incorporated teaching strategies shown to be effective among learners that represent the majority of CHW, and included principles of adult learning theory and culture-based education. Training participants completed pre-, post-, and 6-months post-training knowledge tests, as well as demographic and participant satisfaction surveys. Data analysis based on pre- and post-training knowledge tests (n=30) indicated that Heart 101 significantly increased CVD knowledge by 32% (P < .001, t test). Long-term CVD competency measured at six-months post-training (n = 20) was also shown to be significant (P < .001, t test). Analysis of knowledge by subtopic suggested CHW strengths in clinical aspects of CVD and weaknesses in medical terminology and basic science aspects. These results, along with positive participant satisfaction, suggest that a culturally relevant and interactive course is a strong approach for CVD information dissemination to CHW serving NHPP communities, and provides insight on potential areas for special focus in their training. The demonstrated success of Heart 101 has positive implications for the standardization of CHW education and for their professional development. PMID- 28721315 TI - Insights in Public Health: Capacity Building Using a Bi-Directional Model: University of Hawai'i at Manoa and the Federal University of Rio Grande do Norte Santa Cruz Campus. PMID- 28721317 TI - Ameloblastic Fibrodentinoma: A Case with Varied Patterns of Dysplastic Dentin. AB - Ameloblastic fibrodentinoma is a benign odontogenic tumor belonging to the category of "odontogenic epithelium with odontogenic ectomesenchyme" along with recognition of induction in the form of dentin in atypical or dysplastic forms. The biological behaviour of ameloblastic fibrodentinoma is not very different from ameloblastic fibroma; hence, it is treated similarly by conservative procedures. It is important to understand the histopathogenesis of these rare tumors. Though rare, they are an independent entity awaiting recognition. Here, we report a case of amelobalstic fibrodentinoma in a 14-year-old female patient. PMID- 28721318 TI - Infective Endocarditis Presenting as Bilateral Orbital Cellulitis: An Unusual Case. AB - Orbital cellulitis is a severe and sight-threatening infection of orbital tissues posterior to the orbital septum. The most common causes of orbital cellulitis are rhinosinusitis, orbital trauma, and surgery. Infective endocarditis (IE) is a systemic infection that begins on cardiac valves and spreads by means of the bloodstream to peripheral organs. Septic emboli can spread to any organ including the eyes and can cause focal or diffuse ophthalmic infection. Ocular complications of IE classically include Roth's spots, subconjunctival hemorrhages, chorioretinitis, and endophthalmitis. IE as a cause of orbital cellulitis has been described by only one author in the literature. Here, we present a very rare case of bilateral orbital cellulitis caused by IE. Through this case, we aim to create awareness of the potential for serious ocular complications in IE and provide an overview of the management. PMID- 28721319 TI - Combined Sacroplasty and Iliosacral Fixation Using Triangular Titanium Implants for the Treatment of Sacral Insufficiency Fractures with Concomitant Sacral Instability. AB - Sacral insufficiency fractures (SIFs) are a common, under-recognized cause of debilitating low back pain, particularly in elderly patients with osteoporotic bone disease or risk factors for bone demineralization. Conservative therapy has been the mainstay of treatment for these types of fractures. This places patients at increased risk for the development of secondary illnesses associated with prolonged immobility, which might prevent a full return to the preinjury level of function. Surgical intervention for SIFs has increased over the past two decades in an attempt to overcome these complications and improve patient functionality. Sacroplasty and iliosacral screw stabilization are two specific procedures performed to treat SIFs. The purpose of this case report is to further document the existence of this condition, as well as to detail a novel approach for surgically treating this condition with a combination of the above procedures. PMID- 28721320 TI - Detection of Chronic Kidney Disease by Using Different Equations of Glomerular Filtration Rate in Patients with Type 2 Diabetes Mellitus: A Cross-Sectional Analysis. AB - Introduction Chronic kidney disease (CKD) is a global threat due to its high mortality. It is essential to know the actual magnitude of diabetic CKD to design a specific management program. However, there is limited knowledge regarding the most suitable equation to measure CKD in patients with Type 2 diabetes mellitus (T2DM). This paper aimed to analyze estimated glomerular filtration rate (eGFR) based on different equations to detect the CKD among T2DM. Methods A hospital based cross-sectional study was carried out, and a clinical registry was used to collect 4,042 T2DM patients from a large district hospital in Northeast Thailand. CKD patients were diagnosed when eGFR was less than 60 ml/min/1.73m2. Using Stata statistical software (StataCorp LP, College Station, TX), three standard equations, such as 'modification of diet in renal disease (MDRD-4)', 'chronic kidney disease epidemiology collaboration (CKD-EPI)', and 'Cockcroft-Gault (C-G)' equations, were used to produce eGFR values to report and compare stages of CKD. Results The mean age of the patients was 61.4 (+/- 10.7) years and male to female ratio was 1:1.9. According to the MDRD-4, CKD-EPI, and C-G equation, the prevalence of diabetic CKD was 21.4%, 21.9%, and 31.4%, respectively, and the frequency of CKD Stage 3 to 5 was found to be different among T2DM. About 3,789 (93.9%) measurements appeared to be classified as different stages of CKD (Stages 1 to 5) between MDRD-4 and CKD-EPI equations (kappa: 0.905; 95% confidence interval (CI): 0.83 - 0.97, p < 0.001). However, this study found that the above mentioned agreement was 70.9% between CKD-EPI and C-G equation (kappa: 0.56, 95% CI: 0.44 - 0.67, p < 0.001). Conclusions CKD-EPI equations can overcome the constraint of MDRD-4 and C-G equations to report CKD and can be used in patients with T2DM. PMID- 28721321 TI - Correlation of Ventilation-Perfusion (V/Q) Scan Results as Compared with Clinical Probability of Pulmonary Embolism in African American Population. AB - Introduction Current guidelines suggest the use of the more specific Wells' score could safely reduce the number of unnecessary scans. There is a lack of research to support whether these guidelines apply to the African American population. This study aims to evaluate the correlation of clinical pretest probability of pulmonary embolism (PE) with ventilation-perfusion (V/Q) scan results in a predominantly African American population and to test whether current guidelines based on studies conducted in other populations hold true in this group. Material and Methods A retrospective descriptive study to determine the diagnostic utility of the V/Q scan was conducted among patients who were seen during January 2012 to January 2016. The study population included patients who underwent a V/Q scan for evaluation of PE. One hundred and seventy-five charts were reviewed and 49 were excluded due to poor quality data. A review of the initial history, as well as discharge summaries, was performed. Wells' probability of PE was compared with the results of the scan. Laboratory tests and imaging studies were reviewed and analyzed. Result The median age of the study population was 63.02 +/- 16.12 years. The majority of the study population, 121 patients (92.4%), was African American. Sixty-four (48.9%) VQ scans were done for a low clinical probability for pulmonary embolism as defined by the Wells' clinical score. The most common clinical presentations were shortness of breath (SOB) - 74 (58%), leg pain or swelling - 39 (29.8%), chest pain - 36 (27.4%), and syncope - 4 (3.1%). Sixty-two (96.9 %) patients with low clinical probability had low probability VQ scans (P = 0.03). Among the patients who underwent CT angiography and V/Q scanning, a low probability scan was noted in 25 patients with no pulmonary embolism on CT (96.2 %) (P = 0.006). Conclusions This study showed a strong correlation between low clinical probability and low probability V/Q scans and its utility to safely rule out PE in a predominantly black population. Studies conducted in other populations have detected similar findings. PMID- 28721322 TI - Etiology and Age Distribution of Syncope in a Predominantly African-American Population. AB - BACKGROUND: Syncope, the sudden transient loss of consciousness due to multiple etiologies, usually has worse outcomes in African Americans compared with other races because of other comorbidities. This study aims to identify a correlation between the etiologies of syncope and age in a predominantly African-American sample population to facilitate future investigations with potentially improved specificity to address this condition. METHODS: We reviewed the medical records of 155 patients who presented with syncope concerns to the emergency department at our university hospital. After three charts were discarded due to poor data, the patients were divided into four age groups: <40 years old (25 patients), 40 60 years old (62 patients), 61-80 years old (44 patients), and >80 years old (21 patients). The etiology of syncope was reviewed in each case and categorized as either a vasovagal episode, orthostatic hypotension, pulmonary embolism, and related to cardio, neurologic, drug, or unspecified. RESULTS: For most of the patients in our study population, regardless of age, the etiology of syncope remained unspecified. Vasovagal related was the second most common etiology. The likelihood of having cardiac etiology under the age group of 40 is very low compared with those over 40 years (p = 0.026). Also, the incidence of pulmonary embolism is very low in all age groups with pulmonary embolism as a cause of syncope seen in only three patients (n = 3; 1.95%). CONCLUSIONS: Except for cardiac etiology being more likely in patients over age 40, we found no other correlation of age to syncope etiology. We also found that the etiology of syncope in African-American patients is similar to that of the general population. We recommend physicians to order a relevant workup, when clinical suspicion for syncope is present along with specific etiologies. PMID- 28721323 TI - Endovascular Management of Stroke Patients with Large Vessel Occlusion and Minor Stroke Symptoms. AB - Endovascular mechanical thrombectomy for stroke patients with large vessel occlusion (LVO) in the anterior circulation has become the standard of care based on several major randomized clinical trials. The successful result reported by these trials constitutes what may be the largest achievement in the history of neurological sciences. However, most of these mechanical thrombectomy trials (except for the multicenter randomized clinical trial of endovascular treatment for acute ischemic stroke in the Netherlands, i.e., MR CLEAN and Extending the Time for Thrombolysis in Emergency Neurological Deficits-Intra-Arterial, i.e., EXTEND-IA) excluded stroke patients with minor to mild stroke symptoms with National Institutes of Health Stroke Scale (NIHSS) scores of six to eight or lower. The median NIHSS score for patients who underwent acute endovascular thrombectomy was approximately 15 to 17 in all trials. To date, the evidence is lacking to support the mechanical thrombectomy in patients with acute stroke and LVO with minor to mild severity on NIHSS score. The purpose of this review was to assess the current data, safety and clinical outcomes in stroke patients with minor to mild symptoms who were treated with endovascular thrombectomy. PMID- 28721324 TI - A 39-Year-Old Pregnant Woman with Pulmonary Emboli on Long Term Anticoagulation. AB - We present the case of a 39-year-old pregnant woman with Klippel-Trenaunay syndrome (KTS). We demonstrate the risks of multiple, co-existing pro-thrombotic states (pregnancy, KTS), discuss complications of KTS (deep venous thromboembolisms and pulmonary emboli) and highlight general and disease-specific preventive measures against venous thromboembolic events (VTE). KTS is a rare condition and it's co-existence with pregnancy and VTEs is rarer still. PMID- 28721325 TI - Massive Intraoperative Blood Loss Secondary to Pulmonary Artery Injury During a Video-Assisted Thorascopic Surgery: The Importance of Protocols and Preparedness. AB - Hemorrhagic shock is a potentially devastating surgical condition that can present unexpectedly. This original case report involves a 57-year-old man who experienced unexpected significant blood loss as a result of iatrogenic injury to the pulmonary artery during a video-assisted thorascopic surgery. This case highlights the importance of preparedness and massive transfusion protocols in responding to intraoperative crises of this nature. PMID- 28721326 TI - Tension Pneumocephalus Following Bilateral Craniotomies. AB - Pneumocephalus is defined as a collection of air within the cranial cavity. It is a common finding following head injury with skull base fracture and neurosurgical procedures. Tension pneumocephalus is a rare complication. The diagnosis is clinical and radiological with the characteristic Mount Fuji sign seen on computed tomography (CT). It is a neurosurgical emergency, and early recognition and treatment are vital. PMID- 28721327 TI - Two Catastrophes in One Patient: Drug Reaction with Eosinophilia and Systemic Symptoms and Toxic Shock Syndrome. AB - A 70-year-old, immunocompromised patient presented to the emergency room (ER) five weeks after she was started on clopidogrel. She complained of skin eruption, mouth ulcers, fatigue, and myalgia over the past two weeks. Labs showed severe hyponatremia, acute kidney injury, rhabdomyolysis, hyperkalemia, and elevated liver enzymes. She was treated with steroids and discharged after her condition improved. However, a month later, she returned to the ER, complaining of nausea, vomiting, diarrhea, dizziness, chills, and shortness of breath over the past two days. She was lethargic and had orthostatic hypotension. She deteriorated clinically within a few days, with worsening lethargy and the development of respiratory distress along with profound hypotension. She needed mechanical ventilation and vasopressors. In addition, she had melena, severe thrombocytopenia, and hemolytic anemia. With supportive care, she improved and was discharged after a long stay in the intensive care unit. Retrospectively, the first hospitalization was believed to be caused by drug reaction with eosinophilia and systemic symptoms (DRESS). Treating that with steroids compromised her immune system beyond her pre-existing primary immunodeficiency status. At the time of her second hospitalization, she met the Centers for Disease Control and Prevention (CDC) criteria for a toxic shock syndrome (TSS) diagnosis. Her TSS started four days after a skin biopsy, which was done as part of her skin rash workup. It was thought that the source of the exotoxin that mediated her TSS was her skin, given the temporal relationship of the skin biopsy to her TSS. Another potential source of the exotoxin was the gastrointestinal tract, given the predominant gastrointestinal symptoms she had at the time of her second admission. PMID- 28721328 TI - Dramatic Regression of a Fungating Breast Lesion Treated with Radiation Therapy. AB - Although advances in screening mammography have dramatically improved the early detection of breast cancer, a subset of breast cancer cases still present as locally advanced disease. Some of these patients develop fungating lesions, which are difficult to manage and can have a severe impact on the quality of life. Palliative treatment options include surgery, intra-arterial chemotherapy, and radiation therapy. Herein, we describe the case of a patient who presented with a fungating breast mass and demonstrated an immediate and durable response to radiation therapy with a significantly improved quality of life. PMID- 28721329 TI - Effect of Different Crown Materials on the InterLeukin-One Beta Content of Gingival Crevicular Fluid in Endodontically Treated Molars: An Original Research. AB - INTRODUCTION: Crown materials used in fixed prosthodontics come into close and prolonged contact with the gingiva. OBJECTIVE: The purpose of this study was to evaluate the effect of different crown materials on the interleukin-one beta (IL 1beta) content of the gingival crevicular fluid and to study which crown material causes the highest inflammation on the marginal gingiva on a biochemical basis. MATERIALS AND METHODS: Twenty patients with single endodontically treated tooth were examined. Contralateral teeth were taken as controls. The crown materials in contact with the marginal gingiva were divided into three groups: Group 1- metal, Group2- ceramic, Group 3-zirconia. The collected data were analyzed with International Bibliography of the Social Sciences (IBSS). Statistical Package for the Social Sciences (SPSS) Statistics software 23.0 (IBM Corp, Armonk, New York). All assay procedures were carried out and the results of the collected samples were calculated using the ELISA-AIDTM technique. RESULTS: Multiple comparisons using one-way analysis of variance (ANOVA) between the materials on day zero, 45th and 90th day was highly significant with p=0.0005. Pairwise comparison using Tukey's honest significant difference (HSD) posthoc test was also highly statistically significant with p= 0.0005 except for ceramic & zirconia which were significant at p=0.04 on the 90th day. Multiple comparison using repeated measure of ANOVA with Bonferroni correction between day zero, 45th and 90th day was found to be statistically significant only for zirconia (p=0.002). CONCLUSION: This study was conducted to evaluate the effect of different crown materials on the amount of marginal gingival inflammation by measuring the IL-1beta content in gingival crevicular fluid (GCF). At the end of the three-month analysis, it was seen that the zirconia crowns exhibited the least marginal gingival inflammation. PMID- 28721330 TI - Truebeam Radiosurgery for the Treatment of Trigeminal Neuralgia: Preliminary Results at a Single Institution. AB - INTRODUCTION: Radiosurgery is now an established method of satisfactory pain control in patients with trigeminal neuralgia (TN). The Varian Truebeam STx (Varian Medical Systems, Palo Alto, CA) linear accelerator (LINAC) system is an arc-based, frameless stereotactic radiosurgery system used for the treatment of TN. To our knowledge, there has been only one published series of patient histories that documents the use of a frameless LINAC system for the treatment of TN. We describe the treatment parameters, patient outcomes, and complications associated with the treatment of TN. METHODS: All patients treated with the Truebeam system for TN between 2012 and 2015, with at least a six-month follow up, were identified. A dose of 90 Gy was delivered to the isocenter using a 0.5 cm diameter cone. The cisternal segment of the trigeminal nerve was placed at the location of the LINAC isocenter using an ExacTracTM (Brainlab, Munich, Germany) image guidance system. The radiosurgical dose, Barrow Neurologic Institute pain score (BNI PS), symptom recurrence, magnetic resonance imaging (MRI) radiographic changes, and other complications, including Barrow Neurologic Institute facial numbness score (BNI FN), were analyzed. RESULTS: A total of 18 patients-15 women and 3 men-with a mean age of 58 years (median: 59 years; range: 22-84 years) were treated at our institution. Fourteen patients (78%) had a BNI PS of IIIb or better, which was considered successful treatment. Twelve patients had excellent (BNI PS I) pain relief and two patients had good (BNI PS II-IIIB; recurrence after one year) pain relief. The pain of four patients recurred after a mean of 10 months. CONCLUSION: Truebeam radiosurgery can provide effective and safe treatment for patients suffering from TN. The efficacy appears similar to other frame- and frameless-based systems. PMID- 28721331 TI - Role of Laparoscopy in the Management of Acute Surgical Abdomen Secondary to Phytobezoars. AB - A bezoar is a collection of indigestible material found in the alimentary canal, which can cause mechanical obstruction of the gastrointestinal tract. Phytobezoar is a variant composed of mostly plant material and indigestible fiber. Phytobezoar is a rare cause of small bowel obstruction (SBO) and happens more commonly in patients with risk factors predisposing to impaired gastrointestinal motility. We present a rare case of SBO secondary to phytobezoar in a 60-year-old female patient with type 2 diabetes. There was no prior history of any abdominal surgery. The abdominal computed tomography (CT) scan was inconclusive. Laparoscopy was found to be an effective diagnostic and therapeutic procedure in this patient. PMID- 28721332 TI - To Stent or Not to Stent: A Tale of Two Occlusions. AB - Stenting and balloon angioplasty, along with mechanical thrombectomy, have gained notability as adjunctive treatment options to intravenous tissue plasminogen activator (IV-tPA) for tandem internal carotid artery (ICA) and middle cerebral artery (MCA) occlusions (TIM occlusions). Acute ischemic strokes (AISs) secondary to TIM occlusions are associated with poor patient outcomes primarily due to low recanalization rates following intravenous thrombolysis, consequently prompting the need for more invasive recanalization efforts. Often, the treatment algorithm is based on the success of the initial angioplasty, suspected volume of completed infarction, and whether or not thrombolytics are utilized. Here, we present two patients with AIS due to TIM occlusions where two different treatment modalities were implemented for recanalization efforts. Patient 1 did not receive IV-tPA and was successfully managed with balloon angioplasty and subsequent carotid stenting followed by direct oral anticoagulant (DOAC) administration. Patient 2 received IV-tPA and balloon angioplasty without carotid stenting followed by intracranial mechanical thrombectomy. Complete recanalization was attained in both cases. Administration of IV-tPA can make subsequent carotid stenting a potentially higher-risk treatment option for patients with TIM due to potential hemorrhagic complications in the setting of requisite antiplatelet agents. Each case of AIS resulting from a TIM must be considered unique, and the use of IV thrombolytics, balloon angioplasty, carotid stenting, and mechanical thrombectomy alone or in combination must be tailored to the individual clinical parameters. PMID- 28721333 TI - Pulmonary cryptococcosis in a ruxolitinib-treated patient with primary myelofibrosis. AB - We present the case of a 79-year-old man who showed multiple pulmonary nodules on chest computed tomography (CT) after being treated for 6 months with ruxolitinib, an inhibitor of Janus kinase (JAK) 1 and 2, to treat primary myelofibrosis. We examined the lesions by bronchoscopy, and the biopsy specimen revealed fungus bodies of Cryptococcus with granulomatous inflammation. As a result, the patient was diagnosed with pulmonary cryptococcosis. The patient was treated with fluconazole (200 mg daily for 2 weeks) with concomitant ruxolitinib administration, but the pulmonary lesions progressed. Subsequently, the patient was treated with voriconazole (300 mg daily for 3 weeks), but the lesions worsened further. The administration of ruxolitinib was therefore discontinued, and the dosage of voriconazole was increased to 400 mg daily. Three months later, the pulmonary lesions diminished in size. The present case of pulmonary cryptococcosis occurred in a patient treated with ruxolitinib. Treatment of pulmonary cryptococcosis with concomitant JAK inhibitor administration may result in poor treatment efficacy. It might be better to stop administration of JAK inhibitors, if possible, in patients being treated for pulmonary cryptococcosis. PMID- 28721334 TI - Draft genome sequence of Bradyrhizobium paxllaeri LMTR 21T isolated from Lima bean (Phaseolus lunatus) in Peru. AB - Bradyrhizobium paxllaeri is a prevalent species in root nodules of the Lima bean (Phaseolus lunatus) in Peru. LMTR 21T is the type strain of the species and was isolated from a root nodule collected in an agricultural field in the Peruvian central coast. Its 8.29 Mbp genome encoded 7635 CDS, 71 tRNAs and 3 rRNAs genes. All genes required to stablish a nitrogen-fixing symbiosis with its host were present. The draft genome sequence and annotation have been deposited at GenBank under the accession number MAXB00000000. PMID- 28721336 TI - Post-endovascular aneurysm repair (EVAR) testicular ischemia: A rare complication. AB - Endovascular aneurysm repair (EVAR) is a common modality of treating abdominal aortic aneurysms (AAA). Common complications include endoleak, bleeding, infection, contrast related injuries, and ischemia. We present the case of a patient who experienced a testicular infarction following repair of an infrarenal AAA. We also discuss the implications for this complication and review the available literature for similar cases and treatment options. PMID- 28721335 TI - Investigation of newborns with abnormal results in a newborn screening program for four lysosomal storage diseases in Brazil. AB - Lysosomal storage diseases (LSDs) are genetic disorders, clinically heterogeneous, mainly caused by defects in genes encoding lysosomal enzymes that degrade macromolecules. Several LSDs already have specific therapies that may improve clinical outcomes, especially if introduced early in life. With this aim, screening methods have been established and newborn screening (NBS) for some LSDs has been developed. Such programs should include additional procedures for the confirmation (or not) of the cases that had an abnormal result in the initial screening. We present here the methods and results of the additional investigation performed in four babies with positive initial screening results in a program of NBS for LSDs performed by a private laboratory in over 10,000 newborns in Brazil. The suspicion in these cases was of Mucopolysaccharidosis I - MPS I (in two babies), Pompe disease and Gaucher disease (one baby each). One case of pseudodeficiency for MPS I, 1 carrier for MPS I, 1 case of pseudodeficiency for Pompe disease and 1 carrier for Gaucher disease were identified. This report illustrates the challenges that may be encountered by NBS programs for LSDs, and the need of a comprehensive protocol for the rapid and precise investigation of the babies who have an abnormal screening result. PMID- 28721337 TI - 2016 Revision to the WHO Classification of Acute Myeloid Leukemia. PMID- 28721338 TI - Is Aortic Aneurysm Preventable? AB - Abdominal aortic aneurysm (AAA) is a chronic inflammatory condition, triggered by the local accumulation of macrophages, oxidative stress and damage to the aortic wall. Pro-inflammatory eicosanoids seem to play a significant role in AAA. The pro-inflammatory events seen in AAA could be due to a deficiency of anti inflammatory eicosanoids such as lipoxin A4 (LXA4), resolvins, protectins and maresins as a result of reduced tissue concentrations of their precursors: arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). Thus, an imbalance between pro- and anti-inflammatory eicosanoids may underlie AAA. Angiotensin-II (Ang-II), a pro-inflammatory molecule, seems to have a role in AAA. I propose that AAA is due to the local (abdominal aortic wall) deficiency of AA and other PUFAs and their anti-inflammatory metabolites especially LXA4. The beneficial action of EPA and DHA reported in the animal experimental models of AAA induced by Ang-II infusion can be attributed to their (EPA and DHA) ability to enhance the formation of not only resolvins, protectins and maresins but also LXA4. It is likely that abdominal aortic tissue (endothelial cells, smooth muscle cells and other cells) may be deficient in AA, EPA and DHA, and have defective activity of 5-, 12-, and 15-lipoxygenases and cyclooxygenase, especially COX-2 resulting in decreased formation of LXA4, resolvins, protectins and maresins. Thus, methods designed to enhance the formation of LXA4 and other anti-inflammatory eicosanoids may form a new approach to prevent and manage AAA. PMID- 28721339 TI - The Role of Glucagon-like Peptide-1 Receptor Agonists in the Treatment of Type 2 Diabetes. AB - The role of GLP-1 agonists in the treatment of type 2 diabetes have been shown to be viable options for add-on therapy in diabetic patients, as well as potential monotherapy options. With six available GLP-1 agents, and new combination products in the pipeline, they are a promising drug class for type 2 diabetic patients, especially due to their extended dosing interval and potential weight loss benefits. PMID- 28721340 TI - Post-intensive Care Syndrome: an Overview. AB - Survival of critically unwell patients has improved in the last decade due to advances in critical care medicine. Some of these survivors develop cognitive, psychiatric and /or physical disability after treatment in intensive care unit (ICU), which is now recognized as post intensive care syndrome (PICS). Given the limited awareness about PICS in the medical faculty this aspect is often overlooked which may lead to reduced quality of life and cause a lot of suffering of these patients and their families. Efforts should be directed towards preventing PICS by minimizing sedation and early mobilization during ICU.All critical care survivors should be evaluated for PICS and those having signs and symptoms of it should be managed by a multidisciplinary team which includes critical care physician, neuro-psychiatrist, physiotherapist and respiratory therapist, with the use of pharmacological and non-apharmacological interventions. This can be achieved through an organizational change and improvement, knowing the high rate of incidence of PICS and its adverse effects on the survivor's life and daily activities and its effect on the survivor's family. PMID- 28721341 TI - Effects of Eplerenone on Resistance to Antihypertensive Medication in Patients with Primary or Secondary Hyperaldosteronism. AB - BACKGROUND AND OBJECTIVES: Resistant hypertension is an important problem; nearly half of diagnosed hypertensives are not controlled to target blood pressure levels, and approximately 90% of strokes occur among patients with resistant hypertension. Primary aldosteronism accounts for approximately 20% of resistant hypertension, but the role of secondary hyperaldosteronism in resistant hypertension is seldom considered. We assessed the effects of eplerenone in patients with hypertension and either primary or secondary hyperaldosteronism. METHODS: Patients with a history of resistant hypertension and a supine plasma aldosterone level >= 360 pmol/L were randomized to eplerenone versus placebo in a fully blinded study for one year. A medication intensity score was developed to assess the resistance of hypertension to medication (blood pressure * medication intensity). We assessed the effects of eplerenone on blood pressure and on resistance to concomitant medication. RESULTS: Final results were available in 37 patients (19 on eplerenone and 18 on placebo). Resistance to medication, as assessed by the intensity of concomitant medication required to maintain blood pressure control, was markedly reduced by eplerenone: medication intensity scores declined by -0.50 +/- 1.04 (SD) on placebo versus -2.11 +/- 1.45 with eplerenone (P = 0.0001), the Systolic Resistance Score declined by -80.00 +/- 122.93 on placebo versus -334.05 +/- 21.73 on eplerenone (P = 0.0001), and the Diastolic Resistance Score increased by 1.28 +/- 31.65 on placebo and declined by -40.74 +/ 57.08 on eplerenone (P = 0.009). CONCLUSIONS: Eplerenone significantly reduced resistance to concomitant antihypertensive medication in both primary and secondary hyperaldosteronism. PMID- 28721342 TI - Hepatitis B Virus Genotype E Infection among Egyptian Health Care Workers. AB - BACKGROUND AND OBJECTIVES: Health Care Workers (HCWs) are at a high risk of needle stick injuries and HBV infection in Egypt; this problem is further aggravated by low Hepatitis B (HB) vaccination coverage. Limited data are available on the prevalence of HBV infection in Egyptian HCWs. In this study, we aimed to assess the HBV infection rate and genotypes among Egyptian HCWs. METHODS: Five hundred and sixty-four (564) HCWs were included. Of them, 258 (45.74%) were health care providers and 306 (54.25%) were non-health care providers. All HCWs completed both the study questionnaires and provided a blood sample for HBV testing. Indeed, all HCWs were tested for Hepatitis B surface antigen (HBsAg) and antibody to Hepatitis B core antigen (anti-HBc), by enzyme linked immunosorbent assay. HBVDNA was checked for HCWs who tested positive for HBsAg and/or anti-HBc, by nested Polymerase Chain Reaction (PCR). HBVDNA positive HCWs were further subjected to HBV genotyping. RESULTS: The mean age of included HCWs was 33.0 +/- 9.8 years, of whom 319 (56.56%) were males. The mean duration of health care work was 9.3 +/- 6.7 years. The frequency of HBsAg and anti-HBc were 1.4%, and 24.5%, respectively. Old age and prolonged duration of health care work were significantly associated with anti-HBc seropositivity. Among 140 HCWs positive for HBsAg and/or anti-HBc, 14 (10 %) had positive HBVDNA by PCR. HBV/E (n = 7), HBV/D (n = 3) and co-infection with E and D (n = 4) genotypes were detected. CONCLUSION: Egyptian HCWs have a significantly high rate of HBV exposure. The detection of HBV/E genotype among Egyptian HCWs suggests prevalent transmission of HBV/E among Egyptian populations. PMID- 28721343 TI - Upper Gastrointestinal Bleeding in Patients with End Stage Renal Disease: Causes, Characteristics and Factors Associated with Need for Endoscopic Therapeutic Intervention. AB - BACKGROUND AND OBJECTIVES: The risk of upper gastrointestinal bleeding (UGIB) is increased among the end-stage renal disease (ESRD) patients. The aim of the current study was to describe the causes and characteristics of UGIB in ESRD patients at our center and to assess the need for endoscopic therapeutic intervention (ETI) using Rockall (RS) and Glasgow Blatchford scores (GBS). MATERIAL AND METHODS: All patients with ESRD and UGIB with age >=14 years were included. Frequencies and percentages were computed for categorical variables. Chi square test or Fischer's exact test was used for statistical analysis. RESULTS: A total of 59 subjects had a mean age of 47.25 +/- 15 years.The most common endoscopic findings seen were erosions in 33 (55.9%) patients, followed by ulcers in 18 (30.3%) patients. ETI was required in 33 (55.9%) patients, which included adrenaline injection in 19 (32.3%), hemoclip in 9 (15.2%) and argon plasma coagulation in 5 (8.4%) patients. Factors associated with the need of ETI were identified as: a combined presentation of hematemesis and melena (P=0.033), ulcer (P=0.002) and associated chronic liver disease (P=0.015). Six (10.1%) patients died. Death was more common if ETI was not performed (P=0.018). CONCLUSION: ETI was more commonly required in patients on maintenance hemodialysis with UGIB, who had presence of combined hematemesis and melena, ulcers and associated chronic liver disease. A Glasgow Blatchford score of >14 was helpful in assessing the need for ETI in these patients. PMID- 28721344 TI - Exploring Patient Characteristics and Barriers to Hepatitis C Treatment in Patients on Opioid Substitution Treatment Attending a Community Based Fibro scanning Clinic. AB - BACKGROUND AND OBJECTIVES: Hepatitis C virus (HCV) infection is a major public health issue. There is substandard uptake in HCV assessment and treatment among people who inject drugs (PWID). Community fibroscanning is used to assess disease severity and target treatment. METHODS: A survey was administered to a cohort of chronically HCV infected patients attending a community fibroscanning clinic. Questions targeted diagnosis of HCV, suitability, willingness and barriers to engagement in treatment. Descriptive and regression analysis, with thematic analysis of open-ended data was conducted. RESULTS: There was high acceptance of community fibroscanning among this cohort with over 90% (68) attending. High levels of unemployment (90%) and homelessness (40%) were identified. Most patients were on methadone treatment and had been HCV infected for greater than 10 years with length of time since HCV diagnosis being significantly longer in patients with fibroscan scores > 8.5 kPa (P = 0.016). With each unit increase in methadone dose, the odds of the >8.5 fibroscan group increased by 5.2%. Patient identified barriers to engagement were alcohol and drug use, fear of HCV treatment and liver biopsy, imprisonment, distance to hospital and early morning appointments. CONCLUSION: The study highlights the usefulness of community fibroscanning. Identifying barriers to treatment in this cohort affords an opportunity to increase the treatment uptake. The availability of afternoon clinics and enhanced prison linkage are warranted. PMID- 28721345 TI - Effects of a Low FODMAP Diet and Specific Carbohydrate Diet on Symptoms and Nutritional Adequacy of Patients with Irritable Bowel Syndrome: Preliminary Results of a Single-blinded Randomized Trial. AB - BACKGROUND AND OBJECTIVES: IBS is the most common functional disease of the low gastrointestinal tract. Recently, the interest towards a diet approach has increased, for example, a diet with low content of fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAPs). The aim of the present study is to evaluate the efficacy of a low FODMAP diet and a specific carbohydrate diet (SCD) conducted for 3 months on symptoms and to evaluate the deficiencies of vitamin D and folic acid in patients affected by IBS, matching the Rome IV criteria. METHODS: We evaluated 73 patients divided into 2 groups: one submitted to low FODMAP diet and one to SCD, for 3 months. Patients were assigned to one of the 2 groups randomly and blinded. All the patients filled a visual analogue scale (VAS) to evaluate the severity of symptoms and a diary to evaluate the number of days with symptoms, and this was repeated after 3 months. Final evaluation was made by a blinded investigator. RESULTS: In the end, the patients with low FODMAP diet had a significant improvement in bloating and distension (P = 0.000); the group with SCD instead had a low but not a significant improvement. One way ANOVA showed comparable severity of symptoms in the 2 groups pre-diet (P = 0.215), but a difference in the same symptoms after 12 days (P = 0.000). Tukey test showed a significant improvement in the low FODMAP diet group and only a trend of improvement in the second group of SCD. The vitamin D mean value in both groups at the time of enrollment was 38 ng/mL; in the end, the mean value in the low FODMAP diet group was 32 ng/mL and in the SCD group was 22 ng/mL, with a statistically significant difference. The folic acid mean value at the time of enrollment was 18 mg/dL; in the end, the mean value in the low FODMAP diet group was 15 mg/dL and in the SCD group was 8 mg/dL, with a statistically significant difference. CONCLUSION: Patients affected by IBS seem to have benefitted from a low FODMAP diet but not from an SCD, and a low FODMAP diet doesn't seem to cause vitamin D and folic acid deficiencies. PMID- 28721346 TI - Prediction of Survival Following Percutaneous Biliary Drainage for Malignant Biliary Obstruction. AB - BACKGROUND AND OBJECTIVES: Percutaneous transhepatic biliary drain is an intervention used to relieve malignant biliary obstruction. This study aims to explore survival after biliary drain insertion, predictive factors of survival and effectiveness to reduce total bilirubin level. METHODS: We conducted a retrospective analysis of 72 patients who had malignant biliary obstruction and received biliary drain during the time period between March 2005 and February 2015. RESULTS: Median patients' age was 56 years. 38 (52.7%) were males, 34(47.2%) were females. Median survival post biliary drain insertion was 46 days, 95% C/I (37.92-54.02), range (2-453 days). 1, 3, and 6 month survival rates were 64.7%, 26.5%, and 7.4% respectively. Multivariate analysis by Cox proportional hazards regression model showed the presence of ascites to be significant predictors of survival, other factors analyzed were: total bilirubin, serum creatinine, international normalization ratio, serum albumin, pleural effusion and liver metastasis. CONCLUSION: Survival after biliary drain insertion can vary from few days to few months. Presence of ascites is an independent predictor of survival after this intervention. PMID- 28721347 TI - Peliosis Hepatis Complicating Pregnancy: A Rare Entity. AB - Peliosis hepatis (PH) is a rare, benign condition of the liver characterized by the presence of blood-filled lacunar spaces in the parenchyma. It usually has a chronic presentation and is a rare cause of portal hypertension reported in adult patients. Its etiology is diverse and ranges from infectious agents to tumors to toxic substances and anabolic steroids; however, the cause remains unclear in 25 50% of patients. Similarly, the symptomatology and imaging findings are diverse. Biopsy is the definitive test to diagnose the condition. Herein, we present a case of a young female presenting in her seventh month of gestational amenorrhea with signs of portal hypertension and subsequently diagnosed to have PH. She was managed conservatively and delivered her baby normally. Later, she presented with spontaneous bacterial peritonitis and hepatic encephalopathy and developed hepatorenal syndrome. She later succumbed to her illness. The condition should be kept in the differential diagnosis of the atypical liver masses and liver diseases causing portal hypertension. PMID- 28721348 TI - Systematic genetic screening in a prospective group of Danish patients with pheochromocytoma. AB - Recent guidelines recommend consideration of genetic screening in all newly diagnosed patients with pheochromocytoma. Patients diagnosed with pheochromocytoma in the Region of Southern Denmark during 2006-2013 without previously recognized monogenetic etiology were offered genetic screening for mutations in the VHL, RET, SDHB, SDHC, and SDHD genes. A total of 41 patients were included, and genetic data were available in 35. In four of the 35 patients, a pathogenic variant was identified prior to the diagnosis of pheochromocytoma (von Hippel-Lindau disease, n=2; neurofibromatosis type 1, n=2). The patients carrying a genetic mutation were all younger than 45 years at time of diagnosis of pheochromocytoma, two patients presented with bilateral tumors, and one patient had a positive family history of pheochromocytoma. Genetic screening of the remaining 31 patients did not identify any mutations. The sporadic cases had a median age of 58 years (range 33-80 years). Three of 31 sporadic cases (ages 60, 69, and 76 years at time of diagnosis) presented with bilateral adrenal tumors, one patient had multiple adrenal tumors in both adrenal glands, and no patients had a positive family history of pheochromocytoma. Of the 31 patients, 24 (68.6%) were diagnosed with pheochromocytoma due to evaluation of an adrenal incidentaloma. In conclusion, monogenetic etiology was identified in four of 35 (11.4%) patients diagnosed with pheochromocytoma. PMID- 28721350 TI - Corrigendum: Cerebral Cavernous Malformations: Review of the Genetic and Protein Protein Interactions Resulting in Disease Pathogenesis. AB - [This corrects the article on p. 60 in vol. 3, PMID: 27896269.]. PMID- 28721351 TI - Cerebral Epidural Abscess Secondary to Blastomyces Masquerading as an Epidermoid Tumor. AB - There have been infrequent reports of isolated central nervous system blastomycosis. We report a case of intracranial epidural abscess secondary to Blastomyces dermatitidis in a patient residing in Rhode Island with a history of remote travel to an endemic area. The clinical, radiographic, and pathologic features of this unique case are reviewed. PMID- 28721349 TI - Hepatocellular carcinoma: early-stage management challenges. AB - Hepatocellular carcinoma (HCC) is a major cause of cancer death and is increasing in incidence. This review focuses on HCC surveillance and treatment of early stage disease, which are essential to improving outcomes. Multiple societies have published HCC surveillance guidelines, but screening efforts have been limited by noncompliance and overall lack of testing for patients with undiagnosed chronic liver disease. Treatment of early-stage HCC has become increasingly complex due to expanding therapeutic options and better outcomes with established treatments. Surgical indications for HCC have broadened with improved preoperative liver testing, neoadjuvant therapy, portal vein embolization, and perioperative care. Advances in post-procedural monitoring have improved efficacies of transarterial chemoembolization and radiofrequency ablation, and novel therapies involving delivery of radiochemicals are being studied in small trials. Finally, advances in liver transplantation have allowed for expanded indications beyond Milan criteria with non-inferior outcomes. More clinical trials evaluating new therapies and multimodal regimens are necessary to help clinicians design better treatment algorithms and improve outcomes. PMID- 28721352 TI - Detection of mcr-1-Carrying Escherichia coli Causing Bloodstream Infection in a New York City Hospital: Avian Origins, Human Concerns? AB - The spread of mcr-1 in the United States remains poorly defined. mcr-1-producing Escherichia coli that also carried blaSHV-12 was detected in a hospitalized patient. No additional cases were identified during screening of 801 Gram negative isolates. Genomic sequencing identified an IncX4 mcr-1- harboring plasmid and ST117 clonal background associated with avian pathogenic E coli. PMID- 28721353 TI - Hepatitis E Virus-Associated Meningoencephalitis in a Lung Transplant Recipient Diagnosed by Clinical Metagenomic Sequencing. AB - Hepatitis E virus (HEV) infection uncommonly causes chronic hepatitis and neurologic disease. We describe a case of genotype 3a HEV meningoencephalitis diagnosed by metagenomic next-generation sequencing, illustrating the power of an unbiased molecular approach to microbial testing and the first reported case of HEV infection presumably acquired through lung transplantation. PMID- 28721354 TI - Diagnostic Outcomes After Chest Radiograph Interpretation in Patients With Suspected Tuberculosis and Negative Sputum Smears in a High-Burden Human Immunodeficiency Virus and Tuberculosis Setting. AB - BACKGROUND: Evaluation of patients with suspected tuberculosis and negative sputum smears for acid-fast bacilli (AFB) is challenging, especially in high human immunodeficiency virus coinfection settings where sputum smears have lower sensitivity for detecting AFB. METHODS: We examined the utility of chest radiographs for detecting smear-negative pulmonary tuberculosis. Three hundred sixty sputum smear-negative patients who were referred from primary care clinics in the KwaZulu-Natal province of South Africa were evaluated. Chest radiographs were read by experienced pulmonologists using a previously validated Chest X-Ray Reading and Recording System (CRRS). RESULTS: Agreement between observers using CRRS was high at 91% with a Cohen's kappa of 0.64 (95% confidence interval [CI] = 0.52-0.76). Against a reference standard of sputum culture, sensitivity was 93% (95% CI = 86%-97%), whereas specificity was 14% (95% CI = 10%-19%). Performance against clinical diagnosis (following World Health Organization guidelines) was similar with sensitivity of 92% (95% CI = 88%-95%) and specificity of 20% (95% CI = 13%-28%). CONCLUSION: The low specificity of CRRS in this setting indicates poor diagnostic utility for detecting pulmonary tuberculosis. PMID- 28721355 TI - Simultaneously estimating the task-related and stimulus-evoked components of hemodynamic imaging measurements. AB - Task-related hemodynamic responses contribute prominently to functional magnetic resonance imaging (fMRI) recordings. They reflect behaviorally important brain states, such as arousal and attention, and can dominate stimulus-evoked responses, yet they remain poorly understood. To help characterize these responses, we present a method for parametrically estimating both stimulus-evoked and task-related components of hemodynamic responses from subjects engaged in temporally predictable tasks. The stimulus-evoked component is modeled by convolving a hemodynamic response function (HRF) kernel with spiking. The task related component is modeled by convolving a Fourier-series task-related function (TRF) kernel with task timing. We fit this model with simultaneous electrode recordings and intrinsic-signal optical imaging from the primary visual cortex of alert, task-engaged monkeys. With high [Formula: see text], the model returns HRFs that are consistent across experiments and recording sites for a given animal and TRFs that entrain to task timing independent of stimulation or local spiking. When the task schedule conflicts with that of stimulation, the TRF remains locked to the task emphasizing its behavioral origins. The current approach is strikingly more robust to fluctuations than earlier ones and gives consistently, if modestly, better fits. This approach could help parse the distinct components of fMRI recordings made in the context of a task. PMID- 28721356 TI - Targeted ischemic stroke induction and mesoscopic imaging assessment of blood flow and ischemic depolarization in awake mice. AB - Despite advances in experimental stroke models, confounding factors such as anesthetics used during stroke induction remain. Furthermore, imaging of blood flow during stroke is not routinely done. We take advantage of in vivo bihemispheric transcranial windows for longitudinal mesoscopic imaging of cortical function to establish a protocol for focal ischemic stroke induction in target brain regions using photothrombosis in awake head-fixed mice. Our protocol does not require any surgical steps at the time of stroke induction or anesthetics during either head fixation or photoactivation. In addition, we performed laser speckle contrast imaging and wide-field calcium imaging to reveal the effect of cortical spreading ischemic depolarization after stroke in both anesthetized and awake animals over a spatial scale encompassing both hemispheres. With our combined approach, we observed ischemic depolarizing waves (3 to [Formula: see text]) propagating across the cortex 1 to 5 min after stroke induction in genetically encoded calcium indicator mice. Measures of blood flow by laser speckle were correlated with neurological impairment and lesion volume, suggesting a metric for reducing experimental variability. The ability to follow brain dynamics immediately after stroke as well as during recovery may provide a valuable guide to develop activity-dependent therapeutic interventions to be performed shortly after stroke induction. PMID- 28721357 TI - Whole mouse brain imaging using optical coherence tomography: reconstruction, normalization, segmentation, and comparison with diffusion MRI. AB - An automated massive histology setup combined with an optical coherence tomography (OCT) microscope was used to image a total of [Formula: see text] whole mouse brains. Each acquisition generated a dataset of thousands of OCT volumetric tiles at a sampling resolution of [Formula: see text]. This paper describes techniques for reconstruction and segmentation of the sliced brains. In addition to the measured OCT optical reflectivity, a single scattering photon model was used to compute the attenuation coefficients within each tissue slice. Average mouse brain templates were generated for both the OCT reflectivity and attenuation contrasts and were used with an [Formula: see text]-tissue segmentation algorithm. To better understand the brain tissue OCT contrast origin, one of the mouse brains was acquired using dMRI and coregistered to its corresponding assembled brain. Our results indicate that the optical reflectivity in a fiber bundle varies with its orientation, its fiber density, and the number of fiber orientations it contains. The OCT mouse brain template generation and coregistration to dMRI data demonstrate the potential of this massive histology technique to pursue cross-sectional, multimodal, and multisubject investigations of small animal brains. PMID- 28721358 TI - Utah optrode array customization using stereotactic brain atlases and 3-D CAD modeling for optogenetic neocortical interrogation in small rodents and nonhuman primates. AB - As the optogenetic field expands, the need for precise targeting of neocortical circuits only grows more crucial. This work demonstrates a technique for using Solidworks(r) computer-aided design (CAD) and readily available stereotactic brain atlases to create a three-dimensional (3-D) model of the dorsal region of area visual cortex 4 (V4D) of the macaque monkey (Macaca fascicularis) visual cortex. The 3-D CAD model of the brain was used to customize an [Formula: see text] Utah optrode array (UOA) after it was determined that a high-density ([Formula: see text]) UOA caused extensive damage to marmoset (Callithrix jacchus) primary visual cortex as assessed by electrophysiological recording of spiking activity through a 1.5-mm-diameter through glass via. The [Formula: see text] UOA was customized for optrode length ([Formula: see text]), optrode width ([Formula: see text]), optrode pitch ([Formula: see text]), backplane thickness ([Formula: see text]), and overall form factor ([Formula: see text]). Two [Formula: see text] UOAs were inserted into layer VI of macaque V4D cortices with minimal damage as assessed in fixed tissue cytochrome oxidase staining in nonrecoverable surgeries. Additionally, two [Formula: see text] arrays were implanted in mice (Mus musculus) motor cortices, providing early evidence for long-term tolerability (over 6 months), and for the ability to integrate the UOA with a Holobundle light delivery system toward patterned optogenetic stimulation of cortical networks. PMID- 28721359 TI - Dataset on force measurements of needle insertions into two ex-vivo human livers. AB - A needle-tissue interaction experiment has been carried out, by inserting the inner needle of a trocar needle into two ex-vivo human livers. The dataset contains the forces that act on the needle during insertion and retraction into the livers. In addition, a MATLAB code file is included that provides base-level analysis of the data and generates force-position diagrams of the needle insertions. The dataset is available on Mendeley Data (do1i:10.17632/94s7xd9mzt.2), and is made publicly available to enable other researchers to use it for their own research purposes. For further interpretation and discussion of the data, one is referred to the associated research article entitled "PVA matches human liver in needle-tissue interaction" de Jong et al., 2017. PMID- 28721360 TI - Technical data for concentrated solar power plants in operation, under construction and in project. AB - This article presents technical data for concentrated solar power (CSP) plants in operation, under construction and in project all over the world in the form of tables. These tables provide information about plants (e.g., name of the CSP plant, country of construction, owner of the plant, aim of the plant) and their technical characteristics (e.g., CSP technology, solar power, area of the plant, presence and type of hybridization system, electricity cost, presence and type of TES, power cycle fluid, heat transfer fluid, operating temperature, operating pressure, type of turbine, type and duration of storage, etc.). Further interpretation of the data and discussions on the current state-of-the-art and future trends of CSP can be found in the associated research article (Pelay et al., 2017) [1]. PMID- 28721362 TI - Continued use of MDA-MB-435, a melanoma cell line, as a model for human breast cancer, even in year, 2014. PMID- 28721361 TI - Role of Endoplasmic Reticulum Stress in Learning and Memory Impairment and Alzheimer's Disease-Like Neuropathology in the PS19 and APPSwe Mouse Models of Tauopathy and Amyloidosis. AB - Emerging evidence suggests that endoplasmic reticulum (ER) stress may be involved in the pathogenesis of Alzheimer's disease (AD). Recently, pharmacological modulation of the eukaryotic translation initiation factor-2 (eIF2alpha) pathway was achieved using an integrated stress response inhibitor (ISRIB). While members of this signaling cascade have been suggested as potential therapeutic targets for neurodegeneration, the biological significance of this pathway has not been comprehensively assessed in animal models of AD. The present study investigated the ER stress pathway and its long-term modulation utilizing in vitro and in vivo experimental models of tauopathy (MAPT P301S)PS19 and amyloidosis (APPSwe). We report that thapsigargin induces activating transcription factor-4 (ATF4) in primary cortical neurons (PCNs) derived from rat and APPSwe nontransgenic (nTg) and transgenic (Tg) mice. ISRIB mitigated the induction of ATF4 in PCNs generated from wild-type (WT) but not APPSwe mice despite partially restoring thapsigargin induced translational repression in nTg PCNs. In vivo, C57BL/6J and PS19 mice received prolonged, once-daily administration of ISRIB. While the compound was well tolerated by PS19 and C57BL/6J mice, APPSwe mice treated per this schedule displayed significant mortality. Thus, the dose was reduced and administered only on behavioral test days. ISRIB did not improve learning and memory function in APPSwe Tg mice. While ISRIB did not reduce tau-related neuropathology in PS19 Tg mice, no evidence of ER stress-related dysfunction was observed in either of these Tg models. Taken together, the significance of ER stress and the relevance of these models to the etiology of AD require further investigation. PMID- 28721363 TI - A multifactorial 'Consensus Signature' by in silico analysis to predict response to neoadjuvant anthracycline-based chemotherapy in triple-negative breast cancer. AB - BACKGROUND: Owing to the complex processes required for anthracycline-induced cytotoxicity, a prospectively defined multifactorial Consensus Signature (ConSig) might improve prediction of anthracycline response in triple-negative breast cancer (TNBC) patients, whose only standard systemic treatment option is chemotherapy. AIMS: We aimed to construct and evaluate a multifactorial signature, comprising measures of each function required for anthracycline sensitivity in TNBC. METHODS: ConSigs were constructed based on five steps required for anthracycline function: drug penetration, nuclear topoisomerase IIalpha (topoIIalpha) protein location, increased topoIIalpha messenger RNA (mRNA) expression, apoptosis induction, and immune activation measured by, respectively, HIF1alpha or SHARP1 signature, LAPTM4B mRNA, topoIIalpha mRNA, Minimal Gene signature or YWHAZ mRNA, and STAT1 signature. TNBC patients treated with neoadjuvant anthracycline-based chemotherapy without taxane were identified from publicly available gene expression data derived with Affymetrix HG-U133 arrays (training set). In silico analyses of correlation between gene expression data and pathological complete response (pCR) were performed using receiver operating characteristic curves. To determine anthracycline specificity, ConSigs were assessed in patients treated with anthracycline plus taxane. Specificity, sensitivity, positive and negative predictive value, and odds ratio (OR) were calculated for ConSigs. Analyses were repeated in two validation gene expression data sets derived using different microarray platforms. RESULTS: In the training set, 29 of 147 patients had pCR after anthracycline-based chemotherapy. Various combinations of components were evaluated, with the most powerful anthracycline response predictors being ConSig1: (STAT1+topoIIalpha mRNA+LAPTM4B) and ConSig2: (STAT1+topoIIalpha mRNA+HIF1alpha). ConSig1 demonstrated high negative predictive value (85%) and high OR for no pCR (3.18) and outperformed ConSig2 in validation sets for anthracycline specificity. CONCLUSIONS: With further validation, ConSig1 may help refine selection of TNBC patients for anthracycline chemotherapy. PMID- 28721364 TI - Somatic mutations in leukocytes infiltrating primary breast cancers. AB - BACKGROUND: Malignant transformation requires the interaction of cancer cells with their microenvironment, including infiltrating leukocytes. However, somatic mutational studies have focused on alterations in cancer cells, assuming that the microenvironment is genetically normal. Because we hypothesized that this might not be a valid assumption, we performed exome sequencing and targeted sequencing to investigate for the presence of pathogenic mutations in tumor-associated leukocytes in breast cancers. METHODS: We used targeted sequencing and exome sequencing to evaluate the presence of mutations in sorted tumor-infiltrating CD45-positive cells from primary untreated breast cancers. We used high-depth sequencing to determine the presence/absence of the mutations we identified in breast cancer-infiltrating leukocytes in purified tumor cells and in circulating blood cells. RESULTS: Capture-based sequencing of 15 paired tumor-infiltrating leukocytes and matched germline DNA identified variants in known cancer genes in all 15 primary breast cancer patients in our cohort. We validated the presence of mutations identified by targeted sequencing in infiltrating leukocytes through orthogonal exome sequencing. Ten patients harbored alterations previously reported as somatically acquired variants, including in known leukemia genes (DNTM3A, TET2, and BCOR). One of the mutations observed in the tumor-infiltrating leukocytes was also detected in the circulating leukocytes of the same patients at a lower allele frequency than observed in the tumor-infiltrating cells. CONCLUSIONS: Here we show that somatic mutations, including mutations in known cancer genes, are present in the leukocytes infiltrating a subset of primary breast cancers. This observation allows for the possibility that the cancer cells interact with mutant infiltrating leukocytes, which has many potential clinical implications. PMID- 28721365 TI - Activin-A signaling promotes epithelial-mesenchymal transition, invasion, and metastatic growth of breast cancer. AB - BACKGROUND: Activins belong to the transforming growth factor-beta (TGF-beta) superfamily of cytokines. Although the role of TGF-beta in cancer progression has been highly advocated, the role of activin signaling in cancer is not well known. However, overexpression of activin-A has been observed in several cancers. AIMS: The gene expression profile indicated higher expression of Activin-A in breast tumors. Hence the aim of this study was to evaluate the status and role of Activin signaling pathway in these tumors. METHODS: Microarray analysis was performed to reveal gene expression changes in breast tumors. The results were validated by quantitative PCR and immunohistochemical analysis in two independent sets of normal and tumor samples. Further, correlation of activin expression with survival and distant metastasis was performed to evaluate its possible role in tumor progression. We used recombinant activin-A, inhibitors, overexpression, and knockdown strategies both in vitro and in vivo, to understand the mechanism underlying the protumorigenic role of this signaling pathway. RESULTS: We report that activin-A signaling is hyperactivated in breast cancers as indicated by higher activin-A, phosphoSMAD2, and phosphoSMAD3 levels in advanced breast cancers. Bone morphogenetic proteins and molecules involved in this signaling pathway were downregulated, suggesting its suppression in breast cancers. Activin A expression correlates inversely with survival and metastasis in advanced breast cancers. Further, activin-A promotes anchorage-independent growth, epithelial mesenchymal transition, invasion, angiogenesis, and stemness of breast cancer cells. We show that activin-A-induced phenotype is mediated by SMAD signaling pathway. In addition, activin-A expression affects the tumor-forming ability and metastatic colonization of cancer cells in nude mice. CONCLUSIONS: These results suggest that activin-A has a critical role in breast cancer progression and, hence, targeting this pathway can be a valuable strategy in treating breast cancer patients. PMID- 28721366 TI - Preventing breast cancer now by acting on what we already know. AB - The age-specific rate of breast cancer rises rapidly through premenopausal years and significantly more slowly after menopause. Reproductive factors affect cell proliferation and the accumulation of genetic changes. Lifetime risk of breast cancer is linearly related to the length of the interval from menarche to first birth. Lifestyle changes that accompany industrialization, together with shifting reproductive patterns, drive up incidence rates. Prevention must begin early in the life as almost one-quarter of cases are diagnosed before age 50 in high income countries. This requires greater emphasis on prevention across the life course to address the global burden of breast cancer. PMID- 28721368 TI - A search for synergy in the binding kinetics of Trastuzumab and Pertuzumab whole and F(ab) to Her2. AB - Therapeutic efficacy resulting from combining Trastuzumab and Pertuzumab in the treatment of Her2 overexpressing breast cancer patients has been shown to increase patient survival. This is thought to arise from inhibition of receptor dimerization and the immune tagging of the cancer cells; however, the underlying molecular mechanisms have remained enigmatic. Previously, a molecular modeling study suggested that this resulted from colocalization of the two antibodies on to the extracellular domain of Her2. We report here the experimental characterization of this interaction by measuring the binding kinetics of these two whole antibodies and their F(ab)s to the extracellular domain of Her2 in solution. We found that both antibodies (the whole antibodies and the fragments) colocalized on to Her2, but did not augment the binding of each other. PMID- 28721367 TI - Breast cancer survivors are at an increased risk for osteoporotic fractures not explained by lower BMD: a retrospective analysis. AB - BACKGROUND: An association between higher bone mineral density (BMD) and the diagnosis of breast cancer (BC) has been reported. Data on the risk of osteoporotic fractures in women with BC are conflicting. AIMS: The objective of this study was to assess fracture risk adjusted for BMD in women with and without BC, and to assess whether fracture risk in BC patients is attributed to BMD or BC characteristics. METHODS: Using electronic medical records of patients who underwent dual energy X-ray absorptiometry BMD studies at Soroka University Medical Center between February 2003 and March 2011, we identified women with subsequent diagnosis of osteoporotic fractures. BC status, demographic, health characteristics, BMD, and other laboratory findings were assessed. In BC patients data on grade, stage, and treatment were collected. Primary outcome was osteoporotic fracture, analyzed by Cox proportional hazards regression models. RESULTS: During a median follow-up of 4.9 years in 17,110 women with BMD testing (658 BC patients), 1,193 women experienced an osteoporotic fracture (62 in BC and 1,131 in no-BC groups). In multivariate analysis adjusted for age, body mass index (BMI) and BMD, hazard ratio (HR) for any osteoporotic fracture in women with BC was 1.34 (P=0.026). BMD was similar among women with and without BC who fractured. BC patients who experienced an osteoporotic fracture had a trend for less-advanced BC, lower rates of chemotherapy treatment, and higher rates of tamoxifen treatment. CONCLUSIONS: BC survivors are at increased risk of an osteoporotic fracture, which is not explained by worse BMD. Chemotherapy or aromatase inhibitors did not contribute substantially to fracture risk among our BC survivors. PMID- 28721369 TI - Disparities in breast cancer care and research: report from a Breast Cancer Research Foundation sponsored workshop, 9-10 October 2014. AB - The purpose of this workshop was to bring together diverse stakeholders from the breast cancer research community to discuss critical issues related to disparities in breast cancer care and to identify potential strategies for reducing disparities and inequities in care through research. The workshop format included a series of formal content presentations, participation in break out groups that focused on specific topics highlighted in the content presentations, reporting back of findings and a facilitated discussion that focused on shaping a research agenda. The workshop members concluded that numerous groups of women are at increased risk for disparities in breast cancer care: many patients and survivors suffer disproportionately from inadequate access to high-quality diagnosis and treatment, resulting in more frequent and severe adverse outcomes from the disease. Research on breast cancer disparities provides a major opportunity for reducing the burden of breast cancer. Thus, it is important for the Breast Cancer Research Foundation and other research funders to consider how to best promote research focused on ensuring breast cancer health equity. PMID- 28721370 TI - Breast cancer cell adhesome and degradome interact to drive metastasis. AB - BACKGROUND: Although primary breast tumors are detected early in most cases, it is inevitable that many patients remain at risk for future recurrence and death due to micrometastases. We investigated interactions between the degradome and the adhesome that drive metastasis, and have focused on matrix metalloproteases (MMPs) within the degradome and integrins and E-cadherin within the adhesome. AIMS: The aim of this study is to identify interaction networks between adhesion molecules and degradative enzymes in breast cancer metastasis. METHODS: We compared non-metastatic (BT-474, T47D, MCF7) and metastatic (MDA-MB-231, SUM149, SUM159) human breast cancer cell lines and xenografts, in which we measured growth rate, migration, invasion, colony formation, protein expression, and enzyme activity in vitro and in vivo. RESULTS: The metastatic breast cancer lines and xenografts displayed higher expression and activity levels of MMPs, which was also confirmed by noninvasive imaging in vivo. These metastatic breast cancer models also displayed elevated heterophilic cell-extracellular matrix (ECM) and lower homophilic cell-cell adhesion compared with those of non-metastatic models. This was conferred by an increased expression of the heterophilic cell adhesion molecule integrin beta1 (ITGB1) and a decreased expression of the homophilic cell adhesion molecule E-cadherin. Inhibition of MMPs in metastatic cells led to a reduced expression of ITGB1, and stimulation of ITGB1 resulted in higher MMP activities in metastatic cancer cells, demonstrating reciprocal dependencies between degradome and adhesome. Re-expression of E-cadherin (CDH1) led to an increased expression of the precursor form of ITGB1. CONCLUSIONS: Our results point toward a concerted interdependence of MMPs, ITGB1, and CDH1 that is critical for breast cancer metastasis. PMID- 28721371 TI - Spatiotemporal progression of metastatic breast cancer: a Markov chain model highlighting the role of early metastatic sites. AB - BACKGROUND: Cancer cell migration patterns are critical for understanding metastases and clinical evolution. Breast cancer spreads from one organ system to another via hematogenous and lymphatic routes. Although patterns of spread may superficially seem random and unpredictable, we explored the possibility that this is not the case. AIMS: Develop a Markov based model of breast cancer progression that has predictive capability. METHODS: On the basis of a longitudinal data set of 446 breast cancer patients, we created a Markov chain model of metastasis that describes the probabilities of metastasis occurring at a given anatomic site together with the probability of spread to additional sites. Progression is modeled as a random walk on a directed graph, where nodes represent anatomical sites where tumors can develop. RESULTS: We quantify how survival depends on the location of the first metastatic site for different patient subcategories. In addition, we classify metastatic sites as "sponges" or "spreaders" with implications regarding anatomical pathway prediction and long term survival. As metastatic tumors to the bone (main spreader) are most prominent, we focus in more detail on differences between groups of patients who form subsequent metastases to the lung as compared with the liver. CONCLUSIONS: We have found that spatiotemporal patterns of metastatic spread in breast cancer are neither random nor unpredictable. Furthermore, the novel concept of classifying organ sites as sponges or spreaders may motivate experiments seeking a biological basis for these phenomena and allow us to quantify the potential consequences of therapeutic targeting of sites in the oligometastatic setting and shed light on organotropic aspects of the disease. PMID- 28721372 TI - Prevalence and predictors of androgen receptor and programmed death-ligand 1 in BRCA1-associated and sporadic triple-negative breast cancer. AB - BACKGROUND: Triple-negative breast cancers comprise 15% of breast cancers and are more common in women with BRCA1 mutations. Although most have basal gene expression signatures, others resemble luminal tumors with expression of androgen receptor-related genes and some express the immunoinhibitory protein programmed death-ligand 1 (PD-L1). Given the availability of androgen receptor-targeted and immune therapies for triple-negative breast cancers, determining predictors of these biomarkers is important. AIMS: To determine the prevalence and predictors of androgen receptor and PD-L1 expression in BRCA1-associated and sporadic triple negative breast cancer. METHODS: We studied 197 triple-negative breast cancers: 78 (39.6%) from BRCA1 mutation carriers and 119 (60.4%) from noncarriers. Tumor pathology was reviewed and tissue microarray sections were immunostained for androgen receptor and PD-L1. RESULTS: Androgen receptor expression was seen in 18% of tumors and was significantly less common in tumors from BRCA1 mutation carriers than noncarriers (9.2 vs. 23.7%; P=0.01). Twenty-six percent of cancers expressed PD-L1 with no significant difference in frequency between carriers and noncarriers. Factors predicting androgen receptor expression were lower histologic grade (odds ratio (OR) 4.6; 95% confidence interval (CI) 1.1-19.7), older age at diagnosis (OR 1.3; 95% CI 1.03-1.7) and PD-L1 expression (OR 2.6; 95% CI 1.1-6.1). PD-L1 expression was significantly more common in cancers with lymphocytic infiltrates (OR, 3.3; 95% CI 1.1-10.4) and androgen receptor expression (OR, 3.2; 95% CI 1.4-7.5), and less common in tumors with lymphovascular invasion (OR 0.41; 95% CI 0.18-0.92). CONCLUSIONS: These results identify predictors for androgen receptor and PD-L1 expression among triple negative breast cancers that may lead to better treatment selection and participation in clinical trials. PMID- 28721373 TI - Neither epithelial nor mesenchymal circulating tumor cells isolated from breast cancer patients are tumorigenic in NOD-scid Il2rgnull mice. AB - The quantitative evaluation of circulating EpCAM+ tumor cells (CTCs) in the peripheral blood of breast cancer patients provides an independent predictor of risk of progression in patients with metastatic disease. The present study investigated the tumorigenic potential of CTCs from cryopreserved mobilized leukapheresis products obtained from three metastatic breast cancer patients in remission. Cells were immunomagnetically separated if they expressed either the epithelial cell surface marker EpCAM, or CD90, a mesenchymal stromal cell marker associated with tumorigenic stem-like cancer cells. Cells were injected into the mammary fat pads of NOD-scid Il2rgnull mice. The injection of very large numbers of CTCs (0.3-1.5*106 CTCs per site, 20 sites per sample) in an optimized xenograft model did not result in the establishment of human-derived tumor xenografts. Four orders of magnitude fewer cells of the same CD90+ phenotype, but obtained from metastatic breast cancer pleural effusions, were highly tumorigenic in the same model system. These results favor the interpretation that circulating tumor cell load does not directly bear on metastatic potential, and that tumorigenic circulating breast cancer cells in patients with metastatic breast cancer are exceedingly rare. Furthermore, the CD44+/CD90+ phenotypic signature indicative of tumorigenicity in cells separated from metastatic or primary breast tumors does not have the same significance in circulating tumor cells. PMID- 28721374 TI - Decreased gastrointestinal toxicity associated with a novel capecitabine schedule (7 days on and 7 days off): a systematic review. AB - Capecitabine is widely used in the management of metastatic breast cancer; however, drug delivery is limited by gastrointestinal and other toxicity. We employed mathematical modeling to rationally design an optimized dose and schedule for capecitabine of 2,000 mg twice daily, flat dosing, 7 days on, 7 days off. Preclinical data suggested increased efficacy and tolerability with this novel dosing, and three early-phase clinical trials have suggested a favorable toxicity profile. To further define the tolerability of this regimen, we conducted a systematic review of the gastrointestinal adverse events of patients on these studies. This review demonstrated a favorable gastrointestinal toxicity profile with capecitabine in this novel schedule when given as single agent or in combination therapy with either bevacizumab or lapatinib. No patients discontinued therapy for gastrointestinal toxicity, and there were no grade 4 or 5 gastrointestinal toxicities reported. Grade 3 or greater diarrhea occurred in two (2%); grade 2 or greater mucositis, constipation, and vomiting were reported in three (4%) patients. We conclude that capecitabine administered on a 7 days on, 7 days off schedule has limited gastrointestinal toxicity. Our methodology was based on an analysis of individual patient toxicity data from one phase I single-agent capecitabine and two phase II capecitabine combination studies (with bevacizumab and lapatinib, respectively), focusing specifically on gastrointestinal toxicity. PMID- 28721376 TI - TNF is a key cytokine mediating neutrophil cytotoxic activity in breast cancer patients. AB - We have previously shown a novel antimetastatic role for neutrophils in the premetastatic lung of mice in models of breast cancer. Here we expand on those findings in the context of human breast cancer. We assessed the cytotoxicity of neutrophils from 90 newly diagnosed breast cancer patients, 24 ductal carcinoma in situ patients, 56 metastatic breast cancer patients, and 64 women with no history of cancer. We report that neutrophils from metastatic and newly diagnosed breast cancer patients are significantly more cytotoxic than neutrophils from cancer-free individuals. We hypothesized that tumor-secreted factors 'prime' neutrophils to become cytotoxic. To identify these factors we assayed for cytokines in serum from 54 breast cancer patients and 35 cancer-free controls. Tumor necrosis factor (TNFalpha), MCP-1 (CCL2), and IL1RA significantly correlated with cytotoxicity and directly stimulated neutrophil cytotoxicity ex vivo. RNA-seq analyses found protein kinase C iota (PRKCI) to be over expressed in patient neutrophils relative to neutrophils from cancer-free individuals. PRKCI has been implicated in NADPH oxidase assembly, required for neutrophil mediated cell cytotoxicity. Treatment of human neutrophils with TNF-induced PRKCI expression and cytotoxicity in samples that had low basal levels of PRKCI expression. To date, this work is the first to demonstrate the cytotoxic role of neutrophils in the peripheral blood of a large cohort of breast cancer patients, and that select cytokines appear to mediate the stimulation of neutrophil cytotoxicity. Further functional studies are necessary to identify clinically relevant means of stimulating neutrophil cytotoxicity as an effective barrier against disease progression and metastasis. PMID- 28721375 TI - DNA defects, epigenetics, and gene expression in cancer-adjacent breast: a study from The Cancer Genome Atlas. AB - Recurrence rates after breast-conserving therapy may depend on genomic characteristics of cancer-adjacent, benign-appearing tissue. Studies have not evaluated recurrence in association with multiple genomic characteristics of cancer-adjacent breast tissue. To estimate the prevalence of DNA defects and RNA expression subtypes in cancer-adjacent, benign-appearing breast tissue at least 2 cm from the tumor margin, cancer-adjacent, pathologically well-characterized, benign-appearing breast tissue specimens from The Cancer Genome Atlas project were analyzed for DNA sequence, copy-number variation, DNA methylation, messenger RNA (mRNA) sequence, and mRNA/microRNA expression. Additional samples were also analyzed by at least one of these genomic data types and associations between genomic characteristics of normal tissue and overall survival were assessed. Approximately 40% of cancer-adjacent, benign-appearing tissues harbored genomic defects in DNA copy number, sequence, methylation, or in RNA sequence, although these defects did not significantly predict 10-year overall survival. Two mRNA/microRNA expression phenotypes were observed, including an active mRNA subtype that was identified in 40% of samples. Controlling for tumor characteristics and the presence of genomic defects, this active subtype was associated with significantly worse 10-year survival among estrogen receptor (ER) positive cases. This multi-platform analysis of breast cancer-adjacent samples produced genomic findings consistent with current surgical margin guidelines, and provides evidence that extratumoral RNA expression patterns in cancer-adjacent tissue predict overall survival among patients with ER-positive disease. PMID- 28721377 TI - Internet tools to enhance breast cancer care. AB - Internet tools have become a great aid in the daily practice of physicians who treat breast cancer patients. In cancer care there are frequent and important intersections where major decisions need to be made; these include (1) whether or not to give chemotherapy; (2) how much toxicity to expect, and (3) the life expectancy of the patient, considering non-breast cancer comorbidities. These decisions can be made more accurately using calculators based on data sets of thousands of patients as opposed to physician intuition. Such tools also help patients and caregivers in optimal decision making, as they estimate the absolute benefits and risks of treatment. In this perspective we describe selected internet sites that are useful across several domains of care, including the potential benefits of different adjuvant regimens for early breast cancer, prognosis after neoadjuvant therapy, prognosis for ductal carcinoma in situ, and toxicity and life expectancy estimates. We review the variables required to use the tools, the results obtained, the methods of validation, and the advantages and disadvantages of each tool. PMID- 28721378 TI - Analytical validation of a standardized scoring protocol for Ki67: phase 3 of an international multicenter collaboration. AB - Pathological analysis of the nuclear proliferation biomarker Ki67 has multiple potential roles in breast and other cancers. However, clinical utility of the immunohistochemical (IHC) assay for Ki67 immunohistochemistry has been hampered by unacceptable between-laboratory analytical variability. The International Ki67 Working Group has conducted a series of studies aiming to decrease this variability and improve the evaluation of Ki67. This study tries to assess whether acceptable performance can be achieved on prestained core-cut biopsies using a standardized scoring method. Sections from 30 primary ER+ breast cancer core biopsies were centrally stained for Ki67 and circulated among 22 laboratories in 11 countries. Each laboratory scored Ki67 using three methods: (1) global (4 fields of 100 cells each); (2) weighted global (same as global but weighted by estimated percentages of total area); and (3) hot-spot (single field of 500 cells). The intraclass correlation coefficient (ICC), a measure of interlaboratory agreement, for the unweighted global method (0.87; 95% credible interval (CI): 0.81-0.93) met the prespecified success criterion for scoring reproducibility, whereas that for the weighted global (0.87; 95% CI: 0.7999-0.93) and hot-spot methods (0.84; 95% CI: 0.77-0.92) marginally failed to do so. The unweighted global assessment of Ki67 IHC analysis on core biopsies met the prespecified criterion of success for scoring reproducibility. A few cases still showed large scoring discrepancies. Establishment of external quality assessment schemes is likely to improve the agreement between laboratories further. Additional evaluations are needed to assess staining variability and clinical validity in appropriate cohorts of samples. PMID- 28721379 TI - Breast-cancer-specific mortality in patients treated based on the 21-gene assay: a SEER population-based study. AB - The 21-gene Recurrence Score assay is validated to predict recurrence risk and chemotherapy benefit in hormone-receptor-positive (HR+) invasive breast cancer. To determine prospective breast-cancer-specific mortality (BCSM) outcomes by baseline Recurrence Score results and clinical covariates, the National Cancer Institute collaborated with Genomic Health and 14 population-based registries in the the Surveillance, Epidemiology, and End Results (SEER) Program to electronically supplement cancer surveillance data with Recurrence Score results. The prespecified primary analysis cohort was 40-84 years of age, and had node negative, HR+, HER2-negative, nonmetastatic disease diagnosed between January 2004 and December 2011 in the entire SEER population, and Recurrence Score results (N=38,568). Unadjusted 5-year BCSM were 0.4% (n=21,023; 95% confidence interval (CI), 0.3-0.6%), 1.4% (n=14,494; 95% CI, 1.1-1.7%), and 4.4% (n=3,051; 95% CI, 3.4-5.6%) for Recurrence Score <18, 18-30, and ?31 groups, respectively (P<0.001). In multivariable analysis adjusted for age, tumor size, grade, and race, the Recurrence Score result predicted BCSM (P<0.001). Among patients with node-positive disease (micrometastases and up to three positive nodes; N=4,691), 5-year BCSM (unadjusted) was 1.0% (n=2,694; 95% CI, 0.5-2.0%), 2.3% (n=1,669; 95% CI, 1.3-4.1%), and 14.3% (n=328; 95% CI, 8.4-23.8%) for Recurrence Score <18, 18 30, ?31 groups, respectively (P<0.001). Five-year BCSM by Recurrence Score group are reported for important patient subgroups, including age, race, tumor size, grade, and socioeconomic status. This SEER study represents the largest report of prospective BCSM outcomes based on Recurrence Score results for patients with HR+, HER2-negative, node-negative, or node-positive breast cancer, including subgroups often under-represented in clinical trials. PMID- 28721381 TI - Introducing SEARCHBreast: a virtual resource to facilitate sharing of surplus animal material developed for breast cancer research. AB - Animals studies have made significant contribution to expanding our knowledge of breast cancer. Often material is leftover and archived. SEARCHBreast provides a platform for collaborative sharing of archived material via a dedicated on-line database whereby users can both share and search available tissue. The SEARCHBreast database has information on over 50 different mouse models, including tissue from PDX models, available to share. With thousands of samples freely available, SEARCHBreast should be the first point of call for any researcher looking for animal material to aid their breast cancer research. PMID- 28721380 TI - Learning from big data: are we undertreating older women with high-risk breast cancer? PMID- 28721382 TI - The molecular landscape of high-risk early breast cancer: comprehensive biomarker analysis of a phase III adjuvant population. AB - Breast cancer is a heterogeneous disease and patients are managed clinically based on ER, PR, HER2 expression, and key risk factors. We sought to characterize the molecular landscape of high-risk breast cancer patients enrolled onto an adjuvant chemotherapy study to understand how disease subsets and tumor immune status impact survival. DNA and RNA were extracted from 861 breast cancer samples from patients enrolled onto the United States Oncology trial 01062. Samples were characterized using multiplex gene expression, copy number, and qPCR mutation assays. HR+ patients with a PIK3CA mutant tumor had a favorable disease-free survival (DFS; HR 0.66, P=0.05), however, the prognostic effect was specific to luminal A patients (Luminal A: HR 0.67, P=0.1; Luminal B: HR 1.01, P=0.98). Molecular subtyping of triple-negative breast cancers (TNBCs) suggested that the mesenchymal subtype had the worst DFS, whereas the immunomodulatory subtype had the best DFS. Profiling of immunologic genes revealed that TNBC tumors (n=280) displaying an activated T-cell signature had a longer DFS following adjuvant chemotherapy (HR 0.59, P=0.04), while a distinct set of immune genes was associated with DFS in HR+ cancers. Utilizing a discovery approach, we identified genes associated with a high risk of recurrence in HR+ patients, which were validated in an independent data set. Molecular classification based on PAM50 and TNBC subtyping stratified clinical high-risk patients into distinct prognostic subsets. Patients with high expression of immune-related genes showed superior DFS in both HR+ and TNBC. These results may inform patient management and drug development in early breast cancer. PMID- 28721383 TI - Randomized trial of medroxyprogesterone acetate for the prevention of endometrial pathology from adjuvant tamoxifen for breast cancer: SWOG S9630. AB - The proliferative effect of adjuvant tamoxifen on the endometrium can potentially result in endometrial abnormalities, including cancer in postmenopausal women. We conducted a randomized, controlled trial to assess endometrial pathological diagnoses in postmenopausal women with early stage, ER-positive breast cancer without endometrial pathology at baseline. They were assigned to tamoxifen alone versus tamoxifen plus cyclical medroxyprogesterone acetate (MPA 10 mg for 14 days every 3 months) for 5 years. Endovaginal sonograms (EVS) +/- endometrial biopsies (EMB) were required at baseline, 2 and 5 years. Of 313 patients registered, 296 were eligible and 169 (57%; 89, tamoxifen; 80, tamoxifen+MPA) were evaluable (completed year-2 EVS, with an EMB if stripe width was ?5 mm). Sixty (67%) of these in the tamoxifen arm had an endometrial stripe width ?5 mm (and underwent subsequent EMB) compared with 48 (60%) in the tamoxifen+MPA arm (P=0.40). There were four cases of proliferative endometrium and one simple hyperplasia on the tamoxifen arm (6% (95% confidence interval (CI): 2-13%) among evaluable patients and one proliferative endometrium on the tamoxifen+MPA arm (P=0.11). The overall fraction with benign endometrial abnormalities at year 2 was 3.6% (6/169; 95% CI: 1.3-7.6%), with only 1 (of 102) new benign proliferative event at year 5. The event rate in both arms was much lower than projected, making treatment arm comparisons less informative. A normal endometrium prior to tamoxifen may provide reassurance regarding future endometrial events. However, validation in a larger trial is needed before changing practice in asymptomatic, postmenopausal women. PMID- 28721384 TI - Changes in diet quality in a randomized weight loss trial in breast cancer survivors: the lifestyle, exercise, and nutrition (LEAN) study. AB - Obesity is associated with increased breast cancer recurrence and mortality. Though some post-diagnosis weight loss interventions have achieved weight loss outcomes, it is unclear whether they also improve diet quality. In the Lifestyle, Exercise, and Nutrition (LEAN) study, overweight or obese breast cancer survivors were randomized to either usual care group (n=33) or the 6-month lifestyle intervention (n=67). Dietary intake was assessed at baseline and 6 months using a validated food frequency questionnaire, and overall diet quality was calculated using the Healthy Eating Index (HEI)-2010 (range 0-100). Intervention effects on diet were evaluated with generalized linear models. Among the 81 participants (51 intervention, 30 usual care) with dietary data, the mean baseline HEI score was 70.5 (s.d.=8.8) and was improved at 6 months (intervention group=6.8 point increase vs usual care=3.1, P=0.09). Intervention group participants achieved greater reductions in percent of energy from total fat (-4.2% vs -1.2%; P=0.013) and saturated fat (-2.2% vs -1.1%; P=0.003), and greater increases in fiber (4.8 g per 1000 kcal vs 1.3 g per 1000 kcal; P=0.007) and fruit (0.5 servings vs 0.0 servings; P=0.006) intake. Intervention group participants who lost ?5% body weight (n=27) demonstrated significantly greater improvements in HEI score (10.4 vs 2.8) than those who lost <5% (n=23). The intervention increased fruit and fiber intake and decreased percent energy from fat, and those with greater weight loss achieved greater increases in overall diet quality. These findings support the ability of a weight loss intervention to improve diet among breast cancer survivors. PMID- 28721385 TI - Palmitoylation: a protein S-acylation with implications for breast cancer. AB - Protein S-acylation is a reversible post-translational lipid modification that involves linkage of a fatty acid chain predominantly to a cysteine amino acid via a thioester bond. The fatty acid molecule is primarily palmitate, thus the term 'palmitoylation' is more commonly used. Palmitoylation has been found to modulate all stages of protein function including maturational processing, trafficking, membrane anchoring, signaling range and efficacy, and degradation. In breast cancer, palmitoylation has been shown to control the function of commonly dysregulated genes including estrogen receptors, the epidermal growth factor (EGF) family of receptors, and cancer stem cell markers. Importantly, palmitoylation is a critical factor controlling the formation of complexes at the plasma membrane involving tetraspanins, integrins, and gene products that are key to cell-cell communication. During metastasis, cancer cells enhance their metastatic capacity by interacting with stroma and immune cells. Although aberrant palmitoylation could contribute to tumor initiation and growth, its potential role in these cell-cell interactions is of particular interest, as it may provide mechanistic insight into metastasis, including cancer cell-driven immune modulation. Compelling evidence for a role for aberrant palmitoylation in breast cancer remains to be established. To this end, in this review we summarize emerging evidence and highlight pertinent knowledge gaps, suggesting directions for future research. PMID- 28721386 TI - Relationships between pathology and crystal structure in breast calcifications: an in situ X-ray diffraction study in histological sections. AB - Calcifications are not only one of the most important early diagnostic markers of breast cancer, but are also increasingly believed to aggravate the proliferation of cancer cells and invasion of surrounding tissue. Moreover, this influence appears to vary with calcification composition. Despite this, remarkably little is known about the composition and crystal structure of the most common type of breast calcifications, and how this differs between benign and malignant lesions. We sought to determine how the phase composition and crystallographic parameters within calcifications varies with pathology, using synchrotron X-ray diffraction. This is the first time crystallite size and lattice parameters have been measured in breast calcifications, and we found that these both parallel closely the changes in these parameters with age observed in fetal bone. We also discovered that these calcifications contain a small proportion of magnesium whitlockite, and that this proportion increases from benign to in situ to invasive cancer. When combined with other recent evidence on the effect of magnesium on hydroxyapatite precipitation, this suggests a mechanism explaining observations that carbonate levels within breast calcifications are lower in malignant specimens. PMID- 28721387 TI - AXL-associated tumor inflammation as a poor prognostic signature in chemotherapy treated triple-negative breast cancer patients. AB - A subgroup of triple-negative breast cancer (TNBC) shows epithelial-to mesenchymal transition (EMT) features, which are sustained by the interaction between cancer cells and tumor-associated macrophages (TAMs). In this study, the clinical relevance of 30 EMT-related kinases and the potential cross-talk with TAMs were investigated in a cohort of 203 TNBC patients treated with adjuvant chemotherapy. The prognostic value of the evaluated markers was validated in two independent cohorts of TNBC patients treated with adjuvant chemotherapy (N=95; N=137). In vitro, we investigated the potential synergism between cancer cells and TAMs. We found that the EMT-related kinase AXL showed the highest correlation with the frequency of CD163-positive macrophages (rS=0.503; P<0.0001). Relapsing TNBC patients presented high expression of AXL (P<0.0001) and CD163 (P<0.018), but only AXL retained independent prognostic significance in multivariate analysis (relapse-free survival, P=0.002; overall survival P=0.001). In vitro analysis demonstrated that AXL-expressing TNBC cells were able to polarize human macrophages towards an M2-like phenotype, and modulate a specific pattern of pro tumor cytokines and chemokines. Selective AXL inhibition impaired the activity of M2-like macrophages, reducing cancer cell invasiveness, and restoring the sensitivity of breast cancer cells to chemotherapeutic drugs. These data suggest that the EMT-related kinase AXL overexpressed in cancer cells has prognostic significance, and contributes to the functional skewing of macrophage functions in TNBC. AXL inhibition may represent a novel strategy to target cancer cells, as well as tumor-promoting TAMs in TNBC. PMID- 28721388 TI - Massively parallel sequencing analysis of synchronous fibroepithelial lesions supports the concept of progression from fibroadenoma to phyllodes tumor. AB - Phyllodes tumors (PTs) and fibroadenomas (FAs) are fibroepithelial lesions (FELs) of the breast. Although mutations affecting exon 2 of MED12 are highly recurrent in FAs and PTs, TERT promoter hotspot mutations are frequently found in PTs but are vanishingly rare in FAs. Malignant transformation of benign PTs is well documented, but the progression from FA to PT remains a matter of contention. Here we report on the somatic genetic alterations in multiple ipsilateral synchronous FELs (three FAs, one benign PT, and one malignant PT) occurring in the same patient. DNA samples extracted from each tumor and matched normal tissue were subjected to targeted massively parallel sequencing using the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) assay. This analysis revealed MED12 mutations in all lesions. One FA and the benign PT harbored a MED12Gly44Val mutation, whereas another FA and the malignant PT displayed a MED12Gly44Asp mutation. The remaining FA had an independent distinct MED12Gly44Cys mutation. A formal clonality analysis suggested a clonal relationship between the FELs with identical MED12 mutations (P<0.05). A clonal TERT promoter hotspot mutation was identified exclusively in the malignant PT. The identification of distinct MED12 mutations in multifocal ipsilateral and synchronous FELs supports the notion that co-existing mammary fibroepithelial tumors can arise independently. Conversely, the co-existence of identical MED12 mutations indicates clonal relatedness among FAs and PTs, corroborating the hypothesis that FAs may constitute the substrate from which PTs develop. Our findings also support the notion that acquisition of TERT promoter mutations may drive the progression of FELs. PMID- 28721391 TI - A multi-resolution HEALPix data structure for spherically mapped point data. AB - Data describing entities with locations that are points on a sphere are described as spherically mapped. Several data structures designed for spherically mapped data have been developed. One of them, known as Hierarchical Equal Area iso Latitude Pixelization (HEALPix), partitions the sphere into twelve diamond-shaped equal-area base cells and then recursively subdivides each cell into four diamond shaped subcells, continuing to the desired level of resolution. Twelve quadtrees, one associated with each base cell, store the data records associated with that cell and its subcells. HEALPix has been used successfully for numerous applications, notably including cosmic microwave background data analysis. However, for applications involving sparse point data HEALPix has possible drawbacks, including inefficient memory utilization, overwriting of proximate points, and return of spurious points for certain queries. A multi-resolution variant of HEALPix specifically optimized for sparse point data was developed. The new data structure allows different areas of the sphere to be subdivided at different levels of resolution. It combines HEALPix positive features with the advantages of multi-resolution, including reduced memory requirements and improved query performance. An implementation of the new Multi-Resolution HEALPix (MRH) data structure was tested using spherically mapped data from four different scientific applications (warhead fragmentation trajectories, weather station locations, galaxy locations, and synthetic locations). Four types of range queries were applied to each data structure for each dataset. Compared to HEALPix, MRH used two to four orders of magnitude less memory for the same data, and on average its queries executed 72% faster. PMID- 28721389 TI - Triple-negative breast cancer: the importance of molecular and histologic subtyping, and recognition of low-grade variants. AB - Triple-negative breast cancers (TNBCs), defined by lack of expression of estrogen receptor, progesterone receptor and HER2, account for 12-17% of breast cancers and are clinically perceived as a discrete breast cancer subgroup. Nonetheless, TNBC has been shown to constitute a vastly heterogeneous disease encompassing a wide spectrum of entities with marked genetic, transcriptional, histological and clinical differences. Although most TNBCs are high-grade tumors, there are well characterized low-grade TNBCs that have an indolent clinical course, whose natural history, molecular features and optimal therapy vastly differ from those of high-grade TNBCs. Secretory and adenoid cystic carcinomas are two histologic types of TNBCs underpinned by specific fusion genes; these tumors have an indolent clinical behavior and lack all of the cardinal molecular features of high-grade triple-negative disease. Recent studies of rare entities, including lesions once believed to constitute mere benign breast disease (e.g., microglandular adenosis), have resulted in the identification of potential precursors of TNBC and suggested the existence of a family of low-grade triple negative lesions that, despite having low-grade morphology and indolent clinical behavior, have been shown to harbor the complex genomic landscape of common forms of TNBC, and may progress to high-grade disease. In this review, we describe the heterogeneity of TNBC and focus on the histologic and molecular features of low grade forms of TNBC. Germane to addressing the challenges posed by the so-called triple-negative disease is the realization that TNBC is merely a descriptive term, and that low-grade types of TNBC may be driven by distinct sets of genetic alterations. PMID- 28721390 TI - Randomized phase II trial of fulvestrant alone or in combination with bortezomib in hormone receptor-positive metastatic breast cancer resistant to aromatase inhibitors: a New York Cancer Consortium trial. AB - The proteasome inhibitor bortezomib enhances the effect of the selective estrogen receptor (ER) downregulator (SERD) fulvestrant by causing accumulation of cytoplasmic ER aggregates in preclinical models. The purpose of this trial was to determine whether bortezomib enhanced the effectiveness of fulvestrant. One hundred eighteen postmenopausal women with ER-positive metastatic breast cancer resistant to aromatase inhibitors (AIs) were randomized to fulvestrant alone (Arm A-500 mg intramuscular (i.m.) day -14, 1, 15 in cycle 1, and day 1 of additional cycles) or in combination with bortezomib (Arm B-1.6 mg/m2 intravenous (i.v.) on days 1, 8, 15 of each cycle). The study was powered to show an improvement in median progression-free survival (PFS) from 5.4 to 9.0 months and compare PFS rates at 6 and 12 months (alpha=0.10, beta=0.10). Patients with progression on fulvestrant could cross over to the combination (arm C). Although there was no difference in median PFS (2.7 months in both arms), the hazard ratio for PFS in Arm B versus Arm A (referent) was 0.73 (95% confidence interval (CI)=0.49, 1.09, P=0.06, 1-sided log-rank test, significant at the prespecified 1-sided 0.10 alpha level). At 12 months, the PFS proportion in Arm A and Arm B was 13.6% and 28.1% (P=0.03, 1-sided chi2-test; 95% CI for difference (14.5%)=-0.06, 29.1%). Of 27 patients on arm A who crossed over to the combination (arm C), 5 (18%) were progression-free for at least 24 weeks. Bortezomib likely enhances the effectiveness of fulvestrant in AI-resistant, ER-positive metastatic breast cancer by reducing acquired resistance, supporting additional evaluation of proteasome inhibitors in combination with SERDs. PMID- 28721392 TI - The response to Typhi Vi vaccination is compromised in individuals with primary immunodeficiency. AB - Measurement of an individuals ability to respond to polysaccharide antigens is a crucial test to determine adaptive immunity. Currently the response to Pneumovax(r) is utilized but with the success of Prevnar(r), measurement of the response to Pneumovax may be challenging. The aim of the study was to assess the response to Typhi Vi vaccination in both children and adult control groups and patients with primary immunodeficiency (PID). In the control groups, >95% of the individuals had pre Typhi Vi vaccination concentrations <100 U/mL and there was significant increase in concentration post Typhi Vi vaccination (p<0.0001) with>94% achieving >=3 fold increase in concentration (FI). The response to Typhi Vi vaccination was significantly lower in both children (p = 0.006) and adult (p = 0.002) PID groups when compared to their control groups. 11% and 55% of the children and adult PID groups respectively did not obtain a response >3FI. There were no significant differences between the responses obtained in the children and adult PID groups. When all individuals with PID were separated into those with either hypogammaglobulinemia (HYPO) or common variable immunodeficiency (CVID), both groups had a significantly lower median FI than the control group (19, 95%CI 5-56 vs 59, 95%CI 7-237; p = 0.01 and 1, 95%CI 1-56 vs 32, 95%CI 5 136; p = 0.005). Further, a >3FI differentiated the antibody responses between both the CVID and HYPO groups and their control groups (AUC: 0.83, 95%CI: 0.65 1.00, p = 0.005 and 0.81, 95% CI: 0.65-0.97, p = 0.01). The data suggests that measurement of the response to Typhi Vi vaccination could represent a complementary assay for the assessment of the response to a polysaccharide vaccine. PMID- 28721393 TI - Making workplaces safer: The influence of organisational climate and individual differences on safety behaviour. AB - Current work health and safety practices focus predominately on fostering a safety climate to promote safety behaviours and reduce workplace accidents. Despite the importance of safety climates in accident prevention, recent research has demonstrated that individual factors can also predict work safety behaviour. This study considered the importance of organisational climate together with individual characteristics including differences in personality, impulsiveness, and perceptions of safety within the workplace on safety behaviour. 203 participants consisting of 67 males and 136 females aged 18 to 71 years, completed an online questionnaire. Results revealed that safety behaviour was directly related to safety climate, and conscientiousness. In contrast, neuroticism, and impulsiveness were not significantly related to safety behaviour. The present study findings support previous findings in the literature regarding the importance of safety climate as well as the personality trait of conscientiousness in applying safety behaviours. However, the present study findings did not support previous research in relation to the personality trait of high neuroticism resulting in decreased safety behaviour, nor did not confirm an inverse relationship between high impulsivity and low safety behaviour as theoretical models would suggest. This new finding may warrant further research into the precursors for safety behaviour. PMID- 28721395 TI - The online appeal of the physical shop: How a physical store can benefit from a virtual representation. AB - Consumer behaviour in 2016 shows that (r)etailers need online/offline integration to better serve their clients. An important distinguishing feature of the physical shop is how it can offer consumers a shopping experience. This study uses two experiments to research the extent a fashion store's shopping experience can be presented to consumers via visual material (a regular photo, a 360-degree photo and a virtual reality photo of the shop) without the consumers being in the shop itself. The effects of these visual materials will also be measured in (among others) terms of purchase intention, visiting intention to the physical shop and online visit satisfaction. A theoretical framework is used to substantiate how the three types of pictures can be classified in terms of medium richness. The completed experiments show, among other outcomes, that consumers who saw the virtual reality photo of the shop have a more positive shopping experience, a higher purchase intention, a higher intention to visit the physical shop and more online visit satisfaction than people who have only seen the regular photo or the 360-degree photo of the shop. Enjoyment and novelty seem to partly explain these found effects. PMID- 28721396 TI - Biodiesel byproduct bioconversion to rhamnolipids: Upstream aspects. AB - This study focused on two important aspects of the upstream process: the appropriate use of crude glycerol as a low-cost carbon source, and strain selection. The effect of different crude glycerol concentrations on rhamnolipid biosynthesis by two Pseudomonas aeruginosa strains (wild type LBI and mutant LBI 2A1) was studied. Finally, the synthesized rhamnolipids were characterized by mass spectrometry. When both strains were compared, 50 g/L was the most favorable concentration for both, but P. aeruginosa LBI 2A1 showed an increase in rhamnolipid production (2.55 g/L) of 192% over wild type (1.3 g/L). The higher rhamnolipid production could be related to a possible mechanism developed after the mutation process at high antibiotic concentrations. Mass spectrometry confirmed the glycolipid nature of the produced biosurfactant, and the homologue composition showed a wide mixture of mono and di-rhamnolipids. These results show that high glycerol concentrations can inhibit microbial metabolism, due to osmotic stress, leading to a better understanding of glycerol metabolism towards its optimization in fermentation media. Since P. aeruginosa LBI 2A1 showed higher conversion yields than P. aeruginosa LBI, the use of a mutant strain associated with a low cost carbon source might improve biosurfactant biosynthesis, therefore yielding an important upstream improvement. PMID- 28721394 TI - Interhemispheric disconnectivity in the sensorimotor network in bipolar disorder revealed by functional connectivity and diffusion tensor imaging analysis. AB - BACKGROUND: Little is known regarding interhemispheric functional connectivity (FC) abnormalities via the corpus callosum in subjects with bipolar disorder (BD), which might be a key pathophysiological basis of emotional processing alterations in BD. METHODS: We performed tract-based spatial statistics (TBSS) using diffusion tensor imaging (DTI) in 24 healthy control (HC) and 22 BD subjects. Next, we analyzed the neural networks with independent component analysis (ICA) in 32HC and 25 BD subjects using resting-state functional magnetic resonance imaging. RESULTS: In TBSS analysis, we found reduced fractional anisotropy (FA) in the corpus callosum of BD subjects. In ICA, functional within connectivity was reduced in two clusters in the sensorimotor network (SMN) (right and left primary somatosensory areas) of BD subjects compared with HCs. FC between the two clusters and FA values in the corpus callosum of BD subjects was significantly correlated. Further, the functional within-connectivity was related to Young Mania Rating Scale (YMRS) total scores in the right premotor area in the SMN of BD subjects. LIMITATIONS: Almost all of our BD subjects were taking several medications which could be a confounding factor. CONCLUSIONS: Our findings suggest that interhemispheric FC dysfunction in the SMN is associated with the impaired nerve fibers in the corpus callosum, which could be one of pathophysiological bases of emotion processing dysregulation in BD patients. PMID- 28721397 TI - HIVIS-DNA or HIVISopt-DNA priming followed by CMDR vaccinia-based boosts induce both humoral and cellular murine immune responses to HIV. AB - BACKGROUND: In order to develop a more effective prophylactic HIV-1 vaccine it is important optimize the components, improve Envelope glycoprotein immunogenicity as well as to explore prime-boost immunization schedules. It is also valuable to include several HIV-1 subtype antigens representing the world-wide epidemic. METHODS: HIVIS-DNA plasmids which include Env genes of subtypes A, B and C together with Gag subtypes A and B and RTmut/Rev of subtype B were modified as follows: the Envelope sequences were shortened, codon optimized, provided with an FT4 sequence and an immunodominant region mutated. The reverse transcriptase (RT) gene was shortened to contain the most immunogenic N-terminal fragment and fused with an inactivated viral protease vPR gene. HIVISopt-DNA thus contains fewer plasmids but additional PR epitopes compared to the native HIVIS-DNA. DNA components were delivered intradermally to young Balb/c mice once, using a needle free Biojector(r) immediately followed by dermal electroporation. Vaccinia-based MVA-CMDR boosts including Env gene E and Gag-RT genes A were delivered intramuscularly by needle, once or twice. RESULTS: Both HIVIS-DNA and HIVISopt DNA primed humoral and cell mediated responses well. When boosted with heterologous MVA-CMDR (subtypes A and E) virus inhibitory neutralizing antibodies were obtained to HIV-1 subtypes A, B, C and AE. Both plasmid compositions boosted with MVA-CMDR generated HIV-1 specific cellular responses directed against HIV-1 Env, Gag and Pol, as measured by IFNgamma ELISpot. It was shown that DNA priming augmented the vector MVA immunological boosting effects, the HIVISopt-DNA with a trend to improved (Env) neutralization, the HIVIS-DNA with a trend to better (Gag) cell mediated immune reponses. CONCLUSIONS: HIVIS-DNA was modified to obtain HIVISopt-DNA that had fewer plasmids, and additional epitopes. Even with one DNA prime followed by two MVA-CMDR boosts, humoral and cell-mediated immune responses were readily induced by priming with either DNA construct composition. Priming by HIV-DNA augmented neutralizing antibody responses revealed by boosting with the vaccinia-based heterologous sequences. Cellular and antibody responses covered selected strains representing HIV-1 subtypes A, B, C and CRF01_AE. We assume this is related to the inclusion of heterologous full genes in the vaccine schedule. PMID- 28721398 TI - Calcium-stimulated adenylyl cyclase subtype 1 (AC1) contributes to LTP in the insular cortex of adult mice. AB - Long-term potentiation (LTP) of synaptic transmission in the central nervous system is a key form of cortical plasticity. The insular cortex (IC) is known to play important roles in pain perception, aversive memory and mood disorders. LTP has been recently reported in the IC, however, the signaling pathway for IC LTP remains unknown. Here, we investigated the synaptic mechanism of IC LTP. We found that IC LTP induced by the pairing protocol was N-methyl-D-aspartate receptors (NMDARs) dependent, and expressed postsynaptically, since paired-pulse ratio (PPR) was not affected. Postsynaptic calcium is important for the induction of post-LTP, since the postsynaptic application of BAPTA completely blocked the induction of LTP. Calcium-activated adenylyl cyclase subtype 1 (AC1) is required for potentiation. By contrast, AC8 is not required. Inhibition of Ca2+ permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (CP-AMPARs) or protein kinase M zeta (PKMzeta) reduced the expression of LTP. Our results suggest that calcium-stimulated AC1, but not AC8, can be a trigger of the induction and maintenance of LTP in the IC. PMID- 28721399 TI - Nutritional and functional properties of fishmeal produced from fresh by-products of cod (Gadus morhua L.) and saithe (Pollachius virens). AB - Fresh by-products of whitefish such as cod and saithe is processed to fishmeal (FM) on-board seagoing Norwegian trawlers. The aim of this study was to document the properties of whitefish FM (WFM) protein with respect to, physicochemical and bioactive properties. Analysis of the proximate composition of representative seasonal WFM batches show that the production is robust without much variance. The mean protein (61.9 +/- 1.2), fat (8.9 +/- 1.1%), moisture (5 +/- 1.2%) and ash content (22.4 +/- 0.8%), reflect the use of lean and bony raw-material. The WFM has a low content of free amino acids (0.7%) and biogenic amines (< 1000 mg/kg) that confirm the high quality and freshness of the raw material. Amino acid analysis identified the presence of all nutritionally essential amino acids. The WFM physicochemical properties was comparable to soy-bean meal (SBM) by analysis of solubility, water-holding capacity (WHC), the emulsion stability (ES). Proteolytic degradation of the WFM was used to demonstrate the presence of bioactive peptides with inhibiting activity against angiotensin-converting enzyme (ACE) activity, in vitro. Taken together, WFM produced from fresh by-products is an excellent protein source with attributes of interest beyond the aquafeed market. PMID- 28721400 TI - Weight-adjusted lean body mass and calf circumference are protective against obesity-associated insulin resistance and metabolic abnormalities. AB - BACKGROUND: To test the hypothesis that preserved muscle mass is protective against obesity-associated insulin resistance and metabolic abnormalities, we analyzed the relationship of lean body mass and computed tomography-assessed sectional areas of specific skeletal muscles with insulin resistance and metabolic abnormalities in a healthy cohort. METHODS: A total of 195 subjects without diabetes who had completed a medical examination were included in this study. Various anthropometric indices such as circumferences of the arm, waist, hip, thigh, and calf were measured. Body composition (fat and lean body mass) was determined by bioelectrical impedance analysis. Sectional areas of specific skeletal muscles (iliopsoas, erector spinae, gluteus, femoris, and rectus abdominis muscles) were measured using computed tomography. FINDINGS: Fat and lean body mass were significantly correlated with metabolic abnormalities and insulin resistance indices. When adjusted by weight, relationships of fat and lean body mass with metabolic parameters were mirror images of each other. The weight-adjusted lean body mass negatively correlated with systolic and diastolic blood pressures; fasting plasma glucose, HbA1c, alanine aminotransferase, and triglyceride, and insulin levels; and hepatic insulin resistance indices, and positively correlated with HDL-cholesterol levels and muscle insulin sensitivity indices. Compared with weight-adjusted lean body mass, weight-adjusted sectional areas of specific skeletal muscles showed similar, but not as strong, correlations with metabolic parameters. Among anthropometric measures, the calf circumference best reflected lean body mass, and weight-adjusted calf circumference negatively correlated with metabolic abnormalities and insulin resistance indices. INTERPRETATION: Weight-adjusted lean body mass and skeletal muscle area are protective against weight-associated insulin resistance and metabolic abnormalities. The calf circumference reflects lean body mass and may be useful as a protective marker against obesity-associated metabolic abnormalities. PMID- 28721401 TI - Toward patient-tailored summarization of lung cancer literature. AB - As the volume of biomedical literature increases, it can be challenging for clinicians to stay up-to-date. Graphical summarization systems help by condensing knowledge into networks of entities and relations. However, existing systems present relations out of context, ignoring key details such as study population. To better support precision medicine, summarization systems should include such information to contextualize and tailor results to individual patients. This paper introduces "contextualized semantic maps" for patient-tailored graphical summarization of published literature. These efforts are demonstrated in the domain of driver mutations in non-small cell lung cancer (NSCLC). A representation for relations and study population context in NSCLC was developed. An annotated gold standard for this representation was created from a set of 135 abstracts; F1-score annotator agreement was 0.78 for context and 0.68 for relations. Visualizing the contextualized relations demonstrated that context facilitates the discovery of key findings that are relevant to patient-oriented queries. PMID- 28721402 TI - On the efficiency limit of ZnO/CH3NH3PbI3/CuI perovskite solar cells. AB - Organometal triiodide perovskites are promising, high-performance absorbers in solar cells. Considering the perovskite as a thin film absorber, we solve transport equations and analyse the efficiency of a simple heterojunction configuration as a function of electron-hole diffusion lengths. We found that for a thin film thickness of ?1 MUm the maximum efficiency of ?31% could be achieved at the diffusion length of ~100 MUm. PMID- 28721404 TI - Accurate determination of the charge transfer efficiency of photoanodes for solar water splitting. AB - The oxygen evolution reaction (OER) at the surface of semiconductor photoanodes is critical for photoelectrochemical water splitting. This reaction involves photo-generated holes that oxidize water via charge transfer at the photoanode/electrolyte interface. However, a certain fraction of the holes that reach the surface recombine with electrons from the conduction band, giving rise to the surface recombination loss. The charge transfer efficiency, etat, defined as the ratio between the flux of holes that contribute to the water oxidation reaction and the total flux of holes that reach the surface, is an important parameter that helps to distinguish between bulk and surface recombination losses. However, accurate determination of etat by conventional voltammetry measurements is complicated because only the total current is measured and it is difficult to discern between different contributions to the current. Chopped light measurement (CLM) and hole scavenger measurement (HSM) techniques are widely employed to determine etat, but they often lead to errors resulting from instrumental as well as fundamental limitations. Intensity modulated photocurrent spectroscopy (IMPS) is better suited for accurate determination of etat because it provides direct information on both the total photocurrent and the surface recombination current. However, careful analysis of IMPS measurements at different light intensities is required to account for nonlinear effects. This work compares the etat values obtained by these methods using heteroepitaxial thin-film hematite photoanodes as a case study. We show that a wide spread of etat values is obtained by different analysis methods, and even within the same method different values may be obtained depending on instrumental and experimental conditions such as the light source and light intensity. Statistical analysis of the results obtained for our model hematite photoanode show good correlation between different methods for measurements carried out with the same light source, light intensity and potential. However, there is a considerable spread in the results obtained by different methods. For accurate determination of etat, we recommend IMPS measurements in operando with a bias light intensity such that the irradiance is as close as possible to the AM1.5 Global solar spectrum. PMID- 28721405 TI - Transforming a chemically labile [2+3] imine cage into a robust carbamate cage. AB - The synthesis of a highly acid and base-stable shape-persistent porous carbamate cage is presented. This cage is stable even in hot (100 degrees C) 1 M hydrochloric acid (pH = 0) or in concentrated hydrochloric acid (pH = -1) at room temperature without decomposition. PMID- 28721406 TI - Chemical proteomics reveal CD147 as a functional target of pseudolaric acid B in human cancer cells. AB - CD147 is a glycosylated transmembrane protein highly expressed on the surface of various tumor cells which plays vital roles in tumor invasion, progression and metastasis. We report the discovery of the natural product pseudolaric acid B (PAB) directly targeting CD147 by chemical proteomics utilizing a PAB-derived photoaffinity probe which could serve as a novel type of anticancer reagent. PMID- 28721407 TI - 3D printed reversible shape changing soft actuators assisted by liquid crystal elastomers. AB - In this work, we advance printed active composites by combining 3D printing, printed electronics, and liquid crystal elastomers (LCEs) to achieve soft actuators with free-standing two-way shape changing behaviors. Incorporated LCE strips are activated by Joule heating produced by printed conductive wires, while uniaxial deformation of the LCE strip is utilized as a driving force to achieve bending in the printed composite. The bending behavior of laminated hinges is first characterized in order to obtain a precise control of actuation, which is then exploited to actuate four demonstrative designs: a morphing airplane, a miura-ori structure, a cubic box, and a soft crawler. The soft morphing airplane and miura-ori structure are designed and fabricated with multiple laminated hinges to demonstrate the synergistic actions during actuation. The cubic box is constructed to show the capability of sequential folding by implementing multiple groups of conductive wires to achieve accurately addressable heating with temporal control. Finally, the two-way transformation is utilized as a driving force for the locomotion of a soft crawler stimulated by a periodic rectangular wave current. These examples show the great potential of using the hybrid 3D printing and pick-and-place method and using LCEs to achieve controllable shape change structures for a variety of potential practical applications. PMID- 28721409 TI - Single antibody-antigen interactions monitored via transient ionic current recording using nanopore sensors. AB - Understanding the single molecular protein-protein interaction has great significance in evaluating the affinity of a specific antibody. Herein, the interaction between single alpha-fetal protein (AFP) and its antibody was monitored via transient ionic current recording by using the antibody functionalized nanopore sensors. More importantly, the kinetic evaluation was performed at the single molecule level to determine the dissociation constant of this interaction. This method enables the monitoring of the kinetic antigen antibody interaction in their heterogenetic state without any labelling. Our results provided new insights into the evaluation of the antibody's binding affinity and more into the development of immunoassays for diagnostics. PMID- 28721410 TI - An intrinsic internal standard substrate of Au@PS-b-P4VP for rapid quantification by surface enhanced Raman scattering. AB - Reliable quantification by surface enhanced Raman scattering (SERS) highly depends on the development of a reproducible substrate with excellent anti interference capability. In this work, an intrinsic internal standard (IS) SERS substrate based on a diblock copolymer, polystyrene-block-poly-4-vinylpyridine (PS-b-P4VP), as a template was developed by a modified block copolymer lithography (BCL) technique of reserving the diblock copolymer template. This substrate generated a stable vibration peak at 1066 cm-1 attributed to poly(4 vinylpyridine) (P4VP) which could be used as an intrinsic IS for precise SERS quantification. A series of characterization results showed that the diblock copolymer template endowed this substrate with homogeneous distribution of Au nanoparticles, excellent stability and reproducibility. A minor relative standard deviation (RSDs) of SERS responses at 1066 cm-1 was measured and calculated to be 4.3% from ten different substrates in the same batch, which suggested good substrate-to-substrate reproducibility of this substrate. Finally, this intrinsic IS substrate was successfully applied for the rapid quantification of a trace banned dye, chrysoidine, in food samples with complicated matrices by SERS. It was proved that chrysoidine could be found and quantified to be 0.50 and 0.41 mg L-1 in a positive dried bean curd stick and chilli powder sample respectively with good recoveries by this substrate coupled with SERS. The development of intrinsic IS substrates would benefit rapid and accurate quantification of trace targets in complex samples coupled with SERS analysis. PMID- 28721411 TI - Power output and carrier dynamics studies of perovskite solar cells under working conditions. AB - Perovskite solar cells have emerged as promising photovoltaic systems with superb power conversion efficiency. For the practical application of perovskite devices, the greatest concerns are the power output density and the related dynamics under working conditions. In this study, the working conditions of planar and mesoscopic perovskite solar cells are simulated and the power output density evolutions with the working voltage are highlighted. The planar device exhibits higher capability of outputting power than the mesoscopic one. The transient photoelectric conversion dynamics are investigated under the open circuit, short circuit and working conditions. It is found that the power output and dynamic processes are correlated intrinsically, which suggests that the power output is the competitive result of the charge carrier recombination and transport. The present work offers a unique view to elucidating the relationship between the power output and the charge carrier dynamics for perovskite solar cells in a comprehensive manner, which would be beneficial to their future practical applications. PMID- 28721412 TI - Effect of ligand binding on a protein with a complex folding landscape. AB - Ligand binding to a protein can stabilize it significantly against unfolding. The variation of the folding free energy, DeltaDeltaG0, due to ligand binding can be derived from a simple reaction scheme involving exclusive binding to the native state. One obtains the following expression: , where Kd is the ligand dissociation constant and L is its concentration, R is the universal gas constant and T is the temperature. This expression has been shown to correctly describe experimental results on multiple proteins. In the current work we studied the effect of ligand binding on the stability of the multi-domain protein adenylate kinase from E. coli (AKE). Unfolding experiments were conducted using single molecule FRET spectroscopy, which allowed us to directly obtain the fraction of unfolded protein in a model-free way from FRET efficiency histograms. Surprisingly, it was found that the effect of two inhibitors (Ap5A and AMPPNP) and a substrate (AMP) on the stability of AKE was much smaller than expected based on Kd values obtained independently using microscale thermophoresis. To shed light on this issue, we measured the Kd for Ap5A over a range of chemical denaturant concentrations where the protein is still folded. It was found that Kd increases dramatically over this range, likely due to the population of folding intermediates, whose binding to the ligand is much weaker than that of the native state. We propose that binding to folding intermediates may dominate the effect of ligands on the stability of multi-domain proteins, and could therefore have a strong impact on protein homeostasis in vivo. PMID- 28721413 TI - Spacer type mediated tunable spin crossover (SCO) characteristics of pyrene decorated 2,6-bis(pyrazol-1-yl)pyridine (bpp) based Fe(ii) molecular spintronic modules. AB - A simple "isomer-like" variation of the spacer group in a set of Fe(ii) spin crossover (SCO) complexes designed to probe spin state dependence of electrical conductivity in graphene-based molecular spintronic junctions led to the observation of remarkable variations in the thermal- and light-induced magnetic characteristics, paving a simple route for the design of functional SCO complexes with different temperature switching regimes based on a 2,6-bis(pyrazol-1 yl)pyridine ligand skeleton. PMID- 28721414 TI - Single-component supported lipid bilayers probed using broadband nonlinear optics. AB - Broadband SFG spectroscopy is shown to offer considerable advantages over scanning systems in terms of signal-to-noise ratios when probing well-formed single-component supported lipid bilayers formed from zwitterionic lipids with PC headgroups. The SFG spectra obtained from bilayers formed from DOPC, POPC, DLPC, DMPC, DPPC and DSPC show a common peak at ~2980 cm-1, which is subject to interference between the C-H and the O-H stretches from the aqueous phase, while membranes having transition temperatures above the laboratory temperature produce SFG spectra with at least two additional peaks, one at ~2920 cm-1 and another at ~2880 cm-1. The results validate spectroscopic and structural data from SFG experiments utilizing asymmetric bilayers in which one leaflet differs from the other in the extent of deuteration. Differences in H2O-D2O exchange experiments reveal that the lineshapes of the broadband SFG spectra are significantly influenced by interference from OH oscillators in the aqueous phase, even when those oscillators are not probed by the incident infrared light in our broadband setup. In the absence of spectral interference from the OH stretches of the solvent, the alkyl chain terminal methyl group of the bilayer is found to be tilted at an angle of 15 degrees to 35 degrees from the surface normal. PMID- 28721415 TI - InDrops and Drop-seq technologies for single-cell sequencing. PMID- 28721418 TI - Intermolecular interactions in molecular crystals: what's in a name? AB - Structure-property relationships are the key to modern crystal engineering, and for molecular crystals this requires both a thorough understanding of intermolecular interactions, and the subsequent use of this to create solids with desired properties. There has been a rapid increase in publications aimed at furthering this understanding, especially the importance of non-canonical interactions such as halogen, chalcogen, pnicogen, and tetrel bonds. Here we show how all of these interactions - and hydrogen bonds - can be readily understood through their common origin in the redistribution of electron density that results from chemical bonding. This redistribution is directly linked to the molecular electrostatic potential, to qualitative concepts such as electrostatic complementarity, and to the calculation of quantitative intermolecular interaction energies. Visualization of these energies, along with their electrostatic and dispersion components, sheds light on the architecture of molecular crystals, in turn providing a link to actual crystal properties. PMID- 28721419 TI - Highly fluorescent hyperbranched BODIPY-based conjugated polymer dots for cellular imaging. AB - The first hyperbranched BODIPY-based conjugated polymer dots (Pdots) were reported. The Pdots showed quantum yields of as high as 22%, which is 40% higher than their linear counterparts. The Pdots were successfully applied in cell labelling applications. These results demonstrated that hyperbranched polymers are a very promising material for biological imaging and applications. PMID- 28721420 TI - Adsorption of galloyl catechin aggregates significantly modulates membrane mechanics in the absence of biochemical cues. AB - Physical interactions of four major green tea catechin derivatives with cell membrane models were systemically investigated. Catechins with the galloyl moiety caused the aggregation of small unilamellar vesicles and an increase in the surface pressure of lipid monolayers, while those without did not. Differential scanning calorimetry revealed that, in a low concentration regime (<=10 MUM), catechin molecules are not significantly incorporated into the hydrophobic core of lipid membranes as substitutional impurities. Partition coefficient measurements revealed that the galloyl moiety of catechin and the cationic quaternary amine of lipids dominate the catechin-membrane interaction, which can be attributed to the combination of electrostatic and cation-pi interactions. Finally, we shed light on the mechanical consequence of catechin-membrane interactions using the Fourier-transformation of the membrane fluctuation. Surprisingly, the incubation of cell-sized vesicles with 1 MUM galloyl catechins, which is comparable to the level in human blood plasma after green tea consumption, significantly increased the bending stiffness of the membranes by a factor of more than 60, while those without the galloyl moiety had no detectable influence. Atomic force microscopy and circular dichroism spectroscopy suggest that the membrane stiffening is mainly attributed to the adsorption of galloyl catechin aggregates to the membrane surfaces. These results contribute to our understanding of the physical and thus the generic functions of green tea catechins in therapeutics, such as cancer prevention. PMID- 28721421 TI - A Pr3+ doping strategy for simultaneously optimizing the size and near infrared persistent luminescence of ZGGO:Cr3+ nanoparticles for potential bio-imaging. AB - Spinel-phase Zn2Ga2.98-xGe0.75O8:Cr0.020,Prx (ZGGO:Cr3+,Pr3+) near infrared (NIR) persistent luminescence nanoparticles (PLNPs) with different amounts of Pr3+ dopant were prepared by a hydrothermal method in combination with a subsequent annealing in a vacuum. For these nanoparticles, the averaged particle size decreases from 64 to 37 nm with increasing Pr3+ doping concentration from 0 to 0.025 and Cr3+ and Pr3+ ions are uniformly doped into the interior and surface of a single nanoparticle. It can be found that Pr3+ doping leads to the appearance of more anti-site pairs () around distorted octahedral Cr3+ ions and enhanced NIR emissions around 697 nm, which originate from the 2E(2G) -> 4A2(4F) and 4T2(4F) > 4A2(4F) transitions of the interior and surface Cr3+ ions in the nanoparticles. In particular, for the interior Cr3+ ions in the Pr3+ doped nanoparticles, the enhanced NIR luminescence can be attributed to the suppressed energy transfer of the excited electrons from the 4T2(4F) level to the trap level related to anti site pairs () around the distorted octahedral Cr3+ ions. Our results suggest that Pr3+ doped ZGGO:Cr3+ PLNPs have potential applications for bio-imaging. PMID- 28721422 TI - Towards on-site analysis of complex matrices by solid-phase microextraction transmission mode coupled to a portable mass spectrometer via direct analysis in real time. AB - On-site screening for target analytes in complex matrices, such as biofluids and food specimens, not only requires reliable and portable analytical instrumentation, but also solvent-free and easy-to-use sampling/sample preparation approaches that allow analytes of interest to be isolated from such matrices. The integration of sampling devices with field deployable instruments should be as efficient as possible, and should aim to provide rapid, precise, and accurate results that enable quick on-site decision. In this study, we evaluated solid-phase microextraction-transmission (SPME-TM) coupled to a portable single quadrupole MS system, via direct analysis in real time (DART), as an effective tool for the rapid screening of target analytes in biological and food matrices. Limits of quantitation (LOQ) in the low parts-per-billion levels (<=50 ng mL-1) were attained for most of the investigated analytes with total analysis times under 2 min per sample. Furthermore, we explored the suitability of this technology for on-site rapid molecular profiling of complex matrices. As a proof of-concept, we demonstrate the rapid identification of milk samples from assorted animal and vegetal sources. PMID- 28721423 TI - Structure-property relationships in protic ionic liquids: a thermochemical study. AB - How does cation functionality influence the strength of intermolecular interactions in protic ionic liquids (PILs)? Quantifying the energetics of PILs can be an invaluable tool to answer this fundamental question. With this in view, we have determined the standard molar enthalpy of vaporization, , and the standard molar enthalpy of formation, , of three tertiary ammonium acetate PILs with varying cation functionality, and of their corresponding precursor amines, through a combination of Calvet-drop microcalorimetry, solution calorimetry, and ab initio calculations. The obtained results suggest that these PILs vaporize as their neutral acid and base precursors. We also found a strong correlation between of the PILs and of their corresponding amines. This suggests that, within this series of PILs, the influence of cation modification on their cohesive energies follows a group additivity rule. Finally, no correlation between the of PILs and the extent of proton transfer, as estimated from the difference in aqueous pKa between the precursor acid and the conjugate acid of the precursor base, was observed. PMID- 28721425 TI - Perspective on droplet-based single-cell sequencing. PMID- 28721427 TI - Prevalence of Frailty in Nursing Home Residents According to Various Diagnostic Tools. AB - BACKGROUND: Although the theoretical foundations of frailty are well established in the literature, it remains an evolving concept lacking any unique definition or diagnostic criteria for use in clinical practice and epidemiological research. No consensus exists about the accurate prevalence rates of frailty. The various operational definitions of frailty can at least partly explain such discrepancies. OBJECTIVE: To compare the prevalence of frailty, measured with different diagnostic tools, among elderly nursing home residents. DESIGN: This is an analysis of baseline data collected among the SENIOR (Sample of Nursing home Elderly Individuals: an Observational Research) cohort. SETTING: Nursing homes. POPULATION: A total of 662 volunteer subjects from 28 nursing homes were included in this analysis. Among them, the mean age was 83.2 +/- 8.99 years and 484 (72.5%) of them were women. MEASUREMENT: The percentages of frail and non-frail subjects were calculated according to 10 different definitions. RESULTS: Prevalence of frailty varies from 1.70% (Frailty Index) to 76.3% (Groningen Frailty Indicator) depending on the tool used. CONCLUSIONS: The prevalence of frailty is highly dependent on the diagnostic tool used. It would be necessary to reach a consensus on which diagnostic tools to use if one wishes to have comparable data obtained in epidemiological studies. PMID- 28721426 TI - Co-Localization of Macrophage Inhibitory Factor and Nix in Skeletal Muscle of the Aged Male Interleukin 10 Null Mouse. AB - Chronic inflammation is associated with muscle weakness and frailty in older adults. The antagonistic cross-talk between macrophage migration inhibitory factor (Mif), an anti-apoptotic cytokine and NIP3-like protein X (Nix), a pro apoptotic mitochondrial protein, may play a role in mitochondrial free radical homeostasis and inflammatory myopathies. We examined Nix-Mif interaction in inflammation and aging using young and old, IL-10tm/tm (a rodent model of chronic inflammation) and C57BL/6 mice. In this study, we observed that Nix and Mif were co-localized in skeletal muscles of aged and inflamed mice. We show an inflammation- and age-related association between Nix and Mif gene expression, with the strongest positive correlation observed in old IL-10tm/tm skeletal muscles. The IL-10tm/tm skeletal muscles also had the highest levels of oxidative stress damage. These observations suggest that Nix-Mif cross-talk may play a role in the interface between chronic inflammation and oxidative stress in aging skeletal muscles. PMID- 28721428 TI - Gender and Age Differences in Levels, Types and Locations of Physical Activity among Older Adults Living in Car-Dependent Neighborhoods. AB - BACKGROUND: A thorough understanding of gender differences in physical activity is critical to effective promotion of active living in older adults. OBJECTIVES: To examine gender and age differences in levels, types and locations of physical activity. DESIGN: Cross-sectional observation. SETTING: Car-dependent urban and rural neighborhoods in Worcester County, Massachusetts, USA. PARTICIPANTS: 111 men and 103 women aged 65 years and older. MEASUREMENTS: From 2012 to 2014, participants were queried on type, frequency and location of physical activity. Participants wore an accelerometer for 7 consecutive days. RESULTS: Compared to women, men had a higher mean daily step count (mean (SD) 4385 (2122) men vs. 3671(1723) women, p=0.008). Men reported higher frequencies of any physical activity and moderate-to-vigorous physical activity, and a lower frequency of physical activity inside the home. Mean daily step counts and frequency of physical activity outside the home decreased progressively with age for both men and women. Women had a sharper decline in frequencies of self-reported physical activity. Men had a significant decrease in utilitarian walking, which women did not (p=0.07). Among participants who reported participation in any physical activity (n=190), more women indicated exercising indoors more often (59% vs. 44%, p=0.04). The three most commonly cited locations for physical activity away from home for both genders were streets or sidewalks, shopping malls, and membership-only facilities (e.g., YMCA or YWCA). The most common types of physical activity, performed at least once in a typical month, with over 40% of both genders reporting, included light housework, brisk walking, leisurely walking, and stretching. CONCLUSION: Levels, types and location preferences of physical activity differed substantially by gender. Levels of physical activity decreased progressively with age, with greater decline among women. Consideration of these gender differences is necessary to improve the effectiveness of active living promotion programs among older adults. PMID- 28721429 TI - Frailty and Fear of Falling: The FISTAC Study. AB - OBJECTIVE: To analyze the association between frailty and Fear of Falling (FoF) in a cohort of older adults with previous falls. DESIGN: Cross-sectional study (FISTAC). SETTING: Falls Unit, Complejo Hospitalario Universitario of Albacete (Spain). PARTICIPANTS: 183 adults older than 69 years, from the Falls Unit, with a history of a previous fall in the last year. MEASUREMENTS: FoF was assessed at baseline using the Falls Efficacy Scale International (FES-I) and three questions previously validated. Frailty was assessed with the frailty phenotype criteria. Age, gender, comorbidity, nutritional status, cognitive status and risk of depression were determined. RESULTS: Mean age 78.4, 80.3% women. FoF was present in 140 (76.5%) participants with the three questions and 102 (55.7%) presented high concern of falling with the FES-I. 88.8% of frail older adults presented FoF compared to 62.4% of those who were not frail, and only 37.8% of non frail had a high concern of falling, compared to 77.2% of those who were frail measured with the FES-I. Frail participants had an adjusted risk of FoF that was 3.18 (95% CI 1.32 to 7.65) higher compared to those who were not frail assessed with the three questions and 3.93 (95% CI 1.85 to 8.36) higher concern of falling when using the FES-I scale. Only female sex and depression risk were also associated to FoF in the final adjusted models. CONCLUSION: Frailty is independently associated with the FoF syndrome in older faller subjects. PMID- 28721430 TI - TWO-WAY Bridge between Muscular Dysfunction and Cognitive Impairment: Secondary Analyses of SABE - Bogota Study. AB - BACKGROUND AND OBJECTIVE: Muscular dysfunction and cognitive impairment are both disabling states, affecting especially the elderly. Thus, are important subjects of research. Our goal is to describe the association between these two entities in the elderly. METHODS: This is a secondary analysis from the SABE 2012 Bogota survey, which is a cross-sectional study. We define muscular dysfunction as an abnormal result in gait speed and/or handgrip strength tasks. Cognitive impairment was defined as an abnormal result in Mini Mental State Examination. Other independent variables were measured. RESULTS: A total of 1,564 older adults were included in the analysis. Cognitive impairment showed statistically significant association with both low handgrip strength (OR: 2.25; CI 1.52 - 3.33) and low gait speed (OR: 2.76; CI 1.83 - 4.15) in the adjusted model. CONCLUSION: In older adults, muscular dysfunction is associated with cognitive impairment. New studies should address the causality and temporality of this relationship. PMID- 28721431 TI - Depressive Symptoms, Falls, and Fear of Falling in Old Korean Adults: The Korean Longitudinal Study on Health and Aging (KLoSHA). AB - Fall is a common cause of disability and death in old adults, and much research has been focused on identifying risk factors and developing preventive measures. Yet the majority of preceding research has been focused on physical performance. This study aims to evaluate the association between fall and depressive symptoms in community-dwelling elderly. Cross-sectional data of 431 men and 546 women was collected from old Korean adults living in Seongnam, Korea. Geriatric fall assessment was conducted by self-report questionnaires. Depressive symptoms were assessed by the Center for Epidemiologic Studies Depression Scale. Results indicated that depressive symptoms were associated with both fall and fear of falling in old adults. A clear gender difference was newly discovered, as depression played a stronger role in women. These results imply that clinicians should consider the negative affect of geriatric patients when assessing fall risk. Also, measures against depression might be effective in reducing falls. PMID- 28721432 TI - Influence of Age on Decision-Making Process to Limit or Withdraw Life-Sustaining Treatment in the Intensive Care Unit - A Single Center Prospective Observational Study. AB - BACKGROUND: The increasing age in the industrialized countries places significant demands on intensive care unit (ICU) resources and this triggers debates about end-of-life care for the elderly. OBJECTIVES: We sought to determine the impact of age on the decision-making process to limit or withdraw life-sustaining treatment (DWLST) in an ICU in France. We hypothesized that there are differences in the decision-making process for young and old patients. DESIGN, SETTING, PARTICIPANTS: We prospectively studied end-of-life decision-making for all consecutive admissions (n=390) to a tertiary care university ICU in Toulouse, France over a period of 11 months between January and October 2011. RESULTS: Among the 390 patients included in the study (age >=70yo, n=95; age <70yo, n=295) DWLST were more common for patients 70 years or older (43% for age >=70yo vs. 16% for age <70yo, p <0.0001). Reasons for DWLST were different in the 2 groups, with the 'no alternative treatment options' and 'severity of illness' as the most frequent reasons cited for the younger group whereas it was 'severity of illness' for the older group. 'Advanced age' led to DWLSTs in 43% of the decisions in the group >=70yo (vs. 0% in the group <70yo, p <0.0001). Multivariate logistic regression showed a high SAPS II score and age >=70yo as independent risk factors for DWLSTs in the ICU. We did not find age >=70yo as an independent risk factor for mortality in ICU. CONCLUSION: We found that age >=70yo was an independent risk factor for DWLSTs for patients in the ICU, but not for their mortality. Reasons leading to DWLSTs are different according to the age of patients. PMID- 28721433 TI - Oral Health and the Frail Elderly. AB - INTRODUCTION: The relationships between oral health conditions and frailty have rarely been explored. A systematic review of frailty components and oral health concluded that differences in study population endpoint criteria and study design cannot establish a relationship between frailty and oral health. OBJECTIVE: This study aims to describe the distribution of the OHAT (Oral Health Assessment Tool) score in a population of frail subjects and to assess associated parameters (age, socio-economic status, living conditions, education level, nutritional habits, cognitive functioning, autonomy). DESIGN: Cross-sectional observational study among patients referred to the Geriatric Frailty Clinic. MEASUREMENTS: 1314 patients participated in different standardized tests to evaluate their health status, cognitive and affective functioning, adaptation to usual daily activities, nutritional status, and oral health status. RESULTS: The risk of oral health deterioration was higher with the appearance of frailty: the OHAT increased significantly with the Fried Frailty Score (p<0.001). Physical performance and oral health were correlated (p<0.001). The OHAT score and the MNA (Mini Nutritional Assessment) score were significantly correlated: oral status seemed better for malnourished subjects (p<0.001). Dementia significantly increased the risk of an unhealthy oral status (p<0.001). There was no significant correlation between oral status and depression, just a trend. CONCLUSION: This pilot study establishes a relationship between the OHAT and Fried Frailty Criteria in a population of frail elderly. It must be expanded to follow the distribution of the different items composing the OHAT score (items assessing lips; tongue; gums and tissues; saliva; natural teeth; dentures; oral cleanliness; and dental pain) with different parameters (age, socio-economic status, living conditions, educational level, medical history, drug treatment, nutritional habits, cognitive functioning, disabilities and handicaps). PMID- 28721434 TI - Muscle Measures and Nutritional Status at Hospital Admission Predict Survival and Independent Living of Older Patients - the EMPOWER Study. AB - OBJECTIVES: Older adults with sarcopenia and malnutrition are at risk for co morbidities, hospitalization, institutionalization, and mortality. In case of hospitalization, risks may be further increased, especially in case of suboptimal dietary intake. The aim of our study was to assess whether muscle mass, muscle strength, functional performance, and nutritional status at hospital admission were associated with survival and independent living among older patients three months after discharge. DESIGN, SETTING, PARTICIPANTS: The EMPOWER study was an observational, prospective and longitudinal inception cohort of patients older than 70 years admitted to the VU University Medical Centre in Amsterdam, the Netherlands. MEASUREMENTS: Patients were assessed for demographic and clinical characteristics, measurements of muscle mass (by bioelectrical impedance analysis), handgrip strength (by dynamometry), functional performance (self reported ability to walk), and screened for risk of malnutrition (by SNAQ). Three months after hospital discharge, survival and living situation were assessed by a follow-up telephone interview. RESULTS: The majority of the 378 patients enrolled were living independently at the time of hospitalization (90%) and three months post-discharge (83%). Fifty-two patients died in the period from hospital admission to three months after discharge (survival rate 86%). Higher absolute muscle mass measures and not being malnourished at admission were significantly associated with the likelihood of survival. Handgrip strength and self-reported ability to walk were positively associated with a higher chance of living independently three months after discharge, but not with survival. CONCLUSIONS: Older patients with greater muscle mass and without malnutrition at hospital admission had a higher survival rate, while measures of muscle strength and functional performance were predictive for living independently three months after hospital discharge. Different components of muscle health relate to different relevant outcomes and therefore require investigation of specifically targeted interventions in the hospitalized older population. PMID- 28721435 TI - Effect of a Combined Tai Chi, Resistance Training and Dietary Intervention on Cognitive Function in Obese Older Women. AB - Cognitive decline in older adults is a major public health problem and can compromise independence and quality of life. Exercise and diet have been studied independently and have shown to be beneficial for cognitive function, however, a combined Tai Chi, resistance training, and diet intervention and its influence on cognitive function has not been undertaken. The current study used a 12-week non randomized research design with experiment and control groups to examine the effect of a combined Tai Chi, resistance training, and diet intervention on cognitive function in 25 older obese women. Results revealed improvements in domain specific cognitive function in our sample. Baseline cognitive function was correlated with changes in dietary quality. These findings suggest that Tai Chi and resistance training combined with diet intervention might be beneficial for community-based programs aiming to improve cognitive function. PMID- 28721436 TI - Age at natural menopause and risk of type 2 diabetes: a prospective cohort study. AB - AIMS/HYPOTHESIS: In this study, we aimed to examine the association between age at natural menopause and risk of type 2 diabetes, and to assess whether this association is independent of potential mediators. METHODS: We included 3639 postmenopausal women from the prospective, population-based Rotterdam Study. Age at natural menopause was self-reported retrospectively and was treated as a continuous variable and in categories (premature, <40 years; early, 40-44 years; normal, 45-55 years; and late menopause, >55 years [reference]). Type 2 diabetes events were diagnosed on the basis of medical records and glucose measurements from Rotterdam Study visits. HRs and 95% CIs were calculated using Cox proportional hazards models, adjusted for confounding factors; in another model, they were additionally adjusted for potential mediators, including obesity, C reactive protein, glucose and insulin, as well as for levels of total oestradiol and androgens. RESULTS: During a median follow-up of 9.2 years, we identified 348 individuals with incident type 2 diabetes. After adjustment for confounders, HRs for type 2 diabetes were 3.7 (95% CI 1.8, 7.5), 2.4 (95% CI 1.3, 4.3) and 1.60 (95% CI 1.0, 2.8) for women with premature, early and normal menopause, respectively, relative to those with late menopause (p trend <0.001). The HR for type 2 diabetes per 1 year older at menopause was 0.96 (95% CI 0.94, 0.98). Further adjustment for BMI, glycaemic traits, metabolic risk factors, C-reactive protein, endogenous sex hormone levels or shared genetic factors did not affect this association. CONCLUSIONS/INTERPRETATION: Early onset of natural menopause is an independent marker for type 2 diabetes in postmenopausal women. PMID- 28721437 TI - ERK1 is dispensable for mouse pancreatic beta cell function but is necessary for glucose-induced full activation of MSK1 and CREB. AB - AIMS/HYPOTHESIS: Insufficient insulin secretion from pancreatic beta cells, which is associated with a decrease in beta cell mass, is a characteristic of type 2 diabetes. Extracellular signal-related kinase 1 and 2 (ERK1/2) inhibition in beta cells has been reported to affect insulin secretion, gene transcription and survival, although whether ERK1 and ERK2 play distinct roles is unknown. The aim of this study was to assess the individual roles of ERK1 and ERK2 in beta cells using ERK1 (also known as Mapk3)-knockout mice (Erk1 -/- mice) and pharmacological approaches. METHODS: NAD(P)H, free cytosolic Ca2+ concentration and insulin secretion were determined in islets. ERK1 and ERK2 subplasmalemmal translocation and activity was monitored using total internal reflection fluorescence microscopy. ERK1/2, mitogen and stress-activated kinase1 (MSK1) and cAMP-responsive element-binding protein (CREB) activation were evaluated by western blot and/or immunocytochemistry. The islet mass was determined from pancreatic sections. RESULTS: Glucose induced rapid subplasmalemmal recruitment of ERK1 and ERK2. When both ERK1 and ERK2 were inhibited simultaneously, the rapid transient peak of the first phase of glucose-induced insulin secretion was reduced by 40% (p < 0.01), although ERK1 did not appear to be involved in this process. By contrast, ERK1 was required for glucose-induced full activation of several targets involved in beta cell survival; MSK1 and CREB were less active in Erk1 -/- mouse beta cells (p < 0.01) compared with Erk1 +/+ mouse beta cells, and their phosphorylation could only be restored when ERK1 was re-expressed and not when ERK2 was overexpressed. Finally, the islet mass of Erk1 -/- mice was slightly increased in young animals (4-month-old mice) vs Erk1 +/+ mice (section occupied by islets [mean +/- SEM]: 0.74% +/- 0.03% vs 0.62% +/- 0.04%; p < 0.05), while older mice (10 months old) were less prone to age-associated pancreatic peri-insulitis (infiltrated islets [mean +/- SEM]: 7.51% +/- 1.34% vs 2.03% +/- 0.51%; p < 0.001). CONCLUSIONS/INTERPRETATION: ERK1 and ERK2 play specific roles in beta cells. ERK2 cannot always compensate for the lack of ERK1 but the absence of a clear-cut phenotype in Erk1 -/- mice shows that ERK1 is dispensable in normal conditions. PMID- 28721438 TI - Serum adiponectin predicts fracture risk in individuals with type 2 diabetes: the Fukuoka Diabetes Registry. AB - AIMS/HYPOTHESIS: Serum adiponectin has been reported to impact upon fracture risk in the general population. Although type 2 diabetes is associated with increased fracture risk, it is unclear whether serum adiponectin predicts fractures in individuals with type 2 diabetes. The aim of the study was to prospectively investigate the relationship between serum adiponectin and fracture risk in individuals with type 2 diabetes. METHODS: In this study, data was obtained from The Fukuoka Diabetes Registry, a multicentre prospective study designed to investigate the influence of modern treatments on the prognoses of patients with diabetes mellitus. We followed 4869 participants with type 2 diabetes (mean age, 65 years), including 1951 postmenopausal women (defined as self-reported amenorrhea for >1 year) and 2754 men, for a median of 5.3 years. The primary outcomes were fractures at any site and major osteoporotic fractures (MOFs). RESULTS: During the follow-up period, fractures at any site occurred in 682 participants, while MOFs occurred in 277 participants. Age-adjusted HRs (95% CIs) of any fracture and MOFs for 1 SD increment in log e -transformed serum adiponectin were 1.27 (1.15, 1.40) and 1.35 (1.17, 1.55) in postmenopausal women and 1.22 (1.08, 1.38) and 1.40 (1.15, 1.71) in men, respectively. HRs (95% CIs) of MOFs for hyperadiponectinaemia (>= 20 MUg/ml) were 1.72 (1.19, 2.50) in postmenopausal women and 2.19 (1.23, 3.90) in men. The per cent attributable risk of hyperadiponectinaemia for MOFs was as high as being age >=70 years or female sex. CONCLUSIONS/INTERPRETATION: Higher serum adiponectin levels were significantly associated with an increased risk of fractures at any site and with an increased risk of MOFs in individuals with type 2 diabetes, including postmenopausal women. PMID- 28721440 TI - Selectivity of plasma membrane calcium ATPase (PMCA)-mediated extrusion of toxic divalent cations in vitro and in cultured cells. AB - In the recent years, the toxicity of certain divalent cations has been associated with the alteration of intracellular Ca2+ homeostasis. Among other mechanisms, these cations may affect the functionality of certain Ca2+-binding proteins and/or Ca2+ pumps. The plasma membrane calcium pump (PMCA) maintains Ca2+ homeostasis in eukaryotic cells by mediating the efflux of this cation in a process coupled to ATP hydrolysis. The aim of this work was to investigate both in vitro and in cultured cells if other divalent cations (Sr2+, Ba2+, Co2+, Cd2+, Pb2+ or Be2+) could be transported by PMCA. Current results indicate that both purified and intact cell PMCA transported Sr2+ with kinetic parameters close to those of Ca2+ transport. The transport of Pb2+ and Co2+ by purified PMCA was, respectively, 50 and 75% lower than that of Ca2+, but only Co2+ was extruded by intact cells and to a very low extent. In contrast, purified PMCA-but not intact cell PMCA-transported Ba2+ at low rates and only when activated by limited proteolysis or by phosphatidylserine addition. Finally, purified PMCA did not transport Cd2+ or Be2+, although minor Be2+ transport was measured in intact cells. Moreover, Cd2+ impaired the transport of Ca2+ through various mechanisms, suggesting that PMCA may be a potential target of Cd2+-mediated toxicity. The differential capacity of PMCA to transport these divalent cations may have a key role in their detoxification, limiting their noxious effects on cell homeostasis. PMID- 28721439 TI - Effects of insulin and exercise training on FGF21, its receptors and target genes in obesity and type 2 diabetes. AB - AIMS/HYPOTHESIS: Pharmacological doses of FGF21 improve glucose tolerance, lipid metabolism and energy expenditure in rodents. Induced expression and secretion of FGF21 from muscle may increase browning of white adipose tissue (WAT) in a myokine-like manner. Recent studies have reported that insulin and exercise increase FGF21 in plasma. Obesity and type 2 diabetes are potentially FGF21 resistant states, but to what extent FGF21 responses to insulin and exercise training are preserved, and whether FGF21, its receptors and target genes are altered, remains to be established. METHODS: The effects of insulin during euglycaemic-hyperinsulinaemic clamps and 10 week endurance training on serum FGF21 were examined in individuals with type 2 diabetes and in glucose tolerant overweight/obese and lean individuals. Gene expression of FGF21, its receptors and target genes in muscle and WAT biopsies was evaluated by quantitative real time PCR (qPCR). RESULTS: Insulin increased serum and muscle FGF21 independent of overweight/obesity or type 2 diabetes, and there were no effects associated with exercise training. The insulin-induced increases in serum FGF21 and muscle FGF21 expression correlated tightly (p < 0.001). In WAT, overweight/obesity with and without type 2 diabetes led to reduced expression of KLB, but increased FGFR1c expression. However, the expression of most FGF21 target genes was unaltered except for reduced CIDEA expression in individuals with type 2 diabetes. CONCLUSIONS/INTERPRETATION: Insulin-induced expression of muscle FGF21 correlates strongly with a rise in serum FGF21, and this response appears intact in overweight/obesity and type 2 diabetes. FGF21 resistance may involve reduced KLB expression in WAT. However, increased FGFR1c expression or other mechanisms seem to ensure adequate expression of most FGF21 target genes in WAT. PMID- 28721441 TI - Radiation dose to the operator during fluoroscopically guided spine procedures. AB - PURPOSE: Fluoroscopy is widely used to guide diagnostic and therapeutic spine procedures. The purpose of this study was to quantify radiation incident on the operator (operator Air Kerma) during a wide range of fluoroscopy-guided spine procedures and its correlation with the amount of radiation incident on the patient (Kerma Area Product-KAP). METHODS: We retrospectively included 57 consecutive fluoroscopically guided spine procedures. KAP [Gy cm2] and total fluoroscopy time were recorded for each procedure. An electronic dosimeter recorded the operator Air Kerma [MUGy] for each procedure. Operator Air Kerma for each procedure, correlation between KAP and operator Air Kerma, and between KAP and fluoroscopy time was obtained. RESULTS: Operator Air Kerma was widely variable across procedures, with median value of 6.4 MUGy per procedure. Median fluoroscopy time and median KAP per procedure were 2.6 min and 4.7 Gy cm2, respectively. There was correlation between operator Air Kerma and KAP (r 2 = 0.60), with a slope of 1.6 MUGy Air Kerma per unit Gy cm2 KAP incident on the patient and between fluoroscopy time and KAP (r 2 = 0.63). CONCLUSION: Operator Air Kerma during individual fluoroscopy-guided spine procedures can be approximated from the commonly and readily available information of the total amount of radiation incident on the patient, measured as KAP. PMID- 28721442 TI - Involvement of the cerebral veins in MELAS syndrome? PMID- 28721444 TI - Neovascular glaucoma after proton beam therapy of choroidal melanoma: incidence and risk factors. AB - PURPOSE: To analyze the risk factors for the development of neovascular glaucoma (NVG) of patients with choroidal melanoma after proton beam therapy (PBT). METHOD: Clinical case series, retrospective study. We evaluated 629 consecutive patients receiving proton beam therapy for the treatment of a choroidal melanoma at the oncology service at Charite, Berlin and Helmholtz-Zentrum, Berlin between 05/1998 and 11/2008 regarding the development and risk factors of NVG. Patients with tumor resection, salvage proton beam therapy for recurrent disease and known glaucoma of other origin were excluded from the cohort. RESULTS: Of the 629 patients matching the inclusion criteria, 20.8% developed neovascularization of the iris after a mean time of 2.0 years (range 0.45 to 8.4 years) after PBT. Forty-seven percent of the patients with a neovascularization of the iris developed NVG after a mean time of 2.0 years after PBT, ranging from 5 months to 11.6 years. Univariate analysis revealed tumor height [p < 0.001, hazard ratio (HR): 2.71, 95% confidence interval (CI): 1.36-5.35 for tumors >6 mm <=9 mm and 11.32 (4.03-31.73) for tumors >9 mm], distance of the tumor to the optic disc (p < 0.001, HR: 0.43, 95% CI: 0.24-0.77 for >0 mm <=3 mm and HR: 0.13, 95% CI: 0.04 0.37 for >3 mm), dose to the ciliary body (p < 0.001, HR: 9.21, 95% CI: 5.08 16.71 (21-40 cobalt gray equivalents (CGE), HR 27.23, 95% CI: 6.33-116.97 (41-60 CGE)), dose to the optic disc (p < 0.001, HR: 3.53, 95% CI: 1.11-11.27 (21 40CGE), HR: 5.37, 95% CI: 2.72-10.63 (41-60CGE)), the irradiated length of the optic nerve (p < 0.001, HR: 4.48, 95% CI: 2.47-8.13) and diabetes mellitus (p < 0.05, HR: 2.53, 95% CI: 1.4-4.5) were found to be risk factors for the development of NVG. Multivariate regression analysis identified the dose to the ciliary body [p < 0.001, HR: 4.39, 95% CI: 2.28-8.44 (21-40 CGE), HR: 11.04, 95% CI: 1.97-61.69 (41-60 CGE)], the irradiated length of the optic nerve (p < 0.001, HR: 3.88, 95% CI: 2.11-7.16), the existence of diabetes mellitus (p < 0.01, HR: 1.28, 95% CI: 1.24-4.21) and tumor height [p < 0.05, HR: 2.28, 95% CI: 1.17-4.83 (>6 mm <=9 mm), HR: 3.74, 95% CI: 1.05-13.23, (>9 mm)] to be independent risk factors for the development of NVG. CONCLUSIONS: In the present analysis we found tumor height, dose to the ciliary body, irradiated length of the optic nerve and diabetes mellitus to be risk factors for the development of NVG. Whenever possible, critical structures of the anterior and posterior segment should be spared by beam shaping or changing of the beam entry angle. PMID- 28721443 TI - A diffusion spectrum imaging-based tractographic study into the anatomical subdivision and cortical connectivity of the ventral external capsule: uncinate and inferior fronto-occipital fascicles. AB - PURPOSE: The inferior fronto-occipital fasciculus (IFOF) and uncinate fasciculus (UF) are major fronto-capsular white matter pathways. IFOF connects frontal areas of the brain to parieto-occipital areas. UF connects ventral frontal areas to anterior temporal areas. Both fascicles are thought to subserve higher language and emotion roles. Controversy pertaining to their connectivity and subdivision persists in the literature, however. METHODS: High-definition fiber tractography (HDFT) is a non-tensor tractographic method using diffusion spectrum imaging data. Its major advantage over tensor-based tractography is its ability to trace crossing fiber pathways. We used HDFT to investigate subdivisions and cortical connectivity of IFOF and UF in 30 single subjects and in an atlas comprising averaged data from 842 individuals. A per-subject aligned, atlas-based approach was employed to seed fiber tracts and to study cortical terminations. RESULTS: For IFOF, we observed a tripartite arrangement corresponding to ventrolateral, ventromedial, and dorsomedial frontal origins. IFOF volume was not significantly lateralized to either hemisphere. UF fibers arose from ventromedial and ventrolateral frontal areas on the left and from ventromedial frontal areas on the right. UF volume was significantly lateralized to the left hemisphere. The data from the averaged atlas was largely in concordance with subject-specific findings. IFOF connected to parietal, occipital, but not temporal, areas. UF connected predominantly to temporal poles. CONCLUSION: Both IFOF and UF possess subdivided arrangements according to their frontal origin. Our connectivity results indicate the multifunctional involvement of IFOF and UF in language tasks. We discuss our findings in context of the tractographic literature. PMID- 28721445 TI - A two-step bioprocessing strategy in pentonic acids production from lignocellulosic pre-hydrolysate. AB - Efficient utilization (over needless disposal) of biorefinery pre-hydrolysate is an economically relevant practice for improving biorefinery financial prospects. The liquid fraction obtained after acid hydrolysis pretreatment of lignocellulosic biomass, called pre-hydrolysate, are predominantly comprised of hemicellulosic carbohydrates. Using a two-step bioprocess, the hexoses were selectively fermented to ethanol by S. cerevisiae to clear the path for Gluconobacter oxydans transformation of pentoses to a high purity pentonic acids solution. Finally, approximately 180 g pentonic acids and 19 g ethanol could be produced starting from pre-hydrolysate produced from 1 kg corn stover. The results demonstrate execution of our objective to prove this bioconversion method for producing high purity pentonic acids starting from crude lignocellulosic pre hydrolysate, a wastefully disregarded biorefinery process stream. PMID- 28721446 TI - Rhamnolipids Enhance in Vivo Oral Bioavailability of Poorly Absorbed Molecules. AB - PURPOSE: This report describes the effect of rhamnolipids (RLs) on the tight junctions (TJ) of the intestinal epithelium using the rat in-situ closed loop model. METHODS: We investigated the transport of 5 (6)-carboxyfluorescein (CF) and fluorescein isothiocyanate-labeled dextrans with average molecular weights of 4.4 and 10 kDa (FD-4 and FD-10) when co-administered with different concentrations of RLs. Lactate dehydrogenase (LDH) leakage assay and histopathological examination of treated intestinal loops were used to assess potential toxicity of RLs. Further, the effect of kaempferol on accelerating the resealing of the tight junctions in vivo was also investigated RESULTS: Data shows that administration of different RLs concentrations (1.0-5.0% v/v) increased CF absorption through rat intestine by 2.84- and 15.82-folds with RLs concentrations of 1.0% and 5.0% v/v, respectively. RLs exhibited size-dependent increase on FD-4 and FD-10 absorption. Dosing RLs at 1.0% v/v didn't cause a significant LDH leakage or histopathological changes to intestinal mucosa compared to higher concentrations, which showed a progressive damaging effect. Using kaempferol, a natural flavonoid that stimulates the assembly of the TJs, proved to enhance the recovery of barrier properties of the intestinal mucosa treated with high concentrations of RLs (2.5% and 5% v/v). CONCLUSIONS: These results collectively illustrate the ability of RLs to enhance oral bioavailability of different molecules across the intestinal epithelial membrane in a concentration- and time-dependent fashion. PMID- 28721447 TI - Direct repair of the sagittal band for extensor tendon subluxation caused by finger flicking. AB - PURPOSE: For patients with metacarpophalangeal (MCP) extensor tendon subluxation caused by finger flicking injury, we performed an extensor tendon realignment and direct repair technique. The purpose of this study was to evaluate the clinical outcome after direct repair of the sagittal band in patients with MCP extensor tendon subluxation caused by finger flicking injury and to introduce the repair technique. METHODS: A total of 26 patients with a mean age of 39.9 years were included in the study. The mean time from injury to surgery was 51.3 days. The ruptured sagittal band was reattached to the lateral side of the extensor tendon using a continuous interlocking suture. Patients were evaluated for pain using a visual analog scale (VAS), range of motion, long fingertip pinch strength, disabilities of the arm, shoulder, and hand (DASH) score, and the recurrence of extensor tendon subluxation or dislocation. RESULTS: All patients had full range of motion compared to the uninjured contralateral digit. Long fingertip pinch strength was also comparable to that of the contralateral digit in all patients. The DASH score was also improved from a preoperative average of 28.8 to a postoperative average of 1.0. CONCLUSIONS: Realignment of the extensor tendon and direct repair of the superficial layer of the sagittal band to the extensor digitorum communis (EDC) tendon is recommended as a treatment option in patients with chronic MCP extensor tendon subluxation, as well as for acute MCP extensor tendon subluxation in patients that have failed or could not maintain conservative treatment approaches. PMID- 28721448 TI - [PI-RADS 2.0 for Prostate MRI]. AB - The PI-RADS 2.0 classification was established by an international collaboration of the European Society of Urogenital Radiology (ESUR), the American College of Radiology (ACR), and AdMetech Foundation to globally standardize the acquisition and interpretation of multiparametric prostate magnetic resonance imaging (MRI). The PI-RADS 2.0 aims to improve the detection, localization, staging and risk stratification of patients with suspected or histologically confirmed prostate cancer. Suspicious areas on T2-weighted (T2w) MRI, diffusion-weighted MRI (DWI) and dynamic contrast-enhanced MRI (DCE-MRI) were assessed for the presence of a clinically significant prostate cancer with scale from 1 to 5 with 5 being most likely to represent clinically significant prostate cancer. The dominant sequence to detect significant prostate cancer in the peripheral zone is DWI and for the transition zone T2w images. For the local staging of prostate cancer criteria for the assessment of an extracapsular growth were formulated. PMID- 28721450 TI - Smad3 and Bmal1 regulate p21 and S100A4 expression in myocardial stromal fibroblasts via TNF-alpha. AB - Bmal1, a clock gene, is associated with depression, hypertrophy, metabolic syndrome and diabetes. Smad3, which is involved in the TGF-beta signaling pathway, plays an important role in the regulation of tumor progression, fibrosis, obesity and diabetes. Our previous report showed that Smad3 has circadian expression in mouse livers. In the current study, we focused on the heart, especially on the myocardial stromal fibroblasts because the roles of Bmal1 and Smad3 in this tissue are poorly understood. Bmal1 and Smad3 have circadian expression in mouse hearts, and their circadian expression patterns were similar. Bmal1 expression decreased in the hearts of whole-body Smad3 knockout mice, whereas Smad3 expression had little effect on heart-specific Bmal1 knockout mice. Both Smad3 knockout and heart-specific Bmal1 knockout mice showed increases in p21, S100A4, CD206 and TNF-alpha expression in the myocardial stromal fibroblasts and macrophage compared to control mice. We also examined Smad3, Bmal1 and Dec1 expression in human tissue from old myocardial infarctions. Expression of Smad3, Bmal1 and Dec1 decreased in the stromal fibroblasts of tissue from old myocardial infarctions compared to control cases. On the other hand, p21, S100A4 and TNF-alpha increased in the stromal fibroblasts of tissue from old myocardial infarctions. Furthermore, expression of Smad3, Bmal1 and Dec1 decreased in TNF-alpha treated-NIH3T3 cells but expression of p21 and S100A4 increased. This new evidence suggests that Smad3 and Bmal1 regulate p21 and S100A4 expression in myocardial stromal fibroblasts through TNF-alpha. PMID- 28721449 TI - Role of regulatory T cells in acute myeloid leukemia patients undergoing relapse preventive immunotherapy. AB - Regulatory T cells (Tregs) have been proposed to dampen functions of anti neoplastic immune cells and thus promote cancer progression. In a phase IV trial (Re:Mission Trial, NCT01347996, http://www.clinicaltrials.gov ) 84 patients (age 18-79) with acute myeloid leukemia (AML) in first complete remission (CR) received ten consecutive 3-week cycles of immunotherapy with histamine dihydrochloride (HDC) and low-dose interleukin-2 (IL-2) to prevent relapse of leukemia in the post-consolidation phase. This study aimed at defining the features, function and dynamics of Foxp3+CD25highCD4+ Tregs during immunotherapy and to determine the potential impact of Tregs on relapse risk and survival. We observed a pronounced increase in Treg counts in peripheral blood during initial cycles of HDC/IL-2. The accumulating Tregs resembled thymic-derived natural Tregs (nTregs), showed augmented expression of CTLA-4 and suppressed the cell cycle proliferation of conventional T cells ex vivo. Relapse of AML was not prognosticated by Treg counts at onset of treatment or after the first cycle of immunotherapy. However, the magnitude of Treg induction was diminished in subsequent treatment cycles. Exploratory analyses implied that a reduced expansion of Tregs in later treatment cycles and a short Treg telomere length were significantly associated with a favorable clinical outcome. Our results suggest that immunotherapy with HDC/IL-2 in AML entails induction of immunosuppressive Tregs that may be targeted for improved anti-leukemic efficiency. PMID- 28721451 TI - In focus in HCB. PMID- 28721453 TI - [Aortic valve]. PMID- 28721452 TI - Enhanced efficacy of radiofrequency ablation for hepatocellular carcinoma using a novel vascular disrupting agent, CKD-516. AB - BACKGROUND: CKD-516 is a novel vascular disrupting agent that shuts down intratumoral blood flow. We therefore hypothesized that concomitant administration of CKD-516 would enhance the therapeutic efficacy of radiofrequency ablation (RFA) by reducing heat sink effects. We assessed the effects of the combination of CKD-516 and RFA in a rat orthotopic hepatocellular carcinoma (HCC) model. METHODS: Rat HCC cells (N1-S1) were engrafted into the hepatic lobe of Sprague-Dawley (SD) rats. Mice were randomly divided into two groups: RFA-only and CKD-RFA. In the CKD-RFA group, CKD-516 was administered by intraperitoneal injection 2 h before RFA. Ablation zone size was measured on triphenyltetrazolium chloride-stained specimens. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining was performed to evaluate the area of apoptosis/necrosis in the ablation zone. Immunohistochemistry with anti CD31 antibody was performed to evaluate the effect of CKD-516 on tumor vessels. RESULTS: Ablation zone size was significantly larger in the CKD-RFA group than in the RFA-only group (243.10 +/- 74.39 versus 123.30 +/- 28.17 mm2, p < 0.001). On TUNEL staining, the area of apoptosis/necrosis was also significantly larger in the CKD-RFA group than in the RFA-only group (274.44 +/- 140.78 versus 143.74 +/- 90.13 mm2; p = 0.006). Immunohistochemistry with anti-CD31 antibody revealed patent tumor vessels in the RFA-only group, while collapsed vessels were seen in the CKD-RFA group, indicating a vascular shutdown effect of CKD-516. CONCLUSION: Concomitant administration of CKD-516 during RFA can increase the ablation zone of tumors due to its vascular disrupting effect. PMID- 28721454 TI - Intra-individual variation in hand postures during terrestrial locomotion in Japanese macaques (Macaca fuscata). AB - The primate hand adopts a variety of postures during locomotion. Habitually terrestrial cercopithecine primates are known to use a palmigrade posture at faster speeds to possibly mitigate stresses on the hand skeleton; however, it is unclear whether arboreal or semi-terrestrial species use a similar strategy for adjusting hand posture. Here, we explored intra-individual variation in hand contact patterns during terrestrial locomotion in the Japanese macaque (Macaca fuscata), a semi-terrestrial cercopithecine primate. Two monkeys were required to walk on the ground at their own preferred speeds or were encouraged to move faster for food rewards. The contact area under the hand and ground reaction forces (GRFs) were measured simultaneously using a tactile pressure sensor, and then hand pressures were calculated offline. We found that hand contact patterns could vary within individuals. The monkeys used predominantly a palmigrade posture within the range of speeds covered in this study (0.72-2.56 m s-1). There were two subtypes of palmigrade posture. In one subtype, the hypothenar pad did not contact the substrate, whereas the entire hand contacted the substrate in the other. The palm of the palmigrade hand with total-hand contact experienced similar or lower peak pressure and pressure-time integral than those of the palmigrade hand without hypothenar pad contact even though it experienced higher peak GRFs. The moderate peak pressure experienced by the palmigrade hand with total-hand contact was due to increased contact area under the palm. The total contact area of the fingers and peak GRF to the fingers were relatively unchanged with different patterns of hand contact. These findings provide evidence that when walking on the ground, semi-terrestrial Japanese macaques use a palmigrade posture with total-hand contact to attenuate stresses on hand bones, as do habitually terrestrial species. PMID- 28721455 TI - Volume electron microscopy of the distribution of synapses in the neuropil of the juvenile rat somatosensory cortex. AB - Knowing the proportions of asymmetric (excitatory) and symmetric (inhibitory) synapses in the neuropil is critical for understanding the design of cortical circuits. We used focused ion beam milling and scanning electron microscopy (FIB/SEM) to obtain stacks of serial sections from the six layers of the juvenile rat (postnatal day 14) somatosensory cortex (hindlimb representation). We segmented in three-dimensions 6184 synaptic junctions and determined whether they were established on dendritic spines or dendritic shafts. Of all these synapses, 87-94% were asymmetric and 6-13% were symmetric. Asymmetric synapses were preferentially located on dendritic spines in all layers (80-91%) while symmetric synapses were mainly located on dendritic shafts (62-86%). Furthermore, we found that less than 6% of the dendritic spines establish more than one synapse. The vast majority of axospinous synapses were established on the spine head. Synapses on the spine neck were scarce, although they were more common when the dendritic spine established multiple synapses. This study provides a new large quantitative dataset that may contribute not only to the knowledge of the ultrastructure of the cortex, but also towards defining the connectivity patterns through all cortical layers. PMID- 28721456 TI - Antiangiogenic tyrosine kinase inhibitors in colorectal cancer: is there a path to making them more effective? AB - Antiangiogenic therapy has a proven survival benefit in metastatic colorectal cancer. Inhibition of the VEGF pathway using a variety of extracellular antibody approaches has clear benefit in combination with chemotherapy, while intracellular blockade using tyrosine kinase inhibitors (TKIs) such as sorafenib and regorafenib has had more limited success. Pharmacodynamic modeling using modalities such as DCE-MRI indicates potent antiangiogenic effects of these TKIs, yet numerous combination therapies, primarily with chemotherapy, have failed to demonstrate an additive benefit. The sole comparative study of a single agent TKI against placebo showed a survival benefit of regorafenib in patients with advanced, refractory disease. Preclinical data demonstrate synergy between antiantiogenic TKIs and targeted interventions including autophagy inhibition, and together with a renewed effort to define markers of susceptibility, such combinations may be a way to improve the limited efficacy of this once-promising drug class. PMID- 28721457 TI - Carbon use efficiencies and allocation strategies in Prochlorococcus marinus strain PCC 9511 during nitrogen-limited growth. AB - We studied cell properties including carbon allocation dynamics in the globally abundant and important cyanobacterium Prochlorococcus marinus strain PCC 9511 grown at three different growth rates in nitrogen-limited continuous cultures. With increasing nitrogen limitation, cellular divinyl chlorophyll a and the functional absorption cross section of Photosystem II decreased, although maximal photosynthetic efficiency of PSII remained unaltered across all N-limited growth rates. Chl-specific gross and net carbon primary production were also invariant with nutrient-limited growth rate, but only 20% of Chl-specific gross carbon primary production was retained in the biomass across all growth rates. In nitrogen-replete cells, 60% of the assimilated carbon was incorporated into the protein pool while only 30% was incorporated into carbohydrates. As N limitation increased, new carbon became evenly distributed between these two pools. While many of these physiological traits are similar to those measured in other algae, there are also distinct differences, particularly the lower overall efficiency of carbon utilization. The latter provides new information needed for understanding and estimating primary production, particularly in the nutrient-limited tropical oceans where P. marinus dominates phytoplankton community composition. PMID- 28721458 TI - A functional compartmental model of the Synechocystis PCC 6803 phycobilisome. AB - In the light-harvesting antenna of the Synechocystis PCC 6803 phycobilisome (PB), the core consists of three cylinders, each composed of four disks, whereas each of the six rods consists of up to three hexamers (Arteni et al., Biochim Biophys Acta 1787(4):272-279, 2009). The rods and core contain phycocyanin and allophycocyanin pigments, respectively. Together these pigments absorb light between 400 and 650 nm. Time-resolved difference absorption spectra from wild type PB and rod mutants have been measured in different quenching and annihilation conditions. Based upon a global analysis of these data and of published time-resolved emission spectra, a functional compartmental model of the phycobilisome is proposed. The model describes all experiments with a common set of parameters. Three annihilation time constants are estimated, 3, 25, and 147 ps, which represent, respectively, intradisk, interdisk/intracylinder, and intercylinder annihilation. The species-associated difference absorption and emission spectra of two phycocyanin and two allophycocyanin pigments are consistently estimated, as well as all the excitation energy transfer rates. Thus, the wild-type PB containing 396 pigments can be described by a functional compartmental model of 22 compartments. When the interhexamer equilibration within a rod is not taken into account, this can be further simplified to ten compartments, which is the minimal model. In this model, the slowest excitation energy transfer rates are between the core cylinders (time constants 115-145 ps), and between the rods and the core (time constants 68-115 ps). PMID- 28721459 TI - Measurement of lower limb alignment: there are within-person differences between weight-bearing and non-weight-bearing measurement modalities. AB - PURPOSE: Previous studies have compared weight-bearing mechanical leg axis (MLA) measurements to non-weight-bearing measurement modalities. Most of these studies compared mean or median values and did not analyse within-person differences between measurements. This study evaluates the within-person agreement of MLA measurements between weight-bearing full-length radiographs (FLR) and non-weight bearing measurement modalities (computer-assisted surgery (CAS) navigation or MRI). MATERIALS AND METHODS: Two independent observers measured the MLA on pre- and postoperative weight-bearing FLR in 168 patients. These measurements were compared to non-weight-bearing measurements obtained by CAS navigation or MRI. Absolute differences in individual subjects were calculated to determine the agreement between measurement modalities. Linear regression was used to evaluate the possibility that other independent variables impact the differences in measurements. RESULTS: A difference was found in preoperative measurements between FLR and CAS navigation (mean of 2.5 degrees with limit of agreement (1.96 SD) of 6.4 degrees ), as well as between FLR and MRI measurements (mean of 2.4 degrees with limit of agreement (1.96 SD) of 6.9 degrees ). Postoperatively, the mean difference between MLA measured on FLR compared to CAS navigation was 1.5 degrees (limit of agreement (1.96 SD) of 4.6 degrees ). Linear regression analysis showed that weight-bearing MLA measurements vary significantly from non weight-bearing MLA measurements. Differences were more severe in patients with mediolateral instability (p = 0.010), age (p = 0.049) and >=3 degrees varus or valgus alignment (p = 0.008). CONCLUSION: The clinical importance of this study lies in the finding that there are within-person differences between weight bearing and non-weight-bearing measurement modalities. This has implications for preoperative planning, performing total knee arthroplasty (TKA), and clinical follow-up after TKA surgery using CAS navigation or patient-specific instrumentation. LEVEL OF EVIDENCE: III. PMID- 28721460 TI - The Degree of Shoulder Involvement in Sports (DOSIS) scale is a valid and responsive instrumentation for shoulder assessment in patients after surgery for anterior instability. AB - PURPOSE: The purpose of this study was to evaluate validity and responsiveness of the Degree of Shoulder Involvement in Sport (DOSIS) scale. METHODS: A web-based survey was developed to test the construct validity of the DOSIS scale. Fifty three patients with a median age of 33 years (range 17-59) were included in the study. Convergent validity was evaluated by external correlation (Spearman's rank correlation coefficient, r) of the DOSIS with the Brophy-Marx and Tegner activity scales, the Western Ontario shoulder instability index (WOSI), the Simple Shoulder Test (SST), and the Short-Form 36 (SF-36). Responsiveness was analysed by relative efficiency calculation of the DOSIS versus the Brophy-Marx and Tegner activity scales. RESULTS: The DOSIS showed strong correlation with the Brophy Marx and Tegner activity scales, a moderate correlation with the WOSI and SST scores, and a moderate correlation with the physical functioning, role physical and role emotional subscores of the SF-36. The distribution of the DOSIS scores had no serious ceiling or floor effects. The DOSIS demonstrated lesser responsiveness when compared to the Brophy-Marx and Tegner activity scales. CONCLUSION: The DOSIS showed an adequate validity and responsiveness. The clinical relevance of this study is that the DOSIS scale can be used for sport specific shoulder assessment in patients after surgery for anterior instability. LEVEL OF EVIDENCE: III. PMID- 28721461 TI - Influence of adjuvant detached mindfulness and stress management training compared to pharmacologic treatment in primiparae with postpartum depression. AB - Ten to 15% of mothers experience postpartum depression (PPD). If untreated, PPD may negatively affect mothers' and infants' mental health in the long term. Accordingly, effective treatments are required. In the present study, we investigated the effect of detached mindfulness (DM) and stress management training (SMT) as adjuvants, compared to pharmacologic treatment only, on symptoms of depression in women with PPD. Forty-five primiparae (mean age: M = 24.5 years) with diagnosed PPD and treated with an SSRI (citalopram; CIT) took part in the study. At baseline, they completed questionnaires covering socio demographic data and symptoms of depression. Experts rated also symptoms of depression. Next, participants were randomly assigned to one of the following study conditions: adjuvant detached mindfulness (CIT+DM); adjuvant stress management training (CIT+SMT); control condition (CIT). Self- and experts' ratings were completed at the end of the study 8 weeks later, and again at 8 weeks follow-up. Symptoms of depression decreased significantly over time, but more so in the CIT+DM and CIT+SMT group, compared to the control condition. The pattern of results remained stable at follow-up. In primiparae with PPD and treated with a standard SSRI, adjuvant psychotherapeutic interventions led to significant and longer-lasting improvements. PMID- 28721462 TI - [Outpatient specialist treatment (S 116b new) : Changes pending in outpatient uro oncology]. PMID- 28721463 TI - Exstrophy Bladder - Reconstruction or Diversion for the Underprivileged. AB - The surgical techniques for management of bladder exstrophy epispadias complex have evolved from staged reconstruction, complete primary repair to radical mobilization. Post-operative complications add to the multiplicity of surgical procedures at each step. The end results are variable with many achieving continence rates of 85-89% only after bladder augmentation and clean intermittent catheterization. The situation is further complicated in resource-poor settings, where illiteracy and poverty are the driving factors for choosing a single operative procedure for creation of low pressure reservoir aiming at upper tract preservation and good primary continence. Thus, primary urinary diversion should be offered as a surgical option to patients with limited access to health care facilities. Yogesh's cystorectostomy is a modification of Heitz-Boyer-Hovelacque procedure, wherein the bladder plate is directly anastomosed to the recto-sigmoid pouch, without mobilizing the ureters from their original location. The short term follow-ups are encouraging with all achieving total urinary continence over the ensuing months. The upper tract functions are well preserved, along with huge parental and patient satisfaction and overall improvement in the quality of life. PMID- 28721464 TI - Unexpected UBX expression in the maxilliped of the mystacocarid crustacean Derocheilocharis remanei-evidence for a different way of making a maxilliped? AB - In terms of morphology, crustacean maxillipeds are hybrid appendages. They arise in anterior thoracic segments and display characteristics of both locomotory (thoracic) and feeding (gnathal) appendages. Maxillipeds are functionally integrated with the anterior gnathal appendages. Hox gene expression patterns and immunolabeling with the FP6.87 antibody, which detects conserved epitopes of UBX and ABD-A proteins, reveal that maxillipeds are consistently associated with a shift in the expression of the homeotic gene Ubx. Ubx transcription products or proteins only appear in thoracic segments with a typical locomotory thoracopod and are consistently absent in the maxilliped. This pattern is found in various crustaceans: the copepod Mesocyclops, the mysid Mysidium, the decapods Homarus and Periclimenes, the isopod Porcellio, and the amphipod Parhyale. In Parhyale, which possesses maxillipeds on the first thoracic segment, gene manipulation experiments have shown that a leg-like thoracic appendage can be recovered by mis expressing Ubx in that segment and walking legs can be transformed into maxillipeds by Ubx-knockdown. This survey focuses on the expression of UBX/ABD-A proteins, studied using the FP6.87 antibody, in the larval stages of the mystacocarid crustacean Derocheilocaris remanei. Mystacocarids inhabit the intertidal meiofauna zone of sandy beaches and possess one pair of maxillipeds on the first thoracic segment. Strong UBX/ABD-A expression in the developing maxilliped makes Derocheilocaris unique among crustaceans. Our data might also show that the transformation from locomotory thoracopod to maxilliped cannot be accounted for by the mere presence or absence of UBX, because in mystacocarids, UBX is present in both kinds of limbs. The role of the other Hox gene known to be involved in this transformation, Sex combs reduced (Scr), is unclear. The results presented here may document a new example of a shift in Hox gene function in arthropods. The difference in UBX/ABD-A expression between D. remanei and the copepod maxillipeds is of particular interest because correspondences between the feeding apparatus-including the maxilliped-in mystacocarids and copepods have been suggested as being of phylogenetic significance. PMID- 28721465 TI - Growth of children born to renal transplanted women. AB - : Neonates born to transplanted mothers are exposed to immunosuppressive drugs during gestation and have a higher risk of being born prematurely and small for gestational age than the general population. We have prospectively followed up 27 children born to renal transplanted mothers from a single center and 31 healthy children born at term with adequate weight for gestational age. Comparisons of weight and length measurements were made at birth, 1 month (+/-0.9), 3 months (+/ 1.0), 6 months (+/-1.0), 9 months (+/-1.5), and 12 months (+/-1.49) of age. There were a high rate of prematurity (51.9%) and neonates small for gestational age (40.7%) in the transplant group. At birth, in the transplant group, 28% of neonates had subnormal z-scores for weight and 40%, low z-scores for length. However, at 6 months of age, no significant differences were noticed in mean weight-for-age z-scores between groups (weight -0.43 vs -0.03; length -0.53 vs 0.08). At 12 months of age, comparable mean length-for-age z-scores were observed in both groups (weight 0.01 vs 0.27; length -0.07 vs 0.26). CONCLUSION: Despite high rates of premature births and neonates small for gestational age in the transplant group, there was a good recovery of growth during the first year.. What is Known: * Children born to renal transplanted mothers are exposed to immunosuppressive drugs during gestation [4]. * They have high risk of premature birth and fetal growth restriction, immune alterations at birth, and risk of hospitalization for infection in the first months of life [5]. What is New: * Despite high rates of premature birth and neonates small for gestational age, these infants had good growth recovery by 1 year of age. PMID- 28721466 TI - The MOGE(S) classification for cardiomyopathies: current status and future outlook. AB - Cardiomyopathies are complex diseases of multifactorial pathogenesis and have a high morbidity and mortality. Over the past decades, several revisions of classifications and definitions of cardiomyopathies have been proposed, primarily focusing on the phenotypic characterization of cardiomyopathies. The MOGE(S) classification system published in 2013 encompasses the classification of rapidly growing knowledge on genetic mutations, acquired causes (i.e., intramyocardial inflammation, viral infections), and further conditions involved in the induction of cardiomyopathies (e.g., storage diseases, toxicity). It is based on five attributes, including morphofunctional characteristics (M), organ involvement (O), genetic or familial inheritance pattern (G), etiological annotation (E), and optional information about the heart failure functional status (S). This review summarizes the development, the cornerstones of the MOGE(S) classification, and the published data on the clinical relevance of the MOGE(S) classification. We furthermore discuss new issues which might be considered for future updates of the MOGE(S) classification of cardiomyopathies. PMID- 28721467 TI - A Review of the Safety, Efficacy and Mechanisms of Delivery of Nasal Oxytocin in Children: Therapeutic Potential for Autism and Prader-Willi Syndrome, and Recommendations for Future Research. AB - In this article, we conduct a comprehensive review of existing evidence for the safety and therapeutic potential of intranasal oxytocin in pediatric populations. Unique considerations for dosing and delivery of oxytocin to the nasal passageway in pediatric populations and methods to promote adherence are reviewed. Intranasal oxytocin has been administered to 261 children in three open-label studies and eight randomized controlled trials. To date, the only published results in pediatric populations have focused on autism spectrum disorder (ASD) and Prader-Willi syndrome (PWS). Results regarding efficacy for improving social impairment in ASD are equivocal, partially due to mixed methodological designs, dosing regimens, and outcome measures. At present, there is no randomized controlled evidence that oxytocin provides benefit to individuals with PWS. There is no clear evidence of a link between oxytocin administration and any specific adverse event. Adverse events have been assessed using medical interviews, open reports, checklists, and physiological assessments. Adverse events reports have been largely classified as mild (n = 93), with few moderate (n = 9) or severe (n = 3) events reported. There were 35 additional adverse events reported, without severity ratings. Severe events, hyperactivity and irritability, occurred at first administration in both placebo and oxytocin groups, and subsided subsequent to discontinuation. We note that adverse event monitoring is inconsistent and often lacking, and reporting of its relationship to the study drug is poor. Only one study reported adherence data to suggest high adherence. Recommendations are then provided for the delivery of nasal sprays to the nasal passageway, monitoring, and reporting of efficacy, safety, and adherence for oxytocin nasal spray trials in pediatric populations. PMID- 28721468 TI - Are animal models predictive for human postmortem muscle protein degradation? AB - A most precise determination of the postmortem interval (PMI) is a crucial aspect in forensic casework. Although there are diverse approaches available to date, the high heterogeneity of cases together with the respective postmortal changes often limit the validity and sufficiency of many methods. Recently, a novel approach for time since death estimation by the analysis of postmortal changes of muscle proteins was proposed. It is however necessary to improve the reliability and accuracy, especially by analysis of possible influencing factors on protein degradation. This is ideally investigated on standardized animal models that, however, require legitimization by a comparison of human and animal tissue, and in this specific case of protein degradation profiles. Only if protein degradation events occur in comparable fashion within different species, respective findings can sufficiently be transferred from the animal model to application in humans. Therefor samples from two frequently used animal models (mouse and pig), as well as forensic cases with representative protein profiles of highly differing PMIs were analyzed. Despite physical and physiological differences between species, western blot analysis revealed similar patterns in most of the investigated proteins. Even most degradation events occurred in comparable fashion. In some other aspects, however, human and animal profiles depicted distinct differences. The results of this experimental series clearly indicate the huge importance of comparative studies, whenever animal models are considered. Although animal models could be shown to reflect the basic principles of protein degradation processes in humans, we also gained insight in the difficulties and limitations of the applicability of the developed methodology in different mammalian species regarding protein specificity and methodic functionality. PMID- 28721469 TI - [How does the ileoanal pouch keep its promises? : Functioning of the ileoanal pouch after restorative proctocolectomy]. AB - Restorative proctocolectomy with an ileoanal pouch anastomosis (IAPA) is the surgical therapy of choice for patients with refractory ulcerative colitis and/or associated (pre)neoplastic lesions. It is predominantly performed laparoscopically. Reconstruction with a J-pouch is the most frequently applied variant due to the ideal combination of technical simplicity and good long-term results. In the present review, potential postoperative pouch complications, their risk factors, diagnostics and surgical management, as well as mid-term and long-term quality of life after pouch construction are differentially presented based on the current literature. PMID- 28721470 TI - An Alternative to Moment Closure. AB - Moment closure methods are widely used to analyze mathematical models. They are specifically geared toward derivation of approximations of moments of stochastic models, and of similar quantities in other models. The methods possess several weaknesses: Conditions for validity of the approximations are not known, magnitudes of approximation errors are not easily evaluated, spurious solutions can be generated that require large efforts to eliminate, and expressions for the approximations are in many cases too complex to be useful. We describe an alternative method that provides improvements in these regards. The new method leads to asymptotic approximations of the first few cumulants that are explicit in the model's parameters. We analyze the univariate stochastic logistic Verhulst model and a bivariate stochastic epidemic SIR model with the new method. Errors that were made in early applications of moment closure to the Verhulst model are explained and corrected. PMID- 28721471 TI - Evaluations of Interventions Using Mathematical Models with Exponential and Non exponential Distributions for Disease Stages: The Case of Ebola. AB - Many mathematical models for the disease transmission dynamics of Ebola have been developed and studied, particularly during and after the 2014 outbreak in West Africa. Most of these models are systems of ordinary differential equations (ODEs). One of the common assumptions made in these ODE models is that the duration of disease stages, such as latent and infectious periods, follows an exponential distribution. Gamma distributions have also been used in some of these models. It has been demonstrated that, when the models are used to evaluate disease control strategies such as quarantine or isolation, the models with exponential and Gamma distribution assumptions may generate contradictory results (Feng et al. in Bull Math Biol 69(5):1511-1536, 2007). Several Ebola models are considered in this paper with various stage distributions, including exponential, Gamma and arbitrary distributions. These models are used to evaluate control strategies such as isolation (or hospitalization) and timely burial and to identify potential discrepancies between the results from models with exponential and Gamma distributions. PMID- 28721472 TI - A Model for Transfer of P-Glycoproteins in MCF-7 Breast Cancer Cell Line with Multiple Transfer Rules. AB - In this paper, we consider a direct protein transfer process between cells in co culture. Assuming that cells continually encounter each other, and from some hypotheses on cell-to-cell rules of transfer, we derive discrete and continuous Boltzmann-like integro-differential equations. The novelty of this model is to take into account multiple transfer rules. This new transfer model is used to fit the experimental data of cell-to-cell protein transfer in breast cancer. PMID- 28721473 TI - Biomechanics of the classic metaphyseal lesion: finite element analysis. AB - BACKGROUND: The classic metaphyseal lesion (CML) is strongly associated with infant abuse, but the biomechanics responsible for this injury have not been rigorously studied. Radiologic and CT-pathological correlates show that the distal tibial CML always involves the cortex near the subperiosteal bone collar, with variable extension of the fracture into the medullary cavity. Therefore, it is reasonable to assume that the primary site of bone failure is cortical, rather than intramedullary. OBJECTIVE: This study focuses on the strain patterns generated from finite element modeling to identify loading scenarios and regions of the cortex that are susceptible to bone failure. MATERIALS AND METHODS: A geometric model was constructed from a normal 3-month-old infant's distal tibia and fibula. The model's boundary conditions were set to mimic forceful manipulation of the ankle with eight load modalities (tension, compression, internal rotation, external rotation, dorsiflexion, plantar flexion, valgus bending and varus bending). RESULTS: For all modalities except internal and external rotation, simulations showed increased cortical strains near the subperiosteal bone collar. Tension generated the largest magnitude of cortical strain (24%) that was uniformly distributed near the subperiosteal bone collar. Compression generated the same distribution of strain but to a lesser magnitude overall (15%). Dorsiflexion and plantar flexion generated high (22%) and moderate (14%) localized cortical strains, respectively, near the subperiosteal bone collar. Lower cortical strains resulted from valgus bending, varus bending, internal rotation and external rotation (8-10%). The highest valgus and varus bending cortical strains occurred medially. CONCLUSION: These simulations suggest that the likelihood of the initial cortical bone failure of the CML is higher along the margin of the subperiosteal bone collar when the ankle is under tension, compression, valgus bending, varus bending, dorsiflexion and plantar flexion, but not under internal and external rotation. Focal cortical strains along the medial margins of the subperiosteal bone collar with varus and valgus bending may explain the known tendency for focal distal tibial CMLs to occur medially. Further research is needed to determine the threshold of applied forces required to produce this strong indicator of infant abuse. PMID- 28721474 TI - Single-stick tunneled central venous access using the jugular veins in infants weighing less than 5 kg. AB - BACKGROUND: Despite the demonstrated feasibility of the single-stick technique in the femoral vein, its use in neonates and infants for placing central lines in internal and external jugular veins has not been reported. OBJECTIVE: Describe and assess the safety and efficacy of tunneled jugular central venous catheter placement performed under ultrasound (US) and fluoroscopic guidance in neonates and infants weighing <5 kg using the single-stick technique at three tertiary pediatric hospitals. MATERIALS AND METHODS: Thirty-three children weighing less than 5 kg received tunneled central venous access in either internal or external jugular veins using the single-stick technique. Patient history, procedural records and clinical follow-up documents were retrospectively reviewed. Complication rates were compared to those of 41 patients receiving single-stick femoral central lines. RESULTS: Technical complications occurred during one (3.0%) jugular placement with the patient having a failed right-side attempt with subsequent successful left-side placement. The catheters did not last the entire course of treatment in three (9.1%) patients with jugular lines. One patient had the catheter removed due to concern for infection, one catheter was accidentally removed during dressing changes, and one catheter was displaced and subsequently exchanged. Of patients receiving femoral central lines, 1 (2.4%) had a technical complication and 5 catheters (12.2%) did not last the entire course of treatment. CONCLUSION: The placement of tunneled central venous catheters in neonates/infants <5 kg is safe and technically feasible using the internal/external jugular vein via the single-stick technique. By theoretically reducing the risks of catheter infection by avoiding the diaper area and thrombosis by using larger veins, it may be preferable in certain patient populations. PMID- 28721475 TI - Epithelioid hemangioma of bone: radiologic and magnetic resonance imaging characteristics with histopathological correlation. AB - BACKGROUND: Epithelioid hemangioma is a rare vascular tumor that can occur in soft tissues or bone. The tumor is part of a spectrum of vascular tumors that also includes epithelioid hemangioendothelioma and angiosarcoma. When involving the bone, the tumor usually involves the metaphysis or diaphysis of the long tubular bones and most commonly occurs in adults. It has been rarely reported in pediatric patients, and in these reported patients, the tumor primarily involves the epiphysis. OBJECTIVE: To review three cases of epithelioid hemangioma of bone occurring in pediatric patients involving the epiphysis and to explore the imaging features of this tumor. MATERIALS AND METHODS: Retrospectively review three cases of epithelioid hemangioma occurring in skeletally immature patients. RESULTS: These tumors primarily involved the epiphyses or epiphyseal equivalent bones. One lesion was centered in the metaphysis but extended to the epiphysis. These are three cases presenting in an unusual location and at an unusual age. CONCLUSION: Epithelioid hemangioma, though rare, can occur in pediatric patients and appears to involve the epiphyses in these patients. This is in contrast to the usual age and location reported. Epithelioid hemangioma may be considered for an epiphyseal lesion in a skeletally immature patient. PMID- 28721476 TI - Post-prandial physiology and intestinal morphology of the Pacific hagfish (Eptatretus stoutii). AB - Hagfishes are unique to the vertebrate lineage in that they acquire dissolved nutrients across multiple epithelia including the intestine, gill, and skin. This feat has been attributed to their immersive feeding behavior that likely simultaneously provides benefits (nutrient rich) and potentially adverse (hypercapnia, hypoxia, high environmental ammonia) physiological effects. Examinations have been conducted of the ex vivo transport capabilities of specific nutrients as well as in vivo effects of the hypothesized feeding environments, yet the physiological effects of feeding itself have never been elucidated. We examined the post-prandial physiology of Pacific hagfish (Eptatretus stoutii), identifying changes in oxygen consumption, acid-base balance, ammonia waste excretion, and intestinal morphology following feeding in captivity. Following voluntary feeding, post-prandial oxygen consumption was significantly elevated (1868 +/- 272 umol kg-1 h-1) 8 h following feeding when compared to control resting metabolic oxygen consumption (642 +/- 51 umol kg-1 h 1) and resulted in a factorial metabolic scope of 2.92. Changes in acid-base status were not observed following feeding in either the excreted components or the caudal blood samples; however, a significant alkalosis was observed 8 h post feeding in the major intestinal blood vein. Significant increases (16-fold) in ammonia excretion were recorded in 36 h post-fed hagfish. Finally, significant post-prandial increases in intestinal mucosal thickness and microvilli length were observed, with mucosal thickness remaining significantly increased throughout 36 h and the microvilli length returning to fasted lengths by 36 h. These results demonstrate the post-feeding physiology of the earliest diverging extant craniate and identify correlations between physiology and hindgut morphology 8 h following feeding. PMID- 28721477 TI - Imipenem-resistant Gram-negative bacterial isolates carried by persons upon medical examination in Korea. AB - Carbapenem-resistant Gram-negative bacteria (CR-GNB) have emerged and disseminated worldwide, become a great concern worldwide including Korea. The prevalence of fecal carriage of imipenem-resistant Gram-negative bacteria (IR GNB) in persons in Korea was investigated. Stool samples were collected from 300 persons upon medical examination. Samples were screened for IR-GNB by using MacConkey agar with 2 MUl/ml imipenem. Species were identified by 16S rRNA gene sequence analysis, and antimicrobial susceptibility was determined by the broth microdilution method. In total, 82 IR-GNB bacterial isolates were obtained from 79 (26.3%) out of 300 healthy persons. Multilocus sequence typing analysis showed very high diversity among IR P. aeruginosa, S. maltophilia, and E. cloacae isolates, and pulsed-field gel electrophoresis revealed five main pulsotypes of IR P. mirabilis. As for the presence of metallo-beta-lactamases (MBLs), only one IMP-25-producing S. marcescens isolate was identified. Although only one carbapenemase-producing isolate was identified, the high colonization rates with IR-GNB isolates in this study is notable because carriers may be a reservoir for the dissemination of resistant pathogens within the community as well as in health care institutions. PMID- 28721478 TI - Differentiation of renal cell carcinoma subtypes with different iodine quantification methods using single-phase contrast-enhanced dual-energy CT: areal vs. volumetric analyses. AB - PURPOSE: To investigate the possibility of iodine quantification during a single nephrographic phase in characterizing renal cell carcinoma (RCC) subtypes and if there is a difference between areal and volumetric iodine quantification methods. MATERIALS AND METHODS: This retrospective study included 110 patients with 113 histopathologically confirmed RCCs scanned by dual-energy CT at the nephrographic phase before surgeries. For each lesion, an areal measurement of the iodine concentration with maximum enhancement (I max enhan) and the iodine concentration with maximum area among slices (I max area), as well as a volumetric iodine concentration of the whole-tumor (I volume), were evaluated by two independent radiologists. The diagnostic performances in a single nephrographic phase for characterizing RCC subtypes were evaluated, and three iodine quantification methods were compared with each other. RESULTS: There were significant differences (clear cell vs. papillary and clear cell vs. chromophobe RCC) and no significant differences (papillary vs. chromophobe RCC) at the nephrographic phase in all three methods. The area under the receiver operating characteristic (ROC) curve (AUC) derived from the I max enhan for discriminating clear cell from papillary RCC was significantly higher than that derived from the I max area (P = 0.0357) and the I volume (P = 0.0206), and no significant differences existed among the three methods in distinguishing clear cell RCC from chromophobe RCC. The reliability of all three parameters was very high with an interclass correlation coefficient (ICC) exceeding 0.8. CONCLUSIONS: Iodine quantification in a single nephrographic phase can be used to differentiate RCC subtypes preoperatively, and the areal maximum enhancement iodine quantification would probably be the most appropriate approach. PMID- 28721479 TI - New prostate cancer prognostic grade group (PGG): Can multiparametric MRI (mpMRI) accurately separate patients with low-, intermediate-, and high-grade cancer? AB - PURPOSE: Our objective is to determine the accuracy of multiparametric MRI (mpMRI) in predicting pathologic grade of prostate cancer (PCa) after radical prostatectomy (RP) using simple apparent diffusion coefficient metrics and, specifically, whether mpMRI can accurately separate disease into one of two risk categories (low vs. higher grade) or one of three risk categories (low, intermediate, or high grade) corresponding to the new prognostic grade group (PGG) criteria. METHODS: This retrospective, HIPAA-compliant, IRB-approved study included 140 patients with PCa who underwent 3 T mpMRI with endorectal coil and transrectal ultrasound-guided (TRUS-G) biopsy before RP. MpMRI was used to classify lesions using a two-tier (low-grade/PGG 1 vs. high-grade/PGG 2-5) or a three-tier system (low-grade/PGG 1 vs. intermediate-grade/PGG 2 vs. high grade/PGG 3-5). Accuracy of mpMRI was compared against RP for each system. RESULTS: The predictive accuracy of mpMRI using the two-tier system is higher than when using three-tier system (0.77 and 0.45, respectively). There were similar rates of undergrading between mpMRI and TRUS-G biopsy compared to RP (16% & 21%; respectively); rate of overgrading was higher for mpMRI vs. TRUS-G biopsy compared to RP (42% & 17%, respectively). When mpMRI and TRUS-G biopsy are combined, rate of undergrading is 1.4% and overgrading is 11%. CONCLUSIONS: MpMRI predictive accuracy is higher when using a two-tier vs. a three-tier system, suggesting that advanced metrics may be necessary to delineate intermediate- from high-grade disease. Rates of under- and overgrading decreased when mpMRI and TRUS G biopsy are combined, suggesting that these techniques may be complementary in predicting tumor grade. PMID- 28721480 TI - Intermittent and daily smokers' subjective responses to smoking. AB - RATIONALE: One third of US smokers are intermittent smokers (ITS) who do not smoke daily. Unlike daily smokers (DS), whose smoking is negatively reinforced by withdrawal relief, ITS may be motivated by immediate positive reinforcement. In contrast, incentive salience theory posits hypothesis that "liking" of drug effects fades in established users, such as DS. OBJECTIVE: This study aims to compare ITS' and DS' hedonic responses to smoking. METHODS: Participants were 109 ITS (smoking 4-27 days/month) and 52 DS (smoking daily 5-25 cigarettes/day), aged >=21, smoking >=3 years, and not quitting smoking. For 3 weeks, participants engaged in ecological momentary assessment, carrying an electronic diary that asked them to rate their most recent smoking experience on 0-100 visual analog scales (satisfaction, enjoyment [averaged as "pleasure"], feeling sick, feeling a "rush," enjoying upper respiratory sensations, and immediate craving relief). Hierarchical random effect regression analyzed 4476 ratings. RESULTS: ITS found smoking pleasurable (mean = 69.7 +/- 1.7 [SE]) but significantly less so than DS did (77.6 +/- 2.3; p < 0.006). ITS also reported more aversive response (ITS 18.2 +/- 1.4, DS 11.6 +/- 2.0; p < 0.007). Even though ITS are more likely to smoke at bars/restaurants, when drinking alcohol, or when others were present, they did not report more pleasure in these settings (compared to DS). More extensive smoking experience was unrelated to craving or smoking effects among DS, but predicted greater craving, greater pleasure, and less aversion among ITS. CONCLUSIONS: The findings were largely inconsistent with incentive-salience models of drug use. PMID- 28721481 TI - Changes in voiding function after laparoscopic sacrocolpopexy for advanced pelvic organ prolapse: a cohort study of 76 cases. AB - INTRODUCTION AND HYPOTHESIS: We evaluated changes in voiding function at 3 months after laparoscopic sacrocolpopexy (LSC) for advanced pelvic organ prolapse (POP) patients and identified risk predictors for postoperative voiding dysfunction. METHODS: Seventy-six patients with advanced POP who underwent LSC were enrolled in this retrospective cohort study. Pre- and postoperative objective voiding function was assessed by uroflowmetry plus postvoid residual (PVR) volumes. Voiding dysfunction was defined as a maximum flow rate (Qmax) < 15 ml/s, average flow rate (Qave) < 10 ml/s, or PVR > 50 ml. Statistical analyses were performed using paired-sample t tests, McNemar's tests, and multivariate regression analyses. RESULTS: Thirty patients (39%) showed evidence of voiding dysfunction preoperatively, but two thirds of these patients were asymptomatic. Voiding dysfunction decreased significantly from baseline to 3 months after surgery (39% vs. 21%, p = 0.009), including a decrease among patients with Qave < 10 ml/s (32% vs. 17%, p = 0.043) and PVR > 50 ml (24% vs. 9%, p = 0.019). Voiding difficulty decreased significantly from baseline to 3 months after surgery (32% vs. 9%, p < 0.001); urgency and urinary incontinence symptoms did not exhibit significant improvement (p > 0.05). Multivariate analysis identified Qave < 10 ml/s as the independent predictor of postoperative voiding dysfunction [p = 0.014, odds ratio (OR) = 4.77, 95% confidence interval (CI) 1.37-16.54]. CONCLUSIONS: Preoperative voiding dysfunction is common among patients with POP and significantly improves at 3 months following LSC. A preoperative Qave < 10 ml/s was an independent risk factor for postoperative voiding dysfunction. PMID- 28721482 TI - The impact of urodynamics on treatment and outcomes in women with an overactive bladder: a longitudinal prospective follow-up study. AB - INTRODUCTION AND HYPOTHESIS: The aim of this study was to establish if the management of women with overactive bladder (OAB) and patient-reported outcomes differed based on the findings of urodynamics (UDS). METHODS: A prospective, longitudinal observational study conducted in urogynaecology clinics in 22 UK hospitals participating in the Diagnostic Accuracy of Bladder Ultrasound Study (BUS). A total of 687 women with OAB symptoms or urgency-predominant mixed urinary incontinence were recruited into a diagnostic study that used UDS as the reference standard. Detailed clinical history and International Consultation on Incontinence OAB Short Form (ICIQ-OAB sf) questionnaire responses were obtained before the UDS test was carried out. These questionnaires were subsequently collected at a mean of 7 and 20 months, along with patient global impression of improvement and details on medical and surgical treatments. The relationship between UDS diagnosis and treatment was examined using a multinomial regression model; logistic and repeated measures regressions were used to examine other outcomes. RESULTS: We recruited 687 women and the response rate was 69% at 20 months. Treatment subsequent to UDS was highly associated with diagnosis (p < 0.0001). Women who received treatment concordant with their UDS findings were more likely to report an improvement in bladder symptoms (57% vs 45%; p = 0.02) and ICIQ-OAB sf scores (0.5 points, 95%CI: 0.1 to 0.9; p = 0.02). CONCLUSIONS: Urodynamics influenced treatment decisions made by clinicians in determining treatment pathways in women presenting with OAB. Women treated based on UDS diagnoses appear to have greater reductions in symptoms than those who do not. PMID- 28721483 TI - The effectiveness of mediolateral episiotomy in preventing obstetric anal sphincter injuries during operative vaginal delivery: a ten-year analysis of a national registry. AB - INTRODUCTION AND HYPOTHESIS: Obstetric anal sphincter injuries (OASIS) are associated with an increased risk of faecal incontinence after vaginal delivery. The aim of this retrospective population-based cohort study was to assess whether mediolateral episiotomy is associated with a reduction in the rate of OASIS during operative vaginal delivery. METHODS: We used data from the Dutch Perinatal Registry (Perined) that includes records of almost all births between 2000 and 2010 in The Netherlands. In a cohort of 170,969 primiparous and multiparous women whose delivery was recorded, we estimated the association between mediolateral episiotomy and OASIS following both vacuum and forceps deliveries using univariate and multivariate logistic regression analysis. RESULTS: The incidences of OASIS following vacuum delivery in 130,157 primiparous women were 2.5% and 14% in those with and without a mediolateral episiotomy, respectively (adjusted OR 0.14, 95% CI 0.13-0.15), and in 29,183 multiparous women were 2.0% and 7.5%, respectively (adjusted OR 0.23, 95% CI 0.21-0.27). The incidences of OASIS following forceps delivery in 9,855 primiparous women were 3.4% and 26.7% in those with and without a mediolateral episiotomy, respectively (adjusted OR 0.09, 95% CI 0.07-0.11), and in 1,774 multiparous women were 2.6% and 14.2%, respectively (adjusted OR 0.13, 95% CI 0.08-0.22). CONCLUSIONS: The use of a mediolateral episiotomy during both vacuum delivery and forceps delivery is associated with a fivefold to tenfold reduction in the rate of OASIS in primiparous and multiparous women. PMID- 28721484 TI - A comparison of external fixation and locked intramedullary nailing in the treatment of femoral diaphysis fractures from gunshot injuries. AB - INTRODUCTION: We studied the safety and incidence of complications from the treatment of gunshot-induced femur diaphysis fractures with locked intramedullary nailing in comparison to external fixation. METHODS: Patients who had femoral diaphysis fracture operations due to gunshot injuries (107 femurs of 99 patients) between 2003 and 2014 were retrospectively reviewed, and 66 femurs of 60 patients were place into two groups (Group A: intramedullary nailing-38 femurs of the 36 patients; Group B: external fixator-28 femurs of 24 patients). The mean follow-up was 76.3 months (22-131). The study outcomes were patient complications, infection rate, union time, need for secondary surgery, functional assessment with lower extremity functional scale, and radiological evaluation with orthoroentgenograms. RESULTS: The mean age of the patients was 37.3 +/- 7.4 years in Group A and 39 +/- 6.1 years in Group B. There was no significant difference between the two groups in age, gender or follow-up. There were two deep infections (5.2%) in Group A and one deep infection (3.5%) in Group B. Delayed union was observed in four patients (10.5%) in Group A and in two patients (7.1%) in Group B. There was one non-union (2.6%) and one non-union (3.5%) in Group A and Group B, respectively. There was no significant difference between the two groups in incidence of union, delayed union or deep infection. The mean union time was 3.1 +/- 2.5 months in Group A and 5.8 +/- 1.4 months in Group B. The union time was significantly lower in the intramedullary nailing group (p = 0.023). There were no significant differences between the two groups in regards to radiological and functional evaluation. DISCUSSION: This study showed similar complication rates and functional results both for external fixator and intramedullary nailing for the treatment of femoral diaphysis fractures due to gunshot injuries. LEVEL OF EVIDENCE: Level 3 retrospective comparative clinical study. PMID- 28721485 TI - Non-additive and epistatic effects of HLA polymorphisms contributing to risk of adult glioma. AB - Although genome-wide association studies have identified several susceptibility loci for adult glioma, little is known regarding the potential contribution of genetic variation in the human leukocyte antigen (HLA) region to glioma risk. HLA associations have been reported for various malignancies, with many studies investigating selected candidate HLA polymorphisms. However, no systematic analysis has been conducted in glioma patients, and no investigation into potential non-additive effects has been described. We conducted comprehensive genetic analyses of HLA variants among 1746 adult glioma patients and 2312 controls of European-ancestry from the GliomaScan Consortium. Genotype data were generated with the Illumina 660-Quad array, and we imputed HLA alleles using a reference panel of 5225 individuals in the Type 1 Diabetes Genetics Consortium who underwent high-resolution HLA typing via next-generation sequencing. Case control comparisons were adjusted for population stratification using ancestry informative principal components. Because alleles in different loci across the HLA region are linked, we created multigene haplotypes consisting of the genes DRB1, DQA1, and DQB1. Although none of the haplotypes were associated with glioma in additive models, inclusion of a dominance term significantly improved the model for multigene haplotype HLA-DRB1*1501-DQA1*0102-DQB1*0602 (P = 0.002). Heterozygous carriers of the haplotype had an increased risk of glioma [odds ratio (OR) 1.23; 95% confidence interval (CI) 1.01-1.49], while homozygous carriers were at decreased risk compared with non-carriers (OR 0.64; 95% CI 0.40 1.01). Our results suggest that the DRB1*1501-DQA1*0102-DQB1*0602 haplotype may contribute to the risk of glioma in a non-additive manner, with the positive dominance effect partly explained by an epistatic interaction with HLA-DRB1*0401 DQA1*0301-DQB1*0301. PMID- 28721486 TI - Modulatory effect of lycopene against carbofuran toxicity in African catfish, Clarias gariepinus. AB - In the current study, African catfish, Clarias gariepinus, was exposed to a sublethal concentration of carbofuran (CF) to investigate its negative effects on biochemical and oxidative stress biomarkers. Also, the putative role of lycopene (LYC) administration in alleviating these negative effects was evaluated. Fish were divided into six groups in triplicates as follows: group I was without treatment, group II was orally administered corn oil, group III was orally administered 18 mg LYC/kg body weight, group IV was exposed to 0.121 mg CF/L, group V was orally administered 9 mg LYC/kg body weight and exposed to 0.121 mg CF/L, and group VI was orally administered 18 mg LYC/kg body weight and exposed to 0.121 mg CF/L for 4 weeks. At the end of this period, blood and tissue (liver and kidney) samples were collected and biochemical and oxidative stress biomarkers were analysed. Also, histopathological changes were determined. Carbofuran caused significant increments of glucose, cortisol, aspartic amino transferase, alanine amino transferase, cholesterol, urea, and creatinine; meanwhile, serum acetylcholinesterase, total protein, albumin, and total lipids were significantly reduced. Significant increments in hepatic and renal malondialdehyde (MDA) and superoxide dismutase (SOD) levels and marked reduction in hepatic and renal catalase (CAT), glutathione (GSH), and total antioxidant capacity (TAC) levels were observed in CF-exposed fish comparing to the control group. Treatment with LYC attenuated the CF-induced oxidative stress, and this improvement was more pronounced in fish received the high LYC dose (18 mg/kg body weight). Further, congestion of the central vein with infiltration of mononuclear inflammatory cells, vacuolar necrosis, and haemorrhage was observed in the livers of CF-exposed fish. Oral administration of LYC reduced behavioural changes and histopathological alterations. All the altered biochemical parameters and antioxidant biomarkers were also restored to be near the normal levels. The obtained results evoked that LYC administration alleviated the destructive effects of carbofuran and reduced its toxicity effect on African catfish. PMID- 28721487 TI - Influence of light intensity and spectral composition of artificial light at night on melatonin rhythm and mRNA expression of gonadotropins in roach Rutilus rutilus. AB - In this study we investigated the influence of artificial light at night (ALAN) of different intensities (0, 1, 10, 100 lx) and different colours (blue, green, red) on the daily melatonin rhythm and mRNA expression of gonadotropins in roach Rutilus rutilus, a ubiquitous cyprinid, which occur in standing and moderately flowing freshwater habitats of central Europe. Melatonin concentrations were significantly lowered under nocturnal white light already at 1 lx. Low intensity blue, green and red ALAN lowered the melatonin levels significantly in comparison to a dark control. We conclude that ALAN can disturb melatonin rhythms in roach at very low intensities and at different wavelengths and thus light pollution in urban waters has the potential to impact biological rhythms in fish. However, mRNA expression of gonadotropins was not affected by ALAN during the period of the experiments. Thus, suspected implications of ALAN on reproduction of roach could not be substantiated. PMID- 28721488 TI - Further changes in the cotton leaf curl disease complex: an indication of things to come? AB - Cotton leaf curl disease (CLCuD) has been a problem for cotton production in Pakistan and India since the early 1990s. The disease is caused by begomoviruses associated with a specific satellite, the cotton leaf curl Multan betasatellite (CLCuMB). In 2001, resistance introduced into cotton was broken by a recombinant begomovirus, Cotton leaf curl Kokhran virus strain Burewala (CLCuKoV-Bur). Unusually, in resistant cotton, this virus lacked an intact transcriptional activator protein (TrAP) gene, with the capacity to encode only 35 of the usual ~134 amino acids. Recently, isolates of CLCuKoV-Bur with a longer, but still truncated, TrAP gene have been identified in cotton breeding lines lacking the earlier resistance. This suggests that more pathogenic viruses with a full TrAP could return to cotton if the earlier resistance is not maintained in ongoing breeding efforts to produce CLCuD-resistant cotton varieties. This conclusion is supported by recent studies showing the reappearance of pre-resistance-breaking begomoviruses, with full-length TrAP genes, in cotton. PMID- 28721489 TI - Quality in pathology. PMID- 28721490 TI - FOXA1 and CK14 as markers of luminal and basal subtypes in histologic variants of bladder cancer and their associated conventional urothelial carcinoma. AB - Invasive bladder cancer is diverse, and includes several named histomorphologies that differ from conventional urothelial carcinoma, termed "histologic variants." By transcriptional analysis, bladder cancers can be divided into luminal and basal subtypes. In this paper, we study associations between markers of transcriptional subtypes and variant histology in a retrospective cohort of 309 cystectomy specimens. Histology slides were methodically reviewed for all cases, and variant histology was documented. Immunohistochemistry for FOXA1 (luminal marker) and CK14 (basal maker) was performed on histologic variants and their associated conventional urothelial carcinomas. Invasive carcinoma was present in 270 of the cystectomy specimens, 35% of which contained a histologic variant. Squamous carcinomas expressed higher CK14 levels than micropapillary, nested, and plasmacytoid carcinomas (p < 0.001, Kruskal-Wallis), keeping with the basal character of squamous carcinoma. Likewise, squamous carcinomas expressed lower FOXA1 levels than micropapillary, nested, and plasmacytoid carcinomas (p < 0.001, Kruskal-Wallis), keeping with the luminal character of micropapillary carcinoma, and suggesting that nested and plasmacytoid cancers have luminal character. FOXA1 was expressed at lower levels in conventional urothelial carcinoma associated with squamous carcinoma than conventional urothelial carcinoma associated with micropapillary carcinoma (p = 0.0072, Wilcoxon rank sum). CK14 expression did not differ between conventional urothelial carcinomas associated with squamous versus micropapillary carcinoma (p = 0.89, Wilcoxon rank sum). Instead, CK14 expression was higher in squamous carcinoma than conventional urothelial carcinoma present in the same bladder (p = 0.014, Wilcoxon rank sum, paired). Overall, the findings show that squamous and micropapillary cancers have different expression patterns of CK14 and FOXA1 and suggest that they arise from distinct precursors. PMID- 28721491 TI - Erratum to: Development of an Electromechanical Grade to Assess Human Knee Articular Cartilage Quality. PMID- 28721492 TI - Peristaltic-Like Motion of the Human Fetal Right Ventricle and its Effects on Fluid Dynamics and Energy Dynamics. AB - In both adult human and canine, the cardiac right ventricle (RV) is known to exhibit a peristaltic-like motion, where RV sinus (inflow region) contracts first and the infundibulum (outflow region) later, in a wave-like contraction motion. The delay in contraction between the sinus and infundibulum averaged at 15% of the cardiac cycle and was estimated to produce an intra-ventricular pressure difference of 15 mmHg. However, whether such a contractile motion occurs in human fetuses as well, its effects on hemodynamics remains unknown, and are the subject of the current study. Hemodynamic studies of fetal hearts are important as previous works showed that healthy cardiac development is sensitive to fluid mechanical forces. We performed 4D clinical ultrasound imaging on eight 20-weeks old human fetuses. In five fetal RVs, peristaltic-like contractile motion from the sinus to infundibulum ("forward peristaltic-like motion") was observed, but in one RV, peristaltic-like motion was observed from the infundibulum to sinus ("reversed peristaltic-like motion"), and two RVs contraction delay could not be determined due to poor regression fit. Next, we performed dynamic-mesh computational fluid dynamics simulations with varying extents of peristaltic-like motions for three of the eight RVs. Results showed that the peristaltic-like motion did not affect flow patterns significantly, but had significant influence on energy dynamics: increasing extent of forward peristaltic-like motion reduced the energy required for movement of fluid out of the heart during systolic ejection, while increasing extent of reversed peristaltic-like motion increased the required energy. It is currently unclear whether the peristaltic-like motion is an adaptation to reduce physiological energy expenditure, or merely an artefact of the cardiac developmental process. PMID- 28721493 TI - Modelling of Lesions Associated with Functional Mitral Regurgitation in an Ex Vivo Platform. AB - Functional mitral regurgitation (FMR) is a complex pathology involving valvular and subvalvular structures reconfiguration, and its treatment is considered challenging. There is a lack of experimental models allowing for reliable preclinical FMR treatments' evaluation in a realistic setting. A novel approach to simulate FMR was developed and incorporated into an ex vivo passive beating heart platform. FMR was obtained by dilating the mitral annulus (MA) mainly in the antero-posterior direction and displacing the papillary muscles (PMs) apically and laterally by ad hoc designed and 3D printed dilation and displacing devices. It caused hemodynamic and valve morphology alterations. Isolated MA dilation (MAD) led to significantly increased antero-posterior distance (A-P) and decreased coaptation height (CH), tenting area (TA) and systolic leaflets angulation, resembling clinically recognized type I of mitral regurgitation with normal leaflet motion. Whereas concomitant MAD with PM displacement caused an increase in A-P, TA, CH. This geometrical configuration replicated typical determinants of type IIIb lesion with restricted leaflet motion. The proposed methods provided a realistic and repeatable ex vivo FMR model featuring two lesions clinically associated with the pathology. It bears a promise to be successfully utilized in preclinical studies, clinical training and medical education. PMID- 28721494 TI - A Comprehensive Characterization of Parameters Affecting High-Frequency Irreversible Electroporation Lesions. AB - Several focal therapies are being investigated clinically to treat tumors in which surgery is contraindicated. Many of these ablation techniques, such as radiofrequency ablation and microwave ablation, rely on thermal damage mechanisms which can put critical nerves or vasculature at risk. Irreversible electroporation (IRE) is a minimally invasive, non-thermal technique to destroy tumors. A series of short electric pulses create nanoscale defects in the cell membrane, eventually leading to cell death. Typical IRE protocols deliver a series of 50-100 us monopolar pulses. High frequency IRE (H-FIRE) aims to replace these monopolar pulses with integrated bursts of 0.25-10 us bipolar pulses. Here, we examine ablations created using a broad array of IRE and H-FIRE protocols in a potato tissue phantom model. Our results show that H-FIRE pulses require a higher energy dose to create equivalent lesions to standard IRE treatment protocols. We show that ablations in potato do not increase when more than 40 H-FIRE bursts are delivered. These results show that H-FIRE treatment protocols can be optimized to produce clinically relevant lesions while maintaining the benefits of a non thermal ablation technique. PMID- 28721495 TI - Diversity and survival of artificial lifeforms under sedimentation and random motion. AB - Cellular automata are often used to explore the numerous possible scenarios of what could have occurred at the origins of life and before, during the prebiotic ages, when very simple molecules started to assemble and organise into larger catalytic or informative structures, or to simulate ecosystems. Artificial self maintained spatial structures emerge in cellular automata and are often used to represent molecules or living organisms. They converge generally towards homogeneous stationary soups of still-life creatures. It is hard for an observer to believe they are similar to living systems, in particular because nothing is moving anymore within such simulated environments after few computation steps, because they present isotropic spatial organisation, because the diversity of self-maintained morphologies is poor, and because when stationary states are reached the creatures are immortal. Natural living systems, on the contrary, are composed of a high diversity of creatures in interaction having limited lifetimes and generally present a certain anisotropy of their spatial organisation, in particular frontiers and interfaces. In the present work, we propose that the presence of directional weak fields such as gravity may counter-balance the excess of mixing and disorder caused by Brownian motion and favour the appearance of specific regions, i.e. different strata or environmental layers, in which physical-chemical conditions favour the emergence and the survival of self maintained spatial structures including living systems. We test this hypothesis by way of numerical simulations of a very simplified ecosystem model. We use the well-known Game of Life to which we add rules simulating both sedimentation forces and thermal agitation. We show that this leads to more active (vitality and biodiversity) and robust (survival) dynamics. This effectively suggests that coupling such physical processes to reactive systems allows the separation of environments into different milieux and could constitute a simple mechanism to form ecosystem frontiers or elementary interfaces that would protect and favour the development of fragile auto-poietic systems. PMID- 28721496 TI - Update from third international consultation on stone disease. PMID- 28721497 TI - Normoalbuminuric diabetic kidney disease. AB - Diabetic kidney disease (DKD) is one of the primary causes of end-stage renal disease (ESRD). Early diagnosis is very important in preventing the development of DKD. Urinary albumin excretion rate (UAER) and glomerular filtration rate (GFR) are widely accepted as criteria for the diagnosis and clinical grading of DKD, and microalbuminuria has been recommended as the first clinical sign of DKD. The natural history of DKD has been divided into three stages: normoalbuminuria, microalbuminuria, and macroalbuminuria. However, this clinical paradigm has been questioned recently, as studies have shown that a portion of diabetes mellitus (DM) patients with normoalbuminuria have progressive renal insufficiency, referred to as normoalbuminuric diabetic kidney disease (NADKD) or nonalbuminuric diabetic nephropathy. Epidemiologic research has demonstrated that normoalbuminuric diabetic kidney disease is common, and the large number of NADKD patients suggests that the traditional paradigm needs to be shifted. Currently, the pathogenesis of NADKD remains unclear, but many clinical studies have identified some clinical and pathological features of NADKD. In addition, the long-term outcomes of NADKD patients remain controversial. In this article, we reviewed the latest studies addressing the pathogenesis, pathology, treatment and prevention of NADKD. PMID- 28721498 TI - Functional outcome of intra-articular tibial plateau fractures: the impact of posterior column fractures. AB - ABASTRACT: INTRODUCTION: Although regularly ignored, there is growing evidence that posterior tibial plateau fractures affect the functional outcome. The goal of this study was to assess the incidence of posterior column fractures and its impact on functional outcome and general health status. We aimed to identify all clinical variables that influence the outcome and improve insights in the treatment strategies. METHODS: A retrospective cohort study including 218 intra articular tibial plateau fractures was conducted. All fractures were reclassified and applied treatment was assessed according to the updated three-column concept. Relevant demographic and clinical variables were studied. The patient reported outcome was assessed using the Knee injury and Osteoarthritis Outcome Score (KOOS). RESULTS: Median follow-up was 45.5 (IQR 24.9-66.2) months. Significant outcome differences between operatively and non-operatively treated patients were found for all KOOS subscales. The incidence of posterior column fractures was 61.9%. Posterior column fractures, sagittal malalignment and an increased complication rate were associated with poor outcome. Patients treated according to the updated three-column concept, showed significantly better outcome scores than those patients who were not. We could not demonstrate the advantage of posterior column fracture fixation, due to a limited patient size. CONCLUSION: Our data indicates that implementation of the updated three-column classification concept may improve the surgical outcome of tibial plateau fractures. Failure to recognize posterior column fractures may lead to inappropriate utilization of treatment techniques. The current concept allows us to further substantiate the importance of reduction and fixation of posterior column fractures with restoration of the sagittal alignment. LEVEL OF EVIDENCE: 3. PMID- 28721499 TI - Treg-protected donor lymphocyte infusions: a new tool to address the graft-versus leukemia effect in the absence of graft-versus-host disease in patients relapsed after HSCT. AB - In high-risk acute leukemia patients undergoing haploidentical hematopoietic stem cell transplantation (HSCT), adoptive immunotherapy with T regulatory cells (Tregs) and T conventional cells (Tcons) prevented acute and chronic graft-versus host disease (GvHD), favored post-transplant immunological reconstitution and was associated with a powerful graft-versus-leukemia (GvL) effect. With a particularly innovative approach, we developed a treatment with a Treg-protected donor lymphocyte infusion (DLI) for patients with early relapse after HSCT and we report here the results obtained in the first patient with APL (M3v) relapsed after a second matched allogeneic HSCT (15% blasts and 75% of donor cells in bone marrow). The patient received a first infusion of 2.5 * 106/kg Tregs derived from matched donor followed 7 days later by 5 * 106/kg Tcons. GvL effect was strongly evident as the percentage of leukemic cells decreased to 5%. A second infusion of Tregs (2.5 * 106/kg) and Tcons (2 * 106/kg) was performed. No GvHD was observed. Disease evaluation showed the absence of blastic cells at flow-cytometry, a normal caryotype and full donor chimerism. We also observed NOTCH1 down regulation in peripheral blood. This new immunotherapy approach showed that Treg protected DLI is effective in preventing GvHD and is associated with a strong GvL effect. PMID- 28721500 TI - Early prediction of tumor response to bevacizumab treatment in murine colon cancer models using three-dimensional dynamic contrast-enhanced ultrasound imaging. AB - Due to spatial tumor heterogeneity and consecutive sampling errors, it is critically important to assess treatment response following antiangiogenic therapy in three dimensions as two-dimensional assessment has been shown to substantially over- and underestimate treatment response. In this study, we evaluated whether three-dimensional (3D) dynamic contrast-enhanced ultrasound (DCE-US) imaging allows assessing early changes in tumor perfusion following antiangiogenic treatment (bevacizumab administered at a dose of 10 mg/kg b.w.), and whether these changes could predict treatment response in colon cancer tumors that either are responsive (LS174T tumors) or none responsive (CT26) to the proposed treatment. Our results showed that the perfusion parameters of 3D DCE-US including peak enhancement (PE) and area under curve (AUC) significantly decreased by up to 69 and 77%, respectively, in LS174T tumors within 1 day after antiangiogenic treatment (P = 0.005), but not in CT26 tumors (P > 0.05). Similarly, the percentage area of neovasculature significantly decreased in treated versus control LS174T tumors (P < 0.001), but not in treated versus control CT26 tumors (P = 0.796). Early decrease in both PE and AUC by 45-50% was predictive of treatment response in 100% (95% CI 69.2, 100%) of responding tumors, and in 100% (95% CI 88.4, 100%) and 86.7% (95% CI 69.3, 96.2%), respectively, of nonresponding tumors. In conclusion, 3D DCE-US provides clinically relevant information on the variability of tumor response to antiangiogenic therapy and may be further developed as biomarker for predicting treatment outcomes. PMID- 28721501 TI - Examining transgender health through the International Classification of Functioning, Disability, and Health's (ICF) Contextual Factors. AB - PURPOSE: For many transgender individuals, medical intervention is necessary to live as their desired gender. However, little is known about Contextual Factors (i.e., Environmental and Personal) that may act as facilitators and barriers in the health of transgender individuals. Therefore, this paper sought to examine Contextual Factors of the World Health Organization's International Classification of Functioning, Disability, and Health that may facilitate or negatively impact the physical, psychological, and social functioning of transgender individuals. METHODS: A literature review was conducted to identify Environmental and Personal Factors that may influence transgender individuals' physical, psychological, and social functioning. Seven electronic databases were searched. In total, 154 records were reviewed, and 41 articles and other records met inclusion criteria. RESULTS: Three general themes emerged for Environmental Factors: family and social networks, education, and health care. Three general themes also emerged for Personal Factors: socioeconomic status, race, and age. CONCLUSIONS: Transgender individuals benefit from gender-affirming services, improved family and social support systems, and competent provider care. Educational training programs, including medical curricula or workshops, might provide the greatest benefit in improving transgender health by increasing the knowledge and cultural competency of health professionals working with this population. Given the diversity of gender expression, differences in lived experiences, and potential for enduring persistent "double discrimination" due to the intersectional relationships between socioeconomic status, race, and/or age, health professionals must approach transgender health using a holistic lens such as the World Health Organization's International Classification of Functioning, Disability, and Health. PMID- 28721502 TI - Mucin Cross-Feeding of Infant Bifidobacteria and Eubacterium hallii. AB - Mucus production is initiated before birth and provides mucin glycans to the infant gut microbiota. Bifidobacteria are the major bacterial group in the feces of vaginally delivered and breast milk-fed infants. Among the bifidobacteria, only Bifidobacterium bifidum is able to degrade mucin and to release monosaccharides which can be used by other gut microbes colonizing the infant gut. Eubacterium hallii is an early occurring commensal that produces butyrate and propionate from fermentation metabolites but that cannot degrade complex oligo- and polysaccharides. We aimed to demonstrate that mucin cross-feeding initiated by B. bifidum enables growth and metabolite formation of E. hallii leading to short-chain fatty acid (SCFA) formation. Growth and metabolite formation of co-cultures of B. bifidum, of Bifidobacterium breve or Bifidobacterium infantis, which use mucin-derived hexoses and fucose, and of E. hallii were determined. Growth of E. hallii in the presence of lactose and mucin monosaccharides was tested. In co-culture fermentations, the presence of B. bifidum enabled growth of the other strains. B. bifidum/B. infantis co-cultures yielded acetate, formate, and lactate while co-cultures of B. bifidum and E. hallii formed acetate, formate, and butyrate. In three-strain co-cultures, B. bifidum, E. hallii, and B. breve or B. infantis produced up to 16 mM acetate, 5 mM formate, and 4 mM butyrate. The formation of propionate (approximately 1 mM) indicated cross-feeding on fucose. Lactose, galactose, and GlcNAc were identified as substrates of E. hallii. This study shows that trophic interactions of bifidobacteria and E. hallii lead to the formation of acetate, butyrate, propionate, and formate, potentially contributing to intestinal SCFA formation with potential benefits for the host and for microbial colonization of the infant gut. The ratios of SCFA formed differed depending on the microbial species involved in mucin cross-feeding. PMID- 28721503 TI - Salinity Drives the Virioplankton Abundance but Not Production in Tropical Coastal Lagoons. AB - Viruses are the most abundant components of microbial food webs and play important ecological and biogeochemical roles in aquatic ecosystems. Virioplankton is regulated by several environmental factors, such as salinity, turbidity, and humic substances. However, most of the studies aimed to investigate virioplankton regulation were conducted in temperate systems combining a limited range of environmental variables. In this study, virus abundance and production were determined and their relation to bacterial and limnological variables was assessed in 20 neighboring shallow tropical coastal lagoons that present wide environmental gradients of turbidity (2.32-571 NTU), water color (1.82-92.49 m-1), dissolved organic carbon (0.71-16.7 mM), salinity (0.13-332.10/00), and chlorophyll-a (0.28 to 134.5 MUg L-1). Virus abundance varied from 0.37 * 108 to 117 * 108 virus-like-particle (VLP) mL-1, with the highest values observed in highly salty aquatic systems. Salinity and heterotrophic bacterial abundance were the main variables positively driving viral abundances in these lagoons. We suggest that, with increased salinity, there is a decrease in the protozoan control on bacterial populations and lower bacterial diversity (higher encounter rates with virus specific hosts), both factors positively affecting virus abundance. Virus production varied from 0.68 * 107 to 56.5 * 107 VLP mL-1 h-1 and was regulated by bacterial production and total phosphorus, but it was not directly affected by salinity. The uncoupling between virus abundance and virus production supports that the hypothesis that the lack of grazing pressure on viral and bacterial populations is an important mechanism causing virus abundance to escalate with increasing salt concentrations. PMID- 28721504 TI - Microbial Community Structure and Function Decoupling Across a Phosphorus Gradient in Streams. AB - Phosphorus (P) is a key biological element with important and unique biogeochemical cycling in natural ecosystems. Anthropogenic phosphorus inputs have been shown to greatly affect natural ecosystems, and this has been shown to be especially true of freshwater systems. While the importance of microbial communities in the P cycle is widely accepted, the role, composition, and relationship to P of these communities in freshwater systems still hold many secrets. Here, we investigated combined bacterial and archaeal communities utilizing 16S ribosomal RNA (rRNA) gene sequencing and computationally predicted functional metagenomes (PFMs) in 25 streams representing a strong P gradient. We discovered that 16S rRNA community structure and PFMs demonstrate a degree of decoupling between structure and function in the system. While we found that total phosphorus (TP) was correlated to the structure and functional capability of bacterial and archaeal communities in the system, turbidity had a stronger, but largely independent, correlation. At TP levels of approximately 55 MUg/L, we see sharp differences in the abundance of numerous ecologically important taxa related to vegetation, agriculture, sediment, and other ecosystem inhabitants. PMID- 28721505 TI - Distinct Bloom Dynamics of Toxic and Non-toxic Microcystis (Cyanobacteria) Subpopulations in Hoedong Reservoir (Korea). AB - Despite the importance of understanding the bloom mechanisms that influence cyanobacterial toxin production, the dynamics of toxic Microcystis subpopulations are largely unknown. Here, we quantified both toxic and entire (i.e., toxic and non-toxic) Microcystis populations based on the microcystin synthetase E (mcyE) and 16S ribosomal RNA genes. Samples were collected from pelagic water and sediments twice per week from October to December 2011, and we investigated the effects of physicochemical factors (pH, water temperature, dissolved oxygen, nutrients, etc.) and biological factors (ciliates and zooplankton) on the abundance of toxic and non-toxic Microcystis. During the study period, Microcystis blooms were composed of toxic and non-toxic subpopulations. Resting stage Microcystis in sediment may be closely linked to Microcystis populations in pelagic water and may contribute to the toxic subpopulation composition in surface Microcystis blooms. In pelagic water, the toxic and entire Microcystis population had a significant positive correlation with the pH and water temperature (p < 0.05). However, their responses to changes in environmental factors were thought to be distinct. The ratio of the toxic to non-toxic Microcystis subpopulations was significantly (p < 0.05) enhanced by a lower pH and water temperature and an increase in protozoan grazers, reflecting environmental stresses. These results suggest that the toxic and non-toxic subpopulations of Microcystis have distinct tolerance levels against these stressors. The intracellular microcystin (MC) concentration was positively associated with the abundance of the mcyE-positive Microcystis. By comparison, the MC concentration in pelagic water body (extracellular) increased when Microcystis was lysed due to environmental stresses. PMID- 28721506 TI - Interaction Between a Bacterivorous Ciliate Aspidisca cicada and a Rotifer Lecane inermis: Doozers and Fraggles in Aquatic Flocs. AB - Activated sludge is a semi-natural habitat composed of macroaggregates made by flocculating bacteria and inhabited by numerous protozoans and metazoans, creating a complicated interactome. The activated sludge resembles the biological formation of naturally occurring floc habitats, such as "marine snow." So far, these two types of habitat have been analyzed separately, despite their similarities. We examined the effect of a bacterivorous ciliate, Aspidisca cicada, on the quality of the macroaggregate ecosystem by estimating (i) the floc characteristics, (ii) the proliferation of other bacterivores (rotifers), and (iii) the chemical processes. We found that A. cicada (i) positively affected floc quality by creating flocs of larger size; (ii) promoted the population growth of the rotifer Lecane inermis, an important biological agent in activated sludge systems; and (iii) increased the efficiency of ammonia removal while at the same time improving the oxygen conditions. The effect of A. cicada was detectable long after its disappearance from the system. We therefore claim that A. cicada is a very specialized scavenger of flocs with a key role in floc ecosystem functioning. These results may be relevant to the ecology of any natural and engineered aggregates. PMID- 28721507 TI - The diversity and antibiotic properties of actinobacteria associated with endemic deepwater amphipods of Lake Baikal. AB - The emergence of pathogenic bacteria resistant to antibiotics increases the need for discovery of new effective antimicrobials. Unique habitats such as marine deposits, wetlands and caves or unexplored biological communities are promising sources for the isolation of actinobacteria, which are among the major antibiotic producers. The present study aimed at examining cultivated actinobacteria strains associated with endemic Lake Baikal deepwater amphipods and estimating their antibiotic activity. We isolated 42 actinobacterial strains from crustaceans belonging to Ommatogammarus albinus and Ommatogammarus flavus. To our knowledge, this is the first report describing the isolation and initial characterization of representatives of Micromonospora and Pseudonocardia genera from Baikal deepwater invertebrates. Also, as expected, representatives of the genus Streptomyces were the dominant group among the isolated species. Some correlations could be observed between the number of actinobacterial isolates, the depth of sampling and the source of the strains. Nevertheless, >70% of isolated strains demonstrated antifungal activity. The dereplication analysis of extract of one of the isolated strains resulted in annotation of several known compounds that can help to explain the observed biological activities. The characteristics of ecological niche and lifestyle of deepwater amphipods suggests that the observed associations between crustaceans and isolated actinobacteria are not random and might represent long-term symbiotic interactions. PMID- 28721508 TI - Role of preoperative endoscopy in bariatric surgery. PMID- 28721509 TI - Maintaining Patency of Vascular Access for Haemodialysis. AB - All types of vascular access, a necessity for haemodialysis, are prone to thrombosis and if untreated this results in failure. Thrombosis results from the combination of impaired blood flow, endothelial and vessel wall injury and a propensity towards pro-coagulative states, either intrinsic or aggravated by dialysis or dehydration. The treatment of access thrombosis relies on removal of the clot (thrombectomy) and treatment of the underlying problem. In most cases this is stenosis secondary to neointimal hyperplasia which can occur early (failure to mature) or later. Pharmacological approaches have largely been shown to be ineffective at prevention of thrombosis. The mainstay of preventing access failure may be in surveillance and detecting stenosis prior to occlusion although the optimal protocol to achieve this remains undefined. Management of thrombosed access is via either surgical and radiological approaches. Multiple techniques and devices are available for thrombectomy and the choice is usually based on local expertise and availability rather than evidence as few trials have been performed to allow robust comparisons. This paper outlines the basis of access thrombosis and discusses the currently available techniques for treatment. PMID- 28721510 TI - Increased genitourinary fistula rate after bevacizumab in recurrent cervical cancer patients initially treated with definitive radiochemotherapy and image guided adaptive brachytherapy. AB - BACKGROUND AND PURPOSE: Patients with recurrent cervical cancer (RecCC) who received definitive radiochemotherapy including image-guided adaptive brachytherapy (IGABT) as primary treatment are currently treated in our institution with palliative intent by chemotherapy (CHT) combined with bevacizumab (BEV). We aim to evaluate the risk of gastrointestinal (GI)/genitourinary (GU) fistula formation in these patients. MATERIALS AND METHODS: Data of 35 consecutive patients with RecCC treated initially with radiochemotherapy and IGABT were collected. Known and presumed risk factors associated with fistula formation were evaluated. Fistula rate was compared between patients receiving CHT or CHT+BEV. RESULTS: Of the 35 patients, 25 received CHT and 10 patients received CHT+BEV. Clinical characteristics were comparable. Fistulae were reported in 6 patients: two fistulae (8%) in the CHT group, four (40%) in the CHT+BEV group. GU fistula occurred in the CHT+BEV group only (3/4). Of these 6 patients with fistulae, 5 (83%) had undergone previous invasive procedures after the diagnosis of RecCC and 1 patient had undergone pelvic re-irradiation; 3/6 patients had developed a local recurrence. No other risk factors for fistula formation were identified. CONCLUSION: In patients with RecCC after definitive radiochemotherapy including IGABT, the addition of BEV to CHT may increase the risk for GU fistula formation, particularly after invasive pelvic procedures. Future clinical studies are required to identify predictors for fistula formation to subsequently improve patient selection for the addition of BEV in the RecCC setting. PMID- 28721511 TI - Molecular and phylogenetic characterization of bovine coronavirus virus isolated from dairy cattle in Central Region, Thailand. AB - Bovine coronavirus (BCoV) is involved mainly in enteric infections in cattle. This study reports the first molecular detection of BCoV in a diarrhea outbreak in dairy cows in the Central Region, Thailand. BCoV was molecularly detected from bloody diarrheic cattle feces by using nested PCR. Agarose gel electrophoresis of three diarrheic fecal samples yielded from the 25 samples desired amplicons that were 488 base pairs and sequencing substantiated that have BCoV. The sequence alignment indicated that nucleotide and amino acid sequences, the three TWD isolated in Thailand, were more quite homologous to each other (amino acid at position 39 of TWD1, TWD3 was proline, but TWD2 was serine) and closely related to OK-0514-3strain (virulent respiratory strain; RBCoV).The amino acid sequencing identities among TWD1, TWD2,TWD3, and OK-0514-3 strain were 96.0 to 96.6%, those at which T3I, H65N, D87G, H127Y, andQ136R were changed. In addition, the phylogenetic tree of the hypervariable region S1subunit spike glycoprotein BCoV gene was composed of three major clades by using the 54 sequences generated and showed that the evolutionally distance, TWD1, TWD2, and TWD3 were the isolated group together and most similar to OK-0514-3 strain (98.2 to 98.5% similarity). Further study will develop ELISA assay for serologic detection of winter dysentery disease. PMID- 28721512 TI - Beyond the Institutionalized Fetish of the "Neurosciences": Taking Brain Seriously. AB - In their book Kritik der Neuropsychologie (Giessen: Psychosozial Verlag, 2016, 123 pp. ISBN 978-3-8379-2563-0), Hans Werbik and Gerhard Benetka provide a thorough analysis of the modus operandi of our contemporary neurosciences and their success in promising the public and funding institutions great breakthroughs in understanding the human mind through the study of the brain. As the authors prove such promises are inadequate given the qualities of the human psyche that cannot be reduced to the complex mechanisms of the activation of brain circuits because there cannot be isomorphism between the brain and the ongoing dynamic relating of the mind with the flow of subjective experiencing. The authors provide a scenario for possible solutions coming from cultural psychology which need further advancement of psychology's methodology. PMID- 28721513 TI - Does pyuria always suggest urinary tract infection with common microorganisms? Questions. AB - Genitourinary system tuberculosis (GUTB) is a chronic granulomatous infection in which tuberculous bacilli affect one or more organs in the genitourinary system. In this report, an unusual presentation of miliary tuberculosis was presented as GUTB. A 15-year-old girl presented with complaints of severe abdominal pain and dysuria. Abdominal examination showed tenderness and defense. Pyuria and microscopic hematuria were observed. Acute abdominal causes could not be excluded through abdominal ultrasound. On abdominal computed tomography, a necrotic lesion was detected in the right kidney. Acid-fast bacilli were detected in the urine. Quartet anti-tuberculosis therapy was started. After treatment, static renal scintigraphy with 99mTc-dimer captosuccinic acid and single-photon emission CT imaging showed parenchymal injury. In any suspected patient, voiding symptoms, abdominal or flank pain, sterile pyuria, and hematuria should be kept in mind as the presenting manifestations of GUTB in the differential diagnosis. PMID- 28721514 TI - Does pyuria always suggest urinary tract infection with common microorganisms? Answers. PMID- 28721515 TI - Prolonged intermittent renal replacement therapy in children. AB - Wide ranges of age and weight in pediatric patients makes renal replacement therapy (RRT) in acute kidney injury (AKI) challenging, particularly in the pediatric intensive care unit (PICU), wherein children are often hemodynamically unstable. Standard hemodialysis (HD) is difficult in this group of children and continuous veno-venous hemofiltration/dialysis (CVVH/D) has been the accepted modality in the developed world. Unfortunately, due to cost constraints, CVVH/D is often not available and peritoneal dialysis (PD) remains the common mode of RRT in resource-poor facilities. Acute PD has its drawbacks, and intermittent HD (IHD) done slowly over a prolonged period has been explored as an alternative. Various modes of slow sustained IHD have been described in the literature with the recently introduced term prolonged intermittent RRT (PIRRT) serving as an umbrella terminology for all of these modes. PIRRT has been widely accepted in adults with studies showing it to be as effective as CVVH/D but with an added advantage of being more cost-effective. Pediatric data, though scanty, has been promising. In this current review, we elaborate on the practical aspects of undertaking PIRRT in children as well as summarize its current status. PMID- 28721516 TI - Motor-cognitive dual-tasking under hypoxia. AB - Hypoxic conditions diminish motor performance and cognitive functions, especially when the motor task and the cognitive task are conducted simultaneously. Hypoxia does further increase prefrontal cortex activity which provokes a reduced capability of efficient resource utilisation. This, again, might evoke that the capacity of the limited mental resources of a dual task will be reached at an earlier stage of task complexity. The purpose of our study was to examine whether a cognitive task would increase gait variability to a higher extent under hypoxic as compared to normoxic conditions. 18 young subjects walked on a treadmill with and without performing a cognitive task under normoxic vs. normobar hypoxic conditions. The variability of stride times was calculated and a two-way ANOVA with repeated measurements was performed to compare single-task walking with a dual task under both environmental conditions. Furthermore, we compared the cognitive performance while walking in different conditions with Wilcoxon tests. An interaction effect (F 1,34 = 6.178; p = 0.018; eta p2 = 0.154) was observed indicating that in the dual-task condition, there was a greater increase in gait variability in hypoxic conditions as compared to normoxic conditions. We further observed that under hypoxic conditions, each participant performed worse in the cognitive task while walking (p < 0.001). Hypoxia might decrease the ability of performing a motor-cognitive dual task. We speculate that performing a dual task under hypoxia requires a shift of resources away from prefrontal regions. However, future research should verify this assumption examining prefrontal cortex activity while dual-task walking under normoxic conditions to analyse the haemodynamic responses of the brain. PMID- 28721517 TI - Vision for action and perception elicit dissociable adherence to Weber's law across a range of 'graspable' target objects. AB - A number of studies have reported that grasps and manual estimations of differently sized target objects (e.g., 20 through 70 mm) violate and adhere to Weber's law, respectively (e.g., Ganel et al. 2008a, Curr Biol 18:R599-R601)-a result interpreted as evidence that separate visual codes support actions (i.e., absolute) and perceptions (i.e., relative). More recent work employing a broader range of target objects (i.e., 5 through 120 mm) has laid question to this claim and proposed that grasps for 'larger' target objects (i.e., >20 mm) elicit an inverse relationship to Weber's law and that manual estimations for target objects greater than 40 mm violate the law (Bruno et al. 2016, Neuropsychologia 91:327-334). In accounting for this finding, it was proposed that biomechanical limits in aperture shaping preclude the application of Weber's law for larger target objects. It is, however, important to note that the work supporting a biomechanical account may have employed target objects that approached -or were beyond-some participants' maximal aperture separation. The present investigation examined whether grasps and manual estimations differentially adhere to Weber's law across a continuous range of functionally 'graspable' target objects (i.e., 10,...,80% of participant-specific maximal aperture separation). In addition, we employed a method of adjustment task to examine whether manual estimation provides a valid proxy for a traditional measure of perceptual judgment. Manual estimation and method of adjustment tasks demonstrated adherence to Weber's law across the continuous range of target objects used here, whereas grasps violated the law. Thus, results evince that grasps and manual estimations of graspable target objects are, respectively, mediated via absolute and relative visual information. PMID- 28721518 TI - Illusory visual-depth reversal can modulate sensations of contact surface. AB - To perceive the external world stably, humans must integrate and manage continuous streams of information from various sensory modalities, in addition to drawing on past experiences and knowledge. In this study, we introduce a novel visuo-tactile illusion elicited by a visual-depth-reversal stimulus. The stimulus (a model of a building) was constructed so as to produce the same retinal image as an opaque cuboid, although it actually consisted of only three PVC boards forming a three-dimensional corner with the hollow inside facing the observer. Participants holding the model in their palm, therefore, observed, with both eyes or one eye, a building model that could be interpreted as either a concave or a convex cuboid. That is, tactile information from the contact surface contradicted the visual interpretation of a convex cuboid. Questionnaire and experimental results, however, showed that the building model was stably viewed as a standing cuboid, particularly under monocular observation. Participants also reported feeling a stable touch of the shrinking base of the apparently standing building model, thus ignoring the veridical contact surface. Given that the visual-tactile information was unchanged with or without the illusion and that the experimental task was tactile estimation, it is remarkable that participants failed to perceive actual touch based on the object's appearance. Results indicate the complexity and flexibility of visual-tactile integration processes. We also discuss the possibility that object knowledge influences visual-tactile integration. PMID- 28721519 TI - Variations of cocoon external lipids during wolf spiderlings' development. AB - This study presents the first characterisation of the silk lipids of the cocoons of a wolf spider (Pardosa saltans). Wolf spiders' maternal behaviour is complex and involves guarding a cocoon for several weeks, and so cocoons must emit cues to ensure their care and the development of juveniles. We investigated cues associated with the cocoon silk. We assessed qualitative changes of the lipid contents and the composition of cocoon silk in relation to the development of P. saltans wolf spider juveniles. Gas chromatography-mass spectrometry of P. saltans' cocoon silk revealed 62 different lipid compounds. The compounds were aliphatic alcohols, glycerides, fatty acids and their methylesters containing 13 29 carbon atoms. We reveal for the first time the presence of ethanolamides and phytosterol on cocoon silk. Qualitative and quantitative changes occur during the embryonic period, as some polar compounds, such as diglycerides and ethanolamides, disappeared while hydrocarbons emerge, and fatty acids disappeared later during the post-embryonic period. Qualitative and/or quantitative changes could play a role in tactochemical communication between mothers and their cocoon. However, mothers do not modify their behaviour in relation to the developmental stage of their cocoon. Mothers' behaviour appears to be linked to both internal (physiological state) and external mechanisms (signals from the cocoon). PMID- 28721520 TI - Seed development of Jatropha curcas L. (Euphorbiaceae): integrating anatomical, ultrastructural and molecular studies. AB - KEY MESSAGE: This work provides a detailed histological analysis of the development of Jatropha curcas seeds, together with an assessment of the role of programmed cell death in this process. Seeds of Jatropha curcas are a potential source of raw material for the production of biodiesel, but very little is known about how the architecture of the seeds is shaped by the coordinated development of the embryo, endosperm and maternal tissues, namely integuments and nucellus. This study used standard anatomical and ultrastructural techniques to evaluate seed development and programmed cell death (PCD) in the inner integument was monitored by qPCR. In these studies, we found that the embryo sac formation is of the Polygonum type. We also found that embryogenesis is a slow process and the embryo is nourished by the suspensor at earlier stages and by nutrients remobilized from the lysis of the inner integument at later stages. Two types of programmed cell death contribute to the differentiation of the inner integument that begins at early stages of seed development. In addition, the mature embryo presents features of adaptation to dry environments such as the presence of four seminal roots, water absorbing stomata in the root zone and already differentiated protoxylem elements. The findings in this study fill in gaps related to the ontogeny of J. curcas seed development and provide novel insights regarding the types of PCD occurring in the inner integument. PMID- 28721521 TI - Expression patterns of the native Shrunken-2 promoter in Sorghum bicolor visualised through use of the GFP reporter gene. AB - KEY MESSAGE: The AGPase large subunit (shrunken-2) promoter was demonstrated to be active in the placentochalaza and endosperm of developing grain as well as the root tips in transgenic sorghum. The temporal and spatial expression patterns of the Sorghum bicolor Shrunken-2 (Sh2) promoter were evaluated using the green fluorescence protein reporter gene (gfp) in transgenic sorghum, within the context of upregulating starch biosynthesis in the developing grain. GFP fluorescence was analysed throughout development in various tissue types using confocal laser scanning microscopy techniques. Sh2 promoter activity was first detected in the placentochalaza region of the developing caryopsis and apoplasm adjacent to the nucellar epidermis at 7 days post anthesis (dpa) where fluorescence remained relatively constant until 17 dpa. Fluorescence in this region weakened by 20 dpa and disappeared by 25 dpa. Expression was also detected in the developing endosperm, but not until 12 dpa, continuing until 25 dpa. Whilst the endosperm expression was expected, the fluorescence detected in the placentochalaza was completely unexpected. Although transcript presence does not mean the resulting biochemistry is also present, these preliminary findings may suggest alternate spatial activity of ADP-glucose pyrophosphorylase prior to uptake by the developing grain. Sh2 promoter activity was also unexpectedly detected in the root tips at all developmental time points. Sh2 promoter activity was not detected in any reproductive floral tissue (both pre and post anthesis) or in pollen. Similarly, no expression was detected in leaf tissue at any stage. PMID- 28721522 TI - Acquired partial lipodystrophy after bone marrow transplant during childhood: a novel syndrome to be added to the disease classification list. PMID- 28721523 TI - From endosymbionts to host communities: factors determining the reproductive success of arthropod vectors. AB - Elucidating the factors determining reproductive success has challenged scientists since Darwin, but the exact pathways that shape the evolution of life history traits by connecting extrinsic (e.g., landscape structure) and intrinsic (e.g., female's age and endosymbionts) factors and reproductive success have rarely been studied. Here we collected female fleas from wild rodents in plots differing in their densities and proportions of the most dominant rodent species. We then combined path analysis and model selection approaches to explore the network of effects, ranging from micro to macroscales, determining the reproductive success of these fleas. Our results suggest that female reproductive success is directly and positively associated with their infection by Mycoplasma bacteria and their own body mass, and with the rodent species size and total density. In addition, we found evidence for indirect effects of rodent sex and rodent community diversity on female reproductive success. These results highlight the importance of exploring interrelated factors across organization scales while studying the reproductive success of wild organisms, and they have implications for the control of vector-borne diseases. PMID- 28721525 TI - ["Epidemic" or Peripheral Phenomenon? : A Medical History of the "Cocaine Wave" in the Weimar Republic]. AB - An empirical investigation refutes the popular conception that excessive drug usage was a widespread social phenomenon in the Weimar Republic. Although physicians warned the public and politicians of a "cocaine wave" that threatened the public health, there is no evidence that indicates a significant increase of cocaine use during the twenties. The decisive cause for this moral panic was caused instead by the disease pattern of "Cocainism". The addiction carried the imprint of an infectious disease and would destroy the body, the will, and the civic life of its victims. According to medical doctrine, chronic cocaine consumption also produced the tendency towards deviant sexual activities and criminal activity. For this reason, the use of this substance was in particular linked to deviant social milieus like the so-called Bohemian or demimonde. However, historical sources in fact show that it was primarily a problem of the medical professions. Against the background of the desperate political, social and economic situation in Germany after the First World War, physicians regarded cocaine and morphine addictions as a threat to the hoped for political and biological renewal of the nation. PMID- 28721524 TI - Human iPSC-Derived Cardiomyocytes for Investigation of Disease Mechanisms and Therapeutic Strategies in Inherited Arrhythmia Syndromes: Strengths and Limitations. AB - During the last two decades, significant progress has been made in the identification of genetic defects underlying inherited arrhythmia syndromes, which has provided some clinical benefit through elucidation of gene-specific arrhythmia triggers and treatment. However, for most arrhythmia syndromes, clinical management is hindered by insufficient knowledge of the functional consequences of the mutation in question, the pro-arrhythmic mechanisms involved, and hence the most optimal treatment strategy. Moreover, disease expressivity and sensitivity to therapeutic interventions often varies between mutations and/or patients, underlining the need for more individualized strategies. The development of the induced pluripotent stem cell (iPSC) technology now provides the opportunity for generating iPSC-derived cardiomyocytes (CMs) from human material (hiPSC-CMs), enabling patient- and/or mutation-specific investigations. These hiPSC-CMs may furthermore be employed for identification and assessment of novel therapeutic strategies for arrhythmia syndromes. However, due to their relative immaturity, hiPSC-CMs also display a number of essential differences as compared to adult human CMs, and hence there are certain limitations in their use. We here review the electrophysiological characteristics of hiPSC-CMs, their use for investigating inherited arrhythmia syndromes, and their applicability for identification and assessment of (novel) anti-arrhythmic treatment strategies. PMID- 28721527 TI - FESEM evaluation of smear layer removal using different irrigant activation methods (EndoActivator, EndoVac, PUI and LAI). An in vitro study. AB - OBJECTIVES: This study was to compare the efficacy of EndoActivator, EndoVac, PUI, and LAI methods in removing the smear layer from root canals. MATERIALS AND METHODS: Eighty single-rooted mandibular premolars were decoronated to a standardized length of 15 mm. Specimens were shaped to ProTaper F4 (Dentsply Maillefer) and irrigated with 5.25% NaOCl at 37 degrees C. Teeth were divided into six groups (two control groups [n = 10] and four test groups [n = 15]) according to the final irrigation activation/delivering technique (sonic irrigation [EndoActivator], passive ultrasonic irrigation [PUI], negative apical pressure [EndoVac], and laser activated irrigation [LAI]). Root canals were then split longitudinally and observed with field emission scanning electron microscopy to evaluate the presence of smear layer at 1, 3, 5, and 8 mm from the apex. Scores were analyzed by Kruskal-Wallis and Mann-Whitney U tests. RESULTS: The EndoActivator was significantly more efficient than PUI, LAI, and control groups in removing the smear layer at 3, 5, and 8 mm from the apex. The EndoVac System removed statistically significantly more smear layer than all groups at 1 mm from the apex. At 5 mm from the apex, EndoActivator and EndoVac removed more smear layer than LAI and control groups. At 5 and 8 mm from the apex, PUI and EndoVac did not differ statistically, but both performed statistically better than the control groups. CONCLUSION: In our study, none of the activation/delivery systems completely removed the smear layer from the root canal walls; nevertheless, EV and EA showed, respectively, statistically significant better results at 1, 3, 5, and 8 mm and 3, 5, and 8 mm from the apex. PMID- 28721526 TI - Genetic characterization of human hydatid cysts shows coinfection by Echinococcus canadensis G7 and Echinococcus granulosus sensu stricto G1 in Argentina. AB - Human cystic echinococcosis caused by the larval stage of Echinococcus granulosus sensu lato (s.l.) is a highly endemic disease in the province of Neuquen, Patagonia, Argentina. Human infections with E. granulosus sensu stricto (s.s.) G1 and Echinococcus canadensis G6 were reported in Neuquen in previous studies, whereas four genotypes were identified in livestock: G1, G3, G6, and G7. The aim of this study was to identify the genotypes of E. granulosus s.l. isolates from humans of Neuquen province, Patagonia, Argentina, through the 2005-2014 period. Twenty six hydatid cysts were obtained from 21 patients. The most frequent locations were the liver and lungs. Single cysts were observed in 81.0% of patients, and combined infection of liver and lungs was detected in 9.5% of cases. Partial sequencing of mitochondrial cytochrome c oxidase subunit 1 (cox1) and NADH dehydrogenase subunit 1 (nad1) genes identified the presence of E. granulosus s.s. G1 (n = 11; 42.3%) including three different partial sequences; E. canadensis G6 (n = 14; 53.8%) and E. canadensis G7 (n = 1; 3.9%). Coinfection with G1 and G7 genotypes was detected in one patient who harbored three liver cysts. Most of the liver cysts corresponded to G1 and G6 genotypes. This study presents the first report in the Americas of a human infection with E. canadensis G7 and the second worldwide report of a coinfection with two different species and genotypes of E. granulosus s.l in humans. The molecular diversity of this parasite should be considered to redesign or improve the control program strategies in endemic regions. PMID- 28721529 TI - [Dermoscopy for malignant and benign skin tumors : Indication and standardized terminology]. AB - Dermoscopy has a high diagnostic accuracy in pigmented and nonpigmented malignant and benign skin tumors. These microscopic in vivo examinations with polarized and nonpolarized light are effective in the early detection of malignant skin tumors and reduce the number of unnecessary excisions of benign skin tumors. The selection of the skin lesions is crucial for the diagnostic accuracy of the dermoscopic examination. Not only large pigmented skin lesions, but also small hypo-, de-, or nonpigmented skin lesions, should be examined dermatoscopically as well as skin lesions that have changed in shape and/or color. In clinical routine, research and teaching, the dermoscopic diagnosis should be performed by describing the visible structures, their distribution and colors by means of descriptive and/or metaphoric terminology. Optionally, a diagnostic algorithm can also be used. Especially in benign lesions, the dermatoscopic diagnosis should be uniform for the complete area. Comparison with other nearby skin tumors of the same patient (comparative approach) is helpful in the evaluation of numerous melanocytic skin tumors. If it is unclear whether the lesion is malignant, a biopsy or complete excision should be performed with subsequent histopathological examination. PMID- 28721528 TI - Soft tissue profile changes after Functional Mandibular Advancer or Herbst appliance treatment in class II patients. AB - OBJECTIVE: The objective of the present study is to compare the effects on soft tissue profile in class II patients after treatment with either "Functional Mandibular Advancer" (FMA) or Herbst appliance. MATERIALS AND METHODS: The study included n = 42 patients treated with either FMA (n = 21) or Herbst appliance (n = 21) by the same experienced orthodontist. The treatment followed a single-step advancement protocol. Lateral cephalograms were analyzed through a set of customized measurements. The actual therapeutic effect was calculated using data from a growth survey. After testing for normal distribution and homogeneity of variance, data were analyzed by one-sample Student's t tests and independent Student's t tests. Statistical significance was set at p < 0.05. RESULTS: For both FFAs, significant upper lip retrusion, increase in lower lip's thickness, and length of the lower face occurred. Additionally, significant lower lip retrusion and straightening of the profile were found in FMA and Herbst appliance patients. All remaining variables revealed no significant differences. CONCLUSIONS: Treatment-related changes on the facial soft tissue profile could be regarded similar in class II patients treated with FMA or Herbst appliance. No treatment-related changes that were specific for FMA or Herbst appliance could be identified. Only moderate changes were noted comparing pre- and posttreatment soft tissue profiles. CLINICAL RELEVANCE: Despite proven differences in skeletal and dental treatment effects, the facial profile has not to be taken into consideration when choosing between FMA and Herbst appliance for class II treatment. PMID- 28721530 TI - [Imaging representation of the aorta]. AB - Depending on the type and acuteness, diseases of the aorta can be imaged by a variety of techniques. Modalities and quality of imaging have developed rapidly in recent years. In combination with the clinical assessment of patients, the results obtained by imaging determine the further management. They not only establish the underlying diagnosis but provide the information essential for indications, planning and reassessment of therapy, as well as for evaluation of the clinical course and surveillance. Whereas conventional catheter-guided angiography and intravascular ultrasound are only used in exceptional cases and then in conjunction with interventional therapy, cross-sectional imaging modalities, such as contrast-enhanced computed tomography (CT) angiography and magnetic resonance imaging (MRI) are nowadays the mainstay of diagnostics. Ultrasound techniques are improving steadily and are gaining increasing importance, e. g. for screening purposes and for pretherapeutic and posttherapeutic surveillance. Additional information of therapeutic relevance may be acquired by means of molecular imaging with positron emission tomography (PET) CT. PMID- 28721531 TI - [The value of bariatric surgery in the treatment of diabetes : The STAMPEDE study]. PMID- 28721533 TI - Minimum-Norm Estimation of Motor Representations in Navigated TMS Mappings. AB - Navigated transcranial magnetic stimulation (nTMS) can be applied to locate and outline cortical motor representations. This may be important, e.g., when planning neurosurgery or focused nTMS therapy, or when assessing plastic changes during neurorehabilitation. Conventionally, a cortical location is considered to belong to the motor cortex if the maximum electric field (E-field) targeted there evokes a motor-evoked potential in a muscle. However, the cortex is affected by a broad E-field distribution, which tends to broaden estimates of representation areas by stimulating also the neighboring areas in addition to the maximum E field location. Our aim was to improve the estimation of nTMS-based motor maps by taking into account the E-field distribution of the stimulation pulse. The effect of the E-field distribution was considered by calculating the minimum-norm estimate (MNE) of the motor representation area. We tested the method on simulated data and then applied it to recordings from six healthy volunteers and one stroke patient. We compared the motor representation areas obtained with the MNE method and a previously introduced interpolation method. The MNE hotspots and centers of gravity were close to those obtained with the interpolation method. The areas of the maps, however, depend on the thresholds used for outlining the areas. The MNE method may improve the definition of cortical motor areas, but its accuracy should be validated by comparing the results with maps obtained with direct cortical stimulation of the cortex where the E-field distribution can be better focused. PMID- 28721534 TI - Capsule Commentary on Gryczynski et al., Validation of the TAPS-1: A Four-Item Screening Tool to Identify Unhealthy Substance Use in Primary Care. PMID- 28721532 TI - [Chronic cholestatic liver diseases : Differential diagnosis, pathogenesis and current treatment in adults]. AB - In the long-term course chronic cholestasis regularly leads to fibrotic restructuring and ultimately to functional failure of the liver, independent of the cause. Cholestatic diseases are often clinically asymptomatic. In order to avoid progression, early diagnosis of the underlying disease and a targeted therapy are therefore decisive. The differential diagnoses of chronic cholestasis are broad; therefore, algorithms are of assistance in the diagnostic work-up. A better understanding of the pathogenesis is now leading to the development of new therapeutic agents in addition to ursodeoxycholic acid, which has long been known for its anticholestatic effects. Obeticholic acid and, in the near future, bezafibrate are therapeutic options. The possibilities for genetic diagnostics of unclear cholestasis syndromes improve the understanding of the pathogenesis of many diseases and are being introduced increasingly earlier into the clinical routine. PMID- 28721536 TI - Capsule Commentary on Kalkhoran et al., Patterns of and Reasons for Electronic Cigarette Use in Primary Care Patients. PMID- 28721535 TI - Tricyclic and Tetracyclic Antidepressants for the Prevention of Frequent Episodic or Chronic Tension-Type Headache in Adults: A Systematic Review and Meta Analysis. AB - BACKGROUND: Tension-type headaches are a common source of pain and suffering. Our purpose was to assess the efficacy of tricyclic (TCA) and tetracyclic antidepressants in the prophylactic treatment of tension-type headache. METHODS: We searched the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, the ISI Web of Science, and clinical trial registries through 11 March 2017 for randomized controlled studies of TCA or tetracyclic antidepressants in the prevention of tension-type headache in adults. Data were pooled using a random effects approach. KEY RESULTS: Among 22 randomized controlled trials, eight included a placebo comparison and 19 compared at least two active treatments. Eight studies compared TCAs to placebo, four compared TCAs to selective serotonin reuptake inhibitors (SSRIs), and two trials compared TCAs to behavioral therapies. Two trials compared tetracyclics to placebo. Single trials compared TCAs to tetracyclics, buspirone, spinal manipulation, transcutaneous electrical stimulation, massage, and intra-oral orthotics. High-quality evidence suggests that TCAs were superior to placebo in reducing headache frequency (weighted mean differences (WMD): -4.8 headaches/month, 95% CI: -6.63 to -2.95) and number of analgesic medications consumed (WMD: -21.0 doses/month, 95% CI: -38.2 to -3.8). TCAs were more effective than SSRIs. Low-quality studies suggest that TCAs are superior to buspirone, but equivalent to behavioral therapy, spinal manipulation, intra-oral orthotics, and massage. Tetracyclics were no better than placebo for chronic tension-type headache. CONCLUSIONS: Tricyclic antidepressants are modestly effective in reducing chronic tension-type headache and are superior to buspirone. In limited studies, tetracyclics appear to be ineffective in the prophylactic treatment of chronic tension-type headache. PMID- 28721537 TI - Controlling activation barrier by carbon nanotubes as nano-chemical reactors. AB - The oxidative addition of primary amine on a monocyclic phospholane was studied in confined conditions. This one-step chemical reaction has been investigated using the DFT technique to elucidate the role of confinement in carbon nanotubes on the reaction. Calculations were carried out by a progressive increase of the nanotube diameters from 10 A to 15 A in order to highlight the dependence of the reactivity on the nanotube diameter. First, single point investigations were dedicated to the study of reactants, transition states, and products placed in the different nanotubes while keeping their optimized structure as free compounds. Second, all studied compounds were relaxed inside nanotubes and their geometries were fully optimized. Within these approaches, we proved that the activation barrier could be controlled depending on the confinement, generating a well-controlled catalysis process. PMID- 28721538 TI - [Methamphetamine : Epidemiology, clinical importance and sequelae of abuse]. AB - Methamphetamine (also known as meth and crystal meth) is a highly psychoactive synthetic amphetamine type stimulant, which falls under the German Federal Narcotics Law. The substance is similar to other stimulants but has distinct features with respect to psychoactive effects, clinical symptoms, user characteristics and short and long-term consequences including substance-induced problems and comorbidities. The consumption and misuse of crystal meth is still limited to certain regions in Germany; however, the substance causes significant clinical and public health concerns in the affected regions and beyond due to the associated high potential for misuse and dependence, neurotoxic and neurodegenerative effects as well as many other severe health risks. The new German guidelines for methamphetamine use disorders are now available to provide clinicians with the current knowledge on effective diagnostics and treatment planning. PMID- 28721539 TI - [Computational neuroanatomy and microstructure imaging using magnetic resonance imaging]. AB - BACKGROUND: Current computational neuroanatomy focuses on morphological measurements of the brain using standard magnetic resonance imaging (MRI) techniques. In comparison quantitative MRI (qMRI) typically provides a better tissue contrast and also greatly improves the sensitivity and specificity with respect to the microstructural characteristics of tissue. OBJECTIVE: Current methodological developments in qMRI are presented, which go beyond morphology because this provides standardized measurements of the microstructure of the brain. The concept of in-vivo histology is introduced, based on biophysical modelling of qMRI data (hMRI) for determination of quantitative histology-like markers of the microstructure. RESULTS: The qMRI metrics can be used as direct biomarkers of the microstructural mechanisms driving observed morphological findings. The hMRI metrics utilize biophysical models of the MRI signal in order to determine 3-dimensional maps of histology-like measurements in the white matter. CONCLUSION: Non-invasive brain tissue characterization using qMRI or hMRI has significant implications for both scientific and clinical applications. Both approaches improve the comparability across sites and time points, facilitate multicenter and longitudinal studies as well as standardized diagnostics. The hMRI is expected to shed new light on the relationship between brain microstructure, function and behavior both in health and disease. In the future hMRI will play an indispensable role in the field of computational neuroanatomy. PMID- 28721541 TI - Efficacy and safety of metallic stents in comparison to plastic stents for endoscopic drainage of peripancreatic fluid collections: a meta-analysis and trial sequential analysis. AB - Metallic stents are being increasingly used for endoscopic drainage of peripancreatic fluid collections (PFCs) but their superiority over plastic stents has not been proven. We carried out a meta-analysis to consolidate the results from available studies and to suggest evidence-based recommendations. Studies that compared plastic and metallic stents for endoscopic drainage of PFCs and published before October 2016 were searched. Comparisons were performed for clinical success, adverse events, salvage interventions, mortality, technical success and recurrence. We included six studies with 856 patients (479 in the metallic stent group and 377 in the plastic stent group). The clinical success rate was significantly higher with metallic stents than with plastic stents (Mantel-Haenszel odds ratio [MH-OR] 3.22; 95% CI 1.87-5.54; P < 0.001). The rate of adverse events (MH-OR 0.40; 95% CI 0.24-0.65; P < 0.001) and the need for salvage procedures (MH-OR 0.31; 95% CI 0.13-0.70; P = 0.01) were also significantly lower with the use of metallic stents. Subgroup analysis for the type of PFC also found better results with the metallic stents. The results of Egger's regression test (X-axis intercept at -0.63, P = 0.47) and funnel plot did not suggest any significant publication bias. We conclude that compared to plastic stents, the use of metallic stents for endoscopic drainage of PFCs is associated with significantly better clinical success and significantly lower rates of adverse events and the need for salvage procedures. However, further high-quality randomized trials are required to confirm these findings. PMID- 28721540 TI - Temporal expression of cumulus cell marker genes during in vitro maturation and oocyte developmental competence. AB - PURPOSE: Cumulus cells (CC) play important roles in oocyte development and cumulus expressed genes can be used as markers for oocyte quality. This study aimed to investigate temporal changes in the expression of cumulus marker genes during oocyte maturation as possible biomarkers of embryo developmental competence in ovine. METHODS: Gene expression was assessed in the CC of the BCB+ (developmentally competent) and BCB- (developmentally poor) oocytes at 0, 12, and 24 h of in vitro maturation (IVM). Further, the association between the temporal cumulus gene expression and in vitro oocyte and embryo development was assessed. RESULTS: The maturation and blastocyst formation rates were found significantly greater for the BCB+ than the BCB- oocytes. At the 0 h of IVM, a significant upregulation in the expression of PTGS2, STAR, SDC2, LHR, FGF2, BCL2, IL7RA, HSPA1A, and IFNT was observed in the CC of the poor (BCB-) as compared to the competent (BCB+) oocytes. In contrast, it was observed that as maturation progressed, the cumulus expression of most of the favorable genes was reduced and was found significantly downregulated at the completion of IVM in the poor as compared to the competent oocytes. CONCLUSIONS: The study revealed noticeable differences in the cumulus gene expression profile at different stages of IVM between ovine oocytes of differential developmental ability. The results indicated that the loss of cumulus gene expression along the maturation period in the poor oocytes was related to their intrinsic poor quality in the ovarian follicle. PMID- 28721542 TI - Molecular characterization, modeling, in silico analysis of equine pituitary gonadotropin alpha subunit and docking interaction studies with ganirelix. AB - Equine pituitary gonadotropins (eLH, eFSH, eCG) are heterodimeric glycoprotein hormones with alpha (alpha) and beta (beta) subunits. It is responsible for maintenance of pregnancy in mares during early gestation and fairly valuable for inducing superovulation in animals other than equines. The alpha subunit is common, while beta subunit is species-specific in all glycoprotein hormones. In the present investigation, molecular cloning and in silico characterization including homology modeling and molecular docking analysis of the equine chorionic gonadotropin (eCG) alpha subunit was carried out for gaining structural and functional insights into the eCG alpha subunit and its possible interaction with ganirelix, a gonadotropin-releasing hormone (GnRH) antagonist. The equine chorionic gonadotropin (eCG) alpha subunit expressed in pituitary gland was selected, amplified from total RNA, cloned and sequenced. The in silico analyses were made for homology modelling, structural details, epitope identification and chromosomal localization. Molecular docking studies of eCG alpha were undertaken with a drug ganirelix which is used to control ovulation and has antagonistic activity against GnRH. The protein sequence corresponding to selected open reading frame (ORF) was 99-100% similar with domesticated horse, Przewalski's horse, and 92-93% with Burchell's zebra and donkey. Molecular docking studies revealed the possible interaction of eCG alpha with ganirelix. The possible drug macromolecule interactions were visualized between eCG alpha and ganirelix. The study will provide structural insight into unique sites and an alternate route of gonadotropin suppression applicable to assisted reproductive technologies. PMID- 28721543 TI - [Decision aids in complex polypharmacy : Medication data bases and counselling by clinical pharmacists]. AB - The number of older people with polypharmacy (more than six drugs taken simultaneously) is increasing. The greatest proportion consists of guideline drugs, analgesics and psychopharmaceuticals because in many cases of geriatric multimorbidity several underlying main diseases are present which must be treated according to the guidelines. Polypharmacy is a complex and difficult situation for all treating physicians because substantial side effects and intoxication can be induced but it can also be very difficult to recognize which drug was at fault and how a reduction can be safely made. This article describes the exemplary case of a 77-year-old patient with drug-induced delirium and demonstrates the procedure followed. The question of rapid assistance by the utilization of medication data bases is described and the importance of clinical pharmacists is demonstrated. In the future working with medication data bases will possibly become increasingly more important for physicians and hopefully simpler. The case presented here also shows that the effective and justified reduction of drugs can show a very good effect and is possible. PMID- 28721544 TI - Sleep in older adults and in subjects with dementia. AB - The neuronal structures for the regulation of sleep and wakefulness are located in the brain. This complex network is vulnerable to numerous factors, most importantly neurodegenerative diseases and drugs. The macrostructure and microstructure of sleep change with age. These changes are more pronounced in subjects with dementia. Sleep disorders in subjects with dementia may be independent of dementia or caused by dementia. Furthermore, epidemiological studies reveal that sleep disorders per se may induce dementia by reduction of cerebral clearance of beta-amyloids. The population attributable risk (PAR) of sleep disturbances to the incidence of dementia is estimated to be about 15%; therefore, management of sleep disturbances in older adults and subjects with dementia gives the opportunity of an impact on incidence and course of dementia. Sleep history should be taken from each individual and obvious sleep disturbances, especially sleep apnea, should be managed according to current guidelines. Future studies that concern the incidence and the management of dementia must take into account sleep and sleep disturbances. PMID- 28721546 TI - Health benefits observed after probiotic Lactobacillus fermentum CCM 7421 application in dogs. AB - The importance of the intestinal microbiota has attracted much interest in recent years particularly with respect to ways in which the microbiota can be manipulated in order to improve health. Improving gut health through the use of probiotic microorganisms has become an area of research activity in both human and animal nutrition. However, the amount of research using companion animals is insufficient. The present review evaluates and compares the effects achieved after application of canine-derived probiotic strain Lactobacillus fermentum CCM 7421 to healthy dogs as well as to dogs suffering from gastrointestinal disorders. The experiments involved varying duration of application (4 days-14 days), dosage (107-109 CFU), form of application (fresh culture or lyophilized from) or combination with natural substances. Results from nine independent studies show the ability of probiotic strains to establish themselves in the canine gastrointestinal tract, alter the composition of intestinal microbiota and metabolites (organic acids), and modulate the physiology (serum biochemical parameters) and immunity parameters in dogs. Almost all observed effects were irrespective of dose or duration of probiotic administration. PMID- 28721545 TI - Is topiramate effective for migraine prevention in patients less than 18 years of age? A meta-analysis of randomized controlled trials. AB - BACKGROUND: Mainly based on evidence of success in adults, various medications are commonly used to prevent pediatric migraines. Topiramate has been approved for migraine prevention in children as young as 12 years of age. In this meta analysis, we aimed to assess the currently published data pertaining to the efficacy of topiramate for migraine prevention in patients less than 18 years of age. METHODS: We searched PubMed/Medline, Embase and the Cochrane Library (from inception to April 2017) for randomized controlled trials (RCTs) published in English. Two independent investigators performed data extraction and quality evaluation using the Cochrane Collaboration's tool. The data extracted were analyzed by Review Manager 5.3 software. RESULTS: A total of four RCTs matching the inclusion criteria were included, with an aggregate of 465 patients. Of these patients, 329 were included in the topiramate group, and 136 were included in the placebo group. This meta-analysis revealed that compared with placebo, topiramate failed to decrease the number of patients experiencing a >= 50% relative reduction in headache frequency (n = 465, RR = 1.26, 95% CI = [0.94,1.67], Z = 1.55, P = 0.12) or the number of headache days (n = 465, MD = -0.77, 95% CI = [ 2.31,0.76], Z = 0.99, P = 0.32) but did reduce PedMIDAS scores (n = 205, MD = 9.02, 95% CI = [-17.34, -0.70], Z = 2.13, P = 0.03). Higher rates of side effects and adverse events in the topiramate group than in the placebo group were observed in the included trials. CONCLUSIONS: Topiramate may not achieve a more effective clinical trial endpoint than placebo in the prevention of migraines in patients less than 18 years of age, and topiramate may lead to more side effects or adverse events in the included patients. PMID- 28721547 TI - The Effect on Somatic Growth of Surgical and Catheter Treatment of Secundum Atrial Septal Defects. AB - Historical studies suggest an association between atrial septal defect (ASD) and impaired growth with inconsistent improvement following closure. Limited data exist regarding the impact on growth in the era of transcatheter therapy. To evaluate the effect of closure on growth, we conducted a retrospective review of patients undergoing surgical or transcatheter closure during two time periods. Four hundred patients with isolated secundum ASD were divided into three cohorts: early surgical, contemporary surgical, and transcatheter. Data collected included demographics; height, weight, and body mass index (BMI) percentiles; catheterization hemodynamics; and co-morbidities. For all cohorts, there was no significant change in height or weight percentiles during two years after ASD closure. Age at repair was later for contemporary surgical and transcatheter cohorts (p < 0.0001). In the transcatheter cohort, mean Qp:Qs was 1.65 +/- 0.54, but there was no correlation between greater Qp:Qs and decreased somatic growth. Subgroup analysis for patients with any initial growth percentile <5th percentile demonstrated a significant change in weight and BMI percentiles in the first two years after closure (p < 0.0004). The advent of transcatheter therapy shifted institutional practice to later age at repair for both surgical and transcatheter closure. There was no significant change in weight and height percentiles during two years after closure. Only patients with initial weight and BMI <5th percentile had improved growth after treatment. Concern for impaired growth should not generally be an indication for early ASD repair. However, early repair may be indicated in children with existing significant growth failure. PMID- 28721549 TI - An expected coverage model with a cutoff priority queue. AB - Emergency medical services provide immediate care to patients with various types of needs. When the system is congested, the response to urgent emergency calls can be delayed. To address this issue, we propose a spatial Hypercube approximation model with a cutoff priority queue that estimates performance measures for a system where some servers are reserved exclusively for high priority calls when the system is congested. In the cutoff priority queue, low priority calls are not immediately served-they are either lost or entered into a queue-whenever the number of busy ambulances is equal to or greater than the cutoff. The spatial Hypercube approximation model can be used to evaluate the design of public safety systems that employ a cutoff priority queue. A mixed integer linear programming model uses the Hypercube model to identify deployment and dispatch decisions in a cutoff priority queue paradigm. Our computational study suggests that the improvement in the expected coverage is significant when the cutoff is imposed, and it elucidates the tradeoff between the coverage improvement and the cost to low-priority calls that are "lost" when using a cutoff. Finally, we present a method for selecting the cutoff value for a system based on the relative importance of low-priority calls to high-priority calls. PMID- 28721548 TI - Left atrium passive ejection fraction is the most sensitive index of type 2 diabetes mellitus-related cardiac changes. AB - The aims of this study were to use cardiovascular magnetic resonance (CMR) cine to assess left atrium (LA) and left ventricle (LV) function and structure in normotensive type 2 diabetes mellitus (T2DM) patients and to identify the most sensitive index of those T2DM-related cardiac changes. Fifty T2DM patients with normotension (25 males, age 54.7 +/- 8.7 years, duration of diabetes: 7.5 +/- 5.1 years) and 35 controls (16 males, age: 52.2 +/- 13.2 years) were prospectively enrolled. All patients were scanned using CMR four- and two-chamber long-axis cine to assess LA and LV structure and function. Normotensive T2DM patients were associated with decreased LA total ejection fraction (EF), passive EF and LV end diastolic volume, normal LA active EF and LV myocardial mass and increased LV mass/volume (M/V). LA total EF and passive EF correlated with body mass index, duration of diabetes and M/V. To differentiate between diabetic patients and healthy controls, area under the receiver operating characteristic (ROC) curve (AUC) values were calculated to be 0.763, 0.706, 0.647 and 0.649 for LA passive EF, total EF, LVEDV and M/V, respectively. The addition of LA total EF, LVEDV, M/V and the combination thereof did not significantly improve AUC values in a model containing LA passive EF. Normotensive T2DM patients were associated with LA decreased total ejection fraction, decreased passive EF and LV concentric remodeling. Among these indices, LA passive EF was the most sensitive to T2DM related LA function changes. PMID- 28721550 TI - The ten principles behind arterial pressure. PMID- 28721551 TI - Peri-implant biomechanical responses to standard, short-wide, and double mini implants replacing missing molar supporting hybrid ceramic or full-metal crowns under axial and off-axial loading: an in vitro study. AB - BACKGROUND: The aim of this study was to evaluate the biomechanical response of the peri-implant bone to standard, short-wide, and double mini implants replacing missing molar supporting either hybrid ceramic crowns (Lava Ultimate restorative) or full-metal crowns under two different loading conditions (axial and off-axial loading) using strain gauge analysis. METHODS: Three single-molar implant designs, (1) single, 3.8-mm (regular) diameter implant, (2) single, 5.8-mm (wide) diameter implant, and (3) two 2.5-mm diameter (double) implants connected through a single-molar crown, were embedded in epoxy resin by the aid of a surveyor to ensure their parallelism. Each implant supported full-metal crowns made of Ni-Cr alloy and hybrid ceramic with standardized dimensions. Epoxy resin casts were prepared to receive 4 strain gauges around each implant design, on the buccal, lingual, mesial, and distal surfaces. Results were analyzed statistically. RESULTS: Results showed that implant design has statistically significant effect on peri-implant microstrains, where the standard implant showed the highest mean microstrain values followed by double mini implants, while the short-wide implant showed the lowest mean microstrain values. Concerning the superstructure material, implants supporting Lava Ultimate crowns had statistically significant higher mean microstrain values than those supporting full-metal crowns. Concerning the load direction, off-axial loading caused uneven distribution of load with statistically significant higher microstrain values on the site of off axial loading (distal surface) than the axial loading. CONCLUSIONS: Implant design, superstructure material, and load direction significantly affect peri implant microstrains. PMID- 28721553 TI - Return-to-work outcomes in cancer survivors. PMID- 28721552 TI - High plasma adenosine levels in overweight/obese pregnant women. AB - We aim to investigate whether overweight/obese pregnant women have elevated plasma levels of adenosine associated with increased consumption of high-calorie food. Sixty women were included. They were divided into lean (n = 23 and n = 12) or overweight/obese (n = 7 and n = 18) non-pregnant and pregnant women, respectively. Clinical records and maternal blood samples were collected after informed consent. A self-reported dietary questionnaire was also completed. Plasma adenosine levels were determined with high-performance liquid chromatography. Biochemical parameters, including glucose, total protein, and lipid profile, were determined using standard colorimetric assays. Adenosine levels were higher in pregnant women than in non-pregnant women (18.7 +/- 1.6 vs 10.8 +/- 1.3 nM/MUg protein, respectively, p < 0.0001). Overweight/obese pregnant women (21.9 +/- 2.5 nM/MUg protein) exhibited higher adenosine levels than lean pregnant (14.5 +/- 1.0 nM/MUg protein, p = 0.04) or non-pregnant women (11.7 +/- 1.5 nM/MUg protein, p = 0.0005). Also, pregnant women with elevated weight gain exhibited higher (26.2 +/- 3.7 nM/MUg protein) adenosine levels than those with adequate weight gain (14.9 +/- 1.4 nM/MUg protein, p = 0.03). These differences were not statistically significant compared with those of pregnant women with reduced weight gain (17.4 +/- 2.1 nM/MUg protein, p = 0.053). Body mass index and adenosine only in pregnant women were positively correlated (r = 0.39, p = 0.02). While, polyunsaturated fatty acid (PUFA) consumption was negatively correlated with plasma adenosine levels only in non-pregnant women (r = -0.33, p = 0.03). Pregnancy is associated with high plasma adenosine levels, which are further elevated in pregnant women who are overweight/obese. High PUFA intake might reduce plasma adenosine levels in non-pregnant women. PMID- 28721554 TI - Feasibility of a self-help web-based intervention targeting young cancer patients with sexual problems and fertility distress. AB - PURPOSE: The purpose of the study is to evaluate the feasibility of a self-help web-based intervention to alleviate sexual problems and fertility distress in adolescents and young adults with cancer. METHODS: Twenty-three persons with cancer (19 women and 4 men, age 18-43, 1-5 years post-diagnosis of lymphoma, breast, gynecologic, central nervous system, or testicular cancer) were recruited to test a 2-month web-based program targeting sexual problems or fertility distress. The programs were organized in modules with educational and behavior change content, including texts, illustrations, exercises, and video vignettes. The program also included a discussion forum and an "ask the expert" forum. In addition, the sexuality program offered two telephone consultations. Feasibility (regarding demand, acceptability, preliminary efficacy, and functionality) was evaluated with the website system data, telephone interviews, continuous online evaluations, and study-specific measures. RESULTS: Fifteen participants completed four modules or more. Most of the program features were used and well accepted by these "committed users." The web-based format enabled flexible use by participants with diverse needs. Preliminary efficacy was indicated by self reported increased knowledge and skill in handling sexual problems and fertility distress. The website was easy to use and functioned well technically. CONCLUSIONS: The present study indicated that this web-based intervention was feasible for adolescents and young adults with cancer. The effectiveness of the intervention in decreasing sexual problems and fertility distress will be tested in a population-based randomized controlled trial for adolescents and young adults with cancer. TRIAL REGISTRATION: ISRCTN36621459. PMID- 28721555 TI - The value of physical performance measurements alongside assessment of sarcopenia in predicting receipt and completion of planned treatment in non-small cell lung cancer: an observational exploratory study. AB - INTRODUCTION: The presence of muscle mass depletion is associated with poor outcomes and survival in cancer. Alongside muscle mass, assessment of muscle strength or physical performance is essential for the diagnosis of sarcopenia. Non-small cell lung cancer (NSCLC) is a prevalent form of cancer with high mortality, and Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) is commonly used to assess patients' suitability for treatment. However, a significant proportion of patients with good PS are unable to complete multidisciplinary team (MDT)-planned treatment. Little is known about the ability of objective measurements of physical performance in predicting patients' ability to complete MDT-planned treatment and outcomes in NSCLC. OBJECTIVES: We sought to establish whether physical performance, utilising the short physical performance battery (SPPB), alongside muscle mass measurements, was able to predict receipt and completion of MDT-planned treatment, with a focus on chemotherapy in NSCLC. MATERIALS AND METHODS: Participants with NSCLC treated through a single lung cancer MDT and ECOG PS 0-2 were recruited and the following assessed: body composition [bioelectrical impedance (BIA) and whole body dual-energy X-ray absorptiometry (DXA) in a subset], physical performance (SPPB), PS and nutritional status. We recorded receipt and completion of chemotherapy, as well as any adverse effects, hospitalisations, and treatment delays. RESULTS: We included a total of 62 participants with NSCLC, and in 26 of these, the MDT planned treatment was chemotherapy. Participants with earlier stage disease and weight loss of <10% were more likely to complete MDT-planned treatment (p < 0.001 and p < 0.05). Patients with a higher total SPPB score were more likely to complete more cycles of chemotherapy as well as the full course. Quicker gait speeds and sit-to-stand times were associated with completion of three or more cycles of chemotherapy (all p < 0.05). For every unit increase in SPPB score, there was a 28.2% decrease in adverse events, hospitalisations and delays of chemotherapy (incidence rate ratio 0.718, p = 0.001), whilst ECOG PS showed no correlation with these outcomes. CONCLUSION: Assessing physical performance by SPPB is quick and simple to do in clinical settings and may give better indication of likely chemotherapy treatment course completion than muscle mass alone and ECOG PS. In turn, this may identify specific targets for early functional intervention and impact on MDT decision-making and prudent use of resources. PMID- 28721556 TI - Using taphonomy to infer differences in soft tissues between taxa: an example using basal and derived forms of Solnhofen pterosaurs. AB - In fossilised vertebrates, the presence of soft tissues is the most obvious way to determine aspects of anatomy and functional morphology; however, occurrences are rare and other lines of evidence must be sought to indicate its extent and strength. For example, pterosaurs possessed a large wing membrane that enabled powered flight but other tissues are not widely preserved. A semi-quantitative analysis comparing skeletal articulation and completeness of the pterodactyloid Pterodactylus and non-pterodactyloid pterosaur Rhamphorhynchus from Solnhofen type deposits implies there were anatomical differences between soft-tissue structure and attachments articulating skeletal joints of each. Typically, skeletons of Pterodactylus disarticulate to a greater extent than those of Rhamphorhynchus, which in turn suggests decay progressed to more advanced states in the former. However, this generalisation masks a mosaic of differences between different body parts, for example Rhamphorhynchus tends to lose the wings as complete units but retains a complete and still articulated tail in a greater number of specimens than Pterodactylus. PMID- 28721557 TI - The mystery of a missing bone: revealing the orbitosphenoid in basal Epicynodontia (Cynodontia, Therapsida) through computed tomography. AB - The basal non-mammaliaform cynodonts from the late Permian (Lopingian) and Early Triassic are a major source of information for the understanding of the evolutionary origin of mammals. Detailed knowledge of their anatomy is critical for understanding the phylogenetic transition toward mammalness and the paleobiological reconstruction of mammalian precursors. Using micro-computed tomography (MUCT), we describe the internal morphology of the interorbital region that includes the rarely fossilized orbitosphenoid elements in four basal cynodonts. These paired bones, which are positioned relatively dorsally in the skull, contribute to the wall of the anterior part of the braincase and form the floor for the olfactory lobes. Unlike procynosuchids and the more basal therapsids in which the orbitosphenoids are well developed, dense, and bear a ventral keel, the basal epicynodonts Cynosaurus, Galesaurus, and Thrinaxodon display cancellous, reduced, and loosely articulated orbitosphenoids, a condition shared with many eucynodonts. The hemi-cylindrical orbitosphenoid from which the mammalian condition is derived re-evolved convergently in traversodontid and some probainognathian cynodonts. PMID- 28721558 TI - Effect of swallowing maneuver on fentanyl-induced coughing. PMID- 28721560 TI - Short and Long-Term Stoma Rate in Laparoscopic Lavage Versus Resection in Perforated Diverticulitis: Different Outcomes, Same Results? PMID- 28721561 TI - ENBD is Associated with Decreased Tumor Dissemination Compared to PTBD in Perihilar Cholangiocarcinoma. AB - BACKGROUND: Little is known regarding the risk of tumor dissemination when percutaneous biliary drainage is used before surgical resection of perihilar cholangiocarcinoma (PHC). We aimed to compare the incidence of tumor dissemination after preoperative endoscopic nasobiliary drainage (ENBD) with that after percutaneous transhepatic biliary drainage (PTBD) for PHC. METHODS: Data from 208 consecutive patients who underwent PHC resection between 2000 and 2013 were retrospectively analyzed. The influence of drainage type on incidence of tumor dissemination was examined. Seventy-six patients underwent ENBD (37%), 87 underwent PTBD (42%), and 45 underwent surgery without preoperative biliary drainage (WD, 22%). RESULTS: The respective 2- and 5-year estimated cumulative incidences of tumor dissemination in the ENBD group (11.8/14.6%) were lower than in the PTBD group (28.8/35.9%, p = 0.003) and equivalent to that in the WD group (11.2/15.9%, p = NS). PTBD (hazard ratio [HR] vs. ENBD, 2.80) was an independent risk factor for postoperative tumor dissemination in the multivariate analysis. The 2- and 5-year disease-specific survival rates were higher in the ENBD group (67.6/47.3%) than in the PTBD group (56.6/27.8%, p = 0.032) and equivalent to that in the WD group (64.9/53.8%, p = NS). However, drainage type was not an independent risk factor in multivariate analysis of disease-specific survival. CONCLUSION: For patients with PHC, the associated risk of postoperative tumor dissemination in the ENBD group was lower than in the PTBD group and equivalent to that in the WD group. Thus, ENBD is the ideal procedure for preoperative biliary drainage. PMID- 28721559 TI - Anatomical specificity of the brain in the modulation of Neuroglobin and Cytoglobin genes after chronic bisphenol a exposure. AB - The aim of this study was to investigate the influence of Bisphenol A (BPA) exposure on Neuroglobin (Ngb) and Cytoglobin (Cygb) as well as oxidative stress gene expression in the cerebellum, hippocampus, hypothalamus and cortex. Male Wistar rats were randomly divided into 3 groups: Control and two groups receiving 2 different daily BPA dosages, 5 or 25 mg/kg from postnatal day 50 (PND50) through PND90 and they were euthanized at PND105. In the cortex, we found an increase in Ngb gene expression and also in superoxide dismutase 1 and Catalase (Cat). In the cerebellum, we found an increase in Ngb and Cat, in the hypothalamus, there was a decrease in Cygb and an increase in glutathione peroxidase and Cat and in hypoxia-inducible factor 1 alpha (Hif1alpha) at the low dosage and a decrease in Hif1alpha at the high BPA dosage. Finally, in the hippocampus, we observed a decrease in Ngb and Cygb and an increase in Hif1alpha. In summary, BPA promotes the modulation of both Ngb and Cygb, but such changes occur by different mechanisms depending on the exposure dose and anatomical area. PMID- 28721564 TI - Foreword focus on polyphenols. PMID- 28721562 TI - Reduced energy availability: implications for bone health in physically active populations. AB - PURPOSE: The present review critically evaluates existing literature on the effects of short- and long-term low energy availability (EA) on bone metabolism and health in physically active individuals. METHODS: We reviewed the literature on the short-term effects of low EA on markers of bone metabolism and the long term effects of low EA on outcomes relating to bone health (bone mass, microarchitecture and strength, bone metabolic markers and stress fracture injury risk) in physically active individuals. RESULTS: Available evidence indicates that short-term low EA may increase markers of bone resorption and decrease markers of bone formation in physically active women. Bone metabolic marker responses to low EA are less well known in physically active men. Cross-sectional studies investigating the effects of long-term low EA suggest that physically active individuals who have low EA present with lower bone mass, altered bone metabolism (favouring bone resorption), reduced bone strength and increased risk for stress fracture injuries. CONCLUSIONS: Reduced EA has a negative influence on bone in both the short- and long-term, and every effort should be made to reduce its occurrence in physically active individuals. Future interventions are needed to explore the effects of long-term reduced EA on bone health outcomes, while short-term low EA studies are also required to give insight into the pathophysiology of bone alterations. PMID- 28721563 TI - Terrestrial adaptation of green algae Klebsormidium and Zygnema (Charophyta) involves diversity in photosynthetic traits but not in CO2 acquisition. AB - MAIN CONCLUSION: The basal streptophyte Klebsormidium and the advanced Zygnema show adaptation to terrestrialization. Differences are found in photoprotection and resistance to short-term light changes, but not in CO 2 acquisition. Streptophyte green algae colonized land about 450-500 million years ago giving origin to terrestrial plants. We aim to understand how their physiological adaptations are linked to the ecological conditions (light, water and CO2) characterizing modern terrestrial habitats. A new Klebsormidium isolate from a strongly acidic environment of a former copper mine (Schwarzwand, Austria) is investigated, in comparison to Klebsormidium cf. flaccidum and Zygnema sp. We show that these genera possess different photosynthetic traits and water requirements. Particularly, the Klebsormidium species displayed a higher photoprotection capacity, concluded from non-photochemical quenching (NPQ) and higher tolerance to high light intensity than Zygnema. However, Klebsormidium suffered from photoinhibition when the light intensity in the environment increased rapidly, indicating that NPQ is involved in photoprotection against strong and stable irradiance. Klebsormidium was also highly resistant to cellular water loss (dehydration) under low light. On the other hand, exposure to relatively high light intensity during dehydration caused a harmful over reduction of the electron transport chain, leading to PSII damages and impairing the ability to recover after rehydration. Thus, we suggest that dehydration is a selective force shaping the adaptation of this species towards low light. Contrary to the photosynthetic characteristics, the inorganic carbon (C i ) acquisition was equivalent between Klebsormidium and Zygnema. Despite their different habitats and restriction to hydro-terrestrial environment, the three organisms showed similar use of CO2 and HCO3- as source of Ci for photosynthesis, pointing out a similar adaptation of their CO2-concentrating mechanisms to terrestrial life. PMID- 28721565 TI - A Double-Blinded Randomized Clinical Study on the Therapeutic Effect of Gastrografin in Prolonged Postoperative Ileus After Elective Colorectal Surgery. PMID- 28721566 TI - A Response to Yiasemidou et al. (2017) A Multispecialty Evaluation of Thiel Cadavers for Surgical Training. PMID- 28721567 TI - Modified Double-Layer Anastomosis for Minimally Invasive Esophagectomy: An Effective Way to Prevent Leakage and Stricture. AB - BACKGROUND: Anastomotic leakage and stricture contribute to a large number of mortality and morbidity after esophagectomy. The aim of this work is to evaluate the outcome of modified double-layer hand-sewn esophagogastric anastomosis during minimally invasive esophagectomy for esophageal cancer. METHODS: The clinicopathological data of 176 consecutive esophageal cancer patients who underwent cervical esophagogastric anastomosis using modified double-layer hand sewn technique after radical esophagectomy were retrospectively reviewed. Total minimally invasive approach, including thoracoscopic surgery for thoracic procedure and laparoscopic approach for abdominal procedure, was implemented during the radical Mckeown esophagectomy. Patients were followed up for the assessment of postoperative anastomotic complications including anastomotic leakage and stricture, being the primary outcome measures for this study. RESULTS: Anastomotic leakage occurred in 2 of 176 patients (1.1%); both of the patients experienced only minor leakage and were treated conservatively. There was no significant difference in leakage between patients with and without major comorbidity (p = 0.331). After a mean follow-up of 21.3 months, four patients (4/176, 2.3%) developed benign anastomotic strictures, including those 2 patients experienced postoperative leakage. Symptoms for stricture were improved by endoscopic dilatations in all 4 patients. Besides, there was one case (1/176, 0.6%) of gastric necrosis in this cohort, who was also successfully managed by conservative therapy with no operative mortality. CONCLUSION: This modified double-layer hand-sewn anastomosis is a highly safe and stable technique for esophagogastrostomy, which is an effective way to prevent both anastomotic leakage and stricture. PMID- 28721568 TI - Letter to the Editor: Reply. PMID- 28721569 TI - Management of Enterocutaneous Fistula: Outcomes in 276 Patients. AB - OBJECTIVE: To assess the outcomes of patients with type II intestinal failure due to enterocutaneous fistulae in a tertiary referral centre over a 15 year period. Intestinal failure secondary to enterocutaneous fistula (ECF) requires multidisciplinary management at significant cost. Mortality and morbidity are high. METHODS: Patients were identified from a prospectively collected database of patients requiring inpatient parenteral nutrition (1998-2013). Data collected included: demographics, mode of admission, pathological grouping and outcome. RESULTS: A total of 286 ECF were identified in 278 patients, mean age 64 years (20-96 years) with an equal gender distribution. In total, 112 fistulas developed following an emergency admission, 89 fistulas following an elective admission, and the remainder 85 were transferred from outlying district hospitals. In total, 246 ECF were as a result of previous surgery, 11 occurred following endoscopic procedures, with the remainder occurring spontaneously. All patients received parenteral nutrition (PN). Forty-seven patients overall died from sepsis/multiorgan failure. A total of 154 ECF resolved with aggressive non operative management and 46 died prior to resolution of their fistula or surgery. 74.8% of patients with ECF proximal to the duodenal-jejunal flexure closed without surgery compared to 35.4% with disease distal to the flexure (p = 0.001). Nineteen early operations were performed, with 51 patients undergoing definitive surgery. In-hospital mortality was 19.1% (53/278), with 30-day post-operative mortality from definitive surgery being 9.8% (5/51). CONCLUSION: Mortality remains high and is associated with sepsis. Fistulas proximal to the duodeno jejunal flexure are more likely to close spontaneously. If the fistula fails to close spontaneously care is often prolonged and complex, requiring a dedicated nutrition team. In this series, spontaneous closure was more common in upper GI fistulas. Patients who are not able to be discharged in the interval between fistula formation and definitive surgery have a higher mortality risk. PMID- 28721570 TI - Task Shifting: The Use of Laypersons for Acquisition of Vital Signs Data for Clinical Decision Making in the Emergency Room Following Traumatic Injury. AB - IMPORTANCE: In resource-limited settings, identification of successful and sustainable task-shifting interventions is important for improving care. OBJECTIVE: To determine whether the training of lay people to take vital signs as trauma clerks is an effective and sustainable method to increase availability of vital signs in the initial evaluation of trauma patients. DESIGN: We conducted a quasi-experimental study of patients presenting with traumatic injury pre- and post-intervention. SETTING: The study was conducted at Kamuzu Central Hospital, a tertiary care referral hospital, in Lilongwe, Malawi. PARTICIPANTS: All adult (age >= 18 years) trauma patients presenting to emergency department over a six month period from January to June prior to intervention (2011), immediately post intervention (2012), 1 year post-intervention (2013) and 2 years post intervention (2014). INTERVENTION: Lay people were trained to take and record vital signs. MAIN OUTCOMES AND MEASURES: The number of patients with recorded vital signs pre- and post-intervention and sustainability of the intervention as determined by time-series analysis. RESULTS: Availability of vital signs on initial evaluation of trauma patients increased significantly post-intervention. The percentage of patients with at least one vital sign recorded increased from 23.5 to 92.1%, and the percentage of patients with all vital signs recorded increased from 4.1 to 91.4%. Availability of Glasgow Coma Scale also increased from 40.3 to 88.6%. Increased documentation of vital signs continued at 1 year and 2 years post-intervention. However, the percentage of documented vital signs did decrease slightly after the US-trained medical student and surgeon who trained the trauma clerks were no longer available in country, except for Glasgow Coma Scale. Patients who died during emergency department evaluation were significantly less likely to have vital signs recorded. CONCLUSIONS AND RELEVANCE: The training of lay people to collect vital signs and Glasgow Coma Scale is an effective and sustainable method of task shifting in a resource limited setting. PMID- 28721571 TI - Re: Superselective Transarterial Chemoembolization as an Alternative to Surgery in Symptomatic/Enlarging Liver Hemangiomas. PMID- 28721573 TI - Exposure to silver nanoparticles affects viability and function of natural killer cells, mostly via the release of ions. AB - Natural killer (NK) cells play a crucial role in linking innate and adaptive immune responses, especially during viral infections and tumor surveillance. They have two major effector functions: the killing of stressed/abnormal cells and the release of cytokines. Their activity is regulated via inhibitory and activating surface receptors. At the same time that the production and use of engineered nanoparticles is steadily increasing, the risk for exposure to silver nanoparticles (AgNPs) from consumer products or biomedical applications is growing. Given this, we assessed the effects of 20-nm big AgNPs on NK cells, which represent an important part of the immune system. Our study involved overnight exposure of human blood NK cells to different concentrations of AgNPs, and silver (Ag) ion controls, and analyzing them for viability, surface receptor expression, intracellular markers, cytokine release, and killing potential. Exposure to AgNPs, but not to Ag ion controls, reduced the viability and the cytotoxic potential after polyriboinosinic-polyribocytidylic acid stimulation of NK cells and increased the expression of the inhibitory receptor CD159a. Exposure to AgNPs and Ag ion controls reduced the expression of the activating receptors CD335 and of CD16 and increased the expression of the activating receptor CD314. Overall, exposure to AgNPs changes NK cells' function and phenotype and may present a risk for modulating human immune responses, which should be further investigated. PMID- 28721572 TI - I-FABP is a Novel Marker for the Detection of Intestinal Injury in Severely Injured Trauma Patients. AB - BACKGROUND: Intestinal injury is a rare injury in multiply traumatized patients, and its diagnosis remains difficult. Delayed diagnosis of an intestinal injury increases the risk of sepsis, multiple organ failure and mortality. The intestinal fatty acid-binding protein (I-FABP) is solely expressed in the intestine and is released extracellulary after tissue damage. This study evaluates the validity of I-FABP as an early biomarker to detect an abdominal injury and particularly an injury to the intestine. PATIENTS AND METHODS: Patients with an Abbreviated Injury Scale (AIS) score for abdominal body region (AIS abdomen) >=3 were included in this study from 07/2006 to 12/2014. Of those, ten patients retrospectively had an intestinal injury (int. injury). According to the Injury Severity Score and the AIS abdomen, corresponding patients with an abdominal injury but without an intestinal injury (no int. injury) were included for matched-pair analysis. Twenty healthy volunteers served as controls. Plasma I FABP levels were measured at admission to the emergency room and up to 10 days daily (d1-d10). RESULTS: Median I-FABP levels were significantly higher in the "int. injury" group compared to the "no int. injury" group [2101.0 pg/ml (IQR = 1248.1-4117.8) vs. 351.4 pg/ml (IQR = 287.6-963.3), p < 0.05]. Furthermore, I FABP levels of both groups were significantly higher compared to the control group [Ctrl: 127.2 pg/ml (IQR = 57.4-310.6), p < 0.05]. The time course of I-FABP levels showed a peak on the day of admission and a decline to the control levels in the further post-traumatic course. The development of complications such as single- or multi-organ failure, sepsis, acute respiratory distress syndrome, pneumonia and mortality was higher in the "int. injury" group; however, this difference was not statistically significant. CONCLUSION: This study confirmed our previous observation that I-FABP might be used as a suitable early biomarker for the detection of abdominal injuries in general. In addition and more specific, I-FABP may be a useful and promising parameter in the diagnosis of intestinal injuries. PMID- 28721574 TI - Operant discrimination of relative frequency ratios in black-capped chickadee song. AB - The two-note fee bee song of the black-capped chickadee (Poecile atricapillus) is sung at many different absolute frequencies, but the relative frequencies, or "pitch ratios", between the start and end of the fee note (glissando) and the fee and the bee notes (inter-note interval) are preserved with each pitch-shift. Ability to perceive these ratios and their relative salience varies with sex of the bird and setting: while both sexes appear to perceive changes in the inter note interval, males appear to attend to the glissando in the field, and females appear to attend to both ratios. In this study, we compared directly whether male and female chickadees could discriminate between normal fee bee songs and songs that had one or both of the pitch ratios altered, and whether birds attended to one type of alteration over another. Both sexes learned to discriminate normal from altered songs; songs lacking an inter-note interval were more easily discriminated than songs with only the glissando removed. Females performed slightly better than males, including in the most difficult task with the stimuli lacking the glissando. Our study illustrates the value of using perceptual tasks to directly compare performance between the sexes and to demonstrate the difference between perception of and attention to acoustic features of vocal communication. PMID- 28721576 TI - Experiences of Formal and Informal Caregivers of Older Persons in Singapore. AB - The well-being of informal caregivers in the familial context is increasingly recognized as a critical area of concern affecting the care of older family members. This paper focuses on the dynamics of family caregiving for older members from the work-life perspective, contextualised in the highly developed and rapidly ageing society that is Singapore. Drawing from qualitative research on 30 adult family caregivers and 15 live-in foreign domestic workers (FDWs), the main themes identified from the qualitative interviews were: 1) Stresses and dilemmas faced by family caregivers; 2) Filial responsibility in the caring for one's parents; 3) Coping with work and caregiving - FDWs in family caregiving; 4) Coping with extra help - hiring of FDWs and challenges. This study highlights the complexities when paid and unpaid family care is juxtaposed in the family household. The findings point to the need for improvement in policies, training and support for caregivers. PMID- 28721575 TI - Gastroparesis: Medical and Therapeutic Advances. AB - Gastroparesis is a chronic, bothersome, and often disabling neuromuscular disorder of the upper gastrointestinal tract. The most frequently reported symptoms of gastroparesis include nausea, vomiting, epigastric pain, early satiety, and unintentional weight loss. Etiologies of gastroparesis include diabetes, connective tissue disorders, prior infection, mesenteric ischemia, and post-surgical complications. The largest category of gastroparesis patients is comprised of those in whom no definitive cause can be identified (idiopathic gastroparesis). The individual and societal burden of gastroparesis is substantial. It considerably reduces patients' quality of life accompanied by a significant negative impact to the healthcare system. The current treatments of gastroparesis are less than ideal. Dietary modification may improve symptoms in patients with mild disease. Metoclopramide is the only medication currently approved for the treatment of gastroparesis; however, it is associated with adverse effects in a sizable proportion of patients. Other medications are frequently employed to treat symptoms of nausea and vomiting, although technically all are used off-label since they are not FDA approved for the treatment of gastroparesis. These data highlight the need to identify novel, more effective treatment options for this disabling disease. This review will provide a brief synopsis on the epidemiology, etiology, and impact of gastroparesis, discussing new therapeutic advances. PMID- 28721577 TI - Characterization of motor events in REM sleep behavior disorder. AB - We used video-polysomnography to characterize motor events (ME) in 14 Parkinson's disease (PD-RBD) and 18 idiopathic (iRBD) REM sleep behavior disorder cases. ME occurred predominantly in the upper limbs and were mostly simple, non-emotional, distal and focal. There were no significant differences in ME features between PD RBD and iRBD groups. Our data suggests that RBD ME are mostly non violent. Similarity between PD-RBD and iRBD groups suggests that motor dysfunction does not affect ME features. PMID- 28721579 TI - Survival of Patients with Cystic Fibrosis Depending on Mutation Type and Nutritional Status. AB - The purpose of the study was to evaluate the influence of nutrition and of the severity of mutation type on survival rate in cystic fibrosis (CF) patients. Data were longitudinally collected from 60 hospitalized adult CF patients, aged 18-50. The variables consisted of body mass index (BMI) ratio, Cole's BMI cut-off points, severity of mutation type, and survival rate of CF patients. We found that the mean BMI was strongly associated with the severity of mutation type and was significantly lower in patients with severe mutations of grade I and II. The mutation type significantly affected the patients' survival rate; survival was greater in patients with mild and undefined mutation types. The BMI and Cole's cut-off points also had a significant influence on survival rate. CF patients, who suffered from malnutrition and emaciation, had a shorter survival rate than those with proper nutritional status. In conclusion, the study findings confirmed a significant effect of nutritional status and of mutation type on survival rate of CF patients. PMID- 28721578 TI - Preventive Chair Massage with Algometry to Maintain Psychosomatic Balance in White-Collar Workers. AB - People working at computers often suffer from overload-related muscle pain, and physical and mental discomfort. The aim of the study was to evaluate the effectiveness of chair massage, conducted in the workplace among white-collar workers, in relieving symptoms of musculoskeletal strain related to prolonged sitting posture. The study was conducted in 124 white-collar workers, 55 women and 69 men, aged 33.7 +/- 7.6 years. Subjects were randomly assigned to three groups: chair massage program, relaxing music sessions, and a control group, each of four-week duration. Each group was evaluated before and after the program completion. Pain perception was assessed algometrically as a threshold for compression pain of neck muscles, measured in kg/cm2. The relaxation level was assessed from the heart rate variability. We found that the chair massage increased both the pain threshold in all tested muscles (p < 0.001) and the relaxation level from 31.9% to 41.6% (p < 0.05). In the group with music sessions, muscle pain threshold remained unchanged, except for the trapezoid muscle where it decreased (p < 0.05), while the relaxation level increased from 26.0% to 33.3% (p < 0.05). In both massage and relaxing music groups, there was a significant decrease in muscle tension (p < 0.01). Changes in the control group were inappreciable. We conclude that the chair massage performed in the workplace is an effective method for prevention of musculoskeletal overstrain related to prolonged sitting posture. The program seems worth implementing in various occupational environments. PMID- 28721580 TI - Gene expression profiles of the thermotolerant yeast Saccharomyces cerevisiae strain KKU-VN8 during high-temperature ethanol fermentation using sweet sorghum juice. AB - OBJECTIVES: To investigate gene expression profiles of the thermotolerant yeast Saccharomyces cerevisiae strain KKU-VN8, a potential high-ethanol producer, in response to various stresses during high-temperature ethanol fermentation using sweet sorghum juice (SSJ) under optimal conditions. RESULTS: The maximal ethanol concentration obtained by S. cerevisiae KKU-VN8 using SSJ at 40 degrees C was 66.6 g/l, with a productivity of 1.39 g/l/h and a theoretical ethanol yield of 81%. Quantitative RT-PCR assays were performed to investigate the gene expression profiles of S. cerevisiae KKU-VN8. Differential expression of genes encoding heat shock proteins (HSP82, HSP104, SSA4), genes involved in trehalose metabolism (TPS1, TPS2, NTH1) and genes involved the glycolytic pathway (ADH1, ADH2, CDC19) at various time points during fermentation was observed. The expression levels of HSP82, HSP104, SSA4, ADH1 and CDC19 were significantly higher than those of the controls (10.2-, 4-, 8-, 8.9- and 5.9-fold higher, respectively). In contrast, the expression levels of TPS1, TPS2, NTH1 and ADH2 were approx. 2-fold less than those of the controls. CONCLUSIONS: The highly expressed genes encoding heat shock proteins, HSP82 and SSA4, potentially play an important role in helping S. cerevisiae KKU-VN8 cope with various stresses that occur during high-temperature fermentation, leading to higher ethanol production efficiency. PMID- 28721581 TI - Autophagy regulated by lncRNA HOTAIR contributes to the cisplatin-induced resistance in endometrial cancer cells. AB - OBJECTIVES: To identify whether lncRNAs (long non-coding RNA) participate in the regulation of cisplatin-resistant induced autophagy in endometrial cancer cells. RESULTS: Autophagy activity was significantly boosted in cisplatin-resistant Ishikawa cells, a human endometrial cancer cell line, compared with that in parental Ishikawa cells. After analyzing the overall long noncoding RNA (lncRNA) profiling, a meaningful lncRNA, HOTAIR, was identified. It was down-regulated simultaneously in cisplatin-resistant Ishikawa cells and parental Ishikawa cells treated with cisplatin. RNA interference of HOTAIR reduced the proliferation of cisplatin-resistant Ishikawa cells and enhanced the autophagy activity of cisplatin-resistant Ishikawa cells with or without cisplatin treatment, in addition, beclin-1, multidrug resistance (MDR), and P-glycoprotein (P-gp) were mediated by lncRNA HOTAIR. CONCLUSIONS: It is clear that lncRNAs, specifically HOTAIR, can regulate the cisplatin-resistance ability of human endometrial cancer cells through the regulation of autophagy by influencing Beclin-1, MDR, and P-gp expression. PMID- 28721582 TI - miR-130b-3p/301b-3p negatively regulated Rb1cc1 expression on myogenic differentiation of chicken primary myoblasts. AB - OBJECTIVES: To explore the roles of miR-130b-3p and miR-301b-3p which may regulate Rb1-inducible coiled-coil 1 (Rb1cc1) expression during myogenic differentiation of chicken primary myoblasts. RESULTS: After 4 days of myogenic differentiation, myotubes appeared and after 6 days the cells fused to each other and expression of MyHC could be detected by immunofluorescence staining. TargetScan and RNAhybrid 2.2 showed miR-130b-3p and miR-301b-3p were well complementary with the target site of Rb1cc1 3'-untranslated region (3'-UTR). Using the dual-luciferase assay, we found miR-130b-3p and miR-301b-3p could inhibit Rb1cc1 expression by binding to its 3'-UTR. Real-time PCR showed Rb1cc1 mRNA expression level was almost reciprocal to that of miR-130b-3p or miR-301b-3p during myogenic differentiation. Furthermore, over-expression of miR-130b-3p or miR-301b-3p down-regulated the expression levels of Rb1cc1, myoblast determination protein, myogenin and myosin heavy chain. CONCLUSIONS: miR-130b-3p or miR-301b-3p negatively regulate Rb1cc1 expression to affect myogenic differentiation. PMID- 28721583 TI - Microbial and genetically engineered oils as replacements for fish oil in aquaculture feeds. AB - As the global population grows more of our fish and seafood are being farmed. Fish are the main dietary source of the omega-3 (n-3) long-chain polyunsaturated fatty acids (LC-PUFA), eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids, but these cannot be produced in sufficient quantities as are now required for human health. Farmed fish have traditionally been fed a diet consisting of fishmeal and fish oil, rich in n-3 LC-PUFA. However, the increase in global aquaculture production has resulted in these finite and limited marine ingredients being replaced with sustainable alternatives of terrestrial origin that are devoid of n-3 LC-PUFA. Consequently, the nutritional value of the final product has been partially compromised with EPA and DHA levels both falling. Recent calls from the salmon industry for new sources of n-3 LC-PUFA have received significant commercial interest. Thus, this review explores the technologies being applied to produce de novo n-3 LC-PUFA sources, namely microalgae and genetically engineered oilseed crops, and how they may be used in aquafeeds to ensure that farmed fish remain a healthy component of the human diet. PMID- 28721584 TI - miR-34a attenuates glioma cells progression and chemoresistance via targeting PD L1. AB - OBJECTIVE: To investigate the roles of miR-34a in progression and chemoresistance of glioma cells. RESULTS: Quantitative real-time PCR analysis showed that miR-34a level was lower, but PD-L1 expression level was higher in glioma tissue specimens compared with normal brain tissues and their expression levels were negatively correlated. Ectopic expression of miR-34a inhibited glioma cell proliferation, promoted cell cycle arrest in G1/S phase and cell apoptosis. Additionally, miR 34a/PD-L1 axis was again confirmed and co-expression of PD-L1 with miR-34a mimics attenuated the effects of miR-34a on cell proliferation and apoptosis in glioma cells. Importantly, PD-L1 overexpression resulted in chemoresistance in glioma cells, this effect was attenuated by miR-34a overexpression. CONCLUSIONS: miR-34a inhibits glioma cells progression and chemoresistance via targeting PD-L1. PMID- 28721585 TI - CYP701A26 is characterized as an ent-kaurene oxidase with putative involvement in maize gibberellin biosynthesis. AB - OBJECTIVES: To characterize the ent-kaurene oxidase (KO) involved in maize (Zea mays) gibberellin (GA) biosynthesis. RESULTS: Two putative KO genes were identified in maize based on the homologous alignment. Biochemical characterization indicated that one of them encoded a cytochrome P450 monooxygenase (P450) CYP701A26, which reacted with ent-kaurene to form ent kaurenoic acid, the key intermediate of GA biosynthesis. CYP701A26 showed constitutive expression in active growing tissues and no inducible expression, which led to putative designation of CYP701A26 as the ZmKO. CYP701A26 exhibited substrate promiscuity to catalyze oxidation of other labdane related diterpenes. Another maize KO homologue, CYP701A43 did not show any catalytic activities on ent-kaurene or other tested diterpenes. It exhibited inducible gene expression and might accept unknown substrates to play roles in specialized metabolism for stress response. CONCLUSIONS: CYP701A26 was characterized to exhibit ent-kaurene oxidase activity with substrate promiscuity and might be involved in maize GA biosynthesis, and its homologue CYP701A43 did not show such function and might play roles in stress response. PMID- 28721586 TI - Homology modeling and prediction of the amino acid residues participating in the transfer of acetyl-CoA to arylalkylamine by the N-acetyltransferase from Chryseobacterium sp. AB - OBJECTIVES: To predict the amino acid residues playing important roles in acetyl CoA and substrate binding and to study the acetyl group transfer mechanism of Chryseobacterium sp. 5-3B N-acetyltransferase (5-3B NatA). RESULTS: A 3 dimensional homology model of 5-3B NatA was constructed to compare the theoretical structure of this compound with the structures of previously reported proteins belonging to the bacterial GCN5 N-acetyltransferase family. Homology modeling of the 5-3B NatA structure and a characterization of the enzyme's kinetic parameters identified the essential amino acid residues involved in binding and acetyl-group transfer. 126Leu, 132Leu, and 135Lys were implicated in the binding of phosphopantothenic acid, and 100Tyr and 131Lys in that of adenosyl biphosphate. The data supported the participation of 83Glu and 133Tyr in catalyzing acetyl-group transfer to L-2-phenylglycine. CONCLUSIONS: 5-3B NatA catalyzes the enantioselective N-acetylation of L-2-phenylglycine via a ternary complex comprising the enzyme, acetyl-CoA, and the substrate. PMID- 28721587 TI - Genetically engineered cell lines for alpha1-antitrypsin expression. AB - OBJECTIVES: To establish genetically modified cell lines that can produce functional alpha1-antitrypsin (AAT), by CRISPR/Cas9-assisted homologous recombination. RESULTS: alpha1-Antitrypsin deficiency (AATD) is a monogenic heritable disease that often results in lungs and liver damage. Current augmentation therapy is expensive and in short of supply. To develop a safer and more effective therapeutic strategy for AATD, we integrated the AAT gene (SERPINA1, NG_008290.1) into the AAVS1 locus of human cell line HEK293T and assessed the safety and efficacy of CRISPR/Cas9 on producing potential therapeutic cell lines. Cell clones obtained had the AAT gene integrated at the AAVS1 locus and secreted approx. 0.04 g/l recombinant AAT into the medium. Moreover, the secreted AAT showed an inhibitory activity that is comparable to plasma AAT. CONCLUSIONS: CRISPR/Cas9-mediated engineering of human cells is a promising alternative for generating isogenic cell lines with consistent AAT production. This work sheds new light on the generation of therapeutic liver stem cells for AATD. PMID- 28721588 TI - Impact of highway construction on water bodies: a geospatial assessment. AB - India has witnessed a massive infrastructure boom in the past few years. One of such projects is National Highway-7 (NH-7), a North-South highway connecting Kanyakumari, Tamil Nadu, to Varanasi, Uttar Pradesh, traversing many water bodies. The present study aims to assess the pre- and post-construction impact due to existing, new and widened NH-7 on the physical status of the water bodies, using remote sensing techniques. Satellite images spanning 22 years were procured and analysed for change detection in land use and land cover within the waterbodies. The study indicates that construction activities have led to transformation within the water bodies regarding reduction in area and inter changing of land use and land cover classes, in turn leading to siltation and reduction of recharge. PMID- 28721590 TI - High non-anatomic tunnel position rates in ACL reconstruction failure using both transtibial and anteromedial tunnel drilling techniques. AB - INTRODUCTION: Although it is well known from cadaveric and biomechanical studies that transtibial femoral tunnel (TT) positioning techniques are associated with non-anatomic tunnel positions, controversial data exist as so far no clinical differences could have been found, comparing transtibial with anteromedial techniques (AM). The purpose of the study was to analyze if graft failure following TT ACL reconstruction was more commonly associated with non-anatomic tunnel position in comparison with the AM technique. We hypothesized that, compared to AM techniques, non-anatomic tunnel positions correlate with TT tunnel positioning techniques. MATERIALS AND METHODS: A total of 147 cases of ACL revision surgery were analyzed retrospectively. Primary ACL reconstructions were analyzed regarding the femoral tunnel drilling technique. Femoral and tibial tunnel positions were determined on CT scans using validated radiographic measurement methods. Correlation analysis was performed to determine differences between TT and AM techniques. RESULTS: A total of 101 cases were included, of whom 64 (63.4%) underwent the TT technique and 37 (36.6%) the AM technique for primary ACL reconstruction. Non-anatomic femoral tunnel positions were found in 77.2% and non-anatomical tibial tunnel positions in 40.1%. No correlations were found comparing tunnel positions in TT and AM techniques, revealing non-anatomic femoral tunnel positions in 79.7 and 73% and non-anatomic tibial tunnel positions in 43.7 and 35.1%, respectively (p > 0.05). CONCLUSIONS: Considerable rates of non-anatomic femoral and tibial tunnel positions were found in ACL revisions with both transtibial and anteromedial femoral drilling techniques. Despite the potential of placing tunnels more anatomically using an additional AM portal, this technique does not ensure anatomic tunnel positioning. Consequently, the data highlight the importance of anatomic tunnel positioning in primary ACL reconstruction, regardless of the applied drilling technique. PMID- 28721591 TI - Secondary femur shaft fracture following treatment with cephalomedullary nail: a retrospective single-center experience. AB - AIM: Secondary femur fracture subsequent to treatment of trochanteric fractures with cephalomedullary nailing (i.e., a periprosthetic fracture related to the cephalomedullary nail) is a rare but very severe complication. As such, the aim of this study was to assess the impact of revision surgery and general state of health on mortality and functional outcomes in patients suffering femur fractures following treatment with cephalomedullary nails. MATERIALS AND METHODS: Between 2000 and 2015, 3549 patients presenting with OTA/AO 31A1-3 femur fractures were admitted to our department and subsequently treated with either a Gamma(r) Nail or PFNA(r). Out of this sample population, 42 patients suffered 43 secondary femur shaft fractures (1.2%). The mean follow-up time was 26 +/- 9.7 months. Fractures were classified according to the AO classification and the modified Vancouver classification. Treatment options included ORIF, removing the cephalomedullary nail and fixation with a long nail with or without cerclage wires. General health status was defined according to the ASA Score. Mortality, pre- and postoperative mobility, hospital stay and complications were assessed retrospectively. RESULTS: A total of 14.3% patients died within 90 days following surgery. At least 16.6% patients died due to medical complications strongly related to the surgery. The average time to secondary fracture following initial surgery for trochanteric fracture was 122.7 +/- 32 weeks. The most common fracture types were AO 32A1 (53.5%) and AO 32B1 (23.3), as well as Vancouver C and B1. A time-to-secondary-fracture of less than or longer than 6 months following surgery for trochanteric fracture and ASA Score all had no significant influence on mortality, complications, duration of surgery and postoperative mobility. CONCLUSION: Femoral shaft facture subsequent to fixation of trochanteric fracture with cephalomedullary nails is a severe complication. It leads to prolonged hospital stays and delayed recovery. Postoperative hospital stay mortality rates may be as high as 16.6%. PMID- 28721592 TI - Construction, Purification, and Characterization of a Homodimeric Granulocyte Colony-Stimulating Factor. AB - Granulocyte colony-stimulating factor (G-CSF) has found widespread clinical application, and modified forms with improved biopharmaceutical properties have been marketed as well. PEGylation, the covalent modification of G-CSF with polyethylene glycol (PEG), has a beneficial effect on drug properties, but there are concerns connected to the immunogenicity of PEGylated compounds and bioaccumulation of the synthetic polymer. To overcome challenges connected with chemical modifications, we developed fusion proteins composed of two G-CSF molecules connected via different peptide linkers. Three different homodimeric G CSF proteins were purified, and their in vitro and in vivo activities were determined. A G-CSF dimer, GCSF-Lalpha, was constructed using an alpha-helix forming peptide linker, and it demonstrated an extended half-life in serum with a stronger neutrophil response as compared to the monomeric G-CSF protein. The GCSF Lalpha protein, therefore, might be selected for further studies as a potential drug candidate. PMID- 28721589 TI - Recent developments in polyfluoroalkyl compounds research: a focus on human/environmental health impact, suggested substitutes and removal strategies. AB - Between the late 1940s and early 1950s, humans manufactured polyfluoroalkyl compounds (PFCs) using electrochemical fluorination and telomerisation technologies, whereby hydrogen atoms are substituted by fluorine atoms, thus conferring unnatural and unique physicochemical properties to these compounds. Presently, there are wide ranges of PFCs, and owing to their bioaccumulative properties, they have been detected in various environmental matrices and in human sera. It has thus been suggested that they are hazardous. Hence, this review aims at highlighting the recent development in PFC research, with a particular focus on perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS), the most studied and predominantly found PFCs in various environmental matrices, although recent reports have included perfluorobutane sulfonate (PFBS), which was previously regarded as innocuously harmless, when compared to its counterparts, PFOA and PFOS. As such, proper investigations are thus required for a better understanding of short-chain PFC substitutes, which have been suggested as suitable replacements to long-chained PFCs, although these substitutes have also been suggested to pose various health risks comparable to those associated with long-chain PFCs. Similarly, several novel technologies, such as PFC reduction using zero-valent iron, including removal at point of use, adsorption and coagulation, have been proposed. However, regardless of how efficient removers some of these techniques have proven to be, short-chain PFCs remain a challenge to overcome for scientists, in this regard. PMID- 28721595 TI - Response to Lyn?e: questions about isolated trauma shaking and confessions. PMID- 28721593 TI - Public Policies and Interventions for Diabetes in Latin America: a Scoping Review. AB - PURPOSE OF REVIEW: Successful interventions are needed to diagnose and manage type 2 diabetes (T2DM) in Latin America, a region that is experiencing a significant rise in rates of T2DM. Complementing an earlier review exploring diabetes prevention efforts in Latin America, this scoping review examines the literature on (1) policies and governmental programs intended to improve diabetes diagnosis and treatment in Latin America and (2) interventions to improve diabetes management in Latin America. It concludes with a brief discussion of promising directions for future research. RECENT FINDINGS: Governmental policies and programs for the diagnosis and treatment of diabetes in different Latin American countries have been implemented, but their efficacy to date has not been rigorously evaluated. There are some promising intervention approaches in Latin America to manage diabetes that have been evaluated. Some of these utilize multidisciplinary teams, a relatively resource-intensive approach difficult to replicate in low-resource settings. Other evaluated interventions in Latin America have successfully leveraged mobile health tools, trained peer volunteers, and community health workers (CHWs) to improve diabetes management and outcomes. There are some promising approaches and large-scale governmental efforts underway to curb the growing burden of type 2 diabetes in Latin America. While some of these interventions have been rigorously evaluated, further research is warranted to determine their effectiveness, cost, and scalability in this region. PMID- 28721594 TI - Exome analysis in an Estonian multiplex family with neural tube defects-a case report. AB - INTRODUCTION: Neural tube defects (NTDs) are a group of common and severe congenital birth defects that occur during early embryonic development due to incomplete closure of the neural tube. The genetic architecture of human NTDs, including spina bifida and hydrocephalus, is highly heterogeneous, with multiple genes/loci and both gene-gene and gene-environment interactions involved. Hence, the variation in outcomes also most likely relates to a combination of the severity of different variants in multiple genes and genetic modifiers affecting the biochemical traits. METHODS: Here, we present a multiple-spouse family with one pedigree lineage where three brothers are affected with NTDs-two lumbar spina bifidas without hydrocephalus and one obstructive hydrocephalus. We sequenced the exomes of three NTD patients and their parents. RESULTS: The analysis revealed a heterozygous c.844ins68 variant in CBS, which was carried by all affected individuals and inherited from their mother. All affected individuals had a variable set of additional low frequency deleterious variants in PTK7, PLCD4, IL4I1 or RASSF4 as likely causal loci contributing to the disease development. CONCLUSION: This report extends the current knowledge of the genetic background of NTDs and proposes that common and low frequency variants in genes involved mostly in one-carbon metabolism or planar cell polarity (PCP) pathways can act in an additive manner to increase the genetic risk of the disease. PMID- 28721596 TI - Central adrenal insufficiency following traumatic brain injury: a missed diagnosis in the critically injured. AB - BACKGROUND: High-dose steroid administration is no longer recommended in the treatment of acute traumatic brain injury (TBI) as it failed to prove beneficial in improving patients' outcome. However, a masked benefit of steroid administration in TBI management was that it provided corticosteroid replacement therapy in patients with TBI-related central adrenal insufficiency. CASE PRESENTATION: We report the case of a 12-year-old boy who suffered a severe TBI from a motor vehicle accident that resulted in complete deficiency of anterior pituitary function. Central adrenal insufficiency was not ruled out by a near normal response to a low-dose ACTH test performed on D11. CONCLUSION: Consideration should be given to the empirical treatment of TBI pediatric patients with stress doses of corticosteroids if injury to the hypothalamus or pituitary gland is possible until a formal assessment of the hypothalamic pituitary-adrenal axis can be made. PMID- 28721597 TI - Neuroendoscopic management of posterior third ventricle ependymoma with intraaqueductal and fourth ventricle extension: a case report and review of the literature. AB - INTRODUCTION: Posterior third ventricle ependymomas with intraaqueductal extension are relatively infrequent lesions. Its surgical management represents a formidable technical challenge and includes a wide variety of approaches. Minimally invasive surgery including the endoscopic management can play a crucial role to obtain an optimal clinical outcome. PATIENTS AND METHODS: We report the clinical outcome of an 11-year-old female patient with a 6-year history of recurrent episodes of headache and vomiting. On brain MRI a posterior third ventricle lesion with extension to the aqueduct of Sylvius and fourth ventricle, and associated hydrocephalus was observed. RESULTS: Our management of the lesion included a two-step endoscopic surgery: first an anterior third ventriculostomy and biopsy of the lesion that was reported to be a low-grade ependymoma, and posteriorly an endoscopic-assisted resection of the lesion. Clinical outcome was optimal without neurological sequelae. The postoperative MRI showed a thickened ependymal area on the tumor base of implantation. It was considered to be a remnant of the lesion and subsequently treated with radiotherapy. CONCLUSION: Posterior third ventricle ependymomas with intraaqueductal extension can be endoscopically managed to obtain a successful outcome. PMID- 28721598 TI - A retrospective review of 34 cases of pediatric pituitary adenoma. AB - PURPOSE: The purpose of this paper is to study invasiveness, tumor features and clinical symptoms of pediatric pituitary adenoma, and to discuss some inconclusive results in prior studies. METHODS: We retrospectively reviewed 34 cases of children (<20 year-old) who were pathologically diagnosed with pituitary adenoma and surgically treated from 2010 to 2017. Data of general information, clinical symptoms, invasive behaviors, surgery approaches, and tumor features were collected and analyzed. RESULTS: Sixteen boys and 18 girls aged from 12 to 19 years old were included. Prolactinoma was most suffered, followed by GH-, none and ACTH-secreting pituitary adenoma. Invasive behaviors were observed frequently and suprasellar extensions were most found. Macroadenoma account 70% of all cases. Meanwhile, unlike prior studies, a significant raise of incidence on invasive tumor and pituitary adenoma apoplexy were observed. Craniotomy and transsphenoidal surgery were both applied with zero mortality. Nine cases occurred with transient hypopituitarism and diabetes insipidus. Three cases of tumor recurrence received secondary surgery or radiotherapy. CONCLUSIONS: Invasive behaviors were more frequent than previous prediction. Craniotomy is worth considering for total tumor removal. Pituitary adenoma apoplexy needs further studies since its different features between children and adults in present study. Specialized care and teamwork of neurosurgeons, pediatricians, and endocrinologists are important. PMID- 28721599 TI - Reply to Dr. Ijichi's group. PMID- 28721600 TI - Resveratrol ameliorates hypoxia/ischemia-induced brain injury in the neonatal rat via the miR-96/Bax axis. AB - OBJECTIVE: This study was aimed to investigate the mechanism of resveratrol on amelioration of hypoxia/ischemia (H/I)-induced brain injury. METHODS: The RT-PCR and western blot were used to detect the mRNA and protein expressions, respectively. The PC12 cell induced by OGD/R was as in vitro H/I brain injury model. The luciferase reporter assay was used to prove the relationship between Bax and miR-96, and the cell apoptosis was detected by MTT assay. The loss of MBP+ area in neonatal rats analyzed by immunohistochemistry was to evaluate the extent of brain injury. RESULTS: The miR-96 expression was decreased in the hippocampus and cerebral cortex of neonatal rats with H/I brain injury and the oxygenglucose deprivation/re-oxygenation (OGD/R)-induced PC12 cell, while Bax expression was opposite. And then the H/I rats and OGD/R-induced PC12 cell were treated with resveratrol (RSV); the results showed that the RSV could reverse the miR-96 and Bax expressions. Next, the luciferase reporter assay proved that Bax was a target of miR-96. We used the miR-96 inhibitor to suppress miR-96 expression in OGD/R-induced PC12 cell, and found that RSV regulated Bax expression and prevented OGD/R-induced PC12 cell apoptosis via miR-96. In addition, the immunohistochemistry was used to analyze the loss of MBP+ area in neonatal rats, and the result showed that the RSV significantly reduced the brain damage, increased miR-96 expression, and decreased Bax expression, while inhibition of miR-96 aggravated the brain damage and reversed the effect of RSV. CONCLUSION: Resveratrol ameliorates hypoxia/ischemia-induced brain injury in neonatal rat via the miR-96/ Bax axis. PMID- 28721601 TI - High Survivorship and Few Complications With Cementless Total Wrist Arthroplasty at a Mean Followup of 9 Years. AB - BACKGROUND: Total wrist arthroplasty (TWA) has been described as traditionally being performed with fixation in the radius and carpus with cement. The TWA implant used in our series has been associated with promising results in studies with up to 6 years followup; however, studies evaluating survivorship, pain, and function with this implant are limited. QUESTION/PURPOSE: (1) To report ROM and pain scores after wrist reconstruction with cementless fourth-generation TWA at a mean followup of 9 years (range, 4.8-14.7 years). (2) To report complications of a cementless fourth-generation TWA and the cumulative probability of not undergoing a revision at a mean followup of 9 years. METHODS: This is a retrospective case series of 69 patients who were treated for pancarpal wrist arthritis between 2002 and 2014. Of those, 31 had inflammatory arthritis (rheumatoid arthritis [n = 29], juvenile rheumatoid arthritis [n = 1], and psoriatic arthritis [n = 1]); all of these patients received TWA with the cementless implant studied in this investigation. Another 38 patients had osteoarthritis or posttraumatic arthritis; in this subgroup, 28 patients were 65 years or younger, and all underwent wrist fusion (none were offered TWA). Ten patients with osteoarthritis were older than 65 years and all were offered TWA; of those, eight underwent TWA, and two declined the procedure and instead preferred and underwent total wrist arthrodesis. The mean age of the 39 patients who had TWA was 56 +/- 8.9 years (range, 31-78 years) at the time of surgery; 36 were women and three were men. The patients who underwent TWA were seen at a minimum of 4 years (mean, 9 years; range, 4-15 years), and all had been examined in 2016 as part of this study except for one patient who died 9 years after surgery. The dominant wrist was involved in 60% (25) of the patients. All patients were immobilized for 4 weeks postoperatively and then underwent hand therapy for 4 to 6 weeks. Pain and ROM were gathered before surgery as part of clinical care, and were measured again at latest followup; at latest followup, radiographs were analyzed (by the senior author) for evidence of loosening, defined as any implant migration compared with any previous radiograph with evidence of periimplant osteolysis and bone resorption. Subjective pain score was assessed by a verbal pain scale (0-10) and ROM was measured with a goniometer. Complications were determined by chart review and final examination. Kaplan Meier survival analysis was performed to estimate the cumulative probability of not undergoing a revision. RESULTS: The mean preoperative active ROM was 34o +/- 18 degrees flexion and 36 degrees +/- 18 degrees extension. Postoperatively, the mean active ROM was 37 degrees +/- 14 degrees flexion and 29 degrees +/- 13 degrees extension. The mean difference between the preoperative pain score (8.6 +/- 1.2) and postoperative pain score (0.4 +/- 0.8) was 8.1 +/- 1.9 (p < 0.001). Implant loosening occurred in three (7.7%) patients. No other complications occurred in this series. Kaplan-Meier survivorship analysis estimated the cumulative probability of remaining free from revision as 78% (95% CI, 62%-91%) at 15 years. CONCLUSION: Cementless fourth-generation TWA improves pain while generally preserving the preoperative arc of motion. The cumulative probability of remaining free from revision at 14.7 years after the index procedure is 77.7% (95% CI, 62.0%-91.4%). Future studies should compare alternative approaches for patients with endstage wrist arthritis; such evaluations-which might compare TWA implants, or TWAs with arthrodesis-will almost certainly need to be multicenter, as the problem is relatively uncommon. LEVEL OF EVIDENCE: Level IV, therapeutic study. PMID- 28721603 TI - The 'Disadapted' Animal: Niko Tinbergen on Human Nature and the Human Predicament. AB - This paper explores ethologist Niko Tinbergen's path from animal to human studies in the 1960s and 1970s and his views about human nature. It argues, first, that the confluence of several factors explains why Tinbergen decided to cross the animal/human divide in the mid 1960s: his concern about what he called "the human predicament," his relations with British child psychiatrist John Bowlby, the success of ethological explanations of human behavior, and his professional and personal situation. It also argues that Tinbergen transferred his general adaptationist view of animal behavior to the realm of human biology; here, his concern about disadaptation led him to a view of human behavior that was strongly determined by the species' evolutionary past, a position that I call evolutionary determinism. These ideas can be seen in the work he carried out with his wife, Elisabeth Tinbergen, on autism. The paper concludes that Tinbergen's vision of human nature constitutes another version of what anthropologist Clifford Geertz called in 1966 the "stratigraphic" conception of the human: a view of human nature as a composite of levels in which a universal ancestral biological core is superimposed by psychological and cultural layers that represent accidental variation at best and pathological deviation at worst. PMID- 28721604 TI - A Space of One's Own: Barbosa du Bocage, the Foundation of the National Museum of Lisbon, and the Construction of a Career in Zoology (1851-1907). AB - This paper discusses the life and scientific work of Jose Vicente Barbosa du Bocage (1823-1907), a nineteenth-century Portuguese naturalist who carved a new place for zoological research in Portugal and built up a prestigious scientific career by securing appropriate physical and institutional spaces to the discipline. Although he was appointed professor of zoology at the Lisbon Polytechnic School, an institution mainly devoted to the preparatory training of military officers and engineers, he succeeded in creating the conditions that allowed him to develop consistent research in zoology at this institution. Taking advantage of the reconstruction and further improvement of the building of the Lisbon Polytechnic, following a violent fire in 1843, Bocage transferred a natural history museum formerly located at the Academy of Sciences of Lisbon to his institution, where he conquered a more prestigious place for zoology. Although successive governments were unwilling to meet Bocage's ambitions for the Zoological Section of the newly created National Museum of Lisbon, the collaborators he found in different parts of the Portuguese continental territory and colonial empire supplied him the specimens he needed to make a career as a naturalist. Bocage ultimately became a renowned specialist in Southwestern African fauna thanks to Jose de Anchieta, his finest collaborator. Travels to foreign museums, and the establishment of links with the international community of zoologists, proved fundamental to build up Bocage's national and international scientific reputation, as it will be exemplified by the discussion of his discovery of Hyalonema, a specimen with a controversial identity collected off the Portuguese coast. PMID- 28721605 TI - How to Provide Gadolinium-Free PET/MR Cancer Staging of Children and Young Adults in Less than 1 h: the Stanford Approach. AB - PURPOSE: To provide clinically useful gadolinium-free whole-body cancer staging of children and young adults with integrated positron emission tomography/magnetic resonance (PET/MR) imaging in less than 1 h. PROCEDURES: In this prospective clinical trial, 20 children and young adults (11-30 years old, 6 male, 14 female) with solid tumors underwent 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) PET/MR on a 3T PET/MR scanner after intravenous injection of ferumoxytol (5 mg Fe/kg) and [18F]FDG (2-3 MBq/kg). Time needed for patient preparation, PET/MR image acquisition, and data processing was compared before (n = 5) and after (n = 15) time-saving interventions, using a Wilcoxon test. The ferumoxytol-enhanced PET/MR images were compared with clinical standard staging tests regarding radiation exposure and tumor staging results, using Fisher's exact tests. RESULTS: Tailored workflows significantly reduced scan times from 36 to 24 min for head to mid thigh scans (p < 0.001). These streamlined PET/MR scans were obtained with significantly reduced radiation exposure (mean 3.4 mSv) compared to PET/CT with diagnostic CT (mean 13.1 mSv; p = 0.003). Using the iron supplement ferumoxytol "off label" as an MR contrast agent avoided gadolinium chelate administration. The ferumoxytol-enhanced PET/MR scans provided equal or superior tumor staging results compared to clinical standard tests in 17 out of 20 patients. Compared to PET/CT, PET/MR had comparable detection rates for pulmonary nodules with diameters of equal or greater than 5 mm (94 vs. 100 %), yet detected significantly fewer nodules with diameters of less than 5 mm (20 vs 100 %) (p = 0.03). [18F]FDG-avid nodules were detected with slightly higher sensitivity on the PET of the PET/MR compared to the PET of the PET/CT (59 vs 49 %). CONCLUSION: Our streamlined ferumoxytol-enhanced PET/MR protocol provided cancer staging of children and young adults in less than 1 h with equivalent or superior clinical information compared to clinical standard staging tests. The detection of small pulmonary nodules with PET/MR needs to be improved. PMID- 28721606 TI - Fluid-Structure Finite-Element Modelling and Clinical Measurement of the Wideband Acoustic Input Admittance of the Newborn Ear Canal and Middle Ear. AB - The anatomical differences between the newborn ear and the adult one result in different input admittance responses in newborns than those in adults. Taking into account fluid-structure interactions, we have developed a finite-element model to investigate the wideband admittance responses of the ear canal and middle ear in newborns for frequencies up to 10 kHz. We have also performed admittance measurements on a group of 23 infants with ages between 14 and 28 days, for frequencies from 250 to 8000 Hz with 1/12-octave resolution. Sensitivity analyses of the model were performed to investigate the contributions of the ear canal and middle ear to the overall admittance responses, as well as the effects of the material parameters, measurement location and geometrical variability. The model was validated by comparison with our new data and with data from the literature. The model provides a quantitative understanding of the canal and middle-ear resonances around 500 and 1800 Hz, respectively, and also predicts the effects of the first resonance mode of the middle-ear cavity (around 6 kHz) as well as the first and second standing-wave modes in the ear canal (around 7.2 and 9.6 kHz, respectively), which may explain features seen in our high-frequency-resolution clinical measurements. PMID- 28721607 TI - Access to High Cost Cancer Medicines Through the Lens of an Australian Senate Inquiry-Defining the "Goods" at Stake. AB - Cancer is a major burden on populations and health systems internationally. The development of innovative cancer medicines is seen as a significant part of the solution. These new cancer medicines are, however, expensive, leading to limited or delayed access and disagreements among stakeholders about which medicines to fund. There is no obvious resolution to these disagreements, with stakeholders holding firmly to divergent positions. Access to cancer medicines was recently explored in Australia in a Senate Inquiry into the Availability of New, Innovative, and Specialist Cancer Drugs in Australia. We analysed the resultant Senate Report to identify competing stakeholder values. Our analysis illustrates that there are four main "goods" prioritized by different stakeholders: 1) innovation, 2) compassion, 3) equity, and 4) sustainability. We observe that, with the exception of sustainability, all of these "goods" put pressure on payers to provide access to cancer medicines more quickly and based on less rigorous evaluation processes. We then explore the consequences of giving in to such pressure and suggest that deconstructing the implicit values in calls for "enhanced access" to cancer medicines is necessary so that more nuanced solutions to the challenge of providing access to these high cost medicines can be found. PMID- 28721608 TI - A New Light Trap Model as an Alternative for Controlling Pests in Eucalyptus Plantations. AB - Eucalyptus plantations can be affected by species of defoliating caterpillars. The integrated management of this group primarily involves a monitoring system, natural enemies, and biological products. Alternative control methods, including the use of conventional light traps, have not been adopted, mostly because of their low efficiency. Therefore, a more efficient light trap model was developed. The new model allowed the capture of 3.6 times as many insects as the conventional model, with a 261% gain in control efficiency. The use of this new model represents another integrated management alternative for lepidopteran pests of eucalyptus plantations and other cultured plants. PMID- 28721609 TI - Susceptibility of Diaphorina citri (Hemiptera: Liviidae) and Its Parasitoid Tamarixia radiata (Hymenoptera: Eulophidae) to Entomopathogenic Fungi under Laboratory Conditions. AB - Diaphorina citri (Kuwayama) is a global pest of citrus that transmits the bacteria associated with the disease, Huanglongbing. Entomopathogenic fungi and the parasitoid Tamarixia radiata (Waterston) are important biological control agents of this pest and likely to interact in D. citri populations. As a basis for interaction studies, we determined the susceptibility of nymphs and adults of D. citri and adults of the parasitoid T. radiata to six fungal isolates from the species Beauveria bassiana s.l. (Bals.-Criv.) Vuill. (isolates B1 and B3), Metarhizium anisopliae s.s. (Metsch.) (Ma129 and Ma65) and Isaria fumosorosea Wize (I2 and Pae). We conducted experiments evaluating infection levels in all three insect groups following inoculation with a series of conidial concentrations (1 * 104-1 * 108 conidia mL-1). Results showed that D. citri nymphs and T. radiata were more susceptible to fungal isolates than D. citri adults. Overall, B. bassiana and M. anisopliae isolates caused the greatest infection compared with I. fumosorosea isolates in all three groups of insects. Isolates B1 (B. bassiana) and Ma129 (M. anisopliae) infected a greater proportion of adults and nymphs of D. citri, respectively. Both isolates of B. bassiana caused greater infection in T. radiata compared with isolates of the other fungal species. We propose that isolates B1 and Ma129 are the strongest candidates for control of D. citri. Our results represent the first report of entomopathogenic fungi infecting T. radiata, and the basis for future studies to design a biological control programme that uses both agents more efficiently against D. citri populations. PMID- 28721610 TI - Teaching Neuroimages: "Filling out" in Cavernous Hemangioma of the Cavernous Sinus. PMID- 28721612 TI - Interface effect of natural precipitated dust on the normal flora of Escherichia coli and Staphylococcus epidermidis. AB - This study aimed to evaluate the interface effect between five types of natural precipitated dust and two normal floras. Five kinds of natural dust (FC-1#, FC 2#, FC-15#, FC-18#, and FC-21#) were collected, and particle size and chemical components were detected by laser particle size analyzer and X-ray fluorescence (XRF). The elements, bacterial count, glucose (GLU) consumption, pH, and three biochemical indicators were measured after being co-cultured with Escherichia coli and Staphylococcus epidermidis in vitro. In addition, the changes of bacterial morphology were observed by scanning electron microscopy (SEM). Results showed that most particles contained a high level of SiO2, which diameter ranged from 0.3 to 1.0 MUm. The concentration of Ca showed s significant increase upon interaction with E. coli and S. epidermidis in all dusts (p < 0.01). Moreover, FC 1# and FC-21# induced obvious growth in bacterial count, glucose consumption, and pH after they reacted with two normal floras (p < 0.05). Besides, the results also showed an apparent increase in the concentration of pyruvate, beta galactosidase, and alkaline phosphatase (AKP) after being co-cultured with E. coli and S. epidermidis, in which FC-1# is enhanced in the most obvious. The E. coli interacted with dust made more indentations in surface, and the configuration became thin and long. Some broken bacteria were present, and bacterial wreckage was visible. Plenty of S. epidermidis interacted with dust gathered in the indentations of dust, particularly in pleated surfaces. Further, these findings demonstrated that the alkaline dust with higher Ca content stimulated the growth of bacteria, and irregularly shaped or thin dust would be easier to combine with bacteria and conduct interface effect. PMID- 28721611 TI - Bone-targeting parathyroid hormone conjugates outperform unmodified PTH in the anabolic treatment of osteoporosis in rats. AB - Synthetic parathyroid hormone (PTH) is clinically indicated for the treatment of osteoporosis, through its anabolic effects on parathyroid hormone receptors (PTHRs), located on osteoblast cells. However, the bioavailability of PTH for bone cells is restricted by the short half-life of PTH and the widespread distribution of PTHRs in non-skeletal tissues. To impart affinity for mineralized bone surfaces, bisphosphonate (BP)-mediated PTH analogues were synthesized, characterized, and evaluated in vitro and in vivo. The successful synthesis of PTH-PEG-BP was identified on MALDI-ToF mass spectra; bone-targeting potential was evaluated by hydroxyapatite binding test; and receptor bioactivity was assessed in UMR-106 (rat osteosarcoma) cells that constitutively express PTHRs. Therapeutic efficacy was evaluated using ovariectomized rats that remained untreated for 8 weeks to allow development of osteopenia. Those rats then received daily subcutaneous injections of PTH-PEG-BP, thiol-BP vehicle, or unmodified PTH, and compared to sham-operated healthy rats at 0, 4, 8, 12, and 16 weeks. In vivo micro-CT was conducted on the proximal tibial metaphysis to measure microstructural bone parameters, and new bone formation was detected using dynamic labeling. Bone strength was assessed using three-point bending mechanical testing. Our study determined that PTH-PEG-BP conjugates significantly enhanced PTH targeting to the bone matrix while retaining full PTH bioactivity. Moreover, PTH-PEG-BP conjugates significantly increased trabecular bone quality, anabolic bone formation, and improved bone strength over systemically administered PTH alone. We highlight the promise of a novel class of bone targeting anabolic compound for the treatment of osteoporosis and related bone disorders. PMID- 28721613 TI - Comparative toxicity of seven rare earth elements in sea urchin early life stages. AB - The widespread use of rare earth elements (REEs) in a number of technological applications raises unanswered questions related to REE-associated adverse effects. We have previously reported on the multiple impact of some REEs on the early life stages of the sea urchin Paracentrotus lividus. The present investigation was to evaluate REE toxicity to early life stages in two unrelated sea urchin species, Sphaerechinus granularis and Arbacia lixula. The comparative toxicities were tested of seven REEs, namely yttrium, lanthanum, cerium, neodymium, samarium, europium and gadolinium as chloride salts at concentrations ranging from 10-7 to 10-4 M. The evaluated endpoints included developmental defects and cytogenetic anomalies in REE-exposed embryos/larvae, and decreased fertilization success and offspring damage following sperm exposure. The results showed different toxicity patterns for individual REEs that varied according to test species and to treatment protocol, thus showing toxicity scaling for the different REEs. Further, the observed effects were compared with those reported for P. lividus either following embryo or sperm exposures. S. granularis showed a significantly higher sensitivity both compared to A. lixula and to P. lividus. This study provides clear-cut evidence for distinct toxicity patterns among a series of REEs. The differences in species sensitivity at micromolar REE levels may warrant investigations on species susceptibility to impacts along polluted coasts. PMID- 28721615 TI - Phycoremediation potential of marine microalga Tetraselmis indica on secondary treated domestic sewage for nutrient removal and biodiesel production. AB - Marine microalga Tetraselmis indica (T. indica) was cultivated in secondary treated domestic sewage (STDS) in batch mode. Optimization studies showed that after 14 days of cultivation period, highest biomass yield reached was 0.88 +/- 0.04 g/L at the optimum temperature of 27 +/- 1 degrees C and light intensity of 135 MUmol m-2 s-1. T. indica removed about 60.93% phosphate, 78.46% nitrate, 72.94% chemical oxygen demand (COD), 73.17% biological oxygen demand (BOD), 98.90% total dissolved solids (TDS) and heavy metals (83.11% Cd, 55.67% Ca, 45.12% Cu, 13.67% Mn, 50.88% Pb, and 98.92% Al) from STDS. The level of electrical conductivity was reduced to 0.0974 +/- 0.045 dS/m. The fatty acid methyl ester (FAME) profile showed the presence of palmitic acid (12.91%), oleic acid (35.94%), linoleic acid (14.89%) and eicosanoic acid (12.34%). This study indicates the potential of T. indica for removal of pollutants from STDS and also its capability of biodiesel production. PMID- 28721614 TI - Low doses of chlorpyrifos interfere with spermatogenesis of rats through reduction of sex hormones. AB - Use of pesticides results in indirect effects on human health. We aimed to evaluate implications of toxicological effects of subchronic chlorpyrifos exposure on reproductive function in male rats. A total of 48 adult Wistar male rats were separated into four groups (n = 12). Animals were gavaged with 2.5 mg/kg (T1), 5 mg/kg (T2), or 10 mg/kg (T3) body weight of chlorpyrifos (CPF) or distilled water (control) daily for 30 days. Organ weights, epididymal sperm parameters, DNA integrity, sex hormonal (FHS and LH) levels, and alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), and creatinine concentrations were determined on day 31. Another two sets of (four groups/set; n = 10) animals were orally treated with the same doses of CPF, control animal groups were treated with distilled water only for 30 days, and fertility indices and blood plasma acetylcholine esterase (AchE) were determined on day 31. Exposure to CPF resulted in a significant (p < 0.05) decrease in weights of testis and epididymis. An increase in liver weight resulted in reduced sperm counts and sperm motility and an increase in sperm abnormalities. Significant reduction in serum testosterone (p < 0.01), luteinizing hormone (p < 0.05), and follicular stimulating hormone (p < 0.05) levels was evident in animals treated with the highest dose. A significant decrease in the number of viable implantation sites and pups was observed in female rats mated with the T3 (p < 0.01) and T2 (p < 0.05) males. The ALT, AST, GGT, and creatinine contents were significantly increased (p < 0.05 and p < 0.01, respectively) on CPF exposure. A significant (p < 0.01) reduction in blood plasma AchE enzyme was observed with the highest dose. Our results demonstrated that prolonged exposure of CPF induces spermatogenesis damage, possibly through interference with sex hormones and AchE enzyme resulting in reduction of fertility. Therefore, awareness programs on handling CPF (pesticides) to enhance safety warrant minimization of its hazards. PMID- 28721616 TI - The mining sector of Liberia: current practices and environmental challenges. AB - Liberia is endowed with an impressive stock of mineral reserves and has traditionally relied on mining, namely iron ore, gold, and diamonds, as a major source of income. The recent growth in the mining sector has the potential to contribute significantly to employment, income generation, and infrastructure development. However, the development of these mineral resources has significant environmental impacts that often go unnoticed. This paper presents an overview of the Liberian mining sector from historical, current development, and economic perspectives. The efforts made by government to address issues of environmental management and sustainable development expressed in national and international frameworks, as well as some of the environmental challenges in the mining sector are analyzed. A case study was conducted on one of the iron ore mines (China Union Bong Mines Investment) to analyze the effects of the water quality on the local water environment. The results show that the analyzed water sample concentrations were all above the WHO and Liberia water standard Class I guidelines for drinking water. Finally the paper examines the application of water footprint from a life cycle perspective in the Liberian mining sector and suggests some policy options for water resources management. PMID- 28721617 TI - Effect of membrane property and feed water organic matter quality on long-term performance of the gravity-driven membrane filtration process. AB - This study investigated the influence of membrane property and feed water organic matter quality on the permeate flux and water quality during gravity-driven membrane (GDM) filtration. GDM filtration was continuously carried out over 500 days at hydrostatic pressure of 65 mbar in dead-end mode without any back flushing or membrane cleaning. Three ultrafiltration (UF) membranes (PES-100 kDa, PVDF-120 kDa, and PVDF-100 kDa) and one microfiltration (MF) membrane (PTFE-0.3 MUm) were tested for treating lake water with varied organic matter qualities due to algal growth. The fluxes of the four membranes rapidly decreased to ~8 L/(m2 * h) within a week of GDM filtration. The flux variations were quite similar for the four membranes during the entire GDM filtration, indicating that membrane property has a little effect on the flux. The flux strongly depends on the feed water organic matter quality. The average flux in treating low organics containing water (7-60 days) was ~5 L/(m2 * h) and decreased to ~2 L/(m2 * h) in treating high organics containing water (60-300 days). The accumulation of algal derived biopolymers was mainly responsible for the flux decline by forming biofilms with high permeation resistance. The average flux in 300-500 days increased to ~3.5 L/(m2 * h) when the feed water contained lower levels of biopolymers and higher levels of easily biodegradable organics, which created open and heterogeneous biofilms with lower permeation resistance. Removal efficiency for Escherichia coli was more than 5 log, while the removal efficiency for total bacterial cells was 1 log-2 log for the four membranes, indicating some bacterial regrowth after the filtration. Removal efficiency for the MS2 phage was 2.4 log and 1.5 log for the fouled PES-UF and PTFE-MF membranes. PMID- 28721618 TI - Biological nanopesticides: a greener approach towards the mosquito vector control. AB - Mosquitoes, being a vector for some potentially dreadful diseases, pose a considerable threat to people all around the world. The control over the growth and propagation of mosquitoes comprises conventional pesticides, insect growth regulators and other microbial control agents. However, the usage of these common chemicals and conventional pesticides eventually has a negative impact on human health as well as the environment, which therefore becomes a major concern. The lacuna allows nanotechnology to come into action and exploit nanopesticides. Nanopesticides are majorly divided into two categories-synthetic and biological. Several nanoformulations serve as a promising nanopesticide viz. nanoparticles, e.g. biologically synthesised nanoparticles through plant extracts, nanoemulsions prepared using the essential oils like neem oil and citronella oil and nanoemulsion of conventional pesticides like pyrethroids. These green approaches of synthesising nanopesticides make use of non-toxic and biologically derived compounds and hence are eco-friendly with a better target specificity. Even though there are numerous evidences to show the effectiveness of these nanopesticides, very few efforts have been made to study the possible non-target effects on other organisms prevalent in the aquatic ecosystem. This study focuses on the role of these nanopesticides towards the vector control and its eco-safe property against the other non-target species. PMID- 28721619 TI - Measurements of beta and alpha hexachlorocyclohexane in Juglans regia and Prunus spinosa trees in a contaminated area, central Italy. AB - Vegetables play an important role in the human diet, and the transfer of toxic contaminants from the soil to plants has been little studied for most tree species and their edible portions. In an area affected by hexachlorocyclohexane (HCH) contamination, in the Sacco River Valley (central Italy), measurements of beta- and alpha-HCH isomers were made on different parts of two tree species: Juglans regia and Prunus spinosa. Concentrations were analysed in roots, branches, leaves, fruits, and seeds. A spatial evaluation of the results highlighted an inverse association of contamination with distance from the river, which is the main route of transport in the environment. Results in J. regia showed decreasing values in this order: branches > leaves > husks > nutmeat. Results in P. spinosa showed decreasing values in the following order: branches > leaves > fruits. In J. regia, nutmeat values were all below limit of detection (LOD, 0.0005 mg/kg), except in one case in which a very low concentration of beta HCH was found (0.006 mg/Kg), compliant with maximum residue limits (MRLs). The ability of J. regia to store large quantities of beta-HCH in wooden and leafy parts but not in edible kernels makes this plant a potential and precious tool in remediation and economical reconversion of polluted areas. It is also valuable for food and wood manufacturing. PMID- 28721620 TI - Methane biofiltration in the presence of ethanol vapor under steady and transient state conditions: an experimental study. AB - Methane (CH4) removal in the presence of ethanol vapors was performed by a stone based bed and a hybrid packing biofilter in parallel. In the absence of ethanol, a methane removal efficiency of 55 +/- 1% was obtained for both biofilters under similar CH4 inlet load (IL) of 13 +/- 0.5 gCH4 m-3 h-1 and an empty bed residence time (EBRT) of 6 min. The results proved the key role of the bottom section in both biofilters for simultaneous removal of CH4 and ethanol. Ethanol vapor was completely eliminated in the bottom sections for an ethanol IL variation between 1 and 11 gethanol m-3 h-1. Ethanol absorption and accumulation in the biofilm phase as well as ethanol conversion to CO2 contributed to ethanol removal efficiency of 100%. In the presence of ethanol vapor, CO2 productions in the bottom section increased almost fourfold in both biofilters. The ethanol concentration in the leachate of the biofilter exceeding 2200 gethanol m 3leachate in both biofilters demonstrated the excess accumulation of ethanol in the biofilm phase. The biofilters responded quickly to an ethanol shock load followed by a starvation with 20% decrease of their performance. The return to normal operations in both biofilters after the transient conditions took less than 5 days. Unlike the hybrid packing biofilter, excess pressure drop (up to 1.9 cmH2O m-1) was an important concern for the stone bed biofilter. The biomass accumulation in the bottom section of the stone bed biofilter contributed to 80% of the total pressure drop. However, the 14-day starvation reduced the pressure drop to 0.25 cmH2O m-1. PMID- 28721621 TI - Tolerance of Japanese knotweed s.l. to soil artificial polymetallic pollution: early metabolic responses and performance during vegetative multiplication. AB - The expansion of invasive Japanese knotweed s.l. is of particular concern because of its aptitudes to rapidly colonize diverse environments, especially anthropized habitats generally characterized by their pollution with heavy metals. Whether the presence of heavy metals impacts the performance traits of this plant is a central question to better understand its invasive properties, though no controlled approach to assess these effects was yet reported. In this aim, we undertook greenhouse experiments where rhizome fragments of Japanese knotweed s.l. (Fallopia japonica and Fallopia * bohemica) were grown during 1 and 3 months, in a soil pot artificially polluted or not with heavy metals added in mixture (Cd, Cr, Pb, Zn). Our results showed that (i) the presence of heavy metals delayed rhizome regeneration and induced lowered plant part weights but did not affect plant height after 3 months; (ii) the effect of metals on the metabolic profiles of belowground part extracts was only detectable after 1 month and not after 3 months of growth, though it was possible to highlight the effect of metals independently of time and genotype for root extracts, and torosachrysone seemed to be the most induced compound; and (iii) the hybrid genotype tested was able to accumulate relatively high concentrations of metals, over or close to the highest reported ones for this plant for Cr, Cd and Zn, whereas Pb was not accumulated. These findings evidence that the presence of heavy metals in soil has a low impact on Fallopia sp. overall performance traits during rhizome regeneration, and has a rather stimulating effect on plant growth depending on pollution level. PMID- 28721622 TI - Influence of selected cyclodextrins in sorption-desorption of chlorpyrifos, chlorothalonil, diazinon, and their main degradation products on different soils. AB - Cyclodextrins (CDs) can improve the apparent solubility and bioavailability of a variety of organic compounds through the formation of inclusion complexes; accordingly, they are suitable for application in innovative remediation technologies of contaminated soils. However, the different interactions in the tertiary system CD/contaminant/soil matrix can affect the bioavailability of the inclusion complex through the possible sorption of CD and CD complex in the soil matrix, as well as with the potential of the sorbed CD to form the complex, concurrent with the desorption processes. This work focuses in changes produced by three different CDs in soil sorption-desorption processes of chlorpyrifos (CPF), diazinon (DZN), and chlorothalonil (CTL), and their major degradation products, 3,5,6-trichloro-2-pyridinol (TCP), 2-isopropyl-6-methyl-4-pyrimidinol, and hydroxy-chlorothalonil (OH-CTL). Cyclodextrins used were beta-cyclodextrin (beta-CD), methyl-beta-cyclodextrin (Mbeta-CD), and 2-hydroxypropyl-beta cyclodextrin (HPbeta-CD). The studied soils belong to the orders Andisol, Ultisol, and Mollisol with different organic matter contents, mineral composition, and pH. The apparent sorption constants were significantly lower for the three pesticides in the presence of all CDs. The highest displacement of sorption equilibria was produced by the influence of Mbeta-CD, with the most pronounced effect for CPF, a pesticide strongly sorbed on soils. The same was obtained for TCP and OH-CTL, highlighting the need to assess the risk of generating higher levels of groundwater contamination with polar metabolites if degradation rates are not controlled. The highest desorption efficiency was obtained for the systems CPF-beta-CD, DZN-Mbeta-CD, and CTL-Mbeta-CD. Since the degree of adsorption of the complex is relevant to obtain an increase in the bioavailability of the contaminant, a distribution coefficient for the complexed pesticide in all CD-soil-pesticide system was estimated by using the apparent sorption coefficients, the stability constant for each CD-pesticide complex, and the distribution coefficients of free pesticide. PMID- 28721623 TI - Influence of dissolved organic matter and oil on the biosorption of BTEX by macroalgae in single and multi-solute systems. AB - The effect of dissolved organic matter (DOM) and oil on the removal of the water soluble compounds benzene, toluene, ethylbenzene, and xylene isomers (BTEX) by two low-cost biosorbents Macrocystis pyrifera and Ulva expansa) was evaluated. DOM decreased the adsorption capacity of toluene, ethylbenzene, and xylenes of the two biosorbents. In contrast, the removal of benzene increased under the same conditions in single and multi-solute systems: this effect was dominant in U. expansa biomass treatments. In the presence of DOM and oil in solutions, the removal of BTEX notoriously increased, being oil that contributed the most. Solubility and hydrophobicity of pollutants played a key role in the adsorption process. The attractions between BTEX molecules and biosorbents were governed by pi-pi and hydrophobic interactions. Affinities of biosorbents for BTEX were mainly in the order of X > E > T > B. The Langmuir and Sips equations adjusted the adsorption isotherms for BTEX biosorption in deionized and natural water samples, but in the case of oily systems, the Freundlich equation seemed to have a better fit. The biosorption processes followed a pseudo-second-order rate in all the cases. PMID- 28721624 TI - On the successful use of a simplified model to simulate the succession of toxic cyanobacteria in a hypereutrophic reservoir with a highly fluctuating water level. AB - Many freshwater bodies worldwide that suffer from harmful algal blooms would benefit for their management from a simple ecological model that requires few field data, e.g. for early warning systems. Beyond a certain degree, adding processes to ecological models can reduce model predictive capabilities. In this work, we assess whether a simple ecological model without nutrients is able to describe the succession of cyanobacterial blooms of different species in a hypereutrophic reservoir and help understand the factors that determine these blooms. In our study site, Karaoun Reservoir, Lebanon, cyanobacteria Aphanizomenon ovalisporum and Microcystis aeruginosa alternatively bloom. A simple configuration of the model DYRESM-CAEDYM was used; both cyanobacteria were simulated, with constant vertical migration velocity for A. ovalisporum, with vertical migration velocity dependent on light for M. aeruginosa and with growth limited by light and temperature and not by nutrients for both species. The model was calibrated on two successive years with contrasted bloom patterns and high variations in water level. It was able to reproduce the measurements; it showed a good performance for the water level (root-mean-square error (RMSE) lower than 1 m, annual variation of 25 m), water temperature profiles (RMSE of 0.22-1.41 degrees C, range 13-28 degrees C) and cyanobacteria biomass (RMSE of 1-57 MUg Chl a L-1, range 0-206 MUg Chl a L-1). The model also helped understand the succession of blooms in both years. The model results suggest that the higher growth rate of M. aeruginosa during favourable temperature and light conditions allowed it to outgrow A. ovalisporum. Our results show that simple model configurations can be sufficient not only for theoretical works when few major processes can be identified but also for operational applications. This approach could be transposed on other hypereutrophic lakes and reservoirs to describe the competition between dominant phytoplankton species, contribute to early warning systems or be used for management scenarios. PMID- 28721625 TI - Key indicator tools for shallow slope failure assessment using soil chemical property signatures and soil colour variables. AB - Slope failure has become a major concern in Malaysia due to the rapid development and urbanisation in the country. It poses severe threats to any highway construction industry, residential areas, natural resources and tourism activities. The extent of damages that resulted from this catastrophe can be lessened if a long-term early warning system to predict landslide prone areas is implemented. Thus, this study aims to characterise the relationship between Oxisols properties and soil colour variables to be manipulated as key indicators to forecast shallow slope failure. The concentration of each soil property in slope soil was evaluated from two different localities that consist of 120 soil samples from stable and unstable slopes located along the North-South Highway (PLUS) and East-West Highway (LPT). Analysis of variance established highly significant difference (P < 0.0001) between the locations, the total organic carbon (TOC), soil pH, cation exchange capacity (CEC), soil texture, soil chromaticity and all combinations of interactions. The overall CIELAB analysis leads to the conclusion that the CIELAB variables lightness L*, c* (Chroma) and h* (Hue) provide the most information about soil colour and other related soil properties. With regard to the relationship between colour variables and soil properties, the analysis detected that soil texture, organic carbon, iron oxide and aluminium concentration were the key factors that strongly correlate with soil colour variables at the studied area. Indicators that could be used to predict shallow slope failure were high value of L*(62), low values of c* (20) and h* (66), low concentration of iron (53 mg kg-1) and aluminium oxide (37 mg kg 1), low soil TOC (0.5%), low CEC (3.6 cmol/kg), slightly acidic soil pH (4.9), high amount of sand fraction (68%) and low amount of clay fraction (20%). PMID- 28721626 TI - Fate of antimicrobial resistance genes in response to application of poultry and swine manure in simulated manure-soil microcosms and manure-pond microcosms. AB - This study aimed to determine the occurrence, abundance, and fate of nine important antimicrobial resistance genes (ARGs) (sul1, sul2, tetB, tetM, ermB, ermF, fexA, cfr, and Intl1) in the simulated soil and pond microcosms following poultry and swine manure application. Absolute quantitative PCR method was used to determine the gene copies. The results were modeled as a logarithmic regression (N = mlnt + b) to explore the fate of target genes. Genes sul1, Intl1, sul2, and tetM had the highest abundance following the application of the two manure types. The logarithmic regression model fitted the results well (R 2 values up to 0.99). The reduction rate of all genes (except for the genes fexA and cfr) in manure-pond microcosms was faster than those in manure-soil microcosms. Importantly, sul1, intl1, sul2, and tetM had the lowest reduction rates in all the samples and the low reduction rates of tetM was the first time to be reported. These results indicated that ARG management should focus on using technologies for the ARG elimination before the manure applications rather than waiting for subsequent attenuation in soil or water, particularly the ARGs (such as sul1, intl1, sul2, and tetM investigated in this study) that had high abundance and low reduction rate in the soil and water after application of manure. PMID- 28721627 TI - Two Chinese pedigrees of Blau syndrome with thirteen affected members. AB - Blau syndrome (BS) is a rare autosomal dominant autoinflammatory disease characterized by the clinical triad of dermatitis, arthritis, and uveitis. It is caused by mutations in nucleotide-binding oligomerization domain-containing protein-2 (NOD2) gene. BS has been widely reported in Caucasians but cases documented in China are scarce. We reported two Chinese families with BS, which were by far the two largest pedigrees in the Chinese population. We identified two unrelated families with BS. The phenotypes and genotypes of these patients were reviewed and compared with previous cohorts. The proband of the first family was a 32-year-old Chinese Han woman, who had dermatitis, polyarthritis, and intermittent fever since the age of 6, bilateral panuveitis since 12. During her disease course, she lost her vision and developed hand flexion contractures. The proband of the second family was a 36-year-old Chinese Han woman, who had dermatitis and bilateral panuveitis since the age of 7, persistent polyarthritis since 13. Additional 7 and 4 family members were affected in the first and second families, respectively, and pedigree analysis suggested autosomal dominant inheritance. Genetic testing in both families identified the heterozygous c.1000 C > T, R334W mutation in NOD2 gene. Only one patient had recurrent fever as an expanded manifestation beyond the classical triad. BS can occur in multiple ethnic groups including the Chinese Han population. Our 11 adult patients constituted the largest adult cohort of BS ever reported in China. Lack of recognition of BS led to a significant delay in diagnosis. A considerable percentage of patients did not demonstrate the full spectrum of the classical triad, further complicating the diagnosis. PMID- 28721628 TI - Disease activity, handgrip strengths, and hand dexterity in patients with rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is a chronic inflammatory disease affecting the hand joints and leading to impairment in hand functions. Evaluation of functional impairment is necessary for assessing patient's quality of life, disease activity, and treatment outcome. To date, many scientific studies assessed the disease activity of patients with RA, but little attention has been carried out to assess these patients' hand functions and dexterity. The purposes of this study were to determine the clinical relevance of the Quick Disabilities of the Arm, Shoulder, and Hand (QuickDASH), hand dexterity with the Purdue Pegboard Test (PPT), and handgrip strength and pinch strengths of RA patients and to look into their relation between each other. A prospective trial was performed in women with RA who were followed at the physical medicine and rehabilitation department of our university hospital. Eighty-two women between the ages of 18 and 70, with a diagnosis of RA according to the 2010 American College of Rheumatology/the European League Against Rheumatism (ACR/EULAR) criterion, were recruited to the study. The Disease Activity Scores were determined by using Disease Activity Score-28 (DAS-28). Handgrip strength was measured with a Jamar dynamometer, and lateral, palmar, and tip pinch strengths were measured by a pinchmeter. Hand functions were evaluated with the PPT, and functional outcomes were assessed with the QuickDASH questionnaire. The mean age of the study group was 49.27 +/- 10.69 years. The average values of DAS-28 and the QuickDASH values were found to be 4.22 +/- 1.28 and 38.33 +/- 19.78, consecutively. High correlation was observed between DAS-28 and the QuickDASH values (p < 0.001). The mean grip strengths in both hands were significantly correlated with the QuickDASH values (p < 0.001), and also, DAS-28 values were very significantly correlated with the mean grip strength in the dominant hand (p < 0.001) and in the nondominant hand (p < 0.01). The mean lateral pinch strengths in both hands were correlated statistically significantly with DAS-28 and the QuickDASH scores (p < 0.001). The mean tip pinch strengths in both hands were correlated with DAS-28 scores, but correlation with the QuickDASH scores was seen just in the dominant hand (p < 0.05). There was no correlation between palmar pinch strengths in both hands with the DAS-28 and QuickDASH scores (p > 0.05). DAS-28 was correlated with PPT performance on the dominant hand (p < 0.05), but there was no correlation with the nondominant hand, both hands, and assembly (p > 0.05). The QuickDASH values were not correlated with all PPT performances (p > 0.05). Handgrip strengths of both hands were positively correlated with the PPT performances (p < 0.05). In conclusion, we determined that handgrip strengths were significantly related to disability and disease activity in the RA patients in our study. The QuickDASH is practical to use in clinical practice, and positively correlates with the disease activity. Dexterity measurements with PPT in the RA patient group were found practical and effective in our study. As a result, we can suggest using QuickDASH questionnaire for functional outcomes, handgrip strength measurements for assessment of hand disability and functional impairments, and also dexterity measurements even in patients with low disease activity. PMID- 28721630 TI - In Situ Salification in Polar Solvents: a Paradigm for Enabling Drug Delivery of Weakly Ionic Drugs as Amorphous Solid Dispersion. AB - Solubility challenge for a poorly water-soluble drug gets further intensified when it is weakly ionic because the most common solubility enhancement technique, salt formation, becomes less feasible. Salt screening for such drugs often concludes with either a difficult to crystalize salt or an unstable salt, leading the scientists to explore other solubility enhancement technique like amorphous solid dispersions which is comparatively costlier, time-consuming and may require use of hazardous organic solvents. Present study evaluated in situ salification in polar protic solvents for dissolving poorly water-soluble drug Itraconazole which is weakly ionic and not very amenable to formation of stable inorganic salts. Through systematic selection of solvents, counterions and polymers, an amorphous solid dispersion of drug salt was obtained. In vitro characterizations with polarized light microscopy (PLM), modulated differential scanning calorimetry (mDSC), Fourier transform infrared spectroscopy (FTIR) and X-ray powder diffraction (XRD) confirmed the physical and chemical stability of the amorphous solid dispersion. In vivo pharmacokinetic study showed that the drug salt amorphous solid dispersion achieved 45 times higher plasma exposure compared to crystalline drug. This study provides one of the first data sets for the hypothesis that in situ drug salts can be utilized for manufacturing amorphous solid dispersions of weakly ionic drugs and leverages the solubility advantage of salts and amorphous state. PMID- 28721629 TI - EphA3 targeting reduces in vitro adhesion and invasion and in vivo growth and angiogenesis of multiple myeloma cells. AB - PURPOSE: Multiple myeloma (MM) is a hematologic malignancy characterized by a clonal expansion of plasma cells (PCs) in the bone marrow (BM). Since MM has so far remained incurable, further insights into its pathogenesis and the concomitant identification of new therapeutic targets are urgently needed. The tyrosine kinase receptor EphA3 is known to be involved in various cellular processes including cell viability, cell movement and cell-cell interactions. Recently, EphA3 has emerged as a potential therapeutic target in several hematologic and solid tumors. Here, we aimed to uncover the role of EphA3 in MM. METHODS: EphA3 mRNA and protein expression in primary MM bone marrow plasma cells (BMPCs), in MM-derived cell lines and in healthy controls (HCs) was assessed using qRT-PCR, Western blotting and flow cytometry. The effects of siRNA-mediated EphA3 silencing and anti EphA3 antibody (EphA3mAb) treatment on MM PC trafficking and viability were evaluated using in vitro assays. The effects of EphA3mAb treatment were also assessed in two MM-derived mouse xenograft models. RESULTS: We found that EphA3 was overexpressed in primary MM BMPCs and MM-derived cell lines compared to HCs. We also found that siRNA-mediated EphA3 silencing and EphA3mAb treatment significantly inhibited the ability of MM PCs to adhere to fibronectin and stromal cells and to invade in vitro, without affecting cell proliferation and viability. Gene expression profiling showed that EphA3 silencing resulted in expression modulation of several molecules that regulate adhesion, migration and invasion processes. Importantly, we found that EphA3mAb treatment significantly inhibited in vivo tumor growth and angiogenesis in two MM derived mouse xenograft models. CONCLUSIONS: Our findings suggest that EphA3 plays an important role in the pathogenesis of MM and provide support for the notion that its targeting may represent a novel therapeutic opportunity for MM. PMID- 28721631 TI - 1-Trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo) Alters Cell Cycle Progression in Human Neuroblastoma Cell Lines. AB - 1-Trichloromethyl-1,2,3,4-tetrahydro-beta-carboline, abbreviated as TaClo, is an endogenous neurotoxin capable of formation in the brain through the condensation of neuronal tryptamine with ingested exogenous toxins such as trichloroethylene or chloral hydrate. Due to its structural resemblance to 1-methyl-4-phenyl 1,2,5,6-tetrahydropyridine (MPTP), and similar ability to inhibit mitochondrial complex I, TaClo has been implicated in the etiology of Parkinson's disease. Previous studies have shown the cytotoxicity of TaClo in various cell culture models. In this study, we were interested in identifying the early molecular events within the cell upon exposure to TaClo, a potent mitochondrial toxin. We found increased phosphorylation of 5'-adenosine monophosphate-activated protein kinase (AMPK), induction of autophagy, and a dependence on glycolysis as some of the downstream events to TaClo treatment. Furthermore, TaClo-treated cells undergo accelerated late proliferation but form daughter cells containing fewer neurites, leading to their eventual apoptosis. We also found that TaClo inhibits neuronal prostaglandin E2 synthesis which may play an important role in synaptic plasticity. These results show that TaClo-mediated inhibition of mitochondrial complex I have multiple effects on cellular physiology which are in line with other mitochondrial effectors of Parkinson's disease. PMID- 28721632 TI - Detection and characterization of three zoonotic viruses in wild rodents and shrews from Shenzhen city, China. AB - Diverse species of rodents and shrews, which are abundant worldwide, harbor a variety of viruses; some of these are closely related to human viruses and possess zoonotic potential. Previously studies have demonstrated that the mammarenavirus and hantavirus carried by rodents or shrews could cause diseases in human population. To determine the distribution of zoonotic viruses in Shenzhen city, the major city in southern China with a high population density, we analyzed 225 rodents (Rattus norvegicus and Rattus flavipectus) and 196 shrews (Suncus murinus) from urban and rural districts for the presence of mammarenavirus, hantavirus, and hepatitis E virus (HEV) by RT-PCR targeting the conserved regions. The infection rates for mammarenavirus, hantaviruses, and HEV in rodents and shrews were 3.56%, 6.89%, and 1.66%, respectively. Partial genome fragment analysis indicated that mammarenavirus and hantavirus strains had more than 90% and 99% nucleic acid identity with Cardamones virus and Seoul virus, respectively, which cause diseases in humans. Although the present HEV strains identified are typically found worldwide, phylogenetic analysis demonstrated a divergence of 16%. To our knowledge, the present work is the first report of the prevalence of mammarenavirus, hantaviruses, and rat HEV strains in rodents and shrews from Shenzhen city, China. Our findings highlight the zoonotic potential of rodent- and shrew-borne mammarenavirus and hantavirus, and the biodiversity of rat HEV isolates in Shenzhen city. The present work suggests that utilization of good hygiene habits is important to minimize the risk of zoonosis. PMID- 28721633 TI - Erratum to: Exogenous GDF11 induces cardiac and skeletal muscle dysfunction and wasting. PMID- 28721634 TI - Minimally invasive abdominal cerclage compared to laparotomy: a comparison of surgical and obstetric outcomes. AB - The objective of this study is to report surgical and obstetric outcomes of patients following abdominal cerclage placement through either minimally invasive or open techniques. Subjects of this retrospective cohort study were patients at two referral centers specializing in high-risk pregnancy and minimally invasive gynecologic surgery. Electronic medical records of all patients who underwent abdominal cerclage placement between December 2011 and December 2015 at Yale New Haven Hospital and Bridgeport Hospital were reviewed. The patients included were women who underwent abdominal cerclage placement either during pregnancy or prior to conception. One cohort of women had their abdominal cerclage placed using traditional laparoscopy or robotic-assisted laparoscopy. The other cohort consisted of women whose abdominal cerclage was placed through laparotomy. Electronic medical charts were reviewed to collect baseline demographic and pre procedure obstetric information, as well as surgical and subsequent obstetric outcomes. Eleven minimally invasive and nine open abdominal cerclages were performed during the study period. Seven of the minimally invasive and two open cerclages were done outside of pregnancy. Average operative time was longer in the minimally invasive cohort. Estimated blood loss was typically lower in the minimally invasive group. Length of hospital stay was shorter in the minimally invasive group. Obstetric outcomes were similar between the two cohorts, with a total of nine live births in the minimally invasive group and seven live births in the open group. Minimally invasive abdominal cerclage is a safe alternative when performed by a surgeon with appropriate training and technical skills, and obstetric outcomes are comparable to those after open abdominal cerclage. PMID- 28721635 TI - Causative factors for de novo inguinal hernia after robot-assisted radical prostatectomy. AB - To determine causative factors for de novo inguinal hernia (IH), after robot assisted radical prostatectomy (RARP). This was a retrospective, single-center study, which included patients undergoing RARP for prostate cancer at our institution, from February 2012 to January 2015. Cox proportional hazards models were used to determine the relationships between de novo IH and various factors. A total of 284 patients were included in the analysis. Forty-two (14.7%) patients developed IH at a median period of 8 months after RARP. On multivariate analysis, preoperative international prostate symptom score question 6 > 2, and a patent processus vaginalis were significantly correlated with de novo IH (hazard ratio (HR) 4.17, 95% confidence interval (CI) 2.07-8.37, p < 0.001; HR 3.67, 95% CI 2.36-5.69, p < 0.001). Preoperative urinary straining and a patent processus vaginalis were predictive of de novo IH after RARP. PMID- 28721636 TI - Robotic colorectal surgery: previous laparoscopic colorectal experience is not essential. AB - A background in minimally invasive colorectal surgery (MICS) has been thought to be essential prior to robotic-assisted colorectal surgery (RACS). Our aim was to determine whether MICS is essential prior to starting RACS training based on results from our initial experience with RACS. Two surgeons from our centre received robotic training through the European Academy of Robotic Colorectal Surgery (EARCS). One surgeon had no prior formal MICS training. We reviewed the first 30 consecutive robotic colorectal procedures from a prospectively maintained database between November 2014 and January 2016 at our institution. Fourteen patients were male. Median age was 64.5 years (range 36-82) and BMI was 27.5 (range 20-32.5). Twelve procedures (40%) were performed by the non-MICS trained surgeon: ten high anterior resections (one conversion), one low anterior resection and one abdomino-perineal resection of rectum (APER). The MICS-trained surgeon performed nine high and four low anterior resections, one APER and in addition three right hemicolectomies and one abdominal suture rectopexy. There were no intra-operative complications and two patients required re-operation. Median post-operative stay was five days (range 1-26). There were two 30-day re admissions. All oncological resections had clear margins and median node harvest was 18 (range 9-39). Our case series demonstrates that a background in MICS is not essential prior to starting RACS training. Not having prior MICS training should not discourage surgeons from considering applying for a robotic training programme. Safe and successful robotic colorectal services can be established after completing a formal structured robotic training programme. PMID- 28721637 TI - Cost of hospitalization for firearm injuries by firearm type, intent, and payer in the United States. AB - BACKGROUND: Firearm injuries disproportionately affect young, male, non-White populations, causing substantial individual and societal burden. Annual costs for hospitalized firearm injuries have not been widely described, as most previous cost studies have focused on lifetime costs. We examined a nationally representative database of hospitalizations in the US to estimate per-hospital and overall hospital costs for firearm injuries by intent, type of weapon, and payer source. METHODS: We conducted a retrospective cohort study of all firearm injury hospitalizations in the National Inpatient Sample from 2003 through 2013. The National Inpatient Sample, maintained by the Healthcare Utilization Project, is a stratified and weighted national sample of more than 20% of all hospitals. All admissions for firearm injuries were identified through Ecodes, yielding a weighted total of 336,785 for the study period. Average annual per-patient and overall hospital costs were estimated using generalized linear modelling, controlling for patient and hospital variables. Costs by intent, firearm type, and payer sources were estimated. RESULTS: Annually from 2003 through 2013, 30,617 hospital admissions were for firearm injuries, for an annual rate of 10.1 admissions per 100,000 US population. More than 80% of hospitalizations were among individuals aged 15-44, and rates were nine times higher for males than females and nearly ten times higher for the Black than the White population. More than 60% of admissions were for assaults, and 70% of the injuries that had a known firearm type were from handguns. The average annual admission cost was $622 million. The highest per-admission costs were for injuries from assault weapons ($32,237 per admission) and for legal intervention ($33,462 per admission), but the highest total costs were for unspecific firearm type ($373 million) and assaults ($389 million). A quarter of firearm injury hospitalizations were among the uninsured, yielding average annual total costs of $155 million. CONCLUSION: Hospitals can project that government insurance will be the highest source for firearm injury reimbursement, and depending on healthcare access laws, that many of their firearm injury admissions will not be covered by insurance. PMID- 28721638 TI - Contribution of echocardiography in the diagnosis of definitive infective endocarditis: the infectious disease specialist's point of view. AB - In 1994, the original Duke criteria introduced the usefulness of echocardiography for the diagnosis of definitive infective endocarditis (IE). Recently, the European Society of Cardiology (ESC) highlighted the need of complementary imaging to support the diagnosis of embolic events and cardiac involvement when echocardiography findings are negative or doubtful. We decided to study the usefulness of transthoracic and transesophageal echocardiography (TTE/TEE) for the diagnosis of definitive IE in patients who already benefited from complementary investigations. A retrospective bicentric study was conducted among patients hospitalized for an IE (2006-2017). Modified Duke criteria were calculated for each patient before and after findings of TTE/TEE. Thereafter, patients were classified by the local task force into three groups: excluded, possible, and definitive IE. Overall, 86 episodes were studied. The median patient age was 72 years (18-95). Microorganisms involved were mostly Staphylococcus aureus (32.5%) and Streptococcus spp. (40.7%). The mortality rate was 17.4%. Before echocardiography, there were 3 excluded IE (3.5%), 51 possible IE (59.3%), and 32 definitive IE (37.2%). After echocardiography findings, we observed 62 definitive (72.1%) and 24 possible IE (27.9%) (p < 0.0001). Our cohort revealed that 19.8% of the definitive and possible IE had a normal echocardiography. The rate of septic emboli did not statistically differ between patients who had a contributive or a normal echocardiography (76.5% vs. 76.8%). TTE and TEE play a major role in the diagnosis of definitive IE, even if we consider findings of complementary imaging. Physicians should be wary that definitive IE may present with a non-contributive echocardiography, mentioned as normal. PMID- 28721639 TI - Erratum to: Frequency of germline DNA genetic findings in an unselected prospective cohort of triple-negative breast cancer patients participating in a platinum-based neoadjuvant chemotherapy trial. PMID- 28721640 TI - Erratum to: World Map of Scientific Misconduct. PMID- 28721641 TI - Attributing Agency to Automated Systems: Reflections on Human-Robot Collaborations and Responsibility-Loci. AB - Many ethicists writing about automated systems (e.g. self-driving cars and autonomous weapons systems) attribute agency to these systems. Not only that; they seemingly attribute an autonomous or independent form of agency to these machines. This leads some ethicists to worry about responsibility-gaps and retribution-gaps in cases where automated systems harm or kill human beings. In this paper, I consider what sorts of agency it makes sense to attribute to most current forms of automated systems, in particular automated cars and military robots. I argue that whereas it indeed makes sense to attribute different forms of fairly sophisticated agency to these machines, we ought not to regard them as acting on their own, independently of any human beings. Rather, the right way to understand the agency exercised by these machines is in terms of human-robot collaborations, where the humans involved initiate, supervise, and manage the agency of their robotic collaborators. This means, I argue, that there is much less room for justified worries about responsibility-gaps and retribution-gaps than many ethicists think. PMID- 28721642 TI - A Social Responsibility Guide for Engineering Students and Professionals of all Faith Traditions: An Overview. AB - The development of the various themes of Catholic Social Teaching (CST) is based on numerous papal documents and ecclesiastical statements. While this paper provides a summary of a number of these documents, this paper focuses on two themes: the common good and care of the environment, and on three documents authored by Pope John Paul II in 1990, by Pope Benedict XVI in 2010, and by Pope Francis in 2015. By analyzing these documents from an engineer's perspective, the author proposes a model for Socially Responsible Engineering. The proposed model is intended to serve as a guide for engineering students and practicing engineers of all faith traditions and to those with no faith tradition at all who wish to incorporate CST in the daily conduct of their personal and professional lives; to provide guidance for the professional the author terms the aspiring Socially Responsible Engineer; and to offer engineers a preferred alternative to the undesirable aspects of the technocratic paradigm. While intended primarily for engineers, this document also serves as a guide for those with expertise in social justice and who, by gaining a better understanding of the thought processes of engineers, can become better mentors for engineering students and practicing engineers seeking to incorporate CST into their daily lives. PMID- 28721643 TI - The Scientific Self: Reclaiming Its Place in the History of Research Ethics. AB - How can the history of research ethics be expanded beyond the standard narrative of codification-a story that does not reach back beyond World War II-without becoming so broad as to lose all distinctiveness? This article proposes a history of research ethics focused on the "scientific self," that is, the role-specific identity of scientists as typically described in terms of skills, competencies, qualities, or dispositions. Drawing on three agenda-setting texts from nineteenth century history, biology, and sociology, the article argues that the "revolutions" these books sought to unleash were, among other things, revolts against inherited conceptions of scientific selfhood. They tried to redefine the scientific self in their respective fields of inquiry by advocating particular catalogs of virtues or character traits. These ideals of selfhood, their contested nature notwithstanding, translated into practice in so far as they influenced hiring and selection policies and found their way into educational systems. The project of reclaiming the scientific self as an important subject of study in the history of research ethics is not an antiquarian pursuit, but related to an ethical question faced by scientists today: How are their scientific selves being shaped by funding schemes, research evaluation protocols, and academic hiring policies? PMID- 28721644 TI - Understanding Engineers' Responsibilities: A Prerequisite to Designing Engineering Education : Commentary on "Educating Engineers for the Public Good Through International Internships: Evidence from a Case Study at Universitat Politecnica de Valencia". AB - The development of the curriculum for engineering education (course requirements as well as extra-curricular activities like study abroad and internships) should be based on a comprehensive understanding of engineers' responsibilities. The responsibilities that are constitutive of being an engineer include striving to fulfill the standards of excellence set by technical codes; to improve the idealized models that engineers use to predict, for example, the behavior of alternative designs; and to achieve the internal goods such as safety and sustainability as they are reflected in the design codes. Globalization has implications for these responsibilities and, in turn, for engineering education, by, for example, modifying the collection of possible solutions recognized for existing problems. In addition, international internships can play an important role in fostering the requisite moral imagination of engineering students. PMID- 28721645 TI - Is Cancer Information Exchanged on Social Media Scientifically Accurate? AB - Cancer patients and their caregivers are increasingly using social media as a platform to share cancer experiences, connect with support, and exchange cancer related information. Yet, little is known about the nature and scientific accuracy of cancer-related information exchanged on social media. We conducted a content analysis of 12 months of data from 18 publically available Facebook Pages hosted by parents of children with acute lymphoblastic leukemia (N = 15,852 posts) and extracted all exchanges of medically-oriented cancer information. We systematically coded for themes in the nature of cancer-related information exchanged on personal Facebook Pages and two oncology experts independently evaluated the scientific accuracy of each post. Of the 15,852 total posts, 171 posts contained medically-oriented cancer information. The most frequent type of cancer information exchanged was information related to treatment protocols and health services use (35%) followed by information related to side effects and late effects (26%), medication (16%), medical caregiving strategies (13%), alternative and complementary therapies (8%), and other (2%). Overall, 67% of all cancer information exchanged was deemed medically/scientifically accurate, 19% was not medically/scientifically accurate, and 14% described unproven treatment modalities. These findings highlight the potential utility of social media as a cancer-related resource, but also indicate that providers should focus on recommending reliable, evidence-based sources to patients and caregivers. PMID- 28721646 TI - Non-invasive measures of coronary microcirculation: Taking the long road to the clinic. AB - Although coronary microvascular disease is now a well-recognized entity that is associated with significant morbidity and mortality, current non-invasive strategies cannot differentiate between coronary microvascular disease (CMD) and obstructive epicardial stenosis. While the evaluation of intramyocardial blood volume as a surrogate measure for microvascular health may have limited sensitivity in early-stage disease, this strategy does enable the diagnosis of CMD in the presence of concurrent epicardial disease, bringing us one step further toward improving the management of this disease. Herein, we discuss the advantages and limitations of current non-invasive measures of CMD and the need for further investment in bringing these technologies to the bedside. PMID- 28721647 TI - Rubidium-82 PET imaging is feasible in a rat myocardial infarction model. AB - BACKGROUND: Small-animal myocardial infarct models are frequently used in the assessment of new cardioprotective strategies. A validated quantification of perfusion using a non-cyclotron-dependent PET tracer would be of importance in monitoring response to therapy. We tested whether myocardial PET perfusion imaging is feasible with Rubidium-82 (82Rb) in a small-animal scanner using a rat myocardial infarct model. METHODS: 18 Sprague-Dawley rats underwent permanent coronary artery ligation (infarct group), and 11 rats underwent ischemia reperfusion (reperfusion group) procedure. 82Rb-PET and magnetic resonance imaging (MRI) were conducted before and after the intervention. Perfusion was compared to both left ventricle ejection fraction (LVEF) and infarct size assessed by MRI. RESULTS: Follow-up global 82Rb-uptake correlated significantly with infarct size (infarct group: r = -0.81, P < 0.001 and reperfusion group: r = -0.61, P = 0.04). Only 82Rb-uptake in the infarct group correlated with LVEF. At follow-up, a higher segmental 82Rb-uptake in the infarct group was associated with better wall motion (beta = 0.034, CI [0.028;0.039], P < 0.001, R 2 = 0.30), and inversely associated with scar transmurality (beta = -2.4 [-2.6; -2.2], P < 0.001, R 2 = 0.59). The associations were similar for the reperfusion group. CONCLUSION: 82Rb-PET is feasible in small animal scanners despite the long positron range and enables fast and time-efficient myocardial perfusion imaging in rat models. PMID- 28721648 TI - Recall of Prenatal Counselling Among Obese and Overweight Women from a Canadian Population: A Population Based Study. AB - Objective The objective of this study was to evaluate the recall of prenatal counselling received among overweight and obese women in primary care settings. Methods A sample of 1996 women with singleton, term deliveries and pre-pregnancy BMI >18.5 kg/m2 were identified from the All Our Babies pregnancy cohort. Information on socio-demographic characteristics and women's experiences with prenatal counselling on nutrition, vitamin and mineral supplements, exercise, weight gain, employment, alcohol and drug use, and smoking during pregnancy were collected through questionnaires administered at <25 weeks and 34-36 weeks gestation. Multivariable logistic regression analyses explored the associations between pre-pregnancy BMI and the domains of prenatal counselling, controlling for confounders. Results Women reported high levels of comfort asking questions and satisfaction with their health care provider. Women reported getting information about nutrition (69.3%), weight gain (67.8%), exercise (64.4%), vitamins and minerals supplementation (86.1%). Obese women (211, 10.6%) were more likely than normal weight women (1313, 65.8%) to be Caucasian (p = 0.004), less educated (p = 0.001), and to have been born or lived in Canada for at least 5 years (p = 0.01). There was no difference in the prenatal advice received on nutrition, weight gain and exercise in pregnancy between obese, overweight, and normal weight women. Conclusions for Practice Pre-pregnancy BMI did not appear to influence the recall of prenatal counselling women receive in community health care centers. Given the importance of nutrition and weight gain during pregnancy, and guidelines for weight gain based on pre-pregnancy BMI, there are missed opportunities in knowledge exchange between women and providers in the prenatal period. PMID- 28721649 TI - Health-Related Quality of Life for Women Ever Experiencing Infertility or Difficulty Staying Pregnant. AB - INTRODUCTION: Information on the health-related quality of life (HRQOL) for women with infertility is limited and does not account for the co-occurrence of chronic conditions or emotional distress. METHODS: We used data from state-added questions on reproductive health included in the 2013 Behavioral Risk Factor Surveillance System in seven states. HRQOL indicators included: self-reported health status; number of days in the past 30 days when physical and mental health was not good; number of days in the past 30 days that poor physical or mental health limited activities. We computed rate ratios for HRQOL for women ever experiencing infertility or difficulty staying pregnant compared with women never reporting these conditions; interactions with chronic conditions and depressive disorders were assessed. RESULTS: Of 7,526 respondents aged 18-50 years, 387 (4.9%) reported infertility only and 339 (4.3%) reported difficulty staying pregnant only. Infertility was associated with an increase in average number of days with poor physical health for women with chronic conditions [rate ratio (RR) 1.85, 95% confidence interval (CI) 1.04-3.29] but was protective for women without chronic conditions (RR 0.47, 95% CI 0.29-0.75). Difficulty staying pregnant was associated with an increase in average number of days of limited activity among both women with chronic conditions (RR 2.14, 95% CI 1.32-3.45) and women with depressive disorders (RR 1.72 95% CI 1.14-2.62). DISCUSSION: Many HRQOL measures were poorer for women who had infertility or difficulty staying pregnant compared to their counterparts; the association was modified by presence of chronic conditions and depressive disorders. PMID- 28721650 TI - Prediction of pulmonary metastasis in pulmonary nodules (<=10 mm) detected in patients with primary extrapulmonary malignancy at thin-section staging CT. AB - PURPOSE: To investigate the predictive clinical and imaging factors associated with pulmonary metastasis in pulmonary nodules (PNs) <=10 mm in patients with primary extrapulmonary malignancy (PEPM) on initial CT as well as the inter nodular imaging features in the non-solitary PNs patients, to make a more reliable diagnosis and appropriate management of the PNs at an earlier stage after detection. MATERIALS AND METHODS: 161 patients with PNs <=10 mm were reviewed from April 2013 to December 2013. The nature of PNs were determined on the interval change in imaging features on serial CT images (158 patients) and histologically proven (three patients). Independent predictors of changed PNs on initial CT were examined by multivariate regression analysis. RESULTS: 36.6% of patients developed interval change in nodules size. The average interval of the first change was 65.0 days (29-144 days). Tumor staging of III (P = 0.011) and IV (P < 0.001), the nodules number of 2-4 (P = 0.016), 5-9 (P < 0.001) and 10-20 (P < 0.001), the nodules margin of being smooth (P = 0.001) and slight lobulated (P < 0.001), and nodules with no near short strips (P = 0.001) were significant predictors of changed PNs. For patients with non-solitary PNs, 40.2% had PNs with identical imaging features, the incidence rate of change of which (74.3%) was significantly higher compared with that of varied features (32.7%), P < 0.001; and 94.3% of patients had all nodules per patient showing consistent prognosis. CONCLUSIONS: For PNs <=10 mm in patients with PEPM on baseline CT, the morphological characteristics and primary malignancies stage could differentiate the majority of the PNs. The interval for further CT evaluation of uncertain PNs should be early at 1-3 months after detection, and increased alert is needed for the possibility of pulmonary metastasis when an early interval change was detected. PMID- 28721651 TI - In Vitro Anti-inflammatory and Antioxidant Activities of 3,5,4'-Trihydroxy-6,7 Methylenedioxyflavone-O-Glycosides and Their Aglycone from Leaves of Polygonum tinctorium Lour. AB - Polygonum tinctorium Lour (indigo plant) has been regarded as a useful medicinal plant for traditional herbal medicine. The polyphenolic fraction of indigo leaves exhibited anti-inflammatory activities as determined by the suppressed synthesis of nitric oxide (NO) in cultured RAW264 macrophage cells. The acid hydrolysate of the fraction showed much more potent effect than the unhydrolyzed one. In sharp contrast, those fractions of indigo stems had almost no effect. 3,5,4'-Trihydroxy 6,7-methylenedioxyflavone (TMF)-O-glycosides and tryptanthrin were detected exclusively in the extracts of the leaves. The isolated flavonol species were furthermore tested for their anti-inflammatory activities against the synthesis of NO and prostaglandin E2 in the cultured macrophage cells. More potent anti inflammatory effects were recognized with different aglycones of flavonols than their flavonol O-glycosides. Although the inhibitory effects of TMF were less effective than those of tryptanthrin, the levels of flavonol O-glycosides with TMF were much more abundant than those of tryptanthrin in the leaves. Oral administration of the fraction containing flavonol O-glycosides with TMF into mice revealed the detection of free TMF in the blood circulation, indicating that the aglycone moiety can be cleaved by digestive enzymes and absorbed in the gut. Alternatively, the assay of hydrophilic oxygen radical absorbance capacity revealed that the isolated species of flavonol O-glycosides with TMF and their aglycone had appreciable antioxidant activities. Taken together, our findings suggest that the predominant flavonol O-glycosides with TMF as an aglycone could be promising natural agents for the application to herbal medicine, nutraceuticals, and food additives. PMID- 28721652 TI - Effects of Liquid Hot Water Pretreatment on Enzymatic Hydrolysis and Physicochemical Changes of Corncobs. AB - Liquid hot water (LHW) pretreatment is an efficient chemical-free strategy for enhancing enzymatic digestibility of lignocellulosic biomass for conversion to fuels and chemicals in biorefinery. In this study, effects of LHW on removals of hemicelluloses and lignin from corncobs were studied under varying reaction conditions. LHW pretreatment at 160 degrees C for 10 min promoted the highest levels of hemicellulose solubilization into the liquid phase, resulting into the maximized pentose yield of 58.8% in the liquid and more than 60% removal of lignin from the solid, with 73.1% glucose recovery from enzymatic hydrolysis of the pretreated biomass using 10 FPU/g CelluclastTM. This led to the maximal glucose and pentose recoveries of 81.9 and 71.2%, respectively, when combining sugars from the liquid phase from LHW and hydrolysis of the solid. Scanning electron microscopy revealed disruption of the intact biomass structure allowing increasing enzyme's accessibility to the cellulose microfibers which showed higher crystallinity index compared to the native biomass as shown by x-ray diffraction with a marked increase in surface area as revealed by BET measurement. The work provides an insight into effects of LHW on modification of physicochemical properties of corncobs and an efficient approach for its processing in biorefinery industry. PMID- 28721653 TI - Comparison of Flow Cytometry and ELASA for Screening of Proper Candidate Aptamer in Cell-SELEX Pool. AB - Aptamers are single-stranded RNA or DNA, which bind to their target with high affinity and specificity. Method of isolating aptamers against cell surface protein is called cell-SELEX. Common approach for monitoring cell-SELEX developed aptamers is flow cytometry. Since flow cytometry is costly and requires sophisticated equipments, we suggested implementing easy access, high throughput enzyme-link apta-sorbent assay test (ELASA) to confirm the specificity of aptamers selected through cell-SELEX process. In this regard, we compared ELASA and flow cytometry techniques in order to screen potent candidate aptamers against A2780 Rcis cell line, which were selected by cell-SELEX. The obtained results demonstrated that both ELASA and flow cytometry are identical in terms of sensivity and precision for aptamers selection. Then it could be concluded that ELASA method could be used as a versatile, inexpensive procedure for in vito evaluation of isolated aptamers from cell-SELEX based process. PMID- 28721654 TI - C-Reactive Protein Gene Contributes to the Genetic Susceptibility of Hemorrhagic Stroke in Men: a Case-Control Study in Chinese Han Population. AB - High-sensitivity C-reactive protein (hsCRP) is an inflammatory marker for the prediction and prognosis of ischemic stroke but there is an absence of evidence for cerebral hemorrhagic events. The aim of this study is to investigate the effects of elevated plasma hsCRP and CRP genetic variants on hemorrhagic stroke (HS). Two hundred thirty-six inpatients with HS and 993 age-matched controls from a community-based population were included in a case-control study and four tagging single nucleotide polymorphsims (tagSNPs) at CRP were genotyped. The association of hsCRP elevation and CRP variants with HS was evaluated by multiple logistic regression. HS cases had a higher median (interquartile) of hsCRP with 5.40 (1.30-10.7) mg/L and a proportion of hsCRP elevation (>=3 mg/L, 63.4%) than controls [1.20 (0.80-2.20) mg/L, 16.6%], respectively (P < 0.05 for all). No significant difference of genotype or allele frequency of the four SNPs was observed between HS patients and controls (P > 0.05). Further stratified analysis by gender showed that the variants of rs3093059 (T/C) and rs3091244 (C/T/A) were significantly associated with the decreased risk of HS in men and odds ratios (ORs) and 95% confidence intervals (95% CIs) for additive models were 0.515 (0.294-0.903) and 0.578 (0.349-0.96), respectively, after adjusting for covariates. In HS patients, rs3091244 was positively associated with the hsCRP elevation and rs2794521 was negatively associated with hsCRP elevation (P < 0.05). Our findings suggest that hsCRP elevation is associated with the risk of HS and CRP contributes genetic susceptibility to HS in men as well as hsCRP elevation in HS. PMID- 28721655 TI - The Impact of 'Being There': Psychiatric Staff Attitudes on the Use of Restraint. AB - : The practice of mechanically restraining psychiatric patients is constantly under debate, and staff attitudes are considered a central factor influencing restraining practices. The aim of this study was to explore associations between psychiatric staff members' presence and participation in incidences of restraint and attitudes towards mechanical restraints. METHODS: Staff members (psychiatrists, nurses, paramedical staff; N = 143 working in a government psychiatric hospital in Israel) completed a questionnaire including personal information, participation in incidents of restraint and attitudes towards mechanical restraints. Items were categorized into the following categories: security and care; humiliation and offending; control; order; education and punishment. RESULTS: Compared to those who were not present during restraint, staff members who were present agreed significantly less with statements indicating that restraints are humiliating and offending and agreed more with statements indicating that restraints are used primarily for security and care (p < .05). Among those present in incidences of restraint, staff members who physically participated in restraint agreed significantly more with statements indicating that restraints are a means for security, care and order, and less with statements indicating restraints are humiliating and offending, compared to those present but not physically participating in restraint (p < .05). CONCLUSIONS: These findings highlight the importance of proximity of staff members to incidences of restraints. This may have implications in understanding the professional and social discourse concerning mechanical restraints. PMID- 28721656 TI - CircRNA: a novel type of biomarker for cancer. AB - Circular RNAs (circRNAs) are a class of long, non-coding RNAs molecules that shape a covalently closed continuous loop which have no 5'-3' polarity and contain no polyA tail. CircRNAs also possess relatively jarless framework and are highly tissue-specific expressed in the eukaryotic transcriptome. Emerging evidences have discovered that thousands of endogenous circRNAs are present in mammalian cells and they mediate gene expression at the transcriptional or post transcriptional level by binding to microRNAs or other molecules and then inhibit their function. Similarly, increasing evidence indicates that circRNAs may play a role in the development of several types of diseases, including atherosclerotic vascular disease risk, neurological disorders, prion diseases, osteoarthritis and diabetes. Furthermore, circRNAs exhibit aberrant expression in multiform types of cancer, including colorectal cancer, hepatocellular carcinoma and pancreatic ductal adenocarcinoma. And based on the function of circRNAs in cancer, we believe that circRNAs may serve as diagnostic or tumor promising biomarkers. Moreover, it will provide a new therapeutic target for the treatment of cancer. PMID- 28721658 TI - Microbial Communities in Different Tissues of Atta sexdens rubropilosa Leaf cutting Ants. AB - Bacterial endosymbionts are common in all insects, and symbiosis has played an integral role in ant evolution. Atta sexdens rubropilosa leaf-cutting ants cultivate their symbiotic fungus using fresh leaves. They need to defend themselves and their brood against diseases, but they also need to defend their obligate fungus gardens, their primary food source, from infection, parasitism, and usurpation by competitors. This study aimed to characterize the microbial communities in whole workers and different tissues of A. sexdens rubropilosa queens using Ion Torrent NGS. Our results showed that the microbial community in the midgut differs in abundance and diversity from the communities in the postpharyngeal gland of the queen and in whole workers. The main microbial orders in whole workers were Lactobacillales, Clostridiales, Enterobacteriales, Actinomycetales, Burkholderiales, and Bacillales. In the tissues of the queens, the main orders were Burkholderiales, Clostridiales, Syntrophobacterales, Lactobacillales, Bacillales, and Actinomycetales (midgut) and Entomoplasmatales, unclassified gamma-proteobacteria, and Actinomycetales (postpharyngeal glands). The high abundance of Entomoplasmatales in the postpharyngeal glands (77%) of the queens was an unprecedented finding. We discuss the role of microbial communities in different tissues and castes. Bacteria are likely to play a role in nutrition and immune defense as well as helping antimicrobial defense in this ant species. PMID- 28721657 TI - Biological Decolorization and Degradation of Malachite Green by Pseudomonas sp. YB2: Process Optimization and Biodegradation Pathway. AB - A novel strain Pseudomonas sp. YB2, which was isolated from activated sludge, was studied for biological decolorization and degradation of malachite green (MG). The results show that this aerobic strain is an aerobic bacterium, which has relatively high salt tolerance and high antibiotic resistance. The optimal performance condition for both bacterial growth and decolorization of MG was at 25-35 degrees C and pH 5.0-7.0. It could efficiently decolorize 90.40% MG at a high concentration up to 1500 mg/L in 24 h, and concentrations of MG lower than 1000 mg/L could be completely decolorized in 12 h. The intermediate products of MG were detected using gas chromatography-mass spectrometer, including leucomalachite green, 4,4'-bis(dimethylamino) benzophenone, 4-(dimethylamino) benzophenone, phenol, dimethylaniline. The possible degradation pathways of MG by strain YB2 were proposed. This strain might be potentially useful for biodegradation of MG in real environments. PMID- 28721659 TI - Antimicrobial Activity of Selected Polyphenols and Capsaicinoids Identified in Pepper (Capsicum annuum L.) and Their Possible Mode of Interaction. AB - Antimicrobial activity of pepper polyphenols and capsaicinoids (Coumarin, caffeic acid, narangin, kaempferol, rutin, quercetin, capsaicin, and dihydrocapsaicin) against 13 pathogen bacteria and three beneficial strains was studied using the disk diffusion and microdilution methods. In general, phenolic compounds had the most important activity with the highest inhibition zones obtained with caffeic acid (3.5-20.5 mm), quercetin (4.75-3.5 mm), and kaempferol (7-14 mm). In the determination of the minimal inhibitory concentrations, the effects of both quercetin and kaempferol were more important than caffeic acid. The clinical strains Staphylococcus aureus (319, 14, 8, 32, and 550) were more sensitive to quercetin (0.00195-0.0078 mg L-1) whereas kaempferol was more active against the strains S. aureus (ATCC 6538, 26), S. typhimurium ATCC 13311, and Pseudomonas aeruginosa ATCC 27853 (0.0156-0.125 mg L-1). The interaction between these three polyphenols was studied against S. aureus ATCC 6538 and P. aeruginosa ATCC 27853. Different modes of interaction were observed (synergism, additive, and indifferent), but no antagonism was obtained. The best combination was quercetin and caffeic acid for S. aureus with fractional inhibitory concentration index (FICI) of 0.37, and kaempferol with quercetin for P. aeruginosa (FICI = 0.31). PMID- 28721660 TI - Clinicopathologic and Molecular Characteristics of Familial Cherubism with Associated Odontogenic Tumorous Proliferations. AB - Cherubism is a rare autosomal dominant condition affecting the jaws and caused by mutations in the gene encoding for the adapter protein SH3BP2 that maps to chromosome 4p16.3. Cherubism is characterized by symmetrically developing bone lesions in the maxilla and mandible. The lesions have been radiographically and histopathologically well-described. Here, we present a family with cherubism with two of its members featuring odontogenic tumorous proliferations in association with persistent central giant cell lesions (CGCL). Specifically, the proband, a 25-year-old male, developed a radiolucent lesion characterized histologically by central odontogenic fibroma-like proliferation in association with a CGCL component, while his mother, at age 57, was diagnosed with primary intraosseous odontogenic carcinoma with areas of benign fibro-osseous lesions. In both patients the lesions occurred in the anterior mandible and presented with clinical enlargement. The son underwent incisional biopsy and did not have additional treatment. His mother underwent extensive mandibulectomy due to widespread tumor. The son has two affected children with classic cherubism while a third child at age 5, had not shown any features of the disease. Mutation analysis of three affected members resulted in the identification of a heterozygous mutation in SH3BP2 (c.1244G>C; p.Arg415Pro). To the best of our knowledge, association of cherubism with odontogenic neoplastic lesions has hitherto not been reported in the literature, thus suggesting a relationship between cherubism with disturbed odontogenesis. PMID- 28721662 TI - CTP and DCI: We Need Clarification. PMID- 28721661 TI - Sebaceous Differentiation in Squamous Cell Carcinoma of the Larynx and Adjacent Pharynx: Case Report with Review and Discussion of the Literature. AB - Among the variants of squamous cell carcinoma (SCC) of the head and neck arising in mucosal surfaces, examples with sebaceous differentiation are exceedingly rare. We present a new case of SCC with sebaceous differentiation, developing in the larynx of a 64 year-old male, cigarette smoker and alcohol drinker. The tumor extended transglottically, metastasized to cervical lymph nodes, and killed the patient after 12 months. Comparing this case with four previously reported cases of SCC with sebaceous differentiation, two arising in the larynx and the other two in the adjacent pharynx, all five patients mostly shared the following features: appearance of the tumor in the seventh decade of life, heavy tobacco smoking, alcohol intake in three, surgery as mainstay treatment, tumor size between 2 and 4.7 cm, and regional lymph node metastases in four of them. Out of the four patients with a follow up of 12 months, two died of disease, one was alive with disease, and only one was alive without disease. One patient was lost for follow up. In conclusion, mucosal SCC with sebaceous differentiation is a very rare variant of SCC that when arising in the larynx and anatomically adjacent parts of the pharynx behaves aggressively and bears a dismal prognosis. The recognition of new cases of this entity requires special awareness of its phenotypic features and may be important for further assessment of its behavior. PMID- 28721663 TI - Influence of direct or indirect contact for the cytotoxicity and blood compatibility of spider silk. AB - Spider silk became one of the most-researched biomaterials in the last years due to its unique mechanical strength and most favourable chemical composition for tissue engineering purposes. However, standardized analysis of cytocompatibility is missing. Therefore, the aim of this study was to investigate hemolysis, cytotoxicity of native spider silk as well as influences on the cell culture medium. Changes of cell culture medium composition, osmolarity as well as glucose and lactate content were determined via ELISA measurement. Possible hemolysis and cytotoxicity in vitro of spider silk were performed via measurement of hemoglobin release of human red blood cells or relative metabolic activity of L929 fibroblasts, respectively, according to international standard procedures. In ELISA measurement, no significant changes in medium composition could be found in this study. Spider silk was not hemolytic in direct and indirect testing. However, a borderline cytotoxicity according to definitions was found in indirect cytotoxicity testing. Nevertheless, in direct cytotoxicity testing, relative metabolic activity measurement revealed that spider silk is not cytotoxic under these conditions. This is the first study to conduct standardized tests regarding cytotoxicity and hemolysis of native spider silk, which might be considered inert in cell culture. As neither hemolysis nor cytotoxicity was found in direct contact in standardized procedures, safety in biomedical applications may be assumed. The indirect cytotoxicity seems to play a minor role in vivo. However, a borderline toxicity was revealed, suggesting potential leachables not yet identified. Displays one of the weaving frames used in this study after seeding with the single drop technique described herein. PMID- 28721664 TI - Reciprocal influence of hMSCs/HaCaT cultivated on electrospun scaffolds. AB - Here, we investigated the synergistic effect of electrospun nanofibrous scaffolds made of gelatin /sulfated hyaluronan (sHA) or native hyaluronan (HA)/chondroitin sulfate (CS) and, keratinocytes (HaCaT)-human mesenchymal stem cells (hMSCs) contact co-culture on epithelial differentiation of hMSCs. The hMSCs were co cultured in contact with HaCaT cells for 5 days on electrospun scaffold. Results show that electrospun scaffolds containing sulfated glycosaminoglycans (GAGs) stimulate epithelial differentiation in terms of various protein expression markers (keratin 14, DeltaNp63alpha and Pan-cytokeratin) and gene expression of several dermal proteins (keratin 14, DeltaNp63alpha). Electrospun scaffold independent of GAGs alone did not affect the epithelial differentiation of hMSCs but combination of keratinocyte-hMSC contact co-culture and electrospun scaffold promotes the epithelial differentiation of hMSCs. PMID- 28721666 TI - Erratum to: VOSalophen: a vanadium complex with a stilbene derivative-induction of apoptosis, autophagy, and efficiency in experimental cutaneous leishmaniasis. PMID- 28721665 TI - Micro-computed tomography characterization of tissue engineering scaffolds: effects of pixel size and rotation step. AB - Quantitative assessment of micro-structure of materials is of key importance in many fields including tissue engineering, biology, and dentistry. Micro-computed tomography (u-CT) is an intensively used non-destructive technique. However, the acquisition parameters such as pixel size and rotation step may have significant effects on the obtained results. In this study, a set of tissue engineering scaffolds including examples of natural and synthetic polymers, and ceramics were analyzed. We comprehensively compared the quantitative results of u-CT characterization using 15 acquisition scenarios that differ in the combination of the pixel size and rotation step. The results showed that the acquisition parameters could statistically significantly affect the quantified mean porosity, mean pore size, and mean wall thickness of the scaffolds. The effects are also practically important since the differences can be as high as 24% regarding the mean porosity in average, and 19.5 h and 166 GB regarding the characterization time and data storage per sample with a relatively small volume. This study showed in a quantitative manner the effects of such a wide range of acquisition scenarios on the final data, as well as the characterization time and data storage per sample. Herein, a clear picture of the effects of the pixel size and rotation step on the results is provided which can notably be useful to refine the practice of u-CT characterization of scaffolds and economize the related resources. PMID- 28721667 TI - Molar incisor hypomineralisation (MIH) training manual for clinical field surveys and practice. AB - BACKGROUND: Despite clear assessment criteria, studies of molar incisor hypomineralisation (MIH) and hypomineralised second primary molars (HSPM) are marked by inconsistency in outcome measurements. This has detracted from meaningful comparisons between studies and limited interpretation. AIM: To provide a comprehensive manual as a companion to assist researchers in planning epidemiological studies of MIH and HSPM, with particular reference to outcome measurement. METHODS: This manual begins with a succinct review of the clinical problems and evidence for management of the conditions. The subsequent sections guide researchers through diagnosis of MIH and HSPM and implementation of both the long and short forms of a recently proposed grading system. MIH and HSPM can often be confused with fluorosis, enamel hypoplasia, amelogenesis imperfecta, and white spot lesions but can be distinguished by a number of unique clinical features. Based on the grading system, a standardised protocol is proposed for clinical examinations. Intra and inter-examiner reliability is of key importance when outcome measurement is subjective and should be reported in all epidemiological studies of MIH. The manual concludes with an exercise forum aimed to train examiners in the use of the grading system, with answers provided. CONCLUSION: The use of a standardised protocol, diagnostic and grading criteria will greatly enhance the quality of epidemiological studies of MIH. PMID- 28721668 TI - Quantitative analysis of S. mutans, Lactobacillus and Bifidobacterium found in initial and mature plaques in Thai children with early childhood caries. AB - AIMS: To quantify Streptococcus mutans, lactobacillus and bifidobacterium in initial and mature plaque collected from children with severe early childhood caries (S-ECC) and caries-free (CF) groups and to analyse the association between these bacteria and caries-related factors in each group. STUDY DESIGN: A collection of 120 initial and overnight supra-gingival plaques were collected from Thai children aged 2-5 years-old (S-ECC = 60, CF = 60). Plaque, gingival indices and decayed, missing, filled tooth (dmft) scores were recorded. A questionnaire was used to assess the parents' attitudes and behaviour regarding the child's oral hygiene care and diet. METHODS: After DNA extraction, quantitative real-time polymerase chain reaction (PCR) using fluorescent dye (SYBR green) was performed. RESULTS: Levels of Streptococcus mutans, lactobacillus and bifidobacterium in both initial and mature plaques of S-ECC were significantly higher than those from the caries-free group (p < 0.05). The ratio of S. mutans, lactobacillus, and bifidobacterium to the total bacteria in S ECC was significantly higher than in the caries-free group (p < 0.05). Levels of lactobacillus and bifidobacterium in both plaques significantly correlated with dmft scores and the plaque index, while S. mutans levels only correlated with dmft scores (p < 0.05). Factors that were significantly associated with caries were parents's education, duration of bottle feeding, especially during sleeping and the frequency of consuming cariogenic food between meals (p < 0.05). CONCLUSION: Levels of S. mutans, lactobacillus, bifidobacterium and the ratio of these bacteria to total bacteria in both initial and mature plaques were significantly higher in children with S-ECC and related to dmft scores, oral hygiene and dietary habits. PMID- 28721670 TI - Extending a Tandem Mass Spectral Library to Include MS2 Spectra of Fragment Ions Produced In-Source and MSn Spectra. AB - Tandem mass spectral library searching is finding increased use as an effective means of determining chemical identity in mass spectrometry-based omics studies. We previously reported on constructing a tandem mass spectral library that includes spectra for multiple precursor ions for each analyte. Here we report our method for expanding this library to include MS2 spectra of fragment ions generated during the ionization process (in-source fragment ions) as well as MS3 and MS4 spectra. These can assist the chemical identification process. A simple density-based clustering algorithm was used to cluster all significant precursor ions from MS1 scans for an analyte acquired during an infusion experiment. The MS2 spectra associated with these precursor ions were grouped into the same precursor clusters. Subsequently, a new top-down hierarchical divisive clustering algorithm was developed for clustering the spectra from fragmentation of ions in each precursor cluster, including the MS2 spectra of the original precursors and of the in-source fragments as well as the MSn spectra. This algorithm starts with all the spectra of one precursor in one cluster and then separates them into sub clusters of similar spectra based on the fragment patterns. Herein, we describe the algorithms and spectral evaluation methods for extending the library. The new library features were demonstrated by searching the high resolution spectra of E. coli extracts against the extended library, allowing identification of compounds and their in-source fragment ions in a manner that was not possible before. Graphical Abstract ?. PMID- 28721671 TI - Front-End Electron Transfer Dissociation Coupled to a 21 Tesla FT-ICR Mass Spectrometer for Intact Protein Sequence Analysis. AB - High resolution mass spectrometry is a key technology for in-depth protein characterization. High-field Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS) enables high-level interrogation of intact proteins in the most detail to date. However, an appropriate complement of fragmentation technologies must be paired with FTMS to provide comprehensive sequence coverage, as well as characterization of sequence variants, and post-translational modifications. Here we describe the integration of front-end electron transfer dissociation (FETD) with a custom-built 21 tesla FT-ICR mass spectrometer, which yields unprecedented sequence coverage for proteins ranging from 2.8 to 29 kDa, without the need for extensive spectral averaging (e.g., ~60% sequence coverage for apo-myoglobin with four averaged acquisitions). The system is equipped with a multipole storage device separate from the ETD reaction device, which allows accumulation of multiple ETD fragment ion fills. Consequently, an optimally large product ion population is accumulated prior to transfer to the ICR cell for mass analysis, which improves mass spectral signal-to-noise ratio, dynamic range, and scan rate. We find a linear relationship between protein molecular weight and minimum number of ETD reaction fills to achieve optimum sequence coverage, thereby enabling more efficient use of instrument data acquisition time. Finally, real-time scaling of the number of ETD reactions fills during method-based acquisition is shown, and the implications for LC-MS/MS top-down analysis are discussed. Graphical Abstract ?. PMID- 28721669 TI - Mimicking Parkinson's Disease in a Dish: Merits and Pitfalls of the Most Commonly used Dopaminergic In Vitro Models. AB - Parkinson's disease (PD) is the second most common neurodegenerative disorder and has both unknown etiology and non-curative therapeutic options. Patients begin to present the classic motor symptoms of PD-tremor at rest, bradykinesia and rigidity-once 50-70% of the dopaminergic neurons of the nigrostriatal pathway have degenerated. As a consequence of this, it is difficult to investigate the early-stage events of disease pathogenesis. In vitro experimental models are used extensively in PD research because they present a controlled environment that enables the direct investigation of the early molecular mechanisms that are potentially involved with dopaminergic degeneration, as well as for the screening of potential therapeutic drugs. However, the establishment of PD in vitro models is a controversial issue for neuroscience research not only because it is challenging to mimic, in isolated cell systems, the physiological neuronal environment, but also the pathophysiological conditions experienced by human dopaminergic cells in vivo during the progression of the disease. Since no previous work has attempted to systematically review the literature regarding the establishment of an optimal in vitro model, and/or the features presented by available models used in the PD field, this review aims to summarize the merits and limitations of the most widely used dopaminergic in vitro models in PD research, which may help the PD researcher to choose the most appropriate model for studies directed at the elucidation of the early-stage molecular events underlying PD onset and progression. PMID- 28721672 TI - IR-MALDESI Mass Spectrometry Imaging at 50 Micron Spatial Resolution. AB - High spatial resolution in mass spectrometry imaging (MSI) is crucial to understanding the biology dictated by molecular distributions in complex tissue systems. Here, we present MSI using infrared matrix-assisted laser desorption electrospray ionization (IR-MALDESI) at 50 MUm resolution. An adjustable iris, beam expander, and an aspherical focusing lens were used to reduce tissue ablation diameters for MSI at high resolution. The laser beam caustic was modeled using laser ablation paper to calculate relevant laser beam characteristics. The minimum laser spot diameter on the tissue was determined using tissue staining and microscopy. Finally, the newly constructed optical system was used to image hen ovarian tissue with and without oversampling, detailing tissue features at 50 MUm resolution. Graphical Abstract ?. PMID- 28721673 TI - Gas Flow in the Capillary of the Atmosphere-to-Vacuum Interface of Mass Spectrometers. AB - Numerical simulations of a gas flow through a capillary being a part of mass spectrometer atmospheric interface were performed using a detailed laminar flow model. The simulated interface consisted of atmospheric and forevacuum volumes connected via a thin capillary. The pressure in the forevacuum volume where the gas was expanding after passing through the capillary was varied in the wide range from 10 to 900 mbar in order to study the volume flow rate as well as the other flow parameters as functions of the pressure drop between the atmospheric and forevacuum volumes. The capillary wall temperature was varied in the range from 24 to 150 degrees C. Numerical integration of the complete system of Navier Stokes equations for a viscous compressible gas taking into account the heat transfer was performed using the standard gas dynamic simulation software package ANSYS CFX. The simulation results were compared with experimental measurements of gas flow parameters both performed using our experimental setup and taken from the literature. The simulated volume flow rates through the capillary differed no more than by 10% from the measured ones over the entire pressure and temperatures ranges. A conclusion was drawn that the detailed digital laminar model is able to quantitatively describe the measured gas flow rates through the capillaries under conditions considered. Graphical Abstract ?. PMID- 28721674 TI - Effective Ion Mobility Peak Width as a New Isomeric Descriptor for the Untargeted Analysis of Complex Mixtures Using Ion Mobility-Mass Spectrometry. AB - Ion mobility coupled with mass spectrometry was proven to be an efficient way to characterize complex mixtures such as petroleum samples. However, the identification of isomeric species is difficult owing to the molecular complexity of petroleum and no availability of standard molecules. This paper proposes a new simple indicator to estimate the isomeric content of highly complex mixtures. This indicator is based on the full width at half maximum (FWHM) of the extracted ion mobility peak measured in millisecond or square angstrom that is corrected for instrumental factors such as ion diffusion. This value can be easily obtained without precisely identifying the number of isomeric species under the ion mobility peaks. Considering the Boduszynski model, the ion mobility profile for a particular elemental composition is expected to be a continuum of various isomeric species. The drift time-dependent fragmentation profile was studied and confirmed this hypothesis, a continuous evolution of the fragmentation profile showing that the larger alkyl chain species were detected at higher drift time values. This new indicator was proven to be a fast and efficient method to compare vacuum gas oils for which no difference was found using other analytical techniques. Graphical Abstract ?. PMID- 28721676 TI - Erratum to: Release from PI: An analysis and a model. PMID- 28721675 TI - Callous-Unemotional Traits are Uniquely Associated with Poorer Peer Functioning in School-Aged Children. AB - This study examines externalizing symptoms (attention-deficit/hyperactivity disorder [ADHD], conduct problems, and callous-unemotional [CU] traits) in relation to domains of peer functioning (social competence, loneliness, and close friendship quality), with a specific focus on the role of CU traits. One hundred twenty-four elementary students (grades 3-6; 45% boys) completed multiple measures of peer functioning, and teachers completed measures of externalizing symptoms and social competence. After controlling for demographic variables and other externalizing symptoms, CU traits were significantly associated with poorer peer functioning across all variables except for demands of exclusivity in close friendships. ADHD symptoms were also uniquely associated with poorer social functioning across a number of variables. In contrast, conduct problems were at times associated with better social functioning after controlling for the effects of other externalizing problems. These findings bolster the importance of developing and evaluating social skills interventions for children displaying elevated CU traits. PMID- 28721677 TI - The pervasive nature of uncertainty-a qualitative study of patients with advanced cancer and their informal caregivers. AB - PURPOSE: The aim of this study was to explore the impact of extended cancer survival on broader aspects of life and wellbeing such as occupational, financial and family life for patients with advanced cancer and their nominated informal caregivers. METHODS: In-depth qualitative interviews were transcribed verbatim. A thematic framework was developed from an initial process of open coding and tested iteratively as new data were collected. RESULTS: Twenty-four patient caregiver dyads with advanced ovarian (9), melanoma (9) or lung cancer (6). Patients were aged 39-84 (median 62 years) and caregivers 19-85 (median 54 years). Caregivers were the partners/spouses (15), children (5), siblings (2) and friends (2) of patients. One particular theme, 'uncertainty', encompassed many issues such as planning for the future, providing for one's family, employment and finances. Uncertainties were related to the timescale and trajectory of the disease and lack of control or ability to make plans. There were marked age effects. Accounts from within the same dyad often differed and patients and caregivers rarely discussed concerns with each other. CONCLUSIONS: Both patients and their informal caregivers were challenged by the uncertainties around living with advanced cancer and the lack of a defined trajectory. This impacted many diverse areas of life. Although distressing, dyads seldom discussed these concerns with each other. IMPLICATIONS FOR CANCER SURVIVORS: Uncertainty is a recurrent issue for cancer survivors and their families impacting broad aspects of their lives and their ability to move forward; however, patients and caregivers in this study rarely discussed these concerns together. Uncertainty should be discussed periodically, together, and healthcare professionals could facilitate these discussions. The use of one or more 'trigger questions' in clinic appointments may provide an opportunity to start these dialogues. PMID- 28721678 TI - PIM1: a promising target in patients with triple-negative breast cancer. AB - Triple-negative breast cancers (TNBCs) have poor prognosis, and chemotherapy remains the mainstay of therapy because of lack of discovered possible target. MYC were found overexpressed in TNBCs compared with other subtypes and especially in those resistant to chemotherapy, but the inhibition has been challenging to achieve. Recently, the cooperation of PIM1 and MYC was identified involved in cell proliferation, migration and apoptosis of TNBCs, which has been reported in hematological malignancy and prostatic cancer. Inhibition of PIM1 can promote the apoptosis of tumor cells and enhance sensitivity to chemotherapy. Notably, PIM1 null mice develop normally and are fertile, suggesting the side effects can be tolerated. Thus, PIM1 may be a promising target in TNBCs and further investigation, both in vivo and in vitro, needs to be carried out. PMID- 28721679 TI - Phytochemicals as potential antidotes for targeting NF-kappaB in rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune destructive arthropathy prevalent among people in the age group of 40-70 years. RA induces severe pain, swelling and stiffness of joints resulting in bone damage. RA leads to reduced life expectancy when left untreated. RA is characterized by synovial hyperplasia, infiltration of inflammatory cells resulting in formation of pannus. Synovial hyperplasia is mediated by proinflammatory cytokines, notably IL-1 and TNF-alpha. NF-kappaB is a predominant transcription factor in amplifying the inflammatory response. The translocation of activated NF-kappaB into the nucleus triggers the transcription of several genes that induce proinflammatory cytokine production. The inhibition of NF-kappaB translocation aids blocking the activation of proinflammatory cascades. The quest for more effective and side effect free treatment for RA unveiled phytochemicals as efficacious and promising. Phytochemicals have been a source of therapeutic substances for many ailments from ancient times. Their therapeutic ability helps in developing potent and safe drugs targeting immune inflammatory diseases driven by NF-kappaB including RA. This review highlights the importance of NF-kappaB inflammatory cascade in RA so as to elucidate the crucial role of phytochemicals that inhibit the activity of NF-kappaB. PMID- 28721680 TI - Evaluation of haplotype diversity of Achatina fulica (Lissachatina) [Bowdich] from Indian sub-continent by means of 16S rDNA sequence and its phylogenetic relationships with other global populations. AB - Achatina fulica (Lissachatina fulica) is one of the most invasive species found across the globe causing a significant damage to crops, vegetables, and horticultural plants. This terrestrial snail is native to east Africa and spread to different parts of the world by introductions. India, a hot spot for biodiversity of several endemic gastropods, has witnessed an outburst of this snail population in several parts of the country posing a serious threat to crop loss and also to human health. With an objective to evaluate the genetic diversity of this snail, we have sampled this snail from different parts of India and analyzed its haplotype diversity by means of 16S rDNA sequence information. Apart from this, we have studied the phylogenetic relationships of the isolates sequenced in the present study in relation with other global populations by Bayesian and Maximum-likelihood approaches. Of the isolates sequenced, haplotype 'C' is the predominant one. A new haplotype 'S' from the state of Odisha was observed. The isolates sequenced in the present study clustered with its conspecifics from the Indian sub-continent. Haplotype network analyses were also carried out for studying the evolution of different haplotypes. It was observed that haplotype 'S' was associated with a Mauritius haplotype 'H', indicating the possibility of multiple introductions of A. fulica to India. PMID- 28721682 TI - LncRNA ZFAS1 promotes cell migration and invasion of fibroblast-like synoviocytes by suppression of miR-27a in rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is a systemic and chronic inflammatory disease. Synoviocyte migration and invasion were found to be essential to the pathology of RA. Upregulation of long noncoding RNA ZFAS1 has been observed in cancers and promotes cell migration and invasion. To date, the functions and mechanisms of ZFAS1 in RA have not been revealed. In this study, we analyzed expression pattern of ZFAS1 in RA patients and found that ZFAS1 expression was increased in synovial tissue and fibroblast-like synoviocytes (FLS) from RA patients (RA-FLS) compared with that in healthy donors. Functional assays showed that silence of ZFAS1 suppressed RA-FLS migration and invasion, while overexpression of ZFAS1 showed the opposite effect. Further investigation demonstrated that ZFAS1 directly interacted with miR-27a and decreased miR-27a expression. ZFAS1 promotes RA-FLS migration and invasion in an miR-27a-dependent manner. Taken together, the present study provides the first evidence that ZFAS1 promotes cell migration and invasion through miR-27a in RA-FLS, suggesting that ZFAS1 may be an effective therapeutic target for RA patients. PMID- 28721681 TI - Genetic characterization and disease mechanism of retinitis pigmentosa; current scenario. AB - Retinitis pigmentosa is a group of genetically transmitted disorders affecting 1 in 3000-8000 individual people worldwide ultimately affecting the quality of life. Retinitis pigmentosa is characterized as a heterogeneous genetic disorder which leads by progressive devolution of the retina leading to a progressive visual loss. It can occur in syndromic (with Usher syndrome and Bardet-Biedl syndrome) as well as non-syndromic nature. The mode of inheritance can be X linked, autosomal dominant or autosomal recessive manner. To date 58 genes have been reported to associate with retinitis pigmentosa most of them are either expressed in photoreceptors or the retinal pigment epithelium. This review focuses on the disease mechanisms and genetics of retinitis pigmentosa. As retinitis pigmentosa is tremendously heterogeneous disorder expressing a multiplicity of mutations; different variations in the same gene might induce different disorders. In recent years, latest technologies including whole-exome sequencing contributing effectively to uncover the hidden genesis of retinitis pigmentosa by reporting new genetic mutations. In future, these advancements will help in better understanding the genotype-phenotype correlations of disease and likely to develop new therapies. PMID- 28721684 TI - Pharmacokinetics, microscale distribution, and dosimetry of alpha-emitter-labeled anti-PD-L1 antibodies in an immune competent transgenic breast cancer model. AB - BACKGROUND: Studies combining immune checkpoint inhibitors with external beam radiation have shown a therapeutic advantage over each modality alone. The purpose of these works is to evaluate the potential of targeted delivery of high LET radiation to the tumor microenvironment via an immune checkpoint inhibitor. METHODS: The impact of protein concentration on the distribution of 111In-DTPA anti-PD-L1-BC, an 111In-antibody conjugate targeted to PD-L1, was evaluated in an immunocompetent mouse model of breast cancer. 225Ac-DOTA-anti-PD-L1-BC was evaluated by both macroscale (ex vivo biodistribution) and microscale (alpha camera images at a protein concentration determined by the 111In data. RESULTS: The evaluation of 111In-DTPA-anti-PD-L1-BC at 1, 3, and 10 mg/kg highlighted the impact of protein concentration on the distribution of the labeled antibody, particularly in the blood, spleen, thymus, and tumor. Alpha-camera images for the microscale distribution of 225Ac-DOTA-anti-PD-L1-BC showed a uniform distribution in the liver while highly non-uniform distributions were obtained in the thymus, spleen, kidney, and tumor. At an antibody dose of 3 mg/kg, the liver was dose limiting with an absorbed dose of 738 mGy/kBq; based upon blood activity concentration measurements, the marrow absorbed dose was 29 mGy/kBq. CONCLUSIONS: These studies demonstrate that 225Ac-DOTA-anti-PD-L1-BC is capable of delivering high LET radiation to PD-L1 tumors. The use of a surrogate SPECT agent, 111In DTPA-anti-PD-L1-BC, is beneficial in optimizing the dose delivered to the tumor sites. Furthermore, an accounting of the microscale distribution of the antibody in preclinical studies was essential to the proper interpretation of organ absorbed doses and their likely relation to biologic effect. PMID- 28721683 TI - Mesenchymal Stem/Progenitor Cells Derived from Articular Cartilage, Synovial Membrane and Synovial Fluid for Cartilage Regeneration: Current Status and Future Perspectives. AB - Large articular cartilage defects remain an immense challenge in the field of regenerative medicine because of their poor intrinsic repair capacity. Currently, the available medical interventions can relieve clinical symptoms to some extent, but fail to repair the cartilaginous injuries with authentic hyaline cartilage. There has been a surge of interest in developing cell-based therapies, focused particularly on the use of mesenchymal stem/progenitor cells with or without scaffolds. Mesenchymal stem/progenitor cells are promising graft cells for tissue regeneration, but the most suitable source of cells for cartilage repair remains controversial. The tissue origin of mesenchymal stem/progenitor cells notably influences the biological properties and therapeutic potential. It is well known that mesenchymal stem/progenitor cells derived from synovial joint tissues exhibit superior chondrogenic ability compared with those derived from non-joint tissues; thus, these cell populations are considered ideal sources for cartilage regeneration. In addition to the progress in research and promising preclinical results, many important research questions must be answered before widespread success in cartilage regeneration is achieved. This review outlines the biology of stem/progenitor cells derived from the articular cartilage, the synovial membrane, and the synovial fluid, including their tissue distribution, function and biological characteristics. Furthermore, preclinical and clinical trials focusing on their applications for cartilage regeneration are summarized, and future research perspectives are discussed. PMID- 28721685 TI - Breaking down unitization: Is the whole greater than the sum of its parts? AB - Memory impairments are often observed in aging. Specifically, older adults have difficulty binding together disparate elements (relational memory). We have recently shown that a cognitive strategy known as unitization can mitigate impaired relational learning in the transverse patterning task (TP) in both amnesia and healthy aging. This strategy allows items to be fused together through an interaction such that one item acts upon another. In the context of TP, unitization is comprised of three component processes: (1) fusion, (2) motion, and (3) semantic comprehension of action/consequence sequences. Here, we examine which of these components are sufficient to mitigate age-related impairments. Four groups of older adults were given either the full unitization strategy or one of the three component strategies. Each group of older adults showed impairments in memory for the relations among items under standard training instructions relative to a threshold that marks learning of a winner take-all rule (elemental threshold). However, participants who were given either the full unitization strategy or the action/consequence-only strategy showed improved performance, which was maintained following the 1-hour delay. Therefore, semantically rich action/consequence interactions are sufficient to mitigate age related relational memory impairments. PMID- 28721686 TI - Rationale for, Initiation and Titration of the Basal Insulin/GLP-1RA Fixed-Ratio Combination Products, IDegLira and IGlarLixi, for the Management of Type 2 Diabetes. AB - Type 2 diabetes (T2D) is a progressive disease affecting glucose regulation and a major cause of morbidity and mortality globally. Many patients are not escalated up the treatment ladder appropriately despite failing to achieve glycemic control, with barriers such as fear of hypoglycemia, weight gain, and treatment burden recognized as factors. Exogenous basal insulin is titrated to address control of fasting plasma glucose and may preserve residual beta-cell function, thus promoting a greater endogenous prandial insulin response. Native glucagon like peptide-1 (GLP-1) is a peptide hormone secreted by the gut in response to nutrient ingestion; it increases insulin secretion, inhibits glucagon secretion, and prolongs gastric emptying, thereby lowering overall food intake. As its glucose-lowering action is glucose dependent, a GLP-1 receptor agonist (GLP-1RA) achieves these benefits with a lower risk of hypoglycemia compared with other diabetes therapies. Two products, an insulin degludec/liraglutide combination (IDegLira) and an insulin glargine/lixisenatide combination (IGlarLixi), were approved for use in adults with T2D by the US Food and Drug Administration in 2016. The efficacy and safety of these two basal insulin/GLP-1RA combination products were studied in the DUAL program (NCTs 01336023, 01392573, 01676116, 01618162, 01952145, and 02298192) and the LixiLan program (NCTs 02058160 and 02058147). Compared with basal insulin, insulin/GLP-1RA fixed-ratio combinations are superior at reducing HbA1c with weight neutrality or weight loss rather than weight gain, as well as reduced hypoglycemia rates, and reduced insulin-dose requirement with IDegLira. A combination of different medications may often be required to achieve glycemic control, and fixed-ratio combination products allow such therapies to be given in simple regimens. Clinical trial data for these products highlight the great potential of these agents, not merely their efficacy and safety but also their ease of use and decreased injection burden for patients. PMID- 28721687 TI - Practical Approach to Initiating SGLT2 Inhibitors in Type 2 Diabetes. AB - Sodium-glucose co-transporter 2 (SGLT2) inhibitors are an attractive novel therapeutic option for the treatment of type 2 diabetes. They block the reabsorption of filtered glucose in kidneys, mainly in proximal renal tubules, resulting in increased urinary glucose excretion and correction of the diabetes related hyperglycemia. Beyond improving glucose control, SGLT2 inhibitors offer potential benefits by reducing body weight and blood pressure. On the basis of the efficacy demonstrated in clinical trials, SGLT2 inhibitors are recommended as second- or third-line agents for the management of patients with type 2 diabetes. Beneficial effects on kidney disease progression, cardiovascular and all-cause mortality, and hospitalization for heart failure have also been demonstrated with one SGLT2 inhibitor (empagliflozin). Potential adverse events resulting from their mechanism of action or related to concomitant therapies are reviewed. A treatment algorithm for the adjustment of concomitant therapies after initiating SGLT2 inhibitors is also proposed. PMID- 28721689 TI - Eye taping during anesthesia and chlorhexidine exposure. PMID- 28721688 TI - Morphine and the blood-brain barrier: diffusion, uptake, or efflux? PMID- 28721690 TI - Pre- or postoperative interscalene block and/or general anesthesia for arthroscopic shoulder surgery: a retrospective observational study. AB - PURPOSE: Arthroscopic shoulder surgery can be performed with an interscalene brachial plexus block (ISBPB) alone, ISBPB combined with general anesthesia (GA), or GA alone. Postoperative pain is typically managed with opioids; however, both GA and opioids have adverse effects which can delay discharge. This retrospective study compares the efficacy of four methods of anesthesia management for arthroscopic shoulder surgery. METHODS: Charts of all patients who underwent shoulder surgery by a single surgeon from 2012-2015 were categorized by analgesic regimen: GA only (n = 177), single-shot ISBPB only (n = 124), or pre- vs postoperative ISBPB combined with GA (ISBPB + GA [n = 72] vs GA + ISBPB [n = 52], respectively). The primary outcome measure was the time to discharge from the postanesthesia care unit (PACU). RESULTS: Mean (SD) time in the PACU ranged from 70.5 (39.9) min for ISBPB only to 111.2 (56.9) min for GA only. Use of ISBPB in any combination and regardless of timing resulted in significantly reduced PACU time, with a mean drop of 27.2 min (95% confidence interval [CI], 17.3 to 37.2; P < 0.001). The largest mean pairwise difference was between GA only and ISBPB only, with a mean difference of 40.7 min (95% CI, 25.5 to 55.8; P < 0.001). Use of ISBPB also reduced pain upon arrival at the PACU and, in some cases, upon discharge from the PACU (i.e., ISBPB only but not ISBPB + GA compared with GA). An ISBPB (alone or prior to GA) also reduced analgesic requirements. CONCLUSION: Previously reported benefits of an ISBPB for arthroscopic shoulder surgery are confirmed. Postoperative ISBPBs may also be beneficial for reducing pain and opioid requirements and could be targeted for patients in severe pain upon emergence. A sufficiently powered randomized-controlled trial could determine the relative efficacy, safety, and associated financial implications associated with each method. PMID- 28721692 TI - Left ventricular mechanics are affected in children with celiac disease: A study based on two-dimensional speckle tracking echocardiography. AB - BACKGROUND: An association between cardiomyopathy and celiac disease has been reported, but not frequently. We examined the effects on cardiac mechanics in children with celiac disease (CD) by two-dimensional speckle tracking echocardiography (2DSTE). METHODS: Eighty-one children with CD were compared with a control group comprising 51 healthy children by echocardiographic examination. Children with CD who had been on gluten-free diet for more than 6 months were divided into two different groups: group 1 was positive for serum antitissue transglutaminase antibody (n=48), and group 2 was negative for serum antitissue transglutaminase antibody (n=33). Cardiac functions were evaluated in all children using conventional echocardiography, tissue Doppler imaging (TDI), and 2DSTE methods. RESULTS: For children with CD, the mean age and male:female ratio were 10.1+/-4.0 years and 26/55 (67% female), respectively, which did not differ from the controls. Patients were diagnosed at a mean age of 7.9+/-4.1 years, and the mean follow-up time was 2.37+/-2.98 years. Conventional echocardiography and TDI measurements did not differ between groups. The left ventricular longitudinal and radial strains, and strain rate values were significantly lower in patients with CD, particularly in those with positive antitissue transglutaminase antibody compared with the control group. CONCLUSIONS: Our results suggest that 2DSTE is superior to conventional and TDI echocardiography for evaluating subclinical carditis in children with CD. PMID- 28721691 TI - Occupational therapy for adults with problems in activities of daily living after stroke. AB - BACKGROUND: A stroke occurs when the blood supply to part of the brain is cut off. Activities of daily living (ADL) are daily home-based activities that people carry out to maintain health and well-being. ADLs include the ability to: eat and drink unassisted, move, go to the toilet, carry out personal hygiene tasks, dress unassisted, and groom. Stroke causes impairment-related functional limitations that may result in difficulties participating in ADLs independent of supervision, direction, or physical assistance.For adults with stroke, the goal of occupational therapy is to improve their ability to carry out activities of daily living. Strategies used by occupational therapists include assessment, treatment, adaptive techniques, assistive technology, and environmental adaptations. This is an update of the Cochrane review first published in 2006. OBJECTIVES: To assess the effects of occupational therapy interventions on the functional ability of adults with stroke in the domain of activities of daily living, compared with no intervention or standard care/practice. SEARCH METHODS: For this update, we searched the Cochrane Stroke Group Trials Register (last searched 30 January 2017), the Cochrane Controlled Trials Register (The Cochrane Library, January 2017), MEDLINE (1946 to 5 January 2017), Embase (1974 to 5 January 2017), CINAHL (1937 to January 2017), PsycINFO (1806 to 2 November 2016), AMED (1985 to 1 November 2016), and Web of Science (1900 to 6 January 2017). We also searched grey literature and clinical trials registers. SELECTION CRITERIA: We identified randomised controlled trials of an occupational therapy intervention (compared with no intervention or standard care/practice) where people with stroke practiced activities of daily living, or where performance in activities of daily living was the focus of the occupational therapy intervention. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials, assessed risk of bias, and extracted data for prespecified outcomes. The primary outcomes were the proportion of participants who had deteriorated or were dependent in personal activities of daily living and performance in activities of daily living at the end of follow-up. MAIN RESULTS: We included nine studies with 994 participants in this update. Occupational therapy targeted towards activities of daily living after stroke increased performance scores (standardised mean difference (SMD) 0.17, 95% confidence interval (CI) 0.03 to 0.31, P = 0.02; 7 studies; 749 participants; low-quality evidence) and reduced the risk of poor outcome (death, deterioration or dependency in personal activities of daily living) (odds ratio (OR) 0.71, 95% CI 0.52 to 0.96; P = 0.03; 5 studies; 771 participants; low quality evidence). We also found that those who received occupational therapy were more independent in extended activities of daily living (OR 0.22 (95% CI 0.07 to 0.37); P = 0.005; 5 studies; 665 participants; low-quality evidence). Occupational therapy did not influence mortality (OR: 1.02 (95% CI 0.65 to 1.61); P = 0.93; 8 studies; 950 participants), or reduce the combined odds of death and institutionalisation (OR 0.89 (95% CI 0.60 to 1.32); P = 0.55; 4 studies; 671 participants), or death and dependency (OR 0.89 (95% CI 0.64 to 1.23); P = 0.47; 4 trials; 659 participants). Occupational therapy did not improve mood or distress scores (OR 0.08 (95% CI -0.09 to 0.26); P = 0.35; 4 studies; 519 participants; low-quality evidence). There were insufficient data to determine the effects of occupational therapy on health-related quality of life. We found no studies of consenting carers prior to study participation and therefore there were no carer-related outcomes in our review. There were insufficient data to determine participants' and carers' satisfaction with services.Using GRADE, the quality of evidence was low. The major limitation was the number of studies at unclear risk of selection bias and an inevitable high risk of performance and detection bias, as both participants and occupational therapists could not be blinded to the intervention. In addition, there was a sparseness of data for our outcomes of interest and we downgraded the quality of our evidence for these reasons. AUTHORS' CONCLUSIONS: We found low-quality evidence that occupational therapy targeted towards activities of daily living after stroke can improve performance in activities of daily living and reduce the risk of deterioration in these abilities. Because the included studies had methodological flaws, this research does not provide a reliable indication of the likely effect of occupational therapy for adults with stroke. PMID- 28721693 TI - Towards relational recovery: Nurses' practices with consumers and families with dependent children in mental health inpatient units. AB - Facilitating parent-child and family connections during parental hospitalization provides important opportunities for mental health services to support individual and family recovery. Nurses are often the primary point of contact for families in the inpatient context. They play an integral role in the care provision of consumers and families and in supporting consumers' recovery. The aim of the present qualitative study was to explore nurses' practice with families in inpatient mental health settings in the context of designated family rooms. Three themes were derived from the thematic analysis of semistructured interviews with 20 nurses from four mental health inpatient units. Nurses experienced tensions within their roles in balancing safety and risk, a lack of confidence in family focused practices in relation to role expectations, and challenges in juggling nursing care ideals with the contemporary realities of inpatient practice. A family-centred relational recovery approach is recommended for mental health services, which is underpinned by family-focused policies and processes, and supported at an organizational, managerial, and local-unit level. At an individual level, nurses need professional development on the models of care they practice in, explicit role clarity on their practice with families, and education on evidence-based brief family interventions. PMID- 28721694 TI - Transient left ventricular outflow tract obstruction with systolic anterior motion of the mitral valve: A stunning cause: Non-ST-segment elevation myocardial infarction vs aborted myocardial infarction-triggered takotsubo syndrome? PMID- 28721695 TI - Myopes have significantly higher serum melatonin concentrations than non-myopes. AB - PURPOSE: Experimental animal models of myopia demonstrate that higher melatonin (Mel) and lower dopamine (DA) concentrations actively promote axial elongation. This study explored the association between myopia and serum concentrations of DA and Mel in humans. METHODS: Morning serum concentrations of DA and Mel were measured by solid phase extraction-liquid chromatography-tandem mass spectrometry from 54 participants (age 19.1 +/- 0.81 years) in September/October 2014 (phase 1) and March/April 2016 (phase 2). Axial length (AL), corneal radii (CR) and spherical equivalent refraction (SER) were also recorded. Participants were defined as myopic if non-cycloplegic spherical equivalent refractive error <= 0.50 DS at phase 1. RESULTS: Nine participants were lost to follow up. Mel concentrations were measurable for all myopes (phase 1 n = 25, phase 2 n = 22) and non-myopes (phase 1 n = 29, phase 2 n = 23). SER did not change significantly between phases (p = 0.51). DA concentrations were measurable for fewer myopes (phase 1 n = 13, phase 2 n = 12) and non-myopes (phase 1 n = 23, phase 2 n = 16). Myopes exhibited significantly higher Mel concentrations than non-myopes at phase 1 (Median difference: 10 pg mL-1 , p < 0.001) and at phase 2 (Median difference: 7.3 pg mL-1 , p < 0.001) and lower DA concentrations at phase 2 (Median difference: 4.7 pg mL-1 , p = 0.006). Mel concentrations were positively associated with more negative SER (all r >= -0.53, all p < 0.001), longer AL (all r >= 0.37, all p <= 0.008) and higher AL/CR ratio (all r >= 0.51, all p < 0.001). CONCLUSION: This study reports for the first time in humans that myopes exhibit higher serum Mel concentrations than non-myopes. This may indicate a role for light exposure and circadian rhythm in the human myopic growth mechanism. Further research should focus on younger cohorts exhibiting more dynamic myopic progression and explore the profile of these neurochemicals alongside evaluation of sleep patterns in myopic and non-myopic groups. PMID- 28721696 TI - Usefulness of fragmented QRS in hypertensive patients in the absence of left ventricular hypertrophy. AB - In the absence of left ventricular hypertrophy, importance of fragmented QRS complex (fQRS) in individuals with hypertension is unknown. The authors aimed to evaluate the relationship between blood pressure levels and fQRS in the absence of left ventricular hypertrophy. A total of 548 never-treated patients who underwent 24-hour ambulatory blood pressure monitoring were enrolled. The frequency of fQRS was significantly higher in patients with hypertension than normotension (36.4% vs 17.6%, P<.05). Multivariate logistic regression analysis revealed that systolic blood pressure is significantly associated with presence of fQRS on electrocardiography (odds ratio, 0.931; 95% CI, 0.910-0.9521 [P<.001]) even after adjusting for other confounding factors. Receiver operating characteristic analysis revealed a cutoff value of 147.65 mm Hg for systolic blood pressure to predict presence of fQRS (sensitivity: 51%, specificity: 99%, area under the curve=0.764; 95% CI, 0.717-0.811 [P<.001]). fQRS may be a sign of increased blood pressure and may predict higher fibrotic burden in patients with hypertension. PMID- 28721697 TI - Interventions to reduce consumption of sugar-sweetened beverages or increase water intake: evidence from a systematic review and meta-analysis. AB - A systematic review and meta-analyses were conducted to evaluate the effects of interventions to reduce sugar-sweetened beverages (SSB) or increase water intakes and to examine the impact of behaviour change techniques (BCTs) in consumption patterns. Randomized and nonrandomized controlled trials published after January 1990 and until December 2016 reporting daily changes in intakes of SSB or water in volumetric measurements (mL d-1 ) were included. References were retrieved through searches of electronic databases and quality appraisal followed Cochrane principles. We calculated mean differences (MD) and synthesized data with random effects models. Forty studies with 16 505 participants were meta-analysed. Interventions significantly decreased consumption of SSB in children by 76 mL d-1 (95% confidence interval [CI] -105 to -46; 23 studies, P < 0.01), and in adolescents (-66 mL d-1 , 95% CI -130 to -2; 5 studies, P = 0.04) but not in adults (-13 mL d-1 , 95% CI -44 to 18; 12 studies, P = 0.16). Pooled estimates of water intakes were only possible for interventions in children, and results were indicative of increases in water intake (MD +67 mL d-1 , 95% CI 6 to 128; 7 studies, P = 0.04). For children, there was evidence to suggest that modelling/demonstrating the behaviour helped to reduce SSB intake and that interventions within the home environment had greater effects than school-based interventions. In conclusion, public health interventions - mainly via nutritional education/counselling - are moderately successful at reducing intakes of SSB and increasing water intakes in children. However, on average, only small reductions in SSBs have been achieved by interventions targeting adolescents and adults. Complementary measures may be needed to achieve greater improvements in both dietary behaviours across all age groups. PMID- 28721698 TI - Risk factors for preeclampsia in infertile Chinese women with polycystic ovary syndrome: A prospective cohort study: Methodological issues. PMID- 28721699 TI - Bypass of confirmatory tests for case detection of primary aldosteronism in leaner patients? PMID- 28721700 TI - Blood pressure-lowering efficacy of indapamide SR/amlodipine combination in older patients with hypertension: A post hoc analysis of the NESTOR trial (Natrilix SR vs Enalapril in Hypertensive Type 2 Diabetics With Microalbuminuria). AB - To examine the antihypertensive efficacy and safety of indapamide sustained release (SR)/amlodipine compared with enalapril/amlodipine in patients 65 years and older with uncontrolled blood pressure (BP) on monotherapy, a post hoc analysis of the NESTOR trial (Natrilix SR vs Enalapril in Hypertensive Type 2 Diabetics With Microalbuminuria) was conducted. NESTOR randomized 570 patients (n=197, aged >=65 years) with hypertension (systolic BP 140-180/diastolic BP <110 mm Hg) to indapamide SR 1.5 mg or enalapril 10 mg. If target BP (<140/85 mm Hg) was not achieved at 6 weeks, amlodipine 5 mg was added with uptitration to 10 mg if required. A total of 107 patients aged 65 years and older received dual therapy (53 indapamide SR/amlodipine and 54 enalapril/amlodipine). Amlodipine uptitration occurred in 22 and 24 patients, respectively. At 52 weeks, mean systolic BP (+/-SE) reduction was significantly greater with indapamide SR/amlodipine vs enalapril/amlodipine 6.2+/-2.7 mm Hg (P=.02). Indapamide SR/amlodipine was also associated with a greater BP response rate (88% vs 75%, respectively). Both regimens were well tolerated. Indapamide SR/amlodipine may be more effective than enalapril/amlodipine for lowering systolic BP in patients with hypertension aged 65 years and older. PMID- 28721701 TI - Challenges of connectedness in personal recovery for rural mothers with mental illness. AB - Social connection is a fundamental human need, but challenging for individuals with characteristics that are socially stigmatized. Parenting with mental illness presents obstacles, as well as opportunities, for connection. In the present study, we examined connectedness within a personal recovery paradigm for rural mothers with a mental illness. In-depth interviews with 17 mothers with a mental illness, utilizing constructivist grounded theory, resulted in six categories of meaning, including 'yearning for connection', 'connecting intensely', 'encountering rejection and exclusion', 'choosing isolation', 'being known', and 'finding peers/helping others'. Women expressed a strong desire for connection, but for many, prior experiences of trauma and rejection created barriers to the development of trust, preventing some women from seeking opportunities for connection. Connectedness to self and significant others, and a broader life meaning and purpose can support and expedite personal recovery from mental illness for rural women. However the factors that contribute to the mental illness might also inhibit the development of trust needed to attain social connection. Increasing connectedness in mothers with mental illness is a complex endeavour requiring concerted focus as distinct from other service-delivery goals. The perinatal period could be a key time for intervention. PMID- 28721702 TI - Fragmented QRS: A marker of hypertensive heart disease? PMID- 28721703 TI - ? PMID- 28721704 TI - [Overweight and obesity in the canton of Vaud : projections for 2040]. AB - The worldwide prevalence of obesity has more than doubled since 1980. This global figure needs to be addressed tackled at the local level to face our future challenges at the local level. We attempted to project the prevalence of obesity in the canton of Vaud in the next 25 years. Data from the Enquete suisse sur la sante, a survey conducted every five years since 1992 by the Swiss Federal Office of Public Health, were used. Using different mathematical assumptions, the rate of increase in the prevalence of obesity in Switzerland between 1992 and 2012 was calculated allowing a projection of future prevalences. Between 1992 and 2016, the prevalence of obesity was 9.64%. Effective growth rate of obesity from 2016 to 2040 should be between 16'500 cases and 69'500 cases depending on the uncertainty of the effective prevalence increase over this period. PMID- 28721705 TI - [When weight influences mental health... and reciprocally]. AB - Obesity and mental disorders are frequent diseases in our society and do not always receive the appropriate care. Moreover, it has been proved that obese people suffer more from mental disorders than the general population. This article reviews mental illnesses commonly found in obese people to raise awareness about their screening and treatment in order to improve both weight loss and the quality of life of people who are suffering from it. PMID- 28721706 TI - [Eating disorder and food addiction in a population candidates for a bariatric surgery]. AB - Non stabilized severe eating disorder is a contra-indication for bariatric surgery. Specific cares can stabilize this disorder, and therefore a surgery can be undertaken. In this respect, more and more attention is paid to the concept of food addiction even if its definition is still debated. Some authors, according to neurobiological data, consider food addiction as independent from eating disorder, but others see food addiction as a severe sub-type of eating disorder. To contribute to this debate, we performed a study in our department including 23 subjects candidates for a bariatric surgery and found a significant association between food addiction and eating disorder, independently of the body mass index. Clarification of the food addiction concept should permit to reconsider the specific cares needed by these obese patients. PMID- 28721707 TI - [Towards bariatric surgery : taking your time preserves you from loosing your time]. AB - Obesity has become a worldwide public health concern. Bariatric surgery is nowadays the most effective treatment to lose weight and control somatic comorbidities of this disease. However, a careful preparation of the patients undergoing bariatric surgery seems mandatory, despite the existence of a feeling of emergency that is often shared by the therapeutic team, and thus difficult to handle. In this context, the importance to address psychological issues such as patients' representation of their body while they will be confronted to a major physical transformation cannot be over-emphasized. Taking time is crucial to create a therapeutic context that raises the patients' awareness of their underlying psychological functioning. PMID- 28721708 TI - [Multidisciplinary management of dumping syndromes after bariatric surgery]. AB - Dumping syndromes are a frequent complication of gastric or bariatric surgery and include early and late dumping. Early dumping is a consequence of rapid delivery of hyperosmolar nutrients into the bowel. Late dumping is the result of a reactive hypoglycemia induced by a hyperinsulinemic response. These syndromes are becoming increasingly prevalent with the rising incidence of bariatric surgery. Effective management of these complications requires multidisciplinary collaboration. First line management of early and late dumping syndrome involves specific dietary and behavioral modifications which generally improve the quality of life of patients. PMID- 28721709 TI - [Paradoxal decrease and metabolic effects of BNP in obese patient]. AB - Natriuretic peptides (NP), ANP and BNP, are produced by cardiomyocytes when there is stretching of the ventricular and auricular walls in heart failure (HF). Their vasodilatator and natriuretic effect oppose to volume and pressure overload occurring in HF. Several studies have observed decreased levels of NP in obese and diabetic people and in patients with insulin resistance. This decrease could contribute to hypertension, frequently observed in obesity. NP have also a lipolytic action. Low levels of NP could promote obesity. Therefore in obese patients normal BNP levels cannot a priori exclude HF. Normal values must be adjusted according to obesity degree and heart failure stage. PMID- 28721710 TI - ? PMID- 28721711 TI - ? PMID- 28721712 TI - ? PMID- 28721714 TI - ? PMID- 28721713 TI - ? PMID- 28721715 TI - ? PMID- 28721716 TI - ? PMID- 28721717 TI - Microbial Transglutaminase Used in Bread Preparation at Standard Bakery Concentrations Does Not Increase Immunodetectable Amounts of Deamidated Gliadin. AB - The effect of standard bakery concentrations of microbial transglutaminase (MTG) in wheat bread preparation on the immunoreactivity of sera of celiac disease (CD) patients was investigated. Immunoblotting using monoclonal antibodies specific to unmodified and/or deamidated gliadin showed no differences between control bread and MTG bread. Deamidation of gliadin could not be detected at standard MTG concentrations. Sera of CD patients were characterized using anti-gliadin and anti-deamidated gliadin peptide (DGP) enzyme-linked immunosorbent assay and grouped into DGP high- and low-titer pools. The recognition pattern obtained after using both CD sera pools for immunoblotting did not reveal differences between control and MTG-treated bread protein extracts. Our results indicate that MTG treatment of wheat bread prepared with typical MTG concentrations used in standard bakery processes does not lead to immunodetectable amounts of CD immunotoxic deamidated gliadins. PMID- 28721718 TI - Sensitive Analysis of Nitroguanidine in Aqueous and Soil Matrices by LC-MS. AB - Nitroguanidine, a widely used nitramine explosive, is an environmental contaminant that is refractory, persistent, highly mobile in soils and aquifers, and yet under-researched. Nitroguanidine determination in water and soil poses an analytical challenge due its high hydrophilicity, low volatility, charge neutrality over a wide pH range, and low proton affinity which results in low electrospray interface (ESI)-MS sensitivity. A sensitive method for the determination of nitroguanidine in aqueous and soil matrices was developed. The method is based on reduction by zinc in acidic solution, hydrophobization by derivatization, preconcentration on C18 cartridge, and LC-MS quantification. The demonstrated limit of detection (LOD) reaches 5 ng/L and 22 ng/g in water and soil, respectively. Analysis of a contaminated site demonstrates that it is possible to map a contamination plume that extends over 1 km from the source of the contamination. PMID- 28721721 TI - Unveiling the Concentration-Dependent Grain Growth of Perovskite Films from One- and Two-Step Deposition Methods: Implications for Photovoltaic Application. AB - In order to achieve high-efficiency perovskite solar cells, understanding both the crystal structure and the optoelectronic properties of perovskite layers is of importance. This paper uses crystallization analysis and the modeling study of two different perovskite deposition methods (two- and one-step methods) and thereby shows that the one-step method embodies a film formation process that is dominated by crystal growth, while the dominant mechanism of the two-step procedure is nucleation. Our data based on experimental and theory shows that the one-step recipe is superior in terms of morphology control, and, hence, reproducibility, compared to the two-step recipe. PMID- 28721720 TI - Multicolor Tunable Luminescence Based on Tb3+/Eu3+ Doping through a Facile Hydrothermal Route. AB - Ln3+-doped fluoride is a far efficient material for realizing multicolor emission, which plays an important part in full-color displays, biolabeling, and MRI. However, studies on the multicolor tuning properties of Ln3+-doped fluoride are mainly concentrated on a complicated process using three or more dopants, and the principle of energy transfer mechanism is still unclear. Herein, multicolor tunable emission is successfully obtained only by codoping with Tb3+ and Eu3+ ions in beta-NaGdF4 submicrocrystals via a facile hydrothermal route. Our work reveals that various emission colors can be obtained and tuned from red, orange red, pink, and blue-green to green under single excitation energy via codoping Tb3+ and Eu3+ with rationally changed Eu3+/Tb3+ molar ratio due to the energy transfer between Tb3+ and Eu3+ ions in the beta-NaGdF4 host matrix. Meanwhile, the energy transfer mechanism in beta-NaGdF4: x Eu3+/y Tb3+ (x + y = 5 mol %) submicrocrystals is investigated. Our results evidence the potential of the dopants' distribution density as an effective way for analyzing energy transfer and multicolor-controlled mechanism in other rare earth fluoride luminescence materials. Discussions on the multicolor luminescence under a certain dopant concentration based on single host and wavelength excitation are essential toward the goal of the practical applications in the field of light display systems and optoelectronic devices. PMID- 28721719 TI - Imprinted NanoVelcro Microchips for Isolation and Characterization of Circulating Fetal Trophoblasts: Toward Noninvasive Prenatal Diagnostics. AB - Circulating fetal nucleated cells (CFNCs) in maternal blood offer an ideal source of fetal genomic DNA for noninvasive prenatal diagnostics (NIPD). We developed a class of nanoVelcro microchips to effectively enrich a subcategory of CFNCs, i.e., circulating trophoblasts (cTBs) from maternal blood, which can then be isolated with single-cell resolution by a laser capture microdissection (LCM) technique for downstream genetic testing. We first established a nanoimprinting fabrication process to prepare the LCM-compatible nanoVelcro substrates. Using an optimized cTB-capture condition and an immunocytochemistry protocol, we were able to identify and isolate single cTBs (Hoechst+/CK7+/HLA-G+/CD45-, 20 MUm > sizes > 12 MUm) on the imprinted nanoVelcro microchips. Three cTBs were polled to ensure reproducible whole genome amplification on the cTB-derived DNA, paving the way for cTB-based array comparative genomic hybridization (aCGH) and short tandem repeats analysis. Using maternal blood samples collected from expectant mothers carrying a single fetus, the cTB-derived aCGH data were able to detect fetal genders and chromosomal aberrations, which had been confirmed by standard clinical practice. Our results support the use of nanoVelcro microchips for cTB based noninvasive prenatal genetic testing, which holds potential for further development toward future NIPD solution. PMID- 28721722 TI - Pillar[5]arene-Based Supramolecular Plasmonic Thin Films for Label-Free, Quantitative and Multiplex SERS Detection. AB - Novel plasmonic thin films based on electrostatic layer-by-layer (LbL) deposition of citrate-stabilized Au nanoparticles (NPs) and ammonium pillar[5]arene (AP[5]A) have been developed. The supramolecular-induced LbL assembly of the plasmonic nanoparticles yields the formation of controlled hot spots with uniform interparticle distances. At the same time, this strategy allows modulating the density and dimensions of the Au aggregates, and therefore the optical response, on the thin film with the number of AuNP-AP[5]A deposition cycles. Characterization of the AuNP-AP[5]A hybrid platforms as a function of the deposition cycles was performed by means of visible-NIR absorption spectroscopy, and scanning electron and atomic force microscopies, showing larger aggregates with the number of cycles. Additionally, the surface enhanced Raman scattering efficiency of the resulting AuNP-AP[5]A thin films has been investigated for three different laser excitations (633, 785, and 830 nm) and using pyrene as Raman probe. The best performance was shown by the AuNP-AP[5]A film obtained with two deposition cycles ((AuNP-AP[5]A)2) when excited with a 785 laser line. The optical response and SERS efficiency of the thin films were also simulated using the M3 solver and employing computer aided design models built based on SEM images of the different films. The use of host molecules as building blocks to fabricate (AuNP-AP[5]A)2) films has enabled the ultradetection, in liquid and gas phase, of low molecular weight polyaromatic hydrocarbons, PAHs, with no affinity for gold but toward the hydrophobic AP[5]A cavity. Besides, these plasmonic platforms allowed achieving quantitative detection within certain concentration regimes. Finally, the multiplex sensing capabilities of the AuNP-AP[5]A)2 were evaluated for their ability to detect in liquid and gas phase three different PAHs. PMID- 28721723 TI - Enrichment of Long-Chain Polyunsaturated Fatty Acids by Coordinated Expression of Multiple Metabolic Nodes in the Oleaginous Microalga Phaeodactylum tricornutum. AB - Microalgal long-chain polyunsaturated fatty acids (LC-PUFAs) have emerged as promising alternatives to depleting fish oils. However, the overproduction of LC PUFAs in microalgae has remained challenging. Here, we report a sequential metabolic engineering strategy that systematically overcomes the metabolic bottlenecks and overproduces LC-PUFAs. Malonyl CoA-acyl carrier protein transacylase, catalyzing the first committed step in type II fatty acid synthesis, and desaturase 5b, involved in fatty acid desaturation, were coordinately expressed in Phaeodactylum tricornutum. Engineered microalgae hyper accumulated LC-PUFAs, with arachidonic acid (ARA) and docosahexaenoic acid (DHA) contents of up to 18.98 MUg/mg and 9.15 MUg/mg (dry weight), respectively. Importantly, eicosapentaenoic acid (EPA) was accumulated up to a highest record of 85.35 MUg/mg by metabolic engineering. ARA and EPA were accumulated mainly in triacylglycerides, whereas DHA was found exclusively in phospholipids. Combinatorial expression of these critical enzymes led to the optimal increment of LC-PUFAs without unbalanced metabolic flux and demonstrated the practical feasibility of generating sustainable LC-PUFA production. PMID- 28721724 TI - Addressing the Environment Electrostatic Effect on Ballistic Electron Transport in Large Systems: A QM/MM-NEGF Approach. AB - The effects of the environment in nanoscopic materials can play a crucial role in device design. Particularly in biosensors, where the system is usually embedded in a solution, water and ions have to be taken into consideration in atomistic simulations of electronic transport for a realistic description of the system. In this work, we present a methodology that combines quantum mechanics/molecular mechanics methods (QM/MM) with the nonequilibrium Green's function framework to simulate the electronic transport properties of nanoscopic devices in the presence of solvents. As a case in point, we present further results for DNA translocation through a graphene nanopore. In particular, we take a closer look into general assumptions in a previous work. For this sake, we consider larger QM regions that include the first two solvation shells and investigate the effects of adding extra k-points to the NEGF calculations. The transverse conductance is then calculated in a prototype sequencing device in order to highlight the effects of the solvent. PMID- 28721725 TI - Through-Space Communication Effects on the Electrochemical Reduction of Partially Oxidized Pillar[5]arenes Containing Variable Numbers of Quinone Units. AB - The electrochemical reduction of five partially oxidized pillar[5]arenes containing variable numbers (1-5) of quinone units was investigated in acetonitrile and dichloromethane solutions. The cathodic voltammetric behavior of all the macrocyclic compounds containing two or more quinone units indicates the existence of detectable levels of electronic communication between them. We have also investigated these compounds and their reduced forms using DFT computations. Our computational results indicate the presence of through-space communication between quinone units. PMID- 28721726 TI - 3D Printed "Earable" Smart Devices for Real-Time Detection of Core Body Temperature. AB - Real-time detection of basic physiological parameters such as blood pressure and heart rate is an important target in wearable smart devices for healthcare. Among these, the core body temperature is one of the most important basic medical indicators of fever, insomnia, fatigue, metabolic functionality, and depression. However, traditional wearable temperature sensors are based upon the measurement of skin temperature, which can vary dramatically from the true core body temperature. Here, we demonstrate a three-dimensional (3D) printed wearable "earable" smart device that is designed to be worn on the ear to track core body temperature from the tympanic membrane (i.e., ear drum) based on an infrared sensor. The device is fully integrated with data processing circuits and a wireless module for standalone functionality. Using this smart earable device, we demonstrate that the core body temperature can be accurately monitored regardless of the environment and activity of the user. In addition, a microphone and actuator are also integrated so that the device can also function as a bone conduction hearing aid. Using 3D printing as the fabrication method enables the device to be customized for the wearer for more personalized healthcare. This smart device provides an important advance in realizing personalized health care by enabling real-time monitoring of one of the most important medical parameters, core body temperature, employed in preliminary medical screening tests. PMID- 28721727 TI - Synthesis of Intricate Fused N-Heterocycles via Ring-Rearrangement Metathesis. AB - Herein, a facile synthesis of intricate fused N-heterocycles is disclosed by employing C-H activation and ring-rearrangement metathesis/enyne ring rearrangement metathesis as key steps. Interestingly, some of these N heterocyclic products possess the tricyclic core of epimeloscine, deoxycalyciphylline B, daphlongamine H, isodaphlongamine H, and a bioactive alkaloid, annotinolide A, which shows antiaggregation activity against amyloid beta (Abeta)1-42 peptide aggregation. Moreover, various starting materials required in this protocol are easily assembled via C-X bond annulation of 2-bromo N-protected aniline with norbornadiene or directing group-assisted ruthenium catalyzed C-H activation of N-methoxybenzamide. PMID- 28721728 TI - Reduced Production of Higher Alcohols by Saccharomyces cerevisiae in Red Wine Fermentation by Simultaneously Overexpressing BAT1 and Deleting BAT2. AB - In red wine, the contents of higher alcohols and ethyl carbamate (EC) are two significant health concerns. To reduce the production of higher alcohols by wine yeast YZ22 with low production of EC, one BAT2 was replaced by a BAT1 expression cassette first and then another BAT2 was deleted to obtain the mutant SYBB3. Real time quantitative PCR showed that the relative expression level of BAT1 in SYBB3 improved 28 times compared with that in YZ22. The yields of isobutanol and 3 methyl-1-butanol produced by mutant SYBB3 reduced by 39.41% and 37.18% compared to those by the original strain YZ22, and the total production of higher alcohols decreased from 463.82 mg/L to 292.83 mg/L in must fermentation of Cabernet Sauvignon. Meanwhile, there were no obvious differences on fermentation characteristics of the mutant and parental strain. This research has suggested an effective strategy for decreasing production of higher alcohols in Saccharomyces cerevisiae. PMID- 28721729 TI - Impact of Cl Doping on Electrochemical Performance in Orthosilicate (Li2FeSiO4): A Density Functional Theory Supported Experimental Approach. AB - Safe and high-capacity cathode materials are a long quest for commercial lithium ion battery development. Among various searched cathode materials, Li2FeSiO4 has taken the attention due to optimal working voltage, high elemental abundance, and low toxicity. However, as per our understanding and observation, the electrochemical performance of this material is significantly limited by the intrinsic low electronic conductivity and slow lithium-ion diffusion, which limits the practical capacity (a theoretical value of ~330 mAh g-1). In this report, using first-principles density functional theory based approach, we demonstrate that chlorine doping on oxygen site can enhance the electronic conductivity of the electrode and concurrently improve the electrochemical performance. Experimentally, X-ray diffraction, X-ray photoelectron spectroscopy, and field-emission gun scanning electron microscopy elemental mapping confirms Cl doping in Li2-xFeSiO4-xClx/C (x <= 0.1), while electrochemical cycling performance demonstrated improved performance. The theoretical and experimental studies collectively predict that, via Cl doping, the lithium deinsertion voltage associated with the Fe2+/Fe3+ and Fe3+/Fe4+ redox couples can be reduced and electronic conductivity can be enhanced, which opens up the possibility of utilization of silicate-based cathode with carbonate-based commercial electrolyte. In view of potential and electronic conductivity benefits, our results indicate that Cl doping can be a promising low-cost method to improve the electrochemical performance of silicate-based cathode materials. PMID- 28721730 TI - Heterologous Expression and Characterization of a Novel Chitinase (ChiEn1) from Coprinopsis cinerea and its Synergism in the Degradation of Chitin. AB - Chitinase ChiEn1 did not hydrolyze insoluble chitin but showed hydrolysis and transglycosylation activities toward chitin-oligosaccharides. Interestingly, the addition of ChiEn1 increased the amount of reducing sugars released from chitin powder by endochitinase ChiIII by 105.0%, and among the released reducing sugars the amount of (GlcNAc)2 was increased by 149.5%, whereas the amount of GlcNAc was decreased by 10.3%. The percentage of GlcNAc in the products of chitin powder with the combined ChiIII and ChiEn1 was close to that in the products of chitin oligosaccharides with ChiEn1, rather than that with ChiIII. These results indicate that chitin polymers are first degraded into chitin oligosaccharides by ChiIII and the latter are further degraded to monomers and dimers by ChiEn1, and the synergistic action of ChiEn1 and ChiIII is involved in the efficient degradation of chitin in cell walls during pileus autolysis. The structure modeling explores the molecular base of ChiEn1 action. PMID- 28721731 TI - Self-Assembled Injectable Peptide Hydrogels Capable of Triggering Antitumor Immune Response. AB - Self-assembled peptide hydrogels are particularly appealing for drug delivery, tissue engineering, and antitumor therapy due to various advantageous features including excellent biocompatibility and biodegradability, defined molecular and higher organized structures, and easy availability. However, the poor mechanical and rheological properties of assembled peptide hydrogels cause difficulties in injection, thus limiting further applications. Herein, injectable peptide-based hydrogels with tunable mechanical and rheological properties were obtained by combination with a positively charged poly peptide (poly-l-lysine, PLL). Electrostatic coupling between PLL and a self-assembling dipeptide (Fmoc-FF) provides a smart switch to enable the fibrous hydrogels to be shear-thinning and self-healing, thus leading to the formation of supramolecular hydrogels with rheological properties suitable for injection. The latter can be flexibly adjusted by merely varying the concentration or the molecular weight of the polypeptide to satisfy a variety of requirements in biological applications. The hydrogels, consisting of helical nanofibers stabilized with disulfide bonds, are prepared and further injected for antitumor therapy. The results demonstrate that the helical fibrous hydrogel, without the addition of antigens, immune regulatory factors, and adjuvants, can activate T cell response and efficiently suppress tumor growth. Therefore, injectable hydrogels self-assembled by a combination of small peptides and biomacromolecules present a great potential for biomedical applications, especially for development of a new type of immuno-responsive materials toward antitumor therapy. PMID- 28721732 TI - Radical Addition/Insertion/Cyclization Cascade Reaction To Assemble Phenanthridines from N-Arylacrylamide Using Cyano as a Bridge under Photoredox Catalysis. AB - A radical addition/nitrile insertion/homolytic aromatic substitution (HAS) cascade reaction to prepare 6-quaternary alkylated phenanthridines was developed. The addition of the active methylene radicals which were generated from 2 bromoacetonitrile, ethyl 2-bromoacetate, 2-bromo-N,N-dimethylacetamide, or 2 bromo-1-phenylethan-1-one to carbon-carbon double bonds of N-arylacrylamides followed by the cyano-participating sequential cyclization produced a series of phenanthridines in moderate to good yields under photoredox catalysis. PMID- 28721733 TI - Approach to the Synthesis of 2,3-Disubstituted-3H-quinazolin-4-ones Mediated by Ph3P-I2. AB - Readily available N-substituted amides or their requisite carboxylic acids or acid chlorides have been used to construct 2,3-disubstituted-3H-quinazolin-4-ones in a one-pot procedure. Key transformation in this convergent approach involves Ph3P-I2-mediated formation of amidine upon condensation of an amide or the intermediate amide with methyl anthranilate. Cyclization of the amidine-tethered anthranilate then affords 2,3-disubstituted-3H-quinazolin-4-ones in good to excellent yields under mild conditions. PMID- 28721735 TI - Dynamic Color Displays Using Stepwise Cavity Resonators. AB - High-resolution multicolor printing based on pixelated optical nanostructures is of great importance for promoting advances in color display science. So far, most of the work in this field has been focused on achieving static colors, limiting many potential applications. This inevitably calls for the development of dynamic color displays with advanced and innovative functionalities. In this Letter, we demonstrate a novel dynamic color printing scheme using magnesium-based pixelated Fabry-Perot cavities by gray scale nanolithography. With controlled hydrogenation and dehydrogenation, magnesium undergoes unique metal and dielectric transitions, enabling distinct blank and color states from the pixelated Fabry-Perot resonators. Following such a scheme, we first demonstrate dynamic Ishihara plates, in which the encrypted images can only be read out using hydrogen as information decoding key. We also demonstrate a new type of dynamic color generation, which enables fascinating transformations between black/white printing and color printing with fine tonal tuning. Our work will find wide ranging applications in full-color printing and displays, colorimetric sensing, information encryption and anticounterfeiting. PMID- 28721734 TI - Enantioselective Total Synthesis of Nigelladine A via Late-Stage C-H Oxidation Enabled by an Engineered P450 Enzyme. AB - An enantioselective total synthesis of the norditerpenoid alkaloid nigelladine A is described. Strategically, the synthesis relies on a late-stage C-H oxidation of an advanced intermediate. While traditional chemical methods failed to deliver the desired outcome, an engineered cytochrome P450 enzyme was employed to effect a chemo- and regioselective allylic C-H oxidation in the presence of four oxidizable positions. The enzyme variant was readily identified from a focused library of three enzymes, allowing for completion of the synthesis without the need for extensive screening. PMID- 28721736 TI - Ru-Catalyzed Meta-C-H Benzylation of Arenes with Toluene Derivatives. AB - The Ru-catalyzed meta-C-H benzylation of arenes bearing pyridyl, pyrimidyl, and pyrazolyl directing groups with toluene derivatives has been reported. Heptafluoroisopropyl iodide (iC3F7I) was employed as both a mild oxidant and radical initiator. This reaction showed excellent site-selectivity and tolerated a wide range of functional groups, providing a new strategy for the synthesis of various diarylmethane moieties. PMID- 28721737 TI - A New Water-Soluble Nanomicelle Formed through Self-Assembly of Pectin-Curcumin Conjugates: Preparation, Characterization, and Anticancer Activity Evaluation. AB - Curcumin is a dominating active component of Curcuma longa and has been studied widely because of its prominent biological activities. The extremely low aqueous solubility, stability, and bioavailability of curcumin limit its application in the field of medicine. In this study, we developed pectin-curcumin (PEC-CCM) conjugates that could self-assemble water-soluble nanomicelles in aqueous solution. The structure of PEC-CCM conjugates was characterized by ultraviolet visible spectra, fluorescence spectra, Fourier transform infrared spectroscopy, and 1H nuclear magnetic resonance spectroscopy. The thermal property of PEC-CCM conjugates was investigated by thermogravimetric analysis. It was found that PEC CCM conjugates had formed nanomicelles in aqueous medium via self-assembly. These nanomicelles were observed as small spheres or ellipsoids and aggregated with a size range of 70-190 nm by transmission electron microscopy analysis. In a solution of nanomicelles, the stability of curcumin was improved, and its antioxidant property was preserved. The anticancer activity of PEC-CCM conjugates was quantified by the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay using a hepatic cancer cell line (HepG2), a breast cancer cell line (MCF-7), a cervical cancer cell line (HeLa), and a human normal kidney cell line (293A). It was found that the curcumin of PEC-CCM conjugates had a more significant inhibitory effect on cancer cells and was less cytotoxic to normal cells than free curcumin was. PEC-CCM conjugates have great potential for some food and pharmaceutical applications. PMID- 28721738 TI - Counting bodies? On future engagements with science studies in medical anthropology. AB - Thirty years ago, Nancy Scheper-Hughes and Margaret Lock outlined a strategy for 'future work in medical anthropology' that focused on three bodies. Their article - a zeitgeist for the field - sought to intervene into the Cartesian dualisms characterizing ethnomedical anthropology at the time. Taking a descriptive and diagnostic approach, they defined 'the mindful body' as a domain of future anthropological inquiry and mapped three analytic concepts that could be used to study it: the individual/phenomenological body, the social body, and the body politic. Three decades later, this paper returns to the 'three bodies'. It analyses ethnographic fieldwork on chronic illness, using a rescriptive, practice oriented approach to bodies developed by science studies scholars that was not part of the initial three bodies framework. It illustrates how embodiment was a technical achievement in some practices, while in others bodies did not figure as relevant. This leads to the suggestion that an anthropology of health need not be organized around numerable bodies. The paper concludes by suggesting that future work in medical anthropology might embrace translational competency, which does not have the goal of better definitions (better health, better bodies, etc.) but the goal of better engaging with exchanges between medical and non-medical practices. That health professionals are themselves moving away from bodies to embrace 'planetary health' makes a practice-focused orientation especially crucial for medical anthropology today. PMID- 28721739 TI - Birds, meat, and babies: the multiple realities of fetuses in Qatar. AB - This paper explores miscarriage in a variety of Qatari contexts to reveal the multiple realities of the unborn. During 18 months of ethnographic research, a range of settings in which fetuses emerged were explored. The unborn are represented and imagined differently, particularly in relation to the ways they are located, with multiple beings emerging according to the context and position of the stakeholder. This paper considers fetuses produced within these contexts and considers how they can be different beings simultaneously. The paper reveals how categories meant to define these beings are in flux and are constantly negotiated; it reflects moments of ambiguity. The paper serves as an illustration of the way in which value-afforded pregnancy materials affects the contexts in which they emerge; this then loops back as context dictates the significance of the material, hence multiple realities of these beings. PMID- 28721740 TI - Clinical features and subjective/physiological responses to emotional stimuli in the presence of emotion dysregulation in attention-deficit hyperactivity disorder. AB - INTRODUCTION: Emotion dysregulation (ED) has long been recognized in clinical descriptions of attention-deficit hyperactivity disorder (ADHD), but a renewed interest in ED has advanced research on the overlap between the two entities. Autonomic reactivity (AR) is a neurobiological correlate of emotion regulation; however, the association between ADHD and AR remains unclear. Our aim was to explore the clinical differences, AR, and subjective emotional responses to visual emotional stimuli in ADHD children with and without ED. METHOD: School aged ADHD children with (n = 28) and without (n = 20) ED, according to the definition of deficiency in emotional self-regulation (DESR), and healthy controls (n = 22) were interviewed by using the Schedule for Affective Disorders and Schizophrenia for School Aged Children-Present and Lifetime version (K-SADS PL) to screen frequent psychopathologies for these ages. All subjects were evaluated with Child Behavior Checklist 6-18 (CBCL), the Strengths and Difficulties Questionnaire (SDQ), the McMaster Family Assessment Device (FAD), the School-Age Temperament Inventory (SATI), and Conners' Parent Rating Scale (CPRS-48), which were completed by parents. To evaluate emotional responses, the International Affective Picture System (IAPS) and the subjective and physiological responses (electrodermal activity and heart rate reactivity) to selected pictures were examined. RESULTS: Regarding clinically distinctive features, the ADHD+ED group differed from the ADHD-ED and the control groups in terms of having higher temperamental negative reactivity, more oppositional/conduct problems, and lower prosocial behaviors. In the AR measures, children in the ADHD+ED group rated unpleasant stimuli as more negative, but they still had lower heart rate reactivity (HRR) than the ADHD-ED and control groups; moreover, unlike the two other groups, the ADHD+ED group showed no differences in HRR between different emotional stimuli. CONCLUSION: The presented findings are unique in terms of their ability to clinically and physiologically differentiate between ADHD children with and without ED. PMID- 28721741 TI - The relevance of hippocampal subfield integrity and clock drawing test performance for the diagnosis of Alzheimer's disease and mild cognitive impairment. AB - OBJECTIVES: The clock drawing test (CDT) is one of the worldwide most used screening tests for Alzheimer's disease (AD). MRI studies have identified temporo parietal regions being involved in CDT impairment. However, the contributions of specific hippocampal subfields and adjacent extrahippocampal structures to CDT performance in AD and mild cognitive impairment (MCI) have not been investigated so far. It is unclear whether morphological alterations or CDT score, or a combination of both, are able to predict AD. METHODS: 38 AD patients, 38 MCI individuals and 31 healthy controls underwent neuropsychological assessment and MRI at 3 Tesla. FreeSurfer 5.3 was used to perform hippocampal parcellation. We used a collection of statistical methods to better understand the relationship between CDT and hippocampal formation. We also tested the clinical feasibility of this relationship when predicting AD. RESULTS: Impaired CDT performance in AD was associated with widespread atrophy of the cornu ammonis, presubiculum, and subiculum, whereas MCI subjects showed CDT-related alterations of the CA4-dentate gyrus and subiculum. CDT correlates in AD and MCI showed regional and quantitative overlap. Importantly, CDT score was the best predictor of AD. CONCLUSIONS: Our findings lend support for an involvement of different hippocampal subfields in impaired CDT performance in AD and MCI. CDT seems to be more efficient than subfield imaging for predicting AD. PMID- 28721742 TI - Mindfulness-based stress reduction in middle-aged and older adults with memory complaints: a mixed-methods study. AB - OBJECTIVES: In a rapidly aging world population, an increasingly large group faces age-related decline in cognitive functioning. Cognitive complaints of older adults are often related to worries and concerns associated with age-related functional decline. Mindfulness-Based Stress Reduction (MBSR) can successfully target stress, worry and ruminative thinking, but the applicability of this method in middle-aged and older adults with memory complaints is unclear. METHOD: Patients of a university hospital memory clinic (n = 13), aged 45-85 years, with memory complaints but no diagnosis of cognitive disorder, participated in a standard 8-week MBSR program, consisting of weekly group meetings and a one-day silent retreat. After completion, semi-structured qualitative interviews were conducted. Questionnaires (administered before, one week after and five weeks after the intervention) assessed quality of life, psychological distress (stress, anxiety and depressive symptoms), mindfulness, self-compassion, and subjective memory functioning. Neurocognitive functioning was assessed online, before and after the intervention. RESULTS: The qualitative analysis showed positive effects of the training (e.g. increased serenity), many participants worrying less about memory complaints. The self-reported measures were in line with the results of the qualitative analysis. CONCLUSION: This exploratory mixed-methods study suggests that MBSR is feasible and well received among older individuals with cognitive complaints. PMID- 28721743 TI - Responses of human hepatoma HepG2 cells to silver nanoparticles and polycyclic aromatic hydrocarbons. AB - The nanotechnology has revolutionized the global market with silver nanoparticles (AgNP) occupying a prominent position due to their remarkable anti-bacterial properties. However, there is no data about the adverse and toxic effects of associations of AgNP and ubiquitous compounds, such as polycyclic aromatic hydrocarbons (PAH). In the current study, we investigated the responses of HepG2 cells to realistic concentrations of AgNP (0.09, 0.9, and 9 ng ml-1) and mixture of PAH (30 and 300 ng ml-1), separately and in association. Cell viability and cytotoxicity (neutral red retention and MTT production assays) and proliferation (crystal violet [CV] assay), xenobiotic efflux transporter activity (rhodamine B accumulation assay), ROS levels (dichlorodihydrofluorescein diacetate assay), and lipid peroxidation (pyrenylphosphine-1-diphenyl assay) were analyzed. There was no decreases of cell viability after exposure to AgNP, PAH and most of AgNP + PAH associations, but increases of cell viability/number (CV assay) occurred. Efflux transporter activity was not affected, with exception of one AgNP + PAH associations, ROS levels increased, but lipid peroxidation decreased. Some toxicological interactions occurred, particularly for the highest concentrations of AgNP and PAH, but there is no evidence that these interactions increased the toxicity of AgNP and PAH. PMID- 28721744 TI - Entangled local biologies: genetic risk, bodies and inequities in Brazilian cancer genetics. AB - Engaging recent social science work examining the truth making claims of science and biomedicine, this paper explores how biology is being localised in Brazilian cancer genetics. It draws from ethnographic fieldwork in urban regions of southern Brazil working with and alongside patients, families and practitioners in cancer genetic clinics. It examines how different sorts of 'local biologies' are articulated in the context of research, clinical practice and among implicated patient communities and the way these can 'recursively' move across different spheres and scales of social action to extend and transform the meaning of the biological. It shows how the mattering of the biological in Brazilian cancer genetics is fundamentally informed by questions of inequity and care, even while multiple local biologies may obscure rather than reveal the biopolitics of cancer. In an era of epigenetics this raises new opportunities and challenges for anthropological analysis as intervention. PMID- 28721745 TI - Pesticide genotoxicity in cotton picking women in Pakistan evaluated using comet assay. AB - To control agricultural pests and meet the increasing food demands, pesticides use has been increased substantially over time. Although pesticides are relatively specific to their targets, they can affect non-target organisms and are hazardous for the population around the application areas particularly to the individuals engaged in different types of agricultural activities. This situation is worse in developing and under-developed countries where personal protective equipment is merely used and regulatory guidelines are hardly practiced. In the present study, DNA damage in women exposed to pesticides while picking cotton with bare hands was assessed using single cell gel electrophoresis assay or comet assay. The presence of pesticides in blood serum of exposed individuals was also analyzed using high-performance liquid chromatography. Blood samples were collected from 138 (69 exposed and 69 control) randomly selected females from a major cotton growing area (Bahawalpur District) of the Punjab province of Pakistan. DNA damage, as determined by the mean comet tail length, was significantly higher (p < 0.001) in the exposed group compared to the unexposed. A positive correlation of DNA damage with age and exposure time was also observed. Residues of three pesticides, cyhalothrin, endosulfan, and deltamethrin found significantly higher (p < 0.001) in the serum samples of the exposed group compared to the unexposed. It was observed that the groups with higher mean comet tail length also had a higher concentration of pesticides in their serum samples indicating a positive association of DNA damage and pesticide exposure. The present study suggests that exposure to pesticides leads to DNA damage. PMID- 28721747 TI - Faster VO2 kinetics after priming exercises of different duration but same fatigue. AB - This study compared the responses of two priming exercises of similar fatigue on the adjustment of the oxygen uptake time constant (tauVO2) in cycling. Ten healthy young adults (25 +/- 3 yr) performed: three step transitions from a 20-W baseline to the power output (PO) below the gas exchange threshold (MOD, MODPRE); a 3-min bout (P3MIN) at 90% of peak PO (POpeak), followed by MOD (MOD3MIN); and a 6-min bout (P6MIN) at 80% of POpeak, followed by MOD (MOD6MIN). The O2 supply-to O2 demand ([HHb]/VO2) ratio was calculated for MODPRE, MOD3MIN, and MOD6MIN. Neuromuscular fatigue was measured isometrically pre- and post-priming exercise. Reductions in maximal voluntary contraction (-29 +/- 6 vs -34 +/- 7%) and high frequency doublet amplitude (-48 +/- 13 vs -43 +/- 11%) were not significantly different between P3MIN vs P6MIN, suggesting similar fatigue. tauVO2 for MOD3MIN and MOD6MIN were similar, being ~25% smaller than MODPRE. The [HHb]/VO2 ratio was significantly greater in MODPRE (1.13 +/- 0.12) compared to MOD3MIN (1.02 +/- 0.04) and MOD6MIN (1.02 +/- 0.04). This study showed that priming exercise of shorter duration and higher intensity, was sufficient to accelerate VO2 kinetics similarly to that observed subsequent to P6MIN when the muscle fatigue was similar. PMID- 28721748 TI - Influence of nationality on the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS). AB - OBJECTIVE: In answer to the call for improved accessibility of neuropsychological services to the international community, the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS; MS) was validated in multiple, non English-speaking countries. It was created to monitor processing speed and learning in MS patients, including abbreviated versions of the Symbol Digit Modalities Test, California Verbal Learning Test, 2nd Edition, and the Brief Visuospatial Memory Test, Revised. The objective of the present study was to examine whether participant nationality impacts performance above and beyond common demographic correlates. METHOD: We combined published data-sets from Argentina, Brazil, Czech Republic, Iran, and the U.S.A. resulting in a database of 1,097 healthy adults, before examining the data via multiple regression. RESULTS: Nationality significantly predicted performance on all three BICAMS tests after controlling for age and years of education. Interactions among the core predictor variables were non-significant. CONCLUSION: We demonstrated that nationality significantly influences BICAMS performance and established the importance of the inclusion of a nationality variable when international norms for the BICAMS are constructed. PMID- 28721749 TI - Preservation and stability of cell therapy products: recommendations from an expert workshop. AB - If the field of regenerative medicine is to deliver therapies, rapid expansion and delivery over considerable distances to large numbers of patients is needed. This will demand efficient stabilization and shipment of cell products. However, cryopreservation science is poorly understood by life-scientists in general and in recent decades only limited progress has been made in the technology of preservation and storage of cells. Rapid translation of new developments to a broader range of cell types will be vital, as will assuring a deeper knowledge of the fundamental cell biology relating to successful preservation and recovery of cell cultures. This report presents expert consensus on these and other issues which need to be addressed for more efficient delivery of cell therapies. PMID- 28721752 TI - New Editor-in-Chief for Avian Pathology. PMID- 28721750 TI - Control diet in a high-fat diet study in mice: Regular chow and purified low-fat diet have similar effects on phenotypic, metabolic, and behavioral outcomes. AB - BACKGROUND: Differences in the composition of control diets may confound outcomes in studies investigating dietary effects. OBJECTIVE: We compared the effects of two control diets commonly used in mice studies, chow (SD) and a purified low-fat diet (LFD), in relation to a chronic high-fat diet (HFD). We hypothesized that SD and LFD will have similar effects on phenotypic, metabolic, and behavioral outcomes. METHODS: Fifty-four 5-week-old male C57BL/6J mice were randomly assigned to one of the three dietary interventions (SD, LFD, or HFD) for 18 weeks. At week 16, mice were tested for behavioral changes. Glucose tolerance testing was conducted at week 17 and terminal blood collection at week 18. RESULTS: SD and LFD mice exhibited no differences in cognitive performance on the Y-maze test and comparable anxiety-like behavior in the open-field and elevated zero maze tests. Significant declines in cognitive function and greater anxiety like behavior were observed in the HFD group compared to both SD and LFD. Areas under the glucose tolerance curve were similar for SD and LFD, as were levels of high-density lipoprotein, triglycerides, cytokines, and adipocytokines. Only total cholesterol was significantly higher in LFD mice compared to SD mice. All measures were significantly higher in the HFD group. DISCUSSION: Our data demonstrate that young mice develop similar phenotypic, metabolic, and behavioral profiles when fed SD vs. LFD. The two diets may thus be equally appropriate as controls for an HFD, although some studies may want to consider differences in effects on cholesterol levels. PMID- 28721753 TI - Nintedanib in ovarian cancer. AB - INTRODUCTION: Advanced ovarian cancer remains an unmet clinical need. Angiogenesis is considered a therapeutic target in ovarian cancer, with bevacizumab, a monoclonal antibody against VEGF, being the first drug to show a progression-free survival benefit. Nintedanib is an oral tyrosine kinase inhibitor targeting VEGF receptor 1-3, FGFR 1-3 and PDGFR alpha and beta, which has entered phase III trial development in ovarian cancer. Areas covered: This article reviews the preclinical and clinical efficacy of nintedanib in ovarian cancer, its pharmacokinetic and pharmacodynamics profile, safety issues, together with an overview of clinical trials carried out so far. A literature search was made in PubMed for nintedanib, ovarian cancer, angiogenesis, and on ClinicalTrials.gov site for clinical trials with nintedanib. Expert opinion: An ongoing phase III trial investigating nintedanib combined with first-line chemotherapy in ovarian cancer has shown a statistically significant progression free survival benefit, although there were toxicity issues. The true clinical benefit of nintedanib in ovarian cancer including its optimal treatment setting and dosage still need to be addressed. PMID- 28721754 TI - A model of adaptation for families of elderly patients with dementia: focusing on family resilience. AB - OBJECTIVES: We constructed a model explaining families' positive adaptation in chronic crisis situations such as the problematic behavior of elderly patients with dementia and attendant caregiving stress, based on the family resilience model. Our aim was to devise an adaptation model for families of elderly patients with dementia. METHOD: A survey of problematic behavior in elderly patients with dementia, family stress, family resilience, and family adaptation was conducted with 292 consenting individuals. The collected data were analyzed using structural equation modeling. RESULTS: The communication process, family stress, and problematic behavior of elderly patients with dementia had direct and indirect effects on family adaptation, while belief system, organization pattern, and social support had indirect effects. Specifically, family stress and more severe problematic behavior by elderly patients with dementia negatively influenced family adaptation, while greater family resilience improved such adaptation. CONCLUSION: Interventions aiming to enhance family resilience, based on the results of this study, are required to help families with positive adaptation. Such family programs might involve practical support such as education on the characteristics of elderly persons with dementia and coping methods for their problematic behavior; forming self-help groups for families; revitalizing communication within families; and activating communication channels with experts. PMID- 28721755 TI - ClinicalTrials.gov, stem cells and 'pay-to-participate' clinical studies. AB - Numerous US businesses that engage in direct-to-consumer advertising of stem cell interventions that are not US FDA-approved also recruit clients by listing 'pay to-participate' studies listed on ClinicalTrials.gov . Individuals considering enrolling in such studies and NIH officials responsible for overseeing the database need to be aware that some businesses are using the registry to promote unapproved stem cell interventions that study subjects are charged to receive. Inclusion of such studies in ClinicalTrials.gov reveals that the database needs better screening tools. In particular, screening should evaluate whether studies submitted to the registry have been reviewed and permitted to proceed by the FDA in the case of clinical studies requiring FDA clearance in addition to institutional review board approval. PMID- 28721756 TI - Lycopene Ameliorates Experimental Colitis in Rats via Reducing Apoptosis and Oxidative Stress. AB - Inflammatory bowel disease (IBD) is an inflammatory disorder involving colitis. Lycopene is a naturally occurring carotenoid that has attracted considerable attention as a potential chemopreventive agent. The impact of lycopene on colitis is currently unknown. The aim of this study was to investigate the protective effects of lycopene in a rat model of colitis induced by acetic acid. The animals were randomly divided into the following five groups: the control group, colitis group, colitis + sulfasalazine group as a positive control group, colitis + lycopene and lycopene groups. Colonic mucosal injury was assessed by biochemical and histopathological examinations. Malondialdehyde (MDA), superoxide dismutase (SOD) activity, total antioxidant status (TAS), ceruloplasmin (CPN), total sialic acid and iron (Fe) levels were evaluated in blood samples. MDA, SOD, TAS and DNA fragmentation levels were also measured in colon tissues. MDA (p < 0.05), total sialic acid (p < 0.05) and DNA fragmentation levels (p < 0.01) were significantly higher, and the activity of the antioxidant enzyme were lower in the colitis group than in the control group. Treatments with lycopene in the colitis decreased MDA, total sialic acid and DNA fragmentation levels, while SOD activity (p < 0.05), TAS (in colon p < 0.05; in serum p < 0.01), CPN (p < 0.05) and Fe levels (p < 0.05) were significantly increased. The histopathological evaluation also confirmed the foregoing findings. Treatment with lycopene ameliorated the biochemical and pathological alterations caused by colitis. The results obtained in this study indicate that lycopene may exert protective effects in experimental colitis and might, therefore, be useful for treatment of IBD. PMID- 28721757 TI - Higher childhood intelligence linked to longer life. AB - Higher intelligence in childhood is associated with lower lifetime risk of major causes of death, including heart disease, stroke, smoking-related cancers, respiratory disease and dementia. PMID- 28721759 TI - Menopause symptoms can fool women into quitting cancer drugs. AB - Women are mistaking menopause symptoms for side effects of potentially lifesaving breast cancer drugs, causing them to stop treatment. PMID- 28721758 TI - Mental capacity law. AB - What was the nature of the CPD activity, practice-related feedback and/or event and/or experience in your practice? The article provided information about mental capacity law. It outlined how capacity assessments are undertaken, and how best interests decisions should be made for those who lack capacity. PMID- 28721760 TI - Stroke in childhood. AB - Essential facts About 400 children a year have a stroke in the UK. Many are left with severe disability. While there have been improvements in diagnosis and treatment in recent years, the condition is still not as well recognised as stroke in adults. Experts believe that greater awareness among parents and healthcare professionals could lead to speedier diagnosis and minimise risk of severe long-term health problems. PMID- 28721761 TI - 'Always listen, reflect and learn'. AB - Jodie Deards, winner of the RCNi Nurse Awards 2017 Commitment to Carers category, earned her degree as part of Australia's first cohort of university-trained nurses in 1993. She came to the UK on a two-year working holiday in 2000 but stayed. After 10 years in the renal unit at Lister Hospital in Stevenage, she took up posts as a community diabetes specialist nurse, practice nurse and community matron. Her current role as carers lead has brought her back to Lister Hospital, part of East and North Hertfordshire NHS Trust. PMID- 28721763 TI - 'Run, hide, tell' applies to nurses too. AB - Nursing student Rhiannon Owen was at a cash machine in a busy area of London on a Saturday night when a taxi swerved towards her and the driver screamed at her to run. Looking up, she saw a man three metres away holding a knife with a 12-inch blade. PMID- 28721762 TI - Case of Memories: unlocking the past for former nurses with dementia. AB - Vintage-looking ear syringes, blood pressure monitors and other equipment from the early days of the NHS all feature in a nurse's case being used to help people living with dementia. PMID- 28721764 TI - Your chance to shape the future of the RCN and the profession. AB - Offering you the chance to join a committee is unlikely to set your pulse racing, so let's put it another way: would you like to join a group of dynamic nurses who will help shape the future of the RCN and the wider nursing profession? If the answer is yes, then read on. PMID- 28721765 TI - 'My clinical nurse specialist is always there to offer advice and support'. AB - Joanne King is such a lovely, caring person, and it means a lot as a patient when you're cared for by someone like that. PMID- 28721768 TI - Older nurses more likely not to renew registration since start of revalidation. AB - Increased numbers of older nurses have left the register since the introduction of revalidation, the Nursing and Midwifery Council (NMC) revealed. PMID- 28721766 TI - Nurse who claimed he was a surgeon struck off. AB - A nurse who lied to his doctor wife and friends for seven years about being a leading surgeon has been struck off the Nursing and Midwifery Council (NMC) register. PMID- 28721770 TI - Study to investigate how nurse-led CBT can support women with breast cancer. AB - Breast care nurses are being trained to offer talking therapy in an effort to improve treatment for hot flushes and night sweats. PMID- 28721771 TI - Picture this: photos improve wound management. AB - Harefield Hospital's clinical nurse specialist in surveillance Melissa Rochon introduced Photo at Discharge (PaD) to reduce the impact of surgical site infections (SSIs). PMID- 28721773 TI - Nurses' charity reports steep rise in calls for support. AB - A charity that supports nurses in hardship is concerned at a steep rise in calls since the start of 2016. PMID- 28721775 TI - Student life - Flexible pathway into the profession for support staff. AB - As the shape of the UK nursing workforce changes, partnership working between employers and educational institutions can help recruit and retain staff. PMID- 28721776 TI - It's every nurse's duty to help prevent terrorism. AB - Manchester is my home city and, like many people across the North West and in London, I have been devastated by the appalling terrorist attacks of recent months, which have felt very close to home. We can all be proud of the incredible way that the NHS family responded to the attacks, swiftly and with such heroic professionalism. PMID- 28721777 TI - Standards help to keep nurses and patients safe. AB - The proposed withdrawal of the standards for medicines management is potentially detrimental to nurses and patients. Medicines legislation is extremely complicated. The standards help practitioners understand what is legal and what is illegal, as well as legislation on licenced, off-licence and unlicensed medicines and the impact this could have on them. PMID- 28721778 TI - The government must listen to global advice and invest in the NHS. AB - A recent report from the RCN estimates there are 40,000 registered nurse vacancies in England alone, a figure that has doubled in the past three years. PMID- 28721779 TI - An opportunity to steer the work of the RCN. AB - Are you passionate about your profession and keen to help shape its future? If so, joining an RCN committee could be your opportunity. PMID- 28721780 TI - Why should we pay? AB - Pay all nursing students a salary and implement a two-year contract post qualification so they work at the hospitals they trained at. PMID- 28721782 TI - Review body reaction. AB - Health secretary Jeremy Hunt has pledged to listen to what the pay review body (RB) has to say about the pay cap for nurses. That's all very well, but it is worth remembering that he voted against scrapping the cap in a Commons vote in June. So we won't be holding our breaths for a change of heart. PMID- 28721783 TI - Placement predicament. AB - Regarding the fall in applications for nursing degree courses, the problem is that it is not possible for many people to attend placements as part of nurse training and hold a full-time job at the same time. PMID- 28721785 TI - Creating calm amid confrontation. AB - In my first year of training, I had a placement on a challenging behaviours unit for people with a learning disability. One night shift at about 11.30pm a service user, who I will call Charlotte, became physically and verbally aggressive towards staff members. This was due to an incident earlier in the day with another service user. PMID- 28721784 TI - Win-win for staff and trusts. AB - Health boards should offer more secondments to their existing healthcare support workers and others, to invest in and keep the good staff they already have. PMID- 28721786 TI - Classic Grounded Theory: Applications with Qualitative & Quantitative Data Holton Judith A and Walsh Isabelle Classic Grounded Theory: Applications with Qualitative & Quantitative Data 256pp L28.99 Sage 9781483372549 1483372545 [Formula: see text]. AB - This text fulfils its aim to 'take the reader back to the roots of grounded theory' without compromising its three tenets: exploration, emergence and constant comparative analysis. PMID- 28721787 TI - Patient Safety - Investigating and Reporting Serious Clinical Incidents Kelsey Russell Patient Safety - Investigating and Reporting Serious Clinical Incidents 214pp L29.99 CRC Press 97814981169 1498781160 [Formula: see text]. AB - This book draws on case studies to explain how to recognise a serious incident, how to undertake a root cause analysis and when a duty of candour applies. PMID- 28721789 TI - Mindset shift on PJ paralysis. AB - When I first created #EndPJparalysis, little did I know it would be adopted globally - and particularly across the UK - as a vehicle for enabling patients to get up, dressed and moving while in hospital. PMID- 28721788 TI - Integrated Care in Action: A Practical Guide for Health, Social Care and Housing Supports Miller Robin , Brown Hilary and Mangan Catherine Integrated Care in Action: A Practical Guide for Health, Social Care and Housing Supports 232pp L22.99 Jessica Kingsley 9781849056465 1849056463 [Formula: see text]. AB - The blurb of this book suggests it is about leading, managing and delivering integrated care, but it could be applied to any kind of change in healthcare services. PMID- 28721791 TI - Many women 'unaware' of cervical screening programme. AB - More than a quarter of women who have not had a smear test may not know about the cervical screening programme. PMID- 28721790 TI - Administering and monitoring high-alert medications in acute care. AB - The nurse's primary role in the medication process is to ensure that drugs are administered safely to patients, thus reducing the risk of unnecessary harm or injury. High-alert medications are a particular concern for healthcare professionals, since they are associated with an increased risk of causing patient harm. This article identifies high-risk medications and outlines measures that can be used to prevent potential harm to patients as a result of these medications, including computerised provider order entry, Tall Man lettering, order sets, independent double-checks and proactive patient monitoring. PMID- 28721792 TI - Readers' panel - Should weight problems be raised in a nurse's appraisal? AB - Our experts consider a hot topic of the day. PMID- 28721793 TI - Hospital fire. AB - A nurse-led walk-in centre in Surrey is closed indefinitely after a 'devastating' fire (pictured). PMID- 28721794 TI - Patients given a hotline to matron. AB - Patients and visitors at Arrowe Park and Clatterbridge hospitals on Merseyside have been benefiting from a direct 'hotline' to a matron. PMID- 28721795 TI - 'Golden hellos' could ease recruitment crisis, says peer. AB - The author of an influential report into the future of nursing has called for 'golden hello' incentive payments to boost recruitment to the profession. PMID- 28721796 TI - Managing patients' anxiety about planned medical interventions. AB - Patients are often anxious about planned medical interventions, and those experiencing anxiety are less likely to have the confidence to collaborate with healthcare professionals on their plan of care, and make decisions about consent. They may also find it challenging to follow rehabilitation guidelines, which can affect their long-term recovery. As part of their professional duty, nurses are required to recognise when people are anxious or in distress and respond compassionately, and while acquiring valid consent for any planned medical intervention requires the nurse to explain any risks, they should also attempt to reassure patients. The anxiety that precedes a planned medical intervention has been described as state anxiety; this refers to feelings of discomfort and uncertainty that accompany a situation such as an operation or a diagnostic procedure. Nurses can attempt to reduce any anxiety that patients experience by explaining the planned medical intervention and providing accurate information at the optimum time. This article outlines some of the coping theories that nurses can use to support patients in managing their anxiety about planned medical interventions. PMID- 28721797 TI - Nurses are becoming an endangered species. AB - Like my fellow wildlife enthusiasts, I am concerned about the decline in the number of butterflies. We can only hope that the dry and warm weather at the end of June will have boosted their numbers. PMID- 28721798 TI - In search of meaning. AB - Picture the scene, you are out for a drink with some of your non-nursing friends and they start to moan about their bad days at work. PMID- 28721799 TI - NHS managers are found to improve patient care. AB - Having more managers at NHS trusts has been linked to better performance. PMID- 28721802 TI - Mobile phone use changes the way we navigate obstacles. AB - A study led by scientists at Anglia Ruskin University investigated how mobile phone use affects where people look and how they negotiate an obstacle along their walking path. PMID- 28721800 TI - Sickle cell disease deserves a place in nurse education. AB - Sickle cell disease (SCD) is the most common serious genetic condition in England. According to the National Institute for Health and Care Excellence (NICE), there are an estimated 12,500 to 15,000 people with sickle cell disease in the UK. PMID- 28721803 TI - Stricter air pollution levels could save thousands of lives. AB - Up to 10,000 lives could be saved a year by reducing air pollution, research has found. PMID- 28721804 TI - 'It's change like never before'. AB - With Brexit, new roles and routes into nursing, changes to the student bursary in England, and draft standards for nursing education, there is a lot happening to affect nursing schools. PMID- 28721805 TI - Automated One-pot Radiosynthesis of [11C]S-adenosyl Methionine. AB - BACKGROUND: Glycine N-methyltransferase is an enzyme overexpressed in some neoplastic tissues. It catalyses the methylation of glycine using S-adenosyl methionine (SAM or AdoMet) as substrate. SAM is involved in a great variety of biochemical processes, including transmethylation reactions. Thus, [11C]SAM could be used to evaluate transmethylation activity in tumours. The only method reported for [11C]SAM synthesis is an enzymatic process with several limitations. We propose a new chemical method to obtain [11C]SAM, through a one-pot synthesis. METHOD: The optimization of [11C]SAM synthesis was carried out in the automated TRACERlab(r) FX C Pro module. Different labelling conditions were performed varying methylating agent, precursor amount, temperature and reaction time. The compound was purified using a semipreparative HPLC. Radiochemical stability, lipophilicity and plasma protein binding were evaluated. RESULTS: The optimum labelling conditions were [11C]CH3OTf as the methylating agent, 5 mg of precursor dissolved in formic acid at 60 degrees C for 1 minute. [11C]SAM was obtained as a diastereomeric mixture. Three batches were produced and quality control was performed according to specifications. [11C]SAM was stable in final formulation and in plasma. Log POCT obtained for [11C]SAM was (-2,01 +/- 0,07) (n=4), and its value for plasma protein binding was low. CONCLUSION: A new chemical method to produce [11C]SAM was optimized. The radiotracer was obtained as a diastereomeric mixture with a 53:47 [(R,S)-isomer: (S,S)-isomer] ratio. The compound was within the quality control specifications. In vitro stability was verified. This compound is suitable to perform preclinical and clinical evaluations. PMID- 28721806 TI - L-Tetrahydropalmatine Induces Apoptosis in EU-4 Leukemia Cells by Down-Regulating X-Linked Inhibitor of Apoptosis Protein and Increases the Sensitivity Towards Doxorubicin. AB - BACKGROUND: L-Tetrahydropalmatine (L-THP) is a tetra-hydro protoberberine isoquinoline alkaloid. The phyto-compounds bearing isoquinoline alkaloids have been reported to show a potential effect against a number of human cancers cell lines including leukemia. We hypothesized that L-THP, being an isoquinoline alkaloid, could be a potential molecule against acute lymphoblastic leukemia (ALL), in this study, we evaluate L-THP against p53 deficient leukemia EU-4 cell lines in vitro. METHODS: For the study, p53 null leukemia EU-4 cells were used and treated with LTHP. The extent of apoptosis and viability of cells were determined. Expression of apoptosis related proteins such as XIAP and MDM2 was done by western blot and PCR studies. The expression of MDM2 and XIAP was knocked down by small interfering RNA (siRNA). RESULTS: Outcomes of the study suggested that L-THP caused p53-indipendent apoptosis mediated by XIAP in EU-4 cells. The treatment of L-THP caused a decrease in the levels of XIAP protein with increasing dose and time. L-THP caused down-regulation of XIAP protein via inhibiting the expression of MDM2 and involving proteasomedependent pathway. Also, the outcomes of experiments suggested increased sensitivity of leukemia cells towards doxorubicin due to the inhibition of XIAP by L-THP or by siRNA. CONCLUSION: Findings of the study confirm that L-THP resulted in p53 independent apoptosis via down-regulating XIAP protein by inhibiting MDM2 associated with proteasome-dependent pathway and increased sensitivity of EU-4 cells against doxorubicin. L-THP caused activation of caspase and resulted in apoptosis, L-THP may be a novel molecule for inducing apoptosis specifically in p53 null leukemia EU-4 cells. PMID- 28721807 TI - Developing the Transdisciplinary Aging Research Agenda: New Developments in Big Data. AB - BACKGROUND: Advances in big data analytics can enable more effective and efficient research processes, with important implications for aging research. Translating these new potentialities to research outcomes, however, remains a challenge, as exponentially increasing big data availability is yet to translate into a commensurate era of 'big knowledge,' or exponential increases in biomedical breakthroughs. Some argue that big data analytics heralds a new era associated with the 'end of theory.' According to this perspective, correlation supersedes causation, and science will ultimately advance without theory and hypotheses testing. On the other hand, others argue that theory cannot be subordinate to data, no matter how comprehensive data coverage may ultimately become. OBJECTIVE: Given these two tensions, namely (i) between exponential increases in data that have not translated into exponential increases in biomedical research outputs; and (ii) between the promise of comprehensive data coverage and inductive data-driven modes of enquiry versus theory-driven deductive modes, this critical review seeks to offer useful perspectives of big data analytics and to derive certain theoretical implications for aging research. METHOD: This work offers a critical review of theory and literature relating big data to aging research. RESULT: The rise of big data provides important insights into the theory development process itself, highlighting potential for holistic theoretical assemblage to ultimately enable near real time research capability. CONCLUSION: Big data may represent a new paradigm of aging research that can dramatically increase the rate of scientific breakthroughs, but innovative theory development remains key to this potential. PMID- 28721808 TI - Molecular Tests for the Choice of Cancer Therapy. AB - There are over a dozen of approved cancer drugs, whose administration is tailored to predictive laboratory tests. The examples include estrogen and progesterone receptor status determination for the use of endocrine therapy, HER2 assessment for the administration of HER2-targeting agents, EGFR and ALK gene testing for lung cancer treatment, BRAF analysis in melanoma, etc. While first predictive tests relied on relatively easy laboratory procedures, more recent developments require rather sophisticated assays. For example, administration of PARP inhibitors is tailored to a comprehensive testing of BRCA1 and BRCA2 genes, and is likely to be supplemented in the future by even more systematic assessment of DNA repair pathways. The detection of an androgenindependent splice-variant of androgen-receptor (AR-V7) in castration-resistant prostate cancer is achieved through the isolation of circulating tumor cells (CTCs). The efficacy of immune check-point inhibitors correlates with the overall mutational tumor load, therefore the companion diagnostic assays may involve genome-wide scanning. Integration of next-generation sequencing (NGS) into clinical oncology is expected to boost the use of predictive tests in the forthcoming years. PMID- 28721809 TI - Acellular Spinal Cord Scaffold Implantation Promotes Vascular Remodeling with Sustained Delivery of VEGF in a Rat Spinal Cord Hemisection Model. AB - BACKGROUND: Promoting angiogenesis provides a possible therapeutic approach in treating spinal cord injury (SCI). Vascular endothelial growth factor (VEGF) is a pro-angiogenic substance that is involved in endothelial cell (EC) proliferation, migration, and survival. Exogenous administration of VEGF to the lesion epicenter of the spinal cord has been recently revealed as a potential method for promoting the blood vessel sprouting. METHODS: Spinal cord hemisection in a rat model was established and angiogenesis was studied through implant of an acellular spinal cord scaffold (ASCS) with sustained delivery of VEGF165. The poly (lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) encapsulating VEGF165 were fabricated on basis of an emulsion and solvent evaporation method and conjugated to ASCS by a Genipin (GP) crosslinking technology. The resultant scaffolds were marked as V-ASCS. VEGF165 entrapment efficiency (EE) and released kinetics were determined by an ultraviolet absorption measurement. Angiogenesis and vascular remodeling were observed via a high-resolution micro-CT and analyzed quantitatively by vascular morphometric parameters. Spinal cord histology and Basso, Beattie, and Bresnahan (BBB) locomotor rating scale were further studied. RESULTS: VEGF165 was entrapped with high efficiency (90.8+/-3.1) %. In vitro VEGF165 release kinetics study showed an initial burst of 1.966 MUg mg NPs-1 and 1.045MUg mg V-ASCS-1 respectively in the first 24 hours. In the phase of sustained release, approximately 0.040MUg mg NPs-1 and 0.022MUg mg V-ASCS-1 per day was on going until 720h. In the rat spinal cord hemisection model, implant of V-ASCS at the injured site showed a promotion of angiogenesis and vascular remodeling following SCI. A better outcome can be confirmed histologically. However, functional improvement is limited in the animal model. CONCLUSION: The results indicate that progress of vascular reconstruction is accelerated in the V-ASCS implanted SCI rats. PMID- 28721810 TI - Centralized and Local Color Doppler Ultrasound Reading Agreement for Diagnosis of the Chronic Cerebrospinal Venous Insufficiency in Patients with Multiple Sclerosis. AB - BACKGROUND: An impaired cerebrospinal venous drainage was postulated to be a cofactor in the multifactorial pathogenesis of multiple sclerosis (MS). Chronic cerebrospinal venous insufficiency (CCSVI) is characterized by abnormalities of the main extracranial cerebrospinal venous outflow routes, which can be detected by color Doppler Ultrasound (CDUS) using 5 venous hemodynamic (VH) criteria. Discrepant results between different investigators were reported in the past, therefore the usefulness and applicability of the CCSVI CDUS-based diagnosis in clinical research and practice has been questioned. The reproducibility of proposed criteria for CCSVI detection depends on the blinding, training level, skills of the operator and interpretation of VH criteria. OBJECTIVES: To assess agreement between centralized and local reading of CDUS examination for diagnosis of CCSVI in trained Doppler sonologists. METHODS: This study was performed in 78 MS patients and 28 age- and sex-matched healthy controls (HCs). Extracranial and transcranial CDUS venous hemodynamic assessment was conducted, according to International Society of Neurovascular Disease (ISNVD) recommended criteria, by a single CCSVI-trained expert sonologist blinded to the subject disease status. After the local Doppler sonologist performed the investigation, all images and video clips of the CDUS examination were sent to the centralized reading center, where a second blinded reading was performed by two CCSVI-trained expert sonologists. Statistical analyses were performed comparing accuracy of CCSVI diagnosis (>=2 VH criteria) and each of the 5 individual VH criteria using Cohen kappa statistic, along with positive/negative agreement and Odds ratio (OR) with 95% confidence intervals (95% CI). RESULTS: Diagnosis of CCSVI was obtained in 59.7% of local and 64.3% centralized readers (Kappa, 0.67, p<0.001). Similar Kappa values were obtained for CCSVI diagnosis and individual CCSVI criteria in both MS patients and HCs. The highest Kappa between local and centralized readers was observed for VH criteria 5 (0.93) followed by VH criteria 4 (0.70), VH criteria 1 (0.66), VH criteria 2 (0.64) and VH criteria 3 (0.58). The positive predictive value (PPV) and negative predictive value (NPV) for CCSVI diagnosis were 82.7% and 86,7%, respectively with an OR of 31.1 (95% CI 11.1-87.5, p<0.001). The highest agreement between local and centralized readers was observed for VH criteria 4 (OR 98.7, 95% CI 17.1-569.9, p<0.001) with 72.7% PPV and 97.3% NPV followed by VH criteria 5 (53, 95% CI 13.4-209.2, p<0.001) with 98.1% PPV and 100% NPV value. CONCLUSION: Centralized reading of the CDUS examination for the diagnosis of CCSVI is feasible with high accuracy in CCSVI trained Doppler sonologists. The most reproducible VH criteria between local and centralized readers were VH criteria 4 and 5. PMID- 28721812 TI - Update on Phototherapy in Jaundiced Neonates. AB - BACKGROUND: Even relatively low serum bilirubin concentrations can cause neurodevelopmental impairment in extremely low birth weight (EBWL) infants, while sequelae from hyperbilirubinemia in late preterm and term infants are rare and occur only at very high serum bilirubin levels. Phototherapy is the current treatment of choice. OBJECTIVE: To present an update on the most important issues involved in phototherapy for jaundiced infants. RESULTS: Light absorption by bilirubin in the skin transforms the native Z,Z-bilirubin to conformational photoisomers Z,E-bilirubin and E,Z-bilirubin and structural photoisomers E,Z lumirubin and E,E-lumirubin. Formation and excretion of Z,E-bilirubin and E,Z lumirubin are both important routes of elimination of bilirubin through bile and urine, although the precise contributions of the various photoisomers to the overall elimination of bilirubin are unknown. It appears that the photoisomers of bilirubin are predominantly formed in the plasma, and the rate of formation is affected by the hemoglobin concentration. Phototherapy lights with an emission spectrum of 460-490 nm provide the most efficient bilirubin-reducing light. LEDs should replace fluorescent tubes and halogen spotlights as the preferred light sources. Recent data raise concerns that sick ELBW infants under prolonged phototherapy may have an increased risk of death, though survivors may benefit from reduced rates of neurodevelopmental impairment. Comparison of the efficacy of cycled vs. continuous phototherapy has given divergent results. Changing the infant's position does not increase the efficacy of phototherapy. CONCLUSION: During the last decade, we have made progress in our understanding of how and where phototherapy works and in its practical applications. PMID- 28721813 TI - Mechanisms Involved in the Increased Hemolysis in the Fetus and Newborn. AB - The suicidal death of erythrocytes should be considered a possible cause of hemolysis and plasma bilirubin overload when there is no evidence of an immune mediated hemolytic anemia, no consumptive red blood cell disorder, no morphologic or laboratory data to suggest a problem of the red cell membrane, and no evidence of a quantitative or qualitative defect in hemoglobin synthesis. In neonatal period, xenobiotics, cytokines, osmotic shock, energy depletion, oxidative stress, and variation of temperature may induce an alteration of balance between damaging and protecting factors which can be followed by red cell death. The intraerythrocyte redox balance plays a pivotal role in orchestrating the complex molecular mechanisms leading to eryptosis. Neonatal erythrocytes are a target of extracellular free radicals and, at the same time, are themselves generators of free radicals through the Fenton reaction. This review clarifies the complex mechanisms underlying the susceptibility of neonatal erythrocytes to increased oxidative stress. PMID- 28721814 TI - Refractory Causes of Kernicterus in Developed Countries: Can We Eradicate G6PD Deficiency Triggered and Low-Bilirubin Kernicterus? AB - BACKGROUND: Glucose-6-phosphate dehydrogenase (G6PD) deficiency triggered and low bilirubin kernicterus persist despite current prevention strategies. OBJECTIVE: Review efforts to eradicate bilirubin induced brain injury in these two conditions including novel approaches to risk assessment and hyperbilirubinemia evaluation. RESULT AND CONCLUSION: In the case of G6PD deficiency, a heightened awareness of populations at risk and an expanded kernicterus prevention strategy focused on intensified parental engagement, education and counselling on neonatal jaundice is needed. In the case of low-bilirubin kernicterus, a renewed focus on identifying infants with hypoalbuminemia and implementation of hyperbilirubinemia treatment thresholds based on the bilirubin/albumin ratio is needed. Bilirubin binding panels when commercially available will prove valuable. PMID- 28721811 TI - Moving to the Rhythm with Clock (Circadian) Genes, Autophagy, mTOR, and SIRT1 in Degenerative Disease and Cancer. AB - BACKGROUND: The mammalian circadian clock and its associated clock genes are increasingly been recognized as critical components for a number of physiological and disease processes that extend beyond hormone release, thermal regulation, and sleep-wake cycles. New evidence suggests that clinical behavior disruptions that involve prolonged shift work and even space travel may negatively impact circadian rhythm and lead to multi-system disease. METHODS: In light of the significant role circadian rhythm can hold over the body's normal physiology as well as disease processes, we examined and discussed the impact circadian rhythm and clock genes hold over lifespan, neurodegenerative disorders, and tumorigenesis. RESULTS: In experimental models, lifespan is significantly reduced with the introduction of arrhythmic mutants and leads to an increase in oxidative stress exposure. Interestingly, patients with Alzheimer's disease and Parkinson's disease may suffer disease onset or progression as a result of alterations in the DNA methylation of clock genes as well as prolonged pharmacological treatment for these disorders that may lead to impairment of circadian rhythm function. Tumorigenesis also can occur with the loss of a maintained circadian rhythm and lead to an increased risk for nasopharyngeal carcinoma, breast cancer, and metastatic colorectal cancer. Interestingly, the circadian clock system relies upon the regulation of the critical pathways of autophagy, the mechanistic target of rapamycin (mTOR), AMP activated protein kinase (AMPK), and silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1) as well as proliferative mechanisms that involve the wingless pathway of Wnt/beta-catenin pathway to foster cell survival during injury and block tumor cell growth. CONCLUSION: Future targeting of the pathways of autophagy, mTOR, SIRT1, and Wnt that control mammalian circadian rhythm may hold the key for the development of novel and effective therapies against aging- related disorders, neurodegenerative disease, and tumorigenesis. PMID- 28721815 TI - Conjunctival Icterus - An Important but Neglected Sign of Clinically Relevant Hyperbilirubinemia in Jaundiced Neonates. AB - BACKGROUND: Conjunctival icterus is a largely neglected physical sign that may be helpful in identifying neonates with clinically relevant hyperbilirubinemia by practitioners in the hospital and outpatient clinic or parents at home. OBJECTIVE: A recent NICU based study reported that conjunctival icterus is often a sign of significant (TSB >= 17 mg/dl) hyperbilirubinemia and TSB levels >= 76th 95th percentile on the Bhutani nomogram. In contrast, others report that conjunctival icterus, although frequently present at high TSB levels, may also be detected at lower TSB concentrations; suggesting instead that its absence may help to rule out significant hyperbilirubinemia. RESULT AND CONCLUSION: The current review details the nature of conjunctival icterus and presents new data on its clinical occurrence in relation to TSB levels that re-affirm its correlation with elevated TSB concentrations and use to trigger TSB measurement in the jaundiced neonate. PMID- 28721816 TI - PLGA Nanoparticles and Polysorbate-80-Coated PLGA Nanoparticles Increase the In vitro Antioxidant Activity of Melatonin. AB - BACKGROUND: Melatonin is an endogen substance with several physiological functions, acting as an important antioxidant. Our objective was to prepare nanoparticles composed of poly(lactic-coglycolic acid) (PLGA) coated with polysorbate 80 (PLGA-PS80) or uncoated (PLGA) nanoparticles containing melatonin (MLT) and evaluate their in vitro cytotoxicity over erythrocytes and in vitro antioxidant activity. METHODS: Nanoparticles were obtained by an emulsion-solvent evaporation method and characterized by size, morphology, polydispersity index, zeta potential, encapsulation efficiency, thermal properties and in vitro drug release profile. The in vitro cytotoxicity over erythrocytes was assessed by hemolysis assay and in vitro antioxidant was carried out by colorimetric assay using the radical 2,2-azinobis (3- ethylbenzothiazoline-6-sulfonic acid) diammonium salt) (ABTS.+). RESULTS: Mean size of the PLGA-PS80 and PLGA nanoparticles was 212 and 187 nm, and the encapsulation efficiency of MLT was 26 and 41%, respectively. Nanoparticles were spherical in shape and presented negative zeta potential. MLT was released from nanoparticles following the second order model and PLGA-PS80 presented more prolonged MLT release. CONCLUSION: Cytotoxicity over erythrocytes was assessed and both nanoparticles containing MLT demonstrated lack of hemolysis. Scavenging activity over ABTS.+ demonstrated both nanoparticles containing MLT were more efficient than free drug, and MLT-loaded PLGA nanoparticles presented the higher in vitro antioxidant activity. The study concluded that PLGA and PLGA-PS80 nanoparticles are promising carriers for MLT. PMID- 28721817 TI - Improvement of Thermosensitive Liposome Stability by Cerasome Forming Lipid with Si-O-Si Network Structure. AB - BACKGROUND: Liposomes have been widely used in gene transfection and drug delivery systems due to their excellent biocompatibility and encapsulation ability, especially, the ability to deliver the gene/drug into the cells via the membrane fusion. Thermosensitive liposomes have been proven to be a precise and effective method for cancer treatment in many preclinical studies. But the imperfect crystalline arrangement between grains occurred, resulting in planar defects at the boundaries of membranes, compromising the stability of thermosensitive liposomes. OBJECTIVE: In the present study, we developed a facile method to improve the stability of ordinary thermosensitive liposomes by introducing organic-inorganic hybrid materials with local Si-O-Si net. METHOD: A cerasome forming lipid, N, N-Dihxadecyl-N'- [(3-triethoxysilyl) propyl] urea, was synthesized and then introduced into the thermosensitive lipids to form the composite liposomes (named as cera-liposomes). The effects of the cerasome forming lipid on the cera-liposomes characteristics, including the morphology, drug loading, Zeta potential and stability of vesicles, were investigated. RESULTS: Cera-liposomes were thermosensitive, and they had a loading efficiency over 2 folds more than conventional thermosensitive liposomes. With the enhanced sustain of Si-O-Si, cera-liposomes were able to avoid collapsing and fusing during storage, and had a good resistance to nonionic surfactant. More than 80% drug was still retained after storage of 15 days at room temperature. CONCLUSION: The cerasome forming lipid showed potential in improving the stability of thermosensitive liposomes. This novel kind of cera-liposomes could be a stable and effective drug carrier for anticancer applications. PMID- 28721818 TI - Eurycoma longifolia, A Potential Phytomedicine for the Treatment of Cancer: Evidence of p53-mediated Apoptosis in Cancerous Cells. AB - BACKGROUND: Eurycoma longifolia is a well-documented herbal medicine that has gained widespread recognition due to its versatile pharmacological activities including anticancer, antimalarial, antimicrobial, antioxidant, aphrodisiac, anti inflammatory, anxiolytic, anti-diabetic, antirheumatism and anti-ulcer. Plethora of in vitro and in vivo studies evidenced their excellent antiproliferative and anticancer efficacy against various types of human cancers. OBJECTIVE: This review was aimed to critically analyze the therapeutic viability and anticancer efficacy of Eurycoma longifolia in the treatment of cancer and also to propose its molecular and translational mechanism of cytotoxicity against cancerous cells. RESULTS: Among a range of medicinally active compounds isolated from various parts (roots, stem, bark and leaves) of Eurycoma longifolia, 16 compounds have shown promising anti-proliferative and anticancer efficacies. Eurycomanone, one of the most active medicinal compounds of Eurycoma longifolia, displayed a strong dose-dependent anticancer efficacy against lung carcinoma (A-549 cells) and breast cancer (MCF-7 cells); however, showed moderate efficacy against gastric (MGC-803 cells) and intestinal carcinomas (HT-29 cells). The prime mode of cytotoxicity of Eurycoma longifolia and its medicinal compounds is the induction of apoptosis (programmed cell death) via the up-regulation of the expression of p53 (tumor suppressor protein) and pro-apoptotic protein (Bax) and downregulation of the expression of anti-apoptotic protein (Bcl-2). A remarkable alleviation in the mRNA expression of various cancer-associated biomarkers including heterogeneous nuclear ribonucleoprotein (hnRNP), prohibitin (PHB), annexin-1 (ANX1) and endoplasmic reticulum protein-28 (ERp28) has also been evidenced. CONCLUSION: Eurycoma longifolia and its medicinal constituents exhibit promising anticancer efficacy and thus can be considered as potential complementary therapy for the treatment of various types of human cancers. PMID- 28721819 TI - Research Progress of the Types and Preparation Techniques of Scaffold Materials in Cartilage Tissue Engineering. AB - The management of chondral defects has been a challenge for a long time because of the poor self-healing capacity of articular cartilage. Many approaches ranging from symptomatic treatment to structural cartilage regeneration are not that successful with very limited satisfactory results. Chondral defects caused by tumor, trauma, infection, congenital malformations are very common in clinical trials. It seriously affects the patient's physical function and quality of life. The appearance of cartilage tissue engineering has brought good news for cartilage defect repair. Through this review, we are aimed at reviewing the progress of the types and preparation techniques of scaffold materials in cartilage tissue engineering. PMID- 28721820 TI - Epigenetic Regulations in the Pathogenesis of Periodontitis. AB - BACKGROUND: Periodontitis is a multifactorial infectious disease that affects a large population worldwide. Oral microorganisms and susceptible host have been proposed to be the prerequisite for the development of periodontitis. Recently, the involvement of epigenetic modifications in the development of periodontitis has been suggested. OBJECTIVES: This review aims to detail recent discoveries involving the epigenetic alterations in periodontitis, and discuss the possible epigenetic mechanisms contributing to the expression of periodontitis- related genes. CONCLUSIONS: The expression of inflammatory cytokines during periodontitis is regulated at epigenetic level by mechanisms such as DNA methylation, histone modification and miRNAs. In addition, periodontal pathogens and their virulence factors could induce epigenetic alterations of periodontal tissues, and thus affect the progression and prognosis of periodontitis. The involvement of epigenetic modifications during periodontitis not only advances our knowledge on the pathogenesis of periodontitis, but may also lead to the identification of potential therapeutic targets of this oral disease. PMID- 28721821 TI - Current Perspectives for the use of Gonane Progesteronergic Drugs in the Treatment of Central Hypoventilation Syndromes. AB - BACKGROUND: Central alveolar hypoventilation syndromes (CHS) encompass neurorespiratory diseases resulting from congenital or acquired neurological disorders. Hypercapnia, acidosis, and hypoxemia resulting from CHS negatively affect physiological functions and can be lifethreatening. To date, the absence of pharmacological treatment implies that the patients must receive assisted ventilation throughout their lives. OBJECTIVE: To highlight the relevance of determining conditions in which using gonane synthetic progestins could be of potential clinical interest for the treatment of CHS. METHODS: The mechanisms by which gonanes modulate the respiratory drive were put into the context of those established for natural progesterone and other synthetic progestins. RESULTS: The clinical benefits of synthetic progestins to treat respiratory diseases are mixed with either positive outcomes or no improvement. A benefit for CHS patients has only recently been proposed. We incidentally observed restoration of CO2 chemosensitivity, the functional deficit of this disease, in two adult CHS women by desogestrel, a gonane progestin, used for contraception. This effect was not observed by another group, studying a single patient. These contradictory findings are probably due to the complex nature of the action of desogestrel on breathing and led us to carry out mechanistic studies in rodents. Our results show that desogestrel influences the respiratory command by modulating the GABAA and NMDA signaling in the respiratory network, medullary serotoninergic systems, and supramedullary areas. CONCLUSION: Gonanes show promise for improving ventilation of CHS patients, although the conditions of their use need to be better understood. PMID- 28721822 TI - Opioid Antagonists for Pharmacological Treatment of Gambling Disorder: Are they Relevant? AB - BACKGROUND: To date, no drugs have been approved for gambling disorder. Numerous publications have described the value of opioid antagonists. Indeed, the mesocorticolimbic dopaminergic pathway has been suggested as the underlying cause of reward-seeking behaviour, and it is modulated by the opioid system. OBJECTIVE: This study aims to evaluate the relevance of opioid antagonists for treating GD. METHOD: A systematic literature review was conducted. A search of the PubMed electronic database, PsycINFO and the Cochrane Systematic Review Database without any limits was performed. RESULTS: There is little information concerning the effects of opioid antagonists on GD. The total search with "nalmefene and gambling" without any limits revealed only 11 articles. The search with "naltrexone and gambling" without any limits generated 47 articles. Nevertheless, the best available data support the use of opioid antagonists, particularly in individuals with a history of alcohol use disorder or strong gambling urges. CONCLUSION: Future trials are still needed. Indeed, opioid antagonists effectiveness has been investigated in only a limited number of patients, clinical trials do not reflect the heterogeneity of GD and there is little knowledge of the predictive factors of response to treatments. Moreover, differential affinity to nalmefene for kappa receptors may be associated with a particular effect in a yet to be defined addiction phenotype. Head to head comparisons between naltrexone and nalmefene would be helpful in combining other medication or psychotherapy. The identification of subgroups of patients that are more likely to benefit from opioid antagonists should be a goal. PMID- 28721824 TI - Potential anti-inflammatory effects of hesperidin from the genus Citrus. AB - The benefits of the Mediterranean diet for protecting against many diseases are usually attributed to high consumption of certain foods, characterized by the presence of bioactive substances such as polyphenols. Citrus fruits, which are cultivated and consumed worldwide, are typical products of the Mediterranean diet. Inflammation plays an important role in the pathogenesis of numerous diseases such as arthritis, allergies and neurodegenerative disorders, among others. Dietary polyphenols constitute a large family of bioactive substances with potential beneficial effects against a broad group of diseases. Citrus fruits and juices are a rich source of vitamin C and flavonoids, with a potential effect on the inflammatory response. Hesperidin is a flavonoid present in high concentration in citrus species and has numerous biological properties, principally antioxidant and anti-inflammatory. Several studies have been performed in order to evaluate the effects of hesperidin as anti-inflammatory agent using cellular and animal models and few clinical trials. In the present review, available literature about the anti-inflammatory effects of hesperidin is reported and discussed. Moreover, we also discuss the chemistry, bioavailability and proposed mechanisms of action of hesperidin. PMID- 28721823 TI - Genetic Risk Factors for Glaucoma and Exfoliation Syndrome Identified by Genome wide Association Studies. AB - BACKGROUND: Glaucoma is a neurodegenerative disease characterized by the progressive loss of retinal ganglion cells and optic nerve axons. According to its anatomical features, glaucoma is mainly subdivided into primary open-angle glaucoma (POAG) and primary angle-closure glaucoma (PACG). Exfoliation syndrome (XFS) and glaucoma (XFG) are characterized by the accumulation of extracellular materials in ocular tissues, particularly the lens surface and pupillary border. In addition to the two major forms of glaucoma, XFG is the most common cause of secondary open-angle glaucoma. Recent genome-wide association studies(GWASs) revealed genetic loci associated with each glaucoma subtype. METHODS: Review of literatures regarding GWASs for POAG, PACG and XFS. RESULTS: Several genetic loci were found to be independently associated with POAG, PACG, and XFS by large-scale GWASs. CONCLUSIONS: Genetic studies may not only provide a better understanding of the pathophysiological mechanisms underlying the diseases, but also facilitate the development of new drugs or treatments. PMID- 28721825 TI - Biomarkers associated with stroke risk in atrial fibrillation. AB - Atrial fibrillation is associated with increased risk for cardioembolic stroke. The risk of cardioembolism is not adequately reduced with the administration of oral anticoagulants, since a number of patients continue to experience thromboembolic events despite receiving anti-thrombotic treatment. Several biomarkers have been proposed to predict cardioembolic stroke in patients with atrial fibrillation. Some of them are already used in the clinical practice, such as D-Dimers, Troponin and brain natriuretic peptide. Novel ones such as the inflammatory growth differentiation factor-15, appear to be promising, while the role of micro-RNAs and genetics appear to be useful as well. Even though these biomarkers are associated with an increased risk for thromboembolism, they cannot accurately predict future events. In this light, the use of a scoring system, that would incorporate both circulating biomarkers and clinical factors, might be more useful. Therefore, further research is required to establish a multifactorial scoring system that will identify patients at high-risk for thromboembolism, who will benefit from more intensive treatment and monitoring. PMID- 28721826 TI - Clinical Uses of Melatonin in Neurological Diseases and Mental and Behavioural Disorders. AB - BACKGROUND: Melatonin is a molecule with numerous properties applicable to the treatment of neurological diseases. Among these properties are the following: potent scavenger of oxygen and nitrogen reactive species, anti-inflammatory features, immuno-enhancing nature, and modulation of circadian rhythmicity. Furthermore, low concentrations of melatonin are usually found in patients with neurological diseases and mental disorders. The positive results obtained in experimental models of diverse pathologies, including diseases of the nervous system (e.g., Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, Huntington's disease, epilepsy, headaches, etc.) as well as mental and behavioural disordes (e.g., autism spectrum disorders, attention-deficit hyperactivity disorders, etc.), have served as a basis for the design of clinical trials to study melatonin's possible usefulness in human pathology, although the satisfactory results obtained from the laboratory "bench" are not always applicable to the patient's "bedside". OBJECTIVE: In this article, we review those papers describing the results of the administration of melatonin to humans for various therapeutic purposes in the field of neuropathology. CONCLUSION: Clinical trials with strong methodologies and appropriate doses of melatonin are necessary to support or reject the usefulness of melatonin in neurological diseases. PMID- 28721827 TI - Melatonin as a Pleiotropic Molecule with Therapeutic Potential for Type 2 Diabetes and Cancer. AB - BACKGROUND: The incidence of both type 2 diabetes (T2DM) and cancer is increasing worldwide, making these diseases a global health problem along with increasing healthcare expenditures. The current therapeutic approaches for treating these multifactorial diseases are far from satisfactory. As increasing evidence shows beneficial effects of melatonin (MLT) on typical pathological changes occurring during the development of T2DM and cancer, the present review focuses on molecular aspects of antidiabetic and anticancer activities of MLT and, moreover, discusses several future directions of research regarding MLT application as potential therapeutic agent. METHODS: Critical literature analysis in PubMed central combined with personal expertise. RESULTS: Numerous in vitro and in vivo studies have revealed that MLT possesses a number of antidiabetic health benefits by diminishing hyperglycemia, insulin resistance, oxidative stress, and inflammation through modulating various intracellular signaling pathways or other targets involved in the pathophysiology of this disease. Mounting evidence also indicates that MLT exhibits multi-targeted anticancer effects in numerous human malignancies, mainly resulting from its ability to modulate several signal transduction pathways associated with cell survival, proliferation, and apoptosis. Furthermore, beneficial synergistic action of MLT with chemotherapy and radiotherapy has also been observed. Importantly, no adverse outcomes have been found from the clinical use of MLT, which highlights its therapeutic usefulness, either alone or in combination with other conventional therapies, in cancer treatment. CONCLUSION: The findings described in this review suggest that MLT may confer potential benefits to human health, particularly in respect to T2DM and cancer. PMID- 28721828 TI - miR-149 as a Potential Molecular Target for Cancer. AB - BACKGROUND: MicroRNAs (miRNAs) are frequently dysregulated in cancers and serve as attractive targets for prognostication and therapeutic applications. Besides cancer, the biological functions of miR-149 have been studied in various diseases. This review aims to summarize the reports available in the literature, regarding miR-149 as a molecular target for cancer therapeutics. METHODS: An extensive literature search was conducted using the Pubmed database to sieve out articles related to the roles of miR-149 in carcinogenesis and cancer progression, and potential miRNA-based therapies. A total of 89 publications were selected for inclusion in this review. RESULTS: Depending on the cancer type, miR 149 can behave either as a tumor suppressor or as an 'onco-miR' that promotes tumorigenesis and cancer spread, suggesting that this miRNA has diverse functions. Potential miRNA-based therapies include the use of miRNA mimics, miRNA inhibitors, demethylating agents and circular RNAs. CONCLUSION: Although targeting miRNA is an attractive anti-cancer strategy, not all cancers can be treated by the same miRNA-based strategy. A comprehensive understanding of miRNA regulatory mechanism is also necessary to improve the design of miRNA-based therapeutics and there is a need for safe and efficient delivery methods when using this approach for anti-cancer treatment. PMID- 28721830 TI - Redox State in Atrial Fibrillation Pathogenesis and Relevant Therapeutic Approaches. AB - Myocardial redox state is a critical determinant of myocardial biology, regulating cardiomyocytes' apoptosis, hypertrophy, ion channels function and cardiac contractility and relaxation. Data from animal models have shown that altered myocardial nitroso-redox balance and NADPH oxidases activity are pivotally involved in the pathogenesis of atrial fibrillation. Similarly experimental animal data have demonstrated that increased reactive oxygen / nitrogen species formation in the atrial tissue is associated with altered electrophysiological properties of atrial myocytes and electrical remodeling. Redox-related processes also control atrial fibrosis and structural cardiac remodeling, the hallmarks of permanent atrial fibrillation, suggesting that strategies to cope with increased myocardial oxidative or nitrosative stress could constitute rational therapeutic approaches against atrial fibrillation in humans. Despite the mechanistic evidence linking redox state with atrial fibrillation, clinical studies targeting myocardial oxidative stress (e.g. with statins or antioxidants) have failed to document any solid benefits. In the present review we summarise the current knowledge on myocardial redox state as a determinant of atrial biology and function and its relevance in atrial fibrillation pathogenesis. Potential redox-related therapeutic approaches are also discussed. PMID- 28721831 TI - Transient production of recombinant pharmaceutical proteins in plants: evolution and perspectives. AB - During the last two decades the production of pharmaceutical proteins in plants evolved from proof of concept to established technology adopted by several biotechnological companies. This progress is particularly based on intensive research starting stable genetic transformation and moving to transient expression. Due to its advantages in yield and speed of protein production transient expression platforms became leading plant-based manufacturing technology. Current transient expression methods rely on Agrobacterium-mediated delivery of expression vectors into plant cells. In recent years great advances have been made in improvement of expression vectors, host cell engineering as well as in the development of commercial manufacturing processes. Several GMP certified large-scale production facilities exist around the world to utilize agroinfiltration method. A number of pharmaceutical proteins produced by transient expression are currently in clinical development. The great potential of transient expression platform in respect to rapid response to emerging pandemics was demonstrated by production of experimental ZMapp antibodies against Ebola virus as well as influenza vaccines. This review is focused on current design, status and future perspectives of plant transient expression system for production of biopharmaceutical proteins. PMID- 28721832 TI - Biomarkers associated with bleeding risk in the setting of atrial fibrillation. AB - Background Prevention of thromboembolic disease, mainly stroke, with oral anticoagulants remains a major therapeutic goal in patients with atrial fibrillation. Unfortunately, despite the high efficacy, anticoagulant therapy is associated with a significant risk of, frequently catastrophic, hemorrhagic complications. Among different clinical and laboratory parameters related to an increased risk of bleeding, several biological markers have been recognized and various risk scores for bleeding have been developed. Objectives/ Methods The aim of the present study is to review current evidence regarding the different biomarkers associated with raised bleeding risk in atrial fibrillation. Results Data originating from large cohorts or the recent large-scale trials of atrial fibrillation have linked numerous individual biomarkers to an increased bleeding risk. Such a relation was revealed for markers of cardiac physiology, such as troponin, BNP and NT-proBNP, markers of renal function, such as GFR and Cystatin or hepatic function, markers involving the system of coagulation, such as D-dimer and Von Willebrand factor, hematologic markers, such as low haemoglobin or low platelets, inflammatory markers, such as interleukin-6, other factors such as GDF 15 and vitamin-E and finally genetic polymorphisms. Many such biomarkers are incorporated in the bleeding risk schemata developed for the prediction of the hemorrhagic risk. Conclusions Biomarkers were introduced in clinical practice in order to better estimate the potential risk of haemorrhage in these patients and increase the prognostic impact of clinical risk scores. In the last years this concept is gaining significant importance. PMID- 28721833 TI - Role of Nutrients and Phyto-compounds in the Modulation of Antimicrobial Resistance. AB - BACKGROUND: Antimicrobial resistance is quickly spreading and has become a major public health problem worldwide. If this issue is not resolved, it may cause a shift back to the pre-antibiotics era and infectious disease will again be a serious problem, especially in developing countries. Since the discovery of antibiotics, bacterial resistance has emerged, enabling certain bacteria to withstand antibiotic action. The emergence of antibiotic resistance is fueled by excessive and improper use of antimicrobial agents, especially in developing countries. For this reason, alternatives to or modifications of current treatment methods have been sought. The aim of this review is to highlight the possible synergies of various agents that can augment antibiotic activities. METHODS: A structured literature search was conducted using only papers that have been published in PubMed with the focus on the agents that are likely to modulate antimicrobial resistance. In this review, data was retrieved from the literature regarding the possible synergies that exist between commercially available antimicrobial drugs with agents of interest. The papers included were summarized and analyzed, critiqued and compared for their contents using a conceptual frame work. RESULTS: In total, one hundred and twenty six papers were reviewed. The number of papers that dealt with the different topics included are as follows (): emergence of antimicrobial resistance (22), bioactive phyto-compounds (36) (phytobiologics, and phytochemicals), Antioxidants (40) (N-acetylcysteine, Ambroxol, Ascorbic acid, Glutathione and vitamin E), Peptide synergies (14) (Synthetic cationic alpha-helical AMPs, CopA3, Alafosfalin, PMAP-36, Phosphonopeptide L-norvalyl-L-1-aminoethylphosphonic acid and norcardicin-A), nano-antibiotics (10), drug-compound interactions (4).This review addressed the new strategies using the above compounds in the modulation of antimicrobial resistance to avoid issues related to resistance of bacteria to antibiotics. CONCLUSIONS: The findings of this review confirm that certain compounds can act in synergy with currently used antimicrobials to enhance the potential of antimicrobial agents and thus to reduce the emergence of antimicrobial resistance. Some of these synergies are already being used to enhance the potential of currently used antimicrobial agents. More studies need to be conducted to better understand the mechanism of action of such compounds, and based on the results, new compounds may be sought. PMID- 28721834 TI - The interaction between nutrition and exercise for promoting health and performance. AB - The theme of The Nutrition Society Spring Conference 2017 was on the interaction between nutrition and exercise for promoting healthy ageing, maintaining cognitive function and improving the metabolic health of the population. The importance of this theme is highlighted by the public health issues surrounding obesity, diabetes and the age-related loss of skeletal muscle mass (sarcopenia). The opening symposium provided a historical perspective of both invasive and non invasive methodologies for measuring exercise energetics and energy balance. Data derived from these techniques underpin current understanding regarding the metabolic response to nutrition and exercise. Further symposia examined the importance of skeletal muscle for healthy ageing in older men and postmenopausal women. From a nutritional perspective, the potential for animal- v. plant-based protein sources to offset the age-related decline in muscle mass was discussed. The day concluded by discussing the link(s) between nutrition, exercise and brain function. Day 2 commenced with examples of applied equine research illustrating the link between nutrition/exercise and insulin resistance to those of a human model. The final symposium examined the combined role of nutrition and exercise in reducing risk of type 2 diabetes and dyslipidaemia. The overall conclusion from the meeting was that the interaction between diet and physical activity confers greater benefits to human health and performance than either component alone. PMID- 28721835 TI - Parasites as prey: the effect of cercarial density and alternative prey on consumption of cercariae by four non-host species. AB - In parasites with complex life cycles the transmission of free-living infective stages can be influenced by ambient community diversity, in particular via predation. Here, we experimentally investigated whether parasite density and the presence of alternative prey can alter predation rates on free-living cercarial stages of a marine trematode by several non-host predators. All four predator species consumed increasing numbers of cercariae with an increase in cercarial density, indicating that the removal of cercariae by predators is effective over a range of natural densities as well as in the presence of alternative prey for a number of predators typical of marine ecosystems. However, the relative removal rates and the effects of cercarial density and alternative prey differed among predator species. In barnacles and shrimps, significant interactive effects of cercarial density and alternative prey on cercarial predation occurred while in oysters and crabs cercarial removal rates were unaffected by both factors. As changes in cercarial densities directly translate into changes in infection levels in down-stream hosts in this parasite-host system, the observed predator specific responses suggest that cercarial predation effects on disease risks will depend on the specific species composition of ambient communities and not on non host biodiversity per se. PMID- 28721829 TI - NGS Technologies as a Turning Point in Rare Disease Research , Diagnosis and Treatment. AB - Approximately 25-50 million Americans, 30 million Europeans, and 8% of the Australian population have a rare disease. Rare diseases are thus a common problem for clinicians and account for enormous healthcare costs worldwide due to the difficulty of establishing a specific diagnosis. In this article, we review the milestones achieved in our understanding of rare diseases since the emergence of next-generation sequencing (NGS) technologies and analyze how these advances have influenced research and diagnosis. The first half of this review describes how NGS has changed diagnostic workflows and provided an unprecedented, simple way of discovering novel disease-associated genes. We focus particularly on metabolic and neurodevelopmental disorders. NGS has enabled cheap and rapid genetic diagnosis, highlighted the relevance of mosaic and de novo mutations, brought to light the wide phenotypic spectrum of most genes, detected digenic inheritance or the presence of more than one rare disease in the same patient, and paved the way for promising new therapies. In the second part of the review, we look at the limitations and challenges of NGS, including determination of variant causality, the loss of variants in coding and non-coding regions, and the detection of somatic mosaicism variants and epigenetic mutations, and discuss how these can be overcome in the near future. PMID- 28721836 TI - Assisted reproductive technologies: a hierarchy of risks for conception, pregnancy outcomes and treatment decisions. AB - The use of assisted reproductive technologies (ART) for the treatment of infertility has grown exponentially over the last 20 years, and now accounts for 4% of all births in Australia, and over 1 m births annually around the globe. There is consistent reporting of increased risk of adverse perinatal outcomes and birth defects following infertility treatment. However, change in practice has been stymied by critical knowledge gaps with regards to (a) the relative contribution of patient and treatment factors to adverse outcomes, (b) the independent contribution of specific contemporary treatments and treatment combinations to outcomes, (c) the impact of innovations in laboratory and clinical practice on treatment success and observed risk and (d) changes over time in patient characteristics. Here we summarize key findings from the South Australian Birth Cohort, which is a whole-of-population cohort of over 300,000 births from 1986 to 2002. Relative to spontaneous conceptions, singletons from assisted conception were more likely to be stillborn [odds ratio (OR)=1.82; 95% confidence interval (CI) 1.34-2.48], while survivors as a group were comprehensively disadvantaged at birth, including lower birth weight (OR=2109 g; 95% CI 2129-289), very low birth weight (OR=2.74; 95% CI 2.19-3.43), very preterm birth (OR=2.30; 95% CI 1.82-2.90) and neonatal death (OR=2.04; 95% CI 1.27-3.26). Major birth defects, including cardiac, urogenital and musculoskeletal defects are doubled after fresh ICSI cycles, which is a particular concern as ICSI now accounts for 70% of all treatment cycles globally. Future study is needed to provide contemporary, precise evidence to inform patient and clinic decision making, and generate knowledge for future innovation in ART laboratory methods and clinical practice, thereby optimizing treatment and health outcomes while reducing adverse events. PMID- 28721837 TI - Effects of progressive resistance training combined with a protein-enriched lean red meat diet on health-related quality of life in elderly women: secondary analysis of a 4-month cluster randomised controlled trial. AB - Resistance training (RT) and increased dietary protein are recommended to attenuate age-related muscle loss in the elderly. This study examined the effect of a lean red meat protein-enriched diet combined with progressive resistance training (RT+Meat) on health-related quality of life (HR-QoL) in elderly women. In this 4-month cluster randomised controlled trial, 100 women aged 60-90 years (mean 73 years) from self-care retirement villages participated in RT twice a week and were allocated either 160 g/d (cooked) lean red meat consumed across 2 meals/d, 6 d/week or >=1 serving/d (25-30 g) carbohydrates (control group, CRT). HR-QoL (SF-36 Health Survey questionnaire), lower limb maximum muscle strength and lean tissue mass (LTM) (dual-energy X-ray absorptiometry) were assessed at baseline and 4 months. In all, ninety-one women (91 %) completed the study (RT+Meat (n 48); CRT (n 43)). Mean protein intake was greater in RT+Meat than CRT throughout the study (1.3 (sd 0.3) v. 1.1 (sd 0.3) g/kg per d, P<0.05). Exercise compliance (74 %) was not different between groups. After 4 months there was a significant net benefit in the RT+Meat compared with CRT group for overall HR-QoL and the physical component summary (PCS) score (P<0.01), but there were no changes in either group in the mental component summary (MCS) score. Changes in lower limb muscle strength, but not LTM, were positively associated with changes in overall HR-QoL (muscle strength, beta: 2.2 (95 % CI 0.1, 4.3), P<0.05). In conclusion, a combination of RT and increased dietary protein led to greater net benefits in overall HR-QoL in elderly women compared with RT alone, which was because of greater improvements in PCS rather than MCS. PMID- 28721838 TI - Increased serum ferritin levels are independently associated with carotid atherosclerosis in women. AB - Previous studies have supported the theory that there is a positive association between ferritin and carotid atherosclerosis in Western people. Diet plays an important role in determining serum ferritin concentration. Asian dietary patterns are different from Western dietary patterns, implying that there may be a difference in the association of ferritin with carotid atherosclerosis between Asian and Western people. However, few studies focus on the association between ferritin and carotid atherosclerosis among Asians. The aim of this study was to investigate how serum ferritin levels are associated with carotid atherosclerosis in an Asian adult population. A cross-sectional assessment was performed in 8302 adults in Tianjin, China. Carotid intima-media thickness (IMT) and plaques were assessed using ultrasonography, and serum ferritin was measured using the protein chip-chemiluminescence method. Multiple logistic regression analysis was used to examine the association between quartiles of serum ferritin concentration and carotid atherosclerosis. In the present study, the overall prevalence of IMT and carotid plaques in participants is 29.2 and 22.7 %, respectively. In women, after adjustments for potentially confounding factors, the OR of IMT and carotid plaques by increasing serum ferritin quartiles were 1.00, 1.39 (95 % CI 0.98 1.99), 1.39 (95 % CI 0.99-1.97), 1.81 (95 % CI 1.30-2.55) (P for trend<0.001) and 1.00, 1.24 (95 % CI 0.89-1.73), 1.18 (95 % CI 0.85-1.65), 1.59 (95 % CI 1.15 2.20) (P for trend<0.01), respectively. However, no association was found between serum ferritin and carotid atherosclerosis in men. The study demonstrated that increased serum ferritin levels are independently associated with IMT and carotid plaques in Asian women but not in Asian men. PMID- 28721840 TI - Ogataea haglerorum sp. nov., a novel member of the species complex, Ogataea (Hansenula) polymorpha. AB - Three strains representing a novel species of the Ogataea clade were isolated by W. T. Starmer and H. J. Phaff from rotting tissue of Opuntia phaeacantha in Arizona, USA. Analyses of the sequences of the D1/D2 LSU rRNA gene, ITS1-5.8S ITS2, and translation elongation factor-1alpha (EF-1 alpha) showed that this novel species belongs to the Ogataea polymorpha complex formed by Ogataea angusta, Ogataea parapolymorpha and Ogataea polymorpha. The novel species differs from these species by 4-5 nucleotide substitutions in the D1/D2 domain, by 28-29 nucleotide substitutions in the EF-alpha gene and by 18-24 nucleotide substitutions and 2-5 indels in the ITS-5.8S region. The name Ogataea haglerorum sp. nov. is proposed for this novel species. The type strain is VKPM Y-2583T (=CBS 14645T=UCDFST 17-101T). The Mycobank number is MB 819772. PMID- 28721839 TI - Branched-chain amino acid, meat intake and risk of type 2 diabetes in the Women's Health Initiative. AB - Knowledge regarding association of dietary branched-chain amino acid (BCAA) and type 2 diabetes (T2D), and the contribution of BCAA from meat to the risk of T2D are scarce. We evaluated associations between dietary BCAA intake, meat intake, interaction between BCAA and meat intake and risk of T2D. Data analyses were performed for 74 155 participants aged 50-79 years at baseline from the Women's Health Initiative for up to 15 years of follow-up. We excluded from analysis participants with treated T2D, and factors potentially associated with T2D or missing covariate data. The BCAA and total meat intake was estimated from FFQ. Using Cox proportional hazards models, we assessed the relationship between BCAA intake, meat intake, and T2D, adjusting for confounders. A 20 % increment in total BCAA intake (g/d and %energy) was associated with a 7 % higher risk for T2D (hazard ratio (HR) 1.07; 95 % CI 1.05, 1.09). For total meat intake, a 20 % increment was associated with a 4 % higher risk of T2D (HR 1.04; 95 % CI 1.03, 1.05). The associations between BCAA intake and T2D were attenuated but remained significant after adjustment for total meat intake. These relations did not materially differ with or without adjustment for BMI. Our results suggest that dietary BCAA and meat intake are positively associated with T2D among postmenopausal women. The association of BCAA and diabetes risk was attenuated but remained positive after adjustment for meat intake suggesting that BCAA intake in part but not in full is contributing to the association of meat with T2D risk. PMID- 28721842 TI - Rapid Seafood Species Identification Using Chip-Based Capillary Electrophoresis and Protein Pattern Matching. AB - Authenticity is crucial to the seafood industry, as substitution and mislabeling have important economic, environmental, and food safety consequences. To address this problem, protein profiling and software algorithm techniques were developed to classify fish muscle samples by species. The method uses water-based protein extraction, chip-based microfluidic electrophoresis (Agilent 2100 Bioanalyzer) for the analysis of high abundance fish muscle proteins, and a novel data analysis method for species-specific protein pattern recognition. The method's performance in distinguishing commercially important fish from commonly reported substitutions was evaluated using sensitivity, specificity, and accuracy determinations with all three performance measures at >98% for common substitutions. This study demonstrates that uncooked seafood products of commercially important species of catfish, snapper, and grouper can be rapidly distinguished from commonly substituted species with a high level of confidence. A tiered testing approach to seafood species verification by sequentially applying a rapid screening method and DNA testing is proposed to more effectively ensure accurate product labeling. PMID- 28721841 TI - Genetic characterization of highly pathogenic avian influenza A H5N8 viruses isolated from wild birds in Egypt. AB - A newly emerged H5N8 influenza virus was isolated from green-winged teal in Egypt during December 2016. In this study, we provide a detailed characterization of full genomes of Egyptian H5N8 viruses and some virological features. Genetic analysis demonstrated that the Egyptian H5N8 viruses are highly pathogenic avian influenza viruses. Phylogenetic analysis revealed that the genome of the Egyptian H5N8 viruses was related to recently characterized reassortant H5N8 viruses of clade 2.3.4.4 isolated from different Eurasian countries. Multiple peculiar mutations were characterized in the Egyptian H5N8 viruses, which probably permits transmission and virulence of these viruses in mammals. The Egyptian H5N8 viruses preferentially bound to avian-like receptors rather than human-like receptors. Also, the Egyptian H5N8 viruses were fully sensitive to amantadine and neuraminidase inhibitors. Chicken sera raised against commercial inactivated avian influenza-H5 vaccines showed no or very low reactivity with the currently characterized H5N8 viruses in agreement with the genetic dissimilarity. Surveillance of avian influenza in waterfowl provides early warning of specific threats to poultry and human health and hence should be continued. PMID- 28721843 TI - Treponema rectale sp. nov., a spirochete isolated from the bovine rectum. AB - A Gram-stain-negative, obligatory anaerobic spirochete, CHPAT, was isolated from the rectal tissue of a Holstein-Friesian cow. On the basis of 16S rRNA gene comparisons, CHPAT was most closely related to the human oral spirochete, Treponema parvum, with 88.8 % sequence identity. Further characterisation on the basis of recA gene sequence analysis, cell morphology, pattern of growth and physiological profiling identified marked differences with respect to other recognised species of the genus Treponema. Microscopically, the helical cells measured approximately 1-5 um long and 0.15-0.25 um wide, with two to five irregular spirals. Transmission electron microscopy identified four periplasmic flagella in a 2 : 4 : 2 arrangement. CHPAT grew independently of serum, demonstrated no evidence of haemolytic activity and possessed an in vitro enzyme activity profile that is unique amongst validly named species of the genus Treponema, exhibiting C4 esterase, alpha-galactosidase and beta-galactosidase activity. Taken together, these data indicate that CHPAT represents a novel species of the genus Treponema, for which the name Treponema rectale is proposed. The type strain of Treponema rectale is CHPAT (=DSM 103679T=NCTC 13848T). PMID- 28721844 TI - CD81 large extracellular loop-containing fusion proteins with a dominant negative effect on HCV cell spread and replication. AB - The roles of CD81 in the hepatitis C virus (HCV) life cycle are multiple but remain ill characterized. CD81 is known to interact with the HCV glycoproteins as an attachment factor. It also has an important role in the post-attachment entry process. Its interaction with claudin-1, for example, is vital for viral uptake and trafficking. Furthermore, CD81 and its role in membrane organization and trafficking are thought to play a pivotal role in HCV replication. Some of these functions are particularly limited to human CD81; others can be substituted with CD81 molecules from other species. However, with the exception of the large extracellular loop sequence, the structure-function analysis of CD81 in the HCV infectious cycle remains ill characterized. We describe here the fusion molecules between the large extracellular loops of human or mouse CD81 and lipid-raft associated or unassociated GPI anchors. These fusion molecules have strong antiviral activity in a dominant negative fashion, independent of membrane raft association. Their expression in the hepatoma cell line Huh7.5 blocks HCV uptake, transmission and replication. These molecules will be useful to decipher the various roles of CD81 in the HCV life cycle and transmission in more detail. PMID- 28721845 TI - Combination of polymyxin B and meropenem eradicates persister cells from Acinetobacter baumannii strains in exponential growth. PMID- 28721846 TI - Skin Fungi from Colonization to Infection. AB - Humans are exceptional among vertebrates in that their living tissue is directly exposed to the outside world. In the absence of protective scales, feathers, or fur, the skin has to be highly effective in defending the organism against the gamut of opportunistic fungi surrounding us. Most (sub)cutaneous infections enter the body by implantation through the skin barrier. On intact skin, two types of fungal expansion are noted: (A) colonization by commensals, i.e., growth enabled by conditions prevailing on the skin surface without degradation of tissue, and (B) infection by superficial pathogens that assimilate epidermal keratin and interact with the cellular immune system. In a response-damage framework, all fungi are potentially able to cause disease, as a balance between their natural predilection and the immune status of the host. For this reason, we will not attribute a fixed ecological term to each species, but rather describe them as growing in a commensal state (A) or in a pathogenic state (B). PMID- 28721847 TI - Classical scrapie transmission in ARR/ARR genotype sheep. AB - The ARR allele is considered to provide a very strong resistance against classical scrapie infection in sheep. In this study, we report the occurrence of clinical transmissible spongiform encephalopathy in ARR/ARR sheep, following their inoculation by the intracerebral route with a classical scrapie isolate. On first passage, the disease displayed an incomplete attack rate transmission, with incubation periods exceeding 6 years. On second passage, the obtained prion did not display better abilities to propagate than the original isolate. These transmission results contrasted with the 100 % attack rate and the short incubation periods observed in ARQ/ARQ sheep challenged with the same isolate. These data confirm that ARR/ARR sheep cannot be considered to be fully resistant to classical scrapie. However, they also support the contention that classical scrapie has a very limited capacity to transmit and adapt to ARR/ARR sheep. PMID- 28721848 TI - Evaluation of biofilm-specific antimicrobial resistance genes in Pseudomonas aeruginosa isolates in Farabi Hospital. AB - BACKGROUND: Biofilm produced from Pseudomonas aeruginosa is the cause of infection induced by contact lenses, trauma and post-surgery infection. The aim of this study was to evaluate biofilm formation and the presence of the genes ndvB and tssC1 in ocular infection isolates of P. aeruginosa. METHODS: A total of 92 P. aeruginosa strains were collected from patients with ocular infection referred to Farabi Hospital between March 2014 and July 2015. Antibiotic susceptibility patterns were evaluated by the agar disc-diffusion method according to CLSI guidelines. PCR assays were used to detect ndvB and tssC1, genes associated with resistance in biofilm-producing P. aeruginosa isolates. Biofilm formation ability was examined by crystal violet microtitre plate assay. RESULTS: During the period of study, 92 P. aeruginosa were isolated from ocular infections including keratitis (n=84) and endophthalmitis (n=8). The highest resistance rates were seen against colistin (57.6 %) and gentamicin (50 %) and the lowest resistance rates were seen against imipenem (3.3 %), aztreonam (4.3 %), piperacillin-tazobactam (4.3 %), ceftazidime (4.3 %) and ciprofloxacin (5.4 %). Biofilm production ability was found in 100 % of the isolates. PCR assays showed that of the 92 P. aeruginosa isolates, 96.7 and 90.2 % harboured the genes ndvB and tssC1, respectively. CONCLUSIONS: Our results showed a considerable ability of biofilm production, as well as the occurrence of biofilm-specific antimicrobial resistance genes (ndvB and tssC1), in P. aeruginosa isolates from ocular infections in Farabi Hospital. PMID- 28721849 TI - Effective protection of mice against Shigella flexneri with a new self-adjuvant multicomponent vaccine. AB - PURPOSE: The aim of this study was to develop an immunogenic protective product against Shigella flexneri by employing a simple and safe heat treatment-based strategy. METHODOLOGY: The physicochemical characteristics of naturally produced (OMV) and heat-induced (HT) outer-membrane vesicles from S. flexneri were examined, including a comparison of the protein content of the products. Toxicological and biodistribution studies, and a preliminary experiment to examine the protective effectiveness of HT in a murine model of S. flexneri infection, were also included. RESULTS: This method simultaneously achieves complete bacterial inactivation and the production of the HT vaccine product, leading to a safe working process. The obtained HT complex presented a similar morphology (electron microscopy) and chemical composition to the classical OMV, although it was enriched in some immunogens, such as lipoproteins, OmpA or OmpC, among others. The HT formulation was not toxic and biodistribution studies performed in mice demonstrated that the vaccine product remained in the small intestine after nasal administration. Finally, a single dose of HT administered nasally was able to protect mice against S. flexneri 2a. CONCLUSION: The convenient and safe manufacturing process, and the preliminary biological evaluation, support the use of the self-adjuvanted HT complex as a new vaccine candidate to face shigellosis. Further development is required, such as additional immune analyses, to evaluate whether this new subunit vaccine can be useful in achieving full protection against Shigella. PMID- 28721850 TI - Amphotericin B induces apoptosis-like programmed cell death in Naegleria fowleri and Naegleria gruberi. AB - Naegleria fowleri and Naegleria gruberi belong to the free-living amoebae group. It is widely known that the non-pathogenic species N. gruberi is usually employed as a model to describe molecular pathways in this genus, mainly because its genome has been recently described. However, N. fowleri is an aetiological agent of primary amoebic meningoencephalitis, an acute and fatal disease. Currently, the most widely used drug for its treatment is amphotericin B (AmB). It was previously reported that AmB has an amoebicidal effect in both N. fowleri and N. gruberi trophozoites by inducing morphological changes that resemble programmed cell death (PCD). PCD is a mechanism that activates morphological, biochemical and genetic changes. However, PCD has not yet been characterized in the genus Naegleria. The aim of the present work was to evaluate the typical markers to describe PCD in both amoebae. These results showed that treated trophozoites displayed several parameters of apoptosis-like PCD in both species. We observed ultrastructural changes, an increase in reactive oxygen species, phosphatidylserine externalization and a decrease in intracellular potassium, while DNA degradation was evaluated using the TUNEL assay and agarose gels, and all of these parameters are related to PCD. Finally, we analysed the expression of apoptosis-related genes, such as sir2 and atg8, in N. gruberi. Taken together, our results showed that AmB induces the morphological, biochemical and genetic changes of apoptosis-like PCD in the genus Naegleria. PMID- 28721851 TI - Development and evaluation of a multiple-locus variable-number tandem-repeats analysis assay for subtyping Salmonella Typhi strains from sub-Saharan Africa. AB - PURPOSE: Molecular epidemiological investigations of the highly clonal Salmonella enterica subspecies enterica serovar Typhi (S. Typhi) are important in outbreak detection and in tracking disease transmission. In this study, we developed and evaluated a multiple-locus variable-number tandem-repeats (VNTR) analysis (MLVA) assay for characterization of S. Typhi isolates from sub-Saharan Africa. METHODOLOGY: Twelve previously reported VNTR loci were evaluated and an MLVA assay consisting of five polymorphic loci was adopted. The MLVA assay was developed for use on capillary electrophoresis systems by testing a collection of 50 S. Typhi isolates. This S. Typhi strain panel consisted of six outbreak related isolates and 44 epidemiologically unlinked isolates. Amongst these were nine S.Typhi haplotype H58 isolates. RESULTS: The MLVA assay characterized the 50 isolates into 47 MLVA profiles while PFGE analysis of the same isolates revealed 34 pulsotypes. MLVA displayed higher discriminatory power (Simpson's index of diversity (DI) 0.998 [95 % confidence interval (CI) 0.995-1.000)] as compared to pulsed-field gel electrophoresis [Simpson's DI 0.984 (95 % CI 0.974-0.994)]. CONCLUSION: The MLVA assay presented in this study is a simple, rapid and more accessible tool that serves as a good alternative to other molecular subtyping methods for S. Typhi. PMID- 28721852 TI - Effective identification of Lactobacillus casei group species: genome-based selection of the gene mutL as the target of a novel multiplex PCR assay. AB - Lactobacillus casei,Lactobacillus paracasei and Lactobacillusrhamnosus form a closely related taxonomic group (the L. casei group) within the facultatively heterofermentative lactobacilli. Strains of these species have been used for a long time as probiotics in a wide range of products, and they represent the dominant species of nonstarter lactic acid bacteria in ripened cheeses, where they contribute to flavour development. The close genetic relationship among those species, as well as the similarity of biochemical properties of the strains, hinders the development of an adequate selective method to identify these bacteria. Despite this being a hot topic, as demonstrated by the large amount of literature about it, the results of different proposed identification methods are often ambiguous and unsatisfactory. The aim of this study was to develop a more robust species-specific identification assay for differentiating the species of the L. casei group. A taxonomy-driven comparative genomic analysis was carried out to select the potential target genes whose similarity could better reflect genome-wide diversity. The gene mutL appeared to be the most promising one and, therefore, a novel species-specific multiplex PCR assay was developed to rapidly and effectively distinguish L. casei, L. paracasei and L. rhamnosus strains. The analysis of a collection of 76 wild dairy isolates, previously identified as members of the L. casei group combining the results of multiple approaches, revealed that the novel designed primers, especially in combination with already existing ones, were able to improve the discrimination power at the species level and reveal previously undiscovered intraspecific biodiversity. PMID- 28721853 TI - uS10, a novel Npro-interacting protein, inhibits classical swine fever virus replication. AB - Classical swine fever (CSF) is a severe, febrile and highly contagious disease caused by classical swine fever virus (CSFV) that has resulted in huge economic losses in the pig industry worldwide. CSFV Npro has been actively studied but remains incompletely understood. Few studies have investigated the cellular proteins that interact with Npro and their participation in viral replication. Here, the yeast two-hybrid (Y2H) system was employed to screen Npro-interacting proteins from a porcine alveolar macrophage (PAM) cDNA library, and a blast search of the NCBI database revealed that 15 cellular proteins interact with Npro. The interaction of Npro with ribosomal protein S20, also known as universal S10 (uS10), was further confirmed by co-immunoprecipitation and glutathione S transferase pull-down assays. Furthermore, uS10 overexpression inhibited CSFV replication, whereas the knockdown of uS10 promoted CSFV replication in PAMs. In addition, Npro or CSFV reduced uS10 expression in PAMs in a proteasome-dependent manner, indicating that Npro-uS10 interaction might contribute to persistent CSFV replication. Our previous research showed that CSFV decreases Toll-like receptor 3 (TLR3) expression. The results showed that uS10 knockdown reduced TLR3 expression, and that uS10 overexpression increased TLR3 expression. Notably, uS10 knockdown did not promote CSFV replication following TLR3 overexpression. Conversely, uS10 overexpression did not inhibit CSFV replication following TLR3 knockdown. These results revealed that uS10 inhibits CSFV replication by modulating TLR3 expression. This work addresses a novel aspect of the regulation of the innate antiviral immune response during CSFV infection. PMID- 28721854 TI - Flavitalea antarctica sp. nov., isolated from Fildes Peninsula, Antarctica. AB - A bright-yellow, Gram-stain-negative, rod-shaped, gliding and aerobic bacterium, designated strain AQ6-291T, was isolated from the Fildes Peninsula, Antarctica, and its taxonomic position was investigated by genotypic, phenotypic and chemotaxonomic analyses. Growth occurred at 4-28 degrees C (optimum 20 degrees C) and at pH 5.0-8.0 (optimum pH 7.0). Strain AQ6-291T contained iso-C15 : 1 G, iso-C15 : 0, C16 : 1omega5c, iso-C17 : 0 3-OH and summed feature 3 (comprising C16 : 1omega7c and/or C16 : 1omega6c) as the major cellular fatty acids. The main polar lipids were phosphatidylethanolamine, unknown aminophospholipids, unknown phospholipids, five unknown aminolipids and two unknown polar lipids. MK-7 was the major respiratory quinone. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain AQ6-291T belonged to the genus Flavitalea. The DNA G+C content was 48.1 mol%. On the basis of phenotypic, chemotaxonomic and phylogenetic data, strain AQ6-291T is considered to represent a novel species of the genus Flavitalea, for which the name Flavitalea antarctica sp. nov. is proposed. The type strain is AQ6-291T (=CCTCC AB 2016109T=KCTC 52491T). PMID- 28721855 TI - Cell surface physiology and outer cell envelope impermeability for hydrophobic substances in Burkholderia multivorans. AB - PURPOSE: The purpose of the present study was to obtain a better understanding of the relationship between cell surface physiology and outer cellular envelope permeability for hydrophobic substances in mucoid and non-mucoid B. multivorans strains, as well as in two capsule-deficient derivatives of a mucoid parental strain. METHODOLOGY: Cell surface hydrophobicity properties were determined using the hydrocarbon adherence method, while outer cell envelope accessibility and permeability for non-polar compounds were measured using hydrophobic antimicrobial agent susceptibility and fluorescent probe assays. Extracellular polysaccharide (EPS) production was assessed by cultivating strains of disparate origin on yeast extract agar (YEA) containing different sugars, while the resultant colonial and cellular morphological parameters were assessed macro- and microscopically, respectively.Results/Key findings. The cell surfaces of all the strains were hydrophilic, impermeable to mechanistically disparate hydrophobic antibacterial agents and inaccessible to the hydrophobic probe N-phenyl-1 napthylamine, regardless of EPS phenotype. Supplementation of basal YEA with eight different sugars enhanced macroscopic EPS expression for all but one non mucoid strain, with mannose potentiating the greatest effect. Despite acquisition of the mucoid phenotype, non-mucoid strains remained non-capsulated and capsulation of a hyper-mucoid strain and its two non-mucoid derivative strains was unaffected, as judged by microscopic observation. CONCLUSION: These data support the conclusion that EPS expression and the consistent mucoid phenotype are not necessarily associated with the ability of the outer cell surface to associate with non-polar substances or cellular capsulation. PMID- 28721856 TI - Repeat-Induced Point Mutation and Other Genome Defense Mechanisms in Fungi. AB - Transposable elements have colonized the genomes of nearly all organisms, including fungi. Although transposable elements may sometimes provide beneficial functions to their hosts their overall impact is considered deleterious. As a result, the activity of transposable elements needs to be counterbalanced by the host genome defenses. In fungi, the primary genome defense mechanisms include repeat-induced point mutation (RIP) and methylation induced premeiotically, meiotic silencing by unpaired DNA, sex-induced silencing, cosuppression (also known as somatic quelling), and cotranscriptional RNA surveillance. Recent studies of the filamentous fungus Neurospora crassa have shown that the process of repeat recognition for RIP apparently involves interactions between coaligned double-stranded segments of chromosomal DNA. These studies have also shown that RIP can be mediated by the conserved pathway that establishes transcriptional (heterochromatic) silencing of repetitive DNA. In light of these new findings, RIP emerges as a specialized case of the general phenomenon of heterochromatic silencing of repetitive DNA. PMID- 28721858 TI - Detection of African swine fever virus in the tissues of asymptomatic pigs in smallholder farming systems along the Kenya-Uganda border: implications for transmission in endemic areas and ASF surveillance in East Africa. AB - The persistence of African swine fever virus (ASFV) in endemic areas, with small scale but regular outbreaks in domestic pigs, is not well understood. ASFV has not been detected using conventional diagnosis in these pigs or adjacent populations of resistant African wild pigs, that could act as potential carriers during the outbreaks. However, such data are crucial for the design of evidence based control strategies. We conducted cross-sectional (1107 pigs) and longitudinal (100 pigs) monitoring of ASFV prevalence in local pigs in Kenya and Uganda. The horizontal survey revealed no evidence of ASFV in the serum or blood using either conventional or real-time PCR. One pig consistently tested positive using ELISA, but negative using PCR assays on blood. Interestingly, the isotype of the antibodies from this animal were strongly IgA biased relative to control domestic pigs and warthogs, suggesting a role for mucosal immunity. The tissues from this pig were positive by PCR following post-mortem. Internal organ tissues of 44 healthy pigs (28 sentinel pigs and 16 pigs from slaughter slabs) were tested with four different PCR assays; 15.9 % were positive for ASFV suggesting that healthy pigs carrying ASFV exist in the swine population in the study area. P72 and p54 genotyping of ASFV revealed very limited diversity: all were classified in genotype IX at both loci, as were virtually all viruses causing recent ASF outbreaks in the region. Our study suggests that carrier pigs may play a role in ASF disease outbreaks, although the triggers for outbreaks remain unclear and require further investigation. This study significantly increases scientific knowledge of the epidemiology of ASF in the field in Africa, which will contribute to the design of effective surveillance and control strategies. PMID- 28721859 TI - Immunogenicity and safety of the inactivated hepatitis A vaccine in children with juvenile idiopathic arthritis on methotrexate treatment: a matched case-control study. AB - OBJECTIVES: To describe the immunogenicity and side effects of immunisation against hepatitis A virus (HAV) in JIA patients on methotrexate treatment, who have not been previously exposed to HAV. METHODS: Case-control study performed in JIA patients and healthy controls matched on age and gender. The subjects received two doses of inactivated anti-HAV vaccine (720 mIU/ml) intramuscularly at 0 and 6 months. Seroconversion, seroprotection rates and anti-HAV-IgG titres were measured at 1, 7 and 18 months. Children were monitored for adverse events. RESULTS: 83 JIA patients and 76 controls were enrolled in the study. At one month, seroprotection rates were lower in children with, as compared to those without JIA (48.2% vs. 65%; p=0.05). At 7 and 18 months, rates of seroprotection rose significantly and were similar in both groups. The titre of anti-HAV-IgG was lower in children with JIA than healthy children at all time points (p<0.001). Vaccines were well tolerated. CONCLUSIONS: Two doses of inactivated HAV vaccine were well tolerated and immunogenic in most immunosuppressed children with JIA; however, a single dose of HAV vaccine was insufficient to induce seroprotection in half of the patients. Further studies are required to analyse the long-term immunity against HAV in this population and optimal HAV immunisation regimen. PMID- 28721860 TI - One year in review 2017: systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that predominately affects women. It is characterised by a broad spectrum of clinical manifestations, however, its course and organ involvement are unpredictable. Although over the last few decades an improvement in survival for SLE patients has been observed, pathogenic mechanisms underlying this disease are still unclear. Comorbidities, due to both disease and treatment, as well as multiple aspects of SLE, are under intensive investigation. Following the previous annual reviews of this series, we hereby provide a critical digest of the recent papers on SLE focusing on pathogenesis, clinical and laboratory features, as well as current and new therapeutic strategies published over the last year. PMID- 28721861 TI - Erratum corrige. PMID- 28721863 TI - Canada's feminist foreign aid agenda. PMID- 28721862 TI - Public genomes: the future of the NHS? PMID- 28721864 TI - Curbing the rise in gonococcal AMR. PMID- 28721857 TI - Stress Adaptation. AB - Fungal species display an extraordinarily diverse range of lifestyles. Nevertheless, the survival of each species depends on its ability to sense and respond to changes in its natural environment. Environmental changes such as fluctuations in temperature, water balance or pH, or exposure to chemical insults such as reactive oxygen and nitrogen species exert stresses that perturb cellular homeostasis and cause molecular damage to the fungal cell. Consequently, fungi have evolved mechanisms to repair this damage, detoxify chemical insults, and restore cellular homeostasis. Most stresses are fundamental in nature, and consequently, there has been significant evolutionary conservation in the nature of the resultant responses across the fungal kingdom and beyond. For example, heat shock generally induces the synthesis of chaperones that promote protein refolding, antioxidants are generally synthesized in response to an oxidative stress, and osmolyte levels are generally increased following a hyperosmotic shock. In this article we summarize the current understanding of these and other stress responses as well as the signaling pathways that regulate them in the fungi. Model yeasts such as Saccharomyces cerevisiae are compared with filamentous fungi, as well as with pathogens of plants and humans. We also discuss current challenges associated with defining the dynamics of stress responses and with the elaboration of fungal stress adaptation under conditions that reflect natural environments in which fungal cells may be exposed to different types of stresses, either sequentially or simultaneously. PMID- 28721865 TI - Eliminating acute rheumatic fever and rheumatic heart disease. PMID- 28721866 TI - Offline: The G20 and health-platitudes and broken promises. PMID- 28721868 TI - Staff protest against care conditions for child patients. PMID- 28721867 TI - What lies in the future of the UK's medicine regulation? PMID- 28721869 TI - France bans sodium valproate use in case of pregnancy. PMID- 28721870 TI - Frontline: the vital need for information. PMID- 28721871 TI - Response to Offline: Is the NHS in crisis? PMID- 28721872 TI - Crisis in the National Health Service: a call to action. PMID- 28721873 TI - New mercury pollution threats: a global health caution. PMID- 28721874 TI - Crying wolf: the misuse of hospital data. PMID- 28721875 TI - Intensive speech and language therapy after stroke - Authors' reply. PMID- 28721876 TI - Intensive speech and language therapy after stroke. PMID- 28721877 TI - Science is what we need in the treatment of anxiety disorders. PMID- 28721878 TI - Department of Error. PMID- 28721880 TI - Department of Error. PMID- 28721879 TI - Burnout or depression: both individual and social issue. PMID- 28721882 TI - Why So Challenging to Personalize Radiation Dose? PMID- 28721881 TI - Final Report of a Prospective Randomized Trial to Evaluate the Dose-Response Relationship for Postoperative Radiation Therapy and Pathologic Risk Groups in Patients With Head and Neck Cancer. AB - PURPOSE: To present the long-term and final report of a phase 3 trial designed to assess dose-response relationship for postoperative radiation therapy (PORT) and pathologic risk groups in head and neck cancer. METHODS AND MATERIALS: Patients who underwent primary surgery for American Joint Committee on Cancer stage III or IV squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx and who required PORT were eligible. Patients' primary sites and involved necks were independently assigned to higher- or lower-risk categories based on a cumulative point score representing increasing risk of recurrence. The sites in the lower-risk group were randomized to receive 57.6 or 63 Gy and those in the higher-risk group were randomized to receive 63 or 68.4 Gy, all at 1.8 Gy per fraction. RESULTS: A total of 264 patients were included. The actuarial 5-year locoregional control rate was 67%. A second primary cancer was documented in 27% of patients. The 5- and 10-year freedom-from-distant metastasis rates were 64% and 60%, respectively, whereas the 5- and 10-year overall survival rates were 32% and 20%, respectively. There was no statistically significant difference in tumor control between different dose levels in both the lower- and higher-risk groups. On multivariate analysis, nonwhite race (P=.0003), positive surgical margins (P=.009), extracapsular extension (ECE, P=.01), and treatment package time (TPT) >=85 days (P=.002) were independent correlates of worse locoregional control, whereas age >=57 years (P<.0001), positive surgical margins (P=.01), ECE (P=.026), and TPT >=85 days (P=.003) were independently associated with worse overall survival. CONCLUSIONS: This long-term report of PORT delivered at 1.8 Gy/d to total doses of 57.6 to 68.4 Gy without chemotherapy for head and neck squamous cell carcinoma demonstrated that increasing dose did not significantly improve tumor control. On multivariate analysis, the only significant treatment variable was TPT. The results confirm that positive surgical margins and/or nodal ECE remains the most significant predictive pathologic factors. PMID- 28721883 TI - Patterns of Care for Patients With Early-Stage Glottic Cancer Undergoing Definitive Radiation Therapy: A National Cancer Database Analysis. AB - PURPOSE: To characterize practice patterns, including temporal trends, in fractionation schedules among patients in the United States undergoing definitive radiation therapy for early-stage glottic cancer and to compare overall survival outcomes between fractionation schedules. METHODS AND MATERIALS: We queried the National Cancer Database for patients with TisN0M0, T1N0M0, or T2N0M0 squamous cell carcinoma of the glottic larynx diagnosed between 2004 and 2012 and undergoing definitive radiation therapy. Dose per fraction was calculated to define cohorts undergoing conventional fractionation (CFxn) and hypofractionation (HFxn). Logistic regression was performed to identify predictors of receiving HFxn, and Cox regression was used to determine predictors of death. One-to-one propensity score matching was then used to compare survival between fractionation schedules. RESULTS: The study included 10,539 patients, with 6576 undergoing CFxn and 3963 undergoing HFxn. Patients with T1 disease comprised a majority of each cohort. Use of HFxn increased significantly over the period studied (P<.001), but even in the final year, nearly one-half of patients continued to receive CFxn. Receipt of HFxn was also independently associated with higher income and facility types other than community cancer programs on logistic regression. On multivariate Cox regression, HFxn was associated with improved survival (hazard ratio [HR] for death, 0.90; 95% confidence interval [CI], 0.83-0.97; P=.008), a finding redemonstrated on univariate Cox regression among a well-matched cohort after propensity score matching (HR, 0.88; 95% CI, 0.80-0.96; P=.003). Subgroup Cox multivariate analysis demonstrated a significant survival advantage with HFxn among patients with T1 disease (HR, 0.90; 95% CI, 0.81-0.99; P=.042) but a nonsignificant benefit among those with Tis (HR, 0.86; 95% CI, 0.57-1.30; P=.472) or T2 (HR, 0.88; 95% CI, 0.76-1.02; P=.099) disease. CONCLUSIONS: Use of HFxn is increasing and is associated with improved survival over CFxn. Our findings support the broadened use of HFxn for patients with early-stage glottic cancer undergoing definitive radiation therapy. PMID- 28721884 TI - Dosimetric Predictors of Patient-Reported Xerostomia and Dysphagia With Deintensified Chemoradiation Therapy for HPV-Associated Oropharyngeal Squamous Cell Carcinoma. AB - PURPOSE/OBJECTIVE(S): To estimate the association between different dose-volume metrics of the salivary glands and pharyngeal constrictors with patient reported severity of xerostomia/dysphagia in the setting of deintensified chemoradiation therapy (CRT). METHODS AND MATERIALS: Forty-five patients were treated on a phase 2 study assessing the efficacy of deintensified CRT for favorable-risk, HPV associated oropharyngeal squamous cell carcinoma. Patients received 60 Gy intensity modulated radiation therapy with concurrent weekly cisplatin (30 mg/m2), and reported the severity of their xerostomia/dysphagia (before and after treatment) using the patient-reported outcome version of the Common Terminology Criteria for Adverse Events (CTCAE) (PRO-CTCAE). Individual patient dosimetric data of the contralateral parotid and submandibular glands and pharyngeal constrictors were correlated with changes in PRO-CTCAE severity. A change in severity (from baseline) of >=2 was considered clinically meaningful. Associations between dose-volume metrics and patient outcomes were assessed with receiver operating characteristic (ROC) curve and logistic regression model. RESULTS: Six months after CRT, patients reporting <2 change in xerostomia severity (n=14) had an average Dmean = 22 +/- 9 Gy to the sum of the contralateral glands (parotid + submandibular) compared with the patients reporting >=2 change (n=21), who had an average Dmean = 34 +/- 8 Gy. V15 to V55 for the combined contralateral glands showed the strongest association with xerostomia (area under the curve [AUC] = 0.83-0.86). Based on the regression analysis, a 20% risk of toxicity was associated with V15 = 48%, V25 = 30%, and Dmean=21 Gy. Six months after CRT, patients reporting <2 change in dysphagia severity (n=26) had an average V55 = 76 +/- 13 (%) to the superior pharyngeal constrictor compared with the patients reporting >=2 change in severity (n=9), who had average V55 = 89 +/- 13 (%). V55to V60 had the strongest association with dysphagia (AUC = 0.70-0.75). Based on the regression analysis, a 20% risk of toxicity was associated with V55 = 78%, V60 = 40%. The findings at 12 months were similar. CONCLUSIONS: After deintensified CRT, the rate of patient-reported xerostomia/dysphagia appears to be associated with the V15 of the combined contralateral salivary glands and V55 to V60 of the superior pharyngeal constrictors. PMID- 28721885 TI - NRG Oncology-Radiation Therapy Oncology Group Study 1014: 1-Year Toxicity Report From a Phase 2 Study of Repeat Breast-Preserving Surgery and 3-Dimensional Conformal Partial-Breast Reirradiation for In-Breast Recurrence. AB - PURPOSE: To determine the associated toxicity, tolerance, and safety of partial breast reirradiation. METHODS AND MATERIALS: Eligibility criteria included in breast recurrence occurring >1 year after whole-breast irradiation, <3 cm, unifocal, and resected with negative margins. Partial-breast reirradiation was targeted to the surgical cavity plus 1.5 cm; a prescription dose of 45 Gy in 1.5 Gy twice daily for 30 treatments was used. The primary objective was to evaluate the rate of grade >=3 treatment-related skin, fibrosis, and/or breast pain adverse events (AEs), occurring <=1 year from re-treatment completion. A rate of >=13% for these AEs in a cohort of 55 patients was determined to be unacceptable (86% power, 1-sided alpha = 0.07). RESULTS: Between 2010 and 2013, 65 patients were accrued, and the first 55 eligible and with 1 year follow-up were analyzed. Median age was 68 years. Twenty-two patients had ductal carcinoma in situ, and 33 had invasive disease: 19 <=1 cm, 13 >1 to <=2 cm, and 1 >2 cm. All patients were clinically node negative. Systemic therapy was delivered in 51%. All treatment plans underwent quality review for contouring accuracy and dosimetric compliance. All treatment plans scored acceptable for tumor volume contouring and tumor volume dose-volume analysis. Only 4 (7%) scored unacceptable for organs at risk contouring and organs at risk dose-volume analysis. Treatment-related skin, fibrosis, and/or breast pain AEs were recorded as grade 1 in 64% and grade 2 in 7%, with only 1 (<2%) grade >=3 and identified as grade 3 fibrosis of deep connective tissue. CONCLUSION: Partial-breast reirradiation with 3-dimensional conformal radiation therapy after second lumpectomy for patients experiencing in breast failures after whole-breast irradiation is safe and feasible, with acceptable treatment quality achieved. Skin, fibrosis, and breast pain toxicity was acceptable, and grade 3 toxicity was rare. PMID- 28721886 TI - Effect of Eischens Yoga During Radiation Therapy on Prostate Cancer Patient Symptoms and Quality of Life: A Randomized Phase II Trial. AB - PURPOSE: A randomized phase II study was performed to measure the potential therapeutic effects of yoga on fatigue, erectile dysfunction, urinary incontinence, and overall quality of life (QOL) in prostate cancer (PCa) patients undergoing external beam radiation therapy (RT). METHODS AND MATERIALS: The participants were randomized to yoga and no-yoga cohorts (1:1). Twice-weekly yoga interventions were offered throughout the 6- to 9-week courses of RT. Comparisons of standardized assessments were performed between the 2 cohorts for the primary endpoint of fatigue and the secondary endpoints of erectile dysfunction, urinary incontinence, and QOL before, during, and after RT. RESULTS: From October 2014 to January 2016, 68 eligible PCa patients underwent informed consent and agreed to participate in the study. Of the 68 patients, 18 withdrew early, mostly because of treatment schedule-related time constraints, resulting in 22 and 28 patients in the yoga and no-yoga groups, respectively. Throughout treatment, those in the yoga arm reported less fatigue than those in the control arm, with global fatigue, effect of fatigue, and severity of fatigue subscales showing statistically significant interactions (P<.0001). The sexual health scores (International Index of Erectile Function Questionnaire) also displayed a statistically significant interaction (P=.0333). The International Prostate Symptom Score revealed a statistically significant effect of time (P<.0001) but no significant effect of treatment (P=.1022). The QOL measures had mixed results, with yoga having a significant time by treatment effect on the emotional, physical, and social scores but not on functional scores. CONCLUSIONS: A structured yoga intervention of twice-weekly classes during a course of RT was associated with a significant reduction in pre-existing and RT-related fatigue and urinary and sexual dysfunction in PCa patients. PMID- 28721887 TI - External Beam Radiation Therapy With a Brachytherapy Boost Versus Radical Prostatectomy in Gleason Pattern 5 Prostate Cancer: A Population-Based Cohort Study. AB - PURPOSE: Patients with prostate cancer (PCa) containing Gleason pattern (GP) 5 disease experience a greater and earlier incidence of prostate cancer-specific mortality (PCSM) than general PCa patients. This affords the statistical power to compare PCSM outcomes among different treatment modalities even when restricting the analysis to patients treated in the modern era. The purpose of the present study was to compare the survival outcomes among patients with GP 5 PCa on needle core biopsy or transurethral resection of the prostate who underwent extremely dose-escalated radiation therapy (RT; exemplified by external beam RT with a brachytherapy boost [EBRT + BT]) versus radical prostatectomy (RP) in the modern era. METHODS AND MATERIALS: A total of 7669 men with a diagnosis of GP 5 PCa from 2004 to 2013 who had undergone EBRT + BT or RP were identified using the Surveillance, Epidemiology, and End Results database. After propensity score matching to balance the patient characteristics, PCSM was compared between modalities using a multivariate Fine and Gray competing risk model that accounted for other-cause mortality, with adjustment for age, race, GP, and clinical T stage. RESULTS: Patients treated with RP were younger and had a lower burden of GP 5, lower T stage, and lower other-cause mortality than patients who underwent EBRT + BT. After propensity score matching, no difference was found in PCSM between the RP and EBRT + BT groups (adjusted hazard ratio 1.018; P=.910). The cumulative 5-year PCSM incidence rates were 5.6% and 6.1% for patients undergoing RP and EBRT + BT, respectively. Patients with primary GP 5 experienced significantly greater PCSM than those with secondary GP 5, regardless of the treatment modality. CONCLUSIONS: For patients with GP 5 PCa found on needle core biopsy or transurethral resection of the prostate, RP and EBRT + BT offer equivalent PCSM in a competing risk model after propensity score matching to balance the differences in patient characteristics. PMID- 28721888 TI - Long-Term Quality of Life in Prostate Cancer Patients Treated With Cesium-131. AB - PURPOSE: To evaluate long-term patient-reported quality of life (QOL) scores in men with prostate cancer treated at our institution with 131Cs prostate brachytherapy. METHODS AND MATERIALS: Patients treated more than 4 years ago with 131Cs (n=290) were asked to fill out an Expanded Prostate Cancer Index Composite (EPIC) QOL questionnaire and American Urological Association Symptom Score (AUASS) survey, before treatment and at each follow-up appointment. We compared patients' EPIC and AUA scores at baseline with scores at a last follow-up of at least 4 years after treatment using the Wilcoxon signed-rank test. RESULTS: At a median last follow-up of 5.5 years after treatment with 131Cs prostate brachytherapy there were no clinically significant changes in the EPIC or AUA scores from baseline. There was statistical worsening in the EPIC urinary incontinence subscore. Subset analyses revealed improved QOL outcomes in patients who received external beam radiation therapy or alpha-blocker therapy, whereas androgen deprivation therapy was not associated with differences in QOL change. CONCLUSIONS: Our results demonstrate minimal long-term changes in urinary or bowel patient-reported QOL with 131Cs prostate brachytherapy. These findings suggest that patients treated with this isotope are able to recover and then maintain their baseline QOL in the long term. PMID- 28721889 TI - Clinical Outcomes of Large Brain Metastases Treated With Neurosurgical Resection and Intraoperative Cesium-131 Brachytherapy: Results of a Prospective Trial. AB - PURPOSE: Studies on adjuvant stereotactic radiosurgery to the cavity of resected brain metastases have suggested that larger tumors (>2.0 cm) have greater rates of recurrence and radionecrosis (RN). The present study assessed the effect of permanent low-dose 131Cs brachytherapy on local control and RN in patients treated for large brain metastases. METHODS AND MATERIALS: After institutional review board approval, 42 patients with 46 metastases >=2.0 cm in preoperative diameter were accrued to a prospective trial from 2010 to 2015. Patients underwent surgical resection with intraoperative placement of stranded 131Cs seeds as permanent volume implants in the resection cavity. The primary endpoint was local freedom from progression (FFP). Secondary endpoints included regional and distant FFP, overall survival (OS), and RN rate. Failures 5 to 20 mm from the cavity and dural-based failures were considered regional. A separate analysis was performed for metastases >3.0 cm. RESULTS: Of the 46 metastases, 18 were >3.0 cm in diameter. The median follow-up period was 11.9 months (range 0.6-51.9). The metastases had a median preoperative diameter of 3.0 cm (range 2.0-6.8). The local FFP rate was 100% for all tumor sizes. Regional recurrence developed in 3 of 46 lesions (7%), for a 1-year regional FFP rate of 89% (for tumors >3.0 cm, the FFP rate was 80%, 95% confidence interval 54%-100%). Distant recurrences were found in 19 of 46 lesions (41%), for a 1-year distant FFP rate of 52%. The median OS was 15.1 months, with a 1-year OS rate of 58%. Lesion size was not significantly associated with any endpoint on univariate or multivariate analysis. Radioresistant histologic features resulted in worse survival (P=.036). No cases of RN developed. CONCLUSIONS: Intraoperative 131Cs brachytherapy is a promising and effective therapy for large brain metastases requiring neurosurgical intervention, which can offer improved local control and lower rates of RN compared with stereotactic radiosurgery to the resection cavity. PMID- 28721890 TI - The Prognostic Value of BRAF, C-KIT, and NRAS Mutations in Melanoma Patients With Brain Metastases. AB - PURPOSE: Brain metastases are a common problem in patients with melanoma, but little is known about the effect of gene mutations on survival in these patients. METHODS AND MATERIALS: We created a retrospective multi-institutional database of 823 patients with melanoma and brain metastases diagnosed between 2006 and 2015. Clinical parameters, gene mutation status (BRAF, C-KIT, NRAS), and treatment were correlated with survival. Treatment patterns and outcomes were compared with a prior era (1985-2005). RESULTS: BRAF status was known in 584 of 823 patients (71%). BRAF, NRAS, and C-KIT mutations were present in 51%, 22%, and 11% of tested patients, respectively. The median time from primary diagnosis to brain metastasis was 32 months, and overall median survival (MS) from the time of initial treatment of brain metastases was 10 months. MS for BRAF-positive and BRAF-negative patients was 13 months and 9 months, respectively (P=.02). There was no significant difference in MS in patients with or without NRAS or C-KIT mutations. The time from primary diagnosis to brain metastasis did not vary by mutation and was not associated with survival after the diagnosis of brain metastases. MS for the 1985 to 2005 and 2006 to 2015 cohorts was 6.7 months and 10.0 months, respectively (P<.01). Reflecting treatment-trend changes, use of whole-brain radiation therapy decreased from 48% to 26% during this period. Among BRAF-positive patients, 71% received targeted BRAF and/or MEK inhibitors and 57% received some combination of targeted therapy, chemotherapy, and/or immunotherapy. CONCLUSIONS: For melanoma patients with brain metastases, BRAF positive patients survive longer than BRAF-negative patients and overall survival has improved from 1985-2005 to 2006-2015. PMID- 28721891 TI - Stereotactic Radiosurgery for Trigeminal Neuralgia Improves Patient-Reported Quality of Life and Reduces Depression. AB - PURPOSE: To characterize quality-of-life (QOL) outcomes after stereotactic radiosurgery (SRS) for trigeminal neuralgia (TN). METHODS AND MATERIALS: The EuroQOL 5 Dimensions (EQ-5D) and Patient Health Questionnaire 9 (PHQ-9) were prospectively collected before and after SRS for 50 patients with TN. Pain response and treatment-related facial numbness were classified by Barrow Neurological Institute (BNI) scales. Differences in pooled QOL outcomes were tested with paired t tests and sign tests. The Kaplan-Meier method was used to estimate time-dependent improvements in the EQ-5D index, EQ-5D perceived health status (PHS), PHQ-9 score, and freedom from pain failure (BNI class IV-V) or facial numbness (BNI class III-IV). RESULTS: Following SRS, the 12-month rate of freedom from pain failure was 92% (95% confidence interval [CI], 77%-97%) while the 12-month rate of freedom from facial numbness was 89% (95% CI, 66%-97%). Significant improvements in the EQ-5D index (P<.01), PHS (P=.01), and PHQ-9 (P=.03) were observed, driven by the EQ-5D subscores for self-care and for pain and/or discomfort (P=.02 and P<.01, respectively). At 12 months after SRS, the actuarial rates of improvement in the EQ-5D, PHS, and PHQ-9 were 55% (95% CI, 40% 70%), 59% (95% CI, 40%-76%), and 59% (95% CI, 39%-76%), respectively. The median time to improvement in each of the QOL measures was 9 months (95% CI, 3-36 months) for the EQ-5D index, 5 months (95% CI, 3-36 months) for PHS, and 9 months (95% CI, 3-18 months) for the PHQ-9. On multivariate analysis, only higher prescription dose (86 Gy vs <=82 Gy) was associated with improvement in the EQ-5D index (hazard ratio, 5.73; 95% CI, 1.85-22.33; P<.01). CONCLUSIONS: Patients with TN treated with SRS reported significant improvements in multiple QOL measures, with the therapeutic benefit strongly driven by improvements in pain and/or discomfort and in self-care, along with lower rates of depression. In this analysis, there appears to be a correlation between prescription dose and treatment response as measured by the EQ-5D. PMID- 28721892 TI - Capecitabine With Mitomycin Reduces Acute Hematologic Toxicity and Treatment Delays in Patients Undergoing Definitive Chemoradiation Using Intensity Modulated Radiation Therapy for Anal Cancer. AB - PURPOSE: To assess the impact on acute toxicity of replacing 5-fluorouracil (5 FU) with capecitabine in definitive chemoradiation for patients with anal squamous cell carcinoma (ASCC). METHODS AND MATERIALS: We retrospectively reviewed the records of 107 consecutive patients with nonmetastatic ASCC treated with definitive chemoradiation from January 2009 to May 2014. In 2011, based on the noninferiority of capecitabine versus 5-FU, our institutional practice shifted to use capecitabine instead of 5-FU for ASCC. Of 107 patients, 63 were treated with infusional 5-FU (1000 mg/m2/day for 4 days) and mitomycin C (MMC) (10 mg/m2) during weeks 1 and 5, and 44 patients were treated with capecitabine (825 mg/m2 twice daily) Monday through Friday throughout radiation therapy (RT) and MMC (10 mg/m2) during weeks 1 and 5. The incidence of grade 3 to 4 acute toxicity was compared between the 2 groups. RESULTS: The median age at diagnosis was 59 years, and 78 patients (73%) were female. The patient characteristics were similar between the 2 treatment groups. All patients in both groups were treated with intensity modulated RT (median dose, 56 Gy). In the 5-FU group, 52% experienced grade 3 to 4 neutropenia compared with 20% in the capecitabine group (P=.001). Treatment breaks resulting from toxicity, primarily related to grade 3+ hematologic toxicity, were necessary for 42% of patients treated with 5-FU versus 16% of those treated with capecitabine (P=.006). CONCLUSIONS: Pelvic radiation therapy with MMC plus capecitabine was well tolerated and appeared to have less grade 3+ acute hematologic toxicity and fewer treatment interruptions than in a population of ASCC patients undergoing definitive chemoradiation with MMC and 5 FU. PMID- 28721894 TI - Predictors of Positive Margins After Definitive Resection for Gastric Adenocarcinoma and Impact of Adjuvant Therapies. AB - PURPOSE: Positive margins after definitive resection in gastric adenocarcinoma are associated with inferior outcomes. There are few randomized data to guide optimal adjuvant therapy after positive margins. METHODS: Using the National Cancer Database, we identified 24,619 nonmetastatic gastric adenocarcinoma patients who received diagnoses from 2004 to 2013 and underwent definitive resection to analyze for predictors of positive surgical margins. Of these patients, 2754 had positive margins (11.2%). Multivariate prevalence ratios were used to determine predictors. Survival analyses were performed with a Cox proportional hazards model by use of several methods of propensity score analysis. RESULTS: Increasing T and/or N category, high grade, and lymphovascular invasion predicted higher rates of positive margins. Asian race, treatment at an academic center, and robotic surgery predicted lower rates of positive margins. Among positive-margin patients with adjuvant treatment (n=1021), with a median follow-up period of 55 months, age, comorbidity score, nodal disease, and T4 disease predicted for worse overall survival (OS). Treatment at an academic center was associated with improved OS. Use of adjuvant concurrent chemoradiation therapy (CCRT) was associated with higher OS compared with chemotherapy alone after positive margins (hazard ratio, 0.72; 95% confidence interval, 0.58-0.91; P=.005) after propensity matching adjusting for predictors of OS. The 2-year and 3-year OS for positive-margin patients with chemotherapy alone was 43% and 29%, respectively, compared with 53% and 38%, respectively, with adjuvant CCRT. The log-rank P value for survival was .0015. CONCLUSIONS: Stage, race, treatment center, and surgery approach predict for margin status after resection. Adjuvant CCRT after positive margins is associated with improved OS after accounting for available clinical variables. PMID- 28721893 TI - Multicenter Phase 2 Study of Peri-Irradiation Chemotherapy Plus Intensity Modulated Radiation Therapy With Concurrent Weekly Docetaxel for Inoperable or Medically Unresectable Nonmetastatic Gastric Cancer. AB - PURPOSE: To assess the efficacy and feasibility of concurrent chemoradiation therapy (CCRT) plus preradiation and postradiation chemotherapy for patients with nonmetastatic gastric carcinoma who do not undergo surgery. METHODS AND MATERIALS: Patients with inoperable (due to medical comorbid conditions or patient's refusal to undergo surgery) or unresectable gastric cancer received up to 2 21-day cycles of preradiation and postradiation chemotherapy (docetaxel 37.5 mg/m2 on days 1 and 8, cisplatin 25 mg/m2 on days 1-3, and a continuous infusion of fluorouracil [FU] 750 mg/m2 on days 1-5), respectively. CCRT between preradiation and postradiation chemotherapy was initiated on day 43 and consisted of intensity modulated radiation therapy (50.4 Gy) plus concurrent docetaxel 20 mg/m2 weekly for 6 weeks. RESULTS: 36 patients were evaluable; 21 patients with comorbid conditions were unsuitable for surgery (group 1), 8 had unresectable disease (group 2), and 7 refused surgery (group 3). The clinical complete response (cCR) rate for the 36 evaluable patients was 36% (95% confidence interval [CI], 19%-53%) and the overall response rate was 83% (95% CI, 75%-97%). The median survival time and estimated 2-year survival rate were 25.8 months (95% CI, 7.1-44.5 months) and 52% (95% CI, 38%-67%), respectively. The estimated median OS and 2-year OS rates for groups 1, 2, and 3 were 37.0 months (95% CI, 7.9-66.1 months) and 52% (95% CI, 31%-73%), 17.7 months (95% CI, 7.8-27.6 months) and 20% (95% CI, 0%-49%), and 38.9 months (95% CI, 16.6-58.3 months) and 67% (95% CI, 30%-100%), respectively. Achieving a cCR was associated with significantly better overall survival (P=.004) and progression-free survival (P=.003). The most common grade 3 or greater toxicity during the chemotherapy phase was neutropenia. Common grade 3/4 toxicities during CCRT were nausea and vomiting. CONCLUSIONS: This regimen is tolerable and shows promising efficacy in inoperable or medically unresectable GC. PMID- 28721895 TI - Late Cardiac Toxicity After Mediastinal Radiation Therapy for Hodgkin Lymphoma: Contributions of Coronary Artery and Whole Heart Dose-Volume Variables to Risk Prediction. AB - PURPOSE: Mediastinal radiation therapy (RT) for Hodgkin lymphoma (HL) is associated with late cardiotoxicity, but there are limited data to indicate which dosimetric parameters are most valuable for predicting this risk. This study investigated which whole heart dosimetric measurements provide the most information regarding late cardiotoxicity, and whether coronary artery dosimetry was more predictive of this outcome than whole heart dosimetry. METHODS AND MATERIALS: A random sample of 125 HL patients treated with mediastinal RT was selected, and 3-dimensional cardiac dose-volume data were generated from historical plans using validated methods. Cardiac events were determined by linking patients to population-based datasets of inpatient and same-day hospitalizations and same-day procedures. Variables collected for the whole heart and 3 coronary arteries included the following: Dmean, Dmax, Dmin, dose homogeneity, V5, V10, V20, and V30. Multivariable competing risk regression models were generated for the whole heart and coronary arteries. RESULTS: There were 44 cardiac events documented, of which 70% were ischemic. The best multivariable model included the following covariates: whole heart Dmean (hazard ratio [HR] 1.09, P=.0083), dose homogeneity (HR 0.94, P=.0034), male sex (HR 2.31, P=.014), and age (HR 1.03, P=.0049). When any adverse cardiac event was the outcome, models using coronary artery variables did not perform better than models using whole heart variables. However, in a subanalysis of ischemic cardiac events only, the model using coronary artery variables was superior to the whole heart model and included the following covariates: age (HR 1.05, P<.001), volume of left anterior descending artery receiving 5 Gy (HR 0.98, P=.003), and volume of left circumflex artery receiving 20 Gy (HR 1.03, P<.001). CONCLUSION: In addition to higher mean heart dose, increasing inhomogeneity in cardiac dose was associated with a greater risk of late cardiac effects. When all types of cardiotoxicity were evaluated, the whole heart variable model outperformed the coronary artery models. However, when events were limited to ischemic cardiotoxicity, the coronary artery-based model was superior. PMID- 28721896 TI - Prognostic Importance of the Site of Recurrence in Patients With Metastatic Recurrent Cervical Cancer. AB - PURPOSE: The clinical characteristics and outcomes of patients with metastatic recurrent cervical cancer remain poorly understood. The goals of the present study were to investigate the survival outcomes according to the recurrence site in a large cohort of cervical cancer patients. METHODS AND MATERIALS: Of 1322 patients with primary cervical cancer from 2000 to 2013, 205 with recurrence after primary or adjuvant postoperative radiation were enrolled retrospectively. Aggressive salvage therapy (AST), which was defined as salvage therapy that aimed not only to relieve symptoms but also to ablate recurrent tumors by the single or combined application of surgical resection of local recurrence, metastasectomy, or metastasis-directed irradiation, followed by chemotherapy, was performed according to our institutional guidelines. The patterns of recurrence, application rate and mode of AST, and survival outcomes were evaluated retrospectively under approval from the institutional review board. RESULTS: Regarding the pattern of recurrence, distant-only (DO) recurrence was most common (59.5%), followed by combined (21.5%), central (cervix or vaginal stump; 10.7%), and pelvic (pelvic lymph nodes or pelvic side wall; 8.3%) recurrence. Two subgroups (distant lymph nodes and lung parenchyma) of the DO group demonstrated remarkably good prognosis and were categorized as type A DO; the other subgroups were labeled type B DO. Patients with type A DO recurrence constituted 36% of all recurrences and 83.8% of them received AST. The 5-year overall survival rates were significantly greater in the type A DO group than in the other groups (44.8% in the type A DO group, 12.6% in the pelvic group, and 6.8% in the type B DO group). CONCLUSIONS: We identified a patient subgroup with favorable outcomes after salvage therapy, type A DO, defined as recurrence in the distant lymph nodes only or in the lung parenchyma only. A future prospective trial is needed to investigate whether AST improves survival in this group. PMID- 28721897 TI - Adjuvant Chemoradiation Therapy for Cervical Cancer and Effect of Timing and Duration on Treatment Outcome. AB - PURPOSE: Worse treatment outcomes can be expected with prolongation of the overall treatment time (OTT) during definitive chemoradiation therapy (CRT) for cervical cancer. In the adjuvant setting, data on the relative importance of the OTT and the importance of RT and chemotherapy synchronization are scarce. Using the National Cancer Database, we evaluated the effect of these treatment variables on overall survival in the adjuvant CRT setting. METHODS AND MATERIALS: The present analysis included nonmetastatic cervical cancer patients undergoing hysterectomy followed by adjuvant CRT. The proportional hazard model was used to estimate the effect of prognostic factors (age, comorbidity, race, tumor size, tumor grade, tumor histologic type, number of high-risk pathologic factors) and time-related variables (surgery to RT start interval [SR], OTT [RT start to end dates], package time [from diagnosis date to CRT end date] and optimum CRT synchronization [whether chemotherapy and RT start dates coincided]) on survival. RESULTS: Of 3051 patients, 60% finished RT within 7 weeks and 85% received optimum CRT. Among other factors, univariate analysis identified longer OTT (hazards ratio [HR] 1.33; P<.001), longer SR (HR 1.17; P=.05), and nonoptimum CRT timing (HR 1.21; P=.04) as poor prognosticators. Of these factors, SR (HR 1.20; P=.04) and OTT (HR 1.21; P=.002) retained significance on multivariate analysis. An OTT >7 weeks remained a significant factor even after propensity score matching (P=.04). CONCLUSIONS: The results of our analysis suggest that prolongation of the adjuvant CRT duration >7 weeks is associated with poor survival and SR of <8 weeks should be attempted whenever clinically feasible. PMID- 28721898 TI - Radiation Treatment Time and Overall Survival in Locally Advanced Non-small Cell Lung Cancer. AB - PURPOSE: Prolonged radiation treatment (RT) time (RTT) has been associated with worse survival in several malignancies. The present study investigated whether delays during RT are associated with overall survival (OS) in non-small cell lung cancer (NSCLC). METHODS AND MATERIALS: The National Cancer Database was queried for patients with stage III NSCLC who had received definitive concurrent chemotherapy and fractionated RT to standard doses (59.4-70.0 Gy) and fractionation from 2004 to 2013. The RTT was classified as standard or prolonged for each treatment regimen according to the radiation dose and number of fractions. Cox proportional hazards models were used to evaluate the association between the following factors and OS: RTT, RT fractionation, demographic and pathologic factors, and chemotherapeutic agents. RESULTS: Of 14,154 patients, the RTT was prolonged in 6262 (44.2%). Factors associated with prolonged RTT included female sex (odds ratio [OR] 1.21, P<.0001), black race (OR 1.20, P=.001), nonprivate health insurance (OR 1.30, P<.0001), and lower income (<$63,000 annually, OR 1.20, P<.0001). The median OS was significantly worse for patients with prolonged RTT than that for those with standard RTT (18.6 vs 22.7 months, P<.0001). Furthermore, the OS worsened with each cumulative interval of delay (standard RTT vs prolonged 1-2 days, 20.5 months, P=.009; prolonged 3-5 days, 17.9 months, P<.0001; prolonged 6-9 days, 17.7 months, P<.0001; prolonged >9 days, 17.1 months, P<.0001). On multivariable analysis, prolonged RTT was independently associated with inferior OS (hazard ratio 1.21, P<.0001). Prolonged RTT as a continuous variable was also significantly associated with worse OS (hazard ratio 1.001, P=.0007). CONCLUSIONS: Delays during RT appear to negatively affect survival for patients with locally advanced NSCLC. We have detailed the demographic and socioeconomic barriers influencing prolonged RTT as a method to address the health disparities in this regard. Cumulative interruptions of RT should be minimized. PMID- 28721899 TI - Gaps in Radiation Therapy Awareness: Results From an Educational Multi institutional Survey of US Internal Medicine Residents. AB - PURPOSE: Internists and primary care providers play a growing role in cancer care. We therefore evaluated the awareness of radiation therapy in general and specifically the clinical utility of stereotactic body radiation therapy (SBRT) for early-stage non-small cell lung cancer (NSCLC) among current US internal medicine residents. METHODS AND MATERIALS: A web-based institutional review board approved multi-institutional survey was distributed to US internal medicine residency programs. The survey evaluated trainee demographic characteristics, baseline radiation oncology awareness, knowledge of the role of SBRT for early stage NSCLC, and whether the survey successfully improved awareness. RESULTS: Thirty US internal medicine programs participated, with an overall participant response rate of 46% (1177 of 2551). Of the trainees, 93% (n=1076) reported no radiation oncology education in their residency, 39% (n=452) reported confidence in knowing when to consult radiation oncology in an oncologic emergency, and 26% (n=293) reported confidence in knowing when to consult radiation oncology in the setting of a newly diagnosed cancer. Of the participants, 76% (n=850) correctly identified that surgical resection is the standard treatment in operable early stage NSCLC, but only 50% (n=559) of participants would recommend SBRT to a medically inoperable patient, followed by 31% of participants (n=347) who were unsure of the most appropriate treatment, and 10% (n=117) who recommended waiting to offer palliative therapy. Ninety percent of participants (n=1029) agreed that they would benefit from further training on when to consult radiation oncology. Overall, 96% (n=1072) indicated that the survey increased their knowledge and awareness of the role of SBRT. CONCLUSIONS: The majority of participating trainees received no education in radiation oncology in their residency, reported a lack of confidence regarding when to consult radiation oncology, and overwhelmingly agreed that they would benefit from further training. These findings should serve as a call to increase the educational collaboration between internal medicine and radiation oncology departments to ensure optimal cancer care. PMID- 28721900 TI - Triggering the Abscopal Effect: Is the Quality of the Radiation Important? PMID- 28721901 TI - PSMB8 as a Candidate Marker of Responsiveness to Preoperative Radiation Therapy in Rectal Cancer Patients. AB - PURPOSE: The ability to predict individual responsiveness to cancer therapy is urgently needed. This is particularly true for patients with locally advanced rectal cancer (LARC) because a large proportion are resistant to preoperative chemoradiation therapy (CRT). In this study, we sought to identify markers that could predict response by comparing the gene expression profiles of the tumors of patients who received preoperative CRT. METHODS AND MATERIALS: The basal gene expression profiles of tumors from 22 LARC patients who were responders (n=9) and nonresponders (n=13) to preoperative CRT were analyzed using RNA sequencing (RNA Seq). To validate the RNA-Seq findings, real-time reverse transcriptase polymerase chain reaction (RT-PCR) was performed on tumor samples from an additional 40 LARC patients (n=20 responders; n=20 nonresponders). Candidate genes were stably overexpressed or knocked down in colorectal cancer (CRC) cell lines, and the effect on response to radiation was tested in vitro and also in vivo in a mouse xenograft model. RESULTS: Eight differentially expressed (>16 fold) genes (B3GALT4, HSPA1B, KRBOX1, PPBP, PPP1R18, PSMB8, SLC39A7, and TAP2) associated with the preoperative CRT response were identified (P<.0005). Among these genes, real-time RT-PCR showed that PSMB8 and SLC39A7 were upregulated in the responsive group of the additional 40 LARC patients. In CRC cell lines, PSMB8 overexpression significantly reduced colony formation and increased the apoptosis inducing molecules cleaved caspase-3 and cleaved PARP after 6-Gy irradiation. PSMB8 knockdown increased colony formation and decreased caspase-3 activation and cleaved PARP levels after irradiation. SLC39A7 overexpression had no significant effects on irradiated CSC cells. After irradiation of the xenografted mice, tumors that arose from CRC cell line HCT116 overexpressing PSMB8 grew more slowly than did those from HCT116 with vector alone. CONCLUSION: These results suggest that PSMB8 is a predictive marker of preoperative radiosensitivity in LARC patients. Clinical validation in a larger cohort is now required. PMID- 28721902 TI - Permeability of Brain Tumor Vessels Induced by Uniform or Spatially Microfractionated Synchrotron Radiation Therapies. AB - PURPOSE: To compare the blood-brain barrier permeability changes induced by synchrotron microbeam radiation therapy (MRT, which relies on spatial fractionation of the incident x-ray beam into parallel micron-wide beams) with changes induced by a spatially uniform synchrotron x-ray radiation therapy. METHODS AND MATERIALS: Male rats bearing malignant intracranial F98 gliomas were randomized into 3 groups: untreated, exposed to MRT (peak and valley dose: 241 and 10.5 Gy, respectively), or exposed to broad beam irradiation (BB) delivered at comparable doses (ie, equivalent to MRT valley dose); both applied by 2 arrays, intersecting orthogonally the tumor region. Vessel permeability was monitored in vivo by magnetic resonance imaging 1 day before (T-1) and 1, 2, 7, and 14 days after treatment start. To determine whether physiologic parameters influence vascular permeability, we evaluated vessel integrity in the tumor area with different values for cerebral blood flow, blood volume, edema, and tissue oxygenation. RESULTS: Microbeam radiation therapy does not modify the vascular permeability of normal brain tissue. Microbeam radiation therapy-induced increase of tumor vascular permeability was detectable from T2 with a maximum at T7 after exposure, whereas BB enhanced vessel permeability only at T7. At this stage MRT was more efficient at increasing tumor vessel permeability (BB vs untreated: +19.1%; P=.0467; MRT vs untreated: +44.8%; P<.0001), and its effects lasted until T14 (MRT vs BB, +22.6%; P=.0199). We also showed that MRT was more efficient at targeting highly oxygenated (high blood volume and flow) and more proliferative parts of the tumor than BB. CONCLUSIONS: Microbeam radiation therapy-induced increased tumor vascular permeability is: (1) significantly greater; (2) earlier and more prolonged than that induced by BB irradiation, especially in highly proliferative tumor areas; and (3) targets all tumor areas discriminated by physiologic characteristics, including those not damaged by homogeneous irradiation. PMID- 28721903 TI - Clinical Advances of Hypoxia-Activated Prodrugs in Combination With Radiation Therapy. AB - With the increasing incidence of cancer worldwide, the need for specific, effective therapies is ever more urgent. One example of targeted cancer therapeutics is hypoxia-activated prodrugs (HAPs), also known as bioreductive prodrugs. These prodrugs are inactive in cells with normal oxygen levels but in hypoxic cells (with low oxygen levels) undergo chemical reduction to the active compound. Hypoxia is a common feature of solid tumors and is associated with a more aggressive phenotype and resistance to all modes of therapy. Therefore, the combination of radiation therapy and bioreductive drugs presents an attractive opportunity for synergistic effects, because the HAP targets the radiation resistant hypoxic cells. Hypoxia-activated prodrugs have typically been precursors of DNA-damaging agents, but a new generation of molecularly targeted HAPs is emerging. By targeting proteins associated with tumorigenesis and survival, these compounds may result in greater selectivity over healthy tissue. We review the clinical progress of HAPs as adjuncts to radiation therapy and conclude that the use of HAPs alongside radiation is vastly underexplored at the clinical level. PMID- 28721904 TI - Treatment Planning System Calculation Errors Are Present in Most Imaging and Radiation Oncology Core-Houston Phantom Failures. AB - PURPOSE: The anthropomorphic phantom program at the Houston branch of the Imaging and Radiation Oncology Core (IROC-Houston) is an end-to-end test that can be used to determine whether an institution can accurately model, calculate, and deliver an intensity modulated radiation therapy dose distribution. Currently, institutions that do not meet IROC-Houston's criteria have no specific information with which to identify and correct problems. In the present study, an independent recalculation system was developed to identify treatment planning system (TPS) calculation errors. METHODS AND MATERIALS: A recalculation system was commissioned and customized using IROC-Houston measurement reference dosimetry data for common linear accelerator classes. Using this system, 259 head and neck phantom irradiations were recalculated. Both the recalculation and the institution's TPS calculation were compared with the delivered dose that was measured. In cases in which the recalculation was statistically more accurate by 2% on average or 3% at a single measurement location than was the institution's TPS, the irradiation was flagged as having a "considerable" institutional calculation error. The error rates were also examined according to the linear accelerator vendor and delivery technique. RESULTS: Surprisingly, on average, the reference recalculation system had better accuracy than the institution's TPS. Considerable TPS errors were found in 17% (n=45) of the head and neck irradiations. Also, 68% (n=13) of the irradiations that failed to meet the IROC Houston criteria were found to have calculation errors. CONCLUSIONS: Nearly 1 in 5 institutions were found to have TPS errors in their intensity modulated radiation therapy calculations, highlighting the need for careful beam modeling and calculation in the TPS. An independent recalculation system can help identify the presence of TPS errors and pass on the knowledge to the institution. PMID- 28721905 TI - Inter- and Intrafractional Variation in the 3-Dimensional Positions of Pancreatic Tumors Due to Respiration Under Real-Time Monitoring. AB - PURPOSE: To quantify the 3-dimensional pancreatic tumor motion during the overall treatment course using real-time orthogonal kilovoltage X-ray imaging. METHODS AND MATERIALS: This study included 10 patients with pancreatic cancer who underwent 6-port static intensity modulated radiation therapy with real-time tumor tracking in 15 fractions, except for 1 patient (5 fractions). The tumor and abdominal wall positions were acquired simultaneously during the overall treatment course. Then the tumor motion amplitude and reference positions were determined. RESULTS: The mean tumor amplitudes were 4.9, 6.5, and 13.4 mm in the left-right (LR), anterior-posterior (AP), and superior-inferior (SI) directions, respectively. The intrafractional variations of the reference tumor position were up to 5.4, 10.2, and 10.7 mm in the LR, AP, and SI directions, and those of the reference abdominal position were up to 10.5 mm. The reference tumor position drifted significantly in the AP and SI directions after 10 minutes, and that of abdominal wall motion drifted during the first 15 minutes (P<.05). The interfractional variation of the reference tumor position after setup correction, based on bony structures, was up to 8.9, 9.8, and 11.0 mm in the LR, AP, and SI directions, respectively. CONCLUSIONS: Appropriate respiratory motion management techniques should be applied for the accurate localization of pancreatic tumors. PMID- 28721906 TI - Immune Checkpoint Inhibition in Cancers that Affect the Head and Neck. PMID- 28721907 TI - Breast Cancer: Biology or Stage? PMID- 28721908 TI - PMRT: Please Mind Randomized Trials. PMID- 28721909 TI - Postmastectomy Conundrum. PMID- 28721910 TI - Defining and Shattering the Glass Ceiling in Radiation Oncology. PMID- 28721911 TI - A Clarion Call for Large-Scale Collaborative Studies of Pediatric Proton Therapy. PMID- 28721912 TI - Exosomes and Exosomal MicroRNAs in Prostate Cancer Radiation Therapy. AB - Despite current risk stratification systems using traditional clinicopathologic factors, many localized and locally advanced prostate cancers fail radical treatment (ie, radical prostatectomy, radiation therapy with or without androgen deprivation therapy). Therefore, a pressing need exists for enhanced methods of disease stratification through novel prognostic and predictive tools that can reliably be applied in clinical practice. Exosomes are 50- to 150-nm small vesicles released by cancer cells that reflect the genetic and nongenetic materials of parent cancer cells. Cancer cells can contain distinct sets of microRNA profiles, the expression of which can change owing to stress such as radiation therapy. These alterations or distinctions in contents allow exosomes to be used as prognostic and/or predictive biomarkers and to monitor the treatment response. Additionally, microRNAs have been shown to influence multiple processes in prostate tumorigenesis, including cell proliferation, induction of apoptosis, migration, oncogene inhibition, and radioresistance. Thus, comparative exosomal microRNA profiling at different levels could help portray tumor aggressiveness and response to radiation therapy. Although technical challenges persist in exosome isolation and characterization, recent improvements in microRNA profiling have evolved toward in-depth analyses of the exosomal cargo and its functions. We have reviewed the role of exosomes and exosomal microRNAs in biologic processes of prostate cancer progression and radiation therapy response, with a particular focus on the development of clinical assays for treatment personalization. PMID- 28721914 TI - WHO has a dementia plan, now we need action. PMID- 28721913 TI - Clinical Utility of Epstein-Barr Virus DNA Testing in the Treatment of Nasopharyngeal Carcinoma Patients. AB - Epstein-Barr virus (EBV) DNA analysis has been shown to be useful for early detection, prognostication, and monitoring of treatment response of nasopharyngeal carcinoma (NPC), and the recent literature provides growing evidence of the clinical utility of EBV DNA testing, particularly to inform treatment decisions for NPC patients. Despite the fact that NPC is a rare disease, the NRG Oncology cooperative group has successfully activated a phase 2/3 randomized clinical trial for NPC with international partners and in that process has discovered that the development of a harmonized EBV DNA test is absolutely critical for integration into clinical trials and for future deployment in clinical and central laboratories. In November 2015, the National Cancer Institute (NCI) convened a workshop of international experts in the treatment of NPC and EBV testing to provide a forum for discussing the state of EBV DNA testing and its clinical utility, and to stimulate consideration of future studies and clinical practice guidelines for EBV DNA. This review provides a summary of that discussion. PMID- 28721915 TI - Adding insight to injury: a new era in neurotrauma. PMID- 28721916 TI - Diagnostic biomarkers for Alzheimer's disease: a regulatory view. PMID- 28721917 TI - Genomic profiling and diagnostic biomarkers in Alzheimer's disease. PMID- 28721919 TI - Corrections. PMID- 28721920 TI - Corrections. PMID- 28721921 TI - Corrections. PMID- 28721922 TI - Lessons from the Multidomain Alzheimer Preventive Trial. PMID- 28721924 TI - A better, fairer, and safer world for people with dementia. PMID- 28721923 TI - Lessons from the Multidomain Alzheimer Preventive Trial - Authors' reply. PMID- 28721925 TI - Hildegard of Bingen's remedies for Parkinson's disease. PMID- 28721926 TI - Juan Fortea. PMID- 28721927 TI - Coagulopathy and haemorrhagic progression in traumatic brain injury: advances in mechanisms, diagnosis, and management. AB - Normal haemostasis depends on an intricate balance between mechanisms of bleeding and mechanisms of thrombosis, and this balance can be altered after traumatic brain injury (TBI). Impaired haemostasis could exacerbate the primary insult with risk of initiation or aggravation of bleeding; anticoagulant use at the time of injury can also contribute to bleeding risk after TBI. Many patients with TBI have abnormalities on conventional coagulation tests at admission to the emergency department, and the presence of coagulopathy is associated with increased morbidity and mortality. Further blood testing often reveals a range of changes affecting platelet numbers and function, procoagulant or anticoagulant factors, fibrinolysis, and interactions between the coagulation system and the vascular endothelium, brain tissue, inflammatory mechanisms, and blood flow dynamics. However, the degree to which these coagulation abnormalities affect TBI outcomes and whether they are modifiable risk factors are not known. Although the main challenge for management is to address the risk of hypocoagulopathy with prolonged bleeding and progression of haemorrhagic lesions, the risk of hypercoagulopathy with an increased prothrombotic tendency also warrants consideration. PMID- 28721929 TI - Obstetric hemorrhages at the CHU-Yalgado Ouedraogo of Ouagadougou : etiological, therapeutic, and prognostic aspects. AB - To evaluate the maternal and perinatal prognosis of obstetric hemorrhages in the maternity department of the Yalgado Ouedraogo University Hospital of Ouagadougou. This descriptive cross-sectional study conducted in the four-month period from April through July 2015 included all women consulting on an emergency basis for vaginal bleeding during pregnancy at or after 28 weeks of gestation, or during labor, delivery, or the postpartum period. Obstetric hemorrhages accounted for 6% of admissions. The women's mean age was 27.7 years; 92.5% lived with a partner, and 43.1% were not employed outside the home. A retroplacental hematoma was the leading cause of antepartum hemorrhage, followed by placenta previa. Soft-tissue laceration was the primary cause of postpartum hemorrhage, accounting for 28.4% of these. Maternal morbidity was dominated by anemia with a fatality rate of 5.6%. With six twin pregnancies, there were 166 births : 60 stillbirths, and 106 live births (63.9%). The various neonatal morbidities encountered were mainly growth restriction (33.1%), prematurity (19.9%), and neonatal distress (19.3%). Obstetric hemorrhage, which affects young women who are often uneducated, unemployed, and of relatively low parity, is a serious public health problem. Both the maternal fatality rate and the perinatal mortality rate remain very high. PMID- 28721928 TI - Strategic roadmap for an early diagnosis of Alzheimer's disease based on biomarkers. AB - The diagnosis of Alzheimer's disease can be improved by the use of biological measures. Biomarkers of functional impairment, neuronal loss, and protein deposition that can be assessed by neuroimaging (ie, MRI and PET) or CSF analysis are increasingly being used to diagnose Alzheimer's disease in research studies and specialist clinical settings. However, the validation of the clinical usefulness of these biomarkers is incomplete, and that is hampering reimbursement for these tests by health insurance providers, their widespread clinical implementation, and improvements in quality of health care. We have developed a strategic five-phase roadmap to foster the clinical validation of biomarkers in Alzheimer's disease, adapted from the approach for cancer biomarkers. Sufficient evidence of analytical validity (phase 1 of a structured framework adapted from oncology) is available for all biomarkers, but their clinical validity (phases 2 and 3) and clinical utility (phases 4 and 5) are incomplete. To complete these phases, research priorities include the standardisation of the readout of these assays and thresholds for normality, the evaluation of their performance in detecting early disease, the development of diagnostic algorithms comprising combinations of biomarkers, and the development of clinical guidelines for the use of biomarkers in qualified memory clinics. PMID- 28721930 TI - Pharmacoresistant epileptic eyelid twitching in a child with a mutation in SYNGAP1. AB - SYNGAP1 gene mutation has been associated with epilepsy which is often drug resistant, with seizure types including eyelid myoclonia. However, detailed descriptions, including ictal video-EEG, have not been reported. We report the case of a 4-year-old boy who developed recurrent epileptic eyelid twitching at 1 year and 5 months of age. Seizures gradually increased in frequency to more than 50 times per day and manifested with upward eye deviation, motion arrest, loss of consciousness, and eyelid twitching lasting for five seconds. Ictal EEG showed rhythmic, generalized slow or spike-and-wave complex activity with posterior predominance. Moderate psychomotor developmental delay and unsteady gait were also noted. Neuroimaging results were normal. Seizures were refractory to carbamazepine and levetiracetam but were reduced in frequency by ethosuximide and lamotrigine administration. Genetic analysis identified a c.3583-6 G>A mutation in the SYNGAP1 gene. SYNGAP1 gene analysis should be considered for intellectually disabled patients with early-onset drug resistant eyelid twitching and photosensitivity. Further clinical research on SYNGAP1 function may be necessary to treat epilepsy of this aetiology. [Published with video sequence on www.epilepticdisorders.com]. PMID- 28721931 TI - TS-1 (tegafur/gimeracil/oteracil)-induced systemic lupus erythematosus with skin lesions and anti-Sm antibody. PMID- 28721932 TI - CCR4 and CCR5 expression in a case of subcutaneous panniculitis-like T-cell lymphoma. PMID- 28721933 TI - Transient lesions of the splenium of the corpus callosum following rapid withdrawal of levetiracetam. AB - Transient lesions of the splenium of the corpus callosum are characterized by MRI findings. The lesions are very rare, but significant from a clinical standpoint as differential diagnoses include serious conditions such as encephalitis, meningitis, and neuroleptic malignant syndrome. In addition, it is reported that some are attributed to the withdrawal of antiepileptic drugs. Here, we present a case of transient lesions of the splenium of the corpus callosum following rapid withdrawal of levetiracetam alone. To the best of our knowledge, this is the first report of such a case. Moreover, it is reported that cases of incidental transient lesions of the splenium of the corpus callosum are detected in Japan more often than in other countries, and as a result are prone to over-triage. Taking this into consideration, in the event of transient lesions of the splenium of the corpus callosum, the utmost attention must be paid to clinical symptoms and history relating to any of the aforementioned serious conditions. PMID- 28721934 TI - Contribution of brain CT in the diagnosis of tuberculous meningitis: a case report from Djibouti. AB - Tuberculous meningitis, a serious disease with high mortality and morbidity, remains frequent in countries with endemic tuberculosis. Its non-specific presentation often delays the introduction of appropriate treatment. Its definitive diagnosis requires isolation of Mycobacterium tuberculosis from cerebrospinal fluid, although this test may be negative without conclusively ruling out this diagnosis. A presumptive diagnosis should be reached as soon as possible through a body of clinical evidence, including the lumbar puncture findings. Brain computed tomography (CT) with and without contrast medium injection is helpful for the diagnosis of tuberculous meningitis and its complications. We discuss the features of CT and their value in relation to a case of tuberculous meningitis in Djibouti, as well as the role of CT in managing this disease. PMID- 28721935 TI - Prevalence of eye disease and visual impairment in Ile de la Gonave, Haiti. AB - Epidemiological data describing the prevalence of blindness and visual impairment in Haiti are sparse. The Haitian National Committee for the Prevention of Blindness (CNPC) estimates the prevalence of blindness at 1 %. Other regional data estimate moderate and severe visual impairment at 5% and 22%, respectively. IRIS Mundial (IM) is a non-governmental organization collaborating with the CNPC to develop eye care infrastructure in Haiti. To estimate the prevalence and causes of blindness and visual impairment on the Haitian island of Gonave, to assist in planning of relevant eye care infrastructure. Results from eye exams carried out by a team from IM in January 2013 have been compiled and analyzed. In all, 1724 patients were examined (38% men, 62% women). In the best eye, 87% of patients had visual acuity, 6% had moderate visual impairment, and 7% had severe visual impairment. Moreover, 1% of patients had high myopia, 1% high hyperopia, 1% high astigmatism, and 32% were presbyopic. Clinically significant binocular cataracts were found in 1.5 % of patients, while 2 % were diagnosed with probable glaucoma. Our data give a glimpse of the prevalence of visual impairment and ocular disease on Gonave Island in Haiti. Uncorrected refractive error, cataracts, and glaucoma are confirmed as prevalent conditions in this population and their presence should guide the planning of relevant eye care interventions. PMID- 28721936 TI - Assessing quantitative EEG spectrograms to identify non-epileptic events. AB - To evaluate the sensitivity and specificity of quantitative EEG (QEEG) spectrograms in order to distinguish epileptic from non-epileptic events. Seventeen patients with paroxysmal non-epileptic events, captured during EEG monitoring, were retrospectively assessed using QEEG spectrograms. These patients were compared to a control group of 13 consecutive patients (ages 25-60 years) with epileptic seizures of similar semiology. Assessment of raw EEG was employed as the gold standard against which epileptic and non-epileptic events were validated. QEEG spectrograms, available using Persyst 12 EEG system integration software, were each assessed with respect to their usefulness to distinguish epileptic from non-epileptic seizures. The given spectrogram was interpreted as indicating a seizure if, at the time of the clinically identified event, it showed a visually significant change from baseline. Eighty-two clinically identified paroxysmal events were analysed (46 non-epileptic and 36 epileptic). The "seizure detector trend analysis" spectrogram correctly classified 33/46 (71%) non-epileptic events (no seizure indicated during a clinically identified event) vs. 29/36 (81%) epileptic seizures (seizure indicated during a clinically identified event) (p=0.013). Similarly, "rhythmicity spectrogram", FFT spectrogram, "asymmetry relative spectrogram", and integrated-amplitude EEG spectrogram detected 28/46 (61%), 30/46 (65%), 22/46 (48%) and 27/46 (59%) non epileptic events vs. 27/36 (75%), 25/36 (69%), 25/36 (69%) and 27/36 (75%) epileptic events, respectively. High sensitivities and specificities for QEEG seizure detection analyses suggest that QEEG may have a role at the bedside to facilitate early differentiation between epileptic seizures and non-epileptic events in order to avoid unnecessary administration of antiepileptic drugs and possible iatrogenic consequences. PMID- 28721937 TI - 18F-fluorodeoxyglucose-positron emission tomography is more sensitive than computed tomography in initial staging of patients with an anaplastic T-cell lymphoma first presenting in the skin. AB - BACKGROUND: The role of 18F-fluorodeoxyglucose-positron emission tomography (FDG PET) in the evaluation of anaplastic large-cell lymphoma (ALCL) first presenting in the skin is not well established, while computed tomography (CT) is used as a standard procedure. OBJECTIVES: The aim of this study was to evaluate the use of FDG-PET versus CT at initial staging of ALCL first presenting in the skin. MATERIALS & METHODS: Eleven cases of ALCL first presenting in the skin who underwent both FDG-PET and CT were retrospectively analysed. There were six males and five females, with a mean age of 59.7 years. Results of FDG-PET were compared with those of CT. Biopsy results of lesions served as a reference for the accuracy of PET and CT in the evaluation of local and metastatic lesions. RESULTS: In seven cases (64%), imaging revealed extracutaneous ALCL. FDG-PET results were concordant with CT results in five cases (45%); in four of these cases, FDG-PET was negative, consistent with CT, and one case had cutaneous and extracutaneous lesions detectable on both CT and FDG-PET. FDG-PET and CT were discordant in six cases (55%). Among these six cases, FDG-PET revealed extracutaneous lesions undetected on CT which consequently influenced the therapeutic decision in five cases (45%). CONCLUSION: The sensitivity of CT and FDG-PET was 18% and 64%, respectively. PMID- 28721939 TI - Two faces of competition: target-mediated reverse signalling in microRNA and mitogen-activated protein kinase regulatory networks. AB - Biomolecular regulatory networks are organised around hubs, which can interact with a large number of targets. These targets compete with each other for access to their common hubs, but whether the effect of this competition would be significant in magnitude and in function is not clear. In this review, the authors discuss recent in vivo studies that analysed the system level retroactive effects induced by target competition in microRNA and mitogen-activated protein kinase regulatory networks. The results of these studies suggest that downstream targets can regulate the overall state of their upstream regulators, and thus cannot be ignored in analysing biomolecular networks. PMID- 28721938 TI - Practical clues for diagnosing WWOX encephalopathy. AB - The WW domain-containing oxidoreductase gene is implicated in autosomal recessive disorders of the central nervous system, expressed either as spinocerebellar ataxia or as a severe form with early-infantile epileptic encephalopathy. Here, we describe the electroclinical evolution of these disorders, adding new diagnostic clues based on a case study. The patient, a boy with early-onset epilepsy, presented with profound global developmental delay, persistent hypsarrhythmia, and epileptic spasms, associated with progressive cerebral atrophy without microcephaly. Metabolic disease was excluded. Whole-exome sequencing showed mutations in the WW domain-containing oxidoreductase gene. Our findings extend the phenotypic traits of this aggressive epileptic encephalopathy, with persistent epileptic spasms and hypsarhythmia as a part of the electroclinical phenotype, demonstrating that microcephaly is not mandatory for diagnosis, even when associated with progressive cerebral atrophy. These mutations might be more frequent than expected among early-onset epileptic encephalopathies. We present practical clues for the diagnosis of WWOX encephalopathy in order to avoid unnecessary investigations and ensure appropriate genetic counselling for the families. PMID- 28721940 TI - Isolation, characterisation and enzymatic activity of Streptomyces sp. and its pH control during fermentation process. AB - Streptomyces sp. with grey white mycelium was isolated from Kodiyakkarai marine segment of east coastal of India. The isolate produced spiny spores and did not produce any diffusible pigments. Various biochemical tests were carried out to confirm the isolate classification. The amylolytic enzyme activity was estimated using the isolated strain which was confirmed by golden yellowish zone formation after using the Gram's iodine stain. The amount of amylase produced by the isolate was 6.15 U/ml. Higher living cells always produce better enzymes, so that the process parameters especially pH was maintained in fermentation chamber for higher growth and also for large-scale growth. For maintaining the pH a mathematical process model was developed using the data obtained during the process. The addition of Kalman's filter along with proportional-integral derivative controller gave better stability in pH. By maintaining of pH 7, growth rate was significantly increased from 0.51to 0.59 gm/l on day 5 which are discussed in the results and discussions. PMID- 28721941 TI - Blood glucose concentration control for type 1 diabetic patients: a non-linear suboptimal approach. AB - In this study, a closed-loop treatment strategy is proposed for the control of blood glucose levels in type 1 diabetic patients. Toward this end, a non-linear technique for designing suboptimal tracking controllers, called the state dependent Riccati equation tracker, is used based on a mathematical model of the glucose-insulin regulatory system. Since two state variables of the utilised model are not available to the controller, a non-linear filter is also designed to estimate these variables using the measured blood glucose concentration. Effects of unannounced meals and regular exercise are investigated for a nominal patient and nine diabetic patients with unknown parameters. Numerical simulations are given to show the effectiveness of the proposed treatment strategy even in the presence of parametric uncertainties and the observation noise. PMID- 28721942 TI - Induced dipole in vanadium-doped zinc oxide nanosheets and its effects on photoelectrochemical water splitting. AB - Appropriate control of energy band bending at the interface between semiconductors and electrolytes are closely related to performance of photoelectrochemical (PEC) water splitting. Dipoles formed near the surface of semiconductors induces energy band bending at the interface. Energy band bending control has been demonstrated by employing charged molecules and piezoelectric materials. However, chemical and piezoelectric approaches have demerit of chemical instability and inducement of instantaneous dipole, respectively. To overcome these problems, we adopted the ferroelectric material for PEC water splitting, where spontaneous dipoles in the material can be oriented by applying external electric field. In this work, we hydrothermally synthesized vanadium (V) doped ferroelectric ZnO nanosheets and employed to systematically investigate the dipole effect on performance of V-doped ZnO PEC for water oxidation. Consequently, positively polarized V-doped ZnO photoanode exhibits 125% enhanced water splitting efficiency compared to negatively polarized ones due to favorable band bending for carrier transport from semiconductor to water. PMID- 28721943 TI - Stability, electronic and phononic properties of beta and 1T structures of SiTe x (x = 1, 2) and their vertical heterostructures. AB - By performing first-principles calculations, we predict a novel, stable single layer phase of silicon ditelluride, 1T-[Formula: see text], and its possible vertical heterostructures with single layer beta-SiTe. Structural optimization and phonon calculations reveal that 1T-[Formula: see text] structure has a dynamically stable ground state. Further analysis of the vibrational spectrum at the [Formula: see text] point shows that single layer 1T-[Formula: see text] has characteristic phonon modes at 80, 149, 191 and 294 [Formula: see text]. Electronic-band structure demonstrates that 1T-[Formula: see text] phase exhibits a nonmagnetic metallic ground state with a negligible intrinsic spin-orbit splitting. Moreover, it is shown that similar structural parameters of 1T [Formula: see text] and existing beta-SiTe phases allows construction of 1T-beta heterostructures with a negligible lattice mismatch. In this regard, it is found that two energetically favorable stacking orders, namely AA and [Formula: see text]B, have distinctive shear and layer breathing phonon modes. It is important to note that the combination of semiconducting beta-SiTe and metallic 1T [Formula: see text] building blocks forms ultra-thin Schottky barriers that can be used in nanoscale optoelectronic device technologies. PMID- 28721944 TI - Peroxide induced volatile and non-volatile switching behavior in ZnO-based electrochemical metallization memory cell. AB - We explore the use of cubic-zinc peroxide (ZnO2) as a switching material for electrochemical metallization memory (ECM) cell. The ZnO2 was synthesized with a simple peroxide surface treatment. Devices made without surface treatment exhibits a high leakage current due to the self-doped nature of the hexagonal-ZnO material. Thus, its switching behavior can only be observed when a very high current compliance is employed. The synthetic ZnO2 layer provides a sufficient resistivity to the Cu/ZnO2/ZnO/ITO devices. The high resistivity of ZnO2 encourages the formation of a conducting bridge to activate the switching behavior at a lower operation current. Volatile and non-volatile switching behaviors with sufficient endurance and an adequate memory window are observed in the surface-treated devices. The room temperature retention of more than 104 s confirms the non-volatility behavior of the devices. In addition, our proposed device structure is able to work at a lower operation current among other reported ZnO-based ECM cells. PMID- 28721945 TI - Summaries of articles in this issue. AB - Summaries of the articles in this issue are given in the PDF file. PMID- 28721948 TI - Summaries of articles in this issue. AB - Summaries of the articles in this issue are given in the PDF file. PMID- 28721947 TI - Removal of scatter radiation in paediatric cardiac catheterisation: a randomised controlled clinical trial. AB - OBJECTIVE: This study sought to determine if DNA integrity was compromised by ionising radiation from paediatric cardiac catheterisations and if dose optimisation techniques allowed DNA integrity to be maintained. MATERIALS AND METHODS: Children were imaged using either: (i) an anti-scatter grid (current departmental protocol), (ii) no anti-scatter grid or, (iii) no anti-scatter grid and a 15 cm air-gap between the child and the x-ray detector. Dose area product and image quality were assessed, lifetime attributable cancer risk estimates were calculated and DNA double-strand breakages quantified using the gammaH2AX assay. RESULTS: Consent was obtained from 70 parents/guardians/children. Image quality was sufficient for each procedure performed. Removal of the anti-scatter grid resulted in dose reductions of 20% (no anti-scatter grid) and 30% (15 cm air gap), DNA double-strand break reductions of 30% (no anti-scatter grid) and 20% (15 cm air-gap) and a reduction of radiation-induced cancer mortality risk of up to 45%. CONCLUSION: Radiation doses received during paediatric cardiac catheterisation procedures resulted in a significant increase in DNA damage while maintaining acceptable image quality and diagnostic efficacy. It is feasible to remove the anti-scatter grid resulting in a reduction in DNA damage to the patient. The gammaH2AX assay may be used for assessment of dose optimisation strategies in children. PMID- 28721949 TI - Rising to the challenge: applying biofabrication approaches for better drug and chemical product development. AB - Many industrial sectors, from pharmaceuticals to consumer products, are required to provide data on their products to demonstrate their efficacy and that they are safe for patients, consumers and the environment. This period of testing typically requires the use of animal models, the validity of which has been called into question due to the high rates of attrition across many industries. There is increasing recognition of the limitations of animal models and demands for safety and efficacy testing paradigms which embrace the latest technological advances and knowledge of human biology. This perspective article highlights the potential for biofabrication approaches (encompassing bioprinting and bioassembly strategies) to meet these needs and provides case studies from three different industry sectors to demonstrate the potential for new markets in the bioprinting community. We also present a series of recommendations to create a thriving bioprinting environment. One that operates at the forefront of science, technology and innovation to deliver improved decision-making tools for the more rapid development of medicines, agrichemicals, chemicals and consumer products, and which may reduce our reliance on animals. PMID- 28721950 TI - Summaries of articles in this issue. AB - Summaries of the articles in this issue are given in the PDF file. PMID- 28721951 TI - Recording characteristics of electrical impedance myography needle electrodes. AB - OBJECTIVE: Neurologists and physiatrists need improved tools for the evaluation of skeletal muscle condition. Here we evaluate needle electrical impedance myography (EIM), a new minimally invasive approach to determine muscle status that could ultimately become a bedside tool for the assessment of neuromuscular disorders. APPROACH: We design and study the recording characteristics of tetrapolar EIM needle electrodes combining theory and finite-element model simulations. We then use these results to build and pilot in vivo an EIM needle electrode in the rat gastrocnemius muscle ([Formula: see text]). The dielectric properties of muscle are reported (mean +/- standard deviation). RESULTS: The numerical simulations show that the contribution of subcutaneous fat and muscle tissues to needle EIM data is <3% and >97%, respectively, and the sensed volume is [Formula: see text] cm3. Apparent resistivity [Formula: see text] [Formula: see text] cm and relative permittivity [Formula: see text] (dimensionless) measured at 10 kHz are in good agreement with in vivo dielectric properties reported in the literature. SIGNIFICANCE: The results presented show the feasibility of measuring muscle impedivity in vivo using a needle electrode from 10 kHz to 1 MHz. The development of needle EIM technology can open up a new field of study in electrodiagnostic medicine, with potential applications to both disease diagnosis and biomarker assessment of therapy. PMID- 28721952 TI - Nanocoating covalent organic frameworks on nickel nanowires for greatly enhanced performance supercapacitors. AB - Nanocoatings of covalent organic frameworks (COFs) on nickel nanowires (NiNWs) have been designed and successfully fabricated for the first time, which showed greatly enhanced electrochemical performances for supercapacitors. The specific capacitance of electrodes based on as-fabricated COFs nanocoatings reached up to 314 F g-1 at 50 A g-1, which retained 74% of the specific capacitance under the current density of 2 A g-1. The ultrahigh current density makes the charge discharge process extremely rapid. The outstanding electrochemical performances of COFs nanocoating on NiNWs make it an ideal candidate for supercapacitors. And the nanocoating-design can also give a guidance for application of COFs in high performance energy storages. PMID- 28721953 TI - Community medicine: Beyond boundaries. PMID- 28721954 TI - Out-of-Pocket health expenditure and sources of financing for delivery, postpartum, and neonatal health in urban slums of Bhubaneswar, Odisha, India. AB - BACKGROUND: Out-of-pocket expenditure (OOPE) is an obstacle in the path of getting universal health coverage in India. OBJECTIVE: This study aimed to explore the OOPE, sources of funding, and experience of catastrophic expenditure (CE) for healthcare related to delivery, postpartum, and neonatal morbidity. METHODS: A community-based, cross-sectional survey was conducted among a sample of 240 recently delivered women from the slums of Bhubaneswar, Odisha. Information on background, details of delivery, expenditure on delivery and on morbidities, and sources of funding was collected using a structured interview schedule. RESULTS: Only 29.6% of the households incurred OOPE, and the others incurred either nil OOPE or had a net income because of benefits received from Janani Shishu Suraksha Karyakram (JSSK), Janani Suraksha Yojana (JSY), and "Mamata" schemes of the government. The median total OOPE was found to be 2100 INR (100-38,620). Multivariate analysis found parity, place of delivery, type of delivery, and presence of morbidity to be significantly associated with incurring any OOPE. Nearly 15% of the households incurred OOPE exceeding 40% of the reported monthly household income including 9%, whose OOPE was 100% or more of the reported household monthly income. CONCLUSION: While mechanisms such as JSSK, JSY, and Mamata had benefitted the vast majority, around half of those who did incur OOPE experienced CE. Additional insurance facility for cesarean section delivery might reduce the excessive financial burden on households. PMID- 28721956 TI - Direction of uneven health-care expenditure: Evidence from Northeast India. AB - BACKGROUND: Although the need for ensuring universal coverage in health has received the attention of policymakers under the Millennium Development Goals program, the skewed pattern of health-care expenditure has been increased globally. OBJECTIVE: To find out the pattern of public health-care expenditure in northeastern states of India and also to identify the nature of inter-state variation in health-care expenditure among the states. METHODS: The study was based on the secondary data collected from the State Finance Figures of Budgetary Statistics of Reserve Bank of India. The period of study was 13 years (2002-2003 to 2014-2015). The study used descriptive statistics and composite supply-side index separately for revenue and capital expenditure by randomizing through the population census figures of 2001 and 2011 for examining the pattern of interstate variation in health-care expenditure. RESULTS: It has been observed that the states having higher mean expenditure registered low compound annual growth rate in health expenditure and thereby causing low per capita value and lower value of the composite index. CONCLUSION: Thus, the largely populated state needs the due attention of policymaker in reducing the skewed pattern of health care expenditure. PMID- 28721955 TI - Spatiotemporal clustering of dengue cases in Thiruvananthapuram district, Kerala. AB - BACKGROUND: Dengue cases are increasing in Kerala since 2010. Information on clustering of cases across locations and time periods is vital for disease surveillance and timely control. OBJECTIVES: The objective is to study spatiotemporal clustering of dengue cases and their climatic and physioenvironmental correlates in Thiruvananthapuram district during 2010-2014. METHODS: Health department data on reported cases of dengue were obtained from January 2011 to June 2014. Cases were individually geocoded, using Google Earth. Moran's I index was estimated to analyze spatial autocorrelation using GeoDa software. Space-time clustering across 178 geo-divisions within the district was analyzed using SaTScan software. Correlation analysis was done for space-time clustering with climatic variables. RESULTS: Definite spatial and temporal trends were found on analysis of a total of 8279 dengue cases. Significant spatial autocorrelation (Moran's I = 0.32, P< 0.01) and space-time clusters with very high log-likelihood ratios (P < 0.01) were found across geo-divisions. Pallichal panchayat was the most likely cluster in every year. The monthly incidence of dengue cases showed a significant positive association (P < 0.05) with a 2-month lag of mean minimum temperature (rho = 0.39), 1-month lag of rainfall (rho = 0.33), and 1-month lag of humidity (rho = 0.38). Dengue occurrences showed an inverse association (P < 0.01) with mean maximum temperatures of the respective months (rho= -0.48). CONCLUSION: Spatial analysis using epidemiological tools reveals spatial and temporal clustering of dengue cases within the district and their association with climatic parameters. This information can be used in controlling outbreaks in the future. This work upholds scope and feasibility of geospatial research in public health in India. PMID- 28721957 TI - Nutritional status of Mid-Day Meal programme beneficiaries: A cross-sectional study among primary schoolchildren in Kottayam district, Kerala, India. AB - BACKGROUND: The efficiency of Mid-Day Meal (MDM) Programme in India to ensure the optimum nutritional status of its beneficiaries is rarely studied. OBJECTIVE: This study assessed the nutritional status of 6-10-year-old schoolchildren who were the beneficiaries of MDM and the child-related factors affecting their nutritional status. METHODS: A cross-sectional study was performed among 322 children from 12 randomly selected primary schools in one block panchayat of Kerala state. The background information was collected from children and their parents, and anthropometric measurements of the children were observed. The prevalence of undernutrition was estimated using conventional indices (stunting, underweight, and wasting) and composite index of anthropometric failure (CIAF). Logistic regression analysis was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: The prevalence of CIAF was 45.7% (95% CI: 40.3%-51.1%) and that of stunting, underweight, and wasting were 13.4% (9.7% 17.1%), 38.8% (33.5%-44.1%), and 30.7% (25.7%-35.7%), respectively. The prevalence of wasting (42.6% vs. 28.4%, P = 0.039) and severe underweight (20.4% vs. 7.1%, P = 0.002) was statistically significantly high among occasional/never users compared to regular users of MDM Programme. Children born with <2.5 kg showed an OR of 1.76 (95% CI: 0.99-3.11) for being undernourished compared to children born with normal weight (>=2.5 kg) when adjusted for age, sex, birth order, and illness in the past 2 weeks. CONCLUSION: This study showed a higher prevalence of undernutrition among school-age children who were the beneficiaries of MDM Programme, and this indicates the need for continuous nutritional interventions and surveillance among these children. PMID- 28721958 TI - Cost analysis of a simulation-based training for health workforce in India. AB - BACKGROUND: Training of health-care workforce including doctors, staff nurses, and Auxiliary Nurse Midwives using simulation techniques for skill enhancement have been used in a variety of clinical settings to improve the quality of training. India adopted the skills laboratories model for capacity building of health workers in maternal and child health in Bihar state. OBJECTIVE: Current economic evaluation was performed with the objective of assessing the financial and economic cost of implementing skills laboratories. METHODS: Data on all resources spent for the development of skill laboratory and implementing training during financial year 2011 were collected from Patna district in Bihar state. We used standard methods to estimate the full financial and economic costs of implementing the skills laboratories from a health system perspective. RESULTS: Overall cost of implementing 20 permanent and 10 mobile skills laboratory training in Bihar was Indian Rupee (INR) 8849895 from a financial perspective. The cost was nearly two times higher when using an economic perspective to account for opportunity cost of all resources used. The unit cost of training a participant using permanent and mobile laboratory was INR 6856 and INR 7474, respectively assuming an annual volume of 90 training. The optimum number of training which should be operated annually in a skills laboratory to make it most efficient is about 70-80 training per annum. CONCLUSIONS: Economic implications of skills laboratory organization should be borne while planning scale up in Bihar and other states. Further research on the effectiveness of two models of skill laboratory, that is, permanent and mobile and their cost is recommended. PMID- 28721959 TI - A study of falls among elderly persons in a rural area of Haryana. AB - BACKGROUND: Falls are a common, disabling, and frequently fatal health concern among elderly persons. Assessment of the prevalence of falls and associated factors can lead to the identification of corrective measures, which can help in preventing falls and their consequent effects on health and well-being of the elderly. OBJECTIVES: The objective is to determine the prevalence of falls among elderly persons in a rural area and to study the association of falls with sociodemographic variables and selected health conditions. METHODS: In a community-based, cross-sectional study conducted among 456 elderly persons in a rural area, information regarding sociodemographic details, selected health conditions, and history of falls in the past 12 months was recorded. Univariate analysis followed by stepwise multivariate logistic regression analysis was carried out. The effect of sociodemographic and various health conditions on falls was analyzed using logistic regression analysis. RESULTS: Among the 456 study participants, the prevalence of falls in the past 12 months was 36.6% (95% confidence interval [CI] =32.1-40.0). The prevalence among women was 40.6% (95% CI = 34.5-46.7) and among men was 31.5% (95% CI = 25.0-37.9). Low socioeconomic status, urgency of micturition, knee pain, visual impairment, hearing impairment, functional disability, and depression were significantly associated with falls. CONCLUSIONS: Falls are common among elderly persons. Health programs for the elderly must include prevention of falls and rehabilitation of fall-related injuries. PMID- 28721960 TI - Alcohol consumption, hazardous drinking, and alcohol dependency among the population of Andaman and Nicobar Islands, India. AB - BACKGROUND: Harmful use of alcohol is one of the globally recognized causes of health hazards. There are no data on alcohol consumption from Andaman and Nicobar Islands. OBJECTIVE: The objective of the study was to assess the prevalence and pattern of alcohol use among the population of Andaman and Nicobar Islands, India. METHODS: A representative sample of 18,018 individuals aged >=14 years were chosen by multistage random sampling and administered a structured instrument, a modified version of the Gender, Alcohol, and Culture: An International Study (GENACIS) which included sociodemographic details and Alcohol Use Disorders Identification Test (AUDIT). RESULTS: The overall prevalence of alcohol consumption was 35% among males and over 6.0% in females, aged 14 and above. Two out of every five alcohol users fit into a category of hazardous drinkers. One-fourth of the total users (23%) are alcohol dependents. Both the hazardous drinking and dependent use are high among males compared to females. Almost 18.0% of male drinkers and 12.0% of female drinkers reported heavy drinking on typical drinking occasions. The predominant beverages consumed were in the category of homebrews such as toddy and handia. CONCLUSION: The present study highlights the magnitude of hazardous drinking and alcohol dependence in Andaman and Nicobar Islands, India and the complex sociocultural differences in the pattern of alcohol use. Based on the AUDIT data, among the population of Andaman and Nicobar Islands (aged 14 and above), one out of ten requires active interventions to manage the harmful impact of alcohol misuse. PMID- 28721961 TI - Determinants of child sex ratio in West and South Districts of Tripura, India. AB - BACKGROUND: Indian census 2011 has detected declined child sex ratio in the West and South districts of Tripura State. OBJECTIVES: To find out the sex ratio at birth and to identify the factors affecting child sex ratio in west and south districts of Tripura. METHODS: This community-based cross-sectional study combined with a qualitative component was conducted among 3438 couples chosen by multistage sampling. Quantitative data were collected by a structured interview schedule. Data were analyzed by computer using SPSS version 15.0. Chi-square test was applied for testing the significance of study findings and P < 0.05 was considered statistically significant. Qualitative data were collected by Focus Group Discussions and analyzed by qualitative free listing and pile sorting considering Smith's S value. RESULTS: Sex ratio at birth in West and South Tripura districts during 2013 was found to be 972 and 829 respectively. Son preference was higher among couples irrespective of their literacy, residence, occupation, family type and religion except Christianity. Expenditure at marriage, lesser contribution to parent's family and fears of adverse situations at in law's house after marriage etc. were causes for lesser daughter preference. Very few pregnant women underwent ultrasonography for sex determination of fetus. Girls had differential or delayed medical care and higher death rate. The desire for children was found to be limited after male births. CONCLUSIONS: Low daughter preference was mostly due to economic reasons and prolonged contraception following male birth. Literacy, occupation and residence of study subjects did not modify prevalent higher male preference. PMID- 28721963 TI - Pediatric HIV in India: Current scenario and the way forward. AB - In India, the prevention of parent-to-child transmission and antiretroviral therapy services for HIV-infected mothers and children have been rapidly scaled up over the recent years. Despite these advances, a large number of HIV-infected children are born in every year. A thorough literature review has been done by retrieving related studies (published from the year 2000 onward); using a Medline search and by extracting recent findings from the official websites of the National AIDS Control Organization, UNAIDS, UNICEF, and World Health Organization. The efforts that are made to control pediatric HIV are challenged by a large range of factors such as low health service utilization, poor drug adherence, delayed infant diagnosis, discriminatory attitude of health providers, loss to follow-up, and poor coordination in managing continuum of care. These challenges may be addressed by adopting innovative and effective strategies and strengthening the existing health system. This would bring about a significant reduction in pediatric HIV incidence and improve the outcomes in children who are HIV infected. PMID- 28721962 TI - Urinary tract infection among pregnant women at a secondary level hospital in Northern India. AB - BACKGROUND: Urinary tract infection (UTI) during pregnancy is frequently associated with complications. Currently, in India, there is no regular screening for UTI, and facility for diagnosis of UTI is not available at peripheral government health centers. OBJECTIVE: To estimate the proportion of pregnant women with UTI among antenatal clinic attendees in rural Haryana. METHODS: Eligible participants were pregnant women attending antenatal clinic of secondary care center of rural Haryana from March to May 2015. Consecutive sampling was done to select pregnant women. Interview schedule was administered to the selected women, and midstream urine sample was collected. Urine sample was plated on MacConkey agar, and colony count was done using standard methods. RESULTS: A total of 1253 pregnant women were included in the study. The proportion of women with symptoms of UTI on the basis of history was 33.3% (95% confidence interval [CI] - 30.7, 35.9), and UTI by colony count was 3.3% (95% CI - 2.4, 4.5). The presence of UTI was found to be significantly associated with the presence of any symptom of UTI on multivariate analysis (odds ratio [95% CI] - 7.35 [1.95, 27.77]). CONCLUSIONS: The burden of UTI among pregnant women attending antenatal clinic of a sub-district hospital was considerable, more so among the women that presented with symptoms suggestive of UTI. The study suggested that considering the burden of UTI and its complications, diagnosis of UTI at a resource constrained setting like a secondary care hospital can be done after screening women for symptoms suggestive of UTI. PMID- 28721964 TI - Economic implications of tobacco industry in India: An overview. AB - Tobacco usage has become engraved in the cultural practices of our country since time immemorial. With increased demand comes increased production, employment, and growth of the tobacco industry but for a deadly cost of human lives which fall prey to its use in either forms. In this article, we describe the economic burden faced by the country due to the emerging tobacco epidemic. The need of the hour is to understand the impact faced due to the tobacco industry in the country and to bring in appropriate efforts to reduce loss of economy and human lives. PMID- 28721965 TI - The rise of global health diplomacy: An interdisciplinary concept linking health and international relations. AB - Global health diplomacy (GHD) is relatively a very new field that has yet to be clearly defined and developed though there are various definitions given by different experts from foreign policy, global health, diplomacy, international relations, governance, and law. With the intensification of globalization and increasing gaps between countries, new and reemerging health threats such as HIV/AIDS, tuberculosis, influenza, severe acute respiratory syndrome, Ebola, and Zika and a gradual rethinking on security concepts framed a new political context. The health problems addressed diplomatically have also become diverse ranging from neglected tropical diseases, infectious diseases, sale of unsafe, counterfeit drugs to brain drain crisis. We see that global health has become more diverse as the actors widened and also the interests appealing not only to the traditional humanitarian ideals associated with health but also to the principles grounded in national and global security. Recently, we are witnessing the increased priority given to the GHD because the issue of health is discussed by various actors outside the WHO to shape the global policy for health determinants. In fact, the area of health has become the part of UN Summit Diplomacy involving the G8, G20, BRICS, and the EU. The recent WHO Pandemic Influenza Framework, UN High Level Framework on Prevention and Control of Noncommunicable Diseases, and the WHO Framework Convention on Tobacco Control are some of the examples of long-term negotiation processes for agreements that took place. PMID- 28721966 TI - Use of skin-lightening products among outpatient attendees in a North Indian Hospital. AB - In India, fair skin is a highly valued physical attribute. Skin lightener products comprise 60% of the dermatological market. This cross-sectional study was conducted in the general medical outpatient clinics of Champa Christian Hospital to elucidate the perceptions of fair skin and determinants/pattern of skin lighter use. Demographics, pattern of skin lightener use and incidence of side effects, perceptions of lighter skin tones were the main outcomes and measures studied. The use of skin lighteners was highly prevalent in our study population. Believing that lighter skin is beneficial for self-esteem is a predictor for skin lightener use. Higher education was associated with lower perceived benefits of fairer skin and therefore reduced skin lightener use. Further education and increased community awareness are important to address the issues surrounding potential over-use of skin-lightening products. PMID- 28721967 TI - Sexual behavior of transgenders and their vulnerability to HIV/AIDS in an Urban Area of Eastern India. AB - Transgender (TG) people experience a gender identity that is different from their anatomical sex. For their high-risk sex behavior, they are important group for targeted intervention of HIV/AIDS. The objective of the study was to find the sexual behavior of TG people and to assess few aspects of their vulnerability to HIV/AIDS. This cross-sectional survey was done from June to August 2012, in field practice area of "Kosish," a nongovernmental organization run by TGs in Alipore of Kolkata metropolitan city, India. Information was collected by interviewing 90 TG of 11 selected hotspots using a predesigned questionnaire. Results revealed that 4.5% were illiterate. Drug abuse was reported by 22.2% participants. Inconsistent condom use was found. Venereal disease research laboratory reactivity was found in 11.11%. Nearly 16.7% had experienced sexual violence in the past 3 months. Thus, interventions for overall empowerment of the TGs are recommended. PMID- 28721968 TI - A comment on assessment and comparison of pregnancy outcome among anaemic and nonanaemic primigravida mothers. PMID- 28721969 TI - Assessment and comparison of pregnancy outcome among anemic and nonanemic primigravida mothers. PMID- 28721970 TI - Adverse events following immunization: A challenge in India. PMID- 28721971 TI - Implementation of epidemic disease act: An experience from a North Indian jurisdiction. PMID- 28721973 TI - Inflammatory bowel disease: Clinical screening and transition of care. PMID- 28721972 TI - Ultrasound imaging features of isolated pancreatic tuberculosis. AB - Background and Objectives: Isolated pancreatic tuberculosis (PTB) is extremely rare worldwide. The purpose of this multicenter retrospective study is to analyze imaging features of histologically confirmed isolated PTB in order to determine the diagnostic features of the new methods contrast enhanced ultrasound (CEUS), ultrasound elastography and contrast enhanced endoscopic ultrasound (CE-EUS). Patients and Methods:: We report on a retrospective data collection of 12 cases of PTB confirmed by histology or cytology. All examinations were interpreted by two independent readers in consensus. CEUS, CE-EUS and ultrasound elastography were performed according to the European Federation of Societies for Ultrasound in Medicine and Biology guidelines. Results:: In PTB patients the common bile duct was never dilated. Multiple retroperitoneal lymph nodes are the second important B-mode ultrasound feature detected in 75% of PTB patients. CE-EUS was performed in three PTB patients demonstrating hyperenhancement. On elastography, all PTB lesions were markedly stiffer than surrounding pancreatic parenchyma. Conclusions:: Here we report the first time on CEUS and elastography features of PTB. PTB had some typical imaging features with iso- or hyperenhancement on CE(E) US. PTB is markedly stiffer on elastography. If clinicians are aware of clinical features of PTB and conduct appropriate investigations with multiple modalities including B-mode ultrasound, CEUS, and EUS guided fine needle aspiration, diagnosis of PTB without laparotomy is possible and the disease can be effectively treated with anti-tuberculous drugs. PMID- 28721974 TI - Hepatitis C virus infection and risk of osteoporosis: A meta-analysis. AB - BACKGROUND/AIMS: Hepatitis C virus (HCV) infection is one of the most common infections worldwide. Several epidemiologic studies have suggested that patients with HCV infection might be at an increased risk of osteoporosis. However, the data on this relationship remains inconclusive. This meta-analysis was conducted with the aim to summarize all available evidence. MATERIALS AND METHODS: A literature search was performed using MEDLINE and EMBASE databases from inception to June 2016. Studies that reported relative risks, odd ratios (OR), or hazard ratios comparing the risk of osteoporosis among HCV-infected patients versus those without HCV infection were included. Pooled OR and 95% confidence interval (CI) were calculated using a random-effect, generic inverse variance method. RESULTS: Four studies met our eligibility criteria and were included in the analysis. We found a higher risk of osteoporosis among patients with chronic HCV with OR of 1.65 (95% CI: 0.98-2.77). Sensitivity analysis including only studies with higher quality yielded a higher OR, and the result was statistically significant (OR: 2.47; 95% CI: 1.03-5.93). CONCLUSIONS: Our study demonstrated a higher risk of osteoporosis among HCV-infected patients. Further studies are required to clarify how this risk should be addressed in clinical practice. PMID- 28721975 TI - Effect of long-term proton pump inhibitor administration on gastric mucosal atrophy: A meta-analysis. AB - BACKGROUND/AIMS: Proton pump inhibitors (PPIs) are widely used for the treatment of acid-related gastrointestinal diseases. Recently, some studies have reported that PPIs can alter the gastric mucosal architecture; however, the relationship remains controversial. This meta-analysis study was designed to quantify the association between long-term PPI administration and gastric atrophy. MATERIALS AND METHODS: A PubMed search was conducted to identify studies using the keywords proton pump inhibitors or PPI and gastric atrophy or atrophic gastritis; the timeframe of publication searched was up to May 2016. Heterogeneity among studies was tested with the Q test; odds ratios (OR) and 95% confidence intervals (CI) were calculated. P values were calculated by I2 tests and regarded as statistically significant when <0.05. RESULTS: We identified 13 studies that included 1465 patients under long-term PPI therapy and 1603 controls, with a total gastric atrophy rate of 14.50%. There was a higher presence of gastric atrophy (15.84%; statistically significant) in PPI group compared to the control group (13.29%) (OR: 1.55, 95% CI: 1.00-2.41). CONCLUSIONS: The pooled data suggest that long-term PPI use is associated with increased rates of gastric atrophy. Large-scale multicenter studies should be conducted to further investigate the relationship between acid suppressants and precancerous diseases. PMID- 28721976 TI - Screening irritable bowel syndrome patients for symptoms predictive of crohn's disease using the red flag score. AB - BACKGROUND/AIMS: The diagnosis of inflammatory bowel disease (IBD) is often delayed due to misdiagnosing patients with irritable bowel syndrome (IBS), mostly because of the under-recognition of high-risk features. The red flag score (RFS) has been recently developed to identify patients with higher risk of IBD rather than IBS. The aim of this study is to estimate the prevalence of high-risk features, according to the RFS, among patients diagnosed with IBS who would consequently be candidates for ileocolonoscopic evaluation. PATIENTS AND METHODS: Adult patients with IBS seen at the general medicine clinic were recruited and surveyed using the RFS. Clinical and demographic data were collected. The prevalence of high-risk features, defined as a RFS >5, was calculated. Logistic regression analysis was used to identify predictors of RFS >5. RESULTS: A total of 255 patients with IBS were recruited. The mean age was 30.6 years (+/-9.9 years); 71.4% of patients were women (182/255), and 90.2% were from Saudi Arabia (230/255). More than half of the patients we surveyed (51.4%) had not visited a gastroenterologist previously. The mean RFS was 6.6 (+/-3.6) and 54.9% of patients (140/255) scored more than 5 and accordingly were selected for further investigations. Statistical analysis identified no previous visits to a gastroenterologist as the only significant predictor of RFS >5 (OR = 2.2, 95% CI = 1.3-3.7, P = 0.003). CONCLUSIONS: More than half of the patients known to have IBS are candidates for further investigations to eliminate the possibility of IBD as a diagnosis according to the validated RFS. Patients who did not seek a specialized consultation with a gastroenterologist might be at a higher risk of being misdiagnosed as having IBS. PMID- 28721977 TI - A cross-sectional survey of Saudi gastroenterologists: Transition strategies for adolescents with inflammatory bowel disease. AB - BACKGROUND/AIMS: The transition of adolescents with inflammatory bowel disease (IBD) from pediatric to adult care requires a well-structured standardized protocol to ensure the delivery of optimal healthcare and decrease the risk of nonadherence, hospitalizations, and complications. The aims of this survey are to evaluate current IBD transition practices adopted by gastroenterology services across the Kingdom of Saudi Arabia (KSA) and to identify the major challenges standing in the way of implementing effective transition strategies from the perspectives of pediatric and adult gastroenterologists. PATIENTS AND METHODS: An online survey was distributed to KSA pediatric and adult gastroenterologists through the Kingdom's national gastroenterology association. The questionnaire included closed-ended questions regarding existing institutional transition strategies and perspectives regarding the impact of different factors on their ability to effectively transition adolescents from pediatric to adult care. RESULTS: A total of 80 adult and pediatric gastroenterologists responded to the survey invitation. Most of the participating gastroenterologists worked at a tertiary care center (82.5%). The majority of gastroenterologist (73.8%) reported that they do not follow a defined protocol for transitioning in their current practices. However, a structured transition program was noted to be "very important" by 78.8% of gastroenterologists. The most favored method of transitioning was joint outpatient clinic attended by patient, caregiver, pediatric gastroenterologist, and adult gastroenterologist (35.9%) and the most commonly reported barrier to transitioning was "lack of proper preparation" for transitioning (53.2%). CONCLUSIONS: Although acknowledged by the majority of participants as being "very important," no standardized IBD transition protocol is followed in the majority of practices across KSA. A well-structured national protocol for transitioning adolescents with IBD is needed. PMID- 28721978 TI - Noninvasive biomarkers as surrogate predictors of clinical and endoscopic remission after infliximab induction in patients with refractory ulcerative colitis. AB - BACKGROUND/AIMS: Treatment of refractory ulcerative colitis (UC) is a clinical challenge, and after biological therapy, monitoring clinical and endoscopic responses is fundamental. We aimed to investigate and compare the predictive power of different noninvasive parameters for clinical remission and mucosal healing after infliximab induction therapy in refractory UC patients. PATIENTS AND METHODS: Serum and fecal biomarkers, including hemoglobin, white blood cells, erythrocyte sedimentation rate, C-reactive protein (CRP), and fecal calprotectin (FC), and colonoscopy were assessed in 44 patients with refractory UC before and after (week 12) infliximab induction. Clinical and endoscopic responses were measured by clinical Mayo score and endoscopic Mayo subscore, respectively. RESULTS: After infliximab induction, 54.5% and 65.9% had clinical remission and mucosal healing, respectively. Post-induction CRP and FC were significantly lower in clinical responders versus nonresponders (P = 0.01 and 0.001, respectively) and in patients with mucosal healing than without (P < 0.001). Among all the parameters tested, FC had the best predictive value of clinical remission [Area under the curve (AUC = 0.826)] and mucosal healing (AUC = 0.949). Post-induction FC had 87.5% sensitivity and 89% specificity (cut-off <100 MUg/g) for predicting clinical remission and 89.7% sensitivity and 93.3% specificity (cut-off <58 MUg/g) for predicting mucosal healing. CONCLUSIONS: Post-infliximab induction FC can be used as a surrogate marker for predicting clinical remission and mucosal healing in refractory UC patients. PMID- 28721979 TI - Histological outcomes between hot and cold snare polypectomy for small colorectal polyps. AB - BACKGROUND/AIM: To compare the complete resection rate of hot and cold snare polypectomy for small colorectal polyps. PATIENTS AND METHODS: We retrospectively reviewed the medical records of 233 consecutive patients with 461 colorectal polyps up to 10 mm in diameter that were treated by hot or cold snare polypectomy between April 2014 and August 2016. Lesions treated by hot snare polypectomy (n = 137) and cold snare polypectomy (n = 324) were compared. The histological complete resection rates were evaluated between the two groups. We analyzed the relationship between factors for complete resection and clinical factors using multivariate analysis. RESULTS: There was a significantly higher complete resection rate in hot snare polypectomy than in cold snare polypectomy (70.5% vs. 47.3%; P < 0.001). In the analysis of subgroups categorized according to polyp size, the complete resection rate for hot snare polypectomy was significantly higher than that for cold snare polypectomy among polyps >=6 mm (69.0% vs. 43.5%; P < 0.001). Among polyps <=5 mm, no significant difference regarding the complete resection rate was observed between the methods (81.3% vs. 53.4%; P = 0.057). There was no significant difference in the incidence of adverse events between the two groups. Multivariate analysis revealed that using hot snare polypectomy (odds ratio 3.03; P < 0.001), small lesion size (odds ratio 1.57; P = 0.049), and lesion location in the left colon (odds ratio 1.73; P = 0.007) were independent factors for complete resection. CONCLUSION: Hot snare polypectomy provides a higher complete resection rate than does cold snare polypectomy for larger (6-10 mm) subcentimeter colorectal polyps. PMID- 28721980 TI - Risk of coronary artery disease in celiac disease population. AB - BACKGROUND/AIMS: Celiac disease (CD), a chronic autoimmune condition, is associated with systemic inflammation capable of causing extra intestinal manifestations. Chronic inflammatory process has been implicated in the pathogenesis of accelerated atherosclerosis. Studies examining the burden of coronary artery disease (CAD) in patients with CD are lacking. We evaluated the prevalence of CAD in patients with CD. PATIENTS AND METHODS: Electronic health records from different health care systems were obtained utilizing a Health Insurance Portability and Accountability Act-compliant, patient de-identified web application. Among the 48,642,290 patients, 59,010 were diagnosed with CD. The remaining 48,583,280 patients without CD served as comparison controls. RESULTS: The prevalence of CAD was significantly higher in patients with CD than in the controls [5140 (8.7%) vs. 2119060 (4.4%), P < 0.001], with the odds ratio (OR) being 2.09 (95% confidence interval [CI]: 2.03-2.15, P < 0.0001). There was a similarly higher prevalence among younger patients (age, <65 years) with CD compared with those without CD (3.72% vs 1.98% [OR: 1.85, 95% CI: 1.7488-1.9417, P < 0.0001). CONCLUSIONS: The prevalence of CAD increased nearly two-fold in patients with CD. PMID- 28721981 TI - Detection of clostridium difficile antigen and toxin in stool specimens: Comparison of the C. difficile quik chek complete enzyme immunoassay and GeneXpert C. difficile polymerase chain reaction assay. AB - BACKGROUND/AIMS: Accurate and rapid laboratory diagnosis of Clostridium difficile infections (CDI) remains a significant challenge. A two-step algorithm for detection of toxigenic C. difficile in stool based on initial screening for glutamate dehydrogenase assay followed by confirmation by toxin A+B detection using an enzyme immunoassay (EIA) or molecular assay has been proposed. We aimed to evaluate the C. difficile Quik Chek Complete(r) (QCC-EIA) versus the GeneXpert(r) C. difficile polymerase chain reaction (PCR) assay in this two-step algorithm. MATERIALS AND METHODS: Two hundred and ten liquid stool samples obtained between June 2014 and June 2015 from patients suspected of CDI were tested by the QCC-EIA and GeneXpert PCR assay. The GeneXpert assay was used as the reference standard to calculate the QCC-EIA sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). RESULTS: Of the 210 stool samples tested, 43 (20.5%) were positive by QCC-EIA, while 31 (14.8%) were positive by GeneXpert assay. The sensitivity and specificity of the QCC-EIA were found to be 100 and 93%, respectively; the PPV and NPV were 72 and 100%, respectively. The binary toxin was detected in 12 (38.7%) and tcdC gene deletion in 3 (9.6%). CONCLUSIONS: The low specificity of QCC-EIA makes it less reliable as a confirmatory test for CDI diagnosis. This test may be used as a screening test in a two-step algorithm when combined with a molecular assay or another confirmatory test. PMID- 28721982 TI - Towards supporting greater and lower cost access to direct acting antiviral treatment for hepatitis C for all patients. PMID- 28721983 TI - Current status and future perspectives of sentinel lymph node biopsy in oral cancers. PMID- 28721984 TI - Redefining and reinventing dentistry. PMID- 28721985 TI - Prevalence of dental caries and periodontal disease in a rural area of Faridabad District, Haryana, India. AB - An oral health survey was conducted in 829 individuals in different age groups in Ballabhgarh, Haryana, India, to estimate the prevalence of Dental caries and Periodontal diseases. A survey tool was modified from WHO's STEPwise approach to surveillance and Oral Health Assessment form 2013 from recently released WHO Oral Health Survey: Basic Methods (5th Edition) keeping in mind the South East Asian region. Out of 28 villages, six villages were randomly selected. A random list of study participants (Age-sex specific) was generated from the pooled list of these 6 villages. Local health workes helped in inviting the specific subjects to one centralized location within each village/ locality. The subjects were examined by trained dental surgeons and recordings were done by trained assistants. The prevalence of dental caries in 5-7 year, 12-15 year, 35-44 year and 65-74 year was 33.2%, 31.3%, 64.9% and 50.1% respectively. The prevalence of Periodontal Disease in 35-44 year and 65-74 year found to be 65.2% and 90.4% respectively. Only 37 participants had mucosal lesions, of which leukoplakia and tobacco pouch keratosis was seen in majority. Using the adopted tool, the prevalence of dental caries was found to be highest in 35-44 year (64.9%) age group and the prevalence of periodontal disease was found to be high in 35-44 year (65.2%) age group and highest in 65-74 year (90.4%) age group. Oral health promotion efforts are required to prevent oro-dental diseases in the studied population. PMID- 28721986 TI - Evaluation of analgesic and anti-inflammatory activity of a combination of tramadol-ibuprofen in experimental animals. AB - BACKGROUND: Pain is the major concern of patients attending dental clinics, and satisfactory pain relief has always been difficult to achieve. Since the pathophysiology of pain is a complex, central and peripheral nervous system process, combined analgesic regimens with different mechanisms of action as a multimodal approach are becoming popular among the clinicians and dentists. OBJECTIVES: The aim of the present study was to evaluate the analgesic and anti inflammatory activity of ibuprofen and tramadol when used alone or in combination in animal models of pain and inflammation. ANIMALS AND METHODS: The animals were divided into six groups with six animals in each group. Analgesic activity was assessed by hot plate method in rats and by acetic acid-induced writhing test in mice. Paw edema model in rats after induction with 0.1 mL of 1% carrageenan was used to assess the anti-inflammatory activity. STATISTICAL ANALYSIS: Analysis of variance followed by Tukey's honestly significant difference post hoc test was used for statistical analysis. RESULTS AND CONCLUSION: Combined use of tramadol and ibuprofen provided enhanced analgesic and anti-inflammatory effects in animal models of pain and inflammation. PMID- 28721987 TI - Evaluation of occlusal groove patterns of mandibular first and second molars in an Indian population: A forensic anthropological study. AB - BACKGROUND: The study of dental morphological characteristics is important in anthropological research as it can provide information on the phylogenetic relationship between species, as well as variations and diversities within a population. AIMS AND OBJECTIVES: To determine the prevalence of six types of mandibular second molars in Gujarat state and the results can be used in both forensic anthropological researches and clinical aspects of dental sciences. MATERIALS AND METHODS: This descriptive investigation was undertaken among 1000 students (13-25 years old) in high schools and dental institutes of Gujarat state. The students were selected by cluster sampling method and screened for the number of cusps and groove patterns of mandibular first and second molars. Gender and religion of the students were recorded on prepared forms. STATISTICAL ANALYSIS: It was done with the help of STATAIC-13 software. Descriptive statistics were used to summarize the data and Pearson's Chi-square test was used to check association between variables. Throughout the discussion, level of significance was set at 5%. RESULTS AND CONCLUSION: The high percentage of "+ "shaped groove pattern and low percentage of primitive "y-"shaped pattern in our study shows a tremendous evolutionary trend persisting in this population. The analysis of dental morphological traits is crucial in anthropological research as it can provide data on the phylogenetic relationship between species, as well as variations and diversities within a population. PMID- 28721988 TI - Attitude of bachelor of dental surgery students and interns toward teaching learning process in Government Dental College, Kottayam, Kerala, India. AB - INTRODUCTION: The educational environment affects the academic performance of students. One of the most widely utilized tools for measuring the educational environment is Dundee Ready Education Environment Measure (DREEM). The objective of the study was to assess the attitude toward study environment, as measured using DREEM questionnaire, and to find out the differences in perception of various batches of dental students. MATERIALS AND METHODS: All Bachelor of Dental Surgery students from Government Dental College, Kottayam, Kerala, India, were included in the study. They were given the well-established DREEM questionnaire. A total of 234 students took part in the study, belonging to 2009, 2010, 2011, 2012, 2013, and 2014 batches. DREEM subcategories were analyzed for significance using analysis of variance. The significance of DREEM score across the different batches was further analyzed using post hoc test. RESULTS: Overall, DREEM score was positive (111.14), but there is need for improvement. Individual questions also were given positive score for most questions. The maximum score was obtained for 3rd year students. Similar results are obtained for three of the five subcategories of DREEM. CONCLUSION: The total DREEM score was positive (111.14). The total score as well as the scores for the subcategories was highest in 3rd year dental students. The increase might be due to the excitement of clinical exposure for the first time in 3rd year students. PMID- 28721989 TI - Oral changes in patients undergoing chemotherapy for breast cancer. AB - BACKGROUND: Breast cancer is one of the most common cancers in India. Most of the patients with breast cancer are treated with chemotherapy which has multiple oral complications. AIMS: The objectives of this study were to describe the occurrence of taste disturbances, xerostomia, oral mucositis, oral pigmentation, and candidal and salivary changes among patients receiving chemotherapy for breast cancer. METHODS: Fifty-two women with newly diagnosed breast cancer (without distant metastasis), eligible for adjuvant/neoadjuvant chemotherapy (cyclophosphamide and adriamycin, 4 cycles * 3 weeks), were included in this study. All the observations were noted before, during (after 6 weeks of starting chemotherapy), and after the completion of chemotherapy (after 12 weeks of starting chemotherapy). STATISTICAL ANALYSIS USED: Variables such as mucositis, salivary flow rate, salivary pH, and candidal carriage rate were compared at baseline, and at 1st and 2nd follow-ups using Wilcoxon signed-rank test (P value corrected for alpha for pair-wise comparisons). RESULTS: Mean unstimulated whole salivary flow rate reduced from 0.5 ml/min to 0.3 ml/min, and the mean colony forming units of Candida reduced from 32.3 * 103 cells/ml to 13.1 * 103 cells/ml at the end of the study period. Xerostomia, taste disturbances, and oral mucosal pigmentation increased from 28.8% to 50%. CONCLUSIONS: There was a discernible change in oral mucosal, salivary, and candidal status during the course of the study. PMID- 28721990 TI - Neocondyle distraction osteogenesis in the management of temporomandibular joint ankylosis: Report of five cases with review of literature. AB - INTRODUCTION AND OBJECTIVES: Management of temporomandibular joint (TMJ) ankylosis is a challenging and rather daunting task owing to complex abnormal anatomy and its sequel to craniofacial structures. Various autogenous grafts and alloplastic materials have been tried with variable success for creation of a near-normal joint. In recent years, neocondyle distraction has added a new dimension to the management of TMJ ankylosis. The aim of this paper is to describe the role of neocondyle distraction in TMJ ankylosis. MATERIALS AND METHODS: Neocondyle distraction was carried out in five patients with TMJ ankylosis following gap arthroplasty. Computed tomogram scans were taken before surgery and 1-year postdistraction for surgical planning and postoperative assessment, respectively. The intraoral distractors (KLS Martin, Jacksonville, FL, USA) were used in this study. RESULTS: All five patients reported with adequate mouth opening and functional jaw movements. The procedure was well tolerated by all the patients. None of the patients underwent reankylosis following neocondyle distraction. CONCLUSION: With proper surgical planning and distraction protocol, neocondyle distraction is an effective and safe technique for TMJ reconstruction and preventing reankylosis. PMID- 28721991 TI - Angiogenesis concept in odontogenic keratocyst: A comparative study. AB - CONTEXT: Recent reports have indicated that angiogenesis possibly affects the biologic behavior of the lesions. AIM: Given the different clinical behaviors of odontogenic keratocyst (OKC), the present study was undertaken to evaluate the concept of angiogenesis in pathogenesis and clinical behavior of OKC. SETTING AND DESIGN: This experimental study was carried out on 22 and 24 samples of OKCs and dentigerous cysts (DCs), respectively. METHODS: Immunohistochemical staining was approached using CD34 and vascular endothelial growth factor (VEGF) antibodies. The expression of VEGF was first reported by determining the counts of stained cells, including epithelial cells, fibroblasts, and endothelial cells, followed by the percentage of stained cells in each sample based on a 0-2 scoring system. The counts of CD34+ cells were reported in each group in the form of means +/- standard deviations. In addition, the patterns of blood vessels in the samples prepared from the walls of both cysts were evaluated. STATISTICAL ANALYSIS USED: Mann-Whitney U-test, Chi-squared test, and t-test were used for analysis of data, and statistical significance was defined at p < 0.05. RESULTS: The expression percentage and scores of VEGF and the mean expression rate of CD34 were significantly higher in OKCs than DCs (p = 0.045, 0.000, and p = 0.58). Finally, there was a strong correlation between the expressions of the two markers in the samples (Correlation coefficient = 0.766). CONCLUSION: The present results indicate the angiogenesis may play an important role in the pathogenesis and the unique clinical behavior of OKC. PMID- 28721992 TI - Comparative evaluation of effectiveness of intra-pocket anesthetic gel and injected local anesthesia during scaling and root planing - A split-mouth clinical trial. AB - BACKGROUND AND AIM: Pain control is an important outcome measure for successful periodontal therapy. Injected local anesthesia has been used to secure anesthesia for scaling and root planing (SRP) and continues to be the anesthetic of choice for pain control. Alternatively, intra-pocket anesthetic gel has been used as an anesthetic during SRP. Hence, this clinical trial was done to compare the effectiveness of intra-pocket anesthetic gel and injected local anesthesia during SRP and also to assess the influence of intra-pocket anesthetic gel on treatment outcomes in chronic periodontitis patients. MATERIALS AND METHODS: Fifteen systemically healthy chronic periodontitis patients were recruited. The dental quadrants on right side received either intra-pocket 20% benzocaine gel (Gel group) or infiltration/block by 2% lidocaine with 1:80,000 adrenaline (injection group). Quadrants on the left side received the alternative. Pain perception and patients preference for the type of anesthesia was recorded. Clinical parameters: plaque index, modified gingival index, modified sulcular bleeding index, probing pocket depth, and clinical attachment level were recorded at baseline and 1 month after treatment. RESULTS: No difference was observed in visual analog scale (P > 0.05) and verbal rating scale (P > 0.05) pain perception between gel group and injection group. A slightly increased preference to gel as anesthesia (53% vs. 47%) was observed. The treatment outcome after SRP did not show a significant difference between gel and injection group (P > 0.05). CONCLUSION: Intra-pocket administration of 20% benzocaine gel may be effective for pain control during SRP and may offer an alternative to conventional injection anesthesia. PMID- 28721993 TI - Honey and olive oil as bio-friendly substitutes for formalin and xylene in routine histopathology. AB - BACKGROUND: Formalin has long been the standard fixative and xylene has been the clearing agent for routine histopathology and immunohistochemistry worldwide. In recent years, as a result of increasing concerns about the potential carcinogenicity of formaldehyde and xylene, attempts have been made to find safer alternatives. In the present study, we considered honey as better alternative for formalin and olive oil as safer substitute for xylene. AIMS: The aim of this study was to know whether honey could be a possible substitute for formalin and olive oil could be a possible substitute for xylene. MATERIALS AND METHODS: Thirty routine biopsy tissues of 1-2 cm were taken. The study group was divided into Group A and Group B. Group A were subjected to normal processing. Group B were fixed into honey for 24 h after which it was taken through routine processing, and then immersed in olive oil instead of xylene. All the sections will be stained with routine hematoxylin and eosin staining. Compare the sections of both the methods. RESULTS AND CONCLUSION: The preservation of tissue by honey giving superior result when compared to that of formalin. Olive oil was found to be effective clearing agent compared to xylene. PMID- 28721994 TI - Evaluation of marginal and internal gaps of metal ceramic crowns obtained from conventional impressions and casting techniques with those obtained from digital techniques. AB - BACKGROUND: Accuracy in fit of cast metal restoration has always remained as one of the primary factors in determining the success of the restoration. A well fitting restoration needs to be accurate both along its margin and with regard to its internal surface. AIM: The aim of the study is to evaluate the marginal fit of metal ceramic crowns obtained by conventional inlay casting wax pattern using conventional impression with the metal ceramic crowns obtained by computer-aided design and computer-aided manufacturing (CAD/CAM) technique using direct and indirect optical scanning. MATERIALS AND METHODS: This in vitro study on preformed custom-made stainless steel models with former assembly that resembles prepared tooth surfaces of standardized dimensions comprised three groups: the first group included ten samples of metal ceramic crowns fabricated with conventional technique, the second group included CAD/CAM-milled direct metal laser sintering (DMLS) crowns using indirect scanning, and the third group included DMLS crowns fabricated by direct scanning of the stainless steel model. The vertical marginal gap and the internal gap were evaluated with the stereomicroscope (Zoomstar 4); post hoc Turkey's test was used for statistical analysis. One-way analysis of variance method was used to compare the mean values. RESULTS AND CONCLUSION: Metal ceramic crowns obtained from direct optical scanning showed the least marginal and internal gap when compared to the castings obtained from inlay casting wax and indirect optical scanning. Indirect and direct optical scanning had yielded results within clinically acceptable range. PMID- 28721995 TI - Comparative evaluation of laser-microtextured implant versus machined collar implant for soft and hard tissue attachment: A clinical and radiological study. AB - BACKGROUND: Various mechanical modifications in the collar region of endosseous implants is a challenge for better performance and osseointegration. Here is a comparative evaluation being carried out to find out the effect of the machined collar (MC) and Laser-Lok (LL)-modified titanium implants on the success of implants being commonly advocated in partially edentulous among serving personnel and their families. MATERIALS AND METHODS: Twenty-four patients with appropriate inclusion and exclusion criteria were selected for placement of Biohorizons MC and LL implants in 12 cases each. Aseptic surgical procedure was followed for implant surgery, and clinical parameters such as clinical attachment loss, pocket depth (PD), bleeding on probing, and plaque index (PI), mobility parameters estimated by Periotest value, and radiographic assessment of crestal bone loss (CBL) at interval of 6 months and 1 year were recorded and compared by statistical analysis. RESULTS: Intragroup comparison at 6 and 12 months period for all the parameters were nonsignificant except CBL in Group A (CBL-MC) with 12 cases shows a mean of 0.917 and 1.500, respectively, standard deviation difference = 0.477 (significant) with P < 0.05. Similar significant difference in CBL was observed with superior result in LL implants. CONCLUSION: The presence of LASER textured with microgrooves on the collar of the implants did not increase the PI and sulcular bleeding index. The probing PD was much less as observed in the group of LASER-treated implants in comparison with that of MC group. LL implant had an edge over MC proving success of the laser treatment on collars of implants. PMID- 28721996 TI - Open reduction and internal fixation: Screw injury - Retrospective study. AB - BACKGROUND/AIMS: Open reduction and internal fixation (ORIF) is a standard surgical procedure in jaw trauma and in orthognathic surgery. Insertion of screws is a significant risk for accidental tooth root injury with varying outcomes. Contrary evidences are found in literature due to a variety of study designs. This study was undertaken to address the lacunae and possibly estimate the difference in occurrence of tooth damage during or after ORIF between trauma and planned osteotomies. MATERIALS AND METHODS: In this retrospective study, the data of ORIF in either trauma or orthognathic surgery fulfilling inclusion and exclusion criteria were collected and analyzed. RESULTS: There were 1632 patients fulfilling the inclusion and exclusion criteria and formed the study group, of which 663 were in orthognathic surgery, of whom 210 had bimaxillary orthognathic surgery. In the trauma group, 358 patients had fractures involving both jaws whereas 272 had maxilla alone and 339 had mandibular fractures alone. On comparing the outcome, of the 9073 screws studied, 93.40% were not involved in any contact with the teeth, 6.3% were in category of potential hits (near apices or the root surfaces), and only 0.28% had evidence of root damage with the screws. It is observed that molar and premolar had a significant difference in terms of the type of surgery (P <= 0.05) whereas canine (P = 0.75) and incisor (P = 0.67) showed no statistical difference. CONCLUSION: ORIF when used as mentioned is a safe way for the management of fractures. The incidence of root injury is not uncommon but can be avoided with careful planning and execution. PMID- 28721997 TI - Selection of dental implants based on masticatory load of the patient: A novel approach. AB - PURPOSE: Masticatory load and efficiency vary from one individual to other. Maximum load of one person may be the least load of another. Hence, optimization of dental implants based on the load dissipation of an individual is essential for a better prognosis of implant-supported prosthesis. The aim of the study was to find the appropriate implant dimensions for the particular region based on the masticatory efficiency of the individual. MATERIALS AND METHODS: A two dimensional-threaded implant model was designed, which was duplicated in total 28 models with varying dimensions starting from 3 mm * 8 mm till 6 mm * 14 mm, with an incremental increase of 2 mm in length and 0.5 mm in diameter. All these implant models were surrounded in cancellous bone. Each implant model was loaded from 50 Newtons (N) to 700 N with an incremental increase of 50 N in load in vertical direction to the static model complex. RESULTS: Von Mises stresses were calculated for all the models with different amount of load. The analysis showed that, with an increase in applied masticatory load the smaller dimensional implants showed more stress in the bone, with more stress concentration toward the crest of the implants, and in the apical bone, with respect to the ultimate stress capacity of bone. CONCLUSION: Thus, based on the numerical analysis results, a classification was designed, which will indicate that for a particular amount of masticatory load, a particular dimension of implant has to be selected, rather than just selecting the implant based on the available bone and its dimensions without knowing the load the implant is going to take once it is loaded. PMID- 28721998 TI - In vitro effect of chlorhexidine gel on torque and detorque values of implant abutment screw. AB - PURPOSE: Use of chlorhexidine (CHX) gel to eliminate the malodor of implant cavity may decrease the friction coefficient and effective preload and result in abutment screw loosening. This study aimed to assess the effect of CHX gel on the preload, torque, and detorque values. MATERIALS AND METHODS: This in vitro experimental study was conducted on three groups of five implants. Group A (G1) was the control group and no material was applied to the implant cavity. In Group B (G2), implant cavity was filled with saliva before abutment screw tightening. In Group C (G3), implant cavity was first filled with saliva and then with CHX gel. The abutments were torqued to 24 N/cm2 according to the manufacturer's instructions and were then loosened. These processes were repeated five times. The ratio of the mean percentage of detorque to torque values was measured in all groups. The collected data were analyzed using ANOVA and post hoc Tukey's test. RESULTS: No significant difference was noted between G1 and G2. Group G2 had significantly higher detorque value (p < 0.05). ANOVA detected a significant difference in the mean torque (p < 0.05) and detorque (p < 0.001) values among the three groups. G3 showed maximum difference between torque and detorque values; the minimum difference was noted in G2. CONCLUSION: Application of CHX gel (to decrease the malodor of the implant cavity) decreases the detorque and preload values and increases the risk of screw loosening. PMID- 28721999 TI - Distance M-Me: A novel parameter having significant potential as a predictor of mandibular growth. AB - OBJECTIVES: The purpose of the present study was to investigate the relationship of the measured distance between two mandibular points (distance M-Me) to chronological age and to find out whether the absolute values of distance M-Me could be classified age-wise into a unique range, which could be directly read for predicting the stage of mandibular growth. METHODS AND MATERIALS: The study sample consists of lateral cephalometric records of 65 patients (34 females and 31 males; age range: 6-21 years). Chronological age was calculated in decimal years. Lateral cephalograms were assessed by two independent examiners. Points M and Me were located on the lateral cephalograms, and linear distance between them was measured. RESULTS: Pearson product-moment correlation coefficients showed a high correlation between chronological age and distance M-Me (0.746 for females and 0.869 for males, p < 0.01). When the values of distance M-Me were compared with chronological age, it was possible to make four age groups (for females and males separately), where each group showed a unique range of value for distance M Me. The values increased with increasing age. CONCLUSIONS: Increase in value of distance M-Me with age, showing reduced individual variation, depicts a well conserved linear dimension. Values of distance M-Me can be directly read for predicting the stage of mandibular growth and can be used as a valuable adjunct or substitute to chronological age. PMID- 28722000 TI - Comparative evaluation of shear bond strength of zirconia restorations cleansed various cleansing protocols bonded with two different resin cements: An In vitro study. AB - CONTEXT: Yttria partially stabilized tetragonal zirconia polycrystalline restorations have gained widespread use because of its enhanced strength and esthetics. During the try-in process, zirconia is likely to be contaminated with saliva. This contamination leads to a clear weakening of the bond between restorative material and cement. For this reason, zirconia surface should be cleaned before cementation. Hence, the purpose of this study is to compare the shear bond strength of zirconia restorations cleansed with various surface cleansing protocols bonded with two different resin cements. MATERIALS AND METHODS: Eighty samples of zirconia discs were prepared in the dimensions 2.5 mm diameter and 4.5 mm thickness. They were divided into two groups of each forty samples based on luting cement used. Each group was further subdivided into four subgroups of each (n = 10): Group 1: uncontaminated zirconia blocks, Group 2: saliva-contaminated zirconia blocks and cleaned only with distilled water, Group 3: saliva-contaminated zirconia blocks treated with Ivoclean, and Group 4: saliva contaminated zirconia blocks were air abraded. Eighty human maxillary premolars were then sectioned to expose dentin and were mounted on an acrylic block. A jig was fabricated to bond zirconia with the tooth using two self-adhesive resin cements. The samples were subjected to shear bond strength testing. The data were analyzed using one-way analysis of variance and Tukey's honest significance difference test with a level of significance set at p < 0.05. RESULTS: The mean shear bond strength values of Group 1 and 2 - subgroup B are 10.3 +/- 0.4 and 9.80 +/- 0.7 (saliva-contaminated zirconia, cleansed with distilled water only), respectively, were lowest among all test subgroups and were significantly less than mean values of subgroup C, Group 1 - 20.45 +/- 0.6 and Group 2 - 20.75 +/- 0.4 (Ivoclean group) and subgroup D, Group 1 - 20.90 +/- 0.3 and Group 2 - 20.60 +/- 0.5 (air abrasion group) (p < 0.05) for both test groups. CONCLUSIONS: In a clinical practice, a simple application of Ivoclean can be an effective alternative to air abrasion in removing salivary contaminants and improve resin zirconia bonding. PMID- 28722001 TI - Enamel color changes following orthodontic treatment. AB - OBJECTIVE: To evaluate and compare the effect of various orthodontic bonding systems and clean up procedures on quantitative enamel colour change. MATERIALS AND METHODS: A literature search was done to identify the studies that assessed the quantitative enamel colour change associated with the various bonding systems and cleanup procedures. Electronic database (Pub Med, Cochrane and Google Scholar) were searched. First stage screening was performed and the abstracts were selected according to the initial selection criteria. Full text articles were retrieved and analyzed during second stage screening. The bibliographies were reviewed to identify additional relevant studies. RESULTS: Sixteen full text articles were retrieved. Six were rejected because the methodology was different. There was significant enamel colour change following orthodontic bonding, debonding and clean up procedures. CONCLUSION: Self-etching primers produce less enamel colour change compared to conventional etching. Resin Modified GIC produces least colour change compared to other light cure and chemical cure systems. Polishing following the clean-up procedure reduces the colour change of the enamel. PMID- 28722002 TI - Report of occurrence and endodontic management of three-rooted maxillary first and second premolars in the same individual. AB - Anatomical variations should be kept in mind in clinical and carefully looked for in radiographic evaluation during endodontic treatment of maxillary premolars. These teeth have highly variable root canal morphology. Although three separate roots in the maxillary first premolars have been reported, it is a rarity to find both the first and second premolars possessing three separate roots. This case report describes the diagnosis and endodontic management of maxillary first and second premolars with three canals and three separate roots. Access cavity refinements were required for stress-free entry to the complex anatomy. PMID- 28722003 TI - Severe unintentional extrusion of mineral trioxide aggregate during apexification. AB - The aim of this report was to present the long-term clinical and radiographic outcomes of a case including severe unintentional extrusion of mineral trioxide aggregate (MTA). An 11-year-old boy was referred with a previously traumatized permanent central incisor which was temporarily treated by using calcium hydroxide root canal filling material. Since having an open apex and a large periapical lesion, root canal treatment with MTA apexification was planned. During the apexification process, a huge amount of MTA was unintentionally extruded into periapical tissues. The parents were informed about the complication, and the obturation of the remaining root canal was completed. Clinical and radiographic follow-up was performed for 4 years. Complete healing of periapical lesion was confirmed by the radiographic follow-up at the 48th month. Patients should be followed-up for giving a chance to observe periapical healing without any surgical removal if the MTA is unintentionally extruded. PMID- 28722004 TI - Oral gingival metastasis: A diagnostic dilemma. AB - Oral cavity is a rare target for metastasis with an incidence of 1% among all oral cancers. In 24% of such cases, oral metastasis is the first indication of an undiagnosed primary. Metastatic oral malignancies have been reported in the mandible, tongue, and gingiva. Although gingival metastasis has been reported from lung, prostate, rectal carcinoma in men and carcinoma of breast, adrenal glands, and genitalia in females, gingival metastasis from carcinoma of the penis has not been reported. Herein, a case of metastatic gingival carcinoma that developed after extraction of teeth from primary carcinoma of the penis is presented. An extensive literature search revealed no such similar case reports. PMID- 28722005 TI - A conservative management of iatrogenically damaged distal root of the mandibular second molar. AB - Trauma to the adjacent hard and soft tissue is the most common iatrogenic injury during extraction of the mandibular third molar. As every functional component of the dental arch is of prime importance in contemporary dental practice, the major concern must be in conserving the tooth and its structure as much as possible. The present case discusses the application of this conservative approach for management of iatrogenically damaged distal root of the mandibular second molar during extraction of impacted third molar, in which excessive guttering of alveolar bone and fractured apical third of distal root of 37 was observed radiographically. A conservative and noninvasive approach was successfully achieved to restore the damaged root by the bioactive material. Sealing of the remaining root with mineral trioxide aggregate allowed regeneration of soft and hard tissue around it. PMID- 28722006 TI - Highly-conducting molecular circuits based on antiaromaticity. AB - Aromaticity is a fundamental concept in chemistry. It is described by Huckel's rule that states that a cyclic planar pi-system is aromatic when it shares 4n+2 pi-electrons and antiaromatic when it possesses 4n pi-electrons. Antiaromatic compounds are predicted to exhibit remarkable charge transport properties and high redox activities. However, it has so far only been possible to measure compounds with reduced aromaticity but not antiaromatic species due to their energetic instability. Here, we address these issues by investigating the single molecule charge transport properties of a genuinely antiaromatic compound, showing that antiaromaticity results in an order of magnitude increase in conductance compared with the aromatic counterpart. Single-molecule current voltage measurements and ab initio transport calculations reveal that this results from a reduced energy gap and a frontier molecular resonance closer to the Fermi level in the antiaromatic species. The conductance of the antiaromatic complex is further modulated electrochemically, demonstrating its potential as a high-conductance transistor. PMID- 28722007 TI - Physical properties of the HIV-1 capsid from all-atom molecular dynamics simulations. AB - Human immunodeficiency virus type 1 (HIV-1) infection is highly dependent on its capsid. The capsid is a large container, made of ~1,300 proteins with altogether 4 million atoms. Although the capsid proteins are all identical, they nevertheless arrange themselves into a largely asymmetric structure made of hexamers and pentamers. The large number of degrees of freedom and lack of symmetry pose a challenge to studying the chemical details of the HIV capsid. Simulations of over 64 million atoms for over 1 MUs allow us to conduct a comprehensive study of the chemical-physical properties of an empty HIV-1 capsid, including its electrostatics, vibrational and acoustic properties, and the effects of solvent (ions and water) on the capsid. The simulations reveal critical details about the capsid with implications to biological function. PMID- 28722008 TI - Crustal rheology controls on the Tibetan plateau formation during India-Asia convergence. AB - The formation of the Tibetan plateau during the India-Asia collision remains an outstanding issue. Proposed models mostly focus on the different styles of Tibetan crustal deformation, yet these do not readily explain the observed variation of deformation and deep structures along the collisional zone. Here we use three-dimensional numerical models to evaluate the effects of crustal rheology on the formation of the Himalayan-Tibetan orogenic system. During convergence, a weaker Asian crust allows strain far north within the upper plate, where a wide continental plateau forms behind the orogeny. In contrast, a stronger Asian crust suppresses the plateau formation, while the orogeny accommodates most of the shortening. The stronger Asian lithosphere is also forced beneath the Indian lithosphere, forming a reversed-polarity underthrusting. Our results demonstrate that the observed variations in lithosphere deformation and structures along the India-Asia collision zone are primarily controlled by the strength heterogeneity of the Asian continental crust. PMID- 28722009 TI - Highly variable recurrence of tsunamis in the 7,400 years before the 2004 Indian Ocean tsunami. AB - The devastating 2004 Indian Ocean tsunami caught millions of coastal residents and the scientific community off-guard. Subsequent research in the Indian Ocean basin has identified prehistoric tsunamis, but the timing and recurrence intervals of such events are uncertain. Here we present an extraordinary 7,400 year stratigraphic sequence of prehistoric tsunami deposits from a coastal cave in Aceh, Indonesia. This record demonstrates that at least 11 prehistoric tsunamis struck the Aceh coast between 7,400 and 2,900 years ago. The average time period between tsunamis is about 450 years with intervals ranging from a long, dormant period of over 2,000 years, to multiple tsunamis within the span of a century. Although there is evidence that the likelihood of another tsunamigenic earthquake in Aceh province is high, these variable recurrence intervals suggest that long dormant periods may follow Sunda megathrust ruptures as large as that of the 2004 Indian Ocean tsunami. PMID- 28722010 TI - A shape-shifting redox foldase contributes to Proteus mirabilis copper resistance. AB - Copper resistance is a key virulence trait of the uropathogen Proteus mirabilis. Here we show that P. mirabilis ScsC (PmScsC) contributes to this defence mechanism by enabling swarming in the presence of copper. We also demonstrate that PmScsC is a thioredoxin-like disulfide isomerase but, unlike other characterized proteins in this family, it is trimeric. PmScsC trimerization and its active site cysteine are required for wild-type swarming activity in the presence of copper. Moreover, PmScsC exhibits unprecedented motion as a consequence of a shape-shifting motif linking the catalytic and trimerization domains. The linker accesses strand, loop and helical conformations enabling the sampling of an enormous folding landscape by the catalytic domains. Mutation of the shape-shifting motif abolishes disulfide isomerase activity, as does removal of the trimerization domain, showing that both features are essential to foldase function. More broadly, the shape-shifter peptide has the potential for 'plug and play' application in protein engineering. PMID- 28722011 TI - Accumulating the hydride state in the catalytic cycle of [FeFe]-hydrogenases. AB - H2 turnover at the [FeFe]-hydrogenase cofactor (H-cluster) is assumed to follow a reversible heterolytic mechanism, first yielding a proton and a hydrido-species which again is double-oxidized to release another proton. Three of the four presumed catalytic intermediates (Hox, Hred/Hred and Hsred) were characterized, using various spectroscopic techniques. However, in catalytically active enzyme, the state containing the hydrido-species, which is eponymous for the proposed heterolytic mechanism, has yet only been speculated about. We use different strategies to trap and spectroscopically characterize this transient hydride state (Hhyd) for three wild-type [FeFe]-hydrogenases. Applying a novel set-up for real-time attenuated total-reflection Fourier-transform infrared spectroscopy, we monitor compositional changes in the state-specific infrared signatures of [FeFe] hydrogenases, varying buffer pH and gas composition. We selectively enrich the equilibrium concentration of Hhyd, applying Le Chatelier's principle by simultaneously increasing substrate and product concentrations (H2/H+). Site directed manipulation, targeting either the proton-transfer pathway or the adt ligand, significantly enhances Hhyd accumulation independent of pH. PMID- 28722012 TI - Type III CRISPR-Cas systems produce cyclic oligoadenylate second messengers. AB - In many prokaryotes, type III clustered regularly interspaced short palindromic repeat (CRISPR)-CRISPR-associated (Cas) systems detect and degrade invasive genetic elements by an RNA-guided, RNA-targeting multisubunit interference complex. The CRISPR-associated protein Csm6 additionally contributes to interference by functioning as a standalone RNase that degrades invader RNA transcripts, but the mechanism linking invader sensing to Csm6 activity is not understood. Here we show that Csm6 proteins are activated through a second messenger generated by the type III interference complex. Upon target RNA binding by the interference complex, its Cas10 subunit converts ATP into a cyclic oligoadenylate product, which allosterically activates Csm6 by binding to its CRISPR-associated Rossmann fold (CARF) domain. CARF domain mutations that abolish allosteric activation inhibit Csm6 activity in vivo, and mutations in the Cas10 Palm domain phenocopy loss of Csm6. Together, these results point to an unprecedented mechanism for regulation of CRISPR interference that bears striking conceptual similarity to oligoadenylate signalling in mammalian innate immunity. PMID- 28722013 TI - Stability of iron-bearing carbonates in the deep Earth's interior. AB - The presence of carbonates in inclusions in diamonds coming from depths exceeding 670 km are obvious evidence that carbonates exist in the Earth's lower mantle. However, their range of stability, crystal structures and the thermodynamic conditions of the decarbonation processes remain poorly constrained. Here we investigate the behaviour of pure iron carbonate at pressures over 100 GPa and temperatures over 2,500 K using single-crystal X-ray diffraction and Mossbauer spectroscopy in laser-heated diamond anvil cells. On heating to temperatures of the Earth's geotherm at pressures to ~50 GPa FeCO3 partially dissociates to form various iron oxides. At higher pressures FeCO3 forms two new structures tetrairon(III) orthocarbonate Fe43+C3O12, and diiron(II) diiron(III) tetracarbonate Fe22+Fe23+C4O13, both phases containing CO4 tetrahedra. Fe4C4O13 is stable at conditions along the entire geotherm to depths of at least 2,500 km, thus demonstrating that self-oxidation-reduction reactions can preserve carbonates in the Earth's lower mantle. PMID- 28722014 TI - Universality and chaoticity in ultracold K+KRb chemical reactions. AB - A fundamental question in the study of chemical reactions is how reactions proceed at a collision energy close to absolute zero. This question is no longer hypothetical: quantum degenerate gases of atoms and molecules can now be created at temperatures lower than a few tens of nanokelvin. Here we consider the benchmark ultracold reaction between, the most-celebrated ultracold molecule, KRb and K. We map out an accurate ab initio ground-state potential energy surface of the K2Rb complex in full dimensionality and report numerically-exact quantum mechanical reaction dynamics. The distribution of rotationally resolved rates is shown to be Poissonian. An analysis of the hyperspherical adiabatic potential curves explains this statistical character revealing a chaotic distribution for the short-range collision complex that plays a key role in governing the reaction outcome. PMID- 28722015 TI - TRPV1 regulates excitatory innervation of OLM neurons in the hippocampus. AB - TRPV1 is an ion channel activated by heat and pungent agents including capsaicin, and has been extensively studied in nociception of sensory neurons. However, the location and function of TRPV1 in the hippocampus is debated. We found that TRPV1 is expressed in oriens-lacunosum-moleculare (OLM) interneurons in the hippocampus, and promotes excitatory innervation. TRPV1 knockout mice have reduced glutamatergic innervation of OLM neurons. When activated by capsaicin, TRPV1 recruits more glutamatergic, but not GABAergic, terminals to OLM neurons in vitro. When TRPV1 is blocked, glutamatergic input to OLM neurons is dramatically reduced. Heterologous expression of TRPV1 also increases excitatory innervation. Moreover, TRPV1 knockouts have reduced Schaffer collateral LTP, which is rescued by activating OLM neurons with nicotine-via alpha2beta2-containing nicotinic receptors-to bypass innervation defects. Our results reveal a synaptogenic function of TRPV1 in a specific interneuron population in the hippocampus, where it is important for gating hippocampal plasticity. PMID- 28722016 TI - Silk micrococoons for protein stabilisation and molecular encapsulation. AB - Naturally spun silks generate fibres with unique properties, including strength, elasticity and biocompatibility. Here we describe a microfluidics-based strategy to spin liquid native silk, obtained directly from the silk gland of Bombyx mori silkworms, into micron-scale capsules with controllable geometry and variable levels of intermolecular beta-sheet content in their protein shells. We demonstrate that such micrococoons can store internally the otherwise highly unstable liquid native silk for several months and without apparent effect on its functionality. We further demonstrate that these native silk micrococoons enable the effective encapsulation, storage and release of other aggregation-prone proteins, such as functional antibodies. These results show that native silk micrococoons are capable of preserving the full activity of sensitive cargo proteins that can aggregate and lose function under conditions of bulk storage, and thus represent an attractive class of materials for the storage and release of active biomolecules. PMID- 28722017 TI - The role of age-related T-cell differentiation in patients with renal replacement therapy. AB - Dialysis patients have deficiencies regarding the generation of immune responses and show an increased susceptibility for infections. Persisting uremic conditions are made responsible for the increased aging of their immune system. In this study, we analyzed whether age-related differences in the differentiation of both recent-thymic-emigrant-(RTE)-regulatory (Tregs) and RTE-responder T cells (Tresps) into CD31--memory Tregs/Tresps led to differences in the suppressive activity of naive and memory Tregs on autologous Tresps between healthy volunteers and dialysis patients. We found that regardless of age, the differentiation of RTE-Treg/Tresps into CD31--memory-Treg/Tresps was significantly increased in dialysis patients. By analyzing the age-related differences in the differentiation of Tregs/Tresps, we saw that in healthy volunteers RTE-Tregs differentiate via CD31+-memory Tregs into CD31--memory Tregs, which may strengthen the suppressive activity of the total Treg pool. In contrast RTE-Tresps of healthy volunteers differentiate via mature naive (MN) Tresps into CD31--memory-Tresps, which may weaken the reactivity of the total Tresp pool. Our data revealed that this normal differentiation via MN-Tresps was lost in dialysis patients, suggesting that their Tresps are less sensitive to Treg-mediated immunosuppression. Functional analysis of Tregs on autologous Tresps showed an increasing suppressive activity with age in healthy individuals, who therefore may have a lower risk of developing autoimmune diseases but owing to decreased reactivity of their Tresps are more likely to suffer from infections. In contrast, dialysis patients exhibited a decreasing suppressive activity with age, owing to strengthened Tresp reactivity, which could explain the higher prevalence of chronic inflammatory conditions in these patients. PMID- 28722018 TI - A pro-survival role for the intracellular granzyme B inhibitor Serpinb9 in natural killer cells during poxvirus infection. AB - Intracellular serpins are proposed to inactivate proteases released from lysosome related organelles into the host cell interior, preventing cell death. Serpinb9 opposes the immune cytotoxic protease, granzyme B, and in a number of settings protects cells against granzyme B-mediated cell death. Using a knockout mouse line engineered to express green fluorescent protein under the serpbinb9 promoter, we demonstrate that serpinb9 is vital for host survival during Ectromelia virus infection by maintaining both mature natural killer NK) cells, and activated CD8+ T cells. Serpinb9 expression parallels granzyme B expression within both populations during infection. Maturing serpinb9-null NK cells exhibit higher levels of granzyme B-mediated apoptosis during infection; hence there are fewer mature NK cells, and these cells also have lower cytotoxic potential. Thus the serpinb9-granzyme B axis is important for homeostasis of both major cytotoxic effector cell populations. PMID- 28722019 TI - Sustained accumulation of antigen-presenting cells after infection promotes local T-cell immunity. AB - Antigen-presenting cells (APC), such as dendritic cells (DC) and macrophages, are critical for T-cell-mediated immunity. Although it is established that memory T cells accumulate and persist in peripheral tissues after the resolution of infection, whether this is also the case for APC remains unclear. Here, we report that CCR2-dependent cells infiltrate skin during acute infection with herpes simplex virus (HSV)-1 and subsequently give rise to localized populations of DCs and macrophages. These APC are found at elevated numbers at sites of resolved infection or inflammation compared with unaffected regions of skin. Importantly, this local accumulation of APC is sustained for prolonged periods of time and has important functional consequences, as it promotes interferon-gamma responses by virus-specific CD4+ T cells upon localized challenge infection with HSV-1. Thus, our results highlight how infection history determines long-term changes in immune cell composition in skin and how different types of immune cells accumulate, persist and co-operate to provide optimal immunity at this critical barrier site. PMID- 28722020 TI - A critical role of Gas6/Axl signal in allergic airway responses during RSV vaccine-enhanced disease. AB - Respiratory syncytial virus (RSV) is a common virus that causes lower respiratory infections across a wide range of ages. A licensed RSV vaccine is not available because vaccination with formalin-inactivated RSV (FI-RSV) and the subsequent RSV infection cause not only insufficient induction of neutralizing antibodies but also severe allergic airway responses, termed FI-RSV vaccine-enhanced disease (FI RSV VED). However, the underlying mechanism has not been identified, although a Th2-biased immune response is known to be a hallmark of this disease. Our previous studies have shown that growth arrest-specific 6 (Gas6)/Axl signaling leads to Th2-biased immune responses during fungus-induced allergic airway inflammation. Here, we show that Gas6/Axl signaling also leads to FI-RSV VED and partially identify the mechanism in mice. Inhibiting Gas6/Axl signaling using Gas6-deficient mice, neutralizing antibodies, and a specific inhibitor of Axl attenuated allergic airway hyperresponsiveness, including airway inflammation, goblet cell hyperplasia, and Th2 cytokine production, in addition to increasing interferon-gamma levels and the production of RSV-neutralizing IgG2a in FI-RSV VED. Gas6 was produced in lymph nodes during immunization with FI-RSV. Lymph node cells derived from immunized mice produced high levels of Gas6 and Th2 cytokines, but not IFN-gamma, after restimulation with RSV. Finally, we found that dendritic cells stimulated with RSV-glycoprotein (G protein) produced Gas6 and that Axl signaling suppressed DC maturation and the induction of IL-12 production by the toll-like receptor 4 agonist RSV-fusion protein. Taken together, these results indicate that RSV-G protein-induced Gas6/Axl signaling causes allergic airway responses during FI-RSV VED. PMID- 28722021 TI - Activation of the GABAergic Parafacial Zone Maintains Sleep and Counteracts the Wake-Promoting Action of the Psychostimulants Armodafinil and Caffeine. AB - We previously reported that acute and selective activation of GABA-releasing parafacial zone (PZVgat) neurons in behaving mice produces slow-wave-sleep (SWS), even in the absence of sleep deficit, suggesting that these neurons may represent, at least in part, a key cellular substrate underlying sleep drive. It remains, however, to be determined if PZVgat neurons actively maintain, as oppose to simply gate, SWS. To begin to experimentally address this knowledge gap, we asked whether activation of PZVgat neurons could attenuate or block the wake promoting effects of two widely used wake-promoting psychostimulants, armodafinil or caffeine. We found that activation of PZVgat neurons completely blocked the behavioral and electrocortical wake-promoting action of armodafinil. In some contrast, activation of PZVgat neurons inhibited the behavioral, but not electrocortical, arousal response to caffeine. These results suggest that: (1) PZVgat neurons actively maintain, as oppose to simply gate, SWS and cortical slow wave-activity; (2) armodafinil cannot exert its wake-promoting effects when PZVgat neurons are activated, intimating a possible shared circuit/molecular basis for mechanism of action; (3) caffeine can continue to exert potent cortical desynchronizing, but not behavioral, effects when PZVgat neurons are activated, inferring a shared and divergent circuit/molecular basis for mechanism of action; and 4) PZVgat neurons represent a key cell population for SWS induction and maintenance. PMID- 28722022 TI - Opioid Release after High-Intensity Interval Training in Healthy Human Subjects. AB - Central opioidergic mechanisms may modulate the positive effects of physical exercise such as mood elevation and stress reduction. How exercise intensity and concomitant effective changes affect central opioidergic responses is unknown. We studied the effects of acute physical exercise on the cerebral MU-opioid receptors (MOR) of 22 healthy recreationally active males using positron emission tomography (PET) and the MOR-selective radioligand [11C]carfentanil. MOR binding was measured in three conditions on separate days: after a 60-min aerobic moderate-intensity exercise session, after a high-intensity interval training (HIIT) session, and after rest. Mood was measured repeatedly throughout the experiment. HIIT significantly decreased MOR binding selectively in the frontolimbic regions involved in pain, reward, and emotional processing (thalamus, insula, orbitofrontal cortex, hippocampus, and anterior cingulate cortex). Decreased binding correlated with increased negative emotionality. Moderate-intensity exercise did not change MOR binding, although increased euphoria correlated with decreased receptor binding. These observations, consistent with endogenous opioid release, highlight the role of the MU-opioid system in mediating affective responses to high-intensity training as opposed to recreational moderate physical exercise. PMID- 28722023 TI - Potential Involvement of Impaired BKCa Channel Function in Sensory Defensiveness and Some Behavioral Disturbances Induced by Unfamiliar Environment in a Mouse Model of Fragile X Syndrome. AB - In fragile X syndrome (FXS), sensory hypersensitivity and impaired habituation is thought to result in attention overload and various behavioral abnormalities in reaction to the excessive and remanent salience of environment features that would normally be ignored. This phenomenon, termed sensory defensiveness, has been proposed as the potential cause of hyperactivity, hyperarousal, and negative reactions to changes in routine that are often deleterious for FXS patients. However, the lack of tools for manipulating sensory hypersensitivity has not allowed the experimental testing required to evaluate the relevance of this hypothesis. Recent work has shown that BMS-204352, a BKCa channel agonist, was efficient to reverse cortical hyperexcitability and related sensory hypersensitivity in the Fmr1-KO mouse model of FXS. In the present study, we report that exposing Fmr1-KO mice to novel or unfamiliar environments resulted in multiple behavioral perturbations, such as hyperactivity, impaired nest building and excessive grooming of the back. Reversing sensory hypersensitivity with the BKCa channel agonist BMS-204352 prevented these behavioral abnormalities in Fmr1 KO mice. These results are in support of the sensory defensiveness hypothesis, and confirm BKCa as a potentially relevant molecular target for the development of drug medication against FXS/ASD. PMID- 28722024 TI - Multifunctional nanoparticles as a tissue adhesive and an injectable marker for image-guided procedures. AB - Tissue adhesives have emerged as an alternative to sutures and staples for wound closure and reconnection of injured tissues after surgery or trauma. Owing to their convenience and effectiveness, these adhesives have received growing attention particularly in minimally invasive procedures. For safe and accurate applications, tissue adhesives should be detectable via clinical imaging modalities and be highly biocompatible for intracorporeal procedures. However, few adhesives meet all these requirements. Herein, we show that biocompatible tantalum oxide/silica core/shell nanoparticles (TSNs) exhibit not only high contrast effects for real-time imaging but also strong adhesive properties. Furthermore, the biocompatible TSNs cause much less cellular toxicity and less inflammation than a clinically used, imageable tissue adhesive (that is, a mixture of cyanoacrylate and Lipiodol). Because of their multifunctional imaging and adhesive property, the TSNs are successfully applied as a hemostatic adhesive for minimally invasive procedures and as an immobilized marker for image-guided procedures. PMID- 28722027 TI - Regulation of infection efficiency in a globally abundant marine Bacteriodetes virus. AB - This corrects the article DOI: 10.1038/ismej.2016.81. PMID- 28722025 TI - Nanopore long-read RNAseq reveals widespread transcriptional variation among the surface receptors of individual B cells. AB - Understanding gene regulation and function requires a genome-wide method capable of capturing both gene expression levels and isoform diversity at the single-cell level. Short-read RNAseq is limited in its ability to resolve complex isoforms because it fails to sequence full-length cDNA copies of RNA molecules. Here, we investigate whether RNAseq using the long-read single-molecule Oxford Nanopore MinION sequencer is able to identify and quantify complex isoforms without sacrificing accurate gene expression quantification. After benchmarking our approach, we analyse individual murine B1a cells using a custom multiplexing strategy. We identify thousands of unannotated transcription start and end sites, as well as hundreds of alternative splicing events in these B1a cells. We also identify hundreds of genes expressed across B1a cells that display multiple complex isoforms, including several B cell-specific surface receptors. Our results show that we can identify and quantify complex isoforms at the single cell level. PMID- 28722026 TI - Reconciling irrigated food production with environmental flows for Sustainable Development Goals implementation. AB - Safeguarding river ecosystems is a precondition for attaining the UN Sustainable Development Goals (SDGs) related to water and the environment, while rigid implementation of such policies may hamper achievement of food security. River ecosystems provide life-supporting functions that depend on maintaining environmental flow requirements (EFRs). Here we establish gridded process-based estimates of EFRs and their violation through human water withdrawals. Results indicate that 41% of current global irrigation water use (997 km3 per year) occurs at the expense of EFRs. If these volumes were to be reallocated to the ecosystems, half of globally irrigated cropland would face production losses of >=10%, with losses of ~20-30% of total country production especially in Central and South Asia. However, we explicitly show that improvement of irrigation practices can widely compensate for such losses on a sustainable basis. Integration with rainwater management can even achieve a 10% global net gain. Such management interventions are highlighted to act as a pivotal target in supporting the implementation of the ambitious and seemingly conflicting SDG agenda. PMID- 28722028 TI - Fat-free mass depletion in patients with COPD in Brazil: development of a new cutoff point and its relation with mortality and extrapulmonary manifestations. AB - BACKGROUND/OBJECTIVES: None of the cutoff points for fat-free mass index (FFMI) were tested for the Brazilian population, and it is unknown whether the available ones are able to discriminate extrapulmonary disease manifestations. This cross sectional study aims to develop and validate a cutoff point for FFM depletion based on Brazilian patients with chronic obstructive pulmonary disease (COPD) and to verify its association and of previously published cutoffs with extrapulmonary manifestations. SUBJECTS/METHODS: A new cutoff point was obtained from the best FFMI value for discrimination of preserved exercise capacity in a sample of patients (n=57). The discriminative capacity was assessed in another sample (n=96). The new cutoff point and other previously published ones were tested to discriminate low exercise capacity, physical inactivity, sedentary lifestyle and low quality of life. A receiver operation characteristics curve with area under the curve (AUC) value was plotted and each cutoff points' discriminative capacity was calculated. Cox regression and Kaplan-Meier method assessed the association between the cutoff points and mortality. RESULTS: The new cutoff points for FFMI were 14.65 kg/m2 for women (AUC=0.744; sensitivity (Se)=0.88; specificity (Sp)=0.60) and 20.35 kg/m2 for men (AUC=0.565; Se=0.36; Sp=0.81). The new cutoffs were the best to discriminate poor exercise capacity assessed by walked distance in % predicted and quality of life. Only the new cutoff point was associated with mortality (HR=2.123; 95% CI: 1.03-4.33, P=0.039, log rank P=0.035). CONCLUSIONS: Only the new cutoff point was associated with all-cause mortality, and it had the highest discriminating capacity for exercise capacity and quality of life in Brazilian patients with COPD. PMID- 28722029 TI - Effects of procedure, upright equilibrium time, sex and BMI on the precision of body fluid measurements using bioelectrical impedance analysis. AB - BACKGROUND/OBJECTIVES: Extensive work has addressed the validity of bioimpedance (BIA) measurements and the effect of posture on fluid homeostasis. However, limited research has investigated effects of subject preparation. This study aimed to determine the precision of total body water (TBW) and extracellular water (ECW) measurements using a stand-on multifrequency BIA (MFBIA seca mBCA 514/515), in three pre-test procedures: supine, sitting, and following walking, with specific reference to the influence of sex and body mass index (BMI). SUBJECTS/METHODS: Fifty three healthy, ambulatory men (n=26, age:32.5+/-9.4 years) and women (n=27, age:35.2+/-10.3 years) received repeat MFBIA measurements (six measurements from 0 to 15 min). Agreement and precision were evaluated for each condition and paired time points. RESULTS: Significant TBW sex differences from supine posture were observed for walking (females) and sitting (males) postures. For BMI (?24.9 kg m-2) significant TBW differences from supine were observed for both sitting and walking and significant ECW differences from sitting were also observed with both supine and walking. There was no significant effect of sex or BMI (?25.0 kg m-2) on ECW measures. Irrespective of sex or BMI, there was close agreement in TBW and ECW precision over the three protocols. CONCLUSIONS: Practitioners can have confidence in the precision of TBW and ECW measurements within a 15 min time period and pre-testing conditions (supine, sitting or walking) in healthy subjects, though must be cautious in assessments when pre-test postures change. Further research to examine the impact of pre testing procedures on stand-on MFBIA BIA measurements, including subjects with fluid disturbance, is warranted. PMID- 28722030 TI - Therapeutic lifestyle change diet enriched in legumes reduces oxidative stress in overweight type 2 diabetic patients: a crossover randomised clinical trial. AB - The objective of this study was to investigate whether a diet rich in legumes are associated with oxidative stress among type 2 diabetic patients. In a randomized, controlled, crossover clinical trial, 31 type 2 diabetic patients were randomly assigned to receive 2 diets, each for a period of 8 weeks: (1) The legume-free therapeutic lifestyle change (TLC) diet and (2) the legume-based TLC diet. Both diets were similar except that 2 servings of red meat were replaced by different types of legumes 3 days per week in the legume-based TLC diet. Oxidative stress biomarkers were measured at baseline and after 8 weeks. Compared to the legume free TLC diet, the legume-based TLC diet significantly decreased malondialdehyde (-0.22 versus -0.68 MUmol/l; P=0.002), oxidized-LDL (-0.9 versus -2.3 mU/l; P=0.05) and increased nitric oxide (0.40 versus 0.96 mM/l; P=0.03) and catalase activity (1.2 versus 2.1 Iu/ml; P=0.05). PMID- 28722031 TI - Reply to B.O. Anderson et al. PMID- 28722032 TI - Reply to M. Dhanushkodi. PMID- 28722033 TI - Cell-to-cell communication in cancer: workshop report. AB - Recent advances in cancer biology and the development of new research tools have enabled interrogations of single cells and cell-cell interactions. Emerging technologies are capable of revealing data on the physical characteristics of cells, differences in the genome and proteome between cancerous and healthy cells, and variations in distinct cell subpopulations. Dynamic measurements enable studies that can reveal the evolution of cell characteristics. Cells can also be assembled in vitro or ex vivo into two- and three-dimensional cell environments, allowing for studies of cell-cell interactions and cell signaling. The Memorial Sloan Kettering Cancer Center, in collaboration with the Breast Cancer Research Foundation and the National Cancer Institute, co-organized a workshop as an opportunity for leading researchers in their respective fields to present and discuss scientific research highlights relevant to the utilization of techniques and technologies for studying cell-to-cell communications in cancer. Avenues of future development and the potential for clinical utility were primary features of these discussions. The scientific presentations and extensive ensuing discussions resulted in the identification of a number of research opportunities, which are summarized in this report. PMID- 28722034 TI - Reply to S. Rastogi et al. PMID- 28722035 TI - Reply to M. Dhanushkodi. PMID- 28722036 TI - Quantitative probing of subtle interactions among H-bonds in alpha hydroxy carboxylic acid complexes. AB - Hydrogen (H) bonds are of fundamental importance in a wide range of molecular sciences. While the study of two-center H-bonding AH is well advanced, much remains to be learned in a quantitative and definitive manner for complexes with multiple H-bonds. Exemplary cases are in the category of alpha hydroxy carboxylic acids, i.e., the complexes of glycolic acid with water and formic acid. In glycolic acid, an intramolecular H-bond forms between the carboxyl group and the alpha OH group. The alpha OH stretching frequency may be affected upon complexing with water or formic acid. Direct study of glycolic acid complexes is unfortunately very difficult. However, an aromatic analogue, 9-hydroxy-9-fluorene carboxylic acid (9HFCA), permits detailed and accurate gas phase spectroscopic studies. Since computational analysis establishes that H-bonding is very similar from glycolic acid complexes to 9HFCA complexes, direct studies on 9HFCA complexes by laser spectroscopy also deduce new and subtle information for glycolic acid complexes in terms of molecular structures, binding strength, and collective effects of multiple H-bonds associated with anti-cooperativity and cooperativity. PMID- 28722037 TI - Magnetite hollow microspheres with a broad absorption bandwidth of 11.9 GHz: toward promising lightweight electromagnetic microwave absorption. AB - High-performance magnetite-based hollow spheres with the advantages of low density and low loading content are promising as an ideal lightweight electromagnetic (EM) wave absorption candidate. However, the effective preparation methods for these hollow spheres are still limited, and as a result, materials design and practical applications based on their size-dependent EM microwave attenuation properties are poorly accessible. In this study, high quality magnetite hollow spheres were successfully prepared by a simple, fast, one-step, and scalable plasma dynamic method with sole use of inexpensive precursors (oxygen and mild steel). The experimental results reveal that the as prepared products are hollowed multiple-component magnetite spheres and have a very wide size distribution with a diameter of several tens of nanometers to hundreds of micrometers, which can be further separated into three fractions with different particle size distributions (0-30 MUm, 30-100 MUm, and >100 MUm) by a simple magnetic separation method. The EM wave absorption results demonstrate that the hollow microspheres can exhibit excellent absorption ability with an effective absorption bandwidth (reflection loss <=-10 dB) of 11.9 GHz from 3.7 to 15.6 GHz for an only 2 mm thick test absorber (50 wt% filler) and a maximum RL value of -36 dB at ~8.2 GHz. Moreover, the positions of these resonant absorption peaks strongly depend on the sphere sizes and can be regulated at the L + C band, X band, and Ku band. Strikingly, differing from the nearly negligible microwave absorption for the ground powders, the dominating absorption mechanism for the hollow microspheres could be ascribed to the enhanced magnetic loss and multiple scattering due to the novel hollow magnetic structures, which are beneficial for the attenuation ability and improvements to their permeability and impedance matching. PMID- 28722038 TI - Promises, facts and challenges for graphene in biomedical applications. AB - The graphene family has captured the interest and the imagination of an increasing number of scientists working in different fields, ranging from composites to flexible electronics. In the area of biomedical applications, graphene is especially involved in drug delivery, biosensing and tissue engineering, with strong contributions to the whole nanomedicine area. Besides the interesting results obtained so far and the evident success, there are still many problems to solve, on the way to the manufacturing of biomedical devices, including the lack of standardization in the production of the graphene family members. Control of lateral size, aggregation state (single vs. few layers) and oxidation state (unmodified graphene vs. oxidized graphenes) is essential for the translation of this material into clinical assays. In this Tutorial Review we critically describe the latest developments of the graphene family materials into the biomedical field. We analyze graphene-based devices starting from graphene synthetic strategies, functionalization and processibility protocols up to the final in vitro and in vivo applications. We also address the toxicological impact and the limitations in translating graphene materials into advanced clinical tools. Finally, new trends and guidelines for future developments are presented. PMID- 28722039 TI - Correction: Conceptual design of tetraazaporphyrin- and subtetraazaporphyrin based functional nanocarbon materials: electronic structures, topologies, optical properties, and methane storage capacities. AB - Correction for 'Conceptual design of tetraazaporphyrin- and subtetraazaporphyrin based functional nanocarbon materials: electronic structures, topologies, optical properties, and methane storage capacities' by Rodion V. Belosludov et al., Phys. Chem. Chem. Phys., 2016, 18, 13503-13518. PMID- 28722040 TI - A new set of Cd(ii)-coordination polymers with mixed ligands of dicarboxylate and pyridyl substituted diaminotriazine: selective sorption towards CO2 and cationic dyes. AB - On the basis of a mixed ligand system of L(NH2)2 (6-(pyridin-4-yl)-1,3,5-triazine 2,4-diamine) and dicarboxylic acids, three new Cd(ii) coordination polymers viz. {[Cd0.5(tdc)0.5(L(NH2)2)0.5(H2O)].DMF.H2O}n (1), {[Cd0.5(bdc)0.5(L(NH2)2)(H2O)].DMF.H2O}n (2), and {[Cd(ipa)(L(NH2)2)(DMF)].H2O}n (3) (tdcH2 = thiophene-2,5-dicarboxylic acid, bdcH2 = benzene-1,4-dicarboxylic acid, ipaH2 = benzene-1,3-dicarboxylic acid) were synthesized under diverse reaction conditions and characterized by single crystal X-ray diffraction, PXRD, elemental analysis, IR spectroscopy and TGA. While 1 and 2 revealed 1D chain structures, 3 acquired a 2D square net structural arrangement. Gas adsorption measurements of the desolvated framework 3 showed a moderate uptake of CO2 under ambient conditions with good selectivity over N2 and CH4. The solid state luminescence properties were studied for all three coordination polymers. Moreover, a dye adsorption study on 3 exhibited selective adsorption towards a cationic dye. PMID- 28722041 TI - Ultrafast dynamics and solvent-dependent deactivation kinetics of BODIPY molecular rotors. AB - Molecular rotors based on meso-substituted boron-dipyrromethane (BODIPY) are widely recognized fluorescent viscosity sensors. The viscosity dependence of their fluorescence arises from an efficient excited-state deactivation process that can only occur when molecular-scale motion is not hindered. Here, we use visible and IR pump-probe spectroscopies combined with TD-DFT calculations to show that this fluorescence deactivation takes place through a fast and irreversible process which does not involve intermediate electronic states. Our data indicate that nonradiative excited-state deactivation of BODIPY molecular rotors is practically independent of solvent polarity, but strongly governed by viscoelastic/free volume properties of the local environment in both low- and high-viscosity regimes. PMID- 28722044 TI - Tripartite polyionic complex (PIC) micelles as non-viral vectors for mesenchymal stem cell siRNA transfection. AB - In the context of regenerative medicine, the use of RNA interference mechanisms has already proven its efficiency in targeting specific gene expression with the aim of enhancing, accelerating or, more generally, directing stem cell differentiation. However, achievement of good transfection levels requires the use of a gene vector. For in vivo applications, synthetic vectors are an interesting option to avoid possible issues associated with viral vectors (safety, production costs, etc.). Herein, we report on the design of tripartite polyionic complex micelles as original non-viral polymeric vectors suited for mesenchymal stem cell transfection with siRNA. Three micelle formulations were designed to exhibit pH-triggered disassembly in an acidic pH range comparable to that of endosomes. One formulation was selected as the most promising with the highest siRNA loading capacity while clearly maintaining pH-triggered disassembly properties. A thorough investigation of the internalization pathway of micelles into cells with tagged siRNA was made before showing an efficient inhibition of Runx2 expression in primary bone marrow-derived stem cells. This work evidenced PIC micelles as promising synthetic vectors that allow efficient MSC transfection and control over their behavior, from the perspective of their clinical use. PMID- 28722045 TI - 3D free-standing hierarchical CuCo2O4 nanowire cathodes for rechargeable lithium oxygen batteries. AB - A carbon and binder-free cathode for use in Li-O2 cells which is based on free standing CuCo2O4 nanowires supported on a nickel foam was synthesized by an efficient hydrothermal method. The resulting hierarchical porous and umbrella structures of the hybrid CuCo2O4@Ni foam cathodes present an excellent rate capability and cycle performance. PMID- 28722046 TI - Temperature and composition dependent phase transitions of lead-free piezoelectric (Bi0.5Na0.5)TiO3-BaTiO3 thin films. AB - Extensive studies on (Bi0.5Na0.5)TiO3-BaTiO3 piezoceramics have aroused growing interest in developing high-performance piezoelectric films based on this promising lead-free piezoelectric system. High quality (1 - x%) (Bi0.5Na0.5)TiO3 x% BaTiO3 (x = 0-15) thin films were synthesized on Pt(111)/Ti/SiO2/Si(100) substrates via a sol-gel method. The phase transitions as functions of composition and temperature were investigated by X-ray diffraction (XRD) and temperature-dependent Raman spectra analysis. A morphotropic phase boundary (MPB) located at 5 <= x <= 10 was found in the films, being identical to that in bulk materials. Additionally, complicated structural changes with temperature in a wide composition range were observed, which correspond to the evolution from a low-symmetry ferroelectric phase or a relaxor phase to high-symmetry relaxor phases. The ferroelectricity and piezoelectricity were also systematically studied with an emphasis on the influence of composition and phase structure. A phase diagram focusing on the above two kinds of phase transitions has been proposed in this work. PMID- 28722047 TI - The effect of Hofmeister anions on water structure at protein surfaces. AB - To understand the effects of specific ions on protein-water interactions and the thermodynamic stability of proteins in salt solutions, we use a molecular dynamics (MD) simulation to examine the water structure, orientational distribution, and dynamics near the surface of ubiquitin. In particular, we consider NaCl, NaBF4, NaSCN, and NaClO4 salt solutions containing ubiquitin, where the anions of the latter three salts are well-known chaotropic ions in the Hofmiester anion series. The number of hydrogen bonds (H-bonds) per water molecule is found to decrease significantly at the ubiquitin-water interface, indicating a significant disruption of the water H-bonding network. The distribution of the water H-bond numbers near the protein surface is modulated by dissolved ions, and the extent of the ion effect on the H-bonding network structure follows the order of the Hofmeister anion series, while there are no specific ion effects on water properties at distances larger than 5 A from the protein surface. From detailed analyses of the surface area, volume, and root mean-square deviation (RMSD) of ubiquitin, we show that changes in the properties of the protein could originate from the disruption of the water H-bond network induced by ions with a higher affinity for the protein surface instead of direct protein residue-ion interactions. An interesting observation made here is that the orientational distribution of water molecules at the protein-water interface is close to random, but there is a slight preference for interfacial water molecules with a straddle structure within 2.5 A of the protein surface, where one of the two OH groups points away from the protein surface and the other points toward the surface. In addition, comparing the MD simulation results for ubiquitin solutions with dissolved NaSCN and KSCN, we show that Na+ affects the water H-bonding structure at the protein surface more than K+. It is clear that the H-bonding network structure of water more than one water layer away from the protein surface is not distinguishably different from that of neat water. We thus anticipate that the present work will provide insights into the scale of specific ion effects on the H-bonding structure and orientational distribution of water in the vicinity of protein surfaces in aqueous solutions. PMID- 28722049 TI - Photochrome-doped organic films for photonic keypad locks and multi-state fluorescence. AB - The spectroscopic properties of poly(methyl methacrylate) polymer films doped with two kinds of photochromic molecular switches are investigated. A green fluorescent sulfonyl diarylethene (P1) is combined with either a non-fluorescent diarylethene (P2) or red-fluorescent spiropyran (P3). Photoswitching between the colorless and colored isomers (P1: o-BTFO4 <-> c-BTFO4, P2: o-DTE <-> c-DTE, P3: SP <-> MC) enables the P1 + P2 and P1 + P3 films to be cycled through three distinct states. From the initial state (o-BTFO4 + o-DTE/SP), irradiation with UV light generates the second state (c-BTFO4 + c-DTE/MC), where c-BTFO4 -> c-DTE/MC energy transfer is established. Irradiation with green light then generates the third state (c-BTFO4 + o-DTE/SP), where the energy transfer acceptor is no longer present. Finally, irradiation with blue light regenerates the initial state. For the P1 + P2 film, only one state is fluorescent, with the irradiation inputs required to be entered in the correct order to access this state, acting as a keypad lock. For the P1 + P3 film, the states emit either no fluorescence, red fluorescence, or green fluorescence, all using a common excitation wavelength. Additionally, once the fluorescence is activated with UV light, it undergoes a time-dependent color transition from red to green, due to the pairing of P-type and T-type photochromes. These multi-photochromic systems may be useful for security ink or imaging applications. PMID- 28722050 TI - Database and new models based on a group contribution method to predict the refractive index of ionic liquids. AB - Refractive index is one of the important physical properties, which is widely used in separation and purification. In this study, the refractive index data of ILs were collected to establish a comprehensive database, which included about 2138 pieces of data from 1996 to 2014. The Group Contribution-Artificial Neural Network (GC-ANN) model and Group Contribution (GC) method were employed to predict the refractive index of ILs at different temperatures from 283.15 K to 368.15 K. Average absolute relative deviations (AARD) of the GC-ANN model and the GC method were 0.179% and 0.628%, respectively. The results showed that a GC-ANN model provided an effective way to estimate the refractive index of ILs, whereas the GC method was simple and extensive. In summary, both of the models were accurate and efficient approaches for estimating refractive indices of ILs. PMID- 28722051 TI - Holographic microscope slide in a spatio-temporal imaging modality for reliable 3D cell counting. AB - In the current trend of miniaturization and simplification of imaging flow cytometry, Lab-on-a-Chip (LoC) microfluidic devices represent an innovative and cost-effective solution. In this framework, we propose for the first time a novel platform based on the compactness of a holographic microscope slide (HMS) in combination with the new computational features of space-time digital holography (STDH) that uses a 1D linear sensor array (LSA) instead of 2D CCD or CMOS cameras to respond to real diagnostic needs. In this LoC platform, computational methods, holography, and microfluidics are intertwined in order to provide an imaging system with a reduced amount of optical components and capability to achieve reliable cell counting even in the absence of very accurate flow control. STDH exploits the sample motion into the microfluidic channel to obtain an unlimited field-of-view along the flow direction, independent of the magnification factor. Furthermore, numerical refocusing typical of a holographic modality allows imaging and visualization of the entire volume of the channel, thus avoiding loss of information due to the limited depth of focus of standard microscopes. Consequently, we believe that this platform could open new perspectives for enhancing the throughput by 3D volumetric imaging. PMID- 28722054 TI - Structural complexity induced by topology change in hybrids consisting of hexa peri-hexabenzocoronene and polyhedral oligomeric silsesquioxane. AB - Organic-inorganic hybrids with hexa-peri-hexabenzocoronene (HBC) and polyhedral oligomeric silsesquioxane (POSS) were designed and synthesized. The increase of the POSS content (or a change in topology) results in more complex self-assembled structures. This work provides a new approach for the design and synthesis of materials with sub-10 nm sizes. PMID- 28722055 TI - The amyloid architecture provides a scaffold for enzyme-like catalysts. AB - Natural biological enzymes possess catalytic sites that are generally surrounded by a large three-dimensional scaffold. However, the proportion of the protein molecule that participates in the catalytic reaction is relatively small. The generation of artificial or miniature enzymes has long been a focus of research because enzyme mimetics can be produced with high activity at low cost. These enzymes aim to mimic the active sites without the additional architecture contributed by the protein chain. Previous work has shown that amyloidogenic peptides are able to self-assemble to create an active site that is capable of binding zinc and catalysing an esterase reaction. Here, we describe the structural characterisation of a set of designed peptides that form an amyloid like architecture and reveal that their capability to mimic carbonic anhydrase and serve as enzyme-like catalysts is related to their ability to self-assemble. These amyloid fibril structures can bind the metal ion Zn2+via a three dimensional arrangement of His residues created by the amyloid architecture. Our results suggest that the catalytic efficiency of amyloid-like assembly is not only zinc-dependent but also depends on an active centre created by the peptides which is, in turn, dependent on the ordered architecture. These fibrils have good esterase activity, and they may serve as good models for the evolution of modern day enzymes. Furthermore, they may be useful in designing self-assembling fibrils for applications as metal ion catalysts. This study also demonstrates that the ligands surrounding the catalytic site affect the affinity of the zinc-binding site to bind the substrate contributing to the enzymatic activity of the assembled peptides. PMID- 28722056 TI - Effects of atomic vacancies and temperature on the tensile properties of single walled MoS2 nanotubes. AB - Using molecular dynamics simulations, we study the effects of Mo and S atomic vacancies and different temperatures on the tensile properties of single-walled MoS2 nanotubes through a series of tensile tests. Both armchair and zigzag MoS2 nanotubes under uniaxial tensions show phase transitions. Two types of Mo-S bonds play different roles in this phase transition of MoS2 nanotubes. Moreover, the influences of Mo and S atomic vacancies and temperature on the Young's modulus, ultimate strength and fracture strain of single-walled MoS2 nanotubes are investigated systematically. The results show that Mo and S atomic vacancies have no influence on the Young's modulus of MoS2 nanotubes. However, Mo atomic vacancies result in a significant decrease of ultimate strength and fracture strain of MoS2 nanotubes, while S atomic vacancies have a relatively small influence on the fracture properties of MoS2 nanotubes. With an increase in temperature, the Young's modulus and ultimate strength decrease. When the temperature is higher than 300 K, the fracture is changed from brittle to ductile together with an enhanced fracture strain. PMID- 28722057 TI - Janus particles self-assembled from a small organic atypical asymmetric gemini surfactant. AB - A series of atypical asymmetric gemini surfactants with an amphiphilic carbonate group (-O-CO-O-) have been prepared. Some of these compounds could self-assemble in water into gourd-shaped Janus particles (JPs). Initial results suggested that the formation of JPs was highly likely to be related to their atypical gemini surfactant structure. To our knowledge, this is the first report on JPs that are self-assembled from a single kind of small organic molecule. We believe that our results will be utilized in many fields. PMID- 28722059 TI - Nanofluidics in two-dimensional layered materials: inspirations from nature. AB - With the advance of chemistry, materials science, and nanotechnology, significant progress has been achieved in the design and application of synthetic nanofluidic devices and materials, mimicking the gating, rectifying, and adaptive functions of biological ion channels. Fundamental physics and chemistry behind these novel transport phenomena on the nanoscale have been explored in depth on single-pore platforms. However, toward real-world applications, one major challenge is to extrapolate these single-pore devices into macroscopic materials. Recently, inspired partially by the layered microstructure of nacre, the material design and large-scale integration of artificial nanofluidic devices have stepped into a completely new stage, termed 2D nanofluidics. Unique advantages of the 2D layered materials have been found, such as facile and scalable fabrication, high flux, efficient chemical modification, tunable channel size, etc. These features enable wide applications in, for example, biomimetic ion transport manipulation, molecular sieving, water treatment, and nanofluidic energy conversion and storage. This review highlights the recent progress, current challenges, and future perspectives in this emerging research field of "2D nanofluidics", with emphasis on the thought of bio-inspiration. PMID- 28722058 TI - Activation of Nrf2/ARE signaling pathway attenuates lanthanum chloride induced injuries in primary rat astrocytes. AB - Lanthanum (La) exposure can lead to learning and memory disorder in animals; however, the underlying mechanism of La induced neurotoxicity is still unknown. It has been demonstrated that Nrf2 activation by tert-butylhydroquinone (tBHQ) results in neuroprotection against brain injuries. However, little study has been done with respect to its effect on La induced neurotoxicity. Herein, experiments are undertaken to determine if there is a correlation between La damaged astrocytes and the Nrf2/ARE signalling pathway. Primary rat astrocytes are exposed to 0 mmol L-1, 0.125 mmol L-1, 0.25 mmol L-1 and 0.5 mmol L-1 lanthanum chloride (LaCl3) for 24 hours. The results reveal that LaCl3 increases the apoptosis/necrosis rate of astrocytes, decreases the glutathione (GSH) content, increases reactive oxygen species (ROS) levels and significantly down-regulates Nrf2 as well as the mRNA and protein expression of Nrf2-regulated genes, including NADP(H): dehydrogenase quinone 1 (NQO1), hemeoxygenase-1 (HO-1), superoxide dismutase 2 (SOD2), glutathione peroxidase 1 (GSH-Px1), glutathione-s transferase (GST) and gamma-glutamine cysteine synthase (gamma-GCS) in astrocytes. In addition, it is found that tBHQ displays an antagonistic effect on astrocytes damaged by LaCl3. Therefore, La damaged astrocytes are possibly related to the down-regulated Nrf2/ARE pathway, and treatment with tBHQ clearly activates the Nrf2/ARE signalling pathway, which exerts protection against oxidative stress. PMID- 28722060 TI - Poly(amino acid)-polyester graft copolymer nanoparticles for the acid-mediated release of doxorubicin. AB - Biodegradable polymers have emerged as highly effective drug delivery vehicles. We combine N-carboxyanhydride and O-carboxyanhydride ring opening polymerisations to synthesise a poly(amino acid)-polyester graft copolymer capable of encapsulating, and subsequently releasing doxorubicin via acid-mediated hydrolysis. Consequently, the nanoparticles detailed are extremely promising vehicles for the controlled delivery of chemotherapeutic agents. PMID- 28722061 TI - Bromide-assisted catalytic oxidation of lead(ii) solids by chlorine in drinking water distribution systems. AB - This study investigated the effect of bromide on the oxidation of three lead(ii) solids by chlorine - a redox process critical to the control of lead release in drinking water distribution systems. Bromide had a strong catalytic effect on the oxidation of lead(ii) carbonate solids, but had a limited impact on the oxidation of lead(ii) phosphate. PMID- 28722064 TI - Effect of alkyl branches on the thermal stability of quaternary ammonium cations in organic electrolytes for electrochemical double layer capacitors. AB - Quaternary ammoniums are cations having widespread use in organic electrolytes for high performance electrochemical double layer capacitors (EDLCs) due to their various advantages such as high electrochemical stability and inexpensive production cost. However, the decomposition of quaternary ammoniums via Hofmann elimination hinders their applications for EDLCs operating at elevated temperatures. This study systematically investigates the reactivity of four different quaternary ammoniums (tetraethyl-, triethylmethyl-, diethyldimethyl-, and trimethylethyl-ammonium) in EDLC by utilizing density functional theory calculations and Brownian dynamics simulations complemented with molecular dynamics simulations. It is found that ammonium stability reduces upon increasing the number of ethyl branches that have a stronger positive charge than the methyl groups. However, the contribution of the entropy change to the reaction free energy makes trimethylethylammonium less stable than diethyldimethylammonium at room temperature although the former has less ethyl branches than the latter. Trimethylethylammonium becomes the most stable at a high temperature of 488 K above which the activation free energy becomes effectively negligible and thus the number of reactive sites determines the overall stability. The fundamental understanding of the ammonium decompositions through Hofmann elimination demonstrated in this study is expected to contribute to developing new long-life organic electrolyte systems for high-temperature applications. PMID- 28722066 TI - Synthesis of rare-earth-metal-in-cryptand dications, [Ln(2.2.2-cryptand)]2+, from Sm2+, Eu2+, and Yb2+ silyl metallocenes (C5H4SiMe3)2Ln(THF)2. AB - Cp'2Ln(THF)2 metallocenes (Cp' = C5H4SiMe3) react with 2.2.2-cryptand (crypt) to form Ln2+-in-crypt complexes, [Ln(crypt)(THF)][Cp'3Ln]2 (Ln = Sm, Eu) and [Yb(crypt)][Cp'3Yb]2, that contain Ln2+ ions surrounded only by neutral ligands. A bimetallic, mixed-ligand metallocene/opened-crypt complex of Sm2+, [Sm(C16H32N2O6-kappa2O:kappa2O')SmCp''2], was obtained by KC8 reduction of Cp''2Sm(THF) [Cp'' = C5H3(SiMe3)2] in the presence of crypt. PMID- 28722068 TI - Photoluminescence quantum yield exceeding 80% in low dimensional perovskite thin films via passivation control. AB - Quasi-2D perovskites with the BA : MA molar ratio equal to 3 : 3 show a remarkable PLQY exceeding 80%, thanks to the use of an electron donor as the passivating agent. These films have been applied in LEDs that exhibit high brightness exceeding 1000 cd m-2 and current efficiencies >3 cd A-1. PMID- 28722071 TI - Reversible switching of a supramolecular morphology driven by an amphiphilic bistable [2]rotaxane. AB - An acid/base responsive amphiphilic [2]rotaxane switch containing a hydrophilic macrocycle component and a hydrophobic terminal bulky group was prepared and characterized. The morphology of the supramolecular assemblies formed by the rotaxanes could be switched between spherical vesicles and worm-like micelles using acid/base stimuli, as confirmed by transmission electron microscopy (TEM). PMID- 28722072 TI - Highly efficient Cr2O72- removal of a 3D metal-organic framework fabricated by tandem single-crystal to single-crystal transformations from a 1D coordination array. AB - The single-crystal to single-crystal (SC-SC) transformation from a 1D coordination chain to a 3D coordination network, which is triggered by both solvent and anion exchanges, has been revealed to suffer from a tandem mechanism as proved by isolation of the intermediate state. The resulting porous crystalline material shows a high efficiency for the capture of dichromates (207 mg g-1) via the SC-SC anion-exchange. PMID- 28722073 TI - Bimolecular-induced hierarchical nanoporous LiTi2(PO4)3/C with superior high-rate and cycling performance. AB - We employed a facile bimolecular (glucose and DMEA) assisted hydrothermal reaction and a solid-state reaction to obtain carbon-coated hierarchical LiTi2(PO4)3 on a large scale. The nanoporous material exhibits excellent high rate and cycling performance owing to enhanced electronic conductivity from the ultrathin carbon layer, Ti3+ and the shortened path for Li+ diffusion by nanoporous frameworks. PMID- 28722074 TI - Supramolecular semifluorinated dendrons glued by weak hydrogen-bonds. AB - H-Bonded semifluorinated dendritic polymer networks are generated by association of macromolecules, driven by the weak diaminopyridine (DAP) and thymine (THY) couple. Solvent-dependent morphologies are observed: a continuous film structure when drop-cast from tetrahydrofuran (THF) solution or uniform nanoparticles with a diameter of ~50 nm in toluene. PMID- 28722075 TI - A new route for the synthesis of a Ag nanopore-inlay-nanogap structure: integrated Ag-core@graphene-shell@Ag-jacket nanoparticles for high-efficiency SERS detection. AB - We present a new route for the synthesis of Ag nanopore-inlay-nanogap structures using creviced graphene-shell encapsulated Cu nanoparticles (Cu@G-NPs) as the sacrificial templates. The as-synthesized integrated Ag-core@graphene-shell@Ag jacket nanoparticles (AgC@G@AgJ-NPs) presents "chrysanthemum" shapes that contain abundant sub-10 nm size intraparticle nanopores/nanogaps, which can generate huge enhanced electromagnetic fields to support SERS activity, resulting in an average EF > 107 due to a high-density of intraparticle and interparticle "hot spots". PMID- 28722076 TI - The anomalous halogen bonding interactions between chlorine and bromine with water in clathrate hydrates. AB - Clathrate hydrate phases of Cl2 and Br2 guest molecules have been known for about 200 years. The crystal structure of these phases was recently re-determined with high accuracy by single crystal X-ray diffraction. In these structures, the water oxygen-halogen atom distances are determined to be shorter than the sum of the van der Waals radii, which indicates the action of some type of non-covalent interaction between the dihalogens and water molecules. Given that in the hydrate phases both lone pairs of each water oxygen atom are engaged in hydrogen bonding with other water molecules of the lattice, the nature of the oxygen-halogen interactions may not be the standard halogen bonds characterized recently in the solid state materials and enzyme-substrate compounds. The nature of the halogen water interactions for the Cl2 and Br2 molecules in two isolated clathrate hydrate cages has recently been studied with ab initio calculations and Natural Bond Order analysis (Ochoa-Resendiz et al. J. Chem. Phys. 2016, 145, 161104). Here we present the results of ab initio calculations and natural localized molecular orbital analysis for Cl2 and Br2 guests in all cage types observed in the cubic structure I and tetragonal structure I clathrate hydrates to characterize the orbital interactions between the dihalogen guests and water. Calculations with isolated cages and cages with one shell of coordinating molecules are considered. The computational analysis is used to understand the nature of the halogen bonding in these materials and to interpret the guest positions in the hydrate cages obtained from the X-ray crystal structures. PMID- 28722077 TI - Invasive haemodynamic evaluation of the pulmonary circulation in pulmonary hypertension. AB - The term pulmonary hypertension refers to a serious condition characterised by high pulmonary vascular pressure, mainly as a consequence of various cardiac and respiratory diseases. Current clinical classification of pulmonary hypertension considers five distinct groups. Transthoracic echocardiography represents the first and most important noninvasive screening tool for estimating the probability of pulmonary hypertension. The diagnostic approach to pulmonary hypertension is supported by a proposed algorithm, which identifies the underlying cause. The definitive diagnosis and classification of pulmonary hypertension requires invasive confirmation of an elevated pulmonary artery mean pressure during a right heart catheterisation at rest. Pulmonary artery wedge pressure assessment has a pivotal role in differentiating precapillary from postcapillary pulmonary hypertension. The correct acquisition and interpretation of invasive pulmonary haemodynamic variables play a central role, not only in confirming the diagnosis but also in prognostication and treatment decision making. During right heart catheterisation correct zero levelling of the external pressure transducer and pressure tracing readings at end-expiration should be assured. Obese patients and patients with obstructive lung diseases require special attention, given that spontaneous positive end-expiratory intrathoracic pressures are frequently observed. Because pressure and flow determinations with a fluid-filled flow-directed thermodilution catheter are potentially insufficiently precise, it is recommended to average at least three measurements. Acute vasoreactivity testing is indicated only in selected patients. Recent data suggest that invasive pulmonary haemodynamic measurement during exercise may be more sensitive than resting haemodynamics for early diagnosis, for treatment response assessment and for prognostic purposes. PMID- 28722078 TI - True prevalence of COPD and its association with peripheral arterial disease in the internal medicine ward of a tertiary care hospital. AB - OBJECTIVES: The primary objective was to determine the prevalence of confirmed chronic obstructive pulmonary disease (COPD) in patients aged 45 years or more who were admitted to the internal medicine ward of our tertiary care hospital (HFR Fribourg, Switzerland), and were either "tagged" as having COPD or at risk for COPD. The secondary objective was to determine the prevalence of the association of COPD with peripheral artery disease (PAD) in this population. METHODOLOGY: We evaluated all consecutive patients aged ?45 years, admitted to our internal medicine ward between November 2013 and March 2014. All patients with a diagnosis of COPD, chronic bronchitis and/or lung emphysema in their electronic medical record ("tagged" as COPD) were evaluated for inclusion, as well as patients with at least one classic symptom and one classic risk factor for COPD identified by them on a check-list (patients at risk for COPD). Spirometry, and measurement of ankle-brachial index (ABI) and toe-brachial index when necessary, were performed in each patient once they were clinically stable. RESULTS: One hundred and seventy-two of 888 consecutive patients were included. COPD was found in 81 patients. Amongst the 75 patients tagged as COPD, 65 (87%) were actually suffering from COPD and 10 (13%) carried a false diagnosis. COPD was diagnosed in 16 (16%) of the 97 at-risk patients. PAD was identified in 35 (43%) of patients suffering from confirmed COPD and in 22 (24%) of patients without COPD. There was a significant association between COPD and PAD (p <0.01). CONCLUSION: COPD was identified in 9% of the 888 patients evaluated. The majority of patients tagged as COPD were accurately diagnosed and a substantial proportion of at-risk patients were underdiagnosed. A significant association between COPD and PAD was found. In smokers, spirometry showing COPD is a useful test to detect patients at higher cardiovascular risk. Thus, we suggest that screening for PAD using an ABI should be proposed to every smoker with confirmed COPD. PMID- 28722079 TI - Physicians' experience with follow-up care of childhood cancer survivors - challenges and needs. AB - BACKGROUND: Regular follow-up care is essential for childhood cancer survivors, but we know little about physicians' experience with it. We aimed to describe: (1) involvement of Swiss physicians in follow-up care; (2) content of follow-up care provided; (3) problems encountered; and (4) additional resources needed. MATERIALS AND METHODS: Within this cross-sectional survey we sent adapted questionnaires via professional associations to a sample of medical oncologists (MOs), paediatric oncologists (POs), general practitioners (GPs) and paediatricians (P) in Switzerland. Only oncologists involved in follow-up care were asked to report problems. GPs and Ps not involved in follow-up could indicate why. All physicians were asked about the content of follow-up care provided and additional resources needed. RESULTS: A total of 183 physicians responded (27 MO, 13 PO, 122 GP, 21 P). Involved in follow-up were 81% of MOs, 85% of POs, 39% of GPs and 81% of Ps. Follow-up content differed between oncologists (MO and PO) and generalists (GP and P), with generalists examining or informing less in regard to the former cancer. POs reported more problems than MOs: many POs reported problems with transition of survivors to adult care (91%), and because of financial resources (73%) and time restraints (73%). MOs reported most problems during transition (23%). Not being aware of a survivor was the most common reason for GPs and Ps not participating in follow-up (74%). All groups reported a need for standardised protocols (85-91%) and specialised training (55 73%). GPs (94%) and Ps (100%) additionally desired more support from oncologists. CONCLUSIONS: To improve quality and efficiency of follow-up care a national follow-up care model including standardised protocols and guidelines needs to be developed. PMID- 28722080 TI - [A surgery-oriented classification in conversion therapy of gastric cancer]. AB - Clinical practice showed that some advanced gastric cancer (AGC) patients achieved long-term survival after surgery, whereas some benefited from non surgical treatment. In recent years, with the emergence of new drugs, diversity of treatment and development of multi-disciplinary team, the concept of conversion therapy comes into attention. Owing to diverse phenotypes with scattered cases, publications are mainly case reports or small sample studies from single centers, which makes it hard to acquire high-level evidence. On illustrating the definitions of AGC and conversion therapy, as well as integrating peritoneal metastasis, liver metastasis, No.16 lymph nodes metastasis, cytology positive and organs infiltration (T4b), we tried to classify AGC as resectable IIII( and unresectable IIII(. Resectable IIII( refers to lesions that could be resected as R0 evaluated by present diagnostic modalities, conditions of patients and therapeutic management, in which it is further classified as low-risk and high-risk subtypes, according to operation risk. If R0 is not achieved with the evaluation as above, it is classified as unresectable IIII(, in which it is further classified as conversed, partly conversed and non conversed types after systemic therapy. For AGC patients with unresectable IIII(, operation must be performed more carefully, and the making of treatment protocols, the judge of operational time and the choice of operation procedure should be based on multi-disciplinary team. Such classification is aimed to facilitate clinical application and launch clinical trials, better to explore the characteristics of AGC. PMID- 28722081 TI - [Quality control of radical lymphadenectomy for gastric cancer]. AB - D2 lymphadenectomy is currently the worldwide standard operation for locally advanced gastric cancer. There were no major modifications for extent of standard lymphadenectomy in Japanese gastric cancer treatment guidelines 2014(ver.4). Prophylactic para-arotic lymphadenectomy is not recommended. Although there is no high level evidence, D2+No14v may be beneficial to patients who are suspected to harbor metastasis to No6 node, and D2+No13 lymphadenectomy may be an option in a potentially curative gastrectomy for tumors invading the duodenum. According to the finial results of JCOG1001, bursectomy is not recommended as a standard procedure for cT3/4 gastric cancer. Incidence of gastric cancer is quite high in China while overall operation level of gastric cancer is unequal. How to ensure the quality of radical gastrectomy is a recently important topic meanwhile the lymphadenectomy extent should be standard. Operational quantity per year in hospital and surgeons is considered as the final factors for the quality of radical gastrectomy. Centralization of gastric cancer surgery may be needed for the improvement of gastric cancer care in China. Education and training for the specialist are imperative for good outcomes of gastric cancer surgery. Ex vivo dissection for lymph nodes is effective method of precise staging and individual adjuvant treatment for gastric cancer patients. PMID- 28722082 TI - [Surgical treatment for metastatic gastric cancer]. AB - The incidence of metastatic gastric cancer (MGC) is high and the prognosis is poor with 5-year survival rarely exceeding 5%. Systemic chemotherapy is the cornerstone for MGC in current treatment guidelines. Recent studies have revealed both reduction surgery and conversion surgery can improve patient's prognosis, indicating the value of surgical treatment in MGC. Based on the present therapeutic strategy, we discuss the indication, extent and timing of surgery for MGC. Our conclusions are as followings: the treatment of gastric cancer is chemotherapy-based, target-included and surgery-combined multidisciplinary therapy; patients with single non-curable factor are most likely to benefit from surgery-combined multidisciplinary therapy; the optimal timing for surgery depends on the response to chemotherapy; it is worthwhile to explore the conversion therapy combining target therapy and chemotherapy; the resection of metastasis lesion can be managed according to Japanese guideline; in order to establish high-level evidence, it is necessary to unite experts from different disciplines to conduct clinical trial according to the category of metastasis of gastric cancer. PMID- 28722083 TI - [A perception of the development trend of radiological T staging in gastric cancer through UICC/AJCC 8th edition]. AB - More and more emphases were put on pre-therapy staging following the promotion of multidisciplinary team(MDT) collaboration and individualized medicine in gastric cancer. However, the accuracy of traditional radiology staging system which applies mechanically pathological staging is not satisfactory during clinical practice, therefore, the objectivity of treatment decisions is affected. Under such conditions, the newly introduced staging system from Union for International Cancer Control/American Joint Committee on Cancer(UICC/AJCC)(8th edition) divided out an independent cTNM system for the first time, and summarized the application range, operation specification and staging criteria. Although there are still no unified CT signs for staging, the 8th edition staging system has pointed out the directions for future clinical studies and provides new opportunities for radiology. The recent studies published on issue of cT staging are summarized in this article, including the discrimination of T1 cancer on the basis of peptic ulcers, the cross-sectional location of serosal exposure in bare areas, new rule for cancer at esophagogastric junction and the effect of cT4b change on iconography evaluation. The future prospect of radiomics in T staging of gastric cancer is also discussed. PMID- 28722084 TI - [Postoperative complications after rectal cancer surgery and management]. AB - Although neoadjuvant treatment such as radiotherapy, even chemoradiotherapy has already widely used in middle-low rectal cancer, surgery remains the mainstay of therapy for patients with rectal cancer. Because neoadjuvant chemoradiotherapy combined with surgery was adopted for the locally advanced rectal cancer as a standard treatment based on guidelines, postoperative complications of rectal cancer surgery caused surgeons attention and concern gradually. Some severe complications should seriously affect patient's quality of life, even patient's survival. Therefore, surgeons should be fully aware of the severity of complications, and try to avoid the occurrence of complications. Thoroughly knowing the significance of comprehensive treatment in rectal cancer, meanwhile, realizing associated complications following rectal cancer operation, and choosing reasonable, standard, effective and economic management will result in obvious increase of therapeutic level in rectal cancer surgery in China. Through the literature review combined with our clinical experience, this paper analyzes the reasons of seven associated complications, including intra-operational bleeding, bladder damage, postoperative anastomotic leakage, rectovaginal fistula, postoperative bleeding, postoperative ileus, postoperative anastomotic stenosis and anterior resection syndrome, and shares the managements in order to provide more references to surgeons. PMID- 28722085 TI - [Anatomical planes and landmarks of transanal total mesorectal excision for rectal cancer and prophylaxis of intraoperative complications]. AB - Total mesorectal excision (TME) is a mile-stone procedure in the history of rectal cancer surgery, but the exposure of surgical field of distal rectum is usually poor in patients with male, obese and narrow pelvis, which may lead to tumor residue and relative complications. Recently, a new technique called transanal TME (taTME) is considered to solve the above problems, but most medical centers are still in the learning curve of this procedure. Therefore, anatomical planes and landmarks of taTME for rectal cancer and prophylaxis of intraoperative complications are induced in this paper, which includes posterior plane: angle of anus and distal mesorectum and bleeding of mesorectum; rectosacral fascia and presacral bleeding; lateral and posterior-lateral plane: posterior branches of pelvic plexus and damage of anal function; anterior plane: vessel branches of neurovascular bundle and bleeding. Familiarity with the specific anatomical planes and landmarks plays an important role in shortening the learning curve, decreasing the complications, increasing the success rate of operation and standardization of taTME. PMID- 28722086 TI - [Current surgical strategy of locally recurrent rectal cancer]. AB - The incidence of locally recurrent rectal cancer (LRRC) is less than 10% following treatment for primary rectal cancer, while LRRC usually has serious symptoms and a very low survival rate when lack of treatment. For further efficacy improvement of LRRC operation, recent research topics include preoperative precise evaluation, correct decision, reasonable individual treatment by multidisciplinary collaboration. Surgery remains the only option for potential cure. Studies show R0 resection is the most important prognostic factor. Peking University First Hospital proposes a new classification of LRRC: Pelvic cavity is divided into right pelvic wall, left pelvic wall and posterior sacrococcyx. LRRC is classified as F0 to F3 according to invasion quantity in pelvic wall or sacrococcyx. This classification is more suitable for clinical practice. Though determining the LRRC location by CT, MRI and PET, scientific classification evaluation and correct choice of proper patients using F classification to fix the extent of pelvic wall can effectively elevate the R0 resection rate, and at the same time, can avoid ineffectual high-risk re operation. This article also investigates the efficacy of comprehensive treatment based on preoperative neoadjuvant therapy, intra-operative radiotherapy and re radiotherapy, in order to provide the guidance for the institution of reasonable and scientific treatment strategy in clinic. PMID- 28722087 TI - [Standardized diagnosis and treatment of colorectal liver metastasis]. AB - Colorectal cancer is one of the most common malignancies. The liver is the most common site of distant metastasis, and liver metastasis is the leading cause of death in the patients with colorectal cancer. In recent years, the concept of diagnosis and treatment in colorectal liver metastasis (CLM) and the liver surgery techniques developed rapidly, the standardization of clinical practice elevated obviously, and the survival outcomes of more and more patients were significantly improved. Standardization of diagnosis and treatment in CLM comprised overall assessment of patients' condition and local tumor status based on multidisciplinary team collaboration and then institution of treatment strategy. Standardization of CLM diagnosis should be carried out by abdominal enhancement CT, or liver ultrasound to evaluate the hepatic metastasis. As for suspected CLM, serum AFP and liver MRI are recommended. When resectability is assessed, both surgery techniques (procedures, liver preservation, and resectable lesions outside of liver) and oncology items (synchronism, heterochronism, invasion and progression) must be considered. Due to complicated illness and different prognosis, CLM patients should be carefully classified to receive associated treatment. For CLM patients with resectable or potentially resectable lesions, the aim of treatment is to increase the R0 resection rate and survival. For those with unresectable lesions, the aim is to improve tumor-associated symptoms and maintain the quality of life. PMID- 28722088 TI - [Evaluation of new minimally invasive techniques in gastrointestinal surgery and contemplation on health economics]. AB - With the widespread introduction of minimally invasive surgery (MIS) in late 1987 by laparoscopic cholecystectomy, the practice and expectation of general surgery were changed forever. As the development of scientific technology, new techniques of MIS have sprung up all around the world. 3D laparoscopy surgery, natural orifice transluminal endoscopic surgery, da Vinci surgical system and other new technologies also need time to be verified, and this is the only way all new things should get though. They are very unique in their own right, and all have advantages and disadvantages. None of them is the best, but all of them can be the most suitable technology for a single patient, so we should keep an open mind instead of judging too much. At the same time we should be cautious, but do not exaggerate the advantages and obscure the drawbacks. Identifying the indications and the contraindications is the only way we can benefit the patients. In the pursuit of MIS ideas, as a surgeon, we should rely on advanced medical concepts, technology and equipment, under the premise of being beneficial to the patients, innovating in the norms, practicing in the innovation, seeking the truth in the practice, and moving on forever. In this chapter, author illustrates the history of MIS, evaluates some new gastrointestinal MIS techniques from various angles and makes some discussions on health economics, on purpose to offer some new understandings of new gastrointestinal MIS techniques, eventually benefiting the patients. PMID- 28722089 TI - [How to carry out high quality clinical trial]. AB - Evidence-based medicine derived from large-scale clinical trials has been widely accepted by clinicians, which strongly motivates the clinicians in medical institutions to conduct or participate in clinical trials. However, how to improve the clinical trial quality and management to achieve worldwide acceptance still remains challenging. By analyzing the difficulties faced by the majority of large Chinese clinical institutions and the opportunities during the evolvement of research modes, this paper proposes to improve the quality of clinical trial by closely following the domain development, raising clinical research thinking, ensuring rigorous research design, standardizing the steps and details of each operational session, as well as establishing a collaborative and well communicated team. So far there is limited data support in therapeutic standards and guidelines in China. We have systematically designed and rigorously operated the research program based on the actual situation, whereby we have derived a set of high-quality disease guidelines that are adapted to the national disease characteristics in China. PMID- 28722090 TI - [Evaluation of a new closure technique of large defects after endoscopic full thickness resection]. AB - OBJECTIVE: To investigate the security and efficacy of a new endoscopic closure method of large defects after endoscopic full-thickness resection (EFTR) double purse-string suture using two endoloops and metallic clips via single-channel endoscopy. METHODS: Clinical data of 23 cases with submucosal tumors (SMT) who received endoscopic resection from June 2015 to July 2016 in our National Cancer Center were collected. For gastric and esophageal SMTs or the mucosa layer injured during submucosal tunneling endoscopic resection (STER), double purse string suture was conducted after EFTR. The key steps of closure were as follows: the endoloop was installed onto the delivery system and inserted into the gastric cavity to the defect location with endoscopy and then opened; the clips were transported into the gastric cavity from the biopsy channel; the endoloop was fixed onto the full thickness of gastric wall along the edge of the defect by clips one by one between the interval of about 5 mm; the endoloop was tightened slowly till the entire circumference of the defect was sutured, thus, one purse string suture was done; in accordance with the operation above, another endoloop was released, and the second endoloop was fixed at 5-10 mm to the outer edge of the original one, and tied the endoloop gently; this sequence was continued till there was no gap, thus, the double-purse string suture was finished. A total of 23 patients were enrolled in the study, including 18 with gastric tumor and 5 with esophageal tumor, 15 males and 8 females, with the average age of 56 (19 to 76) years. RESULTS: Eighteen cases of gastric SMT were successfully treated by endoscopic EFTR and double purse-string suture. The esophageal mucosa layer of all the 5 cases of esophageal SMT, including tumors of 3 cases located in cervical esophagus at 15-20 cm from the fore-tooth, 1 esophageal leiomyoma case complicated with squamous cell carcinoma in situ, and 1 case of mucosal layer injury during submucosal tunneling endoscopic resection (STER), was successfully repaired by using double purse-string suture. The mean maximum diameter of tumor was 2.3 cm, and the average suture time was 22.8 min. Postoperative pathology showed that 13 cases were gastrointestinal stromal tumors (GIST), 7 cases were leiomyoma, 2 cases were neurilemmoma, and 1 case was leiomyoma complicated with early squamous cell carcinoma in situ. No severe complications occurred during or after the operation. CONCLUSIONS: The double purse-string suture by using metallic clips and endoloops with single channel endoscope is a relatively safe, easy, and reliable technique for repairing large gastric defect after EFTR. For cervical esophageal SMT, or the SMT combined with superficial mucosal lesions, and for the mucosa layer injury during submucosal tunneling endoscopic resection(STER), double purse-string suture is helpful to perform the closure. PMID- 28722091 TI - [Analysis of lymph node metastasis pattern in gastric cancer patients at stage pN1]. AB - OBJECTIVE: To investigate the lymph node metastasis pattern in pN1 stage gastric cancer patients and to analyze its risk factors. METHODS: Clinicopathological data of 219 patients who underwent radical gastrectomy and were confirmed as pN1 stage gastric cancer between January 2013 and March 2016 were reviewed. All the patients underwent D2 or extended D2(D2+) lymphadenectomy. The overall metastatic rate was calculated. The risk factors associated with lymph node metastasis were analyzed. The pattern of skip lymph node metastasis and clinicopathological factors related to skip metastasis were analyzed. RESULTS: Among 219 patients, 119 patients had only one metastatic lymph node, and 100 patients had two metastatic lymph nodes. The relatively higher sites of lymph node metastasis were station No.3[29.2%(64/219)], No.6[18.3%(40/219)] and No.4[11.4%(25/219)]. Compared to patients with tumor diameter <=5 cm, metastatic rates of station No.3[39.4% (39/99) vs. 20.8%(25/120), P=0.003], No.4[16.2%(16/99) vs. 7.5%(9/120), P=0.045] and No.8[16.2%(16/99) vs. 6.7%(8/120), P=0.025] were significantly higher in those with tumor diameter >5 cm. Skip lymph node metastasis was detected in 56 cases(25.6%) and skip lymph node metastatic rate was significantly higher in patients with tumor diameter >5 cm [34.3%(34/99) vs. 18.3%(22/120), P=0.007]. Logistic regression analysis showed that the tumor size was an independent risk factor for the skip lymph node metastasis in pN1 stage gastric cancer (OR=1.982, 95%CI: 0.978 to 3.921, P=0.033). CONCLUSIONS: The perigastric station No1 lymph node is the main site of early lymph node metastasis of pN1 stage gastric cancer. General pattern of lymph node metastasis is from proximus to distance, while quite a lot of skip lymph node metastases are observed. Tumor size is an important factor affecting the lymph node metastasis and bigger tumor may result in skip lymph node metastasis easily. PMID- 28722092 TI - [Predictive factors of intestinal necrosis in acute mesenteric vascular occlusive diseases]. AB - OBJECTIVE: To explore the predictive factors of intestinal necrosis in acute mesenteric vascular occlusive diseases and its significance for the timing of exploratory laparotomy. METHODS: This retrospective study enrolled 63 patients diagnosed as acute mesenteric vascular occlusive diseases at Peking University People's Hospital between July 1995 and June 2015. Univariate analysis and multivariate logistic regression analysis were used to identify predictive factors for intestinal necrosis. RESULTS: Of 63 patients, 39 were male and 24 were female, with a mean age of (58.8+/-12.7)(31 to 82) years. The overall rate of intestinal necrosis was 46.0%(29/63). Patients with intestinal necrosis had a poorer prognosis than those who did not develop intestinal necrosis (chi2=5.908, P=0.015). In univariate analysis, the predictive factors of intestinal necrosis were systemic inflammatory reactive syndrome (SIRS) (chi2=18.535, P=0.000), shock (chi2=7.775, P=0.007), peritoneal irritation sign (chi2=11.533, P=0.001), changes of intestinal wall and blood signals on ultrasound or CT scans (chi2=14.344, P=0.000), international normalized ratio(INR) (prothrombin time) >=1.2 (chi2=4.498, P=0.034), D-dimer >=1 000 g/L(chi2=6.680, P=0.010), low-density lipoprotein >=270 U/L (chi2=6.513, P=0.011), serum albumin <35 g/L (chi2=3.914, P=0.048), blood urea nitrogen >=6.2 mmol/L (chi2=11.377, P=0.000), pH values <7.35 (chi2=15.887, P=0.000), blood lactate >=2 mmol/L(chi2=17.134, P=0.000), base excess <-1.0 mmol/L (chi2=6.674, P=0.010). According to multivariate logistic regression analysis, SIRS(OR=28.945, 95%CI:2.294 to 365.199, P=0.009), pH values <7.35(OR=13.174, 95%CI:1.157 to 150.027, P=0.038), changes of intestinal wall and blood signals on ultrasound or CT scans(OR=4.857, 95%CI:1.110 to 21.253, P=0.036) were independent predictive factors of intestinal necrosis in patients with acute mesenteric vascular occlusive diseases. CONCLUSIONS: Intestinal necrosis in acute mesenteric vascular occlusive diseases prompts a poor prognosis. When patients with acute mesenteric vascular occlusive diseases are found to have acidosis, SIRS and changes of intestinal wall and blood signals on ultrasound or CT scans, surgeons should be alert to the occurrence of intestinal necrosis and should perform laparotomy promptly in order to take suitable management. PMID- 28722093 TI - [A multicenter, randomized controlled trial of wheat cellulose particles in the treatment of internal hemorrhoids]. AB - OBJECTIVE: To evaluate the efficacy and safety of wheat cellulose particles (testa triticum tricum purify, Fiberform) in the treatment of internal hemorrhoid. METHODS: A multicenter randomized controlled clinical trial was adopted. From October 2015 to July 2016, 60 patients with internal hemorrhoid were enrolled from three medical centers, including Department of Anorectum, Shuguang Hospital of Shanghai University of Traditional Chinese Medicine, Department of Anorectum, The Third Affiliated Hospital of Nanjing University of Chinese Medicine, Department of Anorectum, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine. Enrollment criteria: Patients aging from 18 to 65 years old; being diagnosed with the second or third grade internal hemorrhoid; having good communication skills and being able to complete the records and follow-ups according to the research program requirements. EXCLUSION CRITERIA: Patients combined with other anal diseases, or whose anus tube or rectum suffering occupying lesions; patients currently using other methods and defecation drugs in the treatment of their hemorrhoids; patients in pregnancy or with diseases of heart, liver, kidney or metabolic disorders; patients suffering from constipation due to other diseases and drugs, and long-term laxatives abusers. According to the random number table method, 60 patients were randomly divided into the combined treatment group [30 cases, wheat cellulose particles 1 bag each time, 2 times per day; Diosmin tablet 2 pills, 2 times per day] and the single treatment group [30 cases, Diosmin tablet 2 pills, 2 times per day]. The treatment courses for both groups were 7 days. According to the four-grade scoring method, the efficacy evaluation would be made on six indicators, which were the degree of hematochezia or bleeding, the degree of pain, hemorrhoid prolapse, the shapes and properties of stool, the defecation frequency and the defecation duration. The higher the score a participant got, the more severe the symptom was. The effectiveness was evaluated by the scoring reduction rate, and marked effectiveness and effectiveness were both found to be effective. Incidence of adverse events was compared between two groups before the treatment, and on postoperative 3-day and 7-day respectively. RESULTS: There were no significant differences between two groups in gender, age, internal hemorrhoids gradings, disease course, and onset time as well as the baseline data, such as the degree of hematochezia or bleeding before the treatment, the degree of pain, hemorrhoid prolapse, the shapes and properties of stool, the defecation frequency and the defecation duration (all P>0.05). After the seven-day treatment, there was significant difference in effective rate between combination group and single group [96.7%(29/30) vs. 66.7%(20/30), Z=-4.376, P=0.000]. Meanwhile, the scores of combined group and single group in hematochezia or bleeding were 0(0, 1) and 0(0, 2) (Z=9.241, P=0.002); in shapes and properties of stool were 0(0, 1) and 0(0, 1) (Z=5.364, P=0.021); in defecation frequency were 0(0, 1) and 0(0, 2) (Z=7.552, P=0.006); and in defecation duration were 0(0, 1) and 0(0, 2) (Z=4.425, P=0.035), whose differences were all significant. The scores of pain degree and hemorrhoid prolapse of two groups also decreased, but the difference was not statistically significant (P>0.05). During the treatment, abdominal pain, diarrhea and other adverse reactions were not observed in participants of two groups. CONCLUSION: Combination therapy of wheat cellulose particles (testa triticum tricum purify, Fiberform) can significantly improve the efficacy of internal hemorrhoid with safety and tolerance. PMID- 28722094 TI - [Detection and clinical significance of myeloid-derived suppressor cells in peripheral blood of patients with rectal carcinoma]. AB - OBJECTIVE: To study the expression of myeloid-derived suppressor cells (MDSC) in peripheral blood of patients with rectal carcinoma and to preliminarily explore its clinical significance. METHODS: Blood samples from 76 rectal carcinoma patients who underwent surgery in Department of General Surgery, The Affiliated Cancer Hospital, Zhengzhou University between June and October 2013 were collected before operation, postoperative day 10 and 2 years after operation respectively. Flow cytometry was used to detect MDSC percentage in peripheral blood of 76 rectal carcinoma patients and 40 healthy people. The change of MDSC percentage in peripheral blood of rectal carcinoma patients after treatment was investigated. Furthermore, the relationship of peripheral blood MDSC percentage with clinicopathological characteristics was examined. RESULTS: Preoperative MDSC percentage in peripheral blood of 76 rectal carcinoma patients [(3.52+/-0.68)%] was higher than that of 40 healthy people[(0.92+/-0.21)%], with significant difference (t=3.026, P=0.005). Preoperative MDSC percentage in peripheral blood of rectal carcinoma patients was significantly related with histological classification (t=2.453, P=0.018), depth of tumor invasion (t=2.051, P=0.035), lymph node metastasis (t=2.328, P=0.022), TNM stage (t=2.529, P=0.016). Univariate analysis showed that TNM stage, histological classification, lymph node metastasis, preoperative MDSC percentage in peripheral blood were the prognostic factors in rectal carcinoma. Multivariate analysis showed that TNM stage (HR=2.535, 95%CI: 0.851 to 4.160, P=0.038) and preoperative MDSC percentage in peripheral blood (HR=3.651, 95%CI: 0.877 to 14.263, P=0.031) were independent prognostic factors of rectal carcinoma. MDSC percentage in peripheral blood of rectal carcinoma patients decreased significantly on the postoperative 10-day [(2.41+/-0.46)%] compared to that before operation [(3.52+/-0.68)%], whose difference was statistically significant (t=1.778, P=0.043). During follow-up, tumor recurrence or metastasis was found in 23 patients. MDSC percentage in peripheral blood of rectal carcinoma patients with recurrence or metastasis [(4.37+/-1.23)%] was higher than that of rectal carcinoma patients without recurrence or metastasis [(2.36+/-0.35)%] two years after operation, with statistically significant difference (t=1.982, P=0.039). CONCLUSIONS: MDSC percentage in peripheral blood of rectal carcinoma patients is significantly elevated compared to that of healthy people. Increased MDSC percentage indicates poor prognosis and tumor progression in rectal carcinoma patients. Measurement of peripheral blood MDSC percentage may have a potential clinical value in prognosis prediction of rectal carcinoma. PMID- 28722095 TI - [Correlation of MRI apparent diffusion coeffcient with molecular marker Ki-67 in gastric cancer]. AB - OBJECTIVES: To study the correlation between MRI apparent diffusion coefficient (ADC) and expression of Ki-67 in gastric cancers, and to investigate the application of ADC value in diagnosing the malignance of gastric cancer. METHODS: A retrospective cohort analysis was performed on 87 gastric cancer patients who received MRI examination and radical resection at Zhejiang Provincial Hospital of Traditional Chinese Medicine from November 2014 to August 2015. All the postoperative resected samples were confirmed as gastric cancer. Preoperative MRI examination was performed by using Siemens 3.0-T Verio MRI with following parameters: section thickness 3 mm, gap 1 mm, matrix 182*320, field of view 40 cm. Plain scan was followed by T1-weighted fat suppression technique VIBE 3D(TR3.92/TE1.39,90degree) scans at arterial phase (the 30th second), portal venous phase (the 60th second), lag period (the 90th second), axial planes and coronal planes (the 180th second), and sagittal planes (the 210th second), respectively. ADC value of tumor was measured at b-factor of 800 s/mm2 and ADC map was generated from DWI data on the work station. The expression of Ki-67 in cancer tissue was detected by routine immunohistochemical (SP) staining after surgery. Correlation between ADC value and the expression of Ki-67 in gastric cancer was analyzed. RESULTS: Irregular thickening of the gastric wall and inhomogeneous enhancement of the tumor after injection of the contrast material appeared in gastric cancer. Gastric cancer tissue presented hyperintensity and normal gastric wall presented isointensity in DWI image (b=800 s/mm2). Compared with normal gastric tissue, mean ADC value of gastric cancer tissue was significant lower [(1.114+/-0.265)*10-3 mm2/s vs. (2.032+/-0.202)*10-3 mm2/s, t=26.209, P=0.000]. The ADC values of high-middle differentiation group, middle low differentiation group, low differentiation group and signet ring cell carcinoma/mucinous adenocarcinoma group were (1.347+/-0.234)*10-3 mm2/s, (1.179+/ 0.257)*10-3 mm2/s, (0.996+/-0.185)*10-3 mm2/s and (1.082+/-0.230)*10-3 mm2/s, respectively. The difference of mean ADC value among different tumor stages was significant(F=8.498, P=0.000). Along with the Ki-67 expression up-regulated, the ADC value decreased in cancer tissue. The Ki-67 expressions in cancer tissue was negatively correlated with cancer ADC values (r=-0.570, P=0.000). Furthermore, negative correlations of Ki-67 expressions with ADC values of high-middle differentiation group (r=-0.627, P=0.016), low differentiation group (r=-0.787, P=0.000) and signet ring cell carcinoma/mucinous adenocarcinoma group (r=-0.792, P=0.000) were observed respectively, while Ki-67 expression was not correlated with ADC value of middle-low differentiation group. CONCLUSION: The ADC value of gastric cancer can reflect the level of tumor differentiation, and is negatively correlated with Ki-67 expression in cancer tissues. PMID- 28722096 TI - [Neoadjuvant chemoradiotherapy combined with operation vs. operation alone for resectable esophageal cancer: Meta-analysis on randomized controlled trials]. AB - OBJECTIVE: To compare the treatment outcomes of neoadjuvant chemoradiotherapy (NCRT) combined with operation and operation alone for esophageal cancer. METHODS: Randomized controlled trials(RCTs), comparing the treatment outcomes of NCRT combined with operation to operation alone for esophageal cancer, published from January 1990 to December 2015 were searched from PubMed, Web of Science, and other English-language databases. STATA 10.0 software was used to analyze short term efficacy (R0 resection rate, positive lymph node ratio, postoperative complications and mortality) and long-term outcomes (overall survival rate and local recurrence rate). The publication bias was evaluated by funnel plot and Egger test. RESULTS: A total of 12 RCTs, including 1 872 esophageal cancer patients, were included in the meta-analysis, with 939 cases in NCRT combined with operation group and 943 cases in operation alone group. Meta-analysis of short-term efficacy showed that, as compared to operation alone group, NCRT combined with operation group had higher R0 resection rate (RR=1.19, 95%CI:1.08 to 1.32, P=0.015), lower positive lymph node rate (RR=0.55, 95%CI:0.49 to 0.63, P=0.001), but higher postoperative mortality (RR=1.63, 95%CI:1.09 to 2.45, P=0.018). Postoperative complications were similar between the two groups(RR=1.04, 95%CI:0.91 to 1.18, P=0.558). Meta-analysis of long-term outcomes showed that, as compared to operation alone group, NCRT combined with operation group had lower local recurrence rate (RR=0.50, 95%CI:0.39 to 0.64, P=0.000), and higher overall survival rate (HR=0.75, 95%CI:0.66 to 0.84, P=0.001). Subgroup analysis according to pathological types showed that both squamous cell carcinoma and adenocarcinoma patients in NCRT combined with operation group had higher overall survival rates compared to those in operation alone group (HR=0.80, 95%CI:0.69 to 0.93, P=0.003; HR=0.78, 95%CI:0.70 to 0.88, P=0.003). CONCLUSIONS: NCRT can decrease the staging of esophageal cancer, elevate the R0 resection rate, and ameliorate local recurrence without increasing postoperative complications. Meanwhile NCRT can improve overall survival of esophageal cancer patients even with squamous cell carcinoma and adenocarcinoma. PMID- 28722097 TI - [Research progress of the association of hydrogen sulfide with colorectal cancer and its associated anti-tumor drugs]. AB - As the third confirmed gaseous transmitters, hydrogen sulfide was found to play a vital role in the eternal milieu both physiologically and pathologically. What's intriguing is that, there exists a debate about the role of hydrogen sulfide in the pathogenesis of cancer, especially colorectal cancer. In this manuscript, progress of the effect of low and high dose hydrogen sulfide on the tumorigenesis of colorectal cancer and research on the antitumor new drugs stemmed from the function of hydrogen sulfide is summarized. Recently, the "bell-shape" model of the action of hydrogen sulfide illustrated that hydrogen sulfide was able to promote the progression of tumor in low dose and inhibit the progression of tumor in high dose. Based on these results, both hydrogen sulfide synthesis inhibitors and hydrogen sulfide donors(chimeras with NSAIDs) have been widely studied as potential anti-tumor novel drugs. According to the actual results of present studies, hydrogen sulfide synthesis inhibitors featured by aminooxyacetic acid (AOA) is more promising as a novel kind of drug. The future research based on the relationship between hydrogen sulfide and rectal cancer may bring insights into the development of novel anti-tumor drugs, thus producing tremendous potential clinical value. PMID- 28722098 TI - [What Does Personalized Medicine and Personalized Mental Health Mean for Psychotherapy and Psychotherapy Research? - Or: Why Psychotherapy Research Should and Can be Expanded in Germany (Part 3)]. PMID- 28722099 TI - [Results of a Representative Survey on the Psychosocial Evaluation Before Living Donor Kidney Transplantation in Germany]. AB - Aim Since there is no consensus about how to perform the predonation psychosocial evaluation of living kidney donor candidates, this is conducted differently in German transplant centers. Thus, the goal of the study was to learn more about how psychosocial evaluations are currently conducted in German transplant centers. Methods The psychosocial evaluators of the 38 transplant centers performing kidney transplantations in 2015 were contacted and asked to participate in an anonymous online survey. Results Psychosocial evaluators from 28 (75%) transplant centers responded. In only 30 (4%) of the evaluations contraindications for donation were reported. In most centers the psychosocial evaluation was performed after the completion of all medical tests. The evaluations were realized after only short waiting periods and were reported to be time-consuming. Financial reimbursement was mainly realized by internal cost allocation. In most centers the evaluators used semi-structured interviews. Still, there was limited consensus about structure and content of the psychosocial evaluation. Conclusion Standardization of the psychosocial evaluation process could be helpful to enable comparisons between transplant centers and to achieve equal opportunities for the potential living kidney donors and recipients. PMID- 28722100 TI - [Tailored Care for Functional Vertigo/Dizziness - An Integrative Group Psychotherapy Approach]. AB - Functional vertigo and dizziness (VD) symptoms are highly prevalent and usually accompanied by a strong impairment of quality in everyday and working life. The complaints are often associated with various psychiatric disorders, particularly phobic and other anxiety disorders, depressive or somatoform disorders. Despite this clinical relevance of VD symptoms, studies towards psychotherapeutic treatment options for patients with functional VD are still rare. Thus, the present study outlines a manual for outpatient group therapy for patients with functional VD symptoms. Our approach aims to assist patients in developing an understanding of the interaction between bodily complaints and psychosocial factors while detracting from a purely symptom based focus. The integrative psychotherapeutic treatment program consists of 16 weekly sessions and includes a regular vestibular rehabilitation training as well as disorder-oriented modules towards anxiety and panic disorder, depression, and somatisation. We are currently conducting a randomised controlled trial in order to evaluate the short and long-term effectiveness of the program in reducing VD and further bodily symptoms, vertigo-related social and physical handicap as well as anxiety and depressive complaints. A previously completed pilot trial has led to small to large pre-follow-up-effects on primary and secondary outcome measures. Conclusions regarding acceptance and feasibility of the therapy concept are discussed. PMID- 28722101 TI - [Gilles de la Tourette Syndrome: Symptoms, Causes and Therapy]. AB - Gilles de la Tourette syndrome is a chronic neuropsychiatric movement disease with combined motor tics and at least one vocal tic for a minimum period of 1 year. It typically begins in the childhood (under 18 years of age).Most of the patients with Tourette syndrome have comorbidities, which often impair their quality of life more than the tics themselves.There are reported abnormalities in the cortico-striato-thalamo-cortical regions as well as in the neurotransmission of dopamine and other neurotransmission systems. Genetic and non genetic factors are discussed.In each patient psychoeducation is the basis of treatment. Specific treatment is only needed in more severe tic disorders which cause evident psychosocial impairment.Behavior therapy should be tried before drug treatment. For very severely affected adults, deep brain stimulation is a further treatment option. PMID- 28722102 TI - Expression of CD34 and CD146 vascular markers contributes to the immunological function of the human palatine tonsil. AB - The fundamental function of the palatine tonsil is the immune response to airborne and foodborne pathogenic agents. Small blood vessels have an important role in the provision of a special microenvironment in which the immune response occurs. In this study, we investigated the expression of vascular markers CD34 and CD146 and basal lamina marker - type IV collagen - in the small blood vessels of the human palatine tonsil in the context of their role in the immunological function of the tonsil. The tonsils were collected after tonsillectomy from ten patients with chronic tonsillitis, aged 18-28 years. Five-um-thick paraffin sections were routinely stained with haematoxylin and eosin, while the studied markers (CD34, CD146 and type IV collagen) were detected immunohistochemically using LSAB2/HRP method. CD34 was expressed equally in the capillaries within and below the crypt epithelium, in lymphoid follicles and in high endothelial venules localized para- and interfollicularly. CD146 molecule was expressed on the luminal surface of endothelial cells in the capillaries of the crypt epithelium, while its expression in high endothelial venules was seen on the luminal and lateral surfaces of the cuboidal endothelial cells. In contrast to the basal lamina of intraepithelial capillaries, where collagen IV-immunopositivity is mostly seen as a continuing line, the basal lamina of high endothelial venules was seen as a two- or three-layered structure beneath the cuboidal endothelial cells. The specifics of expression of CD34, CD146, and type IV collagen confirm the morphofunctional specialization of endothelium in crypt epithelium capillaries, and also in endothelium of high endothelial venules, which is directly associated with the role of these vessels in the immune function of the tonsil. PMID- 28722103 TI - Decreased levels of active uPA and KLK8 assessed by [111 In]MICA-401 binding correlate with the seizure burden in an animal model of temporal lobe epilepsy. AB - OBJECTIVE: Urokinase-type plasminogen activator (uPA) and kallikrein-related peptidase 8 (KLK8) are serine proteases that contribute to extracellular matrix (ECM) remodeling after brain injury. They can be labelled with the novel radiotracer [111 In]MICA-401. As the first step in exploring the applicability of [111 In]MICA-401 in tracing the mechanisms of postinjury ECM reorganization in vivo, we performed in vitro and ex vivo studies, assessing [111 In]MICA-401 distribution in the brain in two animal models: kainic acid-induced status epilepticus (KASE) and controlled cortical impact (CCI)-induced traumatic brain injury (TBI). METHODS: In the KASE model, in vitro autoradiography with [111 In]MICA-401 was performed at 7 days and 12 weeks post-SE. To assess seizure burden, rats were monitored using video-electroencephalography (EEG) for 1 month before the 12-week time point. In the CCI model, in vitro autoradiography was performed at 4 days and ex vivo autoradiography at 7 days post-TBI. RESULTS: At 7 days post-SE, in vitro autoradiography revealed significantly decreased [111 In]MICA-401 binding in hippocampal CA3 subfield and extrahippocampal temporal lobe (ETL). In the chronic phase, when animals had developed spontaneous seizures, specific binding was decreased in CA3 and CA1/CA2 subfields of hippocampus, dentate gyrus, ETL, and parietal cortex. Of interest, KASE rats with the highest frequency of seizures had the lowest hippocampal [111 In]MICA-401 binding (r = -0.76, p <= 0.05). Similarly, at 4 days post-TBI, in vitro [111 In]MICA-401 binding was significantly decreased in medial and lateral perilesional cortex and ipsilateral dentate gyrus. Ex vivo autoradiography at 7 days post-TBI, however, revealed increased tracer uptake in perilesional cortex and hippocampus, which was likely related to tracer leakage due to blood-brain barrier (BBB) disruption. SIGNIFICANCE: Strong association of reduced [111 In]MICA-401 binding with seizure burden in the KASE model suggests that analysis of reduced levels of active uPA/KLK8 represents a novel biomarker candidate to be explored as a biomarker for epilepsy severity. However, limited BBB permeability of [111 In]MICA-401 currently limits its application in vivo. PMID- 28722104 TI - The double edge to parasite escape: invasive host is less infected but more infectable. AB - Nonnative species that escape their native-range parasites may benefit not only from reduced infection pathology, but also from relaxed selection on costly immune defenses, promoting reallocation of resources toward growth or reproduction. However, benefits accruing from a reduction in defense could come at the cost of increased infection susceptibility. We conducted common garden studies of the shore crab Hemigrapsus sanguineus from highly parasitized native (Japan) populations and largely parasite-free invasive (USA) populations to test for differences in susceptibility to infection by native-range rhizocephalan parasites, and to explore differences in host resource allocation. Nonnative individuals showed at least 1.8 times greater susceptibility to infection than their native counterparts, and had reduced standing metabolic rates, suggesting that less of their energy was spent on physiological self-maintenance. Our results support an indirect advantage to parasite escape via the relaxation of costly physiological defenses. However, this advantage comes at the cost of heightened susceptibility, a trade-off of parasite escape that is seldom considered. PMID- 28722105 TI - Hepatic CXCL16 is increased in gallstone accompanied with liver injury. AB - BACKGROUND AND AIMS: This study aimed to investigate the relationship between circulating soluble C-X-C chemokine ligand 16 (CXCL16) levels and clinical characteristics of gallstone. METHODS: 93 subjects including 53 subjects with gallstone, 25 subjects with nonalcoholic fatty liver disease (NAFLD), and 40 control subjects were recruited. All gallstone subjects underwent ultrasounds to confirm the gallstone patients. Serum CXCL16 levels and other clinical and biochemical parameters in all subjects were obtained based on standard clinical examination methods. Liver tissues from patients with gallstone undergoing cholecystotomy and healthy subjects were also used to determine the hepatic CXCL16 profiles by IHC staining and real-time quantitative PCR. RESULTS: Serum CXCL16 levels were significantly increased in patients with gallstone and NAFLD as compared to healthy controls (P < 0.001). Hepatic CXCL16 mRNA and protein levels were also significantly increased in gallstone patients following with elevation of hepatic triglycerides and free fatty acid concentration, as compared to those in healthy subjects (P < 0.001). Otherwise, serum CXCL16 levels positively correlated with nonalcoholic fatty liver disease (NAFLD), alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma glutamyl transpeptidase (GGT) and direct bilirubin (P < 0.05), but negatively with total protein and albumin after adjustment with age and gender. Multiple stepwise regression analyses indicated that CXCL16 was independently associated with AST, NAFLD and albumin (P < 0.05, respectively). CONCLUSIONS: Serum CXCL16 levels are significantly increased in patients with gallstone, and are independently associated with liver injury in Chinese population, suggesting that CXCL16 may be a biomarker of liver injury in subjects with gallstone or NAFLD. PMID- 28722106 TI - Anti-inflammatory effects of exercise: role in diabetes and cardiovascular disease. AB - BACKGROUND: Persistent inflammation is involved in the pathogenesis of chronic diseases such as type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). AIMS: The aim of this review was to provide the reader with an update of the mechanisms whereby exercise-induced cytokines may impact cardiometabolic diseases. RESULTS: Evidence exists that interleukin (IL)-1beta is involved in pancreatic beta-cell damage, whereas TNF-alpha is a key molecule in peripheral insulin resistance. In addition, TNF-alpha appears to be involved in the pathogenesis of atherosclerosis and heart failure. A marked increase in IL-6 and IL-10 is provoked by exercise and exerts direct anti-inflammatory effects by an inhibition of TNF-alpha and by stimulating IL-1ra, thereby limiting IL-1beta signalling. Moreover, muscle-derived IL-6 appears to have direct anti inflammatory effects and serves as a mechanism to improve glucose tolerance. In addition, indirect anti-inflammatory effects of long-term exercise are mediated via improvements in body composition. CONCLUSION: Physical activity represents a natural, strong anti-inflammatory strategy with minor side effects and should be integrated in the management of patients with cardiometabolic diseases. PMID- 28722107 TI - The peritoneum: healing, immunity, and diseases. AB - The peritoneum defines a confined microenvironment, which is stable under normal conditions, but is exposed to the damaging effect of infections, surgical injuries, and other neoplastic and non-neoplastic events. Its response to damage includes the recruitment, proliferation, and activation of a variety of haematopoietic and stromal cells. In physiological conditions, effective responses to injuries are organized; inflammatory triggers are eliminated; inflammation quickly abates; and the normal tissue architecture is restored. However, if inflammatory triggers are not cleared, fibrosis or scarring occurs and impaired tissue function ultimately leads to organ failure. Autoimmune serositis is characterized by the persistence of self-antigens and a relapsing clinical pattern. Peritoneal carcinomatosis and endometriosis are characterized by the persistence of cancer cells or ectopic endometrial cells in the peritoneal cavity. Some of the molecular signals orchestrating the recruitment of inflammatory cells in the peritoneum have been identified in the last few years. Alternative activation of peritoneal macrophages was shown to guide angiogenesis and fibrosis, and could represent a novel target for molecular intervention. This review summarizes current knowledge of the alterations to the immune response in the peritoneal environment, highlighting the ambiguous role played by persistently activated reparative macrophages in the pathogenesis of common human diseases. Copyright (c) 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 28722108 TI - The ubiquitin ligase SCFFBXW7alpha promotes GATA3 degradation. AB - GATA3 is a key transcription factor in cell fate determination and its dysregulation has been implicated in various types of malignancies. However, how the abundance and function of GATA3 are regulated remains unclear. Here, we report that GATA3 is physically associated with FBXW7alpha, and FBXW7alpha destabilizes GATA3 through assembly of a SKP1-CUL1-F-box E3 ligase complex. Importantly, we showed that FBXW7alpha promotes GATA3 ubiquitination and degradation in a GSK3 dependent manner. Furthermore, we demonstrated that FBXW7alpha inhibits breast cancer cells survival through destabilizing GATA3, and the expression level of FBXW7alpha is negatively correlated with that of GATA3 in breast cancer samples. This study indicated that FBXW7alpha is a critical negative regulator of GATA3 and revealed a pathway for the maintenance of GATA3 abundance in breast cancer cells. PMID- 28722109 TI - Genomic signatures of pancreatic adenosquamous carcinoma (PASC). AB - In pancreatic cancer, pancreatic adenosquamous carcinoma (PASC) containing both ductal adenocarcinoma and squamous carcinoma in the same tumour represents ~4% of the total incidence. To date, the genomic features of this mixed tumour are still unknown. We analysed the genomes of 17 PASCs and 34 pancreatic ductal adenocarcinomas (PDACs), and showed that PASC carried highly enriched TP53 mutations and 3p loss as compared with PDAC. We also showed that adenomatous and squamous components of PASC harboured comparable genomic alterations, suggesting that the two cellular components develop from the same progenitor cancer cells. Our study has updated genomic knowledge to help with understanding mixed cancers of the pancreas. Copyright (c) 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 28722110 TI - Renal-infiltrating CD11c+ cells are pathogenic in murine lupus nephritis through promoting CD4+ T cell responses. AB - Lupus nephritis (LN) is a major manifestation of systemic lupus erythematosus (SLE), causing morbidity and mortality in 40-60% of SLE patients. The pathogenic mechanisms of LN are not completely understood. Recent studies have demonstrated the presence of various immune cell populations in lupus nephritic kidneys of both SLE patients and lupus-prone mice. These cells may play important pathogenic or regulatory roles in situ to promote or sustain LN. Here, using lupus-prone mouse models, we showed the pathogenic role of a kidney-infiltrating CD11c+ myeloid cell population in LN. These CD11c+ cells accumulated in the kidneys of lupus-prone mice as LN progressed. Surface markers of this population suggest their dendritic cell identity and differentiation from lymphocyte antigen 6 complex (Ly6C)low mature monocytes. The cytokine/chemokine profile of these renal infiltrating CD11c+ cells suggests their roles in promoting LN, which was confirmed further in a loss-of-function in-vivo study by using an antibody-drug conjugate (ADC) strategy targeting CX3 CR1, a chemokine receptor expressed highly on these CD11c+ cells. However, CX3 CR1 was dispensable for the homing of CD11c+ cells into lupus nephritic kidneys. Finally, we found that these CD11c+ cells co localized with infiltrating T cells in the kidney. Using an ex- vivo co-culture system, we showed that renal-infiltrating CD11c+ cells promoted the survival, proliferation and interferon-gamma production of renal-infiltrating CD4+ T cells, suggesting a T cell-dependent mechanism by which these CD11c+ cells promote LN. Together, our results identify a pathogenic kidney-infiltrating CD11c+ cell population promoting LN progression, which could be a new therapeutic target for the treatment of LN. PMID- 28722112 TI - In silico and in vitro prediction of gastrointestinal absorption from potential drug eremantholide C. AB - OBJECTIVES: Analysis of the biopharmaceutical properties of eremantholide C, sesquiterpene lactone with proven pharmacological activity and low toxicity, is required to evaluate its potential to become a drug. METHODS: Preliminary analysis of the physicochemical characteristics of eremantholide C was performed in silico. Equilibrium solubility was evaluated using the shake-flask method, at 37.0 degrees C, 100 rpm during 72 h in biorelevant media. The permeability was analysed using parallel artificial membrane permeability assay, at 37.0 degrees C, 50 rpm for 5 h. The donor compartment was composed of an eremantholide C solution in intestinal fluid simulated without enzymes, while the acceptor compartment consisted of phosphate buffer. KEY FINDINGS: Physicochemical characteristics predicted in silico indicated that eremantholide C has a low solubility and high permeability. In-vitro data of eremantholide C showed low solubility, with values for the dose/solubility ratio (ml): 9448.82, 10 389.61 e 15 000.00 for buffers acetate (pH 4.5), intestinal fluid simulated without enzymes (pH 6.8) and phosphate (pH 7.4), respectively. Also, it showed high permeability, with effective permeability of 30.4 * 10-6 cm/s, a higher result compared with propranolol hydrochloride (9.23 * 10-6 cm/s). CONCLUSIONS: The high permeability combined with its solubility, pharmacological activity and low toxicity demonstrate the importance of eremantholide C as a potential drug candidate. PMID- 28722111 TI - Monoamine oxidase A is highly expressed in classical Hodgkin lymphoma. AB - Monoamine oxidase A (MAOA) is a mitochondrial enzyme that catalyzes oxidative deamination of neurotransmitters and dietary amines and produces H2 O2 . It facilitates the progression of gliomas and prostate cancer, but its expression and functional relevance have not been studied in lymphoma. Here, we evaluated MAOA in 427 cases of Hodgkin and non-Hodgkin lymphoma and in a spectrum of reactive lymphoid tissues by immunohistochemistry on formalin-fixed, paraffin embedded specimens. MAOA was expressed by Hodgkin Reed-Sternberg (HRS) cells in the majority of classical Hodgkin lymphomas (cHLs) (181/241; 75%), with 34.8% showing strong expression. Weak MAOA was also noted in a minority of primary mediastinal large B-cell lymphomas (8/47; 17%) and in a mediastinal gray-zone lymphoma. In contrast, no MAOA was found in non-neoplastic lymphoid tissues, nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL; 0/8) or any other non Hodgkin lymphomas studied (0/123). MAOA was more common in Epstein-Barr virus (EBV)-negative compared to EBV-positive cHL (p < 0.0001) and was especially prevalent in the EBV-negative nodular sclerosing subtype. Similar to primary human lymphoma specimens, most cHL-derived cell lines displayed MAOA activity, whereas non-Hodgkin-lymphoma-derived cell lines did not. The MAOA inhibitor clorgyline reduced the growth of L1236 cells and U-HO1 cells, and shRNA knockdown of MAOA reduced the growth of L1236 cells. Conversely, ectopic overexpression of MAOA increased the growth of MAOA-negative HDLM2 cells. Combined treatment with clorgyline and ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) was more effective in reducing cell growth than either regimen alone. In summary, MAOA is highly expressed in cHL and may reflect the distinct biology of this lymphoma. Further studies on the potential utility of MAOA as a diagnostic marker and therapeutic target are warranted. Copyright (c) 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 28722113 TI - Specialized stomatal humidity responses underpin ecological diversity in C3 bromeliads. AB - The Neotropical Bromeliaceae display an extraordinary level of ecological variety, with species differing widely in habit, photosynthetic pathway and growth form. Divergences in stomatal structure and function, hitherto understudied in treatments of bromeliad evolutionary physiology, could have been critical to the generation of variety in ecophysiological strategies among the bromeliads. Because humidity is a key factor in bromeliad niches, we focussed on stomatal responses to vapour pressure deficit (VPD). We measured the sensitivity of stomatal conductance and assimilation rate to VPD in eight C3 bromeliad species of contrasting growth forms and ecophysiological strategies and parameterised the kinetics of stomatal responses to a step change in VPD. Notably, three tank-epiphyte species displayed low conductance, high sensitivity and fast kinetics relative to the lithophytes, while three xeromorphic terrestrial species showed high conductance and sensitivity but slow stomatal kinetics. An apparent feedforward response of transpiration to VPD occurred in the tank epiphytes, while water-use efficiency was differentially impacted by stomatal closure depending on photosynthetic responses. Differences in stomatal responses to VPD between species of different ecophysiological strategies are closely linked to modifications of stomatal morphology, which we argue has been a pivotal component of the evolution of high diversity in this important plant family. PMID- 28722114 TI - UV-B irradiation differentially regulates terpene synthases and terpene content of peach. AB - Plants generate protective molecules in response to ultraviolet (UV) light. In laboratory experiments, 48 h UV-B irradiation of peach fruits and leaves reduced the flavour-related monoterpene linalool by 60%. No isoprene was detected, but other terpenoids increased significantly, including a threefold accumulation of the sesquiterpene (E,E)-alpha-farnesene, which was also increased by jasmonic acid treatment. RNA sequencing revealed altered transcript levels for two terpene synthases (TPSs): PpTPS1, a TPS-g subfamily member, decreased by 86% and PpTPS2, a TPS-b subfamily member, increased 80-fold. Heterologous expression in Escherichia coli and transient overexpression in tobacco and peach fruits showed PpTPS1 was localized in plastids and associated with production of linalool, while PpTPS2 was responsible for (E,E)-alpha-farnesene biosynthesis in the cytoplasm. Candidate regulatory genes for these responses were identified. Commercial peach production in Asia involves fruit bagging to maintain marketable yield and quality. TPS gene expression and volatile terpenoid production in field experiments, using bags transmitting high UV-B radiation, showed similar effects on peach volatiles to those from laboratory experiments. Bags transmitting less UV-B light ameliorated the reduction in the flavour volatile linalool, indicating that flavour components of peach fruits can be modulated by selecting an appropriate source of environmental screening material. PMID- 28722115 TI - Transcriptional profiling of mechanically and genetically sink-limited soybeans. AB - The absence of a reproductive sink causes physiological and morphological changes in soybean plants. These include increased accumulation of nitrogen and starch in the leaves and delayed leaf senescence. To identify transcriptional changes that occur in leaves of these sink-limited plants, we used RNAseq to compare gene expression levels in trifoliate leaves from depodded and ms6 male-sterile soybean plants and control plants. In both sink-limited tissues, we observed a deferral of the expression of senescence-associated genes and a continued expression of genes associated with leaf maturity. Gene Ontology-terms (GO-terms) associated with growth and development and storage proteins were over-represented in genes that were differentially expressed in sink-limited tissues. We also identified basic helix-loop-helix, auxin response factor, and squamosa binding protein transcription factors expressed in sink-limited tissues, and the senescing control leaves expressed WRKY and NAC transcription factors. We identified genes that were not expressed during normal leaf development but that were highly expressed in sink-limited plants, including the SGR3b "non-yellowing" gene. These differences highlighted several metabolic pathways that were involved in distinct modes of resource partitioning of leaves with the "stay green" phenotype. PMID- 28722117 TI - A single-probe heat pulse method for estimating sap velocity in trees. AB - Available sap flow methods are still far from being simple, cheap and reliable enough to be used beyond very specific research purposes. This study presents and tests a new single-probe heat pulse (SPHP) method for monitoring sap velocity in trees using a single-probe sensor, rather than the multi-probe arrangements used up to now. Based on the fundamental conduction-convection principles of heat transport in sapwood, convective velocity (Vh ) is estimated from the temperature increase in the heater after the application of a heat pulse (DeltaT). The method was validated against measurements performed with the compensation heat pulse (CHP) technique in field trees of six different species. To do so, a dedicated three-probe sensor capable of simultaneously applying both methods was produced and used. Experimental measurements in the six species showed an excellent agreement between SPHP and CHP outputs for moderate to high flow rates, confirming the applicability of the method. In relation to other sap flow methods, SPHP presents several significant advantages: it requires low power inputs, it uses technically simpler and potentially cheaper instrumentation, the physical damage to the tree is minimal and artefacts caused by incorrect probe spacing and alignment are removed. PMID- 28722116 TI - Opioids for cancer-related pain in children and adolescents. AB - BACKGROUND: Pain is a common feature of childhood and adolescence around the world, and for many young people, that pain is chronic. The World Health Organization (WHO) guidelines for pharmacological treatments for children's persisting pain acknowledge that pain in children is a major public health concern of high significance in most parts of the world. Views on children's pain have changed over time and relief of pain is now seen as important. In the past, pain was largely dismissed and was frequently left untreated, and it was assumed that children quickly forgot about painful experiences.We designed a suite of seven reviews in chronic non-cancer pain and cancer pain (looking at antidepressants, antiepileptic drugs, non-steroidal anti-inflammatory drugs, opioids, and paracetamol) to review the evidence for children's pain using pharmacological interventions.As one of the leading causes of mortality and morbidity for children and adolescents in the world today, childhood cancer (and its associated pain) is a major health concern. Cancer pain in infants, children, and adolescents is primarily nociceptive pain with negative long term effects. Cancer-related pain is generally caused directly by the tumour itself such as compressing on the nerve or inflammation of the organs. Cancer-related pain generally occurs as a result of perioperative procedures, nerve damage caused by radiation or chemotherapy treatments, or mucositis. However, this review focused on pain caused directly by the tumour itself such as nerve infiltration, external nerve compression, and other inflammatory events.Opioids are used worldwide for the treatment of pain. Currently available opioids include: buprenorphine, codeine, fentanyl, hydromorphone, methadone, morphine, oxycodone, and tramadol. Opioids are generally available in healthcare settings across most developed countries but access may be restricted in developing countries. To achieve adequate pain relief in children using opioids, with an acceptable grade of adverse effects, the recommended method is to start with a low dose gradually titrated to effect or unacceptable adverse effect in the child. OBJECTIVES: To assess the analgesic efficacy, and adverse events, of opioids used to treat cancer-related pain in children and adolescents aged between birth and 17 years, in any setting. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online, MEDLINE via Ovid and Embase via Ovid from inception to 22 February 2017. We also searched the reference lists of retrieved studies and reviews, and searched online clinical trial registries. SELECTION CRITERIA: Randomised controlled trials (RCTs), with or without blinding, of any dose, and any route, treating cancer related pain in children and adolescents, comparing opioids with placebo or an active comparator. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for eligibility. We planned to use dichotomous data to calculate risk ratio and number needed to treat for one additional event, using standard methods. We assessed GRADE (Grading of Recommendations Assessment, Development and Evaluation) and planned to create a 'Summary of findings' table. MAIN RESULTS: No studies were identified that were eligible for inclusion in this review (very low quality evidence). Several studies tested opioids on adults with cancer-related pain, but none in participants aged from birth to 17 years.We rated the quality of evidence as very low, downgraded due to a lack of available data; no analyses could be undertaken. AUTHORS' CONCLUSIONS: No conclusions can be drawn about efficacy or harm in the use of opioids to treat cancer-related pain in children and adolescents. As a result, there is no RCT evidence to support or refute the use of opioids to treat cancer-related pain in children and adolescents. PMID- 28722118 TI - AT2 R deficiency mediated podocyte loss via activation of ectopic hedgehog interacting protein (Hhip) gene expression. AB - Angiotensin II type 2 receptor (AT2 R) deficiency in AT2 R knockout (KO) mice has been linked to congenital abnormalities of the kidney and urinary tract; however, the mechanisms by which this occurs are poorly understood. In this study, we examined whether AT2 R deficiency impaired glomerulogenesis and mediated podocyte loss/dysfunction in vivo and in vitro. Nephrin-cyan fluorescent protein (CFP) transgenic (Tg) and Nephrin/AT2 RKO mice were used to assess glomerulogenesis, while wild-type and AT2 RKO mice were used to evaluate maturation of podocyte morphology/function. Immortalized mouse podocytes (mPODs) were employed for in vitro studies. AT2 R deficiency resulted in diminished glomerulogenesis in E15 embryos, but had no impact on actual nephron number in neonates. Pups lacking AT2 R displayed features of renal dysplasia with lower glomerular tuft volume and podocyte numbers. In vivo and in vitro studies demonstrated that loss of AT2 R was associated with elevated NADPH oxidase 4 levels, which in turn stimulated ectopic hedgehog interacting protein (Hhip) gene expression in podocytes. Consequently, ectopic Hhip expression activation either triggers caspase-3 and p53-related apoptotic processes resulting in podocyte loss, or activates TGFbeta1 Smad2/3 cascades and alpha-SMA expression to transform differentiated podocytes to undifferentiated podocyte-derived fibrotic cells. We analyzed HHIP expression in the kidney disease database (Nephroseq) and then validated this using HHIP immunohistochemistry staining of human kidney biopsies (controls versus focal segmental glomerulosclerosis). In conclusion, loss of AT2 R is associated with podocyte loss/dysfunction and is mediated, at least in part, via augmented ectopic Hhip expression in podocytes. Copyright (c) 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 28722119 TI - Sexual selection on spontaneous mutations strengthens the between-sex genetic correlation for fitness. AB - A proposed benefit to sexual selection is that it promotes purging of deleterious mutations from populations. For this benefit to be realized, sexual selection, which is usually stronger on males, must purge mutations deleterious to both sexes. Here, we experimentally test the hypothesis that sexual selection on males purges deleterious mutations that affect both male and female fitness. We measured male and female fitness in two panels of spontaneous mutation accumulation lines of the fly, Drosophila serrata, each established from a common ancestor. One panel of mutation accumulation lines limited both natural and sexual selection (LS lines), whereas the other panel limited natural selection, but allowed sexual selection to operate (SS lines). Although mutation accumulation caused a significant reduction in male and female fitness in both the LS and SS lines, sexual selection had no detectable effect on the extent of the fitness reduction. Similarly, despite evidence of mutational variance for fitness in males and females of both treatments, sexual selection had no significant impact on the amount of mutational genetic variance for fitness. However, sexual selection did reshape the between-sex correlation for fitness: significantly strengthening it in the SS lines. After 25 generations, the between sex correlation for fitness was positive but considerably less than one in the LS lines, suggesting that, although most mutations had sexually concordant fitness effects, sex-limited, and/or sex-biased mutations contributed substantially to the mutational variance. In the SS lines this correlation was strong and could not be distinguished from unity. Individual-based simulations that mimick the experimental setup reveal two conditions that may drive our results: (1) a modest to-large fraction of mutations have sex-limited (or highly sex-biased) fitness effects, and (2) the average fitness effect of sex-limited mutations is larger than the average fitness effect of mutations that affect both sexes similarly. PMID- 28722120 TI - Tax-Exempt Hospitals' Investments in Community Health and Local Public Health Spending: Patterns and Relationships. AB - OBJECTIVES: To investigate whether tax-exempt hospitals' investments in community health are associated with patterns of governmental public health spending focusing specifically on the relationship between hospitals' community benefit expenditures and the spending patterns of local health departments (LHDs). STUDY DESIGN: We combined data on tax-exempt hospitals' community benefit spending with data on spending by the corresponding LHD that served the county in which a hospital was located. Data were available for 2 years, 2009 and 2013. Generalized linear regressions were estimated with indicators of hospital community benefit spending as the dependent variable and LHD spending as the key independent variable. PRINCIPAL FINDINGS: Hospital community benefit spending was unrelated to how much local public health agencies spent, per capita, on public health in their communities. CONCLUSIONS: Patterns of local public health spending do not appear to impact the investments of tax-exempt hospitals in community health activities. Opportunities may, however, exist for a more active engagement between the public and private sector to ensure that the expenditures of all stakeholders involved in community health improvement efforts complement one another. PMID- 28722121 TI - The importance of species identity and interactions for multifunctionality depends on how ecosystem functions are valued. AB - Studies investigating how biodiversity affects ecosystem functioning increasingly focus on multiple functions measured simultaneously ("multifunctionality"). However, few such studies assess the role of species interactions, particularly under alternative environmental scenarios, despite interactions being key to ecosystem functioning. Here we address five questions of central importance to ecosystem multifunctionality using a terrestrial animal system. (1) Does the contribution of individual species differ for different ecosystem functions? (2) Do inter-species interactions affect the delivery of single functions and multiple functions? (3) Does the community composition that maximizes individual functions also maximize multifunctionality? (4) Is the functional role of individual species, and the effect of interspecific interactions, modified by changing environmental conditions? (5) How do these roles and interactions change under varying scenarios where ecosystem services are weighted to reflect different societal preferences? We manipulated species' relative abundance in dung beetle communities and measured 16 functions contributing to dung decomposition, plant productivity, nutrient recycling, reduction of greenhouse gases, and microbial activity. Using the multivariate diversity-interactions framework, we assessed how changes in species identity, composition, and interspecific interactions affected these functions in combination with an environmental driver (increased precipitation). This allowed us to identify key species and interactions across multiple functions. We then developed a desirability function approach to examine how individual species and species mixtures contribute to a desired state of overall ecosystem functioning. Species contributed unequally to individual functions, and to multifunctionality, and individual functions were maximized by different community compositions. Moreover, the species and interactions important for maintaining overall multifunctionality depended on the weight given to individual functions. Optimal multifunctionality was context-dependent, and sensitive to the valuation of services. This combination of methodological approaches allowed us to resolve the interactions and indirect effects among species that drive ecosystem functioning, revealing how multiple aspects of biodiversity can simultaneously drive ecosystem functioning. Our results highlight the importance of a multifunctionality perspective for a complete assessment of species' functional contributions. PMID- 28722122 TI - Wet work exposure and hand eczema among healthcare workers: a cross-sectional study. AB - BACKGROUND: Hand eczema is more common in healthcare workers than in the general population. Hands are subject to changing occupational exposures as a result of mandatory hygiene regulations for healthcare workers. OBJECTIVES: To describe exposure to hygiene procedures and investigate the associations between occupational hand washing, use of nonsterile gloves and hand disinfectant, and self-reported hand eczema. METHODS: This was a cross-sectional study; an electronic questionnaire was distributed to 28 762 hospital employees in southern Sweden. Nurses, assistant nurses or physicians constituted the group of healthcare workers analysed. Adjustments were made for sex, age, wet work at home, lifestyle factors and atopic dermatitis. RESULTS: In total, 12 288 (43%) responded, including 9051 healthcare workers. In this group the 1-year prevalence of self-reported hand eczema was 21%. On a daily basis, 30% reported hand washing with soap > 20 times at work, 45% used hand disinfectants > 50 times and 54% wore nonsterile gloves for > 2 h. After adjustment for confounding factors, a dose dependent association with self-reported hand eczema was found for the daily number of hand washes with soap at work and time working with disposable gloves but not for alcoholic disinfectant use. Hand washing outside work was not associated with self-reported hand eczema in the adjusted multivariate analysis. CONCLUSIONS: In this study, we found a higher 1-year prevalence of self-reported hand eczema among Swedish healthcare workers than reported in the general population. Hand washing with soap and use of disposable gloves were associated with the occurrence of self-reported hand eczema in a dose-dependent way. Use of hand disinfectant was not associated with self-reported hand eczema. PMID- 28722123 TI - Value of Biomarkers in the Prevention of Rheumatoid Arthritis. AB - Recent diagnostic advances allow to identify persons in a pre-symptomatic stage of rheumatoid arthritis (RA), opening the way for a preventive therapeutic intervention, which may potentially be curative. We review and discuss existing biomarkers predictive of future onset of RA. A responsible use of biomarkers in clinical settings will require an integration of blood-based tests, imaging techniques, clinical history, environmental risk factors, and family history. PMID- 28722124 TI - Pancreatic undifferentiated carcinoma with osteoclast-like giant cells is genetically similar to, but clinically distinct from, conventional ductal adenocarcinoma. AB - Undifferentiated carcinoma of the pancreas with osteoclast-like giant cells (UCOGC) is currently considered a morphologically and clinically distinct variant of pancreatic ductal adenocarcinoma (PDAC). In this study, we report clinical and pathological features of a series of 22 UCOGCs, including the whole exome sequencing of eight UCOGCs. We observed that 60% of the UCOGCs contained a well defined epithelial component and that patients with pure UCOGC had a significantly better prognosis than did those with an UCOGC with an associated epithelial neoplasm. The genetic alterations in UCOGC are strikingly similar to those known to drive conventional PDAC, including activating mutations in the oncogene KRAS and inactivating mutations in the tumor suppressor genes CDKN2A, TP53, and SMAD4. These results further support the classification of UCOGC as a PDAC variant and suggest that somatic mutations are not the determinants of the unique phenotype of UCOGC. Copyright (c) 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 28722125 TI - A temperature gradient may support mother-infant thermal identification and communication in the breast crawl from birth to breastfeeding. AB - AIM: The human female's nipple-areolar complex (NAC) is the point of arrival of a natural progression from birth to breastfeeding, linked to functional, chemical and biophysical cues that promote the breast crawl soon after birth. We investigated the thermal gradient generated by the lips of the neonate and warmth of the NAC, which may drive the infant directly to the nipple. METHODS: We prospectively studied 41 full-term singleton infants and their mothers at the Policlinico Abano Terme, Italy, between January 1, 2015, and February 28, 2015. NAC and breast quadrant temperatures were assessed 6 +/- 2 hours prepartum and one and two days postpartum, together with the neonates' lip temperature. RESULTS: The temperature of the neonates' lips was significantly lower than the forehead temperature on days one and two postpartum (delta = -1.24 degrees C, p < 0.001 and delta = -1.02 degrees C, p < 0.001, respectively). Thus, the thermal gradient between the NAC and the neonates' lips was -1.66 +/- 1.07 degrees C on day one (p < 0.001) and -1.68 +/- 0.63 degrees C (p < 0.001) on day two postpartum. CONCLUSION: These findings demonstrate, for the first time, that a temperature gradient may support mother-infant thermal identification and communication in the breast crawl and in the natural progression of the continuum from birth to breastfeeding. PMID- 28722126 TI - Investigating the effect of poly-l-lactic acid nanoparticles carrying hypericin on the flow-biased diffusive motion of HeLa cell organelles. AB - OBJECTIVES: In this study, we investigate in human cervical epithelial HeLa cells the intracellular dynamics and the mutual interaction with the organelles of the poly-l-lactic acid nanoparticles (PLLA NPs) carrying the naturally occurring hydrophobic photosensitizer hypericin. METHODS: Temporal and spatiotemporal image correlation spectroscopy was used for the assessment of the intracellular diffusion and directed motion of the nanocarriers by tracking the hypericin fluorescence. Using image cross-correlation spectroscopy and specific fluorescent labelling of endosomes, lysosomes and mitochondria, the NPs dynamics in association with the cell organelles was studied. Static colocalization experiments were interpreted according to the Manders' overlap coefficient. KEY FINDINGS: Nanoparticles associate with a small fraction of the whole-organelle population. The organelles moving with NPs exhibit higher directed motion compared to those moving without them. The rate of the directed motion drops substantially after the application of nocodazole. The random component of the organelle motions is not influenced by the NPs. CONCLUSIONS: Image correlation and cross-correlation spectroscopy are most appropriate to unravel the motion of the PLLA nanocarrier and to demonstrate that the rate of the directed motion of organelles is influenced by their interaction with the nanocarriers. Not all PLLA hypericin NPs are associated with organelles. PMID- 28722127 TI - Contrasting outcomes of species- and community-level analyses of the temporal consistency of functional composition. AB - Multiple anthropogenic drivers affect every natural community, and there is broad interest in using functional traits to understand and predict the consequences for future biodiversity. There is, however, no consensus regarding the choice of analytical methods. We contrast species- and community-level analyses of change in the functional composition for four traits related to drought tolerance using three decades of repeat censuses of trees in the 50-ha Forest Dynamics Plot on Barro Colorado Island, Panama. Community trait distributions shifted significantly through time, which may indicate a shift toward more drought tolerant species. However, at the species level, changes in abundance were unrelated to trait values. To reconcile these seemingly contrasting results, we evaluated species-specific contributions to the directional shifts observed at the community level. Abundance changes of just one to six of 312 species were responsible for the community-level shifts observed for each trait. Our results demonstrate that directional changes in community-level functional composition can result from idiosyncratic change in a few species rather than widespread community-wide changes associated with functional traits. Future analyses of directional change in natural communities should combine community-, species-, and possibly individual-level analyses to uncover relationships with function that can improve understanding and enable prediction. PMID- 28722130 TI - Solubility and molecular interactions of ferulic acid in various (isopropanol + water) mixtures. AB - OBJECTIVE: The solubility of an herbal compound ferulic acid (FA) in various (isopropanol (IPA) + water) mixtures was measured and correlated at temperatures 'T = 298.2 K to 318.2 K' and pressure 'p = 0.1 MPa'. METHODS: The experimental solubilities of FA in mole fraction were determined using a static equilibrium method and correlated with 'Apelblat, Van't Hoff, Yalkowsky and Jouyban-Acree models'. KEY FINDINGS: The maximum mole fraction solubilities of FA were obtained in neat IPA (2.58 * 10-2 at T = 318.2 K) followed by minimum in neat water (4.87 * 10-5 at T = 298.2 K). The activity coefficients of FA in various (IPA + water) mixtures were determined to evaluate the molecular interactions between FA and co solvent mixtures. Strong molecular interactions were seen between FA and neat IPA in comparison with FA and neat water. 'Apparent thermodynamic analysis' indicated an 'endothermic and entropy-driven dissolution' of FA in all (IPA + water) mixtures evaluated. CONCLUSIONS: Isopropanol was investigated as a good cosolvent in the solubility enhancement of FA in water; therefore, it could be used as solubilizer in solubility enhancement and formulation development of FA. PMID- 28722131 TI - Kept in the loop: longitudinal strain-volume relationships for the assessment of left ventricular mechanical performance. PMID- 28722129 TI - Bone Strength Estimated by Micro-Finite Element Analysis (uFEA) Is Heritable and Shares Genetic Predisposition With Areal BMD: The Framingham Study. AB - Genetic factors contribute to the risk of bone fractures, partly because of effects on bone strength. High-resolution peripheral quantitative computed tomography (HR-pQCT) estimates bone strength using micro-finite element analysis (uFEA). The goal of this study was to investigate if the bone failure load estimated by HR-pQCT-based uFEA is heritable and to what extent it shares genetic regulation with areal bone mineral density (aBMD). Bone microarchitecture was measured by HR-pQCT at the ultradistal tibia and ultradistal radius in adults from the Framingham Heart Study (n = 1087, mean age 72 years; 57% women). Radial and tibial failure load in compression were estimated by uFEA. Femoral neck (FN) and ultradistal forearm (UD) aBMD were measured by dual-energy X-ray absorptiometry (DXA). Heritability (h2 ) of failure load and aBMD and genetic correlations between them was estimated adjusting for covariates (age and sex). Failure load values at the non-weight-bearing ultradistal radius and at the weight-bearing ultradistal tibia were highly correlated (r = 0.906; p < 0.001). Estimates of h2 adjusted for covariates were 0.522 for the radius and 0.497 for the tibia. Additional adjustment for height did not impact on the h2 results, but adjustment for aBMD at the UD and FN somewhat decreased h2 point estimates: 0.222 and 0.380 for radius and tibia, respectively. In bivariate analysis, there was a high phenotypic and genetic correlation between covariate-adjusted failure load at the radius and UD aBMD (rhoP = 0.826, rhoG = 0.954, respectively), whereas environmental correlations were lower (rhoE = 0.696), all highly significant (p < 0.001). Similar correlations were observed between tibial failure load and femoral neck aBMD (rhoP = 0.577, rhoG = 0.703, both p < 0.001; rhoE = 0.432, p < 0.05). These data from adult members of families from a population-based cohort suggest that bone strength of distal extremities estimated by micro-finite element analysis is heritable and shares some genetic composition with areal BMD, regardless of the skeletal site. (c) 2017 American Society for Bone and Mineral Research. PMID- 28722128 TI - Solar insolation in springtime influences age of onset of bipolar I disorder. AB - OBJECTIVE: To confirm prior findings that the larger the maximum monthly increase in solar insolation in springtime, the younger the age of onset of bipolar disorder. METHOD: Data were collected from 5536 patients at 50 sites in 32 countries on six continents. Onset occurred at 456 locations in 57 countries. Variables included solar insolation, birth-cohort, family history, polarity of first episode and country physician density. RESULTS: There was a significant, inverse association between the maximum monthly increase in solar insolation at the onset location, and the age of onset. This effect was reduced in those without a family history of mood disorders and with a first episode of mania rather than depression. The maximum monthly increase occurred in springtime. The youngest birth-cohort had the youngest age of onset. All prior relationships were confirmed using both the entire sample, and only the youngest birth-cohort (all estimated coefficients P < 0.001). CONCLUSION: A large increase in springtime solar insolation may impact the onset of bipolar disorder, especially with a family history of mood disorders. Recent societal changes that affect light exposure (LED lighting, mobile devices backlit with LEDs) may influence adaptability to a springtime circadian challenge. PMID- 28722132 TI - Evolution of the selfing syndrome: Anther orientation and herkogamy together determine reproductive assurance in a self-compatible plant. AB - Capacity for autonomous self-fertilization provides reproductive assurance, has evolved repeatedly in the plant kingdom, and typically involves several changes in flower morphology and development (the selfing syndrome). Yet, the relative importance of different traits and trait combinations for efficient selfing and reproductive success in pollinator-poor environments is poorly known. In a series of experiments, we tested the importance of anther-stigma distance and the less studied trait anther orientation for efficiency of selfing in the perennial herb Arabis alpina. Variation in flower morphology among eight self-compatible European populations was correlated with efficiency of self-pollination and with pollen limitation in a common-garden experiment. To examine whether anther-stigma distance and anther orientation are subject to directional and/or correlational selection, and whether this is because these traits affect pollination success, we planted a segregating F2 population at two native field sites. Selection strongly favored a combination of introrse anthers and reduced anther-stigma distance at a site where pollinator activity was low, and supplemental hand pollination demonstrated that this was largely because of their effect on securing self-pollination. The results suggest that concurrent shifts in more than one trait can be crucial for the evolution of efficient self-pollination and reproductive assurance in pollinator-poor habitats. PMID- 28722133 TI - Rheological characterisation of gluten from triticale (x Triticosecale Wittmack). AB - BACKGROUND: Triticale gluten still remains very poorly characterised rheologically. In this study the mechanical spectra of gluten isolated from four triticale cultivars were registered and fitted with Cole-Cole functions yielding the visco-elastic plateau parameters. Master spectra were calculated. A retardation test was performed and used to calculate the composite mechanical spectra and the width of visco-elastic plateau l. Protein fractional composition of triticale flour and gluten was studied using capillary zone electrophoresis. RESULTS: Differentiated HMW-GS/SS compositions were identified in the triticale cultivars studied. The rheological parameters reached the following values: JN0 1.05.10-3 to 2.69.10-3 Pa-1 , GN0 372 to 956 Pa, omega0 0.003 to 0.06 rad s-1 , l 169 to 3121, Je0 1.57.10-3 to 5.03.10-3 Pa-1 , Ge0 199 to 637 Pa and eta0 1.06.107 to 3.93.107 Pa s. CONCLUSIONS: Visco-elastic properties of triticale gluten correspond to the lower end of medium visco-elasticity shown by common wheat gluten. Master spectra and the composite mechanical spectra prove that four triticale glutens exhibit practically an identical type of visco-elastic behaviour of a biopolymeric visco-elastic liquid similar to wheat gluten. The visco-elastic plateau parameters GN0 , JN0 , omega0 and l appeared significantly correlated with the contents of prolamins and secaloglutenins in triticale flours and glutens. (c) 2017 Society of Chemical Industry. PMID- 28722135 TI - ERRATUM. PMID- 28722134 TI - Location, variations, and predictors of epicardial fat mapping using multidetector computed tomography to assist epicardial ventricular tachycardia ablation. AB - BACKGROUND: A significant number of ventricular tachycardia circuits are located close to the epicardial surface and are amendable to epicardial ablation. Epicardial fat often interferes with substrate mapping and ablation, though little is known regarding the distribution of fat and its fluctuation with the cardiac cycle. METHODS: We studied 40 patients who underwent a 64-slice multidetector computed tomography in order to describe patterns of epicardial fat distribution, variation during cardiac cycle, and clinical predictors of epicardial fat. Multiplanar reconstructions were analyzed during systole and diastole in six cross-sections. Epicardial fat thickness was measured across multiple wall segments in each view. RESULTS: Epicardial fat was found to be thicker in areas overlying coronary vasculature (7.8 +/- 2.6 mm vs 3.5 +/- 0.9 mm, P = 0.001), along with the right ventricular wall (3.9 +/- 0.8 mm vs 2.6 +/- 0.6 mm, P = 0.001) and the ventricular base (6.1 +/- 1.7 mm vs 4.6 +/- 1.6 mm, P < 0.01). Epicardial fat thickness increased 27% during systole as compared to diastole (4.9 +/- 2.7 mm vs 6.2 +/- 3.0 mm, P = 0.04). Variation with cardiac cycle was most evident along the right ventricular wall (3.9 +/- 0.8 mm vs 5.0 +/ 1.3 mm, P = 0.001) and nonvascular areas (P = 0.001), especially at the ventricular base (3.7 +/- 1.1 mm vs 5.3 +/- 1.5 mm, P = 0.001). In multivariate logistic regression, we found that age >50 years (P = 0.031) and coronary artery disease (P = 0.023) were statistically correlated with epicardial fat >5-mm thickness and body mass index > 33 (P = 0.052) nearly so. CONCLUSIONS: Baseline epicardial fat thickness >5 mm is common in areas typically targeted during epicardial ablation and further increases during the cardiac cycle. Simple clinical characteristics can identify patients with >5 mm epicardial fat in which preprocedural computed tomography imaging and three-dimensional fat map reconstruction may facilitate epicardial ablation. PMID- 28722136 TI - Changes in interleukin-17A, macrophage-derived chemokine and adiponectin following treatment of psoriasis with calcipotriol plus betamethasone dipropionate aerosol foam: results from the PSO-ABLE study. PMID- 28722138 TI - A Red Blood Cell Model to Estimate the Hemolysis Fingerprint of Cardiovascular Devices. AB - One of the most relevant and open issues within cardiovascular prosthetic hemodynamic performance is a realistic quantification of the damage sustained by red blood cells (RBCs). Specifically, the optimal design of bileaflet mechanical heart valves (BMHVs) requires both low shear stresses along the leaflets and short particle resident times. This study approaches RBC damage estimation by developing a numerical model of RBCs and computing the damage sustained by a set of passive RBCs immersed within in vitro flows. The RBC is modeled as an ellipsoidal shell with size dependent on age. Mechanically, a viscous hyper elastic model was adopted to compute the stress-deformation transmitted by the experimental flow field to the RBC layer. The rupture parameters were calibrated using experimental results on real RBCs submitted to Couette flow. Moreover, the integrated hemolysis index (HI) through a BMHV was computed for a set of RBCs injected in a flow field derived from an in vitro study and for multiple RBC passages. The main results are (1) a good capability of the RBC model to replicate in vitro experiments performed with real RBCs, finding realistic rupture parameters; (2) the spatial distribution for the HI, maximal along the leaflet boundary layer and for long resident times; (3) 90% of HI is produced by the less damaging trajectories, which are favored by local flow dynamics; (4) cumulated HI in 8 days is about 0.01% smaller than the clinical warning threshold, the latter being obtained only after a period of time comparable with the RBC lifetime. PMID- 28722137 TI - Precise and Arbitrary Deposition of Biomolecules onto Biomimetic Fibrous Matrices for Spatially Controlled Cell Distribution and Functions. AB - Advances in nano-/microfabrication allow the fabrication of biomimetic substrates for various biomedical applications. In particular, it would be beneficial to control the distribution of cells and relevant biomolecules on an extracellular matrix (ECM)-like substrate with arbitrary micropatterns. In this regard, the possibilities of patterning biomolecules and cells on nanofibrous matrices are explored here by combining inkjet printing and electrospinning. Upon investigation of key parameters for patterning accuracy and reproducibility, three independent studies are performed to demonstrate the potential of this platform for: i) transforming growth factor (TGF)-beta1-induced spatial differentiation of fibroblasts, ii) spatiotemporal interactions between breast cancer cells and stromal cells, and iii) cancer-regulated angiogenesis. The results show that TGF-beta1 induces local fibroblast-to-myofibroblast differentiation in a dose-dependent fashion, and breast cancer clusters recruit activated stromal cells and guide the sprouting of endothelial cells in a spatially resolved manner. The established platform not only provides strategies to fabricate ECM-like interfaces for medical devices, but also offers the capability of spatially controlling cell organization for fundamental studies, and for high-throughput screening of various biomolecules for stem cell differentiation and cancer therapeutics. PMID- 28722140 TI - Erythrocyte-Membrane-Enveloped Perfluorocarbon as Nanoscale Artificial Red Blood Cells to Relieve Tumor Hypoxia and Enhance Cancer Radiotherapy. AB - Hypoxia, a common feature within many types of solid tumors, is known to be closely associated with limited efficacy for cancer therapies, including radiotherapy (RT) in which oxygen is essential to promote radiation-induced cell damage. Here, an artificial nanoscale red-blood-cell system is designed by encapsulating perfluorocarbon (PFC), a commonly used artificial blood substitute, within biocompatible poly(d,l-lactide-co-glycolide) (PLGA), obtaining PFC@PLGA nanoparticles, which are further coated with a red-blood-cell membrane (RBCM). The developed PFC@PLGA-RBCM nanoparticles with the PFC core show rather efficient loading of oxygen, as well as greatly prolonged blood circulation time owing to the coating of RBCM. With significantly improved extravascular diffusion within the tumor mass, owing to their much smaller nanoscale sizes compared to native RBCs with micrometer sizes, PFC@PLGA-RBCM nanoparticles are able to effectively deliver oxygen into tumors after intravenous injection, leading to greatly relieved tumor hypoxia and thus remarkably enhanced treatment efficacy during RT. This work thus presents a unique type of nanoscale RBC mimic for efficient oxygen delivery into solid tumors, favorable for cancer treatment by RT, and potentially other types of therapy as well. PMID- 28722139 TI - Structure-based release analysis of the JC virus agnoprotein regions: A role for the hydrophilic surface of the major alpha helix domain in release. AB - Agnoprotein (Agno) is an important regulatory protein of JC virus (JCV), BK virus (BKV) and simian virus 40 (SV40) and these viruses are unable to replicate efficiently in the absence of this protein. Recent 3D-NMR structural data revealed that Agno contains two alpha-helices (a minor and a major) while the rest of the protein adopts an unstructured conformation (Coric et al., 2017, J Cell Biochem). Previously, release of the JCV Agno from the Agno-positive cells was reported. Here, we have further mapped the regions of Agno responsible for its release by a structure-based systematic mutagenesis approach. Results revealed that amino acid residues (Lys22, Lys23, Phe31, Glu34, and Asp38) located either on or adjacent to the hydrophilic surface of the major alpha-helix domain of Agno play critical roles in release. Additionally, Agno was shown to strongly interact with unidentified components of the cell surface when cells are treated with Agno, suggesting additional novel roles for Agno during the viral infection cycle. PMID- 28722141 TI - Failure to rescue as a nurse-sensitive indicator. AB - PROBLEM: The aim of this concept analysis was to clarify failure to rescure as a nurse-sensitive indicator. Although the concept of failure to rescue as a nurse sensitive outcome has appeared in the nursing literature for over a decade, conceptual clarity is needed to address its variable and ambiguous use in health care. METHODS: Walker and Avant's eight-stage method of concept analysis was used to explore the concept of failure to rescue in nursing practice. Twenty-one papers were retrieved from Cumulative Index of Nursing and Allied Health Literature (CINAHL) and MEDLINE databases and selected for review and synthesis. RESULTS: Failure to rescue as a nurse-sensitive indicator was found to be a "failing to rescue" process characterized by a cascade of events, including four key attributes: (1) errors of omission in care, (2) failure to recognize changes in patient condition, (3) failure to communicate changes, and (4) failures in clinical decision making. CONCLUSIONS: Nurses have a pivotal role in "failing to rescue" through early recognition, escalation, and intervention of subtle changes signaling complications. Upstream strategies, such as the use of early warning sign indicators, structured communication, and teamwork, shift the discourse from failure to rescue, to processes in nursing practice of good catch events. PMID- 28722142 TI - Lactic Dehydrogenase in the In Vitro Evaluation of Hemolytic Properties of Ventricular Assist Device. AB - Ventricular assist devices (VADs) can effectively improve the survival rate of patients with end-stage heart failure, but the hemolytic complications induced by long-time VAD support have received wide attention recently. The conventional evaluation method of the hemolytic properties of VADs by the indicator of plasma free hemoglobin (PFH) concentration is used but not sensitive enough to meet the needs of the actual examinations. In this study, an experimental method was applied for the evaluation of the injuries and damages caused by VADs to erythrocytes by both indicators of PFH and lactic dehydrogenase (LDH) in the in vitro hemolysis assay of VADs. The changes of LDH and PFH concentrations in plasma with the shear stress and the exposure time under a fixed shear stress were measured and analyzed to investigate the sensitivity and accuracy of the evaluation of erythrocyte damage by LDH. Furthermore, through 24 h in vitro hemolysis tests, the changes of LDH and PFH concentrations in blood samples were measured in combination with the microscopic histological changes and ultrastructural changes of erythrocytes, to assess the possibility of LDH evaluating the hemolysis of VADs. The changes of the concentration of LDH were more sensitive than those of PFH to different shear stress and exposure times, especially lower stress. Meanwhile, in the 24 h in vitro hemolysis assay, the PFH concentration in the blood samples showed no significant changes in the first 8 h, while the LDH concentration increased significantly in the first 3 h, which was consistent with the morphological changes of erythrocytes. Compared with the changes of the PFH concentration, the LDH concentration is sensitive to the damage of erythrocytes caused by VADs. It was considered that LDH could be applied as an additional indicator in the evaluation of erythrocyte damage and hemolytic properties of VADs in combination with the normalized index of hemolysis, for the more accurate assessment of the blood compatibility of VADs. PMID- 28722143 TI - Breast cancer stem cells as last soldiers eluding therapeutic burn: A hard nut to crack. AB - Cancer stem cells (CSCs) are found in many cancer types, including breast carcinoma. Breast cancer stem cells (BCSCs) are considered as seed of cancer formation and they are associated with metastasis and genotoxic drug resistance. Several studies highlighted the presence of BCSCs in tumor microenvironment and they are accentuated with several carcinoma events including metastasis and resistance to genotoxic drugs and they also rebound after genotoxic burn. Stemness properties of a small population of cells in carcinoma have provided clues regarding the role of tumor microenvironment in tumor pathophysiology. Hence, insights in cancer stem cell biology with respect to molecular signaling, genetics and epigenetic behavior of CSCs have been used to modulate tumor drug resistance due to genotoxic drugs and signaling protein inhibitors. This review summarizes major scientific breakthroughs in understanding the contribution of BCSCs towards tumor's capability to endure destruction inflicted by molecular as well as genotoxic drugs. PMID- 28722146 TI - Implementing Clinical Prediction Models: Pushing the Needle Towards Precision Pharmacotherapy. AB - Clinical prediction models promise a future of precision drug therapy. However, very few models are used in practice. Although models can eliminate unwanted clinical guesswork, several barriers hinder model implementation in practice. Here we discuss the less well-recognized barriers hindering model implementation for precision prescribing, highlighting areas that warrant attention, primarily relating to ethical and regulatory considerations that are requisite in paving the way towards a future of precision pharmacotherapy. PMID- 28722144 TI - Mechanisms Involved in Hypersensitivity Reactions to Polysulfone Hemodialysis Membranes. AB - Several cases of patients with anaphylactic or systemic hypersensitivity reactions to polysulfone (PS) hemodialysis (HD) membranes and tolerance to cellulose triacetate (CTA) membranes have recently been reported. To investigate the mechanisms involved in PS hypersensitivity, basophil, T cell, and complement activation were analyzed in acute-phase samples from two patients with systemic reactions to PS-based membranes. Basophil and T cell activation, as well as higher serum tryptase levels were detected in acute-phase samples compared with basal levels. Complement levels (C3 and C4) were decreased in acute-phase samples from PS-allergic patients to a higher extent than in samples from control donors taken at the same time points, indicating complement activation during the acute reactions. An experimental external circuit was established on pediatric membranes after rinsing with low or high priming volumes of saline solution, to analyze basophils, T cells, and complement activation in blood samples from 10 PS allergic and 8 nonallergic HD patients upon contact with PS-based or CTA membranes. Predialysis and postdialysis samples were collected. Basophils from PS allergic patients exhibited increased degranulation, and T cells showed significantly increased activation after contact with PS-based membranes primed with low volumes of saline. No activation was detected in leukocytes from nonallergic patients under the same experimental conditions. Membrane priming with high volumes of saline abrogated activation of basophils and T cells. However, basophils from allergic donors showed significantly higher responses to Fcepsilonc stimulation after contact with PS membranes. Basophil degranulation and elevated serum tryptase levels in allergic patients during acute reactions support the systemic activation of mast cells and basophils during hypersensitivity reactions to PS-based membranes. A leachable component of the membranes might be responsible for cell activation in some patients. PMID- 28722145 TI - Dendrobium nobile Lindl. alkaloids regulate metabolism gene expression in livers of mice. AB - OBJECTIVES: In our previous studies, Dendrobium nobile Lindl. alkaloids (DNLA) has been shown to have glucose-lowering and antihyperlipidaemia effects in diabetic rats, in rats fed with high-fat diets, and in mice challenged with adrenaline. This study aimed to examine the effects of DNLA on the expression of glucose and lipid metabolism genes in livers of mice. METHODS: Mice were given DNLA at doses of 10-80 mg/kg, po for 8 days, and livers were removed for total RNA and protein isolation to perform real-time RT-PCR and Western blot analysis. KEY FINDINGS: Dendrobium nobile Lindl. alkaloids increased PGC1alpha at mRNA and protein levels and increased glucose metabolism gene Glut2 and FoxO1 expression. DNLA also increased the expression of fatty acid beta-oxidation genes Acox1 and Cpt1a. The lipid synthesis regulator Srebp1 (sterol regulatory element-binding protein-1) was decreased, while the lipolysis gene ATGL was increased. Interestingly, DNLA increased the expression of antioxidant gene metallothionein 1 and NADPH quinone oxidoreductase-1 (Nqo1) in livers of mice. Western blot on selected proteins confirmed these changes including the increased expression of GLUT4 and PPARalpha. CONCLUSIONS: DNLA has beneficial effects on liver glucose and lipid metabolism gene expressions, and enhances the Nrf2-antioxidant pathway gene expressions, which could play integrated roles in regulating metabolic disorders. PMID- 28722147 TI - Surface isoelectric focusing (sIEF) with carrier ampholyte pH gradient. AB - Isoelectric focusing (IEF) is a powerful tool for amphoteric protein separations because of high sensitivity, bio-compatibility, and reduced complexity compared to chromatography or mechanical separation techniques. IEF miniaturization is attractive because it enables rapid analysis, easier adaptation to point of care applications, and smaller sample demands. However, existing small-scale IEF tools have not yet been able to analyze single protein spots from array libraries, which are ubiquitous in many pharmaceutical discovery and screening protocols. Thus, we introduce an in situ, novel, miniaturized protein analysis approach that we have termed surface isoelectric focusing (sIEF). Low volume printed sIEF gels can be run at length scales of ~300 MUm, utilize ~0.9 ng of protein with voltages below 10 V. Further, the sIEF device platform is so simple that it can be integrated with protein library arrays to reduce cost; devices demonstrate reusability above 50 uses. An acrylamide monomer solution containing broad-range carrier ampholytes was microprinted with a Nano eNablerTM between micropatterned gold electrodes spaced 300 MUm apart on a glass slide. The acrylamide gel was polymerized in situ followed by protein loading via printed diffusional exchange. A pH gradient formed via carrier ampholyte stacking when electrodes were energized; the gradient was verified using ratiometric pH-sensitive FITC/TRITC dyes. Green fluorescent protein (GFP) and R-phycoerythrin (R-PE) were utilized both as pI markers and to test sIEF performance as a function of electric field strength and ampholyte concentration. Factors hampering sIEF included cathodic drift and pH gradient compression, but were reduced by co-printing non-ionic Synperonic(r) F-108 surfactant to reduce protein-gel interactions. sIEF gels achieved protein separations in <10 min yielding bands < 50 MUm wide with peak capacities of ~8 and minimum pI differences from 0.12 to 0.14. This new sIEF technique demonstrated comparable focusing at ~100 times smaller dimensions than any previous IEF. Further, sample volumes required were reduced four orders of magnitude from 20 MUL for slab gel IEF to 0.002 MUL for sIEF. In summary, sIEF advantages include smaller volumes, reduced power consumption, and microchip surface accessibility to focused bands along with equivalent separation resolutions to prior IEF tools. These attributes position this new technology for rapid, in situ protein library analysis in clinical and pharmaceutical settings. PMID- 28722148 TI - Learning from Dorothy Vaughan: artificial intelligence and the health professions. PMID- 28722150 TI - Lessons in the diagnosis and management of immune thrombocytopenic purpura in children. PMID- 28722149 TI - Masting in wind-pollinated trees: system-specific roles of weather and pollination dynamics in driving seed production. AB - Masting, the highly variable production of synchronized large seed crops, is a common reproductive strategy in plant populations. In wind-pollinated trees, flowering and pollination dynamics are hypothesized to provide the mechanistic link for the well-known relationship between weather and population-level seed production. Several hypotheses make predictions about the effect of weather on annual pollination success. The pollen coupling hypothesis predicts that weather and plant resources drive the flowering effort of trees, which directly translates into the size of seed crops through efficient pollination. In contrast, the pollination Moran effect hypothesis predicts that weather affects pollination efficiency, leading to occasional bumper crops. Furthermore, the recently formulated phenology synchrony hypothesis predicts that Moran effects can arise because of weather effects on flowering synchrony, which, in turn, drives pollination efficiency. We investigated the relationship between weather, airborne pollen, and seed production in common European trees, two oak species (Quercus petraea and Q. robur) and beech (Fagus sylvatica) with a 19-yr data set from three sites in Poland. Our results show that warm summers preceding flowering correlated with high pollen abundance and warm springs resulted in short pollen seasons (i.e., high flowering synchrony) for all three species. Pollen abundance was the best predictor for seed crops in beech, as predicted under pollen coupling. In oaks, short pollen seasons, rather than pollen abundance, correlated with large seed crops, providing support for the pollination Moran effect and phenology synchrony hypotheses. Fundamentally different mechanisms may therefore drive masting in species of the family Fagacae. PMID- 28722151 TI - The antithrombotic and haemostatic effects of LASSBio-752: a synthetic, orally active compound in an arterial and venous thrombosis model in rats. AB - OBJECTIVES: In this work, we further investigated the effect of the compound LASSBio-752 in thrombosis models in rats. METHODS: Arterial and venous thrombosis model, ex-vivo recalcification time and aPTT and PT. KEY FINDINGS: In the venous thrombosis model, oral administration of LASSBio-752 [48.2 mg (100 MUmol)/kg] one hour before the thrombus induction decreased thrombus weight by 37 +/- 0.2%. Interestingly, the antithrombotic action of this compound [48.2 mg (100 MUmol)/kg] occurred at 87.5 +/- 2.1% of inhibition after 24 h of administration and showed a lasting activity. When tested on the arterial thrombosis model, after a 1-h interval, there was already an increase in time to total occlusion of 34 +/- 2.4 min, but the greatest effect was observed at intervals between 6 and 15 h of administration, when no occlusion of the artery was observed. The antithrombotic effect was reduced after 24 h when the occlusion time was 23.8 +/- 2.3 min, close to that of the control, 17.6 +/- 2.0 min. We also observed that bleeding was not excessive in any of the intervals tested. CONCLUSIONS: Our results indicate that compound LASSBio-752 is a potential candidate for utilization in the treatment of thromboembolic diseases. PMID- 28722152 TI - Pilot of the BOOST-ATM: An online transition planning program for adolescents with autism. AB - BACKGROUND: Many adolescents with autism face difficulties with the transition from high school into post-school activities. The Better OutcOmes & Successful Transitions for Autism (BOOST-ATM) is an online transition planning program which supports adolescents on the autism spectrum to prepare for leaving school. This study describes the development of the BOOST-ATM and aimed to determine the feasibility and viability of the program. METHODS: Two pilot studies were conducted. In Pilot A, the BOOST-ATM was trialled by six adolescents on the autism spectrum, their parents, and the professionals who worked with them, to determine its feasibility. In Pilot B, 88 allied health professionals (occupational therapists, speech pathologists, and psychologists) reviewed the BOOST-ATM to determine its viability. RESULTS: Participants rated the BOOST-ATM as a feasible tool for transition planning. The majority of allied health professionals agreed that it was a viable program. Based on participant feedback, the BOOST-ATM was modified to improve usability and feasibility. CONCLUSION: The BOOST-ATM is a viable and feasible program that has the potential to assist adolescents with autism in preparing for transitioning out of high school. Future research will determine the effectiveness of the BOOST-ATM with adolescents across Australia. PMID- 28722153 TI - Pharmacokinetics and safety of the anti-human cytomegalovirus drug letermovir in subjects with hepatic impairment. AB - AIMS: Human cytomegalovirus constitutes a prevalent and serious threat to immunocompromised individuals and requires new treatments. Letermovir is a novel viral-terminase inhibitor that has demonstrated prophylactic/pre-emptive activity against human cytomegalovirus in Phase 2 and 3 transplant trials. As unchanged letermovir is primarily excreted via the liver by bile, this trial aimed to assess the effect of hepatic impairment on letermovir pharmacokinetics. METHODS: Phase 1, open-label, parallel-group pharmacokinetic and safety comparison of multiple once-daily oral letermovir in female subjects with hepatic impairment and healthy matched controls. For 8 days, subjects with moderate hepatic impairment (n = 8) and their matched healthy controls (n = 9) received 60 mg letermovir/day and those with severe hepatic impairment (n = 8) and their matched healthy controls (n = 8) received 30 mg letermovir/day. Pharmacokinetic parameters were determined from blood samples. RESULTS: For subjects with moderate hepatic impairment, maximal observed concentration at steady state (Css,max ) and the area under the concentration vs. time curve over a dosing interval at steady state (AUCtau,ss ) for total letermovir were 1.37-fold (90% confidence interval: 0.87, 2.17) and 1.59-fold (0.98, 2.57) higher, respectively, than in healthy subjects. For subjects with severe hepatic impairment, Css,max and AUCtau,ss values of total letermovir were 2.34-fold (1.91, 2.88) and 3.82 fold (2.94, 4.97) higher, respectively, compared with healthy subjects. CONCLUSIONS: Moderate hepatic impairment increased exposure to letermovir <2 fold, while severe hepatic impairment increased letermovir exposure approximately 4-fold as compared with healthy subjects. Letermovir 60/30 mg/day was generally well-tolerated in subjects with hepatic impairment. PMID- 28722154 TI - Application of headspace solid-phase microextraction followed by gas chromatography coupled with mass spectrometry to determine esters of carboxylic acids and other volatile compounds in Dermestes maculatus and Dermestes ater lipids. AB - A constant problem in veterinary medicine, human healthcare, agriculture, forestry and horticulture is the large number of pests, and the lack of effective methods to combat them which cause no harm to the rest of the environment. It is recommended and desired to reduce the use of chemicals and increase the use of agents based on knowledge acquired in the fields of biology, chemistry and agrochemicals. To learn the defense mechanisms of insects we should consider not only the site of their physiological ability to protect against external factors (cuticle), but also the possibility of chemical protection, formed by all compounds on the surface and in the body of insects. In this study, a procedure was developed to determine the esters of carboxylic acids in insect lipids. Headspace solid-phase microextraction was followed by gas chromatography coupled with gas spectrometry. First, the best conditions were selected for the analysis to obtain the best chromatographic separation. An RTx-5 column was used for this purpose. Polydimethylsiloxane/divinylbenzene (PDMS/DVB) and polyacrylate fibers were used to isolate acid esters. PDMS/DVB fiber achieved the best conditions for the extraction; the extraction time was 50 min, the extraction temperature was 105 degrees C and the desorption time was 10 min at 230 degrees C. These solid phase microextraction conditions were used to analyze volatile compounds extracted from insects belonging to the Dermestidae family. PMID- 28722155 TI - Metabolite availability as a window to view the early embryo microenvironment in vivo. AB - A preimplantation embryo exists independent of blood supply, and relies on energy sources from its in vivo environment (e.g., oviduct and uterine fluid) to sustain its development. The embryos can survive in this aqueous environment because it contains amino acids, proteins, lactate, pyruvate, oxygen, glucose, antioxidants, ions, growth factors, hormones, and phospholipids-albeit the concentration of each component varies by species, stage of the estrous cycle, and anatomical location. The dynamic nature of this environment sustains early development from the one-cell zygote to blastocyst, and is reciprocally influenced by the embryo at each embryonic stage. Focusing on embryo metabolism allowed us to identify how the local environment was deliberately selected to meet the dynamic needs of the preimplantation embryo, and helped reveal approaches to improve the in vitro culture of human embryos for improved implantation rates and pregnancy outcome. PMID- 28722156 TI - Chemometric evaluation of hypericin and related phytochemicals in 17 in vitro cultured Hypericum species, hairy root cultures and hairy root-derived transgenic plants. AB - OBJECTIVES: The objective of this study was to ascertain the presence and correlations among eight important secondary metabolites viz. hypericin, pseudohypericin, emodin, hyperforin, rutin, hyperoside, quercetin and quercitrin in different organs of 17 in vitro cultured Hypericum species, along with H. tomentosum and H. tetrapterum hairy root cultures, and hairy root-derived transgenic plants of H. tomentosum. METHODS: Samples were extracted and analysed by LC-MS. The LC-MS data were subjected to chemometric evaluations for metabolite profiling and correlating the phytochemical compositions in different samples. KEY FINDINGS: Hypericin, pseudohypericin and their proposed precursor emodin were detected in various levels in the leaves of eight Hypericum species. The highest content of hypericins and emodin was found in H. tetrapterum, which contains the studied secondary metabolites in all plant organs. A significant positive correlation between hypericins and emodin was observed both by principal component analysis (PCA) and multidimensional scaling (MDS), indicating the role of emodin as a possible precursor in the biosynthetic pathway of hypericins. Flavonoids were found in all tested plant organs except roots of H. pulchrum. The hairy roots lacked hypericin, pseudohypericin, emodin, hyperforin and rutin. However, the hairy root-derived transgenic plants showed a significant increase in flavonoids. CONCLUSIONS: This study broadens knowledge about the phytochemical composition of selected in vitro cultured Hypericum species, compared to that of hairy root cultures and hairy root-derived transgenic plants. PMID- 28722157 TI - Matching the production of doctors with national needs. AB - CONTEXT: Matching the supply of health workers to need is necessary if a health system is to be sustainable, affordable and fit for purpose. On the 30th anniversary of the 1988 Edinburgh Declaration of the World Federation for Medical Education, levels of compliance with the 10th recommendation, 'Ensure admission policies that match the numbers of students trained with national needs for doctors', warrant review. There are two domains to such a review, concerning, respectively, how well these health needs are known, and whether workforce supply is well matched. METHODS: This is a literature review-based analysis of extant health system planning, which underpins current understanding of national health needs and of the consequent alignment of student selection processes. RESULTS: The core finding is that national need for doctors, and any other health workers, is not confidently known for any jurisdiction. Consequently, validation of student selection processes is impossible against this endpoint and data to validate these processes against the alternative endpoint of a positive impact on health outcomes do not exist. Data do exist to suggest some student selection processes result in desirable career and career location uptakes. PMID- 28722158 TI - Gravitropism interferes with hydrotropism via counteracting auxin dynamics in cucumber roots: clinorotation and spaceflight experiments. AB - Roots of land plants show gravitropism and hydrotropism in response to gravity and moisture gradients, respectively, for controlling their growth orientation. Gravitropism interferes with hydrotropism, although the mechanistic aspects are poorly understood. Here, we differentiated hydrotropism from gravitropism in cucumber roots by conducting clinorotation and spaceflight experiments. We also compared mechanisms regulating hydrotropism and auxin-regulated gravitropism. Clinorotated or microgravity (MUG)-grown cucumber seedling roots hydrotropically bent toward wet substrate in the presence of moisture gradients, but they grew straight in the direction of normal gravitational force at the Earth's surface (1G) on the ground or centrifuge-generated 1G in space. The roots appeared to become hydrotropically more sensitive to moisture gradients under MUG conditions in space. Auxin transport inhibitors significantly reduced the hydrotropic response of clinorotated seedling roots. The auxin efflux protein CsPIN5 was differentially expressed in roots of both clinorotated and MUG-grown seedlings; with higher expression in the high-humidity (concave) side than the low-humidity (convex) side of hydrotropically responding roots. Our results suggest that roots become hydrotropically sensitive in MUG, and CsPIN5-mediated auxin transport has an important role in inducing root hydrotropism. Thus, hydrotropic and gravitropic responses in cucumber roots may compete via differential auxin dynamics established in response to moisture gradients and gravity. PMID- 28722159 TI - Changes are still needed on multiple co-primary endpoints. AB - The Food and Drug Administration in the United States issued a much-awaited draft guidance on 'Multiple Endpoints in Clinical Trials' in January 2017. The draft guidance is well written and contains consistent message on the technical implementation of the principles laid out in the guidance. In this commentary, we raise a question on applying the principles to studies designed from a safety perspective. We then direct our attention to issues related to multiple co primary endpoints. In a paper published in the Drug Information Journal in 2007, Offen et al. give examples of disorders where multiple co-primary endpoints are required by regulators. The standard test for multiple co-primary endpoints is the min test which tests each endpoint individually, at the one-sided 2.5% level, for a confirmatory trial. This approach leads to a substantial loss of power when the number of co-primary endpoints exceeds 2, a fact acknowledged in the draft guidance. We review approaches that have been proposed to tackle the problem of power loss and propose a new one. Using recommendations by Chen et al. for the assessment of drugs for vulvar and vaginal atrophy published in the Drug Information Journal in 2010, we argue the need for more changes and urge a path forward that uses different levels of claims to reflect the effectiveness of a product on multiple endpoints that are equally important and mostly unrelated. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28722160 TI - Placental Proteomics Reveal Insights into Fetal Alcohol Spectrum Disorders. AB - BACKGROUND: Fetal alcohol spectrum disorders (FASD) describe many of the well known neurodevelopmental deficits afflicting children exposed to alcohol in utero. The effects of alcohol on the maternal-fetal interface, especially the placenta, have been less explored. We herein hypothesized that chronic binge alcohol exposure during pregnancy significantly alters the placental protein profile in a rat FASD model. METHODS: Pregnant rats were orogastrically treated daily with alcohol (4.5 g/kg, gestational day [GD] 5 to 10; 6.0 g/kg, GD 11 to 19) or 50% maltose dextrin (isocalorically matched pair-fed controls). On GD 20, placentae were collected, flash-frozen, and stored until tissues were homogenized. Protein lysates were denatured, reduced, captured on a 10-kDa spin filter, and digested. Peptides were eluted, reconstituted, and analyzed by a Q ExactiveTM Hybrid Quadrupole-OrbitrapTM mass spectrometer. RESULTS: Mass spectrometry (MS) analysis identified 2,285 placental proteins based on normalized spectral counts and 2,000 proteins by intensity-based absolute quantification. Forty-five placental proteins were significantly (p < 0.05) altered by gestational alcohol exposure by both quantification approaches. These included proteins directly related to alcohol metabolism; specific isoforms of alcohol dehydrogenase and aldehyde dehydrogenase were up-regulated in the alcohol group. Ingenuity analysis identified ethanol degradation as the most significantly altered canonical pathway in placenta, and fetal/organ development as most altered function, with increased risk for metabolic, neurological, and cardiovascular diseases. Physiological roles of the significantly altered proteins were related to early pregnancy adaptations, implantation, gestational diseases, fetal organ development, neurodevelopment, and immune functions. CONCLUSIONS: We conclude that the placenta is a valuable organ not only to understand FASD etiology but it may also serve as a diagnostic tool to identify novel biomarkers for detecting the outcome of fetal alcohol exposure. Placental MS analysis can offer sophisticated insights into identifying alcohol metabolism related enzymes and regulators of fetal development. PMID- 28722163 TI - Risk of cancer in patients with psoriasis on biological therapies: a systematic review. AB - BACKGROUND: Biological therapies are highly effective in psoriasis, but have profound effects on innate and adaptive immune pathways that may negatively impact on cancer immunosurveillance mechanisms. OBJECTIVES: To investigate the risk of cancer in patients with psoriasis treated with biological therapy. METHODS: We searched MEDLINE, Embase, and the Cochrane Library (up to August 2016) for randomized controlled trials, prospective cohort studies and systematic reviews that reported cancer incidence in people exposed to biological therapy for psoriasis compared with a control population. RESULTS: Eight prospective cohort studies met our inclusion criteria. All the evidence reviewed related to tumour necrosis factor inhibitors (TNFi) with the exception of one study on ustekinumab. An increased risk of nonmelanoma skin cancer (NMSC), particularly squamous cell carcinoma, was reported with TNFi compared with both a general United States population and a rheumatoid arthritis population treated with TNFi. No evidence for increased risk of cancers (reported as all cancers, lymphoma, melanoma, prostate, colorectal and breast cancer) other than NMSC was identified. CONCLUSIONS: There were important limitations to the studies identified including choice of comparator arms, inadequate adjustment for confounding factors and failure to account for latency periods of cancer. There remains a need for ongoing pharmacovigilance in relation to cancer risk and biological therapy; the NMSC signal requires further investigation to determine the risk specifically attributable to biological therapy using prospectively collected data with adjustment for known NMSC risk factors. PMID- 28722162 TI - Cyanidin suppresses autophagic activity regulating chondrocyte hypertrophic differentiation. AB - Cartilage is a kind of special connective tissue which does not contain neither blood vessels nor lymphatics and nerves. Therefore, the damage in cartilage is difficult to be repaired spontaneously. Constructing tissue engineered cartilage provides a new technique for cartilage repairing. Mesenchymal stem cells (MSCs) possess a unique capability of self-renew and can differentiate into pre chondrocytes which are frequently applied as seed cells in tissue engineering. However, in regenerated cartilage the chondrocytes derived from MSCs can hardly maintain homeostasis and preferentially present hypertrophic like phenotype. We investigated the effects of cyanidin, a natural organic compound, on chondrogenic and subsequent hypertrophic differentiation of MSCs in order to seek approaches to inhibit chondrocyte hypertrophy. We evaluated the effects of cyanidin on expression of chondrogenic and hypertrophic marker genes through RT-PCR, Western blot, alcian blue staining, and immunocytochemistry. The results showed that both chondrogenic related genes Sox9, Col2a1, and hypertrophic marker genes Runx2, Col10a1 were inhibited by cyanidin. In addition, we found that cyanidin promoted Nrf2 and p62 expression and suppressed LC3B expression during chondrogenic stage of MSCs. Meanwhile phosphorylation of IkappaBalpha and autophagosome related protein LC3B were inactivated by cyanidin during chondrocyte hypertrophic stage. Furthermore, rapamycin, an autophagy activator, abrogated the inhibitory effect of cyanidin on chondrogenic, and hypertrophic differentiation of MSCs. In conclusion, one potential mechanism of cyanidin, by which the chondrogenic and hypertrophic differentiation of MSCs were inhibited, was due to decreased autophagy activity. Our results indicated that cyanidin was a potential therapeutic agent for keeping mature chondrocyte functions. PMID- 28722164 TI - A unifying explanation for variation in ozone sensitivity among woody plants. AB - Tropospheric ozone is considered the most detrimental air pollutant for vegetation at the global scale, with negative consequences for both provisioning and climate regulating ecosystem services. In spite of recent developments in ozone exposure metrics, from a concentration-based to a more physiologically relevant stomatal flux-based index, large-scale ozone risk assessment is still complicated by a large and unexplained variation in ozone sensitivity among tree species. Here, we explored whether the variation in ozone sensitivity among woody species can be linked to interspecific variation in leaf morphology. We found that ozone tolerance at the leaf level was closely linked to leaf dry mass per unit leaf area (LMA) and that whole-tree biomass reductions were more strongly related to stomatal flux per unit leaf mass (r2 = 0.56) than to stomatal flux per unit leaf area (r2 = 0.42). Furthermore, the interspecific variation in slopes of ozone flux-response relationships was considerably lower when expressed on a leaf mass basis (coefficient of variation, CV = 36%) than when expressed on a leaf area basis (CV = 66%), and relationships for broadleaf and needle-leaf species converged when using the mass-based index. These results show that much of the variation in ozone sensitivity among woody plants can be explained by interspecific variation in LMA and that large-scale ozone impact assessment could be greatly improved by considering this well-known and easily measured leaf trait. PMID- 28722165 TI - Dimorphic ejaculates and sperm release strategies associated with alternative mating behaviors in the squid. AB - Sperm competition is a powerful postcopulatory selective force influencing male adaptations associated with increasing fertilization success, and it is usually related to the evolution of different strategies of ejaculate expenditure between individuals. Ejaculates may also be influenced by additional selective pressures associated with sperm competition, such as timing between insemination and fertilization, female reproductive tract morphology, and fertilization environment. Also, males that adopt alternative mating tactics may face distinct sperm competition pressures, which may lead to the evolution of intraspecific diversity in ejaculates. In loliginid squids, males with alternative reproductive tactics (sneakers and consorts) differ not only in mating behavior, but also transfer spermatophores into two distinct sites within the female. Here, we compared structure and functioning of spermatophores between sneakers and consorts in the squid Doryteuthis plei applying microscopy techniques and in vitro experiments. Sneakers and consorts exhibit differences in spermatophore structure that lead to distinct spermatophoric reactions and spermatangium morphologies. Moreover, in sneakers, sperm release lasts longer and their sperm show an aggregative behavior not detected in consorts. Slow sperm release may be a strategy to guarantee longer sperm provision, given the wide interval between sneaker mating and egg release. For consorts, in turn, intense and quick sperm discharge may be advantageous, as timing between mating and egg-laying is relatively short. Within the complex squid mating system, factors such as (i) different fertilization sites and (ii) interval between mating and egg release may also influence sperm competition, and ultimately shape the evolution of divergent ejaculates between dimorphic males. PMID- 28722166 TI - Choir singing and creative writing enhance emotion regulation in adults with chronic mental health conditions. AB - OBJECTIVES: Adults with mental health conditions commonly experience difficulties with emotion regulation which affect their social functioning. Arts-based groups provide opportunities for shared emotional experiences and emotion regulation. This study explores emotion regulation strategies and the emotional effects of arts-based group participation in adults with mental health problems and in controls. DESIGN AND METHOD: The 62 participants included 39 adults with chronic mental health problems who were members of arts-based groups (ABG) and 23 comparison choir (CC) members who were not specifically experiencing mental health problems. The repeated measures design included self-reports of emotion upon waking (T1), the hour before group (T2), end of the group (T3), and evening (T4), as well as participant notes to explain their emotion ratings at each time. They also completed measures of individual and interpersonal emotion regulation. RESULTS: The ABG participants engaged marginally more in affect worsening strategies than CC (p = .057 and .08), but there were no other group differences. All participants reported a significant increase in positive emotions, F (3, 180) = 28.044, p < .001, np2 = .319; and a decrease in negative emotions during the arts-based activity: F (2.637, 155.597) = 21.09, p < .001, np2 = .263. The influence on positive emotions was short-lived, while the effect on negative emotions lasted until evening. CONCLUSION: Findings show that participation in arts-based groups benefits the emotions of both healthy adults and those experiencing mental health conditions through individual and interpersonal processes. PRACTITIONER POINTS: Individuals with chronic mental health conditions often experience difficulties in emotion processing Participation in arts-based groups was associated with significant increases in positive emotions although these were short-lived Negative emotion was significantly decreased during arts based group activities, and sustained to the evening assessment Adults with chronic mental health conditions were equally able to derive emotional benefits as healthy adults. PMID- 28722167 TI - Assisted autogenic drainage in infants and young children hospitalized with uncomplicated pneumonia, a pilot study. AB - BACKGROUND AND PURPOSE: Pneumonia is the most important respiratory problem in low-to-middle income countries. Airway clearance therapy continues to be used in children with pneumonia and secretion retention; however, there is lack of evidence to support or reject this treatment. This study aimed to investigate the feasibility of a randomized controlled trial (RCT) on the efficacy and safety of assisted autogenic drainage (AAD) compared to standard nursing care in children hospitalized with uncomplicated pneumonia. METHODS: A single-blinded pilot RCT was conducted on 29 children (median age 3.5 months, IQR 1.5-9.4) hospitalized with uncomplicated pneumonia. The intervention group received standard nursing care with additional bi-daily AAD, for 10 to 30 min. The control group only received standard nursing care, unless otherwise deemed necessary by the physician or physiotherapist. The primary outcome measure was duration of hospitalization. The secondary outcome measures included days of fever and supplemental oxygen support; respiratory rate (RR) and heart rate adjusted for age; RR and oxygen saturation pre-, post-, and 1-hr post-treatment; oxygen saturation; adverse events; and mortality. RESULTS: No difference was found for duration of hospitalization (median 7.5 and 7.0 days for the control and intervention groups, respectively); however, Kaplan-Meier analysis revealed a strong tendency towards a shorter time to discharge in the intervention group (p = .06). No significant differences were found for the other outcome measures at time of discharge. No adverse events were reported. Within the intervention group, a significant reduction in RR adjusted for age was found. DISCUSSION: As no adverse events were reported, and AAD did not prolong hospitalization; AAD might be considered as safe and effective in young children with uncomplicated pneumonia. However, a larger multicentred RCT is warranted to determine the efficacy of AAD compared to standard nursing care. PMID- 28722168 TI - Role of palmitoylation of cysteine 415 in functional coupling CB1 receptor to Galphai2 protein. AB - In this study, we investigated the role of CB1 palmitoylation in modulating the functional interaction with G proteins both in the absence and presence of agonist binding. Our data show that the nonpalmitoylated CB1 receptor significantly reduced its association with Galphai2 . The agonist stimulation induced a partial dissociation of Galphai2 proteins from the wild-type receptor, while on the C415A mutant the agonist binding was not able to induce a significant dissociation of Galphai2 from the receptor. The lack of palmitoyl chain seems to hamper the ability of the receptor to functionally interact with the Galphai2 and indicate that the palmitoyl chain is responsible for the functional transmission of the agonist-induced conformational change in the receptor of the G protein. These data were further corroborated by molecular dynamics simulations. Overall these results suggest that palmitoylation of the CB1 receptor finely tunes its interaction with G proteins and serves as a targeting signal for its functional regulation. Of note, the possibility to reversibly modulate the palmitoylation of CB1 receptor may offer a coordinated process of regulation and could open new therapeutic approaches. PMID- 28722169 TI - Prognosis-Based Shoulder Hemiarthroplasty After Resection of Proximal Humeral Malignancy. AB - After wide excision of proximal humeral bony malignancy, prognosis-based reconstruction was performed at Taipei Veterans General Hospital. Bone prosthesis composite (BPC) was carried out among patients with a favored prognosis, while cement-spacer prosthesis composite (CSPC) was preserved for patients with poor prognosis. The aim of our study is to compare the clinical outcomes between the BPC and CSPC reconstruction procedures. From January 2000 to December 2014, we retrospectively reviewed the clinical outcomes of 34 patients who underwent shoulder hemiarthroplasty following wide excision of a malignant lesion of the proximal humerus, 15 of whom were treated with a BPC reconstruction and 19 cases were treated with a CSPC reconstruction. The mean postoperative follow-up was 51.9 months for the BPC group and 29.0 months for the CSPC group. At the end of the study, four patients (two in the BPC group and two in the CSPC group) developed local recurrence. Thirteen patients (1 in the BPC group and 12 in the CSPC group) had died of disease progression. The postoperative visual analogue scale score of BPC and CSPC groups was similar (P = 0.262). Functional outcome, measured using the Musculoskeletal Tumor Society score and shoulder range of motion, favored the BPC procedure (P < 0.001). The CSPC procedure, however, had less complication rate, required less operative time, and had a lower volume of intraoperative blood loss than the BPC procedure (P < 0.001). Although functional outcomes are expected to be more favorable with a BPC procedure, the CSPC procedure continues to be a safe and cost-effective shoulder hemiarthroplasty procedure for patients with low-demanding activities and when a poor disease prognosis is expected. PMID- 28722170 TI - Activation of the B-cell receptor successively activates NF-kappaB and STAT3 in chronic lymphocytic leukemia cells. AB - In chronic lymphocytic leukemia (CLL) cells, both interleukin-6 (IL-6) and the B cell receptor (BCR) activate Janus kinase 2 (JAK2) and induce the phosphorylation of signal transduction and activator of transcription 3 (STAT3) on tyrosine 705 residues. However, whereas IL-6 phosphorylates STAT3 within 15 min, stimulation of the BCR with anti-immunoglobulin M (IgM) antibodies phosphorylates STAT3 in 2 4 hr. Here, we show that this process takes longer because it requires transcriptional activity of NF-kappaB. Using an electromobility shift assay, we found that incubation with IgM antibodies for 4 or 18 hr, but not 15 min, increased NF-kappaB DNA-binding of CLL cells and increased binding was translated to increased transcriptional activity. Hence, 42% of the 83 NF-kappaB target genes were constitutively expressed in all CLL cells prior to any inducible stimuli. However, activation of the BCR increased the number of NF-kappaB target genes with detectable expression by 23%. Remarkably, prolonged incubation with anti-IgM antibodies induced a time-dependent transcription, production and secretion of IL-6 protein. The IgM-induced production of IL-6 prompted the phosphorylation of STAT3 on tyrosine residues. This effect was inhibited by the JAK1/2 inhibitor of the JAK/STAT3 pathway ruxolitinib. Taken together, these results suggest that in CLL cells, constitutive tonic activation of NF-kappaB can be further enhanced by the BCR and that the BCR-induced activation of the JAK/STAT3 pathway depends on the NF-kappaB induced production of IL-6. PMID- 28722172 TI - Intentional learning: A concept analysis. AB - AIM: To use a concept analysis to determine a clear definition of the term "intentional learning" for use in nursing. BACKGROUND: The term intentional learning has been used for years in educational, business, and even nursing literature. It has been used to denote processes leading to higher order thinking and the ability to use knowledge in new situations; both of which are important skills to develop in nursing students. But the lack of a common, accepted definition of the term makes it difficult for nurse educators to base instruction and learning experiences on or to evaluate its overall effectiveness in educating students for diverse, fast-paced clinical practices. DESIGN AND REVIEW METHODS: A concept analysis following the eight-step method developed by Walker and Avant (2011). DATA SOURCES: Empirical and descriptive literature. RESULTS: Five defining attributes were identified: (1) self-efficacy for learning, (2) active, effortful, and engaged learning, (3) mastery of goals where learning is the goal, (4) self-directed learning, and (5) self-regulation of learning. CONCLUSION: Through this concept analysis, nursing will have a clear definition of intentional learning. This will enable nurse educators to generate, evaluate, and test learning experiences that promote further development of intentional learning in nursing students. Nurses in practice will also be able to evaluate if the stated benefits are demonstrated and how this impacts patient care and outcomes. PMID- 28722171 TI - Use of antibiotics during pregnancy and the risk of major congenital malformations: a population based cohort study. AB - AIMS: Few studies have investigated the link between individual antibiotics and major congenital malformations (MCMs) including specific malformations owing to small sample size. We aimed to quantify the association between exposure to gestational antibiotic and the risk of MCMs. METHODS: Using the Quebec pregnancy cohort (1998-2008), we included a total of 139 938 liveborn singleton alive whose mothers were covered by the "Regie de l'assurance maladie du Quebec" drug plan for at least 12 months before and during pregnancy. Antibiotic exposure was assessed in the first trimester and MCMs were identified within the first year of life. RESULTS: After adjusting for potential confounders, clindamycin exposure was associated with an increased risk of MCMs (aOR 1.34, 95% CI 1.02-1.77, 60 exposed cases), musculoskeletal system malformations (aOR 1.67, 95% CI 1.12-2.48, 29 exposed cases) and ventricular/atrial septal defect (aOR 1.81, 95% CI 1.04 3.16, 13 exposed cases). Doxycycline exposure increased the risk of circulatory system malformation, cardiac malformations and ventricular/atrial septal defect (aOR 2.38, 95% CI 1.21-4.67, 9 exposed cases; aOR 2.46, 95% CI 1.21-4.99, 8 exposed cases; aOR 3.19, 95% CI 1.57-6.48, 8 exposed cases, respectively). Additional associations were seen with quinolone (1 defect), moxifloxacin (1 defect), ofloxacin (1 defect), macrolide (1 defect), erythromycin (1 defect) and phenoxymethylpenicillin (1 defect). No link was observed with amoxicillin, cephalosporins and nitrofurantoin. Similar results were found when penicillins were used as the comparator group. CONCLUSIONS: Clindamycin, doxycycline, quinolones, macrolides and phenoxymethylpenicillin in utero exposure were linked to organ-specific malformations. Amoxicillin, cephalosporins and nitrofurantoin were not associated with MCMs. PMID- 28722173 TI - The development of non-essentialist concepts of ethnicity among children in a multicultural London community. AB - Ethnic constancy, the belief that a person cannot change ethnicity, is an important component of ethnic essentialism, the conviction that members of ethnic groups share an immutable underlying essence. Most children in previous research viewed ethnicity as increasingly immutable with age. However, some evidence suggests that children growing up in communities, which define ethnicity primarily in terms of changeable features (e.g., lifestyle) rather than fixed features (e.g., ancestry), may not follow this trajectory. This study examined ethnic constancy development in a community which defined ethnicity primarily in terms of changeable features. It was hypothesized that older children would view ethnicity as more changeable than younger children, but that because of personal investment which increases with age, children would view their own ethnicity as more stable than a peer's ethnicity, entailing a significant interaction between age and self-other. Ninety-two children in three age groups (mean ages 7, 9, and 11 years) from a multicultural school in London were interviewed individually. Their ethnicities were 45% Indian, 16% English, 7% Pakistani, 7% Somali, 2% unknown, and 25% other. Children's explanations were analysed thematically. All hypotheses were supported. Children's conceptions of others' ethnicity as changeable were supported by definitions focusing on religion, and by the concept of freedom of choice. This suggests that in a community in which ethnicity is primarily defined in terms of attributes which are seen as mutable (in this case, religion), children may not essentialize ethnicity. Still, ethnic change may rarely occur in practice due to an emotional commitment to one's own ethnic group. Statement of contribution What is already known on this subject? Most research finds that children develop concept of ethnicity as fixed and essential; But limited evidence of non-essentialist developmental pathways for ethnicity For gender, children assert constancy more for themselves than others What does this study add? Evidence of developmental pathway to non-essentializing, mutable concept of ethnicity Evidence that definitions of ethnicity centred on religion may encourage ethnic non-essentialism Children are more willing to embrace ethnic mutability for others than for themselves. PMID- 28722175 TI - How the Community Shapes Unmet Need for Modern Contraception: An Analysis of 44 Demographic and Health Surveys. AB - Unmet need for modern contraception is a major public health concern in resource constrained countries. Recent research supports the application of social ecological theories to explain how characteristics of a woman's community shape modern contraception use. However, this research focuses largely on individual countries and uses a limited number of community-level effects. We fitted three random-effects logistic regression models to examine associations between 13 community-level variables and the odds of reporting unmet need, unmet need for spacing, and unmet need for limiting for all parous, female respondents in 44 DHS surveys collected in 2010-2015 (n=528,101). Community variables explain significant variance in unmet need between communities. Associations between community variables and unmet need differ by urban and rural residence. The results highlight several commonalities in how the community shapes unmet need across resource-constrained settings and may help in designing structural-level interventions. PMID- 28722176 TI - Comparative study of submerged and surface culture acetification process for orange vinegar. AB - BACKGROUND: The two main acetification methodologies generally employed in the production of vinegar (surface and submerged cultures) were studied and compared for the production of orange vinegar. Polyphenols (UPLC/DAD) and volatiles compounds (SBSE-GC/MS) were considered as the main variables in the comparative study. Sensory characteristics of the obtained vinegars were also evaluated. RESULTS: Seventeen polyphenols and 24 volatile compounds were determined in the samples during both acetification processes. For phenolic compounds, analysis of variance showed significant higher concentrations when surface culture acetification was employed. However, for the majority of volatile compounds higher contents were observed for submerged culture acetification process, and it was also reflected in the sensory analysis, presenting higher scores for the different descriptors. Multivariate statistical analysis such as principal component analysis demonstrated the possibility of discriminating the samples regarding the type of acetification process. Polyphenols such as apigenin derivative or ferulic acid and volatile compounds such as 4-vinylguaiacol, decanoic acid, nootkatone, trans-geraniol, beta-citronellol or alpha-terpineol, among others, were those compounds that contributed more to the discrimination of the samples. CONCLUSION: The acetification process employed in the production of orange vinegar has been demonstrated to be very significant for the final characteristics of the vinegar obtained. So it must be carefully controlled to obtain high quality products. (c) 2017 Society of Chemical Industry. PMID- 28722174 TI - Astrocytes follow ganglion cell axons to establish an angiogenic template during retinal development. AB - Immature astrocytes and blood vessels enter the developing mammalian retina at the optic nerve head and migrate peripherally to colonize the entire retinal nerve fiber layer (RNFL). Retinal vascularization is arrested in retinopathy of prematurity (ROP), a major cause of bilateral blindness in children. Despite their importance in normal development and ROP, the factors that control vascularization of the retina remain poorly understood. Because astrocytes form a reticular network that appears to provide a substrate for migrating endothelial cells, they have long been proposed to guide angiogenesis. However, whether astrocytes do in fact impose a spatial pattern on developing vessels remains unclear, and how astrocytes themselves are guided is unknown. Here we explore the cellular mechanisms that ensure complete retinal coverage by astrocytes and blood vessels in mouse. We find that migrating astrocytes associate closely with the axons of retinal ganglion cells (RGCs), their neighbors in the RNFL. Analysis of Robo1; Robo2 mutants, in which RGC axon guidance is disrupted, and Math5 (Atoh7) mutants, which lack RGCs, reveals that RGCs provide directional information to migrating astrocytes that sets them on a centrifugal trajectory. Without this guidance, astrocytes exhibit polarization defects, fail to colonize the peripheral retina, and display abnormal fine-scale spatial patterning. Furthermore, using cell type-specific chemical-genetic tools to selectively ablate astrocytes, we show that the astrocyte template is required for angiogenesis and vessel patterning. Our results are consistent with a model whereby RGC axons guide formation of an astrocytic network that subsequently directs vessel development. PMID- 28722177 TI - Metformin-induced alterations in nucleotide metabolism cause 5-fluorouracil resistance but gemcitabine susceptibility in oesophageal squamous cell carcinoma. AB - 5-Fluorouracil (5-FU) is a chemotherapeutic agent used to treat a variety of gastric cancers including oesophageal squamous cell carcinoma (OSCC), for which the 5-year mortality rate exceeds 85%. Our study investigated the effects of metformin, an antidiabetic drug with established anti-cancer activity, in combination with 5-FU as a novel chemotherapy strategy, using the OSCC cell lines, WHCO1 and WHCO5. Our results indicate that metformin treatment induces significant resistance to 5-FU in WHCO1 and WHCO5 cells, by more than five- and sixfolds, respectively, as assessed by MTT assay. We show that this is due to global alterations in nucleotide metabolism, including elevated expression of thymidylate synthase and thymidine kinase 1 (established 5-FU resistance mechanisms), which likely result in an increase in intracellular dTTP pools and a "dilution" of 5-FU anabolites. Metformin treatment also increases deoxycytidine kinase (dCK) expression and, as the chemotherapeutic agent gemcitabine relies on dCK for its efficient activity, we speculated that metformin would enhance the sensitivity of OSCC cells to gemcitabine. Indeed we show that metformin pre treatment greatly increases gemcitabine toxicity and DNA fragmentation in comparison to gemcitabine alone. Taken together, our findings show that metformin alters nucleotide metabolism in OSCC cells and while responsible for inducing resistance to 5-FU, it conversely increases sensitivity to gemcitabine, thereby highlighting metformin and gemcitabine as a potentially novel combination therapy for OSCC. PMID- 28722178 TI - CDK9: A key player in cancer and other diseases. AB - Cyclin-Dependent Kinase 9 (CDK9) is part of a functional diverse group of enzymes responsible for cell cycle control and progression. It associates mainly with Cyclin T1 and forms the Positive Transcription Elongation Factor b (p-TEFb) complex responsible for regulation of transcription elongation and mRNA maturation. Recent studies have highlighted the importance of CDK9 in many relevant pathologic processes, like cancer, cardiovascular diseases, and viral replication. Herein we provide an overview of the different pathways in which CDK9 is directly and indirectly involved. PMID- 28722179 TI - Direct Synthesis of Large-Area 2D Mo2 C on In Situ Grown Graphene. AB - As a new member of the MXene group, 2D Mo2 C has attracted considerable interest due to its potential application as electrodes for energy storage and catalysis. The large-area synthesis of Mo2 C film is needed for such applications. Here, the one-step direct synthesis of 2D Mo2 C-on-graphene film by molten copper-catalyzed chemical vapor deposition (CVD) is reported. High-quality and uniform Mo2 C film in the centimeter range can be grown on graphene using a Mo-Cu alloy catalyst. Within the vertical heterostructure, graphene acts as a diffusion barrier to the phase-segregated Mo and allows nanometer-thin Mo2 C to be grown. Graphene templated growth of Mo2 C produces well-faceted, large-sized single crystals with low defect density, as confirmed by scanning transmission electron microscopy (STEM) measurements. Due to its more efficient graphene-mediated charge-transfer kinetics, the as-grown Mo2 C-on-graphene heterostructure shows a much lower onset voltage for hydrogen evolution reactions as compared to Mo2 C-only electrodes. PMID- 28722180 TI - A generic TG-186 shielded applicator for commissioning model-based dose calculation algorithms for high-dose-rate 192 Ir brachytherapy. AB - PURPOSE: A joint working group was created by the American Association of Physicists in Medicine (AAPM), the European Society for Radiotherapy and Oncology (ESTRO), and the Australasian Brachytherapy Group (ABG) with the charge, among others, to develop a set of well-defined test case plans and perform calculations and comparisons with model-based dose calculation algorithms (MBDCAs). Its main goal is to facilitate a smooth transition from the AAPM Task Group No. 43 (TG-43) dose calculation formalism, widely being used in clinical practice for brachytherapy, to the one proposed by Task Group No. 186 (TG-186) for MBDCAs. To do so, in this work a hypothetical, generic high-dose rate (HDR) 192 Ir shielded applicator has been designed and benchmarked. METHODS: A generic HDR 192 Ir shielded applicator was designed based on three commercially available gynecological applicators as well as a virtual cubic water phantom that can be imported into any DICOM-RT compatible treatment planning system (TPS). The absorbed dose distribution around the applicator with the TG-186 192 Ir source located at one dwell position at its center was computed using two commercial TPSs incorporating MBDCAs (Oncentra(r) Brachy with Advanced Collapsed-cone Engine, ACETM, and BrachyVision ACUROSTM) and state-of-the-art Monte Carlo (MC) codes, including ALGEBRA, BrachyDose, egs_brachy, Geant4, MCNP6, and Penelope2008. TPS-based volumetric dose distributions for the previously reported "source centered in water" and "source displaced" test cases, and the new "source centered in applicator" test case, were analyzed here using the MCNP6 dose distribution as a reference. Volumetric dose comparisons of TPS results against results for the other MC codes were also performed. Distributions of local and global dose difference ratios are reported. RESULTS: The local dose differences among MC codes are comparable to the statistical uncertainties of the reference datasets for the "source centered in water" and "source displaced" test cases and for the clinically relevant part of the unshielded volume in the "source centered in applicator" case. Larger local differences appear in the shielded volume or at large distances. Considering clinically relevant regions, global dose differences are smaller than the local ones. The most disadvantageous case for the MBDCAs is the one including the shielded applicator. In this case, ACUROS agrees with MC within [-4.2%, +4.2%] for the majority of voxels (95%) while presenting dose differences within [-0.12%, +0.12%] of the dose at a clinically relevant reference point. For ACE, 95% of the total volume presents differences with respect to MC in the range [-1.7%, +0.4%] of the dose at the reference point. CONCLUSIONS: The combination of the generic source and generic shielded applicator, together with the previously developed test cases and reference datasets (available in the Brachytherapy Source Registry), lay a solid foundation in supporting uniform commissioning procedures and direct comparisons among treatment planning systems for HDR 192 Ir brachytherapy. PMID- 28722182 TI - Risk and Adversity, Parenting Quality, and Children's Social-Emotional Adjustment in Families Experiencing Homelessness. AB - A multimethod, multi-informant design was used to examine links among sociodemographic risk, family adversity, parenting quality, and child adjustment in families experiencing homelessness. Participants were 245 homeless parents (Mage = 31.0, 63.6% African American) and their 4- to 6-year-old children (48.6% male). Path analyses revealed unique associations by risk domain: Higher sociodemographic risk predicted more externalizing behavior and poorer teacher child relationships, whereas higher family adversity predicted more internalizing behavior. Parenting quality was positively associated with peer acceptance and buffered effects of family adversity on internalizing symptoms, consistent with a protective effect. Parenting quality was associated with lower externalizing behavior only when sociodemographic risk was below the sample mean. Implications for research and practice are discussed. PMID- 28722181 TI - Historical biome distribution and recent human disturbance shape the diversity of arbuscular mycorrhizal fungi. AB - The availability of global microbial diversity data, collected using standardized metabarcoding techniques, makes microorganisms promising models for investigating the role of regional and local factors in driving biodiversity. Here we modelled the global diversity of symbiotic arbuscular mycorrhizal (AM) fungi using currently available data on AM fungal molecular diversity (small subunit (SSU) ribosomal RNA (rRNA) gene sequences) in field samples. To differentiate between regional and local effects, we estimated species pools (sets of potentially suitable taxa) for each site, which are expected to reflect regional processes. We then calculated community completeness, an index showing the fraction of the species pool present, which is expected to reflect local processes. We found significant spatial variation, globally in species pool size, as well as in local and dark diversity (absent members of the species pool). Species pool size was larger close to areas containing tropical grasslands during the last glacial maximum, which are possible centres of diversification. Community completeness was greater in regions of high wilderness (remoteness from human disturbance). Local diversity was correlated with wilderness and current connectivity to mountain grasslands. Applying the species pool concept to symbiotic fungi facilitated a better understanding of how biodiversity can be jointly shaped by large-scale historical processes and recent human disturbance. PMID- 28722183 TI - A rare polyglycine type II-like helix motif in naturally occurring proteins. AB - Common structural elements in proteins such as alpha-helices or beta-sheets are characterized by uniformly repeating, energetically favorable main chain conformations which additionally exhibit a completely saturated hydrogen-bonding network of the main chain NH and CO groups. Although polyproline or polyglycine type II helices (PPII or PGII ) are frequently found in proteins, they are not considered as equivalent secondary structure elements because they do not form a similar self-contained hydrogen-bonding network of the main chain atoms. In this context our finding of an unusual motif of glycine-rich PGII -like helices in the structure of the acetophenone carboxylase core complex is of relevance. These PGII -like helices form hexagonal bundles which appear to fulfill the criterion of a (largely) saturated hydrogen-bonding network of the main-chain groups and therefore may be regarded in this sense as a new secondary structure element. It consists of a central PGII -like helix surrounded by six nearly parallel PGII like helices in a hexagonal array, plus an additional PGII -like helix extending the array outwards. Very related structural elements have previously been found in synthetic polyglycine fibers. In both cases, all main chain NH and CO groups of the central PGII -helix are saturated by either intra- or intermolecular hydrogen-bonds, resulting in a self-contained hydrogen-bonding network. Similar, but incomplete PGII -helix patterns were also previously identified in a GTP binding protein and an antifreeze protein. PMID- 28722185 TI - Valsalva maneuver exacerbates left atrial compression in patients with large hiatal hernia. AB - INTRODUCTION: Hiatal hernia (HH) can cause left atrial (LA) compression and impair LA filling. We evaluated the cardiac effects of preload reduction and abdominal strain induced by Valsalva maneuver (VM) in large HH patients. METHODS: LA and left ventricular (LV) dimensions were measured using 2D transthoracic echocardiography at rest and during VM in HH patients (n=55, 70+/-10 years) and controls (n=22, 67+/-6 years). Biplane LV volumes (n=39) and mitral inflow pulse wave Doppler parameters (n=27) were also evaluated. In HH patients, resting LA compression was graded qualitatively (none-mild or moderate-severe). RESULTS: In both controls and HH patients, VM significantly decreased LA (controls, 19+/-2 vs 16+/-3 mm/m2 ; HH, 16+/-5 vs 9+/-5 mm/m2 ) and LV diameters (22+/-3 vs 19+/-3 mm/m2 ; 21+/-3 vs 17+/-3 mm/m2 ) and LV volume (38+/-8 vs 26+/-10 mL/m2 ; 31+/-8 vs 19+/-9 mL/m2 ) (P<.001 for all). VM decreased LA diameter significantly more in HH patients than controls (-42% vs -16%, P<.001). HH patients with none-mild resting LA compression exhibited significantly greater LA diameter reduction than controls (-38+/-23% vs -16+/-13% P=.0003) despite similar resting LA diameters. LV volumes were similarly decreased by VM in HH patients and controls irrespective of resting LA compression severity indicating relative preservation of LV filling. LA diameter correlated inversely with early diastolic filling velocity during VM in HH patients (R=-.43, P=.03) but not controls (R=.18, P=.43). CONCLUSION: VM can markedly exacerbate LA compression in HH patients; however, LV filling is relatively less affected possibly due to augmented early diastolic filling. Conditions associated with decreased preload and increased intra-abdominal pressure may exacerbate the cardiac effects of large HH. PMID- 28722184 TI - Appropriateness of antiplatelet therapy for primary and secondary cardio- and cerebrovascular prevention in acutely hospitalized older people. AB - AIMS: Antiplatelet therapy is recommended for the secondary prevention of cardio- and cerebrovascular disease, but for primary prevention it is advised only in patients at very high risk. With this background, this study aims to assess the appropriateness of antiplatelet therapy in acutely hospitalized older people according to their risk profile. METHODS: Data were obtained from the REPOSI register held in Italian and Spanish internal medicine and geriatric wards in 2012 and 2014. Hospitalized patients aged >=65 assessable at discharge were selected. Appropriateness of the antiplatelet therapy was evaluated according to their primary or secondary cardiovascular prevention profiles. RESULTS: Of 2535 enrolled patients, 2199 were assessable at discharge. Overall 959 (43.6%, 95% CI 41.5-45.7) were prescribed an antiplatelet drug, aspirin being the most frequently chosen. Among patients prescribed for primary prevention, just over half were inappropriately prescribed (52.1%), being mainly overprescribed (155/209 patients, 74.2%). On the other hand, there was also a high rate of inappropriate underprescription in the context of secondary prevention (222/726 patients, 30.6%, 95% CI 27.3-34.0%). CONCLUSIONS: This study carried out in acutely hospitalized older people shows a high degree of inappropriate prescription among patients prescribed with antiplatelets for primary prevention, mainly due to overprescription. Further, a large proportion of patients who had had overt cardio- or cerebrovascular disease were underprescribed, in spite of the established benefits of antiplatelet drugs in the context of secondary prevention. PMID- 28722186 TI - In response to Laboratory assessment of sudden sensorineural hearing loss: A case control study. PMID- 28722187 TI - New roles for cost as an outcome: opportunities and challenges. PMID- 28722188 TI - Preventing Thin Film Dewetting via Graphene Capping. AB - A monolayer 2D capping layer with high Young's modulus is shown to be able to effectively suppress the dewetting of underlying thin films of small organic semiconductor molecule, polymer, and polycrystalline metal, respectively. To verify the universality of this capping layer approach, the dewetting experiments are performed for single-layer graphene transferred onto polystyrene (PS), semiconducting thienoazacoronene (EH-TAC), gold, and also MoS2 on PS. Thermodynamic modeling indicates that the exceptionally high Young's modulus and surface conformity of 2D capping layers such as graphene and MoS2 substantially suppress surface fluctuations and thus dewetting. As long as the uncovered area is smaller than the fluctuation wavelength of the thin film in a dewetting process via spinodal decomposition, the dewetting should be suppressed. The 2D monolayer-capping approach opens up exciting new possibilities to enhance the thermal stability and expands the processing parameters for thin film materials without significantly altering their physical properties. PMID- 28722189 TI - ADAM10 modulates calcitriol-regulated RAGE in cardiomyocytes. AB - BACKGROUND: Receptor for advanced glycation end products (RAGE) signalling plays a critical role in the pathogenesis of cardiovascular disease. Calcitriol modulates cardiac RAGE expression. This study explored the mechanisms underlying the effect of calcitriol on RAGE and soluble RAGE (sRAGE) expression in cardiomyocytes. MATERIALS AND METHODS: Western blot, ELISA, fluorometric assay and PCR analyses were used to evaluate the RAGE, sRAGE, endogenous secretory RAGE (esRAGE), Jun N-terminal kinase (JNK), and a disintegrin and metalloprotease 10 (ADAM10) expression and enzyme activity in HL-1 atrial myocytes without and with calcitriol (10 and 100 nM), nuclear factor-kappaB (NF-kappaB) inhibitor (50 MUg/mL), or ADAM10 inhibitor (5 MUM) incubation for 48 h. RESULTS: Calcitriol (10 nM) significantly reduced RAGE protein expression and increased sRAGE concentrations in HL-1 cardiomyocytes compared with control cells. These changes were associated with increased protein expression and enzyme activity of ADAM10 and higher mRNA expression of esRAGE. In the presence of ADAM10 inhibitor, however, the suppressive effect of calcitriol on RAGE was diminished. Methylglyoxal (500 MUM for 10 min)-mediated JNK phosphorylation was attenuated in the presence of calcitriol (10 nM). Moreover, control and NF-kappaB inhibitor treated HL-1 cells had similar RAGE and sRAGE expression, suggesting that calcitriol-mediated RAGE modulation was independent of NF-kappaB signalling. CONCLUSIONS: We showed that RAGE downregulation and increased sRAGE production by calcitriol were mediated through ADAM10 activation in cardiomyocytes. The results suggest that calcitriol has therapeutic potential in treating RAGE-mediated cardiovascular complications. PMID- 28722190 TI - Estimating population effects of vaccination using large, routinely collected data. AB - Vaccination in populations can have several kinds of effects. Establishing that vaccination produces population-level effects beyond the direct effects in the vaccinated individuals can have important consequences for public health policy. Formal methods have been developed for study designs and analysis that can estimate the different effects of vaccination. However, implementing field studies to evaluate the different effects of vaccination can be expensive, of limited generalizability, or unethical. It would be advantageous to use routinely collected data to estimate the different effects of vaccination. We consider how different types of data are needed to estimate different effects of vaccination. The examples include rotavirus vaccination of young children, influenza vaccination of elderly adults, and a targeted influenza vaccination campaign in schools. Directions for future research are discussed. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28722191 TI - A Chemoproteomics Approach to Investigate Phosphopantetheine Transferase Activity at the Cellular Level. AB - Phosphopantetheinylation is an essential post-translational protein modification to primary and secondary metabolic pathways that ensures bacterial cell viability and virulence, and it is used in the production of many pharmaceuticals. Traditional methods have not provided a comprehensive understanding of these modifications. By using chemical proteomic probes for adenylation and thiolation domains in nonribosomal peptide synthetases (NRPSs), chemoproteomics has been applied to survey and validate the cellular activity of 4-[3-chloro-5 (trifluoromethyl)pyridin-2-yl]-N-(4-methoxypyridin-2-yl)piperazine-1 carbothioamide (ML267), which is a potent and selective small-molecule 4' phosphopantetheinyl transferase (PPTase) inhibitor that attenuates secondary metabolism and viability of bacterial cells. ML267 inhibited Sfp-type PPTase and antagonized phosphopantetheinylation in cells, which resulted in a decrease in phosphopantetheinylated NRPSs and the attenuation of Sfp-PPTase-dependent metabolite production. These results indicate that this chemoproteomics platform should enable a precise interpretation of the cellular activities of Sfp-type PPTase inhibitors. PMID- 28722193 TI - BIOSEPARATIONS-2017. PMID- 28722192 TI - Roles of Fas/FasL-mediated apoptosis and inhibin B in the testicular dysfunction of rats with left-side varicocele. AB - We investigated the role of the Fas/FasL signalling pathway and inhibin B expression in rats with an experimentally induced left-side varicocele. Forty five Sprague Dawley (SD) male rats were randomly divided into three groups in average: control group, sham group and experimental group. The expression of inhibin B in the rat left testis was analysed at the mRNA and protein levels by reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting respectively. The expressions of Fas, FasL and caspase-3 in the left testis were measured by RT-PCR and immunofluorescence. The apoptosis index (AI) was measured by terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL). Both the mRNA and protein of inhibin B were significantly reduced in the experimental group compared with that in the control group or the sham group. The expression of Fas, FasL and caspase-3 in the experimental group was significantly increased compared to that in the control group or the sham group. The concentration of serum inhibin B was also inversely related to circulating FSH concentrations and positively correlated with sperm count. It is concluded that Fas/FasL system may play an important role in apoptosis of rats with experimental varicocele and inhibin B could reflect spermatogenesis function. PMID- 28722194 TI - Effects of cholesterol transport inhibitor U18666A on APP metabolism in rat primary astrocytes. AB - Amyloid beta (Abeta) peptides generated from the amyloid precursor protein (APP) play an important role in the degeneration of neurons and development of Alzheimer's disease (AD). Current evidence indicates that high levels of cholesterol-which increase the risk of developing AD-can influence Abeta production in neurons. However, it remains unclear how altered level/subcellular distribution of cholesterol in astrocytes can influence APP metabolism. In this study, we evaluated the effects of cholesterol transport inhibitor U18666A-a class II amphiphile that triggers redistribution of cholesterol within the endosomal-lysosomal (EL) system-on APP levels and metabolism in rat primary cultured astrocytes. Our results revealed that U18666A increased the levels of the APP holoprotein and its cleaved products (alpha-/beta-/eta-CTFs) in cultured astrocytes, without altering the total levels of cholesterol or cell viability. The cellular levels of Abeta1-40 were also found to be markedly increased, while secretory levels of Abeta1-40 were decreased in U18666A-treated astrocytes. We further report a corresponding increase in the activity of the enzymes regulating APP processing, such as alpha-secretase, beta-secretase, and gamma-secretase as a consequence of U18666A treatment. Additionally, APP-cleaved products are partly accumulated in the lysosomes following cholesterol sequestration within EL system possibly due to decreased clearance. Interestingly, serum delipidation attenuated enhanced levels of APP and its cleaved products following U18666A treatment. Collectively, these results suggest that cholesterol sequestration within the EL system in astrocytes can influence APP metabolism and the accumulation of APP cleaved products including Abeta peptides, which can contribute to the development of AD pathology. PMID- 28722195 TI - Persistent papilloma treated with cryotherapy in three dogs. AB - BACKGROUND: Canine papillomaviruses can affect the mucous membranes and skin of young, old and immunocompromised dogs. Most lesions regress spontaneously over a four to eight week interval; however, in some cases the lesions may persist or progress. Cryotherapy is used as a treatment for papillomavirus induced lesions in veterinary practice but there is limited published evidence regarding its use. OBJECTIVES: To describe the history, lesions and treatment outcomes of three dogs with persistent viral papillomas treated with cryotherapy. ANIMALS: Three client owned dogs. METHODS: Canine viral papilloma lesions were treated with five to six freeze-thaw cycles using liquid nitrogen cryotherapy. RESULTS: All lesions in each case resolved with cryotherapy treatment. Two cases required one treatment and one case required two treatment courses. CONCLUSIONS AND CLINICAL IMPORTANCE: The apparent resolution of these papilloma lesions with cryotherapy suggests that this may be a useful treatment intervention for persistent canine papilloma lesions. Spontaneous resolution may still have taken place; consequently, large scale clinical trials are required to demonstrate unequivocally that this mode of therapy, as with other therapeutic modalities, is really effective in the treatment of canine papillomatosis. PMID- 28722196 TI - Safety of orbital atherectomy in patients with left ventricular systolic dysfunction. AB - OBJECTIVES: We evaluated the angiographic and clinical outcomes in patients with severely calcified lesions and systolic dysfunction who underwent orbital atherectomy (OA). We hypothesized that OA would provide similar outcomes in patients with systolic dysfunction compared with patients with preserved systolic function. BACKGROUND: Systolic dysfunction is associated with an increased risk of adverse clinical events after percutaneous coronary intervention (PCI). The effects of OA in patients with systolic dysfunction are unknown. METHODS: Our analysis retrospectively analyzed 438 patients (n = 69 with EF <= 40%) who underwent OA. The primary endpoint was the rate of major adverse cardiac and cerebrovascular events (MACCE) at 30 days. RESULTS: There were no significant differences between patients with preserved versus reduced systolic function in terms of dissections (0.9% vs. 1.6%, P = 0.51), perforation (0.3% vs. 3.2%, P = 0.07), or no reflow (0.3% vs. 3.2%, P = 0.07). Patients with systolic dysfunction had higher rates of the composite of 30-day MACCE (1.1% vs. 8.7%, P = 0.002) and the individual end points of death (0.3% vs. 7.2%, P < 0.001), and myocardial infarction (0.5% vs. 4.3%, P = 0.03). The rates of target vessel revascularization (0% vs. 0%, P = 1), stroke (0.3% vs. 0%, P > 0.9), and stent thrombosis (0.8% vs. 1.4%, P = 0.5) were low in both groups and did not differ. CONCLUSION: Plaque modification with OA was safe and well tolerated in patients with systolic dysfunction. In this high-risk cohort, adverse clinical outcomes occurred more frequently than in a lower risk population. PMID- 28722197 TI - Simultaneous determination and method validation of difenoconazole, propiconazole and pyraclostrobin in pepper and soil by LC-MS/MS in field trial samples from three provinces, China. AB - A liquid chromatography-electrospray ionization tandem mass spectrometry method was developed for simple and accurate detection of the fungicides difenoconazole, propiconazole and pyraclostrobin in peppers and soil. Three fungicides residues were extracted from samples by acetonitrile and cleaned up by dispersive solid phase extraction before instrumental analysis. The accuracy and precision of the method were evaluated by conducting an intra- and inter-day recovery experiment. The limits of quantification and detection of difenoconazole, propiconazole and pyraclostrobin in pepper and soil were 0.005 and 0.0015 mg/kg, respectively. The recoveries were investigated by spiking pepper and soil at three levels, and were found to be in the ranges 79.62-103.15% for difenoconazole, 85.94-103.35% for propiconazole and 80.14-97.69% for pyraclostrobin, with relative standard deviations <6.5%. Field experiments were conducted in three locations in China. The half-lives of difenoconazole, propiconazole and pyraclostrobin were 5.3-11.5 days in peppers and 6.1-32.5 days in soil. At harvest, pepper samples were found to contain difenoconazole, propiconazole and pyraclostrobin well below the maximum residue limits of European Union at the interval of 21 days after last application following the recommended dosage. PMID- 28722199 TI - Facial expression coding in children and adolescents with autism: Reduced adaptability but intact norm-based coding. AB - Individuals with autism spectrum disorder (ASD) can have difficulty recognizing emotional expressions. Here, we asked whether the underlying perceptual coding of expression is disrupted. Typical individuals code expression relative to a perceptual (average) norm that is continuously updated by experience. This adaptability of face-coding mechanisms has been linked to performance on various face tasks. We used an adaptation aftereffect paradigm to characterize expression coding in children and adolescents with autism. We asked whether face expression coding is less adaptable in autism and whether there is any fundamental disruption of norm-based coding. If expression coding is norm-based, then the face aftereffects should increase with adaptor expression strength (distance from the average expression). We observed this pattern in both autistic and typically developing participants, suggesting that norm-based coding is fundamentally intact in autism. Critically, however, expression aftereffects were reduced in the autism group, indicating that expression-coding mechanisms are less readily tuned by experience. Reduced adaptability has also been reported for coding of face identity and gaze direction. Thus, there appears to be a pervasive lack of adaptability in face-coding mechanisms in autism, which could contribute to face processing and broader social difficulties in the disorder. PMID- 28722198 TI - Male germline recombination of a conditional allele by the widely used Dermo1-cre (Twist2-cre) transgene. AB - Conditional gene knockout using the Cre/loxP system is instrumental in advancing our understanding of the function of genes in a wide range of disciplines. It is becoming increasingly apparent in the literature that recombination mediated by some Cre transgenes can occur in unexpected tissues. Dermo1-Cre (Twist2-Cre) has been widely used to target skeletal lineage cells as well as other mesoderm derived cells. Here we report that Dermo1-Cre exhibits spontaneous male germline recombination activity leading to a Cre-mediated recombination of a floxed Ptk2 (Protein tyrosine kinase 2, also known as Fak [Focal adhesion kinase]) allele but not a floxed Rb1cc1 (RB1 inducible coiled-coil 1, also known as Fip200 [FAK family Interacting Protein of 200 kDa]) allele at high frequency. This ectopic germline activity of Dermo1-Cre occurred in all or none manner in a given litter. We demonstrated that the occurrence of germline recombination activity of Dermo1 Cre transgene can be avoided by using female mice as parental Dermo1-Cre carriers. PMID- 28722200 TI - The Gibraltar Sign: An Anatomic Landmark for Predicting Transverse Sinus Dominance Laterality on Conventional MRI. AB - BACKGROUND AND PURPOSE: Physiologic asymmetry of transverse sinus (TS) caliber is common and can lead to misinterpretation of magnetic resonance venography (MRV) studies of the brain. This retrospective study assesses the ability of multiple anatomic features on axial noncontrast T1-weighted images (T1WIs) of the brain to predict congenital TS dominance. METHODS: One hundred consecutively acquired combined MRI-MRV studies of the brain were reviewed. On noncontrast axial T1WI, each reviewer measured (1) inclination of the groove for the superior sagittal sinus (SSS), (2) angulation of the posterior falx, (3) laterality of the SSS flow void, and (4) laterality of the inferior-most occipital lobe. TS cross-sectional area was measured on noncontrast sagittal 2-dimensional time-of-flight MRV images and served as the reference standard. RESULTS: The bony groove for the SSS sloped down to the right in 65 of 100 patients and correctly predicted right TS dominance in 63 of 65 cases (97% positive predictive value [PPV]). The groove sloped down to the left in 24 of 100 patients and correctly predicted left TS dominance in 22 of 24 cases (92% PPV). Laterality of the SSS flow void, laterality of the inferior-most occipital lobe, and angulation of the posterior falx had 91% PPV, 82% PPV, and 74% PPV for predicting TS dominance, respectively. CONCLUSIONS: Multiple anatomic features seen on conventional axial T1WI can be used to predict the laterality of congenital TS dominance and can help inform the interpretation of MRV studies of the brain. PMID- 28722201 TI - Susceptibility-induced distortion correction in hyperpolarized echo planar imaging. AB - PURPOSE: Echo planar imaging is an attractive rapid imaging readout that can image hyperpolarized compounds in vivo. By alternating the sign of the phase encoding gradient waveform, spatial offsets arising from uncertain frequency shifts can be determined. We show here that blip-reversed echo planar imaging can also be used to correct for susceptibility and B0 inhomogeneity effects that would otherwise produce image-domain distortion in the heart. METHODS: Previously acquired blip-reversed cardiac 3D-Spectral-Spatial echo planar imaging volumetric timecourses of hyperpolarized [1-13 C]pyruvate were distortion corrected by a deformation field estimated by reconstructing signal-to-noise ratio (SNR) weighted progressively subsampled temporally summed images of each metabolite. RESULTS: Reconstructing blip-reversed data as proposed produced volumetric timecourses that overlaid with proton reference images more consistently than without such corrections. CONCLUSION: The method proposed may form an attractive method to correct for image-domain distortions in hyperpolarized echo planar imaging experiments. Magn Reson Med 79:2135-2141, 2018. (c) 2017 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. PMID- 28722202 TI - Medical residents' circadian preferences across specialties. AB - OBJECTIVE: Circadian preference refers to the tendency of individuals to be more alert and effective in the morning (larks) or the evening (owls). Given the rigors of medical residency training and perceived lifestyle differences among specialties, circadian preference may play a role in choice of medical specialty and subsequent job satisfaction during training. This study aimed to determine the circadian preferences of residents across specialties and correlations with specialty choice and job satisfaction. STUDY DESIGN: Single-institution, cross sectional survey. METHODS: The Horne-Ostberg Morningness-Eveningness questionnaire, the standard to identify circadian preference, was modified to include demographic and job satisfaction variables and administered to residents at our tertiary care hospital in 2014. Independent t tests were used to correlate circadian preference and specialty choice, and Spearman's correlations were used to correlate circadian preference and job satisfaction. RESULTS: A total of 160 residents from postgraduate years 1 through 7 and 10 specialties responded. The mean chronotype scores from all specialties met the category of "neither" morning nor evening type. A significant difference occurred between emergency medicine residents and residents from anesthesiology (P = 0.0007), surgery (P < 0.0001), and medicine (P = 0.0005). Residents in the surgical specialties trended toward the morning chronotype, whereas emergency medicine trended toward evening chronotype. There was no significant correlation between chronotype and job satisfaction. CONCLUSION: Although preliminary because of the low response rate, this study points to the potential of considering circadian preference in choice of specialty training and for designing resident on-call schedules. LEVEL OF EVIDENCE: NA. Laryngoscope, 127:2236-2238, 2017. PMID- 28722203 TI - Interaction of Spoonbill with Prospero in Drosophila: Implications in neuroblast development. AB - Identification of Spoon as a suppressor of SCA8 associated neurodegeneration provides us a hint about its role in neuronal development and maintenance. However, a detailed molecular characterization of spoon has not yet been reported. Here, we describe spatial expression pattern of Spoon during Drosophila development. Quantitative real time-PCR and fluorescent RNA-RNA in situ hybridization indicate that Spoon is expressed at relatively high levels in larval brain and photoreceptors of eye-antennal discs. Immunostaining reveals that Spoon is subcellularly localized in the cytoplasm and is also membrane bound. Strong expression is also seen in adult ovary and testes. Spoon on immunostaining exhibits unique pattern of expression in larval brain. We observed that Spoon in the neuroblasts colocalizes with Prospero, a transcription factor regulating genes involved in neuroblast self-renewal or cell-cycle control. Co immunoprecipitation suggests that Spoon and Prospero reside in the same protein complex. Using Drosophila model of SCA8 RNA neuropathy we have also shown that loss of Prospero hinders the suppression of SCA8 associated neurodegeneration by Spoonbill, suggesting Prospero and Spoon might genetically interact and function together. Our study presents Spoon as a novel interacting partner of Prospero and this might be critical in determining the polarized localization of cell fate determinants. PMID- 28722204 TI - Loss of the tumour suppressor gene AIP mediates the browning of human brown fat tumours. AB - Human brown fat tumours (hibernomas) show concomitant loss of the tumour suppressor genes MEN1 and AIP. We hypothesized that the brown fat phenotype is attributable to these mutations. Accordingly, in this study, we demonstrate that silencing of AIP in human brown preadipocytic and white fat cell lines results in the induction of the brown fat marker UCP1. In human adipocytic tumours, loss of MEN1 was found both in white (one of 51 lipomas) and in brown fat tumours. In contrast, concurrent loss of AIP was always accompanied by a brown fat morphology. We conclude that this white-to-brown phenotype switch in brown fat tumours is mediated by the loss of AIP. Copyright (c) 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 28722205 TI - Temperature stability of proteins: Analysis of irreversible denaturation using isothermal calorimetry. AB - The structural stability of proteins has been traditionally studied under conditions in which the folding/unfolding reaction is reversible, since thermodynamic parameters can only be determined under these conditions. Achieving reversibility conditions in temperature stability experiments has often required performing the experiments at acidic pH or other nonphysiological solvent conditions. With the rapid development of protein drugs, the fastest growing segment in the pharmaceutical industry, the need to evaluate protein stability under formulation conditions has acquired renewed urgency. Under formulation conditions and the required high protein concentration (~100 mg/mL), protein denaturation is irreversible and frequently coupled to aggregation and precipitation. In this article, we examine the thermal denaturation of hen egg white lysozyme (HEWL) under irreversible conditions and concentrations up to 100 mg/mL using several techniques, especially isothermal calorimetry which has been used to measure the enthalpy and kinetics of the unfolding and aggregation/precipitation at 12 degrees C below the transition temperature measured by DSC. At those temperatures the rate of irreversible protein denaturation and aggregation of HEWL is measured to be on the order of 1 day-1 . Isothermal calorimetry appears a suitable technique to identify buffer formulation conditions that maximize the long term stability of protein drugs. PMID- 28722206 TI - Alcohol consumption and risk of urothelial cell bladder cancer in the European prospective investigation into cancer and nutrition cohort. AB - Findings on the association between alcohol consumption and bladder cancer are inconsistent. We investigated that association in the European Prospective Investigation into Cancer and Nutrition cohort. We included 476,160 individuals mostly aged 35-70 years, enrolled in ten countries and followed for 13.9 years on average. Hazard ratios (HR) for developing urothelial cell carcinoma (UCC; 1,802 incident cases) were calculated using Cox proportional hazards models. Alcohol consumption at baseline and over the life course was analyzed, as well as different types of beverages (beer, wine, spirits). Baseline alcohol intake was associated with a statistically nonsignificant increased risk of UCC (HR 1.03; 95% confidence interval (CI) 1.00-1.06 for each additional 12 g/day). HR in smokers was 1.04 (95% CI 1.01-1.07). Men reporting high baseline intakes of alcohol (>96 g/day) had an increased risk of UCC (HR 1.57; 95% CI 1.03-2.40) compared to those reporting moderate intakes (<6 g/day), but no dose-response relationship emerged. In men, an increased risk of aggressive forms of UCC was observed even at lower doses (>6 to 24 g/day). Average lifelong alcohol intake was not associated with the risk of UCC, however intakes of spirits > 24 g/day were associated with an increased risk of UCC in men (1.38; 95% CI 1.01-1.91) and smokers (1.39; 95% CI 1.01-1.92), compared to moderate intakes. We found no association between alcohol and UCC in women and never smokers. In conclusion, we observed some associations between alcohol and UCC in men and in smokers, possibly because of residual confounding by tobacco smoking. PMID- 28722207 TI - Antihypertensive drug associated angioedema: effect modification by race/ethnicity. AB - PURPOSE: Assess angioedema risk with exposure to angiotensin converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) compared with beta blockers, by race/ethnicity. METHODS: New-user cohorts of Medicare beneficiaries 65 years or older initiating ACEI, ARB, or beta-blocker treatment from March 2007 to March 2014 were constructed. Angioedema incidence rates by drug and race/ethnicity were computed for 1-30 and 31-365 days of treatment. Cox proportional hazards regression was used to examine angioedema risk between cohorts. RESULTS: Angioedema incidence rates (per 1000 person years) in beta blocker users were 1.80 (whites), 4.11 (blacks), 1.89 (Asians), and 2.10 (Hispanics); in ACEI users, 4.03, 23.77, 2.94, and 4.27; and in ARB users, 1.73, 3.11, 1.10, and 1.90, respectively. Incidence rates were significantly higher in the first 30 days of exposure for all drug * race/ethnic groups. Overall, angioedema risk increased among ACEI users (hazard ratio, 2.91; 95% confidence interval, 2.75-3.07) but not ARB users (0.93, 0.85-1.02) versus beta-blocker users. Angioedema risk with ACEIs versus beta-blockers increased more in blacks (6.28, 5.44-7.24) than whites (2.33, 2.19-2.48), Hispanics (2.04, 1.36-3.07), and Asians (1.48, 0.94-2.35). Compared with white beta-blocker users, angioedema risk was increased 2.9-fold in whites, 20.2-fold in blacks, and 2.3-fold in other race/ethnic groups combined during the first 30 days of ACEI exposure. CONCLUSIONS: There was significant effect modification of angioedema risk by race and ACEI use for blacks, but not for other race/ethnicity groups. Angioedema risk was significantly greater in the first 30 days of exposure for all, and highest among blacks. PMID- 28722208 TI - Proper estimate of residue input as condition for understanding drivers of soil carbon dynamics. PMID- 28722209 TI - Reporting of outcomes in randomized controlled trials on nail psoriasis: a systematic review. AB - BACKGROUND: Harmonization of outcome measures is needed to increase the value of clinical trials on nail psoriasis. OBJECTIVES: To provide the first step in core outcome set (COS) development for nail psoriasis. METHODS: A systematic review was performed to identify outcome instruments and corresponding outcome domains used in (ongoing) randomized controlled trials. RESULTS: Identified outcome domains included clinical signs, quality of life, symptoms and delivery of care. The Nail Psoriasis Severity Index (NAPSI) was the most commonly used measure to assess clinical signs (74% of studies). Other outcome instruments used included the Nail Area Severity score, composite fingernail score, a Physician's Global Assessment, individual nail features or a combination of these. Heterogeneity in type and reporting (e.g. NAPSI 50, NAPSI 75) of outcome instruments was high and characteristics were often insufficiently reported. In total 43% of studies assessed quality of life, with 3% of studies using a nail psoriasis-specific tool. Assessment of symptoms and delivery of care was limited. CONCLUSIONS: Heterogeneity in the type and reporting of nail psoriasis outcome instruments needs to be addressed in the process towards COS development. Sufficient reporting of instrument characteristics should be encouraged. As nail psoriasis is generally assessed secondarily to psoriasis of the skin or joints, collaboration between different research groups in COS development is needed. PMID- 28722210 TI - Plasma microRNA-based signatures to predict 3-year postoperative recurrence risk for stage II and III gastric cancer. AB - Our aim was to identify plasma microRNA (miRNA)-based signatures to predict 3 year postoperative recurrence risk for patients with stage II and III gastric cancer (GC), so as to provide insights for individualized adjuvant therapy. Plasma miRNA expression was investigated in three phases, involving 407 patients recruited from three centers. ABI miRNA microarray and TaqMan Low Density Array were adopted in the discovery phase to identify potential miRNAs. Quantitative reverse-transcriptase polymerase chain reaction was used to assess the expression of selected miRNAs. Logistic regression models were constructed in the training set (n = 170) and validated in the validation set (n = 169). Receiver operating characteristic analyses, survival analyses and subgroup analyses were further used to assess the accuracy of the models. We identified a 7 miRNA classifier and 7miR + pathological factors index that provided high predictive accuracy of GC recurrence (area under the curve = 0.725 and 0.841 in the training set; and 0.627 and 0.771 in the validation set). High-risk patients defined by the signatures had significantly shorter disease-free survival and overall survival than low risk patients. The 7 miRNA classifier is an independent prognostic factor, and could add predictive value to traditional prognostic factors. Subgroup analyses revealed the satisfactory performance persisted regardless of stage, and the two models both displayed high accuracy in stage IIA patients. In conclusion, identified microRNA signature may potentially provide some additional benefit for prediction of disease recurrence in patients with stage II and III GC. PMID- 28722211 TI - Using prescription monitoring program data to characterize out-of-pocket payments for opioid prescriptions in a state Medicaid program. AB - BACKGROUND: Out-of-pocket payment for prescription opioids is believed to be an indicator of abuse or diversion, but few studies describe its epidemiology. Prescription drug monitoring programs (PDMPs) collect controlled substance prescription fill data regardless of payment source and thus can be used to study this phenomenon. OBJECTIVE: To estimate the frequency and characteristics of prescription fills for opioids that are likely paid out-of-pocket by individuals in the Oregon Medicaid program. RESEARCH DESIGN: Cross-sectional analysis using Oregon Medicaid administrative claims and PDMP data (2012 to 2013). SUBJECTS: Continuously enrolled nondually eligible Medicaid beneficiaries who could be linked to the PDMP with two opioid fills covered by Oregon Medicaid. MEASURES: Patient characteristics and fill characteristics for opioid fills that lacked a Medicaid pharmacy claim. Fill characteristics included opioid name, type, and association with indicators of high-risk opioid use. RESULTS: A total of 33 592 Medicaid beneficiaries filled a total of 555 103 opioid prescriptions. Of these opioid fills, 74 953 (13.5%) could not be matched to a Medicaid claim. Hydromorphone (30%), fentanyl (18%), and methadone (15%) were the most likely to lack a matching claim. The 3 largest predictors for missing claims were opioid fills that overlapped with other opioids (adjusted odds ratio [aOR] 1.37; 95% confidence interval [CI], 1.34-1.4), long-acting opioids (aOR 1.52; 95% CI, 1.47 1.57), and fills at multiple pharmacies (aOR 1.45; 95% CI, 1.39-1.52). CONCLUSIONS: Prescription opioid fills that were likely paid out-of-pocket were common and associated with several known indicators of high-risk opioid use. PMID- 28722213 TI - Countering resistance to protected-area extension. AB - The establishment of protected areas is a critical strategy for conserving biodiversity. Key policy directives like the Aichi targets seek to expand protected areas to 17% of Earth's land surface, with calls by some conservation biologists for much more. However, in places such as the United States, Germany, and Australia, attempts to increase protected areas are meeting strong resistance from communities, industry groups, and governments. We examined case studies of such resistance in Victoria, Australia, Bavaria, Germany, and Florida, United States. We considered 4 ways to tackle this problem. First, broaden the case for protected areas beyond nature conservation to include economic, human health, and other benefits, and translate these into a persuasive business case for protected areas. Second, better communicate the conservation values of protected areas. This should include highlighting how many species, communities, and ecosystems have been conserved by protected areas and the counterfactual (i.e., what would have been lost without protected area establishment). Third, consider zoning of activities to ensure the maintenance of effective management. Finally, remind citizens to think about conservation when they vote, including holding politicians accountable for their environmental promises. Without tackling resistance to expanding the protected estate, it will be impossible to reach conservation targets, and this will undermine attempts to stem the global extinction crisis. PMID- 28722212 TI - Active human papillomavirus involvement in Barrett's dysplasia and oesophageal adenocarcinoma is characterized by wild-type p53 and aberrations of the retinoblastoma protein pathway. AB - We have previously demonstrated that transcriptionally active high-risk HPV (hr HPV) is strongly incriminated in Barrett's dysplasia (BD) and oesophageal adenocarcinoma (OAC) using mainly fresh frozen tissue. This study aimed to identify biomarkers of active HPV infection in Barrett's metaplasia, (BM)/BD/OAC by immunohistochemical staining (IHC) of formalin-fixed paraffin embedded (FFPE) tissue for aberrations of p53 and the retinoblastoma (pRb) pathway, which are targets for the viral oncoproteins, E6/E7, respectively. Prospectively, BM (n = 81)/BD (n = 72)/OAC (n = 65) FFPE specimens were subjected to IHC staining for pRb, p16INK4A , cyclin D1 , p53 and RNA in-situ hybridization for E6/E7 transcripts. HPV DNA was determined via PCR in fresh frozen specimens. Viral load measurement (real-time PCR) and Next Generation Sequencing of TP53 was performed. Of 218 patients, 56 were HPV DNA positive [HPV16 (n = 42), 18 (n = 13), 6 (n = 1)]. Viral load was low. Transcriptionally active HPV (DNA+ /RNA+ ) was only found in the dysplastic and adenocarcinoma group (n = 21). The majority of HPV DNA+ /RNA+ BD/OAC were characterized by p 16highINK4A (14/21, 66.7%), pRblow (15/21, 71.4%) and p53low (20/21, 95%) and was significantly different to controls [combination of HPV DNA- /RNA- (n = 94) and HPV DNA+ /RNA- cohorts (n = 22)]. p53low had the strongest association with DNA+ /RNA+ oesophageal lesions (OR = 23.5, 95% CI = 2.94-187.8, p = 0.0029). Seventeen HPV DNA+ /RNA+ BD/OAC identified as p53low, were sequenced and all but one exhibited wild-type status. pRblow /p53low provided the best balance of strength of association (OR = 8.0, 95% CI = 2.6-25.0, p = 0.0003) and sensitivity (71.4%)/specificity (71.6%) for DNA+ /RNA+ BD/OAC. Active HPV involvement in BD/OAC is characterized by wild-type p53 and aberrations of the retinoblastoma protein pathway. PMID- 28722214 TI - Impairment due to combined sleep restriction and alcohol is not mitigated by decaying breath alcohol concentration or rest breaks. AB - OBJECTIVE: Epidemiological and laboratory-based driving simulator studies have shown the detrimental impact of moderate, legal levels of alcohol consumption on driving performance in sleepy drivers. As less is known about the time course of decaying alcohol alongside performance impairment, our study examined impairment and recovery of performance alongside decaying levels of alcohol, with and without sleep restriction. METHODS: Sixteen healthy young males (18-27 years) underwent 4 counterbalanced conditions: Baseline, Alcohol (breath alcohol concentration [BrAC] < 0.05%), Sleep Restriction (5 hr time in bed), and Combined. Participants consumed alcohol (or control drink) ~4.5 hr post wake (12:30 p.m.). To test on the descending limb of alcohol, attention and vigilance test batteries commenced 1 hr after consumption and were completed every 30 min for 2 hr (1:30 p.m.-3:30 p.m.). RESULTS: The Combined condition impaired subjective and objective sleepiness. Here, performance deficits peaked 90 min after alcohol consumption or 30 min after the BrAC peak. Performance did not return to baseline levels until 2.5 hr following consumption, despite receiving rest breaks in between testing. CONCLUSIONS: These findings suggest that (a) falling BrACs are an inadequate guide for performance/safety and (b) rest breaks without sleep are not a safety measure for mitigating performance impairment when consuming alcohol following restricted sleep. PMID- 28722215 TI - Synthesis of Cyclic Peptide Mimetics by the Successive Ring Expansion of Lactams. AB - A successive ring-expansion protocol is reported that enables the controlled insertion of natural and non-natural amino acid fragments into lactams. Amino acids can be installed into macrocycles via an operationally simple and scalable iterative procedure, without the need for high dilution. This method is expected to be of broad utility, especially for the synthesis of medicinally important cyclic peptide mimetics. PMID- 28722216 TI - Primary pulmonary myxoid sarcoma located in interlobar fissure without parenchymal invasion. AB - Primary pulmonary myxoid sarcoma (PPMS), classified as low to intermediate grade malignant myxoid endobronchial tumor, is rarely reported. Most reported cases occurred in lung parenchyme with an endobronchial component. Herein, we report a case of PPMS in a 29-year-old woman that developed in a major fissure of the left lung without parenchymal invasion. Histopathologically, the diagnosis was compatible to PPMS with EWSR1-CREB1 translocation. PMID- 28722217 TI - Personal and situational predictors of everyday snacking: An application of temporal self-regulation theory. AB - OBJECTIVES: This study aims at testing predictions derived from temporal self regulation theory (TST) in relation to discretionary food choices (snacks). TST combines a motivational sphere of influence (cognitions and temporal valuations resulting in intentions) with a momentary sphere (encompassing social and physical environmental cues). This dual approach differs from current health behaviour theories, but can potentially improve our understanding of the interplay of personal and environmental factors in health behaviour self regulation. DESIGN: A mixed event-based and time-based (Ecological Momentary Assessment) study in 61 adults aged between 18 and 64, with a BMI range between 18.34 and 39.78 (M = 25.66, SD = 4.82) over two weeks. METHODS: Participants recorded their food and drink intake for two weeks in real time using electronic diaries. Participants also responded to non-consumption assessments at random intervals throughout each day. Momentary cues (individual, situational, and environmental factors) were assessed both during food logs and non-consumption assessments. Motivational factors, past behaviour, and trait self-regulation were assessed during baseline. RESULTS: Multilevel logistic regression analyses showed that across all snack types, environmental cues and negative affect were associated with an increased likelihood of snacking. Perceiving a cost of healthy eating to occur before eating was associated with an increased likelihood of snacking, whereas intentions and self-regulation were not. CONCLUSIONS: Discretionary food intake is largely guided by momentary cues, and motivational level factors, such as intention and self-regulation, are less important in the initiation of discretionary food intake. Statement of contribution What is already known on this subject? Overweight and obesity are a result of prolonged periods of energy imbalance between energy intake and expenditure (Hill & Peters, ). One of the key behavioural determinants of energy imbalances results from food intake, specifically from discretionary food choices (snacking). Temporal self regulation theory (Hall & Fong, ) takes into account both deliberate and momentary influences on health behaviour, which is especially relevant to exploring the drivers of snacking. What does this study add? Offers new insight into the application of TST in explaining momentary eating behaviours. Snacking initiation is guided by momentary cues, not person-level factors. Dietary interventions should acknowledge the momentary cues that are associated with snacking. PMID- 28722218 TI - Copper, copper-binding protein and cytokeratin 7 in biliary disorders. PMID- 28722219 TI - Preparation and evaluation of tert-leucine derivative functionalized polymeric monoliths for micro-liquid chromatography. AB - In this study, a novel functional monomer N-[1-(alpha naphthyl)ethylaminocarbonyl]-D-tert-leucine-[2-(methacryloyloxy)ethyl] amide (NA D-tert-Leu-MA) was synthesized, and then employed to prepare polymeric monoliths (240 mm * 100 MUm id) functionalized with tert-leucine derivative through a single step thermo-initiated co-polymerization approach or a multi-step post modification approach. The multi-step approach involves the post-modification of a thiol-containing monolith with NA-D-tert-Leu-MA via "thiol-ene"click reaction. The physicochemical properties of the resulting monoliths were characterized by scanning electron microscopy, energy-dispersive X-ray spectrometry and micro liquid chromatography. Good column stability, permeability, efficiency and reproducibility were obtained for the optimized monoliths. The poly (NA-D-tert Leu-MA-co-ethylene dimethacrylate) monolith prepared through the single step co polymerization approach exhibited satisfactory achiral separation performance for various analytes, including phenols, aniline derivatives and intact proteins, while its enantioseparation ability is rather poor. In contrast to that, the monolith prepared through the multi-step post-modification approach showed much higher enantioselectivity for 7-nitro-2,1,3-benzoxadiazole (NBD)-derivatized amino acids. Three NBD-derivatized amino acids (theanine, proline and norleucine) could be baseline enantioseparated. PMID- 28722221 TI - Microstructure and tensile properties of various varieties of rice husk. AB - BACKGROUND: Rice husk is a complex hierarchical assembly of hollow fibers consisting of cellulose, hemicellulose and lignin. In addition, it can also contain pectin and significant amounts of silica. Rice husk can be used in diverse applications and generally in the form of rice husk powder. This study aimed to investigate the structural features and mechanical properties of various varieties of whole rice husks. RESULTS: Rice husk consists of three sections: epidermis, sub-hypodermis and hypodermis. The thickness of these layers, the diameters of the hollow fibers and the wall thickness vary with the variety of rice husk. The elastic modulus is typically between 0.3 and 2.6 GPa, and the ultimate tensile strength varies from 19 to 135 MPa depending on the variety of rice husk. CONCLUSION: Rice husk has a unique hierarchical structure in which the fibers exhibit a staggered perpendicular arrangement and the entire fiber sections are covered by an external shell. The tensile properties vary with the variety of rice husk. The wide range in these tensile properties may be attributed to the size and orientation of the fibers. (c) 2017 Society of Chemical Industry. PMID- 28722220 TI - Developing new targeting strategy for androgen receptor variants in castration resistant prostate cancer. AB - The presence of androgen receptor variant 7 (AR-V7) variants becomes a significant hallmark of castration-resistant prostate cancer (CRPC) relapsed from hormonal therapy and is associated with poor survival of CRPC patients because of lacking a ligand-binding domain. Currently, it still lacks an effective agent to target AR-V7 or AR-Vs in general. Here, we showed that a novel class of agents (thailanstatins, TSTs and spliceostatin A analogs) can significantly suppress the expression of AR-V7 mRNA and protein but in a less extent on the full-length AR expression. Mechanistically, TST-D is able to inhibit AR-V7 gene splicing by interfering the interaction between U2AF65 and SAP155 and preventing them from binding to polypyrimidine tract located between the branch point and the 3' splice site. In vivo, TST-D exhibits a potent tumor inhibitory effect on human CRPC xenografts leading to cell apoptosis. The machinery associated with AR gene splicing in CRPC is a potential target for drugs. Based on their potency in the suppression of AR-V7 responsible for the growth/survival of CRPC, TSTs representing a new class of anti-AR-V agents warrant further development into clinical application. PMID- 28722222 TI - CATALASE2 functions for seedling postgerminative growth by scavenging H2 O2 and stimulating ACX2/3 activity in Arabidopsis. AB - Increased fatty acid beta-oxidation is essential for early postgerminative growth in seedlings, but high levels of H2 O2 produced by beta-oxidation can induce oxidative stress. Whether and how catalase (CAT) functions in fine-tuning H2 O2 homeostasis during seedling growth remain unclear. Here, we report that CAT2 functions in early seedling growth. Compared to the wild type, the cat2-1 mutant, with elevated H2 O2 levels, exhibited reduced root elongation on sucrose (Suc) free medium, mimicking soils without exogenous sugar supply. Treatment with the H2 O2 scavenger potassium iodide rescued the mutant phenotype of cat2-1. In contrast to the wild type, the cat2-1 mutant was insensitive to the CAT inhibitor 3-amino-1,2,4-triazole in terms of root elongation when grown on Suc-free medium, suggesting that CAT2 modulates early seedling growth by altering H2 O2 accumulation. Furthermore, like cat2-1, the acyl-CoA oxidase (ACX) double mutant acx2-1 acx3-6 showed repressed root elongation, suggesting that CAT2 functions in early seedling growth by regulating ACX activity, as this activity was inhibited in cat2-1. Indeed, decreased ACX activity and short root of cat2-1 seedlings grown on Suc-free medium were rescued by overexpressing ACX3. Together, these findings suggest that CAT2 functions in early seedling growth by scavenging H2 O2 and stimulating ACX2/3 activity. PMID- 28722224 TI - Integrating High-Resolution and Solid-State Magic Angle Spinning NMR Spectroscopy and a Transcriptomic Analysis of Soybean Tissues in Response to Water Deficiency. AB - INTRODUCTION: Solid-state NMR (SSNMR) spectroscopy methods provide chemical environment and ultrastructural details that are not easily accessible by other non-destructive, high-resolution spectral techniques. High-resolution magic angle spinning (HR-MAS) has been widely used to obtain the metabolic profile of a heterogeneous sample, combining the resolution enhancement provided by MAS in SSNMR with the shimming and locking procedures in liquid-state NMR. OBJECTIVE: In this work, we explored the feasibility of using the HR-MAS and SSNMR techniques to identify metabolic changes in soybean leaves subjected to water-deficient conditions. METHODOLOGY: Control and water-deficient soybean leaves were analysed using one-dimensional (1D) HR-MAS and SSNMR. Total RNA was extracted from the leaves for the transcriptomic analysis. RESULTS: The 1 H HR-MAS and CP-MAS 13 C{1 H} spectra of soybean leaves grown with and without water deficiency stress revealed striking differences in metabolites. A total of 30 metabolites were identified, and the impact of water deficiency on the metabolite profile of soybean leaves was to induce amino acid synthesis. High expression levels of genes required for amino acid biosynthesis were highly correlated with the compounds identified by 1 H HR-MAS. CONCLUSIONS: The integration of the 1 H HR MAS and SSNMR spectra with the transcriptomic data provided a complete picture of the major changes in the metabolic profile of soybeans in response to water deficiency. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28722223 TI - The role of beta-adrenergic receptors and p38MAPK signaling pathways in physiological processes of cardiosphere-derived cells. AB - The effects of beta adrenergic receptors (beta-ARs) and p38 mitogen-activated protein kinases (MAPK) pathways on cardiosphere-derived cells (CDCs) are largely unknown. This study aimed to investigate the roles of beta-ARs and p38MAPK pathways on the proliferation, apoptosis, and differentiation capacity of CDCs. The CDCs were treated with beta1-AR blocker (Met group), beta2-AR antagonist (ICI group), and p38MAPK inhibitor (SB group), non-selective beta-AR blocker (PRO group), and beta-AR agonist (ISO group). The viability, apoptotic rate and differentiation status of CDCs were determined by MST-1 assay, flow cytometery, and Western blot, respectively. The CDCs viability significantly reduced in ICI group (all P < 0.05), and SB group had a significant high viability after 48 h treatment (P < 0.05). Compared with control group, all treated groups had a low apoptotic rate. After treatment for 72 h, ISO treatment elevated the expression of Nkx2.5, and could partially or fully attenuate the inhibitory effects of beta AR antagonists and/or p38MAPK inhibitor. A similar overall trend of protein expression levels among all groups could be observed between protein pairs of cTnT and beta1-AR as well as c-Kit and beta2-AR, respectively. These results suggested that beta-ARs and p38MAPK signaling pathways play crucial roles in the proliferation and differentiation of CDCs. Our findings should be helpful for better understanding the molecular mechanism underlying the physiological processes of CDCs. PMID- 28722225 TI - High prevalence of erectile dysfunction in diabetes: a systematic review and meta analysis of 145 studies. AB - Erectile dysfunction may be common among men with diabetes, but its prevalence is still debated. We aimed to assess the relative prevalence of erectile dysfunction in diabetes searching major databases from inception to November 2016 for studies reporting erectile dysfunction in men with Type 1 and Type 2 diabetes mellitus. We conducted a meta-analysis of the prevalence [and 95% confidence intervals (95% CIs)] of erectile dysfunction in diabetes compared with healthy controls, calculating the relative odds ratios (ORs) and 95% CIs. A random effect model was applied. From 3747 initial hits, 145 studies were included representing 88 577 men (age: 55.8 +/- 7.9 years). The prevalence of erectile dysfunction in diabetes overall was 52.5% (95% CI, 48.8 to 56.2) after adjusting for publication bias, and 37.5%, 66.3% and 57.7% in Type 1, Type 2 and both types of diabetes, respectively (P for interaction < 0.0001). The prevalence of erectile dysfunction was highest in studies using the Sexual Health Inventory for Men (82.2%, 17 studies, P for interaction < 0.0001). Studies with a higher percentage of people with hypertension moderated our results (beta = 0.03; 95% CI, 0.008 to 0.040; P = 0.003; R2 = 0.00). Compared to healthy controls (n = 5385) men with diabetes (n = 863) were at increased odds of having erectile dysfunction (OR 3.62; 95% CI, 2.53 to 5.16; P < 0.0001; I2 = 67%, k = 8). Erectile dysfunction is common in diabetes, affecting more than half of men with the condition and with a prevalence odds of approximately 3.5 times more than controls. Our findings suggest that screening and appropriate intervention for men with erectile dysfunction is warranted. PMID- 28722226 TI - Biology of SLAC1-type anion channels - from nutrient uptake to stomatal closure. AB - Contents 46 I. 46 II. 47 III. 50 IV. 53 V. 56 VI. 57 58 58 References 58 SUMMARY: Stomatal guard cells control leaf CO2 intake and concomitant water loss to the atmosphere. When photosynthetic CO2 assimilation is limited and the ratio of CO2 intake to transpiration becomes suboptimal, guard cells, sensing the rise in CO2 concentration in the substomatal cavity, deflate and the stomata close. Screens for mutants that do not close in response to experimentally imposed high CO2 atmospheres identified the guard cell-expressed Slowly activating anion channel, SLAC1, as the key player in the regulation of stomatal closure. SLAC1 evolved, though, before the emergence of guard cells. In Arabidopsis, SLAC1 is the founder member of a family of anion channels, which comprises four homologues. SLAC1 and SLAH3 mediate chloride and nitrate transport in guard cells, while SLAH1, SLAH2 and SLAH3 are engaged in root nitrate and chloride acquisition, and anion translocation to the shoot. The signal transduction pathways involved in CO2 , water stress and nutrient-sensing activate SLAC/SLAH via distinct protein kinase/phosphatase pairs. In this review, we discuss the role that SLAC/SLAH channels play in guard cell closure, on the one hand, and in the root-shoot continuum on the other, along with the molecular basis of the channels' anion selectivity and gating. PMID- 28722227 TI - Engineering Single Nanopores on Gold Nanoplates by Tuning Crystal Screw Dislocation. AB - Compared with the large variety of solid gold nanostructures, synthetic approaches for their hollow counterparts are limited, largely confined to chemical and irradiation-based etching of preformed nanostructures. In particular, the preparation of through nanopore structures is extremely challenging. Here, a unique strategy for direct synthesis of gold nanopores in solution without the need for sacrificial templates or postsynthesis processing is reported. By controlling the degree of crystal screw dislocation, a single through pore with diameter ranging from sub-nanometer to tens of nanometers, in the center of large gold nanoplates, can be engineered with precision. Ionic current rectification behaviors are observed using the gold nanopore, potentially enabling new capabilities in biosensing, sequencing, and imaging. PMID- 28722228 TI - Combined effect of using near-infrared spectroscopy for nutritional evaluation of feed ingredients and non-starch polysaccharide carbohydrase complex on performance of broiler chickens. AB - This study was carried out to evaluate the combined effect of using near-infrared spectroscopy (NIRS) for nutritional evaluation of feed ingredients and the addition of non-starch polysaccharide carbohydrase complex (NSP enzymes) on the growth performance of broilers fed diets produced with low-quality wheat and soybean meal. A 2 * 2 trial design was performed, with seven replicates of 40 male Ross 308 broilers per treatment, evaluating the effect of the addition of NSP enzymes and the ingredients' nutritional matrix based on table values or NIRS values. Diets without added enzymes were formulated to reach nutritional requirements, whereas diets with enzymes were reformulated, reducing the apparent metabolizable energy (AME) by 85 kcal/kg. In the overall period (days 0-35), broilers fed diets formulated using NIRS values had higher (P < 0.001) average daily gain (+11.3%) and daily feed intake (+7.2%), and a lower (P < 0.001) feed conversion ratio (-5.3%) compared to those fed diets formulated using table values. When formulating diets for broilers with low-quality feed ingredients, performance can be improved by considering NIRS values and by the addition of NSP enzymes, even with a reduction of AME. These nutritional approaches are efficient in improving broilers' performances by themselves and even more so when they are combined. PMID- 28722229 TI - A transposon-directed epigenetic change in ZmCCT underlies quantitative resistance to Gibberella stalk rot in maize. AB - A major resistance quantitative trait locus, qRfg1, significantly enhances maize resistance to Gibberella stalk rot, a devastating disease caused by Fusarium graminearum. However, the underlying molecular mechanism remains unknown. We adopted a map-based cloning approach to identify the resistance gene at qRfg1 and examined the dynamic epigenetic changes during qRfg1-mediated maize resistance to the disease. A CCT domain-containing gene, ZmCCT, is the causal gene at the qRfg1 locus and a polymorphic CACTA-like transposable element (TE1) c. 2.4 kb upstream of ZmCCT is the genetic determinant of allelic variation. The non-TE1 ZmCCT allele is in a poised state, with predictive bivalent chromatin enriched for both repressive (H3K27me3/H3K9me3) and active (H3K4me3) histone marks. Upon pathogen challenge, this non-TE1 ZmCCT allele was promptly induced by a rapid yet transient reduction in H3K27me3/H3K9me3 and a progressive decrease in H3K4me3, leading to disease resistance. However, TE1 insertion in ZmCCT caused selective depletion of H3K4me3 and enrichment of methylated GC to suppress the pathogen induced ZmCCT expression, resulting in disease susceptibility. Moreover, ZmCCT mediated resistance to Gibberella stalk rot is not affected by photoperiod sensitivity. This chromatin-based regulatory mechanism enables ZmCCT to be more precise and timely in defense against F. graminearum infection. PMID- 28722230 TI - Alkoxides of Trivacant Lacunary Polyoxometalates. AB - Lacunary polyoxometalates (POMs) are useful rigid multidentate inorganic ligands to construct multinuclear metal oxo clusters and inorganic-organic hybrid materials. However, the use of multivacant lacunary POMs often suffers from their undesired condensation reactions at the highly reactive vacant sites. Herein, the introduction of alkoxy protecting groups into the vacant sites of lacunary POMs in organic media is reported for the first time. By reacting organic solvent soluble trivacant lacunary Keggin-type POMs with methanol, six methoxy groups were successfully introduced into the vacant sites, resulting in the formation of the alkoxides TBA4 [A-alpha-XW9 O28 (OCH3 )6 ] (Ix -OMe; X=Si, Ge). These methoxy groups could protect the reactive vacant sites and suppress the undesired dimerization reaction into the corresponding alpha-Dawson-type POMs. Since the introduced monodentate methoxy groups could easily be dissociated by hydrolysis, ISi -OMe could be utilized as the precursor for the synthesis of metal substituted POMs. In addition, by using pentaerythritol as the multidentate alkoxy ligand, the monomeric alkoxide TBA4 [A-alpha-SiW9 O28 {(OCH2 )2 C(CH2 OH)2 }3 ] (ISi -PE) was successfully synthesized. In particular, these multidentate alkoxy groups showed high resistance against hydrolysis. Moreover, by reacting ISi -PE with trivacant lacunary Keggin-type POMs, the dimeric inorganic-organic inorganic hybrid structures TBAn H8-n [(A-alpha-SiW9 O28 ){(OCH2 )2 C(CH2 O)2 }3 (A-alpha-XW9 O28 )] (IISiX -PE; X=Si, Ge) with the same or different heteroatoms (Si and Ge) were successfully synthesized. PMID- 28722232 TI - Rapidly growing cystic vestibular schwannoma with sudden onset facial palsy, ten years after subtotal excision. AB - An elderly male patient diagnosed with a right-sided cystic vestibular schwannoma (CVS) at our center underwent a translabyrinthine approach with a subtotal excision to preserve the facial nerve (FN). The tumor grew slowly for the first 9 years but in the subsequent 2 years grew rapidly, with the patient developing a FN paralysis. Using the previous approach, a second surgery was done and the tumor was excised, leaving behind a sheath of tumor on the facial and lower cranial nerves. This case demonstrates that CVSs show unpredictable growth patterns and need to be followed up for a longer period of time. Laryngoscope, 128:1649-1652, 2018. PMID- 28722231 TI - Bacteria antibiotic resistance: New challenges and opportunities for implant associated orthopedic infections. AB - There has been a dramatic increase in the emergence of antibiotic-resistant bacterial strains, which has made antibiotic choices for infection control increasingly limited and more expensive. In the U.S. alone, antibiotic-resistant bacteria cause at least 2 million infections and 23,000 deaths a year resulting in a $55-70 billion per year economic impact. Antibiotics are critical to the success of surgical procedures including orthopedic prosthetic surgeries, and antibiotic resistance is occurring in nearly all bacteria that infect people, including the most common bacteria that cause orthopedic infections, such as Staphylococcus aureus (S. aureus). Most clinical cases of orthopedic surgeries have shown that patients infected with antibiotic-resistant bacteria, such as methicillin-resistant S. aureus (MRSA), are associated with increased morbidity and mortality. This paper reviews the severity of antibiotic resistance at the global scale, the consequences of antibiotic resistance, and the pathways bacteria used to develop antibiotic resistance. It highlights the opportunities and challenges in limiting antibiotic resistance through approaches like the development of novel, non-drug approaches to reduce bacteria functions related to orthopedic implant-associated infections. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:22-32, 2018. PMID- 28722233 TI - Cooperative interaction of hepatocyte growth factor and neuregulin regulates Schwann cell migration and proliferation through Grb2-associated binder-2 in peripheral nerve repair. AB - The sequential reactive changes in Schwann cell phenotypes in transected peripheral nerves, including dedifferentiation, proliferation and migration, are essential for nerve repair. Even though the injury-induced migratory and proliferative behaviors of Schwann cells resemble epithelial and mesenchymal transition (EMT) in tumors, the molecular mechanisms underlying this phenotypic change of Schwann cells are still unclear. Here we show that the reactive Schwann cells exhibit migratory features dependent on the expression of a scaffolding oncoprotein Grb2-associated binder-2 (Gab2), which was transcriptionally induced by neuregulin 1-ErbB2 signaling following nerve injury. Injury-induced Gab2 expression was dependent on c-Jun, a transcription factor critical to a Schwann cell reprograming into a repair-type cell. Interestingly, the injury-induced activation (tyrosine phosphorylation) of Gab2 in Schwann cells was regulated by an EMT signal, the hepatocyte growth factor-c-Met signaling, but not by neuregulin 1. Gab2 knockout mice exhibited a deficit in nerve repair after nerve transection due to limited Schwann cell migration. Furthermore, Gab2 was required for the proliferation of Schwann cells following nerve injury and in vitro, and was over-expressed in human Schwann cell-derived tumors. In contrast, the tyrosine phosphorylation of Gab1 after nerve injury was principally regulated by the neuregulin 1-ErbB2 signaling and was indispensable for remyelination after crush injury, but not for the proliferation and migration of Schwann cells. Our findings indicate that Gab1 and Gab2 in Schwann cells are nonredundant and play a crucial role in peripheral nerve repair. PMID- 28722235 TI - Analysis of safety-related regulatory actions by Japan's pharmaceutical regulatory agency. AB - PURPOSE: To evaluate the safety-related regulatory actions implemented by Japan's Pharmaceuticals and Medical Devices Agency (PMDA) in 2012. METHODS: We analyzed serious safety issues appended to drug package inserts (PIs) in Japan in 2012. The issues were characterized according to drug class, adverse event, years since drug approval, initiator of regulatory actions, revised section of PI, and evidence source. We also quantified the durations from signal detection to tentative decision and from tentative decision to regulatory action. RESULTS: We identified 144 serious safety issues during the study period, and the majority of evidence originated from spontaneous reports (83.5%). The PMDA initiated regulatory actions for half of all safety issues, and the median duration from drug approval to regulatory action was 8 years (interquartile range [IQR], 3-26.5 years). The median duration was 49 days (IQR, 0-362 days) from signal detection to tentative decision and 84 days (IQR, 63-136 days) from tentative decision to regulatory action. Several safety issues involving older drugs and multiple products had protracted decision-making durations. CONCLUSIONS: Most safety issues led to prompt regulatory actions predominantly based on spontaneous reports. Some safety issues that were not easily detected by the spontaneous reporting system were identified years after approval. In addition, several safety issues required assessments of multiple drug products, which prolonged the decision-making process. PMID- 28722234 TI - Minocycline reduces microgliosis and improves subcortical white matter function in a model of cerebral vascular disease. AB - Chronic cerebral hypoperfusion is a key mechanism associated with white matter disruption in cerebral vascular disease and dementia. In a mouse model relevant to studying cerebral vascular disease, we have previously shown that cerebral hypoperfusion disrupts axon-glial integrity and the distribution of key paranodal and internodal proteins in subcortical myelinated axons. This disruption of myelinated axons is accompanied by increased microglia and cognitive decline. The aim of the present study was to investigate whether hypoperfusion impairs the functional integrity of white matter, its relation with axon-glial integrity and microglial number, and whether by targeting microglia these effects can be improved. We show that in response to increasing durations of hypoperfusion, the conduction velocity of myelinated fibres in the corpus callosum is progressively reduced and that paranodal and internodal axon-glial integrity is disrupted. The number of microglial cells increases in response to hypoperfusion and correlates with disrupted paranodal and internodal integrity and reduced conduction velocities. Further minocycline, a proposed anti-inflammatory and microglia inhibitor, restores white matter function related to a reduction in the number of microglia. The study suggests that microglial activation contributes to the structural and functional alterations of myelinated axons induced by cerebral hypoperfusion and that dampening microglia numbers/proliferation should be further investigated as potential therapeutic benefit in cerebral vascular disease. PMID- 28722236 TI - The membrane-type estrogen receptor G-protein-coupled estrogen receptor suppresses lipopolysaccharide-induced interleukin 6 via inhibition of nuclear factor-kappa B pathway in murine macrophage cells. AB - The female sex hormone estrogen exerts anti-inflammatory effects. The G-protein coupled estrogen receptor (GPER) has been recently identified as a novel membrane type estrogen receptor that can mediate non-genomic estrogenic effects on many cell types. We previously demonstrated that GPER inhibits tumor necrosis factor alpha-induced expression of interleukin 6 (IL-6) through repression of nuclear factor-kappa B (NF-kappaB) promoter activity using human breast cancer cells. Although several reports have indicated that GPER suppresses Toll-like receptor induced inflammatory cytokine expression in macrophages, the molecular mechanisms of the inhibition of cytokine production via GPER remain poorly understood. In the present study, we examined GPER-mediated inhibition of IL-6 expression induced by lipopolysaccharide (LPS) stimulation in a mouse macrophage cell line. We found that the GPER agonist G-1 inhibited LPS-induced IL-6 expression in macrophage cells, and this inhibition was due to the repression of NF-kappaB promoter activity by GPER. G-1 treatment also decreased the phosphorylation of inhibitor of kappaB kinases. Among the mitogen-activated protein kinases, the phosphorylation of c-jun N-terminal kinase (JNK) was increased by G-1. These findings delineate the novel mechanism of the inhibition of LPS-induced IL-6 through GPER-activated JNK-mediated negative regulation of the NF-kappaB pathway in murine macrophage cells, which links anti-inflammatory effects to estrogen. PMID- 28722237 TI - Bone involvement: Histopathological evidence for endoscopic management of sinonasal inverted papilloma. AB - OBJECTIVE: The aim of this study is to provide histopathological evidence for a better understanding of the excision of bone underlying tumor. STUDY DESIGN: Retrospective study. METHODS: Thirty patients with histopathological diagnosis of sinonasal inverted papilloma (SIP) were enrolled. All patients underwent preoperative radiography to define the tumor location. The primary tumor and underlying bone, removed during endoscopic surgery, were examined under microscope. RESULTS: Twenty-five of 30 specimens exhibited bony hyperostosis on computed tomography (CT) images, and 12 of 30 specimens showed evidence of bony lamellar erosion. Both coexisted in 11 cases. Half of the relapse cases (8 of 16) presented bone discontinuity on CT, which indicates a higher propensity for bone involvement when compared with primary SIP. On histopathology, 26 cases presented hyperostosis and 11 cases showed bone invasion. In total, 90% of cases covered both. Sixteen cases showed a growing tendency of inflammatory cells infiltration. CONCLUSION: Histopathological evidence of bone involvement indicates the importance of removal of the underlying bone at the time of endoscopic tumor resection. We hypothesized that bone involvement including bone invasion and osteogenesis may be induced by the tumor, and any microscopic lesion in the bony crevices probably indicates recurrence of SIP. Furthermore, infiltration of inflammatory cells may facilitate bone involvement and cause recurrence. LEVEL OF EVIDENCE: NA. Laryngoscope, 127:2703-2708, 2017. PMID- 28722238 TI - The preparation of microfluidic architecture with monolithic materials using a dual porous silica structure. AB - A microfluidic device (MD) has been developed which features a porous silica (PS) monolithic disk synthesized from tetramethyl orthosilicate, incorporated into the device post-fabrication and sealed in place with a second PS monolithic layer, synthesized from potassium silicate. This dual porous silica (DPS) structure provides a pathway for sample introduction to the MD and offers an ideal platform for solid phase extraction (SPE) methodologies which can be rapidly and efficiently integrated into a chip-based format. All silica disk manufacture and functionalization was carried out in batch to provide a readily scalable method of production. Application of this design for processing samples was demonstrated using two alternative nucleic acid purification chemistries, yielding polymerase chain reaction amplifiable DNA extracted from 150 MUL of human urine in less than 35 min. It is proposed that this DPS system could be further developed for a diverse range of chip-based SPE applications, providing an interface facilitating sample delivery and enabling SPE on-chip. Furthermore, to the author's knowledge it is the first reporting of two different types of PS amalgamated in a single MD. PMID- 28722239 TI - 3D Anisotropic Thermal Conductivity of Exfoliated Rhenium Disulfide. AB - ReS2 represents a different class of 2D materials, which is characterized by low symmetry having 1D metallic chains within the planes and extremely weak interlayer bonding. Here, the thermal conductivity of single-crystalline ReS2 in a distorted 1T phase is determined at room temperature for the in-plane directions parallel and perpendicular to the Re-chains, and the through-plane direction using time-domain thermoreflectance. ReS2 is prepared in the form of flakes having thicknesses of 60-450 nm by micromechanical exfoliation, and their crystalline orientations are identified by polarized Raman spectroscopy. The in plane thermal conductivity is higher along the Re-chains, (70 +/- 18) W m-1 K-1 , as compared to transverse to the chains, (50 +/- 13) W m-1 K-1 . As expected from the weak interlayer bonding, the through-plane thermal conductivity is the lowest observed to date for 2D materials, (0.55 +/- 0.07) W m-1 K-1 , resulting in a remarkably high anisotropy of (130 +/- 40) and (90 +/- 30) for the two in-plane directions. The thermal conductivity and interface thermal conductance of ReS2 are discussed relative to the other 2D materials. PMID- 28722240 TI - An MRI Hyperintense Acute Reperfusion Marker Is Related to Elevated Peripheral Monocyte Count in Acute Ischemic Stroke. AB - BACKGROUND AND PURPOSE: Blood-brain barrier (BBB) disruption detected on magnetic resonance imaging (MRI) in acute ischemic stroke as a hyperintense acute reperfusion marker (HARM) is associated with upregulation of matrix metalloproteinase-9 (MMP-9). Although activated leukocytes, including monocytes, are the main source of MMPs, limited data exist to support relationship between leukocyte activation and BBB disruption in patients with acute ischemic stroke. The goal of this study is to investigate the relationship between neutrophils, lymphocytes, and monocytes with BBB disruption detected as HARM (+) in patients with acute ischemic stroke. METHODS: We conducted a retrospective analysis of prospectively collected data in patients who did not receive any reperfusion therapy with acute (<12 hours) ischemic stroke. MRI scans were obtained at baseline, 24 hours, and 5 days. HARM was evaluated on the 24-hour follow-up scan. RESULTS: Thirty-three patients were studied. HARM was detected in 27% of patients. Median volumes of baseline perfusion (mean transit time [MTT]) deficit (219.4 mL vs. 158.4 mL, P = .029) and DWI infarct growth at 24 hours (18.50 mL vs. .14 mL, P = .017), as well as the median absolute numbers (1 * 103 /mm3 ) of monocytes, were significantly higher in HARM (+) versus HARM (-) patients (0.9 vs. 0.6, p = 0.011). CONCLUSION: Increased monocyte count associated with HARM supports importance of systemic inflammation in BBB disruption in acute ischemic stroke. PMID- 28722241 TI - Mineralized State of the Avian Influenza Virus in the Environment. AB - Although the circulation of avian influenza viruses in humans is limited, they can be transmitted from Aves (birds) to humans, representing a great challenge. Herein, we suggest that influenza viruses from Aves might exist in a mineralized state owing to the high calcium concentrations in the avian intestine. Using two typical influenza viruses as examples, we demonstrate that these viruses can self mineralize in simulated avian intestinal fluid, resulting in egg-like virus mineral structured composites. The mineralized viruses are more robust, with enhanced infectivity and thermostability. More importantly, the mineral exterior of mineralized viruses can alter their cell internalization, expanding the possible tropisms. The discovery of a mineralized state of influenza viruses highlights the integration of nanomaterials and viruses in the environment, which provides a new understanding of avian influenza infection and its control. PMID- 28722242 TI - Therapeutic application of GPR119 ligands in metabolic disorders. AB - GPR119 belongs to the G protein-coupled receptor family and exhibits dual modes of action upon ligand-dependent activation: pancreatic secretion of insulin in a glucose-dependent manner and intestinal secretion of incretins. Hence, GPR119 has emerged as a promising target for treating type 2 diabetes mellitus without causing hypoglycaemia. However, despite continuous efforts by many major pharmaceutical companies, no synthetic GPR119 ligand has been approved as a new class of anti-diabetic agents thus far, nor has any passed beyond phase II clinical studies. Herein, we summarize recent advances in research concerning the physiological/pharmacological effects of GPR119 and its synthetic ligands on the regulation of energy metabolism, and we speculate on future applications of GPR119 ligands for the treatment of metabolic diseases, focusing on non-alcoholic fatty liver disease. PMID- 28722243 TI - Differences between Caucasian and Asian attractive faces. AB - INTRODUCTION: There are discrepancies between the public's current beauty desires and conventional theories and historical rules regarding facial beauty. This photogrammetric study aims to describe in detail mathematical differences in facial configuration between attractive Caucasian and attractive Asian faces. METHODS: To analyse the structural differences between attractive Caucasian and attractive Asian faces, frontal face and lateral face views for each race were morphed; facial landmarks were defined, and the relative photographic pixel distances and angles were measured. Absolute values were acquired by arithmetic conversion for comparison. RESULTS: The data indicate that some conventional beliefs of facial attractiveness can be applied but others are no longer valid in explaining perspectives of beauty between Caucasians and Asians. Racial differences in the perceptions of attractive faces were evident. Common features as a phenomenon of global fusion in the perspectives on facial beauty were revealed. CONCLUSIONS: Beauty standards differ with race and ethnicity, and some conventional rules for ideal facial attractiveness were found to be inappropriate. We must reexamine old principles of facial beauty and continue to fundamentally question it according to its racial, cultural, and neuropsychological aspects. PMID- 28722245 TI - Patient blood management in obstetrics: management of anaemia and haematinic deficiencies in pregnancy and in the post-partum period: NATA consensus statement. PMID- 28722246 TI - Delta-9-tetrahydrocannabinol decreases masticatory muscle sensitization in female rats through peripheral cannabinoid receptor activation. AB - BACKGROUND: This study investigated whether intramuscular injection of delta-9 tetrahydrocannabinol (THC), by acting on peripheral cannabinoid (CB) receptors, could decrease nerve growth factor (NGF)-induced sensitization in female rat masseter muscle; a model which mimics the symptoms of myofascial temporomandibular disorders. METHODS: Immunohistochemistry was used to explore the peripheral expression of cannabinoid receptors in the masseter muscle while behavioural and electrophysiology experiments were employed to assess the functional effects of intramuscular injection of THC. RESULTS: It was found that CB1 and CB2 receptors are expressed by trigeminal ganglion neurons that innervate the masseter muscle and also on their peripheral endings. Their expression was greater in TRPV1-positive ganglion neurons. Three days after intramuscular injection of NGF, ganglion neuron expression of CB1 and CB2, but not TPRV1, was decreased. In behavioural experiments, intramuscular injection (10 MUL) of THC (1 mg/mL) attenuated NGF-induced mechanical sensitization. No change in mechanical threshold was observed in the contralateral masseter muscles and no impairment of motor function was found after intramuscular injections of THC. In anaesthetized rats, the same concentration of THC increased the mechanical thresholds of masseter muscle mechanoreceptors. Co-administration of the CB1 antagonist AM251 blocked the effect of THC on masseter muscle mechanoreceptors while the CB2 antagonist AM630 had no effect. CONCLUSIONS: These results suggest that reduced inhibitory input from the peripheral cannabinoid system may contribute to NGF induced local myofascial sensitization of mechanoreceptors. Peripheral application of THC may counter this effect by activating the CB1 receptors on masseter muscle mechanoreceptors to provide analgesic relief without central side effects. SIGNIFICANCE: Our results suggest THC could reduce masticatory muscle pain through activating peripheral CB1 receptors. Peripheral application of cannabinoids could be a novel approach to provide analgesic relief without central side effects. PMID- 28722244 TI - Risk of liver decompensation with cumulative use of mitochondrial toxic nucleoside analogues in HIV/hepatitis C virus coinfection. AB - PURPOSE: Among patients dually infected with human immunodeficiency virus (HIV) and chronic hepatitis C virus (HCV), use of antiretroviral therapy (ART) containing mitochondrial toxic nucleoside reverse transcriptase inhibitors (mtNRTIs) might induce chronic hepatic injury, which could accelerate HCV associated liver fibrosis and increase the risk of hepatic decompensation and death. METHODS: We conducted a cohort study among 1747 HIV/HCV patients initiating NRTI-containing ART within the Veterans Aging Cohort Study (2002-2009) to determine if cumulative mtNRTI use increased the risk of hepatic decompensation and death among HIV-/HCV-coinfected patients. Separate marginal structural models were used to estimate hazard ratios (HRs) of each outcome associated with cumulative exposure to ART regimens that contain mtNRTIs versus regimens that contain other NRTIs. RESULTS: Over 7033 person-years, we observed 97 (5.6%) decompensation events (incidence rate, 13.8/1000 person-years) and 125 (7.2%) deaths (incidence rate, 17.8 events/1000 person-years). The risk of hepatic decompensation increased with cumulative mtNRTI use (1-11 mo: HR, 1.79 [95% confidence interval (CI), 0.74-4.31]; 12-35 mo: HR, 1.39 [95% CI, 0.68 2.87]; 36-71 mo: HR, 2.27 [95% CI, 0.92-5.60]; >71 mo: HR, 4.66 [95% CI, 1.04 20.83]; P = .045) versus nonuse. Cumulative mtNRTI use also increased risk of death (1-11 mo: HR, 2.24 [95% CI, 1.04-4.81]; 12-35 mo: HR, 2.05 [95% CI, 0.68 6.20]; 36-71 mo: HR, 3.04 [95% CI, 1.12-8.26]; >71 mo: HR, 3.93 [95% CI, 0.75 20.50]; P = .030). CONCLUSIONS: These findings suggest that cumulative mtNRTI use may increase the risk of hepatic decompensation and death in HIV/HCV coinfection. These drugs should be avoided when alternatives exist for HIV/HCV patients. PMID- 28722247 TI - Left ventricular function and regional strain with subtly-tagged steady-state free precession feature tracking. AB - PURPOSE: To provide regional strain and ventricular volume from a single acquisition, using subtly tagged steady-state free precession (SubTag SSFP) feature tracking. MATERIALS AND METHODS: The effects on regional strain of tag strength in gradient recalled echo (GRE) tagging, flip angle in untagged balanced SSFP, and both in SubTag SSFP were examined in the mid left ventricle of 15 healthy volunteers at 3T. Optimal parameters were determined from varying both tag strength and SSFP flip angle using full tag saturation GRE as the reference standard. SubTag SSFP was acquired in 15 additional healthy volunteers for whole heart volume and strain assessment using the optimized parameters. Values measured by two image analysts were compared to clinical reference standards from untagged SSFP (volumes) and GRE tagging (strains). RESULTS: Regional strain accuracy was maintained with decreasing total tagging flip angle (beta); less than 3% differences for beta >= 26 degrees . For untagged SSFP flip angle (alpha), whole-wall strain differences became statistically significant when alpha < 40 degrees . A SubTag SSFP acquisition with alpha = 40 degrees and beta = 46 degrees showed the best combination of tagging strength, blood-myocardial contrast, and tag persistence at end-systole for regional strain estimation. SubTag SSFP also showed excellent agreement with untagged SSFP for volumetrics (percent difference: end-diastolic volume = 0.6%, end-systolic volume = 0.4%, stroke volume = 1.2%, ejection fraction = 0.6%, mass = 1.1%). CONCLUSION: Feature tracking for regional myocardial strain assessment is dependent on image features, mainly the tag strength, persistence, and image contrast. SubTag SSFP balances these criteria to provide accurate regional strain and volumetric assessment in a single acquisition. LEVEL OF EVIDENCE: 1 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2018;47:787-797. PMID- 28722248 TI - Screening of Hallucinogenic Compounds and Genomic Characterisation of 40 Anatolian Salvia Species. AB - INTRODUCTION: Salvia, an important and widely available member of Lamiaceae family. Although comparative analysis on secondary metabolites in several Salvia species from Turkey has been reported, their hallucinogenic chemicals have not been screened thoroughly. OBJECTIVE: This study provides LC-MS/MS analysis of 40 Salvia species for screening their psychoactive constituents of salvinorin A and salvinorin B. 5S-rRNA gene non-coding region of Salvia plants was sequenced, aligned and compared with that sequence of Salvia divinorum plant. METHODOLOGY: Targeted molecules of salvinorin A and salvinorin B were quantified, using LC MS/MS, from all aerial parts of 40 Salvia species, collected from different parts of Turkey. Regions of 5S-rRNA gene from different species were amplified by polymerase chain reaction and DNA sequences were aligned with Salvia divinorum DNA sequences. RESULTS: Very few of the Salvia species (S. recognita, S. cryptantha and S. glutinosa) contained relatively high levels of salvinorin A (212.86 +/- 20.46 MUg/g, 51.50 +/- 4.95 MUg/g and 38.92 +/- 3.74 MUg/g, respectively). Salvinorin B was also found in Salvia species of S. potentillifolia, S. adenocaulon and S. cryptantha as 2351.99 +/- 232.22 MUg/g, 768.78 +/- 75.90 MUg/g and 402.24 +/- 39.71 MUg/g, respectively. The sequences of 5S-rRNA gene of 40 different Salvia species were presented and it was found that none of the Salvia species in Turkey had similar DNA sequence to Salvia divinorum plant. CONCLUSION: This is the first report of screening 40 Salvia species in Turkey according to their psychoactive constituents, salvinorin A and salvinorin B and their genomic structures. It is possible that some of these Salvia species may exhibit some psycho activity. Thus, they need to be screened further. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28722249 TI - Memory in 3-month-old infants benefits from a short nap. AB - A broad range of studies demonstrate that sleep has a facilitating role in memory consolidation (see Rasch & Born, ). Whether sleep-dependent memory consolidation is also apparent in infants in their first few months of life has not been investigated. We demonstrate that 3-month-old infants only remember a cartoon face approximately 1.5-2 hours after its first presentation when a period of sleep followed learning. Furthermore, habituation time, that is, the time to become bored with a stimulus shown repetitively, correlated negatively with the density of infant sleep spindles, implying that processing speed is linked to specific electroencephalographic components of sleep. Our findings show that without a short period of sleep infants have problems remembering a newly seen face, that sleep enhances memory consolidation from a very early age, highlighting the importance of napping in infancy, and that infant sleep spindles may be associated with some aspects of cognitive ability. PMID- 28722250 TI - Residential age care and domiciliary oral health services: Reach-OHT-The development of a metropolitan oral health programme in Sydney, Australia. AB - OBJECTIVE: To describe an oral health care programme for older people in Residential Aged Care Facilities (RACFs) to improve access to care and support facilities. INTRODUCTION: Different models of residential care have been proposed, but few have been comprehensive (providing on-site health promotion and service delivery) or sustainable. METHODS: A partnership model of oral health care, with dental services plus oral health education, was integrated into the community outreach services of a metropolitan hospital department of aged care. The programme provided annual oral health education and training to staff, and on site dental care to 10 (RACFs). RESULTS: None of the RACFs had received organised education or on-site dental service care prior to the programme. At the completion of the third year of the programme, 607 residents (75% of the total bed capacity for the 10 RACFs) had received an annual oral health assessment, and 271 (46.5%) had received on-site dental care. More than 120 nursing and allied health staff had received education and training in oral health support to residents. Oral cleanliness, the proportion not experiencing dental pain and referral for additional care decreased significantly over the period, but dental caries experience and periodontal conditions remained a concern. CONCLUSIONS: Sustainable domiciliary oral health services and oral health education are feasible and practical using a partnership model within the Australian health system. Adaptability, continuity and the use of oral health therapists/dental hygienists in the coordination and management of the programme further contribute to viability. PMID- 28722251 TI - Alteration in the relationship between tanycytes and gonadotrophin-releasing hormone neurosecretory terminals following long-term metabolic manipulation in the sheep. AB - The activity of the hypothalamic-pituitary gonadal axis is influenced by energy reserves, such that an increase or a decrease in adiposity may perturb the secretion and action of gonadotrophin-releasing hormone (GnRH). This is considered to be a result of the signalling of hormones such as leptin, which act upon neuronal systems controlling GnRH secretion. Other work shows plasticity in the relationship between tanycytes and GnRH neurosecretory terminals in the median eminence across the oestrous cycle and we hypothesised that a similar plasticity may occur with altered metabolic status. We studied Lean, Normal and Fat ovariectomised ewes, which displayed differences in gonadotrophin status, and investigated the relationship between tanycytes and GnRH neuroterminals. Under both Lean and Fat conditions, an altered anatomical arrangement between these two elements was observed in the vicinity of the blood vessels of the primary plexus of the hypophysial portal blood system. These data suggest that such plasticity is an important determinant of the rate of secretion of GnRH in animals of differing metabolic status and that this also contributes to the relative hypogonadotrophic condition prevailing with metabolic extremes. PMID- 28722252 TI - Efficient Access to All-Carbon Quaternary and Tertiary alpha-Functionalized Homoallyl-type Aldehydes from Ketones. AB - beta,gamma-Unsaturated aldehydes with all-carbon quaternary or tertiary alpha centers were rapidly assembled from ketones through a unique synthetic operation consisting of 1) C1 homologation, 2) Lewis acid mediated epoxide-aldehyde isomerization, and 3) electrophilic trapping. The synthetic equivalence of a vinyl oxirane and a beta,gamma-unsaturated aldehyde is the key concept of this previously undisclosed tactic. Mechanistic studies and labeling experiments suggest that an aldehyde enolate is a crucial intermediate. The homologating carbenoid formation plays a critical role in determining the chemoselectivity. PMID- 28722253 TI - Late lumen enlargement induced by drug coated balloon in the patient with PTFE covered stent restenosis. AB - We report a case of percutaneous coronary intervention with drug coated balloon (DCB) for the in-stent restenosis of polytetrafluoroethylene-covered stent. One year follow-up angiography was excellent and in-stent lumen enlargement compared with the postprocedure and 6-months follow-up was demonstrated by optical coherent tomography. This case suggested the utility of DCB as a therapeutic option for covered-stent restenosis. PMID- 28722254 TI - Determination of irritant threshold concentrations of multiple tree, grass, weed and mould allergens for intradermal testing of horses residing in the southern USA. AB - BACKGROUND: Appropriate allergen threshold concentrations (TCs) for intradermal testing (IDT) have not been established in horses for many pollen and mould allergens. OBJECTIVES: To determine the TCs in non-allergic horses and describe the frequency of late phase reactions for 26 allergens, including trees, grasses, weeds and moulds in horses residing in the southern Unites States. ANIMALS: Twenty four clinically normal horses in the southern United States. METHODS: Threshold concentrations for different allergens were determined using IDT subjective measurements at 30 minutes. Delayed reactions were evaluated at 4 and 24 h. RESULTS: Threshold concentrations (all PNU/mL) were established for eight tree allergens (black willow 1,000, box elder 1,000, live oak 1,000, pecan 2,000, white ash 4,000, red oak 4,000, red mulberry 2,000 and green ash 2,000); two grass allergens (Johnson grass 250 PNU/mL and Kentucky blue grass 500 PNU/mL); two weeds (carelessweed 1,000 PNU/mL, great ragweed 500 PNU/mL) and one mould (Curvularia 8,000 PNU/mL). The TC was not determined due to excessive reactivity at the lowest concentration tested (1,000 PNU/mL) for bahia and perennial rye grass. Eleven other allergens did not meet the criteria to establish a TC when evaluated at 30 min due to lack of positive reactions. Multiple allergens caused positive reactions in >=10% of horses at 4 h. Reactions at 24 h were rare with the exception of one horse. CONCLUSIONS AND CLINICAL IMPORTANCE: This study identified intradermal TC for multiple pollen and mould allergens in horses. These values may prove useful for optimizing allergen concentrations for IDT of allergic horses. PMID- 28722255 TI - Drug-drug interactions between triazole antifungal agents used to treat invasive aspergillosis and immunosuppressants metabolized by cytochrome P450 3A4. AB - Patients undergoing treatment with immunosuppressant drugs following solid organ or hematopoietic stem cell transplantation are at particular risk for development of serious infections such as invasive aspergillosis. Four triazole antifungal drugs, voriconazole, posaconazole, itraconazole, and isavuconazole, are approved to treat invasive aspergillosis either as first- or second-line therapy. All of these agents are inhibitors of cytochrome P450 3A4, which plays a key role in metabolizing immunosuppressant drugs such as cyclosporine, tacrolimus, and sirolimus. Thus, co-administration of a triazole antifungal drug with these immunosuppressant drugs can potentially increase plasma concentrations of the immunosuppressant drugs, thereby resulting in toxicity, or upon discontinuation, inadvertently decrease the respective concentrations with increased risk of rejection or graft-versus-host disease. In this article, we review the evidence for the extent of inhibition of cytochrome P450 3A4 by each of these triazole antifungal drugs and assess their effects on cyclosporine, tacrolimus, and sirolimus. We also consider other factors affecting interactions of these two classes of drugs. Finally, we examine recommendations and strategies to evaluate and address those potential drug-drug interactions in these patients. PMID- 28722256 TI - Diagnostic and prognostic value of low percentage of glycosylated ferritin in acquired hemophagocytic lymphohistiocytosis: A single-center study. AB - INTRODUCTION: Hemophagocytic lymphohistiocytosis (HLH) is an aggressive and life threatening syndrome characterized by an excessive immune activation. Glycosylated ferritin (GF) level has been proposed as highly specific of HLH. METHODS: We have studied 12 subjects with HLH according to the HLH-04 trial criteria and 11 patients with a clinical and laboratoristic suspicion of HLH. The percentage of GF was measured by an in-house assay. RESULTS: The only biomarkers that were significantly different in the two groups were fraction of GF (P<.001) and the presence of hemophagocytosis in bone marrow (P=.006). Subjects with HLH had significantly lower percentage of GF than patients with other inflammatory conditions mimicking HLH. A fraction of GF <=20% was strongly consistent with a diagnosis of HLH. CONCLUSIONS: Fraction of GF is useful to identify subjects at high risk for early death and therefore in need of early treatment. PMID- 28722257 TI - Mesoporous Tin-Based Oxide Nanospheres/Reduced Graphene Composites as Advanced Anodes for Lithium-Ion Half/Full Cells and Sodium-Ion Batteries. AB - The large volume variations of tin-based oxides hinder their extensive application in the field of lithium-ion batteries (LIBs). In this study, structure design, hybrid fabrication, and carbon-coating approaches have been simultaneously adopted to address these shortcomings. To this end, uniform mesoporous NiO/SnO2 @rGO, Ni-Sn oxide@rGO, and SnO2 @rGO nanosphere composites have been selectively fabricated. Among them, the obtained NiO/SnO2 @rGO composite exhibited a high capacity of 800 mAh g-1 at 1000 mA g-1 after 400 cycles. The electrochemical mechanism of NiO/SnO2 as an anode for LIBs has been preliminarily investigated by ex situ XRD pattern analysis. Furthermore, an NiO/SnO2 @rGO-LiCoO2 lithium-ion full cell showed a high capacity of 467.8 mAh g 1 at 500 mA g-1 after 100 cycles. Notably, the NiO/SnO2 @rGO composite also showed good performance when investigated as an anode for sodium-ion batteries (SIBs). It is believed that the unique mesoporous nanospherical framework, synergistic effects between the various components, and uniform rGO wrapping of NiO/SnO2 shorten the Li+ ion diffusion pathways, maintain sufficient contact between the active material and the electrolyte, mitigate volume changes, and finally improve the electrical conductivity of the electrode. PMID- 28722258 TI - In vitro evaluation of chitosan-coated liposome containing both coenzyme Q10 and alpha-lipoic acid: Cytotoxicity, antioxidant activity, and antimicrobial activity. AB - BACKGROUND: Chitosan-coated liposome containing both coenzyme Q10 and alpha lipoic acid (CCAL) was a novel multifunctional nano delivery system exhibited long-term stability at room temperature and high encapsulation efficiency. Which containing two kinds of antioxidants (coenzyme Q10 and alpha-lipoic acid) and two antibacterial agents (chitosan and alpha-lipoic acid). However, the further biocompatibility, such as cytotoxicity and antioxidant activity, and antimicrobial activity of CCAL, has not been systematically evaluated. OBJECTIVES: This study aims to evaluate the cytotoxicity, antioxidant activity and antimicrobial activity of CCAL. METHODS: This article evaluated the in vitro cytotoxicity and antioxidant activity of CCAL by CCK8 assay, and antimicrobial activity on Staphylococcus aureus and Escherichia coli was investigated. RESULTS: For antioxidant activity study, CCAL displayed significant antioxidant effect when compared with control group (P<.01). Finally, CCAL also exhibited antimicrobial activity, and CCAL showed stronger bactericidal effect with Gram positive bacteria than Gram-negative bacteria. CONCLUSIONS: CCAL could be a potential antioxidant delivery system for cosmetics or pharmaceuticals without cytotoxicity and artificial preservatives free. PMID- 28722259 TI - l-Ornithine and l-lysine stimulate gastrointestinal motility via transient receptor potential vanilloid 1. AB - SCOPE: The gastrointestinal (GI) tract senses and responds to intraluminal nutrients and these interactions often affect GI functions. We found that, among basic amino acids, l-ornithine (Orn) and l-lysine (Lys) stimulated but l-arginine (Arg) suppressed GI motility after oral administration (24 mmol/kg) in mice (Orn and Lys, 14.3 and 26.4% promotion; Arg, 7.7% suppression). We investigated the mechanism of the action of Orn and Lys on GI motility. METHODS AND RESULTS: Orn induced promotion of small intestinal transit was significantly inhibited (p<0.05) by oral administration of capsazepine, a transient receptor potential vanilloid 1 (TRPV1) antagonist. Moreover, the stimulatory effect of Orn and Lys was abolished in TRPV1-knockout mice. In TRPV1-transfected HEK293 cells, Orn and Lys (10 mM) evoked Ca2+ influx, which was blocked by ruthenium red, a TRP channel antagonist. These results suggest that Orn and Lys promote GI motility via activation of TRPV1. The GI motility stimulation by Orn and Lys was also blocked by atropine, a muscarinic acetylcholine receptor (mAChR) antagonist, or NG -nitro l-arginine methyl ester, a nitric oxide (NO) synthase inhibitor. CONCLUSION: Orally administered Orn and Lys stimulate GI motility via TRPV1, mAChR and NO synthase in mice. PMID- 28722260 TI - Effect of long-distance transportation on serum metabolic profiles of steer calves. AB - Long-distance transportation is sometimes inevitable in the beef industry because of the geographic separation of major breeding and fattening areas. Long-distance transportation negatively impacts production and health of cattle, which may, at least partly, result from the disturbance of metabolism during and after transportation. However, alteration of metabolism remains elusive in transported cattle. We investigated the effects of transportation on the metabolomic profiles of Holstein steer calves. Non-targeted analysis of serum concentrations of low molecular weight metabolites was performed by gas chromatography mass spectrometry. Transportation affected 38 metabolites in the serum. A pathway analysis suggested that 26, 10, and 10 pathways were affected immediately after transportation, and 3 and 7 days after transportation, respectively. Some pathways were disturbed only immediately after transportation, likely because of feed and water withdrawal during transit. Nicotinate and nicotinamide metabolism, and citric acid cycle were affected for 3 days after transportation, whereas propionate metabolism, phenylalanine and tyrosine metabolism were affected throughout the experiment. Four pathways were not affected immediately after transportation, but were altered thereafter. These results suggested that many metabolic pathways had marked perturbations during transportation. Metabolites such as citric acid, propionate, tyrosine and niacin can be candidate supplements for mitigating transportation-induced adverse effects. PMID- 28722261 TI - Dietary rice improves growth performance, mucosal enzyme activities and plasma urea nitrogen in weaning piglets. AB - In this study, we evaluated the nutritional functions of rice for weaning piglets. Sixteen weaning piglets with an average initial weight of 7.2 kg were divided into two groups. One group was fed a corn-soybean meal based diet, and the other was fed a rice-soybean meal based diet, containing 50% corn and rice, respectively. A 2 weeks growth trial was conducted and growth performance, intestinal mucosal enzyme activities and plasma urea nitrogen were measured. The average daily gain in rice-fed piglets was significantly higher than that in corn fed piglets and the average daily feed intake tended to be higher in rice-fed piglets than in corn-fed piglets. Maltase and aminopeptidase activities (mol/g tissue) in the jejunum in rice-fed piglets were significantly higher than those in corn-fed piglets, although these enzyme activities were not different in the duodenum. Sucrase and dipeptidyl peptidase IV activities in the two groups were not different in either the duodenum or jejunum. Although the feed (nitrogen) intake was higher in rice-fed piglets, the plasma urea nitrogen in rice-fed piglets was significantly lower (P = 0.006) than that in corn-fed piglets. These results indicate that rice is a good alternative feedstuff for the diet of weaning piglets. PMID- 28722262 TI - BRAF p.V600E-specific immunohistochemical assessment in colorectal cancer endoscopy biopsies is consistent with the mutational profiling. PMID- 28722263 TI - FtSAD2 and FtJAZ1 regulate activity of the FtMYB11 transcription repressor of the phenylpropanoid pathway in Fagopyrum tataricum. AB - Little is known about the molecular mechanism of the R2R3-MYB transcriptional repressors involved in plant phenylpropanoid metabolism. Here, we describe one R2R3-type MYB repressor, FtMYB11 from Fagopyrum tataricum. It contains the SID like motif GGDFNFDL and it is regulated by both the importin protein 'Sensitive to ABA and Drought 2' (SAD2) and the jasmonates signalling cascade repressor JAZ protein. Yeast two hybrid and bimolecular fluorescence complementation assays demonstrated that FtMYB11 interacts with SAD2 and FtJAZ1. Protoplast transactivation assays demonstrated that FtMYB11 acts synergistically with FtSAD2 or FtJAZ1 and directly represses its target genes via the MYB-core element AATAGTT. Changing the Asp122 residue to Asn in the SID-like motif results in cytoplasmic localization of FtMYB11 because of loss of interaction with SAD2, while changing the Asp126 residue to Asn results in the loss of interaction with FtJAZ1. Overexpression of FtMYB11or FtMYB11D126N in F. tataricum hairy roots resulted in reduced accumulation of rutin, while overexpression of FtMYB11D122N in hairy roots did not lead to such a change. The results indicate that FtMYB11 acts as a regulator via interacting with FtSAD2 or FtJAZ1 to repress phenylpropanoid biosynthesis, and this repression depends on two conserved Asp residues of its SID-like motif. PMID- 28722264 TI - Ultrastructure changes in buffalo (Bubalus bubalis) oocytes before and after maturation in vitro with sericin. AB - The aim of this research was to identify the changes in the cytoplasmic ultrastructure of immature and matured oocytes in buffalo (Bubalus bubalis). Oocytes were matured in vitro in tissue culture medium-199 with and without sericin, and then analyzed by light and transmission electron microscopy. The experiment result showed that the nuclear maturation rate of buffalo oocytes was significantly higher in the presence of sericin (80.6%) than without sericin (68.1%) (P < 0.05). The immature oocytes were characterized by cortical granule clusters in the ooplasm and the absence of perivitelline space (PVS). In contrast, the oocytes matured either with or without sericin showed the formation of PVS, erected microvilli, the migration of cortical granules to the cytoplasmic periphery, and the clear appearance of the mitochondria and vesicle in the oolemma. Interestingly, matured oocytes with sericin have smaller cortical granules than do immature oocytes (P < 0.05). In conclusion, supplementation of 0.05% sericin in the maturation medium can enhance the maturation rate of buffalo oocytes. Several cytoplasmic ultrastructures were relocated and modulated during the in vitro maturation process of buffalo oocytes: PVS development, cortical granules migration to periphery, and mitochondria and vesicles in the cortical region. The ultrastructure was similar between the groups with and without sericin. PMID- 28722265 TI - Control of Redox Events by Dye Encapsulation Applied to Light-Driven Splitting of Hydrogen Sulfide. AB - Solar production of hydrogen by consuming low-value waste products is an attractive pathway that has both economic and environmental benefits. Inspired by the reactive pocket of enzymes, a synthetic platform to combine photocatalytic hydrogen evolution with sulfide oxidation in a one-pot process via control over the location of the electron-transfer steps is developed. The redox-active coordination vessel Ni-TFT, which has an octahedral pocket, encapsulates an organic dye to pre-organize for photocatalytic proton reduction via an oxidative quenching pathway using the nickel corners as catalysts, generating molecular hydrogen and the oxidized dye. The oxidized dye is displaced by a neutral dye and oxidizes sulfide once outside the pocket to give element sulfur. The overall reaction constitutes hydrogen sulfide splitting, forming molecular hydrogen and elemental sulfur, which is analogous to the water-splitting reaction. PMID- 28722266 TI - Second generation drug-eluting stents versus bare-metal stents for percutaneous coronary intervention of the proximal left anterior descending artery: An analysis of the BASKET-PROVE I and II trials. AB - OBJECTIVES: To compare mid-term outcomes between patients undergoing proximal left anterior descending artery (LAD) percutaneous coronary intervention (PCI) with second generation drug-eluting stent (DES) or bare-metal stent (BMS). BACKGROUND: PCI with BMS and first-generation DES have shown to be safe options for the treatment of proximal LAD stenosis, however associated with considerable reintervention rates. Overall, second-generation DES has proven to be superior to BMS and first-generation DES, nevertheless, its effect for proximal LAD PCI has not previously been reported. METHODS: We analyzed 2-year outcomes of 1,100 patients from the BASKET-PROVE I and II trials, referred for proximal LAD PCI with second generation DES (n = 680) or BMS (n = 420). RESULTS: The cumulative 2 year incidence of major adverse cardiac events (MACE, composite of cardiac death, myocardial infarction (MI) and target vessel revascularization (TVR)) was lower in second generation DES than in BMS treated patients (7.3% vs. 12.3%; HR 0.57, 95% CI 0.39/0.85), mainly driven by a reduced rate of TVR (3.7% vs. 10.0%; HR 0.35, CI 0.21/0.58). No difference was found in cardiac death (1.9% vs. 1.9%; HR 1.01, CI 0.42/2.44) and MI (4.4% vs. 4.7%; HR 0.93, CI 0.53/1.64). The benefit of DES use seemed to be more prominent in female patients with a reduction in MACE (P for interaction = 0.025). CONCLUSIONS: In patients with proximal LAD stenosis, treatment with second-generation DES was associated with reduced 2-year rates of adverse cardiac events and TVR compared to BMS, with reintervention rates similar to those earlier reported from bypass surgery. PMID- 28722268 TI - Downregulation of microRNA-15a-3p is correlated with clinical outcome and negatively regulates cancer proliferation and migration in human osteosarcoma. AB - In this study, we investigated the expression, correlation to clinical outcomes and biological functions of microRNA-15a-3p (miR-15a-3p) in human osteosarcoma. MiR-15a-3p expressions in osteosarcoma cell lines and clinical tissues of osteosarcoma patients were measured by qPCR. Relevance of endogenous miR-15a-3p to osteosarcoma patients' clinicopathological factors or overall survival was statistically analyzed. In addition, the independence of miR-15a-3p predicting cancer patients' overall survival was analyzed by Cox regression method. Furthermore, in osteosarcoma cell lines, Saos-2 and HOS cells, miR-15a-3p was overexpressed through stable lentiviral transduction. The functional regulations of miR-15a-3p overexpression on cancer ell proliferation and migration were then analyzed. MiR-15a-3p was significantly downregulated in osteosarcoma cell lines and human osteosarcoma tumors. Downregulation of endogenous miR-15a-3p in osteosarcoma tumors was significantly associated with cancer patient's poor clinical outcomes and low survival rate. Also, endogenous miR-15a-3p was confirmed to be an independent biomarker for predicating cancer patients' survival. In Saos-2 and HOS cells, lentivirus-induced miR-15a-3p overexpression had significantly tumor suppressing functions, by inhibiting both proliferation and migration. Significant downregulation of miR-15a-3p in osteosarcoma may be an independent biomarker to predicting cancer patients' poor prognosis. Overexpression miR-15a-3p may be an efficient functional meaning to suppress osteosarcoma development. PMID- 28722267 TI - Simultaneous bright- and black-blood whole-heart MRI for noncontrast enhanced coronary lumen and thrombus visualization. AB - PURPOSE: To develop a 3D whole-heart Bright-blood and black-blOOd phase SensiTive (BOOST) inversion recovery sequence for simultaneous noncontrast enhanced coronary lumen and thrombus/hemorrhage visualization. METHODS: The proposed sequence alternates the acquisition of two bright-blood datasets preceded by different preparatory pulses to obtain variations in blood/myocardium contrast, which then are combined in a phase-sensitive inversion recovery (PSIR)-like reconstruction to obtain a third, coregistered, black-blood dataset. The bright blood datasets are used for both visualization of the coronary lumen and motion estimation, whereas the complementary black-blood dataset potentially allows for thrombus/hemorrhage visualization. Furthermore, integration with 2D image-based navigation enables 100% scan efficiency and predictable scan times. The proposed sequence was compared to conventional coronary MR angiography (CMRA) and PSIR sequences in a standardized phantom and in healthy subjects. Feasibility for thrombus depiction was tested ex vivo. RESULTS: With BOOST, the coronary lumen is visualized with significantly higher (P < 0.05) contrast-to-noise ratio and vessel sharpness when compared to conventional CMRA. Furthermore, BOOST showed effective blood signal suppression as well as feasibility for thrombus visualization ex vivo. CONCLUSION: A new PSIR sequence for noncontrast enhanced simultaneous coronary lumen and thrombus/hemorrhage detection was developed. The sequence provided improved coronary lumen depiction and showed potential for thrombus visualization. Magn Reson Med 79:1460-1472, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. PMID- 28722269 TI - Role of Q177A and K173A/Q177A substitutions in thermostability and activity of the ELBn12 lipase. AB - Thermostable lipases have many applications in detergent industries and in organic synthesis. There are many ways to improve thermal stability of enzymes, for example, higher hydrophobicity, greater structural packing, higher content of the charged residues, and lower thermolabile ones. In this study, thermolabile Gln (sensitive to higher temperatures) was substituted with Ala in native ELBn12 and mutated K173A lipases to examine its effect on thermal stability and activity of the lipases. Single (Q177A) and double mutants (K173A/Q177A) were expressed in Escherichia coli pLysS. The Q177A variant increased both activity and thermostability of the lipase, whereas K173A/Q177A had a negative effect on the lipase activity and only had better thermal stability than the native at 50 degrees C. pH stability of the double mutant between 9.0 and 11 was also lower than the other variants. Stability analysis in the presence of chemicals showed that Q177A mutant had better activity with 50% (v/v) organic solvents. On the other hand, K173A lipase showed increased activity with 1% (w/v) nonionic surfactant, and finally K173A/Q177A had better stability with 10 mM metal ions compared to the native lipase. PMID- 28722270 TI - Retraction: Gold Nanoparticles Immobilized on Electrospun Titanium Dioxide Nanofibers for Catalytic Reduction of 4-Nitrophenol. PMID- 28722271 TI - Beyond glycaemic control: A cross-over, double-blinded, 24-week intervention with liraglutide in type 1 diabetes. AB - AIMS: To investigate the effects of 24 weeks of treatment with liraglutide added to basal/bolus insulin on anthropometric and metabolic parameters in overweight participants with type 1 diabetes. METHODS: In a double-blinded cross-over fashion, 15 participants were randomly assigned (1:1) to receive placebo (saline solution) or liraglutide for 24 weeks including a 1-month titration period from 0.6 to 1.2 to 1.8 mg, in addition to their insulin. The treatment was followed by a 1-month wash-out period. Participants were then assigned to the other treatment for another 24 weeks. Paired rank tests were used to compare the metabolic parameters. RESULTS: There was no treatment effect on HbA1c nor on insulin dose. Heart rate was increased by about 8 beats per minute with liraglutide. There were significant reductions in metabolic measures: weight, body mass index, waist and hip circumferences, body fatness, computed tomography scan abdominal and mid thigh measurements, systolic and diastolic blood pressures (all P <= .05). There was no increase in time spent in hypoglycaemia with liraglutide. CONCLUSIONS: The addition of liraglutide to basal/bolus insulin therapy for 24 weeks in overweight/obese individuals with type 1 diabetes improved the anthropometric and metabolic profiles without an increase in hypoglycaemia. Clinical Trials.gov No: NCT01787916. PMID- 28722272 TI - Development of a thiol-ene based screening platform for enzyme immobilization demonstrated using horseradish peroxidase. AB - Efficient immobilization of enzymes on support surfaces requires an exact match between the surface chemistry and the specific enzyme. A successful match would normally be identified through time consuming screening of conventional resins in multiple experiments testing individual immobilization strategies. In this study we present a versatile strategy that largely expands the number of possible surface functionalities for enzyme immobilization in a single, generic platform. The combination of many individual surface chemistries and thus immobilization methods in one modular system permits faster and more efficient screening, which we believe will result in a higher chance of discovery of optimal surface/enzyme interactions. The proposed system consists of a thiol-functional microplate prepared through fast photochemical curing of an off-stoichiometric thiol-ene (OSTE) mixture. Surface functionalization by thiol-ene chemistry (TEC) resulted in the formation of a functional monolayer in each well, whereas, polymer surface grafts were introduced through surface chain transfer free radical polymerization (SCT-FRP). Enzyme immobilization on the modified surfaces was evaluated by using a rhodamine labeled horseradish peroxidase (Rho-HRP) as a model enzyme, and the amount of immobilized enzyme was qualitatively assessed by fluorescence intensity (FI) measurements. Subsequently, Rho-HRP activity was measured directly on the surface. The broad range of utilized surface chemistries permits direct correlation of enzymatic activity to the surface functionality and improves the determination of promising enzyme-surface candidates. The results underline the high potential of this system as a screening platform for synergistic immobilization of enzymes onto thiol-ene polymer surfaces. (c) 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:1267-1277, 2017. PMID- 28722273 TI - Hydrothermal Synthesis of VO2 Polymorphs: Advantages, Challenges and Prospects for the Application of Energy Efficient Smart Windows. AB - Vanadium dioxide (VO2 ) is a widely studied inorganic phase change material, which has a reversible phase transition from semiconducting monoclinic to metallic rutile phase at a critical temperature of tauc ~ 68 degrees C. The abrupt decrease of infrared transmittance in the metallic phase makes VO2 a potential candidate for thermochromic energy efficient windows to cut down building energy consumption. However, there are three long-standing issues that hindered its application in energy efficient windows: high tauc , low luminous transmittance (Tlum ), and undesirable solar modulation ability (DeltaTsol ). Many approaches, including nano-thermochromism, porous films, biomimetic surface reconstruction, gridded structures, antireflective overcoatings, etc, have been proposed to tackle these issues. The first approach-nano-thermochromism-which is to integrate VO2 nanoparticles in a transparent matrix, outperforms the rest; while the thermochromic performance is determined by particle size, stoichiometry, and crystallinity. A hydrothermal method is the most common method to fabricate high-quality VO2 nanoparticles, and has its own advantages of large scale synthesis and precise phase control of VO2 . This Review focuses on hydrothermal synthesis, physical properties of VO2 polymorphs, and their transformation to thermochromic VO2 (M), and discusses the advantages, challenges, and prospects of VO2 (M) in energy-efficient smart windows application. PMID- 28722275 TI - The role of plant phenology in stomatal ozone flux modeling. AB - Plant phenology plays a pivotal role in the climate system as it regulates the gas exchange between the biosphere and the atmosphere. The uptake of ozone by forest is estimated through several meteorological variables and a specific function describing the beginning and the termination of plant growing season; actually, in many risk assessment studies, this function is based on a simple latitude and topography model. In this study, using two satellite datasets, we apply and compare six methods to estimate the start and the end dates of the growing season across a large region covering all Europe for the year 2011. Results show a large variability between the green-up and dormancy dates estimated using the six different methods, with differences greater than one month. However, interestingly, all the methods display a common spatial pattern in the uptake of ozone by forests with a marked change in the magnitude, up to 1.9 TgO3 /year, and corresponding to a difference of 25% in the amount of ozone that enters the leaves. Our results indicate that improved estimates of ozone fluxes require a better representation of plant phenology in the models used for O3 risk assessment. PMID- 28722274 TI - Mixed mood: The not so united states? PMID- 28722277 TI - In Situ Growth and Wrapping of Aminoanthraquinone Nanowires in 3 D Graphene Framework as Foldable Organic Cathode for Lithium-Ion Batteries. AB - Small conjugated carbonyl compounds are intriguing candidates for organic electrode materials because of their abundance, high theoretical capacity, and adjustable molecular structure. However, their dissolution in aprotic electrolytes and poor conductivity eclipse them in terms of practical capacity, cycle life, and rate capability. Herein, we report a foldable and binder-free nanocomposite electrode consisting of 2-aminoanthraquinone (AAQ) nanowires wrapped within the 3 D graphene framework, which is prepared through antisolvent crystallization followed by a facile chemical reduction and selfassembly process. The nanocomposite exhibited a very high capacity of 265 mA h g-1 at 0.1 C for AAQ, realizing 100 % utilization of active material. Furthermore, the nanocomposite shows superior cycling stability (82 % capacity retention after 200 cycles at 0.2 C and 76 % capacity retention after 1000 cycles at 0.4 C) and excellent rate performance (153 mA h g-1 at 5 C). Particularly, the nanocomposite can deliver the highest capacity of 165 mA h g-1 among all reported anthraquinone and anthraquinone-analogues-based electrodes per mass of the whole electrode, which is essential for practical application. Such outstanding electrochemical performance could be largely attributed to the wrapping structure of the flexible composite, which provides both conductivity and structural integrity. PMID- 28722276 TI - Identification and functional analysis of an ADAMTSL1 variant associated with a complex phenotype including congenital glaucoma, craniofacial, and other systemic features in a three-generation human pedigree. AB - Developmental glaucoma can occur as an isolated or syndromic condition and is genetically heterogeneous. We describe a three-generation family affected with developmental glaucoma, myopia, and/or retinal defects associated with variable craniofacial/dental, auditory, brain, renal, and limb anomalies. Whole-exome sequencing identified a heterozygous c.124T> C, p.(Trp42Arg) allele in ADAMTSL1; cosegregation analysis confirmed the presence of this allele in four affected family members. The mutation affects a highly conserved residue and is strongly predicted to have a deleterious effect on protein function. Trp42 is normally modified by protein C-mannosylation, an unusual post-translational modification. Comparison of ADAMTSL1-WT (also known as punctin-1) and ADAMTSL1-p.Trp42Arg in vitro demonstrated that the latter was not secreted from transfected cells but retained intracellularly. Moreover, ADAMTSL1-p.Trp42Arg reduced secretion of cotransfected wild-type ADAMTSL1, suggesting a dominant negative effect for this mutation. These data imply a multisystem role for ADAMTSL1 and present the first disease-associated variant affecting a C-mannosylation motif. PMID- 28722278 TI - Non-physician health-care workers and voluntary blood donation: an ambiguous relationship. AB - OBJECTIVES: This study aims to assess the knowledge, attitude and practice (KAP) of voluntary blood donation (BD) among the non-physician health-care workers of our institution, to investigate the relationship between these parameters and to determine the predictors of BD practice. BACKGROUND: KAP surveys provide a popular context-specific evidence base for the development of blood transfusion services' strategies and interventions to promote voluntary, non-remunerated BD. However, there are just few studies worldwide assessing KAP of BD among health care workers. METHODS: This is a cross-sectional exploratory study, which took place at the 'Ippokrateio' General Hospital of Thessaloniki, Greece, a tertiary health-care institution. A specially designed, pre-tested questionnaire was distributed to all non-physician health-care workers of the hospital. A total of 1140 questionnaires were distributed. Participation in the study was optional and anonymous. Regarding data analysis, a binary logistic regression analysis was performed to describe the relationship between different elements of KAP of BD and to determine possible predictors of BD practice. RESULTS: The response rate was 25.5% (291 respondents). Logistic regression analysis revealed a positive attitude towards family replacement as an important predictor of both regular and voluntary BD, with male gender also a predictor of the latter. An inconsistency between knowledge, attitude and practice of BD was revealed. CONCLUSIONS: The present study adds valuable data on KAP of BD among health-care workers. This will help blood transfusion services to improve management practices among this group as they have the potential to provide a reliable, stable and safe source of blood products. PMID- 28722279 TI - How Understanding the Role of an Additive Can Lead to an Improved Synthetic Protocol without an Additive: Organocatalytic Synthesis of Chiral Diarylmethyl Alkynes. AB - The use of additives for organic synthesis has become a common tactic to improve the outcome of organic reactions. Herein, by using an organocatalytic process for the synthesis of chiral diarylmethyl alkynes as a platform, we describe how an additive is involved in the improvement of the process. The evolution of an excellent synthetic protocol has been achieved in three stages, from 1) initially no catalyst turnover, to 2) good conversion and enantioselectivity with a superior additive, and eventually 3) even better efficiency and selectivity without an additive. This study is an important and rare demonstration that understanding the role of additive can be so beneficial as to obviate the need for the additive. PMID- 28722280 TI - Enantioselective Synthesis of Acyclic alpha-Quaternary Carboxylic Acid Derivatives through Iridium-Catalyzed Allylic Alkylation. AB - The first highly enantioselective iridium-catalyzed allylic alkylation that provides access to products bearing an allylic all-carbon quaternary stereogenic center has been developed. The reaction utilizes a masked acyl cyanide (MAC) reagent, which enables the one-pot preparation of alpha-quaternary carboxylic acids, esters, and amides with a high degree of enantioselectivity. The utility of these products is further explored through a series of diverse product transformations. PMID- 28722282 TI - Metal-Free Nitrile Diboration through Activation by an Electron-Rich Diborane. AB - Diboration of unsaturated organic compounds is an extremely useful reaction in synthetic chemistry. Herein, we report the first diboration of a nitrile by an electron-rich diborane, mediated by an electrophilic borane. The reaction is metal-free, and all of the reagents are readily available. PMID- 28722281 TI - Collagen organization regulates stretch-initiated pain-related neuronal signals in vitro: Implications for structure-function relationships in innervated ligaments. AB - Injury to the spinal facet capsule, an innervated ligament with heterogeneous collagen organization, produces pain. Although mechanical facet joint trauma activates embedded afferents, it is unclear if, and how, the varied extracellular microstructure of its ligament affects sensory transduction for pain from mechanical inputs. To investigate the effects of macroscopic deformations on afferents in collagen matrices with different organizations, an in vitro neuron collagen construct (NCC) model was used. NCCs with either randomly organized or parallel aligned collagen fibers were used to mimic the varied microstructure in the facet capsular ligament. Embryonic rat dorsal root ganglia (DRG) were encapsulated in the NCCs; axonal outgrowth was uniform and in all directions in random NCCs, but parallel in aligned NCCs. NCCs underwent uniaxial stretch (0.25 +/- 0.06 strain) corresponding to sub-failure facet capsule strains that induce pain. Macroscopic NCC mechanics were measured and axonal expression of phosphorylated extracellular signal-regulated kinase (pERK) and the neurotransmitter substance P (SP) was assayed at 1 day to assess neuronal activation and nociception. Stretch significantly upregulated pERK expression in both random and aligned gels (p < 0.001), with the increase in pERK being significantly higher (p = 0.013) in aligned than in random NCCs. That increase likely relates to the higher peak force (p = 0.025) and stronger axon alignment (p < 0.001) with stretch direction in the aligned NCCs. In contrast, SP expression was greater in stretched NCCs (p < 0.001) regardless of collagen organization. These findings suggest that collagen organization differentially modulates pain-related neuronal signaling and support structural heterogeneity of ligament tissue as mediating sensory function. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:770-777, 2018. PMID- 28722283 TI - Comparative analysis of storage conditions and homogenization methods for tick and flea species for identification by MALDI-TOF MS. AB - Ticks and fleas are vectors for numerous human and animal pathogens. Controlling them, which is important in combating such diseases, requires accurate identification, to distinguish between vector and non-vector species. Recently, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) was applied to the rapid identification of arthropods. The growth of this promising tool, however, requires guidelines to be established. To this end, standardization protocols were applied to species of Rhipicephalus sanguineus (Ixodida: Ixodidae) Latreille and Ctenocephalides felis felis (Siphonaptera: Pulicidae) Bouche, including the automation of sample homogenization using two homogenizer devices, and varied sample preservation modes for a period of 1-6 months. The MS spectra were then compared with those obtained from manual pestle grinding, the standard homogenization method. Both automated methods generated intense, reproducible MS spectra from fresh specimens. Frozen storage methods appeared to represent the best preservation mode, for up to 6 months, while storage in ethanol is also possible, with some caveats for tick specimens. Carnoy's buffer, however, was shown to be less compatible with MS analysis for the purpose of identifying ticks or fleas. These standard protocols for MALDI-TOF MS arthropod identification should be complemented by additional MS spectrum quality controls, to generalize their use in monitoring arthropods of medical interest. PMID- 28722284 TI - Effectiveness of a novel highly flexible-tip guidewire on selective biliary cannulation compared to conventional guidewire: Randomized controlled study. AB - BACKGROUND AND AIM: Endoscopic access to the common bile duct remains difficult in 10% of cases undergoing endoscopic retrograde cholangiopancreatography (ERCP). In the current study, we evaluated the effectiveness of a stiff-shaft and flexible-tip guidewire (Visiglide2(r) ) for selective biliary access. METHODS: We conducted a prospective, randomized controlled study in a single center involving patients with a naive papilla who required biliary cannulation. We randomly allocated the patients to the Visiglide 2 group (group V) or to the conventional guidewire group (group C). Primary success rate of biliary cannulation, cannulation time, number of papillary attempts, number of pancreatic duct cannulations, total procedure time and final success rate were recorded during the endoscopic procedure. RESULTS: Total of 100 patients were enrolled and assigned to groups V (n = 50) and C (n = 50). Primary selective biliary cannulation of group V tended to show a higher success rate than that of group C (group V, 96% (48/50); group C, 86% (43/50); P = 0.08). Final success rate for biliary cannulation was 100% in both groups. Mean times for biliary cannulation were 174.9 s for group V and 363.5 s for group C (P = 0.04). Number of papillary attempts for cannulation was significantly fewer in group V (1.84) than in group C (3.44; P < 0.01). CONCLUSION: Use of Visiglide 2 guidewire might facilitate selective biliary cannulation compared to conventional guidewire in terms of reducing cannulation time and papilla attempts. PMID- 28722286 TI - Fighting fungus with a laser and a hose: Management of a giant Candida albicans implantable cardioverter-defibrillator lead vegetation with simultaneous AngioVac aspiration and laser sheath lead extraction. AB - Infections involving internal cardiac devices can be very challenging to treat, and almost universally require complete device extraction for successful management. Of the pathogens that cause device-related endocarditis, fungi such as Candida albicans are notoriously difficult to manage because of their propensity to produce large vegetations and the need for long-term treatment with potentially toxic medications. Furthermore, individuals who develop fungal, device-associated endocarditis are typically among the most complex patients, with significant comorbidities that place them at high risk for open heart procedures such as surgical device extraction. We present a case of one such patient in whom treatment of Candida albicans device-related endocarditis was managed using AngioVac(r) aspiration of a large right atrial vegetation with simultaneous laser sheath extraction of the implantable cardioverter defibrillator lead. PMID- 28722285 TI - Innate allorecognition by monocytic cells and its role in graft rejection. AB - Innate recognition of microbial products and danger molecules by monocytes and macrophages has been well established; this is mediated primarily by pattern recognition receptors and is central to the activation of innate and adaptive immune cells required for productive immunity. Whether monocytes and macrophages are equipped with an allorecognition system that allows them to respond directly to allogeneic grafts is a topic of much debate. Recent studies provide compelling evidence that these cells can recognize allogeneic entities and that they mediate graft rejection via direct cytotoxicity and priming of alloreactive T cells. In addition, these studies have uncovered a mechanism of innate allorecognition based on detection of the polymorphic molecule signal regulatory protein alpha (SIRPalpha) on donor cells. Further understanding of innate allorecognition and its consequences would provide essential insight into allograft rejection and lead to better therapies for transplant patients. PMID- 28722287 TI - Plasma thiobarbituric acid reactive substances (TBARS) in young adults: Obesity increases fasting levels only in men whereas glucose ingestion, and not protein or lipid intake, increases postprandial concentrations regardless of sex and obesity. AB - SCOPE: Oxidative stress and damage participate in the pathophysiology of obesity and its metabolic complications. We studied the influence of sex, obesity, and ingestion of different macronutrients on fasting and postprandial thiobarbituric acid reactive substances (TBARS), which can be considered as an index of lipid peroxidation and oxidative damage. METHODS AND RESULTS: We studied 19 men and 17 women, out of whom nine men and eight women had obesity. We collected blood samples in the fasting state and, on alternate days, following the ingestion of 300 kcal in the form of glucose, lipids, or proteins. Fasting TBARS concentrations correlated with waist circumference and were increased in obese men compared with nonobese men. This increase was not, however, observed in women. TBARS concentrations showed a marked increase following the ingestion of glucose in parallel to the increase in plasma glucose when considering all subjects as a whole, but did not increase after the oral intake of lipids and proteins. CONCLUSION: Plasma TBARS concentrations are increased in the fasting state only in obese men in association with abdominal adiposity, and increases markedly after the ingestion of glucose, but not after oral intake of lipids and proteins, regardless of sex and obesity. PMID- 28722288 TI - N-Type Organic Thermoelectrics: Improved Power Factor by Tailoring Host-Dopant Miscibility. AB - In this contribution, for the first time, the polarity of fullerene derivatives is tailored to enhance the miscibility between the host and dopant molecules. A fullerene derivative with a hydrophilic triethylene glycol type side chain (PTEG 1) is used as the host and (4-(1,3-dimethyl-2,3-dihydro-1H-benzoimidazol-2 yl)phenyl)dimethylamine n-DMBI) as the dopant. Thereby, the doping efficiency can be greatly improved to around 18% (<1% for a nonpolar reference sample) with optimized electrical conductivity of 2.05 S cm-1 , which represents the best result for solution-processed fullerene derivatives. An in-depth microstructural study indicates that the PTEG-1 molecules readily form layered structures parallel to the substrate after solution processing. The fullerene cage plane is alternated by the triethylene glycol side chain plane; the n-DMBI dopants are mainly incorporated in the side chain plane without disturbing the pi-pi packing of PTEG-1. This new microstructure, which is rarely observed for codeposited thin films from solution, formed by PTEG-1 and n-DMBI molecules explains the increased miscibility of the host/dopant system at a nanoscale level and the high electrical conductivity. Finally, a power factor of 16.7 uW m-1 K-2 is achieved at 40% dopant concentration. This work introduces a new strategy for improving the conductivity of solution-processed n-type organic thermoelectrics. PMID- 28722290 TI - Development of a cardiovascular diseases risk prediction model and tools for Chinese patients with type 2 diabetes mellitus: A population-based retrospective cohort study. AB - AIMS: Evidence-based cardiovascular diseases (CVD) risk prediction models and tools specific for Chinese patients with type 2 diabetes mellitus (T2DM) are currently unavailable. This study aimed to develop and validate a CVD risk prediction model for Chinese T2DM patients. METHODS: A retrospective cohort study was conducted with 137 935 Chinese patients aged 18 to 79 years with T2DM and without prior history of CVD, who had received public primary care services between January 1, 2010 and December 31, 2010. Using the derivation cohort over a median follow-up of 5 years, the interaction effect between predictors and age were derived using Cox proportional hazards regression with a forward stepwise approach. Harrell's C statistic and calibration plot were used on the validation cohort to assess the discrimination and calibration of the models. The web calculator and chart were developed based on the developed models. RESULTS: For both genders, predictors for higher risk of CVD were older age, smoking, longer diabetes duration, usage of anti-hypertensive drug and insulin, higher body mass index, haemoglobin A1c (HbA1c), systolic and diastolic blood pressure, a total cholesterol to high-density lipoprotein-cholesterol (TC/HDL-C) ratio and urine albumin to creatinine ratio, and lower estimated glomerular filtration rate. Interaction factors with age demonstrated a greater weighting of TC/HDL-C ratio in both younger females and males, and smoking status and HbA1c in younger males. CONCLUSION: The developed models, translated into a web calculator and color coded chart, served as evidence-based visual aids that facilitate clinicians to estimate quickly the 5-year CVD risk for Chinese T2DM patients and to guide intervention. PMID- 28722289 TI - Concise Review: A Safety Assessment of Adipose-Derived Cell Therapy in Clinical Trials: A Systematic Review of Reported Adverse Events. AB - The popularity of adipose-derived cell therapy has increased over the last decade, and the number of studies published annually is growing. However, concerns regarding safety in the setting of previous malignancy or the use of allogeneic cells have been raised. We therefore aimed to systematically review all clinical studies using adipose-derived cell therapy to identify reported adverse events with a special focus on risk of thromboembolic, immunological, and oncological safety concerns. Our systematic search resulted in 70 included studies involving more than 1,400 patients that were treated with adipose-derived cell therapy. Safety assessment method was not described in 32 of the included studies. For studies involving systemic or cardiac administration, one case of pulmonary thromboembolism and cases of both myocardial and cerebral infarctions were described. In the setting of allogeneic cell therapy studies, where the production of specific antibodies toward donor cells was examined, it was noted that 19%-34% of patients develop antibodies, but the consequence of this is unknown. With regard to oncological safety, only one case of breast cancer recurrence was identified out of 121 patients. Adipose-derived cell therapy has so far shown a favorable safety profile, but safety assessment description has, in general, been of poor quality, and only adverse events that are looked for will be found. We encourage future studies to maintain a strong focus on the safety profile of cell therapy, so its safeness can be confirmed. Stem Cells Translational Medicine 2017;6:1786-1794. PMID- 28722291 TI - Assessment of hair surface roughness using quantitative image analysis. AB - BACKGROUND/PURPOSE: Focus on the hair and hair cuticle is increasing. The hair cuticle is the first layer to be exposed to damage and the area of primary protection. For such reasons, hair product manufacturers consider cuticle protection important. However, previous studies used only visual assessment to examine the cuticle. This study aimed to obtain the changes in cuticles and measure hair roughness using a HIROX microscope. METHODS: A total of 23 female subjects used the same products daily for 4 weeks. Three hair samples per subject were collected from three different areas of the head. Measurements were taken before and after 4 weeks of daily product use. RESULTS: The hair surface changes were clearly observed on the captured images. Moreover, hair surface roughness was observed using various parameters on HIROX software. After 4 weeks of daily product use, the roughness parameter value of the hair surface was significantly decreased. CONCLUSION: Our result suggests that the hair roughness analytical method using HIROX can be a new paradigm for high-quality quantitative analysis of the hair cuticle. PMID- 28722292 TI - Investigating the origins of political views: biases in explanation predict conservative attitudes in children and adults. AB - We tested the hypothesis that political attitudes are influenced by an information-processing factor - namely, a bias in the content of everyday explanations. Because many societal phenomena are enormously complex, people's understanding of them often relies on heuristic shortcuts. For instance, when generating explanations for such phenomena (e.g., why does this group have low status?), people often rely on facts that they can retrieve easily from memory - facts that are skewed toward inherent or intrinsic features (e.g., this group is unintelligent). We hypothesized that this bias in the content of heuristic explanations leads to a tendency to (1) view socioeconomic stratification as acceptable and (2) prefer current societal arrangements to alternative ones, two hallmarks of conservative ideology. Moreover, since the inherence bias in explanation is present across development, we expected it to shape children's proto-political judgments as well. Three studies with adults and 4- to 8-year-old children (N = 784) provided support for these predictions: Not only did individual differences in reliance on inherent explanations uniquely predict endorsement of conservative views (particularly the stratification-supporting component; Study 1), but manipulations of this explanatory bias also had downstream consequences for political attitudes in both children and adults (Studies 2 and 3). This work contributes to our understanding of the origins of political attitudes. PMID- 28722293 TI - Robotic-assisted percutaneous coronary intervention. AB - Performance of percutaneous coronary intervention (PCI) is associated with several occupational hazards including radiation exposure and musculoskeletal injury. Current methods to mitigate these risks range from suspended radiation suits to adjustable lead-lined glass shields. Robotic-assisted PCI is a novel approach to PCI that utilizes remote-controlled technology to manipulate catheters thereby significantly reducing radiation exposure to the operator and catheterization laboratory staff. Although limited, current evidence indicates that robotic-assisted PCI is associated with a high technical success rate and may have additional advantages over conventional PCI, such as a decreased incidence of geographical miss. However, as the technology is nascent, further studies including larger, randomized controlled trials are needed to expand on the long-term clinical and safety outcomes. PMID- 28722294 TI - Clinical outcomes of balloon angioplasty alone versus nitinol stent implantation in patients with small femoropopliteal artery disease: Observations from the Retrospective Multicenter Analysis for Femoropopliteal Stenting (REAL-FP). AB - OBJECTIVES: We sought to assess whether balloon angioplasty (BA) alone for small femoropopliteal disease improved the outcome following endovascular therapy as compared with stent implantation. BACKGROUND: The optimal strategy of endovascular therapy for small vessel arteries in femoropopliteal disease remains unclear. METHODS: We performed a multicenter retrospective analysis of 337 consecutive patients (371 limbs) with femoropopliteal arteries 4.0 mm or less in diameter and 150 mm or less in length. RESULTS: Cumulative 3-year incidence of primary patency was significantly higher in the BA group than in the stent group (53.8% vs. 34.2%, P = 0.002). While assisted-primary patency and freedom from any major adverse limb events were also significantly higher in the BA group than in the stent group (70.9% vs. 44.2%, P < 0.001 and 60.6% vs. 36.4%, P = 0.001, respectively), secondary patency did not significantly differ between the two groups (86.9% vs. 86.9%, P = 0.67). Predictors of restenosis were diabetes mellitus (hazard ratio [HR], 1.61; 95% confidence interval [CI], 1.14-2.31; P = 0.01), no administration of cilostazol (HR, 1.50; 95% CI, 1.07-2.13; P = 0.02), stent implantation (HR, 1.68; 95% CI, 1.15-2.41; P = 0.01), and lesion length >75.0 mm(HR, 2.09; 95% CI, 1.50-2.92; P < 0.001). CONCLUSIONS: Lesions in small (<4.0 mm diameter) FP vessels demonstrated better primary patency at 3 years when successfully treated with balloon angioplasty alone as opposed to routine or bailout stenting. This difference was especially pronounced for lesions 75 to 150 mm in length. PMID- 28722295 TI - Prevalence, correlates, and impact of coronary calcification on adverse events following PCI with newer-generation DES: Findings from a large multiethnic registry. AB - OBJECTIVES: We sought to determine the prevalence, predictors, and clinical impact of target lesion calcification in patients undergoing percutaneous coronary intervention (PCI) with newer generation drug-eluting stents (DES) and devices. BACKGROUND: Coronary calcification is independently associated with adverse outcomes following PCI. While newer DES and contemporary devices are considered safer and more efficacious, their influence on outcomes following PCI of heavily calcified lesions is unknown. METHODS: We performed a retrospective analysis of a large, multiethnic cohort of patients undergoing PCI with new generation DES at an academic center between 2009 and 2013. Coronary calcification was qualitatively assessed as none/mild, moderate, or severe. Independent demographic, clinical, and anatomic predictors of moderate/severe calcification were identified using logistic regression. Associations between coronary calcification and 1-year MACE (death, myocardial infarction, or target vessel revascularization) were examined using Cox modeling. RESULTS: Compared to patients with none/mild (n = 10,180; 82.0%), those with moderate (n = 1,271; 10.0%) or severe (n = 994; 8.0%) calcification were older, more often Caucasian, had more complex target lesions, and worse renal function. The strongest demographic, clinical, and anatomic correlates of moderate/severe calcification were age, Caucasian race, renal dysfunction, lesion length, and left main location. Unadjusted MACE rates among those with none/mild, moderate, and severe calcification were 8.3, 14.6, and 17.8%, respectively (P < 0.001). After multivariable adjustment, the hazard ratio (95% CI) for MACE associated with moderate or severe coronary calcification was 1.63. CONCLUSIONS: Target lesion calcification remains independently associated with adverse outcomes in patients treated with newer generation DES and modern devices. PMID- 28722297 TI - Assessing Guest-Molecule Diffusion in Heterogeneous Powder Samples of Metal Organic Frameworks through Pulsed-Field-Gradient (PFG) NMR Spectroscopy. AB - Investigation of guest diffusion in porous metal-organic frameworks (MOFs) is of major importance, because many porosity-related properties of MOFs are influenced by diffusion effects. The diffusion of dimethyl sulfoxide (DMSO) in the MOF MIL 53-NH2 (Al) was investigated through pulsed-field-gradient (PFG) NMR spectroscopy. The microporous material was synthesized in small crystallites (under 500 nm), which agglomerated in a large range of particle sizes (from hundreds of nanometers to tens of micrometers), giving a morphologically very heterogeneous sample. No special agglomeration pattern could be observed, which makes a PFG NMR investigation very challenging, yet it represents a realistic situation for the diffusion of guest molecules in porous materials. We were able to distinguish between two diffusion regimes existing in parallel with each other over the total range from 15 to 200 ms of observation times as accessible in the experiments: In the large crystal agglomerates (diameters above 20 MUm), guest movement was found to be subdiffusive, with a time exponent kappa =0.8 (rather than one as for normal diffusion). Guest diffusion in the remaining, smaller host particles followed the pattern of normal diffusion within a bed of spheres of impenetrable external surfaces, with a size distribution in good agreement with that of the material under study. Diffusion in a rather complex system could thus be referred to a two-region model with new potentials for application to systems of intricate topology. PMID- 28722296 TI - A Ligand-Based NMR Screening Approach for the Identification and Characterization of Inhibitors and Promoters of Amyloid Peptide Aggregation. AB - Over the years a significant amount of effort has been put into the development of rapid and reliable methods to monitor the aggregation dynamics of the beta1-42 amyloid peptide in real time. We present an alternative approach based on a suitable reporter or spy molecule and three different NMR experiments: WaterLOGSY, 1 H selective T1 filter, and 19 F T2 filter, for monitoring the initial self-aggregation process kinetics of the beta1-42 amyloid peptide and identifying molecules that retard or accelerate the self-aggregation process. Although the proposed method is not a high-throughput assay, it avoids problems associated with interference events that are sometimes observed in fluorescence based assays. PMID- 28722298 TI - Development of a bedside viable ultrasound protocol to quantify appendicular lean tissue mass. AB - BACKGROUND: Ultrasound is a non-invasive and readily available tool that can be prospectively applied at the bedside to assess muscle mass in clinical settings. The four-site protocol, which images two anatomical sites on each quadriceps, may be a viable bedside method, but its ability to predict musculature has not been compared against whole-body reference methods. Our primary objectives were to (i) compare the four-site protocol's ability to predict appendicular lean tissue mass from dual-energy X-ray absorptiometry; (ii) optimize the predictability of the four-site protocol with additional anatomical muscle thicknesses and easily obtained covariates; and (iii) assess the ability of the optimized protocol to identify individuals with low lean tissue mass. METHODS: This observational cross sectional study recruited 96 university and community dwelling adults. Participants underwent ultrasound scans for assessment of muscle thickness and whole-body dual-energy X-ray absorptiometry scans for assessment of appendicular lean tissue. Ultrasound protocols included (i) the nine-site protocol, which images nine anterior and posterior muscle groups in supine and prone positions, and (ii) the four-site protocol, which images two anterior sites on each quadriceps muscle group in a supine position. RESULTS: The four-site protocol was strongly associated (R2 = 0.72) with appendicular lean tissue mass, but Bland Altman analysis displayed wide limits of agreement (-5.67, 5.67 kg). Incorporating the anterior upper arm muscle thickness, and covariates age and sex, alongside the four-site protocol, improved the association (R2 = 0.91) with appendicular lean tissue and displayed narrower limits of agreement (-3.18, 3.18 kg). The optimized protocol demonstrated a strong ability to identify low lean tissue mass (area under the curve = 0.89). CONCLUSIONS: The four-site protocol can be improved with the addition of the anterior upper arm muscle thickness, sex, and age when predicting appendicular lean tissue mass. This optimized protocol can accurately identify low lean tissue mass, while still being easily applied at the bedside. PMID- 28722300 TI - Digital Subtraction Angiography-Dynavision in Pretreatment Planning for Embolization of Dural Arterio-Venous Fistulas. AB - BACKGROUND AND PURPOSE: We have found DSA-Dynavision with multiplanar reconstruction very helpful in understanding the complex anatomy and planning of treatment of carotico-cavernous fistulas. The purpose of our study was to examine whether using DSA-Dynavision in pretreatment planning results in better outcome after endovascular treatment of dural arterio-venous fistulas (dAVFs). METHODS: Patients with dAVF treated with endovascular embolization were retrospectively identified from our interventional neuroradiology database. Patients were assessed and divided into those with DSA-Dynavision and those without. They were compared for procedural time, angiographic evidence of cure, rates of resolution of cortical venous reflux (CVR), complications, and need for postembolization surgery. RESULTS: Eighty-six percent of 28 patients (mean age 57 years, range 1.67-84 years) had Borden type 3 DAVF; 7% had Borden type 2; and 7% had Borden type 1. DSA-Dynavision was used in 14 of 28 (50%) patients. Fewer patients with DSA-Dynavision required postendovascular embolization surgery (7% vs. 50%, P = .01) and fewer DSA-Dynavision patients had CVR postprocedure (29% vs. 71%, P = .023). Mean procedural time (207 vs. 249 minutes; P = .40); permanent neurological complication rates (7% vs. 7%, P = 1.0); rate of immediate angiographic occlusion (64% vs. 29%, P = .061), and reported resolution of symptoms (79% vs. 53%, P = .18) were not significantly different. There was no significant difference in follow-up (mean: 75 vs 120 weeks, P = .47). CONCLUSION: The use of DSA-Dynavision in planning of endovascular treatment of dAVF is associated with higher rates of elimination of CVR and less need for postembolization surgery. PMID- 28722299 TI - Cost and Health Care Utilization Implications of Bariatric Surgery Versus Intensive Lifestyle and Medical Intervention for Type 2 Diabetes. AB - OBJECTIVE: The aim of this study was to compare the cost and health care utilization of patients with obesity and type 2 diabetes mellitus (T2DM) randomized into either Roux-en-Y gastric bypass (RYGB) surgery or an intensive lifestyle and medical intervention (ILMI). METHODS: This analysis (N = 745) is based on 2-year follow-up of a small randomized controlled trial (RCT); adult patients with obesity and T2DM were recruited between 2011 and 2012 from Kaiser Permanente Washington. Comparisons were made for patients randomized into either RYGB (N = 15) or ILMI (N = 17). RESULTS: There were no significant cost savings for RYGB versus ILMI patients through the follow-up years. Pharmacy cost was lower for RYGB versus ILMI patients by about $900 in year 2 versus year 0; however, inpatient and emergency room costs were higher for surgery patients in follow-up years relative to year 0. Median total cost for nonrandomized patients was higher in year 0 and in year 2 compared to randomized patients. CONCLUSIONS: Bariatric surgery is not cost saving in the short term. Moreover, the costs of patients who enter into RCTs of RYGB may differ from the costs of those who do not enter RCTs, suggesting use of caution when using such data to draw inferences about the general population with obesity. PMID- 28722301 TI - Recent Research Advances in Selective Matrix Metalloproteinase-13 Inhibitors as Anti-Osteoarthritis Agents. AB - Matrix metalloproteinase-13 (MMP-13) plays a key role in the degradation of type II collagen in cartilage and bone in osteoarthritis (OA). The subtle differences between the S1' loop of MMP-13 and that of other MMPs offer a structural base for the design of selective MMP-13 inhibitors to mitigate the unperceived risk associated with inhibiting other MMP isoforms. In this review, we summarize zinc binding and non-zinc-binding selective MMP-13 inhibitors. The zinc-binding MMP-13 inhibitors contain a small set of zinc-binding groups (ZBGs), including hydroxamic acid, pyrimidinetrione, reversed hydroxamic acid and hydantoin, carboxylic acid, 1,2,4,-triazole, and 1,2,4,-triazolone. The non-zinc-binding MMP 13 inhibitors have different structural scaffolds, including diphenyl ethers, biaryls (aryltetrazoliums, arylfurans, pyrazole-indoles), pyrimidines, and aryl/cycloalkyl-fused pyrimidines. This review provides a systematic overview of recent developments in MMP-13 inhibitors for the treatment of OA, with emphasis on their enzyme inhibitory potency, selectivity, and biological activities, and highlights the various binding modes of typical inhibitors with MMP-13. PMID- 28722302 TI - A novel neurological function of rice bran: a standardized rice bran supplement promotes non-rapid eye movement sleep in mice through histamine H1 receptors. AB - SCOPE: Although rice bran has been shown to be associated with a wide spectrum of health benefits, to date, there are no reports on its effects on sleep. We investigated the effect of rice bran on sleep and the mechanism underlying this effect. METHODS AND RESULTS: Electroencephalography was used to evaluate the effects of standardized rice bran supplement (RBS) and doxepin hydrochloride (DH), a histamine H1 receptor (H1 R) antagonist used as a positive control, on sleep in mice. The mechanism of RBS action was investigated using knockout (KO) mice and ex vivo electrophysiological recordings. Oral administration of RBS and DH significantly decreased sleep latency and increased the amount of non-rapid eye movement sleep (NREMS) in mice. Similar to DH, RBS fully inhibited H1 R agonist-induced increase in action potential frequency in tuberomammillary nucleus neurons. In H1 R KO mice, neither RBS nor DH administration led to the increase in NREMS and decrease in sleep latency observed in WT mice. These results indicate that the sleep-promoting effect of RBS is completely dependent on H1 R antagonism. CONCLUSIONS: RBS decreases sleep latency and promotes NREMS through the inhibition of H1 R, suggesting that it could be a promising therapeutic agent for insomnia. PMID- 28722303 TI - Differential Electrochemical Conductance Imaging at the Nanoscale. AB - Electron transfer in proteins is essential in crucial biological processes. Although the fundamental aspects of biological electron transfer are well characterized, currently there are no experimental tools to determine the atomic scale electronic pathways in redox proteins, and thus to fully understand their outstanding efficiency and environmental adaptability. This knowledge is also required to design and optimize biomolecular electronic devices. In order to measure the local conductance of an electrode surface immersed in an electrolyte, this study builds upon the current-potential spectroscopic capacity of electrochemical scanning tunneling microscopy, by adding an alternating current modulation technique. With this setup, spatially resolved, differential electrochemical conductance images under bipotentiostatic control are recorded. Differential electrochemical conductance imaging allows visualizing the reversible oxidation of an iron electrode in borate buffer and individual azurin proteins immobilized on atomically flat gold surfaces. In particular, this method reveals submolecular regions with high conductance within the protein. The direct observation of nanoscale conduction pathways in redox proteins and complexes enables important advances in biochemistry and bionanotechnology. PMID- 28722305 TI - Dynamic Covalent Chemistry of Aldehyde Enamines: BiIII - and ScIII -Catalysis of Amine-Enamine Exchange. AB - The dynamic exchange of enamines from secondary amines and enolizable aldehydes has been demonstrated in organic solvents. The enamine exchange with amines was efficiently catalyzed by Bi(OTf)3 and Sc(OTf)3 (2 mol %) and the equilibria (60 mm) could be attained within hours at room temperature. The formed dynamic covalent systems displayed high stabilities in basic environment with <2 % by product formation within one week after complete equilibration. This study expands the scope of dynamic C-N bonds from imine chemistry to enamines, enabling further dynamic methodologies in exploration of this important class of structures in systems chemistry. PMID- 28722304 TI - Nrf2 as a target for prevention of age-related and diabetic cataracts by against oxidative stress. AB - Cataract is one of the most important causes of blindness worldwide, with age related cataract being the most common one. Agents preventing cataract formation are urgently required. Substantial evidences point out aggravated oxidative stress as a vital factor for cataract formation. Nuclear factor (erythroid derived 2)-like 2 (Nrf2)/Kelch-like erythroid-cell-derived protein with CNC homology (ECH)-associated protein 1 (Keap1) system is considered as one of the main cellular defense mechanisms against oxidative stresses. This review discusses the role of Nrf2 pathway in the prevention of cataracts and highlights that Nrf2 suppressors may augment oxidative stress of the lens, and Nrf2 inducers may decrease the oxidative stress and prevent the cataract formation. Thus, Nrf2 may serve as a promising therapeutic target for cataract treatment. PMID- 28722306 TI - Is intra-procedure three-dimensional transesophageal echocardiogram an alternative to preprocedure multidetector computed tomography for the measurement of the aortic annulus in patients undergoing transcatheter aortic valve replacement? AB - BACKGROUND: The role of three-dimensional transesophageal echocardiography (3DTEE) vs multidetector computed tomography (MDCT) in aortic annular sizing has been poorly defined in patients undergoing transcatheter aortic valve replacements (TAVR). We set to determine the correlation between 3DTEE and MDCT in measuring the aortic annulus prior to TAVR. METHODS: In an observational, retrospective study, we compared aortic annular areas measured by MDCT and 3DTEE in TAVR patients. The aortic annular area was measured by planimetry of images obtained by MDCT pre-TAVR and by intra-TAVR TEE using 3D rendering of the aortic annulus followed by planimetry. Our primary outcome was degree of correlation between mean aortic annulus area by 3DTEE and MDCT. RESULTS: Of the 111 consecutive patients undergoing TAVR who had measurements from both modalities available for comparison between February 2012 and April 2015, 87 met inclusion criteria. The mean aortic annular area by MDCT was 4.44+/-0.88 cm2 and by 3DTEE was 4.33+/-0.78 cm2 . There was a strong positive linear correlation between aortic annular area measurements obtained from these two modalities with mild relative underestimation by 3DTEE (rho=.833). This relationship can be estimated using the predictive formula: [Formula: see text] CONCLUSIONS: Three-dimensional transesophageal echocardiography measurements have a high degree of correlation with MDCT measurements and thus can assist in proper valve prosthesis selection for TAVR. Our study thus supports use of 3DTEE as a reasonable alternative imaging modality in patients undergoing TAVR. PMID- 28722307 TI - Localized Defects on Copper Sulfide Surface for Enhanced Plasmon Resonance and Water Splitting. AB - Surficial defects in semiconductor can induce high density of carriers and cause localized surface plasmon resonance which is prone to light harvesting and energy conversion, while internal defects may cause serious recombination of electrons and holes. Thus, it is significant to precisely control the distribution of defects, although there are few successful examples. Herein, an effective strategy to confine abundant defects within the surface layer of Cu1.94 S nanoflake arrays (NFAs) is reported, leaving a perfect internal structure. The Cu1.94 S NFAs are then applied in photoelectrochemical (PEC) water splitting. As expected, the surficial defects give rise to strong LSPR effect and quick charge separation near the surface; meanwhile, they provide active sites for catalyzing hydrogen evolution. As a result, the NFAs achieve the top PEC properties ever reported for Cux S-based photocathodes. PMID- 28722308 TI - Spectroscopic Discrimination of Diastereomeric Complexes Involving an Axially Chiral Receptor. AB - The infrared multiphoton dissociation (IRMPD) spectra of electrospray ionization (ESI)-formed proton-bound complexes between the axially chiral multifunctional macrocycle MaR and d- and l-phenylalanine (PD and PL ) or d- and l-3,4 dihydroxyphenylalanine (DD and DL ) are recorded in the nu~ =2800-3700 cm-1 region. Whereas the diastereomeric [MaR ?H?PD ]+ and [MaR ?H?PL ]+ complexes do not show any significant spectral differences, the spectrum of [MaR ?H?DD ]+ clearly diverges from that of its [MaR ?H?DL ]+ diastereomer. A comparison of the experimental spectra with the B3LYP/6-31G**-calculated harmonic vibrational frequencies of a number of stable structures indicates the formation, in the ESI source, of very similar spectroscopically active structures, with the protonated amino acid placed outside the flat cavity of the macrocycle and hydrogen-bonded at its O2 center. Different spectral signatures of the [MaR ?H?DD ]+ and [MaR ?H?DL ]+ complexes are attributed to the coexistence of several stable rotamers in the ESI source. PMID- 28722309 TI - Long-term outcomes after acute primary angle closure of Caucasian chronic angle closure glaucoma patients. AB - IMPORTANCE: There is a lack of information about long-term results of chronic angle closure glaucoma following an acute primary angle closure attack in Caucasian patients. PURPOSE: The aim of the study was to report morphological and functional long-term data of chronic angle closure eyes following a monolateral primary angle closure attack and to provide a comparison with their fellow eyes. DESIGN: Observational retrospective case series. PARTICIPANTS: Fifty-seven consecutive patients (114 eyes) underwent long-term follow-up analysis. METHODS: Patients underwent ophthalmic assessment more than 5 years since the angle closure attack. MAIN OUTCOME MEASURES: Intraocular pressure, best-corrected visual acuity, angle assessment, vertical C/D ratio and standard automated perimetry were the main outcome measures. Comparisons were made between angle closure attack eyes and fellow eyes and between phakic and pseudophakic eyes. RESULTS: Mean follow-up time was 5.86 +/- 1.19 years. A significant greater damage in the angle closure eyes compared with fellow eyes in both structural (mean C/D 0.61 +/- 0.16; P < 0.001) and functional (mean deviation: -7.98 +/- 6.46 vs. -4.83 +/- 4.95 dB; P < 0.001) terms was present. Mean IOP was 13.44 +/- 2.78 and 13.89 +/- 2.60 mmHg in angle closure and fellow eyes (P = 0.11). Thirty of 57 (53%) fellow eyes developed chronic angle closure (mean deviation: -7.74 +/ 5.21 dB) even if prophylactic iridotomy was promptly performed. CONCLUSION AND RELEVANCE: Our study prompts ophthalmologists to closely follow patients after an APAC attack to prevent potential glaucoma damage in both APAC and fellow eye. PMID- 28722311 TI - Public health nurses as policy advocates. PMID- 28722310 TI - Capitalizing on Scientific Advances to Improve Access to and Quality of Children's Mental Health Care. AB - The majority of mental health problems begin in childhood or adolescence. The potential benefits of early identification and treatment of such problems are well established, and models of effective mental health interventions for children have proliferated in recent decades. However, barriers in access to care and challenges in assuring delivery of high-quality care significantly limit the public health impact of services for children and families. Specifically, the majority of children who need mental health care do not receive it, and when children are in care, many do not receive interventions that are most likely to have the greatest positive impact. A commitment to social justice requires significant improvement in access to care and quality of care to maximize human potential. The purpose of this manuscript is to highlight promising scientific advances in the development of effective mental health services for children and families, as well as the vexing challenges of actually delivering these services to those most in need. Key challenges to be discussed include disparities in access to care and quality of care, including race/ethnic disparities and complexities of navigating the multi-sector mental health service system for children, and difficulties in implementing effective intervention models more consistently in community care. The authors will propose practice and policy reform recommendations to address these challenges. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28722312 TI - Cryohemolysis test is for what's causing the spherocytosis. PMID- 28722313 TI - Cellular glycosylation senses metabolic changes and modulates cell plasticity during epithelial to mesenchymal transition. AB - Epithelial to mesenchymal transition (EMT) is a developmental program reactivated by tumor cells that leads to the switch from epithelial to mesenchymal phenotype. During EMT, cells are transcriptionally regulated to decrease E-cadherin expression while expressing mesenchymal markers such as vimentin, fibronectin, and N-cadherin. Growing body of evidences suggest that cells engaged in EMT undergo a metabolic reprograming process, redirecting glucose flux toward hexosamine biosynthesis pathway (HBP), which fuels aberrant glycosylation patterns that are extensively observed in cancer cells. HBP depends on nutrient availability to produce its end product UDP-GlcNAc, and for this reason is considered a metabolic sensor pathway. UDP-GlcNAc is the substrate used for the synthesis of major types of glycosylation, including O-GlcNAc and cell surface glycans. In general, the rate limiting enzyme of HBP, GFAT, is overexpressed in many cancer types that present EMT features as well as aberrant glycosylation. Moreover, altered levels of O-GlcNAcylation can modulate cell morphology and favor EMT. In this review, we summarize some of the current knowledge that correlates glucose metabolism, aberrant glycosylation and hyper O-GlcNAcylation supported by HBP that leads to EMT activation. Developmental Dynamics 247:481 491, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 28722314 TI - Prospective motion correction using coil-mounted cameras: Cross-calibration considerations. AB - PURPOSE: Optical prospective motion correction substantially reduces sensitivity to motion in neuroimaging of human subjects. However, a major barrier to clinical deployment has been the time-consuming cross-calibration between the camera and MRI scanner reference frames. This work addresses this challenge. METHODS: A single camera was mounted onto the head coil for tracking head motion. Two new methods were developed: (1) a rapid calibration method for camera-to-scanner cross-calibration using a custom-made tool incorporating wireless active markers, and (2) a calibration adjustment method to compensate for table motion between scans. Both methods were tested at 1.5T and 3T in vivo. Simulations were performed to determine the required mechanical tolerance for repositioning of the camera. RESULTS: The rapid calibration method is completed in a short (<30 s) scan, which is carried out only once per installation. The calibration adjustment method requires no extra scan time and runs automatically whenever the system is used. The mechanical tolerance analysis indicates that most motion (90% reduction in voxel displacement) could be corrected even with far larger camera repositioning errors than are observed in practice. CONCLUSION: The methods presented here allow calibration of sufficient quality to be carried out and maintained with no additional technologist workload. Magn Reson Med 79:1911-1921, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28722315 TI - Association between chronic musculoskeletal pain and executive function in community-dwelling older adults. AB - BACKGROUND: We examined the association of chronic musculoskeletal pain with executive function in community-dwelling older adults. METHOD: This cross sectional study recruited 234 community-dwelling older adults in Japan (mean age: 72.7, women: 62.8%). Chronic musculoskeletal pain was defined as having moderate or more severe pain lasting >= 3 months. Executive function was assessed using the Digit Symbol Substitution Test (DSST), Trail Making Test (TMT) parts A and B, Letter Verbal Fluency Test (LVFT) and Category Verbal Fluency Test (CVFT). RESULTS: Prevalence of chronic musculoskeletal pain was 19% (n = 44). In the univariate analysis, the DSST and CVFT scores were significantly lower in the chronic musculoskeletal pain group than in the control group (DSST: chronic musculoskeletal pain group vs. control group, 40.2 vs. 45.4, respectively, p < 0.05; CVFT: 13.7 vs. 15.6, respectively, p < 0.05), whereas the TMT parts A and B and LVFT scores were not. The multivariate linear regression models adjusted for covariates showed that the chronic musculoskeletal pain group had significantly lower DSST (adjusted beta = -0.13, p < 0.05) and CVFT scores (adjusted beta = 0.17, p < 0.05) than the control group. CONCLUSION: Chronic musculoskeletal pain may interfere with the elements of executive function, processing speed and semantic fluency, in community-dwelling older adults. The association of chronic musculoskeletal pain with executive function requires further investigation. SIGNIFICANCE: Our results suggest an association between moderate-severe chronic musculoskeletal pain and impairments of semantic fluency and processing speed in community-dwelling older adults. PMID- 28722316 TI - The Mincle ligand trehalose dibehenate differentially modulates M1-like and M2 like macrophage phenotype and function via Syk signaling. AB - INTRODUCTION: Macrophages play a significant role in the progression of diseases, such as cancer, making them a target for immune-modulating agents. Trehalose dibehenate (TDB) is known to activate M1-like macrophages via Mincle, however, the effect of TDB on M2-like macrophages, which are found in the tumor microenvironment, has not been studied. METHODS: qRT-PCR, flow cytometry, cytokine ELISA, and Western Blotting were used to study the effect of TDB on GM CSF and M-CSF/IL-4 derived bone marrow macrophages (BMMs) from C57BL/6 and Mincle /- mice. RESULTS: TDB treatment up-regulated M1 markers over M2 markers by GM-CSF BMMs, whereas M-CSF/IL-4 BMMs down-regulated marker gene expression overall. TDB treatment resulted in Mincle-independent down-regulation of CD11b, CD115, and CD206 expression by GM-CSF macrophages and CD115 in M-CSF/IL-4 macrophages. GM CSF BMMs produced of significant levels of proinflammatory cytokines (IL-1beta, IL-6, TNF-alpha), which was Mincle-dependent and further enhanced by LPS priming. M-CSF BMMs produced little or no cytokines in response to TDB regardless of LPS priming. Western blot analysis confirmed that the absence of cytokine production was associated with a lack of activation of the Syk kinase pathway. CONCLUSION: This study illustrates that TDB has the potential to differentially regulate M1- and M2-like macrophages in the tumor environment. PMID- 28722317 TI - Reward Capacity Predicts Leptin Dynamics During Laboratory-Controlled Eating in Women as a Function of Body Mass Index. AB - OBJECTIVE: The role of leptin in mesolimbic signaling of non-food-related rewards has been well established at the preclinical level, yet studies in humans are lacking. The present investigation explored the association between hedonic capacity and leptin dynamics and whether this association differed by BMI class. METHODS: In this cross-sectional study of 75 women (42 with BMIs in the lean range and 33 with BMIs in the obesity range), serum leptin before and after meal consumption was measured. Reward capacity was assessed using the Snaith-Hamilton Pleasure Scale (SHAPS). Multiple regression tested whether reward capacity was associated with the leptin area under the curve (AUC), with an interaction term to test differences between the lean and obesity groups. RESULTS: The interaction of SHAPS by BMI group was robust (beta = -0.40, P = 0.005); among women with obesity, a greater SHAPS score was associated with a lower leptin AUC (beta = 0.35, P = 0.002, adjusted R2 = 0.66). Among those in the lean group, the association was not statistically significant (beta = -0.16, P = 0.252, adjusted R2 = 0.22). Findings were above and beyond BMI and age. CONCLUSIONS: In this sample, a robust negative association between reward capacity and circulating leptin was stronger in women with obesity compared with lean counterparts. These findings suggest that despite likely leptin resistance, inhibitory leptin functioning related to nonfood rewards may be spared in women with obesity. PMID- 28722318 TI - Porous Carbon Nanofibers Encapsulated with Peapod-Like Hematite Nanoparticles for High-Rate and Long-Life Battery Anodes. AB - Fe2 O3 is regarded as a promising anode material for lithium-ion batteries (LIBs) and sodium-ion batteries (SIBs) due to its high specific capacity. The large volume change during discharge and charge processes, however, induces significant cracking of the Fe2 O3 anodes, leading to rapid fading of the capacity. Herein, a novel peapod-like nanostructured material, consisting of Fe2 O3 nanoparticles homogeneously encapsulated in the hollow interior of N-doped porous carbon nanofibers, as a high-performance anode material is reported. The distinctive structure not only provides enough voids to accommodate the volume expansion of the pea-like Fe2 O3 nanoparticles but also offers a continuous conducting framework for electron transport and accessible nanoporous channels for fast diffusion and transport of Li/Na-ions. As a consequence, this peapod-like structure exhibits a stable discharge capacity of 1434 mAh g-1 (at 100 mA g-1 ) and 806 mAh g-1 (at 200 mA g-1 ) over 100 cycles as anode materials for LIBs and SIBs, respectively. More importantly, a stable capacity of 958 mAh g-1 after 1000 cycles and 396 mAh g-1 after 1500 cycles can be achieved for LIBs and SIBs, respectively, at a large current density of 2000 mA g-1 . This study provides a promising strategy for developing long-cycle-life LIBs and SIBs. PMID- 28722319 TI - Immunophenotypic aberrancies in acute lymphoblastic leukemia from 282 Iraqi patients. AB - INTRODUCTION: The identification of aberrancies in leukemia-associated immunophenotype (LAIP) of acute lymphoblastic leukemia (ALL) is quite important in the assessment of minimal residual disease (MRD). This study, the first from Iraq, aimed to assess the frequency and patterns of LAIP among Iraqi patients with ALL, to establish future strategies for evaluating MRD. METHODS: A total of 282 newly diagnosed Iraqi ALL cases were analyzed with six-parameter flow cytometry using a panel of 29 monoclonal antibodies. RESULTS: Immunological subtyping revealed that 85.5% of cases were B-ALL and the remainder T-ALL. LAIP was detected in 97.1% of B-ALL, and in 26.8% of T-ALL. The asynchronous maturation-associated antigen patterns in B-ALL were CD10strong+ /TdTdim+ , CD38dim+ /CD34+ , CD10dim+ /CD34+ , CD10strong /CD20strong+ , CD20strong+ /CD34+, and CD45dim+ /CD20strong+ in 84.6%, while the cross-lineage myeloid expression was seen in 81.3% and aberrant T-cell antigen expression in 6.2%. For T-ALL, asynchronous maturation-associated antigen patterns included the following: CD1a+ /CD5+ /sCD3+ and CD34+ /sCD3+ in 12.2%. Myeloid and B-cell antigen expression were each identified in 7.3% of T-ALL. No significant differences in LAIP were found between children and adults. CONCLUSION: The high rates and the patterns of LAIP particularly in Iraqi B-ALL patients may allow the development of more cost effective strategies for MRD monitoring. PMID- 28722320 TI - Congenital unilateral renal agenesis: Prevalence, prenatal diagnosis, associated anomalies. Data from two birth-defect registries. AB - BACKGROUND: The different mechanisms leading to a solitary kidney should be differentiated because the long-term outcome might be different. The fetal period is the best moment to make a true diagnosis of congenital unilateral renal agenesis (URA). The objective was to determine the prevalence of URA at birth. The secondary objectives were to describe the evolution of sensitivity of prenatal diagnosis over time and the different forms of URA (isolated and associated with other malformations) detected up to 1 year. METHODS: The cases were retrospectively identified through two French population-based birth defect registries (Auvergne and Bas-Rhin) between 1995 and 2013. Stillbirths and fetuses up to 22 weeks of gestation and infants up to 1 year old with URA were included. RESULTS: A total of 177 cases of URA were registered. The prevalence at birth was 4.0/10,000. The overall prenatal prevalence was 3.6/10,000 (isolated URA: 2.8/10,000). URA were isolated (59.9%), associated with isolated contralateral congenital anomaly of kidney or urinary tract (CAKUT) (7.3%) and with other extra renal anomalies (32.8%). The total proportion of contralateral CAKUT was 15%. Only three cases presented an aneuploidy, prenatally detected and conducting to a termination of pregnancy. The sensitivity of prenatal diagnosis improved over time (from 54.2% in 1995 to 1997 to 95.8% in 2010 to 2013; p = 0.002). CONCLUSION: Our study provides estimates of prevalence of URA at birth. A longitudinal cohort from the antenatal period to puberty should be performed to determine the prognosis of the contralateral kidney among these children with isolated, associated with contralateral CAKUT and URA with extra-renal anomalies. Birth Defects Research 109:1204-1211, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28722321 TI - Postsplenectomy vaccination guideline adherence: Opportunities for improvement. AB - BACKGROUND AND PURPOSE: Patients undergoing splenectomy for trauma are at life long risk for rapidly progressive septicemia. The purpose of this study was to investigate long-term patient understanding and follow-up with recommendations regarding their asplenia. METHODS: Patients undergoing splenectomy for trauma January 2010-December 2014 were analyzed. Medical records were reviewed and telephone follow-up interviews were conducted in October-December 2015. Patients were asked a standard set of questions that included hospitalizations, awareness of infectious risks associated with asplenia, need for revaccination, and vaccines they had received since their index hospitalization. FINDINGS: Two hundred forty-four patients underwent splenectomy during the study period. A total of 95 patients (39%) were included in the study. Thirty (32%) had been hospitalized since their trauma admission. Only 46% were aware of the risks for sepsis and the need to revaccinate. Only 7% reported having rapid access to antibiotics. CONCLUSIONS: Despite uniform education prior to discharge, most patients undergoing splenectomy for trauma were unaware of the risks for sepsis and did not follow recommended guidelines for risk reduction. IMPLICATIONS FOR PRACTICE: Improvements that have direct implications for advanced practice included the need to refer for vaccination, educate regarding infection risks, and facilitate rapid access to antibiotic treatment. PMID- 28722324 TI - Spotlights on our sister journals: Angew. Chem. Int. Ed. 31/2017. PMID- 28722323 TI - Branched Aramid Nanofibers. AB - Interconnectivity of components in three-dimensional networks (3DNs) is essential for stress transfer in hydrogels, aerogels, and composites. Entanglement of nanoscale components in the network relies on weak short-range intermolecular interactions. The intrinsic stiffness and rod-like geometry of nanoscale components limit the cohesive energy of the physical crosslinks in 3DN materials. Nature realizes networked gels differently using components with extensive branching. Branched aramid nanofibers (BANFs) mimicking polymeric components of biological gels were synthesized to produce 3DNs with high efficiency stress transfer. Individual BANFs are flexible, with the number of branches controlled by base strength in the hydrolysis process. The extensive connectivity of the BANFs allows them to form hydro- and aerogel monoliths with an order of magnitude less solid content than rod-like nanocomponents. Branching of nanofibers also leads to improved mechanics of gels and nanocomposites. PMID- 28722322 TI - Advanced Methods for Dose and Regimen Finding During Drug Development: Summary of the EMA/EFPIA Workshop on Dose Finding (London 4-5 December 2014). AB - Inadequate dose selection for confirmatory trials is currently still one of the most challenging issues in drug development, as illustrated by high rates of late stage attritions in clinical development and postmarketing commitments required by regulatory institutions. In an effort to shift the current paradigm in dose and regimen selection and highlight the availability and usefulness of well established and regulatory-acceptable methods, the European Medicines Agency (EMA) in collaboration with the European Federation of Pharmaceutical Industries Association (EFPIA) hosted a multistakeholder workshop on dose finding (London 4 5 December 2014). Some methodologies that could constitute a toolkit for drug developers and regulators were presented. These methods are described in the present report: they include five advanced methods for data analysis (empirical regression models, pharmacometrics models, quantitative systems pharmacology models, MCP-Mod, and model averaging) and three methods for study design optimization (Fisher information matrix (FIM)-based methods, clinical trial simulations, and adaptive studies). Pairwise comparisons were also discussed during the workshop; however, mostly for historical reasons. This paper discusses the added value and limitations of these methods as well as challenges for their implementation. Some applications in different therapeutic areas are also summarized, in line with the discussions at the workshop. There was agreement at the workshop on the fact that selection of dose for phase III is an estimation problem and should not be addressed via hypothesis testing. Dose selection for phase III trials should be informed by well-designed dose-finding studies; however, the specific choice of method(s) will depend on several aspects and it is not possible to recommend a generalized decision tree. There are many valuable methods available, the methods are not mutually exclusive, and they should be used in conjunction to ensure a scientifically rigorous understanding of the dosing rationale. PMID- 28722325 TI - Polymer-mediated flocculation of transient CHO cultures as a simple, high throughput method to facilitate antibody discovery. AB - Most biopharmaceutical drugs, especially monoclonal antibodies (mAbs), bispecific antibodies (BsAbs) and Fc-fusion proteins, are expressed using Chinese Hamster Ovary (CHO) cell lines. CHO cells typically yield high product titers and high product quality. Unfortunately, CHO cell lines also generate high molecular weight (HMW) aggregates of the desired product during cell culture along with CHO host cell protein (HCP) and CHO DNA. These immunogenic species, co-purified during Protein A purification, must be removed in a multi-step purification process. Our colleagues have reported the use of a novel polymer-mediated flocculation step to simultaneously reduce HMW, HCP and DNA from stable CHO cell cultures prior to Protein A purification. The objective of this study was to evaluate this novel "smart polymer" (SmP) in a high throughput antibody discovery workflow using transiently transfected CHO cultures. SmP treatment of 19 different molecules from four distinct molecular categories (human mAbs, murine mAbs, BsAbs and Fabs) with 0.1% SmP and 25 mM stimulus resulted in minimal loss of monomeric protein. Treatment with SmP also demonstrated a variable, concentration-dependent removal of HMW aggregates after Protein A purification. SmP treatment also effectively reduced HCP levels at each step of mAb purification with final HCP levels being several fold lower than the untreated control. Interestingly, SmP treatment was able to significantly reduce high concentrations of artificially spiked levels of endotoxin in the cultures. In summary, adding a simple flocculation step to our existing transient CHO process reduced the downstream purification burden to remove impurities and improved final product quality. (c) 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:1393-1400, 2017. PMID- 28722326 TI - A Hydroxamic Acid Anchoring Group for Durable Dye-Sensitized Solar Cells Incorporating a Cobalt Redox Shuttle. AB - A hydroxamic acid group has been employed for the first time as an anchoring group for cobalt-based dye-sensitized solar cells (DSSCs). The porphyrin dye YD2 o-C8HA including a hydroxamic acid anchoring group exhibited a power conversion efficiency (eta) of 6.4 %, which is close to that of YD2-o-C8, a representative porphyrin dye incorporating a conventional carboxylic acid. More importantly, YD2 o-C8HA was found to be superior to YD2-o-C8 in terms of both binding ability to TiO2 and durability of cobalt-based DSSCs. Notably, YD2-o-C8HA photocells revealed a higher eta-value (4.1 %) than YD2-o-C8 (2.8 %) after 500 h illumination. These results suggest that the hydroxamic acid can be used for DSSCs with other transition-metal-based redox shuttle to ensure high cell durability as well as excellent photovoltaic performance. PMID- 28722327 TI - Transforming growth factor-beta, matrix metalloproteinases, and urokinase-type plasminogen activator interaction in the cancer epithelial to mesenchymal transition. AB - Transforming growth factor-beta (TGF-beta) is a pleiotropic factor that acts as a tumor suppressor in the early stages, while it exerts tumor promoting activities in advanced stages of cancer development. One of the hallmarks of cancer progression is the capacity of cancer cells to migrate and invade surrounding tissues with subsequent metastasis to different organs. Matrix metalloproteinases (MMPs) together with urokinase-type plasminogen activator (uPA) and its receptor (uPAR), whose main original function described is the proteolytic degradation of the extracellular matrix, play key cellular roles in the enhancement of cell malignancy during cancer progression. TGF-beta tightly regulates the expression of several MMPs and uPA/uPAR in cancer cells, which in return can participate in TGF-beta activation, thus contributing to tumor malignancy. TGF-beta is one of the master factors in the induction of cancer-associated epithelial to mesenchymal transition (EMT), and recently both MMPs and uPA/uPAR have also been shown to be implicated in the cancer-associated EMT process. In this review, we analyze the main molecular mechanisms underlying MMPs and uPA/uPAR regulation by TGF-beta, as well as their mutual implication in the development of EMT in cancer cells. Developmental Dynamics 247:382-395, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 28722328 TI - Manipulation of Inorganic Atomic-Layer Networks by Solution-Phase Co-assembly. AB - Homogeneous 2D lamellar assemblies of AuI thiolate coordination polymer (ATCP) were obtained by two-ligand co-assembly. The orbital levels and the bandgap of the 2D AuI -S network in the centre of the lamellae can be continuously tuned by means of the capping ligands on both sides, to give a new type of inorganic organic composite semiconductor, the band structure of which can be easily tuned by low-temperature solution-phase co-assembly. Furthermore, the chemical reactivity of these ATCP co-assemblies also proved to be strongly dependent on the organic substituents, with well-tuneable transformation rates to gold nanoparticles. Apparently, this is the first work to demonstrate how organic substituents can continuously tune the electron band structure and chemical reactivity of inorganic atomic layers of semiconductor through co-assembly. PMID- 28722329 TI - Prevalence of Salmonella among waterfowl along the Texas Gulf coast. AB - Migratory waterfowl may play a role in the ecology and transmission of zoonotic pathogens, given their ability to travel long distances and their use of varied habitats. Our objectives were to estimate the prevalence of Salmonella among waterfowl along the Texas Gulf coast and to characterize the isolates. Faecal samples were collected from hunter-harvested waterfowl at four wildlife management areas from September through November, 2016. Standard bacteriologic culture methods were used to isolate Salmonella from samples, and isolates were characterized by serotyping and anti-microbial susceptibility testing. The apparent prevalence of faecal Salmonella shedding was 0.5% (2/375). Serotypes identified were Thompson and Braenderup, and both isolates were susceptible to all anti-microbial agents tested. Although faecal contamination of agricultural fields or surface waters could serve as a potential source of zoonotic Salmonella transmission, waterfowl along the Gulf coast during the fall hunting season appear to pose minimal risk. PMID- 28722330 TI - Tunable Biogenic Manganese Oxides. AB - Influence of the conditions for aerobic oxidation of Mn2+(aq) catalysed by the MnxEFG protein complex on the morphology, structure and reactivity of the resulting biogenic manganese oxides (MnOx ) is explored. Physical characterisation of MnOx includes scanning and transmission electron microscopy, and X-ray photoelectron and K-edge Mn, Fe X-ray absorption spectroscopy. This characterisation reveals that the MnOx materials share the structural features of birnessite, yet differ in the degree of structural disorder. Importantly, these biogenic products exhibit strikingly different morphologies that can be easily controlled. Changing the substrate-to-protein ratio produces MnOx either as nm thin sheets, or rods with diameters below 20 nm, or a combination of the two. Mineralisation in solutions that contain Fe2+(aq) makes solids with significant disorder in the structure, while the presence of Ca2+(aq) facilitates formation of more ordered materials. The (photo)oxidation and (photo)electrocatalytic capacity of the MnOx minerals is examined and correlated with their structural properties. PMID- 28722332 TI - Functionalized Acupuncture Needle as Surface-Enhanced Resonance Raman Spectroscopy Sensor for Rapid and Sensitive Detection of Dopamine in Serum and Cerebrospinal Fluid. AB - It is a challenge to develop a robust sensor for simple, rapid operation and sensitive detection of neurotransmitters in complex specimens. Herein, ferric citrate functionalized gold nanoparticles (CA-FeIII /Au NPs) are utilized to develop a facile sensor based on surface-enhanced resonance Raman spectroscopy (SERRS) for sensitive detection of dopamine (DA). The sensor is prepared by decorating the acupuncture needle with Au NPs, which enables sufficient surface enhanced Raman spectroscopy enhancement. The CA-FeIII structure is highly sensitive and selective for DA due to the formation of the CA-FeIII -DA resonant structure; this indicates the advantages of capturing, carrying, and separating DA molecules from complicated samples in a simple operation. Furthermore, the practical application of the fabricated sensor is validated by the detection of DA in pretreated serum and cerebrospinal fluid of acupuncture-treated mice with detection limits of 0.1 and 2.5 nm DA, respectively. The developed active acupuncture needle sensor has potential benefits for sensitive detection and qualitative identification of DA molecules from biological samples. PMID- 28722333 TI - XIAP inhibitor embelin induces autophagic and apoptotic cell death in human oral squamous cell carcinoma cells. AB - Embelin is an active ingredient of traditional herbal remedies for cancer and other diseases. Recently, it has been suggested that autophagy may play an important role in cancer therapy. However, little data are available regarding the role of autophagy in oral cancers. Therefore, we conducted this study to examine whether Embelin modulates autophagy in Ca9-22. Our results showed that Embelin had anticancer activity against the Ca9-22 human tongue squamous cell, and we observed that autophagic vacuoles were formed by MDC and AO. We also analyzed Embelin-treated Ca9-22 cells for the presence of biochemical markers and found that it directly affected the conversion of LC3-II, the degradation of p62/SQSTM1, full-length cleavage formation of ATG5-ATG12 complex and Beline-1, and caspase activation. Rescue experiments using an autophagy inhibitor showed Embelin-induced cell death in Ca9-22, confirming that autophagy acts as a pro death signal. Furthermore, Embelin exhibited anticancer activity against Ca9-22 via both autophagy and apoptosis. These findings suggest that Embelin may potentially contribute to oral cancer treatment and provide useful information for the development of a new therapeutic agent. PMID- 28722331 TI - Hepatitis C virus and proprotein convertase subtilisin/kexin type 9: a detrimental interaction to increase viral infectivity and disrupt lipid metabolism. AB - From viral binding to the hepatocyte surface to extracellular virion release, the replication cycle of the hepatitis C virus (HCV) intersects at various levels with lipid metabolism; this leads to a derangement of the lipid profile and to increased viral infectivity. Accumulating evidence supports the crucial regulatory role of proprotein convertase subtilisin/kexin type 9 (PCSK9) in lipoprotein metabolism. Notably, a complex interaction between HCV and PCSK9 has been documented. Indeed, either increased or reduced circulating PCSK9 levels have been observed in HCV patients; this discrepancy might be related to several confounders, including HCV genotype, human immunodeficiency virus (HIV) coinfection and the ambiguous HCV-mediated influence on PCSK9 transcription factors. On the other hand, PCSK9 may itself influence HCV infectivity, inasmuch as the expression of different hepatocyte surface entry proteins and receptors is regulated by PCSK9. The aim of this review is to summarize the current evidence about the complex interaction between HCV and liver lipoprotein metabolism, with a specific focus on PCSK9. The underlying assumption of this review is that the interconnections between HCV and PCSK9 may be central to explain viral infectivity. PMID- 28722334 TI - Potential emerging treatment in vitiligo using Er:YAG in combination with 5FU and clobetasol. AB - BACKGROUND: Vitiligo is a pigmentary disorder of skin affecting at least 1% of the world population of all races in both sexes. Its importance is mainly due to subsequent social and psychological problems rather than clinical complications. Various treatment choices are available for vitiligo; however, laser-based courses have shown to give more acceptable results. OBJECTIVE: The aim of this trial was to evaluate the efficacy of Er:YAG laser as a supplementary medicine to topical 5FU and clobetasol in vitiligo patients. METHODS: Two comparable vitiligo patches from 38 eligible patients were randomized to receive topical 5FU and clobetasol in control group and additional Er:YAG laser in intervention group. Major outcomes of interest were the size of patch and pigmentation score at randomization and 2 and 4 months after therapy. RESULTS: Final sample included 18 (47%) male patients and age of 35.66+/-8.04. The performance Er:YAG group was superior in all sites. Reduction in the size of patches was greater in Er:YAG group (p-value=.004). Also, this group showed a higher pigmentation scores in the trial period than control group (p-value<.001). CONCLUSIONS: Greater reduction in the size and increase in pigmentation score was seen in Er:YAG group especially for short periods after therapy and repeating laser sessions may help improving final outcomes. Er:AYG could help in reducing complications of long-term topical treatments, achieving faster response, and improving patient adherence. PMID- 28722335 TI - Protective effects of folic acid on PM2.5-induced cardiac developmental toxicity in zebrafish embryos by targeting AhR and Wnt/beta-catenin signal pathways. AB - Our previous observations indicated that extractable organic matter (EOM) from PM2.5 induced malformations in the heart of zebrafish embryos by activating AhR and inhibiting canonical Wnt/beta-catenin signal pathway. As a nutritional factor, folic acid (FA) is reported to prevent cardiac defects during embryo development. Hence, we hypothesize that FA may prevent PM2.5-induced heart defects by interfering with AhR and Wnt/beta-catenin signaling pathways. Our results showed that FA supplementation alleviated the EOM-induced heart defects in zebrafish embryos, and both AhR inhibitor CH223191 and Wnt activator CHIR99021 enhanced the protective efficiency of FA. Furthermore, FA supplementation attenuated the EOM-induced upregulation of AhR and its target genes including Cyp1a1, Cyp1b1, Ahrra, and Ahrrb. EROD assay confirmed that the EOM agonized Cyp1a1 activity was diminished by FA. The EOM-induced downregulation of beta catenin and its target genes including Nkx2.5, Axin2, Sox9b, and Cox2b were recovered or even overexpressed in embryos exposed to EOM plus FA. In conclusion, our study suggested that FA supplementation protected against PM2.5 cardiac development toxicity by targeting AhR and Wnt/beta-catenin signal pathways. PMID- 28722336 TI - Evidence for the modulation of nociception in mice by central mast cells. AB - BACKGROUND: Hyperalgesia that develops following nerve ligation corresponds temporally and in magnitude with the number of thalamic mast cells located contralateral to the ligature. We tested the possibility that mast cells modulate nociception centrally, similar to their role in the periphery. METHODS: We examined the central effect of two hyperalgesic compounds that induce mast cell degranulation and of stabilized mast cells using cromolyn. RESULTS: Thermal hyperalgesia (tail flick) induced by nerve growth factor (NGF, a neurotrophic compound) and mechanical hyperalgesia (von Frey) induced by dynorphin A (1-17) (opioid compound) each correlated with the per cent of thalamic mast cells that were degranulated. Degranulation of these mast cells by the central injection of compound 48/80, devoid of neurotrophic or opioid activity, was sufficient to recapitulate thermal hyperalgesia. Stabilization of mast cells by central injections of cromolyn produced no analgesic effect on baseline tail flick or von Frey fibre sensitivity, but inhibited thermal hyperalgesia produced by compound 48/80 and tactile hyperalgesia induced by dynorphin and by Freund's complete adjuvant. Finally, chemical nociception produced by the direct activation of nociceptors by formalin (phase I) was not inhibited by centrally injected cromolyn whereas chemical nociception dependent on central sensitization (formalin-phase II and acetic acid-induced abdominal stretches) was. CONCLUSIONS: These convergent lines of evidence suggest that degranulation of centrally located mast cells sensitizes central nociceptive pathways leading to hyperalgesia and tonic chemical sensitivity. SIGNIFICANCE: Hyperalgesia induced by spinal nerve ligation corresponds temporally and in magnitude with degranulation of thalamic mast cells. Here, we provide evidence that hyperalgesia induced by NGF, formalin and dynorphin also may depend on mast cell degranulation in the CNS whereas cromolyn, a mast cell stabilizer, blocks these effects in mice. PMID- 28722337 TI - Validation of brain-derived signals in near-infrared spectroscopy through multivoxel analysis of concurrent functional magnetic resonance imaging. AB - Near-infrared spectroscopy (NIRS) is a convenient and safe brain-mapping tool. However, its inevitable confounding with hemodynamic responses outside the brain, especially in the frontotemporal head, has questioned its validity. Some researchers attempted to validate NIRS signals through concurrent measurements with functional magnetic resonance imaging (fMRI), but, counterintuitively, NIRS signals rarely correlate with local fMRI signals in NIRS channels, although both mapping techniques should measure the same hemoglobin concentration. Here, we tested a novel hypothesis that different voxels within the scalp and the brain tissues might have substantially different hemoglobin absorption rates of near infrared light, which might differentially contribute to NIRS signals across channels. Therefore, we newly applied a multivariate approach, a partial least squares regression, to explain NIRS signals with multivoxel information from fMRI within the brain and soft tissues in the head. We concurrently obtained fMRI and NIRS signals in 9 healthy human subjects engaging in an n-back task. The multivariate fMRI model was quite successfully able to predict the NIRS signals by cross-validation (interclass correlation coefficient = ~0.85). This result confirmed that fMRI and NIRS surely measure the same hemoglobin concentration. Additional application of Monte-Carlo permutation tests confirmed that the model surely reflects temporal and spatial hemodynamic information, not random noise. After this thorough validation, we calculated the ratios of the contributions of the brain and soft-tissue hemodynamics to the NIRS signals, and found that the contribution ratios were quite different across different NIRS channels in reality, presumably because of the structural complexity of the frontotemporal regions. Hum Brain Mapp 38:5274-5291, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28722338 TI - HDR-del: A tool based on Hamming distance for prioritizing pathogenic chromosomal deletions in exome sequencing. AB - High-density oligonucleotide arrays have widely been used to detect pathogenic chromosomal deletions. In addition to high-density oligonucleotide arrays, programs using whole-exome sequencing have become available for estimating copy number variations using depth of coverage. Here, we propose a new statistical method, HDR-del, to prioritize pathogenic chromosomal deletions based on Hamming distance in exome sequencing. In vcf (variant call format) files generated from exome sequencing, hemizygous chromosomal deletion regions lack heterozygous variants and lead to apparent long runs of homozygosity (ROH). In our Hamming distance ratio (HDR)-del approach, we calculate the "difference" in heterozygous status between an affected individual and control individuals using the HDR over all candidate chromosomal deletion regions defined as ROH longer than 1Mbp. Using a suitable test statistic, which is expected to be large for a true pathogenic deletion region, we prioritize candidate chromosomal deletion regions based on this statistic. In our approach, we were able to considerably narrow down true pathogenic chromosomal deletion regions, which were confirmed by high-density oligonucleotide arrays in four mitochondrial disease patients. Our HDR-del approach represents an easy method for detecting chromosomal deletions. PMID- 28722339 TI - Structured pain management reduces patient discomfort after catheter ablation and rhythm device surgery. AB - BACKGROUND: The goal was to test the effectiveness of a structured pain management programme after invasive electrophysiological interventions in cardiology including ablation of atrial fibrillation (AF) or ventricular tachycardia (VT) and implantation, or explantation, of pacemakers or implantable cardioverter defibrillators. METHODS: This was a prospective study with a pre /post-design where a post-intervention group (116 consecutive patients) was compared to a pre-intervention group (102 consecutive patients) after implementation of a structured pain-management programme using the numeric rating scale (NRS 0-10) and classified as moderate-to-severe if NRS > 3. Measurements were recorded every two hours during the first 24 h post-operatively. The location of the pain and the amount of analgesic used were also recorded. RESULTS: The proportion of patients who experienced moderate-to-severe pain after the procedure decreased after initiation of the pain-management program: 47% versus 61%; p = 0.048. This difference was driven primarily by reduced pain late (8-24 h) after the procedure; 16% versus 39%; p < 0.001. The risk to develop late (8-24 h) post-procedural pain was reduced approximately three-fold after implementation of the pain-management programme (OR = 0.32, 95% CI 0.16-0.64, p = 0.001). Multivariate analysis indicated chronic pain, early pain (0-6 h), and type of intervention were associated with late post-interventional pain. In contrast, age, diabetes mellitus, BMI, gender and procedure time were not related. CONCLUSION: The findings illustrate the potential value of a structured pain-management programme. The proportion of patients who experienced moderate-to severe pain after these electrophysiological procedures decreased significantly. SIGNIFICANCE: This is the first exploratory study that evaluates the impact of a multidisciplinary pain-management programme after cardiac electrophysiological interventions. It demonstrates that significant quality improvement is achievable following simple rules together with patient and staff education. The programme reduces the proportion of patients with moderate-to-severe pain after electrophysiological procedures significantly. PMID- 28722340 TI - A Small-Molecule Inhibitor of Prion Replication and Mutant Prion Protein Toxicity. AB - Into the fold: Prion diseases are neurodegenerative disorders characterized by the accumulation in the brain of a self-replicating, misfolded isoform (PrPSc ) of the cellular prion protein (PrPC ). No therapies are available for these pathologies. We capitalized on previously described cell-based assays to screen a library of small molecules, and identified 55, a compound capable of counteracting both prion replication and toxicity. Compound 55 may represent the starting point for the development of a completely new class of therapeutics for prion diseases. PMID- 28722341 TI - Proteomic Analysis of Neuroblastoma-Derived Exosomes: New Insights into a Metastatic Signature. AB - Neuroblastoma (NB) is the most common extracranial pediatric solid tumor. Around 70% of patients with metastatic disease at diagnosis present bone-marrow infiltration, which is considered a marker of poor outcome; however, the mechanism underlying this specific tropism has to be elucidated. Tumor-derived exosomes may support metastatic progression in several tumors by interacting with the microenvironment, and may serve as tumor biomarkers. The main objective of this study is to identify an exosomal signature associated with NB metastatic bone-marrow dissemination. Therefore, the proteomic cargo of exosomes isolated from NB cell lines derived from primary tumor and bone-marrow metastasis is characterized. The comparison among exosomal proteins show 15 proteins exclusively present in primary tumor-derived exosomes, mainly involved in neuronal development, and 6 proteins in metastasis-derived exosomes related to cancer progression. Significant proteins obtain with statistical analysis performed between the two groups, reveal that primary tumor exosomes contain a higher level of proteins involved in extra-cellular matrix (ECM) assembly and adhesion, as well as in neuronal development. Exosomes isolated from bone-marrow metastasis exhibit proteins involved in ameboidal cell migration and mitochondrial activity. This work suggests that proteomic profiling of NB-derived exosomes reflects the tumor stage and may be considered as potential tumor biomarker. PMID- 28722342 TI - Green micellar HPLC analysis of three angiotensin-converting enzyme inhibitors in their mixtures with hydrochlorothiazide and modeling of their retention behavior by fitting to Foley's model. AB - We present an environmentally friendly method for the analysis of three angiotensin-converting enzyme inhibitors and hydrochlorothiazide simultaneously using a green micellar eluent for the first time. The chromatographic separation of enalapril maleate, lisinopril dihydrate, benazepril hydrochloride, and hydrochlorothiazide was implemented on an octadecyl silica column with a solution containing sodium dodecyl sulfate (0.12 M), 1-propyl alcohol (10% v/v), triethylamine (0.3% v/v), and H3 PO4 (0.02 M) at pH 3.6 as the mobile phase and UV detection at 210 nm. Validity of the method was confirmed and it exhibited good linearity within the ranges of 5.0-50.0 MUg/mL for hydrochlorothiazide and 10.0-60.0 MUg/mL for the three angiotensin-converting enzyme inhibitors with a limit of detection of 0.39 to 1.15 MUg/mL for all the studied drugs. The developed micellar high-performance liquid chromatography method enables the quantification of the targeted angiotensin-converting enzyme inhibitors in combined tablets with hydrochlorothiazide by isocratic elution. There is no need for special precautions to prevent broadening and splitting of their chromatographic peaks. The method fulfills the society rights for safe and green analytical methods. The retention behavior of the four studied drugs was fitted to Foley's model and their association equilibria to the micelles (KAM ) and to the surface-modified stationary phase (KAS ) were calculated. PMID- 28722343 TI - Free-Standing Photonic Glasses Fabricated in a Centrifugal Field. AB - One efficient method to obtain disordered colloidal packing is to reduce the stability of colloidal particles by adding electrolytes to the colloidal dispersions. But the correct amount of additional electrolytes must be found empirically. Here, the effect of CaCl2 on polystyrene colloidal dispersions is studied, and a link between the amount of CaCl2 and the corresponding glassy colloidal structure is quantitatively built. A threshold concentration of CaCl2 is found by dynamic light scattering. When exceeding this threshold, different nanoparticle oligomers are observed in the dispersions by analytical ultracentrifugation. The second objective is to achieve free-standing samples, which is required for many optical measurements. A universal method is established, using a centrifugal field to produce robust samples by polymerizing coassembled hydrophilic monomers to form a network, which traps the glassy colloidal structures. Photon time of flight measurements shows that the CaCl2 concentration threshold should not be exceeded. Otherwise an optical shortcut may take place. Thus, the work provides a feasible universal route to prepare macroscopic free-standing photonic glasses from electrostatically stabilized nanoparticles, suitable for further optical investigation. PMID- 28722344 TI - A large-scale assessment of European rabbit damage to agriculture in Spain. AB - BACKGROUND: Numerous small and medium-sized mammal pests cause widespread and economically significant damage to crops all over the globe. However, most research on pest species has focused on accounts of the level of damage. There are fewer studies concentrating on the description of crop damage caused by pests at large geographical scales, or on analysis of the ecological and anthropogenic factors correlated with these observed patterns. We investigated the relationship between agricultural damage by the European rabbit (Oryctolagus cuniculus) and environmental and anthropogenic variables throughout Spain. RESULTS: Rabbit damage was mainly concentrated within the central-southern regions of Spain. We found that rabbit damage increased significantly between the early 2000s and 2013. Greater losses were typical of those areas where farming dominated and natural vegetation was scarce, where main railways and highways were present, and where environmental conditions were generally favourable for rabbit populations to proliferate. CONCLUSION: From our analysis, we suggest that roads and railway lines act as potential corridors along which rabbits can spread. The recent increase in Spain of such infrastructure may explain the rise in rabbit damage reported in this study. Our approach is valuable as a method for assessing drivers of wildlife pest damage at large spatial scales, and can be used to propose methods to reduce human - wildlife conflict. (c) 2017 Society of Chemical Industry. PMID- 28722345 TI - Anti-Markovnikov Hydrofunctionalization of Alkenes: Use of a Benzyl Group as a Traceless Redox-Active Hydrogen Donor. AB - A protocol for the anti-Markovnikov hydrofunctionalization of alkenes has been developed by the use of a benzyl group as a traceless redox-active hydrogen donor. Under copper catalysis and in the presence of CF3 - or N3 -containing hypervalent iodine reagents, a series of homoallylic alcohol derivatives were hydrofunctionalized regioselectivity. A similar principle was also applied to the hydrofunctionalization of alkenols. PMID- 28722346 TI - Progress of Large-Scale Synthesis and Electronic Device Application of Two Dimensional Transition Metal Dichalcogenides. AB - The recent exploration of semiconducting two-dimensional (2D) transition metal dichalcogenides (TMDs) with atomic thickness has taken both the scientific and technological communities by storm. Extensively investigated TMD that are accessible by large-scale synthetic methods materials are remarkably stable, such as MoS2 and WSe2 . They allow superior gate control due to their 2D nature and favorable electronic transport properties, thus suggesting a bright future for digital and RF electronics. In this review, the latest developments in the controlled synthesis of large scale TMDs are firstly introduced by discussing various approaches. The major obstacles that must be overcome to achieve wafer scale, uniform, and high-quality TMD films for practical electronic applications are included. Advances in the electronic transport studies of TMDs are presented, such as doping, contact engineering, and mobility improvement, which contribute to overall device performance. A perspective and a look at the future for this field is provided in closing. PMID- 28722348 TI - Stereospecific 1,3-Aminobromination of Donor-Acceptor Cyclopropanes. AB - Sn(OTf)2 -catalyzed 1,3-aminobromination of donor-acceptor cyclopropanes with various sulfonyl amides or electron-poor anilines and N-bromosuccinimide is reported. These experimentally straightforward reactions occurred with complete regio- and stereospecificity (for anilines) to give gamma-aminated alpha brominated malonic diesters in good to excellent yields (up to 98 %). These compounds served as valuable substrates for subsequent reactions to provide substituted azetidines and gamma-lactams in high yields. PMID- 28722347 TI - FOXO3 longevity interactome on chromosome 6. AB - FOXO3 has been implicated in longevity in multiple populations. By DNA sequencing in long-lived individuals, we identified all single nucleotide polymorphisms (SNPs) in FOXO3 and showed 41 were associated with longevity. Thirteen of these had predicted alterations in transcription factor binding sites. Those SNPs appeared to be in physical contact, via RNA polymerase II binding chromatin looping, with sites in the FOXO3 promoter, and likely function together as a cis regulatory unit. The SNPs exhibited a high degree of LD in the Asian population, in which they define a specific longevity haplotype that is relatively common. The haplotype was less frequent in whites and virtually nonexistent in Africans. We identified distant contact points between FOXO3 and 46 neighboring genes, through long-range physical contacts via CCCTC-binding factor zinc finger protein (CTCF) binding sites, over a 7.3 Mb distance on chromosome 6q21. When activated by cellular stress, we visualized movement of FOXO3 toward neighboring genes. FOXO3 resides at the center of this early-replicating and highly conserved syntenic region of chromosome 6. Thus, in addition to its role as a transcription factor regulating gene expression genomewide, FOXO3 may function at the genomic level to help regulate neighboring genes by virtue of its central location in chromatin conformation via topologically associated domains. We believe that the FOXO3 'interactome' on chromosome 6 is a chromatin domain that defines an aging hub. A more thorough understanding of the functions of these neighboring genes may help elucidate the mechanisms through which FOXO3 variants promote longevity and healthy aging. PMID- 28722349 TI - Global assays of fibrinolysis. PMID- 28722350 TI - Multidimensional Anodized Titanium Foam Photoelectrode for Efficient Utilization of Photons in Mesoscopic Solar Cells. AB - Mesoscopic solar cells based on nanostructured oxide semiconductors are considered as a promising candidates to replace conventional photovoltaics employing costly materials. However, their overall performances are below the sufficient level required for practical usages. Herein, this study proposes an anodized Ti foam (ATF) with multidimensional and hierarchical architecture as a highly efficient photoelectrode for the generation of a large photocurrent. ATF photoelectrodes prepared by electrochemical anodization of freeze-cast Ti foams have three favorable characteristics: (i) large surface area for enhanced light harvesting, (ii) 1D semiconductor structure for facilitated charge collection, and (iii) 3D highly conductive metallic current collector that enables exclusion of transparent conducting oxide substrate. Based on these advantages, when ATF is utilized in dye-sensitized solar cells, short-circuit photocurrent density up to 22.0 mA cm-2 is achieved in the conventional N719 dye-I3- /I- redox electrolyte system even with an intrinsically inferior quasi-solid electrolyte. PMID- 28722351 TI - beta-mangostin suppresses human hepatocellular carcinoma cell invasion through inhibition of MMP-2 and MMP-9 expression and activating the ERK and JNK pathways. AB - beta-mangostin is a dietary xanthone that has been reported to have the anticancer properties in some human cancer cell types. However, the antimetastatic effect and molecular mechanism of beta-mangostin action in human hepatocellular carcinoma (HCC) cells remain unknown. In this study, we found that beta-mangostin did not induce cytotoxicity in human HCC cells (SK-Hep-1, Huh-7 and HA22T/VGH cells). beta-mangostin could inhibit migration and invasion of human HCC cells. Meanwhile, beta-mangostin significantly decreased the protein activities and expression of matrix metalloproteinase (MMP)-2 and MMP-9 via increasing the activation of MEK1/2, ERK1/2, MEK4 and JNK1/2 signaling pathways. Furthermore, using specific inhibitor for ERK1/2 (PD98059) and JNK1/2 (JNKII) significantly restored the expression of MMP-2/-9 and invasion by beta-mangostin treatment in Huh-7 cells. In addition, beta-mangostin effectively restored the protein levels and transcription activity of MMP-2 and MMP-9 in siERK or siJNK transfected Huh-7 cells, concomitantly with promotion on cell migration and invasion. Taken together, these findings are the first to demonstrate the antimetastatic activity of beta-mangostin against human HCC cells, which may act as a promising therapeutic agent for the treatment of HCC. PMID- 28722352 TI - Serpine 1 induces alveolar type II cell senescence through activating p53-p21-Rb pathway in fibrotic lung disease. AB - Senescence of alveolar type 2 (ATII) cells, progenitors of the alveolar epithelium, is implicated in the pathogeneses of idiopathic pulmonary fibrosis (IPF), an aging-related progressive fatal lung disorder with unknown etiology. The mechanism underlying ATII cell senescence in fibrotic lung diseases, however, remains poorly understood. In this study, we report that ATII cells in IPF lungs express higher levels of serpine 1, also known as plasminogen activator inhibitor 1 (PAI-1), and cell senescence markers p21 and p16, compared to ATII cells in control lungs. Silencing PAI-1 or inhibition of PAI-1 activity in cultured rat ATII (L2) cells leads to decreases in p53 serine 18 phosphorylation (p53S18P ), p53 and p21 protein expressions; an increase in retinoblastoma protein phosphorylation (ppRb); and a reduction in the sensitivity to bleomycin- and doxorubicin-induced senescence. Silencing p53, on the other hand, abrogates PAI-1 protein-stimulated p21 expression and cell senescence. In vivo studies, using ATII cell-specific PAI-1 conditional knockout mouse model generated recently in this laboratory, further support the role of PAI-1 in the activation of p53-p21 Rb cell cycle repression pathway, ATII cell senescence, and lung fibrosis induced by bleomycin. This study reveals a novel function of PAI-1 in regulation of cell cycle and suggests that elevation of PAI-1 contributes importantly to ATII cell senescence in fibrotic lung diseases. PMID- 28722354 TI - Risk factors for amputation in patients with diabetic foot infection: a prospective study. AB - There is a variety of diagnostic and therapeutic algorithms for diabetic foot infections (DFIs). Some of them are too difficult to be applied in routine clinical approach. In the routine clinical approach, it is necessary to find new risk factors and end up with a quick and easy assessment of DFIs. In this study, we aimed to evaluate the independent risk factors for osteomyelitis, amputation and major amputation in patients with DFI using standard scoring procedures. We prospectively studied 379 patients with DFI. The variables were analysed using logistic analysis. A total of 126 cases (33.2%) underwent amputation. The odds ratios in the amputation model were 3.09 for osteomyelitis (P < 0.001), 4.90 for arterial stenosis (AS) (P < 0.001), 3.67 for the history of DFI (P = 0.001), 2.47 for ulcer duration >60 days (P = 0.001), 3.10 for ulcer depth > 15 mm (P < 0.001) and 10.28 for fungal DFI (P = 0.015). In this study, the unusual result of well known literature was fungal DFI as an independent risk factor for amputation in patients with DFI. PMID- 28722353 TI - Auramine O, an incense smoke ingredient, promotes lung cancer malignancy. AB - Burning incense to worship deities is a popular religious ritual in large parts of Asia, and is a popular custom affecting more than 1.5 billion adherents. Due to incomplete combustion, burning incense has been well recognized to generate airborne hazards to human health. However, the correlation between burning incense and lung cancer in epidemiological studies remains controversy. Therefore, we speculated that some unknown materials in incense smoke are involved in the initiation or progression of lung cancer. Based on this hypothesis, we identified a major compound auramine O (AuO) from the water soluble fraction of incense burned condensate using mass spectrometry. AuO is commonly used in incense manufacture as a colorant. Due to thermostable, AuO released from burned incenses becomes an unexpected air pollutant. AuO is classified as a Group 2B chemical by the International Agency of Research on Cancer (IARC), however, the damage of AuO to the respiratory system remains elusive. Our study revealed that AuO has no apparent effect on malignant transformation; but, it dramatically promotes lung cancer malignancy. AuO accumulates in the nucleus and induces the autophagy activity in lung tumor cells. AuO significantly enhances migration and invasive abilities and the in vitro and in vivo stemness features of lung tumor cells through activating the expression of aldehyde dehydrogenase family 1 member A1 (ALDH1A1), and ALDH1A1 knockdown attenuates AuO-induced autophagy activity and blocks AuO-induced lung tumor malignancy. In conclusion, we found that AuO, an ingredient of incense smoke, significantly increases the metastatic abilities and stemness characters of lung tumor cells through the activation of ALDH1A1, which is known to be associated with poor outcome and progression of lung cancer. For public health, reducing or avoiding the use of AuO in incense is recommended. PMID- 28722355 TI - Selected birth defects among males following the United States terrorist attacks of 11 September 2001. AB - BACKGROUND: The terrorist attacks of 11 September 2001 (hereafter referred to as 9/11) preceded an increase in male fetal deaths and reduced male live births among exposed gestational cohorts across several geographic locations in the United States, including California. We analyze whether the extreme stressor of 9/11 may have selected against frail males in utero by testing if the prevalence of male births with selected defects in California fell among cohorts exposed to the stressor during gestation. METHODS: We used data from the California Birth Defects Monitoring Program from July 1985 to January 2004 (223 conception cohorts). We included six birth defects that as a group of phenotypes disproportionately affect males. We applied time-series methods and defined as "exposed to 9/11" the cohorts conceived in February, March, April, May, June, July, and August 2001. RESULTS: Three of the seven monthly conception cohorts exposed to 9/11 in utero show lower than expected odds of live born males with the studied defects: February 2001 (odds ratio [OR] = 0.39; 95% confidence interval [CI], 0.21-0.71), May 2001 (OR = 0.36; 95% CI, 0.16-0.81), and August 2001 (OR = 0.51; 95% CI, 0.28-0.93). CONCLUSION: The population-wide stressor of 9/11 precedes a reduction in the risk of live born males with selected birth defects. Our analysis contributes to the understanding of adaptation to stress among pregnant women exposed to large and unexpected ambient stressors. Results further support the notion that the prevalence of live born defects may reflect temporal variation in cohort selection in utero against frail males. Birth Defects Research 109:1277-1283, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28722356 TI - Hansen solubility parameters for assay method optimization of simvastatin, ramipril, atenolol, hydrochlorothiazide and aspirin in human plasma using liquid chromatography with tandem mass spectrometry. AB - A simple, specific, sensitive, validated method was developed using liquid chromatography with tandem mass spectrometry with electrospray ionization of human plasma for the simultaneous estimation of drugs (simvastatin, ramipril, atenolol, hydrochlorothiazide, and aspirin) of PolycapTM capsule used in cardiovascular therapy. The interaction of these actives including internal standards between the stationary and mobile phase were investigated using Hansen solubility parameters. Chromatographic separation was performed on Phenomenex Synergi Polar-RP (30 * 2 mm, 4 MUm) column with a gradient mobile phase composition of acetonitrile and 5 mM ammonium formate for positive mode and 0.1% formic acid in both water and acetonitrile for negative mode. The flow rate and runtime were 1.0 mL/min and 3.5 min, respectively. Sample extraction was done by protein precipitation using acetonitrile, enabling a fast analysis. The calibration ranges from 0.1 to 100, 0.1 to 100, and 1 to 1000 ng/mL for simvastatin, ramipril, and atenolol using internal standard carbamazepine in positive mode, respectively, whereas it was 0.3-300 and 2-2000 ng/mL for hydrochlorothiazide and aspirin using internal standard 7-hydroxy coumarin in negative mode, respectively. Hansen solubility parameters can be used as a high throughput optimizing tool for column and mobile phase selection in bioanalysis. This validated bioanalytical method has the potential for future fixed dose combination based preclinical and clinical studies that can save analysis time. PMID- 28722357 TI - Energy Migration Upconversion in Ce(III)-Doped Heterogeneous Core-Shell-Shell Nanoparticles. AB - One major challenge in upconversion research is to develop new materials and structures to expand the emission spectrum. Herein, a heterogeneous core-shell shell nanostructure of NaYbF4 :Gd/Tm@NaGdF4 @CaF2 :Ce is developed to realize efficient photon upconversion in Ce3+ ions through a Gd-mediated energy migration process. The design takes advantage of CaF2 host that reduces the 4f-5d excitation frequency of Ce3+ to match the emission line of Gd3+ . Meanwhile, CaF2 is isostructural with NaGdF4 and can form a continuous crystalline lattice with the core layer. As a result, effective Yb3+ -> Tm3+ -> Gd3+ -> Ce3+ energy transfer can be established in a single nanoparticle. This effect enables efficient ultraviolet emission of Ce3+ following near infrared excitation into the core layer. The Ce3+ upconversion emission achieved in the core-shell-shell nanoparticles features broad bandwidth and long lifetime, which offers exciting opportunities of realizing tunable lasing emissions in the ultraviolet spectral region. PMID- 28722358 TI - Chemoenzymatic Synthesis of Polypeptides for Use as Functional and Structural Materials. AB - Polypeptides inspired by the natural functional and structural proteins present in living systems are promising materials for various fields in terms of their versatile functionality and physical properties. Designing and synthesizing mimetic sequences of specific peptide motifs in proteins are important for exploring the functionality of natural proteins. Chemoenzymatic polymerization, which utilizes aminolysis (i.e., the reverse reaction of hydrolysis catalyzed by proteases), is a useful technique for synthesizing artificial polypeptide materials and has several advantages, including facile synthesis protocols, environmental friendliness, scalability, and atom economy. In this review, recent progress in chemoenzymatic polypeptide synthesis for the production of functional and structural materials for various applications is summarized in conjunction with the current status of technical challenges in the field. PMID- 28722359 TI - A novel allele, HLA-C*14:02:01:03, identified by full-length genomic sequencing. AB - The HLA-C*14:02:01:03 differs by a single nucleotide at intron 5 (2157 C>T) compared with C*14:02:01:01. PMID- 28722360 TI - ? PMID- 28722361 TI - [Food-dependent exercise-induced anaphylaxis : a stepwise diagnosis]. AB - Food-dependent exercise-induced anaphylaxis (FDEIA) is a potentially severe food allergy. Physical exercise, NSAID, alcohol, infectious diseases and estrogens are recognized cofactors, able to reduce the amount of allergen needed to achieve a threshold for the induction of anaphylaxis. Various kinds of causative food but only a few responsible proteins have been identified. The best known is wheat omega5-gliadine. An oral food challenge remains the gold standard to prove the diagnosis. Its clinical application remains difficult and includes an allergen challenge, a cofactor challenge and a third step which integrates both of them in a single test. Gluten flour and NSAID + alcohol combination seem more efficient than respectively wheat flour and physical exercise in a provocation test condition. PMID- 28722362 TI - [Transient hypogammaglobulinemia of infancy]. AB - Transient hypogammaglobulinemia of infancy is characterized as a reduction of one or more classes of immunoglobulins with a response to vaccines and normal subpopulations of lymphocytes B presenting in the first years of life. The diagnosis is made a posteriori, once the levels of immunoglobulins are normalized, in general between 2 and 4 years of age. Clinical presentation varies : the child may be either asymptomatic or present with recurrent infections, atopy and / or auto-immunity. There are no clinical or immunological features that distinguish this condition from a common variable immunodeficiency (CVID). Because of the risk of severe infections, it is necessary a follow up by a paediatric immunologist. Depending on the presentation and evolution, a prophylaxis with antibiotics or a substitution with immunoglobulins might be indicated. PMID- 28722363 TI - [Erdheim-Chester disease : a differential diagnosis of retroperitoneal fibrosis]. AB - Erdheim-Chester disease is a rare multisystemic non-Langerhans histiocytosis with about 500 reported cases. Typical features include retroperitoneal and perirenal fibrosis (hairy kidney), periaortitis with a coated aorta, osteosclerosis of the lower limbs, and sometimes exophthalmia or diabetes insipidus. Histology is the cornerstone for diagnosis showing an infiltrate with foamy histiocytes and occasional multinucleated giant cells (Touton cells). There is no standard treatment regimen, current options include corticosteroids, interferon alpha, systemic chemotherapy, and radiation therapy ; however, a better understanding of the pathophysiological mechanisms has allowed the emergence of novel targeted treatments such as vemurafenib, imatinib, and anakinra. PMID- 28722364 TI - [Allergy to human seminal plasma]. AB - Hypersensitivity to human seminal plasma is rare, but probably under-diagnosed. It should be suspected in women with unexplained anaphylaxis, vulvo-vaginitis, pelvic pain and dyspareunia. The diagnosis relies on the clinical presentation, the exclusion of other causes, a positive skin test result to seminal plasma and the detection of IgE directed to allergenic proteins (such as prostate specific antigen). Use of condoms is the best preventive measure. Premedication with antihistamines or anti-inflammatory agents is often unreliable. Some patients may benefit from intra-vaginal or subcutaneous desensitization procedures to seminal plasma, which then require to measures to uphold tolerance. In case of pregnancy wish, artificial insemination or in-vitro fertilization with spermatozoids is an alternative to desensitization. PMID- 28722365 TI - [Segmental arterial mediolysis : a differential diagnosis of vasculitis]. AB - Segmental arterial mediolysis (SAM) is a rare non-atherosclerotic, non inflammatory disease of unknown aetiology mostly affecting medium-sized arteries of the splanchnic circulation. Histologically, SAM is characterized by vacuolization and lysis of the arterial media leading to dissection, stenosis/occlusion or aneurysms. Symptoms vary from unspecific abdominal pain to hemorrhagic shock due to vessel rupture. The clinical and radiological presentation can mimic vasculitis, fibromuscular dysplasia or collagen vascular diseases. SAM is often self-limited and may be managed conservatively with adequate blood pressure control in the majority of cases. However, if arterial dissections or aneurysmal ruptures are present, endovascular or surgical treatment should be considered urgently. PMID- 28722366 TI - [Large vessel vasculitis : pathogenesis, diagnostic and medical management]. AB - Large vessels vasculitis includes two diseases : 1) giant cell arteritis, formerly known as Horton's arteritis and 2) Takayasu arteritis. In this article, we will describe and compare the epidemiology, pathogenesis, diagnostic criteria and medical management of both vasculitis. T helper (Th) 1 and Th17 responses, genetic links and the role of viral (varicella zoster) and bacterial infection (Mycoplasma pneumoniae or Chlamydia pneumoniae) will be discussed. Classification criteria, inflammation biomarkers and progress in imaging tools will also be described. Finally, we will review the medical management including corticosteroids, aspirin and biologicals. PMID- 28722367 TI - [Next generation sequencing : a diagnostic tool for inherited immune defects]. AB - Establishing the definitive diagnosis in the case of inherited immune defects (IID) is often challenging because the clinical features can be heterogeneous, atypical and overlapping different disease entities. The next generation sequencing technology (NGS) allows identifying genetic variants that are responsible for the observed clinical presentations. The use of NGS applied to the genes mutated in IIDs or known to be involved in the development, differentiation and regulation of the immune system allows to target hundreds of relevant genes in well characterized patients suspected of carrying inherited immune defects. This approach answers both diagnostic and research needs, facilitates the understanding of the mechanisms that underlie IIDs, and ultimately leads to the discovery of new therapeutic targets. PMID- 28722368 TI - ? PMID- 28722369 TI - ? PMID- 28722370 TI - ? PMID- 28722371 TI - ? PMID- 28722372 TI - ? PMID- 28722373 TI - ? PMID- 28722374 TI - ? PMID- 28722375 TI - ? PMID- 28722376 TI - ? PMID- 28722377 TI - [Sweet's syndrome, a diagnosis to keep in mind]. AB - Sweet's syndrome is a rare neutrophilic dermatosis. Typically, patients present with a sudden onset of tender erythematous skin lesions (papules, nodules, and plaques), of asymetrical distribution, located preferentially on the superior limbs, face and neck, associated whith high fever and neutrophilia. Histologicaly, there is a diffuse infiltrate of neutrophils located in the dermis. Most of the time idiopathic, it may be associated with a respiratory or gastro-intestinal infection, with inflammatory bowel disease, pregnancy and vaccination. A drug-induced form and a malignancy-associated form have been described. Based on illustrations and two clinical cases, we wish to focus on the diagnostic strategy and the management of this disease. PMID- 28722378 TI - [A new vision of skin]. AB - As of today, the skin will never look the same. Indeed, several technologies allowing the observation of the skin at a microscopic level are now coming of age. This magnifies our visual acuity and thus our capacity to recognize various pathological processes. We herein present three different methods of non-invasive skin imaging we have worked with at the CHUV, which revolutionize the practice of dermatology. In vivo confocal microscopy, ex-vivo confocal microscopy and optical coherence tomography are complementary techniques that are now becoming essential for the modern management of skin cancers, among other uses. PMID- 28722379 TI - [Nail changes : diagnostic considerations in everyday medical general practice]. AB - Consultations for nail changes are frequent in everyday practice with direct diagnostic considerations into different directions, traumatism, infection, inflammation being the most common ones, and neoplasia being less frequent. The most common symptom is ungual dystrophia ; that is an alteration or perturbation of ungual growth. It presents differently depending on nature or length of the underlying pathologia. The purpose of this article is to highlight some ungual disorders to help the general practitioner to identify and refer them to the specialist if necessary. PMID- 28722380 TI - [Algorithm to facilitate the management of onychomycosis]. AB - An algorithm is proposed to facilitate the management of onychomycosis and ensure a good therapeutical approach. Its aim is to simplify the diagnosis process by integrating a pertinent anamnesis and physical examination with the classic tool of mycology (direct examination, culture, eventually examination by PCR), in order to give the adequate targeted treatment. PMID- 28722381 TI - [Revision of the dermatophyte species and the nomenclature of these fungi]. AB - Dermatophyte species identification often remains difficult because variation of isolates in the same species, overlapping characters in cultures and problems of nomenclature. DNA sequencing recently allowed the genus and species of these fungi to be reexamined. Species names were revised according to the new nomenclature convention adopted for fungi. The conclusions of this taxonomic study were approved by expert practitioners and searchers working with dermatophytes. Important points about species definition and nomenclature changes were summarized in the present communication. PMID- 28722382 TI - [Evaluation and management of hyperhidrosis]. AB - Hyperhidrosis is excessive sweating beyond what is expected for thermoregulatory needs. Nearly 3 % of the population has hyperhidrosis. It may be primary or secondary to medications or general medical conditions, including diabetes mellitus, hyperthyroidism, Parkinson disease, etc. History taking and clinical examination are essential to differentiate primary from secondary origins. Blood tests and a consultation with a specialist (endocrinologist, neurologist) is sometimes necessary to establish the diagnosis. The management of secondary hyperhidrosis involves the treatment of the underlying cause. For primary hyperhidrosis, it depends on its severity and the sites affected. This article will review the treatments for primary hyperhidrosis. PMID- 28722383 TI - ? PMID- 28722384 TI - ? PMID- 28722385 TI - ? PMID- 28722386 TI - ? PMID- 28722387 TI - ? PMID- 28722388 TI - ? PMID- 28722389 TI - ? PMID- 28722390 TI - ? PMID- 28722391 TI - [Adverse events related to medication in hospitals from the Valencian Community. EPIDEA Study 2005-2013]. AB - OBJECTIVE: To determine the prevalence of Adverse Events related to Medication (AEM) in hospitals of the Valencian Community in the 2005-2013 study period, and to describe the associated risk factors and their impact. METHODS: This study is based on data and methodology of the Study of Prevalence of Adverse Events in hospitals (EPIDEA), since its inception in 2005 until 2013. AEM produced in each year were analyzed. RESULTS: We identified 344 AEM that occurred in 337 patients, among 35,103 patients studied, giving a prevalence of patients with AEM of 0.96% (IC95% 0.89-1.07). The most prevalent intrinsic risk factors for AEM were hypertension, diabetes and cancer. The most prevalent extrinsic risk factors were peripheral venous catheter, urinary catheter and central venous catheter. Therapeutic groups most frequently involved were systemic antibiotics, cardiovascular drugs and antineoplastics. The 61.17% of AEM was classified as moderate, followed by 27.18% as mild and 11.65% as severe. The 33.99% of EAM caused increase of the patient's stay and 39.90% of EAM caused the re-entry of patient. The 58.5% of AEM were avoidable. Mild AEM were avoidable in 46.3%, moderate AEM were avoidable in 60.3% and severe AEM were in 75% (p = 0.013). CONCLUSIONS: The prevalence of patients with AEM in hospitals of the Community of Valencia for the period 2005- 2013 was 0.96%. More than half of AEM were preventable, and preventability increases significantly with the severity of the event. PMID- 28722392 TI - Self-Assembled Curved Macroporous Photonic Crystal-Based Surfactant Detectors. AB - Surfactants are extensively used as detergents, dispersants, and emulsifiers. Thus, wastewater containing high-concentration surfactants discharged to the environment pose a serious threat to the ecosystem. Unfortunately, conventional detection methods for surfactants suffer from the use of sophisticated instruments and cannot perform detections for various surfactants by a single analysis. The article reports the development of simple and sensitive surfactant detection using doctor-blade-coated three-dimensional curved macroporous photonic crystals on a cylindrical rod. The photonic crystals exhibit different hydrophobicities at various angular positions after surface modification. The penetration of aqueous surfactant solutions in the interconnected macropores causes red-shift as well as reduction in amplitude in the optical stop bands, resulting in surfactant detection with visible readout. The correlation between the surface tension, as well as the solution-infiltrated angular position, and the concentration of aqueous surfactant solutions has also been investigated in this study. PMID- 28722393 TI - Multiligand Metal-Phenolic Assembly from Green Tea Infusions. AB - The synthesis of hybrid functional materials using the coordination-driven assembly of metal-phenolic networks (MPNs) is of interest in diverse areas of materials science. To date, MPN assembly has been explored as monoligand systems (i.e., containing a single type of phenolic ligand) where the phenolic components are primarily obtained from natural sources via extraction, isolation, and purification processes. Herein, we demonstrate the fabrication of MPNs from a readily available, crude phenolic source-green tea (GT) infusions. We employ our recently introduced rust-mediated continuous assembly strategy to prepare these GT MPN systems. The resulting hollow MPN capsules contain multiple phenolic ligands and have a shell thickness that can be controlled through the reaction time. These multiligand MPN systems have different properties compared to the analogous MPN systems reported previously. For example, the Young's modulus (as determined using colloidal-probe atomic force microscopy) of the GT MPN system presented herein is less than half that of MPN systems prepared using tannic acid and iron salt solutions, and the disassembly kinetics are faster (~50%) than other, comparable MPN systems under identical disassembly conditions. Additionally, the use of rust-mediated assembly enables the formation of stable capsules under conditions where the conventional approach (i.e., using iron salt solutions) results in colloidally unstable dispersions. These differences highlight how the choice of phenolic ligand and its source, as well as the assembly protocol (e.g., using solution-based or solid-state iron sources), can be used to tune the properties of MPNs. The strategy presented herein expands the toolbox of MPN assembly while also providing new insights into the nature and robustness of metal-phenolic interfacial assembly when using solution-based or solid-state metal sources. PMID- 28722394 TI - Direct Electrospray Printing of Gradient Refractive Index Chalcogenide Glass Films. AB - A spatially varying effective refractive index gradient using chalcogenide glass layers is printed on a silicon wafer using an optimized electrospray (ES) deposition process. Using solution-derived glass precursors, IR-transparent Ge23Sb7S70 and As40S60 glass films of programmed thickness are fabricated to yield a bilayer structure, resulting in an effective gradient refractive index (GRIN) film. Optical and compositional analysis tools confirm the optical and physical nature of the gradient in the resulting high-optical-quality films, demonstrating the power of direct printing of multimaterial structures compatible with planar photonic fabrication protocols. The potential application of such tailorable materials and structures as they relate to the enhancement of sensitivity in chalcogenide glass based planar chemical sensor device design is presented. This method, applicable to a broad cross section of glass compositions, shows promise in directly depositing GRIN films with tunable refractive index profiles for bulk and planar optical components and devices. PMID- 28722395 TI - Salt Removal from Microliter Sample Volumes by Multiple Phase Microelectromembrane Extractions Across Free Liquid Membranes. AB - A new concept for rapid and efficient salt removal from minute volumes of saline samples is presented by using multiple phase microelectromembrane extraction (MU EME). A disposable MU-EME unit is filled with five consecutive plugs of immiscible aqueous and organic solutions; the aqueous sample forms the central phase and is encompassed by two free liquid membranes (FLMs) and two extraction solutions. Salt cations and anions migrate in opposite directions from the sample solution on application of 300 V dc electric potential, cross the neighboring FLM, and are transferred to the corresponding extraction solution. At the same time, the two FLMs selectively eliminate MU-EME transfers of target analytes, which are retained in the sample, and the resulting salt-free sample is then used for subsequent analysis. At optimized conditions (FLMs consisted of 1-pentanol and extraction solutions of deionized water and 100 mM NH4OH), more than 99.3% NaCl was removed from samples containing physiological NaCl concentrations. Simultaneously, more than 95% of model biochemical species (human serum albumin, neurotensin, creatinine, glycine, and alanine) were retained in the samples for subsequent analyses. Good quality capillary electrophoresis with capacitively coupled contactless conductivity detection (CE-C4D) electropherograms and interference-free electrospray ionization mass spectrometry (ESI-MS) spectra of selected biochemical species were obtained after MU-EME salt removal from samples containing micromolar concentrations of the target analytes and 150 mM of NaCl. PMID- 28722396 TI - Novel Ceramic-Grafted Separator with Highly Thermal Stability for Safe Lithium Ion Batteries. AB - The separator is a critical component of lithium-ion batteries (LIBs), which not only allows ionic transport while it prevents electrical contact between electrodes but also plays a key role for thermal safety performance of LIBs. However, commercial separators for LIBs are typically microporous polyolefin membranes that pose challenges for battery safety, due to shrinking and melting at elevated temperature. Here, we demonstrate a strategy to improve the thermal stability and electrolyte affinity of polyethylene (PE) separators. By simply grafting the vinylsilane coupling reagent on the surface of the PE separator by electron beam irradiation method and subsequent hydrolysis reaction into the Al3+ solution, an ultrathin Al2O3 layer is grafted on the surface of the porous polymer microframework without sacrificing the porous structure and increasing the thickness. The as-synthesized Al2O3 ceramic-grafted separator (Al2O3-CGS) shows almost no shrinkage at 150 degrees C and decreases the contact angle of the conventional electrolyte compared with the bare PE separator. Notably, the full cells with the Al2O3-CGSs exhibit better cycling performance and rate capability and also provide stable open circuit voltage even at 170 degrees C, indicating its promising application in LIBs with high safety and energy density. PMID- 28722397 TI - Nanoflakes of Ni-Co LDH and Bi2O3 Assembled in 3D Carbon Fiber Network for High Performance Aqueous Rechargeable Ni/Bi Battery. AB - For aqueous nickel/metal batteries, low energy density and poor rate properties are among the limiting factors for their applications, although they are the energy storage systems with high safety, high capacity, and low production cost. Here, we have developed a class of active materials consisting of porous nanoflakes of Ni-Co hydroxides and Bi2O3 that are successfully assembled on carbon substrates of carbon cloth/carbon nanofiber 3D network (CC/CNF). The combination of the porous Ni-Co hydroxides/Bi2O3 nanoflakes with carbon substrate of 3D network is able to provide a large surface area, excellent conductivity, and promote synergistic effects, as a result of the interaction between the active materials and the carbon matrix. With the porous Ni-Co hydroxides and Bi2O3 nanoflakes, the Ni/Bi battery can deliver a high capacity of ~110 mA h g-1 at a current density of 2 A g-1. About 80% of its capacity (85 mA h g-1) can be retained when the current density increases to 20 A g-1. The full cell can also maintain 93% of the initial capacity after 1000 charge/discharge cycles, showing great potential for Ni/Bi battery. PMID- 28722398 TI - Fractionation and Concentration of High-Salinity Textile Wastewater using an Ultra-Permeable Sulfonated Thin-film Composite. AB - A sulfonated thin-film composite (TFC) nanofiltration membrane was fabricated using 2,2'-benzidinedisulfonic acid (BDSA) and trimesoyl chloride (TMC) on a polyether sulfone substrate by conventional interfacial polymerization. Due to a nascent barrier layer with a loose architecture, the obtained TFC-BDSA-0.2 membrane showed an ultrahigh pure water permeability of 48.1 +/- 2.1 L-1 m-2 h-1 bar-1, and a considerably low NaCl retention ability of <1.8% over a concentration range of 10-100 g L-1. The membrane, which possesses a negatively charged surface, displayed an excellent rejection of over 99% toward Congo red (CR) and allowed the fast fractionation of high-salinity textile wastewater. The prepared membrane required only 3-fold water addition to accomplish the separation of multiple components, whereas the commercial NF270 (Dow) membrane required 4-fold water addition and almost double the length of time. Furthermore, the TFC-BDSA-0.2 membrane was subsequently tested for the dye concentration process. It maintained a high flux of 8.2 L-1 m-2 h-1 bar-1 and a negligible dye loss, even when the concentration factor reached ~10. Finally, by using a 20% alcohol solution as a back-washing medium, a flux recovery ratio (FRR) of 95.6% was achieved with TFC-BDSA-0.2, and the CR rejection ability remained the same. These results prove the outstanding antifouling and solvent-resistant properties of the membrane. PMID- 28722400 TI - Experimental Measurements and Surface Complexation Modeling of U(VI) Adsorption onto Multilayered Graphene Oxide: The Importance of Adsorbate-Adsorbent Ratios. AB - Surface complexation models use experimental adsorption measurements to calculate stability constants that quantify the thermodynamic stability of adsorbed species. However, these constants are often poorly constrained due to nearly complete removal of the solute from solution and/or because the tested adsorbate:adsorbent ratios are not varied sufficiently. Using data sets that quantify the adsorption of U(VI) to multilayered graphene oxide (MLGO), we tested whether three different U(VI):MLGO ratios (3 ppm U; 20-210 mg L-1 MLGO) affect the ability of nonelectrostatic and diffuse layer models to predict U(VI) adsorption behaviors across a range of ionic strength (1-100 mM) and pH (2-9.5) conditions. Model formulations assumed interactions between discrete MLGO surfaces sites and the most abundant aqueous U(VI) complex(es) within a given pH range. We determined that the observed extents of U(VI) binding require adsorption of more than one U(VI) species (UO22+ and uranyl hydroxide(s) and/or carbonate(s)) and calculated the respective stability constants for the important U(VI)-MLGO surface complexes. The results also unequivocally illustrated that models using adsorption data from treatments with higher U(VI):MLGO ratios provide better fits throughout the tested range of experimental conditions, meaning that the U(VI)-MLGO stability constants calculated herein can be confidently applied to a range of natural or engineered systems. PMID- 28722399 TI - Bias-Free Chemically Diverse Test Sets from Machine Learning. AB - Current benchmarking methods in quantum chemistry rely on databases that are built using a chemist's intuition. It is not fully understood how diverse or representative these databases truly are. Multivariate statistical techniques like archetypal analysis and K-means clustering have previously been used to summarize large sets of nanoparticles however molecules are more diverse and not as easily characterized by descriptors. In this work, we compare three sets of descriptors based on the one-, two-, and three-dimensional structure of a molecule. Using data from the NIST Computational Chemistry Comparison and Benchmark Database and machine learning techniques, we demonstrate the functional relationship between these structural descriptors and the electronic energy of molecules. Archetypes and prototypes found with topological or Coulomb matrix descriptors can be used to identify smaller, statistically significant test sets that better capture the diversity of chemical space. We apply this same method to find a diverse subset of organic molecules to demonstrate how the methods can easily be reapplied to individual research projects. Finally, we use our bias free test sets to assess the performance of density functional theory and quantum Monte Carlo methods. PMID- 28722401 TI - Novel Xanthate Complexes for the Size-Controlled Synthesis of Copper Sulfide Nanorods. AB - We present a simple, easily scalable route to monodisperse copper sulfide nanocrystals by the hot injection of a series of novel copper(I) xanthate single source precursors [(PPh3)2Cu(S2COR)] (R = isobutyl, 2-methoxyethyl, 2 ethoxyethyl, 1-methoxy-2-propyl, 3-methoxy-1-butyl, and 3-methoxy-3-methyl-1 butyl), whose crystal structures are also reported. We show that the width of the obtained rods is dependent on the length of the xanthate chain, which we rationalize through a computational study, where we show that there is a relationship between the ground-state energy of the precursor and the copper sulfide rod width. PMID- 28722402 TI - Layered Noble Metal Dichalcogenides: Tailoring Electrochemical and Catalytic Properties. AB - Owing to the anisotropic nature, layered transition metal dichalcogenides (TMDs) have captured tremendous attention for their promising uses in a plethora of applications. Currently, bulk of the research is centered on Group 6 TMDs. Layered noble metal dichalcogenides, in particular the noble metal tellurides, belong to a subset of Group 10 TMDs, wherein the transition metal is a noble metal of either palladium or platinum. We address here a lack of contemporary knowledge on these compounds by providing a comprehensive study on the electrochemistry of layered noble metal tellurides, PdTe2 and PtTe2, and their efficiency as electrocatalysts toward the hydrogen evolution reaction (HER). Observed parallels in the electrochemical peaks of the noble metal tellurides are traced to the tellurium electrochemistry. PdTe2 and PtTe2 can be discriminated by their distinct reduction peaks in the first cathodic scans. Considering the influence of the metal component, PtTe2 outperforms PdTe2 in aspects of charge transfer and electrocatalysis. The heterogeneous electron transfer (HET) rate of PtTe2 is an order of magnitude faster than PdTe2, and a lower HER overpotential of 0.54 V versus reversible hydrogen electrode (RHE) at a current density of -10 mA cm-2 is evident in PtTe2. On PdTe2 and PtTe2 surfaces, adsorption via the Volmer process has been identified as the limiting step for HER. A general phenomenon for the noble metal tellurides is that faster HET rates are observed upon electrochemical reductive pretreatment, whereas slower HET rates occur when the noble metal tellurides are oxidized during pretreatment. PtTe2 becomes successfully activated for HER when subject to oxidative treatment, whereas oxidized or reduced PdTe2 shows a deactivated HER performance. These findings provide fundamental insights that are pivotal to advancing the field of the underemphasized TMDs. Furthermore, electrochemical tuning as a means to tailor specific properties of the TMDs is advantageous for the development of their future applications. PMID- 28722403 TI - Wrinkled Few-Layer Graphene as Highly Efficient Load Bearer. AB - Multilayered graphitic materials are not suitable as load-bearers due to their inherent weak interlayer bonding (for example, graphite is a solid lubricant in certain applications). This situation is largely improved when two-dimensional (2D) materials such as a monolayer (SLG) graphene are employed. The downside in these cases is the presence of thermally or mechanically induced wrinkles which are ubiquitous in 2D materials. Here we set out to examine the effect of extensive large wavelength/amplitude wrinkling on the stress transfer capabilities of exfoliated simply supported graphene flakes. Contrary to common belief we present clear evidence that this type of "corrugation" enhances the load-bearing capacity of few-layer graphene as compared to "flat" specimens. This effect is the result of the significant increase of the graphene/polymer interfacial shear stress per increment of applied strain due to wrinkling and paves the way for designing affordable graphene composites with highly improved stress-transfer efficiency. PMID- 28722404 TI - High-Performance Colorimetric Detection of Thiosulfate by Using Silver Nanoparticles for Smartphone-Based Analysis. AB - Developing thiosulfate (S2O32-) sensors with silver nanoparticles (AgNPs) for analysis of aqueous solutions with the interference of other anions remains challenging. In this study, we propose a new strategy for excellent selective colorimetric detection of S2O32-. The nonmorphological transition of AgNPs leading to a color change from yellow to brown is verified by UV-vis, TEM, DLS, SEM, and XPS analyses. The sensor exhibits high sensitivity with detection limits of 1.0 MUM by naked-eye determination and 0.2 MUM by UV-vis spectroscopy analysis. The linear relationship (R2 = 0.998) between the (A0 - A)/A0 values and S2O32- concentrations from 0.2 MUM to 2.0 MUM indicates that the fabricated AgNPs based colorimetric sensor can be employed for quantitative assay of S2O32-. Colorimetric responses are also monitored using the built-in camera of a smartphone. The sensor shows a linear response to S2O32- in 0-20.0 MUM solutions under the optimized conditions and is thus more suitable for rapid on-site tests than other detection methods. A smartphone application (app) is downloaded under Android or IOS platforms to measure the RGB (red, green, blue) values of the colorimetric sensor after exposure to the analyte. Following data processing, the RGB values are converted into concentration values by using preloaded calibration curves. Confirmatory analysis indicates that the proposed S2O32- colorimetric sensor exhibits feasibility and sensitivity for S2O32- detection in real environmental samples. PMID- 28722405 TI - Effective Approach to Promoting the Proton Conductivity of Metal-Organic Frameworks by Exposure to Aqua-Ammonia Vapor. AB - We explored the proton conductivities of two 3D CoII metal-organic frameworks (MOFs), {[Co3(m-ClPhIDC)2(H2O)6].2H2O}n [1; m-ClPhH3IDC = 2-(m chlorophenyl)imidazole-4,5-dicarboxylic acid] and {[Co3(p ClPhHIDC)3(H2O)3].6H2O}n (2; p-ClPhH3IDC = 2-(p-chlorophenyl)imidazole-4,5 dicarboxylic acid), under water and aqua-ammonia vapors, respectively. The experimental results revealed that the proton conductivities of 1 and 2 at aqua ammonia vapor were 2.89 * 10-2 and 4.25 * 10-2 S/cm, respectively, and approximately 2 orders of magnitude greater than those at water vapor. On the basis of the activation energy, water and ammonia vapor absorption, and powder X ray diffraction patterns, their proton-conduction mechanisms have been discussed. We believe that this is a novel approach to drastically improving the proton conductivity of MOFs. PMID- 28722406 TI - Possible Molecular Mechanisms by Which an Essential Oil Blend from Star Anise, Rosemary, Thyme, and Oregano and Saponins Increase the Performance and Ileal Protein Digestibility of Growing Broilers. AB - Phytogenic feed additives represent a potential alternative to antibiotics with attributed health and growth-promoting effects. Chickens supplemented with an essential oil blend, a Quillaja saponin blend, or a combination of both phytogenic preparations showed a comprehensively and significantly improved apparent ileal digestibility of crude protein and amino acids compared to control birds. Accordingly, holistic transcriptomic analyses of jejunum and liver samples indicated alterations of macromolecule transporters and processing pathways likely culminating in an increased uptake and metabolizing of carbohydrates and fatty acids. Complementary analyses in Caco-2 showed a significant increase in transporter recruitment to the membrane (SGLT1 and PEPT1) after addition of essential oils and saponins. Although the penetrance of effects differed for the used phytogenic feed additives, the results indicate for an overlapping mode of action including local effects at the intestinal border and systemic alterations of macronutrient metabolism resulting in an improved performance of broilers. PMID- 28722407 TI - Quantum Chemical Study of CH3 + O2 Combustion Reaction System: Catalytic Effects of Additional CO2 Molecule. AB - The supercritical carbon dioxide diluent is used to control the temperature and to increase the efficiency in oxycombustion fossil fuel energy technology. It may affect the rates of combustion by altering mechanisms of chemical reactions, compared to the ones at low CO2 concentrations. Here, we investigate potential energy surfaces of the four elementary reactions in the CH3 + O2 reactive system in the presence of one CO2 molecule. In the case of reaction CH3 + O2 -> CH2O + OH (R1 channel), van der Waals (vdW) complex formation stabilizes the transition state and reduces the activation barrier by ~2.2 kcal/mol. Alternatively, covalently bonded CO2 may form a six-membered ring transition state and reduce the activation barrier by ~0.6 kcal/mol. In case of reaction CH3 + O2 -> CH3O + O (R2 channel), covalent participation of CO2 lowers the barrier for the rate limiting step by 3.9 kcal/mol. This is expected to accelerate the R2 process, important for the branching step of the radical chain reaction mechanism. For the reaction CH3 + O2 -> CHO + H2O (R3 channel) with covalent participation of CO2, the activation barrier is lowered by 0.5 kcal/mol. The reaction CH2O + OH -> CHO + H2O (R4 channel) involves hydrogen abstraction from formaldehyde by OH radical. Its barrier is reduced from 7.1 to 0.8 kcal/mol by formation of vdW complex with spectator CO2. These new findings are expected to improve the kinetic reaction mechanism describing combustion processes in supercritical CO2 medium. PMID- 28722409 TI - Conformational Landscape of Tri-n-butyl Phosphate: Matrix Isolation Infrared Spectroscopy and Systematic Computational Analysis. AB - The conformations of tri-n-butyl phosphate (TBP) were studied using matrix isolation infrared spectroscopy and density functional theory (DFT) calculations. TBP was trapped in a N2 matrix using both effusive and supersonic sources, and its infrared spectra were recorded. The computational exploration of TBP is a very demanding problem to confront, due to the presence of a large multitude of conformations in TBP. To simplify the problem, computations were done on model compounds, dimethyl butyl phosphate (DMBP) and dibutyl methyl phosphate (DBMP), to systematically arrive at the conformations of TBP that are expected to contribute to its chemistry at room temperature. Some predictive rules seem to simplify this complex conformational landscape problem. The predictive rules that were formulated enabled us to search the relevant portion of the conformational topography of this molecule. The computations were performed at the B3LYP level of theory using the 6-31++G(d,p) basis set. Vibrational wavenumber calculations were also performed for the various conformers to assign the infrared features of TBP, trapped in solid N2 matrix. PMID- 28722408 TI - Formally Copper(III)-Alkylperoxo Complexes as Models of Possible Intermediates in Monooxygenase Enzymes. AB - Reaction of [NBu4][LCuIIOH] with excess ROOH (R = cumyl or tBu) yielded [NBu4][LCuIIOOR], the reversible one-electron oxidation of which generated novel species with [CuOOR]2+ cores (formally CuIIIOOR), identified by spectroscopy and theory for the case R = cumyl. This species reacts with weak O-H bonds in TEMPO-H and 4-dimethylaminophenol (NMe2PhOH), the latter yielding LCu(OPhNMe2), which was also prepared independently. With the identification of [CuOOR]2+ complexes, the first precedent for this core in enzymes is provided, with implications for copper monooxygenase mechanisms. PMID- 28722410 TI - General Effect of van der Waals Interactions on the Stability of Alkoxy Intermediates on Metal Surfaces. AB - The critical role of noncovalent van der Waals (vdW) interactions in determining the relative thermodynamic stability of alkoxy intermediates has been demonstrated for the Cu(110) surface using a combination of experiment and theory. The results may be significant for the selectivity control of copper based reactions of alcohols. Previous examination of this effect on Au(110) was also extended to include higher molecular weight alcohols; on Cu(110) and Au(110) the hierarchy for the strength of binding of the alkoxys was found to be the same within experimental accuracy, with alkoxy species of greater chain length being more stable. The equilibrium constants governing the competition of alcohol pairs for binding sites of the alkoxys are also similar on the two surfaces. These results reveal the generality of such vdW effects. This work expands the understanding of the role of vdW interactions on the binding efficacy of key reactive intermediates on metal surfaces, a key factor in the rational design of complex and selective catalytic processes. PMID- 28722411 TI - Pathways in the Degradation of Geminal Diazides. AB - The degradation of geminal diazides is described. We show that diazido acetates are converted into tetrazoles through the treatment with bases. The reaction of dichloro ketones with azide anions provides acyl azides, through in situ formation of diazido ketones. We present experimental and theoretical evidence that both fragmentations may involve the generation of acyl cyanide intermediates. The controlled degradation of terminal alkynes into amides (by loss of one carbon) or ureas (by loss of two carbons) is also shown. PMID- 28722412 TI - Rh-Catalyzed Regioselective ortho-C-H Carbenoid Insertion of Diarylazines. AB - The Rh-catalyzed ortho-C-H carbenoid insertion reaction of diarylazines with diazo compounds has been developed. A wide range of ortho-substituted diarylazines have been obtained in moderate to high yields with high regioselectivity at room temperature. The hydrolysis of the products could release ketones or aldehydes, giving access to aromatic 1,5-keto-diesters as valuable synthons for further chemical transformations. PMID- 28722413 TI - Total Synthesis of the Cyclic Carbonate-Containing Natural Product Aspergillusol B from d-(-)-Tartaric Acid. AB - A total synthesis of compound 3 from d-(-)-tartaric acid is reported, thereby establishing that the structure, including relative stereochemistry, originally assigned to the cyclic carbonate-containing natural product aspergillusol B is correct. PMID- 28722414 TI - Mushroom-Derived Indole Alkaloids. AB - Mushrooms are known to produce over 140 natural products bearing an indole heterocycle. In this review, the isolation of these mushroom-derived indole alkaloids is discussed, along with their associated biological activities. PMID- 28722415 TI - Dramatic Modification of Coupled-Plasmon Resonances Following Exposure to Electron Beams. AB - Studies of the plasmon resonances in individual and coupled metal nanoparticles often involve imaging of the nanostructures of interest in an electron microscope. We show that this process can dramatically modify the optical spectra of coupled plasmonic nanoparticles, illustrated here with the case of gold nanorod-nanosphere dimers. The spectral changes are due to the thin, partially conductive carbonaceous layer that deposits onto the particles during imaging. These changes are particularly significant for coupled nanoparticles with subnanometer interparticle gaps but have largely been neglected in previous studies of such structures, including studies intended to probe quantum mechanical effects in plasmon coupling. Accounting for the effects of the carbonaceous layer will lead to a more accurate understanding of such systems. PMID- 28722416 TI - Character of Localization and Microenvironment of Solvatochromic Reichardt's Betaine Dye in Sodium n-Dodecyl Sulfate and Cetyltrimethylammonium Bromide Micelles: Molecular Dynamics Simulation Study. AB - The problem of using surfactant micellar aqueous solutions as reaction media centers on estimating the polarity of the micellar pseudophase. The most popular approach is the utilization of solvatochromic dyes. Among the last, the strongest ones are the dipolar pyridinium N-phenolate dyes. The complication of such approach, however, consists in the nonuniform character of the environment of the indicator fixed in the micellar pseudophase. The aim of this study is to reveal the character of localization and orientation of the standard solvatochromic pyridinium N-phenolate dye, 4-(2,4,6-triphenylpyridinium-1-yl)-2,6 diphenylphenolate, the so-called Reichardt's dye, within the micellar pseudophase of an anionic (sodium n-dodecyl sulfate, SDS) and cationic (cetyltrimethylammonium bromide, CTAB) surfactants using MD simulations. The locus and hydration of the dye are found to be dependent on the surfactant nature. New approaches are proposed to quantitatively describe the state of the dye within the pseudophase. The results confirm the experimental data, which indicate the higher polarity of the interfacial region in the case of the SDS micelles. Because this dye is also used as an interfacial acid-base probe, the corresponding study is simultaneously performed for its protonated, i.e., cationic form. The neutral and protonated forms of the dye are found to be localized and hydrated in a different way in both SDS and CTAB micelles. This should be taken into account when using the Reichardt's dye as an acid-base indicator for estimating the electrical surface potential of micelles. The presented approach may be recommended to shed light upon the locus of other solvatochromic and acid-base indicators in micelles and micellar-like aggregates. PMID- 28722417 TI - Improving the Carrier Lifetime of Tin Sulfide via Prediction and Mitigation of Harmful Point Defects. AB - Tin monosulfide (SnS) is an emerging thin-film absorber material for photovoltaics. An outstanding challenge is to improve carrier lifetimes to >1 ns, which should enable >10% device efficiencies. However, reported results to date have only demonstrated lifetimes at or below 100 ps. In this study, we employ defect modeling to identify the sulfur vacancy and defects from Fe, Co, and Mo as most recombination-active. We attempt to minimize these defects in crystalline samples through high-purity, sulfur-rich growth and experimentally improve lifetimes to >3 ns, thus achieving our 1 ns goal. This framework may prove effective for unlocking the lifetime potential in other emerging thin-film materials by rapidly identifying and mitigating lifetime-limiting point defects. PMID- 28722418 TI - Urine Metabonomics Reveals Early Biomarkers in Diabetic Cognitive Dysfunction. AB - Recently, increasing attention has been paid to diabetic encephalopathy, which is a frequent diabetic complication and affects nearly 30% of diabetics. Because cognitive dysfunction from diabetic encephalopathy might develop into irreversible dementia, early diagnosis and detection of this disease is of great significance for its prevention and treatment. This study is to investigate the early specific metabolites biomarkers in urine prior to the onset of diabetic cognitive dysfunction (DCD) by using metabolomics technology. An ultra-high performance liquid-chromatography-quadrupole time-of-flight-mass spectrometry (UPLC-Q/TOF-MS) platform was used to analyze the urine samples from diabetic mice that were associated with mild cognitive impairment (MCI) and nonassociated with MCI in the stage of diabetes (prior to the onset of DCD). We then screened and validated the early biomarkers using OPLS-DA model and support vector machine (SVM) method. Following multivariate statistical and integration analysis, we found that seven metabolites could be accepted as early biomarkers of DCD, and the SVM results showed that the prediction accuracy is as high as 91.66%. The identities of four biomarkers were determined by mass spectrometry. The identified biomarkers were largely involved in nicotinate and nicotinamide metabolism, glutathione metabolism, tryptophan metabolism, and sphingolipid metabolism. The present study first revealed reliable biomarkers for early diagnosis of DCD. It provides new insight and strategy for the early diagnosis and treatment of DCD. PMID- 28722419 TI - Dynamical Ordering of Hydrogen Molecules Induced by Heat Flux. AB - Achieving a direct nonequilibrium simulation for hydrogen systems has been quite challenging because nuclear quantum effects (NQEs) have to be taken into account. We directly simulated nonequilibrium hydrogen molecules under a temperature gradient with the recently developed nonempirical molecular dynamics method, which describes nonspherical hydrogen molecules with the NQEs. We found dynamical ordering purely induced by heat flux, which should be distinguished from static ordering like orientational alignment, as decelerated translational motions and enhanced intensity of H-H vibrational power spectra despite the little structural ordering. This dynamical ordering, which was enhanced with stronger heat flux while independent of system size, can be regarded as self-solidification of hydrogen molecules for their efficient heat conduction. PMID- 28722420 TI - Salt Promotes Protonation of Amine Groups at Air/Water Interface. AB - Interfacial water reorientation caused by charged Langmuir monolayers consisting of primary fatty amine (ODA) and cationic lipid having quaternary amine headgroup (DPTAP) were investigated by interface-selective vibrational sum-frequency generation spectroscopy. For DPTAP monolayer, initially large sum-frequency intensity from interfacial water OH band decreased steadily by increasing monovalent salt (NaCl, NaI) concentration due to counterion adsorption. On the other hand, ODA/water exhibited significantly smaller sum-frequency intensity than DPTAP/water, implying only small portion of protonated amine group (-NH3+) initially existed. By increasing the ionic strength, however, SF intensity of water OH band was enhanced markedly up to ~1 mM, and then decreased in both NaCl and NaI solutions. By measuring the phase of the sum-frequency spectra, it was found that water dipoles under the ODA headgroup point downward, indicating that the surfaces were always positively charged. This demonstrated that increasing ionic strength facilitates protonation of primary amine headgroups. A simple model based on Poisson-Boltzmann (PB) theory explained this protonation behavior of primary amines. PMID- 28722421 TI - Capillary Rise: Validity of the Dynamic Contact Angle Models. AB - The classical Lucas-Washburn-Rideal (LWR) equation, using the equilibrium contact angle, predicts a faster capillary rise process than experiments in many cases. The major contributor to the faster prediction is believed to be the velocity dependent dynamic contact angle. In this work, we investigated the dynamic contact angle models for their ability to correct the dynamic contact angle effect in the capillary rise process. We conducted capillary rise experiments of various wetting liquids in borosilicate glass capillaries and compared the model predictions with our experimental data. The results show that the LWR equations modified by the molecular kinetic theory and hydrodynamic model provide good predictions on the capillary rise of all the testing liquids with fitting parameters, while the one modified by Joos' empirical equation works for specific liquids, such as silicone oils. The LWR equation modified by molecular self layering model predicts well the capillary rise of carbon tetrachloride, octamethylcyclotetrasiloxane, and n-alkanes with the molecular diameter or measured solvation force data. The molecular self-layering model modified LWR equation also has good predictions on the capillary rise of silicone oils covering a wide range of bulk viscosities with the same key parameter W(0), which results from the molecular self-layering. The advantage of the molecular self layering model over the other models reveals the importance of the layered molecularly thin wetting film ahead of the main meniscus in the energy dissipation associated with dynamic contact angle. The analysis of the capillary rise of silicone oils with a wide range of bulk viscosities provides new insights into the capillary dynamics of polymer melts. PMID- 28722422 TI - First Time View on Human Metabolome Changes after a Single Intake of 3,4 Methylenedioxymethamphetamine in Healthy Placebo-Controlled Subjects. AB - 3,4-Methylenedioxymethamphetamine (MDMA; "ecstasy") is widely consumed recreationally. Little is known about its effects on the human metabolome. Mapping biochemical changes after drug exposure can complement traditional approaches by revealing potential biomarkers of organ toxicity or discovering new metabolomic features in a time- and dose-dependent manner. We aimed to analyze for the first time plasma samples from a randomized, double-blind, placebo controlled crossover study in healthy adults to explore changes in endogenous plasma metabolites following a single intake of MDMA. Plasma samples from 15 subjects taken at four different time points were analyzed with the commercially available AbsoluteIDQ kit (Biocrates). Time series analysis revealed a total of nine metabolites, which showed a significant concentration change after MDMA administration compared with placebo. Paired t tests of the single time points showed statistically significant concentration changes mainly of glycerophospholipids and the metabolic ratio of methionine-sulfoxide over methionine. Changes of this metabolic ratio may be indicative for changes in systemic oxidative stress levels, and the increased amount of glycerophospholipids could be interpreted as an upregulation of energy production. Baseline samples within the experimental study design were crucial for evaluation of metabolomics data as interday individuality within subjects was high otherwise resulting in overestimations of the findings. PMID- 28722423 TI - Generation of a cGMP Indicator with an Expanded Dynamic Range by Optimization of Amino Acid Linkers between a Fluorescent Protein and PDE5alpha. AB - Here we describe the development of a single fluorescent protein (FP)-based cGMP indicator, Green cGull, based on the cGMP binding domain from mouse phosphodiesterase 5alpha. The dynamic range of Green cGull was enhanced to a 7.5 fold fluorescence change upon cGMP binding by optimization of the amino acid linkers between the cGMP binding domain and FP. Green cGull has excitation and emission peaks at 498 and 522 nm, respectively, and specifically responds to cGMP in a dose-dependent manner. Live cell imaging analysis revealed that addition of a nitric oxide (NO) donor induced different cGMP kinetics and was cell-type dependent. We also found that the NO donor induced an increase of intracellular cGMP, while intracellular Ca2+ exhibited a complex profile, as revealed by dual color imaging of cGMP and Ca2+. The results suggest that Green cGull sheds new light on understanding the complex interactions between various signaling molecules by multicolor imaging and that our systematic strategy for expanding the dynamic range of single-FP-based indicators is valuable to generate indicators for molecules of interest. PMID- 28722424 TI - Metabolic Study of Cancer Cells Using a pH Sensitive Hydrogel Nanofiber Light Addressable Potentiometric Sensor. AB - We report a simple, fast, and cost-effective approach that measures cancer cell metabolism and their response to anticancer drugs in real time. Using a Light Addressable Potentiometric Sensor integrated with pH sensitive hydrogel nanofibers (NF-LAPS), we detect localized changes in pH of the media as cancer cells consume glucose and release lactate. NF-LAPS shows a sensitivity response of 74 mV/pH for cancer cells. Cancer cells (MDA MB231) showed a response of ~0.4 unit change in pH compared to virtually no change observed for normal cells (MCF10A). We also observed a drop in pH for the multidrug-resistant cancer cells (MDA-MB-435MDR) in the presence of doxorubicin. However, inhibition of the metabolic enzymes such as hexokinase and lactate dehydrogenase-A suggested an improvement in the efficacy of doxorubicin by decreasing the level of acidification. This approach, based on extracellular acidification, enhances our understanding of cancer cell metabolic modes and their response to chemotherapies, which will help in the development of better treatments, including choice of drugs and dosages. PMID- 28722425 TI - Self-Focused AlScN Film Ultrasound Transducer for Individual Cell Manipulation. AB - Precise cell positioning is indispensable in the fields of biophysics and cellular biology. Acoustic microbeam produced by a highly focused ultrasound transducer has recently been investigated for a particle or cell manipulation. By virtue of the relatively good piezoelectric property, Sc doped AlN film was introduced for a highly focused ultrasound transducer application. Using a sputtering approach, a self-focused AlScN film based device has been designed, fabricated, and characterized at a frequency of ~230 MHz. It had a narrow lateral beam width (~8.2 MUm). The AlScN ultrasound transducer was not only shown to be capable of remote controlling a single 10 MUm polystyrene microsphere in distilled water, but also demonstrated to possess the capability to manipulate without contact individual 10 MUm epidermoid carcinoma cell in two dimensions within a range of hundreds of micrometers in phosphate buffered saline. Most importantly, the cell manipulation was realized in continuous mode and no switch on and -off operation was needed. These results suggest that self-focused AlScN film ultrasound transducer is a promising candidate for biomedical and molecular biology applications. PMID- 28722426 TI - Tunable Volatile-Organic-Compound Sensor by Using Au Nanoparticle Incorporation on MoS2. AB - Controlling the charge concentrations of two-dimensional (2D) materials is a critical requirement for realizing versatility and potential application of these materials in high-performance electronics and sensors. In order to exploit the novel chemical-sensing characteristics of 2D materials for sensitive and selective sensors, various functionalization methods are needed to ensure efficient doping of channels based on 2D materials. In the present study, the gas sensing performance of MoS2 has been significantly enhanced by controlled Au nanoparticle functionalization. By using the difference in reduction potential between the Au precursor and MoS2 work functions, MoS2 prepared by chemical exfoliation process was decorated with nanoparticles with sizes of tens of nanometers. The n-doping effect of Au nanoparticles was observed, that is, these particles were found to have facilitated in electron charge transfer from Au to MoS2. The controlled n-doping effect enables the tuning of the sensing of hydrocarbon-based volatile organic compounds (VOCs) and oxygen-functionalized compounds by MoS2. A significant step has therefore been made with this study toward solving the limitations imposed by previous MoS2-based sensors, which mostly produce a single response to various VOC analytes. This controllable chemical doping process for tuning the VOC-sensing performance of MoS2 can eventually be used in early detection using multichannel sensing systems that have different responses and recognize patterns for target analytes. PMID- 28722427 TI - Fluorescent Chemosensor for Selective Detection of Phosgene in Solutions and in Gas Phase. AB - The detection of highly toxic chemicals in a convenient, fast, and reliable manner is essential for coping with serious threats to humankind and public security caused by unexpected terrorist attacks and industrial accidents. In this paper, a highly selective fluorescent probe has been constructed through o phenylenediamine covalently linking to coumarin (o-Pac), which can respond to phosgene in turn-on fluorescence mode. The response time is less than 0.5 min and the detection limit is as low as 3 nM in solutions. More importantly, the sensor exhibits good selectivity to phosgene over triphosgene and various acyl chlorides. Furthermore, a portable test paper has been fabricated with polystyrene membrane containing o-Pac for real-time selective monitoring of phosgene in gas phase. PMID- 28722428 TI - BSA-Sugar Conjugates as Ideal Building Blocks for SPR-Based Glycan Biosensors. AB - Controlled immobilization of sugar probes is of key importance for the development of glycan biosensors. To this end, a series of BSA-sugar conjugates with different numbers of mannose units are prepared via the squaric acid mediated coupling reaction. The conjugates can absorb directly on gold substrate without any derivation reactions, thus providing a simple and effective method for the construction of SPR-based glycan biosensors. SPR measurements show that the BSA-mannose conjugate with 11 mannoses exhibit the highest affinity to the lectin concanavalin A with a limit of detection of ca. 1.8 nM. Regeneration and specificity of the obtained glycan biosensors are also investigated. PMID- 28722429 TI - Detection of K+ Efflux from Stimulated Cortical Neurons by an Aptamer-Modified Silicon Nanowire Field-Effect Transistor. AB - The concentration gradient of K+ across the cell membrane of a neuron determines its resting potential and cell excitability. During neurotransmission, the efflux of K+ from the cell via various channels will not only decrease the intracellular K+ content but also elevate the extracellular K+ concentration. However, it is not clear to what extent this change could be. In this study, we developed a multiple-parallel-connected silicon nanowire field-effect transistor (SiNW-FET) modified with K+-specific DNA-aptamers (aptamer/SiNW-FET) for the real-time detection of the K+ efflux from cultured cortical neurons. The aptamer/SiNW-FET showed an association constant of (2.18 +/- 0.44) * 106 M-1 against K+ and an either less or negligible response to other alkali metal ions. The alpha-amino-3 hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) stimulation induced an outward current and hyperpolarized the membrane potential in a whole-cell patched neuron under a Na+/K+-free buffer. When neurons were placed atop the aptamer/SiNW-FET in a Na+/K+-free buffer, AMPA (13 MUM) stimulation elevated the extracellular K+ concentration to ~800 nM, which is greatly reduced by 6,7-dinitroquinoxaline-2,3 dione, an AMPA receptor antagonist. The EC50 of AMPA in elevating the extracellular K+ concentration was 10.3 MUM. By stimulating the neurons with AMPA under a normal physiological buffer, the K+ concentration in the isolated cytosolic fraction was decreased by 75%. These experiments demonstrate that the aptamer/SiNW-FET is sensitive for detecting cations and the K+ concentrations inside and outside the neurons could be greatly changed to modulate the neuron excitability. PMID- 28722430 TI - Multi-Amplified Sensing of MicroRNA by a Small DNA Fragment-Driven Enzymatic Cascade Reaction. AB - Combining technological developments such as nanomaterials, DNA nanotechnology, and functional enzymes has great potential to facilitate next generation high performance molecular diagnostic systems. In this work, we describe a microRNA (miRNA) detection assay that combines target recycling and isothermal amplification in an elegantly designed enzyme-mediated cascade reaction. Target recycling is driven by the action of duplex-specific nuclease (DSN), resulting in highly amplified translation of input miRNA to short output DNA fragments. These fragments act as highly specific initiators of rolling circle amplification (RCA), an isothermal reaction that outputs a large volume of polymeric DNAzymes per initiator, and finally a fluorogenic output signal. Based on careful electrophoretic analysis we observed that the DSN produces ca. 10 nt DNA fragments from DNA/miRNA duplexes, regardless of the length of DNA strands. Target recycling yielded ca. 5 orders of magnitude amplification through the DSN assisted recycling system on magnetic particles, and the RCA yielded a further 2 orders of magnitude. The final assay exhibited a limit of detection of 1.8 fM of miRNA spiked into 20% human serum, and showed excellent selectivity for miR-21 versus single base-mismatched sequences and other cancer-related miRNAs. The developed assay was further employed to determine accurate amounts of miR-21 in total RNA samples extracted from human cancer cell lines and normal cells, confirming the applicability of the assay for direct and absolute quantification of mature specific miRNA in real biological samples. PMID- 28722431 TI - Giant O2-Induced Photoluminescence Modulation in Hierarchical Titanium Dioxide Nanostructures. AB - We demonstrate exceptionally large modulation of PL intensity in hierarchical titanium dioxide (TiO2) nanostructures exposed to molecular oxygen (O2). Optical responsivities up to about 1100% at 20% O2 concentrations are observed in hyperbranched anatase-phase hierarchical structures, outperforming those obtainable by commercial TiO2 nanopowders (up to a factor of ~7 for response to synthetic air) and significantly improving the ones typically reported in PL based opto-chemical gas sensing using MOXs. The improved PL response is discussed in terms of the specific morphology of hierarchical structures, characterized by simultaneous presence of small nanoparticles, large surface areas, and large voids. These characteristics guarantee an optimal interplay between photogenerated charges, PL-active centers, and adsorbed gas molecules. The results highlight the potentialities offered by hierarchical structures based on TiO2 or other MOXs and open interesting scenarios toward the development of all optical and/or hybrid (opto/electrical) chemical sensors with improved sensitivity. PMID- 28722432 TI - Benzocoumarin Hydrazine: A Large Stokes Shift Fluorogenic Sensor for Detecting Carbonyls in Isolated Biomolecules and in Live Cells. AB - Detection and quantification of biomolecule carbonylation, a critical manifestation of oxidative stress, allows better understanding of associated disease states. Existing approaches for such analyses require further processing of cells and tissues, which leads to loss of both spatial and temporal information about carbonylated biomolecules in cells. Live cell detection of these species requires sensors that are nontoxic, sufficiently reactive with the biocarbonyl in the intracellular milieu, and detectable with commonly available instrumentation. Presented here is a new fluorescent sensor for biomolecule carbonyl detection: a hydrazine derivative of a benzocoumarin, 7-hydrazinyl-4 methyl-2H-benzo[h]chromen-2-one (BzCH), which meets these requirements. This probe is especially well suited for live cell studies. It can be excited by a laser line common to many fluorescence microscopes. The emission maximum of BzCH undergoes a substantial red shift upon hydrazone formation (from ~430 to ~550 nm), which is the result of fluorophore disaggregation. Additionally, the hydrazone exhibits an exceptionally large Stokes shift (~195 nm). The latter properties eliminate self-quenching of the probe and the need to remove unreacted fluorophore for reliable carbonyl detection. Thus, biomolecule carbonylation can be detected and quantified in cells and in cell extracts in a one-step procedure using this probe. PMID- 28722433 TI - Welcome to the First Anniversary Issue of ACS Sensors. PMID- 28722434 TI - Design Considerations for Silica-Particle-Doped Nitric-Oxide-Releasing Polyurethane Glucose Biosensor Membranes. AB - Nitric oxide (NO)-releasing polymers have proven useful for improving the biocompatibility of in vivo glucose biosensors. Unfortunately, leaching of the NO donor from the polymer matrix remains a critical design flaw of NO-releasing membranes. Herein, a toolbox of NO-releasing silica nanoparticles (SNPs) was utilized to systematically evaluate SNP leaching from a diverse selection of biomedical-grade polyurethane sensor membranes. Glucose sensor analytical performance and NO-release kinetics from the sensor membranes were also evaluated as a function of particle and polyurethane (PU) chemistries. Particles modified with N-diazeniumdiolate NO donors were prone to leaching from PU membranes due to the zwitterionic nature of the NO donor modification. Leaching was minimized (<5% of the entrapped silica over 1 month) in low water uptake PUs. However, SNP modification with neutral S-nitrosothiol (RSNO) NO donors lead to biphasic leaching behavior. Particles with low alkanethiol content (<3.0 wt % sulfur) leached excessively from a hydrogel PU formulation (HP-93A-100 PU), while particles with greater degrees of thiol modification did not leach from any of the PUs tested. A functional glucose sensor was developed using an optimized HP 93A-100 PU membrane doped with RSNO-modified SNPs as the outer, glucose diffusion limiting layer. The realized sensor design responded linearly to physiological concentrations of glucose (minimum 1-21 mM) over 2 weeks incubation in PBS and released NO at >0.8 pmol cm-2 s-1 for up to 6 days with no detectable (<0.6%) particle leaching. PMID- 28722437 TI - Surface Plasmon Resonance Clinical Biosensors for Medical Diagnostics. AB - The design and application of sensors for monitoring biomolecules in clinical samples is a common goal of the sensing research community. Surface plasmon resonance (SPR) and other plasmonic techniques such as localized surface plasmon resonance (LSPR) and imaging SPR are reaching a maturity level sufficient for their application in monitoring biomolecules in clinical samples. In recent years, the first examples for monitoring antibodies, proteins, enzymes, drugs, small molecules, peptides, and nucleic acids in biofluids collected from patients afflicted with a series of medical conditions (Alzheimer's, hepatitis, diabetes, leukemia, and cancers such as prostate and breast cancers, among others) demonstrate the progress of SPR sensing in clinical chemistry. This Perspective reviews the current status of the field, showcasing a series of early successes in the application of SPR for clinical analysis and detailing a series of considerations regarding sensing schemes, exposing issues with analysis in biofluids, and comparing SPR with ELISA, while providing an outlook of the challenges currently associated with plasmonic materials, instrumentation, microfluidics, bioreceptor selection, selection of a clinical market, and validation of a clinical assay for applying SPR sensors to clinical samples. Research opportunities are proposed to further advance the field and transition SPR biosensors from research proof-of-concept stage to actual clinical applications. PMID- 28722436 TI - Potential to Detect Hydrogen Concentration Gradients with Palladium Infused Mesoporous-Titania on D-Shaped Optical Fiber. AB - A distributed sensing capable high temperature D-shaped optical fiber modified with a palladium nanoparticle sensitized mesoporous (~5 nm) TiO2 film, is demonstrated. The refractive index of the TiO2 film was reduced using block copolymer templating in order to realize a mesoporous matrix, accommodating integration with optical fiber. The constructed sensor was analyzed by performing direct transmission loss measurements, and by analyzing the behavior of an integrated fiber Bragg grating. The inscribed grating should reveal whether the refractive index of the composite film experiences changes upon exposure to hydrogen. In addition, with frequency domain reflectometry the distributed sensing potential of the developed sensor for hydrogen concentrations of up to 10% is examined. The results show the possibility of detecting chemical gradients with sub-cm resolution at temperatures greater than 500 degrees C. PMID- 28722438 TI - Graphene Oxide-Upconversion Nanoparticle Based Optical Sensors for Targeted Detection of mRNA Biomarkers Present in Alzheimer's Disease and Prostate Cancer. AB - The development of new sensors for the accurate detection of biomarkers in biological fluids is of utmost importance for the early diagnosis of diseases. Next to advanced laboratory techniques, there is a need for relatively simple methods which can significantly broaden the availability of diagnostic capability. Here, we demonstrate the successful application of a sensor platform based on graphene oxide and upconversion nanoparticles (NPs) for the specific detection of mRNA-related oligonucleotide markers in complex biological fluids. The combination of near-infrared light upconversion with low-background photon counting readout enables reliable detection of low quantities of small oligonucleotide sequences in the femtomolar range. We demonstrate the successful detection of analytes relevant to mRNAs present in Alzheimer's disease as well as prostate cancer in human blood serum. The high performance and relative simplicity of the upconversion NP-graphene sensor platform enables new opportunities in early diagnosis based on specific detection of oligonucleotide sequences in complex environments. PMID- 28722439 TI - Investigation of Polymer-Plasticizer Blends as SH-SAW Sensor Coatings for Detection of Benzene in Water with High Sensitivity and Long-Term Stability. AB - We report the first-ever direct detection of benzene in water at concentrations below 100 ppb (parts per billion) using acoustic wave (specifically, shear horizontal surface acoustic wave, SH-SAW) sensors with plasticized polymer coatings. Two polymers and two plasticizers were studied as materials for sensor coatings. For each polymer-plasticizer combination, the influence of the mixing ratio of the blend on the sensitivity to benzene was measured and compared to commercially available polymers that were used for BTEX (benzene, toluene, ethylbenzene, and xylene) detection in previous work. After optimizing the coating parameters, the highest sensitivity and lowest detection limit for benzene were found for a 1.25 MUm thick sensor coating of 17.5%-by-weight diisooctyl azelate-polystyrene on the tested acoustic wave device. The calculated detection limit was 45 ppb, with actual sensor responses to concentrations down to 65 ppb measured directly. Among the sensor coatings that showed good sensitivity to benzene, the best long-term stability was found for a 1.0 MUm thick coating of 23% diisononyl cyclohexane-1,2-dicarboxylate-polystyrene, which was studied here because it is known to show no detectable leaching in water. The present work demonstrates that, by varying type of plasticizer, mixing ratio, and coating thickness, the mechanical and chemical properties of the coatings can be conveniently tailored to maximize analyte sorption and partial chemical selectivity for a given class of analytes as well as to minimize acoustic-wave attenuation in contact with an aqueous phase at the operating frequency of the sensor device. PMID- 28722440 TI - Life Under the Microscope: Quantifying Live Cell Interactions to Improve Nanoscale Drug Delivery. AB - The behavior of cells and how they react to stimuli is critically important for drug development, drug delivery, and understanding the molecular basis of many diseases. However, we still lack a comprehensive understanding of these interactions, particularly in relation to drug delivery from nanoparticles. This Sensors Issues article discusses the importance of quantifying these interactions and highlights some key areas where advances in sensor technology have the potential to transform our understanding of drug delivery and cell biology. PMID- 28722441 TI - Harnessing the Versatility of Optical Biosensors for Target-Based Small-Molecule Drug Discovery. AB - Optical biosensors entered target-based small-molecule drug discovery more than two decades ago and have since transformed into a value-adding component in the decision-making process. Here, we briefly highlight the major application areas of optical biosensors and focus on desirable profiles of such platforms in order to ensure their effective use in small molecule drug discovery. Furthermore, we will emphasize current technology-based constraints and discuss experimental strategies to address these limitations as well as provide a view of necessary technology improvements for next generation platforms. PMID- 28722442 TI - Sensing Active Heparin by Counting Aggregated Quantum Dots at Single-Particle Level. AB - Developing highly sensitive and highly selective assays for monitoring heparin levels in blood is required during and after surgery. In previous studies, electrostatic interactions are exploited to recognize heparin and changes in light signal intensity are used to sense heparin. In the present study, we developed a quantum dot (QD) aggregation-based detection strategy to quantify heparin. When cationic micelles and fluorescence QDs modified with anti-thrombin III (AT III) are added into heparin sample solution, the AT III-QDs, which specifically bind with heparin, aggregate around the micelles. The aggregated QDs are recorded by spectral imaging fluorescence microscopy and differentiated from single QDs based on the asynchronous process of blue shift and photobleaching. The ratio of aggregated QD spots to all counted QD spots is linearly related to the amount of heparin in the range of 4.65 * 10 -4 U/mL to 0.023 U/mL. The limit of detection is 9.3 * 10 -5 U/mL (~0.1 nM), and the recovery of the spiked heparin at 0.00465 U/mL (~5 nM) in 0.1% human plasma is acceptable. PMID- 28722443 TI - Quantum Dot Nanotoxicity Investigations Using Human Lung Cells and TOXOR Electrochemical Enzyme Assay Methodology. AB - Recent studies have suggested that certain nanomaterials can interfere with optically based cytotoxicity assays resulting in underestimations of nanomaterial toxicity. As a result there has been growing interest in the use of whole cell electrochemical biosensors for nanotoxicity applications. Herein we report application of an electrochemical cytotoxicity assay developed in house (TOXOR) in the evaluation of toxic effects of mercaptosuccinic acid capped cadmium telluride quantum dots (MSA capped CdTe QDs), toward mammalian cells. MSA capped CdTe QDs were synthesized, characterized, and their cytotoxicity toward A549 human lung epithelial cells investigated. The internalization of QDs within cells was scrutinized via confocal microscopy. The cytotoxicity assay is based on the measurement of changes in cellular enzyme acid phosphatase upon 24 h exposure to QDs. Acid phosphatase catalyzes dephosphorylation of 2-naphthyl phosphate to 2 naphthol (determined by chronocoulometry) and is indicative of metabolic activity in cells. The 24 h IC50 (concentration resulting in 50% reduction in acid phosphatase activity) value for MSA capped CdTe QDs was found to be 118 +/- 49 MUg/mL using the TOXOR assay and was in agreement with the MTT assay (157 +/- 31 MUg/mL). Potential uses of this electrochemical assay include the screening of nanomaterials, environmental toxins, in addition to applications in the pharmaceutical, food, and health sectors. PMID- 28722444 TI - Topographically Flat Nanoplasmonic Sensor Chips for Biosensing and Materials Science. AB - Nanoplasmonic sensors typically comprise arrangements of noble metal nanoparticles on a dielectric support. Thus, they are intrinsically characterized by surface topography with corrugations at the 10-100 nm length scale. While irrelevant in some bio- and chemosensing applications, it is also to be expected that the surface topography significantly influences the interaction between solids, fluids, nanoparticles and (bio)molecules, and the nanoplasmonic sensor surface. To address this issue, we present a wafer-scale nanolithography-based fabrication approach for high-temperature compatible, chemically inert, topographically flat, and laterally homogeneous nanoplasmonic sensor chips. We demonstrate their sensing performance on three different examples, for which we also carry out a direct comparison with a traditional nanoplasmonic sensor with representative surface corrugation. Specifically, we (i) quantify the film thickness dependence of the glass transition temperature in poly(methyl metacrylate) thin films, (ii) characterize the adsorption and specific binding kinetics of the avidin-biotinylated bovine serum albumin protein system, and (iii) analyze supported lipid bilayer formation on SiO2 surfaces. PMID- 28722445 TI - Highlighting Cancer Cells with Halochromic Switches. AB - Halochromic coumarin-oxazine prefluorophores and targeting folate ligands can be connected covalently to the side chains of amphiphilic polymers. The resulting macromolecular constructs assemble into nanoparticles in aqueous environments. The prefluorophores do not produce any detectable fluorescence at neutral pH, but are converted into fluorophores with intense visible emission at acidic pH. Protonation opens the oxazine heterocycle to shift bathochromically the coumarin absorption and activate fluorescence with a brightness per nanoparticle approaching 5 * 105 M-1 cm-1. This value translates into a 170-fold enhancement relative to the isolated fluorophores dissolved in organic solvent. The folate ligands direct these multicomponent constructs into acidic intracellular compartments of folate-positive cells, where the prefluorophores switch to the corresponding fluorophores and produce fluorescence. The pH-induced activation of the signaling units ensures negligible background fluorescence from the extracellular matrix, which instead limits considerably the contrast accessible with model systems incorporating conventional nonactivatable fluorophores. Furthermore, no intracellular fluorescence can be detected when the very same measurements are performed with folate-negative cells. Nonetheless, control experiments demonstrate that the covalent connection of the prefluorophores to the polymer backbone of the amphiphilic constructs is essential to ensure selectivity. Model systems with prefluorophores noncovalently encapsulated cannot discriminate folate-positive from -negative cells. Thus, our structural design for the covalent integration of activatable signaling units and targeting ligands within the same nanostructured assembly together with the photophysical properties engineered into the emissive components offer the opportunity to highlight cancer cells selectively with high brightness and optimal contrast. PMID- 28722446 TI - Hierarchical Morphology-Dependent Gas-Sensing Performances of Three-Dimensional SnO2 Nanostructures. AB - Hierarchical morphology-dependent gas-sensing performances have been demonstrated for three-dimensional SnO2 nanostructures. First, hierarchical SnO2 nanostructures assembled with ultrathin shuttle-shaped nanosheets have been synthesized via a facile and one-step hydrothermal approach. Due to thermal instability of hierarchical nanosheets, they are gradually shrunk into cone shaped nanostructures and finally deduced into rod-shaped ones under a thermal treatment. Given the intrinsic advantages of three-dimensional hierarchical nanostructures, their gas-sensing properties have been further explored. The results indicate that their sensing behaviors are greatly related with their hierarchical morphologies. Among the achieved hierarchical morphologies, three dimensional cone-shaped hierarchical SnO2 nanostructures display the highest relative response up to about 175 toward 100 ppm of acetone as an example. Furthermore, they also exhibit good sensing responses toward other typical volatile organic compounds (VOCs). Microstructured analyses suggest that these results are mainly ascribed to the formation of more active surface defects and mismatches for the cone-shaped hierarchical nanostructures during the process of thermal recrystallization. Promisingly, this surface-engineering strategy can be extended to prepare other three-dimensional metal oxide hierarchical nanostructures with good gas-sensing performances. PMID- 28722447 TI - Fluorescence Sensing of Circulating Diagnostic Biomarkers Using Molecular Probes and Nanoparticles. AB - The interplay of photonics, nanotechnology, and biochemistry has significantly improved the identification and characterization of multiple types of biomarkers by optical biosensors. Great achievements in fluorescence-based technologies have been realized, for example, by the advancement of multiplexing techniques or the introduction of nanoparticles to biochemical and clinical research. This review presents a concise overview of recent advances in fluorescence sensing techniques for the detection of circulating disease biomarkers. Detection principles of representative approaches, including fluorescence detection using molecular fluorophores, quantum dots, and metallic and silica nanoparticles, are explained and illustrated by pertinent examples from the recent literature. Advanced detection technologies and material development play a major role in modern biosensing and consistently provide significant improvements toward robust, sensitive, and versatile platforms for early detection of circulating diagnostic biomarkers. PMID- 28722448 TI - Chemical Sensing on a Single SERS Particle. AB - We report a new chemical sensing platform on a single surface-enhanced Raman scattering (SERS) particle. A cabbage-like Au microparticle (CLMP) with high SERS enhancement was applied as an ultrasensitive SERS substrate. A new Raman reporter bis[4,4'-[dithiodiphenyl azo-phenol] (DTDPAP) was synthesized to display multiple fingerprints and high reactivity toward sodium dithionite. The reaction of DTDPAP with sodium dithionite was in situ monitored by SERS on a single CLMP. The DTDPAP fingerprint change is dependent on the sodium dithionite concentration, providing a simple and sensitive method for sodium dithionite profiling. PMID- 28722449 TI - How Large is the Elephant in the Density Functional Theory Room? AB - A recent paper reported highly accurate density functional theory results for atomization energies and dipole moments using a multiwavelet-based method and compared the results with those obtained by standard Gaussian basis sets of the aug-cc-pVXZ type. Typical errors with the large aug-cc-pV5Z basis set were in the 0.2 kcal/mol range with outliers displaying errors of ~2 kcal/mol, and these results could be taken as an indication that Gaussian basis sets in general are unsuitable for achieving high accuracy. We show that by choosing Gaussian basis sets optimized for density functional theory, basis set methods are capable of achieving accuracy comparable to that from the multiwavelet approach. PMID- 28722451 TI - [Basal cell carcinoma and the modalities of its therapy]. AB - Basal cell carcinoma (BCC) also known as basalioma or basal cell cancer, is the most common skin cancer. BCC has a very low metastatic risk. This tumor can cause significant disfigurement by invading surrounding tissues. It occurs mainly in fair-skinned patients with a family history of this cancer. Sunlight is a factor in about two-thirds of these cancers. Standard surgical excision is the treatment of choice. Mohs micrographic surgery is an outpatient or inpatient procedure in which the tumor is surgically excised and then immediately examined under a microscope. Cryosurgery is an old modality for the treatment of many skin cancers. Other treatment options incl. photodynamic therapy, topical immunotherapy, radiation or targeted therapy will be discussed. PMID- 28722450 TI - Two New Sandwich-Type Manganese {Mn5}-Substituted Polyoxotungstates: Syntheses, Crystal Structures, Electrochemistry, and Magnetic Properties. AB - Herein we report two pentanuclear MnII-substituted sandwich-type polyoxotungstate complexes, [{Mn(bpy)}2Na(H2O)2(MnCl)2{Mn(H2O)}(AsW9O33)2]9- and [{Mn(bpy)}2Na(H2O)2(MnCl){Mn(H2O)}2(SbW9O33)2]8- (bpy = 2,2'-bipyridine), whose structures have been obtained by single-crystal X-ray diffraction (SCXRD), complemented by results obtained from elemental analysis, electrospray ionization mass spectrometry, Fourier transform infrared spectroscopy, and thermogravimetric analysis. They consist of two [B-alpha-XW9O33]9- subunits sandwiching a cyclic assembly of the hexagonal [{Mn(bpy)}2Na(H2O)2(MnCl)2{Mn(H2O)}]9+ and [{Mn(bpy)}2Na(H2O)2(MnCl){Mn(H2O)}2]10+ moieties, respectively, and represent the first pentanuclear MnII-substituted sandwich-type polyoxometalates (POMs). Both compounds have been synthesized by reacting MnCl2.4H2O with trilacunary Na9[XW9O33].27H2O (X = AsIII and SbIII) POM precursors in the presence of bpy in a 1 M aqueous sodium chloride solution under mild reaction conditions. SCXRD showed that the alternate arrangement of three five-coordinated MnII ions and two six-coordinated MnII ions with an internal Na cation formed a coplanar six membered ring that was sandwiched between two [B-alpha-XW9O33]9- (X = AsIII and SbIII) subunits. The results of temperature-dependent direct-current (dc) magnetic susceptibility data indicated ferromagnetic interactions between Mn ions in the cluster. Moreover, alternating-current magnetic susceptibility measurements with a dc-biased magnetic field showed the existence of a ferromagnetic order for both samples. Electrochemistry studies revealed the presence of redox processes assigned to the Mn centers. They are associated with the deposition of material on the working electrode surface, possibly MnxOy, as demonstrated by electrochemical quartz crystal microbalance experiments. PMID- 28722452 TI - [Lymphogranuloma venereum]. AB - Lymphogranuloma venereum belongs to the sexually transmitted diseases. The disease is caused by Chlamydia trachomatis serotypes L1, L2 and L3. In the beginning of the 21st century there has been observed a large increase in the incidence of this disease in the world. There is a frequent co-occurrence with other sexually transmitted diseases (HIV, syphilis, gonorrhea, hepatitis C). Predominantly this disease affects homosexuals, in which case the first manifestation of the disease may be proctitis or proctocolitis. PMID- 28722453 TI - [Psoriasis comorbidities]. AB - Psoriasis is a chronic inflammatory skin disease affecting 2-4 % of Central European population. Nowadays, we know that psoriasis is not limited to the skin but is connected with several comorbidities like, psoriatic arthritis (around 25 %), Crohn's disease, ulcerative colitis, Bechterev, non-alcoholic liver steatosis, psychiatric disorders and mainly diseases of the so called metabolic syndrome, like diabetes mellitus type 2, arterial hypertension or dyslipidemia. In the last years, new information is arising which connect psoriasis with sleep apnoe and chronic obstructive pulmonary disease. PMID- 28722454 TI - [Chronic urticaria - new views on diagnosis and treatment of disease]. AB - Interest in chronic urticaria has grown in recent years, largely owing to the advent of new modes treatment especially in the form of the biologic preparation omalizumab. New scientific and clinical findings have not only facilitated a more comprehensive view of the disease but have streamlined the classification and diagnostic approach as well. Diagnostics are no longer burdened by cumbersome and lengthy investigative procedures into the etiology of urticaria, but are much more rapid and targeted bringing about more timely relief of the patient's symptoms. According to recent data, the impact of the illness onto the quality of life of the patient, especially in those with more severe forms of urticaria, can be quite devastating both physically and psychologically compared to other chronic diseases (e.g. coronary artery disease, etc.). PMID- 28722455 TI - [Hidradenitis suppurativa - symptoms, diagnostics, and therapy]. AB - Hidradenitis suppurativa is a chronic skin disorder characterized by recurrent inflammatory nodules, fistulas, abscesses, and scarring mainly in the intertriginous areas with terminal hair and apocrine glands. Hidradenitis suppurativa manifests usually after puberty, in the third life decade and persists for many years. The prevalence of the disease is estimated to be 0,5 % in the Czech Republic. Women are most often affected in the axillary and inguinal parts, while men in the perianal and gluteal areas. The exact pathogenesis is still unknown. It is assumed that hyperkeratosis of the hair follicle leads to its occlusion, dilatation and further rupture when keratin and bacteria are spilled into the dermis causing a massive inflammatory reaction. Smoking and obesity belong to the main triggering factors. Without therapy, the disease is chronic and progressive. The standard therapy depends on the extension of the disorder. For not extensive lesions, treatment consists of topical antiseptics, antibiotics or long- term therapy with systemic antibiotics. In more advanced stages, systemic therapy with TNF-alpha antagonists is needed. Further therapeutic modality is surgical intervention and wide excision of the affected area. Nevertheless, recurrences in the adjacent tissue cannot be avoided. PMID- 28722456 TI - [Hirsutism - etiopathogenesis, diagnostics and treatment]. AB - Hirsutism is defined as excessive terminal hair growth in distribution typical for postpubertal men. It affects approximately 5-10 % of women and most frequently manifests in puberty. Significant cosmetic stigmatization is the usual complaint that brings patient to the doctor and it is crucial to always rule out any primary underlying disease causing hirsutism - benign or malignant. In this review etiopathogenesis, diagnostic procedures and treatment options are discussed. PMID- 28722457 TI - [Diseases affecting the scalp]. AB - The skin of the scalp differs from the skin on the other areas of the body because of a higher density of hair follicles and higher sebum production. These, together with the presence of hair, provide a suitable environment for superficial infections, infestations and inflammatory diseases. The good condition of the scalp has a significant impact on the patient's mental well being and social interaction. The visibility of this part of the skin and the presence of hair itself restrict the range of possible therapeutic agents that can be used due to the complicated application and poor cosmetic outcome. That is the reason why different galenic forms are usually chosen for the scalp compared to the other sites of the skin. The article provides an overview of the most common scalp disorders, the diagnostic approach and recommendations for the treatment. PMID- 28722458 TI - [Androgenetic alopecia in women]. AB - Androgenetic alopecia is one of the most common diagnoses in a hair clinic. It is non-scarring pattern hair losses that affect individuals, independent on severity, age and gender. The incidence of AGA increases within the age. AGA affects women less frequently, is usually milder and is associated with diffuse thinning of the hair scalp. Prompt diagnosis and treatment are essential for obtaining optimal outcome. PMID- 28722459 TI - [Mesotherapy in trichology]. AB - Mesotherapy (from Greek meso = in between, therapeia = treat) is a non-surgical, mostly cosmetic therapy, where active substances are injected intradermally into a depth of about 4 mm. It is an effective and easy-to-use method in the treatment of alopecia. It is effective both in the therapy of androgenetic alopecia and telogen effluvium. In recent years, it has been massively expanded also among non medical fields, which has caused its contradictory perception by professional medical circles outside dermatologists. This article summarizes the possible therapeutic use of mesotherapy using vitamins, trace elements and stem cell extracts. Their effect has been demonstrated in a number of clinical trials. PMID- 28722460 TI - [Psychological consequences of hair loss]. AB - Hair plays an important role in human life. Quantitative or qualitative changes of hair are therefore perceived unfavorably. The psychological consequences of hair loss are described in both androgenic alopecia and alopecia areata. Alopecia areata should be distinguished from other diagnostic units such as trichotillomania. The issue of hair disease requires a multidisciplinary collaboration, in which the dermatologist has a key role to play. PMID- 28722461 TI - [Disorders of water and electrolyte metabolism and changes in acid-base balance in patients with ascitic liver cirrhosis]. AB - In patients with advanced cirrhosis with ascites disorders of water and electrolyte metabolism are often present and they are associated with changes in acid-base balance. These changes can be very complicated, their diagnosis and treatment difficult. Dilutional hyponatremia is the most common disorder. Hyponatremia in these patients is associated with increased morbidity and mortality before and after liver transplantation. Other common disorders include hyperchloremic acidosis, hypokalemia, metabolic alkalosis, lactic acidosis, respiratory alkalosis. If renal impairment occurs (for example hepatorenal syndrome), metabolic acidosis and retention of acid metabolites may develop. The pathogenesis of these conditions applies primarily hemodynamic changes. Activation of renin-angiotensin-aldosterone system and non-osmotic stimulation of antidiuretic hormone trigger serious changes in water and natrium-chloride metabolism. This activation is clinically expressed like oedema, ascites, hydrothorax, low to zero natrium concentration in urine and increased urinary osmolality, which is higher than serum osmolality. In practice, the evaluation can be significantly modified by the ongoing diuretic therapy. Closer monitoring of water and electrolyte metabolism together with acid-base balance in patients with ascitic liver cirrhosis is important, not only in terms of diagnosis but especially in terms of therapy. PMID- 28722462 TI - [Health care provider legal rights and duties connected with the complaints]. AB - The article deals with the complaints in the area of the health care. It revises the practical procedural issues and questions from the view of the health care facilities. The legal provisions are described through the dominant legal principles, i. e. the considering the complaints as the right of the patient and the principle of non-formal procedure connected with the complaints. PMID- 28722463 TI - [The sanctuaries of Asklepios in ancient Athens]. AB - Asklepios was the main healing deity of the Classical Antiquity. After his gradual establishing, his cult expanded throughout the Greek world especially in the 5th century BC, when Asklepios reached also Athens. Around 420 BC, two sanctuaries of his (sc. Asklepieia) were founded there. Such sanctuaries were places of both the worship and therapy. The first one was located in the port of Pireus, the second one on the south slope of the Acropolis. The latter functioned as a centre of the healing cult almost until the end of the 5th century AD. Sometime in the 1st half of the 6th century a Christian basilica was built over the area of the earlier buildings of Asklepieion. PMID- 28722464 TI - Overview of Treatment of Pediatric Acute-Onset Neuropsychiatric Syndrome. PMID- 28722465 TI - Overview on the Surface Functionalization Mechanism and Determination of Surface Functional Groups of Plasma Treated Carbon Nanotubes. AB - The use of carbon materials for many applications is due to the unique diversity of structures and properties ranging from chemical bonds between the carbon atoms of the materials to nanostructures, crystallite alignment, and microstructures. Carbon nanotubes and other nanoscale carbonaceous materials draw much attention due to their physical and chemical properties, such as high strength, high resistance to corrosion, electrical and thermal conductivity, stability and a qualified adsorbent. Carbon-based nanomaterials, which have a relatively large specific area and layered structure, can be used as an adsorbent for efficient removal of organic and inorganic contaminants. However, one of the biggest obstacles to the development of carbon-based nanomaterials adsorbents is insolubility and the lack of functional groups on the surface. There are several approaches to introduce functional groups on carbon nanotubes. One of these approaches, plasma applications, now has an important place in the creation of surface functional groups as a flexible, fast, and environmentally friendly method. This review focuses on recent information concerning the surface functionalization and modification of plasma treated carbon nanotube. This review considers the surface properties, advantages, and disadvantages of plasma-applied carbon nanotubes. It also examines the reaction mechanisms involved in the functional groups on the surface. PMID- 28722466 TI - Assessing the Generalizability of the National Lung Screening Trial: Comparison of Patients with Stage 1 Disease. AB - RATIONALE: The findings of the NLST (National Lung Screening Trial) are the basis for screening high-risk individuals according to age and smoking history. Although screening is covered for eligible Medicare beneficiaries, the generalizability of the NLST in the elderly population has been questioned. OBJECTIVES: Compare outcomes of patients diagnosed with stage 1 non-small cell lung cancer in the NLST to a nationally representative cohort of elderly patients Methods: Analysis of Surveillance, Epidemiology, and End Results (SEER)-Medicare and NLST datasets for patients with stage 1 disease aged 65 to 74 years. MEASUREMENTS AND MAIN RESULTS: Lung cancer-specific mortality, all-cause mortality, and 30-, 60-, and 90-day treatment mortality were measured. When compared with the NLST group undergoing surgery for stage 1 non-small cell lung cancer, those in the SEER-Medicare NLST eligible cohort had no difference in adjusted odds ratios for 30-, 60-, and 90-day surgical mortality (P values = 0.97, 0.65, and 0.46, respectively). Although the 5-year cancer-specific survival did not differ between cohorts (hazard ratio [HR], 0.84 NLST vs. SEER-Medicare NLST eligible; P = 0.21), the adjusted HR estimate for all-cause mortality was better in the NLST cohort (HR, 0.71; P < 0.01). For patients who did not receive surgery for early-stage disease (presumably for curative intent), the outcomes were far worse (13.1, 18.9, 23.9%, for 30-, 60-, and 90-day treatment mortality, respectively). CONCLUSIONS: Elderly patients with minimal comorbid conditions meeting the inclusion criteria of the NLST who underwent surgery had excellent postoperative outcomes and similar lung cancer-specific 5-year survivorship. In those with significant comorbidities or those not undergoing surgery, competing causes of death may diminish the benefit, and there is no evidence to recommend screening in this group. PMID- 28722467 TI - The Influence of Lower Extremity Lean Mass on Landing Biomechanics During Prolonged Exercise. AB - CONTEXT: The extent to which lower extremity lean mass (LELM) relative to total body mass influences one's ability to maintain safe landing biomechanics during prolonged exercise when injury incidence increases is unknown. OBJECTIVES: To examine the influence of LELM on (1) pre-exercise lower extremity biomechanics and (2) changes in biomechanics during an intermittent exercise protocol (IEP) and (3) determine whether these relationships differ by sex. We hypothesized that less LELM would predict higher-risk baseline biomechanics and greater changes toward higher-risk biomechanics during the IEP. DESIGN: Cohort study. SETTING: Controlled laboratory. PATIENTS OR OTHER PARTICIPANTS: A total of 59 athletes (30 men: age = 20.3 +/- 2.0 years, height = 1.79 +/- 0.05 m, mass = 75.2 +/- 7.2 kg; 29 women: age = 20.6 +/- 2.3 years, height = 1.67 +/- 0.08 m, mass = 61.8 +/- 9.0 kg) participated. INTERVENTION(S): Before completing an individualized 90 minute IEP designed to mimic a soccer match, participants underwent dual-energy x ray absorptiometry testing for LELM. MAIN OUTCOME MEASURE(S): Three-dimensional lower extremity biomechanics were measured during drop-jump landings before the IEP and every 15 minutes thereafter. A previously reported principal components analysis reduced 40 biomechanical variables to 11 factors. Hierarchical linear modeling analysis then determined the extent to which sex and LELM predicted the baseline score and the change in each factor over time. RESULTS: Lower extremity lean mass did not influence baseline biomechanics or the changes over time. Sex influenced the biomechanical factor representing knee loading at baseline (P = .04) and the changes in the anterior cruciate ligament-loading factor over time (P = .03). The LELM had an additional influence only on women who possessed less LELM (P = .03 and .02, respectively). CONCLUSIONS: Lower extremity lean mass influenced knee loading during landing in women but not in men. The effect appeared to be stronger in women with less LELM. Continually decreasing knee loading over time may reflect a strategy chosen to avoid injury. A minimal threshold of LELM may be needed to safely perform landing maneuvers, especially during prolonged exercise when the injury risk increases. PMID- 28722468 TI - Evaluating the Recovery Curve for Clinically Assessed Reaction Time After Concussion. AB - CONTEXT: A change in reaction time is one of various clinical measures of neurocognitive function that can be monitored after concussion and has been reported to be among the most sensitive indicators of cognitive impairment. OBJECTIVE: To determine the timeline for clinically assessed simple reaction time to return to baseline after a concussion in high school athletes. DESIGN: Observational study. SETTING: Athletic training room. PATIENTS OR OTHER PARTICIPANTS: Twenty-one high school-aged volunteers. INTERVENTION(S): Participants completed 8 trials of the ruler-drop test during each session. Along with baseline measures, a total of 6 additional test sessions were completed over the course of 4 weeks after a concussion (days 3, 7, 10, 14, 21, and 28). MAIN OUTCOME MEASURE(S): The mean reaction times calculated for all participants from each of the 7 test sessions were analyzed to assess the change in reaction time over the 7 time intervals. RESULTS: After a concussion and compared with baseline, simple reaction time was, on average, 26 milliseconds slower at 48 to 72 hours postinjury (P < .001), almost 18 milliseconds slower on day 7 (P < .001), and about 9 milliseconds slower on day 10 (P < .001). Simple reaction time did not return to baseline levels until day 14 postinjury. CONCLUSIONS: Clinically assessed simple reaction time appeared to return to baseline levels within a timeframe that mirrors other measures of cognitive performance (approximately 14 days). PMID- 28722469 TI - Recent advances in gossypol derivatives and analogs: a chemistry and biology view. AB - Gossypol as a natural occurring polyphenol has been studied in a wide range of therapeutic contexts for a long time. The chemical modifications on gossypol were limited due to the unique chemical properties of polyphenols. The design and synthesis of gossypol derivatives and the exploration of their biological activities are the interest of the synthetic chemists, medicinal chemists and pharmacologists. Thus, the progress of diverse gossypol derivatives and analogs' synthesis, biological activities, mechanism elucidation and drug discovery based on gossypol scaffold is summarized. PMID- 28722471 TI - Simulated annealing molecular dynamics and ligand-receptor contacts analysis for pharmacophore modeling. AB - AIM: Ligand-based pharmacophore modeling requires long list of inhibitors, while pharmacophores based on single ligand-receptor crystallographic structure can be too restricted or promiscuous. METHODOLOGY: This prompted us to combine simulated annealing molecular dynamics (SAMD) with ligand-receptor contacts analysis as means to construct pharmacophore model(s) from single ligand-receptor complex. Ligand-receptor contacts that survive numerous heating-cooling SAMD cycles are considered critical and are used to guide pharmacophore development. RESULTS: This methodology was implemented to develop pharmacophores for acetylcholinesterase and protein kinase C-theta. The resulting models were validated by receiver-operating characteristic analysis and in vitro bioassay. Assay identified four new protein kinase C-theta inhibitors among captured hits, two of which exhibited nanomolar potencies. CONCLUSION: The results illustrate the ability of the new method to extract valid pharmacophores from single ligand protein complex. PMID- 28722470 TI - Novel potent inhibitors of the histone demethylase KDM1A (LSD1), orally active in a murine promyelocitic leukemia model. AB - BACKGROUND: Histone lysine demethylases (KDMs) are well-recognized targets in oncology drug discovery. They function at the post-translation level controlling chromatin conformation and gene transcription. KDM1A is a flavin adenine dinucleotide-dependent amine oxidase, overexpressed in several tumor types, including acute myeloid leukemia, neuroblastoma and non-small-cell lung cancer. Among the many known monoamine oxidase inhibitors screened for KDM1A inhibition, tranylcypromine emerged as a moderately active hit, which irreversibly binds to the flavin adenine dinucleotide cofactor. MATERIAL & METHODS: The KDM1A inhibitors 5a-w were synthesized and tested in vitro and in vivo. The biochemical potency was determined, modulation of target in cells was demonstrated on KDM1A dependent genes and the anti-clonogenic activity was performed in murine acute promyelocytic Leukemia (APL) blasts. An in vivo efficacy experiment was conducted using an established murine promyelocytic leukemia model. RESULTS: We report a new series of tranylcypromine derivatives substituted on the cyclopropyl moiety, endowed with high potency in both biochemical and cellular assays. CONCLUSION: The most interesting derivative (5a) significantly improved survival rate after oral administration in a murine model of promyelocitic leukemia. PMID- 28722472 TI - 1-(Benzenesulfonyl)-1,5-dihydro-4,1-benzoxazepine as a new scaffold for the design of antitumor compounds. AB - AIM: Bozepinib is a potent and selective anticancer compound which chemical structure is made up of a benzofused seven-membered ring and a purine moiety. We previously demonstrated that the purine fragment does not exert antiproliferative effect per se. METHODOLOGY: A series of 1-(benzenesulfonyl)-4,1-benzoxazepine derivatives were synthesized in order to study the influence of the benzofused seven-membered ring in the biological activity of bozepinib by means of antiproliferative, cell cycle and apoptosis studies. RESULTS & CONCLUSION: Our results show that the methyleneoxy enamine sulfonyl function is essential in the antitumor activity of the structures and thus, it is a scaffold suitable for further modification with a view to obtain more potent antitumor compounds. PMID- 28722473 TI - Distribution and diversity of twelve Curcuma species in China. AB - Genus Curcuma a wild species presents an important source of valuable characters for improving the cultivated Curcuma varieties. Based on the collected germplasms, herbariums, field surveys and other literatures, the ecogeographical diversity of Genus Curcuma and its potential distributions under the present and future climate are analysed by DIVA-GIS. The results indicate Genus Curcuma is distributed over 17 provinces in China, and particularly abundant in Guangxi and Guangdong provinces. The simulated current distributions are close to the actual distribution regions. In the future climate, the suitable areas for four Curcuma species will be extended, while for other three species the regions will be significantly decreased, and thus these valuable resources need protecting. PMID- 28722474 TI - When will small molecule lactate dehydrogenase inhibitors realize their potential in the cancer clinic? PMID- 28722475 TI - ANN QSAR workflow for predicting the inhibition of HIV-1 reverse transcriptase by pyridinone non-nucleoside derivatives. AB - AIM: Pyridinone derivatives have high potency against non-nucleoside reverse transcriptase inhibitor (NNRTI)-resistant human immunodeficiency virus type-1 strains. Quantitative structure-activity relationship (QSAR) studies on a series of pyridinone derivatives acting as NNRTIs are very important in designing the next generation of NNRTIs. Methodology & results: The QSAR models were developed using linear (single and forward stepwise) and combined nonlinear artificial neural network (ANN) approaches. ANN provided QSAR model with highly correlating values of 0.963, 0.964, 0.920 and 0.917, corresponding to the biological activity pIC50 of the training, validation, testing and all samples, respectively. CONCLUSION: The nonlinear ANN-QSAR model based on the topological polarizability, geometrical steric, hydrophobicity and substituted benzene functional group indices might be able to help for designing novel pyridinone NNRTIs. PMID- 28722476 TI - Evaluation of resazurin microtiter plate assay and HPLC- photodiode array analysis of the roots of Asparagus adscendens. AB - Asparagus adscendens Roxb. (Asparagaceae), is native to the Himalayas. The present study, for the first time, was undertaken to explore the antimicrobial potential, to determine the minimum inhibitory concentration (MIC) values of the methanol extract of the roots of A. adscendens and its solid-phase extraction (SPE) fractions using resazurin microtitre assay against Gram-positive and negative bacterial-registered strains and to carry out HPLC-photodiode array analysis of the SPE fractions. The methanol extract and all SPE exhibited considerable level of antibacterial potential against Gram-positive bacteria (MIC: 2.5-0.009 mg/mL) than against Gram-negative bacteria (MIC: 1.25-2.5 mg/mL). The use of microtitre plates has the advantage of lower cost, fast and quantitative results. Like other Asparagus species, the presence of phenolic compounds in all SPE fractions was evident in the HPLC-PDA data. PMID- 28722477 TI - Advances toward LSD1 inhibitors for cancer therapy. AB - LSD1 has become an important biologically validated epigenetic target for cancer therapy since its identification in 2004. LSD1 mediates many cellular signaling pathways and is involved in the initiation and development of cancers. Aberrant overexpression of LSD1 has been observed in different types of cancers, and inactivation by small molecules suppresses cancer cell differentiation, proliferation, invasion and migration. To date, a large number of LSD1 inhibitors have been reported, RG6016, GSK-2879552, INCB059872, IMG-7289 and CC-90011 are currently undergoing clinical assessment for the treatment of acute myeloid leukemia, small-cell lung cancer, etc. In this review, we briefly highlight recent advances of LSD1 inhibitors mainly covering the literatures from 2015 to 2017 and tentatively propose our perspectives on the design of new LSD1 inhibitors for cancer therapy. PMID- 28722478 TI - Rho-kinase inhibitors from adlay seeds. AB - Rho-kinase enzymes are one of the most important targets recently identified in our bodies. Several lines of evidence indicate that these enzymes are involved in many diseases and cellular disorders. ROCK inhibitors may have clinical applications for cancer, hypertension, glaucoma, etc. Our study aims to identify the possible involvement of Rho-kinase inhibition to the multiple biological activities of adlay seeds and provide a rationale for their folkloric medicines. Hence, we evaluated Rho-kinase I and II inhibitory activity of the ethanol extract and 28 compounds derived from the seeds. A molecular docking assay was designed to estimate the binding affinity of the tested compounds with the target enzymes. The results of our study suggest a possible involvement of Rho-kinase inhibition to the multiple biological activities of the seeds. Furthermore, the results obtained with the tested compounds revealed some interesting skeletons as a scaffold for design and development of natural Rho-kinase inhibitors. PMID- 28722479 TI - Oxindole-based SYK and JAK3 dual inhibitors for rheumatoid arthritis: designing, synthesis and biological evaluation. AB - AIM: Autoimmune disorders have complex pathophysiology and focus is laid on the development of multitargeted agents. Two well-established kinases: SYK and JAK3, were considered to design dual inhibitors as potential therapeutics using various molecular-modeling approaches. Mehodology: Pharmacophore models for SYK and JAK3 were generated using oxindole-based inhibitors. Furthermore, an in-house database was designed that was screened against the best selected models. The obtained hits were employed for docking analysis and subjected to MM-GBSA analysis and molecular dynamic simulation. RESULTS: Top five oxindole derivatives were synthesized and evaluated for in vitro SYK and JAK3 activity. The most active compound 4a was evaluated for in vivo antiarthritic activity. It showed significant anti-arthritic activity. CONCLUSION: Thus, the designed inhibitors resulted in potential therapeutic agents for rheumatoid arthritis. PMID- 28722480 TI - Efficacy and Safety of Biosimilar SAR342434 Insulin Lispro in Adults with Type 1 Diabetes Also Using Insulin Glargine-SORELLA 1 Study. AB - BACKGROUND: SAR342434 is a biosimilar follow-on of insulin lispro-Humalog(r). This study aimed to show similar efficacy, safety, and immunogenicity of SAR342434 (SAR-Lis) versus insulin lispro-Humalog (Ly-Lis) in adult patients with type 1 diabetes (T1DM) treated with multiple daily injections while using basal insulin glargine (Lantus(r); GLA-100). MATERIALS AND METHODS: SORELLA-1 was a randomized, open-label phase 3 study (NCT02273180). Patients completing the 6 month main study continued on SAR-Lis or Ly-Lis, as randomized, for a 6-month safety extension. Assessments included change in HbA1c, fasting plasma glucose (FPG), seven-point self-monitored plasma glucose (SMPG) profiles, hypoglycemic events, treatment-emergent adverse events (TEAEs), and anti-insulin antibodies (AIAs). RESULTS: Five hundred seven patients were randomized (SAR-Lis n = 253; Ly Lis n = 254). Least square (LS) mean (SEM) change in glycosylated hemoglobin (HbA1c) (baseline to week 26; primary endpoint) was similar in both treatment groups (SAR-Lis: -0.42% [0.051]; Ly-Lis: -0.47% [0.050]). Noninferiority at prespecified 0.3% noninferiority margin and inverse noninferiority were demonstrated (LS mean difference of SAR-Lis vs. Ly-Lis: 0.06% [95% confidence interval: -0.084 to 0.197]). At week 52 (end of extension period) versus week 26, a small HbA1c increase was observed in both groups. FPG and seven-point SMPG profile changes, including postprandial glucose excursions, were similar between groups. At week 52, similar changes in mean daily mealtime and basal insulin doses were observed. Hypoglycemia, TEAEs, and AIAs (incidence, prevalence) did not differ between groups. CONCLUSIONS: Results from this controlled study in patients with T1DM also using GLA-100 support similar efficacy and long-term safety (including immunogenicity) of SAR-Lis and Ly-Lis. PMID- 28722482 TI - An Economic Evaluation of Food Safety Education Interventions: Estimates and Critical Data Gaps. AB - The economic evaluation of food safety interventions is an important tool that practitioners and policy makers use to assess the efficacy of their efforts. These evaluations are built on models that are dependent on accurate estimation of numerous input variables. In many cases, however, there is no data available to determine input values and expert opinion is used to generate estimates. This study uses a benefit-cost analysis of the food safety component of the adult Expanded Food and Nutrition Education Program (EFNEP) in Ohio as a vehicle for demonstrating how results based on variable values that are not objectively determined may be sensitive to alternative assumptions. In particular, the focus here is on how reported behavioral change is translated into economic benefits. Current gaps in the literature make it impossible to know with certainty how many people are protected by the education (what are the spillover effects?), the length of time education remains effective, and the level of risk reduction from change in behavior. Based on EFNEP survey data, food safety education led 37.4% of participants to improve their food safety behaviors. Under reasonable default assumptions, benefits from this improvement significantly outweigh costs, yielding a benefit-cost ratio of between 6.2 and 10.0. Incorporation of a sensitivity analysis using alternative estimates yields a greater range of estimates (0.2 to 56.3), which highlights the importance of future research aimed at filling these research gaps. Nevertheless, most reasonable assumptions lead to estimates of benefits that justify their costs. PMID- 28722481 TI - Clinical Management of Pediatric Acute-Onset Neuropsychiatric Syndrome: Part I Psychiatric and Behavioral Interventions. AB - OBJECTIVE: This article outlines the consensus guidelines for symptomatic treatment for children with Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS) and Pediatric Autoimmune Neuropsychiatric Syndrome Associated with Streptococcal Infection (PANDAS). METHODS: Extant literature on behavioral, psychotherapeutic, and psychopharmacologic treatments for PANS and PANDAS was reviewed. Members of the PANS Research Consortium pooled their clinical experiences to find agreement on treatment of PANS and PANDAS symptoms. RESULTS: Current guidelines result from consensus among the Consortium members. CONCLUSION: While underlying infectious and inflammatory processes in PANS and PANDAS patients are treated, psychiatric and behavioral symptoms need simultaneous treatment to decrease suffering and improve adherence to therapeutic intervention. Psychological, behavioral, and psychopharmacologic interventions tailored to each child's presentation can provide symptom improvement and improve functioning during both the acute and chronic stages of illness. In general, typical evidence-based interventions are appropriate for the varied symptoms of PANS and PANDAS. Individual differences in expected response to psychotropic medication may require marked reduction of initial treatment dose. Antimicrobials and immunomodulatory therapies may be indicated, as discussed in Parts 2 and 3 of this guideline series. PMID- 28722483 TI - Food Safety Practices in the U.S. Meat Slaughter and Processing Industry: Changes from 2005 to 2015. AB - Meat slaughter establishments use a multipronged approach to ensure beef and pork products are safe for human consumption. To determine the approaches most commonly used, we conducted a national survey of federally inspected meat slaughter and processing establishments (376 completed surveys, 66% response rate) in 2015. We compared the results with a survey that was conducted in 2005, albeit of potentially different establishments, by using a similar questionnaire and similar data collection methods, thus allowing for an evaluation of trends in food safety practices over time. The use of some food safety practices has increased over the 10-yr time period, whereas others remained the same or decreased. For example, the use of chemical sanitizers or hot water for food contact surfaces and tools increased from 51 to 93%. As another example, microbiological testing of raw meat after fabrication, in addition to that required by regulation, increased from 50 to 72%. However, the use of organic acid rinse on carcasses in the slaughter area remained the same, at 66% of establishments. Written policies and procedures to control the use of hazardous chemicals decreased from 75 to 65% of establishments. The survey findings can be used to characterize food safety practices and technologies in the meat slaughter and processing industry and identify areas for improvement. PMID- 28722484 TI - Consumer Perceptions of the Safety of Ready-to-Eat Foods in Retail Food Store Settings. AB - To better understand how consumers perceive food safety risks in retail food store settings, a survey was administered to 1,041 nationally representative participants who evaluated possible food safety risks depicted in selected photographs and self-reported their perceptions, attitudes, and behaviors. Participants were shown 12 photographs taken at retail stores portraying either commonly perceived or actual food safety contributing factors, such as cross contamination, product and equipment temperatures, worker hygiene, and/or store sanitation practices. Participants were then asked to specifically identify what they saw, comment as to whether what they saw was safe or unsafe, and articulate what actions they would take in response to these situations. In addition to the survey, focus groups were employed to supplement survey findings with qualitative data. Survey respondents identified risk factors for six of nine actual contributing factor photographs >50% of the time: poor produce storage sanitation (86%, n = 899), cross-contamination during meat slicing (72%, n = 750), bare-hand contact of ready-to-eat food in the deli area (67%, n = 698), separation of raw and ready-to-eat food in the seafood case (63%, n = 660), cross-contamination from serving utensils in the deli case (62%, n = 644), and incorrect product storage temperature (51%, n = 528). On a scale of 1 to 5, where 1 was very unsafe and 5 was very safe, a significant difference was found between average risk perception scores for photographs of actual contributing factors (score of ca. 2.5) and scores for photographs of perceived contributing factors (score of ca. 2.0). Themes from the focus groups supported the results of the survey and provided additional insight into consumer food safety risk perceptions. The results of this study inform communication interventions for consumers and retail food safety professionals aimed at improving hazard identification. PMID- 28722485 TI - Characterization of Nontyphoidal Salmonella Isolates from Asymptomatic Migrant Food Handlers in Peninsular Malaysia. AB - Asymptomatic Salmonella carriers who work as food handlers pose food safety and public health risks, particularly during food preparation, and this has serious implications for the disease burden in society. Therefore, we conducted a study to determine the number of Salmonella carriers in a migrant cohort in several food establishments in three major cities in Peninsular Malaysia. Sociodemographic data and stool samples were collected and analyzed using standard methods of detection and isolation. Antimicrobial susceptibility tests of the positive samples were also performed. A total of 317 migrant food handlers, originating from South and Southeast Asian countries, were recruited voluntarily. Nine (2.8%) stool samples were confirmed to be Salmonella positive. PCR serotyping and pulsed-field gel electrophoresis identified four serotypes as Typhimurium (n = 3), Corvallis (n = 2), Hadar (n = 1), Agona (n = 1) and two unknown serovars. Antimicrobial susceptibility tests revealed that all nine isolates were susceptible to amoxicillin-clavulanic acid, cefotaxime, ceftazidime, ceftriaxone, and gentamycin. However, seven isolates were found to be multidrug resistant to ampicillin, chloramphenicol, trimethoprim sulfamethoxazole, sulfonamides, streptomycin, and tetracycline. This study highlights that carriers of nontyphoidal Salmonella exist among migrant food handlers, which poses a health risk to consumers through food contamination. Our results indicate a need for authorities to enhance food safety awareness in the migrant workers and to reevaluate current health screening methods to include preventive measure such as mandatory stool screening as part of the preemployment and routine health examinations. PMID- 28722486 TI - Neurotoxic effects of subchronic intratracheal Mn nanoparticle exposure alone and in combination with other welding fume metals in rats. AB - Manganese (Mn) is a toxic heavy metal exposing workers in various occupational settings and causing, among others, nervous system damage. Metal fumes of welding, a typical source of Mn exposure, contain a complex mixture of metal oxides partly in nanoparticle form. As toxic effects of complex substances cannot be sufficiently understood by examining its components separately, general toxicity and functional neurotoxicity of a main pathogenic welding fume metal, Mn, was examined alone and combined with iron (Fe) and chromium (Cr), also frequently found in fumes. Oxide nanoparticles of Mn, Mn + Fe, Mn + Cr and the triple combination were applied, in aqueous suspension, to the trachea of young adult Wistar rats for 4 weeks. The decrease of body weight gain during treatment, caused by Mn, was counteracted by Fe, but not Cr. At the end of treatment, spontaneous and evoked cortical electrical activity was recorded. Mn caused a shift to higher frequencies, and lengthened evoked potential latency, which were also strongly diminished by co-application of Fe only. The interaction of the metals seen in body weight gain and cortical activity were not related to the measured blood and brain metal levels. Fe might have initiated protective, e.g. antioxidant, mechanisms with a more general effect. PMID- 28722487 TI - Left ventricular hypertrophy in acute stroke patients with known hypertension. AB - BACKGROUND: Despite effective treatments, hypertension remains uncontrolled in nearly half of the people with hypertension in the United States. Uncontrolled hypertension leads to end organ damage, such as left ventricular hypertrophy (LVH). To identify reasons for uncontrolled hypertension, we interviewed acute stroke patients with a history of hypertension and evaluated for LVH. METHODS: Using a standardized questionnaire, we collected demographic, socioeconomic, and health-care data in 300 acute ischemic and hemorrhagic stroke patients in one hospital. We also collected relevant clinical data from medical records. We analyzed factors associated with echocardiographic LVH as a marker of uncontrolled hypertension in 190 acute stroke patients with a history of hypertension. RESULTS: Overall, 46% (88/190) of patients had LVH. In univariate analysis, lower household income and self-reported poor adherence to hypertension treatment were significantly associated with increased risk of LVH. In multiple logit modeling, only poor adherence to hypertension treatment remained significantly associated with LVH, odds ratio 1.77 (95% CI: 1.01-3.11), p < 0.05. CONCLUSIONS: In acute stroke patients, poor adherence to hypertension treatment is a significant independent predictor of LVH. A clear reason for poor adherence to treatment is elusive in a large proportion of these patients in our study. Further research is needed to identify and develop strategies to combat the key factors responsible for poor adherence to hypertension treatment. PMID- 28722488 TI - Berberine promotes ischemia-induced angiogenesis in mice heart via upregulation of microRNA-29b. AB - BACKGROUND: Berberine has several preventive effects on cardiovascular diseases. Increased expression of miR-29b has been reported to attenuate cardiac remodeling after myocardial infarction (MI). We hypothesized that berberine via an miR-29b dependent mechanism promotes angiogenesis and improves heart functions in mice after MI. METHODS: The MI model was established in mice by ligation of left anterior descending coronary artery. The expression of miR-29b was examined by RT qPCR. Angiogenesis was assessed by immunohistochemistry. RESULTS: Berberine increased miR-29b expression and promoted cell proliferations and migrations in cultured endothelial cells, which were abolished by miR-29b antagomir or AMP activated protein kinase inhibitor compound C. In mice following MI, administration of berberine significantly increased miR-29b expressional level, promoted angiogenesis, reduced infarct size, and improved heart functions after 14 postoperative days. Importantly, these in vivo effects of berberine were ablated by antagonism of miR-29b. CONCLUSION: Berberine via upregulation of miR 29b promotes ischemia-induced angiogenesis and improves heart functions. PMID- 28722489 TI - Treatment of Die-Punch Fractures with 3D Printing Technology. AB - PURPOSE: We evaluated the feasibility, accuracy and effectiveness of applying three-dimensional (3D) printing technology for preoperative planning for die punch fractures. METHODS: A total of 107 patients who underwent die-punch fracture surgery were enrolled in the study. They were randomly divided into two groups: 52 cases in the 3D model group and 55 cases in the routine group. A 3D digital model of each die-punch fracture was reconstructed in the 3D group. The 3D digital model was imported to a 3D printer to build the full solid model. The operation time, blood loss volume, and the number of intraoperative fluoroscopy were recorded. Follow-up was performed to evaluate the patients' surgical outcomes. RESULTS: Treatment of die-punch fractures using the 3D printing approach reduced the number of intraoperative fluoroscopy, blood loss volume, and operation time, but did not improve wrist function compared to those in the routine group. The patients wanted the doctor to use the 3D model to introduce the condition and operative plan because it was easier for them to understand. The orthopedic surgeons thought that the 3D model was useful for communicating with their patients, but their satisfaction with the preoperative plan was much lower than the benefit of using the 3D model to communicate with their patients. CONCLUSIONS: 3D printing technology produced more accurate morphometric information for orthopedists to provide personalized surgical planning and communicate better with their patients. However, it is difficult to use widely in the department of orthopedics. PMID- 28722491 TI - Comparative Effectiveness of Plantar-Massage Techniques on Postural Control in Those With Chronic Ankle Instability. AB - CONTEXT: One of the major concerns after an acute lateral ankle sprain is the potential for development of chronic ankle instability (CAI). The existing research has determined that clinician-delivered plantar massage improves postural control in those with CAI. However, the effectiveness of self administered treatments and the underlying cause of any improvements remain unclear. OBJECTIVES: To determine (1) the effectiveness of a self-administered plantar-massage treatment in those with CAI and (2) whether the postural-control improvements were due to the stimulation of the plantar cutaneous receptors. DESIGN: Crossover study. SETTING: University setting. PATIENTS OR OTHER PARTICIPANTS: A total of 20 physically active individuals (6 men and 14 women) with self-reported CAI. INTERVENTION(S): All participants completed 3 test sessions involving 3 treatments: a clinician-delivered manual plantar massage, a patient-delivered self-massage with a ball, and a clinician-delivered sensory brush massage. MAIN OUTCOME MEASURE(S): Postural control was assessed using single-legged balance with eyes open and the Star Excursion Balance Test. RESULTS: Static postural control improved (P <= .014) after each of the interventions. However, no changes in dynamic postural control after any of the interventions were observed (P > .05). No differences were observed between a clinician-delivered manual plantar massage and either a patient-delivered self massage with a ball or a clinician-delivered sensory brush massage in any postural-control outcome. CONCLUSIONS: In those with CAI, single 5-minute sessions of traditional plantar massage, self-administered massage, and sensory brush massage each resulted in comparable static postural-control improvements. The results also provide empirical evidence suggesting that the mechanism for the postural-control improvements is the stimulation of the plantar cutaneous receptors. PMID- 28722493 TI - Analysis of thirteen predatory publishers: a trap for eager-to-publish researchers. AB - OBJECTIVE: To demonstrate a strategy employed by predatory publishers to trap eager-to-publish authors or researchers into submitting their work. METHODS: This was a case study of 13 potential, possible, or probable predatory scholarly open access publishers with similar characteristics. Eleven publishers were included from Beall's list and two additional publishers were identified from a Google web search. Each publisher's site was visited and its content analyzed. Publishers publishing biomedical journals were further explored and additional data was collected regarding their volumes, details of publications and editorial-board members. RESULTS: Overall, the look and feel of all 13 publishers was similar including names of publishers, website addresses, homepage content, homepage images, list of journals and subject areas, as if they were copied and pasted. There were discrepancies in article-processing charges within the publishers. None of the publishers identified names in their contact details and primarily included only email addresses. Author instructions were similar across all 13 publishers. Most publishers listed journals of varied subject areas including biomedical journals (12 publishers) covering different geographic locations. Most biomedical journals published none or very few articles. The highest number of articles published by any single biomedical journal was 28. Several editorial board members were listed across more than one journals, with one member listed 81 times in different 69 journals (i.e. twice in 12 journals). CONCLUSION: There was a strong reason to believe that predatory publishers may have several publication houses with different names under a single roof to trap authors from different geographic locations. PMID- 28722494 TI - Cost-efficiency analyses for the US of biosimilar filgrastim-sndz, reference filgrastim, pegfilgrastim, and pegfilgrastim with on-body injector in the prophylaxis of chemotherapy-induced (febrile) neutropenia. AB - AIMS: Guidelines recommend prophylaxis with granulocyte colony-stimulating factor for chemotherapy-induced (febrile) neutropenia (CIN/FN) based on regimen myelotoxicity and patient-related risk factors. The aim was to conduct a cost efficiency analysis for the US of the direct acquisition and administration costs of the recently approved biosimilar filgrastim-sndz (Zarxio EP2006) with reference to filgrastim (Neupogen), pegfilgrastim (Neulasta), and a pegfilgrastim injection device (Neulasta Onpro; hereafter pegfilgrastim-injector) for CIN/FN prophylaxis. METHODS: A cost-efficiency analysis of the prophylaxis of one patient during one chemotherapy cycle under 1-14 days' time horizon was conducted using the unit dose average selling price (ASP) and Current Procedural Terminology (CPT) codes for subcutaneous prophylactic injection under four scenarios: cost of medication only (COSTMED), patient self-administration (SELFADMIN), healthcare provider (HCP) initiating administration followed by self administration (HCPSTART), and HCP providing full administration (HCPALL). Two case studies were created to illustrate real-world clinical implications. The analyses were replicated using wholesale acquisition cost (WAC). RESULTS: Using ASP + CPT, cost savings achieved with filgrastim-sndz relative to reference filgrastim ranged from $65 (1 day) to $916 (14 days) across all scenarios. Relative to pegfilgrastim, savings with filgrastim-sndz ranged from $834 (14 days) up to $3,666 (1 day) under the COSTMED, SELFADMIN, and HPOSTART scenarios; and from $284 (14 days) up to $3,666 (1 day) under the HPOALL scenario. Similar to the cost-savings compared to pegfilgrastim, filgrastim-sndz achieved savings relative to pegfilgrastim-injector: from $834 (14 days) to $3,666 (1 day) under the COSTMED scenario, from $859 (14 days) to $3,692 (1 day) under SELFADMIN, from $817 (14 days) to $3,649 (1 day) under HPOSTART, and from $267 (14 days) to $3,649 (1 day) under HPOALL. Cost savings of filgrastim-sndz using WAC + CPT were even greater under all scenarios. CONCLUSIONS: Prophylaxis with filgrastim-sndz, a biosimilar filgrastim, was associated consistently with significant cost savings over prophylaxis with reference filgrastim, pegfilgrastim, and pegfilgrastim-injector, and this across various administration scenarios. PMID- 28722495 TI - Sucrose Non-Fermenting Related Kinase Expression in Ovarian Cancer and Correlation with Clinical Features. AB - Sucrose non-fermenting related kinase (SNRK) is a serine/threonine kinase known to regulate cellular metabolism and adipocyte inflammation. Since alterations in adipocyte metabolism play a role in ovarian cancer metastasis, we investigated the expression of SNRK in benign and malignant human ovarian tissue using immunohistochemistry and qPCR. The number of SNRK positive (+) nuclei is increased in malignant tissue compared to benign tissue (21.03% versus 14.90%, p < .0431). The most strongly stained malignant SNRK+ nuclei were stage 1 compared to stage 2-4 disease. Differential expression of SNRK in early versus late stage disease suggests specific roles for SNRK in ovarian cancer metastasis. PMID- 28722497 TI - Correction to: Wang Y et al., Association of ribosomal protein S6 kinase 1 with cellular radiosensitivity of non-small lung cancer. PMID- 28722496 TI - Lamesticumin G, a new alpha-glucosidase inhibitor from the fruit peels of Lansium parasiticum. AB - A novel onoceranoid triterpene, named lamesticumin G (1) along with four known compounds (2-5) were isolated from the ethyl acetate extract of the fruit peels of Lansium parasiticum. The structure of lamesticumin G (1) was fully characterised using spectroscopic data. Lamesticumin G (1) inhibited alpha glucosidase (maltase) with IC50 value of 2.27 mM, while 2-5 showed no inhibition. PMID- 28722498 TI - Better Prognosis of Senile Patients with Intertrochanteric Femoral Fracture by Treatment with Open Reduction Internal Fixation than by Hip Arthroplasty. AB - PURPOSE: To compare the postoperative survival and mortality rates in intertrochanteric femoral fracture (IFF) patients who underwent either open reduction internal fixation (ORIF) or hip arthroplasty. METHODS: Clinical data from senior patients who had IFF and underwent ORIF or hip arthroplasty were analyzed retrospectively. Survival curves were compared between groups with Kaplan-Meier method and log-rank test. Significant independent prognostic factors were identified by Cox multivariate regression analysis. RESULTS: All patients recovered fully post-surgery. Although 31 patients died during the follow-up period (ORIF, mean 45.4 months; arthroplasty, mean 51.6 months), mortality rate did not differ significantly between the groups. The 1-yr and 2-yr survival rate estimates for the ORIF group were 92.2%, and 86%, respectively; they were 85% and 74% for the arthroplasty group. Average survival lengths for ORIF and arthroplasty groups were 88 and 67 months, respectively. The effect of surgical approaches on survival differed significantly (log-rank test c2 = 6.402, p = 0.011). Multivariate Cox regression model indicated that surgical choice (p = 0.036) was a significant independent risk factor for the prognosis of senile IFF, even with adjustment for age (p = 0.002). CONCLUSION: The overall postoperative prognosis was superior in senile IFF patients treated with ORIF. PMID- 28722500 TI - Post-marketing surveillance study of the long-term use of mizoribine for the treatment of lupus nephritis: 2-Year results. AB - OBJECTIVES: To understand the status of mizoribine use in patients with lupus nephritis (LN) and to collect safety- and efficacy-related data on 2-year treatment with mizoribine. METHODS: A continuous survey was conducted between March 2010 and July 2015. RESULTS: The analysis set included 559 patients (mean age 39.5 years, females 82.6%, mean duration of systemic lupus erythematosus (SLE) 8.4 years, mean duration of LN 5.9 years). Renal function was satisfactory for 6 months, but worsened from 12 months, with significant worsening at 24 months. By the ACR 2006 remission criteria (eGFR >60), at 24 months, 26.5% of patients achieved complete remission, and 63.3% achieved complete or partial remission. The urine protein to creatinine ratio decreased significantly. The SLE Disease Activity Index 2000 score decreased significantly at 12 and 24 months. Overall, 98 (17.5%) patients experienced 124 adverse drug reactions (ADRs); 3.6% experienced serious ADRs. Mizoribine was used with a steroid in 99.3% and an immunosuppressant in 51.2%; tacrolimus was used in 43.8%. The oral steroid dosage decreased from baseline to 24 months. The incidence of ADRs was not significantly different with concomitant tacrolimus use. CONCLUSIONS: The results suggest that long-term mizoribine is safe and effective, even when used with tacrolimus. PMID- 28722499 TI - New brefeldins and penialidins from marine fungus Penicillium janthinellum DT F29. AB - A fermentation of marine fungus Penicillium janthinellum DT-F29 on solid rice medium led to the isolation of three new compounds, brefeldin D (1) and penialidins D-E (5-6), along with other five known brefeldins and penialidins. The structures of above compounds were determined on the basis of MS and NMR analysis. PMID- 28722501 TI - Pediatric endonasal dacryocystorhinostomy: A multicenter series of 116 cases. AB - We report our experience with pediatric endonasal dacryocystorhinostomy (DCR). Multicenter, retrospective, noncomparative study. Cases of pediatric endonasal DCR during 2006-2011 were included from six oculoplastic units. Patients over the age of 16 years were excluded. The outcomes of pediatric endonasal DCR are presented. Indication for surgery, demographics, previous interventions, intraoperative or postoperative complications, follow-up duration, and success rate (defined as significant improvement of epiphora) were evaluated. In total, 116 endonasal DCRs were performed for 103 patients. The mean follow-up period was 8 months (range 3 months to 4 years), with 1 patient lost to follow-up. There were 48 males (mean age 5 years and 9 months) and 50 females (range of 4 months to 16 years), with a total of 98 cases of congenital nasolacrimal duct obstruction (CNLDO) (84.5%) and 18 cases of acquired nasolacrimal duct obstruction (ANLDO) (15.5%). Previous interventions included probing 75.9% (88/116), massaging 43.1% (50/116), and intubation 39.7% (46/116). There were no intraoperative complications. There was one case of postoperative pyogenic granuloma. There were no cases of postoperative infection and postoperative hemorrhage. Ninety percent of procedures were considered successful. Complete symptom resolution was observed in 78% (90/116), significant improvement in 12% (14/116), partial improvement in 2% (2/116), and no improvement in 8% (9/116). In our series, we demonstrated that endonasal DCR is a safe operation and has an overall success rate of 90% for pediatric NLDO. PMID- 28722502 TI - Chemical analysis and antiviral activity evaluation of Baccharis anomala. AB - The chemical composition and antiviral activity of aqueous extract from Baccharis anomala was studied by bioactivity-guided fractionation. Ethanol precipitation and fractionation by molecular permeation allowed the separation of the anti herpes simplex virus 1 (HSV-1) active fraction from aqueous extract (Fraction B). Natural Product Reagent A, FeCl3 and thin-layer chromatography indicated the presence of phenolic compounds in the aqueous extract. Fraction B showed pronounced antiviral activity when tested with HSV-1 strains VR733/ATCC and Acyclovir-resistant 29-R, displaying virucidal but not virustatic activity. PMID- 28722503 TI - North American Congress of Clinical Toxicology (NACCT) Abstracts 2017. PMID- 28722504 TI - Role of tenascin-C in articular cartilage. AB - Tenascin-C (TN-C) is a glycoprotein component of the extracellular matrix (ECM). TN-C consists of four distinct domains, including the tenascin assembly domain, epidermal growth factor-like repeats, fibronectin type III-like repeats, and the fibrinogen-like globe (FBG) domain. This review summarizes the role of TN-C in articular cartilage. Expression of TN-C is associated with the development of articular cartilage but markedly decreases during maturation of chondrocytes and disappears almost completely in adult articular cartilage. Increased expression of TN-C has been found at diseased cartilage and synovial sites in osteoarthritis (OA) and rheumatoid arthritis (RA). TN-C is increased in the synovial fluid in patients with OA and RA. In addition, serum TN-C is elevated in RA patients. TN-C could be a useful biochemical marker for joint disease. The addition of TN-C results in different effects among TN-C domains. TN-C fragments might be endogenous inducers of cartilage matrix degradation; however, full-length TN-C could promote cartilage repair and prevent cartilage degeneration. The deficiency of TN-C enhanced cartilage degeneration in the spontaneous OA in aged joints and surgical OA model. The clinical significance of TN-C effects on cartilage is not straightforward. PMID- 28722505 TI - Lipolytic effect of compounds isolated from leaves of mulberry (Morus alba L.) in 3T3-L1 adipocytes. AB - In this study, 19 known compounds were isolated from mulberry (Morus alba L.) leaves. The lipid accumulation inhibitory activity of the isolated compounds was investigated. Compounds 4 and 12 showed good anti-adipogenic activity based on 3T3-L1 adipocytes with values of 36.6 +/- 9.0 and 34.7 +/- 4.0%, respectively. In addition, compounds 3, 6 and 15 showed significant inhibitory activity with values from 15.4 to 21.2% and compounds 2, 8-9 and 17-18 exhibited weak activity with values ranging from 2.1 to 10.7% at a concentration of 40.0 MUM. These results show the potentiality that mulberry leaf is an excellent inhibitory phytochemical source against lipid accumulation. PMID- 28722506 TI - Diffusion-weighted magnetic resonance imaging of parotid glands before and after abatacept therapy in patients with Sjogren's syndrome associated with rheumatoid arthritis: Utility to evaluate and predict response to treatment. AB - OBJECTIVE: To compare parotid diffusion-weighted images (DWIs) taken before and after abatacept therapy in patients with Sjogren's syndrome (SS) associated with rheumatoid arthritis (RA) and to examine the utility in evaluation and prediction of response to therapy. METHODS: DWIs of the parotid glands taken at baseline and 52 weeks after initiation of abatacept were analyzed in nine SS patients with RA using relative standard deviation (RSD) of the entire glands and signal intensity ratio (SIR) within the residual parenchyma. The correlation between changes in RSD and SIR and changes in salivary secretion based on Saxon's test was examined. Furthermore, baseline characteristics were compared in patients with increased and decreased salivary secretion after treatment. The predictive power of the parameter at baseline was examined using receiver operating characteristic (ROC) analysis. RESULTS: Abatacept improved salivary secretion from 2076 +/- 1535 at baseline to 2857 +/- 1431 mg/2 min at 52 weeks (n = 9, p = .05). Increase of salivary secretion was significantly higher in patients with decreased RSD (n = 6) than increased RSD (n = 3) (1241 +/- 713, -137 +/- 142 mg/2 min, p = .02). The increase and decrease in RSD completely accorded with those of salivary secretion. Furthermore, SIR was the only parameter that was significantly different between patients with posttreatment increase and decrease in salivary secretion (p = .04). ROC analysis showed the sensitivity and specificity of SIR at baseline of >=13.0 * 10-2 for the prediction of the response to abatacept were 75.0% and 83.3%, respectively. CONCLUSIONS: Parotid DWI seems to be useful for evaluating and predicting the response in salivary secretion to abatacept in SS patients with RA. PMID- 28722507 TI - Polyglutamine tracts regulate autophagy. AB - Expansions of polyglutamine (polyQ) tracts in different proteins cause 9 neurodegenerative conditions, such as Huntington disease and various ataxias. However, many normal mammalian proteins contain shorter polyQ tracts. As these are frequently conserved in multiple species, it is likely that some of these polyQ tracts have important but unknown biological functions. Here we review our recent study showing that the polyQ domain of the deubiquitinase ATXN3/ataxin-3 enables its interaction with BECN1/beclin 1, a key macroautophagy/autophagy initiator. ATXN3 regulates autophagy by deubiquitinating BECN1 and protecting it from proteasomal degradation. Interestingly, expanded polyQ tracts in other polyglutamine disease proteins compete with the shorter ATXN3 polyQ stretch and interfere with the ATXN3-BECN1 interaction. This competition results in decreased BECN1 levels and impaired starvation-induced autophagy, which phenocopies the loss of autophagic function mediated by ATXN3. Our findings describe a new autophagy-protective mechanism that may be altered in multiple neurodegenerative diseases. PMID- 28722508 TI - Atg5- and Atg7-dependent autophagy in dopaminergic neurons regulates cellular and behavioral responses to morphine. AB - The molecular basis of chronic morphine exposure remains unknown. In this study, we hypothesized that macroautophagy/autophagy of dopaminergic neurons would mediate the alterations of neuronal dendritic morphology and behavioral responses induced by morphine. Chronic morphine exposure caused Atg5 (autophagy-related 5)- and Atg7 (autophagy-related 7)-dependent and dopaminergic neuron-specific autophagy resulting in decreased neuron dendritic spines and the onset of addictive behaviors. In cultured primary midbrain neurons, morphine treatment significantly reduced total dendritic length and complexity, and this effect could be reversed by knockdown of Atg5 or Atg7. Mice deficient for Atg5 or Atg7 specifically in the dopaminergic neurons were less sensitive to developing a morphine reward response, behavioral sensitization, analgesic tolerance and physical dependence compared to wild-type mice. Taken together, our findings suggested that the Atg5- and Atg7-dependent autophagy of dopaminergic neurons contributed to cellular and behavioral responses to morphine and may have implications for the future treatment of drug addiction. PMID- 28722509 TI - Adaptation of mRNA structure to control protein folding. AB - Comparison of mRNA and protein structures shows that highly structured mRNAs typically encode compact protein domains suggesting that mRNA structure controls protein folding. This function is apparently performed by distinct structural elements in the mRNA, which implies 'fine tuning' of mRNA structure under selection for optimal protein folding. We find that, during evolution, changes in the mRNA folding energy follow amino acid replacements, reinforcing the notion of an intimate connection between the structures of a mRNA and the protein it encodes, and the double encoding of protein sequence and folding in the mRNA. PMID- 28722510 TI - BNIP3L-dependent mitophagy accounts for mitochondrial clearance during 3 factors induced somatic cell reprogramming. AB - Induced pluripotent stem cells (iPSCs) have fewer and immature mitochondria than somatic cells and mainly rely on glycolysis for energy source. During somatic cell reprogramming, somatic mitochondria and other organelles get remodeled. However, events of organelle remodeling and interaction during somatic cell reprogramming have not been extensively explored. We show that both SKP/SKO (Sox2, Klf4, Pou5f1/Oct4) and SKPM/SKOM (SKP/SKO plus Myc/c-Myc) reprogramming lead to decreased mitochondrial mass but with different kinetics and by divergent pathways. Rapid, MYC/c-MYC-induced cell proliferation may function as the main driver of mitochondrial decrease in SKPM/SKOM reprogramming. In SKP/SKO reprogramming, however, mitochondrial mass initially increases and subsequently decreases via mitophagy. This mitophagy is dependent on the mitochondrial outer membrane receptor BNIP3L/NIX but not on mitochondrial membrane potential (DeltaPsim) dissipation, and this SKP/SKO-induced mitophagy functions in an important role during the reprogramming process. Furthermore, endosome-related RAB5 is involved in mitophagosome formation in SKP/SKO reprogramming. These results reveal a novel role of mitophagy in reprogramming that entails the interaction between mitochondria, macroautophagy/autophagy and endosomes. PMID- 28722511 TI - GRWD1, a new player among oncogenesis-related ribosomal/nucleolar proteins. AB - Increasing attention has been paid to certain ribosomal or ribosome biosynthesis related proteins involved in oncogenesis. Members of one group are classified as "tumor suppressive factors" represented by RPL5 and RPL11; loss of their functions leads to cancer predisposition. RPL5 and RPL11 prevent tumorigenesis by binding to and inhibiting the MDM2 ubiquitin ligase and thereby up-regulating p53. Many other candidate tumor suppressive ribosomal/nucleolar proteins have been suggested. However, it remains to be experimentally clarified whether many of these factors can actually prevent tumorigenesis and if so, how they do so. Conversely, some ribosomal/nucleolar proteins promote tumorigenesis. For example, PICT1 binds to and anchors RPL11 in nucleoli, down-regulating p53 and promoting tumorigenesis. GRWD1 was recently identified as another such factor. When overexpressed, GRWD1 suppresses p53 and transforms normal human cells, probably by binding to RPL11 and sequestrating it from MDM2. However, other pathways may also be involved. PMID- 28722512 TI - In silico and in vitro evaluation of two novel oximes (K378 and K727) in comparison to K-27 and pralidoxime against paraoxon-ethyl intoxication. AB - Organophosphate (OP) poisoning is a major global health issue; while compounds from this group have been used intensively over the last century, an effective antidote is still lacking. Oxime-type acetylcholinesterase (AChE) reactivators are used to reactivate the OP inhibited AChE. Pralidoxime is the only US Food and Drug Administration approved oxime for therapeutic use but its efficacy has been disappointing. Two novel oximes (K378 and K727) were investigated in silico and in vitro and compared with an experimental oxime (kamiloxime; K-27) and pralidoxime. In silico the molecular interactions between AChE and oximes were examined and binding energies were assessed. LogP (predicted log of the octanol/water partition coefficient) was estimated. In vitro the intrinsic ability of the oximes to inhibit AChE (IC50) and their reactivation potency (R50) when used in paraoxon inhibited human RBC-AChE was determined. Molecular docking revealed that K378 and K727 bind to the peripheral site(s) with high binding energies in contrast to the central binding of K-27 and pralidoxime. LogP values indicating that the novel compounds are significantly less hydrophilic than K-27 or pralidoxime. IC50 of K378 and K727 were comparable (0.9 and 1 uM, respectively) but orders of magnitude lower than comparators. R50 values revealed their inability to reactivate paraoxon inhibited AChE. It is concluded that the novel oximes K378 and K727 are unlikely to be clinically useful. The in silico and in vitro studies described allow avoidance of unnecessary in vivo animal work and contribute to the reduction of laboratory animal use. PMID- 28722513 TI - Intermediate filaments join the action. PMID- 28722514 TI - Non-autonomous autophagy in germline stem cell proliferation. PMID- 28722515 TI - Construction of a PLGA based, targeted siRNA delivery system for treatment of osteoporosis. AB - Osteoporosis, a systemic skeletal disorder, occurs when bone turnover balance is disrupted. With the identification of the genes involved in the pathogenesis of the disease, studies on development of new treatments has intensified. Short interfering RNA (siRNA) is used to knockdown disease related gene expressions. Targeting siRNA in vivo is challenging. The maintenance of therapeutic plasma level is hampered by clearance of siRNA from the body. Targeted systems are useful in increasing the drug concentration at the target site and decreasing side effects. Aim of the present study was to develop an injectable siRNA delivery system to protect siRNA during systemic distribution and target the siRNA to bone tissue using a thermoresponsive, genetically engineered, elastin like recombinamer (ELR), designed to interact with the mineral component of bone. The delivery system consisted of DNAoligo as a siRNA substitute complexed with the cationic polymer, polyethyleneimine (PEI), at N/P ratio of 20. The complex was encapsulated in poly(lactic acid-co-glycolic acid) (PLGA) nanocapsules. PLGA capsules were characterized by SEM, TEM and XPS. FTIR was used to show the preferential attachment of ELR to HAp. Encapsulation efficiency of the complex in PLGA nanocapsules was 48%. The release kinetics of the complex fits the Higuchi release kinetics. PMID- 28722516 TI - Pre-operative obesity does not predict poorer symptom control and quality of life after lumbar disc surgery. AB - PURPOSE: We aimed to determine whether there was a difference in post-operative symptomatic control and quality of life (QoL) between patients who were obese (BMI >30) and non-obese (BMI <30) pre-operatively. This information may inform the decision making of Physicians and patients whether to proceed to surgery for management of symptomatic lumbar disc prolapse. METHODS: We conducted a prospective questionnaire-based study of QoL and symptom control in 120 patients with postal follow-up at 3 and 12 months after lumbar disc surgery. This study was conducted in two United Kingdom regional neurosurgical units, with ethical approval from the North of Scotland Research Ethics Service (09/S0801/7). RESULTS: 120 patients were recruited; 37 (34.5%) were obese. Follow up was 71% at 3 months and 57% at 12 months. At recruitment, both obese and non-obese patient groups had similar functional status and pain scores. At 3 and 12 months, non obese and obese patients reported similar and significant benefits from surgery (e.g. 12 month SF-36 80.5 vs. 68.8, respectively). In non-obese and obese patients, time to return to work was 47.5 days and 53.8 days, respectively, (p = .345). After 12 months all QoL scores were significantly improved from pre operative levels in both groups. CONCLUSIONS: Obese patients derive significant benefit from lumbar discectomy that it is similar to the benefit experienced by non-obese patients. Obese individuals may achieve excellent results from discectomy and these patients should not be refused surgery on the basis of BMI alone. PMID- 28722517 TI - Introduction to Special Section: Personality Assessment and the Law. PMID- 28722519 TI - Fine Needle Biopsy of Metastases at Retrograde Pyelography, Directed by Fluoroscopy. AB - Percutaneous fine needle aspiration biopsy was performed at retrograde pyelography in order to differentiate between metastatic and scarry involvement of a strictured ureter in a patient earlier operated upon because of malignant teratoma. The method is recommended in patients with malignant diseases where the differential diagnosis is impossible to establish at retrograde pyelography or urography. PMID- 28722518 TI - Effects of pentoxifylline on hemodynamic, hemorheological, and microcirculatory parameters in young SHRs during arterial hypertension development. AB - The most common form of hypertension in young adults is isolated diastolic hypertension. Diastolic arterial pressure is determined by the total peripheral resistance and depends on both vascular hindrance and blood viscosity. The aim of our work was to study the efficiency of pentoxifylline (PTX) in young spontaneously hypertensive rats (SHRs) during the development of arterial hypertension. The effects of a treatment course with PTX (100 mg/kg/day p.o. for 6 weeks, from 5 to 11 weeks old) on the mean, systolic, and diastolic blood pressure (BP); stroke volume; cardiac output; total peripheral resistance (TPR); whole blood viscosity (BV); plasma viscosity; hematocrit; RBC aggregation and deformability; local cerebral blood flow (lCBF); and microvascularization of the visual cortex were studied in SHRs in comparison with control SHRs and Wistar Kyoto rats. PTX-treated SHRs had significantly lower systolic, diastolic, and mean BP (by 24%, 26%, and 15%, respectively) and BV (by 5-9%) and a higher erythrocyte deformability index (by 1.5-2%), lCBF (by 42%), average diameter of capillaries (by 11%), density of the capillary network (by 23%), and percentage of capillaries with a diameter of 3-7 um in comparison with control SHRs. In conclusion, PTX exerted positive effects on the hemodynamic, hemorheological, and microcirculatory parameters in SHRs during the development of arterial hypertension. PMID- 28722530 TI - Are there risk factors for scleroderma-related calcinosis? AB - OBJECTIVES: Pathogenesis and risk factors of scleroderma associated calcinosis is poorly understood and there is no effective treatment. This study was performed to better understand the prevalence and clinical features associated with calcinosis in a cohort of SSc outpatients. METHODS: In this cross-sectional study, we compared clinical characteristics of SSc patients with (SSc-calcinosis) and without calcinosis (SSc-control) seen in the outpatient Rutgers-RWJ Scleroderma Program between 2012 and 2015. Our analysis included clinical characteristics, comorbidities (i.e. osteoporosis), autoantibodies and imaging results. We performed univariable and multivariable regression analyses to determine common factors associated with calcinosis. RESULTS: There were 215 SSc patients, including 65 SSc-calcinosis (81.5% females) and 150 SSc-without calcinosis (controls, 77% females). SSc-calcinosis patients were older (p = .026) with significantly longer disease duration (20 +/- 10.5 years versus 12 +/- 8 years, p < .0001). Limited cutaneous scleroderma was more common (54%) in the calcinosis group. Longer disease duration from non-Raynaud symptoms (OR 3.77; 95%CI 1.26, 11.27) and osteoporosis (OR 3.43; 95%CI 1.15, 10.36) remained independently associated with calcinosis. CONCLUSIONS: Calcinosis was common in both limited and diffuse systemic sclerosis; both longer disease duration and osteoporosis were independently associated with calcinosis. Prospective studies are needed to confirm our findings. PMID- 28722532 TI - Bi-institutional retrospective study on the demographics and basic clinical presentation of hidrocystomas. AB - Hidrocystomas are benign, cystic lesions of eccrine and apocrine sweat glands. The literature on hidrocystomas is sparse, consisting of a handful of case reports and limited retrospective reviews. This is the first known bi institutional, retrospective, chart review aimed to elucidate the demographics and basic clinical presentation of hidrocystomas. Medical records of adult patients with a pathological diagnosis of hidrocystoma from September 1, 2008 to August 1, 2015 in the Oculoplastic and Reconstructive Surgery Service at the Illinois Eye and Ear Infirmary (UIC) and Department of Ophthalmology of Weill Cornell Medical College (Cornell) were reviewed. Children under the age of 18 were not included. Data collection included: gender, race, age at diagnosis, laterality, location, total number of lesions, and recurrence. Results from both institutions were compared against each other and as a whole. A total of 107 patients were diagnosed with hidrocystoma on pathology. The mean age of diagnosis was 56 years (22-85). Hidrocystomas were diagnosed in 69 (64.4%) females and 38 (35.5%) males. Lesions were most commonly found in African American (37.4%), Caucasian (30.8%), and Hispanic (16.8%) patients combined across the two institutions with different patient populations. Lesions were largely unilateral (74.8%) and found on the lower lid (38.6%), lateral canthus (31.2%), upper lid (17.7%), and medial canthus (12.6%). Recurrences were seen in 2.3% of lesions. The majority of recurrences occurred in patients who identified their race as Hispanic (2/5) and Caucasian (3/5). Recurrences were seen in 2 males and 3 females. Apocrine and ecccrine hidrocystomas may be more common in female, African American, Caucasian, and Hispanic patients, presenting most commonly in adults in their mid-fifties. Lesions tend to be unilateral with lower lid lesions being the most prevalent location and medial canthus lesions being the least prevalent location for lesion growth. Recurrences may be most common in Hispanics and Caucasians and less common in African Americans. Although a precise recurrence rate cannot be determined at this time, our data suggests that the recurrence rate is low with current excisional methods. PMID- 28722531 TI - Patterns of renal disease in South Korea: a 20-year review of a single-center renal biopsy database. AB - BACKGROUND: Several registries and centers have reported the results of renal biopsies from different parts of the world. As there are few data regarding the epidemiology of glomerulonephritis (GN) in South Korea, we conducted this study on renal biopsy findings during the last 20 years from a single center. METHODS: Data for 818 patients who underwent renal biopsy at our center between 1992 and 2011 were collected retrospectively. All kidney specimens were examined with light microscopy (LM) and immunofluorescent microscopy (IF). RESULTS: There were 818 cases of native kidney biopsies. In cases of primary GN, the most frequent type of renal pathology in adults (18-59 years) was mesangial proliferative GN (MsPGN, 34.5%) followed by IgA nephropathy (IgAN, 33.3%) and membranous GN (MGN, 8.8%). Indications in adults (18-59 years) were asymptomatic urinary abnormalities (75.3%) followed by nephrotic syndrome (19.8%) and acute kidney injury (AKI, 3.4%). CONCLUSIONS: Among 818 renal biopsy specimens, MsPGN and IgAN were the most frequent biopsy-proven renal diseases. MGN was the third most common cause of primary GN and lupus nephritis (LN) was the most common secondary glomerular disease. Our data contribute to the epidemiology of renal disease in South Korea. PMID- 28722533 TI - An HSP90 co-chaperone controls circadian proteostasis. PMID- 28722534 TI - Valence evaluation with approaching or withdrawing cues: directly testing valence arousal conflict theory. AB - The valence-arousal conflict theory assumes that both valence and arousal will trigger approaching or withdrawing tendencies. It also predicts that the speed of processing emotional stimuli will depend on whether valence and arousal trigger conflicting or congruent motivational tendencies. However, most previous studies have provided evidence of the interaction between valence and arousal only, and have not provided direct proof of the interactive links between valence, arousal and motivational tendencies. The present study provides direct evidence for the relationship between approach-withdrawal tendencies and the valence-arousal conflict. In an empirical test, participants were instructed to judge the valence of emotional words after visual-spatial cues that appeared to be either approaching or withdrawing from participants. A three-way interaction (valence, arousal, and approach-withdrawal tendency) was observed such that the response time was shorter if participants responded to a negative high-arousal stimulus after a withdrawing cue, or to a positive low-arousal stimulus after an approaching cue. These findings suggest that the approach-withdrawal tendency indeed plays a crucial role in valence-arousal conflict, and that the effect depends on the congruency of valence, arousal and tendency at an early stage of processing. PMID- 28722536 TI - Travel burden associated with granulocyte colony-stimulating factor administration in a Medicare aged population: a geospatial analysis. AB - OBJECTIVE: Prophylaxis with granulocyte colony-stimulating factors (G-CSFs) is recommended for patients receiving myelosuppressive chemotherapy regimens with a high risk of febrile neutropenia (FN). G-CSFs should be administered starting the day after chemotherapy, necessitating return trips to the oncology clinic at the end of each cycle. We examined the travel burden related to prophylactic G-CSF injections after chemotherapy in the US. METHODS: We used 2012-2014 Medicare claims data to identify a national cohort of beneficiaries age 65+ with non myeloid cancers who received both chemotherapy and prophylactic G-CSFs. Patient travel origin was based on residence ZIP code. Oncologist practice locations and hospital addresses were obtained from the Medicare Physician Compare and Hospital Compare websites and geocoded using the Google Maps Application Programming Interface (API). Driving distance and time to the care site from each patient ZIP code tabulation area (ZCTA) were calculated using Open Street Maps road networks. Geographic and socio-economic characteristics of each ZCTA from the US Census Bureau's American Community Survey were used to stratify and analyze travel estimates. RESULTS: The mean one-way driving distance to the G-CSF provider was 23.8 (SD 30.1) miles and the mean one-way driving time was 33.3 (SD 37.8) minutes. When stratified by population density, the mean one-way travel time varied from 12.1 (SD 10.1) minutes in Very Dense Urban areas to 76.7 (SD 72.1) minutes in Super Rural areas. About 48% of patients had one-way travel times of <20 minutes, but 19% of patients traveled >=50 minutes one way for G-CSF prophylaxis. Patients in areas with above average concentrations of aged, poor or disabled residents were more likely to experience longer travel. CONCLUSIONS: Administration of G-CSF therapy after chemotherapy can present a significant travel burden for cancer patients. Technological improvements in the form and methods of drug delivery for G-CSFs might significantly reduce this travel burden. PMID- 28722537 TI - Attention bias to threat in mothers with emotional disorders predicts increased offspring anxiety symptoms: a joint cross-sectional and longitudinal analysis. AB - There is convincing evidence of the transmission of anxiety and depression from parents to children; however, mechanisms by which this vulnerability is passed on are unclear. Cognitive models and a small body of cross-sectional research suggest that parental attention biases (ABs) may be one mechanism involved in transmission. Longitudinal associations of maternal and offspring ABs with offspring symptoms have been scarcely studied. Forty-three mothers-child dyads were included. All children (7-12 years old) were diagnosis-free while 24 mothers had a lifetime emotional disorder (anxiety or depression) (high risk, HR) and 19 mothers had no psychiatric diagnoses (low risk, LR). This study examined cross sectional and longitudinal associations of maternal and child AB and child anxiety symptomology at initial and 12-month assessments. ABs were assessed using a visual-probe task with emotional faces. There was a significant cross-sectional but not longitudinal association of increased child anxiety symptoms with increased maternal threat AB for HR but not LR dyads. At the cross-sectional level, increases in HR but not LR offspring anxiety symptomology were associated with maternal threat AB. Larger longitudinal studies are required that examine the interplay between parent-child variables and include multiple time-points of assessment and measures of AB. PMID- 28722535 TI - Persistence of mercury-induced motor and sensory neurotoxicity: systematic review of workers previously exposed to mercury vapor. AB - Elemental mercury (Hg0) is a well-recognized neurotoxicant, but it is uncertain whether and for how long its neurotoxicity persists. Among studies that evaluated previously-exposed workers, only one examined workers during and also years after exposure had ceased. The objective of this review is to create a series of 'synthetic' longitudinal studies to address the question of persistence of Hg0 neurotoxicity in occupationally exposed workers. We systematically reviewed studies describing objective motor and sensory effects in previously-exposed mercury workers. Data from physical examination (PE), neurobehavioral (NB) tests, and electrophysiological studies (EPS) were extracted into structured tables and examined for their consistency and dose-relatedness and then compared with the corresponding results from studies of currently exposed workers. We identified six cohorts that described neurological findings in 1299 workers, examined an average of 4.8-30 years after the cessation of exposure. Historical group mean UHg levels ranged from 23 to >500 MUg/L, with UHg levels >6000 MUg/L in some individuals. Overall, few findings were significant; most were inconsistent across the previous-exposure studies, and in comparisons between studies of previously and currently exposed workers. The results of this systematic review indicate that Hg0-related neurotoxic effects detectable on PE, NB testing, and EPS are substantially reversed over time. To the extent that such effects do persist, they are reported principally in workers who have had very high-dose exposures. In addition, based on the limited available data, those effects reported to persist have been described as having little or no functional significance. PMID- 28722538 TI - Dispersed synthesis of uniform Fe3O4 magnetic nanoparticles via in situ decomposition of iron precursor along cotton fibre for Sudan dyes analysis in food samples. AB - Fe3O4 magnetic nanoparticles, with a negative charge surface, are known to have efficient adsorbent properties, but they tend to be agglomerated into larger aggregates or flocs, which can cause loss of specific area. The addition of cotton fibre, as a stabiliser in preparation of the Fe3O4 nanoparticles, is able to efficiently reduce particle aggregation, and thus, effective particle size, resulting in much greater specific surface area and adsorption sites. Fe3O4 nanoparticles synthesis was accomplished by in situ high-temperature decomposition of the precursor ferric ion in the presence of cotton fibre and ethylene glycol solvent. The morphology of Fe3O4 nanoparticles was characterised by field emission scanning electron microscopy and X-ray diffraction, which confirmed that the magnetic nanoparticles are highly dispersed. These Fe3O4 nanoparticles were used for clean-up and pre-concentration of Sudan dyes in chilli and hot red sauces, prior to their determination by capillary liquid chromatography diode array detection. A comparative study of analyte pre concentration was conducted with magnetic nanoparticles prepared with and without cotton fibre showing that both solid phases adsorb the analytes, but higher recoveries were obtained when using cotton fibre which therefore was selected for extraction of Sudan dyes. PMID- 28722540 TI - Association between serum uric acid level and hypertension in a Chinese elderly rural population. AB - : Previous studies have examined the association between elevated serum uric acid (SUA) level and hypertension; however, the association in the Chinese elderly is still uncertain. A cross-sectional study was performed in a rural district of Beijing. A total of 2,397 participants (967 men and 1,430 women) completed the survey. The SUA levels of participants were categorized into four levels using the quartiles (P25, P50, and P75) as cutoff values. Participant was diagnosed as hyperuricemia if the SUA level was >=417 MUmol/L (male) or >=357 MUmol/L (female). Hypertension was defined as systolic blood pressure (BP) >=140 mmHg and/or diastolic BP >=90 mmHg and/or receiving antihypertensive drug treatment. Multiple logistic regression was used to estimate the association between SUA and hypertension. We found that higher SUA level was associated with the increased risk of hypertension in both sexes, even after adjusting for potential confounding variables. In total, the risk for having hypertension increased by 0.3% per 1 MUmol/L increment in SUA level, increased by 95% for the highest vs. lowest quartile of SUA level, and increased by 111% in the hyperuricemia patients. Moreover, we found that the association was more pronounced in the male participants. There were approximately J-shaped relationships between SUA level (quartiles) and hypertension in all age groups. Higher SUA levels are positively associated with hypertension among the Chinese rural elderly. Further studies are still required to determine the relationship between SUA level and hypertension and to explore its potential biological mechanisms underlying the gender-related association in the elderly population. ABBREVIATIONS: CVD; cardiovascular disease; BMI: body mass index; BP: blood pressure; SUA: serum uric acid; TC: total cholesterol; TG: triglycerides; HDL-C: high-density lipoprotein; LDL-C: low density lipoprotein; FPG: fasting blood glucose; OR: odds ratio; CI: confidence interval; SD: standard deviation. PMID- 28722539 TI - An autophagy-driven pathway of ATP secretion supports the aggressive phenotype of BRAFV600E inhibitor-resistant metastatic melanoma cells. AB - The ingrained capacity of melanoma cells to rapidly evolve toward an aggressive phenotype is manifested by their increased ability to develop drug-resistance, evident in the case of vemurafenib, a therapeutic-agent targeting BRAFV600E. Previous studies indicated a tight correlation between heightened melanoma associated macroautophagy/autophagy and acquired Vemurafenib resistance. However, how this vesicular trafficking pathway supports Vemurafenib resistance remains unclear. Here, using isogenic human and murine melanoma cell lines of Vemurafenib resistant and patient-derived melanoma cells with primary resistance to the BRAFV600E inhibitor, we found that the enhanced migration and invasion of the resistant melanoma cells correlated with an enhanced autophagic capacity and autophagosome-mediated secretion of ATP. Extracellular ATP (eATP) was instrumental for the invasive phenotype and the expansion of a subset of Vemurafenib-resistant melanoma cells. Compromising the heightened autophagy in these BRAFV600E inhibitor-resistant melanoma cells through the knockdown of different autophagy genes (ATG5, ATG7, ULK1), reduced their invasive and eATP secreting capacity. Furthermore, eATP promoted the aggressive nature of the BRAFV600E inhibitor-resistant melanoma cells by signaling through the purinergic receptor P2RX7. This autophagy-propelled eATP-dependent autocrine-paracrine pathway supported the maintenance and expansion of a drug-resistant melanoma phenotype. In conclusion, we have identified an autophagy-driven response that relies on the secretion of ATP to drive P2RX7-based migration and expansion of the Vemurafenib-resistant phenotype. This emphasizes the potential of targeting autophagy in the treatment and management of metastatic melanoma. PMID- 28722541 TI - NOx emission calculations for bulk carriers by using engine power probabilities as weighting factors. AB - : An important marine pollution issue identified by the International Maritime Organization (IMO) is NOx emissions; however, the stipulated method for determining the NOx certification value does not reflect the actual high emission factors of slow-speed two-stroke diesel engines over long-term slow steaming. In this study, an accurate method is presented for calculating the NOx emission factors and total amount of NOx emissions by using the actual power probabilities of the diesel engines in four types of bulk carriers. The proposed method is suitable for all types and purposes of diesel engines, is not restricted to any operating modes, and is highly accurate. Moreover, it is recommended that the IMO stipulated certification value calculation method be modified accordingly to genuinely reduce the amount of NOx emissions. The successful achievement of this level of reduction will help improve the air quality, especially in coastal and port areas, and the health of local residents. IMPLICATIONS: As per the IMO, the NOx emission certification value of marine diesel engines having a rated power over 130 kW must be obtained using specified weighting factor (WF)-based calculation. However, this calculation fails to represent the current actual situation. Effective emission reductions of 6.91% (at sea) and 31.9% (in ports) were achieved using a mathematical model of power probability functions. Thus, we strongly recommend amending the certification value of NOx Technical Code 2008 (NTC 2008) by removing the WF constraints, such that the NOx emissions of diesel engines is lower than the Tier-limits at any load level to obtain genuine NOx emission reductions. PMID- 28722542 TI - Latest developments in the field of stem cell research and regenerative medicine compiled from publicly available information and press releases from nonacademic institutions 1-31 March 2017. PMID- 28722543 TI - Comparison of ovalbumin and ovalbumin epitope peptide for transdermal delivery and vaccination mediated by the photothermal effect of gold nanorods. AB - Transdermal protein delivery is a powerful and attractive method for protein therapy and dermal vaccination compared with other administrations. However, this delivery method is restricted by the low permeability of the stratum corneum (SC), a hydrophobic barrier that restricts the entry of hydrophilic molecules such as proteins. In this study, we developed an improved gel patch system carrying ovalbumin and ovalbumin epitope peptide, and then compared their permeability into the skin. First, the gel patch was placed on mouse skin to allow contact with the polymer coated gold nanorods and then irradiated by a continuous-wave laser. Thermal ablation of the SC improved the permeability and translocation of ovalbumin and the peptide. Fluorescence images showed the translocation was enhanced when the skin was treated with the FITC-modified ovalbumin epitope peptide. However, induction of anti-OVA IgG production after treatment with the FITC-modified ovalbumin epitope peptide was lower than that with FITC-OVA. PMID- 28722544 TI - The greatwall kinase is dominant over PKA in controlling the antagonistic function of ARPP19 in Xenopus oocytes. AB - The small protein ARPP19 plays a dual role during oocyte meiosis resumption. In Xenopus, ARPP19 phosphorylation at S109 by PKA is necessary for maintaining oocytes arrested in prophase of the first meiotic division. Progesterone downregulates PKA, leading to the dephosphorylation of ARPP19 at S109. This initiates a transduction pathway ending with the activation of the universal inducer of M-phase, the kinase Cdk1. This last step depends on ARPP19 phosphorylation at S67 by the kinase Greatwall. Hence, phosphorylated by PKA at S109, ARPP19 restrains Cdk1 activation while when phosphorylated by Greatwall at S67, ARPP19 becomes an inducer of Cdk1 activation. Here, we investigate the functional interplay between S109 and S67-phosphorylations of ARPP19. We show that both PKA and Gwl phosphorylate ARPP19 independently of each other and that Cdk1 is not directly involved in regulating the biological activity of ARPP19. We also show that the phosphorylation of ARPP19 at S67 that activates Cdk1, is dominant over the inhibitory S109 phosphorylation. Therefore our results highlight the importance of timely synchronizing ARPP19 phosphorylations at S109 and S67 to fully activate Cdk1. PMID- 28722546 TI - The Role of Recollection and Familiarity in Nondemented Parkinson's Patients. AB - The aim of the current study was to examine if recollection and familiarity decline in nondemented Parkinson's patients. To do so we compared a sample of older people with Parkinson's disease (n = 32) to a control sample of healthy older people (n = 32) on an associative recognition task in which we manipulated the repetition of the pairs during the study phase (half of the pairs were presented once and half twice) to obtain corrected estimates of recollection, familiarity, and false recognition based on the logic of the process-dissociation procedure. The results clearly show that recollection is impaired but familiarity is preserved in nondemented Parkinson's patients. The results show that memory for pairs in Parkinson's patients relies largely on the familiarity of each item and not on a precise recollection of associative information, supporting the idea that recollection-based monitoring processes are impaired in these patients. PMID- 28722547 TI - Letter Position Coding with Fred Astaire: Inversion of Letter Position Substitution Effects in Reverse Spelled Words. AB - The effects of letter substitutions have been linked to their position within a word (letter position effects). The current study expanded upon previous research by examining letter-position effects for letter substitutions using forward- and reverse-spelled word primes. Often substituting a letter on one side of a word will have a stronger impact on performance than substituting a letter on the other side of a word. In three experiments it was revealed that the letter position effects of substitutions changed places when words were spelled backwards. This occurred when both the target and prime were spelled backwards. This was evidence of a congruency effect of letter-position priming. The ramifications of these results for word recognition and transfer are discussed. However, the need for future research should focus on the possibility of an inversion process/mechanism. PMID- 28722545 TI - tRNA engineering for manipulating genetic code. AB - In ribosomal translation, only 20 kinds of proteinogenic amino acids (pAAs), namely 19 l-amino acids and glycine, are exclusively incorporated into polypeptide chain. To overcome this limitation, various methods to introduce non proteinogenic amino acids (npAAs) other than the 20 pAAs have been developed to date. However, the repertoire of amino acids that can be simultaneously introduced is still limited. Moreover, the efficiency of npAA incorporation is not always sufficient depending on their structures. Fidelity of translation is sometimes low due to misincorporation of competing pAAs and/or undesired translation termination. Here, we provide an overview of efforts to solve these issues, focusing on the engineering of tRNAs. PMID- 28722548 TI - The change-makers of West Africa. AB - West Africa was the focus of global attention during the Ebola virus disease outbreak, when systemic health system weaknesses compounded a serious emergency and complicated response efforts. Following the crisis, calls were made to strengthen health systems, but investments to date have fallen short of delivering the support needed to build strong health systems able to prevent and manage future outbreaks.In part, this reality serves to highlight the shortcomings of the solutions being repeatedly prioritised by external funders and experts, solutions that often fail to consider the wealth of West African evidence and actors actively working to strengthen the leadership and health systems needed to drive and sustainably improve national health outcomes. Unfortunately, this knowledge and experience are rarely heard in the global arena.This journal supplement is a contribution, although small, to changing this practice by putting the perspectives, experiences and knowledge of West Africans on the table. It presents findings from a series of research and capacity development projects in West Africa funded by the International Development Research Centre's Maternal and Child Health programme (formerly Governance for Equity in Health Systems).The evidence presented here centres around two key themes. First, the theme that context matters. The evidence shows how context can change the shape of externally imposed interventions or policies resulting in unintended outcomes. At the same time, it highlights evidence showing how innovative local actors are developing their own approaches, usually low-cost and embedded in the context, to bring about change. Second, the collection of articles discusses the critical need to overcome the existing fragmentation of expertise, knowledge and actors, and to build strong working relationships amongst all actors so they can effectively work together to identify priority issues that can realistically be addressed given the available windows of opportunity.Vibrant West African-led collaborations amongst researchers, decision makers and civil society, which are effectively supported by national, regional and global funding, need to foster, strengthen and use locally-generated evidence to ensure that efforts to strengthen health systems and improve regional health outcomes are successful. The solutions are clearly not to be found in the 'travelling models' of standardised interventions. PMID- 28722549 TI - Adaptive reuse in the healthcare industry: repurposing abandoned buildings to serve medical missions. AB - BACKGROUND: Adaptive reuse-the practice of identifying, acquiring, renovating, and placing back into service a building or similar structure for a purpose different than that for which it was originally designed-offers great potential for addressing the spatial expansion needs of healthcare establishments in a unique and mutually beneficial manner. This repurposing approach, however, has received very little attention in the health sciences literature, diminishing the opportunities of those serving in hospitals, medical clinics, and related care providing institutions to acquire an understanding of the practice. DISCUSSION: The delivery of healthcare services primarily is site based, requiring physical space for physicians, nurses, administrators, and others to carry out the many duties associated with the provision of medical care and attention. But this space often represents a significant expenditure, consuming financial resources which otherwise could be directed toward patient care. Economies on this front are possible through adaptive reuse, permitting more resources to be directed toward mission fulfillment activities. This article directs attention toward adaptive reuse by profiling Willis-Knighton Health System's associated experiences and implementation strategies. Among other things, opportunities and obstacles are discussed, detailed cases are presented, and an operational framework is provided, permitting healthcare providers to understand and make use of this novel practice for addressing spatial expansion needs more affordably. CONCLUSIONS: Since space considerations exist throughout the lives of healthcare establishments, providers must ensure an awareness of methods for productively attending to these requirements. Evidenced by Willis-Knighton Health System's associated experiences and outcomes, adaptive reuse presents an option for more economically addressing spatial requirements, fostering opportunities to expand the delivery of health and medical services. PMID- 28722550 TI - The hub-and-spoke organization design: an avenue for serving patients well. AB - BACKGROUND: The healthcare industry is characterized by intensive, never-ending change occurring on a multitude of fronts. Success in such tumultuous environments requires healthcare providers to be proficient in myriad areas, including the manner in which they organize and deliver services. Less efficient designs drain precious resources and hamper efforts to deliver the best care possible to patients, making it imperative that optimal pathways are identified and pursued. One particular avenue that offers great potential for serving patients efficiently and effectively is known as the hub-and-spoke organization design. DISCUSSION: The hub-and-spoke organization design is a model which arranges service delivery assets into a network consisting of an anchor establishment (hub) which offers a full array of services, complemented by secondary establishments (spokes) which offer more limited service arrays, routing patients needing more intensive services to the hub for treatment. Hub and-spoke networks afford many benefits for healthcare providers, but in order to capitalize fully, proper assembly is required. To advance awareness, knowledge, and use of the hub-and-spoke organization design, this article profiles Willis Knighton Health System's service delivery network which has utilized the model for over three decades. Among other things, the hub-and-spoke organization design is defined, benefits are stipulated, and applications are discussed, permitting healthcare providers essential insights for the establishment and operation of these networks. CONCLUSIONS: The change-rich nature of the healthcare industry places a premium on incorporating advancements that permit health and medical providers to operate as optimally as possible. The hub-and-spoke organization design represents an option that, when deployed correctly, can greatly assist healthcare establishments in their quests to serve patients well. PMID- 28722551 TI - Promoting research to improve maternal, neonatal, infant and adolescent health in West Africa: the role of the West African Health Organisation. AB - West Africa has adopted numerous strategies to counter maternal and infant mortality, provides national maternal and infant health programmes, and hosts many active technical and financial partners and non-governmental organisations. Despite this, maternal and infant morbidity and mortality indicators are still very high. In this commentary, internal actors and officials of the West African Health Organisation (WAHO) examine the regional organisation's role in promoting research as a tool for strengthening maternal and infant health in West Africa.As a specialised institution of the Economic Community of West African States (ECOWAS) responsible for health issues, WAHO's mission is to provide the sub region's population with the highest possible health standards by harmonising Member States' policies, resource pooling, and cooperation among Member States and third countries to collectively and strategically combat the region's health problems. To achieve this, WAHO's main intervention strategy is that of facilitation, as this encourages the generation and use of evidence to inform decision-making and reinforce practice.WAHO's analysis of interventions since 2000 showed that it had effected some changes in research governance, management and funding, as well as in individual and institutional capacity building, research dissemination, collaboration and exchanges between the various stakeholders. It also revealed several challenges such as process ownership, member countries' commitment, weak individual and institutional capacity, mobilisation, and stakeholder commitment. To better strengthen evidence-based decision-making, in 2016, WAHO created a unique programme aimed at improving the production, dissemination and use of research information and results in health programme planning to ultimately improve population health.While WAHO's experiences to date demonstrate how a regional health institution can integrate research promotion into the fight against maternal and infant mortality, the challenges the organisation has encountered also demonstrate the importance of cohesion among actors promoting such an initiative, the importance of leadership and commitment among member country actors steering the process, and the need for collaboration and coordination among all partners in member countries and in the region. PMID- 28722552 TI - Evaluation of regional project to strengthen national health research systems in four countries in West Africa: lessons learned. AB - BACKGROUND: Since the Commission on Health Research for Development (COHRED) published its flagship report, more attention has been focused on strengthening national health research systems (NHRS). This paper evaluates the contribution of a regional project that used a participatory approach to strengthen NHRS in four post-conflict West African countries - Guinea-Bissau, Liberia, Sierra Leone and Mali. METHODS: The data from the situation analysis conducted at the start of the project was compared to data from the project's final evaluation, using a hybrid conceptual framework built around four key areas identified through the analysis of existing frameworks. The four areas are governance and management, capacities, funding, and dissemination/use of research findings. RESULTS: The project helped improve the countries' governance and management mechanisms without strengthening the entire NHRS. In the four countries, at least one policy, plan or research agenda was developed. One country put in place a national health research ethics committee, while all four countries could adopt a research information management system. The participatory approach and support from the West African Health Organisation and COHRED were all determining factors. CONCLUSION: The lessons learned from this project show that the fragile context of these countries requires long-term engagement and that support from a regional institution is needed to address existing challenges and successfully strengthen the entire NHRS. PMID- 28722553 TI - Travelling models and the challenge of pragmatic contexts and practical norms: the case of maternal health. AB - As in other areas of international development, we are witnessing the proliferation of 'traveling models' developed by international experts and introduced in an almost identical format across numerous countries to improve some aspect of maternal health systems in low- and middle-income countries. These policies and protocols are based on 'miracle mechanisms' that have been taken out of their original context but are believed to be intrinsically effective in light of their operational devices.In reality, standardised interventions are, in Africa and elsewhere, confronted with pragmatic implementation contexts that are always varied and specific, and which lead to drifts, distortions, dismemberments and bypasses. The partogram, focused antenatal care, the prevention of mother-to child transmission of HIV or performance-based payment all illustrate these implementation gaps, often caused by the routine behaviour of health personnel who follow practical norms (and a professional culture) that are often distinct from official norms - as is the case with midwives.Experiences in maternal and child health in Africa suggest that an alternative approach would be to start with the daily reality of social and practical norms instead of relying on models, and to promote innovations that emerge from within local health systems. PMID- 28722554 TI - Improving maternal and child health policymaking processes in Nigeria: an assessment of policymakers' needs, barriers and facilitators of evidence-informed policymaking. AB - BACKGROUND: In Nigeria, interest in the evidence-to-policy process is gaining momentum among policymakers involved in maternal, newborn and child health (MNCH). However, numerous gaps exist among policymakers on use of research evidence in policymaking. The objective of this study was to assess the perception of MNCH policymakers regarding their needs and the barriers and facilitators to use of research evidence in policymaking in Nigeria. METHODS: The study design was a cross-sectional assessment of perceptions undertaken during a national MNCH stakeholders' engagement event convened in Abuja, Nigeria. A questionnaire designed to assess participants' perceptions was administered in person. Group consultations were also held, which centred on policymakers' evidence-to-policy needs to enhance the use of evidence in policymaking. RESULTS: A total of 40 participants completed the questionnaire and participated in the group consultations. According to the respondents, the main barriers to evidence use in MNCH policymaking include inadequate capacity of organisations to conduct policy-relevant research; inadequate budgetary allocation for policy-relevant research; policymakers' indifference to research evidence; poor dissemination of research evidence to policymakers; and lack of interaction fora between researchers and policymakers. The main facilitators of use of research evidence for policymaking in MNCH, as perceived by the respondents, include capacity building for policymakers on use of research evidence in policy formulation; appropriate dissemination of research findings to relevant stakeholders; involving policymakers in research design and execution; and allowing policymakers' needs to drive research. The main ways identified to promote policymakers' use of evidence for policymaking included improving policymakers' skills in information and communication technology, data use, analysis, communication and advocacy. CONCLUSION: To improve the use of research evidence in policymaking in Nigeria, there is a need to establish mechanisms that will facilitate the movement from evidence to policy and address the needs identified by policymakers. It is also imperative to improve organisational initiatives that facilitate use of research evidence for policymaking. PMID- 28722555 TI - Understanding the state of health policy and systems research in West Africa and capacity strengthening needs: scoping of peer-reviewed publications trends and patterns 1990-2015. AB - BACKGROUND: The need for locally-driven, locally-generated evidence to guide health policy and systems decision-making and implementation in West Africa remains urgent. Thus, health policy and systems research (HPSR) is a field with great potential for addressing many of the sub-region's intransigent health challenges. This paper presents an analysis of trends and patterns of peer reviewed HPSR publications across the Economic Community of West African States (ECOWAS), to help understand trends and patterns of HPSR publication and the degree of involvement of West African researchers in HPSR evidence generation in the sub-region. Our goal was to use the findings to inform the development of a sub-regional strategy to strengthen HPSR and its use to inform development and improvement of health outcomes. METHODS: A scoping review was conducted over a 25 year period from January 1990 to September 2015. Literature searches were conducted in English and French using Google Scholar, PubMed Central and Cairn.info. RESULTS: A total of 258 articles were retrieved. Of these, 246 were statistically analysed, with 54% having West African lead authors. Two thirds of the papers originated from three out of the 15 countries of the ECOWAS, specifically Nigeria (28.86%), Burkina Faso (21.54%) and Ghana (17.07%). Most authors were based in academic institutions and participation of authors from ministries of health, hospitals and non-governmental organisations was limited. English was the predominant language for publication even for papers originating from Francophone West African countries. There has been a progressive increase in publications over the studied period. CONCLUSION: Despite progressive improvements over time, West Africa remains a weak sub-region in terms of peer reviewed HPSR publications. Within the overall weakness, there is country-to country variation. The fact that only a handful of countries accounted for nearly 70% of the total volume of publications in West Africa attests to the great disparities in individual, institutional and contextual capacities for HPSR evidence generation. Bridging the gap between lead institutions (universities and research centres) and the practice community (ministries, hospitals, non governmental organisations) is indispensable for ensuring the practical use of HPSR evidence. There remains a major need for investments in HPSR capacity building in West Africa. PMID- 28722557 TI - Enhancing the depth and breadth of healthcare services in communities: insights, innovations, and applications. PMID- 28722556 TI - Spanning maternal, newborn and child health (MNCH) and health systems research boundaries: conducive and limiting health systems factors to improving MNCH outcomes in West Africa. AB - BACKGROUND: Despite improvements over time, West Africa lags behind global as well as sub-Saharan averages in its maternal, newborn and child health (MNCH) outcomes. This is despite the availability of an increasing body of knowledge on interventions that improve such outcomes. Beyond our knowledge of what interventions work, insights are needed on others factors that facilitate or inhibit MNCH outcome improvement. This study aimed to explore health system factors conducive or limiting to MNCH policy and programme implementation and outcomes in West Africa, and how and why they work in context. METHODS: We conducted a mixed methods multi-country case study focusing predominantly, but not exclusively, on the six West African countries (Burkina Faso, Benin, Mali, Senegal, Nigeria and Ghana) of the Innovating for Maternal and Child Health in Africa initiative. Data collection involved non-exhaustive review of grey and published literature, and 48 key informant interviews. We validated our findings and conclusions at two separate multi-stakeholder meetings organised by the West African Health Organization. To guide our data collection and analysis, we developed a unique theoretical framework of the link between health systems and MNCH, in which we conceptualised health systems as the foundations, pillars and roofing of a shelter for MNCH, and context as the ground on which the foundation is laid. RESULTS: A multitude of MNCH policies and interventions were being piloted, researched or implemented at scale in the sub-region, most of which faced multiple interacting conducive and limiting health system factors to effective implementation, as well as contextual challenges. Context acted through its effect on health system factors as well as on the social determinants of health. CONCLUSIONS: To accelerate and sustain improvements in MNCH outcomes in West Africa, an integrated approach to research and practice of simultaneously addressing health systems and contextual factors alongside MNCH service delivery interventions is needed. This requires multi-level, multi-sectoral and multi stakeholder engagement approaches that span current geographical, language, research and practice community boundaries in West Africa, and effectively link the efforts of actors interested in health systems strengthening with those of actors interested in MNCH outcome improvement. PMID- 28722558 TI - Situating mobile health: a qualitative study of mHealth expectations in the rural health district of Nouna, Burkina Faso. AB - BACKGROUND: The implementation of mobile health (mHealth) projects in low- and middle-income countries raises high and well-documented expectations among development agencies, policymakers and researchers. By contrast, the expectations of direct and indirect mHealth users are not often examined. In preparation for a proposed intervention in the Nouna Health District, in rural Burkina Faso, this study investigates the expected benefits, challenges and limitations associated with mHealth, approaching these expectations as a form of situated knowledge, inseparable from local conditions, practices and experiences. METHODS: The study was conducted within the Nouna Health District. We used a qualitative approach, and conducted individual semi-structured interviews and group interviews (n = 10). Participants included healthcare workers (n = 19), godmothers (n = 24), pregnant women (n = 19), women with children aged 12-24 months (n = 33), and women of childbearing age (n = 92). Thematic and content qualitative analyses were conducted. RESULTS: Participants expect mHealth to help retrieve patients lost to follow-up, improve maternal care monitoring, and build stronger relationships between pregnant women and primary health centres. Expected benefits are not reducible to a technological realisation (sending messages), but rather point towards a wider network of support. mHealth implementation is expected to present considerable challenges, including technological barriers, organisational challenges, gender issues, confidentiality concerns and unplanned aftereffects. mHealth is also expected to come with intrinsic limitations, to be found as obstacles to maternal care access with which pregnant women are confronted and on which mHealth is not expected to have any significant impact. CONCLUSIONS: mHealth expectations appear as situated knowledges, inseparable from local health-related experiences, practices and constraints. This problematises universalistic approaches to mHealth knowledge, while nevertheless hinting at concrete, expected benefits. Findings from this study will help guide the design and implementation of mHealth initiatives, thus optimising their chances for success. PMID- 28722559 TI - Free versus subsidised healthcare: options for fee exemptions, access to care for vulnerable groups and effects on the health system in Burkina Faso. AB - BACKGROUND: The many forms of healthcare fee exemptions implemented in Burkina Faso since the 2000s have varied between total exemption (free) and cost subsidisation. This article examines both options, their contextual variations and the ways in which they affect access to healthcare for vulnerable people as well as the operation of the health system. This research is part of an interdisciplinary regional program on the elimination of user fees for health services in West Africa (Burkina Faso, Mali and Niger). METHOD: A conceptual framework and a chronological review of policy interventions are used as references to summarise the results of the three qualitative studies presented. Historical reference points are used to describe the emergence of healthcare fee exemption policies in Burkina Faso and the events that influenced their adoption. The joint analysis of opinions on options for fee exemption focuses on the different types of repercussions on access to healthcare and the operation of the health system. RESULTS: In conjunction with the twists and turns of the gradual development of a national health policy and in response to international recommendations, healthcare fee exemptions have evolved since colonisation. The limitations of the changes introduced with cost recovery and the barriers to healthcare access for the poorest people led to the adoption of the current sectorial fee exemptions. The results provide information on the reasons for the changes that have occurred over time. The nuanced perspectives of different categories of people surveyed about fee exemption options show that, beyond the perceived effects on healthcare access and the health system, the issue is one of more equitable governance. CONCLUSIONS: In principle, the fee exemption measures are intended to provide improved healthcare access for vulnerable groups. In practice, the negative effects on the operation of the health system advocate for reforms to harmonise the changes to multifaceted fee exemptions and the actual needs to promote effectiveness and sustainability. PMID- 28722560 TI - Peering beyond the walls of healthcare institutions: a catalyst for innovation. AB - BACKGROUND: Healthcare providers operate in a unique industry characterized by pursuit of perhaps the most noble of missions: the delivery of vital health and medical services to those in need. Distinguishing features abound, differentiating the healthcare industry from others, with such facets having the potential to compel those serving in health and medical establishments to focus exclusively on their selected industry. But directing attention solely within can result in missed opportunities, especially regarding innovation. Many innovations which are well suited for healthcare establishments emerge externally, making at least some exposure beyond the healthcare industry essential for institutions desirous of operating on the innovation frontier. DISCUSSION: True innovation emerges from broad worldviews, allowing healthcare providers to comprehensively understand the current state of the art. With such an understanding, novel tools, techniques, and approaches, regardless of industry of origin, can be examined for their potential to elevate the status and stature of efforts within health and medical establishments. It is this very open, inquisitive mindset that permitted Willis-Knighton Health System to identify and incorporate a range of innovations which originated outside of the healthcare industry. Its embracement of and associated successes with the repurposing approach known as adaptive reuse, the delivery of complex medical services via centers of excellence, and the structuring of operations using the hub-and-spoke organization design, for example, would never have occurred had executives not directed attention externally in search of innovations that could be used within. CONCLUSIONS: Innovations offer key pathways for healthcare providers to enhance the depth and breadth of health and medical services offered in their establishments and communities. By peering beyond the walls of healthcare institutions, providers amplify opportunities to discover novel methods and approaches that potentially can be transferred into their own organizations, benefiting themselves and their patient populations. PMID- 28722561 TI - The quality of free antenatal and delivery services in Northern Sierra Leone. AB - BACKGROUND: The number of maternal deaths in sub-Saharan Africa continues to be overwhelmingly high. In West Africa, Sierra Leone leads the list, with the highest maternal mortality ratio. In 2010, financial barriers were removed as an incentive for more women to use available antenatal, delivery and postnatal services. Few published studies have examined the quality of free antenatal services and access to emergency obstetric care in Sierra Leone. METHODS: A cross sectional survey was conducted in 2014 in all 97 peripheral health facilities and three hospitals in Bombali District, Northern Region. One hundred antenatal care providers were interviewed, 276 observations were made and 486 pregnant women were interviewed. We assessed the adequacy of antenatal and delivery services provided using national standards. The distance was calculated between each facility providing delivery services and the nearest comprehensive emergency obstetric care (CEOC) facility, and the proportion of facilities in a chiefdom within 15 km of each CEOC facility was also calculated. A thematic map was developed to show inequities. RESULTS: The quality of services was poor. Based on national standards, only 27% of women were examined, 2% were screened on their first antenatal visit and 47% received interventions as recommended. Although 94% of facilities provided delivery services, a minority had delivery rooms (40%), delivery kits (42%) or portable water (46%). Skilled attendants supervised 35% of deliveries, and in only 35% of these were processes adequately documented. None of the five basic emergency obstetric care facilities were fully compliant with national standards, and the central and northernmost parts of the district had the least access to comprehensive emergency obstetric care. CONCLUSION: The health sector needs to monitor the quality of antenatal interventions in addition to measuring coverage. The quality of delivery services is compromised by poor infrastructure, inadequate skilled staff, stock-outs of consumables, non functional basic emergency obstetric care facilities, and geographic inequities in access to CEOC facilities. These findings suggest that the health sector needs to urgently investigate continuing inequities adversely influencing the uptake of these services, and explore more sustainable funding mechanisms. Without this, the country is unlikely to achieve its goal of reducing maternal deaths. PMID- 28722562 TI - Centers of excellence in healthcare institutions: what they are and how to assemble them. AB - BACKGROUND: Centers of excellence-specialized programs within healthcare institutions which supply exceptionally high concentrations of expertise and related resources centered on particular medical areas and delivered in a comprehensive, interdisciplinary fashion-afford many advantages for healthcare providers and the populations they serve. To achieve full value from centers of excellence, proper assembly is an absolute necessity, but guidance is somewhat limited. This effectively forces healthcare providers to pursue establishment largely via trial-and-error, diminishing opportunities for success. DISCUSSION: Successful development of a center of excellence first requires the acquisition of a detailed understanding of the delivery model and its benefits. Then, concerted actions must be taken on a particular series of administrative and clinical fronts, treating them in prescribed manners to afford synergies which yield an exceptionally high level of care. To reduce hardships associated with acquiring this rather elusive knowledge, remedy shortcomings in the literature, and potentially bolster community health broadly, this article presents information and insights gleaned from Willis-Knighton Health System's extensive experience assembling and operating centers of excellence. This work is intended to educate and enlighten, but most importantly, supply guidance which will permit healthcare establishments to replicate noted processes to realize their own centers of excellence. CONCLUSIONS: Centers of excellence have the ability to dramatically enhance the depth and breadth of healthcare services available in communities. Given the numerous mutual benefits afforded by this delivery model, it is hoped that the light shed by this article will help healthcare providers better understand centers of excellence and be more capable and confident in associated development initiatives, affording greater opportunities for themselves and their patient populations. PMID- 28722563 TI - The West African experience in establishing steering committees for better collaboration between researchers and decision-makers to increase the use of health research findings. AB - BACKGROUND: Aware of the advantages of a project steering committee (SC) in terms of influencing the development of evidence-based health policies, the West African Health Organisation (WAHO) encouraged and supported the creation of such SCs around four research projects in four countries (Burkina Faso, Nigeria, Senegal and Sierra Leone). This study was conducted to describe the process that was used to establish these committees and its findings aim to assist other stakeholders in initiating this type of process. METHODS: This is a cross sectional, qualitative study of the initiative's four projects. In addition to a literature review and a review of the project documents, an interview guide was used to collect data from 14 members of the SCs, research teams, WAHO and the International Development Research Center. The respondents were selected with a view to reaching data saturation. The technique of thematic analysis by simple categorisation was used. RESULTS: To set up the SCs, a research team in each country worked with health authorities to identify potential members, organise meetings with these members and sought the authorities' approval to formalise the SCs. The SCs' mission was to provide technical assistance to the researchers during the implementation phase and to facilitate the transfer and use of the findings. The 'doing by learning' approach used by each research team, combined with WAHO's catalytic role with each country's Ministry of Health, helped each SC manage its contextual difficulties and function effectively. CONCLUSION: The involvement of technical and financial partners motivated the researchers and ministries of health, who, in turn, motivated other actors to volunteer on the SCs. The 'doing by learning' approach made it possible to develop strategies adapted to each context to create, facilitate and operate each SC and manage its difficulties. To reproduce such an experience, a strong understanding of the local context and the involvement of strong partners are required. PMID- 28722564 TI - Guillain-Barre Syndrome and Chikungunya: Description of All Cases Diagnosed during the 2014 Outbreak in the French West Indies. AB - The Guillain-Barre syndrome (GBS) has been reported as a possible complication of acute chikungunya infection. The chikungunya epidemics, which occurred in Martinique and Guadeloupe in 2014, affected 308,000 people in these two islands. GBS occurred during or immediately after acute chikungunya infection in 13 patients (10 men, three women; mean age: 61 years). Median time from acute chikungunya to GBS onset was 9 days. Twelve patients were treated with intravenous polyvalent immunoglobulins, nine of whom improved within 7 days. Five of 13 patients required mechanical ventilation. Two patients with severe GBS died. At 6 months of follow-up, 7/13 achieved a good functional recovery with no or minor residual symptoms. A 2-fold increase in incidence was observed during the year of chikungunya outbreak. This study supports prior reports suggesting that GBS may be a complication of chikungunya. PMID- 28722565 TI - High Iron Levels Are Associated with Increased Malaria Risk in Infants during the First Year of Life in Benin. AB - The World Health Organization (WHO) estimates that 40% of children in low-income countries are anemic. Therefore, iron supplements are recommended by WHO in areas with high anemia rates. However, some studies have set into question the benefits of iron supplementation in malaria-endemic regions. In Benin, a west African country with high prevalence of anemia and malaria, no iron supplements are given systematically to infants so far despite the WHO recommendations. In this context, we wanted to investigate the effect of iron levels during the first year of life on malarial risk in Benin considering complementary risk factors. We followed 400 women and their offspring between January 2010 and June 2012 in Allada (Benin). Environmental, obstetric, and numerous clinical, maternal, and infant risk factors were considered. In multilevel models, high iron levels were significantly associated with the risk of a positive blood smear (adjusted odds ratio = 2.90, P < 0.001) and Plasmodium falciparum parasitemia (beta estimate = 0.38, P < 0.001). Infants with iron levels in the lowest quartile were less likely to have a positive blood smear (P < 0.001), and the risk increased with higher iron levels. Our results appeal for additional evaluation of the effect of different doses of iron supplements on the infant health status, including malaria incidence. Thus, the health status of infants should be compared between cohorts where iron is given either for prevention or anemia treatment, to better understand the effect of iron supplements on infant health. PMID- 28722566 TI - Molecular Epidemiology of Staphylococcus aureus Skin and Soft Tissue Infections in the Lao People's Democratic Republic. AB - This is the first report of the molecular epidemiology of Staphylococcus aureus from skin and soft tissue infections (SSTI) in Laos. We selected a random sample of 96 S. aureus SSTI isolates received by the Microbiology Laboratory, Mahosot Hospital, Vientiane, between July 2012 and June 2014, including representation from seven referral hospitals. Isolates underwent susceptibility testing by Clinical and Laboratory Standards Institute methods, spa typing and DNA microarray analysis, with whole genome sequencing for rare lineages. Median patient age was 19.5 years (interquartile range 2-48.5 years); 52% (50) were female. Forty-three spa types, representing 17 lineages, were identified. Fifty eight percent (56) of all isolates encoded Panton-Valentine leukocidin (PVL), representing six lineages: half of these patients had abscesses and three had positive blood cultures. The dominant lineage was CC121 (39; 41%); all but one isolate encoded PVL and 49% (19) were from children under five. Staphyococcus argenteus was identified in six (6%) patients; mostly adults > 50 years and with diabetes. Six isolates (6%) belonged to rare lineage ST2885; two possibly indicate cross-infection in a neonatal unit. One isolate from a previously undescribed lineage, ST1541, was identified. Antibiotic resistance was uncommon except for penicillin (93; 97%) and tetracycline (48; 50%). Seven (7%) isolates were methicillin-resistant S. aureus (MRSA), belonging to ST239-MRSA-III, CC59 MRSA-V(T) Taiwan Clone, ST2250-MRSA-IV, ST2885-MRSA-V and CC398-MRSA-V. Globally widespread CC5 and CC30 were absent. There are parallels in S. aureus molecular epidemiology between Laos and neighboring countries and these data highlight the prominence of PVL and suggest infiltration of MRSA clones of epidemic potential from surrounding countries. PMID- 28722567 TI - Bartonella Infection in Hematophagous, Insectivorous, and Phytophagous Bat Populations of Central Mexico and the Yucatan Peninsula. AB - Although emerging nonviral pathogens remain relatively understudied in bat populations, there is an increasing focus on identifying bat-associated bartonellae around the world. Many novel Bartonella strains have been described from both bats and their arthropod ectoparasites, including Bartonella mayotimonensis, a zoonotic agent of human endocarditis. This cross-sectional study was designed to describe novel Bartonella strains isolated from bats sampled in Mexico and evaluate factors potentially associated with infection. A total of 238 bats belonging to seven genera were captured in five states of Central Mexico and the Yucatan Peninsula. Animals were screened by bacterial culture from whole blood and/or polymerase chain reaction of DNA extracted from heart tissue or blood. Bartonella spp. were isolated or detected in 54 (22.7%) bats, consisting of 41 (38%) hematophagous, 10 (16.4%) insectivorous, and three (4.3%) phytophagous individuals. This study also identified Balantiopteryx plicata as another possible bat reservoir of Bartonella. Univariate and multivariate logistic regression models suggested that Bartonella infection was positively associated with blood-feeding diet and ectoparasite burden. Phylogenetic analysis identified a number of genetic variants across hematophagous, phytophagous, and insectivorous bats that are unique from described bat-borne Bartonella species. However, these strains were closely related to those bartonellae previously identified in bat species from Latin America. PMID- 28722568 TI - Epidemiology of Spotted Fever Group Rickettsioses and Acute Undifferentiated Febrile Illness in Villeta, Colombia. AB - Etiology of acute undifferentiated febrile syndrome (AUFS) is often unknown, leading to inaccurate diagnosis and treatment. Villeta town has been identified as an endemic area for spotted fever group (SFG) rickettsioses but little is known about possible amplifier hosts and other Rickettsia species different from Rickettsia rickettsii. Besides, few studies have approached other AUFS etiologies in the region. We investigated the role of dengue, leptospirosis, rickettsioses, human anaplasmosis, and Q fever as possible causes of AUFS in patients from Villeta. Sera specimens and ticks from animals as well as ticks from vegetation were studied for the presence of different Rickettsia spp. Among 104 sera from patients with AUFS, 16.4%, 24.0%, and 2.9% patients seroconverted to dengue, Leptospira, and SFG Rickettsia, respectively, with a case of probable coinfection or cross-reaction with Anaplasma phagocytophilum. None of the samples were reactive for Coxiella burnetii. Sera samples from 74 horses, 118 dogs, and 62 bovines were collected and showed 33.8%, 14.4%, and 50.0% of seroprevalence for SFG Rickettsia, respectively. A total of 1,287 ixodid ticks were collected from animals/vegetation and processed in pools for polymerase chain reaction. Among them, 1.7% was positive for Rickettsia genes, and Rickettsia amblyommii, R. rickettsii, and Rickettsia spp. were found. These results confirm the circulation of dengue, different SFG Rickettsia species and the relevance of other etiologies like leptospirosis and human anaplasmosis. Further studies must identify different epidemiological variables to establish proper surveillance and control programs. PMID- 28722569 TI - Mass Azithromycin and Malaria Parasitemia in Niger: Results from a Community Randomized Trial. AB - Studies designed to determine the effects of mass administration of azithromycin on trachoma have suggested that mass azithromycin distributions may also reduce the prevalence of malaria. These studies have typically examined the impact of a small number of treatments over short durations. In this prespecified substudy of a cluster-randomized trial for trachoma, we compared malaria parasitemia prevalence in 24 communities in Niger randomized to receive either annual or biannual mass azithromycin distributions over 3 years. The 12 communities randomized to annual azithromycin received three treatments during the high transmission season, and the 12 communities randomized to biannual azithromycin received a total of six treatments: three during the high-transmission season and three during the low-transmission season. Blood samples were taken to assess malariometric indices among children in all study communities at a single time point during the high-transmission season after 3 years of the intervention. No significant differences were identified in malaria parasitemia, parasite density, or hemoglobin concentration between the annual and biannual treatment arms. When compared with annual mass azithromycin alone, additional mass azithromycin distributions given during the low-transmission season did not significantly reduce the subsequent prevalence of malaria parasitemia or parasite density after 3 years, as measured during the high-transmission season. PMID- 28722570 TI - Mycobacterium tuberculosis Infection in Close Childhood Contacts of Adults with Pulmonary Tuberculosis is Increased by Secondhand Exposure to Tobacco. AB - Tobacco use is a major risk factor for tuberculosis (TB). Secondhand smoke (SHS) is also a risk factor for TB and to a lesser extent, Mycobacterium tuberculosis infection without disease. We investigated the added risk of M. tuberculosis infection due to SHS exposure in childhood contacts of TB cases in The Gambia. Participants were childhood household contacts aged <= 14 years of newly diagnosed pulmonary TB (PTB) cases. The intensity of exposure to the case was categorized according to whether contacts slept in the same room, same house, or a different house as the case. Contacts were tested with an enzyme-linked immunospot interferon gamma release assay. In multivariate regression models, M. tuberculosis infection was associated with increasing exposure to a case (odds ratios [OR]: 3.9, 95% confidence interval [CI]: 2.11-71.4, P < 0.001]) and with male gender (OR: 1.5 [95% CI: 1.12-2.11], P = 0.008). Tobacco use caused a 3-fold increase in the odds of M. tuberculosis infection in children who slept closest to a case who smoked within the same home compared with a nonsmoking case (OR: 8.0 [95% CI: 2.74-23.29] versus 2.4 [95% CI: 1.17-4.92], P < 0.001). SHS exposure as an effect modifier appears to greatly increase the risk of M. tuberculosis infection in children exposed to PTB cases. Smoking cessation campaigns may be important for reducing transmission of M. tuberculosis to children within households. PMID- 28722571 TI - More Poop, More Precision: Improving Epidemiologic Surveillance of Soil Transmitted Helminths with Multiple Fecal Sampling using the Kato-Katz Technique. AB - Soil-transmitted helminths, or parasitic intestinal worms, are among the most prevalent and geographically widespread parasitic infections in the world. Accurate diagnosis and quantification of helminth infection are critical for informing and assessing deworming interventions. The Kato-Katz thick smear technique, the most widely used laboratory method to quantitatively assess infection prevalence and infection intensity of helminths, has often been compared with other methods. Only a few small-scale studies, however, have considered ways to improve its diagnostic sensitivity. This study, conducted among 4,985 school-age children in an area of rural China with moderate prevalence of helminth infection, examines the effect on diagnostic sensitivity of the Kato-Katz technique when two fecal samples collected over consecutive days are examined and compared with a single sample. A secondary aim was to consider cost-effectiveness by calculating an estimate of the marginal costs of obtaining an additional fecal sample. Our findings show that analysis of an additional fecal sample led to increases of 23%, 26%, and 100% for Ascaris lumbricoides, Trichuris trichiura, and hookworm prevalence, respectively. The cost of collecting a second fecal sample for our study population was approximately USD4.60 per fecal sample. Overall, the findings suggest that investing 31% more capital in fecal sample collection prevents an underestimation of prevalence by about 21%, and hence improves the diagnostic sensitivity of the Kato-Katz method. Especially in areas with light-intensity infections of soil-transmitted helminths and limited public health resources, more accurate epidemiological surveillance using multiple fecal samples will critically inform decisions regarding infection control and prevention. PMID- 28722572 TI - Handwashing in 51 Countries: Analysis of Proxy Measures of Handwashing Behavior in Multiple Indicator Cluster Surveys and Demographic and Health Surveys, 2010 2013. AB - In 2009, a common set of questions addressing handwashing behavior was introduced into nationally representative Demographic and Health Surveys (DHS) and Multiple Indicator Cluster Surveys (MICS), providing large amounts of comparable data from numerous countries worldwide. The objective of this analysis is to describe global handwashing patterns using two proxy indicators for handwashing behavior from 51 DHS and MICS surveys conducted in 2010-2013: availability of soap anywhere in the dwelling and access to a handwashing place with soap and water. Data were also examined across geographic regions, wealth quintiles, and rural versus urban settings. We found large disparities for both indicators across regions, and even among countries within the same World Health Organization region. Within countries, households in lower wealth quintiles and in rural areas were less likely to have soap anywhere in the dwelling and at designated handwashing locations than households in higher wealth quintiles and urban areas. In addition, disparities existed among various geographic regions within countries. This analysis demonstrates the need to promote access to handwashing materials and placement at handwashing locations in the dwelling, particularly in poorer, rural areas where children are more vulnerable to handwashing-preventable syndromes such as pneumonia and diarrhea. PMID- 28722573 TI - Killing of Cryptosporidium sporozoites by Lactoferrin. AB - Intestinal infection caused by Cryptosporidium is a major contributor to diarrhea morbidity and mortality in young children around the world. Current treatments for children suffering from cryptosporidiosis are suboptimal. Lactoferrin is a glycoprotein found in breast milk. It has showed bacteriostatic and antimicrobial activity in the intestine. However, the effects of lactoferrin on the intestinal parasite Cryptosporidium have not been reported. In this study, we investigated the anticryptosporidial activity of human lactoferrin on different stages of Cryptosporidium. Physiologic concentrations of lactoferrin killed Cryptosporidium parvum sporozoites, but had no significant effect on oocysts viability or parasite intracellular development. Since sporozoites are essential for the infection process, our data reinforce the importance of breastfeeding and point to the potential of lactoferrin as a novel therapeutic agent for cryptosporidiosis. PMID- 28722574 TI - Intestinal Parasitic Infections in Human Immunodeficiency Virus-Infected and Noninfected Persons in a High Human Immunodeficiency Virus Prevalence Region of Cameroon. AB - The problem of intestinal parasitic infection in human immunodeficiency virus (HIV)-infected people requires careful consideration in the developing world where poor nutrition is associated with poor hygiene and several coinfecting diseases. Studies have addressed this issue in Cameroon, especially in the low HIV prevalence area. The current study was conducted to determine the prevalence of intestinal parasitosis in people living with HIV (PLHIV) in Adamaoua and to identify associated risk factors. Stool and blood specimens from study participants were screened for intestinal parasites and anti-HIV antibodies, respectively. Of 235 participants, 68 (28.9%) were HIV positive, 38 of them on antiretroviral treatment (ART). The overall prevalence of intestinal parasites was 32.3%. Of 68 PLHIV, 32.3% (22/68) were infected with intestinal parasites, compared with 32.3% (54/167) of the HIV-negative patients. Univariate analysis showed no difference between the prevalence of intestinal parasites among PLHIV and HIV-negative patients (P = 0.69). ART was not associated with the prevalence of intestinal parasites. Multivariate analysis showed that the quality of water and the personal hygiene were the major risk factors associated to intestinal parasitosis. The level of education was associated with HIV serostatus: the higher the level of education, the lower the risk of being infected with HIV (P = 0.00). PLHIV and the general population should be screened routinely for intestinal parasites and treated if infected. PMID- 28722575 TI - Household and Individual Risk Factors for Cholera among Cholera Vaccine Recipients in Rural Haiti. AB - Oral cholera vaccination was used as part of cholera control in Haiti, but the vaccine does not provide complete protection. We conducted secondary data analyses of a vaccine effectiveness study in Haiti to evaluate risk factors for cholera among cholera vaccine recipients. Individuals vaccinated against cholera that presented with acute watery diarrhea and had a stool sample positive for Vibrio cholerae O1 were included as cases. Up to four vaccinated individuals who did not present for treatment of diarrhea were included as controls for each case, and matched by location of residence, enrollment time, and age. We evaluated sociodemographic characteristics and risk factors for cholera. Univariable and multivariable logistic regression were performed to identify risk factors for cholera among vaccinees. Thirty-three vaccine recipients with culture confirmed cholera were included as cases. One-hundred-and-seventeen of their matched controls reported receiving vaccine and were included as controls. In a multivariable analysis, self-reporting use of branded household water disinfection products as a means of treating water (adjusted relative risk [aRR] = 44.3, 95% confidence interval [CI] = 4.19-468.05, P = 0.002), and reporting having a latrine as the main household toilet (aRR = 4.22, 95% CI = 1.23-14.43, P = 0.02), were independent risk factors for cholera. Self-reporting always treating water (aRR = 0.09, 95% CI = 0.01-0.57, P = 0.01) was associated with protection against cholera. The field effectiveness of water, sanitation, and hygiene interventions used in combination with cholera vaccination in cholera control should be measured and monitored over time to identify and remediate shortcomings, and ensure successful impact on disease control. PMID- 28722576 TI - Malaria-Associated Mortality in the Australian Defence Force during the Twentieth Century. AB - Malaria has been a military problem throughout history capable of causing epidemics that stop military operations. Individual mortality was examined from records of the three major wars of the 20th century that involved Australia in which 133 (1914-1919), 92 (1943-1945), and two (1965-1967) soldiers are known to have died with malaria. Those dying were predominately enlisted soldiers with a mean age of 29 years often complicated by other infections such as influenza, pneumonia or scrub typhus. Lethal epidemics of falciparum malaria occurred in Palestine/Syria in October 1918 and New Guinea in September 1943 to March 1944. Although no Australian soldier has died in nearly 50 years from malaria, there were three serious falciparum infections in soldiers in East Timor 1999-2000 who might have died if intensive care had not been provided. Recent military deployments into Africa including United Nations contingents still show falciparum malaria's lethality despite the availability of effective malaria chemoprophylaxis. PMID- 28722577 TI - Risk Factors for Norovirus Gastroenteritis among Nicaraguan Children. AB - Norovirus is a leading cause of pediatric gastroenteritis. Understanding norovirus epidemiology is essential for reducing disease burden. We conducted a case-control study to describe the distribution, clinical features, and risk factors of norovirus gastroenteritis among children < 5 years of age in Leon, Nicaragua. Cases were children testing positive for norovirus and controls were children living in the cases' communities. Study staff interviewed mothers of enrolled cases and controls to obtain detailed exposure information including food, water, and sanitation sources; recent exposures; household characteristics; and handwashing practices. In addition, study staff requested stool samples to be tested for norovirus from select household members. We used descriptive statistics to understand the epidemiologic and clinical features of gastroenteritis episodes. To analyze potential risk factors, we used Firth's penalized logistic regression to estimate crude and adjusted odds ratios (ORs) and corresponding 95% confidence intervals (CIs). There were 102 children with gastroenteritis, 18 cases of norovirus and 31 controls. Norovirus cases occurred later in the year, corresponding to a delay in the rainy season. Cases were more likely to have a household member with norovirus in their stool as compared with controls [crude OR: 13.3 (95% CI: 2.5, 136.2) and adjusted OR: 11.5 (95% CI: 1.6, 223.2)]. In addition, alcohol-based hand sanitizer use among household members was reported for 10 (32%) of controls and but never for cases. Further research is needed to understand household transmission of norovirus in low- and middle income countries and the potential impact of hand sanitizer use. PMID- 28722578 TI - Study of the Salivary Glands in Triatominae (Hemiptera, Reduviidae, Triatominae): Their Color and Application to the Chagas Disease Vector Evolution. AB - Chagas disease is caused by Trypanosoma cruzi and transmitted by feces of a triatomine that has the habit of defecating during blood feeding. The salivary glands of triatomines are important to hematophagy because their saliva is rich in anticoagulant and hemolytic proteins. The salivary glands of some Rhodnius species analyzed are reddish due to the presence of nitrophorins (antihemostatic activity). The present study aimed to analyze the color pattern of the salivary glands of 67 triatomine species to evaluate whether the presence of nitrophorins is a synapomorphy of Rhodnius or the tribe Rhodniini, or if it is shared with triatomines of the tribes Triatomini and Cavernicolini. Since only the species of the tribe Rhoniini present red glands, it is admitted that the presence of nitrophorin proteins is a synapomorphy of the tribe Rhodniini and that this tribe has derived more recently when compared with Triatomini and Cavernicolini. PMID- 28722579 TI - Control of Human Echinococcosis in Xinjiang, China, with 2,544 Surgeries in a Multihospital Network. AB - Human echinococcosis is a serious parasitic disease threatening public health worldwide especially in Xinjiang, China, an undeveloped farming and pastoral area. A multihospital surgical network was applied to improve human echinococcosis control. An innovative surgery network connected the 28 designated public hospitals, which distributed in a vast land of 1,600,000 m2. The surgery network integrated the efficient patient digital information sharing, treatment consulting, patient transfer, and financial support. The 6-year practical outcome of 2,544 surgeries in Xinjiang, China, was retrospectively analyzed. Electronic database and surgery network have been proven especially effective in undeveloped area with vast territory, sparse population, multiple languages, and poor traffic conditions. This network turned out effectively improved patient processing efficiency and decreased the medical cost. PMID- 28722580 TI - Rapid Active Sampling Surveys as a Tool to Evaluate Factors Associated with Acute Gastroenteritis and Norovirus Infection among Children in Rural Guatemala. AB - We examined burden and factors associated with norovirus (NoV) acute gastroenteritis (AGE) among children in rural Guatemala. Children age 6 weeks to 17 years were enrolled into three AGE surveillance groups, using two-stage cluster sampling: a prospective participatory syndromic surveillance (PSS) cohort and two cross-sectional rapid active sampling (RAS) surveys, conducted from April 2015 to February 2016. Epidemiologic and NoV testing data were used to identify factors associated with NoV infection, AGE, and NoV+ AGE. The three cross sectional surveys (PSS enrollment visit, RAS Survey 1, and RAS Survey 2) enrolled 1,239 children, who reported 134 (11%) AGE cases, with 20% of AGE and 11% of non AGE samples positive for NoV. Adjusted analyses identified several modifiable factors associated with AGE and NoV infection. The cross-sectional RAS surveys were practical and cost-effective in identifying population-level risk factors for AGE and NoV, supporting their use as a tool to direct limited public health resources toward high-risk populations. PMID- 28722581 TI - Epidemiology of Diphtheria in India, 1996-2016: Implications for Prevention and Control. AB - Diphtheria is an acute disease caused by exotoxin-producing Corynebacterium diphtheriae. Globally, diphtheria has been showing a declining trend due to effective childhood vaccination programs. A substantial proportion of global burden of diphtheria is contributed by India. Hospital-based surveillance studies as well as diphtheria outbreaks published in last 20 years (1996-2016) indicate that diphtheria cases are frequent among school-going children and adolescents. In some Indian states, Muslim children are affected more. As per the national level health surveys, coverage of three doses of diphtheria vaccine was 80% during 2015-2016. Information about coverage of diphtheria boosters is not routinely collected through these surveys, but is expected to be low. Few studies also indicate low diphtheria immunity among school-going children and adults. The strategies for prevention of diphtheria need to focus on improving coverage of primary and booster doses of diphtheria vaccines administered as a part of Universal Immunization Program as well as introducing diphtheria vaccine for school-going children. PMID- 28722582 TI - Population Movement as a Risk Factor for Malaria Infection in High-Altitude Villages of Tahtay-Maychew District, Tigray, Northern Ethiopia: A Case-Control Study. AB - Key goal and targets of the Ethiopia National Malaria Control Program are to achieve malaria elimination within specific geographical areas with historically low malaria transmission and to reach near-zero malaria transmission in the remaining malarious areas by 2020. However, back and forth population movement between high-transmission and low-transmission area imposes challenge on the success of national malaria control programs. Therefore, examining the effect of human movement and identification of at-risk populations is crucial in an elimination setting. A matched case-control study was conducted among 520 study participants at a community level in low malaria transmission settings in northern Ethiopia. Study participants who received a malaria test were interviewed regarding their recent travel history. Bivariate and multivariate analyses were carried out to determine if the reported travel was related to malaria infection. Younger age (adjusted odds ratio [AOR] = 3.20, 95% confidence interval [CI]: 1.73, 5.89) and travel in the previous month (AOR = 11.40, 95% CI: 6.91, 18.82) were statistically significant risk factors for malaria infection. Other statistically significant factors, including lower educational level (AOR = 2.21, 95% CI: 1.26, 3.86) and nonagricultural in occupation (AOR = 2.0, 95% CI: 1.02, 3.94), were also found as risk factors for malaria infection. Generally, travel history was found to be a strong predictor for malaria acquisition in the high-altitude villages. Therefore, besides the existing efforts in endemic areas, targeting those who frequently travel to malarious areas is crucial to reduce malaria infection risks and possibility of local transmissions in high-altitude areas of northern Ethiopia. PMID- 28722583 TI - A Direct from Blood Reverse Transcriptase Polymerase Chain Reaction Assay for Monitoring Falciparum Malaria Parasite Transmission in Elimination Settings. AB - We describe a novel one-step reverse transcriptase real-time PCR (direct RT-PCR) for Plasmodium falciparum malaria parasites that amplifies RNA targets directly from blood. We developed the assay to identify gametocyte-specific transcripts in parasites from patient blood samples, as a means of monitoring malaria parasite transmission in field settings. To perform the test, blood is added directly to a master mix in PCR tubes and analyzed by real-time PCR. The limit of detection of the assay on both conventional and portable real-time PCR instruments was 100 parasites/mL for 18S rRNA, and 1,000 parasites/mL for asexual (PFE0065W) and gametocyte (PF14_0367, PFGEXP5) mRNA targets. The usefulness of this assay in field studies was explored in samples from individuals living in a high transmission region in Cameroon. The sensitivity and specificity of the assay compared with a standard two-step RT-PCR was 100% for 18S rRNA on both conventional and portable instruments. For PF14_0367, the sensitivity and specificity were 85.7% and 70.0%, respectively, on the conventional instrument and 78.6% and 90%, respectively, on the portable instrument. The concordance for assays run on the two instruments was 100% for 18S rRNA, and 79.2% for PF14_0367, with most discrepancies resulting from samples with low transcript levels. The results show asexual and sexual stage RNA targets can be detected directly from blood samples in a simple one-step test on a field-friendly instrument. This assay may be useful for monitoring malaria parasite transmission potential in elimination settings, where sensitive diagnostics are needed to evaluate the progress of malaria eradication initiatives. PMID- 28722584 TI - Rocky Mountain Spotted Fever and Pregnancy: Four Cases from Sonora, Mexico. AB - We present a series of four pregnant women with Rocky Mountain spotted fever (RMSF) that occurred in Sonora, Mexico, during 2015-2016. Confirmatory diagnoses were made by polymerase chain reaction or serological reactivity to antigens of Rickettsia rickettsii by using an indirect immunofluorescence antibody assay. Each patient presented with fever and petechial rash and was treated successfully with doxycycline. Each of the women and one full-term infant delivered at 36 weeks gestation survived the infection. Three of the patients in their first trimester of pregnancy suffered spontaneous abortions. RMSF should be suspected in any pregnant woman presenting with fever, malaise and rash in regions where R. rickettsii is endemic. PMID- 28722585 TI - School Children's Intestinal Parasite and Nutritional Status One Year after Complementary School Garden, Nutrition, Water, Sanitation, and Hygiene Interventions in Burkina Faso. AB - The potential health benefits of combined agricultural, nutrition, water, sanitation, and hygiene (WASH) interventions are poorly understood. We aimed to determine whether complementary school garden, nutrition, and WASH interventions reduce intestinal parasites and improve school children's nutritional status in two regions of Burkina Faso. A cluster-randomized controlled trial was conducted in the Plateau Central and Center-Ouest regions of Burkina Faso. A total of 360 randomly selected children, aged 8-15 years, had complete baseline and end-line survey data. Mixed regression models were used to assess the impact of the interventions, controlling for baseline characteristics. The prevalence of intestinal parasitic infections decreased both in intervention and control schools, but the decrease was significantly higher in the intervention schools related to the control schools (odds ratio [OR] of the intervention effect = 0.2, 95% confidence interval [CI] = 0.1-0.5). Indices of undernutrition did not decrease at end-line in intervention schools. Safe handwashing practices before eating and the use of latrines at schools were significantly higher in the intervention schools than in the control schools at end-line (OR = 6.9, 95% CI = 1.4-34.4, and OR = 14.9, 95% CI = 1.4-153.9, respectively). Parameters of water quality remained unchanged. A combination of agricultural, nutritional, and WASH related interventions embedded in the social-ecological systems and delivered through the school platform improved several child health outcomes, including intestinal parasitic infections and some WASH-related behaviors. Sustained interventions with stronger household and community-based components are, however, needed to improve school children's health in the long-term. PMID- 28722586 TI - Continuous Excretion of Leptospira borgpetersenii Ballum in Mice Assessed by Viability Quantitative Polymerase Chain Reaction. AB - Rodents are the main reservoir animals of leptospirosis. In this study, we characterized and quantified the urinary excretion dynamics of Leptospira by Mus musculus infected with 2 * 108 virulent Leptospira borgpetersenii serogroup Ballum. Each micturition was collected separately in metabolic cages, at 12 time points from 7 to 117 days post-infection (dpi). We detected Leptospira in all urine samples collected (up to 8 per time point per mouse) proving that Leptospira excretion is continuous with ca. 90% live L. borgpetersenii Ballum, revealed by viability quantitative polymerase chain reaction. Microscopic visualization by Live/Dead fluorescence confirmed this high proportion of live bacteria and demonstrated that L. borgpetersenii Ballum are excreted, at least partly, as bacterial aggregates. We observed two distinct phases in the excretion dynamics, first an increase in Leptospira concentration shed in the urine between 7 and 63 dpi followed by a plateau phase from 63 dpi onward, with up to 3 * 107Leptospira per mL of urine. These two phases seem to correspond to progressive colonization of renal tubules first, then to stable cell survival and maintenance in kidneys. Therefore, chronically infected adult mice are able to contaminate the environment via urine at each micturition event throughout their lifetime. Because Leptospira excretion reached its maximum 2 months after infection, older rodents have a greater risk of contaminating their surrounding environment. PMID- 28722587 TI - Lack of Geospatial Population Structure Yet Significant Linkage Disequilibrium in the Reservoir of Plasmodium falciparum in Bongo District, Ghana. AB - Malaria control in West Africa is impeded by the large reservoir of chronic asymptomatic Plasmodium falciparum infections in the human population. This study aimed to assess the extent of diversity in the P. falciparum reservoir in Bongo District (BD), Ghana, at the end of the dry season, the lowest point in malaria transmission over the course of the year. Analysis of the variation in 12 microsatellite loci was completed for 200 P. falciparum isolates collected from a cross-sectional survey of residents of all ages from two catchment areas in BD. Analysis of the multilocus haplotypes showed high levels of genetic diversity (He = 0.74), no population differentiation yet significant linkage disequilibrium (LD) (ISA = 0.0127, P = 0.006) in BD. Multilocus LD was significant between and within catchment areas even though every haplotype in the population was unique and the majority of individuals (84.0%) harbored multiple-clone infections. The linkage structure among multilocus haplotypes was not associated with sampling location. These data provide the first study with deep sampling of the P. falciparum reservoir in an area of seasonal malaria transmission in West Africa. The co-occurrence of high multiplicity of infection (multiple-clone infections) with significant multilocus LD is surprising given the likelihood of high recombination rates in BD. The results suggest that the linkage structure among multilocus haplotypes has not been shaped by geographic separation of parasite populations. Furthermore, the observed LD levels provide a baseline population genetic metric with putatively neutral markers to evaluate the effects of seasonality and malaria control efforts in BD. PMID- 28722588 TI - Optimizing Direct Membrane and Direct Skin Feeding Assays for Plasmodium falciparum Transmission-Blocking Vaccine Trials in Bancoumana, Mali. AB - Malaria transmission-blocking vaccines (TBV) have been evaluated in field trials in Mali since 2013. However, the assays currently used to measure serum antibody TB activity (TBA) after vaccination are highly variable, in part due to the lack of optimization and standardization for field assays in which mosquitoes feed on gametocytemic blood. Herein, we report a study conducted in Bancoumana village, Mali, where we identify and optimize the parameters that contribute to successful mosquito feeding outcomes in both direct skin feeds (DSFs) and direct membrane feeding assays (DMFA). These parameters include: 1) mosquito age, 2) duration of mosquito starvation prior to feeding, 3) membrane selection for DMFA, 4) anatomical location of DSF feeding (arm, calf, and ankle), and 5) time of day for DSF (dawn or dusk). We found that younger mosquitoes were significantly associated with higher feeding, survival, and infection rates. Longer starvation times were positively, but not significantly, associated with higher infection rates, but were negatively associated with feeding and survival. Membrane type and body location did not affect infection outcome significantly. Although dusk was found to be associated with higher infection rates, this may be confounded by the time from positive blood smear. Based on these findings, we make specific recommendations for optimal feeding parameters in the different assay types to maximize the chance of detecting parasite transmission in a standardized manner. PMID- 28722589 TI - Silencing of Two Vitellogenin Genes Inhibits Oviposition in the Chagas Disease Vector Triatoma infestans (Hemiptera: Reduviidae). AB - RNA interference caused by exogenous double-stranded RNA (dsRNA) is used to downregulate crucial genes to control insects. The reproductive success of all oviparous species depends on vitellogenin (Vg) biosynthesis and its accumulation in the developing oocytes. Adult females of Triatoma infestans were independently injected with two Vg dsRNAs (Vg1 dsRNA or Vg2 dsRNA) or nuclease-free water (control) 24 hours before feeding, and a group of adult females not injected was also analyzed (control). Vg1 and Vg2 messenger RNAs silencing was verified by reverse transcription quantitative polymerase chain reaction. The transcript levels of the Vg1 and Vg2 genes were significantly reduced after dsRNA treatment in fat body and ovary of T. infestans in relation to those detected in individuals injected with nuclease-free water and not injected (controls). Moreover, the present study demonstrated that the silencing of the Vg1 or Vg2 genes inhibits oviposition in the Chagas disease vector T. infestans. These findings may have important implications for the development of novel vector control strategies. PMID- 28722590 TI - A Qualitative Study of Provider Perceptions of Influences on Uptake of Pediatric Hospital Guidelines in Lao PDR. AB - Strategies to improve the quality of hospital care are needed if ongoing gains in child health and survival are to be made. We previously reported on improvements in the quality of case management in hospitals following a guideline-based intervention in Lao PDR, with variation in the degree of change achieved between clinical conditions. This study aims to understand the factors that influenced the uptake of the guideline-based intervention, and its impact on care. This qualitative study was embedded in a mixed-methods evaluation of guideline implementation in nine hospitals in Lao PDR. Focus groups and individual interviews were conducted with 70 health staff from central, provincial, and district hospitals. The interview guide was based on the Theoretical Domains Framework. Inductive content analysis was performed on interview transcripts to identify themes, supported by field notes from the intervention. Findings were triangulated against previously reported quantitative outcomes using driver diagrams. Key influences on guidelines uptake related to the guideline and intervention (filling a void, physical accessibility, comprehensibility, training in guideline use), health staff (behavior regulation, trust in guidelines, and beliefs about consequences), and the environment (social influences particularly consensus and incorporation into clinical norms). The major barrier was family preference for treatments in conflict with guideline recommendations. This study identifies contextual factors that explain, as well as validate previously identified improvements in care following guideline implementation in Lao PDR. It provides novel understanding of why the same intervention may have a differential impact on different clinical conditions. PMID- 28722591 TI - Serological Evidence of Rickettsia spp. in Western Australian Dogs. AB - It has been claimed that dogs can be useful sentinels for public health monitoring of vector-borne infectious diseases, including Rickettsia spp. We used 153 canine blood samples opportunistically collected at Murdoch University Veterinary Hospital and 156 canine sera collected from Aboriginal communities in northwest Western Australia to test for evidence of Rickettsia spp. exposure, using microimmunofluorescence (MIF) in the latter case, and both MIF and polymerase chain reaction (PCR) in the former. Conventional and real-time PCR failed to amplify any Rickettsia spp. DNA. The seroprevalence for spotted fever group/transitional group Rickettsia spp. in Western Australian dogs was 17.3% (54/312), and for typhus group (TG) Rickettsia spp., 18.4% (57/310), with a cut off titer of 1:128. Young dogs (<= 2 years) from Aboriginal communities had significantly lower seropositivity to TG Rickettsia spp. compared with all other groups, and young Perth dogs had a significantly higher seropositivity to TG Rickettsia spp. than all Aboriginal community dogs. PMID- 28722593 TI - The Benjamin H. Kean Travel Fellowship in Tropical Medicine: Assessment of Impact at 15 Years. AB - The Benjamin H. Kean Fellowship in Tropical Medicine is an American Society of Tropical Medicine and Hygiene initiative that provides medical students with funding for international clinical or research experiences lasting at least 1 month. Of the 175 Kean fellows from 1998 to 2013, 140 had current available e mails, and 70 of the 140 (50%) responded to a survey about their fellowship experience. Alumni indicated that the Kean Fellowship had a high impact on their career plans with regard to preparation for (N = 65, 94.2%) and inspiration to pursue (N = 59, 88.1%) a career in tropical medicine and global health. Continued involvement in tropical medicine and global health was common: 52 alumni (74.3%) were currently working in tropical medicine or global health, 49 (71.0%) had done so in the interim between the Kean fellowship and their current position; and 17 of 19 Kean fellows (89.4%) who had completed all medical training and were now in professional practice continued to work in tropical medicine and global health. Alumni had been highly productive academically, publishing a total of 831 PubMed indexed manuscripts, almost all on tropical medicine or global health topics, in the period between their fellowship year and 2013. Alumni reported strengths of the fellowship including funding, networking, and flexibility, and suggested that more networking and career mentoring would enhance the program. The Benjamin H. Kean fellowship program has been highly successful at inspiring and fostering ongoing work by trainees in tropical medicine and global health. PMID- 28722592 TI - A Cluster of Symptomatic and Asymptomatic Infections of Severe Fever with Thrombocytopenia Syndrome Caused by Person-to-Person Transmission. AB - Severe fever with thrombocytopenia syndrome virus (SFTSV) is a novel phlebovirus that was identified to be the etiological pathogen of the emerging infectious disease, severe fever with thrombocytopenia syndrome (SFTS). SFTSV could be transmitted through tick bite. Transmission of SFTSV among humans has also been reported mainly through direct blood contact. In July 2014, a cluster of six suspected SFTS cases occurred in Shandong Province, China. In this cluster, both symptomatic and asymptomatic persons were included. By analyzing the clinical data and results of laboratory tests, and conducting the epidemiological interviews with the cases and their families, risk factors responsible for the transmission were evaluated. The findings suggested that SFTSV transmission among humans may cause asymptomatic infection via personal contact without blood exposure. PMID- 28722594 TI - Fatal Leptospira spp./Zika Virus Coinfection-Puerto Rico, 2016. AB - Coinfection with pathogens that cause acute febrile illness (AFI) can complicate patient diagnosis and management. This report describes a fatal case of Leptospira spp./Zika virus (ZIKV) coinfection in Puerto Rico. The patient presented with a 5-day history of AFI; reported behavioral risk factors for leptospirosis; was diagnosed with possible leptospirosis, dengue, chikungunya, or ZIKV disease; and received appropriate treatment for leptospirosis and dengue. Following a 3-day hospitalization, the patient died due to acute gastrointestinal hemorrhage, and kidney and liver failure. Serologic diagnostic testing for leptospirosis and ZIKV disease was negative; however, molecular diagnostic testing performed postmortem was positive for detection of Leptospira spp. and ZIKV nucleic acid. This case demonstrates the need for continued clinical awareness of leptospirosis in areas experiencing outbreaks of pathogens that cause AFI and the need for evaluation of coinfection with AFI-causing pathogens as a risk factor for increased severity of disease. PMID- 28722595 TI - Multidrug-Resistant Microorganisms Colonizing Lower Extremity Wounds in Patients in a Tertiary Care Hospital, Lima, Peru. AB - Multidrug-resistant organism (MDRO) infections cause high morbidity and mortality, and high costs to patients and hospitals. The study aims were to determine the frequency of MDRO colonization and associated factors in patients with lower-extremity wounds with colonization. A cross-sectional study was designed during November 2015 to July 2016 in a tertiary care hospital in Lima, Peru. A wound swab was obtained for culture and susceptibility testing. MDRO colonization was defined if the culture grew with methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, and/or extended spectrum beta-lactamase (ESBL) microorganisms. The frequency of MDRO wound colonization was 26.8% among the 97 patients enrolled. The most frequent MDRO obtained was ESBL-producing Escherichia coli, which was significantly more frequent in chronic wounds versus acute wounds (17.2% versus 0%, P < 0.05). Infection control measures should be implemented when patients with chronic lower-extremity wounds are admitted. PMID- 28722596 TI - Therapeutic Response in Adult Patients with Nonsevere Chronic Paracoccidioidomycosis Treated with Sulfamethoxazole-Trimethoprim: A Retrospective Study. AB - According to the Brazilian Consensus on Paracoccidioidomycosis (PCM), itraconazole is the drug of choice for treatment. However, the combination of sulfamethoxazole and trimethoprim (SMX-TMP) is most commonly used in clinical practice because of its higher availability in the public health services. The aims of this study were to evaluate the therapeutic response of patients with nonsevere chronic PCM to SMX-TMP and highlight the factors related to treatment failure. An adequate therapeutic response was defined as completely improved disease signs and symptoms after medication use for a minimum of 6 months, followed by normalized hematological and biochemical changes, radiological improvements, and negative mycological examination findings. Medical records were analyzed for 244 patients with nonsevere chronic PCM who were treated between 1998 and 2014. In total, 41.9% of the patients had PCM for >= 8 months. Seven (2.9%) patients were coinfected with human immunodeficiency virus (HIV). The median (25%, 75% percentiles) treatment duration was 21 (10, 25) months. Adequate treatment adherence was reported by 68.3% of patients. In addition, 73.6% of patients exhibited an adequate therapeutic response. The majority (82.6%) of patients who were treated with SMX-TMP for > 24 months displayed an adequate therapeutic response, and the frequency of adequate therapeutic response gradually decreased as the duration of treatment decreased. Treatment nonadherence (P < 0.001) and PCM-HIV coinfection (P = 0.019) were factors associated with therapeutic failure. The study results support the good efficacy of SMX-TMP. Attention should be given to PCM-HIV coinfection, emphasizing the concern of a higher risk of PCM therapeutic failure in these patients. PMID- 28722597 TI - Occult Amebic Liver Abscess as Cause of Extensive Inferior Vena Cava and Hepatic Vein Thrombosis. AB - The most common extraintestinal complication of Entamoeba histolytica is amebic liver abscess (ALA). Hepatic vein and inferior vena cava (IVC) thrombosis are rare but well-documented complications of ALA, typically attributed to mechanical compression and inflammation associated with a large abscess. We present a case of a previously healthy 43-year-old Canadian man presenting with constitutional symptoms and right upper quadrant abdominal pain. He was found to have thrombophlebitis of the IVC, accessory right hepatic vein, and bilateral iliac veins. Extensive investigations for thrombophilia were negative. Magnetic resonance imaging of the liver demonstrated a 3.2-cm focal area of parenchymal abnormality that was reported as presumptive hepatocellular carcinoma, and a 1.9 cm lesion in the caudate lobe with diffusion restriction and peripheral rim enhancement. Despite multiple biopsy attempts, a histopathological diagnosis was not achieved. Abdominal pain and fever 4 months later prompted repeat ultrasound demonstrating a 10.4- * 12.0-cm rim-enhancing fluid attenuation lesion felt to represent a liver abscess. Thick dark "chocolate brown" drainage from the lesion and positive serology for E. histolytica confirmed the diagnosis of ALA acquired from a previous trip to Cuba. The patient was started on treatment with metronidazole and paromomycin and repeat abdominal ultrasound demonstrated resolution of the abscess. This case is the first to demonstrate extensive IVC thrombosis secondary to a relatively small occult ALA and emphasizes the thrombogenic potential of ALA. Amebic infection should be considered as a rare cause of IVC thrombosis in the correct clinical context. PMID- 28722598 TI - Risk Factors for Severe Infection, Hospitalization, and Prolonged Antimicrobial Therapy in Patients with Babesiosis. AB - Babesiosis is an emerging tick-borne disease transmitted by the hard tick Ixodes scapularis, which also transmits Lyme disease. Better gradation of prognostic indicators are needed to determine which patients may develop serious complications requiring hospitalization, and to provide early guidance on appropriate therapy. In this study, we evaluated 128 patients with smear or real time polymerase chain reaction-confirmed Babesia microti infections over a period of 16 years. Patients with asplenia or immunocompromising conditions were more likely to have severe infection (P < 0.01), require hospitalization (P < 0.01), or receive prolonged courses of antimicrobials (P < 0.01). Nausea or vomiting (P < 0.01) and diarrhea (P < 0.01) along with hyperbilirubinemia (P < 0.01) were predictive of severe infection, hospitalization, and prolonged antimicrobial therapy. Patients with concurrent Lyme disease were less likely to require hospitalization and had similar severity of disease and length of antibiotic treatment compared with those without Lyme disease. PMID- 28722600 TI - Ocular Gnathostomiasis-Update of Earlier Survey. AB - Ocular gnathostomiasis is rather a rare food-borne zoonosis caused by infection with the larvae of several species of genus Gnathostoma and is a representative ocular larva migrans syndrome. In our previous literature survey, we found 73 cases of ocular gnathostomiasis reported up to and including 2009, though additional sporadic cases have been reported in Asia and the Americas since that report. Here, we review 10 additional cases reported since 2010, and also update current findings regarding epidemiological and clinical features in affected patients. PMID- 28722599 TI - Assessment of Fecal Exposure Pathways in Low-Income Urban Neighborhoods in Accra, Ghana: Rationale, Design, Methods, and Key Findings of the SaniPath Study. AB - Rapid urbanization has contributed to an urban sanitation crisis in low-income countries. Residents in low-income, urban neighborhoods often have poor sanitation infrastructure and services and may experience frequent exposure to fecal contamination through a range of pathways. There are little data to prioritize strategies to decrease exposure to fecal contamination in these complex and highly contaminated environments, and public health priorities are rarely considered when planning urban sanitation investments. The SaniPath Study addresses this need by characterizing pathways of exposure to fecal contamination. Over a 16 month period, an in-depth, interdisciplinary exposure assessment was conducted in both public and private domains of four neighborhoods in Accra, Ghana. Microbiological analyses of environmental samples and behavioral data collection techniques were used to quantify fecal contamination in the environment and characterize the behaviors of adults and children associated with exposure to fecal contamination. Environmental samples (n = 1,855) were collected and analyzed for fecal indicators and enteric pathogens. A household survey with 800 respondents and over 500 hours of structured observation of young children were conducted. Approximately 25% of environmental samples were collected in conjunction with structured observations (n = 441 samples). The results of the study highlight widespread and often high levels of fecal contamination in both public and private domains and the food supply. The dominant fecal exposure pathway for young children in the household was through consumption of uncooked produce. The SaniPath Study provides critical information on exposure to fecal contamination in low-income, urban environments and ultimately can inform investments and policies to reduce these public health risks. PMID- 28722601 TI - Rabies in Myanmar: Prevalent, Preventable but not Prioritized. AB - Despite the availability of proven measures to prevent the disease, rabies now kills more people in Myanmar than malaria. Although there are challenges in controlling rabies in such a large and culturally diverse country, Myanmar's successful National Malaria Control Program demonstrates what can be achieved with sufficient political, financial, and scientific commitment. Presently, however, Myanmar lacks a comparable program to coordinate the multifaceted approach that is necessary to control rabies. The national government has invested heavily in improving access to postexposure prophylaxis, but there should also be an emphasis on other, more cost-effective strategies, particularly mass canine vaccination, which has been an essential component of successful rabies elimination programs in other countries. Continued health system strengthening is also required to improve primary health care, while decentralization of laboratory diagnostic services is needed to facilitate more timely, rational, and cost-effective use of postexposure prophylaxis. PMID- 28722602 TI - Associations between Household Latrines and the Prevalence of Diarrhea in Idiofa, Democratic Republic of the Congo: A Cross-Sectional Study. AB - Despite the importance of sanitation, few studies have assessed the effects of latrines on the health outcomes of children under 5 years of age. We assessed the relations between latrine coverage and the prevalence of diarrhea in children under 4 years of age. In this cross-sectional study, we analyzed the baseline data obtained as part of a longitudinal survey targeting 720 households in Idiofa, Bandundu, Democratic Republic of the Congo. We categorized latrines according to the presence of each major component and investigated whether diarrhea prevalence of children under 4 years of age is associated with latrine availability and improvement. Latrines have health benefits regardless of whether they are improved. Also worth noting is that comparatively well-equipped and more appropriately managed latrines could prevent child diarrhea more effectively than less equipped or inappropriately managed latrines. Households who have a latrine with a superstructure, roof, and no flies (a partly improved latrine) were found to be 52% less likely to report cases of diarrhea than households with unimproved latrines (adjusted odds ratio [OR] = 0.48, confidence interval [CI] = 0.31-0.76), which are all the other latrines not included in the partly improved latrine category. We have observed the profound protective effect of latrines with a superstructure. This study demonstrates that latrines are associated with significant improvements in health even when they do not fully meet the conditions of improved latrines. This study adds value to the limited evidence on the effect of latrines on health parameters by demonstrating that latrines have correlations with health benefits regardless of whether they are improved, as well as by elucidating the most essential components of improved latrines. PMID- 28722603 TI - Molecular Characterization of Mycobacterium tuberculosis Strains with TB-SPRINT. AB - We evaluated Tuberculosis-Spoligo-Rifampicin-Isoniazid Typing (TB-SPRINT), a microbead-based method for spoligotyping and detection of rifampicin and isoniazid resistance in Mycobacterium tuberculosis. For that, 67 M. tuberculosis complex strains were retrospectively selected. Membrane-based spoligotyping, restriction fragment length polymorphism, DNA sequencing/pyrosequencing of rpoB, katG, and inhA promoter, TB-SPRINT, and SNP typing were performed. Concordance between spoligotyping methods was 99.6% (2,785/2,795 spoligotype data points). For most of the discordant cases, the same lineage was assigned with both methods. Concordance between phenotypic drug susceptibility testing and TB-SPRINT for detecting rifampicin and isoniazid resistance was 98.4% (63/64) and 93.8% (60/64), respectively. Concordance between DNA sequencing/pyrosequencing and TB SPRINT for detecting mutations in rpoB, katG, and inhA were 98.4% (60/61), 100% (64/64), and 96.9% (62/64), respectively. In conclusion, TB-SPRINT is a rapid and easy-to-perform assay for genotyping and detecting drug resistance in a single tube; therefore, it may be a useful tool to improve epidemiological surveillance. PMID- 28722604 TI - Classification and Visualization of Physical and Chemical Properties of Falsified Medicines with Handheld Raman Spectroscopy and X-Ray Computed Tomography. AB - Analytical methods for the detection of substandard and falsified medical products (SFs) are important for public health and patient safety. Research to understand how the physical and chemical properties of SFs can be most effectively applied to distinguish the SFs from authentic products has not yet been investigated enough. Here, we investigated the usefulness of two analytical methods, handheld Raman spectroscopy (handheld Raman) and X-ray computed tomography (X-ray CT), for detecting SFs among oral solid antihypertensive pharmaceutical products containing candesartan cilexetil as an active pharmaceutical ingredient (API). X-ray CT visualized at least two different types of falsified tablets, one containing many cracks and voids and the other containing aggregates with high electron density, such as from the presence of the heavy elements. Generic products that purported to contain equivalent amounts of API to the authentic products were discriminated from the authentic products by the handheld Raman and the different physical structure on X-ray CT. Approach to investigate both the chemical and physical properties with handheld Raman and X-ray CT, respectively, promise the accurate discrimination of the SFs, even if their visual appearance is similar with authentic products. We present a decision tree for investigating the authenticity of samples purporting to be authentic commercial tablets. Our results indicate that the combination approach of visual observation, handheld Raman and X-ray CT is a powerful strategy for nondestructive discrimination of suspect samples. PMID- 28722605 TI - Characterizing Reactivity to Onchocerca volvulus Antigens in Multiplex Bead Assays. AB - Multiplex bead assays (MBAs) may provide a powerful integrated tool for monitoring, evaluation, and post-elimination surveillance of onchocerciasis and co-endemic diseases; however, the specificity and sensitivity of Onchocerca volvulus antigens have not been characterized within this context. An MBA was developed to evaluate three antigens (OV-16, OV-17, and OV-33) for onchocerciasis. Receiver operating characteristics (ROC) analyses were used to characterize antigen performance using a panel of 610 specimens: 109 O. volvulus positive specimens, 426 non-onchocerciasis controls with filarial and other confirmed parasitic infection, and 75 sera from patients with no other parasitic infection. The IgG and IgG4 assays for OV-16 demonstrated sensitivities of 95.4% and 96.3%, and specificities of 99.4% and 99.8%, respectively. The OV-17 IgG and IgG4 assays had sensitivities of 86.2% and 76.1% and specificities of 79.2% and 82.8%. For OV-33, the IgG and IgG4 assays had sensitivities of 90.8% and 96.3%, and specificities of 96.8% and 98.6%. The OV-16 IgG4-based MBA had the best assay characteristics, followed by OV-33 IgG4. The OV-16 IgG4 assay would be useful for monitoring and evaluation using the MBA platform. Further evaluations are needed to review the potential use of OV-33 as a confirmatory test in the context of program evaluations. PMID- 28722606 TI - Assessment of the Acceptability and Feasibility of Child Potties for Safe Child Feces Disposal in Rural Bangladesh. AB - Indiscriminate defecation among young children and the unsafe disposal of their feces increases fecal contamination in the household environment and the risk of diarrheal disease transmission. Improved sanitary technology for children too young to use a latrine may facilitate safe feces disposal and reduce fecal contamination in the household environment. We assessed the acceptability and feasibility of child potties in rural Bangladesh in 2010. Our team introduced child potties into 26 households for 30 days, and conducted semistructured interviews, group discussions, and observations to assess the acceptability and feasibility of their use for parents and children. Residents of this rural Bangladeshi community accepted the child potties and caregivers found them to be a feasible means of managing child feces. The color, shape, design, and size of the potty influenced its acceptability and use. These residents reported that regular use of the potty improved the household's physical environment and caregiver and child personal hygiene. Regular potty use also reduced caregivers' work load by making feces collection and disposal easier. Primary caregivers viewed 4-6 months as the appropriate age to initiate potty training. Sanitation interventions should integrate and emphasize potties for children's feces management to reduce household environmental contamination. PMID- 28722607 TI - Mucosal leishmaniasis: A Retrospective Study of 327 Cases from an Endemic Area of Leishmania (Viannia) braziliensis. AB - Mucosal leishmaniasis (ML) is observed only in about 3% of patients with American tegumentary leishmaniasis (ATL) but has a high potential for destructive, disfiguring, and disabling sequelae. Prior reports of clinical and epidemiologic features of ML are limited by small numbers of cases. In this study, we evaluated changes in the demographic features and clinical presentation of ML in an endemic area of Leishmania braziliensis transmission over a period of 20 years. The charts of 327 patients with ML diagnosed between 1995 and 2014 were reviewed. The majority of patients (67%) were male. Age ranged from 8 months to 103 years, with a median age of 38.5 years (interquartile range: 22-58 years). The greatest number of patients was between 19 and 39 years (31%). Over the study period, there was an increase in patients with ML more than 60 years of age, an increase in ML with concomitant cutaneous lesions, a decrease in the period of time between the documentation of cutaneous lesions and the diagnosis of mucosal disease, and an increase in the frequency of patients presenting with stage I and V of ML. Moreover, there was a positive correlation between severity of mucosal disease and both age and the period of time between cutaneous lesion and mucosal disease. Response to therapy of ML remained similar over a period of 20 years. Despite the improvement in medical care during the study period, the prevalence of ML did not change and severe disease continues to be a major challenge for the management of these patients. PMID- 28722608 TI - Active Tuberculosis Case Finding in Haiti. AB - In 2010, Haiti suffered from a devastating earthquake; data on the impact on the tuberculosis (TB) epidemic are limited. From January to June 2013, we conducted active case finding at the household level in a slum in Port-au-Prince. Community health workers identified individuals with cough >= 2 weeks, and referred them for evaluation. Contact tracing was conducted for patients with active TB. Of an estimated 7,500 residents screened, 394 (5%) had cough and were tested for TB. One hundred (25%) were diagnosed with active TB; 53 (53%) were smear positive. Ninety of these TB index cases provided 317 contacts, and 44 (14%) were diagnosed with active TB; 17 (39%) were smear positive. Overall, 144 TB cases were detected in 6 months (1,920/100,000; national estimate 200/100,000). We found a high burden of undiagnosed TB in Port-au-Prince 3 years after the earthquake. Further assessment of the burden of TB is indicated. PMID- 28722610 TI - Evaluation of a Spotted Fever Group Rickettsia Public Health Surveillance System in Tennessee. AB - Spotted fever group (SFG) rickettsioses are endemic in Tennessee, with ~2,500 cases reported during 2000-2012. Because of this substantial burden of disease, we performed a three-part evaluation of Tennessee's routine surveillance for SFG rickettsioses cases and deaths to assess the system's effectiveness. Tennessee Department of Health (TDH) SFG rickettsioses surveillance records were matched to three patient series: 1) patients with positive serologic specimens from a commercial reference laboratory during 2010-2011, 2) tertiary medical center patients with positive serologic tests during 2007-2013, and 3) patients identified from death certificates issued during 1995-2014 with SFG rickettsiosis related causes of death. Chart reviews were performed and patients were classified according to the Council of State and Territorial Epidemiologists' case definition. Of 254 SFG Rickettsia-positive serologic specimens from the reference laboratory, 129 (51%) met the case definition for confirmed or probable cases of rickettsial disease after chart review. The sensitivity of the TDH surveillance system to detect cases was 45%. Of the 98 confirmed or probable cases identified from the medical center, the sensitivity of the TDH surveillance system to detect cases was 34%. Of 27 patients identified by death certificates, 12 (44%) were classified as confirmed or probable cases; four (33%) were reported to TDH, but none were correctly identified as deceased. Cases of SFG rickettsioses were underreported and fatalities not correctly identified. Efforts are needed to improve SFG rickettsiosis surveillance in Tennessee. PMID- 28722609 TI - Differences in Mortality and Clinical Manifestations of Dengue Hemorrhagic Fever in Taiwan in Different Years: A Comparison for Cases in 2014 and 2015 Epidemics. AB - People in southern Taiwan experienced two major dengue outbreaks in 2014 and 2015. The mortality and clinical features were very different between these 2 years. Dengue virus serotype 1 (DENV-1) caused epidemic outbreak in 2014 and DENV 2 was predominant in 2015. The characteristics of dengue hemorrhagic fever (DHF) cases in the 2 years was analyzed. We conducted a retrospective chart review to analyze the clinical and laboratory features of 206 adult patients with DHF in southern Taiwan in 2014 and 2015. The mortality rate of DHF cases in 2015 was higher than that of cases in 2014 (38.7% versus 12.4%, P < 0.0001). Compared with cases in 2014, DHF cases in 2015 had more complications, such as gastrointestinal bleeding (78.5% versus 61.9%, P = 0.01), severe hepatitis (30.1% versus 8%, P < 0.0001), and myocarditis (14% versus 0.9%, P < 0.0001). Among the mortality cases, diabetes, chronic renal failure, proton-pump inhibitors using, platelet transfusion, and Charlson comorbidity index score (Charlson score) were also higher in 2015. Multivariate analysis for the mortality cases revealed that the risk factors were Charlson score >= 5 (P = 0.02, odds ratio [OR] = 4.07, 95% confidence interval [CI] = 1.244-13.307), severe hepatitis (P < 0.0001, OR = 11.97, 95% CI = 3.831-37.396), and acute renal failure (P < 0.0001, OR = 98.76, 95% CI = 10.847-899.22). DHF cases in 2015 had higher mortality and more complications, such as gastrointestinal bleeding, severe hepatitis, and myocarditis, than in 2014 in southern Taiwan. In the 2-year DHF case series, Charlson score >= 5, severe hepatitis, and acute renal failure were independent significant variables for mortality. PMID- 28722612 TI - The Epidemiology of Scabies and Impetigo in Relation to Demographic and Residential Characteristics: Baseline Findings from the Skin Health Intervention Fiji Trial. AB - Scabies and associated impetigo are under-recognized causes of morbidity in many developing countries. To strengthen the evidence base for scabies control we undertook a trial of mass treatment for scabies. We report on the occurrence and predictors of scabies and impetigo in participants at baseline. Participants were recruited in six island communities and were examined for the presence of scabies and impetigo. In addition to descriptive analyses, logistic regression models were fit to assess the association between demographic variables and outcome of interest. The study enrolled 2051 participants. Scabies prevalence was 36.4% (95% confidence interval [CI] 34.3-38.5), highest in children 5-9 years (55.7%). Impetigo prevalence was 23.4% (95% CI 21.5-25.2) highest in children aged 10-14 (39.0%). People with scabies were 2.8* more likely to have impetigo. The population attributable risk of scabies as a cause of impetigo was 36.3% and 71.0% in children aged less than five years. Households with four or more people sharing the same room were more likely to have scabies and impetigo (odds ratios [OR] 1.6, 95% CI 1.2-2.2 and OR 2.3, 95% CI 1.6-3.2 respectively) compared to households with rooms occupied by a single individual. This study confirms the high burden of scabies and impetigo in Fiji and the association between these two conditions, particularly in young children. Overcrowding, young age, and clinical distribution of lesion are important risk factors for scabies and impetigo. Further studies are needed to investigate whether the decline of endemic scabies would translate into a definite reduction of the burden of associated complications. PMID- 28722613 TI - Why Did Zika Not Explode in Cuba? The Role of Active Community Participation to Sustain Control of Vector-Borne Diseases. AB - As the global public health community develops strategies for sustainable Zika prevention and control, assessment of the Cuban response to Zika provides critical lessons learned. Cuba's early and successful response to Zika, grounded in the country's long-standing dengue prevention and control program, serves as a model of rapid mobilization of intersectoral efforts. Sustaining this response requires applying the evidence generated within the Cuban dengue program that active community participation improves outcomes and is sustainable and cost effective. There is also a need for implementation science efforts to assess the transferability of lessons learned from Zika prevention and control to other pathogens and from one context to another in addition to how to take these efforts to scale. PMID- 28722611 TI - Phase 2a, Open-Label, 4-Escalating-Dose, Randomized Multicenter Study Evaluating the Safety and Activity of Ferroquine (SSR97193) Plus Artesunate, versus Amodiaquine Plus Artesunate, in African Adult Men with Uncomplicated Plasmodium falciparum Malaria. AB - Artemisinin-based combination therapies are recommended as first-line agents for treating uncomplicated Plasmodium falciparum malaria. Ferroquine, a 4 aminoquinolone, is a novel long-acting combination partner for fast-acting drugs like artesunate (AS). We did a small phase 2a, multicenter, open-label, safety focused dose-ranging randomized study of ferroquine at three African hospitals: two Gabonese and one Kenyan. We recruited adult men with symptomatic uncomplicated P. falciparum monoinfection. Four escalating doses of ferroquine (100, 200, 400, and 600 mg) were assessed in sequence, versus an amodiaquine comparator. After a 2:1 randomization (block size three, equating to N = 12 for each ferroquine dose and N = 6 for each of four amodiaquine comparator groups) patients received daily for three consecutive days, either ferroquine + AS (200 mg/day) or amodiaquine (612 mg/day) + AS (200 mg/day). Safety, electrocardiograms, parasite clearance times, efficacy, and pharmacokinetics were assessed to day 28. Seventy-two patients were randomized. Ferroquine + AS showed generally mild increases (Grade 1 toxicity) in alanine aminotransferase (ALT) levels with a dose trend starting at 400 mg. There were two Grade 2 ALT events: one patient receiving 200 mg (3.8 upper limit of normal [ULN], day 7) and one receiving 600 mg (3.3 ULN, day 14), both without increased bilirubin. One ferroquine 100 mg + AS patient after one dose was withdrawn after developing a QTcF interval prolongation > 60 milliseconds over baseline. Parasitemias in all patients cleared quickly, with no recurrence through day 28. Hepatic, as well as cardiac, profiles should be monitored closely in future trials. (ClinicalTrials.gov: NCT00563914). PMID- 28722614 TI - Identification of Risk Factors Associated with Transmission of Plague Disease in Eastern Zambia. AB - Plague is a fatal, primarily rodent-flea-borne zoonotic disease caused by Yersinia pestis. The identification of risk factors of plague was investigated through questionnaire interview and conducting focus group discussion (FGD) in Sinda and Nyimba districts of eastern Zambia. A total of 104 questionnaires were administered to individual respondents and 20 groups consisting of 181 discussants, which comprised FGD team in this study. The study revealed that trapping, transportation, and preparation of rodents for food exposed the community to rodent and their fleas suggesting that plague may have occurred primarily by either flea bites or contact with infected wild rodents. The study also revealed that most people in communities consumed rodents as part of their regular diet; therefore, contact with small wild mammals was a common practice. The mode of transportation of freshly trapped rodents, in particular, carcasses risked human to flea bites. Questionnaire respondents (75%) and FGD discussants (55%) indicated that trappers preferred to carry rodent carcasses in small bags, whereas 55.8% and 20% respectively, reported hunters carrying carcasses in their pockets. Carrying of carcass skewers on trappers' shoulders was reported by 38.4% and 20% of individual respondents and FGD, respectively. All these activities were exposing humans to rodents and their fleas, the natural reservoirs and vectors of plague, respectively. This study also showed that there is a statistically significant (chi2 = 4.6878, P < 0.05), between digging of rodents from their burrows and the presence of fleas on the hunter's bodies or clothes, which exposes humans to potentially flea bites in an enzootic cycle. PMID- 28722615 TI - Assessing the Short-Term Global Health Experience: A Cross-Sectional Study of Demographics, Socioeconomic Factors, and Disease Prevalence. AB - Interest in short-term global health experiences to underserviced populations has grown rapidly in the last few decades. However, there remains very little research on what participants can expect to encounter. At the same time, it has been suggested that in order for physicians and workers to provide safe and effective care, volunteers should have a basic understanding of local culture, health systems, epidemiology, and socioeconomic needs of the community before arriving. Our objective was to add to the limited literature on what short-term global health trips can expect to encounter through a cross-sectional study of patient demographics, socioeconomic markers, and the prevalence of diseases encountered on a short-term medical service trip to Lima, Peru. Descriptive analysis was conducted on clinic data collected from patients living in Pamplona Alta and Pamplona Baja, Lima, Peru, in July 2015. We found that volunteers encountered mainly female patients (70.8%), and that there were significant socioeconomic barriers to care including poverty, poor housing, environmental exposures, and lack of continuity of health care. Analysis of the disease prevalence found a high proportion of acute and chronic musculoskeletal pain in the adult populations (18.8% and 11.4%, respectively), and a high presentation of upper respiratory tract infections (25.4%) and parasites (22.0%) in the pediatric group. These findings can be used by future short-term medical service trips to address potential gaps in care including the organization of weekend clinics to allow access to working men, and the use of patient education and nonpharmacological management of acute and chronic disease. PMID- 28722616 TI - Recurrence of Guinea Worm Disease in Chad after a 10-Year Absence: Risk Factors for Human Cases Identified in 2010-2011. AB - A decade after reporting its last case of Guinea worm disease (GWD), a waterborne parasitic disease targeted for eradication, Chad reported 20 confirmed human cases from 17 villages-10 cases in 2010 and 10 cases in 2011. In 2012, the first GWD dog infections were diagnosed. We conducted a case-control study during April May 2012 to identify human transmission risk factors and epidemiologic links. We recruited 19 cases and 45 controls matched by age, sex, time, and location of exposure based on the case patients' periods of infection 10-14 months earlier. Data were analyzed with simple conditional logistic regression models using Firth penalized likelihood methods. Unusually, GWD did not appear to be associated with household primary water sources. Instead, secondary water sources, used outside the village or other nonprimary sources used at home, were risk factors (matched odds ratio = 38.1, 95% confidence interval = 1.6-728.2). This study highlights the changing epidemiology of GWD in Chad-household primary water sources were not identified as risk factors and few epidemiologic links were identified between the handfuls of sporadic cases per year, a trend that continues. Since this investigation, annual dog infections have increased, far surpassing human cases. An aquatic paratenic host is a postulated mode of transmission for both dogs and humans, although fish could not be assessed in this case-control study due to their near-universal consumption. GWD's evolving nature in Chad underscores the continued need for interventions to prevent both waterborne and potential foodborne transmission until the true mechanism is established. PMID- 28722617 TI - Case Report: Disseminated Shewanella algae Infection with Meningoencephalitis in a Traveler Secondary to Marine Injury in Madagascar. AB - Marine microorganisms such as Shewanella spp., Vibrio spp., and Aeromonas spp. can cause sepsis secondary to a wound infection in the context of swimming. These microorganisms are most often susceptible to fluoroquinolones. Here, we report a unique case of Shewanella algae bacteremia associated with meningoencephalitis and disseminated via hematogenous spread secondary to a skin injury. The patient suffered the injury while swimming in saline water during a cruise holiday in Madagascar, and she was initially treated with amoxicillin. The neurological evolution was unsatisfactory. Better knowledge of such infections (and especially of the context in which they occur), as well as greater familiarity with the susceptibility profile of different marine microorganisms would have allowed health professionals to provide presumptive microbiological diagnosis and effective treatment earlier. PMID- 28722618 TI - Clinical Evidence of Acute Mesoamerican Nephropathy. AB - Mesoamerican nephropathy (MeN), an epidemic of unexplained kidney disease in Central America, affects mostly young, healthy individuals. Its etiology is a mystery that requires urgent investigation. Largely described as a chronic kidney disease (CKD), no acute clinical scenario has been characterized. An understanding of the early disease process could elucidate an etiology and guide treatment and prevention efforts. We sought to document the earliest clinical signs in patients with suspected MeN in a high-risk population in Nicaragua. Physicians at a local hospital identified suspect cases and documented clinical/laboratory data, demographics, and medical histories. Over a 1-year period, physicians identified 255 mostly young (median 29 years), male (89.5%) patients with elevated creatinine or reduced creatinine clearance. Mean serum creatinine (2.0 +/- 0.6 mg/dL) revealed a 2-fold increase from baseline, and half had stage 2 or 3 acute kidney injury. Leukocyturia (98.4%), leukocytosis (81.4%), and neutrophilia (86.2%) predominated. Nausea (59.4%), back pain (57.9%), fever (54.6%), vomiting (50.4%), headache (47.3%), and muscle weakness (45.0%) were common. A typical case of acute MeN presented with elevated (or increased >= 0.3 mg/dL or >= 1.5-fold from baseline) creatinine, no hypertension or diabetes, leukocyturia, and at least two of fever, nausea or vomiting, back pain, muscle weakness, headache, or leukocytosis and/or neutrophilia. Rapid progression (median 90 days) to CKD was recorded in 8.5% of patients. This evidence can serve as the basis of a sensitive and urgently needed case definition for disease surveillance of early-stage, acute MeN. PMID- 28722619 TI - Evaluation of Onchocerciasis Transmission in Tanzania: Preliminary Rapid Field Results in the Tukuyu Focus, 2015. AB - To compare diagnostic tests for onchocerciasis in a setting that has suppressed transmission, a randomized, age-stratified study was implemented in an area in Tanzania that had received 15 rounds of annual mass drug administration (MDA) with ivermectin. Study participants (N = 948) from 11 villages underwent a questionnaire, skin examination, skin snips, and blood draw. The burden of symptomatic disease was low. Ov-16 antibody rapid diagnostic test (RDT) results were positive in 38 (5.5%) participants, with 1 (0.5%), 1 (0.4%), and 2 (0.8%) in children aged 0-5, 6-10, and 11-15 years, respectively. Despite significant impact of MDA on transmission, the area would have failed to meet World Health Organization serologic criteria for stopping MDA if a full evaluation had been conducted. The specificity of the RDT, which is 97-98%, may result in the identification of a number of false positives that would exceed the current stop MDA threshold. PMID- 28722620 TI - Case Report: Infectious Diseases in Pilgrims Visiting the Holy Land. AB - Every year Christian pilgrims from around the world visit the holy sites located around the Sea of Galilee. Some become ill during their stay with infectious diseases that were acquired in their country of origin, and are hospitalized at Poriya Medical Center. They pose a diagnostic challenge due to language barriers, the rarity of these infections in Israel, and the fact that diagnostic tests are not readily available. All patient records from 2015 of Holy Land tourists hospitalized at Poriya Medical Center were screened for the diagnosis of imported zoonotic diseases that are not commonly diagnosed in Israel. Three patients who were on a Holy Land tour were hospitalized during 2015 with laboratory-confirmed diagnostically challenging zoonotic infectious diseases: a 91-year-old priest from Ethiopia diagnosed with relapsing fever due to Borrelia recurrentis, an 85 year-old retired mountaineer from New Hampshire diagnosed with human granulocytic anaplasmosis, and a 57-year-old farmer from central Brazil diagnosed with leptospirosis. These case reports emphasize the importance of considering imported zoonotic infectious diseases and obtaining appropriate diagnostic tests when treating Holy Land travelers to Israel. PMID- 28722621 TI - Health-Care Access during the Ebola Virus Epidemic in Liberia. AB - The Ebola virus disease (EVD) epidemic, which began in West Africa in December 2013, claimed more than 11,000 lives, with more than 4,800 of these deaths occurring in Liberia. The epidemic had an additional effect of paralyzing the health-care systems in affected countries, which led to even greater mortality and morbidity. Little is known about the impact that the epidemic had on the provision of basic health care. During the period from March to May 2015, we undertook a nationwide, community-based survey to learn more about health-care access during the EVD epidemic in Liberia. A cluster sampling strategy was used to administer a structured in-person survey to heads of households located within the catchment areas surrounding all 21 government hospitals in Liberia. A total of 543 heads of household from all 15 counties in Liberia participated in the study; more than half (67%) of urban respondents and 46% of rural respondents stated that it was very difficult or impossible to access health care during the epidemic. In urban areas, only 20-30% of patients seeking care during the epidemic received care, and in rural areas, only 70-80% of those seeking care were able to access it. Patients requiring prenatal and obstetric care and emergency services had the most difficulty accessing care. The results of this survey support the observation that basic health care was extremely difficult to access during the EVD epidemic in Liberia. Our results underscore the critical need to support essential health-care services during humanitarian crises to minimize preventable morbidity and mortality. PMID- 28722622 TI - Side Benefits of Mass Drug Administration for Lymphatic Filariasis on Strongyloides stercoralis Prevalence on Pemba Island, Tanzania. AB - Strongyloides stercoralis, although endemic in many countries, is not included in helminth control programs. Few data are available on the prevalence and morbidity linked to this infection. We compared data from two studies conducted in 1998 and 2013 on Pemba Island, Tanzania, involving 525 and 509 schoolchildren, respectively. In 1998, the diagnostic method used was Harada Mori, whereas in 2013 diagnosis was made by both Koga agar plate and Baermann methods. The prevalence registered was 41% in 1998 and 7% in 2013. This data suggest that the prevalence of S. stercoralis on Pemba was significantly reduced 7 years after the last ivermectin administration for preventive chemotherapy and underlines the importance and impact of large-scale preventive chemotherapy, which often goes beyond its actual target. Preventive chemotherapy with ivermectin should be recommended in areas where S. stercoralis is endemic. PMID- 28722623 TI - The Use of Xenosurveillance to Detect Human Bacteria, Parasites, and Viruses in Mosquito Bloodmeals. AB - Infectious disease surveillance is hindered by several factors, including limited infrastructure and geographic isolation of many resource-poor regions. In addition, the complexities of sample acquisition, processing, and analysis, even in developed regions, can be rate limiting. Therefore, new strategies to survey human populations for emerging pathogens are necessary. Xenosurveillance is a method that utilizes mosquitoes as sampling devices to search for genetic signatures of pathogens in vertebrates. Previously we demonstrated that xenosurveillance can detect viral RNA in both laboratory and field settings. However, its ability to detect bacteria and parasites remains to be assessed. Accordingly, we fed Anopheles gambiae mosquitoes blood that contained Trypanosoma brucei gambiense and Bacillus anthracis. In addition, we determined whether two additional emerging viruses, Middle East Respiratory Syndrome Coronavirus and Zika virus could be detected by this method. Pathogen-specific real-time reverse transcription polymerase chain reaction was used to evaluate the sensitivity of xenosurveillance across multiple pathogen taxa and over time. We detected RNA from all pathogens at clinically relevant concentrations from mosquitoes processed up to 1 day postbloodfeeding. These results demonstrate that xenosurveillance may be used as a tool to expand surveillance for viral, parasitic, and bacterial pathogens in resource-limited areas. PMID- 28722624 TI - Knowledge, Attitude, and Practice of Mothers/Caregivers on Household Water Treatment Methods in Northwest Ethiopia: A Community-Based Cross-Sectional Study. AB - In Ethiopia, ensuring safe drinking water remains a big challenge where waterborne diseases, including diarrhea cause a great harm in many rural communities. Limited knowledge, misinformation, negative attitude, and lack of experience toward best practices of alternative water treatment technologies were among the leading challenges. A community-based cross-sectional study was conducted from June 23 to 30, 2015, in Dabat District. The study participants were selected by using simple random sampling method. Questionnaire-based face-to face interview technique of data collection was used by 20 data collectors under close supervision with six supervisors. From the total of 845 participants with mother-child paired 49.3%, 95% confidence interval [CI] (45.8, 52.5%) had good knowledge, and 54.8%, 95% CI (51.6, 58.3%) had favorable-attitude toward household water treatment. Only 23.1%, 95%CI (20, 26%) of the study participants had practiced household water treatment. Being an urban resident (adjusted odds ratio [AOR]: 2.58, 95% CI: [1.62, 4.11]), having good-knowledge (AOR: 2.62, 95% CI: [1.81, 3.79]), favorable attitude (AOR: 1.45, 95% CI: [1.01, 2.08]), and used unimproved water source (AOR: 1.67, 95% CI: [1.11, 2.50]) were factors associated with household water treatment practices in the district. Despite mothers/caregivers having a fairly good knowledge and positive attitude, their practice of treating drinking water at household level was quite low. Thus, well designed strategy for health education on effective water treatment methods through the national health extension program is recommended. PMID- 28722626 TI - Capacity and Utilization of Blood Culture in Two Referral Hospitals in Indonesia and Thailand. AB - It is generally recommended that sepsis patients should have at least two blood cultures obtained before antimicrobial therapy. From 1995 to 2015, the number of blood cultures taken each year in a 1,100-bed public referral hospital in Ubon Ratchathani northeast Thailand rose from 5,235 to 56,719, whereas the number received in an 840-bed referral public hospital in South Sulawesi, Indonesia, in 2015 was 2,779. The proportion of patients sampled for blood cultures out of all inpatients in South Sulawesi in 2015 (9%; 2,779/30,593) was lower than that in Ubon Ratchathani in 2003 (13%; 8,707/66,515), at a time when health expenditure per capita in the two countries was comparable. Under-use of bacterial cultures may lead to an underestimate and underreporting of the incidence of antimicrobial resistant infections. Raising capacity and utilization of clinical microbiology laboratories in developing countries, at least at sentinel hospitals, to monitor the antimicrobial resistance situation should be prioritized. PMID- 28722625 TI - Respiratory Complications of Plasmodium vivax Malaria: Systematic Review and Meta Analysis. AB - Malaria, a major global public health problem, is mainly caused by Plasmodium falciparum and Plasmodium vivax, and is responsible for nearly half a million deaths annually. Although P. vivax malaria was not believed to cause severe disease, recent robust studies have proved otherwise. However, the clinical spectrum and pathogenesis of severe vivax malaria and, especially, its respiratory complications remain poorly understood. A systematic search for articles reporting respiratory complications associated with vivax malaria was performed in Lilacs, Cochrane, Scielo, Web of Science, and Medline databases irrespective of publication date. Prevalence of acute respiratory distress syndrome (ARDS) and associated mortality among vivax patients were calculated from cross-sectional and longitudinal studies, whereas factors associated with mortality were calculated from data pooled from case reports and series of cases. A total of 101 studies were included (49 cross-sectional or longitudinal and 52 case reports or series of cases). Prevalence of ARDS was 2.8% and 2.2% in children and adults, respectively, with nearly 50% mortality. Moreover, female sex (P = 0.013), having any comorbidity (P = 0.036), lower body temperature (P = 0.032), lower hemoglobin (P = 0.043), and oxygen saturation (P = 0.053) values were significantly associated with mortality. Plasmodium vivax malaria respiratory complications included ARDS and were associated with high mortality. Demographics and clinical characteristics upon presentation to hospital were associated with mortality among patients with respiratory complications in vivax malaria. This study reaffirms the evidence of severe and fatal complications of P. vivax malaria and its associated respiratory complications. PMID- 28722627 TI - Evaluation of Malaria Screening during Pregnancy with Rapid Diagnostic Tests Performed by Community Health Workers in Burkina Faso. AB - One of the current strategies to prevent malaria in pregnancy is intermittent preventive treatment with sulfadoxine-pyrimethamine (IPTp-SP). However, in order for pregnant women to receive an adequate number of SP doses, they should attend a health facility on a regular basis. In addition, SP resistance may decrease IPTp-SP efficacy. New or additional interventions for preventing malaria during pregnancy are therefore warranted. Because it is known that community health workers (CHWs) can diagnose and treat malaria in children, in this study screening and treatment of malaria in pregnancy by CHWs was evaluated as an addition to the regular IPTp-SP program. CHWs used rapid diagnostic tests (RDTs) for screening and artemether-lumefantrine was given in case of a positive RDT. Overall, CHWs were able to conduct RDTs with a sensitivity of 81.5% (95% confidence interval [CI] 67.9-90.2) and high specificity of 92.1% (95% CI 89.9 93.9) compared with microscopy. After a positive RDT, 79.1% of women received artemether-lumefantrine. When treatment was not given, this was largely due to the woman being already under treatment. Almost all treated women finished the full course of artemether-lumefantrine (96.4%). In conclusion, CHWs are capable of performing RDTs with high specificity and acceptable sensitivity, the latter being dependent on the limit of detection of RDTs. Furthermore, CHWs showed excellent adherence to test results and treatment guidelines, suggesting they can be deployed for screen and treat approaches of malaria in pregnancy. PMID- 28722628 TI - Serologic Evidence of Various Arboviruses Detected in White-Tailed Deer (Odocoileus virginianus) in the United States. AB - White-tailed deer (Odocoileus virginianus) are an abundant mammal with a wide geographic distribution in the United States, which make them good sentinels for monitoring arboviral activity across the country. Exposure to various arboviruses has been detected in white-tailed deer, typically in conjunction with another diagnostic finding. To better assess the exposure of white-tailed deer to seven arboviruses, we tested 1,508 sera collected from 2010 to 2016 for antibodies to eastern equine encephalitis (2.5%), Powassan (4.2%), St. Louis encephalitis, (3.7%), West Nile (6.0%), Maguari (19.4%), La Crosse (30.3%), and bluetongue (7.8%) viruses. At least one arbovirus was detected in 51.3%, and exposure to more than one arbovirus was identified in 17.6% of the white-tailed deer sampled. PMID- 28722629 TI - Estimating the Added Utility of Highly Sensitive Histidine-Rich Protein 2 Detection in Outpatient Clinics in Sub-Saharan Africa. AB - Most malaria testing is by rapid diagnostic tests (RDTs) that detect Plasmodium falciparum histidine-rich protein 2 (HRP2). Recently, several RDT manufacturers have developed highly sensitive RDTs (hsRDTs), promising a limit of detection (LOD) orders of magnitude lower than conventional RDTs. To model the added utility of hsRDTs, HRP2 concentration in Angolan outpatients was measured quantitatively using an ultrasensitive bead-based assay. The distribution of HRP2 concentration was bimodal in both afebrile and febrile patients. The conventional RDT was able to detect 81% of all HRP2-positive febrile patients and 52-77% of HRP2-positive afebrile patients. The added utility of hsRDTs was estimated to be greater in afebrile patients, where an hsRDT with a LOD of 200 pg/mL would detect an additional 50-60% of HRP2-positive persons compared with a conventional RDT with a LOD of 3,000 pg/mL. In febrile patients, the hsRDT would detect an additional 10-20% of cases. Conventional RDTs already capture the vast majority of symptomatic HRP2-positive individuals, and hsRDTs would have to reach a sufficiently low LOD approaching 200 pg/mL to provide added utility in identifying HRP2-positive, asymptomatic individuals. PMID- 28722630 TI - The Effects of an Integrated Community Case Management Strategy on the Appropriate Treatment of Children and Child Mortality in Kono District, Sierra Leone: A Program Evaluation. AB - Integrated community case management (iCCM) aims to reduce child mortality in areas with poor access to health care. iCCM was implemented in 2009 in Kono district, Sierra Leone, a postconflict area with high under-five mortality rates (U5MRs). We evaluated iCCM's impact and effects on child health using cluster surveys in 2010 (midterm) and 2013 (endline) to compare indicators on child mortality, coverage of appropriate treatment, timely access to care, quality of care, and recognition of community health workers (CHWs). The sample size was powered to detect a 28% decline in U5MR. Clusters were selected proportional to population size. All households were sampled to measure mortality and systematic random sampling was used to measure coverage in a subset of households. We used program data to evaluate utilization and access; 5,257 (2010) and 3,649 (2013) households were surveyed. U5MR did not change significantly (4.54 [95% confidence interval [CI]: 3.47-5.60] to 3.95 [95% CI: 3.06-4.83] deaths per 1,000 per month (P = 0.4)) though a relative change smaller than 28% could not be detected. CHWs were the first source of care for 52% (2010) and 50.9% (2013) of children. Coverage of appropriate treatment of fever by CHWs or peripheral health units increased from 45.5% [95% CI: 39.2-52.0] to 58.2% [95% CI: 50.5-65.5] (P = 0.01); changes for diarrhea and pneumonia were not significant. The continued reliance on the CHW as the first source of care and improved coverage for the appropriate treatment of fever support iCCM's role in Kono district. PMID- 28722631 TI - Dengue Virus Coinfection in Human Immunodeficiency Virus-1-Infected Patients on the West Coast of Mexico. AB - Dengue virus infection in human immunodeficiency virus (HIV)-positive patients is not well studied. Previous reports suggest a transitory inhibition of the HIV-1 viral load, as well as a benign clinical progression of dengue. The follow-up of six HIV-1-infected patients, diagnosed and hospitalized with dengue virus infection in the State of Colima, Mexico, was carried out to analyze the progression of this viral coinfection. The presence of dengue virus serotype 1 was confirmed through molecular tests. No severe complications were observed in any of the patients during dengue virus infection. Significant alteration of the HIV-1 viral loads was not observed during dengue virus infection and 6 months after coinfection. Further studies are required to understand the pathology, as well as the clinical course, of these viral coinfections. PMID- 28722632 TI - Pilot Intervention Study of Household Ventilation and Fine Particulate Matter Concentrations in a Low-Income Urban Area, Dhaka, Bangladesh. AB - Fine particulate matter (PM2.5) is a risk factor for pneumonia; ventilation may be protective. We tested behavioral and structural ventilation interventions on indoor PM2.5 in Dhaka, Bangladesh. We recruited 59 good ventilation (window or door in >= 3 walls) and 29 poor ventilation (no window, one door) homes. We monitored baseline indoor and outdoor PM2.5 for 48 hours. We asked all participants to increase ventilation behavior, including opening windows and doors, and operating fans. Where permitted, we installed windows in nine poor ventilation homes, then repeated PM2.5 monitoring. We estimated effects using linear mixed-effects models and conducted qualitative interviews regarding motivators and barriers to ventilation. Compared with poor ventilation homes, good ventilation homes were larger, their residents wealthier and less likely to use biomass fuel. In multivariable linear mixed-effects models, ventilation structures and opening a door or window were inversely associated with the number of hours PM2.5 concentrations exceeded 100 and 250 MUg/m3. Outdoor air pollution was positively associated with the number of hours PM2.5 concentrations exceeded 100 and 250 MUg/m3. Few homes accepted window installation, due to landlord refusal and fear of theft. Motivators for ventilation behavior included cooling of the home and sunlight; barriers included rain, outdoor odors or noise, theft risk, mosquito entry, and, for fan use, perceptions of wasting electricity or unavailability of electricity. We concluded that ventilation may reduce indoor PM2.5 concentrations but, there are barriers to increasing ventilation and, in areas with high ambient PM2.5 concentrations, indoor concentrations may remain above recommended levels. PMID- 28722633 TI - Characterization of Sarcoptes scabiei Tropomyosin and Paramyosin: Immunoreactive Allergens in Scabies. AB - Scabies is a human skin disease due to the burrowing ectoparasite Sarcoptes scabiei var. hominis resulting in intense itching and inflammation and manifesting as a skin allergy. Because of insufficient mite material and lack of in vitro propagation system for antigen preparation, scabies is a challenging disease to develop serological diagnostics. For allergen characterization, full length S. scabiei tropomyosin (Sar s 10) was cloned, expressed in pET-15b, and assessed for reactivity with IgE antibodies from human sera. IgE binding was observed to Sar s 10 with sera collected from subjects with ordinary scabies, house dust mite (HDM)-positive and naive subjects and a diagnostic sensitivity of < 30% was observed. S. scabiei paramyosin (Sar s 11) was cloned, and expressed in pET-28a in three overlapping fragments designated Sspara1, Sspara2, and Sspara3. IgE and IgG binding was observed to Sspara2 and Sspara3 antigens with sera collected from ordinary scabies, and HDM-positive subjects, but no binding was observed with sera collected from naive subjects. Sspara2 displayed excellent diagnostic potential with 98% sensitivity and 90% specificity observed for IgE binding and 70% sensitivity for IgG. In contrast, the diagnostic sensitivity of Sspara3 was 84% for IgE binding and 40% for IgG binding. In combination, Sspara2 and Sspara3 provided an IgE sensitivity of 94%. This study shows that IgE binding to Sspara2 and Sspara3 is a highly sensitive method for diagnosis of scabies infestation in clinical practice. The developed enzyme-linked immunosorbent assay helps direct future development of a specific diagnostic tool for scabies. PMID- 28722634 TI - Cystic Echinococcosis in Turkana, Kenya: The Role of Cross-Sectional Screening Surveys in Assessing the Prevalence of Human Infection. AB - Cystic echinococcosis (CE) is a neglected zoonotic disease caused by Echinococcus granulosus. Infection leads to formation of cysts within the viscera of the human host. In the 1980s, the transhumant population of northwest Turkana, Kenya, was found to have the highest prevalence of CE in the world. In 1983, AMREF Health Africa and the Kenya Medical and Research Institute launched a CE Control Program in northwest Turkana, screening and treating the local people. This epidemiological study of CE in Turkana analyses approximately 30 years of surveillance and surgical data. Cyst data were categorized using the World Health Organization CE ultrasound classification system before being analyzed for cyst, patient, and population characteristics, and surveillance data from 1985 are compared with more recent surveillance data to assess changes in prevalence in the control region since the commencement of control activities. In 1985, the prevalence of CE among the Turkana was 5.6%. In 2010-2011 and 2011-2012, calculated CE prevalence rates were 1.9% and 3.8%, respectively. Since the 1980s, the age distribution of people with CE in Turkana has shifted: initially, cases of CE appeared predominantly within younger age groups, but recent data reveal a higher prevalence within older age groups. The frequency of infection in females also significantly decreased. The reduction in CE prevalence from 5.6% in the 1980s to 1.9-3.8% in 2010-2012 and the shift in age distribution of CE-infected individuals over time indicate that the prevalence of CE in Turkana has decreased since the control program began. PMID- 28722635 TI - Early Life Inflammation and Neurodevelopmental Outcome in Bangladeshi Infants Growing Up in Adversity. AB - Exposure to profound adversity can negatively affect the neurodevelopment of children, but biologic mechanisms that underlie this association remain unknown. We sought to determine whether elevated levels of the inflammatory markers C reactive protein (CRP) and soluble CD14 (sCD14) are associated with neurodevelopmental outcomes in Bangladeshi children. A total of 422 infant-mother pairs from an urban slum in Dhaka, Bangladesh were enrolled at birth and followed prospectively. Inflammation was measured with sCD14, interleukin (IL)-1beta, and IL-6 at 18 weeks, and CRP at 6, 18, 40, and 53 weeks. Psychologists assessed cognitive, language, motor, and social emotional development using the Bayley Scales of Infant and Toddler Development at 78 and 104 weeks of age. We tested for the association of inflammatory markers with developmental outcomes, independent of previously identified associations such as malnutrition, family income, and maternal education. Every 10 pg/mL increase in sCD14 was associated with a 1.1-2.0 decrement in cognitive and motor scores at 78 weeks and in all domains at 104 weeks. The cumulative number of CRP elevations that a child experienced in the first year of life, as well as IL-1beta and IL-6 at 18 weeks of age, were also negatively associated with Bayley Scales results. CRP, sCD14, IL-1beta, and IL-6 were associated with lower neurodevelopmental outcomes. Our findings implicate a role of inflammation in the neurodevelopment of children growing up in adversity. PMID- 28722636 TI - Physician Assistants and the Expanding Global Health-Care Workforce. AB - The physician assistant and other types of medical providers with accelerated and focused training were developed to serve the specific health-care needs of individual countries. They have an important role in providing care globally in response to physician shortages. Working in over 50 nations, these clinicians increase access to team-based health care. This perspective explores the successes and challenges of these professionals as an international community. Steps are proposed to increase global awareness and acceptance of these professionals including platforms to increase discussion, scholarly activity, and collaboration. PMID- 28722638 TI - Antibiotic Resistance in Young Children in Kilosa District, Tanzania 4 Years after Mass Distribution of Azithromycin for Trachoma Control. AB - Mass administration of azithromycin (MDA) is integral to trachoma control. Recent studies suggest that MDA may increase drug-resistant pathogens, yet findings from prior studies suggest little long-term impact on resistance. This disparity may be linked to differences in pre-MDA community-level resistance patterns. We describe carriage prevalence and antibiotic resistance patterns for Streptococcus pneumoniae (Spn) (nasopharyngeal swab collection), Staphylococcus aureus (SA) (nasopharyngeal swabs), and Escherichia coli (EC) (rectal swabs) in 1,047 children ages 1-59 months in a district with MDA cessation 4 years ago. Antibiotic susceptibility was evaluated by disk diffusion and Etest. The carriage rates for Spn, SA, and EC were 43.5% (455/1,047), 13.2% (138/1,047), and 61.7% (646/1,047), respectively. Resistance to AZM was observed in 14.3%, 29.0%, and 16.6% of the Spn, SA, and EC isolates, respectively. Spn resistance was variable (0-67%) by hamlet. Future analyses will assess the influence of pre-MDA antibiotic resistance patterns on those observed following MDA. PMID- 28722637 TI - Schistosomiasis in European Travelers and Migrants: Analysis of 14 Years TropNet Surveillance Data. AB - Schistosomiasis remains one of the most prevalent parasitic diseases worldwide and the infection is frequently found in travelers and migrants. The European Network for Tropical Medicine and Travel Health conducted a sentinel surveillance study on imported schistosomiasis between 1997 and 2010. This report summarizes epidemiological and clinical data from 1,465 cases of imported schistosomiasis. Direct pathogen detection and serology were the main diagnostic tools applied. Of these, 486 (33%) cases were identified among European travelers, 231 (16%) among long-term expatriates, and 748 (51%) among non-European immigrants. Overall, only 18.6% of travelers had received pretravel advice; 95% of infections were acquired in the African region. On species level, Schistosoma mansoni was identified in 570 (39%) and Schistosoma haematobium in 318 (22%) cases; 57.5% of patients were symptomatic. Acute symptoms were reported in 27% of patients leading to earlier presentation within 3 months. Praziquantel was used in all patients to treat schistosomiasis. Many infections were detected in asymptomatic patients. In 47.4% of asymptomatic patients infection was detected by microscopy and in 39% by serology or antigen testing. Schistosomiasis remains a frequent infection in travelers and migrants to Europe. Travelers should be made aware of the risk of schistosomiasis infection when traveling to sub-Saharan Africa. Posttravel consultations particularly for returning expatriates are useful given the high potential for detecting asymptomatic infections. PMID- 28722639 TI - Human Cases of Tularemia in Armenia, 1996-2012. AB - A retrospective analysis was conducted of human cases and outbreaks of tularemia in the Republic of Armenia from 1996 to 2012 utilizing geographic information system software. A total of 266 human cases of tularemia were recorded in Armenia from 1996 to 2012, with yearly incidence ranging from 0 to 5.5 cases per 100,000 people. Cases predominantly affected the male population (62.8%), 11-20 year age group (37.2%), agricultural workers (49.6%), and persons residing in rural areas (93.6%). In 2003, a waterborne outbreak involving 158 cases occurred in Kotayk Marz, and in 2007, a foodborne outbreak with 17 cases occurred in Gegharkunik Marz, attributed to exposure of food products to contaminated hay. Geospatial analysis of all cases showed that the majority were associated with the steppe vegetation zone, elevations between 1,400 and 2,300 m, and the climate zone associated with dry, warm summers, and cold winters. Characterization of these environmental factors were used to develop a predictive risk model to improve surveillance and outbreak response for tularemia in Armenia. PMID- 28722640 TI - The Role of Risk Proximity in the Beliefs and Behaviors Related to Mosquito-Borne Diseases: The Case of Chikungunya in French Guiana. AB - Human behaviors are increasingly recognized to play a key role in the spread of infectious diseases. Although a set of social and cognitive determinants has been consistently found to affect the adoption of health protective behaviors aiming to control and prevent a variety of infections, little is currently known about the ecological drivers of these behaviors in epidemic settings. In this article, we took advantage of the outbreak of chikungunya, a reemerging mosquito-borne disease, that occurred in French Guiana in 2014-15 to test empirically the assumption proposed by Zielinski-Gutierrez and Hayden that the proximity of the disease and perceptions of the natural environment may considerably shape public response to an emerging health threat. To achieve this, a cross-sectional survey was conducted among high school students of the region (N = 1462) at an early stage of the epidemic. Surprisingly, spatial analysis of the collected data leads to counterintuitive results as the participants who lived in the most affected area expressed less concern about the disease and practiced preventive behaviors less frequently than did other participants. These paradoxical results may be attributed to the possible activation of risk denial processes which have previously been observed in the risk perception literature, and described by several social and psychological defensiveness theories. PMID- 28722642 TI - The Traditional Audiogram-Can We Do Better? PMID- 28722641 TI - Diagnostic Validation of the RealStar(r) Zika Virus Reverse Transcription Polymerase Chain Reaction Kit for Detection of Zika Virus RNA in Urine and Serum Specimens. AB - With the Zika virus outbreak in South America starting in 2015 and its potential to cause malformation of the fetus in infected women, the need for diagnostic methods became obvious. Until now, only limited data are available on the diagnostic performance of commercial kits. Here, we present data comparing the RealStar(r) Zika Virus RT-PCR Kit 1.0 for detection of Zika virus from 208 serum and urine samples collected in French Guiana with a reference method. Of these, 114 samples tested positive with the RealStar(r) Kit and 111 with the reference method. PMID- 28722643 TI - Aural Rehabilitation for Older Adults with Hearing Loss: Impacts on Quality of Life-A Systematic Review of Randomized Controlled Trials. AB - BACKGROUND: Few systematic reviews have been conducted regarding aural rehabilitation for adults with hearing loss, with none specifically targeting the older adult population. With prevalence rates of hearing loss being highest in older adults, examining the effects of aural rehabilitation on this population is warranted. PURPOSE: To evaluate the effects of aural rehabilitation on quality of life in an older adult population presenting with hearing loss. ELIGIBILITY CRITERIA: Studies with adults presenting with hearing loss, >=50 yr of age, with or without hearing aids, receiving interventions such as auditory training, speech-reading, communication strategies training, speech tracking, counseling, or a combination of approaches, and measuring outcomes related to quality of life, in an individual or group format, with or without significant others and with no limitations as to year of publication. STUDY SELECTION: Searches in six databases, as well as results from hand-searching, gray literature, and cross referencing of articles, yielded 386 articles. Of the 145 assessed as full-text articles for eligibility, 8 studies met inclusion criteria. STUDY APPRAISAL: A component-based risk of bias assessment, as recommended by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. RESULTS: No effect sizes were found in group interventions measuring outcomes related to quality of life, such as mental and emotional functions, environmental factors, participation restrictions, and activity limitations. An intervention effect regarding participation was found for a self-administered home training program, but an effect size was unavailable. Small-to-medium effect sizes were found in one of two individual communication training programs, for which outcomes related to quality of life, such as emotional functions, activities, participation, and environmental factors were measured. The results of the component-based risk of bias assessment indicated that the quality of reporting was poor, thus compromising the internal validity of included primary studies. CONCLUSIONS: Our results indicate that the combined body of evidence in support of aural rehabilitation for older adults with hearing loss is not sufficient to draw any firm conclusions. We identify a need for more rigorous research to guide clinical decision-making. PMID- 28722644 TI - Children Diagnosed with Auditory Processing Disorder and Their Parents: A Qualitative Study about Perceptions of Living with APD. AB - BACKGROUND: Negative psychosocial consequences have been reported for children with auditory processing disorder (APD). The current literature surrounding APD does not sufficiently address the emotional and psychological consequences of living with the disorder. It is recommended that data be collected from multiple sources, including the child living with APD. Subjective reports of the perceptions of children with APD and their families have real-life validity and can inform clinical decisions and guide future research. PURPOSE: The aims of this study were to explore the psychosocial consequences of APD as perceived by children with the disorder and their parents. RESEARCH DESIGN: Qualitative cross sectional study. STUDY SAMPLE: Thirteen participants were interviewed: six children with APD, aged 10-12 yr, and one parent for each child (in one case, two parents participated in the interview). DATA COLLECTION AND ANALYSIS: Semistructured interviews were used to examine the social, emotional, and educational well-being of children with APD. Inductive thematic analysis was conducted to develop themes that illustrated the experiences of living with APD. RESULTS: Three themes were identified forming a causal network conceptual framework that is reciprocal in nature: (1) external factors, (2) internal problems, and (3) coping. The themes revealed how APD impacted negatively on children's psychosocial well-being (internal problems: covert thoughts, overt behaviors) and described the basis for these outcomes (external factors: environmentally based problems, dissatisfaction with support) and the ability of children and their parent(s) to manage the impact of APD (coping: positive, negative). CONCLUSIONS: The three themes identified in this research provide a novel understanding of the experience of APD. The themes reflect the psychosocial consequences of external factors that are created internally through "thought" and expressed externally through "behavior." Pathways to support positive coping strategies while discouraging negative coping strategies will enable children to overcome problems and improve their psychosocial well-being. PMID- 28722645 TI - Verification of a Proposed Clinical Electroacoustic Test Protocol for Personal Digital Modulation Receivers Coupled to Cochlear Implant Sound Processors. AB - BACKGROUND: Guidelines established by the AAA currently recommend behavioral testing when fitting frequency modulated (FM) systems to individuals with cochlear implants (CIs). A protocol for completing electroacoustic measures has not yet been validated for personal FM systems or digital modulation (DM) systems coupled to CI sound processors. In response, some professionals have used or altered the AAA electroacoustic verification steps for fitting FM systems to hearing aids when fitting FM systems to CI sound processors. More recently steps were outlined in a proposed protocol. PURPOSE: The purpose of this research is to review and compare the electroacoustic test measures outlined in a 2013 article by Schafer and colleagues in the Journal of the American Academy of Audiology titled "A Proposed Electroacoustic Test Protocol for Personal FM Receivers Coupled to Cochlear Implant Sound Processors" to the AAA electroacoustic verification steps for fitting FM systems to hearing aids when fitting DM systems to CI users. RESEARCH DESIGN: Electroacoustic measures were conducted on 71 CI sound processors and Phonak Roger DM systems using a proposed protocol and an adapted AAA protocol. Phonak's recommended default receiver gain setting was used for each CI sound processor manufacturer and adjusted if necessary to achieve transparency. STUDY SAMPLE: Electroacoustic measures were conducted on Cochlear and Advanced Bionics (AB) sound processors. In this study, 28 Cochlear Nucleus 5/CP810 sound processors, 26 Cochlear Nucleus 6/CP910 sound processors, and 17 AB Naida CI Q70 sound processors were coupled in various combinations to Phonak Roger DM dedicated receivers (25 Phonak Roger 14 receivers-Cochlear dedicated receiver-and 9 Phonak Roger 17 receivers-AB dedicated receiver) and 20 Phonak Roger Inspiro transmitters. DATA COLLECTION AND ANALYSIS: Employing both the AAA and the Schafer et al protocols, electroacoustic measurements were conducted with the Audioscan Verifit in a clinical setting on 71 CI sound processors and Phonak Roger DM systems to determine transparency and verify FM advantage, comparing speech inputs (65 dB SPL) in an effort to achieve equal outputs. If transparency was not achieved at Phonak's recommended default receiver gain, adjustments were made to the receiver gain. The integrity of the signal was monitored with the appropriate manufacturer's monitor earphones. RESULTS: Using the AAA hearing aid protocol, 50 of the 71 CI sound processors achieved transparency, and 59 of the 71 CI sound processors achieved transparency when using the proposed protocol at Phonak's recommended default receiver gain. After the receiver gain was adjusted, 3 of 21 CI sound processors still did not meet transparency using the AAA protocol, and 2 of 12 CI sound processors still did not meet transparency using the Schafer et al proposed protocol. CONCLUSIONS: Both protocols were shown to be effective in taking reliable electroacoustic measurements and demonstrate transparency. Both protocols are felt to be clinically feasible and to address the needs of populations that are unable to reliably report regarding the integrity of their personal DM systems. PMID- 28722646 TI - Noncongruence between Audiologist and Patient Preferences for Patient Centeredness. AB - BACKGROUND: Trends in preferences of both healthcare providers and patients to patient-centeredness have been emphasized in research. However, an understanding of the nature of preferences to patient-centeredness within the context of the audiologist-patient relationship is needed. PURPOSE: The purpose of this study is to explore the congruence between audiologist and patient preferences for patient centeredness. RESEARCH DESIGN: A cross-sectional survey design was used to gather data from audiologists and patients with hearing loss. STUDY SAMPLE: Participants included 75 audiologists and 105 consecutive patients with hearing loss. DATA COLLECTION AND ANALYSIS: Participants completed the modified Patient-Practitioner Orientation Scale (PPOS) and provided selected demographic information. Data were analyzed using an independent sample t test to evaluate the differences between audiologist and patient congruence. Regression analysis was performed to evaluate factors contributing to preferences for patient-centeredness. RESULTS: Patients had significantly lower scores in PPOS full scale when compared to the audiologists [t(170) = 0.78; p <= 0.001] with a very large effect size (Cohen's d = 1.43). Patients also had significantly lower scores when compared to the audiologists on both the sharing [t(170) = 1.01; p <= 0.001] and caring [t(170) = 0.56; p <= 0.001] subscales. Statistically significant lower scores were noted for patients when compared to audiologists on 12 items on the PPOS. No relationship between any demographic factors and preferences for patient centeredness were found. CONCLUSIONS: The current study results indicated noncongruence in preferences for patient-centeredness among audiologists and patients with hearing loss. Results point toward the need for more research considering the nature and impact of patient-centered audiology practice. PMID- 28722647 TI - What Factors Are Associated with Autonomous and Controlled Motivation for Hearing Help-Seekers? AB - BACKGROUND: Hearing impairment is prevalent in older adults. Motivation is important in people's choice to seek help for their hearing and whether to adopt or not adopt hearing aids. PURPOSE: To investigate associations between sociodemographic and audiometric characteristics and autonomous and controlled motivation among a sample of hearing help-seekers. RESEARCH DESIGN: A quantitative approach was taken for this cross-sectional cohort study. STUDY SAMPLE: A total of 253 adult first-time hearing help-seekers were recruited to the study. DATA COLLECTION AND ANALYSIS: Participants provided sociodemographic information and completed questionnaires adapted from self-determination theory that measured autonomous motivation (motivation that originates from within the self and is aligned with personal values and beliefs) and controlled motivation (motivation that stems from external pressures such as rewards or punishment, or conflicted inner feelings such as guilt or shame). RESULTS: Participants with higher autonomous motivation scores were younger, wanted hearing aids more, and reported greater hearing difficulty in everyday life than those with lower scores. Participants with higher controlled motivation scores were more often referred to the service by others and wanted hearing aids more than those with lower controlled motivation scores. Controlled motivation scores were not associated with perceptions of hearing difficulty in everyday life. CONCLUSION: Relationships among motivation and sociodemographic factors highlight the importance of characterizing autonomous and controlled motivation in first-time hearing help-seekers. Attention to personal characteristics in order to understand motivational processes involved in rehabilitation decisions such as hearing aid adoption may aid in consultations. PMID- 28722648 TI - Perspectives on the Pure-Tone Audiogram. AB - BACKGROUND: The pure-tone audiogram, though fundamental to audiology, presents limitations, especially in the case of central auditory involvement. Advances in auditory neuroscience underscore the considerably larger role of the central auditory nervous system (CANS) in hearing and related disorders. Given the availability of behavioral audiological tests and electrophysiological procedures that can provide better insights as to the function of the various components of the auditory system, this perspective piece reviews the limitations of the pure tone audiogram and notes some of the advantages of other tests and procedures used in tandem with the pure-tone threshold measurement. PURPOSE: To review and synthesize the literature regarding the utility and limitations of the pure-tone audiogram in determining dysfunction of peripheral sensory and neural systems, as well as the CANS, and to identify other tests and procedures that can supplement pure-tone thresholds and provide enhanced diagnostic insight, especially regarding problems of the central auditory system. RESEARCH DESIGN: A systematic review and synthesis of the literature. DATA COLLECTION AND ANALYSIS: The authors independently searched and reviewed literature (journal articles, book chapters) pertaining to the limitations of the pure-tone audiogram. RESULTS: The pure-tone audiogram provides information as to hearing sensitivity across a selected frequency range. Normal or near-normal pure-tone thresholds sometimes are observed despite cochlear damage. There are a surprising number of patients with acoustic neuromas who have essentially normal pure-tone thresholds. In cases of central deafness, depressed pure-tone thresholds may not accurately reflect the status of the peripheral auditory system. Listening difficulties are seen in the presence of normal pure-tone thresholds. Suprathreshold procedures and a variety of other tests can provide information regarding other and often more central functions of the auditory system. CONCLUSIONS: The audiogram is a primary tool for determining type, degree, and configuration of hearing loss; however, it provides the clinician with information regarding only hearing sensitivity, and no information about central auditory processing or the auditory processing of real-world signals (i.e., speech, music). The pure-tone audiogram offers limited insight into functional hearing and should be viewed only as a test of hearing sensitivity. Given the limitations of the pure-tone audiogram, a brief overview is provided of available behavioral tests and electrophysiological procedures that are sensitive to the function and integrity of the central auditory system, which provide better diagnostic and rehabilitative information to the clinician and patient. PMID- 28722650 TI - Correction: Controlling contractile instabilities in the actomyosin cortex. PMID- 28722651 TI - Ephrin-A/EphA specific co-adaptation as a novel mechanism in topographic axon guidance. AB - Genetic hardwiring during brain development provides computational architectures for innate neuronal processing. Thus, the paradigmatic chick retinotectal projection, due to its neighborhood preserving, topographic organization, establishes millions of parallel channels for incremental visual field analysis. Retinal axons receive targeting information from quantitative guidance cue gradients. Surprisingly, novel adaptation assays demonstrate that retinal growth cones robustly adapt towards ephrin-A/EphA forward and reverse signals, which provide the major mapping cues. Computational modeling suggests that topographic accuracy and adaptability, though seemingly incompatible, could be reconciled by a novel mechanism of coupled adaptation of signaling channels. Experimentally, we find such 'co-adaptation' in retinal growth cones specifically for ephrin-A/EphA signaling. Co-adaptation involves trafficking of unliganded sensors between the surface membrane and recycling endosomes, and is presumably triggered by changes in the lipid composition of membrane microdomains. We propose that co-adaptative desensitization eventually relies on guidance sensor translocation into cis signaling endosomes to outbalance repulsive trans-signaling. PMID- 28722652 TI - The packing density of a supramolecular membrane protein cluster is controlled by cytoplasmic interactions. AB - Molecule clustering is an important mechanism underlying cellular self organization. In the cell membrane, a variety of fundamentally different mechanisms drive membrane protein clustering into nanometre-sized assemblies. To date, it is unknown whether this clustering process can be dissected into steps differentially regulated by independent mechanisms. Using clustered syntaxin molecules as an example, we study the influence of a cytoplasmic protein domain on the clustering behaviour. Analysing protein mobility, cluster size and accessibility to myc-epitopes we show that forces acting on the transmembrane segment produce loose clusters, while cytoplasmic protein interactions mediate a tightly packed state. We conclude that the data identify a hierarchy in membrane protein clustering likely being a paradigm for many cellular self-organization processes. PMID- 28722653 TI - Directing visceral white adipocyte precursors to a thermogenic adipocyte fate improves insulin sensitivity in obese mice. AB - Visceral adiposity confers significant risk for developing metabolic disease in obesity whereas preferential expansion of subcutaneous white adipose tissue (WAT) appears protective. Unlike subcutaneous WAT, visceral WAT is resistant to adopting a protective thermogenic phenotype characterized by the accumulation of Ucp1+ beige/BRITE adipocytes (termed 'browning'). In this study, we investigated the physiological consequences of browning murine visceral WAT by selective genetic ablation of Zfp423, a transcriptional suppressor of the adipocyte thermogenic program. Zfp423 deletion in fetal visceral adipose precursors (Zfp423loxP/loxP; Wt1-Cre), or adult visceral white adipose precursors (PdgfrbrtTA; TRE-Cre; Zfp423loxP/loxP), results in the accumulation of beige-like thermogenic adipocytes within multiple visceral adipose depots. Thermogenic visceral WAT improves cold tolerance and prevents and reverses insulin resistance in obesity. These data indicate that beneficial visceral WAT browning can be engineered by directing visceral white adipocyte precursors to a thermogenic adipocyte fate, and suggest a novel strategy to combat insulin resistance in obesity. PMID- 28722654 TI - A lectin receptor kinase as a potential sensor for extracellular nicotinamide adenine dinucleotide in Arabidopsis thaliana. AB - Nicotinamide adenine dinucleotide (NAD+) participates in intracellular and extracellular signaling events unrelated to metabolism. In animals, purinergic receptors are required for extracellular NAD+ (eNAD+) to evoke biological responses, indicating that eNAD+ may be sensed by cell-surface receptors. However, the identity of eNAD+-binding receptors still remains elusive. Here, we identify a lectin receptor kinase (LecRK), LecRK-I.8, as a potential eNAD+ receptor in Arabidopsis. The extracellular lectin domain of LecRK-I.8 binds NAD+ with a dissociation constant of 436.5 +/- 104.8 nM, although much higher concentrations are needed to trigger in vivo responses. Mutations in LecRK-I.8 inhibit NAD+-induced immune responses, whereas overexpression of LecRK-I.8 enhances the Arabidopsis response to NAD+. Furthermore, LecRK-I.8 is required for basal resistance against bacterial pathogens, substantiating a role for eNAD+ in plant immunity. Our results demonstrate that lectin receptors can potentially function as eNAD+-binding receptors and provide direct evidence for eNAD+ being an endogenous signaling molecule in plants. PMID- 28722655 TI - Key steps in unconventional secretion of fibroblast growth factor 2 reconstituted with purified components. AB - FGF2 is secreted from cells by an unconventional secretory pathway. This process is mediated by direct translocation across the plasma membrane. Here, we define the minimal molecular machinery required for FGF2 membrane translocation in a fully reconstituted inside-out vesicle system. FGF2 membrane translocation is thermodynamically driven by PI(4,5)P2-induced membrane insertion of FGF2 oligomers. The latter serve as dynamic translocation intermediates of FGF2 with a subunit number in the range of 8-12 FGF2 molecules. Vectorial translocation of FGF2 across the membrane is governed by sequential and mutually exclusive interactions with PI(4,5)P2 and heparan sulfates on opposing sides of the membrane. Based on atomistic molecular dynamics simulations, we propose a mechanism that drives PI(4,5)P2 dependent oligomerization of FGF2. Our combined findings establish a novel type of self-sustained protein translocation across membranes revealing the molecular basis of the unconventional secretory pathway of FGF2. PMID- 28722657 TI - Amino acid metabolites, mTORC1 and aging. PMID- 28722656 TI - Corrupting the DNA damage response: a critical role for Rad52 in tumor cell survival. AB - The DNA damage response enables cells to survive, maintain genome integrity, and to safeguard the transmission of high-fidelity genetic information. Upon sensing DNA damage, cells respond by activating this multi-faceted DNA damage response leading to restoration of the cell, senescence, programmed cell death, or genomic instability if the cell survives without proper repair. However, unlike normal cells, cancer cells maintain a marked level of genomic instability. Because of this enhanced propensity to accumulate DNA damage, tumor cells rely on homologous recombination repair as a means of protection from the lethal effect of both spontaneous and therapy-induced double-strand breaks (DSBs) in DNA. Thus, modulation of DNA repair pathways have important consequences for genomic instability within tumor cell biology and viability maintenance under high genotoxic stress. Efforts are underway to manipulate specific components of the DNA damage response in order to selectively induce tumor cell death by augmenting genomic instability past a viable threshold. New evidence suggests that RAD52, a component of the homologous recombination pathway, is important for the maintenance of tumor genome integrity. This review highlights recent reports indicating that reducing homologous recombination through inhibition of RAD52 may represent an important focus for cancer therapy and the specific efforts that are already demonstrating potential. PMID- 28722684 TI - Valley precession and valley polarization in graphene with inter-valley coupling. AB - We theoretically investigate the valley precession and valley polarization in graphene under inter-valley coupling. Our results show that the inter-valley coupling can induce valley polarization in graphene and also precess valleys in real space in a manner similar to the Rashba spin-orbit interaction rotating spins. Moreover, using strain modulation, we can achieve high valley polarization with large valley-polarized currents. These findings provide a new way to create and manipulate valley polarization in graphene. PMID- 28722686 TI - On the performance of natural orbital functional approximations in the Hubbard model. AB - Strongly correlated materials are now under intense development, and natural orbital functional (NOF) methods seem to be able to capture the physics of these systems. We present a benchmark based on the Hubbard model for a class of commonly used NOF approximations (also known as reduced density matrix functional approximations). Our findings highlight the importance of imposing ensemble N representability conditions in order to obtain consistent results in systems with either weak or strong electronic correlation, such as the Hubbard system with a varying two-particle interaction parameter. Based on the accuracy of the results obtained using PNOF7, which retrieves a large amount of the total strong nondynamic correlation, the Hubbard model points out that N-representability gives solid foundations for NOF development. PMID- 28722658 TI - The Golgi-localized, gamma ear-containing, ARF-binding (GGA) protein family alters alpha synuclein (alpha-syn) oligomerization and secretion. AB - Several age-related neurodegenerative disorders are associated with protein misfolding and aggregation of toxic peptides. alpha-synuclein (alpha-syn) aggregation and the resulting cytotoxicity is a hallmark of Parkinson's disease (PD) as well as dementia with Lewy bodies. Rising evidence points to oligomeric and pre-fibrillar forms as the pathogenic species, and oligomer secretion seems to be crucial for the spreading and progression of PD pathology. Recent studies implicate that dysfunctions in endolysosomal/autophagosomal pathways increase alpha-syn secretion. Mutation in the retromer-complex protein VPS35, which is involved in endosome to Golgi transport, was suggested to cause familial PD. GGA proteins regulate vesicular traffic between Golgi and endosomes and might work as antagonists for retromer complex mediated transport. To investigate the role of the GGAs in the alpha-syn oligomerization and/or secretion process we utilized protein-fragment complementation assays (PCA). We here demonstrate that GGAs alter alpha-syn oligomer secretion and alpha-syn oligomer-mediated toxicity. Specifically, we determined that GGA3 modifies extracellular alpha-syn species in an exosome-independent manner. Our data suggest that GGA3 drives alpha-syn oligomerization in endosomal compartments and thus facilitates alpha-syn oligomer secretion. Preventing the early events in alpha-syn oligomer release may be a novel approach to halt disease spreading in PD and other synucleinopathies. PMID- 28722685 TI - Neural control of finger movement via intracortical brain-machine interface. AB - OBJECTIVE: Intracortical brain-machine interfaces (BMIs) are a promising source of prosthesis control signals for individuals with severe motor disabilities. Previous BMI studies have primarily focused on predicting and controlling whole arm movements; precise control of hand kinematics, however, has not been fully demonstrated. Here, we investigate the continuous decoding of precise finger movements in rhesus macaques. APPROACH: In order to elicit precise and repeatable finger movements, we have developed a novel behavioral task paradigm which requires the subject to acquire virtual fingertip position targets. In the physical control condition, four rhesus macaques performed this task by moving all four fingers together in order to acquire a single target. This movement was equivalent to controlling the aperture of a power grasp. During this task performance, we recorded neural spikes from intracortical electrode arrays in primary motor cortex. MAIN RESULTS: Using a standard Kalman filter, we could reconstruct continuous finger movement offline with an average correlation of rho = 0.78 between actual and predicted position across four rhesus macaques. For two of the monkeys, this movement prediction was performed in real-time to enable direct brain control of the virtual hand. Compared to physical control, neural control performance was slightly degraded; however, the monkeys were still able to successfully perform the task with an average target acquisition rate of 83.1%. The monkeys' ability to arbitrarily specify fingertip position was also quantified using an information throughput metric. During brain control task performance, the monkeys achieved an average 1.01 bits s-1 throughput, similar to that achieved in previous studies which decoded upper-arm movements to control computer cursors using a standard Kalman filter. SIGNIFICANCE: This is, to our knowledge, the first demonstration of brain control of finger-level fine motor skills. We believe that these results represent an important step towards full and dexterous control of neural prosthetic devices. PMID- 28722687 TI - A comprehensive study of piezomagnetic response in CrPS4 monolayer: mechanical, electronic properties and magnetic ordering under strains. AB - We performed first-principles calculations to investigate the magnetic, mechanical and electronic properties of the tetrachalcogenide CrPS4. Although bulk CrPS4 has been shown to exhibit a low-dimensional antiferromagnetic (AFM) ground state where ferromagnetic (FM) Cr-chains are coupled antiferromagnetically, our calculations indicated that the monolayer can be transformed to an FM material by applying a uniaxial tensile strain of ?4% along the FM Cr-chain direction. The AFM-to-FM transition is explained to be driven by an increase of the exchange interaction induced by a decrease in the distance between the FM Cr-chains. A huge nonlinear piezomagnetism was predicted at the strain-induced magnetic phase boundary. Our study provides insight about rational design of single-layer magnetic materials for a wide range of spintronic devices and energy applications. PMID- 28722688 TI - Spin-dependent Seebeck effects in a graphene superlattice p-n junction with different shapes. AB - We theoretically calculate the spin-dependent transmission probability and spin Seebeck coefficient for a zigzag-edge graphene nanoribbon p-n junction with periodically attached stubs under a perpendicular magnetic field and a ferromagnetic insulator. By using the nonequilibrium Green's function method combining with the tight-binding Hamiltonian, it is demonstrated that the spin dependent transmission probability and spin Seebeck coefficient for two types of superlattices can be modulated by the potential drop, the magnetization strength, the number of periods of the superlattice, the strength of the perpendicular magnetic field, and the Anderson disorder strength. Interestingly, a metal to semiconductor transition occurs as the number of the superlattice for a crossed superlattice p-n junction increases, and its spin Seebeck coefficient is much larger than that for the T-shaped one around the zero Fermi energy. Furthermore, the spin Seebeck coefficient for crossed systems can be much pronounced and their maximum absolute value can reach 528 MUV [Formula: see text] by choosing optimized parameters. Besides, the spin Seebeck coefficient for crossed p-n junction is strongly enhanced around the zero Fermi energy for a weak magnetic field. Our results provide theoretical references for modulating the thermoelectric properties of a graphene superlattice p-n junction by tuning its geometric structure and physical parameters. PMID- 28722689 TI - Compressed H3S: inter-sublattice Coulomb coupling in a high-T C superconductor. AB - Upon thermal annealing at or above room temperature (RT) and at high hydrostatic pressure P ~ 155 GPa, sulfur trihydride H3S exhibits a measured maximum superconducting transition temperature T C ~ 200 K. Various theoretical frameworks incorporating strong electron-phonon coupling and Coulomb repulsion have reproduced this record-level T C. Of particular relevance is that experimentally observed H-D isotopic correlations among T C, P, and annealed order indicate an H-D isotope effect exponent alpha limited to values ? 0.183, leaving open for consideration unconventional high-T C superconductivity with electronic-based enhancements. The work presented herein examines Coulombic pairing arising from interactions between neighboring S and H species on separate interlaced sublattices constituting H3S in the Im[Formula: see text]m structure. The optimal value of the transition temperature is calculated from T C0 = [Formula: see text]Lambdae 2/[Formula: see text] zeta, with Lambda = 0.007465 A, inter-sublattice S-H separation spacing zeta = a 0/[Formula: see text], interaction charge linear spacing [Formula: see text] = a 0 (3/sigma)1/2, average participating charge fraction sigma = 3.43 +/- 0.10 estimated from calculated H-projected electron states, and lattice parameter a 0 = 3.0823 A at P = 155 GPa. The resulting value of T C0 = 198.5 +/- 3.0 K is in excellent agreement with transition temperatures determined from resistivity (196-200 K onsets, 190-197 K midpoints), susceptibility (200 K onset), and critical magnetic fields (203.5 K by extrapolation). Analysis of mid-infrared reflectivity data confirms the expected correlation between boson energy and zeta -1. Suppression of T C below T C0, correlating with increasing residual resistance for < RT annealing, is treated in terms of scattering-induced pair breaking. Correspondences between H3S and layered high-T C superconductor structures are also discussed, and a model considering Compton scattering of virtual photons of energies ? e 2/zeta by inter-sublattice electrons is introduced, illustrating that Lambda ? lambda C, where lambda C is the reduced electron Compton wavelength. PMID- 28722690 TI - Terahertz magnetoplasmon-polaritons with nonlocal corrections for lossy two dimensional electron gas in GaN-based heterostructures. AB - The high electron concentration in GaN-based heterostructures necessitate the consideration of nonlocal corrections in the magnetoconductivity for the study of magnetoplasmon-polaritons (MPPs) in the lossy two dimensional electron gas system with grating couplers. With the complete set of Maxwell equations, the complex dispersion frequency and absorption spectrum are calculated numerically at different magnetic field (B max = 10 T) and plasmon wavevectors (k max = 5 * 107 m-1). Taking the AlGaN/GaN structure as a representative case, we observe the cyclotron resonance and its high order harmonics, as well as the MPP modes. The effective aspect ratio of the grating is determined according to the absorption spectrum. Effects of the nonlocal corrections on the dispersion frequency and absorption spectrum are analyzed in detail. The contributions of LO phonons, electron collisions, THz wave polarizations and retardations are also discussed. PMID- 28722691 TI - Structural Basis of Bone Fragility in Young Subjects with Inflammatory Bowel Disease: A High-resolution pQCT Study of the SWISS IBD Cohort (SIBDC). AB - BACKGROUND: The onset of inflammatory bowel disease (IBD) during childhood/adolescence compromises peak bone mass acquisition and predisposes to fractures later in life. However, the structural basis for bone fragility in young adults with IBD remains unknown. METHODS: One hundred two young subjects from the Swiss IBD cohort were included. Areal bone mineral density (aBMD) at distal radius, hip, and spine as well as morphometric vertebral fractures were assessed using dual-energy x-ray absorptiometry technique. Volumetric (v)BMD, trabecular, and cortical bone microstructure at the distal radius and tibia were assessed by high-resolution peripheral quantitative computed tomography. Areal, vBMD, and microstructure were compared between patients with IBD and healthy matched controls (n = 389). Multiple regression analysis was used to evaluate variables associated with bone microarchitecture and fractures. RESULTS: Clinical fractures were reported in 37 IBD subjects (mean age 23 yrs), mostly of the forearm; 5 subjects had morphometric vertebral fractures. After adjusting for age, sex, and height, tibia trabecular (Tb)vBMD, thickness, and distribution were significantly associated with fractures, whereas aBMD was not. After adjusting for aBMD, radius Tb distribution and tibia (Tb)vBMD and trabecular thickness still remained associated with fractures. Compared with healthy controls, patients with IBD had significantly lower aBMD at all sites, as well as alteration in (Tb)vBMD and trabecular microstructure at the distal radius and tibia, and these alterations were correlated with disease severity. CONCLUSIONS: Young patients with IBD have low aBMD and altered trabecular bone microarchitecture compared with healthy controls. The latter is independently associated with fractures and may predispose increased susceptibility to fragility fractures throughout life. PMID- 28722692 TI - Eczema, Atopic Dermatitis, or Atopic Eczema: Analysis of Global Search Engine Trends. AB - BACKGROUND: The lack of standardized nomenclature for atopic dermatitis (AD) creates challenges for scientific communication, patient education, and advocacy. OBJECTIVE: We sought to determine the relative popularity of the terms eczema, AD, and atopic eczema (AE) using global search engine volumes. METHODS: A retrospective analysis of average monthly search volumes from 2014 to 2016 of Google, Bing/Yahoo, and Baidu was performed for eczema, AD, and AE in English and 37 other languages. Google Trends was used to determine the relative search popularity of each term from 2006 to 2016 in English and the top foreign languages, German, Turkish, Russian, and Japanese. RESULTS: Overall, eczema accounted for 1.5 million monthly searches (84%) compared with 247 000 searches for AD (14%) and 44 000 searches for AE (2%). For English language, eczema accounted for 93% of searches compared with 6% for AD and 1% for AE. Search popularity for eczema increased from 2006 to 2016 but remained stable for AD and AE. CONCLUSIONS: Given the ambiguity of the term eczema, we recommend the universal use of the next most popular term, AD. PMID- 28722693 TI - IKK/NF-kappaB-dependent satellite glia activation induces spinal cord microglia activation and neuropathic pain after nerve injury. AB - Increasing evidence indicates that both microglia and satellite glial cell (SGC) activation play causal roles in neuropathic pain development after peripheral nerve injury; however, the activation mechanisms and their contribution to neuropathic pain remain elusive. To address this issue, we generated Ikkbeta conditional knockout mice (Cnp-Cre/Ikkbeta; cIkkbeta) in which IKK/NF-kappaB dependent proinflammatory SGC activation was abrogated. In these mice, nerve injury-induced spinal cord microglia activation and pain hypersensitivity were significantly attenuated compared to those in control mice. In addition, nerve injury-induced proinflammatory gene expression and macrophage infiltration into the dorsal root ganglion (DRG) were severely compromised. However, macrophages recruited into the DRG had minimal effects on spinal cord microglia activation, suggesting a causal effect for SGC activation on spinal cord microglia activation. In an effort to elucidate the molecular mechanisms, we measured Csf1 expression in the DRG, which is implicated in spinal cord microglia activation after nerve injury. In cIkkbeta mice, nerve injury-induced Csf1 upregulation was ameliorated indicating that IKK/NF-kappaBeta-dependent SGC activation induced Csf1 expression in sensory neurons. Taken together, our data suggest that nerve injury-induced SGC activation triggers Csf1 induction in sensory neurons, spinal cord microglia activation, and subsequent central pain sensitization. PMID- 28722695 TI - Cardiac cycle efficiency and dicrotic pressure variations: new parameters for fluid therapy: An observational study. AB - BACKGROUND: During a fluid challenge, the changes in cardiac performance and peripheral circulatory tone are closely related to the position of the ventricle on the Frank-Starling curve. Some patients have a good haemodynamic response to a fluid challenge, others hardly any response. The early haemodynamic effects of a fluid challenge could predict the final response before the entire fluid volume has been administered. OBJECTIVE: To assess whether a multivariate logistic regression model, including pulse pressure variation (PPV), cardiac cycle efficiency (CCE), arterial elastance and the difference between the dicrotic pressure and both systolic and mean arterial pressure (SAP - Pdic and MAP - Pdic) can predict cardiac responsiveness early during a fluid challenge in comparison with the standard procedure described elsewhere. DESIGN: Observational study. SETTING: Elective surgical patients undergoing laparotomy, enrolled in two Italian University Hospitals. PATIENTS: Fifty adult surgical patients, ventilated with a lung protective strategy, were enrolled and data from 46 were analysed. INTERVENTIONS: A fluid challenge consisting of 500 ml of crystalloid infused over 10 min. MAIN OUTCOME MEASURES AND ANALYSIS: The changes in CCE, arterial elastance, SAP - Pdic and MAP - Pdic were compared using analysis of variance. A multivariate logistic regression analysis utilising baseline values and the first minute measuring a variation statistically significant for the considered variables. RESULTS: At baseline, PPV correctly identified 70% of patients (89% of non-responders; 42% of responders). The model, including baseline PPV, DeltaCCE and DeltaSAP - Pdic, correctly identified the efficiency of fluid challenge in 87% of patients (84.2% of responders; 92.5 of non-responders) after 5 min from fluid challenge infusion. CONCLUSION: In this pilot study conducted in a population of surgical patients mechanically ventilated with a VT less than 8 ml kg, a dynamic model of fluid challenge assessment, including PPV, DeltaCCE and DeltaSAP - Pdic, enhances the prediction of fluid challenge response after 5 min of a 10-min administration. TRIAL REGISTRATION: ACTRN12616001479493. PMID- 28722694 TI - Early life vincristine exposure evokes mechanical pain hypersensitivity in the developing rat. AB - Vincristine (VNC) is commonly used to treat pediatric cancers, including the most prevalent childhood malignancy, acute lymphoblastic leukemia. Although clinical evidence suggests that VNC causes peripheral neuropathy in children, the degree to which pediatric chemotherapeutic regimens influence pain sensitivity throughout life remains unclear, in part because of the lack of an established animal model of chemotherapy-induced neuropathic pain during early life. Therefore, this study investigated the effects of VNC exposure between postnatal days (P) 11 and 21 on mechanical and thermal pain sensitivity in the developing rat. Low doses of VNC (15 or 30 MUg/kg) failed to alter nociceptive withdrawal reflexes at any age examined compared with vehicle-injected littermate controls. Meanwhile, high dose VNC (60 MUg/kg) evoked mechanical hypersensitivity in both sexes beginning at P26 that persisted until adulthood and included both static and dynamic mechanical allodynia. Hind paw withdrawal latencies to noxious heat and cold were unaffected by high doses of VNC, suggesting a selective effect of neonatal VNC on mechanical pain sensitivity. Gross and fine motor function appeared normal after VNC treatment, although a small decrease in weight gain was observed. The VNC regimen also produced a significant decrease in intraepidermal nerve fiber density in the hind paw skin by P33. Overall, the present results demonstrate that high-dose administration of VNC during the early postnatal period selectively evokes a mechanical hypersensitivity that is slow to emerge during adolescence, providing further evidence that aberrant sensory input during early life can have prolonged consequences for pain processing. PMID- 28722696 TI - Hematocrit and Serum Hemoglobin Do Not Influence Values in Computed Tomography Perfusion of Patients With Acute Ischemic Stroke. AB - OBJECTIVE: There is a correlation between both serum hemoglobin (HGB) and hematocrit (HCT) and attenuation values of vessels in noncontrast-enhanced computed tomography (NECT), which could influence calculated perfusion maps in CT perfusion. METHODS: We retrospectively included 45 patients, who presented with acute new neurological symptoms and underwent NECT and CT perfusion (128-row multi detector scanner, coverage: 6.9 cm craniocaudally; 80 kV; 200 mAs; temporal resolution: 2 seconds using 40 mL Ultravist 370 at a flow rate of 5 mL/s) on admission and a follow-up MRI within 1 week of admission. RESULTS: Hematocrit, HGB, and attenuation values did not differ between patients with stroke and controls. A statistically significant correlation was found between HCT and HGB and attenuation values in the internal carotid artery or middle cerebral artery on NECT (P < 0.05). No statistically significant correlation was observed between HCT and HGB and perfusion maps. CONCLUSIONS: Hematocrit and HGB do not influence calculated perfusion maps. There is no need for HCT/HGB-adjusted cerebral blood volume thresholds in stroke patients. PMID- 28722697 TI - Bifid Mandibular Canals Incidence and Anatomical Variations in the Population of Shanghai Area by Cone Beam Computed Tomography. AB - OBJECTIVE: The aim of this study was to analyze the rate, location, and characteristics of bifid mandibular canals (BMCs) in the population of the Shanghai area using cone beam computed tomography to avoid complications during surgical procedures. METHODS: Two hundred eighty patients were recruited for this study, and the presence and morphology of BMCs were evaluated. RESULTS: The occurrence rate of BMCs in the Shanghai area was relatively high compared with that in other populations, reaching 31.1%. In addition, the study also found some far less-common trifid mandibular canals, as well as a peculiarly shaped special type, which we called v-type canal that has yet to be described. CONCLUSIONS: Our study underlined the different characteristics and occurrence rates of BMCs in the population of the Shanghai area and the importance of using cone beam computed tomography for a reliable detection, providing useful information to help prevent presurgery and postsurgery complications. PMID- 28722698 TI - Magnetic Resonance Imaging of Parotid Gland Tumors: Dynamic Contrast-Enhanced Sequence Evaluation. AB - OBJECTIVE: The aim of the study was to evaluate dynamic contrast-enhanced magnetic resonance (MR) imaging in the characterization of parotid gland tumors. METHODS: Fifty-five parotid lesions in 55 patients were retrospectively included. Two observers interpreted 2 reading protocols derived from all MR imaging in 2 distinct sessions, independently and blinded. Benign versus malignant distinction was carried out for protocol 1 (without contrast administration) and protocol 2 (with dynamic contrast-enhanced sequence). Histopathological results after surgical resection were used as the criterion standard. Diagnostic accuracy was compared between protocols using McNemar test. A P values of less than 0.05 indicated significant difference. RESULTS: There was no intraobserver statistical discordance between protocols for both observers (P = 0.27 and P = 1). Interobserver reliability showed moderate agreement for protocol 1 (kappa = 0.591; 95% confidence interval [CI], 0.376-0.806) and 2 (kappa = 0.463, 95% CI, 0.226-0.701). Intraobserver reliability showed moderate agreement for observer 1 (kappa = 0.507; 95% CI, 0.279-0.736) and 2 (kappa = 0.477; 95% CI, 0.241-0.712). CONCLUSIONS: Magnetic resonance imaging protocol including dynamic sequence for the characterization of parotid gland lesion yielded nonsignificant increases in sensitivity, specificity, or positive predictive values, and negative predictive values over noninjected protocol. PMID- 28722699 TI - Added Value of Parotid R2* Values for Evaluation of Sjogren Syndrome: A Preliminary Study. AB - OBJECTIVE: To explore the application of parotid R2* values for evaluating Sjogren syndrome (SS). METHODS: Twenty-four consecutive SS patients and 24 sex matched and age-matched healthy volunteers underwent bilateral parotid 3.0 T magnetic resonance (MR) imaging, including blood oxygenation level dependent sequence. Parotid R2* values of SS patients and volunteers were compared. A receiver operating characteristic analysis was used to evaluate the diagnostic performance of parotid R2* value alone and in combination with MR nodular grade. RESULTS: The left parotid R2* value was significantly lower than the right (P = 0.006) in SS patients. Parotid R2* value in SS patients was significantly lower than that in healthy volunteers (P < 0.001). With a cutoff value of 64.14/s, the sensitivity of the parotid R2* value was 62.5% in the diagnosis of SS. By combining R2* value with MR nodular grade, the sensitivity reached 87.5%. CONCLUSIONS: Parotid R2* value contributed to the diagnosis of Sjogren syndrome combined with MR nodular grade. PMID- 28722700 TI - Detection of Bone Marrow Edema Pattern With Dual-Energy Computed Tomography of the Pig Mandible Treated With Radiotherapy and Surgery Compared With Magnetic Resonance Imaging. AB - OBJECTIVE: The aim of the study was to investigate the accuracy of dual-energy computed tomography (DECT) compared with magnetic resonance (MR) imaging for the detection of edema of the mandible. MATERIALS AND METHODS: Fifteen adult Gottingen mini pigs received irradiation to the mandible with an equivalent dose of 0, 25, 50, or 70 Gy. Six months after irradiation, all animals underwent DECT and MR imaging of the mandible. Magnetic resonance short tau inversion recovery (STIR) was used for the grading of the bone marrow edema (0-3). Dual-energy CT (80 and 140 kVp) was performed, and virtual noncalcium (VNCa) images were calculated. RESULTS: Increased signal intensity at STIR was found in the higher radiation groups. An increase of signal intensity in MR imaging was accompanied by a significant increase in the Hounsfield unit value of the VNCa images of the bone marrow (STIR: 0, 1, 2, 3; mean Hounsfield unit: -103, -90, -76, -34, respectively; P < 0.05; R = 0.388). CONCLUSIONS: The VNCa images derived from DECT are able to demonstrate bone marrow edema in radiation-induced bone changes in the mandible. PMID- 28722701 TI - Susceptibility Weighted With Quantitative Phase Magnetic Resonance Imaging in Differentiation of Various Stages of Hemorrhage and Calcification in Female Pelvic Pathologies: A Preliminary Study. AB - BACKGROUND: The purposes of this study were to assess the value of phase for characterization of female pelvic lesions with hemorrhage in various stages and to differentiate them from calcified lesions at 3.0-T magnetic resonance imaging (MRI). METHODS: Forty-four female patients with hemorrhagic (n = 37) or calcified (n = 7) pelvic pathology underwent conventional MRI including susceptibility weighted imaging with phase information. Hemorrhagic lesions were grouped into acute, subacute, and chronic, and calcified lesions were detected on the basis of conventional imaging findings. Phase quantification of these hemorrhagic and calcified lesions was performed. RESULTS: The phase values significantly differed (P < 0.001) among various stages of hemorrhage, as well as calcification (chronic hemorrhage, -65.09 +/- 9.09 degrees; subacute hemorrhage, -11.41 +/- 4.4 degrees; acute hemorrhage, -42.30 +/- 5.20 degrees; and calcified lesions, 117.55 +/- 12.93 degrees). CONCLUSIONS: Quantitative phase imaging has the potential to differentiate various stages of hemorrhagic and calcified pathologies. This may add value to the conventional MRI in improved characterization of these entities in female pelvic pathologies. PMID- 28722702 TI - Radiofrequency Ablation of Hepatic Tumor: Subjective Assessment of the Perilesional Vascular Network on Contrast-Enhanced Computed Tomography Before and After Ablation Can Reliably Predict the Risk of Local Recurrence. AB - OBJECTIVE: To determine whether simple, subjective analysis of the perilesional vascular network can predict the risk of local recurrence after radiofrequency ablation (RFA) of liver malignancies on contrast-enhanced computed tomography (CECT). METHODS: Contrast-enhanced computed tomography's 103 patients (59 men and 44 women; mean age, 63 years (range, 31-84 years) with 134 lesions who underwent RFA between 2000 and 2010 were retrospectively analyzed. The primary tumors include colorectal carcinoma (58 patients), hepatocellular carcinoma (n = 13), breast carcinoma (n = 8), neuroendocrine tumor (n = 5), and others (n = 19). Three blinded radiologists independently reviewed the CECT (a triple phase liver protocol for hypervascular tumors and a single phase for the hypovascular tumors) before and 6 weeks after RFA and subjectively estimated the width of the ablative margin on a 3-point scale (optimal, 1; suboptimal, 2; and residual tumor, 3). Local recurrence was determined on follow-up CECT. RESULTS: The consensus score was 1 in 94, 2 in 28, and 3 in 12 lesions. kappa among readers was 0.75. Local recurrence occurred in 3 lesions with a score of 1 and 12 lesions with a score of 2. The consensus score was a significant univariate predictor of local recurrence. CONCLUSIONS: Subjective estimation of the width of ablative margin can reliably predict the risk of local recurrence. PMID- 28722703 TI - Deep intronic hotspot variant explaining rhabdoid tumor predisposition syndrome in two patients with atypical teratoid and rhabdoid tumor. AB - About one third of patients with rhabdoid tumors (RT) harbor a heterozygous germline variant in SMARCB1. Molecular diagnosis therefore keeps a crucial place in the diagnosis of RT, and genetic counseling should be systematically recommended. However, immunohistochemistry has progressively replaced molecular tools to assess the status of SMARCB1 in tumors; the necessity of analyzing SMARCB1 status in the tumor may thus be less considered by neuropathologists and pediatric neuro-oncologists. In the present manuscript as aforementioned, we report on two patients with bifocal RT in the first month of life and in whom no germline variant was initially found in the SMARCB1 coding sequence. Careful analysis of SMARCB1 status in the tumors revealed that only one of the two inactivating hits was found in the coding sequence. By sequencing the tumor cells RNA, we were able to detect an insertion with an abnormal sequence, due to the same intronic variant of SMARCB1, which led to the exonisation of the first intron. This cryptic variant was absent in the germline DNA of both patients. Of note, we previously reported one patient with the same deep intronic variant in the germline in a soft tissue RT. To our mind, this additional report on two patients clearly demonstrates that this intronic variant is a new hotspot that should now be systematically added to the germline screening of SMARCB1. We therefore recommend searching for and cautiously interpreting germline analysis if SMARCB1 has not been extensively studied in the tumor. PMID- 28722704 TI - Targeted proteomic assays for quantitation of proteins identified by proteogenomic analysis of ovarian cancer. AB - Mass spectrometry (MS) based targeted proteomic methods such as selected reaction monitoring (SRM) are emerging as a promising tool for verification of candidate proteins in biological and biomedical applications. The Clinical Proteomic Tumor Analysis Consortium (CPTAC) of the National Cancer Institute has investigated the standardization and analytical validation of the SRM assays and demonstrated robust analytical performance on different instruments across different laboratories. An Assay Portal has also been established by CPTAC to provide the research community a resource consisting of large sets of targeted MS-based assays, and a depository to share assays publicly. Herein, we report the development of 98 SRM assays that have been thoroughly characterized according to the CPTAC Assay Characterization Guidance Document; 37 of these passed all five experimental tests. The assays cover 70 proteins previously identified at the protein level in ovarian tumors. The experiments, methods and results for characterizing these SRM assays for their MS response, repeatability, selectivity, stability, and endogenous detection are described in detail. Data are available via PeptideAtlas, Panorama and the CPTAC Assay Portal. PMID- 28722705 TI - Background controlled QTL mapping in pure-line genetic populations derived from four-way crosses. AB - Pure lines derived from multiple parents are becoming more important because of the increased genetic diversity, the possibility to conduct replicated phenotyping trials in multiple environments and potentially high mapping resolution of quantitative trait loci (QTL). In this study, we proposed a new mapping method for QTL detection in pure-line populations derived from four-way crosses, which is able to control the background genetic variation through a two stage mapping strategy. First, orthogonal variables were created for each marker and used in an inclusive linear model, so as to completely absorb the genetic variation in the mapping population. Second, inclusive composite interval mapping approach was implemented for one-dimensional scanning, during which the inclusive linear model was employed to control the background variation. Simulation studies using different genetic models demonstrated that the new method is efficient when considering high detection power, low false discovery rate and high accuracy in estimating quantitative trait loci locations and effects. For illustration, the proposed method was applied in a reported wheat four-way recombinant inbred line population. PMID- 28722706 TI - Sub-national mapping of population pyramids and dependency ratios in Africa and Asia. AB - The age group composition of populations varies substantially across continents and within countries, and is linked to levels of development, health status and poverty. The subnational variability in the shape of the population pyramid as well as the respective dependency ratio are reflective of the different levels of development of a country and are drivers for a country's economic prospects and health burdens. Whether measured as the ratio between those of working age and those young and old who are dependent upon them, or through separate young and old-age metrics, dependency ratios are often highly heterogeneous between and within countries. Assessments of subnational dependency ratio and age structure patterns have been undertaken for specific countries and across high income regions, but to a lesser extent across the low income regions. In the framework of the WorldPop Project, through the assembly of over 100 million records across 6,389 subnational administrative units, subnational dependency ratio and high resolution gridded age/sex group datasets were produced for 87 countries in Africa and Asia. PMID- 28722708 TI - Breaking down barriers. PMID- 28722707 TI - Nutrition, inflammation and cancer. AB - Quantitative and qualitative aspects of nutrition have a profound effect on leukocytes and thereby affect proinflammatory carcinogenic effects or anticancer immune responses. As a result, nutrition affects the incidence, natural progression and therapeutic response of malignant diseases, both in humans and in preclinical animal models. Here we discuss the molecular mechanisms through which alimentary cues modulate metabolic, microbial and neuroendocrine circuitries and thus affect the probability of developing premalignant lesions that progress to clinically manifested disease and the response to therapeutic intervention. We examine each of the connections that compose the triangle of nutrition, immunological and inflammatory reactions and cancer while focusing on the mechanistic aspects of these relationships. PMID- 28722710 TI - Inducing fetal tolerance. PMID- 28722709 TI - Regulation of inflammation by microbiota interactions with the host. AB - The study of the intestinal microbiota has begun to shift from cataloging individual members of the commensal community to understanding their contributions to the physiology of the host organism in health and disease. Here, we review the effects of the microbiome on innate and adaptive immunological players from epithelial cells and antigen-presenting cells to innate lymphoid cells and regulatory T cells. We discuss recent studies that have identified diverse microbiota-derived bioactive molecules and their effects on inflammation within the intestine and distally at sites as anatomically remote as the brain. Finally, we highlight new insights into how the microbiome influences the host response to infection, vaccination and cancer, as well as susceptibility to autoimmune and neurodegenerative disorders. PMID- 28722712 TI - Erratum: Ontogeny and homeostasis of CNS myeloid cells. PMID- 28722714 TI - A current view on inflammation. PMID- 28722713 TI - Tumor immunity requires border patrol to fight the enemy within. PMID- 28722711 TI - Limiting inflammation-the negative regulation of NF-kappaB and the NLRP3 inflammasome. AB - A properly mounted immune response is indispensable for recognizing and eliminating danger arising from foreign invaders and tissue trauma. However, the 'inflammatory fire' kindled by the host response must be tightly controlled to prevent it from spreading and causing irreparable damage. Accordingly, acute inflammation is self-limiting and is normally attenuated after elimination of noxious stimuli, restoration of homeostasis and initiation of tissue repair. However, unresolved inflammation may lead to the development of chronic autoimmune and degenerative diseases and cancer. Here, we discuss the key molecular mechanisms that contribute to the self-limiting nature of inflammatory signaling, with emphasis on the negative regulation of the NF-kappaB pathway and the NLRP3 inflammasome. Understanding these negative regulatory mechanisms should facilitate the development of much-needed therapeutic strategies for treatment of inflammatory and autoimmune pathologies. PMID- 28722715 TI - Erratum: Gut microbial metabolites limit the frequency of autoimmune T cells and protect against type 1 diabetes. PMID- 28722716 TI - Alzheimer's disease microglia. PMID- 28722717 TI - Counting the cost of lineage decisions. PMID- 28722718 TI - Corrigendum: TCRalpha-TCRbeta pairing controls recognition of CD1d and directs the development of adipose NKT cells. PMID- 28722719 TI - Erratum: NLRP12 attenuates colon inflammation by maintaining colonic microbial diversity and promoting protective commensal bacterial growth. PMID- 28722721 TI - Corrigendum: Spontaneous partial loss of the OT-I transgene. PMID- 28722722 TI - MAIT cell heterogeneity. PMID- 28722720 TI - A guiding map for inflammation. AB - Biologists, physicians and immunologists have contributed to the understanding of the cellular participants and biological pathways involved in inflammation. Here, we provide a general guide to the cellular and humoral contributors to inflammation as well as to the pathways that characterize inflammation in specific organs and tissues. PMID- 28722724 TI - NF-kappaB citrullination. PMID- 28722723 TI - Untangling Fc and complement receptors to kill tumors. PMID- 28722726 TI - Non-inflammatory IFN. PMID- 28722727 TI - Biomaterials Science Emerging Investigators 2017. PMID- 28722728 TI - An unprecedented Zn10O4 heteroadamantane cage containing anilido-pyridinate ligand and its activity for ring opening polymerization of l-lactide and epsilon caprolactone. AB - (NPyC2OMe)8Zn10Et4(MU4-O)4 (1) has been synthesized in situ by hydrolysis of ZnEt2 in a one pot process and it was proved by applying X-ray structure analysis that the organozinc anilido-pyridinate moiety encapsulated the zinc oxide cluster, which demonstrated one self-assembled coordinate mode "Zn10O4". Moreover, the catalytic activity was investigated and good activity for l-lactide and epsilon-caprolactone ring opening polymerization was observed with both living and controllable properties. PMID- 28722729 TI - A healable thermo-reversible functional polymer prepared via RAFT polymerization and ultrafast 'click' chemistry using a triazolinedione derivative. AB - This communication reports the preparation and characterization of a functional polymer bearing a pendant indole group via a reversible-addition fragmentation and chain transfer (RAFT) process followed by its modification via an Alder-ene 'click' reaction using a 1,2,4-triazoline-3,5-dione (TAD) derivative. The resultant functional polymer showed thermo-reversible as well as healing characteristics. PMID- 28722725 TI - The monogenic autoinflammatory diseases define new pathways in human innate immunity and inflammation. AB - Autoinflammatory diseases were first recognized nearly 20 years ago as distinct clinical and immunological entities caused by dysregulation in the innate immune system. Since then, advances in genomic techniques have led to the identification of new monogenic disorders and their corresponding signaling pathways. Here we review these monogenic autoinflammatory diseases, ranging from periodic fever syndromes caused by dysregulated inflammasome-mediated production of the cytokine IL-1beta to disorders arising from perturbations in signaling by the transcription factor NF-kappaB, ubiquitination, cytokine signaling, protein folding, type I interferon production and complement activation, and we further examine their molecular mechanisms. We also explore the overlap among autoinflammation, autoimmunity and immunodeficiency, and pose a series of unanswered questions that are expected to be central in autoinflammatory disease research in the coming decade. PMID- 28722730 TI - Tunable in-plane torsional strength of surface functionalized two dimensional nanomaterials. AB - In this paper, the in-plane torsional properties of two dimensional nanomaterials are revealed to be tunable by surface functionalization using molecular dynamics simulations. The torsional strengths of both graphene and graphyne under circular shearing are found to first decrease and then increase anomalously with the increase of the hydrogenation ratio. The minimum strength of such U-shaped strength evolution appears at different hydrogenation ratios H for graphene (H = 50%) and graphyne (H = 70%), demonstrating a correlation between hydrogenation and the unit lattices of 2D nanomaterials. By studying the torsional characteristics of a graphene annulus with varying outer-to-inner boundary radius ratios, the anomalous increase of torsional strength at a high hydrogenation ratio is revealed to be the result of wrinkling deformation as well as chemical bond hybridization. Further analyses of the local stress distribution are carried out for understanding the mechanism of surface hydrogenation tuned in-plane torsional strength of graphene and graphyne. Torsional strength of the graphene annulus with an elliptical outer boundary also shows a U-shaped evolution with hydrogenation ratio, while the shape effect of the graphene annulus can smooth the change of the torsional characteristics with hydrogenation. Our results provide novel insights into the development of 2D nanomaterial-based annular devices. PMID- 28722733 TI - A polyacrylonitrile copolymer-silica template for three-dimensional hierarchical porous carbon as a Pt catalyst support for the oxygen reduction reaction. AB - Herein, we report a novel route to construct a hierarchical three-dimensional porous carbon (3DC) through a copolymer-silica assembly. In the synthesis, silica acts as a hard template and leads to the formation of an interconnected 3D macropore, whereas styrene-co-acrylonitrile polymer has been used as both a carbon source and a soft template for micro- and meso-pores. The obtained 3DC materials possess a large surface area (~550.5 m2 g-1), which facilitates high dispersion of Pt nanoparticles on the carbon support. The 3DC-supported Pt electrocatalyst shows excellent performance in the oxygen reduction reaction (ORR). The easy processing ability along with the characteristics of hierarchical porosity offers a new strategy for the preparation of carbon nanomaterials for energy application. PMID- 28722734 TI - Scavenging and recombination kinetics in radiation chemistry. AB - This work describes stochastic models developed to study the competition between radical scavenging and recombination for simple model systems typical of radiation chemistry, where the reactive particles are tightly clustered and reactions are assumed fully diffusion limited. Three models are developed: a Monte Carlo random flights model with a periodic boundary condition for scavengers, Monte Carlo simulations in which the scavenging rate is calculated from the Smoluchowski theory for diffusion-limited reactions and a modification of the independent reaction times method where the scavengers close to the spur are explicitly included and the scavengers further away are treated as a continuum. The results indicate that the Smoluchowski theory makes a systematic overestimate of the scavenging rate when such competition is present. A correction for the Smoluchowski rate constant is suggested, an analytical justification is presented and it is tested against the simulations, and shown to be a substantial improvement. PMID- 28722735 TI - Lithiation of multilayer Ni/NiO electrodes: criticality of nickel layer thicknesses on conversion reaction kinetics. AB - X-ray reflectivity and transmission electron microscopy (TEM) were used to characterize the morphological changes in thin film electrodes with alternating Ni and NiO layers during lithiation as a function of the Ni buffer layer thickness. Complete lithiation of the active NiO layers occurs only when the thickness of the Ni/NiO bilayers are less than 75 A - a threshold value that is determined by the sum of the Ni quantity in the Ni/NiO bilayer of the multilayer stack. Thicker Ni/NiO bilayers present a kinetic barrier for lithium ion diffusion inside the stack resulting in partial lithiation of the multilayer electrodes in which only the top NiO layer lithiates. Lithiation of NiO layers in a multilayer stack also leads to an interface-specific reaction that is observed to increase the thicknesses of adjacent Ni layers by 3-4 A and is associated with the formation of a low-density Li2O layer, corresponding to an interfacially driven phase separation of the NiO. Rate dependent cyclic voltammetry studies reveal a linear relation between the peak current and scan rate suggesting that the lithiation kinetics are controlled by charge transfer resistance at the liquid-solid interface. PMID- 28722740 TI - Spectroscopic imaging studies of nanoscale polarity and mass transport phenomena in self-assembled organic nanotubes. AB - Synthetic organic nanotubes self-assembled from bolaamphiphile surfactants are now being explored for use as drug delivery vehicles. In this work, several factors important to their implementation in drug delivery are explored. All experiments are performed with the nanotubes immersed in ethanol. First, Nile Red (NR) and a hydroxylated Nile Red derivative (NR-OH) are loaded into the nanotubes and spectroscopic fluorescence imaging methods are used to determine the apparent dielectric constant of their local environment. Both are found in relatively nonpolar environments, with the NR-OH molecules preferring regions of relatively higher dielectric constant compared to NR. Unique two-color imaging fluorescence correlation spectroscopy (imaging FCS) measurements are then used along with the spectroscopic imaging results to deduce the dielectric properties of the environments sensed by mobile and immobile populations of probe molecules. The results reveal that mobile NR molecules pass through less polar regions, likely within the nanotube walls, while immobile NR molecules are found in more polar regions, possibly near the nanotube surfaces. In contrast, mobile and immobile NR OH molecules are found to locate in environments of similar polarity. The imaging FCS results also provide quantitative data on the apparent diffusion coefficient for each dye. The mean diffusion coefficient for the NR dye was approximately two fold larger than that of NR-OH. Slower diffusion by the latter could result from its additional hydrogen bonding interactions with polar triglycine, amine, and glucose moieties near the nanotube surfaces. The knowledge gained in these studies will allow for the development of nanotubes that are better engineered for applications in the controlled transport and release of uncharged, dipolar drug molecules. PMID- 28722744 TI - Electrostatic interactions in concentrated colloidal dispersions. AB - An explicit expression, free from adjustable parameters, is derived for the effective pair interaction between charged colloidal spheres at high concentration in a medium containing an electrolyte. This is accomplished by first considering the electrostatic interaction between two infinite charged plates placed in a stack of identical plates. These act as a reservoir defining the chemical potentials of solvent and electrolyte ions in a way that depends on the plate separation in the stack. The results for the planar case are then applied to a suspension of identical charged spheres. Also for this case the concentration defines the properties of a reservoir quantitatively affecting the particle-particle interaction. At short range this interaction can be determined using the Derjaguin approximation relating the interaction for the planar system to the inter-particle force. In the opposite limit the effective potential around the most probable separation is derived assuming pair-wise additive interactions from nearest neighbors. For very concentrated systems the Derjaguin approximation can be used. For a more dilute system an effective local potential is derived based on solutions of the Poisson-Boltzmann equation in the cell model. PMID- 28722745 TI - Co-catalyzed highly selective C(sp3)-H nitration. AB - A Co-catalyzed highly chemo- and regio-selective nitration of C(sp3)-H was developed. Diverse aliphatic nitro compounds were obtained in good yields, using t-BuONO as a nitrating reagent. Specific nitration of C(sp3)-H instead of C(sp2) H was achieved via a radical process rather than concerted metalation deprotonation. PMID- 28722746 TI - Hospitalization rates among economic immigrants to Canada. AB - BACKGROUND: Economic immigrants generally, and economic class principal applicants (ECPAs) specifically, tend to have better health than other immigrants. However, health outcomes vary among subcategories within this group, especially by sex. DATA AND METHODS: This study examines hospitalization rates among ECPAs aged 25 to 74 who arrived in Canada between 1980 and 2006 as skilled workers, business immigrants, or live-in caregivers. The analysis used two linked databases to estimate age-standardized hospitalization rates (ASHRs) overall and for leading causes by sex. ASHRs of ECPA subcategories were compared with each other and with those of the Canadian-born population. Logistic regression was used to derive odds ratios for hospitalization among ECPAs, by sex. RESULTS: Male and female ECPAs aged 25 to 74 had significantly lower all-cause ASHRs than did the Canadian-born population in the same age range. This pattern prevailed for each ECPA subcategory and for each disease examined. Compared with skilled workers, business immigrants had lower odds of hospitalization; live-in caregivers who arrived after 1992 had higher odds. Adjustment for education, official language proficiency, and world region reduced the strength of or eliminated these associations. INTERPRETATION: Compared with the Canadian-born population, ECPAs generally had low hospitalization rates. Differences were apparent among ECPA subcategories. PMID- 28722742 TI - Characterization of hydrogen bonding motifs in proteins: hydrogen elimination monitoring by ultraviolet photodissociation mass spectrometry. AB - Determination of structure and folding of certain classes of proteins remains intractable by conventional structural characterization strategies and has spurred the development of alternative methodologies. Mass spectrometry-based approaches have a unique capacity to differentiate protein heterogeneity due to the ability to discriminate populations, whether minor or major, featuring modifications or complexation with non-covalent ligands on the basis of m/z. Cleavage of the peptide backbone can be further utilized to obtain residue specific structural information. Here, hydrogen elimination monitoring (HEM) upon ultraviolet photodissociation (UVPD) of proteins transferred to the gas phase via nativespray ionization is introduced as an innovative approach to deduce backbone hydrogen bonding patterns. Using well-characterized peptides and a series of proteins, prediction of the engagement of the amide carbonyl oxygen of the protein backbone in hydrogen bonding using UVPD-HEM is demonstrated to show significant agreement with the hydrogen-bonding motifs derived from molecular dynamics simulations and X-ray crystal structures. PMID- 28722747 TI - Acute care hospitalization of Aboriginal children and youth. AB - BACKGROUND: Research that has examined Aboriginal children's hospitalization rates at the national level has been limited to analyses of areas with large percentages of Aboriginal residents, rather than of Aboriginal individuals. This study uses linked census and administrative data to describe hospitalization patterns among children and youth aged 0 to 19, by Aboriginal identity, for all provinces and territories except Quebec. DATA AND METHODS: The 2006 Census was linked to the 2006/2007-to-2008/2009 Discharge Abstract Database, which contains hospital records from all acute care facilities (except Quebec). Hospital records were examined by Aboriginal identity, as reported to the census, according to International Classification of Diseases chapters based on "the most responsible diagnosis." Age-standardized hospitalization rates (ASHRs) were calculated per 100,000 population, and age-standardized rate ratios (RRs) were calculated for Aboriginal groups relative to non-Aboriginal people. RESULTS: ASHRs were consistently higher among Aboriginal children and youth relative to their non Aboriginal counterparts; rates for children aged 0 to 9 were 1.4 to 1.8 times higher; for youth aged 10 to 19, 2.0 to 3.8 times higher. For all children aged 0 to 9, the leading cause of hospitalization was "diseases of the respiratory system," but RRs for Aboriginal children ranged from 1.7 to 2.5, compared with non-Aboriginal children. Disparities between Aboriginal and non-Aboriginal 10- to 19-year-olds were pronounced for injuries due to assaults (RRs from 4.8 to 10.0), self-inflicted injuries (RRs from 2.7 to 14.2), and pregnancy, childbirth and the puerperium (RRs from 4.1 to 9.8). INTERPRETATION: Additional research is needed to examine reasons for the disparities in hospitalization rates between Aboriginal and non-Aboriginal children and youth. PMID- 28722748 TI - Evolution and plasticity: Divergence of song discrimination is faster in birds with innate song than in song learners in Neotropical passerine birds. AB - Plasticity is often thought to accelerate trait evolution and speciation. For example, plasticity in birdsong may partially explain why clades of song learners are more diverse than related clades with innate song. This "song learning" hypothesis predicts that (1) differences in song traits evolve faster in song learners, and (2) behavioral discrimination against allopatric song (a proxy for premating reproductive isolation) evolves faster in song learners. We tested these predictions by analyzing acoustic traits and conducting playback experiments in allopatric Central American sister pairs of song learning oscines (N = 42) and nonlearning suboscines (N = 27). We found that nonlearners evolved mean acoustic differences slightly faster than did leaners, and that the mean evolutionary rate of song discrimination was 4.3 times faster in nonlearners than in learners. These unexpected results may be a consequence of significantly greater variability in song traits in song learners (by 54-79%) that requires song-learning oscines to evolve greater absolute differences in song before achieving the same level of behavioral song discrimination as nonlearning suboscines. This points to "a downside of learning" for the evolution of species discrimination, and represents an important example of plasticity reducing the rate of evolution and diversification by increasing variability. PMID- 28722749 TI - Rho-associated protein kinases as therapeutic targets for both vascular and parenchymal pathologies in Alzheimer's disease. AB - The causes of late-onset Alzheimer's disease are unclear and likely multifactorial. Rho-associated protein kinases (ROCKs) are ubiquitously expressed signaling messengers that mediate a wide array of cellular processes. Interestingly, they play an important role in several vascular and brain pathologies implicated in Alzheimer's etiology, including hypertension, hypercholesterolemia, blood-brain barrier disruption, oxidative stress, deposition of vascular and parenchymal amyloid-beta peptides, tau hyperphosphorylation, and cognitive decline. The current review summarizes the functions of ROCKs with respect to the various risk factors and pathologies on both sides of the blood-brain barrier and present support for targeting ROCK signaling as a multifactorial and multi-effect approach for the prevention and amelioration of late-onset Alzheimer's disease. This article is part of the Special Issue "Vascular Dementia". PMID- 28722750 TI - Protein kinase D exerts neuroprotective functions during oxidative stress via nuclear factor kappa B-independent signaling pathways. AB - Members of the protein kinase D (PKD) family of serine/threonine kinases are known to exert diverse roles in neuronal stress responses. Here, we show the transient activation and nuclear translocation of endogenous PKD upon oxidative stress induced by H2 O2 treatment in primary neuronal cultures. Using pharmacological inhibition, we show that PKD activity protects neurons from oxidative stress-induced cell death. Although members of the canonical nuclear factor kappa-light-chain-enhancer of activated B cells (NF kappaB) pathway were phosphorylated upon H2 O2 treatment, it was found that the neuronal response to oxidative stress is not executed through the nuclear translocation and activity of RelA. On the other hand, we demonstrate for the first time in neuronal cells, the association of green fluorescent protein-tagged kinase inactive PKD1 with mitochondrial membranes in vivo and the presence of PKD activity in the close vicinity of mitochondria in vitro. Our findings thus support the notion that the neuroprotective role of PKD is exerted independently from NF kappaB signaling and suggest a potential mitochondrial function for PKD in cultured neurons. PMID- 28722751 TI - Graded replacement of maize grain with molassed sugar beet pulp modulated ruminal microbial community and fermentation profile in vitro. AB - BACKGROUND: Molassed sugar beet pulp (Bp) is a viable alternative to grains in cattle nutrition for reducing human edible energy input. Yet little is known about the effects of high inclusion rates of Bp on rumen microbiota. This study used an in vitro approach and the quantitative polymerase chain reaction technique to establish the effects of a graded replacement of maize grain (MG) by Bp on the ruminal microbial community, fermentation profile and nutrient degradation. RESULTS: Six different amounts of Bp (0-400 g kg-1 ), which replaced MG in the diet, were tested using the in vitro semi-continuous rumen simulation technique. The increased inclusion of Bp resulted in greater dietary content and degradation of neutral detergent fibre (P < 0.01). Further, Bp feeding enhanced (P < 0.01) the abundance of genus Prevotella and shifted (P < 0.01) the short chain fatty acid patterns in favour of acetate and propionate and at the expense of butyrate. A total replacement of MG with Bp resulted in an increased daily methane production (P < 0.01). CONCLUSION: Results suggest positive effects of the replacement of MG by Bp especially in terms of stimulating ruminal acetate and propionate fermentation. However, high replacement rates of Bp resulted in lowered utilization of ammonia and higher ruminal methane production. (c) 2017 Society of Chemical Industry. PMID- 28722752 TI - Application of a sensory-instrumental tool to study apple texture characteristics shaped by altitude and time of harvest. AB - BACKGROUND: Texture is important in the preferences of apple consumers. Of the pre-harvest factors affecting fruit quality and especially texture, altitude and subsequent climatic conditions are crucial, determining differences in the physiological mechanisms of fruit growth, ripening stage and chemical composition, as demonstrated by several studies. This work applies a detailed sensory-instrumental protocol developed in a previous paper to investigate the impact of altitude, time of harvest and their cross-effect on sensory characteristics of apple, with a focus on texture. RESULTS: Sensory differences were found in relation to altitude, although the profile results were mainly affected by the time of harvest. Fruit from lower altitude was described as juicier, crunchier and sweeter than samples from higher altitude, which were floury, sourer and more astringent. Texture performance, soluble solids content and titratable acidity corroborated this sensory description. Moreover, anatomical data showed that fruit from lower altitude had a larger volume, a higher number of cells and a higher percentage of intercellular spaces. CONCLUSION: We demonstrated that differences between fruit from various altitudes can be perceived through human senses, and that the proposed sensory-instrumental tool can be used to describe such differences. This study brings more understanding about the impact of altitude and time of harvest on apple sensory properties. This work could support apple producers, from semi-mountainous regions (Alps, Tyrol, etc.), in advertising and valorising their products with their specific characteristics in a more efficient manner. (c) 2017 Society of Chemical Industry. PMID- 28722753 TI - Fruit quality of sweet pepper as affected by foliar Ca applications to mitigate the supply of saline water under a climate change scenario. AB - BACKGROUND: Sweet pepper fruit quality disorders have been related mainly to an unbalanced nutrient supply and non-optimal growth conditions. Increases in the atmospheric CO2 concentration ([CO2 ]) have been associated with a reduction of transpiration, which can affect calcium (Ca) uptake as it is linked closely to water uptake. We investigated whether foliar application of Ca can counterbalance the effects of saline water and elevated [CO2 ]. RESULTS: High CO2 favoured generative growth instead of vegetative growth. Foliar Ca supply did not affect the marketable yield, but reduced the total yield when combined with salinity and 400 umol mol-1 CO2 . Salinity affected negatively the total yield but this was overcome when CO2 was applied. The B and K concentrations were reduced by foliar Ca application, while Ca and Mn were increased at 400 umol mol-1 CO2 . Salinity increased the Mn, Cl, and Na concentrations, regardless of the [CO2 ], and decreased K at 800 umol mol-1 CO2 . The total protein was affected negatively only by elevated [CO2 ], and the total free amino acid concentration was reduced by all treatments. CONCLUSION: The effect of Ca application differed according to the other treatments applied. This procedure should be optimised to overcome future climate impacts on fruit quality. (c) 2017 Society of Chemical Industry. PMID- 28722754 TI - 31 P NMR Evidence for Peroxide Intermediates in Lipid Emulsion Photooxidations: Phosphine Substituent Effects in Trapping. AB - Intralipid is a lipid emulsion used in photodynamic therapy (PDT) for its light scattering and tissue-simulating properties. The purpose of this study is to determine whether or not Intralipid undergoes photooxidation, and we have carried out an Intralipid peroxide trapping study using a series of phosphines [2' dicyclohexylphosphino-2,6-dimethoxy-1,1'-biphenyl-3-sulfonate, 3 (diphenylphosphino)benzenesulfonate, triphenylphosphine-3,3',3''-trisulfonate and triphenylphosphine]. Our new findings are as follows: (1) An oxygen atom is transferred from Intralipid peroxide to the phosphine traps in the dark, after the photooxidation of Intralipid. 3-(Diphenylphosphino)benzenesulfonate is the most suitable trap in the series owing to a balance of nucleophilicity and water solubility. (2) Phosphine trapping and monitoring by 31 P NMR are effective in quantifying the peroxides in H2 O. An advantage of the technique is that peroxides are detected in H2 O; deuterated NMR solvents are not required. (3) The percent yield of the peroxides increased linearly with the increase in fluence from 45 to 180 J cm-2 based on our trapping experiments. (4) The photooxidation yields quantitated by the phosphines and 31 P NMR are supported by the direct 1 H NMR detection using deuterated NMR solvents. These data provide the first steps in the development of Intralipid peroxide quantitation after PDT using phosphine trapping and 31 P NMR spectroscopy. PMID- 28722755 TI - The potential of anti-infectives and immunomodulators as therapies for asthma and asthma exacerbations. AB - Asthma is responsible for approximately 25,000 deaths annually in Europe despite available medicines that maintain asthma control and reduce asthma exacerbations. Better treatments are urgently needed for the control of chronic asthma and reduction in asthma exacerbations, the major cause of asthma mortality. Much research spanning >20 years shows a strong association between microorganisms including pathogens in asthma onset, severity and exacerbation, yet with the exception of antibiotics, few treatments are available that specifically target the offending pathogens. Recent insights into the microbiome suggest that modulating commensal organisms within the gut or lung may also be a possible way to treat/prevent asthma. The European Academy of Allergy & Clinical Immunology Task Force on Anti-infectives in Asthma was initiated to investigate the potential of anti-infectives and immunomodulators in asthma. This review provides a concise summary of the current literature and aimed to identify and address key questions that concern the use of anti-infectives and both microbe- and host based immunomodulators and their feasibility for use in asthma. PMID- 28722756 TI - Effects of alternative cropping systems on globe artichoke qualitative traits. AB - BACKGROUND: Traditionally, globe artichoke cultivation in the Mediterranean basin is based on monoculture and on use of high amounts of nitrogen fertiliser. This raises issues regarding its compatibility with sustainable agriculture. We studied the effect of one typical conventional (CONV) and two alternative cropping systems [globe artichoke in sequence with French bean (NCV1), or in biannual rotation (NCV2) with cauliflower and with a leguminous cover crop in inter-row spaces] on yield, polyphenol and mineral content of globe artichoke heads over two consecutive growing seasons. RESULTS: NCV2 showed statistical differences in terms of fresh product yield with respect to the monoculture systems. In addition, the dihydroxycinnamic acids and dicaffeoylquinic acids of non-conventional samples were one-fold significantly higher than the conventional one. All the samples reported good mineral content, although NCV2 achieved a higher Fe content than conventional throughout the two seasons. After two and three dates of sampling, the CONV samples showed the highest levels of K content. CONCLUSION: In our study, an acceptable commercial yield and quality of 'Spinoso sardo' were achieved by shifting the common conventional agronomic management to more sustainable ones, by means of an accurate choice of cover crop species and rotations introduced in the systems. (c) 2017 Society of Chemical Industry. PMID- 28722757 TI - Discrimination of Polygoni Multiflori radix and Cynanchi Auriculati radix using ultra-high performance liquid chromatography fingerprints and chemical pattern recognition. AB - In this work, a strategy was proposed to discriminate Polygoni Multiflori Radix (PMR) and its adulterant (Cynanchi Auriculati Radix, CAR). Ultra-high performance liquid chromatography (UHPLC) fingerprints were established to analyze samples containing PMR, CAR and mixtures simultaneously. Multivariate classification methods were applied to analyze the obtained UHPLC fingerprints, including principal component analysis (PCA), partial least square discriminant analysis (PLS-DA), soft independent modeling of class analogy (SIMCA), support vector machine discriminant analysis (SVMDA) and counter-propagation artificial neural network (CP-ANN). A plot of PCA score showed that PMR and CAR samples belonged to separate clusters (PMR class and CAR class), and samples of mixtures were located near PMR or CAR classes. Analysis by PLS-DA, SVMDA and CP-ANN performed well for recognition and prediction in terms of PMR and CAR samples. Moreover, the PLS-DA method performed best in the detection of adulterated samples, even if the adulterant was about 25%. PMID- 28722758 TI - Asthma in the elderly and late-onset adult asthma. AB - Elderly asthmatics are at a higher risk for morbidity and mortality from their asthma than younger patients. There are important age-related physiologic and immunologic changes that complicate the presentation, diagnosis, and management of asthma in the aged population. Evidence suggests that elderly asthmatics are more likely to be underdiagnosed and undertreated. Additionally, elderly patients with asthma have highest rates of morbidity and mortality from their disease than younger patients. The underlying airway inflammation of asthma in this age group likely differs from younger patients and is felt to be non-type 2 mediated. While elderly patients are underrepresented in clinical trials, subgroup analysis of large clinical trials suggests they may be less likely to respond to traditional asthma therapies (ie, corticosteroids). As the armamentarium of pharmacologic asthma therapies expands, it will be critical to include elderly asthmatics in large clinical trials so that therapy may be better tailored to this at-risk and growing population. PMID- 28722759 TI - Lifetime reproductive success, selection on lifespan, and multiple sexual ornaments in male European barn swallows. AB - Natural and sexual selection arise when individual fitness varies according to focal traits. Extra-pair paternities (EPPs) can affect the intensity of selection by influencing variance in fitness among individuals. Studies of selection require that individual fitness is estimated using proxies of lifetime reproductive success (LRS). However, estimating LRS is difficult in large, open populations where EPPs cause reallocation of biological paternity. Here, we used extensive field sampling to estimate LRS in a population of barn swallows (Hirundo rustica) to estimate selection on lifespan and ornamental traits of males. We found selection on lifespan mediated both by within- and extra-pair fertilization success and selection on tail length mediated by within- but not extra-pair fertilization success. In addition, we found selection on tail white spots via extra-pair fertilization success after controlling for selection on other traits. These results were not confounded by factors that hamper studies of LRS, including nonexhaustive sampling of offspring and biased sampling of males. Hence, natural and sexual selection mediated by LRS operates on lifespan, tail length, and size of the tail white spots in barn swallows. PMID- 28722760 TI - Patients' and their family members' experiences of participation in care following an acute exacerbation in chronic obstructive pulmonary disease: A phenomenological-hermeneutic study. AB - AIM AND OBJECTIVES: To explore the experiences of patients with chronic obstructive pulmonary disease and their family members relating both to participation in care during hospitalisation for an acute exacerbation in chronic obstructive pulmonary disease, and to the subsequent day-to-day care at home. BACKGROUND: When recovering from an exacerbation, the challenges associated with an unpredictable health condition dominate everyday life for patients and can involve their family members. Proper patient and family participation in care during discharge and follow-up can help patients to improve self-management. However, knowledge of the significance of patient and family participation for recovery and subsequent everyday life is still limited. DESIGN: This study adopted a longitudinal design informed by ethnographic fieldwork principles. METHODS: Participant observations and interviews with 15 patients and 12 family members were conducted on a Danish hospital ward and twice at the participants' homes. A phenomenological-hermeneutic approach inspired by Ricoeur's theory of interpretation guided the data analysis. RESULTS: Participation in care was perceived as valuable, but could be associated with tensions and increased uncertainty. While patients mostly demonstrated a reactive approach to care, family members strived to be more proactive. In hospital, preparing for discharge included an effort to find a balance between powerlessness and influence during interactions with healthcare professionals. At home, managing further recovery and self-management were characterised by navigating between mutual pressure and consideration within the family. CONCLUSION: Family members play an important role in ensuring that patients are seen, heard and understood, but want to be acknowledged more by healthcare professionals. Appropriate interactions with healthcare professionals are crucial in order to support discharge and daily self management. RELEVANCE TO CLINICAL PRACTICE: Knowledge of the challenges that patients with chronic obstructive pulmonary disease and their family members face in participating in care activities could inform future development of family centred care approaches tailored to individual needs. PMID- 28722761 TI - A meta-ethnographic synthesis of midwives' and nurses' experiences of adverse labour and birth events. AB - INTRODUCTION: Health professionals are frequently exposed to traumatic events due to the nature of their work. While traumatic and adverse labour and birth events experienced by women are well researched, less attention has been given to midwives' and nurses' experiences of these events and the impact it has on their lives. AIMS AND OBJECTIVES: To undertake a meta-ethnographic study of midwives' and nurses' experiences of adverse labour and birth events. METHODS: Scopus, CINHAL PLUS, MEDLINE and PUBMED databases were searched using subject headings and keywords. The search was limited to papers published in peer-reviewed journals from 2004-October 2016. Quality appraisal was undertaken using the Critical Appraisal Skills Programme tool. INCLUSION CRITERIA: Papers had to be qualitative or have a substantial qualitative component. Studies were included if they primarily focused on midwives' or nurses' perspectives or experiences of complicated, traumatic or adverse labour and birth events. ANALYTIC STRATEGY: A meta-ethnographic approach was used incorporating methods of reciprocal translation guided by the work of Noblit and Hare (1988, Meta-Ethnography: Synthesizing qualitative studies (Vol. 11). Newbury Park: Sage publications). FINDINGS: Eleven qualitative studies were included in the final sample. Four major themes were (i) feeling the chaos; (ii) powerless, responsible and a failure; (iii) "It adds another scar to my soul"; and (iv) finding a way to deal with it. CONCLUSION: Midwives and nurses feel relatively unprepared when faced with a real-life labour and birth emergency event. While many of the midwives and nurses were traumatised by the experience, some were able to view their encounter as an opportunity to develop their emergency response skills. RELEVANCE TO CLINICAL PRACTICE: Witnessing and being involved in a complicated or adverse labour and birth event can be traumatic for nurses and midwives. Organisational and collegial support needs to be available to enable these health professionals to talk about their feelings and concerns. PMID- 28722763 TI - Isolated drainage of right superior vena cava into left atrium: A rare etiology of childhood central cyanosis. AB - Isolated right superior vena cava drainage into the left atrium (RSVC-LA) is an extremely rare anomaly in the absence of other cardiac or extracardiac abnormalities. The clinical and echocardiographic diagnosis is considered challenging. We report a female infant with cyanosis on crying who was diagnosed as isolated RSVC-LA using conventional and contrast echocardiography, but further confirmation was possible via multidetector CT. The surgical correction was performed with smooth postoperative recovery. In conclusion, isolated RSVC-LA must be in the differential diagnosis of cyanosis in the absence of intracardiac anomalies. Surgical correction is necessary management to guard against brain abscesses or paradoxical embolization. PMID- 28722762 TI - Rapid depuration of mercury in songbirds accelerated by feather molt. AB - Mercury (Hg) is a ubiquitous environmental contaminant that affects avian reproduction and condition, in both aquatic and terrestrial species. Because Hg binds strongly to the keratin of growing feathers, molt is an important avenue for Hg elimination. We investigated the rate of depuration of Hg from songbird blood and organs (brain, kidney, liver, muscle) as a function of molt. We exposed 2 species of captive songbirds, European starling (Sturnus vulgaris) and zebra finch (Taeniopygia guttata), to environmentally relevant dietary Hg (1.2-1.5 mg/kg wet wt) for extended periods of time and then allowed them to depurate on a Hg-free diet for 20 wk. Depuration occurred either while birds were regrowing new feathers or when there was little to no molt occurring. Both species quickly eliminated Hg from blood and reduced Hg concentrations in other tissues by more than 90% over 20 wk. The rate of depuration was more rapid than previously reported in the literature, but depuration in small-bodied songbirds has rarely been studied. Molting birds depurated Hg from their blood more rapidly than nonmolting birds. The effect of molt on Hg retention in other tissues was more difficult to resolve, because by the time we sampled organ tissue, depuration was nearly complete. Our results confirm that molting expedites depuration and raises mechanistic questions about how songbirds depurate Hg stored in their tissues. Environ Toxicol Chem 2017;36:3120-3126. (c) 2017 SETAC. PMID- 28722764 TI - 12-O-tetradecanoylphorbol-13-acetate and EZH2 inhibition: A novel approach for promoting myogenic differentiation in embryonal rhabdomyosarcoma cells. AB - Rhabdomyosarcoma (RMS) is a soft tissue sarcoma that arises from muscle precursors affecting predominately children and young adults. It can be divided into two main classes: embryonal (eRMS) and alveolar rhabodomyosarcomas (aRMS). Despite the expression of early muscle specific genes, RMS cells fail to complete myogenesis even in differentiation conditions. We previously demonstrated that Enhancer Zeste of Homolog 2 (EZH2), the catalytic subunits of PRC2 complex, contributes to inhibit muscle differentiation in eRMS and its down-regulation causes a partial recovery of myogenesis. 12-O-tetradecanoylphorbol-13-acetate (TPA) is a molecule able to induce differentiation in eRMS with a mechanism that involves the protein kinase C (PKC). In this paper we report that treatment with TPA reduces the expression of EZH2 without affecting levels of H3K27me3. The combination of TPA with GSK126, an inhibitor of the catalytic activity of EZH2, has a synergic effect on the induction of muscle differentiation in RD rhabdomyosarcoma cells, suggesting a new therapeutic combinatory approach for RMS treatment. PMID- 28722765 TI - Multivariate association analysis with somatic mutation data. AB - Somatic mutations are the driving forces for tumor development, and recent advances in cancer genome sequencing have made it feasible to evaluate the association between somatic mutations and cancer-related traits in large sample sizes. However, despite increasingly large sample sizes, it remains challenging to conduct statistical analysis for somatic mutations, because the vast majority of somatic mutations occur at very low frequencies. Furthermore, cancer is a complex disease and it is often accompanied by multiple traits that reflect various aspects of cancer; how to combine the information of these traits to identify important somatic mutations poses additional challenges. In this article, we introduce a statistical approach, named as SOMAT, for detecting somatic mutations associated with multiple cancer-related traits. Our approach provides a flexible framework for analyzing continuous, binary, or a mixture of both types of traits, and is statistically powerful and computationally efficient. In addition, we propose a data-adaptive procedure, which is grid search free, for effectively combining test statistics to enhance statistical power. We conduct an extensive study and show that the proposed approach maintains correct type I error and is more powerful than existing approaches under the scenarios considered. We also apply our approach to an exome-sequencing study of liver tumor for illustration. PMID- 28722766 TI - Comparative Analysis of the Radiology of Osteoporotic Vertebral Fractures in Women and Men: Cross-Sectional and Longitudinal Observations from the Canadian Multicentre Osteoporosis Study (CaMos). AB - We compared two methods for osteoporotic vertebral fracture (VF) assessment on lateral spine radiographs, the Genant semiquantitative (GSQ) technique and a modified algorithm-based qualitative (mABQ) approach. We evaluated 4465 women and 1771 men aged >=50 years from the Canadian Multicentre Osteoporosis Study with available X-ray images at baseline. Observer agreement was lowest for grade 1 VFs determined by GSQ. Among physician readers, agreement was greater for VFs diagnosed by mABQ (ranging from 0.62 [95% confidence interval (CI) 0.00-1.00] to 0.88 [0.76-1.00]) than by GSQ (ranging from 0.38 [0.17-0.60] to 0.69 [0.54 0.85]). GSQ VF prevalence (16.4% [95% CI 15.4-17.4]) and incidence (10.2/1000 person-years [9.2; 11.2]) were higher than with the mABQ method (prevalence 6.7% [6.1-7.4] and incidence 6.3/1000 person-years [5.5-7.1]). Women had more prevalent and incident VFs relative to men as defined by mABQ but not as defined by GSQ. Prevalent GSQ VFs were predominantly found in the mid-thoracic spine, whereas prevalent mABQ and incident VFs by both methods co-localized to the junction of the thoracic and lumbar spine. Prevalent mABQ VFs compared with GSQ VFs were more highly associated with reduced adjusted L1 to L4 bone mineral density (BMD) (-0.065 g/cm2 [-0.087 to -0.042]), femoral neck BMD (-0.051 g/cm2 [ 0.065 to -0.036]), and total hip BMD (-0.059 g/cm2 [-0.076 to -0.041]). Prevalent mABQ VFs compared with prevalent GSQ were also more highly associated with incident VF by GSQ (odds ratio [OR] = 3.3 [2.2-5.0]), incident VF by mABQ (9.0 [5.3-15.3]), and incident non-vertebral major osteoporotic fractures (1.9 [1.2 3.0]). Grade 1 mABQ VFs, but not grade 1 GSQ VFs, were associated with incident non-vertebral major osteoporotic fractures (OR = 3.0 [1.4-6.5]). We conclude that defining VF by mABQ is preferred to the use of GSQ for clinical assessments. (c) 2017 American Society for Bone and Mineral Research. PMID- 28722767 TI - Plastic deformation mechanisms in a new Ni-base single crystal superalloy at room temperature. AB - The evolution of dislocation configurations in a new Ni-base single crystal superalloy, M4706, during tensile deformation at room temperature is characterised by transmission electron microscopy. Experimental results show that contrary to previous reports, numerous isolated superlattice stacking faults and extended stacking faults are formed in the slightly deformed specimens with and without tertiary gamma' precipitates. Meanwhile, it is also found that as the plastic deformation proceeds, the dominant deformation mechanism changes from stacking fault shearing to antiphase boundary shearing. Finally, based on experimental observations, the reasons for the formation of these faults and the transition in the deformation mechanism are discussed. PMID- 28722768 TI - International summit on the nutrition of adolescent girls and young women: consensus statement. AB - An international summit focusing on the difficult challenge of providing adequate nutrition for adolescent girls and young women in low- and middle-income countries was held in Portland, Oregon in 2015. Sixty-seven delegates from 17 countries agreed on a series of recommendations that would make progress toward improving the nutritional status of girls and young women in countries where their access to nutrition is compromised. Delegate recommendations include: (1) elevate the urgency of nutrition for girls and young women to a high international priority, (2) raise the social status of girls and young women in all regions of the world, (3) identify major knowledge gaps in the biology of adolescence that could be filled by robust research efforts, (4) and improve access to nutrient-rich foods for girls and young women. Attention to these recommendations would improve the health of young women in all nations of the world. PMID- 28722770 TI - Asbestos-associated genome-wide DNA methylation changes in lung cancer. AB - Previous studies have revealed a robust association between exposure to asbestos and human lung cancer. Accumulating evidence has highlighted the role of epigenome deregulation in the mechanism of carcinogen-induced malignancies. We examined the impact of asbestos on DNA methylation. Our genome-wide studies (using Illumina HumanMethylation450K BeadChip) of lung cancer tissue and paired normal lung from 28 asbestos-exposed or non-exposed patients, mostly smokers, revealed distinctive DNA methylation changes. We identified a number of differentially methylated regions (DMR) and differentially variable, differentially methylated CpGs (DVMC), with individual CpGs further validated by pyrosequencing in an independent series of 91 non-small cell lung cancer and paired normal lung. We discovered and validated BEND4, ZSCAN31 and GPR135 as significantly hypermethylated in lung cancer. DMRs in genes such as RARB (FDR 1.1 * 10-19 , mean change in beta [Delta] -0.09), GPR135 (FDR 1.87 * 10-8 , mean Delta -0.09) and TPO (FDR 8.58 * 10-5 , mean Delta -0.11), and DVMCs in NPTN, NRG2, GLT25D2 and TRPC3 (all with p <0.05, t-test) were significantly associated with asbestos exposure status in exposed versus non-exposed lung tumors. Hypomethylation was characteristic to DVMCs in lung cancer tissue from asbestos exposed subjects. When DVMCs related to asbestos or smoking were analyzed, 96% of the elements were unique to either of the exposures, consistent with the concept that the methylation changes in tumors may be specific for risk factors. In conclusion, we identified novel DNA methylation changes associated with lung tumors and asbestos exposure, suggesting that changes may be present in causal pathway from asbestos exposure to lung cancer. PMID- 28722771 TI - Navigating and negotiating information and support: Experiences of first-time mothers. AB - AIMS AND OBJECTIVES: To examine how first-time mothers in Nova Scotia identified and prioritised their own postpartum needs and where they went for information and support, inclusive of informal or formal programmes and services, social media, family and friends. BACKGROUND: The early postpartum period is an exciting, yet stressful life experience for first-time mothers. Mothers have often turned to families, friends and healthcare professionals for support and information; however, these social networks look differently today due to changes in institutional policies and postpartum healthcare practices, as well as the emergence of online resources and networks. There is currently limited understanding of how online resources have shifted mothers social networking practices and the degree to which programmes and resources are currently meeting the needs of mothers and families. METHODS: Data were collected through focus group interviews in rural and urban Nova Scotia communities (n = 19) and online electronic interviews (n = 18). Data were analysed using feminist poststructuralism and discourse analysis to understand issues of inclusion and health equity for mothers and how relations of power were negotiated by first time mothers in their search for support and information. RESULTS: Most participants were savvy as they critiqued, compared, navigated and negotiated advice and information from various sources, including health professionals, family, friends and online forums. However, they unanimously wanted face-to-face support with other mothers and healthcare professionals. Participants enacted their agency to critically analyse information and support to ensure it matched their own beliefs, values and practices. CONCLUSIONS: It is important to understand first-time mothers' practices and need for face-to-face support, as well as a need for further research with more diverse or marginalised demographics of mothers. PMID- 28722769 TI - Promoter IV-BDNF deficiency disturbs cholinergic gene expression of CHRNA5, CHRM2, and CHRM5: effects of drug and environmental treatments. AB - Brain-derived neurotrophic factor (BDNF) promotes maturation of cholinergic neurons. However, how activity-dependent BDNF expression affects specific cholinergic gene expression remains unclear. This study addressed this question by determining mRNA levels of 22 acetylcholine receptor subunits, the choline transporter (CHT), and the choline acetyltransferase (ChAT) in mice deficient in activity-dependent BDNF via promoter IV (KIV) and control wild-type mice. Quantitative RT-PCR revealed significant reductions in nicotinic acetylcholine receptor alpha 5 (CHRNA5) in the frontal cortex and hippocampus and M5 muscarinic acetylcholine receptor (CHRM5) in the hippocampus, but significant increases in M2 muscarinic acetylcholine receptor (CHRM2) in the frontal cortex of KIV mice compared to wild-type mice. Three-week treatments with fluoxetine, phenelzine, duloxetine, imipramine, or an enriched environment treatment (EET) did not affect the altered expression of these genes except that EET increased CHRNA5 levels only in KIV frontal cortex. EET also increased levels of CHRNA7, CHT, and ChAT, again only in the KIV frontal cortex. The imipramine treatment was most prominent among the four antidepressants; it up-regulated hippocampal CHRM2 and frontal cortex CHRM5 in both genotypes, and frontal cortex CHRNA7 only in KIV mice. To the best of our knowledge, this is the first evidence that BDNF deficiency disturbs expression of CHRNA5, CHRM2, and CHRM5. Our results suggest that promoter IV-BDNF deficiency - which occurs under chronic stress - causes cholinergic dysfunctions via these receptors. EET is effective on CHRNA5, while its compensatory induction of other cholinergic genes or drugs targeting CHRNA5, CHRM2, and CHRM5 may become an alternative strategy to reverse these BDNF-linked cholinergic dysfunctions. PMID- 28722772 TI - Understanding leisure-time physical activity: Voices of people with MS who have moderate-to-severe disability and their family caregivers. AB - BACKGROUND: Physical activity (PA) is beneficial for all people, yet people affected by multiple sclerosis (MS) find regular PA challenging. These people may include individuals with the disease who have moderate-to-severe disability and their family caregivers. For researchers and clinicians to effectively promote PA among caregiver/care-recipient dyads with moderate-to-severe MS, a comprehensive understanding of the shared PA experiences of these dyads would be beneficial. OBJECTIVE: We explored shared experiences of caregiver/care-recipient dyads affected by moderate-to-severe MS about PA and directions for intervention. METHODS: Six focus groups with 23 people with moderate-to-severe MS and 12 family caregivers were conducted. Data were analysed using a constant comparative approach. RESULTS: Three major themes emerged as follows: (i) PA is a continuum, (ii) cycle of disengagement and (iii) cycle of adjustment. The first theme captured the dyads understanding that PA falls along a continuum ranging from highly structured to unstructured activities. Cycle of disengagement captured the experiences of dyads engaging in little or no PA. These dyads perceived internal and external issues as drivers of the cycle of disengagement, while availability of supportive programmes and services or people helped the dyads to break out of the cycle. When the cycle of disengagement was broken, the dyads described moving towards the cycle of adjustment, where they were able to learn skills and take action to incorporate PA into daily routines. CONCLUSION: This research highlights the need to adopt an integrative approach that acknowledges the caregiver/care-recipient dyad with moderate-to-severe MS as a focus for PA intervention. PMID- 28722773 TI - RadH: A Versatile Halogenase for Integration into Synthetic Pathways. AB - Flavin-dependent halogenases are useful enzymes for providing halogenated molecules with improved biological activity, or intermediates for synthetic derivatization. We demonstrate how the fungal halogenase RadH can be used to regioselectively halogenate a range of bioactive aromatic scaffolds. Site directed mutagenesis of RadH was used to identify catalytic residues and provide insight into the mechanism of fungal halogenases. A high-throughput fluorescence screen was also developed, which enabled a RadH mutant to be evolved with improved properties. Finally we demonstrate how biosynthetic genes from fungi, bacteria, and plants can be combined to encode a new pathway to generate a novel chlorinated coumarin "non-natural" product in E. coli. PMID- 28722774 TI - "Promoting continuity of care"-Specialist nurses' role experiences in gynaecological oncology: A qualitative study. AB - AIMS AND OBJECTIVES: To investigate the experiences of specialist nurses in Switzerland concerning their role of caring for women with gynaecological cancer. BACKGROUND: Women with gynaecological cancer often face complex situations, which require an integrative and quality-assured approach by the healthcare system. Specialist nurses can play an important role in supporting these patients. However, in countries where the role of specialist nurses is at a developmental stage, their role lacks clarity. DESIGN: A qualitative descriptive design was chosen to gain insights into experiences of specialist nurses who care for women with gynaecological cancer. METHODS: We conducted three focus groups with 12 specialist nurses to access their experiences with regard to their role. Thematic qualitative text analysis was used to interpret the results. RESULTS: Divided into six main themes, the study results describe specialist nurses' (1) current and (2) aspired role. (A) Counselling, (B) guidance, (C) key contact person and (D) team support are relevant themes in their current role. The themes (E) provision of resources and (F) extended knowledge are relevant to their aspired role. Within their current and aspired roles, the specialist nurses' scope of practice is defined as "promoting continuity of care." CONCLUSIONS: The results indicate aspects of specialist nurses' current and aspired roles. Detailed role descriptions and legal requirements are necessary to further support nurses towards an extended and specialised practice. In the context of gynaecological cancer survivors, services should be developed, where specialist nurses can play an important role in providing continuous care. RELEVANCE TO CLINICAL PRACTICE: To support implementation of specialist nursing in clinical practice, resources have to be mobilised and role descriptions should be provided. By creating an appropriate framework, the specialist nurse can turn into an important support for women with gynaecological cancer, in addition to current healthcare services. PMID- 28722775 TI - Depression recognition and capacity for self-report among ethnically diverse nursing homes residents: Evidence of disparities in screening. AB - AIMS AND OBJECTIVES: To examine agreement between Minimum Data Set clinician ratings and researcher assessments of depression among ethnically diverse nursing home residents using the 9-item Patient Health Questionnaire. BACKGROUND: Although depression is common among nursing homes residents, its recognition remains a challenge. DESIGN: Observational baseline data from a longitudinal intervention study. METHODS: Sample of 155 residents from 12 long-term care units in one US facility; 50 were interviewed in Spanish. Convergence between clinician and researcher ratings was examined for (i) self-report capacity, (ii) suicidal ideation, (iii) at least moderate depression, (iv) Patient Health Questionnaire severity scores. Experiences by clinical raters using the depression assessment were analysed. The intraclass correlation coefficient was used to examine concordance and Cohen's kappa to examine agreement between clinicians and researchers. RESULTS: Moderate agreement (kappa = 0.52) was observed in determination of capacity and poor to fair agreement in reporting suicidal ideation (kappa = 0.10-0.37) across time intervals. Poor agreement was observed in classification of at least moderate depression (kappa = -0.02 to 0.24), lower than the maximum kappa obtainable (0.58-0.85). Eight assessors indicated problems assessing Spanish-speaking residents. Among Spanish speakers, researchers identified 16% with Patient Health Questionnaire scores of 10 or greater, and 14% with thoughts of self-harm whilst clinicians identified 6% and 0%, respectively. CONCLUSION: This study advances the field of depression recognition in long-term care by identification of possible challenges in assessing Spanish speakers. RELEVANCE TO CLINICAL PRACTICE: Use of the Patient Health Questionnaire requires further investigation, particularly among non-English speakers. Depression screening for ethnically diverse nursing home residents is required, as underreporting of depression and suicidal ideation among Spanish speakers may result in lack of depression recognition and referral for evaluation and treatment. Training in depression recognition is imperative to improve the recognition, evaluation and treatment of depression in older people living in nursing homes. PMID- 28722776 TI - Esterified Trehalose Analogues Protect Mammalian Cells from Heat Shock. AB - Trehalose is a disaccharide produced by many organisms to better enable them to survive environmental stresses, including heat, cold, desiccation, and reactive oxygen species. Mammalian cells do not naturally biosynthesize trehalose; however, when introduced into mammalian cells, trehalose provides protection from damage associated with freezing and drying. One of the major difficulties in using trehalose as a cellular protectant for mammalian cells is the delivery of this disaccharide into the intracellular environment; mammalian cell membranes are impermeable to the hydrophilic sugar trehalose. A panel of cell-permeable trehalose analogues, in which the hydrophilic hydroxyl groups of trehalose are masked as esters, have been synthesized and the ability of these analogues to load trehalose into mammalian cells has been evaluated. Two of these analogues deliver millimolar concentrations of free trehalose into a variety of mammalian cells. Critically, Jurkat cells incubated with these analogues show improved survival after heat shock, relative to untreated Jurkat cells. The method reported herein thus paves the way for the use of esterified analogues of trehalose as a facile means to deliver high concentrations of trehalose into mammalian cells for use as a cellular protectant. PMID- 28722777 TI - Nurses' and nurse assistants' beliefs, attitudes and actions related to role and function in an inpatient stroke rehabilitation unit-A qualitative study. AB - AIMS AND OBJECTIVES: To explore nurses' and nurse assistants' beliefs, attitudes and actions related to their function in an inpatient stroke rehabilitation unit. BACKGROUND: Several attempts have been made to describe nurses' roles and functions in inpatient neurorehabilitation. However, current understandings of the contributions that nurses and nurse assistants make to neurorehabilitation remain sparse. DESIGN: Descriptive, interpretive qualitative study. METHODS: Participant observations were conducted during 1 month in a stroke rehabilitation unit at a university hospital in the Capital Region of Denmark. The observations were audiorecorded and field notes were taken on the spot. Semistructured interviews with nurses (N = 8) and nurse assistants (N = 6) were performed. The audiorecorded observations, field notes and interviews were transcribed for inductive and deductive content analysis. RESULTS: Three main categories with underlying subcategories were identified: (i) the importance of professionalism, (ii) striving for visibility, (iii) the importance of structure. CONCLUSION: This study contributes to present understandings of nurses' and nurse assistants' roles and functions in inpatient stroke rehabilitation. We obtained insights into nursing staff's beliefs and attitudes about rehabilitation-as well as their own role and function-and furthermore how the latter affects their actions in daily practice. RELEVANCE TO CLINICAL PRACTICE: The nursing role and function are still not clearly defined. Further education is needed to strengthen the contribution of nursing staff to patients' rehabilitation. Furthermore, focus on developing a professional language and a framework that supports continuity within daily care and rehabilitation is needed. PMID- 28722779 TI - Serial diaphragm ultrasound studies in neuralgic amyotrophy with bilateral phrenic neuropathies. PMID- 28722778 TI - Breast cancer stem cells are involved in Trastuzumab resistance through the HER2 modulation in 3D culture. AB - Breast cancer human cells culture as spheroids develop autophagy and apoptosis, which promotes Trastuzumab resistance in HER2 overexpressing cells. Our aim was to study the association of the hostile environment developed in 3D with the breast cancer stem cells population and the HER2 modulation. Human mammary adenocarcinoma cell lines were cultured as spheroids using the hanging drop method. We generated hypoxia conditions by using a hypoxic chamber and CoCl2 treatment. Breast cancer stem cells were measured with mammosphere assays, the analysis of CD44 + CD24low population by flow cytometry and the pluripotent gene expression by RT-qPCR. HER2 expression was evaluated by flow cytometry and Western blot. MTS assays were conducted to study cell viability. Hostil environment developed in spheroids, defined by hypoxia and autophagy, modulated the response to Trastuzumab. In HER2+ cells with acquired resistance, we observed an increase in the breast cancer stem cell population. In BT474 spheroids, Trastuzumab induced the acquisition of resistance, along with an increase in breast cancer stem cells. Also, in 3D culture conditions we determined a modulation in the HER2 expression. Moreover, breast cancer stem cells showed enhanced HER2 expression. Finally, cells without HER2 gene amplification cultured as spheroids were sensitive to Trastuzumab, diminishing HER2 expression and cancer stem cells. Our findings show that 3D architecture is able to modulate breast cancer stem cell population and HER2 distribution, modifying the cell response to Trastuzumab. PMID- 28722780 TI - Add-on effects of fluvastatin in simeprevir/pegylated-interferon/ribavirin combination therapy for patients with genotype 1 hepatitis C virus infection: A randomized controlled study. AB - BACKGROUND: The Japan Society of Hepatology guidelines indicate that hepatitis C virus (HCV) protease inhibitor combination therapy with simeprevir (SMV), pegylated-interferon (Peg-IFN), and ribavirin (RBV) is a therapeutic option for patients who fail to respond to a direct direct-acting antiviral-containing regimen. However, treatment outcomes have room for improvement. Fluvastatin (FLV) add-on treatment in Peg-IFN and RBV combination therapy for HCV-infected patients significantly improved the sustained virologic response (SVR), but the add-on effect of FLV on SMV combination therapy is not well understood. METHODS: This was a prospective, randomized, multicenter study in which a total of 61 HCV genotype 1b-infected patients were recruited and 60 eligible patients were randomly allocated to two groups that received 12 weeks of SMV/Peg-IFN/RBV followed by 12 weeks of Peg-IFN/RBV with or without 24 weeks of FLV. The SVR rate and adverse events were compared between the two groups. RESULTS: Thirty-one patients were allocated to the FLV add-on group and 29 patients were allocated to the control group. Baseline clinical factors, including median age, baseline platelet count, alanine aminotransferase level, HCV RNA titer, Fibrosis-4 index, and rate of IL28B minor genotype, were all similar between the two groups. The rapid virologic response, end-of-treatment response rates, SVR rates at 24 weeks after treatment, and safety profiles were also similar between the two groups. CONCLUSIONS: This prospective, randomized, multicenter study indicated that FLV had no add-on effect when given with SMV/Peg-IFN/RBV combination therapy for genotype 1b HCV-infected patients. PMID- 28722781 TI - Contribution of pyrethroids in large urban rivers to sediment toxicity assessed with benthic invertebrates Chironomus dilutus: A case study in South China. AB - The importance of pyrethroids as potential stressors to benthic organisms has gradually become evident in urban creeks; however, the occurrence and toxicity of sediment-associated pyrethroids are rarely studied in large rivers. In this context, 10 sediments from a large urban river (Guangzhou reach of the Pearl River in China) were assessed for pyrethroid occurrence and sediment toxicity to the benthic invertebrate Chironomus dilutus. One half of the sediments exhibited lethality to C. dilutus in a 10-d exposure and all surviving midges showed significant change of enzymatic activity. Moreover, mortality occurred during a 20-d exposure for all the sediments, in accordance with the high hazard quotients to benthic species estimated from pyrethroid residues in sediment. Pyrethroids were detectable in all sediments with the concentrations ranging from 2.43 to 61.2 ng/g dry weight, and permethrin and cypermethrin dominated pyrethroid composition. Acute toxic units for pyrethroids ranged from 0.03 to 0.56 (cypermethrin accounted for 13-81%) and showed a direct relationship with sediment mortality among the midges. This is consistent with the studies on small creeks in Guangzhou in which sediment-bound cypermethrin was found as a main stressor to benthic invertebrates. Comparatively, sediment toxicity and pyrethroid residues in large rivers were significantly lower than those in nearby creeks (urban tributaries). The difference may be partially explained by differing flow rates and water-carrying capacity among waterbodies at different scales; further validation is required. Overall, extensive use of pyrethroids has caused a threat to benthic species not only in small creeks but also in large rivers. Environ Toxicol Chem 2017;36:3367-3375. (c) 2017 SETAC. PMID- 28722782 TI - Development of blueberry liquor: influence of distillate, sweetener and fruit quantity. AB - BACKGROUND: In this work different formulations of blueberry liquor were tested and characterised based on their physico-chemical and sensory characteristics. RESULTS: Three factors were evaluated: the distillate used to produce the liquor (wine spirit or grape marc spirit); the sweetener (white sugar or honey) and the fruit quantity (two doses). For each liquor, pH, total acidity, dry soluble solids content, dry extract, alcoholic strength, reducing sugars, colour intensity, methanol content, acetaldehyde and fusel alcohols were determined. Sensory tests were carried out with a trained panel. CONCLUSION: The three factors studied significantly influenced the physico-chemical features of the liquors, being the quantity of fruit the most discriminating factor, except for the volatile compounds which were mainly influenced by the distillate. As regards the sensory analysis, it was found that the most appreciated liquor was that prepared with wine spirit, sugar and a lower dose of blueberry, and the less appreciated formulation was the one made with grape marc spirit, honey and a lower quantity of blueberry. (c) 2017 Society of Chemical Industry. PMID- 28722783 TI - The association of the placental MTHFR 3'-UTR polymorphisms, promoter methylation, and MTHFR expression with preeclampsia. AB - Preeclampsia (PE) is a pregnancy specific complication arises in presence of the placenta and disappears immediately after delivery. Therefore, the aim of the present study was to investigate the possible effects of the placental 3'-UTR rs1537514C>G and rs4846049C>A polymorphisms and DNA methylation of the MTHFR gene on the MTHFR mRNA expression. The placenta of 74 PE pregnant women and 75 normotensive pregnant women were collected after delivery. The methylation status of the MTHFR promoter was assessed with Methylation Specific PCR (MSP). The rs1537514C>G and rs4846049C>A polymorphisms were genotyped using PCR-RFLP method. The mRNA expression levels were measured by Quantitative Real Time PCR. The results showed the lower MTHFR mRNA expression in the placenta of PE women. There was an association between hypermethylation and lower MTHFR mRNA expression in PE women and entire women but not normotensive pregnant women. The frequency of MTHFR rs1537514CG genotype was significantly lower in PE women; however, there was no association between MTHFR rs4846049C>A polymorphism and PE. The combination effects of MTHFR CG/AC genotypes and G-A haplotype of MTHFR rs1537514/rs4846049 polymorphisms were associated with lower risk of PE. The MTHFR rs1537514G (4869G) allele was associated with higher MTHFR mRNA expression in both groups. However, there was no relation between MTHFR rs4846049C>A polymorphism and MTHFR mRNA expression. Our findings showed lower MTHFR mRNA expression in PE women. The MTHFR rs1537514C>G polymorphism was associated with lower PE risk and MTHFR mRNA expression. Lower expression of MTHFR mRNA was observed in the women with the hypermethylated promoter. PMID- 28722784 TI - The universal, collaborative and dynamic model of specialist and advanced nursing and midwifery practice: A way forward? AB - AIMS AND OBJECTIVES: To inform and guide the development of a future model of specialist and advanced nursing and midwifery practice. BACKGROUND: There is a sizable body of empirical literature supporting the unique contributions of specialist and advanced practice roles to health care. However, there is very little international evidence to inform the integration of a future model for advanced or specialist practice in the Irish healthcare system. DESIGN: A qualitative study was conducted to initiate this important area of inquiry. METHODS: Purposive sampling was used to generate a sample of informants (n = 15) for the interviews. Nurses and midwives working in specialist and advanced practice and participants from other areas such as legislative, regulatory, policy, medicine and education were included in the sampling frame. RESULTS: Arguments for a new model of specialist and advanced practice were voiced. A number of participants proposed that flexibility within specialist and advanced practitioner career pathways was essential. Otherwise, there existed the possibility of being directed into specialised "silos," precluding movement to another area of integrated practice. Future specialist and advanced practice education programmes need to include topics such as the development of emotional and political intelligence. CONCLUSION: The contribution of specialist and advanced practice roles to the health service includes providing rapid access to care, seamless patient flow across services, early discharge and lead coordinator of the patient's care trajectory. There was a recommendation of moving towards a universal model to cultivate specialist and advanced nurse and midwife practitioners. RELEVANCE TO CLINICAL PRACTICE: The model design has Universal application in a range of contexts "U." It is Collaborative in its inclusivity of all key stakeholders "C." The model is Dynamic pertinent to accommodating movement of nurses and midwives across health continua rather than plateauing in very specialised "silos" "D." PMID- 28722785 TI - Direct-acting antivirals and recurrence of hepatocellular carcinoma. PMID- 28722786 TI - Oncogenic transformation of lung cells results in distinct exosome protein profile similar to the cell of origin. AB - Lung cancer is responsible for the highest rate of cancer mortality worldwide. Lung cancer patients are often ineligible for tumor biopsies due to comorbidities. As a result, patients may not have the most effective treatment regimens administered. Patients with mutations in the epidermal growth factor receptor (EGFR) have improved survival in response to EGFR tyrosine kinase inhibitors. A noninvasive method of determining EGFR mutations in patients would have promising clinical applications. Exosomes have the potential to be noninvasive novel diagnostic markers in cancer. Using MS analysis, we identify differentially abundant cell and exosome proteins induced by mutations in p53 and EGFR in lung cells. Importantly, mutations in p53 and EGFR alter cell and exosome protein content compared to an isogenic normal lung epithelial cell. For some proteins, mutation had similar effects in the cell of origin and exosomes. Differences between the cells of origin and exosomes were also apparent, which may reflect specific packaging of proteins into exosomes. These findings that mutations alter protein abundance in exosomes suggest that analysis of exosomes may be beneficial in the diagnosis of oncogenic mutations. PMID- 28722787 TI - Synthesis and Direct Sintering of Nanosized (MIV ,MIII )O2-x Hydrated Oxides as Electrolyte Ceramics. AB - Highly reactive and nanosized Th1-x Yx O2-x/2 or Ce0.8 Ln0.2 O1.9 mixed oxides were prepared through the initial precipitation of hydroxide precursors which were further dried under vacuum. Whatever the chemical system investigated, the characterization of the powdered samples evidenced a rapid aging process leading to hydrated oxides. The thermal behavior of these samples was further investigated and first showed a two-step dehydration process, with the successive departure of adsorbed and constitutive water, both yielding a drastic drop of the powders' reactivity (i.e. decrease of the specific surface area). Sintering experiments were then undertaken by starting directly from raw powders and revealed very rapid densification kinetics. Highly densified pellets (above 95 %TD) with a fine grain microstructure were obtained after only 1 hour of heat treatment at 1600 degrees C. This easy and versatile process of precipitation, that can be followed by direct densification of the powders, then appears as a promising option for the elaboration of homogenous ceramic electrolytes. PMID- 28722788 TI - Molecular characterization of haemophilia B patients in southern Brazil. PMID- 28722789 TI - Tailoring of the Tell-us Card communication tool for nurses to increase patient participation using Intervention Mapping. AB - AIMS AND OBJECTIVES: To describe the tailoring of the Tell-us Card intervention for enhanced patient participation to the Dutch hospital setting using Intervention Mapping as a systematic approach. BACKGROUND: Even though patient participation is essential in any patient-to-nurse encounter, care plans often fail to take patients' preferences into account. The Tell-us Card intervention seems promising, but needs to be tailored and tested before implementation in a different setting or on large scale. DESIGN: Description of the Intervention Mapping framework to systematically tailor the Tell-us Card intervention to the Dutch hospital setting. METHODS: Intervention Mapping consists of: (i) identification of the problem through needs assessment and determination of fit, based on patients and nurses interviews and focus group interviews; (ii) developing a logic model of change and matrices, based on literature and interviews; (iii) selection of theory-based methods and practical applications; (iv) producing programme components and piloting; (v) planning for adoption, implementation and sustainability; and (vi) preparing for programme evaluation. RESULTS: Knowledge, attitude, outcome expectations, self-efficacy and skills were identified as the main determinants influencing the use of the Tell-us Card. Linking identified determinants and performance objectives with behaviour change techniques from the literature resulted in a well-defined and tailored intervention and evaluation plan. CONCLUSIONS: The Tell-us Card intervention was adapted to fit the Dutch hospital setting and prepared for evaluation. The Medical Research Council framework was followed, and the Intervention Mapping approach was used to prepare a pilot study to confirm feasibility and relevant outcomes. RELEVANCE TO CLINICAL PRACTICE: This article shows how Intervention Mapping is applied within the Medical Research Council framework to adapt the Tell-us Card intervention, which could serve as a guide for the tailoring of similar interventions. PMID- 28722790 TI - Switching to a rilpivirine/emtricitabine/tenofovir single-tablet regimen in RNA suppressed patients infected with human immunodeficiency virus 1: Effectiveness, safety and costs at 96 weeks. AB - OBJECTIVES: This study evaluates the effectiveness, safety and costs of switching to a rilpivirine/emtricitabine/tenofovir disoproxil fumarate (RPV/FTC/TDF) regimen in treatment-experienced HIV-1-infected patients with sustained virological suppression. METHODS: Observational, prospective study. Study population included all treatment-experienced patients with sustained virological suppression who switched to RPV/FTC/TDF during 2013 in a tertiary hospital. Patients were followed until they completed 96 weeks of treatment. The effectiveness end-point was defined as the proportion of patients who maintained virological suppression at week 96 by intention-to-treat analysis (discontinuation=failure). The safety of RPV/FTC/TDF (incidence of adverse events leading to discontinuation and laboratory abnormalities) and adherence to this regimen were evaluated, and the cost of switching was analysed. RESULTS: One hundred forty-six patients were included. At week 96, 71.9% of patients remained virologically suppressed; 6.8% experienced virological failure. During follow-up, 25.3% of patients discontinued RPV/FTC/TDF (14.4% because of adverse events, mainly renal impairment). Throughout the 96 weeks, there were significant decreases in total cholesterol (TC) (14.0 mg/dL, P<.001), TC/HDL cholesterol ratio (0.4 mg/dL, P=.019) and triglycerides (42.0 mg/dL, P<.001). A slight decrease in glomerular filtration rate was observed (4.3 mL/min/1.73 m2 , P<.001). Switching to RPV/FTC/TDF improved adherence in the subgroup of patients whose previous treatment was based on a twice-daily schedule, although differences did not reach statistical significance. Switching to RPV/FTC/TDF reduced the annual per-patient antiretroviral cost by ?1744 (P<.001). CONCLUSIONS: In virologically suppressed patients, the switch to a RPV/FTC/TDF regimen was associated with a mild but maintained improvement in lipid parameters and a significant reduction in costs. However, the relatively high rates of virological failure and treatment discontinuation because of adverse events make this combination a less favourable choice over other regimens currently available. PMID- 28722792 TI - Largest brain cancer study offers clues to inherited risk. PMID- 28722793 TI - First person: Rainer Storb, MD: The pioneer in bone marrow transplantation continues to push the innovation envelope while inspiring a new generation of researchers. PMID- 28722791 TI - Treatment evaluation using lung sound analysis in asthmatic children. AB - BACKGROUND AND OBJECTIVE: Non-invasive assessment of treatment and prediction of attacks in asthmatic children do not yet exist. Lung sound analysis can non invasively evaluate airway obstruction. We used a recently developed technology for analysing lung sounds using ic700 (index of the chest wall at 700 Hz, sound intensity at 700 Hz) to evaluate response to inhaled corticosteroid (ICS) in asthmatic children. METHOD: Seventy asthmatic children, including infants, underwent lung sound recording in the asymptomatic state prior to and 1, 2, 4, 6 and 8 weeks after ICS treatment, and asthma control was assessed at 10 weeks. The ic700 scores at 4, 6 and 8 weeks were compared with the presence of attack during the following 2 weeks. Subjects were divided into uncontrolled and well controlled groups. RESULTS: The mean ic700 scores of all subjects significantly reduced after 8 weeks of treatment. The mean scores of the uncontrolled group were significantly higher than those of the well-controlled group at 4, 6 and 8 weeks after starting treatment. The ic700 cut-off value for predicting asthma attacks within 2 weeks following the evaluation was set at 0.0. After 6 weeks of treatment, the area under the curve was 0.92 +/- 0.04; the sensitivity, specificity and positive and negative predictive values were 83%, 88% and 88% and 84%, respectively. Similar results were observed at 4 and 8 weeks. CONCLUSION: The ic700 score is useful in assessing the effects of ICS treatment, predicting attack symptoms and identifying asymptomatic asthmatic children at a high risk for asthma attack. PMID- 28722794 TI - Sulfide-producing bacteria linked to higher colon cancer risk in African Americans. PMID- 28722795 TI - Influence of renal function on anticoagulation control in patients with non valvular atrial fibrillation taking vitamin K antagonists. AB - BACKGROUND AND PURPOSE: Chronic kidney disease (CKD) has been related to poor anticoagulation control and an increased risk of bleeding. This study aims to evaluate the association between impaired renal function (eGFR <60 mL/min/1.73 m2 ) and anticoagulation control in patients with non-valvular atrial fibrillation (AF) on vitamin K antagonists (VKA) therapy. We also assessed whether the predictive value of the SAMe-TT2 R2 score prevailed for subgroups both with and without CKD. METHODS: This is an ancillary analysis of 1381 patients from the PAULA study, which was a cross-sectional, retrospective and nationwide multicenter study. RESULTS: A total of 370 patients had eGFR <60 mL/min/1.73 m2 . Anticoagulation control levels progressively worsened across each stage of CKD. Multiple linear regression analysis showed CKD as an independent predictor of time in therapeutic range (TTR). In the subgroup of patients with preserved renal function, female sex, diet affecting INR, polypharmacy and amiodarone were associated with poorer TTR. The SAMe-TT2 R2 score had a significant but modest predictive value for TTR<65% (AUC, area under the curve 0.558, P = .002). In the subgroup of patients with CKD, the SAMe-TT2 R2 (>2 points) showed no significant predictive capacity for TTR (AUC 0.528, P = .354). The average TTR was similar for both sexes (P = .255), but with a higher percentage of males subjects with TTR >=65% (P = .013). CONCLUSION: Chronic kidney disease is associated with poor anticoagulation control in patients with non-valvular AF taking VKA. The SAMe-TT2 R2 score was not predictive of poor TTR in the subgroup with CKD, although a modest predictive value for poor TTR was found in those without CKD. PMID- 28722796 TI - Extended Catalytic Scope of a Well-Known Enzyme: Asymmetric Reduction of Iminium Substrates by Glucose Dehydrogenase. AB - NADP(H)-dependent imine reductases (IREDs) are of interest in biocatalytic research due to their ability to generate chiral amines from imine/iminium substrates. In reaction protocols involving IREDs, glucose dehydrogenase (GDH) is generally used to regenerate the expensive cofactor NADPH by oxidation of d glucose to gluconolactone. We have characterized different IREDs with regard to reduction of a set of bicyclic iminium compounds and have utilized 1 H NMR and GC analyses to determine degree of substrate conversion and product enantiomeric excess (ee). All IREDs reduced the tested iminium compounds to the corresponding chiral amines. Blank experiments without IREDs also showed substrate conversion, however, thus suggesting an iminium reductase activity of GDH. This unexpected observation was confirmed by additional experiments with GDHs of different origin. The reduction of C=N bonds with good levels of conversion (>50 %) and excellent enantioselectivity (up to >99 % ee) by GDH represents a promiscuous catalytic activity of this enzyme. PMID- 28722797 TI - Highly selective enrichment of phosphopeptides by on-chip indium oxide functionalized magnetic nanoparticles coupled with MALDI-TOF MS. AB - Selective and efficient preconcentration is indispensable for low concentration of phosphopeptides in phosphorylated protein-related samples prior to MS-based analysis. Herein, an on-chip system coupled magnetic SPE with MALDI-TOF MS was designed. A metal oxide affinity chromatography material, indium oxide, was coated on the surface of Fe3 O4 magnetic nanoparticles to prepare the adsorbent, spatially confined with an applied magnetic field. The adsorbent exhibited high selectivity for phosphopeptides in tryptic digests of the mixture of beta-casein and BSA (1:1000) and the mixture of beta-casein, BSA, and ovalbumin (1:100:100). Thanking to the enrichment ability and specificity for phosphopeptides with the adsorbent, the on-chip magnetic SPE-MALDI-TOF MS approach showed high sensitivity with a low detection limit of 4 fmol. In addition, the developed approach was used to analyze phosphopetides in non-fat milk digests and human serum successfully. PMID- 28722798 TI - ANGPTL8 (betatrophin) role in diabetes and metabolic diseases. AB - Diabetes is a major disease worldwide that is reaching epidemic levels. Its increased prevalence as well as its association with a high number of complications such as cardiovascular diseases, nephropathy, and retinopathy makes it an important disease for investigation. ANGPTL8 is a recently identified hormone that has been associated with two functionally important processes in the development of type 2 diabetes, insulin resistance as well as lipid metabolism. Initial work has shown that ANGPTL8 was expressed in liver, white adipose, and brown adipose tissues. ANGPTL8 regulates the activity of lipoprotein lipase, which is a key enzyme in lipoprotein lipolysis pathway through its direct interaction with ANGPTL3. It has been also reported that it regulates the replication of beta-cells in response to insulin resistance. As a result, many recent studies have focused on the association of ANGPTL8 with diabetes and obesity as well as its association with various metabolic markers in order to better understand its physiological role in glucose homeostasis and lipid metabolism. In this review, we will highlight some of the key clinical findings, mainly from human studies, that investigated the role of ANGPTL8 in metabolic diseases such as diabetes, obesity, and the metabolic syndrome. PMID- 28722799 TI - County-level Variation in Infant Mortality Reporting at Early Previable Gestational Ages. AB - BACKGROUND: Infant mortality rate (IMR), or number of infant deaths per 1000 livebirths, varies widely across the US While fetal deaths are not included in this measure, reported infant deaths do include those delivered at previable gestations, or <=20 weeks gestation. Variation in reporting of these events may have a significant impact on IMR estimates. METHODS: This retrospective analysis used US National Center for Health Statistics 2007-2013 data from 2391 US counties. Counties were categorised by US region, demographic characteristics, and state-level fetal death reporting requirements. County percentage of fetal deaths among all 17-20 week fetal and infant deaths was evaluated using multivariable linear regression. County-level characteristics were then included in multivariable linear regression to determine the associated change in county IMR. RESULTS: County percentage of deaths at 17-20 weeks reported as fetal ranged from 0% to 100% (mean 63.7%). Every 1 point increase in this percentage was associated with a 0.02 point decrease in county IMR (95% confidence interval (CI) 0.02, 0.03). When county IMRs were recalculated holding the percentage of fetal vs. infant deaths at 17-20 weeks constant at 63.7%, results suggest that the predicted gap in county IMR between Northeast and Midwest regions would narrow by 0.45 points. CONCLUSIONS: Variable reporting of previable fetal and infant deaths may compromise the validity of county IMR comparisons. Improved consistency and accuracy of fetal and infant death reporting is warranted. PMID- 28722800 TI - Role of the Long Non-Coding RNA Growth Arrest-Specific 5 in Glucocorticoid Response in Children with Inflammatory Bowel Disease. AB - Glucocorticoids (GCs) are widely employed in inflammatory, autoimmune and neoplastic diseases, and, despite the introduction of novel therapies, remain the first-line treatment for inducing remission in inflammatory bowel disease (IBD). Given the high incidence of suboptimal response, associated with a significant number of side-effects, that are particularly severe in paediatric patients, the identification of subjects that are most likely to respond poorly to GCs is extremely important. Recent evidence suggests that the long non-coding RNA (lncRNA) GAS5 could be a potential marker of GC resistance. To address this issue, we evaluated the association between the lncRNA GAS5 and the efficacy of steroids, in terms of inhibition of proliferation, in two cell lines derived from colon and ovarian cancers, to confirm the sensitivity and specificity of these lncRNAs. These cells showed a different sensitivity to GCs and revealed differential expression of GAS5 after treatment. GAS5 was up-regulated in GC resistant cells and accumulated more in the cytoplasm compared to the nucleus in response to the drug. The functions of GAS5 were assessed by silencing, and we found that GAS5 knock-down reduced the proliferation during GC treatment. Furthermore, for the first time, we measured GAS5 levels in 19 paediatric IBD patients at diagnosis and after the first cycle of GCs, and we demonstrated an up regulation of the lncRNA in patients with unfavourable steroid response. Our preliminary results indicate that GAS5 could be considered a novel pharmacogenomic marker useful for the personalization of GC therapy. PMID- 28722801 TI - Primary familial brain calcification with a novel SLC20A2 mutation: Analysis of PiT-2 expression and localization. AB - Primary familial brain calcification (PFBC) is an autosomal dominant rare disorder characterized by bilateral and symmetric brain calcifications, and neuropsychiatric manifestations. Four genes have been linked to PFBC: SLC20A2, PDGFRB, PDGFB, and XPR1. In this study, we report molecular and clinical data of a PFBC patient carrying a novel SLC20A2 mutation and we investigate the impact of the mutation on PiT-2 expression and function. Sanger sequencing of SLC20A2, PDGFRB, PDGFB, XPR1 led to the identification of a novel duplication of twelve nucleotides (c.1876_1887dup/ p.Trp626_Thr629dup) in SLC20A2 gene. SLC20A2 encodes for a cell membrane transporter (PiT-2) involved in maintenance of inorganic phosphate homeostasis. We performed an analysis of expression and functionality of PiT-2 protein in patient primary cultured fibroblasts. In patient fibroblasts, the mutation does not affect PiT-2 expression but alter sub-cellular localization. The Pi-uptake assay revealed a less Pi depletion in patient than in control fibroblasts, suggesting that SLC20A2 duplication may impair Pi internalization. This is the first study reporting sub-cellular expression analysis of mutant PiT-2 in primary cultured fibroblasts from a PFBC patient, showing that p.Trp626_Thr629dup in SLC20A2 alters PiT-2 sub-cellular localization and reduces Pi-uptake, leading to onset of PFBC in our patient. PMID- 28722803 TI - News and notes: Conferences. PMID- 28722805 TI - Forum for the History of the Human Sciences. PMID- 28722802 TI - Pathology Imagebase-a reference image database for standardization of pathology. AB - AIMS: Despite efforts to standardize histopathology practice through the development of guidelines, the interpretation of morphology is still hampered by subjectivity. We here describe Pathology Imagebase, a novel mechanism for establishing an international standard for the interpretation of pathology specimens. METHODS AND RESULTS: The International Society of Urological Pathology (ISUP) established a reference image database through the input of experts in the field. Three panels were formed, one each for prostate, urinary bladder and renal pathology, consisting of 24 international experts. Each of the panel members uploaded microphotographs of cases into a non-public database. The remaining 23 experts were asked to vote from a multiple-choice menu. Prior to and while voting, panel members were unable to access the results of voting by the other experts. When a consensus level of at least two-thirds or 16 votes was reached, cases were automatically transferred to the main database. Consensus was reached in a total of 287 cases across five projects on the grading of prostate, bladder and renal cancer and the classification of renal tumours and flat lesions of the bladder. The full database is available to all ISUP members at www.isupweb.org. Non-members may access a selected number of cases. CONCLUSIONS: It is anticipated that the database will assist pathologists in calibrating their grading, and will also promote consistency in the diagnosis of difficult cases. PMID- 28722804 TI - Balancing life and work by unbending gender: Early American women psychologists' struggles and contributions. AB - Women's participation in the work force shifted markedly throughout the twentieth century, from a low of 21 percent in 1900 to 59 percent in 1998. The influx of women into market work, particularly married women with children, put pressure on the ideology of domesticity: an ideal male worker in the outside market married to a woman taking care of children and home (Williams, 2000). Here, we examine some moments in the early-to-mid-twentieth century when female psychologists contested established norms of life-work balance premised on domesticity. In the 1920s, Ethel Puffer Howes, one of the first generation of American women psychologists studied by Scarborough and Furumoto (1987), challenged the waste of women's higher education represented by the denial of their interests outside of the confines of domesticity with pioneering applied research on communitarian solutions to life-work balance. Prominent second-generation psychologists, such as Leta Hollingworth, Lillian Gilbreth, and Florence Goodenough, sounded notes of dissent in a variety of forums in the interwar period. At mid-century, the exclusion of women psychologists from war work galvanized more organized efforts to address their status and life-work balance. Examination of the ensuing uneasy collaboration between psychologist and library scholar Alice Bryan and the influential male gatekeeper E. G. Boring documents gendered disparities in life work balance and illuminates how the entrenched ideology of domesticity was sustained. We conclude with Jane Loevinger's mid-century challenge to domesticity and mother-blaming through her questioning of Boring's persistent focus on the need for job concentration in professional psychologists and development of a novel research focus on mothering. PMID- 28722806 TI - Citation: 2017 Cheiron Book Prize. PMID- 28722807 TI - "The difference being a woman made" Untold Lives in personal and intellectual context. AB - To mark the 30th anniversary of the publication of Scarborough and Furumoto's classic work Untold Lives, and to honor the intellectual legacy of Elizabeth Scarborough (1935-2015), we introduce this special issue devoted to the histories of women, gender, and feminism in psychology. We provide a short biographical sketch of Elizabeth, highlighting her own marriage-career dilemma, then contextualize the publication of Untold Lives within the historiography on women in psychology at that time. We conclude by discussing intersectionality as an analytic framework for the history of psychology as a way to extend and enrich this historiography. PMID- 28722808 TI - An examination of the effect of aerosolized Permanone insecticide on zebra finch susceptibility to West Nile virus. AB - West Nile virus (WNV) is maintained cryptically primarily in avian (passerine) populations, where it is transmitted by Culex spp. mosquitoes. Mosquito-control measures currently include physical activities to reduce mosquito-breeding sites and the application of mosquito larvicides or aerosolized insecticides to kill adults (adulticides) when arboviral diseases such as WNV or Zika virus are detected in mosquito populations. Organochlorine, organophosphorus, carbamate, and pyrethroid insecticides are often used. Previous work suggests an effect of pyrethroids on the immune system in a variety of vertebrates. We examined the effects of exposure to aerosolized Permanone(r) 30:30 insecticide (permethrin and piperonyl butoxide in soy oil vehicle) at approximately 103 to 106 times potential environmental concentrations on the response of captive zebra finches (Taeniopygia guttata) to experimental challenge with WNV. Compared to vehicle control birds, WNV outcome was unchanged (65% of birds produced a viremia) in the "low" exposure (9.52 +/- 3.13 mg/m3 standard deviation [SD] permethrin) group but reduced in the "high" exposure (mean 376.5 +/- 27.9 mg/m3 SD permethrin) group (30% were viremic; p < 0.05). After clearing WNV infection, birds treated with Permanone regained less body mass than vehicle-treated birds (p < 0.001). The present study suggests that exposure to aerosolized Permanone insecticide at levels exceeding typical application rates has the potential to not change or to mildly enhance a bird's resistance to WNV. Environ Toxicol Chem 2017;36:3376 3386. Published 2017 Wiley Periodicals Inc. on behalf of SETAC. This article is a US government work and, as such, is in the public domain in the United States of America. PMID- 28722809 TI - Measuring the outcomes of nursing practice: A Delphi study. AB - AIMS AND OBJECTIVE: To develop nursing-sensitive patient indicators to measure the outcomes of nursing practice. BACKGROUND: Nurses play an important role in the healthcare system, yet there is no consensus on how the impact of nursing work should be evaluated. Limited research has previously examined the views of clinical nurses on the important concepts for measuring nursing practice. DESIGN: A four-round modified Delphi survey sought opinions from patients and nurses about the relevant concepts and their relative priority as indicators of quality nursing practice. METHOD: Round 1 comprised semi-structured interviews with patients and nurses to identify key concepts. Nurses were then asked to participate in three rounds of Delphi survey to identify and rate key concepts from which indicators were developed. Thematic analysis and descriptive statistics were used to analyse the data. RESULTS: By the end of Round 4, the process had generated 103 concepts and participants had agreed on eight overarching constructs, namely care and caring; communication; coordination and collaboration; safety; patient characteristics; workload; Nurses work environment; and organisational characteristics. CONCLUSIONS: Consensus was achieved between nurses on the most important concepts, which can provide the basis for measuring the quality and safety of nursing practice in a comprehensive and holistic way. RELEVANCE TO CLINICAL PRACTICE: The identification of concepts that patients and nurses consider important for measuring nursing practice will guide the development of methods for evaluating nursing in the future. Ensuring that nursing practice is rigorously evaluated has the potential to identify opportunities to improve nursing quality, patient safety and improve health outcomes. PMID- 28722810 TI - Impact of Crude Oil Quality on the Refining Conditions and Composition of Nutraceuticals in Refined Palm Oil. AB - Palm oil is the major vegetable oil used worldwide due to its unique properties. The effect of crude palm oil acidity on the final free fatty acids (FFA) content, neutral oil loss (NOL), and nutraceutical compounds, such as carotenes, total tocols (tocopherols and tocotrienols), squalene, and phytosterols was investigated. A central composite design was employed to study the influence of the refining conditions: temperature (200 to 260 degrees C), steam percentage (0.5% to 3.5%), and initial FFA content (2.2% to 6.0%) on the quality of the refined product. The results revealed that initial palm oil acidity is a statistically important parameter to obtain commercially acceptable values for final FFA content. The increase of temperature presented the most important effect on the reduction of all nutraceutical compounds. The highest tocopherols (88%), phytosterols (98%), and squalene retention (84%) was obtained when applying the mildest temperature (200 degrees C). From the experimental results, 3 equations were generated enabling the prediction of the free fatty acids content, the tocols content, and the losses of neutral oil. Therefore, this work contributes to the understanding and optimization of the process for the production of palm oil with high nutraceutical quality and low free fatty acid contents. PMID- 28722811 TI - Barriers to palliative care in people with chronic obstructive pulmonary disease in home care: A qualitative study of the perspective of professional caregivers. AB - AIMS AND OBJECTIVES: To examine the experiences with palliative care in people with chronic obstructive pulmonary disease among professional caregivers in a Danish home care setting. BACKGROUND: Many patients with advanced chronic obstructive pulmonary disease depend on professional caregivers in the primary sector to provide assistance and care. However, chronic obstructive pulmonary disease patients receive no or only very little palliative care compared to patients with cancer although they may have many burdensome symptoms. DESIGN: Qualitative explorative study. METHODS: In 2013-2014, ten professional caregivers from three districts in a Danish municipality were followed during home visits to patients with chronic obstructive pulmonary disease and individual interviews about palliative care were subsequently conducted. In 2014, 66 professional caregivers, representing eleven home care districts, participated in ten group discussions about palliative care needs in this group of patients. Data were analysed using qualitative descriptive analysis. RESULTS: The study revealed a nonawareness of palliative care for patients with chronic obstructive pulmonary disease among the professional caregivers who expressed vague understanding of palliative care and lack of knowledge about the disease. Organisational barriers, such as lack of time and continuity in patient care, lack of opportunity to discuss palliative care and lack of peer learning were experienced as challenging in the provision of palliative care. Nonawareness and organisational barriers led to difficulties in identifying palliative care needs and reluctance to initiate conversations about palliative care. CONCLUSION: The findings indicate a need for education, training and reflection among professional caregivers in home care. Also, organisational changes may be needed to reduce the barriers to palliative care. RELEVANCE TO CLINICAL PRACTICE: The findings uncovered barriers to palliative care that must be addressed. Targeted educational programmes and organisational changes may increase the ability to identify palliative care needs and initiate and evaluate palliative interventions. PMID- 28722812 TI - Chemical profile of pineapple cv. Vitoria in different maturation stages using electrospray ionization mass spectrometry. AB - BACKGROUND: Pineapple is the fruit of Ananas comosus var. comosus plant, being cultivated in tropical areas and has high energy content and nutritional value. Herein, 30 samples of pineapple cv. Vitoria were analyzed as a function of the maturation stage (0-5) and their physico-chemical parameters monitored. In addition, negative-ion mode electrospray ionization mass spectrometry [ESI(-)FT ICR MS] was used to identify and semi-quantify primary and secondary metabolites present in the crude and phenolic extracts of pineapple, respectively. RESULTS: Physico-chemical tests show an increase in the total soluble solids (TSS) values and in the TSS/total titratable acidity ratio as a function of the maturity stage, where a maximum value was observed in stage 3 (3/4 of the fruit is yellow, which corresponds to the color of the fruit peel). ESI(-)FT-ICR MS analysis for crude extracts showed the presence mainly of sugars as primary metabolites present in deprotonated molecule form ([M - H]- and [2 M - H]- ions) whereas, for phenolic fractions, 11 compounds were detected, being the most abundant in the third stage of maturation. This behavior was confirmed by quantitative analysis of total polyphenols. CONCLUSION: ESI-FT-ICR MS was efficient in identifying primary (carbohydrates and organic acids) and secondary metabolites (13 phenolic compounds) presents in the crude and phenolic extract of the samples, respectively. (c) 2017 Society of Chemical Industry. PMID- 28722813 TI - Knockdown of long non-coding RNA MALAT1 inhibits growth and motility of human hepatoma cells via modulation of miR-195. AB - The metastasis-associated lung adenocarcinoma transcription 1 (Malat1) is a long non-coding RNA (lncRNA), exerts oncogenic role in multiple cancers, including hepatocellular carcinoma (HCC). This study was aimed to investigate its posttranscriptional regulation in HCC cells. RT-PCR was performed to monitor the expression levels of Malat1 in normal liver and HCC cell lines. The expression of Malat1, microRNA (miR)-195, and epidermal growth factor receptor (EGFR) in HepG2 and MHCC97 cells was respectively or synchronously altered by transfection. Then the changes in cell viability, apoptotic cell rate, cell cycle distribution, migration, and invasion were respectively assessed. As a result, we found that Malat1 was highly expressed in HCC cell lines when compared to normal liver cells. Malat1 silence suppressed HCC cells viability, migration and invasion, induced apoptosis, and arrested more cells in G0/G1 phase. Malat1 acted as a circular endogenous RNA (ceRNA) for miR-195. Malat1 silence could not suppress HCC cell growth and motility when miR-195 was knocked down. EGFR was a direct target of miR-195. miR-195 overexpression could not suppress HCC cell growth and motility when the 3'UTR site of EGFR was overexpressed. Furthermore, Malat1 silence blocked the activation of PI3K/AKT and JAK/STAT pathways, while EGFR overexpression activated them. Our study demonstrates Malat1-miR-195-EGFR axis plays a critical role in HCC cells which provided a better understanding of Malat1 in HCC. PMID- 28722814 TI - Health-promoting conversations-A novel approach to families experiencing critical illness in the ICU environment. AB - AIMS AND OBJECTIVES: To identify and describe the outcomes of a nurse-led intervention, "Health-promoting conversations with families," regarding family functioning and well-being in families with a member who was critically ill. BACKGROUND: Families who have a critically ill family member in an intensive care unit face a demanding situation, threatening the normal functioning of the family. Yet, there is a knowledge gap regarding family members' well-being during and after critical illness. DESIGN: The study used a qualitative inductive descriptive design. METHODS: Eight families participated in health-promoting conversations aimed to create a context for change related to the families' identified problems and resources. Fifteen qualitative interviews were conducted with 18 adults who participated in health-promoting conversations about a critical illness in the family. Eight participants were patients (six men, two women) and 10 were family members (two male partners, five female partners, one mother, one daughter, one female grandchild). The interviews were analysed by conventional content analysis. RESULTS: Family members experienced strengthened togetherness, a caring attitude and confirmation through health-promoting conversations. The caring and calming conversations were appreciated despite the reappearance of exhausting feelings. Working through the experience and being confirmed promoted family well-being. CONCLUSION: Health-promoting conversations were considered to be healing, as the family members take part in sharing each other's feelings, thoughts and experiences with the critical illness. RELEVANCE TO CLINICAL PRACTICE: Health-promoting conversations could be a simple and effective nursing intervention for former intensive care patients and their families in any cultural context. PMID- 28722815 TI - Influence of Morphine and Naloxone on Pain Modulation in Rheumatoid Arthritis, Chronic Fatigue Syndrome/Fibromyalgia, and Controls: A Double-Blind, Randomized, Placebo-Controlled, Cross-Over Study. AB - BACKGROUND: Impaired pain inhibitory and enhanced pain facilitatory mechanisms are repeatedly reported in patients with central sensitization pain. However, the exact effects of frequently prescribed opioids on central pain modulation are still unknown. METHODS: A randomized, double-blind, placebo-controlled cross-over trial was carried out. Ten chronic fatigue syndrome (CFS)/fibromyalgia (FM) patients, 11 rheumatoid arthritis (RA) patients and 20 controls were randomly allocated to the experimental (10 mg morphine or 0.2 mg/mL Naloxone) and placebo (2 mL Aqua) group. Pressure pain thresholds (PPTs) and temporal summation at the Trapezius and Quadriceps were assessed by algometry. Conditioned pain modulation (CPM) efficacy and deep tissue pain pressure were assessed by adding ischemic occlusion at the opposite upper arm. RESULTS: Deep tissue pain pressure was lower and temporal summation higher in CFS/FM (P = 0.002 respectively P = 0.010) and RA patients (P = 0.011 respectively P = 0.047) compared to controls at baseline. Morphine had only a positive effect on PPTs in both patient groups (P time = 0.034). Accordingly, PPTs increased after placebo (P time = 0.015), and no effects on the other pain parameters were objectified. There were no significant effects of naloxone nor nocebo on PPT, deep tissue pain, temporal summation or CPM in the control group. CONCLUSIONS: This study revealed anti-hyperalgesia effects of morphine in CFS/FM and RA patients. Nevertheless, these effects were comparable to placebo. Besides, neither morphine nor naloxone influenced deep tissue pain, temporal summation or CPM. Therefore, these results suggest that the opioid system is not dominant in (enhanced) bottom-up sensitization (temporal summation) or (impaired) endogenous pain inhibition (CPM) in patients with CFS/FM or RA. PMID- 28722816 TI - Construction of All-Solid-State Batteries based on a Sulfur-Graphene Composite and Li9.54 Si1.74 P1.44 S11.7 Cl0.3 Solid Electrolyte. AB - Herein an effective way for construction of all-solid-state lithium-sulfur batteries (LSBs) with sulfur/reduced graphene oxide (rGO) and Li9.54 Si1.74 P1.44 S11.7 Cl0.3 solid electrolyte is reported. In the composite cathode, the Li9.54 Si1.74 P1.44 S11.7 Cl0.3 powder is homogeneously mixed with the S/rGO composite to enhance the ionic conductivity. Coupled with a metallic Li anode and solid electrolyte, the designed S/rGO-Li9.54 Si1.74 P1.44 S11.7 Cl0.3 composite cathode exhibits a high specific capacity and good cycling stability. A high initial discharge capacity of 969 mAh g-1 is achieved at a current density of 80 mA g-1 at room temperature and the cell retains a reversible capacity of over 827 mAh g 1 after 60 cycles. The enhanced performance is attributed to the intimate contact between the S/rGO and Li9.54 Si1.74 P1.44 S11.7 Cl0.3 electrolyte, and high electrical conductivity of rGO and high ionic conductivity of the solid electrolyte. PMID- 28722817 TI - Dispersive solid-phase extraction for the determination of trace organochlorine pesticides in apple juices using reduced graphene oxide coated with ZnO nanocomposites as sorbent. AB - In this work, reduced graphene oxide coated with ZnO nanocomposites was used as an efficient sorbent of dispersive solid-phase extraction and successfully applied for the extraction of organochlorine pesticides from apple juice followed by gas chromatography with mass spectrometry. Several experimental parameters affecting the extraction efficiencies, including the amount of adsorbent, extraction time, and the pH of the sample solution, as well as the type and volume of eluent solvent, were investigated and optimized. Under the optimal experimental conditions, good linearity existed in the range of 1.0-200.0 ng/mL for all the analytes with the correlation coefficients (R2 ) ranging from 0.9964 to 0.9994. The limits of detection of the method for the compounds were 0.011 0.053 ng/mL. Good reproducibilities were acquired with relative standard deviations below 8.7% for both intraday and interday precision. The recoveries of the method were in the range of 78.1-105.8% with relative standard deviations of 3.3-6.9%. PMID- 28722818 TI - C-H Carboxylation of Aromatic Compounds through CO2 Fixation. AB - Carbon dioxide (CO2 ) represents the most abundant and accessible carbon source on Earth. Thus the ability to transform CO2 into valuable commodity chemicals through the construction of C-C bonds is an invaluable strategy. Carboxylic acids and derivatives, the main products obtained by carboxylation of carbon nucleophiles by reaction of CO2 , have wide application in pharmaceuticals and advanced materials. Among the variety of carboxylation methods currently available, the direct carboxylation of C-H bonds with CO2 has attracted much attention owing to advantages from a step- and atom-economical point of view. In particular, the prevalence of (hetero)aromatic carboxylic acids and derivatives among biologically active compounds has led to significant interest in the development of methods for their direct carboxylation from CO2 . Herein, the latest achievements in the area of direct C-H carboxylation of (hetero)aromatic compounds with CO2 will be discussed. PMID- 28722819 TI - Self-Targeting, Immune Transparent Plasma Protein Coated Nanocomplex for Noninvasive Photothermal Anticancer Therapy. AB - Cancer cells exhibit specific physiological differences compared to normal cells. Most surface membranes of cancer cells are characterized by high expression of given protein receptors, such as albumin, transferrin, and growth factors that are also present in the plasma of patients themselves, but are lacking on the surface of normal cells. These distinct features between cancer and normal cells can serve as a niche for developing specific treatment strategies. Near-infrared (NIR)-light-triggered therapy platforms are an interesting novel avenue for use in clinical nanomedicine. As a photothermal agent, conducting polymer nanoparticles, such as polypyrrole (PPy), of great NIR light photothermal effects and good biocompatibility, show promising applications in cancer treatments through the hyperthermia mechanism. Autologous plasma proteins coated PPy nanoparticles for hyperthermia therapy as a novel core technology platform to treat cancers through secreted protein acid and rich in cysteine targeting are developed here. This approach can provide unique features of specific targeting toward cancer cell surface markers and immune transparency to avoid recognition and attack by defense cells and achieve prolonged circulation half-life. This technology platform unveils new clinical options for treatment of cancer patients, supporting the emergence of innovative clinical products. PMID- 28722820 TI - Fluorinative Rearrangements of Substituted Phenylallenes Mediated by (Difluoroiodo)toluene: Synthesis of alpha-(Difluoromethyl)styrenes. AB - Phenylallenes undergo fluorinative rearrangement upon the action of (difluoroiodo)toluene in the presence of 20 mol % BF3 ?OEt2 to yield alpha difluoromethyl styrenes. This unprecedented reaction was entirely chemoselective for the internal allene pi bond, and showed remarkable regioselectivity during the fluorination event. Substituted phenylallenes, phenylallenes possessing both phenyl- and alpha-allenyl substituents, and diphenylallenes were investigated, and good functional-group compatibility was observed throughout. The ease with which allenes can be prepared on a large scale, and the operational simplicity of this reaction allowed us to rapidly access fluorine-containing building blocks that have not been accessed by conventional deoxyfluorination strategies. PMID- 28722821 TI - Sensory strategies of postural sway during quiet stance in patients with haemophilic arthropathy. AB - INTRODUCTION: The sensory strategies of postural control in adult haemophilic arthropathy patients are still poorly understood. AIM: To determine sensorial posture-control strategies through postural sway frequency analysis when in a bipedal quiet stance with and without visual stimulus deprivation in healthy subjects and patients with haemophilic arthropathy. Secondarily, to determine the irregularity of postural balance control through sample entropy (SampEn). METHODS: A triaxial accelerometer attached at the L3 level determined the displacement and acceleration of the centre of mass (DCoM and ACoM, respectively) under open- and closed-eyes conditions. Sensorial strategies were studied by spectral analysis of the DCoM signal, divided into low, medium and high frequencies for visual/vestibular, cerebellum and somatosensory strategies respectively. DCoM irregularity was also analysed by SampEn. RESULTS: Fifteen young, healthy subjects and fifteen young, haemophilia patients were included. The mediolateal DCoM and anteroposterior ACoM differed between groups. During the open-eyes condition, haemophiliacs presented limited high and medium frequencies, and more low frequency bands as compared to non-haemophiliacs (P<.05). In the closed-eyes condition, haemophiliacs had a minor percentage of high frequencies but an elevated percentage of low frequencies as compared to non-haemophiliacs (P<.05). Non-haemophiliacs had higher SampEn than haemophiliacs in the mediolateral axis with open- and closed-eyes (P<.05 and <.001, respectively). CONCLUSIONS: The presented results indicate that patients with haemophilic arthropathy, as compared to healthy subjects, have less postural control irregularity and poor somatosensory system contributions that are compensated by more vestibular inputs. PMID- 28722822 TI - Test-retest reliability of wide-pulse high-frequency neuromuscular electrical stimulation evoked force. AB - INTRODUCTION: We compare forces evoked by wide-pulse high-frequency (WPHF) neuromuscular electrical stimulation (NMES) delivered to a nerve trunk versus muscle belly and assess their test-retest intraindividual and interindividual reliability. METHODS: Forces evoked during 2 sessions with WPHF NMES delivered over the tibial nerve trunk and 2 sessions over the triceps surae muscle belly were compared. Ten individuals participated in 4 sessions involving ten 20-s WPHF NMES contractions interspaced by 40-s recovery. Mean evoked force and force time integral of each contraction were quantified. RESULTS: For both nerve trunk and muscle belly stimulation, intraindividual test-retest reliability was good (intraclass correlation coefficient > 0.9), and interindividual variability was large (coefficient of variation between 140% and 180%). Nerve trunk and muscle belly stimulation resulted in similar evoked forces. DISCUSSION: WPHF NMES locations might be chosen by individual preference because intraindividual reliability was relatively good for both locations. Muscle Nerve 57: E70-E77, 2018. PMID- 28722823 TI - Rational Design of a Highly Potent and Selective Peptide Inhibitor of PACE4 by Salt Bridge Interaction with D160 at Position P3. AB - PACE4, a member of the proprotein convertases (PCs) family of serine proteases, is a validated target for prostate cancer. Our group has developed a potent and selective PACE4 inhibitor: Ac-LLLLRVKR-NH2 . In seeking for modifications to increase the selectivity of this ligand toward PACE4, we replaced one of its P3 Val methyl groups with a basic group capable of forming a salt bridge with D160 of PACE4. The resulting inhibitor is eight times more potent than the P3 Val parent inhibitor and two times more selective over furin, because the equivalent salt bridge with furin E257 is not optimal. Moreover, the beta-branched nature of the new P3 residue favors the extended beta-sheet conformation usually associated with substrates of proteases. This work provides new insight for better understanding of beta-sheet backbone-backbone interactions between serine proteases and their peptidic ligands. PMID- 28722824 TI - Local Equilibrium and Retardation Revisited. AB - In modeling solute transport with mobile-immobile mass transfer (MIMT), it is common to use an advection-dispersion equation (ADE) with a retardation factor, or retarded ADE. This is commonly referred to as making the local equilibrium assumption (LEA). Assuming local equilibrium, Eulerian textbook treatments derive the retarded ADE, ostensibly exactly. However, other authors have presented rigorous mathematical derivations of the dispersive effect of MIMT, applicable even in the case of arbitrarily fast mass transfer. We resolve the apparent contradiction between these seemingly exact derivations by adopting a Lagrangian point of view. We show that local equilibrium constrains the expected time immobile, whereas the retarded ADE actually embeds a stronger, nonphysical, constraint: that all particles spend the same amount of every time increment immobile. Eulerian derivations of the retarded ADE thus silently commit the gambler's fallacy, leading them to ignore dispersion due to mass transfer that is correctly modeled by other approaches. We then present a particle tracking simulation illustrating how poor an approximation the retarded ADE may be, even when mobile and immobile plumes are continually near local equilibrium. We note that classic "LEA" (actually, retarded ADE validity) criteria test for insignificance of MIMT-driven dispersion relative to hydrodynamic dispersion, rather than for local equilibrium. PMID- 28722825 TI - A Crystalline pi-Stack Containing Five Stereoisomers: Insights into Conformational Isomorphism, Chirality Inversion, and Disorder. AB - An unprecedented crystal-packing arrangement of a tetramethoxy-bay-substituted perylene bisimide (PBI) consists of three crystallographically independent molecules, that is, an achiral (AC) PBI of saddle-shaped geometry along with two pairs of propeller-like twisted (P)- and (M)-enantiomeric PBI frameworks. All these five conformations are observed within a single pi-stack revealing an intriguing packing sequence with an inversion of chirality from P to M via AC. Nudged elastic band calculations for the isolated molecule show that AC is a local minimum of the P to M interconversion path. In addition, two minor conformations were observed in the crystal, one of which resembles a transition state molecule. Theoretical studies of dimeric and trimeric stacks reveal that the coexistence of all these structures in the crystal lattice is aided by the strong dispersion interactions between PBI cores and perfectly interdigitated dodecyl chains which stabilize energetically higher conformations. PMID- 28722826 TI - Inflammatory profile in X-linked adrenoleukodystrophy patients: Understanding disease progression. AB - X-linked adrenoleukodystrophy (X-ALD) is an inherited disease characterized by progressive inflammatory demyelization in the brain, adrenal insufficiency, and an abnormal accumulation of very long chain fatty acids (VLCFA) in tissue and body fluids. Considering that inflammation might be involved in pathophysiology of X-ALD, we aimed to investigate pro- and anti-inflammatory cytokines in plasma from three different male phenotypes (CCER, AMN, and asymptomatic individuals). Our results showed that asymptomatic patients presented increased levels of pro inflammatory cytokines IL-1beta, IL-2, IL-8, and TNF-alpha and the last one was also higher in AMN phenotype. Besides, asymptomatic patients presented higher levels of anti-inflammatory cytokines IL-4 and IL-10. AMN patients presented higher levels of IL-2, IL-5, and IL-4. We might hypothesize that inflammation in X-ALD is related to plasmatic VLCFA concentration, since there were positive correlations between C26:0 plasmatic levels and pro-inflammatory cytokines in asymptomatic and AMN patients and negative correlation between anti-inflammatory cytokine and C24:0/C22:0 ratio in AMN patients. The present work yields experimental evidence that there is an inflammatory imbalance associated Th1, (IL 2, IL-6, and IFN-gamma), Th2 (IL-4 and IL-10), and macrophages response (TNF alpha and IL-1beta) in the periphery of asymptomatic and AMN patients, and there is correlation between VLCFA plasmatic levels and inflammatory mediators in X ALD. Furthermore, we might also speculate that the increase of plasmatic cytokines in asymptomatic patients could be considered an early biomarker of brain damage and maybe also a predictor of disease progression. PMID- 28722827 TI - Being diagnosed with cancer: The experiences of patients with non-Hodgkin's lymphoma. AB - AIMS AND OBJECTIVES: To explore the lived experiences of patients on receiving a diagnosis of non-Hodgkin's lymphoma. BACKGROUND: Persons with non-Hodgkin's lymphoma are often diagnosed with cancer when at an advanced stage. This may arise due to a lack of screening programmes and delays in help seeking as the symptoms experienced are fairly nonspecific in nature. Consequently, receiving an unexpected diagnosis of non-Hodgkin's lymphoma may pose a psychosocial challenge to the individual. DESIGN: An exploratory qualitative phenomenological design was used. METHODS: Six adult patients diagnosed with non-Hodgkin's lymphoma were recruited and participated in two semi-structured interviews at different timepoints. Transcribed texts were analysed using interpretative phenomenological analysis. RESULTS: Three main themes emerged: "Emotional reaction to the diagnosis," "Struggling with a lack of understanding" and "Searching through past experiences." Most of the participants expressed shock, disbelief and fear at the news of being diagnosed with non-Hodgkin's lymphoma. A sense of relief was expressed by one participant, who could now provide a label to the pain experienced. CONCLUSIONS: This study highlights the responses of patients with non-Hodgkin's lymphoma on receiving a diagnosis. These responses are influenced by their knowledge about the illness, type of symptoms experienced, their own personal circumstances and the manner in which the diagnosis was given. RELEVANCE TO CLINICAL PRACTICE: Nursing care relates to an understanding of the patients' experiences. By reflecting on these findings, nurses are empowered to communicate with persons who have received a diagnosis of non-Hodgkin's lymphoma in a patient sensitive manner, which establishes a relationship of trust and respect. PMID- 28722828 TI - Bioaccumulation-based silver nanoparticle toxicity in Daphnia magna and maternal impacts. AB - In the present study, we tested whether bioaccumulation in specific tissues of Daphnia magna could explain silver nanoparticle (AgNP) toxicity. Daphnids were exposed to different concentrations of well-suspended AgNPs and AgNO3 . The accumulations of Ag in the whole body, gut, and nongut tissues, as well as the mortality of daphnids, were recorded over a period of 7 d. Regression analysis showed a higher degree of positive correlation between the concentration of Ag in the nongut tissues than gut tissues and the mortality of daphnids. The results strongly suggested that the toxicity of AgNPs could be better explained in terms of bioaccumulation of AgNPs in the nongut tissues. We further tested the maternal transfer of AgNPs in daphnids into the next generation using radioactive tracers, which were able to detect as low as 1.0 to 3.2% of total accumulated Ag transferred to the neonates. The AgNPs significantly affected the reproduction process during the first 2 broods after exposure, whereas AgNO3 only had significant effects on the first brood. It is possible that AgNPs have longer adverse effects than AgNO3 on the reproduction of Daphnia. The present study identified the sensitive site of AgNP toxic action in daphnids and documented the extent of maternal transfer and the significant influence of AgNPs on the reproduction of daphnids. Environ Toxicol Chem 2017;36:3359-3366. (c) 2017 SETAC. PMID- 28722829 TI - Megakaryocytes Enhance Mesenchymal Stromal Cells Proliferation and Inhibit Differentiation. AB - Megakaryocytes (MKs) can induce proliferation of calvarial osteoblasts [Ciovacco et al., 2009], but this same phenomenon has not been reported for bone marrow stromal populations from long bones. Bone marrow contains several types of progenitor cells which can be induced to differentiate into multiple cell types. Herein, we examined mesenchymal stromal cell proliferation and osteoblastic differentiation when rabbit or mouse MK were cultured with i) rabbit bone marrow stromal cells, ii) rabbit dental pulp stromal cells, or iii) mouse bone marrow stromal cells. Our results demonstrated that rabbit and mouse stromal cells co cultured with rabbit MK or mouse MK, have significant increases in proliferation on day 7 by 52%, 46%, and 24%, respectively, compared to cultures without MK. Conversely, alkaline phosphatase (ALP) activity was lower at various time points in these cells when cultures contain MK. Similarly, calcium deposition observed at day 14 rabbit bone marrow and dental pulp stromal cells and day 21 mouse bone marrow stromal cells was 63%, 69%, and 30% lower respectively, when co-cultured with MK. Gene expression studies reveal transcriptional changes broadly consistent with increased proliferation and decreased differentiation. Transcript levels of c-fos (associated with cell proliferation) trended higher after 3, 7, and 14 days in culture. Also, expression of alkaline phosphatase, osteonectin, osterix, and osteopontin, which are markers for osteoblast differentiation, showed MK-induced decreases in a cell type and time dependent manner. Taken together, these data suggest that MK play a role in stromal cell proliferation and differentiation, from multiple sites/locations in multiple species. This article is protected by copyright. All rights reserved. PMID- 28722830 TI - Ralfuranones contribute to mushroom-type biofilm formation by Ralstonia solanacearum strain OE1-1. AB - After invasion into intercellular spaces of tomato plants, the soil-borne, plant pathogenic Ralstonia solanacearum strain OE1-1 forms mushroom-shaped biofilms (mushroom-type biofilms, mBFs) on tomato cells, leading to its virulence. The strain OE1-1 produces aryl-furanone secondary metabolites, ralfuranones (A, B, J, K and L), dependent on the quorum sensing (QS) system, with methyl 3 hydroxymyristate (3-OH MAME) synthesized by PhcB as a QS signal. Ralfuranones are associated with the feedback loop of the QS system. A ralfuranone productivity deficient mutant (DeltaralA) exhibited significantly reduced growth in intercellular spaces compared with strain OE1-1, losing its virulence. To analyse the function of ralfuranones in mBF formation by OE1-1 cells, we observed cell aggregates of R. solanacearum strains statically incubated in tomato apoplast fluids on filters under a scanning electron microscope. The DeltaralA strain formed significantly fewer microcolonies and mBFs than strain OE1-1. Supplementation of ralfuranones A, B, J and K, but not L, significantly enhanced the development of mBF formation by DeltaralA. Furthermore, a phcB- and ralA deleted mutant (DeltaphcB/ralA) exhibited less formation of mBFs than OE1-1, although a QS-deficient, phcB-deleted mutant formed mBFs similar to OE1-1. Supplementation with 3-OH MAME significantly reduced the formation of mBFs by DeltaphcB/ralA. The application of each ralfuranone significantly increased the formation of mBFs by DeltaphcB/ralA supplied with 3-OH MAME. Together, our findings indicate that ralfuranones are implicated not only in the development of mBFs by strain OE1-1, but also in the suppression of QS-mediated negative regulation of mBF formation. PMID- 28722831 TI - A new wave in the evaluation of haemophilic arthropathy. PMID- 28722832 TI - The outcomes of haemophilia and its treatment: why we need a core set. PMID- 28722833 TI - Targeted next-generation sequencing using a multigene panel in myeloid neoplasms: Implementation in clinical diagnostics. AB - INTRODUCTION: Detection of mutations in patients with myeloid neoplasms (MNs) has shown great potential for diagnostic and prognostic purposes. Next-generation sequencing (NGS) is currently implemented for the diagnostic profiling of the four major MN subgroups. METHODS: First, we validated the targeted NGS approach using the TruSight Myeloid panel. Next, we screened 287 patients with a clinical suspicion of MN and 61 follow-up patients with documented MN. RESULTS: Validation of the NGS workflow resulted in maximal precision, accuracy, sensitivity, and specificity for gene variants with an allele frequency of at least 5% and a minimal read depth of 300. In our diagnostic screen, we identified at least one somatic mutation in 89% of patients with proven MN. Of the 155 newly diagnosed MN cases, 126 (81%) showed at least one mutation, confirming clonality. Moreover, the co-occurrence of mutated genes in the different MN subentities facilitates their classification and justifies the diagnostic use of a pan-myeloid panel. Furthermore, several of these mutations provide additional prognostic information independently of traditional prognostic scoring systems. CONCLUSION: Pan-myeloid targeted NGS fits elegantly in the routine diagnostic approach of MNs allowing for an improved diagnosis, subclassification, and prognosis. PMID- 28722834 TI - Effects of gastric inhibitory polypeptide, glucagon-like peptide-1 and glucagon like peptide-1 receptor agonists on Bone Cell Metabolism. AB - The relationship between gut and skeleton is increasingly recognized as part of the integrated physiology of the whole organism. The incretin hormones gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are secreted from the intestine in response to nutrient intake and exhibit several physiological functions including regulation of islet hormone secretion and glucose levels. A number of GLP-1 receptor agonists (GLP-1RAs) are currently used in treatment of type 2 diabetes and obesity. However, GIP and GLP-1 cognate receptors are widely expressed suggesting that incretin hormones mediate effects beyond control of glucose homeostasis, and reports on associations between incretin hormones and bone metabolism have emerged. The aim of this MiniReview was to provide an overview of current knowledge regarding the in vivo and in vitro effects of GIP and GLP-1 on bone metabolism. We identified a total of 30 pre-clinical and clinical investigations of the effects of GIP, GLP-1 and GLP 1RAs on bone turnover markers, bone mineral density (BMD), bone microarchitecture and fracture risk. Studies conducted in cell cultures and rodents demonstrated that GIP and GLP-1 play a role in regulating skeletal homeostasis, with pre clinical data suggesting that GIP inhibits bone resorption whereas GLP-1 may promote bone formation and enhance bone material properties. These effects are not corroborated by clinical studies. While there is evidence of effects of GIP and GLP-1 on bone metabolism in pre-clinical investigations, clinical trials are needed to clarify whether similar effects are present and clinically relevant in humans. PMID- 28722835 TI - [What General/Family Medicine Practitioner should Know about Viral Hepatitis]. AB - Viral hepatitis is a systemic disease that predominantly affects the liver. The most common causes of viral hepatitis are fi vehepatotropic viruses A, B, C, D and E; according to duration, it can be acute or chronic. Although clinical course of all viralhepatitides is similar, particular problem is predisposition of hepatitis B and hepatitis C to cause chronic forms of illnesswith severe outcome such as cirrhosis, hepatocellular carcinoma and liver failure. Clinical features include malaise, nausea,anorexia, low grade fever, aversion to smoking, and in clinical status usually we can fi nd hepatomegaly, and seldomsplenomegaly with adenopathy and jaundice. Generally, symptoms are very variable, from usually asymptomatic to fulminant,which in most cases have lethal outcome. There are three stages in acute phase of viral hepatitis: prodromal, icteric andconvalescence. Standard laboratory tests show elevated values of aspartate aminotransferase, alanine aminotransferaseand alkaline phosphatase in acute phase of hepatitis and elevated lactate dehydrogenase in chronic phase. Serum proteinelectrophoresis usually shows decreased albumin fraction and albumin/globulin ratio, as well as increased bilirubin level,positive urobilinogen and disturbance in coagulability factors, i.e. marked prolongation of prothrombin time. For etiology ofeach virus, series of serologic tests are used. In hepatitis A, acute phase of disease is characterized by IgM anti-HAV andpresence of IgG anti-HAV indicates previous exposure. In hepatitis B, appearance of HBsAg in serum is the fi rst evidenceof infection and recovery is connected with appearance of anti-HBsAg along with IgG anti HBcAg. Active forms of chronichepatitis B are characterized by active virus replication, which can be measured with polymerase chain reaction (PCR)HBV DNA. Diagnosis of hepatitis C is based on detection of antibodies to HCV (anti-HCV). Generally, it signifi es that HCVinfection is present but that diagnostic tool is poor for the phase of disease. In these circumstances, diagnosis of hepatitisC may be confi rmed by using an assay for HCV RNA. First line therapy in acute phase is mostly supportive, i.e. bed rest,appropriate diet including palatable meals as tolerated, without overfeeding. Alcohol and hepatotoxic agents (for example,paracetamol, amoxicillin, ketoconazole) should be avoided. In cases with increased tendency of developing chronic formsof hepatitis and complications (cirrhosis, hepatocellular carcinoma), immunomodulators should be administered, e.g.,interferon and/or antiviral agents. The role of family physician/general practitioner is in maintaining preventive measures(vaccination) and education of general population. Special attention needs to be paid to screening and educating high riskpatients with respect to proper diagnostics, laboratory and serologic tests. After establishing the diagnosis, all relevantmeasures should be taken to avoid chronifi cation of disease. In case of chronic hepatitis, consultation with infectiousdisease specialist and/or gastroenterologist is needed in the treatment and follow up of the patient. PMID- 28722836 TI - [Does Routine Pathology Evaluation of Uterine Content Following Evacuation for Abnormal Early Pregnancy Influence Further Management?] AB - The aim was to determine usefulness of routine pathologic evaluation of uterine content after uterine evacuation followingthe diagnosis of abnormal early pregnancy. This retrospective descriptive study performed during a one-year period includedall patients diagnosed with abnormal early pregnancy clinically or by ultrasound in the first trimester. All patients had uterineevacuation. During the study period, 335 women were diagnosed with abnormal early pregnancy and referred for uterineevacuation. Pathology results were available for 312 women included in the analysis. In 272 (87.2%) women, trophoblasttissue was found on examination and therefore intrauterine pregnancy was confirmed. In the remaining 40 patients,trophoblast was not found. In 10 (3.2%) patients, gestational trophoblastic disease was diagnosed, not being suspectedon pre-evacuation assessment. In one patient, suspected molar pregnancy was excluded by pathology evaluation. Basedon 51/312 (16.3 %) patients where pathology examination of uterine content influenced further management and treatment,we believe that routine pathology examination of uterine content after uterine evacuation in the fi rst trimester followingabnormal early pregnancy is justifiable in clinical practice. PMID- 28722837 TI - [Hypertrophic Pyloric Stenosis - Five-Year Retrospective Analysis]. AB - Although the etiology of the disease has not yet been fully clarified in the 21st century, clinical significance of the diseaseis huge because it is frequent in the neonatal period compared with other diseases. Today, owing to advanced diagnosticpossibilities, hypertrophic pyloric stenosis is easily distinguished from other differential diagnoses that are manifested byvomiting as the main symptom. At Department of Pediatric Surgery, Zagreb Children's Hospital, efforts have been investedto successfully manage this and a number of other conditions that affect newborns. We retrospectively analyzed data on40 hospitalized children retrieved from the hospital information system for the 2010-2015 period and present them as abasis for the respective algorithms and future research. Reviewing a range of parameters, we have come to some concreteconclusions. On average, the disease started manifesting on 28th day after birth; 63% of the children developed metabolicalkalosis. Thickness of the muscle wall verified by ultrasound ranged from 3.1 mm to 7 mm. Surgery was performed sevendays after hospitalization and correction of metabolic condition. The average duration of surgery was 48 minutes. The meanlength of hospital stay was 11.64 days, of which 2 days in the intensive care unit. Complications occurred in two patients. PMID- 28722838 TI - [Historical Review of Cesarean Section at King's Maternity Hospital and Midwifery School Zagreb 1908-1918]. AB - This article presents a historical review of the performance of 23 cesarean sections at the King's Maternity Hospital andMidwifery School in Zagreb during the 1908-1918 period. Following prenatal screening by midwives and doctors in thehospital, deliveries in high risk pregnant women were performed at maternity hospitals, not at home. The most commonindication for cesarean section was narrowed pelvis in 65.2% of women, while postpartum febrile condition was the mostcommon complication in the puerperium. Maternal mortality due to sepsis after the procedure was 8.69% and overallperinatal mortality was 36.3% (stillbirths and early neonatal deaths). PMID- 28722839 TI - [Multidisciplinary Management and Neurorehabilitation of Patients with Amyotrophic Lateral Sclerosis]. AB - Patients with amyotrophic lateral sclerosis require comprehensive care with a multidisciplinary approach, which isindividually adjusted to each patient. The goals of neurorehabilitation should be adjusted to the stage of disease. In earlystages, physical therapy is focused on preserving and optimizing motor and respiratory function. At this stage, familyshould be involved to partake in desired activities and be informed regarding the natural course of the disease. In latestages, physical therapy is focused on preventing respiratory complications and contractures, and orthotics may also berecommended. The onset of dysarthria should trigger swallowing and pulmonary function testing. Swallowing maneuversshould be tried at the onset of symptoms, later feeding tubes or percutaneous gastrostomy tube is necessary. Noninvasivemechanical ventilation may delay the need of tracheostomy and invasive mechanical ventilation. The key objectives ofmultidisciplinary teams are to optimize medical care, facilitate communication, and thus to improve the quality of care andquality of life. PMID- 28722840 TI - [Pharmacoeconomics - Challenges for Health Professionals]. AB - Over the last 30 years, medical expenditure has increased throughout the world. The main reasons estimated to laybehind it include aging, ever more chronic diseases and new emerging diseases, new drugs, expanded indications ofcurrent drugs, and development of pharmaceutical industry. A challenge for healthcare professionals is to sustain currentquality of care and enable medical innovations while attempting to contain costs. The overall goal is to demonstrate thepharmacoeconomic value, i.e. a balance of economic, humanistic and clinical outcomes. PMID- 28722841 TI - [Fillagrin - Multifunctional Protein]. AB - Effective physical, chemical, biochemical and immune function of the skin requires a corresponding structure of theepidermis. Filaggrin, one of epidermal proteins, is essential for the formation of corneocytes and intracellular metabolites,which in turn contribute to maintaining the stratum corneum humidity and acidic pH of the skin surface. However, a numberof profilaggrin gene mutations have been described, as well as different inflammatory conditions and different externalfactors that all resulted in filaggrin deficiency. Filaggrin deficiency is recorded in different skin diseases and discoveriesrelated to metabolic processing of filaggrin point to new goals in therapeutic strategies. In this preview, the main propertiesof the formation and metabolism of filaggrin are described, as well as clinical implications of filaggrin deficiency in theetiopathogenesis of some skin diseases. PMID- 28722842 TI - [Carotid Endarterectomy in Patients with Antiaggregation Therapy]. AB - Carotid endarterectomy is a common way of surgical treatment of extracranial carotid artery disease caused byatherosclerosis. Patients are often operated on under local anesthesia with intraoperative application of heparin.Postoperative bleeding occurs in up to 8% of cases, and up to 4.7% of patients need reoperation due to bleeding. TachoSilis a medical sponge consisting of collagen with added human coagulation factors (fibrinogen and thrombin). In contact withwater, blood or bodily fluids, it forms a clot that adheres to the surface. The hypothesis and aim of our study was to showthat TachoSil could be topically administered during surgery on carotid arteries in order to prevent minor bleeding, withoutcausing any local signs of inflammation or infection. The study included a prospective series of consecutive patients thatunderwent surgery for extracranial carotid stenosis with concomitant antiplatelet therapy at Department of Vascular Surgery,Merkur University Hospital in Zagreb. All patients received antiplatelet therapy with aspirin or aspirin and clopidogrel untilthe day before surgery. From April 2, 2012 to February 8, 2013, a total of 24 patients with extracranial carotid artery stenosiswere operated on, along with receiving antiplatelet therapy. All patients received 100 mg of acetylsalicylic acid and/or 75mg of clopidogrel until one day prior to surgery. Patients had been treated with antiplatelet drugs for at least six monthsprior to carotid endarterectomy. Four patients had been on dual antiplatelet therapy (aspirin 100 mg and clopidogrel 75 mg)because of percutaneous transluminal angioplasty (PTA) and a stent placed in pelvic arteries or superficial femoral artery.Due to speech disturbances following clamping of carotid arteries in two study patients a temporary intraluminal shunt wascreated. These two patients underwent longitudinal arteriotomy and longitudinal endarterectomy. Arteriotomy was closedby direct suture without a patch. Following arteriotomy and partial conversion of heparin with protamine, six patients neededadditional individual sutures. Then, protamine was added again to up to the full dose of conversion (50 mg). In 19 patients,only one TachoSil medical sponge (9.5 cm x 4.8 cm) was placed, whereas in fi ve patients two sponges were placed. Noneof the patients (24 of them operated on between April 2, 2012 and February 8, 2013) with TachoSil placed intraoperativelyhad any signs of postoperative wound infection. Carotid artery stenosis is a very common disease the incidence of whichincreases proportionally with age of the population observed. Bleeding is a relatively common and significant complicationfollowing surgical treatment, particularly in case of arterial bleeding. Bleeding and other complications in the neck can bevery serious and challenging for surgical treatment. With the present guidelines for the administration of clopidogrel in theevening before surgery, in some circumstances an increased incidence of postoperative hemorrhage or prolonged durationof surgery can be expected. Intraoperative use of hemostatics may reduce the postoperative bleeding complications.Intraoperative application of TachoSil does not increase the rate of postoperative complications such as infection anddelayed healing. TachoSil may reduce the rate of postoperative complications in carotid surgery. PMID- 28722843 TI - [Anaplastic Thyroid Carcinoma in a 17-Year-Old Female Patient]. AB - Anaplastic carcinoma of thyroid gland is one of the four most malignant tumors in humans. It appears in one or two patientsper million per year. It is very rare in children. A 17-year-old female patient was admitted to the Clinical Department of ENTand Head and Neck Surgery, Split University Hospital Center, for thyroid gland surgery due to rapid growth of a node in thethyroid gland left lobe. Preoperative examination indicated benign nature of changes. Total thyroidectomy with levels VIand VII neck dissection was done. Intraoperative slide of the left lobe was malignant. Positron emission tomography andcomputed tomography were also done. The finding was negative. The patient was examined by an ENT-oncology team andjuvenile radiotherapy was administered. It was found to be carcinoma stage IVa according to TNM classification. One yearafter the operation, the patient was well and had no signs of illness. This case report is a contribution to the existing butscarce knowledge of anaplastic carcinoma of thyroid gland in young patients in the world. PMID- 28722844 TI - [Vascular Vibration Injury and Paget-Shroetter Syndrome]. AB - Paget-Schroetter syndrome is a relatively uncommon condition related to primary thrombosis of the axillary/subclavianvein at the costoclavicular junction. Vibration injury is an unusual cause of this syndrome. We report on a 28-year-old manwho presented with acute onset left arm swelling after whole-day work with a pneumatic drill. Duplex ultrasound confirmedthe presence of a thrombus in his left axillary and subclavian vein, which was treated with low molecular weight heparin,eventually switched to oral anticoagulation. PMID- 28723064 TI - Doxorubicin Intracellular Remote Release from Biocompatible Oligo(ethylene glycol) Methyl Ether Methacrylate-Based Magnetic Nanogels Triggered by Magnetic Hyperthermia. AB - Hybrid nanogels, composed of thermoresponsive polymers and superparamagnetic nanoparticles, are attractive nanocarriers for biomedical applications, being able-as a polymer matrix-to uptake and release high quantities of chemotherapeutic agents and-as magnetic nanoparticles-to be heated when exposed to an alternative magnetic field (AMF), better known as magnetic hyperthermia. Herein, biocompatible, pH-responsive, magnetoresponsive, and thermoresponsive nanogels, based on oligo(ethylene glycol) methyl ether methacrylate monomers and a methacrylic acid comonomer were prepared by conventional precipitation radical copolymerization in water, post-assembled by complexation with iron oxide magnetic nanoparticles (MNPs) of maghemite (gamma-Fe2O3), and loaded with an anticancer drug (doxorubicin, DOX), for remotely controlled drug release by a "hot spot", as an athermal magnetic hyperthermia strategy against cancer. These nanogels, denoted MagNanoGels, with a hydrodynamic diameter from 328 to 460 nm, as a function of the MNP content, have a swelling-deswelling behavior at their volume phase temperature transition around 47 degrees C in a physiological medium (pH 7.5), which is above the human body temperature (37 degrees C). Applying an alternative magnetic field increases the release of DOX by 2-fold, while no macroscopic heating was recorded. This enhanced drug release is due to a shrinking of the polymer network by local heating, as illustrated by the MagNanoGel size decrease under an AMF. In cancer cells, not only do the DOX MagNanoGels internalize DOX more efficiently than free DOX, but also DOX intracellular release can be remotely triggered under an AMF, in athermal conditions, thus enhancing DOX cytotoxicity. PMID- 28723063 TI - Using Cooperatively Folded Peptides To Measure Interaction Energies and Conformational Propensities. AB - The rates and equilibria of the folding of biopolymers are determined by the conformational preferences of the subunits that make up the sequence of the biopolymer and by the interactions that are formed in the folded state in aqueous solution. Because of the centrality of these processes to life, quantifying conformational propensities and interaction strengths is vitally important to understanding biology. In this Account, we describe our use of peptide model systems that fold cooperatively yet are small enough to be chemically synthesized to measure such quantities. The necessary measurements are made by perturbing an interaction or conformation of interest by mutation and measuring the difference between the folding free energies of the wild type (in which the interaction or conformation is undisturbed) and the mutant model peptides (in which the interaction has been eliminated or the conformational propensities modified). With the proper controls and provided that the peptide model system in question folds via a two-state process, these folding free energy differences can be accurate measures of interaction strengths or conformational propensities. This method has the advantage of having high sensitivity and high dynamic range because the energies of interest are coupled to folding free energies, which can be measured with precisions on the order of a few tenths of a kilocalorie by well established biophysical methods, like chaotrope or thermal denaturation studies monitored by fluorescence or circular dichroism. In addition, because the model peptides can be chemically synthesized, the full arsenal of natural and unnatural amino acids can be used to tune perturbations to be as drastic or subtle as desired. This feature is particularly noteworthy because it enables the use of analytical tools developed for physical organic chemistry, especially linear free energy relationships, to decompose interaction energies into their component parts to obtain a deeper understanding of the forces that drive interactions in biopolymers. We have used this approach, primarily with the WW domain derived from the human Pin1 protein as our model system, to assess hydrogen bond strengths (especially those formed by backbone amides), the dependence of hydrogen bond strengths on the environment in which they form, beta-turn propensities of both natural sequences and small molecule beta-turn mimics, and the energetics of carbohydrate-protein interactions. In each case, the combination of synthetic accessibility, the ease of measuring folding energies, and the robustness of the structure of the Pin1 WW domain to mutation enabled us to obtain incisive measurements of quantities that have been challenging to measure by other methods. PMID- 28723065 TI - Advances in Modeling the Stability of Noncovalent Complexes in Charged Droplets with Applications in Electrospray Ionization-MS Experiments. AB - Electrospray ionization mass spectrometry is used extensively to measure the equilibrium constant of noncovalent complexes. In this Perspective, we attempt to present an accessible introduction to computational methodologies that can be applied to determine the stability of weak noncovalent complexes in their journey from bulk solution into the gaseous state. We demonstrate the usage of the methods on two typical examples of noncovalent complexes drawn from a broad class of nucleic acids and transient protein complexes found in aqueous droplets. We conclude that this new emerging direction in the use of simulations can lead to estimates of equilibrium constant corrections due to complex dissociation in the carrier droplet and finding of agents that may stabilize the protein interfaces. PMID- 28723066 TI - Antimony Anchored with Nitrogen-Doping Porous Carbon as a High-Performance Anode Material for Na-Ion Batteries. AB - Antimony represents a class of unique functional materials in sodium-ion batteries with high theoretical capacity (660 mA h g-1). The utilization of carbonaceous materials as a buffer layer has been considered an effective approach to alleviate rapid capacity fading. Herein, the antimony/nitrogen-doping porous carbon (Sb/NPC) composite with polyaniline nanosheets as a carbon source has been successfully achieved. In addition, our strategy involves three processes, a tunable organic polyreaction, a thermal annealing process, and a cost-effective reduction reaction. The as-prepared Sb/NPC electrode demonstrates a great reversible capacity of 529.6 mA h g-1 and an outstanding cycling stability with 97.2% capacity retention after 100 cycles at 100 mA g-1. Even at 1600 mA g-1, a superior rate capacity of 357 mA h g-1 can be retained. Those remarkable electrochemical performances can be ascribed to the introduction of a hierarchical porous NPC material to which tiny Sb nanoparticles of about 30 nm were well-wrapped to buffer volume expansion and improve conductivity. PMID- 28723068 TI - Biomimetic Hybridization of Kevlar into Silk Fibroin: Nanofibrous Strategy for Improved Mechanic Properties of Flexible Composites and Filtration Membranes. AB - Silk, one of the strongest natural biopolymers, was hybridized with Kevlar, one of the strongest synthetic polymers, through a biomimetic nanofibrous strategy. Regenerated silk materials have outstanding properties in transparency, biocompatibility, biodegradability and sustainability, and promising applications as diverse as in pharmaceutics, electronics, photonic devices and membranes. To compete with super mechanic properties of their natural counterpart, regenerated silk materials have been hybridized with inorganic fillers such as graphene and carbon nanotubes, but frequently lose essential mechanic flexibility. Inspired by the nanofibrous strategy of natural biomaterials (e.g., silk fibers, hemp and byssal threads of mussels) for fantastic mechanic properties, Kevlar was integrated in regenerated silk materials by combining nanometric fibrillation with proper hydrothermal treatments. The resultant hybrid films showed an ultimate stress and Young's modulus two times as high as those of pure regenerated SF films. This is not only because of the reinforcing effect of Kevlar nanofibrils, but also because of the increasing content of silk beta sheets. When introducing Kevlar nanofibrils into the membranes of silk nanofibrils assembled by regenerated silk fibroin, the improved mechanic properties further enabled potential applications as pressure-driven nanofiltration membranes and flexible substrates of electronic devices. PMID- 28723067 TI - Structural and Spectroscopic Properties of Assemblies of Self-Replicating Peptide Macrocycles. AB - Self-replication at the molecular level is often seen as essential to the early origins of life. Recently a mechanism of self-replication has been discovered in which replicator self-assembly drives the process. We have studied one of the examples of such self-assembling self-replicating molecules to a high level of structural detail using a combination of computational and spectroscopic techniques. Molecular Dynamics simulations of self-assembled stacks of peptide derived replicators provide insights into the structural characteristics of the system and serve as the basis for semiempirical calculations of the UV-vis, circular dichroism (CD) and infrared (IR) absorption spectra that reflect the chiral organization and peptide secondary structure of the stacks. Two proposed structural models are tested by comparing calculated spectra to experimental data from electron microscopy, CD and IR spectroscopy, resulting in a better insight into the specific supramolecular interactions that lead to self-replication. Specifically, we find a cooperative self-assembly process in which beta-sheet formation leads to well-organized structures, while also the aromatic core of the macrocycles plays an important role in the stability of the resulting fibers. PMID- 28723069 TI - Surface-Localized Sealing of Porous Ultralow-k Dielectric Films with Ultrathin (<2 nm) Polymer Coating. AB - Semiconductor integrated circuit chip industries have been striving to introduce porous ultralow-k (ULK) dielectrics into the multilevel interconnection process in order to improve their chip operation speed by reducing capacitance along the signal path. To date, however, highly porous ULK dielectrics (porosity >40%, dielectric constant (k) <2.4) have not been successfully adopted in real devices because the porous nature causes many serious problems, including noncontinuous barrier deposition, penetration of the barrier metal, and reliability issues. Here, a method that allows porous ULK dielectrics to be successfully used with a multilevel interconnection scheme is presented. The surface of the porous ULK dielectric film (k = 2.0, porosity ~47%) could be completely sealed by a thin (<2 nm) polymer deposited by a multistep initiated chemical vapor deposition (iCVD) process. Using the iCVD process, a thin pore-sealing layer was localized only to the surface of the porous ULK dielectric film, which could minimize the increase of k; the final effective k was less than 2.2, and the penetration of metal barrier precursors into the dielectric film was completely blocked. The pore sealed ULK dielectric film also exhibited excellent long-term reliability comparable to a dense low-k dielectric film. PMID- 28723070 TI - Correction to "Reversibly Actuating Solid Janus Polymeric Fibers". PMID- 28723071 TI - Maleic Anhydride Labeling-Based Approach for Quantitative Proteomics and Successive Derivatization of Peptides. AB - Chemical derivatization is a simple approach for stable-isotope covalent labeling of proteins in quantitative proteomics. Herein we describe the development of a novel maleyl-labeling-based approach for protein quantification. Under optimized conditions, maleic anhydride can serve as a highly efficient reagent to label the amino groups of tryptic peptides. Furthermore, "click chemistry" was successfully applied to obtain the second modification of maleylated peptides via thiol Michael addition reaction. Accurate quantification was further achieved via the first or/and second step stable-isotope labeling in this study. Our data thus demonstrate that the maleyl-labeling-based method is simple, accurate, and reliable for quantitative proteomics. The developed method not only enables an enhanced sequence coverage of proteins by improving the identification of small and hydrophilic peptides, but also enables a controllable, successive, second derivatization of labeled peptides or proteins, and therefore holds a very promising potential for in-depth analysis of protein structures and dynamics. PMID- 28723072 TI - Superposition Principle in Auger Recombination of Charged and Neutral Multicarrier States in Semiconductor Quantum Dots. AB - Application of colloidal semiconductor quantum dots (QDs) in optical and optoelectronic devices is often complicated by unintentional generation of extra charges, which opens fast nonradiative Auger recombination pathways whereby the recombination energy of an exciton is quickly transferred to the extra carrier(s) and ultimately dissipated as heat. Previous studies of Auger recombination have primarily focused on neutral and, more recently, negatively charged multicarrier states. Auger dynamics of positively charged species remains more poorly explored due to difficulties in creating, stabilizing, and detecting excess holes in the QDs. Here we apply photochemical doping to prepare both negatively and positively charged CdSe/CdS QDs with two distinct core/shell interfacial profiles ("sharp" versus "smooth"). Using neutral and charged QD samples we evaluate Auger lifetimes of biexcitons, negative and positive trions (an exciton with an extra electron or a hole, respectively), and multiply negatively charged excitons. Using these measurements, we demonstrate that Auger decay of both neutral and charged multicarrier states can be presented as a superposition of independent elementary three-particle Auger events. As one of the manifestations of the superposition principle, we observe that the biexciton Auger decay rate can be presented as a sum of the Auger rates for independent negative and positive trion pathways. By comparing the measurements on the QDs with the "sharp" versus "smooth" interfaces, we also find that while affecting the absolute values of Auger lifetimes, manipulation of the shape of the confinement potential does not lead to violation of the superposition principle, which still allows us to accurately predict the biexciton Auger lifetimes based on the measured negative and positive trion dynamics. These findings indicate considerable robustness of the superposition principle as applied to Auger decay of charged and neutral multicarrier states, suggesting its generality to quantum-confined nanocrystals of arbitrary compositions and complexities. PMID- 28723073 TI - Experimental Determination of the Ionization Energies of MoSe2, WS2, and MoS2 on SiO2 Using Photoemission Electron Microscopy. AB - The values of the ionization energies of transition metal dichalcogenides (TMDs) are needed to assess their potential usefulness in semiconductor heterojunctions for high-performance optoelectronics. Here, we report on the systematic determination of ionization energies for three prototypical TMD monolayers (MoSe2, WS2, and MoS2) on SiO2 using photoemission electron microscopy with deep ultraviolet illumination. The ionization energy displays a progressive decrease from MoS2, to WS2, to MoSe2, in agreement with predictions of density functional theory calculations. Combined with the measured energy positions of the valence band edge at the Brillouin zone center, we deduce that, in the absence of interlayer coupling, a vertical heterojunction comprising any of the three TMD monolayers would form a staggered (type-II) band alignment. This band alignment could give rise to long-lived interlayer excitons that are potentially useful for valleytronics or efficient electron-hole separation in photovoltaics. PMID- 28723074 TI - Paper-Based Bimodal Sensor for Electronic Skin Applications. AB - We present the development of a flexible bimodal sensor using a paper platform and inkjet printing method, which are suited for low-cost fabrication processes and realization of flexible devices. In this study, we employed a vertically stacked bimodal device architecture in which a temperature sensor is stacked on top of a pressure sensor and operated on different principles, allowing the minimization of interference effects. For the temperature sensor placed in the top layer, we used the thermoelectric effect and formed a closed-loop thermocouple composed of two different printable inks (conductive PEDOT:PSS and silver nanoparticles on a flexible paper platform) and obtained temperature sensing capability over a wide range (150 degrees C). For the pressure sensor positioned in the bottom layer, we used microdimensional pyramid-structured poly(dimethylsiloxane) coated with multiwall carbon nanotube conducting ink. Our pressure sensor exhibits a high-pressure sensitivity over a wide range (100 Pa to 5 kPa) and high-endurance characteristics of 105. Our 5 * 5 bimodal sensor array demonstrates negligible interference, high-speed responsivity, and robust sensing characteristics. We believe that the material, process, two-terminal device, and integration scheme developed in this study have a great value that can be widely applied to electronic skin. PMID- 28723075 TI - Top-down/Bottom-up Mass Spectrometry Workflow Using Dissolvable Polyacrylamide Gels. AB - Biologists' preeminent toolbox for separating, analyzing, and visualizing proteins is SDS-PAGE, yet recovering the proteins embedded in these polyacrylamide media as intact species is a long-standing challenge for mass spectrometry. In conventional workflows, protein mixtures from crude biological samples are electrophoretically separated at high-resolution within N,N' methylene-bis-acrylamide cross-linked polyacrylamide gels to reduce sample complexity and facilitate sensitive characterization. However, low protein recoveries, especially for high molecular weight proteins, often hinder characterization by mass spectrometry. We describe a workflow for top-down/bottom up mass spectrometric analyses of proteins in polyacrylamide slab gels using dissolvable, bis-acryloylcystamine-cross-linked polyacrylamide, enabling high resolution protein separations while recovering intact proteins over a broad size range efficiently. The inferior electrophoretic resolution long associated with reducible gels has been overcome, as demonstrated by SDS-PAGE of crude tissue extracts. This workflow elutes intact proteins efficiently, supporting MS and MS/MS from proteins resolved on biologists' preferred separation platform. PMID- 28723076 TI - Investigation on the Transformation of Absorbed Oxygen at ZnO {1010} Surface Based on a Novel Thermal Pulse Method and Density Functional Theory Simulation. AB - Absorbed oxygen plays a key role in gas sensing process of ZnO nanomaterials. In this work, the transformation of absorbed oxygen on ZnO (1010) and its effects on gas sensing properties to ethanol are studied by a novel thermal pulse method and density functional theory (DFT) simulation. Thermal pulse results reveal that the absorbed O2 molecule dissociates into two individual oxygen adatoms by extracting electrons from ZnO surface layers when temperature is above 443 K. The temperature at which absorbed O2 molecule begins to dissociate is the lowest working temperature for gas sensing. DFT simulation demonstrates the dissociation process of O2 at ZnO (1010) surface, and the activation energy (Ea) of dissociation is calculated to be 351.71 kJ/mol, which suggests that the absorbed O2 molecule is not likely to dissociate at room temperature. The reactions between ethanol and absorbed O2 molecule, as well as reactions between ethanol and O adatom, are also simulated. The results indicate that ethanol cannot react with absorbed O2 molecule, while it can be oxidized by O adatom to acetaldehyde and then to acetic acid spontaneously. Mulliken charge analysis suggests electrons extracted by O adatom return to ZnO after the oxidation of ethanol. PMID- 28723077 TI - Comparison of Methods to Release Mucin-Type O-Glycans for Glycomic Analysis. AB - Mucin-type O-glycans (O-glycans) are one of the most common glycans attached to proteins. To develop an optimized glycomic analysis protocol, O-glycans were released from glycoproteins using hydrazine, ammonia, or sodium hydroxide treatment, followed by hydrophilic interaction liquid chromatography to evaluate O-glycan release. We found that porcine gastric mucin or bovine fetuin treated at 60 degrees C for 6 h with hydrazine gas in the presence of malonic acid yielded O-glycans with only a small amount of degraded, so-called "peeled" products. Ammonia treatment also yielded intact O-glycans but with additional peeled products containing GlcNAc at the reducing end. In contrast, sodium hydroxide treatment yielded mainly peeled glycans, including those containing GlcNAc at the reducing end. Importantly, O-glycans obtained from rat gastric mucin treated with hydrazine and labeled with anthranilic acid had a nearly identical profile following hydrophilic interaction liquid chromatography as permethylated O-glycan alditols analyzed by mass spectroscopy. Taken together, the data suggest that glycan release using hydrazine treatment, followed by high-performance liquid chromatography after fluorescent labeling, is a suitable method for glycomic analysis of mucin-type O-glycans. PMID- 28723078 TI - Covalency Competition in the Quadruple Perovskite CdCu3Fe4O12. AB - Cadmium ions (Cd2+) are similar to calcium ions (Ca2+) in size, whereas the Cd2+ ions tend to form covalent bonds with the neighboring anions because of the high electronegativity. The covalent Cd-O bonds affect other metal-oxygen bonds, inducing drastic changes in crystal structures and electronic states. Herein, we demonstrate high-pressure synthesis, crystal structure, and properties of a new quadruple perovskite CdCu3Fe4O12. This compound exhibits an electronic phase transition accompanying a charge disproportionation of Fe ions without charge ordering below ~200 K, unlike charge-disproportionation transition with rock-salt type charge ordering for CaCu3Fe4O12. First-principle calculations and Mossbauer spectroscopy display that covalent Cd-O bonds effectively suppress the Fe-O bond covalency, resulting in an electronic state different from that of CaCu3Fe4O12. This finding proposes covalency competition among constituent metal ions dominating electronic states of complex metal oxides. PMID- 28723079 TI - Exploring the Role of Carbonate in the Formation of an Organomanganese Tetramer. AB - The formation of metal-oxygen clusters is an important chemical transformation in biology and catalysis. For example, the biosynthesis of the oxygen-evolving complex in the enzyme photosystem II is a complicated stepwise process that assembles a catalytically active cluster. Herein we describe the role that carbonato ligands have in the formation of the known tetrameric complex [Mn(CO)3(MU3-OH)]4 (1). Complex 1 is synthesized in one step via the treatment of Mn2(CO)10 with excess Me3NO.2H2O. Alternatively, when anhydrous Me3NO is used, an OH-free synthetic intermediate (2) with carbonato ligands is produced. Complex 2 produces carbon dioxide, Me3NO.2H2O, and 1 when treated with water. Labeling studies reveal that the MU3-OH ligands in 1 are derived from the water and possibly the carbonato ligands in 2. PMID- 28723081 TI - Fluorescent Molecular Probes for Detection of One-Electron Oxidants Photochemically Generated by Dissolved Organic Matter. AB - We report a dual probe system based on 4'-substituted biphenyl-2-carboxylic acids (BPAs) for analysis of photooxidants generated by dissolved organic matter. The BPA probes are converted to the corresponding benzocoumarins (BZCs) at different rates depending on the mechanism of oxidation; thus, two probes used simultaneously can differentiate strong triplet excited state sensitizers from hydroxylating species such as hydroxyl radical (*OH) present in dissolved organic matter (DOM). Comparison of the ratios of BZC-CH3 and BZC-CF3 product formation using model photooxidants such as NaNO2, a *OH precursor, and model triplet sensitizer lumichrome gave a range of 2 to 250. Application of these probes to DOM isolates and whole natural waters afforded intermediate ratios. Although the oxidation potential of BPAs (>ca. 1.80 V SHE) is significantly higher than the estimated average reduction potential of typical 3CDOM* samples, these results have demonstrated the presence of a small pool of oxidants in the selected DOM isolates and whole water samples that is capable of oxidizing aromatic carboxylates. As an analytical tool, this probe pair can be used between pH 4-6 without affecting the product formation ratio and may find applications in various systems involving complex mixtures of photochemically produced oxidants of differing natures. PMID- 28723080 TI - An Orthogonal Multi-input Integration System to Control Gene Expression in Escherichia coli. AB - In many biotechnological applications, it is useful for gene expression to be regulated by multiple signals, as this allows the programming of complex behavior. Here we implement, in Escherichia coli, a system that compares the concentration of two signal molecules, and tunes GFP expression proportionally to their relative abundance. The computation is performed via molecular titration between an orthogonal sigma factor and its cognate anti-sigma factor. We use mathematical modeling and experiments to show that the computation system is predictable and able to adapt GFP expression dynamically to a wide range of combinations of the two signals, and our model qualitatively captures most of these behaviors. We also demonstrate in silico the practical applicability of the system as a reference-comparator, which compares an intrinsic signal (reflecting the state of the system) with an extrinsic signal (reflecting the desired reference state) in a multicellular feedback control strategy. PMID- 28723082 TI - Mixed Valency in a 3D Semiconducting Iron-Fluoranilate Coordination Polymer. AB - A pair of coordination polymers of composition (NBu4)2[M2(fan)3] (fan = fluoranilate; M = Fe and Zn) were synthesized and structurally characterized. In each case the compound consists of a pair of interpenetrating three-dimensional, (10,3)-a networks in which metal centers are linked by chelating/bridging fluoranilate ligands. Tetrabutylammonium cations are located in the spaces between the two networks. Despite the structural similarity, significant differences exist between (NBu4)2[Fe2(fan)3] and (NBu4)2[Zn2(fan)3] with respect to the oxidation states of the metal centers and ligands. For (NBu4)2[Fe2(fan)3] the structure determination as well as Mossbauer spectroscopy indicate the oxidation state for the Fe is close to +3, which contrasts with the +2 state for the Zn analogue. The differences between the two compounds extends to the ligands, with the Zn network involving only fluoranilate dianions, whereas the average oxidation state for the fluoranilate in the Fe network lies somewhere between -2 and -3. Magnetic studies on the Fe compound indicate short-range ordering. Electrochemical and spectro-electrochemical investigations indicate that the fluoranilate ligand is redox-active in both complexes; a reduced form of (NBu4)2[Fe2(fan)3] was generated by chemical reduction. Conductivity measurements indicate that (NBu4)2[Fe2(fan)3] is a semiconductor, which is attributed to the mixed valency of the fluoranilate ligands. PMID- 28723083 TI - Correction to "Observing Extremely Weak Protein-Protein Interactions with Conventional Single-Molecule Fluorescence Microscopy". PMID- 28723084 TI - Mineral Reactions in Shale Gas Reservoirs: Barite Scale Formation from Reusing Produced Water As Hydraulic Fracturing Fluid. AB - Hydraulic fracturing for gas production is now ubiquitous in shale plays, but relatively little is known about shale-hydraulic fracturing fluid (HFF) reactions within the reservoir. To investigate reactions during the shut-in period of hydraulic fracturing, experiments were conducted flowing different HFFs through fractured Marcellus shale cores at reservoir temperature and pressure (66 degrees C, 20 MPa) for one week. Results indicate HFFs with hydrochloric acid cause substantial dissolution of carbonate minerals, as expected, increasing effective fracture volume (fracture volume + near-fracture matrix porosity) by 56 65%. HFFs with reused produced water composition cause precipitation of secondary minerals, particularly barite, decreasing effective fracture volume by 1-3%. Barite precipitation occurs despite the presence of antiscalants in experiments with and without shale contact and is driven in part by addition of dissolved sulfate from the decomposition of persulfate breakers in HFF at reservoir conditions. The overall effect of mineral changes on the reservoir has yet to be quantified, but the significant amount of barite scale formed by HFFs with reused produced water composition could reduce effective fracture volume. Further study is required to extrapolate experimental results to reservoir-scale and to explore the effect that mineral changes from HFF interaction with shale might have on gas production. PMID- 28723086 TI - Formation of Core-Shell Ethane-Silver Clusters in He Droplets. AB - Ethane core-silver shell clusters consisting of several thousand particles have been assembled in helium droplets upon capture of ethane molecules followed by Ag atoms. The composite clusters were studied via infrared laser spectroscopy in the range of the C-H stretching vibrations of ethane. The spectra reveal a splitting of the vibrational bands, which is ascribed to interaction with Ag. A rigorous analysis of band intensities for a varying number of trapped ethane molecules and Ag atoms indicates that the composite clusters consist of a core of ethane that is covered by relatively small Ag clusters. This metastable structure is stabilized due to fast dissipation in superfluid helium droplets of the cohesion energy of the clusters. PMID- 28723085 TI - Catalytic Allylic Oxidation of Cyclic Enamides and 3,4-Dihydro-2H-Pyrans by TBHP. AB - Allylic oxidation of heteroatom substituted cyclic alkenes by tert-butyl hydroperoxide (70% TBHP in water) using catalytic dirhodium caprolactamate [Rh2(cap)4] forms enone products with a variety of 2-substituted cyclic enamides and 3,4-dihyro-2H-pyrans. These reactions occur under mild reaction conditions, are operationally convenient to execute, and are effective for product formation with as low as 0.25 mol% catalyst loading. With heteroatom stabilization of the intermediate allylic free radical two sites for oxidative product formation are possible, and the selectivity of the oxidative process varies with the heteroatom when R = H. Cyclic enamides produce 4-piperidones in good yields when R = alkyl or aryl, but oxidation of 2H-pyrans also gives alkyl cleavage products. Alternative catalysts for TBHP oxidations show comparable selectivities but give lower product yields. PMID- 28723087 TI - Developing Collaborative QSAR Models Without Sharing Structures. AB - It is widely understood that QSAR models greatly improve if more data are used. However, irrespective of model quality, once chemical structures diverge too far from the initial data set, the predictive performance of a model degrades quickly. To increase the applicability domain we need to increase the diversity of the training set. This can be achieved by combining data from diverse sources. Public data can be easily included; however, proprietary data may be more difficult to add due to intellectual property concerns. In this contribution, we will present a method for the collaborative development of linear regression models that addresses this problem. The method differs from other past approaches, because data are only shared in an aggregated form. This prohibits access to individual data points and therefore avoids the disclosure of confidential structural information. The final models are equivalent to models that were built with combined data sets. PMID- 28723088 TI - Development of a Transferable Reactive Force Field of P/H Systems: Application to the Chemical and Mechanical Properties of Phosphorene. AB - We developed ReaxFF parameters for phosphorus and hydrogen to give a good description of the chemical and mechanical properties of pristine and defected black phosphorene. ReaxFF for P/H is transferable to a wide range of phosphorus- and hydrogen-containing systems including bulk black phosphorus, blue phosphorene, edge-hydrogenated phosphorene, phosphorus clusters, and phosphorus hydride molecules. The potential parameters were obtained by conducting global optimization with respect to a set of reference data generated by extensive ab initio calculations. We extended ReaxFF by adding a 60 degrees correction term, which significantly improved the description of phosphorus clusters. Emphasis was placed on the mechanical response of black phosphorene with different types of defects. Compared to the nonreactive SW potential ( Jiang , J.-W. Nanotechnology 2015 , 26 , 315706 ), ReaxFF for P/H systems provides a significant improvement in describing the mechanical properties of the pristine and defected black phosphorene, as well as the thermal stability of phosphorene nanotubes. A counterintuitive phenomenon is observed that single vacancies weaken the black phosphorene more than double vacancies with higher formation energy. Our results also showed that the mechanical response of black phosphorene is more sensitive to defects in the zigzag direction than that in the armchair direction. In addition, we developed a preliminary set of ReaxFF parameters for P/H/O/C to demonstrate that the ReaxFF parameters developed in this work could be generalized to oxidized phosphorene and P-containing 2D van der Waals heterostructures. That is, the proposed ReaxFF parameters for P/H systems establish a solid foundation for modeling of a wide range of P-containing materials. PMID- 28723089 TI - New Class of Glycoside Hydrolase Mechanism-Based Covalent Inhibitors: Glycosylation Transition State Conformations. AB - The design of covalent inhibitors in glycoscience research is important for the development of chemical biology probes. Here we report the synthesis of a new carbocyclic mechanism-based covalent inhibitor of an alpha-glucosidase. The enzyme efficiently catalyzes its alkylation via either an allylic cation or a cationic transition state. We show this allylic covalent inhibitor has different catalytic proficiencies for pseudoglycosylation and deglycosylation. Such inhibitors have the potential to be useful chemical biology tools. PMID- 28723090 TI - Transformative Heterointerface Evolution and Plasmonic Tuning of Anisotropic Trimetallic Nanoparticles. AB - Multicomponent nanoparticles that incorporate multiple nanocrystal domains into a single particle represent an important class of material with highly tailorable structures and properties. The controlled synthesis of multicomponent NPs with 3 or more components in the desired structure, particularly anisotropic structure, and property is, however, challenging. Here, we developed a polymer and galvanic replacement reaction-based transformative heterointerface evolution (THE) method to form and tune gold-copper-silver multimetallic anisotropic nanoparticles (MAPs) with well-defined configurations, including structural order, particle and junction geometry, giving rise to extraordinarily high tunability in the structural design, synthesis and optical property of trimetallic plasmonic nanoantenna structures. MAPs can easily, flexibly integrate multiple surface plasmon resonance (SPR) peaks and incorporate various plasmonic field localization and enhancement within one structure. Importantly, a heteronanojunction in these MAPs can be finely controlled and hence tune the SPR properties of these structures, widely covering UV, visible and near-infrared range. The development of the THE method and new findings in synthesis and property tuning of multicomponent nanostructures pave ways to the fabrication of highly tailored multicomponent nanohybrids and realization of their applications in optics, energy, catalysis and biotechnology. PMID- 28723091 TI - Protomer-Specific Photochemistry Investigated Using Ion Mobility Mass Spectrometry. AB - The utility of tandem ion mobility mass spectrometry coupled with electronic spectroscopy to investigate protomer-specific photochemistry is demonstrated by measuring the photoisomerization response for protomers of protonated 4 dicyanomethylene-2-methyl-6-para-dimethylaminostyryl-4H-pyran (DCM) molecules. The target DCMH+ species has three protomers that are distinguished by their different collision cross sections with He, N2, and CO2 buffer gases, trends in abundance with ion source conditions, and from their photoisomerization responses. The trans-DCMH+ protomers with the proton located either on the tertiary amine N atom or on a cyano group N atom exhibit distinct S1<- S0 photoisomerization responses, with the maxima in their photoisomerization action spectra occurring at 420 and 625 nm, respectively, consistent with predictions from accompanying electronic structure calculations. The cis-DCMH+ protomers are not distinguishable from one another through ion mobility separation and give no discernible photoisomerization or photodissociation response, suggesting the dominance of other deactivation pathways such as fluorescence. The study demonstrates that isobaric protomers and isomers generated by an electrospray ion source can possess quite different photochemical behaviors and emphasizes the utility of isomer and protomer selective techniques for exploring the spectroscopic and photochemical properties of protonated molecules in the gas phase. PMID- 28723092 TI - Microwave-Assisted Synthesis of Diversely Substituted Quinoline-Based Dihydropyridopyrimidine and Dihydropyrazolopyridine Hybrids. AB - An efficient, catalyst-free, and one-pot three-component procedure for the synthesis of novel and nitrogen rich dihydropyrido[2,3-d]pyrimidines and dihydro 1H-pyrazolo[3,4-b]pyridines bearing a quinoline pharmacophore fragment is provided. Reactions proceeded in DMF under microwave irradiation of three component mixtures of formyl-quinoline derivatives, primary heterocyclic amines and cyclic 1,3-diketones. Interestingly, when conventional heating at reflux was used for the starting 5-amino-1-phenylpyrazole, the corresponding aromatized pyrazolopyridines were obtained as the main products. Single crystal X-ray analysis confirmed unequivocally the structure of both the dihydro- and aromatized products. PMID- 28723093 TI - Plasmonic Aerogels as a Three-Dimensional Nanoscale Platform for Solar Fuel Photocatalysis. AB - We use plasmonic Au-TiO2 aerogels as a platform in which to marry synthetically thickened particle-particle junctions in TiO2 aerogel networks to Au?TiO2 interfaces and then investigate their cooperative influence on photocatalytic hydrogen (H2) generation under both broadband (i.e., UV + visible light) and visible-only excitation. In doing so, we elucidate the dual functions that incorporated Au can play as a water reduction cocatalyst and as a plasmonic sensitizer. We also photodeposit non-plasmonic Pt cocatalyst nanoparticles into our composite aerogels in order to leverage the catalytic water-reducing abilities of Pt. This Au-TiO2/Pt arrangement in three dimensions effectively utilizes conduction-band electrons injected into the TiO2 aerogel network upon exciting the Au SPR at the Au?TiO2 interface. The extensive nanostructured high surface-area oxide network in the aerogel provides a matrix that spatially separates yet electrochemically connects plasmonic nanoparticle sensitizers and metal nanoparticle catalysts, further enhancing solar-fuels photochemistry. We compare the photocatalytic rates of H2 generation with and without Pt cocatalysts added to Au-TiO2 aerogels and demonstrate electrochemical linkage of the SPR generated carriers at the Au?TiO2 interfaces to downfield Pt nanoparticle cocatalysts. Finally, we investigate visible light-stimulated generation of conduction band electrons in Au-TiO2 and TiO2 aerogels using ultrafast visible pump/IR probe spectroscopy. Substantially more electrons are produced at Au-TiO2 aerogels due to the incorporated SPR-active Au nanoparticle, whereas the smaller population of electrons generated at Au-free TiO2 aerogels likely originate at shallow traps in the high surface-area mesoporous aerogel. PMID- 28723095 TI - Facile and Low-Temperature Fabrication of Thermochromic Cr2O3/VO2 Smart Coatings: Enhanced Solar Modulation Ability, High Luminous Transmittance and UV-Shielding Function. AB - In the pursuit of energy efficient materials, vanadium dioxide (VO2) based smart coatings have gained much attention in recent years. For smart window applications, VO2 thin films should be fabricated at low temperature to reduce the cost in commercial fabrication and solve compatibility problems. Meanwhile, thermochromic performance with high luminous transmittance and solar modulation ability, as well as effective UV shielding function has become the most important developing strategy for ideal smart windows. In this work, facile Cr2O3/VO2 bilayer coatings on quartz glasses were designed and fabricated by magnetron sputtering at low temperatures ranging from 250 to 350 degrees C as compared with typical high growth temperatures (>450 degrees C). The bottom Cr2O3 layer not only provides a structural template for the growth of VO2 (R), but also serves as an antireflection layer for improving the luminous transmittance. It was found that the deposition of Cr2O3 layer resulted in a dramatic enhancement of the solar modulation ability (56.4%) and improvement of luminous transmittance (26.4%) when compared to single-layer VO2 coating. According to optical measurements, the Cr2O3/VO2 bilayer structure exhibits excellent optical performances with an enhanced solar modulation ability (DeltaTsol = 12.2%) and a high luminous transmittance (Tlum,lt = 46.0%), which makes a good balance between DeltaTsol and Tlum for smart windows applications. As for UV-shielding properties, more than 95.8% UV radiation (250-400 nm) can be blocked out by the Cr2O3/VO2 structure. In addition, the visualized energy-efficient effect was modeled by heating a beaker of water using infrared imaging method with/without a Cr2O3/VO2 coating glass. PMID- 28723096 TI - Nickel Particles Selectively Confined in the Mesoporous Channels of SBA-15 Yielding a Very Stable Catalyst for DRM Reaction. AB - A series of four Ni catalysts supported on SBA-15 and on a high SiO2 surface area have been prepared by modified impregnation (ImU) and deposition-precipitation (DP) methods. The catalysts have been extensively characterized, including in situ XAS (bulk sensitive) and XPS (surface sensitive) techniques, and their catalytic activities evaluated in the dry reforming reaction of methane (DRM). The combined use of XPS and XAS has allowed us to determine the location of nickel particles on each catalyst after reduction at high temperature (750 degrees C). Both Ni/SiO2-DP and Ni/SBA-15-DP catalysts yield well-dispersed and homogeneous metallic phases mainly located in the mesoporosity of both supports. On the contrary, the Ni/SiO2-ImU and Ni/SBA-15-ImU catalysts present a bimodal distribution of the reduced nickel phase, with nickel metallic particles located out and into the mesoporous structure of SiO2 or the SBA-15 channels. The Ni/SBA 15-DP catalyst was found the most stable and performing system, with a very low level of carbon deposition, about an order of magnitude lower than the equivalent ImU catalyst. This outstanding performance comes from the confinement of small and homogeneous nickel particles in the mesoporous channels of SBA-15, which, in strong interaction with the support, are resistant to sintering and coke deposition during the demanding reaction conditions of DRM. PMID- 28723094 TI - Structure-Activity Relationships Reveal Key Features of 8-Oxoguanine: A Mismatch Detection by the MutY Glycosylase. AB - Base excision repair glycosylases locate and remove damaged bases in DNA with remarkable specificity. The MutY glycosylases, unusual for their excision of undamaged adenines mispaired to the oxidized base 8-oxoguanine (OG), must recognize both bases of the mispair in order to prevent promutagenic activity. Moreover, MutY must effectively find OG:A mismatches within the context of highly abundant and structurally similar T:A base pairs. Very little is known about the factors that initiate MutY's interaction with the substrate when it first encounters an intrahelical OG:A mispair, or about the order of recognition checkpoints. Here, we used structure-activity relationships (SAR) to investigate the features that influence the in vitro measured parameters of mismatch affinity and adenine base excision efficiency by E. coli MutY. We also evaluated the impacts of the same substrate alterations on MutY-mediated repair in a cellular context. Our results show that MutY relies strongly on the presence of the OG base and recognizes multiple structural features at different stages of recognition and catalysis to ensure that only inappropriately mispaired adenines are excised. Notably, some OG modifications resulted in more dramatic reductions in cellular repair than in the in vitro kinetic parameters, indicating their importance for initial recognition events needed to locate the mismatch within DNA. Indeed, the initial encounter of MutY with its target base pair may rely on specific interactions with the 2-amino group of OG in the major groove, a feature that distinguishes OG:A from T:A base pairs. These results furthermore suggest that inefficient substrate location in human MutY homologue variants may prove predictive for the early onset colorectal cancer phenotype known as MUTYH Associated Polyposis, or MAP. PMID- 28723097 TI - Decorating of Ag and CuO on Cu Nanoparticles for Enhanced High Catalytic Activity to the Degradation of Organic Pollutants. AB - Metal/semiconductor composites are promising catalysts with superior catalytic activity. In this work, a Cu/CuO-Ag composite with structure that consisted of Ag and CuO nanoparticles (NPs) decorated on the surface of Cu were fabricated via a facile in situ method. With characterization by transmission electron microscopy (TEM), X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), energy dispersive X-ray spectroscopy (EDX), and inductively coupled plasma atomic emission spectrometry (ICP-AES), the structure and components of the Cu/CuO-Ag composite were well-defined. The Cu/CuO-Ag composite exhibited superior catalytic activities for the reduction of 4-nitrophenol (4-NP) in the presence of NaBH4 with just a trace amount of Ag NPs (1.28 wt %). The reduction reaction is completed in 75 s with an apparent rate constant kapp of 4.60 * 10-2 s-1. The Cu/CuO-Ag composite also showed excellent durable catalytic stability, as no significant activity loss was detected in the consecutive five reaction runs. With the aid of the Sabatier principle and volcano plot, the opportune chemical adsorption energy of the reagent 4-NP on the Cu/CuO-Ag composite was inferred to be the key to its high reaction rate. The CuO NPs as a semiconductor with narrow band gap also could help the Cu/CuO-Ag composite to capture the electrons/hydride ions and increase opportunities for 4-NP to be reduced. Furthermore, the Cu/CuO Ag composite exhibited outstanding activity on the oxidative degradation of methylene blue (MB). This work enriched the bimetal/semiconductor catalyst system and supplied new insight into the catalysis mechanism. PMID- 28723098 TI - A New Area in Main-Group Chemistry: Zerovalent Monoatomic Silicon Compounds and Their Analogues. AB - Monoatomic zerovalent main-group element complexes emerged very recently and attracted increasing attention of both theoretical and experimental chemists. In particular, zerovalent silicon complexes and their congeners (metallylones) stabilized by neutral Lewis donors are of significant importance not only because of their intriguing electronic structure but also because they can serve as useful building blocks for novel chemical species. Featuring four valence electrons as two lone pairs at the central atoms, such complexes may form donor acceptor adducts with Lewis acids. More interestingly, with the central atoms in the oxidation state of zero, they could pave a way to new classes of compounds and functional groups that are otherwise difficult to realize. In this Account, we mainly describe our contributions in the chemistry of monatomic zerovalent silicon (silylone) and germanium (germylone) supported by a chelate bis-N heterocyclic carbene (bis-NHC) ligand in the context of related species developed by other groups in the meantime. Utilizing the bis-NHC stabilized chlorosilyliumylidene [:SiCl]+ and chlorogermyliumylidene [:GeCl]+ as suitable starting materials, we successfully isolated silylone (bis-NHC)Si and germylone (bis-NHC)Ge, respectively. The electronic structures of the latter complexes established by theoretical calculations and spectroscopic data revealed that they are genuine metallylone species with electron-rich silicon(0) and germanium(0) centers. Accordingly, they can react with 1 molar equiv of GaCl3 to form Lewis adducts (bis-NHC)E(GaCl3) (E = Si, Ge) and with 2 molar equiv of ZnCl2 to furnish (bis-NHC)Si(ZnCl2)2. Conversion of the metallylones with elemental chalcogens affords isolable monomeric silicon(II) and germanium(II) monochalcogenides (bis NHC)EX(GaCl3) (X = Se, Te), representing molecular heavier congeners of CO. Moreover, their reaction with elemental chalcogens can also yield monomeric silicon(IV) and germanium(IV) dichalcogenides (bis-NHC)EX2 (X = S, Se, Te) as the first isolable complexes of the molecular congeners of CO2. Moreover, (bis-NHC)Si could even activate CO2 to afford the monomolecular silicon dicarbonate complex (bis-NHC)Si(CO3)2 via the formation of SiO and SiO2 complexes as intermediates. Furthermore, starting with a chelate bis-N-heterocyclic silylene supported [:GeCl]+, we developed two bis-N-heterocyclic silylene stabilized germylone >Fe(CO)4 complexes. Our achievements in the chemistry of metallylones demonstrate that the characteristic of monatomic zerovalent silicon and its analogues can provide novel reaction patterns for access to unprecedented species and even extends the series of functional groups of these elements. With this, we can envision that more interesting zerovalent complexes of the main-group elements with unprecedented reactivity will follow in the near future. PMID- 28723099 TI - Fledging Critical Zone Science for Environmental Sustainability. PMID- 28723100 TI - To Be or Not to Be? Five Guidelines to Avoid Misassignments in Cross-Linking/Mass Spectrometry. AB - The number of publications in the field of chemical cross-linking/mass spectrometry (MS) for deriving protein 3D structures and for probing protein/protein interactions has largely increased during the last years. MS analysis of the large cross-linking data sets requires an automated data analysis by dedicated software tools, but applying scoring procedures with statistical methods does not eliminate the fundamental problems of a misassignment of cross linked products. In fact, we have observed a significant rate of misassigned cross-links in a number of publications, mainly due to the presence of isobaric cross-linked species, an incomplete fragmentation of cross-linked products, and low-mass accuracy fragment ion data. These false assignments will eventually lead to wrong conclusions on the structural information derived from chemical cross linking/MS experiments. In this contribution, we examine the most common sources for misassigning cross-linked products. We propose and discuss rational criteria and suggest five guidelines that might be followed for a reliable and unambiguous identification of cross-links, independent of the software used for data analysis. In the interest of the cross-linking/MS approach, it should be ensured that only high-quality data enter the structural biology literature. Clearly, there is an urgent need to define common standards for data analysis and reporting formats of cross-linked products. PMID- 28723102 TI - Insight into Copper Catalysis: In Situ Formed Nano Cu2O in Suzuki-Miyaura Cross Coupling of Aryl/Indolyl Boronates. AB - A ligand-free copper catalyzed Suzuki-Miyaura coupling of 3,5-diiodopyridine with aryl and indole boronates has been explored in good to excellent yields. In situ generation of nano-Cu2O from CuCl2 under the reaction conditions has been discovered for the first time. The generality of the reaction was further demonstrated by the arylation of 5-iodopyrimidine, iodopyridines, iodobenzenes, and diiodobenzenes and resulted in good to moderate yields. Moreover, bisindole alkaloid Scalaridine A has been successfully synthesized in 60% overall yield. PMID- 28723103 TI - Synthesis of a Tiacumicin B Protected Aglycone. AB - Tiacumicin B is an antibiotic endowed with the remarkable ability to interact with a new biological target, giving it an inestimable potential in the context of the ever-growing and worrisome appearance of resistances of bacteria and mycobacteria to antibiotics. The synthesis of an aglycone of tiacumicin B ready for glycosylation is reported. The key steps of this approach are a [2,3]-Wittig rearrangement, a Pd/Cu-catalyzed allene-alkyne cross-coupling, a E-selective cross-metathesis, and a final ring-size selective macrolactonization. PMID- 28723104 TI - Chemo- and Stereoselective Crotylation of Aldehydes and Cyclic Aldimines with Allylic gem-Diboronate Ester. AB - We report a highly chemo- and stereoselective crotylation of aldehydes and cyclic aldimines with allylic-gem-diboronate ester as a new type of organoboron reagent. The allylic-gem-diboronate ester undergoes the crotylation with aldehydes and cyclic aldimines in excellent stereoselectivity, forming anti-5,6-disubstituted oxaborinin-2-ols or (E)-delta-boryl-anti-homoallylic amines in high efficiency. The reaction shows a wide range of substrate scope and excellent functional group tolerance. The synthetic applications of the obtained products, including stereospecific C-C, C-O, and C-Cl bond formation, are also demonstrated. PMID- 28723105 TI - Electroosmotic Effects on Sample Concentration at the Interface of a Micro/Nanochannel. AB - Electroosmotic effect on electropreconcentration of analytes was investigated at the micro/nanochannel interface for a series of 1-D glass nanochannels with depths of 72, 54, 29, and 9 nm. The electric double layer approaches overlap conditions as the nanochannel depth decreases, suppressing the electroosmotic flow. The nanochannels' electroosmotic flows (MUeonano) were determined and compared to the analyte's (fluorescein) electrophoretic mobility (MUep). For the instances where MUeonano > MUep, the analytes were concentrated on the anodic side of the nanochannel (72, 54, and 29 nm deep channels), whereas when MUeonano < MUep, the analyte was concentrated on the cathodic side of the nanochannel (9 nm deep channel). In order to maintain a stable concentrated sample plug, a "drain" channel was incorporated for increasing the nanochannel electroosmotic flow while decreasing the sample channel electroosmotic flow. A sample preconcentration rate of over 20-fold per second was achieved. Finally, fundamental limits of the nanochannel-based preconcentration are discussed and experimentally demonstrated. PMID- 28723101 TI - Virus-Derived Peptides for Clinical Applications. AB - Novel affinity agents with high specificity are needed to make progress in disease diagnosis and therapy. Over the last several years, peptides have been considered to have fundamental benefits over other affinity agents, such as antibodies, due to their fast blood clearance, low immunogenicity, rapid tissue penetration, and reproducible chemical synthesis. These features make peptides ideal affinity agents for applications in disease diagnostics and therapeutics for a wide variety of afflictions. Virus-derived peptide techniques provide a rapid, robust, and high-throughput way to identify organism-targeting peptides with high affinity and selectivity. Here, we will review viral peptide display techniques, how these techniques have been utilized to select new organism targeting peptides, and their numerous biomedical applications with an emphasis on targeted imaging, diagnosis, and therapeutic techniques. In the future, these virus-derived peptides may be used as common diagnosis and therapeutics tools in local clinics. PMID- 28723106 TI - Proteins Breaking Bad: A Free Energy Perspective. AB - Protein aging may manifest as a mechanical disease that compromises tissue elasticity. As proved recently, while proteins respond to changes in force with an instantaneous elastic recoil followed by a folding contraction, aged proteins break bad, becoming unstructured polymers. Here, we explain this phenomenon in the context of a free energy model, predicting the changes in the folding landscape of proteins upon oxidative aging. Our findings validate that protein folding under force is constituted by two separable components, polymer properties and hydrophobic collapse, and demonstrate that the latter becomes irreversibly blocked by oxidative damage. We run Brownian dynamics simulations on the landscape of protein L octamer, reproducing all experimental observables, for a naive and damaged polyprotein. This work provides a unique tool to understand the evolving free energy landscape of elastic proteins upon physiological changes, opening new perspectives to predict age-related diseases in tissues. PMID- 28723107 TI - Chemical Approaches to Investigate Labile Peptide and Protein Phosphorylation. AB - Protein phosphorylation is by far the most abundant and most studied post translational modification (PTM). For a long time, phosphate monoesters of serine (pSer), threonine (pThr), and tyrosine (pTyr) have been considered as the only relevant forms of phosphorylation in organisms. Recently, several research groups have dedicated their efforts to the investigation of other, less characterized phosphoamino acids as naturally occurring PTMs. Such apparent peculiar phosphorylations include the phosphoramidates of histidine (pHis), arginine (pArg), and lysine (pLys), the phosphorothioate of cysteine (pCys), and the anhydrides of pyrophosphorylated serine (ppSer) and threonine (ppThr). Almost all of these phosphorylated amino acids show higher lability under physiological conditions than those of phosphate monoesters. Furthermore, they are prone to hydrolysis under acidic and sometimes basic conditions as well as at elevated temperatures, which renders their synthetic accessibility and proteomic analysis particularly challenging. In this Account, we illustrate recent chemical approaches to probe the occurrence and function of these labile phosphorylation events. Within these endeavors, the synthesis of site-selectively phosphorylated peptides, in particular in combination with chemoselective phosphorylation strategies, was crucial. With these well-defined standards in hand, the appropriate proteomic mass spectrometry-based analysis protocols for the characterization of labile phosphosites in biological samples could be developed. Another successful approach in this research field includes the design and synthesis of stable analogues of these labile PTMs, which were used for the generation of pHis- and pArg-specific antibodies for the detection and enrichment of endogenous phosphorylated samples. Finally, other selective enrichment techniques are described, which rely for instance on the unique chemical environment of a pyrophosphate or the selective interaction between a phosphoamino acid and its phosphatase. It is worth noting that many of those studies are still in their early stages, which is also reflected in the small number of identified phosphosites compared to that of phosphate monoesters. Thus, many challenges need to be mastered to fully understand the biological role of these poorly characterized and rather uncommon phosphorylations. Taken together, this overview exemplifies recent efforts in a flourishing field of functional proteomic analysis and furthermore manifests the power of modern peptide synthesis to address unmet questions in the life sciences. PMID- 28723108 TI - Oral Exposure to Silver Nanoparticles or Silver Ions May Aggravate Fatty Liver Disease in Overweight Mice. AB - As the applications and environmental release of silver ions and nanoparticles are increasing, increasing human exposure to these pollutants has become an emerging health concern. The impeding effects of such pollutants on susceptible populations are severely under-studied. Here, we demonstrate that silver nanoparticles (Ag NPs), at a dose that causes no general toxicity in normal mice, promotes the progression of fatty liver disease from steatosis to steatohepatitis only in overweight mice. Exposure to Ag+ ions induces the same effects in overweight mice. Ag NPs rather than Ag+ ions cause this disease progression based on our findings that Ag+ ions are partly reduced to Ag NPs in fatty livers, and the toxic effect is correlated with the liver dose of Ag NPs, not Ag+ ions. Furthermore, the Ag NP-induced pro-inflammatory activation of Kupffer cells in the liver, enhancement of hepatic inflammation, and suppression of fatty acid oxidation are identified as key factors in the underlying mechanisms. PMID- 28723109 TI - Fast Surface Acoustic Wave-Based Sensors to Investigate the Kinetics of Gas Uptake in Ultra-Microporous Frameworks. AB - Observation of the kinetics and measurement of the activation energies for gas diffusion in porous materials requires very fast and sensitive sensors. In this work, thin films of metal-organic frameworks (MOFs) with different pore sizes are grown on a surface acoustic wave (SAW) substrate, resulting in very sensitive and specific sensor systems for the detection of various gases at very short time scales. Using specially designed SAW delay lines for the detection, up to 200-nm wide cubic MOF crystals were grown directly from a solution on the sensitive sensor chip area. One example, MFU-4, exhibits a smallest pore aperture of 2.5 A and shows a highly sensitive and specific response to CO2, H2, He, NH3, and H2O. It is shown that such a MOF@SAW sensor responds within milliseconds to gas loading and its sensitivity reaches levels as low as 1 ppmv, currently only limited by the gas mixing system. This unique combination of sensitivity and fast response characteristics allows even for real-time investigations of the sorption kinetics during gas uptake and release. As is typical for SAW sensors, the production of the chips is very straightforward and inexpensive and-combined with the unique properties of the MOFs with their tunable pore sizes and adjustable internal surface properties-holds promise for different sensor applications. PMID- 28723110 TI - Portable Sensor for the Detection of Choline and Its Derivatives Based on Silica Isoporous Membrane and Gellified Nanointerfaces. AB - A portable amperometric ion sensor was fabricated by integrating silica isoporous membrane (SIM) and organogel composed of polyvinyl chloride and 1,2 dichloroethane (PVC-DCE) on a 3D-printed polymer chip. The detection of ionic species in aqueous samples could be accomplished by adding a microliter of sample droplet to the sensor and by identifying the ion-transfer potential and current magnitude at the water/organogel interface array templated by SIM. Thanks to the ultrasmall channel size (2-3 nm in diameter), high channel density (4 * 108 MUm 2), and ultrathin thickness (80 nm) of SIM, the ensemble of nanoscopic water/organogel (nano-W/Gel) interface array behaved like a microinterface with two back-to-back hemispherical mass diffusion zones. So, the heterogeneous ion transfer across the nano-W/Gel interface array generated a steady-state sigmoidal current wave. The detection of choline (Ch) and its derivatives, including acetylcholine (ACh), benzoylcholine (BCh), and atropine (AP), in aqueous samples was examined with this portable sensor. Using differential pulse stripping voltammetry (DPSV), the quantification of these analytes was achieved with a limit of detection (LOD) down to 1 MUM. Moreover, the portable ion sensor was insensitive to various potential interferents that might coexist in vivo, owing to size-/charge-based selectivity and antifouling capacity of SIM. With this priority, the portable ion sensor was able to quantitatively determine Ch and its derivatives in diluted urine and blood samples. The LODs for Ch, ACh, AP, and BCh in urine were 1.12, 1.30, 1.08, and 0.99 MUM, and those for blood samples were 3.61, 3.38, 2.32, and 1.81 MUM, respectively. PMID- 28723111 TI - Augmented Reality for Real-Time Detection and Interpretation of Colorimetric Signals Generated by Paper-Based Biosensors. AB - Colorimetric tests are becoming increasingly popular in point-of-need analyses due to the possibility of detecting the signal with the naked eye, which eliminates the utilization of bulky and costly instruments only available in laboratories. However, colorimetric tests may be interpreted incorrectly by nonspecialists due to disparities in color perception or a lack of training. Here we solve this issue with a method that not only detects colorimetric signals but also interprets them so that the test outcome is understandable for anyone. It consists of an augmented reality (AR) app that uses a camera to detect the colored signals generated by a nanoparticle-based immunoassay, and that yields a warning symbol or message when the concentration of analyte is higher than a certain threshold. The proposed method detected the model analyte mouse IgG with a limit of detection of 0.3 MUg mL-1, which was comparable to the limit of detection afforded by classical densitometry performed with a nonportable device. When adapted to the detection of E. coli, the app always yielded a "hazard" warning symbol when the concentration of E. coli in the sample was above the infective dose (106 cfu mL-1 or higher). The proposed method could help nonspecialists make a decision about drinking from a potentially contaminated water source by yielding an unambiguous message that is easily understood by anyone. The widespread availability of smartphones along with the inexpensive paper test that requires no enzymes to generate the signal makes the proposed assay promising for analyses in remote locations and developing countries. PMID- 28723112 TI - Surfen-Assembled Graphene Oxide for Fluorescence Turn-On Detection of Sulfated Glycosaminoglycans in Biological Matrix. AB - Sulfated glycosaminoglycans (GAGs) not only serve as a biomarker for mucopolysaccharidoses disease but also participate in various biological processes, such as blood clot medication (heparin) and signal transduction (heparan sulfate). However, few fluorescent sensors, such as 1,9 dimethylmethylene blue, have been developed for the detection of sulfated GAGs in the real world. Herein, we fabricated a surfen/few-layer graphene oxide (FLGO) nanocomplex for sensing sulfated GAGs in biological fluids. Surfen molecules are self-assembled onto the surface of FLGO through electrostatic attraction, and their fluorescence was then quenched by the creation of the FLGO-surfen complex (static quenching) and partially combined with the energy transfer from surfen to FLGO (dynamic quenching). The presence of sulfated GAGs resulted in the fluorescence recovery through the formation of the surfen-GAGs complex, which exhibits weak binding to FLGO and keeps surfen molecules away from the FLGO surface. Because FLGO efficiently reduced the fluorescence background from surfen and competed with sulfated GAGs for binding to surfen, surfen-assembled FLGO exhibited higher sensitivity and better selectivity for sulfated GAGs than surfen. The strategy mentioned above was exemplified by the analysis of heparin in human plasma and sulfated GAGs in an artificial cerebrospinal fluid; the limits of detection at a signal-to-noise ratio of 3 for heparin, dermatan sulfate, and heparin sulfate were determined to be 30, 30, and 60 ng/mL, respectively. PMID- 28723113 TI - An Inexpensive, Single Use Carbon-Based Sensor for the Rapid and Early Detection of Hydrocarbon Leaks. AB - A novel fabrication process for a single use, low-cost organic solvent sensor has been developed. The process is simple, and the materials are readily available. Carbon nanomaterials are self-assembled at a water/hexane interface, where the hexane phase contains dissolved paraffin wax. Upon the controlled evaporation of hexane, the paraffin wax precipitates, trapping the carbon nanoparticles at the surface in a paraffin wax backbone, realizing a carbon-nanoparticle-decorated film. The film is hydrophobic and highly electrically conductive. When exposed to hydrocarbons or a mixture of hydrocarbons, the conductive carbon network deteriorates and an increase in film resistivity is monitored. The rate of change in resistivity is proportional to the concentration and composition of organic molecules in contact with the film. PMID- 28723114 TI - Simultaneous Imaging of Three Tumor-Related mRNAs in Living Cells with a DNA Tetrahedron-Based Multicolor Nanoprobe. AB - We constructed a DNA tetrahedron based multicolor nanoprobe, which could simultaneously imaging of three tumor-related mRNAs in living cells through fluorescence restoration caused by competitive chain replacement reaction. The oligonucleotides used to construct the tetrahedron were extended by adding three 21-base recognition sequences modified with different fluorophores (FAM, Cy3, and Cy5) in the 5' end. Three 11-base complementary sequences modified with quencher (BHQ1 for FAM and BHQ2 for Cy3 and Cy5) were hybridized with the recognition sequences to quench the fluorescence. In the presence of the specific mRNA targets, the recognition sequences hybridized with the targets to form longer duplexes and the fluorescence was restored. Compared with previously reported nanoprobes based on DNA tetrahedron, the multicolor nanoprobe can effectively avoid false positive results. PMID- 28723115 TI - Response of Gallium Nitride Chemiresistors to Carbon Monoxide is Due to Oxygen Contamination. AB - We report on the influence of oxygen impurities on the gas sensing properties of gallium nitride (GaN) chemiresistors. As shown by XRD, elemental analysis, and TEM characterization, surface oxidation of GaN-for example, upon contact to ambient air atmosphere-creates an oxidative amorphous layer which provides the sites for the sensing toward CO. Treating this powder under dry ammonia at 800 degrees C converts the oxide layer in nitride, and consequently the sensing performance toward CO is dramatically reduced for ammonia treated GaN gas sensors. Hence the response of GaN sensors to CO is caused by oxygen in the form of amorphous surface oxide or oxynitride. PMID- 28723116 TI - Integrated Magnetic Bead-Quantum Dot Immunoassay for Malaria Detection. AB - Malaria persists as a disease of high morbidity and mortality due to improper diagnosis, overuse of drugs, rapidly evolving drug resistant parasites, and poor disease monitoring. The two common tests used in developing countries, microscopic examination of Glemsa slides and rapid diagnostic tests (RDTs), have limitations associated with variability in specificity and sensitivity, and qualitative outcome. Here we report on an immunoassay using magnetic beads for capture and quantum dots for detection of histidine-rich protein 2 (HRP2). Conventional immunoassays, such as ELISA, and molecular analysis tools, such as PCR, are difficult to implement in low resource settings. Therefore, to provide a proof-of-principle of translation of this assay to low resource settings, we demonstrate HRP2 detection in an automated droplet-based microfluidic device. Droplet-based platforms have the potential to allow translation of molecular detection assays to point-of-care use in low resource settings. PMID- 28723117 TI - Versatile Barometer Biosensor Based on Au@Pt Core/Shell Nanoparticle Probe. AB - There is a high global demand for sensitive, portable, user-friendly, and cost effective biosensors. In this work, we introduce a barometer-based biosensor for the detection of a broad range of targets. The device is operated by measuring the pressure change produced by oxygen (O2) generation in a limited chamber using a portable barometer. The design employs core-shell Au@Pt nanoparticles (Au@PtNPs) as the bioassay probe to catalyze the decomposition of H2O2 and the release of O2. As a proof of concept, we developed barometer-based immunosensors to detect carcinoembryonic antigen (CEA) and ractopamine (Rac). In addition, barometer-based aptasensors for sensitive detection of thrombin and mercury ion (Hg2+) were also developed. In order to facilitate the analysis of results, we have developed smartphone software to calculate, save, and wirelessly trsnsmit the results. Linear detection ranges for detection of CEA, Rac, thrombin, and Hg2+ were 0.025-1.6 ng/mL, 0.0625-4 ng/mL, 4-128 U/L, and 0.25-16 ng/mL, respectively. The detection limit of these four analytes is 0.021 ng/mL, 0.051 ng/mL, 2.4 U/L, and 0.22 ng/mL, respectively. Furthermore, the developed barometer-based biosensors exhibited high specificities for these four analytes. CEA in serum samples, Rac in urine samples, thrombin in serum samples, and Hg2+ in river water samples were measured by the barometer-based biosensors. Obtained results of these targets from barometer-based biosensors were consistent with detection results from traditional methods, indicating that barometer-based biosensors are widely applicable. PMID- 28723118 TI - Valence States Modulation Strategy for Picomole Level Assay of Hg2+ in Drinking and Environmental Water by Directional Self-Assembly of Gold Nanorods. AB - In this study, we present a valence states modulation strategy for picomole level assay of Hg2+ using directional self-assembly of gold nanorods (AuNRs) as signal readout. Hg2+ ions are first controllably reduced to Hg+ ions by appropriate ascorbic acid, and the reduced Hg+ ions react with the tips of the preadded AuNRs and form gold amalgam. Such Hg+ decorated AuNRs then end-to-end self-assemble into one-dimensional architectures by the bridging effects of lysine based on the high affinity of NH2-Hg+ interactions. Correspondingly, the AuNRs' longitudinal surface plasmon resonance is gradually reduced and a new broad band appears at 900-1100 nm region simultaneously. The resulting distinctly ratiometric signal output is not only favorable for Hg2+ ions detection but competent for their quantification. Under optimal conditions, the linear range is 22.8 pM to 11.4 nM, and the detection limit is as low as 8.7 pM. Various transition/heavy metal ions, such as Pb2+, Ti2+, Co2+, Fe3+, Mn2+, Ba2+, Fe2+, Ni2+, Al3+, Cu2+, Ag+, and Au3+, do not interfere with the assay. Because of ultrahigh sensitivity and excellent selectivity, the proposed system can be employed for assaying ultratrace of Hg2+ containing in drinking and commonly environmental water samples, which is difficult to be achieved by conventional colorimetric systems. These results indicate that the present platform possesses specific advantages and potential applications in the assay of ultratrace amounts of Hg2+ ions. PMID- 28723119 TI - Fast-Response and Flexible Nanocrystal-Based Humidity Sensor for Monitoring Human Respiration and Water Evaporation on Skin. AB - We develop a fast-response and flexible nanocrystal-based humidity sensor for real-time monitoring of human activity: respiration and water evaporation on skin. A silicon-nanocrystal film is formed on a polyimide film by spin-coating the colloidal solution and is used as a flexible and humidity-sensitive material in a humidity sensor. The flexible nanocrystal-based humidity sensor shows a high sensitivity; current through the nanocrystal film changes by 5 orders of magnitude in the relative humidity range of 8-83%. The response/recovery time of the sensor is 40 ms. Thanks to the fast response and recovery time, the sensor can monitor human respiration and water evaporation on skin in real time. Due to the flexibility and the fast response/recovery time, the sensor is promising for application in personal health monitoring as well as environmental monitoring. PMID- 28723120 TI - Graphene Oxide Nanoprisms for Sensitive Detection of Environmentally Important Aromatic Compounds with SERS. AB - Recent advances in graphene-based sensors have shown that heavily oxidized (GO) and reduced graphene oxide (rGO) are attractive materials for environmental sensing due to their unique chemical and physical properties. We describe here the fabrication of nanostructured GO assemblies with Ag nanoprisms for improved detection with surface enhanced Raman scattering (SERS). Specifically, 100-MUm sized, periodic-nanoprism-array domains were fabricated on top of the GO layers by GO-assisted lithography (GOAL). The atomically thin GO underlayers are shown to attract cyclic aromatic molecules to the surface, likely via pi-pi stacking interactions. The close proximity of the analyte to GO and nanoprism (NP) tips effectively suppresses fluorescent background and affords a plausible tertiary enhancement of photon emissions via an electron charge transfer (CT) process. The adsorption of analyte to rGO-NP leads to the appearance and/or shift of several Raman bands, which provided a means to gain molecular insights into the graphene enhanced scattering process. The analytical merits were characterized with model compound Rhodamine 6G, where the detection limit could reach subnanomolar concentrations. The nanoprism GO substrates also prove effective for SERS multiplex measurement of several legacy aromatic pollutants. Three tetrachlorobiphenyl isomers could be identified from a mixture using their autonomous nonoverlapping molecular fingerprints, and the substrate offers remarkable trace detection of 2,2',3,3'-tetrachlorobiphenyl (PCB-77). PMID- 28723121 TI - What the Emerging Generation of Researchers Think Is Hot in Sensors. PMID- 28723122 TI - Electrochemical DNA-Based Immunoassay That Employs Steric Hindrance To Detect Small Molecules Directly in Whole Blood. AB - The development of a universal sensing mechanism for the rapid and quantitative detection of small molecules directly in whole blood would drastically impact global health by enabling disease diagnostics, monitoring, and treatment at home. We have previously shown that hybridization between a free DNA strand and its complementary surface-bound strand can be sterically hindered when the former is bound to large antibodies. Here, we exploit this effect to design a competitive antibody-based electrochemical assay, called CeSHHA, that enables the quantitative detection of small molecules directly in complex matrices, such as whole blood or soil. We discuss the importance of this inexpensive assay for point-of-care diagnosis and for treatment monitoring applications. PMID- 28723123 TI - A Both-End Blocked Peroxidase-Mimicking DNAzyme for Low-Background Chemiluminescent Sensing of miRNA. AB - G-quadruplex DNAzymes that exhibited peroxidase-like activity have been shown to be appealing reporters for amplified readout of biosensing events simply by their formation or dissociation in the presence of analytes. For low background signaling, the efficient preblock of DNAzymes is critically important. Herein, we report a both-end blocked DNAzyme beacon strategy for chemiluminescent biosensing. The catalytic activity of peroxidase-mimicking DNAzyme can be inactivated fully by fixing both ends of the DNAzyme sequence, and easily recovered via a strand displace reaction between the miRNA and the block DNA. The efficient block and recovery of DNAzymes provide the both-end blocked beacon the highest signal-to-background ratio (over 25) among the reported DNAzymes for amplification-free detection of miRNA. As a result, the beacon allowed detection of subpicomolar miRNA without any labeling and amplification procedures, which is about 40-fold more sensitive than the traditional hairpin fluorescence beacon. Also, it exhibited excellent discrimination ability that can distinguish single base mismatch miRNA. The simplicity, high sensitivity, and selectivity provided by the beacon make it a promising alternative tool for nucleic acid detection. PMID- 28723124 TI - Fluorescence Quenching of a Conjugated Polymer by Synergistic Amine-Carboxylic Acid and pi-pi Interactions for Selective Detection of Aromatic Amines in Aqueous Solution. AB - Fluorescence sensing of amine in aqueous solution is challenging. The various basicity and chemical structures of amines may lead to poor selectivity in aqueous solution, and selective fluorescence detection of primary aromatic amine is rarely reported. This paper presents design and synthesis of a fluorescent conjugated polymer for rapid and selective sensing of aromatic amines in aqueous solution. The fluorescent conjugated polymer, poly[fluorenyl-alt-p phenyleneethynylene] with pendant carboxylic acid groups and long alky chains, is synthesized via palladium-catalyzed Sonogashira coupling reaction. The fluorescence of the polymer is selectively quenched by the aromatic amines in aqueous solution, whereas the aliphatic amines enhance the fluorescence of the polymer. The high selectivity to the aromatic amines, particularly to the environmentally important p-phenylenediamine, likely originates from the amplified pi-pi fluorescence quenching synergized by amine and carboxylic acid interaction. Our results demonstrate an effective material design strategy that may be extended to fluorescence sensing of other aromatic compounds. PMID- 28723127 TI - Fluorescent Chemosensors with Varying Degrees of Intramolecular Charge Transfer for Detection of a Nerve Agent Mimic in Solutions and in Vapor. AB - Nerve agents are highly toxic organophosphorus compounds, and their possible use in terrorist attacks has led to increasing interest in the development of reliable and accurate methods to detect these lethal chemicals. In this paper, we have prepared six 6-aminoquinolines with various N-substituents as chemosensors for a nerve-agent mimic diethylchlorophosphate (DCP). The chemosensors with the nucleophilic pyridine-N atom as the active site detect DCP via a catalytic hydrolysis approach to form the protonated sensor. The nucleophilicity of the pyridine-N atom depends on the donating ability of the 6-amine group, which affects the intramolecular charge-transfer (ICT) character of sensors and the protonated sensors, leading to different fluorescence-response modes. The effects of the ICT character on the sensing property have been clarified. Among these charge transfer sensors, the sensor 3 displays ratiometric fluorescence response to DCP and a low limit of detection (8 nM). Furthermore, a facile testing strip with 3 has been fabricated with poly(ethylene oxide) for real-time selective monitoring of DCP vapor. PMID- 28723125 TI - Pharmacokinetics-on-a-Chip Using Label-Free SERS Technique for Programmable Dual Drug Analysis. AB - Synergistic effects of dual or multiple drugs have attracted great attention in medical fields, especially in cancer therapies. We provide a programmable microfluidic platform for pharmacokinetic detection of multiple drugs in multiple cells. The well-designed microfluidic platform includes two 2 * 3 microarrays of cell chambers, two gradient generators, and several pneumatic valves. Through the combined use of valves and gradient generators, each chamber can be controlled to infuse different kinds of living cells and drugs with specific concentrations as needed. In our experiments, 6-mercaptopurine (6MP) and methimazole (MMI) were chosen as two drug models and their pharmacokinetic parameters in different living cells were monitored through intracellular SERS spectra, which reflected the molecular structure of these drugs. The dynamic change of SERS fingerprints from 6MP and MMI molecules were recorded during drug metabolism in living cells. The results indicated that both 6MP and MMI molecules were diffused into the cells within 4 min and excreted out after 36 h. Moreover, the intracellular distribution of these drugs was monitored through SERS mapping. Thus, our microfluidic platform simultaneously accomplishes the functions to monitor pharmacokinetic action, distribution, and fingerprint of multiple drugs in multiple cells. Owing to its real-time, rapid-speed, high-precision, and programmable capability of multiple-drug and multicell analysis, such a microfluidic platform has great potential in drug design and development. PMID- 28723128 TI - Calorimetric Biosensing System for Quantification of Urinary Creatinine. AB - In this work, we demonstrate the quantification of creatinine in human urine samples using a microcalorimetric sensing system. The calorimetric sensor is based on an array of microfabricated Y-cut quartz resonators. The piezoelectric quartz is etched down to a thickness of 10 MUm and exhibits a bulk acoustic resonance of 166 MHz. The temperature sensitivity of this high-frequency quartz resonator is 14 600 Hz/K due to the high phenomenological sensitivity of quartz. Most importantly, the quartz sensors and the analyte fluidics are decoupled providing a significantly more robust calorimetric sensing system than directly contacted chip calorimeters. A reference resonator, consisting of a suspended structure held by four arms, was realized to thermal isolation from the bulk quartz by using focused ion beam etching. We employ alginate entrapped creatinine deiminase to transduce urinary creatinine into temperature signatures, permitting the quantification of creatinine. Fairly good agreement with the measured creatinine values in the 5 urine samples using calorimetric and HPLC methods is obtained. PMID- 28723129 TI - Carbon Dioxide in a Supported Ionic Liquid Membrane: Structural and Rotational Dynamics Measured with 2D IR and Pump-Probe Experiments. AB - Supported ionic liquid membranes (SILMs) are porous membranes impregnated with ionic liquids (ILs) and used as advanced carbon capture materials. Here, two dimensional infrared (2D IR) and IR polarization selective pump-probe (PSPP) spectroscopies were used to investigate CO2 reorientation and spectral diffusion dynamics in SILMs. The SILM contained 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonly)imide in the poly(ether sulfone) membrane with average pore size of ~350 nm. Two ensembles of CO2 were observed in the SILM, one in the IL phase in the membrane pores and the other in the supporting membrane polymer. CO2 in the polymer displayed a red-shifted IR absorption spectrum and a shorter vibrational lifetime of the asymmetric stretch mode compared to the IL phase. Despite the relatively large pore sizes, the complete orientational randomization of CO2 and structural fluctuations of the IL (spectral diffusion) in the pores are slower than in the bulk IL by ~2-fold. The implication is that the IL structural change induced by the polymer interface can propagate out from the interface more than a hundred nanometers, influencing the dynamics. The dynamics in the polymer are even slower. This study demonstrates that there are significant differences in the dynamics of ILs in SILMs on a molecular level compared to the bulk IL, and the study of dynamics in SILMs can provide important information for the design of SILMs for CO2 capture. PMID- 28723130 TI - Sequence-Specific beta-Peptide Synthesis by a Rotaxane-Based Molecular Machine. AB - We report on the synthesis and operation of a three-barrier, rotaxane-based, artificial molecular machine capable of sequence-specific beta-homo (beta3) peptide synthesis. The machine utilizes nonproteinogenic beta3-amino acids, a class of amino acids not generally accepted by the ribosome, particularly consecutively. Successful operation of the machine via native chemical ligation (NCL) demonstrates that even challenging 15- and 19-membered ligation transition states are suitable for information translation using this artificial molecular machine. The peptide-bond-forming catalyst region can be removed from the transcribed peptide by peptidases, artificial and biomachines working in concert to generate a product that cannot be made by either machine alone. PMID- 28723131 TI - Characterization and Quantification of Polyquaterniums via Single-Use Polymer Membrane-Based Polyion-Sensitive Electrodes. AB - Two facile, robust, and universal methods by which various polymeric quaternary ammonium salts (polyquaterniums (PQs)) can be quantified and characterized using simple potentiometric polymeric membrane polyion-sensitive electrodes as detectors are described. The two methods are (a) direct detection with polycation sensitive membrane electrodes based on the sodium salt of dinonylnaphthalenesulfonate (NaDNNS), and (b) indirect detection using polyanion sensors based on tridodecylmethylammonium chloride (TDMAC) and dextran sulfate (DS) as a titrant to complex the various polyquaternary species (four different PQs: PQ-2, PQ-6, PQ-10, and poly(2-methacryloxyethyltrimethylammonium) chloride (PMETAC)). Direct detection yields information regarding the charge density of the polycationic species. For the titration method, a series of polyanion sensors doped with TDMAC are used to follow a potentiometric titration of a PQ species using a syringe pump to deliver the titrant. This indirect detection method is more reliable and yields limits of detection in the ppm range for the four PQs examined. The titration method is further explored for detecting excess levels of PQ-6, a common flocculating agent for municipal water supply systems, within the purified water emitted by the Ann Arbor, MI, drinking water treatment plant. PMID- 28723132 TI - Single-Cell Mechanical Characteristics Analyzed by Multiconstriction Microfluidic Channels. AB - A microfluidic device composed of variable numbers of multiconstriction channels is reported in this paper to differentiate a human breast cancer cell line, MDA MB-231, and a nontumorigenic human breast cell line, MCF-10A. Differences between their mechanical properties were assessed by comparing the effect of single or multiple relaxations on their velocity profiles which is a novel measure of their deformation ability. Videos of the cells were recorded via a microscope using a smartphone, and imported to a tracking software to gain the position information on the cells. Our results indicated that a multiconstriction channel design with five deformation (50 MUm in length, 10 MUm in width, and 8 MUm in height) separated by four relaxation (50 MUm in length, 40 MUm in width, and 30 MUm in height) regions was superior to a single deformation design in differentiating MDA-MB-231 and MCF-10A cells. Velocity profile criteria can achieve a differentiation accuracy around 95% for both MDA-MB-231 and MCF-10A cells. PMID- 28723133 TI - Label-Free Nanopore Biosensor for Rapid and Highly Sensitive Cocaine Detection in Complex Biological Fluids. AB - Detection of very low amounts of illicit drugs such as cocaine in clinical fluids like serum continues to be important for many areas in the fight against drug trafficking. Herein, we constructed a label-free nanopore biosensor for rapid and highly sensitive detection of cocaine in human serum and saliva samples based on target-induced strand release strategy. In this bioassay, an aptamer for cocaine was prehybridized with a short complementary DNA. Owing to cocaine specific binding with aptamer, the short DNA strand was displaced from aptamer and translocation of this output DNA through alpha-hemolysin nanopore generated distinct spike-like current blockages. When plotted in double-logarithmic scale, a linear relationship between target cocaine concentration and output DNA event frequency was obtained in a wide concentration range from 50 nM to 100 MUM of cocaine, with the limit of detection down to 50 nM. In addition, this aptamer based sensor method was successfully applied for cocaine detection in complex biological fluids like human saliva and serum samples with great selectivity. Simple preparation, low cost, rapid, label-free, and real sample detection are the motivating factors for practical application of the proposed biosensor. PMID- 28723134 TI - Isoelectric Bovine Serum Albumin: Robust Blocking Agent for Enhanced Performance in Optical-Fiber Based DNA Sensing. AB - Surface blocking is a well-known process for reducing unwanted nonspecific adsorption in sensor fabrication, especially important in the emerging field where DNA/RNA applied. Bovine serum albumin (BSA) is one of the most popular blocking agents with an isoelectric point at pH 4.6. Although it is widely recognized that the adsorption of a blocking agent is strongly affected by its net charge and the maximum adsorption is often observed under its isoelectric form, BSA has long been perfunctorily used for blocking merely in neutral solution, showing poor blocking performances in the optical-fiber evanescent wave (OFEW) based sensing toward DNA target. To meet this challenge, we first put forward the view that isoelectric BSA (iep-BSA) has the best blocking performance and use an OFEW sensor platform to demonstrate this concept. An optical-fiber was covalently modified with amino-DNA, and further coupled with the optical system to detect fluorophore labeled complementary DNA within the evanescent field. A dramatic improvement in the reusability of this DNA modified sensing surface was achieved with 120 stable detection cycles, which ensured accurate quantitative bioassay. As expected, the iep-BSA blocked OFEW system showed enhanced sensing performance toward target DNA with a detection limit of 125 pM. To the best of our knowledge, this is the highest number of regeneration cycles ever reported for a DNA immobilized optical-fiber surface. This study can also serve as a good reference and provide important implications for developing similar DNA-directed surface biosensors. PMID- 28723136 TI - Correction to Insulin Promoter-Driven Gaussia Luciferase-Based Insulin Secretion Biosensor Assay for Discovery of beta-Cell Glucose-Sensing Pathways. PMID- 28723135 TI - Development of Dual-Aptamers for Constructing Sandwich-Type Pancreatic Polypeptide Assay. AB - Pancreatic polypeptide (PP) is a specific biomarker of nonfunctional pancreatic neuroendocrine tumors (NF-pNETs). Clinical significance of PP inspires researchers to make great efforts in developing sensitive and specific sensors. However, there is no existing biosensor for detecting PP that combines facility and functionality. Addressing this challenge, a pair of aptamers which could be used to develop a sandwich assay for PP is reported. First, several high affinity aptamers are screened through graphene oxide-based SELEX, and appropriate dual aptamers which could bind to different epitopes of PP are identified through fluorescence assays. Then the feasibility of the dual-aptamers for constructing the sandwich assay is validated via dynamic light scattering. This sandwich assay shows considerable sensitivity and specificity. The above results imply that the dual-aptamers have the potential toward developing novel sensors for PP in clinical samples. PMID- 28723138 TI - Hand-Held Femtogram Detection of Hazardous Picric Acid with Hydrophobic Ag Nanopillar SERS Substrates and Mechanism of Elasto-Capillarity. AB - Picric acid (PA) is a severe environmental and security risk due to its unstable, toxic, and explosive properties. It is also challenging to detect in trace amounts and in situ because of its highly acidic and anionic character. Here, we assess sensing of PA under nonlaboratory conditions using surface-enhanced Raman scattering (SERS) silver nanopillar substrates and hand-held Raman spectroscopy equipment. The advancing elasto-capillarity effects are explained by molecular dynamics simulations. We obtain a SERS PA detection limit on the order of 20 ppt, corresponding attomole amounts, which together with the simple analysis methodology demonstrates that the presented approach is highly competitive for ultrasensitive analysis in the field. PMID- 28723139 TI - Sensitive Cytokine Assay Based on Optical Fiber Allowing Localized and Spatially Resolved Detection of Interleukin-6. AB - We demonstrated a cytokine detection device based on gold nanoparticle modified silica optical fiber for the monitoring of locally variable cytokine interleukin 6 (IL-6) concentrations using a sandwich immunoassay scheme. The fiber is designed to be introduced into an intrathecal catheter with micrometer-sized holes drilled along its length to enable fluid exchange between the outside and inside of the catheter. An exposed optical fiber (diameter 125 MUm) modified with a layer of gold nanoparticles was functionalized with the IL-6 capture antibody to form the sensing interface. The immunocapture device was incubated with a cytokine solution to capture the analyte. The device was then exposed to the IL-6 detection antibody which was loaded on the fluorescently labeled magnetic nanoparticles, making it possible to quantify the cytokine concentration based on the intensity of fluorescence. A reliable method for quantifying the fluorescent signal on a 3D structure was developed. This device was applied to the detection of cytokine IL-6 with the low limit of detection of 1 pg mL-1 in a sample volume of 1 MUL. The device has the linear detection range of 1-400 pg mL-1 and spatial resolution on the order of 200-450 MUm, and it is capable of detecting localized IL-6 secreted by live BV2 cells following their liposaccharide stimulation. This biological detection system is suitable for monitoring multiple health conditions. PMID- 28723140 TI - Rapid and Label-Free Detection of Interferon Gamma via an Electrochemical Aptasensor Comprising a Ternary Surface Monolayer on a Gold Interdigitated Electrode Array. AB - A label-free electrochemical impedance spectroscopy (EIS) aptasensor for rapid detection (<35 min) of interferon-gamma (IFN-gamma) was fabricated by immobilizing a RNA aptamer capture probe (ACP), selective to IFN-gamma, on a gold interdigitated electrode array (Au IDE). The ACP was modified with a thiol group at the 5' terminal end and subsequently co-immobilized with 1,6-hexanedithiol (HDT) and 6-mercapto-1-hexanolphosphate (MCH) to the gold surface through thiol gold interactions. This ACP/HDT-MCH ternary surface monolayer facilitates efficient hybridization with IFN-gamma and displays high resistance to nonspecific adsorption of nontarget proteins [i.e., fetal bovine serum (FBS) and bovine serum albumin (BSA)]. The Au IDE functionalized with ACP/HDT-MCH was able to measure IFN-gamma in actual FBS solution with a linear sensing range from 22.22 pM to 0.11 nM (1-5 ng/mL) and a detection limit of 11.56 pM. The ability to rapidly sense IFN-gamma within this sensing range makes the developed electrochemical platform conducive toward in-field disease detection of a variety of diseases including paratuberculosis (i.e., Johne's Disease). Furthermore, experimental results were numerically validated with an equivalent circuit model that elucidated the effects of the sensing process and the influence of the immobilized ternary monolayer on signal output. This is the first time that ternary surface monolayers have been used to selectively capture/detect IFN-gamma on Au IDEs. PMID- 28723141 TI - Disperse-and-Collect Approach for the Type-Selective Detection of Matrix Metalloproteinases in Porous Silicon Resonant Microcavities. AB - We report on the design and testing of photonic biosensors for the type-selective detection of different types of matrix metalloproteinases (MMPs). The ability to detect a panel of different MMP types has important implications for prognosis of wound healing. We combine the immunocapture of MMPs on dispersed magnetic nanoparticles modified with antibodies specific for target MMPs (immuno-magNPs) with subsequent MMP detection upon fluorogenic peptide cleavage in porous silicon resonant microcavity (pSiRM) architectures. We report fast, sensitive, and type selective detection of MMPs directly in wound fluid. This study sets the scene for downstream developments of multiparametric biosensors as point-of-care (POC) prognostic tools that may step-change chronic wound management. PMID- 28723142 TI - What Are Clinically Relevant Levels of Cellular and Biomolecular Analytes? AB - The ultimate goal of developing sensors for biomolecular analytes is to offer new tools for the analysis of clinical specimens for biomarkers of disease. It is thus important to understand the types of samples that are routinely used in the clinic for specific indications, and what the typical levels of relevant analytes are in these specimens. This Sensor Issues article summarizes information concerning levels of target molecules and cells that are of interest for the development of new diagnostics for infectious disease and cancer. Having this information in hand helps better define the "needle-in-a-haystack" challenge associated with developing robust sensors with the needed levels of sensitivity and specificity. PMID- 28723143 TI - An Ultrasensitive Plasmonic Nanosensor for Aldehydes. AB - Glucose is the most common but important aldehyde, and it is necessary to create biosensors with high sensitivity and anti-interference to detect it. Under the existence of silver ions and aldehyde compounds, single gold nanoparticles and freshly formed silver atoms could respectively act as core and shell, which finally form a core-shell structure. By observing the reaction between glucose and Tollens' reagent, metallic silver was found to be reduced on the surface of gold nanoparticles and formed Au@Ag nanoparticles that lead to a direct wavelength shift. Based on this principle and combined with in situ plasmon resonance scattering spectra, a plasmonic nanosensor was successfully applied in identifying aldehyde compounds with excellent sensitivity and specificity. This ultrasensitive sensor was successfully further utilized to detect blood glucose in mice serum samples, exhibiting good anti-interference ability and great promise for future clinical application. PMID- 28723144 TI - Inflection Point of the Localized Surface Plasmon Resonance Peak: A General Method to Improve the Sensitivity. AB - The shift of the localized surface plasmon resonance (LSPR) spectrum is widely used in bio- and chemical sensing. Traditionally, the shift is monitored at the peak maximum of the extinction spectrum. We demonstrate that the inflection point at the long wavelength side of the peak maximum shows better refractive index sensitivity than the peak maximum. A consistent improvement in bulk refractive index sensitivity of 18-55% is observed for six different nanoparticles such as spherical particles of different sizes, nanostar and nanorods with different aspect ratios. Local refractive index changes induced by molecular adsorption confirm the superior performance of the method. We contribute this improvement in sensitivity to the change in shape of the LSPR peak in response to an increase of the local refractive index. We further illustrate the advantage of using the inflection point method for analyzing DNA adsorption on U-shaped metamaterials, and for using 17 nm spherical gold nanoparticles for detection of matrix metalloprotease 7 (MMP-7), a biomarker that is heavily up-regulated during certain cancers. With the inflection point, the limit of detection (LOD) for MMP 7 is improved to 0.094 MUg/mL from 0.22 MUg/mL. This improvement may facilitate early diagnosis of salivary and colorectal cancers. We also envision that this generic method can be employed to track minute optical responses in other analytical areas. PMID- 28723145 TI - Seeing the Stars in Broad Daylight-Nanotechnology Solutions To Reduce Noise in Chemical Sensing. PMID- 28723146 TI - Generalized Noise Study of Solid-State Nanopores at Low Frequencies. AB - Nanopore technology has been extensively investigated for analysis of biomolecules, and a success story in this field concerns DNA sequencing using a nanopore chip featuring an array of hundreds of biological nanopores (BioNs). Solid-state nanopores (SSNs) have been explored to attain longer lifetime and higher integration density than what BioNs can offer, but SSNs are generally considered to generate higher noise whose origin remains to be confirmed. Here, we systematically study low-frequency (including thermal and flicker) noise characteristics of SSNs measuring 7 to 200 nm in diameter drilled through a 20-nm thick SiNx membrane by focused ion milling. Both bulk and surface ionic currents in the nanopore are found to contribute to the flicker noise, with their respective contributions determined by salt concentration and pH in electrolytes as well as bias conditions. Increasing salt concentration at constant pH and voltage bias leads to increase in the bulk ionic current and noise therefrom. Changing pH at constant salt concentration and current bias results in variation of surface charge density, and hence alteration of surface ionic current and noise. In addition, the noise from Ag/AgCl electrodes can become predominant when the pore size is large and/or the salt concentration is high. Analysis of our comprehensive experimental results leads to the establishment of a generalized nanopore noise model. The model not only gives an excellent account of the experimental observations, but can also be used for evaluation of various noise components in much smaller nanopores currently not experimentally available. PMID- 28723147 TI - Quantum Dot-Based Molecularly Imprinted Polymers on Three-Dimensional Origami Paper Microfluidic Chip for Fluorescence Detection of Phycocyanin. AB - In this work, we developed a novel strategy using fluorescent quantum dots (QDs) combined with molecularly imprinted polymers (MIPs) on three-dimensional (3D) origami paper-based microfluidic devices for specific recognition and sensitive detection of phycocyanin. This method can realize the liquid phase of QDs@MIPs being transferred to the solid-phase paper base and achieve easy portability for the analysis. Under optimal conditions, we successfully demonstrated the proposed paper@QDs@MIPs 3D microfluidic chip for the sensitive and selective detection of phycocyanin protein target in a simple and robust manner. Our results revealed that the method exhibited a dynamic response to phycocyanin in the range of 10-50 mg/L with a limit of detection of 2 mg/L. Importantly, this device could provide quantitative information very conveniently and show great potential to be further extended to the detection of other proteins or biomarkers for environmental and food safety research. PMID- 28723148 TI - Sub-6 nm Palladium Nanoparticles for Faster, More Sensitive H2 Detection Using Carbon Nanotube Ropes. AB - Palladium (Pd) nanoparticle (NP)-decorated carbon nanotube (CNT) ropes (or CNT@PdNP) are used as the sensing element for hydrogen gas (H2) chemiresistors. In spite of the fact that Pd NPs have a mean diameter below 6 nm and are highly dispersed on the CNT surfaces, CNT@PdNP ropes produce a relative resistance change 20-30 times larger than is observed at single, pure Pd nanowires. Thus, CNT@PdNP rope sensors improve upon all H2 sensing metrics (speed, dynamic range, and limit-of-detection), relative to single Pd nanowires which heretofore have defined the state-of-the-art in H2 sensing performance. Specifically, response and recovery times in air at [H2] ~ 50 ppm are one-sixth of those produced by single Pd nanowires with cross-sectional dimensions of 40 * 100 nm Pd. The LODH2 is <10 ppm versus 300 ppm, and the dynamic range (10 ppm -4%) is nearly twice that afforded by the Pd nanowire. CNT@PdNP rope sensors are prepared by the dielectrophoretic deposition of a single semiconducting CNT rope followed by the electrodeposition of Pd nanoparticles with mean diameters ranging from 4.5 (+/-1) nm to 5.8 (+/-3) nm. The diminutive mean diameter and the high degree of diameter monodispersity for the deposited Pd nanoparticles are distinguishing features of the CNT@PdNP rope sensors described here, relative to prior work on similar systems. PMID- 28723150 TI - Double Imaging Photoelectron Photoion Coincidence Sheds New Light on the Dissociation of State-Selected CH3F+ Ions. AB - The vacuum ultraviolet (VUV) photoionization and dissociative photoionization of methyl fluoride (CH3F) in the 12.2-19.8 eV energy range were investigated by using synchrotron radiation coupled to a double imaging photoelectron photoion coincidence (i2PEPICO) spectrometer. The production of several fragment ions including CH2F+, CHF+, CH3+, and CH2+ as a function of state and internal energy of CH3F+ ions was identified and analyzed, with their individual appearance energies measured through threshold photoelectron spectroscopy. Dynamical information was inferred from electron and ion kinetic energy correlation diagrams measured at chosen fixed photon energies. The detailed mechanisms governing the dissociation of state-selected CH3F+ ions prepared in the X2E, A2A1, and B2E low-lying electronic states as well as outside the Franck-Condon region have been inferred based on the present experimental results and existing theoretical calculations. Both the CH2F+ and CH3+ primary fragment ions have three different channels of production from different electronic states of CH3F+. The spin-orbit splitting states of the F fragment, 2P3/2 and 2P1/2, in the CH3+ + F dissociation channels were assigned and adiabatically correlate to the X2E ground state and the A2A1 electronic state, respectively, with the aid of previous theoretical results. The CH3F+ ions in the high energy part of the X2E ground state are unstable and statistically dissociate to the CH2F+(11A1) and H(2S) fragments along the potential energy curve of the X2E state. The A2A1 electronic state is a repulsive state and exclusively dissociates to the CH3+(11A1') and F(2P1/2) fragments. In addition, the CH2F+, CHF+, CH3+, and CH2+ fragment ions are also produced in the B2E state and in the Franck-Condon gap by indirect processes, such as internal conversion or dissociative autoionization. PMID- 28723149 TI - Cyclewise Operation of Printed MoS2 Transistor Biosensors for Rapid Biomolecule Quantification at Femtomolar Levels. AB - Field-effect transistors made from MoS2 and other emerging layered semiconductors have been demonstrated to be able to serve as ultrasensitive biosensors. However, such nanoelectronic sensors still suffer seriously from a series of challenges associated with the poor compatibility between electronic structures and liquid analytes. These challenges hinder the practical biosensing applications that demand rapid, low-noise, highly specific biomolecule quantification at femtomolar levels. To address such challenges, we study a cyclewise process for operating MoS2 transistor biosensors, in which a series of reagent fluids are delivered to the sensor in a time-sequenced manner and periodically set the sensor into four assay-cycle stages, including incubation, flushing, drying, and electrical measurement. Running multiple cycles of such an assay can acquire a time dependent sensor response signal quantifying the reaction kinetics of analyte receptor binding. This cyclewise detection approach can avoid the liquid-solution induced electrochemical damage, screening, and nonspecific adsorption to the sensor and therefore improves the transistor sensor's durability, sensitivity, specificity, and signal-to-noise ratio. These advantages in combination with the inherent high sensitivity of MoS2 biosensors allow for rapid biomolecule quantification at femtomolar levels. We have demonstrated the cyclewise quantification of Interleukin-1beta in pure and complex solutions (e.g., serum and saliva) with a detection limit of ~1 fM and a total detection time ~23 min. This work leverages the superior properties of layered semiconductors for biosensing applications and advances the techniques toward realizing fast real time immunoassay for low-abundance biomolecule detection. PMID- 28723151 TI - Fusion of Structure and Ligand Based Methods for Identification of Novel CDK2 Inhibitors. AB - Cyclin dependent kinases play a central role in cell cycle regulation which makes them a promising target with multifarious therapeutic potential. CDK2 regulates various events of the eukaryotic cell division cycle, and the pharmacological evidence indicates that overexpression of CDK2 causes abnormal cell-cycle regulation, which is directly associated with hyperproliferation of cancer cells. Therefore, CDK2 is regarded as a potential target molecule for anticancer medication. Thus, to decline CDK2 activity by potential lead compounds has proved to be an effective treatment for cancer. The availability of a large number of X ray crystal structures and known inhibitors of CDK2 provides a gateway to perform efficient computational studies on this target. With the aim to identify new chemical entities from commercial libraries, with increased inhibitory potency for CDK2, ligand and structure based computational drug designing approaches were applied. A druglike library of 50,000 compounds from ChemDiv and ChemBridge databases was screened against CDK2, and 110 compounds were identified using the parallel application of these models. On in vitro evaluation of 40 compounds, seven compounds were found to have more than 50% inhibition at 10 MUM. MD studies of the hits revealed the stability of these inhibitors and pivotal role of Glu81 and Leu83 for binding with CDK2. The overall study resulted in the identification of four new chemical entities possessing CDK2 inhibitory activity. PMID- 28723152 TI - Impact of Environment on the Biomass Composition of Soybean (Glycine max) seeds. AB - Factors including genetics, fertilization, and climatic conditions, can alter the biomass composition of soybean seeds, consequently impacting their market value and usage. This study specifically determined the content of protein and oil, as well as the composition of proteinogenic amino acids and fatty acids in seeds from 10 diverse soybean cultivars grown in four different sites. The results highlighted that different environments produce a different composition for the 10 cultivars under investigation. Specifically, the levels of oleic and linoleic acids, important contributors to oil stability, were negatively correlated. Although the protein and oil contents were higher in some locations, their "quality" was lower in terms of composition of essential amino acids and oleic acid, respectively. Finally, proteinogenic histidine and glutamate were the main contributors to the separation between Central and Northern growing sites. Taken together, these results can guide future breeding and engineering efforts aiming to develop specialized soybean lines. PMID- 28723153 TI - Understanding the Reactivity of CO3.- and NO2. Radicals toward S-Containing and Aromatic Amino Acids. AB - The reactivity of CO3.- and NO2. radicals toward six amino acid side chains namely, cysteine (Cys), methionine (Met), phenylalanine (Phe), tyrosine (Tyr), histidine (His), and tryptophan (Trp), has been explored using state-of-art density functional theory (DFT) and transition state theory (TST). Three reaction mechanisms, namely hydrogen atom abstraction (HAT), radical adduct formation (RAF), and single electron transfer (SET), have been considered for detailed study. While CO3.- radical is highly reactive toward majority of amino acids, the reactivity of NO2. radical is limited. The CO3.- radical creates oxidative damage to amino acid residues predominantly via HAT mechanism with moderate to high rate constant. Kinetic data suggest that tryptophan and tyrosine moiety possess the highest reactivity while the phenylalanine furnishes slow reaction. On the other hand, NO2. radical cannot produce direct damage toward most of the amino acids except tryptophan and histidine. The NO2. radical reacts exclusively by SET mechanism with 6.01 * 106 M-1 s-1 and 4.69 * 102 M-1 s-1 rate constant for Trp and His, respectively. Therefore, the CO3.- radical may cause severe damage to amino acid side chains during oxidative stress conditions, whereas the NO2. radical is mostly inert. Moreover, the reaction of CO3.- and NO2. radicals with amino acid radical intermediates generate variety of oxidation and nitro products which explain the formation of different experimentally characterized biomarkers during oxidative stress. PMID- 28723154 TI - Interruption of Hydrogen Bonding Networks of Water in Carbon Nanotubes Due to Strong Hydration Shell Formation. AB - We present the structures of NaCl aqueous solution in carbon nanotubes with diameters of 1, 2, and 3 nm based on an analysis performed using X-ray diffraction and canonical ensemble Monte Carlo simulations. Anomalously longer nearest-neighbor distances were observed in the electrolyte for the 1-nm-diameter carbon nanotubes; in contrast, in the 2 and 3 nm carbon nanotubes, the nearest neighbor distances were shorter than those in the bulk electrolyte. We also observed similar properties for water in carbon nanotubes, which was expected because the main component of the electrolyte was water. However, the nearest neighbor distances of the electrolyte were longer than those of water in all of the carbon nanotubes; the difference was especially pronounced in the 2-nm diameter carbon nanotubes. Thus, small numbers of ions affected the entire structure of the electrolyte in the nanopores of the carbon nanotubes. The formation of strong hydration shells between ions and water molecules considerably interrupted the hydrogen bonding between water molecules in the nanopores of the carbon nanotubes. The hydration shell had a diameter of approximately 1 nm, and hydration shells were thus adopted for the nanopores of the 2-nm-diameter carbon nanotubes, providing an explanation for the large difference in the nearest-neighbor distances between the electrolyte and water in these nanopores. PMID- 28723155 TI - Inhibiting the Fibrillation of Serum Albumin Proteins in the Presence of Surface Active Ionic Liquids (SAILs) at Low pH: Spectroscopic and Microscopic Study. AB - One of the key necessary steps to prevent human neurological disorders is the efficient disruption of protein aggregation or amyloid fibril. In this article, we have explored the effect of three amphiphilic surface active ionic liquids (SAILs), namely 1-methyl-3-octylimidazolium chloride ([C8mim]Cl), 1-dodecyl-3 methyllimidazolium chloride ([C12mim]Cl), and 1-hexadecyl-3-methyllimidazolium chloride ([C16mim]Cl) having concentrations of 5.8, 0.29, and 0.08 mM, respectively, on bovine serum albumin (BSA) and human serum albumin (HSA) fibril. These SAILs have different alkyl chain length attached to the cationic imidazolium headgroups. Interestingly, it is observed that all of the three SAILs exhibit fibril inhibition at room temperature itself as initially evidenced from thioflavin T (ThT) fluorescence assay study. However, C16mimCl is found as the most efficient quencher having highest quenching constant than the other two analogues. In addition, circular dichroism (CD) data give valuable insights into the conformational changes of BSA fibril as a consequence of interaction with SAILs. The field emission scanning electron microscopy (FESEM) and fluorescence lifetime imaging microscopy (FLIM) confirm the inhibitory effect of SAILs. It is evident from fluorescence correlation spectroscopy (FCS) study that 62% fibril is ruptured in the presence of C8mimCl while C12mimCl and C16mimCl completely destroy the fibrillar morphology. So the inhibition efficiency is related to the hydrophobicity associated with the long alkyl chain attached with the cationic imidazolium headgroup of SAILs. PMID- 28723156 TI - Effect of Drying Rate on Aerosol Particle Morphology. AB - The morphology of aerosol particles impacts their role in the climate system. In the submicron size regime, the morphology of particles that undergo liquid-liquid phase separation is dependent on their size, where for some systems small particles are homogeneous and large particles are phase-separated. We use cryogenic transmission electron microscopy to probe the morphology of model organic aerosol systems. We observe that the transition region (where both homogeneous and phase-separated morphologies are seen) spans 121 nm at the fastest drying rates with a midpoint diameter > 170 nm. By slowing the drying rate over several orders of magnitude, the transition region shifts to smaller diameters (midpoint < 40 nm) and the width narrows to 4 nm. Our results suggest that the size-dependent morphology originates from an underlying finite size effect, rather than solely kinetics, due to the presence of a size dependence even at the slowest drying rates. PMID- 28723157 TI - Role of Graphene in Reducing Fatigue Damage in Cu/Gr Nanolayered Composite. AB - Nanoscale metal/graphene nanolayered composite is known to have ultrahigh strength as the graphene effectively blocks dislocations from penetrating through the metal/graphene interface. The same graphene interface, which has a strong sp2 bonding, can simultaneously serve as an effective interface for deflecting the fatigue cracks that are generated under cyclic bendings. In this study, Cu/Gr composite with repeat layer spacing of 100 nm was tested for bending fatigue at 1.6% and 3.1% strain up to 1,000,000 cycles that showed for the first time a 5-6 times enhancement in fatigue resistance compared to the conventional Cu thin film. Fatigue cracks that are generated within the Cu layer were stopped by the graphene interface, which are evidenced by cross-sectional scanning electron microscopy and transmission electron microscopy images. Molecular dynamics simulations for uniaxial tension of Cu/Gr showed limited accumulation of dislocations at the film/substrate interface, which makes the fatigue crack formation and propagation through thickness of the film difficult in this materials system. PMID- 28723159 TI - Intramolecular Formation of Zwitterionic Intermediates in 1,3-Diaza-Claisen Rearrangements. AB - Isothioureas tethered to bridged-bicyclic tertiary allylic amines can be converted to carbodiimides through reaction with Hg(II) salts. Intramolecular cyclization of the tethered tertiary allylic amines to the carbodiimides afford zwitterionic intermediates that undergo 1,3-diaza-Claisen rearrangements, affording highly substituted tricyclic guanidines. PMID- 28723158 TI - Pd-Catalyzed Decarbonylative Cross-Couplings of Aroyl Chlorides. AB - This report describes a method for Pd-catalyzed decarbonylative cross-coupling that enables the conversion of carboxylic acid derivatives to biaryls, aryl amines, aryl ethers, aryl sulfides, aryl boronate esters, and trifluoromethylated arenes. The success of this transformation leverages the Pd0/Brettphos-catalyzed decarbonylative chlorination of aroyl chlorides, which can then participate in diverse cross-coupling reactions in situ using the same Pd catalyst. PMID- 28723160 TI - Phosphine-Catalyzed Enantioselective [4 + 2] Annulation of o-Quinone Methides with Allene Ketones. AB - A phosphine-catalyzed highly enantioselective [4 + 2] annulation between ortho quinone methides and allene ketones has been developed. The reported method led to the formation of chromane derivatives in high yields and excellent enantioselectivity. This is the first time that ortho-quinone methides are employed in phosphine-mediated cyclization reactions. PMID- 28723161 TI - Phosphines as Efficient Dioxygen Scavengers in Nitrous Oxide Sensors. AB - A current challenge for development of amperometric sensors for the greenhouse gas nitrous oxide (N2O) is their sensitivity toward dioxygen and trace water. The need for aqueous dioxygen scavengers in front of the sensor implies a background signal from penetrating water vapor. In this paper, we introduce substituted phosphines as dioxygen scavengers and demonstrate the application in a dioxygen insensitive N2O sensor. Suitably substituted phosphines have been synthesized to achieve good solubility properties in the electrochemically inert solvent propylene carbonate. Several sensors with and without physical separation of the sensing and dioxygen scavenging compartments were made and compared to current commercial sensors. The use of phosphines soluble in organic solvents as dioxygen scavengers yielded a higher sensitivity, albeit with longer response time. Proof of-concept N2O sensors without the physically separated dioxygen scavenger chamber showed a greatly enhanced sensitivity with a comparable response time, thus demonstrating the possibility for greatly simplified sensor construction. PMID- 28723162 TI - Ultrasensitive Detection of Cancer Prognostic miRNA Biomarkers Based on Surface Plasmon Enhanced Light Scattering. AB - The development of simple yet ultrasensitive biosensing approaches for the detection of cancer prognostic microRNA is an important step toward their successful clinical implementation. We demonstrate the relevance for the detection of circulating miRNA of a novel signal amplification scheme based on surface plasmon resonance enhanced light scattering (SP-LS). In addition to experimental optimization carried out using gold nanoparticle (AuNP) tags conjugated with a monoclonal antibody with high affinity for RNA*DNA hybrid duplexes, simulation modeling was conducted to obtain insights about SP-LS biosensing. SP-LS enabled the detection of miRNA-122 at subpicomolar concentrations within 30 min, and a limit of detection of 2 attomoles (60 fM, 50 MUL) was determined. MiRNA-122 could also be reliably detected in a high concentration background of nontarget miRNA. The proposed SP-LS miRNA detection approach could be readily applied to other miRNA targets of diagnostic importance and further developed to allow for multiplex measurements of miRNA panels. The promising results obtained in this study and advantageous features of SP-LS warrant further development and its application to clinical samples. PMID- 28723163 TI - SensUs: Challenging the Next Generation of Sensor Scientists. PMID- 28723164 TI - Differentiation and Identification of Cachaca Wood Extracts Using Peptide-Based Receptors and Multivariate Data Analysis. AB - It is becoming increasingly important to differentiate complex mixtures, especially in forensics. Cachaca, the most popular alcoholic beverage in Brazil, is made from distilled and fermented sugar cane juice. It contains a mixture of naturally occurring polyphenols known as tannins, whose composition is dictated by the type of wood used to age the beverage. These tannins can be differentiated in an Indicator Displacement Assay (IDA) using peptide-based ternary sensing ensembles. This investigation demonstrates a technique for fingerprinting the identity of the woods used to age cachacas. Unknown cachaca samples were tested against a training set of Brazilian woods in addition to oaks from different countries. Results obtained from the analysis showed that 62.5% of the samples were correctly identified. Furthermore, four samples anonymously added to the pool of unknowns from the training set were identified with 100% accuracy, emphasizing both the promising results obtained from this method of differentiation and the importance of analyzing same-age samples. PMID- 28723165 TI - Kinetic Discrimination of Metal Ions Using DNA for Highly Sensitive and Selective Cr3+ Detection. AB - Most metal sensors are designed for a strong binding affinity toward target metal ions, and the underlying principle relies on binding thermodynamics. The kinetic aspect of binding, however, was rarely explored for sensing. In this work, the binding kinetics of 19 common or toxic metal ions are compared based on a fluorescence quenching assay using DNA oligonucleotides as ligands. Among these metals, Cr3+ shows uniquely slow fluorescence quenching kinetics, and the quenched fluorescence cannot be recovered by EDTA or sulfide. Most other metals quenched fluorescence instantaneously and can be fully recovered by these metal chelators. Various factors such as DNA sequence and length, chelating agent, pH, and fluorophore type were studied to understand the binding mechanism, leading to a unique two-stage binding model for Cr3+. This system has a wide dynamic range of up to 50 MUM Cr3+ and a low limit of detection of 80 nM. It is also useful for measuring Cr3+ in lake water. This work proposes a new metal sensor design by monitoring binding kinetics with Cr3+ being a primary example. PMID- 28723167 TI - Sensitive Detection of MMP9 Enzymatic Activities in Single Cell-Encapsulated Microdroplets as an Assay of Cancer Cell Invasiveness. AB - Matrix metalloproteinases (MMPs) are typically up-regulated in cancer cells, and play a critical role in assisting metastasis by the breakdown of the extracellular matrix. Here we report an effective strategy for cell invasiveness assay by integrating MMP9 functional activity analysis with single cell encapsulated microdroplets. A flow focusing capillary microfluidic device has been assembled using "off-the-shelf" fluidic components for high-throughput generation of microdroplets. Tumor cells, MMP9 specific peptides, and other cofactors can be loaded into the device and encapsulated into individual droplets as dynamic microreactors for proteolytic cleavage of the substrate. This design allows for rapid and robust detection of MMP9 enzymatic activities by fluorescent signals in a few minutes. It represents the first demonstration of quantifying MMP9 enzymatic activities at the single cell level with a high throughput performance. This new technique promises functional evaluation of cancer cell invasiveness for important diagnostic or prognostic applications. PMID- 28723166 TI - Automated 3-D Printed Arrays to Evaluate Genotoxic Chemistry: E-Cigarettes and Water Samples. AB - A novel, automated, low cost, three-dimensional (3-D) printed microfluidic array was developed to detect DNA damage from metabolites of chemicals in environmental samples. The electrochemiluminescent (ECL) detection platform incorporates layer by-layer (LbL) assembled films of microsomal enzymes, DNA and an ECL-emitting ruthenium metallopolymer in ~10 nm deep microwells. Liquid samples are introduced into the array, metabolized by the human enzymes, products react with DNA if possible, and DNA damage is detected by ECL with a camera. Measurements of relative DNA damage by the array assess the genotoxic potential of the samples. The array analyzes three samples simultaneously in 5 min. Measurement of cigarette and e-cigarette smoke extracts and polluted water samples was used to establish proof of concept. Potentially genotoxic reactions from e-cigarette vapor similar to smoke from conventional cigarettes were demonstrated. Untreated wastewater showed a high genotoxic potential compared to negligible values for treated wastewater from a pollution control treatment plant. Reactivity of chemicals known to produce high rates of metabolite-related DNA damage were measured, and array results for environmental samples were expressed in terms of equivalent responses from these standards to assess severity of possible DNA damage. Genotoxic assessment of wastewater samples during processing also highlighted future on-site monitoring applications. PMID- 28723168 TI - Enhanced Room Temperature Oxygen Sensing Properties of LaOCl-SnO2 Hollow Spheres by UV Light Illumination. AB - In this paper, a facile and elegant Green Chemistry method for the synthesis of SnO2 based hollow spheres has been investigated. The influences of doping, crystallite morphology, and operating condition on the O2 sensing performances of SnO2 based hollow-sphere sensors were comprehensively studied. It was indicated that, compared with undoped SnO2, 10 at. % LaOCl-doped SnO2 possessed better O2 sensing characteristics owing to an increase of specific surface area and oxygen vacancy defect caused by LaOCl dopant. More importantly, it was found that O2 sensing properties of the 10 at. % LaOCl-SnO2 sensor were significantly improved by ultraviolet light illumination, which was suited for room-temperature O2 sensing applications. Besides, this sensor also had a better selectivity to O2 with respect to H2, CH4, NH3, and CO2. The remarkable increase of O2 sensing properties by UV light radiation can be explained in two ways. On one hand, UV light illumination promotes the generation of electron-hole pairs and oxygen adsorption, giving rise to high O2 response. On the other hand, UV light activates desorption of oxygen adsorbates when exposed to pure N2, contributing to rapid response/recovery speed. The results demonstrate a promising approach for room-temperature O2 detection. PMID- 28723169 TI - Nanoantenna-Enhanced Infrared Spectroscopic Chemical Imaging. AB - Spectroscopic infrared chemical imaging is ideally suited for label-free and spatially resolved characterization of molecular species, but often suffers from low infrared absorption cross sections. Here, we overcome this limitation by utilizing confined electromagnetic near-fields of resonantly excited plasmonic nanoantennas, which enhance the molecular absorption by orders of magnitude. In the experiments, we evaporate microstructured chemical patterns of C60 and pentacene with nanometer thickness on top of homogeneous arrays of tailored nanoantennas. Broadband mid-infrared spectra containing plasmonic and vibrational information were acquired with diffraction-limited resolution using a two dimensional focal plane array detector. Evaluating the enhanced infrared absorption at the respective frequencies, spatially resolved chemical images were obtained. In these chemical images, the microstructured chemical patterns are only visible if nanoantennas are used. This confirms the superior performance of our approach over conventional spectroscopic infrared imaging. In addition to the improved sensitivity, our technique provides chemical selectivity, which would not be available with plasmonic imaging that is based on refractive index sensing. To extend the accessible spectral bandwidth of nanoantenna-enhanced spectroscopic imaging, we employed nanostructures with dual-band resonances, providing broadband plasmonic enhancement and sensitivity. Our results demonstrate the potential of nanoantenna-enhanced spectroscopic infrared chemical imaging for spatially resolved characterization of organic layers with thicknesses of several nanometers. This is of potential interest for medical applications which are currently hampered by state-of-art infrared techniques, e.g., for distinguishing cancerous from healthy tissues. PMID- 28723170 TI - Highly Efficient Multiple-Anchored Fluorescent Probe for the Detection of Aniline Vapor Based on Synergistic Effect: Chemical Reaction and PET. AB - A multiple-anchored fluorescent probe ((((hexane-1,6-diylbis(2,7-bis(4-formyl) phenyl)-9H-fluorine-9,9-diyl))-bis(hexane-6,1-diyl))-bis(9H-carbazole-9,3,6 triyl))-tetrakis(benzene-4,1-diyl))-tetraformyl-(8FP-2F) with eight aldehyde groups was designed and synthesized. The molecule has four branches and highly twisted structure. Furthermore, it tends to self-assemble into nanospheres, which is beneficial for gaseous analyte penetration and high fluorescence quantum efficiency. Among gaseous analytes, detection of aniline vapor is extraordinarily important in the control of environmental issues and human diseases. Herein, 8FP 2F was introduced to detect aniline vapor with distinguished sensitivity and selectivity via simple Schiff base reaction at room temperature. After exposure to saturate aniline vapor, the 89% fluorescence of 8FP-2F was quenched in 50 s and the detection limit was as low as 3 ppb. Further study showed the suitable HOMO/LUMO energy levels and matched orbital symmetry between probe and aniline molecules ensured chemical reaction and PET process work together. The synergistic effect resulted in a significant sensing performance and fluorescence quenching toward aniline vapor. Moreover, the multiple active sites structure of 8FP-2F means it could be applied for constructing many interesting structures and highly efficient organic optoelectronic functional materials. PMID- 28723171 TI - Detection of Methanol with Fast Response by Monodispersed Indium Tungsten Oxide Ellipsoidal Nanospheres. AB - Indium tungsten oxide ellipsoidal nanospheres were prepared with different In/W ratios by using a simple hydrothermal method without any surfactant for the first time. Sensors based on different In/W ratios samples were fabricated, and one of the samples exhibited better response to methanol compared with others. High content of defective oxygen (Ov) and proper output proportion of In to W might be the main reasons for the better gas sensing properties. The length of the nanosphere was about 150-200 nm, and the width was about 100 nm. Various techniques were applied to investigate the nanospheres. Sensing characteristics toward methanol were investigated. Significantly, the sensor exhibited ultrafast response to methanol. The response time to 400 ppm methanol was no more than 2 s and the recovery time was 9 s at 312 degrees C. Most importantly, the humidity almost had no effect on the response of the sensor fabricated here, which is hard to achieve in gas-sensing applications. PMID- 28723172 TI - Periodically Patterned Au-TiO2 Heterostructures for Photoelectrochemical Sensor. AB - Periodically patterned Au nanorods in TiO2 nanocavities (Au NRs@TiO2) were fabricated via magnetron sputtering followed by a thermal dewetting process. This innovative Au NRs@TiO2 heterostructure was used as a plasmonic sensing platform for photoelectrochemical detection of glucose and lactose. This Au NRs@TiO2 patterned heterostructure possesses superior sensing properties to other Au nanoparticle-based sensors because (i) localized surface plasmon resonance (LSPR) generated at Au/TiO2 interfaces enhanced sensitivity of glucose (lactose) amperometric detection; (ii) periodic Au nanocrystals in TiO2 nanocavities accelerated charge separation and transfer rate, especially under monochromatic blue light irradiation; (iii) discrete planar architectures comprising Au NRs immobilized on TiO2 substrates significantly improved stability and reusability of the sensors. A low detection limit of 1 MUM (10 MUM) and a high sensitivity of 812 MUA mM-1 cm-2 (270 MUA mM-1 cm-2) were achieved on the Au NRs@TiO2 heterostructures for glucose (lactose) detection without the addition of enzymes. Good selectivity and superb stability over more than 8 weeks was also demonstrated using these Au NRs@TiO2 heterostructures for glucose (lactose) detection. Additionally, this cost-efficient technique can be easily extended to other photoelectrochemical sensing systems when considering the combination of sensing and visible or infrared light source enhancement. PMID- 28723173 TI - Laser-Scribed Graphene Electrodes for Aptamer-Based Biosensing. AB - Graphene as a transducer material has produced some of the best-performing sensing approaches to date opening the door toward integrated miniaturized all carbon point-of-care devices. Addressing this opportunity, laser-scribed graphene (LSG) electrodes are demonstrated here as highly sensitive and reliable biosensor transducers in blood serum analysis. These flexible electrodes with large electrochemical surface areas were fabricated using a direct-write laser process on polyimide foils. A universal immobilization approach is established by anchoring 1-pyrenebutyric acid to the graphene and subsequently covalently attaching an aptamer against the coagulation factor thrombin as an exemplary bioreceptor to the carboxyl groups. The resulting biosensor displays extremely low detection limits of 1 pM in buffer and 5 pM in the complex matrix of serum. PMID- 28723175 TI - Synthesis of 1,1-Disubstituted Indenes and Dihydronaphthalenes through C-C/C-C Bond-Forming Pd-Catalyzed Autotandem Reactions. AB - A novel synthesis of 1,1-disubstituted 1H-indenes is described involving the Pd catalyzed cascade reaction between o-bromophenyl-beta-bromostyrenes and N tosylhydrazones in a process comprising the consecutive formation of two Csp3-C bonds on the same carbon atom: the cross-coupling of the N-tosylhydrazone with the alkenyl bromide and the intramolecular Heck reaction on the newly formed double bond. A similar approach has been applied to the preparation of 1,1 disubstituted naphthalenes. PMID- 28723177 TI - One-Minute Fish Freshness Evaluation by Testing the Volatile Amine Gas with an Ultrasensitive Porous-Electrode-Capped Organic Gas Sensor System. AB - In this work, we successfully demonstrate a fast method to determine the fish freshness by using a sensing system containing an ultrasensitive amine gas sensor to detect the volatile amine gas from the raw fish meat. When traditional titration method takes 4 h and complicated steps to test the total volatile basic nitrogen (TVB-N) as a worldwide standard for fish freshness, our sensor takes 1 min to deliver an electrical sensing response that is highly correlated with the TVB-N value. When detecting a fresh fish with a TVB-N as 18 mg/100 g, the sensor delivers an effective ammonia concentration as 100 ppb. For TVB-N as 28-35 mg/100 g, a well-accepted freshness limit, the effective ammonia concentration is as 200 300 ppb. The ppb-regime sensitivity of the sensor and the humidity control in the sensing system are the keys to realizing fast and accurate detection. It is expected that the results in this report enable the development of on-site freshness detection and real-time monitoring in a fish factory. PMID- 28723178 TI - Development of Engineered Bacteriophages for Escherichia coli Detection and High Throughput Antibiotic Resistance Determination. AB - T7 bacteriophages (phages) have been genetically engineered to carry the lacZ operon, enabling the overexpression of beta-galactosidase (beta-gal) during phage infection and allowing for the enhanced colorimetric detection of Escherichia coli (E. coli). Following the phage infection of E. coli, the enzymatic activity of the released beta-gal was monitored using a colorimetric substrate. Compared with a control T7 phage, our T7lacZ phage generated significantly higher levels of beta-gal expression following phage infection, enabling a lower limit of detection for E. coli cells. Using this engineered T7lacZ phage, we were able to detect E. coli cells at 10 CFU.mL-1 within 7 h. Furthermore, we demonstrated the potential for phage-based sensing of bacteria antibiotic resistance profiling using our T7lacZ phage, and subsequent beta-gal expression to detect antibiotic resistant profile of E. coli strains. PMID- 28723179 TI - Multifunctional Nanofibers for Specific Purification and Release of CTCs. AB - Recovering pure and viable circulating tumor cells (CTCs) from blood has been a challenging task for molecular characterization and functional analysis, which has attracted wide attention these days. Herein, we fabricate a thermoresponsive chitosan nanofiber substrate to effectively capture, purify, and release the target cancer cells, assisted by PNIPAAm brushes and DNA hybridization. The PNIPAAm brushes are designed to enable WBCs to detach from aptamer-PNIPAAm chitosan-nanofiber (aptamer-P-CNFs) surfaces during the conformational transition. Meanwhile these specific captured CTCs are retained at a high purity. Moreover, effective and intact release of CTCs from the substrates without any foreign agents is realized by complementary sequences efficiently hybridizing with aptamers, and the specific cell release makes CTCs further purified. The present work provides a new strategy in the design of biointerface for recovering target CTCs from whole blood samples with high purity. PMID- 28723180 TI - Black Phosphorus Quantum Dots as the Ratiometric Fluorescence Probe for Trace Mercury Ion Detection Based on Inner Filter Effect. AB - In this work, a novel ratiometric fluorescence sensor has been constructed for the selective and sensitive detection of Hg2+, which is based on the inner filter effect (IFE) of tetraphenylporphyrin tetrasulfonic acid (TPPS) toward black phosphorus quantum dots (BP QDs). Highly fluorescent BP QDs were successfully synthesized from bulk BP by sonication-assisted solvothermal method via a top down route. In the presence of Hg2+, the IFE originating from spectral overlap between the excitation of BP QDs and the absorption of TPPS is inhibited and the fluorescence of BP QDs is restored. At the same time, the red fluorescence of TPPS is quenched due to its coordination with Mn2+. These phenomena result from the rapid coordination between Mn2+ and TPPS in the presence of Hg2+, which leads to the dramatic decrease of the absorption of TPPS. On the basis of these findings, we design a ratiometric fluorescence sensor for the detection of Hg2+. The as-constructed sensor reveals a good linear response to Hg2+ ranging from 1 to 60 nM with a detection limit of 0.39 nM. Furthermore, the sensing assay is applicable to detecting Hg2+ in real samples. PMID- 28723181 TI - Mixed Self-Assembled Aptamer and Newly Designed Zwitterionic Peptide as Antifouling Biosensing Interface for Electrochemical Detection of alpha Fetoprotein. AB - A sensitive and low-fouling aptasensor for alpha-fetoprotein (AFP) was developed based on mixed self-assembled aptamers and newly designed zwitterionic peptides, where densely immobilized peptides formed an antifouling layer to resist nonspecific protein adsorption, and sparsely attached aptamers acted as the recognizing layer to achieve target binding. The obtained biosensing interface responded to the target AFP with a strikingly selective and sensitive manner, exhibited excellent protein-resistant performance even in complex human serum solution, and showed promising feasibility for the quantitative analysis of AFP in real human serum samples. PMID- 28723182 TI - Cross-Linked Gold-Nanoparticle Membrane Resonators as Microelectromechanical Vapor Sensors. AB - We report a novel approach for the detection of volatile compounds employing electrostatically driven drumhead resonators as sensing elements. The resonators are based on freestanding membranes of alkanedithiol cross-linked gold nanoparticles (GNPs), which are able to sorb analytes from the gas phase. Under reduced pressure, the fundamental resonance frequency of a resonator is continuously monitored while the device is exposed to varying partial pressures of toluene, 4-methylpentan-2-one, 1-propanol, and water. The measurements reveal a strong, reversible frequency shift of up to ~10 kHz, i.e., ~5% of the fundamental resonance frequency, when exposing the sensor to toluene vapor with a partial pressure of ~20 Pa. As this strong shift cannot be explained exclusively by the mass uptake in the membrane, our results suggest a significant impact of analyte sorption on the pre-stress of the freestanding GNP membrane. Thus, our findings point to the possibility of designing highly sensitive resonators, which utilize sorption induced changes in the membrane's pre-stress as primary transduction mechanism. PMID- 28723183 TI - Reflecting on How ACS Sensors Can Help Advance the Field of Sensing. PMID- 28723184 TI - Steric Hindrance Assay for Secreted Factors in Stem Cell Culture. AB - The ex vivo expansion of hematopoietic stem cells is significantly inhibited by secreted proteins that induce negative feedback loops. The ability to effectively monitor these factors is critical for their real-time regulation and control and, by extension, enhancing stem cell expansion. Here, we describe a novel monitoring strategy for the detection of soluble signaling factors in stem cell cultures using a DNA-based sensing mechanism on a chip-based nanostructured microelectrode platform. We combine DNA hybridization engineering with antibody-capturing chemistry in an amplified steric hindrance hybridization assay. This method enables the quantification of important secreted proteins, showcased by the detection of 10 pg.mL-1 level concentrations of three proteins in stem cell culture samples. This approach is the first universal nonsandwich technique that permits pg.mL-1 level quantification of small proteins in stem cell culture media without signal loss. PMID- 28723185 TI - Silanization of Sapphire Surfaces for Optical Sensing Applications. AB - Well-characterized silane layers are essential for optimized attachment of (bio)molecules enabling reliable chem/biosensor performance. Herein, binding properties and orientation of 3-mercaptopropyltrimethoxysilane layers at crystalline sapphire (0001) surfaces were determined by water contact angle measurements, infrared reflection absorption spectroscopy, atomic force microscopy, and X-ray photoelectron spectroscopy. Infrared reflection absorption spectroscopy measurements suggest an almost perpendicular arrangement of the MPTMS molecules to the substrate surface. Adhesion force studies between a silicon nitride AFM tip and modified sapphire, gold, and silicon dioxide substrates were investigated by peak force tapping atomic force microscopy and used to define the silane binding properties on these surfaces. As expected, the Al-O-Si bond was determined to be responsible for the layer formation at the sapphire substrate surface. PMID- 28723186 TI - Ingestible Sensors. AB - Ingestible sensing capsules are fast emerging as a critical technology that has the ability to greatly impact health, nutrition, and clinical areas. These ingestible devices are noninvasive and hence are very attractive for customers. With widespread access to smart phones connected to the Internet, the data produced by this technology can be readily seen and reviewed online, and accessed by both users and physicians. The outputs provide invaluable information to reveal the state of gut health and disorders as well as the impact of food, medical supplements, and environmental changes on the gastrointestinal tract. One unique feature of such ingestible sensors is that their passage through the gut lumen gives them access to each individual organ of the gastrointestinal tract. Therefore, ingestible sensors offer the ability to gather images and monitor luminal fluid and the contents of each gut segment including electrolytes, enzymes, metabolites, hormones, and the microbial communities. As such, an incredible wealth of knowledge regarding the functionality and state of health of individuals through key gut biomarkers can be obtained. This Review presents an overview of the gut structure and discusses current and emerging digestible technologies. The text is an effort to provide a comprehensive overview of ingestible sensing capsules, from both a body physiology point of view as well as a technological view, and to detail the potential information that they can generate. PMID- 28723187 TI - Wearable Flexible and Stretchable Glove Biosensor for On-Site Detection of Organophosphorus Chemical Threats. AB - A flexible glove-based electrochemical biosensor with highly stretchable printed electrode system has been developed as a wearable point-of-use screening tool for defense and food security applications. This disposable-mechanically robust "lab on-a-glove" integrates a stretchable printable enzyme-based biosensing system and active surface for swipe sampling on different fingers, and is coupled with a compact electronic interface for electrochemical detection and real-time wireless data transmission to a smartphone device. Stress-enduring inks are used to print the electrode system and the long serpentine connections to the wireless electronic interface. Dynamic mechanical deformation, bending, and stretching studies illustrate the resilience and compliance of the printed traces against extreme mechanical deformations expected for such on-glove sampling/sensing operation. An organophosphorus hydrolase (OPH)-based biosensor system on the index finger enables rapid on-site detection of organophosphate (OP) nerve-agent compounds on suspicious surfaces and agricultural products following their swipe collection on the thumb finger. The new wireless glove-based biosensor system offers considerable promise for field screening of OP nerve-agents and pesticides in defense and food-safety applications, with significant speed and cost advantages. Such "lab-on-a-glove" demonstration opens the area of flexible wearable sensors to future on-the-hand multiplexed chemical detection in diverse fields. PMID- 28723188 TI - Salt Gradient Improving Signal-to-Noise Ratio in Solid-State Nanopore. AB - As the single molecule detection tool, solid-state nanopores are being applied in more and more fields, such as medicine controlled delivery, ion conductance microscopes, nanosensors, and DNA sequencing. The critical information obtained from nanopores is the signal collected, which is the ionic block current caused by the molecules passing through the pores. However, the information collected is, in part, impeded by the relatively low signal-to-noise ratio of the current solid-state nanopore measurements. Here, we report that using a salt gradient across the nanopore could improve the signal-to-noise ratio when molecules translocate through Si3N4 nanopore. Furthermore, we demonstrate that the improved signal-to-noise ratio is connected with not only the value of surface charge but also that of a salt gradient between cis and trans sides of the nanopore. PMID- 28723189 TI - Ionophore-Based Titrimetric Detection of Alkali Metal Ions in Serum. AB - While the titrimetric assay is one of the most precise analytical techniques available, only a limited list of complexometric chelators is available, as many otherwise promising reagents are not water-soluble. Recent work demonstrated successful titrimetry with ion-exchanging polymeric nanospheres containing hydrophobic complexing agents, so-called ionophores, opening an exciting avenue in this field. However, this method was limited to ionophores of very high affinity to the analyte and exhibited a relatively limited titration capacity. To overcome these two limitations, we report here on solvent based titration reagents. This heterogeneous titration principle is based on the dissolution of all hydrophobic recognition components in a solvent such as dichloromethane (CH2Cl2) where the ionophores are shown to maintain a high affinity to the target ions. HSV (hue, saturation, value) analysis of the images captured with a digital camera provides a convenient and inexpensive way to determine the end point. This approach is combined with an automated titration setup. The titrations of the alkali metals K+, Na+, and Li+ in aqueous solution are successfully demonstrated. The potassium concentration in human serum without pretreatment was precisely and accurately determined as 4.38 mM +/- 0.10 mM (automated titration), which compares favorably with atomic emission spectroscopy (4.47 mM +/- 0.20 mM). PMID- 28723190 TI - In Search of the Ultimate Benzene Sensor: The EtQxBox Solution. AB - In this work we report a comprehensive study leading to the fabrication of a prototype sensor for environmental benzene monitoring. The required high selectivity and ppb-level sensitivity are obtained by coupling a silicon integrated concentration unit containing the specifically designed EtQxBox cavitand to a miniaturized PID detector. In the resulting stand-alone sensor, the EtQxBox receptor acts at the same time as highly sensitive preconcentrator for BTEX and GC-like separation phase, allowing for the selective desorption of benzene over TEX. The binding energies of the complexes between EtQxBox and BTX are calculated through molecular mechanics calculations. The examination of the corresponding crystal structures confirms the trend determined by computational studies, with the number of C-H...N and CH...pi interactions increasing from 6 to 9 along the series from benzene to o-xylene. The analytical performances of EtQxBox are experimentally tested via SPME, using the cavitand as fiber coating for BTEX monitoring in air. The cavitand EFs are noticeably higher than those obtained by using the commercial CAR-DVB-PDMS. The LOD and LOQ are calculated in the ng/m3 range, outperforming the commercial available systems in BTEX adsorption. The desired selective desorption of benzene is achieved by applying a smart temperature program on the EtQxBox mesh, which starts releasing benzene at lower temperatures than TEX, as predicted by the calculated binding energies. The sensor performances are experimentally validated and ppbv level sensitivity toward the carcinogenic target aromatic benzene was demonstrated, as required for environmental benzene exposure monitoring in industrial applications and outdoor environment. PMID- 28723191 TI - Highly Enriched, Controllable, Continuous Aerosol Sampling Using Inertial Microfluidics and Its Application to Real-Time Detection of Airborne Bacteria. AB - We report a novel microfluidic technique for sampling of aerosols into liquids. The two-phase fluid, sampling air and collecting liquid, forms a stratified flow in the curved microchannel. By passing fluids through the curved region, the particles are transferred from air into the liquid phase by the particle centrifugal and drag forces. This microfluidic-based aerosol-into-liquid sampling system, called the MicroSampler, is driven by particle inertial differences. To evaluate the physical particle collection efficiency of the MicroSampler, we used standard polystyrene-latex (PSL) particles ranging in size from 0.6 to 2.1 MUm and measured particle concentrations upstream and downstream of the MicroSampler with an aerodynamic particle sizer. The cutoff diameter of particle collection was selected controlling the air flow velocity (microfluidic air flow of 0.6 L/min showed a particle collection efficiency of ~98% at a particle diameter of 1 MUm), and continuous enriched particle sampling was possible for real-time postprocessing application. With regard to biological collection efficiency, the MicroSampler showed superior microbial recovery (Staphylococcus epidermidis) compared to the conventional BioSampler technique. These results indicate that our MicroSampler can be used as a portable, cost-effective, simple, and continuous airborne microorganism collector for applications in real-time bioaerosol detection. PMID- 28723192 TI - Mechanistic Challenges and Advantages of Biosensor Miniaturization into the Nanoscale. AB - Over the past few decades, there has been tremendous interest in developing biosensing systems that combine high sensitivity and specificity with rapid sample-to-answer times, portability, low-cost operation, and ease-of-use. Miniaturizing the biosensor dimensions into the nanoscale has been identified as a strategy for addressing the functional requirements of point-of-care and wearable biosensors. However, it is important to consider that decreasing the critical dimensions of biosensing elements impacts the two most important performance metrics of biosensors: limit-of-detection and response time. Miniaturization into the nanoscale enhances signal-to-noise-ratio by increasing the signal density (signal/geometric surface area) and reducing background signals. However, there is a trade-off between the enhanced signal transduction efficiency and the longer time it takes to collect target analytes on sensor surfaces due to the increase in mass transport times. By carefully considering the signal transduction mechanisms and reaction-transport kinetics governing different classes of biosensors, it is possible to develop structure-level and device-level strategies for leveraging miniaturization toward creating biosensors that combine low limit-of-detection with rapid response times. PMID- 28723193 TI - Highly Sensitive Squaraine-Based Water-Soluble Far-Red/Near-Infrared Chromofluorogenic Thiophenol Probe. AB - A squaraine-based far-red/near-infrared fluorescent probe (SQ-DNBS) was exploited for thiophenol detection. SQ-DNBS is a colorimetric and "off-on" fluorometric dual-channel "naked-eye" chemosensor showing high selectivity, high sensitivity (detection limit: 9.9 nM), and rapid response to thiophenol in aqueous solution. SQ-DNBS also can be used in practical applications for the detection of thiophenol in water samples. Photophysical and spectral characterization results revealed that the probing mechanism of SQ-DNBS toward thiophenol lies in the thiolate-mediated cleavage reaction. Our discovery demonstrates the potential of the arylmethylene-squaraine skeleton as a promising fluorophore unit to construct high-performance far-red/near-infrared chemosensors. PMID- 28723195 TI - Lanthanide-Labeled Immunochromatographic Strip Assay for the On-Site Identification of Ancient Silk. AB - The on-site identification of ancient silks has long been a key challenge in archeology. Therefore, a rapid, cost-effective, sensitive analytical approach is highly desirable. In this paper, a lanthanide-labeled immunochromatographic strip which is suitable for the on-site identification of ancient silks is described. Compared with the conventional colloidal gold-based immunochromatographic strip, this strip shows much higher analytical sensitivity and better quantitative discrimination. The limit of detection (LOD) of the strip for silk fibroin (SF) was calculated as 8.09 ng/mL, approximately 185 times lower than that of the colloidal gold-based immunochromatographic strip. No cross-reactions with other possible interfering antigens were observed. Moreover, the strip also shows good reproducibility, with a mean recovery of 94.15-102.55% and coefficient of variation of 5.22-17.57% in the repeated tests. Based on the advantages of portability and cost-effectiveness, as well as sensitivity, specificity, and reproducibility, the lanthanide-labeled immunochromatographic strip is a promising tool for on-site detection of ancient relics in archeological fieldwork. PMID- 28723194 TI - Aromatization of 9,10-Dihydroacridine Derivatives: Discovering a Highly Selective and Rapid-Responding Fluorescent Probe for Peroxynitrite. AB - As part of an effort to develop generally applicable strategies for creating probes suitable for detecting important molecular and ionic species, the oxidative aromatization of nonfluorescent 9,10-dihydroacridine derivatives triggered by peroxynitrite (ONOO-) led to the identification of compound 2H, 9 phenyl-9,10-dihydroacridine-4-carboxylic acid, as a rapid-responding fluorescent probe capable of detecting ONOO- with an extraordinary selectivity. Adding a little more than 1 equiv of ONOO- to a solution of 2H resulted in over 100-fold fluorescence enhancement. In sharp contrast, treating 2H with excessive amounts of other oxidants that often interfere with the detection of ONOO- failed to lead to noticeable fluorescence increase. The reaction of ONOO- with 2H shows a similar efficiency in the pH range of 2-8. Low cytotoxicity was observed for 2H and its aromatized product. Bioimaging experiments revealed the promising potential of 2H as a new fluorescent probe for the selective detection of intracellular ONOO-. PMID- 28723196 TI - Label-Free Homogeneous Electroanalytical Platform for Pesticide Detection Based on Acetylcholinesterase-Mediated DNA Conformational Switch Integrated with Rolling Circle Amplification. AB - This study addresses the need for sensitive pesticide assay by reporting a new label-free and immobilization-free homogeneous electroanalytical strategy, which combines acetylcholinesterase (AChE)-catalyzed hydrolysis product-mediated DNA conformational switch and rolling circle amplification (RCA) to detect organophosphorous and carbamate pesticides in a "signal-on" mode. When target pesticides were present, AChE activity was inhibited and could not trigger the following DNA conformational change and the RCA reaction, which results in numerous methylene blue (MB) molecules in a free state, generating a strong electrochemical response. This proposed strategy was highly sensitive for omethoate detection with a detection limit as low as 2.1 MUg/L and a linear range from 10 to 10 000 MUg/L. Furthermore, this strategy was demonstrated to be applicable for pesticide detection in real samples. Thus, this novel label-free homogeneous electroanalytical strategy holds great promise for pesticide detection and can be further exploited for sensing applications in the environment and the food safety field. PMID- 28723199 TI - Rational Design of a Stimuli-Responsive Polymer Electrode Interface Coupled with in Vivo Microdialysis for Measurement of Sialic Acid in Live Mouse Brain in Alzheimer's Disease. AB - Sensitive and selective monitoring of sialic acid (SA) in cerebral nervous system is of great importance for studying the role that SA plays in the pathological process of Alzheimer's disease (AD). In this work, we first reported an electrochemical biosensor based on a novel stimuli-responsive copolymer for selective and sensitive detection of SA in mouse brain. Notably, through synergetic hydrogen-bonding interactions, the copolymer could translate the recognition of SA into their conformational transition and wettability switch, which facilitated the access and enrichment of redox labels and targets to the electrode surface, thus significantly improving the detection sensitivity with the detection limit down to 0.4 pM. Besides amplified sensing signals, the proposed method exhibited good selectivity toward SA in comparison to potential interference molecules coexisting in the complex brain system due to the combination of high affinity between phenylboronic acid (PBA) and SA and the directional hydrogen-bonding interactions in the copolymer. The electrochemical biosensor with remarkable analytical performance was successfully applied to evaluate the dynamic change of SA level in live mouse brain with AD combined with in vivo midrodialysis. The accurate concentration of SA in different brain regions of live mouse with AD has been reported for the first time, which is beneficial for progressing our understanding of the role that SA plays in physiological and pathological events in the brain. PMID- 28723197 TI - In Vivo Biosensing: Progress and Perspectives. AB - In vivo biosensors are emerging as powerful tools in biomedical research and diagnostic medicine. Distinct from "labels" or "imaging", in vivo biosensors are designed for continuous and long-term monitoring of target analytes in real biological systems and should be selective, sensitive, reversible and biocompatible. Due to the challenges associated with meeting all of the analytical requirements, we found relatively few reports of research groups demonstrating devices that meet the strict definition in vivo. However, we identified several case studies and a range of emerging materials likely to lead to significant developments in the field. PMID- 28723200 TI - Flexible, Transparent, and Free-Standing Silicon Nanowire SERS Platform for in Situ Food Inspection. AB - We demonstrated a flexible transparent and free-standing Si nanowire paper (SiNWP) as a surface enhanced Raman scattering (SERS) platform for in situ chemical sensing on warping surfaces with high sensitivity. The SERS activity has originated from the three-dimension interconnected nanowire network structure and electromagnetic coupling between closely separated nanowires in the SiNWP. In addition, the SERS activity can be highly improved by functionalizing the SiNWP with plasmonic Au nanoparticles. The hybrid substrate not only showed excellent reproducibility and stability of the SERS signal, but also maintained the flexibility and transparency of the pristine SiNWP. To demonstrate its potential application in food inspection, the Au nanoparticles-modified SiNWP was directly wrapped onto the lemon surface for in situ identification and detection of the pesticide residues. The results showed that the excellent SERS activity and transparency of the hybrid substrate enabled the detection of the pesticides down to 72 ng/cm2, which was much lower than the permitted residue dose in food safety. PMID- 28723201 TI - Imaging Lysosomal pH Alteration in Stressed Cells with a Sensitive Ratiometric Fluorescence Sensor. AB - The organelle-specific pH is crucial for cell homeostasis. Aberrant pH of lysosomes has been manifested in myriad diseases. To probe lysosome responses to cell stress, we herein report the detection of lysosomal pH changes with a dual colored probe (CM-ROX), featuring a coumarin domain with "always-on" blue fluorescence and a rhodamine-lactam domain activatable to lysosomal acidity to give red fluorescence. With sensitive ratiometric signals upon subtle pH changes, CM-ROX enables discernment of lysosomal pH changes in cells undergoing autophagy, cell death, and viral infection. PMID- 28723202 TI - Structure Guided Design of Protein Biosensors for Phenolic Pollutants. AB - Phenolic aromatic compounds are a major source of environmental pollution. Currently there are no in situ methods for specifically and selectively detecting these pollutants. Here, we exploit the nature's biosensory machinery by employing Acinetobacter calcoaceticus NCIB8250 protein, MopR, as a model system to develop biosensors for selective detection of a spectrum of these pollutants. The X-ray structure of the sensor domain of MopR was used as a scaffold for logic-based tunable biosensor design. By employing a combination of in silico structure guided approaches, mutagenesis and isothermal calorimetric studies, we were able to generate biosensor templates, that can selectively and specifically sense harmful compounds like chlorophenols, cresols, catechol, and xylenols. Furthermore, the ability of native protein to selectively sense phenol as the primary ligand was also enhanced. Overall, this methodology can be extended as a suitable framework for development of a series of exclusive biosensors for accurate and selective detection of aromatic pollutants from real time environmental samples. PMID- 28723203 TI - Multicolor Functional Carbon Dots via One-Step Refluxing Synthesis. AB - Carbon dots are admirable fluorescent nanomaterials due to their low cost, high photostability, excellent biocompatibility, and environmental friendliness. Most conventional carbon dot fabrication approaches produce single-colored fluorescent material in the preparation process; different methods are therefore required to synthesize distinct carbon dots for specific optical applications. In this study, carbon dots carrying different emission colors are prepared through a one-step refluxing process. The emission of these materials can be well-tuned by sodium hydroxide content in the precursor solution. The carbon dots produced are used as sensing probes based on the spectrofluorometric inner filter effect for target molecule detection. Three sensing categories that combine carbon dots and inner filter effect are demonstrated, including direct, metal nanoparticle-assisted, and enzymatic reaction-supported detection. Caffeine, melamine, and fenitrothion are selected as targets to demonstrate the strategies, respectively. These multifunctional carbon dot-based sensors achieve comparable sensitivity toward analytes with a much more convenient preparation route. PMID- 28723204 TI - Crossed Surface Relief Gratings as Nanoplasmonic Biosensors. AB - We present an original, low-cost nanoplasmonic (bio)sensor based on crossed surface relief gratings (CSRGs) generated from orthogonally superimposed surface relief gratings (SRGs) on gold-coated azo-glass substrate. This surface plasmon resonance (SPR)-based sensing approach is unique, since the light transmitted through a CSRG is zero except in the narrow bandwidth where the SPR conversion occurs, enabling quantitative monitoring of only the plasmonic signal from biomolecular interactions in real time. We validated the individual SRG plasmonic signature of CSRGs by observing their respective SPR excitation peaks, and tested them to detect both bulk and near-surface refractive index (RI) changes. Compared to simple SRGs, CSRGs portray a much-improved sensitivity of 647.8 nm/RIU, a resolution on the order of 10-5 RIU, and a figure of merit (FOM) of 14 for bulk RI-change sensing. We also demonstrate their ability to perform as biosensors, through the detection and monitoring of near-surface biomolecular interactions in real time, a first for CSRGs. The minimum detectable concentration of biotin streptavidin binding events was 8.3 nM. Due to their sensing abilities, low cost (<10 cents/unit), ease of fabrication, and inherent suitability for integration with microfluidics, we anticipate that CSRGs will stand as strong candidates in the portable diagnostics arena. PMID- 28723205 TI - Ultrafast Paper Thermometers Based on a Green Sensing Ink. AB - With the use of an ionic liquid as the ultrathermosensitive fluid, a paper thermometer is successfully developed with intrinsic ability of ultrafast response and high stability upon temperature change. The fluidic nature allows the ionic liquid to be easily deposited on paper by pen writing or inkjet printing, affording great promise for large-scale fabrication of low-cost paper sensors. Owing to the advantages of nonvolatilization, excellent continuity and deformability, the thermosensitive ink trapped within the cellulose fibers of paper matrix has no leakage or evaporation at open states, ensuring the excellent stability and repeatability of thermal sensing against arbitrary bending and folding operation. By shortening the heat exchange distance between ionic liquid and samples, it takes only 8 s for the thermometer to reach an electrical equilibrium at a given temperature. Moreover, the paper thermometer can be applied to remotely monitor temperature change with the combination of a wireless communication technology. PMID- 28723206 TI - Evaluating Dye-Labeled DNA Dendrimers for Potential Applications in Molecular Biosensing. AB - DNA nanostructures provide a reliable and predictable scaffold for precisely positioning fluorescent dyes to form energy transfer cascades. Furthermore, these structures and their attendant dye networks can be dynamically manipulated by biochemical inputs, with the changes reflected in the spectral response. However, the complexity of DNA structures that have undergone such types of manipulation for direct biosensing applications is quite limited. Here, we investigate four different modification strategies to effect such dynamic manipulations using a DNA dendrimer scaffold as a testbed, and with applications to biosensing in mind. The dendrimer has a 2:1 branching ratio that organizes the dyes into a FRET-based antenna in which excitonic energy generated on multiple initial Cy3 dyes displayed at the periphery is then transferred inward through Cy3.5 and/or Cy5 relay dyes to a Cy5.5 final acceptor at the focus. Advantages of this design included good transfer efficiency, large spectral separation between the initial donor and final acceptor emissions for signal transduction, and an inherent tolerance to defects. Of the approaches to structural rearrangement, the first two mechanisms we consider employed either toehold-mediated strand displacement or strand replacement and their impact was mainly via direct transfer efficiency, while the other two were more global in their effect using either a belting mechanism or an 8-arm star nanostructure to compress the nanostructure and thereby modulate its spectral response through an enhancement in parallelism. The performance of these mechanisms, their ability to reset, and how they might be utilized in biosensing applications are discussed. PMID- 28723207 TI - Wearable, Flexible, and Multifunctional Healthcare Device with an ISFET Chemical Sensor for Simultaneous Sweat pH and Skin Temperature Monitoring. AB - Real-time daily healthcare monitoring may increase the chances of predicting and diagnosing diseases in their early stages which, currently, occurs most frequently during medical check-ups. Next-generation noninvasive healthcare devices, such as flexible multifunctional sensor sheets designed to be worn on skin, are considered to be highly suitable candidates for continuous real-time health monitoring. For healthcare applications, acquiring data on the chemical state of the body, alongside physical characteristics such as body temperature and activity, are extremely important for predicting and identifying potential health conditions. To record these data, in this study, we developed a wearable, flexible sweat chemical sensor sheet for pH measurement, consisting of an ion sensitive field-effect transistor (ISFET) integrated with a flexible temperature sensor: we intend to use this device as the foundation of a fully integrated, wearable healthcare patch in the future. After characterizing the performance, mechanical flexibility, and stability of the sensor, real-time measurements of sweat pH and skin temperature are successfully conducted through skin contact. This flexible integrated device has the potential to be developed into a chemical sensor for sweat for applications in healthcare and sports. PMID- 28723208 TI - The Triple Roles of Glutathione for a DNA-Cleaving DNAzyme and Development of a Fluorescent Glutathione/Cu2+-Dependent DNAzyme Sensor for Detection of Cu2+ in Drinking Water. AB - Pistol-like DNAzyme (PLDz) is an oxidative DNA-cleaving catalytic DNA with ascorbic acid as cofactor. Herein, glutathione was induced into the reaction system to maintain reduced ascorbic acid levels for higher efficient cleavage. However, data indicated that glutathione played triple roles in PLDz-catalyzed reactions. Glutathione alone had no effect on PLDz, and showed inhibitory effect on ascorbic acid-induced PLDz catalysis, but exhibited stimulating effect on Cu2+ promoted self-cleavage of PLDz. Further analysis of the effect of glutathione/Cu2+ on PLDz indicated that H2O2 played a key role in PLDz catalysis. Finally, we developed a fluorescent Cu2+ sensor (PL-Cu 1.0) based on the relationship between glutathione/Cu2+ and catalytic activity of PLDz. The fluorescent intensity showed a linear response toward the logarithm concentration of Cu2+ over the range from 80 nM to 30 MUM, with a detection limit of 21.1 nM. PL-Cu 1.0 provided only detection of Cu2+ over other divalent metal ions. Ca2+ and Mg2+ could not interfere with Cu2+ detection even at a 1000-fold concentration. We further applied PL-Cu 1.0 for Cu2+ detection in tap and bottled water. Water stored in copper taps overnight had relatively high Cu2+ concentrations, with a maximum 22.3 MUM. Trace Cu2+ (52.2 nM) in deep spring was detected among the tested bottled water. Therefore, PL-Cu 1.0 is feasible to detect Cu2+ in drinking water, with a practical application. PMID- 28723209 TI - Adding New Senses to Your Cell Phone: Opportunities for Gas Sensing. PMID- 28723210 TI - Bipolar Electrodes with 100% Current Efficiency for Sensors. AB - A bipolar electrode (BPE) is an electron conductor that is embedded in the electrolyte solution without the direct connection with the external power source (driving electrode). When the sufficient voltage was provided, the two poles of BPE promote different oxidation and reduction reactions. During the past few years, BPEs with wireless feature and easy integration showed great promise in the various fields including asymmetric modification/synthesis, motion control, targets enrichment/separation, and chemical sensing/biosensing combined with the quantitative relationship between two poles of BPE. In this perspective paper, we first describe the concept and history of the BPE for analytical chemistry and then review the recent developments in the application of BPEs for sensing with ultrahigh current efficiency (etac = iBPE/ichannel) including the open and closed bipolar system. Finally, we offer the guide for possible challenge faced and solution in the future. PMID- 28723211 TI - Improving FoRe: A New Inlet Design for Filtering Samples through Individual Microarray Spots. AB - In this publication we present an improvement to our previously introduced vertical flow microarray, the FoRe array, which capitalizes on the fusion of immunofiltration and densely packed micron test sites. Filtering samples through individual microarray spots allows us to rapidly analyze dilute samples with high throughput and high signal-to-noise. Unlike other flowthrough microarrays, in the FoRe design samples are injected into micron channels and sequentially exposed to different targets. This arrangement makes it possible to increase the sensitivity of the microarray by simply increasing the sample volume or to rapidly reconcentrate samples after preprocessing steps dilute the analyte. Here we present a new inlet system which allows us to increase the analyzed sample volume without compromising the micron spot size and dense layout. We combined this with a model assay to demonstrate that the device is sensitive to the amount of antigen, and as a result, sample volume directly correlates to sensitivity. We introduced a simple technique for analysis of blood, which previously clogged the nanometer-sized pores, requiring only microliter volumes expected from an infant heel prick. A drop of blood is mixed with buffer to separate the plasma before reconcentrating the sample on the microarray spot. We demonstrated the success of this procedure by spiking TNF-alpha into blood and achieved a limit of detection of 18 pM. Compared to traditional protein microarrays, the FoRe array is still inexpensive, customizable, and simple to use, and thanks to these improvements has a broad range of applications from small animal studies to environmental monitoring. PMID- 28723212 TI - Engineering Recombinant Protein Sensors for Quantifying Histone Acetylation. AB - H3K14ac (acetylation of lysine 14 of histone H3) is one of the most important epigentic modifications. Aberrant changes in H3K14ac have been associated with various diseases, including cancers and neurological disorders. Tools that enable detection and quantification of H3K14ac levels in cell extracts and in situ are thus of critical importance to reveal its role in various biological processes. Current detection techniques of specific histone modifications, however, are constrained by tedious sample pretreatments, lack of quantitative accuracy, and reliance on high quality antibodies. To address this issue, we engineered recombinant sensors that are suitable for probing histone acetylation levels using various biological samples. The protein sensor contains recongition domain(s) with sequences derived from the bromodomain of human polybromo-1 (PB1), a natural H3K14ac reader domain. Various sensor designs were tested using nuclear extracts and live cells. The sensor containing dimeric repeats of bromodomain was found most effective in quantifying H3K14ac level in both in vitro and in situ assays. The sensor has a linear detection range of 0.5-50 nM when mixed with nuclear extracts. The sensor colocalizes with H3K14ac antibodies in situ when transfected into human embryonic kidney 293T (HEK293T) cells and is thus capable of providing spatial details of histone modification within the nucleus. Corrected nuclear fluorescence intensity was used to quantify the modification level in situ and found to correlate well with our in vitro assays. Our sensor offers a novel tool to characterize the histone modification level using nuclear extracts and probe histone modification change in live cells. PMID- 28723213 TI - Dual Functional Core-Shell Fluorescent Ag2S@Carbon Nanostructure for Selective Assay of E. coli O157:H7 and Bactericidal Treatment. AB - A dual functional fluorescent core-shell Ag2S@Carbon nanostructure is prepared by a hydrothermally assisted multi-amino synthesis approach with folic acid (FA), polyethylenimine (PEI), and mannoses (Mans) as carbon and nitrogen sources (FA PEI-Mans-Ag2S nanocomposite shortly as Ag2S@C). The nanostructure exhibits strong fluorescent emission at lambdaex/lambdaem = 340/450 nm with a quantum yield of 12.57 +/- 0.52%. Ag2S@C is bound to E. coli O157:H7 via strong interaction with the Mans moiety in Ag2S@C with FimH proteins on the fimbriae tip in E. coli O157:H7. Fluorescence emission from Ag2S@C/E. coli conjugate is closely related to the content of E. coli O157:H7. Thus, a novel procedure for fluorescence assay of E. coli O157:H7 is developed, offering a detection limit of 330 cfu mL-1. Meanwhile, the Ag2S@C nanostructure exhibits excellent antibacterial performance against E. coli O157:H7. A 99.9% sterilization rate can be readily achieved for E. coli O157:H7 at a concentration of 106-107 cfu mL-1 with 3.3 or 10 MUg mL-1 of Ag2S@C with an interaction time of 5 or 0.5 min, respectively. PMID- 28723214 TI - Electrokinetic Manipulation Integrated Plasmonic-Photonic Hybrid Raman Nanosensors with Dually Enhanced Sensitivity. AB - To detect biochemicals with ultrahigh sensitivity, efficiency, reproducibility, and specificity has been the holy grail in the development of nanosensors. In this work, we report an innovative type of photonic-plasmonic hybrid Raman nanosensor integrated with electrokinetic manipulation by rational design, which offers dual mechanisms that enhance the sensitivity for molecule detection directly in solution. For the first time, we integrate large arrays of synthesized plasmonic nanocapsules with densely surface distributed silver (Ag) nanoparticles (NPs) on lithographically patterned photonic crystal slabs via electric-field assembling. With the interdigital microelectrodes, the applied electric fields not only assemble the hybrid plasmonic nanocapsules on photonic crystal slabs, but also generate electrokinetic flows that focus analyte molecules to the Ag hot spots on the nanocapsules for surface-enhanced Raman scattering (SERS) detection. The synergistic effects of plasmonic-photonic resonance and the electrokinetic molecular focusing can promote the SERS enhancement factor (EF) robustly to ~2 * 109. Various molecules including SERS probing molecules, nucleobases, and unsafe food additives can be detected directly from suspension. The innovative mechanism, design, and fabrication reported in this work can inspire a new paradigm for achieving high-performance Raman nanosensors, which is pivotal for lab-on-chip disease diagnosis and environmental protection. PMID- 28723215 TI - Discrimination Cascade Enabled Selective Detection of Single-Nucleotide Mutation. AB - Owing to the significance of single nucleotide mutation (SNM) for personalized medicine, the detection of SNM with high accuracy has recently attracted considerable interest. Here, we present a kinetic method for selective detection of SNM based on a discrimination cascade constructed by combining the toehold strand displacement (TSD) and endonuclease IV (Endo IV) catalyzed hydrolysis. The single-nucleotide specificity of the two DNA reactions allows highly selective detection of all types of single nucleotide changes (including single-nucleotide insertion and deletion), achieving a high discrimination factor with a median of 491 which is comparable with recently reported methods. For the first time, the enzyme assisted nucleic acid assay was characterized by single molecule analysis on total internal reflection fluorescence microscope (TIRFM) suggesting that the two steps do not work independently and the rate of TSD can be tuned by Endo IV facilitated conformation selection. The effective discrimination of the point mutation of BRAF gene in cancer and normal cell line suggests that this method can be a prominent post-PCR genotyping assay. PMID- 28723217 TI - Acid Chlorides as Formal Carbon Dianion Linchpin Reagents in the Aluminum Chloride-Mediated Dieckmann Cyclization of Dicarboxylic Acids. AB - The development of acid chlorides as formal dianion linchpin reagents that enable access to cyclic 2-alkyl- and 2-acyl-1,3-alkanediones from dicarboxylic acids is described herein. Mechanistic experiments relying on 13C-labeling studies confirm the role of acid chlorides as carbon dianion linchpin reagents and have led to a revised reaction mechanism for the aluminum(III)-mediated Dieckmann cyclization of dicarboxylic acids with acid chlorides. PMID- 28723216 TI - Lycopene Inhibits Metastasis of Human Liver Adenocarcinoma SK-Hep-1 Cells by Downregulation of NADPH Oxidase 4 Protein Expression. AB - NADPH oxidase 4 (NOX4), with the sole function to produce reactive oxygen species (ROS), can be a molecular target for disrupting cancer metastasis. Several studies have indicated that lycopene exhibited anti-metastatic actions in vitro and in vivo. However, the role of NOX4 in the anti-metastatic action of lycopene remains unknown. Herein, we first confirmed the anti-metastatic effect of lycopene (0.1-5 MUM) on human liver adenocarcinoma SK-Hep-1 cells. We showed that lycopene significantly inhibited NOX4 protein expression, with the strongest inhibition of 64.3 +/- 10.2% (P < 0.05) at 2.5 MUM lycopene. Lycopene also significantly inhibited NOX4 mRNA expression, NOX activity, and intracellular ROS levels in SK-Hep-1 cells. We then determined the effects of lycopene on transforming growth factor beta (TGF-beta)-induced metastasis. We found that TGF beta (5 ng/mL) significantly increased migration, invasion, and adhesion activity, the intracellular ROS level, matrix metalloproteinase 9 (MMP-9) and MMP 2 activities, the level of NOX4 protein expression, and NOX activity. All these TGF-beta-induced effects were antagonized by the incubation of SK-Hep-1 cells with lycopene (2.5 MUM). Using transient transfection of siRNA against NOX4, we found that the downregulation of NOX4 could mimic lycopene by inhibiting cell migration and the activities of MMP-9 and MMP-2 during the incubation with or without TGF-beta on SK-Hep-1 cells. The results demonstrate that the downregulation of NOX4 plays a crucial role in the anti-metastatic action of lycopene in SK-Hep-1 cells. PMID- 28723218 TI - Aluminum Chloride-Mediated Dieckmann Cyclization for the Synthesis of Cyclic 2 Alkyl-1,3-alkanediones: One-Step Synthesis of the Chiloglottones. AB - Cyclic 2-alkyl-1,3-alkanediones are ubiquitous structural motifs in many natural products of biological importance. Reported herein is an AlCl3.MeNO2-mediated Dieckmann cyclization reaction of general synthetic utility that enables direct access to complex 2-alkyl-1,3-dione building blocks from readily available dicarboxylic acid and acid chloride substrates. This new strategy enables direct synthetic access to the chiloglottone plant pheromones from commercial material in a single synthetic transformation. PMID- 28723219 TI - Factors Governing and Application of the Cope Rearrangement of 3,3-Dicyano-1,5 dienes and Related Studies. AB - Cope and co-workers reported the [3,3] rearrangement of 3,3-dicyano-1,5-dienes in the early 1940s ("The Cope rearrangement"). However, these original substrates have remained largely unstudied until recently. Herein we explore styrene deconjugating Cope rearrangements, a diastereoselective Cope rearrangement/deconjugative alpha-allylation sequence, and factors governing alpha- vs gamma-allylation regioselectivity of Knoevenagel adduct allyl anions. Ultimately, these studies result in the synthesis of diverse and functionally dense polycycloalkane frameworks from abundant reagents using simple chemistry. PMID- 28723221 TI - Accelerating Realtime TDDFT with Block-Orthogonalized Manby-Miller Embedding Theory. AB - Realtime time-dependent density-functional theory (RT-TDDFT) is one of the most practical techniques available to simulate electronic dynamics of molecules and materials. Promising applications of RT-TDDFT to study nonlinear spectra and energy transport demand simulations of large solvated systems over long time scales, which are computationally quite costly. In this paper, we apply an embedding technique developed for ground-state SCF methods by Manby and Miller to accelerate realtime TDDFT. We assess the accuracy and speed of these approximations by studying the absorption spectra of solvated and covalently split chromophores. Our embedding approach is also compared with less accurate, less costly QM/MM charge embeddings. We find that by mixing levels of detail the embedded mean-field theory scheme is a simple, accurate, and effective way to accelerate RT-TDDFT simulations. PMID- 28723220 TI - Constructing Slow-Release Formulations of Ammonium Nitrate Fertilizer Based on Degradable Poly(3-hydroxybutyrate). AB - The present study describes construction and investigation of experimental formulations of ammonium nitrate embedded in a matrix of degradable natural polymer poly-3-hydroxybutyrate [P(3HB)] and P(3HB) blended with wood flour shaped as tablets, some of them coated with P(3HB). Kinetics of ammonium release into soil as dependent on the composition of the polymer matrix was investigated in laboratory experiments. The rates of fertilizer release from formulations coated with a biopolymer layer were considerably (two months or longer) slower than the rates of fertilizer release from uncoated formulations, while release from polymer and composite (polymer/wood flour) formulations occurred with comparable rates. The use of the experimental formulations in laboratory ecosystems with wheat (Triticum aestivum L.) was more effective than application of free ammonium nitrate. The advantage of the slow-release fertilizer formulations is that they are buried in soil together with the seeds, and the fertilizer remains effective over the first three months of plant growth. The use of such slow-release formulations will reduce the amounts of chemicals released into the environment, which will curb their accumulation in food chains of ecosystems and mitigate their adverse effects on the biosphere. PMID- 28723222 TI - Extraction of 2-Phenylethanol (PEA) from Aqueous Solution Using Ionic Liquids: Synthesis, Phase Equilibrium Investigation, Selectivity in Separation, and Thermodynamic Models. AB - This study assessed the effect of ionic liquids (ILs) on extraction of 2 phenylethanol (PEA) from aqueous phase. It consists the synthesis of four new ILs, their physicochemical properties, and experimental solubility measurements in water as well as liquid-liquid phase equilibrium in ternary systems. ILs are an important new media for imaging and sensing applications because of their solvation property, thermal stability, and negligible vapor pressure. However, complex procedures and nonmiscibility with water are often required in PEA extraction. Herein, a facile and general strategy using four ILs as extraction media including the synthesis of new bis(fluorosulfonyl)imide-based ILs, 1-hexyl methylmorpholinium bis(fluorosulfonyl)imide, [HMMOR][FSI], N-octylisoquinolinium bis(fluorosulfonyl)imide, [OiQuin][FSI], 1-butyl-1-methylpyrrolidinium bis(fluorosulfonyl)imide, [BMPYR][FSI], and N-triethyl-N-octylammonium bis(fluorosulfonyl)imide, [N2228][FSI], were investigated. The thermal properties, density, viscosity, and surface tension of new ILs were measured. Calorimetric measurements (DSC) were used to determine the melting point and the enthalpy of melting as well as the glass transition temperature and heat capacity at glass transition of the ILs. The phase equilibrium in binary systems (IL + PEA, or water) and in ternary systems {IL (1) + PEA (2) + water (3)} at temperature T = 308.15 K and ambient pressure are reported. All systems present liquid-liquid equilibrium with the upper critical solution temperature (UCST). All ILs revealed complete miscibility with PEA. In all ternary systems immiscibility gap was observed, which classified measured systems as Treybal's type II. The two partially miscible binaries (IL + water) and (PEA + water) exist in these systems. The discussion contains the specific selectivity and the solute distribution ratio of separation for the used ILs. The commonly used NRTL model was used for the correlation of the experimental binary and ternary systems with acceptable root-mean-square deviation. The prediction of binary and ternary compositions was provided with acceptable deviations using COSMO RS. The data of ternary LLE show the possible use of [HMMOR][FSI] as a good entrainer for the separation of PEA from water using solvent extraction. PMID- 28723223 TI - Free Energy of Binding and Mechanism of Interaction for the MEEVD-TPR2A Peptide Protein Complex. AB - The association between the MEEVD C-terminal peptide from the heat shock protein 90 (Hsp90) and tetratricopeptide repeat A (TPR2A) domain of the heat shock organizing protein (Hop) is a useful prototype to study the fundamental molecular details about the Hop-Hsp90 interaction. We study here the mechanism of binding/unbinding and compute the standard binding free energy and potential of mean force for the association of the MEEVD peptide to the TPR2A domain using the Adaptive Biasing Force (ABF) methodology. We observe conformational changes of the peptide and the protein receptor induced by binding. We measure the binding free energy of -8.4 kcal/mol, which is consistent with experimental estimates. The simulations achieve multiple unbinding and rebinding events along a consistent pathway connecting the binding site to solvent. The MEEVD peptide slowly dissociates disrupting the hydrogen bonds first, then tilting on the side while preserving the interaction with the side chain of residue Asp 5 of the peptide. After this initial displacement, the peptide completely dissociates and moves into the solvent. Rebinding of the MEEVD peptide from the solvent to the receptor binding site occurs slowly through the portal of entry. Unbinding and rebinding go through intermediate states characterized by the peptide interacting with a lateral helix, helix A1, of the receptor with mainly Asp 5, Val 4, and Glu 3 of the peptide. This newly discovered intermediate structure is characterized by numerous contacts with the receptor which lead to complete formation of the bound complex. The structure of the bound complex obtained after rebinding is structurally very similar to the crystal structure of the complex (0.48 A root mean square deviation). The residues Asp 5, Val 4, and Glu 3 adopt conformations and intermolecular contacts with excellent structural similarity with the native ones. Finally, the dissociation and reassociation of MEEVD induce hydration/dehydration transitions, which provide insights on the role of desolvation and solvation processes in protein-peptide binding. PMID- 28723224 TI - High-Throughput Automated Preparation and Simulation of Membrane Proteins with HTMD. AB - HTMD is a programmable scientific platform intended to facilitate simulation based research in molecular systems. This paper presents the functionalities of HTMD for the preparation of a molecular dynamics simulation starting from PDB structures, building the system using well-known force fields, and applying standardized protocols for running the simulations. We demonstrate the framework's flexibility for high-throughput molecular simulations by applying a preparation, building, and simulation protocol with multiple force-fields on all of the seven hundred eukaryotic membrane proteins resolved to-date from the orientation of proteins in membranes (OPM) database. All of the systems are available on www.playmolecule.org . PMID- 28723226 TI - Improving the quality and safety of frozen muscle foods by emerging freezing technologies: A review. AB - Freezing is one of the most widespread used preservation methods for meats including fish meat. Traditional freezing methods such as air blast freezing and cryogenic freezing could induce some quality deterioration such as damage to cell structure, increased drip loss, and poor sensory value. Therefore, novel freezing methods have been developed to minimize the disadvantages of traditional freezing methods. This review describes the enhancement of quality attributes of muscle tissues frozen by novel freezing technologies, including high pressure freezing, electrically and magnetically assisted freezing, ultrasound assisted freezing and antifreeze protein. These quality attributes include microstructure, moisture loss, color, tenderness, protein denaturation, lipid and protein oxidation, and microbial counts. In this review, the principles of these emerging freezing technologies are introduced, and the impacts of these technologies on controlling the formation and growth of ice crystals and on complex changes of protein are also discussed. The current review shows that the novel freezing methods have positive effects on promoting the quality of frozen muscle. At a micro level, the majority of the novel methods have some certain ability on controlling the formation and growth of ice crystals, thus creating smaller, and more homogeneous and regular distribution of ice crystals, leading to better microstructure and enhanced quality attributes of frozen meats. Meanwhile, complex changes of protein take place under some of these novel freezing processes, and therefore the possible negative effect of the changes of protein should also be considered for commercial applications of these technologies in the frozen food industry. PMID- 28723225 TI - Preferential Generation of 15-HETE-PE Induced by IL-13 Regulates Goblet Cell Differentiation in Human Airway Epithelial Cells. AB - Type 2-associated goblet cell hyperplasia and mucus hypersecretion are well known features of asthma. 15-Lipoxygenase-1 (15LO1) is induced by the type 2 cytokine IL-13 in human airway epithelial cells (HAECs) in vitro and is increased in fresh asthmatic HAECs ex vivo. 15LO1 generates a variety of products, including 15 hydroxyeicosatetraenoic acid (15-HETE), 15-HETE-phosphatidylethanolamine (15-HETE PE), and 13-hydroxyoctadecadienoic acid (13-HODE). In this study, we investigated the 15LO1 metabolite profile at baseline and after IL-13 treatment, as well as its influence on goblet cell differentiation in HAECs. Primary HAECs obtained from bronchial brushings of asthmatic and healthy subjects were cultured under air-liquid interface culture supplemented with arachidonic acid and linoleic acid (10 MUM each) and exposed to IL-13 for 7 days. Short interfering RNA transfection and 15LO1 inhibition were applied to suppress 15LO1 expression and activity. IL 13 stimulation induced expression of 15LO1 and preferentially generated 15-HETE PE in vitro, both of which persisted after removal of IL-13. 15LO1 inhibition (by short interfering RNA and chemical inhibitor) decreased IL-13-induced forkhead box protein A3 (FOXA3) expression and enhanced FOXA2 expression. These changes were associated with reductions in both mucin 5AC and periostin. Exogenous 15 HETE-PE stimulation (alone) recapitulated IL-13-induced FOXA3, mucin 5AC, and periostin expression. The results of this study confirm the central importance of 15LO1 and its primary product, 15-HETE-PE, for epithelial cell remodeling in HAECs. PMID- 28723227 TI - Extended-Release Guanfacine Does Not Show a Large Effect on Tic Severity in Children with Chronic Tic Disorders. AB - OBJECTIVE: To evaluate the tolerability, safety, and preliminary efficacy of extended-release guanfacine in children with chronic tic disorders, including Tourette's disorder (collectively referred to as CTD). METHODS: This was a multisite, 8-week, randomized, double-blind, placebo-controlled trial. The primary outcome measure was the Yale Global Tic Severity Scale (YGTSS) total score. Key secondary outcomes included the Improvement item of Clinical Global Impressions-Improvement (CGI-I) scale and the Tic Symptom Self-report (TSSR). Adverse events were monitored at each visit. RESULTS: Thirty-four subjects (23 boys and 11 girls) of ages 6 to 17 years (mean = 11.1 +/- 3.1) with CTD were randomly assigned to extended-release guanfacine (n = 16) or placebo (n = 18). At baseline, the mean YGTSS total score was 26.3 +/- 6.6 for the guanfacine group versus 27.7 +/- 8.7 for the placebo group. Within the guanfacine group (mean final daily dose of 2.6 +/- 1.1 mg, n = 14), the mean YGTSS total score declined to 23.6 +/- 6.42 [t(15) = 1.84, p = 0.08; effect size = 0.35]. The results were similar in the placebo group with a score of 24.7 +/- 10.54 at week 8 [t(17) = 1.83, p = 0.08; effect size = 0.38]. There was no significant difference in the rate of positive response on the CGI-I between the guanfacine group and placebo (19% [3/16] vs. 22% [4/18], p = 1.0). The most common adverse events were fatigue, drowsiness, dry mouth, headache, and irritability. Two subjects in the guanfacine group discontinued early-one because of an adverse event (depressed mood) and one because of lack of efficacy; two subjects in the placebo group discontinued because of lack of efficacy. CONCLUSIONS: This pilot study did not confirm a clinically meaningful effect size within the guanfacine group. These results do not support the launch of a larger efficacy trial for tics in children and adolescents with CTD. PMID- 28723228 TI - Thermal processing of live bivalve molluscs for controlling viruses: On the need for a risk-based design. AB - Norovirus (NoV) and Hepatitis A virus (HAV) are the most important viral hazards associated with human illness following consumption of contaminated bivalve molluscs. The effectiveness of the current EU criteria for heat processing of bivalve molluscs (i.e. raising the temperature of the internal mollusc flesh to at least 90 degrees C for a minimum of 90 seconds) was evaluated using predictive microbiology. A HAV thermal inactivation model was developed based on literature data in mollusc matrices during isothermal heat treatment. Application of the developed model demonstrated that the 90 degrees C-90 s requirement may lead to significantly different virus inactivation depending on the commercial process design. This shows the need for the establishment of a Performance Criterion for bivalve molluscs heat processing which will assure a common specified level of consumer protection. A risk-based approach is described that allows for an effective processing design providing a more transparent and objective relation between the thermal processing targets and public health. Model simulations demonstrate that the F-value is a more appropriate Process Criterion than a single time-temperature combination since it enables the food business operators to design a process that is compliant with the safety requirements while at the same time achieving a desired product quality. PMID- 28723229 TI - The Formation of Nucleobases from the Ultraviolet Photoirradiation of Purine in Simple Astrophysical Ice Analogues. AB - Nucleobases are the informational subunits of RNA and DNA and are essential to all known forms of life. The nucleobases can be divided into two groups of molecules: the pyrimidine-based compounds that include uracil, cytosine, and thymine, and the purine-based compounds that include adenine and guanine. Previous work in our laboratory has demonstrated that uracil, cytosine, thymine, and other nonbiological, less common nucleobases can form abiotically from the UV photoirradiation of pyrimidine in simple astrophysical ice analogues containing combinations of H2O, NH3, and CH4. In this work, we focused on the UV photoirradiation of purine mixed with combinations of H2O and NH3 ices to determine whether or not the full complement of biological nucleobases can be formed abiotically under astrophysical conditions. Room-temperature analyses of the resulting photoproducts resulted in the detection of adenine, guanine, and numerous other functionalized purine derivatives. Key Words: Pyrimidine Nucleobases-Interstellar; Ices-Cometary; Ices-Molecular processes-Prebiotic chemistry. Astrobiology 17, 761-770. PMID- 28723230 TI - Retrograde Endourological Management of Upper Urinary Tract Abnormalities in Patients with Ileal Conduit Urinary Diversion: A Dual-Center Experience. AB - INTRODUCTION: Patients with ileal conduit urinary diversions are at an increased risk of long-term upper urinary tract (UUT) complications, including anastomotic strictures, infections, and urolithiasis. The reconstructed urinary system poses challenges for endoscopic manipulation. We present and describe our dual-center experience in performing retrograde ureteroscopy to treat or diagnose UUT abnormalities in patients with ileal conduit incontinent diversion. PATIENT AND METHODS: We performed a retrospective analysis of medical records for all patients with previous urinary diversion who underwent retrograde ureteroscopic procedures via the ileal loop in our institutions over a 9 year period (between June 2007 and August 2016). RESULTS: Fifty-four procedures were performed in 36 patients. Mean age was 61 (28-90) years. Average time from diversion to ureteroscopic procedure was 13.0 (0.08-53) years. Stone disease was the most common indication for intervention in 35.2% (19/54) of cases, with a stone-free rate of 78.9% (15/19). Other indications included surveillance of transitional cell carcinoma in 22.2% (12/54), diagnostic flexible ureteroscopy (fURS) in 20.4% (11/54), stricture management in 11.1% (6/54), removal of encrusted stent/nephrostomy in 7.4% (4/54), urine leak after diversion in 1.9% (1/54), and miscellaneous in 1.9% (1/54). Successful retrograde access was possible in 74% (40/54) of cases. A long and tortuous ileal segment, too difficult to negotiate, was the most common cause of failure to access the UUT. In 13 out of 54 (24.1%) cases, retrograde fURS was combined with simultaneous percutaneous antegrade access. Six patients (11.1%) developed postprocedural pyrexia requiring additional antibiotic therapy, and one (1.9%) patient required embolization of the renal artery for ongoing bleeding. Median length of stay was 1 day (0-55), with 13 (24%) being performed as day-case procedures. CONCLUSIONS: Retrograde ureteroscopy in patients with ileal conduits can be technically challenging due to distorted anatomy. This procedure can be safely performed in experienced hands with standard endourological equipment. An antegrade approach can be carried out simultaneously, which may be required in a small number of patients. PMID- 28723231 TI - Fear of Cancer Recurrence in an Era of Personalized Medicine. PMID- 28723232 TI - Mechanism for G2 phase-specific nuclear export of the kinetochore protein CENP-F. AB - Centromere protein F (CENP-F) is a component of the kinetochore and a regulator of cell cycle progression. CENP-F recruits the dynein transport machinery and orchestrates several cell cycle-specific transport events, including transport of the nucleus, mitochondria and chromosomes. A key regulatory step for several of these functions is likely the G2 phase-specific export of CENP-F from the nucleus to the cytosol, where the cytoplasmic dynein transport machinery resides; however, the molecular mechanism of this process is elusive. Here, we have identified 3 phosphorylation sites within the bipartite classical nuclear localization signal (cNLS) of CENP-F. These sites are specific for cyclin dependent kinase 1 (Cdk1), which is active in G2 phase. Phosphomimetic mutations of these residues strongly diminish the interaction of the CENP-F cNLS with its nuclear transport receptor karyopherin alpha. These mutations also diminish nuclear localization of the CENP-F cNLS in cells. Notably, the cNLS is phosphorylated in the -1 position, which is important to orient the adjacent major motif for binding into its pocket on karyopherin alpha. We propose that localization of CENP-F is regulated by a cNLS, and a nuclear export pathway, resulting in nuclear localization during most of interphase. In G2 phase, the cNLS is weakened by phosphorylation through Cdk1, likely resulting in nuclear export of CENP-F via the still active nuclear export pathway. Once CENP-F resides in the cytosol, it can engage in pathways that are important for cell cycle progression, kinetochore assembly and the faithful segregation of chromosomes into daughter cells. PMID- 28723233 TI - Treatment patterns and clinical outcomes with pazopanib in patients with advanced soft tissue sarcomas in a compassionate use setting: results of the SPIRE study. AB - BACKGROUND: A named patient program (NPP) was designed to provide patients with advanced soft-tissue sarcoma (aSTS) access to pazopanib, a multitargeted tyrosine kinase inhibitor. The SPIRE study was a retrospective chart review of participating patients. PATIENTS AND METHODS: Eligibility criteria for the NPP and SPIRE mirrored those of the pivotal phase-III study, PALETTE, which compared pazopanib with placebo in patients >=18 years with aSTS and whose disease had progressed during or following prior chemotherapy or were otherwise unsuitable for chemotherapy. Outcomes of interest included treatment patterns, treatment duration, relative dose intensity, progression-free survival (PFS), overall survival (OS), clinical benefit rate, adverse events (AEs) and reasons for treatment discontinuation. RESULTS: A total of 211 patients were enrolled (median age 56 years; 60% female). Most patients received pazopanib in second- and third line therapy (28.0% and 28.4%, respectively), followed by fourth line (19.0%) and >= fifth line (18.5%). The median duration of pazopanib treatment was 3.1 months (95% CI: 2.8-3.8), with a mean daily dose of 715 mg equating to 92% of recommended dose. Median OS was 11.1 months and clinical benefit rate was 46%. There was evidence of some clinical benefit across most histological subtypes. At study end, 40% of patients were alive and of these, 18% remained on pazopanib. Thirteen percent (13%) of patients discontinued pazopanib due to AEs. CONCLUSIONS: The SPIRE study demonstrated activity of pazopanib in heavily pretreated aSTS patients in a compassionate use setting. No new safety concerns were noted. Reassuringly, the relative dose intensity of pazopanib was 92%. PMID- 28723234 TI - Flexible small molecular anti-estrogens with N,N-dialkylated-2,5-diethoxy-4 morpholinoaniline scaffold targets multiple estrogen receptor conformations. AB - Estrogen mediates various cellular processes including cell proliferation, differentiation, growth and mammary gland function. Estrogen Receptors (ERs) are expressed in 70% of breast cancers. Consequently, estrogen mediated ER signaling plays a critical role in breast cancer diagnosis, prognosis, and treatment. ERs are ligand-triggered transcription factors. However, in the absence of a cognate estrogenic ligand, ERs can be activated by a variety of other extracellular signals. Tamoxifen, an anti-estrogen that selectively targets ER, induces substantial regression of breast tumors and an increase in disease-free survival. Tamoxifen mimics estrogen effects in other tissues thereby providing some beneficial effects including reduced risk of osteoporosis. However, breast cancers that initially respond well to tamoxifen tend to develop resistance and resume growth despite the continued presence of the antagonist. Library of compounds with substituted morpholinoaniline scaffold, a set of structurally divergent potential ER antagonists that fit the tamoxifen pharmacophore, were designed to target ER Ligand Binding Domain (LBD) and to recruit co-regulator proteins including BRCA1 over a range of conformational changes. Two of the lead compounds in the library, BR46 and BR47, were found to inhibit estrogen induced cell proliferation and cell viability. Discovery of novel lead molecules targeting ligand binding pockets of hER has provided structural clues toward the development of new breed of small molecule therapeutics for tamoxifen-resistant breast cancers and would complement already existent anti-estrogen therapy. PMID- 28723235 TI - Localization of PP2A-B56 to centromeres in Drosophila. PMID- 28723236 TI - Selective inhibition of host cell signaling for rotavirus antivirals: PI3K/Akt/mTOR-mediated rotavirus pathogenesis. PMID- 28723237 TI - Linking chanelopathies with endoplasmic reticulum associated degradation. PMID- 28723238 TI - The poetics of mourning and faith-based intervention in maladaptive grieving processes in Ethiopia. AB - The paper is an inquiry into the poetics of mourning and faith-based intervention in maladaptive grieving processes in Ethiopia. The paper discusses the ways that loss is signified and analyzes the meanings of ethnocultural and psychospiritual practices employed to deal with maladaptive grief processes and their psychological and emotional after-effects. Hermeneutics provided the methodological framework and informed the analysis. The thesis of the paper is that the poetics of mourning and faith-based social interventions are interactionally based meaning making processes. The paper indicates the limitations of the study and their implications for further inquiry. PMID- 28723240 TI - Rhythmic radiotherapy beats down TGF-beta. PMID- 28723241 TI - The effects of stretch activation on ionic selectivity of the TREK-2 K2P K+ channel. AB - The TREK-2 (KCNK10) K2P potassium channel can be regulated by variety of polymodal stimuli including pressure. In a recent study, we demonstrated that this mechanosensitive K+ channel responds to changes in membrane tension by undergoing a major structural change from its 'down' state to the more expanded 'up' state conformation. These changes are mostly restricted to the lower part of the protein within the bilayer, but are allosterically coupled to the primary gating mechanism located within the selectivity filter. However, any such structural changes within the filter also have the potential to alter ionic selectivity and there are reports that some K2Ps, including TREK channels, exhibit a dynamic ionic selectivity. In this addendum to our previous study we have therefore examined whether the selectivity of TREK-2 is altered by stretch activation. Our results reveal that the filter remains stable and highly selective for K+ over Na+ during stretch activation, and that permeability to a range of other cations (Rb+, Cs+ and NH4+) also does not change. The asymmetric structural changes that occur during stretch activation therefore allow the channel to respond to changes in membrane tension without a loss of K+ selectivity. PMID- 28723239 TI - Disruption of CDK-resistant chromatin association by pRB causes DNA damage, mitotic errors, and reduces Condensin II recruitment. AB - Organization of chromatin structure is indispensible to the maintenance of genome integrity. The retinoblastoma tumor suppressor protein (pRB) mediates both transcriptional repression and chromatin organization, but the independent contributions of these functions have been difficult to study. Here, we utilize a synthetic Rb1 mutant allele (F832A) that maintains pRB association at cell cycle gene promoters, but disrupts a cyclin-dependent kinase (CDK)-resistant interaction with E2F1 to reduce occupancy of pRB on intergenic chromatin. Reduced pRB chromatin association increases spontaneous gammaH2AX deposition and aneuploidy. Our data indicates that the CDK-resistant pRB-E2F1 scaffold recruits Condensin II to major satellite repeats to stabilize chromatin structure in interphase and mitosis through mechanisms that are distinct from silencing of repetitive sequence expression. PMID- 28723242 TI - Interspecific and intraspecific hybrid Epichloe species symbiotic with the North American native grass Poa alsodes. AB - The endophyte presence and diversity in natural populations of Poa alsodes were evaluated along a latitudinal transect from the southern distribution range in North Carolina to New York. Two distinct Epichloe hybrid taxa were identified from 23 populations. Each taxon could easily be distinguished by polymerase chain reaction (PCR) genotyping with primers designed to mating type genes and alkaloid biosynthesis genes that encode key pathway steps for ergot alkaloids, indole diterpenes, lolines, and peramine. The most commonly found Epichloe taxon, Poa alsodes Taxonomic Group-1 (PalTG-1), was detected in 22 populations at high infection frequencies (72-100%), with the exception of one population at high elevation (26% infection). The second taxon, PalTG-2, was observed only in five populations in Pennsylvania constituting 12% of infected samples. Phylogenetic analyses placed PalTG-1 as an interspecific hybrid of E. amarillans and E. typhina subsp. poae ancestors, and it is considered a new hybrid species, which the authors name Epichloe alsodes. PalTG-2 is an intraspecific hybrid of two E. typhina subsp. poae ancestors, similar to E. schardlii from the host Cinna arundinacea, which the authors propose as a new variety, Epichloe schardlii var. pennsylvanica. Epichloe alsodes isolates were all mating type MTA MTB and tested positive for dmaW, easC, perA, and some LOL genes, but only the alkaloid N acetylnorloline was detected in E. alsodes-infected plant material. Epichloe schardlii var. pennsylvanica isolates were all mating type MTB MTB and tested positive for perA, but peramine was not produced. Both E. alsodes and E. schardlii var. pennsylvanica appeared to have complete perA genes, but point mutations were identified in E. alsodes that would render the encoded perA gene nonfunctional. PMID- 28723243 TI - Pathogenicity of Nectriaceous Fungi on Avocado in Australia. AB - Black root rot is a severe disease of young avocado trees in Australia causing black necrotic roots, tree stunting, and leaf drop prior to tree death. Nectriaceous fungi (Nectriaceae, Hypocreales), are commonly isolated from symptomatic roots. This research tested the pathogenicity of 19 isolates from Calonectria, Cylindrocladiella, Dactylonectria, Gliocladiopsis, and Ilyonectria, spp. collected from young avocado trees and other hosts. Glasshouse pathogenicity tests with 'Reed' avocado (Persea americana) seedlings confirmed that Calonectria ilicicola is a severe pathogen of avocado, causing stunting, wilting, and seedling death within 5 weeks of inoculation. Isolates of C. ilicicola from peanut, papaya, and custard apple were also shown to be aggressive pathogens of avocado, demonstrating a broad host range. An isolate of a Calonectria sp. from blueberry and avocado isolates of Dactylonectria macrodidyma, D. novozelandica, D. pauciseptata, and D. anthuriicola caused significant root rot but not stunting within 5 to 9 weeks of inoculation. An isolate of an Ilyonectria sp. from grapevine closely related to Ilyonectria liriodendri, and avocado isolates of Cylindrocladiella pseudoinfestans, Gliocladiopsis peggii, and an Ilyonectria sp. were not pathogenic to avocado. PMID- 28723244 TI - Evaluation of the National Health Service (NHS) Direct Pilot Telehealth Program: Cost-Effectiveness Analysis. AB - OBJECTIVE: To evaluate the cost-effectiveness of a pilot telehealth program applied to a wide population of patients with chronic obstructive pulmonary disease (COPD). DESIGN: Vital signs data were transmitted from the home of the patient on a daily basis using a patient monitoring system for review by community nurse to assist decisions on management. SETTING: Community services for patients diagnosed with COPD. PARTICIPANTS: Two Primary Care Trusts (PCTs) enrolled 321 patients diagnosed with COPD into the telehealth program. Two hundred twenty-seven (n = 227) patients having a complete baseline record of at least 88 days of continuous remote monitoring and meeting all inclusion criteria were included in the statistical analysis. INTERVENTION: Remote monitoring. METHODS: Resource and cost data associated with patient events (inpatient hospitalization, accident and emergency [A&E], and home visits) 12 months before, immediately before and during monitoring, equipment, start-up, and administration were collected and compared to determine cost-effectiveness of the program. MAIN OUTCOME MEASURES: Cost-effectiveness of program, impact on resource usage, and patterns of change in resource usage. RESULTS: Cost-effectiveness was determined for the two PCTs and the two periods before monitoring to provide four separate estimates. Cost-effectiveness had high variance both between the PCTs and between the comparison periods ranging from a saving of L140,800 ($176,000) to an increase of L9,600 ($12,000). The average saving was L1,023 ($1,280) per patient per year. The largest impact was on length of stay with a fall in the average length of inpatient care in PCT1 from 11.5 days in the period 12 months before monitoring to 6.5 days during monitoring, and similarly in PCT2 from 7.5 to 5.2 days. CONCLUSION: There was a wide discrepancy in the results from the two PCTs. This places doubt on outcomes and may indicate also why the literature on cost effectiveness remains inconclusive. The wide variance on savings and the uncertainty of monitoring cost do not allow a definitive conclusion on the cost effectiveness as an outcome of this study. It might well be that the average saving was L1,023 ($1,280) per patient per year, but the variance is too great to allow this to be statistically significant. Each locality-based clinical service provides a service to achieve the same clinical goal, but it does so in significantly different ways. The introduction of remote monitoring has a profound effect on team learning and clinical practice and thus distorts the cost effectiveness evaluation of the use of the technology. Cost-effectiveness studies will continue to struggle to provide a definitive answer because outcome measurements are too dependent on factors other than the technology. PMID- 28723245 TI - Reply: Combining Efforts for Positive Progress in the Graduate Medical Education Match Process. PMID- 28723246 TI - Reply: Combining Efforts for Positive Progress in the Graduate Medical Education Match Process. PMID- 28723247 TI - CAPTURE: A Screening Tool for Chronic Obstructive Pulmonary Disease or Obstructive Airway Disease? PMID- 28723248 TI - Reducing opioid misuse among adolescents through physician education. AB - Increased prescribing of opioids has been associated with an epidemic of nonmedical prescription opioid use in the United States; adolescents and young adults are particularly vulnerable to opioid misuse. The role of physicians as health care providers, educators, and confidants for their adolescent patients equips them to intervene in adolescent opioid misuse. The authors advocate for improving the education of physicians and residents regarding opioid use and misuse among adolescents. To achieve this, we can require residency education that includes opioid misuse and appropriate prescribing, widely disseminate existing resources on management of pain and opioid misuse, and develop pain management and addiction mentorship programs. PMID- 28723249 TI - Experiences of Individuals With Visual Impairments in Integrated Physical Education: A Retrospective Study. AB - PURPOSE: The purpose of this retrospective study was to examine the experiences of adults with visual impairments during school-based integrated physical education (PE). METHOD: An interpretative phenomenological analysis (IPA) research approach was used and 16 adults (ages 21-48 years; 10 women, 6 men) with visual impairments acted as participants for this study. The primary sources of data were semistructured audiotaped telephone interviews and reflective field notes, which were recorded during and immediately following each interview. Thematic development was undertaken utilizing a 3-step analytical process guided by IPA. RESULTS: Based on the data analysis, 3 interrelated themes emerged from the participant transcripts: (a) feelings about "being put to the side," frustration and inadequacy; (b) "She is blind, she can't do it," debilitating feelings from physical educators' attitudes; and (c) "not self-esteem raising," feelings about peer interactions. The 1st theme described the participants' experiences and ascribed meaning to exclusionary practices. The 2nd theme described the participants' frustration over being treated differently by their PE teachers because of their visual impairments. Lastly, "not self-esteem raising," feelings about peer interactions demonstrated how participants felt about issues regarding challenging social situations with peers in PE. CONCLUSIONS: Utilizing an IPA approach, the researchers uncovered 3 interrelated themes that depicted central feelings, experiences, and reflections, which informed the meaning of the participants' PE experiences. The emerged themes provide unique insight into the embodied experiences of those with visual impairments in PE and fill a previous gap in the extant literature. PMID- 28723250 TI - Application of molecular dynamic simulation to study food proteins: A review. AB - This review presents an overview of the application of molecular dynamic simulation to study food proteins. Processing of food using thermal, chemical, radiation, electromagnetic, and mechanical techniques is subject to its macromolecular bio-components such as carbohydrates and proteins to extreme heat, ionic strength, pH, and mechanical deformation. These processing factors affect protein's functional properties such as emulsification, dough formation, gelation, etc., which are associated with changes in their structure. It is difficult to study the structural changes of protein during processing using standard methods like Circular dichroism, Nuclear Magnetic Resonance (NMR), and X ray diffraction. Hence, in this manuscript application of molecular dynamic simulation to visualize and analyze the protein dynamics during processing has been evaluated. Effect of external stresses such as hydration, temperature, and electric field on protein structure have been analyzed and related mechanisms are explained. The response of food proteins to these stresses demonstrated that it is necessary to gain insight into protein dynamics to be able to develop novel and/or modify existing food processing techniques to improve the overall nutritional and organoleptic qualities of processed food products. PMID- 28723251 TI - Addiction severity index profile of persons who reenter treatment for substance use disorders. AB - BACKGROUND: Despite a growing interest in persons with multiple treatment reentries, few studies have defined their clinical profile. The aim of this study was to compare the severity profile of substance use disorder and related problems of persons who reenter treatment with the profile of those who come in for treatment for the first time. METHODS: A data bank containing 6651 Addiction Severity Index (ASI) interviews from 3 rehabilitation centers was used for the analyses. RESULTS: All the ASI composite scores were significantly higher among persons who reentered treatment than among those who came for the first time. CONCLUSION: The results support the hypothesis of a more severe ASI profile and substance use-related problems among persons who reenter treatment compared with those who come for the first time. Consequently, they have greater needs, and the treatment offered should be adjusted accordingly. PMID- 28723252 TI - Across the Continuum: How Inpatient Palliative Care Consultations Are Reported in Hospital Discharge Summaries. AB - BACKGROUND: Inpatient Palliative Care (PC) consultations help develop a patient centered and quality-of-life-focused plan of care for patients with serious illness. Discharge summaries (DSs) are an essential tool to maintain continuity of these care plans across multiple locations and providers. METHODS: We conducted a retrospective chart review of selected DSs of patients who received inpatient PC consultations at the University of Kansas Hospital from July 2011 to May 2015. The study included patients 18 years or older, patients who were discharged alive, and patients who were not discharged with hospice care. Code words and their related phrases, developed by an expert panel of geriatric medicine and palliative medicine physicians, were used to evaluate the DSs. They were categorized into PC, symptom management, hospice and palliative home health, decision making, and plan of care. We also identified whether there was communication between the primary team and PC team, as well as family meeting status in the PC consultation and notes. RESULTS: Of the 961 chart reviews, no code words were found in 22.8% of the DSs. PC was mentioned in only 63.3% and was the only code word in 5.3%. CONCLUSION: More than one in five DSs lacked any code words of the completed PC consultation and more than one in three DSs lacked mention of PC. As DSs are the main source of provider communication, it is critical they reflect the key discussion points from the PC consultation, which will improve the transition of care and provider communication. PMID- 28723254 TI - Possible error in the Danish version of the WHO Quality of Life (WHOQOL-BREF) Questionnaire. AB - BACKGROUND: The WHOQOL-BREF is widely used to measure quality of life. AIMS: The goal of the present study was to use the questionnaire in a doctoral study. METHODS: We studied all the instructions provided by the WHO. RESULTS: In the Danish version of the WHOQOL-BREF there is a discrepancy between the negatively phrased question 9 and both the syntax file and the verbal instructions for coding the data provided by the WHO. CONCLUSIONS: This is a notification of possible error interpretations in projects that use the questionnaire. This could be corrected by manual correction in the coding process or by changing the negatively phrased question 9. PMID- 28723255 TI - Combining Efforts for Positive Progress in the Graduate Medical Education Match Process. PMID- 28723253 TI - End-of-Life Services Among Patients With Cancer: Evidence From Cancer Registry Records Linked With Commercial Health Insurance Claims. AB - PURPOSE: Despite guidelines emphasizing symptom management over aggressive treatment, end-of-life care for persons with cancer in the United States is highly variable. In consultation with a regional collaboration of patients, providers, and payers, we investigated indicators of high-quality end-of-life care to describe patterns of care, identify areas for improvement, and inform future interventions to enhance end-of-life care for patients with cancer. METHODS: We linked insurance claims to clinical information from the western Washington SEER database. We included persons >= 18 years of age who had been diagnosed with an invasive solid tumor between January 1, 2007, and December 31, 2015, and who had a recorded death date, were enrolled in a commercial plan for the last month of life, and made at least one insurance claim in the last 90 days of life. RESULTS: In the last month of life, among 6,568 commercially insured patients, 56.3% were hospitalized and 48.6% underwent at least one imaging scan. Among patients younger than 65 years of age, 31.4% were enrolled in hospice; of those younger than 65 years of age who were not enrolled in hospice, 40.5% had received an opioid prescription. Over time, opioid use in the last 30 days of life among young adults not enrolled in hospice dropped from 44.7% in the period 2007 to 2009 to 42.5% in the period 2010 to 2012 and to 36.7% in the period 2013 to 2015. CONCLUSION: Hospitalization and high-cost imaging scans are burdensome to patients and caregivers at the end of life. Our findings suggest that policies that facilitate appropriate imaging, opioid, and hospice use and that encourage supportive care may improve end-of-life care and quality of life. PMID- 28723256 TI - Quantitative testing of buprenorphine and norbuprenorphine to identify urine sample spiking during office-based opioid treatment. AB - BACKGROUND: Patients may spike urine samples with buprenorphine during office based opioid treatment to simulate adherence to prescribed buprenorphine, potentially to conceal diversion of medications. However, routine immunoassay screens do not detect instances of spiking, as these would simply result in a positive result. The aim of this study was to report on the experience of using quantitative urine testing for buprenorphine and norbuprenorphine to facilitate the identification of urine spiking. METHODS: This is a retrospective chart review of 168 consecutive patients enrolled in outpatient buprenorphine treatment at an urban academic medical setting between May 2013 and August 2014. All urine samples submitted were subjected to quantitative urine toxicology testing for buprenorphine and norbuprenorphine. Norbuprenorphine-to-buprenorphine ratio of less than 0.02 were further examined for possible spiking. Demographic and clinical variables were also extracted from medical records. Clinical and demographic variables of those who did and did not spike their urines were compared. Statistically significant variables from the univariate testing were entered as predictors of spiking in a regression analysis. RESULTS: A total of 168 patients were included, submitting a total of 2275 urine samples. Patients provided on average 13.6 (SD = 9.9) samples, and were in treatment for an average 153.1 days (SD = 142.2). In total, 8 samples (0.35%) from 8 patients (4.8%) were deemed to be spiked. All of the samples suspected of spiking contained buprenorphine levels greater than 2000 ng/mL, with a mean norbuprenorphine level of 11.9 ng/mL. Spiked samples were submitted by 6 patients (75.0%) during the intensive outpatient (IOP) phase of treatment, 2 patients (25.0%) during the weekly phase, and none from the monthly phase. Regression analysis indicated that history of intravenous drug use and submission of cocaine-positive urine samples at baseline were significant predictors of urine spiking. CONCLUSIONS: Even though only a small number of patients were identified to have spiked their urine samples, quantitative testing may help identify urine spiking during office-based opioid treatment with buprenorphine. PMID- 28723257 TI - Reply to Londhe et al.: CAPTURE: A Screening Tool for Chronic Obstructive Pulmonary Disease or Obstructive Airway Disease? PMID- 28723258 TI - Nucleolar structure: Yeast rDNA feels the heat. PMID- 28723259 TI - Inappropriate movement of Rac1 contributes to glucotoxicity of the islet beta cell. PMID- 28723260 TI - Systems Issues in Burnout and Safety: Potential Integrative Health Contributions. PMID- 28723261 TI - Vermont Policy Makers Assess the Effectiveness of Acupuncture Treatment for Chronic Pain in Medicaid Enrollees. PMID- 28723263 TI - Incidence Trends of Cervical Cancer in Adolescents and Young Adults: Brazilian Population Based Data. AB - PURPOSE: High incidence rates for cervical cancer in adolescents and young adults (AYAs: 15-29 years) make this the most common carcinoma in Brazil. Our aim was to analyze the incidence trends for cervical cancer (CC) and in situ neoplasia (IsN) among this age group. METHODS: Incidence data were extracted from 21 Brazilian population-based cancer registries (PBCRs). Tumors with behavior code/3 (malignant) were classified as CC. Tumors with behavior code/2 were classified as IsN. Age-adjusted and age-specific incidence rates were calculated for individuals aged 15-19 years, 20-24 years, and 25-29 years. Incidence trends were evaluated by joinpoint regression analyses. RESULTS: The median incidence rate of CC for AYA in Brazil was 3.63 per 100,000, with the highest rate observed in Recife (27.50 per 100,000). Significant increase in incidence for CC was identified in two PBCRs, with decreased rates for three PBCRs. The median incidence rate of IsN was 16.78 per 100,000 and was highest in Roraima (93.37 per 100,000). Increased incidence rates for IsN were identified in six PBCRs, with significant decreases in two PBCRs. CONCLUSION: The incidence rate for CC among AYA in Brazil is high and warrants intervention in terms of both prevention and control. PMID- 28723262 TI - The risk of inflammatory bowel disease flares after fecal microbiota transplantation: Systematic review and meta-analysis. AB - : Several studies have suggested worsening in inflammatory bowel disease (IBD) activity following fecal microbiota transplantation (FMT). We aimed to assess the risk of worsening in IBD activity following FMT. An electronic search was conducted using MEDLINE (1946-June 2016), EMBASE (1954-June 2016) and Cochrane Central Register of Controlled Trials (2016). Studies in which FMT was provided to IBD patients for IBD management or (Clostridium difficile infection) CDI treatment were included. The primary outcome was the rate of worsening in IBD activity. RESULTS: Twenty-nine studies with 514 FMT-treated IBD patients were included. Range of follow up was 4 weeks to 3 y. The pooled rate of IBD worsening was 14.9% (95% CI 10-21%). Heterogeneity was detected: I2 D 52.1%, Cochran Q test D 58.1, p D 0.01. A priori subgroup analyses were performed. Although not significant, the pooled rate of worsening in IBD activity following FMT for CDI (22.7% (95% CI: 13-36%)) was higher compared with FMT for IBD (11.1% (95% CI 7 17%)). Rates of worsening in IBD after lower GI FMT delivery revealed a higher rate of worsening in IBD activity (16.5% (95% CI: 11-24%)) compared with upper GI delivery (5.6% (95% CI: 2-16%)). Rates of worsening in high quality studies and randomized controls trials (RCTS) suggested a marginal risk of worsening in IBD activity (4.6%, (95% CI: 1.8-11%). Rates of IBD worsening are overall marginal across high quality RCTS. It is unknown if the FMT itself led to the worsening of IBD in this small fraction or if this represents alternative etiologies. PMID- 28723264 TI - Patterns of care and outcomes with the addition of chemotherapy to radiation therapy for stage I nasopharyngeal cancer. AB - PURPOSE: The standard of care for stage I (T1N0) nasopharyngeal cancer (NPC) is definitive radiotherapy (RT). Given the phase III evidence supporting combined chemoradiotherapy (CRT) for stage II NPC, we investigated practice patterns and outcomes associated with administration of chemotherapy to RT alone for stage I NPC. METHODS: The National Cancer Data Base (NCDB) was queried for clinical T1N0 primary NPC cases (2004-2013) receiving curative-intent RT. Patients with unknown RT/chemotherapy status were excluded, as were benign/sarcomatous histologies and receipt of pharyngectomy. Patient, tumor, and treatment parameters were extracted. Logistic regression analysis ascertained factors associated with receipt of additional chemotherapy. Kaplan-Meier analysis was used to evaluate overall survival (OS) between patients receiving RT versus CRT. Cox proportional hazards modeling determined variables associated with receipt of OS. RESULTS: In total, 396 patients were analyzed. Chemotherapy was delivered in 147 patients (37%). On multivariate analysis, patients treated at academic/integrated centers were less likely to receive chemotherapy (p = .008); a racial predilection was noted, as non-black/non-white patients were also less likely to receive chemotherapy (p = .006). Respective 5-year OS in patients receiving RT alone versus CRT were 77% and 75% (p = .428). Receipt of chemotherapy did not independently predict for greater OS (p = .447). CONCLUSIONS: These data do not support the routine addition of chemotherapy to definitive RT for T1N0 NPC. PMID- 28723265 TI - A text-mining analysis of the public's reactions to the opioid crisis. AB - BACKGROUND: Opioid abuse has become an epidemic in the United States. On August 25, 2016, the former Surgeon General of the United States sent an open letter to care providers asking for their help with combatting this growing health crisis. Social media forums such as Twitter allow for open discussions among the public and up-to-date exchanges of information about timely topics such as opioids. Therefore, the goal of the current study is to identify the public's reactions to the opioid epidemic by identifying the most popular topics tweeted by users. METHODS: A text miner, algorithmic-driven statistical program was used to capture 73,235 original tweets and retweets posted within a 2-month time span 15 (August 15, 2016, through October 15, 2016). All tweets contained references to "opioids," "turnthetide," or similar keywords. The sets of tweets were then analyzed to identify the most prevalent topics. RESULTS: The most discussed topics had to do with public figures addressing opioid abuse, creating better treatment options for teen addicts, using marijuana as an alternative for managing pain, holding foreign and domestic drug makers accountable for the epidemic, promoting the "Rx for Change" campaign, addressing double standards in the perceptions and treatment of black and white opioid users, and advertising opioid recovery programs. CONCLUSIONS: Twitter allows users to find current information, voice their concerns, and share calls for action in response to the opioid epidemic. Monitoring the conversations about opioids that are taking place on social media forums such as Twitter can help public health officials and care providers better understand how the public is responding to this health crisis. PMID- 28723266 TI - Age of initiation, psychopathology, and other substance use are associated with time to use disorder diagnosis in persons using opioids nonmedically. AB - BACKGROUND: Nonmedical use of prescription opioids (NMUPO) is an ongoing public health challenge, as NMUPO is associated with psychopathology, other drug use, and fatal overdose. These concomitant risks are greatest in those with opioid use disorder (OUD), but the development of NMUPO-related use disorder is poorly understood. The primary aim of this study was to establish factors associated with the development of and time to OUD among persons engaged in NMUPO. METHODS: Data were from wave 1 of the National Epidemiologic Study on Alcohol and Related Conditions, with 1755 participants endorsing lifetime NMUPO. Analyses used sequential design-based logistic regression for DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) opioid dependence correlates, followed by Cox regression of proportional hazards for correlates (e.g., sociodemographics, age of NMUPO initiation, and psychopathology) of time to dependence in those who developed DSM-IV dependence. RESULTS: Earlier age of NMUPO initiation increased OUD odds (adjusted odds ratio [AOR] = 0.95, 95% confidence interval [CI] = 0.94-0.96) but slowed OUD development (adjusted hazard ratio [AHR] = 1.05, 95% CI = 1.04-1.06) in those who developed OUD (n = 118), after controlling for sociodemographics, psychopathology, and ages of other drug use initiation. Psychopathology and earlier other drug use initiation were associated with higher OUD odds, but only having an alcohol use disorder was associated with shorter time to OUD. CONCLUSIONS: Earlier NMUPO initiation is associated with increased odds of OUD, although those with early initiation had a slower progression to OUD. Programs that prevent early NMUPO initiation, which might lower rates of OUD, and/or identify the later initiators at highest risk for rapid OUD development could have great public health benefits. PMID- 28723267 TI - Effects of drinker self-schema on drinking- and smoking-related information processing and behaviors. AB - BACKGROUND: Co-occurrence of drinking and smoking is prevalent in undergraduate students. A drinker self-schema-cognition about the self as the drinker-is a common identity in undergraduates and a well-known predictor of drinking behaviors. Given that smoking commonly occurs in the context of drinking, a drinker self-schema may be a cognitive mechanism to motivate co-occurring alcohol and tobacco use (i.e., cross-substance facilitation hypothesis). This study was to determine whether the drinker self-schema influences the processing of drinking- and smoking-related information and facilitates the co-occurrence of alcohol and tobacco use in undergraduate students who drink and smoke but do not self-identify as smokers. METHODS: This study was the second phase of a 2-phase study. Of the 330 who completed phase 1 (online survey), 99 completed the phase 2 study. Phase 2 was an in-person session that included a computerized information processing task to measure endorsements and response latencies for drinking- and smoking-related attributes, and a computerized Timeline Followback that was used to measure 90-day alcohol- and tobacco-use behaviors. The 5-item drinker self schema scale, administered in phase 1, was used to measure the strength of the drinker self-schema. RESULTS: A higher drinker self-schema score was associated with more endorsements of positive attributes for drinking and smoking, fewer endorsements of negative attributes for smoking, faster processing of agreements with positive alcohol-use-related attributes, higher levels of drinking and smoking, and more days of co-occurring alcohol and tobacco use. CONCLUSIONS: Findings provide preliminary evidence to support the cross-substance facilitation hypothesis that the drinker self-schema facilitates the processing of not only drinking-related but also smoking-related stimuli and behaviors. Undergraduates who have higher drinker self-schema scores may be vulnerable to co-occurring alcohol and tobacco use. PMID- 28723269 TI - Identification of Antipneumococcal Molecules Effective Against Different Streptococcus pneumoniae Serotypes Using a Resazurin-Based High-Throughput Screen. AB - Streptococcus pneumoniae is a major human pathogen, causing around 1.6 million deaths worldwide each year. By optimizing a resazurin-based assay to detect S. pneumoniae growth in 384-well microplates, we developed a new high-throughput screening (HTS) system for the discovery of antipneumococcal molecules, which was unsuccessful using conventional absorbance measurements. Before applying our protocol to a large-scale screen, we validated the system through a pilot screen targeting about 7,800 bioactive molecules using three different S. pneumoniae serotypes. Primary screenings of a further 27,000 synthetic small molecules facilitated the identification of 3-acyl-2-phenylamino-1,4-dihydropquinolin-4-one (APDQ) derivatives that inhibited growth of S. pneumoniae with MIC90 values <1 MUM (0.03-0.81 MUM). Five selected APDQ derivatives were also active against Staphylococcus aureus but neither Klebsiella pneumoniae nor Pseudomonas aeruginosa, suggesting that APDQ may act specifically against Gram-positive bacteria. Our results both validated and demonstrated the utility of the resazurin-based HTS system for the identification of new antipneumococcal molecules. Moreover, the identified new antipneumococcal molecules in this study may have potential to be further developed as new antibiotics. PMID- 28723270 TI - In the July 2017 Issue of ASSAY.... PMID- 28723268 TI - Assay of Calcium Transients and Synapses in Rat Hippocampal Neurons by Kinetic Image Cytometry and High-Content Analysis: An In Vitro Model System for Postchemotherapy Cognitive Impairment. AB - Postchemotherapy cognitive impairment (PCCI) is commonly exhibited by cancer patients treated with a variety of chemotherapeutic agents, including the endocrine disruptor tamoxifen (TAM). The etiology of PCCI is poorly understood. Our goal was to develop high-throughput assay methods to test the effects of chemicals on neuronal function applicable to PCCI. Rat hippocampal neurons (RHNs) were plated in 96- or 384-well dishes and exposed to test compounds (forskolin [FSK], 17beta-estradiol [ES]), TAM or fulvestrant [FUL], aka ICI 182,780) for 6 14 days. Kinetic Image CytometryTM (KICTM) methods were developed to quantify spontaneously occurring intracellular calcium transients representing the activity of the neurons, and high-content analysis (HCA) methods were developed to quantify the expression, colocalization, and puncta formed by synaptic proteins (postsynaptic density protein-95 [PSD-95] and presynaptic protein Synapsin-1 [Syn-1]). As quantified by KIC, FSK increased the occurrence and synchronization of the calcium transients indicating stimulatory effects on RHN activity, whereas TAM had inhibitory effects. As quantified by HCA, FSK also increased PSD-95 puncta and PSD-95:Syn-1 colocalization, whereas ES increased the puncta of both PSD-95 and Syn-1 with little effect on colocalization. The estrogen receptor antagonist FUL also increased PSD-95 puncta. In contrast, TAM reduced Syn-1 and PSD-95:Syn-1 colocalization, consistent with its inhibitory effects on the calcium transients. Thus TAM reduced activity and synapse formation by the RHNs, which may relate to the ability of this agent to cause PCCI. The results illustrate that KIC and HCA can be used to quantify neurotoxic and neuroprotective effects of chemicals in RHNs to investigate mechanisms and potential therapeutics for PCCI. PMID- 28723271 TI - Development of Three Orthogonal Assays Suitable for the Identification and Qualification of PIKfyve Inhibitors. AB - FYVE-type zinc finger-containing phosphoinositide kinase (PIKfyve) catalyzes the formation of phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2) from phosphatidylinositol 3-phosphate (PI(3)P). PIKfyve has been implicated in multiple cellular processes, and its role in the regulation of toll-like receptor (TLR) pathways and the production of proinflammatory cytokines has sparked interest in developing small-molecule PIKfyve inhibitors as potential therapeutics to treat autoimmune and inflammatory diseases. We developed three orthogonal assays to identify and qualify small-molecule inhibitors of PIKfyve: (1) a purified component microfluidic enzyme assay that measures the conversion of fluorescently labeled PI(3)P to PI(3,5)P2 by purified recombinant full-length human 6His-PIKfyve (rPIKfyve); (2) an intracellular protein stabilization assay using the kinase domain of PIKfyve expressed in HEK293 cells; and (3) a cell based functional assay that measures the production of interleukin (IL)-12p70 in human peripheral blood mononuclear cells stimulated with TLR agonists lipopolysaccharide and R848. We determined apparent Km values for both ATP and labeled PI(3)P in the rPIKfyve enzyme assay and evaluated the enzyme's ability to use phosphatidylinositol as a substrate. We also tested four reference compounds in the three assays and showed that together these assays provide a platform that is suitable to select promising inhibitors having appropriate functional activity and confirmed cellular target engagement to advance into preclinical models of inflammation. PMID- 28723272 TI - Literature Search and Review. PMID- 28723273 TI - The REPAIR Project: Examining the Biological Impacts of Sub-Background Radiation Exposure within SNOLAB, a Deep Underground Laboratory. AB - Considerable attention has been given to understanding the biological effects of low-dose ionizing radiation exposure at levels slightly above background. However, relatively few studies have been performed to examine the inverse, where natural background radiation is removed. The limited available data suggest that organisms exposed to sub-background radiation environments undergo reduced growth and an impaired capacity to repair genetic damage. Shielding from background radiation is inherently difficult due to high-energy cosmic radiation. SNOLAB, located in Sudbury, Ontario, Canada, is a unique facility for examining the effects of sub-background radiation exposure. Originally constructed for astroparticle physics research, the laboratory is located within an active nickel mine at a depth of over 2,000 m. The rock overburden provides shielding equivalent to 6,000 m of water, thereby almost completely eliminating cosmic radiation. Additional features of the facility help to reduce radiological contamination from the surrounding rock. We are currently establishing a biological research program within SNOLAB: Researching the Effects of the Presence and Absence of Ionizing Radiation (REPAIR project). We hypothesize that natural background radiation is essential for life and maintains genomic stability, and that prolonged exposure to sub-background radiation environments will be detrimental to biological systems. Using a combination of whole organism and cell culture model systems, the effects of exposure to a sub-background environment will be examined on growth and development, as well as markers of genomic damage, DNA repair capacity and oxidative stress. The results of this research will provide further insight into the biological effects of low-dose radiation exposure as well as elucidate some of the processes that may drive evolution and selection in living systems. This Radiation Research focus issue contains reviews and original articles, which relate to the presence or absence of low-dose ionizing radiation exposure. PMID- 28723275 TI - Foreword. PMID- 28723274 TI - Identifying Voxels at Risk for Progression in Glioblastoma Based on Dosimetry, Physiologic and Metabolic MRI. AB - Despite the longstanding role of radiation in cancer treatment and the presence of advanced, high-resolution imaging techniques, delineation of voxels at-risk for progression remains purely a geometric expansion of anatomic images, missing subclinical disease at risk for recurrence while treating potentially uninvolved tissue and increasing toxicity. This remains despite the modern ability to precisely shape radiation fields. A striking example of this is the treatment of glioblastoma, a highly infiltrative tumor that may benefit from accurate identification of subclinical disease. In this study, we hypothesize that parameters from physiologic and metabolic magnetic resonance imaging (MRI) at diagnosis could predict the likelihood of voxel progression at radiographic recurrence in glioblastoma by identifying voxel characteristics that indicate subclinical disease. Integrating dosimetry can reveal its effect on voxel outcome, enabling risk-adapted voxel dosing. As a system example, 24 patients with glioblastoma treated with radiotherapy, temozolomide and an anti-angiogenic agent were analyzed. Pretreatment median apparent diffusion coefficient (ADC), fractional anisotropy (FA), relative cerebral blood volume (rCBV), vessel leakage (percentage recovery), choline-to-NAA index (CNI) and dose of voxels in the T2 nonenhancing lesion (NEL), T1 post-contrast enhancing lesion (CEL) or normal appearing volume (NAV) of brain, were calculated for voxels that progressed [NAV >NEL, CEL (N = 8,765)] and compared against those that remained stable [NAV->NAV (N = 98,665)]. Voxels that progressed (NAV->NEL) had significantly different (P < 0.01) ADC (860), FA (0.36) and CNI (0.67) versus stable voxels (804, 0.43 and 0.05, respectively), indicating increased cell turnover, edema and decreased directionality, consistent with subclinical disease. NAV->CEL voxels were more abnormal (1,014, 0.28, 2.67, respectively) and leakier (percentage recovery = 70). A predictive model identified areas of recurrence, demonstrating that elevated CNI potentiates abnormal diffusion, even far (>2 cm) from the tumor and dose escalation >45 Gy has diminishing benefits. Integrating advanced MRI with dosimetry can identify at voxels at risk for progression and may allow voxel level risk-adapted dose escalation to subclinical disease while sparing normal tissue. When combined with modern planning software, this technique may enable risk-adapted radiotherapy in any disease site with multimodal imaging. PMID- 28723276 TI - Can an app help identify psychomotor function impairments during drinking occasions in the real world? A mixed-method pilot study. AB - BACKGROUND: Being able to measure the acute effects of alcohol consumption on psychomotor functions in natural settings could be useful in injury prevention interventions. This study examined the feasibility and acceptability of collecting app-based measures of information processing, working memory, and gait stability during times of typical alcohol consumption among young adults. METHODS: Ten young adults (aged 21-26) with hazardous drinking completed a baseline assessment and ecological momentary assessments (EMA) on 4 consecutive Fridays and Saturdays, every hour from 8 pm to 12 am. EMA assessed alcohol consumption and perceived intoxication, followed by a digit symbol substitution task (DSST), a visuospatial working memory task (VSWMT), and a 5-step tandem gait task (TGT). Exit interviews probed user experiences. Multilevel models explored relationships between estimated blood alcohol concentration (eBAC; mg/dL) and DSST and VSWMT performance. RESULTS: Participants completed 32% of EMA. Higher rates of noninitiation occurred later in the evening and over time. In multilevel models, higher eBAC was associated with lower DSST scores. Eight out of 10 individuals had at least 1 drinking occasion when they did not perceive any intoxication. Lower DSST scores would identify impairment in 45% of these occasions. Exit interviews indicated that adding real-time feedback on task performance could increase awareness of alcohol effects. CONCLUSIONS: Collecting app-based psychomotor performance data from young adults during drinking occasions is feasible and acceptable, but strategies to reduce barriers to task initiation are needed. Mobile DSST is sensitive to eBAC levels and could identify occasions when an individual may not perceive impairments. PMID- 28723277 TI - NS2A comprises a putative viroporin of Dengue virus 2. PMID- 28723278 TI - A case of cannabinoid hyperemesis syndrome with Heliobacter pylori and preeclampsia during pregnancy. AB - BACKGROUND: The condition termed cannabinoid hyperemesis syndrome (CHS) was characterized a decade ago by Allen et al. and includes cyclic episodes of nausea and vomiting and the learned behavior of hot bathing in individuals with chronic cannabis abuse. During pregnancy, the differential diagnosis of this syndrome is challenging, since it can be masked by typical symptoms of early pregnancy or by hyperemesis gravidarum, a complication of early pregnancy associated with excessive nausea and vomiting. CASE DESCRIPTION: The authors herein describe the case of a 21-year-old primigravida patient diagnosed with hyperemesis gravidarum at 6 weeks of gestation and with preeclampsia at 35 weeks. At 30 weeks of gestation, a drug screen was performed that was positive for cannabis; therefore, a diagnosis of CHS was made. After labor induction, the patient delivered an infant who developed normally and had a negative drug test of the umbilical cord blood. Esophagogastroduodenoscopy was performed 9 days post delivery, with biopsies taken of the duodenal, gastric, and esophageal tissues. Moderate chronic gastritis with lymphoid aggregates and slight acute inflammation were noticed, whereas no malignancy, dysplasia, or goblet cell metaplasia was detected. A number of Helicobacter-like organisms were identified by H. pylori immunostaining. CONCLUSION: Presented here is the first case reporting an association of chronic cannabis use with H. pylori colonization and preeclampsia in pregnancy, which brings to light the possible involvement of a cannabinoid related pathway in the link between pregnancy-specific complications and bacterial colonization. PMID- 28723279 TI - Magnetization Transfer Imaging in Treatment-resistant Depression: Structural Evidence of a Functional Derangement That Might Help Guide Therapy? PMID- 28723280 TI - Case 248. PMID- 28723284 TI - Balloon Guide Catheter in Large-Vessel Occlusion Stroke Therapy. PMID- 28723281 TI - Imaging Correlates of Adult Glioma Genotypes. AB - Primary brain tumors, most commonly gliomas, are histopathologically typed and graded as World Health Organization (WHO) grades I-IV according to increasing degrees of malignancy. These grades provide prognostic information and guidance on treatment such as radiation therapy and chemotherapy after surgery. Despite the confirmed value of the WHO grading system, results of a multitude of studies and prospective interventional trials now indicate that tumors with identical morphologic criteria can have highly different outcomes. Molecular markers can allow subtypes of tumors of the same morphologic type and WHO grade to be distinguished and are, therefore, of great interest in personalization of brain tumor treatment. Recent genomic-wide studies have resulted in a far more comprehensive understanding of the genomic alterations in gliomas and provide suggestions for a new molecularly based classification. Magnetic resonance (MR) imaging phenotypes can serve as noninvasive surrogates for tumor genotypes and can provide important information for diagnosis, prognosis, and, eventually, personalized treatment. The newly emerged field of radiogenomics allows specific MR imaging phenotypes to be linked with gene expression profiles. In this article, the authors review the conventional and advanced imaging features of three tumoral genotypes with prognostic and therapeutic consequences: (a) isocitrate dehydrogenase mutation; (b) the combined loss of the short arm of chromosome 1 and the long arm of chromosome 19, or 1p19q codeletion; and (c) methylguanine methyltransferase promoter methylation. (c) RSNA, 2017. PMID- 28723285 TI - Case 244: Systemic Amyloidosis-A Complication of Waldenstrom Macroglobulinemia. AB - History A 68-year-old man was admitted to the hospital for work-up because of generalized fatigue, anorexia, chronic diarrhea, and weight loss. Laboratory work up revealed an erythrocyte sedimentation rate of 58 mm/h (reference range, 3-23 mm/h), a hemoglobin level of 14.1 g/dL (reference range, 13.8-17.5 g/dL), a leukocyte count of 8.1 * 109/L (reference range, [3.4-9.7] * 109/L), a platelet count of 223 * 109/L (reference range, [158-424] * 109/L), an alkaline phosphatase level of 85 U/L (1.42 MUkat/L) (normal level, <142 U/L [2.37 MUkat/L]), a serum creatinine level of 93 MUmol/L (reference range, 79-125 MUmol/L), a serum total protein level of 82 g/L (reference range, 66-81 g/L), a serum albumin level of 39.3 g/L (reference range, 40.2-47.6 g/L), an albumin-to globulin ratio (a test showing relative amounts of major plasma proteins) of 0.92 (reference range, 0.8-2.0), a urine protein level of 15 mg/dL (normal level, <20 mg/dL), a total serum calcium level of 2.46 mmol/L (reference range, 2.14-2.53 mmol/L), and a carcinoembryonic antigen value of 2.69 MUg/L (normal value, <3.4 MUg/L). Serology findings were negative for celiac disease. Thyroid function was normal, as were 5-hydroxyindoleacetic acid and chromogranin A levels. Initial radiologic examination included chest radiography and plain abdominal erect radiography. Gastrointestinal endoscopy was performed to rule out inflammatory bowel disease or gastrointestinal neoplasm as a cause of chronic diarrhea. Endoscopic mucosal resection of two polyps from the cardia and duodenal bulb was performed during esophagogastroduodenoscopy, but histologic findings at hematoxylin-eosin staining were normal. Colonoscopy revealed diverticulosis involving the entire colon. Serum immunoelectrophoresis showed a monoclonal band, which was confirmed to be immunoglobulin Mlambda at immunofixation. After histologic analysis of the bone marrow biopsy specimen, diagnosis of Waldenstrom macroglobulinemia was established, and computed tomography (CT) of the thorax, abdomen, and pelvis was requested to depict lymphadenopathy and organomegaly. On the basis of CT findings, two more specimens considered highly sensitive for the CT diagnosis were obtained via minimally invasive biopsy, but the results were negative. Magnetic resonance (MR) imaging was performed a year later to control the progression of CT findings. PMID- 28723286 TI - Association between Computer-aided Diagnosis-measured Peak Enhancement and Washout Component at Preoperative MR Imaging and Operable Hormone Receptor positive Breast Cancer. PMID- 28723287 TI - Advanced Renal Cell Carcinoma: Role of the Radiologist in the Era of Precision Medicine. AB - For the past decade, advanced renal cell carcinoma (RCC) has been at the forefront of oncologic innovation. Our rapidly evolving understanding of the molecular and genetic basis of RCC has revolutionized the management of advanced RCC; 10 novel molecular targeted agents and immune checkpoint inhibitor have received U.S. Food and Drug Administration approval for treatment of advanced RCC in a little over a decade. Amid this progress, imaging has assumed a central role in metastatic surveillance and follow-up of advanced RCC. State-of-the-art knowledge of the molecular basis of RCC and its treatment and imaging will help ensure that the radiology community remains relevant and central in the care of patients with advanced RCC. This article will review developments in management of advanced RCC from a radiologist's perspective to highlight our clinical role. It will describe how the underlying molecular mechanisms of RCC provide specific targets for novel anticancer agents. The relationship between the mechanisms of action of these novel anticancer agents and the imaging appearance of tumor response will be discussed, along with the available tumor response criteria and their strengths and weaknesses, thus assisting radiologists in response assessment in the setting of clinical trials or routine practice. The class- and drug-specific toxicities and complications associated with the novel anticancer agents will be summarized, since these are frequently missed or misinterpreted and require the radiologist's input in prompt detection and management. The potential role of radiogenomics and texture analysis in the management of advanced RCC will also be discussed. (c) RSNA, 2017. PMID- 28723288 TI - Science to Practice: Can MR Imaging Cell Tracking of Macrophage Infiltration Be Used as a Predictive Imaging Biomarker for Transplanted Stem Cell Rejection? AB - Ferumoxytol-enhanced magnetic resonance (MR) imaging of donor-matched and mismatched stem cell transplants demonstrated decreased signal intensity not only for a xenogeneic mismatch in species but, surprisingly, also for a syngeneic mismatch in sex. MR imaging findings were corroborated with intravital fluorescence microscopy (IVM), where nearly 90% of all ferumoxytol-containing cells were found to be macrophages. Hence, MR imaging cell tracking of infiltrating macrophages may have predictive value in determining whether transplanted stem cell rejection will occur. PMID- 28723289 TI - Diagnostic Outcomes of Screening and Diagnostic Mammography. PMID- 28723290 TI - Mammography Performance Benchmarks in an Era of Value-based Care. PMID- 28723291 TI - Behind the Numbers: Sensitivity Analysis in Cost-Effectiveness Modeling. PMID- 28723292 TI - Richard M. Friedenberg, MD. PMID- 28723294 TI - Richard L. Baron, MD. PMID- 28723295 TI - Use of 8-mm Covered TIPS: Is "Losses without Gains" the End of the Story? PMID- 28723296 TI - Local Ablative Therapy Options for Patients with Inoperable Pancreatic Cancer. PMID- 28723297 TI - Melvyn T. Korobkin, MD. PMID- 28723298 TI - Given Overdiagnosis, Recall Reduction Should Trump DCIS Detection. PMID- 28723301 TI - Maternal occupation and the risk of neural tube defects in offspring. AB - We evaluated the association between maternal occupation and the risk of neural tube defects (NTDs) in offspring. Data for 491 nonsyndromic cases were obtained from the Texas Birth Defects Registry for deliveries between 1999 and 2009. We randomly selected 2,291 controls among all live births in Texas during this time. Maternal occupations were classified using automated software and manual assignment. Multivariable logistic regression analyses were used to examine the relationship between maternal occupation and risk for any NTD, adjusting for maternal race/ethnicity, any diabetes, and maternal body mass index. These analyses were repeated for spina bifida specifically. Some maternal occupations, particularly those related to business/finance, health care practice, and cleaning/maintenance, were significantly associated with increased risk of spina bifida and/or any NTD. Further research is needed to identify the specific occupational exposures related to NTD risk. PMID- 28723299 TI - Support for "Disease-Only" Genotypes and Excess of Homozygosity at the CYTH4 Primate-Specific GTTT-Repeat in Schizophrenia. AB - OBJECTIVE: The role of short tandem repeats (STRs) in the control of gene expression among species is being increasingly understood following the identification of several instances in which certain STRs occur identically, or expand differentially, in primates versus nonprimates. These STRs may regulate genes that participate in characteristics that are associated with the divergence of primates from sibling orders (e.g., brain higher order functions). The CYTH4 gene contains the longest tetranucleotide STR in its core promoter, at 7-repeats, and links to the evolution of human and nonhuman primates. Allele and genotype distribution of this STR were studied in patients affected by schizophrenia (SCZ) and controls. METHODS: High-resolution data were obtained on the allele and genotype distribution of the CYTH4 STR and a novel C > T single-nucleotide polymorphism (SNP) at its immediate upstream sequence in 255 patients with SCZ and 249 controls. Each sample was sequenced twice using the fluorescent dye termination method. RESULTS: Novel alleles were detected at the long extreme of the GTTT-repeat, at 10- and 11-repeats, in the SCZ cases and controls. Excess of homozygosity was observed for the entire range of alleles across the GTTT-repeat and the C > T SNP in the SCZ patients in comparison with the controls (Yates corrected p < 0.011). Three genotypes consisting of the 11-repeat allele (i.e., 11/11, 10/11, and 7/11) were detected only in the SCZ patients (i.e., disease only genotypes), and contributed to 2.3% of the SCZ genotypes (Mid p exact <0.007). The frequency of the 11-repeat allele was estimated at 0.02 and 0.006 in the SCZ patients and controls, respectively (Mid p exact <0.006). CONCLUSION: This indicates that STR genotypes that are absent in the control group may be risk factors for SCZ. Future studies are warranted to test the significance of our findings. PMID- 28723300 TI - Interest in using mobile technology to help self-manage alcohol use among persons living with the human immunodeficiency virus: A Florida Cohort cross-sectional study. AB - BACKGROUND: Alcohol consumption at hazardous levels is more prevalent and associated with poor health outcomes among persons living with the human immunodeficiency virus (HIV; PLWH). Although PLWH are receptive to using technology to manage health issues, it is unknown whether a cell phone app to self-manage alcohol use would be acceptable among PLWH who drink. The objectives of this study were to determine factors associated with interest in an app to self-manage drinking and to identify differences in baseline mobile technology use among PLWH by drinking level. METHODS: The study population included 757 PLWH recruited from 2014 to 2016 into the Florida Cohort, an ongoing cohort study investigating the utilization of health services and HIV care outcomes among PLWH. Participants completed a questionnaire examining demographics, substance use, mobile technology use, and other health behaviors. Multivariable logistic regression was used to identify factors significantly associated with interest in an app to self-manage drinking. We also determined whether mobile technology use varied by drinking level. RESULTS: Of the sample, 40% of persons who drink at hazardous levels, 34% of persons who drink at nonhazardous levels, and 19% of persons who do not drink were interested in a self-management app for alcohol use. Multivariable logistic regression analysis indicated that nonhazardous drinking (adjusted odds ratio [AOR] = 1.78; confidence interval [CI 95%]: 1.10 2.88) and hazardous drinking (AOR = 2.58; CI: 1.60-4.16) were associated with interest, controlling for age, gender, education, and drug use. Regarding mobile technology use, most of the sample reported smartphone ownership (56%), text messaging (89%), and at least one cell phone app (69%). CONCLUSIONS: Regardless of drinking level, overall mobile technology use among PLWH was moderate, whereas PLWH who consumed alcohol expressed greater interest in a cell phone app to self manage alcohol use. This indicates that many PLWH who drink would be interested in and prepared for a mobile technology-based intervention to reduce alcohol consumption. PMID- 28723302 TI - Why use group visits for opioid use disorder treatment in primary care? A patient centered qualitative study. AB - BACKGROUND: Primary care providers are well positioned to respond to the opioid crisis by providing buprenorphine/naloxone (B/N) through shared medical appointments (SMAs). Although quantitative research has been previously conducted on SMAs with B/N, the authors conducted a qualitative assessment from the patients' point of view, considering whether and how group visits provide value for patients. METHODS: Twenty-five participants with opioid use disorder (OUD) who were enrolled in a weekly B/N group visit at a family medicine clinic participated in either of two 1-hour-long focus groups, which were conducted as actual group visits. Participants were prompted with the question "How has this group changed you as a person?" Data were audio-recorded and professionally transcribed and analyzed using a qualitative thematic approach, identifying common communication behaviors and resulting attitudes about the value of the group visit model. RESULTS: Participants demonstrated several communication behaviors that support group members in their recovery, including offering direct emotional support to others struggling with difficult experiences, making an intentional effort to probe about others' lives, venting about heavy situations, joking to lighten the mood, and expressing feelings of gratitude to the entire group. These communication behaviors appear to act as mechanisms to foster a sense of accountability, a shared identity, and a supportive community. Other demonstrated group behaviors may detract from the value of the group experience, including side conversations, tangential comments, and individual participants disproportionately dominating group time. CONCLUSION: The group visit format for delivering B/N promotes group-specific communication behaviors that may add unique value in supporting patients in their recovery. Future research should elucidate whether these benefits can be isolated from those achieved solely through medication treatment with B/N and if similar benefits could be achieved in non-primary care sites. PMID- 28723303 TI - Folate serum levels in Italian women entering an in vitro fertilization program. AB - Italian public health authorities recommend women of childbearing age to assume a daily dose of 0.4 mg of folic acid (FA) from at least one month before conception in order to reduce the risk of having children affected by neural tube defects (NTDs). In this study, folate, homocysteine and vitamin B12 serum levels were determined in 77 women entering an in vitro fertilization program. About 75% of patients had serum folate values compatible with the intake of the recommended dose of FA for at least three months, whereas only the 61% of them reached or exceeded the serum folate concentration regarded as the optimal concentration during the periconceptional period. Mean vitamin B12 serum levels and mean homocysteine plasma levels resulted in normal range in all the women with mean values of 381.2 +/- 2.2 pg/ml and 8.48 +/- 2.2 MUmol/l, respectively. In conclusion, only a portion of women entering an IVF program presents proper folate levels. PMID- 28723304 TI - The quest for durable lesions in catheter ablation of atrial fibrillation - technological advances in radiofrequency catheters and balloon devices. AB - INTRODUCTION: Atrial fibrillation is the most common cardiac arrhythmia and represents a growing clinical, social and economic challenge. Catheter ablation for symptomatic atrial fibrillation has evolved from an experimental procedure into a widespread therapy and offers a safe and effective treatment option. A prerequisite for durable PVI are transmural and contiguous circumferential lesions around the pulmonary veins. However, electrical reconnection of initially isolated pulmonary veins remains a primary concern and is a dominant factor for arrhythmia recurrence during long-term follow up. Areas covered: This article discusses the physiology of lesion formation using radiofrequency-, cryo- or laser- energy for pulmonary vein isolation and provides a detailed review of recent technological advancements in the field of radiofrequency catheters and balloon devices. Finally, future directions and upcoming developments for the interventional treatment of atrial fibrillation are discussed. Expert commentary: Durable conduction block across deployed myocardial lesions is mandatory not only for PVI but for any other cardiac ablation strategy as well. A major improvement urgently expected is the intraprocedural real-time distinction of durable lesions from interposed gaps with only transiently impaired electrical conduction. Furthermore, a simplification of ablation tools used for PVI is required to reduce the high technical complexity of the procedure. PMID- 28723306 TI - Inclusion of Lesbian, Gay, Bisexual, Transgender, Queer, and Intersex Health in Australian and New Zealand Medical Education. AB - PURPOSE: This study aims at establishing the scope of lesbian, gay, bisexual, transgender, queer, and intersex (LGBTQI) health in Australian and New Zealand medical curricula. METHODS: We sent medical school curriculum administrators an online cross-sectional survey. RESULTS: The response rate was 15 medical schools (71%): 14 Australian schools and 1 New Zealand school. Respondents included program directors (n = 5; 33%), course coordinators (n = 4; 27%), Heads of School (n = 2; 13%), one Dean (7%), and three others (20%). Most schools (n = 9; 60%) reported 0-5 hours dedicated to teaching LGBTQI content during the required pre clinical phase; nine schools (60%) reported access to a clinical rotation site where LGBTQI patient care is common. In most schools (n = 9; 60%), LGBTQI specific content is interspersed throughout the curriculum, but five schools (33%) have dedicated modules. The most commonly used teaching modalities include lectures (n = 12; 80%) and small-group sessions (n = 9; 60%). LGBTQI content covered in curricula is varied, with the most common topics being how to obtain information about same-sex sexual activity (80%) and the difference between sexual behavior and identity (67%). Teaching about gender and gender identity is more varied across schools, with seven respondents (47%) unsure about what is taught. Eight respondents (53%) described the coverage of LGBTQI content at their institution as "fair," two (13%) as "good," and two (13%) as "poor," with one respondent (7%) describing the coverage as "very poor." None of the respondents described the coverage as "very good." CONCLUSIONS: Currently, medical schools include limited content on LGBTQI health, most of which focuses on sexuality. There is a need for further inclusion of curriculum related to transgender, gender diverse, and intersex people. PMID- 28723305 TI - Prevalence of primary aldosteronism without hypertension in the general population: Results in Shika study. AB - OBJECTIVE: Recent studies have reported a high prevalence of primary aldosteronism (PA) among hypertensive patients. However, few data exist regarding the prevalence of PA in the general population. Therefore, we examined the prevalence of PA in the general population including normotensive subjects. METHODS: Plasma renin activity (ng/mL/hr), plasma aldosterone concentration (pg/mL) and aldosterone renin ratio (ARR) were determined in 309 subjects aged >40 years in Horimatsu and Higashi-Matsuho district, Shika-machi, Ishikawa, Japan. RESULTS: Among them, 195 subjects (78 males, mean age: 62 +/- 11 years) did not take antihypertensive agents: 113 normotensive subjects and 82 hypertensive subjects. Under these conditions, 68 subjects (13 males, age 62 +/- 10 years) had an ARR >200. In 14 subjects who underwent captopril suppression test, PA was documented in 5 subjects, yielding a minimum prevalence of 2.6% in total subjects (1.8% in normotensive subjects and 3.7% in hypertensive subjects). Interestingly, females subjects demonstrated significant differences in ARR between subjects with age <50 (172 +/- 105) and those with age 51-60 (388 +/- 531), although there were no differences in male subjects. CONCLUSIONS: These results demonstrate that PA including normotensive subjects exists more commonly than that expected in the general population. We suggest further investigation about the cause and progression of PA associated with sex and aging. PMID- 28723308 TI - Percutaneous Trans-Tracheal Endoscopic Approach: A Novel Technique for the Excision of Benign Lesions of Thoracic Trachea. AB - INTRODUCTION: Currently, neoplasms of the trachea and lower airway demand open transcervical approach with or without thoracotomy. We describe here a novel, minimally invasive approach for an intraluminal lesion of the thoracic trachea, called percutaneous trans-tracheal endoscopic approach (PTEA). Apart from obvious advantages over potentially morbid open procedures, this technique has certain peculiar benefits over rigid or flexible bronchoscopic approach. MATERIALS AND METHODS: A 43-year-old male patient had glomus tumor of thoracic trachea. After detailed workup and informed written consent, he was taken up for percutaneous trans-tracheal excision under general anesthesia. The foremost step of the procedure is awake fiberoptic guided intubation, using the microlaryngeal tracheal tube, followed by elective tracheotomy. Subsequently, the lower end of the microlaryngeal tube was carefully pushed further inside the trachea so that the cuff of the tube lies distal to the tumor. The cuff is then inflated so that the operating area is sealed off from lower airway to aid continuous inhalational anesthesia and to prevent aspiration of blood. The surgeon sitting at the head end removed the tumor through tracheotomy under endoscopic guidance. After achieving absolute hemostasis, neck wound was closed. RESULTS: Patient had complete removal of the tumor without any aspiration intraoperatively or in the postoperative period. The anesthetic agent could be delivered uninterrupted through the secured airway, below the operative area separated by sealed cuff of the microlaryngeal tube. CONCLUSIONS: For excision of benign luminal lesions of the lower trachea, the novel approach of PTEA has many distinct and fool proof advantages in comparison to the transoral laryngoscopic/bronchoscopic and the transcervical approaches. PMID- 28723309 TI - Moral distress as experienced by hospital social workers in South Korea and Australia. AB - This exploratory, qualitative research explored the ethical problems faced by hospital social workers in South Korea and Australia, and what and who influenced their decision making using a focus group design. Although dilemmas of boundaries, confidentiality, self-determination, and other complex scenarios found in practice were identified, moral distress, a consequence of the unresolvable conflicts, dominated participants' narratives. This was particularly the case for the Korean social workers in this sample. A thematic analysis of the data yielded three main themes: 'Under pressure-"It's very uncomfortable"'; 'Failing our patients'; and 'Coping and codes'. PMID- 28723307 TI - Nationwide comprehensive gastro-intestinal cancer cohorts: the 3P initiative. AB - BACKGROUND: The increasing sub-classification of cancer patients due to more detailed molecular classification of tumors, and limitations of current trial designs, require innovative research designs. We present the design, governance and current standing of three comprehensive nationwide cohorts including pancreatic, esophageal/gastric, and colorectal cancer patients (NCT02070146). Multidisciplinary collection of clinical data, tumor tissue, blood samples, and patient-reported outcome (PRO) measures with a nationwide coverage, provides the infrastructure for future and novel trial designs and facilitates research to improve outcomes of gastrointestinal cancer patients. MATERIAL AND METHODS: All patients aged >=18 years with pancreatic, esophageal/gastric or colorectal cancer are eligible. Patients provide informed consent for: (1) reuse of clinical data; (2) biobanking of primary tumor tissue; (3) collection of blood samples; (4) to be informed about relevant newly identified genomic aberrations; (5) collection of longitudinal PROs; and (6) to receive information on new interventional studies and possible participation in cohort multiple randomized controlled trials (cmRCT) in the future. RESULTS: In 2015, clinical data of 21,758 newly diagnosed patients were collected in the Netherlands Cancer Registry. Additional clinical data on the surgical procedures were registered in surgical audits for 13,845 patients. Within the first two years, tumor tissue and blood samples were obtained from 1507 patients; during this period, 1180 patients were included in the PRO registry. Response rate for PROs was 90%. The consent rate to receive information on new interventional studies and possible participation in cmRCTs in the future was >85%. The number of hospitals participating in the cohorts is steadily increasing. CONCLUSION: A comprehensive nationwide multidisciplinary gastrointestinal cancer cohort is feasible and surpasses the limitations of classical study designs. With this initiative, novel and innovative studies can be performed in an efficient, safe, and comprehensive setting. PMID- 28723310 TI - Sense of Belonging and Youth Suicidal Behaviors: What Do Communities and Schools Have to Do with It? AB - Situating Thomas Joiner's concept of belonging within an ecological perspective, this study examined the associations between school and community belonging and suicidal ideation and attempts among high school students. The study used data from the 2013 Texas Youth Risk Behavior Survey (N = 2,560). Results demonstrated that community belonging reduced the odds of youth suicidal behaviors. School bullying, feeling unsafe at school, and being threatened or injured at a school increased the odds of suicidal behaviors. Findings suggest that fostering safe and inclusive environments and strengthening youth's experiences of school and community belonging may reduce suicidal behaviors in high school youth. PMID- 28723311 TI - Visual Perceptual Learning and Models. AB - Visual perceptual learning through practice or training can significantly improve performance on visual tasks. Originally seen as a manifestation of plasticity in the primary visual cortex, perceptual learning is more readily understood as improvements in the function of brain networks that integrate processes, including sensory representations, decision, attention, and reward, and balance plasticity with system stability. This review considers the primary phenomena of perceptual learning, theories of perceptual learning, and perceptual learning's effect on signal and noise in visual processing and decision. Models, especially computational models, play a key role in behavioral and physiological investigations of the mechanisms of perceptual learning and for understanding, predicting, and optimizing human perceptual processes, learning, and performance. Performance improvements resulting from reweighting or readout of sensory inputs to decision provide a strong theoretical framework for interpreting perceptual learning and transfer that may prove useful in optimizing learning in real-world applications. PMID- 28723313 TI - Time for an International Consensus on Hypersensitivity Pneumonitis. A Call to Arms. PMID- 28723312 TI - Alcohol, marijuana, and opioid use disorders: 5-Year patterns and characteristics of emergency department encounters. AB - BACKGROUND: Changes in substance use patterns stemming from opioid misuse, ongoing drinking problems, and marijuana legalization may result in new populations of patients with substance use disorders (SUDs) using emergency department (ED) resources. This study examined ED admission trends in a large sample of patients with alcohol, marijuana, and opioid use disorders in an integrated health system. METHODS: In a retrospective design, electronic health record (EHR) data identified patients with >=1 of 3 common SUDs in 2010 (n = 17,574; alcohol, marijuana, or opioid use disorder) and patients without SUD (n = 17,574). Logistic regressions determined odds of ED use between patients with SUD versus controls (2010-2014); mixed-effect models examined 5-year differences in utilization; moderator models identified subsamples for which patients with SUD may have a greater impact on ED resources. RESULTS: Odds of ED use were higher at each time point (2010-2014) for patients with alcohol (odds ratio [OR] range: 5.31-2.13, Ps < .001), marijuana (OR range: 5.45-1.97, Ps < .001), and opioid (OR range: 7.63-4.19, Ps < .001) use disorders compared with controls; odds decreased over time (Ps < .001). Patients with opioid use disorder were at risk of high ED utilization; patients were 7.63 times more likely to have an ED visit in 2010 compared with controls and remained 5.00 (average) times more likely to use ED services. ED use increased at greater rates for patients with alcohol and opioid use disorders with medical comorbidities relative to controls (Ps < .045). CONCLUSIONS: ED use is frequent in patients with SUDs who have access to private insurance coverage and integrated medical services. ED settings provide important opportunities in health systems to identify patients with SUDs, particularly patients with opioid use disorder, to initiate treatment and facilitate ongoing care, which may be effective for reducing excess medical emergencies and ED encounters. PMID- 28723314 TI - You Want It Darker. PMID- 28723315 TI - Pneumonia and the Risk of Cardiovascular Death. Time to Change Our Strategy. PMID- 28723317 TI - Mortality and Cardiovascular Disease in Type 1 and Type 2 Diabetes. PMID- 28723316 TI - When green and red mycology meet: Impressions from an interdisciplinary forum on virulence mechanisms of phyto- and human-pathogenic fungi. AB - Fungal infections pose a constant threat to plants and humans, but detailed knowledge about pathogenesis, immunity, or virulence is rather scarce. Due to the fact that a certain overlap in the armoury of infection exists between plant- and human-pathogenic fungi, an interdisciplinary forum was held in October 2016 at the Institute for Clinical Microbiology, Immunology and Hygiene in Erlangen under the organisational umbrella from two special interest groups of German microbial societies. Scientific exchange and intense discussion of this timely topic was fostered by bringing together renowned experts in their respective fields to present their thoughts and recent findings in the course of a plenary lecture and six themed sessions, accompanied by oral and poster contributions of young researchers. By targeting the topic of fungal virulence mechanisms from various angles and in the context of plant and human hosts, some common grounds and exciting perspectives could be deduced during this vibrant scientific event. PMID- 28723318 TI - Incidence Trends of Type 1 and Type 2 Diabetes among Youths, 2002-2012. PMID- 28723319 TI - The Enduring Challenge of Advanced HIV Infection. PMID- 28723320 TI - Physician Payment Reform - Progress to Date. PMID- 28723321 TI - Subarachnoid Hemorrhage. PMID- 28723322 TI - Heat-Stable Oral Rotavirus Vaccine. PMID- 28723324 TI - Case 22-2017. A 21-Year-Old Woman with Fever, Headache, and Myalgias. PMID- 28723325 TI - Reanalysis of the Crystalloid versus Hydroxyethyl Starch Trial (CHEST). PMID- 28723326 TI - Increasing Lipolysis and Reducing Atherosclerosis. PMID- 28723327 TI - Artemisinin-Resistant Plasmodium falciparum in Africa. PMID- 28723328 TI - Artemisinin-Resistant Plasmodium falciparum in Africa. PMID- 28723329 TI - Managing Uncertainty - Harnessing the Power of Scenario Planning. PMID- 28723330 TI - Active Surveillance for Low-Risk Cancers - A Viable Solution to Overtreatment? PMID- 28723331 TI - Certain about Dying with Uncertainty. PMID- 28723332 TI - Preventing Fat Gain by Blocking Follicle-Stimulating Hormone. PMID- 28723334 TI - ANGPTL3 Inhibition in Homozygous Familial Hypercholesterolemia. PMID- 28723335 TI - Sickle Cell Disease. PMID- 28723336 TI - Sickle Cell Disease. PMID- 28723337 TI - Sickle Cell Disease. PMID- 28723338 TI - Sickle Cell Disease. PMID- 28723333 TI - Enhanced Prophylaxis plus Antiretroviral Therapy for Advanced HIV Infection in Africa. AB - BACKGROUND: In sub-Saharan Africa, among patients with advanced human immunodeficiency virus (HIV) infection, the rate of death from infection (including tuberculosis and cryptococcus) shortly after the initiation of antiretroviral therapy (ART) is approximately 10%. METHODS: In this factorial open-label trial conducted in Uganda, Zimbabwe, Malawi, and Kenya, we enrolled HIV-infected adults and children 5 years of age or older who had not received previous ART and were starting ART with a CD4+ count of fewer than 100 cells per cubic millimeter. They underwent simultaneous randomization to receive enhanced antimicrobial prophylaxis or standard prophylaxis, adjunctive raltegravir or no raltegravir, and supplementary food or no supplementary food. Here, we report on the effects of enhanced antimicrobial prophylaxis, which consisted of continuous trimethoprim-sulfamethoxazole plus at least 12 weeks of isoniazid-pyridoxine (coformulated with trimethoprim-sulfamethoxazole in a single fixed-dose combination tablet), 12 weeks of fluconazole, 5 days of azithromycin, and a single dose of albendazole, as compared with standard prophylaxis (trimethoprim sulfamethoxazole alone). The primary end point was 24-week mortality. RESULTS: A total of 1805 patients (1733 adults and 72 children or adolescents) underwent randomization to receive either enhanced prophylaxis (906 patients) or standard prophylaxis (899 patients) and were followed for 48 weeks (loss to follow-up, 3.1%). The median baseline CD4+ count was 37 cells per cubic millimeter, but 854 patients (47.3%) were asymptomatic or mildly symptomatic. In the Kaplan-Meier analysis at 24 weeks, the rate of death with enhanced prophylaxis was lower than that with standard prophylaxis (80 patients [8.9% vs. 108 [12.2%]; hazard ratio, 0.73; 95% confidence interval [CI], 0.55 to 0.98; P=0.03); 98 patients (11.0%) and 127 (14.4%), respectively, had died by 48 weeks (hazard ratio, 0.76; 95% CI, 0.58 to 0.99; P=0.04). Patients in the enhanced-prophylaxis group had significantly lower rates of tuberculosis (P=0.02), cryptococcal infection (P=0.01), oral or esophageal candidiasis (P=0.02), death of unknown cause (P=0.03), and new hospitalization (P=0.03). However, there was no significant between-group difference in the rate of severe bacterial infection (P=0.32). There were nonsignificantly lower rates of serious adverse events and grade 4 adverse events in the enhanced-prophylaxis group (P=0.08 and P=0.09, respectively). Rates of HIV viral suppression and adherence to ART were similar in the two groups. CONCLUSIONS: Among HIV-infected patients with advanced immunosuppression, enhanced antimicrobial prophylaxis combined with ART resulted in reduced rates of death at both 24 weeks and 48 weeks without compromising viral suppression or increasing toxic effects. (Funded by the Medical Research Council and others; REALITY Current Controlled Trials number, ISRCTN43622374 .). PMID- 28723339 TI - Bronchoscopic Removal of an Obstructing Broncholith. PMID- 28723340 TI - Severe Plantar Warts in an Immunocompromised Patient. PMID- 28723341 TI - Quantitative changes of extravillous trophoblast cells in heavy smoker mothers compared with healthy controls. AB - Maternal smoking during pregnancy can induce structural and functional changes in the placenta. Placentas from heavy smoker (>20 cigarettes per day) mothers and non-smoker healthy controls (n=10 in each group) were enrolled in the present case-control study. Sample selection and sectioning were performed by systematic uniform random sampling (SURS). Selected sections were stained using Masson's trichrome to estimate quantitative parameters of placental extravillous trophoblast cells (EVTs) and the number of EVTs. Differences between groups were evaluated using the Mann-Whitney U-test, with significance set at P<0.05. There was a significant difference in placental weight and the total volume of the placenta between the heavy smoker and control groups (P<0.05). The total volume of EVTs, nucleus diameter, cytoplasm diameter, the volume of the nucleus and cytoplasm and the nucleus to cytoplasm ratio of EVTs were significantly greater in the heavy smoker compared with control group (P<0.05 for all). In placentas from heavy smokers, the total number of EVTs per unit volume of placental bed were significantly greater than in the control group (P<0.05 for both). In conclusion, the findings suggest that maternal smoking could affect fetal health by changing the quantitative parameters of the placenta, and likely the invasive properties of EVTs. PMID- 28723342 TI - Molecular Analysis of Circulating Cell-Free DNA from Lung Cancer Patients in Routine Laboratory Practice: A Cross-Platform Comparison of Three Different Molecular Methods for Mutation Detection. AB - Circulating cell-free DNA (cfDNA), which is isolated from blood plasma, represents a noninvasive source for the detection of mutations conferring resistance against epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in non-small-cell lung cancer patients. In advanced disease stages, performing regular biopsies is often not possible because of the general health condition of the patients. Furthermore, a biopsy of a single tumor lesion or metastasis may not reflect the heterogeneous genotype of the tumor and its metastases. Plasma cfDNA represents an alternative material for molecular monitoring of patients under therapy. Herein, we present a cross-platform comparison of three different molecular methods [digital PCR, next-generation sequencing (NGS), and quantitative PCR] to detect clinically relevant mutations in cfDNA. We validated our workflow with commercially available cfDNA reference material (5.0%, 1.0%, and 0.1% mutation frequency, respectively). Digital PCR and NGS detect reliably 0.1% allele frequency of the EGFR p.T790M mutation. Furthermore, we analyzed 55 cfDNA preparations from patients with lung cancer to compare reliability and sensitivity of the three methods under routine conditions and achieved 96.0% concordance of p.T790M results. A limit of detection for mutation calling using digital PCR (>0.1%) and NGS (>0.2%) was established. In total, 62.5% of known primary EGFR mutations were successfully detected in cfDNA. In 56.0% of the patients with detectable EGFR primary mutations, we identified a resistance conferring the EGFR p.T790M mutation. PMID- 28723343 TI - beta-Catenin is involved in oleanolic acid-dependent promotion of proliferation in human hair matrix cells in an in vitro organ culture model. AB - Oleanolic acid (OA), a pentacyclic triterpenoid compound which can be found in >1600 plants, has been shown to promote hair growth. To study the mechanisms of OA on hair growth, we investigated hair follicle (HF) growth on four different concentration OA using human hair follicle organ culture model. We found that HFs treated with 1 or 10MUg/mL OA showed statistically enhanced elongation of the hair shaft and anagen-like stage. Moreover, higher positive rate of Ki-67, a matrix cellular marker of proliferation, was detected in the same groups treated with 1 or 10MUg/mL than those treated with vehicle. We further demonstrated that beta-catenin, a key Wnt signaling transducer, was highly expressed in the OA treated groups using immunofluorescence stain assay. These results suggest that OA may promote human hair growth by stimulating hair matrix cell proliferation through the Wnt/beta-catenin pathway. PMID- 28723344 TI - Social cognition impairments after aneurysmal subarachnoid haemorrhage: Associations with deficits in interpersonal behaviour, apathy, and impaired self awareness. AB - Behavioural disturbances are frequently found after aneurysmal subarachnoid haemorrhage (aSAH). Social cognition impairments have been suggested as a possible underlying mechanism for behavioural problems. Also, aSAH is likely to result in damage affecting frontal-subcortical circuits underlying social cognition. Therefore, we aimed to investigate social cognition after aSAH and its associations with behavioural problems (deficits in interpersonal behaviour, apathy, and impaired self-awareness) and focal as well as diffuse brain damage. 88 aSAH patients (in the subacute phase post-aSAH) and 60 age-, sex- and education-matched healthy controls participated. Tasks for emotion recognition, Theory of Mind (ToM), and empathy as well as questionnaires were used. Cortical infarctions in frontal and non-frontal areas on MRI, aneurysm circulation and aSAH-related events were taken into account. Compared to healthy controls, aSAH patients performed significantly worse on tasks for emotion recognition, ToM and empathy. Poor performance on ToM and emotion recognition was associated with proxy-ratings indicating impaired interpersonal behaviour and apathy and with indications of impaired self-awareness. No associations were found between deficits in social cognition and frontal or non-frontal cortical lesions on MRI. Also, aneurysm circulation and aSAH-related events such as hydrocephalus, vasospasm, and treatment method did not explain why and how social cognitive deficits did occur after aSAH. In conclusion, emotion recognition, ToM and empathy were clearly impaired in aSAH patients and these deficits were related to apathy and deficits in interpersonal behaviour as reported by proxies and to impaired self-awareness. This association strengthens the assumption of impaired social cognition as an underlying construct of behavioural problems after aSAH. Consequently, social cognition tests and proxy-ratings should be used in clinical practice, irrespective of lesion location on MRI or aneurysm circulation, to improve the detection and treatment of apathy and deficits in interpersonal behaviour after aSAH. PMID- 28723345 TI - alpha-Glucosidase immobilization on chitosan-enriched magnetic composites for enzyme inhibitors screening. AB - In the present study, the chitosan-enriched magnetic composites (MCCs) were prepared by a novel and simple embedding method for the immobilization of alpha glucosidase (alpha-Glu). The immobilized alpha-Glu could be easily separated from the reaction mixture under an external magnetic field owing to the magnetic support. With the MCCs-immobilized alpha-Glu, enzyme activity and stability were studied, and enzyme inhibitors were screened from traditional Chinese medicines (TCMs) and vegetables combined with capillary electrophoresis (CE). The MCCs immobilized alpha-Glu exhibited enhanced pH and temperature tolerance with unchanged optimum pH and temperature of 4.0 and 60 degrees C comparing with free alpha-Glu. Reusability of the immobilized alpha-Glu was significantly improved after immobilization, and it retained 62.2% of its initial activity after 10 repeated cycles. Immobilized alpha-Glu also showed improved storage stability (84.3+/-1.2% after 35days of storage at 4 degrees C). The kinetic parameter Km for immobilized alpha-Glu was calculated to be 0.81mM and the affinity of enzyme towards its substrate was reduced after immobilization. Finally, immobilized alpha-Glu was used to screen enzyme inhibitors from the extracts of TCMs and vegetables. The enhanced pH and temperature tolerance, improved reusability and storage stability of MCCs-immobilized alpha-Glu make it a promising candidate for biotechnological applications. PMID- 28723346 TI - Co-immobilization of Pd and Zn nanoparticles in chitosan/silica membranes for efficient, recyclable catalysts used in ullmann reaction. AB - In this study, an efficient heterogeneous catalyst including palladium (Pd) and zinc (Zn) nanoparticles supported on chitosan/silica (CS/SiO2) composite membrane is synthesized using partially etching of SiO2 technique. N2 sorption isotherm results shows that the prepared Pd-Zn@CS/SiO2 (1/1) porous membrane had a BET surface area of 26.50m2/g. High-resolution transmission electron microscopy (HR TEM) and X-ray photoelectron spectroscopy (XPS), characterization of the catalyst shows that the Pd0 nanoparticles (below 5nm), and Zn0 aggregates (about 10-15nm) dispersed well in the CS/SiO2 matrix. Zinc crystal was also detected by X-ray diffraction study and HR-TEM observation. The prepared Pd-Zn@CS/SiO2 membrane catalyst is highly active for Ullmann reductive homocoupling reactions of aryl iodides and aryl bromides, and can be recycled 5 times without significant loss of activities. This work supplies a successful approach to realize Pd catalysts and Zn reducing reagent co-immobilized in the same carrier material with excellent catalytic performances. PMID- 28723347 TI - Heart rate variability is enhanced by long-lasting pleasant touch at CT-optimized velocity. AB - INTRODUCTION: The present study explores whether long-lasting pleasant touch has positive effects on the stress response, reward sensitivity, mood, and interoceptive awareness. METHODS: 40 participants received either 35min of brush stroking targeting C-tactile fibres (CT) or vibration on the forearm, and rated pleasantness and intensity. Prior and after, stress response (cortisol and heart rate variability), reward sensitivity, mood and interoceptive awareness were measured. RESULTS: Pleasantness decreased over time for both groups, with brush stroking being perceived as more pleasant and intense than vibration. Heart rate variability (SDNN) increased for brush stroking only, and was related to the higher pleasantness and intensity. No significant effect of CT-optimal touch was observed on any of the other measures. DISCUSSION: The beneficial effect of pleasant touch on heart rate variability suggests a neuronal link between CT fibre stimulation and autonomic regulation, and highlights the potential of long lasting touch to improve the physiological response. PMID- 28723348 TI - Central serotonin attenuates LPS-induced systemic inflammation. AB - Serotonin (5-HT) is a neuromodulator involved in several central-mediated mechanisms, such as endocrine processes, behavior, and sleep. Dysfunction of the serotonergic system is mainly linked to psychiatric disorders, but emerging evidence suggests that immune system activation may also alter brain 5-HT signaling. However, whether central 5-HT modulates systemic inflammation (SI) remains unknown. For this purpose, male Wistar rats (280-350g, 8-9weeks) were submitted to the experimental protocols beginning between 9 and 10AM with the performance of injections. The animals were housed at controlled conditions [temperature (25+/-1 degrees C), light (06:00-18:00) and humidity (60-65%)]. Thus, we measured 5-HT and its metabolite 5-hydroxyindole-3-acetic acid (5-HIAA) in the anteroventral preoptic region [(AVPO) - the hierarchically most important region for body temperature (Tb) control] during lipopolysaccharide (LPS)-induced SI. We also combined LPS (100MUg/kg) treatment with intracerebroventricular (icv) injection of 5-HT (5, 10 and 40MUg/MUL) and measured Tb ("hallmark" of SI), AVPO prostaglandin E2 [(PGE2) - an essential mediator of fever] and prostaglandin D2 [(PGD2) - a cryogenic mediator], plasma corticosterone [(CORT) - a stress marker with an endogenous anti-inflammatory effect] and interleukin-6 [(IL-6) - an immune mediator] levels. Detection limits of PGE2, PGD2, CORT and IL-6 assays were 39.1-2500pg/mL, 19.5-2500pg/mL, 0.12-2000MUg/dL, and 0.125-8ng/mL, respectively. We also assessed tail skin temperature [used to calculate heat loss index (HLI)] to assess a key thermoeffector mechanism. As expected we observed LPS-induced increases in Tb, AVPO PGE2 (whereas PGD2 remained unchanged), plasma CORT and IL-6 levels, as well as a decrease in HLI. These changes were accompanied by reduced levels of AVPO 5-HT and 5-HIAA. Furthermore, we also observed a negative correlation between 5-HT and plasma CORT levels. Moreover, icv 5-HT (5, 10 and 40MUg/MUL) microinjection caused a U-shaped dose-response curve in LPS fever, in which the intermediate dose reduced the febrile response. Icv 5-HT (10MUg/MUL) microinjection prevented the LPS-induced increases in AVPO PGE2 (whereas not altering PGD2), plasma CORT and IL-6 levels, as well as preventing reduced HLI. Our data are consistent with the notion that AVPO 5-HT synthesis is down-regulated during SI, favoring AVPO PGE2 synthesis and consequently potentiating the immune response. These results reveal a novel effect of central 5-HT as an anti-inflammatory neuromodulator that may take place during psychiatric disorder treatment with 5-HT reuptake inhibitors as well as suggesting that 5-HT modulation per se is a potential therapeutic approach for inflammatory diseases. PMID- 28723349 TI - There Are Cooler Ways to Die Than Smoking: Urologists of the World, Unite Against This Health Care Tragedy. PMID- 28723350 TI - Smoking and Bladder Cancer: A Systematic Review of Risk and Outcomes. AB - CONTEXT: Cigarette smoking is an established risk factor for urothelial carcinoma. OBJECTIVE: To elucidate the association between pretreatment smoking status, cumulative exposure, and time since smoking cessation and the development of and outcomes for urothelial carcinoma of the bladder (UCB) in patients treated with transurethral resection of the bladder (TURBT) or radical cystectomy (RC). EVIDENCE ACQUISITION: A literature search was performed in September 2014 using the PubMed and Scopus databases limited to articles published in English since 1990. Eight contemporary studies on smoking and UBC development and 26 studies on smoking and UBC prognosis met the inclusion criteria. EVIDENCE SYNTHESIS: Current cigarette smoking increases the risk of UCB incidence by two to fourfold, while smoking cessation attenuates this risk. Smoking status, exposure, and cessation have an evident impact on disease recurrence for patients who undergo TURBT, with weaker associations between smoking and other endpoints for TURBT and RC patients. CONCLUSION: Retrospective evidence suggests that smoking markedly increases UCB risk and may lead to unfavorable outcomes for patients who already have UCB; smoking cessation can attenuate these undesirable effects. PATIENT SUMMARY: Current evidence proves that cigarette smoking is an established risk factor for the development of urothelial carcinoma of the bladder (UCB). There is a growing body of evidence that smoking negatively affects outcomes for UCB patients treated with transurethral resection and/or radical cystectomy, although not uniformly. Long-term smoking cessation seems to mitigate the detrimental effects of smoking in non-muscle-invasive and muscle-invasive bladder cancer. PMID- 28723351 TI - Smoking and Prostate Cancer: A Systematic Review. AB - CONTEXT: Cigarette smoking is the leading cause of death from cancer, although the relationship between smoking and prostate cancer (PCa) is controversial. OBJECTIVE: To evaluate the available evidence of the role of cigarette smoking and PCa development and progression and to discuss possible clinical implications for PCa management. EVIDENCE ACQUISITION: A PubMed search for relevant articles published between 2004 and September 2014 was performed by combining the following PICO (patient population, intervention, comparison, outcome) terms: male, smoking, prostate, prostate cancer, prevention, diagnosis, treatment, and prognosis. Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines were followed. EVIDENCE SYNTHESIS: The association between cigarette smoking and PCa incidence is controversial, particularly in recent series. Current cigarette smoking is associated with an increased risk of PCa death, and the number of cigarettes smoked per day had a dose-response association with PCa mortality. Smokers present a higher risk of biochemical or distant failure after PCa treatment. Several biological mechanisms behind these associations have been proposed, although the molecular mechanisms remain unclear. Further research is required to better understand the role of smoking on PCa development and progression and, particularly, to evaluate the possible effect of smoking cessation on PCa management. CONCLUSIONS: Data from the peer-reviewed literature suggested an association of smoking and aggressive PCa. Although the pathophysiology underlying this association remains unclear, smokers presented higher PCa mortality and worse outcome after treatment. Smoking-cessation counseling should be implemented for patients with PCa, although its effect on PCa progression should be investigated. PATIENT SUMMARY: We looked at the association between smoking and prostate cancer (PCa). Smokers have a higher risk of PCa mortality and worse outcomes after treatment. Smoking cessation should be encouraged in men with or at risk of having PCa. PMID- 28723352 TI - Global and Regional Patterns of Tobacco Smoking and Tobacco Control Policies. AB - CONTEXT: Tobacco smoking is a major worldwide cause of morbidity and mortality from various diseases, including urologic diseases. OBJECTIVE: We reviewed, at global and regional levels, the prevalence and trends of tobacco smoking and legislative and regulatory efforts around tobacco control. We also provided information about electronic cigarette (e-cigarette) use. EVIDENCE ACQUISITION: We used several sources to present the most up-to-date information from national surveys, including the Global Adult Tobacco Survey, the Global Tobacco Control Report, and the Global Youth Tobacco Survey. EVIDENCE SYNTHESIS: Smoking prevalence has been decreasing globally, although trends in smoking vary substantially across countries and by gender. Among men, smoking prevalence in most high-income countries started to decrease in the mid-1990s, followed after a few decades by generally smaller decreases in some low- and middle-income countries (LMICs). However, there has been no change, or there has even been an increase, in smoking prevalence in many other LMICs. Countries with the highest male smoking prevalence are located in East Asia, Southeast Asia, and Eastern Europe. Similar to men, smoking prevalence for women has been decreasing in most high-income countries and some LMICs, although the decrease began later and was slower than that for men. Except in a few countries, smoking is much less common for women than for men. Most countries with the highest smoking prevalence in women are in Europe. Countries that have implemented the best practices for tobacco control, including monitoring, smoke-free policies, cessation programs, health warnings, advertising bans, and taxation, have been able to reduce smoking rates and related harms. E-cigarette use has rapidly increased since its introduction to the market. CONCLUSIONS: Health care providers should advise smoking patients about quitting smoking. Countries must improve the implementation and enforcement of tobacco control policies. Particular attention should be paid to preventing an increase in smoking among women in LMICs. PATIENT SUMMARY: We reviewed smoking prevalence and tobacco control policies in various regions. Countries with more effective tobacco control programs have seen higher reductions in smoking prevalence and, consequently, in smoking-related mortality. Because both longer duration and higher intensity of smoking (amount of tobacco smoked per day) are associated with an increased risk of tobacco-related diseases, smokers should quit smoking as soon as possible. PMID- 28723353 TI - The Link Between Cigarette Smoking and Erectile Dysfunction: A Systematic Review. AB - CONTEXT: Cigarette smoking is an established risk factor for erectile dysfunction (ED). To what extent smoking affects erectile function, however, remains debated. OBJECTIVE: To integrate the available evidence regarding the impact of smoking status and smoking exposure on prevalence, severity, and progression in patients with ED. EVIDENCE ACQUISITION: A systematic search of the literature was conducted using the Medline, Embase, and Scopus databases limited to articles published in English between January 1998 and October 2014. We selected 13 articles according to predefined inclusion criteria and the Preferred Reporting Items for Systematic Reviews and Meta-analysis. EVIDENCE SYNTHESIS: Most of the studies demonstrated an association between smoking and ED. Evidence was also found supporting the beneficial effect of smoking cessation on the restoration of erectile function. We noted marked heterogeneity in patient populations and smoking categorizations across studies, precluding conduct of a meta-analysis. Considerable evidence exists to support the hypothesis/theory that smoking related ED is mainly associated with endothelial impairment, reduction in nitric oxide availability, and imbalance between oxidative and antioxidative reactions increasing oxidative stress. Passive secondhand cigarette smoking, especially with a long-term exposure, can also have a negative impact on erectile function. CONCLUSIONS: Smoking is strongly associated with ED. Endothelial dysfunction together with increased oxidative stress represent major pathophysiologic mechanisms, and smoking cessation may mitigate this effect. PATIENT SUMMARY: Current smoking is significantly associated with erectile dysfunction, and smoking cessation has a beneficial effect on the restoration of erectile function. PMID- 28723354 TI - Tobacco Cessation: A Guide for Clinicians. AB - Smoking behavior is a complex phenomenon that entails innumerable variables. Successful treatment interventions must be based on a comprehensive diagnosis and must consider the whole spectrum of factors influencing smoking behavior and nicotine dependence. PMID- 28723355 TI - We Should Screen Smokers for Bladder and Kidney Cancer. AB - This commentary defends the rationale for screening smokers for bladder and kidney cancer. Some important questions on the use of screening in these malignancies need to be answered. PMID- 28723356 TI - Smoking Status Is Not Sufficient to Accurately Target Patients Who Would Benefit from Screening for Bladder and Kidney Cancer. AB - Until tests become available, smoking avoidance and smoking cessation are the two most critical and realistic policies to promote nonsmoking in 2014. Preventing bladder cancer and renal cell carcinoma is certainly the most important approach to reduce their incidences and patient mortality. PMID- 28723358 TI - Inflammation: A Significant Contributor to Upper-tract Urothelial Carcinoma Prognosis? PMID- 28723357 TI - Impact of Combined Use of Blood-based Inflammatory Markers on Patients with Upper Tract Urothelial Carcinoma Following Radical Nephroureterectomy: Proposal of a Cumulative Marker Score as a Novel Predictive Tool for Prognosis. AB - BACKGROUND: Previous studies showed the prognostic impact of preoperative levels of neutrophil-to-lymphocyte ratio (NLR), plasma fibrinogen, and serum C-reactive protein (CRP) in surgically treated upper tract urothelial carcinoma; however, few papers have discussed the proper use of these indices. OBJECTIVE: To investigate whether combinations of these three markers, as a cumulative marker score (CMS), improve the accuracy of prognostic models following radical nephroureterectomy (RNU). DESIGN, SETTING, AND PARTICIPANTS: A total of 394 patients from multiple institutions were included. Median follow-up was 30 mo. INTERVENTION: All patients underwent RNU without neoadjuvant chemotherapy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Associated outcomes were assessed using multivariate analysis. The CMS was defined as the number of elevated levels of preoperative NLR, plasma fibrinogen, and serum CRP. RESULTS AND LIMITATIONS: Multivariate analyses revealed that an increasing CMS was independently associated with high rates of disease recurrence, cancer-specific mortality, and all-cause mortality following RNU. Addition of the CMS to a model that included standard clinicopathologic predictors significantly improved predictive accuracy by 2.7% for disease recurrence, 3.9% for cancer-specific mortality, and 4.0% for all-cause mortality, which were the highest among other prognostic models using each marker alone or combinations of two. The study is limited by its retrospective nature. CONCLUSIONS: Although the use of each inflammatory marker alone may be as predictive as clinicopathologic indices for prognosis, combinations like CMS can provide more accurate prognostic models following RNU. PATIENT SUMMARY: Elevation of blood-based inflammatory markers may be useful for predicting prognosis because of their low cost and accessibility. Among blood based indices, we examined the efficacy of preoperative neutrophil-to-lymphocyte ratio, plasma fibrinogen, and serum C-reactive protein levels. Although use of each marker alone provides additional prognostic information, the combination of all three markers would be more predictive than any single marker or combinations of two. PMID- 28723359 TI - Minimally Invasive Partial Nephrectomy Versus Laparoscopic Cryoablation for Patients Newly Diagnosed with a Single Small Renal Mass. AB - BACKGROUND: Minimally invasive partial nephrectomy (MIPN) and laparoscopic renal cryoablation (LRC) are two treatment options increasingly used for small renal masses. OBJECTIVE: To compare perioperative, oncologic, and functional outcomes after MIPN and LRC. DESIGN, SETTING, AND PARTICIPANTS: We included 372 consecutive patients newly diagnosed with a single small renal mass and treated with either MIPN or LRC at a single institution. INTERVENTION: MIPN and LRC. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Regression models were used to evaluate the impact of surgical treatment (MIPN vs LRC) on perioperative, oncologic, and functional outcomes. RESULTS AND LIMITATIONS: Overall, 206 patients (55%) underwent MIPN and 166 (45%) were treated with LRC. In multivariate analysis, the rate of postoperative complications was significantly lower in the MIPN compared to the LRC group (20% vs 28%; adjusted difference 11%; p=0.02) after adjusting for age at surgery, American Society of Anesthesiologists score (1 vs 2 vs 3), and tumor size. The median follow-up was similar in the two groups (43 and 39 mo for MIPN and LRC, respectively). In univariate Cox regression analysis, treatment type was not significantly associated with disease-free survival (hazard ratio 1.06, 95% confidence interval [CI] 0.45-2.52; p=0.9). The disease-free survival rate at 5 yr was 92% in MIPN and 93% in LRC patients. In multivariate linear regression analysis, LRC was significantly associated with a higher estimated glomerular filtration rate (eGFR) at 6 mo compared to MIPN (coefficient 4.68, 95% CI 0.06-9.30; p=0.047) after adjusting for age at surgery, tumor size, and preoperative eGFR. There was no significant association between surgical treatment and postoperative eGFR at 3 yr after surgery (coefficient -2.36, 95% CI -7.55 to 2.83; p=0.4). Limitations include the retrospective study design and selection bias. CONCLUSIONS: MIPN and LRC provided similar cancer control and comparable renal function at intermediate term follow-up. Both surgical techniques emerged as viable treatment options for patient newly diagnosed with a single small renal mass. Further multi institutional studies with longer follow-up and nephrometry scores are needed to corroborate our findings. PATIENT SUMMARY: In patients newly diagnosed with a single small renal mass, minimally invasive partial nephrectomy and laparoscopic renal cryoablation provided similar cancer control and comparable renal function at intermediate-term follow-up. PMID- 28723360 TI - Maximally Invasive Ablation Versus Minimally Invasive Partial Nephrectomy. PMID- 28723362 TI - A Comparative Analysis of the Influence of Gender, Pathway Delays, and Risk Factor Exposures on the Long-term Outcomes of Bladder Cancer. AB - BACKGROUND: The relationship between pathway delays and bladder cancer-specific survival is complex because of the influence of tumour- and patient-specific factors. OBJECTIVE: To investigate the influence of tumour factors, patient factors, carcinogen exposure, and pathway delays on the long-term outcome of urothelial bladder cancer (UBC). DESIGN, SETTING, AND PARTICIPANTS: A cohort of 1537 UBC patients were enrolled between January 1, 1991 and June 30, 1992 and followed up for 17.7 yr. The period from the onset of symptoms to first treatment (transurethral resection of bladder tumour, TURBT) was divided into three components of potential delay. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Associations between patient factors, tumour factors, and delay times were analysed using the Pearson chi2 test and the Mann-Whitney U test. Survival was calculated from date of TURBT to date of death or censor date (December 31, 2010). Competing risks of death were assessed with the cumulative incidence function (CIF); CIF comparisons were performed using the Gray test. RESULTS AND LIMITATIONS: At censor, reliable data were available for 1478 patients, of whom 75% had died. Females presented more commonly with muscle-invasive bladder cancer (MIBC; 30% vs 26%) and less frequently with pT1 disease (18% vs 24%; p=0.06) and had a longer total delay time (median 120 d vs 106 d, p=0.02), and those with MIBC had a significantly higher cumulative incidence of death due to UBC (80% vs 67% at 17 yr; p<0.02). Cox regression identified age, smoking status, and tumour stage, grade, and size as the most significant determinants of poor outcome. We did not capture downstream delays associated with cystectomy or radiotherapy. CONCLUSIONS: Female UBC patients present later than males, and our data suggest that delay in referral may be contributory. The relationship between gender, outcomes, delays, and UBC aetiology is complex. PATIENT SUMMARY: We followed a large group of bladder cancer patients for more than 17 yr. The relationship between pathway delays and survival is complex. However, female patients present later than male patients, and our data suggest that delay in referral from general practice may be contributory. PMID- 28723361 TI - Prognostic Model for Predicting Survival in Patients with Disease Recurrence Following Radical Cystectomy. AB - BACKGROUND: Although the natural history of urothelial carcinoma of the bladder (UCB) from radical cystectomy (RC) to disease recurrence (DR) has been investigated intensively, the course of patients who have experienced DR after RC for UCB remains poorly understood. OBJECTIVE: To evaluate the prognostic value of the Bajorin criteria that consists of two risk factors: Karnofsky performance status (KPS) and the presence of visceral metastases (VMs) in patients with DR after RC for UCB. Furthermore, to identify additional factors associated with cancer-specific mortality (CSM) and thus build a multivariable model to predict survival after DR. DESIGN, SETTING, AND PARTICIPANTS: We identified 967 patients with UCB who underwent RC at 17 centers between 1979 and 2012 and experienced DR. Of these, 372 patients had complete data we used for analysis. OUTCOMES MEASUREMENTS AND STATISTICAL ANALYSIS: Univariable Cox regressions analysis was performed. We used a forward stepwise selection process for our final multivariable model. RESULTS AND LIMITATIONS: Within a median follow-up of 18 mo, 266 patients died of disease. Cancer-specific survival at 1 yr was 79%, 76%, and 47% for patients with no (n=105), one (n=180), and two (n=87) risk factors (p<0.001; c-index: 0.604). On multivariable analyses, we found that KPS <80%, higher American Society of Anesthesiologists score, anemia, leukocytosis, and shorter time to DR (all p values <0.034) were independently associated with increased CSM. The combination of time to DR and KPS resulted in improved discrimination (c-index: 0.694). CONCLUSIONS: We confirmed the prognostic value of KPS and VMs in patients with DR following RC for UCB. We also found several other clinical variables to be associated with worse CSM. We developed a model for predicting survival after DR inclusive of time to DR and KPS assessed at DR. If validated, this model could help clinical trial design. PATIENT SUMMARY: We developed a model to predict survival following disease recurrence after radical cystectomy for urothelial carcinoma of the bladder, based on time to disease recurrence and Karnofsky performance status. PMID- 28723363 TI - Case Presentation: A Man with Two Synchronous and Symptomatic Malignancies Related to Smoking. PMID- 28723364 TI - Case Discussion: A Man with Two Synchronous and Symptomatic Malignancies Related to Smoking: The Case for Primary Chemotherapy. PMID- 28723365 TI - Case Discussion: A Man with Two Synchronous and Symptomatic Malignancies Related to Smoking: The Case for Surgery. PMID- 28723366 TI - The Cancer Genome Atlas Project on Muscle-invasive Bladder Cancer. AB - The Cancer Genome Atlas project in bladder cancer reported the integrated genomic analysis of the first 131 patients in 2014. This muscle-invasive cohort was found to have one of the highest somatic mutation rates. The analysis working group will reconvene in early 2015 to begin the final analysis. PMID- 28723367 TI - Urinary Incontinence: Moving the Field Forward. PMID- 28723368 TI - Definition of Success after Surgery for Female Stress Incontinence or Voiding Dysfunction: An Attempt at Standardization. AB - CONTEXT: There is currently no standardized definition of success for surgery for stress urinary incontinence (SUI) and voiding dysfunction (VD) in women. OBJECTIVE: To review the use of outcome measures (OMs) and definitions of success in the literature on SUI and VD surgery in women in an attempt to provide recommendations for future publications. EVIDENCE ACQUISITION: A PubMed search of all English language full-text articles on SUI and VD surgery in women published between 2010 and 2015 was performed. A list of randomized trials and prospective and retrospective studies was obtained. Specific objective and subjective OMs used to define success were reviewed. EVIDENCE SYNTHESIS: Some 95 articles met the inclusion criteria for SUI surgery outcomes. Most trials reported outcomes at 12 mo after surgery. The majority (n=48) reported their primary outcomes using both objective and subjective success measures, 24 defined success using subjective OMs alone, and 23 using objective OMs alone. The OMs most frequently used for objective success were a negative cough stress test (CST), a negative pad test, and the absence of retreatment for SUI. The definition of subjective success most often involved questionnaires. The questionnaires most frequently used were Patient Global Impression of Improvement (PGI-I), Urinary Distress Inventory (UDI)/UDI-6, International Consultation on Incontinence Questionnaire Short Form (ICIQ-SF) and Medical Epidemiologic and Social Aspects of Aging (MESA). Only 11 studies on OMs used for VD surgery were published between 2010 and 2015. The two most common criteria used for success were measurement of postvoid residual urine (PVR) and subjective resolution of VD symptoms. CONCLUSIONS: There is great heterogeneity in the definition of success used after surgery for SUI or VD in women. For SUI surgery, we recommend use of the CST and a 1-h pad test for the definition of objective success, and of the UDI/UDI-6, Incontinence Impact Questionnaire (IIQ), King's Health Questionnaire (KHQ), ICIQ SF, or PGI-I questionnaire for subjective success. For VD surgery, cure should include measurement of PVR and self-reported resolution of VD symptoms. PATIENT SUMMARY: We looked at the definition of success used for surgery for stress urinary incontinence (SUI) and voiding dysfunction (VD) in women. We found that there is great heterogeneity among studies, making study comparison extremely difficult. According to the outcome measures used most frequently, we make recommendations regarding the definition of cure for SUI and VD in women to be used in future publications. PMID- 28723369 TI - Evaluation and Classification of Stress Urinary Incontinence: Current Concepts and Future Directions. AB - CONTEXT: Stress urinary incontinence (SUI) is a common and bothersome problem that frequently requires operative management. Over the past two decades, novel techniques have been introduced into clinical practice. With the greater variety of surgical options now available, there is an increasing focus on selecting the appropriate procedure for the individual patient based on the likely underlying pathophysiologic mechanism. OBJECTIVE: To review the methods used in the evaluation of SUI and the proposed classification systems. EVIDENCE ACQUISITION: A search of the PubMed database for the relevant search terms was conducted, and selected articles were retrieved and reviewed. EVIDENCE SYNTHESIS: Standardised terminology for the description of SUI has been produced by the International Continence Society describing the problem in terms of symptoms, clinical signs, and urodynamic observations. The two major pathophysiologic theories that have emerged over the past 50 yr, urethral hypermobility and intrinsic sphincteric deficiency, have influenced the development and adoption of surgical techniques. It is now recognised that these two entities are not dichotomous but often coexist. The primary aim of the evaluation of the patient presenting with SUI is to confirm the diagnosis and assess symptom severity before instituting conservative treatments. Secondary evaluation consists of more sophisticated techniques that assess anatomy of the bladder neck and urethra under rest and stress (eg, videourodynamics, ultrasound) or direct or indirect physiologic measures of the integrity of the sphincter mechanism. CONCLUSIONS: Classification of patients with SUI into distinct groups based on probable pathophysiologic mechanism could help guide the choice of surgical procedure, but current systems are likely too simplistic, and methods of assessment lack standardisation in techniques and sensitivity. PATIENT SUMMARY: Urinary leakage on exertion, termed stress incontinence, is a common problem that affects many women. There is a need to develop better ways of categorising the underlying causes of leakage to ensure that patients receive the optimal treatments. PMID- 28723370 TI - Evaluation and Management of Postprostatectomy Incontinence: A Systematic Review of Current Literature. AB - CONTEXT: Radical prostatectomy is the most common reason for male stress urinary incontinence. There is still uncertainty about its diagnostic and therapeutic management. OBJECTIVE: To evaluate current evidence regarding the diagnosis and therapy of postprostatectomy incontinence (PPI). EVIDENCE ACQUISITION: A systematic review of the literature was performed in October 2015 using the Medline database. EVIDENCE SYNTHESIS: Diagnosis and conservative treatment of PPI are currently mostly based on expert opinions. Pelvic floor muscle training is the noninvasive treatment of choice of PPI. For invasive management of moderate to severe PPI, the artificial urinary sphincter is still the treatment of choice, but an increasing number of adjustable and nonadjustable, noncompressive as well as compressive devices are used more frequently. However, no randomized controlled trial has yet investigated the outcome of one specific surgical treatment or compared the outcome of different surgical treatment options. CONCLUSIONS: The level of evidence addressing the surgical management of PPI is still unsatisfactory. Further research is urgently needed. PATIENT SUMMARY: Incontinence after the removal of the prostate (postprostatectomy incontinence) is the most common cause of male stress urinary incontinence. First-line therapy is physiotherapy and lifestyle changes. If no satisfactory improvement is obtained, various surgical treatment options are available. The most commonly used is the artificial urinary sphincter, but other treatment options like male slings are also available. PMID- 28723371 TI - Complications of Transvaginal Mesh for Pelvic Organ Prolapse and Stress Urinary Incontinence: Tips for Prevention, Recognition, and Management. AB - CONTEXT: Mesh-related complications following transvaginal management of pelvic organ prolapse (POP) and/or stress urinary incontinence (SUI) have received significant attention in the last decade. OBJECTIVE: We sought to identify patient, product, and technical factors associated with an increased risk of complications after mesh-based transvaginal repair of anterior POP and SUI. In this review we clarify the different pattern of complications after POP and SUI repairs. Our aim is to provide a practical evidence-based guide for physicians to prevent and, if necessary, manage product-associated complications in a stepwise manner. EVIDENCE ACQUISITION: We conducted a comprehensive PubMed search of all English-language articles published from 2010 to June 2016, using these search terms: mesh, pelvic organ prolapse, and stress urinary incontinence. Expert opinion is also provided. EVIDENCE SYNTHESIS: Mesh-related complications are much lower after repair of SUI compared with POP, despite its more frequent use. Vaginal exposure is the most common mesh-specific complication. Patients may present with vaginal discharge, dyspareunia, pain, recurrent urinary tract infection, and/or hematuria. Conversely, patients may be asymptomatic. Small asymptomatic mesh exposures (<0.5cm) may be treated conservatively. Larger exposures will require partial, if not complete, excision with reconstruction. Any mesh encountered within the urinary tract must be fully excised. Following excision, pain may persist in up to 50% of patients. CONCLUSIONS: Vaginal extrusion, persistent pain, and urethral and/or bladder erosion are the three most common product-specific complications following mesh-based repair for SUI or POP. Conservative therapies may be attempted, but most patients ultimately require partial or complete mesh excision. PATIENT SUMMARY: We reviewed the recent literature on mesh-related complications after repair of pelvic organ prolapse (POP) and stress urinary incontinence (SUI). Vaginal exposure, persistent pain, and erosion into the urinary tract are the most common. These often require surgical management, best suited to a urologist with training and experience in this area. Evidence supports mesh use for correction of SUI, whereas the indication for POP repair remains controversial. PMID- 28723372 TI - How to Deal with Pain Following a Vaginal Mesh Insertion. AB - Pain as an isolated complication of vaginal mesh insertion is uncommon, and its pathophysiology not well understood. Management is complex and involves technically demanding surgical mesh removal. Results are reported as good in the majority of cases. PMID- 28723373 TI - Urodynamics Before Surgery for Stress Urinary Incontinence: The Urodynamic Examination Is Still One of the Best Friends of the Surgeon and of Patients with Stress Urinary Incontinence. AB - In the large majority of patients with stress urinary incontinence, urodynamics could provide new information, in comparison to simple clinical examination, and change subsequent management in a relevant percentage of cases. PMID- 28723374 TI - Urodynamics Before Surgery for Stress Urinary Incontinence. AB - Following three noninferiority randomised controlled trials from different countries showing exactly the same results, it is time to translate this evidence into practice. In women undergoing primary surgery for pure stress urinary incontinence or stress-predominant mixed urinary incontinence without voiding difficulties, careful office evaluation including uroflowmetry and postvoid residual urine can replace invasive investigations such as cystometry, saving patients from embarrassment and a risk of urinary infection. PMID- 28723375 TI - The Effects of Exercise on Fatigue, Quality of Life, and Psychological Function for Men with Prostate Cancer: Systematic Review and Meta-analyses. AB - CONTEXT: Conflicting data exists on the role of exercise interventions in patients with prostate cancer (PCa) regarding quality of life (QOL) endpoints. OBJECTIVE: To evaluate the effects of exercise interventions on fatigue, QOL, depression, and anxiety in PCa patients. EVIDENCE ACQUISITION: We searched seven major databases (MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Web of Science, and Scopus) for randomized control trials (RCTs) of supervised exercise interventions for men with PCa from database inception to October 2015. For meta-analyses, studies required standardized fatigue, QOL, or mood-related scales with standard-care control groups. The effect size was measured in terms of mean difference (MD) with 95% confidence interval (CI) for continuous outcomes using a random-effects model. Statistical heterogeneity between studies was assessed using the Cochrane Q test and I2 statistic. EVIDENCE SYNTHESIS: We selected 13 RCTs enrolling 1057 PCa patients (mean age 69.4+/-2.1 yr) undergoing exercise interventions, of which eight studies involving 675 patients qualified for meta-analyses. The study duration varied from 4 wk to 6 mo. A 12-16-wk exercise intervention significantly improved fatigue symptoms (MD 4.83, 95% CI 3.24-6.43; p<0.00001) as assessed according to the Functional Assessment of Cancer Therapy (FACT)-Fatigue scale. Fatigue remained improved at 6 mo (MD 3.60, 95% CI 2.80-5.12; p<0.00001). Furthermore, exercise interventions improved QOL measured using the FACT-General (MD 3.93, 95% CI 1.37-5.92; p = 0.003) and FACT-Prostate (MD 3.85, 95% CI 1.25 6.46; p=0.04) scales. The pooled data did not reveal a significant improvement in depression or anxiety. CONCLUSIONS: Combined evidence from RCTs shows improvement in QOL and fatigue according to FACT scales. No significant differences in depression or anxiety were observed. PATIENT SUMMARY: Exercise improves fatigue and quality-of-life outcomes in patients with prostate cancer. Further studies are necessary to identify patient-specific exercise regimens to optimize these benefits. PMID- 28723376 TI - Ureteral Involvement Is Associated with Poor Prognosis in Upper Urinary Tract Urothelial Carcinoma Patients Treated by Nephroureterectomy: A Multicenter Database Study. AB - BACKGROUND: The prognostic significance of tumor location for patients with upper urinary tract urothelial carcinoma (UUT-UC) has been disputed. Several papers have reported that ureteral cancer is associated with worse prognosis. OBJECTIVE: To investigate the prognostic significance of the presence of ureteral tumors in UUT-UC patients who underwent radical nephroureterectomy (RNU). DESIGN, SETTING, AND PARTICIPANTS: In this multicenter retrospective study, 1068 eligible patients (median follow-up: 40 mo [interquartile range: 17-77 mo]) were divided into three groups based on tumor location: renal pelvic, ureteral, and both-regional (having both renal pelvic and ureteral tumors). The ureteral and both-regional groups were subsequently integrated into the ureteral involvement group to evaluate its prognostic impact. INTERVENTION: All patients underwent RNU. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The prognostic impact of tumor location on survival was analyzed. RESULTS AND LIMITATIONS: The renal pelvic, ureteral, and both-regional groups consisted of 507 (47.5%), 430 (40.3%), and 131 (12.3%) patients, respectively. The ureteral and both-regional groups had a higher rate of lymphovascular invasion and lymph node metastasis compared with the renal pelvic group. The renal pelvic and both-regional tumors presented more frequently with locally advanced stages (pT3/T4) compared with the ureteral tumors. The 5-yr cancer-specific survival (CSS) and progression-free survival (PFS) rates of patients in the ureteral (70.5% and 66.7%, respectively) and both-regional groups (64.8% and 57.8%, respectively) were significantly worse than those in the renal pelvic group (81.9% and 78.1%, respectively). In a multivariate analysis, the presence of ureteral involvement was a significant prognostic factor for CSS (hazard ratio [HR]: 1.50; p=0.006) and PFS (HR: 1.35; p=0.023). This study is inherently limited by the biases associated with its retrospective and multicenter design. CONCLUSIONS: The presence of ureteral involvement had a significant impact on the survival of surgically treated UUT-UC patients associated with a poor prognosis. PATIENT SUMMARY: We demonstrated that the ureteral involvement was associated with poor survival compared with patients with renal pelvic tumor only in upper urinary tract urothelial patients treated by nephroureterectomy. PMID- 28723377 TI - External Validation of the MSKCC and IMDC Risk Models in Patients Treated with Targeted Therapy as a First-line and Subsequent Second-line Treatment: A Japanese Multi-institutional Study. AB - BACKGROUND: Two risk models, the Memorial Sloan Kettering Cancer Center (MSKCC) model and the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model, have been studied in metastatic renal cell carcinoma (mRCC) treated with targeted therapy. OBJECTIVE: To validate externally the predictive accuracies of the MSKCC and IMDC models for prognosis in mRCC patients treated with first-line and subsequent second-line targeted therapy. DESIGN, SETTING, AND PARTICIPANTS: A total of 311 patients were assessed retrospectively. INTERVENTION: All patients underwent targeted therapy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Survival outcomes were assessed using Kaplan-Meier analysis. The predictive ability was evaluated using the c-index. RESULTS AND LIMITATIONS: Regarding to the first-line targeted therapy, the 3-yr overall survival (OS) rates of the MSKCC (p<0.001) and IMDC models (p<0.001) were 76.2% and 77.3%, respectively, in the favorable-risk group; 46.7% and 47.9%, respectively, in the intermediate-risk group; and 13.4% and 15.6%, respectively, in the poor-risk group. The c-indexes were 0.68 for the MSKCC model and 0.69 for the IMDC model in a first-line setting. Regarding the second-line targeted therapy, the 1-yr OS rates of the MSKCC (p<0.001) and IMDC models (p<0.001) were 80.9% and 90.5%, respectively, in the favorable-risk group; 71.4% and 70.6%, respectively, in the intermediate-risk group; and 31.7% and 24.6%, respectively, in the poor-risk group. The c-indexes were 0.66 for the MSKCC model and 0.65 for the IMDC model in the second-line setting. The study is limited by its retrospective nature. CONCLUSIONS: The results may assist physicians in providing more appropriate patient counseling and imply the need for a future prognostic tool in mRCC treated with targeted therapy. PATIENT SUMMARY: Both risk models were useful for the risk stratification in metastatic renal cell carcinoma (mRCC) patients treated with first-line and second-line targeted therapy; however, it might be necessary to further update or optimize the models for our Japanese cohort of mRCC patients. PMID- 28723379 TI - Minilaparoendoscopic Single-site Pyeloplasty: The Best Compromise Between Surgeon's Ergonomy and Patient's Cosmesis (IDEAL Phase 2a). AB - BACKGROUND: Laparoendoscopic single-site (LESS) surgery and minilaparoscopy (ML) represent the evolution of laparoscopy for the treatment of urologic diseases. OBJECTIVE: To describe the technique and report the surgical outcomes of minilaparoendoscopic single-site dismembered pyeloplasty (MILESS-DP), a new technique overcoming the technical limitations of LESS and ML, and equally combining the advantages of both these surgical procedures. DESIGN, SETTING, AND PARTICIPANTS: Twenty consecutive patients underwent MILESS-DP for ureteropelvic junction obstruction. SURGICAL PROCEDURE: The SILS port was inserted through a transumbilical incision and two 3-mm trocars were inserted in the ipsilateral midclavicular line. The sequence of steps of MILESS-DP is comparable to standard laparoscopic dismembered pyeloplasty. MEASUREMENTS: The end points of this study were: (1) feasibility; (2) safety; (3) efficacy; and (4) cosmesis, evaluated using a body image questionnaire. RESULTS AND LIMITATIONS: All patients were symptomatic (100%) and three (15%) had concomitant kidney stones. (1) Feasibility: a conversion to either standard laparoscopic technique or open technique did not occur in any case. Median operative time was 147.3min (interquartile range [IQR]: 110-195min); (2) safety: no intraoperative complications were reported. Only in two patients (10%), a urinoma was postoperatively identified and conservatively treated with an ureteral stent. The median difference in post- and preoperative creatinine and haemoglobin was +0.55mg/dl and -0.76mg/dl (IQR: -0.20/-1.20mg/dl); (3) efficacy: the median postoperative hospital stay was 4.4 d (IQR: 4-9 d). The overall success rate was 95% at the follow-up; (4) cosmesis: all patients were enthusiastic with the appearance of the scars; the median body image score and the median cosmesis score were 19.95 (IQR 19-20) and 23.95 (IQR 23-24), respectively. The limitations of this study are the limited series and short follow-up. CONCLUSIONS: Our phase 2a studies demonstrate that MILESS-DP is a safe and reproducible procedure with excellent cosmetic outcomes and short-term clinical outcomes in the hands of a surgical team with experience in laparoscopy. PATIENT SUMMARY: Minilaparoscopy using 3-mm instruments and laparoendoscopic single-site using a single abdominal incision, still present several technical drawbacks which limit their reproducibility in urology. In order to overcome these technical limitations and equally combining the advantages of both these surgical procedures, we ideated a hybrid technique which we defined minilaparoendoscopic single-site. This study aims to demonstrate that minilaparoendoscopic single-site pyeloplasty is a safe and reproducible procedure with excellent cosmetic outcomes and short-term clinical outcomes in the hands of a surgical team with experience in mini invasive surgery. PMID- 28723378 TI - Dietary Antioxidants and Longitudinal Changes in Lower Urinary Tract Symptoms in Elderly Men: The Osteoporotic Fractures in Men Study. AB - BACKGROUND: Antioxidants can potentially alter the progression of lower urinary tract symptoms (LUTS) through anti-inflammatory mechanisms. OBJECTIVE: To determine if dietary antioxidants are associated with reduced likelihood of LUTS progression or increased likelihood of LUTS remission in untreated elderly men. DESIGN, SETTING, AND PARTICIPANTS: A prospective cohort study of 1670 US men aged 65-100 yr. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Baseline variables included the American Urological Association Symptom Index, dietary intake assessed via a 69-item Block food frequency questionnaire (FFQ), demographics, lifestyle characteristics, quality of life (SF-12), and medication use. LUTS was assessed at four time points over a mean +/- standard deviation period of 6.9+/ 0.4 yr. Group-based trajectory modeling was performed for men without prostate cancer who did not undergo LUTS treatment with medication or surgery during follow-up (n=1670). Analyses were stratified by LUTS symptoms at baseline. For men with mild baseline LUTS, we examined the likelihood of LUTS progression relative to LUTS stability. For men with moderate baseline LUTS, we analyzed the likelihood of both LUTS progression relative to LUTS stability and LUTS remission relative to progression. Odds ratios and 95% confidence intervals were estimated for quartiles of daily antioxidant intake using multivariable logistic regression. RESULTS AND LIMITATIONS: None of the dietary antioxidants (vitamin C, vitamin E, beta-carotene, alpha-carotene, beta-cryptoxanthin, lycopene, lutein/zeaxanthin) was associated with a lower probability of LUTS progression or LUTS remission. The study was limited by use of the brief Block FFQ, which contains only 69 food items and may have biased results toward the null hypothesis because of nondifferential misclassification. CONCLUSIONS: In this large cohort of US men, there were no significant associations between multiple dietary antioxidants and LUTS progression or remission over 7 yr. PATIENT SUMMARY: In a large cohort of elderly men, there were no significant longitudinal associations between multiple dietary antioxidants and lower urinary tract symptoms (LUTS). Our data suggest that dietary antioxidant consumption may not influence the natural history of LUTS in older men. PMID- 28723380 TI - Proteomic Pattern in Overactive Bladder Including Gender Aspects: A Case-control Study. AB - This is a clinical trial update without results. The aim of the trial is to identify a urinary proteomic pattern, including gender aspects, for patients with overactive bladder syndrome in comparison to healthy controls. PMID- 28723381 TI - Efficacy and Safety of OnabotulinumtoxinA in Patients with Urinary Incontinence Due to Neurogenic Detrusor Overactivity: Update of the Pivotal Randomised, Double blind, Placebo-controlled Trials. AB - Bladder injections of 200U onabotulinumtoxinA have similar efficacy in the treatment of urinary incontinence in patients with multiple sclerosis or spinal cord injury. The effect is maintained in the long term without significant adverse events. PMID- 28723382 TI - Case Presentation: Failure of a Midurethral Sling Procedure for Stress Urinary Incontinence in a Female Patient. AB - A clinical case of recurrent stress urinary incontinence after two subsequent synthetic midurethral tapes with protrusion into the urethra is presented. PMID- 28723383 TI - Clinical Case Discussion: Repeat Sling Surgery-Should We Offer a Second Sling? AB - Advantages of secondary sling surgery for persistent or recurrent stress urinary incontinence include low complexity and short operation time, low blood loss, and short hospitalization. Rates of perioperative complications, erosion, and postoperative voiding difficulties are comparable with primary sling surgery. The presence of urethral (hyper)mobility after primary midurethral sling seems to be an important factor affecting success rates of repeat sling surgery. PMID- 28723384 TI - Clinical Case Discussion: Failure of a Midurethral Sling Procedure for Stress Urinary Incontinence in a Female Patient. AB - The patient should have an autologous fascia sling as her next procedure because she has recurrent stress urinary incontinence after two prior transobturator synthetic slings, current urethral erosion, and intrinsic sphincter deficiency. PMID- 28723385 TI - Grey Zone: Urinary Incontinence. AB - Providing high-quality evidence in the field of urinary incontinence is difficult because the value of diagnostic tests must be evaluated through the filter of treatment outcome, and surgical treatments include an unavoidable amount of intrinsic variability. The scientific community should be commended for the gigantic effort made over the years to provide evidence upon which proper patient management can be based. PMID- 28723386 TI - Foam adsorption as an ex situ capture step for surfactants produced by fermentation. AB - In this report, a method for a simultaneous production and separation of a microbially synthesized rhamnolipid biosurfactant is presented. During the aerobic cultivation of flagella-free Pseudomonas putida EM383 in a 3.1L stirred tank reactor on glucose as a sole carbon source, rhamnolipids are produced and excreted into the fermentation liquid. Here, a strategy for biosurfactant capture from rhamnolipid enriched fermentation foam using hydrophobic-hydrophobic interaction was investigated. Five adsorbents were tested independently for the application of this capture technique and the best performing adsorbent was tested in a fermentation process. Cell-containing foam was allowed to flow out of the fermentor through the off-gas line and an adsorption packed bed. Foam was observed to collapse instantly, while the resultant liquid flow-through, which was largely devoid of the target biosurfactant, eluted towards the outlet channel of the packed bed column and was subsequently pumped back into the fermentor. After 48h of simultaneous fermentation and ex situ adsorption of rhamnolipids from the foam, 90% out of 5.5g of total rhamnolipids produced were found in ethanol eluate of the adsorbent material, indicating the suitability of this material for ex situ rhamnolipid capture from fermentation processes. PMID- 28723387 TI - Sigma 1 receptor activation modifies intracellular calcium exchange in the G93AhSOD1 ALS model. AB - Aberrations in intracellular calcium (Ca2+) have been well established within amyotrophic lateral sclerosis (ALS), a severe motor neuron disease. Intracellular Ca2+ concentration is controlled in part through the endoplasmic reticulum (ER) mitochondria Ca2+ cycle (ERMCC). The ER supplies Ca2+ to the mitochondria at close contacts between the two organelles, i.e. the mitochondria-associated ER membranes (MAMs). The Sigma 1 receptor (Sig1R) is enriched at MAMs, where it acts as an inter-organelle signaling modulator. However, its impact on intracellular Ca2+ at the cellular level remains to be thoroughly investigated. Here, we used cultured embryonic mice spinal neurons to investigate the influence of Sig1R activation on intracellular Ca2+ homeostasis in the presence of G93AhSOD1 (G93A), an established ALS-causing mutation. Sig1R expression was increased in G93A motor neurons relative to non-transgenic (nontg) controls. Furthermore, we demonstrated significantly reduced bradykinin-sensitive intracellular Ca2+ stores in G93A spinal neurons, which were normalized by the Sig1R agonist SA4503. Moreover, SA4503 accelerated cytosolic Ca2+ clearance following a) AMPAR activation by kainate and b) IP3R-mediated ER Ca2+ release following bradykinin stimulation in both genotypes. PRE-084 (another Sig1R agonist) did not exert any significant effects on cytosolic Ca2+. Both Sig1R expression and functionality were altered by the G93A mutation, indicating the centrality of Sig1R in ALS pathology. Here, we showed that intracellular Ca2+ shuttling can be manipulated by Sig1R activation, thus demonstrating the value of using the pharmacological manipulation of Sig1R to understand Ca2+ homeostasis. PMID- 28723388 TI - Region-specific impairments in parvalbumin interneurons in social isolation reared mice. AB - Many neuropsychiatric disorders show localized dysfunction in specific cortical regions. The mechanisms underlying such region-specific vulnerabilities are unknown. Post-mortem analyses have demonstrated a selective reduction in the expression of parvalbumin (PV) in GABAergic interneurons in the frontal rather than the sensory cortex of patients with neuropsychiatric disorders such as schizophrenia, autism spectrum disorders, and bipolar disorders. PV neurons are surrounded by perineuronal nets (PNNs), and are protected from oxidative stress. Previous studies have shown that the characteristics of PNNs are brain region specific. Therefore, we hypothesized that PV neurons and PNNs may be targeted in region-specific lesions in the brain. Oxidative stress was induced in mice by rearing them in socially isolated conditions. We systemically examined the distribution of PV neurons and PNNs in the brains of these mice as well as a control group. Our results show that the regions frequently affected in neuropsychiatric disorders show significantly lower PV expression and a lower percentage of PV neurons surrounded by PNNs in the brains of socially isolated mice. These results indicate that PV neurons and PNNs exhibit region-specific vulnerabilities. Our findings may be useful for elucidating the mechanisms underlying region-specific disruption of the brain in neuropsychiatric disorders. PMID- 28723389 TI - Adrenal Lesions: Progress on All Fronts. PMID- 28723390 TI - Work-up of the Incidental Adrenal Mass. AB - CONTEXT: Incidental adrenal masses (or adrenal incidentalomas [AI]) are a common finding during imaging and are present in up to 5% of the computed tomography (CT) scans performed on the general population. The best way to manage these lesions is still under discussion. OBJECTIVE: To evaluate recent literature and available guidelines regarding the work-up of AIs. EVIDENCE ACQUISITION: We used a medical search engine to identify studies published in the past 5 yr regarding AIs. We also evaluated current guidelines and the most relevant papers published before 2010. EVIDENCE SYNTHESIS: Unenhanced and contrast-enhanced CT, with laboratory tests to exclude functional lesions, are the most sensitive and specific methods currently available for the characterisation of adrenal masses. Magnetic resonance imaging, positron emission tomography-CT and fine-needle aspiration biopsy can be used as adjunct diagnostic tools in indeterminate lesions but are rarely indicated. In a relatively high number of indeterminate nodules, follow-up or surgery is suggested, although most of these lesions turn out to be benign. CONCLUSIONS: Various imaging modalities, with CT being most important, are available to diagnose malignant and functional lesions in AIs. An improved identification of benign lesions is warranted to reduce the number of unnecessary surgeries and follow-up examinations in patients with benign lesions. PATIENT SUMMARY: We performed a review of the literature on and guidelines for the management of incidental adrenal masses. It is possible to detect the presence of lesions that require surgery in the majority of cases. Follow-up is required for lesions that are not treated surgically. PMID- 28723391 TI - Management of the Incidental Adrenal Mass. AB - CONTEXT: Incidentally discovered adrenal masses are becoming more common in clinical practice. OBJECTIVE: To review the management of the incidental adrenal mass, including initial evaluation, surveillance, medical therapy, and surgical therapy. EVIDENCE ACQUISITION: A literature search of English-language publications that included the keywords adrenal incidentaloma and incidental adrenal mass was performed through July 2015 using PubMed. Relevant original articles and guidelines on the management of the incidental adrenal mass were ultimately selected for analysis, with the consensus of all authors. EVIDENCE SYNTHESIS: Data from the manuscripts included in this review were synthesized, and findings were categorized into metabolic evaluation, imaging, biopsy, surgical considerations, and follow-up recommendations. CONCLUSIONS: Ideally, management of patients with adrenal incidentalomas should involve a multidisciplinary approach with experienced surgeons, radiologists, and endocrinologists to determine whether such lesions are benign or malignant and functional or nonfunctional and/or whether they require surgical resection. PATIENT SUMMARY: Management of patients with adrenal incidentalomas should involve a multidisciplinary approach with surgeons, radiologists, and endocrinologists to determine whether such lesions are benign or malignant and functional or nonfunctional and/or whether they require surgical resection. PMID- 28723392 TI - Surgical Management of Adrenocortical Carcinoma: Impact of Laparoscopic Approach, Lymphadenectomy, and Surgical Volume on Outcomes-A Systematic Review and Meta analysis of the Current Literature. AB - CONTEXT: Controversy exists regarding the choice for surgical approach and the role of lymph node dissection (LND) in adrenocortical carcinoma (ACC) treatment. ACC surgery is increasingly advocated to be performed in specialist referral centres. OBJECTIVE: To review systematically the evidence of oncologic outcomes for ACC surgery by open adrenalectomy (OA) or laparoscopic adrenalectomy (LA), and for concomitant LND. The influence of surgical volume is also analysed. EVIDENCE ACQUISITION: A systematic review of Ovid Medline, Embase, and the Cochrane Library was performed in June 2015 according to the Preferred Reporting Items for Systematic Review and Meta-analysis statement. Twenty-six publications were selected for inclusion in the analysis. Meta-analyses were performed when appropriate. EVIDENCE SYNTHESIS: Included studies reported on oncologic outcomes after surgical treatment of ACC (11 studies), compared different surgical approaches (7 studies), evaluated the role of LND (3 studies), and analysed the effect of surgical volume on outcome (5 studies). From the available studies and the meta-analysis, no differences were found in the rate of positive surgical margins, disease-free survival, and overall survival between OA and LA in localised disease. In patients with histologically proven positive lymph nodes, a shorter time to recurrence was seen when no proper LND was performed. A trend for better recurrence-free survival and disease-specific survival after LND was found. In high-volume centres, more aggressive and open surgery was performed. In low-volume centres, higher local recurrence and distant metastases rates, and a shorter time to recurrence were seen. Our findings are limited due to the low level of evidence of selected studies, patient and disease heterogeneity, and heterogeneous surgeon populations. CONCLUSIONS: After adequate clinical staging for localised disease, LA is as effective and oncologically safe as OA, as long as oncologic principles are respected. LA should be performed by surgeons with extensive experience in laparoscopic adrenal surgery in high-volume centres. Patients with locally advanced disease and metastatic disease, for debulking purposes, should be operated on extensively with open surgery with adequate margins and concomitant LND to optimise staging, which may contribute to survival in locally advanced disease. PATIENT SUMMARY: Laparoscopic surgery for localised adrenocortical carcinoma is safe and effective when performed by expert surgeons in high-volume centres. Patients with more extensive tumours should be operated with open surgery; lymph node dissection is mainly applied to determine the stage of the disease. PMID- 28723393 TI - The Role of Adrenalectomy in Renal Cancer. AB - CONTEXT: Since the 1960s, routine ipsilateral adrenalectomy (IA) has been considered an integral step in the removal of renal tumors as a part of a radical nephrectomy. However, recent data from the past decade have narrowed the indications for adrenalectomy and called into question the need for adrenalectomy at all in the treatment of renal cell carcinoma (RCC). OBJECTIVE: We sought to identify the role of adrenalectomy in the treatment of RCC. Specifically, we wanted to answer the following questions: What is the incidence of ipsilateral adrenal involvement by cancer? How reliable is preoperative imaging? What is the rate of ipsilateral and contralateral metachronous recurrence? And finally, what are the potential noncancer sequelae from unnecessary removal of the adrenal gland? EVIDENCE ACQUISITION: A systematic literature search of Embase, PubMed, Cochrane, and Ovid Medline was performed to identify studies evaluating the role of adrenalectomy during RCC surgery. Only articles published in English from the years 2000-2015 were included. Case reports, articles about primary adrenal tumors, letters to the editor, and surgical technique papers were excluded. EVIDENCE SYNTHESIS: We found little evidence to suggest that routine IA is associated with a higher risk of short-term surgical or medical complications. We did not find evidence that IA is associated with improved cancer control. Tomographic preoperative imaging of the adrenal gland demonstrating no cancer involvement is rarely wrong (<1% of the time), and the few adrenal lesions missed on imaging can often be identified intraoperatively. Some evidence indicates that IA may be associated with worse long-term survival. Adrenalectomy rates have been decreasing in recent years, reflecting a changing practice pattern. CONCLUSIONS: IA at the time of kidney surgery for a renal mass should be performed only if radiographic or intraoperative evidence indicates adrenal gland involvement. PATIENT SUMMARY: We sought to define the role of adrenalectomy in patients with kidney cancer. Although there are not high-quality studies to answer this question definitively, we conclude that the adrenal gland should be spared unless there is clinical evidence of adrenal involvement. PMID- 28723394 TI - The Perioperative Management of Metabolically Active Tumors. AB - We briefly describe the perioperative management of patients with metabolically active adrenal tumors. The potential intraoperative and postoperative complications that occur in patients with an adrenal tumor are reviewed with emphasis on recognition, treatment, and prevention. PMID- 28723395 TI - Robotic Surgery Is Unnecessary for Adrenalectomy. PMID- 28723396 TI - Is Robotic Surgery Unnecessary for Adrenalectomy? Weighting the Pros and Cons of the Robotic Approach. PMID- 28723397 TI - Expression of PDL1 (B7-H1) Before and After Neoadjuvant Chemotherapy in Urothelial Carcinoma. AB - : Expression of the costimulatory ligand PDL1 (B7-H1) on tumors allows escape from antitumor immunity. PDL1 expression has been reported in urothelial carcinoma (UC), suggesting it could be used as an immunotherapy target. We investigated the impact of cytotoxic neoadjuvant chemotherapy (NAC) on PDL1 expression in UC. Immunohistochemical staining for PDL1 was performed using an anti-B7-H1 monoclonal antibody (5H1) on a tissue microarray with matched pre-NAC and post-NAC UC samples from 40 patients treated between 1999 and 2011. PDL1 expression was significantly higher in post-NAC specimens than in matched pre-NAC specimens (p=0.0235, Wilcoxen's signed rank test). PDL1 expression in pre-NAC tissue did not correlate with clinical or pathologic stage but was associated with recurrence free survival. The increase in PDL1 expression following NAC in our limited cohort has potential to guide optimal combination and sequencing of immune and cytotoxic therapies in UC patients. PATIENT SUMMARY: We investigated the relationship between levels of the drug target PDL1 before and after chemotherapy in patients with bladder cancer. We found that levels of PDL1 increased following chemotherapy. We conclude that this information may help doctors in optimizing the sequence of therapies in bladder cancer. PMID- 28723398 TI - PDL1: The Illusion of an Ideal Biomarker. PMID- 28723399 TI - Follow-up After Treatment for Renal Cell Carcinoma: The Evidence Beyond the Guidelines. AB - CONTEXT: Postoperative follow-up is considered the standard of care for nonmetastatic renal cell carcinoma (RCC). However, level 1 evidence regarding a proper follow-up protocol for RCC is still lacking, making clinical practice extremely heterogeneous. OBJECTIVE: To evaluate systematically and summarise the evidence supporting the current clinical guidelines on follow-up after RCC treatment. EVIDENCE ACQUISITION: A search of Medline, PubMed and Scopus was performed to identify articles published in the last 5 yr addressing the role of follow-up in the RCC setting. Relevant studies were then screened, and the data were extracted, analysed, and summarised. The Preferred Reporting Items for Systematic Reviews and Meta-analysis criteria were applied. EVIDENCE SYNTHESIS: Although several series regarding oncologic outcomes and protocols of surveillance after nephrectomy for localised RCC have been published in the literature, the individual preferences of the treating urologist make the daily clinical scenario extremely heterogeneous regarding follow-up indications and modality. Clinical guidelines support a stage-specific stratification of patient prognosis based on pathologic staging or prognostic models. In the context of a prospectively durable follow-up protocol exposing patients to several imaging tests, concerns about radiation exposure must be taken into account. A better understanding of tumour biology, which would lead to a correct individualisation of patient prognosis through the use of validated prognostic tools, would allow for a more tailored follow-up treatment. CONCLUSIONS: A consensus regarding the pattern and modalities of surveillance after treatment for RCC is still lacking. A standardised evidence-based surveillance protocol that would allow for the early detection of recurrences and limit unnecessary radiation exposure and unwarranted costs is mandatory. PATIENT SUMMARY: A surveillance protocol after treatment for a renal tumour is essential for the early detection and treatment of eventual metastases. A general consensus regarding timing and modalities for follow-up protocol still does not exist, but published evidence commonly sustains some general principles. PMID- 28723400 TI - Follow-up for Renal Cell Carcinoma: Absence of Evidence and Beyond. PMID- 28723401 TI - Wild-type VHL Clear Cell Renal Cell Carcinomas Are a Distinct Clinical and Histologic Entity: A 10-Year Follow-up. AB - BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is an aggressive tumor with 50% risk of metastases at initial diagnosis or at follow-up. An inactivation of the tumor-suppressor gene von Hippel-Lindau (VHL) is present in >70% of sporadic cases by two of three different mechanisms: locus deletion, gene mutation, or promoter hypermethylation. OBJECTIVE: To correlate the complete status of the VHL gene with clinical and pathologic criteria. DESIGN, SETTING, AND PARTICIPANTS: We retrospectively included 98 patients with ccRCC who underwent surgery between 2002 and 2005. VHL gene deletions (71 of 98; 72.4%), mutations (68 of 98; 69.4%), and promoter hypermethylations (13 of 98; 13.3%) were screened by gene copy analysis, gene sequencing, and methylation-specific multiplex ligation-dependent probe amplification, respectively. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Relationships between VHL subgroups and the studied criteria were analyzed using chi-square and Student t tests. Survival was analyzed with the log-rank test and Kaplan-Meier curves. RESULTS AND LIMITATIONS: Compared with ccRCCs with two events (66.3%), tumors with no or one genetic event (33.6%) were associated with a higher nuclear grade IV (p=0.02), metastases (p=0.04), sarcomatoid component (p=0.01), dense lymphocyte infiltrate (p=0.013), and vascular endothelial growth factor overexpression (>30%) (p=0.003), which was also an independent factor after multivariate analysis. Furthermore, wild-type VHL tumors (no inactivating event, 11.2%) were associated with nodal involvement (p=0.019), and patients with this type of tumor had a specific survival of 33 mo compared with patients with ccRCCs having one or two VHL inactivating events (107 mo; p=0.016). The retrospective design with small number of wild-type tumors was a limitation of this work. CONCLUSIONS: This long-term study (10-yr clinical follow-up) confirms that ccRCCs with wild-type VHL are highly aggressive tumors that need to be formally identified. PATIENT SUMMARY: Among activated VHL tumors, the wild-type subgroup defines an aggressive phenotype with worse survival rates, suggesting that these tumors must be more thoroughly screened. PMID- 28723402 TI - Characterization of Clear Cell Renal Cell Carcinoma with a Wild-type von Hippel Lindau Tumor Suppressor Gene: Limitation of Survival Expectations Using Single gene Alteration. PMID- 28723403 TI - Case Presentation: A 63-year-old Man with Bilateral Adrenal Mass and Large Renal Cell Carcinoma. AB - The challenging case of an asymptomatic 63-yr-old man with a large renal cell carcinoma, bilateral adrenal mass, and small pancreatic and pulmonary nodules suspicious for metastases is presented. Treatment strategy is discussed by a surgeon recommending immediate cytoreductive nephrectomy and unilateral adrenalectomy as the first step and a medical oncologist favouring systemic targeted therapy at symptomatic disease progression. PMID- 28723404 TI - Case Discussion: A 63-year-old Man with Bilateral Adrenal Mass and Large Renal Cell Carcinoma-The Case for Surgery. AB - The challenging case of an asymptomatic 63-yr-old man with a large renal cell carcinoma, bilateral adrenal mass, and small pancreatic and pulmonary nodules suspicious for metastases is presented. Treatment strategy is discussed by a surgeon recommending immediate cytoreductive nephrectomy and unilateral adrenalectomy as the first step and a medical oncologist favouring systemic targeted therapy at symptomatic disease progression. PMID- 28723405 TI - Case Discussion: A 63-year-old Male with Bilateral Adrenal Mass and Large Renal Cell Carcinoma: The Case for Chemotherapy. AB - Patients with metastatic clear cell renal cancer should still be considered for cytoreductive nephrectomy, even though the evidence for this relates mainly to the period before modern systemic therapy. Metastasectomy should also be considered when there is a chance of complete surgical clearance. For patients with inoperable progressive metastases there are now a number of effective systemic therapies that should be considered. In the first-line setting, the options include the tyrosine kinase inhibitors sunitinib and pazopanib. PMID- 28723406 TI - Systemic Therapy in Locally Advanced or Metastatic Adrenal Cancers: A Critical Appraisal and Clinical Trial Update. AB - Mitotane and chemotherapy with etoposide, doxorubicin, and cisplatin plus mitotane (EDP-M) are the only therapies with demonstrated efficacy in advanced adrenocortical carcinoma. Prognostic and predictive factors are needed to identify patients who could obtain the best benefit from these treatments. Despite the strong rationale for their use, clinical trials on molecular targeted therapies have failed to demonstrate that these drugs are efficacious in the management of this extremely rare disease. PMID- 28723407 TI - Nano lipid-drug conjugate: An integrated review. AB - Lipid-drug conjugates (LDC), which may also be addressed as lipoidal prodrug, have the therapeutic actives chemically bound to a lipid moiety like fatty acids or phospholipids. Fabricated in nano-size, lipid-drug conjugate forms another breed of lipid nanoparticles. LDCs are prepared in order to increase the drug loading and hence prevent leakage of a highly polar drug from a lipophilic matrix. In turn, it assists to achieve active targeting of therapeutics with reduced side effect by altering the pharmacokinetic profile of the drug. These self-assembled systems take the benefit of metabolic pathways of lipid biochemistry, allowing suitable organ targeting depending upon its size. These lipids because of its similarities with physiological lipids, enhances the solubility of the therapeutic agents and thereby improve the bioavailability. This present review is meant to encompass different aspects related to lipid drug conjugates which include types of lipids and drugs that can be used to develop this type of formulation. Here, we throw light on methods of preparation of lipid drug conjugate, processing them into nanoparticle, its characterization and different applications of lipid drug conjugate. We aim to present a holistic view on lipid drug conjugate as a suitable drug delivery approach. PMID- 28723408 TI - In-line Raman spectroscopic monitoring and feedback control of a continuous twin screw pharmaceutical powder blending and tableting process. AB - The integration of Process Analytical Technology (PAT) initiative into the continuous production of pharmaceuticals is indispensable for reliable production. The present paper reports the implementation of in-line Raman spectroscopy in a continuous blending and tableting process of a three-component model pharmaceutical system, containing caffeine as model active pharmaceutical ingredient (API), glucose as model excipient and magnesium stearate as lubricant. The real-time analysis of API content, blend homogeneity, and tablet content uniformity was performed using a Partial Least Squares (PLS) quantitative method. The in-line Raman spectroscopic monitoring showed that the continuous blender was capable of producing blends with high homogeneity, and technological malfunctions can be detected by the proposed PAT method. The Raman spectroscopy-based feedback control of the API feeder was also established, creating a 'Process Analytically Controlled Technology' (PACT), which guarantees the required API content in the produced blend. This is, to the best of the authors' knowledge, the first ever application of Raman-spectroscopy in continuous blending and the first Raman based feedback control in the formulation technology of solid pharmaceuticals. PMID- 28723409 TI - Layering of different materials to achieve optimal conditions for treatment of painful wounds. AB - Despite a range of advanced wound dressings that can facilitate wound healing, there are still no clinically used dressings for effective local pain management. The latter was the main motivation of the present study. We designed a novel wound dressing with three layers. A macro-porous polyethylene terephthalate (PET) mesh with incorporated lidocaine, a fast-acting local anesthetic, was chosen as the layer in direct contact with the skin. Fast release from this layer enables an immediate pain relieving effect, caused by dressing changes. For the second and third layer, alginate and viscose were chosen respectively. A potential long lasting pain relieving effect was achieved through incorporation of a nonsteroidal anti-inflammatory drug diclofenac into both layers. The chosen dressing structure enables also an unhindered absorption of the wound exudate, which is possible through the macro-porous PET into the alginate layer. Alginate additionally maintains a moist wound environment. Our novel wound dressing was systematically tested in regard of the structural (contact angle measurements, IR spectroscopy, SEM), functional (water retention, air permeability) properties and its biocompatibility (Live/Dead and MTT assays) towards human skin fibroblasts. Combined results confirmed the suitability of the chosen wound dressing composition for a faster and painless wound treatment. PMID- 28723410 TI - Innovative pMDI formulations of spray-dried nanoparticles for efficient pulmonary drug delivery. AB - For drug delivery to the lungs, the aerodynamic size of drug particles plays a predominant role in determining the sites of deposition in the airway, and the particles with the size less than 2MUm are highly expected as they will be preferably delivered to the ideal site of alveolar regions. In this paper, a novel platform technology has been developed, where the water (containing pharmaceutically active agents)-in-oil (w/o) microemulsions were spray-dried to generate nanosized drug particles that were able to be homogeneously dispersed in the propellant to form an exceptionally stable suspensions with no precipitates or flocculates during a long time storage. High fine particle (<5.8MUm) fraction (~70% w/w) was achieved, irrespectively of drug molecular size and storage time. This platform technology works pretty well on chemical drugs (i.e. salbutamol sulphate) and biotherapeutics (i.e. insulin) for the generation of nanoparticles, and the nanoparticle pMDI formulations were homogeneous, stable and of high delivery efficiency to the lungs, representing an ideal way for pulmonary delivery. PMID- 28723411 TI - The risks of biomarker-based epidemiology: Associations of circulating calcium levels with age, mortality, and frailty vary substantially across populations. AB - Recent studies have shown contradictory associations between calcium levels and health outcomes. We suspected these conflicting results were the consequence of more general issues with how biomarkers are analyzed in epidemiological studies, particularly in the context of aging. To demonstrate the risks of typical analyses, we used three longitudinal aging cohort studies and their demographic subsets to analyze how calcium levels change with age and predict risk of mortality and frailty. We show that calcium levels either increase or decrease with age depending on the population, and positively or negatively predict frailty depending on the population and analysis; both age and frailty results showed substantial heterogeneity. Mortality analyses revealed few significant associations but were likely underpowered. Variation in population composition (demographics, diseases, diet, etc.) leads to contradictory findings in the literature for calcium and likely for other biomarkers. Epidemiological studies of biomarkers are particularly sensitive to population composition both because biomarkers generally have non-linear and often non-monotonic relationships with other key variables, notably age and health outcomes, and because there is strong interdependence among biomarkers, which are integrated into complex regulatory networks. Consequently, most biomarkers have multiple physiological roles and are implicated in multiple pathologies. We argue that epidemiological studies of aging using biomarkers must account for these factors, and suggest methods to do this. PMID- 28723412 TI - Identification of a viroid-like RNA in a lychee Transcriptome Shotgun Assembly. AB - In the course of a systematic screen of plant transcriptomic data, the sequence of a novel viroid-like RNA was identified in four contigs in a recent Transcriptome Shotgun Assembly (TSA) from lychee in China. Portions of this sequence are closely related to the central conserved region (CCR) and terminal conserved region (TCR) present in members of the genus Apscaviroid, sequences that are important criteria for viroid classification. RT-PCR with two divergent adjacent primers amplified the full 304 nucleotide sequence of this viroid-like RNA which can be folded into the rod-like secondary structure that is a typical feature of viroids in the family Pospiviroidae. Northern-blot hybridization following denaturing PAGE and sequential polyacrylamide gel electrophoresis (sPAGE) revealed the presence of both circular and linear forms of the viroid like RNA in lychee leaf tissue. Phylogenetic analysis indicates that this RNA groups with known members of the genus Apscaviroid with a maximum pairwise sequence identity of <62%. Field surveys revealed the presence of this viroid like RNA in most lychee samples collected in China; however, it was not found in the accessions in a germplasm collection of lychees that originated from a wide range of other countries. None of the four herbaceous hosts and one woody host tested were susceptible to infection with the lychee viroid-like RNA via agroinoculation and RNA inoculation. The provisional name lychee viroid-like RNA (LVd-like RNA) is proposed for this tentative new species in the genus Apscaviroid. PMID- 28723415 TI - Pharmacology of human trace amine-associated receptors: Therapeutic opportunities and challenges. AB - The discovery in 2001 of a G protein-coupled receptor family, subsequently termed trace amine-associated receptors (TAAR), triggered a resurgence of interest in so called trace amines. Initial optimism quickly faded, however, as the TAAR family presented a series of challenges preventing the use of standard medicinal chemistry and pharmacology technologies. Consequently the development of basic tools for probing TAAR and translating findings from model systems to humans has been problematic. Despite these challenges the last 5years have seen considerable advances, in particular with respect to TAAR1, which appears to function as an endogenous rheostat, maintaining central neurotransmission within defined physiological limits, in part through receptor heterodimerization yielding biased signaling outputs. Regulation of the dopaminergic system is particularly well understood and clinical testing of TAAR1 directed ligands for schizophrenia and psychiatric disorders have begun. In addition, pre-clinical animal models have identified TAAR1 as a novel target for drug addiction and metabolic disorders. Growing evidence also suggests a role for TAARs in regulating immune function. This review critically discusses the current state of TAAR research, highlighting recent developments and focussing on human TAARs, their functions, and clinical implications. Current gaps in knowledge are identified, along with the research reagents and translational tools still required for continued advancement of the field. Through this, a picture emerges of an exciting field on the cusp of significant developments, with the potential to identify new therapeutic leads for some of the major unmet medical needs in the areas of neuropsychiatry and metabolic disorders. PMID- 28723413 TI - Multifunctional molecule ERp57: From cancer to neurodegenerative diseases. AB - The protein disulfide isomerase (PDI) gene family is a protein family classically characterized by endoplasmic reticulum (ER) localization and isomerase and redox activity. ERp57, a prominent multifunctional member of the PDI family, is detected at various levels in multiple cellular localizations outside of the ER. ERp57 has been functionally linked to a host of physiological processes and numerous studies have demonstrated altered expression and aberrant functionality of ERp57 in association with diverse pathological states. Here, we summarize available knowledge of ERp57's functions in subcellular compartments and the roles of dysregulated ERp57 in various diseases toward an emphasis on the potential utility of therapeutic development of ERp57. PMID- 28723416 TI - Unravelling the pharmacologic opportunities and future directions for targeted therapies in gastro-intestinal cancers part 2: Neuroendocrine tumours, hepatocellular carcinoma, and gastro-intestinal stromal tumours. AB - Until the 1990s, cytotoxic chemotherapy has been the cornerstone of medical therapy for gastrointestinal (GI) cancers. Better understanding of the cancer cell molecular biology has led to the therapeutic revolution of targeted therapies, i.e. monoclonal antibodies or small molecule inhibitors directed against proteins that are specifically overexpressed or mutated in cancer cells. These agents, being more specific to cancer cells, were expected to be less toxic than conventional cytotoxic agents. However, their effects have sometimes been disappointing, due to intrinsic or acquired resistance mechanisms, or to an activity restricted to some tumour settings, illustrating the importance of patient selection and early identification of predictive biomarkers of response to these therapies. Targeted agents have provided clinical benefit in many GI cancer types. Particularly, some GI tumours are considered chemoresistant and targeted therapies have offered a new therapeutic base for their management. Hence, somatostatin receptor-directed strategies, sorafenib, and imatinib have revolutioned the management of neuroendocrine tumours (NET), hepatocellular carcinoma (HCC), and gastrointestinal stromal tumours (GIST), respectively, and are now used as first-line treatment in many patients affected by these tumours. However, these agents face problems of resistances and identification of predictive biomarkers from imaging and/or biology. We propose a comprehensive two part review providing a panoramic approach of the successes and failures of targeted agents in GI cancers to unravel the pharmacologic opportunities and future directions for these agents in GI oncology. In this second part, we will focus on NET, HCC, and GIST, whose treatment relies primarily on targeted therapies. PMID- 28723414 TI - Omega-3 polyunsaturated fatty acids as a treatment strategy for nonalcoholic fatty liver disease. AB - Obese and type 2 diabetic (T2DM) patients have a high prevalence of nonalcoholic fatty liver disease (NAFLD). NAFLD is a continuum of chronic liver diseases ranging from benign hepatosteatosis to nonalcoholic steatohepatitis (NASH), cirrhosis and primary hepatocellular cancer (HCC). Because of its strong association with the obesity epidemic, NAFLD is rapidly becoming a major public health concern worldwide. Surprisingly, there are no FDA approved NAFLD therapies; and current therapies focus on the co-morbidities associated with NAFLD, namely, obesity, hyperglycemia, dyslipidemia, and hypertension. The goal of this review is to provide background on the disease process, discuss human studies and preclinical models that have examined treatment options. We also provide an in-depth rationale for the use of dietary omega3 polyunsaturated fatty acid (omega3 PUFA) supplements as a treatment option for NAFLD. This focus is based on recent studies indicating that NASH patients and preclinical mouse models of NASH have low levels of hepatic C20-22 omega3 PUFA. This decline in hepatic PUFA may account for the major phenotypic features associated with NASH, including steatosis, inflammation and fibrosis. Finally, our discussion will address the strengths and limitations of omega3 PUFA supplements use in NAFLD therapy. PMID- 28723417 TI - Long-term morphine delivery via slow release morphine pellets or osmotic pumps: Plasma concentration, analgesia, and naloxone-precipitated withdrawal. AB - AIMS: Slow-release morphine sulfate pellets and osmotic pumps are common routes of chronic morphine delivery in mouse models, but direct comparisons of these drug delivery systems are lacking. In this study, we assessed the efficacy of slow-release pellets versus osmotic pumps in delivering morphine to adult mice. MAIN METHODS: Male C57BL/6NCr mice (8weeksold) were implanted subcutaneously with slow-release pellets (25mg morphine sulfate) or osmotic pumps (64mg/mL, 1.0MUL/h). Plasma morphine concentrations were quantified via LC-MS/MS, analgesic efficacy was determined by tail flick assay, and dependence was assessed with naloxone-precipitated withdrawal behaviors (jumping) and physiological effects (excretion, weight loss). KEY FINDINGS: Morphine pellets delivered significantly higher plasma drug concentrations compared to osmotic pumps, which were limited by the solubility of the morphine sulfate and pump volume/flow rate. Within 96h post-implantation, plasma morphine concentrations were indistinguishable in pellet vs. pump-treated samples. While osmotic pump did not have an antinociceptive effect in the tail flick assay, pumps and pellets induced comparable dependence symptoms (naloxone-precipitated jumping behavior) from 24 72h post-implantation. SIGNIFICANCE: In this study, we compared slow-release morphine pellets to osmotic minipumps for morphine delivery in mice. We found that osmotic pumps and subcutaneous morphine sulfate pellets yielded significantly different pharmacokinetics over a 7-day period, and as a result significantly different antinociceptive efficacy. Nonetheless, both delivery methods induced dependence as measured by naloxone-precipitated withdrawal. PMID- 28723418 TI - Beta3 adrenergic receptor stimulation in human macrophages inhibits NADPHoxidase activity and induces catalase expression via PPARgamma activation. AB - The beta3 adrenergic receptor (beta3-AR) stimulation plays a protective role against preterm labor by blocking myometrial contraction, cytokine production, remodeling and apoptosis. We previously demonstrated that macrophage-induced ROS production in the myometrium was a key element leading to the induction of all these labor-associated features. We thus aimed to investigate if the beta3-AR could be expressed in human macrophages and could trigger its protective role in the myometrium by directly inhibiting ROS production. Using lipopolysaccharide (LPS)-stimulated myometrial samples and cell co-culture experiments, we demonstrated that beta3-AR stimulation inhibits the activation of the NADPH oxidase, leading to the subsequent inhibition of ROS production by macrophages. This antioxidant effect was associated with a potent anti-inflammatory response in macrophages. Furthermore, we observed that beta3-AR leads to the expression of catalase not only in macrophages but also in myometrial cells, thereby preventing the transactivation of myometrial cells by hydrogen peroxide. Pharmacological experiments allowed us to demonstrate that these effects were driven by an Erk1/2 mediated activation of the antioxidant transcription factor PPARgamma. These results suggest that beta3-AR protective effects in the myometrium could be due to its dual antioxidant properties. Further, the effects observed in a macrophage could highlight new applications in chronic inflammatory diseases. PMID- 28723420 TI - Plant and yeast cornichon possess a conserved acidic motif required for correct targeting of plasma membrane cargos. AB - The export of membrane proteins along the secretory pathway is initiated at the endoplasmic reticulum after proteins are folded and packaged inside this organelle by their recruiting into the coat complex COPII vesicles. It is proposed that cargo receptors are required for the correct transport of proteins to its target membrane, however, little is known about ER export signals for cargo receptors. Erv14/Cornichon belong to a well conserved protein family in Eukaryotes, and have been proposed to function as cargo receptors for many transmembrane proteins. Amino acid sequence alignment showed the presence of a conserved acidic motif in the C-terminal in homologues from plants and yeast. Here, we demonstrate that mutation of the C-terminal acidic motif from ScErv14 or OsCNIH1, did not alter the localization of these cargo receptors, however it modified the proper targeting of the plasma membrane transporters Nha1p, Pdr12p and Qdr2p. Our results suggest that mistargeting of these plasma membrane proteins is a consequence of a weaker interaction between the cargo receptor and cargo proteins caused by the mutation of the C-terminal acidic motif. PMID- 28723419 TI - NF-kappaB p65 serine 467 phosphorylation sensitizes mice to weight gain and TNFalpha-or diet-induced inflammation. AB - The NF-kappaB family of transcription factors is essential for an effective immune response, but also controls cell metabolism, proliferation and apoptosis. Its broad relevance and the high connectivity to diverse signaling pathways require a tight control of NF-kappaB activity. To investigate the control of NF kappaB activity by phosphorylation of the NF-kappaB p65 subunit, we generated a knock-in mouse model in which serine 467 (the mouse homolog of human p65 serine 468) was replaced with a non-phosphorylatable alanine (S467A). This substitution caused reduced p65 protein synthesis and diminished TNFalpha-induced expression of a selected group of NF-kappaB-dependent genes. Intriguingly, high-fat fed S467A mice displayed increased locomotor activity and energy expenditure, which coincided with a reduced body weight gain. Although glucose metabolism or insulin sensitivity was not improved, diet-induced liver inflammation was diminished in S467A mice. Altogether, this study demonstrates that phosphorylation of p65 serine 467 augment NF-kappaB activity and exacerbates various deleterious effects of overnutrition in mice. PMID- 28723421 TI - Approaches for Initial Prostate Biopsy and Antibiotic Prophylaxis. AB - CONTEXT: Debate on the optimal technique to use as an initial prostate biopsy (PB) strategy is continually evolving. OBJECTIVE: To review recent advances and current recommendations regarding initial PB and antibiotic prophylaxis. EVIDENCE ACQUISITION: A nonsystematic review of the literature was performed up to October 2014 using the PubMed and Embase databases. Articles were selected with preference for the highest level of evidence in publications within the past 5 yr. EVIDENCE SYNTHESIS: The decision to perform PB is still based on an abnormal digital rectal examination or increased prostate0specific antigen (PSA) level without clear consensus about the absolute cutoff. Several biomarkers have been suggested to improve PSA-based PB decision-making and minimize overdiagnosis and overtreatment. The random 12-core transrectal (TR) ultrasound-guided approach remains the standard-of-care technique for PB. A >12-core scheme may be considered as an alternative in a single patient given his clinical features (large volume, low PSA levels). Transperineal biopsies may only be considered as an alternative to the TR route in special situations. Nevertheless, given the increase in antimicrobial resistance, the impact on the post-biopsy sepsis rate should be assessed in well-designed clinical trials. Imaging-guided targeted PB strategies, combined or not with random PBs, may represent the future of prostate cancer diagnosis by reducing the number of PBs and improving decision-making. CONCLUSIONS: The 12-core TR scheme remains the standard of care for initial PB. The actual trend for PB strategy, with the aim of avoiding overdiagnosis of very low-risk cancers, could rapidly change our current indications and techniques through new biomarkers and imaging-guided targeted strategies. Nevertheless, the cost-benefit balance of these techniques should be closely assessed in the setting of initial PB strategy. PATIENT SUMMARY: This review highlights current recommendations for prostate biopsy and possible advances in the near future. PMID- 28723422 TI - Transrectal Ultrasound (US), Contrast-enhanced US, Real-time Elastography, HistoScanning, Magnetic Resonance Imaging (MRI), and MRI-US Fusion Biopsy in the Diagnosis of Prostate Cancer. AB - CONTEXT: Debates on overdiagnosis and overtreatment of prostate cancer (PCa) are ongoing and there is still huge uncertainty regarding misclassification of prostate biopsy results. Several imaging techniques that have emerged in recent years could overcome over- and underdiagnosis in PCa. OBJECTIVE: To review the literature on transrectal ultrasound (TRUS)-based techniques (contrast enhancement, HistoScanning, elastography) and magnetic resonance imaging (MRI) based techniques for a nonsystematic overview of their benefits and limitations. EVIDENCE ACQUISITION: A comprehensive search of the PubMed database between August 2004 and August 2014 was performed. Studies assessing grayscale TRUS, contrast-enhanced (CE)-TRUS, elastography, HistoScanning, multiparametric MRI (mpMRI), and MRI-TRUS fusion biopsy were included. Publications before 2004 were included if they reported the principle or the first clinical results for these techniques. EVIDENCE SYNTHESIS: Grayscale TRUS alone cannot detect PCa foci (detection rate 23-29%). TRUS-based (elastography) and MRI-based techniques (MRI TRUS fusion biopsy) have significantly improved PCa diagnostics, with sensitivity of 53-74% and specificity of 72-95%. HistoScanning does not provide convincing or homogeneous results (specificity 19-82%). CE-TRUS seems to be user dependent; it is used in a low number of high-volume centers and has wide ranges for sensitivity (54-79%) and specificity (42-95%). For all the techniques reviewed, prospective multicenter studies with consistent definitions are lacking. CONCLUSIONS: Standard grayscale TRUS is unreliable for PCa detection. Among the techniques reviewed, mpMRI and MRI-TRUS fusion biopsy seem to be suitable for enhancing PCa diagnostics. Elastography shows promising results according to the literature. CE-TRUS yields very inhomogeneous results and might not be the ideal technique for clinical practice. The value of HistoScanning must be questioned according to the literature. PATIENT SUMMARY: New imaging modalities such as elastography and magnetic resonance imaging/transrectal ultrasound fusion biopsies have improved the detection of prostate cancer. This may lower the burden of overtreatment as a result of more precise diagnosis. PMID- 28723423 TI - Repeat Prostate Biopsy: Rationale, Indications, and Strategies. AB - BACKGROUND: The inaccuracy of prostate biopsy in detecting and characterising prostate cancer (PCa) has led to a widespread use of repeat biopsy (RB). OBJECTIVE: To summarise the most recent data regarding indication, techniques, and clinical implications of RB. EVIDENCE ACQUISITION: A search of Medline, PubMed, and Scopus identified articles published in the last 7 yr (2008-2014) addressing the role of RB in the PCa setting. Abstracts deemed relevant to the defined review question were screened, and the data were extracted, analysed, and summarised. EVIDENCE SYNTHESIS: RB can be considered either in patients with persistent PCa suspicion after a first negative systematic biopsy or during active surveillance (AS), either to confirm patient enrolment or to monitor the natural progression of the disease. Indication and biopsy techniques differ according to each PCa scenario. Magnetic resonance imaging (MRI)-guided RB has been gaining popularity because of its accuracy in detecting and characterising PCa. Indications for multiple RBs (eg, AS setting) should be carefully evaluated because of the cumulative risk of complications, especially infection. In the next few years, clinical and genetic markers are expected to further improve the ability to determine the need for RB. CONCLUSIONS: RB indications and techniques in persistent PCa suspicion and AS should take into account the evolving field of imaging, management options, and the risk of possible complications. In an RB setting, the introduction in daily clinical practice of MRI-guided targeted biopsy has improved the accuracy in detecting PCa without significantly increasing the risk of finding indolent, low-risk PCa. Referral to specialised care centres should be considered in patients with persistent PCa suspicion to provide the most rationalised management in terms of indication, biopsy technique, complications, pathologic assessment, and, finally, clinical implications of the findings. PATIENT SUMMARY: A man may require a second prostatic biopsy for a number of reasons. In the current report, we describe why, when, and how a patient should undergo rebiopsy of the prostate. PMID- 28723424 TI - Impact of Early Diagnosis of Prostate Cancer on Survival Outcomes. AB - CONTEXT: The relationship between early detection of prostate cancer (PCa) and disease-specific mortality is still the subject of much debate. OBJECTIVE: This review describes developments in PCa mortality rates and disease-stage shift on a population level. The main findings from the randomised screening trials are also discussed. Finally, we consider the expected consequences for the individual man interested in screening. EVIDENCE ACQUISITION: The PubMed database was searched for trials of screening for PCa from inception through October 11, 2014. Supplementary information was collected by cross-referencing the reference lists. EVIDENCE SYNTHESIS: Since the introduction of prostate-specific antigen testing, PCa incidence has risen, and a stage shift towards more favourable disease at diagnosis has been observed. PCa mortality rates are gradually decreasing. Although screening trials show conflicting results, the largest randomised trial of screening for PCa shows a 21% decrease in PCa-specific mortality. After correction for noncompliance and contamination, a risk reduction in PCa-specific mortality of up to 49% has been reported. The main side effect of screening is that some studies have estimated that approximately 50% of detected cases may represent overdiagnosis, which may be reduced by stopping screening in older men and using an individual risk-based approach. CONCLUSIONS: To maximise the benefits while minimising the risk of overdiagnosis, future screening should follow an individual risk-based approach. PATIENT SUMMARY: On a population level, the introduction of screening for prostate cancer (PCa) is associated with more men diagnosed but with more favourable disease. The largest screening study confirmed the reduction in death due to PCa. Individual risk estimation is important to best balance the benefits and potential harms of early detection. PMID- 28723425 TI - Screening for Prostate Cancer: Current Status and Future Directions. PMID- 28723426 TI - Clinical Consultation Guide: How to Optimize the Use of Prostate-specific Antigen in the Current Era. AB - Optimizing the benefits versus harms of prostate-specific antigen screening can be achieved through stratifying screening and biopsy. This clinical consultation guide provides the scientific background and evidence-based recommendations. PMID- 28723427 TI - Will Magnetic Resonance Imaging-guided Biopsy Replace Systematic Biopsy? PMID- 28723428 TI - Will Multiparametric Magnetic Resonance Imaging-guided Biopsies Replace Systematic Biopsies? PMID- 28723429 TI - Systematic Review of the Efficacy and Safety of High-intensity Focussed Ultrasound for Localised Prostate Cancer. AB - CONTEXT: High-intensity focussed ultrasound (HIFU) has been used for 10 yr to treat localised prostate cancer (PCa). OBJECTIVE: To evaluate systematically the evidence on the efficacy and side effects of HIFU in the primary treatment of localised PCa. EVIDENCE ACQUISITION: We performed a critical review and appraisal of Medline (Ovid), PreMedline, Embase, and Cochrane Database of Systematic Reviews publications on HIFU up to May 2013. One systematic review and 18 primary studies, all case series, were eligible. EVIDENCE SYNTHESIS: Outcomes were summarised and evidence was evaluated using Grading of Recommendations, Assessment, Development and Evaluation methodology. Low-quality evidence suggests an overall survival rate after Ablatherm HIFU ranging from 80% to 89% for >5 yr. The PCa survival rate ranges from 97% to 99% for >5 yr. Effect of HIFU on quality of life remains undetermined. Erectile dysfunction was the most frequent adverse event reported from zero but up to 74% of patients. Adverse events affecting the urinary tract occurred in 0.7-31% of patients, bladder outlet obstruction in 4 51.5%, and they were more frequent in patients who had transurethral resection of the prostate the same day or within 2 d of HIFU. Outcomes vary for low- and high risk categories. CONCLUSIONS: Good quality evidence on the efficacy of HIFU treatment for localised PCa is lacking. PATIENT SUMMARY: We reviewed all the data on treatment with high-intensity focussed ultrasound (HIFU) for localised prostate cancer (PCa). The quality of the evidence is very low because the information is based on a series of patients who received HIFU treatment with no comparison with active surveillance or radical treatment. Case series suggest an overall survival rate up to 89% and a PCa survival rate up to 99% after 5 yr, but these numbers vary according to the patient's risk category. Longer term and effects on quality of life are unknown. PMID- 28723430 TI - Known Knowns, Known Unknowns, and Unknown Unknowns of High-intensity Focused Ultrasound for Prostate Cancer. PMID- 28723431 TI - Clinical Perspectives from Randomized Phase 3 Trials on Prostate Cancer: An Analysis of the ClinicalTrials.gov Database. AB - BACKGROUND: It is not easy to overview pending phase 3 trials on prostate cancer (PCa), and awareness of these trials would benefit clinicians. OBJECTIVE: To identify all phase 3 trials on PCa registered in the ClinicalTrials.gov database with pending results. DESIGN AND SETTING: On September 29, 2014, a database was established from the records for 175 538 clinical trials registered on ClinicalTrials.gov. A search of this database for the substring "prostat" identified 2951 prostate trials. Phase 3 trials accounted for 441 studies, of which 333 concerned only PCa. We selected only ongoing or completed trials with pending results, that is, for which the primary endpoint had not been published in a peer-reviewed medical journal. RESULTS AND LIMITATIONS: We identified 123 phase 3 trials with pending results. Trials were conducted predominantly in North America (n=63; 51%) and Europe (n=47; 38%). The majority were on nonmetastatic disease (n=82; 67%), with 37 (30%) on metastatic disease and four trials (3%) including both. In terms of intervention, systemic treatment was most commonly tested (n=71; 58%), followed by local treatment 34 (28%), and both systemic and local treatment (n=11; 9%), with seven (6%) trials not classifiable. The 71 trials on systemic treatment included androgen deprivation therapy (n=34; 48%), chemotherapy (n=15; 21%), immunotherapy (n=9; 13%), other systemic drugs (n=9; 13%), radiopharmaceuticals (n=2; 3%), and combinations (n=2; 3%). Local treatments tested included radiation therapy (n=27; 79%), surgery (n=5; 15%), and both (n=2; 2%). A limitation is that not every clinical trial is registered on ClinicalTrials.gov. CONCLUSION: There are many PCa phase 3 trials with pending results, most of which address questions regarding systemic treatments for both nonmetastatic and metastatic disease. Radiation therapy and androgen deprivation therapy are the interventions most commonly tested for local and systemic treatment, respectively. PATIENT SUMMARY: This report describes all phase 3 trials on prostate cancer registered in the ClinicalTrials.gov database with pending results. Most of these trials address questions regarding systemic treatments for both nonmetastatic and metastatic disease. Radiation therapy and androgen deprivation therapy are the interventions most commonly tested for local and systemic treatment, respectively. PMID- 28723432 TI - Comparison of Two Prostate Cancer Risk Calculators that Include the Prostate Health Index. AB - BACKGROUND: Risk prediction models for prostate cancer (PCa) have become important tools in reducing unnecessary prostate biopsies. The Prostate Health Index (PHI) may increase the predictive accuracy of such models. OBJECTIVES: To compare two PCa risk calculators (RCs) that include PHI. DESIGN, SETTING, AND PARTICIPANTS: We evaluated the predictive performance of a previously developed PHI-based nomogram and updated versions of the European Randomized Study of Screening for Prostate Cancer (ERSPC) RCs based on digital rectal examination (DRE): RC3 (no prior biopsy) and RC4 (prior biopsy). For the ERSPC updates, the original RCs were recalibrated and PHI was added as a predictor. The PHI-updated ERSPC RCs were compared with the Lughezzani nomogram in 1185 men from four European sites. Outcomes were biopsy-detectable PC and potentially advanced or aggressive PCa, defined as clinical stage >T2b and/or a Gleason score >=7 (clinically relevant PCa). RESULTS AND LIMITATIONS: The PHI-updated ERSPC models had a combined area under the curve for the receiver operating characteristic (AUC) of 0.72 for all PCa and 0.68 for clinically relevant PCa. For the Lughezzani PHI-based nomogram, AUCs were 0.75 for all PCa and 0.69 for clinically relevant PCa. For men without a prior biopsy, PHI-updated RC3 resulted in AUCs of 0.73 for PCa and 0.66 for clinically relevant PCa. Decision curves confirmed these patterns, although the number of clinically relevant cancers was low. CONCLUSION: Differences between RCs that include PHI are small. Addition of PHI to an RC leads to further reductions in the rate of unnecessary biopsies when compared to a strategy based on prostate-specific antigen measurement. PATIENT SUMMARY: Risk prediction models for prostate cancer have become important tools in reducing unnecessary prostate biopsies. We compared two risk prediction models for prostate cancer that include the Prostate Health Index. We found that these models are equivalent to each other, and both perform better than the prostate specific antigen test alone in predicting cancer. PMID- 28723433 TI - Adjuvant Radiotherapy in Prostate Cancer Patients Treated with Surgery: The Impact of Age and Tumor Characteristics. AB - BACKGROUND: The overall mortality (OM) and cancer-specific mortality (CSM) benefits of adjuvant radiotherapy (aRT) in treating prostate cancer (PCa) patients with adverse pathologic characteristics at radical prostatectomy (RP) are unclear. OBJECTIVE: To test the impact of aRT on survival in PCa patients treated with RP according to adverse pathologic characteristics (Gleason score [GS] 8-10; pT3b/4, lymph node invasion [LNI]) and age categories (<70 vs >=70 yr). DESIGN, SETTING, AND PARTICIPANTS: A total of 7616 patients with pT3/4 pN0/1 PCa treated with RP between 1995 and 2009 within the Surveillance Epidemiology and End Results-Medicare linked database were included. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Cox regression analysis was used to test the relationship between aRT and CSM, as well as OM in the entire cohort. Stratification was performed according to tumor characteristics and age categories. RESULTS AND LIMITATIONS: In patients with fewer than two adverse pathologic characteristics, aRT did not improve CSM or OM. Conversely, in patients with two or more adverse pathologic characteristics, the 10-yr CSM-free rate was 92% in patients treated with aRT versus 82% in patients treated without aRT (p<0.001). This survival improvement was confirmed in patients aged <70 yr (p=0.01) but not in those >=70 yr (p=0.1). In multivariable analyses, aRT was an independent predictor of lower CSM risk (hazard ratio: 0.45; p=0.02) only among patients aged <70 yr with two or more adverse pathologic characteristics. Similar trends were observed when OM was examined as an end point. CONCLUSIONS: Age and tumor characteristics should be considered in the selection of optimal aRT candidates after surgery. Only patients aged <70 yr with two or more adverse pathologic characteristics (GS 8 10, pT3b/4, LNI) appear to benefit from aRT. PATIENT SUMMARY: The usefulness of adjuvant radiotherapy after surgery for prostate cancer greatly depends on tumor characteristics and patient age. Only patients with advanced local tumor characteristics aged <70 yr seem to benefit from this treatment modality. PMID- 28723434 TI - Long-term Survival Outcomes for Men Who Provided Ejaculate Specimens for Prostate Cancer Research: Implications for Patient Management. AB - BACKGROUND: Determining whether men diagnosed with early prostate cancer (PCa) will live long enough to benefit from interventions with curative intent is difficult. Although validated instruments for predicting patient survival are available, these do not have clinical utility so are not used routinely in practice. OBJECTIVE: To test the hypothesis that volunteers who provided ejaculate specimens had a high survival rate at 10 and 15 yr and beyond. DESIGN, SETTING, AND PARTICIPANTS: A total of 290 patients investigated because of high serum prostate-specific antigen donated ejaculate specimens for research between January 1992 and May 2003. The median age at the time of ejaculation was 63.5 yr. 153 of the donors were diagnosed with PCa and followed up to December 31, 2013. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Survival outcomes were compared with those for the whole population, as indicated by life expectancy tables up to 20 yr. RESULTS AND LIMITATIONS: Men in the PCa group had life expectancies comparable with values listed in life expectancy tables for the whole population. Overall, PCa-specific and relative survival were significantly better for men in the non-PCa and PCa groups in comparison with men diagnosed with PCa in Queensland during the same period. Relative survival for those aged 20-49, 50-64, and >=65 yr was >100% for ejaculate donors and 81.5%, 82.7%, and 65.2%, respectively, for the Queensland Cancer Registry reference at 10 yr. These findings for this highly selected patient cohort support the hypothesis that an ability to provide an ejaculate specimen is associated with a high likelihood of surviving 10-20 yr after donation, whether or not PCa was detected. CONCLUSION: Life expectancy tables may serve as a quick and simple life expectancy indicator for biopsy patients who donate ejaculate. PATIENT SUMMARY: Life expectancy tables indicated survival of up to 20 yr for men who provided ejaculate specimens for prostate cancer research. PMID- 28723435 TI - Case Presentation: Intermediate-risk Prostate Cancer in a Fit 66-year-old Man. PMID- 28723436 TI - Clinical Case Discussion: Intermediate-risk Prostate Cancer: The Case for Active Surveillance. AB - Active surveillance offers men the opportunity to defer immediate local treatment of low risk prostate cancer while preserving a highly functional quality of life. Novel biomarkers and imaging technology will enable physicians to better identify ideal candidates for this approach beyond traditional clinical characteristics. PMID- 28723437 TI - Case Discussion: Intermediate-risk Prostate Cancer: The Case for Radical Treatment. PMID- 28723438 TI - The Future of Prostate Cancer Diagnosis: Biomarkers, Biopsy, Both, or Neither? PMID- 28723439 TI - The Role of Biomarkers and Genetics in the Diagnosis of Prostate Cancer. AB - CONTEXT: Given the pitfalls of prostate-specific antigen (PSA) testing for screening men with asymptomatic prostate cancer (PCa), a number of novel biomarkers have recently been studied that potentially decrease false-positive PSA results and unnecessary biopsies. OBJECTIVE: To review the literature on biomarkers with potential diagnostic utility for PCa by guiding the decision for initial or repeat biopsies in patients with elevated PSA. EVIDENCE ACQUISITION: We conducted a systematic literature review of human clinical studies on diagnostic biomarkers reporting clinicopathologic outcomes. A comprehensive search was performed in the Medline, Scopus, and Web of Science databases for articles from January 2005 through June 2015. EVIDENCE SYNTHESIS: For men presenting with elevated PSA, especially in the 4-10 ng/ml range, who are considered for initial prostate biopsy, two serum-based assays, the Prostate Health Index and the four-kallikrein panel, can help identify patients with an increased risk of significant cancer on biopsy. In the setting of a prior negative biopsy but elevated PSA, urine-based assays detecting prostate cancer antigen 3 and/or transmembrane protease, serine2:v-ets avian erythroblastosis virus E26 oncogene homolog fusion transcript help predict the risk of high-grade cancer on subsequent biopsy. In cases with elevated PSA and an initial negative biopsy, epigenetic analysis can predict cancer diagnosis on subsequent biopsies. The combination of these novel biomarkers with existing nomograms and risk calculators leads to increased predictive accuracy and avoids unnecessary biopsies. CONCLUSIONS: Rapid strides have been made in the discovery of novel biomarkers for guiding biopsy decisions in men suspected of harboring PCa. Although some of them have been approved for specific clinical settings, most of them still await rigorously designed prospective validation studies. PATIENT SUMMARY: Novel urine-, serum-, and tissue-based biomarkers have been validated for guiding decisions on prostate biopsy in asymptomatic men with elevated prostate-specific antigen. Further exploration in this field may help expand their diagnostic and prognostic roles for prostate cancer. PMID- 28723440 TI - Reducing Complications After Surgery: Still a Long Way To Go. PMID- 28723441 TI - Training, Simulation, the Learning Curve, and How to Reduce Complications in Urology. AB - CONTEXT: Urology is at the forefront of minimally invasive surgery to a great extent. These procedures produce additional learning challenges and possess a steep initial learning curve. Training and assessment methods in surgical specialties such as urology are known to lack clear structure and often rely on differing operative flow experienced by individuals and institutions. OBJECTIVE: This article aims to assess current urology training modalities, to identify the role of simulation within urology, to define and identify the learning curves for various urologic procedures, and to discuss ways to decrease complications in the context of training. EVIDENCE ACQUISITION: A narrative review of the literature was conducted through December 2015 using the PubMed/Medline, Embase, and Cochrane Library databases. EVIDENCE SYNTHESIS: Evidence of the validity of training methods in urology includes observation of a procedure, mentorship and fellowship, e-learning, and simulation-based training. Learning curves for various urologic procedures have been recommended based on the available literature. The importance of structured training pathways is highlighted, with integration of modular training to ensure patient safety. CONCLUSIONS: Valid training pathways are available in urology. The aim in urology training should be to combine all of the available evidence to produce procedure-specific curricula that utilise the vast array of training methods available to ensure that we continue to improve patient outcomes and reduce complications. PATIENT SUMMARY: The current evidence for different training methods available in urology, including simulation-based training, was reviewed, and the learning curves for various urologic procedures were critically analysed. Based on the evidence, future pathways for urology curricula have been suggested to ensure that patient safety is improved. PMID- 28723442 TI - Case Discussion: Vesicovaginal Fistula Following a Total Abdominal Hysterectomy: The Case for Abdominal Repair. PMID- 28723443 TI - Clinical Case Discussion: Vaginal Approach for the Management of Vesicovaginal Fistula. AB - Vesicovaginal fistula should be repaired predominantly by a vaginal technique, avoiding the morbidity of abdominal and bladder incisions. The abdominal approach should be considered if concomitant abdominal procedures, such as ureteral reimplantation, must be performed. PMID- 28723444 TI - The European Association of Urology Robotic Training Curriculum: An Update. AB - The European Association of Urology robotic training curriculum is a validated structured program to provide standardized training and to certify surgeons for specific urologic procedures. PMID- 28723445 TI - Grey Areas: Challenges of Developing Guidelines in Adult Urological Trauma. PMID- 28723446 TI - Critical Review of Outcomes from Radical Cystectomy: Can Complications from Radical Cystectomy Be Reduced by Surgical Volume and Robotic Surgery? AB - CONTEXT: Radical cystectomy (RC) is a highly complex procedure with multiple risks for perioperative complications. OBJECTIVE: We reviewed the literature to report perioperative outcomes and the incidence of complications in contemporary RC series. We focused on the potential impact of surgical approach and surgeon volume on these outcomes. EVIDENCE ACQUISITION: A systematic literature search was performed in December 2015 using the Medline, Embase, and Web of Science databases for articles published in English between 2005 and 2015. The search strategy included the terms complications, cystectomy, robotic assisted radical cystectomy, and surgical volume, alone or in combination. Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines were followed. EVIDENCE SYNTHESIS: Our searches retrieved 49 papers. Open RC (ORC) and robot-assisted RC (RARC) are morbid procedures with consistent risk of perioperative complications (mean weighted incidence: 48.7%; range: 27.0-72.5%). Higher hospital and surgeon volumes were associated with reduced risks of perioperative complications. Prior robotic expertise in radical prostatectomy showed a beneficial protective risk on development of complications after RARC. Surgical volume appears to be a good predictor of safety in ORC and RARC. RARC is associated with reduced estimated blood loss and lower perioperative transfusion rates compared with ORC. Further evidence is needed to support the reproducibility of intracorporeal diversion during RARC, beyond large tertiary referral centers. Several strategies have been demonstrated to be effective for reducing the risk of incurring perioperative complications and should be pursued by physicians. CONCLUSIONS: Despite improvements in quality of care, RC remains a challenging procedure with high morbidity, regardless of surgical approach. RARC is a safe procedure with potential advantages in terms of reduced blood loss and transfusion rates. Surgical volume appears to be related to the improvement of perioperative outcomes and complications. PATIENT SUMMARY: Radical cystectomy is a challenging and morbid procedure. The robotic approach has gained popularity and proved to be safe and effective in tertiary referral centers, although further studies are needed to confirm its wide reproducibility. Centers with higher surgical volume have lower incidence of perioperative complications. PMID- 28723447 TI - Complications Following Common Inpatient Urological Procedures: Temporal Trend Analysis from 2000 to 2010. AB - BACKGROUND: Measuring procedure-specific complication-rate trends allows for benchmarking and improvement in quality of care but must be done in a standardized fashion. DESIGN, SETTING, AND PARTICIPANTS: Using the Nationwide Inpatient Sample, we identified all instances of eight common inpatient urologic procedures performed in the United States between 2000 and 2010. This yielded 327218 cases including both oncologic and benign diseases. Complications were identified by International Classification of Diseases, Ninth Revision codes. Each complication was cross-referenced to the procedure code and graded according to the standardized Clavien system. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The Mann-Whitney and chi-square were used to assess the statistical significance of medians and proportions, respectively. We assessed temporal variability in the rates of overall complications (Clavien grade 1-4), length of hospital stay, and in-hospital mortality using the estimated annual percent change (EAPC) linear regression methodology. RESULTS AND LIMITATIONS: We observed an overall reduction in length of stay (EAPC: -1.59; p<0.001), whereas mortality rates remained negligible and unchanged (EAPC: -0.32; p=0.83). Patient comorbidities increased significantly over the study period (EAPC: 2.09; p<0.001), as did the rates of complications. Procedure-specific trends showed a significant increase in complications for inpatient ureterorenoscopy (EAPC: 5.53; p<0.001), percutaneous nephrolithotomy (EAPC: 3.75; p<0.001), radical cystectomy (EAPC: 1.37; p<0.001), radical nephrectomy (EAPC: 1.35; p<0.001), and partial nephrectomy (EAPC: 1.22; p=0.006). Limitations include lack of postdischarge follow-up data, lack of pathologic characteristics, and inability to adjust for secular changes in administrative coding. CONCLUSIONS: In the context of urologic care in the United States, our findings suggest a shift toward more complex oncologic procedures in the inpatient setting, with same-day procedures most likely shifted to the outpatient setting. Consequently, complications have increased for the majority of examined procedures; however, no change in mortality was found. PATIENT SUMMARY: This report evaluated the trends of urologic procedures and their complications. A significant shift toward sicker patients and more complex procedures in the inpatient setting was found, but this did not result in higher mortality. These results are indicators of the high quality of care for urologic procedures in the inpatient setting. PMID- 28723448 TI - A Clinician's Guide to Avoiding and Managing Common Complications During and After Robot-assisted Laparoscopic Radical Prostatectomy. AB - CONTEXT: Robot-assisted radical prostatectomy (RARP) is on the advance globally, and it is essential for surgeons and patients to know the rates of perioperative complications. OBJECTIVE: To provide evidence-based clinical guidance on avoiding and managing common complications during and after RARP in the context of a comprehensive literature review. EVIDENCE ACQUISITION: In concordance with the Preferred Reporting Items for Systematic Reviews and Meta-analysis 2015 statement guidelines, a literature search of the PubMed database from August 1, 2011, to August 31, 2015, using the predefined search terms robot* AND radical prostatectomy, was conducted. The search resulted in 653 unique results that were subsequently uploaded to DistillerSR (Evidence Partners, Ottawa, Canada) for team based screening and processing of references. EVIDENCE SYNTHESIS: Overall, 37 studies met the inclusion criteria and were included. Median rate of overall complication was 12.6% (range: 3.1-42%). Most of the complications were minor (Clavien-Dindo grades 1 and 2). Grade 3 complications comprised the bulk of the major complications with a median rate of 2.7%; grade IV and V complications were exceedingly rare in all reports. CONCLUSIONS: Despite continued adoption of the RARP technique globally, rates of overall complication remain low. Many of the complications experienced during and after RARP can be mitigated and prevented by experience and the implementation of safe techniques. PATIENT SUMMARY: Despite continued adoption of the robot-assisted radical prostatectomy (RARP) technique globally, rates of overall and major complications remain low at 12.6% and 2.7%, respectively. Complications can be minimized and successfully managed using established techniques. RARP is a safe and reproducible technique. PMID- 28723449 TI - Prevention and Management Following Complications from Endourology Procedures. AB - CONTEXT: Endourologic procedures are very common in daily urologic practice for treatment of benign prostatic obstruction, stone disease, urothelial tumors, or stenosis. OBJECTIVE: To characterize the complications following endoscopic procedures, to describe their management, and to gather information about their prevention in current urologic practice. EVIDENCE ACQUISITION: A review of the literature was conducted using PubMed/Medline database to include the most relevant articles on the topic. The search focused on endoscopic approaches for treatment of prostate, bladder, or upper urinary tract disease. Percutaneous approaches and noninvasive extracorporeal techniques were excluded. Complications of endourologic procedures were identified through level 1 evidence, systematic reviews of the literature, or original articles assessing complications as the primary end point. Data about management and prevention of each type of complication were retrieved in a second round using specific keywords. EVIDENCE SYNTHESIS: Complications of endoscopic urologic procedures are specific to each surgical approach. Main complications after prostate surgery include transurethral resection of the prostate syndrome, bleeding and transfusion, acute urinary retention, urinary tract infection, clot retention, postoperative irritative symptoms, ejaculatory dysfunction, urinary incontinence, bladder neck contracture, and urethral stricture. Major complications after transurethral bladder tumor include severe bleeding, transfusion, bladder perforation, and urinary tract infection. The most frequent complications after ureteroscopy are fever and sepsis, bleeding, steinstrasse, and ureteral injury. Overall, the literature is very poor, with no systematic reporting of complications and underuse of classification systems. No clear protocols are available for management of complications, and most are based on studies with low levels of evidence. Good clinical practice recommendations and guidelines give useful support about technical issues, intraoperative safety, and prevention of urinary tract infection. The efficacy of these preventive measures remains poorly investigated. CONCLUSIONS: Complications following endoscopic surgery are potentially numerous and vary with patient characteristics, surgical approach, and type of medical device. Improved standardization and quality of publications are warranted to improve knowledge of these issues, which are directly linked to the level of care. PATIENT SUMMARY: We focused on the potential complications of each endoscopic approach used to treat urologic disease. We described the frequency of these complications and gathered information about how to manage them in the operating theater. We also noted caveats for the literature regarding standardization of reporting and classification systems. PMID- 28723450 TI - Preventing Complications: The Preflight Checklist. AB - Compliance with the World Health Organisation Surgical Safety Checklist is associated with reduction of complications and mortality. PMID- 28723451 TI - The Role of Simulation in Surgical Training. PMID- 28723452 TI - The Role of Simulation in Surgical Training: An Analysis of Controversies. PMID- 28723454 TI - Almost Half a Century of Bacillus Calmette-Guerin Therapy: More to Come? PMID- 28723453 TI - Nonpathogenic Mycobacterium brumae Inhibits Bladder Cancer Growth In Vitro, Ex Vivo, and In Vivo. AB - BACKGROUND: Bacillus Calmette-Guerin (BCG) prevents tumour recurrence and progression in non-muscle-invasive bladder cancer (BC). However, common adverse events occur, including BCG infections. OBJECTIVE: To find a mycobacterium with similar or superior antitumour activity to BCG but with greater safety. DESIGN: In vitro, ex vivo, and in vivo comparisons of the antitumour efficacy of nonpathogenic mycobacteria and BCG. INTERVENTION: The in vitro antitumour activity of a broad set of mycobacteria was studied in seven different BC cell lines. The most efficacious was selected and its ex vivo capacity to activate immune cells and its in vivo antitumour activity in an orthotopic murine model of BC were investigated. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Growth inhibition of BC cells was the primary outcome measurement. Parametric and nonparametric tests were use to analyse the in vitro results, and a Kaplan-Meier test was applied to measure survival in mycobacteria-treated tumour-bearing mice. RESULTS AND LIMITATIONS: Mycobacterium brumae is superior to BCG in inhibiting low-grade BC cell growth, and has similar effects to BCG against high-grade cells. M. brumae triggers an indirect antitumour response by activating macrophages and the cytotoxic activity of peripheral blood cells against BC cells. Although no significant differences were observed between BCG and M. brumae treatments in mice, M. brumae treatment prolonged survival in comparison to BCG treatment in tumour-bearing mice. In contrast to BCG, M. brumae does not persist intracellularly or in tumour-bearing mice, so the risk of infection is lower. CONCLUSIONS: Our preclinical data suggest that M. brumae represents a safe and efficacious candidate as a therapeutic agent for non-muscle-invasive BC. PATIENT SUMMARY: We investigated the antitumour activity of nonpathogenic mycobacteria in in vitro and in vivo models of non-muscle-invasive bladder cancer. We found that Mycobacterium brumae effectively inhibits bladder cancer growth and helps the host immune system to eradicate cancer cells, and is a promising agent for antitumour immunotherapy. PMID- 28723455 TI - The Neutrophil-to-lymphocyte Ratio as a Prognostic Factor for Patients with Urothelial Carcinoma of the Bladder Following Radical Cystectomy: Validation and Meta-analysis. AB - BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) as a marker of systemic inflammatory response has been proposed as a prognostic factor for patients with urothelial carcinoma of the bladder (UCB) following radical cystectomy (RC). OBJECTIVE: To validate NLR as a prognostic biomarker and to perform a pooled meta analysis. DESIGN, SETTING, AND PARTICIPANTS: The NLR was assessed in 4061 patients within 30 days before RC. A systematic review of the literature was undertaken using electronic databases. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Associations with overall survival (OS) and cancer-specific survival (CSS) were evaluated using Cox models. Hazard ratios (HRs) were pooled in a meta analysis using random-effects modeling. RESULTS AND LIMITATIONS: A high NLR (>=2.7) was associated with advanced pathological tumor stages (p<0.001), lymph node involvement (p<0.001), lymphovascular invasion (p=0.008), and positive soft0tissue surgical margins (p=0.001). In multivariate analyses, a high NLR was independently associated with both OS (HR 1.11, 95% confidence interval [CI] 1.01 1.22; p=0.029) and cancer-specific survival (CSS) (HR 1.21, 95% CI 1.07-1.37, p=0.003). The discrimination of the multivariate models increased by 0.2% on inclusion of NLR. Five studies were included in the meta-analysis. The HR for NLR greater than the cutoff was 1.46 (95% CI 1.01-1.92) for OS and 1.51 (95% CI 1.17 1.85) for CSS. Limitations include the retrospective study design and the lack of standardized follow-up. CONCLUSION: In patients with UCB treated with RC, a high preoperative NLR is associated with more advanced tumor stage, lymph node metastasis, and worse prognosis. The NLR may be a readily available and useful biomarker for preoperative prognostic stratification. PATIENT SUMMARY: We investigated the neutrophil-to-lymphocyte ratio (NLR) as a prognostic marker in patients with bladder cancer treated with radical cystectomy. We found that a high NLR is associated with worse oncologic outcomes, suggesting it could play a role in risk stratification. PMID- 28723457 TI - Cost Analysis of the Enhanced Recovery After Surgery Protocol in Patients Undergoing Radical Cystectomy for Bladder Cancer. AB - BACKGROUND: Enhanced recovery after surgery (ERAS) protocols for radical cystectomy (RC) aim to improve patient care, reduce complications, and shorten hospital stay while potentially reducing health care expenditure. OBJECTIVE: Evaluate the ERAS protocol for 30-d global costs relative to standard management in the era immediately preceding the initiation of ERAS for RC. DESIGN, SETTING, AND PARTICIPANTS: Overall, 201 consecutive patients (99 with standard management, 102 with an ERAS protocol) who met inclusion criteria and who underwent open RC at a single institution were evaluated. Resource-based costs were collected for the initial surgical admission and for any readmissions or unscheduled clinic visits within 30 d. INTERVENTION: Implementation of the ERAS protocol. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Line-item billing data were transformed using resource-based cost estimates. Tukey-Kramer least squares mean analysis was performed to adjust for cost differences attributable to patient characteristics on multivariate analysis (age <70 yr, male sex, and Charlson comorbidity score 0 1). Adjusted overall costs for the standard and ERAS cohorts were calculated with each line item assigned to 1 of 10 cost centers to identify specific areas of savings or increased expenditures with implementation of ERAS. RESULTS AND LIMITATIONS: Average 30-d costs were $31 139 with standard management and $26 650 after implementation of ERAS, for savings of $4488 per procedure (p<0.0001). Areas of significant ERAS savings included intensive care unit care ($2056), surgical ward costs ($2029), ancillary treatment ($1279), and supplies ($1238), whereas increased ERAS expenditures included costs for drugs ($2088), home health ($590), and unscheduled outpatient visits ($162). Surgical/anesthesia costs were similar between the standard and ERAS groups at $6405 and $6286 respectively. This was a single-institution study. CONCLUSIONS: In addition to clinical benefits, ERAS for RC at our institution also afforded an average cost savings of $4488 per procedure. PATIENT SUMMARY: In this report, we evaluated the cost center-specific expenditures of the ERAS protocol for RC, demonstrating $4488 savings in 30-d costs relative to standard management. PMID- 28723456 TI - The Impact of Perioperative Blood Transfusion on Survival of Bladder Cancer Patients Submitted to Radical Cystectomy: Role of Anemia Status. AB - BACKGROUND: The prognostic role of perioperative blood transfusion (PBT) in patients who underwent radical cystectomy (RC) for bladder cancer (BCa), although supported by clinical evidence, still remains to be assessed definitively. OBJECTIVE: To investigate the impact of PBT on RC patients for overall survival and after stratifying according to preoperative anemia status and to define whether the oncologic impact may be assumed to be a primary effect of PBT or attributed to the reduced preoperative hemoglobin (Hb) level. DESIGN, SETTING, AND PARTICIPANTS: A total of 1490 consecutive patients with nonmetastatic BCa who underwent RC and pelvic lymph node dissection between January 1990 and August 2013 at a single referral center entered the study. PBT and preoperative Hb levels were statistically correlated with postoperative oncologic outcomes. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Kaplan-Meier analyses were used to evaluate the impact of PBT on overall mortality (OM) and cancer-specific mortality (CSM). Multivariable Cox regression analyses tested the relationship between PBT and the risk of OM and CSM in the overall population and after stratifying patients according to the severity of their anemia. RESULTS AND LIMITATIONS: A total of 580 patients (38.9%) received PBT. Mean postoperative follow-up was 125.13 mo (median: 110 mo). Overall 5- and 10-yr CSM survival rates were 58.3% and 47.6%, respectively. At multivariable Cox regression analyses, PBT could not be associated with an increased risk of either CSM or OM (all p > 0.3). Conversely, preoperative Hb levels were significantly associated with OM (hazard ratio [HR]: 0.88; confidence interval [CI], 0.83-0.95) and CSM (HR: 0.84; 95% CI, 0.77-0.95) (all p<0.001). A significant detrimental effect of PBT on OM (HR: 1.65; 95% CI, 1.08-2.52) and CSM (HR: 1.68; 95% CI, 1.04-2.70) (all p<0.03) was found in patients without preoperative anemia status. CONCLUSIONS: In nonanemic BCa patients proposed for RC, PBT is associated with a significant detrimental effect on CSM and OM. This effect seems to be attributable to the direct impact of PBT, regardless of the preoperative Hb value. PATIENT SUMMARY: In nonanemic patients proposed for radical cystectomy, a negative prognostic impact of perioperative blood transfusion should be taken into account. PMID- 28723458 TI - Adopting Enhanced Recovery Programmes in Radical Cystectomy: Can We Afford Not To? PMID- 28723459 TI - Case Presentation: Vesicovaginal Fistula Following a Total Abdominal Hysterectomy. PMID- 28723460 TI - Beware of Bugs! Hot Issues in Urinary Tract Infections and Inflammation. PMID- 28723461 TI - Inflammatory Markers Have a Role in Renal Cell Carcinoma Prognosis. PMID- 28723462 TI - Against the Role of Inflammatory Markers in Renal Cell Carcinoma Prognosis: The Missing Link Between Evidence of Association and Clinical Applicability. AB - Although an association between inflammatory markers (IMs) and renal cell carcinoma (RCC) prognosis has been proven, how to translate such information into treatment strategy has not been determined. The strongest argument against the use of IMs in the management of patients diagnosed with RCC is the missing link between evidence of association and clinical applicability. PMID- 28723464 TI - How to Use Antimicrobial Prophylaxis in Urological Procedures. AB - A revision of clinical practice in terms of antimicrobial prophylaxis is urgently needed starting from: (1) obtaining information about local pathogen profiles and antimicrobial resistance, (2) evaluating all patient-related risk factors for the development of infectious complications, (3) and prescribing antimicrobials according to the principles of the European Association of Urology guidelines. PMID- 28723463 TI - The Global Prevalence of Infections in Urology (GPUI) Study: A Worldwide Surveillance Study in Urology Patients. AB - The GPIU study is currently the only study registering health care-associated urogenital tract infections, especially in urology patients, in an ongoing surveillance protocol that can help to deliver data on adequate empirical antibiotic therapy in hospitalised urology patients according to guideline recommendations. The annual GPIU study will continue to be performed in November of each year under the URL http://gpiu.esiu.org/. PMID- 28723465 TI - Case Presentation: Mycotic Aortic Aneurysm and Psoas Abscess as a Complication of Bacillus Calmette-Guerin Instillations. AB - To prevent life-threatening aortic ruptures, it is important that primary care physicians and urologists are aware of the symptoms of a mycotic abdominal aortic aneurysm, even several months or years after bacillus Calmette-Guerin therapy. PMID- 28723466 TI - Clinical Case Discussion: Mycotic Aortic Aneurysm and Psoas Abscess as a Complication of Bacillus Calmette-Guerin Instillations. AB - After an infectious complication caused by bacillus Calmette-Guerin (BCG), consider a dose reduction. Treatment of a mycotic aneurysm with an endostent seems safe; however, continuation of BCG after mycotic aneurysm treatment is not advised. PMID- 28723467 TI - Human Papillomavirus Infection and Vaccination in Males. AB - CONTEXT: Human papillomavirus (HPV) is the commonest sexually transmitted pathogen in humans and is linked to the aetiopathogenesis for both benign and malignant disease in men. OBJECTIVE: To evaluate and summarise the evidence for HPV infection and vaccination in men. EVIDENCE ACQUISITION: A search of Medline, PubMed, and Scopus was performed to identify articles published in English within the last 10 yr addressing HPV epidemiology, the natural history of HPV infection and its long-term consequences, and vaccination in men. Relevant studies were then screened, and the data were extracted, analysed, and summarised. The Preferred Reporting Items for Systematic Reviews and Meta-analysis criteria were applied. EVIDENCE SYNTHESIS: HPV has an overall prevalence of >20% among men, although a minority of individuals develop external genital lesions (EGLs). The risk of acquiring a new HPV infection is robustly linked to sexual behaviour, with the most commonly infected sites being the prepuce, shaft, glans, corona, and scrotum. Of all cancer cases among men, 2% are attributable to HPV, and up to 50% of penile cancers are estimated to be either directly or indirectly driven by it, with HPV-16 the subtype most frequently isolated. Currently there are two different vaccines approved for men, with a good immunogenic profile and efficacy of up to 80% against EGLs; however, efficacy data regarding malignant lesions are still limited. CONCLUSIONS: HPV, owing to its high prevalence and harmful consequences for men's health, has recently attracted considerable attention. Novel insights into the natural history of HPV infection, together with the successful development of several efficacious vaccines, have provided valuable tools in the prevention of HPV infections and their related consequences. HPV vaccination appears to be the only reliable method to provide protection against new HPV infections in men. PATIENT SUMMARY: Human papillomavirus (HPV) infection is very common among sexually active men and can lead to more serious consequences, including cancer. Male vaccination is both a safe and efficacious option preventing both HPV infection and its long-term consequences. PMID- 28723468 TI - Trends in Antibiotic Resistance in Urologic Practice. AB - CONTEXT: The significant global upsurge in antimicrobial resistance, particularly among Enterobacteriaceae, represents a serious threat to health care systems. The implications for urologic practice are of particular concern. OBJECTIVE: To review trends in antibiotic resistance in urologic practice. EVIDENCE ACQUISITION: We report current European trends of resistance in Gram-negative uropathogens. EVIDENCE SYNTHESIS: In addition to beta-lactam resistance, Gram negative pathogens are often resistant to multiple drug classes, including aminoglycosides, fluoroquinolones, and carbapenems, commonly used to treat urologic infections. Interest is renewed in old antibiotics, and several new antibiotics are in the pipeline to meet the challenge of treating these infections. In this review, we summarise emerging trends in antimicrobial resistance and its impact on urologic practice. We also review current guidelines on the treatment and prevention of urologic infections with these organisms, and some key antibiotics in the era of resistance. CONCLUSIONS: Increasing antimicrobial resistance represents a challenge to urologic practice for both treatment and prophylaxis. Antibiotic choice should be determined according to risk factors for multidrug resistance. Good knowledge of the local microbial prevalence and resistance profile is required to guide antimicrobial therapy. PATIENT SUMMARY: Antimicrobial resistance represents a challenge in urology. We summarise emerging trends in antimicrobial resistance and review current guidelines on the treatment and prevention of urologic infections, as well as some key antibiotics in the era of resistance. PMID- 28723469 TI - Inflammation, Microbiota, and Prostate Cancer. AB - CONTEXT: Chronic inflammation of the prostate has been associated with preneoplastic lesions and cancer development. Multiple causes have been considered for chronic inflammation of the prostate. Inflammatory cytokines such as interleukins are implicated in prostate carcinogenesis and development. OBJECTIVE: To evaluate literature published on etiological factors, urinary microbiota, morphological features of proliferative inflammatory atrophy and high grade prostate intraepithelial neoplasia, genetic polymorphisms, inflammatory stress, and cytokine signaling. EVIDENCE ACQUISITION: We searched literature from PubMed from 2010 and also included the most important publications from the previous period. EVIDENCE SYNTHESIS: Prostate cancer inflammation and premalignant lesions have been frequently discussed in scientific literature. A limited number of models are available for studying inflammation and premalignant lesions. However, morphological pathology could be complemented by analysis of gene polymorphisms in these patients and appropriate functional studies. CONCLUSIONS: Prostatitis could be caused by bacterial or viral infections, dietary compounds, and changes in testosterone:estradiol ratio. In some cases, the microbiota can exert direct effects on cancer development. Prostate inflammatory atrophy or high grade prostate intraepithelial neoplasia have been associated with response to cellular stress and have been discussed in connection to early cancer development. A large number of genetic polymorphisms have been identified in inflammatory prostate. Genetic and epigenetic alterations may be a consequence of the proinflammatory stress in the prostate. Proinflammatory cytokines interleukin-6 and -8 contribute to prostate malignancy; however, their function was more frequently investigated in cancer tissue rather than in inflammation. PATIENT SUMMARY: We performed a review of recent literature related to prostate inflammation, microbiota, and prostate cancer. New functional approaches are required for a better understanding of the role of inflammation and cancer development. PMID- 28723470 TI - Sexually Transmitted Disease and Male Infertility: A Systematic Review. AB - CONTEXT: Theoretically, sexually transmitted diseases (STDs) have the potential to disrupt male fertility; however, the topic remains controversial. OBJECTIVE: To describe the possible association between STDs and male infertility and to explore possible pathophysiologic mechanisms. EVIDENCE ACQUISITION: We performed a systematic literature review in accordance with the PRISMA guidelines. PubMed, Embase, and the Cochrane Library were searched for articles published before January 1, 2016, using the MeSH terms for a variety of STDs and infertility. The search was restricted to human studies performed in men and published in English. Studies were included if they contained original data on a possible association or a cause-and-effect relationship between STD and male infertility. Studies were considered only if they included an appropriate control group and/or comprehensive laboratory data. Due to heterogeneity in the literature, a qualitative analysis was performed. EVIDENCE SYNTHESIS: Relevant studies on Chlamydia trachomatis, genital mycoplasmas, Neisseria gonorrhoeae, Trichomonas vaginalis, and viral infections were identified. For all pathogens, the studies were contradictory and generally of limited quality. In studies confirming an association, there was a tendency for authors to perform multiple analyses without appropriate corrections and to subsequently focus solely on outcomes that seemed to suggest a positive association; however, the body of literature that does not confirm an association between STDs and male infertility is also of inadequate quality. The data regarding possible pathophysiologic mechanisms are inconclusive. CONCLUSIONS: There may be an association between STDs and male infertility of unknown genesis and possibly with different pathogenic mechanisms for different pathogens. Alternatively, some STDs may cause male infertility, whereas others may not; however, there is hardly a strong correlation. High quality studies of the subject are needed. PATIENT SUMMARY: Sexually transmitted diseases may cause male infertility through unknown mechanisms; however, from the available research, we cannot be sure that there is an association, and more studies are needed. PMID- 28723471 TI - Urinary Tract Infections in Immunocompromised Patients with Diabetes, Chronic Kidney Disease, and Kidney Transplant. AB - CONTEXT: This paper provides a brief overview of urinary tract infections (UTIs) in immunocompromised patients from the perspective of a practicing urologist. OBJECTIVE: The primary objective was to provide an update on UTIs in immunocompromised patients. Diabetes mellitus (DM), chronic kidney disease, and kidney transplant (KT) are the most common clinical cases encountered by urologists. Diagnosis, management, and future research needs are summarised. EVIDENCE ACQUISITION: We conducted a nonsystematic review of the literature. A comprehensive search of the PubMed database between 1996 and 2016 was performed. EVIDENCE SYNTHESIS: Clinical diagnosis of UTIs in immunocompromised patients is challenging. Causative pathogens in DM are slightly different to those in the general population, but without any difference in resistance profiles. Keeping serum glucose under control is the most important preventive measure. The prevalence of UTIs in patients with autosomal dominant polycystic kidney disease (ADPKD) is 21-75%. Lipophilic antibiotics are effective in the treatment of infected cysts, albeit with a trend for lower effectiveness due to increasing resistance rates. UTIs are the most common infections in KT recipients, with a reported rate of 45-72%. Diagnostic challenges exist for both ADPKD and KT patients who develop UTIs. Treatment of UTIs should be tailored according to individual patient characteristics and the severity classification framework suggested by the European Society of Infections in Urology. CONCLUSIONS: The underlying pathophysiology of UTIs in immunocompromised patients is not well known, which limits UTI management, including early diagnosis, treatment, and prevention. Future research to identify patients at higher risk of UTIs is necessary. PATIENT SUMMARY: In this report we looked at patients with a weakened immune system who are more likely to develop a urine infection. We focused on the patient groups most commonly encountered in a urology setting. We found that these patients have a higher risk of urinary infection, but the signs of infection may be different to those in the general population. Early diagnosis is imperative in this group. Further research on early diagnosis and better individualised management strategies are necessary. PMID- 28723472 TI - Human Prostate Tissue-derived Extracellular Matrix as a Model of Prostate Microenvironment. AB - BACKGROUND: Clinical experience highlights the wide heterogeneity of primary prostate cancer (PPCa), even when potentially related to the same grade and stage. Currently available prediction tools and biomarkers do not always allow for early recognition of PPCa aggressive phenotype, sometimes making it impossible to distinguish among men harbouring indolent tumours or life threatening disease. OBJECTIVE: To establish a novel ex vivo/in vitro model suitable to estimate the invasive phenotype of PPCa cells (PPCaC). DESIGN, SETTING, AND PARTICIPANTS: The ability of PPCaC to infiltrate the prostate extracellular matrix (ECM) was used as an index of invasion. ECM was obtained by decellularising 24 NT-prostate specimens from radical prostatectomy. PPCaC were obtained from six tumours with different Gleason patterns and pathological stages. Invasion ability was estimated in direct-cocolture experiments. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The extent of ECM invasion by PPCaC was quantified by counting the number of infiltrated cells. Mann-Whitney test was utilised for statistical comparisons. RESULTS AND LIMITATIONS: Samples of ECM resulted to be free of cells and DNA and with a preserved three-dimensional structure and stromal protein content. The system resulted to be reliable since well characterised normal-, benign-, and malignant-prostate cell lines either re epitheliased or invaded the matrices, according to their specific nature. Similarly, PPCaC invaded the ECMs consistently with their stage and biochemical recurrence. Of notice, this model was able to identify a different invasive phenotype even among tumours with equal Gleason patterns and pathological stages. The small sample size represents a limitation. CONCLUSIONS: We developed an ex vivo/in vitro model able to reproduce the original PPCa-microenvironment and suitable to recognise the inherent invasive behaviour of PPCaC. PATIENT SUMMARY: We developed a novel ex vivo/in vitro system which enables us to uncover which prostate tumours host potentially aggressive cancer cells. The identification of cancer cells with different invasive abilities will likely lead to the identification of new biomarkers to safely predict disease progression. PMID- 28723473 TI - Can Decellularised Prostate Tissue Be Used to Model Tumour Malignancy? AB - This editorial discusses how feasible it will be to predict the invasive capacity of human prostate cancers by measuring their invasion into decellularised extracellular matrix and stresses the multiple factors that affect local metastasis, including immune and stromal cells. PMID- 28723474 TI - Introducing the Twitter Impact Factor: An Objective Measure of Urology's Academic Impact on Twitter. AB - BACKGROUND: Social media use in academia and urology is rising. Specifically, individual journals now have Twitter accounts (Twitter Inc, San Francisco, CA, USA) and regularly tweet academic content. OBJECTIVE: To present and evaluate the Twitter impact factor (TIF), a novel means of measuring a journal's academic influence in the realm of social media. DESIGN, SETTING, AND PARTICIPANTS: Journal Citation Reports (JCR; Thomson Reuters, New York, NY, USA) for 2014 was queried for urologic academic journals. English-language journals with active Twitter accounts since 2013 were included. The total number of followers, tweets, and retweets over a 2-yr period were collected. OUTCOME MEASURES AND STATISTICAL ANALYSIS: Each journal's TIF was calculated based on the number of retweets per original relevant tweet. Comparisons between the TIF and the journal impact factor (JIF) as well as the Klout score were made using the Pearson correlation. RESULTS AND LIMITATIONS: Of 33 journals listed in the JCR for 2014, 7 (21%) had a Twitter presence as of 2013. The number of JCR-listed journals with a Twitter handle increased by 29% in 2014. There was an increase in the mean number of relevant tweets per journal during the study period and a 130% increase in the number of retweets over 1 yr. European Urology (1.80) and BJU International (1.46) had the highest TIFs. The journals with the highest number of Twitter followers were European Urology (5807) and the Journal of Urology (4402). The journals with the highest numbers of relevant tweets were European Urology (1159) and BJU International (1090). There was a positive but statistically insignificant association between the TIF and the JIF (r=0.64, p=0.12). There was a strongly positive linear correlation between the TIF and the Klout score (r=0.84, p=0.0086). CONCLUSIONS: With the increasing use of social media by individuals and academic journals, the TIF can be a useful tool to measure the academic reach and impact of a journal on Twitter. PATIENT SUMMARY: Social media is an increasing part of the way in which practitioners and academicians communicate. The TIF can be used to analyze the impact of journal Twitter feeds and their social media content. PMID- 28723475 TI - Psychological Well-being and Private and Professional Psychosocial Support After Prostate Cancer Surgery: A Follow-up at 3, 12, and 24 Months After Surgery. AB - BACKGROUND: Cross-sectional studies indicate that a cancer patient's partner is important in regard to the patient's psychological well-being. This has yet to be investigated in a large prospective setting. OBJECTIVE: To investigate types of psychosocial support and whether men improved their well-being at 12 and 24 mo after radical prostatectomy. DESIGN, SETTING, AND PARTICIPANTS: In a group of 1446 men participating in the Laparoscopic Prostatectomy Robot Open (LAPPRO) trial reporting low well-being 3 mo after surgery and who also had a more limited social network, we investigated predictors of change in well-being at 12 and 24 mo. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Predictors of outcome were analyzed using log-binomial regression and forward regression. RESULTS AND LIMITATIONS: No one reported high well-being 3 mo after surgery. Of 1370 men reporting low well-being at 3 mo, 479 had improved to high well-being at 12 mo. At least one supportive person increased men's chances of improved well-being at 12 mo compared with 3 mo after surgery (relative risk [RR]: 1.32; 95% confidence interval [CI], 1.10-1.72), as did partner support (RR: 1.91; 95% CI, 1.28-2.86). The more people available for emotional and practical support, the more likely men were to improve their well-being at 12 and 24 mo, especially between 3 and 12 mo (p<0.0001). A limitation is that RRs were influenced by variations in the metrics of patient-reported well-being. CONCLUSIONS: The private network played a critical role regarding improved well-being. Having a partner and people to confide in within one's private network bettered patients' chances of improved well-being. Helping men mobilize support within their private network early on may be important in the recovery process. PATIENT SUMMARY: The link between one's private social network and well-being after prostate cancer surgery remains unclear. We investigated the role of support with many patients having undergone prostate cancer surgery. We found that the private social network was critical to men's well-being. PMID- 28723476 TI - Charting Recent Progress and Challenges in Metastatic Castration-resistant Prostate Cancer: Is There an Optimal Treatment Sequence? AB - CONTEXT: Recent developments in the treatment of metastatic castration-resistant prostate cancer (mCRPC) have led to uncertainty about the optimal sequence of agents. OBJECTIVE: To review and assess treatment options and sequence in patients with mCRPC. EVIDENCE ACQUISITION: To identify data on the optimal use of approved treatments, we searched PubMed for studies on the use of recently approved agents for men with mCRPC published before March 2015. Phase 3 and other key studies were included in the review of efficacy and safety. In this review, we offer our critical interpretation of potential treatment sequences for drug use in the light of our clinical experience. EVIDENCE SYNTHESIS: Since 2004, the treatment landscape for mCRPC has changed dramatically following the approval of docetaxel, abiraterone acetate, enzalutamide, cabazitaxel, denosumab, and radium 223 chloride. To date, only small-scale studies have been undertaken that provide evidence on the sequencing of these treatments. Ideally, randomised, prospective studies would evaluate different sequence options thoroughly so that physicians could make evidence-based decisions, but the number of new agents makes this impractical. When deciding which treatment to prescribe, physicians will need to use the available evidence combined with their own clinical judgement. The potential for cross-resistance between taxanes and hormonal therapies and the possibility that patients might not be suitable for aggressive therapies in later lines should be taken into account. Prevention of complications associated with bone metastases should also be a key consideration because of the major impact these events have on quality of life and healthcare costs. CONCLUSIONS: The recent approval of numerous new agents has resulted in considerable improvements in outcomes for patients with mCRPC. Further studies determining the optimal treatment algorithm, in addition to open discussion of best practice among physicians, are required to ensure patients obtain the maximum possible benefit from their treatment. PATIENT SUMMARY: In recent years a large number of new treatment options have been approved for use in men with prostate cancer. In the absence of clinical trials assessing the use of one option versus another in specific patient groups, it is important to review the currently published evidence to try to understand patients receive the best treatment options in the correct order. PMID- 28723477 TI - Accuracy of Self-reported Smoking Exposure Among Bladder Cancer Patients Undergoing Surveillance at a Tertiary Referral Center. AB - BACKGROUND: Smoking is a risk factor for developing bladder cancer (BCa). Even though continued exposure after diagnosis may adversely affect prognosis, patients may be reluctant to disclose to their physicians that they are currently smoking, leading to inaccurate reporting of exposure and missed opportunities to deliver smoking-cessation advice and treatment in the context of cancer care. OBJECTIVE: We examined the extent of misclassification of recent smoking exposure among patients undergoing BCa surveillance. DESIGN, SETTING, AND PARTICIPANTS: A consecutive sample of 145 patients with a self-reported smoking history and prior initial diagnosis of BCa was recruited from a tertiary referral urology clinic. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Patients were asked if they had smoked a cigarette or used nicotine replacement therapy (NRT) within the past week and whether they lived with a smoker. At the same visit, we collected urine under a biospecimen protocol. We used urinary cotinine, the primary metabolite of nicotine, as an objective biomarker of recent smoking exposure. Nine patients whose urine could not be interpreted for cotinine were excluded. We calculated the smoking status misreporting rate by comparing biochemically verified smoking status (>=31.5 ng/ml vs <31.5 ng/ml) against self-reported current smoking status (yes vs no) while considering recent NRT use. RESULTS AND LIMITATIONS: Overall, 11% (15 of 136) of patients had cotinine values consistent with current smoking. Of these 15 patients, 7 reported being former smokers, resulting in a 47% misclassification rate. However, three of the seven patients who denied smoking in the past week were currently using NRT. Excluding NRT users, the misclassification rate was 33%. CONCLUSIONS: Future studies investigating the impact of postdiagnosis nicotine exposure on BCa outcomes should use biochemical verification combined with self-reported smoking exposure to classify patients accurately. PATIENT SUMMARY: Bladder cancer patients may misreport smoking exposure, thereby missing opportunities for smoking cessation. PMID- 28723478 TI - Low T-cell Receptor Diversity, High Somatic Mutation Burden, and High Neoantigen Load as Predictors of Clinical Outcome in Muscle-invasive Bladder Cancer. AB - BACKGROUND: The success of cancer immunotherapies has highlighted the potent ability of local adaptive immune responses to eradicate cancer cells by targeting neoantigens generated by somatic alterations. However, how these factors interact to drive the natural history of muscle-invasive bladder cancer (MIBC) is not well understood. OBJECTIVE: To investigate the role of immune regulation in MIBC disease progression, we performed massively parallel T-cell receptor (TCR) sequencing of tumor-infiltrating T cells (TILs), in silico neoantigen prediction from exome sequences, and expression analysis of immune-related genes. DESIGN, SETTING, AND PARTICIPANTS: We analyzed 38 MIBC tissues from patients who underwent definitive surgery with a minimum clinical follow-up of 2 yr. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Recurrence-free survival (RFS) was determined. TCR diversity was quantified using Simpson's diversity index. The main analyses involved the Mann-Whitney U test, Kaplan-Meier survival analysis, and Cox proportional hazards models. RESULTS AND LIMITATIONS: Low TCRbeta chain diversity, correlating with oligoclonal TIL expansion, was significantly correlated with longer RFS, even after adjustment for pathologic tumor stage, node status, and receipt of adjuvant chemotherapy (hazard ratio 2.67, 95% confidence interval 1.08-6.60; p=0.03). Patients with both a high number of neoantigens and low TCRbeta diversity had longer RFS compared to those with fewer neoantigens and high TCR diversity (median RFS 275 vs 30 wk; p=0.03). Higher expression of immune cytolytic genes was associated with nonrecurrence among patients with low TCR diversity or fewer neoantigens. Limitations include the sample size and the inability to distinguish CD8+ and CD4+ T cells using TCR sequencing. CONCLUSIONS: These findings are the first to show that detailed tumor immune-genome analysis at definitive surgery can identify molecular patterns of antitumor immune response contributing to better clinical outcomes in MIBC. PATIENT SUMMARY: We discovered that clonal expansion of certain T cells in tumor tissue, possibly targeting cancer-specific antigens, contributes to prevention of bladder cancer recurrence. PMID- 28723479 TI - Infectious Complications of Circumcision and Their Prevention. AB - CONTEXT: A growing body of evidence supports the health benefits of circumcision, but the occurrence of infectious complications is of concern. OBJECTIVE: To review literature presenting past data and studies of infectious complications of circumcision and their prevention. EVIDENCE ACQUISITION: A literature search was conducted of the Cochrane Library, Embase, Turning Research into Practice, PubMed, and Medline databases from their inception through June 25, 2015. Results were closely evaluated, and articles and documents that were not pertinent or redundant were excluded. EVIDENCE SYNTHESIS: Although uncommon, local, systemic, and toxin-related infectious complications of circumcision represent a significant clinical problem. In general, untrained providers create more infectious and noninfectious complications when performing male circumcision than do well-trained providers, regardless of whether they are physicians, nurses, or traditional religious providers. Local complications include staphylococcal and streptococcal infections, cellulitis, impetigo, pyoderma, necrotizing fasciitis, scalded skin syndrome (staphylococcal), Fournier gangrene, glanular necrosis, scrotal abscess, and peritonitis. Ritual circumcision is rarely associated with acquisition of tuberculosis, diphtheria, or herpes virus. Systemic infectious complications include bacteremia, wound sepsis, and meningitis. Circumcision has also been associated with neonatal and adult tetanus. CONCLUSIONS: Infectious complications following circumcision should be reduced with trained and competent practitioners performing the procedure using sterile techniques. PATIENT SUMMARY: Complications of circumcision represent a significant problem. Male circumcision should be performed by trained, competent practitioners using sterile techniques and effective pain management. PMID- 28723480 TI - Grey Zones in the Field of Urinary Tract Infections. AB - Urinary tract infections are a very common clinical problem with various knowledge gaps requiring urgent attention in areas including pathophysiology, diagnosis, antibiotic resistance, and prophylaxis. These grey zones preclude optimal management of urologic patients. PMID- 28723481 TI - Kidney Cancer: Many Important Advances but Still a Lot to Debate. PMID- 28723482 TI - Surveillance of Small Renal Masses in Young Patients: A Viable Option in the Appropriate Candidate. AB - In young patients the risks of intervention for a renal mass are generally low, the perceived oncologic stakes are significant, and the burden for life-long close monitoring is often judged to be unreasonable. Nevertheless, in an appropriately selected patient for whom a period of active surveillance presents significant value, an interval of close clinical monitoring is a safe and reasonable approach. PMID- 28723483 TI - Active Surveillance for Small Renal Masses in Young Patients. AB - We certainly agree with active surveillance for small renal masses 9SRMs). However, it must be in appropriate patients, the elderly and the infirm, in whom the comorbidity risks outweigh the oncologic risks. Evidence to support active surveillance for SRMs in the young is lacking. PMID- 28723484 TI - Update on Radiogenomics of Clear Cell Renal Cell Carcinoma. AB - The goal of radiogenomics is to associate imaging features with gene expression pattern and correlate these features with clinical outcomes. Radiogenomics, by overcoming the histologic heterogeneity of clear cell renal cell carcinoma, has the potential to reflect tumor biology and predict prognosis. PMID- 28723485 TI - Three-dimensional Printing for Renal Cancer and Surgical Planning. AB - Three-dimensional (3D) stereolithographic models provide tactile and anatomic information that offers advantages over digital 3D reconstructions alone. This technology has the potential to alter preoperative surgical planning and significantly enhance successful performance of complex nephron-sparing surgery. PMID- 28723486 TI - Isolated Lung Metastases After Radical Nephrectomy for Clear Cell Carcinoma. AB - Here we describe a case of a biologically indolent renal cell carcinoma. A single lung metastasis was found 1 yr after resection of a pT2bNxM0 Fuhrmann grade 2 tumor. After a further 1 yr, the patient was treated with IFN-alpha and bevacuzimab. Treatment for renal cell carcinoma should be tailored individually for each patient. PMID- 28723487 TI - Clinical Case Discussion: Isolated Lung Metastases After Radical Nephrectomy for Clear Cell Carcinoma: The Case for Surgery. AB - In a stable patient with metastatic renal cell carcinoma, metastasectomy is an option when all the lesions can be resected. Individual informed consent from the patient is most important. PMID- 28723488 TI - Case Discussion: Systemic Therapy for Metastatic Renal Cell Carcinoma. AB - First-line systemic therapy for patients with metastatic renal cell carcinoma should largely entail the use of targeted agents. Depending on the clinical factors, VEGF- or mTOR-directed agents may be appropriate. PMID- 28723489 TI - Immunotherapy for Renal Cancer: Sequencing and Combinations. AB - CONTEXT: Current therapy for renal cell carcinoma (RCC) generally consists of the sequential administration of single agent therapy. Given the advent of T-cell checkpoint inhibitors, the role of combinations including these agents is being intensely interrogated. OBJECTIVE: To evaluate ongoing trials of combinations including immunotherapy and sequencing of agents to treat RCC. EVIDENCE ACQUISITION: Recent data and ongoing trials were analyzed to evaluate the direction of research in this arena. EVIDENCE SYNTHESIS: The favorable therapeutic index of programmed cell death 1/programmed death-ligand 1 inhibitors enable combinations of these agents. Multiple ongoing phase 3 trials are evaluating the first-line therapy of RCC using a combination of programmed cell death 1/programmed death-ligand 1 inhibitors with vascular endothelial growth factor inhibitors or cytotoxic T-lymphocyte-associated protein 4 inhibitors. The role of sequencing using single agent sunitinib and avelumab will be evaluated in a randomized phase 2 trial. The role of vaccine therapy remains unproven. The role of predictive biomarkers to select appropriate therapy requires a greater focus, given the multitude of possible therapies. CONCLUSIONS: Therapy for RCC should be tailored based on both patient and tumor characteristics. Combination therapy and sequencing of single agents may both play roles and are currently undergoing clinical trial evaluation. PATIENT SUMMARY: Combinations of immunotherapy with angiogenesis inhibitors are undergoing vigorous clinical trial evaluations. Sequencing of immunotherapy and antiangiogenic therapy is also undergoing investigation. Clinical trial participation is critically important to develop new drugs and combinations, and biomarkers to select therapy. PMID- 28723490 TI - Renal Preservation and Partial Nephrectomy: Patient and Surgical Factors. AB - CONTEXT: Optimization of the partial nephrectomy (PN) procedure in terms of preservation of functional outcomes is of special importance. OBJECTIVE: To review the most important patient and surgical factors that may influence the three elements that ultimately define the preservation of renal function (RF) after PN: preoperative RF, quantity of parenchyma preserved, and nephron recovery from ischemic insult. EVIDENCE ACQUISITION: A nonsystematic review of the literature was conducted. Relevant databases were searched for studies providing data on surgical, patient, and tumour factors predictive of RF preservation after PN. EVIDENCE SYNTHESIS: Many renal cell carcinoma patients have low RF at baseline or are at risk of rapid progression of chronic kidney disease. A glomerular filtration rate (GFR) of <=45ml/min/1.73m2 after PN is associated with higher risk of a 50% drop in GFR or dialysis. Greater tumor size and complexity are nonmodifiable factors that predict worse postoperative RF, longer warm ischemia time (IT), and greater healthy parenchymal volume loss (HPVL). Global renal ischemic injury can be minimized using off-clamp or selective minimal renal ischemia techniques that vary from simple regional ischemia to more complex techniques such as tertiary or higher-order renal arterial branch clamping. However, the quality and quantity of parenchymal mass preserved are the main predictors of RF after PN, and IT seems to have a secondary role, as long as warm IT is limited or ischemia is hypothermic. HPVL is minimized using enucleation techniques (oncologically equivalent to traditional PN for low-grade tumors in retrospective studies) and reduction of the parenchyma incorporated in renorrhaphy. Evidence on the comparative effectiveness of the various PN surgical approaches (open, laparoscopic, robotic, and thermoablation) in terms of functional outcomes is characterized by low overall quality. CONCLUSIONS: Efforts should be made to optimize the modifiable surgical factors identified for maximum RF preservation after PN. The low quality of evidence regarding the various surgical strategies for preserving RF prevents definitive conclusions. PATIENT SUMMARY: We reviewed the literature to determine the most important modifiable and non-modifiable factors that ultimately influence renal function after partial nephrectomy. The most important factors are the preoperative renal function and the volume of healthy renal parenchyma that the surgeon can spare during tumor resection, as long as the time of renal ischemia is limited. We discuss the strategies that allow optimization of the modifiable factors, ultimately leading to maximization of renal function after partial nephrectomy. PMID- 28723491 TI - Robotic Surgery for Renal Cell Carcinoma with Vena Caval Tumor Thrombus. AB - CONTEXT: Robotic surgery has significantly advanced the minimally-invasive management of kidney tumors with extension into the inferior vena cava requiring caval cross-clamping and tumor thrombectomy. Additional techniques have recently been developed to continue the evolution of this complex procedure and extend its indications. OBJECTIVE: To review the current state of the art as regards robotic nephrectomy with inferior vena cava thrombectomy (RNIT). EVIDENCE ACQUISITION: A systematic review of the Medline database was performed. All literature available through October 2016 was included. EVIDENCE SYNTHESIS: RNIT has been successfully adopted at select centers, but the number of patients reported to date remains limited. Modifications in clamping and tumor thrombus management have been described allowing for multiple options in surgical technique. Early perioperative outcomes appear favorable in comparison with traditional, open surgery, but further experience is needed. CONCLUSIONS: Feasibility and reproducibility of RNIT has been demonstrated, but longer-term outcomes and larger patient numbers are necessary before the role of this procedure is established. PATIENT SUMMARY: Kidney cancers invading the largest vein in the body, the vena cava, require complex surgery for removal. Traditionally this has required a large incision, but newer techniques with robotic surgery that continue to evolve have allowed for a minimally-invasive approach. PMID- 28723492 TI - Validation of Gene Expression Signatures to Identify Low-risk Clear-cell Renal Cell Carcinoma Patients at Higher Risk for Disease-related Death. AB - BACKGROUND: Approximately 5-10% of patients with "low-risk" clear cell renal cell carcinoma (ccRCC), as stratified by externally validated clinicopathologic prognostic algorithms, eventually have disease relapse and die. Improving prognostic algorithms for these low-risk patients could help to provide improved individualized surveillance recommendations. OBJECTIVE: To identify genes that are differentially expressed in patients with low-risk ccRCC who did and did not die of their disease. DESIGN, SETTING, AND PARTICIPANTS: Using the Mayo Clinic Renal Registry, we identified formalin-fixed paraffin-embedded samples from patients with low-risk ccRCC, as defined by Mayo Clinic stage, size, grade, and necrosis score of 0-3. We conducted a nested case-control study between patients who did (cases) and did not (controls) have ccRCC relapse and death, using two independent sets (discovery and validation). We performed RNA sequencing of all samples in the discovery set to identify differentially expressed genes. In the independent validation set, we assessed the top 50 expressed genes using the nCounter Analysis System (NanoString Technologies, Seattle, WA, USA). RESULTS AND LIMITATIONS: In the discovery set of 24 cases and 24 controls, 92 genes were differentially expressed with p<0.001. The top 50 genes were validated in an independent set of 22 cases and 22 controls using linear mixed models. In the validation set, 10 genes remained differentially expressed between the groups. CONCLUSIONS: RNA signatures from formalin-fixed paraffin-embedded blocks can identify patients with low-risk ccRCC who die of their disease. This finding provides an opportunity to help guide improved surveillance in patients with low risk ccRCC. PATIENT SUMMARY: In the current study we identified RNA signatures from low-risk clear cell renal cell carcinoma patients who died from this disease. Improving prognostic algorithms for these low-risk patients could help to provide improved individualized surveillance recommendations. PMID- 28723493 TI - Proteinuria in Patients Undergoing Renal Cancer Surgery: Impact on Overall Survival and Stability of Renal Function. AB - BACKGROUND: Proteinuria is included in the Kidney Disease: Improving Global Outcomes (KDIGO) risk stratification for chronic kidney disease (CKD) in the general population. However, the importance of proteinuria in patients with renal cancer has not been adequately studied. OBJECTIVE: To evaluate the prognostic impact of preoperative proteinuria on overall survival (OS) and renal function stability (RFS) for patients managed with renal cancer surgery. DESIGN, SETTING, AND PARTICIPANTS: From 1999 to 2008, 977 patients who underwent renal cancer surgery had preoperative data recorded for the glomerular filtration rate (GFR) estimated using the CKD Epidemiology Collaboration equation (G1 >=90, G2 60-89, G3a 45-59, G3b 30-44, G4 15-29, and G5 <15ml/min/1.73 m2) and proteinuria status according to a dipstick assay (ANEG, negative or trace protein; APOS, >=30mg/dl). Median follow-up was 8.7 yr (range 7.0-10.7). INTERVENTION: Renal cancer surgery. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: OS and RFS (avoidance of a decline in GFR of >=50% and of dialysis) were analyzed using the Kaplan-Meier method. We performed multivariable Cox regression to evaluate independent predictors for both outcomes. RESULTS AND LIMITATIONS: The 326 patients (33%) with APOS proteinuria status had compromised 5-yr OS compared with ANEG patients (65% vs 77%; p<0.001). They also had lower RFS at 5 yr (72% vs 86%; p<0.001). However, significant differences in OS according to proteinuria status were only observed in the G1, G2, and G3a groups, and differences in RFS in the G3a group. On multivariable analysis for all patients and for the G1, G2, and G3a groups, proteinuria was an independent prognostic factor for OS (both p<0.05). On multivariable analysis for all patients and for those in the G3a group, proteinuria was an independent prognostic factor for RFS (both p<0.05). Limitations include the retrospective study design and potential ascertainment bias. CONCLUSIONS: Proteinuria appears to be a significant and independent predictor of OS and RFS in patients undergoing renal cancer surgery, particularly for certain cohorts, and should be sensibly incorporated into routine management. Further studies, ideally prospective, are required to evaluate the importance of the degree of proteinuria. The generalizability of our findings will also require further investigation. PATIENT SUMMARY: Protein in the urine (proteinuria) is a sign of kidney damage, and kidney cancer patients with proteinuria have worse outcomes after surgery. Assessment of proteinuria should be routinely included in the preoperative evaluation of patients with kidney cancer. PMID- 28723494 TI - Harnessing Proteinuria as a Predictor of Postsurgical Outcomes in Kidney Cancer Patients. PMID- 28723495 TI - Surgical Management and Oncologic Outcomes of Recurrent Venous Tumor Thrombus after Prior Nephrectomy for Renal Cell Carcinoma. AB - BACKGROUND: While the management of a venous tumor thrombus in renal cell carcinoma is well described, there is a paucity of evidence to guide care in patients who recur within the vena cava. OBJECTIVE: To report our experience with patients presenting with recurrent venous tumor thrombi after prior radical nephrectomy. DESIGN, SETTING, AND PARTICIPANTS: A retrospective review of 16 patients from 1970 to 2013 with a history of renal cell carcinoma treated surgically for a recurrent tumor thrombus unrelated to a new renal tumor. INTERVENTION: Recurrent tumor thrombectomy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Intraoperative outcomes, recurrence-free survival, and cancer-specific survival following resection. RESULTS AND LIMITATIONS: Of the 16 patients, three patients were diagnosed with synchronous widely metastatic disease, did not undergo recurrent tumor thrombectomy, and died within 6 mo. Among the remaining 13 repeat surgical patients, the median age was 67 (range: 48-76) yr with a median time from prior nephrectomy to diagnosis of 6 (range: 3-58) mo. Nine patients had known tumor thrombus at nephrectomy, all of whom were thought to have complete tumor thrombectomy at initial surgery. During exploration for recurrent thrombus, surgical resection was completed in 11, with a median blood loss of 2500 (range: 200-7000) ml, and a median transfusion requirement of four (range: 0-18) units. At a median follow-up of 12 mo all patients had recurred and died of disease. The median time to recurrence and death was 4 mo and 12 mo following repeat exploration, respectively. CONCLUSIONS: Recurrent tumor thrombectomy is a technically feasible yet challenging operation. Survival is poor in this population with metastatic progression appreciated in all patients in our series. PATIENT SUMMARY: In this report we evaluated outcomes for patients presenting with vena cava tumor thrombus after prior nephrectomy for renal cell carcinoma. We found that surgical excision is complex yet feasible and that survival following resection was poor. PMID- 28723496 TI - Management of Recurrent Venous Tumor Thrombus Following Inferior Vena Cava Thrombectomy: Is Surgery the Right Answer? PMID- 28723498 TI - Genotyping the Host in the Battle Against Cancer. PMID- 28723497 TI - Pharmacogenomic Markers of Targeted Therapy Toxicity in Patients with Metastatic Renal Cell Carcinoma. AB - BACKGROUND: Targeted therapy (TT) in metastatic renal cell carcinoma (mRCC) may be associated with a high rate of toxicity that undermines treatment efficacy and patient quality of life. Polymorphisms in genes involved in the pharmacokinetic pathways of TTs may predict toxicity. OBJECTIVE: To investigate whether selected single-nucleotide polymorphisms (SNPs) in three core genes involved in the metabolism and transport of sunitinib and the mTOR inhibitors everolimus and temsirolimus are associated with adverse events (AEs). DESIGN, SETTING, AND PARTICIPANTS: Germline DNA was extracted from blood or normal kidney tissue from mRCC patients of Caucasian ethnicity in two cohorts treated with either sunitinib (n=159) or mTOR inhibitors (n=62). Six SNPs in three candidate genes (CYP3A4: rs2242480, rs4646437, and rs2246709; CYP3A5: rs15524; and ABCB1: rs2032582 and rs1045642) were analyzed. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Primary endpoints were grade >=3 AEs for all patients; grade >=3 hypertension in the sunitinib cohort, and any grade pneumonitis in the mTOR inhibitors cohort. A logistic regression model was used to assess the association between SNPs and AEs, with adjustment for relevant clinical factors. RESULTS AND LIMITATIONS: In total, 221 samples were successfully genotyped for the selected SNPs. In the sunitinib cohort, the CYP3A4 rs464637 AG variant was associated with a lower risk of high-grade AEs (odds ratio 0.27, 95% confidence interval 0.08-0.88; p=0.03), but no SNPs were associated with hypertension. In the mTOR inhibitor cohort, none of the selected SNPs was associated with analyzed toxicities. CONCLUSIONS: We observed an association between CYP3A4 polymorphisms and toxicity outcomes in mRCC patients treated with sunitinib, but not with everolimus or temsirolimus. Our findings are exploratory in nature, and further validation in independent and larger cohorts is needed. PATIENT SUMMARY: We found that variants of CYP3A4, a gene involved in drug metabolism, are associated with sunitinib toxicity. This information may help in better selection of patients for targeted therapies in metastatic renal cell carcinoma. PMID- 28723500 TI - The Advent of Psycho-oncology in Metastatic Renal Cell Carcinoma. PMID- 28723499 TI - Prospective Evaluation of the Impact of Antiangiogenic Treatment on Cognitive Functions in Metastatic Renal Cancer. AB - BACKGROUND: Little is known about the cognitive effects of antiangiogenic therapies (AATs) in metastatic renal cell carcinoma (mRCC) and their relation with fatigue. OBJECTIVE: To evaluate the impact of AATs on cognition and its connection with fatigue and quality of life (QoL) in patients with mRCC. DESIGN, SETTING, AND PARTICIPANTS: This prospective study enrolled 75 patients starting AAT as first or second line for mRCC and assessed them at 3 mo (n=58) and 6 mo (n=50). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We assessed objective cognitive decline with a neuropsychological battery of tests and cognitive complaint, fatigue, and QoL with validated self-reported questionnaires using the Fisher exact test, Wilcoxon test, and Spearman correlation coefficient. RESULTS AND LIMITATIONS: A decline of cognitive functions was observed in 18 patients (31%) including 13 without cognitive impairment at baseline. The score of fatigue was increased in all patients except one. A relationship between cognitive complaints and fatigue was observed (p<0.05) but not with objective cognitive decline. Cognitive complaints and fatigue had a significant impact on most of the domains of QoL (p<0.01). A positive correlation was found between fatigue and inflammatory markers but not with cognition. The main limitation of this study is the absence of a control group. CONCLUSIONS: AAT induced cognitive decline in patients with mRCC independently of fatigue. These side effects affecting QoL should be better assessed in clinical trials and taken into account in routine practice. PATIENT SUMMARY: Fatigue is a well-known effect of antiangiogenic therapies (AATs) of cancer. The study performed in patients with treated metastatic renal cancer shows a decline of cognitive functions induced by AATs, such as information-processing speed or working memory, in a third of patients, independently of fatigue. Patients on AATs should be informed of these possible adverse effects. PMID- 28723501 TI - Antioxidants: Is It Simply Too Late Once Lower Urinary Tract Symptoms Are Established? Editorial to [European Urology Focus 2/3 (2016) 310-318]. PMID- 28723502 TI - Is There a Role for Exosome-derived MicroRNAs in Detection of Renal Cell Tumors Using Urine Samples? Editorial to [European Urology Focus 2/2 (2016) 210-218]. PMID- 28723503 TI - Nephron Sparing for Renal Cell Carcinoma: Whenever Possible? AB - Open studies have definitely and repeatedly favoured nephron-sparing surgery in improving overall, cancer-specific, and cardiac disease-specific survival in cases with a normal contralateral kidney. However, the only randomised clinical trial could not confirm this superiority of nephron-sparing surgery over radical nephrectomy. PMID- 28723504 TI - Active Surveillance for Small Renal Masses: When Less is More. AB - CONTEXT: A marked increase in incidentally detected small renal masses (SRMs) has occurred over the past decade. Active surveillance (AS) has emerged as an initial management option for these patients. OBJECTIVE: (1) To determine selection criteria, assess appropriate imaging modalities and surveillance frequencies, and define triggers for delayed intervention (DI) for patients on AS. (2) To describe oncologic outcomes for patients on AS protocols. EVIDENCE ACQUISITION: The PubMed database was queried for English language articles using the keywords "surveillance" and "renal mass" or "renal cell carcinoma" or "kidney cancer." The level of evidence, sample size, study design, and relevance to the review were considered as inclusion criteria. EVIDENCE SYNTHESIS: A total of 69 manuscripts were included in the review. Selection criteria at initial evaluation for patients interested in AS include patient-related factors (eg, age, baseline renal function, other comorbidities), tumor-related factors (size, complexity, history of growth, possible renal mass biopsy), and patient preferences (illness uncertainty, quality of life). Cross-sectional imaging is the preferred initial imaging modality. Surveillance imaging should be performed at frequent intervals (3-4 mo) up front; intervals can be reduced over time if favorable growth kinetics are demonstrated. Delayed intervention (DI) should be considered for rapid tumor growth (eg,>0.5cm/yr), an increase in maximum tumor diameter >3-4cm, malignant renal mass biopsy results, development of symptoms, or patient preferences. Oncologic outcomes in well-controlled studies demonstrate a metastatic rate of 1-2%. Most patients who undergo DI remain eligible for nephron sparing approaches; oncologic outcomes are not compromised by DI strategies. CONCLUSIONS: A period of initial AS is safe for most patients with SRMs. Management decisions should focus on a thorough assessment of risk-benefit trade offs, judiciously integrating patient-related factors, tumor-related factors, and patient preferences. PATIENT SUMMARY: A period of initial active surveillance for kidney masses of <=4cm in diameter is safe in most patients. Frequent imaging and follow-up are necessary to determine if the tumor grows. If delayed intervention becomes necessary, cancer outcomes are not compromised by the initial choice of active surveillance when patients adhere to close follow-up regimens. PMID- 28723505 TI - Delivering Optimal Care for Metastatic Prostate Cancer: A Strengthening Alliance Between Urologists and Medical Oncologists. PMID- 28723506 TI - Biomarkers for Metastatic Castration-resistant Prostate Cancer (mCRPC): Yes or No? Predictive and Response Biomarkers Towards Precision Medicine in mCRPC. AB - Advances in drug development and molecular studies for castration-resistant prostate cancer (CRPC) render the possibility of more efficient and precise patient care through the use of predictive, response, and resistance biomarkers. Thorough scrutiny of assay validation and clinical qualification processes for biomarkers in development, ideally in parallel with clinical trials, is critical for the success of personalised medicine in CRPC management. PMID- 28723507 TI - The Use of Biomarkers to Manage Men with Metastatic Prostate Cancer: One Day, But Not Yet. AB - Metastatic castration-resistant prostate cancer has poor survival outcomes. New prognostic gene panels are being used in developing ways to interrogate the likely natural history of an individual's disease. Biomarker innovations to calculate tumour burden also hold promise for the future, but there is still some way to go to validate and stratify their use. PMID- 28723508 TI - Targeting Adaptive Pathways in Metastatic Treatment-Resistant Prostate Cancer: Update on the Stand Up 2 Cancer/Prostate Cancer Foundation-Supported West Coast Prostate Cancer Dream Team. AB - The Stand Up 2 Cancer/Prostate Cancer Foundation-funded West Coast Dream Team project is a prospective multi-institutional study focused on acquiring metastatic castration-resistant prostate cancer (mCRPC) biopsy tissue at the time of resistance to abiraterone or enzalutamide. It is the first large-scale study designed to analyze mCRPC tissue specifically in this patient population. Study accrual is on target, with 261 out of a planned 300 metastatic tumor biopsies performed by August 2016. Paired biopsies have been completed in 42 patients, with paired genomic data before and after therapy obtained in 26 cases. Accrual is expected to be complete by December 2016. PMID- 28723509 TI - Castration-resistant Prostate Cancer: Preservation of Quality of Life and Well being. AB - Managing optimal health in castrate-resistant prostate cancer is a complex clinical challenge. Quality of life should be assessed with disease-specific validated tools and can be used in clinical practice to assist in considering management options. PMID- 28723510 TI - Case Presentation: Fit Patient with Nonmetastatic Castration-resistant Prostate Cancer, Lower Urinary Tract Symptoms, and Severe Recurrent Haematuria. AB - Patients with castration-resistant prostate cancer still need a urologist or radiation oncologist for treatment of local complications. Symptomatic progression will be reduced with treatment of the primary tumour. PMID- 28723511 TI - Fit Patient with Nonmetastatic Castration-resistant Prostate Cancer, Lower Urinary Tract Symptoms, and Severe Recurrent Haematuria. AB - For biochemical relapse in patients with nonmetastatic castration-resistant prostate cancer previously treated with androgen deprivation alone, external beam radiotherapy to the primary tumour and the pelvic lymph nodes is preferable to radical prostatectomy with lymphadenectomy. PMID- 28723512 TI - Palliative Radical (Cysto-)prostatectomy for Locally Advanced, Symptomatic Castration-resistant Prostate Cancer. AB - Palliative radical (cysto-)prostatectomy is associated with a median symptom-free survival which covers 75-80% of the remaining lifetime in patients with symptomatic locally advanced castration-resistant prostate cancer. PMID- 28723513 TI - The Natural History and Outcome Predictors of Metastatic Castration-resistant Prostate Cancer. AB - CONTEXT: Biomarkers for the treatment of metastatic castration-resistant prostate cancer (mCRPC) are urgently needed by clinicians to facilitate treatment decisions. OBJECTIVE: To review current prognostic and predictive biomarkers in mCRPC. EVIDENCE ACQUISITION: We performed a nonsystematic review of the literature from 2004 to August 2016 by searching in Medline. Cross-matching references were used to search for additional articles. We reviewed clinical research and review articles written in the English language. EVIDENCE SYNTHESIS: Nomograms of prognostic factors (eg, albumin, lactate dehydrogenase) enable clinicians to estimate the prognosis of men with mCRPC. These prognostic tools may aid with when to trigger treatment, therapeutic monitoring, and follow-up. However, validated predictive biomarkers in mCRPC are still lacking. Androgen receptor (AR) splice variants (ie, AR-V7), gene fusions, and point mutations determined using liquid biopsies such as circulating tumor cells (CTCs) or cell free DNA (cfDNA) are promising biomarkers that are the subject of ongoing research. Patient biomarkers (eg, neutrophil-to-lymphocyte ratio) are readily available and come with no extra cost but need further validation before their implementation in clinical practice. CONCLUSIONS: Determination of AR-V7 in CTCs is a big step towards a more personalized treatment approach in mCRPC. Genomic characterization of liquid biopsies such as CTCs, cfDNA, and circulating RNA are noninvasive tools to further personalize treatment in prostate cancer. Clinical parameters are readily available, but are derived from retrospective studies and should be interpreted with care. Only by conducting biomarker-driven studies, rather than large one-size-fits-all trials, will we be able to improve prostate cancer treatment. PATIENT SUMMARY: Several biomarkers are currently under investigation that may predict which patients will respond to specific therapies in the future of metastatic castration-resistant prostate cancer treatment. PMID- 28723514 TI - Optimal Treatment Sequence for Metastatic Castration-resistant Prostate Cancer. AB - CONTEXT: Unprecedented development of therapeutics for prostate cancer in recent years has left clinicians with the challenge of adequately sequencing therapeutic agents to optimise patient benefit. No clear guidelines exist on optimal treatment sequences. OBJECTIVE: To summarise the evidence on first-line activity, cross-resistance, and potential combinations of agents approved for metastatic castration-resistant prostate cancer (mCRPC). EVIDENCE ACQUISITION: A nonsystematic literature search of articles on agent sequencing in mCRPC in PubMed and relevant cancer conferences up to June 2016 was performed. EVIDENCE SYNTHESIS: No definitive evidence on the optimal mCRPC treatment sequence exists. Hormonal agents are preferred for first-line treatment on the basis of favourable toxicity, but no evidence of superiority over chemotherapy exists. Evidence suggests significant cross-resistance between agents in first- and second-line settings. The impact of prior chemotherapy in metastatic hormone-sensitive disease is unknown. No combinations have proven benefit to date. Molecular biomarker assessment in liquid biopsies may aid selection of treatment in the near future. CONCLUSIONS: It is unlikely that a single sequence will be adequate for all mCRPC patients. An individualised strategy that assesses the biological mechanisms of the disease and monitors molecular drivers of progression and resistance to treatment is required to maximise benefit for each patient and bring us closer to the goal of best care. PATIENT SUMMARY: In this review we summarise evidence on the optimal sequence of anticancer drugs for metastatic castration-resistant prostate cancer. No agent has proven superior to another as front-line treatment, and the exact impact of prior treatments on drug efficacy is unknown. Better biomarkers for treatment selection and evaluation of response to treatment will be needed to personalise the optimal sequence for each individual patient. PMID- 28723515 TI - Understanding Mechanisms of Resistance in Metastatic Castration-resistant Prostate Cancer: The Role of the Androgen Receptor. AB - CONTEXT: After initiation of androgen deprivation therapy (ADT), most patients progress to castration-resistant prostate cancer (CRPC) within 2 or 3 yr. In the USA, approximately 67000 men are estimated to have metastatic CRPC. OBJECTIVE: To provide an overview of different mechanisms driving resistance to therapy in metastatic CRPC, with a focus on androgen receptor (AR)-dependent pathways. EVIDENCE ACQUISITION: A Medline search via PubMed was performed using the keywords metastatic castration resistant prostate cancer (mCRPC), castration resistant, CRPC, prostate cancer, androgen resistance, hormone-refractory, hormone-independent, androgen receptor, and androgen receptor axis. Only articles in the English language were included. Abstracts and full-text articles were reviewed and assessed for relevant content. The majority of the articles selected were published between 1993 and 2016. Older studies were included selectively if relevant. EVIDENCE SYNTHESIS: Numerous resistance mechanisms characterize the development of CRPC. The review focuses on AR-dependent pathways, including mechanisms of resistance to new agents. These include reactivation of AR (via AR amplification, mutations, or splice variants), stress-activated pathways, and aberrant activation of AR. CONCLUSIONS: Mechanisms of resistance in CRPC are manifold and require multiple combinations of therapeutic approaches to be overcome. An understanding of the mechanisms by which resistance to ADT develops is the basis for identifying future therapeutic targets. PATIENT SUMMARY: Castration-resistant prostate cancer is characterized by multiple resistance mechanisms to androgen deprivation treatment and remains an incurable disease. An understanding of the mechanisms underlying this resistance is necessary to identify future therapeutic targets. PMID- 28723516 TI - The Molecular Evolution of Castration-resistant Prostate Cancer. AB - CONTEXT: Androgen deprivation therapy (ADT) is the backbone of treatment for advanced prostate cancer. However, castration-resistant prostate cancer (CRPC) nearly invariably develops through a range of different molecular mechanisms accompanied by progression to a more aggressive phenotype. OBJECTIVE: To understand the key molecular mechanisms leading to CRPC and the functional implications of this progression. Understanding molecular evolutionary mechanisms in CRPC is essential for the development of novel curative therapeutic approaches. EVIDENCE ACQUISITION: A systematic literature search to identify relevant original articles was conducted using PubMed. Findings verified in independent studies and supported by in vivo data were prioritised. From the eligible collection, 50 papers were selected. EVIDENCE SYNTHESIS: The majority of CRPC tumours harbour alterations in the androgen receptor (AR) at the DNA, RNA, and/or protein level, and/or other alterations involving the AR signalling pathway, so this central molecule is the focus of this review. To survive and resume growth despite low levels of circulating androgens, prostate cancer cells can also adapt androgen synthesis or induce alternative pathways. CONCLUSIONS: Despite more efficient ADT strategies, most evidence points to persistent AR signalling as a major mechanism of progression to CRPC. Resistance due to transdifferentiation or AR independence is also emerging as a mechanism of resistance. The diversity of potential resistance mechanisms supports the need for combination treatment and serial monitoring for adaptive treatment strategies. PATIENT SUMMARY: In this review, we summarise how prostate cancer cells evade androgen deprivation therapy and become more aggressive. Defining the molecular mechanisms will be critical for the development of new treatment approaches and hence improved survival. PMID- 28723517 TI - Practice Patterns Compared with Evidence-based Strategies for the Management of Androgen Deprivation Therapy-Induced Side Effects in Prostate Cancer Patients: Results of a European Web-based Survey. AB - BACKGROUND: Evidence-based recommendations are available for the management of androgen deprivation therapy (ADT)-induced side effects; however, there are no data on the implementation of the recommendations into daily practice patterns. OBJECTIVE: To compare practice patterns in the management of ADT-induced side effects with evidence-based strategies. DESIGN, SETTING, AND PARTICIPANTS: A European Web-based survey was conducted from January 16, 2015, to June 24, 2015. The 25-item questionnaire was designed with the aid of expert opinion and covered general respondent information, ADT preference per disease stage, patient communication on ADT-induced side effects, and strategies to mitigate side effects. All questions referred to patients with long-term ADT use. Reported practice patterns were compared with available evidence-based strategies. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Following data collection, descriptive statistics were used for analysis. Frequency distributions were compiled and compared using a generalised chi-square test. RESULTS AND LIMITATIONS: In total, 489 eligible respondents completed the survey. Luteinising hormone-releasing hormone-agonist with or without an antiandrogen was the preferred method of ADT in different settings. Patients were well informed about loss of libido (90%), hot flushes (85%), fatigue (67%), and osteoporosis (63%). An osteoporotic and metabolic risk assessment prior to commencing ADT was done by one-quarter of physicians. The majority (85%) took preventive measures and applied at least one evidence-based strategy. Exercise was recommended by three-quarters of physicians who advocate its positive effects; however, only 25% of physicians had access to exercise programmes. Although the minimum sample size was set at 400 participants, the current survey remains susceptible to volunteer and nonresponder bias. CONCLUSIONS: Patients were well informed about several ADT induced complications but uncommonly underwent an osteoporotic and metabolic risk assessment. Nevertheless, physicians partially provided evidence-based strategies for the management of the complications. Physicians often advised exercise to reduce ADT-induced side effects, but programmes were not widely available. PATIENT SUMMARY: Implementation of evidence-based strategies for androgen deprivation therapy-induced side effects in real-life practice patterns should be improved. PMID- 28723518 TI - Mid-term Outcomes Following Salvage Lymph Node Dissection for Prostate Cancer Nodal Recurrence Status Post-radical Prostatectomy. AB - BACKGROUND: Patients with oligometastatic prostate cancer lymph node recurrence can be treated with many options including salvage lymph node dissection (sLND). OBJECTIVE: Evaluation of outcomes of sLND and identification of clinicopathologic features in predicting further biochemical and radiological relapse after sLND for prostate cancer. DESIGN, SETTING, AND PARTICIPANTS: Between November 1, 2009 and March 31, 2015, 117 patients with biochemical recurrence (BCR) after radical prostatectomy (RP) underwent sLND by a single surgeon after a standardized 11C choline positron emission tomography/computed tomography. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Biochemical response (BR) was defined as a prostate specific antigen (PSA) < 0.2ng/ml after sLND, BCR was defined as a PSA greater than 0.2 ng/ml with an increased trend after sLND, and radiological recurrence (RAR) was defined as a positive 11C-choline positron emission tomography/computed tomography imaging study or biopsy proven metastasis after sLND. Kaplan-Meier method was used to assess time to BCR, RAR, and cancer-specific mortality. Preoperative and postoperative predictors of BCR and RAR were assessed with Cox regression analyses. RESULTS AND LIMITATIONS: All patients had confirmed lymph node metastasis on final sLND pathology. Median follow-up after sLND was 20.2 mo (interquartile range: 11.8-33.6). All but one patient had a decrease in PSA while 93/117 (79.5%) patients achieved BR after sLND. In those who achieved BR, a subsequent BCR occurred in 40% of cases (n=37/93). The 5-yr BCR, RAR, and cancer specific mortality-free survival rates were 31%, 51%, and 97% respectively. At multivariate analyses, predictors of both BCR and RAR were pathological stage of the tumor at original RP and whether the nodes were castrate resistant prostate cancer. Given the nonrandomized nature, it is not known how these men would have fared according to survival or quality of life by observation, and/or other systemic therapy. CONCLUSIONS: An optimal candidate for sLND tends to have pT2 at the original RP and a castration sensitive disease state. sLND could be considered part of a multimodal treatment approach in select patients with castrate-resistant prostate cancer in which delayed/reduced cancer progression could be achieved with a cytoreductive surgery. PATIENT SUMMARY: We found that by performing a salvage lymph node dissection there are many men that can experience a biochemical response and eliminate further 11C-choline positron emission tomography/computed tomography radiographic recurrences. PMID- 28723519 TI - Individual Patient Data Analysis of Randomized Clinical Trials: Impact of Black Race on Castration-resistant Prostate Cancer Outcomes. AB - BACKGROUND: Population data suggest that black men have a higher risk of dying from prostate cancer (PCa) than other racial ethnicities. OBJECTIVE: To examine the impact of black race on progression-free survival (PFS) and overall survival (OS) among men with metastatic castration-resistant PCa (mCRPC) enrolled in randomized controlled trials (RCTs). DESIGN, SETTING, AND PARTICIPANTS: A pooled analysis was performed on individual patient data from five modern PCa RCTs available from Project Data Sphere. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Adjusted hazard ratios (HRs) were calculated to compare black and white race regarding PFS and OS. Subgroup analyses of mCRPC trials were performed based on the control arm treatments (mitoxantrone or docetaxel). Relevant covariates were used for adjustment in all analyses. RESULTS AND LIMITATIONS: A total of 1613 patients were included; 77 were black (4.7%). No significant differences between black and white men's baseline characteristics were noted regarding age, performance status, or pretreatment prostate-specific antigen. The pooled HRs for black race for OS and PFS were 1.01 (95% confidence interval [CI], 0.73-1.35) and 1.29 (95% CI, 0.95-1.76), respectively. The median OS for black compared with white men was 254 versus 238 d (p=0.92), respectively, with mitoxantrone and 581 versus 546 d (p=0.53), respectively, with docetaxel. The primary limitation was the relatively small number of black men enrolled in mCRPC clinical trials. CONCLUSIONS: In the context of RCTs, in which patients receive generally uniform treatment, a significant difference in OS for black men could not be detected in mCRPC. Black men continue to be dramatically underrepresented in RCTs, and efforts are needed to increase minority accrual to these trials. PATIENT SUMMARY: We looked at the outcomes of men treated in randomized controlled trials to determine the impact of black race on survival. We found that in the context of modern clinical trials, there does not appear to be a significant difference in survival between black and white races; however, a trend for greater progression in black men was noted. PMID- 28723520 TI - Bone Scan Index as an Imaging Biomarker in Metastatic Castration-resistant Prostate Cancer: A Multicentre Study Based on Patients Treated with Abiraterone Acetate (Zytiga) in Clinical Practice. AB - BACKGROUND: Abiraterone acetate (AA) prolongs survival in metastatic castration resistant prostate cancer (mCRPC) patients. To measure treatment response accurately in bone, quantitative methods are needed. The Bone Scan Index (BSI), a prognostic imaging biomarker, reflects the tumour burden in bone as a percentage of the total skeletal mass calculated from bone scintigraphy. OBJECTIVE: To evaluate the value of BSI as a biomarker for outcome evaluation in mCRPC patients on treatment with AA according to clinical routine. DESIGN, SETTING, AND PARTICIPANTS: We retrospectively studied 104 mCRPC patients who received AA following disease progression after chemotherapy. All patients underwent whole body bone scintigraphy before and during AA treatment. Baseline and follow-up BSI data were obtained using EXINI BoneBSI software (EXINI Diagnostics AB, Lund, Sweden). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Associations between change in BSI, clinical parameters at follow-up, and overall survival (OS) were evaluated using the Cox proportional hazards regression models and Kaplan-Meier estimates. Discrimination between variables was assessed using the concordance index (C-index). RESULTS AND LIMITATIONS: Patients with an increase in BSI at follow-up of at most 0.30 (n=54) had a significantly longer median survival time than those with an increase of BSI >0.30 (n=50) (median: 16 vs 10 mo; p=0.001). BSI change was also associated with OS in a multivariate Cox analysis including commonly used clinical parameters for prognosis (C-index=0.7; hazard ratio: 1.1; p=0.03). The retrospective design was a limitation. CONCLUSIONS: Change in BSI was significantly associated with OS in mCRPC patients undergoing AA treatment following disease progression in a postchemotherapy setting. BSI may be a useful imaging biomarker for outcome evaluation in this group of patients, and it could be a valuable complementary tool in monitoring patients with mCRPC on second-line therapies. PATIENT SUMMARY: Bone Scan Index (BSI) change is related to survival time in metastatic castration-resistant prostate cancer (mCRPC) patients on abiraterone acetate. BSI may be a valuable complementary decision-making tool supporting physicians monitoring patients with mCRPC on second-line therapies. PMID- 28723521 TI - Bone Scan Index and Progression-free Survival Data for Progressive Metastatic Castration-resistant Prostate Cancer Patients Who Received ODM-201 in the ARADES Multicentre Study. AB - BACKGROUND: ODM-201, a new-generation androgen receptor inhibitor, has shown clinical efficacy in prostate cancer (PCa). Quantitative methods are needed to accurately assess changes in bone as a measurement of treatment response. The Bone Scan Index (BSI) reflects the percentage of skeletal mass a given tumour affects. OBJECTIVE: To evaluate the predictive value of the BSI in metastatic castration-resistant PCa (mCRPC) patients undergoing treatment with ODM-201. DESIGN, SETTING, AND PARTICIPANTS: From a total of 134 mCRPC patients who participated in the Activity and Safety of ODM-201 in Patients with Progressive Metastatic Castration-resistant Prostate Cancer clinical trial and received ODM 201, we retrospectively selected all those patients who had bone scan image data of sufficient quality to allow for both baseline and 12-wk follow-up BSI assessments (n=47). We used the automated EXINI bone BSI software (EXINI Diagnostics AB, Lund, Sweden) to obtain BSI data. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We used the Cox proportional hazards model and Kaplan-Meier estimates to investigate the association among BSI, traditional clinical parameters, disease progression, and radiographic progression-free survival (rPFS). RESULTS AND LIMITATIONS: In the BSI assessments, at follow-up, patients who had a decrease or at most a 20% increase from BSI baseline had a significantly longer time to progression in bone (median not reached vs 23 wk, hazard ratio [HR]: 0.20; 95% confidence interval [CI], 0.07-0.58; p=0.003) and rPFS (median: 50 wk vs 14 wk; HR: 0.35; 95% CI, 0.17-0.74; p=0.006) than those who had a BSI increase >20% during treatment. CONCLUSIONS: The on-treatment change in BSI was significantly associated with rPFS in mCRPC patients, and an increase >20% in BSI predicted reduced rPFS. BSI for quantification of bone metastases may be a valuable complementary method for evaluation of treatment response in mCRPC patients. PATIENT SUMMARY: An increase in Bone Scan Index (BSI) was associated with shorter time to disease progression in patients treated with ODM-201. BSI may be a valuable method of complementing treatment response evaluation in patients with advanced prostate cancer. PMID- 28723523 TI - Metastatic Castration-resistant Prostate Cancer: Major Progress Leading to Even More Questions. AB - Treatment of metastatic castration-resistant prostate cancer is complex and we are facing more questions with major practical impact with the available effective drugs. Treatment optimization requires that all clinical partners work together. Survival is linked to the number of regimen used. The androgen pathway is key, while chemotherapy is the other major tool. PMID- 28723522 TI - Efficacy and Safety of Hexanic Lipidosterolic Extract of Serenoa repens (Permixon) in the Treatment of Lower Urinary Tract Symptoms Due to Benign Prostatic Hyperplasia: Systematic Review and Meta-analysis of Randomized Controlled Trials. AB - CONTEXT: A recent Cochrane Collaboration meta-analysis of randomized controlled trials (RCTs) evaluating the efficacy of different extracts of Serenoa repens in relieving lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH) concluded that these extracts were no more effective than placebo. However, among all Serenoa repens extracts, Permixon (Pierre Fabre Medicament, Paris, France) has the highest activity and the most accurate standards of drug preparation and extraction. OBJECTIVE: To evaluate the efficacy and safety of Permixon in the treatment of LUTS/BPH. EVIDENCE ACQUISITION: A systematic review and meta-analysis of the literature was performed in January 2016 using the Medline, Scopus, and Web of Science databases, searching for the term Serenoa repens in all fields of the records. Only RCTs reporting on efficacy and safety of Permixon in the treatment of LUTS/BPH were selected. EVIDENCE SYNTHESIS: The systematic search identified 12 RCTs: 7 compared Permixon with placebo; 2 compared Permixon with tamsulosin; 2 compared Permixon plus tamsulosin with, respectively, placebo plus tamsulosin and tamsulosin alone; and 1 compared Permixon with finasteride. Permixon was significantly more effective than placebo in reducing the number of nocturnal voids (weighted mean difference [WMD] -0.31; p=0.03) and increasing maximum flow rate (Qmax; WMD 3.37; p<0.0001). The rates of overall adverse events (odds ratio [OR] 1.12; p=0.92) and withdrawal (OR 1.52; p=0.60) were similar for Permixon and placebo. Permixon was as effective as tamsulosin monotherapy and short-term therapy with finasteride in improving International Prostate Symptom Score (WMD 1.15; 95% confidence interval [CI], 1.11 to 3.40; p=0.32) and Qmax (WMD -0.16; 95% CI, -0.60 to 0.28; p=0.48). The combination of Permixon and tamsulosin was more effective than Permixon alone for relieving LUTS (WMD 0.31; 95% CI, 0.13-0.48; p<0.01) but not for improving Qmax (WMD 0.10; 95% CI -0.02 to 0.21; p=0.10). Permixon had a favorable safety profile, with a very limited impact with regard to ejaculatory dysfunction compared with tamsulosin (0.5% vs 4%; p=0.007) and with regard to decreased libido and impotence compared with short-term finasteride (2.2% and 1.5% vs 3% and 2.8%, respectively). CONCLUSIONS: The conclusions of the recent Cochrane meta analysis on Serenoa repens in the treatment of LUTS/BPH apparently do not apply to Permixon. Our meta-analysis showed that Permixon decreased nocturnal voids and Qmax compared with placebo and had efficacy in relieving LUTS similar to tamsulosin and short-term finasteride. Moreover, Permixon had a favorable safety profile with a very limited impact on sexual function, which is significantly affected by all other drugs used to treat LUTS/BPH. PATIENT SUMMARY: A systematic review of the literature showed that Permixon was effective for relieving urinary symptoms due to prostate enlargement and improving urinary flow compared with placebo. Permixon had efficacy similar to tamsulosin and short-term finasteride in relieving urinary symptoms. Permixon was well tolerated and had a very limited impact on sexual function. PMID- 28723524 TI - The Rapidly Evolving Role of Imaging in Urology: How to Balance Breakthroughs in Knowledge with Overuse. PMID- 28723525 TI - Improving Staging in Bladder Cancer: The Increasing Role of Multiparametric Magnetic Resonance Imaging. AB - CONTEXT: In bladder cancer (BCa) patients, accurate local and regional tumor staging is required when planning treatment. Clinical understaging frequently occurs and leads to undertreatment of the disease, with a negative impact on survival. An improvement in staging accuracy could be attained by advances in imaging. Magnetic resonance imaging (MRI) is currently the best imaging technique for locoregional staging for several malignancies because of its superior soft tissue contrast resolution with the advantage of avoiding exposure to ionizing radiation. Important improvements in MRI technology have led to the introduction of multiparametric MRI (mpMRI), which combines anatomic and functional evaluation. OBJECTIVE: To review the fundamentals of mpMRI in BCa and to provide a contemporary overview of the available data on the role of this emerging imaging technology. EVIDENCE ACQUISITION: A nonsystematic literature search using the Medline and Cochrane Library databases was performed up to March 2016. Additional articles were retrieved by cross-matching references of selected articles. Only articles reporting complete data with regard to image acquisition protocols, locoregional staging, monitoring response to therapy, and detection of locoregional recurrence after primary treatment in BCa patients were selected. EVIDENCE SYNTHESIS: Standardization of acquisition and reporting protocols for bladder mpMRI is paramount. Combining anatomic and functional sequences improves the accuracy of local tumor staging compared with conventional imaging alone. Diffusion-weighted imaging may distinguish BCa type and grade. Functional sequences are capable of monitoring response to chemotherapy and radiation therapy. Diffusion-weighted imaging enhanced by lymphotropic nanoparticles showed high accuracy in pelvic lymph node staging compared with conventional cross sectional imaging. CONCLUSIONS: In BCa patients, mpMRI appears a promising tool for accurate locoregional staging, predicting tumor aggressiveness and monitoring response to therapy. Further large-scale studies are needed to confirm these findings. PATIENT SUMMARY: Better imaging through improved technology will improve outcomes in bladder cancer patients. We reviewed the emerging use of multiparametric magnetic resonance imaging for staging and monitoring bladder cancer. Multiparametric magnetic resonance imaging appears more accurate than current methods for local and nodal staging and monitoring tumor response to treatment, but requires further investigation. PMID- 28723526 TI - Imaging for Urinary Stones: Update in 2015. AB - CONTEXT: Imaging is essential for the diagnosis and the clinical decision-making process of patients with urinary stones. OBJECTIVE: To assess the benefits and limitations of various imaging techniques by specifically focusing on different phases of stone patients' management. EVIDENCE ACQUISITION: PubMed and Web of Science databases were used to identify studies published in the last 10 yr on this argument. Search terms included 'urolithiasis', nephrolithiasis', or 'urinary stones' in combination (AND) with the terms 'imaging', 'computer tomography', 'ultrasonography', 'intravenous pyelogram', or 'radiation exposure'. Study selection was based on an independent peer-review process of all the authors after the structured data search. EVIDENCE SYNTHESIS: Noncontrast enhanced computer tomography (CT) provides the highest value of diagnostic accuracy for urinary stones. Stone composition can be specifically assessed through the use of dual-energy CT. When information about the anatomy of the renal collecting system is required or alternative pathologies are suspected, CT with contrast injection is recommended. Low-dose protocols allowed a drastic reduction of the effective dose administered to the patient, thus limiting the biological risk due to ionising radiations. Other strategies to contain the radiation exposure include the dual-split bolus dual energy CT and the adaptive statistical image reconstruction. Abdomen ultrasound may be a valid alternative as an initial approach since it does not change the outcome of patients compared with CT, and should be the imaging of choice in children and pregnant women. CONCLUSIONS: Noncontrast-enhanced CT is the most accurate imaging technique to identify urinary stones. Abdomen ultrasound seems to be a valid alternative in the initial evaluation of urinary colic. New low-dose protocols and strategies have been developed to contain radiation exposure, which is a major issue especially in specific circumstances. PATIENT SUMMARY: Noncontrast-enhanced computer tomography has been increasingly used for the diagnosis and management of urinary stones. Low-dose protocols as well as alternative imaging should be considered by clinicians in specific circumstances to minimise radiation exposure. PMID- 28723527 TI - Imaging for Vesicoureteral Reflux and Ureteropelvic Junction Obstruction. AB - CONTEXT: Although the imaging techniques used for diagnosing vesicoureteral reflux (VUR) and ureteropelvic junction obstruction (UPJO) are well determined, there is a need to decrease the numbers of unnecessary imaging and radiation exposure as most of the target population is children. Newer imaging techniques are promising and could be eventually used for follow up in the near future. OBJECTIVE: To review the contemporary literature regarding the imaging techniques used for VUR and UPJO. EVIDENCE ACQUISITION: We conducted a nonsystematic review of the literature. A comprehensive search was performed through PubMed database between 1980 (where maternal ultrasound [US] was first popularized) and 2015 focusing on the last decade. EVIDENCE SYNTHESIS: Conventional US cannot replace voiding cystourethrography in the detection of VUR. Contrast enhanced voiding sonography and direct radionuclide cystography suggest acceptable detection rates of VUR with sensitivity of 71-100% and specificity of 67-100%. Renal US and diuretic radioisotope renography with choice of technetium99m mercaptocetyltriglycine are invaluable imaging modalities for the detection of UPJO. CONCLUSIONS: Despite the concerns about the invasiveness and radiation exposure of conventional voiding cystourethrography, it is still the gold standard technique in the detection of VUR and is superior to the other options in depiction of anatomical details. US and mercaptocetyltriglycine scintigraphy are also the gold standards and will continue to be so in the diagnosis of UPJO. PATIENT SUMMARY: New imaging modalities such as contrast enhanced voiding sonography and direct radionuclide cystography are promising in the detection of vesicoureteral reflux. Major effort in literature is given to decrease the radiation dose of the available imaging techniques. PMID- 28723528 TI - Imaging for Prostate Cancer Recurrence. AB - CONTEXT: Correct identification of metastatic sites in recurrent prostate cancer (PCa) is of crucial importance because it leads to further treatment decisions. OBJECTIVE: To provide an overview on current imaging procedures and their performance in recurrent PCa. EVIDENCE ACQUISITION: Medline search via PubMed was performed with the keywords imaging, recurrent, and prostate cancer as well as more detailed searches including the keywords bone scan, bone scintigraphy, computed tomography, magnetic resonance imaging, positron emission tomography, PET, choline, FDG, prostate-specific membrane antigen, and PSMA, with emphasis on recent literature from 2010 to the present. Non-English published literature was excluded. Abstracts and full-text articles were reviewed and assessed for relevant content. EVIDENCE SYNTHESIS: In diagnostic imaging and particularly with newer technologies like positron emission tomography (PET), a profound lack of prospectively designed studies in recurrent PCa has to be noted. In most studies histologic validation has only been performed in a subset of patient cohorts. Heterogeneity of included patient cohorts, lack of standardized assessment, as well as diverging end points, hamper systematic comparison of different image modalities. Thus evidence for currently used imaging in recurrent PCa is only presented descriptively. CONCLUSIONS: Computed tomography and magnetic resonance imaging (MRI) as well as bone scintigraphy still represent the standard imaging for recurrent PCa; however, particularly for detection of local recurrence, multiparametric MRI is a valuable imaging modality. PET using choline and particularly tracers against prostate-specific membrane antigen might improve visualization of metastatic lesions. These findings need to be validated in prospective trials. PATIENT SUMMARY: Imaging of recurrent prostate cancer (PCa) is important to guide further treatment. Computed tomography, magnetic resonance imaging, and bone scintigraphy represent the current standard. Positron emission tomography, especially with cancer-specific tracers, might improve imaging of recurrent PCa in the future. PMID- 28723529 TI - How to Perform Image-guided Prostate Biopsy: In-bore and Fusion Approaches. AB - The integration of magnetic resonance imaging into urologic routine may be highly beneficial and change our standards for prostate cancer treatment. PMID- 28723530 TI - Small Renal Mass-To Biopsy or Not? The Role of Biopsy in Evaluation. PMID- 28723531 TI - Small Renal Masses: To Biopsy or Not? The Role of Imaging in the Evaluation. AB - Benign renal lesions can often be differentiated from potentially malignant lesions on the basis of their tissue composition and size on computed tomography or magnetic resonance imaging; however, tissue sampling remains necessary to disclose the exact histologic nature of a potentially malignant lesion. PMID- 28723532 TI - Comparative Oncologic and Toxicity Outcomes of Salvage Radical Prostatectomy Versus Nonsurgical Therapies for Radiorecurrent Prostate Cancer: A Meta Regression Analysis. AB - CONTEXT: In the absence of randomised controlled trials comparing the oncologic, toxicity, and functional outcomes of salvage radical prostatectomy (SRP), salvage high-intensity focused ultrasound (SHIFU), salvage brachytherapy (SBT), and salvage cryotherapy (SCT), controversy exists as to the optimal salvage modality in radiorecurrent prostate cancer. OBJECTIVE: We carried out a meta-regression analysis to determine whether there is a difference in oncologic, toxicity, and functional outcomes using data from original publications of salvage modalities in the postradiation setting. EVIDENCE ACQUISITION: We performed a systematic review of PubMed/Medline citations according to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) statement. We included 63 articles in the analysis (25 on SRP, 8 on SHIFU, 16 on SCT, 14 on SBT). EVIDENCE SYNTHESIS: Median values of the following variables were extracted from each study: patient age, length of follow-up, prostate-specific antigen (PSA) before radiotherapy (RT), PSA before salvage therapy, Gleason score before RT, and time interval between RT and salvage therapy. Functional, toxicity, and oncologic outcomes were measured according to rates of impotence, incontinence, fistula formation, urethral strictures, and biochemical recurrence. Meta-regression adjusting for confounders found no significant difference in oncologic outcomes between SRP and nonsurgical salvage modalities. SBT, SCT, and SHIFU appeared to have better continence outcomes than SRP. No significant difference in toxicity outcomes between modalities was found, although limitations such as reporting, selection, and publication bias and between-study heterogeneity must also be considered with these conclusions. CONCLUSIONS: Oncologic outcomes are comparable for SRP and all three nonsurgical salvage modalities. We found no significant differences in toxicity outcomes among modalities; however, SRP appears to be associated with worse rates of urinary incontinence than SBT, SCT, and SHIFU. PATIENT SUMMARY: We performed a meta-regression analysis to compare oncologic, functional, and toxicity outcomes between salvage radical prostatectomy and nonsurgical salvage modalities. Oncologic and toxicity outcomes appear to be similar; however, all nonsurgical salvage modalities may be associated with better continence outcomes. PMID- 28723533 TI - Patient-reported Functional Outcomes Following Open, Laparoscopic, and Robotic Assisted Radical Prostatectomy Performed by High-volume Surgeons at High-volume Hospitals. AB - BACKGROUND: Functional outcomes following radical prostatectomy (RP) have received increased focus with dissemination of minimally invasive approaches. OBJECTIVE: To examine contemporary patient-reported functional outcomes following open RP. (ORP), laparoscopic RP, (LRP), and robotic assisted RP (RARP) performed by high-volume surgeons at high-volume hospitals. DESIGN, SETTINGS, AND PARTICIPANTS: This was a retrospective cohort study of 1686 men with cT1-cT2 prostate cancer treated with ORP (n=441), LRP (n=156), or RARP (n=1089) by high volume surgeons (annual volume >=25 cases) at two academic centers from 2009 to 2012. Surveys containing the Expanded Prostate Cancer Index Composite urinary and sexual domains were administered at a median of 30.5 mo postoperatively. INTERVENTIONS: ORP, LRP, and RARP. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Bother with overall urinary and sexual function was examined and stratified by surgical technique. Logistic regression models evaluated the associations of clinicopathologic features with survey responses. RESULTS AND LIMITATIONS: In total, 6.4% of men reported a moderate or big problem with overall urinary function (ORP 5.8%, LRP 5.1%, RARP 6.8%; p=0.62), whereas 37.3% reported a moderate or big problem with overall sexual function (ORP 37.2%, LRP 36.1%, RARP 37.5%; p=0.95). On multivariable analysis, older age at surgery (odds ratio [OR]: 1.08; p<0.0001) was associated with overall urinary bother, whereas older age at surgery (OR: 1.03; p=0.005), preoperative erectile dysfunction treatment (OR: 2.22; p<0.0001), greater prostate volume (OR: 1.01; p=0.02), and RP Gleason score (7 vs 6: OR: 0.96; p=0.004; 8-10 vs 6: OR: 2.25; p=0.0006) were associated with overall sexual bother. Surgical technique was not associated with either functional outcome. Limitations included selection bias and a retrospective design. CONCLUSIONS: In this study of high-volume surgeons at high-volume hospitals, patients reported excellent functional outcomes independent of surgical technique. These results have implications for patient counseling. PATIENT SUMMARY: In this study of high-volume surgeons at high-volume hospitals, patients reported excellent outcomes for urinary and sexual function following radical prostatectomy regardless of surgical technique. PMID- 28723534 TI - Reporting Bias Leading to Discordant Venous Thromboembolism Rates in the United States Versus Non-US Countries Following Radical Cystectomy: A Systematic Review and Meta-analysis. AB - CONTEXT: Postcystectomy bladder cancer (BCa) patients are at high risk for developing venous thromboembolism (VTE). The literature varies widely in the reporting of VTE in this population. OBJECTIVE: To determine the VTE rate in subjects undergoing radical cystectomy (RC) and highlight specific factors affecting this rate. EVIDENCE ACQUISITION: This meta-analysis was registered with the International Prospective Register of Systematic Reviews (PROSPERO) database, registration number: CRD42015016776. We queried MEDLINE, the Cochrane Library, Embase, Scopus, Cumulative Index to Nursing and Allied Health Literature (CINAHL), and Web of Science. Search terms captured BCa, RC, and VTE. Per the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines, abstracts were reviewed for inclusion/exclusion criteria by two reviewers, and disagreements were resolved by a third reviewer. A search of the gray literature and references of pertinent articles was also performed. The date of our last search was December 15, 2014. For unreported data, authors were contacted. Data were abstracted in duplicate and pooled using a random effects (RE) model. Subgroup analyses and meta-regression were performed to determine risk factors for VTE. EVIDENCE SYNTHESIS: We identified 2927 publications, of which 223 met inclusion criteria for this review. A total of 1 115 634 surgeries were performed on patient population (80% men) with a total of 51 908 VTEs. The VTE rate estimated by the RE model was 3.7%. Due to significant heterogeneity, subgroup and meta-regression analyses were undertaken. These revealed a higher rate of VTE in US studies at 4.49% compared with "westernized" non-US studies at 3.43% and "nonwesternized" non-US based studies at 2.50%. Other important modifiers included minimally invasive surgery at 5.54% versus open surgery at 3.55%, and age. The case-fatality rate of pulmonary emboli was 44%. CONCLUSIONS: VTE is common in patients undergoing RC. Reporting of VTE is heterogeneous and the rate varies according to study-level factors, including surgery type and country of origin. Limitations of this study include the preponderance of observational studies in the final analysis and lack of complete reporting of all variables of interest within each study. PATIENT SUMMARY: In this review, we determined the venous thromboembolism (VTE) rate in postsurgical bladder cancer patients. VTE events did vary significantly among certain subgroups. PMID- 28723535 TI - Serum Adiponectin Predicts Cancer-specific Survival of Patients with Renal Cell Carcinoma. AB - BACKGROUND: Prediction of outcomes in patients with renal cell carcinoma (RCC) is crucial for clinical decision-making. The limited accuracy of conventional prognostic factors such as stage and grade may be increased by the use of biomarkers. OBJECTIVE: To evaluate the association of serum adiponectin and leptin and polymorphisms in the leptin and leptin receptor genes with RCC histopathology and prognosis. DESIGN, SETTING, AND PARTICIPANTS: Adiponectin and leptin levels were measured in preoperative serum samples from 131 consecutive patients with sporadic unilateral RCC. The polymorphisms G-2548A (rs7799039) in the leptin gene (LEP) and Gln223Arg (Q223R, A668G, rs1137101) in the leptin receptor gene (LEPR) were genotyped in 233 patients. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Multivariable associations with RCC-specific survival were analyzed using Cox models. RESULTS AND LIMITATIONS: Median preoperative serum adiponectin was 15.8MUg/ml (interquartile range 10.0-23.1). Adiponectin was lower in patients with distant metastases (p=0.017) or histologic tumor necrosis (p=0.015). On multivariable analysis adjusted for the effects of variables in the Karakiewicz nomogram, each 1-MUg/ml increase in adiponectin was associated with a 8% decrease in the hazard of death from RCC (hazard ratio 0.92, 95% confidence interval 0.86-0.98; p=0.007). The discrimination of the Karakiewicz nomogram increased by 0.6% on inclusion of adiponectin. Leptin levels, LEP G-2548A and LEPR Q223R were not associated with either RCC pathology or outcomes. Limitations include the retrospective study design, the low numbers of patients, and a lack of standardized follow-up. CONCLUSIONS: This study suggests that lower preoperative serum adiponectin is associated with features of biologically aggressive RCC, metastasis, and survival. PATIENT SUMMARY: We assessed the relationship between outcomes and blood levels of adiponectin and leptin and genetic changes in leptin and leptin receptor genes. We found that patients with lower adiponectin levels have more aggressive tumors and poorer survival. PMID- 28723536 TI - Correlation Between Molecular Subclassifications of Clear Cell Renal Cell Carcinoma and Targeted Therapy Response. AB - BACKGROUND: Vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR)-directed therapies are the standard of care in metastatic clear cell renal cell carcinoma (mccRCC) but are not used based on molecular subclassifications of ccRCC. OBJECTIVE: To determine if an association exists between genomic alterations (GAs) detected by comprehensive genomic profiling (CGP) in the course of clinical care and the response to anti-VEGF receptor (VEGFR) and anti-MTOR pathway targeted therapies in a cohort of patients with treated mccRCC. DESIGN, SETTING, AND PARTICIPANTS: CGP, using a Clinical Laboratory Improvement Amendments-certified platform, was performed on 31 formalin-fixed, paraffin-embedded tissue specimens (84% from cytoreductive nephrectomies) obtained from patients with metastatic renal cell carcinoma who had received VEGFR and/or mTOR inhibitors. Duration of treatment (DOT) and extent and duration of clinical response were obtained from review of medical records. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: All classes of GAs-base substitutions, short insertions, deletions, gene fusions, rearrangements, and copy number-were assessed via hybrid capture-based CGP. Descriptive statistics were used to determine the frequency of GAs in groups segregated by the DOT with VEGF-directed agents. RESULTS AND LIMITATIONS: The most common GAs detected in this series were in VHL (70%), PBRM1 (48%), SETD2 (32%), TSC1 (29%), MLL (19%), TERT (16%), ARID1B (16%), and KDM5C (16%). Across 61 administrations of VEGF directed therapy in 27 patients, exceptional responses (DOT >21 mo) were more frequent among patients with GAs in KDM5C, PBRM1, and VHL. Conversely, these patients also featured a lower frequency of GA associated with response to mTOR directed therapy, such as TSC1. CONCLUSIONS: Molecular subclassifications may affect response to VEGF-directed therapy. The predictive and prognostic nature of these molecular subclassifications in the metastatic setting should be explored in an extended series. PATIENT SUMMARY: Comprehensive genomic profiling in the course of clinical care in the community oncology setting can delineate subgroups of patients with advanced kidney cancer who stand to benefit more from specific molecular-targeted agents. PMID- 28723537 TI - Exosomal MicroRNAs Are Diagnostic Biomarkers and Can Mediate Cell-Cell Communication in Renal Cell Carcinoma. AB - BACKGROUND: Apart from an invasive biopsy, currently no tools are available to confirm the diagnosis of clear cell renal cell carcinoma (ccRCC); this resulted in approximately 30% of patients being diagnosed with metastatic disease. OBJECTIVE: To determine whether urinary microRNAs (miRNAs) can serve as biomarkers to confirm the diagnosis of ccRCC. DESIGN, SETTING, AND PARTICIPANTS: Global miRNA expression was assessed in 28 preoperative urine samples from patients with ccRCC and 18 healthy participants. The independent validation set consisted of 81 ccRCC patients, 24 patients with benign lesions, and 33 healthy participants. We extracted both cell-free and exosomal RNA for miRNA expression analysis using miRNA-specific polymerase chain reaction assays. We also investigated exosomal miRNA secretion in cell line models and performed exosome transfer between RCC and endothelial cell types. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Receiver operating characteristic analysis was applied to identify the discrimination power of miRNAs. RESULTS AND LIMITATIONS: Overall, miR-126-3p combined with miR-449a or with miR-34b-5p could significantly distinguish ccRCC patients from healthy participants (miR-126-3p-miR-449a: area under the curve [AUC]: 0.84; 95% confidence interval [CI], 0.7620-0.9151; p<0.001; miR-126-3p-miR-34b-5p: AUC: 0.79; 95% CI, 0.7013-0.8815; p<0.001). The combination of miR-126-3p and miR-34b-5p was also able to distinguish small renal masses (pT1a, <=4cm) from healthy controls (AUC: 0.79; 95% CI, 0.6848-0.8980; p<0.001). Using miR-126-3p and miR-486-5p in combination, we were able to differentiate between benign lesions and ccRCC (AUC: 0.85; 95% CI, 0.7295-0.9615; p<0.01). The expression of a number of miRNAs returned to a level comparable with health after surgery. Kidney cancer cell lines were found to secrete exosomal miR 126-3p, miR-17-5p, miR-21-3p, and miR-25-3p, and these miRNAs were found to be internalized by other cell types. CONCLUSIONS: We identified exosomal miRNAs as potential noninvasive diagnostic urinary biomarkers for ccRCC and provided evidence that miRNAs are secreted by the tumor and can function as a tool for intercellular communication. PATIENT SUMMARY: We identified urinary microRNAs that can serve as diagnostic biomarkers for clear cell renal cell carcinoma. PMID- 28723538 TI - Positron Emission Tomography Scanning for Recurrent Bladder Cancer. AB - The benefit of 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) over CT in detecting distant relapse is uncertain. A means of reducing bladder activity is necessary for useful imaging of bladder wall and pelvic lymph node recurrences with FDG-PET/CT. PMID- 28723539 TI - Case Presentation: Kidney Cancer in Transplanted Kidney. AB - Management of metastatic renal cell carcinoma in kidney graft is challenging. A multidisciplinary team of experts plays a key role in the clinical decision making to balance quality of life and oncological outcome. PMID- 28723540 TI - Clinical Case Discussion: Surgical Management of a De Novo Metastatic Tumour Arising on a Kidney Graft. AB - De novo tumour in a kidney graft is a rare situation that must be addressed by a multidisciplinary team. PMID- 28723541 TI - Clinical Case Discussion: Kidney Cancer in Transplanted Kidney: The Interdisciplinary Nephrologic-Urologic View. AB - Patients with renal tumors following renal transplantation need interdisciplinary management by a nephrologist and an oncologic urologist. PMID- 28723542 TI - Grey Areas: Imaging Terminology and Reporting. PMID- 28723543 TI - Necroptosis: (Last) Message in a Bubble. AB - RIPK3 kinase-mediated phosphorylation of MLKL pseudokinase is the execution event of necroptosis. Two independent reports-in Immunity (Yoon et al., 2017) and Cell (Gong et al., 2017)-reveal that MLKL affects homeostatic membrane trafficking and necroptosis-enhanced bubble formation involving interaction with the ESCRT machinery. PMID- 28723544 TI - Upgrading from iMac to iMicro. AB - In this issue of Immunity, Takata et al. (2017) describe a novel method to differentiate macrophages from iPSCs. These cells, which they call iMacs, are similar to yolk-sac-derived macrophages and are capable of undergoing terminal differentiation into tissue-resident-like macrophages in vitro and in vivo. PMID- 28723545 TI - Spineless Behavior of CX3CR1+ Monocytes in Response to Infection. AB - Sickness in mammals can lead to cognition deficits, although the underlying mechanisms remain elusive. In a recent Nature Medicine article, Garre et al. (2017) report that sickness-induced cortical dendritic spine loss and impaired memory formation is mediated by CX3CR1+ monocyte-derived TNF-alpha. PMID- 28723546 TI - Local Modulation of Antigen-Presenting Cell Development after Resolution of Pneumonia Induces Long-Term Susceptibility to Secondary Infections. AB - Lung infections cause prolonged immune alterations and elevated susceptibility to secondary pneumonia. We found that, after resolution of primary viral or bacterial pneumonia, dendritic cells (DC), and macrophages exhibited poor antigen presentation capacity and secretion of immunogenic cytokines. Development of these "paralyzed" DCs and macrophages depended on the immunosuppressive microenvironment established upon resolution of primary infection, which involved regulatory T (Treg) cells and the cytokine TGF-beta. Paralyzed DCs secreted TGF beta and induced local Treg cell accumulation. They also expressed lower amounts of IRF4, a transcription factor associated with increased antigen-presentation capacity, and higher amounts of Blimp1, a transcription factor associated with tolerogenic functions, than DCs present during primary infection. Blimp1 expression in DC of humans suffering sepsis or trauma correlated with severity and complicated outcomes. Our findings describe mechanisms underlying sepsis- and trauma-induced immunosuppression, reveal prognostic markers of susceptibility to secondary infections and identify potential targets for therapeutic intervention. PMID- 28723547 TI - The P2X7 Receptor in Infection and Inflammation. AB - Adenosine triphosphate (ATP) accumulates at sites of tissue injury and inflammation. Effects of extracellular ATP are mediated by plasma membrane receptors named P2 receptors (P2Rs). The P2R most involved in inflammation and immunity is the P2X7 receptor (P2X7R), expressed by virtually all cells of innate and adaptive immunity. P2X7R mediates NLRP3 inflammasome activation, cytokine and chemokine release, T lymphocyte survival and differentiation, transcription factor activation, and cell death. Ten human P2RX7 gene splice variants and several SNPs that produce complex haplotypes are known. The P2X7R is a potent stimulant of inflammation and immunity and a promoter of cancer cell growth. This makes P2X7R an appealing target for anti-inflammatory and anti-cancer therapy. However, an in-depth knowledge of its structure and of the associated signal transduction mechanisms is needed for an effective therapeutic development. PMID- 28723549 TI - Interleukin-7 Availability Is Maintained by a Hematopoietic Cytokine Sink Comprising Innate Lymphoid Cells and T Cells. AB - Interleukin-7 (IL-7) availability determines the size and proliferative state of the resting T cell pool. However, the mechanisms that regulate steady-state IL-7 amounts are unclear. Using experimental lymphopenic mouse models and IL-7-induced homeostatic proliferation to measure IL-7 availability in vivo, we found that radioresistant cells were the source of IL-7 for both CD4+ and CD8+ T cells. Hematopoietic lineage cells, although irrelevant as a source of IL-7, were primarily responsible for limiting IL-7 availability via their expression of IL 7R. Unexpectedly, innate lymphoid cells were found to have a potent influence on IL-7 amounts in the primary and secondary lymphoid tissues. These results demonstrate that IL-7 homeostasis is achieved through consumption by multiple subsets of innate and adaptive immune cells. PMID- 28723551 TI - Understanding Immunosuppression after Sepsis. AB - Following a severe primary infection or trauma, the risk of developing pneumonia increases due to acquired immune defects collectively known as sepsis-induced immunosuppression. In this issue of Immunity, Roquilly et al. (2017) show that dendritic cells and macrophages developing in the lung after the resolution of a severe infection acquire tolerogenic properties that contribute to persistent immunosuppression and susceptibility to secondary infections. PMID- 28723548 TI - The Fc Domain of Immunoglobulin Is Sufficient to Bridge NK Cells with Virally Infected Cells. AB - Clearance of pathogens or tumor cells by antibodies traditionally requires both Fab and Fc domains of IgG. Here, we show the Fc domain of IgG alone mediates recognition and clearance of herpes simplex virus (HSV1)-infected cells. The human natural killer (NK) cell surface is naturally coated with IgG bound by its Fc domain to the Fcgamma receptor CD16a. NK cells utilize the Fc domain of bound IgG to recognize gE, an HSV1-encoded glycoprotein that also binds the Fc domain of IgG but at a site distinct from CD16a. The bridge formed by the Fc domain between the HSV1-infected cell and the NK cell results in NK cell activation and lysis of the HSV1-infected cell in the absence of HSV1-specific antibody in vitro and prevents fatal HSV1 infection in vivo. This mechanism also explains how bacterial IgG-binding proteins regulate NK cell function and may be broadly applicable to Fcgamma-receptor-bearing cells. PMID- 28723550 TI - Induced-Pluripotent-Stem-Cell-Derived Primitive Macrophages Provide a Platform for Modeling Tissue-Resident Macrophage Differentiation and Function. AB - Tissue macrophages arise during embryogenesis from yolk-sac (YS) progenitors that give rise to primitive YS macrophages. Until recently, it has been impossible to isolate or derive sufficient numbers of YS-derived macrophages for further study, but data now suggest that induced pluripotent stem cells (iPSCs) can be driven to undergo a process reminiscent of YS-hematopoiesis in vitro. We asked whether iPSC derived primitive macrophages (iMacs) can terminally differentiate into specialized macrophages with the help of growth factors and organ-specific cues. Co-culturing human or murine iMacs with iPSC-derived neurons promoted differentiation into microglia-like cells in vitro. Furthermore, murine iMacs differentiated in vivo into microglia after injection into the brain and into functional alveolar macrophages after engraftment in the lung. Finally, iPSCs from a patient with familial Mediterranean fever differentiated into iMacs with pro-inflammatory characteristics, mimicking the disease phenotype. Altogether, iMacs constitute a source of tissue-resident macrophage precursors that can be used for biological, pathophysiological, and therapeutic studies. PMID- 28723552 TI - Immunology of Food Allergy. AB - Many consider food allergy as the "second wave" of the allergy epidemic following the "first wave" of respiratory allergy, i.e., asthma and allergic rhinitis, plaguing westernized countries, with up to 8% of young children and 2%-3% of adults in the United States now affected by hypersensitivity reactions to various foods. In the past decade, there have been great strides in our understanding of the underlying immunopathogenesis of these disorders, which have led to improved diagnostic techniques, management strategies, and therapeutic approaches. Here we will review the most recent understanding of basic mechanisms underlying IgE mediated food allergies and novel therapeutic approaches under investigation for both the prevention and treatment of IgE-mediated food allergies. PMID- 28723553 TI - A Commencement for Eye Commensals. AB - "Paucibacterial" levels of the normal eye surface have left immunologists wondering whether a true microbiome exists there. In this issue of Immunity, St. Leger et al. (2017) address this head-on, discovering a naturally existing commensal in mice that induces gammadeltaT cell-mediated protection from opportunistic infection. PMID- 28723555 TI - ILCs and T Cells Competing for Space: More Than a Numbers Game. AB - T cell homeostasis critically depends on interleukin-7 (IL-7). In this issue of Immunity, Martin et al. (2017) provide evidence that IL-7 availability is regulated through a "cytokine sink" involving innate lymphoid cells that compete for and consume IL-7 and thereby restrict T cell homeostasis in lymphoid organs. PMID- 28723554 TI - Hypoxia-Sensitive COMMD1 Integrates Signaling and Cellular Metabolism in Human Macrophages and Suppresses Osteoclastogenesis. AB - Hypoxia augments inflammatory responses and osteoclastogenesis by incompletely understood mechanisms. We identified COMMD1 as a cell-intrinsic negative regulator of osteoclastogenesis that is suppressed by hypoxia. In human macrophages, COMMD1 restrained induction of NF-kappaB signaling and a transcription factor E2F1-dependent metabolic pathway by the cytokine RANKL. Downregulation of COMMD1 protein expression by hypoxia augmented RANKL-induced expression of inflammatory and E2F1 target genes and downstream osteoclastogenesis. E2F1 targets included glycolysis and metabolic genes including CKB that enabled cells to meet metabolic demands in challenging environments, as well as inflammatory cytokine-driven target genes. Expression quantitative trait locus analysis linked increased COMMD1 expression with decreased bone erosion in rheumatoid arthritis. Myeloid deletion of Commd1 resulted in increased osteoclastogenesis in arthritis and inflammatory osteolysis models. These results identify COMMD1 and an E2F-metabolic pathway as key regulators of osteoclastogenic responses under pathological inflammatory conditions and provide a mechanism by which hypoxia augments inflammation and bone destruction. PMID- 28723556 TI - Peroxisome-Mediated Metabolism Is Required for Immune Response to Microbial Infection. AB - The innate immune response is critical for animal homeostasis and is conserved from invertebrates to vertebrates. This response depends on specialized cells that recognize, internalize, and destroy microbial invaders through phagocytosis. This is coupled to autonomous or non-autonomous cellular signaling via reactive oxygen species (ROS) and cytokine production. Lipids are known signaling factors in this process, as the acute phase response of macrophages is accompanied by systemic lipid changes that help resolve inflammation. We found that peroxisomes, membrane-enclosed organelles central to lipid metabolism and ROS turnover, were necessary for the engulfment of bacteria by Drosophila and mouse macrophages. Peroxisomes were also required for resolution of bacterial infection through canonical innate immune signaling. Reduced peroxisome function impaired the turnover of the oxidative burst necessary to fight infection. This impaired response to bacterial challenge affected cell and organism survival and revealed a previously unknown requirement for peroxisomes in phagocytosis and innate immunity. PMID- 28723557 TI - Crystal Structure of the Human Ribosome in Complex with DENR-MCT-1. AB - The repertoire of the density-regulated protein (DENR) and the malignant T cell amplified sequence 1 (MCT-1/MCTS1) oncoprotein was recently expanded to include translational control of a specific set of cancer-related mRNAs. DENR and MCT-1 form the heterodimer, which binds to the ribosome and operates at both translation initiation and reinitiation steps, though by a mechanism that is yet unclear. Here, we determined the crystal structure of the human small ribosomal subunit in complex with DENR-MCT-1. The structure reveals the location of the DENR-MCT-1 dimer bound to the small ribosomal subunit. The binding site of the C terminal domain of DENR on the ribosome has a striking similarity with those of canonical initiation factor 1 (eIF1), which controls the fidelity of translation initiation and scanning. Our findings elucidate how the DENR-MCT-1 dimer interacts with the ribosome and have functional implications for the mechanism of unconventional translation initiation and reinitiation. PMID- 28723558 TI - Dendritic Cell Lineage Potential in Human Early Hematopoietic Progenitors. AB - Conventional dendritic cells (cDCs) are thought to descend from a DC precursor downstream of the common myeloid progenitor (CMP). However, a mouse lymphoid primed multipotent progenitor has been shown to generate cDCs following a DC specific developmental pathway independent of monocyte and granulocyte poiesis. Similarly, here we show that, in humans, a large fraction of multipotent lymphoid early progenitors (MLPs) gives rise to cDCs, in particular the subset known as cDC1, identified by co-expression of DNGR-1 (CLEC9A) and CD141 (BDCA-3). Single cell analysis indicates that over one-third of MLPs have the potential to efficiently generate cDCs. cDC1s generated from CMPs or MLPs do not exhibit differences in transcriptome or phenotype. These results demonstrate an early imprinting of the cDC lineage in human hematopoiesis and highlight the plasticity of developmental pathways giving rise to human DCs. PMID- 28723559 TI - KMT2A and KMT2B Mediate Memory Function by Affecting Distinct Genomic Regions. AB - Kmt2a and Kmt2b are H3K4 methyltransferases of the Set1/Trithorax class. We have recently shown the importance of Kmt2b for learning and memory. Here, we report that Kmt2a is also important in memory formation. We compare the decrease in H3K4 methylation and de-regulation of gene expression in hippocampal neurons of mice with knockdown of either Kmt2a or Kmt2b. Kmt2a and Kmt2b control largely distinct genomic regions and different molecular pathways linked to neuronal plasticity. Finally, we show that the decrease in H3K4 methylation resulting from Kmt2a knockdown partially recapitulates the pattern previously reported in CK-p25 mice, a model for neurodegeneration and memory impairment. Our findings point to the distinct functions of even closely related histone-modifying enzymes and provide essential insight for the development of more efficient and specific epigenetic therapies against brain diseases. PMID- 28723560 TI - CRKL Mediates p110beta-Dependent PI3K Signaling in PTEN-Deficient Cancer Cells. AB - The p110beta isoform of PI3K is preferentially activated in many tumors deficient in the phosphatase and tensin homolog (PTEN). However, the mechanism(s) linking PTEN loss to p110beta activation remain(s) mysterious. Here, we identify CRKL as a member of the class of PI3Kbeta-interacting proteins. Silencing CRKL expression in PTEN-null human cancer cells leads to a decrease in p110beta-dependent PI3K signaling and cell proliferation. In contrast, CRKL depletion does not impair p110alpha-mediated signaling. Further study showed that CRKL binds to tyrosine phosphorylated p130Cas in PTEN-null cancer cells. Since Src family kinases are known both to be regulated by PTEN and to phosphorylate and activate p130Cas, we tested and found that Src inhibition cooperated with p110beta inhibition to suppress the growth of PTEN-null cells. These data suggest both a potential mechanism linking PTEN loss to p110beta activation and the possible benefit of dual inhibition of Src and PI3K for PTEN-null tumors. PMID- 28723561 TI - Crosstalk between Regulatory T Cells and Tumor-Associated Dendritic Cells Negates Anti-tumor Immunity in Pancreatic Cancer. AB - Regulatory T (Treg) cell infiltration constitutes a prominent feature of pancreatic ductal adenocarcinoma (PDA). However, the immunomodulatory function of Treg cells in PDA is poorly understood. Here, we demonstrate that Treg cell ablation is sufficient to evoke effective anti-tumor immune response in early and advanced pancreatic tumorigenesis in mice. This response is dependent on interferon-gamma (IFN-gamma)-producing cytotoxic CD8+ T cells. We show that Treg cells engage in extended interactions with tumor-associated CD11c+ dendritic cells (DCs) and restrain their immunogenic function by suppressing the expression of costimulatory ligands necessary for CD8+ T cell activation. Consequently, tumor-associated CD8+ T cells fail to display effector activities when Treg cell ablation is combined with DC depletion. We propose that tumor-infiltrating Treg cells can promote immune tolerance by suppressing tumor-associated DC immunogenicity. The therapeutic manipulation of this axis might provide an effective approach for the targeting of PDA. PMID- 28723562 TI - Integrative Genomics Identifies the Molecular Basis of Resistance to Azacitidine Therapy in Myelodysplastic Syndromes. AB - Myelodysplastic syndromes and chronic myelomonocytic leukemia are blood disorders characterized by ineffective hematopoiesis and progressive marrow failure that can transform into acute leukemia. The DNA methyltransferase inhibitor 5 azacytidine (AZA) is the most effective pharmacological option, but only ~50% of patients respond. A response only manifests after many months of treatment and is transient. The reasons underlying AZA resistance are unknown, and few alternatives exist for non-responders. Here, we show that AZA responders have more hematopoietic progenitor cells (HPCs) in the cell cycle. Non-responder HPC quiescence is mediated by integrin alpha5 (ITGA5) signaling and their hematopoietic potential improved by combining AZA with an ITGA5 inhibitor. AZA response is associated with the induction of an inflammatory response in HPCs in vivo. By molecular bar coding and tracking individual clones, we found that, although AZA alters the sub-clonal contribution to different lineages, founder clones are not eliminated and continue to drive hematopoiesis even in complete responders. PMID- 28723563 TI - A Positive Feedback Loop between Sestrin2 and mTORC2 Is Required for the Survival of Glutamine-Depleted Lung Cancer Cells. AB - Proper regulation of mTORC1 and mTORC2 upon nutrient starvation is critical for cancer cell survival. Upregulation of Sestrin2 in response to glutamine deprivation rescues cell death by suppressing mTORC1. However, the contribution of mTORC2 to Sestrin2-mediated mTORC1 suppression remains unclear. Here, we report that both Sestrin2 and mTORC2 are upregulated in glutamine-depleted lung cancer cells. Moreover, glutamine depletion caused Sestrin2 to associate with mTORC2, which was required for the increase in Sestrin2 protein stability and the reduction in mTORC1 activity. Ultimately, differential regulation of mTORC1 and 2 by Sestrin2 reprogramed lipid metabolism and enabled glutamine-depleted lung cancer cells to survive by maintaining energy and redox balance. Importantly, combined inhibition of glutamine utilization and Sestrin2 induced lung cancer cell death both in vitro and in vivo. This study shows that differential Sestrin2 mediated regulation of mTORC1 and mTORC2 is necessary for the survival of glutamine-depleted lung cancer cells. PMID- 28723565 TI - The Transcription Factor Tcf1 Contributes to Normal NK Cell Development and Function by Limiting the Expression of Granzymes. AB - The transcription factor Tcf1 is essential for the development of natural killer (NK) cells. However, its precise role has not been clarified. Our combined analysis of Tcf1-deficient and transgenic mice indicated that Tcf1 guides NK cells through three stages of development. Tcf1 expression directed bone marrow progenitors toward the NK cell lineage and ensured the survival of NK-committed cells, and its downregulation was needed for terminal maturation. Impaired survival of NK-committed cells was due to excessive expression of granzyme B (GzmB) and other granzyme family members, which induced NK cell self-destruction during maturation and following activation with cytokines or target cells. Mechanistically, Tcf1 binding reduced the activity of a Gzmb-associated regulatory element, and this accounted for the reduced Gzmb expression in Tcf1 expressing NK cells. These data identify an unexpected requirement to limit the expression of cytotoxic effector molecules for the normal expansion and function of NK cells. PMID- 28723564 TI - The Lysine Acetyltransferase GCN5 Is Required for iNKT Cell Development through EGR2 Acetylation. AB - The development of CD1d-restricted invariant natural killer T (iNKT) cells, a population that is critical for both innate and adaptive immunity, is regulated by multiple transcription factors, but the molecular mechanisms underlying how the transcriptional activation of these factors are regulated during iNKT development remain largely unknown. We found that the histone acetyltransferase general control non-derepressible 5 (GCN5) is essential for iNKT cell development during the maturation stage. GCN5 deficiency blocked iNKT cell development in a cell-intrinsic manner. At the molecular level, GCN5 is a specific lysine acetyltransferase of early growth responsive gene 2 (EGR2), a transcription factor required for iNKT cell development. GCN5-mediated acetylation positively regulated EGR2 transcriptional activity, and both genetic and pharmacological GCN5 suppression specifically inhibited the transcription of EGR2 target genes in iNKT cells, including Runx1, promyelocytic leukemia zinc finger protein (PLZF), interleukin (IL)-2Rb, and T-bet. Therefore, our study revealed GCN5-mediated EGR2 acetylation as a molecular mechanism that regulates iNKT development. PMID- 28723567 TI - Cold-Inducible SIRT6 Regulates Thermogenesis of Brown and Beige Fat. AB - Promoting development and function of brown and beige fat may reduce obesity. Here, we show that fat SIRT6 expression is markedly induced by cold exposure and a beta-adrenergic agonist. Deletion of SIRT6 in adipose tissue impairs the thermogenic function of brown adipocytes, causing a morphological "whitening" of brown fat, reduced oxygen (O2) consumption, obesity, decreased core body temperature, and cold sensitivity. Fat SIRT6-deleted mice exhibit increased blood glucose levels, severe insulin resistance, and hepatic steatosis. Moreover, SIRT6 deficiency inhibits the browning of white adipose tissue (WAT) following cold exposure or beta3-agonist treatment. Depletion of SIRT6 expression in brown adipocytes reduces expression of thermogenic genes, causing a reduction in cellular respiration. Conversely, SIRT6 overexpression in primary fat cells stimulates the thermogenic program. Mechanistically, SIRT6 interacts with and promotes phospho-ATF2 binding to the PGC-1alpha gene promoter to activate its expression. The present study reveals a critical role for SIRT6 in regulating thermogenesis of fat. PMID- 28723566 TI - Genome-wide RNAi Screen for Fat Regulatory Genes in C. elegans Identifies a Proteostasis-AMPK Axis Critical for Starvation Survival. AB - Organisms must execute metabolic defenses to survive nutrient deprivation. We performed a genome-wide RNAi screen in Caenorhabditis elegans to identify fat regulatory genes indispensable for starvation resistance. Here, we show that opposing proteostasis pathways are principal determinants of starvation survival. Reduced function of cytoplasmic aminoacyl tRNA synthetases (ARS genes) increases fat mass and extends starvation survival, whereas reduced proteasomal function reduces fat and starvation survival. These opposing pathways converge on AMP activated protein kinase (AMPK) as the critical effector of starvation defenses. Extended starvation survival in ARS deficiency is dependent upon increased proteasome-mediated activation of AMPK. When the proteasome is inhibited, neither starvation nor ARS deficiency can fully activate AMPK, leading to greatly diminished starvation survival. Thus, activity of the proteasome and AMPK are mechanistically linked and highly correlated with starvation resistance. Conversely, aberrant activation of the proteostasis-AMPK axis during nutritional excess may have implications for obesity and cardiometabolic diseases. PMID- 28723568 TI - Loss of Hepatic Mitochondrial Long-Chain Fatty Acid Oxidation Confers Resistance to Diet-Induced Obesity and Glucose Intolerance. AB - The liver has a large capacity for mitochondrial fatty acid beta-oxidation, which is critical for systemic metabolic adaptations such as gluconeogenesis and ketogenesis. To understand the role of hepatic fatty acid oxidation in response to a chronic high-fat diet (HFD), we generated mice with a liver-specific deficiency of mitochondrial long-chain fatty acid beta-oxidation (Cpt2L-/- mice). Paradoxically, Cpt2L-/- mice were resistant to HFD-induced obesity and glucose intolerance with an absence of liver damage, although they exhibited serum dyslipidemia, hepatic oxidative stress, and systemic carnitine deficiency. Feeding an HFD induced hepatokines in mice, with a loss of hepatic fatty acid oxidation that enhanced systemic energy expenditure and suppressed adiposity. Additionally, the suppression in hepatic gluconeogenesis was sufficient to improve HFD-induced glucose intolerance. These data show that inhibiting hepatic fatty acid oxidation results in a systemic hormetic response that protects mice from HFD-induced obesity and glucose intolerance. PMID- 28723569 TI - XIAP Loss Triggers RIPK3- and Caspase-8-Driven IL-1beta Activation and Cell Death as a Consequence of TLR-MyD88-Induced cIAP1-TRAF2 Degradation. AB - X-linked Inhibitor of Apoptosis (XIAP) deficiency predisposes people to pathogen associated hyperinflammation. Upon XIAP loss, Toll-like receptor (TLR) ligation triggers RIPK3-caspase-8-mediated IL-1beta activation and death in myeloid cells. How XIAP suppresses these events remains unclear. Here, we show that TLR-MyD88 causes the proteasomal degradation of the related IAP, cIAP1, and its adaptor, TRAF2, by inducing TNF and TNF Receptor 2 (TNFR2) signaling. Genetically, we define that myeloid-specific cIAP1 loss promotes TLR-induced RIPK3-caspase-8 and IL-1beta activity in the absence of XIAP. Importantly, deletion of TNFR2 in XIAP deficient cells limited TLR-MyD88-induced cIAP1-TRAF2 degradation, cell death, and IL-1beta activation. In contrast to TLR-MyD88, TLR-TRIF-induced interferon (IFN)beta inhibited cIAP1 loss and consequent cell death. These data reveal how, upon XIAP deficiency, a TLR-TNF-TNFR2 axis drives cIAP1-TRAF2 degradation to allow TLR or TNFR1 activation of RIPK3-caspase-8 and IL-1beta. This mechanism may explain why XIAP-deficient patients can exhibit symptoms reminiscent of patients with activating inflammasome mutations. PMID- 28723570 TI - Dynamic Control of Dendritic mRNA Expression by CNOT7 Regulates Synaptic Efficacy and Higher Cognitive Function. AB - Translation of mRNAs in dendrites mediates synaptic plasticity, the probable cellular basis of learning and memory. Coordination of translational inhibitory and stimulatory mechanisms, as well as dendritic transport of mRNA, is necessary to ensure proper control of this local translation. Here, we find that the deadenylase CNOT7 dynamically regulates dendritic mRNA translation and transport, as well as synaptic plasticity and higher cognitive function. In cultured hippocampal neurons, synaptic stimulation induces a rapid decrease in CNOT7, which, in the short-term, results in poly(A) tail lengthening of target mRNAs. However, at later times following stimulation, decreased poly(A) and dendritic localization of mRNA take place, similar to what is observed when CNOT7 is depleted over several days. In mice, CNOT7 is essential for hippocampal-dependent learning and memory. This study identifies CNOT7 as an important regulator of RNA transport and translation in dendrites, as well as higher cognitive function. PMID- 28723571 TI - Emi2 Is Essential for Mouse Spermatogenesis. AB - The meiotic functions of Emi2, an inhibitor of the APC/C complex, have been best characterized in oocytes where it mediates metaphase II arrest as a component of the cytostatic factor. We generated knockout mice to determine the in vivo functions of Emi2-in particular, its functions in the testis, where Emi2 is expressed at high levels. Male and female Emi2 knockout mice are viable but sterile, indicating that Emi2 is essential for meiosis but dispensable for embryonic development and mitotic cell divisions. We found that, besides regulating cell-cycle arrest in mouse eggs, Emi2 is essential for meiosis I progression in spermatocytes. In the absence of Emi2, spermatocytes arrest in early diplotene of prophase I. This arrest is associated with decreased Cdk1 activity and was partially rescued by a knockin mouse model of elevated Cdk1 activity. Additionally, we detected expression of Emi2 in spermatids and sperm, suggesting potential post-meiotic functions for Emi2. PMID- 28723572 TI - Robust Identification of Developmentally Active Endothelial Enhancers in Zebrafish Using FANS-Assisted ATAC-Seq. AB - Identification of tissue-specific and developmentally active enhancers provides insights into mechanisms that control gene expression during embryogenesis. However, robust detection of these regulatory elements remains challenging, especially in vertebrate genomes. Here, we apply fluorescent-activated nuclei sorting (FANS) followed by Assay for Transposase-Accessible Chromatin with high throughput sequencing (ATAC-seq) to identify developmentally active endothelial enhancers in the zebrafish genome. ATAC-seq of nuclei from Tg(fli1a:egfp)y1 transgenic embryos revealed expected patterns of nucleosomal positioning at transcriptional start sites throughout the genome and association with active histone modifications. Comparison of ATAC-seq from GFP-positive and -negative nuclei identified more than 5,000 open elements specific to endothelial cells. These elements flanked genes functionally important for vascular development and that displayed endothelial-specific gene expression. Importantly, a majority of tested elements drove endothelial gene expression in zebrafish embryos. Thus, FANS-assisted ATAC-seq using transgenic zebrafish embryos provides a robust approach for genome-wide identification of active tissue-specific enhancer elements. PMID- 28723574 TI - Proteomic Analysis of the Human Tankyrase Protein Interaction Network Reveals Its Role in Pexophagy. AB - Tankyrase 1 (TNKS) and tankyrase 2 (TNKS2) belong to the poly(ADP-ribose) polymerase family of proteins, which use nicotinamide adenine dinucleotide to modify substrate proteins with ADP-ribose modifications. Emerging evidence has revealed the pathological relevance of TNKS and TNKS2, and identified these two enzymes as potential drug targets. However, the cellular functions and regulatory mechanisms of TNKS/2 are still largely unknown. Through a proteomic analysis, we defined the protein-protein interaction network for human TNKS/2 and revealed more than 100 high-confidence interacting proteins with numerous biological functions in this network. Finally, through functional validation, we uncovered a role for TNKS/2 in peroxisome homeostasis and determined that this function is independent of TNKS enzyme activities. Our proteomic study of the TNKS/2 protein interaction network provides a rich resource for further exploration of tankyrase functions in numerous cellular processes. PMID- 28723573 TI - Proteomic and Metabolomic Characterization of a Mammalian Cellular Transition from Quiescence to Proliferation. AB - There exist similarities and differences in metabolism and physiology between normal proliferative cells and tumor cells. Once a cell enters the cell cycle, metabolic machinery is engaged to facilitate various processes. The kinetics and regulation of these metabolic changes have not been properly evaluated. To correlate the orchestration of these processes with the cell cycle, we analyzed the transition from quiescence to proliferation of a non-malignant murine pro-B lymphocyte cell line in response to IL-3. Using multiplex mass-spectrometry-based proteomics, we show that the transition to proliferation shares features generally attributed to cancer cells: upregulation of glycolysis, lipid metabolism, amino-acid synthesis, and nucleotide synthesis and downregulation of oxidative phosphorylation and the urea cycle. Furthermore, metabolomic profiling of this transition reveals similarities to cancer-related metabolic pathways. In particular, we find that methionine is consumed at a higher rate than that of other essential amino acids, with a potential link to maintenance of the epigenome. PMID- 28723575 TI - CRISPR-Mediated Integration of Large Gene Cassettes Using AAV Donor Vectors. AB - The CRISPR/Cas9 system has recently been shown to facilitate high levels of precise genome editing using adeno-associated viral (AAV) vectors to serve as donor template DNA during homologous recombination (HR). However, the maximum AAV packaging capacity of ~4.5 kb limits the donor size. Here, we overcome this constraint by showing that two co-transduced AAV vectors can serve as donors during consecutive HR events for the integration of large transgenes. Importantly, the method involves a single-step procedure applicable to primary cells with relevance to therapeutic genome editing. We use the methodology in primary human T cells and CD34+ hematopoietic stem and progenitor cells to site specifically integrate an expression cassette that, as a single donor vector, would otherwise amount to a total of 6.5 kb. This approach now provides an efficient way to integrate large transgene cassettes into the genomes of primary human cells using HR-mediated genome editing with AAV vectors. PMID- 28723577 TI - Enabling tools for high-throughput detection of metabolites: Metabolic engineering and directed evolution applications. AB - Within the Design-Build-Test Cycle for strain engineering, rapid product detection and selection strategies remain challenging and limit overall throughput. Here we summarize a wide variety of modalities that transduce chemical concentrations into easily measured absorbance, luminescence, and fluorescence signals. Specifically, we cover protein-based biosensors (including transcription factors), nucleic acid-based biosensors, coupled enzyme reactions, bioorthogonal chemistry, and fluorescent and chromogenic dyes and substrates as modalities for detection. We focus on the use of these methods for strain engineering and enzyme discovery and conclude with remarks on the current and future state of biosensor development for application in the metabolic engineering field. PMID- 28723578 TI - Convolutional neural network-based encoding and decoding of visual object recognition in space and time. AB - Representations learned by deep convolutional neural networks (CNNs) for object recognition are a widely investigated model of the processing hierarchy in the human visual system. Using functional magnetic resonance imaging, CNN representations of visual stimuli have previously been shown to correspond to processing stages in the ventral and dorsal streams of the visual system. Whether this correspondence between models and brain signals also holds for activity acquired at high temporal resolution has been explored less exhaustively. Here, we addressed this question by combining CNN-based encoding models with magnetoencephalography (MEG). Human participants passively viewed 1,000 images of objects while MEG signals were acquired. We modelled their high temporal resolution source-reconstructed cortical activity with CNNs, and observed a feed forward sweep across the visual hierarchy between 75 and 200 ms after stimulus onset. This spatiotemporal cascade was captured by the network layer representations, where the increasingly abstract stimulus representation in the hierarchical network model was reflected in different parts of the visual cortex, following the visual ventral stream. We further validated the accuracy of our encoding model by decoding stimulus identity in a left-out validation set of viewed objects, achieving state-of-the-art decoding accuracy. PMID- 28723576 TI - An Atlas of Human Regulatory T Helper-like Cells Reveals Features of Th2-like Tregs that Support a Tumorigenic Environment. AB - Regulatory T cells (Tregs) play a pivotal role in maintaining immunological tolerance, but they can also play a detrimental role by preventing antitumor responses. Here, we characterized T helper (Th)-like Treg subsets to further delineate their biological function and tissue distribution, focusing on their possible contribution to disease states. RNA sequencing and functional assays revealed that Th2-like Tregs displayed higher viability and autocrine interleukin 2 (IL-2)-mediated activation than other subsets. Th2-like Tregs were preferentially found in tissues rather than circulation and exhibited the highest migratory capacity toward chemokines enriched at tumor sites. These cellular responses led us to hypothesize that this subset could play a role in maintaining a tumorigenic environment. Concurrently, Th2-like Tregs were enriched specifically in malignant tissues from patients with melanoma and colorectal cancer compared to healthy tissue. Overall, our results suggest that Th2-like Tregs may contribute to a tumorigenic environment due to their increased cell survival, higher migratory capacity, and selective T-effector suppressive ability. PMID- 28723579 TI - Elucidating high-dimensional cancer hallmark annotation via enriched ontology. AB - MOTIVATION: Cancer hallmark annotation is a promising technique that could discover novel knowledge about cancer from the biomedical literature. The automated annotation of cancer hallmarks could reveal relevant cancer transformation processes in the literature or extract the articles that correspond to the cancer hallmark of interest. It acts as a complementary approach that can retrieve knowledge from massive text information, advancing numerous focused studies in cancer research. Nonetheless, the high-dimensional nature of cancer hallmark annotation imposes a unique challenge. RESULTS: To address the curse of dimensionality, we compared multiple cancer hallmark annotation methods on 1580 PubMed abstracts. Based on the insights, a novel approach, UDT-RF, which makes use of ontological features is proposed. It expands the feature space via the Medical Subject Headings (MeSH) ontology graph and utilizes novel feature selections for elucidating the high-dimensional cancer hallmark annotation space. To demonstrate its effectiveness, state-of-the-art methods are compared and evaluated by a multitude of performance metrics, revealing the full performance spectrum on the full set of cancer hallmarks. Several case studies are conducted, demonstrating how the proposed approach could reveal novel insights into cancers. AVAILABILITY: https://github.com/cskyan/chmannot. PMID- 28723580 TI - Quality assurance of chemical ingredient classification for the National Drug File - Reference Terminology. AB - The National Drug File - Reference Terminology (NDF-RT) is a large and complex drug terminology consisting of several classification hierarchies on top of an extensive collection of drug concepts. These hierarchies provide important information about clinical drugs, e.g., their chemical ingredients, mechanisms of action, dosage form and physiological effects. Within NDF-RT such information is represented using tens of thousands of roles connecting drugs to classifications. In previous studies, we have introduced various kinds of Abstraction Networks to summarize the content and structure of terminologies in order to facilitate their visual comprehension, and support quality assurance of terminologies. However, these previous kinds of Abstraction Networks are not appropriate for summarizing the NDF-RT classification hierarchies, due to its unique structure. In this paper, we present the novel Ingredient Abstraction Network (IAbN) to summarize, visualize and support the audit of NDF-RT's Chemical Ingredients hierarchy and its associated drugs. A common theme in our quality assurance framework is to use characterizations of sets of concepts, revealed by the Abstraction Network structure, to capture concepts, the modeling of which is more complex than for other concepts. For the IAbN, we characterize drug ingredient concepts as more complex if they belong to IAbN groups with multiple parent groups. We show that such concepts have a statistically significantly higher rate of errors than a control sample and identify two especially common patterns of errors. PMID- 28723581 TI - The structure and function of cell membranes studied by atomic force microscopy. AB - The cell membrane, involved in almost all communications of cells and surrounding matrix, is one of the most complicated components of cells. Lack of suitable methods for the detection of cell membranes in vivo has sparked debates on the biochemical composition and structure of cell membranes over half a century. The development of single molecule techniques, such as AFM, SMFS, and TREC, provides a versatile platform for imaging and manipulating cell membranes in biological relevant environments. Here, we discuss the latest developments in AFM and the progress made in cell membrane research. In particular, we highlight novel structure models and dynamic processes, including the mechanical properties of the cell membranes. PMID- 28723583 TI - Label-free high-resolution 3-D imaging of gold nanoparticles inside live cells using optical diffraction tomography. AB - Delivery of gold nanoparticles (GNPs) into live cells has high potentials, ranging from molecular-specific imaging, photodiagnostics, to photothermal therapy. However, studying the long-term dynamics of cells with GNPs using conventional fluorescence techniques suffers from phototoxicity and photobleaching. Here, we present a method for 3-D imaging of GNPs inside live cells exploiting refractive index (RI) as imaging contrast. Employing optical diffraction tomography, 3-D RI tomograms of live cells with GNPs are precisely measured for an extended period with sub-micrometer resolution. The locations and contents of GNPs in live cells are precisely addressed and quantified due to their distinctly high RI values, which was validated by confocal fluorescence imaging of fluorescent dye conjugated GNPs. In addition, we perform quantitative imaging analysis including the segmentations of GNPs in the cytosol, the volume distributions of aggregated GNPs, and the temporal evolution of GNPs contents in HeLa and 4T1 cells. PMID- 28723584 TI - The relationship between growth performance and metabolic rate flexibility varies with food availability in juvenile qingbo (Spinibarbus sinensis). AB - Phenotypic flexibility in traits can allow organisms to cope with environmental challenges. However, the ecological consequences (e.g., growth) of SMR flexibility in fish are poorly understood. Juvenile qingbo (Spinibarbus sinensis) were reared individually with two levels of food resources (satiation or limited) with either continuous feeding (CF) or starvation-refeeding (SR). In the CF experiment, SMR increased when individuals were fed either the satiation or limited diets, but no difference was found in average specific growth rate somatic growth (SGR) between the two food availabilities. The relationship between flexibility in SMR and SGR, feeding efficiency (FE) and food intake (FI) was positive in the satiation group but not in the limited food group. In the SR experiment, the initial SMR of individuals was negatively correlated with the SGR during starvation. During refeeding, the starved individuals increased both body mass and SMR under both food availabilities. Individuals with a greater increase in SMR were fed more and also had greater SGR and FE under the satiation diet, but these results were not observed under the limited diet. The average FE under the limited diet was greater than that under the satiation diet, causing there to be no significant difference in final body mass between the diet treatments at the end of refeeding. Our study suggested that SMR flexibility can allow individuals to maximize their potential growth performance in an environment with changing food availability, and the benefits from greater flexibility in SMR could be offset by their maintenance metabolism under environmental stress. PMID- 28723582 TI - Overexpression and purification of Dicer and accessory proteins for biochemical and structural studies. AB - The Dicer family of ribonucleases plays a key role in small RNA-based regulatory pathways by generating short dsRNA fragments that modulate expression of endogenous genes, or protect the host from invasive nucleic acids. Beginning with its initial discovery, biochemical characterization of Dicer has provided insight about its catalytic properties. However, a comprehensive understanding of how Dicer's domains contribute to substrate-specific recognition and catalysis is lacking. One reason for this void is the lack of high-resolution structural information for a metazoan Dicer in the apo- or substrate-bound state. Both biochemical and structural studies are facilitated by large amounts of highly purified, active protein, and Dicer enzymes have historically been recalcitrant to overexpression and purification. Here we describe optimized procedures for the large-scale expression of Dicer in baculovirus-infected insect cells. We then outline a three-step protocol for the purification of large amounts (3-4mg of Dicer per liter of insect cell culture) of highly purified and active Dicer protein, suitable for biochemical and structural studies. Our methods are general and are extended to enable overexpression, purification and biochemical characterization of accessory dsRNA binding proteins that interact with Dicer and modulate its catalytic activity. PMID- 28723585 TI - Clinical utility of contrast-enhanced spectral mammography as an adjunct for tomosynthesis-detected architectural distortion. AB - OBJECTIVE: Supplement tomosynthesis-detected architectural distortions (AD) with CESM to better characterize malignant vs benign lesions. METHODS: Retrospective review CESM prior to biopsied AD. Pathology: benign, radial scar, or malignant. RESULTS: 49 lesions (45 patients). 29 invasive cancers, 1 DCIS (range, 0.4 4.7cm); 9 radial scars; 10 benign. 37 (75.5%) ADs had associated enhancement. PPV 78.4% (29/37), sensitivity 96.7% (29/30); specificity, 57.9% (11/19); NPV, 91.7% (11/12). False-positive rate 21.6% (8/37); false-negative rate, 8.3% (1/12). Accuracy 81.6% (40/49). CONCLUSIONS: High sensitivity and NPV of CESM in patients with AD is promising as an adjunct tool in diagnosing malignancy and avoiding unnecessary biopsy, respectively. PMID- 28723586 TI - A "Code ICU" expedited review of critically ill patients is associated with reduced emergency department length of stay and duration of mechanical ventilation. AB - PURPOSE: To examine the effect of a system of expedited review of critically ill patients in the Emergency Department (ED) on ED length of stay (LOS) and Intensive Care Unit (ICU) outcomes. MATERIALS AND METHODS: Retrospective cohort study at a tertiary hospital comparing two 12-month periods before and after implementation of a 'Code ICU' system of expedited review of critically ill patients in the ED. All adult ED to ICU admissions were included. Separate analyses were performed for patients intubated prior to ICU admission. RESULTS: 622 and 629 patients were included in each time period. During the intervention period more patients had ED LOS<240min in both the total [199 (32.0%) vs. 243 (38.6%), P=0.014; adjusted OR 1.60, 95% CI 1.14-2.25] and intubated cohorts [145 (51.2%) vs. 172 (61.9%), P=0.011; adjusted OR 1.65, 95% CI 1.16-2.36]. 'Code ICU' intubated patients had a shorter duration of mechanical ventilation, ICU LOS and hospital LOS compared to non-'Code ICU' intubated patients. CONCLUSIONS: A system of rapid review of critically ill patients in the ED was associated with reduced ED LOS and improved ICU outcomes. PMID- 28723587 TI - Evaluation of an Electronic Clinical Decision Support Tool for Incident Elevated BP in Adolescents. AB - OBJECTIVE: To evaluate, among adolescents 10 to 17 years of age with an incident hypertensive blood pressure (BP; >=95th percentile) at a primary care visit, whether TeenBP, a novel electronic health record-linked clinical decision support tool (CDS), improved recognition of elevated BP, and return for follow-up BP evaluation. METHODS: We conducted a pragmatic cluster randomized trial in 20 primary care clinics in a large Midwestern medical group. Ten clinics received the TeenBP CDS, including an alert to remeasure a hypertensive BP at that visit, an alert that a hypertensive BP should be repeated in 1 to 3 weeks, and patient specific order sets. In the 10 usual care (UC) clinics, elevated BPs were displayed in red font in the electronic health record. For comparisons between CDS and UC we used generalized linear mixed models. RESULTS: The study population included 607 CDS patients and 607 UC patients with an incident hypertensive BP. In adjusted analyses, at the index visit, CDS patients were more likely to have their hypertensive BP on the basis of >=2 BP measurements (47.1% vs 27.6%; P = .007) and to have elevated BP (International Classification of Diseases, Ninth Revision code 796.2) diagnosed (28.2% vs 4.2%; P < .001). In a multivariate model adjusted for age, sex, systolic BP percentile, and visit type, rates for repeat BP measurement within 30 days were 14.3% at TeenBP CDS clinics versus 10.6% at UC clinics (P = .07). CONCLUSIONS: The TeenBP CDS intervention significantly increased repeat BP measurement at the index visit and recognition of a hypertensive BP. Rates for follow-up BP measurement at 30 days were low and did not differ between TeenBP and UC subjects. PMID- 28723588 TI - Shared Decision-Making with Parents of Acutely Ill Children: A Narrative Review. AB - BACKGROUND: Shared decision-making (SDM) has mostly been used with adults and parents in the primary care setting, and there is limited knowledge on the use of SDM with parents of acutely ill children. The objective of this study was to review the literature on SDM with parents in the management of acutely ill children. METHODS: We searched MEDLINE, SCOPUS, PsycINFO, the Cochrane Library, and ClinicalTrials.gov for English language studies published from the time of database inception to February, 2017. Study eligibility criterion was use of SDM with parents for children aged 18 years or younger with an acute medical problem. RESULTS: We identified 2 ongoing clinical trials and 10 published studies that met inclusion criteria: 2 using hypothetical SDM scenarios, 1 mixed methods study, and 7 intervention studies. Only 1 study compared an SDM intervention with usual care in a randomized controlled trial. The limited literature shows that parents of acutely ill children have differing preferences for testing and/or treatment, and that they generally want the opportunity to express those preferences through an SDM process. Use of SDM often results in acutely ill children undergoing fewer and/or less intensive testing or treatment, although the effect on outcomes is unclear. CONCLUSIONS: Parents welcome participation in SDM for management decisions with their acutely ill child. Further investigation is needed to determine how best to implement SDM with parents of acutely ill children and to assess the effect of SDM on outcomes. PMID- 28723589 TI - Types of Objects in the Sleep Environment Associated With Infant Suffocation and Strangulation. AB - OBJECTIVE: To investigate the circumstances of death and types and roles of objects present in the sleep environment at the time of death for infants who died from suffocation or strangulation during sleep. METHODS: This study analyzed 1736 reported incidents of accidental suffocation and strangulation in bed (ASSB) of infants younger than 1 year of age. These fatalities occurred from 2000 through 2012 and were reported to the United States Consumer Product Safety Commission. RESULTS: The mean age of ASSB death was 3.76 months (SD, 2.51). Infants younger than 5 months accounted for 67.3% (1168 of 1736) of all reported fatalities and 58.3% (1009 of 1731) were male. Deceased infants were often found in a crib or bassinet (30.6%; 383 of 1253) or in the prone orientation (84.9%; 595 of 701). The most common objects associated with infant ASSB were pillows (24.5%; 425 of 1736), mattresses (21.0%; 364 of 1736), blankets (13.1%; 228 of 1736), and walls (11.5%; 199 of 1736). Wedged (43.3%; 616 of 1424) or positioned on top of an object (25.9%; 369 of 1424) were the most common positions associated with death. Infants were often found wedged between a mattress and wall (30.2%; 181 of 599) or oriented face-down or prone on top of a pillow (52.2%; 187 of 358). Sleep surface sharing was associated with 6.5% (112 of 1736) of ASSB deaths. CONCLUSIONS: Pillows and blankets are objects in sleep environments frequently associated with unintentional suffocation and strangulation of infants. Increased efforts should be made to remove these and other objects from sleep environments of infants. PMID- 28723590 TI - Cardioprotective mitochondrial binding by hexokinase I is induced by a hyperoxic acute thermal insult in the rainbow trout (Oncorhynchus mykiss). AB - Due to the substantial photosynthetic biomass in their habitat, salmonids such as the rainbow trout (Oncorhynchus mykiss) can be subject to hyperoxia in addition to high temperatures associated with climate change. Both stressful conditions increase the incidence of damaging reactive oxygen species (ROS). The mitochondrial association of hexokinase has been shown to increase in the hearts of certain fish experiencing hypoxia in a putative cardioprotective response to oxidative stress. In this study, the mitochondrial association of hexokinase I (HKI) and markers of oxidative damage and metabolic stress were probed to elucidate the cardioprotective role of hexokinase in the rainbow trout. Results showed that the co-administration of hyperoxia and hyperthermia increased the ventricular mitochondrially-bound fraction of HKI, whereas exposure to hyperthermia in normoxia had no effect; in the combined condition there was little evidence of increased stress. A second in vitro study using ventricular strips and isolated cardiomyocytes was undertaken to reconcile the cardioprotective role of HK in the rainbow trout with findings in mammalian studies, confirming that mitochondrial association of HK maintains aerobic efficiency and inhibits apoptosis. Finally, protein sequence analysis suggested that the physiological contributions of HKI and HKII in salmonids vary from those in mammals, further explaining the dynamic nature of the traditionally-inert HKI. Together, these findings help to explain the broader functions of HKI in the salmonid heart, and illustrate the role of complex environmental conditions in defining physiological responses. PMID- 28723591 TI - Molecular characterization and expression analysis of the myostatin gene and its association with growth traits in Noble scallop (Chlamys nobilis). AB - Myostatin (MSTN), also called growth and differentiation factor-8 (GDF-8), is a member of the transforming growth factor-beta (TGF-beta) superfamily and an inhibitor of muscle differentiation and growth. In this report, we identified and characterized a MSTN gene (CnMSTN) from the scallop Chlamys nobilis. The open reading frame of CnMSTN was 1374bp in length, encoding 457 amino acids. The structure of CnMSTN included a putative signal peptide, a TGF-beta propeptide domain, and a conserved TGF-beta domain. Phylogenetic analysis showed that the CnMSTN gene was clustered in the same subgroup with the MSTN gene found in Mollusca. Quantitative real-time PCR showed that the CnMSTN gene was widely expressed in all tissues tested, with the highest expression level observed in the adductor muscle. Six single nucleotide polymorphisms (SNPs) were identified in the promoter region, but no SNP was detected in the exon regions. Association analysis showed that SNP g.-579A/C had significant effects on body mass, soft tissue mass, and adductor muscle mass. The CC and AC genotypes of g.-579A/C had significantly higher growth trait values than that of genotype AA (P<0.05). These results suggest that CnMSTN could be used as a candidate gene for the selective breeding of C. nobilis. PMID- 28723592 TI - Effects of Near Infrared Radiation on DNA. DLS and ATR-FTIR Study. AB - We presume that the primary effect of Near Infrared (NIR) radiation on aqueous solutions of biological molecules concerns modification of hydrogen bonded structures mainly the global and the hydration shell water molecules. Since water has a significant influence on the DNA structure, we expect that the thermal stability of DNA could be modified by NIR radiation. The herring sperm DNA was exposed to NIR radiation (700-1100nm) for 5, 10, and 20min periods. The temperature dependent infrared measurements were done for the thin films formed on the diamond ATR crystal from evaporated DNA solutions exposed and unexposed to NIR radiation. For the NIR-treated samples (at room temperature) the B form was better conserved than in the control sample independently of the irradiation period. Above 50 degrees C a considerable increase in the A form was only observed for 10min NIR exposed samples. The hydrodynamic radius, (Rh), studied by the dynamic light scattering, showed drastic decrease with the increasing irradiation time. Principal components analysis (PCA) allowed to detect the spectral features correlated with the NIR effect and thermal stability of the DNA films. Obtained results strongly support the idea that the photoionization of water by NIR radiation in presence of DNA molecules is the main factor influencing on its physicochemical properties. PMID- 28723593 TI - 12th Tinnitus Seminar and 1st World Tinnitus Congress. PMID- 28723594 TI - Cochlear implantation improves hearing and vertigo in patients after removal of vestibular schwannoma. AB - OBJECTIVES: With rising quality of speech perception in cochlear implant users, the indication widens. Nowadays, cochlear implantation is reasonable even in vestibular schwannoma patients. Speech perception with a cochlear implant is in these patients as promising as in patients with sensorineural hearing loss. However, the impact of cochlear implantation on vertigo and tinnitus after removal of vestibular schwannoma has not been investigated yet. METHODS: In a retrospective study, we analysed 12 patients treated with a cochlear implant after removal of vestibular schwannoma. RESULTS: In addition to a promising hearing perception - all patients reported improvement of vertigo. This improvement was also demonstrated by postural analysis. Improvement of tinnitus was achieved in 50% of the patients. CONCLUSION: Cochlear implantation seems a promising treatment for hearing loss, vertigo and even tinnitus in patients after removal of vestibular schwannoma. However, for successful cochlear implantation with adequate speech perception and improvement of vertigo and tinnitus, functional hearing nerve and intact inner ear anatomy is necessary. PMID- 28723595 TI - Pilot Investigation of a Topographical Filter Dermal Patch in Patients with Tinnitus. AB - OBJECTIVES: A new topographical filter in a dermal administration patch that organizes water molecules has been suggested as an alternative treatment for manifested tinnitus. The aim of this study was to evaluate this patch in a pilot study. MATERIALS AND METHODS: 12 patients were included (10 completed) in an open study all receiving treatment with daily changed patches. The objectives were to evaluate safety and performance of the patch during and after treatment. The primary objective was to evaluate the tinnitus severity (by Tinnitus Severity Questionnaire, TSQ) and tinnitus annoyance (by Visual Analogue Scale, VAS). The secondary objective was to evaluate if the patch could improve the patient's quality of life (by SF-36 Quality of life questionnaire) and sleep initiation time (self-rated). RESULTS: At visit 4, after 21 days of treatment, an improvement (decrease in TSQ score) was seen in 5 responder patients, which was sustained at the post-treatment visit. A marginal increase in TSQ score was seen also initially in 5 non-responder patients, 4 of which were responders post treatment. The rated tinnitus annoyance, quality of life and sleep initiation time did not show significant changes. The safety evaluation did not present any safety concerns. CONCLUSION: This small pilot study indicates that it can be reasonable to recommend on a risk-benefit and safety perspective treatment with the dermal patch to patients with tinnitus as a consumer product based on the lack of other effective alternative treatment. Further and larger studies, and also proven experience, are recommended for stronger evidence. PMID- 28723596 TI - Effectiveness of Group Training of Assertiveness on Social Anxiety among Deaf and Hard of Hearing Adolescents. AB - ABSTRACT: The present study was conducted to compare the effectiveness of assertiveness group training on social anxiety (SAD) between deaf and hearing impaired adolescents. Forty eight (24 deaf and 24 hearing impaired) people participated in this study. First, participants with SAD, i.e. attaining the scores above 40 for Connor's Social Inventory Scale 2000 (SPIN), were selected according to convenience sampling and randomly assigned to two groups, i.e. intervention and control. Then, assertiveness group training was conducted for intervention group within 10 sessions, and immediately after completion of the training sessions, SPIN was re-administered to the two groups. ANCOVA showed that the effectiveness of assertiveness group training on SAD is different between deaf and hearing impaired participants, i.e. assertiveness group training was effective on improvement of SAD in hearing impaired participants but not deaf ones. Therefore, it is recommended to incorporate assertiveness group training in the educational programs developed for adolescents with ear disorders especially hearing impairment. PMID- 28723597 TI - Short Term Results of Intra Tympanic Gentamicin and Dexamethasone on Hearing and Tinnitus in Meniere's disease: A Case Control Study. AB - INTRODUCTION: The role of this study was to evaluate the effectiveness of intra tympanic administration of Gentamicin(40 mgs/ml) and Dexamethasone 0.5 ml(4 mgs/ml) on hearing and tinnitus of patients who had recurrent acute attacks of vertigo, tinnitus and hearing loss. STUDY DESIGN: 60 consecutive patients of Meniere's disease were randomly divided into 3 groups of twenty patients each. Group A included 20 patients who received intra tympanic gentamicin, Group B included 20 patients who received intra tympanic dexamethasone and Group C included 20 patients who received intra tympanic normal saline 0.5 ml. The mean pure tone thresholds at speech frequencies were noted before treatment and 2 weeks, 3 months and 6 months after treatment. Tinnitus was surveyed with a set questionnaire (Tinnitus Handicap Inventory). RESULTS: The mean PTA at speech frequencies for Group A worsened from 50 dB to 62 dB which was statistically significant. Two ears developed profound sensorineural hearing loss. The mean tinnitus handicap inventory grade of group A was 4. Mean was 2 at the end of 6 months which indicates significant reduction of the tinnitus score. Group B patients had a mean PTA at speech frequencies of 42 dB. There was no gain in 12 patients and less than 10 dB in the remaining eight patients and no worsening of hearing was seen. The mean tinnitus handicap inventory grade in Group B was 2.5 and was 2 at 6 months after treatment. Group C patients had a mean PTA of 48 dB before treatment and were same after treatment however the tinnitus handicap grade was 2.5 before the treatment and 2.0 after treatment. CONCLUSION: Intra tympanic gentamicin is more effective in controlling tinnitus as compared to dexamethasone and placebo and there was no marked difference in control of tinnitus between placebo and steroids. There is significant hearing loss with IT Gentamicin and no marked difference between steroid and placebo on hearing. PMID- 28723598 TI - Effects of Tumor Necrosis Factor Blocker on Salicylate-Induced Tinnitus in Mice. AB - OBJECTIVE: Neuroinflammation is considered a novel mechanism for acute tinnitus. Here, we investigated the effects of a tumor necrosis factor (TNF) blocker on the gene expression of inflammatory-cytokine in the cochlea in a tinnitus animal model. METHODS: Enbrel(r) (30 mg/kg, intraperitoneally (i.p.)) were administrated to the mice with the salicylate induced tinnitus for 3 days. Tinnitus score and mRNA expression levels of TNFR1, TNFR2, and N-methyl-d-aspartate receptor subunit 2B (NR2B) and its downstream regulatory element antagonist modulator (DREAM) in the cochlea of mice were measured and compared to the control. RESULTS: The tinnitus score significantly decreased in the Enbrel(r) treated group. The mRNA levels of both TNFR1 and TNFR2 were significantly lower in the treatment than in the control group. The mRNA levels of NR2B and DREAM followed a similar trend. CONCLUSION: we found that treatment with 30 mg/ kg Enbrel(r) decreased salicylate induced behavior associated with tinnitus and reduced the mRNA expression levels of TNFR1/R2, NR2B, and DREAM in the cochlea of mice. These findings supported the hypothesis that neuroinflammation might be a novel mechanism for salicylate induced tinnitus. PMID- 28723599 TI - Management of Benign Paroxysmal Positional Vertigo: A Comparative Study between Epleys Manouvre and Betahistine. AB - ABSTRACT: Benign paroxysmal positional vertigo (BPPV) is the most common peripheral vestibular disorder, accounting for 20% of all vertigo cases. Idiopathic BPPV is most common between the ages of 50 and 70, although the condition is found in all age groups. This study was conducted in our institute on 90 patients who presented to the outpatient department with history of vertigo and were diagnosed with BPPV via a positive Dix Hallpike test. Patients were randomnly placed in three groups of 30 each. Patients in Group A were treated with Epleys manoeuvre alone, in Group B were treated with Epleys Manouvre followed by oral Betahistine and patients in Group C were treated with Betahistine alone. All the patients were followed up after 1 week and 4 weeks following treatment. In our study we found that patients responded better when they were treated with Epleys Manouvre with Betahistine with less relapse and recurrence. Treatment with Epleys manouvre resulted in early improvement of symptoms. It was found in our study that Betahistine as a sole modality of treatment of vertigo in BPPV can be preferred in patients who are unfit to undergo canal repositioning manouvres. PMID- 28723600 TI - Detailed Analysis of High Frequency Auditory Brainstem Response in Patients with Tinnitus: A Preliminary Study. AB - ABSTRACT: Increased spontaneous activity and aberrant neural synchrony is thought to be the underlying cause of tinnitus. The perceived pitch of tinnitus may be dictated by frequency specific neural fibers of the subcortical pathway, or the projection of altered cortical activity by-way-of tonotopic reorganizations. Subcortical neural activity in relation to tinnitus was characterized using ABR measurements. In the present study, 11 patients (21 ears) with constant tonal tinnitus underwent a two-part experiment. Experiment 1 involved click ABR measurements and included two experimental groups: tinnitus with normal hearing from 2000-4000 Hz (GI) and tinnitus with hearing loss within the range of 2000 4000 Hz (GII). Experiment 2 utilized tone burst ABRs matched to each participant's perceived tinnitus pitch and included two experimental groups: tinnitus with normal hearing at the tinnitus pitch (GIa) and tinnitus with hearing loss at the tinnitus pitch (GIIa). These groups were compared to a control group (GIII) of ten monaurally tested (10 ears) participants with normal hearing thresholds at 250-20000 Hz and no tinnitus. Click ABR results indicate significantly prolonged V-III IPLs for GI and GII and a significantly extended absolute V latency for GII only. Tone burst ABRs matched to tinnitus pitch revealed significantly prolonged absolute latencies and IPLs at three of the seven frequencies for GIIa. ABR threshold seeking was completed and revealed negative eHL values for two of the four different stimuli for GI and GIa and four of the eight stimuli for GII and GIIa. Click ABRs results are suggestive of upper brainstem abnormalities for both groups. While GI demonstrated prolonged V-III IPLs, no significant differences were found for GIa. This suggests that there is no frequency specific subcortical characteristic associated with tinnitus with normal hearing. Frequency specific properties for subcortical activity could not be characterized due to varying results of GIIa. PMID- 28723601 TI - A Review of Medicinal Plants for the Treatment of Earache and Tinnitus in Iran. AB - BACKGROUND AND PURPOSE: Despite numerous trials, there has not yet been any definite strategy to reduce replicable long-term tinnitus and earache. Complementary and alternative medical approaches have been used to decrease the symptoms of tinnitus and earache. This study was conducted to report medicinal plants that are used to treat ear disorders, especially earache and tinnitus in different regions of Iran. EVIDENCE ACQUISITIONS: Directory of Open Access Journals (DOAJ), Google Scholar, PubMed, LISTA (EBSCO), Embase, and Web of Science were searched using relevant search terms to retrieve eligible publications. RESULTS: Twenty-three species from sixteen families were used for the treatment of earache and tinnitus in Iran. Plants from families Asteraceae and Lamiaceae were the most commonly used plants for the treatment of earache. Ginkgo biloba was frequently reported for the treatment of tinnitus. CONCLUSION: This study shows the important role of medicinal plants in the treatment of earache and tinnitus in some regions of Iran. The medicinal plants reported in this review can be considered in treatments for earache and tinnitus if examined more extensively in clinical trials. PMID- 28723602 TI - Tinnitus, Anxiety, Depression and Substance Abuse in Rock Musicians a Norwegian Survey. AB - OBJECTIVE: Rock musicians are known to have an increased prevalence of hearing loss and tinnitus. The aims of the present study were to examine the distribution of anxiety and depression symptoms among rock musicians with or without tinnitus and how these mental health indicators and internal locus of control influenced upon their tinnitus symptom concerns and the degree to which the tinnitus affected their lives. DESIGN: The study was a questionnairebased cross-sectional survey of subjects selected from a cohort of rock musicians. We recruited 111 active musicians from the Oslo region, and a control group of 40 non-musicians from the student population at the University of Tromso. RESULTS: Among the rock musicians 19.8% reported permanent tinnitus vs. 0% among the controls. Musicians more often reported anxiety symptoms than controls (35.1% vs. 17.5%), however this prevalence was not different in musicians with and without tinnitus. Tinnitus-affected musicians reported depressive symptoms, significantly more than controls (13.6% vs. 5%). Rock musicians consumed more alcohol than controls, but alcohol consumption was unrelated to severity of tinnitus. Drug abuse was not more prevalent in rock musicians than in controls. Duration of tinnitus, internal locus of control, sleep disturbance and anxiety were significant predictors of how affected and how concerned musicians were about their tinnitus. CONCLUSION: Rock musicians are at risk for the development of chronic tinnitus, and they have an increased prevalence of anxiety. There is an association between chronic tinnitus and depressive symptoms in rock musicians, but our results are ambiguous. Although rock musicians have a chronic exposure to noise, noise induced hearing loss is not the sole causative agent for the development of tinnitus. PMID- 28723603 TI - Ginkgo biloba in the treatment of tinnitus: An updated literature review. AB - INTRODUCTION: Tinnitus is one of the common diseases of the ear that is associated with numerous physical and mental disorders. One of the known mechanisms in the tinnitus area with unknown reason is oxidative events. Based on the prevalence and economic costs and physical- psychological side effects caused by tinnitus and the importance of finding a suitable solution for its prevention and treatment, the need for further studies becomes more obvious in this context. This review article aimed to review studies on the effectiveness of Ginkgo biloba as a medicinal plant on patients with tinnitus. EVIDENCE ACQUISITIONS: Google Scholar, Directory of Open Access Journals (DOAJ), PubMed, LISTA (EBSCO) and Web of Science have been searched. RESULTS: There are many studies on the therapeutic effect of Ginkgo biloba on patients with tinnitus. Most findings are in contrast with each other so that some of studies reported that Ginkgo biloba is effective in the treatment of tinnitus and other studies referred to it as ineffective herbal medicine. Generally, according to the previous studies and the present study, it can mention that the Ginkgo biloba may somewhat improve tinnitus. CONCLUSION: Since tinnitus is multifactorial, it is recommended to evaluate patients individually based on the cause of tinnitus, treatment formulas, and different doses of Ginkgo biloba at the more extensive level in future studies. PMID- 28723604 TI - Possible Joint Involvement of the Cochlea and Semicircular Canals in the Perception of Low-Frequency Tinnitus, Also Called "The Hum" or "Taos Hum". AB - INTRODUCTION: "The hum" or "Taos hum" are common terms of a tinnitus with three remarkable features. OBJECTIVE: A possible common background is reevaluated for the three features of the hum: being sensitive on sound, head rotation, and long distance air travel. MATERIALS AND METHODS: Questionnaires that were originally developed by Frosch were recalculated concerning the question of hum interactions with sounds. The question was split into the two affirmative answers a) "masking", which corresponds to the overrule of the hum by a sound, and b) "beats", which correspond to a nonlinear interaction with the hum as a Van der Pol-like oscillator. RESULTS AND CONCLUSIONS: When interacting with sounds as beats the hum resulted in completely different dependencies with the other two features than when masked by sounds. The simultaneous features of the hum to generate beats and to be removed during head rotation are strongly dependent at an error below 0.1%. The simultaneous features to mask the hum with sounds and to experience a time-lag of its reappearance after long-distance air travel are dependent at an error below 1%. These two pairs of features have no overlapping dependencies. The term hum can be expected to be a collective term for at least two independent manifestations. PMID- 28723605 TI - Tinnitus Patients Suffering from Anxiety and Depression: A Review. AB - OBJECTIVES: To review literature on the link between depression and anxiety in patients suffering from tinnitus. METHOD: A systematic review of published English-language literature was performed using PubMed, Ovid, and Cochrane databases. RESULTS: Of the 56 eligible abstracts 15 were chosen to be included in the review. All articles showed an association of depression and anxiety in tinnitus patients. CONCLUSIONS: Because of the strong association between tinnitus, depression, and anxiety- all tinnitus patients should be screened for psychiatric disorders. Treatment for these complex conditions should involve a multidisciplinary team with cognitive behavioral therapy and possible pharmacological therapy. PMID- 28723606 TI - Visual Snow Syndrome and Its Relationship to Tinnitus. AB - ABSTRACT: Visual snow is a symptom described as the continuous perception of tiny flickering dots in the entire field of vision, similar to static of an analog television. Visual snow syndrome is a cluster of symptoms found highly prevalent in patients that present with visual snow. While most of these symptoms appear to be visual in nature, approximately 63% of patients studied also report continuous bilateral tinnitus. The high correlation of visual-snow-syndrome patients presenting with tinnitus suggests that they may share a common underlying pathophysiology. PMID- 28723607 TI - Production of recombinant porin from Y. pseudotuberculosis in a water-soluble form for pseudotuberculosis diagnostics. AB - OmpF porin from the outer membrane of Yersinia pseudotuberculosis was cloned into pET-40b(+) plasmid. Using E. coli Rosetta (DE3) strain, MX medium, IPTG concentration of 0.2 mm and post-induction cultivation at 14 degrees C overnight allowed us to obtain a water-soluble form of the recombinant protein (rs-OmpF). Rs-OmpF was shown to have the ordered spatial structure at the levels of secondary and tertiary structure. Rs-OmpF was found to be effective as diagnostic antigen in ELISA for pseudotuberculosis diagnostics. PMID- 28723608 TI - Breastfeeding and the gut-brain axis: is there a role for melatonin? AB - The benefits of breastfeeding over formula feed are widely appreciated. However, for many mothers breastfeeding is not possible, highlighting the need for a significant improvement in the contents of formula feed. In this article, the overlooked role of melatonin and the melatonergic pathways in breast milk and in the regulation of wider breast milk components are reviewed. There is a growing appreciation that the benefits of breastfeeding are mediated by its effects in the infant gut, with consequences for the development of the gut-brain axis and the immune system. The melatonergic pathways are intimately associated with highly researched processes in the gut, gut microbiome and gut-brain axis. As the melatonergic pathways are dependent on the levels of serotonin availability as a necessary precursor, decreased melatonin is linked to depression and depression associated disorders. The association of breastfeeding and the gut-brain axis with a host of medical conditions may be mediated by their regulation of processes that modulate depression susceptibility. The biological underpinnings of depression include increased levels of pro-inflammatory cytokines, oxidative stress, kynurenine pathway activity and dysregulation of the hypothalamic pituitary adrenal axis, all of which can decrease melatonergic pathway activity. The inclusion of the melatonergic pathways in the biological interactions of breast milk and gut development has significant theoretical and treatment implications, as well as being important to the prevention of a host of infant-, child- and adult-onset medical conditions. PMID- 28723609 TI - Failure analysis of eleven Gates Glidden drills that fractured intraorally during post space preparation. A retrieval analysis study. AB - The purpose of this study was to determine the failure mechanism of clinically failed Gates Glidden (GG) drills. Eleven retrieved GG drills (sizes #1 to #3) which fractured during root canal preparation were collected and the fracture location was recorded based on macroscopic observation. All fracture surfaces were investigated by a SEM. Then the fractured parts were embedded in acrylic resin and after metallographic preparation, the microstructure and elemental composition was evaluated by SEM and EDS. The Vickers hardness (HV) of all specimens was also determined. Macroscopic examination and SEM analysis showed that the drills failed near the hand piece end by torsional fatigue with fatigue cracks initiating at several locations around the circumference and propagating toward the center. Final fracture followed by a tensile overloading at the central region of cross section. Microstructural analysis, hardness measurements and EDS show that the drills are made of a martensitic stainless steel like AISI 440C. Based on the findings of this study, clinicians should expect fatigue fracture of GG drills that have small size during root canal preparation. Selection of a more fatigue resistant stainless steel alloy and enhancing the instrument design might reduce the incidence of quasi-cleavage fracture on GG drills. PMID- 28723610 TI - Pediatric reference intervals for 29 Ortho VITROS 5600 immunoassays using the CALIPER cohort of healthy children and adolescents. AB - BACKGROUND: Accurate reference intervals (RIs) based on a healthy pediatric population are essential for pediatric test result interpretation. The CALIPER project has recruited a large healthy cohort and completed a series of a priori studies to address gaps in pediatric RIs. As immunoassays from different manufacturers for endocrine and special chemistry markers are not standardized and show marked intermethod differences, direct RI studies are needed for each major analytical platform. Here, we report age- and sex-specific pediatric RIs for 29 immunoassays on the Ortho Clinical Diagnostics (Ortho) VITROS(r) 5600 analyzer. METHODS: Health information and blood samples were collected from healthy pediatric subjects. Using the Ortho VITROS 5600 Integrated System MicroWell Technology, 29 biomarkers were measured. Analyte concentrations were partitioned by age and sex according to the Harris and Boyd method. After removing outliers, age- and sex-specific RIs and corresponding 90% confidence intervals were calculated according to CLSI guidelines. RESULTS: All analytes required age partitioning except beta-human chorionic gonadotropin (beta-hCG), cancer antigen 15-3 (CA15-3), rubella immunoglobulin G (rubella IgG), and vitamin D. Several analytes including estradiol, progesterone, testosterone, follicle stimulating hormone (FSH), luteinizing hormone (LH), free triiodothyronine (FT3), total triiodothyronine (TT3), total thyroxine (TT4), thyroid uptake, ferritin, intact parathyroid hormone (iPTH), total prostate-specific antigen (tPSA), free prostate-specific antigen (fPSA), cancer antigen 125 (CA125), creatine kinase MB (CK-MB), and myoglobin showed sex differences, observed mostly with the onset of puberty. CONCLUSIONS: Complex reference value trends were observed across the pediatric age range for several biomarkers examined on Ortho VITROS immunoassays. The availability of VITROS immunoassay RIs will enable accurate laboratory test interpretation and diagnosis for the pediatric population. As recommended by the CLSI EP28-A3c guidelines, implementation of these RIs should be validated for each laboratory's local pediatric population. PMID- 28723612 TI - Reply to: Planned home birth and the association with neonatal hypoxic ischemic encephalopathy. PMID- 28723611 TI - Parent reported nutritional risk and laboratory indices of cardiometabolic risk and in preschool-aged children. AB - BACKGROUND: Eating habits formed during childhood may contribute to the increasing prevalence of cardiometabolic disorders. Assessing nutritional risk in young children may help to prevent later cardiometabolic disease. The objective of this study was to determine whether parent-reported nutritional risk in preschool-aged children was associated with laboratory indices of cardiometabolic risk, namely leptin and insulin. METHODS: In this cross-sectional study, the relationship between nutritional risk as determined by the parent-completed NutriSTEP(r) questionnaire was assessed and compared to the serum leptin and insulin concentrations, hormones involved in regulation of food intake and biomarkers of adiposity and cardiometabolic risk. The community-based primary care research network for children in Toronto, Canada (TARGet Kids!) was used. The participants were children aged 3-5 years recruited from TARGet Kids! A total of 1856 children were recruited from seven primary care practices. Of these, 1086 children completed laboratory testing. Laboratory data for leptin and insulin were available for 714 and 1054 of those individuals, respectively. RESULTS: The total NutriSTEP(r) score was significantly associated with serum leptin concentrations (p=0.003); for each unit increase in the total NutriSTEP(r) score, there was an increase of 0.01 ng/mL (95% confidence interval [CI] 0.004-0.018) in serum leptin concentrations after adjusting for potential confounders. The total NutriSTEP(r) score was not significantly associated with serum insulin concentration. CONCLUSIONS: Parent reported nutritional risk is associated with serum leptin, but not insulin, concentrations in preschool-aged children. The NutriSTEP(r) questionnaire may be an effective tool for predicting future cardiometabolic risk in preschool-aged children. PMID- 28723613 TI - Mixture model-based association analysis with case-control data in genome wide association studies. AB - Multilocus haplotype analysis of candidate variants with genome wide association studies (GWAS) data may provide evidence of association with disease, even when the individual loci themselves do not. Unfortunately, when a large number of candidate variants are investigated, identifying risk haplotypes can be very difficult. To meet the challenge, a number of approaches have been put forward in recent years. However, most of them are not directly linked to the disease penetrances of haplotypes and thus may not be efficient. To fill this gap, we propose a mixture model-based approach for detecting risk haplotypes. Under the mixture model, haplotypes are clustered directly according to their estimated disease penetrances. A theoretical justification of the above model is provided. Furthermore, we introduce a hypothesis test for haplotype inheritance patterns which underpin this model. The performance of the proposed approach is evaluated by simulations and real data analysis. The results show that the proposed approach outperforms an existing multiple testing method. PMID- 28723678 TI - Carrier transport dynamics in Mn-doped CdSe quantum dot sensitized solar cells. AB - In this work quantum dot sensitized solar cells (QDSSCs) were fabricated with CdSe and Mn-doped CdSe quantum dots (QDs) using the SILAR method. QDSSCs based on Mn-doped CdSe QDs exhibited improved incident photon-to-electron conversion efficiency. Carrier transport dynamics in the QDSSCs were studied using the intensity modulated photocurrent/photovoltage spectroscopy technique, from which transport and recombination time constants could be derived. Compared to CdSe QDSSCs, Mn-CdSe QDSSCs exhibited shorter transport time constant, longer recombination time constant, longer diffusion length, and higher charge collection efficiency. These observations suggested that Mn doping in CdSe QDs could benefit the performance of solar cells based on such nanostructures. PMID- 28723679 TI - Preparation and application of N-doped carbon nanotube arrays on graphene fibers. AB - A new kind of carbon hybrid material with a unique structure and outstanding mechanical and functional properties is reported in this article. Nitrogen-doped carbon nanotube (CNT) arrays with inside located Ni particles are in situ grown on the surface of phenolic carbon modified graphene fibers during their conversion from graphene oxide fibers. The carbon hybrid fibers exhibit not only high tensile strength and elongation at the break, but also excellent flexibility since the CNT arrays cover all the surface of the highly strong graphene fiber. This well-constructed carbon material would be suitable for catalysts, polymer composites, hydrogen storage, oxygen reduction reaction etc. PMID- 28723680 TI - Meiotic Recombination in the Giraffe (G. reticulata). AB - Recently, the reticulated giraffe (G. reticulata) was identified as a distinct species, which emphasized the need for intensive research in this interesting animal. To shed light on the meiotic process as a source of biodiversity, we analysed the frequency and distribution of meiotic recombination in 2 reticulated giraffe males. We used immunofluorescence detection of synaptonemal complex protein (SYCP3), meiotic double strand breaks (DSB, marked as RAD51 foci) in leptonema, and crossovers (COs, as MLH1 foci) in pachynema. The mean number of autosomal MLH1 foci per cell (27), which resulted from a single, distally located MLH1 focus observed on most chromosome arms, is one of the lowest among mammalian species analysed so far. The CO/DSB conversion ratio was 0.32. The pseudoautosomal region was localised in the Xq and Yp termini by FISH and showed an MLH1 focus in 83% of the pachytene cells. Chromatin structures corresponding to the nucleolus organiser regions were observed in the pachytene spermatocytes. The results are discussed in the context of known data on meiosis in Cetartiodactyla, depicting that the variation in CO frequency among species of this taxonomic group is mostly associated with their diploid chromosome number. PMID- 28723681 TI - Inhibition of Necroptosis Attenuates Kidney Inflammation and Interstitial Fibrosis Induced By Unilateral Ureteral Obstruction. AB - BACKGROUND: Inflammation plays a crucial role in renal interstitial fibrosis, the pathway of chronic kidney diseases. Necroptosis is a novel form of regulated cell death, which plays a potential role in inflammation and renal diseases. The small molecule necrostatin-1 (Nec-1) is a specific inhibitor of necroptosis. This study was aimed at determining the role of necroptosis, RIP1/RIP3/mixed lineage kinase domain-like (MLKL) signaling pathway, in renal inflammation and interstitial fibrosis related to primitive tubulointerstitial injury. It was also aimed at evaluating the effect of Nec-1 in renal fibrosis induced by unilateral ureteral obstruction (UUO). METHODS: Renal histology, immunohistochemistry, western blot, and real-time polymerase chain reaction were performed using UUO C57BL/6J mice model. Moreover, we tested whether Nec-1 was renal-protective in the interstitial fibrosis kidney. Mice were exposed to UUO and injected intraperitoneal with Nec-1 or vehicle. RESULTS: The levels of RIP1/RIP3/MLKL protein and mRNA were increased in the obstructed kidneys 7 days after UUO; this was accompanied by changes in renal pathological lesions. Renal histological examination showed lesser renal damage in Nec-1-treated UUO mice. Renal inflammation, assessed by tumor necrosis factor-alpha, interleukin-1beta, and monocyte chemotactic protein-1 was markedly attenuated by Nec-1. Furthermore, Nec-1 treatment also significantly reduced TGF beta and alpha-smooth muscle actin, indicating lesser renal interstitial fibrosis. CONCLUSION: These findings suggest that the participation of necroptosis in UUO is partly demonstrated. And necroptosis inhibition may have a potential role in the treatment of diseases with increased inflammatory response and interstitial fibrosis in renal. PMID- 28723682 TI - Release of Danger-Associated Molecular Patterns following Chemotherapy Does Not Induce Immunoparalysis in Leukemia Patients. AB - Chemotherapy may result in the release of danger-associated molecular patterns (DAMPs), which can cause immunoparalysis (deactivation of the immune system). We investigated DAMPs following chemotherapy and their relationship with markers of immunoparalysis in leukemia patients. In 6 patients with acute myeloid leukemia or myelodysplastic syndrome and 12 healthy subjects, DAMPs, cytokines, and markers of immunoparalysis were determined before and during the first week after chemotherapy initiation. In the patients, plasma levels of nuclear DNA (a marker of general DAMP release) were profoundly increased before chemotherapy and further increased 4-6 h afterwards, while the specific DAMP mitochondrial DNA showed only a trend towards increase. Circulating cytokine levels did not change following chemotherapy. Leukocyte cytokine production capacity and HLA-DR expression were similar in patients and healthy controls until day 4 when leukocytes were found to be virtually absent. In conclusion, in the early phase following chemotherapy in leukemia patients, increased DAMP release does not induce immunoparalysis. PMID- 28723683 TI - Very-Low-Dose Lenalidomide for Elderly and/or Frail Multiple Myeloma Patients: Lower Might Be Better. PMID- 28723684 TI - Validation of an Instrument to Measure Patients' Intentions and Ability to Change Attitudes and Behavior. AB - BACKGROUND: The efficacy of specific interventions also of mind-body medicine is also dependent on the patients' ability to engage in these interventions and to perceive and change health-affecting attitudes and behaviors. The aim was to validate a 13-item instrument to measure (1) the patients' perception of specific attitudes and behaviors that are assumed to have a negative influence on the health situation, (2) their intention to change them, and (3) the implementation of the intended changes in their life affairs. PATIENTS AND METHODS: Anonymous cross-sectional survey among 512 patients with chronic pain conditions (mean age 42.6 +/- 11.4 years; 58% women) using standardized instruments. RESULTS: After the elimination of 4 items, an explorative factor analysis of the 9 remaining items indicated 2 factors that would explain 57% of the variance: Perceptions/Intentions (5 items; Cronbach's alpha = 0.75) and Ability/ Implementation (4 items; alpha = 0.77). Factor 2 correlated moderately to strongly with internal adaptive coping strategies (AKU) and situational awareness (CPSC), and weakly with mental health (SF-36), life satisfaction (BMLSS), and low depressive symptoms (BDI) and escape from illness (Escape). Factor 1 correlated weakly with age and adaptive coping strategies (AKU). CONCLUSIONS: The final 9 item Perception, Intention and Ability to Change (PIAC) scale was approved as a short, practicable and promising instrument, which should be further evaluated in the context of training and intervention programs, particularly with respect to its predictive relevance. PMID- 28723685 TI - Downregulation of Macrophage-Derived T-UCR uc.306 Associates with Poor Prognosis in Hepatocellular Carcinoma. AB - BACKGROUND/AIMS: Increasing evidence suggests that T-UCRs are involved in the development of cancer. In this study, we evaluated the role of a macrophage derived T-UCR, uc.306, in the prognosis of hepatitis B (HBV)-related hepatocellular carcinoma (HCC). METHODS: The uc.306 was obtained by screening microassay data obtained during the polarization of U937 cells from the M2 to M1 phenotype. Uc.306 and macrophage molecule markers were detected by qPCR. Immunohistochemical (IHC) assays were used to examine the M1/M2 status of 90 paired HCC tissues. Kaplan-Meier tests and multivariable Cox regression models were used to analyze predictive confidences, survival, and risk factors. RESULTS: In total, 2,977 differentially expressed T-UCRs were obtained, of which 257 showed fold changes >1.5. The uc.306 was upregulated in M1 cells and was predicted to be involved in the Wnt pathway. The IHC results showed that M1 macrophages (CD68+) were present in the para-tumor tissues, while the M2 phenotype (CD163+) was mainly in the HCC tissues. Uc.306 had a lower expression in the HCC tissues than in that of the para-tumor tissues in 30 paired HCC training sets (P < 0.0001), and 252 paired HCC testing sets (P < 0.0001). Low expression of uc.306 was significantly associated with a shorter overall survival (P < 0.05). CONCLUSIONS: The uc.306 may be a promising biomarkerfor HBV-related HCC, providing a novel marker for the prognosis of HCC. PMID- 28723686 TI - Population-Based Study on the Epidemiology of Meniere's Disease. AB - BACKGROUND AND OBJECTIVE: Meniere's disease (MD) is a disorder of the inner ear typically showing recurrent acute episodes of vertigo, hearing loss, and tinnitus. Epidemiologic studies on MD are scarce. We assessed the incidence rates (IRs) of MD and describe the characteristics of MD cases, comparing them to control patients without recorded evidence of MD. STUDY DESIGN: We conducted a retrospective population-based follow-up study and a nested case-control analysis using data from the UK-based Clinical Practice Research Datalink. METHODS: We identified patients between 18 and 79 years of age with an incident MD diagnosis between January 1993 and December 2014. We assessed the IRs of betahistine treated MD. In the nested case-control analysis, we matched 4 controls to each MD case on sex, age, general practice, years of active history in the database, and calendar time. We conducted a chi2 test to present p values in order to compare the prevalence of demographics, comorbidities, and co-medication between cases and controls. RESULTS: We identified 5,508 MD cases and 22,032 MD-free controls (65.4% females). The overall IR for MD in the UK was 13.1 per 100,000 person years. More cases were female, and the mean age at diagnosis was 55.4 +/- 13.7 years. Smoking and alcohol consumption were less prevalent among MD cases. Depression, other affective disorders, sleeping disorders, anxiety, and migraine were more prevalent among MD cases than among controls. CONCLUSIONS: MD is uncommon in primary care in the UK with a preponderance among females. PMID- 28723687 TI - Small Intestine Submucosa Is a Potential Material for Intrauterine Adhesions Treatment in a Rat Model. AB - OBJECTIVE: To study whether small intestine submucosa (SIS) could be a treatment option for preventing the formation of intrauterine adhesions (IUAs). METHODS: The IUAs model was established by mechanical curettage and infectious injury in a rat model. One uterine horn of the rat model was treated with the transplantation of SIS (SIS group) and the other one was left without any treatment (control group). The endometrium was evaluated with endometrial thickness, number of glands and fibrosis area. The endometrial receptive factors were detected by quantitative real-time polymerase chain reaction The number and location of embryos were documented to assess the function of endometrium. RESULTS: In the SIS group, endometrial thickness was significantly thicker than that in the control group on the 14th and 21st day and the percentage of fibrosis area was significantly lower during the entire observation process (p < 0.05). The number of glands was similar between the 2 groups (p > 0.05). Receptive factors changed as follows: in the SIS group, the expression of uteroglobin was higher and peaked on the 21st day (3.42-fold, p < 0.05); the HOXA10 level was significantly higher on the 10th day (2.16-fold, p < 0.05), and it then decreased. More embryos were seen in SIS horns (5.13 vs. 1.25, p < 0.05). CONCLUSIONS: SIS could be a potential physical barrier for the formation of IUAs. It contributes to the regeneration of and improvement of the receptivity of endometrium, and helps in the implantation and development of embryos in a rat model. PMID- 28723688 TI - Trigonelline Inhibits Inflammation and Protects beta Cells to Prevent Fetal Growth Restriction during Pregnancy in a Mouse Model of Diabetes. AB - BACKGROUND: As an active component from traditional Chinese medicine, trigonelline has a protective effect on diabetes. This study evaluated the protective effects of trigonelline on diabetic mice during pregnancy. METHODS: Diabetes was induced in female mice by intraperitoneal injection for continuous 5 day of 40 mg/kg/day streptozotocin. Female mice were divided into 4 groups after they were allowed to mate with normal male mice: nondiabetic, nondiabetic treated with trigonelline (70 mg/kg) for 18 days, diabetic, and diabetic treated with trigonelline (70 mg/kg). RESULTS: Diabetic pregnant mice had significantly higher levels of blood glucose, serum total cholesterol, triglyceride, insulin, and leptin but lower serum omentin-1 level and insulin sensitivity index than the nondiabetic ones. Trigonelline improved the hyperglycemia, dyslipidemia, insulin resistance, and adipocytokine of diabetic pregnant mice. Diabetic pregnant mice had significantly reduced fetus numbers, fetal weight, and fetal/placental ratio, which were reversed by trigonelline. Trigonelline prevented the increase in proinflammatory cytokines and reduced interleukin-10 level in placenta of diabetic pregnant mice. Trigonelline increased beta-cell replication and the decreased beta-cell mass, and decreased the beta-cell apoptosis of diabetic pregnant mice. CONCLUSION: These findings suggest that trigonelline protects diabetic pregnancy partly by suppressing inflammation, regulating the secretion of adipocytokines, increasing beta-cell mass, replication, and decreasing beta cell apoptosis. PMID- 28723689 TI - A Randomized Controlled Trial of Green Tea Beverages on the in vivo Radical Scavenging Activity in Human Skin. AB - BACKGROUND: Oxidative stress plays an important role in the pathogenesis of various skin diseases. Thus, the antioxidant network of the skin relies on the uptake of exogenous antioxidants to ensure cell protection against radical formation. Green tea is one of the main sources of polyphenolic antioxidant compounds, but only few data are available on its cutaneous antioxidant effects. METHODS: The radical scavenging properties of Benifuuki and Yabukita green tea were investigated in the human skin. Thirty-two participants who met the inclusion criteria were randomized to consume 3 cups per day of either Benifuuki tea, Yabukita tea, or water (control group) for 2 weeks. Electron paramagnetic resonance (EPR) spectroscopy was applied to measure the radical scavenging capacity of the skin in vivo before and after the intervention. RESULTS: Both Yabukita and Benifuuki tea led to an increase in the radical scavenging activity of the skin by 28 and 29%, respectively, and the difference was significant when compared to the control group. Benifuuki tea, previously reported to be superior in bioavailability due to a highly absorbable methylated catechin, did not prove to be more effective than the common Yabukita tea. CONCLUSION: The results show that green tea enhances the radical scavenging capacity of the skin and support the hypothesis that green tea may offer protection against cutaneous oxidative stress. PMID- 28723690 TI - Distribution of Human Papillomavirus Genotypes among Women in Mashhad, Iran. AB - OBJECTIVE: Cervical cancer is the third most common malignancy in females. Since the human papillomavirus (HPV) genotype can vary geographically, it is essential to define its genotypic distribution before establishing health care policies and vaccination programs in any given area. The aim of this study was to determine the frequency of HPV types in women in Mashhad, Iran. METHODS: We used nested PCR and reverse dot-blot hybridization for genotyping. The study included 143 cervical cytology samples from Mashhad with confirmed papillomavirus infection by molecular methods. RESULTS: We found that 74.1% of HPV types were in high-risk groups, including genotypes 16, 18, 39, 52, 58, 66, 68, and 73. Coinfection was detected in 56.4% of the cases. The low-risk group, comprising 25.9%, included genotypes 6, 11, 42, and 44/55. CONCLUSIONS: Prevention, early diagnosis, and early treatment have been proven to reduce the mortality rate of cervical cancer. Therefore, an accurate diagnosis of the genotype of the virus in infected patients is very important. PMID- 28723691 TI - High Cost of Hospitalization for Colonic Diverticular Bleeding Depended on Repeated Bleeding and Blood Transfusion: Analysis with Diagnosis Procedure Combination Data in Japan. AB - BACKGROUND: Bleeding from a colonic diverticulum is serious in aged patients. The aim of this study was to determine the risk factors for high-cost hospitalization of colonic diverticular bleeding using the diagnosis procedure combination (DPC) data. METHODS: From January 2009 to December 2015, 78 patients with colonic diverticular bleeding were identified by DPC data in Saga Medical School Hospital. All patients underwent colonic endoscopy within 3 days. The patients were divided into 2 groups: the low-cost group (DPC cost of <500,000 yen) and the high-cost group (DPC cost of >500,000 yen). RESULTS: Univariate analysis revealed that aging, hypertension, rebleeding, a low hemoglobin concentration at admission, and blood transfusion were risk factors for high hospitalization cost. Multivariate analysis revealed that rebleeding (OR 5.3; 95% CI 1.3-21.3; p = 0.017) and blood transfusion (OR 3.8; 95% CI 1.01-14.2; p = 0.048) were definite risk factors for high hospitalization cost. CONCLUSION: Rebleeding and blood transfusion were related to high hospitalization cost for colonic diverticular bleeding. PMID- 28723692 TI - Angiotensin II Regulates Dendritic Cells through Activation of NF-kappaB /p65, ERK1/2 and STAT1 Pathways. AB - BACKGROUND: Activation of dendritic cells (DCs) is necessary to initiate immune responses. Angiotensin II (Ang II) has been reported to have a proinflammatory and immunomodulatory function. However, the role of Ang II in regulation of DCs and the underlying mechanisms remain illdefined. METHODS: The effects of Ang II on the proliferation, maturation, phagocytosis, migration, and communication with T cells of DCs were analysed utilizing MTT, flow cytometry, ELISA, transwell assay and mixed lymphocyte culture. RESULTS: We found that Ang II treatment significantly inhibited proliferation and phagocytic activity of DCs, but promoted the DC maturation and migration well as the expression of pro inflammatory cytokines by DCs. In addition, Ang II also stimulated DC-mediated T cell proliferation. These effects were associated with activation of p65/NF kappaB, ERK1/2 and STAT1 signaling pathways in DCs. CONCLUSIONS: Our results demonstrate that Ang II activates DCs partially through p65/NF-kappaB, ERK1/2 and STAT1 pathways, and suggest a potential therapeutic target of DC-mediated inflammatory disorders. PMID- 28723693 TI - Upregulation of microRNA-876 Induces Endothelial Cell Apoptosis by Suppressing Bcl-Xl in Development of Atherosclerosis. AB - BACKGROUND/AIMS: The injury and apoptotic cell death of endothelial cells hallmark the development of atherosclerosis (AS), characterized by dysregulation of lipid homeostasis, immune responses, and formation of coronary plaques. However, the mechanisms underlying the initiation of endothelial cell apoptosis remain ill-defined. Recent evidence suggests a role of microRNAs in the processes of AS-associated endothelial cell apoptosis. Thus, we studied this question in the current study. METHODS: AS was developed in ApoE (-/-) mice suppled with high fat diet (HFD), compared to ApoE (-/-) mice suppled with normal diet (ND). Mouse endothelial cells were isolated from the aortic arch using flow cytometry based on their expression of Pecam-1. Oxidized low-density lipoprotein (ox-LDL) were used to treat human aortic endothelial cells (HAECs) as an in vitro model for AS. Gene expression was quantified by RT-qPCR and protein levels were analyzed by Western blotting. Apoptosis was evaluated by FITC Annexin V Apoptosis essay and by TUNEL staining. Prediction of the binding between miRNAs and 3'-UTR of mRNA from the target gene was performed by bioinformatics analyses and confirmed by a dual luciferase reporter assay. RESULTS: HFD mice, but not ND mice, developed AS in 12 weeks. Significantly reduced endothelial cell marks and significantly increased mesenchymal cell marks were detected in the aortic arch of the HFD mice, compared to the ND mice. The endothelial cell apoptosis was significantly higher in HFD mice, seemingly due to functional suppression of protein translation of anti-apoptotic Bcl-Xl protein through upregulation of miR-876. Similar results were obtained from in vitro study. Inhibition of miR-876 abolished the effects of ox-LDL-induced apoptotic cell death of HAECs. CONCLUSION: AS-associated endothelial cell apoptosis may partially result from downregulation of Bcl-Xl, through upregulation of miR-876 that binds and suppresses translation of Bcl-Xl mRNA. PMID- 28723694 TI - Exosomes: A Cancer Theranostics Road Map. AB - Interindividual variability is yet to be fully characterized, and for this, optimum patient stratification and companion diagnostics are still lacking. Especially when complex disease phenotypes and/or polygenic diseases are considered, patient monitoring and disease management become rather challenging, while acquired resistance to therapy and/or toxicity events are among the unmet needs in the clinic. No doubt, biomarkers are of great importance to disease management and tailor-made theranostics. Microfluidics has gathered great attention lately, mostly due to its low-invasive nature compared to tissue biopsies. Low invasiveness becomes greatly advantageous for microfluidics practices as the latter mirror cell biology revolutionizing cancer diagnostics and management. Recent advances in microfluidics hold the promise of robust clinical diagnostics after they have demonstrated effective exosome separation. We feel that microfluidics-based exosome isolation techniques, if cost-effective, could be implemented in the clinic and/or resource-scarce settings. This article (a) discusses exosomes, (b) comments on the first microfluidic advances in the field of cancer theranostics, (c) presents such advances in exosomes as complementary to liquid biopsies with an emphasis on circulating tumor cells, and (d) proposes a road map for future developments. PMID- 28723695 TI - Renoprotective Procedures with a Cold Ischemia Time of <60 min Minimize the Deterioration of Kidney Function in Open Nephron-Sparing Surgery for Renal Cell Carcinoma. AB - INTRODUCTION: We evaluated whether nephron sparing surgery (NSS) combined with meticulous suturing of the cut stump under clamping with cooling is beneficial for oncological outcomes and also assessed the relationship between cold ischemia time and deterioration of renal function. METHODS: One hundred and six patients with renal cell carcinoma (RCC) were subjected to this procedure. Oncological outcomes and renal function according to the estimated glomerular filtration rate (eGFR) and the tubular excretion rate on renoscintigraphy before and at 12 months after surgery were evaluated. RESULTS: Cancer recurrences were observed in 2 patients with past history of RCC; however, no patient died of cancer. Renal function was evaluated depending on 4 different ischemia times. All groups did not show a remarkable decrease of renal function in terms of eGFR. Renoscintigraphy revealed the deterioration of the affected kidney in patients with >60 min ischemia. CONCLUSION: The renoprotective procedure of NSS provided maximum preservation of renal function until 60 min of cold ischemia time. PMID- 28723697 TI - The History and Future of Ablative Neurosurgery for Major Depressive Disorder. AB - BACKGROUND: There is an urgent need to develop safe and effective treatments for patients with treatment-resistant depression (TRD). Several neurosurgical procedures have been developed to treat the dysfunctional brain circuits implicated in major depression. OBJECTIVES: This review describes the most common ablative procedures used to treat major depressive disorder: anterior cingulotomy, subcaudate tractotomy, limbic leucotomy, and anterior capsulotomy. The efficacy and safety of each are discussed and compared with other current and emerging modalities, including deep brain stimulation (DBS) and MR-guided focused ultrasound (MRgFUS). METHODS: The PubMed and MEDLINE electronic databases were used in this study, through July 2016. Keywords, including "treatment resistant depression," and "ablative neurosurgery," etc. were used to generate reference hits. RESULTS: Approximately a third to half of patients who underwent ablative procedures achieved a treatment response and/or remission. The efficacy and safety profiles corresponding to both ablative procedures and DBS were very similar. CONCLUSIONS: The longitudinal experience with ablative procedures shows that there remains an important role for accurate, discrete lesions in disrupting affective circuitry in the treatment of TRD. New modalities, such as MRgFUS, have the potential to further improve the accuracy of ablative procedures, while enhancing safety by obviating the need for open brain surgery. PMID- 28723696 TI - Advanced Glycation End-Products Downregulate HoxA9EC through Activation of Nuclear Factor Kappa B by Reciprocal Interaction. AB - Advanced glycation end-products (AGEs) have been recognized as an important pathophysiological mechanism in endothelial dysfunction during diabetic atherogenesis. Homeobox (Hox) genes have been identified as playing a regulatory role in the adult cardiovascular system. Regulation of HoxA9EC is involved in diabetic endothelial dysfunction, but the mechanism of HoxA9EC regulation has remained undefined. Here, we sought to investigate how HoxA9EC is regulated in AGE-induced endothelial dysfunction and to explore the mechanism involved. We used human umbilical venous endothelial cells (HUVECs) cocultured with AGEs, and examined endothelial nitric oxide synthase (eNOS) activation, nitric oxide (NO) release, cell migration, and the expression of HoxA9EC and nuclear factor kappa B (NF-kappaB). AGEs suppressed eNOS activation, NO release, and the migration of HUVECs. Knockout of HoxA9EC also reduced eNOS activation, NO release, and the migration of HUVECs, and the enhancement of HoxA9EC improved the function of HUVECs. Furthermore, AGEs downregulated HoxA9EC expression and activated NF kappaB, and the depression of HoxA9EC was significantly attenuated by the NF kappaB inhibitor. On the other hand, knockout of HoxA9EC activated NF-kappaB and the enhancement of HoxA9EC suppressed NF-kappaB activation. In conclusion, AGEs could induce endothelial dysfunction through NF-kappaB-dependent HoxA9EC downregulation by reciprocal interaction, and the enhancement of HoxA9EC expression could attenuate the impairment. PMID- 28723698 TI - Application, technical issues, and interpretation of C1q for graft outcome. AB - PURPOSE OF REVIEW: Significant interest and controversy surround the use of C1q for determining risk of antibody-mediated rejection (AMR) and graft loss. Alternate models for predicting outcomes have been proposed. This review focuses on the correlation of currently utilized assays for outcome, together with the technical and theoretical limitations, to distill current thinking. RECENT FINDINGS: Results demonstrate that C1q status is significantly correlated with AMR and graft loss. There is general consensus that C1q is more clinically relevant for graft outcome than neat IgG MFI. IgG titers, subclass, and other complement assays have now been studied to determine if they are more relevant. Only IgG3 and possibly C3d fixation have shown added value to C1q for outcome correlation. Direct parallel titer comparisons of C1q and IgG are lacking and the correlation is unknown. SUMMARY: Overall, results confirm the correlation with C1q+ donor-specific antibody (DSA) for AMR and graft loss. The association is stronger posttransplant. C1q+ de novo antibody appears to be especially detrimental portending graft loss in about 1-2.5 years post detection. Recommendations to biopsy and treat at time of de novo C1q+ antibody detection have been suggested by several groups. PMID- 28723699 TI - Intraoperative bleeding in patients with osteogenesis imperfecta type III treated by Fassier-Duval femoral rodding: analysis of risk factors. AB - The surgical treatment of osteogenesis imperfecta (OI) is negatively influenced by clinical features such as osteoporosis, limb deformities and bone changes caused by bisphosphonate therapy. Blood loss during femoral nailing surgeries in patients with OI is a serious problem. Platelet anomalies have been associated with an elevation of the serum pyrophosphate originating from the platelets during clotting, even if the causality with the platelet dysfunction has not yet been established. To identify predictive risk factors regarding intraoperative bleeding, a retrospective analysis was conducted on 23 patients aged between 6 and 13 years, affected by OI type III, who were treated to correct femoral deformities or to perform an osteosynthesis for femoral shaft fractures, using the Fassier-Duval telescopic nail. Osteotomies were performed in 14 cases of deformities and in two out of seven cases of fractures. A survey about the bleeding had been obtained by calculating the sum of the blood aspirated and that lost with the gauzes or present on the surgical drapes. To obtain an estimate of the intraoperative blood losses, one must resort to a calculation based on an algorithm that evaluates the ratio between the effective blood loss divided by the total blood volume expected as per age and weight (gamma distribution). The average blood loss was 237.4 ml (0.12 gamma). In seven cases, it was necessary to perform postoperative transfusions, owing to an average blood loss of 502.8 ml (0.27 gamma). Patients aged less than 10 years had a minor blood loss. A greater number of osteotomies was associated with a significant increase of average bleeding (P=0.046). Patients who were never treated with bisphosphonates showed a significantly greater bleeding rate (P=0.048). Patients affected by OI type III have a high risk of severe blood loss during surgery, even caused by the platelet disfunction, which characterizes this OI type. In addition to this predisposing factor, there are other risk factors to consider in preoperative surgical planning. In patients who were never treated with bisphosphonates, the bleeding was higher than in the ones treated with bisphosphonates since at least 1 year. The effects of bisphosphonates on bone tissue (such as the medullar canal narrowing and the bone cortex thickening) could reduce the spongious bone amount and the bleeding. Inhibiting the farnesyl pyrophosphate synthase enzyme and reducing the prenylation of many plasma proteins, including the methylene tetrahydrofolate reductase, the bisphosphonates could lead to an alteration of the coagulation cascade. The correlation found with the intake of bisphosphonates, capable of inhibiting the action of the farnesyl pyrophosphate synthase enzyme, thus influencing coagulation, requires further prospective studies with research of the methylene tetrahydrofolate reductase mutation in patients with OI type III undergoing surgical procedures. The number of osteotomies, the patient's age and the intake of bisphosphonates for at least 1 year seem to be the best predictive factors for blood loss. PMID- 28723700 TI - Pediatric supracondylar humerus fractures: is surgeon experience a surrogate for the need of open reduction? AB - Although there are many factors that are likely to influence the need for open reduction and percutaneous pinning (ORPF) in the treatment of pediatric supracondylar humerus fractures (SCHFs), the role of surgeon's experience (as represented by the total number of surgically treated SCHFs) on the need for ORPF has seldom been investigated. We reviewed the data on all completely displaced, pediatric SCHFs that were treated surgically by a single, fellowship-trained, pediatric orthopedic surgeon over the first 10 years of the surgeon's clinical practice. The incidence of ORPF was calculated as the percentage of open reductions among surgically treated, completely displaced, consecutive SCHFs at any given time during the 10-year period. From September 2005 to August 2015, a total of 212 completely displaced SCHFs were treated surgically at our institution by a single surgeon. When analyzing the incidence of ORPFs among surgically treated, completely displaced SCHFs at any given time, a bimodal curve was found: there was an increasing slope over the first 30 surgically treated SCHFs, with a progressive decreasing slope afterward. The incidence of ORPF within the first 10, 20, and 30 surgically treated, completely displaced SCHFs was 10.0, 30.0, and 26.7%, respectively, decreasing to 16.0, 9.0, 6.7, and 5.0% within the first 50, 100, 150, and 200 surgeries, respectively. The incidence of ORPF was almost 17-fold higher within the first 30 surgically treated, completely displaced SCHFs (17%), when compared with the following 182 (1.1%) cases (P<0.00001). Although it is likely that many factors influence the need for ORPF in the treatment of completely displaced SCHFs, surgeon's experience appears to play a significant role. Strategies aimed to accelerate the learning curve in the treatment of pediatric SCHFs should be undertaken. PMID- 28723701 TI - Scalp Block: Tool for Diagnosis in Postoperative Headache of Unknown Origin. PMID- 28723702 TI - Reducing falls in the inpatient hospital setting. AB - AIM: This quality improvement project's objective was to introduce and assess a process change to potentially reduce fall rates on an inpatient medical-surgical unit. METHODS: The Iowa Model of Evidence-Based Practice was used to guide the implementation of this project. This project was piloted over a 3-month period from October to December 2016 on a 38-bed medical-surgical unit at a community based hospital in the southeastern United States. Prior to the implementation of this quality improvement project, staff received falls education using a modified pre-existing falls prevention protocol, with a focus on increasing the consistency of bed/chair alarm use for patients identified as being at risk for falling. Preintervention and postintervention fall rates were statistically compared to assess for change in practice. RESULTS: The average monthly preintervention fall rate was 8.67 falls/1000 patient days, as compared with 5.07 falls postintervention, which resulted in an overall decrease of 44.5% in the average number of falls per month. CONCLUSION: This project illustrated that education and a consistent risk stratification for bed/chair alarm use may be an important component of an effective evidence-based falls prevention program. PMID- 28723703 TI - Management of chest pain in the French emergency healthcare system: the prospective observational EPIDOULTHO study. AB - OBJECTIVE: The aim of this paper was to describe the epidemiology, and diagnostic and therapeutic strategies that emergency physicians use to manage patients presenting with chest pain at all three levels of the French emergency medical system - that is, dispatch centres (SAMUs: the medical emergency system), which operate the mobile intensive care units (MICUs), and hospitals' emergency departments (EDs), with a focus on acute coronary syndrome (ACS). PATIENTS AND METHODS: All patients with chest pain who contacted a SAMU and/or were managed by a MICU and/or were admitted into an ED were included in a 1-day multicentre prospective study carried out in January 2013. Data on diagnostic and therapeutic management and disposition were collected. An in-hospital follow-up was performed. RESULTS: In total, 1339 patients were included: 537 from SAMU, 187 attended by a MICU and 615 in EDs. Diagnosing ACS was the main diagnostic strategy of the French emergency care system, diagnosed in 16% of SAMU patients, 25% of MICU patients and 10% of ED patients. Among patients calling the SAMU, 76 (14%) received only medical advice, 15 (8%) patients remained at home after being seen by a MICU and 454 (74%) were discharged from an ED. CONCLUSION: Management of chest pain at the three levels of the French medical emergency system is mainly oriented towards ruling out ACS. The strategy of diagnostic management is based on minimizing missed diagnoses of ACS. PMID- 28723704 TI - Trends and territorial inequalities of incidence and survival of childhood leukaemia and their relations to socioeconomic status in Hungary, 1971-2015. AB - The Hungarian Childhood Cancer Registry, a population-based national registry of the Hungarian Paediatric Haemato-Oncology Network founded in 1971, monitors the incidence and mortality of childhood cancer. Our aims were to carry out a longitudinal study to investigate the trends and spatial inequalities of incidence and survival of leukaemia, and the association between survival and deprivation in Hungary. All cases of childhood leukaemia and myelodysplasia were analysed (3157 cases, 1971-2015, age: 0-14 years). Time trends and the annual percentage change in direct standardized incidence and mortality were assessed. Survival and association with deprivation were assessed using the Kaplan-Meier method and Cox regression. Incidence rates of leukaemia (23.5-56.0/million) increased with an average annual percent change (AAPC) of 1%, determined by an increase in the incidence of acute lymphoblastic leukaemia (14.6-39.2/million, AAPC: 1.25%). Kaplan-Meier analysis showed a significant improvement in overall survival over the study period. Starting from 25% of cases surviving 5 years in the 70s; the overall 5-year survival reached 80% by 2010. Survival differences were observed with sex, leukaemia type and age at diagnosis. A reverse association was found in the survival probability of leukaemia by degree of deprivation. The Cox proportional hazards model verified a significant reverse association with deprivation [hazard ratio=1.08 (1.04-1.12)]. This is the first nationwide study to confirm the prognostic role of deprivation on the basis of a large cohort of patients with childhood leukaemia during a 45-year period. To maintain further improvement in treatment results, it is important to detect inequalities. Our results showed that deprivation may also be important in the survival of leukaemia. PMID- 28723705 TI - Dietary guidelines in type 2 diabetes: the Nordic diet or the ketogenic diet? AB - PURPOSE OF REVIEW: To highlight recent developments in research regarding nutrition therapies for type 2 diabetes mellitus (T2DM) with a focus on the different approaches of the Nordic diet and the ketogenic diet. RECENT FINDINGS: Recent short-term studies have revealed that similar beneficial outcomes are seen after different dietary treatments for T2DM, with different approaches resulting in comparable weight loss and impacts on metabolic factors. SUMMARY: More individualized approaches in nutrition therapy should be considered for T2DM patients and clinical guidelines should reflect this. More studies, especially long-term studies, are urgently needed on the impacts of the diets on different health parameters. Such studies should be prioritized because of the high and increasing prevalence of T2DM and because dietary changes may have greater benefits than previously thought. Furthermore, studies that focus on patient compliance to different types of diets, and personal and environmental factors that may affect compliance, are needed. PMID- 28723706 TI - Oral shedding of herpesviruses in HIV-infected patients with varying degrees of immune status. AB - OBJECTIVE: Herpesvirus shedding in the oral cavity was analyzed to determine if presence in the oral compartment correlates with systemic changes in HIV associated immune deficiency as measured by CD4 cell counts, plasma HIV viral load and presence of AIDS-defining events. DESIGN: A5254 is a multicenter, cross sectional, single-visit study to evaluate oral complications of HIV/AIDS and determine the association between clinical appearance, herpesvirus shedding, and immune status as ascertained by CD4 cell count and HIV viral load. In total, 307 HIV-infected individuals were evaluated and throat wash collected. METHODS: Fisher's exact test and Kruskal-Wallis test were used to assess the association between presence of herpesviruses and the state of immunodeficiency as stratified by a combination of CD4 cell count and HIV viral load. Relationship between pathogens and HIV viral load in plasma was modeled by logistic regression. RESULTS: The presence of cytomegalovirus (CMV) and herpes simplex virus-1 in throat wash was associated with decreased CD4 cell counts. By contrast, Kaposi sarcoma-associated herpesvirus and Epstein-Barr virus were similarly detectable across all levels of CD4 cell counts. One unit increase in log10 (HIV viral load) was associated with 1.31 times higher odds of detecting CMV in throat wash when controlling for oral candidiasis, CD4 cell count, and sites (95% confidence interval 1.04-1.65, P = 0.02). CONCLUSION: Oral CMV shedding was significantly higher in highly immunocompromised HIV participants. Our finding supports the recommendations to start antiretroviral therapy independent of CD4 cell count as this may have the added benefit to lower the risk of herpesvirus transmission among persons infected with HIV and their partners. PMID- 28723708 TI - Subclinical herpesvirus shedding among HIV-1-infected men on antiretroviral therapy. AB - OBJECTIVE: We evaluated the subclinical shedding of six different herpesviruses in antiretroviral drug-treated HIV-positive [HIV(+)] MSM, and determined how this is associated with markers of inflammation and immune activation. METHODS: We obtained blood, semen, throat washing, urine, and stool from 15 antiretroviral treated HIV-1-infected MSM with CD4 T-cell reconstitution, and 12 age-matched HIV negative [HIV (-)] MSM from the Multicenter AIDS Cohort Study at four timepoints over 24 weeks to measure DNA levels of cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpes simplex virus 1 and 2, human herpesvirus 6 (HHV6), and HHV8. T-cell activation and plasma levels of soluble markers of inflammation and activation were also measured at the corresponding timepoints. RESULTS: HIV(+) participants had a trend for higher total herpesvirus shedding rate. HIV(+) participants also had a significantly higher rate of shedding EBV and CMV compared with the HIV(-) group. Herpesvirus shedding was mostly seen in throat washings. In the HIV(+) group, herpesvirus shedding rate inversely correlated with plasma levels of interferon gamma-induced protein 10 and soluble CD163. CMV DNA levels negatively correlated with levels of T-cell activation. There was a trend for a positive correlation between EBV shedding rate and plasma soluble CD14. HHV6 shedding rate negatively correlated with plasma levels of interleukin-6, soluble CD163, and interferon gamma-induced protein 10. Correlations were not observed among HIV(-) individuals. CONCLUSION: Among treated HIV-infected MSM, there are higher subclinical shedding rates of some herpesviruses that occur in different body compartments and negatively correlate with levels of inflammation and immune activation. PMID- 28723709 TI - Delivering preexposure prophylaxis to pregnant and breastfeeding women in Sub Saharan Africa: the implementation science frontier. PMID- 28723711 TI - Epidemiology of autoimmune and inflammatory diseases in a French nationwide HIV cohort. AB - BACKGROUND: HIV infection and inflammatory and autoimmune diseases (IADs) are both related to immune dysfunction. Epidemiological data on IAD in patients living with HIV (PLHIV) are scarce. The aim of this study was thus to estimate the prevalence of 26 IAD among PLHIV followed in a large French multicenter cohort in the combination antiretroviral therapy (cART) era (from January 2000 to July 2013), and to describe their occurrence according to cART onset, the immuno virological status of patients and hepatitis C virus (HCV) and/or hepatitis B virus coinfection. METHOD AND RESULTS: During the study period, 33 403 PLHIV were included in the Dat'AIDS cohort; 1381 patients with an IAD were identified. The most prevalent IADs were psoriasis, sarcoidosis, rheumatoid arthritis, ankylosing spondyloarthritis, Grave's disease, autoimmune hemolytic anemia, immune thrombocytopenia and chronic inflammatory bowel disease. In contrast, the prevalence of systemic lupus erythematosus and multiple sclerosis were low. Most patients (59%) developed IAD after HIV infection with a mean delay of 10.6 +/- 6.4 years. Compared with the entire cohort, HCV coinfection was significantly more frequent in patients with psoriasis, Grave's disease and immune thrombocytopenia, and chronic hepatitis B in patients was more frequent in those with immune thrombocytopenia and autoimmune hemolytic anemia. Among patients developing IAD after the diagnosis of HIV infection, 572 (70%) were on antiretroviral therapy and 419 of them (73%) had undetectable HIV viral load. CONCLUSION: Our study showed that some IAD are not rare among PLHIV and occur mostly in patients with immuno-virological control under cART. The higher frequency of HCV or hepatitis B virus coinfection for some IAD is also confirmed. PMID- 28723710 TI - Controlled attenuation parameter and magnetic resonance spectroscopy-measured liver steatosis are discordant in obese HIV-infected adults. AB - OBJECTIVE: Hepatic steatosis is common in HIV-infected individuals. Magnetic resonance spectroscopy (MRS) is the preferred noninvasive method for hepatic steatosis measurement but is expensive. Controlled attenuation parameter (CAP) also assesses hepatic steatosis and is conveniently performed concomitantly with transient elastography. We aimed to assess the accuracy of CAP in the setting of HIV infection. DESIGN: Cross-sectional study. METHODS: CAP and MRS were performed in 82 study participants (39 HIV monoinfected; seven hepatitis C virus (HCV) monoinfected; 21 HIV/HCV coinfected; 15 with neither infection). We used concordance correlation coefficients to compare log-transformed and standardized CAP and MRS values and linear regression to examine factors associated with CAP and MRS-measured hepatic steatosis (MRS-HS). The accuracy of CAP to detect at least mild hepatic steatosis, defined as MRS-liver fat fraction more than 0.05, and the factors associated with discordance between CAP and MRS were evaluated. RESULTS: Overall, CAP-measured hepatic steatosis and MRS-HS correlated moderately well (rc = 0.63; P < 0.001), and correlation was strongest in the HIV monoinfected group (rc = 0.67; P < 0.001). Body composition factors (higher BMI, waist circumference, visceral and abdominal subcutaneous adipose tissue) and insulin resistance were significantly associated with both greater CAP-measured hepatic steatosis and MRS-HS. Using a validated CAP cut-off of at least 238 dB/m, sensitivity and specificity for at least mild hepatic steatosis were 84% and 75% in the entire cohort; 89% and 80% in the HIV-monoinfected group. Participants with higher body composition parameters were more likely to be misclassified as having hepatic steatosis by CAP. CONCLUSION: Our findings suggest CAP is an acceptable noninvasive surrogate for hepatic steatosis in HIV-infected individuals but may overestimate hepatic steatosis prevalence, especially in individuals with high BMI. Evaluation of factors that improve CAP accuracy and determination of optimal cut-offs are warranted. PMID- 28723712 TI - The role of oncogenic human papillomavirus determination for diagnosis of high grade anal intraepithelial neoplasia in HIV-infected MSM. AB - OBJECTIVE: To assess the oncogenic human papillomavirus (HPV) determination and the cotesting HPV and anal cytology value to detect high-grade anal intraepithelial neoplasia (HGAIN) in a cohort of HIV-MSM. DESIGN AND METHODS: Prospective study of HIV-infected MSM who underwent screening for anal dysplasia. Screening program includes anal cytology, HPV testing, and high-resolution anoscopy (HRA) at each visit. Histological samples were obtained if suspicious lesions were revealed by HRA. Sensitivity and specificity of the different tests were calculated by using histological results of HRA-guided biopsy as the reference test for HGAIN diagnosis. RESULTS: From May 2009 to August 2016, 692 HIV-infected MSM underwent 1827 anal cytologies, 1841 HRA examinations, and 1607 HPV testing. At first screening visit, anal cytology results were abnormal in 418 (60.4%) of 692 patients, and oncogenic HPV genotypes were found in 482 (79.5%) of 606 patients. Anal cytology showed a sensitivity of 89.2% [95% confidence interval (CI); 80.7-94.2] and a specificity of 44.2% (95% CI; 40.2-48.2) to detect HGAIN. Oncogenic HPV testing had 90.4% sensitivity (95% CI; 82-86.8) and 24.4% specificity (95% CI; 20.8-28.3). Cotesting showed a 97.4% sensitivity (95% CI; 91-99.3) and 14% specificity (95% CI; 11.2-17.3). In patients with atypical squamous cells of uncertain significance on cytology, oncogenic HPV testing had 91.3% sensitivity and 28.3% specificity to detect HGAIN. CONCLUSION: Abnormal cytology and oncogenic HPV determination showed similar sensitivity for detecting HGAIN. The two tests used together improved the sensitivity but with lowered specificity. In our opinion, HPV testing does not improve HGAIN detection and should not replace anal cytology as a standard screening test for HIV-infected MSM. PMID- 28723713 TI - Somatotopic Fascicular Lesions of the Brachial Plexus Demonstrated by High Resolution Magnetic Resonance Neurography. AB - OBJECTIVES: The aim of this study was to evaluate whether high-resolution brachial plexus (BP) magnetic resonance neurography (MRN) is capable of (1) distinguishing patients with compressive neuropathy or noncompressive plexopathy from age- and sex-matched controls, (2) discriminating between patients with compressive neuropathy and noncompressive plexopathy, and (3) detecting spatial lesion patterns suggesting somatotopic organization of the BP. MATERIALS AND METHODS: Thirty-six patients (50.9 +/- 12.7 years) with clinical symptoms, nerve conduction studies, and needle electromyography findings suggestive of brachial plexopathy and 36 control subjects matched for age and sex (50.8 +/- 12.6 years) underwent high-resolution MRN of the BP. Lesion determination and localization was performed by 2 blinded neuroradiologists at the anatomical levels of the plexus trunks and cords. RESULTS: By applying defined criteria of structural plexus lesions on high-resolution MRN, all patients were correctly rated as affected, whereas 34 of 36 controls were correctly rated as unaffected by independent and blinded reading from 2 neuroradiologists with overall good to excellent interrater reliability. In all cases, plexopathies with a compressive etiology (n = 12) were correctly distinguished from noncompressive plexopathies with inflammatory origin (n = 24). Pathoanatomical contiguity of lesion from trunk into cord level allowed recognition of distinct somatotopical patterns of fascicular involvement, which correlated closely with the spatial distribution of clinical symptoms and electrophysiological data. CONCLUSIONS: Brachial plexus MRN is highly accurate for differentiating patients with symptomatic plexopathy from healthy controls and for distinguishing patients with compressive neuropathy and noncompressive plexopathy. Furthermore, BP MRN revealed evidence for somatotopic organization of the BP. Therefore, as an addition to functional information of electrodiagnostic studies, anatomical information gained by BP MRN may help to improve the efficiency and accuracy of patient care. PMID- 28723714 TI - Vent Incisions to Facilitate Peripheral Unfolding of the DMEK Graft. AB - PURPOSE: To present the results of 15 cases in which a modified technique of Descemet membrane endothelial keratoplasty (DMEK) with vent incisions was used to assist unfolding of tight peripheral inward folds. METHODS: This is a retrospective case series of 15 consecutive eyes that underwent a modified vent incision technique for DMEK. Six oblique, small-size (1 mm) vent incisions parallel to the limbus and 3.5 mm from the center were performed after descemetorhexis. The graft was opened with standard no-touch techniques and was partially attached to the stroma with air injection. Then, in cases with remaining tight inward folds despite gentle corneal tapping, jets of balanced salt solution were pulsed through the vent incisions directed at the peripheral folds to achieve complete unfolding. RESULTS: Descemet membrane endothelial keratoplasty was performed in 2 phakic eyes (14%) and 13 pseudophakic eyes (86%). Six cases (40%) required fluid injection through the vent incisions: 3 corresponded to grafts from younger donors (54, 41, and 29 years old), and 3 had a 9.0-mm-sized graft. Complete graft unfolding was successfully achieved in 14 cases (93%), and in 1 case (7%), peripheral folds remained because of spontaneous bleeding in the anterior chamber. A clear cornea was achieved in all cases, and there were no postoperative complications associated with the vent incisions. CONCLUSIONS: This technique provides a different DMEK no-touch approach that could be used in challenging cases of graft unfolding such as young donors and/or large-sized grafts. It may also avoid excessive unfolding times and direct manipulation that are related to higher endothelial cell loss. PMID- 28723715 TI - Novel weight-based dose threshold for 18F-NaF PET-CT imaging using advanced PET CT systems: a potential tool for reducing radiation burden. AB - BACKGROUND: Fluorine-18-sodium fluoride (F-NaF) PET/CT is an important tool for detecting and evaluating metastatic bone cancer. Besides traditional dose metrics, recent methods such as real-time dose mapping, dose calculation from DICOM information, and their relevance to entrance skin exposure are currently in use to reduce the radiation burden. In this study, we have analyzed the data of 1062 patients retrospectively to evaluate patterns of absorbed dose for institutional weight-based dose protocol as compared with fixed dose method guidelines of Society of Nuclear Medicine and Molecular Imaging (SNMMI). PATIENTS AND METHODS: The effective dose imparted by F-NaF (internal exposure) was calculated by using coefficient 0.089 mrem/mCi (0.024 mSv/MBq) according to ICRP publication 106. To estimate the effective dose from whole-body CT scan (external exposure), volume CT dose index (mGy) and dose length product (mGy cm) were directly obtained from the display screen of CT workstation. Effective dose was calculated by multiplying DLP (mGy cm) with ICRP conversion coefficient 'k' 0.015 (mSv/mGy cm). RESULTS: Of the total 1062 patients, there were metastases in 44% (464), probable malignancy in 9% (96), negative findings in 40.5% (433), equivocal findings in 3% (32), and probable benignancy in 3.5% (37). All patients were injected with an institutional agreed protocol of 2.22 MBq/kg (0.06 mCi/kg). The mean injected activity for entire population came out to be 4.79+/-0.99 mCi. The mean effective absorbed doses were 3.37+/-0.70 and 5.5+/-1.35 mSv for F-NaF alone and CT alone, respectively. The mean cumulative effective dose of combined F-NaF PET and CT scan was calculated to be 8.8+/-1.8 mSv. The minimum absorbed dose for our method was as follows: 1.37 mSv for Kuwait Cancer Control Center vs. 4.44 mSv for SNMMI. Absorbed dose for maximum injected activity was as follows: 5.7 mSv for Kuwait Cancer Control Center vs. 8.88 mSv for SNMMI. Our weight-based doses were also lower when compared with minimum and maximum absorbed doses of technetium-99m-methylene diphosphonate as per SNMMI guidelines (i.e. 4.21 and 6.32 mSv, respectively). CONCLUSION: Our weight-based dose protocol showed a significant reduction in absorbed doses (i.e. 69.14% for F-NaF and 67.45% for technetium-99m-methylene diphosphonate) when compared with fixed dose method guidelines of SNMMI. It is suggested that further prospective studies may be performed in adult population, to evaluate dosimetry efficacy of F-NaF at a low dose of 0.06 mCi/kg as inferred in our current study. PMID- 28723716 TI - Refining the management of patients with hepatocellular carcinoma integrating 11C choline PET/CT scan into the multidisciplinary team discussion. AB - OBJECTIVE: The aim of this study was to report the impact of C-choline PET/CT on the management of patients with hepatocellular carcinoma (HCC) and incorporate into a refined algorithm combining diagnostic imaging and multidisciplinary team (MDT) discussion. PATIENTS AND METHODS: From February 2010 to February 2016, the charts of all patients discussed in the liver MDT were revised. Suspected or confirmed HCC lesions or Barcelona Clinic Liver Cancer stages A, B or C with a C choline PET/CT performed in our hospital were included in the analyses. Overall, 73 patients (male : female=59 : 14; median age: 75 years) were enrolled. Forty two (57%) patients were newly diagnosed, whereas 31 (43%) came to our attention at disease recurrence. Seven (10%) patients were Barcelona Clinic Liver Cancer stage 0, 31 (42%) patients were stage A, 15 (20%) patients were stage B, and 18 (25%) patients were stage C. The reference standards for ultimate imaging validation were either histology or MDT consensus. A minimum follow-up of 6 months was established. RESULTS: Overall eight (10%) patients were initially referred for chemotherapy (sorafenib), 43 (59%) for surgery, two (3%) for surgery or transarterial embolization, five (7%) for follow-up only, one (1%) for extrahepatic radiotherapy, seven (10%) for stereotactic body radiation therapy of the liver, six (8%) for transarterial embolization, and one (1%) for liver transplant. After C-choline PET/CT and MDT discussion, in seven patients the diagnosis changed, in six patients the treatment was changed, and in nine patients both the diagnosis and the treatment were changed. Overall, in 30% of our patients, the diagnosis or treatment was altered on the basis of our algorithm of management. CONCLUSION: The incorporation of C-choline PET/CT into the MDT discussion altered the diagnosis/treatment of one-third of HCC patients. We propose a novel diagnostic algorithm to be refined in referral centers for HCC management. PMID- 28723717 TI - Localized muscle vibration reverses quadriceps muscle hypotrophy and improves physical function: a clinical and electrophysiological study. AB - Quadriceps weakness has been associated with knee osteoarthritis (OA). High frequency localized muscle vibration (LMV) has been proposed recently for quadriceps strengthening in patients with knee OA. The purpose of this study was (a) to investigate the clinical effectiveness of high-frequency LMV on quadriceps muscle in patients with knee OA and (b) to disentangle, by means of surface electromyography (sEMG), the underlying mechanism. Thirty patients, aged between 40 and 65 years, and clinically diagnosed with knee OA were included in this randomized, controlled, single-blinded pilot study. Participants were randomly assigned to two groups: a study group treated with LMV, specifically set for muscle strengthening (150 Hz), by means of a commercial device VIBRA, and a control group treated with neuromuscular electrical stimulation. Clinical outcome was measured using the Western Ontario and McMaster Universities Osteoarthritis Index, Visual Analogue Scale, knee range of motion, Timed Up and Go test, and Stair climbing test. To assess changes in muscle activation and fatigue a subgroup of 20 patients was studied with the use of sEMG during a sustained isometric contraction. The LMV group showed a significant change in Western Ontario and McMaster Universities Osteoarthritis Index score, Visual Analogue Scale score, Timed Up and Go test, Stair Climbing Test, and knee flexion. These improvements were not significant in patients treated with neuromuscular electrical stimulation. sEMG analysis suggested an increased involvement of type II muscle fibers in the group treated with LMV. In conclusion, the present study supports the effectiveness of local vibration in muscle function and clinical improvement of patients with knee OA. PMID- 28723718 TI - Three-dimensional head-mounted gaming task procedure maximizes effects of vestibular rehabilitation in unilateral vestibular hypofunction: a randomized controlled pilot trial. AB - Considering the emerging advantages related to virtual reality implementation in clinical rehabilitation, the aim of the present study was to discover possible (i) improvements achievable in unilateral vestibular hypofunction patients using a self-assessed head-mounted device (HMD)-based gaming procedure when combined with a classical vestibular rehabilitation protocol (HMD group) as compared with a group undergoing only vestibular rehabilitation and (ii) HMD procedure-related side effects. Therefore, 24 vestibular rehabilitation and 23-matched HMD unilateral vestibular hypofunction individuals simultaneously underwent a 4-week rehabilitation protocol. Both otoneurological measures (vestibulo-ocular reflex gain and postural arrangement by studying both posturography parameters and spectral values of body oscillation) and performance and self-report measures (Italian Dizziness Handicap Inventory; Activities-specific Balance Confidence scale; Zung Instrument for Anxiety Disorders, Dynamic Gait Index; and Simulator Sickness Questionnaire) were analyzed by means of a between-group/within-subject analysis of variance model. A significant post-treatment between-effect was found, and the HMD group demonstrated an overall improvement in vestibulo-ocular reflex gain on the lesional side, in posturography parameters, in low-frequency spectral domain, as well as in Italian Dizziness Handicap Inventory and Activities-specific Balance Confidence scale scores. Meanwhile, Simulator Sickness Questionnaire scores demonstrated a significant reduction in symptoms related to experimental home-based gaming tasks during the HMD procedure. Our findings revealed the possible advantages of HMD implementation in vestibular rehabilitation, suggesting it as an innovative, self-assessed, low-cost, and compliant tool useful in maximizing vestibular rehabilitation outcomes. PMID- 28723719 TI - Clinical Application of a Transurethral Holmium Laser Excision of Exposed Polypropylene Mesh at Lower Urinary Tract: Single Surgeon Experience With Long term Follow-up. AB - PURPOSE: The aim of this study was to evaluate the clinical application of a transurethral holmium laser excision of exposed polypropylene mesh as an effective minimally invasive surgical approach in patients with lower urinary tract mesh erosion following the transvaginal placement of polypropylene mesh. METHODS: A retrospective analysis was conducted on the data of 22 patients with exposed polypropylene mesh in the lower urinary tract that was managed using the transurethral holmium laser technique. The patients were divided into 2 groups based on the type of mesh surgery: a midurethral sling (MUS) group (n = 18) and a pelvic organ prolapse (POP) group (n = 4). The surgical outcomes were compared. RESULTS: The mean time follow-up after the first surgery was 23.2 months, and 14 patients (64%) reported symptomatic improvement. During outpatient follow-up, eroded residual mesh and failed re-epithelialization were discovered in 6 patients. The recurrence rates in the MUS and POP groups after the first surgery were 22% and 50%, respectively. The recurrence-free periods of each group were 30.5 versus 13.5 months, respectively. Whereas 5 patients had successful epithelialization of the surgical wound following the second endoscopic surgery, 1 patient in the POP group required a third endoscopic surgery because of persistent mesh erosion. CONCLUSIONS: The excision of exposed polypropylene mesh using a transurethral holmium laser following MUS appears to be a feasible option because of potentially low rates of complication and recurrent stress incontinence. However, minimally invasive approach using holmium laser may not be as successful for mesh erosion after transvaginal mesh repair for POP. PMID- 28723720 TI - Trends in Hysteropexy and Apical Support for Uterovaginal Prolapse in the United States from 2002 to 2012. AB - OBJECTIVES: Our objective was to describe trends in hysteropexy and apical support for uterovaginal prolapse (UVP) from 2002 to 2012 in the United States. We identified patient and hospital variables associated with hysteropexy and apical support. METHODS: We used the Nationwide Inpatient Sample and International Classification of Diseases, Ninth Revision codes to identify a population of women 18 years or older with UVP undergoing pelvic organ prolapse surgery from January 1, 2002, to December 31, 2012. Procedures were categorized as (1) hysteropexy, (2) obliterative with uterine preservation, (3) hysterectomy with apical support, (4) hysterectomy without apical support, and (5) other reconstruction without apical support. Categories were dichotomized into those with and without apical support. We used survey weights to obtain nationally representative estimates; chi and linear and logistic regression compared procedure groups. RESULTS: An estimated 815,184 hospital discharges of pelvic organ prolapse procedures for UVP occurred from 2002 to 2012. During this time, hysteropexies increased from 1.81% to 5.00% (P < 0.0001). From 2002 to 2012, hysterectomies with apical support increased (10.07% to 32.51%, P < 0.0001), hysterectomy without apical support decreased (27.14% to 17.12%, P < 0.0001), and reconstruction without apical support decreased (59.07% to 40.48%, P < 0.0001). In most recent years 2011 to 2012, 60% of women with UVP underwent inpatient surgery without an apical procedure. Age 52 years or older, Medicare payment, Northeast region, and urban teaching hospitals were associated with increased odds of apical support for UVP (P < 0.001 for all). CONCLUSIONS: Hysteropexy significantly increased in the United States from 2002 to 2012, although the overall proportion remains low. While hysterectomy without apical support is decreasing, approximately 60% of inpatient procedures performed for UVP do not address the apex. PMID- 28723721 TI - Instrument Adaptation, Modification, and Validation for Cultural Beliefs About Colorectal Cancer Screening Among Korean Americans. AB - BACKGROUND: Studies on colorectal cancer (CRC) screening among Korean Americans (KAs) lack culturally sensitive, reliable, and validated belief scales. OBJECTIVE: The purpose of this study was to adapt, modify, and validate instruments measuring cultural beliefs (physical space, health temporal orientation, personal control, colon cancer fatalism, and health fatalism) about CRC screening in KAs. METHODS: In phase I, instrument adaptation and modification (translation from English into Korean, individual interviews using cognitive interviewing, and expert reviews) were used to make existing cultural beliefs instruments culturally appropriate for KAs. In phase II, instrument validation (pilot test and cross-sectional survey) was used to examine the psychometric properties of the instrument among 202 KAs. RESULTS: Construct validity and reliability of the final Korean version of the instruments were examined using exploratory and confirmatory factor analyses and internal consistency reliability. Exploratory factor analysis using all of the cultural beliefs items resulted in 5 factors accounting for 46.55% of the variance. Factor loadings were greater than 0.40 for most items to be added to the scales reflecting Korean cultural perspectives. Cronbach's alphas for all the cultural beliefs subscales were greater than .70. CONCLUSIONS: Findings from this study show that KAs have unique cultural beliefs that should be reflected in the instruments used for CRC screening research with this population. IMPLICATIONS FOR PRACTICE: The revised instrument could be useful in accurately measuring cultural beliefs among KAs and in developing culturally sensitive interventions to increase CRC screening behaviors among KAs. PMID- 28723722 TI - Complementary and Alternative Medicine Use and Symptom Burden in Women Undergoing Chemotherapy for Breast Cancer in Malaysia. AB - BACKGROUND: Complementary and alternative medicine (CAM) is commonly used for cancer- and chemotherapy-related symptoms. Nurses are likely to encounter many CAM users in their practice. OBJECTIVE: The aims of this study were to assess CAM use and examine the symptom burden of CAM and non-CAM users among patients with breast cancer who are undergoing chemotherapy. METHODS: A CAM use questionnaire and the Side-Effect Burden Scale were administered to 546 patients. Complementary and alternative medicine use was categorized as mind-body practices (MBPs), natural products (NPs), or traditional medicine (TM). RESULTS: We identified 386 CAM users (70.7%) in this study. The CAM users reported a higher marginal mean total symptom burden score (40.39 +/- 2.6) than non-CAM users (36.93 +/- 3.21), although this difference was not statistically significant (P = .09). Triple modality (MBP-NP-TM) CAM users had a significantly higher marginal mean total symptom burden score (47.44 +/- 4.12) than single-modality (MBP) users (34.09 +/- 4.43). The risk of having a high total symptom burden score was 12.9-fold higher among the MBP-NP-TM users than among the MBP users. CONCLUSIONS: Complementary and alternative medicine use is common among Malaysian patients who are undergoing chemotherapy for breast cancer. However, CAM and non-CAM users reported similar symptom burdens, although single-modality use of MBP is likely associated with a lower symptom burden. IMPLICATIONS FOR PRACTICE: Nurses should keep abreast of current developments and trends in CAM use. Understanding CAM use and the related symptom burden will allow nurses to initiate open discussion and guide their patients in seeking additional information or referrals for a particular therapy. PMID- 28723723 TI - Sociodemographic Predictors of Anal Cancer Screening and Follow-up in Human Immunodeficiency Virus-Infected Individuals. AB - BACKGROUND: Anal cancer in the United States is generally rare; however, human immunodeficiency virus (HIV)-infected individuals are 28 times more likely to be given a diagnosis of anal cancer than the general population. OBJECTIVE: The aim of this study was to examine the rates and sociodemographic predictors of anal cancer screening and follow-up anoscopy in a sample of HIV-infected individuals. METHODS: Data for this study (n = 200) were derived from a retrospective chart review of randomly selected HIV-infected individuals. Data analyses included Pearson's correlation coefficient statistic to examine bivariate associations and logistic regression modeling for prediction of anal Papanicolaou test screening and follow-up anoscopy. RESULTS: Screening rates and follow-up after an abnormal anal Pap test were low. Women were less likely to be screened for anal cancer (odds ratio [OR], 0.244; P = .007). Men who have sex with men were almost 4 times more likely to be screened for anal cancer (OR, 3.7; P = .02). Men who have sex with men were 6 times more likely to have follow-up after an abnormal anal Pap test compared with heterosexual men or women of any sexual orientation (OR, 6.88; P = .002). CONCLUSIONS: High-risk groups for anal cancer should be targeted for preventative measures as part of a cancer prevention plan to decrease the personal and clinical burden associated with anal cancer. IMPLICATIONS FOR PRACTICE: Cancer prevention is a multistep process that requires screening and follow-up efforts, where healthcare providers play a vital role in these efforts. Findings from this study can inform strategies to improve screening and follow-up rates in HIV-infected individuals. PMID- 28723724 TI - Coping Strategies Used by Breast, Prostate, and Colorectal Cancer Survivors: A Literature Review. AB - BACKGROUND: Individual coping strategies are a fundamental element underpinning psychosocial distress. OBJECTIVE: The aim of this study was to describe coping strategies and their measurement used by survivors of breast, prostate, and/or colorectal cancer after treatment. METHODS: A search of electronic databases (PubMed, CINAHL, and PsycINFO) was conducted from January 1980 to March 2015. Data were extracted using standardized forms and included studies that explored the coping mechanisms of survivorship of breast, prostate, or colorectal cancer. RESULTS: Two thousand one hundred forty-seven studies were retrieved for potential inclusion; 19 publications met the inclusion criteria and were included in the review. CONCLUSIONS: Breast, prostate, and colorectal cancer survivors seem to use different coping strategies that varied throughout the survivorship trajectory. Breast cancer survivors highlighted the importance of accepting their diagnosis and engaging in physical activities that provided social and emotional support. Personality seemed to have a significant effect on coping for prostate cancer survivors. Colorectal cancer survivors emphasized the importance of seeking information to master self-management and return to social activities. IMPLICATIONS FOR PRACTICE: Understanding coping strategies, during the survivorship trajectories, is essential to planning contemporary care after cancer treatment. Nurses and other healthcare professionals may use this knowledge to improve quality of life and decrease distress after diagnosis. PMID- 28723725 TI - Meningeal melanomatosis following discontinuation of dabrafenib: implications for the maintenance of long-term complete remission. AB - A subset of 10-20% of patients under continuous BRAF inhibitor monotherapy achieve long-term progression-free and overall survival. Definitive criteria for the safe cessation of BRAF inhibitor monotherapy in treatment-responsive melanoma patients are lacking. We report a patient who remained in complete remission (CR) for 5 years under dabrafenib. The treatment was withdrawn because of concerns about cardiac toxicity. Four months thereafter the patient developed neurological symptoms, including diplopia and bilateral visual loss. Meningeal melanomatosis and parenchymal brain metastases were diagnosed. Extracerebral metastases were excluded. Reinduction of dabrafenib, combined with trametinib, led to the rapid relief of the neurological symptoms, and a partial remission was confirmed radiologically. Unfortunately, the response was not maintained and the patient died 9 months later. This observation demonstrates that discontinuation of BRAF inhibition can result in loss of disease control. On the basis of this observation, we suggest that BRAF-targeted therapy should be withdrawn only when the risks of continued treatment exceed the risk for disease relapse. However, future studies are urgently required to confirm and quantify the risk for rapid disease relapse following withdrawal of BRAF inhibitor monotherapy. PMID- 28723726 TI - Impact of socioeconomic status and district of residence on cutaneous malignant melanoma prognosis: a survival study on incident cases between 1991 and 2011 in the province of Ferrara, northern Italy. AB - The aim of this study was to analyse the impact of socioeconomic status (SES) on the prognosis of patients with invasive malignant melanoma (MM) incident from 1991 to 2011 in the province of Ferrara, northern Italy. A total of 750 patients provided by the Area Vasta Emilia Centrale Cancer Registry were included in this retrospective cohort study. Prognosis was analysed in terms of overall survival and specific survival. The study determinants were the patients' SES and district of residence. The confounding effect of sex, age, period and TNM stage at diagnosis was evaluated. In the study population, neither overall survival nor specific survival showed significant differences among different layers of SES and districts of residence. The risk for death from MM was lower for the female sex [hazard risk (HR)=0.68, 95% confidence interval (CI): 0.50-0.94] and for diagnoses made in the most recent period (2005-2011: HR=0.56, 95% CI: 0.36-0.89 with respect to 1991-1997). A worse prognosis was observed in patients older than 70 years at the time of diagnosis (HR=2.33, 95% CI: 1.39-3.91 with respect to the <40-year age group) and in patients with more than pT1 tumours (up to 20 times for pT4 tumours). SES and district of residence did not constitute prognostic factors for MM patients residing in the province of Ferrara. Homogeneity in MM staging, treatment and follow-up strategies due to the relatively small extent of the study area and the presence of a single university hospital of reference, as well as less marked social and economic differences among the study patients in comparison with other previously analysed populations, may account for this finding. PMID- 28723727 TI - Longitudinal analysis of motor symptoms and histopathology in woozy mice, a model of cerebellar ataxia. AB - Woozy (wz) mice develop ataxia and carry a mutation in the Sil1 gene. Homozygous wz mice have been characterized histopathologically, but no details of their motor function have been reported. In the present study, to comprehensively understand the relationship between symptomatic progression and pathological feature, we evaluated motor function and neurodegeneration with age from presymptomatic to terminal stages. We evaluated the motor function of homozygous and heterozygous wz mice aged from 5 to 71 weeks. Motor function was evaluated using the rotarod test, the footprint test, and the parallel rod floor test. Furthermore, we carried out a histopathological analysis of the mice at several ages. Impairment of motor function in homozygous wz mice began at around 11 weeks of age and became markedly worse until around 14 weeks. Heterozygous wz mice did not show motor dysfunction until 71 weeks of age. Features of cerebellar ataxia were evaluated using the footprint test and the parallel rod floor test. In addition to the observation of ubiquitin-positive aggregates at 6 weeks of age, Purkinje cell loss at 9 weeks of age and cerebellar atrophy were confirmed by histopathology. Apart from the cerebellar changes, we detected no other pathology that could contribute toward ataxia. In heterozygous wz mice, only minimal formation of ubiquitin-positive aggregates was observed. Homozygous wz mice showed adult-onset ataxia with progressive neurodegeneration of the cerebellum. Homozygous wz mice might be useful as an animal model of diseases showing adult onset ataxia because of cerebellar neurodegeneration. PMID- 28723728 TI - Memory-related functional connectivity in visual processing regions varies by prior emotional context. AB - Memory retrieval involves the reactivation of processes that were engaged at encoding. Using a Generalized Linear Model to test for effects of valence, our prior study suggests that memory for information previously encoded in a negative context reengages sensory processing regions at retrieval to a greater extent than positive. Here, we used partial least squares analyses of the same dataset to determine whether this valence-specific processing was one of the dominant patterns in the retrieval data. Trials previously paired with a face revealed a strong pattern of emotion that did not vary by valence, but for trials previously paired with a scene, an extensive network of regions was active during recollection of trials paired with negative content. These same regions were negatively correlated with recollection of trials paired with positive content. These results confirm that, despite no emotional content present during the time of retrieval, strong patterns of emotional study context are present in the data. Moreover, at least for trials paired with scenes at encoding, valence-specific networks are linked to episodic memory recollection, providing further support for recapitulation of sensory processing during recollection of negative emotional information. PMID- 28723730 TI - Phenibut (beta-Phenyl-gamma-Aminobutyric Acid) Psychosis. PMID- 28723731 TI - Combined Effect of CYP2B6 Genotype and Other Candidate Genes on a Steady-State Serum Concentration of Methadone in Opioid Maintenance Treatment. AB - BACKGROUND: A considerable interindividual variability in methadone pharmacokinetics is seen in patients on methadone maintenance treatment. The aim of this study was to clarify the impact of the reduced function CYP2B6*6 variant allele together with variants in other candidate genes on a steady-state methadone concentration in a naturalistic setting. METHODS: Information of methadone serum concentration, dose, age, sex, and CYP2C9, CYP2C19, and CYP2D6 genotypes were collected from a routine therapeutic drug monitoring database, whereas variant alleles in CYP2B6 and CYP3A5 were retrospectively genotyped. Linear mixed model analyses were used to study the impact of gene variants on methadone serum concentration/dose (C/D) ratios, including age, sex, and time since the last dose intake as covariates. RESULTS: Overall, 155 serum samples from 62 patients were included in this study. The estimated mean methadone C/D ratios was 17.8 nmol.L.mg for homozygous carriers of CYP2B6*6, which was significantly (P < 0.001) higher than noncarriers (9.2 nmol.L.mg). There was no difference in C/D ratios between heterozygous carriers of CYP2B6*6 (9.1 nmol.L.mg) and noncarriers. An increase in mean methadone C/D ratios was also seen for homozygous carriers of CYP3A5*3 and heterozygous carriers of CYP2C9*2 or *3 and CYP2C19*2 or *3. CONCLUSIONS: Patients homozygous for CYP2B6*6 had a >90% higher methadone C/D ratio. Genotyping of CYP2B6 may therefore be of value when assessing dose requirements in methadone maintenance treatment. PMID- 28723729 TI - Wnt signaling in cardiovascular disease: opportunities and challenges. AB - PURPOSE OF REVIEW: Cardiometabolic diseases increasingly afflict our aging, dysmetabolic population. Complex signals regulating low-density lipoprotein receptor-related protein (LRP) and frizzled protein family members - the plasma membrane receptors for the cadre of Wnt polypeptide morphogens - contribute to the control of cardiovascular homeostasis. RECENT FINDINGS: Both canonical (beta catenin-dependent) and noncanonical (beta-catenin-independent) Wnt signaling programs control vascular smooth muscle (VSM) cell phenotypic modulation in cardiometabolic disease. LRP6 limits VSM proliferation, reduces arteriosclerotic transcriptional reprogramming, and preserves insulin sensitivity while LRP5 restrains foam cell formation. Adipose, skeletal muscle, macrophages, and VSM have emerged as important sources of circulating Wnt ligands that are dynamically regulated during the prediabetes-diabetes transition with cardiometabolic consequences. Platelets release Dkk1, a LRP5/LRP6 inhibitor that induces endothelial inflammation and the prosclerotic endothelial-mesenchymal transition. By contrast, inhibitory secreted frizzled-related proteins shape the Wnt signaling milieu to limit myocardial inflammation with ischemia-reperfusion injury. VSM sclerostin, an inhibitor of canonical Wnt signaling in bone, restrains remodeling that predisposes to aneurysm formation, and is downregulated in aneurysmal vessels by epigenetic methylation. SUMMARY: Components of the Wnt signaling cascade represent novel targets for pharmacological intervention in cardiometabolic disease. Conversely, strategies targeting the Wnt signaling cascade for other therapeutic purposes will have cardiovascular consequences that must be delineated to establish clinically useful pharmacokinetic-pharmacodynamic relationships. PMID- 28723732 TI - Role of anesthesia in endovascular stroke therapy. AB - PURPOSE OF REVIEW: Recent randomized clinical trials have demonstrated strong efficacy of endovascular therapy (EVT) for acute ischemic stroke (AIS) from large vessel occlusions; in the USA alone, tens of thousands of patients annually may benefit. The impact of the type of anesthesia used during mechanical thrombectomy on patient outcomes remains controversial. This review discusses the current literature on the effects of anesthesia type on patient outcome following endovascular stroke therapy. RECENT FINDINGS: EVT is the standard of treatment for intracranial large vessel occlusions. Recent studies show that general anesthesia is associated with negative clinical outcome in AIS patients undergoing EVT. Two of the possible mechanisms of this finding are systolic hypotension and hypocapnia. However, the only published randomized controlled studies to date, sedation vs. intubation for endovascular stroke treatment and anesthesia during stroke showed no difference in short-term clinical outcome between EVT patients treated with general anesthesia and conscious sedation and improved longer-term outcome in the general anesthesia group. SUMMARY: Retrospective reports, and the 2015 American Heart Association/American Stroke Association Guideline (focused update of the 2013 guidelines for the early management of patients with AIS regarding endovascular treatment) based on these reports, are in favor of sedation (conscious sedation) over general anesthesia for endovascular stroke thrombectomy. However, the two randomized controlled prospective studies published provide inconclusive evidence as to the best anesthetic practice for endovascular stroke therapy. More randomized clinical trials are needed to optimize anesthetic patient care in AIS. PMID- 28723733 TI - Hering's Law in Congenital Ptosis: Evaluation of the Contralateral Response to Unilateral Congenital Ptosis Repair. AB - PURPOSE: To determine the applicability and clinical relevance of Hering's law for the eyelids in cases of congenital ptosis. METHODS: A retrospective chart review and digital photograph analysis of patients who underwent unilateral congenital ptosis repair at a tertiary, university-based, Oculoplastics clinic was conducted. Pre- and postoperative eyelid height (marginal reflex distance), upper eyelid symmetry, and brow position were determined using ImageJ analysis software. Changes in these values, and the relationship between the change in ipsi- and contralateral eyelid heights and brow positions, were determined. RESULTS: In 51 patients, the mean change in contralateral upper eyelid position (marginal reflex distance) following unilateral repair was -0.5 mm with 29% (n = 15) demonstrating a greater than 1 mm contralateral descent. The contralateral brow position remained stable with a mean change of +0.1 mm. No significant differences were seen between the 15 patients who demonstrated a contralateral upper eyelid descent greater than 1 mm and the remainder of the cohort in terms of amblyopia rate (p = 0.71), mean preoperative marginal reflex distance (p = 0.14), mean change in ipsilateral marginal reflex distance (p = 0.32), mean change in contralateral brow position (p = 0.44), or mean postoperative upper eyelid asymmetry (1.3 mm vs. 1.2 mm). Overall, the mean upper eyelid asymmetry improved from 2.6 mm preoperatively to 1.2 mm postoperatively. None of the 51 patients underwent subsequent contralateral ptosis repair. CONCLUSIONS: Hering's law for the eyelids applies to cases of congenital ptosis but has little clinical significance due to improved upper eyelid asymmetry following unilateral surgery. PMID- 28723734 TI - Transcanalicular Diode Laser-Assisted Revision Surgery for Failed Dacryocystorhinostomy With or Without Distal or Common Canalicular Obstruction. AB - PURPOSE: To report the outcomes of transcanalicular diode laser-assisted revision surgery for failed dacryocystorhinostomy with/without distal or common canalicular obstruction. METHODS: The medical records and recorded videos of consecutive transcanalicular diode laser-assisted revision surgeries performed for failed dacryocystorhinostomy between May 2011 and May 2015 were reviewed. Cases of unavailability of video and cases lost to follow up after surgery were excluded from the study. With respect to the level of obstruction, lacrimal drainage systems were divided into Group 1 (obstruction at the level of the ostium) and Group 2 (obstruction at the level of the distal or common canaliculus). Data associated with anatomical and functional success were analyzed. RESULTS: Revision dacryocystorhinostomy surgeries were performed on 68 patients during the study period. Transcanalicular diode laser-assisted revision surgeries were performed on 48 eyes of 39 patients. Mean follow-up period after revision surgery was 13.3 +/- 12.6 months. Overall, anatomical success rate was 83.3% (40/48) and functional success rate was 68.8% (33/48). Anatomical success rates and functional success rates in the 2 groups showed no significant difference (80.0% [24/30] vs. 86.7% [13/15], p = 0.699; 70.0% [21/30] vs. 66.7% [10/15], p = 1.000, respectively). CONCLUSIONS: Transcanalicular diode laser assisted revision surgery may be an alternative technique for failed dacryocystorhinostomy. Distal or common canalicular obstruction did not affect the outcomes of revision surgeries. PMID- 28723735 TI - Microanatomical Location of Hyaluronic Acid Gel Following Injection of the Upper Lip Vermillion Border: Comparison of Needle and Microcannula Injection Technique. AB - PURPOSE: To compare needle and microcannula injection techniques in regards to the microanatomical location of hyaluronic acid (HA) gel injected in the upper lip vermillion border of cadaver specimens. METHODS: The upper lip vermillion border was injected transcutaneously with HA gel in 8 fresh hemifaces of 4 female human cadavers. Each hemiface was injected by a single experienced injector, the right side using a 27-gauge microcannula and the left side using a 30-gauge needle. A 2-cm region of each lip was excised lateral to a point 1-cm lateral to the philtrum. Specimens were fixed in 95% alcohol, embedded in paraffin, and stained with hematoxylin-eosin for histologic examination. RESULTS: Most HA injected with either a needle or a microcannula was located within the orbicularis oris muscle, and the remaining HA resided within the subcutaneous fat. In 3/4 right (microcannula) hemifaces, 100% of the HA was located within the muscle. Only 2/4 left (needle) hemifaces had at least 95% of the HA located within the muscle. Overall, in right (microcannula) hemifaces, 93% of the filler was located within the muscle, and in left (needle) hemifaces, 79% of the filler was located within the muscle (p =0.14). CONCLUSIONS: Most HA filler injected into the vermillion border after either microcannula or needle injection resides within the orbicularis oris muscle rather than in a subcutaneous/submucosal location. Injection with a microcannula shows a trend for more uniform intramuscular location compared with needle injection. PMID- 28723736 TI - Timing of preoperative antibiotic prophylaxis in 54,552 patients and the risk of surgical site infection: A systematic review and meta-analysis. AB - The aim of the study was to assess the effect of timing of preoperative surgical antibiotic prophylaxis (SAP) on surgical site infection (SSI) and compare the different timing intervals.The benefit of routine use of SAP prior to surgery has long been recognized. However, the optimal timing has not been defined. For the purpose of developing recommendations for the World Health Organization guideline for SSI prevention, a systematic review and meta-analysis of all relevant evidence was conducted.Major medical databases were searched from 1990 to 2016. The primary outcome was SSI after preoperative-SAP comparing different timing intervals. Adjusted odds ratios (OR) with 95% confidence intervals (CI) were extracted and pooled for each comparison with a random effects model.Fourteen papers with 54,552 patients were included in this review. In a quantitative analysis, there was no significant difference when SAP was administered 120-60 minutes prior to incision compared to administration 60-0 minutes prior to incision. Studies investigating different timing intervals within the last 60 minutes time frame reported contradictive results. The risk of SSI almost doubled when SAP was administered after first incision (OR:1.89; 95%CI:[1.05-3.40]) and was 5 times higher when administered more than 120 minutes prior to incision (OR5.26; 95%CI:[3.29-8.39]).Administration of antibiotic prophylaxis more than 120 minutes before incision or after incision is associated a higher risk of surgical site infections than administration less than 120 minutes before incision. Within this 120-minute time frame prior to incision, no differential effects could be identified. The broadly accepted recommendation to administer prophylaxis within a 60-minute time frame prior to incision could not be substantiated. PMID- 28723737 TI - How to choose when implants of adjacent height both fit the disc space properly in single-level cervical artificial disc replacement. AB - In cervical artificial disc replacement (C-ADR), sometimes we encountered with such cases that implants of adjacent height both fit the target disc space properly. No study was available discussing the choice of implant height and the clinical outcomes under such circumstance. The purpose of this study was to evaluate the impact of different implant heights on the clinical outcomes and radiographic results when the implants of adjacent height both fit the disc space properly. This retrospective study included 34 patients underwent single-level C ADR at the C5-C6 level at our institution. In these 34 patients, implant with either 5 mm height or 6 mm height fit the surgical level properly without overstretching the disc space or the facet joint space. Clinical outcomes were evaluated using the Japanese Orthopedic Association score, visual analog scale (VAS), and Neck Disability Index. Radiographic assessments were conducted on static and dynamic radiographs for the determination of the disc space height, intersegmental range of motion (ROM), and the ROM of the functional spinal unit (FSU) at the surgical level. The baseline information of the patients, such as age, gender, weight, follow-up time, and diagnosis, was similar between the 2 groups (P > .05). Postoperative mean VAS in group B was significantly lower than that in group A (2.1 +/- 0.7 vs. 2.7 +/- 1.0, P < .05). The mean VAS decrease in group B was significantly larger than that in group A (5.3 +/- 0.8 vs. 4.6 +/- 1.1, P < .05). Significant difference was found in the postoperative disc height of the surgical segment between the 2 groups (6.4 +/- 0.4 mm vs. 7.5 +/- 0.5 mm, P < .05). No significant differences were noted in the intersegmental ROM and ROM of the FSU between the 2 groups both before the surgery and at the last follow-up (P > .05). No hypermobility or instability was observed in these patients. Our results suggested that when implants of adjacent height both fit the disc space properly, using the larger implant could result in better pain relief without the risk of segmental hypermobility in patients underwent single-level C-ADR at the C5-C6 level. PMID- 28723738 TI - Phosphatase and tensin homolog (PTEN) is down-regulated in human NK/T-cell lymphoma and corrects with clinical outcomes. AB - Nasal-type natural killer/T-cell (NK/T-cell) lymphoma is a more aggressive sub group of non-Hodgkin lymphoma, which is more common in Asia. The phosphatase and tensin homolog (PTEN) was originally discovered as a candidate tumor suppressor mutated and lost in various cancers. However, its clinical value and role in NK/T cell lymphoma remain to be further explored. In the present study, we analyzed PTEN protein expression in 60 cases of human NK/T-cell lymphoma tissues and 40 cases of control nasal mucosa tissues specimens by immunohistochemical analysis. As a result, positive rate of PTEN protein expression in NK/T-cell lymphoma tissues (33.3%) is significantly lower than that of control nasal mucosa tissues (85.0%) (P < .01). However, no significant association was found between PTEN protein expression and sex, age, tumor location, clinical staging (Ann Arbor staging), or serum lactate dehydrogenase level (P > .05). Instead, PTEN protein was inversely corrected with Ki-67 expression, indicating a functional role in PTEN in human NK/T-cell lymphoma (P < .05). For clinical outcomes, PTEN positive rate significantly increased in objective response group (CR+PR) (43.5%) compared with SD+PD group (18.9%). Furthermore, overexpression of PTEN contributed to chemotherapy sensitivity to different doses of cisplatin (DDP) in human NK/T-cell lymphoma SNK-6 cells. These results suggest that PTEN may regulate chemotherapy sensitivity of NK/T-cell lymphoma and contribute to clinical outcomes. These findings indicate PTEN to be a potential target anti-tumor therapeutics for NK/T cell lymphoma. PMID- 28723739 TI - Efficacy and safety of bivalirudin versus heparin in patients with diabetes mellitus undergoing percutaneous coronary intervention: A meta-analysis of randomized controlled trials. AB - BACKGROUND: The efficacy and safety of bivalirudin (Biva) versus heparin in patients with diabetes mellitus (DM) who undergo percutaneous coronary intervention (PCI) remain controversial. Our meta-analysis was undertaken to evaluate the efficacy and safety of Biva compared with those of heparin in patients with diabetes undergoing PCI. METHODS: We searched PubMed, EMBASE, Cochrane Library, and Clinical Trials.gov databases for randomized controlled trials (RCTs). The primary efficacy endpoint was the incidence of major adverse cardiovascular events (MACE), and the primary safety endpoint was the incidence of major bleeding. Secondary efficacy endpoints were incidence of net adverse clinical events (NACE), myocardial infarction (MI), and death. The pooled risk ratio (RR) with the corresponding 95% confidence intervals (CIs) were used to assess the efficacy and safety of Biva versus heparin. RESULTS: Eleven RCTs met the inclusion criteria, and 8428 patients were included. No significant difference was observed in the subgroup and overall risk of MACE (RR 0.87; 95% CI 0.74-1.02; P = .08; I = 39%) and NACE (RR 0.81; 95% CI 0.61-1.07; P = .14; I = 71%). Biva had an effect similar to that of heparin on the endpoint of death (RR 0.75; 95% CI 0.56-1.02; P = .07; I = 0) and MI (RR 0.92; 95% CI 0.67-1.26; P = .59; I = 0) but decreased the risk of major bleeding (RR 0.63; 95% CI 0.52-0.75; P < .00001; I = 0%). CONCLUSION: The use of Biva and heparin is associated with a similar risk of MACE, NACE, death, and MI. Biva decreases the risk of major bleeding more significantly than heparin. PMID- 28723740 TI - Case report: multiple systemic disseminated tuberculosis mimicking lymphoma on 18F-FDG PET/CT. AB - RATIONALE: F-fluorodeoxyglucose positron emission tomography/computed tomography (F-18 FDG PET/CT) has an important role in the diagnosis of various malignancies. However, F-18 FDG can also exhibit intense accumulation in tissues in inflammatory conditions such as active tuberculosis (TB) and sarcoidosis. PATIENT CONCERNS: We report a case of a 52-year-old female with irritable cough. CT showed a lung mass with multiple bilateral lung nodules, and sarcoidosis was suspected. F-18 FDG PET/CT was undertaken for the diagnosis and showed intense uptake of FDG in the mass in the lower lobe of the right lung, multiple lymph nodes, liver, and spleen. The maximum standardized uptake value of F-18 FDG was 43.58. This pattern of involvement most likely represents lymphomatous involvement. DIAGNOSES: Histopathology suggested tubercular involvement. INTERVENTION AND OUTCOMES: The patient received anti-TB treatment and recovered. LESSONS: Abovementioned extent and distribution of F-18 FDG in tubercular lesion is relatively rare, thus, one must be observant and aware with regards to TB being a strong mimic of lymphoma in endemic regions. PMID- 28723741 TI - Characterization of small (<=3 cm) hepatic lesions with atypical enhancement feature and hypointensity in hepatobiliary phase of gadoxetic acid-enhanced MRI in cirrhosis: A STARD-compliant article. AB - It is difficult to characterize the nodular lesions in cirrhotic liver if typical enhancement pattern is not present on dynamic contrast-enhanced imagings. Although the signal intensity of the hepatobiliary phase in gadoxetic acid enhanced magnetic resonance imaging (MRI) is helpful for characterization of the lesions, some dysplastic nodules may also exhibit low signal intensity in the hepatobiliary phase. We aimed to assess the usefulness of gadoxetic acid (Gd-EOB DTPA)-enhanced MRI including diffusion-weighted imaging (DWI) for differentiation between atypical small hepatocellular carcinomas (HCCs) and dysplastic nodules showing low signal intensity (SI) in the hepatobiliary phase, and to evaluate the MRI findings in determining the histological grade of atypical HCCs in patients with cirrhosis.A total of 43 cirrhotic patients with a small (<=3 cm) liver nodule (n = 25, HCC; n = 18, dysplastic nodule) who underwent Gd-EOB-DTPA enhanced MRI and pathologic confirmation were retrospectively reviewed. Atypical HCC was defined as not showing arterial hyperenhancement and delayed washout on dynamic MRI.High SI on both T2WI and DWI (sensitivity 80.0%, specificity 100%, positive predictive value 100%, negative predictive value 78.3%) was the most specific feature to differentiate atypical HCCs from dysplastic nodules. High SI on both T2WI and DWI (100% vs 61.5%, P = .039) or low SI on pre-enhanced T1WI (83.3% vs 30.8%, P = .021) was more frequent observed in Edmonson grade II-III HCCs compared with those in grade I HCCs.The combination of DWI and T2WI is most useful for the differentiation of atypical small HCCs from dysplastic nodules showing low SI in the hepatobiliary phase. Combination of DWI and T2WI or pre enhanced T1WI seems to be useful for predicting the histological grade of atypical HCCs. PMID- 28723742 TI - Liver transplantation using the otherwise-discarded partial liver resection graft with hepatic benign tumor: Analysis of a preliminary experience on 15 consecutive cases. AB - RATIONALE: The shortage of available donor organs limits the development of liver transplantation. This case-serial study presents a novel way to expand the donor pool by using the other-wise discarded partial liver resection graft with hepatic benign tumor. PATIENT CONCERNS: From 2012 to 2016, 15 patients with hepatic lesions were admitted to our hospital. 12 patients suffered from right epigastric discomfort and 3 patients worried about uncertain diagnosis. INTERVENTIONS: Regular hepatic lobectomy was performed for all patients and after back-table management the resected partial liver grafts were used for patients with end stage liver disease for liver transplantation. OUTCOMES: All patients had improved liver function within 1 week of transplantation. Patients had no serious small-for-size syndrome despite graft-to-recipient weight ratio less than 0.8%. Back-table hepatic venous reconstruction with prosthetic vascular grafts was performed without serious early complications, and late thrombosis in vessel graft did not affect liver function. Postoperative computed tomography scans demonstrated a remarkable growth in graft volume and a continuous decrease in hemangioma in recipients using the grafts with hemangioma. One patient died from pulmonary embolism on day 7 after transplant, and the rest of 14 recipients had been surviving well, especially recipient 1 for more than 4 years, although 3 recipients had tumor recurrence and had been treated with sorafenib. DIAGNOSES: The postoperative pathological diagnosis reported cavernous hemangioma (n = 11), perivascular epithelioid cell tumor (n = 2), inflammatory pseudotumor for (n = 1), and focal nodular hyperplasia (n = 1). LESSONS: The partial liver grafts with hepatic benign tumors are safe for liver transplantation. In addition, prosthetic vascular grafts can be used for hepatic venous outflow reconstruction, especially in right lobe liver transplantation. PMID- 28723743 TI - Analysis of HPV distribution in patients with cervical precancerous lesions in Western China. AB - Cervical human papillomavirus (HPV) infection is a dangerous disease, whose subtypes exhibit different distribution patterns in particular countries, regions, and races. In this study, the HPV distribution in patients with cervical precancerous lesions in Western China was investigated to assess a probability for prevention of cervical cancer and the clinical application of an HPV vaccine in China. The retrospective study of patients with different HPV subtypes and cervical precancerous lesions, who have undergone loop eelectrosurgical excision procedure, cold knife conization, or a total hysterectomy in our hospital from January 2016 to August 2016, was performed. All patients were tested for 27 HPV subtypes via the liquid suspension chip technology (Luminex 200). A total of 3393 cases of cervical intraepithelial neoplasia (CIN) were investigated, including 1098 cases of CIN I, 762 cases of CIN II, and 1533 cases of CIN III. The overall HPV infection rate was 82.58%. The high-risk HPV infection rate was 76.61%, and the low-risk rate was 9.88%. The most common 5 subtypes were HPV16, HPV52, HPV58, HPV33, and HPV18. The patients were grouped into 6 age groups: <=20, 21 to 30, 31 to 40, 41 to 50, 50 to 64, and >=65. The HPV subtypes' distribution varied across different age groups. In patients with cervical precancerous lesions in Western China, the top 5 HPV subtypes with the highest infection rates were HPV16, HPV52, HPV58, HPV33, and HPV18. The rate of cervical precancerous lesions unrelated to HPV was 17.42%. Thus, HPV screening with no cytology may leave unobserved about 20% of cervical precancerous lesions, which is worth of significant clinical attention. PMID- 28723744 TI - Association between bowel habits and quality of bowel preparation for colonoscopy. AB - The effectiveness of colonoscopy is highly dependent on the quality of bowel preparation. Although many studies have previously evaluated the role of cleansing methods and dosing regimens, few have examined the association between bowel habits and subsequent bowel preparation. Here, we aimed to evaluate the impact of bowel habits on the quality of bowel preparation.A total of 404 patients who underwent a total colonoscopy and completed a personal bowel habit questionnaire at Korea University Hospital between December 2012 and December 2013 were enrolled. The usual stool form of patients was classified into 7 categories according to the Bristol Stool Scale (BSS). The quality of bowel preparation was determined during colonoscopy according to the Ottawa Bowel Preparation Scale (OBPS). Segment scores of >=3 or total OBPS scores of >7 were defined as poor bowel preparation.Poor bowel preparation was reported in 9.4% of observed colonoscopies. The odds ratio (OR) of poor bowel preparation being associated with infrequent bowel movements (<3/week) was 5.00 (95% confidence interval [CI], 1.91-13.1, P = .001). BSS types 1 and 2 tended to have an association with poor bowel preparation, but the association was statistically insignificant (OR: 2.38; 95% CI, 0.90-6.33, P = .082). After adjusting for age, sex, drinking, presence of diabetes mellitus, and bowel preparation regimen, infrequent bowel movement (<3/week) was still significantly associated with poor bowel preparation. When subdividing by colonic segment, it was significantly associated with poor bowel preparation in all segments.Infrequent bowel movement (<3/week) was significantly associated with poor bowel preparation. PMID- 28723745 TI - Evaluation of the predictive value of red blood cell distribution width for onset of cerebral infarction in the patients with obstructive sleep apnea hypopnea syndrome. AB - Red blood cell distribution width (RDW) is a risk factor for the complications caused by obstructive sleep apnea hypopnea syndrome (OSAHS). This study was aimed to evaluate the predictive value of RDW for the occurrence of cerebral infarction in patients with OSAHS.We conducted a prospective study of 129 consecutive patients who were admitted to the Sleep Laboratory of in the Tenth People's Hospital of Shanghai (China) with complaints of snoring, apnea, or daytime sleepiness. All patients underwent polysomnography between June 2011 and May 2012. In total, 90 patients met the study criteria and were included in the study; there are 71 men and 19 women.RDW correlated positively with the apnea hypopnea index (AHI) (P = .00, r = 0.76). Logistic regression analysis showed correlations between each variation and cerebral infarction, high blood pressure (odds ratio [OR] = 4.72, P = .220), diabetes (OR = 2.67, P = .490), hyperlipidemia (OR = 7.42, P = .190), RDW (OR = 58.24, P = .020), and AHI (OR = 243.92, P = .001). RDW >= 15% showed a higher predictive value for the occurrence of cerebral infarction in patients with OSAHS (area under curve 0.837; sensitivity 0.919; specificity 0.755), with positive and negative predictive values of 0.697 and 0.938, respectively.RDW correlates positively with AHI. RDW values >=15% are predictive for the occurrence of cerebral infarction in patients with OSAHS. PMID- 28723746 TI - Effects of hyperbaric oxygen therapy on depression and anxiety in the patients with incomplete spinal cord injury (a STROBE-compliant article). AB - Little research has been done on the effects of hyperbaric oxygen (HBO) on depression and anxiety after spinal cord injury (SCI). The aim of this study was to investigate the effects of HBO on psychological problems and never function, especially on depression and anxiety in the patients with incomplete SCI (ISCI).Sixty patients with ISCI combined with depression and anxiety were randomly divided into HBO group (20 cases), psychotherapy group (20 cases), and conventional rehabilitation control group (20 cases). All patients received routine rehabilitation therapy. However, in HBO group and psychotherapy group, patients also received HBO and psychotherapy, respectively. These therapies lasted for a total of 8 weeks (once a day and 6 days per week). Before and after 8 weeks of treatment, depression and anxiety, nerve function, and activities of daily living were, respectively, evaluated according to Hamilton Depression (HAMD) scale, Hamilton Anxiety (HAMA) scale, American Spinal Injury Association score, and functional independence measure score in all patients.After 8 weeks of treatment, HAMD score was significantly lower in both HBO group and psychotherapy group than in control group (all P < .05), but there was no statistical difference in HAMD score between HBO group and psychotherapy group (P > .05). HAMA score was significantly lower in HBO group than in control group (P < .05), but there was no statistical difference in HAMA score between HBO group and psychotherapy group, and between psychotherapy group and control group (all P > .05). After 8 weeks of treatment, American Spinal Injury Association and functional independence measure scores were significantly higher in HBO group than in both psychological and control groups, and also higher in psychotherapy group than in control group (all P < .05).The effects of HBO on depression and anxiety are similar to that of psychotherapy. HBO can significantly improve nerve function and activities of daily living in the patients with ISCI, which either psychotherapy or routine rehabilitation therapy can not substitute. PMID- 28723747 TI - Injury of optic radiation and visual field defect in a patient with aneurysmal subarachnoid hemorrhage: A case report. AB - RATIONALE: Little is known about optic radiation (OR) injury following aneurysmal subarachnoid hemorrhage (SAH). In the current study, we report on a patient who showed a visual field defect and injury of the OR following aneurysmal SAH, using diffusion tensor tractography (DTT). PATIENT CONCERNS: At 4 weeks from onset, when a 62-year old female started rehabilitation, she complained of a visual field defect. Peripheral field defects were detected on both eyes using the Humphrey visual field test. DIAGNOSES: The patient underwent aneurysm clipping for a ruptured aneurysm in the left posterior communicating artery and extraventricular drainage (the left prefrontal approach) for subarachnoid hemorrhage. She also underwent conservative management for intracerebral hemorrhage in the left internal capsule detected at 2 days after onset. INTERVENTIONS: DTT data were acquired at 4 weeks after onset OUTCOMES:: Regarding DTT parameters, fiber numbers of both ORs of the patient were decreased over 2 standard deviations of that of 7 age- and sex-matched normal subjects normal control subjects. However, the value of fractional anisotropy was similar to that of normal control subjects. On the configuration of the OR of the patient, both ORs were thinner than those of normal control subjects. LESSONS: Injury of the OR was demonstrated in a patient with a visual field defect following aneurysmal SAH, using DTT. PMID- 28723748 TI - Clinical characteristics and mutation spectrum of GLA in Korean patients with Fabry disease by a nationwide survey: Underdiagnosis of late-onset phenotype. AB - Fabry disease is a rare X-linked lysosomal storage disorder caused by an alpha galactosidase A deficiency. The progressive accumulation of globotriaosylceramide (GL-3) results in life-threatening complications, including renal, cardiac, and cerebrovascular diseases. This study investigated the phenotypic and molecular spectra of GLA mutations in Korean patients with Fabry disease using a nationwide survey.This study included 94 patients from 46 independent pedigrees: 38 adult males, 46 symptomatic females, and 10 pediatric males. Each diagnosis was based on an enzyme assay and GLA gene mutation analysis.The mean age at presentation was 24 years (range, 5-65 years); however, the diagnoses were delayed by 21 +/- 19 years after the onset of symptoms. Those patients with late-onset Fabry disease were diagnosed by family screening or milder symptoms at a later age. Forty different mutations were identified: 20 missense (50%), 10 nonsense (25%), 8 frameshift (20%), and 2 splice site (5%) mutations. Five of them were novel. IVS4+919G>A (c.936+919 G>A) was not detected among the 6505 alleles via newborn screening using dried blood spots. Enzyme replacement therapy (ERT) was performed in all the males and pediatric patients, whereas 75% of the symptomatic females underwent ERT for 4.2 +/- 3.6 years.This study described the demographic data, wide clinical spectrum of phenotypes, and GLA mutation spectrum of Fabry disease in Korea. Most of the patients had classical Fabry disease, with a 4 times higher incidence than that of late-onset Fabry disease, indicating an underdiagnosis of mild, late-onset Fabry disease. PMID- 28723749 TI - Effects of sealing the intramedullary femoral canal in total knee arthroplasty: A randomized study. AB - BACKGROUND: This study investigates the clinical effects of sealing the femoral canal by intramedullary alignment instrumentation in total knee arthroplasty (TKA). METHODS: One hundred twenty consecutive patients with knee osteoarthritis, who underwent unilateral TKA, were enrolled in the study and equally randomized into 2 groups: the sealing group and the control group. In the sealing group, the femoral canal was sealed with autogenous bone and cement using intramedullary alignment instrumentation, while the femoral hole was left open for patients in the control group. Blood loss, hemoglobin (Hb) reduction, and other parameters were recorded, as well as the duration of hospital stay and complications. The Hospital for Special Surgery (HSS) knee score was used to assess knee function at the final follow-up appointment. RESULTS: The calculated blood loss, hidden blood loss, transfusion requirements, drainage volume, and Hb reduction measurements were significantly different (P < .05) between the 2 groups. There were no significant differences in the surgery time, intraoperative blood loss, length of hospital stay, HSS score or complications between the 2 groups (P > .05). CONCLUSIONS: Sealing the intramedullary canal with autologous bone and a cement plug is an effective method for reducing blood loss and decreasing blood transfusion requirements during TKA procedures that have increasing complication rates. PMID- 28723750 TI - Sphincter-preserving surgery for low-middle rectal cancer: Can we predict feasibility with high-resolution magnetic resonance imaging? AB - The study proposed to evaluate the feasibility of predicting sphincter-sparing surgery (SSS) preoperatively in low-middle rectal cancer by using magnetic resonance (MR).The study included both retrospective and prospective design. In the retrospective design, the distance from lower edge of tumor to upper margin of the internal sphincter (Dis1) and distance to anal verge (Dis2) were measured on MR, the distance to anal verge recorded by colonoscopy (Dis3) and digital rectal examination (Dis4) were also obtained. ROC analysis was conducted and cut off value was determined with overall and stratified analysis. The prospective part was designed to validate the predictive capability of the optimal distance.The retrospective design included 278 patients with middle or lower rectal adenocarcinoma, the prospective design included 106 patients with neoadjuvant therapies. The primary outcome was the actual surgical method and pathological distal resection margin. Dis1 obtained from MRI presented better performance than other distances in determining the surgical approach, with AUC of 0.997 (95% CI, 0.934-1.000). Dis1 was selected as the optimal distance and a cut-off value of 2 cm was determined. Dis1 and the cut-off value were also validated in the prospective sample, with AUC of 0.996 (95% CI, 0.989-1.000) and an overall accuracy of 99.1%.MR-based distance from lower edge of tumor to upper margin of the internal sphincter could be used to help the surgeons to predict the feasibility of SSS preoperatively. PMID- 28723751 TI - Early laparotomy and timely reconstruction for patients with abdominal electrical injury: Five Case Reports and Literature Review. AB - INTRODUCTION: High-tension electricity can cause devastating injuries that may result in abdominal wall loss, visceral damage, and sometimes major threat to life. The visceral organ may be exposed after debridement and require flap cover, but the tensile strength of abdominal wall may be lack even if flap transplanted. METHODS: From April 2007 through May 2015, 5 patients with severe abdominal electrical injury were treated at our hospital. Exploratory laparotomy was performed based on their clinical manifestations and debridement findings of abdominal wall at early stage, and decision regarding technique for reconstruction of abdominal wall was based on an assessment of the location and extent of the defect. Medical records were reviewed for these data. RESULTS: Clinical evaluation and debridement findings of the abdomen revealed 4 patients with suspicious visceral damage. Laparotomy was performed in 4 cases, and revealed obvious lesion in 3 cases, including segmental necrosis of small intestine, partial necrosis of diaphragm, left liver and gastric wall, and greater omentum. Five patients underwent abdominal wall reconstruction using island retrograde latissimus dorsi myocutaneous flap or free/island composite anterolateral thigh myocutaneous flap. All flaps survived, abdominal bulging occurred in 3 cases after follow-up of 12 to 36 months. CONCLUSIONS: The clinical manifestations and wound features of abdomen collectively suggest a possible requirement of laparotomy for severe abdominal electrical burns. Retrograde latissimus dorsi myocutaneous flap or composite anterolateral thigh myocutaneous flap is an effective option for reconstruction of abdominal wall loss, the long term complication of abdominal bulging, however, remains a significant clinical challenge. PMID- 28723752 TI - Full covered self-expandable metal stents for the treatment of anastomotic leak using a silk thread. AB - To evaluate the safety and effectiveness of fixation of the fully covered self expandable metal stent (SEMS) placement using a silk thread for complete closure of an anastomotic leak. An anastomotic leak is a life-threatening complication after gastrectomy. Although the traditional treatment of choice was surgical re intervention, an endoscopic SEMS can be used alternatively.During the study period, we retrospectively reviewed consecutive patients who received a modified covered SEMS capable of being fixed using a silk thread (Shim technique) due to an anastomotic leak after gastrectomy to prevent stent migration. Demographic data, stent placement and removal, clinical success, time to resolution, and complications were evaluated.A total of 7 patients underwent fully covered SEMS with a silk thread placement for an anastomotic leak after gastrectomy to treat gastric cancer. The patients' mean age was 71.3 +/- 8.0 years. Man sex was predominant (85.7%). All patients' American Society of Anesthesiologists (ASA) scores were between I and III. Total gastrectomy was performed in 5 patients (71.4%) and proximal gastrectomy was performed in 2 patients (28.6%). The time between gastrectomy and stent insertion was 22.3 +/- 11.1 days. The size of the leaks was 27.1 +/- 11.1 mm. Technical success and complete leak closure were achieved in all patients. Stent migration was absent. All stents were removed between 4 and 6 weeks. Delayed esophageal stricture was found in 1 patient (14.2) and successfully resolved after endoscopic balloon dilation.For an anastomotic leak after gastrectomy, fully covered SEMS placement with a silk thread is an effective and safe treatment option without stent migration. The stent extraction time between 4 and 6 weeks was optimal without severe complications. PMID- 28723753 TI - Tumor necrosis factor alpha-238G/A polymorphism and risk of breast cancer: An update by meta-analysis. AB - BACKGROUND: The association between the tumor necrosis factor-alpha gene (TNF-a) 238G/A polymorphism and the breast cancer has been analyzed in several studies, but the results have been inconclusive. We then performed a meta-analysis to get a precise estimation of the association. METHODS: Eight case-control studies with a total of 37,257 cases and 39,564 controls were identified by searching the ISI Web of Knowledge database and the PubMed database up to August 2014. RESULTS: Overall, no association was found between TNF-alpha-238G/A polymorphism and breast cancer in any of genetic model (additive model OR = 1.06, 95%CI: 0.94 1.21, Pheterogeneity = .02; homozygous model OR = 1.04, 95%CI: 0.83-1.30, Pheterogeneity = .98; dominant model OR = 1.06, 95%CI: 0.92-1.21, Pheterogeneity = .01; recessive model OR = 1.04, 95%CI: 0.83-1.30, Pheterogeneity = .98). Furthermore, no significant association was identified when stratified by ethnicity (Caucasian, Asian). CONCLUSION: This meta-analysis indicated that the TNF-alpha-238G/A polymorphism is not associated with breast cancer risk in the overall population. PMID- 28723754 TI - An economic analysis of high-dose imatinib, dasatinib, and nilotinib for imatinib resistant chronic phase chronic myeloid leukemia in China: A CHEERS-compliant article. AB - BACKGROUND: The aim of the study was to test the cost-effectiveness of dasatinib compared to high-dose imatinib and nilotinib in Chinese patients who were diagnosed with imatinib-resistant chronic myeloid leukemia in the chronic phase (CML-CP). METHODS: A Markov model combined with clinical effectiveness, utility, and cost data was used. The sensitivity analyses were conducted to determine the robustness of the model outcomes. The impact of patient assistance programs (PAPs) was assessed. RESULTS: Treatment with dasatinib is expected to produce 3.65, 0.59, and 0.15 more quality-adjusted life years (QALYs) in comparison with high-dose imatinib (600 and 800 mg) and nilotinib, respectively. When a PAP was available, dasatinib yielded an incremental cost of $16,417 per QALY compared to imatinib (600 mg) and was cost-saving compared to imatinib (800 mg) and nilotinib. CONCLUSION: When PAP is available in the Chinese setting, dasatinib is likely to be a cost-effective strategy for patients with CML-CP standard-dose imatinib resistance. The results should be carefully explained due to the assumptions and limitations used in the study. PMID- 28723755 TI - Comparison of free-hand fluoroscopic guidance and electromagnetic navigation in distal locking of femoral intramedullary nails. AB - BACKGROUND: Although the method has been used widely, one of the greatest challenges for intramedullary nailing is to position the distal locking screw. A new technology, the electromagnetic navigation system, is a radiation-free way to locate the position of the drill bit and provide 3-dimensional real-time feedback of location and orientation of the drill bit relative to the locking holes. The purpose of our study was to evaluate the reliability and efficiency of the free hand technique compared to the new electromagnetic navigation system. METHODS: Fifty-four patients with femoral fracture who needed treatment with intramedullary nails were divided into 2 groups. One group including 26 patients underwent distal locking using the standard free-hand method, whereas the electromagnetic navigation system was used with the other 29 patients. Intraoperative fluoroscopy exposure times, screw insertion times, and healing times were recorded; these parameters were used for comparison between the 2 groups. RESULTS: There were 17 males and 9 females who had femoral intramedullary nails using the free-hand technique, whereas 21 males and 8 females received intramedullary nails using the electromagnetic navigation system. The mean time of distal locking was 19.5 +/- 6.0 minutes in the free-hand (FH) group, whereas the time was 6.1 +/- 1.4 minutes in the electromagnetic (ET) group. The exposure time for the FH group was 26.8 +/- 13.3 seconds and 2.2 +/- 1.1 seconds for the ET group. Healing time proved to be comparable in the FH and ET groups (16.4 +/- 3.7 weeks vs 15.1 +/- 2.8 weeks). CONCLUSION: Under the premise of achieving the same effect, the electromagnetic navigation system has the advantage of less distal locking time and less radiation dose. PMID- 28723756 TI - Pulmonary pleomorphic carcinoma: A case report and review of the literature. AB - RATIONALE: Pleomorphic carcinoma (PC) is a rare malignancy of the lung. It has a dual-cell component of spindle and/or giant cells, and of epithelial cells. PATIENT CONCERNS AND DIAGNOSES: We presented a case of PC. A 69-year-old healthy asymptomatic woman who was occasionally found an abnormal shadow on her chest X rays. A computerized tomography scan showed a mass located in the left lingular lobe and the percutaneous lung biopsy pathology confirmed sarcomatoid cancer. INTERVENTIONS AND OUTCOMES: The patient underwent pneumonectomy. A diagnosis of PC was confirmed after surgery through immunohistochemistry. The pathological stage was T2aN0M0 (Ib). Due to the patient's refusal, adjuvant chemotherapy was not taken and she has been living disease free for 12 months after the surgery. LESSONS: PC of the lung represents a rare pathological entity. Surgical resection remains the cornerstone of the treatment and may offer the possibility of long time survival in early-stage patients. More cases of PC should be reported to establish an optimal management. PMID- 28723757 TI - Comprehensive comparing percutaneous endoscopic lumbar discectomy with posterior lumbar internal fixation for treatment of adjacent segment lumbar disc prolapse with stable retrolisthesis: A retrospective case-control study. AB - The study was to comprehensively compare the postoperative outcome and imaging parameter characters in a short/middle period between the percutaneous endoscopic lumbar discectomy (PELD) and the internal fixation of bone graft fusion (the most common form is posterior lumbar interbody fusion [PLIF]) for the treatment of adjacent segment lumbar disc prolapse with stable retrolisthesis after a previous lumbar internal fixation surgery.In this retrospective case-control study, we collected the medical records from 11 patients who received PELD operation (defined as PELD group) for and from 13 patients who received the internal fixation of bone graft fusion of lumbar posterior vertebral lamina decompression (defined as control group) for the treatment of the lumbar disc prolapse combined with stable retrolisthesis at Department of Spine Surgery, the Third Hospital of Hebei Medical University (Shijiazhuang, China) from May 2010 to December 2015. The operation time, the bleeding volume of perioperation, and the rehabilitation days of postoperation were compared between 2 groups. Before and after surgery at different time points, ODI, VAS index, and imaging parameters (including Taillard index, inter-vertebral height, sagittal dislocation, and forward bending angle of lumbar vertebrae) were compared.The average operation time, the blooding volume, and the rehabilitation days of postoperation were significantly less in PELD than in control group. The ODI and VAS index in PELD group showed a significantly immediate improving on the same day after the surgery. However, Taillard index, intervertebral height, sagittal dislocation in control group showed an immediate improving after surgery, but no changes in PELD group till 12-month after surgery. The forward bending angle of lumbar vertebrae was significantly increased and decreased in PELD and in control group, respectively.PELD operation was superior in terms of operation time, bleeding volume, recovery period, and financial support, if compared with lumbar internal fixation operation. Radiographic parameters reflect lumber structure changes, which could be observed immediately after surgery in both methods; however, the recoveries on nerve function and pain relief required a longer time, especially after PLIF operation. PMID- 28723758 TI - Total knee arthroplasty conversion after a failed lateral closing wedge high tibial osteotomy with knee hyperextension and secondary ankle degeneration: A case report. AB - RATIONALE: High tibial osteotomy (HTO) has been used widely for medial compartment knee osteoarthritis to correct the deformity and relieve symptoms, especially in young patients who are willing to maintain the high activity level. However, the change of bone morphology, ligament imbalance, limb malalignment, and other complications may influence the short-term outcomes of HTO. Some cases may even require conversion to TKA shortly after HTO because of the loss of correction or pain due to accelerated osteoarthritis. PATIENT CONCERNS: A 43-year old female patient presented with persistent pain of both the left knee and the ankle. She underwent a lateral closing wedge HTO two years ago. Radiographies showed The Kellgren-Lawrence (K-L) grade IV osteoarthritic change and hyperextension (HE) of the left knee and the degeneration of the left ankle. DIAGNOSES: A failed lateral closing wedge high tibial osteotomy with knee hyperextension and secondary ankle degeneration. INTERVENTION: A posterior stabilized TKA conversion and postoperative rehabilitation were performed. OUTCOMES: The operation corrected the HE deformity and relieved the pain at the level of the left knee. However, the secondary change of the left ankle was irreversible. LESSONS: A failed lateral closing wedge HTO might speed up the degeneration of the knee and increase extra technical issues in the following TKA. What is more, the secondary osteoarthritis and deformity of the ankle cannot be ignored. PMID- 28723759 TI - Determining the relationship of kinesiophobia with respiratory functions and functional capacity in ankylosing spondylitis. AB - Ankylosing spondylitis (AS) is a common inflammatory rheumatic disease that affects the axial skeleton, causes inflammatory lower back pain, and structural and functional disorders, which affect quality of life negatively.The purpose of this study is to investigate the effects of kinesiophobia in AS on pulmonary function tests (PFTs) and functional performance.Thirty-one individuals with AS (n = 19 male, n = 12 female) who were suitable on the basis of the Modified New York (MNY) criteria were included in the study. The participants were given the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), the Bath Ankylosing Spondylitis Functional Index (BASFI), the Bath Ankylosing Spondylitis Metrology Index (BASMI), in addition to the Tampa Scale for Kinesiophobia (TKS), PFTs, respiratory muscle strength, pain evaluation, and 6-minute walking test (6MWT).The mean values were found as the following: TKS, 41.65 +/- 7.59; pain visual analog scale (VAS) score, 6.23 +/- 2.86; forced vital capacity (%) (FVC), 75.35% +/- 17.92%; forced expiratory volume in first second (%) (FEV1), 73.45% +/ 17.20%; FEV1/FVC (%), 75.58% +/- 15.99%; peak expiratory flow (%) (PEF), 54,90% +/- 20.21%; forced expiratory flow at 25% to 75% (FEF25-75), 77.71% +/- 27.05%; maximal inspiratory pressure (MIP), 62.06 +/- 31.68; maximal expiratory pressure (MEP), 95.94 +/- 36.60; 6MWT, 445.88 +/- 99.48. The scores obtained in TKS were found related to the values of FVC (%), FEV1 (%), chest expansion, BASFI, modified Schober test, lumbar lateral flexion, cervical rotation, and total BASMI score (r = -0.43, -0.36, -0.41, 0.42, -0.49, -0.56, -0.52, 0.56, respectively; P < .05).Kinesiophobia is a condition that may arise in individuals with AS, which has negative effects. Physiotherapists have a responsibility to eliminate kinesiophobia beliefs and prefer therapy method in line with this responsibility. PMID- 28723760 TI - Bioinformatics analysis to identify the critical genes, microRNAs and long noncoding RNAs in melanoma. AB - Melanoma, which is usually induced by ultraviolet light exposure and the following DNA damage, is the most dangerous skin cancer. The purpose of the present study was to screen key molecules involved in melanoma.Microarray data of E-MTAB-1862 were downloaded from the ArrayExpress database, which included 21 primary melanoma samples and 11 benign nevus samples. In addition, the RNASeq version 2 and microRNA (miRNA) sequencing data of cutaneous melanoma were downloaded from The Cancer Genome Atlas database. After identifying the differentially expressed genes (DEGs) using Limma package, enrichment analysis and protein-protein interaction (PPI) network analysis were performed separately for them using DAVID software and Cytoscape software. In addition, survival analysis and regulatory network analysis were further performed by log-rank test and Cytoscape software, respectively. Moreover, real-time reverse transcription polymerase chain reaction (RT-PCR) was performed to further verify the expression patterns of several selected DEGs.A total of 382 DEGs were identified in primary melanoma samples, including 206 upregulated genes and 176 downregulated genes. Functional enrichment analysis showed that COL17A1 was enriched in epidermis development. In the PPI network, CXCL8 (degree = 29) and STAT1 (degree = 28) had higher degrees and could interact with each other. Survival analysis showed that 21 DEGs, 55 long noncoding RNAs (lncRNAs) and 32 miRNAs were found to be associated with prognosis. Furthermore, several regulatory relationships were found in the lncRNA-gene regulatory network (such as RP11-361L15.4 targeting COL17A1) and the miRNA-gene regulatory network (such as hsa-miR-375 targeting CCL27 and hsa-miR-375 targeting insulin-like growth factor 1 receptor [IGF1R]). Real-time RT-PCR results showed that the overall direction of differential expression was consistent except COL17A1.CXCL8 interacted with STAT1, CCL27, and IGF1R targeted by hsa-miR-375, and COL17A1 targeted by RP11-361L15.4 might function in the development and progression of melanoma, which should be verified by more detailed experiments. PMID- 28723761 TI - Efficacy of the prophylactic use of octreotide for the prevention of complications after pancreatic resection: An updated systematic review and meta analysis of randomized controlled trials. AB - BACKGROUND: The use of octreotide prophylaxis in the prevention of complications after pancreatic resection remains controversial. The aim of this systematic review and meta-analysis was to evaluate the efficacy of octreotide prophylactic treatment to prevent complications after pancreatic resection. METHODS: Five databases (PubMed, Medline, SinoMed, Embase, and Cochrane Library) were searched for eligible studies from 1980 to November 2016 with the limitation of human subjects and randomized controlled trials (RCTs). Data were extracted independently and were analyzed using RevMan statistical software version 5.3 (Cochrane Collaboration, http://tech.cochrane.org/revman/download). Weighted mean differences (WMDs), risk ratios (RRs), and 95% confidence intervals (CIs) were calculated. Cochrane Collaboration risk of bias tool was used to assess the risk of bias. RESULTS: Twelve RCTs comprising 1902 patients were identified as eligible. The methodological quality of the trials ranged from low to moderate. A pooled analysis of effectiveness based on the data from each study revealed that octreotide could significantly reduce the rate of pancreatic fistula (PF) after pancreatic resection (RR = 0.75, 95% CI = 0.57-0.98, P = .04). The same findings were discovered in multicenter and European subgroups with a subgroup analysis; no obvious differences were noted in American, Asian, and single-center subgroup analyses. An equal effect was observed between the use or non-use of octreotide groups regarding mortality (RR = 1.24, 95% CI = 0.77-2.02, P = .38). Octreotide had no advantages in regards to mortality improvement. The total numbers of complications associated with the use or non-use of octreotide were similar (RR = 0.77, 95% CI = 0.58-1.03, P = .08). Among the high-risk group, octreotide was more effective in reducing complications (RR = 0.61, 95% CI = 0.46-0.82, P = .0009). Compared with the patients who did not receive prophylactic treatment, the patients who underwent pancreatic resection benefited from octreotide because it had better efficacy in preventing fluid collection and postoperative pancreatitis. CONCLUSION: The prophylactic use of octreotide is suitable for preventing postoperative complications, especially PF and fluid collection as well as postoperative pancreatitis. However, no obvious differences were noted regarding mortality. In view of the clinical heterogeneity and varying definitions of PF, whether these conclusions are broadly applicable should be further determined in future studies. PMID- 28723762 TI - Recombinant human TSH stimulated thyroglobulin levels at remnant ablation predict structural incomplete response to treatment in patients with differentiated thyroid cancer. AB - In patients with differentiated thyroid cancer, stimulated thyroglobulin (sTg) levels after thyroid hormone withdrawal (THW) at remnant ablation (RA) and at 6 to 12 months are known to have good prognostic value. This study aimed to evaluate the prognostic impacts and best cutoff values of sTg levels under recombinant human thyroid stimulating hormone (rhTSH) treatment at RA and at follow-up. A total of 151 patients were enrolled, of whom 77 were followed up with rhTSH-stimulated Tg (rhTSH-sTg) and 74 with THW-stimulated Tg (THW-sTg) at 6 to 12 months after rhTSH-aided RA. Risk stratification, response to treatment (excellent, indeterminate, biochemical incomplete, and structural incomplete response [SIR]), and clinical outcome were accessed by revised American Thyroid Association (ATA) guideline criteria. Seven out of 151 (4.6%) patients were confirmed to have SIR during the median follow-up of 79.0 months; 3 in the rhTSH group and 4 in the THW group. One hundred thirty-two out of 151 (87.4%) patients were confirmed to have excellent response; 68 (51.5%) in the rhTSH group and 64 (48.5%) in the THW group. The cutoff values of sTg for predicting SIR to treatment at rhTSH-aided RA, THW-sTg, and rhTSH-sTg were 4.64 ng/mL (sensitivity 85.7%, specificity 76.4%, negative predictive value [NPV] 99.2%), 2.41 ng/mL (sensitivity 100%, specificity 94.3%, NPV 100%), and 1.02 ng/mL (sensitivity 66.7%, specificity 94.6%, NPV 98.6%), respectively. sTg levels using rhTSH at both RA and follow-up has a high NPV and are as effective as using THW for predicting SIR. The risk classification according to the revised ATA guidelines can be used effectively to supplement rhTSH-aided sTg levels to predict better clinical outcomes. PMID- 28723763 TI - The diagnostic value of assays for circulating tumor cells in hepatocellular carcinoma: A meta-analysis. AB - PURPOSE: Circulating tumor cells (CTCs) are considered potential biomarkers for the detection of hepatocellular carcinoma (HCC). Many studies have attempted to explore this role, but the results are variable. We conducted the first comprehensive meta-analysis to evaluate the diagnostic value of CTC assay for HCC patients. Additional prognostic value was also assessed. EXPERIMENTAL DESIGN: All articles included in our study were assessed using QUADAS guidelines after a literature search. Using bivariate generalized linear mixed model and random effects model, effect measures such as pooled sensitivity/specificity, positive likelihood ratios/negative likelihood ratios (NLRs), diagnostic odds ratios, hazard ratios (HRs), risk ratios, and corresponding 95% confidence intervals (95% CIs) were calculated. We used receiver operating characteristic curves and area under the curve (AUC) to summarize overall test performance. Heterogeneity, publication bias, subgroup, and sensitivity analyses were also performed. RESULTS: A total of 2256 subjects including 998 HCC patients in 20 studies were recruited in this meta-analysis. Although the overall diagnostic accuracy of the CTC assay was high (AUC 0.93, 95% CI: [0.90-0.95]), there was a high probability of error rate (NLR 0.33, 95% CI: [0.23, 0.48]). The results were more robust when nonmagnetic-activated isolation was used, compared with magnetic-activated isolation subgroup (NLR: 0.18 vs. 0.41; z = 2.118, P = .034). CTCs positivity was significantly associated with relapse-free survival (HR 2.417, 95% CI: [1.421 3.250]; P < .001), overall survival (HR 3.59, 95% CI: [1.984-6.495]; P < .001), and some clinical characteristics. CONCLUSION: CTC assay is not recommended as an independent HCC diagnostic tool, but is associated with poor clinicopathologic characteristics of HCC patients and could indicate poor prognosis. PMID- 28723764 TI - Increased nuchal translucency in fetuses with a normal karyotype-diagnosis and management: An observational study. AB - The use of nuchal translucency (NT) in 1992 by Nicolaides et al was a major breakthrough in screening for chromosomal aneuploidies at the end of the first trimester. However, pathological conditions other than chromosomal aneuploidies are also associated with increased NT, which can also be detected in normal fetuses. This study sought to evaluate the causes of this ultrasound sign in a group of patients from Iasi, Romania.During the decade-long study period, there were 71 certified cases involving increased NT; the patients in these cases underwent diagnostic amniocentesis and karyotyping.In most of the examined cases (55 cases, 78%), there was no aneuploidy. The remaining cases involved trisomy 21 (T21) (18%), trisomy 18 (T18) (2%), or triploidy (2%). In most cases, the indication for amniocentesis was increased NT alone (81%), whereas the remaining cases also involved advanced maternal age (5.5%), abnormal serologic markers (10%), or other ultrasound signs (3.5%) (2 cases-cardiac anomalies and fetal hydrops). A favorable pregnancy outcome at term was achieved in 40 cases (56% from total, 72% from euploid pregnancies); kidney anomalies or nonlethal cardiac conditions were observed in 12 cases (17%), 6 of which involved complications associated with premature onset of labor, and miscarriages occurred in 6 cases. Three cases were lost at follow-up.Although it is common practice to assume that increased NT is an indication for amniocentesis, both literature results and our study findings indicate that the majority of cases with increased NT involve no aneuploidy and result in a favorable outcome if no other anomaly is present. Better evidence-based management of such cases could be promoted by conducting larger, multicenter studies, and following cases for longer periods. PMID- 28723765 TI - Perioperative management of intracardiac leiomyomatosis: An observational cohort study. AB - Intracardiac leiomyomatosis (ICLM) is a rare condition in which the benign tumor extends into the right heart chambers through inferior vena cava. The best surgical approach still remains unclear.We present a retrospective cohort of 36 patients diagnosed with ICLM in Peking Union Medical College Hospital between 2002 and 2016.The mean patient age was 44.5 (range 25-55) years. The clinical manifestations were various, including shortness of breath, chest tightness, edema of the lower extremities, palpitations, syncope, etc. Cardiac function of 30 patients (80%) remained mildly influenced, classified as New York Heart Association (NYHA) I-II. After careful preoperative evaluation, 19 patients underwent 1-stage operation while the other 17 patients underwent 2-stage operations. The original surgical plans were changed in 5 patients (14%) due to intraoperative transesophageal echocardiography (TEE) monitoring, with the tumor directly extracted through abdominal approach or right atrium without cardiopulmonary bypass and/or deep hypothermic circulatory arrest. Complete resection was achieved in 32 patients (89%). Despite increased volume of blood loss (P < .05), patients undergoing 1-stage operation had significantly shorter operation time, anesthesia time as well as hospital length of stay (P < .05), compared with 2-stage operations. The postoperative complication rates were not different between the 2 groups (P = .684). During mean follow-up time of 36.1 months, recurrence occurred in 7 patients (23%) but all are survived.Precise and full-scale preoperative evaluation of both the tumor anatomy and the patient's tolerability to the surgery should be performed. TEE plays a crucial role in guidance of surgical decision making, and 1-stage extraction of tumor through either abdominal approach or right atrium may be possible. PMID- 28723766 TI - Lady with wings: a case report of giant neurofibromatosis type I. AB - RATIONALE: Neurofibromatosis type I (NF-I) accounts for approximately 90% of neurofibromatosis. NF-I is an autosomal dominant genetic disease which results from the gene mutation of NF-I situated in chromosome 17q11.2. PATIENT CONCERNS: A 32-year-old lady presented with a giant wing like structure on her back which started growing from her childhood. DIAGNOSIS: A diagnosis of NF-I was confirmed as she presented with multiple cutaneous nodules, multiple cafe-au-lait macules of different sizes, scoliosis deformity, and positive family history of neurofibroma. INTERVENTIONS: Surgical excision of tumor and multiple Z plasty reconstruction of the back was carried out. OUTCOMES: The excised neurofibroma weighed 6.7 kg containing thickened nerves, nerve roots, and circuitous vessels. The histopathological report confirmed plexiform and diffuse type cutaneous neurofibroma without any malignant transformation. Surgical excision and reconstruction with regular follow-up is an excellent choice of treatment for such a giant neurofibroma as in this case. LESSONS: NF-I is a genetic disease which could present as a giant cutaneous neurofibroma. One of the treatment options for giant neurofibromas causing deformity and physical disability is by surgical excision and histopathological examination with regular follow-up for NF I recurrence. PMID- 28723767 TI - Return of the cadaver: Key role of anatomic dissection for plastic surgery resident training. AB - Successful Plastic Surgery Residency training is subjected to evolving society pressure of lower hourly work weeks imposed by external committees, labor laws, and increased public awareness of patient care quality. Although innovative measures for simulation training of surgery are appearing, there is also the realization that basic anatomy training should be re-enforced and cadaver dissection is of utmost importance for surgical techniques.In the development of new technology for implantable neurostimulatory electrodes for the management of phantom limb pain in amputee patients, a design of a cadaveric model has been developed with detailed steps for innovative transfascicular insertion of electrodes. Overall design for electrode and cable implantation transcutaneous was established and an operating protocol devised.Microsurgery of the nerves of the upper extremities for interfascicular electrode implantation is described for the first time. Design of electrode implantation in cadaver specimens was adapted with a trocar delivery of cables and electrodes transcutaneous and stabilization of the electrode by suturing along the nerve. In addition, the overall operating arena environment with specific positions of the multidisciplinary team necessary for implantable electrodes was elaborated to assure optimal operating conditions and procedures during the organization of a first-in-man implantation study.Overall importance of plastic surgery training for new and highly technical procedures is of importance and particularly there is a real need to continue actual cadaveric training due to patient variability for nerve anatomic structures. PMID- 28723768 TI - Detection of incidental cardiac findings in noncardiac chest computed tomography. AB - The aim of the study was to estimate the rate of incidental cardiac findings (ICF) in patients undergoing noncardiac chest CT.An experienced radiologist retrospectively reviewed 237 consecutive patients (147 males and 90 females with median age of 69 years) undergoing a noncardiac chest CT. ICF at targeted review were compared to those mentioned in original reports (chi test).At review, >=1 ICF was detected in 124/237 patients (52%), for a total of 229 ICF, 158 of them (69%) not originally mentioned. Valvular calcifications were unmentioned in 23/23 (100%) patients, main pulmonary artery dilation in 21/22 (96%), coronary calcifications in 69/86 (80%), right or left atrial dilation in 7/11 (64%), aortic atherosclerosis in 29/62 (47%), and ascending aorta dilatation in 8/18 (44%). All 6 pericardial effusions were originally mentioned. No association with sex (P >= .189); positive correlation with age (P < .001).Half of patients undergoing noncardiac chest CT presented >=1 ICF, independently from sex but increasing with age. Moreover, 69% of detectable ICFs were not originally mentioned. PMID- 28723769 TI - Overlooked diagnosis of infected paratracheal air cysts in patients with respiratory symptoms: Case report. AB - RATIONALE: Infected paratracheal air cysts as the focus of respiratory symptoms can be overlooked in practice because of nonspecific symptoms and physician's scant knowledge for this entity. We report 2 cases of infected paratracheal air cyst diagnosed at chest computed tomography (CT) and bronchoscopy/endobronchial ultrasound. PATIENT CONCERN: Two patients visited our hospital with respiratory symptoms, including cough, sputum, and fever. DIAGNOSES: Chest CT showed paratracheal cystic lesions with air-fluid level in the thoracic inlet. In the first patient, endobronchial ultrasound revealed a right paratracheal hypoechoic mass corresponding to the lesion on CT scan. In the second patient, bronchoscopy revealed purulent discharge from a dimpling at posterolateral wall of trachea, which was the opening of communication between the trachea and infected paratracheal air cyst. INTERVENTIONS: Both patients received antibiotic treatment. OUTCOME: After medical treatment, the patients' symptoms were improved. Follow-up chest CT scans showed air-filled paratracheal air cysts without internal fluid or rim enhancement. LESSONS: A physician should pay attention to paratracheal air cyst in patients with respiratory symptoms when their lungs are clear on CT scan. PMID- 28723770 TI - Initial application of transanal endoscopic microsurgery for high-risk lower rectal gastrointestinal stromal tumor after imatinib mesylate neoadjuvant chemotherapy: A case report. AB - RATIONALE: The lower rectal gastrointestinal stromal tumor (GIST) is a rare entity and warrants special attentions because of the considerations of preserving of anal and urinal functions. Neoadjuvant therapy with imatinib mesylate (IM) has achieved great success in GIST, which potentially extends the applications of function-preserving minimally invasive surgical procedures. Transanal endoscopic microsurgery (TEM) is a well-developed minimally invasive technique for benign tumors in lower rectum. Herein, we reported the initial application of TEM for high risk GIST after IM treatment. PATIENT CONCERNS: A 52 year-old woman suffered mild lower abdominal pain and perianal discomfort. Physical examination found a soft mass 4 cm far away from anal verge. Rectal MRI and transrectal ultrasound (TRUS) showed that there was a 1.9 * 1.6 cm submucosal mass in the lower rectum. The incisional biopsy was performed and the pathological result reported it was a high-risk GIST. DIAGNOSES: High-risk lower rectal GIST. INTERVENTIONS: IM was given for neoadjuvant therapy. Then TEM was adopted to resect the residual tumor. IM was restored 4 weeks after surgery. OUTCOMES: The final pathological results reported the margin was clear. After an 18-month follow up, no recurrence and metastasis was found and the patient had a satisfactory anal and urinal functions. LESSONS: TEM in combination with IM could be a practical strategy for the high-risk lower rectal GIST simultaneously to achieve curative resection and to preserve the anal and urinal functions that can significantly improve the life quality of the patients. PMID- 28723771 TI - Malignant melanoma misdiagnosed as diabetic foot ulcer: A case report. AB - RATIONALE: Acral lentiginous melanoma (AML) does not exhibit the classic signs of malignant melanoma. ALM is frequently misdiagnosed because of its unusual sites and atypical clinical morphologies, which lead to poor prognosis. PATIENT CONCERNS: A female patient aged 78 years was presented to our center with two ulcers on her right foot. Diabetic foot ulcer was considered as the primary diagnosis. The ulcers failed to improve after 2 weeks' therapy. DIAGNOSES: An incisional biopsy of the lesion revealed malignant melanoma. INTERVENTIONS: The patient received wide excision, skin grafting as well as biotherapy. OUTCOMES: The lesion was healed and no other metastasis has been founded until now. LESSONS: Clinicians must maintain a high level of suspicion in distinguishing malignant melanoma from other more benign skin lesions of the foot. The need for early biopsy of ulcer, even when clinical suspicion is low, can not be overemphasized. Only in this way can we reduce misdiagnosis rate and improve survival rate in patients with foot ulcer. PMID- 28723772 TI - Anatomic investigation of lumbar transforaminal fenestration approach and its clinical application in far lateral disc herniation. AB - Treating lumbar disease at the intervertebal foramina is controversial because we lack an approach providing sufficient exposure and preserving spinal stability. The primary objective of this study was to investigate the feasibility of the transforaminal fenestration (TFF) approach for treating lumbar disease involving the intervertebal foramina.In the anatomic study of 30 adult cadaveric lumbar spine specimens, the TFF approach was used from L1 to S1. The scope of resection was measured manually and on 3D CT images. 3D CT images of the lumbar spine of 31 adult patients were collected, and the scope of resection needed during the TFF approach was defined and measured from L1 to S1. In total, 30 patients (14 men) with lumbar FLDH underwent microendoscopic discectomy (MED) via the TFF approach. The results were evaluated with visual analog scale (VAS), Oswestry Disability Index (ODI), Short Form-36 survey (SF-36), and the MacNab scale.In cadavers, the TFF approach provided sufficient exposure to the posterolateral aspect of the disc and the exiting nerve root at all segments. At L1 to L4, a relatively small part of the isthmus and facet joint was resected; at L4 to S1, a relatively large part of the isthmus and facet joint was resected, so luniform fenestration was needed to preserve a more inferior articular process and continuity of the isthmus. Treatment with MED via the TFF approach was successful in the 30 patients with significantly relieved of symptom after operation. In total, 24 patients were followed for a mean of 24 months. The VAS, ODI, SF-36 physical component, and mental component summary scores at the final follow-up improved significantly compared with preoperative data (P < .05), and excellent results were obtained in 19 patients and good results in 6 according to the Macnab scale.The TFF approach can provide sufficient exposure to the lumbar intervertebal foramina with preservation of stability and can be used effectively with MED to treat lumbar FLDH. PMID- 28723773 TI - Development and validation of risk-stratification delirium prediction model for critically ill patients: A prospective, observational, single-center study. AB - : The objective is to develop a model based on risk stratification to predict delirium among adult critically ill patients and whether early intervention could be provided for high-risk patients, which could reduce the incidence of delirium.We designed a prospective, observational, single-center study. We examined 11 factors, including age, APACHE-II score, coma, emergency operation, mechanical ventilation (MV), multiple trauma, metabolic acidosis, history of hypertension, delirium and dementia, and application of Dexmedetomidine Hydrochloride. Confusion assessment method for the intensive care unit (CAM-ICU) was performed to screen patients during their ICU stay. Multivariate logistic regression analysis was used to develop the model, and we assessed the predictive ability of the model by using the area under the receiver operating characteristics curve (AUROC).From May 17, 2016 to September 25, 2016, 681 consecutive patients were screened, 61 of whom were excluded. The most frequent reason for exclusion was sustained coma 30 (4.4%), followed by a length of stay in the ICU < 24 hours 18 (2.6%) and delirium before ICU admission 13 (1.9%). Among the remaining 620 patients (including 162 nervous system disease patients), 160 patients (25.8%) developed delirium, and 64 (39.5%) had nervous system disease. The mean age was 55 +/- 18 years old, the mean APACHE-II score was 16 +/ 4, and 49.2% of them were male. Spearman analysis of nervous system disease and incidence of delirium showed that the correlation coefficient was 0.186 (P < .01). We constructed a prediction model that included 11 risk factors. The AUROC was 0.78 (95% CI 0.72-0.83).We developed the model using 11 related factors to predict delirium in critically ill patients and further determined that prophylaxis with Dexmedetomidine Hydrochloride in delirious ICU patients was beneficial. Patients who suffer from nervous system disease are at a higher incidence of delirium, and corresponding measures should be used for prevention. TRIAL REGISTRATION: ChiCTR-OOC-16008535. PMID- 28723774 TI - Relationship between first dorsal sacral foramen and lumbar facet joint connecting line in South Korea populations: Retrospective study. AB - The first sacral nerve root block (S1 nerve root block) is a practical procedure for patients with radiating lower back pain. In general, S1 nerve root block is performed under x-ray fluoroscopy. It is necessary to adjust the position of the patient and angle of fluoroscopy to properly visualize the first dorsal sacral foramen (dorsal S1 foramen). The purpose of this study was to analyze the location of dorsal S1 foramen and lumbar facet joint in S1 nerve root block.A total of 388 patients undergoing x-ray fluoroscopy-guided S1 nerve root block in the prone position were examined. X-ray fluoroscopy was fixed at the corresponding location of facet joint of L4-5 and L5-S1. The relationship of the connecting line vertical to L5-S1 facet joint and upper margin sacrum was evaluated. The surface anatomical relationships between dorsal S1 foramen and lumbar facet joint were assessed.Based on the localization of dorsal S1 foramen, the line drawn from point to upper margin sacrum passed through the dorsal S1 foramen in all cases. The horizontal distance from the spinous process to the dorsal S1 foramen was 25.9 +/- 3.0 mm for men and 26.2 +/- 1.4 mm for women. The horizontal distance from the between posterior superioriliac spine to the dorsal S1 foramen was 26.2 +/- 2.7 mm for men and 26.8 +/- 1.7 mm for women. The vertical distance from the upper margin of sacrum to dorsal S1 foramen to the dorsal S1 foramen was 45.6 +/- 6.5 mm for men and 43.8 +/- 6.0 mm for women.The connecting line vertical to L5-S1 facet joint and upper margin sacrum is located on the same line from the dorsal S1 foramen. For difficult cases of locating dorsal S1 foramen, the lumbar facet joint can assist in predicting the vertical location of the dorsal S1 foramen. PMID- 28723775 TI - The neutrophil-to-lymphocyte ratio could be a good diagnostic marker and predictor of relapse in patients with adult-onset Still's disease: A STROBE compliant retrospective observational analysis. AB - The neutrophil-to-lymphocyte ratio (NLR) is the proportion of absolute neutrophil count to lymphocytes on routine complete blood count (CBC) tests, and has been studied as a simple marker of the systemic inflammatory response. This study was performed to investigate whether the NLR could be used as a tool to diagnose and predict prognosis in cases of adult-onset Still's disease (AOSD).We retrospectively reviewed 164 patients with suspected AOSD. Among 164 patients with suspected AOSD, 37 patients received another diagnosis (such as viral infection) and were compared with the 127 patients who received a diagnosis of AOSD. Laboratory tests including CBCs, ferritin, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) level, and the NLR were evaluated.AOSD patients showed higher neutrophil counts, lower lymphocyte counts, higher NLRs, and higher levels of ferritin, ESR, and CRP than non-AOSD patients (all P < .001). In receiver operating characteristic (ROC) curve analysis of the NLR for diagnosis of AOSD, the area under the curve (AUC) was highest at 0.967 (95% CI = 0.940 0.993) with a cutoff value of 3.08. The cutoff value showed the greatest sensitivity (91.7%), specificity (68.4%), and AUC value (0.967) as a diagnostic tool for AOSD. The NLR and treatment appeared to be significant prognostic factors for relapse, but only age showed a significant relationship with death. Furthermore, the NLR was significantly higher in patients with macrophage activation syndrome than in hemophagocytic lymphohistiocytosis (HLH) patients (P = .007). In ROC analysis, the NLR with a cutoff value of 5.86 showed a sensitivity of 89.4%, specificity of 87.8%, and AUC of 0.794.The NLR can be used as a diagnostic tool and predictor of relapse in AOSD, and for differential diagnosis of HLH. PMID- 28723776 TI - A case of idiopathic hypertrophic pachymeningitis presenting with chronic headache and multiple cranial nerve palsies: A case report. AB - RATIONALE: Idiopathic hypertrophic pachymeningitis (IHP) is a rare condition, characterized by a chronic fibrosing inflammatory process usually involving either the intracranial or spinal dura mater, but rarely both. Here, we report a rare case of IHP affecting both the intracranial and spinal dura mater. We also discussed the diagnosis, management, and outcome of IHP. PATIENT CONCERNS: We reviewed the case of a 60-year-old woman presenting with chronic headache, multiple cranial nerve palsies and gait disturbance. Magnetic resonance imaging (MRI) of her head revealed thickened and contrast-enhanced dura in the craniocervical region as well as obstructive hydrocephalus and cerebellar tonsillar herniation. The patient had a suboccipital craniectomy and posterior decompression through C1 plus a total laminectomy. The dura was partially resected to the extent of the bony decompression, and a duroplasty was performed. DIAGNOSES: Microscopic examination of the surgically resected sample showed chronic inflammatory changes, lymphoplasmacytic cell infiltration, fibrous tissue hyperplasia, and hyaline degeneration. Blood tests to evaluate the secondary causes of hypertrophic pachymeningitis (HP) were unremarkable. INTERVENTIONS: Steroid was used to treat suspected IHP. OUTCOMES: Postoperatively, the patient showed gradual improvement in her headache, glossolalia, and bucking. Prior to discharge, a follow-up MRI showed improvement of the dura mater thickening. LESSONS: IHP is a chronic inflammatory disorder of the dura mater that usually causes neurological deficits. Clinical manifestations of IHP, MRI findings, and laboratory abnormalities are the essential components for making an accurate diagnosis. When the radiological or laboratory evaluation is uncertain, but neurological deficits are present, a prompt surgical approach should be considered. Postoperative steroid therapy and close observation for recurrence are necessary to ensure a good long-term outcome. PMID- 28723778 TI - Thoracic splenosis mimicking a pleuropneumonia: A case report. AB - RATIONALE: Splenosis is the development of one or more heterotopic splenic tissue autoimplants following rupture of the spleen and remains mostly asymptomatic. PATIENT CONCERNS: We report a case of a 50-year old post-traumatic splenectomized man admitted for a left side community acquired pneumonia resistant to antibiotics. DIAGNOSES: The diagnosis of intrathoracic ectopic spleen was suspected because of the history of spleen trauma with diaphragm rupture and the absence of Howell-Jolly bodies. INTERVENTIONS: Technetium (Tc)-m colloid scintigraphy SPECT, fused with CT scan showed an intense radionuclide uptake on hyper vascularized masses without any additional pathologic uptake and confirmed the diagnosis of thoracic splenosis. OUTCOMES: Despite any lifelong penicillin prophylaxis, he had no history of infections eight years after the diagnosis. LESSONS: Physician must be aware of this differential diagnosis and of its consequences. Depending on its size and location, it may lead to incorrect diagnosis (tumor, empyema, abscess ...), treatment and invasive procedures while the diagnosis of splenosis only relies upon imaging studies associated with functionnal study of the uptake of particles or cells. PMID- 28723777 TI - Short outcome comparison of elderly patients versus nonelderly patients treated with transjugular intrahepatic portosystemic stent shunt: A propensity score matched cohort study. AB - A transjugular intrahepatic portosystemic stent shunt (TIPSS) has been widely used to treat portal hypertension and its complications. However, no established guidelines mentioned whether age was a risk factor for the treatment of TIPSS.The aim is to determine whether age is a risk factor for poor outcomes following TIPSS.The retrospective cohort study included 134 patients who received TIPSS treatment from 2003 to 2016. The adverse events after the TIPSS treatment were compared after propensity score matching to reduce the effect of selection bias. Multivariate logistic regression was conducted to confirm the potential confounders for rebleeding (RB) and ascites after TIPSS therapy.After excluding 10 patients, 124 patients were analyzed. Among them, 37 patients were included in the elderly group. In the propensity score matched cohort (32 pairs), there was no significant difference between the elderly group and the nonelderly group in terms of the event after TIPSS therapy (All P > .05). Multivariate logistic regression analysis revealed that hypertension (OR 13.246, 95% CI: [1.29, 136.073]; P = .03) was an independent risk factor for RB. In addition, smoking (OR 4.48, 95% CI: [1.43, 14.033]; P = .01) and preascites (OR 6.7, 95% CI: [2.04, 22.005]; P = .002) were independent risk factors for ascites after TIPSS treatment.Age is not an independent risk factor for poor outcomes following the treatment of TIPSS. Smoking and preascites are independent risk factors for patients' ascites, and hypertension is an independent risk factor for patients' RB after TIPSS therapy. PMID- 28723779 TI - Can operations achieve good outcomes in elderly patients with Sanders II-III calcaneal fractures? AB - The aim of this study was to compare the clinical effect of operative treatment and nonoperative treatment for elderly patients with Sanders II-III calcaneal fractures.The study consisted of 60 patients with Sanders II-III calcaneal fractures who were treated in our institution from January 2007 to April 2012. The clinical effect between the operative treatment group of 32 patients and the nonoperative treatment group of 28 patients was studied. Bohler angle, Gissane angle, subtalar joint motion, calcaneal width, and calcaneal height were measured before and after treatment, and these indexes were also measured on the uninjured foot. All patients were followed-up for at least 2 years, and at the last follow up, we evaluated foot function that was assessed with the American Orthopaedic Foot and Ankle Society (AOFAS) ankle-hindfoot score system. A 10-cm visual analog scale (VAS) was used to measure the degree of pain.Bohler angle, Gissane angle, calcaneal width, and calcaneal height, which were preoperatively and postoperatively measured, had a significant difference in the operative group (P < .001), but there was no significant difference between pretreatment and post treatment in the nonoperative group. Subtalar joint motion was measured pre treatment and post-treatment and had a significant difference in the 2 groups. When we compared the values of Bohler angle, Gissane angle, subtalar joint motion, calcaneal width, and calcaneal height between post-treatment and the uninjured foot, there was no significant difference in the operative group, but there was a significant difference in the nonoperative group. The values measured after treatment in the 2 groups had a significant difference. Finally, the AOFAS score in the operative group and the nonoperative group were 83.4 +/- 9.7 and 74.7 +/- 10.3, respectively, and there was a significant difference (P < .001). Also, the 10-cm VAS had a significant difference between the 2 groups.Good clinical result could be obtained with operative treatment in elderly patients with Sanders II-III calcaneal fractures. Open reduction and internal fixation should be performed if there is no surgical contraindication. PMID- 28723781 TI - Assessment of optic disc and ganglion cell layer in diabetes mellitus type 2. AB - The purpose of this study was to compare the optic disc parameters, retinal nerve fiber (RNFL), and macular ganglion cell layers between patients with diabetes mellitus (DM) type 2 and healthy controls.In this cross-sectional study, 69 eyes of 69 diabetic patients without diabetic retinopathy and 47 eyes of 47 healthy controls were included. Optic disc parameters (i.e., rim area, disc area, cup to disc ratio, cup volume), RNFL, and macular ganglion cell-inner plexiform layers (GCL + IPL) thickness were measured by means of spectral domain optical coherence tomography.There were not statistically significant differences between the diabetic patients and healthy controls in terms of RNFL thickness (P = .32), rim area (P = .20), disc area (P = .16), cup volume (P = .12), and average macular GCL + IPL thickness (P = .11). Nevertheless, binocular RNFL thickness symmetry percentage (P =.03), average cup to disc ratio (P = .02), and superior-nasal macular GCL + IPL thickness (P = .04) were statistically significantly different in the diabetic and control groups.Diabetic patients without retinopathy have more binocular RNFL thickness asymmetry, higher cup to disc ratio, and thinner sectoral macular GCL + IPL when compared to healthy controls. Our results may support the statement that DM causes inner retinal neurodegenerative changes. PMID- 28723780 TI - The relationship between ITPA rs1127354 polymorphisms and efficacy of antiviral treatment in Northeast Chinese CHC patients. AB - This prospective study investigated the relationship between 2 inosine triphosphatase (ITPA) polymorphisms (rs7270101 and rs1127354) and the efficacy of ribavirin-based antiviral therapy in hepatitis C virus (HCV)-infected Chinese patients.A total of 906 patients diagnosed with chronic hepatitis C receiving pegylated interferon (PEG-IFN) plus ribavirin combination therapy between January 2011 and January 2014 from 5 hepatitis centers in Northeast China were enrolled. The patients were divided into genotype 1 and non-genotype 1 groups according to the genotype of infected HCV. ITPA single nucleotide polymorphism (SNP) genotyping was performed for all patients. Ribavirin-induced hemolytic anemia and virological response (VR) were monitored during treatment and follow-up. Multivariate regression analysis was used to analyze the predictors for sustained virological response (SVR).IPTA rs7270101 variants were not detected. IPTA rs1127354 variants were detected and showed no difference between the genotype 1 and non-genotype 1 groups. IPTA rs1127354 genotype CC was related to a higher incidence of ribavirin-induced hemolytic anemia. For patients who received >80% of the planned ribavirin dose, rs1127354 variants and related ITPase were related to better SVR. Multivariate analysis showed that IPTA rs1127354 non-genotype CC, HCV genotype, a baseline HCV RNA level <4 * 10 IU/mL, IL-28B rs12979860 genotype CC, and low liver fibrosis were independent predictors for SVR during the combination therapy.IPTA rs1127354 variants and related ITPase were not only related with ribavirin-induced hemolytic anemia but also directly affected the SVR to PEG-IFN plus ribavirin combination therapy in Chinese HCV-infected patients. PMID- 28723782 TI - Endovascular balloon angioplasty versus stenting in patients with Takayasu arteritis: A meta-analysis. AB - BACKGROUND: Symptomatic or significant vascular lesions of Takayasu arteritis (TA) need interventions. Although percutaneous transluminal angioplasty with balloon is a less invasive and safe method, stent implantation in TA can be an alternative option. However, superiority between balloon angioplasty and stenting in TA is not conclusive. METHODS: A meta-analysis comparing balloon angioplasty and stenting outcomes was performed using the MEDLINE and EMBASE databases. RESULTS: A total of 7 studies on 266 patients and 316 lesions were included. Balloon angioplasty was performed in 186 lesions and stenting in 130 lesions. There were no significant differences in the incidence of both restenosis and other complications between balloon angioplasty and stenting [odds ratio (OR) = 2.39, 95% confidence interval (CI) = 0.66-8.66, P = .18; OR = 1.80, 95% CI = 0.49 6.65, P = .38, respectively]. In the renal arteries, the risk of restenosis in stenting was significantly higher than that in balloon angioplasty (OR = 4.40, 95% CI = 2.14-9.02, P < .001). The clinical efficacy of improving renal hypertension between balloon angioplasty and stenting at the renal artery lesions was similar (OR = 0.65, 95% CI = 0.28-1.51, P = .31); however, acute vascular complications were significantly fewer in stenting than in balloon angioplasty (OR = 0.07, 95% CI = 0.02-0.29, P < .001). CONCLUSION: This meta-analysis found that balloon angioplasty can yield better results in renal artery interventions than stenting. Nonetheless, it is desirable to avoid vessel dissections during balloon angioplasty, which can eventually require stent implantations. PMID- 28723783 TI - Novel surgical management of cyclodialysis cleft via anterior chamber perfusion: Case report. AB - RATIONALE: Cyclodialysis cleft is a relatively rare but severe condition with persistent ocular hypotony, which can cause morphologic changes and visual loss. Here we report a case of a traumatic cyclodialysis cleft that was successfully managed with direct cyclopexy via anterior chamber perfusion. During the operation, if there is aqueous humor flowing out of the deep scleral incision, the cleft is not closed, and surgery should continue until there is no aqueous outflow. PATIENT CONCERNS: A 66-year-old man was treated for severe blunt ocular trauma of the left eye and a resultant cyclodialysis cleft, lens subluxation, choroidal detachment and a cataract. His intraocular pressure was 6 mm Hg, he presented with a shallow anterior chamber, phacodonesis, iridodonesis, 360 degrees ciliary body detachment, and a suspicious cyclodialysis cleft in the 5 to 8 o'clock position. DIAGNOSES:: ocular blunt trauma (left eye), cyclodialysis cleft (left eye), lens subluxation (left eye), choroidal detachment (left eye), cataract (both eyes). INTERVENTIONS: The cataract was extracted by phacoemulsification and a posterior chamber intraocular lens was implanted with 2 capsular tension rings, one in the lens bag and the other in the ciliary sulcus. Throughout the following month, intraocular pressure fluctuated between 4 and 6 mm Hg and the ciliary body failed to reattach. A cyclopexy via anterior chamber perfusion was thus deemed necessary and performed. OUTCOMES: After cyclopexy, intraocular pressure increased to 27 mm Hg and decreased to 16 mm Hg after brinzolamide eye drops treatment twice daily for 4 days. Subsequently intraocular pressure stabilized between 10 to 21mm Hg. Complete closure of the cyclodialysis cleft was confirmed with ultrasound biomicroscopy. LESSONS: Cyclopexy via anterior chamber perfusion for patients with cyclodialysis cleft is a simple, safe, and efficient technique that ensures a successful surgery. PMID- 28723784 TI - Thrombocytopenia in pregnancy with different diagnoses: Differential clinical features, treatments, and outcomes. AB - To investigate the clinical features and perinatal treatment of thrombocytopenia induced by different causes during pregnancy.Clinical data from 195 pregnant women with thrombocytopenia attending 2 tertiary hospitals from January 2014 to October 2016 were retrospectively studied. The obtained data were analyzed with SPSS 19.0 software.There were 117 (60.0%), 55 (28.2%), and 23 cases (11.8%) of pregnancy-associated thrombocytopenia (PAT), idiopathic thrombocytopenia (ITP), and hypertensive disorder in pregnancy (PIH), respectively. The percentage of nulliparous women, gestational age at delivery, date of diagnosis of thrombocytopenia, and delivery mode significantly differed between the patients in these 3 groups (P < .05). Patients with PIH had a higher percentage of premature delivery and of lower birth weight infants than patients in the other 2 groups. The 3 groups had similar incidences of postpartum hemorrhage, rates of stillbirth, and neonatal Apgar scores at 5 minutes. PAT and PIH patients had different platelet counts after delivery compared with at diagnosis, whereas the platelet counts of the ITP patients were similar at diagnosis and after delivery. ITP patients in the nontreatment group and the treatment group had significantly different platelet counts (P < .05), and in the treatment group, the maternal platelet count did not differ for treatment with intravenous immunoglobulin (IVIg) versus corticosteroids.The causes of thrombocytopenia in pregnancy are diverse, and the clinical features vary widely. Timely analysis is needed to determine the primary cause of thrombocytopenia, and appropriate therapy should then be selected to effectively improve the prognosis of pregnancies. PMID- 28723785 TI - Asymptomatic congenital tuberculosis: A case report. AB - RATIONALE: Congenital tuberculosis (TB) is described as a rare, but severe disease. In contrast to the cases with severe symptoms reported so far, we describe a child with asymptomatic congenital TB. PATIENT CONCERNS: An 8-week-old girl was investigated because of newly diagnosed TB in her mother, which complained about cough since 21 weeks gestation. Lung biopsy tissue specimens of the mother revealed necrotizing granuloma with a single acid-fast bacillus (AFB) and Mycobacterium tuberculosis (MTB) was detected by polymerase chain reaction. Bronchoalveolar lavage was negative for AFB smear and culture, arguing against postnatal transmission of MTB. TB contact investigations were negative. The child, at the age of 8 weeks at first assessment, was in an excellent general condition and diagnosed with congenital TB by culture-positive lung TB and exclusion of postnatal transmission. DIAGNOSES: The child fulfilled Cantwell criteria to diagnose congenital TB. INTERVENTIONS: Ambulatory anti-tuberculosis treatment was initiated for 6 months. OUTCOMES: The 18 months follow-up was uneventful. LESSONS: This case of asymptomatic congenital TB in a young child illustrates the diagnostic difficulties in congenital TB and raises the question whether congenital TB is underestimated. PMID- 28723786 TI - Risk factors of lymph node metastasis in lung squamous cell carcinoma of 3 cm or less in diameter. AB - Through literature review we cannot find an efficient risk factor of lymph node metastasis in lung squamous cell carcinoma (SCC). This study aimed to investigate the risk factors of pathological lymph node status in patients with lung SCC of 3 cm or less in diameter, to provide some reference for the fellow surgeons in the decision of operative option.In total, we analyzed 154 patients with lung SCC of 3 cm or less in diameter who underwent lobectomy or bilobectomy or pneumonectomy with systematic lymph node dissection. The relationship between lymph node status and clinical characteristics were examined.Lymph node metastases were present in 48 patients (31.2%) of the study subjects. Multivariate analysis indicated that, age <60 years old (P = .007), tumor location of central-type (P = .003), tumor long axis >2 cm but <=3 cm (P = .047) were associated with lymph node metastasis, and their odd ratios (OR) were 3.120, 3.359, and 5.196, respectively. Group analysis of the 74 peripheral lung SCC showed that those with the tumor long axis <=2 cm had a lower rate of lymph node metastasis (7.9% vs 27.8%, P = .025).Age <60 years old, tumor location of central-type, and tumor long axis >2 cm but <=3 cm are risk factors of lymph node metastasis in lung SCC. Systematic lymph node dissection or sampling is recommended when tumor central-type location and/or long axis >2 cm in lung SCC are present. PMID- 28723787 TI - Late emergence of macular sparing in a stroke patient: Clinical Case Report. AB - RATIONALE: Occlusive cerebrovascular disease is the most common cause of homonymous hemianopia (HH) with macular sparing. PATIENT CONCERNS: A 61-year-old man came to our ophthalmology clinic complaining of right-side hemianopia. Ophthalmic examination, visual field (VF) examination, and brain magnetic resonance imaging (MRI) were performed. DIAGNOSES: He had right HH without macular sparing on the initial VF test. And brain MRI 6 days after the visual symptoms began revealed a left occipital infarction. INTERVENTIONS AND OUTCOMES: Thirty-seven days after the onset, his follow-up 24-2 VF examination showed HH with bilateral macular sparing, which was not apparent in the initial VF examination. About 4 months after the stroke, his central 10-2 VF examination also showed HH with bilateral macular sparing. LESSONS: We report a case of HH with a dramatic improvement in central vision several days after an occipital infarction. To our knowledge, this is the first case to show macular sparing developing after several days. PMID- 28723788 TI - Protective effect of the microcatheter placed at the normal vertebral artery in intracranial stent-assisted angioplasty for vertebral artery stenosis: A case report. AB - RATIONALE: A carefully designed intracranial stent-assisted angioplasty (SAA) is presented here that may prevent subsequent branch artery occlusion. PATIENT CONCERNS: A 72-year-old man with a 3-month history of progressive and intermittent vertigo without any obvious trigger, accompanied by nausea. DIAGNOSES: Intracranial atherosclerotic disease. INTERVENTIONS: the patient underwent intracranial SAA in accordance with the procedure described here. OUTCOMES: The patient's paroxysmal vertigo completely subsided, with no complications during the short-term follow-up. LESSONS: This novel intracranial SAA procedure is safe and may reduce the risk of subsequent artery occlusion. PMID- 28723789 TI - Measuring the impact of emergency medical services (EMS) on out-of-hospital cardiac arrest survival in a developing country: A key metric for EMS systems' performance. AB - Out-of-hospital cardiac arrest (OHCA) can be used to evaluate the overall performance of the emergency medical services' (EMS) system. This study assessed the impact of EMS on OHCA survival rates in a setting where the prehospital system is underdeveloped.A retrospective chart review was carried out over a 5 year period of all adult OHCA patients admitted to the emergency department (ED) of a tertiary care center in Lebanon.A total of 271 patients with OHCA (179 [66.1%] men, mean age of 69.9 [standard deviation = 15.0 years] were enrolled. The most common OHCA location was residence/home (58.7%). The majority of arrests were witnessed (51.7%) with 6.1% witnessed by EMS; 211 patients (75.6%) were transported to the ED by EMS. Prehospital cardiopulmonary resuscitation (CPR) was done by EMS for 43.2% of the patients, whereas only 4.4% received CPR from a family member/bystander. Prehospital automated external defibrillator use was documented in 1.5% of cases in the prehospital setting. Only 2 patients had return of spontaneous circulation prior to ED arrival. Most patients (96.7%) were resuscitated in the ED. Patients presented to the ED mostly in asystole (79.3%). Forty-three patients (15.9%) survived to hospital admission and 13 (4.8%) were discharged alive with over half of them (53.8%) had a good neurological outcome upon discharge (cerebral performance category 1 or 2).Survival of EMS-treated OHCA victims in Lebanon is not as expected. Medical oversight of EMS activities is needed to link EMS activities to clinical outcomes and improve survival from cardiac arrest in Lebanon. PMID- 28723790 TI - Relationship of medial gastrocnemius relative fascicle excursion and ankle joint power and work performance during gait in typically developing children: A cross sectional study. AB - Muscle fascicles lengthen in response to chronic passive stretch through in series sarcomere addition in order to maintain an optimum sarcomere length. In turn, the muscles' force generating capacity, maximum excursion, and contraction velocity is enhanced. Thus, longer fascicles suggest a greater capacity to develop joint power and work. However, static fascicle length measurements may not be taking sarcomere length differences into account. Thus, we considered relative fascicle excursions through passive ankle dorsiflexion may better correlate with the capacity to generate joint power and work than fascicle length. Therefore, the aim of the present study was to determine if medial gastrocnemius relative fascicle excursions correlate with ankle joint power and work generation during gait in typically developing children. A sample of typically developing children (n = 10) were recruited for this study and data analysis was carried out on 20 legs. Medial gastrocnemius relative fascicle excursion from resting joint angle to maximum dorsiflexion was estimated from trigonometric relations of medial gastrocnemius pennation angle and thickness obtained from B-mode real-time ultrasonography. Furthermore, a three-dimensional motion capture system was used to obtain ankle joint work and power during the stance phase of gait. Significant correlations were found between relative fascicle excursion and peak power absorption (-) r(14) = -0.61, P = .012 accounting for 31% variability, positive work r(18) = 0.56, P = .021 accounting for 31% variability, and late stance positive work r(15) = 0.51, P = .037 accounting for 26% variability. The large unexplained variance may be attributed to mechanics of neighboring structures (e.g., soleus or Achilles tendon mechanics) and proximal joint kinetics which may also contribute to ankle joint power and work performance, and were not taken into account. Further studies are encouraged to provide greater insight on the relationship between relative fascicle excursions and joint function. PMID- 28723791 TI - Arthritis secondary to meningococcal disease: A case series of 7 patients. AB - Arthritis secondary to invasive meningococcemia is rare and has been described as a direct result of bacteremia or as immunoallergic-type arthritis, related to the immune complex. Only a few case series have been reported.This multicenter study aimed to describe the clinical characteristics and therapeutic outcomes of arthritis secondary to meningococcal infection.We performed a 5-year retrospective study. We included all patients with inflammatory joint symptoms and proven meningococcal disease defined by the identification of Neisseria meningitidis in blood, cerebrospinal fluid, or synovial fluid. Septic arthritis was defined by the identification of N meningitidis in joint fluid. Immune mediated arthritis was considered to be arthritis occurring after at least 1 day of invasive meningococcal disease without positive joint fluid culture.A total of 7 patients (5 males) with joint symptoms and meningococcal disease were identified. The clinical presentation was mainly oligoarticular and the knee was the most frequent joint site. Five patients had septic arthritis and 4 had immune mediated arthritis; 2 had septic arthritis followed by immune-mediated arthritis. Immune-mediated arthritis occurred 3 to 7 days after meningococcal meningitis, and treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) led to improvement without complications.Physicians must be vigilant to the different clinical presentations in patients with arthritis associated with invasive meningococcal disease. If immune-mediated arthritis is suspected, NSAIDs are usually efficient. PMID- 28723792 TI - Concomitant stromal tumor and early cancer of the stomach: What should be done? AB - Concomitant gastric stromal tumor (GST) and gastric cancer (GC) is uncommon; even more uncommon is a concomitant GST and early stage GC (EGC). Tumor resection by endoscopic submucosal dissection (ESD) for concomitant GST and EGC has not been reported. We sought to define the clinical importance of detection of concomitant GST and EGC during the first esophagogastroduodenoscopy (EGD), and compare the clinical outcomes of ESD versus radical surgery for the treatment of concomitant GST and EGC. Our investigation was a retrospective cohort study. Patients with concomitant GST and EGC who underwent ESD or radical surgery were enrolled at the university-affiliated hospital from January 2005 to January 2015. The detection rate of concomitant GST and EGC during the first EGD was 3/25 (12%). Among 25 patients, 14 underwent ESD and 11 underwent surgery. Mean operation time and hospital stay were significantly shorter in the ESD group than the surgery group. There were no significant differences in terms of rates of en bloc resection, complete resection, and early complications. Late complications were more common in the surgery group than in the ESD group. The median follow-up duration was 58.9 months. Three- or 5-year overall survival rates were 100% for both groups and no patient died of EGC and GST. There was no local recurrence in the 2 groups; however, 3 metachronous EGC lesions were found during the follow-up period in the ESD group as follows: the simultaneous occurrence of GST and EGC was uncommon; the detection rate of concomitant GST and EGC was very low at the first EGD; and ESD appeared to be a safe, efficient, and popular treatment option for concomitant GST and EGC, that met the ESD absolute indication, and the outcomes were comparable to those achieved with surgery. PMID- 28723793 TI - Prognostic value of neutrophil-to-lymphocyte ratio for nasopharyngeal carcinoma: A meta-analysis. AB - BACKGROUND: The prognostic value of the neutrophil-to-lymphocyte ratio (NLR) for nasopharyngeal carcinoma (NPC) remains controversial. This study was designed to provide a more accurate assessment of the prognostic value, based on a meta analysis. METHODS: A comprehensive search for relevant studies published before June 2016 was performed using the PubMed, Cochrane Library, and Web of Science databases. The correlations of NLR with overall survival (OS) and progression free survival (PFS) were evaluated for NPC. Hazard ratios (HRs) and associated 95% confidence intervals (CIs) were calculated to estimate the effects. RESULTS: Six studies with a total of 4359 NPC patients were included in this meta analysis. The pooled results showed that, among patients with NPC, elevated pretreatment NLR was associated with poorer OS (HR = 1.74, 95% CI = 1.45-2.10) and PFS (HR = 1.48, 95% CI = 1.30-1.69). Subgroup analyses indicated that the use of different cut-off values for NLR (<3 or >=3) did not affect the consistent prognostic value of NLR for OS or PFS. No significant heterogeneity or publication bias was observed among the included studies for OS or PFS (P > .05). CONCLUSIONS: This meta-analysis indicates that elevated pretreatment NLR might be a valuable predicative biomarker of poor prognosis for patients with NPC. PMID- 28723794 TI - Thrombosis and antiphospholipid antibody syndrome during acute Q fever: A cross sectional study. AB - Q fever is a neglected and potentially fatal disease. During acute Q fever, antiphospholipid antibodies are very prevalent and have been associated with fever, thrombocytopenia, acquired heart valve disease, and progression to chronic endocarditis. However, thrombosis, the main clinical criterion of the 2006 updated classification of the antiphospholipid syndrome, has not been assessed in this context. To test whether thrombosis is associated with antiphospholipid antibodies and whether the criteria for antiphospholipid syndrome can be met in patients with acute Q fever, we conducted a cross-sectional study at the French National Referral Center for Q fever.Patients included were diagnosed with acute Q fever in our Center between January 2007 and December 2015. Each patient's history and clinical characteristics were recorded with a standardized questionnaire. Predictive factors associated with thrombosis were assessed using a rare events logistic regression model. IgG anticardiolipin antibodies (IgG aCL) assessed by an enzyme-linked immunosorbent assay were tested on the Q fever diagnostic serum. A dose-dependent relationship between IgG aCL levels and thrombosis was tested using a receiver operating characteristic (ROC) analysis.Of the 664 patients identified for inclusion in the study, 313 (47.1%) had positive IgG aCL and 13 (1.9%) were diagnosed with thrombosis. Three patients fulfilled the antiphospholipid syndrome criteria. After multiple adjustments, only positive IgG aCL (relative risk, 14.46 [1.85-113.14], P = .011) were independently associated with thrombosis. ROC analysis identified a dose-dependent relationship between IgG aCL levels and occurrence of thrombosis (area under curve, 0.83, 95%CI [0.73-0.93], P < .001).During acute Q fever, antiphospholipid antibodies are associated with thrombosis, thrombocytopenia, and acquired valvular heart disease. Antiphospholipid antibodies should be systematically assessed in acute Q fever patients. Hydroxychloroquine, which has been previously shown to antagonize IgG aCL pathogenic properties, should be tested in acute Q fever patients with anticardiolipin antibodies to prevent antiphospholipid-associated complications.Key Point: In addition to fever, thrombocytopenia and acquired valvular heart disease, antiphospholipid antibodies are associated with thrombosis during acute Q fever. PMID- 28723795 TI - Comparison of postoperative pain between laparoscopic and robot-assisted partial nephrectomies for renal tumors: A propensity score matching analysis. AB - Robot-assisted partial nephrectomy (RAPN) has emerged as an alternative to laparoscopic partial nephrectomy (LPN) for removal of renal tumors. Several advantages of robotic surgery have been reported, but there is no comparative study on postoperative pain between the 2 techniques. Therefore, we compared the postoperative numerical rating scale (NRS) of pain intensity between patients who underwent LPN and those who underwent RAPN.We included 705 patients who underwent either LPN (n = 200) or RAPN (n = 505) for renal tumors between January 2000 and September 2016. After 1:1 propensity score matching, the final analysis included 142 patients each in the LPN and RAPN groups. The primary endpoint was postoperative NRS of pain intensity. The secondary endpoints were opioid requirement, opioid-related complications, and duration of hospital stay.Preoperative and intraoperative values of propensity score matched patients (n = 284) were not significantly different between the LPN and RAPN groups. There was no significant difference in NRS of pain intensity between the 2 groups. Opioid requirement was different between the 2 groups on postoperative day (POD) 0 (12.4 vs 11.3 mg of morphine-equivalent dose), but not from POD 1 to POD 4. The incidence of opioid-related complications and duration of hospital stay were not significantly different between the 2 groups.Postoperative pain was not significantly different between patients who underwent RAPN and those who underwent LPN. This result provides a potentially useful knowledge of postoperative pain characteristics in RAPN and LPN. PMID- 28723796 TI - Moist exposed burn ointment for treating pressure ulcers: A multicenter randomized controlled trial. AB - BACKGROUND: Pressure ulcers often seriously affect the quality of life of patients. Moist Exposed Burn Ointment (MEBO) has been developed to treat patients with pressure ulcers. The present study aimed to evaluate the efficacy and safety of MEBO in the treatment of pressure ulcers in Chinese patients. METHODS: Seventy two patients with pressure ulcers were randomly assigned to 2 groups who received a placebo or MEBO for 2 months. The primary outcomes included the wound surface area (WSA) and pressure ulcer scale for healing (PUSH) tool. The secondary outcomes included a visual analog scale (VAS), questionnaire of ulcer status, and adverse effects. RESULTS: Sixty-seven patients completed the study. After 2 months of treatment, the difference of mean change from the baseline was greater for MEBO (vs placebo) for WSA mean (SD) -6.0 (-8.8, -3.3), PUSH Tool -2.6 (-4.7, 1.5), and VAS score -2.9 (-4.4, -1.7). On the basis of the questionnaire, the pressure ulcers were "completely healed" (50.0% vs 16.7%) (P < .05) in patients after 2 months of treatment with MEBO versus placebo. No major adverse effects were found in the 2 groups. CONCLUSION: We showed that MEBO is effective and well tolerated for improving wound healing in Chinese patients with pressure ulcers. PMID- 28723797 TI - Correlation between elevated platelet count and immunoglobulin levels in the early convalescent stage of Kawasaki disease. AB - Kawasaki disease (KD) may be an acute systemic immune-mediated disease which occurs after infection of unknown KD pathogen(s). The aim of this study is to evaluate the changes in platelet count and immunoglobulin (Ig) levels (IgG, IgM, IgA, and IgE) during hospitalization.Forty-three patients with complete KD who received intravenous Ig at 2 g/kg were enrolled in South Korea. The platelet count and Ig levels of the patients were examined twice at presentation and around discharge (mean 6.2 +/- 2.4 days apart) and the relationships between platelet level and Ig levels were evaluated.The mean patient age was 31 +/- 18 months; 28 patients were male and 15 were female. The values of all parameters measured, with the exception of IgE, were significantly increased at the second examination compared with their values at presentation. These values gradually increased over time after fever onset, over periods ranging from 2 to 16 days. The extent by which platelet levels increased over these 2 time points was correlated with the extents by which IgG (P < .01), IgM (P < .01), and IgA levels (P = .01) increased.Both the platelet count and the Ig (IgG, IgM, and IgA) levels increased with a correlation each other during the early convalescent stage of KD. This finding suggests that all Ig subtypes except IgE and platelets may be involved in the recovery from KD and that the extent of increased parameters may reflect the degree of systemic inflammation in acute KD. PMID- 28723799 TI - Transarterial chemoembolization combined with Huaier granule for the treatment of primary hepatic carcinoma: Safety and efficacy. AB - To evaluate the safety and efficacy of transarterial arterial chemoembolization (TACE) with gelatin sponge particles (GSPs-TACE) and Huaier granule to treat primary hepatic carcinoma (PHC).A series of 62 patients with PHC were included between June 2009 and December 2011, and randomly assigned to a control (n = 31) or an experimental group (n = 31). The control patients received TACE with 350 to 560 MUm GSPs plus lobaplatin chemotherapy. Patients in the experimental group received TACE plus Huaier granule. Treatment safety and mid-to-long-term efficacy were evaluated.Follow-up ranged from 12 to 24 months with a mean of 28.7 months. The 6- and 12-month overall survivals were 100% and 93.5% in the experimental group and 90.3% and 80.6% in control group, respectively. The difference in overall survival at 12 months was significant (chi = 5.213, P < .05), but the difference in median survival in the experimental group (20.6 months) and control group (17.1 months) patients was not significant (chi = 0.745, P > .05). The number of TACE procedures in the experimental group (2.9 +/- 8.7) and control group (4.1 +/- 7.3) patients was significantly different (chi = 7.262, P < .05). The 6-month (87.1% vs. 73.3%, chi = 5.945) and 12-month (72.4% vs. 64.3%, chi = 6.384) tumor objective response rates in the experimental and control groups were significantly different (P < .05). There were no statistically significant differences in the occurrence of treatment-related adverse reactions in the 2 groups.Transarterial chemoembolization with GSPs and Huaier granule was safe and effective for treating PHC patients. PMID- 28723798 TI - The safety and effectiveness of robot-assisted versus laparoscopic TME in patients with rectal cancer: A meta-analysis and systematic review. AB - BACKGROUND: The aim of this study was to assess the safety and effectiveness of robotic-assisted versus laparoscopic total mesorectal excision (TME) in patients with rectal cancer. METHODS: We systematically searched PubMed, EMBASE, Cochrane library, Web of science, and Chinese Biomedical Literature Database up to July 2016 to identify case-controlled studies that compared robotic TME (RTME) with laparoscopic TME (LTME) for rectal cancer. GRADE was used to interpret the primary outcomes of this meta-analysis. RESULTS: We included 17 case-control studies (3601 participants: 1726 underwent RTME and 1875 LTME for rectal cancer) that compared RTME with LTME for rectal cancer. We found no statistically significant differences between techniques for local recurrence [odds ratio (OR) = 0.68, P = .216] and overall survival at 3 years (OR = 0.71, P = 1.140), complications (OR = 1.02, P = .883), positive circumferential resection margin (PCRM) (OR = 0.80, P = .256), the first passing flatus [weighted mean difference (WMD) = -0.11, P = .130], reoperation (OR = 0.66, P = .080), estimated blood loss (EBL) (WMD = -12.45, P = .500), and length of stay in hospital (LOS) (WMD = 0.69, P = .089). Compared with LTME, RTME was associated with lower rate of conversion (OR = 0.35, P < .001), urinary retention (OR = 0.41, P = .025), and longer operative time (WMD = 57.43, P < .001). The overall quality of evidence was poor in all outcomes. CONCLUSION: RTME in patients with rectal cancer was associated with a lower rate of conversion and less incidence of urinary retention. Generally, operative time in RTME was significantly longer than in LTME. The long-term oncological and function outcomes of RTME seem to be equivalent with LTME. Therefore, analysis of current studies to date did not indicate a major benefit of RTME over LTME. PMID- 28723800 TI - Effects of somatostatin/octreotide treatment in neonates with congenital chylothorax. AB - The influence of somatostatin/octreotide treatment on outcomes of neonates with congenital chylothorax remains controversial. We retrospectively reviewed our experience with somatostatin/octreotide therapy in neonates with this very rare disease.Fourteen neonates with congenital chylothorax who were treated with somatostatin (3.5-7 MUg/kg/h, before 2016) or octreotide (1-6 MUg/kg/h, after January 2016), along with traditional management between 2013 and 2016, were retrospectively reviewed in this observational study. Their daily volumes of pleural drainage and parameters of respiratory support were recorded, and the potential side effects of somatostatin/octreotide were screened.Four patients (28.6%) had a unilateral presentation of pleural effusion, whereas 10 patients (71.4%) had a bilateral presentation. Twelve patients (85.7%) survived until discharge without later recurrence or death, whereas 2 patients (14.3%) died within the first 3 days after birth. Somatostatin/octreotide treatment was maintained for a median period of 6 days (range 1-16 days). The chest tube was removed after a median duration of 14 days (range 2-51 days), and no patient needed pleurodesis or thoracic duct ligation surgery. The average daily drain output within 3 days post-treatment (median 62 mL, range 10-651 mL) was significantly lower than that before treatment (median 133 mL, range 70-620 mL) (P = .002). The need for ventilation support was reduced in most patients (85.7%) after the initiation of somatostatin/octreotide therapy. No serious side effects were identified.Somatostatin/octreotide treatment reduced pleural drainage and respiratory support without significant side effects. Further randomized controlled studies with more patients are necessary to ascertain the benefits of somatostatin/octreotide in neonates with congenital chylothorax. PMID- 28723801 TI - Multidisciplinary approach and long-term follow-up in a series of 640 consecutive patients with sarcoidosis: Cohort study of a 40-year clinical experience at a tertiary referral center in Barcelona, Spain. AB - Cohort studies of large series of patients with sarcoidosis over a long period of time are scarce. The aim of this study is to report a 40-year clinical experience of a large series of patients at Bellvitge University Hospital, a tertiary university hospital in Barcelona, Spain. Diagnosis of sarcoidosis required histological confirmation except in certain specific situations. All patients underwent a prospective study protocol. Clinical assessment and follow-up of patients were performed by a multidisciplinary team.From 1976 to 2015, 640 patients were diagnosed with sarcoidosis, 438 of them (68.4%) were female (sex ratio F/M 2:1). The mean age at diagnosis was 43.3 +/- 13.8 years (range, 14-86 years), and 613 patients (95.8%) were Caucasian. At diagnosis, 584 patients (91.2%) showed intrathoracic involvement at chest radiograph, and most of the patients had normal pulmonary function. Erythema nodosum (39.8%) and specific cutaneous lesions (20.8%) were the most frequent extrapulmonary manifestations, but there was a wide range of organ involvement. A total of 492 patients (76.8%) had positive histology. Follow-up was carried out in 587 patients (91.7%), over a mean of 112.4 +/- 98.3 months (range, 6.4-475 months). Corticosteroid treatment was administered in 255 patients (43.4%), and steroid-sparing agents in 49 patients (7.7%). Outcomes were as follows: 111 patients (18.9%) showed active disease at the time of closing this study, 250 (42.6%) presented spontaneous remission, 61 (10.4%) had remission under treatment, and 165 (28.1%) evolved to chronic sarcoidosis; among them, 115 (19.6%) with mild disease and 50 (8.5%) with moderate to severe organ damage. A multivariate analysis showed that at diagnosis, age more than 40 years, the presence of pulmonary involvement on chest radiograph, splenic involvement, and the need of treatment, was associated with chronic sarcoidosis, whereas Lofgren syndrome and mediastinal lymphadenopathy on chest radiograph were indicators of good outcome.Sarcoidosis is a multisystem disease with protean clinical-radiographic manifestations. Although almost half of patients follow a spontaneous resolution or under treatment, a significant number of them may have several degrees of organ damage. This study emphasizes the value of a multidisciplinary approach and long-term follow-up by specialized teams in sarcoidosis. PMID- 28723802 TI - Tocilizumab for uncontrollable systemic inflammatory response syndrome complicating adult-onset Still disease: Case report and review of literature. AB - RATIONALE: Adult-onset Still disease (AOSD) is a rare systemic inflammatory disease of unknown etiology characterized by evanescent salmon-pink rash, fever spikes, arthralgia, and lymphadenopathy. AOSD usually has a good prognosis, but it can sometimes be fatal, especially when it is complicated by systemic inflammatory response syndrome (SIRS) and multiple organ failure. PATIENT CONCERNS: A previously healthy 26-year-old woman was referred to our hospital for persistent high fever and mild systemic edema. Five days later, the patient presented with dyspnea, hypotension, and anuria. Anasarca developed with massive pleural effusion, ascites, and systemic edema, resulting in an increase of 47 kg in body weight. DIAGNOSES: The patient was diagnosed as AOSD after infection, malignancy, hematologic disorders, and other autoimmune diseases were excluded. INTERVENTIONS: We administered tocilizumab, an IL-6 receptor inhibitor, intravenously in addition to cyclosporine, prednisolone, plasma exchange, and continuous hemodiafiltration. OUTCOMES: The patient's systemic condition improved. After stabilization by all medications, the patient was managed and responded to tocilizumab alone. To the best of our knowledge, this was the first case of severe SIRS complicating AOSD that was successfully treated with an anti- IL-6 receptor antibody. LESSONS: SIRS should not be overlooked in a patient with steroid-resistant AOSD and edema. Inhibitors of the IL-6 receptor can be used safely and effectively to control AOSD complicated with severe SIRS. PMID- 28723803 TI - Leukoencephalopathy with calcifications and cysts: A case report. AB - RATIONALE: Leukoencephalopathy with calcifications and cysts (LCC) is an uncommon entity characterized by edematous leukoencephalopathy, cerebral calcifications, and parenchymal cysts. Due to its rarity, the clinical, radiological, and histopathological features have yet to be well elucidated. PATIENT CONCERNS: The first case is a 35-year-old female who was asymptomatic. A giant intracranial cyst was incidentally detected radiologically, and it was slowly growing in the recent 10 years. The second case is a 20-year-old female who presented with a 1 month history of headache. Brain computed tomography showed multiple asymmetric calcifications in the bilateral basal ganglia and white matter. Magnetic resonance imaging revealed a cyst in the right parietal lobe. DIAGNOSES: They were diagnosed with LCC. INTERVENTIONS AND OUTCOMES: The first patient underwent surgical resection of the intracranial cyst, and the second patient received a stereotactic biopsy. The patients performed well postoperatively. LESSONS: LCC can be found at any age. A young age seems to be associated with severer symptoms. The clinical manifestations can be variable and aggressive. The potential pathogenic basis still needs further research. PMID- 28723804 TI - Microvessel density as a prognostic factor in esophageal squamous cell cancer patients: A meta-analysis. AB - BACKGROUND: To date, literature has emerged that shows contradictory results about the prognostic role of microvessel density (MVD) in esophageal squamous cell cancer (ESCC). The aim of the study set out to evaluate the correlation between MVD and the prognosis of ESCC. METHODS: Identified publications from various databases were obtained and reviewed. A meta-analysis was performed to evaluate the prognostic role of MVD among ESCC patients. RESULTS: A total of 11 eligible studies containing 891 ESCC cases were included in the meta-analysis. The pooled hazard ratio for overall survival was 2.39 (95% confidence interval 1.92-2.96, P < .001). Heterogeneity among the studies was not significant, and publication bias was not found. Subgroup analyses were also performed on different issues, such as districts, antibodies, and median age. CONCLUSION: High MVD is a prognostic factor among ESCC that indicated worse prognosis in these patients. More studies are needed, and through abundant evidence, the topic could be re-evaluated by then. PMID- 28723805 TI - Acute pancreatitis induced by etoposide-lobaplatin combination chemotherapy used for the treatment of lung cancer: A case report and literature review. AB - RATIONALE: Drug-induced pancreatitis (DIP) is a rare type of pancreatitis that is not usually observed in the clinical practice. It is generally difficult to distinguish from acute pancreatitis (AP) induced by other causes. PATIENT CONCERNS: Here, we report a 62-year-old Chinese female patient with "small cell lung cancer" as the initial presentation. Because the patient could not bear the surgical treatment, the chemotherapy composed of lobaplatin and etoposide was performed. Three days later, the patient displayed sudden abdominal pain, distension, nausea, and vomiting without obvious inducements. Laboratory tests showed that the levels of serum and urine amylase were enhanced; abdominal computed tomography (CT) result showed the enlargement of the pancreas, peripancreatic effusion, and a rough edge, which suggested the diagnosis of AP. The patient had no history of biliary tract disease, alcoholism, binge overeating, hyperlipidemia, and hereditary pancreatitis. DIAGNOSES: The patient was diagnosed with DIP. INTERVENTIONS: The chemotherapy was stopped at once and we performed fluid resuscitation, pain alleviation, prophylactic antibiotics, and nutritional support, etc on the patient. Later, the patient's clinical symptoms were obviously relieved, and she recovered successfully. OUTCOMES: The chemotherapy was continued, but later, the patient showed abdominal pain, distension, nausea, and vomiting again. The levels of serum amylase and urine amylase were enhanced again. Further imaging examination strongly indicated the recurrence of AP. LESSONS: We should raise awareness of the clinicians regarding DIP, thereby enabling its timely diagnosis and accurate treatment, as well as promoting the rational and safe use of drugs. PMID- 28723806 TI - The serum pepsinogen levels for risk assessment of gastric neoplasms: New proposal from a case-control study in Korea. AB - To decrease the gastric cancer related mortality rate, endoscopic screening is widely performed in Korea. However, a precise method for identifying those at a high risk of gastric neoplasms has not been established. This study aims to evaluate serum pepsinogen (PG) levels for risk assessment of gastric neoplasms. Between August 2014 and March 2016, a total of 398 subjects, including 87 with gastric neoplasms, were enrolled in this study. On the basis of the serum PG I/II ratio, the enrolled subjects were classified into 4 groups: group A, PG I/II ratio >4; group B, >3 and <=4; group C, >2 and <=3; group D, <=2. Compared with group A, a stepwise increase in the risk of gastric neoplasm was observed from group B [odds ratio (OR) = 9.9, 95% confidence interval (95% CI) = 4.0-24.4] to group C (OR = 20.9, 95% CI = 8.7-50.5) to group D (OR = 37.3, 95% CI = 14.3 97.4). The optimal cutoff value of the serum PG I/II ratio for predicting gastric neoplasms was 4.5, with a sensitivity of 97.7% and a specificity of 57.6%. A decrease in the serum PG I/II ratio was strongly associated with an increased risk of gastric neoplasms. The serum PG I/II ratio can be used to identify those at a high risk of gastric neoplasms in Korean population. PMID- 28723807 TI - Can patients with femoral neck fracture benefit from preoperative thromboprophylaxis?: A prospective randomized controlled trial. AB - BACKGROUND: The effectiveness of preoperative thromboprophylaxis remains obscure in patients with femoral neck fracture. The purpose of the current study was to investigate whether these patients benefit from preoperative thromboprophylaxis. METHODS: In this prospective, randomized controlled trial, a total of 80 patients with femoral neck fracture were randomly assigned to receive either rivaroxaban or conservative treatment before surgery. For all patients, color Doppler ultrasound of both lower extremities was performed immediately after admission. The primary efficacy outcome was venous thromboembolism (VTE) defined as deep vein thrombosis (DVT) or pulmonary embolism (PE). The primary safety outcome was major bleeding. RESULT: Compared with conservative treatment, rivaroxaban could significantly reduce the incidence of DVT from 19.5% (8/41) to 2.6% (1/39) (P = .016). Preoperatively, there were a total of 9 occurrences of DVT including 8 DVT in the conservative treatment group and 1 in the oral rivaroxaban group. All cases of DVT were asymptomatic, with 8 of them diagnosed as isolated muscular calf vein thromboses. There were no differences between the 2 groups in terms of the overall incidence of major bleeding. CONCLUSION: Thromboprophylaxis with rivaroxaban prior to surgery can effectively reduce the risk of preoperative DVT for patients with femoral neck fracture without increasing the risk of bleeding. PMID- 28723809 TI - Creating a Fair, High-Quality, Affordable Health Care System for All. PMID- 28723808 TI - Continuous use of metformin can improve survival in type 2 diabetic patients with ovarian cancer: A retrospective study. AB - Evidence indicates that type 2 diabetes may stimulate the initiation and progression of several types of cancer. Metformin, a drug most commonly used to treat type 2 diabetes, may inhibit cancer cell growth and reduce the risk of cancer. However, evidence of the antitumor effects of metformin on ovarian cancer is still limited.In this study, we retrospectively examined the effects of metformin on ovarian cancer patients with diabetes at our institution.We identified 568 consecutive patients who were newly diagnosed with ovarian cancer and treated between January 2011 and March 2014. Patients with International Federation of Gynecology and Obstetrics (FIGO) stage I to IV epithelial ovarian, fallopian, or peritoneal cancer were included. Patients with type 1 diabetes, incomplete records (including medication records) and any other cancer before their ovarian cancer diagnosis, as well as those diagnosed with diabetes more than 6 months after their ovarian cancer diagnosis, were excluded. Out of 568 patients, 48 (8.5%) patients with type 2 diabetes continuously used metformin, 34 (5.9%) patients with type 2 diabetes did not take metformin, 22 (3.9%) patients with type 2 diabetes discontinued metformin, and 464 (81.7%) ovarian cancer patients were nondiabetic controls. Longer progression-free survival (PFS) and overall survival (OS) were observed in ovarian cancer patients with diabetes who were taking metformin than in diabetic patients not taking metformin, diabetic patients who discontinued metformin, and nondiabetic ovarian cancer patients (P = .001). After adjusting for possible confounders, metformin use was associated with a lower risk for disease relapse [hazard ratio (HR) = 0.34; 95% confidence interval (CI): 0.27-0.67; P < .01] and disease-related death (HR = 0.29; 95% CI: 0.13-0.58, P = .03) among ovarian cancer patients with diabetes.Metformin use may decrease the risk for disease recurrence and death in patients with ovarian cancer, but the drug treatment must be continuous. PMID- 28723810 TI - Let's Get Real About Health Care Reform. AB - In light of the ongoing debate about health care policy in the United States, including efforts to repeal and replace the Affordable Care Act, it will be critically important for the academic community to engage in the dialogue. Developing a viable approach to health care reform requires an understanding of the interaction and interdependence between choice, cost, and coverage in a competitive and functional market-based system. Some institutions have implemented models that indicate the feasibility of providing high-quality, efficient patient care while working within fixed budgets. The academic community must stay engaged in these conversations because of its moral commitment to equitable access to health care for all. Academic medical centers will also have to define and protect their roles in an evolving health care delivery system in the United States. PMID- 28723811 TI - The Afya Bora Fellowship: An Innovative Program Focused on Creating an Interprofessional Network of Leaders in Global Health. AB - PROBLEM: Most current health professions education programs are focused on the development of clinical skills. As a result, they may not address the complex and interconnected nature of global health. Trainees require relevant clinical, programmatic, and leadership skills to meet the challenges of practicing in an increasingly globalized environment. APPROACH: To develop health care leaders within sub-Saharan Africa, the Afya Bora Consortium developed a one-year fellowship for medical doctors and nurses. Fellows from nine institutions in the United States and sub-Saharan Africa participate in 12 learning modules focused on leadership development and program management. Classroom-based training is augmented with an experiential apprenticeship component. OUTCOMES: Since 2011, 100 fellows have graduated from the program. During their apprenticeships, fellows developed projects beneficial to their development and to host organizations. The program has developed fellows' skills in leadership, lent expertise to local organizations, and built knowledge in local contexts. Most fellows have returned to their countries of origin, thus building local capacity. U.S.-based fellows examine global health challenges from regional perspectives and learn from sub-Saharan African experts and peers. NEXT STEPS: The Consortium provides ongoing support to alumni through career development awards and alumni network engagement with current and past fellow cohorts. The Consortium expanded from its initial network of five countries to six and continues to seek opportunities for geographical and institutional expansion. PMID- 28723812 TI - Effects of 12-Week Resistance Training on Sprint and Jump Performances in Competitive Adolescent Rugby Union Players. AB - Harries, SK, Lubans, DR, Buxton, A, MacDougall, THJ, and Callister, R. Effects of 12-week resistance training on sprint and jump performances in competitive adolescent rugby union players. J Strength Cond Res 32(10): 2762-2769, 2018 Sprint performance is an important characteristic for success in many sports, including rugby union. Resistance training is used to increase muscular fitness (i.e., strength, endurance, and power) and may also be effective for improving sprint and jump performances. The aims of this study were to examine the effects of resistance training using 2 different periodized programs (linear and daily undulating) on sprint and jump performances and explore relationships between performance measures. Sixteen male (16.9 +/- 1.0 years) adolescent rugby union players participated in 12 weeks of resistance training. A further 10 male (15.5 +/- 1.0 years) participants were recruited as a control group. Assessments of strength (box squat), 10- and 20-m sprint (electronically timed), and jump height (maximal unloaded (body mass only) and loaded (body mass + 10 kg) countermovement jumps) were conducted before and after 12 weeks training. Large to very large increases in 1 repetition maximum box squat (linear: 33.9%; p < 0.001; effect size (ES) = 1.64; daily undulating: 44.5%; p < 0.001; ES = 2.33) were observed after training. Small decreases were seen in 10-m (linear: -1.6%; p = 0.171; ES = -0.84; daily undulating: -2.5%; p = 0.038; ES = -0.36) and 20-m (linear: -0.5%; p = 0.506; ES = -0.20; daily undulating: -1.7%; p = 0.047; ES = -0.27) sprint times. Small-to-moderate associations between changes in lower-body strength and improvements in 10- and 20-m sprint times were found. Resistance training increases lower-body strength in adolescent rugby union players and increases in lower-body strength may transfer to improved sprinting performance with improvements after daily undulating periodized resistance training slightly superior. PMID- 28723813 TI - Effect of Resistance Training on Blood Pressure and Autonomic Responses in Treated Hypertensives. AB - Trevizani, GA, Seixas, MB, Benchimol-Barbosa, PR, Vianna, JM, da Silva, LP, and Nadal, J. Effect of resistance training on blood pressure and autonomic responses in treated hypertensives. J Strength Cond Res 32(5): 1462-1470, 2018-This study evaluated the effect of resistance training (RT) on heart rate variability (HRV) and on blood pressure (BP) responses to acute and short-term exposure in treated hypertensive (HT) subjects. Twenty-one men participated in the study, 8 HT under drug treatment regimen and achieving adequate BP control before inclusion and 13 normotensive (NT). The RT protocol consisted of 12 sessions with eight exercises (leg extension, leg press, leg curl, bench press, seated row, triceps push-down, seated calf flexion, and seated arm curl) performed for two sets of 15-20 repetitions with 50% of one repetition maximum with 2-minute rest intervals in between sets, 3*/week. Heartbeat measurements were taken before and after RT, and BP was measured at the beginning and at the end of each session after 10-minute rest. The repeated measures analysis of variance (effect: group vs. training) evaluated BP and HRV responses. Effect size (ES) calculation measured the magnitude of the RT effect on these variables. There was a statistically significant reduction in postexercise systolic BP in both groups (p = 0.040), without significant change in resting BP along RT (p = 0.159). Regarding HRV, it was observed a reduced sympathetic-vagal balance (training interaction vs. group: p = 0.058, ES = -0.83) in HT subjects. Resistance training promotes a significant acute reduction of BP in the HT and NT groups and provides a slight benefit of cardiac autonomic balance in the HT. PMID- 28723814 TI - Validation of the 3-min all-out exercise test for shuttle running prescription. AB - A 3-min all-out exercise test (3MT) for running has been developed to determine critical speed (CS) and finite capacity for running speeds >CS (D') which allow for the prediction of time limits (TLIMs) associated with running different distances. Most team sports require shuttle running; however, the 3MT was validated for uninterrupted, track running and not shuttle running. The purpose of this study was to examine the efficacy of shuttle running 3MT to determine critical speed (CS) and D'. A total of 12 subjects were tested using a baseline 3MT along with three separate distance time-trials of all-out shuttle running to determine true CS and D'. The 3MT (2.94 +/- 0.39 m.s) and the true CS (3.00 +/- 0.36 m.s) for shuttle running did not differ (p = 0.71) and had a coefficient of variation (CV) of 7.7%. Conversely, D' from the 3MT exceeded true D' by 42 m (p = 0.04, CV = 36%). The TLIMs estimated for the 3 different distances were within ~2 to 6% (p = 0.60). Based on these outcomes, the shuttle run 3MT may offer a suitable method for prescribing shuttle running interval training. PMID- 28723815 TI - Effect of Energy Drink Consumption on Power and Velocity of Selected Sport Performance Activities. AB - Jacobson, BH, Hester, GM, Palmer, TB, Williams, K, Pope, ZK, Sellers, JH, Conchola, EC, Woolsey, C, and Estrada, C. Effect of energy drink consumption on power and velocity of selected sport performance activities. J Strength Cond Res 32(6): 1613-1618, 2018-Energy drinks (ED) comprise a multibillion dollar market focused on younger, active, and competitive individuals. Marketing includes claims of improved alertness and performance. The purpose of this study was to assess power (W) and velocity (m.s) of a simulated, isolated forehand stroke (FHS), and a countermovement vertical jump (CVJ) before and after ingestion of a commercially available energy shot (ES) or a placebo (PL). Healthy college-aged men and women (N = 36) volunteers were randomly placed in the ES or PL. Before and 30 minutes after ingesting either the ES or PL, participants performed 3 FHSs and CVJs. Power and velocity of each performance was measured using a linear velocity transducer and the highest value for each measure was used for subsequent analysis. The ES group demonstrated a significant (p = 0.05) increase in velocity and W for the FHS, but not for the CVJ. All measures remained unchanged in the PL group for both, the FHS and CVJ. Females demonstrated a significant increase in velocity over males in FHS, but not in CVJ. It was concluded that while the dose of stimulants in the ES was adequate to improve performance of smaller muscle groups, it may not have been sufficient to affect the larger muscle groups of the lower legs which contribute to the CVJ. While the ES used in the present study contained a caffeine dosage within the NCAA limit and did improve performance for the upper body, it must be noted that there are health risks associated with ED consumption. PMID- 28723816 TI - Importance of physical qualities for speed and change of direction ability in elite female soccer players. AB - The purpose of this study was to determine the importance of physical qualities for speed and change of direction (CoD) ability in female soccer players. Data were collected on 10 female soccer players who were part of a professional English Women's Super League team. Player assessments included anthropometric (stature and body mass), body composition (dual-energy X-ray absorptiometry), speed (10m, 30m sprint), CoD ability (505 agility), aerobic (Yo-Yo Intermittent Recovery Test), lower-body strength (bilateral knee extensions) and power (countermovement jump [CMJ], squat jump [SJ], 30cm drop jump [DJ]) measures. The relationships between the variables were evaluated using eigenvector analysis and Pearson correlation analysis. Multiple linear regression revealed that the performance variables (10 and 20m speed, mean 505, and CoD deficit mean) can be predicted with almost 100% accuracy (i.e. adjusted R > 0.999) using various combinations of the predictor variables (DJ height, CMJ height, SJ height, lean body mass). An increase of one standard deviation (SD) in DJ height was associated with reductions of -5.636 and -9.082 SD in 10 m and 20 m sprint times. A one SD increase in CMJ also results in a reduction of -3.317 and -0.922 SD respectively in mean 505 and CoD deficit mean values. This study provides comparative data for professional English female soccer players that can be used by strength and conditioning coaches when monitoring player development and assessing the effectiveness of training programmes. Findings highlight the importance of developing reactive strength to improve speed and CoD ability in female soccer players. PMID- 28723817 TI - A Systematic Review of the Effects of Resistance Training on Body Image. AB - The purpose of this systematic review was to identify and appraise the literature that has specifically tested the independent effects of resistance training (i.e., weightlifting) on body image in adults. A comprehensive search of electronic databases PubMed, Scopus, PsycNET, and Web of Science for relevant studies published in peer-reviewed journals through December 2016 was conducted, and PRISMA guidelines were followed. Inclusion criteria were that a study had to be (a) written in English, (b) published in a peer-reviewed journal, (c) conducted an assessment of body image using a validated scale before and after a stand-alone resistance training intervention (i.e., not coupled with another mode of treatment), and (d) excluded participants younger than 18 years. Methodological quality was assessed using the Physiotherapy Evidence Database (PEDro) scale. A total of 7,324 studies were identified, and 11 were included in this review. The majority (8 of 11) of studies concluded that resistance training can significantly improve multiple dimensions of body image, including body satisfaction, appearance evaluation, and social physique anxiety; however, only 3 studies were considered high quality based on their PEDro score, and several methodological limitations exist. Overall, resistance training seems to have the potential to improve body image in adults, but future high-quality studies with more rigorous testing methods and study designs are needed. PMID- 28723818 TI - Somatotype And Body Composition In Young Soccer Players According To The Playing Position And Sport Success. AB - Soccer players undergo an evolution in their body composition throughout the growth and passage through the different base stages, that is, childhood, puberty and adolescence. The aim of this study was to analyze the morphology and body composition of U14, U16, and U19 soccer players, taking into account in addition, their sport success endorsed through the regularity participation and their relation with the different playing positions occupied during competition (goalkeeper, external defender, central defender, midfielder and forward/extreme). For that, a total of 174 male young soccer players were evaluated anthropometrically. Dominant somatotype of the players was, according to their playing position: meso-endomorphic in goalkeepers, central for external defenders, balanced ectomorph in central defenders, balanced mesomorph in the case of midfielders, and meso-ectomorph in forwards/extremes. Taking into account that sport performance is directly mediated by the body composition of athletes, the differences found suggest a marked specialization between the goalkeepers and forwards, establishing significant differences between them. Further studies would be needed to evaluate the influence of individual maturation development versus sports training on the conformation of a certain anthropometric profile of a soccer player and its relation with the different playing positions occupied on the pitch during the game. PMID- 28723819 TI - Exploring game dynamics in padel. Implications for assessment and training. AB - A better understanding of in-game competition demands potentially improves coaching strategy and quality. However, there is very limited information about game patterns in padel, a very modern racket sport born in the 70'. The purpose of this study was therefore to quantify and classify game dynamics during the match in professional padel players through a multivariate decision tree approach including technical, spatial and effectiveness indicators. The results determined three main game styles strongly defined by the court zone (net, middle and baseline). Additionally, particular technical, spatial and effectiveness indicators were identified in each zone. In net and middle areas (offence) stood the use of volleys and over-head strokes on the center lane to both keep a positional advantage and solve the point. Conversely in the baseline (defense), the use of corner side walls and the domain of lobs showed to be relevant. It is also remarkable the high rate of backhand groundstrokes, involving over four out of ten actions. This information may have relevant implications for coaches working in padel by providing a novel hierarchically organization of game dynamics, which helps in designing training and conditioning programs close to real competitive situations. PMID- 28723820 TI - Effects of Cardiovascular Fitness and Body Composition on Maximal Core Temperature in Collegiate Football Players During Preseason. AB - McClelland, JM, Godek, SF, Chlad, PS, Feairheller, DL, and Morrison, KE. Effects of cardiovascular fitness and body composition on maximal core temperature in collegiate football players during preseason. J Strength Cond Res 32(6): 1662 1670, 2018-This study evaluated the effects of body mass index (BMI) and aerobic fitness (V[Combining Dot Above]O2max) on maximal core temperature values (Tcmax) in 17 National Collegiate Athletic Association Division III football players during preseason. The subjects included 9 backs (BKs) and 8 linemen (LM). V[Combining Dot Above]O2max testing was performed 1 week before preseason. Core temperature was monitored by ingestible sensor every 10 minutes during practices on day 4 (D1), day 5 (D2), day 7 (D3), and postacclimatization on day 14 (D4). Wet bulb globe temperature (WBGT) was recorded on each collection day. Independent, paired t-tests and Pearson's correlations were performed (alpha = 0.05). There were no significant correlations between V[Combining Dot Above]O2max and Tcmax on D1 (WBGT = 29.07 degrees C) or D2 (WBGT = 30.93 degrees C), but on D3 (WBGT = 31.39 degrees C) there was a nonsignificant moderate negative correlation (r = -0.564, p = 0.090). There were no significant correlations between BMI and Tcmax on D1 or D2, but on D3 there was a nonsignificant moderate positive correlation (r = 0.596, p = 0.069). Paired t-tests revealed that overall Tcmax (D1-3) (38.56 +/- 0.32 degrees C) was statistically higher (p = 0.002) than D4 (38.16 +/- 0.30 degrees C). Independent t-tests between groups showed that the Tcmax values during preacclimatization (D1-D3) were significantly higher in LM (38.50 +/- 0.37 degrees C) than BKs (38.16 +/- 0.35 degrees C) (p = 0.007). V[Combining Dot Above]O2max was significantly lower (p = 0.006) in LM (36.89 +/- 6.40 ml.kg.min) than BKs (47.44 +/- 7.09 ml.kg.min), and BMI was significantly higher (p = 0.019) in LM (35.59 +/- 4.00 kg.m) than BKs (28.68 +/- 3.38 kg.m). The results of this study demonstrate that LM are significantly less fit than BKs and have a greater BMI. When WBGT was the highest on D3, the results suggest that those with lower V[Combining Dot Above]O2max and higher BMI experienced a higher Tcmax. PMID- 28723821 TI - Can a balance wristband influence postural control? AB - Top sports performances cannot be achieved without a high level of postural control. Balance wristbands purport to improve the mental and physical balance of the wearer. It is still unclear, however, whether these wristbands can indeed enhance postural control. Our purpose was to ascertain by means of computerized dynamic posturography whether balance wristbands can improve postural stability.In this randomized controlled single-blind clinical study, posturography was used to assess postural control in 179 healthy subjects with or without a balance wristband. Tests were also performed with the subjects blinded as to whether they were wearing an intact or a defective wristband. An analysis of variance (ANOVA) was used to detect significant differences (P < 0.05).Stability indexes did not reveal significant differences in postural control between wearing and not wearing a wristband.Our study did not provide evidence for an improvement in postural stability. Since the single-blind trials too revealed no significant differences, a placebo effect could be ruled out. PMID- 28723822 TI - Biomechanical differences in female basketball and soccer players during multi directional jump landings. AB - Anterior cruciate ligament injury prevention programs are less successful in basketball than soccer and may be due to distinct movement strategies that these athletes develop from sport-specific training. The purpose of this study was to identify biomechanical differences between female basketball and soccer players during multi-directional jump landings. Lower extremity biomechanics of eighty nine female athletes who played competitive basketball (n=40) or soccer (n=49) at the middle- or high-school level were analyzed with three-dimensional motion analysis during a drop vertical jump (DVJ), double- (SAG-DL) and single-leg forward jump (SAG-SL), and double- (FRONT-DL) and single-leg (FRONT-SL) lateral jump. Basketball players landed with less hip and/or knee excursion during all tasks (p<.05) except for the SAG-SL task, where basketball players landed with greater peak hip flexion angles (p=.04). The FRONT-SL task elicited the most distinct sport-specific differences, including decreased hip adduction (p<.001) angles, increased hip internal rotation (p=.003), and increased relative knee external rotation (p=.001) excursions in basketball players. Additionally, the FRONT-SL task elicited greater forces in knee abduction (p=.003) and lesser forces in hip adduction (p=.001) and knee external rotation (p<.001) in basketball players. Joint energetics were different during the FRONT-DL task, as basketball players exhibited less sagittal plane energy absorption at the hip (p<.001), and greater hip (p<.001) and knee (p=.001) joint stiffness. Sport specific movement strategies were identified during all jump landing tasks, such that soccer players exhibited a more protective landing strategy than basketball players, justifying future efforts toward sport-specific ACL injury prevention programs. PMID- 28723823 TI - Association Between Television Viewing and Parent-Child Reading in the Early Home Environment. AB - OBJECTIVE: This study examines whether there is an association between time spent by preschoolers in parent-child shared book reading versus TV viewing in two distinct samples. METHODS: Data were used from both the preschool wave of the Early Childhood Longitudinal Study Cohort, a nationally representative sample of 4-year-olds (N = 8900), as well as a low-income, rural sample of children enrolled in the Preschool Experience in Rural Classrooms study (N = 407). Information regarding frequency of shared book reading and daily TV consumption was obtained through caregiver report. A regression approach was used to estimate how the frequency of parent-child book reading accounted for variance in TV consumption. Estimated marginal mean values were then compared for the amount of TV viewed by children who were reported as being read to daily, frequently, occasionally, and not at all. RESULTS: Parent-child book reading was negatively associated with the amount of TV viewed by children in both samples. Specifically, television consumption was significantly lower for children who were read to daily as compared to those who were read to occasionally. This inverse association was not moderated by contextual factors including maternal education, household size, and composition, or time spent in nonparental care. CONCLUSION: This study provides empirical support for an inverse association between TV viewing and parent-child book reading activities. Implications for policy and practice are discussed. PMID- 28723824 TI - A National Profile of Attention-Deficit Hyperactivity Disorder Diagnosis and Treatment Among US Children Aged 2 to 5 Years. AB - OBJECTIVE: Clinical guidelines provide recommendations for diagnosis and treatment of attention-deficit hyperactivity disorder (ADHD), with specific guidance on caring for children younger than 6 years. This exploratory study describes ADHD diagnosis and treatment patterns among young children in the United States using 2 nationally representative parent surveys. METHODS: The National Survey of Children's Health (2007-2008, 2011-2012) was used to produce weighted prevalence estimates of current ADHD and ADHD medication treatment among US children aged 2 to 5 years. The National Survey of Children with Special Health Care Needs (2009-2010) provided additional estimates on types of medication treatment and receipt of behavioral treatment among young children with special health care needs (CSHCN) with ADHD. RESULTS: In 2011 to 2012, 1.5% of young children (approximately 237,000) had current ADHD compared to 1.0% in 2007 to 2008. In 2011 to 2012, 43.7% of young children with current ADHD were taking medication for ADHD (approximately 104,000). In young CSHCN with ADHD, central nervous system stimulants were the most common medication type used to treat ADHD, and 52.8% of young CSHCN with current ADHD had received behavioral treatment for ADHD in the past year. CONCLUSION: Nearly a quarter million In young CSHCN have current ADHD, with a prevalence that has increased by 57% from 2007 to 2008 to 2011 to 2012. The demographic patterns of diagnosis and treatment described in this study can serve as a benchmark to monitor service use patterns of young children diagnosed with ADHD over time. PMID- 28723825 TI - Feasibility of Conducting Autism Biomarker Research in the Clinical Setting. AB - OBJECTIVE: Recruitment and completion of research activities during regular clinical care has the potential to increase research participation in complex neurodevelopmental disorders. We evaluated the feasibility, and effect on clinical care, of conducting biomarker research within a subspecialty clinical visit for autism spectrum disorder (ASD). METHODS: Children, aged 5 to 10 years, were recruited by providers in ASD clinics at 5 institutions. Biomarkers collected were growth measurements, head circumference, neurologic and dysmorphology examinations, digit ratio (2D:4D) measurement, and platelet serotonin and urinary melatonin sulfate excretion levels. Parents completed the Aberrant Behavior Checklist-Community and a medical/demographic questionnaire. Cognitive level was abstracted from the medical record. Parents and clinicians completed surveys on the effect of the study on the clinical visit. RESULTS: Eighty-three children and their caregivers participated. Factors limiting participation included difficulty reaching families by phone and parent concern about the study blood draw requirement. All children completed at least 4 of 7 planned research activities. Demographic factors, educational placement, and child behavior were not associated with completion of study activities. Lower nonverbal cognitive function was weakly associated with fewer activities completed. Forty-four percent of clinicians reported an effect of the research study on the clinical visit. However, neither parent-reported nor clinician reported effect was associated with the degree of study activity completion. CONCLUSION: Recruiting study participants in the context of scheduled ASD clinical visits required significant effort. However, once recruited, participants completed most study activities, regardless of behavioral symptom severity. Research activities did not adversely affect the clinical visit. PMID- 28723826 TI - Clinical Research by Developmental and Behavioral Pediatrics Specialists: Which Models Work Best? PMID- 28723827 TI - Neurocognitive and Symptom Trajectories of ADHD from Childhood to Early Adolescence. AB - OBJECTIVE: This longitudinal study investigated changes in neurocognitive functioning from childhood to early adolescence in a sample of children diagnosed with DSM-IV attention-deficit hyperactivity disorder (ADHD). It also compared the neurocognitive trajectories of children who continued to meet the diagnostic criteria for ADHD at follow-up and those in partial remission. METHODS: Children diagnosed with ADHD (N = 55) were tested at baseline (M = 7.7 years, SD = 1.5) and 4 years later (M = 11.7 years, SD = 1.5) on measures of intellectual, academic, and executive functioning. Group and individual analyses were used to examine neurocognitive functioning over this period. RESULTS: Intellectual function was stable over the 4-year interval. Reliable change analyses highlighted variability in academic performance. Approximately half the sample showed a reliable decline in at least 1 academic subject with almost a third showing reliable improvement. Executive functions generally followed a stable or improving course, with significant improvements on measures of information processing, attentional control, cognitive flexibility, and goal setting. There was some evidence of better neurocognitive performance in those with partial symptom remission at follow-up. CONCLUSION: Study findings emphasize the importance of monitoring academic performance in children with ADHD, including examination of change at the individual level. Declines in academic performance were observed, despite stable intellectual and improving executive function. Early cognitive functioning did not predict symptom remission; however, reduced symptoms at follow-up were associated with better executive function. PMID- 28723828 TI - Social Disparities in Early Intervention Service Use and Provider-Reported Outcomes. AB - OBJECTIVE: To describe social disparities in early intervention (EI) service use and provider-reported outcomes. METHODS: Secondary data analysis of administrative data to ascertain EI service use of all EI and discipline-specific services and child and family characteristics. Adjusted logistic regression models estimated the odds of receiving each type of core EI service. Adjusted median regression models estimated differences in EI intensity for each type of core EI service. Adjusted ordinal regression models estimated the association between each type of EI therapy service and provider estimates of children's global functional improvement. RESULTS: Children with a diagnosis (b = 0.8, SE = 0.2) and those whose caregiver had 12 years of education or less (b = 0.6, SE = 0.3) had higher EI intensity. Black, non-Hispanic (BNH) children had nearly 75% lower odds of receiving physical therapy (PT) (odds ratio [OR] = 0.3, 95% confidence interval [CI], 0.1-0.7) and greater odds of receiving speech therapy (ST) (OR = 3.4, 95% CI, 1.3-9.3) than their white, non-Hispanic (WNH) peers. BNH children who received PT received about an hour less per month (b = -0.7, SE = 0.4) than their WNH peers. Hispanic children (b = 1.0, SE = 0.3) and those with higher family income (b = 0.7, SE = 0.3) received greater intensity of PT compared with their peers who are WNH and from low-income families. Publically insured children had lower intensity of occupational therapy (b = -0.5, SE = 0.3) and ST (b = -0.6, SE = 0.3). Greater intensity of EI services was not associated with greater provider-perceived improvement. CONCLUSION: Results suggest disparities, by race and family income, in receipt of EI therapy services. These findings highlight opportunities to customize and coordinate care for improved EI access and care quality. PMID- 28723829 TI - Prognostic implication of early ventricular fibrillation among patients with ST elevation myocardial infarction. AB - OBJECTIVE: The aim of this study was to analyze the prognosis of patients presenting early ventricular fibrillation (VF) in the setting of ST elevation myocardial infarction (STEMI). PATIENTS AND METHODS: Among patients included in the ARIAM (Analisis del Retraso en el Infarto Agudo de Miocardio) registry with the diagnosis of STEMI, those who received primary revascularization and were admitted in the first 12 h were analyzed retrospectively. RESULTS: From January 2007 to January 2012, 8340 patients were included in the STEMI cohort and 680 (8.2%) of them presented with VF before admission to the ICU (VF). This group comprised younger patients with fewer comorbidities. They received more often primary angioplasty (33.7 vs. 24.9%; P<0.001), had more prevalence of Killip class greater than or equal to 2 at admission (37.5 vs. 17.8%; P<0.001), and suffered more often cardiogenic shock (18.5 vs. 5.9%, P<0.001). By logistic regression analysis, VF was associated with a greater in-hospital mortality [odds rate (OR): 2.08, 95% confidence interval (CI): 1.57-2.81, P<0.001]. After a propensity score matching process, VF was associated with in-hospital mortality (OR: 1.53, 95% CI: 1.05-2.25, P=0.028). However, when analyzing patients treated by primary angioplasty, the mortality was not significantly related to VF (OR: 0.86, 95% CI: 0.45-1.61, P=0.628). CONCLUSION: Our results show that VF before ICU admission was an independent predictor of in-hospital outcome in a cohort of patients in whom fibrinolysis was the most used revascularization therapy. However, this prognostic value was not found in patients treated with primary angioplasty. PMID- 28723830 TI - Early versus delayed coronary artery bypass graft surgery for patients with non ST elevation myocardial infarction. AB - BACKGROUND: Although coronary artery bypass graft surgery (CABG) has been proven to have mortality and morbidity benefits in patients with non-ST elevation myocardial infarction and multivessel disease, the appropriate timing of this procedure remains unclear. Therefore, we proposed a propensity score-matched analysis comparing the clinical outcomes between patients who underwent CABG within the first 48 h of admission (early CABG) and patients who underwent CABG after 48 h of admission (delayed CABG). PATIENTS AND METHODS: Using the largest inpatient care database in the USA, the Nationwide Inpatient Sample, we identified patients with a primary diagnosis of acute myocardial infarction using the ICD 9-DM diagnosis codes. We then performed propensity score-matching analysis to control for 24 possible confounders. RESULTS: We identified 31 969 patients in the Nationwide Inpatient Sample database with a primary diagnosis of acute myocardial infarction who underwent CABG. The mean age of the cohort was 64.5+/-11.5 years and 33.4% were female. After performing propensity-matching analysis, we obtained a subset of 1555 patients in each group, with a mean age of 64.7+/-10.1 years; the male to female ratio was ~4 : 1. The incidence of hemorrhage, shock, and cardiac, pulmonary, and renal complications was comparable between the two groups. The incidence of mortality was not statistically significant between the two groups (2% in the early CABG vs. 1.8% in the delayed CABG, P=0.695). The mortality risk factors were as follows: age more than 70 years [odds ratio (OR): 3.42, 95% confidence interval (CI): 1.85-6.34, P<0.001]; cardiogenic shock (OR: 3.22, 95% CI: 1.35-7.67, P=0.008); and mechanical circulatory support with balloon counterpulsation (OR: 2.93, 95% CI: 1.45-5.90, P=0.003). CONCLUSION: CABG performed within 48 h of admission does not significantly increase the risk for in-hospital mortality compared with undergoing the procedure after 48 h of admission in propensity-matched patients. PMID- 28723832 TI - Patient-Perceived Facilitators of and Barriers to Electronic Portal Use: A Systematic Review. AB - This systematic review describes characteristics of portal users and their perceptions of this emerging technology. Recent empirical evidence (2010-2016) was reviewed to answer three questions: (1) What are the characteristics of electronic patient portal users? (2) What are patient-perceived facilitators of electronic patient portal use? (3) What are patient-perceived barriers to electronic patient portal use? Characteristics of portal users are described according to three broad categories: demographic characteristics, patterns of use, and complexity and duration of disease. Three themes were found related to patient-perceived facilitators of use: provider encouragement, access/control over health information, and enhanced communication; two themes were found related to patient-perceived barriers to use: lack of awareness/training and privacy and security concerns. Understanding a patient's perception of technology is paramount in optimizing use. These insights will allow for development of better products and clinical processes that facilitate broad goals of improved use of information technology. Policy and practice implications are discussed, as well as suggestions for future research. PMID- 28723833 TI - Concordance of Motion Sensor and Clinician-Rated Fall Risk Scores in Older Adults. AB - As the older adult population in the United States continues to grow, developing reliable, valid, and practical methods for identifying fall risk is a high priority. Falls are prevalent in older adults and contribute significantly to morbidity and mortality rates and rising health costs. Identifying at-risk older adults and intervening in a timely manner can reduce falls. Conventional fall risk assessment tools require a health professional trained in the use of each tool for administration and interpretation. Motion sensor technology, which uses three-dimensional cameras to measure patient movements, is promising for assessing older adults' fall risk because it could eliminate or reduce the need for provider oversight. The purpose of this study was to assess the concordance of fall risk scores as measured by a motion sensor device, the OmniVR Virtual Rehabilitation System, with clinician-rated fall risk scores in older adult outpatients undergoing physical rehabilitation. Three standardized fall risk assessments were administered by the OmniVR and by a clinician. Validity of the OmniVR was assessed by measuring the concordance between the two assessment methods. Stability of the OmniVR fall risk ratings was assessed by measuring test retest reliability. The OmniVR scores showed high concordance with the clinician rated scores and high stability over time, demonstrating comparability with provider measurements. PMID- 28723831 TI - Effect of Intrathecal Bupivacaine Dose on the Success of External Cephalic Version for Breech Presentation: A Prospective, Randomized, Blinded Clinical Trial. AB - BACKGROUND: Breech presentation is a leading cause of cesarean delivery. The use of neuraxial anesthesia increases the success rate of external cephalic version procedures for breech presentation and reduces cesarean delivery rates for fetal malpresentation. Meta-analysis suggests that higher-dose neuraxial techniques increase external cephalic version success to a greater extent than lower-dose techniques, but no randomized study has evaluated the dose-response effect. We hypothesized that increasing the intrathecal bupivacaine dose would be associated with increased external cephalic version success. METHODS: We conducted a randomized, double-blind trial to assess the effect of four intrathecal bupivacaine doses (2.5, 5.0, 7.5, 10.0 mg) combined with fentanyl 15 MUg on the success rate of external cephalic version for breech presentation. Secondary outcomes included mode of delivery, indication for cesarean delivery, and length of stay. RESULTS: A total of 240 subjects were enrolled, and 239 received the intervention. External cephalic version was successful in 123 (51.5%) of 239 patients. Compared with bupivacaine 2.5 mg, the odds (99% CI) for a successful version were 1.0 (0.4 to 2.6), 1.0 (0.4 to 2.7), and 0.9 (0.4 to 2.4) for bupivacaine 5.0, 7.5, and 10.0 mg, respectively (P = 0.99). There were no differences in the cesarean delivery rate (P = 0.76) or indication for cesarean delivery (P = 0.82). Time to discharge was increased 60 min (16 to 116 min) with bupivacaine 7.5 mg or higher as compared with 2.5 mg (P = 0.004). CONCLUSIONS: A dose of intrathecal bupivacaine greater than 2.5 mg does not lead to an additional increase in external cephalic procedural success or a reduction in cesarean delivery. PMID- 28723834 TI - Talking with a doctor during a visit elicits increases in systolic and diastolic blood pressure. AB - OBJECTIVE: To investigate the impact of talking with doctors on blood pressure (BP) in outpatients. PATIENTS AND METHODS: This study included 122 hypertensive and 78 normotensive outpatients. BP was measured initially in silence with oscillometric BP monitors three times at 1-min intervals as follows: pre-1, pre 2, and pre-3. BP was then measured with the same device immediately, at 3 min, and at 5 min after talking commenced as follows: during-1, during-3, and during 5. When talking stopped, BP was measured again as post-1, post-3, and post-5. The increments in BP and heart rate (HR) were the differences during and pre-3 values. RESULTS: Systolic blood pressure/diastolic blood pressure (SBP/DBP) increased significantly at 1 min during talking compared with pre-3 values. The maximum increment of SBP was 9.1 mmHg, occurring at 3 min and continuing up to 5 min during the talking stage. The maximum increment of DBP was 4.5 mmHg and that of HR was 2.7 bpm, both occurring at 1 min. When talking stopped, the SBP and DBP significantly decreased immediately. SBP at 5 min, DBP at 3 min, and HR at 1 min were similar to their pre-3 values. Logistic multifactor analysis showed that pre SBP3 level (R=0.141, P=0.023) was an independent factor, but anxiety scale, age, sex, BMI, and hypertension history were not independent factors. CONCLUSION: The maximum SBP increment is 9.1 mmHg and DBP increment is 4.5 mmHg during 5 min of talking with doctor. Meanwhile, the increased SBP needs about 5 min to return to the baseline level. PMID- 28723835 TI - A Modified Supine Position Facilitates Bladder Function in Patients Undergoing Percutaneous Coronary Intervention: A Randomized Controlled Clinical Trial. AB - BACKGROUND: Percutaneous coronary intervention (PCI) is currently the most common intervention for cardiovascular disease. Standard care after PCI typically involves a period of bed rest in the supine position, but this position creates voiding difficulties. OBJECTIVE: This study aimed to determine whether a modified supine position could facilitate bladder emptying after PCI. METHOD: A randomized controlled trial involving 300 patients was conducted. Patients in the intervention group were nursed in the supine position with the bed tilted 20 degrees upright and with a pillow between their feet and the end of the bed. Patients in the control group received standard care, which was supine positioning. RESULTS: One hundred fifty patients were allocated to the intervention group (100 men, 50 women), and 150 were allocated to the control group (103 men, 47 women). Baseline data did not differ between the 2 groups. Patients in the intervention group had significantly better bladder function as evidenced by a shorter time to the first void (5 vs 15 minutes) and fewer patients requiring voiding assistance (8.6% vs 35.3%). Residual urinary volumes were also much lower in the intervention group (88.71 vs 248.22 mL, P < .001). CONCLUSIONS: This study demonstrates that a modified supine position can reduce the incidence of impaired micturition and the preservation of normal bladder function after PCI. PMID- 28723836 TI - Subjective Versus Objective Estimated Cardiovascular Disease Risk and Adherence to Physical Activity in African American Women. AB - BACKGROUND: Cardiovascular disease (CVD) is the leading cause of death for African American (AA) women in the United States. Despite high prevalence of CVD risk factors, AA women perceive their CVD risk as low. OBJECTIVE: Our objectives were to (1) identify relationships between subjective (self-reported perceived) CVD risk and objective CVD risk estimated by the American College of Cardiology/American Heart Association atherosclerotic CVD (ASCVD) risk estimator, (2) identify demographic and psychosocial factors associated with subjective perceived risk and discrepancy with objective estimated CVD risk, and (3) determine whether subjective perceived CVD risk was associated with physical activity (PA) adherence. METHODS: This was a secondary data analysis of data collected from a 12-month lifestyle PA intervention conducted with 281 AA women. Subjective perceived CVD risk was measured by 1 question; objective estimated CVD risk was calculated using the ASCVD score. Women were categorized by congruence or discrepancy between subjective perceived and objective estimated CVD risk. RESULTS: Subjective perceived CVD risk and objective ASCVD risk scores were both low. Approximately 20% subjectively perceived their risk as lower than objective ASCVD scores. Atherosclerotic CVD risk discrepancy groups differed by depressed mood symptoms. Participants reported many perceived barriers to PA. Perceived CVD risk was not related to PA adherence. CONCLUSIONS: The significance of associated CVD risk factors may be underestimated by AA women, leading to discrepancy between subjective and objective risk estimates. Research is needed to clarify relationships among perceived risk, estimated risk using risk calculators such as ASCVD, and health behavior. PMID- 28723837 TI - Minimum Effective Volume of Lidocaine for Ultrasound-Guided Costoclavicular Block. AB - BACKGROUND AND OBJECTIVES: This dose-finding study aimed to determine the minimum effective volume in 90% of patients (MEV90) of lidocaine 1.5% with epinephrine 5 MUg/mL for ultrasound-guided costoclavicular block. METHODS: Using an in-plane technique and a lateral-to-medial direction, the block needle was positioned in the middle of the 3 cords of the brachial plexus in the costoclavicular space. The entire volume of lidocaine was deposited in this location. Dose assignment was carried out using a biased-coin-design up-and-down sequential method, where the total volume of local anesthetic administered to each patient depended on the response of the previous one. In case of failure, the next subject received a higher volume (defined as the previous volume with an increment of 2.5 mL). If the previous patient had a successful block, the next subject was randomized to a lower volume (defined as the previous volume with a decrement of 2.5 mL), with a probability of b = 0.11, or the same volume, with a probability of 1 - b = 0.89. Success was defined, at 30 minutes, as a minimal score of 14 of 16 points using a sensorimotor composite scale. Patients undergoing surgery of the elbow, forearm, wrist, or hand were prospectively enrolled until 45 successful blocks were obtained. This clinical trial was registered with ClinicalTrials.gov (ID NCT02932670). RESULTS: Fifty-seven patients were included in the study. Using isotonic regression and bootstrap confidence interval, the MEV90 for ultrasound guided costoclavicular block was estimated to be 34.0 mL (95% confidence interval, 33.4-34.4 mL). All patients with a minimal composite score of 14 points at 30 minutes achieved surgical anesthesia intraoperatively. CONCLUSIONS: For ultrasound-guided costoclavicular block, the MEV90 of lidocaine 1.5% with epinephrine 5 MUg/mL is 34 mL. Further dose-finding studies are required for other concentrations of lidocaine, other local anesthetic agents, and multiple injection techniques. PMID- 28723839 TI - Buddy-aid battlefield pain management. PMID- 28723838 TI - Transcatheter pulmonary valve implantation: valve technology and procedural outcome. AB - PURPOSE OF REVIEW: Procedural technique and short-term outcomes of transcatheter pulmonary valve implantation (TPVI) have been widely described. The purpose of this article is to provide an update on current valve technology, and to focus on recent data surrounding TPVI in the dilated right ventricular outflow tract (RVOT), hybrid interventions, significant outcomes, and procedural costs. RECENT FINDINGS: Transcatheter valve technology has expanded with current trials evaluating self-expandable valves that can be implanted in dilated RVOTs. Until those valves are widely available, hybrid techniques have been shown to offer a potential alternative in these patients, as well as in patients of small size. Although medium-term results of TPVI have shown 5-year freedom from reintervention or replacement of 76%, new data have underlined some concerns relating to bacterial endocarditis after the procedure. Procedural costs remain a concern, but vary greatly between institutions and healthcare systems. SUMMARY: TPVI has emerged as one of the most innovative procedures in the treatment of patients with dysfunctional RVOT and pulmonary valves. Further device development is likely to expand the procedure to patients of smaller size and with complex, dilated RVOTs. PMID- 28723842 TI - Reduced Neuromuscular Performance in Amenorrheic Elite Endurance Athletes. AB - INTRODUCTION: Secondary functional hypothalamic amenorrhea (SFHA) is common among female athletes, especially in weight-sensitive sports. The aim of this study was to investigate the link between SFHA and neuromuscular performance in elite endurance athletes. METHODS: Sixteen eumenorrheic (EUM) and 14 SFHA athletes from national teams and competitive clubs participated. Methods included gynecological examination, body composition (dual-energy x-ray absorptiometry), resting metabolic rate and work efficiency, exercise capacity, knee muscular strength (KMS) and knee muscular endurance (KME), reaction time (RT), blood sampling performed on the third to fifth days of the menstrual cycle, and 7-d assessment of energy availability. RESULTS: SFHA athletes had lower estrogen (0.12 +/- 0.03 vs 0.17 +/- 0.09 nmol.L, P < 0.05), triiodothyronine (T3) (1.4 +/- 0.2 vs 1.7 +/- 0.3 nmol.L, P < 0.01), and blood glucose (3.8 +/- 0.3 vs 4.4 +/- 0.3 mmol.L, P < 0.001) but higher cortisol levels (564 +/- 111 vs 400 +/- 140 nmol.L, P < 0.05) compared with EUM athletes. SFHA had a lower body weight (55.0 +/- 5.8 vs 60.6 +/ 7.1 kg, P < 0.05), but no difference in exercise capacity between groups was found (56.4 +/- 5.8 vs 54.0 +/- 6.3 mL O2.min.kg). RT was 7% longer, and KMS and KME were 11% and 20% lower compared with EUM athletes. RT was negatively associated with glucose (r = -0.40, P < 0.05), T3 (r = -0.37, P < 0.05), and estrogen (r = -0.43, P < 0.05), but positively associated with cortisol (r = 0.38, P < 0.05). KMS and KME correlated with fat-free mass in the tested leg (FFMleg; r = 0.52, P < 0.001; r = 0.58, P < 0.001) but were negatively associated with cortisol (r = -0.42, P < 0.05; r = -0.59, P < 0.001). FFMleg explained the differences in KMS, while reproductive function and FFMleg independently explained the variability in KME. CONCLUSIONS: We found lower neuromuscular performance among SFHA compared with EUM athletes linked to a lower FFMleg, glucose, estrogen, T3, and elevated cortisol levels. PMID- 28723840 TI - Cervical spine evaluation and clearance in the intoxicated patient: A prospective Western Trauma Association Multi-Institutional Trial and Survey. AB - BACKGROUND: Intoxication often prevents clinical clearance of the cervical spine (Csp) after trauma leading to prolonged immobilization even with a normal computed tomography (CT) scan. We evaluated the accuracy of CT at detecting clinically significant Csp injury, and surveyed participants on related opinions and practice. METHODS: A prospective multicenter study (2013-2015) at 17 centers. All adult blunt trauma patients underwent structured clinical examination and imaging including a Csp CT, with follow-up thru discharge. alcohol- and drug intoxicated patients (TOX+) were identified by serum and/or urine testing. Primary outcomes included the incidence and type of Csp injuries, the accuracy of CT scan, and the impact of TOX+ on the time to Csp clearance. A 36-item survey querying local protocols, practices, and opinions in the TOX+ population was administered. RESULTS: Ten thousand one hundred ninety-one patients were prospectively enrolled and underwent CT Csp during the initial trauma evaluation. The majority were men (67%), had vehicular trauma or falls (83%), with mean age of 48 years, and mean Injury Severity Score (ISS) of 11. The overall incidence of Csp injury was 10.6%. TOX+ comprised 30% of the cohort (19% EtOH only, 6% drug only, and 5% both). TOX+ were significantly younger (41 years vs. 51 years; p < 0.01) but with similar mean Injury Severity Score (11) and Glasgow Coma Scale score (13). The TOX+ cohort had a lower incidence of Csp injury versus nonintoxicated (8.4% vs. 11.5%; p < 0.01). In the TOX+ group, CT had a sensitivity of 94%, specificity of 99.5%, and negative predictive value (NPV) of 99.5% for all Csp injuries. For clinically significant injuries, the NPV was 99.9%, and there were no unstable Csp injuries missed by CT (NPV, 100%). When CT Csp was negative, TOX+ led to longer immobilization versus sober patients (mean, 8 hours vs. 2 hours; p < 0.01), and prolonged immobilization (>12 hrs) in 25%. The survey showed marked variations in protocols, definitions, and Csp clearance practices among participating centers, although 100% indicated willingness to change practice based on these data. CONCLUSION: For intoxicated patients undergoing Csp imaging, CT scan was highly accurate and reliable for identifying clinically significant spine injuries, and had a 100% NPV for identifying unstable injuries. CT-based clearance in TOX+ patients appears safe and may avoid unnecessary prolonged immobilization. There was wide disparity in practices, definitions, and opinions among the participating centers. LEVEL OF EVIDENCE: Diagnostic tests or criteria, level II. PMID- 28723843 TI - No Superior Adaptations to Carbohydrate Periodization in Elite Endurance Athletes. AB - PURPOSE: The present study investigated the effects of periodic carbohydrate (CHO) restriction on endurance performance and metabolic markers in elite endurance athletes. METHODS: Twenty-six male elite endurance athletes (maximal oxygen consumption (VO2max), 65.0 mL O2.kg.min) completed 4 wk of regular endurance training while being matched and randomized into two groups training with (low) or without (high) CHO manipulation 3 d.wk. The CHO manipulation days consisted of a 1-h high-intensity bike session in the morning, recovery for 7 h while consuming isocaloric diets containing either high CHO (414 +/- 2.4 g) or low CHO (79.5 +/- 1.0 g), and a 2-h moderate bike session in the afternoon with or without CHO. VO2max, maximal fat oxidation, and power output during a 30-min time trial (TT) were determined before and after the training period. The TT was undertaken after 90 min of intermittent exercise with CHO provision before the training period and both CHO and placebo after the training period. Muscle biopsies were analyzed for glycogen, citrate synthase (CS) and beta-hydroxyacyl coenzyme A dehydrogenase (HAD) activity, carnitine palmitoyltransferase (CPT1b), and phosphorylated acetyl-CoA carboxylase (pACC). RESULTS: The training effects were similar in both groups for all parameters. On average, VO2max and power output during the 30-min TT increased by 5% +/- 1% (P < 0.05) and TT performance was similar after CHO and placebo during the preload phase. Training promoted overall increases in glycogen content (18% +/- 5%), CS activity (11% +/- 5%), and pACC (38% +/- 19%; P < 0.05) with no differences between groups. HAD activity and CPT1b protein content remained unchanged. CONCLUSIONS: Superimposing periodic CHO restriction to 4 wk of regular endurance training had no superior effects on performance and muscle adaptations in elite endurance athletes. PMID- 28723844 TI - Associations of Physical Activity Intensities with Markers of Insulin Sensitivity. AB - BACKGROUND: Objectively measured physical activity (PA) intensity has traditionally been categorized as light, moderate, and vigorous using laboratory calibrated cut points. The relative contribution of time spent across a spectrum of accelerometer-determined intensities on health outcomes is less clear. PURPOSE: This study aimed to assess the relationship between objectively measured PA intensity on a continuous scale and markers of insulin sensitivity (IS). METHODS: Participants at high risk of type 2 diabetes mellitus were recruited from primary care (Leicestershire, UK). PA was measured using an ActiGraph accelerometer. Fasting and postchallenge glucose and insulin levels were assessed using an oral glucose tolerance test. IS was calculated using the Matsuda-IS and the HOMA-IS indices. Log-linear regression modeling was used to assess the relationship between PA intensity, in increments of 500 counts per minute, with markers of IS. Models were controlled for known confounders. RESULTS: Complete data were available for 569 participants. PA intensity was favorably associated with fasting and 2 h of insulin and IS, with the association increasing in magnitude with each increment of 500 counts per minute. Differences in HOMA-IS per 10 min of PA ranged from 12.4% (95% confidence interval = 3.7%-21.8%) to 26.8% (11.0%-44.7%) within the moderate-intensity PA category (from 2000-2499 to 3500-3999 counts per minute). For Matsuda-IS, these differences were 22.0% (10.3% 34.9%) and 34.7% (13.9%-59.3%), respectively. Significant associations for fasting insulin were no longer observed after controlling for body mass index, whereas differences associated with 2-h insulin and IS were attenuated but still significant. CONCLUSION: PA of any intensity may positively influence glucose regulation and insulin sensitivity in individuals at high risk of type 2 diabetes mellitus in a dose-response manner. Further research is required to identify the intensity thresholds at which clinically relevant benefits occur in this population. PMID- 28723845 TI - LEAN SIX SIGMA TECHNIQUES TO IMPROVE OPHTHALMOLOGY CLINIC EFFICIENCY. AB - PURPOSE: Ophthalmologists serve an increasing volume of a growing elderly population undergoing increasingly complex outpatient medical care, including extensive diagnostic testing and treatment. The resulting prolonged patient visit times ("patient flow times") limit quality, patient and employee satisfaction, and represent waste. Lean Six Sigma process improvement was used in a vitreoretinal practice to decrease patient flow time, demonstrating that this approach can yield significant improvement in health care. METHODS: Process flow maps were created to determine the most common care pathways within clinic. Three months' visits from the electronic medical record system, which tracks patient task times at each process step in the office were collected. Care tasks and care pathways consuming the greatest time and variation were identified and modified. Follow-up analysis from 6 weeks' visits was conducted to assess improvement. RESULTS: Nearly all patients took one of five paths through the office. Patient flow was redesigned to reduce waiting room time by having staff members immediately start patients into one of those five paths; staffing was adjusted to address high demand tasks, and scheduling was optimized around derived predictors of patient flow times. Follow-up analysis revealed a statistically significant decline in mean patient flow time by 18% and inpatient flow time SD by 4.6%. Patient and employee satisfaction scores improved. CONCLUSION: Manufacturing industry techniques, such as Lean and Six Sigma, can be used to improve patient care, minimize waste, and enhance patient and staff satisfaction in outpatient clinics. PMID- 28723846 TI - VALUE OF FRACTAL ANALYSIS OF OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY IN VARIOUS STAGES OF DIABETIC RETINOPATHY. AB - PURPOSE: To use fractal dimensional analysis to investigate retinal vascular disease patterns in patients with diabetic retinopathy using spectral domain optical coherence tomography angiography. METHODS: A retrospective study was conducted which included 49 eyes from 26 control subjects and 58 eyes from 35 patients known to have diabetic retinopathy. Of the 58 eyes with known retinopathy, 31 were categorized as nonproliferative diabetic retinopathy (13 mild, 9 moderate, and 9 severe) and 27 were categorized as proliferative diabetic retinopathy. Optical coherence tomography angiography images were acquired using the RTVue XR Avanti (Optovue, Inc). Automated segmentation was obtained through both the superficial and deep capillary plexuses for each eye. Grayscale optical coherence tomography angiography images were standardized and binarized using ImageJ (National Institutes of Health). Fractal box-counting analyses were conducted using Fractalyse (TheMA). Fractal dimensions (FDs) and correlation coefficient of the superficial and deep capillary plexuses were compared between control eyes and those in various stages of diabetic retinopathy. RESULTS: The superficial and deep capillary plexuses from diabetic and control eyes were analyzed. The average FD for diabetic eyes was significantly lower than in control eyes in the superficial plexus (P = 2.4 * 10) and in the deep capillary plexus (P = 1.87 * 10 ) with a more statistically significant difference noted in the deep capillary plexus. When analyzing diabetic patients without edema noted on optical coherence tomography, the FD was significantly reduced in the superficial (P = 0.001) and deep (P = 1.49 * 10) plexuses. When analyzing diabetic patients with edema noted on optical coherence tomography, the FD was significantly reduced in the superficial (P = 2.0 * 10) and deep (P = 1.85 * 10) plexuses. CONCLUSION: The optical coherence tomography angiography FD is significantly lower in both superficial and deep capillary plexuses in eyes with all stages studied of diabetic retinopathy. The results were more often significant for the deep capillary plexus. The use of fractal analysis provides an objective criterion to assess microvascular disease burden in diabetic retinopathy. PMID- 28723847 TI - BLINDNESS RELATED TO PRESUMED RETINAL TOXICITY AFTER USING PERFLUOROCARBON LIQUID DURING VITREORETINAL SURGERY. AB - PURPOSE: To describe the presumed retinal toxicity after using specific batches of perfluorocarbon liquid ALA OCTA (Alamedics, Dornstadt, Germany) in pars plana vitrectomy. METHODS: This is an observational retrospective consecutive case series analyses of patients operated on pars plana vitrectomy for retinal detachment or intraocular lens subluxation, using the 150141 or 200114 batches of perfluorocarbon liquid ALA OCTA as assistance during the surgery in a single center. Patients were included in this report if they manifested retinal toxicity signs throughout the follow-up, such as retinal and retinal pigment epithelium atrophy, disk paleness, and intensive macular fibrosis. Spectral domain optical coherence tomography (Spectralis; Heidelberg Engineering, Heidelberg, Germany) and Ultra-Wide Field 200 degrees retinal camera (Optos P200Tx; Optos, Scotland, United Kingdom) images, electrophysiological tests, and visual fields were performed to analyze the retinal structure and functionality. RESULTS: Seven of 80 patients showed all the described signs of toxicity, after a mean follow-up of 34.29 days (range: 10-87) since surgery. Four patients needed a second pars plana vitrectomy because of tractional retinal detachment and proliferative vitreoretinopathy, and two of them underwent a third surgery because of redetachment. All patients experienced amaurosis or central scotoma, with a final best-corrected visual acuity ranging from 20/200 to light perception. CONCLUSION: Presumed toxic batches of perfluorocarbon liquid may cause massive retinal toxicity. A rapid suspicion, a correct traceability of surgical products, and informing health authorities are fundamental to prevent further cases of toxicity. PMID- 28723848 TI - PROGRESSION OF MACULAR ATROPHY IN EYES WITH TYPE 1 NEOVASCULARIZATION AND AGE RELATED MACULAR DEGENERATION RECEIVING LONG-TERM INTRAVITREAL ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR THERAPY: An Optical Coherence Tomographic Angiography Analysis. AB - PURPOSE: To evaluate the size and location of macular atrophy in eyes with Type-1 neovascularization (NV) and age-related macular degeneration receiving chronic intravitreal anti-vascular endothelial growth factor therapy. METHODS: A retrospective review of a case series of 27 eyes with Type-1 NV and retinal pigment epithelial detachment (PED) having a minimum of 12 months follow-up was performed. Demographic information and visual acuity at baseline and the final follow-up were collected. Spectral-domain optical coherence tomography (OCT) and near-infrared reflectance were analyzed at 6-month intervals to detect and measure macular atrophy. Location and area (in square millimeter) of macular atrophy were measured using Heidelberg software tools. Also, OCT angiography was used to colocalize the area of Type-1 NV flow versus the location of atrophy. RESULTS: Twenty-seven eyes of 27 patients were included in this analysis. The median visual acuity was 20/50, mean age was 82.7 years, and mean number of injections was 29.5. A larger percentage of eyes (59.3%) developed atrophy predominantly eccentric to the PED versus predominantly overlying the PED (11.1%) when measured with spectral-domain OCT and near-infrared imaging. At the final follow-up, there was a larger area of atrophy surrounding the fibrovascular PED (mean, 3.326 mm) than overlying it (mean, 0.542 mm), and this was statistically significant (P = 0.0118). En-face OCT images were overlaid with OCT angiography in 11 eyes, and a predominantly eccentric pattern of atrophy was identified in 9 of 11 eyes. Using this method, the mean area of atrophy predominantly overlying the Type-1 NV was 1.652 mm (range of 0-10.464 mm), whereas the area of atrophy predominantly eccentric to the neovascular complex was 4.345 mm (range of 0.705 13.758 mm), and this was statistically significant (P = 0.0465). The average rate of atrophy progression was 1.04 mm/year (SD 0.938). CONCLUSION: With long-term anti-vascular endothelial growth factor therapy for eyes with Type-1 NV secondary to age-related macular degeneration, macular atrophy tends to develop predominantly eccentric to the PED and the neovascular flow imaged on OCT angiography. With chronic vascular endothelial growth factor suppression, Type-1 NV may evolve into a multilayered PED that may confer a protective effect to the overlying retinal pigment epithelium and outer retina. PMID- 28723849 TI - COMPARATIVE ANALYSIS OF RETINAL REATTACHMENT SURGERY WITH OR WITHOUT INTERNAL LIMITING MEMBRANE PEELING TO PREVENT POSTOPERATIVE MACULAR PUCKER. AB - PURPOSE: To determine whether internal limiting membrane (ILM) peeling during pars plana vitrectomy for rhegmatogenous retinal detachment reduces the incidence of epiretinal membrane (ERM) formation. METHODS: In this retrospective study, preoperative, intraoperative, and postoperative data from all eyes undergoing pars plana vitrectomy for rhegmatogenous retinal detachment between January 2007 and December 2013 was analyzed. All cases with at least 1-year of follow-up were included. Data collection included vision, intraoperative complications, occurrence of ERM, and spectral domain optical coherence tomography characteristics. The OCTs were retrieved for all eyes and were graded by a single masked grader. RESULTS: Out of 159 eyes recruited, ILM peeling was done in 78 eyes (49%). Overall occurrence of ERM was 20%. Seven eyes (9%) in ILM peeling group and 25 eyes in the non-ILM peeling group (31%) showed ERM (P = 0.001). Postoperative vision was significantly better in eyes that had ILM peeling (0.48 +/- 0.4 logarithm of the minimum angle of resolution [20/63] vs. 0.77 +/- 0.6 logarithm of the minimum angle of resolution [20/125], P = 0.003). In multivariable models adjusting for type of tamponade, ILM peeling reduced the likelihood of ERM formation by 75% (P = 0.01). CONCLUSION: Internal limiting membrane peeling during pars plana vitrectomy for rhegmatogenous retinal detachment significantly reduces ERM formation in the postoperative period and is associated with better visual and anatomical outcomes. PMID- 28723851 TI - INDOCYANINE GREEN ANGIOGRAPHY OF PACHYCHOROID PIGMENT EPITHELIOPATHY. AB - PURPOSE: To compare choroidal hyperpermeability and vessel density between eyes with central serous chorioretinopathy (CSC), those with pachychoroid pigment epitheliopathy (PPE) and those with uncomplicated pachychoroid (UCP). METHODS: We retrospectively reviewed indocyanine green angiography images of 60 patients with unilateral active CSC who had PPE (36 eyes) or UCP (24 eyes) in their fellow eyes. We used color thresholding of indocyanine green angiography images to determine choroidal vessel density. RESULTS: The mean choroidal thickness of eyes with CSC was greater than that of eyes with PPE or UCP, but this difference was not statistically significant (P = 0.46). There was no significant difference between the PPE (92%) and CSC (93%) groups regarding choroidal hyperpermeability (P = 0.76), but both of these groups had higher choroidal permeability than the UCP group (50%) (both P < 0.001). In 30 (90%) of 33 eyes with PPE who had choroidal hyperpermeability, retinal pigment epithelium alterations were in the region of hyperpermeability. Choroidal vessel density did not differ between the PPE and UCP groups (P = 0.57). CONCLUSION: Pachychoroid pigment epitheliopathy is forme fruste of CSC. There is no difference between complicated and UCP regarding subfoveal choroidal thickness and choroidal vessel density. The main difference between these groups is choroidal hyperpermeability. PMID- 28723852 TI - Effects of a Skin Barrier Cream on Management of Incontinence-Associated Dermatitis in Older Women: A Cluster Randomized Controlled Trial. AB - PURPOSE: The purpose of this study was to examine the effects of a skin barrier cream with moisturization and skin-protectant characteristics for improving the severity of incontinence-associated dermatitis (IAD) pertaining to the skin physiology and appearance. We measured the following outcomes: (1) skin physiological characteristics indicating skin protection and enhancement of the skin's moisture barrier (stratum corneum hydration, dermis hydration level, transepidermal water loss, and skin pH); and (2) changes in skin appearance (the degree of erythema and pigmentation, and the sulcus cutis condition). DESIGN: Single-blind, cluster randomized controlled trial. SUBJECTS AND SETTING: The study was conducted in a long-term care facility in Japan between November 7, 2011, and May 6, 2012. We used block randomization to obtain a random sample of 6 (4 experimental and 2 control) out of 10 available wards. All subjects were elderly women with IAD of the buttock or inner thigh. We assessed 295 patients, but only 33 met inclusion criteria; 18 were allocated to the experimental group and 15 were allocated to the control group. METHODS: All participants were managed with cleansing with a skin cleanser and application of a moisturizer daily. In addition, a skin barrier cream designed to enhance the skin's moisture barrier and act as a protective barrier was applied to the skin of patients in the experimental group 3 times a day when absorptive briefs were changed. Skin physiological and appearance characteristics were scored only at the buttock or thigh area. All data were collected on days 1 and 14 of the study. RESULTS: Univariate analysis found that the erythema index was lower in the intervention group than in the control group at day 14 (P = .004). Multivariate analysis found significant associations between use of the skin barrier cream and increased stratum corneum hydration (beta= .443, P = .031), decreased skin pH (beta=-.439, P = .020), and magnitude of erythema (beta=-.451, P = .018). CONCLUSIONS: Study findings suggest that a barrier cream designed to enhance the skin's moisture barrier and act as a skin protectant increased stratum corneum hydration, reduced cutaneous pH, and reduced erythema. PMID- 28723854 TI - Use of Colorectal Cancer Screening Among People With Mobility Disability. AB - GOALS: We aimed to assess use of colorectal cancer screening (CRCS) as per United States Preventive Task Force guidelines among people with mobility disability using a nationally representative data set. BACKGROUND: Individuals with mobility disability have decreased access to health care services, but the impact of mobility disability on CRCS has not been investigated. STUDY: Data from the 2013 National Health Interview Survey were used to estimate sociodemographic characteristics of adults with mobility disability, prevalence of CRCS, and odds of CRCS given mobility disability among Americans aged 50 to 75. RESULTS: In total, 56.8% of the entire sample (n=81,953,585) were up-to-date with CRCS. Mobility disability was not associated with CRCS status on univariable analysis but was significantly associated after adjustment for covariates including age and comorbidities, with an inverse relationship between the degree of mobility disability and odds of CRCS. Odds ratio for CRCS given progressively severe disability were 0.78 (0.66 to 0.93), 0.71 (0.53 to 0.94), 0.65 (0.31 to 1.19). CONCLUSIONS: The present study indicates reduced CRCS among people with mobility disability and highlights the need for CRCS to be especially targeted toward this group. Future research should identify the specific systemic, social, and/or physical barriers to CRCS for this subgroup so that they can be addressed. PMID- 28723853 TI - High-Frequency Ultrasound: Description of Sacral Tissue Characteristics in Healthy Adults. AB - OBJECTIVES: The purpose of this study was to describe selected sacral tissue characteristics in a convenience sample of healthy volunteer subjects. DESIGN: Descriptive. SAMPLE AND SETTING: Fifty healthy volunteers in a clinical learning center in a school of nursing. METHODS: Sacral scans were obtained using a 20-MHz ultrasound scanning system in 3 positions: prone and 60 degrees and 90 degrees side-lying from the back. The images were analyzed by software in the ultrasound program using quantitative parameters of dermal thickness and density (dermal median intensity and derived number of low-echogenic pixels to total pixels [LEP:TP] ratio). RESULTS: In general, average values were as follows: dermal thickness between 2.32 and 2.65 mm; median pixel intensity between 102 and 112; and the LEP:TP ratio between 0.39 and 0.56. There were significant differences in sacral tissue characteristics between measures of thickness and dermal density (median intensity and LEP:TP ratio) by subject side-lying position (60 degrees and 90 degrees ) versus prone position, with all P values less than .0001. CONCLUSIONS: Overall, the ranges were consistent across measures of thickness and dermal density except for systematic differences between side-lying and prone positions. When comparing thickness, median intensity, or LEP:TP ratio, it is important to report subject position. To best recognize tissue inflammation indicative of pressure injuries before surface changes are seen, it is useful to understand healthy high-frequency ultrasound sacral tissue characteristics. It is anticipated that quantitative assessment of dermal thickness, density, and LEP:TP ratio could help identify individuals with incipient pressure injury. PMID- 28723855 TI - Four-year Outcomes After Cessation of Tenofovir in Immune-tolerant Chronic Hepatitis B Patients. AB - GOALS: To study the long-term outcome after cessation of antiviral therapy in immune-tolerant patients. BACKGROUND: Experience in the treatment of immune tolerant chronic hepatitis B is scanty. Some immune-tolerant patients may receive temporary antiviral therapy, such as for prevention of vertical transmission at pregnancy or prophylaxis for chemotherapy. STUDY: This was a follow-up study of a phase 2 trial at 2 centers. Immune-tolerant patients received tenofovir disoproxil fumarate and/or emtricitabine for 4 years and were followed for another 4 years after treatment cessation. Virological relapse was defined as hepatitis B virus (HBV) DNA>2000 IU/mL; clinical relapse was defined as HBV DNA>2000 IU/mL; and alanine aminotransferase (ALT)>2 times the upper limit of normal. RESULTS: In total, 20 patients stopped treatment and were followed up for 206+/-14 weeks. All patients developed virological relapse at posttreatment week 4 (HBV DNA, 7.07+/-1.45 log IU/mL). A total of 10 (50%) patients developed clinical relapse at 15+/-11 weeks (highest ALT, 1149 U/L). In total, 11 (55%) patients were restarted on antiviral therapy; 4 achieved complete HBV DNA suppression and 1 achieved hepatitis B e antigen (HBeAg) seroconversion. Among the 9 patients not restarted on therapy, 2 patients had HBeAg seroconversion with normal ALT and HBV DNA of 7.12 and 1.62 IU/mL, respectively. The remaining 7 untreated patients continued to have positive HBeAg, high HBV DNA, and normal ALT. CONCLUSIONS: Rapid virological relapse is universal and clinical relapse is common after stopping antiviral therapy in patients with immune-tolerant chronic hepatitis B. HBeAg seroconversion is rare regardless of treatment reinitiation. PMID- 28723857 TI - The Clinical and Economic Effects of Targeted Bowel Preparation: Results of a Decision Analysis. AB - BACKGROUND: Colonoscopy bowel preparation failure is common, costly, and clinically harmful. Prediction models can identify patients at high risk for preparation failure, but they are rarely used. GOALS: To investigate the clinical and economic effects of using a more intensive preparation upfront (a "targeted" strategy) for patients identified as high risk for preparation failure. STUDY: We developed a Markov decision analytic model to compare usual care with a targeted strategy. Usual care consisted of a 4 L preparation, followed by a 2-day preparation in the event of preparation failure. The targeted strategy consisted of a 4 L preparation for low-risk patients, and upfront 2 days preparation for high-risk patients. Base-case values were gathered from literature review. Under each strategy, we calculated days spent preparing for, or undergoing, colonoscopy (patient burden), and cost per patient (payer perspective). Sensitivity analyses were performed. RESULTS: In the base case, the targeted strategy resulted in a similar patient burden compared with usual care (2.56 vs. 2.51 d, respectively). However, it substantially reduced cost per patient ($1254 vs. $1343) by reducing the number of colonoscopies. In sensitivity analyses, the targeted strategy reduced cost across the entire plausible range of risk of preparation failure and prediction model sensitivity and specificity. The targeted strategy resulted in less patient burden than usual care when (1) preparation failure risk exceeded 20%; (2) prediction sensitivity exceeded 73%; or (3) prediction specificity exceeded 76%. CONCLUSIONS: Targeted bowel preparation is likely to reduce costs associated with repeat colonoscopy with minimal effect on patient burden. PMID- 28723856 TI - Fecal Matrix Metalloprotease-9 and Lipocalin-2 as Biomarkers in Detecting Endoscopic Activity in Patients With Inflammatory Bowel Diseases. AB - BACKGROUND: Fecal biomarkers are emerging tools in the assessment of mucosal healing in inflammatory bowel diseases (IBD). GOALS: We aimed to evaluate the accuracy of fecal matrix metalloprotease-9 (MMP-9) and fecal lipocalin-2 (LCN-2) compared with calprotectin in detecting endoscopic activity in IBD STUDY:: Overall, 86 IBD adults underwent colonoscopy consecutively and prospectively, with Crohn's disease Endoscopic Index of Severity (CDEIS) in Crohn's disease (CD) patients or Mayo endoscopic subscore calculation for ulcerative colitis (UC) patients, and stool collection. Fecal calprotectin was measured using quantitative immunochromatographic testing. Fecal MMP-9 and LCN-2 was quantified by enzyme-linked immunosorbent assay. MMP-9 and LCN-2 thresholds were determined using receiver operating curves. RESULTS: In 54 CD patients, fecal calprotectin, MMP-9 and LCN-2 correlated with CDEIS and were significantly increased in patients with endoscopic ulcerations. MMP-9 >350 ng/g detected endoscopic ulceration in CD with a sensitivity of 90.0% and a specificity of 63.6%, compared with fecal calprotectin >250 MUg/g (sensitivity=90.5% and specificity=59.1%). Fecal LCN-2 demonstrated lower performances than the 2 other biomarkers (sensitivity=85.7% and specificity=45.5%).In 32 UC patients, fecal MMP-9, LCN-2, and calprotectin levels were significantly increased in patients with endoscopic activity. In UC patients, fecal MMP-9 >900 ng/g had the best efficacy to detect endoscopic activity (sensitivity=91.0% and specificity=80.0%, compared with fecal calprotectin >250 MUg/g (sensitivity=86.4% and specificity=80.0%) and LCN-2 >6700 ng/g (sensitivity=82.0% and specificity=80.0%). CONCLUSIONS: Fecal MMP-9 is a reliable biomarker in detecting endoscopic activity in both UC and CD patients. PMID- 28723858 TI - Maternal Hepatitis B Virus Infection and Pregnancy Outcomes: A Hospital-based Case-control Study in Wuhan, China. AB - GOALS: To examine the impact of maternal hepatitis B virus infection on pregnancy outcomes. BACKGROUND: Studies regarding hepatitis B virus infection and pregnancy outcomes are limited with inconsistent results, and none of them have evaluated the effect of maternal viral load in pregnancy on pregnancy outcomes. STUDY: A hospital-based case-control study was conducted. In total, 1728 hepatitis B surface antigen (HBsAg)-positive women who delivered consecutively at Wuhan Women and Children Medical and Healthcare Center, Wuhan, China, from June 2008 to May 2015, were compared with 1497 HBsAg-negative women giving birth in the same hospital during the same period who were randomly identified and selected from the computerized medical record database in parallel. Univariate and multivariate logistic regression models were constructed. RESULTS: After adjusting for confounding variables, maternal HBsAg carriage was associated with increased risk of pregnancy-induced hypertension [adjusted odds ratio (aOR)=2.20; 95% confidence interval (CI), 1.30-3.73], fetal distress (aOR=1.40; 95% CI, 1.09-1.78), cesarean delivery (aOR=1.70; 95% CI, 1.45-1.99), and macrosomia (aOR=1.68; 95% CI, 1.19 2.37). Moreover, maternal viral load in the second trimester was significantly associated with risk of preterm birth (aOR for each log10 copy/mL increase, 1.18; 95% CI, 1.01-1.39) among HBsAg carriers after adjustment for maternal age, employment, parity, history of abortion, and prenatal body mass index. CONCLUSIONS: Maternal HBsAg carriage was associated with several adverse pregnancy outcomes. Furthermore, hepatitis B viral activity in pregnancy might have certain effects on pregnancy outcomes. Careful surveillance of maternal HBsAg status as well as viral activity in the second trimester among HBsAg carriers is warranted. PMID- 28723859 TI - Determinants of Follow-up Care for Patients With Celiac Disease. AB - GOALS: This study aimed to investigate follow-up patterns among celiac disease (CD) patients. BACKGROUND: Gender factors are important in CD with women diagnosed more frequently than men despite equal seropositivity in screening studies. To determine if gender influences postdiagnosis care, we performed a retrospective cohort study investigating the impact of gender and mode of presentation on follow-up patterns after diagnosis. STUDY: The study included adults with biopsy-proven CD presenting to a single tertiary care center between 2005 and 2014. The primary exposure was at least 1 visit with a CD specialist. The primary outcome was >=2 follow-up visits, including office visits and endoscopic procedures. Data extracted included whether patients had tissue transglutaminase antibodies performed by our laboratory. RESULTS: We analyzed 708 patients of which 70.5% were female. Follow-up was good with a majority of patients (69%) having at least 1 follow-up visit. On bivariate analysis, patients least likely to follow-up were ages 18 to 29 (P=0.03) and women with atypical presentations (P=0.003). After adjusting for potential confounders, individuals over age 65 were significantly more likely to attend at least 2 follow-up visits (odds ratio, 2.07; 95% confidence interval, 1.21-3.55; P=0.0079). Individuals with an abnormal baseline tissue transglutaminase antibody value in our laboratory were significantly more likely to follow-up (odds ratio, 1.99; 95% confidence interval, 1.39-2.85; P=0.0002). CONCLUSIONS: Gender had no impact on follow-up patterns despite prior studies demonstrating an impact on diagnosis rates. Future attention should focus on retaining young patients and those with atypical modes of presentation. PMID- 28723860 TI - Higher Thioguanine Nucleotide Metabolite Levels are Associated With Better Long term Outcomes in Patients With Inflammatory Bowel Diseases. AB - GOALS: The aim of this study was to assess whether sustained 6 thioguaninenucleotide (6-TGN) levels were associated with improved long-term outcomes in patients with inflammatory bowel diseases (IBD). BACKGROUND: Cross sectional data have shown that thiopurine metabolites are correlated with clinical efficacy in patient receiving thiopurines for IBD but the role for serial measurements through treatment course is unclear. STUDY: We conducted a retrospective cohort study including patients with IBD on thiopurine monotherapy and had serial 6-TGN levels measured. Predictive variables included demographics, disease phenotype, 6-TGN levels (nadir, median, and peak levels). The primary outcome was the development of a disease relapse. The secondary outcome was the need for IBD surgery. RESULTS: Two hundred eighteen 6-TGN samples from 87 patients were analyzed. Nadir and median 6-TGN levels were significantly higher in patients who did not relapse [185 and 233 pmol per 8*10 red blood cells (RBCs)] as compared with levels in patients who did relapse (150 and 167 pmol per 8*10 RBCs, P=0.025) but there was no significant difference in peak 6-TGN level. When adjusted for confounding factors, a nadir 6-TGN level >=161 and a median 6 TGN level >=264 were associated with a significant decrease in the rate of disease exacerbation (hazard ratio: 0.5; 95% confidence interval, 0.26-0.87; P=0.016 and hazard ratio: 0.4; 95% confidence interval, 0.2-0.82; P=0.14). CONCLUSIONS: Serial thiopurine metabolite level assessments and dose adjustment aiming to maintain higher 6-TGN levels may be helpful to improve long-term outcomes in patients with IBD. PMID- 28723861 TI - Medicaid and Uninsured Hepatocellular Carcinoma Patients Have More Advanced Tumor Stage and Are Less Likely to Receive Treatment. AB - GOALS: To evaluate the impact of insurance status on tumor stage at diagnosis, treatment received, and overall survival among adults with hepatocellular carcinoma (HCC). BACKGROUND: Insurance status affects access to care, which impacts timely access to cancer screening for early detection and treatment. STUDY: Using the 2007 to 2012 Surveillance, Epidemiology, and End Results (SEER) database, we retrospectively evaluated US adults with HCC. Insurance status included Medicare/commercial insurance (MC), Medicaid (MA), and no insurance (NI). HCC tumor stage was evaluated using SEER staging system and Milan criteria. HCC treatment and survival were evaluated using multivariate logistic regression and Cox proportional hazards models. RESULTS: Among 32,388 HCC patients (71.2% MC, 23.9% MA, and 4.9% NI), patients with MA or NI were significantly less likely to have localized tumor stage at time of diagnosis compared with MC [NI vs. MC; odds ratio, 0.41; 95% confidence interval (CI), 0.78-0.92; P<0.001]. MA and NI patients were less likely to receive treatment, and specifically less likely to receive surgical resection or liver transplantation compared with MC patients, even after correcting for tumor stage at diagnosis (odds of surgical resection or liver transplant in NI vs. MC: odds ratio, 0.26; 95% CI, 0.21-0.33; P<0.001). NI patients (hazard ratio, 1.39; 95% CI, 1.29-1.50; P<0.001) had significantly lower survival compared with MC patients. CONCLUSIONS: Among US adults with HCC, MA, or NI patients had more advanced tumor stage at diagnosis, lower rates treatment, and significantly lower overall survival. Ensuring equal insurance coverage may improve access to care and mitigate some disparities in HCC outcomes. PMID- 28723862 TI - Risk of Colorectal Cancer in Chronic Kidney Disease: A Systematic Review and Meta Analysis. AB - BACKGROUND: Association between chronic kidney disease and colorectal cancer (CRC) remains unclear. GOALS: To assess the risk of CRC in patients with various chronic kidney diseases before and after kidney transplantation. STUDY: Electronic databases were searched for cohort studies assessing the risk of CRC in patients with chronic kidney diseases. The primary outcome was the risk of CRC among studies that reported the risk as standardized incidence rate (SIR). RESULTS: Fifty-four studies, including 1,208,767 patients that reported the incidence of CRC in chronic kidney diseases were identified. SIR of CRC were obtained from 17 retrospective cohort studies. Among the 3 studies (4 reports) that included chronic kidney disease patients without kidney transplantation, there was a significant increased risk of CRC (pooled SIR 1.18) (95% confidence interval, 1.01-1.37; P=0.033). High heterogeneity was seen (I=85.6%), and metaregression showed that there were positive correlations between the risk of CRC and the proportions of males, age and follow-up period. Among the 15 studies (17 reports) that included postkidney transplant patients, the pooled SIR was significantly increased at 1.40 (95% confidence interval, 1.15-1.71; P=0.00080). High heterogeneity was seen (I=88.9%), and metaregression showed that the follow up period correlated with the risk of CRC. CONCLUSIONS: In the present systematic review and meta-analysis, we demonstrated that patients with chronic kidney disease, regardless of a history of transplant, have a significant increased risk of CRC. A more intensive surveillance for CRC is required in this population. PMID- 28723863 TI - Factors Associated With Classification of Hyperplastic Polyps as Sessile Serrated Adenomas/Polyps on Morphologic Review. AB - BACKGROUND: Distinguishing sessile serrated adenomas/polyp (SSA/P), a subset of serrated polyps, from hyperplastic polyps (HPs) remains a challenge and has surveillance implications. Our goal was to identify clinical and pathologic factors associated with serrated polyps originally read as HPs being reassessed as SSA/Ps versus confirmed as HPs. METHODS: Data were collected from consecutive patients with a right-sided HP and a corresponding comparison group with conventional adenomas between 1993 and 2003. Two experienced gastrointestinal pathologists, blinded to polyp and clinical factors, reinterpreted the HPs using current SSA/P classification criteria. These HPs were classified as SSA/P when diagnostic histologic feature(s) were present in at least 3 crypts. Analyses, conducted on a per polyp basis, examined the factors associated with risk of individual HPs being reassessed as SSA/Ps as opposed to being confirmed as HPs. RESULTS: Of the 702 HPs (355 adults), 188 (26.8%) were reclassified as SSA/Ps. Predictors of HPs being reinterpreted as SSA/Ps included: size >=5 mm [odds ratio (OR), 2.09; 95% confidence interval (CI), 1.34-3.26], proximal location (OR, 2.83; 95% CI, 1.69-4.74), synchronous adenomas with advanced pathology (OR, 2.61; 95% CI, 1.22-5.55) and >=1 synchronous HPs (other than HP being reassessed) reclassified as SSA/Ps (OR, 11.76; 95% CI, 6.75-20.49). CONCLUSIONS: Because HP versus SSP is not very reproducible the predictors of SSA/P that we identified, including size, location, and synchronous lesions, can offer some additional help to endoscopists when determining surveillance intervals in patients with serrated polyps. In addition, observed association between SSA/P with advanced conventional neoplasia (but not low-grade adenomas) suggests 2 distinct groups of patient predisposition, one with both advanced conventional and important serrated precursors (SSA/P) and the other largely restricted to nonadvanced conventional adenomas and HPs only. Whether the association reported here has to do with SSA/P diagnosis per se or generally larger size of SSA/P remains to be determined in future studies. PMID- 28723864 TI - Sacral Neuromodulation for Fecal Incontinence: A Review of the Central Mechanisms of Action. AB - OBJECTIVE: Fecal incontinence (FI) has a devastating effect on the quality of life and results in social isolation. Sacral neuromodulation (SNM) is proven to be an effective, minimal invasive treatment modality for FI. Despite the increasing application of SNM, the exact mechanisms of action remain unclear. The initial assumption of peripheral motor neurostimulation is not supported by increasing evidence, which report effects of SNM outside the pelvic floor. A new hypothesis states that afferent signals to the brain are essential for a successful therapy. This study aimed to review relevant studies on the central mechanism of SNM in FI. METHODS: Clinical and experimental studies on the central mechanisms, both brain and spinal cord, of SNM for FI up to December 2015 were evaluated. RESULTS: In total, 8 studies were found describing original data on the central mechanism of SNM for FI. Four studies evaluated the central effects of SNM in a clinical setting and 4 studies evaluated the central effects of SNM in an experimental animal model. Results demonstrated a variety of (sub)cortical and spinal changes after induction of SNM. CONCLUSION: Review of literature demonstrated evidence for a central mechanism of action of SNM for FI. The corticoanal pathways, brainstem, and specific parts of the spinal cord are involved. PMID- 28723865 TI - MicroRNA-106b-5p regulates cisplatin chemosensitivity by targeting polycystic kidney disease-2 in non-small-cell lung cancer. AB - Systemic therapy with cytotoxic agents remains one of the main treatment methods for non-small-cell lung cancer (NSCLC). Cisplatin is a commonly used chemotherapeutic agent, that, when combined with other drugs, is an effective treatment for NSCLC. However, effective cancer therapy is hindered by a patient's resistance to cisplatin. Unfortunately, the potential mechanism underlying such resistance remains unclear. In this study, we explored the mechanism of microRNA 106b-5p (miR-106b-5p), which is involved in the resistance to cisplatin in the A549 cell line of NSCLC. Quantitative real-time PCR was used to test the expression of miR-106-5p in the A549 and the A549/DDP cell line of NSCLC. The cell counting kit-8 assay was used to detect cell viability. Flow cytometry was used to measure cell cycle and cell apoptosis. Luciferase reporter assays and western blot were performed to confirm whether polycystic kidney disease-2 (PKD2) is a direct target gene of miR-106b-5p. Immunohistochemistry was performed to examine the distribution of PKD2 expression in patients who are sensitive and resistant to cisplatin. The experiments indicated that the expression of miR-106b 5p was significantly decreased in A549/DDP compared with that in A549. MiR-106b 5p affected the tolerance of cells to cisplatin by negatively regulating PKD2. Upregulation of miR-106b-5p or downregulation of PKD2 expression can cause A549/DDP cells to become considerably more sensitive to cisplatin. The results showed that miR-106b-5p enhanced the sensitivity of A549/DDP cells to cisplatin by targeting the expression of PKD2. These findings suggest that the use of miR 106b-5p may be a promising clinical strategy in the treatment of NSCLC. PMID- 28723866 TI - A case of resistance to tyrosine kinase inhibitor therapy: small cell carcinoma transformation concomitant with plasma-genotyped T790M positivity. AB - Although non-small-cell lung cancer patients with epidermal growth factor receptor (EGFR) mutations are responsive to EGFR-tyrosine kinase inhibitors, drug resistances are always inevitable. The secondary somatic EGFR threonine methionine substitution at position 790 (T790M) mutation accounts for ~50% of acquired resistance mechanisms. Small cell lung cancer (SCLC) transformation is a relatively rare mechanism, but has recently attracted considerable attention. The coexistence of both the mechanisms in one patient is much more scarce in clinic. In this case report, we described a 37-year-old woman who underwent refractory after second-line gefitinib therapy and was confirmed to have SCLC transformation without the T790M mutation in the left lobar nodule, but concomitant with the plasma-genotyped EGFR T790M mutation. Our case report uncovered the underling relationship between SCLC transformation and the T790M mutation, and the fluid biopsy approach may help overcome the problem of heterogeneity in acquired resistance to EGFR-tyrosine kinase inhibitors. PMID- 28723868 TI - Screening of medicinal plant phytochemicals as natural antagonists of p53-MDM2 interaction to reactivate p53 functioning. AB - In most types of cancer, overexpression of murine double minute 2 (MDM2) often leads to inactivation of p53. The crystal structure of MDM2, with a 109-residue amino-terminal domain, reveals that MDM2 has a core hydrophobic region to which p53 binds as an amphipathic alpha helix. The interface depends on the steric complementarity between MDM2 and the hydrophobic region of p53. Especially, on p53's triad, amino acids Phe19, Trp23 and Leu26 bind to the MDM2 core. Results from studies suggest that the structural motif of both p53 and MDM2 can be attributed to similarities in the amphipathic alpha helix. Thus, in the current investigation it is hypothesized that the similarity in the structural motif might be the cause of p53 inactivation by MDM2. Hence, molecular docking and phytochemical screening approaches are appraised to inhibit the hydrophobic cleft of MDM2 and to stop p53-MDM2 interaction, resulting in reactivation of p53 activity. For this purpose, a library of 2295 phytochemicals were screened against p53-MDM2 to find potential candidates. Of these, four phytochemicals including epigallocatechin gallate, alvaradoin M, alvaradoin E and nordihydroguaiaretic acid were found to be potential inhibitors of p53-MDM2 interaction. The screened phytochemicals, derived from natural extracts, may have negligible side effects and can be explored as potent antagonists of p53-MDM2 interactions, resulting in reactivation of the normal transcription of p53. PMID- 28723867 TI - Prediction of severe toxicity in adult patients under treatment with 5 fluorouracil: a prospective cohort study. AB - 5-Fluorouracil (5-FU) has long been used for the treatment of gastrointestinal tumors harboring interindividual variability in both the pharmacokinetic and the pharmacogenetic profiles, which in turn may lead to life-threatening toxicities. We carried out a prospective cohort study of adult patients initiating treatment with 5-FU between 2013 and 2015. Primary exposures of interest were the methylenetetrahydrofolate reductase single nucleotide polymorphism in exons 4 and 7 and 5'-untranslated region-thymidylate synthase VNTR genotypes, in addition to baseline clinical and demographic variables. The primary outcome was the time to the occurrence of severe toxicity. We used a Cox regression model to evaluate patients' survival and toxicity experience and its association with baseline characteristics and a priori determined genetic polymorphisms. A total of 197 patients were included, 40.1% developed severe toxicity during follow-up. Variables that were significantly associated with developing severe toxicity were the European Organization for Research and Treatment of Cancer functional score [hazard ratio (HR): 0.98; 95% confidence interval (CI): 0.97-0.99]; type of tumor [anus (HR: 2.50; 95% CI: 1.07-5.82), head and neck/esophagus/stomach (HR: 2.95; 95% CI: 1.64-5.33)] and 5-FU continuous infusion regimens over 4-5 days (HR: 9.35; 95% CI: 2.68-32.59). We found a significant association between baseline functional status, type of tumor and continuous infusion regimens and the occurrence of severe toxicity during the follow-up of patients receiving 5-FU. No association was found with the genotypic variants evaluated. Future validation and modeling of an everyday easy-to-use score to predict toxicity among these subgroup of patients remains warranted. PMID- 28723869 TI - Chronic Disseminated Salmonellosis in a Patient With Interleukin-12p40 Deficiency. AB - Interleukin (IL)-12 is composed of p35 and p40 subunits; in this case, IL-12p40 deficiency is a rare genetic etiology of Mendelian susceptibility to mycobacterial disease. Salmonellosis has been reported in almost half of these patients and mostly present in recurrent extraintestinal form. In this report, we described an 18-month-old boy with absence of IL-12p40 production suffering from chronic disseminated nontyphoidal salmonellosis. To the best of our knowledge, this is the first-reported case. PMID- 28723870 TI - Osteoarticular Infections Caused by Streptococcus pneumoniae in Children in the Post-Pneumococcal Conjugate Vaccine Era. AB - BACKGROUND: Pneumococcal osteoarticular infections (OAIs) are an uncommon manifestation of invasive pneumococcal disease (IPD). We describe the demographic characteristics, hospitalization rate, serotype distribution and antibiotic susceptibility of children with pneumococcal OAI over a 16-year period. METHODS: We identified patients <=18 years old with pneumococcal OAI at 8 children's hospitals in the United States (2000-2015). Pneumococcal isolates were collected prospectively. Serotyping and antibiotic susceptibility were performed in a central laboratory. RESULTS: We identified 97 (3.3%) patients with pneumococcal OAI out of 2943 patients with IPD. Over 60% of the children were <2 years old. Septic arthritis (56.7%, 55/97) was the most common pneumococcal OAI, followed by osteomyelitis (25.8%, 25/97) and septic arthritis with concomitant osteomyelitis (17.5%, 17/97). Hospitalization for pneumococcal OAI overall decreased from 6.8 [95% confidence interval (CI): 5.2-8.6] to 4.4 (95% CI: 3.0-6.3) per 100,000 admissions from 2000-2009 to 2010-2015 (-35%, P = 0.05). Hospitalization for pneumococcal OAI caused by PCV13 serotypes decreased from 4.6 (95% CI: 3.4-6.2) to 0.9 (95% CI: 0.3-1.9) per 100,000 admissions from 2000-2009 to 2010-2015 ( 87%, P < 0.0001). Overall, 12% of isolates had a penicillin minimal inhibitory concentration> 2 ug/mL, 3% a ceftriaxone minimal inhibitory concentration> 1 ug/mL and 15% were clindamycin resistant; these proportions remained unchanged after the introduction of PCV13. Serotypes 19A and 35B were responsible for penicillin and ceftriaxone nonsusceptible isolates in 2010-2015. CONCLUSIONS: Pneumococcal OAI represents 3% of all IPD, affecting mainly healthy infants and young children. Hospitalization for pneumococcal OAI caused by PCV13 serotypes dramatically decreased (-87%) after the introduction of PCV13. PMID- 28723871 TI - Optimal Anti-Retroviral Prophylaxis in Infants At High-Risk of Acquiring Human Immunodeficiency Virus: A Systematic Review. AB - INTRODUCTION: The risk of perinatal HIV infection can be dramatically reduced through maternal antiretroviral therapy (ART) and infant antiretroviral (ARV) postnatal prophylaxis. The 2013 WHO guidelines recommended four to six weeks of nevirapine or zidovudine as post-natal prophylaxis, with possible extension to 12 weeks for high-risk breastfed infants. A systematic review was undertaken to determine if there is evidence for the WHO to recommend enhanced or extended prophylaxis for high-risk infants. METHODS: Cochrane CENTRAL, EMBASE, PubMed databases from 2005-2015, as well as CROI and IAS abstracts were searched. Cohort studies and randomized controlled trials (RCTs) examining the use of combination or prolonged regimens in HIV-exposed infants were included. 1185 studies were screened by title and abstract and 45 full-text articles were examined in further detail. RESULTS AND DISCUSSION: Of the four included studies, three examined multi-drug prophylaxis regimens in formula-fed, high-risk, HIV-exposed infants. Multi-drug regimens were shown to significantly reduce transmission rates, compared to single-drug regimens; however, there was no significant difference between two- and three-drug regimens. An RCT examining prolonged ARV prophylaxis in a breastfed population showed that six months of nevirapine resulted in lower HIV transmission rates compared to a standard six-week nevirapine regimen. CONCLUSIONS: The limited available evidence suggests that using combination ARV regimens in high-risk infants reduces intrapartum transmission and that using prolonged prophylaxis in breastfed infants reduces breastfeeding transmission rates. However, the additional benefit of combination or prolonged regimens in the context of maternal ART remains unclear. PMID- 28723872 TI - Marked Underreporting of Pertussis Requiring Hospitalization in Infants as Estimated by Capture-Recapture Methodology, Germany, 2013-2015. AB - BACKGROUND: In Germany, pertussis became notifiable in eastern federal states in 2002 and nationwide in March 2013. Infants are at greatest risk for severe disease, with a high proportion requiring hospitalization. We implemented enhanced hospital-based surveillance to estimate the incidence of pertussis requiring hospitalization among infants in Germany and to determine the proportion of infants hospitalized with pertussis too young to have been vaccinated. METHODS: Enhanced surveillance was implemented within a nationwide hospital surveillance network (ESPED). We defined cases as children less than 1 year of age hospitalized due to laboratory-confirmed pertussis with disease onset from 01/07/2013-30/06/2015. We matched cases to those ascertained in the national statutory notification system, and estimated incidence using capture-recapture methodology. RESULTS: The estimated annual incidence of pertussis requiring hospitalization in infants was 52/100,000 infants (95% confidence interval [CI] 48-57/100,000), with 39% under-reporting to the national notification system. During the two epidemiologic years under-reporting decreased from 46% to 32% and was lower in eastern than western federal states (21% vs. 40%). Within ESPED, 154 of 240 infants (64%) were younger than or still at the age recommended for the first vaccine dose; 55 (23%) could have received one or more vaccine doses. Median length of hospitalization was 9 days (IQR 5-13 days) and 18% required intensive care treatment. CONCLUSIONS: Our study revealed a high burden of pertussis in infants with marked under-reporting, especially in western federal states where notification was only recently established. Strategies for the prevention of severe pertussis. PMID- 28723873 TI - Total Disc Arthroplasty Versus Anterior Interbody Fusion in the Lumbar Spine Have Relatively a Few Differences in Readmission and Short-term Adverse Events. AB - STUDY DESIGN: Retrospective matched cohort study of prospectively collected data. OBJECTIVE: To compare rates of adverse events and readmission between lumbar total disc arthroplasty (TDA) and anterior lumbar interbody fusion (ALIF) using the American College of Surgeons National Surgical Quality Improvement Program database. SUMMARY OF BACKGROUND DATA: TDA and ALIF may be considered for similar degenerative indications. However, there have been a few large-cohort comparison studies of short-term clinical outcomes for these procedures. METHODS: The 2011 2015 NSQIP databases were retrospectively queried to identify patients who underwent elective stand-alone ALIF and TDA. After propensity matching, the association of procedure type with adverse events and readmission was determined using McNemar's test. Operative time and postoperative length of stay (LOS) were compared using multivariate linear regression. Risk factors for adverse events were determined using multivariate Poisson regression. RESULTS: In total, 1801 ALIF and 255 TDA patients were identified. After matching with propensity scores, there were no significant differences in the rates of any adverse event, serious adverse events, individual adverse events, or readmission other than blood transfusion, which occurred more frequently in the ALIF cohort (3.92% vs. 0.39%, P = 0.007). Operative time was not significantly different between the two cohorts, but postoperative LOS was significantly longer for ALIF cases (+0.28 days, P < 0.001). When evaluating 10 preoperative variables as potential risk factors for adverse events and readmission after TDA and ALIF, the majority of results were similar. CONCLUSION: The only identified differences in perioperative outcomes between TDA and ALIF were a 3.53% higher incidence of blood transfusion and 0.28-day longer LOS for the ALIF group. These results suggest overall similar short-term general-health outcomes between the two groups, and that the choice between the two procedures, for the appropriately selected patient, should be based on longer-term functional outcomes. LEVEL OF EVIDENCE: 3. PMID- 28723876 TI - Point of View. PMID- 28723877 TI - Human Spinal Bone Dust as a Potential Local Autograft: In Vitro Potent Anabolic Effect on Human Osteoblasts. AB - STUDY DESIGN: In vitro Study. OBJECTIVE: To evaluate the effect that factors released from human posterior spinal bone dust have on primary human osteoblast growth and maturation. SUMMARY OF BACKGROUND DATA: Bone dust, created during spinal fusion surgeries, has the potential to be used as an autologous bone graft by providing a source of viable autologous osteoblasts and mesenchymal stem cells with osteogenic potential. Till date, no information is available on whether bone dust also provides a source of anabolic factors with the potential to enhance osteoblast proliferation and maturation, which would enhance its therapeutic potential. METHODS: Bone dust was collected from consenting patients undergoing elective posterior spinal fusion surgeries, and primary human osteoblasts were cultured from patients undergoing elective hip or knee arthroplasty. Growth factors and cytokines released by bone dust were quantified using enzyme-linked immunosorbent assay. Primary human osteoblast proliferation and gene expression in response to bone dust were assessed using H-thymidine incorporation and real time polymerase chain reaction, respectively. RESULTS: Human bone dust released anabolic cytokines (IL-1beta and IL-6) and growth factors (TGF-beta, VEGF, FGF Basic, and PDGF-BB) in increasing concentrations over a 7-day period. In vitro, the anabolic factors released by bone dust increased osteoblast proliferation by 7-fold, compared with osteoblasts cultured alone. In addition, the factors released from bone dust up-regulated a number of osteoblastic genes integral to osteoblast differentiation, maturation, and angiogenesis. CONCLUSION: This study is the first to demonstrate that human posterior spinal bone dust released anabolic factors that potently enhance osteoblast proliferation and the expression of genes that favor bone healing and bone union. As bone dust is anabolic and its harvest is fast, simple, and safe to perform, spinal surgeons should be encouraged to 'recycle' bone dust and harness the regenerative potential of this free autologous bone graft. LEVEL OF EVIDENCE: N/A. PMID- 28723878 TI - Evolution of Surgery for Adolescent Idiopathic Scoliosis Over 20 Years: Have Outcomes Improved? AB - STUDY DESIGN: Retrospective review of a prospective adolescent idiopathic scoliosis (AIS) registry. OBJECTIVE: To study the evolution of the operative approach, outcomes, and complication rates in AIS surgery over the past 20 years. SUMMARY OF BACKGROUND DATA: Surgical techniques in AIS surgery have evolved considerably over the past 20 years. We study the trends in the operative management of AIS over this period and their impact on perioperative outcomes. METHODS: A total of 1819 AIS patients (1995-2013) with 2-year F/U were studied. Operative approach, perioperative parameters, major complication rates, and SRS outcomes were assessed. Linear regression was used to assess the trend of changes over 5-year quartiles. RESULTS: Mean age at surgery was 14.6 +/- 2.1 years, 80.2% were females, and this remained consistent throughout. Operative time, EBL/level, and LOS decreased over the 20 years (P < 0.0001). The use of antifibrinolytic (AF) increased from 6.7% to 68.8% in the past 10 years (P < 0.0001). Number of levels fused increased and LIV was more distal (in relation to stable vertebrae) over time in Lenke 1 and 2 curves (levels fused 7.97-9.94, P < 0.0001 and 9.8 11.0, P=0.0134, respectively). Anterior spinal fusion (ASF) in Lenke 1 curves decreased from 81% in the first quartile to 0% in the last (P = 0.0429). ASF for Lenke 5 curves evolved from 78% in the second quartile to 0 in the last. Thoracoplasty performance decreased from 76% to 20.3% (P = 0.1632). All screw constructs in PSF cases increased from 0% to 98.4% (P = 0.0095). Two-year major complication rates decreased over time (18.7%-5.1%; P = 0.0173). Increased improvement in SRS scores were observed in pain, image, function, and total domains. CONCLUSION: Evolution of surgical technique in AIS over the past 20 years has resulted in a cessation of anterior only surgery, increasing use of all screw constructs, less blood loss, greater use of AF, shorter operative times and LOS, lower major complications rates, and greater improvements in SRS scores. LEVEL OF EVIDENCE: 2. PMID- 28723879 TI - Suppression of Sympathetic Nerve Sprouting by Local Administration of an alpha antagonist Around the Dorsal Root Ganglion in a Lumbar Radiculopathy Model. AB - STUDY DESIGN: Animal experimental study with intervention. OBJECTIVE: The purpose of this study was to elucidate whether local administration of an alpha antagonist around the dorsal root ganglion (DRG) suppressed sympathetic nerve sprouting, from the acute to the chronic pain development phase, in a lumbar radiculopathy model using immunohistochemical methods. SUMMARY OF BACKGROUND DATA: The abnormal sympathetic-somatosensory interaction may underlie some forms of neuropathic pain. There were several reports suggesting alpha-antagonists are effective to treat neuropathic pain. However, its pathophysiological mechanisms remain obscure. METHODS: We used 70 male Sprague-Dawley rats. After root constriction (RC), rats received a series of three local injections of the nonselective alpha-antagonist phentolamine around the DRG for 3 days. There were three groups of rats: those that were injected from the day of surgery and those injected from day 4 and third group injected from day 11. The control rats were subjected to RC but equal-volume normal saline injections, and the naive rats were not subjected to any surgical procedures. At the 14th postoperative day, the left L5 DRG was removed, embedded in paraffin, and sectioned. Sections were then immunostained with antibodies to tyrosine hydroxylase (TH). To quantify the extent of the presence of sympathetic nerve fibers, we counted TH-immunoreactive fibers in the DRG using a light microscope equipped with a micrometer graticule. We counted the squares of the graticule, which contained TH-immunoreactive fibers for each of five randomly selected sections of the DRG. RESULTS: In the naive group, TH-immunoreactive fibers were scarce in the DRG. alpha-antagonist injections from postoperative day 0 and 4 suppressed sympathetic nerve sprouting compared with the control group. alpha-antagonist injections from postoperative day 11 had no suppressant effect compared with the control group. CONCLUSION: The alpha-antagonist administered around the DRG could suppress neural plastic changes in the early phase after nerve injury. LEVEL OF EVIDENCE: N/A. PMID- 28723880 TI - Prevalence and clinical characteristics of white-coat hypertension based on different definition criteria in untreated and treated patients. AB - BACKGROUND AND AIM: The prevalence and associated risks of white-coat hypertension (WCH) are still a matter of debate. We aimed to assess differences in prevalence and associated conditions of WCH defined on the basis of the normality of all daytime, night-time, and 24-h blood pressure (BP), only daytime, or only 24-h BP. METHODS: We selected 115 708 patients (45 020 untreated and 70 688 treated) from the Spanish Ambulatory BP Monitoring Registry. WCH was estimated in patients with elevated office BP (>=140 and/or 90 mmHg) by using normal daytime (<135/85) BP, normal 24-h BP (<130/80), or normal daytime, night time (<120/70) and 24-h BP. Demographic and clinical data (associated risk factors and organ damage) were compared among groups. RESULTS: Prevalence of WCH was 41.3, 35.2, and 26.1% in untreated, and 45.8, 38.9, and 27.2% in treated patients with elevated office BP, by using the criteria of daytime, 24-h, or all ambulatory periods. Compared with the normotensive group, WCH defined by normal daytime, night-time, and 24-h BP did not significantly differ in terms of other cardiovascular risk factors or organ damage. In contrast, patients from other groups (either only normal daytime BP or 24-h BP) had significantly more prevalence of diabetes, dyslipidaemia, microalbuminuria, left ventricular hypertrophy, reduced renal function, and previous history of cardiovascular disease. CONCLUSION: Prevalence of WCH is dependent on definition criteria. Only diagnostic criteria which considers the normality of all ambulatory periods identifies patients with cardiovascular risk similar to normotensive patients. These results support using such criteria for a more accurate definition of WCH. PMID- 28723881 TI - Correlation Between PaO2/FIO2 and Peripheral Capillary Oxygenation/FIO2 in Burned Children With Smoke Inhalation Injury. AB - OBJECTIVES: Determine whether the peripheral capillary oxygenation/FIO2 ratio correlates with the PaO2/FIO2 ratio in burned children with smoke inhalation injury, with the goal of understanding if the peripheral capillary oxygenation/FIO2 ratio can serve as a surrogate for the PaO2/FIO2 ratio for the diagnosis of acute respiratory distress syndrome. DESIGN: Retrospective chart review. SETTING: Shriners Hospitals for Children-Galveston. PATIENTS: All burned children with smoke inhalation injury who were admitted from 1996 to 2014 and had simultaneously obtained peripheral capillary oxygenation, FIO2 and PaO2 measurements. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Two hundred seventy-three patients (63% male, 8 +/- 5 yr, 53% +/- 24% total body surface area burns) were analyzed. Peripheral capillary oxygenation/FIO2 ratios were divided into four subgroups based on peripheral capillary oxygenation values (<= 100%, <= 98%, <= 95%, and <= 92%). Significance was accepted at r greater than 0.81. The r (number of matches) was 0.66 (23,072) for less than or equal to 100%, 0.87 (18,932) for less than or equal to 98%, 0.89 (7,056) for less than or equal to 95%, and 0.93 (4,229) for less than or equal to 92%. In the subgroup of patients who developed acute respiratory distress syndrome, r was 0.65 (8,357) for less than or equal to 100%, 0.89 (7,578) for less than or equal to 98%, 0.89 (4,115) for less than or equal to 95%, and 0.91 (2,288) less than or equal to 92%. CONCLUSIONS: PaO2/FIO2 and peripheral capillary oxygenation/FIO2 strongly correlate in burned children with smoke inhalation injury, with a peripheral capillary oxygenation of less than 92% providing the strongest correlation. Thus, peripheral capillary oxygenation/FIO2 ratio may be able to serve as surrogate for PaO2/FIO2, especially when titrating FIO2 to achieve a peripheral capillary oxygenation of 90-95% (i.e., in the acute respiratory distress syndrome range). PMID- 28723882 TI - Altered Carnitine Homeostasis in Children With Increased Pulmonary Blood Flow Due to Ventricular Septal Defects. AB - OBJECTIVES: Congenital heart disease with increased pulmonary blood flow results in progressive pulmonary vascular endothelial dysfunction and associated increased perioperative morbidity. Using our ovine model of congenital heart disease with increased pulmonary blood flow, we have previously demonstrated progressive endothelial dysfunction associated with disruption in carnitine homeostasis, mitochondrial dysfunction, decreased nitric oxide signaling, and enhanced reactive oxygen species generation. However, potential alterations in these parameters in patients with congenital heart disease have not been investigated. The objective of this study was to test the hypothesis that children with increased pulmonary blood flow will have evidence of altered carnitine homeostasis, mitochondrial dysfunction, decreased nitric oxide levels, and increased reactive oxygen species generation. DESIGN: A prospective single center cohort study. SETTING: A tertiary care cardiac ICU/PICU. PATIENTS: Arterial blood samples from 18 patients with congenital heart disease associated with increased pulmonary blood flow (ventricular septal defect), 20 with congenital heart disease without increased pulmonary blood flow (tetralogy of Fallot), and 10 without heart disease (controls) were obtained. INTERVENTIONS: Plasma levels of total carnitine, free carnitine, acylcarnitine, and lactate-to pyruvate ratios, an indicator of mitochondrial function, were determined and compared. In addition, levels of superoxide and hydrogen peroxide were determined and compared in patients with ventricular septal defect and controls. Statistical analysis was performed using an unpaired t test and analysis of variance. MEASUREMENTS AND MAIN RESULTS: Baseline acylcarnitine levels (25.7 +/- 13 vs 12.7 +/- 8.3; p < 0.05), the acylcarnitine-to-free carnitine ratio (0.8 +/- 0.1 vs 0.3 +/- 0.05; p < 0.05), and the lactate-to-pyruvate ratio were higher in ventricular septal defect (27.5 +/- 3.8 vs 11.1 +/- 4.1, p < 0.05) than tetralogy of Fallot; there were no differences between tetralogy of Fallot and control. Superoxide and H2O2 levels were also higher in ventricular septal defect compared with controls, and NOx levels were lower in ventricular septal defect patients compared with tetralogy of Fallot and controls (p < 0.05). CONCLUSIONS: These data suggest that increased pulmonary blood flow from ventricular septal defect results in altered carnitine and mitochondrial homeostasis, decreased nitric oxide signaling, and increased reactive oxygen species production. These data are consistent with our animal data demonstrating that altered carnitine homeostasis results in mitochondrial dysfunction, increased reactive oxygen species production, and decreased bioavailable nitric oxide. Since disruption of carnitine metabolism may contribute to endothelial dysfunction, carnitine supplementation may attenuate endothelial dysfunction associated with increased pulmonary blood flow and warrants further investigation. PMID- 28723883 TI - The American College of Critical Care Medicine Clinical Practice Parameters for Hemodynamic Support of Pediatric and Neonatal Septic Shock: Executive Summary. PMID- 28723884 TI - Preoperative Anemia as a Simple Prognostic Factor in Patients with Urinary Bladder Cancer. AB - BACKGROUND To evaluate the incidence of preoperative anemia and its prognostic role in patients with urinary bladder cancer (BC). MATERIAL AND METHODS A total of 317 patients diagnosed with BC were enrolled in this retrospective cohort study. Univariate and multivariate analysis was used to identify independent prognostic factors and Kaplan-Meier survival analysis was applied to examine the influence of anemia on survival. RESULTS 109 patients (34.4%) were anemic with a median preoperative hemoglobin of 114 g/L (interquartile range 104 to 122.5). After a median of 6 years follow-up (range: 2 to 8 years), the median recurrence free survival (RFS), progression-free survival (PFS), and overall survival (OS) in anemic patients were significantly lower than non-anemic patients (p<=0.001). Multivariate Cox analysis indicated that anemia remained an independent predictor of RFS and OS (p=0.010, 0.007). CONCLUSIONS Anemic patients with BC are likely to have a shorter RFS and OS than non-anemic patients, and anemia is an independent predictor of RFS and OS. PMID- 28723885 TI - Term vs. preterm cord blood cells for the prevention of preterm brain injury. AB - BACKGROUNDWhite matter brain injury in preterm infants can induce neurodevelopmental deficits. Umbilical cord blood (UCB) cells demonstrate neuroprotective properties, but it is unknown whether cells obtained from preterm cord blood (PCB) vs. term cord blood (TCB) have similar efficacy. This study compared the ability of TCB vs. PCB cells to reduce white matter injury in preterm fetal sheep.METHODSHypoxia-ischemia (HI) was induced in fetal sheep (0.7 gestation) by 25 min umbilical cord occlusion. Allogeneic UCB cells from term or preterm sheep, or saline, were administered to the fetus at 12 h after HI. The fetal brain was collected at 10-day post HI for assessment of white matter neuropathology.RESULTSHI (n=7) induced cell death and microglial activation and reduced total oligodendrocytes and CNPase+myelin protein in the periventricular white matter and internal capsule when compared with control (n=10). Administration of TCB or PCB cells normalized white matter density and reduced cell death and microgliosis (P<0.05). PCB prevented upregulation of plasma tumor necrosis factor (TNF)-a, whereas TCB increased anti-inflammatory interleukin (IL) 10 (P<0.05). TCB, but not PCB, reduced circulating oxidative stress.CONCLUSIONSTCB and PCB cells reduced preterm HI-induced white matter injury, primarily via anti-inflammatory actions. The secondary mechanisms of neuroprotection appear different following TCB vs. PCB administration. PMID- 28723886 TI - Prolonged viral replication and longitudinal viral dynamic differences among respiratory syncytial virus infected infants. AB - BackgroundLongitudinal respiratory syncytial virus (RSV) dynamics have not been well studied despite the existence of factors favoring prolonged RSV replication including high mutation rates allowing rapid evolution and potential escape from immune control. We therefore measured viral load in previously RSV-naive infants over prolonged time spans.MethodsDuring 2014-2015, quantitative nasal aspirates were collected from 51 RSV-PCR+ infants. Multiple parallel assessments of viral loads were quantified at each collected time point using a well-validated real time quantitative reverse transcriptase polymerase chain reaction assay. After observing viral load rebound phenomenon in some infants, the viral dynamics of 27 infants with sufficient longitudinal viral load data points were analyzed using the pre-defined criteria for viral rebound. Additional analyses were performed comparing age with viral rebound, viral clearance rates, and viral load area under-the-curve (AUCVL).ResultsThe 51 infants (303 nasal aspirate samples; mean of 5.9 per patient) exhibited slower than expected viral clearance. Lower age trended toward slower viral clearance and greater AUCVL. Six infants had detectable viral loads >=1 month after symptom onset. Ten of twenty-seven evaluable subjects exhibited viral rebound and this rebound was age-dependent (P=0.0259). All but one rebounder were <70 days old.ConclusionInfants struggle to control primary RSV infections allowing prolonged viral replication and previously undescribed viral rebound; likely representing viral mutational immune escape. PMID- 28723887 TI - In vitro and in vivo characterization of poractant alfa supplemented with budesonide for safe and effective intratracheal administration. AB - BackgroundThe intratracheal (IT) administration of budesonide using surfactant as a vehicle has been shown to reduce the incidence of bronchopulmonary dysplasia (BPD) in preterm infants. The objective of this study was to characterize the in vitro characteristics and in vivo safety and efficacy of the extemporaneous combination of budesonide and poractant alfa.MethodsThe stability, minimum surface tension, and viscosity of the preparation were evaluated by means of high performance liquid chromatography (HPLC), Wilhelmy balance, and Rheometer, respectively. The safety and efficacy of the IT administration of the mixture were tested in two respiratory distress syndrome (RDS) animal models: twenty seventh day gestational age premature rabbits and surfactant-depleted adult rabbits.ResultsA pre-formulation trial identified a suitable procedure to ensure the homogeneity and stability of the formulation. Wilhelmy Balance tests clarified that budesonide supplementation has no detrimental effect on poractant alfa surface tension activity. The addition of budesonide to poractant alfa did not affect the physiological response to surfactant treatment in both RDS animal models, and was associated to a significant reduction of lung inflammation in surfactant-depleted rabbits.ConclusionOur in vitro and in vivo analysis suggests that the IT administration of a characterized extemporaneous combination of poractant alfa and budesonide is a safe and efficacious procedure in the context of RDS. PMID- 28723888 TI - Association between supraclavicular brown adipose tissue composition at birth and adiposity gain from birth to 6 months of age. AB - BackgroundBrown adipose tissue (BAT) is associated with higher energy expenditure and lower adiposity in adults. However, the relationship between BAT composition and adiposity in early life is unknown. The objective of this study was to test the hypothesis that brown fat composition at birth is prospectively associated with adiposity gain during the first 6 months of postnatal life.MethodsN=35 healthy infants were followed up prospectively from intrauterine life and birth through 6 months of age. Dixon magnetic resonance imaging (MRI) scans were conducted during the neonatal period to characterize supraclavicular BAT composition. Dual-energy X-ray absorptiometry to assess total body composition was performed within the first and sixth months of life.ResultsAfter adjusting for potential confounding factors, a more brown-like composition (smaller fat fraction) of the supraclavicular BAT depot was associated with a smaller increase in percent body fat over the first 6 months of postnatal life.ConclusionsA more brown-like BAT composition at birth appears to be protective against excess adiposity gain in early life. Newborn BAT tissue may constitute a target for prevention strategies against the subsequent development of obesity. PMID- 28723889 TI - Distinct timescales of population coding across cortex. AB - The cortex represents information across widely varying timescales. For instance, sensory cortex encodes stimuli that fluctuate over few tens of milliseconds, whereas in association cortex behavioural choices can require the maintenance of information over seconds. However, it remains poorly understood whether diverse timescales result mostly from features intrinsic to individual neurons or from neuronal population activity. This question remains unanswered, because the timescales of coding in populations of neurons have not been studied extensively, and population codes have not been compared systematically across cortical regions. Here we show that population codes can be essential to achieve long coding timescales. Furthermore, we find that the properties of population codes differ between sensory and association cortices. We compared coding for sensory stimuli and behavioural choices in auditory cortex and posterior parietal cortex as mice performed a sound localization task. Auditory stimulus information was stronger in auditory cortex than in posterior parietal cortex, and both regions contained choice information. Although auditory cortex and posterior parietal cortex coded information by tiling in time neurons that were transiently informative for approximately 200 milliseconds, the areas had major differences in functional coupling between neurons, measured as activity correlations that could not be explained by task events. Coupling among posterior parietal cortex neurons was strong and extended over long time lags, whereas coupling among auditory cortex neurons was weak and short-lived. Stronger coupling in posterior parietal cortex led to a population code with long timescales and a representation of choice that remained consistent for approximately 1 second. In contrast, auditory cortex had a code with rapid fluctuations in stimulus and choice information over hundreds of milliseconds. Our results reveal that population codes differ across cortex and that coupling is a variable property of cortical populations that affects the timescale of information coding and the accuracy of behaviour. PMID- 28723890 TI - Metabolism: Energy sensing through a sugar diphosphate. PMID- 28723891 TI - The lysosomal potassium channel TMEM175 adopts a novel tetrameric architecture. AB - TMEM175 is a lysosomal K+ channel that is important for maintaining the membrane potential and pH stability in lysosomes. It contains two homologous copies of a six-transmembrane-helix (6-TM) domain, which has no sequence homology to the canonical tetrameric K+ channels and lacks the TVGYG selectivity filter motif found in these channels. The prokaryotic TMEM175 channel, which is present in a subset of bacteria and archaea, contains only a single 6-TM domain and functions as a tetramer. Here, we present the crystal structure of a prokaryotic TMEM175 channel from Chamaesiphon minutus, CmTMEM175, the architecture of which represents a completely different fold from that of canonical K+ channels. All six transmembrane helices of CmTMEM175 are tightly packed within each subunit without undergoing domain swapping. The highly conserved TM1 helix acts as the pore-lining inner helix, creating an hourglass-shaped ion permeation pathway in the channel tetramer. Three layers of hydrophobic residues on the carboxy terminal half of the TM1 helices form a bottleneck along the ion conduction pathway and serve as the selectivity filter of the channel. Mutagenesis analysis suggests that the first layer of the highly conserved isoleucine residues in the filter is primarily responsible for channel selectivity. Thus, the structure of CmTMEM175 represents a novel architecture of a tetrameric cation channel whose ion selectivity mechanism appears to be distinct from that of the classical K+ channel family. PMID- 28723892 TI - Global forest loss disproportionately erodes biodiversity in intact landscapes. AB - Global biodiversity loss is a critical environmental crisis, yet the lack of spatial data on biodiversity threats has hindered conservation strategies. Theory predicts that abrupt biodiversity declines are most likely to occur when habitat availability is reduced to very low levels in the landscape (10-30%). Alternatively, recent evidence indicates that biodiversity is best conserved by minimizing human intrusion into intact and relatively unfragmented landscapes. Here we use recently available forest loss data to test deforestation effects on International Union for Conservation of Nature Red List categories of extinction risk for 19,432 vertebrate species worldwide. As expected, deforestation substantially increased the odds of a species being listed as threatened, undergoing recent upgrading to a higher threat category and exhibiting declining populations. More importantly, we show that these risks were disproportionately high in relatively intact landscapes; even minimal deforestation has had severe consequences for vertebrate biodiversity. We found little support for the alternative hypothesis that forest loss is most detrimental in already fragmented landscapes. Spatial analysis revealed high-risk hot spots in Borneo, the central Amazon and the Congo Basin. In these regions, our model predicts that 121-219 species will become threatened under current rates of forest loss over the next 30 years. Given that only 17.9% of these high-risk areas are formally protected and only 8.9% have strict protection, new large-scale conservation efforts to protect intact forests are necessary to slow deforestation rates and to avert a new wave of global extinctions. PMID- 28723893 TI - In vivo CRISPR screening identifies Ptpn2 as a cancer immunotherapy target. AB - Immunotherapy with PD-1 checkpoint blockade is effective in only a minority of patients with cancer, suggesting that additional treatment strategies are needed. Here we use a pooled in vivo genetic screening approach using CRISPR-Cas9 genome editing in transplantable tumours in mice treated with immunotherapy to discover previously undescribed immunotherapy targets. We tested 2,368 genes expressed by melanoma cells to identify those that synergize with or cause resistance to checkpoint blockade. We recovered the known immune evasion molecules PD-L1 and CD47, and confirmed that defects in interferon-gamma signalling caused resistance to immunotherapy. Tumours were sensitized to immunotherapy by deletion of genes involved in several diverse pathways, including NF-kappaB signalling, antigen presentation and the unfolded protein response. In addition, deletion of the protein tyrosine phosphatase PTPN2 in tumour cells increased the efficacy of immunotherapy by enhancing interferon-gamma-mediated effects on antigen presentation and growth suppression. In vivo genetic screens in tumour models can identify new immunotherapy targets in unanticipated pathways. PMID- 28723894 TI - Cysteine protease cathepsin B mediates radiation-induced bystander effects. AB - The radiation-induced bystander effect (RIBE) refers to a unique process in which factors released by irradiated cells or tissues exert effects on other parts of the animal not exposed to radiation, causing genomic instability, stress responses and altered apoptosis or cell proliferation. Although RIBEs have important implications for radioprotection, radiation safety and radiotherapy, the molecular identities of RIBE factors and their mechanisms of action remain poorly understood. Here we use Caenorhabditis elegans as a model in which to study RIBEs, and identify the cysteine protease CPR-4, a homologue of human cathepsin B, as the first RIBE factor in nematodes, to our knowledge. CPR-4 is secreted from animals irradiated with ultraviolet or ionizing gamma rays, and is the major factor in the conditioned medium that leads to the inhibition of cell death and increased embryonic lethality in unirradiated animals. Moreover, CPR-4 causes these effects and stress responses at unexposed sites distal to the irradiated tissue. The activity of CPR-4 is regulated by the p53 homologue CEP-1 in response to radiation, and CPR-4 seems to exert RIBEs by acting through the insulin-like growth factor receptor DAF-2. Our study provides crucial insights into RIBEs, and will facilitate the identification of additional RIBE factors and their mechanisms of action. PMID- 28723895 TI - Visible-light-driven methane formation from CO2 with a molecular iron catalyst. AB - Converting CO2 into fuel or chemical feedstock compounds could in principle reduce fossil fuel consumption and climate-changing CO2 emissions. One strategy aims for electrochemical conversions powered by electricity from renewable sources, but photochemical approaches driven by sunlight are also conceivable. A considerable challenge in both approaches is the development of efficient and selective catalysts, ideally based on cheap and Earth-abundant elements rather than expensive precious metals. Of the molecular photo- and electrocatalysts reported, only a few catalysts are stable and selective for CO2 reduction; moreover, these catalysts produce primarily CO or HCOOH, and catalysts capable of generating even low to moderate yields of highly reduced hydrocarbons remain rare. Here we show that an iron tetraphenylporphyrin complex functionalized with trimethylammonio groups, which is the most efficient and selective molecular electro- catalyst for converting CO2 to CO known, can also catalyse the eight electron reduction of CO2 to methane upon visible light irradiation at ambient temperature and pressure. We find that the catalytic system, operated in an acetonitrile solution containing a photosensitizer and sacrificial electron donor, operates stably over several days. CO is the main product of the direct CO2 photoreduction reaction, but a two-pot procedure that first reduces CO2 and then reduces CO generates methane with a selectivity of up to 82 per cent and a quantum yield (light-to-product efficiency) of 0.18 per cent. However, we anticipate that the operating principles of our system may aid the development of other molecular catalysts for the production of solar fuels from CO2 under mild conditions. PMID- 28723897 TI - Cancer: A precision approach to tumour treatment. PMID- 28723896 TI - Maternal H3K27me3 controls DNA methylation-independent imprinting. AB - Mammalian sperm and oocytes have different epigenetic landscapes and are organized in different fashions. After fertilization, the initially distinct parental epigenomes become largely equalized with the exception of certain loci, including imprinting control regions. How parental chromatin becomes equalized and how imprinting control regions escape from this reprogramming is largely unknown. Here we profile parental allele-specific DNase I hypersensitive sites in mouse zygotes and morula embryos, and investigate the epigenetic mechanisms underlying these allelic sites. Integrated analyses of DNA methylome and tri methylation at lysine 27 of histone H3 (H3K27me3) chromatin immunoprecipitation followed by sequencing identify 76 genes with paternal allele-specific DNase I hypersensitive sites that are devoid of DNA methylation but harbour maternal allele-specific H3K27me3. Interestingly, these genes are paternally expressed in preimplantation embryos, and ectopic removal of H3K27me3 induces maternal allele expression. H3K27me3-dependent imprinting is largely lost in the embryonic cell lineage, but at least five genes maintain their imprinted expression in the extra embryonic cell lineage. The five genes include all paternally expressed autosomal imprinted genes previously demonstrated to be independent of oocyte DNA methylation. Thus, our study identifies maternal H3K27me3 as a DNA methylation independent imprinting mechanism. PMID- 28723899 TI - Cognition: Neurons couple up to make decisions. PMID- 28723898 TI - Fructose-1,6-bisphosphate and aldolase mediate glucose sensing by AMPK. AB - The major energy source for most cells is glucose, from which ATP is generated via glycolysis and/or oxidative metabolism. Glucose deprivation activates AMP activated protein kinase (AMPK), but it is unclear whether this activation occurs solely via changes in AMP or ADP, the classical activators of AMPK. Here, we describe an AMP/ADP-independent mechanism that triggers AMPK activation by sensing the absence of fructose-1,6-bisphosphate (FBP), with AMPK being progressively activated as extracellular glucose and intracellular FBP decrease. When unoccupied by FBP, aldolases promote the formation of a lysosomal complex containing at least v-ATPase, ragulator, axin, liver kinase B1 (LKB1) and AMPK, which has previously been shown to be required for AMPK activation. Knockdown of aldolases activates AMPK even in cells with abundant glucose, whereas the catalysis-defective D34S aldolase mutant, which still binds FBP, blocks AMPK activation. Cell-free reconstitution assays show that addition of FBP disrupts the association of axin and LKB1 with v-ATPase and ragulator. Importantly, in some cell types AMP/ATP and ADP/ATP ratios remain unchanged during acute glucose starvation, and intact AMP-binding sites on AMPK are not required for AMPK activation. These results establish that aldolase, as well as being a glycolytic enzyme, is a sensor of glucose availability that regulates AMPK. PMID- 28723900 TI - The natural history of acute Ebola Virus Disease among patients managed in five Ebola treatment units in West Africa: A retrospective cohort study. AB - INTRODUCTION: Previous studies of Ebola Virus Disease (EVD) have focused on clinical symptoms and Ebola virus (EBOV) cycle threshold (CT) values recorded at patient triage. Our study explores EVD symptoms and EBOV CT values from onset of illness to recovery or death in a diverse population of patients. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed clinical care data from EBOV positive patients admitted to five Ebola treatment units in West Africa from 2014-2015. Prevalence of clinical signs/symptoms and CT values were explored using descriptive statistics. Logistic regression was used to examine their association with mortality. Survival was analyzed using Kaplan-Meier estimators from symptom onset date to death. During the first week of illness, dyspnea (OR = 2.44, 95% CI: 1.07-5.85) and tachycardia (OR = 10.22, 95% CI: 2.20-56.71) were associated with higher odds of mortality. Dyspnea (OR = 2.33, 95% CI: 1.210-4.581), bleeding (OR = 2.51, 95% CI: 1.219-5.337), and diarrhoea (OR = 2.79, 95% CI: 1.171-6.970) at any point during the illness course were associated with higher odds of mortality. Higher initial (OR = 0.85, 95% CI: 0.81-0.89) and mean (OR = 0.60, 95% CI: 0.53-0.66) CT values were associated with lower odds of mortality. CT values reached their nadir after 3-5 days of illness and then rose in both survivors and non-survivors until recovery or death. CONCLUSIONS/SIGNIFICANCE: Our study demonstrates the population prevalence of clinical signs/symptoms and EBOV CT values over time in a large, diverse cohort of patients with EVD, as well as associations between symptoms/EBOV CT values and mortality. These findings have implications on surveillance, operational planning, and clinical care for future EVD outbreaks. PMID- 28723901 TI - 2b-RAD genotyping for population genomic studies of Chagas disease vectors: Rhodnius ecuadoriensis in Ecuador. AB - BACKGROUND: Rhodnius ecuadoriensis is the main triatomine vector of Chagas disease, American trypanosomiasis, in Southern Ecuador and Northern Peru. Genomic approaches and next generation sequencing technologies have become powerful tools for investigating population diversity and structure which is a key consideration for vector control. Here we assess the effectiveness of three different 2b restriction site-associated DNA (2b-RAD) genotyping strategies in R. ecuadoriensis to provide sufficient genomic resolution to tease apart microevolutionary processes and undertake some pilot population genomic analyses. METHODOLOGY/PRINCIPAL FINDINGS: The 2b-RAD protocol was carried out in-house at a non-specialized laboratory using 20 R. ecuadoriensis adults collected from the central coast and southern Andean region of Ecuador, from June 2006 to July 2013. 2b-RAD sequencing data was performed on an Illumina MiSeq instrument and analyzed with the STACKS de novo pipeline for loci assembly and Single Nucleotide Polymorphism (SNP) discovery. Preliminary population genomic analyses (global AMOVA and Bayesian clustering) were implemented. Our results showed that the 2b RAD genotyping protocol is effective for R. ecuadoriensis and likely for other triatomine species. However, only BcgI and CspCI restriction enzymes provided a number of markers suitable for population genomic analysis at the read depth we generated. Our preliminary genomic analyses detected a signal of genetic structuring across the study area. CONCLUSIONS/SIGNIFICANCE: Our findings suggest that 2b-RAD genotyping is both a cost effective and methodologically simple approach for generating high resolution genomic data for Chagas disease vectors with the power to distinguish between different vector populations at epidemiologically relevant scales. As such, 2b-RAD represents a powerful tool in the hands of medical entomologists with limited access to specialized molecular biological equipment. PMID- 28723902 TI - Seed size and its rate of evolution correlate with species diversification across angiosperms. AB - Species diversity varies greatly across the different taxonomic groups that comprise the Tree of Life (ToL). This imbalance is particularly conspicuous within angiosperms, but is largely unexplained. Seed mass is one trait that may help clarify why some lineages diversify more than others because it confers adaptation to different environments, which can subsequently influence speciation and extinction. The rate at which seed mass changes across the angiosperm phylogeny may also be linked to diversification by increasing reproductive isolation and allowing access to novel ecological niches. However, the magnitude and direction of the association between seed mass and diversification has not been assessed across the angiosperm phylogeny. Here, we show that absolute seed size and the rate of change in seed size are both associated with variation in diversification rates. Based on the largest available angiosperm phylogenetic tree, we found that smaller-seeded plants had higher rates of diversification, possibly due to improved colonisation potential. The rate of phenotypic change in seed size was also strongly positively correlated with speciation rates, providing rare, large-scale evidence that rapid morphological change is associated with species divergence. Our study now reveals that variation in morphological traits and, importantly, the rate at which they evolve can contribute to explaining the extremely uneven distribution of diversity across the ToL. PMID- 28723903 TI - Automatic analysis and 3D-modelling of Hi-C data using TADbit reveals structural features of the fly chromatin colors. AB - The sequence of a genome is insufficient to understand all genomic processes carried out in the cell nucleus. To achieve this, the knowledge of its three dimensional architecture is necessary. Advances in genomic technologies and the development of new analytical methods, such as Chromosome Conformation Capture (3C) and its derivatives, provide unprecedented insights in the spatial organization of genomes. Here we present TADbit, a computational framework to analyze and model the chromatin fiber in three dimensions. Our package takes as input the sequencing reads of 3C-based experiments and performs the following main tasks: (i) pre-process the reads, (ii) map the reads to a reference genome, (iii) filter and normalize the interaction data, (iv) analyze the resulting interaction matrices, (v) build 3D models of selected genomic domains, and (vi) analyze the resulting models to characterize their structural properties. To illustrate the use of TADbit, we automatically modeled 50 genomic domains from the fly genome revealing differential structural features of the previously defined chromatin colors, establishing a link between the conformation of the genome and the local chromatin composition. TADbit provides three-dimensional models built from 3C-based experiments, which are ready for visualization and for characterizing their relation to gene expression and epigenetic states. TADbit is an open-source Python library available for download from https://github.com/3DGenomes/tadbit. PMID- 28723904 TI - Impact of mass drug administration for elimination of lymphatic filariasis in Nepal. AB - BACKGROUND: Lymphatic filariasis (LF) is a neglected tropical disease transmitted by mosquitoes. Nepal has implemented a national effort to eliminate LF by 2020 through mass drug administration (MDA) using diethylcarbamazine (DEC) and albendazole (ALB). We assessed the impact of MDAs on LF in selected districts of Nepal after the recommended six MDA rounds had been completed. METHODOLOGY AND PRINCIPAL FINDINGS: Baseline surveys were conducted in seven districts and mapping data were used as baseline in the other three districts before starting MDA in 2009. LF antigen (Ag) prevalence ranged from 1.06% to 20% among districts included in the baseline and mapping study. The number of people who received DEC and ALB were recorded during each MDA round and population-based cluster surveys were conducted at least once in each district during the life of the program. The reported MDA coverage in five districts was consistently at least 65%. Two districts achieved the targeted coverage in four out of five rounds and the rest three districts achieved the target only in the first round. A pre-transmission assessment survey (pre-TAS) was conducted in one sentinel site and at least one spot check site in each of the districts after five MDA rounds. In pre-TAS, all the sites of five districts (Pyuthan, Arghakhanchi, Kaski, Bhaktapur, and Kathmandu) and all but one spot check site of Lalitpur district had LF Ag < 2% (ranging from 0.0% to 1.99%). Transmission assessment survey (TAS) was conducted in six evaluation units (EUs) consisting of six districts qualified on pre-TAS. Though MDA coverage of 65% was not achieved in three districts (Kathmandu, Lalitpur and Bhaktapur), Nepal government in consultation with World Health Organization (WHO) decided to conduct TAS. All six EUs achieved the LF Ag threshold required to stop MDA in TAS, despite the low reported MDA coverage in those three districts. CONCLUSIONS: Although Nepal has achieved significant progress towards LF elimination, five rounds of MDA were not sufficient to disrupt the transmission cycle in all districts, probably because of high baseline prevalence. PMID- 28723905 TI - Evolution of anti-Trypanosoma cruzi antibody production in patients with chronic Chagas disease: Correlation between antibody titers and development of cardiac disease severity. AB - Chagas disease is one of the most important endemic infections in Latin America affecting around 6-7 million people. About 30-50% of patients develop the cardiac form of the disease, which can lead to severe cardiac dysfunction and death. In this scenario, the identification of immunological markers of disease progression would be a valuable tool for early treatment and reduction of death rates. In this observational study, the production of anti-Trypanosoma cruzi antibodies through a retrospective longitudinal follow-up in chronic Chagas disease patients' cohort and its correlation with disease progression and heart commitment was evaluated. Strong inverse correlation (rho = -0.6375, p = 0.0005) between anti-T. cruzi IgG1 titers and left ventricular ejection fraction (LVEF) in chronic Chagas cardiomyopathy (CCC) patients were observed after disease progression. Elevated levels of anti-T. cruzi IgG3 titers were detected in all T. cruzi-infected patients, indicating a lack of correlation of this IgG isotype with disease progression. Furthermore, low levels of anti-T. cruzi IgG2, IgG4, and IgA were detected in all patients through the follow-up. Although without statistical significance anti-T. cruzi IgE tends to be more reactive in patients with the indeterminate form (IND) of the disease (p = 0.0637). As this study was conducted in patients with many years of chronic disease no anti-T. cruzi IgM was detected. Taken together, these results indicate that the levels of anti-T. cruzi IgG1 could be considered to seek for promising biomarkers to predict the severity of chronic Chagas disease cardiomyopathy. PMID- 28723906 TI - Genomic prediction with parallel computing for slaughter traits in Chinese Simmental beef cattle using high-density genotypes. AB - Genomic selection has been widely used for complex quantitative trait in farm animals. Estimations of breeding values for slaughter traits are most important to beef cattle industry, and it is worthwhile to investigate prediction accuracies of genomic selection for these traits. In this study, we assessed genomic predictive abilities for average daily gain weight (ADG), live weight (LW), carcass weight (CW), dressing percentage (DP), lean meat percentage (LMP) and retail meat weight (RMW) using Illumina Bovine 770K SNP Beadchip in Chinese Simmental cattle. To evaluate the abilities of prediction, marker effects were estimated using genomic BLUP (GBLUP) and three parallel Bayesian models, including multiple chains parallel BayesA, BayesB and BayesCpi (PBayesA, PBayesB and PBayesCpi). Training set and validation set were divided by random allocation, and the predictive accuracies were evaluated using 5-fold cross validations. We found the accuracies of genomic predictions ranged from 0.195+/ 0.084 (GBLUP for LMP) to 0.424+/-0.147 (PBayesB for CW). The average accuracies across traits were 0.327+/-0.085 (GBLUP), 0.335+/-0.063 (PBayesA), 0.347+/-0.093 (PBayesB) and 0.334+/-0.077 (PBayesCpi), respectively. Notably, parallel Bayesian models were more accurate than GBLUP across six traits. Our study suggested that genomic selections with multiple chains parallel Bayesian models are feasible for slaughter traits in Chinese Simmental cattle. The estimations of direct genomic breeding values using parallel Bayesian methods can offer important insights into improving prediction accuracy at young ages and may also help to identify superior candidates in breeding programs. PMID- 28723908 TI - Sorting cells by their density. AB - Sorting cells by their type is an important capability in biological research and medical diagnostics. However, most cell sorting techniques rely on labels or tags, which may have limited availability and specificity. Sorting different cell types by their different physical properties is an attractive alternative to labels because all cells intrinsically have these physical properties. But some physical properties, like cell size, vary significantly from cell to cell within a cell type; this makes it difficult to identify and sort cells based on their sizes alone. In this work we continuously sort different cells types by their density, a physical property with much lower cell-to-cell variation within a cell type (and therefore greater potential to discriminate different cell types) than other physical properties. We accomplish this using a 3D-printed microfluidic chip containing a horizontal flowing micron-scale density gradient. As cells flow through the chip, Earth's gravity makes each cell move vertically to the point where the cell's density matches the surrounding fluid's density. When the horizontal channel then splits, cells with different densities are routed to different outlets. As a proof of concept, we use our density sorter chip to sort polymer microbeads by their material (polyethylene and polystyrene) and blood cells by their type (white blood cells and red blood cells). The chip enriches the fraction of white blood cells in a blood sample from 0.1% (in whole blood) to nearly 98% (in the output of the chip), a 1000x enrichment. Any researcher with access to a 3D printer can easily replicate our density sorter chip and use it in their own research using the design files provided as online Supporting Information. Additionally, researchers can simulate the performance of a density sorter chip in their own applications using the Python-based simulation software that accompanies this work. The simplicity, resolution, and throughput of this technique make it suitable for isolating even rare cell types in complex biological samples, in a wide variety of different research and clinical applications. PMID- 28723907 TI - Auditory and visual distractors disrupt multisensory temporal acuity in the crossmodal temporal order judgment task. AB - The ability to synthesize information across multiple senses is known as multisensory integration and is essential to our understanding of the world around us. Sensory stimuli that occur close in time are likely to be integrated, and the accuracy of this integration is dependent on our ability to precisely discriminate the relative timing of unisensory stimuli (crossmodal temporal acuity). Previous research has shown that multisensory integration is modulated by both bottom-up stimulus features, such as the temporal structure of unisensory stimuli, and top-down processes such as attention. However, it is currently uncertain how attention alters crossmodal temporal acuity. The present study investigated whether increasing attentional load would decrease crossmodal temporal acuity by utilizing a dual-task paradigm. In this study, participants were asked to judge the temporal order of a flash and beep presented at various temporal offsets (crossmodal temporal order judgment (CTOJ) task) while also directing their attention to a secondary distractor task in which they detected a target stimulus within a stream visual or auditory distractors. We found decreased performance on the CTOJ task as well as increases in both the positive and negative just noticeable difference with increasing load for both the auditory and visual distractor tasks. This strongly suggests that attention promotes greater crossmodal temporal acuity and that reducing the attentional capacity to process multisensory stimuli results in detriments to multisensory temporal processing. Our study is the first to demonstrate changes in multisensory temporal processing with decreased attentional capacity using a dual task paradigm and has strong implications for developmental disorders such as autism spectrum disorders and developmental dyslexia which are associated with alterations in both multisensory temporal processing and attention. PMID- 28723909 TI - Reliability, convergent validity and factor structure of the DASS-21 in a sample of Vietnamese adolescents. AB - OBJECTIVES: To assess the internal consistency, latent structure and convergent validity of the Depression, Anxiety and Stress Scale-21 (DASS-21) among adolescents in Vietnam. METHOD: An anonymous, self-completed questionnaire was conducted among 1,745 high school students in Hanoi, Vietnam between October, 2013 and January, 2014. Confirmatory factor analyses were performed to assess the latent structure of the DASS-21. Factorial invariance between girls and boys was examined. Cronbach alphas and correlation coefficients between DASS-21 factor scores and the domain scores of the Duke Health Profile Adolescent Vietnamese validated version (ADHP-V) were calculated to assess DASS-21 internal consistency and convergent validity. RESULTS: A total of 1,606/ 1,745 (92.6%) students returned the questionnaire. Of those, 1,387 students provided complete DASS-21 data. The scale demonstrated adequate internal consistency (Cronbach alpha: 0.761 to 0.906). A four-factor model showed the best fit to the data. Items loaded significantly on a common general distress factor, the depression, and the anxiety factors, but few on the stress factor (p<0.05). DASS-21 convergent validity was confirmed with moderate correlation coefficients (-0.47 to -0.66) between its factor scores and the ADHP-V mental health related domains. CONCLUSIONS: The DASS-21 is reliable and suitable for use to assess symptoms of common mental health problems, especially depression and anxiety among Vietnamese adolescents. However, its ability in detecting stress among these adolescents may be limited. Further research is warrant to explore these results. PMID- 28723910 TI - Estimating mono- and bi-phasic regression parameters using a mixture piecewise linear Bayesian hierarchical model. AB - The dynamics of tumor burden, secreted proteins or other biomarkers over time, is often used to evaluate the effectiveness of therapy and to predict outcomes for patients. Many methods have been proposed to investigate longitudinal trends to better characterize patients and to understand disease progression. However, most approaches assume a homogeneous patient population and a uniform response trajectory over time and across patients. Here, we present a mixture piecewise linear Bayesian hierarchical model, which takes into account both population heterogeneity and nonlinear relationships between biomarkers and time. Simulation results show that our method was able to classify subjects according to their patterns of treatment response with greater than 80% accuracy in the three scenarios tested. We then applied our model to a large randomized controlled phase III clinical trial of multiple myeloma patients. Analysis results suggest that the longitudinal tumor burden trajectories in multiple myeloma patients are heterogeneous and nonlinear, even among patients assigned to the same treatment cohort. In addition, between cohorts, there are distinct differences in terms of the regression parameters and the distributions among categories in the mixture. Those results imply that longitudinal data from clinical trials may harbor unobserved subgroups and nonlinear relationships; accounting for both may be important for analyzing longitudinal data. PMID- 28723911 TI - Male reproductive system and spermatogenesis of Limodromus assimilis (Paykull 1790). AB - Based on advanced light and electron microscopy, we describe the male reproductive system and sperm development of Limodromus assimilis. The genital tract consists of pairs of uni-follicular testes, spermatic ducts with diverticula regions, seminal vesicles, accessory glands, an unpaired ejaculatory duct and an aedeagus containing an internal sac equipped with sclerotic scales. Based on their morphology, we draw conclusions about their functions. After spermatogenesis within the follicle, the spermatozoa become released from the sperm cysts. The single spermatozoa move into the diverticula of the vasa deferentia I. Here, they become attached to central rods (spermatostyles), forming secondary conjugates (spermiozeugmata). The coordinated flagella movement of the conjugates possibly improves sperm velocity. Using super-resolution microscopy, we identified highly condensed reticulate chromatin in the lancet shaped spermatozoa heads and the mitochondrial derivates of the flagella, likely formed by genomic and mitochondrial DNA, respectively. The results show, for the first time, sperm bundle formation in a Platynini species mainly corresponding to that found in Pterostichini species. PMID- 28723912 TI - Ginger and the beetle: Evidence of primitive pollination system in a Himalayan endemic alpine ginger (Roscoea alpina, Zingiberaceae). AB - The Himalayan endemic alpine genus Roscoea, like other members of ginger family, exhibits the combination of floral traits that would fit pollination by long distant foragers such as bees, birds or flies. We studied the pollination biology of Roscoea alpina, observed potential floral visitors and determined their foraging behaviour, visitation frequency and pollination efficiency, to seek evidence in support of the pollination syndrome hypothesis. We also measured the floral spectra of R. alpina flowers to evaluate if signals fit with the currently known framework for observed floral visitors. We found that R. alpina have autonomous selfing and pollinator-mediated crossing, but lack apomixis. We observed that a beetle (Mylabris sp.), and a moth (Macroglossum nycteris) visit the flowers of R. alpina for pollen and nectar feeding respectively. Our field observations, the stigmatic pollen count and fruit set data indicated that the visit by the beetle was legitimate, while that of the moth was illegitimate. Emasculated flowers visited by beetles set as many fruits and seeds/fruit as auto selfed and naturally pollinated flowers, while emasculated flowers excluded from beetle visits did not set fruit and seed; indicating that a single visit of a beetle to the flowers of R. alpina can facilitate pollination. We found that flower spectral signal of R. alpina does not fit typical spectra previously reported for beetle or bee-visited flowers. Our results suggest that, to ensure reproductive success in alpine habitat, R. alpina has evolved autonomous selfing as a predominant mode of reproduction, while beetle pollination would promote genetic diversity of this plant species. The visitation of beetles to the flowers of R. alpina, despite floral signal mismatch with the classically associated beetle vision, suggests that a different visual processing may operate in this plant-pollinator interaction at high altitudes. PMID- 28723914 TI - Safety and pharmacodynamics of dalazatide, a Kv1.3 channel inhibitor, in the treatment of plaque psoriasis: A randomized phase 1b trial. AB - BACKGROUND: Dalazatide is a specific inhibitor of the Kv1.3 potassium channel. The expression and function of Kv1.3 channels are required for the function of chronically activated memory T cells, which have been shown to be key mediators of autoimmune diseases, including psoriasis. OBJECTIVE: The primary objective was to evaluate the safety of repeat doses of dalazatide in adult patients with mild to-moderate plaque psoriasis. Secondary objectives were to evaluate clinical proof of concept and the effects of dalazatide on mediators of inflammation in the blood and on chronically activated memory T cell populations. METHODS: Patients (n = 24) were randomized 5:5:2 to receive dalazatide at 30 mcg/dose, 60 mcg/dose, or placebo twice weekly by subcutaneous injection (9 doses total). Safety was assessed on the basis of physical and neurological examination and laboratory testing. Clinical assessments included body-surface area affected, Psoriasis Area and Severity Index (PASI), and investigator and patient questionnaires. RESULTS: The most common adverse events were temporary mild (Grade 1) hypoesthesia (n = 20; 75% placebo, 85% dalazatide) and paresthesia (n = 15; 25% placebo, 70% dalazatide) involving the hands, feet, or perioral area. Nine of 10 patients in the 60 mcg/dose group had a reduction in their PASI score between baseline and Day 32, and the mean reduction in PASI score was significant in this group (P < 0.01). Dalazatide treatment reduced the plasma levels of multiple inflammation markers and reduced the expression of T cell activation markers on peripheral blood memory T cells. LIMITATIONS: The study was small and drug treatment was for a short duration (4 weeks). CONCLUSION: This study indicates that dalazatide is generally well tolerated and can improve psoriatic skin lesions by modulating T cell surface and activation marker expression and inhibiting mediators of inflammation in the blood. Larger studies of longer duration are warranted. PMID- 28723913 TI - Prebiotic selection for motifs in a model of template-free elongation of polymers within compartments. AB - The transition from prelife where self-replication does not occur, to life which exhibits self-replication and evolution, has been a subject of interest for many decades. Membranes, forming compartments, seem to be a critical component of this transition as they provide several concurrent benefits. They maintain localized interactions, generate electro-chemical gradients, and help in selecting cooperative functions as they arise. These functions pave the way for the emergence and maintenance of simple metabolic cycles and polymers. In the context of origin of life, evolution of information-carrying molecules and RNA based enzymes within compartments has been subject to intensive theoretical and experimental research. Hence, many experimental efforts aim to produce compartments that contain elongating polynucleotides (also referred to as protocells), which store information and perform catalysis. Despite impressive experimental progress, we are still relatively ignorant about the dynamics by which elongating polynucleotides can produce more sophisticated behaviors. Here we perform computer simulations to couple information production through template free elongation of polymers with dividing compartments. We find that polymers with a simple ability-biasing the concentration of monomers within their own compartment-can acquire a selective advantage in prelife. We further investigate whether such a mechanism allows for cooperative dynamics to dominate over purely competitive ones. We show that under this system of biased monomer addition, even without template-directed self-replication, genetic motifs can emerge, compete, cooperate, and ultimately survive within the population. PMID- 28723915 TI - Key findings from a prospective trauma registry at a regional hospital in Southwest Cameroon. AB - INTRODUCTION: Trauma is a leading cause of morbidity and mortality worldwide. Data characterizing the burden of trauma in Cameroon is limited. Regular, prospective injury surveillance can address the shortcomings of existing hospital administrative logs and medical records. This study aims to characterize trauma as seen at the emergency department (ED) of Limbe Regional Hospital (LRH) and assess the completeness of data obtained by a trauma registry. METHODS AND FINDINGS: From January 2008 to October 2013, we prospectively captured data on injured patients using a strategically designed, context-relevant trauma registry instrument. Indicators around patient demographics, injury characteristics, delays in accessing care, and treatment outcomes were recorded. Descriptive, bivariate, and multivariate statistical analyses were conducted. About 5,617 patients, aged from 0.5-95years (median age of 26 years), visited the LRH ED with an injury; 67% were male. Students (27%) were the most affected occupation category. Road traffic injuries (RTIs) (56%), assault (22%), and domestic injuries (13%) were the leading causes of injury. Two-thirds of RTIs were motorcycle-related. Working in transportation (AOR 4.42, p<0.001) and law enforcement (AOR 1.73, p = 0.004) were significant predictors of having a RTI. The trauma registry showed a significant improvement in completeness of all data (p<0.001) and it improved over time compared with previous administrative records. However, proportions of missing data still ranged from 0.5% to 8.2% and involved respiratory rate or Glasgow Coma scale. CONCLUSIONS: Implementation of a context-appropriate trauma registry in resource-constrained settings is feasible. Providing valuable, high-quality data, the trauma registry can inform trauma care quality improvement efforts and policy development. Study findings indicate the need for injury prevention interventions and policies that will prioritize high risks groups, such as those aged 20-29 years, and those in occupations requiring frequent road travel. The high incidence of motorcycle-related injuries is concerning and calls for a proactive solution. PMID- 28723916 TI - Stakeholders' views and experiences of care and interventions for addressing frailty and pre-frailty: A meta-synthesis of qualitative evidence. AB - Frailty is a common condition in older age and is a public health concern which requires integrated care and involves different stakeholders. This meta-synthesis focuses on experiences, understanding, and attitudes towards screening, care, intervention and prevention for frailty across frail and healthy older persons, caregivers, health and social care practitioners. Studies published since 2001 were identified through search of electronic databases; 81 eligible papers were identified and read in full, and 45 papers were finally included and synthesized. The synthesis was conducted with a meta-ethnographic approach. We identified four key themes: Uncertainty about malleability of frailty; Strategies to prevent or to respond to frailty; Capacity to care and person and family-centred service provision; Power and choice. A bottom-up approach which emphasises and works in synchrony with frail older people's and their families' values, goals, resources and optimisation strategies is necessary. A greater employment of psychological skills, enhancing communication abilities and tools to overcome disempowering attitudes should inform care organisation, resulting in more efficient and satisfactory use of services. Public health communication about prevention and management of frailty should be founded on a paradigm of resilience, balanced acceptance, and coping. Addressing stakeholders' views about the preventability of frailty was seen as a salient need. PMID- 28723917 TI - Evidence base and practice variation in acute care processes for knee and hip arthroplasty surgeries. AB - BACKGROUND: Lack of evidence contributes to unnecessary variation in treatment costs and outcomes. This study aimed to identify from interventions historically used for total knee or hip arthroplasty (TKA, THA): i) if routine use is supported by high-level evidence; ii) whether surgeon use aligns with the evidence. METHODS: Part 1: Systematic search of electronic library databases for systematic reviews and practice guidelines concerning seven acute-care interventions. Intervention-specific recommendations concerning routine use were extracted by assessors. Part 2: Prospective medical record audit of the acute care received by 1900 patients involving 120 orthopaedic surgeons. Surgeon use per intervention was summarized using caterpillar plots. Surgeon-specific routine and non-routine use was defined as use in >= 90% and <= 10% of patients, respectively. Primary analysis included only surgeons contributing >= 10 patients. RESULTS: Continuous passive motion (TKA): Routine use not recommended; 85.7% of surgeons did not use it routinely. Tranexamic Acid: Routine use recommended; 26.9% of surgeons used it routinely. Cryotherapy: Routine use not recommended; 45.7% of surgeons used it routinely for TKA; 31.8% used it routinely for THA. Intra-articular drainage: Routine use not recommended for TKA, but possible benefits for THA; 5.7% of surgeons used it routinely for TKA, 0.0% used it routinely for THA. Antibiotic loaded bone cement: Routine use for TKA not supported, recommendations for use for THA are inconsistent; 90.0% of surgeons used it routinely for TKA, 100.0% used it routinely for THA. Patella resurfacing (TKA): No recommendation could be made; 57.1% of surgeons routinely resurfaced the patella. Indwelling urinary catheterisation: Routine use recommended; 59.6% of surgeons used it routinely. CONCLUSION: Recommendations for routine use or not exist for some of the acute-care interventions examined. Surgeon practices vary widely even in the presence of high-level recommendations. It is unclear whether further evidence alone would lessen unwarranted practice variation. PMID- 28723918 TI - Heterogeneity of p53 dependent genomic responses following ethanol exposure in a developmental mouse model of fetal alcohol spectrum disorder. AB - Prenatal ethanol exposure can produce structural and functional deficits in the brain and result in Fetal Alcohol Spectrum Disorder (FASD). In rodent models acute exposure to a high concentration of alcohol causes increased apoptosis in the developing brain. A single causal molecular switch that signals for this increase in apoptosis has yet to be identified. The protein p53 has been suggested to play a pivotal role in enabling cells to engage in pro-apoptotic processes, and thus figures prominently as a hub molecule in the intracellular cascade of responses elicited by alcohol exposure. In the present study we examined the effect of ethanol-induced cellular and molecular responses in primary somatosensory cortex (SI) and hippocampus of 7-day-old wild-type (WT) and p53-knockout (KO) mice. We quantified apoptosis by active caspase-3 immunohistochemistry and ApopTagTM labeling, then determined total RNA expression levels in laminae of SI and hippocampal subregions. Immunohistochemical results confirmed increased incidence of apoptotic cells in both regions in WT and KO mice following ethanol exposure. The lack of p53 was not protective in these brain regions. Molecular analyses revealed a heterogeneous response to ethanol exposure that varied depending on the subregion, and which may go undetected using a global approach. Gene network analyses suggest that the presence or absence of p53 alters neuronal function and synaptic modifications following ethanol exposure, in addition to playing a classic role in cell cycle signaling. Thus, p53 may function in a way that underlies the intellectual and behavioral deficits observed in FASD. PMID- 28723919 TI - Level of physical activity and aerobic capacity associate with quality of life in patients with temporal lobe epilepsy. AB - Epilepsy is more than seizures and includes a high risk of comorbidities and psychological disorders, leading to poor quality of life (QOL). Earlier studies have showed a sedentary lifestyle in people with epilepsy (PWE), which could contribute to poorer health and psychological problems. The purpose of the present study was to compare habits of physical activity (PA), aerobic capacity, and QOL between PWE and healthy controls in order to identify the necessity of intervention of habits and information on physical exercise (PE) and to better understand the importance of PE for PWE. The study included 38 patients with temporal lobe epilepsy and 20 normal controls. Both groups answered the WHOQOL Bref, which assesses the level of QOL, and IPAQ to evaluate the level of PA. In addition, they were submitted to a treadmill maximal cardiopulmonary effort test to identify physical capacity. The continuous variables were compared between groups by t-test and a general linear model, and the frequencies were compared by Chi-Square test through SPSS software. There was no difference in the level of PA between groups by questionnaire evaluation. However, there were significant differences in overall QOL, physical health, and level of PA in relation to work and physical capacity between groups; controls demonstrated better scores than PWE. Controls presented better physical capacity than PWE by cardiopulmonary effort test. According to intra-group analyses, PWE who were physically active had better QOL than inactive PWE. The study concluded that questionnaires about PE may not be the best instrument of evaluation, as demonstrated by the discrepancy of results compared to the validated objective cardiopulmonary evaluation of level of PA and physical capacity in this study. PMID- 28723920 TI - Temperature modulates dengue virus epidemic growth rates through its effects on reproduction numbers and generation intervals. AB - Epidemic growth rate, r, provides a more complete description of the potential for epidemics than the more commonly studied basic reproduction number, R0, yet the former has never been described as a function of temperature for dengue virus or other pathogens with temperature-sensitive transmission. The need to understand the drivers of epidemics of these pathogens is acute, with arthropod borne virus epidemics becoming increasingly problematic. We addressed this need by developing temperature-dependent descriptions of the two components of r-R0 and the generation interval-to obtain a temperature-dependent description of r. Our results show that the generation interval is highly sensitive to temperature, decreasing twofold between 25 and 35 degrees C and suggesting that dengue virus epidemics may accelerate as temperatures increase, not only because of more infections per generation but also because of faster generations. Under the empirical temperature relationships that we considered, we found that r peaked at a temperature threshold that was robust to uncertainty in model parameters that do not depend on temperature. Although the precise value of this temperature threshold could be refined following future studies of empirical temperature relationships, the framework we present for identifying such temperature thresholds offers a new way to classify regions in which dengue virus epidemic intensity could either increase or decrease under future climate change. PMID- 28723921 TI - Postnatal dexamethasone, respiratory and neurodevelopmental outcomes at two years in babies born extremely preterm. AB - IMPORTANCE: Postnatal dexamethasone is associated with reduction in bronchopulmonary dysplasia. There remains, however, concern that its short-term benefits are accompanied by long-term adverse effects e.g. poorer neurodevelopmental outcomes. OBJECTIVE: Our aim was to determine the effects of administration of postnatal dexamethasone on respiratory and neurodevelopmental outcome at two years of age after adjusting for neonatal and infant risk factors. MATERIALS AND METHODS: The study included 412 infants born at 23-28 weeks of gestation, 29% had received postnatal dexamethasone. Two outcomes were examined, respiratory hospital admissions in the past 12 months and neurodevelopmental impairment. Logistic regression, adjusted for sex, birthweight z-score, gestation, maternal smoking, oxygen dependency at 36 weeks, airleak, patent ductus arteriosus, pulmonary haemorrhage, major ultrasound abnormality, mode of ventilation and age at assessment, was undertaken. RESULTS: After adjustment, postnatal dexamethasone was associated with significantly increased proportions of both respiratory hospital readmission: (0.35 vs 0.15, difference = 0.20; 95% CI: 0.08, 0.31) and neurodevelopmental impairment (0.59 vs 0.45, difference = 0.14; 95% CI: 0.02, 0.26). CONCLUSIONS: Postnatal dexamethasone use in extremely preterm infants is associated with increased risks of respiratory hospital admissions and neurodevelopmental impairment. These associations were not explained by excess neonatal morbidities. PMID- 28723922 TI - Temporal progression of PARP activity in the Prph2 mutant rd2 mouse: Neuroprotective effects of the PARP inhibitor PJ34. AB - Peripherin (peripherin/rds) is a membrane-associated protein that plays a critical role in the morphogenesis of rod and cone photoreceptor outer segments. Mutations in the corresponding PRPH2 gene cause different types of retinal dystrophies characterized by a loss of photoreceptors. Over activation of poly ADP-ribose polymerase (PARP) was previously shown to be involved in different animal models for hereditary retinal dystrophies. This includes the rd2 mouse, which suffers from a human homologous mutation in the PRPH2 gene. In the present study, we show that increased retinal PARP activity and poly-ADP-ribosylation of proteins occurs before the peak of rd2 photoreceptor degeneration. Inhibition of PARP activity with the well-characterized PARP inhibitor PJ34 decreased the levels of poly-ADP-ribosylation and photoreceptor cell death. These results suggest a causal involvement of PARP in photoreceptor degeneration caused by peripherin mutations and highlight the possibility to use PARP inhibition for the mutation-independent treatment of hereditary retinal dystrophies. PMID- 28723923 TI - On the mechanism of Candida tropicalis biofilm reduction by the combined action of naturally-occurring anthraquinones and blue light. AB - The photoprocesses involved in the photo-induced Candida tropicalis biofilm reduction by two natural anthraquinones (AQs), rubiadin (1) and rubiadin-1-methyl ether (2), were examined. Production of singlet oxygen (1O2) and of superoxide radical anion (O2*-) was studied. Although it was not possible to detect the triplet state absorption of any AQs in biofilms, observation of 1O2 phosphorescence incubated with deuterated Phosphate Buffer Solution, indicated that this species is actually formed in biofilms. 2 was accumulated in the biofilm to a greater extent than 1 and produced measurable amounts of O2*- after 3h incubation in biofilms. The effect of reactive oxygen species scavengers on the photo-induced biofilm reduction showed that Tiron (a specific O2*- scavenger) is most effective than sodium azide (a specific 1O2 quencher). This suggests that O2*- formed by electron transfer quenching of the AQs excited states, is the main photosensitizing mechanism involved in the photo-induced antibiofilm activity, whereas 1O2 participation seems of lesser importance. PMID- 28723924 TI - A context for the last Neandertals of interior Iberia: Los Casares cave revisited. AB - INTRODUCTION AND OBJECTIVES: Although the Iberian Peninsula is a key area for understanding the Middle to Upper Paleolithic transition and the demise of the Neandertals, valuable evidence for these debates remains scarce and problematic in its interior regions. Sparse data supporting a late Neandertal persistence in the Iberian interior have been recently refuted and hence new evidence is needed to build new models on the timing and causes of Neandertal disappearance in inland Iberia and the whole peninsula. In this study we provide new evidence from Los Casares, a cave located in the highlands of the Spanish Meseta, where a Neandertal-associated Middle Paleolithic site was discovered and first excavated in the 1960's. Our main objective is twofold: (1) provide an updated geoarcheological, paleoenvironmental and chronological framework for this site, and (2) discuss obtained results in the context of the time and nature of the last Neandertal presence in Iberia. METHODS: We conducted new fieldwork in an interior chamber of Los Casares cave named 'Seno A'. Our methods included micromorphology, sedimentology, radiocarbon dating, Uranium/Thorium dating, palinology, microfaunal analysis, anthracology, phytolith analysis, archeozoology and lithic technology. Here we present results on site formation processes, paleoenvironment and the chronological setting of the Neandertal occupation at Los Casares cave-Seno A. RESULTS AND DISCUSSION: The sediment sequence reveals a mostly in situ archeological deposit containing evidence of both Neandertal activity and carnivore action in level c, dated to 44,899-42,175 calendar years ago. This occupation occurred during a warm and humid interval of Marine Isotopic Stage 3, probably correlating with Greenland Interstadial 11, representing one of the latest occurrences of Neandertals in the Iberian interior. However, overlying layer b records a deterioration of local environments, thus providing a plausible explanation for the abandonment of the site, and perhaps for the total disappearance of Neandertals of the highlands of inland Iberia during subsequent Greenland Stadials 11 or 10, or even Heinrich Stadial 4. Since layer b provided very few signs of human activity and no reliable chronometric results, and given the scarce chronostratigrapic evidence recorded so far for this period in interior Iberia, this can only be taken as a working hypothesis to be tested with future research. Meanwhile, 42,000 calendar years ago remains the most plausible date for the abandonment of interior Iberia by Neandertals, possibly due to climate deterioration. Currently, a later survival of this human species in Iberia is limited to the southern coasts. PMID- 28723925 TI - Immunologic response to vaccine challenge in pregnant PTPN22 R620W carriers and non-carriers. AB - OBJECTIVES: Influenza infection is a significant cause of respiratory morbidity among pregnant women. Seasonal influenza vaccination engages innate immune receptors to promote protective immunity. A coding polymorphism (R620W) in PTPN22 imparts elevated risk for human infection and autoimmune disease, predisposes to diminished innate immune responses, and associates with reduced immunization responses. We sought to quantify the effects of PTPN22-R620W on humoral and cell mediated immune responses to the inactivated influenza vaccine among healthy pregnant women. STUDY DESIGN: Immune responses were measured in healthy pregnant R620W carrier (n = 17) and non-carrier (n = 33) women receiving the 2013 quadrivalent inactivated influenza vaccine (Fluzone). Hemagglutination inhibition assays were performed to quantify neutralizing antibodies; functional influenza reactive CD4 T cells were quantified by flow cytometry, and influenza-specific CD8 T cells were enumerated with MHC Class I tetramers. Antibody seroconversion data were evaluated by Chi-square analysis, and the Mann-Whitney or Wilcoxon signed-rank tests were applied to T cell response data. RESULTS: PTPN22 R620W carrier (n = 17) and non-carrier (n = 33) groups did not differ in age, parity, BMI, gestational age at time of vaccine, or history of prior influenza vaccination. After Fluzone exposure, 51.5% of non-carriers met criteria for antibody seroconversion to H1N1 influenza, compared with 23.5% of R620W carriers (p = 0.06). Influenza-reactive CD4 T cells showed modest increase at days 9-15 after vaccination in both R620W carriers and non-carriers (p = 0.02 and p = 0.04, respectively). However, there was no difference in overall response between the two groups (p = 0.6). The vaccine did not result in significant induction of influenza-specific CD8 T cells in either group. CONCLUSIONS: There was no significant difference among healthy pregnant R620W carriers and non-carriers in H1N1 antibody seroconversion rates after influenza vaccination. Studies of larger cohorts will be needed to define the effect of PTPN22 risk allele carriage on antibody and T cell responses to influenza vaccination during pregnancy. PMID- 28723926 TI - GhSOS1, a plasma membrane Na+/H+ antiporter gene from upland cotton, enhances salt tolerance in transgenic Arabidopsis thaliana. AB - Upland cotton (Gossypium hirsutum L.), an important source of natural fiber, can tolerate relatively high salinity and drought stresses. In the present study, a plasma membrane Na+/H+ antiporter gene, GhSOS1, was cloned from a salt-tolerant genotype of G. hirsutum, Zhong 9807. The expression level of GhSOS1 in cotton roots was significantly upregulated in the presence of high concentrations of NaCl (200 mM), while its transcript abundance was increased when exposed to low temperature and drought stresses. Localization analysis using onion epidermal cells showed that the GhSOS1 protein was localized to the plasma membrane. The overexpression of GhSOS1 in Arabidopsis enhanced tolerance to salt stress, as indicated by a lower MDA content and decreased Na+/K+ ratio in transgenic plants. Moreover, the transcript levels of stress-related genes were significantly higher in GhSOS1 overexpression lines than in wild-type plants under salt treatment. Hence, GhSOS1 may be a potential target gene for enhancing salt tolerance in transgenic plants. PMID- 28723927 TI - Piped water supply interruptions and acute diarrhea among under-five children in Addis Ababa slums, Ethiopia: A matched case-control study. AB - BACKGROUND: The problem of intermittent piped water supplies that exists in low- and middle-income countries is particularly severe in the slums of sub-Saharan Africa. However, little is known about whether there is deterioration of the microbiological quality of the intermittent piped water supply at a household level and whether it is a factor in reducing or increasing the occurrence of acute diarrhea among under-five children in slums of Addis Ababa. This study aimed to determine the association of intermittent piped water supplies and point of-use (POU) contamination of household stored water by Escherichia coli (E. coli) with acute diarrhea among under-five children in slums of Addis Ababa. METHODS: A community-based matched case-control study was conducted from November to December, 2014. Cases were defined as under-five children with acute diarrhea during the two weeks before the survey. Controls were matched by age and neighborhood with cases by individual matching. Data were collected using a pre tested structured questionnaire and E. coli analysis of water from piped water supplies and household stored water. A five-tube method of Most Probable Number (MPN)/100 ml standard procedure was used for E. coli analysis. Multivariable conditional logistic regression with 95% confidence interval (CI) was used for data analysis by controlling potential confounding effects of selected socio demographic characteristics. MAIN FINDINGS: During the two weeks before the survey, 87.9% of case households and 51.0% of control households had an intermittent piped water supply for an average of 4.3 days and 3.9 days, respectively. POU contamination of household stored water by E. coli was found in 83.3% of the case households, and 52.1% of the control households. In a fully adjusted model, a periodically intermittent piped water supply (adjusted matched odds ratio (adjusted mOR) = 4.8; 95% CI: 1.3-17.8), POU water contamination in household stored water by E. coli (adjusted mOR = 3.3; 95% CI: 1.1-10.1), water retrieved from water storage containers using handle-less vessels (adjusted mOR = 16.3; 95% CI: 4.4-60.1), and water retrieved by interchangeably using vessels both with and without handle (adjusted mOR = 5.4; 95% CI: 1.1-29.1) were independently associated with acute diarrhea. CONCLUSION: We conclude that provision of continuously available piped water supplies and education of caregivers about proper water retrieval methods of household stored water can effectively reduce POU contamination of water at the household level and thereby reduce acute diarrhea among under-five children in slums of Addis Ababa. Promotion of household water treatment is also highly encouraged until the City's water authority is able to deliver continuously available piped water supplies. PMID- 28723928 TI - ErbB activation signatures as potential biomarkers for anti-ErbB3 treatment in HNSCC. AB - Head and neck squamous cell carcinoma (HNSCC) accounts for 3-5% of all tumor types and remains an unmet medical need with only two targeted therapies approved to date. ErbB3 (HER3), the kinase-impaired member of the EGFR/ErbB family, has been implicated as a disease driver in a number of solid tumors, including a subset of HNSCC. Here we show that the molecular components required for ErbB3 activation, including its ligand neuregulin-1 (NRG1), are highly prevalent in HNSCC and that HER2, but not EGFR, is the major activating ErbB3 kinase partner. We demonstrate that cetuximab treatment primarily inhibits the ERK signaling pathway and KTN3379, an anti-ErbB3 monoclonal antibody, inhibits the AKT signaling pathway, and that dual ErbB receptor inhibition results in enhanced anti-tumor activity in HNSCC models. Surprisingly, we found that while NRG1 is required for ErbB3 activation, it was not sufficient to fully predict for KTN3379 activity. An evaluation of HNSCC patient samples demonstrated that NRG1 expression was significantly associated with expression of the EGFR ligands amphiregulin (AREG) and transforming growth factor alpha (TGFalpha). Furthermore, NRG1-positive HNSCC cell lines that secreted high levels of AREG and TGFalpha or contained high levels of EGFR homodimers (H11D) demonstrated a better response to KTN3379. Although ErbB3 and EGFR activation are uncoupled at the receptor level, their respective signaling pathways are linked through co-expression of their respective ligands. We propose that NRG1 expression and EGFR activation signatures may enrich for improved efficacy of anti-ErbB3 therapeutic mAb approaches when combined with EGFR-targeting therapies in HNSCC. PMID- 28723929 TI - Clinical utility of the Structured Observation of Motor Performance in Infants within the child health services. AB - AIM: This study aimed to evaluate the clinical utility of the Structured Observation of Motor Performance in Infants (SOMP-I) when used by nurses in routine child healthcare by analyzing the nurses' SOMP-I assessments and the actions taken when motor problems were suspected. METHOD: Infants from three child health centers in Uppsala County, Sweden, were consecutively enrolled in a longitudinal study. The 242 infants were assessed using SOMP-I by the nurse responsible for the infant as part of the regular well-child visits at as close to 2, 4, 6 and 10 months of age as possible. The nurses noted actions taken such as giving advice, scheduling an extra follow-up or referring the infant to specialized care. The infants' motor development was reassessed at 18 months of age through review of medical records or parental report. RESULTS: The assessments of level of motor development at 2 and 10 months showed a distribution corresponding to the percentile distribution of the SOMP-I method. Fewer infants than expected were assessed as delayed at 4 and 6 months or deficient in quality at all assessment ages. When an infant was assessed as delayed in level or deficient in quality, the likelihood of the nurse taking actions increased. This increased further if both delay and quality deficit were found at the same assessment or if one or both were found at repeated assessments. The reassessment of the motor development at 18 months did not reveal any missed infants with major motor impairments. INTERPRETATION: The use of SOMP-I appears to demonstrate favorable clinical utility in routine child healthcare as tested here. Child health nurses can assess early motor performance using this standardized assessment method, and using the method appears to support them the clinical decision-making. PMID- 28723930 TI - Does culture create craving? Evidence from the case of menstrual chocolate craving. AB - Craving is considered a key characteristic of diverse pathologies, but evidence suggests it may be a culture-bound construct. Almost 50% of American women crave chocolate specifically around the onset of menstruation. Research does not support popular accounts implicating physiological factors in menstrual chocolate craving etiology. We tested the novel hypothesis that greater menstrual craving prevalence in the U.S. is the product of internalized cultural norms. Women of diverse backgrounds (n = 275) reported on craving frequency and triggers and completed validated measures of acculturation. Foreign-born women were significantly less likely to endorse menstrual chocolate craving (17.3%), compared to women born to U.S.-born parents (32.7%, p = .03) and second generation immigrants (40.9%, p = .001). Second generation immigrant and foreign born women endorsing menstrual chocolate craving reported significantly greater U.S. acculturation and lower identification with their native culture than non menstrual cravers (all p < .001). Findings inform our understanding of food cravings, with important implications for the study of cravings in other domains. PMID- 28723931 TI - Why aren't people with young onset dementia and their supporters using formal services? Results from the INSPIRED study. AB - BACKGROUND/AIMS: Despite reporting high levels of burden, supporters of people with young onset dementia (YOD) underuse formal community services. Previous quantitative studies in YOD are of limited utility in guiding service design because they did not consider important contextual barriers to service use. The aim of this study was to identify all relevant barriers and describe the service features considered most important to improving uptake by people with YOD and their supporters. METHODS: Eighty-six people with consensus-confirmed YOD (mean onset age 55.3 years) and/or their primary supporter participated in quantitative interviews, and 50 also participated in one of seven qualitative focus groups. Interview participants reported levels of community service use and reasons for non-use, functional impairment, behavioural and psychological symptoms, supporter burden, social network, and informal care provision. Focus group participants expanded on reasons for non-use and aspects of an ideal service. RESULTS: Although at least one community service was recommended to most participants (96.8%), 66.7% chose not to use one or more of these. Few of the clinical or demographic factors included here were related to service use. Qualitative analyses identified that lack of perceived need, availability, and YOD-specific barriers (including ineligibility, unaffordability, lack of security, lack of childcare) were commonly reported. Five aspects of an ideal service were noted: unique, flexibile, affordable, tailored, and promoting meaningful engagement. CONCLUSION: People with YOD and their families report that formal community services do not meet their personal and psychological needs. Researchers can provide ongoing assessment of program feasibility, suitability, and generalisability. PMID- 28723932 TI - The nucleoid occlusion factor Noc controls DNA replication initiation in Staphylococcus aureus. AB - Successive division events in the spherically shaped bacterium Staphylococcus aureus are oriented in three alternating perpendicular planes. The mechanisms that underlie this relatively unique pattern of division and coordinate it with chromosome segregation remain largely unknown. Thus far, the only known spatial regulator of division in this organism is the nucleoid occlusion protein Noc that inhibits assembly of the cytokinetic ring over the chromosome. However, Noc is not essential in S. aureus, indicating that additional regulators are likely to exist. To search for these factors, we screened for mutants that are synthetic lethal with Noc inactivation. Our characterization of these mutants led to the discovery that S. aureus Noc also controls the initiation of DNA replication. We show that cells lacking Noc over-initiate and mutations in the initiator gene dnaA suppress this defect. Importantly, these dnaA mutations also partially suppress the division problems associated with Deltanoc. Reciprocally, we show that over-expression of DnaA enhances the over-initiation and cell division phenotypes of the Deltanoc mutant. Thus, a single factor both blocks cell division over chromosomes and helps to ensure that new rounds of DNA replication are not initiated prematurely. This degree of economy in coordinating key cell biological processes has not been observed in rod-shaped bacteria and may reflect the challenges posed by the reduced cell volume and complicated division pattern of this spherical pathogen. PMID- 28723933 TI - Comparative repeatome analysis on Triatoma infestans Andean and Non-Andean lineages, main vector of Chagas disease. AB - Triatoma infestans is the most important Chagas disease vector in South America. Two main evolutionary lineages, named Andean and non-Andean, have been recognized by geographical distribution, phenetic and genetic characteristics. One of the main differences is the genomic size, varying over 30% in their haploid DNA content. Here we realize a genome wide analysis to compare the repetitive genome fraction (repeatome) between both lineages in order to identify the main repetitive DNA changes occurred during T. infestans differentiation process. RepeatExplorer analysis using Illumina reads showed that both lineages exhibit the same amount of non-repeat sequences, and that satellite DNA is by far the major component of repetitive DNA and the main responsible for the genome size differentiation between both lineages. We characterize 42 satellite DNA families, which are virtually all present in both lineages but with different amount in each lineage. Furthermore, chromosomal location of satellite DNA by fluorescence in situ hybridization showed that genomic variations in T. infestans are mainly due to satellite DNA families located on the heterochromatic regions. The results also show that many satDNA families are located on the euchromatic regions of the chromosomes. PMID- 28723935 TI - Responses of molluscan communities to centuries of human impact in the northern Adriatic Sea. AB - In sediment cores spanning ~500 years of history in the Gulf of Trieste, down core changes in molluscan community structure are characterized by marked shifts in species and functional composition. Between the 16th and 19th century, a strong heavy metal contamination of the sediments, most notably by Hg, together with the effects of natural climatic oscillations (increased sedimentation and organic enrichment) drive community changes. Since the early 20th century up to 2013, the combined impacts of cultural eutrophication, frequent hypoxic events and intensifying bottom trawling replace heavy metal contamination and climatic factors as the main drivers. The pollution-tolerant and opportunistic bivalve Corbula gibba and the scavenging gastropod Nassarius pygmaeus significantly increase in abundance during the 20th century, while species more sensitive to disturbances and hypoxia such as Turritella communis and Kurtiella bidentata become rare or absent. An infaunal life habit and scavenging emerge as the dominant life strategies during the late 20th century. Down-core shifts in the proportional abundances of molluscan species and functional groups represent a sensitive proxy for past ecological changes and reveal a century-long anthropogenic impact as the main driver behind these processes in the northern Adriatic Sea, offering also a unique perspective for other shallow marine ecosystems worldwide. PMID- 28723936 TI - Social sensing of urban land use based on analysis of Twitter users' mobility patterns. AB - A number of recent studies showed that digital footprints around built environments, such as geo-located tweets, are promising data sources for characterizing urban land use. However, challenges for achieving this purpose exist due to the volume and unstructured nature of geo-located social media. Previous studies focused on analyzing Twitter data collectively resulting in coarse resolution maps of urban land use. We argue that the complex spatial structure of a large collection of tweets, when viewed through the lens of individual-level human mobility patterns, can be simplified to a series of key locations for each user, which could be used to characterize urban land use at a higher spatial resolution. Contingent issues that could affect our approach, such as Twitter users' biases and tendencies at locations where they tweet the most, were systematically investigated using 39 million geo-located Tweets and two independent datasets of the City of Chicago: 1) travel survey and 2) parcel-level land use map. Our results support that the majority of Twitter users show a preferential return, where their digital traces are clustered around a few key locations. However, we did not find a general relation among users between the ranks of locations for an individual-based on the density of tweets-and their land use types. On the contrary, temporal patterns of tweeting at key locations were found to be coherent among the majority of users and significantly associated with land use types of these locations. Furthermore, we used these temporal patterns to classify key locations into generic land use types with an overall classification accuracy of 0.78. The contribution of our research is twofold: a novel approach to resolving land use types at a higher resolution, and in-depth understanding of Twitter users' location-related and temporal biases, promising to benefit human mobility and urban studies in general. PMID- 28723934 TI - The relationship between adiposity and bone density in U.S. children and adolescents. AB - OBJECTIVE: In adults, obesity has been associated with several health outcomes including increased bone density. Our objective was to evaluate the association between percent body fat and fat mass with bone mineral density (BMD) in a nationally representative population of children and adolescents. STUDY DESIGN: A total of 8,348 participants 8-18 years of age from the National Health and Nutrition Examination Survey (NHANES) 1999-2006 had whole body DXA scans performed. We conducted linear regressions to examine the relationship between percent body fat and fat mass with outcome variables of total body, pelvic and lumbar spine areal BMD (aBMD), controlling for lean body mass and assessing for gender and race/ethnicity interactions. RESULTS: We found evidence of gender and race/ethnicity interactions with percent body fat and total fat mass for the different BMD areas. Generally, there were decreases in total body aBMD (p<0.001) and lumbar spine aBMD (p<0.001) with increasing percent body fat and total fat mass, with less consistent patterns for pelvic aBMD. CONCLUSION: Our findings of regional differences in the relationship of adiposity to aBMD in children and adolescents with significant interactions by gender and race/ethnicity emphasizes the need for further investigations to understand the impact of adiposity on bone health outcomes. PMID- 28723937 TI - Electricity system based on 100% renewable energy for India and SAARC. AB - The developing region of SAARC (South Asian Association for Regional Cooperation) is home to a large number of people living below the poverty line. In future, providing affordable, universally accessible, reliable, low to zero carbon electricity in this region will be the main aim. A cost optimal 100% renewable energy system is simulated for SAARC for the year 2030 on an hourly resolved basis. The region was divided into 16 sub-regions and three different scenarios were set up based on the level of high voltage direct current (HVDC) grid connections. The results obtained for a total system levelised cost of electricity (LCOE) showed a decrease from 71.6 ?/MWh in a decentralized to 67.2 ?/MWh for a centralized grid connected scenario. An additional scenario was simulated to show the benefits of integrating industrial gas production and seawater reverse osmosis desalination demand, and showed the system cost decreased by 5% and total electricity generation decreased by 1%. The results show that a 100% renewable energy system could be a reality in the SAARC region with the cost assumptions used in this research and it may be more cost competitive than nuclear and fossil carbon capture and storage (CCS) alternatives. One of the limitations of this study is the cost of land for installation of renewables which is not included in the LCOE calculations, but regarded as a minor contribution. PMID- 28723938 TI - Gender differences in cerebral metabolism for color processing in mice: A PET/MRI Study. AB - INTRODUCTION: Color processing is a central component of mammalian vision. Gender related differences of color processing revealed by non-invasive functional transcranial Doppler ultrasound suggested right hemisphere pattern for blue/yellow chromatic opponency by men, and a left hemisphere pattern by women. MATERIALS AND METHODS: The present study measured the accumulation of [18F]fluorodeoxyglucose ([18F]FDG) in mouse brain using small animal positron emission tomography and magnetic resonance imaging (PET/MRI) with statistical parametric mapping (SPM) during light stimulation with blue and yellow filters compared to darkness condition. RESULTS: PET revealed a reverse pattern relative to dark condition compared to previous human studies: Male mice presented with left visual cortex dominance for blue through the right eye, while female mice presented with right visual cortex dominance for blue through the left eye. We applied statistical parametric mapping (SPM) to examine gender differences in activated architectonic areas within the orbital and medial prefrontal cortex and related cortical and sub-cortical areas that lead to the striatum, medial thalamus and other brain areas. The metabolic connectivity of the orbital and medial prefrontal cortex evoked by blue stimulation spread through a wide range of brain structures implicated in viscerosensory and visceromotor systems in the left intra-hemispheric regions in male, but in the right-to-left inter hemispheric regions in female mice. Color functional ocular dominance plasticity was noted in the right eye in male mice but in the left eye in female mice. CONCLUSIONS: This study of color processing in an animal model could be applied in the study of the role of gender differences in brain disease. PMID- 28723939 TI - Assessing health-related resiliency in HIV+ Latin women: Preliminary psychometric findings. AB - BACKGROUND: HIV-associated vulnerabilities-especially those linked to psychological issues-and limited mental health-treatment resources have the potential to adversely affect the health statuses of individuals. The concept of resilience has been introduced in the literature to shift the emphasis from vulnerability to protective factors. Resilience, however, is an evolving construct and is measured in various ways, though rarely among underserved, minority populations. Herein, we present the preliminary psychometric properties of a sample of HIV-seropositive Puerto Rican women, measured using a newly developed health-related resilience scale. METHODS AND DESIGN: The Resilience Scales for Children and Adolescents, an instrument with solid test construction properties, acted as a model in the development (in both English and Spanish) of the HRRS, providing the same dimensions and most of the same subscales. The present sample was nested within the Hispanic-Latino longitudinal cohort of women (HLLC), that is part of the NeuroAIDS Research Program at the University of Puerto Rico (UPR), Medical Sciences Campus (MSC). Forty-five consecutively recruited, HIV+ women from the HLLC completed a demographic survey, the HRRS, and the Beck Depression Inventory-I, Spanish version. RESULTS: The results demonstrate excellent overall internal consistency for the total HRRS score (alpha = 0.95). Each of the dimensional scores also evidenced acceptable internal consistency (alpha >= 0.88). All the dimensional and subscale content validity indices were above the 0.42 cut-off. Analysis revealed a significant negative correlation between the HRRS total score and BDI-I-S (r(45) = -0.453, p < 0.003). CONCLUSION: Albeit preliminary in nature, the present study provides support for the HRRS as a measure to assess resilience among individuals living with chronic medical conditions. Minority populations, especially non-English speaking ones, are understudied across the field of medicine, and when efforts are made to include these patient groups, measurement is rarely tailored to their unique cultural and linguistic experiences. The HRRS is a measure that addresses these notable voids in the medical literature. PMID- 28723940 TI - Modeling the dynamics of chromosomal alteration progression in cervical cancer: A computational model. AB - Computational modeling has been applied to simulate the heterogeneity of cancer behavior. The development of Cervical Cancer (CC) is a process in which the cell acquires dynamic behavior from non-deleterious and deleterious mutations, exhibiting chromosomal alterations as a manifestation of this dynamic. To further determine the progression of chromosomal alterations in precursor lesions and CC, we introduce a computational model to study the dynamics of deleterious and non deleterious mutations as an outcome of tumor progression. The analysis of chromosomal alterations mediated by our model reveals that multiple deleterious mutations are more frequent in precursor lesions than in CC. Cells with lethal deleterious mutations would be eliminated, which would mitigate cancer progression; on the other hand, cells with non-deleterious mutations would become dominant, which could predispose them to cancer progression. The study of somatic alterations through computer simulations of cancer progression provides a feasible pathway for insights into the transformation of cell mechanisms in humans. During cancer progression, tumors may acquire new phenotype traits, such as the ability to invade and metastasize or to become clinically important when they develop drug resistance. Non-deleterious chromosomal alterations contribute to this progression. PMID- 28723941 TI - Heat treatment as a universal technical solution for silcrete use? A comparison between silcrete from the Western Cape (South Africa) and the Kalahari (Botswana). AB - Heat treatment was one of the first transformative technologies in the southern African Middle Stone Age (MSA), with many studies in the Cape coastal zone of South Africa identifying it as an essential step in the preparation of silcrete prior to its use in stone tool manufacture. To date, however, no studies have investigated whether heat treatment is necessary for all silcrete types, and how geographically widespread heat treatment was in the subcontinent. The aim of this study is to investigate experimentally whether heat treatment continued further north into the Kalahari Desert of Botswana and northernmost South Africa, the closest area with major silcrete outcrops to the Cape. For this we analyse the thermal transformations of silcrete from both regions, proposing a comprehensive model of the chemical, crystallographic and 'water'-related processes taking place upon heat treatment. For the first time, we also explore the mobility of minor and trace elements during heat treatment and introduce a previously undescribed mechanism-steam leaching-causing depletion of a limited number of elements. The results of this comparative study reveal the Cape and Kalahari silcrete to respond fundamentally differently to heat treatment. While the former can be significantly improved by heat, the latter is deteriorated in terms of knapping quality. These findings have important implications for our understanding of the role of fire as a technical solution in MSA stone tool knapping, and for the extension of its use in southern Africa. Silcrete heat treatment-at least in the form we understand it today-may have been a strictly regional phenomenon, confined to a narrow zone along the west and south coast of the Cape. On the basis of our findings, silcrete heat treatment should not be added as a new trait on the list of behaviours that characterise the MSA of the southern African subcontinent. PMID- 28723942 TI - Comparative analysis of vaginal microbiota sampling using 16S rRNA gene analysis. AB - BACKGROUND: Molecular methods such as next-generation sequencing are actively being employed to characterize the vaginal microbiota in health and disease. Previous studies have focused on characterizing the biological variation in the microbiota, and less is known about how factors related to sampling contribute to the results. Our aim was to investigate the impact of a sampling device and anatomical sampling site on the quantitative and qualitative outcomes relevant for vaginal microbiota research. We sampled 10 Finnish women representing diverse clinical characteristics with flocked swabs, the Evalyn(r) self-sampling device, sterile plastic spatulas and a cervical brush that were used to collect samples from fornix, vaginal wall and cervix. Samples were compared on DNA and protein yield, bacterial load, and microbiota diversity and species composition based on Illumina MiSeq sequencing of the 16S rRNA gene. We quantified the relative contributions of sampling variables versus intrinsic variables in the overall microbiota variation, and evaluated the microbiota profiles using several commonly employed metrics such as alpha and beta diversity as well as abundance of major bacterial genera and species. RESULTS: The total DNA yield was strongly dependent on the sampling device and to a lesser extent on the anatomical site of sampling. The sampling strategy did not affect the protein yield or the bacterial load. All tested sampling methods produced highly comparable microbiota profiles based on MiSeq sequencing. The sampling method explained only 2% (p-value = 0.89) of the overall microbiota variation, markedly surpassed by intrinsic factors such as clinical status (microscopy for bacterial vaginosis 53%, p = 0.0001), bleeding (19%, p = 0.0001), and the variation between subjects (11%, p-value 0.0001). CONCLUSIONS: The results indicate that different sampling strategies yield comparable vaginal microbiota composition and diversity. Hence, past and future vaginal microbiota studies employing different sampling strategies should be comparable in the absence of other technical confounders. The Evalyn(r) self sampling device performed equally well compared to samples taken by a clinician, and hence offers a good-quality microbiota sample without the need for a gynecological examination. The amount of collected sample as well as the DNA and protein yield varied across the sampling techniques, which may have practical implications for study design. PMID- 28723943 TI - Stress enhances model-free reinforcement learning only after negative outcome. AB - Previous studies found that stress shifts behavioral control by promoting habits while decreasing goal-directed behaviors during reward-based decision-making. It is, however, unclear how stress disrupts the relative contribution of the two systems controlling reward-seeking behavior, i.e. model-free (or habit) and model based (or goal-directed). Here, we investigated whether stress biases the contribution of model-free and model-based reinforcement learning processes differently depending on the valence of outcome, and whether stress alters the learning rate, i.e., how quickly information from the new environment is incorporated into choices. Participants were randomly assigned to either a stress or a control condition, and performed a two-stage Markov decision-making task in which the reward probabilities underwent periodic reversals without notice. We found that stress increased the contribution of model-free reinforcement learning only after negative outcome. Furthermore, stress decreased the learning rate. The results suggest that stress diminishes one's ability to make adaptive choices in multiple aspects of reinforcement learning. This finding has implications for understanding how stress facilitates maladaptive habits, such as addictive behavior, and other dysfunctional behaviors associated with stress in clinical and educational contexts. PMID- 28723944 TI - Application of mass spectrometry to elucidate the pathophysiology of Encephalitozoon cuniculi infection in rabbits. AB - Encephalitozoon cuniculi is a microsporidian species which can induce subclinical to serious disease in mammals including rabbits, a definitive natural host. The pathophysiology of infection has not been comprehensively elucidated. In this exploratory study, we utilized two mass spectrometry approaches: first, the analysis of the humoral response by profiling the microsporidian antigens as revealed by Western blot screening, and second, implementing the iTRAQ(r) labeling protocol to focus on the changes within the host proteome during infection. Seven E. cuniculi proteins were identified at one-dimensional gel regions where specific seropositive reaction was observed by Western blot, including polar tube protein 3, polar tube protein 2, and for the first time reported: heat shock related 70kDa protein, polysaccharide deacetylase domain containing protein, zinc finger protein, spore wall and anchoring disk complex protein EnP1, and translation elongation factor 1 alpha. In addition, there was a significant increase of nine host proteins in blood samples from E. cuniculi diseased rabbits in comparison with non-diseased control subjects undergoing various inflammatory processes. This included serum paraoxonase, alpha-1 antiproteinase F precursor and alpha-1-antiproteinase S-1 which have presumptive catalytic activity likely related to infection control, and cystatin fetuin-B type, an enzyme regulator that has been poorly studied to date. Notably, 11 proteins were found to be statistically increased in rabbits with neurological versus renal clinical presentation of E. cuniculi infection. Overall, this novel analysis based on mass spectrometry has provided new insights on the inflammatory and humoral responses during E. cuniculi infection in rabbits. PMID- 28723945 TI - Haematological and CD4+ T cells reference ranges in healthy adult populations in Gojjam zones in Amhara region, Ethiopia. AB - INTRODUCTION: Establishing national population haematological and immunological reference ranges are essential for clinical management of patients. However, there is scarcity of information on community based haematological reference ranges established from Ethiopian population. Therefore, this study aimed at determining haematological and CD4+ T cells reference ranges in healthy adults from East and West Gojjam zones, Ethiopia. METHODS: Community based cross sectional study was conducted from May 2015 to December 2015 in healthy adult residents of Gojjam zone. A total of 481(246 females and 235 males) healthy adults enrolled in the study. Healthy adults were defined by medical history, physical examination and laboratory screening for HIV, HBV, HCV and intestinal parasitosis. Haematological parameters were measured using haematology analyzer MindrayBC320 (Mindray Biomedical electronic Corporation, China). CD4+Tcells were enumerated using FACS count (Becton Dickinson). RESULTS: The median age of the participants was 25 years. The overall median and 95th percentile of CD4+ T cells count were 869 cells/mm3 and396-1598 cells/mm3, respectively. Females had a significantly higher CD4+ T cell counts compared to males (P = 0.002). The 95th percentile range for red blood cells (RBCs) was 3.93-6.1 x 106cells/mm3and for hematocrit (Hct) was 40-58% while for hemoglobin (Hb) was 15.69-17.84g/dl. Males had significantly higher values of RBC and Hct than females (P < 0.001). Females (120-379 x 106 cells/mm3) had significantly higher platelet counts than males (106-352 x106 cells/mm3) (P < 0.001). The overall median of WBC was6.78 x103/mm3and its95thpercentile range was3.5-11.5 x103/mm3. The overall 95th percentile range of MCV, MCH and MCHC were 89.5-107.5 fl, 28-34 pg and 30 33.2g/dl, respectively. The higher mean absolute count of RBCs was found in the youngest age groups (P = 0.03). The mean count of RBCs and Hct were significantly higher in highschool completed and above than other participants (P < 0.001). The lower and upper limit of platelet counts was significantly higher in highland (118 -383x106 cells/mm3) compared to lowland residents (107-352 x106 cells/mm3) (P < 0.001). Moreover, it was significantly higher in residents with better monthly income (124-383 x106 cells/mm3) compared to the counters (115-368 x106 cells/mm3) (P = 0.02). CONCLUSIONS: Some of the haematological and CD4+ T cells reference ranges of the healthy adults in this study showed variations with the reference ranges used and reported so far in Ethiopia, Africa and Western countries. We recommend further study considering gender, altitude, and residency in other parts of Ethiopia to establish national reference ranges for Ethiopian population. PMID- 28723947 TI - The effect of order of dwells on the first dwell gaze bias for eventually chosen items. AB - The relationship between choice and eye movement has gained marked interest. The gaze bias effect, i.e., the tendency to look longer at items that are eventually chosen, has been shown to occur in the first dwell (initial cohesion of fixations for an item). In the two-alternative forced-choice (2AFC) paradigm, participants would look at one of the items first (defined as first look; FL), and they would then move and look at another item (second look; SL). This study investigated how the order in which the chosen items were looked at modulates the first dwell gaze bias effect. Participants were asked to assert their preferences and perceptual 2AFC decisions about human faces (Experiment 1) and daily consumer products (Experiment 2), while their eye movements were recorded. The results showed that the first dwell gaze bias was found only when the eventually chosen item was looked at after another one; the chosen item was looked at for longer as compared to the not-chosen item in the SL, but not in the FL. These results indicate that participants actively allocate more time to looking at a subsequently chosen item only after they perceive both items in the SL. Therefore, the selective encoding seems to occur in the early comparison stage of visual decision making, and not in the initial encoding stage. These findings provide insight into the relationship between choice and eye movement. PMID- 28723946 TI - The mitochondrial genome of the terrestrial carnivorous plant Utricularia reniformis (Lentibulariaceae): Structure, comparative analysis and evolutionary landmarks. AB - The carnivorous plants of the family Lentibulariaceae have attained recent attention not only because of their interesting lifestyle, but also because of their dynamic nuclear genome size. Lentibulariaceae genomes span an order of magnitude and include species with the smallest genomes in angiosperms, making them a powerful system to study the mechanisms of genome expansion and contraction. However, little is known about mitochondrial DNA (mtDNA) sequences of this family, and the evolutionary forces that shape this organellar genome. Here we report the sequencing and assembly of the complete mtDNA from the endemic terrestrial Brazilian species Utricularia reniformis. The 857,234bp master circle mitochondrial genome encodes 70 transcriptionaly active genes (42 protein-coding, 25 tRNAs and 3 rRNAs), covering up to 7% of the mtDNA. A ltrA-like protein related to splicing and mobility and a LAGLIDADG homing endonuclease have been identified in intronic regions, suggesting particular mechanisms of genome maintenance. RNA-seq analysis identified properties with putative diverse and important roles in genome regulation and evolution: 1) 672kbp (78%) of the mtDNA is covered by full-length reads; 2) most of the 243kbp intergenic regions exhibit transcripts; and 3) at least 69 novel RNA editing sites in the protein-coding genes. Additional genomic features are hypothetical ORFs (48%), chloroplast insertions, including truncated plastid genes that have been lost from the chloroplast DNA (5%), repeats (5%), relics of transposable elements mostly related to LTR retrotransposons (5%), and truncated mitovirus sequences (0.4%). Phylogenetic analysis based on 32 different Lamiales mitochondrial genomes corroborate that Lentibulariaceae is a monophyletic group. In summary, the U. reniformis mtDNA represents the eighth largest plant mtDNA described to date, shedding light on the genomic trends and evolutionary characteristics and phylogenetic history of the family Lentibulariaceae. PMID- 28723948 TI - Integrative functional analyses using rainbow trout selected for tolerance to plant diets reveal nutrigenomic signatures for soy utilization without the concurrence of enteritis. AB - Finding suitable alternative protein sources for diets of carnivorous fish species remains a major concern for sustainable aquaculture. Through genetic selection, we created a strain of rainbow trout that outperforms parental lines in utilizing an all-plant protein diet and does not develop enteritis in the distal intestine, as is typical with salmonids on long-term plant protein-based feeds. By incorporating this strain into functional analyses, we set out to determine which genes are critical to plant protein utilization in the absence of gut inflammation. After a 12-week feeding trial with our selected strain and a control trout strain fed either a fishmeal-based diet or an all-plant protein diet, high-throughput RNA sequencing was completed on both liver and muscle tissues. Differential gene expression analyses, weighted correlation network analyses and further functional characterization were performed. A strain-by-diet design revealed differential expression ranging from a few dozen to over one thousand genes among the various comparisons and tissues. Major gene ontology groups identified between comparisons included those encompassing central, intermediary and foreign molecule metabolism, associated biosynthetic pathways as well as immunity. A systems approach indicated that genes involved in purine metabolism were highly perturbed. Systems analysis among the tissues tested further suggests the interplay between selection for growth, dietary utilization and protein tolerance may also have implications for nonspecific immunity. By combining data from differential gene expression and co-expression networks using selected trout, along with ontology and pathway analyses, a set of 63 candidate genes for plant diet tolerance was found. Risk loci in human inflammatory bowel diseases were also found in our datasets, indicating rainbow trout selected for plant-diet tolerance may have added utility as a potential biomedical model. PMID- 28723949 TI - Post-Traumatic Stress Disorder and other mental disorders in the general population after Lorca's earthquakes, 2011 (Murcia, Spain): A cross-sectional study. AB - AIMS: To describe the prevalence and severity of mental disorders and to examine differences in risk among those with and without a lifetime history prior to a moderate magnitude earthquake that took place in Lorca (Murcia, Spain) at roughly the mid-point (on May 11, 2011) of the time interval in which a regional epidemiological survey was already being carried out (June 2010 -May 2012). METHODS: The PEGASUS-Murcia project is a cross-sectional face-to-face interview survey of a representative sample of non-institutionalized adults in Murcia. Main outcome measures are prevalence and severity of anxiety, mood, impulse and substance disorders in the 12 months previous to the survey, assessed using the Composite International Diagnostic Interview (CIDI 3.0). Sociodemographic variables, prior history of any mental disorder and earthquake-related stressors were entered as independent variables in a logistic regression analysis. FINDINGS: A total number of 412 participants (response rate: 71%) were interviewed. Significant differences in 12-month prevalence of mental disorders were found in Lorca compared to the rest of Murcia for any (12.8% vs 16.8%), PTSD (3.6% vs 0.5%) and other anxiety disorders (5.3% vs 9.2%) (p<= 0.05 for all). No differences were found for 12-month prevalence of any mood or any substance disorder. The two major predictors for developing a 12-month post-earthquake mental disorder were a prior mental disorder and the level of exposure. Other risk factors included female sex and low-average income. CONCLUSIONS: PTSD and other mental disorders are commonly associated with earthquake disasters. Prior mental disorders and the level of exposure to the earthquakes are the most important for the development of a consequent mental disorder and this recognition may help to identify those individuals that may most benefit from specific therapeutic intervention. PMID- 28723950 TI - High affinity anti-TIM-3 and anti-KIR monoclonal antibodies cloned from healthy human individuals. AB - We report here the cloning of native high affinity anti-TIM-3 and anti-KIR IgG monoclonal antibodies (mAbs) from peripheral blood mononuclear cells (PBMC) of healthy human donors. The cells that express these mAbs are rare, present at a frequency of less than one per 105 memory B-cells. Using our proprietary multiplexed screening and cloning technology CellSpotTM we assessed the presence of memory B-cells reactive to foreign and endogenous disease-associated antigens within the same individual. When comparing the frequencies of antigen-specific memory B-cells analyzed in over 20 screening campaigns, we found a strong correlation of the presence of anti-TIM-3 memory B-cells with memory B-cells expressing mAbs against three disease-associated antigens: (i) bacterial DNABII proteins that are a marker for Gram negative and Gram positive bacterial infections, (ii) hemagglutinin (HA) of influenza virus and (iii) the extracellular domain of anaplastic lymphoma kinase (ALK). One of the native anti KIR mAbs has similar characteristics as lirilumab, an anti-KIR mAb derived from immunization of humanized transgenic mice that is in ongoing clinical trials. It is interesting to speculate that these native anti-TIM-3 and anti-KIR antibodies may function as natural regulatory antibodies, analogous to the pharmacological use in cancer treatment of engineered antibodies against the same targets. Further characterization studies are needed to define the mechanisms through which these native antibodies may function in healthy and disease conditions. PMID- 28723951 TI - CD8+ T cells provide immune protection against murine disseminated endotheliotropic Orientia tsutsugamushi infection. AB - Scrub typhus, caused by a Gram-negative obligately intracellular coccobacillus, Orientia tsutsugamushi, is a long neglected but important tropical disease. Orientia tsutsugamushi causes illness in one million people each year, and 1 billion people are at risk. Without appropriate diagnosis and treatment, the disease can cause severe multiorgan failure with a case fatality rate of 7-15%. The current gaps in knowledge of immunity include the unknown mechanisms of host immunity to O. tsutsugamushi. Using an intravenous (i.v.) disseminated infection mouse model, we observed that more CD8+ T cells than CD4+ T cells were present in the spleen of infected mice at 12 dpi. We also determined that Treg cells and the proportion of T cells producing IL-10 were significantly increased from 6 dpi, which correlated with the onset of illness, body weight loss, and increased bacterial loads. We further studied CD8-/-, MHC I-/- and wild type control (WT) C57BL/6J mice to determine the importance of CD8+ T cells and MHC I molecules. After infection with an ordinarily sub-lethal dose of O. tsutsugamushi, all CD8-/ and MHC I-/- mice were moribund between 12 and 15 dpi, whereas all WT mice survived. Bacterial loads in the lung, kidney, liver and spleen of CD8-/- and MHC I-/- mice were significantly greater than those in WT mice. Interferon-gamma (IFN gamma) and granzyme B mRNA levels in the liver of CD8-/- and MHC I-/- mice were significantly greater than in WT mice. In addition, more severe histopathologic lesions were observed in CD8-/- mice. Finally, adoptive transfer confirmed a major role of immune CD8+ T cells as well as a less effective contribution by immune CD8 T cell-depleted splenocytes in protection against O. tsutsugamushi infection. These studies demonstrated the critical importance of CD8+ T cells in the host immune response during O. tsutsugamushi infection. PMID- 28723953 TI - Analysis of the differential gene and protein expression profile of the rolled leaf mutant of transgenic rice (Oryza sativa L.). AB - The importance of leaf rolling in rice (Oryza sativa L.) has been widely recognized. Although several studies have investigated rice leaf rolling and identified some related genes, knowledge of the molecular mechanism underlying rice leaf rolling, especially outward leaf rolling, is limited. Therefore, in this study, differential proteomics and gene expression profiling were used to analyze rolled leaf mutant of transgenic rice in order to investigate differentially expressed genes and proteins related to rice leaf rolling. To this end, 28 differentially expressed proteins related to rolling leaf traits were isolated and identified. Digital expression profiling detected 10 genes related to rice leaf rolling. Some of the proteins and genes detected are involved in lipid metabolism, which is related to the development of bulliform cells, such as phosphoinositide phospholipase C, Mgll gene, and At4g26790 gene. The "omics" level techniques were useful for simultaneously isolating several proteins and genes related to rice leaf rolling. In addition, the results of the analysis of differentially expressed proteins and genes were closely consistent with those from a corresponding functional analysis of cellular mechanisms; our study findings might form the basis for further research on the molecular mechanisms underlying rice leaf rolling. PMID- 28723952 TI - Evidence for prehistoric origins of the G2019S mutation in the North African Berber population. AB - The most common cause of the monogenic form of Parkinson's disease known so far is the G2019S mutation of the leucine-rich repeat kinase 2 (LRRK2) gene. Its frequency varies greatly among ethnic groups and geographic regions ranging from less than 0.1% in Asia to 40% in North Africa. This mutation has three distinct haplotypes; haplotype 1 being the oldest and most common. Recent studies have dated haplotype 1 of the G2019S mutation to about 4000 years ago, but it remains controversial whether the mutation has a Near-Eastern or Moroccan-Berber ancestral origin. To decipher this evolutionary history, we genotyped 10 microsatellite markers spanning a region of 11.27 Mb in a total of 57 unrelated Moroccan PD patients carrying the G2019S mutation for which the Berber or Arab origin was established over 3 generations based on spoken language. We estimated the age of the most recent common ancestor for the 36 Arab-speaking and the 15 Berber-speaking G2019S carriers using the likelihood-based method with a mutation rate of 10-4. Data analysis suggests that the shortest haplotype originated in a patient of Berber ethnicity. The common founder was estimated to have lived 159 generations ago (95% CI 116-224) for Arab patients, and 200 generations ago (95% CI 123-348) for Berber patients. Then, 29 native North African males carrying the mutation were assessed for specific uniparental markers by sequencing the Y chromosome (E-M81, E-M78, and M-267) and mitochondrial DNA (mtDNA) hypervariable regions (HV1 and HV2) to examine paternal and maternal contributions, respectively. Results showed that the autochthonous genetic component reached 76% for mtDNA (Eurasian and north African haplogroups) and 59% for the Y-chromosome (E-M81 and E-M78), suggesting that the G2019S mutation may have arisen in an autochthonous DNA pool. Therefore, we conclude that LRRK2 G2019S mutation most likely originated in a Berber founder who lived at least 5000 years ago (95% CI 3075-8700). PMID- 28723954 TI - Association between urinary biomarkers of total sugars intake and measures of obesity in a cross-sectional study. AB - Obesity is an important modifiable risk factor for chronic diseases. While there is increasing focus on the role of dietary sugars, there remains a paucity of data establishing the association between sugar intake and obesity in the general public. The objective of this study was to investigate associations of estimated sugar intake with odds for obesity in a representative sample of English adults. We used data from 434 participants of the 2005 Health Survey of England. Biomarkers for total sugar intake were measured in 24 h urine samples and used to estimate intake. Linear and logistic regression analyses were used to investigate associations between biomarker-based estimated intake and measures of obesity (body mass intake (BMI), waist circumference and waist-to-hip ratio) and obesity risk, respectively. Estimated sugar intake was significantly associated with BMI, waist circumference and waist-to-hip ratio; these associations remained significant after adjustment for estimated protein intake as a marker of non sugar energy intake. Estimated sugar intake was also associated with increased odds for obesity based on BMI (OR 1.02; 95%CI 1.00-1.04 per 10g), waist circumference (1.03; 1.01-1.05) and waist-to-hip ratio (1.04; 1.02-1.06); all OR estimates remained significant after adjusting for estimated protein intake. Our results strongly support positive associations between total sugar intake, measures of obesity and likelihood of being obese. It is the first time that such an association has been shown in a nationally-representative sample of the general population using a validated biomarker. This biomarker could be used to monitor the efficacy of public health interventions to reduce sugar intake. PMID- 28723955 TI - Crystal structure and functional characterization of an isoaspartyl dipeptidase (CpsIadA) from Colwellia psychrerythraea strain 34H. AB - Isoaspartyl dipeptidase (IadA) is an enzyme that catalyzes the hydrolysis of an isoaspartyl dipeptide-like moiety, which can be inappropriately formed in proteins, between the beta-carboxyl group side chain of Asp and the amino group of the following amino acid. Here, we have determined the structures of an isoaspartyl dipeptidase (CpsIadA) from Colwellia psychrerythraea, both ligand free and that complexed with beta-isoaspartyl lysine, at 1.85-A and 2.33-A resolution, respectively. In both structures, CpsIadA formed an octamer with two Zn ions in the active site. A structural comparison with Escherichia coli isoaspartyl dipeptidase (EcoIadA) revealed a major difference in the structure of the active site. For metal ion coordination, CpsIadA has a Glu166 residue in the active site, whereas EcoIadA has a post-translationally carbamylated-lysine 162 residue. Site-directed mutagenesis studies confirmed that the Glu166 residue is critical for CpsIadA enzymatic activity. This residue substitution from lysine to glutamate induces the protrusion of the beta12-alpha8 loop into the active site to compensate for the loss of length of the side chain. In addition, the alpha3 beta9 loop of CpsIadA adopts a different conformation compared to EcoIadA, which induces a change in the structure of the substrate-binding pocket. Despite CpsIadA having a different active-site residue composition and substrate-binding pocket, there is only a slight difference in CpsIadA substrate specificity compared with EcoIadA. Comparative sequence analysis classified IadA-containing bacteria and archaea into two groups based on the active-site residue composition, with Type I IadAs having a glutamate residue and Type II IadAs having a carbamylated-lysine residue. CpsIadA has maximal activity at pH 8-8.5 and 45 degrees C, and was completely inactivated at 60 degrees C. Despite being isolated from a psychrophilic bacteria, CpsIadA is thermostable probably owing to its octameric structure. This is the first conclusive description of the structure and properties of a Type I IadA. PMID- 28723956 TI - Psychosis risk research versus daily prognosis uncertainties: A qualitative study of French youth psychiatrists' attitudes toward predictive practices. AB - BACKGROUND: Over the last twenty years, predicting psychosis has become a priority of both research and policies. Those approaches include the use of the At Risk Mental State category (ARMS) and of standardized predictive tools. In comparison to most developed countries, early interventions programs are only little developed in France. However, cases of young patients presenting unclear symptoms that might be a beginning psychosis or might as well reflect some adolescent unease are commonplace in psychiatry. Yet little is known about the routine practices of youth psychiatrists regarding psychosis risk management. Do they anticipate mental disorders? METHOD: The Grounded Theory is an agreed-upon qualitative method in social science field that links subjective experiences (individual narratives) to social processes (professional norms and mental health policies). 12 French youth psychiatrists were interviewed about psychosis early management and their daily prognosis practices with teenagers. RESULTS: If all participants were aware of early intervention programs, most of them did not make use of standardized scales. Psychiatrists' reluctance toward a psychosis risk standardized assessment was shaped by three difficulties: first the gap between theoretical knowledge and practice; second their impossibility to make reliable prognoses; and third, the many uncertainties surrounding medical judgment, adolescence and the nature of psychosis. Nevertheless, they provided their young patients with multiple months follow up without disclosing any risk category. CONCLUSION: Anticipating a psychosis onset remains a highly uncertain task for psychiatrists. In France, psychiatrists' inconspicuous risk management might be supported by the universal costs coverage that is not conditional on a diagnosis disclosure. PMID- 28723957 TI - Brain synchronization during perception of facial emotional expressions with natural and unnatural dynamics. AB - Research on the perception of facial emotional expressions (FEEs) often uses static images that do not capture the dynamic character of social coordination in natural settings. Recent behavioral and neuroimaging studies suggest that dynamic FEEs (videos or morphs) enhance emotion perception. To identify mechanisms associated with the perception of FEEs with natural dynamics, the present EEG (Electroencephalography)study compared (i) ecologically valid stimuli of angry and happy FEEs with natural dynamics to (ii) FEEs with unnatural dynamics, and to (iii) static FEEs. FEEs with unnatural dynamics showed faces moving in a biologically possible but unpredictable and atypical manner, generally resulting in ambivalent emotional content. Participants were asked to explicitly recognize FEEs. Using whole power (WP) and phase synchrony (Phase Locking Index, PLI), we found that brain responses discriminated between natural and unnatural FEEs (both static and dynamic). Differences were primarily observed in the timing and brain topographies of delta and theta PLI and WP, and in alpha and beta WP. Our results support the view that biologically plausible, albeit atypical, FEEs are processed by the brain by different mechanisms than natural FEEs. We conclude that natural movement dynamics are essential for the perception of FEEs and the associated brain processes. PMID- 28723958 TI - Can single molecule localization microscopy be used to map closely spaced RGD nanodomains? AB - Cells sense and respond to nanoscale variations in the distribution of ligands to adhesion receptors. This makes single molecule localization microscopy (SMLM) an attractive tool to map the distribution of ligands on nanopatterned surfaces. We explore the use of SMLM spatial cluster analysis to detect nanodomains of the cell adhesion-stimulating tripeptide arginine-glycine-aspartic acid (RGD). These domains were formed by the phase separation of block copolymers with controllable spacing on the scale of tens of nanometers. We first determined the topology of the block copolymer with atomic force microscopy (AFM) and then imaged the localization of individual RGD peptides with direct stochastic optical reconstruction microscopy (dSTORM). To compare the data, we analyzed the dSTORM data with DBSCAN (density-based spatial clustering application with noise). The ligand distribution and polymer topology are not necessary identical since peptides may attach to the polymer outside the nanodomains and/or coupling and detection of peptides within the nanodomains is incomplete. We therefore performed simulations to explore the extent to which nanodomains could be mapped with dSTORM. We found that successful detection of nanodomains by dSTORM was influenced by the inter-domain spacing and the localization precision of individual fluorophores, and less by non-specific absorption of ligands to the substratum. For example, under our imaging conditions, DBSCAN identification of nanodomains spaced further than 50 nm apart was largely independent of background localisations, while nanodomains spaced closer than 50 nm required a localization precision of ~11 nm to correctly estimate the modal nearest neighbor distance (NDD) between nanodomains. We therefore conclude that SMLM is a promising technique to directly map the distribution and nanoscale organization of ligands and would benefit from an improved localization precision. PMID- 28723959 TI - A novel surveillance approach for disaster mental health. AB - BACKGROUND: Disasters have substantial consequences for population mental health. Social media data present an opportunity for mental health surveillance after disasters to help identify areas of mental health needs. We aimed to 1) identify specific basic emotions from Twitter for the greater New York City area during Hurricane Sandy, which made landfall on October 29, 2012, and to 2) detect and map spatial temporal clusters representing excess risk of these emotions. METHODS: We applied an advanced sentiment analysis on 344,957 Twitter tweets in the study area over eleven days, from October 22 to November 1, 2012, to extract basic emotions, a space-time scan statistic (SaTScan) and a geographic information system (QGIS) to detect and map excess risk of these emotions. RESULTS: Sadness and disgust were among the most prominent emotions identified. Furthermore, we noted 24 spatial clusters of excess risk of basic emotions over time: Four for anger, one for confusion, three for disgust, five for fear, five for sadness, and six for surprise. Of these, anger, confusion, disgust and fear clusters appeared pre disaster, a cluster of surprise was found peri disaster, and a cluster of sadness emerged post disaster. CONCLUSIONS: We proposed a novel syndromic surveillance approach for mental health based on social media data that may support conventional approaches by providing useful additional information in the context of disaster. We showed that excess risk of multiple basic emotions could be mapped in space and time as a step towards anticipating acute stress in the population and identifying community mental health need rapidly and efficiently in the aftermath of disaster. More studies are needed to better control for bias, identify associations with reliable and valid instruments measuring mental health, and to explore computational methods for continued model fitting, causal relationships, and ongoing evaluation. Our study may be a starting point also for more fully elaborated models that can either prospectively detect mental health risk using real-time social media data or detect excess risk of emotional reactions in areas that lack efficient infrastructure during and after disasters. As such, social media data may be used for mental health surveillance after large scale disasters to help identify areas of mental health needs and to guide us in our knowledge where we may most effectively intervene to reduce the mental health consequences of disasters. PMID- 28723960 TI - A validation of 11 body-condition indices in a giant snake species that exhibits positive allometry. AB - Body condition is a gauge of the energy stores of an animal, and though it has important implications for fitness, survival, competition, and disease, it is difficult to measure directly. Instead, body condition is frequently estimated as a body condition index (BCI) using length and mass measurements. A desirable BCI should accurately reflect true body condition and be unbiased with respect to size (i.e., mean BCI estimates should not change across different length or mass ranges), and choosing the most-appropriate BCI is not straightforward. We evaluated 11 different BCIs in 248 Burmese pythons (Python bivittatus), organisms that, like other snakes, exhibit simple body plans well characterized by length and mass. We found that the length-mass relationship in Burmese pythons is positively allometric, where mass increases rapidly with respect to length, and this allowed us to explore the effects of allometry on BCI verification. We employed three alternative measures of 'true' body condition: percent fat, scaled fat, and residual fat. The latter two measures mostly accommodated allometry in true body condition, but percent fat did not. Our inferences of the best performing BCIs depended heavily on our measure of true body condition, with most BCIs falling into one of two groups. The first group contained most BCIs based on ratios, and these were associated with percent fat and body length (i.e., were biased). The second group contained the scaled mass index and most of the BCIs based on linear regressions, and these were associated with both scaled and residual fat but not body length (i.e., were unbiased). Our results show that potential differences in measures of true body condition should be explored in BCI verification studies, particularly in organisms undergoing allometric growth. Furthermore, the caveats of each BCI and similarities to other BCIs are important to consider when determining which BCI is appropriate for any particular taxon. PMID- 28723961 TI - Dysfunctional GPR40/FFAR1 signaling exacerbates pain behavior in mice. AB - We previously showed that activation of G protein-coupled receptor 40/free fatty acid receptor 1 (GPR40/FFAR1) signaling modulates descending inhibition of pain. In this study, we investigated the involvement of fatty acid-GPR40/FFAR1 signaling in the transition from acute to chronic pain. We used GPR40/FFAR1 knockout (GPR40KO) mice and wild-type (WT) mice. A plantar incision was performed, and mechanical allodynia and thermal hyperalgesia were evaluated with a von Frey filament test and plantar test, respectively. Immunohistochemistry was used to localize GPR40/FFAR1, and the levels of free fatty acids in the hypothalamus were analyzed with liquid chromatography-tandem mass spectrometry. The repeated administration of GW1100, a GPR40/FFAR1 antagonist, exacerbated the incision-induced mechanical allodynia and significantly increased the levels of phosphorylated extracellular signal-regulated kinase in the spinal cord after low threshold touch stimulation in the mice compared to vehicle-treated mice. The levels of long-chain free fatty acids, such as docosahexaenoic acid, oleic acid, and palmitate, which are GPR40/FFAR1 agonists, were significantly increased in the hypothalamus two days after the surgery compared to levels in the sham group. Furthermore, the incision-induced mechanical allodynia was exacerbated in the GPR40KO mice compared to the WT mice, while the response in the plantar test was not changed. These findings suggested that dysfunction of the GPR40/FFAR1 signaling pathway altered the endogenous pain control system and that this dysfunction might be associated with the development of chronic pain. PMID- 28723962 TI - Surface functionalization-specific binding of coagulation factors by zinc oxide nanoparticles delays coagulation time and reduces thrombin generation potential in vitro. AB - Zinc oxide nanoparticles (ZnO NPs) have many biomedical applications such as chemotherapy agents, vaccine adjuvants, and biosensors but its hemocompatibility is still poorly understood, especially in the event of direct contact of NPs with blood components. Here, we investigated the impact of size and surface functional groups on the platelet homeostasis. ZnO NPs were synthesized in two different sizes (20 and 100 nm) and with three different functional surface groups (pristine, citrate, and L-serine). ZnO NPs were incubated with plasma collected from healthy rats to evaluate the coagulation time, kinetics of thrombin generation, and profile of levels of coagulation factors in the supernatant and coronated onto the ZnO NPs. Measurements of plasma coagulation time showed that all types of ZnO NPs prolonged both active partial thromboplastin time and prothrombin time in a dose-dependent manner but there was no size- or surface functionalization-specific pattern. The kinetics data of thrombin generation showed that ZnO NPs reduced the thrombin generation potential with functionalization-specificity in the order of pristine > citrate > L-serine but there was no size-specificity. The profile of levels of coagulation factors in the supernatant and coronated onto the ZnO NPs after incubation of platelet-poor plasma with ZnO NPs showed that ZnO NPs reduced the levels of coagulation factors in the supernatant with functionalization-specificity. Interestingly, the pattern of coagulation factors in the supernatant was consistent with the levels of coagulation factors adsorbed onto the NPs, which might imply that ZnO NPs simply adsorb coagulation factors rather than stimulating these factors. The reduced levels of coagulation factors in the supernatant were consistent with the delayed coagulation time and reduced potential for thrombin generation, which imply that the adsorbed coagulation factors are not functional. PMID- 28723963 TI - Impact of thyroid function abnormalities on reproductive hormones during menstrual cycle in premenopausal HIV infected females at NAUTH, Nnewi, Nigeria. AB - BACKGROUND: This was a prospective study designed to evaluate the impact of thyroid function abnormalities on reproductive hormones during menstrual cycle in HIV infected females at Nnamdi Azikiwe University Teaching Hospital Nnewi, South East Nigeria. METHODS: The study randomly recruited 35 Symptomatic HIV infected females and 35 Symptomatic HIV infected females on antiretroviral therapy (HAART) for not less than six weeks from an HIV clinic and 40 apparently heathy control females among the hospital staff of NAUTH Nnewi. They were all premenopausal females with regular menstrual cycle and aged between 15-45 years. Blood samples were collected at follicular and luteal phases of their menstrual cycle for assay of Thyroid indices (FT3, FT4 and TSH) and Reproductive indices (FSH, LH, Estrogen, Progesterone, Prolactin and Testosterone) using ELISA method. RESULTS: The result showed significantly higher FSH and LH but significantly lower progesterone (prog) and estrogen (E2) in the test females compared to control females at both phases of menstrual cycle (P<0.05). There was significantly lower FT3 but significantly higher TSH value in Symptomatic HIV females (P<0.05). FSH, LH and TSH values were significantly lowered while prog and FT3 were significantly higher in Symptomatic HIV on ART compared to Symptomatic HIV females (P<0.05). FT3, FT4, Prog and E2 were inversely correlated while FSH and LH were positively correlated with duration of HIV infection in HIV females (P<0.05 respectively). There was a direct correlation between CD4+ count and FT3 while inverse correlation was found between CD4+ count and TSH levels (P<0.05). DISCUSSION: The present study demonstrated hypothyroidism with a significant degree of primary hypogonadism in Symptomatic HIV infected females at both follicular and luteal phases of menstrual cycle which tends to normalize on treatments. PMID- 28723964 TI - Development of the Korean Adult Reading Test (KART) to estimate premorbid intelligence in dementia patients. AB - We aimed to develop a word-reading test for Korean-speaking adults using irregularly pronounced words that would be useful for estimation of premorbid intelligence. A linguist who specialized in Korean phonology selected 94 words that have irregular relationship between orthography and phonology. Sixty cognitively normal elderly (CN) and 31 patients with Alzheimer's disease (AD) were asked to read out loud the words and were administered the Wechsler Adult Intelligence Scale, 4th edition, Korean version (K-WAIS-IV). Among the 94 words, 50 words that did not show a significant difference between the CN and the AD group were selected and constituted the KART. Using the 30 CN calculation group (CNc), a linear regression equation was obtained in which the observed full-scale IQ (FSIQ) was regressed on the reading errors of the KART, where education was included as an additional variable. When the regressed equation computed from the CNc was applied to 30 CN individuals of the validation group (CNv), the predicted FSIQ adequately fit the observed FSIQ (R2 = 0.63). In addition, independent sample t-test showed that the KART-predicted IQs were not significantly different between the CNv and AD groups, whereas the performance of the AD group was significantly worse in the observed IQs. In addition, an extended validation of the KART was performed with a separate sample consisted of 84 CN, 56 elderly with mild cognitive impairment (MCI), and 43 AD patients who were administered comprehensive neuropsychological assessments in addition to the KART. When the equation obtained from the CNc was applied to the extended validation sample, the KART-predicted IQs of the AD, MCI and the CN groups did not significantly differ, whereas their current global cognition scores significantly differed between the groups. In conclusion, the results support the validity of KART-predicted IQ as an index of premorbid IQ in individuals with AD. PMID- 28723965 TI - The prevalence and metabolic characteristics of polycystic ovary syndrome in the Qatari population. AB - OBJECTIVE: The prevalence of polycystic ovary syndrome (PCOS) in the Qatari population is unknown and hence the estimated impact on the local population cannot be determined. The purpose of this study was to estimate the prevalence and metabolic features of PCOS among Qatari women. DESIGN: Cross sectional analysis. PATIENTS: 3,017 Qatari subjects volunteered to be phenotyped and genotyped for the Qatar Biobank from which all women between the ages of 18-40 years were identified (750). MEASUREMENTS: 720 women had testosterone and sex hormone binding globulin (SHBG) measurements. PCOS was diagnosed according the National Institute of Health (NIH) Guidelines of a raised androgen level (free androgen index >4.5 or a raised total testosterone) and menstrual irregularity after the exclusion of other conditions. RESULTS: All results are reported as mean value of PCOS versus control. 87 of 720 women fulfilled the NIH guidelines (12.1%) for PCOS specifically using a free androgen index greater than 4.5 or a total testosterone greater than 2.7nmol/l and menstrual irregularity. Subjects were heavier with a more metabolic profile of a greater systolic and diastolic blood pressure, higher levels of C reactive protein, insulin (p<0.01) and HbA1c (P<0.02), and decreased HDL levels (p<0.01). Pulse wave velocity as a marker of arterial stiffness was also increased (p<0.05). CONCLUSIONS: By NIH guidelines the prevalence of PCOS in this Qatari cohort was 12.1% that would likely reflect 20% by Rotterdam criteria, with a markedly more metabolic phenotype than Qatari controls. PMID- 28723966 TI - Activated carbon, a useful medium to bind chlordecone in soil and limit its transfer to growing goat kids. AB - Chlordecone (Kepone) (CLD) is a highly persistent pesticide which was extensively used in the French West Indies; high levels of CLD can still currently be found in large agricultural areas. As CLD transfers from soil to animals mainly via involuntary ingestion, the consumption of foodstuffs derived from animals raised in contaminated areas may significantly contribute to exposure of humans to CLD. The present study was designed to test the efficacy of two different activated carbons (ACs) sources in limiting CLD transfer from soil to animal. Three soils (ASs) were prepared according to the OECD guideline 207. One standard soil (SS) lacking AC, and two modified preparations of SS supplemented with 2% coconut based activated carbon (ORBO), SSO or with 2% lignite-based one (DARCO), SSD. All three soils were spiked with 10 MUg of kepone per g of dry matter and aged for three weeks. This study involved 15 goat kids randomly assigned to the 3 experimental groups (n = 5/group), which were fed the experimental matrices at an exposure dose of 10 MUg CLD per kg of body weight per day. After 21 d of oral exposure, CLD in adipose tissue and liver were analysed by LC-MS-MS. A significant decrease of 63.7% and 74.7% of CLD concentrations in adipose tissue and liver, respectively, were obtained from animals exposed using SS containing DARCO as compared to those receiving only SS. Decreases in CLD levels of 98.2% (adipose tissue) and 98.7% (liver) were obtained for animals exposed using SS containing ORBO. This study leads us to conclude that (i) the presence of AC in CLD-contaminated soil strongly reduces CLD bioavailability, and (ii) the efficacy depends on the nature and characteristics of the AC used. PMID- 28723967 TI - Epitope determination of immunogenic proteins of Neisseria gonorrhoeae. AB - Neisseria gonorrhoeae is the causative organism of gonorrhoea, a sexually transmitted disease that globally accounts for an estimated 80 to 100 million new infections per year. Increasing resistances to all common antibiotics used for N. gonorrhoeae treatment pose the risk of an untreatable disease. Further knowledge of ways of infection and host immune response are needed to understand the pathogen-host interaction and to discover new treatment alternatives against this disease. Therefore, detailed information about immunogenic proteins and their properties like epitope sites could advance further research in this area. In this work, we investigated immunogenic proteins of N. gonorrhoeae for linear epitopes by microarrays. Dominant linear epitopes were identified for eleven of the nineteen investigated proteins with three polyclonal rabbit antibodies from different immunisations. Identified linear epitopes were further examined for non specific binding with antibodies to Escherichia coli and the closely related pathogen Neisseria meningitidis. On top of that, amino acids crucial for the antibody epitope binding were detected by microarray based alanine scans. PMID- 28723969 TI - Matrixlysis, an improved sample preparation method for recovery of Mycobacteria from animal tissue material. AB - Mycobacterium caprae, a member of the Mycobacterium tuberculosis complex, is the main causative agent of bovine tuberculosis in alpine regions. Bacterial culture is the gold standard in bovine tuberculosis diagnostic but takes up to twelve weeks. This increases the time and costs for stocks affected with bovine tuberculosis. Hence this study focused on the implementation of a fast and precise mycobacterial detection method and compared it with currently used methods. Matrix lysis is a chemical lysis using high concentrations of urea to solubilize bovine and red deer tissue and was used to detect even smallest amounts or non-visible lesions of mycobacteria. A total of 64 samples collected from 44 animals (37 red deer and 7 cattle) were tested by Matrix lysis. Forty three of these samples were used for Mycobacterium tuberculosis complex detection by quantitative PCR and other 21 for subtyping the genetically different variants of M. caprae. Furthermore, three Matrix lysis samples were used for Next Generation Sequencing. Our results confirm that Matrix lysis is a fast and precise method for detecting Mycobacterium tuberculosis complex in native tissue samples. However, at the moment it reaches its limits when the samples were analyzed by Next Generation Sequencing and RD4 subtyping. PMID- 28723968 TI - New library construction method for single-cell genomes. AB - A central challenge in sequencing single-cell genomes is the accurate determination of point mutations, phasing of these mutations, and identifying copy number variations with few assumptions. Ideally, this is accomplished under as low sequencing coverage as possible. Here we report our attempt to meet these goals with a novel library construction and library amplification methodology. In our approach, single-cell genomic DNA is first fragmented with saturated transposition to make a primary library that uniformly covers the whole genome by short fragments. The library is then amplified by a carefully optimized PCR protocol in a uniform and synchronized fashion for next-generation sequencing. Each step of the protocol can be quantitatively characterized. Our shallow sequencing data show that the library is tightly distributed and is useful for the determination of copy number variations. PMID- 28723970 TI - Barriers and facilitators of HIV vaccine and prevention study participation among Young Black MSM and transwomen in New York City. AB - BACKGROUND: Black men who have sex with men (MSM), and Transwomen (TW) shoulder disproportionate burden of HIV. However, they are unrepresented in HIV vaccine trials. We investigated the perceptions of that factors associated with HIV vaccine trials participation among Black MSM and TW in New York. METHODS: Self administered online questionnaires were administered to 18-29 years of NYC residents who identified as Black MSM and TW, assessing demographics, awareness and willingness to participate in HIV vaccine trials, barriers and facilitators associated with willingness, and sexual behaviors. Frequency summation was performed to determine barriers and facilitators, and logistic regression analysis was performed to determine factors association with expressed willingness. RESULTS: Black MSM and TW who reported engaging in risk behaviors had a 61% lower likelihood of participating in HIV vaccine trials when compared to those who did not report engaging in any risk behavior. Facilitators associated with trial participation were: cash compensation, confidentiality regarding participation, public transportation vouchers, gift cards, and food or grocery vouchers as potential facilitators for trial participation. Conversely, fear of side effects from the vaccine, concerns about testing positive on routine HIV testing due to an HIV vaccine, limited knowledge of research trials, and fear of being judged as HIV-positive were perceived as barriers. CONCLUSIONS: These findings provided insights into the considerations and perceptions of Black MSM and TW towards HIV vaccine trials. However, further studies are needed to delineate the complex mechanisms underlying the decision-making process and establish approaches to increase study participation in this population. PMID- 28723972 TI - Correction: Chaperone-Mediated Autophagy Protein BAG3 Negatively Regulates Ebola and Marburg VP40-Mediated Egress. AB - [This corrects the article DOI: 10.1371/journal.ppat.1006132.]. PMID- 28723973 TI - Hypoalbuminemia at admission predicts the development of acute kidney injury in hospitalized patients: A retrospective cohort study. AB - BACKGROUND: Development of acute kidney injury (AKI) is common and is associated with poor outcomes. We aimed to determine whether hypoalbuminemia (HA) at admission could be a risk factor for the development of AKI and mortality in hospitalized patients. METHODS: We enrolled patients who were admitted to Seoul National University Bundang Hospital from January 2013 to December 2013. HA at admission was defined as a serum albumin level < 3.4 mg/dL measured within two days after admission. AKI was defined as an increase in the serum creatinine level by >=0.3 mg/dL or >=1.5 times of the baseline value during the hospital stay. RESULTS: A total of 19,472 patients were enrolled and divided into HA and normoalbuminemia (NA) groups at admission. The incidence of AKI was 10.7% (340/3179) in the HA group and 4.1% (662/16293) in the NA group (adjusted odds ratio [OR], 1.243; 95% confidence interval [CI], 1.069-1.445; P = 0.005). The hazard ratios for the 30-day, 90-day, and 1-year mortality were 1.873 (95% CI, 1.383-2.537; P < 0.001), 1.710 (95% CI, 1.410-2.072; P < 0.001), and 1.372 (95% CI, 1.214-1.551; P < 0.001), compared to the NA group. In patients with AKI, albumin replacement improved renal recovery (OR, 2.605; 95% CI, 1.450-4.681; P = 0.001). The mortality rate was not different according to albumin replacement. CONCLUSIONS: HA is associated with the development of AKI and high mortality in hospitalized patients. Replacement of albumin after the development of AKI may contribute to renal recovery. Further clinical trials are warranted. PMID- 28723971 TI - Termination factor Rho: From the control of pervasive transcription to cell fate determination in Bacillus subtilis. AB - In eukaryotes, RNA species originating from pervasive transcription are regulators of various cellular processes, from the expression of individual genes to the control of cellular development and oncogenesis. In prokaryotes, the function of pervasive transcription and its output on cell physiology is still unknown. Most bacteria possess termination factor Rho, which represses pervasive, mostly antisense, transcription. Here, we investigate the biological significance of Rho-controlled transcription in the Gram-positive model bacterium Bacillus subtilis. Rho inactivation strongly affected gene expression in B. subtilis, as assessed by transcriptome and proteome analysis of a rho-null mutant during exponential growth in rich medium. Subsequent physiological analyses demonstrated that a considerable part of Rho-controlled transcription is connected to balanced regulation of three mutually exclusive differentiation programs: cell motility, biofilm formation, and sporulation. In the absence of Rho, several up-regulated sense and antisense transcripts affect key structural and regulatory elements of these differentiation programs, thereby suppressing motility and biofilm formation and stimulating sporulation. We dissected how Rho is involved in the activity of the cell fate decision-making network, centered on the master regulator Spo0A. We also revealed a novel regulatory mechanism of Spo0A activation through Rho-dependent intragenic transcription termination of the protein kinase kinB gene. Altogether, our findings indicate that distinct Rho controlled transcripts are functional and constitute a previously unknown built in module for the control of cell differentiation in B. subtilis. In a broader context, our results highlight the recruitment of the termination factor Rho, for which the conserved biological role is probably to repress pervasive transcription, in highly integrated, bacterium-specific, regulatory networks. PMID- 28723974 TI - Alginate hydrogels allow for bioactive and sustained release of VEGF-C and VEGF-D for lymphangiogenic therapeutic applications. AB - Lymphatic dysfunction is associated with the progression of many cardiovascular disorders due to their role in maintaining tissue fluid homeostasis. Promoting new lymphatic vessels (lymphangiogenesis) is a promising strategy to reverse these cardiovascular disorders via restoring lymphatic function. Vascular endothelial growth factor (VEGF) members VEGF-C and VEGF-D are both potent candidates for stimulating lymphangiogenesis, though maintaining spatial and temporal control of these factors represents a challenge to developing efficient therapeutic lymphangiogenic applications. Injectable alginate hydrogels have been useful for the controlled delivery of many angiogenic factors, including VEGF-A, to stimulate new blood vasculature. However, the utility of these tunable hydrogels for delivering lymphangiogenic factors has never been closely examined. Thus, the objective of this study was to utilize ionically cross-linked alginate hydrogels to deliver VEGF-C and VEGF-D for potential lymphangiogenic applications. We demonstrated that lymphatic endothelial cells (LECs) are sensitive to temporal presentation of VEGF-C and VEGF-D but with different responses between the factors. The greatest LEC mitogenic and sprouting response was observed for constant concentrations of VEGF-C and a high initial concentration that gradually decreased over time for VEGF-D. Additionally, alginate hydrogels provided sustained release of radiolabeled VEGF-C and VEGF-D. Finally, VEGF-C and VEGF-D released from these hydrogels promoted a similar number of LEC sprouts as exogenously added growth factors and new vasculature in vivo via a chick chorioallantoic membrane (CAM) assay. Overall, these findings demonstrate that alginate hydrogels can provide sustained and bioactive release of VEGF-C and VEGF-D which could have applications for therapeutic lymphangiogenesis. PMID- 28723975 TI - A view not to be missed: Salient scene content interferes with cognitive restoration. AB - Attention Restoration Theory (ART) states that built scenes place greater load on attentional resources than natural scenes. This is explained in terms of "hard" and "soft" fascination of built and natural scenes. Given a lack of direct empirical evidence for this assumption we propose that perceptual saliency of scene content can function as an empirically derived indicator of fascination. Saliency levels were established by measuring speed of scene category detection using a Go/No-Go detection paradigm. Experiment 1 shows that built scenes are more salient than natural scenes. Experiment 2 replicates these findings using greyscale images, ruling out a colour-based response strategy, and additionally shows that built objects in natural scenes affect saliency to a greater extent than the reverse. Experiment 3 demonstrates that the saliency of scene content is directly linked to cognitive restoration using an established restoration paradigm. Overall, these findings demonstrate an important link between the saliency of scene content and related cognitive restoration. PMID- 28723976 TI - Benefits of fading in perceptual learning are driven by more than dimensional attention. AB - Individuals learn to classify percepts effectively when the task is initially easy and then gradually increases in difficulty. Some suggest that this is because easy-to-discriminate events help learners focus attention on discrimination-relevant dimensions. Here, we tested whether such attentional spotlighting accounts are sufficient to explain easy-to-hard effects in auditory perceptual learning. In two experiments, participants were trained to discriminate periodic, frequency-modulated (FM) tones in two separate frequency ranges (300-600 Hz or 3000-6000 Hz). In one frequency range, sounds gradually increased in similarity as training progressed. In the other, stimulus similarity was constant throughout training. After training, participants showed better performance in their progressively trained frequency range, even though the discrimination-relevant dimension across ranges was the same. Learning theories that posit experience-dependent changes in stimulus representations and/or the strengthening of associations with differential responses, predict the observed specificity of easy-to-hard effects, whereas attentional-spotlighting theories do not. Calibrating the difficulty and temporal sequencing of training experiences to support more incremental representation-based learning can enhance the effectiveness of practice beyond any benefits gained from explicitly highlighting relevant dimensions. PMID- 28723977 TI - Effect of inter-train interval on the induction of repetition suppression of motor-evoked potentials using transcranial magnetic stimulation. AB - Repetition suppression (RS) is evident as a weakened response to repeated stimuli after the initial response. RS has been demonstrated in motor-evoked potentials (MEPs) induced with transcranial magnetic stimulation (TMS). Here, we investigated the effect of inter-train interval (ITI) on the induction of RS of MEPs with the attempt to optimize the investigative protocols. Trains of TMS pulses, targeted to the primary motor cortex by neuronavigation, were applied at a stimulation intensity of 120% of the resting motor threshold. The stimulus trains included either four or twenty pulses with an inter-stimulus interval (ISI) of 1 s. The ITI was here defined as the interval between the last pulse in a train and the first pulse in the next train; the ITIs used here were 1, 3, 4, 6, 7, 12, and 17 s. RS was observed with all ITIs except with the ITI of 1 s, in which the ITI was equal to ISI. RS was more pronounced with longer ITIs. Shorter ITIs may not allow sufficient time for a return to baseline. RS may reflect a startle-like response to the first pulse of a train followed by habituation. Longer ITIs may allow more recovery time and in turn demonstrate greater RS. Our results indicate that RS can be studied with confidence at relatively short ITIs of 6 s and above. PMID- 28723978 TI - Instruments for the assessment of suicide risk: A systematic review evaluating the certainty of the evidence. AB - BACKGROUND: Instruments have been developed to facilitate suicide risk assessment. We aimed to evaluate the evidence for these instruments including assessment of risk of bias and diagnostic accuracy for suicide and suicide attempt. METHODS: PubMed (NLM), PsycInfo, Embase, Cinahl and the Cochrane Library databases were searched until December 2014. We assessed risk of bias with QUADAS 2. The average sensitivity and specificity of each instrument was estimated and the certainty of the evidence was assessed with GRADE. We considered instruments with a sensitivity > 80% and a specificity > 50% to have sufficient diagnostic accuracy. RESULTS: Thirty-five relevant studies were identified but 14 were considered to have high risk of bias, leaving 21 studies evaluating altogether 15 risk assessment instruments. We could carry out meta-analyses for five instruments. For the outcome suicide attempt SAD PERSONS Scale had a sensitivity of 15% (95% CI 8-24) and specificity of 97% (96-98), and the Manchester Self-Harm Rule (MSHR) a sensitivity of 97% (97-97) and a specificity of 20% (20-21). ReACT, which is a modification of MSHR, had a similar low specificity, as did the Sodersjukhuset Self Harm Rule. For the outcome suicide, the Beck Hopelessness Scale had a sensitivity of 89% (78-95) and specificity of 42% (40-43). CONCLUSIONS: Most suicide risk assessment instruments were supported by too few studies to allow for evaluation of accuracy. Among those that could be evaluated, none fulfilled requirements for sufficient diagnostic accuracy. PMID- 28723979 TI - OUTCOME AND NUTRITIONAL ASSESSMENT OF CHRONIC LIVER DISEASE PATIENTS USING ANTHROPOMETRY AND SUBJECTIVE GLOBAL ASSESSMENT. AB - BACKGROUND:: Protein-calorie malnutrition is common in chronic liver disease (CLD) but adequate clinical tools for nutritional assessment are not defined. OBJECTIVE:: In CLD patients, it was aimed: 1. Characterize protein-calorie malnutrition; 2. Compare several clinical, anthropometric and functional tools; 3. Study the association malnutrition/CLD severity and malnutrition/outcome. METHODS:: Observational, prospective study. Consecutive CLD ambulatory/hospitalised patients were recruited from 01-03-2012 to 31-08-2012, studied according with age, gender, etiology, alcohol consumption and CLD severity defined by Child-Turcotte-Pugh. Nutritional assessment used subjective global assessment, anthropometry, namely body-mass index (BMI), triceps skinfold, mid upper arm circumference, mid arm muscular circumference and handgrip strength. Patients were followed during two years and survival data was recorded. RESULTS:: A total of 130 CLD patients (80 men), aged 22-89 years (mean 60 years) were included. Most suffered from alcoholic cirrhosis (45%). Hospitalised patients presented more severe disease ( P <0.001) and worst nutritional status defined by BMI ( P =0.002), mid upper arm circumference ( P <0.001), mid arm muscular circumference ( P <0.001), triceps skinfold ( P =0.07) and subjective global assessment ( P <0.001). A third presented deficient/low handgrip strength. Alcohol consumption ( P =0.03) and malnutrition detected by BMI ( P =0.03), mid upper arm circumference ( P =0.001), triceps skinfold ( P =0.06), mid arm muscular circumference ( P =0.02) and subjective global assessment ( P <0.001) were associated with CLD severity. From 25 patients deceased during follow-up, 17 patients were severely malnourished according with triceps skinfold. Malnutrition defined by triceps skinfold predicted mortality ( P <0.001). CONCLUSION:: Protein calorie malnutrition is common in CLD patients and alcohol plays an important role. Triceps skinfold is the most efficient anthropometric parameter and is associated with mortality. Nutritional assessment should be considered mandatory in the routine care of CLD patients. PMID- 28723980 TI - PRELIMINARY RESULTS OF TOPICAL HEPATIC HYPOTHERMIA IN A MODEL OF LIVER ISCHEMIA/REPERFUSION INJURY IN RATS. AB - BACKGROUND: Ischemia/reperfusion causes organ damage but it is mandatory in hepatic transplantation, trauma and other complex liver surgeries, when Pringle maneuver is applied to minimize bleeding during these procedures. It is well known that liver ischemia/reperfusion leads to microcirculatory disturbance and cellular injury. In this setting hypothermia is known to reduce oxygen demand, lowering intracellular metabolism. OBJECTIVE:: To evaluate the effects of hypothermia in liver ischemia/reperfusion injury, using a new model of topic isolated liver hypothermia. METHODS: We used male Wistar rats weighting about 250 grams, kept in ad libitum feeding regime and randomly divided into two groups of nine animals: 1) Normothermic group, rats were submitted to normothermic ischemia of the median and left hepatic lobes, with subsequent resection of right and caudate lobes during liver reperfusion; and 2) Hypothermic group, rats were submitted to liver ischemia under hypothermia at 10 degrees C. Liver ischemia was performed for 45 minutes. The animals were euthanized 48 hours after liver reperfusion for blood and liver tissue sampling. RESULTS: The transaminases analyses showed a significant decrease of AST and ALT in Hypothermic group (P<0.01) compared to Normothermic group (1403+/-1234 x 454+/-213 and 730+/-680 x 271+/-211 U/L, respectively). Histology showed severe necrosis in 50% and mild necrosis in 50% of cases in Normothermic group, but severe necrosis in 10% and mild or absent necrosis 90% of the cases in hypothermic group. CONCLUSION:: A simplified model of liver ischemia/reperfusion that simulates orthotopic liver autotransplantion was demonstrated. Topical hypothermia of isolated hepatic lobules showed liver protection, being a viable and practical method for any kind of in vivo liver preservation study. PMID- 28723981 TI - INTESTINAL MICROBIOTA IN DIGESTIVE DISEASES. AB - BACKGROUND: In recent years, especially after the development of sophisticated metagenomic studies, research on the intestinal microbiota has increased, radically transforming our knowledge about the microbiome and its association with health maintenance and disease development in humans. Increasing evidence has shown that a permanent alteration in microbiota composition or function (dysbiosis) can alter immune responses, metabolism, intestinal permeability, and digestive motility, thereby promoting a proinflammatory state. Such alterations can mainly impair the host's immune and metabolic functions, thus favoring the onset of diseases such as diabetes, obesity, digestive, neurological, autoimmune, and neoplastic diseases. This comprehensive review is a compilation of the available literature on the formation of the complex intestinal ecosystem and its impact on the incidence of diseases such as obesity, non-alcoholic steatohepatitis, irritable bowel syndrome, inflammatory bowel disease, celiac disease, and digestive neoplasms. CONCLUSION:: Alterations in the composition and function of the gastrointestinal microbiota (dysbiosis) have a direct impact on human health and seem to have an important role in the pathogenesis of several gastrointestinal diseases, whether inflammatory, metabolic, or neoplastic ones. PMID- 28723982 TI - ASSESSMENT OF NUTRITIONAL STATUS OF CHILDREN AND ADOLESCENTS WITH SPASTIC QUADRIPLEGIC CEREBRAL PALSY. AB - BACKGROUND: : Due to several factors, such as gastrointestinal's diseases and difficulty in feeding, children with Spastic Quadriplegic Cerebral Palsy tend to present nutritional deficits. OBJECTIVE: : To assess the nutritional status of pediatric patients with Spastic Quadriplegic Cerebral Palsy according to reference curves for this population and with the measures of folds and circumferences, obtained by the upper arm circumference and triceps skin fold. METHODS: : The data were obtained from: knee-height, estimated height, weight, upper arm circumference, and triceps skin fold. Values of folds and circumferences were compared with Frisancho, and specific curves for these patients were used as reference. The relationship between the values in the growth curve for healthy children, Z-Score, and comparison with the reference curve were verified by Fisher's exact test. We adopted the significance level of 5%. RESULTS: : We evaluated 54 patients. The mean age was 10.2 years, and 34 were male, 25 fed by gastrostomy and 29, orally. The frequency of low weight by the reference curve was 22.22%. More than half of the patients presented the parameters indicating lean mass below the 5th percentile. The height of all patients was classified as adequate for the age by the reference curve. CONCLUSION:: Low weight was found in 22% of patients, and there is a greater tendency to present reduced muscle mass and increased fat mass, showing the need for evaluation and appropriate interventions for patients with Spastic Quadriplegic Cerebral Palsy. PMID- 28723983 TI - COMMENT ON "PREVALENCE OF DYSPEPTIC SYMPTOMS AND HEARTBURN OF ADULTS IN BELO HORIZONTE, BRAZIL". PMID- 28723984 TI - Satisfaction with nursing care in drug users: the evolution of a scale. AB - Objectives: To identify the degree of satisfaction with nursing care, the significant variables and contribute to the evolution of the scale. Methods: Descriptive, correlational, cross study, with 180 drug users. Data collected using the scale called "Satisfaction of users with the Nursing Health Center26", between February and December 2012 in three treatment units in the region of Lisbon and Vale do Tejo, Portugal. Results: Users indicated 83.3% satisfaction. The dimension "Information individualization" was the most marked (98.5%). The more stability in the programs, abstinence from stimulants and benzodiazepines and more nursing interventions, the greater the satisfaction. Better working conditions, specializing in mental health, younger ages and less experience of nurses also contributed to satisfaction. Four items of the scale were extracted, assuming new SUCECS22 designation. Conclusions: Satisfaction was high, influenced by structural variables of users, nurses and working conditions. The scale has proved suitable for assessment in this population. PMID- 28723985 TI - Rural women and violence situation: access and accessibility limits to the healthcare network. AB - Objective: To analyze the access and accessibility to the healthcare network of women dwelling in rural contexts undergoing violence situation, as seen from the professionals' speeches. Method: A qualitative, exploratory, descriptive study with professionals from the healthcare network services about coping with violence in four municipalities in the northern region of Rio Grande do Sul. The information derived from interviews, which have been analyzed by thematic modality. Results: (Lack of) information of women, distance, restricted access to transportation, dependence on the partner and (lack of) attention by professionals to welcome women undergoing violence situation and (non) articulation of the network are factors that limit the access and, as a consequence, they result in the lack of confrontation of this problem. Conclusion: To bring closer the services which integrate the confrontation network of violence against women and to qualify professionals to welcome these situations are factors that can facilitate the access and adhesion of rural women to the services. PMID- 28723986 TI - The contributions of digital technologies in the teaching of nursing skills: an integrative review. AB - Objective: To analyze the contributions of digital educational technologies used in teaching nursing skills. Method: Integrative literature review, search in five databases, from 2006 to 2015 combining the descriptors 'education, nursing', 'educational technology', 'computer-assisted instruction' or related terms in English. Results: Sample of 30 articles grouped in the thematic categories 'technology in the simulation with manikin', 'incentive to learning' and 'teaching of nursing skills'. It was identified different formats of digital educational technologies used in teaching Nursing skills such as videos, learning management system, applications, hypertext, games, virtual reality simulators. Conclusions: These digital materials collaborated in the acquisition of theoretical references that subsidize the practices, enhancing the teaching and enable the use of active learning methods, breaking with the traditional teaching of demonstrating and repeating procedures. PMID- 28723987 TI - Impaired religiosity and spiritual distress in people living with HIV/AIDS. AB - Objective: To verify the inference of Nursing Diagnoses, Impaired religiosity and Spiritual distress in people living with HIV/AIDS. Methods: This is a cross sectional study with a quantitative approach, performed in a specialized Service CenteR of Recife, Pernambuco, from June to November 2015. The results related to 52 people living with HIV/AIDS and that were interviewed were analyzed by three nurse judges. Results: Spiritual distress was estimated at 73.1% (38), Impaired religiosity at 36.5% (19), with an average number of defining characteristics of 3.88 +/- 2.05 and 2.55+/-0.69. The main defining characteristic for Impaired religiosity was: "reports a need to reconnect with previous beliefs" (92.3%); and for Spiritual distress, it was: "Expresses a lack of purpose in life/expresses lack of meaning in life" (86.5%). Conclusions: The results point to the need to consider the religious-spiritual dimension in care protocols and research in nursing. PMID- 28723988 TI - Brazilian research groups in nursing: comparison of 2006 and 2016 profiles. AB - Objective: To compare the profile of nursing research groups registered at the CNPq Research Groups Directory in 2006 and 2016. Method: Descriptive and documentary analysis, The data has been collected in 2006 and in 2016, with parameterized search with the term "nursing" at the CNPq Research Groups Directory. The selected variables have been organized in a Microsoft Office Exce spreadsheetl. Results: The research groups have increased from 251 in 2006 to 617 in 2016, with important increase of the number of participants, among students and researchers. There was a decrease of the number of groups without students. However, 22% remain without undergraduate students' participation. Conclusions: It has been observed an important increase regarding the interest on research activities, when comparing both scenarios. The nursing research groups reflect structural and political advances in generation of science, technology and innovation, however, the undergraduate students' and the foreign researchers' participation should still be encouraged. PMID- 28723989 TI - Knowledge translation: a challenge in providing nursing care. PMID- 28723990 TI - Development, Inequality and International Cooperation in Health. PMID- 28723991 TI - Health inequalities: a global perspective. AB - The objective of this article is to present health inequalities as a global problem which afflicts the populations of the poorest countries, but also those of the richest countries, and whose persistence represents one of the most serious and challenging health problems worldwide. Two components of global inequalities are highlighted: inequalities between groups within the same society, and inequalities between nations. The understanding that many of these inequalities are unjust, and therefore inequities, is largely derived from the inequalities that are identified between the various social groups of a given society. Inequalities between different societies and nations, while relevant and often of greater magnitude, are not always considered to be unjust. There have been several proposed solutions, which vary according to different theoretical interpretations and explanations. At the global level, the most plausible thesis has focused on improving global governance mechanisms. While that latter are attractive and have some arguments in their favor, they are insufficient because they do not incorporate an understanding of how the historical process of the constitution of the nations occurred and the importance of the position of each country in the global productive system. PMID- 28723992 TI - Social inequalities in the face of scientific and technological development: an antinomy or an historic problem? AB - This paper aims to conduct a conceptual analysis of the relationship between scientific and technical progress and social equality, or the reduction of inequalities. We examine this relationship by drawing on three theoretical perspectives: 1) ethical economics, championed by classical economic thinkers and centered on utilitarian self-interest, 2) Mainstream theories of economic development espousing the endogenous link between labor productivity growth and technical progress, 3) the critique of theories of economic development that emerged in the second half of the twentieth century, including Celso Furtado's critique of the theory of underdevelopment, emphasizing the prevalence of egalitarian tendencies, and ecological economics, which suggest alternative paths to those set by "classical" theories of development. The fundamental antinomy posed by the title of this article, characterized by an intrinsic contradiction between technical progress and social equality, strictly presupposes the ethical economics perspective, dominated by the social relations that constitute the "social order". PMID- 28723993 TI - Healthcare and development: a dialog with the thinking of Celso Furtado. AB - Understanding that conditions of health are dependent on more general nationwide factors relating to the level of development means admitting that 'sectorization' of health service is something that tends to limit the formation of knowledge. It also points to the importance of investigating the relationship between health and development, including issues about the processes that feed the persistence of the polarization between modernization and exclusion which has been a history of Brazil's contemporary development. This paper, based on a review of the literature, aims to look more deeply at the structural conditioning factors of the relationship between health and development, and their reproduction in the formation of contemporary knowledge, based on a dialog with the ideas of Celso Furtado. It concludes that a 'virtuous' articulation between health and development calls for policies that are able to reconcile the antagonistic factors represented by the interests of capitalism, and the interests of social wellbeing, in a harmonious co-existence. In Furtado's conception, this would be possible, if the process of social homogenization is correlated with an efficient production system that has a degree of technological autonomy. PMID- 28723994 TI - Structural Cooperation, the Fiocruz experience. AB - This article examines the structural approach to health cooperation, focusing on its meaning as a method for promoting institutional policies to improve management models. We draw attention to the differences between this approach and the traditional disease-based approach, showing that the structural approach is centered on health systems, reinforces global governance, and embodies the Sustainable Development Goals (SDG), thus taking on a multi-sectoral dimension. This approach leverages the maximum potential of international cooperation by establishing structuring networks and promoting relations between partner countries through their national health institutions, schools of public health, and technical staff. By way of example, we show that this approach is applied in the Union of South American Nations (UNASUL, acronym in Portuguese) and Community of Portuguese-speaking Countries (CPLP, acronym in Portuguese), especially in Africa. Finally, we underline the importance of this approach for South-South relations, where it addresses the real necessities of partner countries, unlike North-South cooperation that is characterized by power asymmetries, especially within the economic and technical-scientific dimensions. PMID- 28723995 TI - The Alma-Ata Decade: the crisis of development and international health. AB - The paper analyzes formulations in the area of international health at the time of the International Conference on Primary Health Care, held in Alma Ata, Kazakhstan, in 1978. It is set within the context of the broader debate on development and international cooperation throughout the 1970s. Three sets of concepts and prescriptive formulations were examined namely: the New International Economic Order (NIEO), the Dag Hammarskjold Report (DHR) and the Basic Human Needs Approach (BHN). They were compared with the proposals in documents from the World Health Organization and in the statements from Halfdan Mahler, its director. As a whole, this set of formulations and proposals share a broad spectrum of terms and notions, as well as much of the expectations for change and tensions that existed in the classic period of development during the later years of the post-war era. PMID- 28723996 TI - Bioethical Dimensions of International Cooperation for Health: still a controversial issue? AB - This essay stresses the importance of undertaking a critical analysis of international cooperation for health based upon reflections on diplomacy, acknowledging the ethical limits and possibilities of cooperation within this context. It emphasizes the importance of adopting an historical perspective, highlighting the circumstances surrounding the consolidation of the current international system, whereby, after two world wars, the victorious countries created the United Nations Organization, which today brings together all the world's nations, notwithstanding the fact that the majority of countries are in favor of significant changes to its institutional framework. It also stresses the importance of the bioethics dimension, despite the systematic disregard of principles adopted in relevant UN documents, especially in view of inequalities pari passu with asymmetries of knowledge and enjoyment of innovations that separate nations. This reflection also suggests that South-South cooperation is fundamental to the analysis of the inequality and dependence that demarcate North South and East-West bipolarity. These reflections are, in short, important guiding elements for deepening analysis and resolutions in the arena of international cooperation for health, leaving aside catastrophic visions and idealistic illusions. PMID- 28723997 TI - Access to health care as a human right in international policy: critical reflections and contemporary challenges. AB - Using the United Nations (UN) and its subordinate body, the World Health Organization (WHO), as a frame of reference, this article explores access to healthcare as a human right in international intergovernmental policies. First, we look at how the theme of health is treated within the UN, focusing on the concept of global health. We then discuss the concept of global health from a human rights perspective and go on to outline the debate surrounding universal coverage versus universal access as a human right, addressing some important ethical questions. Thereafter, we discuss universal coverage versus universal access using the critical and constructivist theories of international relations as a frame of reference. Finally, it is concluded that, faced with the persistence of huge global health inequalities, the WHO began to reshape itself, leaving behind the notion of health as a human right and imposing the challenge of reducing the wide gap that separates international intergovernmental laws from reality. PMID- 28723998 TI - Citizen participation and the health policies of Unasur. AB - This paper examines how the Union of South American Nations (Unasur) concerned itself with ensuring democracy and participation in the construction of health policies. It aims to explain the meaning of health democracy, and its importance for making the right to health effective. The concern is that the decision on these politics of the bloc should be in harmony with the interests of their citizens, so as to identify ethical activity of the States in international relations. An analysis was made of the documents of constitution, and resolutions on health policy, of this bloc, and statements were found with objectives and principles about democracy and citizen participation; but no institutionalization of mechanisms that might make participative democracy in health operational was found. PMID- 28723999 TI - Moving towards South-South International Health: debts and challenges in the regional health agenda. AB - The aim of this paper is twofold. First, it aims to investigate the increased interest in health as an important dimension of the foreign policy and diplomatic concerns together with the emergence of a new framework for regional health integration and regional health diplomacy. Second, it seeks to understand the role and practices of new regional blocs in the field of health and whether they are conducting to the emergence of new strategies for addressing health regional policies in South America. The regional policy process relates to health as a right. Thus, some practices and processes in social policy are setting new standards for political and social cohesion in the construction of new regionalism. Health crosses national, regional, and global agendas in a multi directional fashion, rather than via one-way, top-down policy transfer. A special feature of Unasur is upholding regional health sovereignty despite the unique fact that member countries retain national autonomy. Unasur has projected foreign policy that promotes social values in ways that seem innovative. Experience as Unasur shows that regional organisms can become a game changer in global diplomacy and an influential actor in the international agenda. Resumen El objetivo de este articulo es doble. En primer lugar,investigar el creciente interes en la salud como una dimension importante de la politica exterior, en sintonia con el surgimiento de un nuevo marcopara la integracion regional y la diplomacia en salud. En segundo lugar, comprender el papel y las practicas de los nuevos bloques regionales en el campo de la salud y si estasconducena la emergencia de nuevas estrategias para abordar las politicas sanitarias regionales en America del Sur. Los nuevos procesos de integracion regional se refieren a la salud como un derecho. Asi, algunas practicas y procesos de la politica regional estan estableciendo nuevos patrones de cohesion politica y social en el avancede un nuevo regionalismo. La salud en este proceso de formulacion e implementacion de la politica regional,atraviesa las agendas nacionales, regionales y globales de forma multidireccional. Un valor agregado de Unasur es su propuesta de avanzar es pos de una mayor soberania regional en salud, a pesar del hecho de que los paises miembros mantienen su autonomia nacional. En este sentido, Unasur ha proyectado una politica exterior que promueve principios y valores a partir de un enfoque innovador. El caso de Unasur muestra que los organismos regionales tienen el potencial para cambiar las reglas (y el resultado) del juego en la diplomacia global y convertirse en actores influyentes en la agenda internacional. PMID- 28724000 TI - Differences and inequalities in relation to access to renal replacement therapy in the BRICS countries. AB - End-stage renal disease (ESRD) is an important public health problem, especially in developing countries due to the high level of economic resources needed to maintain patients in the different programs that make up renal replacement therapy (RRT). To analyze the differences and inequalities involved in access to RRT in the BRICS countries (Brazil, Russian Federation, India, China and South Africa). This is an applied, descriptive, cross-sectional, quantitative and qualitative study, with documentary analysis and a literature review. The sources of data were from national censuses and scientific publications regarding access to RRT in the BRICS countries. There is unequal access to RRT in all the BRICS countries, as well as the absence of information regarding dialysis and transplants (India), the absence of effective legislation to inhibit the trafficking of organs (India and South Africa) and the use of deceased prisoners as donors for renal transplants (China). The construction of mechanisms to promote the sharing of benefits and solidarity in the field of international cooperation in the area of renal health involves the recognition of bioethical issues related to access to RRT in the BRICS countries. PMID- 28724001 TI - Food marketing targeting children: unveiling the ethical perspectives in the discourse on self-regulation. AB - When it comes to food marketing, children are one of the major targets. Regulatory actions can play a strategic role in health protection. The objective of this research was to characterize the ethical perspective in the discourse against state regulatory actions on food marketing directed at children, aiming to understand the context of the discourse's production and how it creates meaning. The methodology adopted was qualitative, with documentary analysis and use of concepts and procedures from Discourse Analysis. The work of Hans Jonas, specifically his Responsibility Principle, and Garrafa and Port's Intervention Bioethics oriented the analysis. The self-regulation discourse analysis showed an ethical perspective in which relations of consumption predominate over the children's vulnerability. The rhetorical excess is constant, as well as the use of resources like naturalization, untruthfulness, ideological dissimulation and euphemism. An erasure of social conflicts takes place, and an ahistorical perspective is present. The discourse does not align with Jonas' Responsibility Principle, nor those of Intervention Bioethics. Lastly, the ethical perspective of the discourse represents a double paradox, because it is a business discourse that hides its competitive roots and metamorphoses into an ethical one. PMID- 28724002 TI - Challenges in a product development partnership: a malaria treatment case study. AB - This paper examines the development of a treatment - a fixed-dose combination of artesunate and mefloquine - in Brazil, from three points of view: in terms of access to medication; to record and report successes; and to look at the lessons learned. This product development took place in the ambit of a public-private partnership. Semi-structured interviews were held with key actors involved in the different phases of the development, and documents were analyzed. Two important points of reference orienting the design of the study and analysis were: a logical model for access to medication; and evaluation of programs. It is concluded that there were several successes over the course of the project, but insufficient attention was given in the project's architecture to planning of adoption of the product: irregularities in demand caused difficulties in planning and production, and adoption of the product was irregular in the Americas. It is concluded that the project can be considered to have been successful: the product was created, and the aims were met - strengthening of institutional and individual capacities and alliances, and advocacy. However, there were weaknesses in the process, which need to be mitigated in future projects of the same type. PMID- 28724003 TI - Global health and Brazilian foreign policy: the negotiations on innovation and intellectual property. AB - Since the TRIPS Agreement (Agreement on Trade-Related Aspects of Intellectual Property Rights) came into effect, Brazil, like other developing countries, has become more assertive in multilateral negotiations and begun to argue that the present international system of intellectual property should be better adapted to its needs and interests. In doing so, the country has emphasized that intellectual property is not a subject exclusively associated with trade, but also with public health and human rights. This paper discusses the activity of the Brazilian government in multilateral negotiations that involve public health, innovation and intellectual property. The conclusion from looking at Brazil's diplomatic activity in this area is that Brazil has been a protagonist in this debate, seeking solutions that mitigate the adverse effect of the present international intellectual property system on access to drugs, and other medical technologies, in the developing countries. PMID- 28724004 TI - International cooperation and shortage of doctors: an analysis of the interaction between Brazil, Angola and Cuba. AB - The shortage of doctors, especially in remote areas, is a critical issue for the development of national health systems and has thus been the focus of a number of international cooperation projects. An exploratory and qualitative study was conducted to examine cooperation between Brazil, Angola and Cuba. A nonsystematic literature review was conducted of selected open access articles and official documents addressing relevant health cooperation initiatives. Previously selected characteristics of actions designed to redress the shortage of doctors were compared. It was concluded that the interactions between the three countries were fruitful and potentially beneficial for the health of the population of these countries. South-South cooperation between these countries showed positive results in the educational and regulatory dimensions and adopted a non-dependence perspective that seeks to strengthen endogenous capacity, which are important factors for evaluating the structural components of health systems. PMID- 28724005 TI - Human resources for health: global crisis and international cooperation. AB - From the 1990s onwards, national economies became connected and globalized. Changes in the demographic and epidemiological profile of the population highlighted the need for further discussions and strategies on Human Resources for Health (HRH). The health workforce crisis is a worldwide phenomenon. It includes: difficulties in attracting and retaining health professionals to work in rural and remote areas, poor distribution and high turnover of health staff particularly physicians, poor training of health workforces in new sanitation and demographic conditions and the production of scientific evidence to support HRH decision making, policy management, programs and interventions. In this scenario, technical cooperation activities may contribute to the development of the countries involved, strengthening relationships and expanding exchanges as well as contributing to the production, dissemination and use of technical scientific knowledge and evidence and the training of workers and institutional strengthening. This article aims to explore this context highlighting the participation of Brazil in the international cooperation arena on HRH and emphasizing the role of the World Health Organization in confronting this crisis that limits the ability of countries and their health systems to improve the health and lives of their populations. PMID- 28724006 TI - Development cooperation in water and sanitation: is it based on the human rights framework? AB - The water and sanitation sector is verifiably receiving increased attention and funding through international development cooperation. Not least because of the way that it affects incentives and institutions in partner countries, development cooperation can have either positive or negative effects on human rights though. The consolidated frameworks for the human rights to water and sanitation is becoming linked to the international community's coordinated development efforts, as evidenced notably in the 2030 Agenda for Sustainable Development. However, a review of major funders' official policies for development cooperation in the sector suggests that many only partially endorse the frameworks for the human rights to water and sanitation. An observation of development cooperation flows to the sector allows the hypothesis to be advanced that worldwide inequalities in access to these services may be reduced through a full and clear application of the human rights framework in development cooperation activities. The article presents findings of this research and explores key stakes for development cooperation in the water and sanitation sector that are relevant for their ability to either negatively or positively contribute to the realization of human rights. PMID- 28724007 TI - (Mal)nutrition and the new epidemiological trend in a context of development and inequalities. AB - The current context of intense social, economic and political transformations has contributed to changes in the health profile of the population and generated discussions about the impact of these changes on the reorganization of society. At the present moment, the increase in non-communicable illnesses and diseases raises major concerns about the paradox of malnutrition and obesity. Based on an in-depth reading and interpretation of texts, documents and databases, this article discusses issues related to nutrition, considering the dimensions of shortages and excesses, the evolution of nutrition over time, and the connection with the new epidemiological trend. We begin with a conceptual characterization, the historical background and the anthropological connections with the guiding theme of the article. We then describe the prevalence, distribution and secular trend of malnutrition and obesity, as well as the temporal relationship with the new epidemiological trend in Brazil within a context of development and inequalities. Finally, we reflect on the issue of (mal)nutrition in post modernity, the new interests at stake in the health-disease process, as well as international experiences and strategies of partnerships designed to overcome these problems. We conclude by discussing some current advances and challenges in relation to the complexity and speed of contemporary changes. PMID- 28724008 TI - An analysis of the major challenges and obstacles for international technical cooperation in health, Brazil-Mozambique. AB - Health has become a priority issue on the agenda in relation to Brazilian international technical cooperation in the last decade. This applies to Mozambique which is a strategic partner of Brazil's when one takes into consideration the volume of projects that have been undertaken between the two countries and the available resources on offer. There has been a shift in the foreign policy paradigm which has resulted in a new Brazilian foreign policy posture that promotes bilateral agreements and international cooperation. On conducting a retrospective and current analysis it is clear that there are, however, major obstacles and challenges for bilateral agreements and technical international cooperation that require in-depth study and which need to be dealt with in the area of health. This paper seeks to identify and analyze these obstacles with a view to providing proposals for ways forward. It takes the approach of using the methodology of reviewing specialized journals on this topic as well as using qualitative research from the main actors and institutions involved in bilateral cooperation. PMID- 28724009 TI - The dialog between health and foreign policy in Brazilian cooperation in human milk banks. AB - Mother's milk is the primary source of nourishment in early infancy. When this source is unavailable, secondary sources may be used, such as human milk banks. The first milk bank in Brazil was created in 1943, and they have been used ever since. A national model was developed through a number of phases, culminating in the Brazilian Network of Human Milk Banks. This gave rise to a number of international cooperation projects, with the Brazilian model particularly relevant for developing nations. The main objective of this analysis is to understand what drives Brazil to promote milk banks internationally. To do this we tried to understand the relationship between health and foreign policy, expressed here as soft power, as here the two areas dialog with one another. The results include gains in both areas and the affirmation of health as a central goal of the national interest cluster of the case. PMID- 28724010 TI - Management of Primary Care: a challenge for international cooperation in health. AB - The need to resolve immediate problems in basic healthcare systems and the decisions that must be made in the daily management of healthcare centers must reach beyond awareness of common sense, and be reinforced by the evidence sought in scientific knowledge that will provide a new look at the facts and phenomena that happen on a daily basis. This article examines an experience of triangular cooperation in health between Angola, Brazil and Japan, which took place in Luanda, Angola between 2011 and 2014. The "Project to Strengthen the Healthcare Through the Development of Human Resources at the Josina Hospital and in other Healthcare Services, and to Revitalize Primary Healthcare in Angola (ProForsa)", with the involvement of Fiocruz as the party executing the primary healthcare component. This is an innovative role in technical cooperation as a tool of political action. A training program with multiple possibilities enabled technical-political partnerships in an approach for "structuring cooperation in health". The article analyzes how interventions in international cooperation in health management may create scientific evidence that, together with the local political context, can transform organizational elements such as healthcare centers, their clinical management and physical infrastructure. PMID- 28724011 TI - The AIDS Epidemic and the Mozambican Society of Medicines: an analysis of Brazilian cooperation. AB - This article analyzes the Brazilian South South Cooperation in Health in Mozambique, specifically the fight against the AIDS Epidemic through the Antiretroviral Factory, in light of the concept of Structural Cooperation in Health, and with a basis in the literature on Cooperation for Development and Global Health. Thus, the article is divided into four parts: (i) a historical bibliographic review of health as an International Relations issue; (ii) an overview of the field of health in Mozambique; (iii) an historical-political conceptual debate about both types of International Cooperation for Development: North-South Cooperation and South-South Cooperation; (iv) a study about the antiretroviral factory, better known as the Mozambican Society of Medicines (Sociedade Mocambicana de Medicamentos). Through a case study, our goal is to verify if the Brazilian actions in Mozambique are in accordance with the concepts defended by the Structural Cooperation in Health, as well as to create new inquiries for academic debate. PMID- 28724012 TI - Health surveillance and response on a regional scale: a preliminary study of the Zika virus fever case. AB - Although awareness of the Zika virus has existed since the 1950s, only recently has it attracted the interest of the international community. In 2015 and 2016, the virus spread throughout Brazil and suspicions on the possible relation between parallel increases in neurological disorders and the infection arose. By November 2015, this concern had developed into a National Public Health Emergency. On February 1, 2016, WHO formally declared its suspicion that this was a Public Health Emergency of International Concern (PHEIC), and sent a response in accordance with International Health Regulations (2005). Zika is present in almost all South American countries, and PAHO/WHO, Unasur, and Mercosur are developing responsive actions to the epidemic. The aim of this article is to present a critical analysis of the regional South American and Brazilian responses of February through September 2016, in respect of this PHEIC announcement, utilizing qualitative methodologies via bibliographical examination and document analysis. In this context, the PAHO/WHO played a prominent role as compared with the other organizations. Moreover, the political environment of the region also played a major role in the instability of both Mercosur and Unasur, which could impact the capacity and effectiveness of the response. PMID- 28724013 TI - Interview: inequality the key concept when discussing health internationally. AB - Economic, scientific and technological development, and innovation have influence in the inequalities between countries, especially in terms of the differences between their populations' level of health and wellbeing. The phenomenon is see not only between countries, but also within them. How these inequalities can be reduced and how to examine health in the international context are the themes of this interview with Gastao Wagner, President of the Brazilian Collective Health Association (Associacao Brasileira de Saude Coletiva, or Abrasco). PMID- 28724014 TI - Prescription medication by physiotherapists: a Brazilian view of the United Kingdom, Canada, Australia and New Zealand. AB - Many health systems (HS) have adopted novel models of care which have included non-medical prescription (NMP) by physiotherapists. The aim of this study was to verify in the literature the existence of this practice and its possible benefits. A literature review was carried out through search on Science Direct, PubMed, SciELO, Lilacs and Google Scholar, and in the World Confederation for Physical Therapy and Chartered Society of Physiotherapy websites. In recent decades the United Kingdom adopted the NMP for health professionals, followed by Canada. In Australia and New Zealand physiotherapists have acted in the prescription and administration of medications under medical orders, which is the first step into independent prescription. Brazilian physiotherapists cannot prescribe any medication, despite of high demands from patients in the Brazilian HS, shortage of physicians in many regions and bureaucracy in accessing health services. The adoption of NMP by physiotherapists may play an important role in the HS, and it seems to be an inevitable achievement in the next years in Australia and New Zealand. The main benefits include decreasing bureaucracy for assistance, population demands for medication as well as major professional refinement. PMID- 28724015 TI - Anti-bullying interventions in schools: a systematic literature review. AB - This paper presents a systematic literature review addressing rigorously planned and assessed interventions intended to reduce school bullying. The search for papers was performed in four databases (Lilacs, Psycinfo, Scielo and Web of Science) and guided by the question: What are the interventions used to reduce bullying in schools? Only case-control studies specifically focusing on school bullying without a time frame were included. The methodological quality of investigations was assessed using the SIGN checklist. A total of 18 papers composed the corpus of analysis and all were considered to have high methodological quality. The interventions conducted in the revised studies were divided into four categories: multi-component or whole-school, social skills training, curricular, and computerized. The review synthesizes knowledge that can be used to contemplate practices and intervention programs in the education and health fields with a multidisciplinary nature. PMID- 28724016 TI - Deinstitutionalization of long stay patients in a psychiatric hospital in Rio de Janeiro. AB - Critical Time Intervention (CTI) is a time-limited mental health intervention offered to people with mental disorders during critical/transition periods. This study assesses the impact of CTI-BR on social performance and quality of life within a population in the process of deinstitutionalization, after long-term hospitalization in a psychiatric institution. The study population was split into two groups, one of which received CTI plus the regular care. Results showed no advantage of the intervention compared to the regular programs provided by the institution. When study participants are analyzed as a group, we found positive improvement regarding their social functioning and self-perception of their mental-health. Results show that it is possible for elderly patients discharged from long-term psychiatric care to live in residential facilities in the community, supervised by clinical teams. PMID- 28724017 TI - Food risk regulation: the tensions of the Brazilian Health Surveillance System. AB - This article addresses the dynamics of Brazilian food control practices, highlighting their special risk-related features and the types of intervention, as well as the recently adopted instruments to control risks related to the nutritional composition of food and their institutional repercussions. Food regulation in Brazil dates back to the First Republic. The practice has been remodeled over the years, due to both the increasing complexity of the risks and the introduction of new institutional operational mechanisms. In recent years, with the adoption of instruments such as agreements and terms of commitments established between government and industry and designed to control risks, it has become possible to identify widening gaps in regulatory competence. The adoption of mechanisms without the participation of consumers, with elastic deadlines for compliance by industries and insusceptible to inspection, represents a setback in the democratic process and the practice of health regulation of food currently under way in Brazil. PMID- 28724018 TI - Different patterns of social support perceived and their association with physical (hypertension, diabetes) or mental diseases in the context of primary health care. AB - This work discusses the relationship between hypertension, diabetes, anxiety, depression, and social support in primary health care. This research aimed to identify the association between physical disease, mental disease, support network and perceived social support in the research sample. This is a cross sectional study inserted in a larger research project funded by the Pan American Health Organization and carried out in 2002 in Petropolis, RJ. The sample consisted of 714 patients with ages ranging from 18 to 65 years old. Results showed association between variables from support network either with evidence of hypertension or diabetes, or with the existence of common mental disorders, but with different patterns. Associations with the perceived support were positive in patients with hypertension and diabetes; Common Mental Disorder patients showed negative associations, inversely associated to the level of mental disease. PMID- 28724019 TI - Profile of mortality from external causes among Seventh-day Adventists and the general populations. AB - This paper aimed to compare the profile of mortality from external causes among Seventh-day Adventists and the general population of Espirito Santo from 2003 to 2009. A search of Adventists was performed in the nominal database of the Mortality Information System containing data on Adventists provided by the administrative offices of the institution. Deaths from external causes occurred during the study period were then divided into two groups: Adventists and the general population. Adventists had lower proportional mortality from external causes (10%) than the general population (19%), and males were the main reason for this difference. In both groups, deaths prevailed in the 20-29 years age group. Deaths from accidental causes were most significant among Adventists (68.08%), while deaths from intentional causes related to assault and self inflicted injuries were more significant in the general population (53.67% of all deaths). The standardized mortality ratio for external causes was 41.3, thus, being Adventist reduced mortality by 58.7%. It is believed that the benefit of Adventists observed for mortality from external causes is related to this group's abstinence from alcohol consumption. PMID- 28724021 TI - ? AB - [This corrects the article doi: 10.1590/1413-81232017224.31382016]. PMID- 28724020 TI - The home care teaching and learning process in undergraduate health care degree courses. AB - Home care, one of the services provided by the health system, requires health practitioners who are capable of understanding its specificities. This study aimed to build a substantive theory that describes experiences of home care teaching and learning during undergraduate degree courses in nursing, pharmacy, medicine, nutrition, dentistry and occupational therapy. A qualitative analysis was performed using the grounded theory approach based on the results of 63 semistructured interviews conducted with final year students, professors who taught subjects related to home care, and recent graduates working with home care, all participants in the above courses. The data was analyzed in three stages - open coding, axial coding and selective coding - resulting in the phenomenon Experiences of home care teaching and learning during the undergraduate health care degree courses. Its causes were described in the category Articulating knowledge of home care, strategies in the category Experiencing the unique nature of home care, intervening conditions in the category Understanding the multidimensional characteristics of home care, consequences in the category Changing thinking about home care training, and context in the category Understanding home care in the health system. Home care contributes towards the decentralization of hospital care. PMID- 28724022 TI - [Characteristics of sexual violence against adolescent and adult women reported by the public health services in Santa Catarina State, Brazil]. AB - Sexual violence against women is a form of gender violence and both a severe human rights violation and public health problem. This ecological, descriptive, and temporal series study aims to analyze sexual violence against pre-adolescent, adolescent, and adult females in Santa Catarina State, Brazil, based on data from the Information System for Notifiable Diseases, in order to describe the characteristics of cases of sexual violence perpetrated against women, reported by health professionals from 2008 a 2013. A total of 15,508 cases of violence were reported, including 2,010 cases of sexual violence (12.9%). Cases of violence totaled 950 reports in the 10 to 14 year bracket (47.3%), 450 in the 15 to 19 year bracket (22.4%), and 610 (30.3%) in women 20 years or older (adults). Adolescent females suffered violence by a single aggressor, at home, at night, with vaginal penetration, and with greater tendency to repeated assault and pregnancy as a result. For females 10 to 14 and 15 to 19 years of age, the aggressors were unknown in 32.9% and 33.1% of the reports, respectively. Adult women were sexually assaulted either at home or on public byways, at night or in the early morning hours, by a single aggressor, with vaginal penetration in more than half of the cases, with more physical injuries, and with more subsequent suicide attempts. The information should contribute to awareness-raising of policymakers, health professionals, researchers, and health field professors concerning the importance of reporting violence in order to help develop interventions to prevent such violence against women. PMID- 28724023 TI - [Maternal depressive symptoms and anxiety and interference in the mother/child relationship based on a prenatal cohort: an approach with structural equations modeling]. AB - This study aimed to investigate the association between maternal depressive symptoms and anxiety and interference in the mother/child relationship, using structural equations modeling. Data were used from a prospective cohort study initiated during the prenatal period with 1,140 mothers in Sao Luis, Maranhao State, Brazil. Data were collected during prenatal care and when the children reached two years of age. Interference in the mother/child relationship was measured with the Postpartum Bonding Questionnaire - PBQ (N = 1,140). In the initial theoretical model, socioeconomic status determined the maternal demographic, psychosocial, and social support factors, which determined the outcome, i.e., the mother/child relationship. Adjustments were performed by structural equations modeling, using Mplus 7.0. The final model showed good fit (RMSEA = 0.047; CFI = 0.984; TLI = 0.981). Depressive symptoms in pregnancy and the postpartum were associated with higher PBQ scores, indicating interference in the mother/child relationship. The greatest effect was from depressive symptoms in pregnancy. Other factors associated with higher PBQ scores were lower social support, unfavorable socioeconomic status, and living without a partner, by indirect association. Anxiety symptoms and maternal age were not associated with the mother/child relationship. The results suggest that identifying and treating depression in pregnancy and postpartum can improve mother/child bonding in childhood. PMID- 28724024 TI - Stigma related to bipolar disorder in the perception of psychiatrists from Belo Horizonte, Minas Gerais State, Brazil. AB - This research sought to understand meanings and implications of the stigma related to bipolar disorder in relation to social processes and local cultural value systems. Seven semidirected individual interviews were performed with psychiatrists (from Belo Horizonte city, Minas Gerais State, Brazil) and analyzed with referential from the Medical Anthropology. Some potential stigmatizing views about bipolar disorder patients were endorsed by respondents related to biomedical model of bipolar disorder. They claimed about the extreme trivialization of this diagnosis nowadays and observed that, in spite of the mitigation of stigma related to bipolar disorder over time, it remains an important issue, especially at labor fields and as a cause of refusal of treatment. PMID- 28724025 TI - [Mediating variables: an opportunity for in-depth investigation of violence from a public health perspective?] PMID- 28724026 TI - [Level of implementation of the Program for Safety and Health at Work in Antioquia, Colombia]. AB - This study describes the level of implementation of the Program for Safety and Health at Work in companies located in the Department of Antioquia, Colombia, and associated factors. A cross-sectional survey included 73 companies with more than 50 workers each and implementation of the program. A total of 65 interviews were held, in addition to 73 checklists and process reviews. The companies showed suboptimal compliance with the management model for workplace safety and health proposed by the International Labor Organization (ILO). The component with the best development was Organization (87%), and the worst was Policy (67%). Company executives contended that the causes of suboptimal implementation were the limited commitment by area directors and scarce budget resources. Risk management mostly aimed to comply with the legal requirements in order to avoid penalties, plus documenting cases. There was little implementation of effective checks and controls to reduce the sources of work accidents. The study concludes that workers' health management lacks effective strategies. PMID- 28724027 TI - [The beginning of human life: ethical and legal perspectives in the context of biotechnological progress]. AB - Questions concerning the beginning of human life have pervaded society since antiquity. In the post-modern world, scientific and technological advances have fueled discussions on the issue, such that debates previously concentrated on abortion now also focus on biotechnological interventions. The article addresses the latter, reflecting on the extent to which human dignity can be considered a (hermeneutic) reference in establishing ethical and legal parameters for biotechnological advances in the definition of the beginning of human life. The study's method was critical hermeneutic ethics, with ethics at the center of the process of understanding and interpretation, observing the contours of facticity. No consensus was found on the beginning of human life, so it is essential to engage in dialogue with the new reality resulting from biotechnological advances in the process of defining ethical and legal principles for protecting the embryo and human nature, with human dignity as the reference. PMID- 28724028 TI - Commentary on Chavez-Ayala et al.'s "Violencia y la Salud Mental Asociados a Pensar o Haber Intentado Emigrar Internacionalmente por Adolescentes Mexicanos". PMID- 28724029 TI - [Psychosocial stress at work and alcohol consumption patterns in offshore oil workers]. AB - The objectives were to assess the association between psychosocial stress at work and alcohol consumption patterns in offshore oil workers. This was a cross sectional study of 210 workers on offshore oil rigs in the state of Rio de Janeiro, Brazil, from July to September 2014. The data collection instrument was a self-completed multidimensional questionnaire. Exposure to stress was measured by the demand-control model and alcohol consumption pattern was measured with the Alcohol Use Disorders Identification Test (AUDIT). Statistical analyses were based on the multivariate logistic regression model. Participants' mean age was 32.9 years (SD +/- 8.1 years). Most were married (62.9%) and reported having a religion (84.5%); 15.2% reported abusive levels of alcohol consumption, 20.3% had finished university, and 56.6% had fewer than 5 years of offshore experience. All the participants were subject to 12-hour daily shifts for 15 days followed by 15 days off, and 62.4% worked on fixed shifts. The multivariate analyses showed that workers exposed to workplace stress (OR = 3.30; 95%CI: 1.18-9.27) had higher odds of alcohol abuse when compared to unexposed workers. The results help elucidate what is still a controversial issue in the literature, i.e., the relationship between psychosocial stress and alcohol consumption, and point to the need for further studies. PMID- 28724030 TI - [Violence and mental health issues among Mexican adolescents that have considered or attempted cross-border migration]. AB - The aim of this study was to estimate the role of victimization by violence among Mexican adolescents that have considered or attempted migrating to the United States, including mental health variables (emotional self-esteem, self-esteem in school, depression, suicidal ideation, and attempted suicide) as mediators of the effects. The study used a cross-sectional design with a stratified cluster sample of 13,198 adolescents from the 2nd Mexican National Survey on Exclusion, Intolerance, and Violence in public schools in 2009. The analysis used the regression models proposed by Baron & Kenny. Prevalence of having considered or attempted cross-border migration was 23.1%. Mean age was 16.36 years. Female adolescents constituted 54.9% of the sample, and 56% were lower-income. Mental health variables that acted as partial mediators were suicidal ideation (35.9%), depression (19.2%), attempted suicide (17.7%), emotional self-esteem (6.2%), and self-esteem in school (3.4%) for moderate family violence, and emotional self esteem (17.5%) for social rejection in school and suicidal ideation (8.1%) for physical harm in school. Female adolescents showed greater impact from mediators than men in considering or having attempted cross-border migration. The study discusses the importance of incorporating the prevention of violence in the social contexts studied here and incorporating mental health in dealing with violence in adolescents and in public health programs in transit areas for illegal migrants. PMID- 28724031 TI - Methodological challenges in the use of focus groups with people with severe mental illness. AB - This study addresses the practical, methodological and ethical challenges that were found in three studies that used focus groups with people with severe mental illness, in the context of community mental health services in Brazil. Focus groups are a powerful tool in health research that need to be better discussed in research with people with severe mental illness, in the context of community mental health facilities. This study is based on the authors' experience of conducting and analyzing focus groups in three different cities - Campinas, Rio de Janeiro and Salvador - between 2006-2010. The implementation of focus groups with people with severe mental illness is discussed in the following categories; planning, group design, sampling, recruitment, group interview guides, and conduction. The importance of connecting mental healthcare providers as part of the research context is emphasized. Ethical issues and challenges are highlighted, as well as the establishment of a sensitive and empathic group atmosphere, wherein mutual respect can facilitate interpersonal relations and enable people diagnosed with severe mental illness to make sense of the experience. We emphasize the relevance of the interaction between clinical and research teams in order to create collaborative work, achieve inquiry aims, and elicit narratives of mental health users and professionals. PMID- 28724032 TI - AMB Guidelines Program. PMID- 28724033 TI - Ethical issues on the "synthetic" phosphoethanolamine clinical trial. AB - Notwithstanding its approval by the National Committee for Ethics in Research (Conep) on April 19, 2016, a trial of the so-called "synthetic" phosphoethanolamine (syn-phospho) pill in cancer patients raises ethical concerns. An analysis by a laboratory contracted by the Ministry of Science, Technology and Innovation (MCTI) revealed that syn-phospho contained a great amount of impurities and did not meet standards of pharmaceutical quality required for an investigational drug. Cytotoxicity against human tumor cell lines and in vivo rodent xenograft tumor assays consistently failed to demonstrate a potential anticancer activity of syn-phospho. Preclinical safety studies of syn phospho were also insufficient to support a trial of this investigational drug in cancer patients. Moreover, the ethical approval decision apparently overlooked two previous findings that suggested a possible enhancement of mammary carcinoma cell proliferation by phosphoethanolamine, and an apparent increase in lung metastases (rat implanted tumor assay) by syn-phospho. The syn-phospho risk benefit ratio is clearly unfavorable and, thus, this trial in cancer patients does not fulfill a key requirement to make a clinical research ethical. There are also concerns regarding whether the study design is robust enough (scientific validity), and the social value of the trial of syn-phospho in cancer patients is questionable. PMID- 28724034 TI - Phototherapy with PUVA: Versatility and efficacy in dermatoses. PMID- 28724035 TI - Spontaneous carotid dissection. AB - Carotid dissection is a rare occurrence but it is the main cause of stroke in individuals aged less than 45 years, and can be the etiology in up to 25% of strokes in young adults. We report a case with classic image of ying yang on vascular ultrasound, which was treated according to the best available medical evidence, yielding a favorable outcome. PMID- 28724036 TI - Clinical pharmacology profile of care in Hepatology clinic. AB - Since 2010, the Clinical Gastroenterology and Hepatology Division of the Central Institute of Hospital das Clinicas of the University of Sao Paulo Medical School (HC-FMUSP, in the Portuguese acronym) has been developing specialized electives assistance activities in the Outpatient Specialty Clinic, Secondary Level, in Sao Paulo NGA-63 Varzea do Carmo. The objective of this study was to analyze the pharmacotherapeutic profile of patients. This is a cross-sectional and retrospective study in which patients were seen at the Hepatology sector and the results were submitted to descriptive statistics. During the study period, 492 patients were treated at the clinic, with a mean age of 58.9 years and frequency of 61.2% female and 74.8% living in Sao Paulo. This population was served by various other medical specialties (cardiology and endocrine among others) and the major liver diagnoses were: chronic hepatitis B and C and fatty liver. Comorbidities were also identified, such as diabetes, hypertension and dyslipidemia. Most patients took their medication in the Basic Health Units. We found that 30% of patients use of more than five medications and the most prescribed were omeprazole 208 (42.3%), metformin 132 (26.8%) and losartan 80 (16.3%). Because it is an adult/elderly population, with several comorbidities and polymedication, it is important to be aware of the rational use of medication. The multidisciplinary team is important in applying correct conducts for the safe use of medicines, to reduce the burden on health spending and improving the quality of life of patients. PMID- 28724037 TI - Impact of biological therapy on body composition of patients with Chron's disease. AB - Introduction:: Protein-energy malnutrition in Crohn's disease (CD) has been reported in 20 to 92% of patients, and is associated with increased morbidity and mortality and higher costs for the health system. Anti-TNF drugs are a landmark in the clinical management, promoting prolonged remission in patients with CD. It is believed that the remission of this disease leads to nutritional recovery. The effect of biological therapy on body composition and nutritional status is unclear. Method:: Prospective study of body assessment by bioelectrical impedance method in patients with moderate to severe CD undergoing treatment with infliximab. The main outcome was the body composition before and after 6 months of anti-TNF therapy. Results:: There was a predominance of females (52%) with a mean age of 42+/-12 years. Most patients were eutrophic at baseline and remained so. There was an increase in all parameters of body composition after anti-TNF treatment: BMI (22.9+/-3.2 versus 25+/-3.8; p=0.005), waist circumference (88.1+/ 6.7 versus 93.9+/-7.7; p=0.002), lean mass index (17.5+/-2.2 versus 18.2+/-2.3; p=0.000) and fat mass index (5.5+/-2.3 versus 6.8+/-2.3; p=0.000). Phase angle remained unchanged (6.2 versus 6.8; p=0.94). Conclusion:: After therapy with IFX, all components of body composition increased, except for phase angle. The substantial increase in fat mass index and waist circumference led to concern regarding cardiovascular risk and, thus, to the need for further studies. PMID- 28724038 TI - Sexual addiction in drug addicts: The impact of drug of choice and poly addiction. AB - Objective:: To compare the risk of comorbid sexual addiction in a sample of individuals with a diagnosis of substance dependence, stratifying the sample by drug of choice as well as by mono versus polysubstance addiction. Method:: All data were collected at Santa Casa de Sao Paulo, Brazil. The study sample comprised all alcohol or drug dependents admitted to the Addiction Treatment Unit between November 2013 and August 2014. A generalized linear model with a binomial distribution was performed to compare the odds of having a Sexual Addiction Screening Test (SAST) score greater than 6 points in the subgroups analyzed. Results:: A total of 133 participants were included in our analysis, all reporting cocaine/crack and/or alcohol as drug of choice. Polysubstance addicts had a significant higher risk of a positive screening for sexual addiction compared to monosubstance addicts, age-sex adjusted odds ratios of sexual addiction being respectively 2.72 (95CI 1.1-6.71) and 0.37 (95CI 0.15-0.91). The odds of a SAST score greater than 6 was not statistically different between the cocaine/crack and alcohol groups, respectively 0.38 (95CI 0.14-1.02) and 2.67 (95CI 0.98-7.25). We found a significant relation between stronger drug addiction and greater levels of sexual addiction in the cocaine/crack group (p=0.0012), but not in the alcohol group. Conclusion:: Our study reinforces the importance of assessing sexual behavior of drug addicts in clinical practice, especially considering users of multiple substances or with severe dependence. PMID- 28724039 TI - Treatment of digital ulcers in systemic sclerosis: Case series study of thirteen patients and discussion on outcome. AB - Introduction:: In systemic sclerosis (SSc), digital ulcers (DU) are debilitating and recurrent. They are markers of prognosis and are associated with disability and mortality. Treatment strategies have been developed to block the proposed mechanisms of this complication. Objective:: Clinical description of a population of SSc patients with DU, treatment, complications and outcome. Method:: Analysis of 48 SSc patients meeting 2013 ACR-EULAR criteria, followed between 1999-2015; 13 patients had DU. Treatment protocol applied included cycles of 21 days of alprostadil, which can be repeated in the absence of DU healing. After DU healing, bosentan was initiated. Results:: DU healing was achieved with intravenous prostanoid in 12 patients; seven patients required repeated treatment for DU healing. Twelve patients were later treated with bosentan; three of them experienced recurrence of DU, while one was anti-B2-GPI positive. Four patients had soft tissue loss and three other suffered digital amputation, these being late diagnosis. Conclusion:: Younger patients and early referrals had better outcomes. Endothelin receptor antagonist toxicity should be monitored, particularly in patients previously exposed to hepatotoxic drugs. PMID- 28724040 TI - Cardiac remodeling indicators in adolescent athletes. AB - Objective:: The idea that different sports and physical training type results in different cardiac adaptations has been widely accepted. However, this remodelling process among different sport modalities is still not fully understood. Thus, the current study aims to investigate the heart morphology variation associated with a set of different modalities characterized by distinct models of preparation and different methods and demands of training and completion. Method:: The sample comprises 42 basketball players, 73 roller hockey players, 28 judo athletes and 21 swimmers. Anthropometry was assessed by a single and experienced anthropometrist and the same technician performed the echocardiographic exams. Analysis of variance was used to study age, body size and echocardiograph parameters as well as different sport athlete's comparison. Results:: Basketball players are taller (F=23.448; p<0.001; ES-r=0.553), heavier (F=6.702; p<0.001; ES r=0.334) and have a greater body surface area (F=11.896; p<0.001; ES-r=0.427). Basketball and hockey players have larger left auricle diameters compared with judo athletes (F=3.865; p=0.011; ES-r=0.316). Interventricular end-diastolic septal thickness (F=7.287; p<0.001; ES-r=0.347) and left ventricular posterior wall thickness (F=8.038; p<0.001; ES-r=0.362) of the judokas are smaller compared to the mean values of other sports participants. In addition, relative left parietal ventricular wall thickness is lower among swimmers compared with judokas (F=4.127; p=0.008; ES-r=0.268). Conclusion:: The major contributors to changes in heart morphology are for the most part associated with sport-specific training and competition and the specific dynamics and adaptive mechanisms imposed by each sport. PMID- 28724041 TI - Effect of rhubarb on extravascular lung water in patients with acute respiratory distress syndrome. AB - Objective:: The aim of this study was to evaluate the effect of rhubarb on extravascular lung water (EVLW) in patients with acute respiratory distress syndrome (ARDS). Method:: A total of 80 patients with ARDS were randomly divided into a treatment group (40 cases) and control group (40 cases). Patients in the treatment group received rhubarb (30.0 g/d) and patients in the control group received conventional therapy for seven consecutive days. Extravascular lung water index (EVLWI) and pulmonary vascular permeability index (PVPI) were determined using pulse contour cardiac output (PiCCO) technology, and the oxygenation index was measured by blood gas analysis at baseline and on days 3, 5 and 7 after treatment. Results:: The oxygenation index was higher and the levels of EVLWI and PVPI were lower after treatment in the two groups; however, these indexes showed significant differences on the 5th and 7th days after rhubarb treatment compared with the results in the control group (p<0.05). Conclusion:: Rhubarb can decrease EVLWI and PVPI, and improve oxygenation in patients with ARDS. PMID- 28724042 TI - Hyperglycemia in critical patients: Determinants of insulin dose choice. AB - Objective:: To identify factors that can determine the choice of intermittent subcutaneous regular insulin dose in critically ill patients with hyperglycemia. Method: : Cross-sectional study in a general adult ICU with 26 beds, data collected between September and October 2014. The variables analyzed were: sex, age, previous diagnosis of diabetes mellitus, use of corticosteroids, use of lactulose, sepsis, fasting, enteral nutrition, use of dextrose 5% in water, NPH insulin prescription and blood glucose level. Patients with one or more episodes of hyperglycemia (blood glucose greater than 180 mg/dL) were included as a convenience sample, not consecutively. Those with continuous insulin prescription were excluded from analysis. Results:: We included 64 records of hyperglycemia observed in 22 patients who had at least one episode of hyperglycemia. The median administered subcutaneous regular human insulin was 6 IU and among the factors evaluated only blood glucose levels were associated with the choice of insulin dose administered. Conclusion:: Clinical characteristics such as diet, medications and diagnosis of diabetes mellitus are clearly ignored in the decision-making regarding insulin dose to be administered for glucose control in critically ill patients with hyperglycemia. PMID- 28724043 TI - Compulsory notification at skilled nursing facilities. AB - Introduction:: Notifiable diseases (NDs) encompass conditions of high clinical severity and/or contagious. Being closed communities, long-term care facilities (LTCF) are places that deserve attention on their own, but one might be left wondering: what is the reality of NDs at Brazilian LTCFs? Objective:: To determine the prevalence and type of NDs at large LTCF. Method:: Active search for NDs conducted by the Hospital Infection Control Committee (HICC) in 459 beds. Due to the low turnover of patients, the monthly list kept by the HICC on NDs was analyzed. Data were grouped into males and females, and into elderly (age >= 60 years) and non-elderly (age <= 59 years). Results:: 31 diseases in 29 patients (6.9% of all inpatients - 19 males and 10 females): 23 cases of hepatitis C, five of hepatitis B, two of human immunodeficiency virus (HIV), and one case of renal tuberculosis. One patient with hepatitis B and another HIV-positive also had hepatitis C. There was no statistical significance in the comparison of the two groups with the total number of other institutionalized patients - by age and gender - for total number of NDs and cases of hepatitis C (p>0.05). Conclusion: : Chronic NDs and those requiring chronic treatment observed in this study suggest that Brazil needs more studies to define the dynamics of these diseases at LTCFs. PMID- 28724044 TI - Alcohol and tobacco use and the diseases treated in general practice. AB - Objective:: To characterize the use of alcohol and tobacco and correlate both to the diseases of outpatients in a general practice outpatient clinic. Method:: The ASSIST (Alcohol, Smoking and Substance Involvement Screening Test) questionnaire was answered by 300 randomly chosen subjects assigned to different groups according to the diseases being treated at the Outpatient General and Teaching Clinic of the Department of Internal Medicine, Hospital das Clinicas of the University of Sao Paulo's School of Medicine (HC-FMUSP, in the Portuguese acronym), Sao Paulo, Brazil. The consumption of tobacco and alcohol was characterized and its correlation with the groups of diseases being treated was calculated using Chi-square and Pearson test statistics. Results:: Compared to alcohol, tobacco use was more prevalent, more intense and showed more health-, social-, legal- and financial-related damage. Tobacco smoking presented a positive significant (p<0.0001) correlation with respiratory diseases. According to the questionnaire's criteria, few alcohol users would be referred to clinical interventions in comparison to smokers. Conclusion:: Respiratory diseases and tobacco use were well correlated based on the ASSIST questionnaire. The preventive value of the questionnaire was more evident in relation to tobacco than alcohol consumption. PMID- 28724045 TI - Spinal tumors in children. AB - Introduction:: Spinal tumors are rare in the pediatric population, presenting many specific peculiarities when compared to adults. We have performed a broad narrative review to describe the most common spinal tumors in children, discussing their main characteristics and management options. Method:: The authors have performed an extensive review of the peer-reviewed literature addressing the aforementioned objectives. Results:: Multimodality radiological studies (plain films, 3D computed tomography scan and magnetic resonance imaging) are necessary for proper evaluation and differential diagnosis of spinal tumors in children. In selected cases nuclear medicine imaging is used to improve the chances of a more accurate diagnosis. As a general rule, a fine needle biopsy is recommended after radiological evaluation to confirm the tumor's histology. Primary bone tumors can be divided into benign bone tumors, mostly represented by vertebral hemangiomas, osteoid osteomas, osteoblastomas, aneurismal bone cysts, and eosinophilic granulomas, and malign or aggressive tumors, such as Ewing's or osteogenic sarcomas. Secondary bone tumors (spinal metastases) comprise different tumor histologies, and treatment is mainly based on tumor's radiosensitivity. The characteristics and treatment options of the main spinal tumors are discussed in details. Conclusion:: Spinal tumors in children are rare lesions that demand a thorough understanding of their main characteristics for their proper management. Understanding the nuances of spinal tumors in children is of paramount importance for improving outcomes and chances of cure. PMID- 28724046 TI - Breast cancer screening in Brazil. Barriers related to the health system. AB - Objective:: Identify factors related to the health system that lead to a late diagnosis of breast cancer in Brazil. Method:: We performed a systematic review in the PubMed and LILACS databases using as keywords "Breast cancer," "system of health" and "Brazil or Brasil." We evaluated the content of the articles using the PRISMA methodology based on PICTOS. The final date was 12/16/2015. We were able to identify 94 publications in PubMed and 43 publications in LILACS. After assessing the title and summary, and excluding 21 repeated publications, we selected 51 publications for full evaluation. At this stage, we excluded 21 articles, with 30 publications remaining for study. Results:: The population coverage is low, and there are problems related to the quality of mammography. Patients with lower income, nonwhite and less educated are more vulnerable. We observed punctual and initial experiences in breast cancer screening. Diagnosis and treatment flows must be improved. The inequality in mortality reflects the differences related to screening structure and treatment. Better results are observed in well-structured services. Conclusion:: There are several barriers in the health system leading to advanced stage at diagnosis and limiting the survival outcomes. The establishment of a rapid and effective order for diagnosis and treatment, based on hierarchical flow, are important steps to be improved in the public health context. PMID- 28724047 TI - Correlation between virulence markers of Helicobacter pylori in the oral cavity and gastric biopsies. AB - BACKGROUND:: The clinical outcome of Helicobacter pylori infection has been associated with virulence factors. The presence of these factors is useful as molecular markers in the identification of the high risk for developing severe gastric pathologies. OBJECTIVE:: To correlate the presence of virulence markers cagA and bab2A of H. pylori in oral and gastric biopsy samples. METHODS:: An observational, prospective, descriptive, and cross-sectional study was carried out between September 2011 and September 2012. Patients suffering dyspepsia with indication for upper gastrointestinal video endoscopy who attended the Gastroenterology Service of the Hospital Dr. Julio C. Perrando were included. Epidemiological investigation was completed. To detect the bacteria and their virulence genes, samples of saliva, dental plaque and gastric biopsy were taken and processed by PCR. RESULTS:: Sixty-one patients were selected for this study (30 women and 31 men). H. pylori was detected in 31 gastric biopsies and 31 oral samples. Significant difference between oral and gastric samples was found in cagA genotype. Agreement between oral and gastric genotypes was found in 38.7% of samples from the same patient. CONCLUSION:: This study is the first in provide information about the genotypes of the Argentinean Northeast H. pylori strains. Despite the high prevalence of H. pylori infection, the most of patients had less virulent genotypes in oral cavity and gastric tissue. The cagA / babA2 combination was not frequent in the samples studied. There was not a statistical correlation between the virulence genes and gastroduodenal or oral diseases. Although in some patients the same genotype was found both in oral and gastric samples, it cannot be ensure that they corresponding to the same strain because a DNA sequencing was not performed. PMID- 28724048 TI - Impact of alcohol consumption among patients in hepatitis C virus treatment. AB - BACKGROUND: : Recent studies have questioned the recommendation of abstinence from alcohol for at least 6 months for alcoholic patients to be treated for hepatitis C. OBJECTIVE:: The present study aimed to assess the impact of alcohol consumption among patients undergoing hepatitis C treatment. METHODS:: In this cross-sectional study, 121 patients [78 (64.5%) men; 28-70 years] were evaluated. They were divided as follows: patients who consumed <12 g of ethanol/day throughout life (Group 1), 12-59 g/day (Group 2) and >=60 g/day (Group 3). Patients were treated with pegyla-ted-interferon plus ribavirin. RESULTS:: These three groups could not be distinguished in terms of the severity of liver fibrosis and frequency of HCV genotype-1 infection. In Group 3, treatment discontinuation (32.4%) was higher than in the Group 1 (9.4%) or Group 2 (0%), it was higher among patients who drank during treatment (66.7% vs 21.4%) and among those who had not been abstinent for at least 6 months (72.7% vs 15.4%). Moderate alcohol drinkers showed good adherence and did not discontinue the treatment. The frequencies of sustained viral response among patients in Group 3 (44.4%) were similar to those in Group 1 (61%) and Group 2 (68.4%). CONCLUSION:: Heavy drinkers more often discontinued treatment for hepatitis C, but those that received this treatment had acceptable sustained viral response rates. These results suggest that heavy drinkers should not be systematically excluded from the treatment, but they should be monitored to avoid drinking and abandoning treatment, mainly those who have not been abstinent for at least 6 months. PMID- 28724049 TI - Hepatitis B status in hemodialysis patients. AB - BACKGROUND: Patients on chronic dialysis present a high prevalence of hepatitis B virus infection. Despite infection-control practices, surveillance of serological markers, and hepatitis B vaccination, there are still outbreaks of the disease in dialysis centers. OBJECTIVE: This study aims to assess the serologic and vaccination status for hepatitis B in hemodialysis patients. METHODS: This cross sectional study assessed serologic markers and hepatitis B vaccination status of chronic kidney disease patients on regular dialysis program in Sao Carlos, SP, Brazil. Patients without information about hepatitis B status (anti-HBc, HBsAg and anti-HBs) were referred for testing. Individuals with uncertain or incomplete immunization status and without serological conversion (anti-HBs <10mIU/mL) were referred to vaccination, with adverse effects monitored. RESULTS: The study included 130 from a total of 181 dialysis patients. The majority were male (63.8%), mean age 53.9 years. All patients were already screened and negative for HBsAg, and 73.8% were vaccinated against hepatitis B (59.2% complete and 14.6% incomplete schedule), with a seroconversion rate of 75.3%. Only 11 (8.5%) patients had prior dosage of anti-HBc (negative). Among the 47 patients referred for anti-HBc testing, four were anti-HBc positive and one indeterminate. Of the total of patients referred to immunization, 34 have actually received HBV vaccine; among them five had mild adverse effects. CONCLUSION: Despite the benefit of dosing of anti-HBc and anti-HBs before admission to dialysis, economic constraints have reduced the screening to only HBsAg. Since occult HBV infection has already been demonstrated in hemodialysis patients, the measure of anti-HBc should be encouraged. PMID- 28724050 TI - Higher MELD score increases the overall cost on the waiting list for liver transplantation: a micro-costing analysis based study. AB - BACKGROUND:: The pre-transplant period is complex and includes lots of procedures. The severity of liver disease predisposes to a high number of hospitalizations and high costs procedures. Economic evaluation studies are important tools to handle costs on the waiting list for liver transplantation. OBJECTIVE: : The objective of the present study was to evaluate the total cost of the patient on the waiting list for liver transplantation and the main resources related to higher costs. METHODS: : A cost study in a cohort of 482 patients registered on waiting list for liver transplantation was carried out. In 24 months follow-up, we evaluated all costs of materials, medicines, consultations, procedures, hospital admissions, laboratorial tests and image exams, hemocomponents replacements, and nutrition. The total amount of each resource or component used was aggregated and multiplied by the unitary cost, and thus individual cost for each patient was obtained. RESULTS: : The total expenditure of the 482 patients was US$ 6,064,986.51. Outpatient and impatient costs correspond to 32.4% of total cost (US$ 1,965,045.52) and 67.6% (US$ 4,099,940.99) respectively. Main cost drivers in outpatient were: medicines (44.31%), laboratorial tests and image exams (31.68%). Main cost drivers regarding hospitalizations were: medicines (35.20%), bed use in ward and ICU (26.38%) and laboratorial tests (13.72%). Patients with MELD score between 25-30 were the most expensive on the waiting list (US$ 16,686.74 +/- 16,105.02) and the less expensive were those with MELD below 17 (US$ 5,703.22 +/- 9,318.68). CONCLUSION: : Total costs on the waiting list for liver transplantation increased according to the patient's severity. Individually, hospitalizations, hemocomponents reposition and hepatocellular carcinoma treatment were the main cost drivers to the patient on the waiting list. The longer the waiting time, the higher the total cost on list, causing greater impact on health systems. PMID- 28724052 TI - Erratum. AB - [This corrects the article doi: 10.1590/1519-6984.00416]. PMID- 28724051 TI - Obesity and Crohn's disease: what comes first, the egg or the chicken? PMID- 28724053 TI - Erratum. AB - [This corrects the article doi: 10.1590/1519-6984.09215]. PMID- 28724054 TI - Effects of a structured education program on glycemic control in type 1 diabetes. AB - OBJECTIVE: Diabetes mellitus is associated with significant morbidity and mortality, and education is known to play a key role in managing this disease. This study addresses the effects of a structured education program (SEP) on self care in subjects with type 1 diabetes mellitus (T1DM). The aim was to evaluate the effect of a SEP on glycemic control, knowledge, and skills associated with diabetes care in subjects with T1DM. SUBJECTS AND METHODS: A total of 47 adults with T1DM were followed up for 20 months (32 participated in the SEP and 15 served as a control group). The SEP consisted of workshops, individualized care, 24-hour distant support, and a questionnaire assessing knowledge of diabetes care. Glycosylated hemoglobin (HbA1c) levels were measured before and after the SEP implementation. RESULTS: Compared with pre-SEP levels, the mean HbA1c levels decreased by approximately 20% (21 mmol/mol) at 1 year, with a further 11% reduction (10 mmol/mol) observed 8 months later (p < 0.001). Knowledge about diabetes care increased by 37% between the pre-SEP and post-SEP questionnaires (p < 0.005). CONCLUSION: Relevant improvements occurred after SEP activities. The sustained decrease in HbA1c levels and the overall increase in knowledge and confidence regarding diabetes care reinforce the importance, necessity, and positive outcomes of a SEP intervention in T1DM. PMID- 28724055 TI - Bone turnover after bariatric surgery. AB - OBJECTIVE: The aim of the present study was to evaluate parameters of bone and mineral metabolism after bariatric surgery. SUBJECTS AND METHODS: This sectional study included data from medical records from 61 bariatric surgery (BS) patients (minimum period of 6 months after the procedure) and from 30 class II and III obese patients as a control group (Cont), consisting of daily dietary intake of macronutrients, calcium and sodium, serum 25(OH)D and parathyroid hormone (PTH) and other biochemical serum and urinary parameters. Bone alkaline phosphatase (BAP), leptin, fibroblast growth factor-23 (FGF-23) and deoxypyridinoline (DPYD) were determined from available banked serum and urinary samples. RESULTS: Mean body mass index (BMI), median energy, carbohydrate, protein and sodium chloride consumption were significantly lower in the BS versus Cont, but calcium and lipids were not. No significant differences were found in ionized calcium, 25(OH)D, PTH and fibroblast growth factor 23 (FGF-23) between groups. Mean serum BAP was significantly higher for BS versus Cont and had a positive correlation with time after the surgical procedure. Mean serum leptin was significantly lower and median urinary DPYD higher in BS versus Cont. CONCLUSION: The present study showed an increase in bone markers of both bone formation and resorption among bariatric patients up to more than 7 years after the surgical procedure, suggesting that an increased bone turnover persists even at a very long-term follow-up in such patients. PMID- 28724056 TI - Prevalence of pancreatic autoantibodies in non-diabetic patients with autoimmune thyroid disease and its relation to insulin secretion and glucose tolerance. AB - OBJECTIVE: We evaluated the prevalence of glutamic acid decarboxylase (GADA) and tyrosine phosphatase-protein antibodies (IA2A), their titers and their relation to first phase insulin response (FPIR) and glucose tolerance in autoimmune thyroid diseases (ATDs) patients. SUBJECTS AND METHODS: Graves' disease (GD; n = 181) and Hashimoto's thyroiditis (HT; n = 143) patients in addition to healthy controls (n = 93) were studied. Secondly, FPIR and oral glucose tolerance tests (OGTT) were performed in 11 anti-pancreatic islet-cell (+) and in 20 anti pancreatic-cell (-) patients. RESULTS: There was a non significant trend for higher prevalence of GADA positivity in GD vs HT (7.2% vs 2% p = 0.06), but the GADA titers were higher in HT. We also did not find a significant difference in IA2 prevalence (0.7% vs 0.0%) between these two groups or compared to the control group. In the subsequent analysis, low FPIR was found in 10% of these patients but without statistical difference for OGTT between pancreatic antibody-positive and -negative patients. CONCLUSION: A trend for greater prevalence of GADA was observed for GD patients than for HT or control. However, the titers of these autoantibodies were higher in HT patients, but there was no significant relation to insulin secretion and glucose tolerance at that moment and stage of autoimmune diseases. PMID- 28724057 TI - Impaired flow-mediated dilation response and carotid intima-media thickness in patients with type 1 diabetes mellitus with a mean disease duration of 4.1 years. AB - OBJECTIVE: This study aimed at assessing the endothelial function in patients with Type 1 diabetes (T1DM) using flow-mediated dilation (FMD) response and carotid artery intima-media thickness (CIMT). MATERIALS AND METHODS: This study enrolled 32 T1DM patients (mean disease duration 4.1 years) and 28 age-matched controls (CTL Group). Endothelial function and CIMT were assessed with high resolution ultrasound using standardized offline measurements. RESULTS: FMD was significantly lower in patients in the T1DM Group (8.9 +/- 3.2%) compared with those in the CTL Group (13.3 +/- 4.3%; P-value < 0.0001). Similarly, CIMT differed significantly between T1DM patients (0.525 +/- 0.03 mm) and controls (0.508 +/- 0.03 mm; P-value = 0.041). Even though, the values are within the normal range for age. CONCLUSIONS: Patients with T1DM have impaired endothelial function characterized by reduced FMD when compared to controls. However, vascular remodeling as seen by increases in CIMT was not found in this study. PMID- 28724058 TI - Search for DQ2.5 and DQ8 alleles using a lower cost technique in patients with type 1 diabetes and celiac disease in a population of southern Brazil. AB - OBJECTIVE: To evaluate the frequency of DQ2.5 and DQ8 alleles using the Tag single-nucleotide polymorphism (Tag-SNP) technique in individuals with type 1 diabetes mellitus (T1DM) and celiac disease (CD) in southern Brazil. MATERIALS AND METHODS: In a prospective design, we performed the search for DQA1*0501 and DQB1*0201 alleles for DQ2.5 and DQB1*0302 for DQ8 through Real-Time Polymerase Chain Reaction (RT-PCR) technique, using TaqMan Genotyping Assays (Applied Biosystems, USA). The diagnosis of CD was established by duodenal biopsy and genotypic determination performed by StepOne Software v2.3. Allelic and genotypic frequencies were compared between groups using Chi-square and Fisher's exact tests and the multiple comparisons using Finner's adjustment. RESULTS: Three hundred and sixty two patients with a median age of 14 years were divided into 3 groups: T1DM without CD (264); T1DM with CD (32) and CD without T1DM (66). In 97% of individuals with T1DM and CD and 76% of individuals with CD without T1DM, respectively, the alleles DQ2.5 and/or DQ8 were identified (p < 0.001). DQ2.5 was more common in individuals with CD (p = 0.004) and DQ8 was more common in individuals with type 1 diabetes (p = 0.008). CONCLUSIONS: The evaluation of the alleles for DQ2.5 and DQ8 by Tag-SNP technique showed a high negative predictive value among those with T1DM, similar to that described by the conventional technique. The high frequency of DQ8 alleles in individuals with T1DM did not allow differentiating those at higher risk of developing T1DM. PMID- 28724059 TI - Screening tests for distal symmetrical polyneuropathy in Latin American patients with type 2 diabetes mellitus. AB - OBJECTIVE: This cross sectional study intended to evaluate two bedside tests (Neuropad and VibraTip) as screening tools for distal symmetrical polyneuropathy (DSPN) in Latin American patients with type 2 diabetes mellitus (T2D). SUBJECTS AND METHODS: Ninety-three Colombian patients diagnosed with T2D were recruited. Anthropometric variables, glycemic control parameters, lipid profile and renal function were assessed for each patient. DSPN was defined by a Michigan Neuropathy Screening Instrument (MNSI) clinical score greater than 2. Both Neuropad and Vibratip tests were applied to each patient. Contingency analyses were performed to evaluate the diagnostic power of both tools. RESULTS: The prevalence of DSPN determined clinically by MNSI was 25.8%. DSPN in these patients was associated with age, worsening renal function, and insulin treatment. The sensitivity and specificity of the Neuropad test for DSPN was 66.6% and 63% respectively. Its negative predictive value (NPV) was 84.6%. The VibraTip test exhibited a sensitivity of 54.1% and specificity of 91.3%, with a NPV of 85.1%. CONCLUSION: Neuropad and VibraTip are reliable screening tools for DSPN in Latin American population. VibraTip presents a considerable diagnostic power for DSPN in this population. Further studies regarding the cost effectiveness of these tools in clinical practice are needed. PMID- 28724060 TI - Genome-Wide Association Mapping of Crown Rust Resistance in Oat Elite Germplasm. AB - Oat crown rust, caused by f. sp. , is a major constraint to oat ( L.) production in many parts of the world. In this first comprehensive multienvironment genome wide association map of oat crown rust, we used 2972 single-nucleotide polymorphisms (SNPs) genotyped on 631 oat lines for association mapping of quantitative trait loci (QTL). Seedling reaction to crown rust in these lines was assessed as infection type (IT) with each of 10 crown rust isolates. Adult plant reaction was assessed in the field in a total of 10 location-years as percentage severity (SV) and as infection reaction (IR) in a 0-to-1 scale. Overall, 29 SNPs on 12 linkage groups were predictive of crown rust reaction in at least one experiment at a genome-wide level of statistical significance. The QTL identified here include those in regions previously shown to be linked with seedling resistance genes , , , , , and and also with adult-plant resistance and adaptation-related QTL. In addition, QTL on linkage groups Mrg03, Mrg08, and Mrg23 were identified in regions not previously associated with crown rust resistance. Evaluation of marker genotypes in a set of crown rust differential lines supported as the identity of . The SNPs with rare alleles associated with lower disease scores may be suitable for use in marker-assisted selection of oat lines for crown rust resistance. PMID- 28724061 TI - Multi-Locus Mixed Model Analysis Of Stem Rust Resistance In Winter Wheat. AB - Genome-wide association mapping is a powerful tool for dissecting the relationship between phenotypes and genetic variants in diverse populations. With the improved cost efficiency of high-throughput genotyping platforms, association mapping is a desirable method of mining populations for favorable alleles that hold value for crop improvement. Stem rust, caused by the fungus f. sp. is a devastating disease that threatens wheat ( L.) production worldwide. Here, we explored the genetic basis of stem rust resistance in a global collection of 1411 hexaploid winter wheat accessions genotyped with 5390 single nucleotide polymorphism markers. To facilitate the development of resistant varieties, we characterized marker-trait associations underlying field resistance to North American races and seedling resistance to the races TTKSK (Ug99), TRTTF, TTTTF, and BCCBC. After evaluating several commonly used linear models, a multi-locus mixed model provided the maximum statistical power and improved the identification of loci with direct breeding application. Ten high-confidence resistance loci were identified, including SNP markers linked to and and at least three newly discovered resistance loci that are strong candidates for introgression into modern cultivars. In the present study, we assessed the power of multi-locus association mapping while providing an in-depth analysis for its practical ability to assist breeders with the introgression of rare alleles into elite varieties. PMID- 28724062 TI - Increasing Genomic-Enabled Prediction Accuracy by Modeling Genotype * Environment Interactions in Kansas Wheat. AB - Wheat ( L.) breeding programs test experimental lines in multiple locations over multiple years to get an accurate assessment of grain yield and yield stability. Selections in early generations of the breeding pipeline are based on information from only one or few locations and thus materials are advanced with little knowledge of the genotype * environment interaction (G * E) effects. Later, large trials are conducted in several locations to assess the performance of more advanced lines across environments. Genomic selection (GS) models that include G * E covariates allow us to borrow information not only from related materials, but also from historical and correlated environments to better predict performance within and across specific environments. We used reaction norm models with several cross-validation schemes to demonstrate the increased breeding efficiency of Kansas State University's hard red winter wheat breeding program. The GS reaction norm models line effect (L) + environment effect (E), L + E + genotype environment (G), and L + E + G + (G * E) effects) showed high accuracy values (>0.4) when predicting the yield performance in untested environments, sites or both. The GS model L + E + G + (G * E) presented the highest prediction ability ( = 0.54) when predicting yield in incomplete field trials for locations with a moderate number of lines. The difficulty of predicting future years (forward prediction) is indicated by the relatively low accuracy ( = 0.171) seen even when environments with 300+ lines were included. PMID- 28724063 TI - Evaluation of Genetic Diversity and Host Resistance to Stem Rust in USDA NSGC Durum Wheat Accessions. AB - The USDA-ARS National Small Grains Collection (NSGC) maintains germplasm representing global diversity of small grains and their wild relatives. To evaluate the utility of the NSGC durum wheat ( L. ssp. ) accessions, we assessed genetic diversity and linkage disequilibrium (LD) patterns in a durum core subset containing 429 lines with spring growth habit originating from 64 countries worldwide. Genetic diversity estimated using wheat single-nucleotide polymorphism (SNP) markers showed considerable diversity captured in this collection. Average LD decayed over a genetic distance to within 3 cM at = 0.2, with a fast LD decay for markers linked at >5 cM. We evaluated accessions for resistance to wheat stem rust, caused by a fungal pathogen, Pers. Pers. f. sp. Eriks. and E. Henn (), using races from both eastern Africa and North America, at seedling and adult plant stages. Five accessions were identified as resistant to all stem rust pathogen races evaluated. Genome-wide association analysis detected 17 significant associations at the seedling stage with nine likely corresponding to , , and and the remaining potentially being novel genes located on six chromosomes. A higher frequency of resistant accessions was found at the adult plant stage than at the seedling stage. However, few significant associations were detected possibly a result of strong G * E interactions not properly accounted for in the mixed model. Nonetheless, the resistant accessions identified in this study should provide wheat breeders with valuable resources for improving stem rust resistance. PMID- 28724064 TI - Genetic Characterization of the Soybean Nested Association Mapping Population. AB - A set of nested association mapping (NAM) families was developed by crossing 40 diverse soybean [ (L.) Merr.] genotypes to the common cultivar. The 41 parents were deeply sequenced for SNP discovery. Based on the polymorphism of the single nucleotide polymorphisms (SNPs) and other selection criteria, a set of SNPs was selected to be included in the SoyNAM6K BeadChip for genotyping the parents and 5600 RILs from the 40 families. Analysis of the SNP profiles of the RILs showed a low average recombination rate. We constructed genetic linkage maps for each family and a composite linkage map based on recombinant inbred lines (RILs) across the families and identified and annotated 525,772 high confidence SNPs that were used to impute the SNP alleles in the RILs. The segregation distortion in most families significantly favored the alleles from the female parent, and there was no significant difference of residual heterozygosity in the euchromatic vs. heterochromatic regions. The genotypic datasets for the RILs and parents are publicly available and are anticipated to be useful to map quantitative trait loci (QTL) controlling important traits in soybean. PMID- 28724065 TI - Comparative Mapping and Targeted-Capture Sequencing of the Gametocidal Loci in Aegilops sharonensis. AB - Gametocidal (Gc) chromosomes or elements in species such as Eig are preferentially transmitted to the next generation through both the male and female gametes when introduced into wheat ( L.). Furthermore, any genes, such as genes that control agronomically important traits, showing complete linkage with Gc elements, are also transmitted preferentially to the next generation without the need for selection. The mechanism for the preferential transmission of the Gc elements appears to occur by the induction of extensive chromosome damage in any gametes that lack the Gc chromosome in question. Previous studies on the mechanism of the Gc action in indicates that at least two linked elements are involved. The first, the element, induces chromosome breakage in gametes, which have lost the Gc elements while the second, the element, prevents the chromosome breakage action of the breaker element in gametes which carry the Gc elements. In this study, we have used comparative genomic studies to map 54 single nucleotide polymorphism (SNP) markers in an 4S introgression segment in wheat and have also identified 18 candidate genes in for the breaker element through targeted sequencing of this 4S introgression segment. This valuable genomic resource will aide in further mapping the Gc locus that could be exploited in wheat breeding to produce new, superior varieties of wheat. PMID- 28724066 TI - Strategies for Selecting Crosses Using Genomic Prediction in Two Wheat Breeding Programs. AB - The single most important decision in plant breeding programs is the selection of appropriate crosses. The ideal cross would provide superior predicted progeny performance and enough diversity to maintain genetic gain. The aim of this study was to compare the best crosses predicted using combinations of mid-parent value and variance prediction accounting for linkage disequilibrium (V) or assuming linkage equilibrium (V). After predicting the mean and the variance of each cross, we selected crosses based on mid-parent value, the top 10% of the progeny, and weighted mean and variance within progenies for grain yield, grain protein content, mixing time, and loaf volume in two applied wheat ( L.) breeding programs: Instituto Nacional de Investigacion Agropecuaria (INIA) Uruguay and CIMMYT Mexico. Although the variance of the progeny is important to increase the chances of finding superior individuals from transgressive segregation, we observed that the mid-parent values of the crosses drove the genetic gain but the variance of the progeny had a small impact on genetic gain for grain yield. However, the relative importance of the variance of the progeny was larger for quality traits. Overall, the genomic resources and the statistical models are now available to plant breeders to predict both the performance of breeding lines per se as well as the value of progeny from any potential crosses. PMID- 28724067 TI - Multitrait, Random Regression, or Simple Repeatability Model in High-Throughput Phenotyping Data Improve Genomic Prediction for Wheat Grain Yield. AB - High-throughput phenotyping (HTP) platforms can be used to measure traits that are genetically correlated with wheat ( L.) grain yield across time. Incorporating such secondary traits in the multivariate pedigree and genomic prediction models would be desirable to improve indirect selection for grain yield. In this study, we evaluated three statistical models, simple repeatability (SR), multitrait (MT), and random regression (RR), for the longitudinal data of secondary traits and compared the impact of the proposed models for secondary traits on their predictive abilities for grain yield. Grain yield and secondary traits, canopy temperature (CT) and normalized difference vegetation index (NDVI), were collected in five diverse environments for 557 wheat lines with available pedigree and genomic information. A two-stage analysis was applied for pedigree and genomic selection (GS). First, secondary traits were fitted by SR, MT, or RR models, separately, within each environment. Then, best linear unbiased predictions (BLUPs) of secondary traits from the above models were used in the multivariate prediction models to compare predictive abilities for grain yield. Predictive ability was substantially improved by 70%, on average, from multivariate pedigree and genomic models when including secondary traits in both training and test populations. Additionally, (i) predictive abilities slightly varied for MT, RR, or SR models in this data set, (ii) results indicated that including BLUPs of secondary traits from the MT model was the best in severe drought, and (iii) the RR model was slightly better than SR and MT models under drought environment. PMID- 28724068 TI - Genome-wide Association Mapping of Qualitatively Inherited Traits in a Germplasm Collection. AB - Genome-wide association (GWA) has been used as a tool for dissecting the genetic architecture of quantitatively inherited traits. We demonstrate here that GWA can also be highly useful for detecting many major genes governing categorically defined phenotype variants that exist for qualitatively inherited traits in a germplasm collection. Genome-wide association mapping was applied to categorical phenotypic data available for 10 descriptive traits in a collection of ~13,000 soybean [ (L.) Merr.] accessions that had been genotyped with a 50,000 single nucleotide polymorphism (SNP) chip. A GWA on a panel of accessions of this magnitude can offer substantial statistical power and mapping resolution, and we found that GWA mapping resulted in the identification of strong SNP signals for 24 classical genes as well as several heretofore unknown genes controlling the phenotypic variants in those traits. Because some of these genes had been cloned, we were able to show that the narrow GWA mapping SNP signal regions that we detected for the phenotypic variants had chromosomal bp spans that, with just one exception, overlapped the bp region of the cloned genes, despite local variation in SNP number and nonuniform SNP distribution in the chip set. PMID- 28724069 TI - A Distinct Genetic Cluster in Cultivated Chickpea as Revealed by Genome-wide Marker Discovery and Genotyping. AB - The accurate description of plant biodiversity is of utmost importance to efficiently address efforts in conservation genetics and breeding. Herein, we report the successful application of a genotyping-by-sequencing (GBS) approach in chickpea ( L.), resulting in the characterization of a cultivated germplasm collection with 3187 high-quality single nucleotide polymorphism (SNP) markers. Genetic structure inference, principal component analysis, and hierarchical clustering all indicated the identification of a genetic cluster corresponding to black-seeded genotypes traditionally cultivated in Southern Italy. Remarkably, this cluster was clearly distinct at both genetic and phenotypic levels from germplasm groups reflecting commercial chickpea classification into and seed types. Fixation index estimates for individual polymorphisms pointed out loci and genomic regions that might be of significance for the diversification of agronomic and commercial traits. Overall, our findings provide information on genetic relationships within cultivated chickpea and highlight a gene pool of great interest for the scientific community and chickpea breeding, which is limited by the low genetic diversity available in the primary gene pool. PMID- 28724070 TI - Marker-Trait Association Analysis of Iron and Zinc Concentration in Lentil (Lens culinaris Medik.) Seeds. AB - Lentil ( Medik.) seeds are relatively rich in iron (Fe) and zinc (Zn), making lentil a potential crop to aid in the global battle against human micronutrient deficiency. Understanding the genetic basis for uptake of seed Fe and Zn is required to increase sustainable concentrations of these minerals in seeds. The objectives of this study were to characterize genetic variation in seed Fe and Zn concentration and to identify molecular markers associated with these traits across diverse lentil accessions. A set of 138 cultivated lentil accessions from 34 countries were evaluated in four environments (2 sites * 2 yr) in Saskatchewan, Canada. The collection was genotyped using 1150 single-nucleotide polymorphism (SNP) markers that are distributed across the lentil genome. The germplasm tested exhibited a wide range of variation for seed Fe and Zn concentration. The marker-trait association analysis detected two SNP markers tightly linked to seed Fe and one linked to seed Zn concentration (-log10 >= 4.36). Additional markers were detected at -log10 >= 3.06. A number of putative candidate genes underlying detected loci encode Fe- and Zn-related functions. This study provides insight into the genetics of seed Fe and Zn concentration of lentil and opportunities for marker-assisted selection to improve micronutrient concentration as part of micronutrient biofortification programs. PMID- 28724071 TI - Haplotypes Phased from Population Transcriptomes Detecting Selection in the Initial Adaptation of Miscanthus lutarioriparius to Stressful Environments. AB - Adaptation is a characteristic that enhances the survival or reproduction of organisms; selection is the critical process leading to adaptive evolution. Therefore, detecting selection is important in studying evolutionary biology. Changes in allele frequency are fundamental to adaptive evolution. The allele frequency of entire genes at the genomic scale is more intensive and precise for analyzing selection effects, compared with simple sequence repeat and single nucleotide polymorphism (SNP) alleles from nuclear gene fragments. Here, we analyzed 29,094 SNPs derived from 80 individuals of 14 L. Liou ex S.L. Chen & Renvoize populations planted near their native habitat (Jiangxia, Hubei Province, JH) and a stressful environment (Qingyang, Gansu Province, QG) to detect selection during initial adaptation. The nucleotide diversity of over 60% of genes was decreased in QG compared with JH, suggesting that most genes were undergoing selection in the stressful environment. We explored a new approach based on haplotype data inferred from RNA-seq data to analyze the change in frequency between two sites and to detect selection signals. In total, 402 and 51 genes were found to be targets of positive and negative selection, respectively. Among these candidate genes, the enrichment of abiotic stress-response genes and photosynthesis-related genes might have been responsible for establishment in the stressful environment. This is the first study assessing the change in allele frequency at the genomic level during adaptation. The method in which allele frequency detects selection during initial adaptation using population RNA-seq data would be useful for developing evolutionary biology. PMID- 28724072 TI - Genome-Wide Analysis of Tar Spot Complex Resistance in Maize Using Genotyping-by Sequencing SNPs and Whole-Genome Prediction. AB - Tar spot complex (TSC) is one of the most destructive foliar diseases of maize ( L.) in tropical and subtropical areas of Central and South America, causing significant grain yield losses when weather conditions are conducive. To dissect the genetic architecture of TSC resistance in maize, association mapping, in conjunction with linkage mapping, was conducted on an association-mapping panel and three biparental doubled-haploid (DH) populations using genotyping-by sequencing (GBS) single-nucleotide polymorphisms (SNPs). Association mapping revealed four quantitative trait loci (QTL) on chromosome 2, 3, 7, and 8. All the QTL, except for the one on chromosome 3, were further validated by linkage mapping in different genetic backgrounds. Additional QTL were identified by linkage mapping alone. A major QTL located on bin 8.03 was consistently detected with the largest phenotypic explained variation: 13% in association-mapping analysis and 13.18 to 43.31% in linkage-mapping analysis. These results indicated that TSC resistance in maize was controlled by a major QTL located on bin 8.03 and several minor QTL with smaller effects on other chromosomes. Genomic prediction results showed moderate-to-high prediction accuracies in different populations using various training population sizes and marker densities. Prediction accuracy of TSC resistance was >0.50 when half of the population was included into the training set and 500 to 1,000 SNPs were used for prediction. Information obtained from this study can be used for developing functional molecular markers for marker-assisted selection (MAS) and for implementing genomic selection (GS) to improve TSC resistance in tropical maize. PMID- 28724074 TI - High-Resolution Genetic and Physical Mapping of the Eastern Filbert Blight Resistance Region in 'Jefferson' Hazelnut (Corylus avellana L.). AB - Eastern filbert blight (EFB), caused by the pyrenomycete (Peck) E. Muller, is a devastating disease of European hazelnut ( L) in the US Pacific Northwest. A dominant allele at a single locus from the obsolete pollenizer 'Gasaway' confers a high level of resistance to EFB. To identify the gene responsible for resistance, we initiated map-based cloning efforts in a population of 1488 seedlings that segregated for resistance. Chromosome walking was initiated using primers designed from eight previously identified random amplified polymorphic DNA markers linked to resistance. The bacterial artificial chromosome (BAC) library was screened using the primer pairs in a polymerase chain reaction-based pooling and subpooling strategy. Here, we report construction of a high resolution genetic map and a physical map of the resistance region. Further, we sequenced BACs in the resistance region and identified and annotated the coding sequences. In seven contigs <1 cM from the resistance locus, 233 genes were predicted. The putative genes were compared with sequences in GenBank using a BLASTP search. Fifty-one markers were placed on the high-resolution genetic map, including markers newly developed from the BACs. Segregation in the mapping population placed the resistance locus in a single contig of three BACs (43F13, 66C22, and 85B7). Two of the putative genes are in the p-loop NTPase and F-box super-families localized in a 135-kb BAC, which have previously been shown to have disease-resistance properties. Further mapping, complementation, and expression tests of the genes in these BACs is essential to confirm which confer resistance to EFB. PMID- 28724075 TI - A Comprehensive Image-based Phenomic Analysis Reveals the Complex Genetic Architecture of Shoot Growth Dynamics in Rice (Oryza sativa). AB - Early vigor is an important trait for many rice ( L.)-growing environments. However, genetic characterization and improvement for early vigor is hindered by the temporal nature of the trait and strong genotype * environment effects. We explored the genetic architecture of shoot growth dynamics during the early and active tillering stages by applying a functional modeling and genomewide association (GWAS) mapping approach on a diversity panel of ~360 rice accessions. Multiple loci with small effects on shoot growth trajectory were identified, indicating a complex polygenic architecture. Natural variation for shoot growth dynamics was assessed in a subset of 31 accessions using RNA sequencing and hormone quantification. These analyses yielded a gibberellic acid (GA) catabolic gene, , which could influence GA levels to regulate vigor in the early tillering stage. Given the complex genetic architecture of shoot growth dynamics, the potential of genomic selection (GS) for improving early vigor was explored using all 36,901 single-nucleotide polymorphisms (SNPs) as well as several subsets of the most significant SNPs from GWAS. Shoot growth trajectories could be predicted with reasonable accuracy using the 50 most significant SNPs from GWAS (0.37 0.53); however, the accuracy of prediction was improved by including more markers, which indicates that GS may be an effective strategy for improving shoot growth dynamics during the vegetative growth stage. This study provides insights into the complex genetic architecture and molecular mechanisms underlying early shoot growth dynamics and provides a foundation for improving this complex trait in rice. PMID- 28724076 TI - GBS-Based Genomic Selection for Pea Grain Yield under Severe Terminal Drought. AB - Terminal drought is the main stress that limits pea ( L.) grain yield in Mediterranean-climate regions. This study provides an unprecedented assessment of the predictive ability of genomic selection (GS) for grain yield under severe terminal drought using genotyping-by-sequencing (GBS) data. Additional aims were to assess the GS predictive ability for different GBS data quality filters and GS models, comparing intrapopulation with interpopulation GS predictive ability and to perform genome-wide association (GWAS) studies. The yield and onset of flowering of 315 lines from three recombinant inbred line (RIL) populations issued by connected crosses between three elite cultivars were assessed under a field rainout shelter. We defined an adjusted yield, which is associated with intrinsic drought tolerance, as the yield deviation from the value expected as a function of onset of flowering (which correlated negatively with grain yield). Total polymorphic markers ranged from approximately 100 (minimum of eight reads per locus, maximum 10% genotype missing data) to over 7500 markers (minimum of four reads, maximum 50% missing rate). Best predictions were provided by Bayesian Lasso (BL) or ridge regression best linear unbiased prediction (rrBLUP), rather than support vector regression (SVR) models, with at least 400-500 markers. Intrapopulation GS predictive ability exceeded 0.5 for yield and onset of flowering in all populations and approached 0.4 for the adjusted yield of a population with high trait variation. Genomic selection was preferable to phenotypic selection in terms of predicted yield gains. Interpopulation GS predictive ability varied largely depending on the pair of populations. GWAS revealed extensive colocalization of markers associated with high yield and early flowering and suggested that they are concentrated in a few genomic regions. PMID- 28724077 TI - Physical Map of the Short Arm of Bread Wheat Chromosome 3D. AB - Bread wheat ( L.) is one of the most important crops worldwide. Although a reference genome sequence would represent a valuable resource for wheat improvement through genomics-assisted breeding and gene cloning, its generation has long been hampered by its allohexaploidy, high repeat content, and large size. As a part of a project coordinated by the International Wheat Genome Sequencing Consortium (IWGSC), a physical map of the short arm of wheat chromosome 3D (3DS) was prepared to facilitate reference genome assembly and positional gene cloning. It comprises 869 contigs with a cumulative length of 274.5 Mbp and represents 85.5% of the estimated chromosome arm size. Eighty-six Mbp of survey sequences from chromosome arm 3DS were assigned in silico to physical map contigs via next-generation sequencing of bacterial artificial chromosome pools, thus providing a high-density framework for physical map ordering along the chromosome arm. About 60% of the physical map was anchored in this single experiment. Finally, 1393 high-confidence genes were anchored to the physical map. Comparisons of gene space of the chromosome arm 3DS with genomes of closely related species [ (L.) P.Beauv., rice ( L.), and sorghum [ (L.) Moench] and homeologous wheat chromosomes provided information about gene movement on the chromosome arm. PMID- 28724078 TI - Genome-Wide Association Study of Developing Leaves' Heat Tolerance during Vegetative Growth Stages in a Sorghum Association Panel. AB - Heat stress reduces grain yield and quality worldwide. Enhancing heat tolerance of crops at all developmental stages is one of the essential strategies required for sustaining agricultural production especially as frequency of temperature extremes escalates in response to climate change. Although heat tolerance mechanisms have been studied extensively in model plant species, little is known about the genetic control underlying heat stress responses of crop plants at the vegetative stage under field conditions. To dissect the genetic basis of heat tolerance in sorghum [ (L.) Moench], we performed a genome-wide association study (GWAS) for traits responsive to heat stress at the vegetative stage in an association panel. Natural variation in leaf firing (LF) and leaf blotching (LB) were evaluated separately for 3 yr in experimental fields at three locations where sporadic heat waves occurred throughout the sorghum growing season. We identified nine single-nucleotide polymorphisms (SNPs) that were significantly associated with LF and five SNPs that were associated with LB. Candidate genes near the SNPs were investigated and 14 were directly linked to biological pathways involved in plant stress responses including heat stress response. The findings of this study provide new knowledge on the genetic control of leaf traits responsive to heat stress in sorghum, which could aid in elucidating the genetic and molecular mechanisms of vegetative stage heat tolerance in crops. The results also provide candidate markers for molecular breeding of enhanced heat tolerance in cereal and bioenergy crops. PMID- 28724079 TI - Single-Step Genomic and Pedigree Genotype * Environment Interaction Models for Predicting Wheat Lines in International Environments. AB - Genomic prediction models have been commonly used in plant breeding but only in reduced datasets comprising a few hundred genotyped individuals. However, pedigree information for an entire breeding population is frequently available, as are historical data on the performance of a large number of selection candidates. The single-step method extends the genomic relationship information from genotyped individuals to pedigree information from a larger number of phenotyped individuals in order to combine relationship information on all members of the breeding population. Furthermore, genomic prediction models that incorporate genotype * environment interactions (G * E) have produced substantial increases in prediction accuracy compared with single-environment genomic prediction models. Our main objective was to show how to use single-step genomic and pedigree models to assess the prediction accuracy of 58,798 CIMMYT wheat ( L.) lines evaluated in several simulated environments in Ciudad Obregon, Mexico, and to predict the grain yield performance of some of them in several sites in South Asia (India, Pakistan, and Bangladesh) using a reaction norm model that incorporated G * E. Another objective was to describe the statistical and computational challenges encountered when developing the pedigree and single-step models in such large datasets. Results indicate that the genomic prediction accuracy achieved by models using pedigree only, markers only, or both pedigree and markers to predict various environments in India, Pakistan, and Bangladesh is higher (0.25-0.38) than prediction accuracy of models that use only phenotypic prediction (0.20) or do not include the G * E term. PMID- 28724081 TI - Genome-Wide Screening for Lectin Motifs in Arabidopsis thaliana. AB - For more than three decades, served as a model for plant biology research. At present only a few protein families have been studied in detail in . This study focused on all sequences with lectin motifs in the genome of . Based on amino acid sequence similarity (BLASTp searches), 217 putative lectin genes were retrieved belonging to 9 out of 12 different lectin families. The domain organization and genomic distribution for each lectin family were analyzed. Domain architecture analysis revealed that most of these lectin gene sequences are linked to other domains, often belonging to protein families with catalytic activity. Many protein domains identified are known to play a role in stress signaling and defense, suggesting a major contribution of the putative lectins in development and plant defense. This genome-wide screen for different lectin motifs will help to unravel the functional characteristics of lectins. In addition, phylogenetic trees and WebLogos were created and showed that most lectin sequences that share the same domain architecture evolved together. Furthermore, the amino acids responsible for carbohydrate binding are largely conserved. Our results provide information about the evolutionary relationships and functional divergence of the lectin motifs in . PMID- 28724080 TI - QTLs Associated with Crown Root Angle, Stomatal Conductance, and Maturity in Sorghum. AB - Three factors that directly affect the water inputs in cropping systems are root architecture, length of the growing season, and stomatal conductance to water vapor (). Deeper-rooted cultivars will perform better under water-limited conditions because they can access water stored deeper in the soil profile. Reduced limits transpiration rate () and thus throughout the vegetative phase conserves water that may be used during grain filling in water-limited environments. Additionally, growing early-maturing varieties in regions that rely on soil-stored water is a key water management strategy. To further our understanding of the genetic basis underlying root depth, growing season length, and we conducted a quantitative trait locus (QTL) study. A QTL for crown root angle (a proxy for root depth) new to sorghum was identified in chromosome 3. For , a QTL in chromosome seven was identified. In a follow-up field study it was determined that the QTL for was associated with reduced but not with net carbon assimilation rate () or shoot biomass. No differences in guard-cell length or stomatal density were observed among the lines, leading to the conclusion that the observed differences in must be explained by partial stomatal closure. The well-studied maturity gene was identified in the QTL for maturity. The transgressive segregation of the population was explained by the possible interaction of with other loci. Finally, the most probable position of the genes underlying the QTLs and candidate genes were proposed. PMID- 28724082 TI - Prospective Targeted Recombination and Genetic Gains for Quantitative Traits in Maize. AB - Advances in clustered regularly interspaced short palindromic repeats (CRISPR) technology have allowed targeted recombination in specific DNA sequences in yeast (). My objective was to determine if the selection gains from targeted recombination are large enough to warrant the development of targeted recombination technology in plants. Genomewide marker effects for quantitative traits in two maize ( L.) experiments were used to identify targeted recombination points that would maximize the per-chromosome genetic gains in a given cross. With nontargeted recombination in the intermated B73 * Mo17 population, selecting the best out of 180 recombinant inbreds led to a 7.1% gain for testcross yield. Having one targeted recombination on each of the 10 maize chromosomes led to a predicted gain of 15.3% for yield. Targeted recombination therefore led to a predicted relative efficiency () of (0.153 / 0.071) = 212% of targeted recombination compared with nontargeted recombination. For the five other traits in the intermated B73 * Mo17 population and for four traits in 45 other maize crosses, the values ranged from 105 to 600%. The targeted recombination points differed among traits and crosses. Predicted gains increased when the number of targeted recombinations per chromosome increased from one to two. Overall, the results suggested that targeted recombination could double the selection gains for quantitative traits in maize and that the development of targeted recombination technology is worthwhile. Empirical experiments with current marker-assisted breeding procedures are needed to validate the per chromosome predicted gains. PMID- 28724083 TI - Identification of Candidate Genes Responsible for Stem Pith Production Using Expression Analysis in Solid-Stemmed Wheat. AB - The wheat stem sawfly (WSS) is an economically important pest of wheat in the Northern Great Plains. The primary means of WSS control is resistance associated with the single quantitative trait locus (QTL) , which controls most stem solidness variation. The goal of this study was to identify stem solidness candidate genes via RNA-seq. This study made use of 28 single nucleotide polymorphism (SNP) makers derived from expressed sequence tags (ESTs) linked to contained within a 5.13 cM region. Allele specific expression of EST markers was examined in stem tissue for solid and hollow-stemmed pairs of two spring wheat near isogenic lines (NILs) differing for the QTL. Of the 28 ESTs, 13 were located within annotated genes and 10 had detectable stem expression. Annotated genes corresponding to four of the ESTs were differentially expressed between solid and hollow-stemmed NILs and represent possible stem solidness gene candidates. Further examination of the 5.13 cM region containing the 28 EST markers identified 260 annotated genes. Twenty of the 260 linked genes were up-regulated in hollow NIL stems, while only seven genes were up-regulated in solid NIL stems. An -methyltransferase within the region of interest was identified as a candidate based on differential expression between solid and hollow-stemmed NILs and putative function. Further study of these candidate genes may lead to the identification of the gene(s) controlling stem solidness and an increased ability to select for wheat stem solidness and manage WSS. PMID- 28724084 TI - Comparison of Models and Whole-Genome Profiling Approaches for Genomic-Enabled Prediction of Septoria Tritici Blotch, Stagonospora Nodorum Blotch, and Tan Spot Resistance in Wheat. AB - The leaf spotting diseases in wheat that include Septoria tritici blotch (STB) caused by , Stagonospora nodorum blotch (SNB) caused by , and tan spot (TS) caused by pose challenges to breeding programs in selecting for resistance. A promising approach that could enable selection prior to phenotyping is genomic selection that uses genome-wide markers to estimate breeding values (BVs) for quantitative traits. To evaluate this approach for seedling and/or adult plant resistance (APR) to STB, SNB, and TS, we compared the predictive ability of least squares (LS) approach with genomic-enabled prediction models including genomic best linear unbiased predictor (GBLUP), Bayesian ridge regression (BRR), Bayes A (BA), Bayes B (BB), Bayes Cpi (BC), Bayesian least absolute shrinkage and selection operator (BL), and reproducing kernel Hilbert spaces markers (RKHS-M), a pedigree-based model (RKHS-P) and RKHS markers and pedigree (RKHS-MP). We observed that LS gave the lowest prediction accuracies and RKHS-MP, the highest. The genomic-enabled prediction models and RKHS-P gave similar accuracies. The increase in accuracy using genomic prediction models over LS was 48%. The mean genomic prediction accuracies were 0.45 for STB (APR), 0.55 for SNB (seedling), 0.66 for TS (seedling) and 0.48 for TS (APR). We also compared markers from two whole-genome profiling approaches: genotyping by sequencing (GBS) and diversity arrays technology sequencing (DArTseq) for prediction. While, GBS markers performed slightly better than DArTseq, combining markers from the two approaches did not improve accuracies. We conclude that implementing GS in breeding for these diseases would help to achieve higher accuracies and rapid gains from selection. PMID- 28724085 TI - Quantitative Trait Loci Mapping for Spike Characteristics in Hexaploid Wheat. AB - Wheat ( L.) spike characteristics determine the number of grains produced on each spike and constitute key components of grain yield. Understanding of the genetic basis of spike characteristics in wheat, however, is limited. In this study, genotyping-by-sequencing (GBS) and the iSelect 9K assay were used on a doubled haploid (DH) soft red winter wheat population that showed a wide range of phenotypic variation for spike traits. A genetic map spanning 2934.1 cM with an average interval length of 3.4 cM was constructed. Quantitative trait loci (QTL) analysis involving additive effects, epistasis (QQ) and QTL * environment (QE), and epistasis * environment (QQE) interactions detected a total of 109 QTL, 13 QE, and 20 QQ interactions in five environments. Spike characteristics were mainly determined by additive effects and were fine-tuned by QQ, QE, and QQE. Major QTL / explained up to 30.9% of the phenotypic variation for spike length (SL) and fertile spikelet number, .1 explained up to 15.6% of the phenotypic variation of grain number per spikelet, and explained up to 80.2% of the phenotypic variation for spike compactness. Additionally, QTL for correlated spike characteristics formed QTL clusters on chromosomes 1A, 5A, 2B, 3B, 5B, 1D, and 5D. This study expands the understanding of the genetic basis of spike characteristics in hexaploid wheat. A number of stable QTL detected in this study have potential to be used in marker-assisted selection. Additionally, the genetic map generated in this study could be used to study other traits of economic importance. PMID- 28724086 TI - Long-term Changes in Grassland Soil Phosphorus with Fertilizer Application and Withdrawal. AB - Long-term phosphorus (P) applications can increase soil P concentrations in excess of agronomic optima, posing a risk to water quality. Once fertilization stops, however, it may take time for soil P concentrations to decline. Whereas P fertilization adds orthophosphate, little is known about changes in other soil P forms during P buildup and drawdown. This study examined changes in P pools (total P, Olsen P, Mehlich P, and water-extractable P) and P forms determined by P-nuclear magnetic resonance spectroscopy (P-NMR) in grazed grassland plots from Northern Ireland. Between 1994 and 1999, all plots received 8.3 kg P ha yr with variable rates of nitrogen (100-500 kg N ha yr). From 2000 to 2005, plots received 0, 20, 40, or 80 kg P ha yr and 250 kg N ha yr; from 2005 to 2010, no P fertilizer was applied to any plots. In 2005, soil P pool concentrations at the highest P fertilization rates were significantly elevated compared with those in 2000 but had decreased to 2000 concentrations by 2010. In soils receiving no P, soil P pool concentrations were significantly lower than those in 1994 only in 2010. There were few changes in P forms determined by P-NMR. Orthophosphate followed the same trend observed for the soil P pools; total organic P, total inositol phosphates, and total orthophosphate monoesters and diesters were highest in 2010 in the soil receiving no P fertilizer for 10 yr. For these soils, fertilizer application and cessation influenced inorganic P more than organic P. PMID- 28724087 TI - Nitrate Leaching from Winter Cereal Cover Crops Using Undisturbed Soil-Column Lysimeters. AB - Cover crops are important management practices for reducing nitrogen (N) leaching, especially in the Chesapeake Bay watershed, which is under total maximum daily load (TMDL) restraints. Winter cereals are common cool-season crops in the Bay watershed, but studies have not directly compared nitrate-N (NO-N) leaching losses from these species. A 3-yr cover crop lysimeter study was conducted in Beltsville, MD, to directly compare NO-N leaching from a commonly grown cultivar of barley ( L.), rye ( L.), and wheat ( L.), along with a no-cover control, using eight tension-drained undisturbed soil column lysimeters in a completely randomized design with two replicates. The lysimeters were configured to exclude runoff and to estimate NO-N leaching and flow-weighted NO-N concentration (FWNC). The temporal pattern of NO-N leaching showed a consistent highly significant ( < 0.001) effect of lower NO-N leaching with cover crops compared with no cover but showed only small and periodically significant ( < 0.05) effects among the cultivars of barley, rye, and wheat covers. Nitrate-N leaching was more affected by the quantity of establishment-season (mid-October to mid-December) precipitation than by cover crop species. For example, compared with no cover, winter cereal covers reduced NO-N leaching 95% in a dry year and 50% in wet years, with corresponding reductions in FWNC of 92 and 43%, respectively. These results are important for scientists, nutrient managers, and policymakers because they directly compare NO-N leaching from winter cereal covers and expand knowledge for developing management practices for winter cereals that can improve water quality and increase N efficiency in cropping systems. PMID- 28724088 TI - In Vitro and In Vivo Assessment of Aqueously Extractable Estrogens in Poultry Manure after Pilot-scale Composting. AB - Poultry manure contains free and conjugated forms of the natural estrogens 17beta estradiol and estrone, which can be transported to receiving waters via runoff when land-applied. Previous studies have demonstrated estrogens in runoff from poultry manure-amended fields but have not tracked changes in estrogenicity within this water over time. Microbial conversion of conjugated estrogens (a major portion of water-extractable estrogens) to parent forms may result in temporary increases in estrogenicity in natural water bodies. The present study created 80-L batches of simulated poultry manure runoff, which were investigated over 10 d for estrogenicity by bioluminescent yeast estrogen screen assay and fathead minnow () vitellogenin induction model. The efficacy of different compost conditions (in-vessel aeration +/- turning, and piling) on reduction/elimination of aqueously extractable estrogens in poultry manure was also investigated. Results indicate 3- to 10-fold increases in estrogenicity in various poultry manure mixtures during 10-d observations. Estrogenicity returned to low levels in postcompost treatments but remained elevated in the precompost treatment. Aerated compost resulted in >75% reductions in initial, peak, and 10-d mean estrogenicity in aqueous mixtures (0.3, 0.8, and 0.5 ng 17beta-estradiol equivalents [EEQ] L, respectively) compared with the precompost mixture (1.4, 4.8, and 2.1 ng EEQ L, respectively). Estrogenicity was significantly higher in the aqueous extract from the piled treatment than the aerated treatment, and 10-d exposure of male fish to the piled treatment resulted in statistically significant vitellogenin induction. Collectively, our results suggest a need to investigate estrogenicity in surface waters for several days after receiving manure-influenced runoff. PMID- 28724089 TI - Grower Analysis of Organic Matter Amendments in California Orchards. AB - Organic matter amendments supply crop nutrients and enhance soil health, yet information specific to orchards is lacking. A survey was conducted to analyze use of these materials by California almond [ (Mill.) D.A. Webb] growers. Significant differences were observed for benefits, concerns, and accessibility to manure and green waste sources and between users and nonusers. Use patterns were significantly influenced by heavy and light users, farm size, and geographic region. Enhanced soil biology was the main benefit attributed to organic matter amendments by both users and nonusers. Nonusers showed greater concern for food safety compared to users, and all growers reported greater concern for food safety from manure. The greatest adoption of organic matter amendments occurred on small farms (<=170 ha) located in the north San Joaquin Valley in California. Greater accessibility to manure correlated with presence of dairy farms. Poorer accessibility ratings by nonusers suggest access is a barrier to adoption, as opposed to nonusers having an undesirable view of the practice. Common management included applying organic matter amendments during tree dormancy from manure sources in composted forms with no-till. Heavy users on small farms exhibited the greatest year-to-year consistency and were more flexible with selection of sources and diverse in application methods. Large farms (>170 ha) were less likely to use organic matter amendments every year and less likely to apply them on all their farm area. This study identifies a number of strategies to fill knowledge gaps, increase practice awareness, and overcome barriers to adoption. PMID- 28724090 TI - Transformation of Organic Matter and the Emissions of Methane and Ammonia during Storage of Liquid Manure as Affected by Acidification. AB - Acidification of livestock manure can reduce emission of the greenhouse gases methane (CH) and nitrous oxide (NO), as well as ammonia (NH). We examined the relation between emission of these gases and transformation of organic matter as affected by acidification. Liquid cattle manure was acidified with sulfuric acid to pH 5.5 at a pilot scale (100 L), and we measured effects on CH, NO, CO and NH emissions and on transformation of pH buffer components and organic matter. Acidification reduced NH emissions by 62% (47 d) and emission of CH by 68% (57 d). Emissions of NO were negligible, probably due to the absence of a surface crust. Reductions in NH and CH emission were highest at the start but declined over time concomitantly with a gradual increase in the stored liquid manure pH. Acidification did not significantly affect CO emissions. Emission of CO was high, five- to ten-fold of CH emissions, until Day 16 of storage, after which the CO emission rate declined to around twice the CH emission rate; consequently, the majority of C loss during the early stages of storage was CO. Cumulative emission of C in CO and CH closely matched depletion of dissolved organic carbon (DOC), suggesting that DOC may be a predictor for CH emission from dilute slurries. volatile fatty acid and total ammoniacal nitrogen concentrations in surface layers were substantially higher than at the center of stored liquid manure, perhaps resulting from microbial activity at the surface. This pattern deserves attention when predicting NH emission from stored slurry. PMID- 28724091 TI - Effect of Environmental Conditions on the Degradation of Florasulam in Typical Soils of Northern China. AB - The widespread use of florasulam in China makes residues from this herbicide in soil a serious concern due to their potential to pollute the soil environment and groundwater. Accelerating the degradation of these residues will reduce their pollution potential. In this study, we investigated the degradation and adsorption of florasulam in four typical soils in northern China and examined the degradation of florasulam in Inceptisols at different temperatures, soil moisture contents, and pH values, as well as the influence of microorganisms and the use of organic matter and biogas slurry as soil amendments. The half-lives of florasulam in the four soils were 13.6 d (Ultisols), 13.9 d (Vertisols), 15.1 d (Alfisols), and 19.3 d (Inceptisols), and the adsorption ability of the four soils followed the order Inceptisols > Alfisols > Vertisols > Ultisols. Florasulam degradation rates increased as temperature and soil moisture increased and as soil pH decreased (from 8.0 to 6.0). Adding a small amount of organic matter to the soil increased the florasulam degradation rates. The use of biogas slurry also increased the degradation rates. Florasulam half-life in unsterilized soil ( = 19.3 d) was significantly shorter than in sterilized soil ( = 113.4 d). These results provide agricultural producers and environmental managers useful information for reducing the environmental risk associated with florasulam use. PMID- 28724092 TI - Can Biochar Covers Reduce Emissions from Manure Lagoons While Capturing Nutrients? AB - The unique physical and chemical properties of biochars make them promising materials for odor, gas, and nutrient sorption. Floating covers made from organic materials (biocovers) are one option for reducing odor and gas emissions from livestock manure lagoons. This study evaluated the potential of floating biochar covers to reduce odor and gas emissions while simultaneously sorbing nutrients from liquid dairy manure. This new approach has the potential to mitigate multiple environmental problems. Two biochars were tested: one made via gasification of Douglas fir chips at 650 degrees C (FC650), and the other made from a mixture of Douglas fir [ (Mirb.) Franco] bark and center wood pyrolyzed at 600 degrees C (HF600). The HF600 biocover reduced mean headspace ammonia concentration by 72 to 80%. No significant reduction was found with the FC650 biocover. Nutrient uptake ranged from 0.21 to 4.88 mg N g biochar and 0.64 to 2.70 mg P g biochar for the HF600 and FC650 biochars, respectively. Potassium ranged from a loss of 4.52 to a gain of 2.65 mg g biochar for the FC650 and HF600 biochars, respectively. The biochars also sorbed Ca, Mg, Na, Fe, Al, and Si. In a separate sensory evaluation, judges assessed odor offensiveness and odor threshold of five biocover treatments including four biochars applied over dairy manure. Reductions in mean odor offensiveness and mean odor threshold were observed in three treatments compared with the control. These results show that biochar covers hold promise as an effective practice for reducing odor and gas emissions while sorbing nutrients from liquid dairy manure. PMID- 28724093 TI - Persistence of Ascaris spp. Ova in Tropical Soil Cultivated with Eucalyptus and Fertilized with Municipal Biosolids. AB - In many countries, the main reason for severely restricting or outright banning the land application of class B biosolids is the lack of risk assessment for adverse human health impacts. Among pathogens that are not often studied are helminth ova, including that of the spp. Almost all of the knowledge about the persistence of spp. ova in soils fertilized with biosolids is based on studies developed in North America, Europe, and Asia. These studies have almost always been conducted under temperate climate conditions, which may cause erroneous interpretations when the conclusions are extrapolated to tropical regions such as those found in Brazil. This team evaluated the persistence of viable spp. ova in a sandy Quartzipsamment tropical soil, previously planted with * hybrid () and fertilized with biosolids, over a 52-wk period. During the reporting period, the average temperature of soil and biosolids fluctuated between 15 and 30 degrees C, and the average moisture of biosolids fluctuated between 60 and 90%. The estimated persistence time of viable spp. ova after land application was estimated at close to 7 wk, indicating that ova may not be viable for as long as it has been shown to be in studies of more temperate areas. The relationship of temperature with persistence of viable spp. ova in a tropical soil was stronger than moisture content, suggesting that temperature substantially contributed to their nonviability over the course of the experiment. PMID- 28724094 TI - Temperature Impacts on Soil Microbial Communities and Potential Implications for the Biodegradation of Turfgrass Pesticides. AB - Maintaining healthy turfgrass often results in the use of pesticides to manage weed, insect, and disease pests. To identify and understand potential nontarget impacts of pesticide usage while still maintaining attractive and functional turfgrass sites, it is important to improve our understanding of how pesticides degrade in various environments throughout the growing season. Temperature heavily influences microbial community composition and activity, and the microbial community often heavily influences pesticide degradation in soil ecosystems. Pesticide transformation products generated through the action of soil microbial degradation networks can vary in their toxicity, with the potential result that a pesticide applied in the spring at 10 degrees C could produce different transformation products with different toxicological impacts than the sample pesticide applied to the same site at 22 degrees C. The objective of this review is to examine past research surrounding soil microbial activity related to pesticide degradation and provide a foundation for how the soil microbiome interacts with pesticides and how seasonal temperature variations may influence those interactions. PMID- 28724095 TI - Modeling the Effects of Onsite Wastewater Treatment Systems on Nitrate Loads Using SWAT in an Urban Watershed of Metropolitan Atlanta. AB - Onsite wastewater treatment systems (OWTSs) can be a source of nitrogen (N) pollution in both surface and ground waters. In metropolitan Atlanta, GA, >26% of homes are on OWTSs. In a previous article, we used the Soil Water Assessment Tool to model the effect of OWTSs on stream flow in the Big Haynes Creek Watershed in metropolitan Atlanta. The objective of this study was to estimate the effect of OWTSs, including failing systems, on nitrate as N (NO-N) load in the same watershed. Big Haynes Creek has a drainage area of 44 km with mainly urban land use (67%), and most of the homes use OWTSs. A USGS gauge station where stream flow was measured daily and NO-N concentrations were measured monthly was used as the outlet. The model was simulated for 12 yr. Overall, the model showed satisfactory daily stream flow and NO-N loads with Nash-Sutcliffe coefficients of 0.62 and 0.58 for the calibration period and 0.67 and 0.33 for the validation period at the outlet of the Big Haynes Watershed. Onsite wastewater treatment systems caused an average increase in NO-N load of 23% at the watershed scale and 29% at the outlet of a subbasin with the highest density of OWTSs. Failing OWTSs were estimated to be 1% of the total systems and did not have a large impact on stream flow or NO-N load. The NO-N load was 74% of the total N load in the watershed, indicating the important effect of OWTSs on stream loads in this urban watershed. PMID- 28724096 TI - Hydrology and Soil Manipulations of Iron-Rich Ditch Mesocosms Provide Little Evidence of Phosphorus Capture within the Profile. AB - Agricultural drainage ditches function as first-order streams and affect nutrient management. Soil mesocosms from a ditch featuring a vertical (increasing upward) gradient in iron (Fe) and phosphorus (P) were subjected to hydraulic and soil treatments. These manipulations mimicked aspects of dredging and controlled drainage and inspected the soil release and retention of P. Treatments did not remove P from simulated groundwater. Throughput water either gained in P (lack of dredging, especially under Fe-reducing conditions) or had P concentrations indistinguishable from input water (dredging). Undredged mesocosms, when Fe reducing, released Fe and P simultaneously. Simultaneous release of P and Fe from our Fe-reducing mesocosms indicates a mechanism whereby P capture occurs by Fe precipitation upon emergence to aerated surficial waters. Upwelling and surficial phases of ditch hydrology and the lowering of the ditch surface on dredging complicate interpretation of traditional means of describing ditch P retention and release. PMID- 28724097 TI - Influence of Long-term Application of Feedlot Manure Amendments on Water Repellency of a Clay Loam Soil. AB - Long-term application of feedlot manure to cropland may increase the quantity of soil organic carbon (C) and change its quality, which may influence soil water repellency. The objective was to determine the influence of feedlot manure type (stockpiled vs. composted), bedding material (straw [ST] vs. woodchips [WD]), and application rate (13, 39, or 77 Mg ha) on repellency of a clay loam soil after 17 annual applications. The repellency was determined on all 14 treatments using the water repellency index ( index), the water drop penetration time (WDPT) method, and molarity of ethanol (MED) test. The C composition of particulate organic matter in soil of five selected treatments after 16 annual applications was also determined using C nuclear magnetic resonance-direct polarization with magic angle spinning (NMR-DPMAS). Manure type had no significant ( > 0.05) effect on index and WDPT, and MED classification was similar. Mean index and WDPT values were significantly greater and MED classification more hydrophobic for WD than ST. Application rate had no effect on the index, but WDPT was significantly greater and MED classification more hydrophobic with increasing application rate. Strong ( > 0.7) but nonsignificant positive correlations were found between index and WDPT versus hydrophobic (alkyl + aromatic) C, lignin at 74 ppm (O-alkyl), and unspecified aromatic compounds at 144 ppm. Specific aromatic compounds also contributed more to repellency than alkyl, O-alkyl, and carbonyl compounds. Overall, all three methods consistently showed that repellency was greater for WD than ST-amended clay loam soil, but manure type had no effect. PMID- 28724098 TI - Nitrogen, Sulfur, and Oxygen Isotope Ratios of Animal- and Plant-Based Organic Fertilizers Used in South Korea. AB - Organic fertilizers are increasingly used in agriculture in Asia and elsewhere. Tracer techniques are desirable to distinguish the fate of nutrients added to agroecosystems with organic fertilizers from those contained in synthetic fertilizers. Therefore, we determined the nitrogen, sulfur, and oxygen isotope ratios of nitrogen- and sulfur-bearing compounds in animal- and plant-based organic fertilizers (ABOF and PBOF, respectively) used in South Korea to evaluate whether they are isotopically distinct. The deltaN values of total and organic nitrogen for ABOF ranged from +7 to +190/00 and were higher than those of PBOF (generally <+60/00). This suggests that ABOFs have distinct deltaN values suitable for tracing these fertilizer compounds in the plant-soil-water system, whereas PBOFs have similar deltaN values to synthetic fertilizers. However, deltaO values for nitrate (deltaO) from organic fertilizer samples (<+17.00/00) were consistently lower than those of synthetic nitrate-containing fertilizers. The deltaS values of total sulfur, organic sulfur compounds (e.g., carbon-bonded sulfur and hydriodic acid-reducible sulfur), and sulfate for ABOFs yielded wide and overlapping ranges of +0.3 to +6.3, +0.9 to +7.2, and -2.6 to +14.20/00, whereas those for PBOFs varied from -3.4 to +7.7, +1.4 to +9.4, and -4.1 to +12.50/00, respectively, making it challenging to distinguish the fate of sulfur compounds from ABOF and PBOF in the environment using sulfur isotopes. We conclude that the deltaN values of ABOFs and the O values of organic fertilizers are distinct from those of synthetic fertilizers and are a promising tool for tracing the fate of nutrients added by organic fertilizers to agroecosystems. PMID- 28724099 TI - Use of delta15N and delta18O Values for Nitrate Source Identification under Irrigated Crops: A Cautionary Vadose Zone Tale. AB - Source nitrogen (N) identification of leachate or groundwater nitrate is complicated by N source mixing and N and oxygen (O) isotope fractionation caused by microbial N transformations. This experiment examined the deltaN and deltaO values in leachate collected over 1 yr at 55 cm below raspberry ( L.) plots receiving either synthetic fertilizer (FT) or poultry manure (MT). The large ranges of deltaN (FT: -2.4 to +8.70/00, MT: +1.6 to +9.60/00) and deltaO (FT: 9.9 to -0.30/00, MT: -10.9 to +1.70/00) values in leachate collected under crop rows prohibited the reliable identification of the applied N sources on individual sampling dates. However, the mass-weighted average deltaN (FT: +3.20/00, MT: +7.30/00) values in leachate were significantly different and can be explained by accounting for the estimated contributions of nitrate and deltaN values of the various N sources, including applied fertilizer (-0.70/00) or manure (+7.90/00), nitrate-rich irrigation water (+9.00/00), and nitrate from soil N mineralization and nitrification (FT: +3.70/00, MT: +4.60/00; the seasonal timing of which is unknown). This study illustrates the importance of characterizing all major N sources and considering the seasonal variation of these sources and of N cycling processes, as they contribute to the deltaN values of leachate. PMID- 28724100 TI - Ammonia and Nitrous Oxide Emissions from Broiler Houses with Downtime Windrowed Litter. AB - An emerging poultry manure management practice is in-house windrowing to disinfect the litter. However, this practice is likely to increase emissions of ammonia (NH) and nitrous oxide (NO) from the windrowed litter. The objective of this study was to quantitatively compare NH and NO emissions from broiler houses with and without in-house windrowing. Two broiler houses at a commercial farm were used to compare the NH and NO emissions. Gas emission measurements were conducted continuously and simultaneously for both the control house (without windrowing) and the house with windrowing during the same production periods. The house emission rates were calculated by multiplying the hourly mean gas concentrations and the ventilation rates. The windrowed litter temperature was significantly higher than that of the control litter. The impact of downtime (the time lapse between flocks, during which the bird house is empty) windrowing litter on pathogen reduction was inconclusive because of very low or no recovery of both and spp. from control or windrowed litter samples, respectively. The windrowing house NH emissions were 26.2 and 16.6 kg d house, whereas for the control house, they were 14.6 and 12.8 kg d house in 2012 and 2013, respectively. The NO emissions from the windrowing house were also higher than those from the control house. The total NH and NO emissions from broiler houses practicing windrowing litter management were estimated to be 35.0 and 4.43 g bird, respectively, compared with 31.9 and 3.89 g bird for the control house, respectively. PMID- 28724101 TI - Assessment of the Effects of Total Emission Control Policies on Surface Water Quality in China: 2004 to 2014. AB - Water quality deterioration is a problem throughout the globe, especially in China. The Chinese government established national total emission control (TEC) policies related to the nation's surface water quality over the past 10 yr to restore, protect, and promote healthy water quality. The objective of this study is to evaluate the effects of China's TEC policies by analyzing three water quality constituents (ammonium nitrogen [NH-N], dissolved oxygen [DO], and the permanganate index [COD]) at 73 monitoring stations, which account for most of the surface waters of eastern China. The seasonal Mann-Kendall test revealed that approximately 60, 50, and 65% of stations had nonsignificant trends for COD, NH N, and DO, respectively. Concentrations of COD and NH-N significantly (alpha = 0.05) decreased by 27.4 and 38.4% at the monitoring stations over the 11-yr study period, whereas DO significantly (alpha = 0.05) increased by 24.7%. Correlation analysis indicated that the water quality improved at approximately 30% (COD) and 20% (NH-N) of monitoring sites with the reduction of water pollutant emissions from industrial sources. A seasonal pattern was observed for the three water quality parameters at most of the stations but not at a regional scale. Results also indicated that COD concentrations decreased significantly (alpha = 0.05) at most river stations but increased significantly (alpha = 0.05) at nearly all lake stations, suggesting that TEC in China might be more effective for rivers than for lakes and reservoirs. Although there are many nonsignificant relationships with the water quality constituents selected as top pollutants in China, a few noticeable significant relationships were established. PMID- 28724102 TI - Impact of Biochar Organic and Inorganic Carbon on Soil CO2 and N2O Emissions. AB - Biochar has been shown to influence soil CO and NO emissions following application to soil, but the presence of carbonates in biochars has largely confounded efforts to differentiate among labile and recalcitrant C pools in biochar and establish their timeframe of influence. Understanding the mechanism, magnitude, and duration of biochar C pools' influence on C and N dynamics is imperative to successful implementation of biochar for C sequestration. Here we therefore aim to assess biochar organic and inorganic C pool impacts on CO and NO emissions from soil amended with two untreated biochars, inorganic carbon (as NaCO), acid (HCl) and bicarbonate (NaHCO) extracts of the biochars, and acid and bicarbonate/acid-washed biochars during a 140-d soil incubation. We hypothesized that (i) both biochar labile organic carbon (LOC) and inorganic carbon (IC) pools contribute significantly to short-term (<1 mo) CO emissions from biochar-amended soil, (ii) biochars will influence the size of soil NH and NO pools, and (iii) changes in soil inorganic N pools will affect soil NO emissions. All biochar, biochar extract, and carbonate treatments (12 total) increased CO produced during the initial <=48 h of the incubation relative to controls, indicating that both biochar LOC and IC contribute to CO emissions. Of these treatments, only bicarbonate extracts of the biochars increased total C losses significantly. However, treatment impacts on soil NO production were not significant despite significant effects of select treatments on inorganic N pools. Overall, results indicate that biochars contain small LOC and IC pools that are stabilized by a larger recalcitrant organic C pool. PMID- 28724103 TI - Nematode Community Response to Green Infrastructure Design in a Semiarid City. AB - Urbanization affects ecosystem function and environmental quality through shifts in ecosystem fluxes that are brought on by features of the built environment. Green infrastructure (GI) has been suggested as a best management practice (BMP) to address urban hydrologic and ecological impacts of the built environment, but GI practice has only been studied from a limited set of climatic conditions and disciplinary approaches. Here, we evaluate GI features in a semiarid city from the perspective of soil ecology through the application of soil nematode community analysis. This study was conducted to investigate soil ecological interactions in small-scale GI as a means of assessing curb-cut rain garden basin design in a semiarid city. We looked at the choice of mulching approaches (organic vs. rock) and how this design choice affects the soil ecology of rain basins in Tucson, AZ. We sampled soils during the monsoon rain season and assessed the soil nematode community as a bioindicator of soil quality and biogeochemical processes. We found that the use of organic mulch in GI basins promotes enhanced soil organic matter contents and larger nematode populations. Nematode community indices point to enhanced food web structure in streetscape rain garden basins that are mulched with organic material. Results from this study suggest that soil management practices for GI can help promote ecological interactions and ecosystem services in urban ecosystems. PMID- 28724104 TI - Fate Characterization of Benzene Kresoxim-Methyl (a Strobilurin Fungicide) in Different Aerobic Soils. AB - Benzene kresoxim-methyl (BKM) is a promising broad-spectrum strobilurin fungicide widely used to control fungal pathogens in crops. However, information on its environmental fate is limited. To broaden our understanding of this fungicide's kinetic fate in aerobic soils, we labeled BKM with C on its benzoate ring and used ultralow-level liquid scintillation counting coupled with high-performance liquid chromatography analysis. Results show that degradation, mineralization, and bound residue (BR) formation of BKM was controlled by soil type and microbial community composition. Degradation of BKM followed first-order dynamics, and the half-lives () were 51.7, 30.8, and 26.8 d for clay, loamy, and saline soils, respectively. After 100 d, about 0.13, 4.35, and 5.94% of the initial C-BKM was mineralized, and 14.43, 19.90, and 28.81% was formed as BRs in the clay, loamy, and saline soils, respectively. About 60 to 85% of the C-BKM residue in soil was extractable; of this fraction, 30 to 50% was composed of incomplete degradation intermediates. Up to 40% of extractable C-BKM in soil was readily available. Our results suggest that BKM and its incomplete intermediates had a relatively long persistence in soil, which may lead to exposure for nontarget organisms. Soil microbes may play a dominant role in controlling the fate of BKM in soil as sterilization sharply decreased its mineralization rate from 4.35 to 0.03%, increased from 30.8 to 85.6 d, and decreased the BR fraction from 19.90 to 3.25%. PMID- 28724105 TI - Nitrifying Kinetics and the Persistence of Nitrite in the Seine River, France. AB - Although a higher oxidation rate for nitrite than for ammonia generally prevents nitrite accumulation in oxic waters, nitrite concentrations in the Seine River (1 31 MUM) exceed European norms. We investigated the kinetics of in situ ammonia- and nitrite-oxidizing communities in river water and wastewater treatment plant (WWTP) effluents to determine the role of pelagic nitrification in the origin and persistence of nitrite downstream of Paris. The main source of nitrite is the major Parisian WWTP, and its persistence, up to tens of kilometers downstream of the plant, is explained by low ammonia and nitrite oxidation rates and high river flow. Furthermore, similar nitrite and ammonia oxidation rates preclude a rapid consumption of both preexisting nitrite and nitrite produced by ammonia oxidation. Maximum ammonia oxidation rates are two to three times higher downstream than upstream of the WWTP, indicating the input of ammonia oxidizers and ammonia from the WWTP. In both river water and WWTP effluents, nitrite oxidizers were unable to oxidize all available nitrite. In the human-impacted Seine River, this phenomenon might be due to mixotrophy. This study highlights the low resilience of the river to nitrite contamination as well as the importance of managing nitrite, nitrifiers, and organic matter concentrations in WWTP effluents to avoid nitrite persistence in rivers. PMID- 28724107 TI - ACS324.1 JOURNAL OF ENVIRONMENTAL QUALITY EDITORIAL BOARD 2016 Annual Reports. PMID- 28724106 TI - Potential Environmental Benefits from Blending Biosolids with Other Organic Amendments before Application to Land. AB - Biosolids disposal to landfill or through incineration is wasteful of a resource that is rich in organic matter and plant nutrients. Land application can improve soil fertility and enhance crop production but may result in excessive nitrate N (NO-N) leaching and residual contamination from pathogens, heavy metals, and xenobiotics. This paper evaluates evidence that these concerns can be reduced significantly by blending biosolids with organic materials to reduce the environmental impact of biosolids application to soils. It appears feasible to combine organic waste streams for use as a resource to build or amend degraded soils. Sawdust and partially pyrolyzed biochars provide an opportunity to reduce the environmental impact of biosolids application, with studies showing reductions of NO-N leaching of 40 to 80%. However, other organic amendments including lignite coal waste may result in excessive NO-N leaching. Field trials combining biosolids and biochars for rehabilitation of degraded forest and ecological restoration are recommended. PMID- 28724108 TI - Yellow Perch (Perca flavescens) Mercury Unaffected by Wildland Fires in Northern Minnesota. AB - Wildland fire can alter mercury (Hg) cycling on land and in adjacent aquatic environments. In addition to enhancing local atmospheric Hg redeposition, fire can influence terrestrial movement of Hg and other elements into lakes via runoff from burned upland soil. However, the impact of fire on water quality and the accumulation of Hg in fish remain equivocal. We investigated the effects of fire specifically, a low-severity prescribed fire and moderate-severity wildfire-on young-of-the-year yellow perch () and lake chemistry in a small remote watershed in the Boundary Waters Canoe Area Wilderness in northeastern Minnesota. We used a paired watershed approach: the fire-affected watershed was compared with an adjacent, unimpacted (reference) watershed. Prior to fire, upland organic horizons in the two study watersheds contained 1549 MUg Hg m on average. Despite a 19% decrease in upland organic horizon Hg stocks due to the moderate severity wildfire fire, fish Hg accumulation and lake productivity were not affected by fire in subsequent years. Instead, climate and lake water levels were the strongest predictors of lake chemistry and fish responses in our study lakes over 9 yr. Our results suggest that low- to moderate-severity wildland fire does not alter lake productivity or Hg accumulation in young-of-the-year yellow perch in these small, shallow lakes in the northern deciduous and boreal forest region. PMID- 28724110 TI - Coal-Bed Methane Water: Effects on Soil Properties and Camelina Productivity. AB - Every year, the production of coal-bed natural gas in the Powder River Basin results in the discharge of large amounts of coal-bed methane water (CBMW) in Wyoming; however, no sustainable disposal methods for CBMW are currently available. A greenhouse study was conducted to evaluate the potential to use CBMW as a source of irrigation water for camelina [ (L.) Crantz]. We assessed the effects of three CBMW concentrations (0% [1:0], 50% [1:1], and 100% [0:1] tap water to CBMW) on selected soil properties, growth, seed oil, and fatty acid composition of three camelina cultivars: Blaine Creek, Ligena, and Pronghorn. The 100% CBMW reduced seed and estimated biofuel yields by 24 and 23%, respectively, but increased the oil content by 3%, relative to the control. Additionally, the 100% CBMW visibly affected soil through formation of surface crust due to elevated levels of sodium (653 mg Na kg). The 50% CBMW had no significant effects on the seed yield, estimated biofuel yield, and oil content, but the soil Na levels were still high (464 mg kg), which could pose a long-term impact on soil structure. The CBMW tended to reduce the total saturated fatty acid, but it had no significant effects on the total monounsaturated or polyunsaturated fatty acids of camelina seeds. Overall, CBMW diluted with an equal amount of good quality water could be used to irrigate camelina in the short term. Afterward, only good-quality water would have to be used until the accumulated dissolved solids are flushed out. PMID- 28724111 TI - Agricultural Conservation Planning Framework: 3. Land Use and Field Boundary Database Development and Structure. AB - Conservation planning information is important for identifying options for watershed water quality improvement and can be developed for use at field, farm, and watershed scales. Translation across scales is a key issue impeding progress at watershed scales because watershed improvement goals must be connected with implementation of farm- and field-level conservation practices to demonstrate success. This is particularly true when examining alternatives for "trap and treat" practices implemented at agricultural-field edges to control (or influence) water flows through fields, landscapes, and riparian corridors within agricultural watersheds. We propose that database structures used in developing conservation planning information can achieve translation across conservation planning scales, and we developed the Agricultural Conservation Planning Framework (ACPF) to enable practical planning applications. The ACPF comprises a planning concept, a database to facilitate field-level and watershed-scale analyses, and an ArcGIS toolbox with Python scripts to identify specific options for placement of conservation practices. This paper appends two prior publications and describes the structure of the ACPF database, which contains land use, crop history, and soils information and is available for download for 6091 HUC12 watersheds located across Iowa, Illinois, Minnesota, and parts of Kansas, Missouri, Nebraska, and Wisconsin and comprises information on 2.74 * 10 agricultural fields (available through /). Sample results examining land use trends across Iowa and Illinois are presented here to demonstrate potential uses of the database. While designed for use with the ACPF toolbox, users are welcome to use the ACPF watershed data in a variety of planning and modeling approaches. PMID- 28724112 TI - Desert Vegetation Forty Years after an Oil Spill. AB - Deserts are the most frequent locations of terrestrial crude oil contaminations. Nevertheless, the long-term effects of petroleum hydrocarbons on desert ecosystems are still unknown, which makes risk assessment and decision making concerning remediation difficult. This study examined the long-term effects of petroleum hydrocarbons on perennial desert vegetation. The study site was a hyper arid area in the south of Israel, which was contaminated by a crude oil spill in 1975. The contaminated area was compared to uncontaminated reference areas. The composition of perennial plants 40 yr after the oil spill was not significantly affected by the contamination. However, the size distribution of the two most dominant shrub species, Baker and (Moq.) Iljin., and the only tree species, Savi and (Forssk.) Hayne, were different from the reference. These differences can be explained by decreased recruitment. The estimated recruitment of in the last 40 yr post oil spill was 74% less than recruitment in the reference area. Low recruitment of may in the future lead to the loss of tree cover, which would change the entire ecosystem, as are keystone species on which a number of microorganisms, plants, and animals rely. Remediation of oil spills and preventative measures are recommended. PMID- 28724113 TI - Cost Sharing and Mental Health Care: A Cautionary Tale From the Netherlands. PMID- 28724114 TI - Oral Macrolides for the Dermatologic Manifestations of Blau Syndrome. PMID- 28724115 TI - The Efficacy of a Gain-Switched 311-nm Titanium:Sapphire Laser in the Treatment of Vitiligo: A Pilot Study of 14 Patients. PMID- 28724117 TI - What Becomes of the Brokenhearted. PMID- 28724116 TI - Use of Prescription Smoking Cessation Medications After Myocardial Infarction Among Older Patients in Community Practice. PMID- 28724118 TI - Emergency Medical Services Response Times in Rural, Suburban, and Urban Areas. PMID- 28724119 TI - Arrhythmia in Bone Marrow Transplant Unit. PMID- 28724120 TI - Scrotal Ulceration and Pyrexia. PMID- 28724121 TI - Converting Bystanders to Immediate Responders: We Need to Start in High School or Before. PMID- 28724122 TI - Association Between Patient Age and Lymph Node Positivity in Thin Melanoma. AB - Importance: More than half of all new melanoma diagnoses present as clinically localized T1 melanoma, yet sentinel lymph node biopsy (SLNB) is controversial in this population given the overall low yield. Guidelines for SLNB have focused on pathologic factors, but patient factors, such as age, are not routinely considered. Objectives: To identify indicators of lymph node (LN) metastasis in thin melanoma in a large, generalizable data set and to evaluate the association between patient age and LN positivity. Design, Setting, and Participants: A retrospective cohort study using the National Cancer Database, an oncology database representing patients from more than 1500 hospitals throughout the United States, was performed (2010-2013). Data analysis was conducted from October 1, 2016, to January 15, 2017. A total of 8772 patients with clinical stage I 0.50 to 1.0 mm thin melanoma undergoing wide excision and surgical evaluation of regional LNs were included for study. Main Outcome and Measures: The primary outcome of interest was presence of melanoma in a biopsied regional LN. Clinicopathologic factors associated with LN positivity were characterized, using logistic regression. Age was categorized as younger than 40 years, 40 to 64 years, and 65 years or older for multivariable analysis. Classification tree analysis was performed to identify high-risk groups for LN positivity. Results: Among the study cohort (n = 8772), 333 patients had nodal metastases, for an overall positivity rate of 3.8% (95% CI, 3.4%-4.2%). A total of 4087 (54.0%) patients were women. Median age was 56 years (interquartile range [IQR], 46-67) in patients with negative LNs and 52 years (IQR, 41-61) in those with positive LNs (P < .001). In multivariable analysis, younger age, female sex, thickness of 0.76 mm or larger, increasing Clark level, mitoses, ulceration, and lymphovascular invasion were independently associated with LN positivity. In decision tree analysis, patient age was identified as an important risk stratifier for LN metastases, after mitoses and thickness. Patients younger than 40 years with category T1b tumors 0.50 to 0.75 mm, who would generally not be recommended for SLNB, had an LN positivity rate of 5.6% (95% CI, 3.3%-8.6%); conversely, patients 65 years or older with T1b tumors 0.76 mm or larger, who would generally be recommended for SLNB, had an LN positivity rate of only 3.9% (95% CI, 2.7%-5.3%). Conclusions and Relevance: Patient age is an important factor in estimating lymph node positivity in thin melanoma independent of traditional pathologic factors. Age therefore should be taken into consideration when selecting patients for nodal biopsy. PMID- 28724124 TI - Gender Confirmation Surgery and Terminology in Transgender Health. PMID- 28724123 TI - Assessment of Insulin Resistance Among Drug-Naive Patients With First-Episode Schizophrenia in the Context of Hormonal Stress Axis Activation. PMID- 28724125 TI - Comparison of Wound Complications After Immediate, Delayed, and Secondary Breast Reconstruction Procedures. AB - Importance: Few data are available concerning surgical site infection (SSI) and noninfectious wound complications (NIWCs) after delayed (DR) and secondary reconstruction (SR) compared with immediate reconstruction (IR) procedures in the breast. Objective: To compare the incidence of SSI and NIWCs after implant and autologous IR, DR, and SR breast procedures after mastectomy. Design, Setting, and Participants: This retrospective cohort study included women aged 18 to 64 years undergoing mastectomy from January 1, 2004, through December 31, 2011. Data were abstracted from a commercial insurer claims database in 12 states and analyzed from January 1, 2015, through February 7, 2017. Exposures: Reconstruction within 7 days of mastectomy was considered immediate. Reconstruction more than 7 days after mastectomy was considered delayed if the mastectomy did not include IR or secondary if the mastectomy included IR. Main Outcomes and Measures: International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes for SSI and NIWCs. Results: Mastectomy was performed in 17 293 women (mean [SD] age, 50.4 [8.5] years); 61.4% of women had IR or DR. Among patients undergoing implant reconstruction, the incidence of SSI was 8.9% (685 of 7655 women) for IR, 5.7% (21 of 369) for DR, and 3.2% (167 of 5150) for SR. Similar results were found for NIWCs. In contrast, the incidence of SSI was similar after autologous IR (9.8% [177 of 1799]), DR (13.9% [19 of 137]), and SR (11.6% [11 of 95]) procedures. Compared with women without an SSI after implant IR, women with an SSI after implant IR were significantly more likely to have another SSI (47 of 412 [11.4%] vs 131 of 4791 [2.7%]) and an NIWC (24 of 412 [5.8%] vs 120 of 4791 [2.5%]) after SR. The incidence of SSI (24 of 379 [6.3%] vs 152 of 5286 [2.9%]) and NIWC (22 of 379 [5.8%] vs 129 of 5286 [2.4%]) after implant SR was higher in women who had received adjuvant radiotherapy. Wound complications after IR were associated with significantly more breast surgical procedures (mean of 1.92 procedures [range, 0-9] after implant IR and 1.11 [range, 0-6] after autologous IR) compared with women who did not have a complication (mean of 1.37 procedures [range, 0-8] after implant IR and 0.87 [range, 0-6] after autologous IR). Conclusions and Relevance: The incidence of SSI and NIWCs was slightly higher for implant IR compared with delayed or secondary implant reconstruction. Women who had an SSI or NIWC after implant IR had a higher risk for subsequent complications after SR and more breast operations. The risk for complications should be carefully balanced with the psychosocial and technical benefits of IR. Select high-risk patients may benefit from consideration of delayed rather than immediate implant reconstruction to decrease breast complications after mastectomy. PMID- 28724127 TI - In Treating Sepsis, Questions About Timing and Mandates. PMID- 28724126 TI - Comparative Outcomes After Percutaneous Coronary Intervention Among Black and White Patients Treated at US Veterans Affairs Hospitals. AB - Importance: Current comparative outcomes among black and white patients treated with percutaneous coronary intervention (PCI) in the Veterans Affairs (VA) health system are not known. Objective: To compare outcomes between black and white patients undergoing PCI in the VA health system. Design, Setting, and Participants: This study compared black and white patients who underwent PCI between October 1, 2007, and September 30, 2013, at 63 VA hospitals using data recorded in the VA Clinical Assessment, Reporting, and Tracking System for Cardiac Catheterization Laboratories (CART-CL) program. A generalized linear mixed model with a random intercept for site assessed the relative difference in odds of outcomes between black and white patients. The setting was integrated institutionalized hospital care. Excluded were all patients of other races or those with multiple listed races and those with missing data regarding race or the diagnostic cardiac catheterization. The dates of analysis were January 7, 2016, to April 17, 2017. Exposure: Percutaneous coronary intervention at a VA hospital. Main Outcomes and Measures: The primary outcome was 1-year mortality. Secondary outcomes were 30-day all-cause readmission rates, 30-day acute kidney injury, 30-day blood transfusion, and 1-year readmission rates for myocardial infarction. In addition, variations in procedural and postprocedural care were examined, including the use of intravascular ultrasound, optical coherence tomography, fractional flow reserve measurements, bare-metal stents, postprocedural medications, and radial access. Results: A total of 42 391 patients (13.3% black and 98.4% male; mean [SD] age, 65.2 [9.1] years) satisfied the inclusion and exclusion criteria. In unadjusted analyses, black patients had higher rates of 1-year mortality (7.1% vs 5.9%, P < .001) as well as secondary outcomes of 30-day acute kidney injury (20.8% vs 13.8%, P < .001), 30-day blood transfusion (3.4% vs 2.7%, P < .01), and 1-year readmission rates for myocardial infarction (3.3% vs 2.7%, P = .01) compared with white patients. After adjustment for demographics, comorbidities, and procedural characteristics, odds for 1-year mortality (odds ratio, 1.04; 95% CI, 0.90-1.19) were not different between black and white patients. There were also no differences in secondary outcomes with the exception of a higher rate of adjusted 30-day acute kidney injury (odds ratio, 1.22; 95% CI, 1.10-1.36). Conclusions and Relevance: While black patients had a higher rate of mortality than white patients in unadjusted analyses, race was not independently associated with 1-year mortality among patients undergoing PCI in VA hospitals. PMID- 28724128 TI - Topical Corticosteroid Phobia in Atopic Dermatitis: A Systematic Review. AB - Importance: Topical corticosteroid (TCS) phobia refers to the negative feelings and beliefs related to TCSs experienced by patients and patients' caregivers. This phenomenon may be a major contributing factor in treatment failure in patients with atopic dermatitis, yet it has been sparsely described in the literature. Objective: To systematically assess the nomenclature, prevalence, origins, and effect on treatment adherence of TCS phobia in atopic dermatitis. Evidence Review: A literature search was conducted using specific eligibility criteria across electronic databases, including Ovid (MEDLINE, EMBASE), PubMed, and Web of Science, for articles published from January 1, 1946, to October 31, 2016. Included articles must have assessed TCS phobia in patients with atopic dermatitis or their caregivers. Quality ratings of studies were based on a modified version of the Oxford Centre for Evidence-Based Medicine quality rating scheme for individual studies. Findings: Of the 490 articles identified by literature search, 16 met the eligibility criteria. All studies were cross sectional. Topical corticosteroid phobia prevalence ranged from 21.0% (95% CI, 15.8%-26.2%) to 83.7% (95% CI, 81.9%-85.5%). There was significant variation in how phobia was defined, ranging from concern to irrational fear. Questionnaires used to assess for TCS phobia included 1 to 69 questions. In the 2 studies that compared nonadherence between a phobia group and a nonphobia group, patients in both phobia groups were found to have a significantly higher rate of nonadherence (49.4% vs 14.1% and 29.3% vs 9.8%). The sources from which patients were receiving information about corticosteroids included physicians, friends and relatives, broadcast media, print media, and the internet. Conclusions and Relevance: Features of TCS phobia are commonly reported by patients across cultures and may be associated with a higher rate of nonadherence. Patients with TCS phobia and the sources from which patients are receiving information about corticosteroids may be targetable for intervention to increase adherence to treatment regimens. The nomenclature and assessment methods for TCS phobia used in studies, however, lack standardization, precluding quantitative comparison and extrapolation of data. Additional research, using standardized definitions and methods of assessment, is needed to better characterize this phenomenon and evaluate the efficacy of potential interventions. PMID- 28724129 TI - Association of Cost Sharing With Mental Health Care Use, Involuntary Commitment, and Acute Care. AB - Importance: A higher out-of-pocket price for mental health care may lead not only to cost savings but also to negative downstream consequences. Objective: To examine the association of higher patient cost sharing with mental health care use and downstream effects, such as involuntary commitment and acute mental health care use. Design, Setting, and Participants: This difference-in differences study compared changes in mental health care use by adults, who experienced an increase in cost sharing, with changes in youths, who did not experience the increase and thus formed a control group. The study examined all 2 780 558 treatment records opened from January 1, 2010, through December 31, 2012, by 110 organizations that provide specialist mental health care in the Netherlands. Data analysis was performed from January 18, 2016, to May 9, 2017. Exposures: On January 1, 2012, the Dutch national government increased the out-of pocket price of mental health services for adults by up to ?200 (US$226) per year for outpatient treatment and ?150 (US$169) per month for inpatient treatment. Main Outcomes and Measures: The number of treatment records opened each day in regular specialist mental health care, involuntary commitment, and acute mental health care, and annual specialist mental health care spending. Results: This study included 1 448 541 treatment records opened from 2010 to 2012 (mean [SD] age, 41.4 [16.7] years; 712 999 men and 735 542 women). The number of regular mental health care records opened for adults decreased abruptly and persistently by 13.4% (95% CI, -16.0% to -10.8%; P < .001) per day when cost sharing was increased in 2012. The decrease was substantial and significant for severe and mild disorders and larger in low-income than in high-income neighborhoods. Simultaneously, in 2012, daily record openings increased for involuntary commitment by 96.8% (95% CI, 87.7%-105.9%; P < .001) and for acute mental health care by 25.1% (95% CI, 20.8%-29.4%; P < .001). In contrast to our findings for adults, the use of regular care among youths increased slightly and the use of involuntary commitment and acute care decreased slightly after the reform. Overall, the cost-sharing reform was associated with estimated savings of ?13.4 million (US$15.1 million). However, for adults with psychotic disorder or bipolar disorder, the additional costs of involuntary commitment and acute mental health care exceeded savings by ?25.5 million (US$28.8 million). Conclusions and Relevance: Higher cost sharing for seriously ill and low-income patients could discourage treatment of vulnerable populations and create substantial downstream costs. PMID- 28724131 TI - Gender Confirmation Surgery and Terminology in Transgender Health. PMID- 28724130 TI - Early Postimplant Speech Perception and Language Skills Predict Long-Term Language and Neurocognitive Outcomes Following Pediatric Cochlear Implantation. AB - Purpose: We sought to determine whether speech perception and language skills measured early after cochlear implantation in children who are deaf, and early postimplant growth in speech perception and language skills, predict long-term speech perception, language, and neurocognitive outcomes. Method: Thirty-six long term users of cochlear implants, implanted at an average age of 3.4 years, completed measures of speech perception, language, and executive functioning an average of 14.4 years postimplantation. Speech perception and language skills measured in the 1st and 2nd years postimplantation and open-set word recognition measured in the 3rd and 4th years postimplantation were obtained from a research database in order to assess predictive relations with long-term outcomes. Results: Speech perception and language skills at 6 and 18 months postimplantation were correlated with long-term outcomes for language, verbal working memory, and parent-reported executive functioning. Open-set word recognition was correlated with early speech perception and language skills and long-term speech perception and language outcomes. Hierarchical regressions showed that early speech perception and language skills at 6 months postimplantation and growth in these skills from 6 to 18 months both accounted for substantial variance in long-term outcomes for language and verbal working memory that was not explained by conventional demographic and hearing factors. Conclusion: Speech perception and language skills measured very early postimplantation, and early postimplant growth in speech perception and language, may be clinically relevant markers of long-term language and neurocognitive outcomes in users of cochlear implants. Supplemental materials: https://doi.org/10.23641/asha.5216200. PMID- 28724132 TI - Applying an Integrative Framework of Executive Function to Preschoolers With Specific Language Impairment. AB - Purpose: The first goal of this research was to compare verbal and nonverbal executive function abilities between preschoolers with and without specific language impairment (SLI). The second goal was to assess the group differences on 4 executive function components in order to determine if the components may be hierarchically related as suggested within a developmental integrative framework of executive function. Method: This study included 26 4- and 5-year-olds diagnosed with SLI and 26 typically developing age- and sex-matched peers. Participants were tested on verbal and nonverbal measures of sustained selective attention, working memory, inhibition, and shifting. Results: The SLI group performed worse compared with typically developing children on both verbal and nonverbal measures of sustained selective attention and working memory, the verbal inhibition task, and the nonverbal shifting task. Comparisons of standardized group differences between executive function measures revealed a linear increase with the following order: working memory, inhibition, shifting, and sustained selective attention. Conclusion: The pattern of results suggests that preschoolers with SLI have deficits in executive functioning compared with typical peers, and deficits are not limited to verbal tasks. A significant linear relationship between group differences across executive function components supports the possibility of a hierarchical relationship between executive function skills. PMID- 28724133 TI - A Nationwide Analysis of Cost Variation for Autologous Free Flap Breast Reconstruction. AB - Importance: Cost variation among hospitals has been demonstrated for surgical procedures. Uncovering these differences has helped guide measures taken to reduce health care spending. To date, the fiscal consequence of hospital variation for autologous free flap breast reconstruction is unknown. Objective: To investigate factors that influence cost variation for autologous free flap breast reconstruction. Design, Setting, and Participants: A secondary cross sectional analysis was performed using the Healthcare Cost and Utilization Project National Inpatient Sample database from 2008 to 2010. The dates of analysis were September 2016 to February 2017. The setting was a stratified sample of all US community hospitals. Participants were female patients who were diagnosed as having breast cancer or were at high risk for breast cancer and underwent autologous free flap breast reconstruction. Main Outcomes and Measures: Variables of interest included demographic data, hospital characteristics, length of stay, complications (surgical and systemic), and inpatient cost. The study used univariate and generalized linear mixed models to examine associations between patient and hospital characteristics and cost. Results: A total of 3302 patients were included in the study, with a median age of 50 years (interquartile range, 44-57 years). The mean cost for autologous free flap breast reconstruction was $22 677 (interquartile range, $14 907-$33 391). Flap reconstructions performed at high-volume hospitals were significantly more costly than those performed at low-volume hospitals ($24 360 vs $18 918, P < .001). Logistic regression demonstrated that hospital volume correlated with increased cost (Exp[beta], 1.06; 95% CI, 1.02-1.11; P = .003). Fewer surgical complications (16.4% [169 of 1029] vs 23.7% [278 of 1174], P < .001) and systemic complications (24.2% [249 of 1029] vs 31.2% [366 of 1174], P < .001) were experienced in high volume hospitals compared with low-volume hospitals. Flap procedures performed in the West were the most expensive ($28 289), with a greater odds of increased expenditure (Exp[beta], 1.53; 95% CI, 1.46-1.61; P < .001) compared with the Northeast. A significant difference in length of stay was found between the West and Northeast (odds ratio, 1.25; 95% CI, 1.17-1.33). Conclusions and Relevance: There is significant cost variation among patients undergoing autologous free flap breast reconstruction. Experience, as measured by a hospital's volume, provides quality health care with fewer complications but is more costly. Longer length of stay contributed to regional cost variation and may be a target for decreasing expenditure, without compromising care. In the era of bundled health care payment, strategies should be implemented to eliminate cost variation to condense spending while still providing quality care. PMID- 28724135 TI - I Do Not Have Heart Disease-Should I Be Taking Aspirin? PMID- 28724140 TI - Gender Confirmation Surgery and Terminology in Transgender Health-Reply. PMID- 28724134 TI - Association of Implantable Cardioverter Defibrillators With Survival in Patients With and Without Improved Ejection Fraction: Secondary Analysis of the Sudden Cardiac Death in Heart Failure Trial. AB - Importance: Improvement in left ventricular ejection fraction (EF) to >35% occurs in many patients with reduced EF at baseline. To our knowledge, whether implantable cardioverter defibrillator (ICD) therapy improves survival for these patients is unknown. Objective: To examine the efficacy of ICD therapy in reducing risk of all-cause mortality and sudden cardiac death among patients with an EF <=35% at baseline, with or without an improvement in EF to >35% during follow-up. Design, Setting, and Participants: This retrospective analysis examined data collected in the Sudden Cardiac Death in Heart Failure Trial (SCD HeFT), which randomly assigned 2521 patients to placebo, amiodarone, or ICD between 1997 and 2001. A subset of 1902 participants (75.4%) of the SCD-HeFT had a repeated assessment of EF a mean (SD) of 13.5 (6) months after randomization. We stratified these patients by EF <=35% and >35% based on the first repeated EF measurement after randomization and compared all-cause mortality in 649 patients randomized to placebo vs 624 patients randomized to ICD. Follow-up started with the repeated EF assessment. Analysis was performed between January 2016 and July 2016. Exposures: Implantable cardioverter-defibrillator therapy. Main Outcomes and Measures: All-cause mortality and sudden cardiac death. Results: Of the included 1273 patients, the mean (SD) age was 59 (12) years, and 977 (76.7%) were male and 1009 (79.3%) were white. Repeated EF was >35% in 186 participants (29.8%) randomized to ICD and 185 participants (28.5%) randomized to placebo. During a median follow-up of 30 months, the all-cause mortality rate was lower in the ICD vs placebo group, both in patients whose EF remained <=35% (7.7 vs 10.7 per 100 person-year follow-up) and in those whose EF improved to >35% (2.6 vs 4.5 per 100 person-year follow-up). Compared with placebo, the adjusted hazard ratio for the effect of ICD on mortality was 0.64 (95% CI, 0.48-0.85) in patients with a repeated EF of <=35% and 0.62 (95% CI, 0.29-1.30) in those with a repeated EF >35%. There was no interaction between treatment assignment and repeated EF for predicting mortality. Conclusions and Relevance: Among participants in the SCD HeFT who had a repeated EF assessment during the course of follow-up, those who had an improvement in EF to >35% accrued a similar relative reduction in mortality with ICD therapy as those whose EF remained <=35%. Prospective randomized clinical trials are needed to test ICD efficacy in patients with an EF >35%. Trial Registration: clinicaltrials.gov Identifier: NCT01114269. PMID- 28724141 TI - Selecting Patients With Thin Melanoma for Sentinel Lymph Node Biopsy-This Time It's Personal. PMID- 28724142 TI - The Aging Physician and the Medical Profession: A Review. AB - Importance: The issue of the aging physician and when to cease practice has been controversial for many years. There are reports of prominent physicians who practiced after becoming dangerous in old age, but the profession has not demonstrated the ability to prevent this. A mandatory retirement age could be discriminatory and take many competent physicians out of practice and risk a physician shortage. An increasing body of evidence regarding the relationship between physicians' age and performance has led organizations, such as the American College of Surgeons, to revisit this challenge. Observations: Since 1975, the number of practicing physicians older than 65 years in the United States has increased by more than 374%, and in 2015, 23% of practicing physicians were 65 years or older. Research shows that between ages 40 and 75 years, the mean cognitive ability declines by more than 20%, but there is significant variability from one person to another, indicating that while some older physicians are profoundly impaired, others retain their ability and skills. There are age-based requirements for periodic testing and/or retirement for many professions including pilots, judges, air traffic controllers, Federal Bureau of Investigation employees, and firefighters. While there are not similar requirements for physicians, a few hospitals have introduced mandatory age-based evaluations. Conclusions: As physicians age, a required cognitive evaluation combined with a confidential, anonymous feedback evaluation by peers and coworkers regarding wellness and competence would be beneficial both to physicians and their patients. While it is unlikely that this will become a national standard soon, individual health care organizations could develop policies similar to those present at a few US institutions. In addition, large professional organizations should identify a range of acceptable policies to address the aging physician while leaving institutions flexibility to customize the approach. Absent robust professional initiatives in this area, regulators and legislators may impose more draconian measures. PMID- 28724143 TI - Potentially Avoidable Surgical Intensive Care Unit Admissions and Disposition Delays. AB - Importance: High health care costs encourage initiatives that avoid overuse of resources and identify opportunities to promote appropriate care. Objective: To investigate the causes of potentially avoidable surgical intensive care unit (SICU) admissions and disposition delays to determine whether targeted interventions could decrease these stays. Design, Setting, and Participants: This prospective, observational study focused on potentially avoidable SICU days, as determined by observers with input from the rounding intensivists at a 24-bed open SICU at an urban, academic hospital. The preintervention phase occurred from April 6 through June 21, 2015; after implementation of targeted interventions, the postintervention phase occurred from April 4 through June 28, 2016. Data collected included demographic characteristics, reason for admission, and length of stay. All patients admitted to the SICU during the preintervention and postintervention phases were included in the analysis. Interventions: Based on results collected in the preintervention phase, targeted interventions were designed and implemented from July 1, 2015, through March 31, 2016, including (1) reducing SICU care for minor traumatic brain injury, (2) optimizing postoperative airway management, (3) enhancing communication between services regarding transfers to the SICU, (4) identifying and facilitating more timely end-of-life conversations and supportive care consultations, and (5) encouraging early disposition of patients to floor beds. Main Outcomes and Measures: Changes in the proportion of potentially avoidable SICU days owing to potentially avoidable admissions and/or disposition delays. Results: A total of 459 patients (253 men [55.1%] and 206 women [44.9%]; median age, 62 years [interquartile range, 46-75 years]) were admitted during the preintervention and postintervention phases. Of 261 patients admitted during the preintervention period and 245 during the postintervention period, median SICU and hospital length of stay remained unchanged. A reduction was noted in the percentage of postintervention SICU days owing to potentially avoidable admissions (152 of 1168 days [13%] vs 118 of 1338 days [8.8%]; P = .001) and disposition delays (138 of 1168 days [11.8%] vs 97 of 1338 days [7.2%]; P < .001). During the postintervention period, decreases were noted in the SICU days related to the most common sources of potentially avoidable admissions (SICU stay <=24 hours, airway concerns, and somnolence) and disposition delays (end-of-life decisions and floor bed unavailable) as well as in the overall rate of potentially avoidable days (269 of 1168 days [23%] vs 205 of 1338 days [15.3%]; P < .001). Conclusions and Relevance: Nearly one-fourth of SICU days could be categorized as potentially avoidable. Targeted interventions resulted in a significant reduction of potentially avoidable SICU days. PMID- 28724144 TI - Evolution of Surgical Aortic Valve Replacement in the Era of Transcatheter Valve Technology. PMID- 28724145 TI - Tense Marking in the English Narrative Retells of Dual Language Preschoolers. AB - Purpose: This longitudinal study investigated the emergence of English tense marking in young (Spanish-English) dual language learners (DLLs) over 4 consecutive academic semesters, addressing the need for longitudinal data on typical acquisition trajectories of English in DLL preschoolers. Method: Language sample analysis was conducted on 139 English narrative retells elicited from 39 preschool-age (Spanish-English) DLLs (range = 39-65 months). Growth curve models captured within- and between-individual change in tense-marking accuracy over time. Tense-marking accuracy was indexed by the finite verb morphology composite and by 2 specifically developed adaptations. Individual tense markers were systematically described in terms of overall accuracy and specific error patterns. Results: Tense-marking accuracy exhibited significant growth over time for each composite. Initially, irregular past-tense accuracy was higher than regular past-tense accuracy; over time, however, regular past-tense marking outpaced accuracy on irregular verbs. Conclusions: These findings suggest that young DLLs can achieve high tense-marking accuracy assuming 2 years of immersive exposure to English. Monitoring the growth in tense-marking accuracy over time and considering productive tense-marking errors as partially correct more precisely captured the emergence of English tense marking in this population with highly variable expressive language skills. Supplemental Materials: https://doi.org/10.23641/asha.5176942. PMID- 28724146 TI - Community Participation in Medical Education. PMID- 28724147 TI - Community and Interns' Perspectives on Community-Participatory Medical Education: From Passive to Active Participation. AB - BACKGROUND AND OBJECTIVES: The use of community-based medical education as a method of learning primary care is now common worldwide. However, in many cases community participation remains passive. This study sought to explore the effects of introducing community members into medical education as active teachers. Medical education taught directly by community members might be a key to comprehensive community-based learning. METHODS: This study was conducted in Japan at two postgraduate programs in community hospitals. We asked 10 community groups and 10 interns to join our 2-year "participatory" community curriculum continuously. Questionnaires completed by 10 interns and 77 community members were analyzed quantitatively. Audio-recorded and transcribed interview data from 10 interns and 39 community members were read iteratively and analyzed qualitatively. RESULTS: Community members who participated in groups with the interns gave higher scores on approval of and willingness to participate in such experiences. Interns scored higher on their view of the importance and preferences to work with the community. In the qualitative analysis, health oriented behavior, social connectedness, and shaping community orientation among doctors emerged as important for community members. Important themes that emerged from the interns' interviews were: taking responsibility for shared understanding, community-oriented focus, valuing community nurses, and tension from competing demands. CONCLUSIONS: Interaction between interns and community members had positive effects for both. Community-participatory medical education could present a further step in the evolution of community-based medical education, one that is closest to community. Finding a balance between the time dedicated to working at the hospital and in the community proved to be essential to the success of this curriculum. PMID- 28724148 TI - Integrative Medicine in Residency: Feasibility and Effectiveness of an Online Program. AB - BACKGROUND AND OBJECTIVES: Online curricular interventions in residency have been proposed to address challenges of time, cost, and curriculum consistency. This study is designed to determine the feasibility and effectiveness of a longitudinal, multisite online curriculum in integrative medicine (IMR) for residents. METHODS: Residents from eight family medicine programs undertook the 200-hour online IMR curriculum. Their medical knowledge (MK) scores at completion were compared to a control group from four similar residency programs. Study and control groups were comparable in baseline demographics, and MK scores. Course completion, MK scores, and course evaluations were assessed. RESULTS: Of 186 IMR residents, 76.9% met completion requirements. The IMR group showed statistically significant higher MK scores at residency completion, the control group did not (IMR: 79.2% vs. CONTROL: 53.2% mean correct). Over three-fourths of IMR participants (range 79-92%) chose the top two rating categories for each course evaluation item. In an exit survey, ability to access the curriculum for 1 additional year and intention to utilize IM approaches after residency were the highest ranked items. CONCLUSIONS: The demonstrated feasibility, effectiveness, and positive evaluations of the IMR curriculum indicate that a multisite, online curricular intervention is a potentially viable approach to offering new curriculum with limited on-site faculty expertise for other family medicine residencies. PMID- 28724149 TI - Using Reflections to Evaluate the STFM Behavioral Science/Family Systems Educator Fellowship. AB - BACKGROUND AND OBJECTIVES: A group of family medicine educators identified a need and developed a 1-year fellowship for early career behavioral science educators. This occurred in response to a reduction in previous opportunities and resources. The program was designed to shape and mentor new behavioral science faculty teaching in family medicine departments and programs. Quantitative data analysis from pre- and post-fellowship survey data from years 1-4 confirmed fellowship objectives were met. METHODS: The 1-year fellowship, developed by senior faculty in STFM features a blend of classroom style learning, mentored small-group interactions, reflective writing and a scholarly project requirement. As one aspect of program evaluation, reflective writings submitted by fellows and faculty were analyzed using qualitative methodology for themes related to curricular objectives. RESULTS: From 2010-2013, 44 fellows completed the program. Authors analyzed reflective writings from 15 fellows and 6 small-group mentors. Four overarching themes emerged: emerging professional competence, evolving professional identity, connectedness, and generativity. An unexpected finding was that the fellowship mentors benefited in ways parallel to that of the fellows. CONCLUSIONS: A qualitative analytical approach to examining the reflective writings of fellowship participants yielded confirmation that program goals were achieved. In addition, a commitment to "paying it forward" as ongoing and future leaders in family medicine education resulted for both fellows and faculty mentors. PMID- 28724150 TI - Pregnancy Options Counseling and Abortion Referrals Among US Primary Care Physicians: Results From a National Survey. AB - BACKGROUND AND OBJECTIVES: Primary care physicians (PCPs) can play a critical role in addressing unintended pregnancy through high-quality options counseling and referrals. METHODS: We surveyed a nationally representative sample of 3,000 PCPs in general, family, and internal medicine on practices and opinions related to options counseling for unintended pregnancy. We assessed predictors of physician practices using multivariable logistic regression weighted for sampling design and differential non-response. RESULTS: Response rate was 29%. Seventy-one percent believed residency training in options counseling should be required, and 69% believed PCPs have an obligation to provide abortion referrals even in the presence of a personal objection to abortion. However, only 26% reported routine options counseling when caring for women with unintended pregnancy compared to 60% who routinely discuss prenatal care. Among physicians who see women seeking abortion, 62% routinely provide referrals, while 14% routinely attempt to dissuade women. Family physicians were more likely to provide routine options counseling when seeing patients with unintended pregnancy than internal medicine physicians (32% vs 21%, P=0.002). In multivariable analyses, factors associated with higher odds of routine abortion referrals were more years in practice (OR=1.03 for each additional year, 95% CI: 1.00-1.05), identifying as a woman vs a man (OR=2.11, 95% CI: 1.31-3.40), practicing in a hospital vs private primary care/multispecialty setting (OR=3.17, 95% CI: 1.10-9.15), and no religious affiliation of practice vs religious affiliation (OR for Catholic affiliation=0.27, 95% CI: 0.11-0.66; OR for other religious affiliation=0.36, 95% CI: 0.15-0.83). Personal Christian religious affiliation among physicians who regularly attend religious services vs no religious affiliation was associated with lower odds of counseling (OR=0.48, 95% CI: 0.26-0.90) and referrals (OR=0.31, 95% CI: 0.15-0.62), and higher odds of abortion dissuasion (OR=4.03, 95% CI: 1.46-11.14). CONCLUSIONS: Findings reveal the need to support fuller integration of options counseling and abortion referrals in primary care, particularly through institutional and professional society guidelines and training opportunities to impart skills and highlight the professional obligation to provide non-directive information and support to women with unintended pregnancy. PMID- 28724151 TI - Assessment of Addiction Medicine Training in Family Medicine Residency Programs: A CERA Study. AB - BACKGROUND AND OBJECTIVES: Substance use disorder (SUD) is a widespread problem but physicians may feel inadequately prepared to provide addiction care. We sought to assess current addiction medicine curricula in US family medicine residencies (FMRs) and evaluate barriers to improving or implementing addiction medicine curricula. METHODS: Questions regarding addiction medicine training were added to the December 2015 Council of Academic Family Medicine Educational Research Alliance (CERA) survey to US FMR program directors to evaluate each FMR's curriculum, potential workforce production, perceived barriers to improving or implementing curricula and faculty training in addiction medicine. RESULTS: Of 461 FMR directors, 227 (49.2%) responded; 28.6% reported a required addiction medicine curricula. Regional variations of having a required curriculum ranged from 41.3% in the Northeast to 20.0% in the South (P=0.07). Of residencies, 31.2% had at least one graduate obtain a buprenorphine prescription waiver in the past year and 8.6% had at least one graduate pursue an addiction medicine fellowship in the past 5 years. Lack of faculty expertise was the most commonly cited barrier to having a curriculum, with only 36.2% of programs having at least one buprenorphine waivered faculty member, 9.4% an addiction medicine board certified faculty, and 5.5% a fellowship trained faculty. CONCLUSIONS: Few FMRs have addiction medicine curricula and most graduates do not seek additional training. Multifaceted efforts, including developing model national curricula, training existing faculty, and recruiting addiction trained faculty, may improve addiction medicine training in family medicine residencies to better address the growing SUD epidemic. PMID- 28724152 TI - Cost of Incremental Expansion of an Existing Family Medicine Residency Program. AB - BACKGROUND AND OBJECTIVES: Expanding residency training programs to address shortages in the primary care workforce is challenged by the present graduate medical education (GME) environment. The Medicare funding cap on new GME positions and reductions in the Health Resources and Services Administration (HRSA) Teaching Health Center (THC) GME program require innovative solutions to support primary care residency expansion. Sparse literature exists to assist in predicting the actual cost of incremental expansion of a family medicine residency program without federal or state GME support. METHODS: In 2011 a collaboration to develop a community health center (CHC) academic medical partnership (CHAMP), was formed and created a THC as a training site for expansion of an existing family medicine residency program. The cost of expansion was a critical factor as no Federal GME funding or HRSA THC GME program support was available. Initial start-up costs were supported by a federal grant and local foundations. Careful financial analysis of the expansion has provided actual costs per resident of the incremental expansion of the residencyRESULTS: The CHAMP created a new THC and expanded the residency from eight to ten residents per year. The cost of expansion was approximately $72,000 per resident per year. CONCLUSIONS: The cost of incremental expansion of our residency program in the CHAMP model was more than 50% less than that of the recently reported cost of training in the HRSA THC GME program. PMID- 28724153 TI - Actual and Standardized Patient Evaluations of Medical Students' Skills. AB - BACKGROUND AND OBJECTIVES: Physicians must communicate effectively with patients. Actual patients (APs) rarely evaluate medical students' clinical skills; instead, standardized patients (SPs) provide proxy ratings. It is unclear how well SP ratings mirror AP experiences. The aim of this study was to compare AP and SP assessments of medical students' communication skills and professionalism. We hypothesized that their perspectives would be similar, but distinct, and offer insight about how to more reliably include the patient's voice in medical education. METHODS: Using a mixed methods design, data were gathered from both APs and SPs using a modified SEGUE (Set the stage, Elicit information, Give information, Understand the patient's perspective, End the encounter) framework. Authors analyzed Likert-scale surveys using Spearman's rho (rho) correlations, and qualitatively analyzed open-ended comments about students' interpersonal skills and professionalism. RESULTS: For APs, the domains of "trusted the student," "discussed treatment," and "reviewed next steps" were positively correlated with whether they would recommend the student to others (rho.89, rho.89, rho.88, respectively, all P<.001). For SPs, feeling like they "trusted the student," "student appeared professionally competent," and "made personal connection" were most highly correlated with recommending the student to others (rho.86, rho.86, rho.76, respectively, all P<.001). CONCLUSIONS: Feedback from APs provides unique perspectives, complementing those of SPs, and prompts insights into incorporating patients' voices and values into training. Students may benefit from learning experiences focused on sharing and clarifying information. Providing opportunities for deliberate practice and feedback during both AP and SP encounters may enhance mastery of these skills. PMID- 28724154 TI - Mapping Residency Global Health Experiences to the ACGME Family Medicine Milestones. AB - BACKGROUND AND OBJECTIVES: Global health (GH) experiences are a unique part of family medicine (FM) training that offer an opportunity for residents to demonstrate development across a multitude of the milestones recently implemented by the Accreditation Council for Graduate Medical Education (ACGME). The GH experience presents an opportunity for resident development, and including a component of written reflection can provide tangible evidence of development in areas that can be difficult to assess. METHODS: A mixed methods approach was used to integrate quantitative (frequency) data with qualitative content from the written reflections of 12 of our FM residents who participated in GH experiences. RESULTS: Written reflections touched on each of the 22 milestones, although some milestones were noted more frequently than others. The most commonly identified milestones fell within the competency areas of systems-based practice, professionalism, and practice-based learning and improvement. Our qualitative approach allowed us to gain an appreciation of the unique experiences that demonstrated growth across the various milestones. CONCLUSIONS: We conclude that any program that offers GH experiences should incorporate some form of written reflection to maximize resident growth and offer evaluative faculty a window into that development. PMID- 28724155 TI - A Family Systems Curriculum: Back to the Future? AB - BACKGROUND AND OBJECTIVES: Although both residents and teaching faculty endorse its value, a recent review of family medicine residency programs confirms minimal formal family systems theory training. We consider the historical context of family systems training in family medicine and other competing priorities in practice and residency curricula. METHODS: We developed a longitudinal family systems curriculum, delivered in the third year of a 4-year residency program, and evaluated 2 years of the program using scales to assess self-reported confidence, knowledge and skills. RESULTS: Our curriculum evaluation showed significant improvement in all self-rating scales for all resident participants. CONCLUSIONS: We concluded the curriculum was successful in generating greater appreciation of family systems thinking and increased self-reported knowledge and skills for intervening and supporting families in the clinical setting. Further study is needed to evaluate change in clinical practice and whether these changes will be sustainable. PMID- 28724156 TI - Premonitions. PMID- 28724157 TI - Final Touches. PMID- 28724161 TI - Burnout: Lewin's Heuristic, Athletes' Preparation, and Unionization. PMID- 28724162 TI - [Psychosis, Intoxication or Serotonin Syndrome? - A 20-Year Old Male with Ziprasidone und Sertraline]. AB - A young male with schizophrenia, dependence syndrome (multiple drug use) and a severe depressive episode develops a serotonin syndrome with Sertraline and Ziprasidone. Making the correct diagnosis, although potentially challenging, remains vital. PMID- 28724163 TI - [How Active is the Catholic Church in the Prevention of Sexual Abuse? Preliminary Results of the MHG-Study]. AB - OBJECTIVE: A subproject of the study "Sexual abuse of minors by Catholic priests and deacons in the authority of the German Bishops' conference" deals with aspects of prevention. METHOD: Structured questions were used to record objective data on preventive work. The questionnaire was completed in all 27 dioceses of Germany. RESULTS: The average hourly rate available for the work of the prevention officers is about 30 hours per week. At the end of 2014, 59 % of clerics were involved in preventive training. The temporal extent of prevention training differs greatly between individual dioceses. DISCUSSION: The Catholic Church of Germany has undertaken extensive efforts to implement a comprehensive prevention work to avoid sexual abuse of minors within catholic institutions. However, there are considerable differences between the individual dioceses. PMID- 28724164 TI - Predictive Characteristics of Elevated 1-Hour Glucose Challenge Test Results for Gestational Diabetes. PMID- 28724165 TI - Cytogenotoxicity of Inclusion Complexes of Diazepam with 2-Hydroxypropyl-beta cyclodextrin. AB - Background Diazepam, as one of the most frequent prescribed drug from 1,4 benzodiazepine group, has certain limitations in pharmaceutical technology due to its poor solubility in water. By forming inclusion complexes with 2-hydroxypropyl beta-cyclodextrin, diazepam's biopharmaceutical properties can be greatly improved. Aim Aim of this research was to in vitro evaluate genotoxicity of prepared novel complexes of diazepam and their influence on proliferation of human peripheral blood lymphocytes. Methods For identification of possible genotoxicity of diazepam inclusion complexes, cytokinesis-block micronucleus assay has been chosen. Evaluated concentrations of two diazepam inclusion complexes were 0.2 ug/mL, 0.5 ug/mL and 1.0 ug/mL in cell culture. For a reference, in vitro cytogenotoxicity evaluation of diazepam alone has been conducted as well. Results Neither one of the diazepam, complexed nor non complexed, in given concentrations showed genotoxicity, induced genetic damage or loss of genetic material. Conclusions Nuclear division index values, as indicators of cytostaticity and cytotoxicity suggested that investigated inclusion diazepam complexes induced accelerated proliferation of human peripheral blood lymphocytes in vitro, therefore possibly shortening the duration and dynamics of the cell cycle. PMID- 28724166 TI - Iron Pharmacokinetics in Women with Iron Deficiency Anaemia Following A Single Oral Dose of a Novel Formulation of Tardyferon (Prolonged Release Ferrous Sulphate). AB - Numerous iron-containing preparations are available on the market; these vary in dosage, salt, chemical state of iron (ferric or ferrous) and in the iron delivery process (immediate or prolonged-release). Tardyferon(r) is a prolonged-release tablet containing 80 mg ferrous sulphate. The formulation has recently been modified; changes to the excipients which constitute the inert formulation matrix have allowed a decrease in tablet size for easier swallowing. The aim of this multicenter open-label study was to characterize the serum pharmacokinetics of iron in non-pregnant women aged 23-45 years with iron deficiency anaemia (IDA) following single oral administration of 160 mg Tardyferon(r) under fasting conditions. Blood samples were collected from the 29 participants before dosing and until 24 h post-dosing. Serum iron concentrations were determined using a routine colorimetric analytical method; pharmacokinetic parameters were derived using a non-compartmental approach. In these patients, median time to maximum serum concentrations (Tmax) was 4 h. Serum profiles were consistent with prolonged release; iron levels were elevated up to 12 h after dosing, with mean C12h still more than 7 times higher than baseline (CT0), and mean C2h and C8h representing 69.7% and 81.9% of the Cmax, respectively. In vitro dissolution testing performed on the clinical batch also demonstrated prolonged release of iron from this formulation. A single oral dose of 160 mg Tardyferon(r) administered under fasting conditions to this target population resulted in a long-lasting release of iron in the gastrointestinal tract, leading to optimal iron absorption. Moreover, Tardyferon(r) was well tolerated. PMID- 28724167 TI - In vitro Controlled Release of two new Tuberculocidal Adamantane Aminoethers from Solid Pharmaceutical Formulations (II). AB - The aim of the present investigation was to develop matrix tablet formulations for the in vitro controlled release of two new tuberculocidal adamantane aminoethers (compounds III and IV), congeneric to the adamantane derivative SQ109, which is in final clinical trials, and aminoethers (I) and (II), using carefully selected excipients, such as polyvinylpyrrolidone, sodium alginate and lactose. The tablets were prepared using the direct compression method and dissolution experiments were conducted using the US Pharmacopoeia type II apparatus (paddle method) in gastric and intestinal fluids. The results suggest that both analogues, albeit more lipophilic than SQ109, and aminoethers (I) and (II), have the requisite in vitro release characteristics for oral administration. In conclusion, these formulations merit further assessment by conducting in vivo studies, at a later stage. PMID- 28724168 TI - ? AB - For patients with type 2 diabetes mellitus, glucagon-like peptide-1 receptor agonists (GLP-1RAs) generally exert robust glucose-lowering effects that are at least as effective as insulin. As monotherapies, changes from baseline in HbA1c with GLP-1RAs ranged from -1.9 to -0.7% in phase 3 trials. In addition, GLP-1RAs confer a low risk of hypoglycaemia and have a body-weight advantage (changes from baseline ranging from -4.0 to -0.4 kg). There is also evidence of significant reductions in risk for cardiovascular events with some of these agents, with a number of other trials underway. Gastrointestinal adverse events typically increase with GLP-1RAs, although these are generally mild to moderate in intensity and rarely require treatment discontinuation. The GLP-1RAs that are commercially available or in development vary in structure and pharmacokinetics. These differences affect the frequency of administration and can also affect their relative efficacy and safety. This review summarizes the findings of phase 3 glycaemic control trials of available GLP-1RAs and considers them in the context of the distinct clinical needs of individual patients. PMID- 28724169 TI - ? AB - Background Vitamin D deficiency represents a global health problem, affecting children and adolescents worldwide. Objects To confirm that vitamin D deficiency can present as a spectrum of clinical pictures. Methods We diagnosed nutritional rickets in a 10-month-old infant of Senegal origin with several risk factors for vitamin D deficiency. As many of these factors affected also his cohabitant relatives, we evaluate infant's family members (mother and 4 brothers) looking for other vitamin D deficiency-related comorbidities. Results 3 brothers had asymptomatic vitamin D deficiency and 2 of them (9.8 and 13.4 years-old) showed secondary hyperparathyroidism. The fourth brother (11.3 years-old) had nutritional rickets. Their mother was affected by osteomalacia. None of them received vitamin D supplementation. Conclusion Vitamin D deficiency may present as a spectrum of clinical pictures, representing a continuum ranging from asymptomatic/subtle conditions to overt rickets/osteomalacia. Immigrant families are at high risk for vitamin D deficiency at every age. If a case of symptomatic vitamin D deficiency is recognized, then the evaluation of the all family members is recommended, as they can have the same and/or other risk factors for vitamin D deficiency. PMID- 28724170 TI - Circulating Insulin-like Growth Factor-1 and Insulin-like Growth Factor Binding Protein-3 predict Three-months Outcome after Ischemic Stroke. AB - Reports on neuroprotective effects of Insulin-like growth factor-1 (IGF-1) and Insulin-like growth factor binding protein-3 (IGFBP-3) in ischemic brain tissue are inconsistent. The aim of this study was to determine if plasma levels of IGF 1 and IGFBP-3 in acute stroke patients are indicative of 3 months functional outcome. Plasma levels were measured via chemiluminescence immunoassay in heparin blood samples of patients included in the EARLY trial (NCT00562588). Plasma samples were drawn on admission and 8 days post-stroke. Neurological deficits were assessed via modified Rankin Scale (mRS) 3 months post-stroke, resulting in favorable (mRS=0-2) or unfavorable (mRS=3-6) outcome. A multiple binary logistic regression including IGF-1 and IGFBP-3 levels and confounders was conducted. Out of 404 included patients, 89 patients had an unfavorable outcome. Mean mRS on admission as well as 3 months post-stroke was 2 (+/-1). Low IGF-1 levels (day 8) were independently associated with a decreased risk of an unfavorable outcome (OR 0.61; 95%CI 0.37-0.99; p=0.044). Low IGFBP-3 levels (day 8) were independently associated with an unfavorable outcome (OR 2.75; 95%CI 1.56-4.84; p<0.001). Low IGFBP-3 levels and high IGF-1 levels in the subacute phase are predictive of unfavorable outcome 3 months after stroke. PMID- 28724171 TI - Beta-glucan, inositol and digestive enzymes improve quality of life of patients with inflammatory bowel disease and irritable bowel syndrome. AB - OBJECTIVE: To evaluate the efficacy of a mixture of beta-glucan, inositol and digestive enzymes in improving gastrointestinal symptoms in patients affected by inflammatory bowel disease (IBD)-irritable bowel syndrome (IBS). PATIENTS AND METHODS: The study was conducted at the IBD Unit of the University of Catanzaro. Forty-three IBD patients with IBS symptoms were included in the study. IBD diagnosis was performed by clinical, endoscopic, histological and radiological criteria. Patients were in clinical remission and in treatment only with systemical and topical mesalamine. All study participants fulfilled the Rome III criteria for the diagnosis of IBS. The study participants were randomized into 2 groups: group A (n=23) received conventional treatment (systemical and topical mesalamine) plus a mixture of beta-glucan, inositol and digestive enzymes (one tablet after lunch and dinner) for four consecutive weeks; group B (n=20) received only conventional treatment. The prevalence and intensity of gastrointestinal (GI) symptoms were evaluated both at the enrollment (T0) and after four weeks of treatment (T1). RESULTS: Patients who received mesalamine plus the mixture of beta-glucan, inositol and digestive enzymes (group A) reported a reduction in abdominal pain together with reduction in bloating and flatulence after four weeks of treatment. Importantly, an overall improvement in the general well-being has been recorded. Patients who underwent only mesalamine treatment (group B) reported a mild reduction in the evacuative urgency without any other improvements. CONCLUSIONS: We have shown that supplementation with a mixture of beta-glucan, inositol and digestive enzymes reduces bloating, flatulence and abdominal pain, improving the overall clinical condition of IBD IBS patients. PMID- 28724172 TI - Favorable effects of myo-inositol, selenomethionine or their combination on the hydrogen peroxide-induced oxidative stress of peripheral mononuclear cells from patients with Hashimoto's thyroiditis: preliminary in vitro studies. AB - OBJECTIVE: The aim of this study was to assess whether blood mononuclear cells (PBMC) from Hashimoto's thyroiditis (HT) and control women, were protected from in vitro H2O2-induced oxidative stress after addition of antioxidants. PATIENTS AND METHODS: PBMC, from 8 HT women and 3 healthy women (controls), were cultured in the presence of 200 uM H2O2 alone, with subsequent addition of myo-inositol (Myo) (0.25, 0.5, 1.0 uM), selenomethionine (SelMet) (0.25, 0.5, 1.0 uM), or their combination (0.25+0.25, 0.5+0.5, 1.0+1.0 uM). PBMC proliferation, vitality, genotoxicity (Comet score) and secretion in the medium of the chemokines CXCL10 [IP10], CCL2 e CXCL9 [MIG] were the indices measured. RESULTS: PBMC proliferation was decreased by H2O2 alone, and it decreased further and dose-dependently in either group (greatest decrease with Myo+SelMet in HT). H2O2 alone decreased vitality by 5% in controls and 10% in the HT group, but vitality was rescued by the three additions. The addition of H2O2 alone increased the Comet score at +505% above baseline in controls and +707% in HT women. In either group, each addition dose-dependently contrasted genotoxicity. Concentrations of chemokines in the medium were increased by H2O2 alone, and in HT women more than in controls. Each addition dose-dependently decreased these concentrations in either group, and often below baseline levels, with Myo+SelMet being the most potent addition (up to approximately -80% of baseline). CONCLUSIONS: The tested antioxidants exert beneficial effects on PBMC exposed in vitro to H2O2-induced oxidative stress in both control and HT women. Particularly, the association Myo+SelMet is the most effective. After the demonstration of a favorable in vitro outcomes in a large cohort of HT patients, we could predict favorable in vivo outcomes given by the same supplement. Thus, one can select HT patients with a high chance of benefit from supplementation. PMID- 28724173 TI - A comparative study between myo-inositol and metformin in the treatment of insulin-resistant women. AB - OBJECTIVE: Insulin resistance (IR) is a common disorder, which can impair female fertility and is characterized by phenotypic heterogeneity. Life-style treatment and insulin sensitizers are commonly used in the management of women with IR and consequent hyperinsulinemia, in order to restore the normal endocrinological and clinical parameters. Metformin (MET) is considered one of the first approaches to this pathology but new evidences are showing promising results using myo-inositol (MYO) in the management of this pathology. The aim of this retrospective data analysis was to evaluate the therapeutic efficacy of MYO (4 g myo-inositol plus 400 mcg folic acid/day) versus MET (on average 1225 mg/day) treatment in a heterogeneous group of IR patients. The focus was on progesterone and prolactin levels, menstrual cycle disorders, pregnancy rates, serum fasting glucose and insulin levels. PATIENTS AND METHODS: Records about 6 months treatment (MYO or MET or both insulin sensitizers) at 237 women in reproductive age were analyzed retrospectively. The patients showed symptoms of IR without diabetes or pre diabetes. RESULTS: All the groups showed a significant improvement (p<0.05) in prolactin and progesterone level after the treatment. Furthermore, the treated groups reported a significant improvement in the menstrual cycle disorders, while the only life-style group showed an increase but not statistically significant (p>0.05). CONCLUSIONS: MYO and MET, associated with life-style, had both significant beneficial effects on serum progesterone and prolactin levels, menstrual cycle disorders and pregnancy rates in patients without severe carbohydrate metabolism malfunctions. Nevertheless, no significant differences were found between the MET and the MYO groups. Significant results in hormone levels and symptoms were reached with the combination of both treatments, whereas fasting serum insulin levels were slightly improved. Furthermore, the body mass index (BMI) was moderately but not significantly higher in MET and MET+MYO group. PMID- 28724174 TI - Editorial - Modern approach to the infertile male: the use of andrositol(r) test (myo-inositol in diagnostics). PMID- 28724175 TI - Myo-inositol and selenium reduce the risk of developing overt hypothyroidism in patients with autoimmune thyroiditis. AB - OBJECTIVE: The beneficial effects obtained by myo-inositol in association with seleno-methionine in patients affected by subclinical hypothyroidism have been recently demonstrated. Here, we evaluate the immune-modulating effect of myo inositol in association with seleno-methionine in patients with euthyroid autoimmune thyroiditis (AT). PATIENTS AND METHODS: Twenty-one consecutive Caucasian patients with newly diagnosed euthyroid chronic AT were evaluated. All subjects were treated with myo-inositol in association with selenium (600 mg/83 mg) tablets, twice per day, for six months. A complete thyroid assessment was done before the treatment, and after six months. RESULTS: After the treatment thyroid-stimulating hormone (TSH) levels significantly declined with respect to basal values, overall in patients with an initial TSH value in the high normal range (2.1= 1 hour);2. type of extravasate (parenteral nutrition fluid or other fluids or medications);3. amount of saline used (< 500 mL or >= 500 mL); and4. PMA at injury (< 37 completed weeks or >= 37 completed weeks). SEARCH METHODS: We used the standard search strategy of the Cochrane Neonatal Review Group to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 1), MEDLINE via PubMed (1966 to 2 February 2017), Embase (1980 to 2 February 2017), and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1982 to 2 February 2017). We also searched clinical trial databases, conference proceedings, and reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. We used the Google Scholar search tool for reverse citations of relevant articles. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-randomised controlled trials comparing saline irrigation with or without hyaluronidase infiltration versus no intervention or normal wound care for the management of extravasation injury in neonates. DATA COLLECTION AND ANALYSIS: Three review authors independently reviewed and identified articles for possible inclusion in this review. We used the GRADE approach to assess the quality of evidence. MAIN RESULTS: We found no eligible studies. Our search revealed 10 case reports or case series describing successful outcomes with different interventions for this condition. AUTHORS' CONCLUSIONS: To date, no RCTs have examined the effects of saline irrigation with or without prior hyaluronidase infiltration for management of extravasation injury in neonates. Saline irrigation is frequently reported in the literature as an intervention for management of extravasation injury in neonates. Research should focus first on evaluating the efficacy and safety of this intervention through RCTs. It will also be important for investigators to determine effect size by examining the timing of the intervention, the nature of the infusate, and severity of injury at the time of intervention. PMID- 28724195 TI - Thyroxin Use Is Associated With Increased Risk of Thyroid Cancer in Patients With Hypothyroidism. AB - Despite evidence linking thyroxin use and breast cancer, little is known regarding the risk of other cancers with thyroxin use. The purpose of this case control study was to evaluate the association of thyroid cancer with primary hypothyroidism based on a population-based database. The data for this case control study were retrieved from the Taiwan Longitudinal Health Insurance Database 2005. We included 1285 patients with thyroid cancer as cases and 3855 sex- and age-matched subjects as controls. We used conditional logistic regression to examine the association of thyroid cancer with previously diagnosed hypothyroidism. We found that a prior hypothyroidism diagnosis was found among 37 cases (2.88%) and 33 controls (0.86%). Conditional logistic regression analysis revealed that the cases were more likely to have been previously diagnosed with hypothyroidism than controls (adjusted OR, 3.01; 95%CI, 1.85-4.89). We also found that thyroid cancer was significantly associated with hypothyroidism patients who were regular thyroxin users (adjusted OR, 8.68; 95%CI, 4.34-17.34). However, we failed to observe a significant association between thyroid cancer and hypothyroidism patients who were irregular thyroxin users. This investigation detected a novel association between thyroid cancer and thyroxin use in patients with primary hypothyroidism. PMID- 28724196 TI - A local agreement pattern measure based on hazard functions for survival outcomes. AB - Assessing agreement is often of interest in biomedical and clinical research when measurements are obtained on the same subjects by different raters or methods. Most classical agreement methods have been focused on global summary statistics, which cannot be used to describe various local agreement patterns. The objective of this work is to study the local agreement pattern between two continuous measurements subject to censoring. In this article, we propose a new agreement measure based on bivariate hazard functions to characterize the local agreement pattern between two correlated survival outcomes. The proposed measure naturally accommodates censored observations, fully captures the dependence structure between bivariate survival times and provides detailed information on how the strength of agreement evolves over time. We develop a nonparametric estimation method for the proposed local agreement pattern measure and study theoretical properties including strong consistency and asymptotical normality. We then evaluate the performance of the estimator through simulation studies and illustrate the method using a prostate cancer data example. PMID- 28724197 TI - Discrimination and Characterization of Two Mediterranean Species from the Laurencia Complex (Rhodomelacea) Using an NMR-Based Metabolomic Approach. AB - Generic and specific determination among the Laurencia complex is a challenging task. DNA barcoding combined with phenotypic investigations are mandatory for species differentiation. In this study, two morphologically different members of the Laurencia complex were investigated using untargeted 1 H-NMR-based metabolomics. Twenty-one population samples were collected in order to evaluate both temporal and geographical homogeneity. Data obtained from 1 H-NMR analysis followed by statistical analysis allowed a clear separation of all the samples into two groups. DNA mitochondrial tests confirmed this pattern and identified the two species as Laurenciella sp. and Laurencia obtusa. In addition, metabolites responsible of this discrimination were investigated directly in crude extracts by 13 C-NMR using an in-house computer-assisted method. The combination of both untargeted (1 H) and targeted (13 C) NMR-based metabolomic approaches proves to be a powerful and complementary approach to discriminate species from the Laurencia complex. PMID- 28724198 TI - Direct and Topoisomerase II Mediated DNA Damage by Bis-3-chloropiperidines: The Importance of Being an Earnest G. AB - Bis-3-chloropiperidines are a new class of DNA-active compounds capable of alkylating nucleobases and inducing strand cleavage. In this study, we investigated the reactivity of these mustard-based agents with both single- and double-stranded DNA constructs. Polyacrylamide gel electrophoresis (PAGE) and electrospray ionization mass spectrometry (ESI-MS) were used to obtain valuable insight into their mechanism at the molecular level and to investigate their time and concentration-dependent activity. The results revealed the preferential formation of mono- and bifunctional adducts at nucleophilic guanine sites. In a stepwise fashion, alkylation was followed by depurination and subsequent strand scission at the ensuing apurinic site. We demonstrated that the covalent modifications introduced by this new class of compounds can inhibit the activity of essential DNA-processing proteins, such as topoisomerase IIalpha, thereby suggesting that bis-3-chloropiperidines may have excellent anticancer potential. PMID- 28724199 TI - Antidiabetic potential: in vitro inhibition effects of some natural phenolic compounds on alpha-glycosidase and alpha-amylase enzymes. AB - alpha-Glycosidase is a catalytic enzyme and it destroys the complex carbohydrates into simple absorbable sugar units. The natural phenolic compounds were tested for their antidiabetic properties as alpha-glycosidase and alpha-amylase inhibitors. The phenolic compounds investigated in this study have been used as antidiabetic common medicines. This paper aimed to consider their capability to inhibit alpha-amylase and alpha-glycosidase, two significant enzymes defined in serum glucose adjustment. These examination recorded impressive inhibition profiles with IC50 values in the range of 137.36-737.23 nM against alpha-amylase and 29.01-157.96 nM against alpha-glycosidase. PMID- 28724200 TI - Effect of Memantine on Serum Levels of Neuron-Specific Enolase and on the Glasgow Coma Scale in Patients With Moderate Traumatic Brain Injury. AB - Traumatic brain injury (TBI) is a major cause of disability and death globally. Despite significant progress in neuromonitoring and neuroprotection, pharmacological interventions have failed to generate favorable results. We examined the effect of memantine on serum levels of neuron-specific enolase (NSE), a marker of neuronal damage, and the Glasgow Coma Scale (GCS) in patients with moderate TBI. Patients were randomly assigned to the control group (who received standard TBI management) and the treatment group (who, alongside their standard management, received enteral memantine 30 mg twice daily for 7 days). Patients' clinical data, GCS, findings of head computed tomography, and serum NSE levels were collected during the study. Forty-one patients were randomized into the control and treatment groups, 19 and 22 patients respectively. Baseline characteristics and serum NSE levels were not significantly different between the 2 groups. The mean serum NSE levels for the memantine and the control groups on day 3 were 7.95 +/- 2.86 and 12.33 +/- 7.09 ng/mL, respectively (P = .05), and on day 7 were 5.03 +/- 3.25 and 10.04 +/- 5.72 ng/mL, respectively (P = .003). The mean GCS on day 3 was 12.3 +/- 2.0 and 10.9 +/- 1.9 in the memantine and control groups, respectively (P = .03). Serum NSE levels and GCS changes were negatively correlated (r = -0.368, P = .02). Patients with moderate TBI who received memantine had significantly reduced serum NSE levels by day 7 and marked improvement in their GCS scores on day 3 of the study. PMID- 28724202 TI - Population Pharmacokinetics of Lenalidomide in Healthy Volunteers and Patients With Hematologic Malignancies. AB - A population pharmacokinetic (PopPK) model of lenalidomide was developed using data pooled from 13 clinical studies (dose range, 5-400 mg) in participants who were considered to have adequate capability for renal excretion of lenalidomide (creatinine clearance [CrCl] > 50 mL/min). The analysis population included 305 healthy volunteers and 83 patients with multiple myeloma or myelodysplastic syndromes. A 1-compartment model with linear absorption and elimination described well the observed data for both healthy volunteers and patients. Covariate analysis suggested lenalidomide apparent clearance was positively correlated with CrCl, and lenalidomide volume of distribution was positively correlated with body weight. Both pharmacokinetic parameters were reduced by 29% in patients, independent of the effect of CrCl or body weight. Despite their statistical significance, effects of study population and body weight are considered clinically unimportant in adult patients with CrCl > 50 mL. After accounting for the above effects, body weight had no significant effect on CL/F, whereas age, sex, race, and mild hepatic impairment had no significant effect on either lenalidomide parameter. The PopPK model should be useful for future modeling of lenalidomide pharmacokinetics in the pediatric population and for further comparison of pharmacokinetic properties among structurally similar immunomodulatory drugs. PMID- 28724201 TI - Variations in the Bioactive Compounds Composition and Biological Activities of Loofah (Luffa cylindrica) Fruits in Relation to Maturation Stages. AB - The present work aimed to determine the antioxidant and antiproliferative potential of Luffa cylindrica fruits collected at two different maturation stages and to identify and compare their functional components composition. The MeOH extracts of L. cylindrica fruits harvested at 60 - 65 days after seeding (S1) and 85 - 90 days after seeding (S2) were investigated for their antioxidant activity using various assays. Furthermore, the antiproliferative activity of the extracts against HeLa human cervical cancer cells was explored with xCELLigence real time cell analyzer, while the effect of the samples on the membrane integrity of the same cell line was assessed using LDH cytotoxicity leakage assay. Ultimately, the phytochemicals were analyzed using GC/MS and HPLC/TOF-MS. The S1 sample had higher contents and more diversity in the phenolic compounds composition than S2. Furthermore, the S1 extract showed the highest antioxidant and antiproliferative activity, while the S2 extract had higher cytotoxicity towards HeLa cells. The findings revealed that the time of harvest has a big impact on the phytochemicals content and activity and that harvesting L. cylindrica at an early stage before the beginning of the development of the cellulose fibrous system is recommended for a rich phytochemical composition and efficient antioxidant and antiproliferative activities. PMID- 28724203 TI - Huprine X Attenuates The Neurotoxicity Induced by Kainic Acid, Especially Brain Inflammation. AB - Huprine X (HX) is a synthetic anticholinesterasic compound that exerts a potent inhibitory action on acetylcholinesterase (AChE) activity, an agonist effect on cholinergic receptors, neuroprotective activity in different neurotoxicity models in vivo and in vitro and cognition enhancing effects in non-transgenic (C57BL/6) and transgenic (3xTg-AD, APPswe) mice. In this study, we assessed the ability of HX (0.8 mg/kg, 21 days) to prevent the damage induced by kainic acid (KA; 28 mg/kg) regarding apoptosis, glia reactivity and neurogenesis in mouse brain. KA administration significantly modified the levels of pAkt1, Bcl2, pGSK3beta, p25/p35, increased the glial cell markers and reduced the neurogenesis process. We also observed that pre-treatment with HX significantly reduced the p25/p35 ratio and increased synaptophysin levels, which suggests a protective effect against apoptosis and an improvement of neuroplasticity. The increase in GFAP (88%) and Iba-1 (72%) induced by KA was totally prevented by HX pre-treatment, underlying a relevant anti-inflammatory action of the anticholinesterasic drug. Our findings highlight the potential of HX, in particular, and of AChEIs, in general, to treat a number of diseases that course with both cognitive deficits and chronic inflammatory processes. PMID- 28724204 TI - Gait and Balance Impairment after Acute Methanol Poisoning. AB - Neurological sequelae including gait impairment were reported in survivors after methanol intoxication; however, no systematic study has been published so far. We aimed to analyse gait and balance impairment in a group of Czech methanol poisoning survivors. We examined 43 patients (age 46 +/- 13 years) 2-8 months after methanol poisoning and 43 healthy controls. Investigations contained a shortened version of Falls Efficacy Scale (FES), clinical tests of gait and balance including Timed Up and Go test (TUG) and gait analysis using GaitRite(r) system, neurological and neuropsychological examination, brain imaging, EMG and tests of alcohol consumption. Nineteen patients admitted balance and gait impairment according to FES. Mild to moderate parkinsonian signs showed seven patients. Patients were slower (8.8 versus 5.7 s, p < 0.001) and performed more steps (11.1 versus 7.9, p < 0.001) in TUG compared with the controls. Gait analysis revealed shorter step length (76.5 versus 88.7 cm, p < 0.001), increased double support phase (18.8 versus 15.5%, p < 0.001) and wider base of support (11.3 versus 9.6 cm, p = 0.006) in patients. Eleven patients had deficit of executive function and performed higher cadence compared to the patients with normal execution (122.7 versus 115.0 step/min., p = 0.025). Lower limb polyneuropathy was verified in nine patients, without relation with gait or balance parameters. Neuroimaging revealed lesions mainly in the basal ganglia. Methanol poisoning survivors presented slower wide-based gait with shortened steps corresponding with frontal gait disorder. Higher stepping cadence associated with executive deficit supported the evidence of frontal lobe dysfunction related to impairment of basal ganglia and connections in frontal cortico-basal ganglia loops. PMID- 28724206 TI - Vital Signs: Health Care-Associated Legionnaires' Disease Surveillance Data From 20 States and a Large Metropolitan Area-United States, 2015. AB - BACKGROUND: Legionnaires' disease, a severe pneumonia, is typically acquired through inhalation of aerosolized water containing Legionella bacteria. Legionella can grow in the complex water systems of buildings, including health care facilities. Effective water management programs could prevent the growth of Legionella in building water systems. METHODS: Using national surveillance data, Legionnaires' disease cases were characterized from the 21 jurisdictions (20 U.S. states and one large metropolitan area) that reported exposure information for >=90% of 2015 Legionella infections. An assessment of whether cases were health care-associated was completed; definite health care association was defined as hospitalization or long-term care facility residence for the entire 10 days preceding symptom onset, and possible association was defined as any exposure to a health care facility for a portion of the 10 days preceding symptom onset. All other Legionnaires' disease cases were considered unrelated to health care. RESULTS: A total of 2,809 confirmed Legionnaires' disease cases were reported from the 21 jurisdictions, including 85 (3%) definite and 468 (17%) possible health care-associated cases. Among the 21 jurisdictions, 16 (76%) reported 1-21 definite health care-associated cases per jurisdiction. Among definite health care-associated cases, the majority (75, 88%) occurred in persons aged >=60 years, and exposures occurred at 72 facilities (15 hospitals and 57 long-term care facilities). The case fatality rate was 25% for definite and 10% for possible health care-associated Legionnaires' disease. CONCLUSIONS AND IMPLICATIONS FOR PUBLIC HEALTH PRACTICE: Exposure to Legionella from health care facility water systems can result in Legionnaires' disease. The high case fatality rate of health care-associated Legionnaires' disease highlights the importance of case prevention and response activities, including implementation of effective water management programs and timely case identification. PMID- 28724207 TI - Immune-Electrical Connection. PMID- 28724208 TI - 2017 American Transplant Congress Focuses on Hot Issues. PMID- 28724209 TI - Rare Late Complication After Percutaneous Liver Biopsy. PMID- 28724210 TI - Dandelion root extract suppressed gastric cancer cells proliferation and migration through targeting lncRNA-CCAT1. AB - Gastric cancer (GC) is one of the most common tumors worldwide. Standard treatment after early detection involves surgical excision (recurrence is possible), and metastatic gastric cancer is refractory to immuno-, radio-, and most harmful chemotherapies. Various natural compounds have shown efficacy in killing different cancers, albeit not always specifically. In this study, we show that dandelion root extract (DRE) specifically and effectively suppresses proliferation and migration in human gastric cells without inducing toxicity in noncancerous cells. Long noncoding RNAs (lncRNAs) are known to promote tumorigenesis in many cancer types. Here, we showed that the lncRNA colon cancer associated transcript-1 (CCAT1) was down-regulated in dandelion-treated GC cells. Furthermore, downregulation of CCAT1 inhibited proliferation and migration of gastric cells. We also found that DRE exerted its function in GC cells partially through targeting CCAT1. This data will provide a basis on which further research in cancer treatment through DRE can be executed. PMID- 28724211 TI - Dexmedetomidine preconditioning protects against retinal ischemia/reperfusion injury and inhibits inflammation response via toll-like receptor 4 (TLR4) pathway. AB - BACKGROUND: Retinal ischemia/reperfusion (I/R) injury is one of significant cause of visual dysopia and causes inflammatory response. Dexmedetomidine is widely applied to general/local anaesthesia and has been reported to have extensive anti inflammatory effect. However, the role of dexmedetomidine in retinal I/R injury is currently unknown. This study investigates the effect of dexmedetomidine preconditioning on retinal I/R injury and explore the related signal mechanism toll-like receptor 4 (TLR4) pathway. METHODS: Retinal I/R injury model were established with SD rats through periocular injection. Retinal damage was quantified by measuring the thickness of retinal layers, cell counts of retinal ganglion cells (RGCs) and electroretinography (ERG). Apoptosis of retinal cell was detected by TUNEL assay. Protein and mRNA expression of glial fibrillary acidic protein (GFAP) were measured by western blot and real-time quantitate PCR. Bax, Bcl-2 and nuclear factor-kappaB (NF-kappaB) in retinas were detected by western blot. RESULTS: ERG and HE staining showed that dexmedetomidine preconditioning significantly inhibited the histologic damage induced by I/R injury, which expresses apparent concentration dependent. TUNEL demonstrated that apoptosis of retinal cells were reduced by dexmedetomidine. The expression of NF kappaB and GFAP were decreased compared I/R blank group. CONCLUSION: Dexmedetomidine preconditioning suppresses retinal I/R injury and shows effective anti-inflammatory effect by inhibiting TLR4/NF-kappaB expression. PMID- 28724212 TI - The effects of microRNA-98 inhibits cell proliferation and invasion by targeting STAT3 in nasopharyngeal carcinoma. AB - MicroRNA-98 (miR-98) is downregulated in many tumors, and is closely related to tumor progression. In addition, it shows anticarcinogenic functions in various tumor. However, few study show that the biological function and regulatory mechanisms of miR-98 in nasopharyngeal carcinoma (NPC) progression. The identification and its target genes which regulate by dysregulated miRNAs may strengthen our understanding of the molecular mechanisms of NPC. In this study, we observe that miR-98 is not only significantly reduced in NPC tissues, but also decreased markedly in NPC cell lines. Moreover, silencing miR-98 expression studies not only show miR-98 induced cell proliferation, migration and invasion in vitro, but also it promoted xenograft tumor growth in vivo in NPC. Furthermore, western blot assay was used to detected the level of STAT3 protein and we demonstrate that miR-98 regulate cells poliferation, migration and invasion through directly modulating functional target STAT3 by directly binding its 3'-UTR. These findings illustrate miR-98 as a anticarcinogenic functions through targeting STAT3, the miR-98/STAT3 pathway gives new clues for understanding NPC carcinogenesis and provides novel therapeutic targetsfor NPC. PMID- 28724213 TI - Characterization of serum estradiol level and tissue estrogen receptor immunostaining with clinical response and reproductive factor changes in Chinese female patients with esophageal squamous cell carcinoma. AB - Pre-menopausal female patients have a prolonged survival than post-menopausal patients, indicating that estrogen and/or estrogen receptor (ER) may have some biological effects on prognosis. ER expression in cancer tissue has been reported to be a significant prognostic marker in multiple human cancers. However, the prognostic value of estrogen and/or ER on female patients with esophageal squamous cell carcinoma (ESCC) is rarely reported. The present study was undertaken to elucidate the associations of serum estradiol level, tissue estrogen receptor alpha (ERalpha) and estrogen receptor beta (ERbeta) expression with clinical response and reproductive factor changes in 387 female ESCC patients. Radioimmunoassay revealed that serum estradiol level was higher in pre menopausal than those in peri-menopausal and post-menopausal patients. Furthermore, patients with higher serum estradiol level appeared to have a better survival. Immunostaining results suggested that ERalpha positive (+) expression was mainly located in cytoplasm of tumor cells with a positive rate of 69.9% and ERbeta (+) was mainly located in nucleus of tumor cells with a positive rate of 64.9%. We did not find the relations of ER expression with tumor invasion (P>0.05), lymph node metastasis (P>0.05), TNM staging (P>0.05) and treatment method (P>0.05). Surprisingly, ERalpha (+) expression was higher in post menopausal patients than those in pre-menopausal patients (P<0.05). Patients with number of pregnancy>=4 have a higher ERbeta (+) expression than those patients with<=3 (P<0.05). Univariate and multivariate survival analysis showed that ERbeta (+) expression in addition to ERalpha (-) expression are favorable prognostic markers in female ESCC patients (P<0.05). Further related study is needed to in-depth explore the potential mechanisms of ERalpha and ERbeta in survival of female patients with ESCC. PMID- 28724214 TI - Potential protective effects of alpha-pinene against cytotoxicity caused by aspirin in the IEC-6 cells. AB - Alpha-pinene is a key compound of the essential oils extracted from many species of coniferous trees. It is known for its biological activities. The aim of the present study was to determine the preventive effect of alpha-pinene on aspirin induced toxicity in vitro, using IEC-6 cells, and to investigate its antioxidant activities. The antioxidant activities were determined by 1,1-diphenyl-2 picrylhydrazyl (DPPH) and ferric reducing antioxidant power (FRAP). The cytotoxicity and oxidative stress were detected by cell viability, antioxidant enzyme activity, malondialdehyde (MDA) and GSH production, and the activation of MAPK pathways. The results indicated that alpha-pinene revealed an important antioxidant activity. It was evaluated by DPPH test (EC50=310+/-10MUg/mL) and FRAP test (EC50=238+/-18.92MUg/mL). The co-exposure of alpha-pinene with aspirin on cells significantly increased the survival of cells and the level of GSH, and decreased the levels of MDA and total SOD and the activity of Mn-SOD. In addition, the activation of p38 and JNK was blocked by alpha-pinene. Therefore, these findings suggest that alpha-pinene can protect IEC-6 cells against aspirin induced oxidative stress. PMID- 28724215 TI - Melatonin inhibits proliferation and invasion via repression of miRNA-155 in glioma cells. AB - Melatonin, an indolamine mostly synthesized in the pineal gland, exerts the anti cancer effect by various mechanisms in glioma cells. Our previous study showed that miR-155 promoted glioma cell proliferation and invasion. However, the question of whether melatonin may inhibit glioma by regulating miRNAs has not yet been addressed. In this study, we found that melatonin (100MUM, 1MUM and 1nM) significantly inhibited the expression of miR-155 in human glioma cell lines U87, U373 and U251. Especially, the lowest expression of miR-155 was detected in 1MUM melatonin-treated glioma cells. Melatonin (1MUM) inhibits cell proliferation of U87 by promoting cell apoptosis. Nevertheless, melatonin had no effect on cell cycle distribution of U87 cells. Moreover, U87 cells treated with 1MUM melatonin presented significantly lower migration and invasion ability when compared with control cells. Importantly, melatonin inhibited c-MYB expression, and c-MYB knockdown reduced miR-155 expression and migration and invasion in U87 cells. Taken together, for the first time, our findings show that melatonin inhibits miR 155 expression and thereby represses glioma cell proliferation, migration and invasion, and suggest that melatonin may downregulate the expression of miR-155 via repression of c-MYB. This will provide a theoretical basis for revealing the anti-glioma mechanisms of melatonin. PMID- 28724216 TI - The extract from Punica granatum (pomegranate) peel induces apoptosis and impairs metastasis in prostate cancer cells. AB - Prostate cancer is a big threat to male for its poor prognosis and high mortality rate. Natural compounds are important resources of many anticancer drugs. Pomegranate is a kind of antioxidant-rich fruit and its peel and seed has potential anticancer activities. In this study, we aimed to investigate the effects of pomegranate peel extract (PoPx) on the apoptosis and metastasis of prostate cancer cells and the related mechanism. We found that PoPx showed growth inhibition on prostate cancer cells. Nuclei morphological and flow cytometer (FCM) analysis indicated that PoPx could induce prostate cancer apoptosis. Further investigation indicated that mitochondrial mediated intrinsic pathway is involved in the apoptosis. Exposure to PoPx led to loss of mitochondrial transmembrane potential (Deltaym), accumulation of reactive oxygen species (ROS). Western blot analysis showed that PoPx could increase the expression ratio of Bax/Bcl2 and activation of apoptosis executor caspase 3. Wound healing assay and transwell migration and invasion assay implied that PoPx has the potential to inhibit migration and invasion, two critical steps in prostate cancer metastasis. Downregulation of MMP2/MMP9 and upregulation of TIMP2 showed accordance with the inhibition of migration and invasion. In summary, the present data showed that PoPx could be a promising drug candidate to treat prostate cancer, showing us a better way to develop novel drugs from natural compounds. PMID- 28724217 TI - Chondroprotective and anti-nociceptive effects of caffeoylquinic acid in osteoarthritis by downregulating catabolic activity and oxidative damage in chondrocytes. AB - We evaluated the chondroprotective and anti-nociceptive effects of caffeoylquinic acid (CA) in a rat osteoarthritis (OA) model. Monosodium iodoacetate was injected intra-articularly in the rats to produce OA. The rats were divided into three groups: control, OA group, which received vehicle, and the CA-treated group, which received CA (50mg/kg, p.o.) for 14days. At the end of the protocol, pain was estimated by observing the paw withdrawal threshold and latency. Degeneration of cartilage was assessed through histomorphological and microscopical examination of joints. Levels of mRNA were estimated in interleukin-1beta (IL 1beta)- and IL-6-stimulated chondrocytes. The results suggested that treatment with CA significantly attenuated the degeneration of cartilage and pain in OA rats. The histopathology study revealed that the number of osteoclast cells was reduced significantly in the CA-treated group. Moreover, expression levels of inducible nitric oxide synthase (iNOS), nitrotyrosine, IL-6, and IL-1beta were decreased significantly in the CA-treated group versus the OA group. Additionally, CA reduced the expression of metalloproteinase with thrombospondin motifs-5 (ADAMTS-5), matrix metalloproteinase-13 (MMP-13), and MMP-3, and tissue inhibitor of metalloproteinases-1 (TIMP-1) was enhanced in IL-1beta-stimulated chondrocytes. The c-jun N-terminal kinase (JNK) level was reduced significantly (p<0.01) in the CA-treated group. In conclusion, treatment with CA protected against degradation of articular cartilage in the OA rat by balancing the homeostasis of cartilage extracellular matrix (CEM) and by reducing oxidative stress. CA affects OA on the basis of its strong anti-inflammatory and anti oxidant properties. PMID- 28724218 TI - Roadside verges as habitats for endangered lizard-orchids (Himantoglossum spp.): Ecological traps or refuges? AB - Alterations in traditional land use practices have led to severe declines in the area of semi-natural grasslands, thereby seriously threatening plant and animal species dependent on these habitats. Small anthropogenic managed habitats, like roadsides can act as refuges and might play an important role in conserving these species. Colonization of roadside verges by endangered lizard orchids (Himantoglossum spp.) has long been known, but few studies have systematically explored the suitability of roadside habitats for these orchids and the impact of roads on them. In this paper we present results of targeted surveys of three lizard orchid taxa on roadsides from eight European countries. During these surveys we searched for lizard orchids inhabiting roadside verges and recorded their distance from road, aspects of the roadside environment, as well as vegetative and reproductive characteristics of individual plants. We found large numbers of lizard orchids on roadside verges. Distance from roads was not uniformly distributed: orchids occurred more closely to roads than expected by chance. This suggests that regular management of roadsides (e.g. mowing) might enhance colonization and survival of lizard orchids. On the other hand, we also found that close proximity to roads negatively affects reproductive success, suggesting that the immediate vicinity of roads might act as an ecological trap (i.e. favorable in terms of colonization and survival but unfavorable in terms of reproduction). Nonetheless, the fact that significant and viable populations are maintained at roadsides suggests that traditionally managed roadside verges may allow long-term persistence of lizard orchid populations and may serve as refuges in a landscape context. PMID- 28724219 TI - Forecasting PM2.5 induced male lung cancer morbidity in China using satellite retrieved PM2.5 and spatial analysis. AB - The present study predicts a spatial distribution of lung cancer morbidity in Chinese males due to exposure to PM2.5 concentration from 2010 to 2015. A spatial autocorrelation method was used to evaluate the spatial relationship between the lung cancer morbidities from 2006 to 2009 and satellite-derived PM2.5 atmospheric levels. A comprehensive grey correlation degree analysis was carried out to assess the simultaneous and lag associations between the lung cancer morbidity and PM2.5 concentration. These relationships were subsequently applied to predict male lung cancer morbidity in a specific year. Annual mean PM2.5 levels in this specific year and previous 8years were used as 9 independent variables to establish four statistical models. These models include ridge regression (RR), partial least squares regression (PLSR), support vector regression (SVR), and the combined forecasting model (CFM) to predict the male lung cancer morbidity in China from 2010 to 2015. The model error evaluations suggested that the partial least squares regression model performed the best in the male lung cancer morbidity forecast. We calculated the male lung cancer morbidity by the optimal method among the established statistical forecasting models at 1948 sites in China. The gridded morbidity distribution from 2010 to 2015 across the country was obtained by Kriging interpolation method. Results showed that the male lung cancer morbidity increased significantly from western to eastern China, except for the far north region. This spatial pattern is in line with the spatial distribution of PM2.5 concentration, manifesting a significant relationship between PM2.5 concentration level and lung cancer morbidity in Chinese males. PMID- 28724220 TI - Influence of temperature in pollution-induced community tolerance approaches used to assess effects of copper on freshwater phototrophic periphyton. AB - By measuring levels of tolerance to toxicants in microbial communities using functional toxicity tests under controlled conditions, pollution-induced community tolerance (PICT) approaches offer an effect-based tool to assess the ecological risk of chemicals in aquatic systems. However, induced tolerance of exposed microbial communities cannot always be attributed solely to the presence of toxicants as various environmental factors, such as temperature, can also be involved. Several PICT studies have been conducted to assess the effects of copper (Cu) on phototrophic periphyton, but little is known about the influence of temperature on the response of these microbial communities to acute and chronic exposure to Cu. Here, we report on a microcosm approach to assess the effects of two contrasting temperatures (18 degrees C and 28 degrees C) on (i) the baseline level of Cu tolerance in non-Cu-exposed phototrophic periphyton (i.e. effect of temperature on tolerance baseline), (ii) Cu tolerance acquisition by phototrophic periphyton in response to a 3-week chronic exposure to Cu at a nominal concentration of 60MUgL-1 (i.e. effect of temperature on PICT selection) and (iii) tolerance measured during short-term toxicity tests (i.e. effect of temperature on PICT detection). The aim was to evaluate how temperature conditions during the different phases of the PICT approaches may modify the causal relationship between chronic Cu exposure and measured Cu tolerance levels. Our results evidence the influence of temperature both on the basal capacity of phototrophic periphyton to tolerate subsequent exposure to Cu (i.e. influence on tolerance baseline) and on its capacity to acquire tolerance following chronic exposure to Cu (i.e. influence on PICT selection). Hence temperature must be considered when using PICT to establish causal links between chronic Cu exposure and effects on phototrophic periphyton. PMID- 28724221 TI - Impact of the NSAID diclofenac on survival, development, behaviour and health of embryonic and juvenile stages of brown trout, Salmo trutta f. fario. AB - The NSAID diclofenac is controversially discussed with respect to its environmental relevance. Since further information is need to assess whether diclofenac should be included as substance of priority in the EU water framework directive, we investigated the impact of this analgesic on the embryonic development of brown trout (Salmo trutta f. fario) from fertilized egg until the end of sac-fry stage and studied effects in juvenile fish six months post hatch. Embryos were exposed to five test concentrations (0.1, 0.5, 1, 10, 100MUg/L) over 127days at 7 degrees C. None of the treatments affected mortality, hatching, development or heart rate. Six months old juveniles exposed to five concentrations (0.1, 1, 10, 100, 200MUg/L) over 25days at 7 degrees C, however, showed increased mortality, reaching significance at 100MUg/L. Furthermore, a significantly higher proportion of juvenile animals bore injuries at concentrations higher 10MUg/L. Neither the levels of the stress protein Hsp70, nor the amount of lipid peroxides was affected by any of the treatments. Histological analyses of gill, liver and kidney revealed visible tissue reactions in fish from all experimental groups. Histological responses in livers of diclofenac-exposed fish outstripped the status of laboratory control fish, particularly when exposed to the two highest concentrations. Chemical analyses of fish muscle tissue revealed concentration-dependent uptake of DCF into the animal, but no relevant bioconcentration. Our study supports earlier findings indicating a lower sensitivity of trout early life stages compared to older individuals, suggesting that studies for risk assessment of diclofenac should predominantly focus on later life stages. Furthermore, fish mortality was found to increase with rising diclofenac concentrations, and the lowest observed effect concentration of 10MUg/L on the organismic level emphasises the classification of diclofenac as a micropollutant that requires close attention. PMID- 28724222 TI - Development of a soft extraction method for sulfamethoxazole and transformation products from agricultural soils: Effects of organic matter co-extraction on the environmental availability assessment. AB - The recycling of biosolids and livestock manure in agriculture may lead to the introduction of antibiotic residues, i.e., parent molecule and transformation products, into amended soils. Their fate in soils can be approached through the assessment of their environmental availability. In this work, the environmental availability of sulfamethoxazole (SMX) and three transformation products (N4 acetyl-SMX, 3-amino-5-methylisoxazole, aniline) was assessed in soils amended with sludge compost or cow manure throughout a three-month incubation, using soft extractions with CaCl2, EDTA or cyclodextrin solutions. First, the freeze-storage of soil samples was shown to decrease the SMX extractability. The SMX extractability depended on the initial concentration, the amendment type and the extracting solution at day 0. From 1.9% up to 63% of the SMX total content was initially extractable. The lowest fractions were quantified in EDTA extracts in which the dissolved organic matter was the most complex and responsible for high matrix effects in mass spectrometry compared to CaCl2 extracts. The purification of cyclodextrin extracts highly reduced the matrix effects, but CaCl2 was considered as the most suitable extractant. SMX extractability strongly decreased after the first 8days of incubation to finally reach 0.4-0.8% after 84days, whatever the initial conditions. This high decrease could be related to humification observed through the increasing complexity of extracted dissolved organic matter. Very low levels of transformation products were quantified throughout the incubation period. The low environmental availability of SMX was mainly due to its sorption on soil organic matter and resulted in its low biotransformation in these amended soils. PMID- 28724223 TI - Chromium (VI) adsorption from wastewater using porous magnetite nanoparticles prepared from titanium residue by a novel solid-phase reduction method. AB - Porous magnetite nanoparticles were successfully synthesized by reduction of titanium residue with pyrite under nitrogen protection, and characterized by X ray diffraction, Fourier transform infrared spectroscopy, scanning electron microscopy, energy dispersive X-ray spectroscopy, vibrating sample magnetometer, X-ray photoelectron spectroscope, zeta potential and Brunauer-Emmett-Teller method. The XRD analysis confirmed the formation of porous magnetite nanoparticles with single spinel structure. The SEM image demonstrated that porous magnetite nanoparticles displayed spherical shape with the average diameter of ~51nm. The surface area of porous magnetite nanoparticles with high magnetic moment (78emu.g-1) was 11.1m2g-1. The experimental results revealed that equilibrium adsorption behavior of Cr(VI) was well described by Langmuir isotherm model with the maximum adsorption capacity of 14.49mgg-1 at 298.15K, and kinetic data was found to fit well with pseudo-second-order model. The adsorption rate for Cr(VI) was controlled by both boundary layer diffusion and intraparticle diffusion. Thermodynamics analysis showed that the adsorption processes of Cr(VI) were endothermic and spontaneous. In addition, the adsorption of Cr(VI) on porous magnetite nanoparticles was classified as chemisorption adsorption, which depended on electrostatic attraction accompanied with reduction of Cr(VI) to Cr(III). Porous magnetite nanoparticles were readily regenerated and used repeatedly for Cr(VI) adsorption at least five cycles. Furthermore, the experimental results indicate that porous magnetite nanoparticles have a promising application for Cr(VI) adsorption from wastewater. PMID- 28724224 TI - Assessing natural and anthropogenic influences on water discharge and sediment load in the Yangtze River, China. AB - The water discharge and sediment load of rivers are changing substantially under the impacts of climate change and human activities, becoming a hot issue in hydro environmental research. In this study, the water discharge and sediment load in the mainstream and seven tributaries of the Yangtze River were investigated by using long-term hydro-meteorological data from 1953 to 2013. The non-parametric Mann-Kendall test and double mass curve (DMC) were used to detect trends and abrupt change-points in water discharge and sediment load and to quantify the effects of climate change and human activities on water discharge and sediment load. The results are as follows: (1) the water discharge showed a non significant decreasing trend at most stations except Hukou station. Among these, water discharge at Dongting Lake and the Min River basin shows a significant decreasing trend with average rates of -13.93*108m3/year and -1.8*108m3/year (P<0.05), respectively. However, the sediment load exhibited a significant decreasing trend in all tributaries of the Yangtze River. (2) No significant abrupt change-points were detected in the time series of water discharge for all hydrological stations. In contrast, significant abrupt change-points were detected in sediment load, most of these changes appeared in the late 1980s. (3) The water discharge was mainly influenced by precipitation in the Yangtze River basin, whereas sediment load was mainly affected by climate change and human activities; the relative contribution ratios of human activities were above 70% for the Yangtze River. (4) The decrease of sediment load has directly impacted the lower Yangtze River and the delta region. These results will provide a reference for better resource management in the Yangtze River Basin. PMID- 28724225 TI - Seasonal variations in the occurrence of perfluoroalkyl substances in water, sediment and fish samples from Ebro Delta (Catalonia, Spain). AB - The main objective of this study was to assess the concentration levels and the seasonal variations of 13 poly- and perfluoroalkyl substances (PFASs) in different compartments (water, sediments and fish) of the Ebro Delta (NE Spain) and surrounding coastal areas. Perfluorooctanoic acid (PFOA) was the most frequently detected compound in waters and sediments. Perfluorocarboxylic acids (PFCAs) were the compounds found at the highest concentrations in water samples. On the other hand, sediments were more enriched in perfluorooctanesulfonate (PFOS) (range<1.02-22.6ng/g dw). Waters and sediments showed a different seasonal trend. While waters were characterised by a substantial constant level of PFASs over the year, sediments showed a progressive decrease from autumn to summer, revealing the great influence that environmental conditions exert on PFAS distribution in sediments. As regards fish samples, in spite of the ban of its production, PFOS was the most frequently detected compound in seawater fishes, in agreement with its high persistency, bioaccumulation and biomagnification. Moreover, PFASs showed to be more distributed in the skin rather than in muscle tissues. In addition, river fishes were characterised by very high PFAS levels (?PFAS range from 63.8ng/g ww to 938ng/g ww), with perfluoroalkyl carboxylic acids being more concentrated than sulfonates. The PFASs concentrations in water, sediment, and biota revealed that one of the studied sites, Isla de Buda was the most contaminated site of the Ebro Delta. These results are consistent with its location at the final part of the estuary, where many irrigation channels are collected together. PMID- 28724226 TI - Application of a crustacean bioassay to evaluate a multi-contaminated (metal, PAH, PCB) harbor sediment before and after electrokinetic remediation using eco friendly enhancing agents. AB - Electrokinetic (EK) remediation can be a suitable technology for treating contaminated dredged harbor sediment, stored on terrestrial disposal sites. Citric acid (CA) and biosurfactants (rhamnolipids and saponin) were chosen as enhancing agents for simultaneous metal (Cd, Cr, Cu, Pb, Zn) and PAH/PCB removal by EK because of their potential low toxicity with a view to site restoration. Three EK runs were performed using a periodic voltage (1Vcm-1) and various concentrations of agents. The best combination of CA (0.2molL-1) and saponin (0.85gL-1) did not remove high amounts of metals (4.4-15.8%) and provided only slightly better results for PAH and PCB removal (29.2% and 38.2%, respectively). The harbor sediment was highly resistant to metal and organics mobilization and transport because of an aged contamination, a high buffering capacity, a very low hydraulic permeability and a high organic matter content. The efficiency of the EK process was also assessed by measuring the acute toxicity of the EK-treated sediment on E. affinis copepods exposed to sediment elutriates. Fortunately, the use of CA and biosurfactants did not significantly impact on sediment toxicity. Some treated sediment sections, particularly those near the anode compartment, were statistically more toxic than the raw sediment. More particularly, E. affinis copepods were significantly sensitive to low pH values and oxidative conditions, to Cu, and to a lesser extent to Pb amounts. The speciation of these metals probably changed in these pH and redox conditions so that they became more easily leachable and bioavailable. In contrast, toxicity was negatively correlated to PAH and PCB amounts after EK treatment, probably due to the production of oxidized metabolites of PAHs and PCBs. PMID- 28724228 TI - A new method for correlation analysis of compositional (environmental) data - a worked example. AB - Most data in environmental sciences and geochemistry are compositional. Already the unit used to report the data (e.g., MUg/l, mg/kg, wt%) implies that the analytical results for each element are not free to vary independently of the other measured variables. This is often neglected in statistical analysis, where a simple log-transformation of the single variables is insufficient to put the data into an acceptable geometry. This is also important for bivariate data analysis and for correlation analysis, for which the data need to be appropriately log-ratio transformed. A new approach based on the isometric log ratio (ilr) transformation, leading to so-called symmetric coordinates, is presented here. Summarizing the correlations in a heat-map gives a powerful tool for bivariate data analysis. Here an application of the new method using a data set from a regional geochemical mapping project based on soil O and C horizon samples is demonstrated. Differences to 'classical' correlation analysis based on log-transformed data are highlighted. The fact that some expected strong positive correlations appear and remain unchanged even following a log-ratio transformation has probably led to the misconception that the special nature of compositional data can be ignored when working with trace elements. The example dataset is employed to demonstrate that using 'classical' correlation analysis and plotting XY diagrams, scatterplots, based on the original or simply log transformed data can easily lead to severe misinterpretations of the relationships between elements. PMID- 28724227 TI - Carbon and nitrogen allocation strategy in Posidonia oceanica is altered by seawater acidification. AB - Rising atmospheric CO2 causes ocean acidification that represents one of the major ecological threats for marine biota. We tested the hypothesis that long term exposure to increased CO2 level and acidification in a natural CO2 vent system alters carbon (C) and nitrogen (N) metabolism in Posidonia oceanica L. (Delile), affecting its resilience, or capability to restore the physiological homeostasis, and the nutritional quality of organic matter available for grazers. Seawater acidification decreased the C to N ratio in P. oceanica tissues and increased grazing rate, shoot density, leaf proteins and asparagine accumulation in rhizomes, while the maximum photochemical efficiency of photosystem II was unaffected. The 13C-dilution in both structural and non-structural C metabolites in the acidified site indicated quali-quantitative changes of C source and/or increased isotopic fractionation during C uptake and carboxylation associated with the higher CO2 level. The decreased C:N ratio in the acidified site suggests an increased N availability, leading to a greater storage of 15N-enriched compounds in rhizomes. The amount of the more dynamic C storage form, sucrose, decreased in rhizomes of the acidified site in response to the enhanced energy demand due to higher shoot recruitment and N compound synthesis, without affecting starch reserves. The ability to modulate the balance between stable and dynamic C reserves could represent a key ecophysiological mechanism for P. oceanica resilience under environmental perturbation. Finally, alteration in C and N dynamics promoted a positive contribution of this seagrass to the local food web. PMID- 28724229 TI - Microbial association with the dynamics of particulate organic carbon in response to the amendment of elevated CO2-derived wheat residue into a Mollisol. AB - As the chemical quality of crop residue is likely to be affected by elevated CO2 (eCO2), residue amendments may influence soil organic carbon (SOC) sequestration. However, in Mollisols, the dynamics of the SOC fractions in response to amendment with wheat residue produced under eCO2 and the corresponding microbial community composition remain unknown. Such investigation is essential to residue management, which affects the soil quality and productivity of future farming systems. To narrow this knowledge gap, 13C-labeled shoot and root residue derived from ambient CO2 (aCO2) or eCO2 were amended into Mollisols and incubated for 200days. The soil was sampled during the incubation period to determine the residue-C retained in the three SOC fractions, i.e., coarse intra-aggregate particulate organic C (coarse iPOC), fine iPOC and mineral-associated organic C (MOC). The soil bacterial community was assessed using a MiSeq sequencing instrument. The results showed that the increase in SOC concentrations attributable to the application of the wheat residue primarily occurred in the coarse iPOC fraction. Compared with the aCO2-derived shoot residue, the amendment of eCO2-derived shoot residue resulted in greater SOC concentrations, whereas no significant differences (P>0.05) were observed between the aCO2- and eCO2-derived roots. Principal coordinates analysis (PCoA) showed that the residue amendment significantly (P<=0.05) altered the bacterial community composition compared with the non-residue amendment. Additionally, the bacterial community in the aCO2 derived shoot treatment differed from those in the other residue treatments until day 200 of the incubation period. The eCO2-derived shoot treatment significantly increased (P<=0.05) the relative abundances of the genera Acidobacteriaceae_(Subgroup_1)_uncultured, Bryobacter, Candidatus_Solibacter, Gemmatimonas and Nitrosomonadaceae_uncultured, whereas the opposite trend was observed in Nonomuraea, Actinomadura, Streptomyces and Arthrobacter (P<=0.05). These results imply that the response of the microbial community to the eCO2 derived shoot treatment is associated with its contribution to the POC fractions. PMID- 28724230 TI - Excessive input of phosphorus significantly affects microbial Fe(III) reduction in flooded paddy soils by changing the abundances and community structures of Clostridium and Geobacteraceae. AB - Microbial Fe(III) reduction can make an excellent contribution to the bioremediation of contaminated environments and potentially reduce methanogenesis. Excessive input of phosphorus (P) by P fertilizer application and eutrophied irrigation water might have a substantial influence on the process of microbial Fe(III) reduction in flooded paddy soils. To evaluate the effect of P application on microbial Fe(III) reduction, the responses of Clostridium and Geobacteraceae communities to different concentrations of P addition (CK: 0mmolPkg-1 soil; P1: 3.3mmolPkg-1 soil; P2: 20mmolPkg-1 soil) were investigated in anaerobically incubated paddy slurries. P addition significantly inhibited Fe(III) reduction during the early stage of incubation (from days 0 to 20). Compared with the CK treatment, the maximum Fe(III) reduction rate (Vmax) in treatments P1 and P2 remarkably decreased by 0.281 and 0.439mg.g-1.d-1, respectively. However, the addition of P had no significant effect on Fe(III) reduction during the later stage of incubation (after 20days). The abundances of Clostridium and Geobacteraceae were suppressed by P addition, and the suppression effect was more obvious with higher P concentration. P addition significantly changed the community structures of Clostridium and Geobacteraceae during the entire incubation. The communities of Clostridium and Geobacteraceae were closely correlated with the process of Fe(III) reduction. In conclusion, P addition could inhibit the microbial reduction of Fe(III) during the early stage of incubation by reducing the abundances and altering the community structures of Clostridium and Geobacteraceae, however, the inhibition could be eliminated with increased incubation time. This study demonstrates that soil microbial communities are sensitive to excessive P application, which can jointly impact relevant biogeochemical processes in flooded paddy soils. PMID- 28724231 TI - Arsenic speciation in aquifer sediment under varying groundwater regime and redox conditions at Jianghan Plain of Central China. AB - At Jianghan Plain of central Yangtze basins where the health of >73, 000 people has been affected by long term intake of high arsenic groundwater, over 100 sediment samples from four boreholes at the field monitoring sites were collected and analyzed to delineate the distribution and speciation of As in the shallow aquifer sediment. Results showed that sediment As concentration is generally dependent on the lithological conditions, with the higher As concentration present in fine particle sediment, especially in the silty sand layers underlying clay or silty clay layers. High As concentration in the sediment mainly occurred in three different depth ranges: <5m, 15-35m, and >35m. Both the groundwater regime and redox conditions played important roles in controlling sediment As speciation. Arsenate (86%) was the dominated As species in the near surface sediment. As the redox turned to be reducing, arsenite (64%) became the dominant species in the underlying clay and silty clay layers. But in the silty sand aquifer near the boundary of unconfined aquifer and confined aquifer, arsenate (85%) became the dominant species again as results of redox potential elevation. In the deep medium to coarse sand aquifers (>35m deep), As-sulfides (49%-63%) were the main species of As. The speciation and reactivity of sediment As strongly controlled the spatial distribution of groundwater As concentration, while seasonal variation in groundwater As concentration and speciation affected the content and speciation of sediment As. PMID- 28724232 TI - Postoperative atrial fibrillation: The truth is stranger than fiction. PMID- 28724233 TI - Examining the impact of active clearance of chest drainage catheters on postoperative atrial fibrillation. AB - OBJECTIVE: Postoperative atrial fibrillation (POAF) is one of the most frequent complications encountered after heart surgery, and significantly increases complications and mortality. An obstructed chest tube, leaving unevacuated blood around the heart and lungs, can lead to atrial inflammation, which can trigger POAF. The aim of this study was to assess the effectiveness of chest drainage incorporating an active tube clearance (ATC) system in reducing the rate of POAF. METHODS: This retrospective analysis based on 300 consecutive patients undergoing heart surgery compared 142 patients allocated to an ATC drainage protocol with 158 controls managed with standard chest drainage. Using a 1:1 propensity score match, 214 patients were included in paired analysis (107 in each group). The primary endpoint was POAF. RESULTS: Unmatched patients managed with ATC chest drainage protocol had a reduction of 34% in their POAF rate compared with those managed with standard drains (23% vs 35%, P = .01). In the matched cohort, ATC was associated with a reduction of 31% in the rate of POAF (24% vs 35%, P = .09) and a trend toward shorter postoperative length of stay (5.0 [4.0; 7.0] vs 6.0 [5.0; 8.0], P = .08). In multivariable analysis, chest drainage with ATC showed a protective effect on POAF with odds ratio of 0.5 (95% confidence interval, 0.1 0.9; P = .02). CONCLUSIONS: The use of an ATC chest drainage protocol may be associated with reduced POAF. Our results suggest that efforts to maintain chest tube patency could be useful to reduce the incidence of POAF. PMID- 28724234 TI - Posterior pericardial drainage: Could improving chest tube patency provide the same benefits? PMID- 28724235 TI - Choice of second pericardial drainage tube for posterior placement. PMID- 28724236 TI - Posterior pericardial drainage by any means may improve outcomes after cardiac surgery. PMID- 28724237 TI - Use of resuscitated donor hearts for transplantation: Same results either side of Atlantic Ocean. PMID- 28724238 TI - To use or not to use post-cardiopulmonary resuscitation donor hearts? PMID- 28724239 TI - Old Europe carefully looks at a new heart: Cardiac arrest-resuscitated donors should not be turned down for heart transplant at first glance. PMID- 28724240 TI - Successful, neutral, or negative? PMID- 28724241 TI - Cell therapies: The next-generation clinical trials. PMID- 28724242 TI - Do not throw the baby with the water bath! PMID- 28724243 TI - Extensively and multi drug-resistant Acinetobacter baumannii recovered from technosol at a dump site in Croatia. AB - In a karst pit above City of Rijeka in Croatia the hazardous industrial waste was continuously disposed from 1955 to 1990, and later it was periodically used as an illegal dump site. The surface part of a technosol at the edge of dump was analysed mineralogically, geochemically and bacteriologically. From the technosol rich in petroleum hydrocarbons and heavy metals three isolates of Acinetobacter baumannii were recovered. Isolates from technosol shared many features that are previously described for clinically isolates: the affiliation to IC1 and 2, multi drug resistant (MDR) or extensively drug-resistant (XDR) antibiotic resistance profile, carbapenem resistance mediated by blaOXA72 and blaOXA23 genes, and the expression of virulence factors. In in vitro conditions, isolates were able to survive in contact with technosol during 58days of monitoring. The most probable source of A. baumannii in technosol was the illegally disposed hospital waste. Proper management and disposal of human solid waste is mandatory to prevent the spread of clinically important A. baumannii in nature. PMID- 28724244 TI - Evaluating mercury concentrations and body condition in American alligators (Alligator mississippiensis) at Merritt Island National Wildlife Refuge (MINWR), Florida. AB - Concentrations of mercury (Hg) are not well studied in free-ranging wildlife. Atmospheric deposition patterns of Hg have been studied in detail and have been modeled for both global and specific locations and often correlate to environmental impact. However, monitoring the impact of Hg deposition in wildlife is complicated due to local environmental conditions that can affect the transformation of atmospheric Hg to the biologically available forms (e.g., rainfall, humidity, pH, the ability of the environment to methylate Hg), as well as affect the accessibility to organisms for sampling. In this study, Hg concentrations in blood samples from a population of American alligators (Alligator mississippiensis) at Merritt Island National Wildlife Refuge (MINWR), FL, USA, over a seven-year period (2007 to 2014; n=174 individuals) were examined to assess Hg variation in the population, as well as the difference in Hg concentration as a function of health status. While most of this population is healthy, 18 individuals with low body mass indices (BMI, defined in this study) were captured throughout the sampling period. These alligators exhibited significantly elevated Hg concentrations compared to their age/sex/season matched counterparts with normal BMI, suggesting that health status should be taken into account when examining Hg concentrations and effects. Alligator blood Hg concentrations were related to the interaction of age/size, sex, and season. This study illustrates the value of a routinely monitored population of large predators in a unique coastal wetland ecosystem, and illuminates the value of long-term environmental exposure assessment. PMID- 28724245 TI - Radioactively-hot particles detected in dusts and soils from Northern Japan by combination of gamma spectrometry, autoradiography, and SEM/EDS analysis and implications in radiation risk assessment. AB - After the March 11, 2011, nuclear reactor meltdowns at Fukushima Dai-ichi, 180 samples of Japanese particulate matter (dusts and surface soils) and 235 similar U.S. and Canadian samples were collected and analyzed sequentially by gamma spectrometry, autoradiography, and scanning electron microscopy with energy dispersive X-ray analysis. Samples were collected and analyzed over a five-year period, from 2011 to 2016. Detectable levels of 134Cs and 137Cs were found in 142 of 180 (80%) Japanese particulate matter samples. The median radio-cesium specific activity of Japanese particulate samples was 3.2kBqkg-1+/-1.8kBqkg-1, and the mean was 25.7kBqkg-1 (sigma=72kBqkg-1). The U.S. and Canadian mean and median radio-cesium activity levels were <0.03kBqkg-1. U.S. and Canadian samples had detectable 134Cs and 137Cs in one dust sample out of 32 collected, and four soils out of 74. The maximum US/Canada radio-cesium particulate matter activity was 0.30+/-0.10kBqkg-1. The mean in Japan was skewed upward due to nine of the 180 (5%) samples with activities >250kBqkg-1. This skewness was present in both the 2011 and 2016 sample sets. >300 individual radioactively-hot particles were identified in samples from Japan; composed of 1% or more of the elements cesium, americium, radium, polonium, thorium, tellurium, or strontium. Some particles reached specific activities in the MBqMUg-1 level and higher. No cesium containing hot particles were found in the U.S. sample set. Only naturally occurring radionuclides were found in particles from the U.S. background samples. Some of the hot particles detected in this study could cause significant radiation exposures to individuals if inhaled. Exposure models ignoring these isolated hot particles would potentially understate human radiation dose. PMID- 28724247 TI - Persistent organic pollutants and risk of diabetes and obesity on healthy adults: Results from a cross-sectional study in Spain. AB - Environmental exposure to persistent organic pollutants (POPs) has been reported to be relevant in the population of the Canary Islands (Spain), especially that of organochlorine pesticides. On the other hand, the population of this archipelago presents a high prevalence of type 2 diabetes (T2D), and it has been recently reported that environmental chemical contamination could play a role in the development of this disease. We performed a cross-sectional study in a representative sample from this archipelago to evaluate whether serum levels of selected POPs could be considered as risk factors for diabetes in this population. Serum levels of 30 POPs were determined in 429 adults (9.3% with T2D). We found that serum levels of p,p'-DDE (DDE), PCB-153 and PCB-118 were significantly higher among subjects having diabetes than in non-diabetic subjects (p=0.001, p=0.046, and p<0.0001, respectively). We observed a positive correlation between serum p,p'-DDE and glucose levels. Serum p,p'-DDE was identified as a risk factor for diabetes in univariate analysis in the whole series, and it remained as an independent risk factor for diabetes in subjects with serum glucose <126mg/dL (multivariate analysis, Exp(B)=1.283, CI 95% (1.023 1.611), p=0.031). Those normoglycemic subjects that are most exposed to p,p'-DDE (95th percentile: serum p,p'-DDE>5MUg/L) seem to be those people at higher risk. Our results showed that p,p'-DDE levels were significantly higher among subjects having diabetes. These findings should be considered by public health Authorities to implement measures devoted to minimize human exposure to pollutants that could be harmful to the population. PMID- 28724246 TI - Health consequences of electric lighting practices in the modern world: A report on the National Toxicology Program's workshop on shift work at night, artificial light at night, and circadian disruption. AB - The invention of electric light has facilitated a society in which people work, sleep, eat, and play at all hours of the 24-hour day. Although electric light clearly has benefited humankind, exposures to electric light, especially light at night (LAN), may disrupt sleep and biological processes controlled by endogenous circadian clocks, potentially resulting in adverse health outcomes. Many of the studies evaluating adverse health effects have been conducted among night- and rotating-shift workers, because this scenario gives rise to significant exposure to LAN. Because of the complexity of this topic, the National Toxicology Program convened an expert panel at a public workshop entitled "Shift Work at Night, Artificial Light at Night, and Circadian Disruption" to obtain input on conducting literature-based health hazard assessments and to identify data gaps and research needs. The Panel suggested describing light both as a direct effector of endogenous circadian clocks and rhythms and as an enabler of additional activities or behaviors that may lead to circadian disruption, such as night-shift work and atypical and inconsistent sleep-wake patterns that can lead to social jet lag. Future studies should more comprehensively characterize and measure the relevant light-related exposures and link these exposures to both time-independent biomarkers of circadian disruption and biomarkers of adverse health outcomes. This information should lead to improvements in human epidemiological and animal or in vitro models, more rigorous health hazard assessments, and intervention strategies to minimize the occurrence of adverse health outcomes due to these exposures. PMID- 28724248 TI - Exposure to particulate air pollution during early pregnancy is associated with placental DNA methylation. AB - Maternal exposure to particulate matter with aerodynamic diameter <10MUm (PM10) during pregnancy results in adverse birth outcomes. Changes in placental DNA methylation might mediate those adverse effects. In this study, we examined the associations between prenatal PM10 exposure and DNA methylation of LINE1, HSD11B2 and NR3C1 in human placenta. One hundred and eighty-one mother newborn pairs (80 fetal growth restriction newborns, 101 normal newborns) participated in this study. The average PM10 exposure of each trimester and of the whole pregnancy was calculated using daily air pollution concentration data. Placental DNA methylation was measured by quantitative polymerase chain reaction pyrosequencing. Placental LINE-1 DNA methylation was reversely associated with first trimester PM10 exposure 1.78% (-beta=1.78, 95% CI: -3.35, -0.22%), while placental HSD11B2 DNA methylation was associated with both first and second trimester PM10 exposure, and relatively increased by 1.03% (95% CI: 0.07, 1.98%) and 2.33% (95% CI: 0.69, 3.76%) for each 10MUg/m3 increase in exposure to PM10. Those associations were much more evident in fetal growth restriction newborns than those in normal newborns. In summary, early pregnancy PM10 exposure was associated with placental DNA methylation of LINE1 and HSD11B2, suggesting that such methylation alterations might mediate PM-induced reproductive and developmental toxicity. PMID- 28724249 TI - Occurrence and source apportionment of atmospheric halogenated flame retardants in Lhasa City in the Tibetan Plateau, China. AB - Active air samples were collected in Lhasa, one of the highest cities in the world (3650m above sea level) located in the Tibetan Plateau, and were analyzed for 38 halogenated flame retardants (HFRs), including polybrominated diphenyl ethers (PBDEs), non-PBDE brominated flame retardants (NBFRs) and dechlorane plus (DPs). The median concentrations of PBDEs, NBFRs and DPs were 40, 23 and 0.21pg/m3, respectively. Correlation analysis indicated the common source and/or similar environmental behavior for several HFRs. The Clausius-Clapeyron equation was applied to diagnose the sources of lower molecular weight HFRs (LMW-HFRs), which suggested that the gaseous LMW-HFRs at Lhasa were more controlled by regional or long-range atmospheric transport rather than the temperature-driven evaporation from local contaminated surfaces. Finally, the potential source contribution function model was applied to assess the influences of air parcels on the atmospheric concentrations of HFRs in Lhasa, which suggested that the sources of higher molecular weight HFRs (HMW-HFRs) were mostly originated from local emissions, while the others were originated from long-range atmospheric transport. PMID- 28724250 TI - Reuse water: Exposure duration, seasonality and treatment affect tissue responses in a model fish. AB - Partially remediated gray (reuse) water will likely find increasing use in a variety of applications owing to the increasing scarcity of freshwater. We aimed to determine if a model fish, the goldfish, could sense reuse water using olfaction (smell), and if 30min or 7d (acute) and 60d (sub-chronic) exposures would affect their olfactory responses to natural odorants. We examined olfaction as previous studies have found that numerous chemicals can impair the olfactory sense, which is critical to carrying out numerous life-sustaining behaviors from feeding to mating. We also examined if fish olfactory and liver tissues would mount a response in terms of biotransformation enzyme gene expression, and whether treatment of reuse water with UV/H2O2 ameliorated adverse effects following reuse water exposure. We found that fish olfactory tissue responded to reuse water as it would to a natural odorant and that UV/H2O2 treatment had no influence on this. With acute exposures, olfactory impairment was apparent regardless of water type (e.g. responses of 23-55% of control), but in sub chronic exposures, only the untreated reuse water caused olfactory impairment. The exposure of fish to reuse water increased the expression of one enzyme (CYP1A; >2.5-6.5 fold change) and reuse water treatment with UV/H2O2 reversed the effect. There was a seasonal effect that was likely due to changes in water quality (60d summer exposure impaired olfaction whereas spring and fall exposures did not). Overall, the data suggest that reuse water may be detected by olfaction, impair olfactory responses in fish receiving unavoidable exposures, and that exposure duration and season are important factors to consider regarding adverse effects. PMID- 28724251 TI - Concurrent exposures to nonylphenol, bisphenol A, phthalates, and organophosphate pesticides on birth outcomes: A cohort study in Taipei, Taiwan. AB - Prenatal exposure to phenols, phthalates (PAEs), and organophosphate (OP) pesticides may increase the risk of abnormal birth outcomes. However, many previous studies have examined exposure to a limited number of chemical classes or exposure profiles limited to a specific stage of pregnancy. This study aims to characterize the concurrent exposure scenario throughout pregnancy by simultaneously monitoring internal doses of several endocrine-disrupting compounds (EDCs), including 2 phenols (nonylphenol (NP) and bisphenol A (BPA)), 9 PAEs, and 6 OP pesticide metabolites and to assess the relationships between concurrent exposure to EDCs and infant birth weight, length, and head and chest circumference. One hundred and sixty two women provided three spot urine samples at approximately 11 and 26weeks gestation and at delivery. We applied multivariable linear regression and ridge regression models to estimate the effects of separate and correlated exposures. Multivariable linear regression models revealed that women with short birth-length infants had significantly higher urinary second-trimester NP levels (50th percentile, 5.03MUg/g creatinine) (beta=-0.47cm; 95% CI=-0.93 to -0.01). Similarly significant relationships were observed between second-trimester mono-methyl phthalate (MMP) exposure and short birth length, second-trimester SigmaPAEs and short birth length, second-trimester SigmaPAEs exposure and reduced head and chest circumference, second-trimester diethylphosphate (DEP) exposure and reduced birth weight and length, and second trimester SigmaDEPs exposure and short birth length. Women with urinary BPA above the 75th percentile or SigmaPAEs levels above the 50th percentile in the third trimester had infants with significantly reduced head circumference. These observations suggest that the second trimester may be the critical stage of susceptibility for fetal development. In ridge regression models, for which women with fewer measures for exposure to NP, BPA, MMP, SigmaPAEs, DEP and SigmaDEPs simultaneously were available, no relationships were found with infant size at birth. Additional studies with larger sample sizes are warranted. PMID- 28724252 TI - Effect of operating conditions on speciation and bioavailability of trace metals in submerged anaerobic membrane bioreactors. AB - This study investigated the effect of changes in pH (7, 6.5 and 6), hydraulic retention time (HRT) (6h, 4h, and 2h), solids retention time (SRT) (100d and 25d) on the speciation of trace metals (TMs) in submerged anaerobic membrane bioreactors (SAMBRs). The results showed that the metal retention capacity of SAMBRs reduced when the pH, HRT and SRT were reduced i.e. up to 21.9%, 39.1%, and 17.1%, respectively, but it was also found that the speciation of these TMs generally shifted towards highly bioavailable fractions i.e. Soluble and Exchangeable. The degree of shifting in speciation depended on the affinity of the TMs for anaerobic sludge and their sensitivity to the changes. TMs with the most and the least significant changes in speciation were Fe and Mn, respectively. PMID- 28724253 TI - Acceleration of organic removal and electricity generation from dewatered oily sludge in a bioelectrochemical system by rhamnolipid addition. AB - Conversion of biomass energy of dewatered oily sludge to electricity is the rate limiting process in bioelectrochemical system (BES). In this study, 2mgg-1 rhamnolipids were added to dewatered oily sludge, resulting in a significant enhancement in maximum power density from 3.84+/-0.37 to 8.63+/-0.81Wm-3, together with an increase in total organic carbon (TOC) and total petroleum hydrocarbon (TPH) removal from 24.52+/-4.30 to 36.15+/-2.79mgg-1 and 29.51+/-3.30 to 39.80+/-2.47mgg-1, respectively. Rhamnolipids can also enhance the solubilization and promote the hydrolysis of dewatered oily sludge with increases in SOCD from 14.93+/-2.44 to 18.40+/-0.08mgg-1 and VFAs from 1.02+/-0.07 to 1.39+/-0.12mgg-1. Furthermore, bacteria related to substrate degradation were predominant in dewatered oily sludge, and bacteria related to the sulfate/sulfide cycle were significantly enriched by rhamnolipid addition. PMID- 28724254 TI - Effects of calcium on the performance, bacterial population and microbial metabolism of a denitrifying phosphorus removal system. AB - A sequencing batch reactor was operated to study the effects of influent Ca2+ on the efficiency, bacterial population, and microbial metabolism of denitrifying phosphorus removal system. Results showed that high Ca2+ loading (>=80mg/L) significantly inhibited the performance of simultaneous nitrogen and phosphorus removal. The abundance of phosphorus removal-related organisms (Dechloromonas and Candidatus Accumulibacter) decreased with increasing Ca2+ concentration from 20 to 140mg/L, while the abundance of glycogen-accumulating organisms and other bacteria increased. Metabolomic analyses revealed that the metabolic profiles of microbial community were also affected by high influent Ca2+ concentrations. 3 Hydroxybutyrate, acetate, alanine, and glutamate were the main differentiated metabolites in the system. An accumulation of amino acids and a reduction of nucleotides and amines were important response to high Ca2+ loading. Long-term Ca2+ loading had a reversible effect on the denitrifying phosphorus removal system as it could revive after a 50-day recovery process. PMID- 28724255 TI - Effects of organic composition on the anaerobic biodegradability of food waste. AB - This work investigated the influence of carbohydrates, proteins and lipids on the anaerobic digestion of food waste (FW) and the relationship between the parameters characterising digestion. Increasing the concentrations of proteins and lipids, and decreasing carbohydrate content in FW, led to high buffering capacity, reduction of proteins (52.7-65.0%) and lipids (57.4-88.2%), and methane production (385-627 mLCH4/g volatile solid), while achieving a short retention time. There were no significant correlations between the reduction of organics, hydrolysis rate constant (0.25-0.66d-1) and composition of organics. Principal Component Analysis revealed that lipid, C, and N contents as well as the C/N ratio were the principal components for digestion. In addition, methane yield, the final concentrations of total ammonia nitrogen and free ammonia nitrogen, final pH values, and the reduction of proteins and lipids could be predicted by a second-order polynomial model, in terms of the protein and lipid weight fraction. PMID- 28724256 TI - First study to explore the feasibility of applying microbial fuel cells into constructed wetlands for COD monitoring. AB - Chemical oxygen demand (COD) is one of the major targets to remove in constructed wetlands (CWs) system. Traditional method for COD measurement is a complex, time consuming and highly toxic reagents participated procedure. In this study, microbial fuel cell (MFC) was successfully integrated into CW for indicating COD concentration. Results showed that there are two linear correlations between bioelectrical signals (output voltage from MFC) and COD concentration (acetate), which are COD from 0 to 500mg/L (101.99+/-7.42 to 631.74+/-7.41mV, R2=0.9710) and then from 500 to 1000mg/L (631.74+/-7.41 to 668.46+/-0.01mV, R2=0.9245). Furthermore, results also revealed the specificity of the system in terms of different types of carbon source. Overall, this work presented the feasibility of using CW-MFC for in-situ sensing COD during the wastewater treatment process, which will be a promising technique for water quality monitoring within CWs. PMID- 28724257 TI - Efficient coproduction of gluconic acid and xylonic acid from lignocellulosic hydrolysate by Zn(II)-selective inhibition on whole-cell catalysis by Gluconobacter oxydans. AB - With Zn(II)-selective inhibition on the whole-cell catalysis of Gluconobacter oxydans NL71, gluconic acid and xylonic acid were coproduced efficiently from the hydrolysate of corn stover. Further metabolism of gluconic acid to the by-product 2-ketogluconic acid was prevented by addition of 10g/L ZnCl2. Remarkably, yields of 93.91% of gluconic acid and 93.36% of xylonic acid were obtained with the supplement of ZnCl2 in the synthetic medium, without by-product production. After optimization of the concentrations of ZnCl2 and inocula of the strain, maximum amounts of gluconic acid and xylonic acid were coproduced at titers of 63.01g/L and 33.81g/L, with an overall utilization of 100% of the sugars in the enzymatic hydrolysate of corn stover. The results showed execution of our objective to prove this novel bioconversion method for simultaneously producing gluconic acid and xylonic acid, which would benefit subsequent studies on the comprehensive utilization of lignocellulosic materials. PMID- 28724258 TI - LLDT-288, a novel triptolide analogue exhibits potent antitumor activity in vitro and in vivo. AB - (14S)-14beta-(1-(2-morpholinoethyl)-1H-indazol-5-ylamino)mthylepitriptolide (LLDT 288) was a novel C14beta-heterocycle aminomethyl substituent triptolide analogue, which showed comparable cytotoxicity to triptolide. Here we demonstrated that LLDT-288 displayed broad-spectrum, potent antitumor activity, effectively against drug-resistance cancer cells, and induced apoptosis in vitro, but exerted low toxicity. Moreover, it exhibited a remarkable microsomal stability, and showed no inhibitory effects on different cytochrome P450 isoforms. In vivo, orally administration of LLDT-288 exhibits promising efficacy in human prostate (PC-3) xenograft mice model with obviously low toxicity. Further, the in vivo metabolic studies suggested that LLDT-288 was extensively metabolized in rats and mainly excreted in the form of metabolites in the feces. PMID- 28724259 TI - Herbal pre-conditioning induces proliferation and delays senescence in Wharton's Jelly Mesenchymal Stem Cells. AB - BACKGROUND: Mesenchymal Stem Cells (MSCs) are multipotent stem cells which are being explored for various clinical applications. Isolation and in-vitro expansion of MSCs remain important in achieving desired cell number for the therapy. However, in-vitro proliferation of MSCs is often associated with senescence and early onset of apoptosis which limits its therapeutic ability and long term clinical use. Tinospora cordifolia and Withania somnifera are used widely in Ayurveda: the traditional Indian system of medicine and are reported to have rejuvenating and anti-aging potential. In the present study, we investigated the effect of Tinospora cordifolia and Withania somnifera on proliferation and senescence of wharton's jelly MSCs (WJMSCs) in-vitro. METHODS: WJMSCs were treated in culture medium with Tinospora cordifolia leaf and Withania somnifera root extracts to examine their effect on proliferation and senescence properties of WJMSCs. Proliferation of WJMSCs was assayed by cell count, MTT, BrdU incorporation assay, cell cycle analysis and Ki67 mRNA expression. Senescence was demonstrated using beta-galactosidase senescence assay and associated mRNA markers. RESULTS: Culture medium supplemented with Tinospora cordifolia leaf and Withania somnifera root extracts exhibited significant increase in proliferation of WJMSCs as evidenced by cell count and MTT assay. Cell cycle analysis using propidium iodide showed increase in G2/M phase and decrease in apoptotic cells. BrdU incorporation and upregulation of proliferation marker ki67 by RT PCR showed increased DNA synthesis/proliferation in Tinospora cordifolia and Withania somnifera extract treated MSCs. Delayed senescence was confirmed by beta galactosidase senescence assay and down regulation of senescence marker p21. CONCLUSION: Our results demonstrate for the first time that Tinospora cordifolia and Withania somnifera extracts support proliferation and inhibit senescence in WJMSCs making them suitable candidates as supplements for in-vitro expansion without affecting the cell viability indicating its non-toxic nature. PMID- 28724260 TI - Pleuropterus multiflorus (Hasuo) mediated straightforward eco-friendly synthesis of silver, gold nanoparticles and evaluation of their anti-cancer activity on A549 lung cancer cell line. AB - Pleuropterus multiflorus (Hasuo) is a widely used medicinal plant in Korea and China for treating amnesia, isnomia, heart throbbing etc. With the constructive idea of promoting the wide-spread usage of P. multiflorus, we propose its indirect usage in the form of biologically active silver (Pm-AgNPs) and gold nanoparticles (Pm-AuNPs). The synthesized nanoparticles were predominantly spherical, crystalline with the Z-average hydrodynamic diameter of 274.8nm and 104.8nm respectively. Also, proteins and phenols were identified as the major players involved in their synthesis and stability. Further, Pm-AgNPs at 25MUg/mL were significantly cytotoxic to lung cancer cells, whereas, Pm-AuNPs were not cytotoxic to both normal keratinocyte and lung cancer cells even at 100MUg/mL. In addition, further evaluation of the anti-cancer activity of these new nanoparticles, such as migration and apoptosis, shown that Pm-AgNPs have a potential therapeutic effect on A549 lung cancer cell treatment. To the best of our knowledge, this is the first report dissecting out the ability of the endemic P. multiflorus for the synthesis of bioactive silver and gold nanoparticle which would open up doors for its extensive usage in medicinal field. PMID- 28724261 TI - Development of a sandwich enzyme-linked immunosorbent assay for dTMP-GH fusion protein by rational immunogen selection. AB - dTMP-GH is a chimeric protein containing a tandem dimer of thrombopoietin mimetic peptide (dTMP) fused to human growth hormone (hGH) prepared previously by our team. It shows significant bioactivity in promoting thrombocytopoiesis, but detection of intact dTMP-GH in plasma is still a challenge due to the presence of endogenous hGH. In this study, a rabbit polyclonal antibody with high affinity to dTMP was obtained with a BSA-conjugated immunogen composed of 20 amino acids sequence spanning two TMP and the linker. A monoclonal antibody termed as 3B2 was screened out by using immunizing mice with whole dTMP-GH, which was proved to simultaneously interact with rhGH, TMP-GH, and dTMP-GH, respectively. In this study, we developed a specific and sensitive sandwich enzyme-linked immunosorbent assay (ELISA) with two antibodies (one polyclonal and one HRP-conjugated monoclonal) to quantify dTMP-GH. The polyclonal antibody and HRP-conjugated monoclonal antibody 3B2 were applied as the capture antibody and detection antibody, respectively. A good correlation between ELISA and bicinchoninic acid (BCA) assay in the quantification of diluted dTMP-GH was observed (r2 = 0.996). Meanwhile, the standard curve of this ELISA method was found in a linear relationship between 0.2 and 10 ng/mL in the presence of rabbit plasma. In vivo experiments demonstrate that the newly developed method is effective to detect dTMP-GH in rabbits, which paves the way for further pharmacokinetic evaluation. PMID- 28724262 TI - Phytohormones and induction of plant-stress tolerance and defense genes by seed and foliar inoculation with Azospirillum brasilense cells and metabolites promote maize growth. AB - Azospirillum spp. are plant-growth-promoting bacteria used worldwide as inoculants for a variety of crops. Among the beneficial mechanisms associated with Azospirillum inoculation, emphasis has been given to the biological nitrogen fixation process and to the synthesis of phytohormones. In Brazil, the application of inoculants containing A. brasilense strains Ab-V5 and Ab-V6 to cereals is exponentially growing and in this study we investigated the effects of maize inoculation with these two strains applied on seeds or by leaf spray at the V2.5 stage growth-a strategy to relieve incompatibility with pesticides used for seed treatment. We also investigate the effects of spraying the metabolites of these two strains at V2.5. Maize growth was promoted by the inoculation of bacteria and their metabolites. When applied via foliar spray, although A. brasilense survival on leaves was confirmed by confocal microscopy and cell recovery, few cells were detected after 24 h, indicating that the effects of bacterial leaf spray might also be related to their metabolites. The major molecules detected in the supernatants of both strains were indole-3-acetic acid, indole-3-ethanol, indole-3-lactic acid and salicylic acid. RT-PCR of genes related to oxidative stress (APX1, APX2, CAT1, SOD2, SOD4) and plant defense (pathogenesis-related PR1, prp2 and prp4) was evaluated on maize leaves and roots. Differences were observed according to the gene, plant tissue, strain and method of application, but, in general, inoculation with Azospirillum resulted in up-regulation of oxidative stress genes in leaves and down-regulation in roots; contrarily, in general, PR genes were down-regulated in leaves and up-regulated in roots. Emphasis should be given to the application of metabolites, especially of Ab-V5 + Ab-V6 that in general resulted in the highest up-regulation of oxidative-stress and PR genes both in leaves and in roots. We hypothesize that the benefits of inoculation of Azospirillum on seeds or by leaf spray, as well as of leaf spraying of Azospirillum metabolites, are strongly correlated with the synthesis of phytohormones and by eliciting genes related to plant-stress tolerance and defense against pathogens. PMID- 28724263 TI - Mutagenesis and characterization of a Bacillus amyloliquefaciens strain for Cinnamomum camphora seed kernel oil extraction by aqueous enzymatic method. AB - The purpose of the present study was to increase the proteinase activity of the strain NCU116 by combining ultraviolet irradiation and N-methyl-N'-nitro-N nitroso guanidine treatment, in order to enhance the efficiency of Cinnamomum camphora seed kernel oil (CCSKO) extraction by aqueous enzymatic method (AEM). The mutated strain, designated as NCU116-1, was screened out by the ratio of hydrolytic zone diameter to colony diameter on skim milk plate. The proteinase activity (9116.1 U/ml) of NCU116-1 was increased by 31.9% compared with the parental strain. The extracellular enzymes produced by NCU116-1 included proteinase, pectase, glucoamylase, cellulase and amylase. The proteinase had the maximum activity at 50 degrees C. Its optimum temperature and pH value were approximately 45 degrees C and 8.0 respectively. Mn2+ was an activator of neutral proteinase. The glucoamylase had the maximum activity at 35 degrees C, and was activated by Cu2+, Fe3+ and Mn2+. Its optimum temperatures and pH value were 35 degrees C and 8.0 respectively. The pectinase had the maximum activity at 40 degrees C, and was activated by Ca2+ and Mn2+. Its optimum temperatures and pH value were 35-40 degrees C and 6.0 respectively. The optimum conditions of CCSKO extraction by AEM were also investigated. The results suggested that the best amount of enzyme solution and enzymolysis time were 20% (v/v) and 4 h, respectively. The oil extraction rate was 95.2% under these conditions. Thus, a suitable mutated strain was selected for CCSKO extraction by AEM and the optimum extraction conditions were determined. PMID- 28724264 TI - Erratum to Nanostructured Silica/Gold-Cellulose-Bonded Amino-POSS Hybrid Composite via Sol-Gel Process and Its Properties. PMID- 28724265 TI - Facile Synthesis of SiO2@C Nanoparticles Anchored on MWNT as High-Performance Anode Materials for Li-ion Batteries. AB - Carbon-coated silica nanoparticles anchored on multi-walled carbon nanotubes (SiO2@C/MWNT composite) were synthesized via a simple and facile sol-gel method followed by heat treatment. Scanning and transmission electron microscopy (SEM and TEM) studies confirmed densely anchoring the carbon-coated SiO2 nanoparticles onto a flexible MWNT conductive network, which facilitated fast electron and lithium-ion transport and improved structural stability of the composite. As prepared, ternary composite anode showed superior cyclability and rate capability compared to a carbon-coated silica counterpart without MWNT (SiO2@C). The SiO2@C/MWNT composite exhibited a high reversible discharge capacity of 744 mAh g 1 at the second discharge cycle conducted at a current density of 100 mA g-1 as well as an excellent rate capability, delivering a capacity of 475 mAh g-1 even at 1000 mA g-1. This enhanced electrochemical performance of SiO2@C/MWNT ternary composite anode was associated with its unique core-shell and networking structure and a strong mutual synergistic effect among the individual components. PMID- 28724266 TI - Preparation and Enhanced Catalytic Hydrogenation Activity of Sb/Palygorskite (PAL) Nanoparticles. AB - A Sb/palygorskite (PAL) composite was synthesized by a facile solvothermal process and applied in catalytic hydrogenation of p-nitrophenol for the first time. It was found that the Sb nanoparticles with the sizes of 2-5 nm were well dispersed on the fiber of PAL, while partial aggregated Sb nanoparticles with sizes smaller than 200 nm were also loaded on the PAL. The Sb/PAL composite with 9.7% Sb mass amounts showed outstanding catalytic performance by raising the p nitrophenol conversion rate to 88.3% within 5 min, which was attributed to the synergistical effect of Sb and PAL nanoparticles facilitating the adsorption and catalytic hydrogenation of p-nitrophenol. PMID- 28724268 TI - Efficient Expansion of SALL4-Transduced Umbilical Cord Blood Derived CD133+Hematopoietic Stem Cells. AB - Hematopoietic stem cells (HSCs) were characterized by self-renewal and multilineage potential. Umbilical cord blood-derived (UCB) as an alternative source of HSCs is widely used especially in children for stem cells transplant (SCT). The main limitation in using UCB for transplantation especially in adults is low cell dose. To overcome this limitation besides using double dose UCB, ex vivo expansion is the most important way to increase cell number for transplantation. HSCs are mainly isolated using CD133 or CD34. CD133, as the most primitive marker, shows important physiological role in maintenance and expansion of HSCs. SALL4 plays crucial role in the development and maintaining the pluripotency and self-renewal ability of embryonic stem cells (ESCs) as well as HSCs. Moreover, SALL4 act as a regulator of HSCs expansion, normal hematopoiesis, and hematological malignancies. In the present study, CD133+ cells positively selected and ex vivo expanded in SALL-4 and GFP-transduced group. CD133 expression assessed using flow cytometry at day 0, 7 and 10. Moreover, multilineage differentiation and proliferation potential of expanded cells in both groups evaluated using colony forming unit (CFU) assay, and cells count assay. Karyotyping analysis was performed to assess any chromosomal instability after 7 days of expansion. Obtained results demonstrated that SALL-4 transduced cells showed significant increase in cell number compared to control group. Moreover, immunophenotyping results showed higher expression level of CD133 at day 7 and 10 following expansion in SALL-4 transduced (62 % and 42%) compared to control group (51% and 20.6%). Our results illustrated that SALL4 could act as a positive factor for the expansion of CD133+ derived UCB cells besides maintaining self-renewal and differentiation ability of expanded cell without any numerical and structural chromosomal aberrations . PMID- 28724267 TI - Association of Neo Angiogenesis by CD34 Expression and Clinicopathologic Features in Squamous Cell Carcinoma of Cervix. AB - Tumor angiogenesis is one of the most important factors in tumor progression. In this study, the angiogenesis of cervical squamous cell carcinoma (SCC) and its association with prognostic factors was assessed by using CD34 immunostaining marker. The microvessel density in 40 patients with cervical SCC was studied in three areas of the tumor; stromal and peripheral tumor area (combined) central stromal tumor area and peripheral tumor area and the relationship of microvascular density and survival was also evaluated. The count of CD34 is correlated with younger age, the presence of perineural invasion and metastasis to lymph nodes. High peripheral tumor angiogenesis is also correlated with lower disease-free tumor survival. According to the findings of the present study, CD34 expression, especially in peripheral tumor areas, can be used as a prognostic marker in cervical SCC. PMID- 28724269 TI - Association of Human Methionine Synthase-A2756G Transition With Prostate Cancer: A Case-Control Study and in Silico Analysis. AB - Methionine synthase (MTR) is one of the key enzymes of folate pathway, which play a key role in the construction, repair, and methylation of DNA. In this study, an association of MTR A2756G gene transition with prostate cancer in men populations of Kashan-Iran was investigated by a case-control study and an in silico analysis. The 200 samples including 100 patients with prostate cancer, as case group and 100 healthy men, as control group included in this study. MTR-A2756G genotyping was performed by PCR-RFLP technique. Some in silico tools used to evaluate the effects of A2756G transition on the structure and function of MTR. Results showed that the AG genotype (OR: 2.4014, 95% CI: 1.3216-4.3636, P=0.0040), and GG genotype (OR: 3.6324, 95% CI: 1.2629-10.4475, P=0.0167) and G allele (OR: 2.0120, 95% CI: 1.3098-3.0905, P=0.0014) were associated with prostate cancer. In silico analysis showed that polymorphisms of the enzyme protein might change properties of MTR such as relative mutability and flexibility, which leads to alteration of stability and function of the enzyme. Based on the results, an MTR-A2756G polymorphism which changes activity and stability of the methionine synthase associated with prostate cancer in men. It is a preliminary study and is presenting data for future comprehensive study for making a clinical conclusion that this gene transition is a biomarker for susceptibility to prostate cancer. PMID- 28724271 TI - Comparison of Histopathologic Features of Endometrial Cancer Based on Menopausal Status and Safety of Ovarian Preservation in Premenopausal Women. AB - The aim of this study was to investigate the frequency of coexisting ovarian malignancy and to determine whether ovarian preservation is feasible in premenopausal endometrial cancer (EC) patients. The data of 251 patients with endometrioid type endometrial cancer were retrospectively reviewed. We classified patients into two groups based on menopausal status. Information regarding patient age, preoperative and intraoperative evaluations, pathology reports, and follow-up results were abstracted from medical records. Coexisting ovarian malignancy was detected in 2 (4.3%) of 46 patients in premenopausal group and in 11 (5.3%) of 205 patients in postmenopausal group. Both patients in premenopausal group with coexisting ovarian malignancy had lymph node involvement and grade 2 tumors, while 5 (45.4%) of 11 patients in postmenopausal group had lymph node involvement and 9 (81.8%) of 11 patients had grade 3 tumors. Incidence of coexisting ovarian malignancies in premenopausal women with EC should not be underestimated. Owing to that thorough preoperative evaluation and an extensive intraoperative evaluation is critical for the decision of preserving ovaries. PMID- 28724270 TI - Synergistic Effects of Ad-Libitum Low-Dose Fructose Drinking and Low-Dose Streptozotocin Treatment in Wistar Rats: A Mild Model of Type 2 Diabetes. AB - To develop a convenient animal model of T2D by pretreatment with low-dose 10% w/v fructose (FRC) solution followed by the injection of low doses of streptozotocin (STZ) in Wistar rats. For this 8-week experimental study; rats were first fed a standard chow ad-libitum diet and either tap water (n=40) or 10% w/v FRC solution (n=40) for 4 weeks. Next, rats in each category were randomly allocated to 4 subgroups (n=10 each) of low-dose STZ (25,35, and 45 mg/kg). The final mean fasting blood sugar (FBG) of FRC+STZ45 (197+/-55.87 mg/dl) were significantly higher than that of the STZ45 (P=0.015) and FRC (P=0.019) groups. FRC+STZ45 showed the highest insulin resistance demonstrated by insulin tolerance test [area under the curve (AUC) of insulin tolerance test; P<0.05]. AUC was not significantly different between the STZ45 and non-STZ groups and between FRC and non-FRC fed groups. Furthermore, FBG levels did not differ between FRC and non FRC groups. Body weight measurement showed that the FRC+STZ45 group had the lowest body weight compared to all other groups. Our data provide the evidence that FRC and STZ45 synergistically could induce hyperglycemia and insulin resistance in Wistar rats. Here we presented a feasible model for initial forms of T2D by employing pretreatment with low-dose FRC solution and treatment with low-dose STZ. PMID- 28724272 TI - Patients' Characteristics, Histopathological Findings, and Tumor Stage in Different Types of Malignant Melanoma: A Retrospective Multicenter Study. AB - Cutaneous malignant melanoma (CMM) is currently the most fatal of skin cancers accounting for 50000 deaths annually. Five distinct melanomas are described histopathologically: superficial spreading, lentigo maligna, nodular, acral lentiginous and mucosal melanoma. The aim of this study was to investigate the characteristics of patients with various types of malignant melanoma and evaluate histopathological findings. In this retrospective study, we obtained our data from the records of 111 patients with melanoma. Biopsied specimens were collected and re-evaluated. Demographic information and histopathological findings were noted. SPSS 16 was used for analyzing data. Chi-square and one-way ANOVA was conducted for comparing categorical and numerical variables respectively. The mean age of patients was 59.33+/-14.68 years old. Most common melanoma type was acral lentiginous (40.5%), followed by nodular (35.1%) and mucosal (10.8%). The highest tumor thickness was viewed in nodular melanoma followed by mucosal melanoma. The highest rate of metastasis, microsatellitosis, perineural invasion and Clark level of the invasion were reported in nodular and acral lentiginous respectively. The most frequent rate of ulceration and vascular invasion was reported in mucosal melanoma. Distribution of melanoma types varies largely in different regions. Lack of classic presentations in some types necessitate specific public education about warning signs. Histopathological and pathological characteristics in melanoma can aid in better staging and management of the tumor. PMID- 28724273 TI - Effects of Inhaled Salbutamol on Sport-Specific Fitness of Non-Asthmatic Football Players. AB - In this article, we investigated the effectiveness of inhaled salbutamol withtherapeutic dose on the sport-specific performance of non-asthmatic young football players. In a double-blinded, randomised placebo controlled trial with 2 treatment, 2-period crossover design, twenty participants who were non-asthmatic junior professional football players were randomly allocated to two groups. Fifteen minutes before sport-specific fitness testing, each group randomly received 2 inhalations (200 micrograms) of salbutamol or placebo, respectively. After 1 week wash-out period, each participant has tested again, this time with the alternative inhaler. The primary outcomes were the differences between salbutamol and placebo groups in six tests of 7*30-m repeated sprint, Loughborough soccer dribbling, vertical jump, agility, Loughborough soccer passing, 20-m multistage shuttle run. A total of twenty players did two test batteries completely. There was no significant difference between salbutamol and placebo users in the tests [Treatment effect (CI95%); 7*30 sprint: -2.4 (-7.6 2.9), dribbling: -3.8 (-12.2-4.5), vertical jump: -1.2 (-3.7-1.3), agility: -0.4 (-0.9-0.1), passing: 0.2 (-12-12.4), shuttle run distance: -112 (-503.2-279.2)]. Furthermore, no period or carry-over effects were detected. It seems that single therapeutic dose of inhaled salbutamol (200 micrograms) does not appear to improve football related performance. PMID- 28724274 TI - The Correlation Between Liver Fat Content and Ulcerative Colitis Disease Severity. AB - To evaluate the association between disease severity and hepatic steatosis in patients with ulcerative colitis (UC) and non-alcoholic steatohepatitis (NASH). Consecutively selected UC patients admitted to the gastroenterology clinic were enrolled in the study. UC severity was assessed by Truelove and Witts classification. Patients with severe UC were excluded from the study. NASH was determined based on persistently elevated serum aminotransferase levels and detection of fatty liver ultrasound. Patients with other etiologies for elevated aminotransferase levels were excluded. Liver fat content (LFC) was assessed by measuring liver fat score (LFS). One hundred patients (42% male) were included in the study. According to liver ultrasound examination, 62 (%) patients were identified with grade 1 fatty liver disease, and 38 (%) patients were classified as advanced (grade 2 and 3) fatty liver disease. Sixty-one patients had left sided UC and (46%) had mild UC disease severity index. LFS was significantly higher in UC patients with the moderate disease than patients with mild disease (3.53+/-2.68 vs. 5.89+/-2.85, respectively; P<0.01). Nevertheless, no significant difference was observed in LFS regarding UC extension. There was no significant difference between NASH ultrasound grades in view of UC severity and extension. LFC might be associated with UC severity. PMID- 28724275 TI - A Case Report of Paraneoplastic Pemphigus Associated With Retroperitoneal Inflammatory Myofibroblastic Tumor. AB - Paraneoplastic pemphigus (PNP) is an autoimmune bullous disease associated with underlying neoplasms, both malignant and benign. The most constant clinical presentation of PNP is the presence of intractable stomatitis. Herein we present a 25-year-old male with a 3-month history of refractory stomatitis especially involving the lips and widespread vesiculobullous eruption on his trunk and extremities. The diagnosis of PNP was confirmed based on histological and serological results. Investigation for the underlying neoplasm revealed a retroperitoneal tumorous mass which was biopsied and diagnosed as the inflammatory myofibroblastic tumor (IMT). The tumor was surgically excised, and different treatment regimens were used to treat the mucocutaneous lesions. Skin lesions responded favorably to treatment, but oral stomatitis still persists which is the case in most PNP patients. This combination of PNP and IMT has rarely been reported in the literature. Treatment started with corticosteroid and rituximab then tumor excised. PMID- 28724276 TI - Fatal Small Intestinal Ischemia Due to Methamphetamine Intoxication: Report of a Case With Autopsy Results. AB - Methamphetamine is one of the most common abused drugs, so its various effects on different body organs should be familiar to all physicians. Regarding its gastrointestinal sequels, there are few reports of ischemic colitis induced by its vasoconstrictive effects. This is the first report of isolated small intestinal infarction resulting in death following methamphetamine toxicity. A 40 year-old woman with a past history of medical treatment for obesity referred to hospital with severe chest and back pain, perspiration, nausea, agitation, high blood pressure, bradycardia and subsequent lethargy and vasomotor instability. Cardiac evaluations were normal, and a toxicologic urinalysis revealed methamphetamine. Later, abdominal pain predominated, and ultrasonography revealed signs of bowel infarction. She did not consent to surgery and succumbed afterward. At autopsy gangrene and perforation of distal ileum were found. The cause of death was determined as intestinal gangrene following methamphetamine toxicity. Methamphetamine has anorectic effects and so is used in some "diet pills"; Consumers may not even know they are using methamphetamine. Hence in cases of either known MA abuse or those using unknown weight reduction drugs presenting with gastrointestinal complaints or abdominal pain, intestinal ischemia should be kept in mind and if plausible, intervened promptly. PMID- 28724277 TI - Suicide by Fire Extinguisher Powder Ingestion: A Case Report. AB - A 51-year-old man committed suicide by swallowing the contents of a fire extinguisher. A few hours after his suicide attempt, he was referred to the medical center for poisoning. At the time of admission, the patient was conscious with stable vital signs. The patient complained of burning lips and mouth, mentioning diarrhea. Initial treatments included gastric lavage with activated charcoal, while paraclinical measures were requested. The patient had undergone hypernatremia (Na: 152 mEq/l) and metabolic alkalosis. Treatment focused on the adjustment of sodium level and alkalosis. On the first day of hospitalization, the patient experienced recurrent episodes of tonic-clonic seizure along with the loss of consciousness. On the third day of hospitalization, the patient developed respiratory arrest followed by cardiac arrest and death. PMID- 28724278 TI - Reductions in Eosinophil Biomarkers by Benralizumab in Patients With Asthma. PMID- 28724279 TI - Alterations in Striatal Circuits Underlying Addiction-Like Behaviors. AB - Drug addiction is a severe psychiatric disorder characterized by the compulsive pursuit of drugs of abuse despite potential adverse consequences. Although several decades of studies have revealed that psychostimulant use can result in extensive alterations of neural circuits and physiology, no effective therapeutic strategies or medicines for drug addiction currently exist. Changes in neuronal connectivity and regulation occurring after repeated drug exposure contribute to addiction-like behaviors in animal models. Among the involved brain areas, including those of the reward system, the striatum is the major area of convergence for glutamate, GABA, and dopamine transmission, and this brain region potentially determines stereotyped behaviors. Although the physiological consequences of striatal neurons after drug exposure have been relatively well documented, it remains to be clarified how changes in striatal connectivity underlie and modulate the expression of addiction-like behaviors. Understanding how striatal circuits contribute to addiction-like behaviors may lead to the development of strategies that successfully attenuate drug-induced behavioral changes. In this review, we summarize the results of recent studies that have examined striatal circuitry and pathway-specific alterations leading to addiction like behaviors to provide an updated framework for future investigations. PMID- 28724280 TI - Management of Benign and Malignant Pancreatic Duct Strictures. AB - The diagnosis and management of pancreatic strictures, whether malignant or benign, remain challenging. The last 2 decades have seen dramatic progress in terms of both advanced imaging and endoscopic therapy. While plastic stents remain the cornerstone of the treatment of benign strictures, the advent of fully covered metal stents has initiated a new wave of interest in calibrating the pancreatic duct with fewer sessions. In malignant disease, palliation remains the priority and further data are necessary before offering systematic pancreatic stenting. PMID- 28724281 TI - The virtual asthma guideline e-learning program: learning effectiveness and user satisfaction. AB - BACKGROUND/AIMS: Effective educational tools are important for increasing adherence to asthma guidelines and clinical improvement of asthma patients. We developed a computer-based interactive education program for asthma guideline named the Virtual Learning Center for Asthma Management (VLCAM). We evaluated the usefulness of program in terms of its effects on user awareness of asthma guideline and level of satisfaction. METHODS: Physicians-in-training at tertiary hospitals in Korea were enrolled in a cross-sectional questionnaire survey. The e learning program on asthma guideline was conducted over a 2-week period. We investigated changes in the awareness of asthma guideline using 35-item self administered questionnaire aiming at assessing physicians' knowledge, attitude, and practice. Satisfaction with the program was scored on 4-point Likert scales. RESULTS: A total of 158 physicians-in-training at six tertiary hospitals completed the survey. Compared with baseline, the overall awareness obtained from the scores of knowledge, attitude, and practice was improved significantly. Participants were satisfied with the VLCAM program in the following aspects: helpfulness, convenience, motivation, effectiveness, physicians' confidence, improvement of asthma management, and willingness to recommend. All items in user satisfaction questionnaires received high scores over 3 points. Moreover, the problem-based learning with a virtual patient received the highest user satisfaction among all parts of the program. CONCLUSIONS: Our computer-based e learning program is useful for improving awareness of asthma management. It could improve adherence to asthma guidelines and enhance the quality of asthma care. PMID- 28724282 TI - Survival Nomograms after Curative Neoadjuvant Chemotherapy and Radical Surgery for Stage IB2-IIIB Cervical Cancer. AB - Purpose: The purpose of this study was to develop nomograms for predicting the probability of overall survival (OS) and progression-free survival (PFS) in locally advanced cervical cancer treated with neoadjuvant chemotherapy and radical surgery. Materials and Methods: Nomograms to predict the 5-year OS rates and the 2-year PFS rates were constructed. Calibration plots were constructed, and concordance indices were calculated. Evaluated variableswere body mass index, age, tumor size, tumor histology, grading, lymphovascular space invasion, positive parametria, and positive lymph nodes. Results: In total 245 patients with locally advanced cervical cancer who underwent neoadjuvant chemotherapy and radical surgery were included for the construction of the nomogram. The 5-year OS and PFS were 72.6% and 66%, respectively. Tumor size, grading, and parametria status affected the rate of OS, whereas tumor size and positive parametria were the main independent PFS prognostic factors. Conclusion: We constructed a nomogram based on clinicopathological features in order to predict 2-year PFS and 5-year OS in locally advanced cervical cancer primarily treated with neoadjuvant chemotherapy followed by radical surgery. This tool might be particularly helpful for assisting in the follow-up of cervical cancer patients who have not undergone concurrent chemoradiotherapy. PMID- 28724283 TI - Lung Cancer Screening with Low-Dose CT in Female Never Smokers: Retrospective Cohort Study with Long-term National Data Follow-up. AB - Purpose: Because of growing concerns about lung cancer in female never smokers, chest low-dose computed tomography (LDCT) screening is often performed although it has never shown clinical benefits. We examinewhether or not female never smokers really need annual LDCT screening when the initial LDCT showed negative findings. Materials and Methods: This retrospective cohort study included 4,365 female never smokers aged 40 to 79 years who performed initial LDCT from Aug 2002 to Dec 2007. Lung cancer diagnosis was identified from the Korea Central Cancer Registry Database registered until December 31, 2013. We calculated the incidence, cumulative probability, and standardized incidence ratio (SIR) of lung cancer by Lung Imaging Reporting and Data System (Lung-RADS) categories showed on initial LDCT. Results: After median follow-up of 9.69 years, 22 (0.5%) had lung cancer. Lung cancer incidence for Lung-RADS category 4 was 1,848.4 (95% confidence interval [CI], 1,132.4 to 3,017.2) per 100,000 person-years and 16.4 (95% CI, 7.4 to 36.4) for categories 1, 2, and 3 combined. The cumulative probability of lung cancer for category 4 was 10.6% at 5 years and 14.8% at 10 years while they were 0.07% and 0.17% when categories 1, 2, and 3 were combined. The SIR for subjects with category 4 was 43.80 (95% CI, 25.03 to 71.14), which was much higher than 0.47 (95% CI, 0.17 to 1.02) for categories 1, 2, and 3 combined. Conclusion: Considering the low risk of lung cancer development in female never smokers, it seems unnecessary to repeat annual LDCT screening for at least 5 years or even longer unless the initial LDCT showed Lung-RADS category 4 findings. PMID- 28724284 TI - Inter-alpha Inhibitor H4 as a Potential Biomarker Predicting the Treatment Outcomes in Patients with Hepatocellular Carcinoma. AB - Purpose: Early prediction of treatment outcomes represents an essential step towards increased treatment efficacy and survival in patients with hepatocellular carcinoma (HCC). In this study, we performed two-dimensional electrophoresis (2 DE) followed by protein profiling to identify biomarkers predictive of therapeutic outcomes in patients with HCC who received liver-directed therapy (LDTx) involving local radiotherapy (RT), and studied the underlying mechanisms of the identified proteins. Materials and Methods: 2-DE analysis was conducted by pooling sera from patients with a good or poor prognosis; serum proteomic profiles of the two groups were compared and analyzed using matrixassisted laser desorption/ionization time-of-flight mass spectrometry. Identified proteins were confirmed via enzyme-linked immunosorbent assay. An invasion assay was performed after overexpression and knockdown of target protein in Huh7 cells. Results: Levels of inter-alpha inhibitor H4 (ITIH4), fibrinogen gamma chain, keratin 9/1 complex, carbonic anhydrase I, and carbonmonoxyhemoglobin S were changed by more than 4-fold in response to LDTx. In particular, pre-LDTx ITIH4 expression was more than 5-fold higher in patients with a good prognosis, compared to patients with a poor prognosis. The migration ability of Huh7 cells was significantly suppressed and enhanced by ITIH4 overexpression and knockdown, respectively. The tumors of patients with HCC and a good prognosis expressed high levels of ITIH4, compared to those of patients with a poor prognosis. Conclusion: Taken together, ITIH4 may be a potential therapeutic target that could inhibit cancer metastasis, as well as a prognostic marker for patients with HCC who are receiving LDTx. PMID- 28724285 TI - Elucidating Potential Energy Surfaces for Singlet O2 Reactions with Protonated, Deprotonated, and Di-Deprotonated Cystine Using a Combination of Approximately Spin-Projected Density Functional Theory and Guided-Ion-Beam Mass Spectrometry. AB - The reactivity of cystine toward electronically excited singlet O2 (a1Deltag) has been long debated, despite the fact that most organic disulfides are susceptible to oxidation by singlet O2. We report a combined experimental and computational study on reactions of singlet O2 with gas-phase cystine at different ionization and hydration states, aimed to determine reaction outcomes, mechanisms, and potential energy surfaces (PESs). Ion-molecule collisions of protonated and di deprotonated cystine ions with singlet O2, in both the absence and the presence of a water ligand, were measured over a center-of-mass collision energy (Ecol) range from 0.1 to 1.0 eV, using a guided-ion-beam scattering tandem mass spectrometer. No oxidation was observed for these reactant ions except collision induced dissociation at high energies. Guided by density functional theory (DFT) calculated PESs, reaction coordinates were established to unravel the origin of the nonreactivity of cystine ions toward singlet O2. To account for mixed open- and closed-shell characters, singlet O2 and critical structures along reaction coordinates were evaluated using broken-symmetry, open-shell DFT with spin contamination errors removed by an approximate spin-projection method. It was found that collision of protonated cystine with singlet O2 follows a repulsive potential surface and possesses no chemically significant interaction and that collision-induced dissociation of protonated cystine is dominated by loss of water and CO. Collision of di-deprotonated cystine with singlet O2, on the other hand, forms a short-lived electrostatically bonded precursor complex at low Ecol. The latter may evolve to a covalently bonded persulfoxide, but the conversion is blocked by an activation barrier lying 0.39 eV above reactants. At high Ecol, C-S bond cleavage dominates the collision-induced dissociation of di-deprotonated cystine, leading to charge-separated fragmentation. Cross section for the ensuing fragment ion H2NCH(CO2-)CH2SS* was measured as a function of Ecol, and the mechanism of charge-separated fragmentation was discussed. It was also found that the reaction of deprotonated cystine with singlet O2 follows a similar mechanism as that of di-deprotonated cystine, but with an even higher activation barrier (0.72 eV). PMID- 28724286 TI - Deep-Dive Targeted Quantification for Ultrasensitive Analysis of Proteins in Nondepleted Human Blood Plasma/Serum and Tissues. AB - Mass spectrometry-based targeted proteomics (e.g., selected reaction monitoring, SRM) is emerging as an attractive alternative to immunoassays for protein quantification. Recently we have made significant progress in SRM sensitivity for enabling quantification of low nanograms per milliliter to sub-naograms per milliliter level proteins in nondepleted human blood plasma/serum without affinity enrichment. However, precise quantification of extremely low abundance proteins (e.g., <= 100 pg/mL in blood plasma/serum) using targeted proteomics approaches still remains challenging, especially for these samples without available antibodies for enrichment. To address this need, we have developed an antibody-independent deep-dive SRM (DD-SRM) approach that capitalizes on multidimensional high-resolution reversed-phase liquid chromatography (LC) separation for target peptide separation and enrichment combined with precise selection of target peptide fractions of interest, significantly improving SRM sensitivity by ~5 orders of magnitude when compared to conventional LC-SRM. Application of DD-SRM to human serum and tissue provides precise quantification of endogenous proteins at the ~10 pg/mL level in nondepleted serum and at <10 copies per cell level in tissue. Thus, DD-SRM holds great promise for precisely measuring extremely low abundance proteins or protein modifications, especially when high-quality antibodies are not available. PMID- 28724287 TI - Active Solvent Modulation: A Valve-Based Approach To Improve Separation Compatibility in Two-Dimensional Liquid Chromatography. AB - Two-dimensional liquid chromatography (2D-LC) is increasingly being viewed as a viable tool for solving difficult separation problems, ranging from targeted separations of structurally similar molecules to untargeted separations of highly complex mixtures. In spite of this performance potential, though, many users find method development challenging and most frequently cite the "incompatibility" between the solvent systems used in the first and second dimensions as a major obstacle. This solvent strength related incompatibility can lead to severe peak distortion and loss of resolution and sensitivity in the second dimension. In this paper, we describe a novel approach to address the incompatibility problem, which we refer to as Active Solvent Modulation (ASM). This valve-based approach enables dilution of 1D effluent with weak solvent prior to transfer to the 2D column but without the need for additional instrument hardware. ASM is related to the concept we refer to as Fixed Solvent Modulation (FSM), with the important difference being that ASM allows toggling of the diluent stream during each 2D separation cycle. In this work, we show that ASM eliminates the major drawbacks of FSM including complex elution solvent profiles, baseline disturbances, and slow 2D re-equilibration and demonstrate improvements in 2D separation quality using both simple small molecule probes and degradants of heat-treated bovine insulin as case studies. We believe that ASM will significantly ease method development for 2D-LC, providing a path to practical methods that involve both highly complementary 1D and 2D separations and sensitive detection. PMID- 28724289 TI - Deuterohemin-Peptide Enzyme Mimic-Embedded Metal-Organic Frameworks through Biomimetic Mineralization with Efficient ATRP Catalytic Activity. AB - An enzyme mimic harboring iron porphyrin (DhHP-6) embedded in zeolite imidazolate framework-8 (ZIF-8) was constructed through a biomimetic mineralization approach to obtain composite DhHP-6@ZIF-8. The composite was then used as a catalyst in the atom transfer radical polymerization (ATRP) of poly(ethylene glycol) methyl ether methacrylate (PEGMA500) in which poly(PEGMA500) could be synthesized with monomer conversion of 76.1% and Mn of 45 900 g/mol, stronger than that obtained when using free DhHP-6 as a catalyst. More importantly, it could efficiently overcome the drawbacks of free DhHP-6 and achieve the easy separation of DhHP-6 from the catalytic system and the elimination of iron residues in the synthesized polymer. In addition, it exhibited an enhanced recyclability with monomer conversion of 75.7% after five cycles and favorable stability during the ATRP reaction with <3.0% of DhHP-6 release within 100 h. Thus, the enzyme mimic-ZIF-8 composite developed through biomimetic mineralization can be potentially used as an effective catalyst for preparing well-defined polymers with biomedical applications. PMID- 28724290 TI - Identifying and Breaking Scaling Relations in Molecular Catalysis of Electrochemical Reactions. AB - Improving molecular catalysis for important electrochemical proton-coupled electron transfer (PCET) reactions, such as the interconversions of H+/H2, O2/H2O, CO2/CO, and N2/NH3, is an ongoing challenge. Synthetic modifications to the molecular catalysts are valuable but often show trade-offs between turnover frequency (TOF) and the effective overpotential required to initiate catalysis (etaeff). Herein, we derive a new approach for improving efficiencies-higher TOF at lower etaeff-by changing the concentrations and properties of the reactants and products, rather than by modifying the catalyst. The dependence of TOF on etaeff is shown to be quite different upon changing, for instance, the pKa of the acid HA versus the concentration or partial pressure of a reactant or product. Using the electrochemical reduction of dioxygen catalyzed by iron porphyrins in DMF as an example, decreasing [HA] 10-fold lowers etaeff by 59 mV and decreases the TOF by a factor of 10. Alternatively, a 10-fold decrease in Ka(HA) also lowers etaeff by 59 mV but only decreases the TOF by a factor of 2. This approach has been used to improve a catalytic TOF by 104 vs the previously reported scaling relationship developed via synthetic modifications to the catalyst. The analysis has the potential to predict improved efficiency and product selectivity of any molecular PCET catalyst, based on its mechanism and rate law. PMID- 28724291 TI - Kinetic Model for Two-Step Nucleation of Peptide Assembly. AB - Intermediate dynamic assemblies are increasingly seen as necessary for the initial desolvation and organization of biomaterials to achieve their final crystalline order. Here we present a general peptide assembly model for two-step nucleation. The model predicts the phase transitions and equilibria between different phases by employing a combination of the Flory-Huggins parameter, the particle growth constant, and the binding energy to assemblies. Monte Carlo simulations are used to demonstrate how the system evolves from pure solution phases to the final thermodynamic assembly phase via an intermediate metastable particle phase. The final state of the system is determined by the solubility of the particle and assembly phases, where the phase with the lower solubility accumulates. A rare three-phase equilibrium exists when the solubilities of the particles and assemblies are similar. Experimental support for this model is achieved with assembly of the amyloid peptide Ac-KLVFFAE-NH2 (Abeta(16-22)) in mixed acetonitrile/water systems. Increasing the acetonitrile concentration decreases the number of particles, increases the particle size, and accelerates the assembly rate, all consistent with acetonitrile increasing the Abeta(16-22) peptide's solubility of particles but with little influence on the stability of the assemblies. Taken together, our model captures the transition from the metastable particle phase to the higher order peptide assembly through two-step nucleation. PMID- 28724288 TI - Proton-Based Structural Analysis of a Heptahelical Transmembrane Protein in Lipid Bilayers. AB - The structures and properties of membrane proteins in lipid bilayers are expected to closely resemble those in native cell-membrane environments, although they have been difficult to elucidate. By performing solid-state NMR measurements at very fast (100 kHz) magic-angle spinning rates and at high (23.5 T) magnetic field, severe sensitivity and resolution challenges are overcome, enabling the atomic-level characterization of membrane proteins in lipid environments. This is demonstrated by extensive 1H-based resonance assignments of the fully protonated heptahelical membrane protein proteorhodopsin, and the efficient identification of numerous 1H-1H dipolar interactions, which provide distance constraints, inter residue proximities, relative orientations of secondary structural elements, and protein-cofactor interactions in the hydrophobic transmembrane regions. These results establish a general approach for high-resolution structural studies of membrane proteins in lipid environments via solid-state NMR. PMID- 28724292 TI - Adsorption of Proteins on Colloidal Lignin Particles for Advanced Biomaterials. AB - Coating of colloidal lignin particles (CLPs), or lignin nanoparticles (LNPs), with proteins was evaluated in order to establish a safe, self-assembly mediated modification technique to tune their surface chemistry. Gelatin and poly- l lysine formed the most pronounced protein corona on the CLP surface, as determined by dynamic light scattering (DLS) and zeta potential measurements. Spherical morphology of individual protein coated CLPs was confirmed by transmission electron (TEM) and atomic force (AFM) microscopy. A mechanistic adsorption study with several random coiled and globular model proteins was carried out using quartz crystal microbalance with dissipation monitoring (QCM D). The three-dimensional (3D) protein fold structure and certain amino acid interactions were decisive for the protein adsorption on the lignin surface. The main driving forces for protein adsorption were electrostatic, hydrophobic, and van der Waals interactions, and hydrogen bonding. The relative contributions of these interactions were highly dependent on the ionic strength of the surrounding medium. Capillary electrophoresis (CE) and Fourier transform infrared spectroscopy (FTIR) provided further evidence of the adsorption-enhancing role of specific amino acid residues such as serine and proline. These results have high impact on the utilization of lignin as colloidal particles in biomedicine and biodegradable materials, as the protein corona enables tailoring of the CLP surface chemistry for intended applications. PMID- 28724293 TI - Spotlights: Volume 8, Issue 14. PMID- 28724294 TI - Healing, spirituality, and palliative care. PMID- 28724295 TI - Healing in modern medicine. PMID- 28724296 TI - The influence of relationships on the meaning making process: patients' perspectives. AB - BACKGROUND: The diagnosis of a chronic or life limiting illness followed by treatment often requires an adjustment to life goals and expectations. With added existential concerns, patients' struggle to redefine life meaning while also finding ways to alleviate any distress that may occur. Central to the work of many scholars, meaning making is thought to be a vital component of negotiating traumatic life events while also essential to the positive adjustment in chronic illness and healing. Information gained from science about meaning making is an important link to the medical community as it provides physicians with insight to increase patient centered care. The purpose of this qualitative study was to expand our understanding of meaning making for an individual diagnosed with a chronic or life limiting illness. Also, to explore the connection, if any, to how meaning making may lead to an outcome of psychosocial spiritual healing or exacerbate distress. METHODS: The goal of this secondary data analysis was to examine the influences of meaning making to determine its impact on a patient's sense of healing. This study utilized data collected during in-person interviews using a convenience sample of 30 palliative care patients. The original study was conducted at three different locations: the National Institutes of Health Clinical Center (NIH), a large research institution in Bethesda, Maryland; Johns Hopkins Suburban Hospital, a community hospital in Bethesda, Maryland; and Mobile Medical Care (Mobile Med), a community clinic located in Rockville, Maryland. A total of 56 potential participants were approached based on convenience sampling with 30 participants enrolled (54%). RESULTS: The overall theme that emerged indicated a strong emphasis on meaning making through relationships, specifically an increase of meaning in family relationships, the connection to friends, and a change in compassion towards others. CONCLUSIONS: Further investigation is needed to explore relationships as a variable in finding meaning during life limiting illness among patients, loved ones and their physicians. It is clear that developing meaning is a central mechanism to the construct of healing. PMID- 28724297 TI - "Living in the moment" among cancer survivors who report life-transforming change. AB - BACKGROUND: Some cancer survivors say that while coping with their illness they have had what they identify as a highly beneficial, personal, life-transforming change (LTC; a self-subscribed condition among participants in this study, not a researcher-defined construct). Previously we found that the content of LTC was highly individual; but certain features of the LTC process were quite uniform. For example, LTC was driven by a very rational desire to remain genuinely functional as a person in the midst of highly stressful circumstances. Our purpose is to further understand LTC by analysis of participants' critique of questionnaire items on positive subjective outcomes. METHODS: We obtained a set of 67 positive psychosocial questionnaire items from the Psychosocial Impact of Illness (PII) item bank development team of the National Institutes of Health (NIH) Patient-Reported Outcomes Measurement Information Systems (PROMIS) initiative. The PII items are sourced from a variety of instruments, representing more than one theory of personal growth. This enabled a grounded theory approach, allowing a theory of LTC to emerge from the data. Each of nine cancer survivors participated in a single, two-part session: an hour-long semi-structured qualitative interview regarding their LTC (previously reported), then individually critiquing the 67 items in terms of relevance and importance to their self-reported LTC experience (their critique is analyzed in this article). The PII items were grouped into 20 researcher-defined conceptual themes and average scores for each theme were computed and compared. RESULTS: The theme "living in the moment" (LITM; sometimes referred to as "Being in the moment" in other literature) scored significantly higher than other themes. Qualitative interview transcripts revealed that participants spontaneously used LITM as a coping tactic that reduced worries to manageable levels. These participants noticed subsequently that LITM also produced unexpected substantial benefits in many aspects of their lives unrelated to cancer. This experience motivated increased use of LITM that led to LTC beyond coping with cancer. CONCLUSIONS: LITM can be a practical, effective coping tactic to manage worries and promote adaptation to the challenges of a life-threatening illness. Participant interviews indicated the motivation for LITM is not traumatic experience, but seems to be conservation of their own personal resources for coping with increased stresses. Hobfoll's conservation of resources model appears to be more consistent with LITM among our participants than Tedeshi's posttraumatic growth (PTG) model. Several PII items that represent LITM have unfortunately been removed from the current PROMIS PII item bank, indicating a need for improved of item selection criteria. Further research is needed first to identify or develop assessment items that more effectively capture the precursors and phases of LITM, and then develop interventions that facilitate LITM and LTC for patients. PMID- 28724298 TI - Definitions of healing and healing interventions across different cultures. AB - For centuries healing has been embedded in non-Western cultures. Traditional cultures believe that healing is derived from the divine and utilize a holistic approach to healing including the body, mind, and spirit. The community and environment are key elements in individual healing along with herbal remedies and ceremonies. Western cultures have accepted some traditional methods of relaxation and exercise, such as yoga and tai chi. In this paper we will examine some similar themes of traditional practices to better understand traditional patients' healing paradigm and find new tools as practitioners of Western medicine. PMID- 28724299 TI - Spirituality in adolescent patients. AB - Adolescence, the transition between childhood and adulthood, represents a time of rapid biological, neurocognitive, and psychosocial changes. These changes have important implications for the development and evolution of adolescent spirituality, particularly for adolescents with chronic or life-limiting illnesses. To contribute positively to adolescent spiritual formation, palliative care teams benefit from understanding the normative changes expected to occur during adolescence. This paper provides a narrative review of adolescent spirituality while recognizing the role of religious, familial, and cultural influences on spiritual development during the teenage years. By giving explicit attention to the contextual norms surrounding adolescence and still recognizing each adolescent-aged patient as unique, palliative care teams can help adolescents transition toward meaningful and sustainable spiritual growth. This paper reviews the clinical and research implications relevant to integrating adolescent spiritual health as part of comprehensive palliative care. PMID- 28724300 TI - Spirituality in young adults with end-stage cancer: a review of the literature and a call for research. AB - Existing research finds that spiritual wellness may enhance quality of life in those with end-stage cancer. Unfortunately, much of the literature is focused on the spirituality of those in middle and older adulthood, leaving questions about the spirituality of young adults facing life-threatening illness. This article reviews the current landscape of spirituality in young adults with cancer. In addition, this paper serves as a call for research to consider the development of spirituality in this unique population. The literature shows that young adults with cancer are less likely to use mental health services compared to other age groups with cancer. Research tends to be restricted to early young adulthood with a focus on spiritual or religious practices and less about the meaning of spirituality in the context of their illness. A review of the development of spirituality in healthy young adults helps to build the framework to ask questions about what may be occurring for those with life-threatening illness. PMID- 28724301 TI - Sacred space and the healing journey. AB - Sacred space and spirituality have long been used to heal the mind, body, and spirit. This article illuminates the origins of sacred space and its role as a healing environment from the first human construct, the burial mound, to the 5th Century BCE Greek healing city of Epidaurus. It then examines the role of spirituality as one of the necessary human institutions for a healthy society, according to the Italian philosopher Giambattista Vico. The conclusion then surveys three contemporary healing environments' architecture, the Department of Veteran Affairs Healing Environment Design Guideline (VAHEDG), and how these sacred spaces mend individual and community ailments. PMID- 28724302 TI - Efficacy and safety of vedolizumab as a treatment option for moderate to severe refractory ulcerative colitis in two patients after liver transplant due to primary sclerosing cholangitis. AB - Vedolizumab is a humanized IgG1 monoclonal antibody that selectively blocks the lymphocyte integrin alpha4beta7 and prevents its interaction with endothelial adhesion molecules and subsequent transmigration to the gastrointestinal tract. The drug was approved in 2014 for the induction and maintenance treatment of ulcerative colitis and moderate to severe Crohn's disease that is refractory or intolerant to conventional treatment with corticoids and immunosuppressants and/or anti-TNFalpha drugs. However, inflammatory bowel disease has a variable behavior following liver transplant. One third of patients with ulcerative colitis associated with primary sclerosing cholangitis are expected to deteriorate despite receiving immunosuppression to prevent rejection. There is limited experience with anti-TNFalpha agents in patients with inflammatory bowel disease in the setting of liver transplantation and the studies to date involve a limited number of cases. The efficacy and safety data of vedolizumab in this situation are unreliable and very preliminary. We present two cases with the aim to present the efficacy and safety of vedolizumab after one year of treatment in two patients who underwent a transplant due to primary sclerosing cholangitis. One case had de novo post-transplant ulcerative colitis refractory to two anti TNFalpha drugs (golimumab and infliximab). The other patient had a colostomy due to fulminant colitis and developed severe ulcerative proctitis refractory to infliximab after reconstruction with an ileorectal anastomosis. PMID- 28724303 TI - Direct percutaneous endoscopic jejunostomy using single-balloon enteroscopy without fluoroscopy: a case series. AB - BACKGROUND: Direct percutaneous endoscopic jejunostomy (DPEJ) is a useful method to provide enteral nutrition to individuals when gastric feeding is not possible or contraindicated. The aim of this study was to analyze the efficacy and safety of DPEJ tube placement with the Gauderer-Ponsky technique by the pull method, using single-balloon enteroscopy (SBE) without fluoroscopy. METHODS: This is a retrospective analysis of patients undergoing SBE for DPEJ placement in a referral hospital between January 2010 and March 2016. Technical success, clinical success and procedure related complications were recorded. RESULTS: Twenty-three patients were included (17 males, median age 71 years, range 37-93 years). The most frequent indications for DPEJ were gastroesophageal cancer (n = 10) and neurological disease (n = 8). Eighty-seven percent of the patients had a contraindication to percutaneous endoscopic gastrostomy (PEG) and PEG was unsuccessful in the remaining patients. The technical success rate was 83% (19/23), transillumination was not possible in three patients and an accidental exteriorization of the bumper resulting in a jejunal perforation occurred in one patient. The clinical success was 100% (19/19). The median follow-up was five months (range 1-35 months). Apart from the case of jejunal perforation and the two cases of accidental exteriorization, there were no other complications during follow-up. The 6-month survival was 65.8% and the 1-year survival was 49.3%. CONCLUSION: DPEJ can be carried out successfully via SBE without fluoroscopy with a low rate of significant adverse events. Although, leaving the overtube in place during the bumper pulling can be useful for distal jejunal loops, it can be safely removed in proximal loops to minimize complications. PMID- 28724304 TI - Synchronous intraductal papillary mucinous neoplasm and a pancreatic neuroendocrine tumor: more than a coincidence? AB - BACKGROUND: Although the association between intraductal papillary mucinous neoplasm of the pancreas (IPMN) and pancreatic neuroendocrine tumor (PNET) has been increasingly reported, whether this association is real or coincidence remains unclear. We report a case of synchronous IPMN and a PNET which were diagnosed preoperatively and discuss the tumorigenesis, clinicopathological features and management of these rare tumors based on the published literature. CASE REPORT: A 56-year-old male was incidentally diagnosed with a 14 mm branch duct IPMN and a 3.6 mm non-functional PNET during an evaluation due to persistent upper abdominal pain via endoscopic ultrasound. Close follow-up of the patient was decided as the IPMN had no worrisome features. A review of twenty-two previously reported cases of synchronous IPMN and PNET indicated that: a) only seven cases were diagnosed preoperatively; b) abdominal pain was the main presenting symptom; c) IPMN was the dominant tumor and presented with low grade dysplasia; d) the PNET was small and non-functional and had an indolent behavior; and e) only one case underwent radiologic follow-up. DISCUSSION: IPMN are associated with other pancreatic and extrapancreatic malignancies. Thus, the entire pancreatic parenchyma should be examined closely during the evaluation of an IPMN in order to exclude other pancreatic lesions, for example, a PNET. PMID- 28724305 TI - The complexity of evaluating and increasing adherence in inflammatory bowel disease. AB - Inflammatory bowel diseases (IBDs), due to their chronic and progressive nature, require lifelong treatment to relief and/or prevent inflammation and symptoms, obtaining mucosal healing at best. Therefore, adherence to treatment is an essential topic to address when treating patients with IBD. Nonetheless, adherence remains a common and complex issue in IBD care. Patient characteristics such as young age, male sex and employment has previously been verified as possible predictors of non-adherence. Additionally, evaluating adherence in itself is a challenge since both accurate and easy-to-use screening tools as well as golden standards are lacking. PMID- 28724306 TI - New psychological therapies for irritable bowel syndrome: mindfulness, acceptance and commitment therapy (ACT). AB - The current goal of treatment in irritable bowel syndrome (IBS) focuses primarily on symptom management and attempts to improve quality of life. Several treatments are at the disposal of physicians; lifestyle and dietary management, pharmacological treatments and psychological interventions are the most used and recommended. Psychological treatments have been proposed as viable alternatives or compliments to existing care models. Most forms of psychological therapies studied have been shown to be helpful in reducing symptoms and in improving the psychological component of anxiety/depression and health-related quality of life. According to current NICE/NHS guidelines, physicians should consider referral for psychological treatment in patients who do not respond to pharmacotherapy for a period of 12 months and develop a continuing symptom profile (described as refractory irritable bowel syndrome). Cognitive behavioral therapy (CBT) is the best studied treatment and seems to be the most promising therapeutic approach. However, some studies have challenged the effectiveness of this therapy for irritable bowel syndrome. One study concluded that cognitive behavioral therapy is no more effective than placebo attention control condition and another study showed that the beneficial effects wane after six months of follow-up. A review of mind/body approaches to irritable bowel syndrome has therefore suggested that alternate strategies targeting mechanisms other than thought content change might be helpful, specifically mindfulness and acceptance-based approaches. In this article we review these new psychological treatment approaches in an attempt to raise awareness of alternative treatments to gastroenterologists that treat this clinical syndrome. PMID- 28724307 TI - Per-oral endoscopic myotomy (POEM): a new endoscopic treatment for achalasia. AB - BACKGROUND/AIMS: Per-oral endoscopic myotomy (POEM) is a new minimally invasive technique to treat achalasia. METHODS: We performed a review of the literature of POEM with a special focus on technical details and the results obtained with this technique in patients with achalasia and other esophageal motility disorders. RESULTS: Thousands of POEM procedures have been performed worldwide since its introduction in 2008. The procedure is based on the creation of a mucosal entry point in the proximal esophagus to reach the cardia through a submucosal tunnel and then perform a myotomy of the muscular layers of the cardia, esophagogastric junction and distal esophagus, as performed in a Heller myotomy. The clinical remission rate ranges from 82 to 100%. Although no randomized studies exist and available data are from single-center studies, no differences have been found between laparoscopic Heller myotomy (LHM) and POEM in terms of perioperative outcomes, short-term outcomes (12 months) and long-term outcomes (up to three years). Procedure time and length of hospital stay were lower for POEM. Post-POEM reflux is a concern, and controversial data have been reported compared to LHM. The technique is safe, with no reported deaths related to the procedure and an adverse event rate comparable to surgery. Potential complications include bleeding, perforation, aspiration and insufflation-related adverse events. Thus, this is a complex technique that needs specific training even in expert hands. The indication for this procedure is widening and other motor hypercontractil esophageal disorders have been treated by POEM with promising results. POEM can be performed in complicated situations such as in pediatric patients, sigmoid achalasia or after failure of previous treatments. CONCLUSIONS: POEM is an effective treatment for achalasia and is a promising tool for other motor esophageal disorders. It is a safe procedure but, due to its technical difficulty and possible associated complications, the procedure should be performed in referral centers by trained endoscopists. PMID- 28724308 TI - EUS-guided recanalization of complete gastrointestinal strictures. AB - BACKGROUND AND AIM: Complete gastrointestinal strictures are a technically demanding problem. In this setting, an anterograde technique is associated with a high risk of complications and a combined anterograde-retrograde technique requires a prior ostomy. Our aim was to assess the outcome of a first case series for the management of complete gastrointestinal strictures using endoscopic ultrasound (EUS)-guided puncture as a novel endoscopic approach. PATIENTS AND METHODS: This retrospective case-series describes four cases that were referred for treatment of complete benign gastrointestinal strictures, three upper and one lower. Recanalization was attempted with EUS-guided puncture using a 22G or 19G needle and contrast filling was visualized by fluoroscopy. Afterwards, a cystotome and/or a dilator balloon were used under endoscopic and fluoroscopic guidance. A fully covered metal stent was placed in two cases, keeping the strictures open in order to prevent another stricture. Feasibility, adverse events, efficacy and the number of dilations required after recanalization were evaluated. RESULTS: Technical and clinical success was achieved in three of the four cases (75%). A first dilation was performed using a dilator balloon in all successful cases and fully covered metal stents were used in two cases. These patients underwent a consecutive number of balloon dilatations (range 1-4) and all three were able to eat a soft diet. No adverse events were related to the EUS guided approach. In the failed case with a long stricture (> 3 cm), an endoscopic rendezvous technique was attempted which caused a pneumothorax requiring a chest tube placement. CONCLUSION: EUS-guided recanalization, as a first approach in the treatment of complete digestive stricture, is a feasible and promising procedure that can help to avoid major surgery. PMID- 28724309 TI - Effects of long term device-guided slow breathing on sympathetic nervous activity in hypertensive patients: a randomized open-label clinical trial. AB - PURPOSE: Device-guided slow breathing (DGB) is indicated as nonpharmacological treatment for hypertension. The sympathetic nerve activity (SNA) reduction may be one of the mechanisms involved in blood pressure (BP) decrease. The aim of this study is to evaluate the long-term use of DGB in BP and SNA. SUBJECTS AND METHODS: Hypertensive patients were randomized to listen music (Control Group-CG) or DGB (aim to reduce respiratory rate to less than 10 breaths/minute during 15 minutes/day for 8 weeks). Before and after intervention ambulatory blood pressure monitoring (ABPM), catecholamines and muscle sympathetic nerve activity (MSNA) by microneurography were performed. RESULTS: 17 volunteers in the DGB and 15 in the CG completed the study. There was no change in office BP before and after intervention in both groups. There was a reduction in systolic and diastolic BP in the awake period by ABPM only in the CG (131 +/- 10/92 +/- 9 vs 128 +/- 10/88 +/- 8mmHg, p < 0.05). In relation to SNA, no difference in catecholamines was observed. In the volunteers who had a microneurography record, there was no change the MSNA (bursts/minute): DGB (17(15-28) vs 19(13-22), p = 0.08) and CG (22(17-23) vs 22(18-24), p = 0.52). CONCLUSION: Long-term DGB did not reduce BP, catecholamines levels or MSNA in hypertensive patients. ClinicalTrials.gov identifier: NCT01390727. PMID- 28724310 TI - Non-guideline-recommended prescribing of proton pump inhibitors: implications for the future and reducing over usage. AB - Drs Godman and Fadare review the paper by Mares-Garcia and colleagues in Spain regarding the extent of non-guideline recommended prescribing (NGRP) of proton pump inhibitors (PPIs) in ambulatory care. NGRP of PPIs is an increasing public health concern given the implications of overuse of PPIs on infection rates, osteoporosis and chronic kidney disease as well as increasing polypharmacy rates. Costs are less of an issue especially where there are low prices for generic PPIs; the main focus is on improving the quality of PPI prescribing. Encouragingly, Mares-Garcia and colleagues identified key factors associated with NGRP, providing direction to others. PMID- 28724311 TI - Characterization of complete mitochondrial genomes of indigenous Mayans in Mexico. AB - BACKGROUND: The authors have previously published the complete mitochondrial genome (mitogenome) sequences of two indigenous Mesoamerican populations, Mazahua (n = 25) and Zapotec (n = 88). METHODS: This study determined the complete mitogenome sequences of nine unrelated individuals from the indigenous Maya population living in Mexico. RESULTS: Their mitogenome sequences could be classified into either of the haplogroups A2 and C1. Surprisingly, there were no mitogenome sequences (haplotypes) that the Maya, Mazahua, and Zapotec people share in common. CONCLUSIONS: This indicates that no genetic exchange, at least matrilineally, has occurred among them. PMID- 28724312 TI - In vitro skin decontamination of paraoxon - wet-type cleansing effect of selected detergents. AB - The aim of this study was to determine optimal conditions for in vitro skin decontamination using water and detergents as decontamination agents and to test the cleansing efficiency of selected detergents. Experiments were performed using a peristaltic pump for showering of pig skin in modified static diffusion cells. Several conditions were tested including different flow rates (from 5 to 33 ml s 1), quantity of rinsing fluid (from 40 to 400 ml) and concentration of detergents (2; 5; 10%). Further, several types of detergents/commercial decontamination agents were evaluated under the selected conditions to find the most effective means of decontamination. The amount of paraoxon removed from the skin surface following wet-type decontamination was detected in the rinsing fluid spectrophotometrically after hydrolysis of paraoxon - a model contaminant. The efficacy of rinsing by water/Spolapon AES 253 increased with flow rate up to 25 ml s-1 and a rinsing volume of 200 ml. Lutensol AT 25 achieved maximum efficacy at the lowest tested concentration (2%). A flow rate of 16 ml s-1, rinsing volume of 100 ml (values from the middle part of the sigmoid curve) and 5% concentration of decontaminant solution were used for further evaluation of detergents as cleansing agents under the selected conditions. Cetylpyridinium bromide (cationic surfactant), carbethopendecinii bromidum (cationic surfactant) and polyoxyethylene-10-tridecyl ether (non-ionic surfactant), SDS (anionic surfactant), althosan MB (cationic surfactant), sodium dodecylbenzene sulphonate (anionic surfactant), neodekont (mixture), tergitol NPX (non-ionic surfactant), Korynt P (non-ionic surfactant) were found to be the most effective. These decontaminants were able to wash away more than 92% of paraoxon from the contaminated skin. PMID- 28724313 TI - Treatment strategies for comorbid conditions lower residual risk in patients with treated hypertension: FOURIER and other randomized outcome trials. PMID- 28724314 TI - Developing combination of artesunate with paclitaxel loaded into poly-d,l-lactic co-glycolic acid nanoparticle for systemic delivery to exhibit synergic chemotherapeutic response. AB - OBJECTIVES: Paclitaxel (PTX) has been indicated for the treatment of a variety of solid tumors, whereas artesunate (ART) has been reported to have the potential for use in combination chemotherapy. In this study, the combination of ART and PTX was prepared in nanoparticle to induce the synergic effect and improve therapeutic efficiency in treatment of breast cancer. METHODS: Dual anticancer agents (PTX and ART) were loaded into Poly-D,L-lactic-co-glycolic acid (PLGA) nanoparticle (NP) by solvent evaporation technique from oil-in-water emulsion, stabilized with Tween 80. Physicochemical properties of obtained nanoparticles (PTX-ART-NPs) were characterized including particle size (Z), polydispersity index (PDI), zeta potentials (ZP), encapsulation efficiency (EE), and in-vitro drug release. Combination index (CI) was calculated to determine the synergic effect of the combination and select the best ratio of ART and PTX. The final NPs analyzed intracellular uptake, cytotoxicity assay, and apoptosis study. RESULTS: The final NP had a small size (around 120 nm) with a narrow size distribution (PDI <0.3). EE values for each drug were 87.8 +/- 1.1% and 99.5 +/- 0.1% for ART and PTX, respectively, and drugs were released from NPs in a controlled release pattern. All combinations of PTX and ART had CI values under 1, which confirmed the synergic effects. Meanwhile, NP preparation increased cytotoxicity on three breast cancer cell-lines comparable to free drugs. CONCLUSIONS: Combination of ART- and PTX-loaded PLGA NP showed promising results for anticancer therapy, especially for breast cancer treatment. PMID- 28724315 TI - Persistent atrial fibrillation vs paroxysmal atrial fibrillation: differences in management. AB - INTRODUCTION: Atrial fibrillation (AF) is the most common human arrhythmia. AF is a progressive disease, initially being nonsustained and induced by trigger activity, and progressing towards persistent AF through alteration of the atrial myocardial substrate. Treatment of AF aims to decrease the risk of stroke and improve the quality of life, by preventing recurrences (rhythm control) or controlling the heart rate during AF (rate control). In the last 20 years, catheter-based and, less frequently, surgical and hybrid ablation techniques have proven more successful compared with drug therapy in achieving rhythm control in patients with AF. However, the efficiency of ablation techniques varies greatly, being highest in paroxysmal and lowest in long-term persistent AF. Areas covered: In this review, we discuss the fundamental differences between paroxysmal and persistent AF and the potential impact of those differences on patient management, emphasizing the available therapeutic strategies to achieve rhythm control. Expert commentary: Treatment to prevent AF recurrences is suboptimal, particularly in patients with persistent AF. Emerging technologies, such as documentation of atrial fibrosis using magnetic resonance imaging and documentation of electrical substrate using advanced electrocardiographic imaging techniques are likely to provide valuable insights about patient-specific tailoring of treatments. PMID- 28724316 TI - Molecular diagnosis of autosomal dominant polycystic kidney disease. AB - INTRODUCTION: Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease that accounts for 5-10% of end-stage renal disease in developed countries. Mutations in PKD1 and PKD2 account for a majority of cases. Mutation screening of PKD1 is technically challenging largely due to the complexity resulting from duplication of its first 33 exons in six highly homologous pseudogenes (i.e. PKD1P1-P6). Protocol using locus-specific long-range and nested PCR has enabled comprehensive PKD1 mutation screening but is labor intensive and costly. Here, the authors review how recent advances in Next Generation Sequencing are poised to transform and extend molecular diagnosis of ADPKD. Areas covered: Key original research articles and reviews of the topic published in English identified through PubMed from 1957-2017. Expert commentary: The authors review current and evolving approaches using targeted resequencing or whole genome sequencing for screening typical as well as challenging cases (e.g. cases with no detectable PKD1 and PKD2 mutations which may be due to somatic mosaicism or other cystic disease; and complex genetics such as bilineal disease). PMID- 28724317 TI - Who among patients with acquired brain injury returned to work after occupational rehabilitation? The rapid-return-to-work-cohort-study. AB - BACKGROUND: Acquired brain injury (ABI) is known to be severely disabling. On average, 40% of employees return to work (RTW) within two years after injury. There is, however, limited research on what might contribute to successful RTW. AIM: To examine factors that might impact the time-to first RTW for patients with ABI, participating in a RTW-program. METHODS: The study was designed as a cohort study of patients on sick leave due to mild or moderate ABI (n = 137). The mean age of the patients was 51 years, and 58% were men. The most common diagnoses were stroke (75%) and traumatic brain injury (12%). Data were collected through questionnaires, and combined with register data on sickness absence. Survival analyses were used to analyse the effect of different variables on time to first RTW (full or partial), at one- and two-year follow-up. RESULTS: Generally, women (HR = 0.447; CI: 0.239-0.283) had higher RTW-rates than men, and patients with non-comorbid impairments returned to work earlier than patients with multiple impairments. Although not statistically significant, receiving individual consultations and participating in group-sessions were generally associated with a delayed RTW at both follow-up-times. The only service-related factor significantly associated with delayed RTW was meetings with the social insurance office (HR = 0.522; CI: 0.282-0.965), and only at one-year follow-up. CONCLUSIONS: Women and patients with non-comorbid impairments returned to work earlier than men and patients with multiple impairments. There seems to be an association between intense and long-lasting participation in the RTW program and prolonged time-to first-RTW, even after controlling for level of cognitive impairments and comorbidity. Implications for Rehabilitation Acquired brain injury (ABI) is known to be severely disabling, and persons with ABI often experience difficulties in regard to returning to work. This study provides information on prognostic factors that might contribute to return to work (RTW) for patients with acquired brain injury, both at the individual level, but also in regard to service and timing characteristics. Knowledge about such factors provide rehabilitation professionals with information about effective service components that might help patients with ABI to RTW, and thus makes it possible to adapt and adjust the services to the patient's situation. Furthermore, having more knowledge on factors that contribute to RTW gives clinics the opportunity to select patients that might benefit the most from these services, thereby making them more effective. PMID- 28724318 TI - Validation of the salivary urea and creatinine tests as screening methods of chronic kidney disease in Vietnamese patients. AB - OBJECTIVES: The aims of this case control study were to correlate the serum and salivary urea as well as creatinine levels; and to evaluate salivary urea and creatinine as noninvasive alternatives to serum for creatinine estimation in chronic kidney disease (CKD) patients. METHODS: Blood and saliva samples were collected from 112 CKD patients and 108 subjects without CKD for quantitative analysis of urea and creatinine. Spearman's correlation coefficients between salivary and serum urea as well as creatinine were obtained. Receiver operating characteristic analysis was done to assess the diagnostic tests of salivary urea and creatinine. Cut-off values were determined based on the best trade-off between the sensitivity and specificity for both salivary urea and creatinine. RESULTS: Salivary urea and creatinine concentrations were significantly higher in CKD patients than those in control subjects; and increased by the stages of the severity of the disease. The positive correlation was significantly found between salivary and serum creatinine (r = 0.90) and between salivary and serum urea (r = 0.73). Area under the curve for salivary urea was 0.76 and a cut-off value of 14.25 mmol/L gave a sensitivity of 82.9% and specificity of 57.8%. Area under the curve for salivary creatinine was 0.92 and a cut-off value of 0.24 mg/dL gave a sensitivity of 86.5% and specificity of 87.2%. CONCLUSIONS: Both salivary urea and creatinine have a high capacity for serum creatinine estimation. Salivary urea and creatinine tests can be used as low-cost, easily accessible and noninvasive tools for screening, diagnosing, monitoring treatment outcomes and ascertaining prognosis of chronic kidney disease. PMID- 28724319 TI - Cerebral hemorrhage as the initial manifestation in patients with systemic cancer. AB - BACKGROUND: Cerebral hemorrhage as well as ischemic stroke is one of the common complications among patients with cancer. Ischemic stroke could be the initial manifestation in some patients with cancer. Meanwhile, some patients with cancer also could present cerebral hemorrhage as the initial manifestation, and further studies are required to determine whether these patients have their unique clinical features. AIM: To investigate the clinical features and underlying pathogenesis of concealed systemic cancer patients with cerebral hemorrhage as the initial manifestation. METHODS: The clinical data of patients with concealed systemic cancer who presented cerebral hemorrhage as the initial manifestation registered at the First Affiliated Hospital of Guangxi Medical University from January 2010 to December 2015 were prospectively collected and analyzed. RESULTS: Seventeen systemic cancer patients with cerebral hemorrhage as the initial manifestation (0.02%) were ultimately enrolled from 8,326 patients with cerebral hemorrhage. Three patients had traditional risk factors, but the other 14 patients did not. The common subtypes of malignancy were lung cancer, liver cancer, gastric carcinoma, rectal cancer and melanoma. Most patients (11/17, 64.7%) had elevated plasma levels of cancer biochemical markers, including cancer antigen (CA)125, CA153 and CA199, carcino-embryonic antigen, and alpha fetal protein. Coagulopathy was observed in 15 patients. CONCLUSION: The concealed systemic cancer patients with cerebral hemorrhage as the initial manifestation may lack conventional vascular risk factors but did present coagulopathy and elevated plasma levels of cancer biochemical markers. Coagulopathy might be responsible for the cerebral hemorrhage. PMID- 28724320 TI - Statins and venous thromboembolism: do they represent a viable therapeutic agent? AB - INTRODUCTION: Venous thromboembolism (VTE) is an important cause of preventable morbidity and mortality. Though anticoagulants are effective in preventing VTE, they are associated with major bleeding risk. The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (known as statins), are well established for the primary and secondary prevention of cardiovascular disease via their lipid lowering properties. Emerging evidence suggests that statins may play a role in the prevention of VTE, but the evidence has been uncertain. Areas covered: This review summarizes the available epidemiological and interventional evidence on the role of statins in VTE prevention; the postulated biologic mechanisms involved; outlines areas of outstanding uncertainty; and the implications for clinical practice. Expert commentary: The body of evidence indicates statins may also play a potential role in the primary and secondary prevention of VTE. Further evidence is however warranted. There is insufficient evidence to recommend the use of statins to replace anticoagulants in VTE prevention. However, guideline bodies should review the overall evidence and consider including statin therapy as an adjunct to anticoagulant therapy in VTE prevention in specific patient populations. Statin therapy instead of anticoagulants may be considered in patients who are not candidates for anticoagulant therapy and in some low VTE risk patients. PMID- 28724322 TI - Predictors of urinary incontinence between abdominal obesity and non-obese male adults. AB - OBJECTIVES: To investigate factors that may be associated with urinary incontinence (UI) in abdominal obese and non-obese adult males. METHODS: Data were analyzed for 2671 men (>=40 years of age) who participated in the National Health and Nutrition Examination Survey (2005-2008). We define abdominal obesity as a waist circumference >102 cm. Men with Incontinence Severity Index >=3 were defined as having UI. Logistic regression analyses were used to identify factors associated with stress and urge UI. RESULTS: Multivariate analysis found that in abdominal obese men, stress UI was associated with enlarged prostate (odds ratio [OR] = 2.20, 95% confidence interval [CI]: 1.16-4.16), chronic respiratory tract disease (OR = 2.78, 95% CI: 1.55-4.97), and major depression (OR = 4.79, 95% CI: 1.79-12.84). In non-obese men, arthritis was associated with stress UI (odds ratio = 3.37, 95% CI: 1.06-10.73). Urge UI in abdominally obese men was associated with age >=65 years (OR = 1.67, 95% CI: 1.05-2.67), being non-Hispanic black (OR = 1.63, 95% CI: 1.06-2.52), and with enlarged prostate (OR = 2.30, 95% CI: 1.54-3.40), arthritis (OR = 1.39, 95% CI: 1.03-1.88), and major depression (OR = 2.96, 95% CI: 1.89-4.64). Urge UI in non-obese men was associated with current smoking (OR = 1.79, 95% CI: 1.01-3.17), major depression (OR = 2.60, 95% CI: 1.33-5.09) and vitamin D deficiency (OR = 1.61, 95% CI: 1.01-2.59). CONCLUSION: Factors associated with urinary incontinence varied with abdominal obesity status and type of UI. The findings identify important contributors to urinary incontinence that clinicians should consider to help manage and effectively treat the condition. PMID- 28724321 TI - Diospyros kaki calyx inhibits immediate-type hypersensitivity via the reduction of mast cell activation. AB - CONTEXT: Diospyros kaki L. (Ebenaceae) fruit is widely distributed in Asia and is known to exert anti-inflammatory and antithrombotic effects. OBJECTIVE: We evaluated the inhibitory effect of aqueous extract of D. kaki calyx (AEDKC) on mast cell-mediated immediate-type hypersensitivity and underlying mechanism of action. MATERIALS AND METHODS: For in vivo, ovalbumin (OVA)-induced active systemic anaphylaxis (ASA) and immunoglobulin (Ig) E-mediated passive cutaneous anaphylaxis (PCA) models were used. In the ASA, AEDKC (1-100 mg/kg) was orally administered 3 times during 14 days. In the PCA, AEDKC was orally treated 1 h before the antigen challenge. The control drug dexamethasone was used to compare the effectiveness of AEDKC. For in vitro, IgE-stimulated RBL-2H3 cells and primary cultured peritoneal mast cells were used to determine the role of AEDKC (0.01-1 mg/mL). RESULTS: Oral administration of AEDKC dose dependently suppressed rectal temperature decrease and increases in serum histamine, total IgE, OVA specific IgE, and interleukin (IL)-4 in the ASA. In the PCA, AEDKC reduced Evans blue pigmentation. Compared to dexamethasone (10 mg/kg), AEDKC (100 mg/kg) showed similar inhibitory effects in vivo. AEDKC concentration dependently suppressed the release of histamine and beta-hexosaminidase through the reduction of intracellular calcium in mast cells. In addition, AEDKC decreased the expression and secretion of tumour necrosis factor-alpha and IL-4 by the reduction of nuclear factor-kappaB. The inhibitory potential of AEDKC (1 mg/mL) was similar with dexamethasone (10 MUM) in vitro. CONCLUSIONS: We suggest that AEDKC may be a potential candidate for the treatment of mast cell-mediated allergic diseases. PMID- 28724324 TI - Strong impact of ethnicity on effectiveness of the first trimester maternal serum screen of fetal Down syndrome. AB - OBJECTIVES: The objective of this study is to compare the effectiveness of first trimester maternal serum screening (MSS) for fetal Down syndrome among Thai women between the method using Caucasian reference ranges with racial factor correction (CRR-RC) and that using Thai reference ranges (TRR). METHODS: A prospective database of MSS was accessed. The levels of PAPP-A and beta-hCG were calculated to determine their MoMs (multiple of medians) by two methods: (1) CRR-RC for Asian women and (2) TRR. The MoMs from both methods were used to determine the fetal risk. RESULTS: Of 24,885 women including 36 fetuses with Down syndrome, the detection rates were significantly higher with TRR when compared with CRR-RC, 77.8 and 63.9%, respectively, p < .001. Additionally, the false-positive rates were significantly lower with TRR when compared to CRR-RC (7.5 versus 12.5%, respectively, p < .001) Conclusions: The effectiveness of MSS was much better by using our own reference ranges rather than the method of racial factor correction. The important insight is that ethnicity strongly impacts on the effectiveness that cannot be completely corrected by ethnic factor. MSS derived by the CRR-RC in other regions should be interpreted with high precaution, especially where the biophysical characteristics of the women are much different from Caucasian population. PMID- 28724323 TI - Evidence that disrupted orienting to evaluative social feedback undermines error correction in rejection sensitive women. AB - For individuals high in Rejection Sensitivity (RS), a learned orientation to anxiously expect rejection from valued others, negative feedback from social sources may disrupt engagement with learning opportunities, impeding recovery from mistakes. One context in which this disruption may be particularly pronounced is among women high in RS following evaluation by a male in authority. To investigate this prediction, 40 college students (50% female) answered general knowledge questions followed by immediate performance feedback and the correct answer while we recorded event-related potentials. Error correction was measured with a subsequent surprise retest. Performance feedback was either nonsocial (asterisk/tone) or social (male professor's face/voice). Attention and learning were indexed respectively by the anterior frontal P3a (attentional orienting) and a set of negative-going waveforms over left inferior-posterior regions associated with successful encoding. For women, but not men, higher RS scores predicted poorer error correction in the social condition. A path analysis suggested that, for women, high RS disrupted attentional orienting to the social-evaluative performance feedback, which affected subsequent memory for the correct answer by reducing engagement with learning opportunities. These results suggest a mechanism for how social feedback may impede learning among women who are high in RS. PMID- 28724325 TI - Use and timing of surfactant administration: impact on neonatal outcomes in extremely low gestational age infants born in Canadian Neonatal Intensive Care Units. AB - BACKGROUND: Use, timing and doses of surfactant in preterm infants are variable in practice in modern NICUs. OBJECTIVE: The objective of this study is to explore the association between use and timing of surfactant administration and common neonatal adverse outcomes in preterm infants with gestational age (GA) < 28 weeks. MATERIAL AND METHODS: Neonates admitted to a participating Canadian Neonatal Network NICU between 2013 and 2015 were studied. Infants were divided into three groups based on surfactant administration: none, early (within 30 min of life), and late surfactant (>30 min). The primary outcome was a composite of >=2 predefined outcomes: bronchopulmonary dysplasia (BPD), retinopathy of prematurity (ROP) and severe neurological injury (intraventricular hemorrhage or intraventricular hemorrhage (IVH) grade III/IV +/- periventricular leukomalacia). RESULTS: Of 2512 eligible neonates, 430 were in the early, and 1228 were in the late surfactant group. There was no difference in the primary outcome (p = .88). There was a slightly lower risk of late onset sepsis [25% versus 29%, adjusted odds ratio (aOR): 0.8; 95% CI: 0.6-0.9] and ROP (12.4 versus 15%, aOR: 0.7; 95% CI: 0.5-0.9) in the early surfactant group. CONCLUSIONS: In preterm neonates, early administration of surfactant within 30 min of life was not associated with an increased risk of the primary composite outcome, but did have decreased rates of late onset sepsis and ROP. PMID- 28724326 TI - STING signalling: an emerging common pathway in autoimmunity and cancer. AB - The equipoise between the disease states of cancer and autoinflammation has perhaps been underappreciated in clinical practice and biomedical research. However, since the discover of STING (stimulator of interferon genes) as an integral regulator of innate immunity, a wealth of information has implicated this signaling pathway in both of these diseases. Under cellular homeostasis, STING serves to detect - and promote immune defense against - DNA viruses and intracellular bacteria, as described in its initial discovery. The role of STING has since been expanded to include tumor surveillance and immune responses to cancer; indeed, defective STING responses are associated with certain cancers. Conversely, constitutive activation of this pathway can result in autoinflammatory disease, whereby STING is over-stimulated by self-DNA. This review explores the current state of STING research, concluding that further elucidation of the details of the STING pathway may offer novel therapeutics for these diseases, which are of considerable clinical gravity. PMID- 28724327 TI - Gemcitabine hydrochloride-loaded liposomes and nanoparticles: comparison of encapsulation efficiency, drug release, particle size, and cytotoxicity. AB - The aim of this study is to formulate and compare the physicochemical properties of negatively charged liposomes and poly(lactide-co-glycolide) (PLGA) nanoparticles loaded with gemcitabine hydrochloride. The influence of the formulation variables on the liposome and nanoparticle properties on particle size, zeta potential, encapsulation efficiency, and drug release was evaluated. Although the PEGylated nanoparticles and PEGylated liposomes were of the same size (~200 nm), the encapsulation efficiency was 1.4 times higher for PEGylated liposomes than for PEGylated nanoparticles. The optimized formulation of PEGylated liposomes and PEGylated nanoparticles had 26.1 +/- 0.18 and 18.8 +/- 1.52% encapsulation efficiency, respectively. The release of drug from the PEGylated liposomes and PEGylated nanoparticles exhibited a biphasic pattern that was characterized by a fast initial release during the first 2 h followed by a slower continuous release. Transmission electron microscopy (TEM) images identified separate circular structures of the liposomes and nanoparticles. The in vitro cytotoxicity of the optimized formulations was assessed in MCF-7 and MDA MB-231 cells, and the results showed that the cytotoxicity effect of the gemcitabine hydrochloride-loaded liposomes and nanoparticles was more than commercial product Gemko(r) and gemcitabine hydrochloride solution. PMID- 28724328 TI - Smart tetrazole-based antibacterial nanoparticles as multifunctional drug carriers for cancer combination therapy. AB - Due to multidrug resistance of cancer tissues and immune-suppression of cancerous patients during chemotherapy in one hand and the use of tetrazole derivatives in medicine because of its anticancer, antifungal, and antiviral properties, on the other, we were encouraged to design novel smart antibacterial nanocomposites based polymer of tetrazole as dual anticancer drug delivery systems. The structures of nanocomposites characterized by FTIR, 1H NMR, FESEM-EDX, and TGA analyzes and antibacterial activity of smart carriers were evaluated by determination of minimum inhibitory concentration (MIC) values against some bacteria and fungi. Then, the pH-responsive manner of both nanocomposites was proved by checking their release profiles at pH of the physiological environment (pH 7.4) and pH of tumor tissues (mildly acidic). Finally, the potential antitumoral activity of these nanocomposite systems against MCF7 cell lines was evaluated by MTT assay and cell cycle studies. The results demonstrated that the novel developed nanocomposites not only meet our expectations about simultaneous release of two anticancer drugs according to the predicted profile but also showed antibacterial and anticancer properties in vitro experimental. Moreover, it was proved that these carriers have tremendous potential in multifunctional drug delivery in cancer therapy. PMID- 28724329 TI - New heart failure pharmacotherapy in clinical trials: a hope in progress. PMID- 28724330 TI - Immunotherapy advances for mesothelioma treatment. AB - INTRODUCTION: Mesothelioma is a rare type of cancer that is strongly tied to asbestos exposure. Despite application of different modalities such as chemotherapy, radiotherapy and surgery, patient prognosis remains very poor and therapies are ineffective. Much research currently focuses on the application of novel approaches such as immunotherapy towards this disease. Areas covered: The types, stages and aetiology of mesothelioma are detailed, followed by a discussion of the current treatment options such as radiotherapy, surgery, and chemotherapy. A description of innate and adaptive immunity and the principles and justification of immunotherapy is also included. Clinical trials for different immunotherapeutic modalities are described, and lastly the article closes with an expert commentary and five-year view, the former of which is summarised below. Expert commentary: Current efforts for novel mesothelioma therapies have been limited by attempting to apply treatments from other cancers, an approach which is not based on a solid understanding of mesothelioma biology. In our view, the influence of the hostile, hypoxic microenvironment and the gene expression and metabolic changes that resultantly occur should be characterised to improve therapies. Lastly, clinical trials should focus on overall survival rather than surrogate endpoints to avoid bias and inaccurate reflections of treatment effects. PMID- 28724332 TI - Common and distinct neural networks involved in fMRI studies investigating morality: an ALE meta-analysis. AB - Morality is an important social construct necessary for understanding what is right and wrong. Neuroimaging studies investigating morality have used a wide variety of paradigms and implicated many different brain areas. Yet, it remains unclear whether differences amongst morality tasks are the cause for such heterogeneous findings. Therefore, in the present study, a series of activation likelihood estimation (ALE) meta-analyses were conducted on 123 datasets (inclusive of 1963 participants) to address this question. The ALE meta-analyses revealed a series of common brain areas associated with all moral tasks, including medial prefrontal cortex, lateral orbitofrontal cortex, amygdala, temporoparietal junction, and precuneus. However, individual and contrast analyses also revealed unique networks associated with each moral modality, suggesting that different moral tasks recruit specialised brain regions. PMID- 28724331 TI - Randomized double-blinded pilot clinical study of the antidiabetic activity of Balanites aegyptiaca and UPLC-ESI-MS/MS identification of its metabolites. AB - CONTEXT: Balanites aegyptiaca Del. (Zygophyllaceae) fruits are traditionally known for the treatment of hyperglycaemia. Several in vitro and in vivo studies proposed some mechanisms of action. However, clinical trials in human beings were never reported to date. OBJECTIVES: To investigate the antidiabetic efficacy of the 70% ethanol extract of the pericarps of B. aegyptiaca (BE) within a nutritional intervention in elderly people. MATERIALS AND METHODS: Ultra performance electrospray ionization-mass spectroscopy (UPLC-ESI-MS/MS) analysis was used for metabolic profiling of BE which was incorporated in hard gelatine capsules (400 mg/day) and tested on 30 type 2 diabetes (T2D) Egyptian patients for 8 weeks. According to sex, age and body mass index participants were divided into two equivalent groups, placebo and treatment. RESULTS: Thirteen compounds were identified in BE using UPLC-ESI-MS/MS analysis among which five steroidal saponins, seven phenolic compounds and a sterol glucoside. At the end of the 8 week treatment, the treated group showed 26.88% decrease in 2 h postprandial plasma glucose relative to 2.6% increase in the placebo group, while fasting plasma glucose was reduced to 10.3%. Treatment with BE capsules for 8 weeks produced significant reduction in the plasma triglyceride, total cholesterol and low-density lipoprotein cholesterol by 9.0, 12.76 and 21.35%, respectively, with 29.8% increase in the high-density lipoprotein cholesterol. Plasma alanine transaminase and aspartate transaminase were reduced by 42.6 and 43.3%, respectively. DISCUSSION AND CONCLUSION: Administration of the BE capsules to T2D resulted in significant improvements in the glycaemic markers and the lipid profile, without adverse effects or hypoglycaemia. PMID- 28724334 TI - High Expectations. PMID- 28724333 TI - The impact of acute management on the occurrence of medical complications during the specialized spinal cord injury acute hospitalization following motor-complete cervical spinal cord injury. AB - CONTEXT/OBJECTIVE: Determine the impact of early admission and complete perioperative management in a specialized spinal cord injury (SCI) trauma center (SCI-center) on the occurrence of medical complications following tetraplegia. DESIGN: A retrospective comparative cohort study of prospectively collected data involving 116 individuals was conducted. Group 1 (N=87) was early managed in a SCI-center promptly after the trauma, whereas Group 2 (N=29) was surgically and preoperatively managed in a non-specialized (NS) center before being transferred to the SCI-center. Bivariate comparisons and multivariate logistic regression analyses were used to assess the relationship between the type of acute care facility and the occurrence of medical complications. Length of stay (LOS) in acute care was also compared. SETTING: Single Level-1 trauma center. PARTICIPANTS: Individuals with acute traumatic motor-complete cervical SCI. INTERVENTIONS: Not applicable Outcome measures: The occurrence of complications during the SCI-center stay. RESULTS: There was a similar rate of complications between the two groups. However, the LOS was greater in Group 2 (p=0.04). High cervical injuries (C1-C4) showed an important tendency to increase the likelihood of developing a complication, while high cervical injuries and increased trauma severity increased the odds of developing respiratory complications. CONCLUSION: Although complication rates were similar in non-specialized and specialized centers, peri-operative management in a non-specialized center required a longer length of stay. Prompt transfer to a SCI-center may optimize the care trajectory by favoring earlier transfer to rehabilitation. PMID- 28724336 TI - Vaccinations among athletes: evidence and recommendations. PMID- 28724335 TI - Exploring the potential for using drug indications to prevent look-alike and sound-alike drug errors. AB - BACKGROUND: Look-alike, sound-alike (LASA) drug names are a cause of medication errors with resulting patient harm and healthcare costs. This study assessed to which extent the use of the generic drug name, therapeutic class, health problem, and the U.S. Food and Drug Administration (FDA)-approved indications might be used to differentiate LASA drug pairs. RESEARCH DESIGN AND METHODS: We collected information about LASA drug pairs reported by the FDA to have look-alike sound alike similarities. To assess potential for differentiating LASA drug pairs, we compared the following drug characteristics: generic name, therapeutic class, health problem, and FDA-approved indication. RESULTS: For the 33 FDA reported LASA drug pairs we identified a total of 432 FDA-approved indications. Using the generic name, therapeutic class, health problem and drug indication we were able to differentiate 8 (24.2%), 24 (72.7%), 25 (75.8%) and 26 (78.8%), respectively of the 33 LASA drug pairs. Using the generic name, therapeutic class, and health problem we were able to distinguish 31 (7.2%), 212 (49.1%), and 269 (62.3%), respectively of the 432 FDA-approved indications for the LASA drug pairs. CONCLUSIONS: Including the FDA-approved indication in the drug prescription may be used to differentiate LASA drug pairs and thus, prevent wrong drug medication errors. PMID- 28724337 TI - Handedness effects of imagined fine motor movements. AB - Previous studies of movement imagery have found inter-individual differences in the ability to imagine whole-body movements. The majority of these studies have used subjective scales to measure imagery ability, which may be confounded by other factors related to effort. Madan and Singhal [2013. Introducing TAMI: An objective test of ability in movement imagery. Journal of Motor Behavior, 45(2), 153-166. doi: 10.1080/00222895.2013.763764 ] developed the Test of Ability in Movement Imagery (TAMI) to address these confounds by using a multiple-choice format with objectively correct responses. Here we developed a novel movement imagery questionnaire targeted at assessing movement imagery of fine-motor hand movements. This questionnaire included two subscales: Functionally-involved Movement (i.e., tool-related) and Isolated Movement (i.e., hand-only). Hand dominance effects were observed, such that right-handed participants were significantly better at responding to right-hand questions compared to left-hand questions for both imagery types. A stronger handedness effect was observed for Functionally-involved Movement imagery, and it did not correlate with the Edinburgh Handedness Inventory. We propose that the Functionally-involved Movement imagery subscale provides an objective hand imagery test that induces egocentric spatial processing and a greater involvement of memory processes, potentially providing a better skill-based measure of handedness. PMID- 28724338 TI - Increased skills usage statistically mediates symptom reduction in self-guided internet-delivered cognitive-behavioural therapy for depression and anxiety: a randomised controlled trial. AB - Cognitive-behavioural therapy (CBT) is an effective treatment for clinical and subclinical symptoms of depression and general anxiety, and increases life satisfaction. Patients' usage of CBT skills is a core aspect of treatment but there is insufficient empirical evidence suggesting that skills usage behaviours are a mechanism of clinical change. This study investigated if an internet delivered CBT (iCBT) intervention increased the frequency of CBT skills usage behaviours and if this statistically mediated reductions in symptoms and increased life satisfaction. A two-group randomised controlled trial was conducted comparing internet-delivered CBT (n = 65) with a waitlist control group (n = 75). Participants were individuals experiencing clinically significant symptoms of depression or general anxiety. Mixed-linear models analyses revealed that the treatment group reported a significantly higher frequency of skills usage, lower symptoms, and higher life satisfaction by the end of treatment compared with the control group. Results from bootstrapping mediation analyses revealed that the increased skills usage behaviours statistically mediated symptom reductions and increased life satisfaction. Although skills usage and symptom outcomes were assessed concurrently, these findings support the notion that iCBT increases the frequency of skills usage behaviours and suggest that this may be an important mechanism of change. PMID- 28724340 TI - Pharmacological therapeutics in Friedreich ataxia: the present state. AB - INTRODUCTION: Friedreich ataxia (FRDA) is a progressive, inherited, neurodegenerative disease for which there is currently no cure or approved treatment. FRDA is caused by deficits in the production and expression of frataxin, a protein found in the mitochondria that is most likely responsible for regulating iron-sulfur cluster enzymes within the cell. A decrease in frataxin causes dysfunction of adenosine triphosphate synthesis, accumulation of mitochondrial iron, and other events leading to downstream cellular dysfunction. Areas covered: Therapeutic development for FRDA currently focuses on improving mitochondrial function and finding ways to increase frataxin expression. Additionally, the authors will review potential approaches aimed at iron modulation and genetic modulation. Finally, gene therapy is progressing rapidly and is being explored as a treatment for FRDA. Expert commentary: The collection of multiple therapeutic approaches provides many possible ways to treat FRDA. Although the mitochondrial approaches are not thought to be curative, as the primary frataxin deficit will remain, they may still produce improvements in quality of life and slowing of progression. Therapies aimed at frataxin restoration are more likely to truly modify the disease, with gene therapy as the best possibility to alter the course of the disease from both a cardiac and neurological perspective. PMID- 28724339 TI - Influence of cerebrovascular reactivity on outcome of the patients with >=50% symptomatic unilateral middle cerebral artery stenosis. AB - : Purpose/aim of the study: Cerebrovascular reactivity (CVR) reflects the vasodilatory reserve of cerebral resistance vessels, which is an important marker for assessing cerebrovascular disease. The present study is to investigate whether CVR impairment increases adverse long-term outcome risk of patients with >= 50% symptomatic unilateral middle cerebral artery (MCA) stenosis (ischemic stroke (IS) or transient ischemic attack (TIA)). MATERIAL AND METHODS: Digital subtraction angiography (DSA) was used to assess the degree of stenosis, and perfusion CT and 5% CO2 inhalation were adopted to evaluate CVR. Patients with >= 50% symptomatic unilateral MCA stenosis were assigned to non-CVR impairment group and CVR impairment group according to CVR status. The long-term follow-up endpoint was composite of any IS ( in the territory of the studied MCA) or death within 12 months. RESULTS: Seventy-three patients with >= 50% symptomatic unilateral MCA stenosis, involving 31 non-CVR impairment cases and 42 CVR impairment cases, were included in the present study. Finally, IS occurred in six CVR impairment patients, and no endpoint happened in the non-CVR impairment group. Therefore, the annual rate of IS was 14.29% in the CVR impairment group and 0% in the non-CVR impairment group (P = 0.035). Besides, further Kaplan-Meier analysis found CVR impairment was closely associated with the IS risk (Kaplan Meier Log-rank 4.719, P = 0.030). CONCLUSIONS: Our results showed that for patients with >= 50% symptomatic unilateral MCA stenosis, there was significant difference between non-CVR impairment cases and CVR impairment cases in the annual rate of IS. It suggests that CVR impairment increases the risk of adverse long-term outcomes. PMID- 28724341 TI - Of significance and relevance. PMID- 28724342 TI - Periodontal disease and intra-amniotic complications in women with preterm prelabor rupture of membranes. AB - OBJECTIVE: Periodontal disease is frequently suggested as a possible causal factor for preterm delivery. The link between periodontal disease and preterm delivery is a possible translocation of periopathogenic bacteria to the placenta and amniotic fluid as well as a systemic response to this chronic inflammatory disease. However, there is a lack of information on whether there is an association between clinical periodontal status in women with preterm prelabor rupture of membranes (PPROM) and the presence of microbial invasion of the amniotic cavity (MIAC) and intra-amniotic inflammation (IAI). Therefore, the main aim of this study was to evaluate the incidence and severity of periodontal disease in women with PPROM. The secondary aim was to characterize an association between periodontal status and the presence of intra-amniotic PPROM complications (MIAC and/or IAI). MATERIALS AND METHODS: Seventy-eight women with PPROM at gestational ages between 24 + 0 and 36 + 6 weeks were included in this study. The samples of amniotic fluid were obtained at admission via transabdominal amniocentesis, and amniotic fluid interleukin (IL)-6 concentrations were determined using a point-of-care test. All women had a full-mouth recording to determine the periodontal and oral hygiene status. Probing pocket depth and clinical attachment loss were measured at four sites on each fully erupted tooth. RESULTS: In total, 45% (35/78) of women with PPROM had periodontal disease. Mild, moderate, and severe periodontal disease was present in 19% (15/78), 19% (15/78), and 6% (5/78) of women, respectively. The presence of MIAC and IAI was found in 28% (22/78) and 26% (20/78) of women, respectively. Periopathogenic bacteria (2 * Streptococcus intermedius and 1 * Fusobacterium nucleatum) was found in the amniotic fluid of 4% (3/78) of women. There were no differences in periodontal status between women with MIAC and/or IAI and women without these intra-amniotic complications. CONCLUSIONS: The presence of MIAC and IAI was not related to the periodontal status of women with PPROM. PMID- 28724344 TI - Corrigendum. PMID- 28724343 TI - Vero cell technology for rapid development of inactivated whole virus vaccines for emerging viral diseases. AB - INTRODUCTION: Rapid development and production of vaccines against emerging diseases requires well established, validated, robust technologies to allow industrial scale production and accelerated licensure of products. Areas covered: A versatile Vero cell platform has been developed and utilized to deliver a wide range of candidate and licensed vaccines against emerging viral diseases. This platform builds on the 35 years' experience and safety record with inactivated whole virus vaccines such as polio vaccine. The current platform has been optimized to include a novel double inactivation procedure in order to ensure a highly robust inactivation procedure for novel emerging viruses. The utility of this platform in rapidly developing inactivated whole virus vaccines against pandemic (-like) influenza viruses and other emerging viruses such as West Nile, Chikungunya, Ross River and SARS is reviewed. The potential of the platform for development of vaccines against other emerging viruses such as Zika virus is described. Expert commentary: Use of this platform can substantially accelerate process development and facilitate licensure because of the substantial existing data set available for the cell matrix. However, programs to provide vaccines against emerging diseases must allow alternative clinical development paths to licensure, without the requirement to carry out large scale field efficacy studies. PMID- 28724345 TI - Simultaneous bilateral total knee arthroplasty in hemophilia: is it recommended? AB - INTRODUCTION: Simultaneous bilateral total knee arthroplasty (TKA) is a potentially cost-saving manner of caring for patients with hemophilia who have bilateral symptomatic hemophilic knee arthropathy. Because factor VIII is used only once in bilateral TKA, it is performed in hemophilia to reduce costs. Areas covered: This article reviews the potential role of simultaneous bilateral TKA in patients with hemophilia. Expert commentary: Although two recent reports have mentioned the benefits of simultaneous bilateral TKA in patients with hemophilia, the data are still scant and preliminary. The two systematic reviews and the meta analyses on bilateral TKA in patients without hemophilia have shown that there are more complications with bilateral TKA than with unilateral TKA. This article calls the potential risks of this technique to the attention of hemophilia specialists. The current use of simultaneous bilateral TKA in patients with hemophilia is unadvised, and raising false expectations in these patients should be avoided. Prospective studies in the specific field of TKA in patients with hemophilia are needed. PMID- 28724346 TI - Biosensing Technologies for Therapeutic Drug Monitoring. AB - Therapeutic drug monitoring (TDM) is the clinical practice of measuring pharmaceutical drug concentrations in patients' biofluids at designated intervals to allow a close and timely control of their dosage. This practice allows for rapid medical intervention in case of toxicity-related issues and/or adjustment of dosage to better fit the therapeutic demand. Currently, TDM is performed in centralized laboratories employing instruments, such as immunoassay analyzers and mass spectrometers that can be run only by trained personnel. However the time required for the preparation, samples analysis, and data processing, together with the related financial cost, severely affects the application of TDM in medical practices. Therefore, a new generation of analytical tools is necessary to respond to the timely need of drug administration or reduction aiming at effectively treating oncologic patients. Technological advances in the field of nanosciences and biosensors offer the unique opportunity to address such issues. The interest for the so-called nanobiosensors is considerably increasing, particularly in drug discovery and clinical chemistry, even though there are only few examples reporting their use for TDM. The techniques employing nanobiosensors are mainly based on electrochemical, optical, and mass detection systems. In this review we described the most promising methodologies that, in our opinion, will bring TDM towards the next stage of clinical practice in the future. PMID- 28724347 TI - Use of a special Brazilian red-light emitting railroad worm Luciferase in bioassays of NEK7 protein Kinase and Creatine Kinase. AB - BACKGROUND: Luciferases, enzymes that catalyze bioluminescent reactions in different organisms, have been extensively used for bioanalytical purposes. The most well studied bioluminescent system is that of firefly and other beetles, which depends on a luciferase, a benzothiazolic luciferin and ATP, and it is being widely used as a bioanalytical reagent to quantify ATP. Protein kinases are proteins that modify other proteins by transferring phosphate groups from a nucleoside triphosphate, usually ATP. METHODS: Here, we used a red-light emitting luciferase from Phrixotrix hirtus railroad worm to determine the activity of kinases in a coupled assay, based on luminescence that is generated when luciferase is in the presence of its substrate, the luciferin, and ATP. RESULTS: In this work we used, after several optimization reactions, creatine kinase isoforms as well as NEK7 protein kinase in the absence or presence of ATP analogous inhibitors to validate this new luminescence method. CONCLUSION: With this new approach we validated a luminescence method to quantify kinase activity, with different substrates and inhibition screening tests, using a novel red-light emitting luciferase as a reporter enzyme. PMID- 28724348 TI - Efficacy and safety of polymer-free stent versus polymer-permanent drug-eluting stent in patients with acute coronary syndrome: a meta-analysis of randomized control trials. AB - BACKGROUND: The efficacy and safety of polymer-free stent (PFS) versus permanent polymer drug-eluting stent (PPDES) in patients undergoing percutaneous coronary intervention (PCI) remain controversial. Our meta-analysis was undertaken to evaluate and compare the efficacy and safety of PFS with those of PPDES in patients undergoing PCI. METHODS: We searched PubMed, Cochrane Library, EMBASE, and Clinical Trials.gov databases for randomized controlled trials (RCTs). The primary endpoints were incidence of stent thrombosis (ST) and target-lesion revascularization (TLR). The secondary endpoints included the incidence of major adverse cardiovascular events (MACE), myocardial infarction (MI), cardiac death (CD), late lumen loss (LLL), and diameter stenosis (DS). Subgroup analyses were also conducted based on the follow-up time. RESULTS: Eleven RCTs met the including criteria, and 8616 patients were included in the study. No significant differences were observed between PFS and PPDES treatments in the incidence of ST (RR 0.90; 95% CI: 0.62-1.31; P = 0.58; I 2 = 0), TLR (RR 0.87; 95% CI: 0.76 1.00; P = 0.05; I 2 = 37%), CD (RR 0.89; 95% CI: 0.72-1.10; P = 0.28; I 2 = 0), MI (RR 0.87; 95% CI: 0.71-1.05; P = 0.15; I 2 = 0), LLL (SMD 0.01; 95% CI: -0.29 0.30; P = 0.96; I2 = 90%), and DS (SMD -0.01; 95% CI: - 0.25 to 0.23; P = 0.93; I2 = 83%). Meanwhile, the patients with PFS had a lower incidence of MACE (RR 0.87; 95% CI: 0.78-0.97; P = 0.01; I 2 = 0) than those with PPDES. CONCLUSION: In the overall analysis, patients with PFS presented a lower risk of MACE versus PPDES, but no significant difference were obtained in the risk of ST, TLR, MI, CD, DDD and DS. In the Short term follow up, patients with PSF presented a lower risk of TLR compared with PPDES. PMID- 28724349 TI - 16S rRNA gene-based association study identified microbial taxa associated with pork intramuscular fat content in feces and cecum lumen. AB - BACKGROUND: Intramuscular fat (IMF) that deposits among muscle fibers or within muscle cells is an important meat quality trait in pigs. Previous studies observed the effects of dietary nutrients and additives on improving the pork IMF. Gut microbiome plays an important role in host metabolism and energy harvest. Whether gut microbiota exerts effect on IMF remains unknown. RESULTS: In this study, we investigated the microbial community structure of 500 samples from porcine cecum and feces using high-throughput 16S rRNA gene sequencing. We found that phylogenetic composition and potential function capacity of microbiome varied between two types of samples. Bacteria wide association study identified 119 OTUs significantly associated with IMF in the two types of samples (FDR < 0.1). Most of the IMF-associated OTUs belong to the bacteria related to polysaccharide degradation and amino acid metabolism (such as Prevotella, Treponema, Bacteroides and Clostridium). Potential function capacities related to metabolisms of carbohydrate, energy and amino acids, cell motility, and membrane transport were significantly associated with IMF content. FishTaco analysis suggested that the shifts of potential function capacities of microbiome associated with IMF might be caused by the IMF-associated microbial taxa. CONCLUSIONS: This study firstly evaluated the contribution of gut microbiome to porcine IMF content. The results presented a potential capacity for improving IMF through modulating gut microbiota. PMID- 28724350 TI - A random effects meta-analysis model with Box-Cox transformation. AB - BACKGROUND: In a random effects meta-analysis model, true treatment effects for each study are routinely assumed to follow a normal distribution. However, normality is a restrictive assumption and the misspecification of the random effects distribution may result in a misleading estimate of overall mean for the treatment effect, an inappropriate quantification of heterogeneity across studies and a wrongly symmetric prediction interval. METHODS: We focus on problems caused by an inappropriate normality assumption of the random effects distribution, and propose a novel random effects meta-analysis model where a Box-Cox transformation is applied to the observed treatment effect estimates. The proposed model aims to normalise an overall distribution of observed treatment effect estimates, which is sum of the within-study sampling distributions and the random effects distribution. When sampling distributions are approximately normal, non-normality in the overall distribution will be mainly due to the random effects distribution, especially when the between-study variation is large relative to the within-study variation. The Box-Cox transformation addresses this flexibly according to the observed departure from normality. We use a Bayesian approach for estimating parameters in the proposed model, and suggest summarising the meta analysis results by an overall median, an interquartile range and a prediction interval. The model can be applied for any kind of variables once the treatment effect estimate is defined from the variable. RESULTS: A simulation study suggested that when the overall distribution of treatment effect estimates are skewed, the overall mean and conventional I 2 from the normal random effects model could be inappropriate summaries, and the proposed model helped reduce this issue. We illustrated the proposed model using two examples, which revealed some important differences on summary results, heterogeneity measures and prediction intervals from the normal random effects model. CONCLUSIONS: The random effects meta-analysis with the Box-Cox transformation may be an important tool for examining robustness of traditional meta-analysis results against skewness on the observed treatment effect estimates. Further critical evaluation of the method is needed. PMID- 28724352 TI - A permutation-based non-parametric analysis of CRISPR screen data. AB - BACKGROUND: Clustered regularly-interspaced short palindromic repeats (CRISPR) screens are usually implemented in cultured cells to identify genes with critical functions. Although several methods have been developed or adapted to analyze CRISPR screening data, no single specific algorithm has gained popularity. Thus, rigorous procedures are needed to overcome the shortcomings of existing algorithms. METHODS: We developed a Permutation-Based Non-Parametric Analysis (PBNPA) algorithm, which computes p-values at the gene level by permuting sgRNA labels, and thus it avoids restrictive distributional assumptions. Although PBNPA is designed to analyze CRISPR data, it can also be applied to analyze genetic screens implemented with siRNAs or shRNAs and drug screens. RESULTS: We compared the performance of PBNPA with competing methods on simulated data as well as on real data. PBNPA outperformed recent methods designed for CRISPR screen analysis, as well as methods used for analyzing other functional genomics screens, in terms of Receiver Operating Characteristics (ROC) curves and False Discovery Rate (FDR) control for simulated data under various settings. Remarkably, the PBNPA algorithm showed better consistency and FDR control on published real data as well. CONCLUSIONS: PBNPA yields more consistent and reliable results than its competitors, especially when the data quality is low. R package of PBNPA is available at: https://cran.r-project.org/web/packages/PBNPA/ . PMID- 28724351 TI - Impact of a lay-led home-based intervention programme on quality of life in community-dwelling pre-frail and frail older adults: a randomized controlled trial. AB - BACKGROUND: Due to the demographic ageing process and the increasing number of pre-frail and frail individuals, new lifestyle interventions to enhance the quality of life (QoL) in community-dwelling older adults are necessary. Therefore, we performed a randomised controlled trial (RCT) to compare effects of a lay-led home-based physical and nutritional intervention programme with social support alone on different QoL domains in community-dwelling pre-frail and frail older adults. METHODS: In this analysis within a RCT (12 weeks), lay volunteers visited one-on-one pre-frail or frail older adults at home twice a week. Participants in the physical training and nutritional intervention (PTN) group performed six strength exercises and discussed main nutritional issues during each visit. The social support (SOSU) group received home visits twice a week for social exchanges. The QoL was assessed with the WHOQOL-BREF and the WHOQOL-OLD instruments. Analyses of covariance (ANCOVA) were used to examine differences between groups with baseline values as the covariate. Changes within groups were assessed with paired t-tests. RESULTS: Eighty participants (n = 39 in the PTN group and n = 41 in the SOSU group) were included. No significant differences were found between the two groups except in past, present and future activities domain [beta = 3.66 (95% confidence interval 0.13 to 7.18)] in favour of the PTN group. However, there was some evidence of greater within group improvements in the PTN group particularly in overall QoL, social relations and social participation. In the SOSU group, no significant effect was observed in any QoL domain. CONCLUSION: A combination of a home-based physical and nutritional intervention was not more effective compared to social support alone, on QoL in community-dwelling pre-frail and frail older adults. However, the small but significant improvement within the PTN group suggests that a home-based physical and nutritional intervention delivered by volunteers may influence the QoL in a positive way. TRIAL REGISTRATION: The study protocol was registered on 6 November 2013 at ClinicalTrials.gov (identifier: NCT01991639 ). PMID- 28724353 TI - Marfan syndrome and cardiovascular complications: results of a family investigation. AB - BACKGROUND: Cardiovascular complications in Marfan syndrome (MFS) make all its seriousness. Taking as a basis the Ghent criteria, we conducted a family screening from an index case. The objective was to describe the clinical characteristics of MFS anomalies and to detect cardiovascular complications in our patients. CASE PRESENTATION: Six subjects were evaluated. Patients had to be in the same uterine siblings of the index case or be a descendant. The objective was to search for MFS based on the diagnostic criteria of Ghent and, subsequently, detecting cardiovascular damage. The average age was 24 years. The examination revealed three cases of sudden death in a context of chest pain. Five subjects had systemic involvement with a score >= 7 that allowed to the diagnosis of MFS. Two patients had simultaneously ectopia lentis and myopia. In terms of cardiovascular damage, there were three cases of dilatation of the aortic root, two cases of aortic dissection of Stanford's type A with severe aortic regurgitation in one case and moderate in the other. There were three patients with moderate mitral regurgitation with a case by valve prolapse. CONCLUSION: The family screening is crucial in Marfan syndrome. It revealed serious cardiovascular complications including sudden death and aortic dissection. PMID- 28724355 TI - Urban-rural differences in the association between access to healthcare and health outcomes among older adults in China. AB - BACKGROUND: Studies have shown that inadequate access to healthcare is associated with lower levels of health and well-being in older adults. Studies have also shown significant urban-rural differences in access to healthcare in developing countries such as China. However, there is limited evidence of whether the association between access to healthcare and health outcomes differs by urban rural residence at older ages in China. METHODS: Four waves of data (2005, 2008/2009, 2011/2012, and 2014) from the largest national longitudinal survey of adults aged 65 and older in mainland China (n = 26,604) were used for analysis. The association between inadequate access to healthcare (y/n) and multiple health outcomes were examined-including instrumental activities of daily living (IADL) disability, ADL disability, cognitive impairment, and all-cause mortality. A series of multivariate models were used to obtain robust estimates and to account for various covariates associated with access to healthcare and/or health outcomes. All models were stratified by urban-rural residence. RESULTS: Inadequate access to healthcare was significantly higher among older adults in rural areas than in urban areas (9.1% vs. 5.4%; p < 0.01). Results from multivariate models showed that inadequate access to healthcare was associated with significantly higher odds of IADL disability in older adults living in urban areas (odds ratio [OR] = 1.58-1.79) and rural areas (OR = 1.95-2.30) relative to their counterparts with adequate access to healthcare. In terms of ADL disability, we found significant increases in the odds of disability among rural older adults (OR = 1.89-3.05) but not among urban older adults. Inadequate access to healthcare was also associated with substantially higher odds of cognitive impairment in older adults from rural areas (OR = 2.37-3.19) compared with those in rural areas with adequate access to healthcare; however, no significant differences in cognitive impairment were found among older adults in urban areas. Finally, we found that inadequate access to healthcare increased overall mortality risks in older adults by 33-37% in urban areas and 28-29% in rural areas. However, the increased risk of mortality in urban areas was not significant after taking into account health behaviors and baseline health status. CONCLUSIONS: Inadequate access to healthcare was significantly associated with higher rates of disability, cognitive impairment, and all-cause mortality among older adults in China. The associations between access to healthcare and health outcomes were generally stronger among older adults in rural areas than in urban areas. Our findings underscore the importance of providing adequate access to healthcare for older adults-particularly for those living in rural areas in developing countries such as China. PMID- 28724354 TI - Novel Plasmodium falciparum metabolic network reconstruction identifies shifts associated with clinical antimalarial resistance. AB - BACKGROUND: Malaria remains a major public health burden and resistance has emerged to every antimalarial on the market, including the frontline drug, artemisinin. Our limited understanding of Plasmodium biology hinders the elucidation of resistance mechanisms. In this regard, systems biology approaches can facilitate the integration of existing experimental knowledge and further understanding of these mechanisms. RESULTS: Here, we developed a novel genome scale metabolic network reconstruction, iPfal17, of the asexual blood-stage P. falciparum parasite to expand our understanding of metabolic changes that support resistance. We identified 11 metabolic tasks to evaluate iPfal17 performance. Flux balance analysis and simulation of gene knockouts and enzyme inhibition predict candidate drug targets unique to resistant parasites. Moreover, integration of clinical parasite transcriptomes into the iPfal17 reconstruction reveals patterns associated with antimalarial resistance. These results predict that artemisinin sensitive and resistant parasites differentially utilize scavenging and biosynthetic pathways for multiple essential metabolites, including folate and polyamines. Our findings are consistent with experimental literature, while generating novel hypotheses about artemisinin resistance and parasite biology. We detect evidence that resistant parasites maintain greater metabolic flexibility, perhaps representing an incomplete transition to the metabolic state most appropriate for nutrient-rich blood. CONCLUSION: Using this systems biology approach, we identify metabolic shifts that arise with or in support of the resistant phenotype. This perspective allows us to more productively analyze and interpret clinical expression data for the identification of candidate drug targets for the treatment of resistant parasites. PMID- 28724356 TI - A one-year follow-up study of chronic pain in community-dwelling older adults with and without neuropathic pain. AB - BACKGROUND: Chronic, mostly musculoskeletal pain is common among older adults. Little is known about the prognosis of chronic pain and the neuropathic pain qualities in older adults. We studied a cohort of community-dwelling older adults, clinically assessed their pain states, classified their type of pain (nociceptive, neuropathic or combined) and followed them up for a year. METHODS: At baseline, a geriatrician clinically examined all study patients and classified their type of pain in collaboration with a pain specialist. Pain, quality of life and mental health were measured by questionnaires (BPI, GDS-15, BAI and SF-36) and reassessed after 1 year. RESULTS: Despite chronic pain, all patients from the baseline cohort continued to live independently at 1 year. A total of 92 of 106 (87%) patients returned the follow-up questionnaire. Nociceptive pain on its own was present in 48 patients, whereas 44 patients also had neuropathic pain. Most patients (96%) had several pain states at baseline, and 13 patients reported a new pain state at follow-up. On average, there were no significant changes in the pain intensity, pain interference, mood or quality of life in either group between baseline and follow-up. Changes in pain were observed at the individual level, and both intensity and interference of pain at the follow-up had a negative correlation with the baseline value. CONCLUSIONS: On average, chronic pain was persistent in our patients, but they were able to live independently despite their pain. At the individual level, both relief and exacerbation of pain were observed, supporting the notion that pain is not inevitable and unremitting among older adults. PMID- 28724357 TI - Genome analysis of E. coli isolated from Crohn's disease patients. AB - BACKGROUND: Escherichia coli (E. coli) has been increasingly implicated in the pathogenesis of Crohn's disease (CD). The phylogeny of E. coli isolated from Crohn's disease patients (CDEC) was controversial, and while genotyping results suggested heterogeneity, the sequenced strains of E. coli from CD patients were closely related. RESULTS: We performed the shotgun genome sequencing of 28 E. coli isolates from ten CD patients and compared genomes from these isolates with already published genomes of CD strains and other pathogenic and non-pathogenic strains. CDEC was shown to belong to A, B1, B2 and D phylogenetic groups. The plasmid and several operons from the reference CD-associated E. coli strain LF82 were demonstrated to be more often present in CDEC genomes belonging to different phylogenetic groups than in genomes of commensal strains. The operons include carbon-source induced invasion GimA island, prophage I, iron uptake operons I and II, capsular assembly pathogenetic island IV and propanediol and galactitol utilization operons. CONCLUSIONS: Our findings suggest that CDEC are phylogenetically diverse. However, some strains isolated from independent sources possess highly similar chromosome or plasmids. Though no CD-specific genes or functional domains were present in all CD-associated strains, some genes and operons are more often found in the genomes of CDEC than in commensal E. coli. They are principally linked to gut colonization and utilization of propanediol and other sugar alcohols. PMID- 28724358 TI - Quality of care and quality of life of people with dementia living at green care farms: a cross-sectional study. AB - BACKGROUND: Many countries are introducing smaller, more home-like care facilities that represent a radically new approach to nursing home care for people with dementia. The green care farm is a new type of nursing home developed in the Netherlands. The goal of this study was to compare quality of care, quality of life and related outcomes in green care farms, regular small-scale living facilities and traditional nursing homes for people with dementia. METHODS: A cross-sectional design was used. Three types of nursing homes were included: (1) green care farms; (2) regular small-scale living facilities; (3) traditional nursing homes. All participating nursing homes were non-profit, collectively funded nursing homes in the south of the Netherlands. One hundred and fifteen residents with a formal diagnosis of dementia were included in the study. Data on quality of care was gathered and consisted of outcome indicators (e.g. falling incidents, pressure ulcers), structure indicators (e.g. hours per resident per day), and process indicators (e.g. presence, accessibility and content of protocols on care delivery). Furthermore, questionnaires on cognition, dependence in activities of daily living, quality of life, social engagement, neuropsychiatric symptoms, agitation, and depression were used. RESULTS: Data showed that quality of care was comparable across settings. No large differences were found on clinical outcome measures, hours per resident per day, or process indicators. Higher quality of life scores were reported for residents of green care farms in comparison with residents of traditional nursing homes. They scored significantly higher on the Quality of Life - Alzheimer's disease Scale (p < 0.05, ES = 0.8) indicating a better quality of life. In addition, residents of green care farms scored higher on three quality of life domains of the Qualidem: positive affect, social relations and having something to do (p < 0.05, ES > 0.7). No differences with regular small-scale living facilities were found. CONCLUSIONS: Green care farms seem to be a valuable alternative to existing nursing homes. This is important as people with dementia are a heterogeneous group with varying needs. In order to provide tailored care there also is a need for a variety of living environments. PMID- 28724359 TI - The burden of HIV on Tuberculosis patients in the Volta region of Ghana from 2012 to 2015: implication for Tuberculosis control. AB - BACKGROUND: The impact of HIV on TB, and the implications for TB control, has been acknowledged as a public health challenge. It is imperative therefore to assess the burden of HIV on TB patients as an indicator for monitoring the control efforts of the two diseases in this part of the world. This study aimed at determining the burden of HIV infection in TB patients. METHODS: We conducted a retrospective review of TB registers in five districts of the Volta Region of Ghana. Prevalence of TB/HIV co-infection was determined. Bivariate and multivariate logistic regression were used to identify the predictors of HIV infection among TB patients and statistical significance was set at p-value <0.05. RESULTS: Of the 1772 TB patients, 1633 (92.2%) were tested for HIV. The overall prevalence of TB/HIV co-infection was (18.2%; 95% CI: 16.4-20.1). The prevalence was significantly higher among females (24.1%; 95%CI: 20.8-27.7), compared to males (15.1%; 95% CI: 13.1-17.4) (p < 0.001) and among children <15 years of age (27.0%; 95% CI: 18.2-38.1), compared to the elderly >=70 years (3.5%; 95% CI: 1.6-7.4) (p < 0.001). Treatment success rate was higher among patients with only TB (90%; 95% CI: 88.1-91.5) than among TB/HIV co-infected patients (77.0%; 95% CI: 71.7-81.7) (p < 0.001). Independent predictors of HIV infection were found to be: being female (AOR: 1.79; 95% CI: 1.38-2.13; p < 0.001); smear negative pulmonary TB (AOR: 1.84; 95% CI: 1.37-2.47; p < 0.001); and patients registered in Hohoe, Kadjebi, and Kpando districts with adjusted odds ratios of 1.69 (95% CI: 1.13-2.54; p = 0.011), 2.29 (95% CI: 1.46-3.57; p < 0.001), and 2.15 (95% CI: 1.44-3.21; p < 0.001) respectively. Patients >=70 years of age and those registered in Keta Municipal were less likely to be HIV positive with odds ratios of 0.09 (95% CI: 0.04-0.26; p < 0.001) and 0.62 (95% CI: 0.38 0.99; p = 0.047) respectively. CONCLUSION: TB/HIV co-infection rate in five study districts of the Volta region is quite high, occurs more frequently in female patients than males; among smear negative pulmonary TB patients, and children <15 years of age. Findings also demonstrate that HIV co-infection affects TB treatment outcomes adversely. Strengthening the TB/HIV collaborative efforts is required in order to reduce the burden of co-infection in patients. PMID- 28724360 TI - Injury of ascending reticular activating system associated with delayed post hypoxic leukoencephalopathy: a case report. AB - BACKGROUND: Delayed post-hypoxic leukoencephalopathy (DPHL) is a demyelinating syndrome characterized by neurological relapse after an initial recovery from hypoxic brain injury. We describe a patient with impaired consciousness following DPHL, concurrent with injury of the ascending reticular activating system (ARAS) shown using diffusion tensor tractography (DTT). CASE PRESENTATION: A 50-year-old male patient was in a drowsy mental state after exposure to carbon monoxide (CO) for about ten hours. About a day after the CO exposure, his mental state recovered to an alert condition. However, his consciousness deteriorated to drowsy 24 days after the exposure and worsened to a semi-coma state at 26 days after onset. When he started rehabilitation six weeks after the CO exposure, he had impaired consciousness, with a Glasgow Coma Scale score of 8 and a Coma Recovery Scale-Revised score of 8. On 6-week DTT, decreased neural connectivity of the upper ARAS between the intralaminar thalamic nucleus and the cerebral cortex was observed in both frontal cortices, basal forebrains, basal ganglia and thalami. The lower dorsal ARAS was not reconstructed on the right side, and was thin on the left side. The lower ventral ARAS was not reconstructed on either side. CONCLUSIONS: Using DTT, we demonstrated injury of the ARAS in a patient with impaired consciousness following DPHL. Our result suggests that injury of the ARAS is a plausible pathogenetic mechanism of impaired consciousness in patients with DPHL. PMID- 28724361 TI - Serum melatonin levels in survivor and non-survivor patients with traumatic brain injury. AB - BACKGROUND: Circulating levels of melatonin in patients with traumatic brain injury (TBI) have been determined in a little number of studies with small sample size (highest sample size of 37 patients) and only were reported the comparison of serum melatonin levels between TBI patients and healthy controls. As to we know, the possible association between circulating levels of melatonin levels and mortality of patients with TBI have not been explored; thus, the objective of our current study was to determine whether this association actually exists. METHODS: This multicenter study included 118 severe TBI (Glasgow Coma Scale <9) patients. We measured serum levels of melatonin, malondialdehyde (to assess lipid peroxidation) and total antioxidant capacity (TAC) at day 1 of severe TBI. We used mortality at 30 days as endpoint. RESULTS: We found that non-survivor (n = 33) compared to survivor (n = 85) TBI patients showed higher circulating levels of melatonin (p < 0.001), TAC (p < 0.001) and MDA (p < 0.001). We found that serum melatonin levels predicted 30-day mortality (Odds ratio = 1.334; 95% confidence interval = 1.094-1.627; p = 0.004), after to control for GCS, CT findings and age. We found a correlation between serum levels of melatonin levels and serum levels of TAC (rho = 0.37; p < 0.001) and serum levels of MDA (rho = 0.24; p = 0.008). CONCLUSIONS: As to we know, our study is the largest series providing circulating melatonin levels in patients with severe TBI. The main findings were that non-survivors had higher serum melatonin levels than survivors, and the association between serum levels of melatonin levels and mortality, peroxidation state and antioxidant state. PMID- 28724362 TI - Prevalence of chronic kidney disease in Peruvian primary care setting. AB - BACKGROUND: Chronic Kidney Disease (CKD) is a worldwide public health problem. There are few studies in Latin America, especially in primary care settings. Our objective was to determine the prevalence, stages, and associated factors of CKD in primary care setting. METHODS: We did a retrospective secondary analysis of a database from the Diabetes and Hypertension Primary Care Center of the Peruvian Social Security System (EsSalud) in Lima, Peru. We defined CKD as the presence of eGFR <60 mL/min and/or albuminuria >30 mg/day in 24 h, according to Kidney Disease: Improving Global Outcomes (KDIGO). Factors associated with CKD were evaluated with Poisson Regression models; these factors included age, gender, type 2 diabetes mellitus (DM2), hypertension (HTN), body mass index (BMI), and uric acid. Associations were described as crude and adjusted prevalence ratios (PR) and their 95% confidence intervals (95% CI). RESULTS: We evaluated 1211 patients (women [59%], mean age 65.8 years [SD: 12.7]). Prevalence of CKD was 18%. Using the estimated glomerular filtration rate (eGFR), the prevalence was 9.3% (95% CI 5.3 - 13.3) in patients without HTN or DM2; 20.2% (95% CI 17.6 - 22.8) in patients with HTN, and 23.9% (95% CI 19.4 - 28.4) in patients with DM2. The most common stages were 1 and 2 with 41.5% and 48%, respectively. Factors associated with CKD in the adjusted analysis were: age in years (PR = 1.03, 95% CI 1.01 - 1.04), DM2 (PR = 3.37, 95% CI 1.09 - 10.39), HTN plus DM2 (PR = 3.90, 95% CI 1.54 - 9.88), and uric acid from 5 to <7 mg/dL (PR = 2.04, 95% CI 1.31 - 3.19) and >=7 mg/dL (PR = 5.19, 95% CI 3.32 - 8.11). CONCLUSIONS: Prevalence of CKD in the primary care setting population was high. CKD is more frequent in the early stages of the disease, and individuals with hypertension, DM2, older age and hyperuricemia have higher prevalence of CKD. PMID- 28724363 TI - Comparing patient and healthcare worker experiences during a dengue outbreak in Singapore: understanding the patient journey and the introduction of a point-of care test (POCT) toward better care delivery. AB - BACKGROUND: In the aftermath of an upsurge in the number of dengue cases in 2013 and 2014, the SD BIOLINE Dengue Duo rapid diagnostic Point-of-Care Test (POCT) kit was introduced in Tan Tock Seng Hospital, Singapore in June 2013. It is known that the success of POCT usage is contingent on its implementation within the health system. We evaluated health services delivery and the Dengue Duo rapid diagnostic test kit application in Singapore from healthcare workers' perspectives and patient experiences of dengue at surge times. METHODS: Focus group discussions were conducted with dengue patients, from before and after the POCT implementation period. In-depth interviews with semi-structured components with healthcare workers were carried out. A patient centred process mapping technique was used for evaluation, which mapped the patient's journey and was mirrored from the healthcare worker's perspective. RESULTS: Patients and healthcare workers confirmed a wide range of symptoms in adults, making it challenging to determine diagnosis. There were multiple routes to help seeking, and no 'typical patient journey', with patients either presenting directly to the hospital emergency department, or being referred there by a primary care provider. Patients groups diagnosed before and after POCT implementation expressed some differences between speed of diagnoses and attitudes of doctors, yet shared negative feelings about waiting times and a lack of communication and poor information delivery. However, the POCT did not in its current implementation do much to help waiting times. Healthcare workers expressed that public perceptions of dengue in recent years was a major factor in changing patient management, and that the POCT kit was helpful in improving the speed and accuracy of diagnoses. CONCLUSIONS: Health service delivery for dengue patients in Singapore was overall perceived to be of an acceptable clinical standard, which was enhanced by the introduction of the POCT. However, improvements can be focused on Adapting to outbreaks by reducing and rendering Waiting experiences more comfortable; Advancing education about symptom recognition, while also Recognising better communication strategies; and Expanding follow-up care options. This is presented as the Dengue AWARE model of care delivery. PMID- 28724364 TI - Tamoxifen reverses epithelial-mesenchymal transition by demethylating miR-200c in triple-negative breast cancer cells. AB - BACKGROUND: Although the efficacy of tamoxifen (TAM) for breast cancer has been attributed to inducing cell cycle arrest and apoptosis by inhibiting estrogen receptor (ER) signaling, recent evidence indicates that TAM also possesses ER independent antitumor activity through an unclear mechanism. The present study investigated the anti-tumor mechanism of TAM on mesenchymal triple-negative breast cancer (TNBC). METHODS: The inhibitory effect of TAM on tumor migration and metastasis was analyzed by transwell chamber in vitro and by murine xenograft model in vivo. The promoter sequence of miR-200c was predicted by an online CpG island predictor. Relative expression of miR-200c was measured by quantitative real-time PCR. RESULTS: After treatment with TAM, mesenchymal TNBC cells (MCF 7/ADR and MDA-MB-231) morphologically changed from mesenchymal to epithelial types. Meanwhile, cell migration ability was also significantly decreased in ER positive breast cancer cells after exposure to TAM. Consistent with these in vitro results, TAM significantly suppressed lung metastasis rate of mesenchymal TNBC cells in murine xenograft tumors. miRNA array analysis of two types of breast cancer cells showed that miR-200c expression was inhibited in mesenchymal TNBC cells, but increased after TAM treatment due to demethylation of miR-200c promoters. CONCLUSIONS: Our results indicate that TAM inhibits cell migration and enhances chemosensitivity of mesenchymal TNBC cells by reversing their EMT-like property; and that this EMT-reversal effect results from upregulation of miR-200c through demethylating its promoter. To our knowledge, this is the first explanation of a non-ER-related mechanism for the effect of TAM on mesenchymal TNBC cells. PMID- 28724365 TI - Leflunomide is equally efficacious and safe compared to low dose rituximab in refractory rheumatoid arthritis given in combination with methotrexate: results from a randomized double blind controlled clinical trial. AB - BACKGROUND: The standard dose of rituximab used in rheumatoid arthritis (RA) is 1000 mg but recent studies have shown that low dose (500 mg) is also effective. Efficacy of low dose rituximab in rheumatoid arthritis (RA) refractory to first line non-biologic Disease Modifying Anti Rheumatic Drugs (DMARDs), compared to leflunomide is unknown. In a tertiary care referral setting, we conducted a randomized, double blind controlled clinical trial comparing the efficacy and safety of low-dose rituximab-methotrexate combination with leflunomide methotrexate combination. METHODS: Patients on methotrexate (10-20 mg/week) with a Disease Activity Score (DAS) > 3.2 were randomly assigned to rituximab (500 mg on days 1 and 15) or leflunomide (10-20 mg/day). The primary end-point was ACR20 at 24 weeks. Sample of 40 had 70% power to detect a 30% difference. ACR50, ACR70, DAS, EULAR good response, CD3 + (T cell), CD19 + (B cell) and CD19 + CD27+ (memory B cell) counts, tetanus and pneumococcal antibody levels were secondary end points. RESULTS: Baseline characteristics were comparable in the two groups. At week 24, ACR20 was 85% vs 84% (p = 0.93), ACR50 was 60% vs. 64% (p = 0.79) and ACR70 was 35% vs 32% (P = 0.84), in rituximab and in leflunomide groups respectively. Serious adverse events were similar. With rituximab there was significant reduction in B cells (p < 0.001), memory B cells (p < 0.001) and pneumococcal antibody levels (P < 0.05) without significant changes in T cells (p = 0.835) and tetanus antibody levels (p = 0.424) at 24 weeks. With leflunomide, significant reduction in memory B cells (p < 0.01) and pneumococcal antibody levels (p < 0.01) occurred without significant changes in B cells (P > 0.05), T cells (P > 0.05) or tetanus antibody levels (P > 0.05). CONCLUSIONS: Leflunomide methotrexate combination is as efficacious as low-dose rituximab-methotrexate combination at 24 weeks, in RA patient's refractory to initial DMARDs. The high responses seen in both groups have favorable cost implications for patients in developing countries. Changes in immune parameters with leflunomide are novel and need further characterization. TRIAL REGISTRATION: The trial was registered with the Sri Lanka Clinical Trials Registry (SLCTR), a publicly accessible primary registry linked to the registry network of the International Clinical Trials Registry Platform of the WHO (WHO-ICTRP) (registration number: SLCTR/2008/008 dated 16th May 2008). PMID- 28724366 TI - Predicting progression of mild cognitive impairment to dementia using neuropsychological data: a supervised learning approach using time windows. AB - BACKGROUND: Predicting progression from a stage of Mild Cognitive Impairment to dementia is a major pursuit in current research. It is broadly accepted that cognition declines with a continuum between MCI and dementia. As such, cohorts of MCI patients are usually heterogeneous, containing patients at different stages of the neurodegenerative process. This hampers the prognostic task. Nevertheless, when learning prognostic models, most studies use the entire cohort of MCI patients regardless of their disease stages. In this paper, we propose a Time Windows approach to predict conversion to dementia, learning with patients stratified using time windows, thus fine-tuning the prognosis regarding the time to conversion. METHODS: In the proposed Time Windows approach, we grouped patients based on the clinical information of whether they converted (converter MCI) or remained MCI (stable MCI) within a specific time window. We tested time windows of 2, 3, 4 and 5 years. We developed a prognostic model for each time window using clinical and neuropsychological data and compared this approach with the commonly used in the literature, where all patients are used to learn the models, named as First Last approach. This enables to move from the traditional question "Will a MCI patient convert to dementia somewhere in the future" to the question "Will a MCI patient convert to dementia in a specific time window". RESULTS: The proposed Time Windows approach outperformed the First Last approach. The results showed that we can predict conversion to dementia as early as 5 years before the event with an AUC of 0.88 in the cross-validation set and 0.76 in an independent validation set. CONCLUSIONS: Prognostic models using time windows have higher performance when predicting progression from MCI to dementia, when compared to the prognostic approach commonly used in the literature. Furthermore, the proposed Time Windows approach is more relevant from a clinical point of view, predicting conversion within a temporal interval rather than sometime in the future and allowing clinicians to timely adjust treatments and clinical appointments. PMID- 28724367 TI - Prognostic significance of perigastric tumor deposits in patients with primary gastric cancer. AB - BACKGROUND: The presence and the prognostic significance of perigastric tumor deposits (TDs) in primary gastric cancer have not been extensively studied. The aim of this study was to evaluate the prognostic significance perigastric TDs in primary gastric cancer. METHODS: From 2005 to 2010, 1250 patients underwent R0 gastrectomy at the Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, China. Out of 1250 patients, 132 patients with perigastric TDs were identified. Additionally, 132 patients with staged matched gastric cancer without tumor deposits were selected as a control group. RESULTS: Perigastric TDs were observed in 132 (10.5%) of the 1250 patients with gastric cancer who underwent R0 gastrectomy. There were 94 males (71.21%) and 38 females (28.79%) (2.47:1). The mean age was 57.21 years. Clinicopathologic characteristics between the two groups matched well. There was a significant difference in the overall survival of those with and without TDs by univariate (p<0.05) and multivariate (p < 0.05) survival analysis. The 1-, 3-and 5-year overall survival rates of patients with TDswere69.6%, 39.3%, and 24.2%, respectively, and were significantly poorer than those of the staged matched control group. There was no correlation between the number of TDs and patient survival in patients with gastric cancer (p>0.05); however, when comparing each pT tumor group with the perigastric TD group, the stage T4 survival rate was very similar to that observed in patients with TDs. CONCLUSIONS: Perigastric TDs are an independent predictive prognostic factor for gastric cancer and may be appropriately considered a form of serosal invasion. We suggest that TDs should be included in TNM staging system for better outcomes. PMID- 28724368 TI - Utilizing patient data from the veterans administration electronic health record to support web-based clinical decision support: informatics challenges and issues from three clinical domains. AB - BACKGROUND: The US Veterans Administration (VA) has developed a robust and mature computational infrastructure in support of its electronic health record (EHR). Web technology offers a powerful set of tools for structuring clinical decision support (CDS) around clinical care. This paper describes informatics challenges and design issues that were confronted in the process of building three Web-based CDS systems in the context of the VA EHR. METHODS: Over the course of several years, we implemented three Web-based CDS systems that extract patient data from the VA EHR environment to provide patient-specific CDS. These were 1) the VACS (Veterans Aging Cohort Study) Index Calculator which estimates prognosis for HIV+ patients, 2) Neuropath/CDS which assists in the medical management of patients with neuropathic pain, and 3) TRIM (Tool to Reduce Inappropriate Medications) which identifies potentially inappropriate medications in older adults and provides recommendations for improving the medication regimen. RESULTS: The paper provides an overview of the VA EHR environment and discusses specific informatics issues/challenges that arose in the context of each of the three Web-based CDS systems. We discuss specific informatics methods and provide details of approaches that may be useful within this setting. CONCLUSIONS: Informatics issues and challenges relating to data access and data availability arose because of the particular architecture of the national VA infrastructure and the need to link to that infrastructure from local Web-based CDS systems. Idiosyncrasies of VA patient data, especially the medication data, also posed challenges. Other issues related to specific functional needs of individual CDS systems. The goal of this paper is to describe these issues so that our experience may serve as a useful foundation to assist others who wish to build such systems in the future. PMID- 28724369 TI - Acculturation and other risk factors of depressive disorders in individuals with Turkish migration backgrounds. AB - BACKGROUND: Acculturation is a long-term, multi-dimensional process occurring when subjects of different cultures stay in continuous contact. Previous studies have suggested that elevated rates of depression among different migrant groups might be due to patterns of acculturation and migration related risk factors. This paper focused on prevalence rates of depressive disorders and related risk factors among individuals with Turkish migration backgrounds. METHODS: A population-based sample of 662 individuals with Turkish migration backgrounds were interviewed by bilingual interviewers using a standardised diagnostic interview for DSM-IV-TR and ICD-10 diagnoses (CIDI DIA-X Version 2.8). Associations between 12-month prevalence rates of depressive disorders with potential risk factors were assessed, including gender, age, socioeconomic status, acculturation status and migration status. RESULTS: 12-month prevalence rates of any depressive disorder were 29.0%, 14.4% of major depressive disorder (MDD) and 14.7% of dysthymia. Older age and low socioeconomic status were most consistently related to higher risks of depressive disorders. Acculturation status showed associations with subtypes of depressive disorder. Associations differed between men and women. Symptom severity of MDD was linked to gender, with females being more affected by severe symptoms. CONCLUSION: The prevalence of depressive disorders is high in individuals with Turkish migration backgrounds, which can be partly explained by older age, low socioeconomic status and acculturation pressures. Only a limited number of risk factors were assessed. Acculturation in particular is a complex process which might not be sufficiently represented by the applied measures. Further risk factors have to be identified in representative samples of this migrant group. PMID- 28724370 TI - Facing unemployment: study protocol for the implementation and evaluation of a community-based intervention for psychological well-being promotion. AB - BACKGROUND: Economic crises and unemployment have profound impact on mental health and well-being. Main goal of the Healthy Employment (HE) project is to enhance intersectoral actions promoting mental health among unemployed, namely through the implementation and effectiveness-evaluation of short-term and sustainable group interventions. METHODS: The project follows a RE-AIM-based (Reach, Effectiveness, Adoption, Implementation and Maintenance) framework for assessing a cognitive-behavioural and psychoeducational intervention that has been developed for promoting mental health among unemployed people. It is a short term group intervention (five sessions, four hours each, 20 unemployed persons per group) focused on mental health literacy, interpersonal communication and of emotional regulation. Implementation of the intervention will be carried out by clinical psychologists, following a standardized procedure manual. Effectiveness will be assessed through a randomized field study with two arms (intervention and control). Participants are unemployed people (18-65 years old, both genders, having at least nine years of formal education) registered at public employment centres from different geographical regions for less than 12 months (including first-job seekers). Allocation to arms of the study will follow a random match-to case process, considering gender, age groups and educational level. Three moments of evaluation will occur: before intervention (baseline), immediately after its ending and three months later. Main outcomes are mental health literacy, mental health related personal and perceived stigma, psychological well-being, satisfaction with life and resilience. Intention-to-treat and per-protocol analyses will be conducted. Cohen's d coefficient and odds ratio will be used for assessing the size of the intervention effect, when significant. DISCUSSION: Scientific and clinical knowledge will be applied to promote/protect psychological well-being of unemployed people. While the first phases of the project are funded by the European Economic Area Grants, long-term assessments of the intervention require a larger timeframe. Further funding and institutional support will be sought for this purpose. Already established intersectoral collaborations are key-assets to reach long-term sustainability of this project. TRIAL REGISTRATION: The study was registered with the Australian New Zealand Clinical Trials Registry; Prospectively registered number: ACTRN12616001432404 ; date of registration: 13 October 2016. PMID- 28724371 TI - Association between full service and fast food restaurant density, dietary intake and overweight/obesity among adults in Delhi, India. AB - BACKGROUND: The food environment has been implicated as an underlying contributor to the global obesity epidemic. However, few studies have evaluated the relationship between the food environment, dietary intake, and overweight/obesity in low- and middle-income countries (LMICs). The aim of this study was to assess the association of full service and fast food restaurant density with dietary intake and overweight/obesity in Delhi, India. METHODS: Data are from a cross sectional, population-based study conducted in Delhi. Using multilevel cluster random sampling, 5364 participants were selected from 134 census enumeration blocks (CEBs). Geographic information system data were available for 131 CEBs (n = 5264) from a field survey conducted using hand-held global positioning system devices. The number of full service and fast food restaurants within a 1-km buffer of CEBs was recorded by trained staff using ArcGIS software, and participants were assigned to tertiles of full service and fast food restaurant density based on their resident CEB. Height and weight were measured using standardized procedures and overweight/obesity was defined as a BMI >=25 kg/m2. RESULTS: The most common full service and fast food restaurants were Indian savory restaurants (57.2%) and Indian sweet shops (25.8%). Only 14.1% of full service and fast food restaurants were Western style. After adjustment for age, household income, education, and tobacco and alcohol use, participants in the highest tertile of full service and fast food restaurant density were less likely to consume fruit and more likely to consume refined grains compared to participants in the lowest tertile (both p < 0.05). In unadjusted logistic regression models, participants in the highest versus lowest tertile of full service and fast food restaurant density were significantly more likely to be overweight/obese: odds ratio (95% confidence interval), 1.44 (1.24, 1.67). After adjustment for age, household income, and education, the effect was attenuated: 1.08 (0.92, 1.26). Results were consistent with further adjustment for tobacco and alcohol use, moderate physical activity, and owning a bicycle or motorized vehicle. CONCLUSIONS: Most full service and fast food restaurants were Indian, suggesting that the nutrition transition in this megacity may be better characterized by the large number of unhealthy Indian food outlets rather than the Western food outlets. Full service and fast food restaurant density in the residence area of adults in Delhi, India, was associated with poor dietary intake. It was also positively associated with overweight/obesity, but this was largely explained by socioeconomic status. Further research is needed exploring these associations prospectively and in other LMICs. PMID- 28724372 TI - Comparison of artificial graft versus autograft in anterior cruciate ligament reconstruction: a meta-analysis. AB - BACKGROUND: Critically evaluation and summarization for the outcomes between autografts and artificial grafts using in anterior cruciate ligament (ACL) reconstruction have not been performed currently. The purpose of this study is to compare the clinical outcomes between artificial ligaments and autografts at a short- to mid-term follow-up. METHODS: A computerized search of the databases was conducted including Medline, Embase, and the Cochrane library. Only prospective or retrospective comparative studies with a minimum 2-year follow-up and a minimum sample size of 15 for each group were considered for inclusion. Two independent reviewers performed data extraction and methodological quality assessment. A Mantel-Haenszel analysis was used for pooling of results. Sensitivity analysis was performed in order to maintain the stability of results. RESULTS: Seven studies were included in this study. The total sample size was 403 (autograft group: 206 patients; synthetic graft group: 197 patients). Four studies were randomized controlled trials. Two studies were retrospective comparative studies and one study was non-randomized prospective comparative study. In terms of instrumented laxity, patient-oriented outcomes and complications, no significant difference was occurred between new artificial ligaments and autografts. But the results of IKDC grades and instrumented laxity were worsen in early artificial ligaments compared to autografts. CONCLUSIONS: The outcomes of new generation of artificial ligaments are similar to autografts at a short- to mid-term follow-up. However, the early artificial ligaments are not suggested for ACL reconstruction compared to autografts. PMID- 28724374 TI - Cost-Effectiveness of isoniazid preventive therapy among HIV-infected patients clinicaly screened for latent tuberculosis infection in Dar es Salaam, Tanzania: A prospective Cohort study. AB - BACKGROUND: One of the reasons why Isoniazid preventive therapy (IPT) for Tuberculosis (TB) is not widely used in low income countries is concerns on cost of excluding active TB. We analyzed the cost-effectiveness of IPT provision in Tanzania having ruled out active TB by a symptom-based screening tool. METHODS: Data on IPT cost-effectiveness was prospectively collected from an observational cohort study of 1283 HIV-infected patients on IPT and 1281 controls; followed up for 24 months. The time horizon for the analysis was 2 years. Number of TB cases prevented and deaths averted were used for effectiveness. A micro costing approach was used from a provider perspective. Cost was estimated on the basis of clinical records, market price or interviews with medical staff. We annualized the cost at a discount of 3%. A univariate sensitivity analysis was done. Results are presented in US$ at an average annual exchange rate for the year 2012 which was Tanzania shillings 1562.4 for 1 US $. RESULTS: The number of TB cases prevented was 420/100,000 persons receiving IPT. The number of deaths averted was 979/100,000 persons receiving IPT. Incremental cost due to IPT provision was US$ 170,490. The incremental cost effective ratio was US $ 405.93 per TB case prevented and US $ 174.15 per death averted. These costs were less than 3 times the 768 US $ Gross Domestic Product (GDP) per capita for Tanzania in the year 2014, making IPT provision after ruling out active TB by the symptom-based screening tool cost-effective. The results were robust to changes in laboratory and radiological tests but not to changes in recurrent, personnel, medication and utility costs. CONCLUSION: IPT should be given to HIV-infected patients who screen negative to symptom-based TB screening questionnaire. Its cost effectiveness supports government policy to integrate IPT to HIV/AIDS care and treatment in the country, given the availability of budget and the capacity of health facilities. PMID- 28724373 TI - Changing nutrition care practices in hospital: a thematic analysis of hospital staff perspectives. AB - BACKGROUND: Many patients are admitted to hospital and are already malnourished. Gaps in practice have identified that care processes for these patients can be improved. Hospital staff, including management, needs to work towards optimizing nutrition care in hospitals to improve the prevention, detection and treatment of malnutrition. The objective of this study was to understand how staff members perceived and described the necessary ingredients to support change efforts required to improve nutrition care in their hospital. METHODS: A qualitative study was conducted using purposive sampling techniques to recruit participants for focus groups (FG) (n = 11) and key informant interviews (n = 40) with a variety of hospital staff and management. Discussions based on a semi-structured schedule were conducted at five diverse hospitals from four provinces in Canada as part of the More-2-Eat implementation project. One researcher conducted 2-day site visits over a two-month period to complete all interviews and FGs. Interviews were transcribed verbatim while key points and quotes were taken from FGs. Transcripts were coded line-by-line with initial thematic analysis completed by the primary author. Other authors (n = 3) confirmed the themes by reviewing a subset of transcripts and the draft themes. Themes were then refined and further detailed. Member checking of site summaries was completed with site champions. RESULTS: Participants (n = 133) included nurses, physicians, food service workers, dietitians, and hospital management, among others. Discussion regarding ways to improve nutrition care in each specific site facilitated the thought process during FG and interviews. Five main themes were identified: building a reason to change; involving relevant people in the change process; embedding change into current practice; accounting for climate; and building strong relationships within the hospital team. CONCLUSIONS: Hospital staff need a reason to change their nutrition care practices and a significant change driver is perceived and experienced benefit to the patient. Participants described key ingredients to support successful change and specifically engaging the interdisciplinary team to effect sustainable improvements in nutrition care. TRIAL REGISTRATION: Retrospectively registered ClinicalTrials.gov Identifier: NCT02800304 , June 7, 2016. PMID- 28724375 TI - Bilateral idiopathic retinal vasculitis following coxsackievirus A4 infection: a case report. AB - BACKGROUND: Coxsackieviruses are members of a group of viruses called the enteroviruses, which may cause respiratory and gastrointestinal symptoms, erythema, meningoencephalitis, myocarditis, pericarditis, and myositis. Unilateral acute idiopathic maculopathy caused by coxsackievirus A16 has been associated with hand, foot, and mouth disease, but only a few reports describe retinitis associated with coxsackievirus serotype B3 or B4. We report a case of bilateral multifocal obstructive retinal vasculitis that developed after coxsackievirus A4 infection. CASE PRESENTATION: A 60-year-old woman was referred to our department with bilateral visual disturbance that developed following flu like symptoms. At the initial examination, best corrected visual acuity was 20/200 in the right eye and 20/50 in the left eye. The critical flicker frequency (CFF) was 23 Hz in the right eye and 27 Hz in the left eye. Fine white keratic precipitates with infiltrating cells were presented in the anterior chamber of both eyes, and multifocal retinal ischemic lesions were observed in the macula and posterior pole of both eyes. The retinal lesions corresponded with scotomas observed in Goldmann visual field test. On spectral domain-optical coherence tomography (SD-OCT), retinal lesions were depicted as hyper-reflective regions in the inner retina layers in both eyes, and disruption of ellipsoid line in the left eye., Fluorescein angiography exhibited findings indicative of multifocal obstructive retinal vasculitis. The patient had a history of current hypertension treated with oral therapy and glaucoma treated with latanoprost eye drops. Blood test for coxsackievirus antibody titers revealed that A4, A6, A9, B1, B2, B3, and B5 were positive (titers: 8-32). Abdominal skin biopsy of necrotic tissue suggested vascular damage caused by coxsackievirus. The general symptoms improved after 6 weeks, and the multifocal retinal ischemic lesions were partially resolved with residual slightly hard exudates. Only coxsackievirus A4 antibody titer increased from 4 to 32-fold after 14 months. However, hyper-reflective regions and disruption of the inner retinal layers on SD-OCT persisted especially in the right eye, and residual paracentral scotoma was observed in the right eye. CONCLUSION: The present case suggests that coxsackievirus A4 causes bilateral multifocal obstructive retinal vasculitis with irreversible inner retinal damage. PMID- 28724376 TI - Sonication contribution to identifying prosthetic joint infection with Ralstonia pickettii: a case report and review of the literature. AB - BACKGROUND: In the context of an increase number of primary and revision total hip and total knee arthroplasty performed yearly, an increased risk of complication is expected. Prosthetic joint infection (PJI) remains the most common and feared arthroplasty complication. Ralstonia pickettii is a Gram negative bacterium, that has also been identified in biofilms. It remains an extremely rare cause of PJI. There is no report of an identification of R. pickettii on an extracted spacer loaded with antibiotic. CASE PRESENTATION: We present the case of an 83-years-old Caucasian male patient, that underwent a right cemented total hip replacement surgery. The patient is diagnosed with an early PJI with no isolated microorganism. A debridement and change of mobile parts is performed. At the beginning of 2016, the patient in readmitted into the Orthopedic Department for sever, right abdominal and groin pain and elevated serum erythrocyte sedimentation rate and C-reactive protein. A joint aspiration is performed with a negative microbiological examination. A two-stage exchange with long interval management is adopted, and a preformed spacer loaded with gentamicin was implanted. In July 2016, based on the proinflammatory markers evolution, a shift a three-stage exchange strategy is decided. In September 2016, a debridement, and changing of the preformed spacer loaded with gentamicin with another was carried out. Bacteriological examination of the tissues sampled intraoperatively was positive for Pseudomonas aeruginosa. From the sonication fluid, no bacteria were isolated on culture or identified using the bbFISH assay. During the hospitalization period, the patient received i.v. ceftazidime 3x2g/day and p.o. ciprofloxacin 2x750mg/day, antibiotic therapy that was continued after discharge with p.o. ciprofloxacin 2x750mg/day for 6 weeks. In February 2017, a reimplantation of a revision prosthesis is performed. The retrieved spacer is sonicated, and after 4 days of incubation of the sonication fluid, R. pickettii is isolated. A long term antibiotic therapy with cotrimoxazole being prescribed. CONCLUSIONS: Bacteria culture of sonication fluid remains the gold standard in diagnosing prosthetic joint infections. R. pickettii remains an extremely rare cause of prosthetic joint infection. Optimal management of R. pickettii prosthetic joint infections of has not been established. PMID- 28724378 TI - Erratum to: Significance of the urokinase-type plasminogen activator and its receptor in the progression of focal segmental glomerulosclerosis in clinical and mouse models. PMID- 28724377 TI - Combination therapy for melanoma with BRAF/MEK inhibitor and immune checkpoint inhibitor: a mathematical model. AB - BACKGROUND: The B-raf gene is mutated in up to 66% of human malignant melanomas, and its protein product, BRAF kinase, is a key part of RAS-RAF-MEK-ERK (MAPK) pathway of cancer cell proliferation. BRAF-targeted therapy induces significant responses in the majority of patients, and the combination BRAF/MEK inhibitor enhances clinical efficacy, but the response to BRAF inhibitor and to BRAF/MEK inhibitor is short lived. On the other hand, treatment of melanoma with an immune checkpoint inhibitor, such as anti-PD-1, has lower response rate but the response is much more durable, lasting for years. For this reason, it was suggested that combination of BRAF/MEK and PD-1 inhibitors will significantly improve overall survival time. RESULTS: This paper develops a mathematical model to address the question of the correlation between BRAF/MEK inhibitor and PD-1 inhibitor in melanoma therapy. The model includes dendritic and cancer cells, CD 4+ and CD 8+ T cells, MDSC cells, interleukins IL-12, IL-2, IL-6, IL-10 and TGF- beta, PD-1 and PD-L1, and the two drugs: BRAF/MEK inhibitor (with concentration gamma B ) and PD-1 inhibitor (with concentration gamma A ). The model is represented by a system of partial differential equations, and is used to develop an efficacy map for the combined concentrations (gamma B ,gamma A ). It is shown that the two drugs are positively correlated if gamma B and gamma A are at low doses, that is, the growth of the tumor volume decreases if either gamma B or gamma A is increased. On the other hand, the two drugs are antagonistic at some high doses, that is, there are zones of (gamma B ,gamma A ) where an increase in one of the two drugs will increase the tumor volume growth, rather than decrease it. CONCLUSIONS: It will be important to identify, by animal experiments or by early clinical trials, the zones of (gamma B ,gamma A ) where antagonism occurs, in order to avoid these zones in more advanced clinical trials. PMID- 28724379 TI - Regulation of glucose uptake in lymphoma cell lines by c-MYC- and PI3K-dependent signaling pathways and impact of glycolytic pathways on cell viability. AB - BACKGROUND: Changes in glucose and energy metabolism contribute to the altered phenotype of cancer cells and are the basis for positron emission tomography with 18F-fluoro-2-deoxy-D-glucose (FDG) to visualize tumors in vivo. The molecular background of the enhanced glucose uptake and its regulation in lymphoma cells is not fully clarified and may provide new possibilities to reverse the altered metabolism. Thus in this study we investigated regulation of glucose uptake by different signaling pathways. Furthermore, the effect of the glucose analog 2 deoxy-D-glucose (2-DG) alone and in combination with other inhibitors on cell survival was studied. METHODS: An FDG uptake assay was established and uptake of FDG by lymphoma cells was determined after incubation with inhibitors of the c MYC and the PI3K signalling pathways that are known to be activated in lymphoma cells and able to regulate glucose metabolism. Inhibitors of MAPK signalling pathways whose role in altered metabolism is still unclear were also investigated. Expression of mRNAs of the glucose transporter 1 (GLUT1), hexokinase 2 (HK2), glucose-6-phosphatase (G6Pase) and lactate dehydrogenase A (LDHA) and of the glucose metabolism-regulating micro RNAs (miRNA) miR21, -23a, 133a, -133b, -138-1 and -143 was determined by RT-PCR. Cell viability was analysed by MTT assay. RESULTS: Treatment with the c-MYC inhibitor 10058-F4 and inhibitors of the PI3K/mTOR pathway diminished uptake of FDG in all three cell lines, while inhibition of MAPK pathways had no effect on glucose uptake. Expression of glycolysis-related genes and miRNAs were diminished, although to a variable degree in the three cell lines. The c-MYC inhibitor, the PI3K inhibitor LY294002, the mTOR inhibitor Rapamycin and 2-DG all diminished the number of viable cells. Interestingly, in combination with 2-DG, the c-MYC inhibitor, LY294002 and the p38 MAPK inhibitor SB203580 had synergistic effects on cell viability in all three cell lines. CONCLUSIONS: c-MYC- and PI3K/mTOR-inhibitors decreased viability of the lymphoma cells and led to decreased glucose uptake, expression of glycolysis-associated genes, and glucose metabolism-regulating miRNAs. Inhibition of HK by 2-DG reduced cell numbers as a single agent and synergistically with inhibitors of other intracellular pathways. Thus, targeted inhibition of the pathways investigated here could be a strategy to suppress the glycolytic phenotype of lymphoma cells and reduce proliferation. PMID- 28724381 TI - The Human Resources for Health Effort Index: a tool to assess and inform Strategic Health Workforce Investments. AB - BACKGROUND: Despite its importance, the field of human resources for health (HRH) has lagged in developing methods to measure its status and progress in low- and middle-income countries suffering a workforce crisis. Measures of professional health worker densities and distribution are purely numerical, unreliable, and do not represent the full spectrum of workers providing health services. To provide more information on the multi-dimensional characteristics of human resources for health, in 2013-2014, the global USAID-funded CapacityPlus project, led by IntraHealth International, developed and tested a 79-item HRH Effort Index modeled after the widely used Family Planning Effort Index. METHODS: The index includes seven recognized HRH dimensions: Leadership and Advocacy; Policy and Governance; Finance; Education and Training; Recruitment, Distribution, and Retention; Human Resources Management; and Monitoring, Evaluation, and Information Systems. Each item is scored from 1 to 10 and scores are averaged with equal weights for each dimension and overall. The questionnaire is applied to knowledgeable informants from public, nongovernmental organization, and private sectors in each country. A pilot test among 49 respondents in Kenya and Nigeria provided useful information to improve, combine, and streamline questions. CapacityPlus applied the revised 50-item questionnaire in 2015 in Burkina Faso, Dominican Republic, Ghana, and Mali, among 92 respondents. Additionally, the index was applied subnationally in the Dominican Republic (16 respondents) and in a consensus-building meeting in Mali (43 respondents) after the national application. RESULTS: The results revealed a range of scores between 3.7 and 6.2 across dimensions, for overall scores between 4.8 and 5.5. Dimensions with lower scores included Recruitment, Distribution, and Retention, while Leadership and Advocacy had higher scores. CONCLUSIONS: The tool proved to be well understood and provided key qualitative information on the health workforce to assist in health systems strengthening. It is expected that subsequent applications should provide more information for comparison purposes, to refine aspects of the questionnaire and to correlate scores with measures of service outputs and outcomes. PMID- 28724380 TI - The use of entertainment and communication technologies before sleep could affect sleep and weight status: a population-based study among children. AB - BACKGROUND: Short sleep duration and poor sleep quality have been demonstrated to be associated with childhood obesity. It has been suggested that electronic entertainment and communication devices (EECDs) including TVs, computers, tablets, video games and cell phones interfere with sleep in children and youth. The aim of this study was to assess the impact that the use of EECDs in the hour before bedtime has on sleep and weight status to inform sleep promotion interventions and programs to prevent childhood obesity. METHODS: A provincially representative sample of 2334 grade 5 children and their parents in Alberta, Canada was surveyed. Parents reported their child's bedtime and wake-up time along with how often their child snored, felt sleepy during the day, woke-up at night and woke-up in the morning feeling unrefreshed. Sleep duration, sleep quality and sleep efficiency were derived from these indicators. Parents also reported on the presence of EECDs in their child's bedroom, while children reported use of EECDs during the day and frequency of using each of these devices during the hour before sleep. The height and weight of children were measured. Multivariable mixed effect linear and logistic regression models were used to determine how sleep duration, sleep quality, sleep efficiency and weight status are influenced by (i) access to EECDs in children's bedrooms, (ii) use of EECDs during the hour before sleep, and (iii) calming activities specifically reading during the hour before sleep. RESULTS: Sleep duration was shorter by -10.8 min (cell phone), -10.2 min (computer) and -7.8 min (TV) for those with bedroom access to and used these EECDs during the hour before sleep compared to no access and no use. Good sleep quality was hindered by bedroom access to and use of all EECDs investigated during the hour before sleep, particularly among users of cell phones (OR = 0.64, 95% CI: 0.58-0.71) and computers (OR = 0.72, 95% CI: 0.65 0.80). Very good sleep efficiency was decreased by access to and frequent use of a TV (54%), cell phone (52%), tablet (51%) and video games (51%). Odds of obesity were doubled by bedroom access to and use of a TV and computer during the hour before sleep. Children who rarely read a printed book in the bedroom during the hour before sleep had a shorter sleep duration and poorer sleep quality and sleep efficiency compared to their peers. Having access to an EECD in the bedroom was associated with increased obesity despite frequently reading during the hour before sleep. CONCLUSIONS: Our findings suggest that sleep duration, sleep quality, sleep efficiency and weight status are better among children who do not have EECDs in the bedroom and frequently read a book during the hour before sleep as opposed to those who use EECDs during this hour. Education of limits against EECD use by parents may improve sleep outcomes. These findings will inform health promotion messages and may give rise to national recommendations regarding EECD use. TRIAL REGISTRATION: ClinicalTrials.gov NCT01914185 . Registered 31 July 2013 Retrospectively registered. PMID- 28724382 TI - Activation of cannabinoid receptor type 2 attenuates surgery-induced cognitive impairment in mice through anti-inflammatory activity. AB - BACKGROUND: Neuroinflammation plays a major role in postoperative cognitive dysfunction (POCD). Accumulated evidence indicates that cannabinoid receptor type 2 (CB2R) can mediate anti-inflammatory and immunomodulatory effects in part by controlling microglial activity. However, the impact of CB2R on postoperative cognition has not been investigated. We hypothesized that CB2R is involved in surgery-induced cognitive impairment in adult mice. METHODS: Adult C57BL/6 mice were subjected to intramedullary fixation surgery for tibial fracture under isoflurane anesthesia and CB2R agonist (JWH133) or CB2R antagonist (AM630) treatment. The mice were trained 24 h prior to surgery using a fear conditioning protocol and assessed in a novel context on postoperative days 1, 3, and 7 to evaluate cognitive function. Open-field testing was performed to evaluate the locomotor activity of the mice. The expression levels of IL-1beta, TNF-alpha, MCP 1, and CB2R in the hippocampus and prefrontal cortex were assessed by Western blotting; the expression of microglial marker CD11b in the CA1 area of the hippocampus and medial prefrontal cortex was assessed by immunostaining. RESULTS: The mice displayed no changes in locomotor activity after surgery and drug treatments. The mice exhibited impaired hippocampal-dependent memory accompanied by an increased expression of proinflammatory factors in the hippocampus and prefrontal cortex 1, 3, and 7 days after surgery, while hippocampal-independent memory remained unaffected at the same time points. JWH133 treatment attenuated surgery-induced memory loss, while AM630 treatment aggravated surgery-induced memory loss, paralleled by a decreased or increased expression of proinflammatory factors in the hippocampus and prefrontal cortex. The expression of CB2R in the hippocampus and prefrontal cortex was upregulated following surgery; however, it was downregulated by postoperative treatment with JWH133. Similarly, the expression of CD11b in the CA1 area of the hippocampus and medial prefrontal cortex was upregulated following surgery and downregulated by postoperative treatment with JWH133. CONCLUSIONS: These findings indicate that CB2R may modulate the neuroinflammatory and cognitive impairment in a mouse model of orthopedic surgery, and the activation of CB2R may effectively ameliorate the hippocampal-dependent memory loss of mice in the early postoperative stage. PMID- 28724383 TI - Molecular characterization and genetic relatedness of clinically Acinetobacter baumanii isolates conferring increased resistance to the first and second generations of tetracyclines in Iran. AB - BACKGROUND: The increasing resistance of Acinetobacter baumannii to antibiotics has recently been regarded as a notable therapeutic difficulty. Evaluating resistance rates of some A. baumannii isolates to tetracyclines had an impact on understanding the antibiotic resistance dissemination. By comparing genetic characteristics and relatedness of A. baumannii isolates, we are able to determine the transition dynamics of outbreak isolates. METHODS: A total of 72 non-duplicate isolates of A. baumannii were recovered in 2011 and 2015 and minimum inhibitory concentration (MIC) range distribution of the isolates to tetracyclines was performed by broth micro dilution (BMD) assay, and to determine the lineage relatedness of the outbreak isolates repetitive extragenic palindromic element based on polymerase chain reaction (rep-PCR) and international clonal (ICs) investigations were performed. RESULTS: Resistance rates to tetracycline, doxycycline and minocycline in 2011 were 73, 2 and 0%, while these rates in 2015 increased up to 90, 84 and 52%, respectively. The tetB existed in 100% of all the isolates of both years. tetA was not found in any of the isolates. According to the rep-PCR assays, up to 83% of all isolates clustered distinctly and only 6% of isolates had a common root. The percentage rates of IC1 decreased from 42% in 2011 to 22% in 2015, while those of IC2 increased from 28 to 36%, from 2011 to 2015. CONCLUSIONS: Our data showed that resistance to the first and second generations of tetracyclines is on the rise and the clonal transition dynamics of isolates are in progress in our hospital. PMID- 28724384 TI - Deficiency of PI3-Kinase catalytic isoforms p110gamma and p110delta in mice enhances the IL-17/G-CSF axis and induces neutrophilia. AB - BACKGROUND: Phosphoinositide 3-kinase gamma (PI3Kgamma) and PI3Kdelta are second messenger-generating enzymes with key roles in proliferation, differentiation, survival, and function of leukocytes. Deficiency of the catalytic subunits p110gamma and p110delta of PI3Kgamma and PI3Kdelta in p110gamma/delta-/- mice leads to defective B- and T-cell homeostasis. Here we examined the role of p110gamma and p110delta in the homeostasis of neutrophils by analyzing p110gamma /-, p110delta-/- and p110gamma/delta-/- mice. METHODS: Neutrophils and T cells in leukocyte suspensions from the bone marrow (BM), blood, spleen and lung were analyzed by flow cytometry. Serum concentrations of IL-17, of the neutrophilic growth factor G-CSF, and of the neutrophil mobilizing CXC chemokines CXCL1/KC and CXCL2/MIP-2 were measured by Bio-Plex assay. Production of G-CSF and CXCL1/KC by IL-17-stimulated primary lung tissue cells were determined by ELISA, whereas IL 17-dependent signaling in lung tissue cells was analyzed by measuring Akt phosphorylation using immunoblot. RESULTS: We found that in contrast to single knock-out mice, p110gamma/delta-/- mice exhibited significantly elevated neutrophil counts in blood, spleen, and lung. Increased granulocytic differentiation stages in the bone marrow of p110gamma/delta-/- mice were paralleled by increased serum concentrations of G-CSF, CXCL1/KC, and CXCL2/MIP-2. As IL-17 induces neutrophilia via the induction of G-CSF and CXC chemokines, we measured IL-17 and IL-17-producing T cells. IL-17 serum concentrations and frequencies of IL-17+ splenic T cells were significantly increased in p110gamma/delta-/- mice. Moreover, IFN-gamma+, IL-4+, and IL-5+ T cell subsets were drastically increased in p110gamma/delta-/- mice, suggesting that IL-17+ T cells were up-regulated in the context of a general percentage increase of other cytokine producing T cell subsets. CONCLUSIONS: We found that p110gamma/delta deficiency in mice induces complex immunological changes, which might in concert contribute to neutrophilia. These findings emphasize a crucial but indirect role of both p110gamma and p110delta in the regulation of neutrophil homeostasis. PMID- 28724385 TI - Increase of cytosolic phospholipase A2 as hydrolytic enzyme of phospholipids and autism cognitive, social and sensory dysfunction severity. AB - BACKGROUND: Autism is neurodevelopmental disorder that is characterized by developmental, behavioral, social and sensory abnormalities. Researchers have focused in last years in immunological alteration and inflammation as a hot subject in autism field. This work aims to study the alteration in phospholipids (PE, PS, and PC) together with the change in cPLA2 concentration as the main phospholipid hydrolytic enzyme in autistic patients compared to control. It was also extended to find a correlation between these biomarkers and severity of autism measured as childhood autism rating scale (CARS), Social responsiveness scale (SRS), and Short sensory profile (SSP). METHODS: Phospholipids (PE, PS, PC) and cPLA2 as biochemical parameters were determined in the plasma of 48 Saudi autistic male patients, categorized as mild-moderate and severe as indicated by their Childhood Autism Rating Scale (CARS), social responsiveness scale (SRS) and short sensory profile (SSP) and compared to 40 age- and gender-matched control samples. RESULTS: The reported data demonstrate significantly lower levels of PE, PS, and PC together with a significant increase in cPLA2. While association between severity of autism and impaired phospholipid concentration was completely lacked, an association between cPLA2 and impaired sensory processing was observed. CONCLUSIONS: The impaired phospholipid level and remarkable increased in cPLA2 concentration asserted their roles in the etiology of autism. Receiver operating characteristic analysis together with predictiveness diagrams proved that the measured parameters could be used as predictive biomarkers of clinical symptoms and provide significant guidance for future therapeutic strategy to re establish physiological homeostasis. PMID- 28724386 TI - Engineering microbial cell factories for the production of plant natural products: from design principles to industrial-scale production. AB - Plant natural products (PNPs) are widely used as pharmaceuticals, nutraceuticals, seasonings, pigments, etc., with a huge commercial value on the global market. However, most of these PNPs are still being extracted from plants. A resource conserving and environment-friendly synthesis route for PNPs that utilizes microbial cell factories has attracted increasing attention since the 1940s. However, at the present only a handful of PNPs are being produced by microbial cell factories at an industrial scale, and there are still many challenges in their large-scale application. One of the challenges is that most biosynthetic pathways of PNPs are still unknown, which largely limits the number of candidate PNPs for heterologous microbial production. Another challenge is that the metabolic fluxes toward the target products in microbial hosts are often hindered by poor precursor supply, low catalytic activity of enzymes and obstructed product transport. Consequently, despite intensive studies on the metabolic engineering of microbial hosts, the fermentation costs of most heterologously produced PNPs are still too high for industrial-scale production. In this paper, we review several aspects of PNP production in microbial cell factories, including important design principles and recent progress in pathway mining and metabolic engineering. In addition, implemented cases of industrial-scale production of PNPs in microbial cell factories are also highlighted. PMID- 28724387 TI - Risk factors for acute surgical site infections after lumbar surgery: a retrospective study. AB - BACKGROUND: Currently, many scholars are concerned about the treatment of postoperative infection; however, few have completed multivariate analyses to determine factors that contribute to the risk of infection. Therefore, we conducted a multivariate analysis of a retrospectively collected database to analyze the risk factors for acute surgical site infection following lumbar surgery, including fracture fixation, lumbar fusion, and minimally invasive lumbar surgery. METHODS: We retrospectively reviewed data from patients who underwent lumbar surgery between 2014 and 2016, including lumbar fusion, internal fracture fixation, and minimally invasive surgery in our hospital's spinal surgery unit. Patient demographics, procedures, and wound infection rates were analyzed using descriptive statistics, and risk factors were analyzed using logistic regression analyses. RESULTS: Twenty-six patients (2.81%) experienced acute surgical site infection following lumbar surgery in our study. The patients' mean body mass index, smoking history, operative time, blood loss, draining time, and drainage volume in the acute surgical site infection group were significantly different from those in the non-acute surgical site infection group (p < 0.05). Additionally, diabetes mellitus, chronic obstructive pulmonary disease, osteoporosis, preoperative antibiotics, type of disease, and operative type in the acute surgical site infection group were significantly different than those in the non-acute surgical site infection group (p < 0.05). Using binary logistic regression analyses, body mass index, smoking, diabetes mellitus, osteoporosis, preoperative antibiotics, fracture, operative type, operative time, blood loss, and drainage time were independent predictors of acute surgical site infection following lumbar surgery. CONCLUSIONS: In order to reduce the risk of infection following lumbar surgery, patients should be evaluated for the risk factors noted above. PMID- 28724389 TI - Ataxia in children: think about vitamin E deficiency ! (comment on: ataxia in children: early recognition and clinical evaluation). AB - A recent article from Pavone et al. published in the Italian Journal of Pediatrics entitled "Ataxia in children: early recognition and clinical evaluation" made an exhaustive overview of the large spectrum of pediatric ataxias. However, we would underline the importance of considering hereditary ataxia due to isolated vitamin E deficiency as a specific and treatable cause of child ataxia. We present a short clinical and therpeutic synopsis of this peculiar genetic etiology, frequently encountred in the mediterranean region. PMID- 28724388 TI - O-GlcNAc regulation of autophagy and alpha-synuclein homeostasis; implications for Parkinson's disease. AB - Post-translational modification on protein Ser/Thr residues by O-linked attachment of beta-N-acetyl-glucosamine (O-GlcNAcylation) is a key mechanism integrating redox signaling, metabolism and stress responses. One of the most common neurodegenerative diseases that exhibit aberrant redox signaling, metabolism and stress response is Parkinson's disease, suggesting a potential role for O-GlcNAcylation in its pathology. To determine whether abnormal O GlcNAcylation occurs in Parkinson's disease, we analyzed lysates from the postmortem temporal cortex of Parkinson's disease patients and compared them to age matched controls and found increased protein O-GlcNAcylation levels. To determine whether increased O-GlcNAcylation affects neuronal function and survival, we exposed rat primary cortical neurons to thiamet G, a highly selective inhibitor of the enzyme which removes the O-GlcNAc modification from target proteins, O-GlcNAcase (OGA). We found that inhibition of OGA by thiamet G at nanomolar concentrations significantly increased protein O-GlcNAcylation, activated MTOR, decreased autophagic flux, and increased alpha-synuclein accumulation, while sparing proteasomal activities. Inhibition of MTOR by rapamycin decreased basal levels of protein O-GlcNAcylation, decreased AKT activation and partially reversed the effect of thiamet G on alpha-synuclein monomer accumulation. Taken together we have provided evidence that excessive O GlcNAcylation is detrimental to neurons by inhibition of autophagy and by increasing alpha-synuclein accumulation. PMID- 28724390 TI - Examining the impact of a province-wide physical education policy on secondary students' physical activity as a natural experiment. AB - BACKGROUND: The purpose of this paper is to examine the impact of a province-wide physical education (PE) policy on secondary school students' moderate to vigorous physical activity (MVPA). METHODS: Policy: In fall 2008, Manitoba expanded a policy requiring a PE credit for students in grades 11 and 12 for the first time in Canada. The PE curriculum requires grades 11 and 12 students to complete a minimum of 55 h (50% of course hours) of MVPA (e.g., >=30 min/day of MVPA on >=5 days a week) during a 5-month semester to achieve the course credit. STUDY DESIGNS: A natural experimental study was designed using two sub-studies: 1) quasi-experimental controlled pre-post analysis of self-reported MVPA data obtained from census data in intervention and comparison [Prince Edward Island (PEI)] provinces in 2008 (n = 33,619 in Manitoba and n = 2258 in PEI) and 2012 (n = 41,169 in Manitoba and n = 4942 in PEI); and, 2) annual objectively measured MVPA in cohorts of secondary students in intervention (n = 447) and comparison (Alberta; n = 224) provinces over 4 years (2008 to 2012). ANALYSIS: In Study 1, two logistic regressions were conducted to model the odds that students accumulated: i) >=30 min/day of MVPA, and ii) met Canada's national recommendation of >=60 min/day of MVPA, in Manitoba versus PEI after adjusting for grade, sex, and BMI. In Study 2, a mixed effects model was used to assess students' minutes of MVPA per day per semester in Manitoba and Alberta, adjusting for age, sex, BMI, school location and school SES. RESULTS: In Study 1, no significant differences were observed in students achieving >=30 (OR:1.13, 95% CI:0.92, 1.39) or >=60 min/day of MVPA (OR:0.92, 95% CI: 0.78, 1.07) from baseline to follow-up between Manitoba and PEI. In Study 2, no significant policy effect on students' MVPA trajectories from baseline to last follow-up were observed between Manitoba and Alberta overall (-1.52, 95% CI:-3.47, 0.42), or by covariates. CONCLUSIONS: The Manitoba policy mandating PE in grades 11 and 12 had no effect on student MVPA overall or by key student or school characteristics. However, the effect of the PE policy may be underestimated due to the use of a nonrandomized research design and lack of data assessing the extent of policy implementation across schools. Nevertheless, findings can provide evidence about policy features that may improve the PE policy in Manitoba and inform future PE policies in other jurisdictions. PMID- 28724391 TI - Hormone receptor status of a first primary breast cancer predicts contralateral breast cancer risk in the WECARE study population. AB - BACKGROUND: Previous population-based studies have described first primary breast cancer tumor characteristics and their association with contralateral breast cancer (CBC) risk. However, information on influential covariates such as treatment, family history of breast cancer, and BRCA1/2 mutation carrier status was not available. In a large, population-based, case-control study, we evaluated whether tumor characteristics of the first primary breast cancer are associated with risk of developing second primary asynchronous CBC, overall and in subgroups of interest, including among BRCA1/2 mutation non-carriers, women who are not treated with tamoxifen, and women without a breast cancer family history. METHODS: The Women's Environmental Cancer and Radiation Epidemiology Study is a population-based case-control study of 1521 CBC cases and 2212 individually matched controls with unilateral breast cancer. Detailed information about breast cancer risk factors, treatment for and characteristics of first tumors, including estrogen receptor (ER) and progesterone receptor (PR) status, was obtained by telephone interview and medical record abstraction. Multivariable risk ratios (RRs) and 95% confidence intervals (CIs) were estimated in conditional logistic regression models, adjusting for demographics, treatment, and personal medical and family history. A subset of women was screened for BRCA1/2 mutations. RESULTS: Lobular histology of the first tumor was associated with a 30% increase in CBC risk (95% CI 1.0-1.6). Compared to women with ER+/PR+ first tumors, those with ER-/PR- tumors had increased risk of CBC (RR = 1.4, 95% CI 1.1-1.7). Notably, women with ER-/PR- first tumors were more likely to develop CBC with the ER-/PR- phenotype (RR = 5.4, 95% CI 3.0-9.5), and risk remained elevated in multiple subgroups: BRCA1/2 mutation non-carriers, women younger than 45 years of age, women without a breast cancer family history, and women who were not treated with tamoxifen. CONCLUSIONS: Having a hormone receptor negative first primary breast cancer is associated with increased risk of CBC. Women with ER-/PR- primary tumors were more likely to develop ER-/PR- CBC, even after excluding BRCA1/2 mutation carriers. Hormone receptor status, which is routinely evaluated in breast tumors, may be used clinically to determine treatment protocols and identify patients who may benefit from increased surveillance for CBC. PMID- 28724392 TI - A prospective study assessing agreement and reliability of a geriatric evaluation. AB - BACKGROUND: The present study takes place within a geriatric program, aiming at improving the diagnosis and management of geriatric syndromes in primary care. Within this program it was of prime importance to be able to rely on a robust and reproducible geriatric consultation to use as a gold standard for evaluating a primary care brief assessment tool. The specific objective of the present study was thus assessing the agreement and reliability of a comprehensive geriatric consultation. METHOD: The study was conducted at the outpatient clinic of the Service of Geriatric Medicine, University of Lausanne, Switzerland. All community dwelling older persons aged 70 years and above were eligible. Patients were excluded if they hadn't a primary care physician, they were unable to speak French, or they were already assessed by a geriatrician within the last 12 months. A set of 9 geriatricians evaluated 20 patients. Each patient was assessed twice within a 2-month delay. Geriatric consultations were based on a structured evaluation process, leading to rating the following geriatric conditions: functional, cognitive, visual, and hearing impairment, mood disorders, risk of fall, osteoporosis, malnutrition, and urinary incontinence. Reliability and agreement estimates on each of these items were obtained using a three-way Intraclass Correlation and a three-way Observed Disagreement index. The latter allowed a decomposition of overall disagreement into disagreements due to each source of error variability (visit, rater and random). RESULTS: Agreement ranged between 0.62 and 0.85. For most domains, geriatrician-related error variability explained an important proportion of disagreement. Reliability ranged between 0 and 0.8. It was poor/moderate for visual impairment, malnutrition and risk of fall, and good/excellent for functional/cognitive/hearing impairment, osteoporosis, incontinence and mood disorders. CONCLUSIONS: Six out of nine items of the geriatric consultation described in this study (functional/cognitive/hearing impairment, osteoporosis, incontinence and mood disorders) present a good to excellent reliability and can safely be used as a reference (gold standard) to evaluate the diagnostic performance of a primary care brief assessment tool. More objective/significant measures are needed to improve reliability of malnutrition, visual impairment, and risk of fall assessment before they can serve as a safe gold standard of a primary care tool. PMID- 28724393 TI - Methicillin-resistant Staphylococcus aureus emerged long before the introduction of methicillin into clinical practice. AB - BACKGROUND: The spread of drug-resistant bacterial pathogens poses a major threat to global health. It is widely recognised that the widespread use of antibiotics has generated selective pressures that have driven the emergence of resistant strains. Methicillin-resistant Staphylococcus aureus (MRSA) was first observed in 1960, less than one year after the introduction of this second generation beta lactam antibiotic into clinical practice. Epidemiological evidence has always suggested that resistance arose around this period, when the mecA gene encoding methicillin resistance carried on an SCCmec element, was horizontally transferred to an intrinsically sensitive strain of S. aureus. RESULTS: Whole genome sequencing a collection of the first MRSA isolates allows us to reconstruct the evolutionary history of the archetypal MRSA. We apply Bayesian phylogenetic reconstruction to infer the time point at which this early MRSA lineage arose and when SCCmec was acquired. MRSA emerged in the mid-1940s, following the acquisition of an ancestral type I SCCmec element, some 14 years before the first therapeutic use of methicillin. CONCLUSIONS: Methicillin use was not the original driving factor in the evolution of MRSA as previously thought. Rather it was the widespread use of first generation beta-lactams such as penicillin in the years prior to the introduction of methicillin, which selected for S. aureus strains carrying the mecA determinant. Crucially this highlights how new drugs, introduced to circumvent known resistance mechanisms, can be rendered ineffective by unrecognised adaptations in the bacterial population due to the historic selective landscape created by the widespread use of other antibiotics. PMID- 28724394 TI - Development of newborn screening connect (NBS connect): a self-reported patient registry and its role in improvement of care for patients with inherited metabolic disorders. AB - BACKGROUND: Newborn Screening Connect (NBS Connect) is a web-based self-reported patient registry and resource for individuals and families affected by disorders included in the newborn screening panel. NBS Connect was launched in 2012 by Emory University after years of planning and grassroots work by professionals, consumers, and industry. Individuals with phenylketonuria (PKU), maple syrup urine disease (MSUD) or tyrosinemia (TYR) have been recruited through distribution of outreach materials, presentations at parent organization meetings and direct recruitment at clinic appointments. Participants complete online profiles generating data on diagnosis, treatment, symptoms, outcomes, barriers to care, and quality of life. Resources such as education materials, information on the latest research and clinical trials, recipes, interactive health tracking systems, and professional support tools are described. In addition, to examine the ability of NBS Connect to generate data that guides hypothesis-driven research, data pertaining to age at diagnosis, bone health, and skin conditions in individuals with PKU were assessed. The objective of this paper is to describe the development of NBS Connect and highlight its data, resources and research contributions. RESULTS: In September 2016, NBS Connect had 442 registered participants: 314 (71%) individuals with PKU, 68 (15%) with MSUD, 20 (5%) with TYR, and 40 (9%) with other disorders on the NBS panel. Age at diagnosis was less than 4 weeks in 285 (89%) of 319 respondents to this question and between 1 month and 14 years in 29 (9%) individuals. Of 216 respondents with PKU, 33 (15%) had a DXA scan in the past year. Of 217 respondents with PKU, 99 (46%) reported at least one skin condition. CONCLUSIONS: NBS Connect was built and refined with feedback from all stakeholders, including individuals with inherited metabolic disorders. Based on patient-reported data, future studies can be initiated to test hypotheses such as the relationship between PKU and skin conditions. Patient registries like NBS Connect can inform hypothesis-driven research, contributing to knowledge generation and following the current trend in moving from traditional medicine towards evidence-based practice. NBS Connect will help clinicians understand long-term outcomes of rare disorders, contributing to better patient care and quality of life. PMID- 28724395 TI - Blockchain technology for improving clinical research quality. AB - Reproducibility, data sharing, personal data privacy concerns and patient enrolment in clinical trials are huge medical challenges for contemporary clinical research. A new technology, Blockchain, may be a key to addressing these challenges and should draw the attention of the whole clinical research community.Blockchain brings the Internet to its definitive decentralisation goal. The core principle of Blockchain is that any service relying on trusted third parties can be built in a transparent, decentralised, secure "trustless" manner at the top of the Blockchain (in fact, there is trust, but it is hardcoded in the Blockchain protocol via a complex cryptographic algorithm). Therefore, users have a high degree of control over and autonomy and trust of the data and its integrity. Blockchain allows for reaching a substantial level of historicity and inviolability of data for the whole document flow in a clinical trial. Hence, it ensures traceability, prevents a posteriori reconstruction and allows for securely automating the clinical trial through what are called Smart Contracts. At the same time, the technology ensures fine-grained control of the data, its security and its shareable parameters, for a single patient or group of patients or clinical trial stakeholders.In this commentary article, we explore the core functionalities of Blockchain applied to clinical trials and we illustrate concretely its general principle in the context of consent to a trial protocol. Trying to figure out the potential impact of Blockchain implementations in the setting of clinical trials will shed new light on how modern clinical trial methods could evolve and benefit from Blockchain technologies in order to tackle the aforementioned challenges. PMID- 28724396 TI - Pathogenic roles of CXCL10 signaling through CXCR3 and TLR4 in macrophages and T cells: relevance for arthritis. AB - BACKGROUND: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by uncontrolled joint inflammation and destruction of bone and cartilage. We previously reported that C-X-C motif chemokine 10 (CXCL10; also called IP-10) has important roles in joint inflammation and bone destruction in arthritis. However, the specific mechanisms by which CXCL10 regulates the recruitment of inflammatory cells and the production of osteoclastogenic cytokines in RA progression are not fully understood. METHODS: Bone marrow derived macrophages and CD4+ T cells were isolated from wild-type (WT), Cxcl10 -/ , and Cxcr3 -/- mice. CXCL10-induced migration was performed using a Boyden chamber, and CXCL10-stimulated production of osteoclastogenic cytokines was measured by quantitative real-time PCR and ELISA. Collagen antibody-induced arthritis (CAIA) was induced by administration of collagen type II antibodies and lipopolysaccharide to the mice. Clinical scores were analyzed and hind paws were collected for high-resolution micro-CT, and histomorphometry. Serum was used to assess bone turnover and levels of osteoclastogenic cytokines. RESULTS: CXCL10 increased the migration of inflammatory cells through C-X-C chemokine receptor 3 (CXCR3)-mediated, but not toll-like receptor 4 (TLR4)-mediated, ERK activation. Interestingly, both receptors CXCR3 and TLR4 were simultaneously required for CXCL10-stimulated production of osteoclastogenic cytokines in CD4+ T cells. Furthermore, calcineurin-dependent NFATc1 activation was essential for CXCL10 induced RANKL expression. In vivo, F4/80+ macrophages and CD4+ T cells robustly infiltrated into synovium of WT mice with CAIA but were significantly reduced in both Cxcl10 -/- and Cxcr3 -/- mice. Serum concentrations of osteoclastogenic cytokines and bone destruction were also reduced in the knockout mice, leading to attenuated progression of arthritis. CONCLUSION: These findings highlight the importance of CXCL10 signaling in the pathogenesis of RA and provide previously unidentified details of the mechanisms by which CXCL10 promotes the development of arthritis. PMID- 28724397 TI - Partial uniparental isodisomy of chromosome 16 unmasks a deleterious biallelic mutation in IFT140 that causes Mainzer-Saldino syndrome. AB - BACKGROUND: The ciliopathies represent an umbrella group of >50 clinical entities that share both clinical features and molecular etiology underscored by structural and functional defects of the primary cilium. Despite the advances in gene discovery, this group of entities continues to pose a diagnostic challenge, in part due to significant genetic and phenotypic heterogeneity and variability. We consulted a pediatric case from asymptomatic, non-consanguineous parents who presented as a suspected ciliopathy due to a constellation of retinal, renal, and skeletal findings. RESULTS: Although clinical panel sequencing of genes implicated in nephrotic syndromes yielded no likely causal mutation, an oligo-SNP microarray identified a ~20-Mb region of homozygosity, with no altered gene dosage, on chromosome 16p13. Intersection of the proband's phenotypes with known disease genes within the homozygous region yielded a single candidate, IFT140, encoding a retrograde intraflagellar transport protein implicated previously in several ciliopathies, including the phenotypically overlapping Mainzer-Saldino syndrome (MZSDS). Sanger sequencing yielded a maternally inherited homozygous c.634G>A; p.Gly212Arg mutation altering the exon 6 splice donor site. Functional studies in cells from the proband showed that the locus produced two transcripts: a majority message containing a mis-splicing event that caused a premature termination codon and a minority message homozygous for the p.Gly212Arg allele. Zebrafish in vivo complementation studies of the latter transcript demonstrated a loss of function effect. Finally, we conducted post-hoc trio-based whole exome sequencing studies to (a) test the possibility of other causal loci in the proband and (b) explain the Mendelian error of segregation for the IFT140 mutation. We show that the proband harbors a chromosome 16 maternal heterodisomy, with segmental isodisomy at 16p13, likely due to a meiosis I error in the maternal gamete. CONCLUSIONS: Using clinical phenotyping combined with research based genetic and functional studies, we have characterized a recurrent IFT140 mutation in the proband; together, these data are consistent with MZSDS. Additionally, we report a rare instance of a uniparental isodisomy unmasking a deleterious mutation to cause a ciliary disorder. PMID- 28724398 TI - Whole genome sequencing identifies a novel ALMS1 gene mutation in two Chinese siblings with Alstrom syndrome. AB - BACKGROUND: Alstrom syndrome is a rare multi-systemic disorder with a broad spectrum of symptoms. This syndrome is characterized by childhood retinal degeneration; sensorineural hearing loss; obesity; type 2 diabetes mellitus; cardiomyopathy; systemic fibrosis; and pulmonary, hepatic, and renal failure. CASE PRESENTATION: A Chinese quartet family with two siblings predominantly affected by cone-rod dystrophy and short stature were recruited. The craniofacial dysmorphism and on-set age-of-cone-rod dystrophy in the proband showed a minor intrafamilial variability. Whole genome sequencing was performed to provide the full spectrum of the two siblings' genetic variations. In this study, we present the patients' clinical features and our interpretation of the whole genome sequencing data. After examining the data, we focus on two compound heterozygous mutations, (c.3902C > A, p.S1301X; c.6436C > T, p.R2146X) in ALMS1, which are shared by two siblings. CONCLUSION: We reported a novel ALMS1 mutation. Whole genome sequencing is a powerful tool to provide the full spectrum of genetic variations for heterogeneous disorders such as Alstrom syndrome. PMID- 28724399 TI - Health needs, access to healthcare, and perceptions of ageing in an urbanizing community in India: a qualitative study. AB - BACKGROUND: India's elderly population is rising at an unprecedented rate, with a majority living in rural areas. Health challenges associated with ageing, changing social networks and limited public health infrastructure are issues faced by the elderly and caregivers. We examined perceptions of health needs of the elderly across local stakeholders in an urbanizing rural area. METHODS: The qualitative study was conducted among participants in the Andhra Pradesh Children and Parents Study (APCAPS) site in Rangareddy district, Telangana. We collected data using focus group discussions and interviews among communities (n = 6), health providers (n = 9) and administrators (n = 6). We assessed stakeholders' views on the influence of urbanization on health issues faced and interventions for alleviating these challenges. We used a conceptual-analytical model to derive themes and used an inductive approach to organizing emerging codes as per a priori themes. These were organized as per thematic groups and ranked by different authors in order of importance. Bronfebrenner's theory was used to understand stakeholder perspectives and suggest interventions within four identified spheres of influence - individual, household, community and services. RESULTS: Stakeholders reported frailty, lack of transport and dependence on others as factors impacting health access of the elderly. Existing public health systems were perceived as overburdened and insensitive towards the elderly. Urbanization was viewed positively, but road accidents, crime and loneliness were significant concerns. Interventions suggested by stakeholders included health service outreach, lifestyle counseling, community monitoring of healthcare and engagement activities. CONCLUSIONS: We recommend integrating outreach services and lifestyle counseling within programs for care of the elderly. Community institutions can play an important role in the delivery and monitoring of health and social services for the elderly. PMID- 28724400 TI - Detection of IL-9 producing T cells in the PBMCs of allergic asthmatic patients. AB - BACKGROUND: Interleukin-9 (IL-9) was reported as an active participant in the pathogenesis of allergic asthma. This study aimed to investigate the major source ofIL-9 and its effect on interferon gamma (IFN-gamma) and immunoglobulin (Ig) secretion by B cells. METHODS: We isolated peripheral blood mononuclear cells from children with allergic asthma and healthy children. IL-9, IL-4 and IFN-gamma expression were detected by ELISA, ELISpot and Flowcytometry. Expression of transcription factor PU.1 was measured by Western Blot. We evaluated the effect of IL-9 on B cell activation and Ig production. RESULTS: Results showed that compared with healthy children, levels of IL-9, IL-4 and PU.1 were elevated and levels of IFN-gamma were lower in children with allergic asthma. IL-9-expressing CD4+ T cells did not co-express IL-4. Exogenous IL-9 inhibited IFN-gamma production in a dose-dependent manner. Antigen-specific Th9 cells existed in children with house dust mite allergic asthma. IL-9 up-regulated expression of CD69 and CD25 on B cells and combination of IL-9 and IL-4 enhanced IgE production. CONCLUSIONS: In conclusion, our results showed that Th9 cells may be the major source of IL-9 in children with allergic asthma. In these patients, IL 9 impairs IFN-gamma production and synergistically promotes IL-4-induced IgE secretion. PMID- 28724401 TI - Deciphering functional diversification within the lichen microbiota by meta omics. AB - BACKGROUND: Recent evidence of specific bacterial communities extended the traditional concept of fungal-algal lichen symbioses by a further organismal kingdom. Although functional roles were already assigned to dominant members of the highly diversified microbiota, a substantial fraction of the ubiquitous colonizers remained unexplored. We employed a multi-omics approach to further characterize functional guilds in an unconventional model system. RESULTS: The general community structure of the lichen-associated microbiota was shown to be highly similar irrespective of the employed omics approach. Five highly abundant bacterial orders-Sphingomonadales, Rhodospirillales, Myxococcales, Chthoniobacterales, and Sphingobacteriales-harbor functions that are of substantial importance for the holobiome. Identified functions range from the provision of vitamins and cofactors to the degradation of phenolic compounds like phenylpropanoid, xylenols, and cresols. CONCLUSIONS: Functions that facilitate the persistence of Lobaria pulmonaria under unfavorable conditions were present in previously overlooked fractions of the microbiota. So far, unrecognized groups like Chthoniobacterales (Verrucomicrobia) emerged as functional protectors in the lichen microbiome. By combining multi-omics and imaging techniques, we highlight previously overlooked participants in the complex microenvironment of the lichens. PMID- 28724402 TI - A dual colour fluorescence in situ hybridization (FISH) assay for identifying the zoonotic malaria parasite Plasmodium knowlesi with a potential application for the specific diagnosis of knowlesi malaria in peripheral-level laboratories of Southeast Asia. AB - BACKGROUND: Plasmodium knowlesi is primarily responsible for zoonotic malaria in several Southeast Asian countries. Precise identification of the parasite in the blood of patients presently relies on an expensive and elaborate PCR procedure because microscopic examination of blood and other available field identification techniques lack adequate specificity. Therefore, the use of a simple and inexpensive dual-colour fluorescence in situ hybridization (FISH) assay, analogous to FISH assays recently described for Plasmodium falciparum and Plasmodium vivax, was investigated as a potential tool for identifying P. knowlesi. RESULTS: A P. knowlesi 18S rDNA sequence-based DNA probe was used to test thin blood smears of P. knowlesi by FISH, and fluorescence viewed in a light microscope fitted with a light emitting diode light source and appropriate emission and barrier filters. The limit of detection in the P. knowlesi FISH assay was 84 parasites per MUl in infected monkey blood and 61 parasites per MUl for P. knowlesi cultured in human blood. The P. knowlesi-specific FISH probe detected only P. knowlesi and not P. falciparum, Plasmodium malariae, Plasmodium ovale, P. vivax or a panel of other human blood-borne pathogens. A previously described Plasmodium genus-specific probe used simultaneously in the P. knowlesi FISH assay reacted with all tested Plasmodium species. CONCLUSIONS: To our knowledge, this is the first description of a FISH assay for P. knowlesi that is potentially useful for diagnosing infections in remote laboratories in endemic countries. PMID- 28724403 TI - The association between attention deficit/hyperactivity disorder and internet addiction: a systematic review and meta-analysis. AB - BACKGROUND: This study aimed to analyze the association between Attention Deficit/Hyperactivity Disorder (ADHD) and Internet addiction (IA). METHODS: A systematic literature search was performed in four online databases in total including CENTRAL, EMBASE, PubMed and PsychINFO. Observational studies (case control, cross-sectional and cohort studies) measuring the correlation between IA and ADHD were screened for eligibility. Two independent reviewers screened each article according to the predetermined inclusion criteria. A total of 15 studies (2 cohort studies and 13 cross-sectional studies) met our inclusion criteria and were included in the quantitative synthesis. Meta-analysis was conducted using RevMan 5.3 software. RESULTS: A moderate association between IA and ADHD was found. Individuals with IA were associated with more severe symptoms of ADHD, including the combined total symptom score, inattention score and hyperactivity/impulsivity score. Males were associated with IA, whereas there was no significant correlation between age and IA. CONCLUSIONS: IA was positively associated with ADHD among adolescents and young adults. Clinicians and parents should pay more attention to the symptoms of ADHD in individuals with IA, and the monitoring of Internet use of patients suffering from ADHD is also necessary. Longitudinal studies controlling for baseline mental health are needed. PMID- 28724404 TI - Temporal trends of dialysis requiring acute kidney injury after orthotopic cardiac and liver transplant hospitalizations. AB - BACKGROUND: The epidemiology and outcomes of acute kidney injury (AKI) in prevalent non-renal solid organ transplant recipients is unknown. METHODS: We assessed the epidemiology of trends in acute kidney injury (AKI) in orthotopic cardiac and liver transplant recipients in the United States. We used the Nationwide Inpatient Sample to evaluate the yearly incidence trends (2002 to 2013) of the primary outcome, defined as AKI requiring dialysis (AKI-D) in hospitalizations after cardiac and liver transplantation. We also evaluated the trend and impact of AKI-D on hospital mortality and adverse discharge using adjusted odds ratios (aOR). RESULTS: The proportion of hospitalizations with AKI (9.7 to 32.7% in cardiac and 8.5 to 28.1% in liver transplant hospitalizations; ptrend<0.01) and AKI-D (1.63 to 2.33% in cardiac and 1.32 to 2.65% in liver transplant hospitalizations; ptrend<0.01) increased from 2002-2013. This increase in AKI-D was explained by changes in race and increase in age and comorbidity burden of transplant hospitalizations. AKI-D was associated with increased odds of in hospital mortality (aOR 2.85; 95% CI 2.11-3.80 in cardiac and aOR 2.00; 95% CI 1.55-2.59 in liver transplant hospitalizations) and adverse discharge [discharge other than home] (aOR 1.97; 95% CI 1.53-2.55 in cardiac and 1.91; 95% CI 1.57-2.30 in liver transplant hospitalizations). CONCLUSIONS: This study highlights the growing burden of AKI-D in non-renal solid organ transplant recipients and its devastating impact, and emphasizes the need to develop strategies to reduce the risk of AKI to improve health outcomes. PMID- 28724405 TI - Environmental drivers of viral community composition in Antarctic soils identified by viromics. AB - BACKGROUND: The Antarctic continent is considered the coldest and driest place on earth with simple ecosystems, devoid of higher plants. Soils in the ice-free regions of Antarctica are known to harbor a wide range of microorganisms from primary producers to grazers, yet their ecology and particularly the role of viruses is poorly understood. In this study, we examined the virus community structures of 14 soil samples from the Mackay Glacier region. METHODS: Viral communities were extracted from soil and the dsDNA was extracted, amplified using single-primer amplification, and sequenced using the Ion Torrent Proton platform. Metadata on soil physico-chemistry was collected from all sites. Both read and contig datasets were analyzed with reference-independent and reference-dependent methods to assess viral community structures and the influence of environmental parameters on their distribution. RESULTS: We observed a high heterogeneity in virus signatures, independent of geographical proximity. Tailed bacteriophages were dominant in all samples, but the incidences of the affiliated families Siphoviridae and Myoviridae were inversely correlated, suggesting direct competition for hosts. Viruses of the families Phycodnaviridae and Mimiviridae were present at significant levels in high-diversity soil samples and were found to co-occur, implying little competition between them. Combinations of soil factors, including pH, calcium content, and site altitude, were found to be the main drivers of viral community structure. CONCLUSIONS: The pattern of viral community structure with higher levels of diversity at lower altitude and pH, and co-occurring viral families, suggests that these cold desert soil viruses interact with each other, the host, and the environment in an intricate manner, playing a potentially crucial role in maintaining host diversity and functioning of the microbial ecosystem in the extreme environments of Antarctic soil. PMID- 28724406 TI - Iodine concentration calculated by dual-energy computed tomography (DECT) as a functional parameter to evaluate thyroid metabolism in patients with hyperthyroidism. AB - BACKGROUND: Thyroid function in patients with Grave's disease is usually evaluated by thyroid scintigraphy with radioactive iodine. Recently, dual-energy computed tomography (DECT) with two different energy X-rays can calculate iodine concentrations and can be applied for iodine measurements in thyroid glands. This study aimed to assess the potential use of DECT for the functional assessment of the thyroid gland. METHODS: Thirteen patients with Grave's disease treated at our hospital from May to September 2015 were included in this retrospective study. Before treatments, all subjects had undergone both iodine scintigraphy [three and 24 h after oral administration of 123I (20 MUCi)] and non-enhanced DECT. The region of interests (ROIs) were placed in both lobes of the thyroid glands, and CT values (HU: Hounsfield unit) and iodine concentrations (mg/mL) calculated from DECT images were measured. The correlation between CT values and iodine concentrations from DECT in the thyroid gland was evaluated and then the iodine concentrations were compared with radioactive iodine uptake ratios by thyroid scintigraphy. RESULTS: Mean (+/-SD) 123I uptake increased from 46.3 (+/-22.2) % (range, 11.1-80.1) at 3 h, to 66.5 (+/-15.2) % (range, 40.0-86.1) at 24 h (p < 0.01). CT values ranged from 34.5 to 98.7 HU [mean: 67.8 (+/-18.6)], while the iodine concentrations calculated with DECT ranged from 0.0 to 1.3 mg/mL [mean: 0.5 (+/-0.4)]. A moderate positive correlation between CT values and the calculated iodine concentrations in the thyroid gland was seen (R = 0.429, p < 0.05). A significant negative correlation between 123I uptake at 3 h and iodine concentration by DECT were seen (R = -0.680, p < 0.05), although no correlation was observed between 123I uptake at 3 h and CT values (p = 0.087). No correlation was observed between 123I uptake at 24 h and CT values (p = 0.153) or that between 123I uptake at 24 h and iodine concentration by DECT (p = 0.073). CONCLUSION: The negative correlation of 123I uptake at 3 h with iodine concentration evaluated by DECT was better than that observed with simple CT value. DECT may have a potential role in the evaluation of iodine turnover in hyperthyroid patients. PMID- 28724407 TI - Characterization of the cytochrome P450 monooxygenase genes (P450ome) from the carotenogenic yeast Xanthophyllomyces dendrorhous. AB - BACKGROUND: The cytochromes P450 (P450s) are a large superfamily of heme containing monooxygenases involved in the oxidative metabolism of an enormous diversity of substrates. These enzymes require electrons for their activity, and the electrons are supplied by NAD(P)H through a P450 electron donor system, which is generally a cytochrome P450 reductase (CPR). The yeast Xanthophyllomyces dendrorhous has evolved an exclusive P450-CPR system that specializes in the synthesis of astaxanthin, a carotenoid with commercial potential. For this reason, the aim of this work was to identify and characterize other potential P450 genes in the genome of this yeast using a bioinformatic approach. RESULTS: Thirteen potential P450-encoding genes were identified, and the analysis of their deduced proteins allowed them to be classified in ten different families: CYP51, CYP61, CYP5139 (with three members), CYP549A, CYP5491, CYP5492 (with two members), CYP5493, CYP53, CYP5494 and CYP5495. Structural analyses of the X. dendrorhous P450 proteins showed that all of them have a predicted transmembrane region at their N-terminus and have the conserved domains characteristic of the P450s, including the heme-binding region (FxxGxRxCxG); the PER domain, with the characteristic signature for fungi (PxRW); the ExxR motif in the K-helix region and the oxygen-binding domain (OBD) (AGxDTT); also, the characteristic secondary structure elements of all the P450 proteins were identified. The possible functions of these P450s include primary, secondary and xenobiotic metabolism reactions such as sterol biosynthesis, carotenoid synthesis and aromatic compound degradation. CONCLUSIONS: The carotenogenic yeast X. dendrorhous has thirteen P450-encoding genes having potential functions in primary, secondary and xenobiotic metabolism reactions, including some genes of great interest for fatty acid hydroxylation and aromatic compound degradation. These findings established a basis for future studies about the role of P450s in the carotenogenic yeast X. dendrorhous and their potential biotechnological applications. PMID- 28724408 TI - Learning intraprofessional collaboration by participating in a consultation programme: what and how did primary and secondary care trainees learn? AB - BACKGROUND: A growing number of patients require overview and management in both primary and secondary care. This situation requires that primary and secondary care professionals have well developed collaborative skills. While knowledge about interprofessional collaboration and education is rising, little is known about intraprofessional collaboration and education between physicians of various disciplines. This study examines a newly developed consultation programme for trainees in general practice and internal medicine to acquire intraprofessional collaboration skills. METHODS: Focus groups were conducted with trainees and their supervisors and mentors to explore what and how the trainees learned by participating in the consultation programme. RESULTS: Trainees reported that they gained knowledge about and skills in collaboration and consultation they could not have gained otherwise. Furthermore, the programme gave the opportunity to gain other competencies relevant for becoming the medical expert trainees they are expected to be. Learning outcomes were comparable to those described in interprofessional education literature. Interaction, by meeting each other and by discussing cases with mentors or supervisors, appeared to be a key factor in the learning process. Meetings, discussing preconceptions and enthusiasm of the mentors and supervisors facilitated the learning. Technical problems and lack of information hampered the learning. These influencing factors are important for future development of intraprofessional learning programmes. CONCLUSIONS: Participants in an innovative consultation programme for GP- and IM-trainees reported that they acquired consultation and collaboration skills they could not have gained otherwise. Interaction appeared to be an important factor in the learning process. The findings of this study can inform developers of intraprofessional education programmes between primary and secondary care trainees. PMID- 28724409 TI - Hybrid assembly with long and short reads improves discovery of gene family expansions. AB - BACKGROUND: Long-read and short-read sequencing technologies offer competing advantages for eukaryotic genome sequencing projects. Combinations of both may be appropriate for surveys of within-species genomic variation. METHODS: We developed a hybrid assembly pipeline called "Alpaca" that can operate on 20X long read coverage plus about 50X short-insert and 50X long-insert short-read coverage. To preclude collapse of tandem repeats, Alpaca relies on base-call corrected long reads for contig formation. RESULTS: Compared to two other assembly protocols, Alpaca demonstrated the most reference agreement and repeat capture on the rice genome. On three accessions of the model legume Medicago truncatula, Alpaca generated the most agreement to a conspecific reference and predicted tandemly repeated genes absent from the other assemblies. CONCLUSION: Our results suggest Alpaca is a useful tool for investigating structural and copy number variation within de novo assemblies of sampled populations. PMID- 28724410 TI - Identification and characterization of long non-coding RNAs in subcutaneous adipose tissue from castrated and intact full-sib pair Huainan male pigs. AB - BACKGROUND: Long non-coding RNAs (lncRNAs) regulate adipose tissue metabolism, however, their function on testosterone deficiency related obesity in humans is less understood. For this research, intact and castrated male pigs are the best model animal because of their similar proportional organ sizes, cardiovascular systems and metabolic features. RESULTS: We identified lncRNAs in subcutaneous adipose tissue by deep RNA-sequencing using the intact and castrated Huainan male pigs. The results showed that castration reduced serum testosterone but increased body fatness-related traits (serum triglyceride levels, backfat thickness, intramuscular fat content, and adipocyte size). Meanwhile, 343 lncRNAs from subcutaneous adipose tissue were identified, including 223 intergenic lncRNAs (lincRNAs), 68 anti-sense lncRNAs, and 52 intronic lncRNAs. It was predicted that there were 416 recognition sites for C/EBPalpha in the 303 lncRNA promoter region, and 13 adipogenesis-promoting miRNAs and five adipogenesis-depressing miRNAs target these lncRNAs. Eighteen lncRNAs, including nine up- and nine down regulated had more than 2-fold differential expression between the castrated and intact male pigs (q-value < 0.05). Functional analysis indicated that these 18 lncRNAs and their target genes were involved in fatty acid, insulin, and the adipocytokine signaling pathway. We further analyzed the features of a conserved mouse lncRNA gene ENSMUST00000189966 and found it mainly expressed in the cell nucleus and target the Nuclear Receptor Subfamily 2 Group F Member 2 (NR2F2) gene. In 3 T3-L1 cells, differentiation down-regulated their expression, but dihydrotestosterone (DHT) significantly up-regulated their expression in a concentration-dependent manner (P < 0.05). CONCLUSIONS: These results suggested that lncRNAs and their target genes might participated in the castration-induced fat deposition and provide a new therapeutic target for combatting testosterone deficiency-related obesity. PMID- 28724411 TI - A qualitative study exploring perceptions and attitudes of community pharmacists about extended pharmacy services in Lahore, Pakistan. AB - BACKGROUND: In recent decades, community pharmacies reported a change of business model, whereby a shift from traditional services to the provision of extended roles was observed. However, such delivery of extended pharmacy services (EPS) is reported from the developed world, and there is scarcity of information from the developing nations. Within this context, the present study was aimed to explore knowledge, perception and attitude of community pharmacists (CPs) about EPS and their readiness and acceptance for practice change in the city of Lahore, Pakistan. METHODS: A qualitative approach was used to gain an in-depth knowledge of the issues. By using a semi-structured interview guide, 12 CPs practicing in the city of Lahore, Pakistan were conveniently selected. All interviews were audio-taped, transcribed verbatim, and were then analyzed for thematic contents by the standard content analysis framework. RESULTS: Thematic content analysis yielded five major themes. (1) Familiarity with EPS, (2) current practice of EPS, (3) training needed to provide EPS, (4) acceptance of EPS and (5) barriers toward EPS. Majority of the CPs were unaware of EPS and only a handful had the concept of extended services. Although majority of our study respondents were unaware of pharmaceutical care, they were ready to accept practice change if provided with the required skills and training. Lack of personal knowledge, poor public awareness, inadequate physician-pharmacist collaboration and deprived salary structures were reported as barriers towards the provision of EPS at the practice settings. CONCLUSION: Although the study reported poor awareness towards EPS, the findings indicated a number of key themes that can be used in establishing the concept of EPS in Pakistan. Over all, CPs reported a positive attitude toward practice change provided to the support and facilitation of health and community based agencies in Pakistan. PMID- 28724412 TI - Assessment of genome annotation using gene function similarity within the gene neighborhood. AB - BACKGROUND: Functional annotation of bacterial genomes is an obligatory and crucially important step of information processing from the genome sequences into cellular mechanisms. However, there is a lack of computational methods to evaluate the quality of functional assignments. RESULTS: We developed a genome scale model that assigns Bayesian probability to each gene utilizing a known property of functional similarity between neighboring genes in bacteria. CONCLUSIONS: Our model clearly distinguished true annotation from random annotation with Bayesian annotation probability >0.95. Our model will provide a useful guide to quantitatively evaluate functional annotation methods and to detect gene sets with reliable annotations. PMID- 28724413 TI - Smoking-related general and cause-specific mortality in Estonia. AB - BACKGROUND: Tobacco smoking is known to be the single largest cause of premature death worldwide. The aim of present study was to analyse the effect of smoking on general and cause-specific mortality in the Estonian population. METHODS: The data from 51,756 adults in the Estonian Genome Center of the University of Tartu was used. Information on dates and causes of death was retrieved from the National Causes of Death Registry. Smoking status, general survival, general mortality and cause-specific mortality were analysed using Kaplan-Meier estimator and Cox proportional hazards models. RESULTS: The study found that smoking reduces median survival in men by 11.4 years and in women by 5.8 years. Tobacco smoking produces a very specific pattern in the cause of deaths, significantly increasing the risks for different cancers and cardiovascular diseases as causes of death for men and women. This study also identified that external causes, such as alcohol intoxication and intentional self-harm, are more prevalent causes of death among smokers than non-smokers. Additionally, smoking cessation was found to reverse the increased risks for premature mortality. CONCLUSIONS: Tobacco smoking remains the major cause for losses of life inducing cancers and cardiovascular diseases. In addition to the common diseases, external causes also reduce substantially the years of life. External causes of death indicate that smoking has a long-term influence on the behaviour of smokers, provoking self destructive behaviour. Our study supports the idea, that tobacco smoking generates complex harm to our health increasing mortality from both somatic and mental disorders. PMID- 28724414 TI - Effects of feeding drunken horse grass infected with Epichloe gansuensis endophyte on animal performance, clinical symptoms and physiological parameters in sheep. AB - BACKGROUND: Many reports showed that grass-endophyte symbiosis induced livestock poisoned. Yet, there is no study evaluating clinical symptoms and physiological parameters in sheep fed Epichloe gansuensis endophyte-infected grass. The objective of the present study was to investigate these indexes by feeding sheep with endophyte-infected A. inebrians (E+ Group) or endophyte-free A. inebrians (E Group) drunken horse grass or alfalfa hay (Control Group). RESULTS: The Epichloe endophyte caused obvious toxicity symptoms in the sheep fed E+ A. inebrians, with 1 of the 5 sheep having died by the 35th day. The feed intake and body weight gain of the E+ Group were significantly less than the E- and control groups (P < 0.05). Serum concentrations of alanine aminotransferase (ALT, 45.5 mmol/L) and aspartate aminotransferase for the E+ group (AST, 139.3 mmol/L) were significantly (P < 0.05) greater than for the E- (ALT, 31.2 mmol/L; AST, 78.6 mmol/L) and control (ALT, 32.6 mmol/L; AST, 56.6 mmol/L) groups at the fifth week; serum concentration of creatinine for the E+ group (63.8 mmol/L) was also significantly (P < 0.05) greater than for E- (56.6 mmol/L) and control groups (58.5 mmol/L). Meanwhile, urine biochemical indices for the E+ group indicated that ketone and occult blood were significantly (P < 0.05) elevated compared to the other groups while urine pH values were significantly (P < 0.05) acidic. The relative weight of heart, brain, liver, lung and kidney for Group E+ were almost two fold more than the other groups, but uterus weight was about half that found for Group E- or Control. CONCLUSIONS: We conclude that the Epichloe endophyte infection is the cause of A. inebrians toxicity to sheep. Interestingly, none of the measured parameters differed significantly between E- and the control groups, which implied that drunken horse grass could be utilized efficiently by sheep when not infected by the Epichloe endophyte. PMID- 28724415 TI - Identification and characterization of the antiplasmodial activity of Hsp90 inhibitors. AB - BACKGROUND: The recent reduction in mortality due to malaria is being threatened by the appearance of Plasmodium falciparum parasites that are resistant to artemisinin in Southeast Asia. To limit the impact of resistant parasites and their spread across the world, there is a need to validate anti-malarial drug targets and identify new leads that will serve as foundations for future drug development programmes targeting malaria. Towards that end, the antiplasmodial potential of several Hsp90 inhibitors was characterized. Because, the Hsp90 chaperone has been suggested as a good drug target against multiple parasitic infections including malaria. RESULTS: Chemically diverse sets of Hsp90 inhibitors, evaluated in clinical trials as anti-cancer agents, were tested against the malaria parasite. Most of the compounds showed strong antiplasmodial activity in growth inhibition assays against chloroquine sensitive and resistant strains. There was a good agreement between the compound in vitro anti-parasitic activity and their affinity against the Plasmodium chaperone. The two most potent Hsp90 inhibitors also showed cytocidal activity against two P. falciparum strains. Their antiplasmodial activity affected all parasite forms during the malaria blood cycle. However, the compounds activity against the parasite showed no synergy when combined with anti-malarial drugs, like chloroquine or DHA. DISCUSSION: The Hsp90 inhibitors anti-parasitic activity correlates with their affinity to their predicted target the P. falciparum chaperone Hsp90. However, the most effective compounds also showed high affinity for a close homologue, Grp94. This association points to a mode of action for Hsp90 inhibitors that correlate compound efficacy with multi-target engagement. Besides their ability to limit parasite replication, two compounds also significantly impacted P. falciparum viability in vitro. Finally, a structural analysis suggests that the best hit represents a promising scaffold to develop parasite specific leads according. CONCLUSION: The results shown that Hsp90 inhibitors are lethal against the malaria parasite. The correlation between biochemical and in vitro data strongly supports Hsp90 as a drug target against the malaria parasite. Furthermore, at least one Hsp90 inhibitor developed as anticancer therapeutics could serve as starting point to generate P. falciparum-specific lead compounds. PMID- 28724417 TI - Examining the role of unmeasured confounding in mediation analysis with genetic and genomic applications. AB - BACKGROUND: In mediation analysis if unmeasured confounding is present, the estimates for the direct and mediated effects may be over or under estimated. Most methods for the sensitivity analysis of unmeasured confounding in mediation have focused on the mediator-outcome relationship. RESULTS: The Umediation R package enables the user to simulate unmeasured confounding of the exposure mediator, exposure-outcome, and mediator-outcome relationships in order to see how the results of the mediation analysis would change in the presence of unmeasured confounding. We apply the Umediation package to the Genetic Epidemiology of Chronic Obstructive Pulmonary Disease (COPDGene) study to examine the role of unmeasured confounding due to population stratification on the effect of a single nucleotide polymorphism (SNP) in the CHRNA5/3/B4 locus on pulmonary function decline as mediated by cigarette smoking. CONCLUSIONS: Umediation is a flexible R package that examines the role of unmeasured confounding in mediation analysis allowing for normally distributed or Bernoulli distributed exposures, outcomes, mediators, measured confounders, and unmeasured confounders. Umediation also accommodates multiple measured confounders, multiple unmeasured confounders, and allows for a mediator-exposure interaction on the outcome. Umediation is available as an R package at https://github.com/SharonLutz/Umediation A tutorial on how to install and use the Umediation package is available in the Additional file 1. PMID- 28724416 TI - Protective effects of chebulic acid on alveolar epithelial damage induced by urban particulate matter. AB - BACKGROUND: Chebulic acid (CA) isolated from T. chebula, which has been reported for treating asthma, as a potent anti-oxidant resources. Exposure to ambient urban particulate matter (UPM) considered as a risk for cardiopulmonary vascular dysfunction. To investigate the protective effect of CA against UPM-mediated collapse of the pulmonary alveolar epithelial (PAE) cell (NCI-H441), barrier integrity parameters, and their elements were evaluated in PAE. METHODS: CA was acquired from the laboratory previous reports. UPM was obtained from the National Institutes of Standards and Technology, and these were collected in St. Louis, MO, over a 24-month period and used as a standard reference. To confirm the protection of PAE barrier integrity, paracellular permeability and the junctional molecules were estimated with determination of transepithelial electrical resistance, Western Blotting, RT-PCR, and fluorescent staining. RESULTS: UPM aggravated the generation of reactive oxygen species (ROS) in PAE and also decreased mRNA and protein levels of junction molecules and barrier integrity in NCI-H441. However, CA repressed the ROS in PAE, also improved barrier integrity by protecting the junctional parameters in NCI-H411. CONCLUSIONS: These data showed that CA resulted in decreased UPM-induced ROS formation, and the protected the integrity of the tight junctions against UPM exposure to PAE barrier. PMID- 28724418 TI - Improved recovery of regional left ventricular function after PCI of chronic total occlusion in STEMI patients: a cardiovascular magnetic resonance study of the randomized controlled EXPLORE trial. AB - BACKGROUND: The Evaluating Xience and left ventricular function in PCI on occlusiOns afteR STEMI (EXPLORE) trial did not show a significant benefit of percutaneous coronary intervention (PCI) of the concurrent chronic total occlusion (CTO) in ST-segment elevation myocardial infarction (STEMI) patients on global left ventricular (LV) systolic function. However a possible treatment effect will be most pronounced in the CTO territory. Therefore, we aimed to study the effect of CTO PCI compared to no-CTO PCI on the recovery of regional LV function, particularly in the CTO territory. METHODS: Using cardiovascular magnetic resonance (CMR) we studied 180 of the 302 EXPLORE patients with serial CMR (baseline and 4 months follow-up). Segmental wall thickening (SWT) was quantified on cine images by an independent core laboratory. Dysfunctional segments were defined as SWT < 45%. Dysfunctional segments were further analyzed by viability (transmural extent of infarction (TEI) <=50%.). All outcomes were stratified for randomization treatment. RESULTS: In the dysfunctional segments in the CTO territory recovery of SWT was better after CTO PCI compared to no-CTO PCI (DeltaSWT 17 +/- 27% vs 11 +/- 23%, p = 0.03). This recovery was most pronounced in the dysfunctional but viable segments(TEI < 50%) (DeltaSWT 17 +/- 27% vs 11 +/ 22%, p = 0.02). Furthermore in the CTO territory, recovery of SWT was significantly better in the dysfunctional segments in patients with Rentrop grade 2-3 collaterals compared to grade 0-1 collaterals to the CTO (16 +/- 26% versus 11 +/- 24%, p = 0.04). CONCLUSION: CTO PCI compared with no-CTO PCI is associated with a greater recovery of regional systolic function in the CTO territory, especially in the dysfunctional but viable segments. Further research is needed to evaluate the use of CMR in selecting post-STEMI patients for CTO PCI and the effect of regional LV function recovery on clinical outcome. TRIAL REGISTRATION: Trialregister.nl NTR1108 , Date registered NTR: 30-okt-2007. PMID- 28724420 TI - Legal access to medications: a threat to Brazil's public health system? AB - BACKGROUND: In Brazil, health is fundamental human right guaranteed by the Constitution of 1988, which created the Brazilian Universal Health System (Sistema Unico de Saude - SUS). The SUS provides medications for outpatient care via policy of pharmaceutical assistance (PA) programmes. Despite the advances in PA policies which include the improvement in access to medications, there has been a significant increase in lawsuits related to health products and services. This study aimed to characterize the medication processes filed between 2010 and 2014 against the Secretary of State for Health of Sao Paulo (State Health Department of Sao Paulo - SES/SP), in Brazil, following PA policies. METHODS: This descriptive study used secondary data on medication lawsuits filed against the SES/SP between 2010 and 2014. The data source was the S-Codes computerized system. RESULTS: In the period evaluated, the number of lawsuits filed concerning health-related products increased approximately 63%; requests for medications were predominant. Approximately 30% of the medications involved in court proceedings were supplied via PA programmes. With regard to medications supplied via specialized component, 81.3% were prescribed in disagreement with the protocols published by the Ministry of Health. Insulin glargine was the most requested medication (6.3%), followed by insulin aspart (3.3%). Because there is no scientific evidence that either of these medicines is superior for the treatment of diabetes, neither of them has been incorporated into the SUS by the National Commission for Technology Incorporation. The judicial data showed that most of the lawsuits involved normal proceedings (i.e., individual demands), were filed by private lawyers, and named the State of Sao Paulo as the sole defendant, demonstrating the individual nature of these claims. The data indicate inequality in the distribution between the number of cases and lawyers and the number of lawsuits and prescribers, evidencing the concentration of lawyers and physicians in filing lawsuits. CONCLUSION: The judicialization of health in the State of Sao Paulo with the characteristics presented herein is a threat to the SUS. PMID- 28724419 TI - Real-life clinical practice results with vinflunine in patients with relapsed platinum-treated metastatic urothelial carcinoma: an Italian multicenter study (MOVIE-GOIRC 01-2014). AB - BACKGROUND: Vinflunine is the only chemotherapeutic agent shown to improve survival in platinum-refractory patients with metastatic transitional cell carcinoma of the urothelium (TCCU) in a phase III clinical trial, which led to product registration for this indication in Europe. The aim of this study was to assess the efficacy of vinflunine and to evaluate the prognostic significance of risk factors in a large, unselected cohort of patients with metastatic TCCU treated according to routine clinical practice. METHODS: This was a retrospective multicenter study. Italian cancer centers were selected if, according to the Registry of the Italian Medicines Agency (AIFA), at least four patients had been treated with vinflunine between February 2011 and June 2014, after first- or second-line platinum-based chemotherapy. The primary objective was to test whether the efficacy measured by overall survival (OS) in the registration study could be confirmed in routine clinical practice. Multivariate analysis was carried out using Cox proportional hazard model. RESULTS: A total of 217 patients were treated in 28 Italian centers. Median age was 69 years (IQR 62-76) and 84% were male; Eastern Cooperative Oncology Group performance status (ECOG PS) was >= 1 in 53% of patients. The median number of cycles was 4 (IQR 2-6); 29%, 35%, and 36% received an initial dose of 320 mg/m2, 280 mg/m2 or a lower dose, respectively. Median progression-free survival (PFS) and OS for the entire population was 3.2 months (2.6-3.7) and 8.1 months (6.3-8.9). A complete response was observed in six patients, partial response in 21, stable disease in 60, progressive disease in 108, with a disease control rate of 40%. Multivariate analysis showed that ECOG PS, number of metastatic sites and liver involvement were unfavorable prognostic factors for OS. Toxicity was mild, and grade 3-4 adverse effects were mainly: neutropenia (9%), anemia (6%), asthenia/fatigue (7%) and constipation (5%). CONCLUSIONS: In routine clinical practice the results obtained with VFL seem to be better than the results of the registration trial and reinforce evidence supporting its use after failure of a platinum-based chemotherapy. PMID- 28724421 TI - Efficacy and safety of mycophenolate mofetil in patients with IgA nephropathy: an update meta-analysis. AB - BACKGROUND: The application of mycophenolate mofetil (MMF) in treating patients with immunoglobulin A nephropathy (IgAN) remains uncertain. This update meta analysis was performed to re-evaluate the therapeutic potential of MMF in IgAN. METHODS: Articles were obtained by searching the electronic databases without language restriction. Randomized controlled trials studying the role of MMF in treating IgAN were collected. The quality of included studies was critically evaluated. Data analyses were performed by using RevMan 5.3 software. RESULTS: A total of 297 articles were screened and eight articles were finally included. Among the eight randomized controlled trials, five and three were high quality and low quality, respectively. Both fixed-effect and random-effect model were used. Pooled results by combining all the eight studies suggested that IgAN patients in MMF group had a higher remission rate than that in control group. Compared to placebo or corticosteroid monotherapy, MMF monotherapy exerted a higher remission rate and side effect rate in both main analysis and subgroup analysis by human race. Compared to corticosteroid plus other immunosuppressive agent therapy, corticosteroid plus MMF therapy had a higher remission rate, lower serum creatinine doubling rate, progression to end-stage renal disease rate and side effects rate. Subgroup analysis by therapeutic regimen further confirmed these results between corticosteroid plus MMF therapy and corticosteroid plus cyclophosphamide therapy. Funnel-plot displayed a symmetrical figure, indicating no publication bias existed. CONCLUSIONS: MMF has the potential in treatment of IgAN, especially for Asians. The evidence currently available shows that MMF monotherapy has a more efficacy but higher side effects when compared to placebo or corticosteroid monotherapy in treatment of Asians with IgAN. While MMF combined with corticosteroid regimen has a more efficacy and lower side effects when compared with corticosteroid plus cyclophosphamide regimen. PMID- 28724422 TI - Assessment of eating disorders with the diabetes eating problems survey - revised (DEPS-R) in a representative sample of insulin-treated diabetic patients: a validation study in Italy. AB - BACKGROUND: The purpose of the study was to evaluate in a sample of insulin treated diabetic patients, with type 1 or type 2 diabetes, the psychometric characteristics of the Italian version of the DEPS-R scale, a diabetes-specific self-report questionnaire used to analyze disordered eating behaviors. METHODS: The study was performed on 211 consecutive insulin-treated diabetic patients attending two specialist centers. Lifetime prevalence of eating disorders (EDs) according to DSM-IV and DSM-5 criteria were assessed by means of the Module H of the Structured Clinical Interview for DSM IV Axis I Disorder and the Module H modified, according to DSM-5 criteria. The following questionnaires were administered: DEPS-R and the Eating Disorder Inventory - 3 (EDI-3). Test/retest reproducibility was assessed on a subgroup of 70 patients. The factorial structure, internal consistency, test-retest reliability and concurrent validity of DEPS-R were assessed. RESULTS: Overall, 21.8% of the sample met criteria for at least one DSM-5 diagnosis of ED. A "clinical risk" of ED was observed in 13.3% of the sample. Females displayed higher scores at DEPS-R, a higher percentage of at least one diagnosis of ED and a higher clinical risk for ED. A high level of reproducibility and homogeneity of the scale were revealed. A significant correlation was detected between DEPS-R and the 3 ED risk scales of EDI-3. CONCLUSIONS: The data confirmed the overall reliability and validity of the scale. In view of the significance and implications of EDs in diabetic patients, it should be conducted a more extensive investigation of the phenomenon by means of evaluation instruments of demonstrated validity and reliability. PMID- 28724423 TI - Effectiveness and cost-effectiveness of telephone-based cognitive-behavioural therapy in primary care: study protocol of TIDe - telephone intervention for depression. AB - BACKGROUND: Despite the availability of evidence-based treatments for depression, a large proportion of patients remains untreated or adequate treatment is initiated with delay. This situation is particularly critical in primary care, where not only most individuals first seek help for their mental health problems, but also depressive disorders - particularly mild to moderate levels of severity are highly prevalent given the high comorbidity of chronic somatic conditions and depression. Improving the access for evidence-based treatment, especially in primary care, is hence a priority challenge in the mental health care agenda. Telephone usage is widespread and has the potential of overcoming many barriers that individuals suffering from mental health problems are facing: Its implementation for treatment delivery presents an option for optimisation of treatment pathways and outcomes. METHODS/DESIGN: This paper details the study protocol for a randomised controlled trial (RCT) evaluating the effectiveness of a telephone-administered short-term cognitive-behavioural therapy (T-CBT) for depression as compared to treatment as usual (TAU) in the Swiss primary care setting. The study aims at randomising a total of 216 mildly to moderately depressed patients, which are either identified by their General Practitioners (GPs) or who self-refer to the study programme in consultation with their GP. The trial will examine whether telephone-delivered, manualised treatment leads to clinically significant reduction in depression at follow-up. It will further investigate the cost-effectiveness and acceptability of the intervention in the primary care setting. DISCUSSION: Conducting a low-intensity treatment on the telephone allows for greater flexibility for both patient and therapist, can grant more anonymity and can thus lead to less hesitation in the patient about whether to attempt treatment or not. In order to benefit from this approach, large-scale studies need to prove superior effectiveness and cost-effectiveness of telephone-delivered therapy over routine care for patients with mild to moderate depression. TRIAL REGISTRATION: ClinicalTrials.gov NCT02667366 . Registered on 3 December 2015. PMID- 28724424 TI - The traditional lunch pattern is inversely correlated with body mass index in a population-based study in Brazil. AB - BACKGROUND: The association of obesity and dietary patterns has been well documented in scientific literature; however, information on the impact of meal patterns on obesity is scarce. The objective of this study was to investigate the association of adherence to lunch patterns and body mass index (BMI) in a representative sample of individuals aged 20 years or older in Sao Paulo. METHODS: Data for 933 participants were retrieved from the Health Survey of Sao Paulo (ISA-Capital 2008), a cross-sectional population-based survey. The usual dietary intake of individuals with at least one 24-h recall was estimated by the Multiple Source Method. The definition of lunch was self-reported by the participant. Five lunch patterns were derived from twenty-two food groups by exploratory factor analysis: Traditional, Western, Sweetened juice, Salad, and Meats. To estimate the effect of lunch patterns on BMI, we used a generalized linear model with link identity and inverse Gaussian distribution. Analyses were adjusted by age, gender, household income per capita, physical activity levels, smoking status, alcohol consumption, total energy intake, and misreporting status. RESULTS: The greater adherence to the traditional pattern at the lunch meal was associated with lower BMI, only in insufficiently active individuals (beta = -0.78; 95% CI -1.57; -0.02). CONCLUSIONS: The traditional Brazilian lunch pattern might protect the insufficiently active individuals against obesity. PMID- 28724425 TI - Using the Uganda National Panel Survey to analyze the effect of staple food consumption on undernourishment in Ugandan children. AB - BACKGROUND: The United Nations' Millennium Development Goals Report, 2015, documents that, since 1990, the number of stunted children in sub-Saharan Africa has increased by 33% even though it has fallen in all other world regions. Recognizing this, in 2011 the Government of Uganda implemented a 5-year Nutrition Action Plan. One important tenet of the Plan is to lessen malnutrition in young children by discouraging over-consumption of nutritionally deficient, but plentiful, staple foods, which it defines as a type of food insecurity. METHODS: We use a sample of 6101 observations on 3427 children age five or less compiled from three annual waves of the Uganda National Panel Survey to measure undernourishment. We also use the World Health Organization's Child Growth Standards to create a binary variable indicating stunting and another indicating wasting for each child in each year. We then use random effects to estimate binary logistic regressions that show that greater staple food concentrations affect the probability of stunting and wasting. RESULTS: The estimated coefficients are used to compute adjusted odds ratios (OR) that estimate the effect of greater staple food concentration on the likelihood of stunting and the likelihood of wasting. Controlling for other relevant covariates, these odds ratios show that a greater proportion of staple foods in a child's diet increases the likelihood of stunting (OR = 1.007, p = 0.005) as well as wasting (OR = 1.011, p = 0.034). Stunting is confirmed with subsamples of males only (OR = 1.006, p = 0.05) and females only (OR = 1.008, p = 0.027), suggesting that the finding is not gender specific. Another subsample of children aged 12 months or less, most of whom do not yet consume solid food, shows no statistically significant relationship, thus supporting the validity of the other findings. CONCLUSION: Diets containing larger proportions of staple foods are associated with greater likelihoods of both stunting and wasting in Ugandan children. Other causes of stunting and wasting identified in past research are also confirmed with the Uganda data. Finally, the analysis provides clues to other possible causes of undernourishment in young children. PMID- 28724426 TI - High expression of ETS2 predicts poor prognosis in acute myeloid leukemia and may guide treatment decisions. AB - BACKGROUND: ETS2 is a downstream effector of the RAS/RAF/ERK pathway, which plays a critical role in the development of malignant tumor. However, the clinical impact of ETS2 expression in AML remains unknown. METHODS: In this study, we evaluated the prognostic significance of ETS2 expression using two relatively large cohorts of AML patients. RESULTS: In the first cohort, compared to low expression of ETS2 (ETS2 low), high expression of ETS2 (ETS2 high) showed significant shorter OS, EFS and RFS in the current treatments including the allogeneic HCT group (n = 72) and the chemotherapy group (n = 100). Notably, among ETS2 high patients, those received allogeneic HCT had longer OS, EFS and RFS than those with chemotherapy alone (allogeneic HCT, n = 39 vs. chemotherapy, n = 47), but treatment modules play insignificant role in the survival of ETS2 low patients (allogeneic HCT, n = 33 vs. chemotherapy, n = 53). Moreover, gene/microRNA expression data provides insights into the biological changes associated with varying ETS2 expression levels in AML. The prognostic value of ETS2 was further validated in the second AML cohort (n = 329). CONCLUSIONS: Our results indicate that ETS2 high is a poor prognostic factor in AML and may guide treatment decisions towards allogeneic HCT. PMID- 28724428 TI - Mirroring the CANTOS revolution: is anti-inflammatory therapy for diabetes just around the corner? PMID- 28724427 TI - Curcumin: the spicy modulator of breast carcinogenesis. AB - Worldwide breast cancer is the most common cancer in women. For many years clinicians and the researchers are examining and exploring various therapeutic modalities for breast cancer. Yet the disease has remained unconquered and the quest for cure is still going on. Present-day strategy of breast cancer therapy and prevention is either combination of a number of drugs or a drug that modulates multiple targets. In this regard natural products are now becoming significant options. Curcumin exemplifies a promising natural anticancer agent for this purpose. This review primarily underscores the modulatory effect of curcumin on the cancer hallmarks. The focus is its anticancer effect in the complex pathways of breast carcinogenesis. Curcumin modulates breast carcinogenesis through its effect on cell cycle and proliferation, apoptosis, senescence, cancer spread and angiogenesis. Largely the NFkB, PI3K/Akt/mTOR, MAPK and JAK/STAT are the key signaling pathways involved. The review also highlights the curcumin mediated modulation of tumor microenvironment, cancer immunity, breast cancer stem cells and cancer related miRNAs. Using curcumin as a therapeutic and preventive agent in breast cancer is perplexed by its diverse biological activity, much of which remains inexplicable. The information reviewed here should point toward potential scope of future curcumin research in breast cancer. PMID- 28724429 TI - The noncoding RNA HOXD-AS1 is a critical regulator of the metastasis and apoptosis phenotype in human hepatocellular carcinoma. AB - BACKGROUND: Despite accumulating evidence that long noncoding RNAs (lncRNAs) are associated with cancer development in multiple types of cancer, the biological roles of many lncRNAs in human hepatocellular carcinoma (HCC) metastasis have not been well characterized. METHODS: A lncRNA+ mRNA human gene expression microarray analysis was used to identify differentially expressed lncRNAs in metastatic HCC tissues compared to non-metastatic tissue. RESULTS: We observed remarkable overexpression of HOXD-AS1 in metastatic cancer tissues. In vitro and in vivo gain- or loss-of-function studies re-affirmed that HOXD-AS1 is able to facilitate cancer metastasis and inhibit apoptosis. Moreover, we identified that HOXD-AS1 upregulated the Rho GTPase activating protein 11A (ARHGAP11A) by competitively binding to microRNA-19a (miR19a), resulting in induced metastasis. Interestingly, the regulator of G-protein signaling 3 (RGS3), a potential inhibitor of the MEK ERK1/2 signaling axis, was also found to be downregulated by ectopic HOXD-AS1 overexpression, leading to a remarkably reduced apoptotic effect. CONCLUSIONS: The present investigation strongly indicates that HOXD-AS1 is an oncogenic lncRNA that promotes HCC metastasis and that its pro-metastatic phenotype can partially be attributed to the HOXD-AS1/miR19a/ARHGAP11A signaling axis. PMID- 28724430 TI - EGFR modulates monounsaturated fatty acid synthesis through phosphorylation of SCD1 in lung cancer. AB - BACKGROUND: Epidermal growth factor receptor (EGFR), a well-known oncogenic driver, contributes to the initiation and progression of a wide range of cancer types. Aberrant lipid metabolism including highly produced monounsaturated fatty acids (MUFA) is recognized as a hallmark of cancer. However, how EGFR regulates MUFA synthesis in cancer remains elusive. This is the focus of our study. METHODS: The interaction between EGFR and stearoyl-CoA desaturase-1 (SCD1) was detected byco-immunoprecipitation. SCD1 protein expression, stability and phosphorylation were tested by western blot. The synthesis of MUFA was determined by liquid chromatography-mass spectrometry. The growth of lung cancer was detected by CCK-8 assay, Annexin V/PI staining, colony formation assay and subcutaneous xenograft assay. The expression of activated EGFR, phosphorylated and total SCD1 was tested by immunohistochemistry in 90 non-small cell lung cancersamples. The clinical correlations were analyzed by Chi-square test, Kaplan Meier survival curve analysis and Cox regression. RESULTS: EGFR binds to and phosphorylates SCD1 at Y55. Phosphorylation of Y55 is required for maintaining SCD1 protein stability and thus increases MUFA level to facilitate lung cancer growth. Moreover, EGFR-stimulated cancer growth depends on SCD1 activity. Evaluation of non-small cell lung cancersamples reveals a positive correlation among EGFR activation, SCD1 Y55 phosphorylation and SCD1 protein expression. Furthermore, phospho-SCD1 Y55 can serve as an independent prognostic factor for poor patient survival. CONCLUSIONS: Ourstudy demonstrates that EGFR stabilizes SCD1 through Y55 phosphorylation, thereby up-regulating MUFA synthesis to promote lung cancer growth. Thus, we provide the first evidence that SCD1 can be subtly controlled by tyrosine phosphorylation and uncover a previously unknown direct linkage between oncogenic receptor tyrosine kinase and lipid metabolism in lung cancer. We also propose SCD1 Y55 phosphorylation as a potential diagnostic marker for lung cancer. PMID- 28724431 TI - Biological embedding of childhood adversity: from physiological mechanisms to clinical implications. AB - BACKGROUND: Adverse psychosocial exposures in early life, namely experiences such as child maltreatment, caregiver stress or depression, and domestic or community violence, have been associated in epidemiological studies with increased lifetime risk of adverse outcomes, including diabetes, heart disease, cancers, and psychiatric illnesses. Additional work has shed light on the potential molecular mechanisms by which early adversity becomes "biologically embedded" in altered physiology across body systems. This review surveys evidence on such mechanisms and calls on researchers, clinicians, policymakers, and other practitioners to act upon evidence. OBSERVATIONS: Childhood psychosocial adversity has wide ranging effects on neural, endocrine, immune, and metabolic physiology. Molecular mechanisms broadly implicate disruption of central neural networks, neuroendocrine stress dysregulation, and chronic inflammation, among other changes. Physiological disruption predisposes individuals to common diseases across the life course. CONCLUSIONS: Reviewed evidence has important implications for clinical practice, biomedical research, and work across other sectors relevant to public health and child wellbeing. Warranted changes include increased clinical screening for exposures among children and adults, scale-up of effective interventions, policy advocacy, and ongoing research to develop new evidence-based response strategies. PMID- 28724432 TI - The role of peer victimization in the physical activity and screen time of adolescents: a cross-sectional study. AB - BACKGROUND: Negative peer experiences may lead adolescents with overweight and obesity to be less active and engage in more sitting-related behaviors. Our study is among the first to empirically test these associations and hypothesized that 1) peer victimization would mediate the negative association between body weight status and moderate-to-vigorous physical activity (MVPA), and 2) peer victimization would mediate the positive association between body weight status and screen time. Differences by gender were also explored. METHODS: Participants were a part of the Year 1 data (2012-2013) from the COMPASS study, a prospective cohort study of high school students in Ontario and Alberta, Canada. The final sample consisted of 18,147 students in grades 9 to 12 from 43 Ontario secondary schools. The predictor variable was weight status (non-overweight vs. overweight/obese), the mediator was peer victimization, and the outcome variables were screen time and MVPA. Multilevel path analysis was conducted, controlling for clustering within schools and covariates. A few differences were observed between males and females; therefore, the results are stratified by gender. RESULTS: For both males and females peer victimization partially mediated the association between weight status and screen time. Specifically, females with overweight/obesity reported 34 more minutes/day of screen time than did females who were not overweight and 2 of these minutes could be attributed to experiencing peer victimization. Similarly, males who were overweight/obese reported 13 more minutes/day of screen time than the males who were not overweight and 1 of these minutes could be attributed to experiencing more victimization. Males and females who were overweight/obese also reported less MVPA compared to those who were not overweight; however, peer victimization did not mediate these associations in the hypothesized direction. CONCLUSIONS: We found that higher rates of peer victimization experienced by adolescents with overweight and obesity partially explained why they engaged in more screen time than adolescents who were not overweight. However, the effects were small and may be of limited practical significance. Because this is one of the first studies to investigate these associations, more research is needed before bully prevention or conflict resolution training are explored as intervention strategies. PMID- 28724433 TI - GridSample: an R package to generate household survey primary sampling units (PSUs) from gridded population data. AB - BACKGROUND: Household survey data are collected by governments, international organizations, and companies to prioritize policies and allocate billions of dollars. Surveys are typically selected from recent census data; however, census data are often outdated or inaccurate. This paper describes how gridded population data might instead be used as a sample frame, and introduces the R GridSample algorithm for selecting primary sampling units (PSU) for complex household surveys with gridded population data. With a gridded population dataset and geographic boundary of the study area, GridSample allows a two-step process to sample "seed" cells with probability proportionate to estimated population size, then "grows" PSUs until a minimum population is achieved in each PSU. The algorithm permits stratification and oversampling of urban or rural areas. The approximately uniform size and shape of grid cells allows for spatial oversampling, not possible in typical surveys, possibly improving small area estimates with survey results. RESULTS: We replicated the 2010 Rwanda Demographic and Health Survey (DHS) in GridSample by sampling the WorldPop 2010 UN-adjusted 100 m * 100 m gridded population dataset, stratifying by Rwanda's 30 districts, and oversampling in urban areas. The 2010 Rwanda DHS had 79 urban PSUs, 413 rural PSUs, with an average PSU population of 610 people. An equivalent sample in GridSample had 75 urban PSUs, 405 rural PSUs, and a median PSU population of 612 people. The number of PSUs differed because DHS added urban PSUs from specific districts while GridSample reallocated rural-to-urban PSUs across all districts. CONCLUSIONS: Gridded population sampling is a promising alternative to typical census-based sampling when census data are moderately outdated or inaccurate. Four approaches to implementation have been tried: (1) using gridded PSU boundaries produced by GridSample, (2) manually segmenting gridded PSU using satellite imagery, (3) non-probability sampling (e.g. random-walk, "spin-the pen"), and random sampling of households. Gridded population sampling is in its infancy, and further research is needed to assess the accuracy and feasibility of gridded population sampling. The GridSample R algorithm can be used to forward this research agenda. PMID- 28724434 TI - Individual contextual factors in the validation of the Bernese pain scale for neonates: protocol for a prospective observational study. AB - BACKGROUND: The Bernese Pain Scale for Neonates (BPSN) is a multidimensional pain assessment tool that is already widely used in clinical settings in the German speaking areas of Europe. Recent findings indicate that pain responses in preterm neonates are influenced by individual contextual factors, such as gestational age (GA), gender and the number of painful procedures experienced. Currently, the BPSN does not consider individual contextual factors. Therefore, the aim of this study is the validation of the BPSN using a large sample of neonates with different GAs. Furthermore, the influence of individual contextual factors on the variability in pain reactions across GA groups will be explored. The results will be used for a modification of the BPSN to account for individual contextual factors in future clinical pain assessment in neonates. METHODS AND DESIGN: This prospective multisite validation study with a repeated measures design will take place in three university hospital neonatal intensive care units (NICUs) in Switzerland (Bern, Basel and Zurich). To examine the impact of GA on pain responses and their variability, the infants will be stratified into six GA groups ranging from 24 0/7 to 42 0/7. Among preterm infants, 2-5 routine capillary heel sticks within the first 14 days of life, and among full-term infants, two heel sticks during the first days of life will be documented. For each heel stick, measurements will be video recorded for each of three phases: baseline, heel stick, and recovery. The infants' pain responses will be rated according to the BPSN by five nurses who are blinded as to the number of each heel stick and as to the measurement phases. Individual contextual factors of interest will be extracted from patient charts. DISCUSSION: Understanding and considering the influence of individual contextual factors on pain responses in a revised version of the BPSN will help the clinical staff to more appropriately assess pain in neonates, particularly preterm neonates hospitalized in NICUs. Pain assessment is a first step toward appropriate and efficient pain management, which itself is an important factor in later motor and cognitive development in this vulnerable patient population. TRIAL REGISTRATION: The study is registered in the database of Clinical Trial gov. Study ID-number: NCT 02749461 . Registration date: 12 April 2016. PMID- 28724436 TI - Expanding the phenotype of reciprocal 1q21.1 deletions and duplications: a case series. AB - BACKGROUND: Recurrent reciprocal 1q21.1 deletions and duplications have been associated with variable phenotypes. Phenotypic features described in association with 1q21.1 microdeletions include developmental delay, craniofacial dysmorphism and congenital anomalies. The 1q21.1 reciprocal duplication has been associated with macrocephaly or relative macrocephaly, frontal bossing, hypertelorism, developmental delay, intellectual disability and autism spectrum disorder. METHODS: Our study describes seven patients, who were referred to us for developmental delay/intellectual disability, dysmorphic features and, in some cases, congenital anomalies, in whom we identified 1q21.1 CNVs by array-CGH. RESULTS: Our data confirm the extreme phenotypic variability associated with 1q21.1 microdeletion and microduplication. We observed common phenotypic features, described in previous studies, but we also described, for the first time, congenital hypothyroidism in association with 1q21.1 deletion and trigonocephaly associated with 1q21.1 duplication. CONCLUSIONS: The aim of this study is to contribute to the definition of the phenotype associated with reciprocal 1q21.1 deletions and duplications. PMID- 28724435 TI - WW domain-binding protein 2: an adaptor protein closely linked to the development of breast cancer. AB - The WW domain is composed of 38 to 40 semi-conserved amino acids shared with structural, regulatory, and signaling proteins. WW domain-binding protein 2 (WBP2), as a binding partner of WW domain protein, interacts with several WW domain-containing proteins, such as Yes kinase-associated protein (Yap), paired box gene 8 (Pax8), WW-domain-containing transcription regulator protein 1 (TAZ), and WW-domain-containing oxidoreductase (WWOX) through its PPxY motifs within C terminal region, and further triggers the downstream signaling pathway in vitro and in vivo. Studies have confirmed that phosphorylated form of WBP2 can move into nuclei and activate the transcription of estrogen receptor (ER) and progesterone receptor (PR), whose expression were the indicators of breast cancer development, indicating that WBP2 may participate in the progression of breast cancer. Both overexpression of WBP2 and activation of tyrosine phosphorylation upregulate the signal cascades in the cross-regulation of the Wnt and ER signaling pathways in breast cancer. Following the binding of WBP2 to the WW domain region of TAZ which can accelerate migration, invasion and is required for the transformed phenotypes of breast cancer cells, the transformation of epithelial to mesenchymal of MCF10A is activated, suggesting that WBP2 is a key player in regulating cell migration. When WBP2 binds with WWOX, a tumor suppressor, ER transactivation and tumor growth can be suppressed. Thus, WBP2 may serve as a molecular on/off switch that controls the crosstalk between E2, WWOX, Wnt, TAZ, and other oncogenic signaling pathways. This review interprets the relationship between WBP2 and breast cancer, and provides comprehensive views about the function of WBP2 in the regulation of the pathogenesis of breast cancer and endocrine therapy in breast cancer treatment. PMID- 28724437 TI - The lncRNA CASC15 regulates SOX4 expression in RUNX1-rearranged acute leukemia. AB - BACKGROUND: Long non-coding RNAs (lncRNAs) play a variety of cellular roles, including regulation of transcription and translation, leading to alterations in gene expression. Some lncRNAs modulate the expression of chromosomally adjacent genes. Here, we assess the roles of the lncRNA CASC15 in regulation of a chromosomally nearby gene, SOX4, and its function in RUNX1/AML translocated leukemia. RESULTS: CASC15 is a conserved lncRNA that was upregulated in pediatric B-acute lymphoblastic leukemia (B-ALL) with t (12; 21) as well as pediatric acute myeloid leukemia (AML) with t (8; 21), both of which are associated with relatively better prognosis. Enforced expression of CASC15 led to a myeloid bias in development, and overall, decreased engraftment and colony formation. At the cellular level, CASC15 regulated cellular survival, proliferation, and the expression of its chromosomally adjacent gene, SOX4. Differentially regulated genes following CASC15 knockdown were enriched for predicted transcriptional targets of the Yin and Yang-1 (YY1) transcription factor. Interestingly, we found that CASC15 enhances YY1-mediated regulation of the SOX4 promoter. CONCLUSIONS: Our findings represent the first characterization of this CASC15 in RUNX1 translocated leukemia, and point towards a mechanistic basis for its action. PMID- 28724438 TI - Synergy between dinotefuran and fipronil against the cat flea (Ctenocephalides felis): improved onset of action and residual speed of kill in adult cats. AB - BACKGROUND: The cat flea, Ctenocephalides felis felis (C. felis), is a cosmopolitan hematophagous ectoparasite, and is considered to be the most prevalent flea species in both Europe and the USA. Clinical signs frequently associated with flea bites include pruritus, dermatitis and in severe cases even pyodermatitis and alopecia. Ctenocephalides felis is also a vector for several pathogens and is an intermediate host for the cestode Dipylidium caninum. Treatment of cats with a fast-acting pulicide, that is persistently effective in protecting the animal against re-infestation, is therefore imperative to their health. In addition, a rapid onset of activity ("speed of kill") may also reduce the risks of disease transmission and flea allergic dermatitis. The aim of this study was to evaluate the in vitro insecticidal activity and potential synergism between dinotefuran and fipronil against C. felis. A further aim was to evaluate the onset of activity and residual speed of kill of the combination in vivo on cats artificially infested with C. felis. METHODS: In the first study, the insecticidal activity of dinotefuran and fipronil separately and dinotefuran/fipronil (DF) in combination, at a fixed ratio (2:1), was evaluated using an in vitro coated-vial bioassay. In the second study, the onset of activity against existing flea infestations and residual speed of kill of DF against artificial flea infestations on cats was assessed in vivo. Onset of activity against existing flea infestations was assessed in terms of knock-down effect within 2 h post-treatment and onset of speed of kill assessed at 3 h, 6 h and 12 h post-treatment. Residual speed of kill was evaluated 6 h and 48 h after infestation, over a period of six weeks post-treatment. RESULTS: In vitro results revealed that the DF combination was synergistic and more potent against fleas than either compound alone. The combination also proved effective when tested in vivo. Efficacy was > 97% [geometric mean (GM) and arithmetic mean (AM)] at 3 h after treatment, and >= 99.8% (GM and AM) at 6 h and 12 h post-treatment. At 6 h after flea re-infestations, the efficacy of DF remained >= 90.8% (GM and AM) for up to 28 days, and at 42 days post-treatment persistent efficacy was still >= 54.3% (GM and AM). At 48 h after flea re-infestations, DF remained almost fully effective for up to 28 days, with efficacies >= 99.4% (GM and AM) and was persistently >= 93.0% (GM and AM) effective for up to 42 days post-treatment. CONCLUSIONS: The combination of dinotefuran and fipronil in a single formulation exhibited strong synergistic insecticidal activity against C. felis in vitro, and also proved effective on artificially infested cats. This activity had a rapid onset that persisted for 6 weeks against re-infestations of C. felis on cats. The rapid curative insecticidal effect was observed as early as 3 h after treatment, and as early as 6 h after re-infestations for up to 6 weeks post-treatment. The insecticidal activity profile of DF makes it an optimal candidate for the protection of cats against flea infestations, and possibly also associated diseases. PMID- 28724439 TI - Genetic deficiency of Wnt5a diminishes disease severity in a murine model of rheumatoid arthritis. AB - BACKGROUND: Rheumatoid arthritis (RA) is a common autoimmune disease characterized by chronic inflammation of the joints, leading to bone erosion and joint dysfunction. Despite the recent successes of disease-modifying anti rheumatic drugs (DMARDs), there is still clinical need for understanding the development and molecular etiology of RA. Wnts are developmental morphogens whose roles in adult pathology are poorly characterized. Wnt5a is a member of the non canonical family of Wnts that modulates a wide range of cell processes, including differentiation, migration, and inflammation. Wnt5a has been implicated as a possible contributor to arthritis and it is upregulated in synovial fibroblasts from RA patients. METHODS: We investigated the role of endogenous Wnt5a in RA. Tamoxifen-inducible, Wnt5a knockout (Wnt5a cKO) mice and littermate controls were monitored for arthritis development and joint pathology using the K/BxN serum transfer-induced arthritis (STIA) model. To explore a role of Wnt5a in osteoclast fusion, bone marrow-derived monocytes (BMDMs) were differentiated in vitro. RESULTS: Wnt5a cKO mice were resistant to arthritis development compared to control littermates as assessed by ankle thickness and histologic measurements. Some parameters of inflammation were reduced in the Wnt5a cKO mice, including the extent of polymononuclear cell infiltration and extra-articular inflammation. Wnt5a cKO mice also exhibited less cartilage destruction and a reduction in osteoclast activity with concomitant reduction in tartrate-resistant acid phosph atase (TRAP), cathepsin K (CTSK), macrophage colony-stimulating factor (MCSF), matrix metalloproteinase (MMP)2 and MMP9 in the arthritic joints. Treatment of BMDMs with Wnt5a enhanced osteoclast fusion and increased the expression of dendrocyte-expressed seven transmembrane protein (DCSTAMP) and MMP9, that are necessary for osteoclast formation and activity. CONCLUSIONS: These data suggest that Wnt5a modulates the development of arthritis by promoting inflammation and osteoclast fusion, and provide the first mouse genetic evidence of a role for endogenous Wnt5a in autoimmune disease. PMID- 28724441 TI - Computed tomography during initial management and mortality among hemodynamically unstable blunt trauma patients: a nationwide retrospective cohort study. AB - BACKGROUND: Although many hemodynamically unstable trauma patients undergo computed tomography (CT) to identify a source of bleeding, this practice is currently only recommended by a few guidelines. To clarify whether CT has harmful effects among these patients, we examined the association between CT during initial management and mortality among unstable blunt trauma patients. METHODS: This was a retrospective cohort study based on Japan Trauma Data Bank 2004-2014 registry data. Study population was adult blunt trauma patients with hypotension on arrival. The primary outcome was the in-hospital mortality. Two types of analyses were performed to adjust for confounding factors including propensity score inverse probability of treatment weighted (IPTW) and instrumental variable (IV) analysis. RESULTS: Among 5,809 patients who met inclusion criteria, 5,352 (92.1%) underwent CT. The No CT group was more likely to have severe physiological conditions and lower probability of survival than those of the CT group. In IPTW analysis adjusting for measured confounders, we found a significant protective effect of undergoing CT on in-hospital mortality (excess deaths: -20.6 per 100 patients, 95% CI -26.2 to -14.9). In IV analysis adjusting both for measured and unmeasured confounders, the association between CT and mortality was not statistically significant (excess deaths: -4.1 per 100 patients, 95% CI -23.1 to 14.8). DISCUSSION: We did not find clinically meaningful harmful effect of CT on survival for unstable blunt trauma patients even after adjusting both for measured and unmeasured confounders. CONCLUSIONS: Our results did not support the recommendation of current guideline. We suggest physicians should consider CT as one of the diagnostic options even when patients are unstable. PMID- 28724440 TI - Bottleneck in secretion of alpha-amylase in Bacillus subtilis. AB - Amylase plays an important role in biotechnology industries, and Gram-positive bacterium Bacillus subtilis is a major host to produce heterogeneous alpha amylases. However, the secretion stress limits the high yield of alpha-amylase in B. subtilis although huge efforts have been made to address this secretion bottleneck. In this question-oriented review, every effort is made to answer the following questions, which look simple but are long-standing, through reviewing of literature: (1) Does alpha-amylase need a specific and dedicated chaperone? (2) What signal sequence does CsaA recognize? (3) Does CsaA require ATP for its operation? (4) Does an unfolded alpha-amylase is less soluble than a folded one? (5) Does alpha-amylase aggregate before transporting through Sec secretion system? (6) Is alpha-amylase sufficient stable to prevent itself from misfolding? (7) Does alpha-amylase need more disulfide bonds to be stabilized? (8) Which secretion system does PrsA pass through? (9) Is PrsA ATP-dependent? (10) Is PrsA reused after folding of alpha-amylase? (11) What is the fate of PrsA? (12) Is trigger factor (TF) ATP-dependent? The literature review suggests that not only the most of those questions are still open to answers but also it is necessary to calculate ATP budget in order to better understand how B. subtilis uses its energy for production and secretion. PMID- 28724442 TI - Impact of obesity on the response to tumor necrosis factor inhibitors in axial spondyloarthritis. AB - BACKGROUND: Few studies have investigated the impact of obesity on the response to tumor necrosis factor inhibitors (TNFi) in patients with axial spondyloarthritis (axSpA). The aim of our study was to investigate the impact of different body mass index (BMI) categories on TNFi response in a large cohort of patients with axSpA. METHODS: Patients with axSpA within the Swiss Clinical Quality Management (SCQM) program were included in the current study if they fulfilled the Assessment in Spondyloarthritis International Society (ASAS) criteria for axSpA, started a first TNFi after recruitment, and had available BMI data as well as a baseline and follow-up visit at 1 year (+/-6 months). Patients were categorized according to BMI: normal (BMI 18.5 to <25), overweight (BMI 25 30), and obese (BMI >30). We evaluated the proportion of patients achieving the 40% improvement in ASAS criteria (ASAS40), as well as Ankylosing Spondylitis Disease Activity Score (ASDAS) improvement and status scores at 1 year. Patients having discontinued the TNFi were considered nonresponders. We controlled for age, sex, HLA-B27, axSpA type, BASDAI, BASMI, elevated C-reactive protein (CRP), current smoking, enthesitis, physical exercise, and co-medication with disease modifying antirheumatic drugs, as well as with nonsteroidal anti-inflammatory drugs in multiple adjusted logistic regression analyses. RESULTS: A total of 624 axSpA patients starting a first TNFi were considered in the current study (332 patients of normal weight, 204 patients with overweight, and 88 obese patients). Obese individuals were older, had higher BASDAI levels, and had a more important impairment of physical function in comparison to patients of normal weight, while ASDAS and CRP levels were comparable between the three BMI groups. An ASAS40 response was reached by 44%, 34%, and 29% of patients of normal weight, overweight, and obesity, respectively (overall p = 0.02). Significantly lower odds ratios (ORs) for achieving ASAS40 response were found in adjusted analyses in obese patients versus patients with normal BMI (OR 0.27, 95% confidence interval (CI) 0.09-0.70). The respective adjusted ASAS40 OR in overweight versus normal weight patients was 0.62 (95% CI 0.24-1.14). Comparable results were found for the other outcomes assessed. CONCLUSIONS: Obesity is associated with significantly lower response rates to TNFi in patients with axSpA. PMID- 28724443 TI - Metagenomics of urban sewage identifies an extensively shared antibiotic resistome in China. AB - BACKGROUND: Antibiotic-resistant pathogens are challenging treatment of infections worldwide. Urban sewage is potentially a major conduit for dissemination of antibiotic resistance genes into various environmental compartments. However, the diversity and abundance of such genes in wastewater are not well known. METHODS: Here, seasonal and geographical distributions of antibiotic resistance genes and their host bacterial communities from Chinese urban sewage were characterized, using metagenomic analyses and 16S rRNA gene based Illumina sequencing, respectively. RESULTS: In total, 381 different resistance genes were detected, and these genes were extensively shared across China, with no geographical clustering. Seasonal variation in abundance of resistance genes was observed, with average concentrations of 3.27 * 1011 and 1.79 * 1012 copies/L in summer and winter, respectively. Bacterial communities did not exhibit geographical clusters, but did show a significant distance-decay relationship (P < 0.01). The core, shared resistome accounted for 57.7% of the total resistance genes, and was significantly associated with the core microbial community (P < 0.01). The core human gut microbiota was also strongly associated with the shared resistome, demonstrating the potential contribution of human gut microbiota to the dissemination of resistance elements via sewage disposal. CONCLUSIONS: This study provides a baseline for investigating environmental dissemination of resistance elements and raises the possibility of using the abundance of resistance genes in sewage as a tool for antibiotic stewardship. PMID- 28724444 TI - Adaptation effects in static postural control by providing simultaneous visual feedback of center of pressure and center of gravity. AB - BACKGROUND: The benefit of visual feedback of the center of pressure (COP) on quiet standing is still debatable. This study aimed to investigate the adaptation effects of visual feedback training using both the COP and center of gravity (COG) during quiet standing. METHODS: Thirty-four healthy young adults were divided into three groups randomly (COP + COG, COP, and control groups). A force plate was used to calculate the coordinates of the COP in the anteroposterior (COPAP) and mediolateral (COPML) directions. A motion analysis system was used to calculate the coordinates of the center of mass (COM) in both directions (COMAP and COMML). The coordinates of the COG in the AP direction (COGAP) were obtained from the force plate signals. Augmented visual feedback was presented on a screen in the form of fluctuation circles in the vertical direction that moved upward as the COPAP and/or COGAP moved forward and vice versa. The COP + COG group received the real-time COPAP and COGAP feedback simultaneously, whereas the COP group received the real-time COPAP feedback only. The control group received no visual feedback. In the training session, the COP + COG group was required to maintain an even distance between the COPAP and COGAP and reduce the COGAP fluctuation, whereas the COP group was required to reduce the COPAP fluctuation while standing on a foam pad. In test sessions, participants were instructed to keep their standing posture as quiet as possible on the foam pad before (pre-session) and after (post-session) the training sessions. RESULTS: In the post-session, the velocity and root mean square of COMAP in the COP + COG group were lower than those in the control group. In addition, the absolute value of the sum of the COP - COM distances in the COP + COG group was lower than that in the COP group. Furthermore, positive correlations were found between the COMAP velocity and COP COM parameters. CONCLUSIONS: The results suggest that the novel visual feedback training that incorporates the COPAP-COGAP interaction reduces postural sway better than the training using the COPAP alone during quiet standing. That is, even COPAP fluctuation around the COGAP would be effective in reducing the COMAP velocity. PMID- 28724445 TI - Sustained benefit from combined plasmapheresis and allogeneic mesenchymal stem cells transplantation therapy in systemic sclerosis. AB - BACKGROUND: Systemic sclerosis (SSc) is an autoimmune disease involving the skin and several internal organs. Most therapies available for this disease are symptomatic. Given the difficulty in treating SSc, we conducted this study to investigate the effect of combined plasmapheresis (PE) and allogeneic mesenchymal stem cells transplantation (MSCT) therapy on SSc. METHODS: Fourteen patients underwent three repeated PE treatments with subsequent pulse cyclophosphamide on days 1, 3 and 5. Patients received a single MSCT (1 * 106 cells/kg of body weight) on day 8. During follow up, evaluations performed included complete physical examination, serologic testing, and organ function. RESULTS: The mean modified Rodnan skin score (MRSS) improved from 20.1 +/- 3.1 to 13.8 +/- 10.2 (P < 0.001) at 12 months of follow up. Three patients had interstitial lung disease, all had improvement of lung function and improved computed tomography (CT) images after 12 months of combined therapy. This combined treatment also significantly decreased the anti-Scl70 autoantibody titer and serum transforming growth factor beta and vascular endothelial growth factor levels during follow up. CONCLUSION: The results indicate that PE combined with MSCT is a feasible treatment associated with possible clinical benefit for SSc patients. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00962923 . Registered on 19 August 2009. PMID- 28724447 TI - Blood donation practice and its associated factors among health professionals of University of Gondar Hospital, Northwest Ethiopia: a cross sectional study. AB - BACKGROUND: Blood donation has remained a challenge in developing countries, like Ethiopia. In Ethiopia there is a high reliance on family surrogate and waged blood donors which carries an attendant increased risk of transfusion transmissible infection. Health workers are expected to practice blood donation so as to create a good image to the public. A study on blood donation behavior may improve successful implementation of the blood donation programs. METHODS: An institution based cross-sectional study was deployed from January to June 2015. An aggregate of 427 health workers were included in the study by using simple random sampling technique. Data were collected by using pre tested and structured questionnaire via self-administrated method. Descriptive and summary statistics were employed. Bivariate and multiple logistic regressions were computed. Odds ratios and their 95% confidence intervals were calculated to determine the level of significance. RESULTS: A total of 427 participants were included in the final analysis (response rate = 100%). Among these participants, 33.2% of them practice blood donation. Age above 25 years [AOR = 1.8 (95% CI 1.1, 3.0)], health professionals' knowledge of blood donation [AOR = 1.9 (95% CI 1.1, 3.1)], health professionals' attitude towards blood donation [AOR = 3.0, 95% CI 1. 8, 4.9)], and the presence of family members or relatives who received blood [AOR = 5.4, 95% CI 3.7, 8.7)] were significantly and independently associated with blood donation behavior of health professionals. CONCLUSIONS: Blood donation practice of health professionals in this study was found to be low as compared to other studies conducted in developing countries. Health professionals' knowledge, attitude, age and the presence of family members or relatives who received blood before were independently associated with blood donation practice. Thus, awareness has to be created for health professionals to improve blood donation practices. PMID- 28724446 TI - Economic burden of malaria inpatients during National Malaria Elimination Programme: estimation of hospitalization cost and its inter-province variation. AB - BACKGROUND: Apart from its direct impact on public health and well-being, malaria had placed significant socioeconomic burden on both individuals and whole health systems. This study was conducted to investigate the hospitalization cost of malaria and explore the inter-province variation during the National Malaria Elimination Programme in China. METHODS: Information on medical expenditure for malaria treatment was extracted from inpatient medical records in Henan, Hainan and Guangxi Province. The costs were adjusted to the price in 2014 and converted to USD (United States Dollars). Non-parametric and parametric methods were employed to estimate hospitalization costs and non-parametric bootstrap method was used for the comparison of hospitalization costs among sample provinces and to estimate the uncertainty of differences in inter-province hospitalization costs. RESULTS: The hospitalization cost and daily cost of 426 malaria inpatients were 929.8 USD and 143.12 USD respectively. The average length of stay was 11.95 days. The highest cost of hospitalization services occurred in tertiary hospitals (956 USD per episode). Whereas the lowest ones occurred in internal departments (424 USD). Medications, laboratory tests and supportive resources for treatment were the most important components of hospitalization costs, respectively responsible for 45.31, 24.70, and 20.09% of the total hospitalization costs. The hospitalization cost per episode in Henan Province was significantly higher than that in Hainan an in Guangxi Province, with incremental costs of 713 USD (95% confidence interval 419.70, 942.50) and of 735.58 USD (95% CI 606.50, 878.00), respectively. The differences in the daily costs between Henan and Hainan along with Guangxi provinces were 75.33 USD (95% CI 40.33, 96.67) and 93.56 USD (95% CI 83.58, 105.28), respectively. CONCLUSIONS: Although the prevalence of malaria cases has considerably declined, the direct hospitalization costs of malaria in the household remain high and the inter-province variations need to be seriously considered in the formulation the further interventions regarding hospitalization cost control. This study suggests that economic risk protection mechanisms targeting at malaria inpatients should be redesigned. The drug price addition policy in public hospitals should be gradually reformed or abolished coupling with increasing government subsidies along with the charges for treatment services to reduce the hospitalization cost. The policy for cost control in the provincial hospitals should be implemented in comparison with the policy in other provinces, where the status of economic and geography are similar. PMID- 28724448 TI - Systemic insecticide treatment of the canine reservoir of Trypanosoma cruzi induces high levels of lethality in Triatoma infestans, a principal vector of Chagas disease. AB - BACKGROUND: Despite large-scale reductions in Chagas disease prevalence across Central and South America, Trypanosoma cruzi infection remains a considerable public health problem in the Gran Chaco region where vector-borne transmission persists. In these communities, peridomestic animals are major blood-meal sources for triatomines, and household presence of infected dogs increases T. cruzi transmission risk for humans. To address the pressing need for field-friendly, complementary methods to reduce triatomine infestation and interrupt T. cruzi transmission, this study evaluated the systemic activity of three commercial, oral, single dose insecticides Fluralaner (Bravecto(r)), Afoxolaner (NexGard(r)) and Spinosad (Comfortis(r)) in canine feed-through assays against Triatoma infestans, the principal domestic vector species in the Southern Cone of South America. METHODS: Twelve healthy, outbred dogs were recruited from the Zoonosis Surveillance and Control Program in Santa Cruz, Bolivia, and randomized to three treatment groups, each containing one control and three treated dogs. Following oral drug administration, colony-reared second and third stage T. infestans instars were offered to feed on dogs for 30 min at 2, 7, 21, 34 and 51 days post treatment. RESULTS: Eighty-five per cent (768/907) of T. infestans successfully blood-fed during bioassays, with significantly higher proportions of bugs becoming fully-engorged when exposed to Bravecto(r) treated dogs (P < 0.001) for reasons unknown. Exposure to Bravecto(r) or NexGard(r) induced 100% triatomine mortality in fully- or semi-engorged bugs within 5 days of feeding for the entire follow-up period. The lethality effect for Comfortis(r) was much lower (50-70%) and declined almost entirely after 51 days. Instead Comfortis(r) treatment resulted in substantial morbidity; of these, 30% fully recovered whereas 53% remained morbid after 120 h, the latter subsequently unable to feed 30 days later. CONCLUSIONS: A single oral dose of Fluralaner or Afoxolaner was safe and well tolerated, producing complete triatomine mortality on treated dogs over 7.3 weeks. While both drugs were highly efficacious, more bugs exposed to Fluralaner took complete blood-meals, and experienced rapid knock-down. Coupled with its longer residual activity, Fluralaner represents an ideal insecticide for development into a complementary, operationally-feasible, community-level method of reducing triatomine infestation and potentially controlling T. cruzi transmission, in the Gran Chaco region. PMID- 28724450 TI - Variation in species composition and infection rates of Anopheles mosquitoes at different altitudinal transects, and the risk of malaria in the highland of Dirashe Woreda, south Ethiopia. AB - BACKGROUND: The transmission of malaria is heterogeneous, and varies due to altitude. The information on whether the transmission of malaria is indigenous or imported to highland areas is scarce. Therefore, this study aimed to assess the species composition and infection rates of Anopheles at different altitudinal transects, and the risk of malaria if any in the highland of Dirashe Woreda, South Ethiopia. METHODS: This study was conducted in Gato (low altitude; average elevation of 1273 m), Onota (mid-altitude; average elevation of 1707 m) and Layignaw-Arguba (high altitude; average elevation of 2337 m) from August 2015 to April 2016. Anopheles mosquitoes were sampled using Centers for Disease Control and Prevention (CDC) light traps from thirty houses (ten houses from each village). The circum-sporozoite proteins (CSPs) rate and entomological inoculation rate (EIR) of Anopheles mosquitoes were estimated. For the epidemiological survey, malaria cases were collected from laboratory registration books of selected health facilities from (August 2015-April 2016). A cross sectional survey was done to collect data on malaria vector control activities in each village (August-September 2015). RESULTS: One thousand two hundred sixty eight Anopheles mosquitoes comprising Anopheles arabiensis, An. demeilloni, An. cinereus, An. pharoensis, An. funestus-group, An. pretoriensis, An. christyi, An. ardensis and An. tenebrosus were identified in the study area. Anopheles arabiensis was the dominant species in Gato, whereas An. demeilloni was the dominant species in Layignaw-Arguba. Five mosquitoes, three An. arabiensis from Gato and two An. demeilloni from Layignaw-Arguba, were positive for Plasmodium falciparum CSPs. Plasmodium falciparum CSP rate was 0.4% (95% CI: 0.08-1.15) for An. arabiensis in Gato, and it was 0.64% (95% CI: 0.08-2.3) for An. demeilloni from Layignaw-Arguba. The P. falciparum EIR of An. arabiensis was 8.6 (95% CI: 2.4-33.4) infectious bites/person/nine-months in Gato. Plasmodium falciparum parasite was dominant in Gato (88%) and Onota (57.5%), whereas in Layignaw-Arguba P. vivax (59.4%) occurred most frequently. Increased malaria cases were observed in children age 5-14 years in Gato (P < 0.05), whereas in Onota and Layignaw Arguba there was no statistically significant difference in malaria cases among the age groups. Households owning at least one long lasting insecticidal net were 92.7% in the study area, and 77.6% slept under the net during the preceding night of the survey. About 64.4% of the households in Gato were protected by the indoor residual spray. However, the spraying was done when the density of local malaria vectors was low. CONCLUSION: Incrimination of Plasmodium CSP positive Anopheles species and the presence of malaria in children under five years in high altitude Layignaw-Arguba may justify the existence of indigenous malaria transmission and the need for effective malaria control. Further investigation and confirmation using more sensitive molecular techniques are however needed to consider An. demeilloni as a proven vector of malaria in Ethiopia. PMID- 28724451 TI - WHY DO SOCIETIES WITH HIGHER AVERAGE COGNITIVE ABILITY HAVE LOWER INCOME INEQUALITY? THE ROLE OF REDISTRIBUTIVE POLICIES. AB - SummaryPast studies suggest that, across nations, the average cognitive ability of a population is negatively associated with income inequality; societies with higher average cognitive ability tend to have lower levels of income inequality. However, it is not clear why. This paper proposes that social transfers from the wealthy to the poor may be a major mechanism by which some societies achieve lower income inequality than others, because more intelligent individuals may be more likely to have a preference for such transfers. Publicly available societal level data were analysed in a series of multiple regression models. The empirical results in this study replicate the earlier finding that societies with higher cognitive ability have lower levels of income inequality, but the association is entirely mediated by social transfers. Social transfers therefore appear to be the primary mechanism by which societies with higher levels of cognitive ability achieve lower income inequality. PMID- 28724452 TI - Exercise, energy expenditure and energy balance, as measured with doubly labelled water. AB - The doubly labelled water method for the measurement of total daily energy expenditure (TDEE) over 1-3 weeks under daily living conditions is the indicated method to study effects of exercise and extreme environments on energy balance. Subjects consume a measured amount of doubly labelled water (2H2 18O) to increase background enrichment of body water for 18O and 2H, and the subsequent difference in elimination rate between 18O and 2H, as measured in urine, saliva or blood samples, is a measure for carbon dioxide production and thus allows calculation of TDEE. The present review describes research showing that physical activity level (PAL), calculated as TDEE (assessed with doubly labelled water) divided by resting energy expenditure (REE, PAL = TDEE/REE), reaches a maximum value of 2.00 2.40 in subjects with a vigorously active lifestyle. Higher PAL values, while maintaining energy balance, are observed in professional athletes consuming additional energy dense foods to compete at top level. Exercise training can increase TDEE/REE in young adults to a value of 2.00-2.40, when energy intake is unrestricted. Furthermore, the review shows an exercise induced increase in activity energy expenditure can be compensated by a reduction in REE and by a reduction in non-exercise physical activity, especially at a negative energy balance. Additionally, in untrained subjects, an exercise-induced increase in activity energy expenditure is compensated by a training-induced increase in exercise efficiency. PMID- 28724449 TI - Novel promoters and coding first exons in DLG2 linked to developmental disorders and intellectual disability. AB - BACKGROUND: Tissue-specific integrative omics has the potential to reveal new genic elements important for developmental disorders. METHODS: Two pediatric patients with global developmental delay and intellectual disability phenotype underwent array-CGH genetic testing, both showing a partial deletion of the DLG2 gene. From independent human and murine omics datasets, we combined copy number variations, histone modifications, developmental tissue-specific regulation, and protein data to explore the molecular mechanism at play. RESULTS: Integrating genomics, transcriptomics, and epigenomics data, we describe two novel DLG2 promoters and coding first exons expressed in human fetal brain. Their murine conservation and protein-level evidence allowed us to produce new DLG2 gene models for human and mouse. These new genic elements are deleted in 90% of 29 patients (public and in-house) showing partial deletion of the DLG2 gene. The patients' clinical characteristics expand the neurodevelopmental phenotypic spectrum linked to DLG2 gene disruption to cognitive and behavioral categories. CONCLUSIONS: While protein-coding genes are regarded as well known, our work shows that integration of multiple omics datasets can unveil novel coding elements. From a clinical perspective, our work demonstrates that two new DLG2 promoters and exons are crucial for the neurodevelopmental phenotypes associated with this gene. In addition, our work brings evidence for the lack of cross annotation in human versus mouse reference genomes and nucleotide versus protein databases. PMID- 28724454 TI - Long-Term Care Facility (LTCF) Residents Colonized With Multidrug-Resistant (MDR) Klebsiella pneumoniae Lineages Frequently Causing Infections in Portuguese Clinical Institutions. PMID- 28724453 TI - Decrease in Vancomycin-Resistant Enterococcus Colonization After Extensive Renovation of a Unit Dedicated to the Treatment of Hematologic Malignancies and Hematopoietic Stem-Cell Transplantation. AB - OBJECTIVE While a direct relation between hospital construction and concomitant infection rates has been clearly established, few data are available regarding the environmental decontamination effects of renovation in which surfaces are replaced and regarding subsequent infection incidence. DESIGN Retrospective clinical study with vancomycin-resistant Enterococcus (VRE) molecular strain typing and environmental cultures. SETTING A regional referral center for acute leukemia and hematopoietic stem-cell transplantation. PATIENTS Overall, 536 consecutive hospital admissions for newly diagnosed acute leukemia or a first autologous or allogeneic stem-cell transplantation were reviewed. INTERVENTION During 2009-2010, our unit underwent complete remodeling including replacement of all surfaces. We assessed the effects of this construction on the incidence of hospital-acquired VRE colonization before, during, and after the renovation. RESULTS We observed a sharp decrease in VRE colonization rates (hazard ratio, <0.23; 95% confidence interval, 0.18-0.44; P<.0001) during the first year after the renovation, with a return to near baseline rates thereafter. The known risk factors for VRE colonization appeared to be stable over the study interval. Environmental cultures outside of patient rooms revealed several contaminated areas that are commonly touched by unit personnel. Multilocus sequence typing of VRE isolates that were cryopreserved over the study interval showed that dominant strains prior to construction disappeared and were replaced by other strains after the renovation. CONCLUSIONS Unit reconstruction interrupted endemic transmission of VRE, which resumed with novel strains upon reopening. Contamination of environmental surfaces and shared equipment may play an important role in endemic transmission of VRE. Infect Control Hosp Epidemiol 2017;38:1055-1061. PMID- 28724455 TI - A seroprevalence study to determine the frequency of hantavirus infection in people exposed to wild and pet fancy rats in England. AB - Recent cases of acute kidney injury due to Seoul hantavirus infection from exposure to wild or pet fancy rats suggest this infection is increasing in prevalence in the UK. We conducted a seroprevalence study in England to estimate cumulative exposure in at-risk groups with contact with domesticated and wild rats to assess risk and inform public health advice. From October 2013 to June 2014, 844 individual blood samples were collected. Hantavirus seroprevalence amongst the pet fancy rat owner group was 34.1% (95% CI 23.9-45.7%) compared with 3.3% (95% CI 1.6-6.0) in a baseline control group, 2.4% in those with occupational exposure to pet fancy rats (95% CI 0.6-5.9) and 1.7% with occupational exposure to wild rats (95% CI 0.2-5.9). Variation in seroprevalence across groups with different exposure suggests that occupational exposure to pet and wild rats carries a very low risk, if any. However incidence of hantavirus infection among pet fancy rat owners/breeders, whether asymptomatic, undiagnosed mild viral illness or more severe disease may be very common and public health advice needs to be targeted to this at-risk group. PMID- 28724456 TI - Identifying dietary differences between Scotland and England: a rapid review of the literature. AB - OBJECTIVE: Rates of premature mortality have been higher in Scotland than in England since the 1970s. Given the known association of diet with chronic disease, the study objective was to identify and synthesise evidence on current and historical differences in food and nutrient intakes in Scotland and England. DESIGN: A rapid review of the peer-reviewed and grey literature was carried out. After an initial scoping search, Medline, CINAHL, Embase and Web of Science were searched. Relevant grey literature was also included. Inclusion criteria were: any date; measures of dietary intake; representative populations; cross-sectional or observational cohort studies; and English-language publications. Study quality was assessed using the Quality Assessment Tool for Observational Cohort and Cross sectional Studies. A narrative synthesis of extracted information was conducted. RESULTS: Fifty publications and reports were included in the review. Results indicated that children and adults in Scotland had lower intakes of vegetables and vitamins compared with those living in England. Higher intakes of salt in Scotland were also identified. Data were limited by small Scottish samples, difficulty in finding England-level data, lack of statistical testing and adjustment for key confounders. CONCLUSIONS: Further investigation of adequately powered and analysed surveys is required to examine more fully dietary differences between Scotland and England. This would provide greater insight into potential causes of excess mortality in Scotland compared with England and suitable policy recommendations to address these inequalities. PMID- 28724457 TI - The association between food insecurity and academic achievement in Canadian school-aged children. AB - OBJECTIVE: Education is a crucial social determinant of health. Food insecurity can be detrimental to children's academic achievement, potentially perpetuating a cycle of poverty and food insecurity. We aimed to assess the relationship between food insecurity and academic achievement in Canadian school-aged children. DESIGN: Cross-sectional study of children and parents. Parents completed the short-form Household Food Security Survey Module and questions about income and education level (socio-economic status). Children completed FFQ. Data were prospectively linked to children's performance on standardized exams written one year later. Mixed-effect logistic regression was employed to assess the relationship between food insecurity and likelihood of meeting academic expectations adjusting for socio-economic status, diet quality and potential confounders. SETTING: Nova Scotia, Canada in 2011-2012. SUBJECTS: Students (n 4105) in grade 5 (10-11 years; 2167 girls) and their parents. RESULTS: Low food security was reported by 9.8 % of households; very low food security by 7.1 % of households. Students from low-income households and reporting poor diet quality were less likely to do well in school. Children who lived in households reporting very low food security had 0.65 times the odds (OR=0.65; 95 % CI 0.44, 0.96) of meeting expectations for reading and 0.62 times the odds (OR=0.62; 95 % CI 0.45, 0.86) of meeting expectations for mathematics. CONCLUSIONS: Very low household insecurity is associated with poor academic achievement among children in Nova Scotia. PMID- 28724458 TI - Clinical and therapeutic potential of protein kinase PKR in cancer and metabolism. AB - The protein kinase R (PKR, also called EIF2AK2) is an interferon-inducible double stranded RNA protein kinase with multiple effects on cells that plays an active part in the cellular response to numerous types of stress. PKR has been extensively studied and documented for its relevance as an antiviral agent and a cell growth regulator. Recently, the role of PKR related to metabolism, inflammatory processes, cancer and neurodegenerative diseases has gained interest. In this review, we summarise and discuss the involvement of PKR in several cancer signalling pathways and the dual role that this kinase plays in cancer disease. We emphasise the importance of PKR as a molecular target for both conventional chemotherapeutics and emerging treatments based on novel drugs, and its potential as a biomarker and therapeutic target for several pathologies. Finally, we discuss the impact that the recent knowledge regarding PKR involvement in metabolism has in our understanding of the complex processes of cancer and metabolism pathologies, highlighting the translational research establishing the clinical and therapeutic potential of this pleiotropic kinase. PMID- 28724459 TI - Characteristics of Enterobacteriaceae Isolates Coharboring Distinct Carbapenemase Genes. PMID- 28724460 TI - Health and well-being promotion strategies for 'hard to reach' older people in England: a mapping exercise. AB - BACKGROUND: Older people from deprived areas, the oldest old and those from ethnic minorities engage less in health promotion interventions and related research, potentially generating inequities. Aim To explore and map the extent to which such 'hard to reach' groups of older people, are the focus of local health and well-being strategies in England. METHODS: Document analysis of current health and well-being promotion strategies in a purposive sample of 10 localities in England with high proportions of some or all of the three hard to reach groups. Documents were analysed using an interpretive approach. Findings A total of 254 documents were retrieved and reviewed. Much of the content of the documents was descriptive and reported the implications for resources/services of population ageing rather than actual initiatives. All localities had an Older People's Strategy. Strategies to counter deprivation included redistribution of winter fuel payments, income maximisation, debt reduction and social inclusion initiatives, a focus on older owner occupiers and recruitment of village 'agents' to counter rural deprivation. The needs of the oldest old were served by integrated services for older people, a community alarm service with total coverage of the 85+ population, and dietary advice. The needs of black and minority ethnic (BME) older people were discussed in all localities and responses included community work with BME groups, attention to housing needs and monitoring of service use by BME older people. Three other themes that emerged were: use of telecare technologies; a challenge to the idea of 'hard to reach' groups; and outreach services to those at most risk. CONCLUSIONS: Document analysis revealed a range of policy statements that may indicate tailoring of policy and practice to local conditions, the salience of national priorities, some innovative local responses to policy challenges and even dissenting views that seek to redefine the policy problem. PMID- 28724461 TI - Tuberculous otitis media: a resurgence? AB - OBJECTIVE: Tuberculosis is a global health problem that is especially prevalent in developing countries such as India. Recently, atypical presentation has become more common and a high index of suspicion is essential. This study analysed the various presenting symptoms and signs of tuberculous otitis media and the role of diagnostic tests, with the aim of formulating criteria for the diagnosis. METHODS: A total of 502 patients underwent tympanomastoidectomy over a two-year period. Microbiological and histopathological examinations and polymerase chain reaction analysis of tissue taken during tympanomastoidectomy were performed. RESULTS: A total of 25 patients (5 per cent) were diagnosed with tuberculous otitis media. Severe mixed hearing loss, facial palsy, labyrinthine fistula, post aural fistula, perichondritis and extradural abscess were noted. CONCLUSION: There seems to be a resurgence in tuberculous otitis media in India. Microbiological, histopathological and polymerase chain reaction tests for tuberculosis are helpful for its diagnosis. PMID- 28724462 TI - Longitudinal analyses of correlated response efficiencies of fillet traits in Nile tilapia. AB - Recent studies with Nile tilapia have shown divergent results regarding the possibility of selecting on morphometric measurements to promote indirect genetic gains in fillet yield (FY). The use of indirect selection for fillet traits is important as these traits are only measurable after harvesting. Random regression models are a powerful tool in association studies to identify the best time point to measure and select animals. Random regression models can also be applied in a multiple trait approach to analyze indirect response to selection, which would avoid the need to sacrifice candidate fish. Therefore, the aim of this study was to investigate the genetic relationships between several body measurements, weight and fillet traits throughout the growth period and to evaluate the possibility of indirect selection for fillet traits in Nile tilapia. Data were collected from 2042 fish and was divided into two subsets. The first subset was used to estimate genetic parameters, including the permanent environmental effect for BW and body measurements (8758 records for each body measurement, as each fish was individually weighed and measured a maximum of six times). The second subset (2042 records for each trait) was used to estimate genetic correlations and heritabilities, which enabled the calculation of correlated response efficiencies between body measurements and the fillet traits. Heritability estimates across ages ranged from 0.05 to 0.5 for height, 0.02 to 0.48 for corrected length (CL), 0.05 to 0.68 for width, 0.08 to 0.57 for fillet weight (FW) and 0.12 to 0.42 for FY. All genetic correlation estimates between body measurements and FW were positive and strong (0.64 to 0.98). The estimates of genetic correlation between body measurements and FY were positive (except for CL at some ages), but weak to moderate (-0.08 to 0.68). These estimates resulted in strong and favorable correlated response efficiencies for FW and positive, but moderate for FY. These results indicate the possibility of achieving indirect genetic gains for FW and by selecting for morphometric traits, but low efficiency for FY when compared with direct selection. PMID- 28724463 TI - China's National Health Guiding Principles: a perspective worthy of healthcare reform. AB - For countries faced with much talk but little action on healthcare reform, China's National Health Guiding Principles (CNHGP), with its 60-year history, may provide a new perspective. There are four values of CNHGP for healthcare reform. First, these principles provide an innovative strategic framework for healthcare reform with three levels, from 'One priority population' to 'Four approaches' and then to 'Two aims.' The second is the importance of mass/grassroots participation, which runs through all three levels of CNHGP. The third value is that the CNHGP used nonspecific social approaches, an innovation in healthcare delivery that addressed the social determinants of health. The fourth value is the integration between Chinese traditional medicine and Western medicine. PMID- 28724464 TI - Refractory Longitudinally Extensive Transverse Myelitis Responsive to Cyclophosphamide. AB - Severe longitudinally extensive transverse myelitis (LETM) can cause quadriplegia, marked sensory dysfunction, and respiratory failure. Some patients are unresponsive to conventional immune therapy. We report two cases of severe immune-mediated LETM requiring intensive care admission that failed to respond to high-dose corticosteroids, plasma exchange, intravenous immunoglobulin, and rituximab. Disease cessation and significant recovery was achieved after cyclophosphamide induction. In patients with severe acute immune-mediated LETM who fail to respond to corticosteroids and plasma exchange, cyclophosphamide induction should be considered. This agent and regimen provides a robust immunosuppressive response and can be induced rapidly. Cyclophosphamide effects and supportive evidence are discussed. PMID- 28724465 TI - Visual speech fills in both discrimination and identification of non-intact auditory speech in children. AB - To communicate, children must discriminate and identify speech sounds. Because visual speech plays an important role in this process, we explored how visual speech influences phoneme discrimination and identification by children. Critical items had intact visual speech (e.g. baez) coupled to non-intact (excised onsets) auditory speech (signified by /-b/aez). Children discriminated syllable pairs that differed in intactness (i.e. baez:/-b/aez) and identified non-intact nonwords (/-b/aez). We predicted that visual speech would cause children to perceive the non-intact onsets as intact, resulting in more same responses for discrimination and more intact (i.e. baez) responses for identification in the audiovisual than auditory mode. Visual speech for the easy-to-speechread /b/ but not for the difficult-to-speechread /g/ boosted discrimination and identification (about 35-45%) in children from four to fourteen years. The influence of visual speech on discrimination was uniquely associated with the influence of visual speech on identification and receptive vocabulary skills. PMID- 28724466 TI - Home Environment as a Predictor of Long-Term Executive Functioning following Early Childhood Traumatic Brain Injury. AB - OBJECTIVES: This study examined the relationship of the home environment to long term executive functioning (EF) following early childhood traumatic brain injury (TBI). METHODS: Participants (N=134) were drawn from a larger parent study of 3- to 6-year-old children hospitalized for severe TBI (n=16), complicated mild/moderate TBI (n=44), or orthopedic injury (OI; n=74), recruited prospectively at four tertiary care hospitals in the United States and followed for an average of 6.8 years post-injury. Quality of the home environment, caregiver psychological distress, and general family functioning were assessed shortly after injury (i.e., early home) and again at follow-up (i.e., late home). Participants completed several performance-based measures of EF at follow-up. Hierarchical regression analyses examined the early and late home environment measures as predictors of EF, both as main effects and as moderators of group differences. RESULTS: The early and late home environment were inconsistent predictors of long-term EF across groups. Group differences in EF were significant for only the TEA-Ch Walk/Don't Walk subtest, with poorer performance in the severe TBI group. However, several significant interactions suggested that the home environment moderated group differences in EF, particularly after complicated mild/moderate TBI. CONCLUSIONS: The home environment is not a consistent predictor of long-term EF in children with early TBI and OI, but may moderate the effects of TBI on EF. The findings suggest that interventions designed to improve the quality of stimulation in children's home environments might reduce the long-term effects of early childhood TBI on EF. (JINS, 2018, 24, 11-21). PMID- 28724467 TI - Differential associations between sensory loss and neuropsychiatric symptoms in adults with and without a neurocognitive disorder. AB - BACKGROUND: To investigate the differential associations between sensory loss and neuropsychiatric symptoms among older adults with and without diagnosed neurocognitive disorder. METHODS: The sample comprised 1,393 adults (52.3% men) aged between 72 and 79 years from a community-based cohort study. There were 213 cases of mild and 64 cases of major neurocognitive disorders. The main outcome was number of informant reported symptoms on the Neuropsychiatric Inventory (NPI). Sensory loss was defined by visual acuity worse the 0.3 logMAR (6/12 or 20/40) and self-reported hearing problems. RESULTS: Clinically relevant NPI symptoms were reported in 182 (13.1%) participants, but no individual symptom occurred in more than 5% of the total sample. Among participants diagnosed with a major neurocognitive disorder, those with any sensory loss had over three times (95%CI: 1.72-11.78) greater rates of NPI symptoms than those with unimpaired levels of sensory functioning. There were no differences in the number of neuropsychiatric symptoms by type of sensory loss, and no additional risk associated with a dual sensory loss compared to a single sensory loss. There was no evidence of an association between sensory loss and number of neuropsychiatric symptoms among cognitively healthy adults. CONCLUSIONS: The extent to which this association is the result of underlying neuropathology, unmet need, or interpersonal factors is unclear. These findings have significant implications for dementia care settings, including hospitals and respite care, as patients with sensory loss are at increased risk of neuropsychiatric symptoms and may require additional psychosocial support. Interventions to manage sensory loss and reduce the impact of sensory limitations on neuropsychiatric symptoms are needed. PMID- 28724469 TI - Comorbidity indices: a call for the integration of physical and mental health. AB - Comorbidity indices are commonly used in health services research as a measure of, or as a control for, the severity of a person's medical state. Currently, there is not a comorbidity index for mental health diagnoses, despite the fact that almost half of Americans have a diagnosable mental health condition at least once in their lifetime. This commentary calls for the integration of mental and behavioral health in comorbidity indices to appropriately account for the role of mental health in overall morbidity and mortality. PMID- 28724468 TI - A combined high-sugar and high-saturated-fat dietary pattern is associated with more depressive symptoms in a multi-ethnic population: the HELIUS (Healthy Life in an Urban Setting) study. AB - OBJECTIVE: To identify a high-sugar (HS) dietary pattern, a high-saturated-fat (HF) dietary pattern and a combined high-sugar and high-saturated-fat (HSHF) dietary pattern and to explore if these dietary patterns are associated with depressive symptoms. DESIGN: We used data from the HELIUS (Healthy Life in an Urban Setting) study and included 4969 individuals aged 18-70 years. Diet was assessed using four ethnic-specific FFQ. Dietary patterns were derived using reduced rank regression with mono- and disaccharides, saturated fat and total fat as response variables. The nine-item Patient Health Questionnaire (PHQ-9) was used to assess depressive symptoms by using continuous scores and depressed mood (identified using the cut-off point: PHQ-9 sum score >=10). SETTING: The Netherlands. RESULTS: Three dietary patterns were identified; an HSHF dietary pattern (including chocolates, red meat, added sugars, high-fat dairy products, fried foods, creamy sauces), an HS dietary pattern (including sugar-sweetened beverages, added sugars, fruit (juices)) and an HF dietary pattern (including high-fat dairy products, butter). When comparing extreme quartiles, consumption of an HSHF dietary pattern was associated with more depressive symptoms (Q1 v. Q4: beta=0.18, 95 % CI 0.07, 0.30, P=0.001) and with higher odds of depressed mood (Q1 v. Q4: OR=2.36, 95 % CI 1.19, 4.66, P=0.014). No associations were found between consumption of the remaining dietary patterns and depressive symptoms. CONCLUSIONS: Higher consumption of an HSHF dietary pattern is associated with more depressive symptoms and with depressed mood. Our findings reinforce the idea that the focus should be on dietary patterns that are high in both sugar and saturated fat. PMID- 28724470 TI - Effect of glycerol supplementation during early lactation on milk yield, milk composition, nutrient digestibility and blood metabolites of dairy buffaloes. AB - This study was conducted to evaluate the effect of increasing levels of glycerol in the diet on milk yield and composition, diet digestibility and some blood metabolites of dairy buffaloes in early lactation. A total of 24 buffaloes were blocked by average milk yield, parity and BW and then randomly assigned to three treatments: control without glycerol (CON); low glycerol (LG): control plus glycerol at 150 ml/day per buffalo; and high glycerol (HG): control plus glycerol at 300 ml/day per buffalo. The experimental period lasted for 60 days. Feeding LG and HG decreased (P<0.0001) dry matter intake compared with the CON. Buffaloes supplemented with LG and HG produced more milk (P<0.01) and had a greater (P<0.0001) yield of fat-corrected milk (3.5%) than those buffaloes fed control treatment. Glycerol-supplemented buffaloes showed a positive energy status indicated by reduced concentrations of non-esterified fatty acids and beta hydroxybutyrate. Feeding LG and HG tended to increase (P?0.10) concentrations of milk fat, and serum total protein and globulin and significantly decreased (P?0.05) milk urea nitrogen and somatic cells counts (SCCs) compared to the CON group. Inclusion of LG and HG had no effect on organic matter and non-fiber carbohydrate digestion, but improved dry matter (P=0.02), CP (P=0.09), ether extract (P=0.03), NDF (P=0.07) and ADF (P=0.03) digestion. PMID- 28724471 TI - What influences diet quality in older people? A qualitative study among community dwelling older adults from the Hertfordshire Cohort Study, UK. AB - OBJECTIVE: To explore influences on diet in a group of community-dwelling older adults in the UK. DESIGN: Data were collected through focus group discussions with older people; discussions were audio-recorded, transcribed verbatim and transcripts analysed thematically. SETTING: Hertfordshire, UK. SUBJECTS: Participants were sampled purposively from the Hertfordshire Cohort Study, focusing on those whose diets had been assessed at two time points: 1998-2001 and 2011. RESULTS: Ninety-two adults participated (47 % women; 74-83 years) and eleven focus groups were held. A number of age-related factors were identified that were linked to food choices, including lifelong food experiences, retirement, bereavement and medical conditions, as well as environmental factors (such as transport). There appeared to be variability in how individuals responded to these influences, indicating that other underlying factors may mediate the effects of age-related factors on diet. Discussions about 'keeping going', being motivated to 'not give up', not wanting to be perceived as 'old', as well as examples of resilience and coping strategies, suggest the importance of mediating psychological factors. In addition, discussion about social activities and isolation, community spirit and loneliness, indicated the importance of social engagement as an influence on diet. CONCLUSIONS: Interventions to promote healthier diets in older age should take account of underlying psychological and social factors that influence diet, which may mediate the effects of age-related factors. PMID- 28724473 TI - Secondary cardiac cancer mimicking inferior ST elevation myocardial infarction - diagnosed using point-of-care ultrasound in the emergency department. PMID- 28724472 TI - Appraisal of the Preparedness of Midwives and Nurses in Bahrain to Conduct Early Screening for Zika Virus Infection in Pregnant Women. AB - OBJECTIVE: To appraise the awareness and knowledge levels of midwives and nurses concerning early screening for Zika virus (ZIKV) infection among pregnant women attending health care facilities in Bahrain. METHODS: This was a cross-sectional, purposely chosen study of Bahraini and expatriate midwives, nurses, and supervisors employed in gynecology/obstetrics and labor wards of Salmanya hospital, a maternity hospital, 4 private hospitals, and health centers in Bahrain. The chosen individuals were invited to participate in a survey on awareness and knowledge of early screening for ZIKV infection. RESULTS: Of 266 midwives and nurses employed in the study sites, 170 (64%) consented to participate in the study. Of those who agreed to participate, 76 were midwives and 94 were nurses. Admittedly, 39% of midwives and nurses were unaware of ZIKV infection. The grand mean knowledge score in the study was 39%. Expatriate midwives and nurses scored better than did Bahrainis (P<0.001). The grand mean knowledge scores of evening and night shift duty participants were significantly higher than those of the day duty participants. CONCLUSIONS: The awareness and knowledge scores of midwives and nurses concerning ZIKV infection were inadequate, which supported our hypothesis. By harnessing modern technology and support systems, lifelong learning can be used as a means to enhance preparedness for public health crises such as ZIKV. (Disaster Med Public Health Preparedness. 2018;12:7-13). PMID- 28724474 TI - Human behavioral influences and milk quality control programs. AB - Mastitis is a major disease affecting the herds of dairy farmers worldwide. One of the indicators directly related to the widespread infection of this disease in herds is the bulk tank somatic cell count (BTSCC). Recent studies have shown that one of the risk factors associated with mastitis is the human factor. Therefore, understanding the influence of humans is essential to control and prevent the disease. The main goal of this study was to determine whether the motivations and barriers perceived by farmers could explain the variation in the BTSCC. This study was conducted at 75 dairy farms in southern Brazil. In the interviews with farmers, a survey based on Likert scale items was used to collect data. Structural equation models were used to explain the subjectivity in the ratio of observed variables and latent variables elucidating the possible causal relationships between the variables. The model indicated that some of the variation in the BTSCC can be explained by the farmer's behavior, which is elucidated by his/her motivations and barriers. The correlations between motivations and the BTSCC and between barriers and the BTSCC were positive. These findings suggest that variations in the BTSCC can be explained by the motivations and barriers perceived by farmers and that the Fogg Behavior Model used in this study can be used to explain how human behaviors influence mastitis control. This study also indicates that consulting companies focused on improving milk quality should pay attention to the human factor to reduce these barriers. PMID- 28724475 TI - Blood profile and meat quality of Holstein-Friesian steers finished on total mixed ration or flaxseed oil-supplemented pellet mixed with reed canary grass haylage. AB - Holstein-Friesian steer beef production is renowned globally as a secondary product of the milk industry. Grass feeding is a common practice in raising Holstein steers because of its low cost. Furthermore, grass feeding is an alternative way to produce beef with a balanced n-6 to n-3 fatty acids (FAs) ratio. However, the performance and meat quality of Holstein-Friesian cattle is more likely to depend on a high-quality diet. The aim of this study was to observe whether feeding two mixed diets; a corn-based total mixed ration (TMR) with winter ryegrass (Lolium perenne) or flaxseed oil-supplemented pellets with reed canary grass haylage (n-3 mix) provided benefits on carcass weight, meat quality and FA composition compared with cattle fed with reed canary grass (Phalaris arundinacea) haylage alone. In all, 15 21-month-old Holstein-Friesian steers were randomly assigned to three group pens, were allowed free access to water and were fed different experimental diets for 150 days. Blood samples were taken a week before slaughter. Carcass weight and meat quality were evaluated after slaughter. Plasma lipid levels and aspartate aminotransferase (AST), gamma glutamyl transpeptidase (GGT), creatine kinase (CK) and alkaline phosphatase (ALP) activities were determined. Diet did not affect plasma triglyceride levels and GGT activity. Plasma cholesterol levels, including low-density and high density lipoproteins, were higher in both mixed-diet groups than in the haylae group. The highest activities of plasma AST, CK and ALP were observed in the haylage group, followed by n-3 mix and TMR groups, respectively. Carcass weight was lower in the haylage group than in the other groups and no differences were found between the TMR and n-3 mix groups. Although the n-3 mix-fed and haylage fed beef provided lower n-6 to n-3 FAs ratio than TMR-fed beef, the roasted beef obtained from the TMR group was more acceptable with better overall meat physicochemical properties and sensory scores. According to daily cost, carcass weight and n-6 to n-3 FAs ratio, the finishing diet containing flaxseed oil supplemented pellets and reed canary grass haylage at the as-fed ratio of 40 : 60 could be beneficial for the production of n-3-enriched beef. PMID- 28724477 TI - Oliver Sacks: Our Correspondence About Twins/Twin Research: Vanishing Twins Syndrome; Discordant Sex in MZ Twins; Pregnancy Outcomes in IVF and ICSI Conceived Twins/Print and Media: Superfetated Twins; Twins Discordant for Smoking; Twins in Fashion; Yale University Twin Hockey Players; Conjoined Twin Visiting Professor. AB - The late neurologist and author, Oliver Sacks, published an insightful 1986 review of Marjorie Wallace's book, The Silent Twins, in the New York Times. Taking exception to his assertion about Sir Francis Galton, I wrote a letter to the Times' editor. The letter was unpublished, but it brought a wonderful response from Sacks himself that is reproduced and examined. Next, brief reviews of twin research concerning the vanishing twin syndrome (VTS), discordant sex in a monozygotic (MZ) twin pair, and multiple pregnancy outcomes from assisted reproductive technology (ART) are presented. This section is followed by popular coverage of superfetated twins, smoking-discordant co-twins, twins in fashion, Yale University twin hockey players, and a visiting professor who was a conjoined twin. PMID- 28724478 TI - The STOPPA Twin Study Explains the Exhaled Nitric Oxide and Asthma Link by Genetics and Sensitization. AB - BACKGROUND: The link between asthma and exhaled nitric oxide (FENO) is not completely understood. The aim of this study was to estimate the association between FENO and asthma, taking genetics, sensitization, and inhaled corticosteroids (ICS) into account. METHODS: A total of 681 twins (53% monozygotic [MZ] and 47% dizygotic [DZ]) from the population-based STOPPA study (mean age 12.6 years) were recruited and information on FENO (parts per billion), parental report of current asthma, sensitization to airborne allergens (Phadiatop; IgE >=0.35 kUA/l), and ICS-treatment was collected. We estimated the association between FENO and asthma, sensitization, and ICS in all twins and within pairs (DZ and MZ) to address shared genetic and environmental factors. Linear regression of log-transformed FENO was used and results presented as exponentiated regression coefficients (exp[beta]), with 95% confidence interval (CI). RESULTS: We found an association between asthma and FENO in all twins, exp(beta) 1.31 [1.11, 1.54]. In within-pairs analysis, the association was stronger within DZ pairs discordant for FENO, exp(beta) 1.50 [1.19, 1.89], compared to MZ pairs, exp(beta) 1.07 [0.84, 1.37], p = .049. There was no difference in FENO in non-sensitized children with asthma, compared to children with neither asthma nor sensitization, exp(beta) 0.89 [0.77, 1.03]. However, increased FENO was associated with sensitization, exp(beta) 1.48 [1.30, 1.69], and with sensitization together with asthma, exp(beta) 1.98 [1.57, 2.51], in all twins and within DZ pairs discordant for FENO, but not in MZ pairs. The FENO asthma association remained in DZ pairs without regular ICS-treatment. CONCLUSIONS: The association between FENO and asthma is explained by genetics and sensitization. PMID- 28724479 TI - Holocene Selection for Variants Associated With General Cognitive Ability: Comparing Ancient and Modern Genomes. AB - Human populations living during the Holocene underwent considerable microevolutionary change. It has been theorized that the transition of Holocene populations into agrarianism and urbanization brought about culture-gene co evolution that favored via directional selection genetic variants associated with higher general cognitive ability (GCA). To examine whether GCA might have risen during the Holocene, we compare a sample of 99 ancient Eurasian genomes (ranging from 4.56 to 1.21 kyr BP) with a sample of 503 modern European genomes (Fst = 0.013), using three different cognitive polygenic scores (130 SNP, 9 SNP and 11 SNP). Significant differences favoring the modern genomes were found for all three polygenic scores (odds ratios = 0.92, p = 001; .81, p = 037; and .81, p = .02 respectively). These polygenic scores also outperformed the majority of scores assembled from random SNPs generated via a Monte Carlo model (between 76.4% and 84.6%). Furthermore, an indication of increasing positive allele count over 3.25 kyr was found using a subsample of 66 ancient genomes (r = 0.22, pone tailed = .04). These observations are consistent with the expectation that GCA rose during the Holocene. PMID- 28724480 TI - Neuroticism and the Overlap Between Autistic and ADHD Traits: Findings From a Population Sample of Young Adult Australian Twins. AB - Neuroticism, a 'Big Five' personality trait, has been associated with sub clinical traits of both autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD). The objective of the current study was to examine whether causal overlap between ASD and ADHD traits can be accounted for by genetic and environmental risk factors that are shared with neuroticism. We performed twin-based structural equation modeling using self-report data from 12 items of the Neo Five-Factor Inventory Neuroticism domain, 11 Social Responsiveness Scale items, and 12 Adult ADHD Self-Report Scale items obtained from 3,170 young adult Australian individual twins (1,081 complete pairs). Univariate analysis for neuroticism, ASD, and ADHD traits suggested that the most parsimonious models were those with additive genetic and unique environmental components, without sex limitation effects. Heritability of neuroticism, ASD, and ADHD traits, as measured by these methods, was moderate (between 40% and 45% for each respective trait). In a trivariate model, we observed moderate phenotypic (between 0.45 and 0.62), genetic (between 0.56 and 0.71), and unique environmental correlations (between 0.37and 0.55) among neuroticism, ASD, and ADHD traits, with the highest value for the shared genetic influence between neuroticism and self-reported ASD traits (r g = 0.71). Together, our results suggest that in young adults, genetic, and unique environmental risk factors indexed by neuroticism overlap with those that are shared by ASD and ADHD. PMID- 28724484 TI - Echocardiographic Parameters of Clinically Normal Geriatric Rhesus Macaques (Macacamulatta). AB - The goal of this study was to generate reference intervals for echocardiographic variables in a population of clinically normal geriatric rhesus macaques (Macaca mulatta). To do this, we studied 51 animals (age, 18-29 y; weight, 5.24-17.04 kg). The normal values for cardiac indices, including geometry and systolic and diastolic function, were determined by 2D, M-mode, spectral Doppler, and tissue Doppler echocardiography under ketamine hydrochloride sedation. Statistical correlations between the echocardiographic parameters and age, body weight, sex, and heart rate were investigated. All echocardiographic indices were acquired, and their reference intervals were established. Multiple weak to strong correlations emerged between variables and echocardiographic parameters, but no moderate or strong correlations between body weight or sex and these parameters were noted. Of the 51 geriatric rhesus macaques evaluated, 36 (71%) fulfilled the criteria for diastolic dysfunction. Valve regurgitation, especially tricuspid regurgitation (43%), and aortic regurgitation (51%) also were common in geriatric rhesus macaques. Although these findings merit follow-up, they are unlikely to have clinical significance given their prevalence in these apparently healthy animals. PMID- 28724483 TI - Using White-tailed Deer (Odocoileus virginianus) in Infectious Disease Research. AB - Between 1940 and 2004, more than 335 emerging infectious disease events were reported in the scientific literature. The majority (60%) of these events involved zoonoses, most of which (72%) were of wildlife origin or had an epidemiologically important wildlife host. Because this trend of increasing emerging diseases likely will continue, understanding the pathogenesis, transmission, and diagnosis of these diseases in the relevant wildlife host is paramount. Achieving this goal often requires using wild animals as research subjects, which are vastly different from the traditional livestock or laboratory animals used by most universities and institutions. Using wildlife in infectious disease research presents many challenges but also provides opportunities to answer questions impossible to address by using traditional models. Cervid species, especially white-tailed deer (Odocoileus virginianus), elk (Cervus canadensis), and red deer (Cervus elaphus), are hosts or sentinels for several important pathogens, some of which are zoonotic. The long history of infectious disease research using white-tailed deer, conducted at ever-increasing levels of sophisticated biosecurity, demonstrates that this type of research can be conducted safely and that valuable insights can be gained. The greatest challenges to using wildlife in infectious disease research include animal source, facility design, nutrition, animal handling, and enrichment and other practices that both facilitate animal care and enhance animal wellbeing. The study of Mycobacterium bovis infection in white-tailed deer at the USDA's National Animal Disease Center serves to illustrate one approach to address these challenges. PMID- 28724485 TI - Effects of Breeding Configuration on Maternal and Weanling Behavior in Laboratory Mice. AB - Although numerous studies have evaluated the effect of housing density on the wellbeing of laboratory mice, little is known about the effect of breeding configuration on mouse behavior. The 8th edition of the Guide for the Care and Use of Laboratory Animals lists the recommended minimal floor area per animal for a female mouse and her litter as 51 in.2 We sought to determine the effects of pair, trio, and harem breeding configurations on the maternal and weanling behavior of C57BL/6J (B6) and 129S6/SvEvTac (129) mice on the basis of nest scores and performance in pup retrieval tests, open-field test (OFT), elevated plus maze, and tail suspension test; we concurrently evaluated cage microenvironment, reproductive indices, and anatomic and clinical pathology. Harem breeding configurations enhanced B6 maternal behaviors as evidenced by significantly shorter pup retrieval times. Trio- and harem-raised B6 weanlings showed increased exploratory behaviors, as evidenced by greater time spent in the center of the OFT, when compared with pair-raised B6 mice. Conversely, breeding configuration did not alter pup retrieval times for 129 mice, and on the day of weaning trio- and harem-raised 129 mice demonstrated increased anxiety-like behavior, as evidenced by greater time spent in the periphery of the OFT, when compared with pair-raised counterparts. Behavioral differences were not noted on subsequent days for either strain. Trio- and harem-raised B6 and 129 weanling mice had significantly higher weaning weights than weanlings raised in a pair breeding configuration. Trio and harem breeding in a standard 67-in.2 shoebox cage did not detrimentally affect the evaluated welfare parameters in either C57BL/6J or 129S6/SvEvTac mice. PMID- 28724486 TI - Behavioral Characteristics of Adult Zebrafish (Danio rerio) after MS222 Anesthesia for Fin Excision. AB - The health of laboratory animals is an ethical responsibility of researchers and a critical determinant of experimental outcome. Therefore, all husbandry procedures should be evaluated for their effects on mortality, behavior, and physiology to maximize animal welfare and minimize experimental variability. For adult zebrafish, the excision of a small portion of the caudal fin (that is, 'fin clipping') under MS222 anesthesia is a common procedure to obtain tissue for genotyping. The potential effect of this procedure on behavioral and physiologic assays of feeding, anxiety, and stress has not previously been assessed. Here, we evaluated feeding behavior, anxiety-associated behaviors, and physiologic indicators of stress at multiple time points within 24 h after performing a standard fin-clip procedure under MS222 anesthesia. Within 1 h of the procedure, fin-clipped fish showed a mild increase in anxiety and exhibited reduced feeding; however, these effects were short-lived, and the fish exhibited baseline levels of anxiety and feeding by 6 and 24 h after fin clipping. Together with the zebrafish's ability to regenerate fin tissue and the low mortality associated with fin clipping, our data support the continued practice of this technique under MS222 anesthesia as a routine husbandry procedure that is unlikely to alter experimental outcomes related to feeding, anxiety, or stress. PMID- 28724487 TI - Effect of Wearing a Telemetry Jacket on Behavioral and Physiologic Parameters of Dogs in the Open-Field Test. AB - Safety pharmacology studies in dogs often integrate behavioral assessments made using video recording with physiologic measurements collected by telemetry. However, whether merely wearing the telemetry vest affects canine behavior and other parameters has not been evaluated. This pilot study assessed the effect of a telemetry vest on behavioral and physiologic responses to an environmental stressor, the sounds of a thunderstorm, in Labrador retrievers. Dogs were assigned to one of 2 experimental groups (Vest and No-Vest, n = 8 dogs per group) by using a matched pairs design, with a previously determined, sound-associated anxiety score as the blocking variable. Dogs were individually retested with the same standardized sound stimulus (thunderstorm) in an open-field arena, and their behavioral responses were video recorded. Video analysis of locomotor activity and anxiety-related behavior and manual determination of heart rate and body temperature were performed; results were compared between groups. Vest wearing did not affect total locomotor activity or rectal body temperature but significantly decreased heart rate by 8% and overall mean anxiety score by 34% during open-field test sessions. Our results suggest that the use of telemetry vests in dogs influences the measurement of physiologic parameters and behaviors that are assessed in safety pharmacology studies. PMID- 28724488 TI - Genetic Characterization of a Captive Colony of Pigtailed Macaques (Macaca nemestrina). AB - Effective colony management is critical to guarantee the availability of captive NHP as subjects for biomedical research. Pigtailed macaques (Macaca nemestrina) are an important model for the study of human and nonhuman primate diseases and behavior. Johns Hopkins University hosts one of the largest captive colonies of pigtailed macaques in the United States. In this study, we used 56 single nucleotide polymorphisms (SNP) to characterize this population of pigtailed macaques, understand their population structure, and assess the effectiveness of their colony management. The results demonstrate that the colony has maintained a high level of genetic diversity, with no loss of heterozygosity since its origin, and low levels of inbreeding and genetic subdivision. PMID- 28724489 TI - Population Genetic Structure of the Cayo Santiago Colony of Rhesus Macaques (Macaca mulatta). AB - The rhesus macaque population at Cayo Santiago increases annually and is in urgent need of control. In-depth assessments of the colony's population genetic and pedigree structures provide a starting point for improving the colony's long term management program. We evaluated the degree of genetic variation and coefficients of inbreeding and kinship of the Cayo Santiago colony by using pedigree and short tandem repeat (STR) data from 4738 rhesus macaques, which represent 7 extant social groups and a group of migrant males. Information on each animal's parentage, sex, birth date, and date of death or removal from the island were used to generate estimates of mean kinship, kinship value, gene value, genome uniqueness (GU), founder equivalents (fe), and founder genome equivalents (fg). Pedigree and STR analyses revealed that the social groups have not differentiated genetically from each other due to male-mediated gene flow (that is, FST estimates were in the negative range) and exhibit sufficient genetic variation, with mean estimates of allele numbers and observed and expected heterozygosity of 6.57, 0.72, and 0.70, respectively. Estimates of GU, fe, and fg show that a high effective number of founders has affected the colony's current genetic structure in a positive manner. As demographic changes occur, genetic and pedigree matrices need to be monitored consistently to ensure the health and wellbeing of the Cayo Santiago colony. PMID- 28724490 TI - Murine Astrovirus Infection and Transmission in Neonatal CD1 Mice. AB - Murine astrovirus (MuAstV) is a recently identified, widespread infection among laboratory mice. Our goal was to determine the duration of MuAstV infection, susceptibility of pups, and efficacy of soiled-bedding sentinels and environmental monitoring. Eight CD1 dams and their litters of 3-d-old pups and 8 CD1 dams and their litters of 13-d-old mice were inoculated orally with MuAstV. Neither dams nor offspring demonstrated any clinical signs, and MuAstV had little to no effect on weight gain in pups. MuAstV RNA was detected in feces from 15 of the 16 dams through postnatal day (PND) 21, and 9 dams were still shedding MuAstV at PND 42. MuAstV RNA was highest in intestines of mice. Low levels of MuAstV RNA were sporadically detected in the spleen, liver, and kidney. MuAstV was detected in 97% of feces from 3- to 9-wk-old mice born to infected dams. Several weanlings became pregnant, and intestines from their pups were MuAstV-negative at PND 0 through 5. Weekly swabs of cages housing MuAstV-infected mice were MuAstV positive through PND 42. Swabs of the rear exhaust manifold of the ventilated rack were MuAstV-positive at 21 through 56 d after inoculation. In addition, 98% of sentinels that received soiled bedding from dams and their litters and 83% of sentinels that received soiled bedding from weaned mice were MuAstV-positive. Feces from most sentinels exposed to soiled bedding that had been stored for 1, 2 or 3 wk before addition of the sentinels were MuAstV-positive. PMID- 28724491 TI - Comparison of Antemortem and Environmental Samples for Zebrafish Health Monitoring and Quarantine. AB - Molecular diagnostic assays offer both exquisite sensitivity and the ability to test a wide variety of sample types. Various types of environmental sample, such as detritus and concentrated water, might provide a useful adjunct to sentinels in routine zebrafish health monitoring. Similarly, antemortem sampling would be advantageous for expediting zebrafish quarantine, without euthanasia of valuable fish. We evaluated the detection of Mycobacterium chelonae, M. fortuitum, M. peregrinum, Pseudocapillaria tomentosa, and Pseudoloma neurophilia in zebrafish, detritus, pooled feces, and filter membranes after filtration of 1000-, 500-, and 150-mL water samples by real-time PCR analysis. Sensitivity varied according to sample type and pathogen, and environmental sampling was significantly more sensitive than zebrafish sampling for detecting Mycobacterium spp. but not for Pseudocapillaria neurophilia or Pseudoloma tomentosa. The results of these experiments provide strong evidence of the utility of multiple sample types for detecting pathogens according to each pathogen's life cycle and ecological niche within zebrafish systems. In a separate experiment, zebrafish subclinically infected with M. chelonae, M. marinum, Pleistophora hyphessobryconis, Pseudocapillaria tomentosa, or Pseudoloma neurophilia were pair-spawned and individually tested with subsets of embryos from each clutch that received no rinse, a fluidizing rinse, or were surface-disinfected with sodium hypochlorite. Frequently, one or both parents were subclinically infected with pathogen(s) that were not detected in any embryo subset. Therefore, negative results from embryo samples may not reflect the health status of the parent zebrafish. PMID- 28724493 TI - Oral Transmucosal Detomidine Gel in New Zealand White Rabbits (Oryctolagus cuniculus). AB - Handling and restraining rabbits for routine procedures may be impossible without prior sedation, result in unnecessary stress or injury to the rabbit or handler, and increase experimental variability. Parenteral administration of sedatives can cause stress also, as well as localized pain and tissue damage, especially in fractious animals. Detomidine hydrochloride, an alpha2-adrenergic receptor agonist, is commercially available in an oral transmucosal (OTM) gel formulation that is FDA-approved for sedation and restraint in horses. This study investigated the efficacy and safety of detomidine gel as an alternative to injectable sedation in rabbits. Eight adult male New Zealand White rabbits each received 0.6, 1.2, or 1.8 mg/kg OTM detomidine gel. Physiologic parameters and sedation scores (SS) were assessed at 10-min intervals from before administration until 100 min afterward. Histopathology of cardiac tissue was scored through 12 d after dosing. Gel administration increased the SS in all rabbits, but none of the animals developed clinically effective sedation (SS of 10 or greater, based on 5 reflex responses on a 3- or 4-point scale). The SS did not differ among dosage groups, and the time-dose interaction was not statistically significant. Heart rate decreased rapidly in all rabbits, with no difference among dosage groups, and there was no effect of time or dosage on peripheral capillary oxygen saturation. Minimal to mild degenerative changes were seen in the myocardium of all treated rabbits, but myocyte necrosis, inflammation, fibrosis, and mural thrombi-reported previously in rabbits that had received parenteral detomidine did not occur. OTM detomidine gel was safely and easily administered to rabbits, but the duration and level of sedation were unpredictable. The use of OTM detomidine as a sole agent to facilitate handling and restraint of rabbits does not offer advantages over existing parenteral regimens. PMID- 28724492 TI - Evaluation of Pain Assessment Techniques and Analgesia Efficacy in a Female Guinea Pig (Cavia porcellus) Model of Surgical Pain. AB - Guinea pigs (Cavia porcellus) are a frequently used species in research, often involving potentially painful procedures. Therefore, evidence-based recommendations regarding analgesia are critically needed to optimize their wellbeing. Our laboratory examined the efficacy of carprofen and extended-release (ER) buprenorphine, alone and as a multimodal combination, for relieving postsurgical pain in guinea pigs. Animals were assessed by using evoked (mechanical hypersensitivity), nonevoked (video ethogram, cageside ethogram, time to-consumption test), and clinical (weight loss) measurements for 96 h during baseline, anesthesia-analgesia, and hysterectomy conditions. In addition, ER buprenorphine was evaluated pharmacologically. Guinea pigs treated with a single analgesic showed increased mechanical sensitivity for at least 96 h and indices of pain according to the video ethogram for as long as 8 h, compared with levels recorded during anesthesia-analgesia. In contrast, animals given both analgesics demonstrated increased mechanical sensitivity and behavioral evidence of pain for only 2 h after surgery compared with anesthesia-analgesia. The cageside ethogram and time-to-consumption tests failed to identify differences between conditions or treatment groups, highlighting the difficulty of identifying pain in guinea pigs without remote observation. Guinea pigs treated with multimodal analgesia or ER buprenorphine lost at least 10% of their baseline weights, whereas weight loss in carprofen animals was significantly lower (3%). Plasma levels for ER buprenorphine exceeded 0.9 ng/mL from 8 to 96 h after injection. Of the 3 analgesia regimens evaluated, multimodal analgesia provided the most effective pain control in guinea pigs. However the weight loss in the ER buprenorphine treated animals may need to be considered during analgesia selection. PMID- 28724494 TI - Pharmacokinetics of a Novel, Transdermal Fentanyl Solution in Rhesus Macaques (Macaca mulatta). AB - Rhesus macaques (Macaca mulatta) are the most commonly used NHP biomedical model and experience both research and clinical procedures requiring analgesia. Opioids are a mainstay of analgesic therapy. A novel, transdermal fentanyl solution (TFS) has been developed as a long-acting, single-administration topical opioid and was reported to provide at least 4 d of effective plasma concentrations in beagles (Canis familiaris). To evaluate the pharmacokinetic profile of TFS in healthy adult rhesus macaques, we used a 2-period, 2-treatment crossover study of a single topical administration of 1.3 (25) and 2.6 mg/kg (50 MUL/kg) TFS. TFS was applied to the clipped dorsal skin of adult rhesus macaques (n = 6; 3 male, 3 female) under ketamine sedation (10 mg/kg IM). We hypothesized that TFS in rhesus macaques would provide at least 4 d of effective plasma concentrations (assumed to be >= 0.2 ng/mL, based on human studies). Plasma fentanyl concentrations were determined by liquid chromatography-tandem mass spectrometry before drug administration and at 0, 0.5, 1, 2, 4, 8, 12, 24, 36, 48, 60, 72, 96, 120, 144, 168, 240, 336, 408, and 504 h afterward. Noncompartmental pharmacokinetic analysis was performed. For each dose (1.3 and 2.6 mg/kg), respectively, the maximal plasma concentration was 1.95 +/- 0.40 and 4.19 +/- 0.69 ng/mL, occurring at 21.3 +/- 4.1 and 30.7 +/- 8.7 h; the AUC was 227.3 +/- 31.7 and 447.0 +/- 49.1 h/ng/mL, and the terminal elimination half-life was 93.7 +/- 7.1 and 98.8 +/- 5.4 h. No adverse effects were noted after drug administration at either dose. Macaques maintained plasma fentanyl concentrations of 0.2 ng/mL or greater for at least 7 d after 1.3 mg/kg and at least 10 d after 2.6 mg/kg topical administration of TFS. A single TFS dose may provide efficacious analgesia to rhesus macaques and reduce stress, discomfort, and risk to animals and personnel. PMID- 28724495 TI - Minimum Alveolar Concentration and Cardiopulmonary Effects of Isoflurane in Ring tailed Lemurs (Lemur catta). AB - The goal of this study was to determine the minimum alveolar concentration (MAC) and cardiopulmonary effects of isoflurane in ring-tailed lemurs (Lemur catta). The MAC of isoflurane was determined by using a tail-clamp stimulus in adult ring tailed lemurs (6 male, 4 female). Once MAC was determined, another group of 10 adult ring-tailed lemurs (5 male, 5 female) were anesthetized and instrumented similarly as the previous group and maintained at 0.5, 1, 1.5, and 2 times MAC for 15 min each with no external stimulation. Five lemurs were exposed to increasing concentrations (that is, 0.5 times MAC increasing to 2 times MAC), and the other 5 animals were exposed to decreasing concentrations. MAC of isoflurane for ringtailed lemurs was 1.9%. The animals became hypotensive, but no significant differences were found in heart rate or systolic, mean, and diastolic blood pressures at the different multiples of MAC examined. At 1 MAC, all lemurs developed a moderate respiratory acidosis, which became more severe at 2 MAC. Given these findings, isoflurane at 0.5 to 2 times MAC in ringtailed lemurs does not result in predictable depression of blood pressure, but hypoventilation occurs at 1 MAC or greater. PMID- 28724496 TI - Effects of Time and Storage Conditions on the Chemical and Microbiologic Stability of Diluted Buprenorphine for Injection. AB - Buprenorphine is a partial MU-opioid agonist used for analgesia. Due to the small size of laboratory rodents, buprenorphine HCl is typically diluted 10- or 20-fold with a sterile diluent, such as saline, for accurate dosing. Protocols for preparing and storing diluted buprenorphine vary by institution, and little published information is available regarding stability and beyond-use dating of specific buprenorphine preparations. The purpose of this study was to determine the chemical and microbiologic stability of diluted buprenorphine stored for a maximum of 180 d. Buprenorphine HCl was diluted 1:10 into sterile bacteriostatic saline by using aseptic technique. Diluted samples were stored in glass vials or plastic syringes, protected from light, and maintained at refrigerated or room temperature for as long as 180 d. Aerobic and anaerobic cultures on all stored samples were negative for bacterial and fungal growth. According to HPLC analysis, diluted buprenorphine stored in glass vials experienced less than 10% loss when stored for 180 d at either refrigerated or room temperature. However, the concentration of buprenorphine stored in syringes declined rapidly to more than 80% loss at room temperature and 28% loss in the refrigerator after 180 d. According to the results of this study, diluted buprenorphine stored in glass vials retains more than 90% of the initial concentration and is microbiologically stable for 180 d. However, our data suggest that, regardless of the duration, storing diluted buprenorphine in plastic syringes is inadvisable. PMID- 28724497 TI - A Redesign Approach for Improving Animal Care Services for Researchers. AB - Because a research institution's animal care and use program oversees the provision of services specified in approved protocols designed by researchers, the effective provision of services within these programs is paramount to ensuring the humane care and treatment of research animals in accordance with federal, state, and local regulations and institutional policies. To improve the services provided to researchers through animal care and use programs, we investigated the relationship between the researchers who conduct these types of studies and the veterinary operations that provide care and treatment for research animals. Through a case study conducted at a leading public research university, we used an action-research approach to redesign aspects of the process through which researchers and the veterinary operations interact by using the Design for Six Sigma methodology. Using this structured approach for building quality into the design of a process to better serve customers, we identified and prioritized researchers' expectations regarding the role of veterinary operations in supporting their animal research activities. In addition, ideas for addressing researchers' top-rated needs were generated through focus groups. By updating online resources, creating checklists and newsletters, and hiring additional veterinary staff, the services provided were amended to provide researchers with increased access to valuable information, improved clarity regarding the process for obtaining access to research facilities, and enhanced support for animal care services. PMID- 28724498 TI - Patients with HIV and coronary disease: are we meeting national guidelines? AB - Cardiovascular disease (CVD) has a higher incidence in patients with HIV infection. This study sought to determine whether HIV-infected patients with established CVD were being managed according to national guidelines. Data were collected from Australian general practitioners for 77 HIV-infected patients with a median age of 59 (range 54-64). There was good adherence to guidelines with regards to anti-platelet (84%; n=65; 95% confidence interval (CI) 74-92%) and statin therapy (97%; n=75; 95% CI 91-100%), despite a failure to meet cholesterol targets, with only 31% (n=24; 95% CI 21-42%) of the cohort meeting low-density lipoprotein target values. Similarly, there was limited adherence to guidelines regarding the prescriptions of medications for those with established hypertension (66%; n=51; 95% CI 55-77%), body mass index targets met (40%; n=31; 95% CI 29-52%), and depression screening (32%; n=25; 95% CI 22-44%). This Australian audit provides insight into adherence to guidelines for individuals with CVD and HIV, suggesting that current screening and management practices for these patients falls short of guidelines, particularly in relation to cholesterol management. PMID- 28724499 TI - Peripheral arterial disease outcomes and association with suPAR: A bridge to myeloid precursors or mast cells or both? PMID- 28724500 TI - A 20-year review of pediatric pregnant trauma from a Level I trauma center. AB - BACKGROUND: Trauma in pregnancy remains an important but understudied public health issue. We aimed to determine the prevalence of interpersonal violence in our pregnant trauma population (including pediatric) over the last 20 years, from our Level I trauma center. METHODS: We conducted a descriptive, retrospective chart review to identify all pregnant trauma patients between Jan 1993 and Sept 2013. Pediatric was <=18 years of age. We evaluated demographics, mechanism of injury, injury location, disposition, and outcome data. RESULTS: We treated 438 pregnant patients at our center over 20 years. 378 (86%) were adult and 60 (14%) were pediatric. Intentional injuries occurred in 89 (20%) patients. The pediatric pregnant patients experienced a significantly higher proportion of intentional, interpersonal violence (33% vs. 18%, p = 0.007) compared to adults. Patients presenting after intentional, interpersonal violence had a higher mortality compared to non-intentional 5% vs 1% (p = 0.019). CONCLUSIONS: Pediatric pregnant trauma patients remain at risk of interpersonal violence, especially firearm related injury. Screening should be instituted by obstetricians and pediatricians for primary prevention. PMID- 28724501 TI - Noise exposure alters long-term neural firing rates and synchrony in primary auditory and rostral belt cortices following bimodal stimulation. AB - We previously demonstrated that bimodal stimulation (spinal trigeminal nucleus [Sp5] paired with best frequency tone) altered neural tone-evoked and spontaneous firing rates (SFRs) in primary auditory cortex (A1) 15 min after pairing in guinea pigs with and without noise-induced tinnitus. Neural responses were enhanced (+10 ms) or suppressed (0 ms) based on the bimodal pairing interval. Here we investigated whether bimodal stimulation leads to long-term (up to 2 h) changes in tone-evoked and SFRs and neural synchrony (correlate of tinnitus) and if the long-term bimodal effects are altered following noise exposure. To obviate the effects of permanent hearing loss on the results, firing rates and neural synchrony were measured three weeks following unilateral (left ear) noise exposure and a temporary threshold shift. Simultaneous extra-cellular single-unit recordings were made from contralateral (to noise) A1 and dorsal rostral belt (RB); an associative auditory cortical region thought to influence A1, before and after bimodal stimulation (pairing intervals of 0 ms; simultaneous Sp5-tone and +10 ms; Sp5 precedes tone). Sixty and 120 min after 0 ms pairing tone-evoked and SFRs were suppressed in sham A1; an effect only preserved 120 min following pairing in noise. Stimulation at +10 ms only affected SFRs 120 min after pairing in sham and noise-exposed A1. Within sham RB, pairing at 0 and +10 ms persistently suppressed tone-evoked and SFRs, while 0 ms pairing in noise markedly enhanced tone-evoked and SFRs up to 2 h. Together, these findings suggest that bimodal stimulation has long-lasting effects in A1 that also extend to the associative RB that is altered by noise and may have persistent implications for how noise damaged brains process multi-sensory information. Moreover, prior to bimodal stimulation, noise damage increased neural synchrony in A1, RB and between A1 and RB neurons. Bimodal stimulation led to persistent changes in neural synchrony in intact A1 and RB that were also altered by noise exposure. Given that increases in neural synchrony following noise may be consistent with tinnitus onset, these data implicate that both A1 and RB may be involved in the etiology of phantom sound perception. These data also suggest that noise alters the effects of bimodal stimulation on neural synchrony in A1 and RB; an effect that may also lead to changes in tinnitus perception. PMID- 28724502 TI - Preoperative clinic: Non-essential cost or catalyst for process efficiency, safety and care outcomes? PMID- 28724503 TI - Twenty-five years of gene therapy for genetic diseases and leukemia: The road to marketing authorization of the first ex vivo gene therapies. PMID- 28724504 TI - TOTAL evidence for drug eluting stent efficacy and safety in STEMI patients. PMID- 28724505 TI - Readmission to hospital of medical patients - A cohort study. AB - INTRODUCTION: The incidence of acute readmissions is higher among elderly medical patients than in the general population. Risk factor identification is needed in order to prevent readmissions. OBJECTIVE: To estimate the incidence of acute readmissions among medical patients >=65years discharged from departments of internal medicine and to identify risk factors associated with readmissions. MATERIAL AND METHODS: We included patients discharged between 1st of January 2011 and 1st of December 2014 and collected data regarding primary diagnosis and comorbidities. The primary outcome was acute readmission within 30days of discharge. We determined risk factors using a multivariable Cox proportional hazards model. RESULTS: Out of 21,634 discharged patients, 3432 (15.9%) patients had an acute readmission. Risk factors were: age per decade (HR: 1.06, 95%CI: 1.02-1.11), male sex (HR: 1.07, 95%CI: 1.00-1.15), receiving home care service (personal care) (HR: 1.33, 95%CI: 1.15-1.55), nursing home residency (HR: 1.30, 95%CI: 1.14-1.48), a previous admission within six months (HR: 1.59, 95%CI: 1.48 1.72), increased length of index admission (HR: 1.14, 95%CI: 1.11-1.17), and moderate or high level of comorbidities (HR: 1.22, 95%CI: 1.13-1.32, HR: 1.52, 95%CI: 1.38-1.67, respectively). CONCLUSION: Around one in six patients had an acute readmission and we identified several risk factors. The risk factors a previous hospital admission within six months, a long or very long length of index admission and a high level of comorbidities were strong risk factors for an acute readmission. PMID- 28724506 TI - The use of non-steroidal anti-inflammatory drugs for patent ductus arteriosus closure in preterm infants. AB - Over the last four decades, non-steroidal anti-inflammatory drugs have been widely used to induce closure of the patent ductus arteriosus (PDA) in preterm infants. Evidence to support this practice is lacking, despite performance of >50 randomized trials. The credibility of those trials may have been compromised by high rates of open treatment in controls, era of study prior to advent of modern practices, or inclusion of insufficient numbers of very immature infants. Meta analyses show little impact of those factors on main conclusions. Essentially all trials reporting important long-term outcomes (other than mortality) initiated treatment within five days after birth, so no evidence regarding later treatment is available. Accruing clinical experience suggests that long-term outcomes are not compromised, and may be improved, with non-interventional management strategies. Future studies to identify preterm infants at greatest risk of potential harm from a persistent PDA, particularly after the second postnatal week, are urgently needed. PMID- 28724507 TI - Comparison of endocranial morphology according to age in one-piece fronto-orbital advancement using a distraction in craniosynostotic plagiocephaly. AB - The capacity for cranial remodelling is known to be better at younger ages. The timing of cranioplasty could affect the axis of the skull base. We investigated whether age at the time of distraction is related to the outcome of endocranial morphology correction. In this retrospective study, we investigated the surgical outcome of 14 patients with unilateral craniosynostotic plagiocephaly who underwent one-piece fronto-orbital advancement without bandeau by using a distraction technique between April 2005 and December 2015. Satisfactory results were achieved in all 14 patients with unilateral coronal suture craniosynostosis. An average distraction of 27.3 mm was obtained without detachment from the dura mater. The endocranial angulation of the anteroposterior axis was reduced from 165.4 degrees to 173.5 degrees on average, and the average total change was 8.1 degrees . Between patients aged <1 year and those >1 year, there was a statistically significant difference in the postoperative endocranial angulation of the anteroposterior axis after 3 months (p = 0.003). The distraction techniques resulted in better correction of endocranial morphology. This indicates that the changes in the skull base axis after one-piece fronto-orbital advancement without bandeau are related to the remodelling capacity of the skull base in growing children based on the dura mater. PMID- 28724508 TI - Superselective retrograde lymphatic duct embolization for management of postoperative lymphatic leak. AB - Lymphatic leak is a well-documented complication following neck dissection surgeries. When conservative methods fail to control the leak, thoracic duct embolization becomes an option. Transabdominal access is the standard for this procedure; however, it is not always feasible. We discuss a technique of selective lymphatic vessel embolization utilizing retrograde transvenous access. PMID- 28724509 TI - Youth Oriented Activity Trackers: Comprehensive Laboratory- and Field-Based Validation. AB - BACKGROUND: Commercial activity trackers are growing in popularity among adults and some are beginning to be marketed to children. There is, however, a paucity of independent research examining the validity of these devices to detect physical activity of different intensity levels. OBJECTIVES: The purpose of this study was to determine the validity of the output from 3 commercial youth oriented activity trackers in 3 phases: (1) orbital shaker, (2) structured indoor activities, and (3) 4 days of free-living activity. METHODS: Four units of each activity tracker (Movband [MB], Sqord [SQ], and Zamzee [ZZ]) were tested in an orbital shaker for 5-minutes at three frequencies (1.3, 1.9, and 2.5 Hz). Participants for Phase 2 (N=14) and Phase 3 (N=16) were 6-12 year old children (50% male). For Phase 2, participants completed 9 structured activities while wearing each tracker, the ActiGraph GT3X+ (AG) research accelerometer, and a portable indirect calorimetry system to assess energy expenditure (EE). For Phase 3, participants wore all 4 devices for 4 consecutive days. Correlation coefficients, linear models, and non-parametric statistics evaluated the criterion and construct validity of the activity tracker output. RESULTS: Output from all devices was significantly associated with oscillation frequency (r=.92 .99). During Phase 2, MB and ZZ only differentiated sedentary from light intensity (P<.01), whereas the SQ significantly differentiated among all intensity categories (all comparisons P<.01), similar to AG and EE. During Phase 3, AG counts were significantly associated with activity tracker output (r=.76, .86, and .59 for the MB, SQ, and ZZ, respectively). CONCLUSIONS: Across study phases, the SQ demonstrated stronger validity than the MB and ZZ. The validity of youth-oriented activity trackers may directly impact their effectiveness as behavior modification tools, demonstrating a need for more research on such devices. PMID- 28724511 TI - Apps for Health-Related Education in Pharmacy Practice: Needs Assessment Survey Among Patients Within a Large Metropolitan Area. AB - BACKGROUND: Patient education resources are crucial to the effectiveness of prescribed pharmacotherapy. However, user interest and patient preference for these materials is lacking. Regardless of the field, nearly every article on designing mHealth apps references the lack of end-user involvement as a key flaw to sustainable design. The traditional paper-based methods of patient education are difficult to tailor to a patient's specific needs and learning styles, but a customizable app might be beneficial. OBJECTIVE: Regarding a mobile app for patient education, the objectives of the study were to (1) quantify patient interest, (2) determine desirable features, and (3) determine if a relationship exists between patient variables and interest in an iPad app for patient education. METHODS: A paper-based questionnaire was developed and administered to consenting patients receiving care within three sites: two suburban outpatient sites where ambulatory care services are provided and one urban hospital site where ambulatory care transition services are provided. RESULTS: A total of 121 surveys were completed. Most respondents were female (64/120, 53.3%), between 50 and 70 years of age, white/Caucasian (94/120, 78.3%), owned at least one technology device, and knew what an iPad was. Diabetes was the most common disease state (43/120, 35.8%), followed by heart failure (27/120, 22.5%), history of venous thromboembolism (VTE) (21/120, 17.5%), and asthma/chronic obstructive pulmonary disease (17/120, 14.2%). Overall interest in a mobile health app for patient education was 63.7% (72/113). Interest increased to 68.4% (78/114) if a health care provider recommended it. Respondents with one chronic health condition were more likely to be interested in an app compared to those with two or more. Respondents with a history of VTE were mostly likely to be interested in using an app on their own accord, while respondents with diabetes were mostly likely to be interested if their health care provider recommended it. CONCLUSIONS: This preliminary needs assessment identified that patients are interested in using mHealth apps for health-related education in pharmacy practice, particularly if their health care provider recommends it. PMID- 28724510 TI - Social Media Engagement and HIV Testing Among Men Who Have Sex With Men in China: A Nationwide Cross-Sectional Survey. AB - BACKGROUND: Many interventions find that social media engagement with health promotion materials can translate into behavioral changes. However, only a few studies have examined the ways in which specific actions on various social media platforms are correlated with health behaviors. OBJECTIVE: The objective of this study was to examine the association between social media use and HIV testing behaviors among Chinese men who have sex with men (MSM). METHODS: In July 2016, a Web-based survey was conducted to recruit MSM in 8 Chinese cities through Blued (Blue City Holdings Ltd.), the world's largest gay mobile phone app. Data on sociodemographic variables, social media use platforms and behaviors, sexual behaviors, and HIV testing histories were collected. HIV testing-related social media use was defined as having ever engaged with HIV testing content on social media, which was further divided into observing (ie, receiving), endorsing (eg, liking and sharing), and contributing (eg, posting or commenting on HIV testing materials). Confirmatory factor analysis (CFA) was conducted to determine the best division of HIV testing-related social media use. Univariate and multivariable logistic regressions were used to examine the association between HIV testing-related social media use and HIV testing behaviors. RESULTS: A total of 2105 individuals participated in the survey. Among them, 46.75% (984) were under the age of 24 years, 35.43% (746) had high school education or less, and 47.74% (587) had condomless sex in the last 3 months. More than half of the respondents (58.14%, 1224/2105) reported HIV testing-related social media use. Additionally, HIV testing-related social media use, especially on multifunctional platforms such as WeChat, was found to be associated with recent HIV testing (adjusted odds ratio [aOR] 2.32, 95% CI 1.66-3.24). Contributing on social media was correlated with recent HIV testing (aOR 2.10, 95% CI 1.40-3.16), but neither observing (aOR 0.66, 95% CI 0.38-1.15) nor endorsing (aOR 1.29, 95% CI 0.88-1.90) were correlated. CONCLUSIONS: Our data suggest that social media use, particularly on multifunctional platforms such as WeChat and with contributing behaviors, is correlated with HIV testing among MSM in China. Campaigns that promote active participant contribution on social media beyond passive observation and endorsement of promotional materials are needed. This study has implications for the design and implementation of social media interventions to promote HIV testing. PMID- 28724512 TI - The Health Buddies App as a Novel Tool to Improve Adherence and Knowledge in Atrial Fibrillation Patients: A Pilot Study. AB - BACKGROUND: Atrial fibrillation (AF) constitutes an important risk for stroke, especially in an ageing population. A new app (Health Buddies) was developed as a tool to improve adherence to non-vitamin K antagonist oral anticoagulants (NOACs) in an elderly AF population by providing a virtual contract with their grandchildren, spelling out daily challenges for both. OBJECTIVE: The aim of this pilot study was to assess the feasibility and usability of the Health Buddies app in AF patients. METHODS: Two workshops were conducted to steer app development and to test a first prototype. The feasibility of the finalized app was investigated by assessing the number of eligible AF patients (based on current prescription of NOACs, the presence of grandchildren between 5 and 15 years old, availability of a mobile phone, computer, or tablet), and the proportion of those who were willing to participate. Participants had to use the app for 3 months. The motivation of the patients to use the app was assessed based on the number of logins to the app. Their perception of its usefulness was examined by specific questionnaires. Additionally, the effects on knowledge level about AF and its treatment, and adherence to NOAC intake were investigated. RESULTS: Out of 830 screened AF patients, 410 were taking NOACs and 114 were eligible for inclusion. However, only 3.7% (15/410) of the total NOAC population or 13.2% of the eligible patients (15/114) were willing to participate. The main reasons for not participating were no interest to participate in general or in the concept in particular (29/99, 29%), not feeling comfortable using technology (22/99, 22%), no interest by the grandchildren or their parents (20/99, 20%), or too busy a lifestyle (12/99, 12%). App use significantly decreased towards the end of the study period in both patients (P=.009) and grandchildren (P<.001). NOAC adherence showed a taking adherence and regimen adherence of 88.6% (SD 15.4) and 81.8% (SD 18.7), respectively. Knowledge level increased from 64.6% (SD 14.7) to 70.4% (SD 10.4) after 3 months (P=.09). The app scored positively on clarity, novelty, stimulation, and attractiveness as measured with the user experience questionnaire. Patients evaluated the educational aspect of this app as a capital gain. CONCLUSIONS: Only a small proportion of the current AF population seems eligible for the innovative Health Buddies app in its current form. Although the app was positively rated by its users, a large subset of patients was not willing to participate in this study or to use the app. Efforts have to be made to expand the target group in the future. PMID- 28724513 TI - Development of a Tailored HIV Prevention Intervention for Single Young Men Who Have Sex With Men Who Meet Partners Online: Protocol for the myDEx Project. AB - BACKGROUND: New cases of human immunodeficiency virus (HIV) among young men who have sex with men (YMSM), aged 18 to 24, underscore the importance of developmentally-informed HIV programs for YMSM. We developed an online intervention focused on risk reduction strategies across different sexual partner types. Intervention activities focus on assisting YMSM reflect on their partner seeking behaviors, develop sexual decision-making rules to reduce their HIV risks, and consider the adoption of HIV prevention behaviors. OBJECTIVE: This pilot, randomized controlled trial (RCT) aims to examine the feasibility, acceptability, and preliminary efficacy of a tailored, Web-based HIV prevention intervention for single YMSM. METHODS: We designed a prospective RCT of online recruited cis-gender men (N=180) who reported recent unprotected anal intercourse, self-report as HIV negative or are unaware of their HIV status, and meet sexual partners through online dating apps. Individuals in the control arm receive an attention-control condition that includes HIV/sexually transmitted infection (STI) information currently available on sex education websites. Individuals in the intervention arm receive a 6-session Web-based program tailored on their demographic information, partner-seeking behaviors and relationship desires, and prior sexual attitudes and behaviors. This tailored content will match HIV prevention messages and safer sex skills with YMSM's outcome expectancies when meeting new partners and thereby help them consider how to integrate safer sex practices into different partner types. Study assessments are taken at baseline, 30-, 60-, and 90-day follow-ups. Intervention acceptability and preliminary efficacy will be explored in sexual risk behaviors and HIV/STI testing. RESULTS: The RCT launched in November 2016 and is ongoing. To date, 180 eligible individuals have been enrolled, consented, and randomized. Of the 120 individuals in the intervention arm, 51.7% (62/120) identify as non Hispanic white and half of the control arm identifies as non-Hispanic white. There were no differences observed by arm for race and/or ethnicity, age, or sexual orientation. CONCLUSIONS: Although there are in-person evidence-based interventions with proven efficacy for YMSM, few HIV/STI prevention interventions delivered online exist. Online interventions may ease access to comprehensive HIV/STI education among YMSM and allow personalized content to be delivered. The online intervention that we developed, myDEx, aims to alleviate the gaps within HIV prevention for YMSM by utilizing tailored, Web-based content with the goal of developing skills for same-sex dating and relationship building, while reducing their risks for HIV/STI. TRIAL REGISTRATION: ClinicalTrials.gov NCT02842060; https://clinicaltrials.gov/ct2/show/NCT02842060 (Archived by WebCite at http://www.webcitation.org/6rcJdxF9v). PMID- 28724514 TI - Paediatrician jailed for downloading child porn is struck off. PMID- 28724516 TI - Regulatory data are hidden in plain sight. PMID- 28724517 TI - Prenatal antidepressant use and risk of autism. PMID- 28724518 TI - Effect of diet and physical activity based interventions in pregnancy on gestational weight gain and pregnancy outcomes: meta-analysis of individual participant data from randomised trials. AB - Objective To synthesise the evidence on the overall and differential effects of interventions based on diet and physical activity during pregnancy, primarily on gestational weight gain and maternal and offspring composite outcomes, according to women's body mass index, age, parity, ethnicity, and pre-existing medical condition; and secondarily on individual complications.Design Systematic review and meta-analysis of individual participant data (IPD). Data sources Major electronic databases from inception to February 2017 without language restrictions.Eligibility criteria for selecting studies Randomised trials on diet and physical activity based interventions in pregnancy.Data synthesis Statistical models accounted for clustering of participants within trials and heterogeneity across trials leading to summary mean differences or odds ratios with 95% confidence intervals for the effects overall, and in subgroups (interactions).Results IPD were obtained from 36 randomised trials (12 526 women). Less weight gain occurred in the intervention group than control group (mean difference -0.70 kg, 95% confidence interval -0.92 to -0.48 kg, I2=14.1%; 33 studies, 9320 women). Although summary effect estimates favoured the intervention, the reductions in maternal (odds ratio 0.90, 95% confidence interval 0.79 to 1.03, I2=26.7%; 24 studies, 8852 women) and offspring (0.94, 0.83 to 1.08, I2=0%; 18 studies, 7981 women) composite outcomes were not statistically significant. No evidence was found of differential intervention effects across subgroups, for either gestational weight gain or composite outcomes. There was strong evidence that interventions reduced the odds of caesarean section (0.91, 0.83 to 0.99, I2=0%; 32 studies, 11 410 women), but not for other individual complications in IPD meta-analysis. When IPD were supplemented with study level data from studies that did not provide IPD, the overall effect was similar, with stronger evidence of benefit for gestational diabetes (0.76, 0.65 to 0.89, I2=36.8%; 59 studies, 16 885 women).Conclusion Diet and physical activity based interventions during pregnancy reduce gestational weight gain and lower the odds of caesarean section. There is no evidence that effects differ across subgroups of women. PMID- 28724521 TI - Shehan Hettiaratchy: Planning the next 10 steps. PMID- 28724519 TI - Antidepressants during pregnancy and autism in offspring: population based cohort study. AB - Objectives To study the association between maternal use of antidepressants during pregnancy and autism spectrum disorder (ASD) in offspring.Design Observational prospective cohort study with regression methods, propensity score matching, sibling controls, and negative control comparison.Setting Stockholm County, Sweden.Participants 254 610 individuals aged 4-17, including 5378 with autism, living in Stockholm County in 2001-11 who were born to mothers who did not take antidepressants and did not have any psychiatric disorder, mothers who took antidepressants during pregnancy, or mothers with psychiatric disorders who did not take antidepressants during pregnancy. Maternal antidepressant use was recorded during first antenatal interview or determined from prescription records.Main outcome measure Offspring diagnosis of autism spectrum disorder, with and without intellectual disability.Results Of the 3342 children exposed to antidepressants during pregnancy, 4.1% (n=136) had a diagnosis of autism compared with a 2.9% prevalence (n=353) in 12 325 children not exposed to antidepressants whose mothers had a history of a psychiatric disorder (adjusted odds ratio 1.45, 95% confidence interval 1.13 to 1.85). Propensity score analysis led to similar results. The results of a sibling control analysis were in the same direction, although with wider confidence intervals. In a negative control comparison, there was no evidence of any increased risk of autism in children whose fathers were prescribed antidepressants during the mothers' pregnancy (1.13, 0.68 to 1.88). In all analyses, the risk increase concerned only autism without intellectual disability.Conclusions The association between antidepressant use during pregnancy and autism, particularly autism without intellectual disability, might not solely be a byproduct of confounding. Study of the potential underlying biological mechanisms could help the understanding of modifiable mechanisms in the aetiology of autism. Importantly, the absolute risk of autism was small, and, hypothetically, if no pregnant women took antidepressants, the number of cases that could potentially be prevented would be small. PMID- 28724520 TI - Cost saving is nothing to be proud of. PMID- 28724522 TI - WHO urges countries to fight tobacco industry's interference. PMID- 28724523 TI - Savolitinib Heads for Phase III Trial in PRCC. AB - A phase II trial of savolitinib, a MET inhibitor, found that the drug induced partial responses in some patients with papillary renal cell carcinoma and was well tolerated, prompting drug makers Chi-Med and AstraZeneca to launch a phase III study. PMID- 28724524 TI - Assignment of weight-based antibody units for four additional serotypes to a human anti-pneumococcal standard reference serum 007sp. AB - The pneumococcal ELISA reference standard serum, Lot 89SF, has been in use since 1990 and was replaced with a new reference standard serum, 007sp in 2013. This serum was generated under an FDA-approved clinical protocol, where 278 adult volunteers were immunized with the 23-valent unconjugated polysaccharide vaccine, Pneumovax II(r), and a unit of blood was obtained twice within 120 days following immunization. Pooled serum was prepared from the plasma, filled at 6ml per vial and lyophilised. Five independent laboratories participated in bridging the serotype specific IgG assignments for 89SF to 007sp to establish equivalent reference values for 13 pneumococcal capsular serotypes (1,3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F) using the WHO reference ELISA. A subsequent follow up study established equivalent reference values for an additional seven serotypes (8, 10A, 11A, 12F, 15B, 22F, 33F). In this study three laboratories assigned weight-based IgG concentrations in mcg/mL of serum to 007sp for four additional serotypes; 2, 9N, 17F and 20A. This study completes the assignment of serotypes in 89SF to 007sp. In addition, the IgG antibody assignments for a 12 member WHO QC serum panel were extended to cover the four additional serotypes. Agreement was excellent with a concordance correlation coefficient (rc) > 0.996 when each laboratory was compared to the assigned values for the 12 WHO QC sera. The 007sp preparation has replaced 89SF as the pneumococcal reference standard. Sufficient quantities of 007sp are projected to be available for the next 25 years. PMID- 28724526 TI - Lysosomes convene to keep the synapse clean. AB - In neurons, lysosomes regulate alpha-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid receptor levels at the plasma membrane, although their presence at distal dendrites is controversial. In this issue, Goo et al. (2017. J. Cell Biol. https://doi.org/10.1083/jcb.201704068) show for the first time that neuronal activity positions lysosomes at the dendritic spines to facilitate synaptic remodeling through local protein degradation. PMID- 28724525 TI - TRIM37, a novel E3 ligase for PEX5-mediated peroxisomal matrix protein import. AB - Most proteins destined for the peroxisomal matrix depend on the peroxisomal targeting signals (PTSs), which require the PTS receptor PEX5, whose deficiency causes fatal human peroxisomal biogenesis disorders (PBDs). TRIM37 gene mutations cause muscle-liver-brain-eye (mulibrey) nanism. We found that TRIM37 localizes in peroxisomal membranes and ubiquitylates PEX5 at K464 by interacting with its C terminal 51 amino acids (CT51), which is required for PTS protein import. PEX5 mutations (K464A or DeltaCT51), or TRIM37 depletion or mutation, reduce PEX5 abundance by promoting its proteasomal degradation, thereby impairing its functions in cargo binding and PTS protein import in human cells. TRIM37 or PEX5 depletion induces apoptosis and enhances sensitivity to oxidative stress, underscoring the cellular requirement for functional peroxisomes. Therefore, TRIM37-mediated ubiquitylation stabilizes PEX5 and promotes peroxisomal matrix protein import, suggesting that mulibrey nanism is a new PBD. PMID- 28724528 TI - A forceful connection: mechanoregulation of oncogenic YAP. PMID- 28724527 TI - The spread of prion-like proteins by lysosomes and tunneling nanotubes: Implications for neurodegenerative diseases. AB - Progression of pathology in neurodegenerative diseases is hypothesized to be a non-cell-autonomous process that may be mediated by the productive spreading of prion-like protein aggregates from a "donor cell" that is the source of misfolded aggregates to an "acceptor cell" in which misfolding is propagated by conversion of the normal protein. Although the proteins involved in the various diseases are unrelated, common pathways appear to be used for their intercellular propagation and spreading. Here, we summarize recent evidence of the molecular mechanisms relevant for the intercellular trafficking of protein aggregates involved in prion, Alzheimer's, Huntington's, and Parkinson's diseases. We focus in particular on the common roles that lysosomes and tunneling nanotubes play in the formation and spreading of prion-like assemblies. PMID- 28724530 TI - The Population Health Benefits Of A Healthy Lifestyle: Life Expectancy Increased And Onset Of Disability Delayed. AB - A key determinant of population health is the behavioral profile of a population. Nearly 80 percent of Americans reach their fifties having smoked cigarettes, been obese, or both. It is unknown to what extent risky behaviors (for example, smoking, having a poor diet, being physically inactive, and consuming an excessive amount of alcohol) collectively are reducing the health and life expectancy of the US population, or what improvements might be achievable in their absence. Using data from the Health and Retirement Study, we studied people ages fifty and older who had never smoked, who were not obese, and who consumed alcohol moderately. Compared to the whole US population, those with such a favorable behavioral profile had a life expectancy at age fifty that was seven years longer, and they experienced a delay in the onset of disability of up to six years. These results provide a benchmark for evaluating the massively damaging effects that behavioral risks have on health at older ages and the importance of prioritizing policies to implement behavioral-based interventions. PMID- 28724529 TI - Coactivators and general transcription factors have two distinct dynamic populations dependent on transcription. AB - SAGA and ATAC are two distinct chromatin modifying co-activator complexes with distinct enzymatic activities involved in RNA polymerase II (Pol II) transcription regulation. To investigate the mobility of co-activator complexes and general transcription factors in live-cell nuclei, we performed imaging experiments based on photobleaching. SAGA and ATAC, but also two general transcription factors (TFIID and TFIIB), were highly dynamic, exhibiting mainly transient associations with chromatin, contrary to Pol II, which formed more stable chromatin interactions. Fluorescence correlation spectroscopy analyses revealed that the mobile pool of the two co-activators, as well as that of TFIID and TFIIB, can be subdivided into "fast" (free) and "slow" (chromatin interacting) populations. Inhibiting transcription elongation decreased H3K4 trimethylation and reduced the "slow" population of SAGA, ATAC, TFIIB and TFIID In addition, inhibiting histone H3K4 trimethylation also reduced the "slow" populations of SAGA and ATAC Thus, our results demonstrate that in the nuclei of live cells the equilibrium between fast and slow population of SAGA or ATAC complexes is regulated by active transcription via changes in the abundance of H3K4me3 on chromatin. PMID- 28724531 TI - The Tobacco-Free Village Program: Helping Rural Areas Implement and Achieve Goals of Tobacco Control Policies in India. AB - India has 274 million tobacco users and a tobacco use prevalence of 38% in rural areas. Tobacco consumption causes 1 million deaths and costs the health system nearly US$23 billion annually. Tobacco control policies exist but lack proper implementation. In this article, we review the Tobacco-free Village (TfV) program conducted in Maharashtra state in India and describe its process to help villages in rural India achieve "tobacco-free" status (i.e., the sale and use of tobacco are prohibited by law). We reviewed program documents and conducted 22 qualitative interviews with program staff and village-level stakeholders. From 2008 to 2014, Salaam Mumbai Foundation implemented the TfV program in 60 villages in Maharashtra state. The program used a number of strategies to help villages become tobacco free, including collaborating with a community-based organization, leveraging existing health workers, conducting a situation analysis, training health workers, engaging stakeholders, developing TfV assessment criteria, mobilizing the community, conducting health education, imposing sanctions, and offering incentives. By 2014, 4 villages had achieved tobacco-free status according to 11 assessment criteria. Successful villages demonstrated strong local leader involvement, ownership of the program, and commitment to the cause by residents. The TfV program faced barriers including poor motivation of health workers, difficulty in changing social norms of tobacco use, and refusal of local vendors to stop tobacco sales due to financial losses. This low-cost, community driven program holds promise for helping public health practitioners and governments implement and achieve the goals of tobacco control policies, especially in resource-scarce settings. PMID- 28724532 TI - What's that abdominal mass? PMID- 28724533 TI - Prevention and management of procedural pain in the neonate: an update, American Academy of Pediatrics, 2016. PMID- 28724534 TI - m6aViewer: software for the detection, analysis, and visualization of N6 methyladenosine peaks from m6A-seq/ME-RIP sequencing data. AB - Recent methods for transcriptome-wide N6-methyladenosine (m6A) profiling have facilitated investigations into the RNA methylome and established m6A as a dynamic modification that has critical regulatory roles in gene expression and may play a role in human disease. However, bioinformatics resources available for the analysis of m6A sequencing data are still limited. Here, we describe m6aViewer-a cross-platform application for analysis and visualization of m6A peaks from sequencing data. m6aViewer implements a novel m6A peak-calling algorithm that identifies high-confidence methylated residues with more precision than previously described approaches. The application enables data analysis through a graphical user interface, and thus, in contrast to other currently available tools, does not require the user to be skilled in computer programming. m6aViewer and test data can be downloaded here: http://dna2.leeds.ac.uk/m6a. PMID- 28724536 TI - Authors' reply to Wicks. PMID- 28724535 TI - Priming in a permissive type I-C CRISPR-Cas system reveals distinct dynamics of spacer acquisition and loss. AB - CRISPR-Cas is a bacterial and archaeal adaptive immune system that uses short, invader-derived sequences termed spacers to target invasive nucleic acids. Upon recognition of previously encountered invaders, the system can stimulate secondary spacer acquisitions, a process known as primed adaptation. Previous studies of primed adaptation have been complicated by intrinsically high interference efficiency of most systems against bona fide targets. As such, most primed adaptation to date has been studied within the context of imperfect sequence complementarity between spacers and targets. Here, we take advantage of a native type I-C CRISPR-Cas system in Legionella pneumophila that displays robust primed adaptation even within the context of a perfectly matched target. Using next-generation sequencing to survey acquired spacers, we observe strand bias and positional preference that are consistent with a 3'-5' translocation of the adaptation machinery. We show that spacer acquisition happens in a wide range of frequencies across the plasmid, including a remarkable hotspot that predominates irrespective of the priming strand. We systematically characterize protospacer sequence constraints in both adaptation and interference and reveal extensive flexibilities regarding the protospacer adjacent motif in both processes. Lastly, in a strain with a genetically truncated CRISPR array, we observe increased interference efficiency, which, when coupled with forced maintenance of a targeted plasmid, provides a useful experimental system to study spacer loss. Based on these observations, we propose that the Legionella pneumophila type I-C system represents a powerful model to study primed adaptation and the interplay between CRISPR interference and adaptation. PMID- 28724537 TI - "Ethicolegal restrictions" restrict data sharing where it might help. PMID- 28724538 TI - Learning together. PMID- 28724539 TI - Racial and ethnic disparities in hematologic malignancies. AB - Racial and ethnic disparities in patients with solid malignancies have been well documented. Less is known about these disparities in patients with hematologic malignancies. With the advent of novel chemotherapeutics and targeted molecular, cellular, and immunologic therapies, it is important to identify differences in care that may lead to disparate outcomes. This review provides a critical appraisal of the empirical research on racial and ethnic disparities in incidence, survival, and outcomes in patients with hematologic malignancies. The review focuses on patients with acute myeloid leukemia, acute lymphocytic leukemia, multiple myeloma, non-Hodgkin lymphoma, Hodgkin lymphoma, myeloproliferative neoplasms, and myelodysplastic syndrome. The review discusses possible causes of racial and ethnic disparities and also considers future directions for studies to help decrease disparities. PMID- 28724540 TI - Targeting BCL-2 in B-cell lymphomas. AB - The B-cell leukemia/lymphoma-2 (BCL-2) family of proteins governs the intrinsic pathway of mitochondrial apoptosis. Dysregulation of BCL-2 has long been known to be a crucial part of the pathophysiology of B-cell lymphomas; however, several early attempts to target this pathway therapeutically were unsuccessful because of toxicity, lack of efficacy, or both. Recently, a highly potent and selective oral BCL-2 antagonist, venetoclax, was approved in chronic lymphocytic leukemia, where it has proven to be highly active, even in patients with high-risk del(17p) disease. Venetoclax has also demonstrated efficacy in other B-cell non-Hodgkin lymphoma subtypes, in particular mantle cell lymphoma and follicular lymphoma. Here, I review the history of targeting BCL-2 in B-cell lymphomas, and I discuss recent data on venetoclax used as monotherapy and in combination with monoclonal antibodies, chemotherapy, and other novel agents. I also discuss how genomic and functional approaches such as BH3 profiling may allow us to prioritize novel agent combinations for further study in clinical trials. These approaches may also help us to understand resistance mechanisms to BCL-2-selective therapy and how to overcome resistance. Finally, I provide my perspective on how to move BCL 2-directed therapies forward toward a goal of developing well-tolerated, time limited combination regimens with curative potential for patients with B-cell lymphomas. PMID- 28724542 TI - Sex and disability: time to treat all women as individuals. PMID- 28724541 TI - STIM1 and STIM2 cooperatively regulate mouse neutrophil store-operated calcium entry and cytokine production. AB - Neutrophils are key effector cells of the innate immune system. Calcium-dependent signaling pathways initiated by store-operated calcium entry (SOCE) are known to regulate neutrophil activation; however, the precise mechanism of this process remains unclear. STIM1 and STIM2 are calcium-sensing molecules that link calcium depletion of the endoplasmic reticulum with opening of plasma membrane calcium channels. Although a role for STIM1 in neutrophil SOCE and activation has been established, the function of STIM2 is unknown. Here we use mice with conditional ablation of Stim1 and/or Stim2 to investigate the role of STIM2 in neutrophil activation. We demonstrate that loss of STIM2 results in decreased SOCE, particularly at lower doses of agonists. Reactive oxygen species (ROS) production, degranulation, and phagocytosis are normal in the absence of STIM2, suggesting STIM1 is the dominant calcium sensor required for classical short-term neutrophil responses. However, neutrophil cytokine production required STIM2, but not STIM1, at least in part as a result of redox regulation of cytokine gene expression. In vivo loss of STIM2 results in lower cytokine levels and protection from mortality in a mouse model of systemic inflammatory response syndrome. These data, combined with previous studies focusing on STIM1, define distinct but cooperative functions for STIM1 and STIM2 in modulating neutrophil bactericidal and cytokine responses. PMID- 28724543 TI - Cervical cancer screening in rural Bhutan with the careHPV test on self-collected samples: an ongoing cross-sectional, population-based study (REACH-Bhutan). AB - OBJECTIVES: The Bhutanese Screening Programme recommends a Pap smear every 3 years for women aged 25-65 years, and coverage ranges from 20% to 60%, being especially challenging in rural settings. The 'REACH-Bhutan' study was conducted to assess the feasibility and outcomes of a novel approach to cervical cancer screening in rural Bhutan. DESIGN: Cross-sectional, population-based study of cervical cancer screening based on the careHPV test on self-collected samples. SETTING: Women were recruited in rural primary healthcare centres, that is, Basic Health Units (BHU), across Bhutan. PARTICIPANTS: Overall, 3648 women aged 30-60 were invited from 15 BHUs differing in accessibility, size and ethnic composition of the population. INTERVENTIONS: Participants provided a self-collected cervicovaginal sample and were interviewed. Samples were tested using careHPV in Thimphu (the Bhutanese capital) referral laboratory. MAIN OUTCOME MEASURES: Screening participation by geographic area, centre, age and travelling time. Previous screening history and careHPV positivity by selected characteristics of the participants. RESULTS: In April/May 2016, 2590 women (median age: 41) were enrolled. Study participation was 71% and significantly heterogeneous by BHU (range: 31%-96%). Participation decreased with increase in age (81% in women aged 30-39 years; 59% in >=50 years) and travelling time (90% in women living <30 min from the BHU vs 62% among those >6 hours away). 50% of participants reported no previous screening, with the proportion of never-screened women varying significantly by BHU (range: 2%-72%). 265 women (10%; 95% CI 9% to 11%) were careHPV positive, with a significant variation by BHU (range: 5%-19%) and number of sexual partners (prevalence ratio for >=3 vs 0-1, 1.55; 95% CI 1.05 to 2.27). CONCLUSIONS: Community-based cervical cancer screening by testing self-collected samples for human papillomavirus (HPV) can achieve high coverage in rural Bhutan. However, solutions to bring self-collection, HPV testing and precancer treatment closer to the remotest villages are needed. PMID- 28724545 TI - Magnetic resonance spectroscopy in preterm infants: association with neurodevelopmental outcomes. AB - OBJECTIVE: To compare magnetic resonance spectroscopy (MRS) metabolite ratios in preterm infants at term-equivalent age with those in term infants and to evaluate the association between MRS metabolites and neurodevelopmental outcomes at 18 months corrected age in preterm infants. DESIGN: We studied infants born at a gestational age <37 weeks and weighing <1500 g during 2009-2013 using MRS at term equivalent age. Infants with major brain abnormalities were excluded. The ratios of N-acetylaspartate (NAA) to creatine (Cre), NAA to choline-containing compounds (Cho) and Cho to Cre in the frontal white matter and thalamus were measured using multivoxel point-resolved proton spectroscopy sequence. Neurodevelopmental outcomes were assessed at 18 months corrected age. RESULTS: Thirty-three preterm infants and 16 term infants were enrolled in this study. Preterm infants with normal development at 18 months showed significantly lower NAA/Cho ratios in the frontal white matter than term infants. There were no differences in the Cre/Cho ratios between preterm and term infants. At 18 months corrected age, 9 preterm infants with a mild developmental delay showed significantly lower NAA/Cho ratios in the thalamus than 24 preterm infants with normal development. CONCLUSIONS: Preterm infants at term-equivalent age showed reduced MRS metabolites (NAA/Cho) compared with term infants. Decreased NAA/Cho ratios in the thalamus were associated with neurodevelopmental delay at 18 months corrected age in preterm infants. PMID- 28724544 TI - MICA-Expressing Monocytes Enhance Natural Killer Cell Fc Receptor-Mediated Antitumor Functions. AB - Natural killer (NK) cells are large granular lymphocytes that promote the antitumor response via communication with other cell types in the tumor microenvironment. Previously, we have shown that NK cells secrete a profile of immune stimulatory factors (e.g., IFNgamma, MIP-1alpha, and TNFalpha) in response to dual stimulation with the combination of antibody (Ab)-coated tumor cells and cytokines, such as IL12. We now demonstrate that this response is enhanced in the presence of autologous monocytes. Monocyte enhancement of NK cell activity was dependent on cell-to-cell contact as determined by a Transwell assay. It was hypothesized that NK cell effector functions against Ab-coated tumor cells were enhanced via binding of MICA on monocytes to NK cell NKG2D receptors. Strategies to block MICA-NKG2D interactions resulted in reductions in IFNgamma production. Depletion of monocytes in vivo resulted in decreased IFNgamma production by murine NK cells upon exposure to Ab-coated tumor cells. In mice receiving trastuzumab and IL12 therapy, monocyte depletion resulted in significantly greater tumor growth in comparison to mock-depleted controls (P < 0.05). These data suggest that NK cell-monocyte interactions enhance NK cell antitumor activity in the setting of monoclonal Ab therapy for cancer. Cancer Immunol Res; 5(9); 778-89. (c)2017 AACR. PMID- 28724546 TI - High-protein diet improves sensitivity to cholecystokinin and shifts the cecal microbiome without altering brain inflammation in diet-induced obesity in rats. AB - High-protein diet (HPD) curtails obesity and/or fat mass, but it is unknown whether it reverses neuroinflammation or alters glucose levels, CCK sensitivity, and gut microbiome in rats fed a Western diet (WD)-induced obesity (DIO). Male rats fed a WD (high fat and sugar) for 12 wk were switched to a HPD for 6 wk. Body composition, food intake, meal pattern, sensitivity to intraperitoneal CCK 8S, blood glucose, brain signaling, and cecal microbiota were assessed. When compared with a normal diet, WD increased body weight (9.3%) and fat mass (73.4%). CCK-8S (1.8 or 5.2 nmol/kg) did not alter food intake and meal pattern in DIO rats. Switching to a HPD for 6 wk reduced fat mass (15.7%) with a nonsignificantly reduced body weight gain, normalized blood glucose, and decreased feeding after CCK-8S. DIO rats on the WD or switched to a HPD showed comparable microbial diversity. However, in HPD versus WD rats, there was enrichment of 114 operational taxonomic units (OTUs) and depletion of 188 OTUs. Of those, Akkermansia muciniphila (enriched on a HPD), an unclassified Clostridiales, a member of the RF39 order, and a Phascolarctobacterium were significantly associated with fat mass. The WD increased cytokine expression in the hypothalamus and dorsal medulla that was unchanged by switching to HPD. These data indicate that HPD reduces body fat and restores glucose homeostasis and CCK sensitivity, while not modifying brain inflammation. In addition, expansion of cecal Akkermansia muciniphila correlated to fat mass loss may represent a potential peripheral mechanism of HPD beneficial effects. PMID- 28724548 TI - Bradykinin does not acutely sensitize the reflex pressor response during hindlimb skeletal muscle stretch in decerebrate rats. AB - Hindlimb skeletal muscle stretch (i.e., selective activation of the muscle mechanoreflex) in decerebrate rats evokes reflex increases in blood pressure and sympathetic nerve activity. Bradykinin has been found to sensitize mechanogated channels through a bradykinin B2 receptor-dependent mechanism. Moreover, bradykinin B2 receptor expression on sensory neurons is increased following chronic femoral artery ligation in the rat (a model of simulated peripheral artery disease). We tested the hypothesis that injection of bradykinin into the arterial supply of a hindlimb in decerebrate, unanesthetized rats would acutely augment (i.e., sensitize) the increase in blood pressure and renal sympathetic nerve activity during hindlimb muscle stretch to a greater extent in rats with a ligated femoral artery than in rats with a freely perfused femoral artery. The pressor response during static hindlimb muscle stretch was compared before and after hindlimb arterial injection of 0.5 ug of bradykinin. Injection of bradykinin increased blood pressure to a greater extent in "ligated" (n = 10) than "freely perfused" (n = 10) rats. The increase in blood pressure during hindlimb muscle stretch, however, was not different before vs. after bradykinin injection in freely perfused (14 +/- 2 and 15 +/- 2 mmHg for pre- and post bradykinin, respectively, P = 0.62) or ligated (15 +/- 3 and 14 +/- 2 mmHg for pre- and post-bradykinin, respectively, P = 0.80) rats. Likewise, the increase in renal sympathetic nerve activity during stretch was not different before vs. after bradykinin injection in either group of rats. We conclude that bradykinin did not acutely sensitize the pressor response during hindlimb skeletal muscle stretch in freely perfused or ligated decerebrate rats. PMID- 28724549 TI - Identification of new tumor suppressor genes in triple-negative breast cancer. AB - Although genomic sequencing has provided a better understating of the genetic landmarks in triple-negative breast cancer (TNBC), functional validation of candidate cancer genes (CCG) remains unsolved. In this study, we used a transposon mutagenesis strategy based on a two-step Sleeping Beauty (SB) forward genetic screen to identify and validate new tumor suppressors (TS) in this disease. We generated 120 siRNAs targeting 40 SB-identified candidate breast cancer TS genes and used them to downregulate expression of these genes in four human TNBC cell lines. Among CCG whose SB-mediated genetic mutation resulted in increased cellular proliferation in all cell lines tested, the genes ADNP, AP2B1, TOMM70A and ZNF326 showed tumor suppressor (TS) activity in tumor xenograft studies. Subsequent studies showed that ZNF326 regulated expression of multiple EMT and cancer stem cell (CSC) pathway genes. It also modulated expression of TS genes involved in the regulation of migration and cellular invasion and was a direct transcriptional activator of genes that regulate CSC self-renewal. ZNF326 expression associated with TNBC patient survival, with ZNF326 protein levels showing a marked reduction in TNBC. Our validation of several new tumor suppressor genes in TNBC demonstrate the utility of two-step forward genetic screens in mice, and offer an invaluable tool to identify novel candidate therapeutic pathways and targets. PMID- 28724547 TI - Long-term effects of a renin inhibitor versus a thiazide diuretic on arterial stiffness and left ventricular diastolic function in elderly hypertensive patients. AB - Arterial stiffness and cardiac function are important predictors of cardiovascular events in patients with hypertension, even with adequate blood pressure (BP) control. We evaluated whether a direct renin inhibitor, aliskiren, reduces arterial stiffness and modulates left ventricular function compared with a diuretic, hydrochlorothiazide, in elderly hypertensive patients. Twenty-one hypertensive patients [67 +/- 14 (SD) yr] were randomly assigned to receive 6-mo aliskiren (n = 11) or hydrochlorothiazide (n = 10)-based therapy. We assessed beta-stiffness of the local arteries, arterial elastance (Ea), and echocardiographic variables, including early (E) and late (A) mitral inflow velocity, deceleration time of E, early (E') and late (A') diastolic mitral annular velocity, and left ventricular end-systolic elastance (Ees) before and after treatment. BP decreased similarly (P < 0.001) after both therapies. beta Stiffness of the carotid artery decreased after aliskiren but increased after hydrochlorothiazide treatment (aliskiren: 6.42 +/- 2.34 pre vs. 5.07 +/- 1.29 post; hydrochlorothiazide: 5.05 +/- 1.78 vs. 7.25 +/- 2.68, P = 0.001 for interaction). beta-Stiffness of the femoral and radial arteries were not different after either treatment. Different from aliskiren, E decreased (73 +/- 16 vs. 67 +/- 14 cm/s, P = 0.026), and the deceleration time was prolonged (218 +/- 40 vs. 236 +/- 35 ms, P = 0.032) after hydrochlorothiazide therapy, whereas the E/A, and E' remained unchanged after both treatments. Ea and Ees decreased after aliskiren therapy (both P < 0.05), whereas the Ea/Ees (ventricular-arterial coupling) was maintained after both treatments. Thus, aliskiren decreased the stiffness of carotid artery and left ventricular end-systolic elastance with maintenance of ventricular-arterial coupling without any effects on diastolic filling, while hydrochlorothiazide increased carotid arterial stiffness and slowed early diastolic filling in elderly hypertensive patients. PMID- 28724550 TI - Diet and exercise in pregnancy. PMID- 28724551 TI - Evaluation of a pilot police-led suicide early alert surveillance strategy in the UK. AB - INTRODUCTION: Those bereaved by suicide are at increased risk of psychological harm, which can be reduced with the provision of timely support. This paper outlines an evaluation of a pilot police-led suicide strategy, in comparison to a coroner-led suicide strategy looking at the number, and length of time it takes for deaths to be recorded for each strategy. Additionally, the police-led strategy offers timely contact from support services for bereaved individuals. We examined what impact this offer of support had on the capacity of support services. METHODS: A mixed methods evaluation compared how long it took for suspected suicides to be recorded using both strategies. The number of referrals received by support services during the pilot strategy were compared with those from previous years. A feedback focus group, and interviews, were held with key stakeholders. RESULTS: The coroner strategy was more consistent at identifying suspected suicides; however, reports were filed quicker by the police. Bereaved individuals were willing to share contact details with police officers and consent for referral to support services which lead to increased referrals. The focus group and interviews revealed that the pilot police strategy needs better integration into routine police practice. CONCLUSIONS: This strategy has the potential to deliver a real benefit to those bereaved by suicide; however, there are still aspects which could be improved. PMID- 28724552 TI - Cost of injury care in India: cross-sectional analysis of National Sample Survey 2014. AB - BACKGROUND: Injuries account for nearly 10% of total deaths in India and this burden is likely to rise. We aimed to estimate the out-of-pocket (OOP) expenditure and catastrophic expenditure due to hospitalisation or outpatient care as a result of any injury and factors associated with incurring catastrophic expenditure. METHODS: Secondary analysis of nationally representative data for India collected by National Sample Survey Organization in 2014, reporting on health service utilisation and healthcare-related OOP expenditure by income quintiles and by type of health facility (public or private). RESULTS: The median expenditure per episode of hospitalisation due to any injury was US$156, and it was three times higher among the richest quintile compared with the poorest quintile (p<0.001). There was a significantly higher prevalence (p<0.001) of catastrophic expenditure among the poorest quintile (32%) compared with the richest (21%). Mean private sector OOP hospitalisation expenditure was five times higher than in the public sector (p<0.001). Medicines accounted for 37% and 58% of public sector hospitalisation and outpatient care, respectively. Patients treated in a private facility, hospitalised for over 7 days, in the poorest wealth quintiles and of general caste had higher odds of incurring catastrophic expenditure. CONCLUSION: People who sustain an injury have a high risk of catastrophic household expenditure, particularly for those in lowest income quartiles. There is a clear need for publicly funded risk protection mechanisms targeting the poor. Promotion of generic medicines and subsidisation for the poorest wealth quintile may also reduce OOP expenditure in public sector facilities. PMID- 28724553 TI - US Republican attempt to repeal and replace Affordable Care Act collapses. PMID- 28724554 TI - Prevalence of Human Papillomavirus in Self-Taken Samples from Screening Nonattenders. AB - The Copenhagen Self-Sampling Initiative (CSi) has shown how human papillomavirus (HPV)-based self-sampling can be used to increase screening participation among 23,632 nonattenders in the Capital Region of Denmark. In this study, we describe HPV prevalence and genotype frequency in 4,824 self-samples as determined by three HPV assays (the CLART, Onclarity, and Hybrid Capture 2 [HC2] assays) and compare the results with those for physician-taken follow-up samples. The HPV self-sample findings were also compared to the findings for a reference population of 3,347 routinely screened women from the Horizon study, which had been undertaken in the same screening laboratory. Nonattenders had an HPV prevalence of 11.3% as determined by the CLART assay, which was lower than that for women from the Horizon study (18.5%). One-third of the CSi women who tested HPV positive by self-sampling tested HPV negative on the physician-taken follow up sample. The CLART and Onclarity assays agreed on 64% (95% confidence interval [CI], 60 to 68%) of the HPV-positive self-taken samples. When the HC2 assay results were added into a three-way comparison, the level of agreement decreased to 27% (95% CI, 24 to 29%). Our findings suggest that further validation of HPV assays on self-taken samples is needed for optimal HPV detection and correct clinical management of HPV-positive women. PMID- 28724555 TI - Susceptibility Testing for the Polymyxins: Two Steps Back, Three Steps Forward? AB - Optimizing and standardizing susceptibility testing for the polymyxins have become pressing issues, given the rise in multidrug-resistant Gram-negative bacilli. Recently, both the CLSI and EUCAST have recommended broth microdilution (BMD) (without polysorbate) as the reference method for polymyxin susceptibility testing. In this issue, K. L. Chew et al. (J Clin Microbiol 55:2609-2616, 2017, https://doi.org/10.1128/JCM.00268-17) compare the performances of three commercial BMD panels and the Etest to the reference, BMD, for polymyxin B and colistin, using 76 Enterobacteriaceae isolates (21 of which were mcr-1 positive). Although none of the commercial BMD panels strictly met FDA performance standards in this evaluation, possibly because of the small number isolates tested, the Sensititre panel achieved >90% categorical agreement for both polymyxin compounds. These results also reaffirm CLSI and EUCAST guidance that gradient diffusion testing, which had unacceptable error rates, should be abandoned. In a simulated analysis with lowered breakpoints (susceptible, <=1 mg/liter; intermediate, 2 mg/liter; resistant, >=4 mg/liter), error rates and agreement were improved across the various methods and the rate of detection of mcr-1 positive isolates improved. These observations, taken together with recent pharmacokinetic data on optimizing target attainment for the polymyxins, suggest that more-stringent (lower) breakpoints may be reasonable, although such an approach may be limited by the inherent reliability of current testing methodologies and a lack of robust clinical correlative data, which are sorely needed. PMID- 28724556 TI - Performance Assessment of a Trypanosoma cruzi Chimeric Antigen in Multiplex Liquid Microarray Assays. AB - Diagnosing chronic Chagas disease (CD) requires antibody-antigen detection methods, which are traditionally based on enzymatic assay techniques whose performance depend on the type and quality of antigen used. Previously, 4 recombinant chimeric proteins from the Instituto de Biologia Molecular do Parana (IBMP-8.1 to 8.4) comprising immuno-dominant regions of diverse Trypanosoma cruzi antigens showed excellent diagnostic performance in enzyme-linked immunosorbent assays. Considering that next-generation platforms offer improved CD diagnostic accuracy with different T. cruzi-specific recombinant antigens, we assessed the performance of these chimeras in liquid microarrays (LMAs). The chimeric proteins were expressed in Escherichia coli and purified by chromatography. Sera from 653 chagasic and 680 healthy individuals were used to assess the performance of these chimeras in detecting specific anti-T. cruzi antibodies. Accuracies ranged from 98.1 to 99.3%, and diagnostic odds ratio values were 3,548 for IBMP-8.3, 4,826 for IBMP-8.1, 7,882 for IBMP-8.2, and 25,000 for IBMP-8.4. A separate sera bank (851 samples) was employed to assess cross-reactivity with other tropical diseases. Leishmania, a pathogen with high similarity to T. cruzi, showed cross reactivity rates ranging from 0 to 2.17%. Inconclusive results were negligible (0 to 0.71%). Bland-Altman and Deming regression analysis based on 200 randomly selected CD-positive and negative samples demonstrated interchangeability with respect to CD diagnostic performance in both singleplex and multiplex assays. Our results suggested that these chimeras can potentially replace antigens currently used in commercially available assay kits. Moreover, the use of multiplex platforms, such as LMA assays employing 2 or more IBMP antigens, would abrogate the need for 2 different testing techniques when diagnosing CD. PMID- 28724557 TI - The Human Virome: Implications for Clinical Practice in Transplantation Medicine. AB - Advances in DNA sequencing technology have provided an unprecedented opportunity to study the human virome. Transplant recipients and other immunocompromised hosts are at particular risk for developing virus-related pathology; thus, the impact of the virome on health and disease may be even more relevant in this population. Here, we discuss technical considerations in studying the human virome, the current literature on the virome in transplant recipients, and near future applications of sequence-based findings that can further our understanding of viruses in transplantation medicine. PMID- 28724558 TI - Molecular Diagnostics Update for the Emerging (If Not Already Widespread) Sexually Transmitted Infection Agent Mycoplasma genitalium: Just About Ready for Prime Time. AB - Mycoplasma genitalium is an important and emerging agent of sexually transmitted infection in females and males, carrying the potential for postinfection genital tract sequelae. Past efforts to identify this organism on a routine basis, which were problematic due to the fastidious nature of the bacterium and its antigenic intricacies, have recently become supplemented by molecular diagnostics. A number of these assays are available commercially. This minireview describes the format and performance indices of a number of M. genitalium DNA- and RNA-based amplification assays; many of these assays have contributed to an improved clinical and epidemiologic understanding of this organism. PMID- 28724559 TI - Identification of Leishmania by Matrix-Assisted Laser Desorption Ionization-Time of Flight (MALDI-TOF) Mass Spectrometry Using a Free Web-Based Application and a Dedicated Mass-Spectral Library. AB - Human leishmaniases are widespread diseases with different clinical forms caused by about 20 species within the Leishmania genus. Leishmania species identification is relevant for therapeutic management and prognosis, especially for cutaneous and mucocutaneous forms. Several methods are available to identify Leishmania species from culture, but they have not been standardized for the majority of the currently described species, with the exception of multilocus enzyme electrophoresis. Moreover, these techniques are expensive, time-consuming, and not available in all laboratories. Within the last decade, mass spectrometry (MS) has been adapted for the identification of microorganisms, including Leishmania However, no commercial reference mass-spectral database is available. In this study, a reference mass-spectral library (MSL) for Leishmania isolates, accessible through a free Web-based application (mass-spectral identification [MSI]), was constructed and tested. It includes mass-spectral data for 33 different Leishmania species, including species that infect humans, animals, and phlebotomine vectors. Four laboratories on two continents evaluated the performance of MSI using 268 samples, 231 of which were Leishmania strains. All Leishmania strains, but one, were correctly identified at least to the complex level. A risk of species misidentification within the Leishmania donovani, L. guyanensis, and L. braziliensis complexes was observed, as previously reported for other techniques. The tested application was reliable, with identification results being comparable to those obtained with reference methods but with a more favorable cost-efficiency ratio. This free online identification system relies on a scalable database and can be implemented directly in users' computers. PMID- 28724560 TI - Accurate Detection of Methicillin-Resistant Staphylococcus aureus in Mixtures by Use of Single-Bacterium Duplex Droplet Digital PCR. AB - Accurate and rapid identification of methicillin-resistant Staphylococcus aureus (MRSA) is needed to screen MRSA carriers and improve treatment. The current widely used duplex PCR methods are not able to differentiate MRSA from coexisting methicillin-susceptible S. aureus (MSSA) or other methicillin-resistant staphylococci. In this study, we aimed to develop a direct method for accurate and rapid detection of MRSA in clinical samples from open environments, such as nasal swabs. The new molecular assay is based on detecting the cooccurrence of nuc and mecA markers in a single bacterial cell by utilizing droplet digital PCR (ddPCR) with the chimeric lysin ClyH for cell lysis. The method consists of (i) dispersion of an intact single bacterium into nanoliter droplets, (ii) temperature-controlled release of genomic DNA (gDNA) by ClyH at 37 degrees C, and (iii) amplification and detection of the markers (nuc and mecA) using standard TaqMan chemistries with ddPCR. Results were analyzed based on MRSA index ratios used for indicating the presence of the duplex-positive markers in droplets. The method was able to achieve an absolute limit of detection (LOD) of 2,900 CFU/ml for MRSA in nasal swabs spiked with excess amounts of Escherichia coli, MSSA, and other mecA-positive bacteria within 4 h. Initial testing of 104 nasal swabs showed that the method had 100% agreement with the standard culture method, while the normal duplex qPCR method had only about 87.5% agreement. The single bacterium duplex ddPCR assay is rapid and powerful for more accurate detection of MRSA directly from clinical specimens. PMID- 28724561 TI - Management of antithrombotic agents in patients undergoing flexible bronchoscopy. AB - Bleeding is one of the most feared complications of flexible bronchoscopy. Although infrequent, it can be catastrophic and result in fatal outcomes. Compared to other endoscopic procedures, the risk of morbidity and mortality from the bleeding is increased, as even a small amount of blood can fill the tracheobronchial tree and lead to respiratory failure. Patients using antithrombotic agents (ATAs) have higher bleeding risk. A thorough understanding of the different ATAs is critical to manage patients during the peri-procedural period. A decision to stop an ATA before bronchoscopy should take into account a variety of factors, including indication for its use and the type of procedure. This article serves as a detailed review on the different ATAs, their pharmacokinetics and the pre- and post-bronchoscopy management of patients receiving these medications. PMID- 28724562 TI - The role of macrophages in interstitial lung diseases: Number 3 in the Series "Pathology for the clinician" Edited by Peter Dorfmuller and Alberto Cavazza. AB - The finding of collections of macrophages/histiocytes in lung biopsy and bronchoalveolar lavage is relatively common in routine practice. This morphological feature in itself is pathological, but the exact clinical significance and underlying disease should be evaluated together with clinical data, functional respiratory and laboratory tests and imaging studies.Morphological characteristics of macrophages and their distribution along the different pulmonary structures should be examined carefully by pathologists. Indeed, haemosiderin-laden macrophages are associated with smoking-related diseases when pigment is fine and distribution is bronchiolocentric, while alveolar haemorrhage or pneumoconiosis are the main concerns when pigment is chunky or coarse and the macrophages show an intra-alveolar or perilymphatic location, respectively. In the same way, pulmonary accumulation of macrophages with foamy cytoplasm is generally associated with pathologies leading to broncho bronchiolar obstruction (e.g. diffuse panbronchiolitis, hypersensitivity pneumonia or cryptogenic organising pneumonia) or alternatively to exogenous lipoid pneumonia, some drug toxicity (e.g. amiodarone exposure or toxicity) and metabolic disorders (e.g. type B Niemann-Pick disease).This pathology-based perspectives article is aimed at concisely describing the diagnostic possibilities when faced with collection of macrophages in lung biopsy and cytology. PMID- 28724563 TI - Management of anticoagulant and antiplatelet therapy in patients undergoing interventional pulmonary procedures. AB - There has been great progress in antithrombotic therapy over the past several years. Its use has increased with the advent of novel anticoagulants, as these medications do not require frequent blood tests for monitoring. Antithrombotic therapy is aimed at reducing the risk of thromboembolic events in patients with atrial fibrillation, coronary artery disease, deep vein thrombosis, valvular heart disease and pulmonary embolism. These patients are often critically ill and frequently undergo urgent interventions requiring discontinuation of anticoagulant or antiplatelet therapy which can increase the risk of thrombosis; however, continuing these agents can lead to increased risk of haemorrhage.The purpose of this article is to summarise the literature surrounding the safety of using antiplatelet and anticoagulant therapies in patients undergoing interventional pulmonary procedures. PMID- 28724564 TI - Bronchoscopy and bleeding risk. PMID- 28724565 TI - The answer is not always in black and white: a frequently missed diagnosis in a child presenting with elbow pain. PMID- 28724566 TI - BET 1: Lidocaine with propofol to reduce pain on injection. AB - A short review was carried out to see if mixing lidocaine with propofol is a safe and effective method in reducing the commonly reported pain at the injection site. Four relevant papers were found using the described search strategy. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these papers are tabulated. Although a promising idea, a paucity of good quality evidence suggests further needed research. PMID- 28724568 TI - BET 2: Poor evidence on whether teaching cognitive debiasing, or cognitive forcing strategies, lead to a reduction in errors attributable to cognition in emergency medicine students or doctors. AB - A short review was carried out to see if teaching cognitive forcing strategies reduces cognitive error in the practice of emergency medicine. Two relevant papers were found using the described search strategy. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these papers are tabulated. There is currently little evidence that teaching cognitive forcing strategies reduces cognitive error in the practice of emergency medicine. PMID- 28724569 TI - A 7-month-old with 'loss of muscle control'. PMID- 28724570 TI - Childhood thyroid function, body composition and cardiovascular function. AB - OBJECTIVE: The cardiovascular system is a known target for thyroid hormone. Early life cardiovascular alterations may lead to a higher risk of cardiovascular disease in adulthood. Little is known about the effects of thyroid hormone on cardiovascular function during childhood, including the role of body composition in this association. DESIGN: Population-based prospective cohort of children (n = 4251, median age 6 years, 95% range: 5.7-8.0 years). METHODS: Thyroid-stimulating hormone (TSH) and free thyroxine (FT4) concentrations were measured to assess thyroid function. Left ventricular (LV) mass was assessed with echocardiography. Arterial stiffness was assessed with carotid-femoral pulse wave velocity (CFPWV). Systolic and diastolic blood pressure (BP) was measured. Body composition was assessed by dual-energy X-ray absorptiometry scan. RESULTS: FT4 was inversely associated with LV mass (P = 0.002), and with lean body mass (P < 0.0001). The association of FT4 with LV mass was partially mediated through variability in lean body mass (55% mediated effect). TSH was inversely associated with LV mass (P = 0.010), predominantly in boys. TSH was positively associated with systolic and diastolic BP (both P < 0.001). FT4 was positively associated with CFPWV and diastolic BP (P < 0.0001, P = 0.008, respectively), and the latter association attenuated after adjustment for CFPWV. CONCLUSIONS: At the age of 6 years, higher FT4 is associated with lower LV mass (partially through effects on lean body mass) and with higher arterial stiffness, which may lead to higher BP. Our data also suggest different mechanisms via which TSH and FT4 are associated with cardiovascular function during early childhood. PMID- 28724571 TI - Comparison of Recruitment Strategy Outcomes in the National Children's Study. AB - BACKGROUND AND OBJECTIVES: In 2000, the US Congress authorized the National Institutes of Health to conduct a prospective national longitudinal study of environmental influences on children's health and development from birth through 21 years. Several recruitment methodologies were piloted to determine the optimal strategy for a main National Children's Study. METHODS: After an initial pilot recruitment that used a household enumeration strategy performed poorly, the National Children's Study Vanguard Study developed and evaluated the feasibility, acceptability, and cost of 4 alternate strategies to recruit a large prospective national probability sample of pregnant women and their newborn children. We compare household-based recruitment, provider-based recruitment, direct outreach, and provider-based sampling (PBS) strategies with respect to overall recruitment success, efficiency, cost, and fulfillment of scientific requirements. RESULTS: Although all 5 strategies achieved similar enrollment rates (63%-81%) among eligible women, PBS achieved the highest recruitment success as measured by the ratio of observed-to-expected newborn enrollees per year of 0.99, exceeding those of the other strategies (range: 0.35-0.48). Because PBS could reach the enrollment target through sampling of high volume obstetric provider offices and birth hospitals, it achieved the lowest ratio of women screened to women enrolled and was also the least costly strategy. With the exception of direct outreach, all strategies enrolled a cohort of women whose demographics were similar to county natality data. CONCLUSIONS: PBS demonstrated the optimal combination of recruitment success, efficiency, cost, and population representativeness and serves as a model for the assembly of future prospective probability-based birth cohorts. PMID- 28724572 TI - A New Case of Congenital Malabsorptive Diarrhea and Diabetes Secondary to Mutant Neurogenin-3. AB - Congenital diarrheal disorders are a group of rare enteropathies that often present with life-threatening diarrhea in the first weeks of life. Enteric anendocrinosis, characterized by a lack of intestinal enteroendocrine cells due to recessively inherited mutations in the Neurogenin-3 (NEUROG3) gene, has been described as a cause of congenital malabsorptive diarrhea. Diabetes mellitus also is typically associated with NEUROG3 mutations, be it early onset or a later presentation. Here we report a case of a 16-year-old male patient with severe malabsorptive diarrhea from birth, who was parenteral nutrition dependent and who developed diabetes mellitus at 11 years old. To the best of our knowledge, only 9 cases of recessively inherited NEUROG3 mutations have been reported in the literature to date. Our patient presents with several remarkable differences compared with previously published cases. This report can contribute by deepening our knowledge on new aspects of such an extremely rare disease. PMID- 28724573 TI - A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma. AB - We conducted a first-in-human study of intravenous delivery of a single dose of autologous T cells redirected to the epidermal growth factor receptor variant III (EGFRvIII) mutation by a chimeric antigen receptor (CAR). We report our findings on the first 10 recurrent glioblastoma (GBM) patients treated. We found that manufacturing and infusion of CAR-modified T cell (CART)-EGFRvIII cells are feasible and safe, without evidence of off-tumor toxicity or cytokine release syndrome. One patient has had residual stable disease for over 18 months of follow-up. All patients demonstrated detectable transient expansion of CART EGFRvIII cells in peripheral blood. Seven patients had post-CART-EGFRvIII surgical intervention, which allowed for tissue-specific analysis of CART EGFRvIII trafficking to the tumor, phenotyping of tumor-infiltrating T cells and the tumor microenvironment in situ, and analysis of post-therapy EGFRvIII target antigen expression. Imaging findings after CART immunotherapy were complex to interpret, further reinforcing the need for pathologic sampling in infused patients. We found trafficking of CART-EGFRvIII cells to regions of active GBM, with antigen decrease in five of these seven patients. In situ evaluation of the tumor environment demonstrated increased and robust expression of inhibitory molecules and infiltration by regulatory T cells after CART-EGFRvIII infusion, compared to pre-CART-EGFRvIII infusion tumor specimens. Our initial experience with CAR T cells in recurrent GBM suggests that although intravenous infusion results in on-target activity in the brain, overcoming the adaptive changes in the local tumor microenvironment and addressing the antigen heterogeneity may improve the efficacy of EGFRvIII-directed strategies in GBM. PMID- 28724574 TI - The microvascular niche instructs T cells in large vessel vasculitis via the VEGF Jagged1-Notch pathway. AB - Microvascular networks in the adventitia of large arteries control access of inflammatory cells to the inner wall layers (media and intima) and thus protect the immune privilege of the aorta and its major branches. In autoimmune vasculitis giant cell arteritis (GCA), CD4 T helper 1 (TH1) and TH17 cells invade into the wall of the aorta and large elastic arteries to form tissue-destructive granulomas. Whether the disease microenvironment provides instructive cues for vasculitogenic T cells is unknown. We report that adventitial microvascular endothelial cells (mvECs) perform immunoregulatory functions by up-regulating the expression of the Notch ligand Jagged1. Vascular endothelial growth factor (VEGF), abundantly present in GCA patients' blood, induced Jagged1 expression, allowing mvECs to regulate effector T cell induction via the Notch-mTORC1 (mammalian target of rapamycin complex 1) pathway. We found that circulating CD4 T cells in GCA patients have left the quiescent state, actively signal through the Notch pathway, and differentiate into TH1 and TH17 effector cells. In an in vivo model of large vessel vasculitis, exogenous VEGF functioned as an effective amplifier to recruit and activate vasculitogenic T cells. Thus, systemic VEGF co opts endothelial Jagged1 to trigger aberrant Notch signaling, biases responsiveness of CD4 T cells, and induces pathogenic effector functions. Adventitial microvascular networks function as an instructive tissue niche, which can be exploited to target vasculitogenic immunity in large vessel vasculitis. PMID- 28724575 TI - A multidirectional gravity-assist algorithm that enhances locomotor control in patients with stroke or spinal cord injury. AB - Gait recovery after neurological disorders requires remastering the interplay between body mechanics and gravitational forces. Despite the importance of gravity-dependent gait interactions and active participation for promoting this learning, these essential components of gait rehabilitation have received comparatively little attention. To address these issues, we developed an adaptive algorithm that personalizes multidirectional forces applied to the trunk based on patient-specific motor deficits. Implementation of this algorithm in a robotic interface reestablished gait dynamics during highly participative locomotion within a large and safe environment. This multidirectional gravity-assist enabled natural walking in nonambulatory individuals with spinal cord injury or stroke and enhanced skilled locomotor control in the less-impaired subjects. A 1-hour training session with multidirectional gravity-assist improved locomotor performance tested without robotic assistance immediately after training, whereas walking the same distance on a treadmill did not ameliorate gait. These results highlight the importance of precise trunk support to deliver gait rehabilitation protocols and establish a practical framework to apply these concepts in clinical routine. PMID- 28724576 TI - Erratum for the Research Article: "Neoadjuvant chemotherapy induces breast cancer metastasis through a TMEM-mediated mechanism" by G. S. Karagiannis, J. M. Pastoriza, Y. Wang, A. S. Harney, D. Entenberg, J. Pignatelli, V. P. Sharma, E. A. Xue, E. Cheng, T. M. D'Alfonso, J. G. Jones, J. Anampa, T. E. Rohan, J. A. Sparano, J. S. Condeelis, M. H. Oktay. PMID- 28724578 TI - Induction of Regulatory T Cells and Its Regulation with Insulin-like Growth Factor/Insulin-like Growth Factor Binding Protein-4 by Human Mesenchymal Stem Cells. AB - Human mesenchymal stem cells (MSCs) are multipotent and exert anti-inflammatory effects, but the underlying mechanism remains to be elucidated. In the current study, we investigated the regulatory mechanism of regulatory T cell (Treg) induction through the growth factors released by human MSCs. Human naive CD4+ T cells were stimulated with anti-CD3/28 Abs and cocultured with human MSC culture supernatant for 48 h. The proliferation and cytokine production of CD4+ T cells and surface molecule expression on CD4+ T cells were evaluated. The proliferation of anti-CD3/28 Abs-stimulated CD4+ T cells was suppressed by the addition of human MSC culture supernatant; in addition, the production of IL-10 and IL-4 increased. The human MSC culture supernatant induced CD4+FOXP3+ Tregs that expressed CD25, CTLA-4, glucocorticoid-induced TNFR-related protein, insulin-like growth factor (IGF)-1R, and IGF-2R, showing antiproliferative activity against CD4+ T cells. In addition, the induction of Tregs by human MSC culture supernatant was enhanced by the addition of IGF and suppressed by the inhibition of IGF-1R. In contrast, a significant amount of IGF binding protein (IGFBP)-4, an inhibitor of IGF action, was detected in the human MSC culture supernatant. After neutralization of IGFBP-4 in the human MSC culture supernatant by anti-IGFBP-4 Ab, Treg numbers increased significantly. Thus, our results raise the possibility that human MSC actions also involve a negative-regulatory mechanism that suppresses Treg proliferation by releasing IGFBP-4. The results of this study suggest that regulation of IGF may be important for treatments using human MSCs. PMID- 28724579 TI - Novel Bivalent Viral-Vectored Vaccines Induce Potent Humoral and Cellular Immune Responses Conferring Protection against Stringent Influenza A Virus Challenge. AB - Seasonal influenza viruses are a common cause of acute respiratory illness worldwide and generate a significant socioeconomic burden. Influenza viruses mutate rapidly, necessitating annual vaccine reformulation because traditional vaccines do not typically induce broad-spectrum immunity. In addition to seasonal infections, emerging pandemic influenza viruses present a continued threat to global public health. Pandemic influenza viruses have consistently higher attack rates and are typically associated with greater mortality compared with seasonal strains. Ongoing strategies to improve vaccine efficacy typically focus on providing broad-spectrum immunity; although B and T cells can mediate heterosubtypic responses, typical vaccine development will augment either humoral or cellular immunity. However, multipronged approaches that target several Ags may limit the generation of viral escape mutants. There are few vaccine platforms that can deliver multiple Ags and generate robust cellular and humoral immunity. In this article, we describe a novel vaccination strategy, tested preclinically in mice, for the delivery of novel bivalent viral-vectored vaccines. We show this strategy elicits potent T cell responses toward highly conserved internal Ags while simultaneously inducing high levels of Abs toward hemagglutinin. Importantly, these humoral responses generate long-lived plasma cells and generate Abs capable of neutralizing variant hemagglutinin-expressing pseudotyped lentiviruses. Significantly, these novel viral-vectored vaccines induce strong immune responses capable of conferring protection in a stringent influenza A virus challenge. Thus, this vaccination regimen induces lasting efficacy toward influenza. Importantly, the simultaneous delivery of dual Ags may alleviate the selective pressure that is thought to potentiate antigenic diversity in avian influenza viruses. PMID- 28724577 TI - In situ expansion of engineered human liver tissue in a mouse model of chronic liver disease. AB - Control of both tissue architecture and scale is a fundamental translational roadblock in tissue engineering. An experimental framework that enables investigation into how architecture and scaling may be coupled is needed. We fabricated a structurally organized engineered tissue unit that expanded in response to regenerative cues after implantation into mice with liver injury. Specifically, we found that tissues containing patterned human primary hepatocytes, endothelial cells, and stromal cells in a degradable hydrogel expanded more than 50-fold over the course of 11 weeks in mice with injured livers. There was a concomitant increase in graft function as indicated by the production of multiple human liver proteins. Histologically, we observed the emergence of characteristic liver stereotypical microstructures mediated by coordinated growth of hepatocytes in close juxtaposition with a perfused vasculature. We demonstrated the utility of this system for probing the impact of multicellular geometric architecture on tissue expansion in response to liver injury. This approach is a hybrid strategy that harnesses both biology and engineering to more efficiently deploy a limited cell mass after implantation. PMID- 28724580 TI - IL-7 Restores T Lymphocyte Immunometabolic Failure in Septic Shock Patients through mTOR Activation. AB - T lymphocyte alterations are central to sepsis pathophysiology, whereas related mechanisms remain poorly understood. We hypothesized that metabolic alterations could play a role in sepsis-induced T lymphocyte dysfunction. Samples from septic shock patients were obtained at day 3 and compared with those from healthy donors. T cell metabolic status was evaluated in the basal condition and after T cell stimulation. We observed that basal metabolic content measured in lymphocytes by nuclear magnetic resonance spectroscopy was altered in septic patients. Basal ATP concentration, oxidative phosphorylation (OXPHOS), and glycolysis pathways in T cells were decreased as well. After stimulation, T lymphocytes from patients failed to induce glycolysis, OXPHOS, ATP production, GLUT1 expression, glucose entry, and proliferation to similar levels as controls. This was associated with significantly altered mTOR, but not Akt or HIF-1alpha, activation and only minor AMPKalpha phosphorylation dysfunction. IL-7 treatment improved mTOR activation, GLUT1 expression, and glucose entry in septic patients' T lymphocytes, leading to their enhanced proliferation. mTOR activation was central to this process, because rapamycin systematically inhibited the beneficial effect of recombinant human IL-7. We demonstrate the central role of immunometabolism and, in particular, mTOR alterations in the pathophysiology of sepsis-induced T cell alterations. Our results support the rationale for targeting metabolism in sepsis with recombinant human IL-7 as a treatment option. PMID- 28724581 TI - MRI evidence of acute inflammation in leukocortical lesions of patients with early multiple sclerosis. AB - OBJECTIVE: To identify gadolinium-enhancing lesions affecting the cortex of patients with early multiple sclerosis (MS) and to describe the frequency and evolution of these lesions. METHODS: We performed a retrospective, observational, longitudinal analysis of MRI scans collected as part of the Betaseron vs Copaxone in Multiple Sclerosis with Triple-Dose Gadolinium and 3T MRI Endpoints (BECOME) study. Seventy-five patients with early-stage MS were scanned monthly, over a period of 12-24 months, using 3T MRI after administration of triple-dose gadolinium. A total of 1,188 scans were included in the analysis. A total of 139 were selected using an image pipeline algorithm that integrated the image information from cortical gray matter masks and gadolinium-enhancing lesion masks. These scans were evaluated to identify gadolinium-enhancing lesions affecting the cortex. RESULTS: The total number of gadolinium-enhancing lesions was 2,044. The number of gadolinium-enhancing lesions affecting the cortex was 120 (6%), 95% of which were leukocortical. The number of patients who showed gadolinium-enhancing lesions affecting the cortex was 27 (36%). The number of gadolinium-enhancing lesions affecting the cortex at baseline was 25 (21%) and the number of new lesions that developed in follow-up scans was 49 (41%). The number of persistent lesions was 46 (38%). CONCLUSIONS: The presence of enhancing lesions affecting the cortex and adjacent white matter, although transient and not frequent, suggests that at least some cortical lesions are related to blood brain barrier disruption. Our data support the concept that there may be an acute inflammatory phase in the development of leukocortical MS lesions. CLINICALTRIALSGOV IDENTIFIER: NCT00176592. PMID- 28724583 TI - Anoctamins (TMEM16 proteins): Functions and involvement in neurologic disease. PMID- 28724582 TI - Pretreatment seizure semiology in childhood absence epilepsy. AB - OBJECTIVE: To determine seizure semiology in children with newly diagnosed childhood absence epilepsy and to evaluate associations with short-term treatment outcomes. METHODS: For participants enrolled in a multicenter, randomized, double blind, comparative-effectiveness trial, semiologic features of pretreatment seizures were analyzed as predictors of treatment outcome at the week 16 to 20 visit. RESULTS: Video of 1,932 electrographic absence seizures from 416 participants was evaluated. Median seizure duration was 10.2 seconds; median time between electrographic seizure onset and clinical manifestation onset was 1.5 seconds. For individual seizures and by participant, the most common semiology features were pause/stare (seizure 95.5%, participant 99.3%), motor automatisms (60.6%, 86.1%), and eye involvement (54.9%, 76.5%). The interrater agreement for motor automatisms and eye involvement was good (72%-84%). Variability of semiology features between seizures even within participants was high. Clustering analyses revealed 4 patterns (involving the presence/absence of eye involvement and motor automatisms superimposed on the nearly ubiquitous pause/stare). Most participants experienced more than one seizure cluster pattern. No individual semiologic feature was individually predictive of short-term outcome. Seizure freedom was half as likely in participants with one or more seizure having the pattern of eye involvement without motor automatisms than in participants without this pattern. CONCLUSIONS: Almost all absence seizures are characterized by a pause in activity or staring, but rarely is this the only feature. Semiologic features tend to cluster, resulting in identifiable absence seizure subtypes with significant intraparticipant seizure phenomenologic heterogeneity. One seizure subtype, pause/stare and eye involvement but no motor automatisms, is specifically associated with a worse treatment outcome. PMID- 28724584 TI - VCP-related multisystem proteinopathy presenting as early-onset Parkinson disease. PMID- 28724585 TI - Effect of gluten-free diet on cerebellar MR spectroscopy in gluten ataxia. AB - OBJECTIVE: To evaluate the effect of gluten free diet (GFD) on magnetic resonance spectroscopy (MRS) of the cerebellum in patients with gluten ataxia (GA). METHODS: Patients with GA, defined as sporadic ataxia with positive antigliadin antibodies in the absence of an alternative cause, routinely undergo MRS at baseline and after the introduction of GFD as part of their clinical care. We present our experience of the effect of GFD on MRS of the cerebellum. RESULTS: A total of 117 consecutive patients with GA were included in this report. Sixty three were on strict GFD with elimination of antigliadin antibodies, 35 were on GFD but were still positive for antigliadin antibodies, and 19 patients opted not to go on GFD. The N-acetylaspartate (NAA)/creatine (Cr) area ratio from the cerebellar vermis increased in 62 out of 63 (98%) patients on strict GFD, in 9 of 35 (26%) patients on GFD but positive antibodies, and in only 1 of 19 (5%) patients not on GFD. The NAA/Cr ratio decreased in all 14 ataxia control patients (cerebellar variant of multisystem atrophy). There were no differences in the MRS results between those patients who had and those who did not have enteropathy (celiac disease) within each group. CONCLUSIONS: The demonstration of increased NAA/Cr ratio on repeat scanning following strict GFD strengthens previous findings of clinical improvement of the ataxia in patients with GA. The presence of enteropathy is not a prerequisite for such improvement; therefore patients with positive serology and negative duodenal biopsy should still be treated with strict GFD. PMID- 28724586 TI - Cardiovascular health in young adulthood and structural brain MRI in midlife: The CARDIA study. AB - OBJECTIVE: To examine the association between the American Heart Association (AHA) Life's Simple 7 (LS7) metric and brain structure. METHODS: We determined cardiovascular health (CVH) according to the AHA LS7, assigning 0, 1, or 2 points for meeting poor, intermediate, or ideal criteria for the 7 components (range 0 14) at baseline (aged 18-30 years in 1985-1986) and year 25 follow-up examination for 518 participants of the Coronary Artery Risk Development in Young Adults (CARDIA) brain MRI substudy. Visit-based CVH score and average score was assessed in relation to percent of intracranial volume of normal tissue of the whole brain, gray matter, and white matter, and abnormal tissue volume of white matter at year 25 using multivariable linear, logistic, and quantile regression, after adjustment for age, sex, race, field center, educational attainment, and alcohol consumption. RESULTS: Mean percentage of whole brain volume, normal gray matter, and normal white matter was 81.3% (+/-2.5), 42.9% (+/-2.0), and 38.4% (+/-2.0). Greater CVH score at baseline (per each additional point at year 0: 0.1%, 95% confidence limits 0.01-0.3; p < 0.05) and average CVH score were associated with greater percentage of whole brain volume (per each additional point in average score: 0.2%, 95% confidence limits 0.04-0.3; p < 0.05). Visit-based or average CVH score was not significantly associated with normal gray or white matter volume or abnormal white matter volume. CONCLUSIONS: Maintaining ideal levels of cardiovascular health, determined by the LS7, in young adulthood is associated with greater whole brain volume in middle age but not regional differences in structure. PMID- 28724587 TI - Florbetapir imaging in cerebral amyloid angiopathy-related hemorrhages. AB - OBJECTIVE: To assess whether 18F-florbetapir, a PET amyloid tracer, could bind vascular amyloid in cerebral amyloid angiopathy (CAA) by comparing cortical florbetapir retention during the acute phase between patients with CAA-related lobar intracerebral hemorrhage (ICH) and patients with hypertension-related deep ICH. METHODS: Patients with acute CAA-related lobar ICH were prospectively enrolled and compared with patients with deep ICH. 18F-florbetapir PET, brain MRI, and APOE genotype were obtained for all participants. Cortical florbetapir standard uptake value ratio (SUVr) was calculated with the whole cerebellum used as a reference. Patients with CAA and those with deep ICH were compared for mean cortical florbetapir SUVr values. RESULTS: Fifteen patients with acute lobar ICH fulfilling the modified Boston criteria for probable CAA (mean age = 67 +/- 12 years) and 18 patients with acute deep ICH (mean age = 63 +/- 11 years) were enrolled. Mean global cortical florbetapir SUVr was significantly higher among patients with CAA-related ICH than among patients with deep ICH (1.27 +/- 0.12 vs 1.12 +/- 0.12, p = 0.001). Cortical florbetapir SUVr differentiated patients with CAA-ICH from those with deep ICH (area under the curve = 0.811; 95% confidence interval [CI] 0.642-0.980) with a sensitivity of 0.733 (95% CI 0.475-0.893) and a specificity of 0.833 (95% CI 0.598-0.948). CONCLUSIONS: Cortical florbetapir uptake is increased in patients with CAA-related ICH relative to those with deep ICH. Although 18F-florbetapir PET can label vascular beta-amyloid and might serve as an outcome marker in future clinical trials, its diagnostic value in acute CAA related ICH seems limited in clinical practice. PMID- 28724588 TI - Automatic measurement of prosody in behavioral variant FTD. AB - OBJECTIVE: To help understand speech changes in behavioral variant frontotemporal dementia (bvFTD), we developed and implemented automatic methods of speech analysis for quantification of prosody, and evaluated clinical and anatomical correlations. METHODS: We analyzed semi-structured, digitized speech samples from 32 patients with bvFTD (21 male, mean age 63 +/- 8.5, mean disease duration 4 +/- 3.1 years) and 17 matched healthy controls (HC). We automatically extracted fundamental frequency (f0, the physical property of sound most closely correlating with perceived pitch) and computed pitch range on a logarithmic scale (semitone) that controls for individual and sex differences. We correlated f0 range with neuropsychiatric tests, and related f0 range to gray matter (GM) atrophy using 3T T1 MRI. RESULTS: We found significantly reduced f0 range in patients with bvFTD (mean 4.3 +/- 1.8 ST) compared to HC (5.8 +/- 2.1 ST; p = 0.03). Regression related reduced f0 range in bvFTD to GM atrophy in bilateral inferior and dorsomedial frontal as well as left anterior cingulate and anterior insular regions. CONCLUSIONS: Reduced f0 range reflects impaired prosody in bvFTD. This is associated with neuroanatomic networks implicated in language production and social disorders centered in the frontal lobe. These findings support the feasibility of automated speech analysis in frontotemporal dementia and other disorders. PMID- 28724589 TI - Affective prosody in frontotemporal dementia: The importance of "pitching it right". PMID- 28724591 TI - Evidence for environment-dependent introgression of adaptive genes between two red oak species with different drought adaptations. AB - PREMISE OF THE STUDY: Introgression of adaptive alleles between hybridizing species is likely an important mechanism to generate new genetic variation for adaptation to rapidly changing environmental conditions. Oaks provide a model for the study of adaptive gene introgression because environmental selection maintains high interspecific differentiation at a few outlier loci and species specific adaptations despite recurrent interspecific gene flow. Previously, we identified a CONSTANS-like gene under strong divergent selection between drought tolerant Quercus ellipsoidalis and drought-averse Quercus rubra. Neighboring (parapatric) populations of both species were fixed for alternate alleles, Q. ellipsoidalis for allele 138 and Q. rubra for allele 141. METHODS: In this study, we analyzed introgression of these outlier alleles in sympatric and in parapatric Q. rubra/Q. ellipsoidalis populations. KEY RESULTS: We found evidence that environmental selection affected the level and direction of outlier allele introgression. Thus, in the face of symmetric interspecific gene flow, outlier allele introgression was asymmetric and introgression of allele 138 into Q. rubra was consistently higher than introgression of allele 141 into Q. ellipsoidalis in sympatric populations, but the opposite pattern was found in parapatric populations. Furthermore, the rate of introgression of outlier alleles between species in sympatric stands was related to soil quality (i.e., soil water holding capacity, nutrient availability). CONCLUSIONS: This pattern suggests that introgression of adaptive genes between these two red oak species is strongly affected by environmental selection and is an important mechanism for species' adaptation to changing environmental conditions in a changing climate. PMID- 28724590 TI - Long-term antithrombotic treatment in intracranial hemorrhage survivors with atrial fibrillation. AB - OBJECTIVE: To perform a systematic review and meta-analysis of studies reporting recurrent intracranial hemorrhage (ICH) and ischemic stroke (IS) in ICH survivors with atrial fibrillation (AF) during long-term follow-up. METHODS: A comprehensive literature search including MEDLINE, EMBASE, Cochrane library, clinical trials registry was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. We considered studies capturing outcome events (ICH recurrence and IS) for >=3 months and treatment exposure to vitamin K antagonists (VKAs), antiplatelet agents (APAs), or no antithrombotic medication (no-ATM). Corresponding authors provided aggregate data for IS and ICH recurrence rate between 6 weeks after the event and 1 year of follow-up for each treatment exposure. Meta-analyses of pooled rate ratios (RRs) were conducted with the inverse variance method. RESULTS: Seventeen articles met inclusion criteria. Seven observational studies enrolling 2,452 patients were included in the meta-analysis. Pooled RR estimates for IS were lower for VKAs compared to APAs (RR = 0.45, 95% confidence interval [CI] 0.27 0.74, p = 0.002) and no-ATM (RR = 0.47, 95% CI 0.29-0.77, p = 0.002). Pooled RR estimates for ICH recurrence were not significantly increased across treatment groups (VKA vs APA: RR = 1.34, 95% CI 0.79-2.30, p = 0.28; VKA vs no-ATM: RR = 0.93, 95% CI 0.45-1.90, p = 0.84). CONCLUSIONS: In observational studies, anticoagulation with VKA is associated with a lower rate of IS than APA or no-ATM without increasing ICH recurrence significantly. A randomized controlled trial is needed to determine the net clinical benefit of anticoagulation in ICH survivors with AF. PMID- 28724592 TI - Vascular development in very young conifer seedlings: Theoretical hydraulic capacities and potential resistance to embolism. AB - PREMISE OF THE STUDY: Conifers have the highest rates of mortality during their first year, often attributed to water stress; yet, this tree life stage is the least studied in terms of hydraulic properties. Previous work has revealed correlations between xylem anatomy to both hydraulic transport capacity and resistance to hydraulic dysfunction. In this study, we compared xylem anatomical and plant functional traits of Pseudotsuga menziesii, Larix occidentalis, and Pinus ponderosa seedlings over the first 10 wk of growth to evaluate potential maximum hydraulic capabilities and resistance to drought-induced embolism. We hypothesized that, based on key functional traits of the xylem, predicted xylem embolism resistance of the species will reflect their previously determined drought tolerances with L. occidentalis, P. menziesii, and P. ponderosa in order of least to most embolism-resistant xylem. METHODS: Xylem and pit anatomical characteristics and additional hydraulic-related functional traits were compared at five times during the first 10 wk of growth using confocal laser scanning microscopy (CLSM). KEY RESULTS: Based on thickness to span ratio, torus to pit aperture overlap, and torus thickness, primary xylem appeared to be not only more hydraulically conductive but also less embolism-resistant than secondary xylem. By week 10, P. menziesii was predicted to have the most embolism-resistant xylem followed by P. ponderosa and L. occidentalis. CONCLUSIONS: Theoretical measurements suggest that hydraulic transport capacities and vulnerability to embolism varied for each species over the first 10 wk of growth; thus, the timing of germination and onset of limited soil moisture is critical for growth and survival of seedlings. PMID- 28724593 TI - Less is more: Independent loss-of-function OCIMENE SYNTHASE alleles parallel pollination syndrome diversification in monkeyflowers (Mimulus). AB - PREMISE OF THE STUDY: Pollinator-mediated selection on flower phenotypes (e.g., shape, color, scent) is key to understanding the adaptive radiation of angiosperms, many of which have evolved specialized relationships with a particular guild of animal pollinators (e.g., birds, bats, moths, bees). E-beta Ocimene, a monoterpene produced by OCIMENE SYNTHASE (OS) in Mimulus lewisii, is a floral scent important in attracting the species' bumblebee pollinators. The taxa closely related to M. lewisii have evolved several different pollination syndromes, including hummingbird pollination and self pollination (autogamy). We are interested in how floral scent variation contributed to species diversification in this clade. METHODS: We analyzed variation in E-beta-ocimene emission within this Mimulus clade and explored its molecular basis through a combination of DNA sequencing, reverse transcriptase PCR, and enzyme functional analysis in vitro. KEY RESULTS: We found that none of the taxa, other than M. lewisii, emitted E-beta-ocimene from flowers. But the molecular basis underlying loss of E-beta-ocimene emission is unique in each taxon, including deletion, missense, or frameshift mutations in the OS gene, and potential posttranscriptional downregulation. CONCLUSIONS: The molecular evidence suggests that parallel loss-of-function in OS is the best explanation for the observed pattern of E-beta-ocimene emission, likely as the result of natural selection. PMID- 28724594 TI - Harnessing plant spectra to integrate the biodiversity sciences across biological and spatial scales. PMID- 28724595 TI - Hypertensive encephalopathy mimicking cerebral vasculitis with pontine oedema, cerebellar white matter lesions and multiple cerebral infarctions. AB - A 47-year-old man with poorly controlled hypertension presented with headaches, right-sided weakness and dysarthria. CT and MRI scans of the brain showed widespread abnormalities including significant pontine oedema, basal ganglia and corona radiata infarctions and cerebellar white matter high signal. Imaging of the intracerebral vasculature also demonstrated wall irregularities. Initially a central nervous system inflammatory disorder was thought to be the most likely diagnosis, possibly acute demyelinating encephalomyelitis or cerebral vasculitis, and the patient was treated with high-dose intravenous steroids. The diagnosis of hypertensive encephalopathy was made because (1) the patient was hypertensive and (2) the patients MRI findings resolved with antihypertensive treatment.Blood pressure treatment was instigated from admission, and the patients symptoms improved with resolution of the radiological abnormalities. PMID- 28724596 TI - Severe destructive nasopharyngeal granulomatosis with polyangiitis with superimposed skull base Pseudomonas aeruginosa osteomyelitis. AB - Skull base osteomyelitis in the setting of granulomatosis with polyangiitis (GPA) is rare and entails significant diagnostic challenges. We present a case of a 65 year-old Caucasian man with a history of rheumatoid arthritis, off immunosuppression for 18 months, who presented with 2 years of chronic headaches, severe fatigue, saddle nose deformity and 20-kilogram unintentional weight loss. Maxillofacial CT revealed an extensive destructive sinonasal and erosive skull base process. Laboratory evaluation showed equivocal elevation of antiproteinase 3 antibodies with negative antineutrophil cytoplasmic antibody panel. Biopsy of the skull base/clivus revealed necrotising granulomatous inflammation with focal vasculitis consistent with GPA, and multiple bone cultures were positive for Pseudomonas aeruginosa This patient was diagnosed concurrently with GPA and P. aeruginosa skull base osteomyelitis. He was started on a 6-week course of cefepime intravenously and oral prednisone, with the plan to initiate rituximab infusion 2 weeks after initiation of antibiotic therapy. PMID- 28724597 TI - Multifocal septic arthritis, gluteal abscess and spondylodiscitis by Streptococcus dysgalactiae subspecies equisimilis after an intramuscular injection. AB - We present the case of a 63-year-old man, admitted for hand cellulitis and acute kidney injury. A Streptococcus dysgalactiae subsp equisimilis (SDSE) was isolated in blood cultures and despite directed intravenous antibiotherapy, the patient evolved unfavourably, with dorsolumbar spondylodiscitis, multifocal septic arthritis and abscesses. CT also showed densification of the gluteal muscles, multiple air bubbles in the psoas, paraspinal muscles and spinal canal that were associated with an intramuscular injection administered 1 week earlier for a backache. After escalation of the antibiotherapy and intensive supportive measures, the patient showed improvement and was discharged after 8 weeks of antibiotherapy.The incidence of invasive SDSE infections has been growing, especially in immunosupressed patients. In this case, despite no predisposing factor identified, it evolved to severe sepsis. The intramuscular injection, a trivialised but not harmless procedure, was the assumed port of entry, as previously described in another case report. PMID- 28724598 TI - Cystometrography of meningitis-retention syndrome. AB - Although the combination of acute urinary retention and aseptic meningitis has not been well recognised, this combination can be referred to as meningitis retention syndrome (MRS). We report a case of MRS with urodynamic follow-up. A 29 year-old man developed fever and headache, and after 7 days, he developed sudden urinary retention. Neurological examination indicated stiff neck, hyper-reflexes of the lower extremities. Cerebrospinal fluid examination showed mononuclear leucocytosis, increased protein level. Myelin basic protein was absent. MRI of the brain and spinal cord were normal. Cystometrography revealed an atonic bladder. The diagnosis was MRS. After 11 days of hospital day, his symptoms reduced rapidly, and on the 12th day, cystometrography revealed normal pattern. In mild cases, the symptoms reduced and the urodynamic examination improved rapidly. Although MRS is a rare symptom, its urodynamic assessment is important. PMID- 28724599 TI - A case of congenital coronary-pulmonary fistulas presenting as spontaneous mediastinal haemorrhage. AB - Coronary artery fistulas are rare anomalous vascular connections between coronary arteries and a cardiac chamber or a central vessel, without an intervening capillary bed. Coronary-pulmonary fistulas are a distinct subset of coronary artery fistulas. We present the case of a previously healthy 63-year-old-man who presented with chest pain and was found to have mediastinal haemorrhage. Upon further investigations, he was found to have multiple coronary-pulmonary fistulas with pseudoaneurysm formation in three of the fistulas. Two of these pseudoaneurysms showed inflammatory changes indicative of recent bleed. These were determined to be the source of the mediastinal bleeding and patienta?TMs initial presentation. The patient was managed medically after obtaining multiple expert opinions from various institutions. PMID- 28724600 TI - Consumptive hypothyroidism in solitary cutaneous haemangioma. PMID- 28724601 TI - Focused assessment with sonography for trauma (FAST) identifies liver injury following cardiopulmonary resuscitation. AB - Liver trauma is a recognised rare complication of cardiopulmonary resuscitation (CPR) and may be difficult to detect. We report a case of intraperitoneal haemorrhage due to liver injury following CPR in a 50-year-old man admitted to the intensive care unit. The haemorrhage was diagnosed with focused assessment with sonography for trauma (FAST). FAST can rapidly and easily diagnose liver injury. FAST is recommended for excluding haemoperitoneum in patients who are haemodynamically unstable after resuscitation. PMID- 28724602 TI - The clinical and prognostic value of polo-like kinase 1 in lung squamous cell carcinoma patients: immunohistochemical analysis. AB - Polo-like kinase 1 (PLK1) has been suggested to serve as oncogene in most human cancers. The aim of our study is to present more evidence about the clinical and prognostic value of PLK1 in lung squamous cell carcinoma patients. The status of PLK1 was observed in lung adenocarcinoma, lung squamous cell carcinoma and normal lung tissues through analyzing microarray data set (GEO accession number: GSE1213 and GSE 3627). PLK1 mRNA and protein expressions were detected in lung squamous cell carcinoma and normal lung tissues by using qRT-PCR and immunohistochemistry. In our results, the levels of PLK1 in lung squamous cell carcinoma tissues were higher than that in lung adenocarcinoma tissues. Compared with paired adjacent normal lung tissues, the PLK1 expression was increased in lung squamous cell carcinoma tissues. Furthermore, high-expression of PLK1 protein was correlated with differentiated degree, clinical stage, tumor size, lymph node metastasis, and distant metastasis. The univariate and multivariate analyses showed PLK1 protein high-expression was an unfavorable prognostic biomarker for lung squamous cell carcinoma patients. In conclusion, High-expression of PLK1 is associated with the aggressive progression and poor prognosis in lung squamous cell carcinoma patients. PMID- 28724603 TI - Effects of microRNA-136 on melanoma cell proliferation, apoptosis, and epithelial mesenchymal transition by targetting PMEL through the Wnt signaling pathway. AB - The study aims to evaluate the effects of miR-136 on the proliferation, apoptosis, and epithelial-mesenchymal transition (EMT) of melanoma cells by targetting premelanosome protein (PMEL) through the Wnt signaling pathway. After establishment of melanoma mouse models, melanoma (model group) and normal tissues (normal group) were collected. Immunohistochemistry was performed to determine PMEL protein concentration. Mouse melanoma cells were assigned into control, blank, negative control (NC), miR-136 mimics, miR-136 inhibitors, siRNA-PMEL, and miR-136 inhibitors + siRNA-PMEL, LiC1 (Wnt signaling pathway activator), and siRNA-PMEL+ LiCl groups. MTT, Scratch test, Transwell assay, and flow cytometry were performed to measure cell proliferation, migration, invasion, and apoptosis. Quantitative real-time PCR (qRT-PCR) and Western blotting were performed to evaluate miR-136, PMEL, beta-catenin, Wnt3a, Bcl-2, Bax, Caspase, E-cadherin, and N-cadherin expressions. PMEL is highly expressed in melanoma tissues. MiR-136, Bax, Caspase, and E-cadherin expressions decreased in the model group, whereas PMEL, beta-catenin, Bcl-2, Wnt3a, and N-cadherin expressions increased. Bax, Caspase, and E-cadherin expressions increased in the miR-136 mimics and siRNA PMEL groups, whereas the expressions decreased in the miR-136 inhibitors group and LiC1 group. PMEL, beta-catenin, Bcl-2, Wnt3a, and N-cadherin expressions, cell proliferation, migration, and invasion decreased, and the apoptosis rate inceased in the miR-136 mimics and siRNA-PMEL groups; whereas the tendencies were opposite to those in the miR-136 inhibitors group and LiC1 group. In the siRNA PMEL+ LiCl group, PMEL expression decreased. These findings indicated that overexpression of miR-136 inhibits melanoma cell EMT, proliferation, migration, invasion, and promotes apoptosis by targetting PMEL through down-regulation of the Wnt signaling pathway. PMID- 28724604 TI - A simple toolset to identify endogenous post-translational modifications for a target protein: a snapshot of the EGFR signaling pathway. AB - Identification of a novel post-translational modification (PTM) for a target protein, defining its physiologic role, and studying its potential crosstalk with other PTMs is a challenging process. A set of highly sensitive tools termed Signal-Seeker kits was developed, which enables rapid and simple detection of post-translational modifications on any target protein. The methodology for these tools utilizes affinity purification of modified proteins from a cell or tissue lysate and immunoblot analysis. These tools utilize a single lysis system that is effective at identifying endogenous, dynamic PTM changes, as well as the potential crosstalk between PTMs. As a proof-of-concept experiment, the acetylation, tyrosine phosphorylation, SUMOylation 2/3, and ubiquitination profiles of the EGFR - Ras - c-Fos axis were examined in response to EGF stimulation. All 10 previously identified PTMs of this signaling axis were confirmed using these tools, and it also identified acetylation as a novel modification of c-Fos. This axis in the EGF/EGFR signaling pathway was chosen because it is a well-established signaling pathway with proteins localized in the membrane, cytoplasmic, and nuclear compartments that ranged in abundance from 4.18x108 (EGFR) to 1.35x104 (c-Fos) molecules per A431 cell. These tools enabled the identification of low abundance PTMs, such as c-Fos Ac, at 17 molecules per cell. These studies highlight how pervasive PTMs are, and how stimulants like EGF induce multiple PTM changes on downstream signaling axis. Identification of endogenous changes and potential crosstalk between multiple PTMs for a target protein or signaling axis will provide regulatory mechanistic insight to investigators. PMID- 28724605 TI - Heterozygous loss-of-function mutation in Odd-skipped related 1 (Osr1) is associated with vesicoureteric reflux, duplex systems, and hydronephrosis. AB - Odd-skipped related 1 (Osr1) is a transcriptional repressor that plays critical roles in maintaining the mesenchymal stem cell population within the developing kidney. Here, we report that newborn pups with a heterozygous null mutation in Osr1 exhibit a 21% incidence of vesicoureteric reflux and have hydronephrosis and urinary tract duplications. Newborn pups have a short intravesical ureter, resulting in a less competent ureterovesical junction which arises from a delay in urinary tract development. We describe a new domain of Osr1 expression in the ureteral mesenchyme and within the developing bladder in the mouse. OSR1 was sequenced in 186 children with primary vesicoureteric reflux, and 17 have single nucleotide polymorphisms. Fifteen children have a common synonymous variant, rs12329305, one child has a rare nonsynonymous variant, rs3440471, and one child has a rare 5'-UTR variant, rs45535040 The impact of these SNPs is not clear; therefore, the role of OSR1 in human disease remains to be elucidated. Osr1 is a candidate gene implicated in the pathogenesis of vesicoureteric reflux and congenital abnormalities of the kidney and urinary tract in mice. PMID- 28724606 TI - Sex and gender differences in hypertensive kidney injury. AB - Hypertension is a complex, multifaceted disorder, affecting ~1 in 3 adults in the United States. Although hypertension occurs in both men and women, there are distinct sex differences in the way in which they develop hypertension, with women having a lower incidence of hypertension until the sixth decade of life. Despite observed sex differences in hypertension, little is known about the molecular mechanisms underlying the development of hypertension in females, primarily because of their underrepresentation in both clinical and experimental animal studies. The first goal of this review is to provide a concise overview of the participation of women in clinical trials, including a discussion of the importance of including females in basic science research, as recently mandated by the National Institutes of Health. The remaining portion of the review is dedicated to identifying clinical and experimental animal studies that concentrate on gender and sex differences in hypertensive kidney disease, ending with a proposed role for T cells in mediating sex differences in blood pressure. PMID- 28724607 TI - Renal hemodynamic effects of glucagon-like peptide-1 agonist are mediated by nitric oxide but not prostaglandin. AB - The incretin hormone, glucagon-like peptide-1 (GLP-1), is known for responding to dietary fat and carbohydrate. It elicits effects on pancreas, gut, and brain to stabilize blood glucose levels. We have previously reported that the GLP-1 agonist, exenatide, vasodilates the kidney and suppresses proximal reabsorption. The present study was undertaken to determine whether the renal effects of exenatide are mediated by nitric oxide (NO) and/or prostaglandins. Inulin clearance (glomerular filtration rate, GFR) and urine flow rate (UV) were measured in anesthetized rats before and during exenatide infusion (1 nmol/h iv). Animals were pretreated with cyclooxygenase (COX) inhibitor (meclofenamate), NO synthase (NOS) inhibitor (NG-monomethyl-l-arginine, l-NMMA), NO clamp (l-NMMA + sodium nitroprusside), or placebo. Effectiveness of COX inhibition was tested by measuring urinary prostaglandin E2 (UPGE2). Effectiveness of NOS blockade and NO clamp was determined by urinary NO degradation products (UNOx). Exenatide increased GFR, UV, UPGE2, and UNOx. Pretreatment with meclofenamate reduced UPGE2 by 75% and reduced the effect of exenatide on UPGE2 by 30% but did not modify the effects of exenatide on GFR or UV. Pretreatment with l-NMMA reduced UNOx and the impact of exenatide on GFR and UV by 50%. Pretreatment by NO clamp did not prevent UNOx from increasing during exenatide but blunted the effects of exenatide on GFR and UV. In conclusion, exenatide is a potent renal vasodilator and diuretic in the rat. These effects of exenatide are insensitive to COX inhibition but are mediated, in part, by NO. PMID- 28724608 TI - ErbB4 deletion accelerates renal fibrosis following renal injury. AB - Tubulointerstitial fibrosis (TIF) is a prominent factor in the progression of chronic kidney disease regardless of etiology. Avian erythroblastic leukemia viral oncogene homolog 4 (ErbB4) expression levels were inversely correlated to renal fibrosis in human fibrotic kidneys. In both unilateral ureteral obstruction (UUO) and ischemia-reperfusion injury followed by uninephrectomy (IRI/UNx) mouse models, expression levels of ErbB4 were elevated in the early stage of renal injury. Using mice with global ErbB4 deletion except for transgenic rescue in cardiac tissue ( ErbB4-/-ht+), we determined that UUO induced similar injury in proximal tubules compared with wild-type mice but more severe injury in distal nephrons. TIF was apparent earlier and was more pronounced following UUO in ErbB4 /-ht+ mice. With ErbB4 deletion, UUO injury inhibited protein kinase B phosphorylation and increased the percentage of cells in G2/M arrest. There was also increased nuclear immunostaining of yes-associated protein and increased expression of phospho-Mothers against decapentaplegic homolog 3, snail1, and vimentin. These results indicate that ErbB4 deletion accelerates the development and progression of renal fibrosis in obstructive nephropathy. Similar results were found in a mouse IRI/UNx model. In conclusion, increased expression of ErbB4 in the early stages of renal injury may reflect a compensatory effect to lessen tubulointerstitial injury. PMID- 28724609 TI - Thy-1+/- fibroblast subsets in the human peritoneum. AB - Fibrotic thickening of the peritoneum develops in patients receiving peritoneal dialysis (PD) for renal failure. For unknown reasons, however, in some patients it progresses to extensive fibrosis that compromises dialysis capacity of the peritoneum. It is increasingly clear that fibroblasts display large heterogeneity not only between but also within tissues. Differential surface expression of thymocyte differentiation antigen 1 (Thy-1) has been shown to identify functionally distinct fibroblast subsets in several organs. Here, we isolated Thy 1+/- subsets of human peritoneal fibroblasts (HPFB) and analyzed them in terms of profibrotic myofibroblast features. In healthy individuals, Thy-1+ cells constituted ~45% of the HPFB population found in the greater omentum but were not detected in the parietal peritoneum. When propagated in culture and compared with Thy-1- cells, omentum-derived Thy-1+ HPFB consistently displayed an increased expression of alpha-smooth muscle actin, collagen I, and transforming growth factor-beta1. They also showed greater proliferation capacity and enhanced contractile properties. The number of Thy-1+ HPFB increased significantly in PD patients and made up more than 70 and 95% of all HPFB found in the omentum and parietal peritoneum, respectively. These data indicate that the expansion of Thy 1+ fibroblasts may contribute to fibrotic thickening of the peritoneal membrane during PD. PMID- 28724610 TI - Developing better mouse models to study cisplatin-induced kidney injury. AB - Cisplatin is a potent chemotherapeutic used for the treatment of many types of cancer. However, its dose-limiting side effect is nephrotoxicity leading to acute kidney injury (AKI). Patients who develop AKI have an increased risk of mortality and are more likely to develop chronic kidney disease (CKD). Unfortunately, there are no therapeutic interventions for the treatment of AKI. It has been suggested that the lack of therapies is due in part to the fact that the established mouse model used to study cisplatin-induced AKI does not recapitulate the cisplatin dosing regimen patients receive. In recent years, work has been done to develop more clinically relevant models of cisplatin-induced kidney injury, with much work focusing on incorporation of multiple low doses of cisplatin administered over a period of weeks. These models can be used to recapitulate the development of CKD after AKI and, by doing so, increase the likelihood of identifying novel therapeutic targets for the treatment of cisplatin-induced kidney injury. PMID- 28724612 TI - Regulation of PDZ domain-containing 1 (PDZK1) expression by hepatocyte nuclear factor-1alpha (HNF1alpha) in human kidney. AB - In the renal proximal tubule the secretion and reabsorption of glomerularly filtrated compounds is realized by a functional network of uptake and efflux transporters. The activity and localization of several transporters expressed at the apical tubular membrane are regulated by the membrane-associated protein PDZ domain-containing 1 (PDZK1). We aimed to characterize the transcriptional regulation of this modulator of renal transport. Coexpression analyses of PDZK1 and putative regulators were performed using human kidney samples. Protein and mRNA expression of PDZK1 in renal proximal tubule epithelial cells after adenoviral transfer and siRNA knockdown of transcription factor hepatocyte nuclear factor-1alpha (HNF1alpha) was assessed by quantitative real-time PCR and Western blot analysis. Transactivation of the PDZK1 promoter was quantified in cell-based reporter gene assays. Subsequently, the binding of HNF1alpha to the PDZK1 promoter was verified by in silico analyses and chromatin immunoprecipitation assay. HNF1alpha positively regulated the promoter activity of PDZK1. Adenoviral overexpression of HNF1alpha in renal proximal tubule epithelial cells (RPTEC) increased PDZK1 mRNA and protein expression, whereas siRNA knockdown of HNF1alpha resulted in decreased expression of PDZK1. Our results show that HNF1alpha, which has previously been described as a modulator of several transporters of the renal transportosome, is also a key determinant of PDZK1 transcription. PMID- 28724611 TI - Tumor necrosis factor-alpha, kidney function, and hypertension. AB - Hypertension is considered to be a low-grade inflammatory condition characterized by the presence of various proinflammatory cytokines. Tumor necrosis factor-alpha (TNF-alpha) is a constituent of the proinflammatory cytokines that is associated with salt-sensitive hypertension (SSH) and related renal injury. Elevated angiotensin II (ANG II) and other factors such as oxidative stress conditions promote TNF-alpha formation. Many recent studies have provided evidence that TNF alpha exerts a direct renal action by regulating hemodynamic and excretory function in the kidney. The cytokine incites a strong natriuretic response and plays a part in regulation of the intrarenal renin-angiotensin system. The exact mechanistic role of TNF-alpha in the development of SSH is as yet poorly understood. While TNF-alpha antagonism has been shown to attenuate hypertensive responses in many hypertensive animal models, contrasting findings demonstrate that the direct systemic administration of TNF-alpha usually induces hypotensive as well as natriuretic responses, indicating a counterregulatory role of TNF alpha in SSH. Differential activities of two cell surface receptors of TNF-alpha (receptor type 1 and type 2) may explain the contradictory functions of TNF-alpha in the setting of hypertension. This short review will evaluate ongoing research studies that investigate the action of TNF-alpha within the kidney and its role as an influential pathophysiological variable in the development of SSH and renal injury. This information may help to develop specific TNF-alpha receptor targeting as an effective treatment strategy in this clinical condition. PMID- 28724614 TI - Nuclear mTOR acts as a transcriptional integrator of the androgen signaling pathway in prostate cancer. AB - Androgen receptor (AR) signaling reprograms cellular metabolism to support prostate cancer (PCa) growth and survival. Another key regulator of cellular metabolism is mTOR, a kinase found in diverse protein complexes and cellular localizations, including the nucleus. However, whether nuclear mTOR plays a role in PCa progression and participates in direct transcriptional cross-talk with the AR is unknown. Here, via the intersection of gene expression, genomic, and metabolic studies, we reveal the existence of a nuclear mTOR-AR transcriptional axis integral to the metabolic rewiring of PCa cells. Androgens reprogram mTOR chromatin associations in an AR-dependent manner in which activation of mTOR dependent metabolic gene networks is essential for androgen-induced aerobic glycolysis and mitochondrial respiration. In models of castration-resistant PCa cells, mTOR was capable of transcriptionally regulating metabolic gene programs in the absence of androgens, highlighting a potential novel castration resistance mechanism to sustain cell metabolism even without a functional AR. Remarkably, we demonstrate that increased mTOR nuclear localization is indicative of poor prognosis in patients, with the highest levels detected in castration-resistant PCa tumors and metastases. Identification of a functional mTOR targeted multigene signature robustly discriminates between normal prostate tissues, primary tumors, and hormone refractory metastatic samples but is also predictive of cancer recurrence. This study thus underscores a paradigm shift from AR to nuclear mTOR as being the master transcriptional regulator of metabolism in PCa. PMID- 28724615 TI - Glioblastoma cellular cross-talk converges on NF-kappaB to attenuate EGFR inhibitor sensitivity. AB - In glioblastoma (GBM), heterogeneous expression of amplified and mutated epidermal growth factor receptor (EGFR) presents a substantial challenge for the effective use of EGFR-directed therapeutics. Here we demonstrate that heterogeneous expression of the wild-type receptor and its constitutively active mutant form, EGFRvIII, limits sensitivity to these therapies through an interclonal communication mechanism mediated by interleukin-6 (IL-6) cytokine secreted from EGFRvIII-positive tumor cells. IL-6 activates a NF-kappaB signaling axis in a paracrine and autocrine manner, leading to bromodomain protein 4 (BRD4) dependent expression of the prosurvival protein survivin (BIRC5) and attenuation of sensitivity to EGFR tyrosine kinase inhibitors (TKIs). NF-kappaB and survivin are coordinately up-regulated in GBM patient tumors, and functional inhibition of either protein or BRD4 in in vitro and in vivo models restores sensitivity to EGFR TKIs. These results provide a rationale for improving anti-EGFR therapeutic efficacy through pharmacological uncoupling of a convergence point of NF-kappaB mediated survival that is leveraged by an interclonal circuitry mechanism established by intratumoral mutational heterogeneity. PMID- 28724616 TI - Marburg virus survivor immune responses are Th1 skewed with limited neutralizing antibody responses. AB - Until recently, immune responses in filovirus survivors remained poorly understood. Early studies revealed IgM and IgG responses to infection with various filoviruses, but recent outbreaks have greatly expanded our understanding of filovirus immune responses. Immune responses in survivors of Ebola virus (EBOV) and Sudan virus (SUDV) infections have provided the most insight, with T cell responses as well as detailed antibody responses having been characterized. Immune responses to Marburg virus (MARV), however, remain almost entirely uncharacterized. We report that immune responses in MARV survivors share characteristics with EBOV and SUDV infections but have some distinct differences. MARV survivors developed multivariate CD4+ T cell responses but limited CD8+ T cell responses, more in keeping with SUDV survivors than EBOV survivors. In stark contrast to SUDV survivors, rare neutralizing antibody responses in MARV survivors diminished rapidly after the outbreak. These results warrant serious consideration for any vaccine or therapeutic that seeks to be broadly protective, as different filoviruses may require different immune responses to achieve immunity. PMID- 28724617 TI - Human venous valve disease caused by mutations in FOXC2 and GJC2. AB - Venous valves (VVs) prevent venous hypertension and ulceration. We report that FOXC2 and GJC2 mutations are associated with reduced VV number and length. In mice, early VV formation is marked by elongation and reorientation ("organization") of Prox1hi endothelial cells by postnatal day 0. The expression of the transcription factors Foxc2 and Nfatc1 and the gap junction proteins Gjc2, Gja1, and Gja4 were temporospatially regulated during this process. Foxc2 and Nfatc1 were coexpressed at P0, and combined Foxc2 deletion with calcineurin-Nfat inhibition disrupted early Prox1hi endothelial organization, suggesting cooperative Foxc2-Nfatc1 patterning of these events. Genetic deletion of Gjc2, Gja4, or Gja1 also disrupted early VV Prox1hi endothelial organization at postnatal day 0, and this likely underlies the VV defects seen in patients with GJC2 mutations. Knockout of Gja4 or Gjc2 resulted in reduced proliferation of Prox1hi valve-forming cells. At later stages of blood flow, Foxc2 and calcineurin Nfat signaling are each required for growth of the valve leaflets, whereas Foxc2 is not required for VV maintenance. PMID- 28724618 TI - Initiation of Sevelamer and Mortality among Hemodialysis Patients Treated with Calcium-Based Phosphate Binders. AB - BACKGROUND AND OBJECTIVES: Prior studies have shown that sevelamer attenuates progression of arterial calcification and may reduce the risk of death compared with calcium-based phosphate binders. In clinical practice, however, sevelamer is used not only as an alternative but also as an add-on therapy in patients already being treated with calcium-based phosphate binders. We analyzed the Dialysis Outcomes and Practice Patterns Study (DOPPS) data to test the hypothesis that the initiation of sevelamer is associated with improved survival in patients on hemodialysis treated with calcium-based phosphate binders. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We included 12,564 patients from DOPPS phase 3 and phase 4 (2005-2011) who were prescribed calcium-based phosphate binders at baseline or before sevelamer treatment. Mortality risk was assessed using a sequential stratification method to identify as-yet-untreated patients who were appropriately matched to the newly treated patients on the basis of their risk of death. RESULTS: Of 12,564 patients, 2606 were subsequently treated with sevelamer hydrochloride or sevelamer carbonate. After beginning sevelamer therapy, mean serum phosphorus levels decreased by 0.3 mg/dl in the first 4 months and gradually decreased thereafter. We matched 2501 treated patients with at least one as-yet-untreated patient. Patients treated with sevelamer had a 14% lower risk for mortality compared with as-yet-untreated patients (hazard ratio, 0.86; 95% confidence interval, 0.76 to 0.97). Similar results were observed in the sensitivity analyses when changing the matching calipers or the treated and as yet-untreated ratios, and by using propensity score matching. CONCLUSIONS: The use of sevelamer as an add-on or alternative therapy to calcium-based phosphate binders is associated with improved survival in patients on maintenance hemodialysis. PMID- 28724619 TI - Plant Glandular Trichomes: Natural Cell Factories of High Biotechnological Interest. AB - Multicellular glandular trichomes are epidermal outgrowths characterized by the presence of a head made of cells that have the ability to secrete or store large quantities of specialized metabolites. Our understanding of the transcriptional control of glandular trichome initiation and development is still in its infancy. This review points to some central questions that need to be addressed to better understand how such specialized cell structures arise from the plant protodermis. A key and unique feature of glandular trichomes is their ability to synthesize and secrete large amounts, relative to their size, of a limited number of metabolites. As such, they qualify as true cell factories, making them interesting targets for metabolic engineering. In this review, recent advances regarding terpene metabolic engineering are highlighted, with a special focus on tobacco (Nicotiana tabacum). In particular, the choice of transcriptional promoters to drive transgene expression and the best ways to sink existing pools of terpene precursors are discussed. The bioavailability of existing pools of natural precursor molecules is a key parameter and is controlled by so-called cross talk between different biosynthetic pathways. As highlighted in this review, the exact nature and extent of such cross talk are only partially understood at present. In the future, awareness of, and detailed knowledge on, the biology of plant glandular trichome development and metabolism will generate new leads to tap the largely unexploited potential of glandular trichomes in plant resistance to pests and lead to the improved production of specialized metabolites with high industrial or pharmacological value. PMID- 28724620 TI - Thioredoxin-Mediated ROS Homeostasis Explains Natural Variation in Plant Regeneration. AB - Plant regeneration is fundamental to basic research and agricultural applications. The regeneration capacity of plants varies largely in different genotypes, but the reason for this variation remains elusive. Here, we identified a novel thioredoxin DCC1 in determining the capacity of shoot regeneration among Arabidopsis (Arabidopsis thaliana) natural variation. Loss of function of DCC1 resulted in inhibited shoot regeneration. DCC1 was expressed mainly in the inner tissues of the callus and encoded a functional thioredoxin that was localized in the mitochondria. DCC1 protein interacted directly with CARBONIC ANHYDRASE2 (CA2), which is an essential subunit of the respiratory chain NADH dehydrogenase complex (Complex I). DCC1 regulated Complex I activity via redox modification of CA2 protein. Mutation of DCC1 or CA2 led to reduced Complex I activity and triggered mitochondrial reactive oxygen species (ROS) production. The increased ROS level regulated shoot regeneration by repressing expression of the genes involved in multiple pathways. Furthermore, linkage disequilibrium analysis indicated that DCC1 was a major determinant of the natural variation in shoot regeneration among Arabidopsis ecotypes. Thus, our study uncovers a novel regulatory mechanism by which thioredoxin-dependent redox modification regulates de novo shoot initiation via the modulation of ROS homeostasis and provides new insights into improving the capacity of plant regeneration. PMID- 28724621 TI - MILDEW RESISTANCE LOCUS O Function in Pollen Tube Reception Is Linked to Its Oligomerization and Subcellular Distribution. AB - Sexual reproduction in flowering plants requires communication between synergid cells and a tip-elongating pollen tube (PT) for the successful delivery of sperm cells to the embryo sac. The reception of the PT relies on signaling within the synergid cell that ultimately leads to the degeneration of the receptive synergid and PT rupture, releasing the sperm cells for double fertilization. In Arabidopsis (Arabidopsis thaliana), NORTIA, a member of the MILDEW RESISTANCE LOCUS O (MLO) family of proteins, plays a critical role in the communication processes regulating PT reception. In this study, we determined that MLO function in PT reception is dependent on MLO protein localization into a Golgi-associated compartment before PT arrival, indicating that PT-triggered regulation of the synergid secretory system is important for synergid function during pollination. Additionally, a structure-function analysis revealed that MLO homooligomerization, mediated by the amino-terminal region of the protein, and carboxyl-terminal tail identity both contribute to MLO activity during PT reception. PMID- 28724623 TI - Determined. PMID- 28724622 TI - Transcription Factor MYB26 Is Key to Spatial Specificity in Anther Secondary Thickening Formation. AB - Successful fertilization relies on the production and effective release of viable pollen. Failure of anther opening (dehiscence), results in male sterility, although the pollen may be fully functional. MYB26 regulates the formation of secondary thickening in the anther endothecium, which is critical for anther dehiscence and fertility. Here, we show that although the MYB26 transcript shows expression in multiple floral organs, the MYB26 protein is localized specifically to the anther endothecium nuclei and that it directly regulates two NAC domain genes, NST1 and NST2, which are critical for the induction of secondary thickening biosynthesis genes. However, there is a complex relationship of regulation between these genes and MYB26. Using DEX-inducible MYB26 lines and overexpression in the various mutant backgrounds, we have shown that MYB26 up regulates both NST1 and NST2 expression. Surprisingly normal thickening and fertility rescue does not occur in the absence of MYB26, even with constitutively induced NST1 and NST2, suggesting an additional essential role for MYB26 in this regulation. Combined overexpression of NST1 and NST2 in myb26 facilitates limited ectopic thickening in the anther epidermis, but not in the endothecium, and thus fails to rescue dehiscence. Therefore, by a series of regulatory controls through MYB26, NST1, NST2, secondary thickening is formed specifically within the endothecium; this specificity is essential for anther opening. PMID- 28724624 TI - The Gift. PMID- 28724625 TI - Amplification of Misfolded Prion Proteins in Blood and Cerebrospinal Fluid for Detection of Creutzfeldt-Jakob Disease. PMID- 28724626 TI - Aerodynamic modelling of a Cretaceous bird reveals thermal soaring capabilities during early avian evolution. AB - Several flight modes are thought to have evolved during the early evolution of birds. Here, we use a combination of computational modelling and morphofunctional analyses to infer the flight properties of the raven-sized, Early Cretaceous bird Sapeornis chaoyangensis-a likely candidate to have evolved soaring capabilities. Specifically, drawing information from (i) mechanical inferences of the deltopectoral crest of the humerus, (ii) wing shape (i.e. aspect ratio), (iii) estimations of power margin (i.e. difference between power required for flight and available power from muscles), (iv) gliding behaviour (i.e. forward speed and sinking speed), and (v) palaeobiological evidence, we conclude that S. chaoyangensis was a thermal soarer with an ecology similar to that of living South American screamers. Our results indicate that as early as 125 Ma, some birds evolved the morphological and aerodynamic requirements for soaring on continental thermals, a conclusion that highlights the degree of ecological, functional and behavioural diversity that resulted from the first major evolutionary radiation of birds. PMID- 28724627 TI - Using step width to compare locomotor biomechanics between extinct, non-avian theropod dinosaurs and modern obligate bipeds. AB - How extinct, non-avian theropod dinosaurs locomoted is a subject of considerable interest, as is the manner in which it evolved on the line leading to birds. Fossil footprints provide the most direct evidence for answering these questions. In this study, step width-the mediolateral (transverse) distance between successive footfalls-was investigated with respect to speed (stride length) in non-avian theropod trackways of Late Triassic age. Comparable kinematic data were also collected for humans and 11 species of ground-dwelling birds. Permutation tests of the slope on a plot of step width against stride length showed that step width decreased continuously with increasing speed in the extinct theropods (p < 0.001), as well as the five tallest bird species studied (p < 0.01). Humans, by contrast, showed an abrupt decrease in step width at the walk-run transition. In the modern bipeds, these patterns reflect the use of either a discontinuous locomotor repertoire, characterized by distinct gaits (humans), or a continuous locomotor repertoire, where walking smoothly transitions into running (birds). The non-avian theropods are consequently inferred to have had a continuous locomotor repertoire, possibly including grounded running. Thus, features that characterize avian terrestrial locomotion had begun to evolve early in theropod history. PMID- 28724628 TI - Stiffness distribution in insect cuticle: a continuous or a discontinuous profile? AB - Insect cuticle is a biological composite with a high degree of complexity in terms of both architecture and material composition. Given the complex morphology of many insect body parts, finite-element (FE) models play an important role in the analysis and interpretation of biomechanical measurements, taken by either macroscopic or nanoscopic techniques. Many previous studies show that the interpretation of nanoindentation measurements of this layered composite material is very challenging. To develop accurate FE models, it is of particular interest to understand more about the variations in the stiffness through the thickness of the cuticle. Considering the difficulties of making direct measurements, in this study, we use the FE method to analyse previously published data and address this issue numerically. For this purpose, sets of continuous or discontinuous stiffness profiles through the thickness of the cuticle were mathematically described. The obtained profiles were assigned to models developed based on the cuticle of three insect species with different geometries and layer configurations. The models were then used to simulate the mechanical behaviour of insect cuticles subjected to nanoindentation experiments. Our results show that FE models with discontinuous exponential stiffness gradients along their thickness were able to predict the stress and deformation states in insect cuticle very well. Our results further suggest that, for more accurate measurements and interpretation of nanoindentation test data, the ratio of the indentation depth to cuticle thickness should be limited to 7% rather than the traditional '10% rule'. The results of this study thus might be useful to provide a deeper insight into the biomechanical consequences of the distinct material distribution in insect cuticle and also to form a basis for more realistic modelling of this complex natural composite. PMID- 28724629 TI - WITHDRAWN: Abrogation of heat shock factor 1 (Hsf1) phosphorylation deregulates its activity and lowers activation threshold, leading to obesity in mice. AB - This article has been withdrawn by the authors. During preparation of this manuscript, a number of errors occurred in the preparation/assembly of Figs 2D, 2E, S1C, S1E, and S4. The authors apologize for not acknowledging that Fig. 6E and 6J represented the same samples and therefore the beta-actin immunoblot was reused. These presentation errors do not impact the underlying scientific findings of the article and the article is being withdrawn so that a corrected manuscript can be submitted for publication. We are sorry for any problems or issues that this may have caused the scientific community. PMID- 28724630 TI - Altered Met receptor phosphorylation and LRP1-mediated uptake in cells lacking carbohydrate-dependent lysosomal targeting. AB - Acid hydrolases utilize a carbohydrate-dependent mechanism for lysosomal targeting. These hydrolases acquire a mannose 6-phosphate tag by the action of the GlcNAc-1-phosphotransferase enzyme, allowing them to bind receptors and traffic to endosomes. Loss of GlcNAc-1-phosphotransferase results in hydrolase hypersecretion and profound lysosomal storage. Little, however, is known about how these cellular phenotypes affect the trafficking, activity, and localization of surface glycoproteins. To address this question, we profiled the abundance of surface glycoproteins in WT and CRISPR-mediated GNPTAB-/- HeLa cells and identified changes in numerous glycoproteins, including the uptake receptor LRP1 and multiple receptor tyrosine kinases. Decreased cell surface LRP1 in GNPTAB-/- cells corresponded with a reduction in its steady-state level and less amyloid beta-40 (Abeta40) peptide uptake. GNPTAB-/- cells displayed elevated activation of several kinases including Met receptor. We found increased Met phosphorylation within both the kinase and the docking domains and observed that lower concentrations of pervanadate were needed to cause an increase in phospho-Met in GNPTAB-/- cells. Together, these data suggested a decrease in the activity of the receptor and non-receptor protein-tyrosine phosphatases that down-regulate Met phosphorylation. GNPTAB-/- cells exhibited elevated levels of reactive oxygen species, known to inactivate cell surface and cytosolic phosphatases by oxidation of active site cysteine residues. Consistent with this mode of action, peroxide treatment of parental HeLa cells elevated phospho-Met levels whereas antioxidant treatment of GNPTAB-/- cells reduced phospho-Met levels. Collectively, these findings identify new mechanisms whereby impaired lysosomal targeting can impact the activity and recycling of receptors. PMID- 28724631 TI - The Axl kinase domain in complex with a macrocyclic inhibitor offers first structural insights into an active TAM receptor kinase. AB - The receptor tyrosine kinase family consisting of Tyro3, Axl, and Mer (TAM) is one of the most recently identified receptor tyrosine kinase families. TAM receptors are up-regulated postnatally and maintained at high levels in adults. They all play an important role in immunity, but Axl has also been implicated in cancer and therefore is a target in the discovery and development of novel therapeutics. However, of the three members of the TAM family, the Axl kinase domain is the only one that has so far eluded structure determination. To this end, using differential scanning fluorimetry and hydrogen-deuterium exchange mass spectrometry, we show here that a lower stability and greater dynamic nature of the Axl kinase domain may account for its poor crystallizability. We present the first structural characterization of the Axl kinase domain in complex with a small-molecule macrocyclic inhibitor. The Axl crystal structure revealed two distinct conformational states of the enzyme, providing a first glimpse of what an active TAM receptor kinase may look like and suggesting a potential role for the juxtamembrane region in enzyme activity. We noted that the ATP/inhibitor binding sites of the TAM members closely resemble each other, posing a challenge for the design of a selective inhibitor. We propose that the differences in the conformational dynamics among the TAM family members could potentially be exploited to achieve inhibitor selectivity for targeted receptors. PMID- 28724632 TI - Hydrogen peroxide produced by superoxide dismutase SOD-2 activates sperm in Caenorhabditis elegans. AB - Superoxide dismutase (SOD) is a ubiquitous antioxidant enzyme that catalytically converts the superoxide radical to hydrogen peroxide (H2O2). In mammals, high SOD activity is detectable in sperm and seminal plasma, and loss of SOD activity has been correlated with male infertility; however, the underlying mechanisms of sperm infertility remain to be clarified. Here we report that the deletion of two major SOD genes in Caenorhabditis elegans, sod-1 and sod-2, causes sperm activation defects, leading to a significant reduction in brood size. By examining the reactivity to the sperm activation signals Pronase and triethanolamine, we found that sod-1;sod-2 double mutant sperm cells display defects in pseudopod extension. Neither the content nor oxidative modification of major sperm protein, an essential cytoskeletal component for crawling movement, were significantly affected in sod-1;sod-2 mutant sperm. Surprisingly, H2O2, the dismutation product of SOD, could activate sod-1;sod-2 mutant sperm treated with Pronase. Moreover, the H2O2 scavenger ebselen completely inhibited pseudopod extension in wild-type sperm treated with Pronase, and H2O2 could directly induce pseudopod extension in wild-type sperm. Analysis of Pronase-triggered sperm activation in sod-1 and sod-2 single mutants revealed that sod-2 is required for pseudopod extension. These results suggest that SOD-2 plays an important role in the sperm activation of C. elegans by producing H2O2 as an activator of pseudopod extension. PMID- 28724633 TI - Conformationally organized lysine isosteres in Streptococcus pyogenes M protein mediate direct high-affinity binding to human plasminogen. AB - The binding of human plasminogen (hPg) to the surface of the human pathogen group A Streptococcus pyogenes (GAS) and subsequent hPg activation to the protease plasmin generate a proteolytic surface that GAS employs to circumvent host innate immunity. Direct high-affinity binding of hPg/plasmin to pattern D GAS is fully recapitulated by the hPg kringle 2 domain (K2hPg) and a short internal peptide region (a1a2) of a specific subtype of bacterial surface M protein, present in all GAS pattern D strains. To better understand the nature of this binding, critical to the virulence of many GAS skin-tropic strains, we used high resolution NMR to define the interaction of recombinant K2hPg with recombinant a1a2 (VKK38) of the M protein from GAS isolate NS455. We found a 2:1 (m/m) binding stoichiometry of K2hPg/VKK38, with the lysine-binding sites of two K2hPg domains anchored to two regions of monomeric VKK38. The K2hPg/VKK38 binding altered the VKK38 secondary structure from a helical apo-peptide with a flexible center to an end-to-end K2hPg-bound alpha-helix. The K2hPg residues occupied opposite faces of this helix, an arrangement that minimized steric clashing of K2hPg We conclude that VKK38 provides two conformational lysine isosteres that each interact with the lysine-binding sites in K2hPg Further, the adoption of an alpha-helix by VKK38 upon binding to K2hPg sterically optimizes the side chains of VKK38 for maximal binding to K2hPg and minimizes steric overlap between the K2hPg domains. The mechanism for hPg/M protein binding uncovered here may facilitate targeting of GAS virulence factors for disease management. PMID- 28724634 TI - Adaptor protein p62 promotes skin tumor growth and metastasis and is induced by UVA radiation. AB - Skin cancer is the most common cancer, and exposure to ultraviolet (UV) radiation, namely UVA and UVB, is the major risk factor for skin cancer development. UVA is significantly less effective in causing direct DNA damage than UVB, but UVA has been shown to increase skin cancer risk. The mechanism by which UVA contributes to skin cancer remains unclear. Here, using RNA-Seq, we show that UVA induces autophagy and lysosomal gene expression, including the autophagy receptor and substrate p62. We found that UVA activates transcription factor EB (TFEB), a known regulator of autophagy and lysosomal gene expression, which, in turn, induces p62 transcription. Next, we identified a novel relationship between p62 and cyclooxygenase-2 (COX-2), a prostaglandin synthase critical for skin cancer development. COX-2 expression was up-regulated by UVA induced p62, suggesting that p62 plays a role in UVA-induced skin cancer. Moreover, we found that p62 stabilizes COX-2 protein through the p62 ubiquitin associated domain and that p62 regulates prostaglandin E2 production in vitro In a syngeneic squamous cell carcinoma mouse model, p62 knockdown inhibited tumor growth and metastasis. Furthermore, p62-deficient tumors exhibited reduced immune cell infiltration and increased cell differentiation. Because prostaglandin E2 is known to promote pro-tumorigenic immune cell infiltration, increase proliferation, and inhibit keratinocyte differentiation in vivo, this work suggests that UVA-induced p62 acts through COX-2 to promote skin tumor growth and progression. These findings expand our understanding of UVA-induced skin tumorigenesis and tumor progression and suggest that targeting p62 can help prevent or treat UVA-associated skin cancer. PMID- 28724635 TI - Heterodimers of the transcriptional factors NFATc3 and FosB mediate tissue factor expression for 15(S)-hydroxyeicosatetraenoic acid-induced monocyte trafficking. AB - Tissue factor (TF) is expressed in vascular and nonvascular tissues and functions in several pathways, including embryonic development, inflammation, and cell migration. Many risk factors for atherosclerosis, including hypertension, diabetes, obesity, and smoking, increase TF expression. To better understand the TF-related mechanisms in atherosclerosis, here we investigated the role of 12/15 lipoxygenase (12/15-LOX) in TF expression. 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE), the major product of human 15-LOXs 1 and 2, induced TF expression and activity in a time-dependent manner in the human monocytic cell line THP1. Moreover, TF suppression with neutralizing antibodies blocked 15(S)-HETE-induced monocyte migration. We also found that NADPH- and xanthine oxidase-dependent reactive oxygen species (ROS) production, calcium/calmodulin-dependent protein kinase IV (CaMKIV) activation, and interactions between nuclear factor of activated T cells 3 (NFATc3) and FosB proto-oncogene, AP-1 transcription factor subunit (FosB) are involved in 15(S)-HETE-induced TF expression. Interestingly, NFATc3 first induced the expression of its interaction partner FosB before forming the heterodimeric NFATc3-FosB transcription factor complex, which bound the proximal AP-1 site in the TF gene promoter and activated TF expression. We also observed that macrophages from 12/15-LOX-/- mice exhibit diminished migratory response to monocyte chemotactic protein 1 (MCP-1) and lipopolysaccharide compared with WT mouse macrophages. Similarly, compared with WT macrophages, monocytes from 12/15-LOX-/- mice displayed diminished trafficking, which was rescued by prior treatment with 12(S)-HETE, in a peritonitis model. These observations indicate that 15(S)-HETE-induced monocyte/macrophage migration and trafficking require ROS-mediated CaMKIV activation leading to formation of NFATc3 and FosB heterodimer, which binds and activates the TF promoter. PMID- 28724636 TI - Predictive imaging biomarkers relevant for functional and anatomical outcomes during ranibizumab therapy of diabetic macular oedema. AB - BACKGROUND/AIMS: The objective is to identify imaging biomarkers in optical coherence tomography predicting functional/anatomical outcomes in diabetic macular oedema (DMO). METHODS: The presented study is a post hoc analysis of the RESTORE/RESTORE-extension studies. Best-corrected visual acuity (BCVA) was analysed using general estimating equation models using treatment group/morphological features as predictor variables. In addition, linear multiple regression models analysed BCVA gain up to 12 and 36 months with BCVA/morphological baseline characteristics as independent predictor variables. The correlations between central retinal thickness (CRT)/BCVA were calculated as Spearman's/Pearson's correlation coefficients. RESULTS: A weak negative linear correlation between CRT/BCVA was observed in all study arms at baseline (r=-0.34, p<0.001) and at month 36 (r=-0.26, p<0.001). Patients with baseline height of intraretinal cystoid fluid (IRC) <=380 um had better baseline BCVA compared with patients with IRC height >380 um (64.84+/-10.63 vs 61.66+/-9.92 letters; p=0.0071, respectively), which was maintained until the end of month 12 (70.5+/ 12.33 vs 67.0+/-14.09 letters; p=0.0252, respectively). With laser, there was a trend for patients with subretinal fluid (SRF) at baseline to lose BCVA letters at month 12 (-5.38+/-16.54 vs 2.49+/-9.72 letters; p=0.1038), whereas ranibizumab patients trended towards higher BCVA gains (10.28+/-7.14 vs 6.76+/-7.67; p=0.0563), compared with those without SRF. With combined therapy, all patients had similar BCVA gains regardless of SRF (p=0.3768). CONCLUSION: With ranibizumab treatment, the height of IRC spaces at baseline was a better predictor of functional/anatomical improvement than CRT alone. There was also a trend for SRF to show a positive impact on ranibizumab therapy response and a negative impact on laser therapy response. PMID- 28724637 TI - Predictors of mortality in Middle East respiratory syndrome (MERS). AB - We evaluated the clinical characteristics, cytokine/chemokine concentrations, viral shedding and antibody kinetics in 30 patients with Middle East respiratory syndrome (MERS), including 6 non-survivors admitted to 3 MERS-designated hospitals. Old age, low albumin, altered mentality and high pneumonia severity index score at admission were risk factors for mortality. In addition, severe signs of inflammation at initial presentation (at hospital days 1-4), such as high inducible protein-10 (p=0.0013), monocyte chemoattractant protein-1 (p=0.0007) and interleukin 6 (p=0.0007) concentrations, and poor viral control (high viral load at hospital days 5-10, p<0.001) without adequate antibody titres (low antibody titre at hospital days 11-16, p=0.07) during the course of disease, were associated with mortality. PMID- 28724638 TI - Smoking, telomere length and lung function decline: a longitudinal population based study. AB - Telomere shortening is associated with COPD and impaired lung function in cross sectional studies, but there is no longitudinal study. We used data from 448 participants recruited as part of the French follow-up of the European Community Respiratory Health Survey. We found no relationship between telomere length at baseline and FEV1 decline after 11 years of follow-up. However, heavy smoking was associated with an accelerated FEV1 decline in individuals with short telomeres, but not in subjects with longer telomeres (p for interaction p=0.08). Our findings suggest that short telomere length in peripheral leucocytes might be a marker for increased susceptibility to the effect of smoking. PMID- 28724639 TI - Production of reactive persulfide species in chronic obstructive pulmonary disease. AB - BACKGROUND: Oxidative stress is a major aetiological factor driving chronic obstructive pulmonary disease (COPD). Recently recognised as potent antioxidants, reactive persulfide and polysulfide species are biosynthesised by cystathionine beta-synthase and cystathionine gamma-lyase. The production of reactive persulfide and polysulfide species in the lungs of patients with COPD remain unknown. OBJECTIVES: The aim of this study was to examine the production of reactive persulfides and polysulfides, such as glutathione persulfide (GSSH), cysteine persulfide (CysSSH) and glutathione trisulfide (GSSSH), in lung-resident cells and epithelial lining fluid (ELF) obtained from patients with mild to moderate COPD. METHODS: Lung tissues, primary lung cells, ELF and sputum were obtained. The amounts of reactive persulfides and polysulfides in the cells and ELF were measured by liquid chromatography-tandem mass spectrometry with beta-(4 hydroxyphenyl) ethyl iodoacetamide as a trapping agent for hydroper/polysulfides. The amounts of synthases in the lung tissues, sputum and primary cells were quantified. RESULTS: The amounts of GSSH, CysSSH and GSSSH were decreased in the lung cells and ELF from patients with COPD. The amounts of reactive persulfides and polysulfides in the lung cells had a positive correlation with the degree of airflow limitation. By contrast, the amounts of the synthases were increased in the lung tissues and sputum cells of patients with COPD. CONCLUSIONS: We have identified a decrease in reactive persulfide and polysulfide species in the lungs of patients with COPD. These data suggest that the newly detected antioxidants reactive persulfides and polysulfides could be associated with the redox balance in the lungs of patients with COPD. PMID- 28724641 TI - Owners' perception of veterinary medical emergencies. PMID- 28724640 TI - Defining the path: lung cancer CT screening in Europe. PMID- 28724642 TI - Fructose: back to the future? PMID- 28724643 TI - A review of the characteristics of dietary fibers relevant to appetite and energy intake outcomes in human intervention trials. AB - Background: Many intervention studies have tested the effect of dietary fibers (DFs) on appetite-related outcomes, with inconsistent results. However, DFs comprise a wide range of compounds with diverse properties, and the specific contribution of these to appetite control is not well characterized.Objective: The influence of specific DF characteristics [i.e., viscosity, gel-forming capacity, fermentability, or molecular weight (MW)] on appetite-related outcomes was assessed in healthy humans.Design: Controlled human intervention trials that tested the effects of well-characterized DFs on appetite ratings or energy intake were identified from a systematic search of literature. Studies were included only if they reported 1) DF name and origin and 2) data on viscosity, gelling properties, fermentability, or MW of the DF materials or DF-containing matrixes.Results: A high proportion of the potentially relevant literature was excluded because of lack of adequate DF characterization. In total, 49 articles that met these criteria were identified, which reported 90 comparisons of various DFs in foods, beverages, or supplements in acute or sustained-exposure trials. In 51 of the 90 comparisons, the DF-containing material of interest was efficacious for >=1 appetite-related outcome. Reported differences in material viscosity, MW, or fermentability did not clearly correspond to differences in efficacy, whereas gel-forming DF sources were consistently efficacious (but with very few comparisons).Conclusions: The overall inconsistent relations of DF properties with respect to efficacy may reflect variation in measurement methodology, nature of the DF preparation and matrix, and study designs. Methods of DF characterization, incorporation, and study design are too inconsistent to allow generalized conclusions about the effects of DF properties on appetite and preclude the development of reliable, predictive, structure-function relations. Improved standards for characterization and reporting of DF sources and DF containing materials are strongly recommended for future studies on the effects of DF on human physiology. This trial was registered at http://www.crd.york.ac.uk/PROSPERO as CRD42015015336. PMID- 28724644 TI - The effect of magnesium supplementation on blood pressure in individuals with insulin resistance, prediabetes, or noncommunicable chronic diseases: a meta analysis of randomized controlled trials. AB - Background: To our knowledge, the effect of magnesium supplementation on blood pressure (BP) in individuals with preclinical or noncommunicable diseases has not been previously investigated in a meta-analysis, and the findings from randomized controlled trials (RCTs) have been inconsistent.Objective: We sought to determine the pooled effect of magnesium supplementation on BP in participants with preclinical or noncommunicable diseases.Design: We identified RCTs that were published in English before May 2017 that examined the effect of magnesium supplementation on BP in individuals with preclinical or noncommunicable diseases through PubMed, ScienceDirect, Cochrane, clinicaltrials.gov, SpringerLink, and Google Scholar databases as well as the reference lists from identified relevant articles. Random- and fixed-effects models were used to estimate the pooled standardized mean differences (SMDs) with 95% CIs in changes in BP from baseline to the end of the trial in both systolic blood pressure (SBP) and diastolic blood pressure (DBP) between the magnesium-supplementation group and the control group.Results: Eleven RCTs that included 543 participants with follow-up periods that ranged from 1 to 6 mo (mean: 3.6 mo) were included in this meta-analysis. The dose of elemental magnesium that was used in the trials ranged from 365 to 450 mg/d. All studies reported BP at baseline and the end of the trial. The weighted overall effects indicated that the magnesium-supplementation group had a significantly greater reduction in both SBP (SMD: -0.20; 95% CI: -0.37, -0.03) and DBP (SMD: -0.27; 95% CI: -0.52, -0.03) than did the control group. Magnesium supplementation resulted in a mean reduction of 4.18 mm Hg in SBP and 2.27 mm Hg in DBP.Conclusion: The pooled results suggest that magnesium supplementation significantly lowers BP in individuals with insulin resistance, prediabetes, or other noncommunicable chronic diseases. PMID- 28724645 TI - Effect of maternal high dosages of folic acid supplements on neurocognitive development in children at 4-5 y of age: the prospective birth cohort Infancia y Medio Ambiente (INMA) study. AB - Background: The benefits of the use of folic acid supplements (FASs) during the periconception period to prevent neural tube defects and to ensure normal brain development in offspring are well known. There is concern, however, about the long-term effects of the maternal use of high dosages of FASs that exceed the Tolerable Upper Intake Level (UL) (>=1000 MUg/d) on child neurocognitive outcomes.Objective: The objective of the study was to examine the association between the use of high dosages of FASs during pregnancy and child neuropsychological development at ages 4-5 y.Design: The multicenter prospective mother-child cohort study, the Infancia y Medio Ambiente (INMA) Project, was conducted in 4 regions of Spain: Asturias, Sabadell, Gipuzkoa, and Valencia. Pregnant women were recruited between 2003 and 2008. Data on 1682 mother-child pairs were included in the final analyses. The pregnant women completed an interviewer-administered questionnaire that was validated to estimate typical dietary folate intake and the use of FASs at 10-13 and 28-32 wk of gestation. Neuropsychological development scores at 4-5 y of age were estimated with the use of the McCarthy Scales of Children's Abilities. Multiple linear regression and meta-analysis were used to obtain combined-effect estimates.Results: During the periconception period, one-third of the women (n = 502) took FAS dosages >=1000 MUg/d. The use of FAS dosages >=1000 MUg/d in this period was negatively associated with several neuropsychological outcomes scores in children: global verbal (beta = -2.49; 95% CI: -4.71, -0.27), verbal memory (beta = -3.59; 95% CI: -6.95, -0.23), cognitive function of posterior cortex (beta = -2.31; 95% CI: 4.45, -0.18), and cognitive function of left posterior cortex (beta = -3.26; 95% CI: -5.51, -1.01).Conclusions: The use of FAS dosages exceeding the UL (>=1000 MUg/d) during the periconception period was associated with lower levels of cognitive development in children aged 4-5 y. The use of FAS dosages >=1000 MUg/d during pregnancy should be monitored and prevented as much as possible, unless medically prescribed. PMID- 28724646 TI - Association between microbiota-dependent metabolite trimethylamine-N-oxide and type 2 diabetes. AB - Background: The association of trimethylamine-N-oxide (TMAO), a microbiota dependent metabolite from dietary choline and carnitine, with type 2 diabetes was inconsistent.Objective: We evaluated the association of plasma TMAO with newly diagnosed type 2 diabetes and the potential modification of TMAO-generating enzyme flavin monooxygenase 3 (FMO3) polymorphisms.Design: This was an age- and sex-matched case-control study of 2694 participants: 1346 newly diagnosed cases of type 2 diabetes and 1348 controls. Concentrations of plasma TMAO were measured, and FMO3 E158K polymorphisms (rs2266782) were genotyped.Results: Medians (IQRs) of plasma TMAO concentration were 1.47 MUmol/L (0.81-2.20 MUmol/L) for controls and 1.77 MUmol/L (1.09-2.80 MUmol/L) for type 2 diabetes cases. From the lowest to the highest quartiles of plasma TMAO, the multivariable adjusted ORs of type 2 diabetes were 1.00 (reference), 1.38 (95% CI: 1.08, 1.77), 1.64 (95% CI: 1.28, 2.09), and 2.55 (95% CI: 1.99, 3.28) (P-trend < 0.001); each SD of ln-transformed plasma TMAO was associated with a 38% (95% CI: 26%, 51%) increment in ORs of type 2 diabetes. The FMO3 rs2266782 polymorphism was not associated with type 2 diabetes. The positive association between plasma TMAO and type 2 diabetes was consistent in each rs2266782 genotype group, and no significant interaction was observed (P = 0.093).Conclusions: Our results suggested that higher plasma TMAO was associated with increased odds of newly diagnosed type 2 diabetes and that this association was not modified by the FMO3 rs2266782 polymorphism. This study was registered at clinicaltrials.gov as NCT03130894. PMID- 28724647 TI - Physiological responses to fluctuating temperatures are characterized by distinct transcriptional profiles in a solitary bee. AB - Exposure to stressful low temperatures during development can result in the accumulation of deleterious physiological effects called chill injury. Metabolic imbalances, disruptions in ion homeostasis and oxidative stress contribute to the increased mortality of chill-injured insects. Interestingly, survival can be significantly increased when chill-susceptible insects are exposed to a daily warm-temperature pulse during chilling. We hypothesize that warm pulses allow for the repair of damage associated with chill injury. Here, we describe transcriptional responses during exposure to a fluctuating thermal regime, relative to constant chilled temperatures, during pupal development in the alfalfa leafcutting bee, Megachile rotundata, using a combination of RNA-seq and qPCR. Pupae were exposed to either a constant, chilled temperature of 6 degrees C, or 6 degrees C with a daily pulse of 20 degrees C for 7 days. RNA-seq after experimental treatment revealed differential expression of transcripts involved in construction of cell membranes, oxidation-reduction and various metabolic processes. These mechanisms provide support for shared physiological responses to chill injury across taxa. The large number of differentially expressed transcripts observed after 7 days of treatment suggests that the initial divergence in expression profiles between the two treatments occurred upstream of the time point sampled. Additionally, the differential expression profiles observed in this study show little overlap with those differentially expressed during temperature stress in the diapause state of M. rotundata While the mechanisms governing the physiological response to low-temperature stress are shared, the specific transcripts associated with the response differ between life stages. PMID- 28724648 TI - Mass scaling of metabolic rates in carabid beetles (Carabidae) - the importance of phylogeny, regression models and gas exchange patterns. AB - The origin of the allometric relationship between standard metabolic rate (MR) and body mass (M), often described as MR=aMb , remains puzzling, and interpretation of the mass-scaling exponent, b may depend on the methodological approach, shapes of residuals, coefficient of determination (r2) and sample size. We investigated the mass scaling of MRs within and between species of Carabidae beetles. We used ordinary least squares (OLS) regression, phylogenetically generalized least squares (PGLS) regression and standardized major axis (SMA) regression to explore the effects of different model-fitting methods and data clustering caused by phylogenetic clades (grade shift) and gas exchange patterns (discontinuous, cyclic and continuous). At the interspecific level, the relationship between MR and M was either negatively allometric (b<1) or isometric (b=1), depending on the fitting method. At the intraspecific level, the relationship either did not exist or was isometric or positively allometric (b>1), and the fit was significantly improved after the analyzed dataset was split according to gas exchange patterns. The studied species originated from two distinct phylogenetic clades that had different intercepts but a common scaling exponent (OLS, 0.61) that was much shallower than the scaling exponent for the combined dataset for all species (OLS, 0.71). The best scaling exponent estimates were obtained by applying OLS while accounting for grade shifts or by applying PGLS. Overall, we show that allometry of MR in insects can depend heavily on the model fitting method, the structure of phylogenetic non-independence and ecological factors that elicit different modes of gas exchange. PMID- 28724649 TI - Significant Associations of Neurological Complications of Herpes Zoster With Stroke in Rheumatoid Arthritis Patients. AB - BACKGROUND: Accumulating evidence suggests an increased risk of stroke after herpes zoster (HZ). This risk is elevated in immunocompromised patients. The incidence of HZ in Asia is higher than in Western countries. However, the epidemiology of HZ and HZ-related stroke among rheumatoid arthritis (RA) patients in Asia remains unclear. METHODS AND RESULTS: We conducted a retrospective cohort study using a population-based database to investigate the epidemiology of HZ in RA patients in Taiwan during the period of 2000-2011. A total of 27 609 newly diagnosed and eligible RA cases were identified, and 110 436 non-RA cases were matched for age and sex at a ratio of 4:1. HZ risk increased by 2.53-fold (P<0.0001) in RA patients compared with the general population. Exposure to corticosteroids (adjusted odds ratio=1.73, P<0.0001), adalimumab (adjusted odds ratio=1.61, P=0.002), and rituximab (adjusted odds ratio=2.06, P=0.008) was associated with an increased risk of HZ in RA patients. A significant association between the use of methotrexate or corticosteroids and HZ risk was dose-dependent (Ptrend<0.0001). Elevated risk of stroke was observed in RA patients with HZ (adjusted hazard ratio=1.27, P=0.047), particularly in those with neurological complications (adjusted hazard ratio=1.54, P=0.015). A 2.30-fold significantly increased risk of stroke within 90 days after HZ occurrence was observed in RA patients compared with those without HZ (P=0.02). Furthermore, death risk increased in RA patients with HZ (adjusted hazard ratio=1.18, P=0.026). CONCLUSIONS: The risk of HZ and HZ-related stroke has increased in RA patients. Monitoring the occurrence of HZ in RA patients and preventing HZ-related stroke or mortality during a specific immunosuppressive therapy are important. PMID- 28724650 TI - Dynamic Relation of Changes in Weight and Indices of Fat Distribution With Cardiac Structure and Function: The Dallas Heart Study. AB - BACKGROUND: Obesity may increase heart failure risk through cardiac remodeling. Cross-sectional associations between adiposity and cardiac structure and function have been elucidated, but the impact of longitudinal changes in adiposity on cardiac remodeling is less well understood. METHODS AND RESULTS: Participants in the Dallas Heart Study without cardiovascular disease or left ventricular dysfunction underwent assessment of body weight, anthropometrics, and cardiac magnetic resonance imaging at baseline and 7 years later. Associations between changes in indices of generalized and central adiposity with changes in left ventricular mass, volume, mass/volume ratio (concentricity), wall thickness, and ejection fraction were assessed using multivariable linear regression. The study cohort (n=1262) mean age was 44 years with 57% women, 44% black, and 36% obese participants. At follow-up, 41% had >=5% weight gain, and 15% had >=5% weight loss. Greater weight gain was associated with younger age, lower risk factor burden, and lower body mass index at baseline. In multivariable models adjusting for age, sex, race, comorbid conditions at baseline and follow-up, baseline adiposity, and cardiac measurement, increasing weight was associated with increases in left ventricular mass (beta=0.10, P<0.0001), wall thickness (beta=0.10, P<0.0001), and concentricity (beta=0.06, P=0.002), with modest effects on end-diastolic volume (beta=0.04, P=0.044) and ejection fraction (beta=0.05, P=0.046). Similar results were seen with other adiposity indices. CONCLUSIONS: Concentric left ventricular remodeling is the predominant phenotype linked to increasing adiposity in middle age. Our findings support the importance of weight management to prevent secular changes in adiposity, concentric remodeling, and eventual heart failure over time. PMID- 28724651 TI - Hyperkalemia After Initiating Renin-Angiotensin System Blockade: The Stockholm Creatinine Measurements (SCREAM) Project. AB - BACKGROUND: Concerns about hyperkalemia limit the use of angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARBs), but guidelines conflict regarding potassium-monitoring protocols. We quantified hyperkalemia monitoring and risks after ACE-I/ARB initiation and developed and validated a hyperkalemia susceptibility score. METHODS AND RESULTS: We evaluated 69 426 new users of ACE-I/ARB therapy in the Stockholm Creatinine Measurements (SCREAM) project with medication initiation from January 1, 2007 to December 31, 2010, and follow-up for 1 year thereafter. Three fourths (76%) of SCREAM patients had potassium checked within the first year. Potassium >5 and >5.5 mmol/L occurred in 5.6% and 1.7%, respectively. As a comparison, we propensity-matched new ACE-I/ARB users to 20 186 new beta-blocker users in SCREAM: 64% had potassium checked. The occurrence of elevated potassium levels was similar between new beta blocker and ACE-I/ARB users without kidney disease; only at estimated glomerular filtration rate <60 mL/min per 1.73 m2 were risks higher among ACE-I/ARB users. We developed a hyperkalemia susceptibility score that incorporated estimated glomerular filtration rate, baseline potassium level, sex, diabetes mellitus, heart failure, and the concomitant use of potassium-sparing diuretics in new ACE I/ARB users; this score accurately predicted 1-year hyperkalemia risk in the SCREAM cohort (area under the curve, 0.845, 95% CI: 0.840-0.869) and in a validation cohort from the US-based Geisinger Health System (N=19 524; area under the curve, 0.818, 95% CI: 0.794-0.841), with good calibration. CONCLUSIONS: Hyperkalemia within the first year of ACE-I/ARB therapy was relatively uncommon among people with estimated glomerular filtration rate >60 mL/min per 1.73 m2, but rates were much higher with lower estimated glomerular filtration rate. Use of the hyperkalemia susceptibility score may help guide laboratory monitoring and prescribing strategies. PMID- 28724652 TI - Correlation of Admission Heart Rate With Angiographic and Clinical Outcomes in Patients With Right Coronary Artery ST-Segment Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention: HORIZONS-AMI (The Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction) Trial. AB - BACKGROUND: Bradycardia on presentation is frequently observed in patients with right coronary artery ST-segment elevation myocardial infarction, but it is largely unknown whether it predicts poor angiographic or clinical outcomes in that patient population. We sought to determine the prognostic implications of admission heart rate (AHR) in patients with ST-segment elevation myocardial infarction and a right coronary artery culprit lesion. METHODS AND RESULTS: We analyzed 1460 patients with ST-segment elevation myocardial infarction and a right coronary artery culprit lesion enrolled in the randomized HORIZONS-AMI (Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction) trial who underwent primary percutaneous coronary intervention. Patients presenting with high-grade atrioventricular block were excluded. Outcomes were examined according to AHR range (AHR <60, 61-79, 80-99, and >=100 beats per minute). Baseline and procedural characteristics did not vary significantly with AHR except for a more frequent history of diabetes mellitus, longer symptom-to-balloon time, more frequent cardiogenic shock, and less frequent restoration of thrombolysis in myocardial infarction 3 flow in patients with admission tachycardia (AHR >100 beats per minute). Angiographic analysis showed no significant association between AHR and lesion location or complexity. On multivariate analysis, admission bradycardia (AHR <60 beats per minute) was not associated with increased 1-year mortality (hazard ratio 1.33; 95% CI 0.41 4.34, P=0.64) or major adverse cardiac events (hazard ratio 1.08; 95% CI 0.62 1.88, P=0.78), whereas admission tachycardia was a strong independent predictor of mortality (hazard ratio 5.02; 95% CI 1.95-12.88, P=0.0008) and major adverse cardiac events (hazard ratio 2.20; 95% CI 1.29-3.75, P=0.0004). CONCLUSIONS: In patients with ST-segment elevation myocardial infarction and a right coronary artery culprit lesion undergoing primary percutaneous coronary intervention, admission bradycardia was not associated with increased mortality or major adverse cardiac events at 1 year. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00433966. PMID- 28724653 TI - Haplodeficiency of Ataxia Telangiectasia Mutated Accelerates Heart Failure After Myocardial Infarction. AB - BACKGROUND: Cell senescence is involved in the process of organ damage and repair; however, the underlying molecular mechanism needs to be further explored. METHODS AND RESULTS: Senescence-related genes (ie, p21, p53, and ataxia telangiectasia mutated [ATM]) were shown to be elevated after myocardial infarction (MI) in both mouse and human hearts. Ten- to 12-week-old male wild type littermates (ATM+/+) and ATM heterozygous mice (ATM+/-) were subjected to MI. Cardiac echography showed that ATM haplodeficiency did not affect the survival rate but aggravated heart failure at day 28 post MI. Histologic analysis showed increased fibrosis in the noninfarct area of ATM+/- mice compared with that in ATM+/+ mice. Senescence-associated beta-galactosidase staining showed that the number of senescent fibroblasts was decreased when ATM was haplodeficient both in vivo and in vitro. Costaining of alpha-smooth muscle actin with p53 or p19 showed fewer senescent myofibroblasts in ATM+/- mouse hearts. Moreover, angiogenesis was also examined using the endothelial markers CD31 both at early (day 7) and late stages (day 28) after MI, and ATM haplodeficiency reduced angiogenesis after MI. Finally, cardiac fibroblasts were isolated from infarcted mouse heart and the medium were tested for its capacity of endothelial tubing formation, revealing that ATM haplodeficiency led to lower vascular endothelial growth factor production from cardiac fibroblast and reduced capacity of endothelial tube formation in vitro. CONCLUSIONS: The present study shows that ATM haplodeficiency decreases fibroblast senescence and vascular endothelial growth factor production and impaired angiogenesis in response to MI, leading to accelerated heart failure. PMID- 28724654 TI - Mfsd2a (Major Facilitator Superfamily Domain Containing 2a) Attenuates Intracerebral Hemorrhage-Induced Blood-Brain Barrier Disruption by Inhibiting Vesicular Transcytosis. AB - BACKGROUND: Blood-brain barrier (BBB) disruption aggravates brain injury induced by intracerebral hemorrhage (ICH); however, the mechanisms of BBB damage caused by ICH remain elusive. Mfsd2a (major facilitator superfamily domain containing 2a) has been known to play an essential role in BBB formation and function. In this study, we investigated the role and underlying mechanisms of Mfsd2a in BBB permeability regulation after ICH. METHODS AND RESULTS: Using ICH models, we found that Mfsd2a protein expression in perihematomal brain tissues was significantly decreased after ICH. Knockdown and knockout of Mfsd2a in mice markedly increased BBB permeability, neurological deficit score, and brain water contents after ICH, and these were rescued by overexpressing Mfsd2a in perihematomas. Moreover, we found that Mfsd2a regulation of BBB permeability after ICH correlated with changes in vesicle number. Expression profiling of tight junction proteins showed no differences in Mfsd2a knockdown, Mfsd2a knockout, and Mfsd2a overexpression mice. However, using electron microscopy following ICH, we observed a significant increase in pinocytotic vesicle number in Mfsd2a knockout mice and decreased the number of pinocytotic vesicles in mouse brains with Mfsd2a overexpression. Finally, using multiple reaction monitoring, we screened out 3 vesicle trafficking-related proteins (Srgap2, Stx7, and Sec22b) from 31 vesicle trafficking-related proteins that were markedly upregulated in Mfsd2a knockout mice compared with controls after ICH. CONCLUSIONS: In summary, our results suggest that Mfsd2a may protect against BBB injury by inhibiting vesicular transcytosis following ICH. PMID- 28724655 TI - Sex Differences in the Use of Oral Anticoagulants for Atrial Fibrillation: A Report From the National Cardiovascular Data Registry (NCDR(r)) PINNACLE Registry. AB - BACKGROUND: Despite higher thromboembolism risk, women with atrial fibrillation have lower oral anticoagulation (OAC) use compared to men. The influence of the CHA2DS2-VASc score or the introduction of non-vitamin K OACs on this relationship is not known. METHODS AND RESULTS: Using the PINNACLE National Cardiovascular Data Registry from 2008 to 2014, we compared the association of sex with OAC use (warfarin or non-vitamin K OACs) overall and by CHA2DS2-VASc score and examined temporal trends in OAC use by sex. Multivariable regression models assessed the association between sex and OAC use in those with CHA2DS2-VASc scores >=2. Temporal analyses assessed changes in OAC use by sex over time. Of the 691 906 atrial fibrillation patients, 48.5% were women. Women were significantly less likely than men to use any OAC overall (56.7% versus 61.3%; P<0.001) and at all levels of CHA2DS2-VASc score (adjusted risk ratio 9% to 33% lower, all P<0.001). Compared to other thromboembolic risk factors, female sex was associated with lower use of OAC (risk ratio 0.90, 95%CI 0.90-0.91). Over time, non-vitamin K OAC use increased at a slightly higher rate in women (56.2% increase per year, 95%CI 54.6% to 57.9%) compared to men (53.6% increase per year, 95%CI 52.0% to 55.2%), yet women remained less likely to receive any OAC at all time points (P<0.001). CONCLUSIONS: Among patients with atrial fibrillation, women were significantly less likely to receive OAC at all levels of the CHA2DS2-VASc score. Despite increasing non-vitamin K OAC use, women had persistently lower rates of OAC use compared to men over time. PMID- 28724656 TI - Dietary Flavonoid Intake Reduces the Risk of Head and Neck but Not Esophageal or Gastric Cancer in US Men and Women. AB - Background: Flavonoids are bioactive polyphenolic compounds found in fruits, vegetables, and beverages of plant origin. Previous studies have shown that flavonoid intake reduces the risk of certain cancers; however, few studies to date have examined associations of flavonoids with upper gastrointestinal cancers or used prospective cohorts.Objective: Our study examined the association between intake of flavonoids (anthocyanidins, flavan-3-ols, flavanones, flavones, flavonols, and isoflavones) and risk of head and neck, esophageal, and gastric cancers.Methods: The NIH-AARP Diet and Health Study is a prospective cohort study that consists of 469,008 participants. Over a mean 12-y follow-up, 2453 head and neck (including 1078 oral cavity, 424 pharyngeal, and 817 laryngeal), 1165 esophageal (890 adenocarcinoma and 275 squamous cell carcinoma), and 1297 gastric (625 cardia and 672 noncardia) cancer cases were identified. We used Cox proportional hazards regression models to estimate HRs and CIs for the associations between flavonoid intake assessed at study baseline and cancer outcomes. For 56 hypotheses examined, P-trend values were adjusted using the Benjamini-Hochberg (BH) procedure for false discovery rate control.Results: The highest quintile of total flavonoid intake was associated with a 24% lower risk of head and neck cancer (HR: 0.76; 95% CI: 0.66, 0.86; BH-adjusted 95% CI: 0.63, 0.91; P-trend = 0.02) compared with the lowest quintile. Notably, anthocyanidins were associated with a 28% lower risk of head and neck cancer (HR: 0.72; 95% CI: 0.62, 0.82; BH-adjusted 95% CI: 0.59, 0.87; P-trend = 0.0005), and flavanones were associated with a 22% lower risk of head and neck cancer (HR: 0.78; 95% CI: 0.68, 0.89; BH-adjusted 95% CI: 0.64, 0.94; P-trend: 0.02). No associations between flavonoid intake and risk of esophageal or gastric cancers were found.Conclusions: Our results indicate that flavonoid intake is associated with lower head and neck cancer risk. These associations suggest a protective effect of dietary flavonoids on head and neck cancer risk, and thus potential as a risk reduction strategy. PMID- 28724657 TI - Prenatal Lipid-Based Nutrient Supplements Do Not Affect Pregnancy or Childbirth Complications or Cesarean Delivery in Bangladesh: A Cluster-Randomized Controlled Effectiveness Trial. AB - Background: Pregnancy and childbirth complications and cesarean delivery are common in Bangladesh.Objective: We evaluated the effect of lipid-based nutrient supplements for pregnant and lactating women (LNS-PL) on pregnancy and childbirth complications and cesarean delivery.Methods: We conducted the Rang-Din Nutrition Study, a cluster-randomized controlled effectiveness trial within a community health program in rural Bangladesh. We enrolled 4011 pregnant women in early pregnancy. Women in 48 clusters received iron and folic acid (IFA; 60 mg Fe + 400 MUg folic acid/d) and women in 16 clusters received LNS-PL (20 g/d, 118 kcal) containing essential fatty acids and 22 vitamins and minerals. Pregnancy and childbirth complications and the cesarean delivery rate were secondary outcomes of the study.Results: Women in the LNS-PL group did not differ significantly from the IFA group with respect to mean systolic blood pressure at 36 wk gestation (113 and 112 mm Hg; P = 0.17), diastolic blood pressure at 36 wk gestation (68.9 and 68.7 mmHg; P = 0.88), or mean total number of pregnancy and childbirth complications (0.32 and 0.31; P = 0.86). They also did not differ significantly with respect to the prevalence of high blood pressure at 36 wk (1.74% and 2.03%; P = 0.62), antepartum hemorrhage (0.83% and 1.39%; P = 0.21), prolonged labor (8.34% and 8.79%; P = 0.68), early rupture of membranes (9.30% and 8.45%; P = 0.43), convulsions (1.57% and 1.08%; P = 0.24), high blood pressure in labor (1.54% and 1.19%; P = 0.46), obstructed labor (2.83% and 2.91%; P = 0.90), any complications during pregnancy or childbirth (35.9% and 37.1%; P = 0.64), episiotomy (6.31% and 6.44%; P = 0.90), or cesarean delivery (15.6% and 14.2%; P = 0.48).Conclusion: Compared with IFA, antenatal LNS-PL did not increase or decrease pregnancy and childbirth complications or cesarean delivery among women in rural Bangladesh. This trial was registered at clinicaltrials.gov as NCT01715038. PMID- 28724660 TI - Human Milk Oligosaccharides: Potent Weapons in the Battle against Rotavirus Infection. PMID- 28724658 TI - A Daily Dose of 5 mg Folic Acid for 90 Days Is Associated with Increased Serum Unmetabolized Folic Acid and Reduced Natural Killer Cell Cytotoxicity in Healthy Brazilian Adults. AB - Background: The effects of high-dose folic acid (FA) supplementation in healthy individuals on blood folate concentrations and immune response are unknown.Objective: The aim of the study was to evaluate the effects of daily consumption of a tablet containing 5 mg FA on serum folate; number and cytotoxicity of natural killer (NK) cells; mRNA expression of dihydrofolate reductase (DHFR), methylenetetrahydrofolate reductase (MTHFR), interferon gamma (IFNG), tumor necrosis factor alpha (TNFA), and interleukin 8 (IL8) genes; and concentrations of serum inflammatory markers.Methods: This prospective clinical trial was conducted in 30 healthy Brazilian adults (15 women), aged 27.7 y (95% CI: 26.4, 29.1 y), with a body mass index (in kg/m2) of 23.1 (95% CI: 22.0, 24.3). Blood was collected at baseline and after 45 and 90 d of the intervention. Serum folate concentrations were measured by microbiological assay and HPLC tandem mass spectrometry [folate forms, including unmetabolized folic acid (UMFA)]. We used real-time polymerase chain reaction to assess mononuclear leukocyte mRNA expression and flow cytometry to measure the number and cytotoxicity of NK cells.Results: Serum folate concentrations increased by ~5 fold after the intervention (P < 0.001), and UMFA concentrations increased by 11.9- and 5.9-fold at 45 and 90 d, respectively, when compared with baseline (P < 0.001). UMFA concentrations increased (>1.12 nmol/L) in 29 (96.6%) participants at day 45 and in 26 (86.7%) participants at day 90. We observed significant reductions in the number (P < 0.001) and cytotoxicity (P = 0.003) of NK cells after 45 and 90 d. Compared with baseline, DHFR mRNA expression was higher at 90 d (P = 0.006) and IL8 and TNFA mRNA expressions were higher at 45 and 90 d (P = 0.001 for both).Conclusion: This noncontrolled intervention showed that healthy adults responded to a high-dose FA supplement with increased UMFA concentrations, changes in cytokine mRNA expression, and reduced number and cytotoxicity of NK cells. This trial was registered at www.ensaiosclinicos.gov.br as RBR-2pr7zp. PMID- 28724659 TI - Human Milk Microbial Community Structure Is Relatively Stable and Related to Variations in Macronutrient and Micronutrient Intakes in Healthy Lactating Women. AB - Background: The human milk microbiome has been somewhat characterized, but little is known about changes over time and relations with maternal factors such as nutrient intake.Objective: We sought to characterize the human milk microbiome and described associations with maternal nutrient intake, time postpartum, delivery mode, and body mass index (BMI; in kg/m2).Methods: Milk samples (n = 104) and 24-h diet recalls were collected 9 times from 21 healthy lactating women from day 2 to 6 mo postpartum. Women were classified by BMI as healthy weight (<25) or overweight or obese (>=25). Bacterial taxa were characterized with the use of the high-throughput sequencing of the 16S ribosomal RNA gene.Results: The milk microbiome was relatively constant over time, although there were small changes in some of the lesser-abundant genera. Relative abundances of several taxa were associated with BMI, delivery mode, and infant sex. For instance, overweight and obese mothers produced milk with a higher relative abundance of Granulicatella than did healthy-weight women (1.8% +/- 0.6% compared with 0.4% +/ 0.2%, respectively; P < 0.05). Relative abundances of several bacterial taxa were also associated with variations in maternal dietary intake. For example, intakes of saturated fatty acids (rs = -0.59; P = 0.005) and monounsaturated fatty acids (rs = -0.46; P = 0.036) were inversely associated with the relative abundance of Corynebacterium; total carbohydrates (rs = -0.54; P = 0.011), disaccharides (rs = -0.47; P = 0.031), and lactose (rs = -0.51; P = 0.018) were negatively associated with Firmicutes; and protein consumption was positively correlated with the relative abundance of Gemella (rs = 0.46; P = 0.037).Conclusions: Factors associated with variations in the human milk microbiome are complex and may include maternal nutrient intake, maternal BMI, delivery mode, and infant sex. Future studies designed to investigate the relation between maternal nutrient intake and the milk microbiome should strive to also evaluate dietary supplement usage and analyze the collected milk for its nutrient content. PMID- 28724661 TI - Fermented Soy Product Intake Is Inversely Associated with the Development of High Blood Pressure: The Japan Public Health Center-Based Prospective Study. AB - Background: Randomized controlled studies have investigated the short-term effect of soy product intake on blood pressure (BP) in normotensive people. To our knowledge, no prospective studies exist on the effect of habitual intake of fermented soy products, separate from total soy products, on BP in the general population.Objective: We examined the association between the habitual intake of soy products, including fermented soy products, and the development of high BP during a 5-y period among participants in a population-based prospective cohort study in Japan.Methods: The study included normotensive participants aged 40-69 y at baseline (926 men and 3239 women) who completed 2 questionnaires and whose BP was measured at the baseline survey between 1993 and 1994 and the 5-y follow-up in the Japan Public Health Center-Based Prospective Study Cohort II. The intake of soy products was assessed with a food-frequency questionnaire. High BP was defined as systolic blood pressure >=130 mm Hg, diastolic blood pressure >=85 mm Hg, or antihypertensive medication use. ORs and 95% CIs of high BP by frequency of soy products (miso, natto, and tofu) consumption, intake of total and fermented soy products, and intake of isoflavones from total and fermented soy products were estimated with the use of multiple logistic regression analysis.Results: Multivariable-adjusted ORs of high BP for the highest compared with the lowest tertile of total and fermented soy product intake were 1.03 (95% CI: 0.84, 1.25; P-trend = 0.786) and 0.72 (95% CI: 0.56, 0.92; P-trend = 0.009), respectively. The frequency of nonfermented soy product (tofu) intake was not associated with the development of high BP (P-trend = 0.597).Conclusions: The intake of fermented soy products, but not total or nonfermented soy products, was inversely associated with developing high BP in men and women with normal BP. PMID- 28724663 TI - PD-L1 Expression and Immune Escape in Melanoma Resistance to MAPK Inhibitors. AB - Purpose: To examine the relationship between immune activity, PD-L1 expression, and tumor cell signaling, in metastatic melanomas prior to and during treatment with targeted MAPK inhibitors.Experimental Design: Thirty-eight tumors from 17 patients treated with BRAF inhibitor (n = 12) or combination BRAF/MEK inhibitors (n = 5) with known PD-L1 expression were analyzed. RNA expression arrays were performed on all pretreatment (PRE, n = 17), early during treatment (EDT, n = 8), and progression (PROG, n = 13) biopsies. HLA-A/HLA-DPB1 expression was assessed by IHC.Results: Gene set enrichment analysis (GSEA) of PRE, EDT, and PROG melanomas revealed that transcriptome signatures indicative of immune cell activation were strongly positively correlated with PD-L1 staining. In contrast, MAPK signaling and canonical Wnt/-beta-catenin activity was negatively associated with PD-L1 melanoma expression. The expression of PD-L1 and immune activation signatures did not simply reflect the degree or type of immune cell infiltration, and was not sufficient for tumor response to MAPK inhibition.Conclusions: PD-L1 expression correlates with immune cells and immune activity signatures in melanoma, but is not sufficient for tumor response to MAPK inhibition, as many PRE and PROG melanomas displayed both PD-L1 positivity and immune activation signatures. This confirms that immune escape is common in MAPK inhibitor-treated tumors. This has important implications for the selection of second-line immunotherapy because analysis of mechanisms of immune escape will likely be required to identify patients likely to respond to such therapies. Clin Cancer Res; 23(20); 6054-61. (c)2017 AACR. PMID- 28724662 TI - The Role of Antibiotics in Modulating Virulence in Staphylococcus aureus. AB - Staphylococcus aureus is often involved in severe infections, in which the effects of bacterial virulence factors have great importance. Antistaphylococcal regimens should take into account the different effects of antibacterial agents on the expression of virulence factors and on the host's immune response. A PubMed literature search was performed to select relevant articles on the effects of antibiotics on staphylococcal toxin production and on the host immune response. Information was sorted according to the methods used for data acquisition (bacterial strains, growth models, and antibiotic concentrations) and the assays used for readout generation. The reported mechanisms underlying S. aureus virulence modulation by antibiotics were reviewed. The relevance of in vitro observations is discussed in relation to animal model data and to clinical evidence extracted from case reports and recommendations on the management of toxin-related staphylococcal diseases. Most in vitro data point to a decreased level of virulence expression upon treatment with ribosomally active antibiotics (linezolid and clindamycin), while cell wall-active antibiotics (beta-lactams) mainly increase exotoxin production. In vivo studies confirmed the suppressive effect of clindamycin and linezolid on virulence expression, supporting their utilization as a valuable management strategy to improve patient outcomes in cases of toxin-associated staphylococcal disease. PMID- 28724664 TI - Biochemical, Molecular, and Clinical Characterization of Succinate Dehydrogenase Subunit A Variants of Unknown Significance. AB - Purpose: Patients who inherit a pathogenic loss-of-function genetic variant involving one of the four succinate dehydrogenase (SDH) subunit genes have up to an 86% chance of developing one or more cancers by the age of 50. If tumors are identified and removed early in these high-risk patients, they have a higher potential for cure. Unfortunately, many alterations identified in these genes are variants of unknown significance (VUS), confounding the identification of high risk patients. If we could identify misclassified SDH VUS as benign or pathogenic SDH mutations, we could better select patients for cancer screening procedures and remove tumors at earlier stages.Experimental Design: In this study, we combine data from clinical observations, a functional yeast model, and a computational model to determine the pathogenicity of 22 SDHA VUS. We gathered SDHA VUS from two primary sources: The OHSU Knight Diagnostics Laboratory and the literature. We used a yeast model to identify the functional effect of a VUS on mitochondrial function with a variety of biochemical assays. The computational model was used to visualize variants' effect on protein structure.Results: We were able to draw conclusions on functional effects of variants using our three prong approach to understanding VUS. We determined that 16 (73%) of the alterations are actually pathogenic, causing loss of SDH function, and six (27%) have no effect upon SDH function.Conclusions: We thus report the reclassification of the majority of the VUS tested as pathogenic, and highlight the need for more thorough functional assessment of inherited SDH variants. Clin Cancer Res; 23(21); 6733-43. (c)2017 AACR. PMID- 28724665 TI - The c.1085A>G Genetic Variant of CSF1R Gene Regulates Tumor Immunity by Altering the Proliferation, Polarization, and Function of Macrophages. AB - Purpose: Targeting tumor-associated macrophages with colony-stimulating factor 1 receptor (CSF-1R) inhibition reveals a strategy for cancer therapy. Here, we studied the impact of CSF1R germline genetic variant on CSF-1R signaling and the susceptibility to CSF-1R inhibitors.Experimental designs:CSF1R germline genetic variants were studied in 140 cancer patients. CSF-1R phosphorylation, endocytosis, and macrophage polarization were measured as the response to CSF-1 stimulation. Tumor-associated macrophages in surgical specimens and sensitivity to CSF-1R inhibitors were used to determine macrophage function.Results: A CSF1R c.1085A>G genetic variant causing the change of histidine to arginine in the domain of receptor dimerization was identified as a high allele frequency in Eastern Asian population. Cancer patients with this variant allele had less M2 like tumor-associated macrophages accompanied by low VEGF expression in tumor tissues. Importantly, CSF1R genetic variant was significantly associated with disease-free survival in colorectal, endometrial, and ovarian cancer. In terms of differentiation, macrophages with CSF1R c.1085A>G genetic variant displayed a refractory response to CSF-1 stimulation and macrophage survival was sensitive to CSF-1R inhibitors with IC50 of 0.1 to 1 nmol/L range. On contrast, CSF-1 induced a prominent phosphorylation and rapid endocytosis of CSF-1R, leading to an M2 like dominant polarization in macrophages with CSF1R c.1085 genotype A_A, in which CSF-1R inhibitors of PLX3397, BLZ945, and GW2580 inhibited macrophage survival with IC50 of 10 to 100 nmol/L range.Conclusions: The CSF1R c.1085A>G genetic variant regulates tumor immunity by altering the polarization and function of macrophages. This genetic variant confers the sensitivity to CSF-1R inhibitors, implying as a biomarker in targeting CSF-1R signaling for cancer treatment. Clin Cancer Res; 23(20); 6021-30. (c)2017 AACR. PMID- 28724667 TI - Germline Mutations in Cancer Susceptibility Genes in a Large Series of Unselected Breast Cancer Patients. AB - Purpose: The prevalence of mutations in cancer susceptibility genes such as BRCA1 and BRCA2 and other cancer susceptibility genes and their clinical relevance are largely unknown among a large series of unselected breast cancer patients in the Chinese population.Experimental Design: A total of 8,085 consecutive unselected Chinese breast cancer patients were enrolled. Germline mutations in 46 cancer susceptibility genes were detected using a 62-gene panel.Results: Pathogenic mutations were identified in 9.2% of patients among the 8,085 unselected breast cancer patients. Of these, 5.3% of patients carried a BRCA1 or BRCA2 mutation (1.8% in BRCA1 and 3.5% in BRCA2), 2.9% carried other breast cancer susceptibility genes (BOCG) and 1.0% carried another cancer susceptibility genes. Triple-negative breast cancers had the highest prevalence of BRCA1/2 mutations (11.2%) and other BOCG mutations (3.8%) among the four molecular subgroups, whereas ER-/PR-HER2+ breast cancers had the lowest mutations in BRCA1/2 (1.8%) and BOCG (1.6%). In addition, BRCA1 mutation carriers had a significant worse disease-free survival [unadjusted hazard ratio (HR) 1.60; 95% confidence interval (CI) 1.10-2.34; P = 0.014] and disease-specific survival (unadjusted HR 1.96; 95% CI, 1.03-3.65; P = 0.040) than did non-carriers, whereas no significant difference in survival was found between BRCA2 mutation carriers and non carriers.Conclusions: 9.2% of breast cancer patients carry a pathogenic mutation in cancer susceptibility genes in this large unselected series. Triple-negative breast cancers have the highest prevalence of mutations in BRCA1 /2 and other breast cancer susceptibility genes among the four molecular subgroups, whereas ER /PR-HER2+ breast cancers had the lowest mutations in these genes. Clin Cancer Res; 23(20); 6113-9. (c)2017 AACR. PMID- 28724668 TI - Mortality Rates and Cause of Death Among Former Prison Inmates in North Carolina. AB - BACKGROUND Inmates face challenges upon release from prison, including increased risk of death. We examine mortality among former inmates in North Carolina, including both violent and nonviolent deaths.METHODS A retrospective cohort study among former North Carolina inmates released between 2008 and 2010 were linked with North Carolina mortality data to determine cause of death. Inmates were followed through December 31, 2012. Mortality rates among former inmates were compared with deaths among North Carolina residents using standardized mortality ratios (SMRs).RESULTS Among former inmates (N = 41,495), there were 926 deaths during the study period. Compared to the North Carolina general population, SMRs were higher for all-cause mortality for total deaths (SMR = 2.10, 95% CI: 1.97 2.24), heart disease (SMR = 4.45, 95% CI: 3.64-5.34), cancer (SMR = 3.92, 95% CI: 3.34-4.62), suicide (SMR = 14.46, 95% CI: 10.28-19.76), and homicide (SMR = 7.98, 95% CI: 6.34-10.03).DISCUSSION The death rate among former North Carolina inmates is significantly higher than that of other North Carolina residents. Although more research is needed, identifying areas for interventions is essential for reducing the risk of death among this population. PMID- 28724666 TI - BRAF Inhibitors Amplify the Proapoptotic Activity of MEK Inhibitors by Inducing ER Stress in NRAS-Mutant Melanoma. AB - Purpose: NRAS mutations in malignant melanoma are associated with aggressive disease requiring rapid antitumor intervention, but there is no approved targeted therapy for this subset of patients. In clinical trials, the MEK inhibitor (MEKi) binimetinib displayed modest antitumor activity, making combinations a requisite. In a previous study, the BRAF inhibitor (BRAFi) vemurafenib was shown to induce endoplasmic reticulum (ER) stress that together with inhibition of the RAF-MEK ERK (MAPK) pathway amplified its proapoptotic activity in BRAF-mutant melanoma. The present study investigated whether this effect might extent to NRAS-mutant melanoma, in which MAPK activation would be expected.Experimental Design and Results: BRAFi increased pERK, but also significantly increased growth inhibition and apoptosis induced by the MEKi in monolayer, spheroids, organotypic, and patient-derived tissue slice cultures of NRAS-mutant melanoma. BRAFi such as encorafenib induced an ER stress response via the PERK pathway, as detected by phosphorylation of eIF2alpha and upregulation of the ER stress-related factors ATF4, CHOP, and NUPR1 and the proapoptotic protein PUMA. MEKi such as binimetinib induced the expression of the proapoptotic protein BIM and activation of the mitochondrial pathway of apoptosis, the latter of which was enhanced by combination with encorafenib. The increased apoptotic rates caused by the combination treatment were significantly reduced through siRNA knockdown of ATF4 and BIM, confirming its critical roles in this process.Conclusions: The data presented herein encourage further advanced in vivo and clinical studies to evaluate MEKi in combination with ER stress inducing BRAFi as a strategy to treat rapidly progressing NRAS-mutant melanoma. Clin Cancer Res; 23(20); 6203-14. (c)2017 AACR. PMID- 28724670 TI - Policy Forum:Minding the Gap. PMID- 28724669 TI - Seeds of HOPE: Incorporating Community-Based Strategies to Implement a Weight Loss and Empowerment Intervention in Eastern North Carolina. AB - Seeds of HOPE (Health, Opportunities, Partnerships, and Empowerment) was a community-based participatory research project designed to implement an evidence based weight loss and empowerment intervention aimed at increasing self-efficacy through peer support. HOPE Works, its model, has yielded significant weight loss and increases in participants' ability to set and achieve goals, including in consumption of fruits and vegetables and in physical activity.METHODS The Seeds of HOPE project was implemented through 3 peer leader recruitment approaches using Circle Leaders. Study participants met in hope circles to discuss various topics aimed at developing healthier lifestyles. Changes at 6-month intervals were assessed in health behaviors, weight, and hope. One-way ANOVA was used to test differences in mean change in weight and hope across the 3 recruitment approaches.RESULTS Study participants (N = 146) lost weight (-3.3 pounds, P = 0.003, 95% CI: -5.40 - -1.27). Fruit consumption significantly increased (P = 0.04, 95% CI: 0.01-0.41) while no changes in vegetable consumption or physical activity were observed. No differences based on different leader recruitment approaches were found.LIMITATIONS There were limitations in the power to fully detect differences across Circle Leader recruitment approaches; loss-to-follow up and representativeness of the sample were present. Further research is needed to determine if these approaches would be successful in other rural counties, with different genders, or with individuals in urban and/or higher socioeconomic populations.CONCLUSIONS Participants found modest success in weight loss and fruit consumption. Authors find that community engagement strategies are helpful in finding mutually acceptable adaptations to implement interventions such as Seeds of HOPE in diverse communities. PMID- 28724671 TI - Accountable Care Communities. AB - Accountable care communities are a new health model that involves multiple stakeholders working together to improve the health and well-being of their communities by addressing social determinants of health. Stakeholders include health care delivery systems, public health organizations, and community organizations. In an accountable care community, the stakeholders commit to share responsibility, resources, and data to improve community health indicators. Accountable care communities are a promising model to both decrease medical costs and improve health outcomes by placing greater emphasis on addressing social and economic issues that ultimately define health. This issue of the NCMJ highlights accountable care communities in other states and provides an overview of how accountable care community initiatives are working in North Carolina to improve the overall health of our communities. PMID- 28724672 TI - Accountable Care Communities: Moving from Health Care Delivery Systems to Systems of Health. AB - Research has shown that individuals' health outcomes often have more to do with the conditions in which they live, learn, work, and age than the medical care they receive. However, traditional health care is not designed to address the social, behavioral, and economic factors (eg, housing, transportation, access to healthy food, education, and health behaviors) that impact health outcomes. Accountable care communities are showing that it is possible to design systems that are successful at both addressing social and economic factors and improving population health. PMID- 28724673 TI - Hennepin Health-An Accountable Care Model for Vulnerable Medicaid Populations. PMID- 28724674 TI - Mission Health Partners: A Community-Based Social Determinants Driven Accountable Care Organization. AB - Mission Health Partners Accountable Care Organization's population health strategy is based on the idea that improvements in outcomes are best achieved by addressing social determinants gaps for its members. Our network of service providers and a process for referrals and tracking streamlines the limited resources available to meet these needs. PMID- 28724675 TI - Community Partnerships and Clinical Integration. PMID- 28724676 TI - Collaborating for Community Health. AB - The Greensboro Housing Coalition was founded 27 years ago to advocate for fair, safe, decent, and affordable housing for low- to moderate-income individuals. We advocate in 4 primary service areas: foreclosure prevention/homeowner counseling, homelessness prevention/ rental housing counseling, healthy homes, and our Community Centered Health Initiative. PMID- 28724677 TI - Cross-Community Collaboration in Cabarrus County. AB - Collaborative action is a part of Cabarrus Health Alliance's mission statement. This commentary highlights several community-based initiatives that the Alliance has used to contribute to the Healthiest Cities & Counties Challenge, and demonstrates the importance of using cross-sector partnerships to address health disparities within low-income populations. PMID- 28724678 TI - Collaboration is Critical: Working Together to Optimize Health in Our Communities. AB - Clinical care accounts for only 20% of health outcomes, with social determinants of health including environment, health behaviors, and economics accounting for the remaining 80%. Providers ought to address social determinants of health and, more and more are joining community partnerships to do so. PMID- 28724679 TI - Improving Health Outcomes in a Rural Community: Roanoke Valley Community Health Initiative. AB - For the past 7 years, The Roanoke Valley Community Health Initiative has made inroads in the fight against obesity in Halifax County. The group has leveraged valuable resources to maximize collective impact in the Roanoke Valley. The Health Initiative's work continues to be a catalyst for positive change across the region. PMID- 28724680 TI - Craving to Make a Difference in a Rural Community. PMID- 28724681 TI - The Accountable Care Workforce: Bridging the Health Divide in North Carolina. AB - Accountable care communities form as health care entities partner with communities to more fully address population health. This partnership requires an adaptable, boundary spanning, and diverse workforce, as well as flexible regulatory and governing structures that adapt to changing payment models, task shifting, and new roles in health care. PMID- 28724682 TI - From the Memphis Model to the North Carolina Way: Lessons Learned from Emerging Health System and Faith Community Partnerships. AB - National health care policy has encouraged health systems to develop community partnerships designed to decrease costs and readmissions, particularly for underserved populations. This commentary describes and compares the Congregational Health Network's Memphis Model to early local efforts at clinical faith community partnerships in North Carolina, which we call "The North Carolina Way." Necessary components for building robust health system and congregational partnerships to address social determinants of health and impact health care utilization include partnership growth, allocation of health system resources, community trust, and time. PMID- 28724683 TI - Roadmap to Value Driven Health Care. AB - Uncertainty over future health care costs is a major concern to business and acts as a throttle, limiting new investment. This article discusses how the North Carolina Chamber is committed to making North Carolina a top-10 state for health care value, thus creating a robust business environment across the state. PMID- 28724684 TI - Getting What You Pay For. PMID- 28724685 TI - Claims Data to Improve Health in North Carolina: A Report from the NCIOM Task Force on All-Payer Claims Database March 2017. PMID- 28724686 TI - Utilization of Drug Monitoring System in North Carolina. PMID- 28724687 TI - Direct and trans-generational effects of male and female gut microbiota in Drosophila melanogaster. AB - There is increasing evidence of the far-reaching effects of gut bacteria on physiological and behavioural traits, yet the fitness-related consequences of changes in the gut bacteria composition of sexually interacting individuals remain unknown. To address this question, we manipulated the gut microbiota of fruit flies, Drosophila melanogaster, by monoinfecting flies with either Acetobacter pomorum (AP) or Lactobacillus plantarum (LP). Re-inoculated individuals were paired in all treatment combinations. LP-infected males had longer mating duration and induced higher short-term offspring production in females compared with AP-infected males. Furthermore, females of either re inoculation state mated with AP-infected males were more likely to have zero offspring after mating, suggesting a negative effect of AP on male fertility. Finally, we found that the effects of male and female gut bacteria interacted to modulate their daughters', but not sons' body mass, revealing a new trans generational effect of parental gut microbiota. In conclusion, this study shows direct and trans-generational effects of the gut microbiota on mating and reproduction. PMID- 28724688 TI - Dopamine D1 receptor activation leads to object recognition memory in a coral reef fish. AB - Object recognition memory is the ability to identify previously seen objects and is an adaptive mechanism that increases survival for many species throughout the animal kingdom. Previously believed to be possessed by only the highest order mammals, it is now becoming clear that fish are also capable of this type of memory formation. Similar to the mammalian hippocampus, the dorsolateral pallium regulates distinct memory processes and is modulated by neurotransmitters such as dopamine. Caribbean bicolour damselfish (Stegastes partitus) live in complex environments dominated by coral reef structures and thus likely possess many types of complex memory abilities including object recognition. This study used a novel object recognition test in which fish were first presented two identical objects, then after a retention interval of 10 min with no objects, the fish were presented with a novel object and one of the objects they had previously encountered in the first trial. We demonstrate that the dopamine D1-receptor agonist (SKF 38393) induces the formation of object recognition memories in these fish. Thus, our results suggest that dopamine-receptor mediated enhancement of spatial memory formation in fish represents an evolutionarily conserved mechanism in vertebrates. PMID- 28724689 TI - California scrub-jays reduce visual cues available to potential pilferers by matching food colour to caching substrate. AB - Some animals hide food to consume later; however, these caches are susceptible to theft by conspecifics and heterospecifics. Caching animals can use protective strategies to minimize sensory cues available to potential pilferers, such as caching in shaded areas and in quiet substrate. Background matching (where object patterning matches the visual background) is commonly seen in prey animals to reduce conspicuousness, and caching animals may also use this tactic to hide caches, for example, by hiding coloured food in a similar coloured substrate. We tested whether California scrub-jays (Aphelocoma californica) camouflage their food in this way by offering them caching substrates that either matched or did not match the colour of food available for caching. We also determined whether this caching behaviour was sensitive to social context by allowing the birds to cache when a conspecific potential pilferer could be both heard and seen (acoustic and visual cues present), or unseen (acoustic cues only). When caching events could be both heard and seen by a potential pilferer, birds cached randomly in matching and non-matching substrates. However, they preferentially hid food in the substrate that matched the food colour when only acoustic cues were present. This is a novel cache protection strategy that also appears to be sensitive to social context. We conclude that studies of cache protection strategies should consider the perceptual capabilities of the cacher and potential pilferers. PMID- 28724690 TI - Correction to 'High-protein paternal diet confers an advantage to sons in sperm competition'. PMID- 28724691 TI - Drought-induced starvation of aardvarks in the Kalahari: an indirect effect of climate change. AB - Aardvarks (Orycteropus afer) are elusive burrowing mammals, predominantly nocturnal and distributed widely throughout Africa except for arid deserts. Their survival may be threatened by climate change via direct and indirect effects of increasing heat and aridity. To measure their current physiological plasticity, we implanted biologgers into six adult aardvarks resident in the semi-arid Kalahari. Following a particularly dry and hot summer, five of the study aardvarks and 11 other aardvarks at the study site died. Body temperature records revealed homeothermy (35.4-37.2 degrees C) initially, but heterothermy increased progressively through the summer, with declining troughs in the nychthemeral rhythm of body temperature reaching as low as 25 degrees C before death, likely due to starvation. Activity patterns shifted from the normal nocturnal to a diurnal mode. Our results do not bode well for the future of aardvarks facing climate change. Extirpation of aardvarks, which play a key role as ecosystem engineers, may disrupt stability of African ecosystems. PMID- 28724692 TI - Enhancing Studies of Pharmacodynamic Mechanisms via Measurements of Metabolic Flux: Fundamental Concepts and Guiding Principles for Using Stable Isotope Tracers. AB - Drug discovery and development efforts are largely based around a common expectation, namely, that direct or indirect action on a cellular process (e.g., statin-mediated enzyme inhibition or insulin-stimulated receptor activation) will have a beneficial impact on physiologic homeostasis. To expand on this, one could argue that virtually all pharmacologic interventions attempt to influence the flow of "traffic" in a biochemical network, irrespective of disease or modality. Since stable isotope tracer kinetic methods provide a measure of traffic flow (i.e., metabolic flux), their inclusion in study designs can yield novel information regarding pathway biology; the application of such methods requires the integration of knowledge in physiology, analytical chemistry, and mathematical modeling. Herein, we review the fundamental concepts that surround the use of tracer kinetics, define basic terms, and outline guiding principles via theoretical and experimental problems. Specifically, one needs to 1) recognize the types of biochemical events that change isotopic enrichments, 2) appreciate the distinction between fractional turnover and flux rate, and 3) be aware of the subtle differences between tracer kinetics and pharmacokinetics. We hope investigators can use the framework presented here to develop applications that address their specific questions surrounding biochemical flux, and thereby gain insight into the pathophysiology of disease states, and examine pharmacodynamic mechanisms. PMID- 28724693 TI - New Peptide Inhibitor of Dipeptidyl Peptidase IV, EMDB-1 Extends the Half-Life of GLP-2 and Attenuates Colitis in Mice after Topical Administration. AB - Protease inhibition has become a possible new approach in inflammatory bowel disease (IBD) therapy. A serine exopeptidase, dipeptidyl peptidase IV (DPP IV), is responsible for the inactivation of incretin hormone, glucagon-like peptide 2 (GLP-2), a potent stimulator of intestinal epithelium regeneration and growth. Recently, we showed that the novel peptide analog of endomorphin-2, Tyr-Pro-D ClPhe-Phe-NH2 (EMDB-1) is a potent blocker of DPP IV and has an inhibitory effect on gastrointestinal (GI) smooth muscle contractility. The aim of this study was to characterize the anti-inflammatory effect and mechanism of action of EMDB-1 in the mouse GI tract. We used two models of experimental colitis (induced by TNBS and DSS). The anti-inflammatory effect of EMDB-1 was assessed by the determination of macroscopic score, ulcer score, colonic wall thickness, as well as myeloperoxidase activity. Additionally, we measured the expression of GLP-2, GLP2R, and DPP IV in the colon of control and colitic animals treated with the test compound. The expression of GLP-2 and GLP2R in the serum and colon of IBD patients and healthy control subjects has been assessed. We showed that EMDB-1 elevates the half-life of GLP-2 in vitro and attenuates acute, semichronic, and relapsing TNBS as well as DSS-induced colitis in mice after topical administration. The anti-inflammatory action of EMDB-1 is associated with changes in the level of colonic GLP-2 but not DPP IV expression. Our results validate DPP IV as a pharmacological target for the anti-IBD drugs, and its inhibitors based on natural substrates, such as EMDB-1, have the potential to become valuable anti inflammatory therapeutic agents. PMID- 28724694 TI - Role of long-chain acyl-CoAs in the regulation of mycolic acid biosynthesis in mycobacteria. AB - One of the dominant features of the biology of Mycobacterium tuberculosis, and other mycobacteria, is the mycobacterial cell envelope with its exceptional complex composition. Mycolic acids are major and very specific components of the cell envelope and play a key role in its architecture and impermeability. Biosynthesis of mycolic acid (MA) precursors requires two types of fatty acid synthases, FAS I and FAS II, which should work in concert in order to keep lipid homeostasis tightly regulated. Both FAS systems are regulated at their transcriptional level by specific regulatory proteins. FasR regulates components of the FAS I system, whereas MabR and FadR regulate components of the FAS II system. In this article, by constructing a tight mabR conditional mutant in Mycobacterium smegmatis mc2155, we demonstrated that sub-physiological levels of MabR lead to a downregulation of the fasII genes, inferring that this protein is a transcriptional activator of the FAS II system. In vivo labelling experiments and lipidomic studies carried out in the wild-type and the mabR conditional mutant demonstrated that under conditions of reduced levels of MabR, there is a clear inhibition of biosynthesis of MAs, with a concomitant change in their relative composition, and of other MA-containing molecules. These studies also demonstrated a change in the phospholipid composition of the membrane of the mutant strain, with a significant increase of phosphatidylinositol. Gel shift assays carried out with MabR and PfasII as a probe in the presence of different chain-length acyl-CoAs strongly suggest that molecules longer than C18 can be sensed by MabR to modulate its affinity for the operator sequences that it recognizes, and in that way switch on or off the MabR-dependent promoter. Finally, we demonstrated the direct role of MabR in the upregulation of the fasII operon genes after isoniazid treatment. PMID- 28724695 TI - Caryolan-1-ol, an antifungal volatile produced by Streptomyces spp., inhibits the endomembrane system of fungi. AB - Streptomyces spp. have the ability to produce a wide variety of secondary metabolites that interact with the environment. This study aimed to discover antifungal volatiles from the genus Streptomyces and to determine the mechanisms of inhibition. Volatiles identified from Streptomyces spp. included three major terpenes, geosmin, caryolan-1-ol and an unknown sesquiterpene. antiSMASH and KEGG predicted that the volatile terpene synthase gene clusters occur in the Streptomyces genome. Growth inhibition was observed when fungi were exposed to the volatiles. Biological activity of caryolan-1-ol has previously not been investigated. Fungal growth was inhibited in a dose-dependent manner by a mixture of the main volatiles, caryolan-1-ol and the unknown sesquiterpene, from Streptomyces sp. S4-7. Furthermore, synthesized caryolan-1-ol showed similar antifungal activity. Results of chemical-genomics profiling assays showed that caryolan-1-ol affected the endomembrane system by disrupting sphingolipid synthesis and normal vesicle trafficking in the fungi. PMID- 28724696 TI - Is leukostasis a crucial step or epiphenomenon in the pathogenesis of diabetic retinopathy? AB - Leukostasis in the retinal microvasculature in animal model studies of diabetes is associated with the development of diabetes-like retinopathy. Therefore, it is generally assumed that adhesion of leukocytes is a central event inciting a chronic, low-grade form of inflammation that causes the vascular abnormalities that are specific for the early stages of diabetic retinopathy (DR), which culminate in diabetic macular edema, proliferative DR, and vision loss in humans. Here, we review the literature critically with respect to leukostasis and assess its pathologic consequences in the human diabetic retina. First, we review the pathologic processes that are known to be involved in the development of human DR. Then, we summarize experimental evidence for the role of leukostasis in the development of DR and the mechanisms involved in leukostasis in the retina. Based on our critical review, we conclude that leukostasis may be an epiphenomenon of the diabetic retinal milieu, rather than a crucial, specific step in the development of human DR. PMID- 28724697 TI - Facts and values: on the acceptability of risks in children's sport using the example of rugby - a narrative review. AB - A clash of values has been identified between those who assert that:1. all childhood injuries, regardless of origin, are inherently undesirable and should be prevented and;2. those who believe that some measure of injury to children is an acceptable compromise for the physical benefits associated with physical activity and the development of abilities to appraise and deal with risks.A debate regarding whether the tackles and collisions permitted in schools' rugby represent acceptable risks, and what steps should be taken if they do not, exemplifies the issue.Questions regarding the magnitude of injury risks in sport are issues of fact and can be quantified via the results of injury surveillance studies. Risks are neither high nor low in isolation; they are relatively high or low with reference to other activities or across groups participating in an activity. Issues of the acceptability of a given degree of risk are value dependent. Research regarding perceptions of risk reveals wide variations in the degree of risk people view as acceptable. Factors impacting on risk perception include whether the risks are well known and understood, whether they are 'dread' risks and the degree to which people undertake the risks voluntarily and feel they have control over them.Based on the evidence currently available, the risks to children playing rugby do not appear to be inordinately high compared with those in a range of other childhood sports and activities, but better comparative information is urgently needed. Further evidence, however, should not necessarily be expected to result in the resolution of acceptable risk debates-pre-existing values shape our perspectives on whether new evidence is relevant, valid and reliable. PMID- 28724698 TI - Acute Achilles tendon rupture. AB - This is one of a series of occasional articles highlighting conditions that may be more common than many doctors realise or may be missed at first presentation. The series advisers are Anthony Harnden, professor of primary care, Department of Primary Care Health Sciences, University of Oxford, and Richard Lehman, general practitioner, Banbury. To suggest a topic for this series, please email us at practice@bmj.com. PMID- 28724700 TI - Neurotransmission: peptide transmitters turn 36. PMID- 28724699 TI - Early career researchers: an interview with Jeremy Goldbogen. AB - Jeremy Goldbogen is an Assistant Professor at the Hopkins Marine Station, Stanford University, USA, where he studies the integrative biology of vertebrate filter feeders from forage fish to baleen whales. He received his Bachelor's degree in Zoology from the University of Texas, Austin, USA, before moving to the Scripps Institution of Oceanography and then the University of British Columbia for his PhD, which he completed in 2010 in the laboratory of Bob Shadwick. After a short postdoc at Scripps, Goldbogen moved to continue his postdoc training at the Cascadia Research Collective in Olympia, Washington. PMID- 28724701 TI - Integrative physiology of transcellular and paracellular intestinal absorption. AB - Glucose absorption by the small intestine has been studied for nearly a century. Despite extensive knowledge about the identity, functioning and regulation of the relevant transporters, there has been and there remains controversy about how these transporters work in concert to determine the overall epithelial absorption of key nutrients (e.g. sugars, amino acids) over a wide range of dietary and/or luminal concentrations. Our broader, integrative understanding of intestinal absorption requires more than the reductionist dissection of all the components and their elaboration at molecular and genetic levels. This Commentary emphasizes the integration of discrete molecular players and processes (including paracellular absorption) that, in combination, determine the overall epithelial absorption of key nutrients (e.g. sugars, amino acids) and putative anti nutrients (water-soluble toxins), and the integration of that absorption with other downstream processes related to metabolic demands. It identifies historic key advances, controversies and future research ideas, as well as important perspectives that arise through comparative as well as biomedical physiological research. PMID- 28724703 TI - Hormonal responsiveness to stress is negatively associated with vulnerability to angling capture in fish. AB - Differences in behavior and physiology amongst individuals often alter relative fitness levels in the environment. However, the ideal behavioral/physiological phenotype in a given environment may be altered by human activity, leading to an evolutionary response in the affected population. One example of this process can be found in fisheries (including recreational freshwater fisheries), where selective capture and harvest of individuals with certain phenotypes can drive evolutionary change. While some life history traits and behavioral tendencies influencing capture likelihood have been studied, the physiological mechanisms driving this vulnerability remain poorly understood. To address this, we assessed how two major physiological characteristics (hormonal responsiveness to stress and metabolic phenotype) and one behavioral characteristic (boldness) impact the likelihood of an individual being captured by anglers. Largemouth bass, Micropterus salmoides, derived from a population artificially selected for differential angling vulnerability were assessed for boldness and for stress responsiveness (as indicated by plasma cortisol levels) following an air-exposure challenge. Largemouth bass were then stocked into a pond where experimental angling trials took place, and a subset of captured and uncaptured fish were afterwards assessed for metabolic phenotype. The results showed that stress responsiveness was the primary driver of angling vulnerability, with individuals that experienced lower rises in cortisol following the air-exposure challenge more likely to be captured. Neither boldness nor metabolic phenotype influenced capture probability. The results from this study indicate that fisheries-induced selective pressure may act on physiology, potentially altering stress responsiveness and its associated behaviors in populations exploited by recreational anglers. PMID- 28724702 TI - Stereopsis in animals: evolution, function and mechanisms. AB - Stereopsis is the computation of depth information from views acquired simultaneously from different points in space. For many years, stereopsis was thought to be confined to primates and other mammals with front-facing eyes. However, stereopsis has now been demonstrated in many other animals, including lateral-eyed prey mammals, birds, amphibians and invertebrates. The diversity of animals known to have stereo vision allows us to begin to investigate ideas about its evolution and the underlying selective pressures in different animals. It also further prompts the question of whether all animals have evolved essentially the same algorithms to implement stereopsis. If so, this must be the best way to do stereo vision, and should be implemented by engineers in machine stereopsis. Conversely, if animals have evolved a range of stereo algorithms in response to different pressures, that could inspire novel forms of machine stereopsis appropriate for distinct environments, tasks or constraints. As a first step towards addressing these ideas, we here review our current knowledge of stereo vision in animals, with a view towards outlining common principles about the evolution, function and mechanisms of stereo vision across the animal kingdom. We conclude by outlining avenues for future work, including research into possible new mechanisms of stereo vision, with implications for machine vision and the role of stereopsis in the evolution of camouflage. PMID- 28724704 TI - Physiological responses to short-term thermal stress in mayfly (Neocloeon triangulifer) larvae in relation to upper thermal limits. AB - Understanding species' thermal limits and their physiological determinants is critical in light of climate change and other human activities that warm freshwater ecosystems. Here, we ask whether oxygen limitation determines the chronic upper thermal limits in larvae of the mayfly Neocloeon triangulifer, an emerging model for ecological and physiological studies. Our experiments are based on a robust understanding of the upper acute (~40 degrees C) and chronic thermal limits of this species (>28 degrees C, <=30 degrees C) derived from full life cycle rearing experiments across temperatures. We tested two related predictions derived from the hypothesis that oxygen limitation sets the chronic upper thermal limits: (1) aerobic scope declines in mayfly larvae as they approach and exceed temperatures that are chronically lethal to larvae; and (2) genes indicative of hypoxia challenge are also responsive in larvae exposed to ecologically relevant thermal limits. Neither prediction held true. We estimated aerobic scope by subtracting measurements of standard oxygen consumption rates from measurements of maximum oxygen consumption rates, the latter of which was obtained by treating with the metabolic uncoupling agent carbonyl cyanide-4 (trifluoromethoxy) pheylhydrazone (FCCP). Aerobic scope was similar in larvae held below and above chronic thermal limits. Genes indicative of oxygen limitation (LDH, EGL-9) were only upregulated under hypoxia or during exposure to temperatures beyond the chronic (and more ecologically relevant) thermal limits of this species (LDH). Our results suggest that the chronic thermal limits of this species are likely not driven by oxygen limitation, but rather are determined by other factors, e.g. bioenergetics costs. We caution against the use of short-term thermal ramping approaches to estimate critical thermal limits (CTmax) in aquatic insects because those temperatures are typically higher than those that occur in nature. PMID- 28724705 TI - Apparent changes in body insulation of juvenile king penguins suggest an energetic challenge during their early life at sea. AB - Little is known about the early life at sea of marine top predators, like deep diving king penguins (Aptenodytes patagonicus), although this dispersal phase is probably a critical phase in their life. Apart from finding favourable foraging sites, they have to develop effective prey search patterns as well as physiological capacities that enable them to capture sufficient prey to meet their energetic needs. To investigate the ontogeny of their thermoregulatory responses at sea, we implanted 30 juvenile king penguins and 8 adult breeders with a small data logger that recorded pressure and subcutaneous temperature continuously for up to 2.5 years. We found important changes in the development of peripheral temperature patterns of foraging juvenile king penguins throughout their first year at sea. Peripheral temperature during foraging bouts fell to increasingly lower levels during the first 6 months at sea, after which it stabilized. Most importantly, these changes re-occurred during their second year at sea, after birds had fasted for ~4 weeks on land during their second moult. Furthermore, similar peripheral temperature patterns were also present in adult birds during foraging trips throughout their breeding cycle. We suggest that rather than being a simple consequence of concurrent changes in dive effort or an indication of a physiological maturation process, these seasonal temperature changes mainly reflect differences in thermal insulation. Heat loss estimates for juveniles at sea were initially high but declined to approximately half after ~6 months at sea, suggesting that juvenile king penguins face a strong energetic challenge during their early oceanic existence. PMID- 28724706 TI - Question 1 What is the best sedative to give as premedication for neonatal intubation? PMID- 28724707 TI - Towards evidence based medicine for paediatricians. PMID- 28724708 TI - Question 2 Probiotics in acute infectious diarrhoea: should we run with it? PMID- 28724709 TI - 'Caution, this treatment is a placebo. It might work, but it might not': why emerging mechanistic evidence for placebo effects does not legitimise complementary and alternative medicines in sport. PMID- 28724711 TI - Sham surgery versus labral repair or biceps tenodesis for type II SLAP lesions of the shoulder: a three-armed randomised clinical trial. PMID- 28724710 TI - Sedentary time in older men and women: an international consensus statement and research priorities. AB - Sedentary time is a modifiable determinant of poor health, and in older adults, reducing sedentary time may be an important first step in adopting and maintaining a more active lifestyle. The primary purpose of this consensus statement is to provide an integrated perspective on current knowledge and expert opinion pertaining to sedentary behaviour in older adults on the topics of measurement, associations with health outcomes, and interventions. A secondary yet equally important purpose is to suggest priorities for future research and knowledge translation based on gaps identified. A five-step Delphi consensus process was used. Experts in the area of sedentary behaviour and older adults (n=15) participated in three surveys, an in-person consensus meeting, and a validation process. The surveys specifically probed measurement, health outcomes, interventions, and research priorities. The meeting was informed by a literature review and conference symposium, and it was used to create statements on each of the areas addressed in this document. Knowledge users (n=3) also participated in the consensus meeting. Statements were then sent to the experts for validation. It was agreed that self-report tools need to be developed for understanding the context in which sedentary time is accumulated. For health outcomes, it was agreed that the focus of sedentary time research in older adults needs to include geriatric-relevant health outcomes, that there is insufficient evidence to quantify the dose-response relationship, that there is a lack of evidence on sedentary time from older adults in assisted facilities, and that evidence on the association between sedentary time and sleep is lacking. For interventions, research is needed to assess the impact that reducing sedentary time, or breaking up prolonged bouts of sedentary time has on geriatric-relevant health outcomes. Research priorities listed for each of these areas should be considered by researchers and funding agencies.This consensus statement has been endorsed by the following societies: Academy of Geriatric Physical Therapy, Exercise & Sports Science Australia, Canadian Centre for Activity and Aging, Society of Behavioral Medicine, and the National Centre for Sport and Exercise Medicine. PMID- 28724712 TI - World Health Organisation to develop global action plan to promote physical activity: time for action. PMID- 28724713 TI - Treating SLAP II lesions with sham surgery. PMID- 28724714 TI - Sedentary time in older adults: a critical review of measurement, associations with health, and interventions. AB - : Sedentary time (ST) is an important risk factor for a variety of health outcomes in older adults. Consensus is needed on future research directions so that collaborative and timely efforts can be made globally to address this modifiable risk factor. In this review, we examined current literature to identify gaps and inform future research priorities on ST and healthy ageing. We reviewed three primary topics:(1) the validity/reliability of self-report measurement tools, (2) the consequences of prolonged ST on geriatric-relevant health outcomes (physical function, cognitive function, mental health, incontinence and quality of life) and(3) the effectiveness of interventions to reduce ST in older adults. METHODS: A trained librarian created a search strategy that was peer reviewed for completeness. RESULTS: Self-report assessment of the context and type of ST is important but the tools tend to underestimate total ST. There appears to be an association between ST and geriatric-relevant health outcomes, although there is insufficient longitudinal evidence to determine a dose-response relationship or a threshold for clinically relevant risk. The type of ST may also affect health; some cognitively engaging sedentary behaviours appear to benefit health, while time spent in more passive activities may be detrimental. Short-term feasibility studies of individual-level ST interventions have been conducted; however, few studies have appropriately assessed the impact of these interventions on geriatric-relevant health outcomes, nor have they addressed organisation or environment level changes. Research is specifically needed to inform evidence-based interventions that help maintain functional autonomy among older adults.This consensus statement has been endorsed by the following societies: Academy of Geriatric Physical Therapy, Exercise & Sports Science Australia, Canadian Centre for Activity and Aging, Society of Behavioral Medicine, and the National Centre for Sport and Exercise Medicine. PMID- 28724715 TI - Adaptation of the pathological tendon: you cannot trade in for a new one, but perhaps you don't need to? PMID- 28724716 TI - Beware the 'luck' capstone. PMID- 28724717 TI - Can pre-race aspirin prevent sudden cardiac death during marathons? PMID- 28724718 TI - Poor Reliability and Poor Adherence to Self-Monitoring of Blood Glucose Are Common in Women With Gestational Diabetes Mellitus and May Be Associated With Poor Pregnancy Outcomes. AB - OBJECTIVE: To evaluate the compliance with self-monitoring of blood glucose (SMBG) and the reliability of diabetes logbooks in women with gestational diabetes mellitus (GDM), as well as the associated determinants and outcomes. RESEARCH DESIGN AND METHODS: We prospectively selected French-speaking women with newly diagnosed GDM who had been referred to our diabetes management program and understood SMBG principles. At the next follow-up visit, we collected SMBG results from glucose meters and logbooks. We analyzed pregnancy outcomes. RESULTS: Data were analyzed over 13 +/- 3 days in 91 women. Only 61.5% had performed >=80% of the required tests. Poor compliance was associated with a family history of diabetes, social deprivation, and non-European origin. The average time between pre- and postprandial tests was 141 +/- 20 min, with 46.5% of women performing >=80% of postprandial measurements 100-140 min after meals. Inadequate timing was associated with ethnicity and higher HbA1c at baseline. A total of 23.1% of women had <90% matched values in diary and meter memory, and a poor concordance was associated with a family history of diabetes. Poor adherence was associated with more preeclampsia (12.2 vs. 1.9%, P = 0.049), and inadequate postprandial test timing with a higher HbA1c at delivery (5.3 +/- 0.4 vs. 5.0 +/- 0.3% [34 +/- 2 vs. 31 +/- 2 mmol/mol], P < 0.01), despite more frequent insulin therapy. CONCLUSIONS: Although women with GDM are considered to be highly motivated, SMBG adherence and reliability are of concern and may be associated with poor gestational prognosis, suggesting that caregivers should systematically check the glucose meter memory to improve GDM management. PMID- 28724719 TI - Opioid K receptor variant is associated with a delayed onset of dyskinesias in Parkinson's disease. PMID- 28724720 TI - Diagnosis of multiple sclerosis: a multicentre study to compare revised McDonald 2010 and Filippi-2010 criteria. PMID- 28724721 TI - Hypothalamic atrophy is related to body mass index and age at onset in amyotrophic lateral sclerosis. PMID- 28724722 TI - Effect of directional pulling on mechanical protein degradation by ATP-dependent proteolytic machines. AB - AAA+ proteases and remodeling machines couple hydrolysis of ATP to mechanical unfolding and translocation of proteins following recognition of sequence tags called degrons. Here, we use single-molecule optical trapping to determine the mechanochemistry of two AAA+ proteases, Escherichia coli ClpXP and ClpAP, as they unfold and translocate substrates containing multiple copies of the titinI27 domain during degradation initiated from the N terminus. Previous studies characterized degradation of related substrates with C-terminal degrons. We find that ClpXP and ClpAP unfold the wild-type titinI27 domain and a destabilized variant far more rapidly when pulling from the N terminus, whereas translocation speed is reduced only modestly in the N-to-C direction. These measurements establish the role of directionality in mechanical protein degradation, show that degron placement can change whether unfolding or translocation is rate limiting, and establish that one or a few power strokes are sufficient to unfold some protein domains. PMID- 28724723 TI - Nucleoredoxin guards against oxidative stress by protecting antioxidant enzymes. AB - Cellular accumulation of reactive oxygen species (ROS) is associated with a wide range of developmental and stress responses. Although cells have evolved to use ROS as signaling molecules, their chemically reactive nature also poses a threat. Antioxidant systems are required to detoxify ROS and prevent cellular damage, but little is known about how these systems manage to function in hostile, ROS-rich environments. Here we show that during oxidative stress in plant cells, the pathogen-inducible oxidoreductase Nucleoredoxin 1 (NRX1) targets enzymes of major hydrogen peroxide (H2O2)-scavenging pathways, including catalases. Mutant nrx1 plants displayed reduced catalase activity and were hypersensitive to oxidative stress. Remarkably, catalase was maintained in a reduced state by substrate interaction with NRX1, a process necessary for its H2O2-scavenging activity. These data suggest that unexpectedly H2O2-scavenging enzymes experience oxidative distress in ROS-rich environments and require reductive protection from NRX1 for optimal activity. PMID- 28724724 TI - BRCT-domain protein BRIT1 influences class switch recombination. AB - DNA double-strand breaks (DSBs) serve as obligatory intermediates for Ig heavy chain (Igh) class switch recombination (CSR). The mechanisms by which DSBs are resolved to promote long-range DNA end-joining while suppressing genomic instability inherently associated with DSBs are yet to be fully elucidated. Here, we use a targeted short-hairpin RNA screen in a B-cell lymphoma line to identify the BRCT-domain protein BRIT1 as an effector of CSR. We show that conditional genetic deletion of BRIT1 in mice leads to a marked increase in unrepaired Igh breaks and a significant reduction in CSR in ex vivo activated splenic B cells. We find that the C-terminal tandem BRCT domains of BRIT1 facilitate its interaction with phosphorylated H2AX and that BRIT1 is recruited to the Igh locus in an activation-induced cytidine deaminase (AID) and H2AX-dependent fashion. Finally, we demonstrate that depletion of another BRCT-domain protein, MDC1, in BRIT1-deleted B cells increases the severity of CSR defect over what is observed upon loss of either protein alone. Our results identify BRIT1 as a factor in CSR and demonstrate that multiple BRCT-domain proteins contribute to optimal resolution of AID-induced DSBs. PMID- 28724725 TI - Protein diversity in discrete structures at the distal tip of the trypanosome flagellum. AB - The distal end of the eukaryotic flagellum/cilium is important for axonemal growth and signaling and has distinct biomechanical properties. Specific flagellum tip structures exist, yet their composition, dynamics, and functions are largely unknown. We used biochemical approaches to identify seven constituents of the flagella connector at the tip of an assembling trypanosome flagellum and three constituents of the axonemal capping structure at the tips of both assembling and mature flagella. Both tip structures contain evolutionarily conserved as well as kinetoplastid-specific proteins, and component assembly into the structures occurs very early during flagellum extension. Localization and functional studies reveal that the flagella connector membrane junction is attached to the tips of extending microtubules of the assembling flagellum by a kinesin-15 family member. On the opposite side, a kinetoplastid-specific kinesin facilitates attachment of the junction to the microtubules in the mature flagellum. Functional studies also suggest roles of several other components and the definition of subdomains in the tip structures. PMID- 28724726 TI - Costs of services for homeless people with mental illness in 5 Canadian cities: a large prospective follow-up study. AB - BACKGROUND: Limited evidence on the costs of homelessness in Canada is available. We estimated the average annual costs, in total and by cost category, that homeless people with mental illness engender from the perspective of society. We also identified individual characteristics associated with higher costs. METHODS: As part of the At Home/Chez Soi trial of Housing First for homeless people with mental illness, 990 participants were assigned to the usual-treatment (control) group in 5 Canadian cities (Vancouver, Winnipeg, Toronto, Montreal and Moncton) between October 2009 and June 2011. They were followed for up to 2 years. Questionnaires ascertained service use and income, and city-specific unit costs were estimated. We adjusted costs for site differences in sample characteristics. We used generalized linear models to identify individual-level characteristics associated with higher costs. RESULTS: Usable data were available for 937 participants (94.6%). Average annual costs (excluding medications) per person in Vancouver, Winnipeg, Toronto, Montreal and Moncton were $53 144 (95% confidence interval [CI] $46 297-$60 095), $45 565 (95% CI $41 039-$50 412), $58 972 (95% CI $52 237-$66 085), $56 406 (95% CI $50 654-$62 456) and $29 610 (95% CI $24 995 $34 480), respectively. Net costs ranged from $15 530 to $341 535. Distributions of costs across categories varied significantly across cities. Lower functioning and a history of psychiatric hospital stays were the most important predictors of higher costs. INTERPRETATION: Homeless people with mental illness generate very high costs for society. Programs are needed to reorient this spending toward more effectively preventing homelessness and toward meeting the health, housing and social service needs of homeless people. PMID- 28724727 TI - A cross-scale trophic cascade from large predatory fish to algae in coastal ecosystems. AB - Trophic cascades occur in many ecosystems, but the factors regulating them are still elusive. We suggest that an overlooked factor is that trophic interactions (TIs) are often scale-dependent and possibly interact across spatial scales. To explore the role of spatial scale for trophic cascades, and particularly the occurrence of cross-scale interactions (CSIs), we collected and analysed food-web data from 139 stations across 32 bays in the Baltic Sea. We found evidence of a four-level trophic cascade linking TIs across two spatial scales: at bay scale, piscivores (perch and pike) controlled mesopredators (three-spined stickleback), which in turn negatively affected epifaunal grazers. At station scale (within bays), grazers on average suppressed epiphytic algae, and indirectly benefitted habitat-forming vegetation. Moreover, the direction and strength of the grazer algae relationship at station scale depended on the piscivore biomass at bay scale, indicating a cross-scale interaction effect, potentially caused by a shift in grazer assemblage composition. In summary, the trophic cascade from piscivores to algae appears to involve TIs that occur at, but also interact across, different spatial scales. Considering scale-dependence in general, and CSIs in particular, could therefore enhance our understanding of trophic cascades. PMID- 28724728 TI - Global decline of bumblebees is phylogenetically structured and inversely related to species range size and pathogen incidence. AB - Conservation biology can profit greatly from incorporating a phylogenetic perspective into analyses of patterns and drivers of species extinction risk. We applied such an approach to analyse patterns of bumblebee (Bombus) decline. We assembled a database representing approximately 43% of the circa 260 globally known species, which included species extinction risk assessments following the International Union fo Conservation of Nature Red List categories and criteria, and information on species traits presumably associated with bumblebee decline. We quantified the strength of phylogenetic signal in decline, range size, tongue length and parasite presence. Overall, about one-third of the assessed bumblebees are declining and declining species are not randomly distributed across the Bombus phylogeny. Susceptible species were over-represented in the subgenus Thoracobombus (approx. 64%) and under-represented in the subgenus Pyrobombus (approx. 6%). Phylogenetic logistic regressions revealed that species with small geographical ranges and those in which none of three internal parasites were reported (i.e. Crithidia bombi, Nosema spp. or Locustacarus buchneri) were particularly vulnerable. Bumblebee evolutionary history will be deeply eroded if most species from threatened clades, particularly those stemming from basal nodes, become finally extinct. The habitat of species with restricted distribution should be protected and the importance of pathogen tolerance/resistance as mechanisms to deal with pathogens needs urgent research. PMID- 28724729 TI - Food web persistence in fragmented landscapes. AB - Habitat destruction, characterized by patch loss and fragmentation, is a key driver of biodiversity loss. There has been some progress in the theory of spatial food webs; however, to date, practically nothing is known about how patch configurational fragmentation influences multi-trophic food web dynamics. We develop a spatially extended patch-dynamic model for different food webs by linking patch connectivity with trophic-dependent dispersal (i.e. higher trophic levels displaying longer-range dispersal). Using this model, we find that species display different sensitivities to patch loss and fragmentation, depending on their trophic position and the overall food web structure. Relative to other food webs, omnivory structure significantly increases system robustness to habitat destruction, as feeding on different trophic levels increases the omnivore's persistence. Additionally, in food webs with a dispersal-competition trade-off between species, intermediate levels of habitat destruction can enhance biodiversity by creating refuges for the weaker competitor. This demonstrates that maximizing patch connectivity is not always effective for biodiversity maintenance, as in food webs containing indirect competition, doing so may lead to further species loss. PMID- 28724730 TI - Stacked Bt maize and arthropod predators: exposure to insecticidal Cry proteins and potential hazards. AB - Genetically engineered (GE) crops with stacked insecticidal traits expose arthropods to multiple Cry proteins from Bacillus thuringiensis (Bt). One concern is that the different Cry proteins may interact and lead to unexpected adverse effects on non-target species. Bi- and tri-trophic experiments with SmartStax maize, herbivorous spider mites (Tetranychus urticae), aphids (Rhopalosiphum padi), predatory spiders (Phylloneta impressa), ladybeetles (Harmonia axyridis) and lacewings (Chrysoperla carnea) were conducted. Cry1A.105, Cry1F, Cry3Bb1 and Cry34Ab1 moved in a similar pattern through the arthropod food chain. By contrast, Cry2Ab2 had highest concentrations in maize leaves, but lowest in pollen, and lowest acquisition rates by herbivores and predators. While spider mites contained Cry protein concentrations exceeding the values in leaves (except Cry2Ab2), aphids contained only traces of some Cry protein. Predators contained lower concentrations than their food. Among the different predators, ladybeetle larvae showed higher concentrations than lacewing larvae and juvenile spiders. Acute effects of SmartStax maize on predator survival, development and weight were not observed. The study thus provides evidence that the different Cry proteins do not interact in a way that poses a risk to the investigated non target species under controlled laboratory conditions. PMID- 28724731 TI - Cascading effects of predator activity on tick-borne disease risk. AB - Predators and competitors of vertebrates can in theory reduce the density of infected nymphs (DIN)-an often-used measure of tick-borne disease risk-by lowering the density of reservoir-competent hosts and/or the tick burden on reservoir-competent hosts. We investigated this possible indirect effect of predators by comparing data from 20 forest plots across the Netherlands that varied in predator abundance. In each plot, we measured the density of questing Ixodes ricinus nymphs (DON), DIN for three pathogens, rodent density, the tick burden on rodents and the activity of mammalian predators. We analysed whether rodent density and tick burden on rodents were correlated with predator activity, and how rodent density and tick burden predicted DON and DIN for the three pathogens. We found that larval burden on two rodent species decreased with activity of two predator species, while DON and DIN for all three pathogens increased with larval burden on rodents, as predicted. Path analyses supported an indirect negative correlation of activity of both predator species with DON and DIN. Our results suggest that predators can indeed lower the number of ticks feeding on reservoir-competent hosts, which implies that changes in predator abundance may have cascading effects on tick-borne disease risk. PMID- 28724732 TI - Integrating regulatory surveys and citizen science to map outbreaks of forest diseases: acute oak decline in England and Wales. AB - The number of emerging tree diseases has increased rapidly in recent times, with severe environmental and economic consequences. Systematic regulatory surveys to detect and establish the distribution of pests are crucial for successful management efforts, but resource-intensive and costly. Volunteers who identify potential invasive species can form an important early warning network in tree health; however, what these data can tell us and how they can be best used to inform and direct official survey effort is not clear. Here, we use an extensive dataset on acute oak decline (AOD) as an opportunity to ask how verified data received from the public can be used. Information on the distribution of AOD was available as (i) systematic regulatory surveys conducted throughout England and Wales, and (ii) ad hoc sightings reported by landowners, land managers and members of the public (i.e. 'self-reported' cases). By using the available self reported cases at the design stage, the systematic survey could focus on defining the boundaries of the affected area. This maximized the use of available resources and highlights the benefits to be gained by developing strategies to enhance volunteer efforts in future programmes. PMID- 28724734 TI - Hydrothermal vent fields discovered in the southern Gulf of California clarify role of habitat in augmenting regional diversity. AB - Hydrothermal vent communities are distributed along mid-ocean spreading ridges as isolated patches. While distance is a key factor influencing connectivity among sites, habitat characteristics are also critical. The Pescadero Basin (PB) and Alarcon Rise (AR) vent fields, recently discovered in the southern Gulf of California, are bounded by previously known vent localities (e.g. Guaymas Basin and 21 degrees N East Pacific Rise); yet, the newly discovered vents differ markedly in substrata and vent fluid attributes. Out of 116 macrofaunal species observed or collected, only three species are shared among all four vent fields, while 73 occur at only one locality. Foundation species at basalt-hosted sulfide chimneys on the AR differ from the functional equivalents inhabiting sediment hosted carbonate chimneys in the PB, only 75 km away. The dominant species of symbiont-hosting tubeworms and clams, and peripheral suspension-feeding taxa, differ between the sites. Notably, the PB vents host a limited and specialized fauna in which 17 of 26 species are unknown at other regional vents and many are new species. Rare sightings and captured larvae of the 'missing' species revealed that dispersal limitation is not responsible for differences in community composition at the neighbouring vent localities. Instead, larval recruitment limiting habitat suitability probably favours species differentially. As scenarios develop to design conservation strategies around mining of seafloor sulfide deposits, these results illustrate that models encompassing habitat characteristics are needed to predict metacommunity structure. PMID- 28724733 TI - Early evolution of radial glial cells in Bilateria. AB - Bilaterians usually possess a central nervous system, composed of neurons and supportive cells called glial cells. Whereas neuronal cells are highly comparable in all these animals, glial cells apparently differ, and in deuterostomes, radial glial cells are found. These particular secretory glial cells may represent the archetype of all (macro) glial cells and have not been reported from protostomes so far. This has caused controversial discussions of whether glial cells represent a homologous bilaterian characteristic or whether they (and thus, centralized nervous systems) evolved convergently in the two main clades of bilaterians. By using histology, transmission electron microscopy, immunolabelling and whole-mount in situ hybridization, we show here that protostomes also possess radial glia-like cells, which are very likely to be homologous to those of deuterostomes. Moreover, our antibody staining indicates that the secretory character of radial glial cells is maintained throughout their various evolutionary adaptations. This implies an early evolution of radial glial cells in the last common ancestor of Protostomia and Deuterostomia. Furthermore, it suggests that an intraepidermal nervous system-composed of sensory cells, neurons and radial glial cells-was probably the plesiomorphic condition in the bilaterian ancestor. PMID- 28724735 TI - Dual function of the pectoral girdle for feeding and locomotion in white-spotted bamboo sharks. AB - Positioned at the intersection of the head, body and forelimb, the pectoral girdle has the potential to function in both feeding and locomotor behaviours although the latter has been studied far more. In ray-finned fishes, the pectoral girdle attaches directly to the skull and is retracted during suction feeding, enabling the ventral body muscles to power rapid mouth expansion. However, in sharks, the pectoral girdle is displaced caudally and entirely separate from the skull (as in tetrapods), raising the question of whether it is mobile during suction feeding and contributing to suction expansion. We measured three dimensional kinematics of the pectoral girdle in white-spotted bamboo sharks during suction feeding with X-ray reconstruction of moving morphology, and found the pectoral girdle consistently retracted about 11 degrees by rotating caudoventrally about the dorsal scapular processes. This motion occurred mostly after peak gape, so it likely contributed more to accelerating captured prey through the oral cavity and pharynx, than to prey capture as in ray-finned fishes. Our results emphasize the multiple roles of the pectoral girdle in feeding and locomotion, both of which should be considered in studying the functional and evolutionary morphology of this structure. PMID- 28724736 TI - Phenotypic shift in Wolbachia virulence towards its native host across serial horizontal passages. AB - Vertical transmission mode is predicted to decrease the virulence of symbionts. However, Wolbachia, a widespread vertically transmitted endosymbiont, exhibits both negative and beneficial effects on arthropod fitness. This 'Jekyll and Hyde' behaviour, as well as its ability to live transiently outside host cells and to establish new infections via horizontal transmission, may reflect the capacity of Wolbachia to exhibit various phenotypes depending on the prevailing environmental constraints. To study the ability of Wolbachia to readily cope with new constraints, we forced this endosymbiont to spread only via horizontal transmission. To achieve this, we performed serial horizontal transfers of haemolymph from Wolbachia-infected to naive individuals of the isopod Armadillidium vulgare. Across passages, we observed phenotypic changes in the symbiotic relationship: (i) The Wolbachia titre increased in both haemolymph and nerve cord but remained stable in ovaries; (ii) Wolbachia infection was benign at the beginning of the experiment, but highly virulent, killing most hosts after only a few passages. Such a phenotypic shift after recurrent horizontal passages demonstrates that Wolbachia can rapidly change its virulence when facing new environmental constraints. We thoroughly discuss the potential mechanism(s) underlying this phenotypic change, which are likely to be crucial for the ongoing radiation of Wolbachia in arthropods. PMID- 28724737 TI - Stress hormones predict a host superspreader phenotype in the West Nile virus system. AB - Glucocorticoid stress hormones, such as corticosterone (CORT), have profound effects on the behaviour and physiology of organisms, and thus have the potential to alter host competence and the contributions of individuals to population- and community-level pathogen dynamics. For example, CORT could alter the rate of contacts among hosts, pathogens and vectors through its widespread effects on host metabolism and activity levels. CORT could also affect the intensity and duration of pathogen shedding and risk of host mortality during infection. We experimentally manipulated songbird CORT, asking how CORT affected behavioural and physiological responses to a standardized West Nile virus (WNV) challenge. Although all birds became infected after exposure to the virus, only birds with elevated CORT had viral loads at or above the infectious threshold. Moreover, though the rate of mortality was faster in birds with elevated CORT compared with controls, most hosts with elevated CORT survived past the day of peak infectiousness. CORT concentrations just prior to inoculation with WNV and anti inflammatory cytokine concentrations following viral exposure were predictive of individual duration of infectiousness and the ability to maintain physical performance during infection (i.e. tolerance), revealing putative biomarkers of competence. Collectively, our results suggest that glucocorticoid stress hormones could directly and indirectly mediate the spread of pathogens. PMID- 28724738 TI - Early life manipulations of vasopressin-family peptides alter vocal learning. AB - Vocal learning from social partners is crucial for the successful development of communication in a wide range of species. Social interactions organize attention and enhance motivation to learn species-typical behaviour. However, the neurobiological mechanisms connecting social motivation and vocal learning are unknown. Using zebra finches (Taeniopygia guttata), a ubiquitous model for vocal learning, we show that manipulations of nonapeptide hormones in the vasopressin family (arginine vasotocin, AVT) early in development can promote or disrupt both song and social motivation. Young male zebra finches, like human infants, are socially gregarious and require interactive feedback from adult tutors to learn mature vocal forms. To investigate the role of social motivational mechanisms in song learning, in two studies, we injected hatchling males with AVT or Manning compound (MC, a nonapeptide receptor antagonist) on days 2-8 post-hatching and recorded song at maturity. In both studies, MC males produced a worse match to tutor song than controls. In study 2, which experimentally controlled for tutor and genetic factors, AVT males also learned song significantly better compared with controls. Furthermore, song similarity correlated with several measures of social motivation throughout development. These findings provide the first evidence that nonapeptides are critical to the development of vocal learning. PMID- 28724739 TI - Distinct spinning patterns gain differentiated loading tolerance of silk thread anchorages in spiders with different ecology. AB - Building behaviour in animals extends biological functions beyond bodies. Many studies have emphasized the role of behavioural programmes, physiology and extrinsic factors for the structure and function of buildings. Structure attachments associated with animal constructions offer yet unrealized research opportunities. Spiders build a variety of one- to three-dimensional structures from silk fibres. The evolution of economic web shapes as a key for ecological success in spiders has been related to the emergence of high performance silks and thread coating glues. However, the role of thread anchorages has been widely neglected in those models. Here, we show that orb-web (Araneidae) and hunting spiders (Sparassidae) use different silk application patterns that determine the structure and robustness of the joint in silk thread anchorages. Silk anchorages of orb-web spiders show a greater robustness against different loading situations, whereas the silk anchorages of hunting spiders have their highest pull-off resistance when loaded parallel to the substrate along the direction of dragline spinning. This suggests that the behavioural 'printing' of silk into attachment discs along with spinneret morphology was a prerequisite for the evolution of extended silk use in a three-dimensional space. This highlights the ecological role of attachments in the evolution of animal architectures. PMID- 28724740 TI - Grasshopper mice employ distinct vocal production mechanisms in different social contexts. AB - Functional changes in vocal organ morphology and motor control facilitate the evolution of acoustic signal diversity. Although many rodents produce vocalizations in a variety of social contexts, few studies have explored the underlying production mechanisms. Here, we describe mechanisms of audible and ultrasonic vocalizations (USVs) produced by grasshopper mice (genus Onychomys). Grasshopper mice are predatory rodents of the desert that produce both loud, long distance advertisement calls and USVs in close-distance mating contexts. Using live-animal recording in normal air and heliox, laryngeal and vocal tract morphological investigations, and biomechanical modelling, we found that grasshopper mice employ two distinct vocal production mechanisms. In heliox, changes in higher-harmonic amplitudes of long-distance calls indicate an airflow induced tissue vibration mechanism, whereas changes in fundamental frequency of USVs support a whistle mechanism. Vocal membranes and a thin lamina propria aid in the production of long-distance calls by increasing glottal efficiency and permitting high frequencies, respectively. In addition, tuning of fundamental frequency to the second resonance of a bell-shaped vocal tract increases call amplitude. Our findings indicate that grasshopper mice can dynamically adjust motor control to suit the social context and have novel morphological adaptations that facilitate long-distance communication. PMID- 28724741 TI - Body height and immune efficacy: testing body stature as a signal of biological quality. AB - According to the good genes hypothesis and energy allocation theory, human adult body height may reflect biological quality. An important aspect of this quality is immune system functioning (ISF). The aim of this study was to evaluate the relationship between ISF and body height in healthy people. The ISF was determined by several important innate (total complement and lysozyme activity, neutrophil function) and adaptive immune parameters (lymphocytes, IgA and IgG, and response to the flu vaccine). Overall, 96 males and 97 females were subjected to flu vaccination, and of these, 35 males and 34 females were subjected to tetanus. Blood samples were collected before and four weeks after vaccination. Immunomodulatory factors, participant's age, body fat, and free testosterone levels, were controlled. There was no association between body height and all analysed immune parameters for both sexes. That might suggest that in Western society, a women's preference for taller men is not related to 'good genes for immune competence'. We propose the novel Immunity Priority Hypothesis that explains the lack of relationship between adult body stature and ISF. This hypothesis, however, does not contradict the signalling role of a man's body height as a morphological marker of biological quality. PMID- 28724742 TI - The Myokine Irisin Is Released in Response to Saturated Fatty Acids and Promotes Pancreatic beta-Cell Survival and Insulin Secretion. AB - This study explored the role of irisin as a new pancreatic beta-cell secretagogue and survival factor and its potential role in the communication between skeletal muscle and pancreatic beta-cells under lipotoxic conditions. Recombinant irisin stimulated insulin biosynthesis and glucose-stimulated insulin secretion (GSIS) in a PKA-dependent manner and prevented saturated fatty acid-induced apoptosis in human and rat pancreatic beta-cells, as well as in human and murine pancreatic islets, via AKT/BCL2 signaling. Treatment of myotubes with 0.5 mmol/L palmitate for 4 h, but not with oleate, promoted an increase in irisin release in the culture medium. Moreover, increased serum levels of irisin were observed in mice fed with a high-fat diet. Mouse serum rich in irisin and the conditioned medium from myotubes exposed to palmitate for 4 h significantly reduced apoptosis of murine pancreatic islets and insulin-secreting INS-1E cells, respectively, and this was abrogated in the presence of an irisin-neutralizing antibody. Finally, in vivo administration of irisin improved GSIS and increased beta-cell proliferation. In conclusion, irisin can promote beta-cell survival and enhance GSIS and may thus participate in the communication between skeletal muscle and beta-cells under conditions of excess saturated fatty acids. PMID- 28724743 TI - Improving the healthcare response to domestic violence and abuse in sexual health clinics: feasibility study of a training, support and referral intervention. AB - OBJECTIVES: Sexual health and gynaecological problems are the most consistent and largest physical health differences between abused and non-abused female populations. Sexual health services are well placed to identify and support patients experiencing domestic violence and abuse (DVA). Most sexual health professionals have had minimal DVA training despite English National Institute for Health and Care Excellence recommendations. We sought to determine the feasibility of an evidence-based complex DVA training intervention in female sexual health walk-in services (IRIS ADViSE: Identification and Referral to Improve Safety whilst Assessing Domestic Violence in Sexual Health Environments). METHODS: An adaptive mixed method pilot study in the female walk-in service of two sexual health clinics. Following implementation and evaluation at site 1, the intervention was refined before implementation at site 2. The intervention comprised electronic prompts, multidisciplinary training sessions, clinic materials and simple referral pathways to IRIS ADViSE advocate-educators (AEs). The pilot lasted 7 weeks at site 1 and 12 weeks at site 2. Feasibility outcomes were to assign a supportive DVA clinical lead, an IRIS ADViSE AE employed by a local DVA service provider, adapt electronic records, develop local referral pathways, assess whether enquiry, identification and referral rates were measurable. RESULTS: Both sites achieved all feasibility outcomes: appointing a supportive DVA clinical lead and IRIS ADViSE AE, establishing links with a local DVA provider, adapting electronic records, developing local referral pathways and rates of enquiry, identification and referral were found to be measurable. Site 1: 10% enquiry rate (n=267), 4% identification rate (n=16) and eight AE referrals. Site 2: 61% enquiry rate (n=1090), a 7% identification rate (n=79) and eight AE referrals. CONCLUSIONS: IRIS ADViSE can be successfully developed and implemented in sexual health clinics. It fulfils the unmet need for DVA training. Longer-term evaluation is recommended. PMID- 28724744 TI - Ten years transmission of the new variant of Chlamydia trachomatis in Sweden: prevalence of infections and associated complications. AB - OBJECTIVES: In 2006, a new variant of Chlamydia trachomatis (nvCT) was discovered in Sweden. It has a deletion in the plasmid resulting in failed detection by the single target systems from Abbott and Roche used at that time, whereas the third system used, from Becton Dickinson (BD), detects nvCT. The proportion of nvCT was initially up to 65% in counties using Abbott/Roche systems. This study analysed the proportion of nvCT from 2007 to 2015 in four selected counties and its impact on chlamydia-associated complications. METHODS: C. trachomatis-positive specimens collected from 2007 to 2015 were analysed by a specific PCR to identify nvCT cases. Genotyping was performed by multilocus sequence typing (MLST) and ompA sequencing. Ectopic pregnancy and pelvic inflammatory disease records were extracted from the national registers. RESULTS: In total, 5101 C. trachomatis positive samples were analysed. The nvCT proportion significantly decreased in the two counties using Roche systems, from 56% in 2007 to 6.5% in 2015 (p<0.001). In the two counties using BD systems, a decrease was also seen, from 19% in 2007 to 5.2% in 2015 (p<0.001). Fifteen nvCT cases from 2015 and 102 cases from 2006 to 2009 had identical MLST profiles. Counties using Roche/Abbott systems showed higher mean rates of ectopic pregnancy and pelvic inflammatory disease compared with counties using BD systems. CONCLUSIONS: The nvCT proportion has decreased in all counties and converged to a low prevalence irrespective of previous rates. Genotyping showed that nvCT is clonal and genetically stable. Failing detection only marginally affected complication rates. PMID- 28724745 TI - RNA-Seq Identifies Circulating miR-125a-5p, miR-125b-5p, and miR-143-3p as Potential Biomarkers for Acute Ischemic Stroke. AB - RATIONALE: Currently, there are no blood-based biomarkers with clinical utility for acute ischemic stroke (IS). MicroRNAs show promise as disease markers because of their cell type-specific expression patterns and stability in peripheral blood. OBJECTIVE: To identify circulating microRNAs associated with acute IS, determine their temporal course up to 90 days post-stroke, and explore their utility as an early diagnostic marker. METHODS AND RESULTS: We used RNA sequencing to study expression changes of circulating microRNAs in a discovery sample of 20 patients with IS and 20 matched healthy control subjects. We further applied quantitative real-time polymerase chain reaction in independent samples for validation (40 patients with IS and 40 matched controls), replication (200 patients with IS, 100 healthy control subjects), and in 72 patients with transient ischemic attacks. Sampling of patient plasma was done immediately upon hospital arrival. We identified, validated, and replicated 3 differentially expressed microRNAs, which were upregulated in patients with IS compared with both healthy control subjects (miR-125a-5p [1.8-fold; P=1.5*10-6], miR-125b-5p [2.5-fold; P=5.6*10-6], and miR-143-3p [4.8-fold; P=7.8*10-9]) and patients with transient ischemic attack (miR-125a-5p: P=0.003; miR-125b-5p: P=0.003; miR-143 3p: P=0.005). Longitudinal analysis of expression levels up to 90 days after stroke revealed a normalization to control levels for miR-125b-5p and miR-143-3p starting at day 2 while miR-125a-5p remained elevated. Levels of all 3 microRNAs depended on platelet numbers in a platelet spike-in experiment but were unaffected by chemical hypoxia in Neuro2a cells and in experimental stroke models. In a random forest classification, miR-125a-5p, miR-125b-5p, and miR-143 3p differentiated between healthy control subjects and patients with IS with an area under the curve of 0.90 (sensitivity: 85.6%; specificity: 76.3%), which was superior to multimodal cranial computed tomography obtained for routine diagnostics (sensitivity: 72.5%) and previously reported biomarkers of acute IS (neuron-specific enolase: area under the curve=0.69; interleukin 6: area under the curve=0.82). CONCLUSIONS: A set of circulating microRNAs (miR-125a-5p, miR 125b-5p, and miR-143-3p) associates with acute IS and might have clinical utility as an early diagnostic marker. PMID- 28724746 TI - TPL2 (Therapeutic Targeting Tumor Progression Locus-2)/ATF4 (Activating Transcription Factor-4)/SDF1alpha (Chemokine Stromal Cell-Derived Factor-alpha) Axis Suppresses Diabetic Retinopathy. AB - RATIONALE: Diabetic retinopathy is characterized by vasopermeability, vascular leakage, inflammation, blood-retinal barrier breakdown, capillary degeneration, and neovascularization. However, the mechanisms underlying the association between diabetes mellitus and progression retinopathy remain unclear. OBJECTIVE: TPL2 (tumor progression locus 2), a serine-threonine protein kinase, exerts a pathological effect on vascular angiogenesis. This study investigated the role of Nepsilon-(carboxymethyl)lysine, a major advanced glycation end products, and the involved TPL2-related molecular signals in diabetic retinopathy using models of in vitro and in vivo and human samples. METHODS AND RESULTS: Serum Nepsilon (carboxymethyl)lysine levels and TPL2 kinase activity were significantly increased in clinical patients and experimental animals with diabetic retinopathy. Intravitreal administration of pharmacological blocker or neutralizing antibody inhibited TPL2 and effectively suppressed the pathological characteristics of retinopathy in streptozotocin-induced diabetic animal models. Intravitreal VEGF (vascular endothelial growth factor) neutralization also suppressed the diabetic retinopathy in diabetic animal models. Mechanistic studies in primary human umbilical vein endothelial cells and primary retinal microvascular endothelial cells from streptozotocin-diabetic rats, db/db mice, and samples from patients with diabetic retinopathy revealed a positive parallel correlation between Nepsilon-(carboxymethyl)lysine and the TPL2/chemokine SDF1alpha (stromal cell-derived factor-alpha) axis that is dependent on endoplasmic reticulum stress-related molecules, especially ATF4 (activating transcription factor-4). CONCLUSIONS: This study demonstrates that inhibiting the Nepsilon-(carboxymethyl)lysine-induced TPL2/ATF4/SDF1alpha axis can effectively prevent diabetes mellitus-mediated retinal microvascular dysfunction. This signaling axis may include the therapeutic potential for other diseases involving pathological neovascularization or macular edema. PMID- 28724747 TI - Interleukin-1 Receptor in Seizure Susceptibility after Traumatic Injury to the Pediatric Brain. AB - Epilepsy after pediatric traumatic brain injury (TBI) is associated with poor quality of life. This study aimed to characterize post-traumatic epilepsy in a mouse model of pediatric brain injury, and to evaluate the role of interleukin-1 (IL-1) signaling as a target for pharmacological intervention. Male mice received a controlled cortical impact or sham surgery at postnatal day 21, approximating a toddler-aged child. Mice were treated acutely with an IL-1 receptor antagonist (IL-1Ra; 100 mg/kg, s.c.) or vehicle. Spontaneous and evoked seizures were evaluated from video-EEG recordings. Behavioral assays tested for functional outcomes, postmortem analyses assessed neuropathology, and brain atrophy was detected by ex vivo magnetic resonance imaging. At 2 weeks and 3 months post injury, TBI mice showed an elevated seizure response to the convulsant pentylenetetrazol compared with sham mice, associated with abnormal hippocampal mossy fiber sprouting. A robust increase in IL-1beta and IL-1 receptor were detected after TBI. IL-1Ra treatment reduced seizure susceptibility 2 weeks after TBI compared with vehicle, and a reduction in hippocampal astrogliosis. In a chronic study, IL-1Ra-TBI mice showed improved spatial memory at 4 months post injury. At 5 months, most TBI mice exhibited spontaneous seizures during a 7 d video-EEG recording period. At 6 months, IL-1Ra-TBI mice had fewer evoked seizures compared with vehicle controls, coinciding with greater preservation of cortical tissue. Findings demonstrate this model's utility to delineate mechanisms underlying epileptogenesis after pediatric brain injury, and provide evidence of IL-1 signaling as a mediator of post-traumatic astrogliosis and seizure susceptibility.SIGNIFICANCE STATEMENT Epilepsy is a common cause of morbidity after traumatic brain injury in early childhood. However, a limited understanding of how epilepsy develops, particularly in the immature brain, likely contributes to the lack of efficacious treatments. In this preclinical study, we first demonstrate that a mouse model of traumatic injury to the pediatric brain reproduces many neuropathological and seizure-like hallmarks characteristic of epilepsy. Second, we demonstrate that targeting the acute inflammatory response reduces cognitive impairments, the degree of neuropathology, and seizure susceptibility, after pediatric brain injury in mice. These findings provide evidence that inflammatory cytokine signaling is a key process underlying epilepsy development after an acquired brain insult, which represents a feasible therapeutic target to improve quality of life for survivors. PMID- 28724748 TI - Depressed Synaptic Transmission and Reduced Vesicle Release Sites in Huntington's Disease Neuromuscular Junctions. AB - Huntington's disease (HD) is a progressive and fatal degenerative disorder that results in debilitating cognitive and motor dysfunction. Most HD studies have focused on degeneration of the CNS. We previously discovered that skeletal muscle from transgenic R6/2 HD mice is hyperexcitable due to decreased chloride and potassium conductances. The progressive and early onset of these defects suggest a primary myopathy in HD. In this study, we examined the relationship between neuromuscular transmission and skeletal muscle hyperexcitability. We used an ex vivo preparation of the levator auris longus muscle from male and female late stage R6/2 mice and age-matched wild-type controls. Immunostaining of the synapses and molecular analyses revealed no evidence of denervation. Physiologically, we recorded spontaneous miniature endplate currents (mEPCs) and nerve-evoked EPCs (eEPCs) under voltage-clamp, which, unlike current-clamp records, were independent of the changes in muscle membrane properties. We found a reduction in the number of vesicles released per action potential (quantal content) in R6/2 muscle, which analysis of eEPC variance and morphology indicate is caused by a reduction in the number of vesicle release sites (n) rather than a change in the probability of release (prel). Furthermore, analysis of high frequency stimulation trains suggests an impairment in vesicle mobilization. The depressed neuromuscular transmission in R6/2 muscle may help compensate for the muscle hyperexcitability and contribute to motor impersistence.SIGNIFICANCE STATEMENT Recent evidence indicates that Huntington's disease (HD) is a multisystem disorder. Our examination of neuromuscular transmission in this study reveals defects in the motor nerve terminal that may compensate for the muscle hyperexcitability in HD. The technique we used eliminates the effects of the altered muscle membrane properties on synaptic currents and thus provides hitherto the most detailed analysis of synaptic transmission in HD. Clinically, the striking depression of neurotransmission we found may help explain the motor impersistence in HD patients. Therapies that target the highly accessible peripheral nerve and muscle system provide a promising new avenue to lessen the debilitating motor symptoms of HD. PMID- 28724749 TI - Columnar Segregation of Magnocellular and Parvocellular Streams in Human Extrastriate Cortex. AB - Magnocellular versus parvocellular (M-P) streams are fundamental to the organization of macaque visual cortex. Segregated, paired M-P streams extend from retina through LGN into V1. The M stream extends further into area V5/MT, and parts of V2. However, elsewhere in visual cortex, it remains unclear whether M-P derived information (1) becomes intermixed or (2) remains segregated in M-P dominated columns and neurons. Here we tested whether M-P streams exist in extrastriate cortical columns, in 8 human subjects (4 female). We acquired high resolution fMRI at high field (7T), testing for M- and P-influenced columns within each of four cortical areas (V2, V3, V3A, and V4), based on known functional distinctions in M-P streams in macaque: (1) color versus luminance, (2) binocular disparity, (3) luminance contrast sensitivity, (4) peak spatial frequency, and (5) color/spatial interactions. Additional measurements of resting state activity (eyes closed) tested for segregated functional connections between these columns. We found M- and P-like functions and connections within and between segregated cortical columns in V2, V3, and (in most experiments) area V4. Area V3A was dominated by the M stream, without significant influence from the P stream. These results suggest that M-P streams exist, and extend through, specific columns in early/middle stages of human extrastriate cortex.SIGNIFICANCE STATEMENT The magnocellular and parvocellular (M-P) streams are fundamental components of primate visual cortical organization. These streams segregate both anatomical and functional properties in parallel, from retina through primary visual cortex. However, in most higher-order cortical sites, it is unknown whether such M-P streams exist and/or what form those streams would take. Moreover, it is unknown whether M-P streams exist in human cortex. Here, fMRI evidence measured at high field (7T) and high resolution revealed segregated M-P streams in four areas of human extrastriate cortex. These results suggest that M P information is processed in segregated parallel channels throughout much of human visual cortex; the M-P streams are more than a convenient sorting property in earlier stages of the visual system. PMID- 28724750 TI - Disruption of a Structurally Important Extracellular Element in the Glycine Receptor Leads to Decreased Synaptic Integration and Signaling Resulting in Severe Startle Disease. AB - Functional impairments or trafficking defects of inhibitory glycine receptors (GlyRs) have been linked to human hyperekplexia/startle disease and autism spectrum disorders. We found that a lack of synaptic integration of GlyRs, together with disrupted receptor function, is responsible for a lethal startle phenotype in a novel spontaneous mouse mutant shaky, caused by a missense mutation, Q177K, located in the extracellular beta8-beta9 loop of the GlyR alpha1 subunit. Recently, structural data provided evidence that the flexibility of the beta8-beta9 loop is crucial for conformational transitions during opening and closing of the ion channel and represents a novel allosteric binding site in Cys loop receptors. We identified the underlying neuropathological mechanisms in male and female shaky mice through a combination of protein biochemistry, immunocytochemistry, and both in vivo and in vitro electrophysiology. Increased expression of the mutant GlyR alpha1Q177K subunit in vivo was not sufficient to compensate for a decrease in synaptic integration of alpha1Q177Kbeta GlyRs. The remaining synaptic heteromeric alpha1Q177Kbeta GlyRs had decreased current amplitudes with significantly faster decay times. This functional disruption reveals an important role for the GlyR alpha1 subunit beta8-beta9 loop in initiating rearrangements within the extracellular-transmembrane GlyR interface and that this structural element is vital for inhibitory GlyR function, signaling, and synaptic clustering.SIGNIFICANCE STATEMENT GlyR dysfunction underlies neuromotor deficits in startle disease and autism spectrum disorders. We describe an extracellular GlyR alpha1 subunit mutation (Q177K) in a novel mouse startle disease mutant shaky Structural data suggest that during signal transduction, large transitions of the beta8-beta9 loop occur in response to neurotransmitter binding. Disruption of the beta8-beta9 loop by the Q177K mutation results in a disruption of hydrogen bonds between Q177 and the ligand binding residue R65. Functionally, the Q177K change resulted in decreased current amplitudes, altered desensitization decay time constants, and reduced GlyR clustering and synaptic strength. The GlyR beta8-beta9 loop is therefore an essential regulator of conformational rearrangements during ion channel opening and closing. PMID- 28724751 TI - Tomo-Seq Identifies SOX9 as a Key Regulator of Cardiac Fibrosis During Ischemic Injury. AB - BACKGROUND: Cardiac ischemic injury induces a pathological remodeling response, which can ultimately lead to heart failure. Detailed mechanistic insights into molecular signaling pathways relevant for different aspects of cardiac remodeling will support the identification of novel therapeutic targets. METHODS: Although genome-wide transcriptome analysis on diseased tissues has greatly advanced our understanding of the regulatory networks that drive pathological changes in the heart, this approach has been disadvantaged by the fact that the signals are derived from tissue homogenates. Here we used tomo-seq to obtain a genome-wide gene expression signature with high spatial resolution spanning from the infarcted area to the remote to identify new regulators of cardiac remodeling. Cardiac tissue samples from patients suffering from ischemic heart disease were used to validate our findings. RESULTS: Tracing transcriptional differences with a high spatial resolution across the infarcted heart enabled us to identify gene clusters that share a comparable expression profile. The spatial distribution patterns indicated a separation of expressional changes for genes involved in specific aspects of cardiac remodeling, such as fibrosis, cardiomyocyte hypertrophy, and calcium handling (Col1a2, Nppa, and Serca2). Subsequent correlation analysis allowed for the identification of novel factors that share a comparable transcriptional regulation pattern across the infarcted tissue. The strong correlation between the expression levels of these known marker genes and the expression of the coregulated genes could be confirmed in human ischemic cardiac tissue samples. Follow-up analysis identified SOX9 as common transcriptional regulator of a large portion of the fibrosis-related genes that become activated under conditions of ischemic injury. Lineage-tracing experiments indicated that the majority of COL1-positive fibroblasts stem from a pool of SOX9 expressing cells, and in vivo loss of Sox9 blunted the cardiac fibrotic response on ischemic injury. The colocalization between SOX9 and COL1 could also be confirmed in patients suffering from ischemic heart disease. CONCLUSIONS: Based on the exact local expression cues, tomo-seq can serve to reveal novel genes and key transcription factors involved in specific aspects of cardiac remodeling. Using tomo-seq, we were able to unveil the unknown relevance of SOX9 as a key regulator of cardiac fibrosis, pointing to SOX9 as a potential therapeutic target for cardiac fibrosis. PMID- 28724752 TI - The Fluid Mechanics of Transcatheter Heart Valve Leaflet Thrombosis in the Neosinus. AB - BACKGROUND: Transcatheter heart valve (THV) thrombosis has been increasingly reported. In these studies, thrombus quantification has been based on a 2 dimensional assessment of a 3-dimensional phenomenon. METHODS: Postprocedural, 4 dimensional, volume-rendered CT data of patients with CoreValve, Evolut R, and SAPIEN 3 transcatheter aortic valve replacement enrolled in the RESOLVE study (Assessment of Transcatheter and Surgical Aortic Bioprosthetic Valve Dysfunction With Multimodality Imaging and Its Treatment with Anticoagulation) were included in this analysis. Patients on anticoagulation were excluded. SAPIEN 3 and CoreValve/Evolut R patients with and without hypoattenuated leaflet thickening were included to study differences between groups. Patients were classified as having THV thrombosis if there was any evidence of hypoattenuated leaflet thickening. Anatomic and THV deployment geometries were analyzed, and thrombus volumes were computed through manual 3-dimensional reconstruction. We aimed to identify and evaluate risk factors that contribute to THV thrombosis through the combination of retrospective clinical data analysis and in vitro imaging in the space between the native and THV leaflets (neosinus). RESULTS: SAPIEN 3 valves with leaflet thrombosis were on average 10% further expanded (by diameter) than those without (95.5+/-5.2% versus 85.4+/-3.9%; P<0.001). However, this relationship was not evident with the CoreValve/Evolut R. In CoreValve/Evolut Rs with thrombosis, the thrombus volume increased linearly with implant depth (R2=0.7, P<0.001). This finding was not seen in the SAPIEN 3. The in vitro analysis showed that a supraannular THV deployment resulted in a nearly 7-fold decrease in stagnation zone size (velocities <0.1 m/s) when compared with an intraannular deployment. In addition, the in vitro model indicated that the size of the stagnation zone increased as cardiac output decreased. CONCLUSIONS: Although transcatheter aortic valve replacement thrombosis is a multifactorial process involving foreign materials, patient-specific blood chemistry, and complex flow patterns, our study indicates that deployed THV geometry may have implications on the occurrence of thrombosis. In addition, a supraannular neosinus may reduce thrombosis risk because of reduced flow stasis. Although additional prospective studies are needed to further develop strategies for minimizing thrombus burden, these results may help identify patients at higher thrombosis risk and aid in the development of next-generation devices with reduced thrombosis risk. PMID- 28724753 TI - Electrical Stimulation of the Pulvinar Disrupts Control of Spatially Directed Actions. PMID- 28724754 TI - Relevance of the Proteolytic Processing of Reelin by ADAMTS-3 in Brain Functions. PMID- 28724755 TI - Trim33 is essential for macrophage and neutrophil mobilization to developmental or inflammatory cues. AB - Macrophages infiltrate and establish in developing organs from an early stage, often before these have become vascularized. Similarly, leukocytes, in general, can quickly migrate through tissues to any site of wounding. This unique capacity is rooted in their characteristic amoeboid motility, the genetic basis of which is poorly understood. Trim33 (also known as Tif1-gamma), a nuclear protein that associates with specific DNA-binding transcription factors to modulate gene expression, has been found to be mainly involved in hematopoiesis and gene regulation mediated by TGF-beta. Here, we have discovered that in Trim33 deficient zebrafish embryos, primitive macrophages are unable to colonize the central nervous system to become microglia. Moreover, both macrophages and neutrophils of Trim33-deficient embryos display a reduced basal mobility within interstitial tissues, and a profound lack of a response to inflammatory recruitment signals, including local bacterial infections. Correlatively, Trim33 deficient mouse bone marrow-derived macrophages display a strongly reduced three dimensional amoeboid mobility in fibrous collagen gels. The transcriptional regulator Trim33 is thus revealed as being essential for the navigation of macrophages and neutrophils towards developmental or inflammatory cues within vertebrate tissues. PMID- 28724756 TI - Lysosomal targeting of SIDT2 via multiple YxxPhi motifs is required for SIDT2 function in the process of RNautophagy. AB - RNA degradation is an essential process for maintaining cellular homeostasis. Previously, we discovered a novel RNA degradation system, RNautophagy, during which direct import of RNA into lysosomes in an ATP-dependent manner followed by degradation takes place. The putative nucleic acid transporter SID-1 transmembrane family member 2 (SIDT2) predominantly localizes to lysosomes and mediates the translocation of RNA into lysosomes during RNautophagy. However, little is known about the mechanisms of sorting SIDT2 to lysosomes. Here, we show that three cytosolic YxxPhi motifs (in which x is any amino acid and Phi is an amino acid with a bulky hydrophobic side chain) are required for the lysosomal localization of SIDT2, and that SIDT2 interacts with adaptor protein complexes AP 1 and AP-2. We also find that localization to lysosomes by these three motifs is necessary for SIDT2 function in the process of RNautophagy, and that SIDT2 strikingly increases endogenous RNA degradation at the cellular level. To our knowledge, this is the first study to report an endogenous intracellular protein for which overexpression substantially increased intracellular RNA degradation. This study provides new insight into lysosomal targeting of proteins and intracellular RNA degradation, and further confirms the critical function of SIDT2 in RNautophagy.This article has an associated First Person interview with the first author of the paper. PMID- 28724757 TI - Molecular anatomy of the early events in STIM1 activation - oligomerization or conformational change? AB - Decreased luminal endoplasmic reticulum (ER) Ca2+ concentration triggers oligomerization and clustering of the ER Ca2+ sensor STIM1 to promote its association with plasma membrane Orai1 Ca2+ channels leading to increased Ca2+ influx. A key step in STIM1 activation is the release of its SOAR domain from an intramolecular clamp formed with the STIM1 first coiled-coil (CC1) region. Using a truncated STIM1(1-343) molecule that captures or releases the isolated SOAR domain depending on luminal ER Ca2+ concentrations, we analyzed the early molecular events that control the intramolecular clamp formed between the CC1 and SOAR domains. We found that STIM1 forms constitutive dimers, and its CC1 domain can bind the SOAR domain of another STIM1 molecule in trans. Artificial oligomerization failed to liberate the SOAR domain or activate STIM1 unless the luminal Ca2+-sensing domains were removed. We propose that the release of SOAR from its CC1 interaction is controlled by changes in the orientation of the two CC1 domains in STIM1 dimers. Ca2+ unbinding in the STIM1 luminal domains initiates the conformational change allowing SOAR domain liberation and clustering, leading to Orai1 channel activation. PMID- 28724758 TI - The ShcD phosphotyrosine adaptor subverts canonical EGF receptor trafficking. AB - Shc family signalling adaptors connect activated transmembrane receptors to proximal effectors, and most also contain a sequence involved in clathrin mediated receptor endocytosis. Notably, this AP2 adaptin-binding motif (AD) is absent from the ShcD (also known as Shc4) homolog, which also uniquely promotes ligand-independent phosphorylation of the epidermal growth factor receptor (EGFR). We now report that cultured cells expressing ShcD exhibit reduced EGF uptake, commensurate with a decrease in EGFR surface presentation. Under basal conditions, ShcD colocalises with the EGFR and facilitates its phosphorylation, ubiquitylation and accumulation in juxtanuclear vesicles identified as Rab11 positive endocytic recycling compartments. Accordingly, ShcD also functions as a constitutive binding partner for the E3 ubiquitin ligase Cbl. EGFR phosphorylation and focal accumulation likewise occur upon ShcD co-expression in U87 glioma cells. Loss of ShcD phosphotyrosine-binding function or insertion of the ShcA AD sequence each restore ligand acquisition through distinct mechanisms. The AD region also contains a nuclear export signal, indicating its multifunctionality. Overall, ShcD appears to possess several molecular permutations that actively govern the EGFR, which may have implications in development and disease. PMID- 28724759 TI - Cholesterol 25-Hydroxylase Inhibits Porcine Reproductive and Respiratory Syndrome Virus Replication through Enzyme Activity-Dependent and -Independent Mechanisms. AB - Cholesterol 25-hydroxylase (CH25H) has recently been identified as a host restriction factor that exerts antiviral effects by catalyzing the production of 25-hydroxycholesterol (25HC). CH25H can be rapidly induced upon infection with some viruses. Porcine reproductive and respiratory syndrome virus (PRRSV), an arterivirus, has ranked among the most important swine pathogens since it was discovered in the late 1980s. In this study, we found that PRRSV infection significantly downregulated the expression of CH25H in cells by a so-far unknown mechanism, suggesting that CH25H exerts antiviral activity against PRRSV. Indeed, overexpression of CH25H inhibited PRRSV replication, whereas knockdown of CH25H by short interfering RNA (siRNA) promoted PRRSV infection. The anti-PRRSV effect of 25HC operates via inhibition of viral penetration. Interestingly, a CH25H mutant (CH25H-M) lacking hydroxylase activity still inhibited PRRSV infection. Screening using a yeast two-hybrid system followed by coimmunoprecipitation and immunofluorescence colocalization analyses confirmed that both CH25H and CH25H-M interact with the nonstructural protein 1 alpha (nsp1alpha) of PRRSV. Unexpectedly, the expression of nsp1alpha decreased following coexpression with CH25H or CH25H-M. Detailed analyses demonstrated that CH25H/CH25H-M could degrade nsp1alpha through the ubiquitin-proteasome pathway and that site K169 in the nsp1alpha protein is the key site of ubiquitination. Taken together, our findings demonstrate that CH25H restricts PRRSV replication by targeting viral penetration as well as degrading nsp1alpha, revealing a novel antiviral mechanism used by CH25H.IMPORTANCE PRRSV has been a continuous threat to the global swine industry, and current vaccines are insufficient to provide sustainable control. CH25H has been found to exert a broad antiviral effect; thus, it is an attractive target for the development of anti-PRRSV drugs. Here, we demonstrate that CH25H is an interferon-stimulated gene that is highly expressed in porcine alveolar macrophages. CH25H exerts its anti-PRRSV effect not only via the production of 25HC to inhibit viral penetration but also by degrading viral protein through the ubiquitin-proteasome pathway, suggesting that CH25H is a candidate for the development of antiviral therapeutics. However, PRRSV infection appears to actively decrease CH25H expression to promote viral replication, highlighting the complex game between PRRSV and its host. PMID- 28724760 TI - UV Radiation Activates Toll-Like Receptor 9 Expression in Primary Human Keratinocytes, an Event Inhibited by Human Papillomavirus 38 E6 and E7 Oncoproteins. AB - Several lines of evidence indicate that cutaneous human papillomavirus (HPV) types belonging to the beta genus of the HPV phylogenetic tree synergize with UV radiation in the development of skin cancer. Accordingly, the E6 and E7 oncoproteins from some beta HPV types are able to deregulate pathways related to immune response and cellular transformation. Toll-like receptor 9 (TLR9), in addition to playing a role in innate immunity, has been shown to be involved in the cellular stress response. Using primary human keratinocytes as experimental models, we have shown that UV irradiation (and other cellular stresses) activates TLR9 expression. This event is closely linked to p53 activation. Silencing the expression of p53 or deleting its encoding gene affected the activation of TLR9 expression after UV irradiation. Using various strategies, we have also shown that the transcription factors p53 and c-Jun are recruited onto a specific region of the TLR9 promoter after UV irradiation. Importantly, the E6 and E7 oncoproteins from beta HPV38, by inducing the accumulation of the p53 antagonist DeltaNp73alpha, prevent the UV-mediated recruitment of these transcription factors onto the TLR9 promoter, with subsequent impairment of TLR9 gene expression. This study provides new insight into the mechanism that mediates TLR9 upregulation in response to cellular stresses. In addition, we show that HPV38 E6 and E7 are able to interfere with this mechanism, providing another explanation for the possible cooperation of beta HPV types with UV radiation in skin carcinogenesis.IMPORTANCE Beta HPV types have been suggested to act as cofactors in UV-induced skin carcinogenesis by altering several cellular mechanisms activated by UV radiation. We show that the expression of TLR9, a sensor of damage-associated molecular patterns produced during cellular stress, is activated by UV radiation in primary human keratinocytes (PHKs). Two transcription factors known to be activated by UV radiation, p53 and c-Jun, play key roles in UV-activated TLR9 expression. The E6 and E7 oncoproteins from beta HPV38 strongly inhibit UV-activated TLR9 expression by preventing the recruitment of p53 and c-Jun to the TLR9 promoter. Our findings provide additional support for the role that beta HPV types play in skin carcinogenesis by preventing activation of specific pathways upon exposure of PHKs to UV radiation. PMID- 28724761 TI - ISG15 Modulates Type I Interferon Signaling and the Antiviral Response during Hepatitis E Virus Replication. AB - Hepatitis E virus (HEV), a single-stranded positive-sense RNA virus, generally causes self-limiting acute viral hepatitis, although chronic HEV infection has recently become a significant clinical problem in immunocompromised individuals, especially in solid-organ transplant recipients. Innate immunity, via the type I interferon (IFN) response, plays an important role during the initial stages of a viral infection. IFN-stimulated gene 15 (ISG15), an IFN-induced ubiquitin-like protein, is known to have an immunomodulatory role and can have a direct antiviral effect on a wide spectrum of virus families. In the present study, we investigated the antiviral effect as well as the potential immunomodulatory role of ISG15 during HEV replication. The results revealed that HEV induced high levels of ISG15 production both in vitro (Huh7-S10-3 liver cells) and in vivo (liver tissues from HEV-infected pigs); however, ISG15 is not required for virus replication. We also demonstrated that ISG15 silencing potentiates enhanced type I IFN-mediated signaling, resulting in an increase in the type I IFN-mediated antiviral effect during HEV replication. This observed enhanced type I IFN signaling correlated with an increase in IFN-stimulated gene expression levels during HEV replication. Furthermore, we showed that PKR and OAS1 played important roles in the ISG15-mediated type I IFN sensitivity of HEV. Taken together, the results from this study suggest that ISG15 plays an important immunomodulatory role and regulates HEV sensitivity to exogenous type I IFN.IMPORTANCE Hepatitis E virus (HEV) infection typically causes self-limiting acute viral hepatitis. However, chronic HEV infection has recently become a significant clinical problem in immunocompromised patients. Pegylated interferon (IFN) has been used to treat chronic HEV infection in solid-organ transplant patients with some success. However, the mechanism behind the type I IFN-mediated antiviral effect against HEV remains unclear. This report demonstrates that ISG15 induced by HEV replication in Huh7-S10-3 human liver cells plays an immunomodulatory role by negatively regulating type I IFN signaling and, thus, HEV sensitivity to type I IFN. Our results also show that PKR and OAS1 play important roles in the ISG15 mediated type I IFN sensitivity of HEV. PMID- 28724762 TI - Stability of Cucumber Necrosis Virus at the Quasi-6-Fold Axis Affects Zoospore Transmission. AB - Cucumber necrosis virus (CNV) is a member of the genus Tombusvirus and has a monopartite positive-sense RNA genome. CNV is transmitted in nature via zoospores of the fungus Olpidium bornovanus As with other members of the Tombusvirus genus, the CNV capsid swells when exposed to alkaline pH and EDTA. We previously demonstrated that a P73G mutation blocks the virus from zoospore transmission while not significantly affecting replication in plants (K. Kakani, R. Reade, and D. Rochon, J Mol Biol 338:507-517, 2004, https://doi.org/10.1016/j.jmb.2004.03.008). P73 lies immediately adjacent to a putative zinc binding site (M. Li et al., J Virol 87:12166-12175, 2013, https://doi.org/10.1128/JVI.01965-13) that is formed by three icosahedrally related His residues in the N termini of the C subunit at the quasi-6-fold axes. To better understand how this buried residue might affect vector transmission, we determined the cryo-electron microscopy structure of wild-type CNV in the native and swollen state and of the transmission-defective mutant, P73G, under native conditions. With the wild-type CNV, the swollen structure demonstrated the expected expansion of the capsid. However, the zinc binding region at the quasi-6 fold at the beta-annulus axes remained intact. By comparison, the zinc binding region of the P73G mutant, even under native conditions, was markedly disordered, suggesting that the beta-annulus had been disrupted and that this could destabilize the capsid. This was confirmed with pH and urea denaturation experiments in conjunction with electron microscopy analysis. We suggest that the P73G mutation affects the zinc binding and/or the beta-annulus, making it more fragile under neutral/basic pH conditions. This, in turn, may affect zoospore transmission.IMPORTANCECucumber necrosis virus (CNV), a member of the genus Tombusvirus, is transmitted in nature via zoospores of the fungus Olpidium bornovanus While a number of plant viruses are transmitted via insect vectors, little is known at the molecular level as to how the viruses are recognized and transmitted. As with many spherical plant viruses, the CNV capsid swells when exposed to alkaline pH and EDTA. We previously demonstrated that a P73G mutation that lies inside the capsid immediately adjacent to a putative zinc binding site (Li et al., J Virol 87:12166-12175, 2013, https://doi.org/10.1128/JVI.01965-13) blocks the virus from zoospore transmission while not significantly affecting replication in plants (K. Kakani, R. Reade, and D. Rochon, J Mol Biol 338:507 517, 2004, https://doi.org/10.1016/j.jmb.2004.03.008). Here, we show that the P73G mutant is less stable than the wild type, and this appears to be correlated with destabilization of the beta-annulus at the icosahedral 3-fold axes. Therefore, the beta-annulus appears not to be essential for particle assembly but is necessary for interactions with the transmission vector. PMID- 28724763 TI - Species Specificity of Vaccinia Virus Complement Control Protein for the Bovine Classical Pathway Is Governed Primarily by Direct Interaction of Its Acidic Residues with Factor I. AB - Poxviruses display species tropism-variola virus is a human-specific virus, while vaccinia virus causes repeated outbreaks in dairy cattle. Consistent with this, variola virus complement regulator SPICE (smallpox inhibitor of complement enzymes) exhibits selectivity in inhibiting the human alternative complement pathway and vaccinia virus complement regulator VCP (vaccinia virus complement control protein) displays selectivity in inhibiting the bovine alternative complement pathway. In the present study, we examined the species specificity of VCP and SPICE for the classical pathway (CP). We observed that VCP is ~43-fold superior to SPICE in inhibiting bovine CP. Further, functional assays revealed that increased inhibitory activity of VCP for bovine CP is solely due to its enhanced cofactor activity, with no effect on decay of bovine CP C3-convertase. To probe the structural basis of this specificity, we utilized single- and multi amino-acid substitution mutants wherein 1 or more of the 11 variant VCP residues were substituted in the SPICE template. Examination of these mutants for their ability to inhibit bovine CP revealed that E108, E120, and E144 are primarily responsible for imparting the specificity and contribute to the enhanced cofactor activity of VCP. Binding and functional assays suggested that these residues interact with bovine factor I but not with bovine C4(H2O) (a moiety conformationally similar to C4b). Mapping of these residues onto the modeled structure of bovine C4b-VCP-bovine factor I supported the mutagenesis data. Taken together, our data help explain why the vaccine strain of vaccinia virus was able to gain a foothold in domesticated animals.IMPORTANCE Vaccinia virus was used for smallpox vaccination. The vaccine-derived virus is now circulating and causing outbreaks in dairy cattle in India and Brazil. However, the reason for this tropism is unknown. It is well recognized that the virus is susceptible to neutralization by the complement classical pathway (CP). Because the virus encodes a soluble complement regulator, VCP, we examined whether this protein displays selectivity in targeting bovine CP. Our data show that it does exhibit selectivity in inhibiting the bovine CP and that this is primarily determined by its amino acids E108, E120, and E144, which interact with bovine serine protease factor I to inactivate bovine C4b-one of the two subunits of CP C3-convertase. Of note, the variola complement regulator SPICE contains positively charged residues at these positions. Thus, these variant residues in VCP help enhance its potency against the bovine CP and thereby the fitness of the virus in cattle. PMID- 28724764 TI - Rab5 and Rab11 Are Required for Clathrin-Dependent Endocytosis of Japanese Encephalitis Virus in BHK-21 Cells. AB - During infection Japanese encephalitis virus (JEV) generally enters host cells via receptor-mediated clathrin-dependent endocytosis. The trafficking of JEV within endosomes is controlled by Rab GTPases, but which Rab proteins are involved in JEV entry into BHK-21 cells is unknown. In this study, entry and postinternalization of JEV were analyzed using biochemical inhibitors, RNA interference, and dominant negative (DN) mutants. Our data demonstrate that JEV entry into BHK-21 cells depends on clathrin, dynamin, and cholesterol but not on caveolae or macropinocytosis. The effect on JEV infection of dominant negative (DN) mutants of four Rab proteins that regulate endosomal trafficking was examined. Expression of DN Rab5 and DN Rab11, but not DN Rab7 and DN Rab9, significantly inhibited JEV replication. These results were further tested by silencing Rab5 or Rab11 expression before viral infection. Confocal microscopy showed that virus particles colocalized with Rab5 or Rab11 within 15 min after virus entry, suggesting that after internalization JEV moves to early and recycling endosomes before the release of the viral genome. Our findings demonstrate the roles of Rab5 and Rab11 on JEV infection of BHK-21 cells through the endocytic pathway, providing new insights into the life cycle of flaviviruses.IMPORTANCE Although Japanese encephalitis virus (JEV) utilizes different endocytic pathways depending on the cell type being infected, the detailed mechanism of its entry into BHK-21 cells is unknown. Understanding the process of JEV endocytosis and postinternalization will advance our knowledge of JEV infection and pathogenesis as well as provide potential novel drug targets for antiviral intervention. With this objective, we used systematic approaches to dissect this process. The results show that entry of JEV into BHK-21 cells requires a low-pH environment and that the process occurs through dynamin-, actin , and cholesterol-dependent clathrin-mediated endocytosis that requires Rab5 and Rab11. Our work provides a detailed picture of the entry of JEV into BHK-21 cells and the cellular events that follow. PMID- 28724765 TI - The Translesion Polymerase Pol eta Is Required for Efficient Epstein-Barr Virus Infectivity and Is Regulated by the Viral Deubiquitinating Enzyme BPLF1. AB - Epstein-Barr virus (EBV) infection and lytic replication are known to induce a cellular DNA damage response. We previously showed that the virally encoded BPLF1 protein interacts with and regulates several members of the translesion synthesis (TLS) pathway, a DNA damage tolerance pathway, and that these cellular factors enhance viral infectivity. BPLF1 is a late lytic cycle gene, but the protein is also packaged in the viral tegument, indicating that BPLF1 may function both early and late during infection. The BPLF1 protein expresses deubiquitinating activity that is strictly conserved across the Herpesviridae; mutation of the active site cysteine results in a loss of enzymatic activity. Infection with an EBV BPLF1 knockout virus results in decreased EBV infectivity. Polymerase eta (Pol eta), a specialized DNA repair polymerase, functions in TLS and allows for DNA replication complexes to bypass lesions in DNA. Here we report that BPLF1 interacts with Pol eta and that Pol eta protein levels are increased in the presence of functional BPLF1. BPLF1 promotes a nuclear relocalization of Pol eta molecules which are focus-like in appearance, consistent with the localization observed when Pol eta is recruited to sites of DNA damage. Knockdown of Pol eta resulted in decreased production of infectious virus, and further, Pol eta was found to bind to EBV DNA, suggesting that it may allow for bypass of damaged viral DNA during its replication. The results suggest a mechanism by which EBV recruits cellular repair factors, such as Pol eta, to sites of viral DNA damage via BPLF1, thereby allowing for efficient viral DNA replication.IMPORTANCE Epstein-Barr virus is the causative agent of infectious mononucleosis and infects approximately 90% of the world's population. It causes lymphomas in individuals with acquired and innate immune disorders and is strongly associated with Hodgkin's lymphoma, Burkitt's lymphoma, diffuse large B-cell lymphomas, nasopharyngeal carcinoma (NPC), and lymphomas that develop in organ transplant recipients. Cellular DNA damage is a major determinant in the establishment of oncogenic processes and is well studied, but there are few studies of endogenous repair of viral DNA. This work evaluates how EBV's BPLF1 protein and its conserved deubiquitinating activity regulate the cellular DNA repair enzyme polymerase eta and recruit it to potential sites of viral damage and replication, resulting in enhanced production of infectious virus. These findings help to establish how EBV enlists and manipulates cellular DNA repair factors during the viral lytic cycle, contributing to efficient infectious virion production. PMID- 28724767 TI - Integrity of the Linker of Nucleoskeleton and Cytoskeleton Is Required for Efficient Herpesvirus Nuclear Egress. AB - Herpesvirus capsids assemble in the nucleus, while final virion maturation proceeds in the cytoplasm. This requires that newly formed nucleocapsids cross the nuclear envelope (NE), which occurs by budding at the inner nuclear membrane (INM), release of the primary enveloped virion into the perinuclear space (PNS), and subsequent rapid fusion with the outer nuclear membrane (ONM). During this process, the NE remains intact, even at late stages of infection. In addition, the spacing between the INM and ONM is maintained, as is that between the primary virion envelope and nuclear membranes. The linker of nucleoskeleton and cytoskeleton (LINC) complex consists of INM proteins with a luminal SUN (Sad1/UNC 84 homology) domain connected to ONM proteins with a KASH (Klarsicht, ANC-1, SYNE homology) domain and is thought to be responsible for spacing the nuclear membranes. To investigate the role of the LINC complex during herpesvirus infection, we generated cell lines constitutively expressing dominant negative (dn) forms of SUN1 and SUN2. Ultrastructural analyses revealed a significant expansion of the PNS and the contiguous intracytoplasmic lumen, most likely representing endoplasmic reticulum (ER), especially in cells expressing dn-SUN2. After infection, primary virions accumulated in these expanded luminal regions, also very distant from the nucleus. The importance of the LINC complex was also confirmed by reduced progeny virus titers in cells expressing dn-SUN2. These data show that the intact LINC complex is required for efficient nuclear egress of herpesviruses, likely acting to promote fusion of primary enveloped virions with the ONM.IMPORTANCE While the viral factors for primary envelopment of nucleocapsids at the inner nuclear membrane are known to the point of high resolution structures, the roles of cellular components and regulators remain enigmatic. Furthermore, the machinery responsible for fusion with the outer nuclear membrane is unsolved. We show here that dominant negative SUN2 interferes with efficient herpesvirus nuclear egress, apparently by interfering with fusion between the primary virion envelope and outer nuclear membrane. This identifies a new cellular component important for viral egress and implicates LINC complex integrity in nonconventional nuclear membrane trafficking. PMID- 28724766 TI - A Unique T-Cell Receptor Amino Acid Sequence Selected by Human T-Cell Lymphotropic Virus Type 1 Tax301-309-Specific Cytotoxic T Cells in HLA-A24:02 Positive Asymptomatic Carriers and Adult T-Cell Leukemia/Lymphoma Patients. AB - We previously reported that the T-cell receptor (TCR) repertoire of human T-cell lymphotropic virus type 1 (HTLV-1) Tax301-309-specific CD8+ cytotoxic T cells (Tax301-309-CTLs) was highly restricted and a particular amino acid sequence motif, the PDR motif, was conserved among HLA-A*24:02-positive (HLA-A*24:02+) adult T-cell leukemia/lymphoma (ATL) patients who had undergone allogeneic hematopoietic cell transplantation (allo-HSCT). Furthermore, we found that donor derived PDR+ CTLs selectively expanded in ATL long-term HSCT survivors with strong CTL activity against HTLV-1. On the other hand, the TCR repertoires in Tax301-309-CTLs of asymptomatic HTLV-1 carriers (ACs) remain unclear. In this study, we directly identified the DNA sequence of complementarity-determining region 3 (CDR3) of the TCR-beta chain of Tax301-309-CTLs at the single-cell level and compared not only the TCR repertoires but also the frequencies and phenotypes of Tax301-309-CTLs between ACs and ATL patients. We did not observe any essential difference in the frequencies of Tax301-309-CTLs between ACs and ATL patients. In the single-cell TCR repertoire analysis of Tax301-309-CTLs, 1,458 Tax301-309-CTLs and 140 clones were identified in this cohort. Tax301-309-CTLs showed highly restricted TCR repertoires with a strongly biased usage of BV7, and PDR, the unique motif in TCR-beta CDR3, was exclusively observed in all ACs and ATL patients. However, there was no correlation between PDR+ CTL frequencies and HTLV 1 proviral load (PVL). In conclusion, we have identified, for the first time, a unique amino acid sequence, PDR, as a public TCR-CDR3 motif against Tax in HLA A*24:02+ HTLV-1-infected individuals. Further investigations are warranted to elucidate the role of the PDR+ CTL response in the progression from carrier state to ATL.IMPORTANCE ATL is an aggressive T-cell malignancy caused by HTLV-1 infection. The HTLV-1 regulatory protein Tax aggressively promotes the proliferation of HTLV-1-infected lymphocytes and is also a major target antigen for CD8+ CTLs. In our previous evaluation of Tax301-309-CTLs, we found that a unique amino acid sequence motif, PDR, in CDR3 of the TCR-beta chain of Tax301 309-CTLs was conserved among ATL patients after allo-HSCT. Furthermore, the PDR+ Tax301-309-CTL clones selectively expanded and showed strong cytotoxic activities against HTLV-1. On the other hand, it remains unclear how Tax301-309-CTL repertoire exists in ACs. In this study, we comprehensively compared Tax-specific TCR repertoires at the single-cell level between ACs and ATL patients. Tax301-309 CTLs showed highly restricted TCR repertoires with a strongly biased usage of BV7, and PDR, the unique motif in TCR-beta CDR3, was conserved in all ACs and ATL patients, regardless of clinical subtype in HTLV-1 infection. PMID- 28724769 TI - Simian T Lymphotropic Virus 1 Infection of Papio anubis: tax Sequence Heterogeneity and T Cell Recognition. AB - Baboons naturally infected with simian T lymphotropic virus (STLV) are a potentially useful model system for the study of vaccination against human T lymphotropic virus (HTLV). Here we expanded the number of available full-length baboon STLV-1 sequences from one to three and related the T cell responses that recognize the immunodominant Tax protein to the tax sequences present in two individual baboons. Continuously growing T cell lines were established from two baboons, animals 12141 and 12752. Next-generation sequencing (NGS) of complete STLV genome sequences from these T cell lines revealed them to be closely related but distinct from each other and from the baboon STLV-1 sequence in the NCBI sequence database. Overlapping peptides corresponding to each unique Tax sequence and to the reference baboon Tax sequence were used to analyze recognition by T cells from each baboon using intracellular cytokine staining (ICS). Individual baboons expressed more gamma interferon and tumor necrosis factor alpha in response to Tax peptides corresponding to their own STLV-1 sequence than in response to Tax peptides corresponding to the reference baboon STLV-1 sequence. Thus, our analyses revealed distinct but closely related STLV-1 genome sequences in two baboons, extremely low heterogeneity of STLV sequences within each baboon, no evidence for superinfection within each baboon, and a ready ability of T cells in each baboon to recognize circulating Tax sequences. While amino acid substitutions that result in escape from CD8+ T cell recognition were not observed, premature stop codons were observed in 7% and 56% of tax sequences from peripheral blood mononuclear cells from animals 12141 and 12752, respectively.IMPORTANCE It has been estimated that approximately 100,000 people suffer serious morbidity and 10,000 people die each year from the consequences associated with human T lymphotropic virus (HTLV) infection. There are no antiviral drugs and no preventive vaccine. A preventive vaccine would significantly impact the global burden associated with HTLV infections. Here we provide fundamental information on the simian T lymphotropic virus (STLV) naturally transmitted in a colony of captive baboons. The limited viral sequence heterogeneity in individual baboons, the identity of the viral gene product that is the major target of cellular immune responses, the persistence of viral amino acid sequences that are the major targets of cellular immune responses, and the emergence in vivo of truncated variants in the major target of cellular immune responses all parallel what are seen with HTLV infection of humans. These results justify the use of STLV-infected baboons as a model system for vaccine development efforts. PMID- 28724768 TI - Synthetic Toll-Like Receptor 4 (TLR4) and TLR7 Ligands Work Additively via MyD88 To Induce Protective Antiviral Immunity in Mice. AB - We previously demonstrated that the combination of synthetic small-molecule Toll like receptor 4 (TLR4) and TLR7 ligands is a potent adjuvant for recombinant influenza virus hemagglutinin, inducing rapid and sustained immunity that is protective against influenza viruses in homologous, heterologous, and heterosubtypic murine challenge models. Combining the TLR4 and TLR7 ligands balances Th1 and Th2-type immune responses for long-lived cellular and neutralizing humoral immunity against the viral hemagglutinin. Here, we demonstrate that the protective response induced in mice by this combined adjuvant is dependent upon TLR4 and TLR7 signaling via myeloid differentiation primary response gene 88 (MyD88), indicating that the adjuvants function in vivo via their known receptors, with negligible off-target effects, to induce protective immunity. The combined adjuvant acts via MyD88 in both bone marrow derived and non-bone marrow-derived radioresistant cells to induce hemagglutinin specific antibodies and protect mice against influenza virus challenge. The protective efficacy generated by immunization with this adjuvant and recombinant hemagglutinin antigen is transferable with serum from immunized mice to recipient mice in a homologous, but not a heterologous, H1N1 viral challenge model. Depletion of CD4+ cells after an established humoral response in immunized mice does not impair protection from a homologous challenge; however, it does significantly impair recovery from a heterologous challenge virus, highlighting an important role for vaccine-induced CD4+ cells in cross-protective vaccine efficacy. The combination of the two TLR agonists allows for significant dose reductions of each component to achieve a level of protection equivalent to that afforded by either single agent at its full dose.IMPORTANCE Development of novel adjuvants is needed to enhance immunogenicity to provide better protection from seasonal influenza virus infection and improve pandemic preparedness. We show here that several dose combinations of synthetic TLR4 and TLR7 ligands are potent adjuvants for recombinant influenza virus hemagglutinin antigen induction of humoral and cellular immunity against viral challenges. The components of the combined adjuvant work additively to enable both antigen and adjuvant dose sparing while retaining efficacy. Understanding an adjuvant's mechanism of action is a critical component for preclinical safety evaluation, and we demonstrate here that a combined TLR4 and TLR7 adjuvant signals via the appropriate receptors and the MyD88 adaptor protein. This novel adjuvant combination contributes to a more broadly protective vaccine while demonstrating an attractive safety profile. PMID- 28724770 TI - rgs-CaM Detects and Counteracts Viral RNA Silencing Suppressors in Plant Immune Priming. AB - Primary infection of a plant with a pathogen that causes high accumulation of salicylic acid in the plant typically via a hypersensitive response confers enhanced resistance against secondary infection with a broad spectrum of pathogens, including viruses. This phenomenon is called systemic acquired resistance (SAR), which is a plant priming for adaption to repeated biotic stress. However, the molecular mechanisms of SAR-mediated enhanced inhibition, especially of virus infection, remain unclear. Here, we show that SAR against cucumber mosaic virus (CMV) in tobacco plants (Nicotiana tabacum) involves a calmodulin-like protein, rgs-CaM. We previously reported the antiviral function of rgs-CaM, which binds to and directs degradation of viral RNA silencing suppressors (RSSs), including CMV 2b, via autophagy. We found that rgs-CaM mediated immunity is ineffective against CMV infection in normally growing tobacco plants but is activated as a result of SAR induction via salicylic acid signaling. We then analyzed the effect of overexpression of rgs-CaM on salicylic acid signaling. Overexpressed and ectopically expressed rgs-CaM induced defense reactions, including cell death, generation of reactive oxygen species, and salicylic acid signaling. Further analysis using a combination of the salicylic acid analogue benzo-(1,2,3)-thiadiazole-7-carbothioic acid S-methyl ester (BTH) and the Ca2+ ionophore A23187 revealed that rgs-CaM functions as an immune receptor that induces salicylic acid signaling by simultaneously perceiving both viral RSS and Ca2+ influx as infection cues, implying its autoactivation. Thus, secondary infection of SAR-induced tobacco plants with CMV seems to be effectively inhibited through 2b recognition and degradation by rgs-CaM, leading to reinforcement of antiviral RNA silencing and other salicylic acid-mediated antiviral responses.IMPORTANCE Even without an acquired immune system like that in vertebrates, plants show enhanced whole-plant resistance against secondary infection with pathogens; this so-called systemic acquired resistance (SAR) has been known for more than half a century and continues to be extensively studied. SAR-induced plants strongly and rapidly express a number of antibiotics and pathogenesis-related proteins targeted against secondary infection, which can account for enhanced resistance against bacterial and fungal pathogens but are not thought to control viral infection. This study showed that enhanced resistance against cucumber mosaic virus is caused by a tobacco calmodulin-like protein, rgs-CaM, which detects and counteracts the major viral virulence factor (RNA silencing suppressor) after SAR induction. rgs-CaM-mediated SAR illustrates the growth versus defense trade-off in plants, as it targets the major virulence factor only under specific biotic stress conditions, thus avoiding the cost of constitutive activation while reducing the damage from virus infection. PMID- 28724771 TI - Intracellular Colocalization of Influenza Viral RNA and Rab11A Is Dependent upon Microtubule Filaments. AB - Influenza A virus (IAV) consists of eight viral RNA (vRNA) segments that are replicated in the host cell nucleus and transported to the plasma membrane for packaging into progeny virions. We have previously proposed a model where subcomplexes of vRNA are exported from the nucleus and assembled en route to the plasma membrane. However, the role of host cytoskeletal proteins in the cytoplasmic assembly of IAV vRNA segments remains unknown. Previous studies have suggested that IAV vRNA segments are transported via Rab11A-containing recycling endosomes (RE) and use both microtubules (MT) and actin. Rab11A RE transport primarily along MT; therefore, investigation of the role of MT in vRNA assembly is warranted. We explored the role of MT in vRNA assembly and replication by using multiple IAV strains in various cell types, including primary human airway epithelial cells. We observed that Rab11A localization was altered in the presence of MT-depolymerizing drugs, but growth of IAV in all of the cell types tested was unchanged. Fluorescent in situ hybridization was performed to determine the role of MT in the assembly of multiple vRNA segments. Unexpectedly, we found that vRNA-vRNA association in cytoplasmic foci was independent of MT. Given the disparity of localization between Rab11A and vRNA segments in the absence of intact MT filaments, we analyzed the three-dimensional spatial relationship between Rab11A and vRNA in the cytoplasm of infected cells. We found that Rab11A and vRNA colocalization is dependent upon dynamic MT filaments. Taken together, our data suggest that cytoplasmic transport of influenza vRNA may include a Rab11A RE-independent mechanism.IMPORTANCE IAV infections cause a large public health burden through seasonal epidemics and sporadic pandemics. Pandemic IAVs emerge through reassortment of vRNA in animal or human hosts. Elucidation of the mechanism of intracellular dynamics of IAV assembly is necessary to understand reassortment. Our results describing the role of MT in vRNA transport and assembly expand upon previous studies characterizing vRNA assembly. This study is the first to assess the role of MT in influenza virus replication in human bronchial airway epithelial cells. In addition, we present novel data on the role of MT in facilitating the association between distinct vRNA segments. Interestingly, our results suggest that progressive assembly of vRNA segments may be cell type dependent and that vRNA may be transported through the cytoplasm without Rab11A RE in the absence of intact MT. These results enhance our understanding of vRNA assembly and the role of cytoskeletal proteins in that process. PMID- 28724772 TI - Binding of Herpes Simplex Virus 1 UL20 to GODZ (DHHC3) Affects Its Palmitoylation and Is Essential for Infectivity and Proper Targeting and Localization of UL20 and Glycoprotein K. AB - Herpes simplex virus 1 (HSV-1) UL20 plays a crucial role in the envelopment of the cytoplasmic virion and its egress. It is a nonglycosylated envelope protein that is regulated as a gamma1 gene. Two-hybrid and pulldown assays demonstrated that UL20, but no other HSV-1 gene-encoded proteins, binds specifically to GODZ (also known as DHHC3), a cellular Golgi apparatus-specific Asp-His-His-Cys (DHHC) zinc finger protein. A catalytically inactive dominant-negative GODZ construct significantly reduced HSV-1 replication in vitro and affected the localization of UL20 and glycoprotein K (gK) and their interactions but not glycoprotein C (gC). GODZ is involved in palmitoylation, and we found that UL20 is palmitoylated by GODZ using a GODZ dominant-negative plasmid. Blocking of palmitoylation using 2 bromopalmitate (2-BP) affected the virus titer and the interaction of UL20 and gK but did not affect the levels of these proteins. In conclusion, we have shown that binding of UL20 to GODZ in the Golgi apparatus regulates trafficking of UL20 and its subsequent effects on gK localization and virus replication. We also have demonstrated that GODZ-mediated UL20 palmitoylation is critical for UL20 membrane targeting and thus gK cell surface expression, providing new mechanistic insights into how UL20 palmitoylation regulates HSV-1 infectivity.IMPORTANCE HSV-1 UL20 is a nonglycosylated essential envelope protein that is highly conserved among herpesviruses. In this study, we show that (i) HSV-1 UL20 binds to GODZ (also known as DHHC3), a Golgi apparatus-specific Asp-His-His-Cys (DHHC) zinc finger protein; (ii) a GODZ dominant-negative mutant and an inhibitor of palmitoylation reduced HSV-1 titers and altered the localization of UL20 and glycoprotein K; and (iii) UL20 is palmitoylated by GODZ, and this UL20 palmitoylation is required for HSV-1 infectivity. Thus, blocking of the interaction of UL20 with GODZ, using a GODZ dominant-negative mutant or possibly GODZ shRNA, should be considered a potential alternative therapy in not only HSV-1 but also other conditions in which GODZ processing is an integral component of pathogenesis. PMID- 28724773 TI - NKp46 Recognizes the Sigma1 Protein of Reovirus: Implications for Reovirus-Based Cancer Therapy. AB - The recent approval of oncolytic virus for therapy of melanoma patients has increased the need for precise evaluation of the mechanisms by which oncolytic viruses affect tumor growth. Here we show that the human NK cell-activating receptor NKp46 and the orthologous mouse protein NCR1 recognize the reovirus sigma1 protein in a sialic-acid-dependent manner. We identify sites of NKp46/NCR1 binding to sigma1 and show that sigma1 binding by NKp46/NCR1 leads to NK cell activation in vitro Finally, we demonstrate that NCR1 activation is essential for reovirus-based therapy in vivo Collectively, we have identified sigma1 as a novel ligand for NKp46/NCR1 and demonstrated that NKp46/NCR1 is needed both for clearance of reovirus infection and for reovirus-based tumor therapy.IMPORTANCE Reovirus infects much of the population during childhood, causing mild disease, and hence is considered to be efficiently controlled by the immune system. Reovirus also specifically infects tumor cells, leading to tumor death, and is currently being tested in human clinical trials for cancer therapy. The mechanisms by which our immune system controls reovirus infection and tumor killing are not well understood. We report here that natural killer (NK) cells recognize a viral protein named sigma1 through the NK cell-activating receptor NKp46. Using several mouse tumor models, we demonstrate the importance of NK cells in protection from reovirus infection and in reovirus killing of tumors in vivo Collectively, we identify a new ligand for the NKp46 receptor and provide evidence for the importance of NKp46 in the control of reovirus infections and in reovirus-based cancer therapy. PMID- 28724774 TI - Histopathology of Veins Obtained at Hemodialysis Arteriovenous Fistula Creation Surgery. AB - Stenosis from venous neointimal hyperplasia is common in native arteriovenous fistulas (AVFs). However, the preexisting histologic characteristics of veins at fistula creation, and associations thereof with baseline patient factors, have not been well characterized. In this study, we conducted histologic analysis of a segment of the vein used for anastomosis creation, obtained during AVF creation from 554 of the 602 participants in the multicenter Hemodialysis Fistula Maturation Cohort Study. We quantified intimal and medial areas and lengths of the internal and external elastic lamina by morphometry and assessed venous wall cells by immunohistochemistry, extracellular matrix with Movat stain, and calcium deposition by alizarin red stain. We also studied a representative subset of veins for markers of monocyte/macrophage content, cell proliferation, apoptosis, and neoangiogenesis. Neointima occupied >20% of the lumen in 57% of fully circumferential vein samples, and neointimal hyperplasia associated positively with age and inversely with black race. The neointima was usually irregularly thickened, sometimes concentric, and contained alpha-smooth muscle actin expressing cells of smooth muscle or myofibroblast origin. Proteoglycans admixed with lesser amounts of collagen constituted the predominant matrix in the neointima. In 82% of vein samples, the media of vessel walls contained large aggregates of collagen. A minority of veins expressed markers of inflammation, cell proliferation, cell death, calcification, or neoangiogenesis. In conclusion, we observed preexisting abnormalities, including neointimal hyperplasia and prominent accumulation of extracellular matrix, in veins used for AVF creation from a substantial proportion of this cohort. PMID- 28724775 TI - N-Degradomic Analysis Reveals a Proteolytic Network Processing the Podocyte Cytoskeleton. AB - Regulated intracellular proteostasis, controlled in part by proteolysis, is essential in maintaining the integrity of podocytes and the glomerular filtration barrier of the kidney. We applied a novel proteomics technology that enables proteome-wide identification, mapping, and quantification of protein N-termini to comprehensively characterize cleaved podocyte proteins in the glomerulus in vivo We found evidence that defined proteolytic cleavage results in various proteoforms of important podocyte proteins, including those of podocin, nephrin, neph1, alpha-actinin-4, and vimentin. Quantitative mapping of N-termini demonstrated perturbation of protease action during podocyte injury in vitro, including diminished proteolysis of alpha-actinin-4. Differentially regulated protease substrates comprised cytoskeletal proteins as well as intermediate filaments. Determination of preferential protease motifs during podocyte damage indicated activation of caspase proteases and inhibition of arginine-specific proteases. Several proteolytic processes were clearly site-specific, were conserved across species, and could be confirmed by differential migration behavior of protein fragments in gel electrophoresis. Some of the proteolytic changes discovered in vitro also occurred in two in vivo models of podocyte damage (WT1 heterozygous knockout mice and puromycin aminonucleoside-treated rats). Thus, we provide direct and systems-level evidence that the slit diaphragm and podocyte cytoskeleton are regulated targets of proteolytic modification, which is altered upon podocyte damage. PMID- 28724777 TI - Speed invariance of tactile texture perception. AB - The nervous system achieves stable perceptual representations of objects despite large variations in the activity patterns of sensory receptors. Here, we explore perceptual constancy in the sense of touch. Specifically, we investigate the invariance of tactile texture perception across changes in scanning speed. Texture signals in the nerve have been shown to be highly dependent on speed: temporal spiking patterns in nerve fibers that encode fine textural features contract or dilate systematically with increases or decreases in scanning speed, respectively, resulting in concomitant changes in response rate. Nevertheless, texture perception has been shown, albeit with restricted stimulus sets and limited perceptual assays, to be independent of scanning speed. Indeed, previous studies investigated the effect of scanning speed on perceived roughness, only one aspect of texture, often with impoverished stimuli, namely gratings and embossed dot patterns. To fill this gap, we probe the perceptual constancy of a wide range of textures using two different paradigms: one that probes texture perception along well-established sensory dimensions independently and one that probes texture perception as a whole. We find that texture perception is highly stable across scanning speeds, irrespective of the texture or the perceptual assay. Any speed-related effects are dwarfed by differences in percepts evoked by different textures. This remarkable speed invariance of texture perception stands in stark contrast to the strong dependence of the texture responses of nerve fibers on scanning speed. Our results imply neural mechanisms that compensate for scanning speed to achieve stable representations of surface texture.NEW & NOTEWORTHY Our brain forms stable representations of objects regardless of viewpoint, a phenomenon known as invariance that has been described in several sensory modalities. Here, we explore invariance in the sense of touch and show that the tactile perception of texture does not depend on scanning speed. This perceptual constancy implies neural mechanisms that extract information about texture from the response of nerve fibers such that the resulting neural representation is stable across speeds. PMID- 28724778 TI - Eupnea, tachypnea, and autoresuscitation in a closed-loop respiratory control model. AB - How sensory information influences the dynamics of rhythm generation varies across systems, and general principles for understanding this aspect of motor control are lacking. Determining the origin of respiratory rhythm generation is challenging because the mechanisms in a central circuit considered in isolation may be different from those in the intact organism. We analyze a closed-loop respiratory control model incorporating a central pattern generator (CPG), the Butera-Rinzel-Smith (BRS) model, together with lung mechanics, oxygen handling, and chemosensory components. We show that 1) embedding the BRS model neuron in a control loop creates a bistable system; 2) although closed-loop and open-loop (isolated) CPG systems both support eupnea-like bursting activity, they do so via distinct mechanisms; 3) chemosensory feedback in the closed loop improves robustness to variable metabolic demand; 4) the BRS model conductances provide an autoresuscitation mechanism for recovery from transient interruption of chemosensory feedback; and 5) the in vitro brain stem CPG slice responds to hypoxia with transient bursting that is qualitatively similar to in silico autoresuscitation. Bistability of bursting and tonic spiking in the closed-loop system corresponds to coexistence of eupnea-like breathing, with normal minute ventilation and blood oxygen level and a tachypnea-like state, with pathologically reduced minute ventilation and critically low blood oxygen. Disruption of the normal breathing rhythm, through either imposition of hypoxia or interruption of chemosensory feedback, can push the system from the eupneic state into the tachypneic state. We use geometric singular perturbation theory to analyze the system dynamics at the boundary separating eupnea-like and tachypnea like outcomes.NEW & NOTEWORTHY A common challenge facing rhythmic biological processes is the adaptive regulation of central pattern generator (CPG) activity in response to sensory feedback. We apply dynamical systems tools to understand several properties of a closed-loop respiratory control model, including the coexistence of normal and pathological breathing, robustness to changes in metabolic demand, spontaneous autoresuscitation in response to hypoxia, and the distinct mechanisms that underlie rhythmogenesis in the intact control circuit vs. the isolated, open-loop CPG. PMID- 28724776 TI - Inhibitory circuits of the mammalian main olfactory bulb. AB - Synaptic inhibition critically influences sensory processing throughout the mammalian brain, including the main olfactory bulb (MOB), the first station of sensory processing in the olfactory system. Decades of research across numerous laboratories have established a central role for granule cells (GCs), the most abundant GABAergic interneuron type in the MOB, in the precise regulation of principal mitral and tufted cell (M/TC) firing rates and synchrony through lateral and recurrent inhibitory mechanisms. In addition to GCs, however, the MOB contains a vast diversity of other GABAergic interneuron types, and recent findings suggest that, while fewer in number, these oft-ignored interneurons are just as important as GCs in shaping odor-evoked M/TC activity. Here I challenge the prevailing centrality of GCs. In this review, I first outline the specific properties of each GABAergic interneuron type in the rodent MOB, with particular emphasis placed on direct interneuron recordings and cell type-selective manipulations. On the basis of these properties, I then critically reevaluate the contribution of GCs vs. other interneuron types to the regulation of odor-evoked M/TC firing rates and synchrony via lateral, recurrent, and other inhibitory mechanisms. This analysis yields a novel model in which multiple interneuron types with distinct abundances, connectivity patterns, and physiologies complement one another to regulate M/TC activity and sensory processing. PMID- 28724780 TI - A reduced somatosensory gating response in individuals with multiple sclerosis is related to walking impairment. AB - When identical stimuli are presented in rapid temporal succession, neural responses to the second stimulation are often weaker than those observed for the first. This phenomenon is termed sensory gating and is believed to be an adaptive feature that helps prevent higher-order cortical centers from being flooded with unnecessary information. Recently, sensory gating in the somatosensory system has been linked to deficits in tactile discrimination. Additionally, studies have linked poor tactile discrimination with impaired walking and balance in individuals with multiple sclerosis (MS). In this study, we examine the neural basis of somatosensory gating in patients with MS and healthy controls and assess the relationship between somatosensory gating and walking performance. We used magnetoencephalography to record neural responses to paired-pulse electrical stimulation applied to the right posterior tibial nerve. All participants also walked across a digital mat, which recorded their spatiotemporal gait kinematics. Our results showed the amplitude of the response to the second stimulation was sharply reduced only in controls, resulting in a significantly reduced somatosensory gating in the patients with MS. No group differences were observed in the amplitude of the response to the first stimulation nor the latency of the neural response to either the first or second stimulation. Interestingly, the altered somatosensory gating responses were correlated with aberrant spatiotemporal gait kinematics in the patients with MS. These results suggest that inhibitory GABA circuits may be altered in patients with MS, which impacts somatosensory gating and contributes to the motor performance deficits seen in these patients.NEW & NOTEWORTHY We aimed to determine whether somatosensory gating in patients with multiple sclerosis (MS) differed compared with healthy controls and whether a relationship exists between somatosensory gating and walking performance. We found reduced somatosensory gating responses in patients with MS, and these altered somatosensory gating responses were correlated with the mobility impairments. These novel findings show that somatosensory gating is impaired in patients with MS and is related to the mobility impairments seen in these patients. PMID- 28724779 TI - Chronic pain alters spatiotemporal activation patterns of forearm muscle synergies during the development of grip force. AB - It is largely unknown how the CNS regulates multiple muscle systems in the presence of pain. This study used muscle synergy analysis to investigate multiple forearm muscles in individuals with chronic elbow pain during the development of grip force. Eleven individuals with chronic elbow pain and 11 healthy age-matched control subjects developed grip force to 15% and 30% of maximum voluntary contraction (MVC). Surface electromyography was obtained from six forearm muscles during force development before nonnegative matrix factorization was performed. The relationship between muscle synergies and standard clinical tests of elbow pain were examined by linear regression. During grip force development to 15% MVC the pain group had a lower number of forearm muscle synergies, increased similarity in spatial activation patterns, increased cocontraction of forearm flexors, and a greater magnitude of muscle weightings across the forearm when performing the task. During the 30% MVC grip the numbers of muscle synergies were the same for both groups; however, the pain group had lower activation and reduced variability in the timing of peak activation. The timing of peak activation was delayed in the pain group regardless of the task, and performing the grip in different wrist postures did not affect muscle synergy characteristics in either group. Although localized pain causes direct dysfunction of an affected muscle, this study provides evidence that the timing and amplitude of agonist and antagonist muscle activity are also affected with chronic pain.NEW & NOTEWORTHY Muscle activation patterns of individuals with chronic elbow pain are simplified compared with healthy individuals. This is apparent as individuals with pain exhibit fewer forearm muscle synergies, and increased similarity of activation patterns between forearm muscles, when performing pain-free isometric gripping. As such, even during pain-free tasks it is possible to observe changes in motor control in people with chronic pain. PMID- 28724781 TI - Muscle disuse caused by botulinum toxin injection leads to increased central gain of the stretch reflex in the rat. AB - Botulinum toxin (Btx) is used in children with cerebral palsy and in other neurological patients to diminish spasticity and reduce the risk of development of contractures. We investigated changes in the central gain of the stretch reflex circuitry in response to Btx injection in the triceps surae muscle in rats. Experiments were performed in 21 rats. Eight rats were a control group, and 13 rats were injected with 6 IU of Btx in the left triceps surae muscle. Two weeks after Btx injection, larger monosynaptic reflexes (MSR) were recorded from the left (injected) than the right (noninjected) L4 + L5 ventral roots following stimulation of the corresponding dorsal roots. A similar increase on the left side was observed in response to stimulation of descending motor tracts, suggesting that increased excitability of spinal motor neurons may at least partly explain the increased reflexes. However, significant changes were also observed in postactivation depression of the MSR, suggesting that plastic changes in transmission from Ia afferent to the motor neurons also may be involved. The data demonstrate that muscle paralysis induced by Btx injection is accompanied by plastic adaptations in the central stretch reflex circuitry, which counteract the antispastic effect of Btx.NEW & NOTEWORTHY Injection of botulinum toxin into ankle muscles causes increased gain of stretch reflex. This is caused by adaptive changes in regulation of transmitter release from Ia afferents and increased excitability of spinal motor neurons. PMID- 28724782 TI - Dissecting patterns of preparatory activity in the frontal eye fields during pursuit target selection. AB - We investigated the composition of preparatory activity of frontal eye field (FEF) neurons in monkeys performing a pursuit target selection task. In response to the orthogonal motion of a large and a small reward target, monkeys initiated pursuit biased toward the direction of large reward target motion. FEF neurons exhibited robust preparatory activity preceding movement initiation in this task. Preparatory activity consisted of two components, ramping activity that was constant across target selection conditions, and a flat offset in firing rates that signaled the target selection condition. Ramping activity accounted for 50% of the variance in the preparatory activity and was linked most strongly, on a trial-by-trial basis, to pursuit eye movement latency rather than to its direction or gain. The offset in firing rates that discriminated target selection conditions accounted for 25% of the variance in the preparatory activity and was commensurate with a winner-take-all representation, signaling the direction of large reward target motion rather than a representation that matched the parameters of the upcoming movement. These offer new insights into the role that the frontal eye fields play in target selection and pursuit control. They show that preparatory activity in the FEF signals more strongly when to move rather than where or how to move and suggest that structures outside the FEF augment its contributions to the target selection process.NEW & NOTEWORTHY We used the smooth eye movement pursuit system to link between patterns of preparatory activity in the frontal eye fields and movement during a target selection task. The dominant pattern was a ramping signal that did not discriminate between selection conditions and was linked, on trial-by-trial basis, to movement latency. A weaker pattern was composed of a constant signal that discriminated between selection conditions but was only weakly linked to the movement parameters. PMID- 28724783 TI - Intra- and intersegmental influences among central pattern generating networks in the walking system of the stick insect. AB - To efficiently move around, animals need to coordinate their limbs. Proper, context-dependent coupling among the neural networks underlying leg movement is necessary for generating intersegmental coordination. In the slow-walking stick insect, local sensory information is very important for shaping coordination. However, central coupling mechanisms among segmental central pattern generators (CPGs) may also contribute to this. Here, we analyzed the interactions between contralateral networks that drive the depressor trochanteris muscle of the legs in both isolated and interconnected deafferented thoracic ganglia of the stick insect on application of pilocarpine, a muscarinic acetylcholine receptor agonist. Our results show that depressor CPG activity is only weakly coupled between all segments. Intrasegmental phase relationships differ between the three isolated ganglia, and they are modified and stabilized when ganglia are interconnected. However, the coordination patterns that emerge do not resemble those observed during walking. Our findings are in line with recent studies and highlight the influence of sensory input on coordination in slowly walking insects. Finally, as a direct interaction between depressor CPG networks and contralateral motoneurons could not be observed, we hypothesize that coupling is based on interactions at the level of CPG interneurons.NEW & NOTEWORTHY Maintaining functional interleg coordination is vitally important as animals locomote through changing environments. The relative importance of central mechanisms vs. sensory feedback in this process is not well understood. We analyzed coordination among the neural networks generating leg movements in stick insect preparations lacking phasic sensory feedback. Under these conditions, the networks governing different legs were only weakly coupled. In stick insect, central connections alone are thus insufficient to produce the leg coordination observed behaviorally. PMID- 28724784 TI - Representing delayed force feedback as a combination of current and delayed states. AB - To adapt to deterministic force perturbations that depend on the current state of the hand, internal representations are formed to capture the relationships between forces experienced and motion. However, information from multiple modalities travels at different rates, resulting in intermodal delays that require compensation for these internal representations to develop. To understand how these delays are represented by the brain, we presented participants with delayed velocity-dependent force fields, i.e., forces that depend on hand velocity either 70 or 100 ms beforehand. We probed the internal representation of these delayed forces by examining the forces the participants applied to cope with the perturbations. The findings showed that for both delayed forces, the best model of internal representation consisted of a delayed velocity and current position and velocity. We show that participants relied initially on the current state, but with adaptation, the contribution of the delayed representation to adaptation increased. After adaptation, when the participants were asked to make movements with a higher velocity for which they had not previously experienced with the delayed force field, they applied forces that were consistent with current position and velocity as well as delayed velocity representations. This suggests that the sensorimotor system represents delayed force feedback using current and delayed state information and that it uses this representation when generalizing to faster movements.NEW & NOTEWORTHY The brain compensates for forces in the body and the environment to control movements, but it is unclear how it does so given the inherent delays in information transmission and processing. We examined how participants cope with delayed forces that depend on their arm velocity 70 or 100 ms beforehand. After adaptation, participants applied opposing forces that revealed a partially correct representation of the perturbation using the current and the delayed information. PMID- 28724785 TI - Orthodontic treatment-induced temporal alteration of jaw-opening reflex excitability. AB - The impairment of orofacial motor function during orthodontic treatment needs to be addressed, because most orthodontic patients experience pain and motor excitability would be affected by pain. In the present study, the temporal alteration of the jaw-opening reflex excitability was investigated to determine if orthodontic treatment affects orofacial motor function. The excitability of jaw-opening reflex evoked by electrical stimulation on the gingiva and recorded bilaterally in the anterior digastric muscles was evaluated at 1 (D1), 3 (D3), and 7 days (D7) after orthodontic force application to the teeth of right side; morphological features (e.g., osteoclast genesis and tooth movement) were also evaluated. To clarify the underlying mechanism of orthodontic treatment-induced alteration of orofacial motor excitability, analgesics were administrated for 1 day. At D1 and D3, orthodontic treatment significantly decreased the threshold for inducing the jaw-opening reflex but significantly increased the threshold at D7. Other parameters of the jaw-opening reflex were also evaluated (e.g., latency, duration and area under the curve of anterior digastric muscles activity), and only the latency of the D1 group was significantly different from that of the other groups. Temporal alteration of the jaw-opening reflex excitability was significantly correlated with changes in morphological features. Aspirin (300 mg.kg-1.day-1) significantly increased the threshold for inducing the jaw-opening reflex, whereas a lower dose (75-150 mg.kg-1.day-1) of aspirin or acetaminophen (300 mg.kg-1.day-1) failed to alter the jaw-opening reflex excitability. These results suggest that an increase of the jaw-opening reflex excitability can be induced acutely by orthodontic treatment, possibly through the cyclooxygenase activation.NEW & NOTEWORTHY It is well known that motor function is affected by pain, but the effect of orthodontic treatment-related pain on the trigeminal motor excitability has not been fully understood. We found that, during orthodontic treatment, trigeminal motor excitability is acutely increased and then decreased in a week. Because alteration of trigeminal motor function can be evaluated quantitatively by jaw-opening reflex excitability, the present animal model may be useful to search for alternative approaches to attenuate orthodontic pain. PMID- 28724786 TI - Emergent cortical circuit dynamics contain dense, interwoven ensembles of spike sequences. AB - Temporal codes are theoretically powerful encoding schemes, but their precise form in the neocortex remains unknown in part because of the large number of possible codes and the difficulty in disambiguating informative spikes from statistical noise. A biologically plausible and computationally powerful temporal coding scheme is the Hebbian assembly phase sequence (APS), which predicts reliable propagation of spikes between functionally related assemblies of neurons. Here, we sought to measure the inherent capacity of neocortical networks to produce reliable sequences of spikes, as would be predicted by an APS code. To record microcircuit activity, the scale at which computation is implemented, we used two-photon calcium imaging to densely sample spontaneous activity in murine neocortical networks ex vivo. We show that the population spike histogram is sufficient to produce a spatiotemporal progression of activity across the population. To more comprehensively evaluate the capacity for sequential spiking that cannot be explained by the overall population spiking, we identify statistically significant spike sequences. We found a large repertoire of sequence spikes that collectively comprise the majority of spiking in the circuit. Sequences manifest probabilistically and share neuron membership, resulting in unique ensembles of interwoven sequences characterizing individual spatiotemporal progressions of activity. Distillation of population dynamics into its constituent sequences provides a way to capture trial-to-trial variability and may prove to be a powerful decoding substrate in vivo. Informed by these data, we suggest that the Hebbian APS be reformulated as interwoven sequences with flexible assembly membership due to shared overlapping neurons.NEW & NOTEWORTHY Neocortical computation occurs largely within microcircuits comprised of individual neurons and their connections within small volumes (<500 MUm3). We found evidence for a long-postulated temporal code, the Hebbian assembly phase sequence, by identifying repeated and co-occurring sequences of spikes. Variance in population activity across trials was explained in part by the ensemble of active sequences. The presence of interwoven sequences suggests that neuronal assembly structure can be variable and is determined by previous activity. PMID- 28724787 TI - Disrupted apical exocytosis of cargo vesicles causes enteropathy in FHL5 patients with Munc18-2 mutations. AB - Familial hemophagocytic lymphohistiocytosis 5 (FHL5) is an autosomal recessive disease caused by mutations in STXBP2, coding for Munc18-2, which is required for SNARE-mediated membrane fusion. FHL5 causes hematologic and gastrointestinal symptoms characterized by chronic enteropathy that is reminiscent of microvillus inclusion disease (MVID). However, the molecular pathophysiology of FHL5 associated diarrhea is poorly understood. Five FHL5 patients, including four previously unreported patients, were studied. Morphology of duodenal sections was analyzed by electron and fluorescence microscopy. Small intestinal enterocytes and organoid-derived monolayers displayed the subcellular characteristics of MVID. For the analyses of Munc18-2-dependent SNARE-protein interactions, a Munc18 2 CaCo2-KO model cell line was generated by applying CRISPR/Cas9 technology. Munc18-2 is required for Slp4a/Stx3 interaction in fusion of cargo vesicles with the apical plasma membrane. Cargo trafficking was investigated in patient biopsies, patient-derived organoids, and the genome-edited model cell line. Loss of Munc18-2 selectively disrupts trafficking of certain apical brush-border proteins (NHE3 and GLUT5), while transport of DPPIV remained unaffected. Here, we describe the molecular mechanism how the loss of function of Munc18-2 leads to cargo-selective mislocalization of brush-border components and a subapical accumulation of cargo vesicles, as it is known from the loss of polarity phenotype in MVID. PMID- 28724788 TI - Multiparametric immune profiling in HPV- oral squamous cell cancer. AB - Evaluation of T lymphocyte frequency provides prognostic information for patients with oral squamous cell cancer (OSCC). However, the effect of simultaneously evaluating T cell frequency and assessing suppressive elements and defects in antigen-processing machinery (APM) has not been clarified. Simultaneous characterization of CD3+, CD8+, FoxP3+, CD163+, and PD-L1+ cells using multispectral imaging was performed on sections from 119 patients with HPV- OSCC. Expression of beta2-microglobulin, MHC class I heavy chain, and large multifunctional peptidase 10 was quantified, and all data were correlated with patient outcome. We found that, consistent with previous reports, high numbers of CD8+ T cells at the invasive margin correlated significantly with prolonged overall survival (OS), while the number of FoxP3+ or PD-L1+ cells did not. Compiling the number of FoxP3+ or PD-L1+ cells within 30 MUm of CD8+ T cells identified a significant association with a high number of suppressive elements close to CD8+ T cells and reduced OS. Integrating this information into a cumulative suppression index (CSI) increased correlation with OS. Incorporating tumor expression levels of APM components with CSI further improved prognostic power. This multiparametric immune profiling may be useful for stratifying patients with OSCC for clinical trials. PMID- 28724789 TI - Red blood cell beta-adrenergic receptors contribute to diet-induced energy expenditure by increasing O2 supply. AB - Diet-induced obesity (DIO) represents the major cause for the current obesity epidemic, but the mechanism underlying DIO is unclear. beta-Adrenergic receptors (beta-ARs) play a major role in sympathetic nervous system-mediated (SNS mediated) diet-induced energy expenditure (EE). Rbc express abundant beta-ARs; however, a potential role for rbc in DIO remains untested. Here, we demonstrated that high-fat, high-caloric diet (HFD) feeding increased both EE and blood O2 content, and the HFD-induced increases in blood O2 level and in body weight gain were negatively correlated. Deficiency of beta-ARs in rbc reduced glycolysis and ATP levels, diminished HFD-induced increases in both blood O2 content and EE, and resulted in DIO. Importantly, specific activation of cAMP signaling in rbc promoted HFD-induced EE and reduced HFD-induced tissue hypoxia independent of obesity. Both HFD and pharmacological activation cAMP signaling in rbc led to increased glycolysis and ATP levels. These results identify a previously unknown role for rbc beta-ARs in mediating the SNS action on HFD-induced EE by increasing O2 supply, and they demonstrate that HFD-induced EE is limited by blood O2 availability and can be augenmented by increased O2 supply. PMID- 28724790 TI - MED12 regulates a transcriptional network of calcium-handling genes in the heart. AB - The Mediator complex regulates gene transcription by linking basal transcriptional machinery with DNA-bound transcription factors. The activity of the Mediator complex is mainly controlled by a kinase submodule that is composed of 4 proteins, including MED12. Although ubiquitously expressed, Mediator subunits can differentially regulate gene expression in a tissue-specific manner. Here, we report that MED12 is required for normal cardiac function, such that mice with conditional cardiac-specific deletion of MED12 display progressive dilated cardiomyopathy. Loss of MED12 perturbs expression of calcium-handling genes in the heart, consequently altering calcium cycling in cardiomyocytes and disrupting cardiac electrical activity. We identified transcription factors that regulate expression of calcium-handling genes that are downregulated in the heart in the absence of MED12, and we found that MED12 localizes to transcription factor consensus sequences within calcium-handling genes. We showed that MED12 interacts with one such transcription factor, MEF2, in cardiomyocytes and that MED12 and MEF2 co-occupy promoters of calcium-handling genes. Furthermore, we demonstrated that MED12 enhances MEF2 transcriptional activity and that overexpression of both increases expression of calcium-handling genes in cardiomyocytes. Our data support a role for MED12 as a coordinator of transcription through MEF2 and other transcription factors. We conclude that MED12 is a regulator of a network of calcium-handling genes, consequently mediating contractility in the mammalian heart. PMID- 28724791 TI - Mitochondrial DNA-enriched microparticles promote acute-on-chronic alcoholic neutrophilia and hepatotoxicity. AB - Over the last several years, one of the major advances in the field of alcoholic liver disease research was the discovery that binge alcohol consumption induced neutrophilia and hepatic neutrophil infiltration in chronically ethanol-fed mice and human subjects with excessive alcohol use (EAU); however, the underlying mechanisms remain obscure. Here, we demonstrated that chronic EAU patients with a history of recent excessive drinking (EAU + RD) had higher serum levels of mitochondrial DNA (mtDNA)-enriched microparticles (MPs) than EAU without recent drinking (EAU - RD) and healthy controls, which correlated positively with circulating neutrophils. Similarly, mice with chronic-plus-binge (E10d + 1B) ethanol feeding also had markedly elevated serum levels of mtDNA-enriched MPs, with activation of hepatic ER stress and inflammatory responses. Inhibition of ER stress by gene KO or inhibitors attenuated ethanol-induced elevation of mtDNA enriched MPs, neutrophilia, and liver injury. The data from the study of hepatocyte-specific deletion of the protein kinase RNA-like ER kinase (Perk) gene in mice and of cultured hepatocytes demonstrated that hepatocytes were the main source of mtDNA-enriched MPs after ethanol feeding. Finally, administration of mtDNA-enriched MPs isolated from E10d+1B-fed mice caused neutrophilia in mice. In conclusion, E10d + 1B ethanol consumption activates hepatic ER stress-dependent mtDNA-enriched MP release, leading to neutrophilia and liver injury. PMID- 28724792 TI - Pediatric and adult dilated cardiomyopathy represent distinct pathological entities. AB - Pediatric dilated cardiomyopathy (DCM) is the most common indication for heart transplantation in children. Despite similar genetic etiologies, medications routinely used in adult heart failure patients do not improve outcomes in the pediatric population. The mechanistic basis for these observations is unknown. We hypothesized that pediatric and adult DCM comprise distinct pathological entities, in that children do not undergo adverse remodeling, the target of adult heart failure therapies. To test this hypothesis, we examined LV specimens obtained from pediatric and adult donor controls and DCM patients. Consistent with the established pathophysiology of adult heart failure, adults with DCM displayed marked cardiomyocyte hypertrophy and myocardial fibrosis compared with donor controls. In contrast, pediatric DCM specimens demonstrated minimal cardiomyocyte hypertrophy and myocardial fibrosis compared with both age-matched controls and adults with DCM. Strikingly, RNA sequencing uncovered divergent gene expression profiles in pediatric and adult patients, including enrichment of transcripts associated with adverse remodeling and innate immune activation in adult DCM specimens. Collectively, these findings reveal that pediatric and adult DCM represent distinct pathological entities, provide a mechanistic basis to explain why children fail to respond to adult heart failure therapies, and suggest the need to develop new approaches for pediatric DCM. PMID- 28724794 TI - APOL1 variants change C-terminal conformational dynamics and binding to SNARE protein VAMP8. AB - APOL1 variants in African populations mediate resistance to trypanosomal infection but increase risk for kidney diseases through unknown mechanisms. APOL1 is expressed in glomerular podocytes and does not vary with underlying kidney disease diagnoses or APOL1 genotypes, suggesting that the kidney disease associated variants dysregulate its function rather than its localization or abundance. Structural homology searches identified vesicle-associated membrane protein 8 (VAMP8) as an APOL1 protein interactor. VAMP8 colocalizes with APOL1 in the podocyte, and the APOL1:VAMP8 interaction was confirmed biochemically and with surface plasmon resonance. APOL1 variants attenuate this interaction. Computational modeling of APOL1's 3-dimensional structure, followed by molecular dynamics simulations, revealed increased motion of the C-terminal domain of reference APOL1 compared with either variant, suggesting that the variants stabilize a closed or autoinhibited state that diminishes protein interactions with VAMP8. Changes in ellipticity with increasing urea concentrations, as assessed by circular dichroism spectroscopy, showed higher conformational stability of the C-terminal helix of the variants compared with the reference protein. These results suggest that reference APOL1 interacts with VAMP8-coated vesicles, a process attenuated by variant-induced reduction in local dynamics of the C-terminal. Disordered vesicular trafficking in the podocyte may cause injury and progressive chronic kidney diseases in susceptible African Americans subjects. PMID- 28724793 TI - A BAG3 chaperone complex maintains cardiomyocyte function during proteotoxic stress. AB - Molecular chaperones regulate quality control in the human proteome, pathways that have been implicated in many diseases, including heart failure. Mutations in the BAG3 gene, which encodes a co-chaperone protein, have been associated with heart failure due to both inherited and sporadic dilated cardiomyopathy. Familial BAG3 mutations are autosomal dominant and frequently cause truncation of the coding sequence, suggesting a heterozygous loss-of-function mechanism. However, heterozygous knockout of the murine BAG3 gene did not cause a detectable phenotype. To model BAG3 cardiomyopathy in a human system, we generated an isogenic series of human induced pluripotent stem cells (iPSCs) with loss-of function mutations in BAG3. Heterozygous BAG3 mutations reduced protein expression, disrupted myofibril structure, and compromised contractile function in iPSC-derived cardiomyocytes (iPS-CMs). BAG3-deficient iPS-CMs were particularly sensitive to further myofibril disruption and contractile dysfunction upon exposure to proteasome inhibitors known to cause cardiotoxicity. We performed affinity tagging of the endogenous BAG3 protein and mass spectrometry proteomics to further define the cardioprotective chaperone complex that BAG3 coordinates in the human heart. Our results establish a model for evaluating protein quality control pathways in human cardiomyocytes and their potential as therapeutic targets and susceptibility factors for cardiac drug toxicity. PMID- 28724795 TI - ALX receptor ligands define a biochemical endotype for severe asthma. AB - BACKGROUND: In health, inflammation resolution is an active process governed by specialized proresolving mediators and receptors. ALX/FPR2 receptors (ALX) are targeted by both proresolving and proinflammatory ligands for opposing signaling events, suggesting pivotal roles for ALX in the fate of inflammatory responses. Here, we determined if ALX expression and ligands were linked to severe asthma (SA). METHODS: ALX expression and levels of proresolving ligands (lipoxin A4 [LXA4], 15-epi-LXA4, and annexin A1 [ANXA1]), and a proinflammatory ligand (serum amyloid A [SAA]) were measured in bronchoscopy samples collected in Severe Asthma Research Program-3 (SA [n = 69], non-SA [NSA, n = 51] or healthy donors [HDs, n = 47]). RESULTS: Bronchoalveolar lavage (BAL) fluid LXA4 and 15-epi-LXA4 were decreased and SAA was increased in SA relative to NSA. BAL macrophage ALX expression was increased in SA. Subjects with LXA4loSAAhi levels had increased BAL neutrophils, more asthma symptoms, lower lung function, increased relative risk for asthma exacerbation, sinusitis, and gastroesophageal reflux disease, and were assigned more frequently to SA clinical clusters. SAA and aliquots of LXA4loSAAhi BAL fluid induced IL-8 production by lung epithelial cells expressing ALX receptors, which was inhibited by coincubation with 15-epi-LXA4. CONCLUSIONS: Together, these findings have established an association between select ALX receptor ligands and asthma severity that define a potentially new biochemical endotype for asthma and support a pivotal functional role for ALX signaling in the fate of lung inflammation. TRIAL REGISTRATION: Severe Asthma Research Program 3 (SARP-3; ClinicalTrials.gov NCT01606826)FUNDING Sources. National Heart, Lung and Blood Institute, the NIH, and the German Society of Pediatric Pneumology. PMID- 28724796 TI - Host interleukin 6 production regulates inflammation but not tryptophan metabolism in the brain during murine GVHD. AB - Graft-versus-host disease (GVHD) induces pathological damage in peripheral target organs leading to well-characterized, organ-specific clinical manifestations. Patients with GVHD, however, can also have behavioral alterations that affect overall cognitive function, but the extent to which GVHD alters inflammatory and biochemical pathways in the brain remain poorly understood. In the current study, we employed complementary murine GVHD models to demonstrate that alloreactive donor T cells accumulate in the brain and affect a proinflammatory cytokine milieu that is associated with specific behavioral abnormalities. Host IL-6 was identified as a pivotal cytokine mediator, as was host indoleamine 2,3 dioxygenase (IDO-1), which was upregulated in GVHD in an IL-6-dependent manner in microglial cells and was accompanied by dysregulated tryptophan metabolism in the dorsal raphe nucleus and prefrontal cortex. Blockade of the IL-6 signaling pathway significantly reduced donor T cell accumulation, inflammatory cytokine gene expression, and host microglial cell expansion, but did not reverse GVHD induced tryptophan metabolite dysregulation. Thus, these results indicate that inhibition of IL-6 signaling attenuates neuroinflammation, but does not reverse all of the metabolic abnormalities in the brain during GVHD, which may also have implications for the treatment of neurotoxicity occurring after other T cell based immune therapies with IL-6-directed approaches. PMID- 28724797 TI - Increasing the level of peroxisome proliferator-activated receptor gamma coactivator-1alpha in podocytes results in collapsing glomerulopathy. AB - Inherited and acquired mitochondrial defects have been associated with podocyte dysfunction and chronic kidney disease (CKD). Peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC1alpha) is one of the main transcriptional regulators of mitochondrial biogenesis and function. We hypothesized that increasing PGC1alpha expression in podocytes could protect from CKD. We found that PGC1alpha and mitochondrial transcript levels are lower in podocytes of patients and mouse models with diabetic kidney disease (DKD). To increase PGC1alpha expression, podocyte-specific inducible PGC1alpha-transgenic mice were generated by crossing nephrin-rtTA mice with tetO-Ppargc1a animals. Transgene induction resulted in albuminuria and glomerulosclerosis in a dose-dependent manner. Expression of PGC1alpha in podocytes increased mitochondrial biogenesis and maximal respiratory capacity. PGC1alpha also shifted podocytes towards fatty acid usage from their baseline glucose preference. RNA sequencing analysis indicated that PGC1alpha induced podocyte proliferation. Histological lesions of mice with podocyte-specific PGC1alpha expression resembled collapsing focal segmental glomerular sclerosis. In conclusion, decreased podocyte PGC1alpha expression and mitochondrial content is a consistent feature of DKD, but excessive PGC1alpha alters mitochondrial properties and induces podocyte proliferation and dedifferentiation, indicating that there is likely a narrow therapeutic window for PGC1alpha levels in podocytes. PMID- 28724798 TI - Hepatic JAK2 protects against atherosclerosis through circulating IGF-1. AB - Atherosclerosis is considered both a metabolic and inflammatory disease; however, the specific tissue and signaling molecules that instigate and propagate this disease remain unclear. The liver is a central site of inflammation and lipid metabolism that is critical for atherosclerosis, and JAK2 is a key mediator of inflammation and, more recently, of hepatic lipid metabolism. However, precise effects of hepatic Jak2 on atherosclerosis remain unknown. We show here that hepatic Jak2 deficiency in atherosclerosis-prone mouse models exhibited accelerated atherosclerosis with increased plaque macrophages and decreased plaque smooth muscle cell content. JAK2's essential role in growth hormone signalling in liver that resulted in reduced IGF-1 with hepatic Jak2 deficiency played a causal role in exacerbating atherosclerosis. As such, restoring IGF-1 either pharmacologically or genetically attenuated atherosclerotic burden. Together, our data show hepatic Jak2 to play a protective role in atherogenesis through actions mediated by circulating IGF-1 and, to our knowledge, provide a novel liver-centric mechanism in atheroprotection. PMID- 28724800 TI - Siglec-G represses DAMP-mediated effects on T cells. AB - The role of negative regulators or suppressors of the damage-associated molecular pattern-mediated (DAMP-mediated) stimulation of innate immune responses is being increasingly appreciated. However, the presence and function of suppressors of DAMP-mediated effects on T cells, and whether they can be targeted to mitigate T cell-dependent immunopathology remain unknown. Sialic acid-binding immunoglobulin like lectin G (Siglec-G) is a negative regulator of DAMP-mediated responses in innate immune cells, but its T cell-autonomous role is unknown. Utilizing loss-of function-based (genetic knockout) and gain-of-function-based (agonist) approaches, we demonstrate that in the presence of certain DAMPs, Siglec-G suppressed in vitro and in vivo T cell responses. We also demonstrate that its T cell-autonomous role is critical for modulating the severity of the T cell mediated immunopathology, graft-versus-host disease (GVHD). Enhancing the Siglec G signaling in donor T cells with its agonist, a CD24Fc fusion protein, ameliorated GVHD while preserving sufficient graft-versus-tumor (GVT) effects in vivo. Collectively, these data demonstrate that Siglec-G is a potentially novel negative regulator of T cell responses, which can be targeted to mitigate GVHD. PMID- 28724799 TI - Galantamine alleviates inflammation and insulin resistance in patients with metabolic syndrome in a randomized trial. AB - BACKGROUND: Metabolic syndrome (MetS) is an obesity-driven condition of pandemic proportions that increases the risk of type 2 diabetes and cardiovascular disease. Pathophysiological mechanisms are poorly understood, though inflammation has been implicated in MetS pathogenesis. The aim of this study was to assess the effects of galantamine, a centrally acting acetylcholinesterase inhibitor with antiinflammatory properties, on markers of inflammation implicated in insulin resistance and cardiovascular risk, and other metabolic and cardiovascular indices in subjects with MetS. METHODS: In this randomized, double-blind, placebo controlled trial, subjects with MetS (30 per group) received oral galantamine 8 mg daily for 4 weeks, followed by 16 mg daily for 8 weeks or placebo. The primary outcome was inflammation assessed through plasma levels of cytokines and adipokines associated with MetS. Secondary endpoints included body weight, fat tissue depots, plasma glucose, insulin, homeostasis model assessment of insulin resistance (HOMA-IR), cholesterol (total, HDL, LDL), triglycerides, BP, heart rate, and heart rate variability (HRV). RESULTS: Galantamine resulted in lower plasma levels of proinflammatory molecules TNF (-2.57 pg/ml [95% CI -4.96 to 0.19]; P = 0.035) and leptin (-12.02 ng/ml [95% CI -17.71 to -6.33]; P < 0.0001), and higher levels of the antiinflammatory molecules adiponectin (2.71 MUg/ml [95% CI 1.93 to 3.49]; P < 0.0001) and IL-10 (1.32 pg/ml, [95% CI 0.29 to 2.38]; P = 0.002) as compared with placebo. Galantamine also significantly lowered plasma insulin and HOMA-IR values, and altered HRV. CONCLUSION: Low-dose galantamine alleviates inflammation and insulin resistance in MetS subjects. These findings support further study of galantamine in MetS therapy. TRIAL REGISTRATION: ClinicalTrials.gov, number NCT02283242. FUNDING: Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) and Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq), Brazil, and the NIH. PMID- 28724801 TI - TCR-ligand dissociation rate is a robust and stable biomarker of CD8+ T cell potency. AB - Despite influencing many aspects of T cell biology, the kinetics of T cell receptor (TCR) binding to peptide-major histocompatibility molecules (pMHC) remain infrequently determined in patient monitoring or for adoptive T cell therapy. Using specifically designed reversible fluorescent pMHC multimeric complexes, we performed a comprehensive study of TCR-pMHC off-rates combined with various functional assays on large libraries of self/tumor- and virus-specific CD8+ T cell clones from melanoma patients and healthy donors. We demonstrate that monomeric TCR-pMHC dissociation rates accurately predict the extent of cytotoxicity, cytokine production, polyfunctionality, cell proliferation, activating/inhibitory receptor expression, and in vivo antitumor potency of naturally occurring antigen-specific CD8+ T cells. Our data also confirm the superior binding avidities of virus-specific T cells as compared with self/tumor specific T cell clonotypes (n > 300). Importantly, the TCR-pMHC off-rate is a more stable and robust biomarker of CD8+ T cell potency than the frequently used functional assays/metrics that depend on the T cell's activation state, and therefore show major intra- and interexperimental variability. Taken together, our data show that the monomeric TCR-pMHC off-rate is highly useful for the ex vivo high-throughput functional assessment of antigen-specific CD8+ T cell responses and a strong candidate as a biomarker of T cell therapeutic efficacy. PMID- 28724803 TI - Increased de novo ceramide synthesis and accumulation in failing myocardium. PMID- 28724802 TI - Partially exhausted tumor-infiltrating lymphocytes predict response to combination immunotherapy. AB - BACKGROUND: Programmed death 1 (PD-1) inhibition activates partially exhausted cytotoxic T lymphocytes (peCTLs) and induces tumor regression. We previously showed that the peCTL fraction predicts response to anti-PD-1 monotherapy. Here, we sought to correlate peCTL and regulatory T lymphocyte (Treg) levels with response to combination immunotherapy, and with demographic/disease characteristics, in metastatic melanoma patients. METHODS: Pretreatment melanoma samples underwent multiparameter flow cytometric analysis. Patients were treated with anti-PD-1 monotherapy or combination therapy, and responses determined by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) criteria. peCTL and Treg levels across demographic/disease variables were compared. Low versus high peCTL (<=20% vs. >20%) were defined from a previous study. RESULTS: One hundred and two melanoma patients were identified. The peCTL fraction was higher in responders than nonresponders. Low peCTL correlated with female sex and liver metastasis, but not with lactate dehydrogenase (LDH), tumor stage, or age. While overall response rates (ORRs) to anti-PD-1 monotherapy and combination therapy were similar in high-peCTL patients, low-peCTL patients given combination therapy demonstrated higher ORRs than those who received monotherapy. Treg levels were not associated with these factors nor with response. CONCLUSION: In melanoma, pretreatment peCTL fraction is reduced in women and in patients with liver metastasis. In low-peCTL patients, anti-PD-1 combination therapy is associated with significantly higher ORR than anti-PD-1 monotherapy. Fewer tumor infiltrating peCTLs may be required to achieve response to combination immunotherapy. TRIAL REGISTRATION: UCSF IRB Protocol 138510FUNDING. NIH DP2 AR068130, K08-AR062064, AR066821, and Burroughs Wellcome CAMS-1010934 (M.D.R.). Amoroso and Cook Fund, and the Parker Institute for Cancer Immunotherapy (A.I.D.). PMID- 28724804 TI - Pediatric dilated cardiomyopathy hearts display a unique gene expression profile. AB - Our previous work showed myocellular differences in pediatric and adult dilated cardiomyopathy (DCM). However, a thorough characterization of the molecular pathways involved in pediatric DCM does not exist, limiting the development of age-specific therapies. To characterize this patient population, we investigated the transcriptome profile of pediatric patients. RNA-Seq from 7 DCM and 7 nonfailing (NF) explanted age-matched pediatric left ventricles (LV) was performed. Changes in gene expression were confirmed by real-time PCR (RT-PCR) in 36 DCM and 21 NF pediatric hearts and in 20 DCM and 10 NF adult hearts. The degree of myocyte hypertrophy was investigated in 4 DCM and 7 NF pediatric hearts and in 4 DCM and 9 NF adult hearts. Changes in gene expression in response to pluripotency-inducing factors were investigated in neonatal rat ventricular myocytes (NRVMs). Transcriptome analysis identified a gene expression profile in children compared with adults with DCM. Additionally, myocyte hypertrophy was not observed in pediatric hearts but was present in adult hearts. Furthermore, treatment of NRVMs with pluripotency-inducing factors recapitulated changes in gene expression observed in the pediatric DCM heart. Pediatric DCM is characterized by unique changes in gene expression that suggest maintenance of an undifferentiated state. PMID- 28724805 TI - Diabetic retinopathy: current understanding, mechanisms, and treatment strategies. AB - Diabetic retinopathy (DR) causes significant visual loss on a global scale. Treatments for the vision-threatening complications of diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR) have greatly improved over the past decade. However, additional therapeutic options are needed that take into account pathology associated with vascular, glial, and neuronal components of the diabetic retina. Recent work indicates that diabetes markedly impacts the retinal neurovascular unit and its interdependent vascular, neuronal, glial, and immune cells. This knowledge is leading to identification of new targets and therapeutic strategies for preventing or reversing retinal neuronal dysfunction, vascular leakage, ischemia, and pathologic angiogenesis. These advances, together with approaches embracing the potential of preventative or regenerative medicine, could provide the means to better manage DR, including treatment at earlier stages and more precise tailoring of treatments based on individual patient variations. PMID- 28724807 TI - Let's face it: The potential of periocular aesthetics. PMID- 28724806 TI - Nicotinamide mononucleotide requires SIRT3 to improve cardiac function and bioenergetics in a Friedreich's ataxia cardiomyopathy model. AB - Increasing NAD+ levels by supplementing with the precursor nicotinamide mononucleotide (NMN) improves cardiac function in multiple mouse models of disease. While NMN influences several aspects of mitochondrial metabolism, the molecular mechanisms by which increased NAD+ enhances cardiac function are poorly understood. A putative mechanism of NAD+ therapeutic action exists via activation of the mitochondrial NAD+-dependent protein deacetylase sirtuin 3 (SIRT3). We assessed the therapeutic efficacy of NMN and the role of SIRT3 in the Friedreich's ataxia cardiomyopathy mouse model (FXN-KO). At baseline, the FXN-KO heart has mitochondrial protein hyperacetylation, reduced Sirt3 mRNA expression, and evidence of increased NAD+ salvage. Remarkably, NMN administered to FXN-KO mice restores cardiac function to near-normal levels. To determine whether SIRT3 is required for NMN therapeutic efficacy, we generated SIRT3-KO and SIRT3-KO/FXN KO (double KO [dKO]) models. The improvement in cardiac function upon NMN treatment in the FXN-KO is lost in the dKO model, demonstrating that the effects of NMN are dependent upon cardiac SIRT3. Coupled with cardio-protection, SIRT3 mediates NMN-induced improvements in both cardiac and extracardiac metabolic function and energy metabolism. Taken together, these results serve as important preclinical data for NMN supplementation or SIRT3 activator therapy in Friedreich's ataxia patients. PMID- 28724808 TI - Using intravitreal bevacizumab (Avastin(r)) - Indian Scenario. PMID- 28724809 TI - A tale of two drugs: Off and on-label. PMID- 28724810 TI - Updates on upper eyelid blepharoplasty. AB - The human face is composed of small functional and cosmetic units, of which the eyes and periocular region constitute the main point of focus in routine face-to face interactions. This dynamic region plays a pivotal role in the expression of mood, emotion, and character, thus making it the most relevant component of the facial esthetic and functional unit. Any change in the periocular unit leads to facial imbalance and functional disharmony, leading both the young and the elderly to seek consultation, thus making blepharoplasty the surgical procedure of choice for both cosmetic and functional amelioration. The applied anatomy, indications of upper eyelid blepharoplasty, preoperative workup, surgical procedure, postoperative care, and complications would be discussed in detail in this review article. PMID- 28724811 TI - Quantitative physiological measurements to evaluate the response of antivascular endothelial growth factor treatment in patients with neovascular diseases. AB - Antivascular endothelial growth factor (VEGF) treatment is still used intravitreally worldwide for various neovascular diseases, despite other available, approved treatments. We performed a systematic search of the literature focused on visual physiology studies. We used the online biomedical search engine PubMed and searched key words including "M-chart," "Preferential Hyperacuity Perimetry," "microperimetry," (MP) "electroretinography," and "contrast sensitivity" to estimate treatment efficacy of anti-VEGF treatments in a quantitative manner. Many studies were identified which used a variety of methodologies, disease entities, injected agents, and patient populations, making it difficult to obtain a direct comparison of their results. However, favorable functional outcomes achieved using current quantitative methods would lend further confidence to the effectiveness of a treat-and-extend protocol using intravitreal anti-VEGF for the management of patients with neovascular diseases. Despite anti-VEGF's wide use, a well-designed longitudinal multicenter study to systematically evaluate and compare different physiological methods or parameters in patients with neovascular diseases is still lacking, though it would benefit therapeutic decisions. PMID- 28724812 TI - Use of glycerol-preserved corneas for corneal transplants. AB - PURPOSE: This study was carried out to see the results of glycerol-preserved cornea (GPC) in emergency situation when fresh corneal tissue was not available. The aim was to study the outcome of corneal transplantation using GPC. METHODS: This was a retrospective study. The medical records of all the patients were reviewed, who underwent keratoplasty using "GPC" during the period from October 2011 to December 2015. The indication of keratoplasty, duration of preservation of the GPC, and its outcome were analyzed. Descriptive statistics were applied. RESULTS: Out of the 222 penetrating keratoplasty (PKP) performed over the study period, the GPC was used in 34 patients (males = 31, 91.2%) aged 15-74 years. Therapeutic keratoplasty was performed in all cases in this cohort except one in which tectonic keratoplasty was done. The primary indication of PKP (91.2%) was infectious keratitis. Of these, 20 (64.5%) patients presented with perforated corneal ulcers. Post-PKP, ocular anatomy was preserved in 91.2%, and visual acuity of perception of light positive and accurate projection of rays in all the quadrants was obtained in 76.5% cases. Complications included glaucoma (n = 12, 35.1%), phthisis bulbi (n = 2, 5.9%), and graft reinfection and endophthalmitis after PKP (n = 1, 2.9%). The secondary procedure post-GPC and PKP were trabeculectomy with mitomycin C (n = 7, 58.3%) in patients not controlled on topical antiglaucoma medication. Optical keratoplasty was performed in (n = 3) 8.8% patients and triple procedure in (n = 2) 5.8% patients with good visual acuity postprocedure. CONCLUSIONS: Acellular GPCs are useful in emergency keratoplasty to avoid loss of vision and can save the eye. PMID- 28724813 TI - Correlation between the graft-host junction of penetrating keratoplasty by anterior segment-optical coherence tomography and the magnitude of postoperative astigmatism. AB - PURPOSE: This study aimed to evaluate the alignment pattern of the graft-host junction after penetrating keratoplasty (PK) by anterior segment-optical coherence tomography (AS-OCT) and to correlate this pattern with the magnitude of postoperative astigmatism. METHODS: This retrospective observational study was carried out on forty patients who underwent PK from February 2013 to August 2014. AS-OCT was performed, and the graft-host junctions were classified into well apposed junction, malapposed junction, and equally apposed junction. Mal apposition is subdivided into gap and protrusion. The correlations between clinical characteristics, wound profiles from the AS-OCT, and the magnitude of postoperative astigmatism by Sirius camera (Costruzione Strumenti Oftalmici [CSO], Florence, Italy (CSO, Sirius), were analyzed. RESULTS: Graft-host junctions from forty patients were analyzed; 18 eyes had well-apposed junctions, ten eyes had malapposed junctions, and 12 had equally apposed junctions. The mean cylinder was -9.44 +/- -4.00D in well-apposed group, -13.40 +/- -5.01D in malapposed group, and -4.67 +/- -0.94D in equally apposed group. Alignment pattern of the graft-host junction correlated significantly with the magnitude of astigmatism (P = 0.034). Preoperative corneal diseases did not have an effect on the magnitude of astigmatism (P = 0.123). CONCLUSION: The alignment pattern of the graft-host junction by AS-OCT can explain the postoperative astigmatism after PK where it correlates significantly with the magnitude of astigmatism. PMID- 28724814 TI - Comparison of intraocular pressure measurements using Goldmann tonometer, I-care pro, Tonopen XL, and Schiotz tonometer in patients after Descemet stripping endothelial keratoplasty. AB - PURPOSE: Post-Descemet stripping endothelial keratoplasty (DSEK) patients are prone for intraocular pressure (IOP) elevations and glaucoma. Corneal characteristics influence various IOP measuring devices in various ways. The aim of this study was to evaluate the agreement between four different IOP measuring devices: Goldmann applanation tonometer (GAT), I-care pro, Tonopen XL, and Schiotz tonometr in patients who underwent DSEK. METHODS: This was a prospective comparative study using a convenience cohort of post-DSEK patients with compact grafts. Post-DSEK patients had IOP measured using GAT, I-care Pro, Tonopen XL, and Schiotz tonometer. Measurements were compared and agreement assessed. Wilcoxon signed-rank test was used for comparison of means as variables did not show a normal distribution. Bland-Altman plots were used for assessing agreement. RESULTS: Thirty eyes of 24 patients were included in the study. Mean time from DSEK surgery was 25.31 +/- 13.05 months. Mean IOP with GAT, I-care pro, Tonopen XL, and Schiotz tonometer was 13.99 +/- 3.76, 13.92 +/- 3.36, 13.31 +/- 3.89, and 12.83 +/- 4.07, respectively. GAT, I-care pro, and Tonopen XL had similar mean IOP measurements (P = 0.135 and P = 0.551, respectively), while Schiotz tonometry measurements were higher (P = 0.046). Bland-Altman plots show good agreement between GAT, Tonopen XL, and I-care pro. GAT and Schiotz tonometry show less agreement, with large variations in the differences of measured IOP. CONCLUSIONS: IOP measurements in post-DSEK patients showed good agreement between GAT and either Tonopen XL or I-care pro. Schiotz tonometer has large variations in this patient group. IOP measurements and IOP difference between devices were not dependent on central corneal thickness. PMID- 28724815 TI - Efficacy and safety of intraoperative intracameral mydriasis in manual small incision cataract surgery - A randomized controlled trial. AB - PURPOSE: The purpose of this study is to assess the efficacy and safety of intracameral mydriatic solution, as compared to preoperative topical mydriatics, in patients undergoing manual small incision cataract surgery (MSICS) under peribulbar anesthesia. To assess the sustainability of intracameral mydriasis in MSICS by monitoring pupil size at specific junctures during the surgery. METHODS: This trial recruited 127 patients, who underwent MSICS under peribulbar block. Mydriasis in topical group was achieved with preoperative topical dilating drops while patients in intracameral group were taken up for surgery without dilation, and mydriasis was achieved intraoperatively with intracameral solution. Pupil sizes were measured serially, at six different junctures during surgery. Time duration of surgery, any intraoperative complications and first postoperative day visual acuity, corneal edema score, and anterior chamber inflammation score were noted in all patients. RESULTS: Mean pupil size just before peribulbar block was 7.3 mm in topical group and 3.3 mm in intracameral group (P < 0.001). Mean pupil size in intracameral group increased to 7.3 mm 30 s after injecting intracameral dilating solution. Mean pupil size in both groups progressively reduced, reaching 5.5 mm (topical group) and 6.2 mm (intracameral group) just before intraocular lens implantation (P = 0.001), and measured 5.1 mm and 5.5 mm, respectively, at the end of surgery (P = 0.048). On first postoperative day, there was no significant difference in distribution of corneal edema scores, AC inflammation scores, and in median logMAR visual acuity between the two groups. CONCLUSIONS: MSICS can be performed effectively and safely utilizing intracameral mydriatic solution, without the use of preoperative dilating drops. TRIAL REGISTRATION: CTRI/2016/06/007036. PMID- 28724816 TI - Four-year incidence and progression of visual impairment in a South Indian population with diabetes. AB - PURPOSE: The aim of this study is to investigate the 4-year incidence and progression of visual impairment (VI) and the associated risk factors for incident VI in a South Indian population with type 2 diabetes. METHODS: A total of 634 participants with type 2 diabetes were found eligible after 4 years. Visual acuity (VA) was estimated using the modified Early Treatment Diabetic Retinopathy Study protocol. VA in the better eye was considered for the assessment of VI based on the World Health Organization criteria. Mild VI was defined as VA <20/40 but up to 20/60, moderate VI as VA <20/60 but up to 20/200, severe VI as VA <20/200 but up to 10/200, and blindness as VA worse than 10/200. RESULTS: The 4-year incidence of any VI, mild VI, moderate VI, severe VI, and blindness was 21.7%, 18.3%, 3.4%, 0.0%, and 0.0%, respectively; of the 13 participants with VI at baseline, 12 (92%) showed worsening/progression of VI on follow-up. Multiple logistic regression showed that nuclear cataract of grades >4.0 (odds ratio [OR]: 2.612 [1.148-5.942], P = 0.022) and lower socioeconomic score (OR: 0.965 [95% confidence interval, (0.933-0.998)], P = 0.040) were associated with the risk of future incident VI. Refractive error (47%) and cataract (30%) were identified as the leading causes of incident VI at follow-up. CONCLUSIONS: VI seems to be a significant problem among diabetic participants in the South Indian population. Refractive error and cataract are the leading but treatable causes of incident VI in this population and would benefit from intervention. PMID- 28724817 TI - Real-world evidence of safety profile of intravitreal bevacizumab (Avastin) in an Indian scenario. AB - PURPOSE: The purpose of this study was to evaluate the safety profile of intravitreal bevacizumab (Avastin) as an off-label pharmacotherapeutic agent for various ocular conditions. METHODS: Retrospective analysis was carried out on 3806 injections of 1761 patients that were administered with intravitreal bevacizumab injection at a tertiary eye care center in India. The injections were administered on a pro re nata basis for various indications such as age-related macular degeneration (AMD), diabetic macular edema (DME), and retinal vein occlusion (RVO). RESULTS: The mean age of the patients was 61.8 +/- 11.59 years. A total of 59.2% of the patients were men and 40.8% women. The most common indications for which the injection was administered were DME (27.5%), AMD (26%), and branch RVO (12.3%). Among the ocular side effects, endophthalmitis was seen in three eyes (0.08%), retinal breaks in none of the eyes whereas 35 eyes had a rise in intraocular pressure (IOP) >21 mmHg (0.9%). Preexisting glaucoma was present in four eyes while remaining 31 eyes did not have any history of glaucoma. IOP rise was significantly more in eyes with preexisting glaucoma as compared to nonglaucomatous eyes (P = 0.04). No systemic adverse events were noted in our study population. CONCLUSION: Our study provides real-world evidence regarding the safety profile of intravitreal bevacizumab (Avastin). These data suggest that bevacizumab is a safe and economical pharmacotherapeutic agent that can be administered for a variety of ocular disorders. Analyzing the safety of bevacizumab is necessary for a developing country like India as the majority of the population cannot afford the costly ranibizumab as compared to bevacizumab for ocular healthcare. PMID- 28724818 TI - To assess knowledge and attitude of parents toward children suffering from strabismus in Indian subcontinent. AB - PURPOSE: Strabismus and anisometropia are the most common causes of amblyopia. It can be easily prevented or treated if detected early. With the changing socio cultural-economic milieu of the society, the perspectives of strabismus in society are gradually changing but still adequate knowledge, awareness, and attitude of parents toward strabismus will help in preventing amblyopia and aid in the proper psychosocial adaptation of such children. This study aimed to assess knowledge and attitude of parents toward children suffering from strabismus. METHODS: A prospective study was carried out from January 1 to February 29, 2016, through a structured questionnaire to assess the level of knowledge and attitude of parents of children suffering from strabismus. RESULTS: One hundred and twenty parents of children with strabismus were interviewed through a questionnaire. Education level of 78 parents was less than graduation (60%) and of 42 parents (40%) was graduation or higher. The majority of the parents, i.e., 116 (96.67%) were bothered due to strabismus. One hundred and one (84.17%) parents felt that their child's strabismus was noticed by others during interaction. Seventy-four (61.67%) parents felt that their children will have difficulty in making friends. Ninety (75%) parents felt uncomfortable if someone asked something about their child's strabismus. One hundred and ten (91.67%) parents considered strabismus as cosmetic stigma. CONCLUSION: Some parents, especially from the lower educated segment, had poor understanding of strabismus, thus resulting in late presentation and ineffective countermeasures. The key to prevent strabismic amblyopia and its psychosocial impacts is to provide health education regarding strabismus. PMID- 28724819 TI - Stability and effects of muscle transplantation for very large angle esotropia: A study of 22 patients. AB - PURPOSE: A very large angle esotropia is characterized by an angle more than 80 prism diopters (pd). A single eye surgery would not correct such a large angle. Supramaximal recessions and resection would lead to restriction of ocular motility. We present a series of 22 patients with large angle esotropia treated with muscle transplantation. METHODS: A total of 22 patients (14 males and 8 females) were included in the study. All the patients had a minimum of 80 base out deviation in primary position. All patients underwent thorough preoperative orthoptic checkup and refraction. The patients were followed up on day 1, day 30, at 6 months, at 1 year, and 2 years. All the patients underwent standard muscle transplantation, where the resected extra stump of lateral rectus was transplanted to the medial rectus using 6-0 prolene which was recessed by a standard recession technique. RESULTS: The mean age of the 22 patients was 32.21 +/- 13.1 years. The mean preoperative angle was 92.4 +/- 13.5 pd base out. The mean postoperative angle at 2-year follow-up was 12.3 +/- 9.9 pd. The average correction achieved per mm was 4.1 +/- 0.3 pd. The adduction restriction was <1 in all the patients at the end of 2 years except one patient. The abduction was normal in all the patients. CONCLUSION: The true muscle transplantation is a safe alternate option for large angle esotropia when uniocular surgery is desired. The surgical results are stable in long-term and therefore a viable option. PMID- 28724820 TI - A rare case of cleft number nine associated with atypical cleft number two. AB - The incidence of the craniofacial cleft is rare ranging between 1.43 and 4.85/100,000 births. Tessier number nine cleft being the rarest, there are a few reports of detailed ophthalmologic examinations performed in them. In this study, 1-day-old female neonate delivered by normal vaginal delivery at term, weighing 1480 g presented with right eye dystopia, cleft extending through the lateral third of the upper eyelid, brow ending at the temporal region, conjunctival congestion, clear cornea 10 mm in diameter, normal anterior chamber, pupil 2 mm reactive to light, clear lens, and normal fundus. Cleft extended downward from the right medial canthus involving the nasal ala and left forearm had an oblique crease with camptodactyly. We thus report a case of anterior segment abnormality with an oblique craniofacial cleft. The cause of which is unclear, amniotic band syndrome being a possible cause. PMID- 28724821 TI - Epipalpebral conjunctival chondroid choristoma: Interesting developmental anomaly presenting in an adult. AB - Ocular choristomas are uncommon lesions chiefly presenting in children. Choristomas may contain dermal and epidermal components, muscle, cartilage, bone, etc. They are usually seen in epibulbar conjunctiva, but epipalpebral location is uncommon. We present a case of epipalpebral chondroid choristoma presenting in an adult patient. PMID- 28724822 TI - An unusual presentation of lacrimal gland dirofilariasis. AB - Dirofilariasis is a helminthic infection caused by filarial parasite of the genus Dirofilaria. It is a common zoonotic disease mostly affecting canines and uncommon in humans. It is endemic to Mediterranean countries, with few reports from other parts of the world. The clinical forms in humans are pulmonary, subcutaneous, and ocular. Ocular involvement is rare. We report a case of lacrimal gland dirofilariasis, an unusual ocular presentation which masquerades as a lacrimal gland tumor. Ours would be the third reported case in the world and first in India. This case was managed with excision of the lacrimal gland mass. Postoperatively the patient recovered completely and there has been no recurrence in the 1-year follow-up. PMID- 28724823 TI - Topography-guided neutralization technique for the management of flap complication in laser in situ keratomileusis. AB - A 29-year-old male was referred following a flap loss after the creation of a thin, irregular flap with a visual acuity of logMAR 0.1 with -2.0 DS-2.75 DC * 175 degrees . Corneal topography and anterior segment optical coherence tomography revealed an irregular corneal curvature and epithelial profile. Phototherapeutic keratectomy (PTK) followed by Topography - Guided Custom Ablation Treatment (TCAT), as a modification of the topographic neutralization technique protocol, was planned to regularize the corneal surface and treat the residual refractive error. Postoperatively, the patient showed a best-corrected visual acuity of logMAR 0 with a refractive error of -1 DC * 90 degrees . Regularization of topography and epithelial thickness was seen along with a reduction in astigmatism and higher order aberrations. We report the use of PTK followed by TCAT as a novel method to treat a case of intraoperative flap loss during laser in situ keratomileusis. PMID- 28724824 TI - Late onset Descemet's membrane detachment 20 years after penetrating keratoplasty. AB - This paper reports a case of spontaneous Descemet's Membrane (DM ) detachment 20 years after penetrating keratoplasty (PK). The patient presented with acute onset blurred vision in the right eye associated with mild ocular discomfort. There was no prior history of trauma. The patient had undergone PK in the right eye 20 years back. Detailed ophthalmic examination showed best corrected visual acuity of hand movements close to face in the right eye and 20/80 in the left eye. The right eye showed diffuse graft edema but no congestion, epithelial defect, or loss of continuity of graft-host junction to suggest a traumatic etiology. Anterior segment optical coherence tomography showed DM break with a detachment in the right eye, which was treated with an intracameral C3F8 injection. DM break with detachment post-PK has been very sparsely reported in literature and is an important differential to remember when faced with an edematous graft, in addition to the diagnosis of graft rejection or failure. PMID- 28724825 TI - A rare case of overlapping Sturge-Weber syndrome and Klippel-Trenaunay syndrome associated with bilateral refractory childhood glaucoma. AB - A 6-year-old girl presented with blurred vision and was found to have elevated intraocular pressure (IOP) and glaucomatous optic disc damage in both eyes. She also displayed capillary malformations on the face (port-wine stain), upper back and all four limbs, angiomatosis in the brain and had hypertrophy of the left upper and lower limbs typical of overlapping Sturge-Weber syndrome and Klippel Trenaunay syndromes. She was initially managed with IOP lowering topical medications but required trabeculectomy in the right eye followed by Ahmed valve implantation in both eyes. Despite multiple measures over a 7-year period, her IOP still remained uncontrolled with gradual progression of the glaucomatous damage. This case exhibits a very rare occurrence of overlapping syndromes reported only a handful of times in literature. Most cases with Sturge-Weber syndrome have ipsilateral glaucoma affecting the eye on the same side as the port wine stain. This case presented with bilateral refractory childhood glaucomas, which is exceedingly rare. PMID- 28724826 TI - Bilateral normal tension glaucoma: Can this be nutritional? AB - Normal tension glaucoma (NTG) also known as low tension glaucoma, presents with optic nerve head and visual field damage in the absence of high intraocular pressure (<21 mmHg). There are several patients of NTG seen in our clinics who have repeatable visual field defects, which may or may not correlate with the disc appearance, but are labeled as glaucoma. Ruling out ischemic, nutritional, and other causes of one-time damage are important before diagnosing an NTG. We report 3 such cases that were misdiagnosed and referred as NTG. All three cases were not glaucomatous and had typical features of nutritional optic neuropathy. The typical clinical features, visual field and imaging abnormalities seen in these two conditions and their management is highlighted in this article. Misdiagnosis leads to inappropriate investigations and treatment, but more importantly would lead to worsening of undiagnosed underlying disease. PMID- 28724827 TI - Angioid streaks in a case of Camurati-Engelmann disease. AB - Camurati-Engelmann disease (CED) is a rare autosomal dominant disease with various phenotypic expressions. The hallmark of the disease is bilateral symmetric diaphyseal hyperostosis of the long bones with progressive involvement of the metaphysis. Ocular manifestations occur rarely and mainly result from bony overgrowth of the orbit and optic canal stenosis. We report a case of CED showing angioid streaks (ASs) in both fundi with no macular involvement and discuss the possible theories of the pathogenesis of AS in this disease. PMID- 28724828 TI - Ring-shaped myelinated retinal nerve fibers at fovea. AB - We aim to report an unusual case of myelinated retinal nerve fibers (MRNFs) at fovea. A 39-year-old woman presented with visual impairment and her visual acuity was 20/80 in the right eye. Ophthalmologic examination revealed MRNF lesions at inferior and superior poles of optic disc in the right eye. Furthermore, a ring shaped MRNF lesion with feathery edges was observed at fovea. MRNF lesions are rarely seen at macula, and to our knowledge, this is the first report of an MRNF lesion at fovea. PMID- 28724829 TI - Case report of a secondary macular hole closure after intravitreal bevacizumab therapy in a patient with retinal pigment epithelial detachment. AB - We describe a case of macular hole (MH) closure after intravitreal bevacizumab therapy for an underlying pigment epithelial detachment (PED) due to exudative age-related macular degeneration (AMD). The 73-year-old Caucasian female presented with reduced visual acuity (20/80) of the left eye and metamorphopsia for approximately 6 months. Spectral domain optical coherence tomography revealed a subfoveal PED due to AMD with an associated MH. To treat the exudative component of the pathology, we started intravitreal bevacizumab therapy, consecutively leading to reduction of the height of PED and allowing closure of the MH. Detachment recurred during further follow-up, but the MH remained closed. MHs and exudative AMD are common diseases, which rarely occur simultaneously. To the best of our knowledge (search via PubMed for "MH," "PED," "age-related macular degeneration"), no other case with the persistent closure of an MH associated with PED during intravitreal antivascular endothelial growth factor therapy and despite recurrent PED has been published to date. PMID- 28724830 TI - Drug-resistant coagulase-negative staphylococcal endophthalmitis following dexamethasone intravitreal implant. AB - A 60-year-old female came to our hospital with defective vision due to persistent diabetic macular edema and was treated with intravitreal ozurdex implant in the right eye. Three days later, the patient presented with diminution of vision, ocular pain, congestion, and hypopyon with no fundus view. B-scan ultrasonography showed vitritis, and diagnosis of endophthalmitis was made. Subsequently, 25 gauge pars plana vitrectomy was performed along with intravitreal vancomycin and amikacin and removal of implant. On culture, there was growth of coagulase negative staphylococcus which was resistant to ofloxacin antibiotic. A week following treatment, there was significant improvement in the patient's sign and symptoms with improvement in vision. Our case demonstrated that acute endophthalmitis can occur following dexamethasone intravitreal implant. PMID- 28724831 TI - No split, no tenotomy transposition procedure for complete abducens palsy. AB - Abducens palsy is one of the commonly encountered cranial nerve palsies in strabismus clinic. For large-angle esotropia, due to complete abducens palsies, various vertical recti transposition (VRT) procedures have been described. Hummelsheim and Jensen's procedure are especially popular among them. Risk of anterior segment ischemia and induced vertical deviation postVRT prompt to search for better procedures to correct the esotropia and also improve the abduction. Modified Nishida's procedure (no split, no tenotomy transposition) is one of the newly described procedure in this direction. We describe three cases of complete abducens nerve palsy treated by this procedure. PMID- 28724832 TI - Safe surgery checklist for cataract surgery in ophthalmic day centres in India. PMID- 28724833 TI - Comment on: Visual function of children with visual and other disabilities in Oman: A case series. PMID- 28724834 TI - Erratum: Allergen specific exposure associated with high immunoglobulin E and eye rubbing predisposes to progression of keratoconus. AB - [This corrects the article DOI: 10.4103/ijo.IJO_217_17.]. PMID- 28724835 TI - Erratum: Immediate sequential bilateral cataract surgery: A 5 year retrospective analysis of 2470 eyes from a tertiary care eye center in South India. AB - [This corrects the article DOI: 10.4103/ijo.IJO_947_16.]. PMID- 28724836 TI - Prothrombin Complex Concentrate for Vitamin K Antagonist-Associated Intracranial Hemorrhage - Global Evidence and the Japanese Perspective. AB - Patients receiving vitamin K antagonists (VKAs) are at increased risk of bleeding. Intracranial hemorrhage (ICH) is a major cause of morbidity and mortality in this population, and is a particular concern among Japanese clinicians, given reports of an elevated risk of this bleeding type in patients of Asian ethnicity. Patients with VKA-associated ICH require rapid international normalized ratio (INR) reversal, and treatment guidelines suggest the use of prothrombin complex concentrates (PCCs) or plasma for this purpose. Although European and US guidelines recommend PCCs for the treatment of VKA-associated major bleeding, they do not make a specific recommendation in the setting of ICH, owing to the lack of comparative evidence. In contrast, Japanese guidelines recommend the use of PCCs rather than plasma for VKA reversal in patients with ICH; however, these agents are not currently licensed in Japan for this indication. Here we review the available evidence on the use of PCCs for the treatment of VKA-associated ICH, both globally and specifically in Japanese settings. Overall, the evidence reviewed here supports the use of PCC for rapid VKA reversal in these patients. PMID- 28724837 TI - Chemical Analysis of Counterfeit Hepatitis C Drug Found in Japan. AB - In January 2017, counterfeits of the hepatitis C drug 'HARVONI(r) Combination Tablets' (HARVONI(r)) were found at a pharmacy chain through unlicensed suppliers in Japan. A total of five lots of counterfeit HARVONI(r) (samples 1-5) bottles were found, and the ingredients of the bottles were all in tablet form. Among them, two differently shaped tablets were present in two of the bottles (categorized as samples 2A, 2B, 4A, and 4B). We analyzed the total of seven samples by high-resolution LC-MS, GC-MS and NMR. In samples 2A, 3 and 4B, sofosbuvir, the active component of another hepatitis C drug, SOVALDI(r) Tablets 400 mg (SOVALDI(r)), was detected. In sample 4A, sofosbuvir and ledipasvir, the active components of HARVONI(r), were found. A direct comparison of the four samples and genuine products showed that three samples (2A, 3, 4B) are apparently SOVALDI(r) and that sample 2A is HARVONI(r). In samples 1 and 5, several vitamins but none of the active compounds usually found in HARVONI(r) (i.e., sofosbuvir and ledipasvir) were detected. Our additional investigation indicates that these two samples are likely to be a commercial vitamin supplement distributed in Japan. Sample 2B, looked entirely different from HARVONI(r) and contained several herbal constitutents (such as ephedrine and glycyrrhizin) that are used in Japanese Kampo formulations. A further analysis indicated that sample 2B is likely to be a Kampo extract tablet of Shoseiryuto which is distributed in Japan. Considering this case, it is important to be vigilant to prevent a recurrence of distribution of counterfeit drugs. PMID- 28724838 TI - Csk Regulates Blood Pressure by Controlling the Synthetic Pathways of Aldosterone. AB - BACKGROUND: Blood pressure is regulated by a network of diverse physiological pathways. The C-terminal Src kinase (CSK) locus (15q24) is associated with blood pressure in various ethnic groups. It was recently reported thatCskinsufficiency increases blood pressure through Src. The mechanisms of hypertension inCsk+/-mice are examined further in this study.Methods and Results:To identify a causal component responsible for hypertension inCsk+/-, the heart rate was measured by electrocardiogram and plasma volume by Evans blue dilution. Plasma volume increased inCsk+/-compared with wild-types, while the heart rate did not change. Plasma sodium and aldosterone levels rose consistently inCsk+/-vs. wild-types, and spironolactone, a mineralocorticoid receptor antagonist, reduced blood pressure. The amounts of Sgk1 and Na+/K+-ATPase (NKA) increased in the kidney ofCsk+/-compared with wild-types. It was also found that Cyp11b2 (aldosterone synthase) was upregulated in the adrenal glands ofCsk+/-, and that Csk was enriched in the zona glomerulosa of adrenals, the major site of aldosterone production in the normal mouse. CONCLUSIONS: The results of the present study identify a physiological pathway by which blood pressure is regulated, in which the insufficiency ofCskinduces aldosterone production with zonal specificity in the adrenal glands, increasing sodium reabsorption and plasma volume and thus resulting in hypertension. PMID- 28724839 TI - Effect of Recurrent Mitral Regurgitation After Mitral Valve Repair in Patients With Degenerative Mitral Regurgitation. AB - BACKGROUND: This study investigated the consequences of recurrent mitral regurgitation (MR) after mitral valve (MV) repair in patients with degenerative MR and risk factors for recurrence.Methods and Results:From January 1990 to December 2015, 792 patients underwent MV repair due to degenerative MR. Recurrent MR was defined as moderate-to-severe MR on follow-up echocardiography. Mean follow-up duration was 8.71+/-5.58 years. During the follow-up period, MR recurred in 133 (16.8%) patients, and the MR recurrence-free rate at 20 years was 77.5+/-2.0%. In the recurrence group, the degree of MR decreased in 8 (6.0%) patients and was aggravated in 46 (34.6%) patients. Recurrent MR was associated with increased mortality and adverse left ventricular (LV) remodeling. Independent risk factors for MR recurrence were MV repair performed before 2000, preoperative atrial fibrillation, high LV end-diastolic dimension (LVEDD), prolapse of the isolated anterior leaflet or multiple segments, and absence of ring annuloplasty. Predictors of MR progression were high LVEDD and repair without artificial chordae implantation. CONCLUSIONS: Recurrent MR after MV repair in patients with degenerative MR showed a tendency to progress and was associated with increased mortality and adverse LV remodeling. Early referral for MV repair before development of atrial fibrillation and LV enlargement may reduce the risk of MR recurrence. Moreover, artificial chordae implantation and ring annuloplasty may assure the long-term durability of MV repair. PMID- 28724840 TI - Exposure to Parental Smoking in Childhood is Associated with High C-Reactive Protein in Adulthood: The Cardiovascular Risk in Young Finns Study. AB - AIM: Children exposed to parental smoking are at increased long-term risk of subclinical atherosclerosis in adulthood. However, it has not been quantified if exposure to parental smoking in childhood is associated with adult systemic inflammation. This study aimed to determine if childhood exposure to parental smoking was associated with high-sensitivity C-reactive protein (hsCRP) in adulthood. METHODS: This longitudinal analysis of 2,511 participants used data from the Cardiovascular Risk in Young Finns Study, a prospective cohort of Finnish children. In 1980 or 1983, parents self-reported their smoking status and serum hsCRP was collected up to 31 years later in adulthood. RESULTS: Compared with children with non-smoking parents, the relative risk of developing high hsCRP (>3 mg/L) in adulthood increased among those with 1 or both parents who smoked [relative risk (RR), 1.3; 95%confidence interval (CI), 1.0-1.8] after adjustment for socioeconomic status, cardiovascular risk factors, and smoking status in childhood and adulthood. Moreover, children exposed to mother smoking [RR, 2.4; 95% CI, 1.3-4.2] had highest risk of developing high hsCRP in adulthood compared with those exposed to father smoking [RR, 1.6; 95% CI, 1.2-2.3] and both parents smoking [RR, 1.4; 95% CI, 0.9-2.0]. CONCLUSION: Our findings suggest that children exposed to parental smoking are at increased risk of having high hsCRP in adulthood. Limiting children's exposure to passive smoking may have long-term benefits on general low-grade inflammation. PMID- 28724843 TI - The Complex Structure of the Mouse Placental Labyrinth Revealed by Double Immunofluorescence Labeling of Slc2a1 and Gjb2. PMID- 28724841 TI - Sphingosine 1-Phosphate and Atherosclerosis. AB - Sphingosine 1-phosphate (S1P) is a potent lipid mediator that works on five kinds of S1P receptors located on the cell membrane. In the circulation, S1P is distributed to HDL, followed by albumin. Since S1P and HDL share several bioactivities, S1P is believed to be responsible for the pleiotropic effects of HDL. Plasma S1P levels are reportedly lower in subjects with coronary artery disease, suggesting that S1P might be deeply involved in the pathogenesis of atherosclerosis. In basic experiments, however, S1P appears to possess both pro atherosclerotic and anti-atherosclerotic properties; for example, S1P possesses anti-apoptosis, anti-inflammation, and vaso-relaxation properties and maintains the barrier function of endothelial cells, while S1P also promotes the egress and activation of lymphocytes and exhibits pro-thrombotic properties. Recently, the mechanism for the biased distribution of S1P on HDL has been elucidated; apolipoprotein M (apoM) carries S1P on HDL. ApoM is also a modulator of S1P, and the metabolism of apoM-containing lipoproteins largely affects the plasma S1P level. Moreover, apoM modulates the biological properties of S1P. S1P bound to albumin exerts both beneficial and harmful effects in the pathogenesis of atherosclerosis, while S1P bound to apoM strengthens anti-atherosclerotic properties and might weaken the pro-atherosclerotic properties of S1P. Although the detailed mechanisms remain to be elucidated, apoM and S1P might be novel targets for the alleviation of atherosclerotic diseases in the future. PMID- 28724842 TI - Short-term effect of back school based on cognitive behavioral therapy involving multidisciplinary collaboration. AB - ObjectivesThe purpose of this study was to develop a comprehensive back school program that included elements of CBT (Cognitive Behavioral Therapy), implement this through multidisciplinary collaboration, and ascertain its effectiveness as a pilot study. DesignThis school was implemented in the form of five 90-minute group sessions held every other week.MethodsParticipants comprised 7 chronic low back pain patients with poor improvement in the usual treatment. Practitioners were orthopaedic surgeon, physical therapist, and a clinical psychologist. This school contents were patient education, self-monitoring, back exercise, relaxation, stress management, cognitive restructuring, activity pacing, and exposure. ResultsFrom the Wilcoxon signed-rank test, each score of four scales or items (sense of control, PCS (pain catastrophizing), PASS-20 (escape/avoidance), FFD (finger-floor distance)) after this program significantly improved. Results of calculating the effect size, sense of control (d=0.55) is 'moderate', the PCS (d=1.12) and the PASS-20 (d=1.64) were 'large'.ConclusionsThis back school may be useful for physical function and psychological variables which much related to pain management and daily disabilities in patients with poor respond to standard orthopaedic treatment. PMID- 28724844 TI - A Review of the Active Treatments for Toxic Epidermal Necrolysis. AB - Toxic epidermal necrolysis (TEN) is a severe adverse drug reaction associated with the separation of skin and mucous membranes at the dermal-epidermal junction. Although it is rare, many treatments have been trialed because of its high mortality rate. Active interventions performed to date include the use of systemic corticosteroids, intravenous immunoglobulins (IVIg), cyclosporine, plasmapheresis, anti-tumor necrosis factor drugs and N-acetylcysteine, but none has been established as the most effective therapy. IVIg and short-term high-dose corticosteroids were regarded as the most promising treatments for TEN in a comprehensive review of all reported TEN cases from 1975-2003. When used with an appropriate dose and timing, the beneficial effects of IVIg can be maximized. Although no randomized controlled trials have been conducted, cyclosporine and plasmapheresis are considered to be beneficial. As no gold standard for active intervention for TEN has been established, the choice of treatment relies partly on the available guidelines and the experience of the dermatologist. There is still much to be investigated regarding the pathogenesis of TEN, and new findings may contribute to the identification of an effective active intervention strategy. PMID- 28724845 TI - Ultrasonography-Based Classification and Reporting System for the Malignant Risk of Thyroid Nodules. AB - OBJECTIVE: The aim of this study was to test the predictive value of a Thyroid Imaging Reporting and Data System (TI-RADS) for malignant thyroid nodules. METHODS: Ultrasonographic data was examined for 910 thyroid nodules with histopathologically confirmed diagnoses. Nodules were placed into incomplete (category 0) or complete final categories (1, 2, 3a, 3b, 3c, 4, or 5) based on the presence and number of ultrasonographic features of malignancy, and the predictive value for the malignancy of nodules in categories 2-4 was assessed. RESULTS: The overall rate of malignancy among thyroid nodules included in the study was 59.34%. The rate of malignancy gradually increased according to TI-RADS categories as follows: category 2, 5.4%; category 3 (a-c), 36% to 92%; and category 4, 99.0%. When nodules of category 2 were counted as benign, the reliability of the TI-RADS classification for determining the risk of malignancy was as follows; sensitivity, 98.15%; specificity, 47.84%; positive predictive value, 73.31%; negative predictive value, 94.65%; and odds ratio, 48.61. CONCLUSIONS: The TI-RADS classification used in this study is relatively simple and provides a reliable measure of the risk of malignancy of thyroid nodules. PMID- 28724846 TI - Metabolic and Inflammatory Changes with Orlistat and Sibutramine Treatment in Obese Malaysian Subjects. AB - INTRODUCTION: Obesity is associated with numerous health problems, particularly metabolic and cardiovascular complications. This study aimed to assess the effects that, nine months of pharmacological intervention with orlistat or sibutramine, on obese Malaysians' body weight and compositions, metabolic profiles and inflammatory marker. METHODS: Seventy-six obese subjects were randomly placed into two groups. The first group received three daily 120 mg dosages of orlistat for nine months (n=39), and the second group received a once daily 10 or 15 mg dosage of sibutramine for nine months (n=37). Baseline measurements for weight, body mass index (BMI), waist circumference (WC), body fat percentage (BF), visceral fat (VF), adiponectin, fasting plasma glucose (FPG), fasting insulin, pancreatic B cell secretory capacity (HOMA%B), insulin sensitivity (HOMA%S), insulin resistance (HOMA-IR) and serum high sensitivity C reactive protein (hs-CRP) were performed and repeated during the sixth and ninth months of treatment. RESULTS: Twenty-four subjects completed the trial in both groups. For both groups, weight, BMI, WC, BF, VF, HOMA-IR and hs-CRP were significantly lower at the end of the nine month intervention. However, there were no significant differences between the two groups for these parameters with nine months treatment. There was a significant decrease in FPG in orlistat group; while fasting insulin and HOMA%B reduced in sibutramine group. For both groups, there were also significant increases in adiponectin levels and HOMA%S at the end of the nine month intervention. CONCLUSION: Nine months of treatment with orlistat and sibutramine not only reduced weight but also significantly improved BMI, WC, BF, VF, FPG, adiponectin, fasting insulin, HOMA%B, HOMA%S, HOMA-IR and hs-CRP. These improvements could prove useful in the reduction of metabolic and cardiovascular risks in obese subjects. PMID- 28724847 TI - A Case of Primary Bacterial Pericarditis with Recurrent Cardiac Tamponade. AB - Cardiac tamponade is an important and potentially lethal complication of acute pericarditis. However, recurrence of cardiac tamponade is rare when it is treated appropriately. We present a 49-year-old man with bacterial pericarditis and recurrent cardiac tamponade, which was caused by the rupture of an upper part of the left atrium (LA). According to the autopsy findings, bacteremia from Staphylococcus aureus developed on a substrate of poorly controlled diabetes mellitus and spread to the pericardium via the blood. Subsequently, tissue necrosis developed from the pulmonary trunk and aorta to the LA, leading to recurrence of cardiac rupture and cardiac tamponade. PMID- 28724848 TI - Laparoscopic Excision of a Uterine Adenomatoid Tumor and a Coexisting Ovarian Teratoma: A Case Report and Literature Review. AB - Adenomatoid tumors (ATs) are rare, benign neoplasms occurring mainly in reproductive organs such as the uterus, ovaries, fallopian tubes, and testes. Uterine adenomatoid tumors (UATs) are generally incidentally diagnosed during histopathological examination of excisional biopsies performed for other indications, most commonly uterine leiomyomas. We herein present a 38-year-old woman who underwent laparoscopic excision of a uterine leiomyoma and a right ovarian teratoma. Microscopic examination of the excisional biopsy revealed that the enucleated uterine tumor was composed of proliferating glandular tissue covered with single-layered cells that were surrounded by proliferating smooth muscle cells, corresponding exactly to the features of UATs. The excised ovarian cyst was confirmed to be a typical mature cystic teratoma. According to these histopathological findings, the patient was finally diagnosed with a UAT and coexisting teratoma. No recurrence was detected up to 6 months after excision. To the best of our knowledge, this is the eighth case report on laparoscopically enucleated UATs. Although recurrence risk may be low in UATs, further case reports are necessary to elucidate the safety and validity of laparoscopic excision for UATs. PMID- 28724849 TI - The Ilizarov Mini-External Fixator for the Treatment of First Metatarsal Fracture: A Case Report. AB - Forefoot fractures are frequently accompanied by severe soft tissue damage. Therefore, treatment should focus not only on fractures but also on soft tissue damage, for which external fixation can be used as a surgical option. A 63-year old woman presented to the emergency clinic of our hospital with forefoot pain after a motorcycle accident. Comminuted fracture of the proximal part of the metatarsal was diagnosed. Because of the swollen foot and fracture comminution, an operation using the Ilizarov mini external fixator was performed to prevent further damage to the soft tissue. Weight-bearing was permitted seven weeks after the operation, and the extraction of the apparatus was performed nine weeks postoperatively. One year later, the patient had no pain and had returned to ballroom dancing, a hobby which she performed five days a week, with no difficulties. Our results suggest that the Ilizarov mini external fixator should be considered not only for temporary treatment, but also for the entire duration of treatment of first metatarsal fractures associated with severe soft tissue damage. PMID- 28724850 TI - Spatiotemporal Dynamics of Total Viable Vibrio spp. in a NW Mediterranean Coastal Area. AB - A cellular approach combining Direct Viable Counting and Fluorescent In Situ Hybridization using a one-step multiple-probe technique and Solid Phase Cytometry (DVC-FISH-SPC) was developed to monitor total viable vibrios and cover the detection of a large diversity of vibrios. FISH combined three probes in the same assay and targeted sequences located at different positions on the 16S rRNA of Vibrio and Aliivibrio members. We performed a 10-month in situ study to investigate the weekly dynamics of viable vibrios relative to culturable counts at two northwestern Mediterranean coastal sites, and identified the key physicochemical factors for their occurrence in water using a multivariate analysis. Total viable and culturable cell counts showed the same temporal pattern during the warmer season, whereas the ratios between both methods were inverted during the colder seasons (<15 degrees C), indicating that some of the vibrio community had entered into a viable but non-culturable (VBNC) state. We confirmed that Seawater Surface Temperature explained 51-62% of the total variance in culturable counts, and also showed that the occurrence of viable vibrios is controlled by two variables, pheopigment (15%) and phosphate (12%) concentrations, suggesting that other unidentified factors play a role in maintaining viability. PMID- 28724852 TI - Is Childhood Exposure to Parental Smoking a Risk Factor for Future Cardiovascular Disease? PMID- 28724851 TI - Potential risk of viral transmission from flying foxes to domestic animals and humans on the southern coast of West Java, Indonesia. AB - Flying foxes have been considered to be involved in the transmission of serious infectious diseases to humans. Using questionnaires, we aimed to determine the direct and/or indirect contacts of flying foxes in an Indonesian nature conservation area with domestic animals and humans living in the surrounding area. We surveyed 150 residents of 10 villages in West Java. Villages were classified into 3 groups: inside and/or within 1 km from the outer border of the conservation area and 1-5 km or 5-10 km away from the reserve's outer border. Data were collected by direct interview using a structured questionnaire consisting of the respondent characteristics (age, sex and occupation); histories of contacts between flying foxes and humans, dogs and other domestic animals; and knowledge about infectious diseases, mainly rabies, in flying foxes. We found that flying foxes from the nature conservation area often enter residential areas at night to look for food, especially during the fruit season. In these residential areas, flying foxes had direct contacts with humans and a few contacts with domestic animals, especially dogs. People who encounter flying foxes seldom used personal protective equipment, such as leather gloves, goggles and caps. The residents living around the conservation area mostly had poor knowledge about flying foxes and disease transmission. This situation shows that the population in this region is at a quite high risk for contracting infectious diseases from flying foxes. PMID- 28724853 TI - School-Based Interventions Aimed at the Prevention and Treatment of Adolescents Affected by the 2011 Great East Japan Earthquake: A Three-Year Longitudinal Study. AB - How natural disasters affect the psychological state of adolescents has not been well studied. Thus, we examined the effect of a natural disaster on high-school aged youth and considered the most effective forms of support following such a disaster. We examined students from two high schools that were near the epicenter of the 9.0-magnitude Great East Japan Earthquake, which struck the Tohoku coastal area on March 11, 2011, causing severe damage to the region. The questionnaires measuring depression, anxiety, and post-traumatic stress reaction (PTSR) was administered to the students 3 times between July 2012 and August 2014; students who scored above the cut-off values of these measures were considered high-risk students. School teachers, nurses, and counselors provided a school-based intervention for all high-risk students identified in the survey. Data were analyzed using the Kruskal-Wallis H-test. Survey data revealed that 860 of the 1,432 (55.9%) high school students were at high risk of psychological trauma in 2012. This rate did not change substantially in the following 2 years, reaching 1,059 of 1,488 (69.1%) in 2013, and 949 of 1,430 (62.7%) in 2014. Depression and PTSR scores were significantly lower after the intervention (for 2nd and 3rd grade students in 2013 and 2014) compared to before (for the initial 2012 survey). However, there were no significant differences between the 1st grade students for all three years. Thus, school-based interventions involving psychological testing and interviews might reduce the rates of depression and PTSR in high school students. PMID- 28724854 TI - Improvement of Pulmonary Function after Comprehensive Obesity Rehabilitation Program in Obese Patients. AB - Obesity is a major risk factor of cardiovascular, osteoarthritis, metabolic and pulmonary disorders, and exercise is an efficient method for treating obesity. However, obese patients often complain of dyspnea on exertion, which makes it difficult to continue exercise program. Obesity is also known to have an adverse effect on pulmonary function. The purpose of this study was to examine the effects of a comprehensive obesity rehabilitation (COR) program on pulmonary function in Japanese patients with morbid obesity. We enrolled 29 Japanese obese patients (14 males and 15 females) with BMI > 29 and an average age of 42.2 +/- 11.7 years, who underwent the COR program for 1-3 months. Our COR program included a calorie-restricted diet, nutritional counseling, exercise training, and health education. We focused on the changes in pulmonary function, anticipating that changes in ventilation volume may contribute to improving exercise tolerance. After the intervention, all the subjects had lost weight, with a mean value of 12.0 kg (P < 0.001). We found that the lung volume compartment was significantly increased after our COR program, and that there is a strong positive correlation between a change in expiratory reserve volume and the weight loss (r = 0.74, P < 0.01). Through the COR program, body fat mass was significantly reduced, while the skeletal muscle mass remained more or less unchanged, which is advantageous for improvement in exercise tolerance. In conclusion, our COR program is helpful to improve the pulmonary function of patients with obesity. PMID- 28724855 TI - Decreased Fatty Acid beta-Oxidation Is the Main Cause of Fatty Liver Induced by Polyunsaturated Fatty Acid Deficiency in Mice. AB - Insufficient intake of polyunsaturated fatty acids (PUFA) causes fatty liver. The mechanism responsible is primarily related to increased lipogenesis and decreased FA degradation based on rodent studies. However, these studies were limited by the fact that the typical PUFA-deficient diets contained insufficient amounts of long-chain FA, the PUFA-containing diets were primarily composed of n-3 PUFA enriched oil, and the intake of PUFA was excessive compared with the physiological requirement. To address these issues, mice were fed a PUFA deficient diet containing long-chain FA at a standard fed level and then were orally fed a n-3/n-6-balanced PUFA-containing oil [PUFA (+)] or a PUFA-deficient oil [PUFA (-)] at physiological relevant levels (0.1 mL/mouse/2d). We compared these groups and examined whether fatty liver in PUFA deficiency was attributable to both the effects of increased lipogenesis and decreased FA catabolism. Compared with the PUFA (+) group, the PUFA (-) group showed increases in liver triglyceride and serum FA content. Hepatic gene expression of several mitochondrial beta-oxidation enzymes, the serum 3-hydroxybutyrate level, and DNA binding ability of peroxisome proliferator-activated receptor alpha (PPARalpha) were increased in the PUFA (+) group, whereas these adaptive responses were significantly attenuated in the PUFA (-) group. The hepatic expression of typical lipogenesis genes did not differ between the groups. Therefore, fatty liver in PUFA deficiency is attributable to suppression of the FA-degrading system probably from decreased PPARalpha adaptive responsiveness, and PUFA may be an essential factor for PPARalpha functioning. This finding is helpful for managing clinical situations having a risk of PUFA deficiency. PMID- 28724856 TI - ? PMID- 28724857 TI - ? PMID- 28724859 TI - Relationship between Interdental Spacing and Colonization by Streptococcus mutans in Children. AB - The purpose of this study was to investigate the relationship between interdental spacing in the upper incisors and other associated factors with colonization by Streptococcus mutans in children. A total of 47 children aged between 24 and 36 months with no decayed cavities were enrolled in the study. Models were obtained to evaluate interdental spacing in the upper anterior region. The relationships between S. mutans colonization and number of erupted teeth, interdental spacing, diet, and oral hygiene behavior were investigated. S. mutans was detected in the saliva of 14 children (29.8%). No sociodemographic variable was associated with colonization by S. mutans. Neither number of erupted teeth nor children's age showed an influence on colonization by S. mutans. However, children with interdental spacing in the upper incisors were less likely to show colonization by S. mutans (15.8%) than those without (39.3%). Furthermore, children who ceased breast-and/or bottle-feeding by 15 months of age were less likely to show colonization by S. mutans (22.7%) than those who continued feeding until 19 months of age or more (46.2%). PMID- 28724858 TI - Antibacterial Effect of Azadirachta indica (Neem) or Curcuma longa (Turmeric) against Enterococcus faecalis Compared with That of 5% Sodium Hypochlorite or 2% Chlorhexidine in vitro. AB - The purpose of this study was to compare the antibacterial properties of Azadirachta indica (neem) or Curcuma longa (turmeric) against Enterococcus faecalis with those of 5% sodium hypochlorite or 2% chlorhexidine as root canal irrigants in vitro. The activity of neem, chlorhexidine, sodium hypochlorite, or turmeric against E. faecalis was measured on agar plates using the agar diffusion method. The tube dilution method was used to determine the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of the irrigants used. Chlorhexidine or neem exhibited the greatest antibacterial activity when used as endodontic irrigants against E. faecalis, followed by sodium hypochlorite. No statistically significant difference was observed between neem, sodium hypochlorite, or chlorhexidine. The MIC of neem was 1: 128, which was similar to that of chlorhexidine. The MBC for each of these irrigants was 1: 16. Neem yielded antibacterial activity equivalent to 2% chlorhexidine or sodium hypochlorite against E. faecalis, suggesting that it offers a promising alternative to the other root canal irrigants tested. PMID- 28724860 TI - New Approach to 3D Printing of Facial Prostheses Using Combination of Open Source Software and Conventional Techniques: A Case Report. AB - The wax sculpting of a maxillofacial prosthesis is challenging, time-consuming, and requires great skill. Rapid prototyping (RP) systems allow these hurdles to be overcome by enabling the creation of a customized 3D model of the desired prosthesis. Geomagic and Mimics are the most suitable software programs with which to design such prostheses. However, due to the high cost of these applications and the special training required to operate them, they are not widely used. Additionally, ill-fitting margins and other discrepancies in the final finished products of RP systems are also inevitable. Therefore, this process makes further treatment planning difficult for the maxillofacial prosthodontist. Here, we report the case of a 62-year-old woman who attended our clinic. Initially, she had presented with a right facial defect. This was later diagnosed as a squamous cell carcinoma and resected. The aim of this report is to describe a new technique for the 3D printing of facial prostheses which involves the combined use of open-source software, an RP system, and conventional methods of fabrication. The 3D design obtained was used to fabricate a maxillofacial prosthesis to restore the defect. The patient was happy with the esthetic outcome. This approach is relatively easy and cheap, does not require a high degree of non-medical training, and is beneficial in terms of clinical outcome. PMID- 28724861 TI - Carcinoma of Maxillary Gingiva with Non-specific Cervical Lymph Node Swelling. AB - Swelling of the cervical lymph nodes may indicate lymphadenitis, malignant lymphoma, or metastasis. Lymph nodes larger than 10 mm on computed tomography (CT) are strongly indicative of postoperative metastasis from carcinoma. Here, we report a case of large, inflamed lymph nodes mimicking metastasis. The patient was a 76-year-old woman who experienced discomfort in the left-side maxillary gingiva commencing in August 2011. By September, the area had become painful, causing her to visit the Tokyo Dental College Chiba Hospital, at which time a 75*50-mm swollen ulcer was observed in the maxillary gingiva on the left side. A CT image revealed a neoplastic lesion between the alveolar bone on the left side of the maxilla and the base of the maxillary sinus, together with evidence of osteoclastic activity. The bilateral cervical lymph nodes were Level II and had a uniform interior of approximately 5 mm. The lesion was subsequently excised under general anesthesia. At 34 days postoperatively, CT imaging revealed bilateral 40 mm internal heterogeneous lymphadenopathy at Level II. No inflammation of the maxillary gingiva was observed, however, and blood tests revealed no inflammatory findings. Bilateral cervical lymph node metastasis was diagnosed based on CT and oral cavity observation. Radical neck dissection of left cervical region was performed under general anesthesia. Histopathological examination of the lymph nodes revealed no metastasis at Levels I-V, however. The reason for this increase in lymph node size is discussed. PMID- 28724862 TI - Clinical and Radiographic Success of Electrosurgical Pulpectomy in Primary Teeth. AB - A pulpectomy requires the swift extraction of the inflamed tissue. Moreover, the speed of treatment is especially important in the case of uncooperative children. Conventional pulpectomies, however, often require an extended treatment period, which can therefore cause problems with such patients. Electrosurgical methods have been applied to pulpotomies for a number of years. However, to the best of our knowledge, no studies to date have assessed its application to pulpectomies. The aim of this study was to compare clinical and radiographic success rates over a 6-month follow-up period between conventional and electrosurgical pulpectomies. A total of 50 children aged 4 to 8 years were enrolled in this randomized clinical trial. A pulpectomy of the first and second primary molar teeth was seen as the optimal treatment plan in all these patients. One group was treated using the conventional method (C group, 25 teeth) and the other with electrosurgery (ES group, 25 teeth). The patients were evaluated for the presence of pain, mobility, abscess, sinus tract, erythema, tenderness to percussion, internal and external root resorption, and radiolucency. Clinical and radiographic success rates and total working time were assessed. The Fisher's exact test and Mann-Whitney U-test were used for the statistical analysis. After 6 months of follow-up, the clinical and radiographic success rates were 90.5 and 85.7%, respectively, in the ES group, compared with 88.9 and 72.2%, respectively, in the C group. No statistically significant difference was observed between the two groups (p>0.05). Working time, however, was significantly shorter in the ES group (p<0.001). This suggests that pulpectomy with electrosurgery reduces treatment time, and is therefore quite useful in situations where duration of the treatment course is of crucial concern. PMID- 28724863 TI - Factors Associated with Number of Present Teeth in Adults in Japanese Urban City. AB - The purpose of this study was to identify which factors were associated with number of present teeth (PT) in older adults as their clarification might contribute to maintaining the number of PT in this population. These factors were investigated by means of a questionnaire on oral health condition, general health behavior, and anamnesis of diabetes mellitus together with a dental examination. Data were obtained from a total of 7,741 Japanese subjects (2,623 males and 5,118 females), all of whom were aged 40, 50, or 60 years. Significant differences were observed in the mean number of PT between a positive or negative response to questions on anamnesis of diabetes mellitus, current smoking, and having loose teeth in all age groups in males; significant differences were also observed for current smoking, lower intake of dairy milk products, having loose teeth, no experience of tooth brushing instruction, and poor oral hygiene status in all age groups in females. Stepwise logistic regression analysis revealed having loose teeth (odds ratio [OR], 1.82), gingival swelling (OR, 1.40), an anamnesis of diabetes mellitus (OR, 1.72), current smoking (OR, 1.86), lower intake of dairy milk products (OR, 1.22), preference for salty seasonings (OR, 1.23), frequent sweet intake (OR, 1.29), no experience of tooth brushing instruction (OR, 1.38), and poor oral hygiene (OR, 2.04) as significant risk factors for the number of PT being <24 after adjusting for age and sex. These results indicate that an anamnesis of diabetes mellitus, a history of smoking, the presence of loose teeth, and poor oral hygiene status in a self-reported evaluation of oral health might correlate with <24 PT in older adults. PMID- 28724864 TI - Anatomic and Histological Study of Lingual Nerve and Its Clinical Implications. AB - Although the risk of injuring the lingual nerve in the mandibular molar area during dental treatment is high, it can be repaired by nerve grafting. However, from the perspective of clinical dentistry, the pathway and histomorphometric characteristics of this nerve remain to be documented in detail. The purpose of the present study was to morphologically elucidate the pathway of the lingual nerve to clarify its significance in a clinical setting. A histomorphometric analysis was also performed in consideration of nerve grafting. The vertical distance between the occlusal plane and the superior margin of the lingual nerve showed a gradual decrease from the premolar toward the distal molar area. This suggests that the risk of injuring the lingual nerve increases gradually toward the distal area. The average total fascicular area of the lingual nerve was 1.90 mm2, which was larger than that of the sural nerve. It is the first-choice donor nerve for grafting. Therefore, even though the total fascicular area of the donor nerve is a little smaller than that of the recipient nerve, nerve grafting should be successful. PMID- 28724865 TI - Proposal of a New Index Based on Signal-to-Noise Ratio for Low-contrast Detectability in Computed Tomographic Imaging. AB - The low-contrast detectability of computed tomography (CT) images is commonly evaluated by the contrast-to-noise ratio (CNR) because of its convenience to measure. However, the correlation between CNR and visual detectability is poor because the CNR is a simple index determined by both the contrast of the object and the standard deviation of the image noise. On the other hand, the signal-to noise ratio (SNR), especially SNR based on the statistical decision theory model (SNRS, D) and SNR based on the matched-filter model (SNRM) are considered superior to CNR. In this study, we investigated a new physical image quality index for evaluating low-contrast detectability (SNRA), which is approximately derived from SNRS, D and SNRM. The new index, which was calculated using the object size, contrast of the object and the noise power spectrum, provided good approximations when the diameter of the rod object was equal and >5 mm. The diameter dependency of the SNRA was also found to provide better sensitivity than the sensitivities of CNR and object-specific CNR, similar to SNRS, D and SNRM. The results suggested that the proposed convenient index should be useful for evaluating the low-contrast detectability of CT images. PMID- 28724866 TI - Effect of Reduced Tube Voltage on Diagnostic Accuracy of CT Colonography. AB - The normal tube voltage in computed tomography colonography (CTC) is 120 kV. Some reports indicate that the use of a low tube voltage (lower than 120 kV) technique plays a significant role in reduction of radiation dose. However, to determine whether a lower tube voltage can reduce radiation dose without compromising diagnostic accuracy, an evaluation of images that are obtained while maintaining the volume CT dose index (CTDIvol) is required. This study investigated the effect of reduced tube voltage in CTC, without modifying radiation dose (i.e. constant CTDIvol), on image quality. Evaluation of image quality involved the shape of the noise power spectrum, surface profiling with volume rendering (VR), and receiver operating characteristic (ROC) analysis. The shape of the noise power spectrum obtained with a tube voltage of 80 kV and 100 kV was not similar to the one produced with a tube voltage of 120 kV. Moreover, a higher standard deviation was observed on volume-rendered images that were generated using the reduced tube voltages. In addition, ROC analysis revealed a statistically significant drop in diagnostic accuracy with reduced tube voltage, revealing that the modification of tube voltage affects volume-rendered images. The results of this study suggest that reduction of tube voltage in CTC, so as to reduce radiation dose, affects image quality and diagnostic accuracy. PMID- 28724867 TI - Evaluation of the Patient Exposure in General Radiography for Some Facilities: Comparison with DRL and Evaluation of the Difference among Facilities. AB - The first diagnostic reference levels (DRLs 2015) in Japan were published in June 2015. The purpose of this study was to compare the calculated entrance surface doses with the values of DRLs 2015, and evaluate differences in patient exposure among facilities. Semiconductor dosimeter was installed, and dosimetry was performed using equipment and radiographic condition of each facility. As a result, a dose higher than the value of DRLs 2015 was used in 12 kinds of examination. In child chest examination, the doses of the three facilities (0.26 mGy, 0.28 mGy, 0.60 mGy) exceeded the value of DRLs 2015 (0.2 mGy). Review of the radiographic condition is necessary because the doses exceeding DRLs 2015 tended to have a high current time product. The examination with the largest difference between facilities was the lateral of thoracic spine, with a difference of about 46 times, and the examination with the smallest difference was the ankle joint, with a difference of about three times. When reviewing, it is necessary to focus mainly on examinations that have a large difference between facilities. In the future, it can be said that it is necessary to set diagnostic reference range (DRR) or achievable dose (AD) to understand how high or low dose of the own facility are compared with facilities nationwide. PMID- 28724868 TI - 3. Explanation of the DRLs 2015 Published in Japan. PMID- 28724869 TI - 4. Pathology of Prostate Cancer. PMID- 28724870 TI - Introduction of Measurement Section. PMID- 28724871 TI - Let's Join the Diagnostic Imaging Group and Deeply Explore the Radiation Technology. PMID- 28724872 TI - Learning Advanced Medical Technology and Think about the Future, etc. PMID- 28724873 TI - Points of Attention When Selling a Medical Device for Human to a Veterinary Hospital. PMID- 28724874 TI - Paradigm Shift in Radiological Technology. PMID- 28724875 TI - Idarucizumab: a quick and effective antidote administered prior to coronary artery bypass surgery and mitral valve annuloplasty in a patient treated with dabigatran. PMID- 28724876 TI - Diurnal and nocturnal serum melatonin concentrations after treatment with continuous positive airway pressure in patients with obstructive sleep apnea. AB - INTRODUCTION Melatonin secretion, one of the main factors controlling the sleep wake rhythm, may be disrupted in patients with sleep disorders. OBJECTIVES The aim of the study was to evaluate the profile of circadian melatonin secretion in patients with obstructive sleep apnea (OSA) and to assess the impact of 2-day and 3-month treatment with continuous airway pressure (CPAP) on diurnal and nocturnal serum melatonin levels. PATIENTS AND METHODS Serum melatonin levels were evaluated in 71 untreated patients with OSA and 18 healthy controls at 6 time points: 10 AM, 2 PM, 6 PM, 10 PM, 2 AM, and 6 AM. The measurements were repeated after 2 days and 3 months of CPAP treatment. RESULTS Melatonin secretion rhythm was altered in 25.4% of the patients with OSA. In patients with preserved secretion rhythm, the serum melatonin level was significantly lower at 2 AM and 6 AM, compared with healthy controls: 68.2 pg/ml (interquartile range [IQR], 30.1 109.8 pg/ml) vs 109.1 pg/ml (IQR, 63-167.9 pg/ml), P = 0.02 and 40.8 pg/ml (IQR, 20.8-73.2 pg/ml) vs 67.7 pg/ml (IQR, 32.7-131.7 pg/ml), P = 0.04, respectively. Melatonin levels did not change significantly after the 2-day and 3-month CPAP treatment. However, at 3 months, a shift of the peak melatonin concentration to 2 AM was observed in patients with an altered secretion rhythm. CONCLUSIONS OSA has a significant effect on serum melatonin levels. Neither short-term nor long-term CPAP treatment significantly changes melatonin concentrations; however, our results seem to indicate that a 3-month CPAP treatment may be helpful in restoring the physiological rhythm of melatonin secretion in patients with OSA. PMID- 28724878 TI - Relationship between knowledge of cardiovascular disease risk factors and watching educational television materials. Malopolska CArdiovascular PReventive Intervention Study (M--CAPRI). AB - INTRODUCTION The current guidelines on cardiovascular disease (CVD) prevention in clinical practice emphasizes the importance of education in the media for population--based approaches. OBJECTIVES The aim of the study was to assess the relationship between knowledge of CVD risk factors and watching educational television materials in the adult population. PATIENTS AND METHODS After 22 months of repeated broadcasting of educational television materials, which addressed problems related to CVD, a postal survey was conducted on a random sample of 5000 persons aged 18 years or older. The questionnaire included information on demographics, personal and family history of CVD, educational materials, and knowledge of the risk factors. A multivariate logistic regression was used to assess the relationship between the knowledge of each risk factor and watching educational materials. RESULTS A total of 1129 questionnaires were sent back and used for the analysis. There were 208 participants (18%) who watched the educational materials. The median number of the risk factors listed was 4 (interquartile range, 2-5) for persons who watched the materials and 2 (interquartile range, 0-4) for those who did not watch them. After adjustment for age, sex, education, place of residence, and personal and family history of CVD, the participants who watched the educational materials were 2 to 5 times more likely to have knowledge on particular risk factors, with the exception of hypercholesterolemia for which the relationship was not significant. CONCLUSIONS A strong, plausible relationship revealed by our study supports the idea that in the adult population, better knowledge of CVD risk factors was the effect of watching educational materials. PMID- 28724879 TI - Infectious complications in patients with cardiac implantable electronic devices: risk factors, prevention, and prognosis. AB - INTRODUCTION Cardiac implantable electronic device (CIED) infections still constitute a significant challenge. The knowledge of risk factors for CIED infections is crucial for preventing infections and reducing mortality rates. OBJECTIVES The aim of this study was to assess the risk factors and long-term survival of patients with CIED infections. PATIENTS AND METHODS We analyzed the clinical data of 1837 patients (including 750 [40.9%] patients with CIED infections), who underwent transvenous lead extraction at a single institution between 2006 and 2015. We compared the clinical and procedure-related factors for all types of CIED infections: isolated pocket infection (IPI), isolated lead related infective endocarditis (ILRIE), and lead-related infective endocarditis with coexisting pocket infection (LRIE + PI). We also analyzed long-term survival rates. RESULTS The development of IPI and LRIE + PI depended mainly on age, male sex, number of leads, presence of implantable cardioverter-defibrillator (ICD) or cardiac resynchronization therapy defibrillator (CRT--D), and the number of previous procedures. The factors that determined ILRIE included chronic kidney disease (CKD), ICD/CRT-D, lead loops, and intracardiac lead abrasion. Chronic anticoagulation and antiplatelet treatment protected against the development of infection. Long-term survival was significantly related to age, heart failure, diabetes mellitus, CKD, malignancy, and chronic atrial fibrillation. CONCLUSIONS The development of all types of CIED infection was associated mainly with procedure-related factors, while long--term mortality was dependent on clinical factors. The dissimilarity of factors affecting the development of IPI and ILRIE confirms that there are 2 variants of CIED infection. The protective effects of chronic anticoagulation and antiplatelet treatment should prompt us to consider such therapy in the prevention of CIED infection. PMID- 28724880 TI - Immediate and long-term outcomes of native aortic coarctation and postsurgical aortic recoarctation treated with stent implantation: a single-center experience. AB - INTRODUCTION Stent implantation has become the treatment of choice for native aortic coarctation (CoA) and postsurgical aortic recoarctation (reCoA) in adults and adolescents. OBJECTIVES This study aimed to compare the immediate and long term outcomes of patients with native CoA and postsurgical reCoA who underwent stent implantation in our center. PATIENTS AND METHODS The data of 136 patients with native CoA and reCoA who underwent stent implantation between May 1999 and December 2016 were retrospectively analyzed. The study population was divided into 2 groups: 108 patients with native CoA and 28 patients with reCoA. Clinical and procedural characteristics and immediate and long-term outcomes after the intervention were compared between the groups. The use of antihypertensive drugs was analyzed in all patients. RESULTS There were no significant differences in the clinical characteristics of the study groups. The gradient before the intervention was significantly higher in the native CoA than in the reCoA group (P = 0.011), and the diameter of stenosis before the intervention was smaller in the native CoA group compared with the ReCoA group (P = 0.003). Procedural treatment was successful in 77.8% of the patients with native CoA and 78.5% of those with reCoA. There were no differences in the immediate and long-term outcomes between the groups. The antihypertensive treatment was tapered or discontinued in about 34% of the study population. CONCLUSIONS Stenting is an effective and safe procedure in patients with native CoA and reCoA, with good late outcomes. PMID- 28724881 TI - Effect of carotid endarterectomy on retinal function in asymptomatic patients with hemodynamically significant carotid artery stenosis. AB - INTRODUCTION The corrective effect of carotid endarterectomy (CEA) on impaired ophthalmic artery flow in patients with significant internal carotid artery (ICA) stenosis presenting with ocular ischemic syndrome (ie, symptomatic patients) is well established. However, there is no clear evidence regarding the efficacy of CEA for improvement of neuroretinal function in patients without symptoms of ocular ischemic syndrome. OBJECTIVES We aimed to determine the effects of CEA on retinal function in asymptomatic patients with hemodynamically significant ICA stenosis. PATIENTS AND METHODS We enrolled 46 patients with ICA stenosis referred for CEA. Full-field electroretinogram (ERG), pattern ERG, and pattern visual evoked potentials, as well as optical coherence tomography and ophthalmologic examination of both eyes were performed 1 day before and 3 months after CEA. We analyzed eyes ipsilateral (EIE) and contralateral (ECE) to CEA. RESULTS We observed an increase in several ERG wave parameters in both eye groups, compared with baseline values: rod b-wave amplitudes (P <0.00001 for EIE and P = 0.0001 for ECE); rod-cone a-wave (P = 0.02 for EIE) and b-wave (P = 0.001 for EIE and P = 0.01 for ECE) amplitudes; cone single flash a-wave (P = 0.05 for EIE and P = 0.004 for ECE) and b-wave (P <0.0001 for EIE and P <0.0001 for ECE) amplitudes; cone 30-Hz flicker amplitudes (P = 0.0003 for EIE and P <0.0001 for ECE); and oscillatory potential wave index amplitudes (P <0.00001 for EIE). CONCLUSIONS The amplitudes of the standard full-field ERG were significantly increased following CEA in EIE and, to a lesser extent, in ECE. Multimodality ERG may represent a unique tool for investigating the effects of carotid revascularization on neuroretinal function in asymptomatic patients with ICA stenosis. PMID- 28724882 TI - Using beta-lactam antibiotics in patients with a history of beta-lactam allergy: current concepts. AB - beta-lactams are the most widely used antibiotic family, but they are also the most common cause of drug-induced hypersensitivity reactions. The estimated prevalence of reported penicillin allergy ranges between 9% and 12%, although a high percentage of patients with a history of penicillin allergy have no subsequent reactions on reexposure to beta-lactams. A self-reported penicillin allergy has been associated with antimicrobial resistance, increased cost, intensive care admission, and death, making it essential to establish an accurate diagnosis. In addition to a thorough clinical history, diagnostic methods include skin tests, in vitro tests, and drug-challenge tests. In this review, the diagnosis and management of patients with self-reported penicillin allergy is discussed, including the recently introduced antimicrobial stewardship strategy. PMID- 28724883 TI - Calcium preparations do not inhibit allergic reactions: a randomized controlled trial. AB - INTRODUCTION Massive consumption of dietary supplements, including vitamins and minerals, has recently become a serious health issue in Europe. Their use may negatively affect the pharmacological activity of various medications, including antiallergic drugs. Calcium preparations are commonly used in some European countries as a popular remedy for allergy-related skin reactions, such as itching, erythema, and wheals, as well as insect bites. However, so far there have been no reliable studies to prove their action. OBJECTIVES The aim of this randomized, double-blind, placebo-controlled study was to investigate the efficacy of calcium salts in allergic reactions, using an allergen-induced skin prick test (SPT). PATIENTS AND METHODS Forty adult volunteers with allergic rhinoconjunctivitis or asthma (or both) were recruited to receive oral calcium carbonate (1000 mg) or placebo 3 times a day for 3 days. SPTs were performed with 11 aeroallergen extracts at baseline and at 4 and 72 hours after drug administration. The wheal diameter was measured. We also used the visual analog scale to evaluate the intensity of pruritus. RESULTS There was no difference in the wheal size or pruritus between patients receiving calcium or placebo at any of the time points (P >0.05). Calcium preparations were well tolerated. CONCLUSIONS We found no evidence to support the efficacy of calcium preparations in allergy-related skin reactions associated with itching and wheals. Calcium preparations do not suppress SPT responses; moreover, their use in allergic patients should be discouraged due to their possible interference with the absorption of antiallergic drugs. PMID- 28724884 TI - Effects of Zinc Finger Protein A20 on Lipopolysaccharide (LPS)-Induced Pulmonary Inflammation/Anti-Inflammatory Mediators in an Acute Lung Injury/Acute Respiratory Distress Syndrome Rat Model. AB - BACKGROUND The aim of this study was to investigate the effects of zinc finger protein A20 on lipopolysaccharide (LPS)-induced pulmonary inflammation/anti inflammatory mediators in an acute lung injury/acute respiratory distress syndrome (ALI/ARDS) rat model. MATERIAL AND METHODS Forty-eight ALI/ARDS rats were selected and assigned into normal saline (NS) (injected with NS), LPS (injected with LPS), LPS-C1 (injected with pEGFP-C1, NS and LPS), and A20 groups (injected with pEGFP-C1-A20, NS, and LPS). The wet/dry (W/D) ratio of rat lung tissues and total protein concentration and the number of neutrophils in bronchoalveolar lavage fluid (BALF) were detected. Enzyme-linked immunosorbent assay (ELISA) and qRT-PCR were applied to detect the protein and mRNA expressions of A20, IL-10, and TNF-alpha, respectively. Western blotting was employed to detect the protein expressions of A20, nuclear factor-kappa B (NF-kappaB) p65 and NF-kappaB p-P65 in rat lung tissues. RESULTS Compared with the NS group, the W/D ratio of rat lung tissues and total protein concentration and the number of neutrophils in BALF in the other 3 groups increased significantly. The protein and mRNA expressions of A20, IL-10, and TNF-alpha were significantly higher in the LPS group than in the NS group. The protein and mRNA expressions of A20 and IL-10 were significantly up-regulated and the expression of TNF-alpha, NF-kappaB p65, and NF-kappaB p-P65 was significantly down-regulated in rats injected with A20 compared to those in the LPS group. CONCLUSIONS The study provided evidence that zinc finger protein A20 can alleviate pulmonary inflammation by inhibiting TNF-alpha, NF-kappaB p65, and NF-kappaB p-P65 expressions and promoting IL-10 expression. PMID- 28724885 TI - Invasive Ductal Carcinoma within a Benign Phyllodes Tumor. AB - BACKGROUND Phyllodes tumor (PT) is a rare neoplasm of the breast. Concomitant PT with invasive ductal carcinoma (IDC) is an even rarer occurrence. When ductal carcinoma in situ (DCIS) or IDC are detected within the specimen, the management changes from wide local excision to further staging work-up, including sentinel node biopsy and radiation. CASE REPORT We report the case of a 70-year-old presented with right breast mass whose pathology showed benign PT with concomitant IDC and DCIS. The patient elected for a wide excision of the mass with sentinel lymph node biopsy, which did not show any involvement. The patient was started on appropriate therapy. She is currently doing well. CONCLUSIONS This case highlights the importance of wide local excision for PT as well as prudent histologic examination to rule out other malignant components, as the presence of IDC distinctly changes management. PMID- 28724886 TI - Modulation of RNA primer formation by Mn(II)-substituted T7 DNA primase. AB - Lagging strand DNA synthesis by DNA polymerase requires RNA primers produced by DNA primase. The N-terminal primase domain of the gene 4 protein of phage T7 comprises a zinc-binding domain that recognizes a specific DNA sequence and an RNA polymerase domain that catalyzes RNA polymerization. Based on its crystal structure, the RNA polymerase domain contains two Mg(II) ions. Mn(II) substitution leads to elevated RNA primer synthesis by T7 DNA primase. NMR analysis revealed that upon binding Mn(II), T7 DNA primase undergoes conformational changes near the metal cofactor binding site that are not observed when the enzyme binds Mg(II). A machine-learning algorithm called linear discriminant analysis (LDA) was trained by using the large collection of Mn(II) and Mg(II) binding sites available in the protein data bank (PDB). Application of the model to DNA primase revealed a preference in the enzyme's second metal binding site for Mn(II) over Mg(II), suggesting that T7 DNA primase activity modulation when bound to Mn(II) is based on structural changes in the enzyme. PMID- 28724887 TI - First Ornithomimid (Theropoda, Ornithomimosauria) from the Upper Cretaceous Djadokhta Formation of Togrogiin Shiree, Mongolia. AB - The Upper Cretaceous Djadokhta Formation has been intensively surveyed for its fossil vertebrate fauna for nearly a century. Amongst other theropods, dromaeosaurids and parvicursorines are common in the formation, but ornithomimosaurs are extremely rare. A new ornithomimosaur material was discovered from the Djadokhta Formation, represented by eolian deposits, of the Togrogiin Shiree locality, Mongolia. This is only the third ornithomimosaur specimen reported from this formation, and includes the astragalus, the calcaneum, the third distal tarsal, and a complete pes. The new material is clearly belonged to Ornithomimidae by its arctometatarsalian foot condition and has the following unique characters; unevenly developed pair of concavities of the third distal tarsal, curved contacts between the proximal ends of second and fourth metatarsals, the elongate fourth digit, and a laterally inclined medial condyle on phalanx IV-1. These diagnostic characters of the Djadokhtan ornithomimosaur indicate that this is a new taxon. Our phylogenetic analysis supports three clades within derived ornithomimosaurs, and the new taxon is placed a member of the derived ornithomimosaurs. The present specimen is the first ornithomimid record from eolian Togrogiin Shiree locality, and is indicative of their capability to adapt to arid environments. PMID- 28724888 TI - CrossCheck: an open-source web tool for high-throughput screen data analysis. AB - Modern high-throughput screening methods allow researchers to generate large datasets that potentially contain important biological information. However, oftentimes, picking relevant hits from such screens and generating testable hypotheses requires training in bioinformatics and the skills to efficiently perform database mining. There are currently no tools available to general public that allow users to cross-reference their screen datasets with published screen datasets. To this end, we developed CrossCheck, an online platform for high throughput screen data analysis. CrossCheck is a centralized database that allows effortless comparison of the user-entered list of gene symbols with 16,231 published datasets. These datasets include published data from genome-wide RNAi and CRISPR screens, interactome proteomics and phosphoproteomics screens, cancer mutation databases, low-throughput studies of major cell signaling mediators, such as kinases, E3 ubiquitin ligases and phosphatases, and gene ontological information. Moreover, CrossCheck includes a novel database of predicted protein kinase substrates, which was developed using proteome-wide consensus motif searches. CrossCheck dramatically simplifies high-throughput screen data analysis and enables researchers to dig deep into the published literature and streamline data-driven hypothesis generation. CrossCheck is freely accessible as a web-based application at http://proteinguru.com/crosscheck. PMID- 28724889 TI - Aptamer-mediated survivin RNAi enables 5-fluorouracil to eliminate colorectal cancer stem cells. AB - The development of chemoresistance and inability in elimination of cancer stem cells are among the key limitations of cancer chemotherapy. Novel molecular therapeutic strategies able to overcome such limitations are urgently needed for future effective management of cancer. In this report, we show that EpCAM-aptamer guided survivin RNAi effectively downregulated survivin both in colorectal cancer cells in vitro and in a mouse xenograft model for colorectal cancer. When combined with the conventional chemotherapeutic agents, the aptamer-guided survivin RNAi was able to enhance the sensitivity towards 5-FU or oxaliplatin in colorectal cancer stem cells, increase apoptosis, inhibit tumour growth and improve the overall survival of mice bearing xenograft colorectal cancer. Our results indicate that survivin is one of the key players responsible for the innate chemoresistance of colorectal cancer stem cells. Thus, aptamer-mediated targeting of survivin in cancer stem cells in combination with chemotherapeutic drugs constitutes a new avenue to improve treatment outcome in oncologic clinics. PMID- 28724890 TI - Centrosomal protein 55 activates NF-kappaB signalling and promotes pancreatic cancer cells aggressiveness. AB - Centrosomal protein 55 (CEP55) is a microtubule-bundling protein that participants in cell mitosis. It is overexpressed in several solid tumours and promotes the growth and invasion of cancer cells. However, the role of CEP55 in pancreatic cancer (PANC) remains unclear. Herein, upregulated expression of CEP55 (associated with poor prognosis) was detected in PANC using quantitative real time reverse transcription PCR, western blotting, and immunohistochemistry. Cell migration, colony formation, wound-healing, and Transwell matrix penetration assays, revealed that upregulation of CEP55 promoted PANC cells proliferation, migration, and invasion in vitro, whereas knockdown of CEP55 attenuated it. In an in vivo murine model, CEP55 overexpression accelerated PANC cells tumourigenicity, together with upregulation of the protein levels of invasion related proteins matrix metalloproteinase (MMP)2, MMP9, and proliferation-related protein Cyclin D1. Downregulation of CEP55 had the reverse effect. Moreover, the nuclear factor kappaB (NF-kappaB)/IkappaBalpha signalling pathway, which was activated in CEP55-transduced PANC cells and inhibited in CEP55-silenced PANC cells, contributed to CEP55-mediated PANC cell aggressiveness. This study provided new insights into the oncogenic roles of CEP55 and the mechanism by which the NF-kappaB pathway is hyperactivated in patients with PANC, indicating that CEP55 is a valuable prognostic factor and a potential therapeutic target in PANC. PMID- 28724891 TI - Hypoxia-inducible factor-1 alpha is involved in RIP-induced necroptosis caused by in vitro and in vivo ischemic brain injury. AB - Necroptosis, a novel type of programmed cell death, is involved in stroke-induced ischemic brain injury. Although studies have sought to explore the mechanisms of necroptosis, its signaling pathway has not yet to be completely elucidated. Thus, we used oxygen-glucose deprivation (OGD) and middle cerebral artery occlusion (MCAO) models mimicking ischemic stroke (IS) conditions to investigate mechanisms of necroptosis. We found that OGD and MCAO induced cell death, local brain ischemia and neurological deficit, while zVAD-fmk (zVAD, an apoptotic inhibitor), GSK'872 (a receptor interacting protein kinase-3 (RIP3) inhibitor), and combined treatment alleviated cell death and ischemic brain injury. Moreover, OGD and MCAO upregulated protein expression of the triggers of necroptosis: receptor interacting protein kinase-1 (RIP1), RIP3 and mixed lineage kinase domain-like protein (MLKL). The upregulation of these proteins was inhibited by GSK'872, combination treatments and RIP3 siRNA but not zVAD treatment. Intriguingly, hypoxia-inducible factor-1 alpha (HIF-1alpha), an important transcriptional factor under hypoxic conditions, was upregulated by OGD and MCAO. Similar to their inhibitory effects on aforementioned proteins upregulation, GSK'872, combination treatments and RIP3 siRNA decreased HIF-1alpha protein level. These findings indicate that necroptosis contributes to ischemic brain injury induced by OGD and MCAO and implicate HIF-1alpha, RIP1, RIP3, and MLKL in necroptosis. PMID- 28724892 TI - Sexual and non-sexual social preferences in male and female white-eyed bulbuls. AB - While the function of ornaments shaped by sexual selection is to attract mates or drive off rivals, these signals may also evolve through social selection, in which the social context affects the fitness of signallers and receivers. Classical 'mate choice' experiments often reveal preferences for ornaments, but few studies have considered whether these are strictly sexual or reflect general social preferences. Indeed, an alternative possibility is that ornaments evolve through 'non-sexual social selection' (hereafter 'social selection'). We examined the role of ornamentation (yellow ventral patch) and familiarity (individuals recognize group mates with which they have had previous interactions) on mate choice (opposite-sex stimuli preference) and social choice (same-sex stimuli preference) in both male and female white-eyed bulbuls (Pycnonotus xanthopygos). In the mate choice test, females preferred unfamiliar males with increased yellow. There were no biologically important differences in male preferences based on familiarity or intensity of patch colour. In the social choice test, females preferred to associate with familiar females. Males preferred to associate with familiar males but also preferred to associate with less ornamented males. Our results suggest that ornamentation and familiarity are important features, playing different roles in males and females, in both social and sexual selection processes. PMID- 28724893 TI - The effect of metformin on survival of patients with pancreatic cancer: a meta analysis. AB - We conducted a meta-analysis to analyse the effect of metformin on survival of pancreatic cancer patients at various stages. We performed a systematic search of PubMed, Embase, Cochrane, and Web of Science to identify all relevant studies. Summary hazard ratios (HR) of survival and 95% confidence intervals (95% CI) were calculated with a fixed or random effects model according to inter-study heterogeneity. Nine retrospective cohort studies and two randomized controlled trials (RCTs) were eligible. There was a significant improvement in survival (HR = 0.86, 95% CI 0.76-0.97; P < 0.05) in the metformin group compared with control. Subgroup analysis indicated that metformin improved survival in patients with resection (HR = 0.79, 95% CI 0.69-0.91; P < 0.05) and patients with locally advanced tumors (HR = 0.68, 95% CI 0.55-0.84; P < 0.05) but not in patients with metastatic tumors, even when RCT data were included (HR = 0.99, 95% CI 0.70-1.40; P > 0.05), or were excluded (HR = 0.89, 95% CI 0.61-1.31; P > 0.05). This meta analysis indicated that the effect of metformin does correlate with tumor stage but should be prudently considered given the limited and variable studies performed to data. PMID- 28724894 TI - Self-viewing is associated with negative affect rather than reward in highly narcissistic men: an fMRI study. AB - Subclinical narcissism is a personality trait with two faces: According to social cognitive theories it is associated with grandiosity and feelings of superiority, whereas psychodynamic theories emphasize vulnerable aspects like fluctuating self esteem and emotional conflicts. The psychodynamic view, however, is commonly not supported by self-report studies on subclinical narcissism. Personality neuroscience might help to better understand the phenomenon of narcissism beyond the limits of self-report research. While social-cognitive theory would predict that self-relevant processing should be accompanied by brain activity in reward related areas in narcissistic individuals, psychodynamic theory would suggest that it should be accompanied by activation in regions pointing to negative affect or emotional conflict. In this study, extreme groups of high and low narcissistic individuals performed a visual self-recognition paradigm during fMRI. Viewing one's own face (as compared to faces of friends and strangers) was accompanied by greater activation of the dorsal and ventral anterior cingulate cortex (ACC) in highly narcissistic men. These results suggest that highly narcissistic men experience greater negative affect or emotional conflict during self-relevant processing and point to vulnerable aspects of subclinical narcissism that might not be apparent in self-report research. PMID- 28724895 TI - Efficient two-step photocarrier generation in bias-controlled InAs/GaAs quantum dot superlattice intermediate-band solar cells. AB - We studied the effects of the internal electric field on two-step photocarrier generation in InAs/GaAs quantum dot superlattice (QDSL) intermediate-band solar cells (IBSCs). The external quantum efficiency of QDSL-IBSCs was measured as a function of the internal electric field intensity, and compared with theoretical calculations accounting for interband and intersubband photoexcitations. The extra photocurrent caused by the two-step photoexcitation was maximal for a reversely biased electric field, while the current generated by the interband photoexcitation increased monotonically with increasing electric field intensity. The internal electric field in solar cells separated photogenerated electrons and holes in the superlattice (SL) miniband that played the role of an intermediate band, and the electron lifetime was extended to the microsecond scale, which improved the intersubband transition strength, therefore increasing the two-step photocurrent. There was a trade-off relation between the carrier separation enhancing the two-step photoexcitation and the electric-field-induced carrier escape from QDSLs. These results validate that long-lifetime electrons are key to maximising the two-step photocarrier generation in QDSL-IBSCs. PMID- 28724896 TI - Unprecedented drought over tropical South America in 2016: significantly under predicted by tropical SST. AB - Tropical and sub-tropical South America are highly susceptible to extreme droughts. Recent events include two droughts (2005 and 2010) exceeding the 100 year return value in the Amazon and recurrent extreme droughts in the Nordeste region, with profound eco-hydrological and socioeconomic impacts. In 2015-2016, both regions were hit by another drought. Here, we show that the severity of the 2015-2016 drought ("2016 drought" hereafter) is unprecedented based on multiple precipitation products (since 1900), satellite-derived data on terrestrial water storage (since 2002) and two vegetation indices (since 2004). The ecohydrological consequences from the 2016 drought are more severe and extensive than the 2005 and 2010 droughts. Empirical relationships between rainfall and sea surface temperatures (SSTs) over the tropical Pacific and Atlantic are used to assess the role of tropical oceanic variability in the observed precipitation anomalies. Our results indicate that warmer-than-usual SSTs in the Tropical Pacific (including El Nino events) and Atlantic were the main drivers of extreme droughts in South America, but are unable to explain the severity of the 2016 observed rainfall deficits for a substantial portion of the Amazonia and Nordeste regions. This strongly suggests potential contribution of non-oceanic factors (e.g., land cover change and CO2-induced warming) to the 2016 drought. PMID- 28724897 TI - X-ray crystallographic structure of a bacterial polysialyltransferase provides insight into the biosynthesis of capsular polysialic acid. AB - Polysialic acid (polySia) is a homopolymeric saccharide that is associated with some neuroinvasive pathogens and is found on selective cell types in their eukaryotic host. The presence of a polySia capsule on these bacterial pathogens helps with resistance to phagocytosis, cationic microbial peptides and bactericidal antibody production. The biosynthesis of bacterial polySia is catalysed by a single polysialyltransferase (PST) transferring sialic acid from a nucleotide-activated donor to a lipid-linked acceptor oligosaccharide. Here we present the X-ray structure of the bacterial PST from Mannheimia haemolytica serotype A2, thereby defining the architecture of this class of enzymes representing the GT38 family. The structure reveals a prominent electropositive groove between the two Rossmann-like domains forming the GT-B fold that is suitable for binding of polySia chain products. Complex structures of PST with a sugar donor analogue and an acceptor mimetic combined with kinetic studies of PST active site mutants provide insight into the principles of substrate binding and catalysis. Our results are the basis for a molecular understanding of polySia biosynthesis in bacteria and might assist the production of polysialylated therapeutic reagents and the development of novel antibiotics. PMID- 28724899 TI - Carrier dynamics of Mn-induced states in GaN thin films. AB - GaN-based materials are widely used for light emission devices, but the intrinsic property of wide bandgap makes it improper for photovoltaic applications. Recently, manganese was doped into GaN for absorption of visible light, and the conversion efficiency of GaN-based solar cells has been greatly improved. We conducted transient optical measurements to study the carrier dynamics of Mn doped GaN. The lifetime of carriers in the Mn-related intermediate bands (at 1.5 eV above the valence band edge) is around 1.7 ns. The carrier relaxation within the Mn-induced bandtail states was on the order of a few hundred picoseconds. The relaxation times of different states are important parameters for optimization of conversion efficiency for intermediate-band solar cells. PMID- 28724898 TI - Improvement in the production of the human recombinant enzyme N acetylgalactosamine-6-sulfatase (rhGALNS) in Escherichia coli using synthetic biology approaches. AB - Previously, we demonstrated production of an active recombinant human N acetylgalactosamine-6-sulfatase (rhGALNS) enzyme in Escherichia coli as a potential therapeutic alternative for mucopolysaccharidosis IVA. However, most of the rhGALNS produced was present as protein aggregates. Here, several methods were investigated to improve production and activity of rhGALNS. These methods involved the use of physiologically-regulated promoters and alternatives to improve protein folding including global stress responses (osmotic shock), overexpression of native chaperones, and enhancement of cytoplasmic disulfide bond formation. Increase of rhGALNS activity was obtained when a promoter regulated under sigma s was implemented. Additionally, improvements were observed when osmotic shock was applied. Noteworthy, overexpression of chaperones did not have any effect on rhGALNS activity, suggesting that the effect of osmotic shock was probably due to a general stress response and not to the action of an individual chaperone. Finally, it was observed that high concentrations of sucrose in conjunction with the physiological-regulated promoter proU mod significantly increased the rhGALNS production and activity. Together, these results describe advances in the current knowledge on the production of human recombinant enzymes in a prokaryotic system such as E. coli, and could have a significant impact on the development of enzyme replacement therapies for lysosomal storage diseases. PMID- 28724900 TI - Enhanced differential expression statistics for data-independent acquisition proteomics. AB - We describe a new reproducibility-optimization method ROPECA for statistical analysis of proteomics data with a specific focus on the emerging data independent acquisition (DIA) mass spectrometry technology. ROPECA optimizes the reproducibility of statistical testing on peptide-level and aggregates the peptide-level changes to determine differential protein-level expression. Using a 'gold standard' spike-in data and a hybrid proteome benchmark data we show the competitive performance of ROPECA over conventional protein-based analysis as well as state-of-the-art peptide-based tools especially in DIA data with consistent peptide measurements. Furthermore, we also demonstrate the improved accuracy of our method in clinical studies using proteomics data from a longitudinal human twin study. PMID- 28724901 TI - Real-Time and Label-Free Chemical Sensor-on-a-chip using Monolithic Si-on-BaTiO3 Mid-Infrared waveguides. AB - Chip-scale chemical detection is demonstrated by using mid-Infrared (mid-IR) photonic circuits consisting of amorphous silicon (a-Si) waveguides on an epitaxial barium titanate (BaTiO3, BTO) thin film. The highly c-axis oriented BTO film was grown by the pulsed laser deposition (PLD) method and it exhibits a broad transparent window from lambda = 2.5 MUm up to 7 MUm. The waveguide structure was fabricated by the complementary metal-oxide-semiconductor (CMOS) process and a sharp fundamental waveguide mode has been observed. By scanning the spectrum within the characteristic absorption regime, our mid-IR waveguide successfully perform label-free monitoring of various organic solvents. The real time heptane detection is accomplished by measuring the intensity attenuation at lambda = 3.0-3.2 MUm, which is associated with -CH absorption. While for methanol detection, we track the -OH absorption at lambda = 2.8-2.9 MUm. Our monolithic Si on-BTO waveguides establish a new sensor platform that enables integrated photonic device for label-free chemical detection. PMID- 28724902 TI - Human pursuance of equality hinges on mental processes of projecting oneself into the perspectives of others and into future situations. AB - In the pursuance of equality, behavioural scientists disagree about distinct motivators, that is, consideration of others and prospective calculation for oneself. However, accumulating data suggest that these motivators may share a common process in the brain whereby perspectives and events that did not arise in the immediate environment are conceived. To examine this, we devised a game imitating a real decision-making situation regarding redistribution among income classes in a welfare state. The neural correlates of redistributive decisions were examined under contrasting conditions, with and without uncertainty, which affects support for equality in society. The dorsal anterior cingulate cortex (dACC) and the caudate nucleus were activated by equality decisions with uncertainty but by selfless decisions without uncertainty. Activation was also correlated with subjective values. Activation in both the dACC and the caudate nucleus was associated with the attitude to prefer accordance with others, whereas activation in the caudate nucleus reflected that the expected reward involved the prospective calculation of relative income. The neural correlates suggest that consideration of others and prospective calculation for oneself may underlie the support for equality. Projecting oneself into the perspective of others and into prospective future situations may underpin the pursuance of equality. PMID- 28724903 TI - Co-expression network analysis of toxin-antitoxin loci in Mycobacterium tuberculosis reveals key modulators of cellular stress. AB - Research on toxin-antitoxin loci (TA loci) is gaining impetus due to their ubiquitous presence in bacterial genomes and their observed roles in stress survival, persistence and drug tolerance. The present study investigates the expression profile of all the seventy-nine TA loci found in Mycobacterium tuberculosis. The bacterium was subjected to multiple stress conditions to identify key players of cellular stress response and elucidate a TA-coexpression network. This study provides direct experimental evidence for transcriptional activation of each of the seventy-nine TA loci following mycobacterial exposure to growth-limiting environments clearly establishing TA loci as stress-responsive modules in M. tuberculosis. TA locus activation was found to be stress-specific with multiple loci activated in a duration-based response to a particular stress. Conditions resulting in arrest of cellular translation led to greater up regulation of TA genes suggesting that TA loci have a primary role in arresting translation in the cell. Our study identifed higBA2 and vapBC46 as key loci that were activated in all the conditions tested. Besides, relBE1, higBA3, vapBC35, vapBC22 and higBA1 were also upregulated in multpile stresses. Certain TA modules exhibited co-activation across multiple conditions suggestive of a common regulatory mechanism. PMID- 28724904 TI - Hypertonic saline infusion suppresses apoptosis of hippocampal cells in a rat model of cardiopulmonary resuscitation. AB - Hypertonic saline (HS) attenuates cerebral edema, improves microcirculation perfusion and alleviates inflammation. However, whether the beneficial effect of HS on neurological function after cardiopulmonary resuscitation (CPR) in rat model of asphyxial cardiac arrest (CA) is mediated via attenuating apoptosis of neurons is not known. We studied the neuroprotective effect of HS in rats after CA and CPR, and explored the likely underlying mechanisms. Animals were randomly assigned to 4 equal groups (n = 15 each) according to the different infusions administered during resuscitation: control (C), normal saline (NS), hypertonic saline (HS), and hydroxyethyl starch (HES) groups. NDS at 12, 24, 48 and 72 h post-ROSC in the HS group were significantly higher than those in the NS and HES groups. Western blot analysis demonstrated a significant increase in Bcl-2 expression in HS, as compared to that in the NS and HES groups. However, Bax and Caspase-3 expressions in HS were significantly lower than that in the NS and HES groups. The apoptosis rate in HS was significantly lower than that in the NS and HES groups, suggesting HS treatment during resuscitation could effectively suppress neuronal cell apoptosis in hippocampal CA1 post-ROSC and improve neuronal function. PMID- 28724905 TI - Flowering time in banana (Musa spp.), a day neutral plant, is controlled by at least three FLOWERING LOCUS T homologues. AB - Banana is an important day neutral food crop with a long flowering/fruiting cycle that is affected by hot summers or cold winters in different places. Manipulating its life cycle requires an understanding of its flowering time machinery to bypass these stresses. Twelve FLOWERING LOCUS T (FT) and two TWIN SISTER OF FT (TSF) members were isolated from banana and their organization and expression pattern studied during development in two varieties that differ in flowering time namely Grand Nain (AAA genotype) and Hill banana (AAB genotype). The expression of at least 3 genes namely MaFT1, MaFT2 and MaFT5 (and to some extent MaFT7) increases just prior to initiation of flowering. These four genes and five others (MaFT3, MaFT4, MaFT8, MaFT12 and MaTSF1 could suppress the delayed flowering defect in the Arabidopsis ft-10 mutant and induce early flowering upon over expression in the Col-0 ecotype. Most genes are diurnally regulated and differentially expressed during development and in various vegetative and reproductive tissues suggesting roles besides flowering. Subtle amino acid changes in these FT/TSF-like proteins provide interesting insights into the structure/function relationships of banana FTs vis-a-vis Arabidopsis. The studies provide a means for manipulation of flowering in banana for better management of resources and to reduce losses through abiotic stresses. PMID- 28724906 TI - Reciprocal carbonyl-carbonyl interactions in small molecules and proteins. AB - Carbonyl-carbonyl n->pi* interactions where a lone pair (n) of the oxygen atom of a carbonyl group is delocalized over the pi* orbital of a nearby carbonyl group have attracted a lot of attention in recent years due to their ability to affect the 3D structure of small molecules, polyesters, peptides, and proteins. In this paper, we report the discovery of a "reciprocal" carbonyl-carbonyl interaction with substantial back and forth n->pi* and pi->pi* electron delocalization between neighboring carbonyl groups. We have carried out experimental studies, analyses of crystallographic databases and theoretical calculations to show the presence of this interaction in both small molecules and proteins. In proteins, these interactions are primarily found in polyproline II (PPII) helices. As PPII are the most abundant secondary structures in unfolded proteins, we propose that these local interactions may have implications in protein folding.Carbonyl carbonyl pi* non covalent interactions affect the structure and stability of small molecules and proteins. Here, the authors carry out experimental studies, analyses of crystallographic databases and theoretical calculations to describe an additional type of carbonyl-carbonyl interaction. PMID- 28724907 TI - Measuring the olfactory bulb input-output transformation reveals a contribution to the perception of odorant concentration invariance. AB - Humans and other animals can recognize an odorant as the same over a range of odorant concentrations. It remains unclear whether the olfactory bulb, the brain structure that mediates the first stage of olfactory information processing, participates in generating this perceptual concentration invariance. Olfactory bulb glomeruli are regions of neuropil that contain input and output processes: olfactory receptor neuron nerve terminals (input) and mitral/tufted cell apical dendrites (output). Differences between the input and output of a brain region define the function(s) carried out by that region. Here we compare the activity signals from the input and output across a range of odorant concentrations. The output maps maintain a relatively stable representation of odor identity over the tested concentration range, even though the input maps and signals change markedly. These results provide direct evidence that the mammalian olfactory bulb likely participates in generating the perception of concentration invariance of odor quality.Humans and animals recognize an odorant across a range of odorant concentrations, but where in the olfactory processing pathway this invariance is generated is unclear. By measuring and comparing olfactory bulb outputs to inputs, the authors show that the olfactory bulb participates in generating the perception of odorant concentration invariance. PMID- 28724908 TI - Design and discovery of novel monastrol-1,3,5-triazines as potent anti-breast cancer agent via attenuating Epidermal Growth Factor Receptor tyrosine kinase. AB - A novel series of hybrid analogues of monastrol-1,3,5-triazine were designed and developed via one-pot synthesis using Bi(NO3)3 as a catalyst. Entire compounds were evaluated for their anticancer activity against HeLa (cervical cancer), MCF 7 (breast cancer), HL-60 (Human promyelocytic leukemia), HepG2 (Hepatocellular carcinoma) and MCF 12A (normal epithelial breast cell line) using MTT assay, where they showed highest inhibitory activity against MCF-7. The molecules were also found to be non-toxic to MCF 12A cells. These molecules showed considerable inhibitory percentage against Epidermal Growth Factor Receptor tyrosine kinase (EGFR-TK), in in-vitro assay. Molecular docking study was carried out on the analogs and reference compound (Erlotinib) into the ATP binding site of EGFR-TK domain (PDB ID:1M17) to elucidate vital structural residues necessary for bioactivity. The effect of most active compound 7l was also estimated in-vivo in DMBA induced mammary tumor in female Sprague-Dawley rats. The effect of anti breast cancer effect of 7l was quantified on the basis of tumour incidence, body weight and tumor volume in DMBA-induced rats. Its effect on biochemical parameters, such as antioxidant status (SOD, CAT, GPX and GSH) and lipid peroxidation was also studied. The compound 7l showed inhibition of EGFR downstream signalling in the western blot analysis. PMID- 28724909 TI - Investigation of pyrophosphate versus ATP substrate selection in the Entamoeba histolytica acetate kinase. AB - Acetate kinase (ACK; E.C. 2.7.2.1), which catalyzes the interconversion of acetate and acetyl phosphate, is nearly ubiquitous in bacteria but is present only in one genus of archaea and certain eukaryotic microbes. All ACKs utilize ATP/ADP as the phosphoryl donor/acceptor in the respective directions of the reaction (acetate + ATP [Formula: see text] acetyl phosphate + ADP), with the exception of the Entamoeba histolytica ACK (EhACK) which uses pyrophosphate (PPi)/inorganic phosphate (Pi) (acetyl phosphate + Pi [Formula: see text] acetate + PPi). Structural analysis and modeling of EhACK indicated steric hindrance by active site residues constricts entry to the adenosine pocket as compared to ATP-utilizing Methanosarcina thermophila ACK (MtACK). Reciprocal alterations were made to enlarge the adenosine pocket of EhACK and reduce that of MtACK. The EhACK variants showed a step-wise increase in ADP and ATP binding but were still unable to use these as substrates, and enzymatic activity with Pi/PPi was negatively impacted. Consistent with this, ATP utilization by MtACK variants was negatively affected but the alterations were not sufficient to convert this enzyme to Pi/PPi utilization. Our results suggest that controlling access to the adenosine pocket can contribute to substrate specificity but is not the sole determinant. PMID- 28724910 TI - Investigating glycemic potential of rice by unraveling compositional variations in mature grain and starch mobilization patterns during seed germination. AB - Rice lines with slower starch digestibility provide opportunities in mitigating the global rise in type II diabetes and related non-communicable diseases. However, screening for low glycemic index (GI) in rice breeding programs is not possible due to time and cost constraints. This study evaluated the feasibility of using in vitro cooked grain amylolysis, starch mobilization patterns during seed germination, and variation in starch structure and composition in the mature seed to differentiate patterns of starch digestibility. Mobilization patterns of total starch, resistant starch, amylose and amylopectin chains, and free sugars during seed germination revealed that the process is analogous to digestion in the human gastrointestinal tract. The combination of these biochemical markers can be used as an alternative measure to predict GI. Additionally, transcriptome analysis of stored mRNA transcripts in high and low GI lines detected differences in starch metabolism and confirmed the importance of seed storage pathways in influencing digestibility. Pathway analyses supported by metabolomics data revealed that resistant starch, cell wall non-starch polysaccharides and flavonoids potentially contribute to slower digestibility. These new insights can guide precision breeding programs to produce low GI rice with acceptable cooking quality to help mitigate the burden of diet-associated lifestyle diseases. PMID- 28724911 TI - Honokiol inhibits c-Met-HO-1 tumor-promoting pathway and its cross-talk with calcineurin inhibitor-mediated renal cancer growth. AB - Honokiol (HNK) is a small molecule with potent anti-inflammatory and anti tumorigenic properties; yet the molecular targets of HNK are not well studied. Hyperactivation of the receptor tyrosine kinase c-Met and overexpression of the cytoprotective enzyme heme oxygenase-1 (HO-1) play a critical role in the growth and progression of renal cell carcinoma (RCC). Interestingly, the calcineurin inhibitor (CNI) cyclosporine A (CsA), an immunosuppressant used to prevent allograft rejection, can also increase the risk of RCC in transplant patients. We studied the potential role of c-Met signaling axis on CNI-induced renal tumor growth and tested the anti-tumor efficacy of HNK. Importantly, CNI treatment promoted c-Met induction and enhanced c-Met-induced Ras activation. We found that HNK treatment effectively down-regulated both c-Met phosphorylation and Ras activation in renal cancer cells. It inhibited the expression of both c-Met- and CNI-induced HO-1, and promoted cancer cell apoptosis. In vivo, HNK markedly inhibited CNI-induced renal tumor growth; and it decreased the expression of phospho-c-Met and HO-1 and reduced blood vessel density in tumor tissues. Our results suggest a novel mechanism(s) by which HNK exerts its anti-tumor activity through the inhibition of c-Met-Ras-HO-1 axis; and it can have significant therapeutic potential to prevent post-transplantation cancer in immunosuppressed patients. PMID- 28724912 TI - Annual variations of monsoon and drought detected by GPS: A case study in Yunnan, China. AB - The Global Positioning System (GPS) records monsoonal precipitable water vapor (PWV) and vertical crustal displacement (VCD) due to hydrological loading, and can thus be applied jointly to diagnose meteorological and hydrological droughts. We have analyzed the PWV and VCD observations during 2007.0-2015.0 at 26 continuous GPS stations located in Yunnan province, China. We also obtained equivalent water height (EWH) derived from the Gravity Recovery And Climate Experiment (GRACE) and precipitation at these stations with the same period. Then, we quantified the annual variations of PWV, precipitation, EWH and VCD and provided empirical relationships between them. We found that GPS-derived PWV and VCD (positive means downward movement) are in phase with precipitation and GRACE derived EWH, respectively. The annual signals of VCD and PWV show linearly correlated amplitudes and a two-month phase lag. Furthermore, the results indicate that PWV and VCD anomalies can also be used to explore drought, such as the heavy drought during winter/spring 2010. Our analysis results verify the capability of GPS to monitor monsoon variations and drought in Yunnan and show that a more comprehensive understanding of the characteristics of regional monsoon and drought can be achieved by integrating GPS-derived PWV and VCD with precipitation and GRACE-derived EWH. PMID- 28724913 TI - Time-averaged disease activity fits better joint destruction in rheumatoid arthritis. AB - Disease activity of rheumatoid arthritis (RA), evaluated as Disease Activity Score (DAS), is associated with joint destruction. Since joint destruction reflects the history of disease activities, we hypothesized that time-averaged disease activity would better correlate with joint destruction than one-time disease activity. We recruited RA patients in IORRA (n = 557) and KURAMA (n = 204) cohorts, and calculated time-averaged DAS28 to model a modified Sharp/van der Heijde score (SHS). We evaluated the fitting of the model using time-averaged DAS28 among 1000 models in which we randomly picked up one-time DAS28. We also used clinical disease activity index (CDAI) or data in the BeSt study (European population). After conditioning on autoantibody and disease duration, time averaged DAS28 showed significant improvement of model fitting compared with one time DAS28 in both cohorts (p = 0.001 and 0.034, respectively). Time-averaged CDAI also showed a better fit. Integration of multiple DAS fit SHS better in the BeSt study. A good fit of time-averaged DAS could be observed using five to six time points of DAS. In conclusion, time-averaged disease activity fits the joint destruction model better than one-time disease activity. Usage of time-averaged disease activity as a covariate would increase the power of studies to identify novel correlates of joint destruction. PMID- 28724914 TI - Enhanced Learning through Multimodal Training: Evidence from a Comprehensive Cognitive, Physical Fitness, and Neuroscience Intervention. AB - The potential impact of brain training methods for enhancing human cognition in healthy and clinical populations has motivated increasing public interest and scientific scrutiny. At issue is the merits of intervention modalities, such as computer-based cognitive training, physical exercise training, and non-invasive brain stimulation, and whether such interventions synergistically enhance cognition. To investigate this issue, we conducted a comprehensive 4-month randomized controlled trial in which 318 healthy, young adults were enrolled in one of five interventions: (1) Computer-based cognitive training on six adaptive tests of executive function; (2) Cognitive and physical exercise training; (3) Cognitive training combined with non-invasive brain stimulation and physical exercise training; (4) Active control training in adaptive visual search and change detection tasks; and (5) Passive control. Our findings demonstrate that multimodal training significantly enhanced learning (relative to computer-based cognitive training alone) and provided an effective method to promote skill learning across multiple cognitive domains, spanning executive functions, working memory, and planning and problem solving. These results help to establish the beneficial effects of multimodal intervention and identify key areas for future research in the continued effort to improve human cognition. PMID- 28724915 TI - Quinolinate Phosphoribosyltransferase is an Antiviral Host Factor Against Hepatitis C Virus Infection. AB - HCV infection can decrease NAD+/NADH ratio, which could convert lipid metabolism to favor HCV replication. In hepatocytes, quinolinate phosphoribosyl transferase (QPRT) catabolizes quinolinic acid (QA) to nicotinic acid mononucleotide (NAMN) for de novo NAD synthesis. However, whether and how HCV modulates QPRT hence the lipogenesis is unknown. In this work, we found QPRT was reduced significantly in livers of patients or humanized C/OTg mice with persistent HCV infection. Mechanistic studies indicated that HCV NS3/4A promoted proteasomal degradation of QPRT through Smurf2, an E3 ubiquitin-protein ligase, in Huh7.5.1 cells. Furthermore, QPRT enzymatic activity involved in suppression of HCV replication in cells. Activation of QPRT with clofibrate (CLO) or addition of QPRT catabolite NAD both inhibited HCV replication in cells, probably through NAD+-dependent Sirt1 inhibition of cellular lipogenesis. More importantly, administration of CLO, a hypolipidemic drug used in clinics, could significantly reduce the viral load in HCV infected C/OTg mice. Take together, these results suggested that HCV infection triggered proteasomal degradation of QPRT and consequently reduced de novo NAD synthesis and lipogenesis, in favor of HCV replication. Hepatic QPRT thus likely served as a cellular factor that dampened productive HCV replication. PMID- 28724916 TI - Involvement of the p62/NRF2 signal transduction pathway on erythrophagocytosis. AB - Erythrophagocytosis, the phagocytic removal of damaged red blood cells (RBC), and subsequent phagolysosome biogenesis are important processes in iron/heme metabolism and homeostasis. Phagolysosome biogenesis implies the interaction of nascent phagosomes with endocytic compartments and also autophagy effectors. Here, we report that besides recruitment of microtubule-associated protein-1 light chain 3 (LC3), additional autophagy machinery such as sequestosome 1 (p62) is also acquired by single-membrane phagosomes at very early stages of the phagocytic process and that its acquisition is very important to the outcome of the process. In bone marrow-derived macrophages (BMDM) silenced for p62, RBC degradation is inhibited. P62, is also required for nuclear translocation and activation of the transcription factor Nuclear factor E2-related Factor 2 (NRF2) during erythrophagocytosis. Deletion of the Nrf2 allele reduces p62 expression and compromises RBC degradation. In conclusion, we reveal that erythrophagocytosis relies on an interplay between p62 and NRF2, potentially acting as protective mechanism to maintain reactive oxygen species at basal levels and preserve macrophage homeostasis. PMID- 28724917 TI - Endocannabinoids Have Opposing Effects On Behavioral Responses To Nociceptive And Non-nociceptive Stimuli. AB - The endocannabinoid system is thought to modulate nociceptive signaling making it a potential therapeutic target for treating pain. However, there is evidence that endocannabinoids have both pro- and anti-nociceptive effects. In previous studies using Hirudo verbana (the medicinal leech), endocannabinoids were found to depress nociceptive synapses, but enhance non-nociceptive synapses. Here we examined whether endocannabinoids have similar bidirectional effects on behavioral responses to nociceptive vs. non-nociceptive stimuli in vivo. Hirudo were injected with either the 2-arachidonoylglycerol (2-AG) or anandamide and tested for changes in response to nociceptive and non-nociceptive stimuli. Both endocannabinoids enhanced responses to non-nociceptive stimuli and reduced responses to nociceptive stimuli. These pro- and anti-nociceptive effects were blocked by co-injection of a TRPV channel inhibitor, which are thought to function as an endocannabinoid receptor. In experiments to determine the effects of endocannabinoids on animals that had undergone injury-induced sensitization, 2 AG and anandamide diminished sensitization to nociceptive stimuli although the effects of 2-AG were longer lasting. Sensitized responses to non-nociceptive stimuli were unaffected 2-AG or anandamide. These results provide evidence that endocannabinoids can have opposing effects on nociceptive vs. non-nociceptive pathways and suggest that cannabinoid-based therapies may be more appropriate for treating pain disorders in which hyperalgesia and not allodynia is the primary symptom. PMID- 28724918 TI - Contrast enhancement of biological nanoporous materials with zinc oxide infiltration for electron and X-ray nanoscale microscopy. AB - We show that using infiltration of ZnO metal oxide can be useful for high resolution imaging of biological samples in electron and X-ray microscopy. The method is compatible with standard fixation techniques that leave the sample dry, such as finishing with super critical CO2 drying, or simple vacuum drying up to 95 degrees C. We demonstrate this technique can be applied on tooth and brain tissue samples. We also show that high resolution X-ray tomography can be performed on biological systems using Zn K edge (1s) absorption to enhance internal structures, and obtained the first nanoscale 10 KeV X-ray absorption images of the interior regions of a tooth. PMID- 28724919 TI - Generally Applicable Transformation Protocols for Fluorescent Nanodiamond Internalization into Cells. AB - Fluorescent nanodiamonds (FNDs) are promising nanoprobes, owing to their stable and magnetosensitive fluorescence. Therefore they can probe properties as magnetic resonances, pressure, temperature or strain. The unprecedented sensitivity of diamond defects can detect the faint magnetic resonance of a single electron or even a few nuclear spins. However, these sensitivities are only achieved if the diamond probe is close to the molecules that need to be detected. In order to utilize its full potential for biological applications, the diamond particle has to enter the cell. Some model systems, like HeLa cells, readily ingest particles. However, most cells do not show this behavior. In this article we show for the first time generally applicable methods, which are able to transport fluorescent nanodiamonds into cells with a thick cell wall. Yeast cells, in particular Saccharomyces cerevisiae, are a favored model organism to study intracellular processes including aging on a cellular level. In order to introduce FNDs in these cells, we evaluated electrical transformation and conditions of chemical permeabilization for uptake efficiency and viability. 5% DMSO (dimethyl sulfoxide) in combination with optimized chemical transformation mix leads to high uptake efficiency in combination with low impact on cell biology. We have evaluated all steps in the procedure. PMID- 28724920 TI - Interleukin-36beta provides protection against HSV-1 infection, but does not modulate initiation of adaptive immune responses. AB - Interleukin-36 (IL-36) represents three cytokines, IL-36alpha, IL-36beta and IL 36gamma, which bind to the same receptor, IL-1RL2; however, their physiological function(s) remain poorly understood. Here, the role of IL-36 in immunity against HSV-1 was examined using the flank skin infection mouse model. Expression analyses revealed increased levels of IL-36alpha and IL-36beta mRNA in infected skin, while constitutive IL-36gamma levels remained largely unchanged. In human keratinocytes, IL-36alpha mRNA was induced by HSV-1, while IL-1beta and TNFalpha increased all three IL-36 mRNAs. The dominant alternative splice variant of human IL-36beta mRNA was isoform 2, which is the ortholog of the known mouse IL-36beta mRNA. Mice deficient in IL-36beta, but not IL-36alpha or IL-36gamma, succumbed more frequently to HSV-1 infection than wild type mice. Furthermore, IL-36beta-/- mice developed larger zosteriform skin lesions along infected neurons. Levels of HSV-1 specific antibodies, CD8+ cells and IFNgamma-producing CD4+ cells were statistically equal in wild type and IL-36beta-/- mice, suggesting similar initiation of adaptive immunity in the two strains. This correlated with the time at which HSV-1 genome and mRNA levels in primary skin lesions started to decline in both wild type and IL-36beta-/- mice. Our data indicate that IL-36beta has previously unrecognized functions protective against HSV-1 infection. PMID- 28724921 TI - Saliva and tooth biofilm bacterial microbiota in adolescents in a low caries community. AB - The oral cavity harbours a complex microbiome that is linked to dental diseases and serves as a route to other parts of the body. Here, the aims were to characterize the oral microbiota by deep sequencing in a low-caries population with regular dental care since childhood and search for association with caries prevalence and incidence. Saliva and tooth biofilm from 17-year-olds and mock bacteria communities were analysed using 16S rDNA Illumina MiSeq (v3-v4) and PacBio SMRT (v1-v8) sequencing including validity and reliability estimates. Caries was scored at 17 and 19 years of age. Both sequencing platforms revealed that Firmicutes dominated in the saliva, whereas Firmicutes and Actinobacteria abundances were similar in tooth biofilm. Saliva microbiota discriminated caries affected from caries-free adolescents, with enumeration of Scardovia wiggsiae, Streptococcus mutans, Bifidobacterium longum, Leptotrichia sp. HOT498, and Selenomonas spp. in caries-affected participants. Adolescents with B. longum in saliva had significantly higher 2-year caries increment. PacBio SMRT revealed Corynebacterium matruchotii as the most prevalent species in tooth biofilm. In conclusion, both sequencing methods were reliable and valid for oral samples, and saliva microbiota was associated with cross-sectional caries prevalence, especially S. wiggsiae, S. mutans, and B. longum; the latter also with the 2-year caries incidence. PMID- 28724922 TI - HD 66051, an eclipsing binary hosting a highly peculiar, HgMn-related star. AB - HD 66051 is an eclipsing system with an orbital period of about 4.75 d that exhibits out-of-eclipse variability with the same period. New multicolour photometric observations confirm the longevity of the secondary variations, which we interpret as a signature of surface inhomogeneities on one of the components. Using archival and newly acquired high-resolution spectra, we have performed a detailed abundance analysis. The primary component is a slowly rotating late B type star (T eff = 12500 +/- 200 K; log g = 4.0, v sin i = 27 +/- 2 km s-1) with a highly peculiar composition reminiscent of the singular HgMn-related star HD 65949, which seems to be its closest analogue. Some light elements as He, C, Mg, Al are depleted, while Si and P are enhanced. Except for Ni, all the iron-group elements, as well as most of the heavy elements, and in particular the REE elements, are overabundant. The secondary component was estimated to be a slowly rotating A-type star (T eff ~ 8000 K; log g = 4.0, v sin i ~ 18 km s-1). The unique configuration of HD 66051 opens up intriguing possibilities for future research, which might eventually and significantly contribute to the understanding of such diverse phenomena as atmospheric structure, mass transfer, magnetic fields, photometric variability and the origin of chemical anomalies observed in HgMn stars and related objects. PMID- 28724923 TI - Contrasting evolutionary patterns between two haplogroups of Haematobia exigua (Diptera: Muscidae) from the mainland and islands of Southeast Asia. AB - Uncovering the hidden diversity and evolutionary history of arthropods of medico veterinary importance could have significant implications for vector-borne disease control and epidemiological intervention. The buffalo fly Haematobia exigua is an obligate bloodsucking ectoparasite of livestock. As an initial step towards understanding its population structures and biogeographic patterns, we characterized partial cytochrome c oxidase subunit I (COI) and cytochrome b (Cytb) sequences of H. exigua from three distinct geographic regions in Southeast Asia. We detected two distinct mitochondrial haplogroups of H. exigua in our surveyed geographic regions. Haplogroup I is widespread in the Southeast Asian mainland whereas haplogroup II is generally restricted to the type population Java Island. Both haplogroups were detected co-occurring on Borneo Island. Additionally, both haplogroups have undergone contrasting evolutionary histories, with haplogroup I exhibited a high level of mitochondrial diversity indicating a population expansion during the Pleistocene era dating back to 98,000 years ago. However, haplogroup II presented a low level of mitochondrial diversity which argues against the hypothesis of recent demographic expansion. PMID- 28724924 TI - Neuron-autonomous transcriptome changes upon ischemia/reperfusion injury. AB - Ischemic stroke and the following reperfusion, an acute therapeutic intervention, can cause irreversible brain damages. However, the underlying pathological mechanisms are still under investigation. To obtain a comprehensive, real-time view of the cell-autonomous mechanisms involved in ischemic stroke and reperfusion, we applied the next-generation sequencing (NGS) technology to characterize the temporal changes in gene expression profiles using primarily cultured hippocampal neurons under an oxygen-glucose deprivation/reperfusion (OGD/R) condition. We first identified the differentially expressed genes (DEGs) between normal cultured neurons, neurons with OGD, and neurons with OGD followed by reperfusion for 6 h, 12 h, and 18 h, respectively. We then performed bioinformatics analyses, including gene ontological (GO) and pathway analysis and co-expression network analysis to screen for novel key pathways and genes involved in the pathology of OGD/R. After we confirmed the changes of selected key genes in hippocampal cultures with OGD/R, we further validated their expression changes in an in vivo ischemic stroke model (MCAO). Finally, we demonstrated that prevention of the up-regulation of a key gene (Itga5) associated with OGD/R promoted hippocampal neuronal survival. Our research thereby provided novel insights into the molecular mechanisms in ischemic stroke pathophysiology and potential targets for therapeutic intervention after ischemic stroke. PMID- 28724925 TI - A comparative study of five physiological key parameters between four different human trophoblast-derived cell lines. AB - The human placenta plays a crucial role as the interface between mother and fetus. It represents a unique tissue that undergoes morphological as well as functional changes on the cellular and tissue level throughout pregnancy. To better understand how the placenta works, a variety of techniques has been developed to re-create this complex physiological barrier in vitro. However, due to the low availability of freshly isolated primary cells, choriocarcinoma cell lines remain the usual suspects as in vitro models for placental research. Here, we present a comparative study on the functional aspects of the choriocarcinoma cell lines BeWo, JAR and Jeg-3, as well as the first trimester trophoblast cell line ACH-3P as placental in vitro barrier models for endocrine and transport studies. Functional assays including tight junction immunostaining, sodium fluorescein retardation, trans epithelial resistance, glucose transport, hormone secretion as well as size-dependent polystyrene nanoparticle transport were performed using the four cell types to evaluate key functional parameters of each cell line to act a relevant in vitro placental barrier model. PMID- 28724926 TI - Enhanced anti-metastatic and anti-tumorigenic efficacy of Berbamine loaded lipid nanoparticles in vivo. AB - Research on metastasis is gaining momentum for effective cancer management. Berbamine (BBM) has the potency to act as a therapeutic in multiple cancers and cancer metastasis. However, the major limitation of the compound includes poor bioavailability at the tumor site due to short plasma half-life. Here, our major objective involved development of lipid based nanoparticles (NPs) loaded with BBM with an aim to circumvent the above problem. Moreover its, therapeutic potentiality was evaluated through various in vitro cellular studies and in vivo melanoma primary and experimental lung metastatic tumor model in C57BL/6 mice. Results of different cellular experiments demonstrated enhanced therapeutic efficacy of BBM-NPs in inhibiting metastasis, cell proliferation and growth as compared to native BBM in highly metastatic cancer cell lines. Further, in vivo results demonstrated suppression of primary B16F10 melanoma tumor growth in C57BL/6 mice model treated with BBM-NPs than that of native BBM. Importantly, a moderately cytotoxic dose of BBM-NPs was able to significantly suppress the incidence of B16F10 cells lung metastasis in vivo. Results indicated development of an effective approach for aggressive metastatic cancer. PMID- 28724927 TI - Dual functionality nanobioconjugates targeting intracellular bacteria in cancer cells with enhanced antimicrobial activity. AB - Bacterial drug resistance has emerged as a serious global threat mandating the development of novel methodologies that allow facile modulation of antimicrobial action in a controlled fashion. Conjugating antibiotics to nanoparticles helps to meet this goal by increasing the drug's overall avidity, bioavailability and easier internalisation into mammalian cells, targeting bacteria that otherwise escape antibacterial action by host cell-localisation. We used polymyxin B sulfate (PMB) and sushi peptide as model drugs against Gram-negative bacteria and established their enhanced antimicrobial activity on Escherichia coli (E. coli) cells after conjugation to gold nanoparticles (AuNPs). The efficacy of the bioconjugates was also tested on Salmonella typhi (S. typhi) bacteria infected into cervical cancer cells (HeLa) and further improved through specific targeting via folate receptors. Our results demonstrate significantly lower inhibitory concentration values for sushi-NP assemblies as compared to free drug, especially at optimal drug loading levels. No major cytotoxicity was observed in mammalian cells alone. PMID- 28724928 TI - On wakefulness fluctuations as a source of BOLD functional connectivity dynamics. AB - Human brain dynamics and functional connectivity fluctuate over a range of temporal scales in coordination with internal states and environmental demands. However, the neurobiological significance and consequences of functional connectivity dynamics during rest have not yet been established. We show that the coarse-grained clustering of whole-brain dynamic connectivity measured with magnetic resonance imaging reveals discrete patterns (dynamic connectivity states) associated with wakefulness and sleep. We validate this using EEG in healthy subjects and patients with narcolepsy and by matching our results with previous findings in a large collaborative database. We also show that drowsiness may account for previous reports of metastable connectivity states associated with different levels of functional integration. This implies that future studies of transient functional connectivity must independently monitor wakefulness. We conclude that a possible neurobiological significance of dynamic connectivity states, computed at a sufficiently coarse temporal scale, is that of fluctuations in wakefulness. PMID- 28724929 TI - Risk factors for prolonged hypotension in patients with pheochromocytoma undergoing laparoscopic adrenalectomy: a single-center retrospective study. AB - Prolonged hypotension during pheochromocytoma resection is a significant complication. We sought to investigate the predictors of prolonged hypotension in patients with pheochromocytoma undergoing laparoscopic adrenalectomy (LA). Patients with pheochromocytoma who underwent LA between 2012 and 2015 were surveyed. Patients were considered to have prolonged hypotension if they had a mean arterial blood pressure <60 mmHg or required >=30 consecutive minutes of catecholamine support intraoperatively. Among 123 patients, 54 (43.9%) developed prolonged hypotension requiring >=30 consecutive minutes of catecholamine support. Compared with patients with nonprolonged hypotension, those with prolonged hypotension had higher levels of urinary norepinephrine (P = 0.011), epinephrine (P < 0.001), and dopamine (P = 0.019) preoperatively, and a higher incidence of vital organ injury postoperatively (P = 0.039). Multivariate logistic analysis showed that independent predictors for prolonged hypotension were multiples of the normal reference upper limit value of urinary epinephrine (odds ratio, 1.180; 95% confidence interval, 1.035-1.345) and dopamine (odds ratio, 4.375; 95% confidence interval, 1.207-15.855). The levels of preoperative urinary epinephrine and dopamine are clinical predictors for prolonged hypotension in patients with pheochromocytoma undergoing LA. Using these parameters, clinicians can assess and manage this patient population more effectively. PMID- 28724930 TI - Assessment of different techniques for 3D superimposition of serial digital maxillary dental casts on palatal structures. AB - Serial 3-dimensional dental model superimposition provides a risk-free, detailed evaluation of morphological alterations on a patient's mouth. Here, we evaluated accuracy and precision of five palatal areas, used for superimposition of maxillary 3D digital dental casts. Sixteen pre- and post-orthodontic treatment dental casts of growing patients (median time lapse: 15.1 months) were superimposed on each palatal area using the iterative closest point algorithm. Area A (medial 2/3 of the third rugae and a small area dorsal to them) was considered the gold standard, due to high anatomical stability. Areas B, C, and D added a distal extension along the midpalatal raphe, an anterior extension to the second rugae, and the remaining palatal surface, respectively. Area E was similar to A, located more posteriorly. Non parametric multivariate models showed minimal or no effect on accuracy and precision by operator, time point, or software settings. However, the choice of superimposition area resulted in statistically significant differences in accuracy and clinically significant differences in detected tooth movement (95% limits of agreement exceeding 1 mm and 3 degrees ). Superimposition on area A provided accurate, reproducible, and precise results. Outcomes were comparable for area B, but deteriorated when alternative areas were used. PMID- 28724931 TI - Assessing the shock state of the lunar highlands: Implications for the petrogenesis and chronology of crustal anorthosites. AB - Our understanding of the formation and evolution of the primary lunar crust is based on geochemical systematics from the lunar ferroan anorthosite (FAN) suite. Recently, much effort has been made to understand this suite's petrologic history to constrain the timing of crystallisation and to interpret FAN chemical diversity. We investigate the shock histories of lunar anorthosites by combining Optical Microscope (OM) 'cold' cathodoluminescence (CL)-imaging and Fourier Transform Infrared (FTIR) spectroscopy analyses. In the first combined study of its kind, this study demonstrates that over ~4.5 Ga of impact processing, plagioclase is on average weakly shocked (<15 GPa) and examples of high shock states (>30 GPa; maskelynite) are uncommon. To investigate how plagioclase trace element systematics are affected by moderate to weak shock (~5 to 30 GPa) we couple REE+Y abundances with FTIR analyses for FAN clasts from lunar meteorite Northwest Africa (NWA) 2995. We observe weak correlations between plagioclase shock state and some REE+Y systematics (e.g., La/Y and Sm/Nd ratios). This observation could prove significant to our understanding of how crystallisation ages are evaluated (e.g., plagioclase-whole rock Sm-Nd isochrons) and for what trace-elements can be used to differentiate between lunar lithologies and assess magma source compositional differences. PMID- 28724932 TI - Simultaneous Identification of Ten Bacterial Pathogens Using the Multiplex Ligation Reaction Based on the Probe Melting Curve Analysis. AB - Pathogenic Vibrio spp., Aeromonas spp. and Plesiomonas shigelloides are associated with human gastroenteritis and wound infections, as well as fish diseases. The comprehensive and accurate identification of these pathogens is crucial for the current public health. The present study describes the development of a multiplex assay for the simultaneous identification of ten bacterial pathogens in a single reaction by using a multiplex ligation reaction based on probe melting curve analysis (MLMA). The specificity for target genes was 100%, as assessed with a panel of 67 bacterial pathogens, which indicated no cross-reactions. The detection limit of this assay ranged from 0.8 * 107 CFU/mL to 1.5 * 108 CFU/mL at the pure bacterial culture level and from 0.1 ng to 1.0 ng at the DNA level. The MLMA assay was used to detect ten species of pathogens in 269 clinical and seafood samples, and for further validation, the results were compared with the conventional culture method. The results indicated greater than 90% sensitivity and 100% specificity for each bacterial pathogen tested, and the kappa correlation for all the pathogens ranged from 0.95 to 1.00. Overall, this assay is well suited for public health laboratories for its high throughput, accuracy, and low cost. PMID- 28724933 TI - Derivative Technology of DNA Barcoding (Nucleotide Signature and SNP Double Peak Methods) Detects Adulterants and Substitution in Chinese Patent Medicines. AB - Lonicerae japonicae Flos has been used to produce hundred kinds of Chinese patent medicines (CPMs) in China. Economically motivated adulterants have been documented, leading to market instability and a decline in consumer confidence. ITS2 has been used to identify raw medicinal materials, but it's not suitable for the identification of botanical extracts and complex CPMs. Therefore, a short barcode for the identification of processed CPMs would be profitable. A 34 bp nucleotide signature (5' CTAGCGGTGGTCGTACGATAGCCAATGCATGAGT 3') was developed derived from ITS2 region of Eucommiae Folium based on unique motifs. Mixtures of powdered Lonicerae japonicae Flos and Lonicerae Flos resulted in double peaks at the expected SNP (Single Nucleotide Polymorphisms) positions, of which the height of the peaks were roughly indicative of the species' ratio in the mixed powder. Subsequently we tested 20 extracts and 47 CPMs labelled as containing some species of Lonicera. The results revealed only 17% of the extracts and 22% of the CPMs were authentic, others exist substitution or adulterant; 7% were shown to contain both of two adulterants Eucommiae Folium and Lonicerae Flos. The methods developed in this study will widely broaden the application of DNA barcode in quality assurance of natural health products. PMID- 28724934 TI - Full-color, large area, transmissive holograms enabled by multi-level diffractive optics. AB - We show that multi-level diffractive microstructures can enable broadband, on axis transmissive holograms that can project complex full-color images, which are invariant to viewing angle. Compared to alternatives like metaholograms, diffractive holograms utilize much larger minimum features (>10 um), much smaller aspect ratios (<0.2) and thereby, can be fabricated in a single lithography step over relatively large areas (>30 mm *30 mm). We designed, fabricated and characterized holograms that encode various full-color images. Our devices demonstrate absolute transmission efficiencies of >86% across the visible spectrum from 405 nm to 633 nm (peak value of about 92%), and excellent color fidelity. Furthermore, these devices do not exhibit polarization dependence. Finally, we emphasize that our devices exhibit negligible absorption and are phase-only holograms with high diffraction efficiency. PMID- 28724935 TI - Histone deacetylase 3 is required for iNKT cell development. AB - NKT cells are a distinct subset that have developmental requirements that often differ from conventional T cells. Here, we show that NKT-specific deletion of Hdac3 results in a severe reduction in the number of iNKT cells, particularly of NKT1 cells. In addition, there is decreased cytokine production by Hdac3 deficient NKT2 and NKT17 cells. Hdac3-deficient iNKT cells have increased cell death that is not rescued by transgenic expression of Bcl-2 or Bcl-xL. Hdac3 deficient iNKT cells have less Cyto-ID staining and lower LC3A/B expression, indicative of reduced autophagy. Interestingly, Hdac3-deficient iNKT cells also have lower expression of the nutrient receptors GLUT1, CD71 and CD98, which would increase the need for autophagy when nutrients are limiting. Therefore, Hdac3 is required for iNKT cell development and differentiation. PMID- 28724937 TI - Bootstrap quantification of estimation uncertainties in network degree distributions. AB - We propose a new method of nonparametric bootstrap to quantify estimation uncertainties in functions of network degree distribution in large ultra sparse networks. Both network degree distribution and network order are assumed to be unknown. The key idea is based on adaptation of the "blocking" argument, developed for bootstrapping of time series and re-tiling of spatial data, to random networks. We first sample a set of multiple ego networks of varying orders that form a patch, or a network block analogue, and then resample the data within patches. To select an optimal patch size, we develop a new computationally efficient and data-driven cross-validation algorithm. The proposed fast patchwork bootstrap (FPB) methodology further extends the ideas for a case of network mean degree, to inference on a degree distribution. In addition, the FPB is substantially less computationally expensive, requires less information on a graph, and is free from nuisance parameters. In our simulation study, we show that the new bootstrap method outperforms competing approaches by providing sharper and better-calibrated confidence intervals for functions of a network degree distribution than other available approaches, including the cases of networks in an ultra sparse regime. We illustrate the FPB in application to collaboration networks in statistics and computer science and to Wikipedia networks. PMID- 28724936 TI - An engineered protein antagonist of K-Ras/B-Raf interaction. AB - Ras is at the hub of signal transduction pathways controlling cell proliferation and survival. Its mutants, present in about 30% of human cancers, are major drivers of oncogenesis and render tumors unresponsive to standard therapies. Here we report the engineering of a protein scaffold for preferential binding to K-Ras G12D. This is the first reported inhibitor to achieve nanomolar affinity while exhibiting specificity for mutant over wild type (WT) K-Ras. Crystal structures of the protein R11.1.6 in complex with K-Ras WT and K-Ras G12D offer insight into the structural basis for specificity, highlighting differences in the switch I conformation as the major defining element in the higher affinity interaction. R11.1.6 directly blocks interaction with Raf and reduces signaling through the Raf/MEK/ERK pathway. Our results support greater consideration of the state of switch I and provide a novel tool to study Ras biology. Most importantly, this work makes an unprecedented contribution to Ras research in inhibitor development strategy by revealing details of a targetable binding surface. Unlike the polar interfaces found for Ras/effector interactions, the K-Ras/R11.1.6 complex reveals an extensive hydrophobic interface that can serve as a template to advance the development of high affinity, non-covalent inhibitors of K-Ras oncogenic mutants. PMID- 28724938 TI - A Novel Role for RARalpha Agonists as Apolipoprotein CIII Inhibitors Identified from High Throughput Screening. AB - Elevated triglyceride (TG) levels are well-correlated with the risk for cardiovascular disease (CVD). Apolipoprotein CIII (ApoC-III) is a key regulator of plasma TG levels through regulation of lipolysis and lipid synthesis. To identify novel regulators of TG levels, we carried out a high throughput screen (HTS) using an ApoC-III homogenous time resolved fluorescence (HTRF) assay. We identified several retinoic acid receptor (RAR) agonists that reduced secreted ApoC-III levels in human hepatic cell lines. The RARalpha specific agonist AM580 inhibited secreted ApoC-III by >80% in Hep3B cells with an EC50 ~2.9 nM. In high fat diet induced fatty-liver mice, AM580 reduced ApoC-III levels in liver as well as in plasma (~60%). In addition, AM580 treatment effectively reduced body weight, hepatic and plasma TG, and total cholesterol (TC) levels. Mechanistically, AM580 suppresses ApoC-III synthesis by downregulation of HNF4alpha and upregulation of SHP1 expression. Collectively, these studies suggest that an RARalpha specific agonist may afford a new strategy for lipid lowering and CVD risk reduction. PMID- 28724939 TI - Fatty Acid Uptake in T Cell Subsets Using a Quantum Dot Fatty Acid Conjugate. AB - Fatty acid (FA) metabolism directly influences the functional capabilities of T cells in tumor microenvironments. Thus, developing tools to interrogate FA-uptake by T cell subsets is important for understanding tumor immunosuppression. Herein, we have generated a novel FA-Qdot 605 dye conjugate with superior sensitivity and flexibility to any of the previously commercially available alternatives. For the first time, we demonstrate that this nanoparticle can be used as a specific measure of fatty acid uptake by T cells both in-vitro and in-vivo. Flow cytometric analysis shows that both the location and activation status of T cells determines their FA uptake. Additionally, CD4+ Foxp3+ regulatory T cells (Tregs) uptake FA at a higher rate than effector T cell subsets, supporting the role of FA metabolism for Treg function. Furthermore, we are able to simultaneously detect glucose and fatty acid uptake directly within the tumor microenvironment. Cumulatively, our results suggest that this novel fluorescent probe is a powerful tool to understand FA utilization within the tumor, thereby providing an unprecedented opportunity to study T cell FA metabolism in-vivo. PMID- 28724940 TI - Dispersive 2D Cherenkov radiation on a dielectric nano-film. AB - We report a modified two-dimensional Cherenkov radiation, which occurs on a high index dielectric nano-film driven by uniformly moving electron-beam. It is essentially different from the ordinary Cherenkov radiation in that, in the nondispersive medium, it shows unique dispersion characteristics-the waves with higher frequencies radiate at larger Cherenkov angles. Its radiation frequency and direction are essentially determined by structure parameters as well as the beam-velocity. By means of fully electromagnetic simulations and theoretical analyses, we explored the mechanism and requirements of this radiation. This new Cherenkov radiation may lead to promising applications in a broad range of fields. PMID- 28724941 TI - Novel small RNA spike-in oligonucleotides enable absolute normalization of small RNA-Seq data. AB - Normalization of high-throughput small RNA sequencing (sRNA-Seq) data is required to compare sRNA levels across different samples. Commonly used relative normalization approaches can cause erroneous conclusions due to fluctuating small RNA populations between tissues. We developed a set of sRNA spike-in oligonucleotides (sRNA spike-ins) that enable absolute normalization of sRNA-Seq data across independent experiments, as well as the genome-wide estimation of sRNA:mRNA stoichiometries when used together with mRNA spike-in oligonucleotides. PMID- 28724942 TI - Physiological oxygen tension reduces hepatocyte dedifferentiation in in vitro culture. AB - Primary hepatocytes cultured in vitro are a powerful tool to study the functions of hepatocytes and to evaluate the metabolism and toxicity of new drugs. However, in vitro culture of hepatocytes has proven to be very difficult. Ordinary culture conditions lead to dedifferentiation of hepatocytes, resulting in rapid change in cell morphology and significant reduction in specific cell functions. In the current study, we show that hepatocyte dedifferentiation is a rapid process under 21% O2 conditions. Hepatocytes cultured in 21% O2 undergo epithelial-to mesenchymal transition (EMT), obtain fibroblast-like morphology, and show decreased hepatic functions. In contrast, 5% O2 is very effective in maintaining the epithelial morphology and many functions of the primary hepatocytes cultured in vitro for up to five days. These functions include albumin production, glycogen storage, LDL-uptake and CYP450-mediated drug metabolism. Furthermore, we find that 5% O2 can relieve the production of reactive oxygen species (ROS) and decrease the level of DNA damage in primary cultured hepatocytes. In addition, we also show that blocking the ERK and GSK-3beta pathways can inhibit the dedifferentiation of hepatocytes to a certain extent. Lowering the oxygen tension in cell culture is easily achievable, we believe it could be combined with other methods, such as the use of small molecule cocktails and 3D culture, to maintain proliferation and functions of primary hepatocytes in vitro. PMID- 28724943 TI - AIM2 Inflammasome-Mediated Pyroptosis in Enterovirus A71-Infected Neuronal Cells Restricts Viral Replication. AB - Encephalomyelitis is a well-known complication of hand, foot, and mouth disease (HFMD) due to Enterovirus 71 (EV71) infection. Viral RNA/antigens could be detected in the central nervous system (CNS) neurons in fatal encephalomyelitis but the mechanisms of neuronal cell death is not clearly understood. We investigated the role of absent in melanoma 2 (AIM2) inflammasome in neuronal cell death, and its relationship to viral replication. Our transcriptomic analysis, RT-qPCR, Western blot, immunofluorescence and flow cytometry studies consistently showed AIM2 gene up-regulation and protein expression in EV-A71 infected SK-N-SH cells. Downstream AIM2-induced genes, CARD16, caspase-1 and IL 1beta were also up-regulated and caspase-1 was activated to form cleaved caspase 1 p20 subunits. As evidenced by 7-AAD positivity, pyroptosis was confirmed in infected cells. Overall, these findings have a strong correlation with decreases in viral titers, copy numbers and proteins, and reduced proportions of infected cells. AIM2 and viral antigens were detected by immunohistochemistry in infected neurons in inflamed areas of the CNS in EV-A71 encephalomyelitis. In infected AIM2-knockdown cells, AIM2 and related downstream gene expressions, and pyroptosis were suppressed, resulting in significantly increased virus infection. These results support the notion that AIM2 inflammasome-mediated pyroptosis is an important mechanism of neuronal cell death and it could play an important role in limiting EV-A71 replication. PMID- 28724944 TI - Non-Mono-Exponential Analysis of Diffusion-Weighted Imaging for Treatment Monitoring in Prostate Cancer Bone Metastases. AB - Diffusion-weighted imaging quantified using the mono-exponential model has shown great promise for monitoring treatment response in prostate cancer bone metastases. The aim of this prospective study is to evaluate whether non-mono exponential diffusion models better describe the water diffusion properties and may improve treatment response assessment. Diffusion-weighted imaging data of 12 treatment-naive patients with 34 metastases acquired before and at one, two, and three months after initiation of antiandrogen treatment are analysed using the mono-exponential, the intravoxel incoherent motion, the stretched exponential, and the statistical model. Repeatability of the fitted parameters and changes under therapy are quantified. Model preference is assessed and correlation coefficients across times are calculated to delineate the relationship between the prostate-specific antigen levels and the diffusion parameters as well as between the diffusion parameters within each model. There is a clear preference for non-mono-exponential diffusion models at all time points. Particularly the stretched exponential is favoured in approximately 60% of the lesions. Its parameters increase significantly in response to treatment and are highly repeatable. Thus, the stretched exponential may be utilized as a potential optimal model for monitoring treatment response. Compared with the mono exponential model, it may provide complementary information on tissue properties and improve response assessment. PMID- 28724945 TI - Effect of septal flash on right ventricular systolic function in left bundle branch block patients with preserved left ventricular ejection fraction. AB - A leftward motion of the ventricular septum prior to ejection, known as the septal flash (SF), is frequently observed in patients with left bundle-branch block (LBBB). We investigated whether the abnormal motion of the ventricular septum affects right ventricle (RV) contractile performance in LBBB patients with preserved left ventricular ejection fraction (LVEF). Forty-four patients with complete LBBB were selected using standard 12-lead electrocardiograms (ECGs), with 30 healthy individuals serving as controls. According to the presence of SF, patients with LBBB were allocated to two subgroups: those with SF (LBBB-SF, n = 24) and those without SF (LBBB-NSF, n = 20). RV longitudinal strain (LS) decreased in LBBB patients with preserved LVEF compared to control subjects (p = 0.002). And RV LS decreased significantly in LBBB-SF patients compared to NSF LBBB patients (p = 0.04). RV LS correlated negatively with involved septal myocardial segments of SF (r = -0.36, p = 0.02), but did not correlate with the magnitude of SF. RV contractile performance deceased in LBBB patients with preserved LVEF. SF, particularly the extent of this phenomenon, may further affect RV contractile performance. PMID- 28724946 TI - Diastolic Augmentation Index Improves Radial Augmentation Index in Assessing Arterial Stiffness. AB - Arterial stiffness is an important risk factor for cardiovascular events. Radial augmentation index (AI r ) can be more conveniently measured compared with carotid-femoral pulse wave velocity (cfPWV). However, the performance of AI r in assessing arterial stiffness is limited. This study proposes a novel index AI rd , a combination of AI r and diastolic augmentation index (AI d ) with a weight alpha, to achieve better performance over AI r in assessing arterial stiffness. 120 subjects (43 +/- 21 years old) were enrolled. The best-fit alpha is determined by the best correlation coefficient between AI rd and cfPWV. The performance of the method was tested using the 12-fold cross validation method. AI rd (r = 0.68, P < 0.001) shows a stronger correlation with cfPWV and a narrower prediction interval than AI r (r = 0.61, P < 0.001), AI d (r = -0.17, P = 0.06), the central augmentation index (AI c ) (r = 0.61, P < 0.001) or AI c normalized for heart rate of 75 bpm (r = 0.65, P < 0.001). Compared with AI r (age, P < 0.001; gender, P < 0.001; heart rate, P < 0.001; diastolic blood pressure, P < 0.001; weight, P = 0.001), AI rd has fewer confounding factors (age, P < 0.001; gender, P < 0.001). In conclusion, AI rd derives performance improvement in assessing arterial stiffness, with a stronger correlation with cfPWV and fewer confounding factors. PMID- 28724947 TI - Marker-trait association analysis of frost tolerance of 672 worldwide pea (Pisum sativum L.) collections. AB - Frost stress is one of the major abiotic stresses causing seedling death and yield reduction in winter pea. To improve the frost tolerance of pea, field evaluation of frost tolerance was conducted on 672 diverse pea accessions at three locations in Northern China in three growing seasons from 2013 to 2016 and marker-trait association analysis of frost tolerance were performed with 267 informative SSR markers in this study. Sixteen accessions were identified as the most winter-hardy for their ability to survive in all nine field experiments with a mean survival rate of 0.57, ranging from 0.41 to 0.75. Population structure analysis revealed a structured population of two sub-populations plus some admixtures in the 672 accessions. Association analysis detected seven markers that repeatedly had associations with frost tolerance in at least two different environments with two different statistical models. One of the markers is the functional marker EST1109 on LG VI which was predicted to co-localize with a gene involved in the metabolism of glycoproteins in response to chilling stress and may provide a novel mechanism of frost tolerance in pea. These winter-hardy germplasms and frost tolerance associated markers will play a vital role in marker-assisted breeding for winter-hardy pea cultivar. PMID- 28724948 TI - Transgenic Chickens Expressing the 3D8 Single Chain Variable Fragment Protein Suppress Avian Influenza Transmission. AB - The 3D8 single chain variable fragment (scFv) is a mini-antibody that causes unusual sequence-independent nuclease activity against all types of nucleic acids. We used recombinant lentiviruses to generate transgenic chickens expressing the 3D8 scFv gene under the control of the chicken beta-actin promoter. From 420 injected embryos, 200 chicks (G0) hatched and were screened for the 3D8 scFv using PCR, and 15 chicks were identified as transgenic birds expressing the transgene in their semen. The G0 founder birds were mated with wild-type hens to produce seven transgenic chicks (G1). 3D8 scFv expression in the chicken embryonic fibroblasts (CEFs) was verified by RT-PCR and Western blot analysis. Immunofluorescence staining for 3D8 scFv in the CEFs revealed that the 3D8 scFv protein was primarily cytosolic. To identify 3D8 scFv anti-viral activity, wild-type and two transgenic CEF lines were infected with H9N2 avian influenza virus (AIV). We selected one line of transgenic chickens that exhibited the lowest number of plaque-forming units to be challenged with H9N2 virus. The challenge experiment revealed that contact exposed transgenic chickens expressing 3D8 scFv exhibited suppressed viral shedding. This results suggest that the transgenic chickens developed in this study could be useful for controlling potential within-flock AIV transmission. PMID- 28724949 TI - Overexpression of SlPRE2, an atypical bHLH transcription factor, affects plant morphology and fruit pigment accumulation in tomato. AB - The basic helix-loop-helix (bHLH) proteins are a large family of transcription factors that control various developmental processes in eukaryotes, but the biological roles of most bHLH proteins are not very clear, especially in tomato. In this study, a PRE-like atypical bHLH gene was isolated and designated as SlPRE2 in tomato. SlPRE2 was highly expressed in immature-green fruits, moderately in young leaves, flowers, and mature-green fruits. To further research the function of SlPRE2, a 35 S:PRE2 binary vector was constructed and transformed into wild type tomato. The transgenic plants showed increased leaf angle and stem internode length, rolling leaves with decreased chlorophyll content. The water loss rate of detached leaves was increased in young transgenic lines but depressed in mature leaves. Besides, overexpression of SlPRE2 promoted morphogenesis in seedling development, producing light-green unripening fruits and yellowing ripen fruits with reduced chlorophyll and carotenoid accumulation in pericarps, respectively. Quantitative RT-PCR analysis showed that expression of the chlorophyll related genes, such as GOLDEN 2-LIKE and RbcS, were decreased in unripening 35 S:PRE2 fruit, and carotenoid biosynthesis-related genes PHYTOENE SYNTHASE1A and zeta-CAROTENE DESATURASE in ripening fruit were also down regulated. These results suggest that SlPRE2 affects plant morphology and is a negative regulator of fruit pigment accumulation. PMID- 28724950 TI - Nanocapsules Containing Neem (Azadirachta Indica) Oil: Development, Characterization, And Toxicity Evaluation. AB - In this study, we prepared, characterized, and performed toxicity analyses of poly(epsilon-caprolactone) nanocapsules loaded with neem oil. Three formulations were prepared by the emulsion/solvent evaporation method. The nanocapsules showed a mean size distribution around 400 nm, with polydispersity below 0.2 and were stable for 120 days. Cytotoxicity and genotoxicity results showed an increase in toxicity of the oleic acid + neem formulations according to the amount of oleic acid used. The minimum inhibitory concentrations demonstrated that all the formulations containing neem oil were active. The nanocapsules containing neem oil did not affect the soil microbiota during 300 days of exposure compared to the control. Phytotoxicity studies indicated that NC_20 (200 mg of neem oil) did not affect the net photosynthesis and stomatal conductance of maize plants, whereas use of NC_10 (100:100 of neem:oleic acid) and NC_15 (150:50 of neem:oleic acid) led to negative effects on these physiological parameters. Hence, the use of oleic acid as a complement in the nanocapsules was not a good strategy, since the nanocapsules that only contained neem oil showed lower toxicity. These results demonstrate that evaluation of the toxicity of nanopesticides is essential for the development of environmentally friendly formulations intended for applications in agriculture. PMID- 28724952 TI - Global alterations in areas of suitability for maize production from climate change and using a mechanistic species distribution model (CLIMEX). AB - At the global level, maize is the third most important crop on the basis of harvested area. Given its importance, an assessment of the variation in regional climatic suitability under climate change is critical. CliMond 10' data were used to model the potential current and future climate distribution of maize at the global level using the CLIMEX distribution model with climate data from two general circulation models, CSIRO-Mk3.0 and MIROC-H, assuming an A2 emissions scenario for 2050 and 2100. The change in area under future climate was analysed at continental level and for major maize-producing countries of the world. Regions between the tropics of Cancer and Capricorn indicate the highest loss of climatic suitability, contrary to poleward regions that exhibit an increase of suitability. South America shows the highest loss of climatic suitability, followed by Africa and Oceania. Asia, Europe and North America exhibit an increase in climatic suitability. This study indicates that globally, large areas that are currently suitable for maize cultivation will suffer from heat and dry stresses that may constrain production. For the first time, a model was applied worldwide, allowing for a better understanding of areas that are suitable and that may remain suitable for maize. PMID- 28724951 TI - N-terminal pro-brain natriuretic peptide and associated factors in the general working population: a baseline survey of the Uranosaki cohort study. AB - Few data on clinical characteristics associated with N-terminal pro-brain natriuretic peptide (NT-proBNP) or the clinical value of measuring NT-proBNP in the working population are available. The aim of the present study was to investigate the levels of NT-proBNP and their association with clinical variables in the Japanese general working population by using baseline data from the Uranosaki cohort study. In the study, the plasma concentration of NT-proBNP and some biomarkers were measured in addition to the standard health checkups at the workplace. Questionnaires regarding health-related quality of life (HR-QOL) were also completed. A total of 2140 participants were enrolled in the study. Plasma levels of NT-proBNP were positively associated with age, female sex, systolic blood pressure, pulse pressure, prevalent hypertension, smoking habit, high density lipoprotein cholesterol (HDL-C), and prevalent proteinuria, and negatively associated with body mass index, lipid profiles except HDL-C, uric acid, renal function, and hemoglobin. Both the plasma concentration of high molecular weight adiponectin and that of high-sensitivity troponin T were positively and independently associated with NT-proBNP. In addition, the HR-QOL score regarding sleep disorder was independently associated with NT-proBNP. Thus, we have obtained evidence that the plasma NT-proBNP is affected by several clinical variables in the general working population. PMID- 28724953 TI - Antimicrobial Efficacy and Synergy of Metal Ions against Enterococcus faecium, Klebsiella pneumoniae and Acinetobacter baumannii in Planktonic and Biofilm Phenotypes. AB - The effects of metal ion solutions (silver, copper, platinum, gold and palladium) were determined individually and in combination against Enterococcus faecium, Acinetobacter baumannii and Klebsiella pneumoniae. Platinum, gold and palladium showed the greatest antimicrobial efficacy in zone of inhibition (ZoI) assays. When tested in combinations using ZoI assays, gold/platinum, gold/palladium and platinum/palladium were indicative of synergy. Microbial inhibitory concentration demonstrated platinum and gold against Enterococcus faecium, platinum against Klebsiella pneumoniae and platinum and silver against Acinetobacter baumannii were optimal. Minimal bactericidal concentrations determined the greatest bactericidal activity was again platinum gold and palladium against all three bacteria. Fractional Inhibitory Concentration (FIC) studies demonstrated that the silver/platinum combination against Enterococcus faecium, and silver/copper combination against Acinetobacter baumannii demonstrated antimicrobial synergy. Following crystal violet biofilm assays for single metal ion solutions, antimicrobial efficacies were demonstrated for all the metals against all the bacteria Synergistic assays against biofilms demonstrated gold/palladium, gold/platinumand platinum/palladium resulted in the greatest antimicrobial efficacy. Overall, platinum, palladium and gold metal ion solutions in individual use or combination demonstrated the greatest antimicrobial efficacies against planktonic or biofilm bacteria. This work demonstrates the potential for using a range of metal ions, as biocidal formulations against both planktonic or biofilm bacteria. PMID- 28724954 TI - Loss of X-linked Protocadherin-19 differentially affects the behavior of heterozygous female and hemizygous male mice. AB - Mutations in the X-linked gene Protocadherin-19 (Pcdh19) cause female-limited epilepsy and mental retardation in humans. Although Pcdh19 is known to be a homophilic cell-cell adhesion molecule, how its mutations bring about female specific disorders remains elusive. Here, we report the effects of Pcdh19 knockout in mice on their development and behavior. Pcdh19 was expressed in various brain regions including the cerebral cortex and hippocampus. Although Pcdh19-positive cells were evenly distributed in layer V of wild-type cortices, their distribution became a mosaic in Pcdh19 heterozygous female cortices. In cortical and hippocampal neurons, Pcdh19 was localized along their dendrites, showing occasional accumulation on synapses. Pcdh19 mutants, however, displayed no detectable abnormalities in dendrite and spine morphology of layer V neurons. Nevertheless, Pcdh19 hemizygous males and heterozygous females showed impaired behaviors including activity defects under stress conditions. Notably, only heterozygous females exhibited decreased fear responses. In addition, Pcdh19 overexpression in wild-type cortices led to ectopic clustering of Pcdh19-positive neurons. These results suggest that Pcdh19 is required for behavioral control in mice, but its genetic loss differentially affects the male and female behavior, as seen in human, and they also support the hypothesis that the mosaic expression of Pcdh19 in brains perturbs neuronal interactions. PMID- 28724955 TI - Mushroom lectin overcomes hepatitis B virus tolerance via TLR6 signaling. AB - Currently, chronic hepatitis B virus (HBV) infection remains a serious public health problem in the world. Recombinant HBV vaccine, as a preventive strategy against HBV infection, generates high antibody level, but it is not effective to activate innate and cellular immunity for chronic HBV infection therapy. Lectins from mushroom are natural and active proteins which have been shown important biological functions. However, little is known about the immunological mechanism engaged by mushroom lectins. Here we report that, lectin from Pleurotus ostreatus (POL) stimulated innate response by activating Toll-like receptor 6 signal pathway of dendritic cells. Subsequently POL enhanced HBV specific antibody level and follicular helper T cells response which overcame HBV tolerance in transgenic mice. This study suggests a novel mechanism for POL acting on immune response and a therapeutic approach to break HBV tolerance. PMID- 28724956 TI - Mapping resistance responses to Sclerotinia infestation in introgression lines of Brassica juncea carrying genomic segments from wild Brassicaceae B. fruticulosa. AB - Sclerotinia stem rot (Sclerotinia sclerotiorum) is a major disease of Brassica oilseeds. As suitable donors to develop resistant cultivars are not available in crop Brassicas, we introgressed resistance from a wild Brassicaceae species, B. fruticulosa. We produced 206 B. juncea-B. fruticulosa introgression lines (ILs). These were assessed for pollen grain fertility, genome size variations and resistance responses to Sclerotinia following stem inoculations under disease conducive conditions. Of these, 115 ILs showing normal fertility and genome size were selected for cytogenetic characterization using florescent genomic in situ hybridization (Fl-GISH). B. fruticulosa segment substitutions were indicated in 28 ILs. These were predominantly terminal and located on B-genome chromosomes. A final set of 93 highly fertile and euploid (2n = 36) ILs were repeat-evaluated for their resistance responses during 2014-15. They were also genotyped with 202 transferable and 60 candidate gene SSRs. Association mapping allowed detection of ten significant marker trait associations (MTAs) after Bonferroni correction. These were: CNU-m157-2, RA2G05, CNU-m353-3, CNU-m442-5, ACMP00454-2, ACMP00454-3, EIN2-3-1, M641-1, Na10D09-1 and Na10D11-1. This is the first time such a molecular mapping technique has been deployed with introgression lines carrying genomic segments from B. fruticulosa, and the first to show that they possess high levels of resistance against S. sclerotiorum. PMID- 28724957 TI - Heterologous prion-forming proteins interact to cross-seed aggregation in Saccharomyces cerevisiae. AB - The early stages of protein misfolding remain incompletely understood, as most mammalian proteinopathies are only detected after irreversible protein aggregates have formed. Cross-seeding, where one aggregated protein templates the misfolding of a heterologous protein, is one mechanism proposed to stimulate protein aggregation and facilitate disease pathogenesis. Here, we demonstrate the existence of cross-seeding as a crucial step in the formation of the yeast prion [PSI +], formed by the translation termination factor Sup35. We provide evidence for the genetic and physical interaction of the prion protein Rnq1 with Sup35 as a predominant mechanism leading to self-propagating Sup35 aggregation. We identify interacting sites within Rnq1 and Sup35 and determine the effects of breaking and restoring a crucial interaction. Altogether, our results demonstrate that single-residue disruption can drastically reduce the effects of cross seeding, a finding that has important implications for human protein misfolding disorders. PMID- 28724958 TI - Viral driven epigenetic events alter the expression of cancer-related genes in Epstein-Barr-virus naturally infected Burkitt lymphoma cell lines. AB - Epstein-Barr virus (EBV) was identified as the first human virus to be associated with a human malignancy, Burkitt's lymphoma (BL), a pediatric cancer endemic in sub-Saharan Africa. The exact mechanism of how EBV contributes to the process of lymphomagenesis is not fully understood. Recent studies have highlighted a genetic difference between endemic (EBV+) and sporadic (EBV-) BL, with the endemic variant showing a lower somatic mutation load, which suggests the involvement of an alternative virally-driven process of transformation in the pathogenesis of endemic BL. We tested the hypothesis that a global change in DNA methylation may be induced by infection with EBV, possibly thereby accounting for the lower mutation load observed in endemic BL. Our comparative analysis of the methylation profiles of a panel of BL derived cell lines, naturally infected or not with EBV, revealed that the presence of the virus is associated with a specific pattern of DNA methylation resulting in altered expression of cellular genes with a known or potential role in lymphomagenesis. These included ID3, a gene often found to be mutated in sporadic BL. In summary this study provides evidence that EBV may contribute to the pathogenesis of BL through an epigenetic mechanism. PMID- 28724959 TI - Hepatic metabolic effects of Curcuma longa extract supplement in high-fructose and saturated fat fed rats. AB - The metabolic effects of an oral supplementation with a Curcuma longa extract, at a dose nutritionally relevant with common human use, on hepatic metabolism in rats fed a high fructose and saturated fatty acid (HFS) diet was evaluated. High resolution magic-angle spinning NMR and GC/MS in combination with multivariate analysis have been employed to characterize the NMR metabolite profiles and fatty acid composition of liver tissue respectively. The results showed a clear discrimination between HFS groups and controls involving metabolites such as glucose, glycogen, amino acids, acetate, choline, lysophosphatidylcholine, phosphatidylethanolamine, and beta-hydroxybutyrate as well as an increase of MUFAs and a decrease of n-6 and n-3 PUFAs. Although the administration of CL did not counteract deleterious effects of the HFS diet, some metabolites, namely some n-6 PUFA and n-3 PUFA, and betaine were found to increase significantly in liver samples from rats having received extract of curcuma compared to those fed the HFS diet alone. This result suggests that curcuminoids may affect the transmethylation pathway and/or osmotic regulation. CL extract supplementation in rats appears to increase some of the natural defences preventing the development of fatty liver by acting on the choline metabolism to increase fat export from the liver. PMID- 28724960 TI - SgRNA Expression of CRIPSR-Cas9 System Based on MiRNA Polycistrons as a Versatile Tool to Manipulate Multiple and Tissue-Specific Genome Editing. AB - CRISPR/Cas9-mediated genome editing is a next-generation strategy for genetic modifications. Typically, sgRNA is constitutively expressed relying on RNA polymerase III promoters. Polymerase II promoters initiate transcription in a flexible manner, but sgRNAs generated by RNA polymerase II promoter lost their nuclease activity. To express sgRNAs in a tissue-specific fashion and endow CRISPR with more versatile function, a novel system was established in a polycistron, where miRNAs (or shRNAs) and sgRNAs alternately emerged and co expressed under the control of a single polymerase II promoter. Effective expression and further processing of functional miRNAs and sgRNAs were achieved. The redundant nucleotides adjacent to sgRNA were degraded, and 5'- cap structure was responsible for the compromised nuclease capacity of sgRNA: Cas9 complex. Furthermore, this strategy fulfilled conducting multiplex genome editing, as well as executing neural- specific genome editing and enhancing the proportion of homologous recombination via inhibiting NHEJ pathway by shRNA. In summary, we designed a new construction for efficient expression of sgRNAs with miRNAs (shRNAs) by virtue of RNA polymerase II promoters, which will spur the development of safer, more controllable/regulable and powerful CRISPR/Cas9 system mediated genome editing in a wide variety of further biomedical applications. PMID- 28724961 TI - Coherence properties of different light sources and their effect on the image sharpness and speckle of holographic displays. AB - Coherence properties of different light sources and how they affect the image quality of holographic display are investigated. Temporal coherence is related to the intrinsic spectrum bandwidth of the light source, while spatial coherence can be affected by the size of the light source and propagation distance in use. These two coherence properties are measured for various light sources of diode pumped solid-state (DPSS) laser, laser diode (LD), light emitting diode (LED), super luminescent light emitting diode (sLED) and micro light emitting diode (mLED) in different settings, together with the quality of the holographic reconstructed images. Although the image sharpness and speckle are related to both coherence parameters, our results and subsequent analysis show that the spatial coherence can be linked directly to the image sharpness and the temporal coherence to the speckle. This will provide a quantitative way not only to optimize the image quality between uniformity and sharpness but also to determine the safety power level for different light sources when viewing the produced images by human eyes directly. PMID- 28724962 TI - Novel transcriptional signatures for sputum-independent diagnostics of tuberculosis in children. AB - Pediatric tuberculosis (TB) is challenging to diagnose, confirmed by growth of Mycobacterium tuberculosis at best in 40% of cases. The WHO has assigned high priority to the development of non-sputum diagnostic tools. We therefore sought to identify transcriptional signatures in whole blood of Indian children, capable of discriminating intra-thoracic TB disease from other symptomatic illnesses. We investigated the expression of 198 genes in a training set, comprising 47 TB cases (19 definite/28 probable) and 36 asymptomatic household controls, and identified a 7- and a 10-transcript signature, both including NOD2, GBP5, IFITM1/3, KIF1B and TNIP1. The discriminatory abilities of the signatures were evaluated in a test set comprising 24 TB cases (17 definite/7 probable) and 26 symptomatic non-TB cases. In separating TB-cases from symptomatic non-TB cases, both signatures provided an AUC of 0.94 (95%CI, 0.88-1.00), a sensitivity of 91.7% (95%CI, 71.5-98.5) regardless of culture status, and 100% sensitivity for definite TB. The 7-transcript signature provided a specificity of 80.8% (95%CI, 60.0-92.7), and the 10-transcript signature a specificity of 88.5% (95%CI, 68.7 96.9%). Although warranting exploration and validation in other populations, our findings are promising and potentially relevant for future non-sputum based POC diagnostic tools for pediatric TB. PMID- 28724963 TI - Midnolin is a novel regulator of parkin expression and is associated with Parkinson's Disease. AB - Midnolin (MIDN) was first discovered in embryonic stem cells, but its physiological and pathological roles are, to date, poorly understood. In the present study, we therefore examined the role of MIDN in detail. We found that in PC12 cells, a model of neuronal cells, MIDN localized primarily to the nucleus and intracellular membranes. Nerve growth factor promoted MIDN gene expression, which was attenuated by specific inhibitors of extracellular signal-regulated kinases 1/2 and 5. MIDN-deficient PC12 cells created using CRISPR/Cas9 technology displayed significantly impaired neurite outgrowth. Interestingly, a genetic approach revealed that 10.5% of patients with sporadic Parkinson's disease (PD) had a lower MIDN gene copy number whereas no copy number variation was observed in healthy people, suggesting that MIDN is involved in PD pathogenesis. Furthermore, the expression of parkin, a major causative gene in PD, was significantly reduced by CRISPR/Cas9 knockout and siRNA knockdown of MIDN. Activating transcription factor 4 (ATF4) was also down-regulated, which binds to the cAMP response element (CRE) in the parkin core promoter region. The activity of CRE was reduced following MIDN loss. Overall, our data suggests that MIDN promotes the expression of parkin E3 ubiquitin ligase, and that MIDN loss can trigger PD-related pathogenic mechanisms. PMID- 28724964 TI - Highly selective tungstate transporter protein TupA from Desulfovibrio alaskensis G20. AB - Molybdenum and tungsten are taken up by bacteria and archaea as their soluble oxyanions through high affinity transport systems belonging to the ATP-binding cassette (ABC) transporters. The component A (ModA/TupA) of these transporters is the first selection gate from which the cell differentiates between MoO42-, WO42- and other similar oxyanions. We report the biochemical characterization and the crystal structure of the apo-TupA from Desulfovibrio desulfuricans G20, at 1.4 A resolution. Small Angle X-ray Scattering data suggests that the protein adopts a closed and more stable conformation upon ion binding. The role of the arginine 118 in the selectivity of the oxyanion was also investigated and three mutants were constructed: R118K, R118E and R118Q. Isothermal titration calorimetry clearly shows the relevance of this residue for metal discrimination and oxyanion binding. In this sense, the three variants lost the ability to coordinate molybdate and the R118K mutant keeps an extremely high affinity for tungstate. These results contribute to an understanding of the metal-protein interaction, making it a suitable candidate for a recognition element of a biosensor for tungsten detection. PMID- 28724965 TI - Polymorphic Transitions in Cerium-Substituted Zirconolite (CaZrTi2O7). AB - Compounds with the formulae CaZr1-xCexTi2O7 with x = 0.1-0.5 were synthesized by solid state reaction. Cerium was used as a surrogate for actinide elements. A transition from the 2M polymorph to the 4M polymorph (expanded unit cell due to cation ordering) in zirconolite was observed with increasing cerium content. The presence of both tri- and tetravalent Ce, contrary to formulation, was confirmed using X-ray absorption near edge spectroscopy, suggesting substitution on both Ca and Zr sites. Sintering was carried out via spark plasma sintering, during which the perovskite phase (Ca0.4Ce0.4TiO3) was stabilized due to the reducing conditions of this technique. Scanning electron microscopy and energy dispersive spectrometry revealed that the 2M polymorph was dilute in Ce content in comparison to the 4M-zirconolite. High temperature X-ray diffraction was used to detail the kinetics of perovskite to zirconolite transition. It was found that CaCeTi2O7 (cubic pyrochlore) formed as an intermediate phase during the transition. Our results show that a transition from 2M- to 4M-zirconolite occurs with increasing Ce content and can be controlled by adjusting the PO2 and the heat treatment temperature. PMID- 28724966 TI - Acetylation-induced TDP-43 pathology is suppressed by an HSF1-dependent chaperone program. AB - TDP-43 pathology marks a spectrum of multisystem proteinopathies including amyotrophic lateral sclerosis, frontotemporal lobar degeneration, and sporadic inclusion body myositis. Surprisingly, it has been challenging to recapitulate this pathology, highlighting an incomplete understanding of TDP-43 regulatory mechanisms. Here we provide evidence supporting TDP-43 acetylation as a trigger for disease pathology. Using cultured cells and mouse skeletal muscle, we show that TDP-43 acetylation-mimics promote TDP-43 phosphorylation and ubiquitination, perturb mitochondria, and initiate degenerative inflammatory responses that resemble sporadic inclusion body myositis pathology. Analysis of functionally linked amyotrophic lateral sclerosis proteins revealed recruitment of p62, ubiquilin-2, and optineurin to TDP-43 aggregates. We demonstrate that TDP-43 acetylation-mimic pathology is potently suppressed by an HSF1-dependent mechanism that disaggregates TDP-43. Our study illustrates bidirectional TDP-43 processing in which TDP-43 aggregation is targeted by a coordinated chaperone response. Thus, activation or restoration of refolding mechanisms may alleviate TDP-43 aggregation in tissues that are uniquely susceptible to TDP-43 proteinopathies.TDP-43 aggregation is linked to various diseases including amyotrophic lateral sclerosis. Here the authors show that acetylation of the protein triggers TDP-43 pathology in cultured cells and mouse skeletal muscle, which can be cleared through an HSF1-dependent chaperone mechanism that disaggregates the protein. PMID- 28724967 TI - A balancing act: RNA binding protein HuR/TTP axis in endometriosis patients. AB - Endometriosis, a major reproductive pathology affecting 8-10% of women is characterized by chronic inflammation and immune dysfunction. Human antigen R (HuR) and Tristetraprolin (TTP) are RNA binding proteins that competitively bind to cytokines involved in inflammation including: tumor necrosis factor alpha (TNF alpha), granulocyte macrophage colony stimulating factor (GM-CSF), interleukin 6 (IL-6) among others, and stabilize and destabilize them, respectively. The aim of this study was to examine RNA binding protein (RNABP) HuR/TTP axis in endometriosis patients compared to menstrual stage matched healthy fertile controls in hopes of better understanding their contribution to the pathogenesis of endometriosis. Additionally, using a targeted in vitro siRNA approach, we examined whether knock-down of TTP can play a functional role on other RNABPs that competitively bind to inflammatory targets of TTP in both endometriotic and endometrial epithelial cell lines. Our results suggest that RNABPs TTP and HuR are dysregulated in endometriotic lesions compared to matched eutopic patient samples as well endometrium from healthy controls. Silencing of TTP in endometriotic and endometrial epithelial cells revealed differential response to inflammatory cytokines and other RNABPs. Our results suggest potential involvement of HuR/TTP RNA binding protein axis in regulation of inflammation in endometriosis. PMID- 28724968 TI - Ce3+-ion, Surface Oxygen Vacancy, and Visible Light-induced Photocatalytic Dye Degradation and Photocapacitive Performance of CeO2-Graphene Nanostructures. AB - Cerium oxide nanoparticles (CeO2 NPs) were fabricated and grown on graphene sheets using a facile, low cost hydrothermal approach and subsequently characterized using different standard characterization techniques. X-ray photoelectron spectroscopy and electron paramagnetic resonance revealed the changes in surface states, composition, changes in Ce4+ to Ce3+ ratio, and other defects. Transmission electron microscopy (TEM) and high resolution TEM revealed that the fabricated CeO2 NPs to be spherical with particle size of ~10-12 nm. Combination of defects in CeO2 NPs with optimal amount of two-dimensional graphene sheets had a significant effect on the properties of the resulting hybrid CeO2-Graphene nanostructures, such as improved optical, photocatalytic, and photocapacitive performance. The excellent photocatalytic degradation performances were examined by monitoring their ability to degrade Congo red ~94.5% and methylene blue dye ~98% under visible light irradiation. The photoelectrode performance had a maximum photocapacitance of 177.54 Fg-1 and exhibited regular capacitive behavior. Therefore, the Ce3+-ion, surface-oxygen vacancies, and defects-induced behavior can be attributed to the suppression of the recombination of photo-generated electron-hole pairs due to the rapid charge transfer between the CeO2 NPs and graphene sheets. These findings will have a profound effect on the use of CeO2-Graphene nanostructures for future energy and environment-related applications. PMID- 28724969 TI - Pathways to clinical CLARITY: volumetric analysis of irregular, soft, and heterogeneous tissues in development and disease. AB - Three-dimensional tissue-structural relationships are not well captured by typical thin-section histology, posing challenges for the study of tissue physiology and pathology. Moreover, while recent progress has been made with intact methods for clearing, labeling, and imaging whole organs such as the mature brain, these approaches are generally unsuitable for soft, irregular, and heterogeneous tissues that account for the vast majority of clinical samples and biopsies. Here we develop a biphasic hydrogel methodology, which along with automated analysis, provides for high-throughput quantitative volumetric interrogation of spatially-irregular and friable tissue structures. We validate and apply this approach in the examination of a variety of developing and diseased tissues, with specific focus on the dynamics of normal and pathological pancreatic innervation and development, including in clinical samples. Quantitative advantages of the intact-tissue approach were demonstrated compared to conventional thin-section histology, pointing to broad applications in both research and clinical settings. PMID- 28724970 TI - Classification of skin phenotypes caused by diabetes mellitus using complex scattering parameters in the millimeter-wave frequency range. AB - The pathological skin phenotype caused by hyperglycemia is an important indicator for the progress of diabetes mellitus. An early detection of diabetes assures an early intervention to regulate the carbohydrate metabolism. In this publication a non-invasive detection principle based on the measurement of complex scattering parameters in the millimeter-wave frequency range is presented. The measurement principle provides evidence of the applicability for the identification of different glycemic states in animal models. The method proposed here can be used to predict diabetes status in animal models and is interesting for application on humans in view of safeness of millimeter-wave radiation. Furthermore the complex scattering parameters give important information about the anatomic varieties between the analyzed skin samples of the different mice strains. In contrast to other methods, our approach is less sensitive to skin variations between animals. PMID- 28724971 TI - Computational design of a symmetrical beta-trefoil lectin with cancer cell binding activity. AB - Computational protein design has advanced very rapidly over the last decade, but there remain few examples of artificial proteins with direct medical applications. This study describes a new artificial beta-trefoil lectin that recognises Burkitt's lymphoma cells, and which was designed with the intention of finding a basis for novel cancer treatments or diagnostics. The new protein, called "Mitsuba", is based on the structure of the natural shellfish lectin MytiLec-1, a member of a small lectin family that uses unique sequence motifs to bind alpha-D-galactose. The three subdomains of MytiLec-1 each carry one galactose binding site, and the 149-residue protein forms a tight dimer in solution. Mitsuba (meaning "three-leaf" in Japanese) was created by symmetry constraining the structure of a MytiLec-1 subunit, resulting in a 150-residue sequence that contains three identical tandem repeats. Mitsuba-1 was expressed and crystallised to confirm the X-ray structure matches the predicted model. Mitsuba-1 recognises cancer cells that express globotriose (Galalpha(1,4)Galbeta(1,4)Glc) on the surface, but the cytotoxicity is abolished. PMID- 28724972 TI - Asymptomatic Transmission and the Dynamics of Zika Infection. AB - Following the 2013-14 outbreak in French Polynesia, the Zika virus (ZIKV) epidemic spread widely to many countries where Aedes Aegypti as the main transmitting vector is endemic. The lack of a second wave of ZIKV infection in most affected regions may suggest that a sufficiently high level of herd immunity was reached during the first wave. We developed an agent-based transmission model to investigate the role of asymptomatic infection on the likelihood of observing a second wave, while accounting for its relative transmissibility. We found that, as the relative transmissibility of asymptomatic infection increases, a second wave is more likely to occur, despite an increase in the attack rate during the first wave. When the reproduction number varies between 1.9 and 2.8 based on estimates for Antioquia, Colombia, the attack rate varies between 4% and 26% for a low (below 10%) effectiveness of interventions in blunting the ZIKV transmission from symptomatic cases to mosquitoes. Moreover, the fraction of cases due to sexual transmission is estimated below 4% of the cumulative incidence. Our analyses underscore the need to quantify the transmissibility of asymptomatic infections, without which the overall attack rates and the level of herd immunity cannot be accurately estimated. PMID- 28724973 TI - Alternatives to mineral oil adjuvants in vaccines against Aeromonas salmonicida subsp. salmonicida in rainbow trout offer reductions in adverse effects. AB - In an effort to reduce the frequency and severity of adverse reactions seen from the use of mineral oil adjuvants in salmonid fish, the effects of two alternative adjuvants were assessed, focusing on the induction of adverse effects as well as protection. Using rainbow trout (Oncorhynchus mykiss) as recipients, injection vaccines based on formalin-inactivated Aeromonas salmonicida subspecies salmonicida were formulated with CpG oligodeoxynucleotides, the liposomal cationic adjuvant formulation 01 (CAF01) or with Freund's incomplete adjuvant and administered intraperitoneally. Control groups of unvaccinated, Tris-buffered saline-injected or bacterin-injected individuals were included, and each group included in the study held a total number of 240 individuals. Subsequently, individuals from each group were examined for differences in Fulton's condition factor, macro- and microscopic pathological changes, as well as protection against experimental infection with A. salmonicida. While adverse effects were not eliminated, reductions in microscopic and macroscopic adverse effects, in particular, were seen for both the nucleotide- and liposome-based vaccine formulations. Furthermore, the induced protection appears similar to that of the benchmark formulation, thus introducing viable, potential alternative types of adjuvants for use in future fish vaccines. PMID- 28724974 TI - Effects of exogenous thymosin beta4 on carbon tetrachloride-induced liver injury and fibrosis. AB - The present study investigated the effects of exogenous thymosin beta4 (TB4) on carbon tetrachloride (CCl4)-induced acute liver injury and fibrosis in rodent animals. Results showed that both in mice and rats CCl4 rendered significant increases in serum alanine aminotransferase and aspartate aminotransferase, hepatic malondialdehyde formation, decreases in antioxidants including superoxide dismutase and glutathione, and up-regulated expressions of transforming growth factor-beta1, alpha-smooth muscle actin, tumor necrosis factor-alpha and interleukin-1beta in the liver tissues. Hydroxyproline contents in the rat livers were increased by CCl4. Histopathological examinations indicated that CCl4 induced extensive necrosis in mice livers and pseudo-lobule formations, collagen deposition in rats livers. However, all these changes in mice and rats were significantly attenuated by exogenous TB4 treatment. Furthermore, up-regulations of nuclear factor-kappaB p65 protein expression by CCl4 treatment in mice and rats livers were also remarkably reduced by exogenous TB4 administration. Taken together, findings in this study suggested that exogenous TB4 might prevent CCl4 induced acute liver injury and subsequent fibrosis through alleviating oxidative stress and inflammation. PMID- 28724975 TI - Theoretical study of superionic phase transition in Li2S. AB - We have studied temperature-induced superionic phase transition in Li2S, which is one of the most promising Li-S battery cathode material. Concentration of ionic carriers at low and high temperature was evaluated from thermodynamics of defects (using density functional theory) and detailed balance condition (using ab initio molecular dynamics (AIMD)), respectively. Diffusion coefficients were also obtained using AIMD simulations. Calculated ionic conductivity shows that superionic phase transition occurs at T = 900 K, which is in agreement with reported experimental values. The superionic behavior of Li2S is found to be due to thermodynamic reason (i.e. a large concentration of disordered defects). PMID- 28724976 TI - Gene expression reversal toward pre-adult levels in the aging human brain and age related loss of cellular identity. AB - It was previously reported that mRNA expression levels in the prefrontal cortex at old age start to resemble pre-adult levels. Such expression reversals could imply loss of cellular identity in the aging brain, and provide a link between aging-related molecular changes and functional decline. Here we analyzed 19 brain transcriptome age-series datasets, comprising 17 diverse brain regions, to investigate the ubiquity and functional properties of expression reversal in the human brain. Across all 19 datasets, 25 genes were consistently up-regulated during postnatal development and down-regulated in aging, displaying an "up-down" pattern that was significant as determined by random permutations. In addition, 113 biological processes, including neuronal and synaptic functions, were consistently associated with genes showing an up-down tendency among all datasets. Genes up-regulated during in vitro neuronal differentiation also displayed a tendency for up-down reversal, although at levels comparable to other genes. We argue that reversals may not represent aging-related neuronal loss. Instead, expression reversals may be associated with aging-related accumulation of stochastic effects that lead to loss of functional and structural identity in neurons. PMID- 28724977 TI - Therapeutic targeting of HMGB1 during experimental sepsis modulates the inflammatory cytokine profile to one associated with improved clinical outcomes. AB - Sepsis remains a significant health burden and a major clinical need exists for therapeutics to dampen the excessive and uncontrolled immune activation. Nuclear protein high mobility group box protein 1 (HMGB1) is released following cell death and is a late mediator in sepsis pathogenesis. While approaches targeting HMGB1 have demonstrated reduced mortality in pre-clinical models of sepsis, the impact of HMGB1 blockade on the complex septic inflammatory milieu and the development of subsequent immunosuppression remain enigmatic. Analysis of plasma samples obtained from septic shock patients established an association between increased HMGB1 and non-survival, higher APACHE II scores, and increased pro inflammatory cytokine responses. Pre-clinically, administration of neutralising ovine anti-HMGB1 polyclonal antibodies improved survival in murine endotoxaemia and caecal ligation and puncture-induced sepsis models, and altered early cytokine profiles to one which corresponded to patterns observed in the surviving patient cohort. Additionally, anti-HMGB1 treated murine sepsis survivors were significantly more resistant to secondary bacterial infection and exhibited altered innate immune cell phenotypes and cytokine responses. These findings demonstrate that anti-HMGB1 antibodies alter inflammation in murine sepsis models and reduce sepsis mortality without potentiating immunosuppression. PMID- 28724979 TI - Impairment of Coronary Endothelial Function by Hypoxia-Reoxygenation Involves TRPC3 Inhibition-mediated KCa Channel Dysfunction: Implication in Ischemia Reperfusion Injury. AB - Despite increasing knowledge of the significance of calcium-activated potassium (KCa) and canonical transient receptor potential (TRPC) channels in endothelial physiology, no studies so far have investigated the link between these two distinct types of channels in the control of vascular tone in pathological conditions. We previously demonstrated that hypoxia-reoxygenation (H-R) inhibits endothelial KCa and TRPC3 channels in porcine coronary arteries (PCAs). The present study further investigated whether modulation of TRPC3 is involved in H-R induced KCa channel inhibition and associated vasodilatory dysfunction using approaches of wire myography, whole-cell voltage-clamp, and coimmunoprecipitation. Pharmacological inhibition or siRNA silencing of TRPC3 significantly suppressed bradykinin-induced intermediate- and small-conductance KCa (IKCa and SKCa) currents in endothelial cells of PCAs (PCAECs). TRPC3 protein exists in physical association with neither IKCa nor SKCa. In H-R-exposed PCAECs, the response of IKCa and SKCa to bradykinin-stimulation and to TRPC3-inhibition was markedly weakened. Activation of TRPC3 channels restored H-R-suppressed KCa currents in association with an improved endothelium-derived hyperpolarizing factor (EDHF)-type vasorelaxation. We conclude that inhibition of TRPC3 channels contributes to H-R-induced suppression of KCa channel activity, which serves as a mechanism underlying coronary endothelial dysfunction in ischemia-reperfusion (I R) injury and renders TRPC3 a potential target for endothelial protection in I-R conditions. PMID- 28724978 TI - Economic factors influencing zoonotic disease dynamics: demand for poultry meat and seasonal transmission of avian influenza in Vietnam. AB - While climate is often presented as a key factor influencing the seasonality of diseases, the importance of anthropogenic factors is less commonly evaluated. Using a combination of methods - wavelet analysis, economic analysis, statistical and disease transmission modelling - we aimed to explore the influence of climatic and economic factors on the seasonality of H5N1 Highly Pathogenic Avian Influenza in the domestic poultry population of Vietnam. We found that while climatic variables are associated with seasonal variation in the incidence of avian influenza outbreaks in the North of the country, this is not the case in the Centre and the South. In contrast, temporal patterns of H5N1 incidence are similar across these 3 regions: periods of high H5N1 incidence coincide with Lunar New Year festival, occurring in January-February, in the 3 climatic regions for 5 out of the 8 study years. Yet, daily poultry meat consumption drastically increases during Lunar New Year festival throughout the country. To meet this rise in demand, poultry production and trade are expected to peak around the festival period, promoting viral spread, which we demonstrated using a stochastic disease transmission model. This study illustrates the way in which economic factors may influence the dynamics of livestock pathogens. PMID- 28724980 TI - Handheld Co-Axial Bioprinting: Application to in situ surgical cartilage repair. AB - Three-dimensional (3D) bioprinting is driving major innovations in the area of cartilage tissue engineering. Extrusion-based 3D bioprinting necessitates a phase change from a liquid bioink to a semi-solid crosslinked network achieved by a photo-initiated free radical polymerization reaction that is known to be cytotoxic. Therefore, the choice of the photocuring conditions has to be carefully addressed to generate a structure stiff enough to withstand the forces phisiologically applied on articular cartilage, while ensuring adequate cell survival for functional chondral repair. We recently developed a handheld 3D printer called "Biopen". To progress towards translating this freeform biofabrication tool into clinical practice, we aimed to define the ideal bioprinting conditions that would deliver a scaffold with high cell viability and structural stiffness relevant for chondral repair. To fulfill those criteria, free radical cytotoxicity was confined by a co-axial Core/Shell separation. This system allowed the generation of Core/Shell GelMa/HAMa bioscaffolds with stiffness of 200KPa, achieved after only 10 seconds of exposure to 700 mW/cm2 of 365 nm UV-A, containing >90% viable stem cells that retained proliferative capacity. Overall, the Core/Shell handheld 3D bioprinting strategy enabled rapid generation of high modulus bioscaffolds with high cell viability, with potential for in situ surgical cartilage engineering. PMID- 28724981 TI - Prediction of size-resolved number concentration of cloud condensation nuclei and long-term measurements of their activation characteristics. AB - Atmospheric aerosol particles acting as cloud condensation nuclei (CCN) are key elements in the hydrological cycle and climate. To improve our understanding of the activation characteristics of CCN and to obtain accurate predictions of their concentrations, a long-term field campaign was carried out in the Yangtze River Delta, China. The results indicated that the CCN were easier to activate in this relatively polluted rural station than in clean (e.g., the Amazon region) or dusty (e.g., Kanpur-spring) locations, but were harder to activate than in more polluted urban areas (e.g., Beijing). An improved method, using two additional parameters-the maximum activation fraction and the degree of heterogeneity, is proposed to predict the accurate, size-resolved concentration of CCN. The value ranges and prediction uncertainties of these parameters were evaluated. The CCN predicted using this improved method with size-resolved chemical compositions under an assumption that all particles were internally mixed showed the best agreement with the long-term field measurements. PMID- 28724982 TI - Primary phonological planning units in spoken word production are language specific: Evidence from an ERP study. AB - It is widely acknowledged in Germanic languages that segments are the primary planning units at the phonological encoding stage of spoken word production. Mixed results, however, have been found in Chinese, and it is still unclear what roles syllables and segments play in planning Chinese spoken word production. In the current study, participants were asked to first prepare and later produce disyllabic Mandarin words upon picture prompts and a response cue while electroencephalogram (EEG) signals were recorded. Each two consecutive pictures implicitly formed a pair of prime and target, whose names shared the same word initial atonal syllable or the same word-initial segments, or were unrelated in the control conditions. Only syllable repetition induced significant effects on event-related brain potentials (ERPs) after target onset: a widely distributed positivity in the 200- to 400-ms interval and an anterior positivity in the 400- to 600-ms interval. We interpret these to reflect syllable-size representations at the phonological encoding and phonetic encoding stages. Our results provide the first electrophysiological evidence for the distinct role of syllables in producing Mandarin spoken words, supporting a language specificity hypothesis about the primary phonological units in spoken word production. PMID- 28724983 TI - Bio-inspired interlocking random 3-D structures for tactile and thermal sensing. AB - Hierarchical nanostructures are tailored and used routinely in nature to accomplish tasks with high performance. Their formation in nature is accomplished without the use of any patterning process. Inspired by the performance of such structures, we have combined 2-D nanosheets with 1-D nanorods for functioning as electronic skin. These structures made in high density without any patterning process can be easily assembled over large areas. They can sense pressures as low as 0.4 Pa, with a response time in milliseconds. Further, these structures can also detect temperature changes with a non-linear response in the 298-400 K range, which is similar to skins perception of thermal stimuli. We illustrate this effect by showing that the device can differentiate between two 10 ul water droplets which are at room temperature and 323 K respectively. PMID- 28724984 TI - pH and Urea Estimation in Urine Samples using Single Fluorophore and Ratiometric Fluorescent Biosensors. AB - Kidney diseases remain often undiagnosed due to inefficient screening methods available at patient's disposal. Early diagnosis and effective management of kidney problems can best be addressed by the development of biosensors for commonly occurring clinical biomarkers. Here we report the development of single fluorophore and dual fluorophore ratiometric biosensors based on alginate microspheres for pH and urea analysis in urine samples. A facile method of air driven atomization was used for developing these polymeric fluorophore and enzyme based biosensors. Ratiometric biosensors were developed using layer-by-layer coating of polyelectrolyte conjugated to reference fluorophores. Biosensing studies using these biosensors showed that samples in pathophysiological range can be measured having pH range of 4-8 and urea levels between 0-50 mM. Testing of urine samples using these biosensors showed that both pH and urea detection can be accurately performed without interference. Thus, we believe that FITC Dextran and FITC-Dextran/RuBpy based pH and urea biosensors show a great potential to be translated as a point of care device for pH and urea biosensing in early detection and continuous monitoring of kidney diseases. PMID- 28724985 TI - Increased neural noise and impaired brain synchronization in fibromyalgia patients during cognitive interference. AB - Fibromyalgia (FM) and other chronic pain syndromes are associated with cognitive dysfunction and attentional deficits, but the neural basis of such alterations is poorly understood. Dyscognition may be related to high levels of neural noise, understood as increased random electrical fluctuations that impair neural communication; however, this hypothesis has not yet been tested in any chronic pain condition. Here we compared electroencephalographic activity (EEG) in 18 FM patients -with high self-reported levels of cognitive dysfunction- and 22 controls during a cognitive control task. We considered the slope of the Power Spectrum Density (PSD) as an indicator of neural noise. As the PSD slope is flatter in noisier systems, we expected to see shallower slopes in the EEG of FM patients. Higher levels of neural noise should be accompanied by reduced power modulation and reduced synchronization between distant brain locations after stimulus presentation. As expected, FM patients showed flatter PSD slopes. After applying a Laplacian spatial filter, we found reduced theta and alpha power modulation and reduced midfrontal-posterior theta phase synchronization. Results suggest higher neural noise and impaired local and distant neural coordination in the patients and support the neural noise hypothesis to explain dyscognition in FM. PMID- 28724986 TI - Core shell lipid-polymer hybrid nanoparticles with combined docetaxel and molecular targeted therapy for the treatment of metastatic prostate cancer. AB - Many prostate cancers relapse after initial chemotherapy treatment. Combining molecular and chemotherapy together with encapsulation of drugs in nanocarriers provides effective drug delivery and toxicity reduction. We developed core shell lipid-polymer hybrid nanoparticles (CSLPHNPs) with poly (lactic-co-glycolic acid) (PLGA) core and lipid layer containing docetaxel and clinically used inhibitor of sphingosine kinase 1 (SK1) FTY720 (fingolimod). We show for the first time that FTY720 (both free and in CSLPHNPs) re-sensitizes castrate resistant prostate cancer cells and tumors to docetaxel, allowing a four-fold reduction in effective dose. Our CSLPHNPs showed high serum stability and a long shelf life. CSLPHNPs demonstrated a steady uptake by tumor cells, sustained intracellular drug release and in vitro efficacy superior to free therapies. In a mouse model of human prostate cancer, CSLPHNPs showed excellent tumor targeting and significantly lower side effects compared to free drugs, importantly, reversing lymphopenia induced by FTY720. Overall, we demonstrate that nanoparticle encapsulation can improve targeting, provide low off-target toxicity and most importantly reduce FTY720-induced lymphopenia, suggesting its potential use in clinical cancer treatment. PMID- 28724987 TI - The asymmetric impact of global warming on US drought types and distributions in a large ensemble of 97 hydro-climatic simulations. AB - Projection of future drought is often involved large uncertainties from climate models, emission scenarios as well as drought definitions. In this study, we investigate changes in future droughts in the conterminous United States based on 97 1/8 degree hydro-climate model projections. Instead of focusing on a specific drought type, we investigate changes in meteorological, agricultural, and hydrological drought as well as the concurrences. Agricultural and hydrological droughts are projected to become more frequent with increase in global mean temperature, while less meteorological drought is expected. Changes in drought intensity scale linearly with global temperature rises under RCP8.5 scenario, indicating the potential feasibility to derive future drought severity given certain global warming amount under this scenario. Changing pattern of concurrent droughts generally follows that of agricultural and hydrological droughts. Under the 1.5 degrees C warming target as advocated in recent Paris agreement, several hot spot regions experiencing highest droughts are identified. Extreme droughts show similar patterns but with much larger magnitude than the climatology. This study highlights the distinct response of droughts of various types to global warming and the asymmetric impact of global warming on drought distribution resulting in a much stronger influence on extreme drought than on mean drought. PMID- 28724988 TI - Continental shelves as potential resource of rare earth elements. AB - The results of this study allow the reassessment of the rare earth elements (REE) external cycle. Indeed, the river input to the oceans has relatively flat REE patterns without cerium (Ce) anomalies, whereas oceanic REE patterns exhibit strong negative Ce anomalies and heavy REE enrichment. Indeed, the processes at the origin of seawater REE patterns are commonly thought to occur within the ocean masses themselves. However, the results from the present study illustrate that seawater-like REE patterns already occur in the truly dissolved pool of river input. This leads us to favor a partial or complete removal of the colloidal REE pool during estuarine mixing by coagulation, as previously shown for dissolved humic acids and iron. In this latter case, REE fractionation occurs because colloidal and truly dissolved pools have different REE patterns. Thus, the REE patterns of seawater could be the combination of both intra-oceanic and riverine processes. In this study, we show that the Atlantic continental shelves could be considered potential REE traps, suggesting further that shelf sediments could potentially become a resource for REE, similar to metalliferous deep sea sediments. PMID- 28724989 TI - Impact of interfacial molecular orientation on radiative recombination and charge generation efficiency. AB - A long standing question in organic electronics concerns the effects of molecular orientation at donor/acceptor heterojunctions. Given a well-controlled donor/acceptor bilayer system, we uncover the genuine effects of molecular orientation on charge generation and recombination. These effects are studied through the point of view of photovoltaics-however, the results have important implications on the operation of all optoelectronic devices with donor/acceptor interfaces, such as light emitting diodes and photodetectors. Our findings can be summarized by two points. First, devices with donor molecules face-on to the acceptor interface have a higher charge transfer state energy and less non radiative recombination, resulting in larger open-circuit voltages and higher radiative efficiencies. Second, devices with donor molecules edge-on to the acceptor interface are more efficient at charge generation, attributed to smaller electronic coupling between the charge transfer states and the ground state, and lower activation energy for charge generation.Molecular orientation profoundly affects the performance of donor-acceptor heterojunctions, whilst it has remained challenging to investigate the detail. Using a controllable interface, Ran et al. show that the edge-on geometries improve charge generation at the cost of non radiative recombination loss. PMID- 28724991 TI - Benchmarking selected computational gene network growing tools in context of virus-host interactions. AB - Several available online tools provide network growing functions where an algorithm utilizing different data sources suggests additional genes/proteins that should connect an input gene set into functionally meaningful networks. Using the well-studied system of influenza host interactions, we compare the network growing function of two free tools GeneMANIA and STRING and the commercial IPA for their performance of recovering known influenza A virus host factors previously identified from siRNA screens. The result showed that given small (~30 genes) or medium (~150 genes) input sets all three network growing tools detect significantly more known host factors than random human genes with STRING overall performing strongest. Extending the networks with all the three tools significantly improved the detection of GO biological processes of known host factors compared to not growing networks. Interestingly, the rate of identification of true host factors using computational network growing is equal or better to doing another experimental siRNA screening study which could also be true and applied to other biological pathways/processes. PMID- 28724992 TI - Opposite, bidirectional shifts in excitation and inhibition in specific types of dorsal horn interneurons are associated with spasticity and pain post-SCI. AB - Spasticity, a common complication after spinal cord injury (SCI), is frequently accompanied by chronic pain. The physiological origin of this pain (critical to its treatment) remains unknown, although spastic motor dysfunction has been related to the hyperexcitability of motoneurons and to changes in spinal sensory processing. Here we show that the pain mechanism involves changes in sensory circuits of the dorsal horn (DH) where nociceptive inputs integrate for pain processing. Spasticity is associated with the DH hyperexcitability resulting from an increase in excitation and disinhibition occurring in two respective types of sensory interneurons. In the tonic-firing inhibitory lamina II interneurons, glutamatergic drive was reduced while glycinergic inhibition was potentiated. In contrast, excitatory drive was boosted to the adapting-firing excitatory lamina II interneurons while GABAergic and glycinergic inhibition were reduced. Thus, increased activity of excitatory DH interneurons coupled with the reduced excitability of inhibitory DH interneurons post-SCI could provide a neurophysiological mechanism of central sensitization and chronic pain associated with spasticity. PMID- 28724993 TI - Prediction of presynaptic and postsynaptic neurotoxins by combining various Chou's pseudo components. AB - Presynaptic and postsynaptic neurotoxins are two groups of neurotoxins. Identification of presynaptic and postsynaptic neurotoxins is an important work for numerous newly found toxins. It is both costly and time consuming to determine these two neurotoxins by experimental methods. As a complement, using computational methods for predicting presynaptic and postsynaptic neurotoxins could provide some useful information in a timely manner. In this study, we described four algorithms for predicting presynaptic and postsynaptic neurotoxins from sequence driven features by using Increment of Diversity (ID), Multinomial Naive Bayes Classifier (MNBC), Random Forest (RF), and K-nearest Neighbours Classifier (IBK). Each protein sequence was encoded by pseudo amino acid (PseAA) compositions and three biological motif features, including MEME, Prosite and InterPro motif features. The Maximum Relevance Minimum Redundancy (MRMR) feature selection method was used to rank the PseAA compositions and the 50 top ranked features were selected to improve the prediction accuracy. The PseAA compositions and three kinds of biological motif features were combined and 12 different parameters that defined as P1-P12 were selected as the input parameters of ID, MNBC, RF, and IBK. The prediction results obtained in this study were significantly better than those of previously developed methods. PMID- 28724994 TI - High-resolution, on-chip RF photonic signal processor using Brillouin gain shaping and RF interference. AB - Integrated microwave photonics has strongly emerged as a next-generation technology to address limitations of conventional RF electronics for wireless communications. High-resolution RF signal processing still remains a challenge due to limitations in technology that offer sub-GHz spectral resolution, in particular at high carrier frequencies. In this paper, we present an on-chip high resolution RF signal processor, capable of providing high-suppression spectral filtering, large phase shifts and ns-scale time delays. This was achieved through tailoring of the Brillouin gain profiles using Stokes and anti-Stokes resonances combined with RF interferometry on a low-loss photonic chip with strong opto acoustic interactions. Using an optical power of <40 mW, reconfigurable filters with a bandwidth of ~20 MHz and an extinction ratio in excess of 30 dB are synthesized. Through the concept of vector addition of RF signals we demonstrate, almost an order of magnitude amplification in the phase and delay compared to devices purely based upon the slow-light effect of Brillouin scattering. This concept allows for versatile and power-efficient manipulation of the amplitude and phase of RF signals on a photonic chip for applications in wireless communications including software defined radios and beam forming. PMID- 28724995 TI - The Expression of Formyl Peptide Receptor 1 is Correlated with Tumor Invasion of Human Colorectal Cancer. AB - Formyl peptide receptors (FPRs) are G protein-coupled chemoattractant receptors expressed mainly in phagocytic leukocytes. High expression of FPRs has also been detected in several cancers but the functions of FPR1 in tumor invasion and metastasis is poorly understood. In this study, we investigated the expression of FPRs in primary human colorectal cancer (CRC) and analyzed the association of FPRs expression with clinicopathological parameters. The levels of FPRs mRNA, especially those of FPR1, were significantly higher in colorectal tumors than in distant normal tissues and adjacent non-tumor tissues. FPR1 mRNA expression was also associated with tumor serosal infiltration. FPR1 protein expression was both in the colorectal epitheliums and tumor infiltrating neutrophils/macrophages. Furthermore, the functions of FPR1 in tumor invasion and tissue repair were investigated using the CRC cell lines SW480 and HT29. Higher cell surface expression of FPR1 is associated with significantly increased migration in SW480 cells compared with HT29 cells that have less FPR1 membrane expression. Finally, genetic deletion of fpr1 increased the survival rate of the resulting knockout mice compared with wild type littermates in a mouse model of colitis-associated colorectal cancer. Our data demonstrate that FPR1 may play an important role in tumor cell invasion in CRC patients. PMID- 28724996 TI - Dynamics of high viscosity contrast confluent microfluidic flows. AB - The laminar nature of microfluidic flows is most elegantly demonstrated via the confluence of two fluids forming two stable parallel flows within a single channel meeting at a highly stable interface. However, maintenance of laminar conditions can become complicated when there is a large viscosity contrast between the neighbouring flows leading to unique instability patterns along their interface. Here, we study the dynamics of high viscosity contrast confluent flows - specifically a core flow made of highly viscous glycerol confined by sheath flows made of water within a microfluidic flow focusing system. Our experiments indicate the formation of tapered core structures along the middle of the channel. Increasing the sheath flow rate shortens the tapered core, and importantly induces local instability patterns along the interface of core-sheath flows. The dynamics of such tapered core structures is governed by the intensity of instability patterns and the length of the core, according to which the core structure can experience stable, disturbed, broken or oscillated regimes. We have studied the dynamics of tapered core structures under these regimes. In particular, we have analysed the amplitude and frequency of core displacements during the broken core and oscillating core regimes, which have not been investigated before. PMID- 28724997 TI - Nitrogen-doped Carbon Dots Mediated Fluorescent on-off Assay for Rapid and Highly Sensitive Pyrophosphate and Alkaline Phosphatase Detection. AB - In this report, a novel fluorescent sensing platform using nitrogen-doped carbon dots (N-CDs) as probes for fluorescence signal transmission has been designed for the detection of significant biomolecules pyrophosphate (PPi) and alkaline phosphatase (ALP). The high fluorescent N-CDs could be selectively quenched by Cu2+, and recovered by the addition of PPi because PPi preferentially binds to Cu2+. Once ALP was introduced into the system, ALP can specifically hydrolyze PPi into Pi, the intense fluorescence of N-CDs could be quenched again due to the recombination of the as-released Cu2+ with N-CDs. So, fluorescence of N-CDs is regulated by an ALP-triggered reaction. Based on this strategy, we demonstrated that N-CDs could serve as a very effective fluorescent sensing platform for label free, sensitive and selective detection of PPi and ALP with low detection limit of 0.16 MUM and 0.4 U/L for PPi and ALP, respectively. Moreover, the assay time is just around 0.5 min for PPi and 30 min for ALP. This developed strategy shows remarkable advantages including sensitive, rapid, simple, convenient, and low cost and so forth. Furthermore, this method was also successfully applied to monitor ALP in human serum, which indicates its great potential for practical applications in biological and clinical diagnosis. PMID- 28724998 TI - Effect of defects controlled by preparation condition and heat treatment on the ferromagnetic properties of few-layer graphene. AB - Magnetism in graphene has stimulated extensive studies to search for novel metal free magnetic device. In this paper, we use a synthesis method far from equilibrium state named self-propagating high temperature synthesis (SHS) to produce few-layer graphene with different defect contents and then use a heat treatment process (vacuum-annealing and air-cooling) to further control the defects in graphene. We find that the type and content of defects in graphene can be controlled by adjusting the mole ratio of reactants (Mg: CaCO3) for SHS reaction and the temperature of the subsequent heat treatment. The deviation of the ratio of reactants from stoichiometric ratio benefits the production of graphene with higher concentration of defects. It is indicated that the temperature of the heat treatment has remarkable influences on the structure of graphene, Raman-sensitive defects can be recovered partly by heat treatment while IR-sensitive defects are closely related with the oxidation and decomposition of the oxygen-containing groups at elevated temperature. This work indicates that SHS is a promising method to produce graphene with special magnetism, and the heat treatment is an effective way to further adjust the magnetism of graphene. This work sheds light on the study to develop carbon materials with controlled ferromagnetism. PMID- 28724999 TI - X-Ray Phase Contrast Tomography Reveals Early Vascular Alterations and Neuronal Loss in a Multiple Sclerosis Model. AB - The degenerative effects of multiple sclerosis at the level of the vascular and neuronal networks in the central nervous system are currently the object of intensive investigation. Preclinical studies have demonstrated the efficacy of mesenchymal stem cell (MSC) therapy in experimental autoimmune encephalomyelitis (EAE), the animal model for multiple sclerosis, but the neuropathology of specific lesions in EAE and the effects of MSC treatment are under debate. Because conventional imaging techniques entail protocols that alter the tissues, limiting the reliability of the results, we have used non-invasive X-ray phase contrast tomography to obtain an unprecedented direct 3D characterization of EAE lesions at micro-to-nano scales, with simultaneous imaging of the vascular and neuronal networks. We reveal EAE-mediated alterations down to the capillary network. Our findings shed light on how the disease and MSC treatment affect the tissues, and promote X-ray phase-contrast tomography as a powerful tool for studying neurovascular diseases and monitoring advanced therapies. PMID- 28725000 TI - Trivalent Y3+ ionic sensor development based on (E)-Methyl-N'-nitrobenzylidene benzenesulfonohydrazide (MNBBSH) derivatives modified with nafion matrix. AB - (E)-Methyl-N'-nitrobenzylidene-benzenesulfonohydrazide (MNBBSH) compounds were synthesized using a condensation procedure from the derivatives of nitrobenzaldehyde and 4-Methyl-benzenesulfonylhydrazine, which crystallized in ethanol and methanol as well as characterized by FTIR, UV-Vis, 1H-NMR, and 13C NMR. MNBBSH structure was confirmed using a single crystal X-ray diffraction technique and used for the detection of selective yttrium ion (Y3+) by I-V system. A thin layer of MNBBSH was deposited onto a glassy carbon electrode (GCE) with 5% nafion for the sensitive and selective Y3+ sensor. The modified MNBBSH/GCE sensor is exhibited the better electrochemical performances such as sensitivity, limit of detection (LOD), linear dynamic range (LDR), limit of quantification (LOQ), short response time, and long term storage ability towards the selective metal ion (Y3+). The calibration curve of 2-MNBBSH/GCE sensor was plotted at +1.1 V over a broad range of Y3+ concentration. Sensitivity, LOD, LDR and LOQ of the fabricated sensor towards Y3+ were calculated from the calibration curve and found as 1.90 pAMUM-1 cm-2, 10.0 pM, 1.0 nM~1.0 mM and 338.33 mM respectively. The 2-MNBBSH/Nafion/GCE sensor was applied to the selective determination of Y3+ in spiked samples such as industrial effluent and real water samples from different sources, and found acceptable and reasonable results. PMID- 28724990 TI - Large meta-analysis of genome-wide association studies identifies five loci for lean body mass. AB - Lean body mass, consisting mostly of skeletal muscle, is important for healthy aging. We performed a genome-wide association study for whole body (20 cohorts of European ancestry with n = 38,292) and appendicular (arms and legs) lean body mass (n = 28,330) measured using dual energy X-ray absorptiometry or bioelectrical impedance analysis, adjusted for sex, age, height, and fat mass. Twenty-one single-nucleotide polymorphisms were significantly associated with lean body mass either genome wide (p < 5 * 10-8) or suggestively genome wide (p < 2.3 * 10-6). Replication in 63,475 (47,227 of European ancestry) individuals from 33 cohorts for whole body lean body mass and in 45,090 (42,360 of European ancestry) subjects from 25 cohorts for appendicular lean body mass was successful for five single-nucleotide polymorphisms in/near HSD17B11, VCAN, ADAMTSL3, IRS1, and FTO for total lean body mass and for three single-nucleotide polymorphisms in/near VCAN, ADAMTSL3, and IRS1 for appendicular lean body mass. Our findings provide new insight into the genetics of lean body mass.Lean body mass is a highly heritable trait and is associated with various health conditions. Here, Kiel and colleagues perform a meta-analysis of genome-wide association studies for whole body lean body mass and find five novel genetic loci to be significantly associated. PMID- 28725002 TI - Precipitates and Particles Coarsening of 9Cr-1.7W-0.4Mo-Co Ferritic Heat Resistant Steel after Isothermal Aging. AB - The precipitates obtained by EPE technology from the 9Cr-1.7W-0.4Mo-Co ferritic heat-resistant steel subject to isothermal aging were investigated using SEM, TEM and XRD. The particle size distribution and the coarsening kinetics of M23C6 with duration of isothermal aging were also analyzed with or without consideration of Laves phase. The results show that the isolated dislocations were detected in delta ferrite interior, and the precipitates on delta ferrite and martensite boundaries are obviously larger than other locations. Fe2W-Laves phase can only be found as duration of aging time to 2000 h, and is preferential to form adjacent to M23C6 particles. The small M23C6 particles firstly coarsen, but the large M23C6 are relatively stable during short aging. The total coarsening rate of M23C6 precipitates is 9.75 * 10-28m3s-1, and the coarsening of M23C6 depends on the formation of Laves phase. PMID- 28725001 TI - 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)-elicited effects on bile acid homeostasis: Alterations in biosynthesis, enterohepatic circulation, and microbial metabolism. AB - 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a persistent environmental contaminant which elicits hepatotoxicity through activation of the aryl hydrocarbon receptor (AhR). Male C57BL/6 mice orally gavaged with TCDD (0.01-30 ug/kg) every 4 days for 28 days exhibited bile duct proliferation and pericholangitis. Mass spectrometry analysis detected a 4.6-fold increase in total hepatic bile acid levels, despite the coordinated repression of genes involved in cholesterol and primary bile acid biosynthesis including Cyp7a1. Specifically, TCDD elicited a >200-fold increase in taurolithocholic acid (TLCA), a potent G protein-coupled bile acid receptor 1 (GPBAR1) agonist associated with bile duct proliferation. Increased levels of microbial bile acid metabolism loci (bsh, baiCD) are consistent with accumulation of TLCA and other secondary bile acids. Fecal bile acids decreased 2.8-fold, suggesting enhanced intestinal reabsorption due to induction of ileal transporters (Slc10a2, Slc51a) and increases in whole gut transit time and intestinal permeability. Moreover, serum bile acids were increased 45.4-fold, consistent with blood-to-hepatocyte transporter repression (Slco1a1, Slc10a1, Slco2b1, Slco1b2, Slco1a4) and hepatocyte-to-blood transporter induction (Abcc4, Abcc3). These results suggest that systemic alterations in enterohepatic circulation, as well as host and microbiota bile acid metabolism, favor bile acid accumulation that contributes to AhR-mediated hepatotoxicity. PMID- 28725003 TI - Distribution of salicifoline in freeze-fixed stems of Magnolia kobus as observed by cryo-TOF-SIMS. AB - Alkaloids are basic nitrogen-containing chemicals that have important physiological and pharmacological characteristics. Many vascular plant species contain alkaloids, and their roles in planta are of interest. However, the detailed distribution of alkaloids remains unclear because of their low water solubility and low concentrations in plants. In this study, we visualized the distribution of salicifoline, a water-soluble quaternary ammonium alkaloid, in the freeze-fixed stems of Magnolia kobus by cryo time-of-flight secondary ion mass spectrometry. Most of the salicifoline was distributed in living phloem tissues. In the xylem, salicifoline was detected in ray cells, lignifying wood fibres, and in vessels in the latest annual ring. The salicifoline distribution in the xylem varied with the cell wall formation stage. These results provide new insights into the storage, transportation, and role of the alkaloid salicifoline in M. kobus. PMID- 28725004 TI - Shift of large-scale atmospheric systems over Europe during late MIS 3 and implications for Modern Human dispersal. AB - Understanding the past dynamics of large-scale atmospheric systems is crucial for our knowledge of the palaeoclimate conditions in Europe. Southeastern Europe currently lies at the border between Atlantic, Mediterranean, and continental climate zones. Past changes in the relative influence of associated atmospheric systems must have been recorded in the region's palaeoarchives. By comparing high resolution grain-size, environmental magnetic and geochemical data from two loess palaeosol sequences in the Lower Danube Basin with other Eurasian palaeorecords, we reconstructed past climatic patterns over Southeastern Europe and the related interaction of the prevailing large-scale circulation modes over Europe, especially during late Marine Isotope Stage 3 (40,000-27,000 years ago). We demonstrate that during this time interval, the intensification of the Siberian High had a crucial influence on European climate causing the more continental conditions over major parts of Europe, and a southwards shift of the Westerlies. Such a climatic and environmental change, combined with the Campanian Ignimbrite/Y-5 volcanic eruption, may have driven the Anatomically Modern Human dispersal towards Central and Western Europe, pointing to a corridor over the Eastern European Plain as an important pathway in their dispersal. PMID- 28725005 TI - Endothelial Dysfunction in Severe Preeclampsia is Mediated by Soluble Factors, Rather than Extracellular Vesicles. AB - In severe early-onset preeclampsia (sPE) the placenta releases soluble angiogenesis-regulating proteins, trophoblast-derived fragments, and extracellular vesicles (EVs). Their relative importance in disease pathogenesis is not presently understood. We explanted placental villi from healthy and sPE women then separated the media into: total-conditioned, EV-depleted and EV enriched media. Three fractions were compared for; angiogenic protein secretion by ELISA, angiogenic and inflammation gene mRNA expression and leukocyte adhesion assay. sPE placental villi secreted significantly less PlGF (70 +/- 18 pg/mL) than preterm controls (338 +/- 203; p = 0.03). sFlt-1:PlGF ratios in total conditioned (115 +/- 29) and EV-depleted media (136 +/- 40) from sPE placental villi were significantly higher than in EV-enriched media (42 +/- 12; p < 0.01) or any preterm or term media. Fluorescent-labeled EVs derived across normal gestation, but not from sPE, actively entered HUVECs. From sPE placental villi, the soluble fraction, but not EV-enriched fraction, significantly repressed angiogenesis (0.83 +/- 0.05 fold, p = 0.02), induced HO-1 mRNA (15.3 +/- 5.1 fold, p < 0.05) and induced leukocyte adhesion (2.2 +/- 0.4 fold, p = 0.04). Soluble media (total-conditioned and EV-depleted media) from sPE placental villi induced endothelial dysfunction in HUVEC, while the corresponding EV-enriched fraction showed no such effects. Our data suggest that soluble factors including angiogenesis-regulating proteins, dominate the vascular pathology of this disease. PMID- 28725006 TI - Diffusive, Displacive Deformations and Local Phase Transformation Govern the Mechanics of Layered Crystals: The Case Study of Tobermorite. AB - Understanding the deformation mechanisms underlying the mechanical behavior of materials is the key to fundamental and engineering advances in materials' performance. Herein, we focus on crystalline calcium-silicate-hydrates (C-S-H) as a model system with applications in cementitious materials, bone-tissue engineering, drug delivery and refractory materials, and use molecular dynamics simulation to investigate its loading geometry dependent mechanical properties. By comparing various conventional (e.g. shear, compression and tension) and nano indentation loading geometries, our findings demonstrate that the former loading leads to size-independent mechanical properties while the latter results in size dependent mechanical properties at the nanometer scales. We found three key mechanisms govern the deformation and thus mechanics of the layered C-S-H: diffusive-controlled and displacive-controlled deformation mechanisms, and strain gradient with local phase transformations. Together, these elaborately classified mechanisms provide deep fundamental understanding and new insights on the relationship between the macro-scale mechanical properties and underlying molecular deformations, providing new opportunities to control and tune the mechanics of layered crystals and other complex materials such as glassy C-S-H, natural composite structures, and manmade laminated structures. PMID- 28725007 TI - Far- and deep-ultraviolet surface plasmon resonance sensors working in aqueous solutions using aluminum thin films. AB - Surface plasmon resonance (SPR) sensors detect refractive index changes on metal thin films and are frequently used in aqueous solutions as bio- and chemical sensors. Recently, we proposed new SPR sensors using aluminum (Al) thin films that work in the far- and deep-ultraviolet (FUV-DUV, 120-300 nm) regions and investigated SPR properties by an attenuated total reflectance (ATR) based spectrometer. The FUV-DUV-SPR sensors are expected to have three advantages compared to visible-SPR sensors: higher sensitivity, material selectivity, and surface specificity. However, in this study, it was revealed that the Al thin film on a quartz prism cannot be used as the FUV-DUV-SPR sensor in water solutions. This is because its SPR wavelength shifts to the visible region owing to the presence of water. On the other hand, the SPR wavelength of the Al thin film on the sapphire prism remained in the DUV region even in water. In addition, the SPR wavelength shifted to longer wavelengths with increasing refractive index on the Al thin film. These results mean that the Al thin film on the sapphire prism can be used as the FUV-DUV-SPR sensor in solutions, which may lead to the development of novel and sophisticated SPR sensors. PMID- 28725008 TI - Methylglyoxal and Advanced Glycation End products: Insight of the regulatory machinery affecting the myogenic program and of its modulation by natural compounds. AB - Methylglyoxal (MG) is a reactive dicarbonyl intermediate and a precursor of advanced glycation end products (AGEs). The authors investigated the role played by AGEs in muscle myopathy and the amelioration of its effects by curcumin and gingerol. In addition to producing phenotypical changes, MG increased oxidative stress and reduced myotube formation in C2C12 cells. RAGE (receptor for AGEs) expression was up-regulated and MYOD and myogenin (MYOG) expressions were concomitantly down-regulated in MG-treated cells. Interestingly, AGE levels were higher in plasma (~32 fold) and muscle (~26 fold) of diabetic mice than in control mice. RAGE knock-down (RAGEkd) reduced the expressions of MYOD and MYOG and myotube formation in C2C12 cells. In silico studies of interactions between curcumin or gingerol and myostatin (MSTN; an inhibitor of myogenesis) and their observed affinities for activin receptor type IIB (ACVRIIB) suggested curcumin and gingerol reduce the interaction between MSTN and ACVRIIB. The findings of this study suggest enhanced AGE production and subsequent RAGE-AGE interaction obstruct the muscle development program, and that curcumin and gingerol attenuate the effect of AGEs on myoblasts. PMID- 28725010 TI - Glucose Deficiency Elevates Acid-Sensing Ion Channel 2a Expression and Increases Seizure Susceptibility in Temporal Lobe Epilepsy. AB - Brain hypometabolism is a common epilepsy-related finding in both patients and animal models. Fluorodeoxyglucose positron emission tomography studies have shown that recurrent seizures lead to reduced glucose metabolism in certain brain regions, but no studies have definitively determined whether this induces epileptogenesis. There is evidence that acid-sensing ion channel 2a (ASIC2a) affects epilepsy susceptibility. Transcription factor CP2 (TFCP2) regulates ASIC2a expression. We report that suppressed TFCP2 expression and elevated ASIC2a expression were associated with glucose hypometabolism in the hippocampi of humans with epilepsy and of rat epilepsy model brains. In cultured PC12 cells, we determined that glucose deficiency led to TFCP2 downregulating ASIC2a. Moreover, electrophysiological recordings from cultured rat hippocampal slices showed that ASIC2a overexpression resulted in more action potentials in CA1 pyramidal neurons and increased seizure susceptibility. Our findings suggest that hippocampal glucose hypometabolism elevates ASIC2a expression by suppressing TFCP2 expression, which further enhances the intrinsic excitability of CA1 pyramidal neurons and increases seizure susceptibility in patients with temporal lobe epilepsy. PMID- 28725009 TI - The salivary microbiome as an indicator of carcinogenesis in patients with oropharyngeal squamous cell carcinoma: A pilot study. AB - This study aimed to undertake an initial, comparative analysis of the oral salivary microbiome of patients with oral and oropharyngeal squamous cell carcinoma versus healthy controls. This project, conceived as a pilot study, included 11 patients (1 female, 10 male, mean age 61.6 yrs., SD = 8.2 yrs.) and 11 healthy controls (1 female, 10 male, mean age 46.7 yrs., SD = 15.1 yrs.). Samples of saliva were analysed by high-throughput sequencing of the 16S rRNA gene using the MiSeq platform. Sequence data revealed microbial changes that may mirror disease progression and reflect clinical preconditions such as age, alcohol consumption, tumour size, lymph node status, smoking habit, and tumour HPV-positivity. Consequently, mapping microbial changes in patients with oral and oropharyngeal squamous cell carcinomas might improve our understanding of the pathobiology of the disease, and help in the design of novel diagnostic and treatment strategies. PMID- 28725011 TI - Observed trends in the magnitude and persistence of monthly temperature variability. AB - Climate variability is critically important for nature and society, especially if it increases in amplitude and/or fluctuations become more persistent. However, the issues of whether climate variability is changing, and if so, whether this is due to anthropogenic forcing, are subjects of ongoing debate. Increases in the amplitude and persistence of temperature fluctuations have been detected in some regions, e.g. the North Pacific, but there is no agreed global signal. Here we systematically scan monthly surface temperature indices and spatial datasets to look for trends in variance and autocorrelation (persistence). We show that monthly temperature variability and autocorrelation increased over 1957-2002 across large parts of the North Pacific, North Atlantic, North America and the Mediterranean. Furthermore, (multi)decadal internal climate variability appears to influence trends in monthly temperature variability and autocorrelation. Historically-forced climate models do not reproduce the observed trends in temperature variance and autocorrelation, consistent with the models poorly capturing (multi)decadal internal climate variability. Based on a review of established spatial correlations and corresponding mechanistic 'teleconnections' we hypothesise that observed slowing down of sea surface temperature variability contributed to observed increases in land temperature variability and autocorrelation, which in turn contributed to persistent droughts in North America and the Mediterranean. PMID- 28725012 TI - Phycocyanin attenuates pulmonary fibrosis via the TLR2-MyD88-NF-kappaB signaling pathway. AB - Our aim was to investigate the effects of phycocyanin (PC) on bleomycin (BLM) induced pulmonary fibrosis (PF). In this study, C57 BL/6 wild-type (WT) mice and toll-like receptor (TLR) 2 deficient mice were treated with PC for 28 days following BLM exposure. Serum and lung tissues were collected on days 3, 7 and 28. Data shows PC significantly decreased the levels of hydroxyproline (HYP), vimentin, surfactant-associated protein C (SP-C), fibroblast specific protein-1 (S100A4) and alpha-smooth muscle actin (alpha-SMA) but dramatically increased E cadherin and podoplanin (PDPN) expression on day 28. Moreover, PC greatly decreased the levels of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF alpha) and myeloperoxidase (MPO) at the earlier time. Reduced expression of key genes in the TLR2 pathway was also detected. Compared with WT mice, TLR2 deficient mice exhibited less injury, and the protective effect of PC was partly diminished in this background. These data indicate the anti-fibrotic effects of PC may be mediated by reducing W/D ratio, MPO, IL-6, TNF-alpha, protecting type I alveolar epithelial cells, inhibiting fibroblast proliferation, attenuating epithelial-mesenchymal transitions (EMT) and reducing oxidative stress. The TLR2 MyD88-NF-kappaB pathway plays an important role in PC-mediated reduction in pulmonary fibrosis. PMID- 28725014 TI - Su-Schrieffer-Heeger chain with one pair of [Formula: see text]-symmetric defects. AB - The topologically nontrivial edge states induce [Formula: see text] transition in Su-Schrieffer-Heeger (SSH) chain with one pair of gain and loss at boundaries. In this study, we investigated a pair of [Formula: see text]-symmetric defects located inside the SSH chain, in particular, the defects locations are at the chain centre. The [Formula: see text] symmetry breaking of the bound states leads to the [Formula: see text] transition, the [Formula: see text]-symmetric phases and the localized states were studied. In the broken [Formula: see text] symmetric phase, all energy levels break simultaneously in topologically trivial phase; however, two edge states in topologically nontrivial phase are free from the influence of the [Formula: see text]-symmetric defects. We discovered [Formula: see text]-symmetric bound states induced by the [Formula: see text] symmetric local defects at the SSH chain centre. The [Formula: see text] symmetric bound states significantly increase the [Formula: see text] transition threshold and coalesce to the topologically protected zero mode with vanishing probabilities on every other site of the left-half chain and the right-half chain, respectively. PMID- 28725013 TI - Baseline value of intrahepatic HBV DNA over cccDNA predicts patient's response to interferon therapy. AB - Methodology for accurate quantification of intra-hepatic cccDNA has long been a technical challenge, yet it is highly desired in the clinic. Here, we developed a sensitive method for quantification of intrahepatic cccDNA in liver biopsies from patients, which allowed to predict patient's response to interferon therapy at baseline. Twenty-five patients with HBeAg+ CHB were recruited and liver biopsies were obtained at baseline and 1-year after interferon treatment, respectively. Both intrahepatic cccDNA and HBV DNA were absolutely quantified by a droplet digital PCR amplification system. Patients were categorized as either responder or non-responder group based on their HBeAg status 1-year after interferon therapy. Levels of both intrahepatic HBV DNA and HBV cccDNA were significantly reduced after interferon treatment among the responders, but not the non responders, in comparison with their levels at baseline. Baseline values of intrahepatic HBV DNA over cccDNA significantly correlated with patient's response to PEG-IFN therapy (P = 0.000). In addition, HBeAg seroconversion also correlates with a significant reduction in intrahepatic pgRNA production among the responders after interferon therapy (P = 0.030). In conclusion, our results suggest that baseline value of intrahepatic HBV DNA over cccDNA may be a preferable indicator for selecting appropriate patients for IFN-based therapy in the clinic. PMID- 28725015 TI - All-printed highly sensitive 2D MoS2 based multi-reagent immunosensor for smartphone based point-of-care diagnosis. AB - Immunosensors are used to detect the presence of certain bio-reagents mostly targeted at the diagnosis of a condition or a disease. Here, a general purpose electrical immunosensor has been fabricated for the quantitative detection of multiple bio-reagents through the formation of an antibody-antigen pair. The sensors were fabricated using all printing approaches. 2D transition metal dichalcogenide (TMDC) MoS2 thin film was deposited using Electrohydrodynamic atomization (EHDA) on top of an interdigitated transducer (IDT) electrode fabricated by reverse offset printing. The sensors were then treated with three different types of antibodies that were immobilized by physisorption into the highly porous multi-layered structure of MoS2 active layer. BSA was used as blocking agent to prevent non-specific absorption (NSA). The sensors were then employed for the targeted detection of the specific antigens including prostate specific antigen (PSA), mouse immunoglobulin-G (IgG), and nuclear factor kappa light-chain-enhancer of activated B cells (NF-kappaB). IgG was then selected to test the sensors for point of care (POC) diagnosis through a specially designed electronic readout system for sensors and interfacing it with a smartphone using Bluetooth connection. The sensors showed promising performance in terms of stability, specificity, repeatability, sensitivity, limit of detection (LoD), and range of detection (RoD). PMID- 28725016 TI - Strong geologic methane emissions from discontinuous terrestrial permafrost in the Mackenzie Delta, Canada. AB - Arctic permafrost caps vast amounts of old, geologic methane (CH4) in subsurface reservoirs. Thawing permafrost opens pathways for this CH4 to migrate to the surface. However, the occurrence of geologic emissions and their contribution to the CH4 budget in addition to recent, biogenic CH4 is uncertain. Here we present a high-resolution (100 m * 100 m) regional (10,000 km2) CH4 flux map of the Mackenzie Delta, Canada, based on airborne CH4 flux data from July 2012 and 2013. We identify strong, likely geologic emissions solely where the permafrost is discontinuous. These peaks are 13 times larger than typical biogenic emissions. Whereas microbial CH4 production largely depends on recent air and soil temperature, geologic CH4 was produced over millions of years and can be released year-round provided open pathways exist. Therefore, even though they only occur on about 1% of the area, geologic hotspots contribute 17% to the annual CH4 emission estimate of our study area. We suggest that this share may increase if ongoing permafrost thaw opens new pathways. We conclude that, due to permafrost thaw, hydrocarbon-rich areas, prevalent in the Arctic, may see increased emission of geologic CH4 in the future, in addition to enhanced microbial CH4 production. PMID- 28725017 TI - Stoichiometry of natural bacterial assemblages from lakes located across an elevational gradient. AB - Heterotrophic bacteria are thought to be phosphorus-rich organisms with relatively homeostatic stoichiometry, but the elemental composition of natural bacterial communities has rarely been assessed. Here we tested whether bacterial stoichiometry changes with the trophic status of lakes by assessing the elemental composition of the bacterial-dominated (hereafter microbial) fraction together with that of the dissolved and seston fractions in 11 lakes situated along an elevational gradient. The stoichiometry of these three size-fractions was analyzed during the thermal stratification and mixing periods in composite water samples and in the water layer of the deep chlorophyll-a maximum. In addition, we analyzed the relative abundance of the most common bacterial groups in the lakes. Our results show that the microbial fraction was always enriched in phosphorus compared to the dissolved fraction, irrespectively of the lake trophic status. Further, they indicate that the elemental composition of bacteria in mountain lakes is at least seasonally very dynamic, resulting not only from changes in the nutrient ratios of the resource itself, but probably from changes in the composition of the dominant bacterial taxa too, though at the taxonomic level analyzed, we did not find evidence for this. PMID- 28725018 TI - Morphology Transition Engineering of ZnO Nanorods to Nanoplatelets Grafted Mo8O23 MoO2 by Polyoxometalates: Mechanism and Possible Applicability to other Oxides. AB - A new fundamental mechanism for reliable engineering of zinc oxide (ZnO) nanorods to nanoplatelets grafted Mo8O23-MoO2 mixed oxide with controlled morphology, composition and precise understanding of the nanoscale reaction mechanism was developed. These hybrid nanomaterials are gaining interest due to their potential use for energy, catalysis, biomedical and other applications. As an introductory section, we demonstrate a new expansion for the concept 'materials engineering' by discussing the fabrication of metal oxides nanostructures by bottom-up approach and carbon nanoparticles by top-down approach. Moreover, we propose a detailed mechanism for the novel phenomenon that was experienced by ZnO nanorods when treated with phosphomolybdic acid (PMA) under ultra-sonication stimulus. This approach is expected to be the basis of a competitive fabrication approach to 2D hybrid nanostructures. We will also discuss a proposed mechanism for the catalytic deposition of Mo8O23-MoO2 mixed oxide over ZnO nanoplatelets. A series of selection rules (SRs) which applied to ZnO to experience morphology transition and constitute Abdelmohsen theory for morphology transition engineering (ATMTE) will be demonstrated through the article, besides a brief discussion about possibility of other oxides to obey this theory. PMID- 28725019 TI - High dose sertraline monotherapy fails to protect rhesus macaques from lethal challenge with Ebola virus Makona. AB - The recent epidemic of Ebola virus disease in West Africa resulted in an unprecedented number of cases and deaths. Due to the scope of the outbreak combined with the lack of available approved treatment options, there was strong motivation to investigate any potential drug which had existing data reporting anti-Ebola activity. Drugs with demonstrated antiviral activity in the nonhuman primate models already approved for another indication or for which there was existing safety data were considered to be priorities for evaluation by the World Health Organization. Sertraline hydrochloride was reported to have anti-Ebola activity in vitro alone and in combination with other approved drugs. Although the efficacy was less than 100% in the murine model, the established safety profile of this product, the potential benefit alone and in combination, as well as the lack of other available options prioritized this compound for testing in the Ebola virus intramuscular rhesus macaque challenge model. Using a blinded dosing strategy, we demonstrated that high dose sertraline monotherapy provided no benefit for the prevention of Ebola virus disease in rhesus macaques with regards to reduction of viral load, morbidity, or survival highlighting the challenges of translating results between in vitro and in vivo models. PMID- 28725020 TI - Neuronal imaging with ultrahigh dynamic range multiphoton microscopy. AB - Multiphoton microscopes are hampered by limited dynamic range, preventing weak sample features from being detected in the presence of strong features, or preventing the capture of unpredictable bursts in sample strength. We present a digital electronic add-on technique that vastly improves the dynamic range of a multiphoton microscope while limiting potential photodamage. The add-on provides real-time negative feedback to regulate the laser power delivered to the sample, and a log representation of the sample strength to accommodate ultrahigh dynamic range without loss of information. No microscope hardware modifications are required, making the technique readily compatible with commercial instruments. Benefits are shown in both structural and in-vivo functional mouse brain imaging applications. PMID- 28725021 TI - Bovine milk-derived exosomes from colostrum are enriched with proteins implicated in immune response and growth. AB - Exosomes are extracellular vesicles secreted by multiple cell types into the extracellular space. They contain cell-state specific cargos which often reflects the (patho)physiological condition of the cells/organism. Milk contains high amounts of exosomes and it is unclear whether their cargo is altered based on the lactation stage of the organism. Here, we isolated exosomes from bovine milk that were obtained at various stages of lactation and examined the content by quantitative proteomics. Exosomes were isolated by OptiPrep density gradient centrifugation from milk obtained from cow after 24, 48 and 72 h post calving. As control, exosomes were also isolated from cows during mid-lactation period which has been referred to as mature milk (MM). Biochemical and biophysical characterization of exosomes revealed the high abundance of exosomes in colostrum and MM samples. Quantitative proteomics analysis highlighted the change in the proteomic cargo of exosomes based on the lactation state of the cow. Functional enrichment analysis revealed that exosomes from colostrum are significantly enriched with proteins that can potentially regulate the immune response and growth. This study highlights the importance of exosomes in colostrum and hence opens up new avenues to exploit these vesicles in the regulation of the immune response and growth. PMID- 28725023 TI - Surface Energy Driven Cubic-to-Hexagonal Grain Growth of Ge2Sb2Te5 Thin Film. AB - Phase change memory (PCM) is a promising nonvolatile memory to reform current commercial computing system. Inhibiting face-centered cubic (f-) to hexagonal (h ) phase transition of Ge2Sb2Te5 (GST) thin film is essential for realizing high density, high-speed, and low-power PCM. Although the atomic configurations of f- and h-lattices of GST alloy and the transition mechanisms have been extensively studied, the real transition process should be more complex than previous explanations, e.g. vacancy-ordering model for f-to-h transition. In this study, dynamic crystallization procedure of GST thin film was directly characterized by in situ heating transmission electron microscopy. We reveal that the equilibrium to h-phase is more like an abnormal grain growth process driven by surface energy anisotropy. More specifically, [0001]-oriented h-grains with the lowest surface energy grow much faster by consuming surrounding small grains, no matter what the crystallographic reconfigurations would be on the frontier grain-growth boundaries. We argue the widely accepted vacancy-ordering mechanism may not be indispensable for the large-scale f-to-h grain growth procedure. The real-time observations in this work contribute to a more comprehensive understanding of the crystallization behavior of GST thin film and can be essential for guiding its optimization to achieve high-performance PCM applications. PMID- 28725022 TI - Action video games improve reading abilities and visual-to-auditory attentional shifting in English-speaking children with dyslexia. AB - Dyslexia is characterized by difficulties in learning to read and there is some evidence that action video games (AVG), without any direct phonological or orthographic stimulation, improve reading efficiency in Italian children with dyslexia. However, the cognitive mechanism underlying this improvement and the extent to which the benefits of AVG training would generalize to deep English orthography, remain two critical questions. During reading acquisition, children have to integrate written letters with speech sounds, rapidly shifting their attention from visual to auditory modality. In our study, we tested reading skills and phonological working memory, visuo-spatial attention, auditory, visual and audio-visual stimuli localization, and cross-sensory attentional shifting in two matched groups of English-speaking children with dyslexia before and after they played AVG or non-action video games. The speed of words recognition and phonological decoding increased after playing AVG, but not non-action video games. Furthermore, focused visuo-spatial attention and visual-to-auditory attentional shifting also improved only after AVG training. This unconventional reading remediation program also increased phonological short-term memory and phoneme blending skills. Our report shows that an enhancement of visuo-spatial attention and phonological working memory, and an acceleration of visual-to auditory attentional shifting can directly translate into better reading in English-speaking children with dyslexia. PMID- 28725024 TI - A novel de novo mutation in CSNK2A1: reinforcing the link to neurodevelopmental abnormalities and dysmorphic features. PMID- 28725025 TI - An atypical case of SPG56/CYP2U1-related spastic paraplegia presenting with delayed myelination. AB - Hereditary spastic paraplegia (HSP) is a neurological disorder characterized by a progressive spasticity and muscle weakness of the lower limbs. It is divided into two subtypes, uncomplicated and complicated forms. Biallelic mutations in the cytochrome P450 2U1 gene (CYP2U1) are associated with spastic paraplegia type 56 (SPG56), manifesting both uncomplicated and complicated HSP. Accompanying clinical features include intellectual disability, dystonia, cerebellar ataxia, subclinical peripheral neuropathy, visual impairment, as well as abnormalities in brain magnetic resonance imaging. As a rare clinical feature, delayed myelination has previously been reported in only two patients with CYP2U1 mutations. Here, we report a patient with SPG56 with novel compound heterozygous mutations in CYP2U1 which were identified by whole exome sequencing. Our patient exhibited complex features together with delayed myelination, broadening the phenotypic spectrum of SPG56, and implying that CYP2U1 should be screened in HSP with delayed myelination. PMID- 28725026 TI - Microbiome analysis and confocal microscopy of used kitchen sponges reveal massive colonization by Acinetobacter, Moraxella and Chryseobacterium species. AB - The built environment (BE) and in particular kitchen environments harbor a remarkable microbial diversity, including pathogens. We analyzed the bacterial microbiome of used kitchen sponges by 454-pyrosequencing of 16S rRNA genes and fluorescence in situ hybridization coupled with confocal laser scanning microscopy (FISH-CLSM). Pyrosequencing showed a relative dominance of Gammaproteobacteria within the sponge microbiota. Five of the ten most abundant OTUs were closely related to risk group 2 (RG2) species, previously detected in the BE and kitchen microbiome. Regular cleaning of sponges, indicated by their users, significantly affected the microbiome structure. Two of the ten dominant OTUs, closely related to the RG2-species Chryseobacterium hominis and Moraxella osloensis, showed significantly greater proportions in regularly sanitized sponges, thereby questioning such sanitation methods in a long term perspective. FISH-CLSM showed an ubiquitous distribution of bacteria within the sponge tissue, concentrating in internal cavities and on sponge surfaces, where biofilm-like structures occurred. Image analysis showed local densities of up to 5.4 * 1010 cells per cm3, and confirmed the dominance of Gammaproteobacteria. Our study stresses and visualizes the role of kitchen sponges as microbiological hot spots in the BE, with the capability to collect and spread bacteria with a probable pathogenic potential. PMID- 28725027 TI - Strong Coherent Light Amplification with Double Electromagnetically Induced Transparency Coherences. AB - We experimentally demonstrate coherent amplification of probe field in a tripod type atoms driven by strong coupling, signal and weak probe fields. We suppress linear and nonlinear atomic absorptions for resonant and near resonant probe via double electromagnetically induced transparency (DEIT). Combining these advantages of suppressed absorption along with temperature- or atomic-density controlled transfer of population(ToP) between hyperfine ground states, we can induce near-resonant amplification of probe through stimulated Raman scattering(SRS) pumped by low-intensity signal field. The increased population difference of initial and final states of SRS due to increased ToP rate, together with reduced absorption at the second EIT window in an optically thick Cesium vapor, gives rise to highly effective coherent amplification. PMID- 28725028 TI - Detection and quantitation of copy number variation in the voltage-gated sodium channel gene of the mosquito Culex quinquefasciatus. AB - Insecticide resistance is typically associated with alterations to the insecticidal target-site or with gene expression variation at loci involved in insecticide detoxification. In some species copy number variation (CNV) of target site loci (e.g. the Ace-1 target site of carbamate insecticides) or detoxification genes has been implicated in the resistance phenotype. We show that field-collected Ugandan Culex quinquefasciatus display CNV for the voltage gated sodium channel gene (Vgsc), target-site of pyrethroid and organochlorine insecticides. In order to develop field-applicable diagnostics for Vgsc CN, and as a prelude to investigating the possible association of CN with insecticide resistance, three assays were compared for their accuracy in CN estimation in this species. The gold standard method is droplet digital PCR (ddPCR), however, the hardware is prohibitively expensive for widespread utility. Here, ddPCR was compared to quantitative PCR (qPCR) and pyrosequencing. Across all platforms, CNV was detected in ~10% of mosquitoes, corresponding to three or four copies (per diploid genome). ddPCR and qPCR-Std-curve yielded similar predictions for Vgsc CN, indicating that the qPCR protocol developed here can be applied as a diagnostic assay, facilitating monitoring of Vgsc CN in wild populations and the elucidation of association between the Vgsc CN and insecticide resistance. PMID- 28725029 TI - Prominent differences in left ventricular performance and myocardial properties between right ventricular and left ventricular-based pacing modes in rats. AB - Biventricular pacing is an important modality to improve left ventricular (LV) synchronization and long-term function. However, the biological effects of this treatment are far from being elucidated and existing animal models are limited and demanding. Recently, we introduced an implanted device for double-site epicardial pacing in rats and echocardiographically demonstrated favorable effects of LV and biventricular (LV-based) pacing modes typically observed in humans. Here, this new animal model was further characterized. Electrodes were implanted either on the right atria (RA) and right ventricle (RV) or on the RV and LV. Following recovery, rats were either used for invasive hemodynamic measurements (pressure-volume analysis) or exposed to sustained RV vs. biventricular tachypacing for 3 days. RV pacing compromised, while LV-based pacing modes markedly enhanced cardiac performance. Changes in LV performance were associated with prominent compensatory changes in arterial resistance. Sustained RV tachypacing increased the electrocardiogram QTc interval by 7.9 +/- 3.1 ms (n = 6, p < 0.05), dispersed refractoriness between the right and left pacing sites and induced important molecular changes mainly in the early activated septal tissue. These effects were not observed during biventricular tachypacing (n = 6). Our results demonstrate that the rat is an attractive new model to study the biological consequences of LV dyssynchrony and resynchronization. PMID- 28725030 TI - A Practical Model Evaluating Antiviral Cytokines by Natural Killer Cells in Treatment Naive Patients with Chronic Hepatitis B Virus Infection. AB - Natural killer (NK) cells play a major role in anti-viral immunity as first line defense during hepatitis B infection, particularly in untreated patients whose T cells functions are profoundly impaired. Cytokine interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha produced by NK cells are important anti-viral factors. However, there is lack of a quantifiable model to evaluate cytokine responses by NK cells. In this study, almost half of the patients (47.9%) beyond treatment criteria had high cytokine activity, although it was lower than those recommended for antiviral therapy (78.2%). Moreover, we developed a model that low levels of HBsAg, HBcAb, and albumin and high fibrosis values predicted strong antiviral cytokine production by NK cells. Based on the cut-off score (0.361) obtained from the multivariable model, patients with 67%, 8%, 92%, and 74% in immune-active (IA), immune-tolerant (IT), immune-inactive (IC), and grey zone (GZ), respectively, showed active antiviral cytokines produced by NK cells. These results suggest that those who possess activated cytokine responses beyond the current treatment criteria may have potential implications for the timing of antiviral therapy to achieve better virus control. PMID- 28725031 TI - Polarization-entangled photon pair sources based on spontaneous four wave mixing assisted by polarization mode dispersion. AB - Photonic-based qubits and integrated photonic circuits have enabled demonstrations of quantum information processing (QIP) that promises to transform the way in which we compute and communicate. To that end, sources of polarization entangled photon pair states are an important enabling technology. However, such states are difficult to prepare in an integrated photonic circuit. Scalable semiconductor sources typically rely on nonlinear optical effects where polarization mode dispersion (PMD) degrades entanglement. Here, we directly generate polarization-entangled states in an AlGaAs waveguide, aided by the PMD and without any compensation steps. We perform quantum state tomography and report a raw concurrence as high as 0.91 +/- 0.01 observed in a 1,100-nm-wide waveguide. The scheme allows direct Bell state generation with an observed maximum fidelity of 0.90 +/- 0.01 from another (800-nm-wide) waveguide. Our demonstration paves the way for sources that allow for the implementation of polarization-encoded protocols in large-scale quantum photonic circuits. PMID- 28725032 TI - Remora cranial vein morphology and its functional implications for attachment. AB - Remora fishes adhere to, and maintain long-term, reversible attachment with, surfaces of varying roughness and compliance under wetted high-shear conditions using an adhesive disc that evolved from the dorsal fin spines typical of other fishes. Evolution of this complex hierarchical structure required extensive reorganization of the skull and fin spines, but the functional role of the soft tissues of the disc are poorly understood. Here I show that remora cranial veins are highly-modified in comparison to those of other vertebrates; they are transposed anteriorly and enlarged, and lie directly ventral to the disc on the dorsum of the cranium. Ancestrally, these veins lie inside the neurocranium, in the dura ventral to the brain, and return blood from the eyes, nares, and brain to the heart. Repositioning of these vessels to lie in contact with the ventral surface of the disc lamellae implies functional importance associated with the adhesive mechanism. The position of the anterior cardinal sinus suggests that it may aid in pressurization equilibrium during attachment by acting as a hydraulic differential. PMID- 28725033 TI - Interferometric rotating point spread function. AB - Rotating point spread functions (PSF), such as the double helix (DH) PSF, are widely used in localization-based super-resolution imaging because of their large working depth range. In this article, we propose an interferometric DH PSF (iDH PSF) using two opposed objective lenses as in the 4Pi microscope. In the proposed iDH PSF, the super-resolution in the axial PSF is transferred to the azimuthal rotation. Moreover, we design an iDH PSF whose imaging range reaches 3 MUm, which is roughly 3 times as much as that which can be obtained by using other interferometric localization-based super-resolution imaging methods. PMID- 28725035 TI - Systemic lupus erythematosus: A repertoire for disaster. PMID- 28725034 TI - Common shared genetic variation behind decreased risk of breast cancer in celiac disease. AB - There is epidemiologic evidence showing that women with celiac disease have reduced risk of later developing breast cancer, however, the etiology of this association is unclear. Here, we assess the extent of genetic overlap between the two diseases. Through analyses of summary statistics on densely genotyped immunogenic regions, we show a significant genetic correlation (r = -0.17, s.e. 0.05, P < 0.001) and overlap (P permuted < 0.001) between celiac disease and breast cancer. Using individual-level genotype data from a Swedish cohort, we find higher genetic susceptibility to celiac disease summarized by polygenic risk scores to be associated with lower breast cancer risk (ORper-SD, 0.94, 95% CI 0.91 to 0.98). Common single nucleotide polymorphisms between the two diseases, with low P-values (P CD < 1.00E-05, P BC <= 0.05), mapped onto genes enriched for immunoregulatory and apoptotic processes. Our results suggest that the link between breast cancer and celiac disease is due to a shared polygenic variation of immune related regions, uncovering pathways which might be important for their development. PMID- 28725036 TI - Paediatric rheumatic disease: What is the best definition of clinical remission in JIA? AB - This corrects the article DOI: 10.1038/nrrheum.2017.105. PMID- 28725037 TI - Bursting dynamics in the normal and failing hearts. AB - A failing heart differs from healthy hearts by an array of symptomatic characteristics, including impaired Ca2+ transients, upregulation of Na+/Ca2+ exchanger function, reduction of Ca2+ uptake to sarcoplasmic reticulum, reduced K+ currents, and increased propensity to arrhythmias. While significant efforts have been made in both experimental studies and model development to display the causes of heart failure, the full process of deterioration from a healthy to a failing heart yet remains deficiently understood. In this paper, we analyze a highly detailed mathematical model of mouse ventricular myocytes to disclose the key mechanisms underlying the continual transition towards a state of heart failure. We argue that such a transition can be described in mathematical terms as a sequence of bifurcations that the healthy cells undergo while transforming into failing cells. They include normal action potentials and [Ca2+]i transients, action potential and [Ca2+]i alternans, and bursting behaviors. These behaviors where supported by experimental studies of heart failure. The analysis of this model allowed us to identify that the slow component of the fast Na+ current is a key determining factor for the onset of bursting activity in mouse ventricular myocytes. PMID- 28725038 TI - Genomic characterization of novel IncFII-type multidrug resistant plasmids p0716 KPC and p12181-KPC from Klebsiella pneumoniae. AB - This study aimed to genetically characterize two fully-sequenced novel IncFII type multidrug resistant (MDR) plasmids, p0716-KPC and p12181-KPC, recovered from two different clinical Klebsiella pneumoniae isolates. p0716-KPC and p12181-KPC had a very similar genomic content. The backbones of p0716-KPC/p12181-KPC contained two different replicons (belonging to a novel IncFII subtype and the Rep_3 family), the IncFIIK and IncFIIY maintenance regions, and conjugal transfer gene sets from IncFIIK-type plasmids and unknown origins. p0716-KPC and p12181 KPC carried similar three accessory resistance regions, namely DeltaTn6209, a MDR region, and the bla KPC-2 region. Resistance genes bla KPC-2, mph(A), strAB, aacC2, qacEDelta1, sul1, sul2, and dfrA25, which are associated with transposons, integrons, and insertion sequence-based mobile units, were located in these accessory regions. p0716-KPC carried two additional resistance genes: aphA1a and bla TEM-1. Together, our analyses showed that p0716-KPC and p12181-KPC belong to a novel IncFII subtype and display a complex chimeric nature, and that the carbapenem resistance gene bla KPC-2 coexists with a lot of additional resistance genes on these two plasmids. PMID- 28725039 TI - Surface chemistry and germination improvement of Quinoa seeds subjected to plasma activation. AB - Plasma treatment is recognized as a suitable technology to improve germination efficiency of numerous seeds. In this work Quinoa seeds have been subjected to air plasma treatments both at atmospheric and low pressure and improvements found in germination rate and percentage of success. Seed water uptake by exposure to water vapor, although slightly greater for plasma treated seeds, did not justify the observed germination improvement. To identify other possible factors contributing to germination, the chemical changes experienced by outer parts of the seed upon plasma exposure have been investigated by X-ray photoemission spectroscopy (XPS) and scanning electron microscopy (SEM-EDX). XPS revealed that the outer layers of the Quinoa plasma treated seeds were highly oxidized and appeared enriched in potassium ions and adsorbed nitrate species. Simultaneously, SEM-EDX showed that the enrichment in potassium and other mineral elements extended to the seed pericarp and closer zones. The disappearance from the surface of both potassium ions and nitrate species upon exposure of the plasma treated seeds to water vapor is proposed as a factor favoring germination. The use of XPS to study chemical changes at seed surfaces induced by plasma treatments is deemed very important to unravel the mechanisms contributing to germination improvement. PMID- 28725040 TI - Artificial dielectric polarizing-beamsplitter and isolator for the terahertz region. AB - We demonstrate a simple and effective strategy for implementing a polarizing beamsplitter for the terahertz spectral region, based on an artificial dielectric medium that is scalable to a range of desired frequencies. The artificial dielectric medium consists of a uniformly spaced stack of metal plates, which is electromagnetically equivalent to a stacked array of parallel-plate waveguides. The operation of the device relies on both the lowest-order, transverse-electric and transverse-magnetic modes of the parallel-plate waveguide. This is in contrast to previous work that relied solely on the transverse-electric mode. The fabricated polarizing beamsplitter exhibits extinction ratios as high as 42 dB along with insertion losses as low as 0.18 dB. Building on the same idea, we also demonstrate an isolator with non-reciprocal transmission, providing high isolation and low insertion loss at a select design frequency. The performance of our isolator far exceeds that of other experimentally demonstrated terahertz isolators, and indeed, even rivals that of commercially available isolators for optical wavelengths. Because these waveguide-based artificial dielectrics are low loss, inexpensive, and easy to fabricate, this approach offers a promising new route for polarization control of free-space terahertz beams. PMID- 28725041 TI - A screen for novel hepatitis C virus RdRp inhibitor identifies a broad-spectrum antiviral compound. AB - Hepatitis C virus (HCV) is a global pathogen and infects more than 185 million individuals worldwide. Although recent development of direct acting antivirals (DAA) has shown promise in HCV therapy, there is an urgent need for the development of more affordable treatment options. We initiated this study to identify novel inhibitors of HCV through screening of compounds from the National Cancer Institute (NCI) diversity dataset. Using cell-based assays, we identified NSC-320218 as a potent inhibitor against HCV with an EC50 of 2.5 MUM and CC50 of 75 MUM. The compound inhibited RNA dependent RNA polymerase (RdRp) activity of all six major HCV genotypes indicating a pan-genotypic effect. Limited structure function analysis suggested that the entire molecule is necessary for the observed antiviral activity. However, the compound failed to inhibit HCV NS5B activity in vitro, suggesting that it may not be directly acting on the NS5B protein but could be interacting with a host protein. Importantly, the antiviral compound also inhibited dengue virus and hepatitis E virus replication in hepatocytes. Thus, our study has identified a broad-spectrum antiviral therapeutic agent against multiple viral infections. PMID- 28725042 TI - Global deregulation of ginseng products may be a safety hazard to warfarin takers: solid evidence of ginseng-warfarin interaction. AB - Recent global deregulation of ginseng as the table food raises our concern about the possible ginseng-warfarin interaction that could be life-threatening to patients who take warfarin for preventing fatal strokes and thromboembolism while using ginseng products for bioenergy recovery. Here we show that quality-control ginsenosides, extracted from ginseng and containing its major active ingredients, produce dose- and time-dependent antagonism in rats against warfarin's anti coagulation assessed by INR and rat thrombosis model. The interactions between ginsenosides and warfarin on thrombosis, pharmacokinetics, activities of coagulation factors and liver cytochrome P450 isomers are determined by using thrombosis analyzer, UPLC/MS/MS, ELISA and real-time PCR, respectively. The antagonism correlates well with the related pharmacokinetic interaction showing that the blood plateaus of warfarin reached by one-week warfarin administration are significantly reduced after three-week co-administration of warfarin with ginsenosides while 7-hydroxywarfarin is increased. The one-week warfarin and three-week warfarin-ginsenosides regimen result in restoring the suppressed levels by warfarin of the coagulating factors II, VII and protein Z, and significantly enhance activities of P450 3A4 and 2C9 that metabolize warfarin. The present study, for the first time, provides the solid evidence to demonstrate the warfarin-ginsenoside interaction, and warns the warfarin users and regulation authorities of the dangerous interaction. PMID- 28725043 TI - Mucin 2 silencing promotes colon cancer metastasis through interleukin-6 signaling. AB - Downregulation of Mucin 2 (MUC2) expression is associated with early carcinogenesis events in colon cancer. MUC2 plays a role in the progression of colon cancer, and reduced MUC2 protein expression correlates with increased interleukin-6 (IL-6) expression. However, the interaction between MUC2 and IL-6 in colorectal cancer metastasis remains unclear. We systematically analyzed MUC2 and IL-6 expression and determined the survival of cancer patients with high or low MUC2 and IL-6 expression using the Oncomine and PrognoScan databases, respectively. This analysis identified downregulation of MUC2 and overexpression of IL-6 in colon cancer but not in normal colon tissue, and this expression pattern was correlated with poor survival of colon cancer patients. We examined the effects of MUC2 on colon cancer metastasis and used vector-mediated application of short hairpin RNA (shRNA) to suppress MUC2 expression. MUC2 suppressed the migration of colon cancer cells in vitro and dramatically diminished liver metastases in vivo. Treatment with IL-6 increased signal transducer and activator of transcription 3 (STAT3) phosphorylation, promoted checkpoint kinase 2 (Chk2) activation, attenuated cAMP response element-binding protein (CREB) phosphorylation, and suppressed E-cadherin protein expression in MUC2-silenced HT-29 cancer cells. Most importantly, MUC2 is a potential prognostic indicator for colon cancer. PMID- 28725044 TI - Cord blood NK cells engineered to express IL-15 and a CD19-targeted CAR show long term persistence and potent antitumor activity. AB - Chimeric antigen receptors (CARs) have been used to redirect the specificity of autologous T cells against leukemia and lymphoma with promising clinical results. Extending this approach to allogeneic T cells is problematic as they carry a significant risk of graft-versus-host disease (GVHD). Natural killer (NK) cells are highly cytotoxic effectors, killing their targets in a non-antigen-specific manner without causing GVHD. Cord blood (CB) offers an attractive, allogeneic, off-the-self source of NK cells for immunotherapy. We transduced CB-derived NK cells with a retroviral vector incorporating the genes for CAR-CD19, IL-15 and inducible caspase-9-based suicide gene (iC9), and demonstrated efficient killing of CD19-expressing cell lines and primary leukemia cells in vitro, with marked prolongation of survival in a xenograft Raji lymphoma murine model. Interleukin 15 (IL-15) production by the transduced CB-NK cells critically improved their function. Moreover, iC9/CAR.19/IL-15 CB-NK cells were readily eliminated upon pharmacologic activation of the iC9 suicide gene. In conclusion, we have developed a novel approach to immunotherapy using engineered CB-derived NK cells, which are easy to produce, exhibit striking efficacy and incorporate safety measures to limit toxicity. This approach should greatly improve the logistics of delivering this therapy to large numbers of patients, a major limitation to current CAR-T-cell therapies. PMID- 28725045 TI - Genomic epidemiology of global Klebsiella pneumoniae carbapenemase (KPC) producing Escherichia coli. AB - The dissemination of carbapenem resistance in Escherichia coli has major implications for the management of common infections. bla KPC, encoding a transmissible carbapenemase (KPC), has historically largely been associated with Klebsiella pneumoniae, a predominant plasmid (pKpQIL), and a specific transposable element (Tn4401, ~10 kb). Here we characterize the genetic features of bla KPC emergence in global E. coli, 2008-2013, using both long- and short read whole-genome sequencing. Amongst 43/45 successfully sequenced bla KPC-E. coli strains, we identified substantial strain diversity (n = 21 sequence types, 18% of annotated genes in the core genome); substantial plasmid diversity (>=9 replicon types); and substantial bla KPC-associated, mobile genetic element (MGE) diversity (50% not within complete Tn4401 elements). We also found evidence of inter-species, regional and international plasmid spread. In several cases bla KPC was found on high copy number, small Col-like plasmids, previously associated with horizontal transmission of resistance genes in the absence of antimicrobial selection pressures. E. coli is a common human pathogen, but also a commensal in multiple environmental and animal reservoirs, and easily transmissible. The association of bla KPC with a range of MGEs previously linked to the successful spread of widely endemic resistance mechanisms (e.g. bla TEM, bla CTX-M) suggests that it may become similarly prevalent. PMID- 28725046 TI - The Location of the Deepest Point of the Eyeball Determines the Optic Disc Configuration. AB - Tilted and rotated appearances are hallmarks of the myopic optic disc. As the eyeball grows axially, the posterior pole elongates not only globally but in a localized manner as well. In this process, the optic disc is pulled towards the deepest point of the elongated eyeball, which might result in a change in optic disc configuration. Thus, we hypothesized that analyzing the variation of posterior pole contour can play a major role in understanding optic disc configuration in myopic subjects. By analyzing consecutive images of swept source OCT coronal sections at the posterior pole, the deepest interface between Bruch's membrane and the choroid could be identified as the deepest point of the eyeball (DPE). The location and the properties of the DPE differed significantly between the 125 eyes of non-glaucomatous myopic group and the 40 eyes of non-glaucomatous emmetropic group classified based on 24 mm axial length. The results suggested that the larger disc to DPE angle and the larger disc to DPE depth strongly predicts the optic disc torsion degree and the optic disc tilt. Our findings suggest that identifying the posterior pole profile plays a major role in understanding the optic disc alterations found in myopic subjects. PMID- 28725047 TI - Warming effects on the urban hydrology in cold climate regions. AB - While approximately 338 million people in the Northern hemisphere live in regions that are regularly snow covered in winter, there is little hydro-climatologic knowledge in the cities impacted by snow. Using observations and modelling we have evaluated the energy and water exchanges of four cities that are exposed to wintertime snow. We show that the presence of snow critically changes the impact that city design has on the local-scale hydrology and climate. After snow melt, the cities return to being strongly controlled by the proportion of built and vegetated surfaces. However in winter, the presence of snow masks the influence of the built and vegetated fractions. We show how inter-year variability of wintertime temperature can modify this effect of snow. With increasing temperatures, these cities could be pushed towards very different partitioning between runoff and evapotranspiration. We derive the dependency of wintertime runoff on this warming effect in combination with the effect of urban densification. PMID- 28725048 TI - CD300f:IL-5 cross-talk inhibits adipose tissue eosinophil homing and subsequent IL-4 production. AB - Eosinophils and their associated cytokines IL-4 and IL-5 are emerging as central orchestrators of the immune-metabolic axis. Herein, we demonstrate that cross talk between the Ig-superfamily receptor CD300f and IL-5 is a key checkpoint that modifies the ability of eosinophils to regulate metabolic outcomes. Generation of Il5 Tg /Cd300f -/- mice revealed marked and distinct increases in eosinophil levels and their production of IL-4 in the white and brown adipose tissues. Consequently, Il5 Tg /Cd300f -/- mice had increased alternatively activated macrophage accumulation in the adipose tissue. Cd300f -/- mice displayed age related accumulation of eosinophils and macrophages in the adipose tissue and decreased adipose tissue weight, which was associated with decreased diet-induced weight gain and insulin resistance. Notably, Il5 Tg /CD300f -/- were protected from diet-induced weight gain and glucose intolerance. These findings highlight the cross-talk between IL-5 receptor and CD300f as a novel pathway regulating adipose tissue eosinophils and offer new entry points for therapeutic intervention for obesity and its complications. PMID- 28725049 TI - Loss of Calreticulin Uncovers a Critical Role for Calcium in Regulating Cellular Lipid Homeostasis. AB - A direct link between Ca2+ and lipid homeostasis has not been definitively demonstrated. In this study, we show that manipulation of ER Ca2+ causes the re distribution of a portion of the intracellular unesterified cholesterol to a pool that is not available to the SCAP-SREBP complex. The SREBP processing pathway in ER Ca2+ depleted cells remained fully functional and responsive to changes in cellular cholesterol status but differed unexpectedly in basal activity. These findings establish the role of Ca2+ in determining the reference set-point for controlling cellular lipid homeostasis. We propose that ER Ca2+ status is an important determinant of the basal sensitivity of the sterol sensing mechanism inherent to the SREBP processing pathway. PMID- 28725050 TI - Carrier-Mediated and Energy-Dependent Uptake and Efflux of Deoxynivalenol in Mammalian Cells. AB - Deoxynivalenol (DON) is one of the most abundant mycotoxins and exerts many adverse effects on humans and animals. To date, the transporting mechanism of DON in mammalian cells remains unclear. In this study, the parallel artificial membrane permeability assay (PAMPA), Transwell models and metabolic inhibitors were used to determine the possible transporting mechanisms of DON in Caco-2, MDCK and HepG2 cells. PAMPA and Transwell models showed reduced passive transport and increased intestinal absorption, indicating a carrier-mediated transporting mechanism. Furthermore, higher unidirectional transport of DON was observed in the basolateral-to-apical direction than in the apical-to-basolateral direction, indicating the existence of efflux proteins. Interestingly, DON was accumulated in the nucleus, and no DON was detected in mitochondria, indicating that the nucleus may be the main target organelle of DON. Moreover, the use of various transporter inhibitors in different cells shows that organic anion transporters, organic cation transporters, and organic anion-transporting polypeptides participate in DON uptake, and P-glycoprotein is the major efflux protein. Importantly, DON uptake is strongly inhibited by metabolic inhibitors and is highly dependent on temperature. In summary, carrier-mediated and energy dependent uptake and efflux mechanisms for DON in mammalian cells are reported, aiding in improving our understanding of its toxicological mechanisms. PMID- 28725052 TI - Monolithically-Integrated TE-mode 1D Silicon-on-Insulator Isolators using Seedlayer-Free Garnet. AB - The first experimental TE-mode silicon-on-insulator (SOI) isolators using Faraday Rotation are here realized to fill the 'missing link' in source-integrated near infrared photonic circuits. The isolators are simple 1D 2-element waveguides, where garnet claddings and longitudinal magnetic fields produce nonreciprocal mode conversion, the waveguide equivalent of Faraday Rotation (FR). Quasi-phase matched claddings are used to overcome the limitations of birefringence. Current experimental SOI isolators use nonreciprocal phase shift (NRPS) in interferometers or ring resonators, but to date NRPS requires TM-modes, so the TE modes normally produced by integrated lasers cannot be isolated without many ancillary polarisation controls. The presented FR isolators are made via lithography and sputter deposition, which allows facile upscaling compared to the pulsed laser deposition or wafer bonding used in the fabrication of NRPS devices. Here, isolation ratios and losses of 11 dB and 4 dB were obtained, and future designs are identified capable of isolation ratios >30 dB with losses <6 dB. PMID- 28725051 TI - Mammographic density, blood telomere length and lipid peroxidation. AB - Extensive mammographic density is a strong risk factor for breast cancer, but may also be an indicator of biological age. In this study we examined whether mammographic density is related to blood telomere length, a potential marker of susceptibility to age-related disease. We measured mammographic density by a computer assisted method and blood telomere length using a validated PCR method. Urinary malondialdehyde (MDA), a marker of lipid peroxidation, was measured in 24 hour urine collections. In the 342 women examined telomere length was negatively correlated with age, was lower in postmenopausal compared to premenopausal women and in smokers compared to non-smokers, and was positively correlated with urinary MDA. Telomere length was not associated with percent mammographic density or dense area, before or after adjustment for risk factors and MDA. However, there was a significant interaction between telomere length and MDA in their association with mammographic density. At lower levels of MDA, mammographic density and telomere length were inversely associated; while at high levels of MDA, there was evidence of a J-shaped association between mammographic density and telomere length. Further work is need to replicate these results and to examine the association of mammographic density with age-related chronic disease and mortality. PMID- 28725053 TI - Cyclic di-GMP regulates Mycobacterium tuberculosis resistance to ethionamide. AB - Tuberculosis is still on the top of infectious diseases list on both mobility and mortality, especially due to drug-resistance of Mycobacterium tuberculosis (M.tb). Ethionamide (ETH) is one of effective second line anti-TB drugs, a synthetic compound similar to isoniazid (INH) structurally, with existing severe problem of ETH resistance. ETH is a prodrug, which is activated by Etha inside M.tb, and etha is transcriptionally repressed by Ethr. We found that c-di-GMP could bind Ethr, enhanced the binding of Ethr to the promoter of etha, and then repressed the transcription of etha, thus caused resistance of M.tb to ETH. Through docking analysis and in vitro validation, we identified that c-di-GMP binds 3 amino acids of Ethr, i.e., Q125, R181 and E190, while the first 2 were the major binding sites. Homology analysis showed that Ethr was highly conservative among mycobacteria. Further docking analysis showed that c-di-GMP preferentially bound proteins of TetR family at the junction hole of symmetric dimer or tetramer proteins. Our results suggest a possible drug-resistance mechanism of ETH through the regulation of Ethr by c-di-GMP. PMID- 28725054 TI - Quantifying Magnetic Sensitivity of Radical Pair Based Compass by Quantum Fisher Information. AB - The radical pair (RP) based compass is considered as one of the principal models of avian magnetoreception. Different from the conventional approach where the sensitivity of RP based compass is described by the singlet yield, we introduce the quantum Fisher information (QFI), which represents the maximum information about the magnetic field's direction extracted from the RP state, to quantify the sensitivity of RP based compass. The consistency between our results and experimental observations suggests that the QFI may serve as a measure to describe the sensitivity of RP based compass. Besides, within the framework of quantum metrology, we give two specific possible measurement schemes and find that the conventional singlet yield is corresponding to the measurement of total angular momentum. Moreover, we show that the measurement of fluctuation of the total magnetic moment is much more accurate than the singlet yield measurement, and is close to the optimal measurement scheme. Finally, the effects of entanglement and decoherence are also discussed in the spirit of our approach. PMID- 28725055 TI - Pressure-induced anomalous valence crossover in cubic YbCu5-based compounds. AB - A pressure-induced anomalous valence crossover without structural phase transition is observed in archetypal cubic YbCu5 based heavy Fermion systems. The Yb valence is found to decrease with increasing pressure, indicating a pressure induced crossover from a localized 4f 13 state to the valence fluctuation regime, which is not expected for Yb systems with conventional c-f hybridization. This result further highlights the remarkable singularity of the valence behavior in compressed YbCu5-based compounds. The intermetallics Yb2Pd2Sn, which shows two quantum critical points (QCP) under pressure and has been proposed as a potential candidate for a reentrant Yb2+ state at high pressure, was also studied for comparison. In this compound, the Yb valence monotonically increases with pressure, disproving a scenario of a reentrant non-magnetic Yb2+ state at the second QCP. PMID- 28725056 TI - Serum albumin and osmolality inhibit Bdellovibrio bacteriovorus predation in human serum. AB - We evaluated the bactericidal activity of Bdellovibrio bacteriovorus, strain HD100, within blood sera against bacterial strains commonly associated with bacteremic infections, including E. coli, Klebsiella pneumoniae and Salmonella enterica. Tests show that B. bacteriovorus HD100 is not susceptible to serum complement or its bactericidal activity. After a two hour exposure to human sera, the prey populations decreased 15- to 7,300-fold due to the serum complement activity while, in contrast, the B. bacteriovorus HD100 population showed a loss of only 33%. Dot blot analyses showed that this is not due to the absence of antibodies against this predator. Predation in human serum was inhibited, though, by both the osmolality and serum albumin. The activity of B. bacteriovorus HD100 showed a sharp transition between 200 and 250 mOsm/kg, and was progressively reduced as the osmolality increased. Serum albumin also acted to inhibit predation by binding to and coating the predatory cells. This was confirmed via dot blot analyses and confocal microscopy. The results from both the osmolality and serum albumin tests were incorporated into a numerical model describing bacterial predation of pathogens. In conclusion, both of these factors inhibit predation and, as such, they limit its effectiveness against pathogenic prey located within sera. PMID- 28725057 TI - Efficient generation of single domain antibodies with high affinities and enhanced thermal stabilities. AB - Single domain antibodies (sdAbs), made of natural single variable regions of camelid or cartilaginous fish antibodies, or unpaired variable regions of mouse or human IgGs, are some of the more promising biologic modalities. However, such conventional sdAbs have difficulties of either using unwieldy animals for immunization or having high affinity deficiencies. Herein, we offer a versatile method to generate rabbit variable domain of heavy chain (rVH) derived sdAbs with high affinities (K D values of single digit nM or less) and enhanced thermal stabilities (equal to or even higher than those of camelid derived sdAbs). It was found that a variety of rVH binders, including those with high affinities, were efficiently acquired using an rVH-displaying phage library produced at a low temperature of 16 degrees C. By a simple method to introduce an additional disulfide bond, their unfolding temperatures were increased by more than 20 degrees C without severe loss of binding affinity. Differential scanning calorimetry analysis suggested that this highly efficient thermal stabilization was mainly attributed to the entropic contribution and unique thermodynamic character of the rVHs. PMID- 28725059 TI - Use of a Novel Submucosal Tunneling and Endoscopic Resection (STER) Technique for the Removal of an Esophageal Leiomyoma. PMID- 28725058 TI - Identification of a Flavonoid Glucosyltransferase Involved in 7-OH Site Glycosylation in Tea plants (Camellia sinensis). AB - Flavonol glycosides, which are often converted from aglycones in a process catalyzed by UDP-glycosyltransferases (UGTs), play an important role for the health of plants and animals. In the present study, a gene encoding a flavonoid 7 O-glycosyltransferase (CsUGT75L12) was identified in tea plants. Recombinant CsUGT75L12 protein displayed glycosyltransferase activity on the 7-OH position of multiple phenolic compounds. In relative comparison to wild-type seeds, the levels of flavonol-glucosides increased in Arabidopsis seeds overexpressing CsUGT75L12. In order to determine the key amino acid residues responsible for the catalytic activity of the protein, a series of site-directed mutagenesis and enzymatic assays were performed based on the 3D structural modeling and docking analyses. These results suggested that residue Q54 is a double binding site that functions as both a sugar receptor and donor. Residues H56 and T151, corresponding to the basic active residues H20 and D119 of VvGT1, were not irreplaceable for CsUGT75L12. In addition, residues Y182, S223, P238, T239, and F240 were demonstrated to be responsible for a 'reversed' sugar receptor binding model. The results of single and triple substitutions confirmed that the function of residues P238, T239, and F240 may substitute or compensate with each other for the flavonoid 7-O-glycosyltransferase activity. PMID- 28725060 TI - Enigma of Intestinal Gas in Irritable Bowel Syndrome. PMID- 28725061 TI - Reply to Dai et al. PMID- 28725062 TI - Dive to the Underwater World: A Water Immersion Technique for Endoscopic Submucosal Dissection of Gastric Neoplasms. PMID- 28725063 TI - Pneumatosis Cystoides Coli Related to Acarbose Treatment. PMID- 28725065 TI - Continuing Medical Education Questions: July 2017: Colorectal Cancer Screening: Recommendations for Physicians and Patients from the U.S. Multi-Society Task Force on Colorectal Cancer. PMID- 28725064 TI - Editorial: Stopping Pancreatic Cyst Surveillance? AB - The management of patients with pancreatic cysts, especially presumed branch duct intraductal papillary mucinous neoplasms (BD-IPMNs), remains a challenge. BD IPMNs carry a very low risk of malignancy and occur in predominantly older individuals who often die from causes not related to their pancreatic disease. The specific decision to stop surveillance of presumed low risk BD-IPMNs (those without either worrisome features (WF) or high risk stigmata (HRS)) is controversial, and needs to balance the real risk of malignancy or developing malignancy and IPMN-related mortality, with the patient's life expectancy, quality of life expectations, and mortality from non-pancreatic-related causes. With improved life expectancy, improved survival from non-pancreatic malignancies, rising health costs, and growing detection of ever smaller presumed BD-IPMNs, this issue is becoming ever more critical. PMID- 28725067 TI - Continuing Medical Education: July 2017: ACG and CAG Clinical Guideline: Management of Dyspepsia. PMID- 28725066 TI - Editorial: Best Practices in Surveillance of Barrett's Esophagus. AB - Endoscopic surveillance in Barrett's esophagus (BE) has numerous limitations and thus provides several opportunities for improving the effectiveness of our current surveillance strategies. Several risk stratification and prediction tools have been investigated to identify patients at highest risk for progression to esophageal adenocarcinoma (EAC). Persistence of non-dysplastic BE (NDBE) has been proposed as an indicator of lower risk of progression to EAC. This editorial highlights the variable results and methodologies in studies evaluating persistence of NDBE as a risk stratification tool in the surveillance of BE patients and provides guidance for optimizing outcomes in BE patients enrolled in surveillance programs. PMID- 28725068 TI - Response to Uno. PMID- 28725069 TI - GI Fellowship Training Programs. PMID- 28725071 TI - Inferior Cava Vein Syndrome and Heart Compression Due to a Giant Liver Cyst. PMID- 28725072 TI - Pneumatosis Intestinalis Due to Extrinsic Compression From a Large Renal Cyst. PMID- 28725073 TI - Which Regimens Should Be Used and Which Rejected for the Treatment of Helicobacter pylori? PMID- 28725074 TI - Continuing Medical Education: July 2017: Colorectal Cancer Screening: Recommendations for Physicians and Patients from the U.S. Multi-Society Task Force on Colorectal Cancer. PMID- 28725076 TI - Continuing Medical Education Questions: July 2017: ACG and CAG Clinical Guideline: Management of Dyspepsia. PMID- 28725075 TI - Eosinophilic Esophagitis: Leaky Gullet or Leaky Gut? AB - Eosinophilic esophagitis (EoE) is a food allergen disorder driven by antigen recognition in the gastrointestinal tract. The study by Warners et al., strongly supports the esophageal epithelium as the area of disturbed permeability and primary target for initiation of the TH2-induced allergic pathway. In contrast, small bowel assessment reveals a lack of clear change in aspects of permeability compared to controls. It is not clear, however, if the available testing used for this purpose accurately assesses the mechanisms by which antigen recognition may occur in this organ. As a result, the role of the small bowel in EoE remains unclear. PMID- 28725077 TI - Nationwide Studies of Hematological Malignancies in Inflammatory Bowel Disease. PMID- 28725078 TI - Is Viral Hepatitis Decreasing in the United States? PMID- 28725079 TI - The Risk of Gallstone Disease Following Colectomy for Ulcerative Colitis. PMID- 28725080 TI - Response to Georgopoulos et al. PMID- 28725081 TI - Response to Pellicano. PMID- 28725082 TI - Retention and Separation Changes of Ternary and Quaternary Alkaloids from Chelidonium majus L. by TLC Under the Influence of External Magnetic Field. AB - Thin layer techniques proved their usefulness in the analysis of plant extract material. Thanks to their low operation costs, high sample throughput and possibility to gather chromatographic data for the whole sample in a single act, they allowed to find, and in some cases identify, active ingredients often hidden in sophisticated plant extract matrices. It was also proved that the presence of a magnetic field changes the retention of some substances, and moreover changes the separation efficiency of chromatographic systems. In the presented experiment, retention, efficiency and separation abilities of TLC chromatographic systems for mixtures of alkaloids under the influence of magnetic field depending on inductivity of the magnetic field, the saturation of chromatographic chamber and quantity of chromatographed substances were investigated. The results obtained were tested on real plant extracts that revealed the ability of chromatography in a magnetic field for separation of ternary and quaternary alkaloids from Chelidonium majus L. Our experiments proved that the presence of magnetic field induction lines perpendicular to the chromatographic plate plane can influence the width and retention of chromatographed substances, and can be considered as a tool for separation adjustment of plant extracts containing ternary and quaternary alkaloids. PMID- 28725083 TI - Estimation of Nonlinear Adsorption Isotherms in Gradient Elution RP-LC of Peptides in the Presence of an Adsorbing Additive. AB - ABSTRACT: In electrostatic repulsive interaction chromatography, using a charged surface hybrid sorbent carrying positive charges can improve the peak shape of peptides in reversed-phase liquid chromatography (RP-LC), especially in overloaded conditions, compared with standard C18 sorbents. However, the positive surface charges can interact with anionic additives commonly used in peptide separations, e.g., trifluoroacetic acid (TFA), complicating adsorption isotherm estimation. We investigated how the competition for available adsorption sites between TFA and two peptides influenced the adsorption isotherm in gradient elution. A model accounting for the competition with TFA was compared with a model neglecting TFA adsorption. We found that the two models predicted elution profiles with the same accuracy. We also found that the adsorption isotherms were extremely similar in shape, leading to the conclusion that neglecting the competition with TFA is a valid approximation enabling faster and more robust adsorption isotherm estimation for the studied type of sorbent. GRAPHICAL ABSTRACT: PMID- 28725084 TI - Development of a Single-Drop Microextraction with Derivatization Procedure for Analysis of Volatile Fatty Acids in Water Samples. AB - A single-drop microextraction (SDME) was developed for the analysis of volatile fatty acids (VFAs) (C2-C7) in water by gas chromatography (GC) with flame ionization detection. The significant parameters affecting the SDME performance such as selection of microextraction solvent, extraction time, stirring rate, sample pH and temperature, and ionic strength were studied and optimized. To lower limits of detection, derivatization of VFAs by N-methyl-N-(tert butyldimethylsilyl)trifluoroacetamide (MTBSTFA) was performed. The method developed requires very short time of extraction and derivatization (13 min) and it is characterized by a good precision (max RSD = 11.4%), linearity and relatively low limits of detection (from 8.3 mg L-1 for acetic acid to 0.008 mg L 1 for heptanoic acid). The results of the SDME in combination with GC show promising potential for the analysis of VFAs in water samples. PMID- 28725085 TI - Multidimensional poverty, household environment and short-term morbidity in India. AB - Using the unit data from the second round of the Indian Human Development Survey (IHDS-II), 2011-2012, which covered 42,152 households, this paper examines the association between multidimensional poverty, household environmental deprivation and short-term morbidities (fever, cough and diarrhoea) in India. Poverty is measured in a multidimensional framework that includes the dimensions of education, health and income, while household environmental deprivation is defined as lack of access to improved sanitation, drinking water and cooking fuel. A composite index combining multidimensional poverty and household environmental deprivation has been computed, and households are classified as follows: multidimensional poor and living in a poor household environment, multidimensional non-poor and living in a poor household environment, multidimensional poor and living in a good household environment and multidimensional non-poor and living in a good household environment. Results suggest that about 23% of the population belonging to multidimensional poor households and living in a poor household environment had experienced short-term morbidities in a reference period of 30 days compared to 20% of the population belonging to multidimensional non-poor households and living in a poor household environment, 19% of the population belonging to multidimensional poor households and living in a good household environment and 15% of the population belonging to multidimensional non-poor households and living in a good household environment. Controlling for socioeconomic covariates, the odds of short-term morbidity was 1.47 [CI 1.40-1.53] among the multidimensional poor and living in a poor household environment, 1.28 [CI 1.21-1.37] among the multidimensional non-poor and living in a poor household environment and 1.21 [CI 1.64-1.28] among the multidimensional poor and living in a good household environment compared to the multidimensional non-poor and living in a good household environment. Results are robust across states and hold good for each of the three morbidities: fever, cough and diarrhoea. This establishes that along with poverty, household environmental conditions have a significant bearing on short-term morbidities in India. Public investment in sanitation, drinking water and cooking fuel can reduce the morbidity and improve the health of the population. PMID- 28725086 TI - The fertility of internal migrants to Kinshasa. AB - The rapid population growth of many African cities has important implications for population health, yet little is known about factors contributing to increasing population, such as the fertility of internal migrants. We examine whether in migrants to Kinshasa have different fertility patterns than lifetime Kinshasa residents, and identify characteristics of migrants that may explain differences in fertility. We also use detailed migration histories to examine whether fertility differs by features of migration. We use representative data from the PMA2020 Project for 2197 women in Kinshasa, including 340 women who moved to Kinshasa. We examine differences between migrants and non-migrants in fertility and other fertility-related characteristics. We also examine whether fertility differs by duration of residence in Kinshasa, number of lifetime moves, age at first migration, urban/rural classification of birthplace, and the distinction between intra-Kinshasa migration and migration to Kinshasa.. Migrants have significantly higher fertility than permanent Kinshasa residents, but the difference is relatively small in magnitude. This higher fertility appears due in part to patterns of contraceptive use among migrants. There is noteworthy heterogeneity among migrants: higher fertility among migrants is associated with longer duration in Kinshasa, more lifetime moves, urban-Kinshasa migration, older age at first migration, and moving to Kinshasa from outside (as opposed to intra Kinshasa migration). PMID- 28725087 TI - Psychosynthesis: A Foundational Bridge Between Psychology and Spirituality. AB - Pastoral psychologists have long tried to establish a working model that encompasses the seemingly conflicting disciplines of science and religion. Psychosynthesis, a transpersonal psychology and therapeutic approach, offers such a model of the human personality, in which the psychological and spiritual perspectives can converge. This article explores psychosynthesis psychology and therapy as a theoretical framework for pastoral psychology. Although psychosynthesis psychotherapy relies on an array of techniques, it fundamentally works with the clients' will while emphasizing, exploring, and cultivating their relationships on all levels-intrapersonal, interpersonal, and with the Higher Self. In addition to the subconscious, psychosynthesis includes a higher psychological plane, called the superconscious, from which our higher ethical, aesthetic, scientific, and spiritual values are derived. This article begins by introducing psychosynthesis concepts and techniques. It then provides qualitative findings showing that psychosynthesis counseling helped to awaken spirituality in three out of eleven clients who had formerly identified themselves as atheists. In addition, testimonies are included that show that psychosynthesis counseling also helped all eleven clients to attain personal growth. Finally, the counselor describes her experience of psychosynthesis as a Christian in the therapeutic setting. The framework of psychosynthesis psychology and its techniques are viable methodologies for anyone searching to incorporate spiritual growth into a psychological working model. PMID- 28725088 TI - Self-Disclosure and Spiritual Well-Being in Pastors Seeking Professional Psychological Help. AB - Pastoral mental health is a topic that has only rarely been researched empirically in the psychological literature, yet a pastor's mental health can have a significant impact on churches, communities, and even nations (Royal and Thompson, Journal of Psychology and Christianity,31(3), 195-204, 2012). One of the thoughts prompting this research is that evangelical pastors might be expected to resist the findings of psychological research and lack understanding of specific mental illnesses they are potentially facing. Combined with historical and cultural dynamics that could influence resistance to professional psychological help, evangelical pastors have personal, internal factors that could also strengthen resistance, including the researched issues of self disclosure flexibility and spiritual well-being. A correlational research design with multivariate regression was used to determine potentially significant or predictive relationships between the relevant factors. Among evangelical seminary students (N = 251) preparing for parish-based pastoral ministry, this research determined that no significant relationship, predictive or otherwise, existed between self-disclosure flexibility, spiritual well-being, and attitudes toward seeking professional psychological help. Implications include a shift in focus toward external factors influencing pastors' help-seeking attitudes, such as the need for the mental health community to develop connections with evangelical pastors and the development of more support for Christian mental health professionals in the larger evangelical community. PMID- 28725089 TI - A Psychometric Evaluation of the Santa Clara Strength of Religious Faith Questionnaire among Students from Poland and Chile. AB - This study verifies the psychometric properties of the Santa Clara Strength of Religious Faith Questionnaire (SCSORFQ). This measure consists of 10 items regarding strength of religious faith, regardless of religious denomination or affiliation. Participants were 177 students from Chile and 393 students from Poland. The SCSORFQ method is a reliable measure with good internal consistency evaluated by the alpha-Cronbach coefficient. Factor analysis statistically confirmed the unidimensional structure of the SCSORFQ. The strength of religious faith in both student groups was moderate to strong correlated with public or private aspects of religiousness and strong correlated with spiritual experiences. It was weakly correlated with the cognitive indicator of well-being as satisfaction with life as well as with existential variables like hope and meaning of life. The results confirm that the SCSORFQ is psychometrically sound and is therefore recommended for use by researchers studying the construct of religiousness. PMID- 28725090 TI - European economies in terms of energy dependence. AB - The sustainable development and energy security are currently the priority challenges for the European Union countries. The sustainable and stable development of European economies is closely dependent on the stable access to energy resources. The constant increase of the demand for electricity requires long-term planning of the common European policy. The aim of the article is to analyse the fuel and energy resources situation of the member states with regard to their energy balances and with the determination of their import dependence in relation to fossil fuels, such as: coal, oil and natural gas. Based on the collected statistical data the analysis of clusters was presented in order to separate homogenous subsets, that is groups of the European Union Member States. The squared Euclidean distance has been adopted as the measure of similarities of the member states in the clusters, and the k-means algorithm has been used as the method of grouping. As a result of the analysis seven clusters were selected groups of homogenous countries in terms of the import dependence due to the major energy resources (oil, natural gas and coal). The results of the paper can constitute bases for shaping the appropriate long-term common energy policy for the listed potential groups of countries. Statistical data were collected based on the Eurostat publication. PMID- 28725091 TI - An analytical solution for steady flow of a Quemada fluid in a circular tube. AB - An analytical solution is obtained for steady flow of Quemada-type fluids in a circular tube driven by a constant pressure gradient. Expressions are derived for velocity distribution and for volumetric flow rate as a function of pressure gradient or wall shear stress. PMID- 28725092 TI - Special Interests and the Media: Theory and an Application to Climate Change. AB - A journalist reports to a voter on an unknown, policy-relevant state. Competing special interests can make claims that contradict the facts but seem credible to the voter. A reputational incentive to avoid taking sides leads the journalist to report special interests' claims to the voter. In equilibrium, the voter can remain uninformed even when the journalist is perfectly informed. Communication is improved if the journalist discloses her partisan leanings. The model provides an account of persistent public ignorance on climate change that is consistent with narrative and quantitative evidence. PMID- 28725093 TI - Western classical music development: a statistical analysis of composers similarity, differentiation and evolution. AB - This paper proposes a statistical analysis that captures similarities and differences between classical music composers with the eventual aim to understand why particular composers 'sound' different even if their 'lineages' (influences network) are similar or why they 'sound' alike if their 'lineages' are different. In order to do this we use statistical methods and measures of association or similarity (based on presence/absence of traits such as specific 'ecological' characteristics and personal musical influences) that have been developed in biosystematics, scientometrics, and bibliographic coupling. This paper also represents a first step towards a more ambitious goal of developing an evolutionary model of Western classical music. PMID- 28725094 TI - Evolution of three Nobel Prize themes and a Nobel snub theme in chemistry: a bibliometric study with focus on international collaboration. AB - In this study, three chemistry research themes closely associated with the Nobel Prize are bibliometrically analyzed-Ribozyme, Ozone and Fullerene-as well as a research theme in chemistry not associated with the Nobel Prize (a Nobel snub theme): Brunauer-Emmett-Teller equation. We analyze, based on an algorithmically constructed publication-level classification system, the evolution of the four themes with respect to publication volume and international collaboration, using two datasets, one of them a subset of highly cited publications, for each considered time period. The focus of the study is on international collaboration, where co-occurrence of country names in publications is used as a proxy for international collaboration. For all four themes, especially for Brunauer-Emmett Teller equation, the publication volumes increase considerably from the earliest period to the later periods. The international collaboration rate shows an increasing trend for each theme. For Ozone, Fullerene and Brunauer-Emmett-Teller equation, the international collaboration rate tend to be higher for the highly cited publications compared to full datasets. With regard to the evolution of number of countries per international publication and per highly cited international publication, a vast majority of the distributions are positively skewed, with a large share of publications with two countries. With respect to the last four periods of the study, the concentration to two countries per publication is more pronounced for the Brunauer-Emmett-Teller equation theme compared to the three Nobel Prize themes. PMID- 28725095 TI - With whom do researchers collaborate and why? AB - Although research collaboration has been studied extensively, we still lack understanding regarding the factors stimulating researchers to collaborate with different kinds of research partners including members of the same research center or group, researchers from the same organization, researchers from other academic and non-academic organizations as well as international partners. Here, we provide an explanation of the emergence of diverse collaborative ties. The theoretical framework used for understanding research collaboration couples scientific and technical human capital embodied in the individual with the social organization and cognitive characteristics of the research field. We analyze survey data collected from Slovenian scientists in four scientific disciplines: mathematics; physics; biotechnology; and sociology. The results show that while individual characteristics and resources are among the strongest predictors of collaboration, very different mechanisms underlie collaboration with different kinds of partners. International collaboration is particularly important for the researchers in small national science systems. Collaboration with colleagues from various domestic organizations presents a vehicle for resource mobilization. Within organizations collaboration reflects the elaborated division of labor in the laboratories and high level of competition between different research groups. These results hold practical implications for policymakers interested in promoting quality research. PMID- 28725096 TI - Quality assessment of scientific outputs using the BWM. AB - Assessing the quality of scientific outputs (i.e. research papers, books and reports) is a challenging issue. Although in practice, the basic quality of scientific outputs is evaluated by committees/peers (peer review) who have general knowledge and competencies. However, their assessment might not comprehensively consider different dimensions of the quality of the scientific outputs. Hence, there is a requirement to evaluate scientific outputs based on some other metrics which cover more aspects of quality after publishing, which is the aim of this study. To reach this aim, first different quality metrics are identified through an extensive literature review. Then a recently developed multi-criteria methodology (best worst method) is used to find the importance of each quality metric. Finally, based on the importance of each quality metric and the data which are collected from Scopus, the quality of research papers published by the members of a university faculty is measured. The proposed model in this paper provides the opportunity to measure quality of research papers not only by considering different aspects of quality, but also by considering the importance of each quality metric. The proposed model can be used for assessing other scientific outputs as well. PMID- 28725097 TI - Surviving the Holocaust: Socio-demographic Differences Among Amsterdam Jews. AB - This study determined the victimisation rate among Amsterdam Jews and socio demographic differences in surviving the Holocaust. After linking a registration list of over 77,000 Jewish inhabitants in 1941 to post-war lists of Jewish victims and survivors, the victimisation rate lies between 74.3 and 75.3 %. Differences in survival chances and risk of being killed are examined by using multivariable logistic and Cox regression analyses. While male Jews had a reduced risk of death, in the end their survival chances hardly differed from females. Though Jews aged 6-14 and 31-50 initially had a lower risk of death, in the end compared with Jews aged 15-30 they had lower survival chances, just as Jews aged 50+. For Jews aged 0-5, it was the other way around. Immigrants showed better survival chances than native Jews. German Jews showed better survival chances than Dutch Jews, but Polish and other Jewish nationals showed highest survival chances. Jews who had abandoned Judaism had better survival chances than Jews belonging to an Israelite congregation. Divorced, widowed and unmarried adult Jews had better survival chances than married Jews and their children; Jews married to non-Jews, however, had one of the highest survival chances. Jews in the two highest social classes had better survival chances than jobless Jews. These findings indicate that survival was not random but related to socio demographic characteristics. This sheds light on demographic consequences of conflict and violence: Nazi persecution reduced the Amsterdam Jewish community drastically, and socio-demographic differences in survival impacted the post-war Jewish population structure. PMID- 28725098 TI - Choosing to Remain Childless? A Comparative Study of Fertility Intentions Among Women and Men in Italy and Britain. AB - Pathways to childlessness may differ not only between individuals but also at the population level. This paper investigates differences in childlessness by comparing two countries-Britain and Italy-where levels of childlessness are high in comparison with many other European countries, but which have distinct fertility trajectories and family regimes. Using data from two large, representative national samples of women and men of reproductive age in a co residential partnership, it presents a rich analysis of the characteristics associated with intended childlessness, net of the aspects associated with being childless at interview. Although childlessness intentions are generally comparable between men and women of the same age, results show a link between socio-economic disadvantage and childlessness for British men as well as the importance of men's employment for childbearing decisions in Italy. These findings support the view that pathways into childlessness are gendered and highlight the importance of partnership context in the understanding of fertility intentions. Then, the level of childlessness at interview is comparable across the two countries. However, a higher proportion of respondents in Italy is only provisionally childless, whereas a larger proportion of British respondents intends to remain childless. Framing these differences in fertility intentions within the wider context of family and fertility regimes allows insight into the extent to which observed levels of lifetime childlessness at the population level might result from a specific combination of intended childlessness, postponed decisions leading to involuntary childlessness, or constraints affecting abilities to achieve intentions at the individual level. PMID- 28725099 TI - Changes in Employment Uncertainty and the Fertility Intention-Realization Link: An Analysis Based on the Swiss Household Panel. AB - How do changes in employment uncertainty matter for fertility? Empirical studies on the impact of employment uncertainty on reproductive decision-making offer a variety of conclusions, ranging from gender and socio-economic differences in the effect of employment uncertainty on fertility intentions and behaviour, to the effect of employment on changes in fertility intentions. This article analyses the association between a change in subjective employment uncertainty and fertility intentions and behaviour by distinguishing male and female partners' employment uncertainty, and examines the variation in these associations by education. Using a sample of men and women living in a couple from the Swiss Household Panel (SHP 2002-2011), we examine through multinomial analysis how changes in employment uncertainty and selected socio-demographic factors are related to individual childbearing decisions. Our results show strong gendered effects of changes in employment uncertainty on the revision of reproductive decisions among the highly educated population. PMID- 28725100 TI - Does Women's Empowerment in Agriculture Matter for Children's Health Status? Insights from Northern Ghana. AB - Given that women in rural communities in developing countries are responsible for the nutrition and health-related decisions affecting children in their care, their empowerment may influence the health status of their children. The association between women's empowerment, measured by using a recently developed Women's Empowerment in Agriculture Index, and children's health status is examined for a sample of households in Northern Ghana applying a Multiple Indicators Multiple Causes (MIMIC) model. The MIMIC approach is used to link multiple indicator variables with multiple independent variables through a "single underlying" latent variable. Height-for-age and weight-for-height z scores are used as indicators of the underlying children's health status and women's empowerment in agriculture and control variables are used as the multiple independent variables. Our results show that neither the composite empowerment score used to capture women's empowerment in agriculture nor its decomposed components are statistically significant in their association with the latent children's health status. However, the associations between children's health status and control variables such as mother's education, child's age, household's hunger scale and residence locale are statistically significant. Results also confirm the existence of the 'single underlying' common latent variable. Of the two health status indicators, height-for-age scores and weight-for- height scores, the former exhibited a relatively stronger association with the latent health status. While promoting women's empowerment to enhance their ability to make strategic life choices, it is important to carefully consider how the achievement of these objectives will impact the women's well-being and the well being of the children in their care. PMID- 28725101 TI - Social Policies and Families in Stress: Gender and Educational Differences in Work-Family Conflict from a European Perspective. AB - In modern welfare states, family policies may resolve the tension between employment and care-focused demands. However these policies sometimes have adverse consequences for distinct social groups. This study examined gender and educational differences in working parents' perceived work-family conflict and used a comparative approach to test whether family policies, in particular support for child care and leave from paid work, are capable of reducing work family conflict as well as the gender and educational gaps in work-family conflict. We use data from the European Social Survey 2010 for 20 countries and 5296 respondents (parents), extended with information on national policies for maternity and parental leave and child care support from the OECD Family Database. Employing multilevel analysis, we find that mothers and the higher educated report most work-family conflict. Policies supporting child care reduce the level of experienced work-family conflict; family leave policy appears to have no alleviating impact on working parents' work-family conflict. Our findings indicate that family policies appear to be unable to reduce the gender gap in conflict perception and even widen the educational gap in work-family conflict. PMID- 28725102 TI - The influence of social relationship on food tolerance in wolves and dogs. AB - ABSTRACT: Food sharing is relatively widespread across the animal kingdom, but research into the socio-ecological factors affecting this activity has predominantly focused on primates. These studies do suggest though that food tolerance is linked to the social relationship with potential partners. Therefore, the current study aimed to assess the social factors which influence food tolerance in two canids: wolves and dogs. We presented wolves and dogs with two paradigms: dyadic tolerance tests and group carcass feedings. In the dyadic setting, the affiliative relationship with a partner was the most important factor, with a strong bond promoting more sharing in both species. In the group setting, however, rank was the primary factor determining feeding behavior. Although the dominant individuals of both species defended the carcass more than subordinates, in the dogs, the subordinates mostly stayed away from the resource and the most dominant individual monopolized the food. In the wolves, the subordinates spent as much time as dominant individuals in proximity to, and feeding from, the carcass. Furthermore, subordinate wolves were more able to use persistence strategies than the dogs were. Feeding interactions in the wolves, but not dogs, were also modulated by whether the carcass was on the ground or hanging from a tree. Overall, the social relationship with a partner is important in food distribution in wolves and dogs, but the precise effects are dependent on species and feeding context. We consider how the different socio-ecologies of the two species may be linked to these findings. SIGNIFICANCE STATEMENT: Despite the fact that food sharing is relatively widespread in the animal kingdom, the specific factors underlying whether an animal will share with a specific individual are little understood. When it comes to decisions about food sharing in wolves and dogs, friendship is the deciding factor if it is just two of you, but in a bigger group rank position decides your access to the spoils. What is more, it seems that rank positioning is even more important in dogs than wolves as dominant dogs keep the food for themselves while each wolf pack member has a chance to eat. This is the first evidence that the importance of the social relationship in food sharing is dependent on the feeding context in canids. PMID- 28725103 TI - Will I Fit in and Do Well? The Importance of Social Belongingness and Self Efficacy for Explaining Gender Differences in Interest in STEM and HEED Majors. AB - Throughout the world, the labor market is clearly gender segregated. More research is needed to explain women's lower interest in STEM (Science, Technology, Engineering and Mathematics) majors and particularly to explain men's lower interest in HEED (Health care, Elementary Education, and the Domestic spheres) majors. We tested self-efficacy (competence beliefs) and social belongingness expectations (fitting in socially) as mediators of gender differences in interest in STEM and HEED majors in a representative sample of 1327 Swedish high school students. Gender differences in interest in STEM majors strongly related to women's lower self-efficacy for STEM careers and, to a lesser degree, to women's lower social belongingness expectations with students in STEM majors. Social belongingness expectations also partly explained men's lower interest in HEED majors, but self-efficacy was not an important mediator of gender differences in interest in HEED. These results imply that interventions designed to lessen gender segregation in the labor market need to focus more on the social belongingness of students in the gender minority. Further, to specifically increase women's interest in STEM majors, we need to counteract gender stereotypical competence beliefs and assure women that they have what it takes to handle STEM careers. PMID- 28725104 TI - Analysis of Dependently Truncated Data in Cox Framework. AB - Truncation is a known feature of bone marrow transplant (BMT) registry data, for which the survival time of a leukemia patient is left truncated by the waiting time to transplant. It was recently noted that a longer waiting time was linked to poorer survival. A straightforward solution is a Cox model on the survival time with the waiting time as both truncation variable and covariate. The Cox model should also include other recognized risk factors as covariates. In this paper we focus on estimating the distribution function of waiting time and the probability of selection under the aforementioned Cox model. PMID- 28725105 TI - Porcine reproductive and respiratory syndrome virus (PRRSV) in pig meat. AB - Porcine reproductive and respiratory syndrome, caused by the porcine reproductive and respiratory syndrome virus (PRRSV), is an economically important disease in the swine industry. Previous studies demonstrated the presence of the virus in pig meat and its transmissibility by oral consumption. This study further analyzed the infectivity of PRRSV in commercial pig meat. Fresh bottom meat pieces (n = 1500) randomly selected over a period of 2 y from a pork ham boning plant located in Quebec, Canada, were tested by reverse transcriptase polymerase chain reaction (RT-PCR). Each trimmed meat was stored in the plant freezer, subsampled weekly for up to 15 wk, and tested with quantitative RT-PCR to determine the viral load. Meat infectivity was evaluated using specific pathogen free piglets, each fed with approximately 500 g of meat at the end of the storage time. Genotype-specific RT-PCR confirmed the presence of PRRSV mainly during cold weather in 0.73% of the fresh meat pieces. Wild and vaccine strains of genotype 2 were detected. Porcine reproductive and respiratory syndrome virus nucleic acid was stable in meat stored at around -20 degrees C during the 15 wk. Serological and molecular analysis showed the transmission of infection by a majority of PRRSV positive meat pieces (5/9) fed orally to naive recipients. The results confirmed a low prevalence of PRRSV in market's pig meat, and virus transmissibility by oral consumption to naive recipients even after several weeks of storage in a commercial freezer. It occurred mainly with meat harboring the highest PRRSV RNA copies, in the range of 109 copies per 500 g of meat, with both wild type and vaccine-related strains. PMID- 28725106 TI - Development of porcine circovirus 2 (PCV2) open reading frame 2 DNA vaccine with different adjuvants and comparison with commercial PCV2 subunit vaccine in an experimental challenge. AB - The objective of this study was to compare the protection against challenge with porcine circovirus 2 (PCV2) induced by an experimental vaccine based on open reading frame (ORF) 2 of PCV2 DNA plus an adjuvant (aluminum hydroxide, cobalt oxide, or liposome) and a commercial PCV2 subunit vaccine. A total of 35 colostrum-fed, cross-bred, conventional piglets were randomly divided into 7 groups. The commercial vaccine was more efficacious against PCV2 challenge than the 4 experimental vaccines according to immunologic, virologic, and pathological outcomes. The pigs inoculated with the experimental vaccine containing the liposome adjuvant had significantly higher levels (P < 0.05) of neutralizing antibodies and interferon-gamma-secreting cells, and significantly lower levels (P < 0.05) of PCV2 viremia than the pigs inoculated with the other experimental vaccines. The pigs inoculated with the experimental vaccines containing either the liposome adjuvant or the cobalt oxide adjuvant had significantly lower lymphoid lesion scores (P < 0.05) than the pigs in the group inoculated with the PCV2 DNA vaccine dissolved in phosphate-buffered saline. Liposome proved to be a potent adjuvant that efficiently enhanced both humoral and cellular immune responses induced by the PCV2 DNA vaccine. PMID- 28725107 TI - Retrospective study of the relationship of Torque teno sus virus 1a and Torque teno sus virus 1b with porcine circovirus associated disease. AB - Genus Iotatorquevirus consists of 2 species, Torque teno sus virus 1a and Torque teno sus virus 1b, which are ubiquitous in swine populations, and are widely reported in association with porcine circovirus associated disease (PCVAD). To evaluate the relationship with PCVAD, 100 formalin-fixed paraffin-embedded tissue samples were used to detect both Iotatorquevirus species by nested PCR and sequencing. Sixty-eight PCVAD cases were selected as well as 32 porcine circovirus type 2 (PCV2) non-affected cases. Overall, 33 of the 100 cases were positive for Torque teno sus virus 1a and 8 of 100 were positive for Torque teno sus virus 1b. Only 24 of 68 (35%) PCVAD cases were positive for Torque teno sus virus 1a; 39% (9/23) of post-weaning multisystemic wasting syndrome, and 33% (15/45) of PCV2-associated reproductive failure cases. Among PCV2 non-affected cases, 28% were positive for Torque teno sus virus 1a and 6% were positive for Torque teno sus virus 1b. Torque teno sus virus 1b was not detected in PCV2 associated reproductive failure cases. Regardless of the PCV2-status, a lower frequency of both Iotatorquevirus species was found than depicted in other reports and there was no statistical relationship with PCVAD (chi 2 < 0.01). Given the worldwide genomic variability of Iotatorquevirus species, it is feasible that species prevalent in Mexico share a lower nucleotide sequence identity, leading to different pathogenic potential. PMID- 28725108 TI - Identification of the linear ligand epitope on classical swine fever virus that interacts with porcine kidney 15 cells. AB - Binding of the viral ligand to a specific receptor is the first step of virus entry into target cells. The envelope proteins Erns, E1, and E2 of classical swine fever virus (CSFV) are involved in the interaction with host cell receptors to mediate CSFV infection. The aim of this investigation was to identify epitopes that bind to porcine kidney (PK)-15 cells to prevent CSFV infection. Ten peptides representing Erns, E1, and E2 were synthesized. Immunohistochemical study showed that the SE24 peptide, which is derived from the E2 amino acid sequence, could effectively bind to PK-15 cells. Similarly, a flow cytometry assay demonstrated that SE24 binding to PK-15 cells could be blocked by CSFV. The binding of SE24 with PK-15 cells leads to decreased CSFV infection of PK-15 cells in a dose dependent manner. These results suggest a potential new strategy for the prevention and control of CSFV infection that requires further investigation. PMID- 28725109 TI - Direct repeat unit (dru) typing and antimicrobial resistance of methicillin resistant Staphylococcus pseudintermedius isolated from dogs in Atlantic Canada. AB - There are few reports investigating the characterization of methicillin-resistant Staphylococcus pseudintermedius (MRSP) in dogs in Canada and none from Atlantic Canada. The objectives of this study were to strain type MRSP isolates cultured at a regional diagnostic laboratory using direct repeat unit (dru) typing and to describe their antimicrobial resistance profiles. Ninety-four isolates recovered from dogs between 2010 and 2012 had dru typing, cluster analysis, and antimicrobial susceptibility testing done. The majority of isolates belonged to type dt11a (30.9%), dt10h (24.5%), dt9a (18.1%), and dt11af (10.6%) with the remaining 15.9% of isolates distributed among 13 dru types. The predominant dru types identified were similar in Ontario; however, cluster 9a appears to be less common in Atlantic Canada. A significant difference in the distribution of clusters among Atlantic provinces was detected (P = 0.01). Resistance to >= 2 non beta-lactam antimicrobials was observed in 71.4% of the isolates. The MRSP isolates from this study were notably less resistant than those reported in the literature. A more comprehensive study of the MRSP dru types could help further elucidate the distribution of this pathogen in Canada. PMID- 28725110 TI - The impact of carboplatin and toceranib phosphate on serum vascular endothelial growth factor (VEGF) and metalloproteinase-9 (MMP-9) levels and survival in canine osteosarcoma. AB - In this pilot study, 10 dogs with osteosarcoma (OSA) were treated with amputation and subsequent carboplatin chemotherapy (300 mg/m2 IV q3wk * 4 doses) followed by toceranib phosphate (2.75 mg/kg PO q48h starting at day 14 post carboplatin). Monthly clinical monitoring and serum measurements of vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9) were acquired. No dogs were removed from the study due to toxicity. Levels of VEGF and MMP-9 did not change over time. Seven dogs died related to local recurrence and/or pulmonary or bone metastasis and the remainder died of other causes. Median OSA-free survival was 238 d with 34% 1-year progression-free survival. Median overall survival was 253 d with 30% alive at 1.5 y and 10% alive at 2 y. Although this regimen was well tolerated, survival times did not exceed previously published data from dogs treated with amputation plus chemotherapy alone. PMID- 28725111 TI - Oxidative stress and food supplementation with antioxidants in therapy dogs. AB - The objective of this study was to evaluate the ability of a long-term antioxidant-supplemented diet to regulate the oxidative stress and general health status of dogs involved in animal-assisted intervention (AAI) programs. Oxidative stress is a consequence of the accumulation of reactive oxygen species (ROS). Exercise-induced oxidative stress can increase muscle fatigue and fiber damage and eventually leads to impairment of the immune system. A randomized, placebo controlled, crossover clinical evaluation was conducted with 11 healthy therapy dogs: 6 females and 5 males of different breeds and with a mean age of 2.7 +/- 0.8 y (mean +/- SEM). The dogs were divided into 2 groups, 1 fed a high quality commercial diet without antioxidants (CD) and the other a high quality commercial diet supplemented with antioxidants (SD) for 18 wk. After the first 18 wk, metabolic parameters, reactive oxygen metabolite-derivatives (d-ROMs), and biological antioxidant potential (BAP) levels were monitored and showed a significant reduction of d-ROMs, triglycerides, and creatinine values in the SD group (P < 0.05) and a significant increase in amylase values in the CD group (P < 0.01). At the end of this period, groups were crossed over and fed for another 18 wk. A significant decrease in amylase and glutamate pyruvate transaminase (GPT) values was observed in the CD and SD group, respectively (P < 0.05). In conclusion, a controlled, balanced antioxidant diet may be a valid approach to restoring good cell metabolism and neutralizing excess free radicals in therapy dogs. PMID- 28725112 TI - Evaluation of transmission infrared spectroscopy and digital and optical refractometers to identify low immunoglobulin G concentrations in alpaca serum. AB - This study aimed to evaluate the digital Brix and optical serum total protein (STP) refractometers for measuring concentrations of serum immunoglobulin G (IgG) in alpacas and compare them to IgG concentrations measured by the reference method of radial immunodiffusion (RID) assay. The appropriate cutoff point for Brix and STP refractometers and the transmission infrared (TIR) spectroscopy method was determined for low IgG concentrations (< 10 g/L). Serum samples were collected from alpacas (N = 169) and tested by both refractometers. The correlation between Brix % and STP was high [correlation coefficient (r) = 0.99]. However, the correlation coefficients between Brix % and STP with serum RID-IgG concentrations were only 0.56 and 0.55, respectively. Twenty-one (12.4%) of 169 alpaca serum samples had IgG concentrations of < 10 g/L. Using receiver operator characteristic curve (ROC) analysis, the optimal cutoff points for the TIR assay, digital Brix, and optical STP refractometers for assessing low IgG (RID < 10 g/L) were 13 g/L, 8.8%, and 50 g/L, respectively. The TIR assay showed higher sensitivity (Se = 95.2%) and specificity (Sp = 96.8%) than either the digital Brix (Se = 90.5% and Sp = 65.5%) or optical STP (Se = 81% and Sp = 73.7%) refractometers for assessing alpacas with low IgG. In conclusion, the Brix and STP refractometers lack accuracy in measuring alpaca IgG concentrations, but may be useful for screening animals for low serum IgG. However, the TIR assay with a cutoff point of 13 g/L was more appropriate for identifying low IgG than either refractometer. Another study that focuses on neonatal crias is recommended in order to evaluate the usefulness of these assays for field diagnosing of failure of transfer of passive immunity (FTPI). PMID- 28725113 TI - Cystic duct pressures after ligation with a novel absorbable device in an ex vivo caprine cholecystectomy model. AB - Laparoscopic cholecystectomy is the standard of care in human medicine for gall bladder disease. Although infrequently reported in veterinary literature, laparoscopic cholecystectomy is an option for uncomplicated gall bladder disease in canine patients. Due to the risk of cystic duct ligature slippage or clip dislodgement, we wanted to explore the use of a LigaTie; a novel absorbable medical device modeled after a cable tie. Our object was to describe the use of the LigaTie in a caprine cadaveric study of cholecystectomies as a model for canine patients and demonstrate the leak pressure of the cystic duct compared with cholecystectomies performed with 2 large endoscopic hemoclips. Samples of caprine gall bladder, liver, and cystic duct were collected. The cystic duct was ligated with either 2 large endoscopic hemoclips or a LigaTie. Maximum cystic duct pressure was recorded. Results showed that there was no statistically significant difference in the maximum cystic duct pressure achieved for cystic ducts ligated with 2 large endoscopic hemoclips or the LigaTie (P = 0.865). No leakage was observed from the cystic duct, hemoclip, or LigaTie site in either group. Supraphysiologic pressures were achieved in both groups and high pressure occlusion of the infusion pump determined the maximum intraluminal pressure achieved. Based on these results, the LigaTie may provide advantages in minimally invasive surgery, especially when considering ligation of a friable or thickened cystic duct during laparoscopic cholecystectomy. Future in vivo studies are warranted to determine minimally invasive maneuverability, tissue interaction, complications, and outcomes. PMID- 28725114 TI - Evaluation of serum symmetric dimethylarginine in dogs with heartworm infection. AB - This study evaluated the circulating levels of serum symmetric dimethylarginine (SDMA) in 12 dogs with different severities of heartworm disease (HWD) and assessed the biochemical renal markers (blood urea nitrogen, creatinine). Dogs were classified into 2 groups based on the severity of clinical signs. Group A - asymptomatic to mild clinical signs, group B - moderate to severe clinical signs. The serum SDMA levels were higher in dogs in group B. Although the serum SDMA levels in dogs in group A were also higher than those of the control dogs, the difference was not statistically significant. There was a good correlation between renal markers and severity of clinical signs. This study demonstrated that the glomerular filtration rate was significantly decreased in dogs in group A; therefore, earlier detection of renal impairment is required for successful management of dogs with HWD. PMID- 28725115 TI - Maternal and fetal arterial blood gas data in normotensive, singleton, isoflurane anesthetized sheep at 124-126 days of gestation. AB - The aim of this case series was to describe the differences between maternal and fetal blood-gas results during anesthesia. Sixteen singleton adult merino ewes weighing 60.1 +/- 5.1 kg at 125.7 d (124 to 126 d) gestation were anesthetized. Maternal (radial) and fetal (umbilical) arterial blood gas samples were collected 79 +/- 6 min after the start of anesthesia if maternal mean arterial pressure (MAP) was stable and > 65 mmHg. Fetal pH, partial arterial pressure of oxygen (PaO2), glucose, arterial hemoglobin oxygen saturation (SaO2), sodium, and chloride were significantly lower and fetal partial arterial pressure of carbon dioxide (PaCO2), lactate, hematocrit, total hemoglobin, potassium, and calcium were significantly higher than maternal blood-gas values. Fetal pH, PaO2, and BE were lower and fetal lactate was higher than fetal umbilical arterial samples previously reported, which may indicate a non-reassuring fetal status. Further refinement of the ovine experimental model is warranted with fetal monitoring during maternal anesthesia. PMID- 28725116 TI - Towards an improved estimate of antimicrobial use in animals: Adjusting the "population correction unit" calculation. AB - International comparisons of animal antimicrobial use (AMU) have typically been based on total national estimates of antimicrobials sales standardized by the national animal biomass calculated as the population correction unit (PCU). The objective of this paper was to compare the currently accepted PCU calculation with that of the adjusted population correction unit (APCU), which re-evaluates the standard animal weights used in the calculation and accounts for animal lifespan. The APCU calculation resulted in substantial changes to the 2009 national biomass estimates for cattle, pigs, and poultry in 8 European countries and Canada. The estimated national biomass for cattle increased 35% to 43%, while the estimated national biomass of pigs and poultry typically decreased by approximately 51% and 87%, respectively. Among the 9 countries, the total national APCU ranged from an increase of 1% to a decrease of 40% relative to PCU, and these differences were statistically significant. Adjusted population correction unit is preferred over PCU in comparing and contrasting AMU among animals with different lifespans because it is more transparently derived and is a reasonable approximation of the animal biomass at risk of antimicrobial treatment. PMID- 28725117 TI - The effect of fast and slow decisions on risk taking. AB - We experimentally compare fast and slow decisions in a series of experiments on financial risk taking in three countries involving over 1700 subjects. To manipulate fast and slow decisions, subjects were randomly allocated to responding within 7 seconds (time pressure) or waiting for at least 7 or 20 seconds (time delay) before responding. To control for different effects of time pressure and time delay on measurement noise, we estimate separate parameters for noise and risk preferences within a random utility framework. We find that time pressure increases risk aversion for gains and risk taking for losses compared to time delay, implying that time pressure increases the reflection effect of Prospect Theory. The results for gains are weaker and less robust than the results for losses. We find no significant difference between time pressure and time delay for loss aversion (tested in only one of the experiments). Time delay also leads to less measurement noise than time pressure and unconstrained decisions, and appears to be an effective way of decreasing noise in experiments. PMID- 28725118 TI - Share capitalism and worker wellbeing. AB - We show that worker wellbeing is determined not only by the amount of compensation workers receive but also by how compensation is determined. While previous theoretical and empirical work has often been preoccupied with individual performance-related pay, we find that the receipt of a range of group performance schemes (profit shares, group bonuses and share ownership) is associated with higher job satisfaction. This holds conditional on wage levels, so that pay methods are associated with greater job satisfaction in addition to that coming from higher wages. We use a variety of methods to control for unobserved individual and job-specific characteristics. We suggest that half of the share-capitalism effect is accounted for by employees reciprocating for the "gift"; we also show that share capitalism helps dampen the negative wellbeing effects of what we typically think of as "bad" aspects of job quality. PMID- 28725119 TI - VLBI observations of GNSS-satellites: from scheduling to analysis. AB - The possibility of observing satellites with the very long baseline interferometry (VLBI) technique has been discussed for several years in the geodetic community, with observations of either existing satellites of the global navigation satellite systems or of satellites dedicated to realise a space tie. Such observations were carried out using the Australian telescopes in Hobart and Ceduna which, for the first time, integrated all the necessary steps: planning the observations (automated scheduling), correlation of the data and the generation of a series of time delay observables suitable for a subsequent geodetic analysis. We report on the development of new and the adaptation of existing routines for observing and data processing, focusing on technology development. The aim was to use methods that are routinely used in geodetic VLBI. A series of test experiments of up to six hours duration was performed, allowing to improve the observations from session to session and revealing new problems still to be solved. The newly developed procedures and programs now enable more observations. Further development assumed, this bears the prospect of being directly applied to the observation of dedicated space-tie satellites. PMID- 28725120 TI - Implementation of a Cooking Bus intervention to support cooking in schools in Wales, UK. AB - PURPOSE: The teaching of cooking is an important aspect of school-based efforts to promote healthy diets among children, and is frequently done by external agencies. Within a limited evidence base relating to cooking interventions in schools, there are important questions about how interventions are integrated within school settings. The purpose of this paper is to examine how a mobile classroom (Cooking Bus) sought to strengthen connections between schools and cooking, and drawing on the concept of the sociotechnical network, theorise the interactions between the Bus and school contexts. DESIGN/METHODOLOGY/APPROACH: Methods comprised a postal questionnaire to 76 schools which had received a Bus visit, and case studies of the Bus' work in five schools, including a range of school sizes and urban/rural locations. Case studies comprised observation of Cooking Bus sessions, and interviews with school staff. FINDINGS: The Cooking Bus forged connections with schools through aligning intervention and schools' goals, focussing on pupils' cooking skills, training teachers and contributing to schools' existing cooking-related activities. The Bus expanded its sociotechnical network through post-visit integration of cooking activities within schools, particularly teachers' use of intervention cooking kits. RESEARCH LIMITATIONS/IMPLICATIONS: The paper highlights the need for research on the long term impacts of school cooking interventions, and better understanding of the interaction between interventions and school contexts. ORIGINALITY/VALUE: This paper adds to the limited evidence base on school-based cooking interventions by theorising how cooking interventions relate to school settings, and how they may achieve integration. PMID- 28725121 TI - A comparison of the omega and posterior approaches on patient reported function and radiological outcomes following total hip replacement. AB - BACKGROUND: The omega approach represents a modification of the lateral approach to the hip for joint replacement. It was developed to reduce the potential for gluteus muscle dysfunction and thereby improve functional outcome following hip replacement. METHODS: A cohort of 415 consecutive hip replacements receiving the same type of cemented femoral component were followed up at a mean of three years postoperatively and invited to complete functional outcome and satisfaction scores. RESULTS: There were no differences between the omega and the posterior approach in terms of post-operative Oxford Hip Score, Short Form-12 score, patient satisfaction and a range of radiographic parameters. CONCLUSIONS: The omega approach appears to perform equally to the posterior approach in this cohort of patients. PMID- 28725122 TI - Two-incisions direct anterior approach for THR: Surgical technique and early outcome. AB - PURPOSE: In recent times the direct anterior approach for total hip replacement has gained considerable interest among orthopaedic surgeons because of the relative muscle-sparing nature than other surgical approaches. However, critics believe that this approach is associated with steep learning curve and high complication rates, mainly attributed to a more limited exposure to the femur. In order to make femoral access easier and implantation of acetabulum in anatomic plane, we designed a "two incisions anterior approach technique" for total hip replacement. The aim of the present study is to determine safety of this technique with respect to perioperative complications as well as early clinical outcome. METHODS: A retrospective review is carried out on a consecutive series of patients who underwent primary total hip replacement by the single surgeon through the two incisions direct anterior approach from 01/2014 to 11/2014. We analysed peri-operative complications and clinical outcome at two years' follow up. RESULTS: We observed 01(0.9%) intra-operative complication; calcar fracture and 01(0.9%) anterior dislocation in first post-operative week. All patients reported improvement of their symptoms. The mean modified oxford hip score was significantly better from 25(11-37), preoperatively to 46.97(33-48) at mean latest follow-up. The mean modified Merle d'Aubigne-Postel score improved to 16.84(12-18) from 9.25 (4-14) preoperatively. CONCLUSION: The described surgical technique is simple and reproducible technique for easier exposure of femur and insertion of acetabulum in anatomic plane for total hip replacement through direct anterior approach. Easier and better femoral access helps to place implant in anatomical position as well as reduces the risk of femoral fracture associated with inadequate femoral exposure. The added advantage of this technique is, risks of injury to lateral femoral cutaneous nerve can be minimised by careful dissection and isolation of the nerve. PMID- 28725123 TI - Polymicrobial pyogenic flexor tenosynovitis of the index finger and first ray resulting from autophagia. AB - Pyogenic flexor tenosynovitis (PFT) is a well known infectious condition of the hand, involving the inoculation of the flexor tendon sheath with microorganisms. Many cases have been reported, common causes including direct inoculation by a puncture wound and deep lacerations extending into the flexor tendon sheath. In this report, we present a case of a 50 year old female with PFT resulting from autophagia (consuming one's own body parts, in our case, fingers) successfully treated with irrigation and debridement, amputation of the index finger at the metacarpophalangeal joint and antibiotic therapy. PMID- 28725124 TI - Reconstruction of the distal tibia following resection of aggressive bone tumours using a custom-made megaprosthesis. AB - OBJECTIVE: Largest, single-centre study of clinical and functional outcomes of patients who underwent endoprosthetic replacement (EPR) for aggressive distal tibial bone tumours. METHOD: Retrospective observational study of eight patients was undertaken. RESULTS: Median follow-up was 77 months (range 13-276). Cumulative five and ten year survival was 63% and 42% respectively. Three patients developed either disease recurrence or metastases post-surgery. One patient developed deep infection requiring washout and suppressive antibiotics. No patients required revision surgery. The median MSTS score at last follow up was 66%. CONCLUSIONS: EPR of the distal tibia is a viable option and provides good function outcomes. PMID- 28725125 TI - From dental science to clinical practice: Knowledge translation and evidence based dentistry principles. AB - It has been claimed that in order to decrease the gap between what we know and what we do, research findings must be translated from knowledge to action. Such practices better enable dentists to make evidence-based decisions instead of personal ideas and judgments. To this end, this literature review aims to revisit the concepts of knowledge translation and evidence-based dentistry (EBD) and depict their role and influence within dental education. It addresses some possible strategies to facilitate knowledge translation (KT), encourage dental students to use EBD principles, and to encourage dental educators to create an environment in which students become self-directed learners. It concludes with a call to develop up-to-date and efficient online platforms that could grant dentists better access to EBD sources in order to more efficiently translate research evidence into the clinic. PMID- 28725126 TI - Odontogenic myxoma: A review with report of an uncommon case with recurrence in the mandible of a teenage male. AB - We describe a 13-year-old boy with recurrence of an odontogenic myxoma of the mandible. We review the existing published literature on the lesion, emphasizing the similarities and differences among lesions in the differential diagnosis. Odontogenic myxoma is an uncommon benign tumor that mainly affects the mandible, with a peak incidence in the second to fourth decades of life and predilection for the female sex. Clinical, radiological, and histopathological features should be considered when making a diagnosis. Several of these characteristics overlap with those of other benign and some malignant tumors. Odontogenic myxoma is known for recurrence. The treatment plan should consider the age and sex of the patient and the site and size of the lesion. Reconstructive surgery may be required, but should be delayed until after an adequate follow-up to rule out recurrence. PMID- 28725127 TI - Assessment of the influence of gender and skin color on the preference of tooth shade in Saudi population. AB - AIM: The aim of the study was to evaluate the influence of gender and skin color on the preference of different teeth shades in general population. MATERIALS AND METHODS: Two standardized frontal smile photographs of male and female subjects were manipulated using photoshop to represent 4 skin colors [(type II, III, IV, and V) (Fitzpatrick scale)]. The teeth shades under each skin color were digitally manipulated to represent one of 6 teeth shades (BL1, BL2, BL3, BL4, B1 and A1). A questionnaire assessed demographic characteristics (age, nationality, gender, education level, occupation, and income) along with the satisfaction of their smiles. Male and female set of pictures with combination of skin colors and teeth shades were presented and participants were asked to select the most esthetically pleasing teeth shade with regard to gender and skin color. Cross tabulations and chi-squared tests were used to perform the statistical analyses (alpha = 0.05). RESULTS: Three hundred and thirty-six (60.4% male; 39.6% female) individuals participated in the study. The difference in the preferred teeth shades was significant among the male and female photographs across all skin colors (p < 0.05). Lighter teeth shades were preferred among female subjects compared to male subjects with the same skin color. In addition, lighter teeth shades were preferred among subjects with a lighter skin color and vice versa (p < 0.05). CONCLUSION: Gender and skin color influences the perception of teeth shades among general population. Therefore, lighter tooth shades (BL1, BL2) for lighter skin color and comparatively darker tooth shades (BL4, B1, A1) for darker skin individuals should be prescribed as these are perceived as natural among Saudi population. PMID- 28725128 TI - Quality of communication between dentists and dental laboratory technicians for fixed prosthodontics in Riyadh, Saudi Arabia. AB - : The fabrication of a clinically acceptable dental prosthesis requires proper communication between the dentist and the dental technician. Prosthodontic educators have been concerned with this interaction and communication. Fixed prosthodontics laboratories revealed that the technicians are often dissatisfied with the information provided in work authorizations. OBJECTIVE: To evaluate the quality of communication between dentists and laboratory technicians via work authorizations for fixed prosthodontics in both governmental and private dental laboratories in Riyadh area from the technician's perspective. METHODS: A sample of 66 dental laboratories, including all government dental laboratories and a selected number of randomly chosen private dental laboratories from each district of Riyadh (40%), participated in the survey. A questionnaire was developed to include questions related to the following areas of work authorization: clarity and accuracy of instructions, patient information, type of prosthesis, choice of materials, design and shade of the prosthesis and type of porcelain glaze. The questionnaire was answered in a face-to-face interview by technicians who were qualified in fixed prosthetic work. Data were analyzed through parametric tests (T-test and one-way ANOVA) to identify significant values (P < 0.05). RESULTS: This survey showed a lack of communication between dentists and dental laboratories regarding the following: marginal design, pontic design, staining diagram, type of porcelain and glaze needed for the prosthesis. Significant differences were observed between the government and private dental laboratories. There was a greater lack of communication between the dentists and government laboratory technicians in Riyadh. There was no statistically significant difference between private laboratories of different areas in Riyadh city (P < 0.05). CONCLUSION: The quality of communication between dentists and dental technicians in Riyadh can sometimes be inadequate, and governmental laboratories have a lower level of communication. PMID- 28725129 TI - Estimation of fluoride concentration in drinking water and common beverages in United Arab Emirates (UAE). AB - OBJECTIVE: To assess fluoride concentration in drinking water which include tap water of 4 emirates - Abu Dhabi, Dubai, Sharjah and Ajman plus bottled water, commonly available soft drinks & juices in United Arab Emirates. METHODS: Five different samples of tap water collected from each of the four emirates of UAE: Ajman, Sharjah, Abu Dhabi and Dubai; twenty-two brands of bottled water and fifteen brands of popular cold beverages, purchased from different supermarkets in U.A.E were tested using ion selective electrode method and the fluoride concentration was determined. RESULTS: The mean fluoride content of tap water samples was 0.14 mg F/L with a range of 0.04-0.3 mg F/L; with Ajman tap water samples showing the highest mean fluoride content of 0.3 mg F/L. The mean fluoride content for both bottled drinking water and beverages was 0.07 mg F/L with a range of 0.02-0.50 mg F/L and 0.04-0.1 mg F/L respectively. Majority (68.2%) of the bottled water are produced locally within U.A.E while a few (31.8%) are imported. CONCLUSIONS: The tap water, bottled water and beverages available in U.A.E show varying concentrations of fluoride, however none showed the optimal level necessary to prevent dental caries. Dental professionals in U.A.E should be aware of the fluoride concentrations before prescribing fluoride supplements to children. PMID- 28725130 TI - Role of community pharmacists in providing oral health advice in the Eastern province of Saudi Arabia. AB - OBJECTIVE: To determine the frequency of patients seeking oral health advice and willingness of community pharmacists to provide oral health information in the Eastern Province of Saudi Arabia. METHODS: A cross-sectional study with sample size (n = 332) of randomly selected community pharmacists across the province. The questionnaire comprised of 25 questions divided into 3 sections. Frequency distributions of different categorical variables were calculated and Pearson's chi-square tests were performed to compare categorical variables. Statistical significance was determined at p-value <0.05%. SPSS version 22 was used for statistical analyses. RESULTS: Of the 332 pharmacists, 279 agreed to participate in the study, yielding a response rate of 84%. About 71% of pharmacists provided less than 30 oral health advices and 29% of them gave >=30 oral health advices daily. Oral ulcer (64.2%), dental pain (59.5%) and bleeding gums (54.5%) were the three most common oral conditions encountered by the pharmacists. More pharmacists (90%) were approached for advice about tooth whitening products, tooth brush and mouth wash in large cities compared with 66.7% of pharmacists in small cities of the province. Lack of interaction with dental professionals was recognized the most important barrier to providing oral health services to the clients. Almost one third (35.8%) had formal oral health training in their undergraduate program and only 26.5% of them were always confident in providing oral health advices. Majority (93.5%) of respondents recognized their important role in providing oral health advices and 98.2% were enthusiastic to provide oral health information. CONCLUSIONS: Community pharmacists are approached frequently for oral healthcare advices. Majority of them had no oral health training. Almost all of them were willing to provide oral health information in the community. It is essential to provide continuous oral health education to the pharmacists to better serve oral health needs of the community. PMID- 28725132 TI - A novel method of constructing compactly supported orthogonal scaling functions from splines. AB - A novel construction of compactly supported orthogonal scaling functions and wavelets with spline functions is presented in this paper. Let [Formula: see text] be the center B-spline of order n, except for the case of order one, we know [Formula: see text] is not orthogonal. But by the formula of orthonormalization procedure, we can construct an orthogonal scaling function corresponding to [Formula: see text]. However, unlike [Formula: see text] itself, this scaling function no longer has compact support. To induce the orthogonality while keeping the compact support of [Formula: see text], we put forward a simple, yet efficient construction method that uses the formula of orthonormalization procedure and the weighted average method to construct the two scale symbol of some compactly supported orthogonal scaling functions. PMID- 28725131 TI - Oral Kaposi Sarcoma in HIV-seronegative Saudi patient: Literature review and case report. AB - Kaposi Sarcoma (KS) is an intermediate neoplasm affecting the endothelial cells of mucous membranes and skin. It arises most commonly among HIV-infected individuals. We present an intra-oral KS in an 80-year-old Saudi male patient, who is HIV-seronegative, non-immunosuppressed, and with no history of organ transplantation. The patient was treated with fractionated radiation therapy, and had no recurrence in the 48 months of follow-up. The clinical disease, histologic features, and treatment modality used, as well as the relative literature are presented in this paper. PMID- 28725133 TI - Rate of convergence by Kantorovich-Szasz type operators based on Brenke type polynomials. AB - The present paper deals with the approximation properties of the univariate operators which are the generalization of the Kantorovich-Szasz type operators involving Brenke type polynomials. We investigate the order of convergence by using Peetre's K-functional and the Ditzian-Totik modulus of smoothness and study the degree of approximation of the univariate operators for continuous functions in a Lipschitz space, a Lipschitz type maximal function and a weighted space. The rate of approximation of functions having derivatives equivalent with a function of bounded variation is also obtained. PMID- 28725134 TI - Fourier series of finite products of Bernoulli and Genocchi functions. AB - In this paper, we consider three types of functions given by products of Bernoulli and Genocchi functions and derive some new identities arising from Fourier series expansions associated with Bernoulli and Genocchi functions. Furthermore, we will express each of them in terms of Bernoulli functions. PMID- 28725135 TI - Adaptive group bridge estimation for high-dimensional partially linear models. AB - This paper studies group selection for the partially linear model with a diverging number of parameters. We propose an adaptive group bridge method and study the consistency, convergence rate and asymptotic distribution of the global adaptive group bridge estimator under regularity conditions. Simulation studies and a real example show the finite sample performance of our method. PMID- 28725137 TI - Psychological Determinants of Entrepreneurial Success and Life-Satisfaction. AB - The presented study focused on different stages of the entrepreneurial process. The first group comprised those starting a new business and the second group those who have been through the whole process of creating a new business and have now been operating in the market. The general aim of the article was to examine the relationship between action orientation, hope, goal commitment, entrepreneurial success, and life satisfaction, and to determine the role of psychological characteristics (hope, action orientation) in the entrepreneurial process. The hypotheses were tested on a sample of 344 potential entrepreneurs in the prelaunch stage and 127 actual entrepreneurs in the post-launch stage. To analyze these relationships, multiple-group analysis was conducted. PMID- 28725136 TI - Sex-Specific Effect of Recalled Parenting on Affective and Cognitive Empathy in Adulthood. AB - Previous research has demonstrated the influence of parenting on the development of children's empathy. However, few studies have considered the impact of parents on empathy in adulthood, specific components of empathy, or the importance of parent and child biological sex. In the present study, 226 participants (71 men) completed online versions of the Parental Bonding Instrument (Parker et al. British Journal of Medical Psychology, 52, 1-10 1979), Empathy Quotient (Baron Cohen and Wheelwright Journal of Autism and Developmental Disorders, 34, 163-175 2004), and Interpersonal Reactivity Index (Davis JSAS Catalog of Selected Documents in Psychology, 10, 85 1980). Paternal care and overprotection influenced affective empathy in men, whilst maternal overprotection predicted affective empathy in women. Further, maternal care related to cognitive empathy in men, whilst none of the parental care variables related to cognitive empathy in women. Findings are discussed in relation to sex differences in childhood parenting experiences on adult cognitive and affective empathy. PMID- 28725138 TI - Comparative assessment of saliva and plasma for drug bioavailability and bioequivalence studies in humans. AB - Aims: To study the pharmacokinetics of selected drugs in plasma and saliva matrixes in healthy human volunteers, and to suggest using non-invasive saliva sampling instead of plasma as a surrogate in bioavailability and bioequivalence (BA/BE) studies. Methods: Four different pilot BA/BE studies were done in 12-18 healthy humans. Saliva and plasma samples were collected for 3-5 half life values of metformin, tolterodine, rosuvastatin, and paracetamol after oral dosing. Saliva and plasma samples were assayed using LC-MSMS, and then pharmacokinetic parameters were calculated by non-compartmental analysis using Kinetica program. Effective intestinal permeability (Peff) values were also optimized to predict the actual average plasma profile of each drug by Nelder-Mead algorithm of the Parameter Estimation module using SimCYP program. Results: All studied drugs showed salivary excretion with strong correlation coefficients between saliva and plasma concentrations. The optimized Peff ranged 1.44-68.3 * 10-4 cm/s for the drugs under investigation. Saliva/plasma concentrations ratios ranged 0.17-1.5. Inter and intra individual variability of primary pharmacokinetic parameters in saliva matrix was either close to or higher than plasma matrix. This requires larger sample size in saliva studies for some drugs. Conclusion: Our results suggest that there is a potential in BA/BE studies for saliva to be considered as a surrogate for plasma concentration, which goes along with drug regulations. The use of saliva instead of plasma in such studies makes them non-invasive, easy and with a lower clinical burden. PMID- 28725139 TI - Hybrid polymeric matrices for oral modified release of Desvenlafaxine succinate tablets. AB - Purpose: Desvenlafaxine succinate (DSV) is a water soluble anti-depressant drug, which is rapidly absorbed after oral administration exaggerating its side effects. The current work aimed to prepare controllable release DSV matrix to reduce DSV side effects related to its initial burst. Methods: Fifteen DSV matrix formulations were prepared using different polymers, polymer/drug ratios and matrix excipients and characterized using Differential Scanning Calorimetry (DSC), infrared (IR) spectroscopy, water uptake and in vitro DSV release. The release kinetics were calculated to determine the drug release mechanism. Ex-vivo DSV absorption via rat intestinal mucosal cells and the calculation of the apparent permeability coefficient (Papp) were performed using everted sac technique. Results: Maltodextrin was the best matrix excipient (F7 and F10) showing acceptable decrease in the initial burst compared to the innovator. The addition of negatively charged polymers sodium carboxy methyl cellulose (SCMC) or sodium alginate resulted in an interaction that was proved by DSC and IR findings. This interaction slowed DSV release. F10 showed an excellent absorption of more than 80% of DSV after 4 h and the highest similarity factor with the innovator (84.7). Conclusion: A controllable release pattern of DSV was achieved using Methocel, Maltodextrin and SCMC. The obtained results could be used as a platform to control the release of cationic water soluble drugs that suffer from side effects associated with their initial burst after oral administration. PMID- 28725140 TI - Formulation and pharmacokinetics of multi-layered matrix tablets: Biphasic delivery of diclofenac. AB - The rapid availability of the drug at the site of action followed by maintaining its effect for a long period of time is of great clinical importance. Thus, the purpose of the present study was to prepare and evaluate multi-layered matrix tablets of diclofenac using Eudragit RL/RS blend to achieve both immediate and sustained therapeutic effects. Diclofenac potassium (25 mg) was incorporated in an outer immediate release layer to provide immediate pain relief whereas diclofenac sodium (75 mg) was incorporated in the inner core to provide extended drug release. Wet granulation was employed to prepare the inner core of the tablets that were further layered with an immediate release drug layer in the perforated pan coater. The in-vitro and in-vivo performance of the developed formulation was compared with the marketed products Voltaren(r) SR 75 mg and Cataflam(r) 25 mg. The in-vitro drug release of the prepared formulation showed similarity (f2 = 66.19) to the marketed product. The pharmacokinetic study showed no significant difference (p > 0.05) in AUC0-24 and Cmax between the test and reference formulations. The AUC0-24 values were 105.36 +/- 83.3 and 92.87 +/- 55.53 MUg h/ml whereas the Cmax values were 11.25 +/- 6.87 and 12.97 +/- 8.45 MUg/ml, for the test and reference, respectively. The multi-layered tablets were proved to be bioequivalent with the commercially available tablets and were in agreement with the observed in-vitro drug release results. Stable physical characteristics and drug release profiles were observed in both long term and accelerated conditions stability studies. PMID- 28725141 TI - High-performance thin-layer chromatography based concurrent estimation of biomarkers ent-phyllanthidine and rutin in the dried aerial parts of Flueggea virosa. AB - The biomarkers are needed to be defined for standardization purposes so that safe and effective herbal formulations can be catered to the society. There is an urgent need for statistical support of herbal drugs because most of the herbal products are still used in the non-standardized form. This study is based on the development of a simple and sensitive RP-HPTLC method for concurrent estimation of two biomarkers ent-phyllanthidine and rutin in the methanol extract of aerial parts of Flueggea virosa. The developed method was found to be simple, economic and sensitive. Separation and quantification were performed with acetonitrile: water (4:6 V/V) used as the mobile phase on glass-backed RP-HPTLC plate. Detection of absorption maxima and quantification was done at 310 nm of UV region. The developed chromatographic system was found to give a sharp band for ent-phyllanthidine and rutin at Rf 0.73 +/- 0.01 and 0.68 +/- 0.01, respectively. The linearity ranges for ent-phyllanthidine, and rutin were found to be 200-1600 ngband-1 and 100-1400 ngband-1, respectively, with correlation coefficients (r2 values) of 0.998 and 0.997, respectively. The percentage of ent-phyllanthidine and rutin was found to be 9.121 +/- 0.02% and 1.018 +/- 0.04% (w/w), respectively. The resolution of bands and separation of constituents in FVME exhibited the perfect optimization of the developed method. The validation statistics supports the proposed method for standardizing crude drugs as well as formulations of a natural product containing ent-phyllanthidine and rutin. PMID- 28725142 TI - Rhanterium epapposum Oliv. essential oil: Chemical composition and antimicrobial, insect-repellent and anticholinesterase activities. AB - The essential oil (EO) of the aerial parts of Rhanterium epapposum Oliv. (Asteraceae), was obtained by hydrodistillation. The oil was subsequently analyzed by both GC-FID and GC-MS, simultaneously. Forty-five components representing 99.2% of the oil composition were identified. The most abundant compounds were camphene (38.5%), myrcene (17.5%), limonene (10.1%) and alpha pinene (8.7%). Referring to the ethnobotanical utilization, an insecticidal assay was performed, where the oil repelled the yellow fever mosquito Aedes aegypti L. at a minimum effective dose (MED of 0.035 +/- 0.010 mg/cm2) compared to the positive control DEET (MED of 0.015 +/- 0.004 mg/cm2). Additionally, the in vitro antimicrobial activity against a panel of pathogens was determined using a microdilution method. The acetyl- and butyrylcholine esterase inhibitory activities were measured using the colorimetric Ellman method. The bioassay results showed that the oil was rather moderate in antimicrobial and cholinesterase inhibitions when compared to the standard compounds. PMID- 28725143 TI - Pharmacy Malpractice: The rate and prevalence of dispensing high-risk prescription-only medications at community pharmacies in Saudi Arabia. AB - OBJECTIVE: To assess the compliance of community pharmacies with the regulations that prohibit the dispensing of prescription-only medications in the absence of a physician prescription in Saudi Arabia. METHOD: A cross-sectional study was conducted in the period between October 2014 and January 2015. A list of 10 prescription-only medications were selected to be studied. 150 community pharmacies were visited across 6 major regions in Saudi Arabia to assess the prevalence of non-compliance among community pharmacies. Pharmacies were selected in random and researchers (disguised as patients) requested to purchase prescription-only medications in the absence of a prescription. Not all medications were purchased at once. Data were recorded per pharmacy, where pharmacies that approved dispense of the selected drug were scored as non compliant and the pharmacies that rejected dispense of the selected drug were scored as compliant. Compliance rate was calculated per region per drug. Pharmacies based in governmental hospitals were visited in parallel. A total of 20 were visited. Data and statistical analysis were performed using Statistical Analyses Software (SAS 9.3). RESULTS: A total of 150 pharmacies were visited over a period of 3 months. On average, the percent approved dispense of prescription only drugs across 6 regions in Saudi Arabia is 63% and the percent rejected dispense is 37% representing a significant non-compliance rate regarding the selected list of medications in this study. The frequency of dispense per medication across 6 major regions in Saudi Arabia is as follows: Isosorbide dinitrate (86%), Enoxaparin (82%), nitroglycerin (74%), Propranolol (73%), Verapamil (70%), Warfarin (65%), Methyldopa (64%), Ciprofloxacin (57%) and Codeine (4%). CONCLUSIONS: Non-compliance of community pharmacies with the law of pharmaceutical practice is at an alarming rate in the Kingdom of Saudi Arabia and authoritative figures must intervene to impede and combat such activities. PMID- 28725144 TI - Comparative study of antioxidant activity and validated RP-HPTLC analysis of rutin in the leaves of different Acacia species grown in Saudi Arabia. AB - The present study assessed the comparative antioxidant potential of the ethanol extract (EE) of leaves of four Acacia species (Acacia salicina, AS; Acacia laeta, AL; Acacia hamulosa AH; and Acacia tortilis, AT) grown in Saudi Arabia, including RP-HPTLC quantification of antioxidant biomarker rutin. In vitro DPPH radical scavenging and beta-carotene-linoleic acid bleaching assays showed the promising antioxidant activities of Acacia extracts: ASEE (IC50: 60.39 and 324.65 MUg/ml) >ALEE (IC50: 217.06 and 423.36 MUg/ml) >ATEE (IC50: 250.13 and 747.50 MUg/ml) >AHEE (IC50: 255.83 and 417.28 MUg/ml). This was comparable to rutin tested at 500 MUg/ml. Further, a RP- HPTLC densitometric method was developed (acetonitrile:water; 6:4; v/v) using glass-backed RP-18 silica gel F254 plate, and scanned at UV max 254 nm. The method was validated as per the ICH guidelines. Analysis of the validated RP-HPTLC displayed an intense peak (Rf = 0.65 +/- 0.004) of rutin that was estimated (MUg/mg dry weight) to be highest in ASEE (10.42), followed by ALEE (2.67), AHEE (1.36) and ATEE (0.31). Taken together, presence of rutin strongly supported the high antioxidant property of the tested Acacia species, especially Acacia salicina. The developed RP-HPTLC method therefore, affirms its application in the quality control of commercialized herbal drugs or formulation containing rutin. PMID- 28725145 TI - HIV pharmaceutical care in primary healthcare: Improvement in CD4 count and reduction in drug-related problems. AB - Background: Highly active antiretroviral therapy (HAART) is complex and many factors contribute to a patient's response to initial therapy including adherence, drug effectiveness, and tolerance. Close HAART follow-up is needed, particularly when there are concurrent therapies such as prophylactic antibiotics and medications for the treatment of comorbidities. Objective: To assess the effectiveness of pharmacist intervention in reducing drug related problems in HIV/AIDS outpatients (intervention group) and in improving clinical parameters in the intervention group compared to the control group. Methods: We conducted a prospective controlled intervention study with patients paired by gender and initial T CD4+ lymphocyte (CD4) count. HIV-infected patients of a public outpatient service were enrolled for the study by consecutive and convenience sampling. Patients selected for the study were divided into a control group and an intervention group. Both groups were followed for one year; however, only the intervention group received pharmaceutical care. The primary outcome was the drug related problem (DRP) analysis for the intervention group. Secondary outcomes were CD4 count and viral load evaluation for both groups. Results: There was a total of 143 patients enrolled in this study, with 53 (37.06%) patients in the control group and 90 (62.94%) patients in the intervention group. A total of 202 pharmacist interventions with 193 pharmacist-patient and 9 pharmacist-physician interventions were proposed. After one year of pharmaceutical care, a reduction of 38.43% between the initial and final DRP was found (p = 0.0001). The most common DRPs found were related to medication safety. The intervention group showed a mean increase of 84% for the CD4 count in comparison with that observed in the control group. The viral load was not significantly different between the final and initial mean values for both groups. Conclusion: Pharmacist appointments enabled identification, prevention, and solving of drug related problems, especially those related to drug safety. Also, pharmacist interventions improved adherence and increased HAART effectiveness as suggested by the higher elevation in the CD4 count seen in the intervention group in comparison with the control group. PMID- 28725146 TI - LC-ESI-MS/MS profiling of phenolics from Eleutherococcus spp. inflorescences, structure-activity relationship as antioxidants, inhibitors of hyaluronidase and acetylcholinesterase. AB - Nature is a source of many plant-based molecules used as pro- or drugs. Eleutherococcus species are native to Asia and the North Russia, and are traditionally used to treat various diseases. In turn, neither secondary metabolites of the species cultivated in the West Europe nor the bioactivity is known. No differences in the phenols and flavonoids content in the inflorescences were found. The richest in polyphenols was E. giraldii (5.18 mg/g), while in flavonoids it was E. gracilistylus (1.80 mg/g). Using LC-ESI-MS/MS, protocatechuic and trans-caffeic acids have been identified as the most abundant compounds in E. gracilistylus, E. giraldii, E. senticosus (833.4; 855.6; 614.7 and 280.8; 156.0; 167.6 MUg/g DE). It was observed that all species were able to chelate Fe2+ with the EC50 value of 0.2, 0.6, 0.3 mg/mL for E. gracilistylus, E. giraldii, E. senticosus, respectively. E. gracilistylus exhibited the strongest antiperoxidation and anti-DPPH* activity (EC50 3.2 and 0.48 mg/mL). The weak inhibitory potential has been observed in case of AChE inhibition at the level of 16.17 and 12.2% for E. gracilistylus, E. giraldii. We report for the first time that the extracts inhibited Hyal activity in the range from 16.4 to 60.7%. To our best knowledge, no information was available on this activity of the inflorescences and this provides a background to study inflorescences in more detail. Considering the SAR, an antioxidant activity may be correlated with a high amount of protocatechuic and trans-caffeic acids and their chemical structure. PMID- 28725147 TI - Shortage of psychotropic medications in community pharmacies in Saudi Arabia: Causes and solutions. AB - Background: Patients with mental disorders, such as depression and anxiety, who seek medical care in private psychiatric clinics in Riyadh, Saudi Arabia, have recently expressed concerns to doctors about difficulty in filling psychotropic medications, such as Amitriptyline and Aripiprazole, at retail community pharmacies. Objectives: The aim of this study was to investigate whether there is a shortage of some commonly prescribed psychotropic medications in retail community pharmacies in Saudi Arabia, and if so, to explore the possible reasons behind the shortage of these medications. Methods: The availability of 28 commonly prescribed psychotropic medications was checked in multiple retail community pharmacies in 4 different regions of Saudi Arabia. Further, potential reasons behind the shortage of some psychotropic medications in retail community pharmacies were also explored. Results: Amitriptyline, Amoxapine, Aripiprazole, Bupropion, Buspirone, Duloxetine, Haloperidol, Hydroxyzine, Lithium, Prochlorperazine, Procyclidine, Promethazine, Thioridazine, Trazodone, and Trifluoperazine were unavailable in over half of the 248 community pharmacies surveyed. Four possible reasons behind the shortage of these medications were reported by 31 pharmacists working in different retail community pharmacies' purchasing departments, with a majority (58.06%) reporting the primary reason for a shortage of these medications that they are slow-moving items with low profit margins. Conclusions: The findings of this study should expedite the reform process in both the Ministry of Health and the Saudi Food and Drug Authority (SFDA) to publish and enforce an essential list of medications for retail community pharmacies, which should include the most commonly prescribed psychotropic medications. PMID- 28725148 TI - Isolation, biological evaluation and validated HPTLC-quantification of the marker constituent of the edible Saudi plant Sisymbrium irio L. AB - Phytochemical investigation and chromatographic purification of the n-hexane fraction of the aerial parts of the edible Saudi plant Sisymbrium irio led to the isolation of beta-sitosterol (1), stigmasterol (2) and beta-sitosterol-beta-d glucoside (3). The cytotoxic effects of the n-hexane, dichloromethane, ethyl acetate and n-butanol fractions were tested against three cancer cell lines viz., MCF-7, HCT-116 and HepG2, using the crystal violet staining (CVS) method, while the antibacterial activity against a number of pathogenic bacterial strains, was also estimated using the broth microdilution assay. The n-hexane fraction showed potent cytotoxic activities against all tested human cancer cell lines (IC50: 11.7-13.4 MUg/mL), while the dichloromethane fraction was particularly potent against HCT-116 cells (IC50: 5.42 MUg/mL). On the other hand, the n-hexane and EtOAc fractions demonstrated significant inhibitory activities against the Gram positive bacteria S. pyogenes and C. perfringens; and the Gram negative bacterium S. enteritidis. Our results warrant the therapeutic potential of S. irio as nutritional supplement to reduce the risk of contemporary diseases. Additionally, a validated high performance thin-layer chromatography (HPTLC) method was developed for the quantitative analysis of biomarker beta-sitosterol glucoside (isolated in high quantity) from the n-hexane fraction. The system was found to furnish a compact, sharp, symmetrical and high resolution band for beta sitosterol glucoside (Rf = 0.43 +/- 0.002). The limit of detection (LOD) and limit of quantification (LOQ) for beta-sitosterol glucoside was found to be 21.84 and 66.18 ng band-1, respectively. beta-sitosterol glucoside was found to be present only in n-hexane fraction (2.10 MUg/mg of dried fraction) while it was absent in the other fractions of S. irio which validated the high cytotoxic and antibacterial activity of n-hexane fraction of S. irio. PMID- 28725149 TI - Using an integrated information system to reduce interruptions and the number of non-relevant contacts in the inpatient pharmacy at tertiary hospital. AB - Patient care is provided by a multidisciplinary team of healthcare professionals intended for high-quality and safe patient care. Accordingly, the team must work synergistically and communicate efficiently. In many hospitals, nursing and pharmacy communication relies mainly on telephone calls. In fact, numerous studies have reported telephone calls as a source of interruption for both pharmacy and nursing operations; therefore, the workload increases and the chance of errors raises. This report describes the implementation of an integrated information system that possibly can reduce telephone calls through providing real-time tracking capabilities and sorting prescriptions urgency, thus significantly improving traceability of all prescriptions inside pharmacy. The research design is based on a quasi-experiment using pre-post testing using the continuous improvement approach. The improvement project is performed using a six step method. A survey was conducted in Prince Sultan Military Medical City (PSMMC) to measure the volume and types of telephone calls before and after implementation to evaluate the impact of the new system. Beforehand of the system implementation, during the two-week measurement period, all pharmacies received 4466 calls and the majority were follow-up calls. Subsequently of the integrated system rollout, there was a significant reduction (p > 0.001) in the volume of telephone calls to 2630 calls; besides, the calls nature turned out to be more professional inquiries (p > 0.001). As a result, avoidable interruptions and workload were decreased. PMID- 28725150 TI - Development and evaluation of Ketoprofen sustained release matrix tablet using Hibiscus rosa-sinensis leaves mucilage. AB - Currently, the use of natural gums and mucilage is of increasing importance in pharmaceutical formulations as valuable drug excipient. Natural plant-based materials are economic, free of side effects, biocompatible and biodegradable. Therefore, Ketoprofen matrix tablets were formulated by employing Hibiscus rosa sinensis leaves mucilage as natural polymer and HPMC (K100M) as a synthetic polymer to sustain the drug release from matrix system. Direct compression method was used to develop sustained released matrix tablets. The formulated matrix tablets were evaluated in terms of physical appearance, weight variation, thickness, diameter, hardness, friability and in vitro drug release. The difference between the natural and synthetic polymers was investigated concurrently. Matrix tablets developed from each formulation passed all standard physical evaluation tests. The dissolution studies of formulated tablets revealed sustained drug release up to 24 h compared to the reference drug Apo Keto(r) SR tablets. The dissolution data later were fitted into kinetic models such as zero order equation, first order equation, Higuchi equation, Hixson Crowell equation and Korsmeyer-Peppas equation to study the release of drugs from each formulation. The best formulations were selected based on the similarity factor (f2) value of 50% and more. Through the research, it is found that by increasing the polymers concentration, the rate of drug release decreased for both natural and synthetic polymers. The best formulation was found to be F3 which contained 40% Hibiscus rosa-sinensis mucilage polymer and showed comparable dissolution profile to the reference drug with f2 value of 78.03%. The release kinetics of this formulation has shown to follow non-Fickian type which involved both diffusion and erosion mechanism. Additionally, the statistical results indicated that there was no significant difference (p > 0.05) between the F3 and reference drug in terms of MDT and T50% with p-values of 1.00 and 0.995 respectively. PMID- 28725151 TI - Chemical constituents of Helichrysum italicum (Roth) G. Don essential oil and their antimicrobial activity against Gram-positive and Gram-negative bacteria, filamentous fungi and Candida albicans. AB - The aerial parts of Helichrysum italicum (Roth) G. Don were subjected to hydrodistillation to obtain essential oils which had been analyzed by gas chromatography and gas chromatography coupled with mass spectrometry and tested for antimicrobial activity against 12 bacteria, two yeasts and four fungi by agar diffusion method. The essential oil yielded 0.44% (v/w) and 67 compounds accounting for 99.24% of the oil were identified with a high content of oxygenated sesquiterpenes (61.42%). The most oxygenated sesquiterpene compounds were alpha-Cedrene (13.61%), alpha-Curcumene (11.41%), Geranyl acetate (10.05%), Limonene (6.07%), Nerol (5.04%), Neryl acetate (4.91%) and alpha-Pinene (3.78%). The antimicrobial activity of the essential oil was assayed by using the disk diffusion method on Escherichia coli ATCC 25922, Staphylococcus aureus ATCC 6538, Micrococcus luteus ATCC 4698, Klebsiella pneumonia ATCC 4352, Enterococcus cereus ATCC 2035, Bacillus cereus ATCC 10876, Staphylococcus epidermidis ATCC 12228, Bacillus subtilis ATCC 9372, Pseudomonas aeruginosa ATCC 27853, Enterococcus faecalis ATCC 49452, Proteus mirabilis ATCC 35659, Listeria monocytogenes ATCC 15313 and yeasts Candida albicans ATCC 10231, Saccharomyces cerevisiae ATCC 9763 and fungi, Fusarium solani var. coeruleum, Aspergillus niger, Alternaria alternata, Ascochyta rabiei. H. italicum inhibited the growth of all the tested microorganisms except three bacteria, E. coli ATCC 25922, K. pneumonia ATCC 4352 and L. monocytogenes ATCC 15313. The most sensitive bacterium was E. cereus ATCC 2035 with minimum inhibitory and bactericidal concentrations of 0.79 MUg ml-1. A minimum fungistatic and fungicide concentration of 6.325 MUg ml-1 and 12.65 MUg ml-1 respectively was obtained with C. albicans ATCC 10231 and S. cerevisiae ATCC 9763. However the four fungi were more resistant with fungistatic minimum concentration ranging from 6.325 MUg ml-1 to 50.6 MUg ml-1 and a fungicide minimum concentration of 50.6 MUg ml-1. This antimicrobial activity could be attributed to the essential oil chemical composition. Thus this study represents a first step in the study of the chemical composition of H. italicum (Roth) G. Don collected from north Algeria and its antimicrobial properties. PMID- 28725152 TI - Analysis of inorganic and organic constituents of myrrh resin by GC-MS and ICP MS: An emphasis on medicinal assets. AB - The aim of the present investigation was to explore the constituents of the Arabian myrrh resin obtained from Commiphora myrrha. The organic and inorganic composition of the myrrh gum resin has been investigated using gas chromatography mass spectrometry (GC-MS) and inductively coupled plasma-mass spectrometry (ICP MS). Analysis executed by ICP-MS reveals the presence of various inorganic elements in significant amount in the myrrh resin. The elements that were found to be present in large amounts include calcium, magnesium, aluminum, phosphorus, chlorine, chromium, bromine and scandium. The important organic constituents identified in the myrrh ethanolic extract include limonene, curzerene, germacrene B, isocericenine, myrcenol, beta selinene, and spathulenol,. The present work complements other myrrh associated investigations done in the past and provides additional data for the future researches. PMID- 28725153 TI - Ovulation induction by metformin among obese versus non-obese women with polycystic ovary syndrome. AB - OBJECTIVES: There is some evidence that the efficacy of metformin as an ovulation stimulation agent depends on the body mass index (BMI) of the treated anovulatory women with polycystic ovary syndrome (PCOS). The aim of this study was to examine the likelihood of successful ovulation among obese (BMI ?30 kg/m2) versus non obese (BMI <30 kg/m2) women with PCOS. METHODS: A total of 243 medical charts of women with PCOS who visited King Khaled University Hospital (KKUH) in Riyadh, Saudi Arabia, between 2006 and 2012 were reviewed. Patients' sociodemographic, laboratory, and medical data were collected. Descriptive statistics and multiple logistic regression analyses were performed to compare the patients' baseline data and successful ovulation among the obese and non-obese anovulatory women with PCOS, respectively. RESULTS: One hundred and nine women with PCOS who were prescribed metformin for ?3 months were included in the study. Almost 60% of the women who were included in the study were obese. The likelihood of ovulation among obese women with PCOS was 77.9% (odds ratio = 0.221, 95% CI 0.052-0.947, P = 0.042) less than that in their non-obese counterparts. CONCLUSION: The findings of this study suggest that metformin is more effective as an ovulation stimulation agent when administered to non-obese women with PCOS. Lifestyle modifications such as diet and exercise should be emphasized upon as an integral part of any treatment plan for PCOS. PMID- 28725154 TI - New constituents triterpene ester and sugar derivatives from Panax ginseng Meyer and their evaluation of antioxidant activities. AB - Panax ginseng C. A. Meyer (Araliaceae), is a well-known herb and used in the old established system of Oriental remedy, especially in Japan, China and Korea. Four new compounds characterized as (cis)- 7beta,11alpha,19,21-tetra-O-decanoyl-18, 22beta-dihydroxy-dammar-1-en-3-one (1), 3beta,4alpha,12beta-trihydroxystigmast-5 en-21-yl octadecan-9',12'-dienoate (2), dammar-12, 24-dien-3alpha, 6beta, 15alpha triol-3alpha-D-arabinopyranosyl-6beta-L-arabinopyranoside (3) and dammar-24-en 3alpha, 6beta, 16alpha, 20beta-tetraol-3alpha-D-arabinopyranosyl-6beta-D arabinopyranoside (4) were isolated and established from the ethyl acetate and butanol extracts of the roots of P. ginseng. Their structures were established on the basis of spectral data and chemical reactions. Natural compounds indicative a great reservoir of materials and compounds with evolved biological activity, including antioxidant. Compounds 1-4 were investigated in vitro for antioxidant potential using ferric reducing antioxidant power (FRAP), the Nitric oxide (NO) scavenging activity, reducing power, phosphomolybdenum and 1,1-diphenyl-2 picrylhydrazyl (DPPH) radical scavenging actions, and the decision showed the compounds 3and 4 have probablyessential antioxidant properties than the compounds 1and 2 presented weak activity. PMID- 28725155 TI - A case of severe erythema nodosum induced by methimazole. AB - Erythema nodosum (EN), is the most common variant of septal panniculitis and is possibly a delayed hypersensitivity reaction triggered by a wide range of antigenic stimuli. Hypersensitivity reactions due to medications have been recognized as a cause of 3-10% of EN cases. Case reports of EN associated with the anti-thyroid drugs are quite rarely reported in the literature even if there is a common use of anti-thyroid drugs. We report an EN case due to methimazole. The complaints of patients arose immediately fifteen days after the beginning of methimazole treatment. To the best of our knowledge, this case report is the first of an erythema nodosum induced by methimazole. PMID- 28725156 TI - Vaccine on-demand service: One shot or a sustainable prevention? PMID- 28725157 TI - Borderline personality disorder and related constructs as risk factors for intimate partner violence perpetration. AB - In this manuscript we systematically reviewed 29 articles from 2010 to 2014 that addressed the association between borderline personality disorder (BPD) and intimate partner violence (IPV) perpetration, with particular attention paid to the role of perpetrator sex. Our primary objective was to provide a summary of (1) the operationalization and measurement of BPD and IPV, (2) mechanisms of the BPD-IPV association, and (3)the current understanding of the role of perpetrator sex related to BPD and IPV. We observed three distinct operational definitions of BPD which are measured in a variety of ways. IPV measurement tends to be more consistent. Further, emotion perception, impulsivity, attachment, and substance use are proposed mechanisms to explain the BPD IPV relation. The findings regarding potential perpetrator sex differences in the BPD-IPV association are mixed. Finally, we also provide recommendations for future research and clinical practice. PMID- 28725158 TI - Continuum theory of gene expression waves during vertebrate segmentation. AB - The segmentation of the vertebrate body plan during embryonic development is a rhythmic and sequential process governed by genetic oscillations. These genetic oscillations give rise to traveling waves of gene expression in the segmenting tissue. Here we present a minimal continuum theory of vertebrate segmentation that captures the key principles governing the dynamic patterns of gene expression including the effects of shortening of the oscillating tissue. We show that our theory can quantitatively account for the key features of segmentation observed in zebrafish, in particular the shape of the wave patterns, the period of segmentation and the segment length as a function of time. PMID- 28725159 TI - Importance of social capital at the workplace for return to work among women with a history of long-term sick leave: a cohort study. AB - BACKGROUND: The workplace is an essential source of social capital for many people; it provides mutual support and gives meaning to life. However, few prospective studies have thoroughly investigated the importance of aspects of social capital in the workplace. The aim of this study was to investigate the associations between aspects of social capital (social support, sense of community, and quality of leadership) at the workplace, and work ability, working degree, and vitality among women with a history of long-term sick leave from human service organizations. METHODS: A longitudinal cohort study was performed among women with a history of long-term sick leave. The study started in 2005, and the women were followed up at 6 months, 1 year, and 6 years using self reported questionnaires (baseline n = 283). Linear mixed models were used for longitudinal analysis of the repeated measurements of prospective degree of work ability, working degree, and vitality. Analyses were performed with different models; the explanatory variables for each model were social support, sense of community, and quality of leadership and time. RESULTS: Social capital in terms of quality of leadership (being good at solving conflicts and giving high priority to job satisfaction), sense of community (co-operation between colleagues) and social support (help and support from immediate superiors and colleagues) increased the women's work ability score (WAS) as well as working degree over time. Additionally, social capital in terms of quality of leadership increased the women's vitality score over time. CONCLUSIONS: A sustainable return to-work process among individuals with a history of long-term sick leave, going in and out of work participation, could be supported with social support, good quality of leadership, and a sense of community at the workplace. The responsibility for the rehabilitation process can not be reduced to an individual problem, but ought to include all stakeholders involved in the process, such as managers, colleagues, health care services, and the social security agency. PMID- 28725160 TI - Significance of quality of care for quality of life in persons with dementia at risk of nursing home admission: a cross-sectional study. AB - BACKGROUND: Quality of life in persons with dementia is, in large part, dependent on the quality of care they receive. Investigating both subjective and objective aspects of quality of care may reveal areas for improvement regarding their care, which information may ultimately enable persons with dementia to remain living in their own homes while maintaining quality of life. The aim of this study was to 1) describe self-reported quality of life in persons with dementia at risk of nursing home admission. 2) describe subjective and objective aspects of quality of care, 3) investigate the significance of quality of care for quality of life. METHODS: A cross-sectional interview study design was used, based on questionnaires about quality of life (QoL-AD) and different aspects of quality of care (CLINT and quality indicators). The sample consisted of 177 persons with dementia living in urban and rural areas in Skane County, Sweden. Descriptive and comparative statistics (Mann-Whitney U-test) were used to analyse the data. RESULTS: Based upon Lawton's conceptual framework for QoL in older people, persons with pain showed significantly lower quality of life in the dimensions behavioural competence (p = 0.026) and psychological wellbeing (p = 0.006) compared with those without pain. Satisfaction with care seemed to have a positive effect on quality of life. The overall quality of life was perceived high even though one-third of the persons with dementia had daily pain and had had a weight loss of >=4% during the preceding year. Furthermore, 23% of the persons with dementia had fallen during the last month and 40% of them had sustained an injury when falling. CONCLUSION: This study indicates need for improvements in home care and services for persons with dementia at risk for nursing home admission. Registered nurses are responsible for nursing interventions related to pain, patient safety, skin care, prevention of accidents, and malnutrition. Therefore, it is of great importance for nurses to have knowledge about areas that can be improved to be able to tailor interventions and thereby improve quality of care outcomes such as quality of life in persons with dementia living at home. PMID- 28725161 TI - EP300 single nucleotide polymorphism rs20551 correlates with prolonged overall survival in diffuse large B cell lymphoma patients treated with R-CHOP. AB - BACKGROUND: Rituximab combined with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) is used as standard frontline regimen for diffuse large B cell lymphoma (DLBCL). The landscape of somatic mutations in DLBCL revealed that inactivation of EP300 plays an important role in lymphomagenesis. A common EP300 single nucleotide polymorphism (SNP) rs20551 results in the substitution of valine for isoleucine at codon 997 close to the Bromodomain. However, the association between SNP rs20551 and clinical prognosis in DLBCL patients treated with R-CHOP is unknown. METHODS: In this study we analyzed the EP300 SNP rs20551 and prognosis of 226 DLBCL patients who treated with R-CHOP or R-CHOP-like regimes from 2002 to 2013. Determination of the EP300 SNP rs20551 from genomic DNA was obtained by Sanger chain termination sequencing. RESULT: In this study, the frequency of the A and G allele of the EP300 SNP rs20551 in 226 patients were 92.5 and 7.5%, respectively. We did not observe obvious correlation between patients' disease features and the EP300 SNP rs20551. But the patients with genotype AA had a higher 5-year overall survival rate than those with genotype GA (77.0% vs. 64.7%, p = 0.045). Furthermore, multivariate Cox regression analysis showed that the GA genotype of EP300 SNP rs20551 was an independent poor prognostic factor for DLBCL patients treated with Rituximab-chemotherapy (p = 0.009, HR 2.956, 95% CI 1.315-6.645). CONCLUSION: This study suggests that EP300 SNP rs20551 might be a useful biomarker to predict the long-term outcome of R CHOP in DLBCL patients. PMID- 28725162 TI - The prognostic value of miR-126 expression in non-small-cell lung cancer: a meta analysis. AB - OBJECTIVE: Non-small cell lung cancer (NSCLC) is a leading cause of cancer related death. Growing evidence from recent studies have shown indicated that microRNA-126 (miR-126) played an important role in the progression of NSCLC. However, the potential value of miR-126 expression in prognosis of NSCLC remains to be fully elucidated. Here, we carried out a meta-analysis to assess the potential prognostic value of miR-126 for NSCLC. METHODS: PubMed, Embase, the Cochrane library, Web of Science, CNKI and WanFang database, as well as the reference of included studies, were searched to recognize pertinent studies until April 30, 2017. New castle-Ottawa scale was used to evaluate the quality of studies. Pooled hazard ratio (HR) with 95% confidence interval (CI) for overall survival (OS) was extracted by using a fixed-effects or a random-effects model on the basis of heterogeneity. Publication bias was evaluated by using Begg's tests. RESULTS: We identified four eligible trials involving 666 non-small-cell lung cancer patients in this meta-analysis. The results indicated that a high level of miR-126 played a favorable role in the overall survival (HR 0.73, 95% CI 0.61 0.86, fixed-effects model). There was no bias existed in this study. CONCLUSIONS: Our study showed that high expression level of miR-126 was a promising positive factor for OS for non-small cell lung cancer patients, and miR-126 might be a potential target for non-small-cell lung cancer therapy in the future. PMID- 28725163 TI - Examining the influence of specificity ligands and ATP-competitive ligands on the overall effectiveness of bivalent kinase inhibitors. AB - BACKGROUND: Identifying selective kinase inhibitors remains a major challenge. The design of bivalent inhibitors provides a rational strategy for accessing potent and selective inhibitors. While bivalent kinase inhibitors have been successfully designed, no comprehensive assessment of affinity and selectivity for a series of bivalent inhibitors has been performed. Here, we present an evaluation of the structure activity relationship for bivalent kinase inhibitors targeting ABL1. METHODS: Various SNAPtag constructs bearing different specificity ligands were expressed in vitro. Bivalent inhibitor formation was accomplished by synthesizing individual ATP-competitive kinase inhibitors containing a SNAPtag targeting moiety, enabling the spontaneous self-assembly of the bivalent inhibitor. Assembled bivalent inhibitors were incubated with K562 lysates, and then subjected to affinity enrichment using various ATP-competitive inhibitors immobilized to sepharose beads. Resulting eluents were analyzed using Tandem Mass Tag (TMT) labeling and two-dimensional liquid chromatography-tandem mass spectrometry (2D-LC-MS/MS). Relative binding affinity of the bivalent inhibitor was determined by calculating the concentration at which 50% of a given kinase remained bound to the affinity matrix. RESULTS: The profiling of three parental ATP-competitive inhibitors and nine SNAPtag conjugates led to the identification of 349 kinase proteins. In all cases, the bivalent inhibitors exhibited enhanced binding affinity and selectivity for ABL1 when compared to the parental compound conjugated to SNAPtag alone. While the rank order of binding affinity could be predicted by considering the binding affinities of the individual specificity ligands, the resulting affinity of the assembled bivalent inhibitor was not predictable. The results from this study suggest that as the potency of the ATP competitive ligand increases, the contribution of the specificity ligand towards the overall binding affinity of the bivalent inhibitor decreases. However, the affinity of the specificity components in its interaction with the target is essential for achieving selectivity. CONCLUSION: Through comprehensive chemical proteomic profiling, this work provides the first insight into the influence of ATP-competitive and specificity ligands binding to their intended target on a proteome-wide scale. The resulting data suggest a subtle interplay between the ATP-competitive and specificity ligands that cannot be accounted for by considering the specificity or affinity of the individual components alone. PMID- 28725164 TI - Cost-effectiveness of cervical cancer screening and preventative cryotherapy at an HIV treatment clinic in Kenya. AB - OBJECTIVE: This study evaluated the potential cost-effectiveness of cervical cancer screening in HIV treatment clinics in Nairobi, Kenya. METHODS: A Markov model was used to project health outcomes and costs of cervical cancer screening and cryotherapy at an HIV clinic in Kenya using cryotherapy without screening, visual inspection with acetic acid (VIA), Papanicolaou smear (Pap), and testing for human papillomavirus (HPV). Direct and indirect medical and non-medical costs were examined from societal and clinic perspectives. RESULTS: Costs of cryotherapy, VIA, Pap, and HPV for women with CD4 200-500 cells/mL were $99, $196, $219, and $223 from a societal perspective and $19, $94, $124, and $113 from a clinic perspective, with 17.3, 17.1, 17.1, and 17.1 years of life expectancy, respectively. Women at higher CD4 counts (>500 cells/mL) given cryotherapy VIA, Pap, and HPV resulted in better life expectancies (19.9+ years) and lower cost (societal: $49, $99, $115, and $102; clinic: $13, $51, $71, and $56). VIA was less expensive than HPV unless HPV screening could be reduced to a single visit. CONCLUSIONS: Preventative cryotherapy was the least expensive strategy and resulted in highest projected life expectancy, while VIA was most cost-effective unless HPV could be reduced to a single visit. PMID- 28725165 TI - Cost effectiveness of pre-referral antimalarial treatment in severe malaria among children in sub-Saharan Africa. AB - BACKGROUND: In 2013, 78% of malaria deaths occurred in children aged 5 years and below, in sub-Saharan Africa. Treatment of severe malaria requires a health facility with inpatient care. However, in most sub-Sahara African countries, access to health facilities is a major problem. Pre-referral antimalarial treatments aim to delay the progress of severe malaria as patients seek to access health facilities. Rectal artesunate can be administered in the community as a pre-referral treatment in rural hard-to-reach areas. In Kenya, though pre referral rectal artesunate has been included in the National Guidelines for pre referral treatment, it is yet to be implemented in the public healthcare system. It is important, therefore, to establish its cost-utility compared to current parenteral treatments. This study evaluated the cost-utility of provision of pre referral treatments by community health workers compared to similar services at a primary health facility. METHODS: This was a decision model-based cost-utility analysis, comparing pre-referral antimalarial treatments provided by: community health workers (CHWs), primary health facility, direct access to a tertiary health facility and no access to treatment. A theoretical cohort, of 1000 children, who were below 5 years old; residing in rural hard-to-reach areas, was taken as the reference population. Data was collected through key informant interviews, to assess the costs, while key measures of effectiveness, were obtained from existing studies. The key measure of outcomes was Disability Adjusted Life Years (DALYS) averted. Probabilistic sensitivity analysis was carried out to assess the robustness of the model. RESULTS: Provision of rectal pre-referral treatment by community health workers was estimated to avert 13,276 DALYs, at a cost of $68,428 for a cohort of 1000 children. Provision of rectal pre-referral treatment at a primary health facility was estimated to avert 9993 DALYs, at a cost of $73,826 for a cohort of 1000 children, while going directly to a tertiary health facility was estimated to avert 15,801 DALYs, at a cost of $114,903 for a cohort of 1000 children. The incremental cost effectiveness ratios for provision of pre-referral treatment by community health care and primary health workers were $5.11 and $7.30 per DALYs averted respectively. CONCLUSION: Use of CHWs was more cost effective than provision of pre-referral treatments at a primary health facility especially, with high referral compliance. Rectal artesunate can easily be administered by community health workers, unlike parenteral pre-referral interventions. PMID- 28725166 TI - Tuberculosis and HIV are the leading causes of adult death in northwest Ethiopia: evidence from verbal autopsy data of Dabat health and demographic surveillance system, 2007-2013. AB - BACKGROUND: Reliable data on causes of death form the basis for building evidence on health policy, planning, monitoring, and evaluation. In Ethiopia, the majority of deaths occur at home and civil registration systems are not yet functional. The main objective of verbal autopsy (VA) is to describe the causes of death at the community or population level where civil registration and death certification systems are weak and where most people die at home without having had contact with the health system. METHODS: Causes of death were classified and prepared based on the International Classification of Diseases (ICD-10). The cause of a death was ascertained based on an interview with next of kin or other caregivers using a standardized questionnaire that draws information on signs, symptoms, medical history, and circumstances preceding death. The cause of death, or the sequence of causes that led to death, is assigned based on the data collected by the questionnaire. The complete VA questionnaires were given to two blinded physicians and reviewed independently. A third physician was assigned to review the case when disagreements in diagnosis arose. RESULTS: Communicable diseases (519 deaths [48.0%]), non-communicable diseases (377 deaths [34.8%]), and external causes (113 deaths [10.4%]) were the main causes of death between 2007 and 2013. Of communicable diseases, tuberculosis (207 deaths [19.7%]), HIV/AIDS (96 deaths [8.9%]) and meningitis (76 deaths [7.0%]) were the most common causes of death. CONCLUSION: Tuberculosis, HIV/AIDS, and meningitis were the most common causes of deaths among adults. Death due to non-communicable diseases showed an increasing trend. Increasing community awareness of infections and their interrelationships, tuberculosis case finding, effective local TB programs, successful treatment, and interventions for HIV are supremely important. PMID- 28725167 TI - Genetic risk between the CACNA1I gene and schizophrenia in Chinese Uygur population. AB - BACKGROUND: Schizophrenia (SCZ) is a common mental disorder with high heritability, and genetic factors play a major role in the pathogenesis. Recent researches indicated that the CACNA1I involved in calcium channels probably affect the potential pathogenesis of SCZ. RESULTS: In this study, we attempted to investigate whether the CACNA1I gene contributes the risk to SCZ in the Uighur Chinese population, and performed a case-control study involving 985 patient samples and 1218 normal controls to analyze nine SNPs within the CACNA1I gene. Among these sites, six SNPs were significantly associated with SCZ in the allele distribution: rs132575 (adjusted Pallele = 0.039, OR = 1.159), rs713860 (adjusted Pallele = 0.039, OR = 0.792), rs738168 (adjusted Pallele = 0.039, OR = 0.785), rs136805 (adjusted Pallele = 0.014, OR = 1.212), rs5757760 (adjusted Pallele = 0.042, OR = 0.873) and rs5750871 (adjusted Pallele = 0.039, OR = 0.859). In addition, two SNPs turned to be risk factors for SCZ not only in the allele distribution, but also in the genotype distribution: rs132575 (adjusted Pgenotype = 0.037) and rs136805 (adjusted Pgenotype = 0.037). CONCLUSIONS: Overall, the present study provided evidence that significant association exists between the CACNA1I gene and SCZ in the Uighur Chinese population, subsequent validation of functional analysis and genetic association studies are needed to further extend this study. PMID- 28725168 TI - Comprehensive Registry of Esophageal Cancer in Japan, 2010. PMID- 28725169 TI - Postoperative delirium after pharyngolaryngectomy with esophagectomy: a role for ramelteon and suvorexant. AB - BACKGROUND: Postoperative delirium is common after extensive surgery, and is known to be associated with sleeping medications. In this study, we aimed to investigate the relationships between sleeping medications and postoperative delirium after pharyngolaryngectomy with esophagectomy. METHODS: We performed a retrospective analysis of 65 patients who underwent pharyngolaryngectomy with esophagectomy at Shizuoka Cancer Center Hospital between January 2012 and March 2016. All data were assessed by two psychiatrists, and univariate and multivariate analyses were performed. RESULTS: Postoperative delirium developed in 9 (13.8%) patients, with most cases (77.8%) occurring between postoperative day (POD) 1 and POD 3. Of the 24 patients taking a minor tranquilizer after surgery, 8 (33.3%) became delirious, but, of the remaining 41 patients taking ramelteon with or without suvorexant, only one (2.4%) became delirious after surgery. Moreover, of the 16 patients taking both ramelteon and suvorexant, no postoperative delirium was observed. Ramelteon with or without suvorexant was significantly associated with a decreased rate of postoperative delirium compared with minor tranquilizer use (p = 0.001). Multivariate analysis confirmed that the use of ramelteon with or without suvorexant was the only significant preventive factor of postoperative delirium (odds ratio 0.060, p = 0.013). CONCLUSION: The use of ramelteon with or without suvorexant was the only significant preventive factor of postoperative delirium after pharyngolaryngectomy with esophagectomy. However, using minor tranquilizers was associated with postoperative delirium. We recommend ramelteon with or without suvorexant for preventing postoperative delirium after pharyngolaryngectomy with esophagectomy. PMID- 28725171 TI - Spontaneous twin pregnancy with live births after cryopreservation and re implantation of ovarian tissue. PMID- 28725170 TI - Helicobacter pylori infection status had no influence on upper gastrointestinal symptoms: a cross-sectional analysis of 3,005 Japanese subjects without upper gastrointestinal lesions undergoing medical health checkups. AB - BACKGROUND: This study aimed to evaluate the influence of Helicobacter pylori infection and its eradication on the upper gastrointestinal symptoms of relatively healthy Japanese subjects. METHODS: A total of 3,005 subjects (male/female: 1,549/1,456) undergoing medical health checkups were enrolled in the present study, at five hospitals in Saga, Japan, from January to December 2013. They had no significant findings following upper gastrointestinal endoscopy. All subjects completed a questionnaire that addressed a frequency scale for symptoms of gastroesophageal reflux disease. The questionnaire comprised seven questions regarding reflux symptoms and seven regarding acid related dyspepsia, which were answered with a score based on the frequency of symptoms. Helicobacter pylori infection was identified by a rapid urease test and/or H. pylori antibody titer, and an eradication history was confirmed by the subjects' medical records. RESULTS: Helicobacter pylori infection was positive in 894 subjects out of 3,005 (29.8%). Eradication of Helicobacter pylori was successfully achieved in 440 subjects of 458 treated. Helicobacter pylori infection had no influence on the acid-related dyspepsia evaluated by the questionnaire, whereas the mean reflux score was relatively high in the Helicobacter pylori native negative subjects compared to Helicobacter pylori native positive. Eradication of Helicobacter pylori and time span after the eradication had no effect on the upper gastrointestinal symptoms evaluated by the questionnaire. CONCLUSION: Helicobacter pylori infection and history of eradication did not affect acid-related dyspepsia symptoms in Japanese healthy subjects. PMID- 28725172 TI - An original and effective technique to improve exposure in open surgery. AB - BACKGROUND: Exposure, especially when the organs are enlarged, remains one of the most important issue in open surgery. Considering this constraint appears critical in the progress of the surgical procedure. We highlight our technique which affords optimal exposure and improves manipulation and extraction of enlarged organs. RESULTS: This original and effective technique is derived from an obstetrical device used to perform an assisted vaginal delivery. It improves exposure, reduces tissue manipulation, and enhances removal of the surgical specimen during hysterectomies and myomectomies. It can be similarly helpful sometimes to grasp and remove (by mini laparotomy) enlarged adnexa during laparoscopic procedures. Moreover, this trick appears particularly suited in case of obese patients. CONCLUSION: This new technique procures a real benefit for both the patient and the surgeon in terms of ergonomics and safety. PMID- 28725173 TI - Identification of multiple dityrosine bonds in materials composed of the Drosophila protein Ultrabithorax. AB - The recombinant protein Ultrabithorax (Ubx), a Drosophila melanogaster Hox transcription factor, self-assembles into biocompatible materials in vitro that are remarkably extensible and strong. Here, we demonstrate that the strength of Ubx materials is due to intermolecular dityrosine bonds. Ubx materials auto fluoresce blue, a characteristic of dityrosine, and bind dityrosine-specific antibodies. Monitoring the fluorescence of reduced Ubx fibers upon oxygen exposure reveals biphasic bond formation kinetics. Two dityrosine bonds in Ubx were identified by site-directed mutagenesis followed by measurements of fiber fluorescent intensity. One bond is located between the N-terminus and the homeodomain (Y4/Y296 or Y12/Y293), and another bond is formed by Y167 and Y240. Fiber fluorescence closely correlates with fiber strength, demonstrating that these bonds are intermolecular. To our knowledge, this is the first identification of specific residues that participate in dityrosine bonds in protein-based materials. The percentage of Ubx molecules harboring both bonds can be decreased or increased by mutagenesis, providing an additional mechanism to control the mechanical properties of Ubx materials. Duplication of tyrosine containing motifs in Ubx increases dityrosine content in Ubx fibers, suggesting these motifs could be inserted in other self-assembling proteins to strengthen the corresponding materials. PMID- 28725174 TI - Altered Functional Connectivity Following an Inflammatory White Matter Injury in the Newborn Rat: A High Spatial and Temporal Resolution Intrinsic Optical Imaging Study. AB - Very preterm newborns have an increased risk of developing an inflammatory cerebral white matter injury that may lead to severe neuro-cognitive impairment. In this study we performed functional connectivity (fc) analysis using resting state optical imaging of intrinsic signals (rs-OIS) to assess the impact of inflammation on resting-state networks (RSN) in a pre-clinical model of perinatal inflammatory brain injury. Lipopolysaccharide (LPS) or saline injections were administered in postnatal day (P3) rat pups and optical imaging of intrinsic signals were obtained 3 weeks later. (rs-OIS) fc seed-based analysis including spatial extent were performed. A support vector machine (SVM) was then used to classify rat pups in two categories using fc measures and an artificial neural network (ANN) was implemented to predict lesion size from those same fc measures. A significant decrease in the spatial extent of fc statistical maps was observed in the injured group, across contrasts and seeds (*p = 0.0452 for HbO2 and **p = 0.0036 for HbR). Both machine learning techniques were applied successfully, yielding 92% accuracy in group classification and a significant correlation r = 0.9431 in fractional lesion volume prediction (**p = 0.0020). Our results suggest that fc is altered in the injured newborn brain, showing the long-standing effect of inflammation. PMID- 28725175 TI - How Different EEG References Influence Sensor Level Functional Connectivity Graphs. AB - Highlights: Hamming Distance is applied to distinguish the difference of functional connectivity networkThe orientations of sources are testified to influence the scalp Functional Connectivity Graph (FCG) from different references significantlyREST, the reference electrode standardization technique, is proved to have an overall stable and excellent performance in variable situations. The choice of an electroencephalograph (EEG) reference is a practical issue for the study of brain functional connectivity. To study how EEG reference influence functional connectivity estimation (FCE), this study compares the differences of FCE resulting from the different references such as REST (the reference electrode standardization technique), average reference (AR), linked mastoids (LM), and left mastoid references (LR). Simulations involve two parts. One is based on 300 dipolar pairs, which are located on the superficial cortex with a radial source direction. The other part is based on 20 dipolar pairs. In each pair, the dipoles have various orientation combinations. The relative error (RE) and Hamming distance (HD) between functional connectivity matrices of ideal recordings and that of recordings obtained with different references, are metrics to compare the differences of the scalp functional connectivity graph (FCG) derived from those two kinds of recordings. Lower RE and HD values imply more similarity between the two FCGs. Using the ideal recording (IR) as a standard, the results show that AR, LM and LR perform well only in specific conditions, i.e., AR performs stable when there is no upward component in sources' orientation. LR achieves desirable results when the sources' locations are away from left ear. LM achieves an indistinct difference with IR, i.e., when the distribution of source locations is symmetric along the line linking the two ears. However, REST not only achieves excellent performance for superficial and radial dipolar sources, but also achieves a stable and robust performance with variable source locations and orientations. Benefitting from the stable and robust performance of REST vs. other reference methods, REST might best recover the real FCG of EEG. Thus, REST based FCG may be a good candidate to compare the FCG of EEG based on different references from different labs. PMID- 28725176 TI - A Potential Animal Model of Maladaptive Palatable Food Consumption Followed by Delayed Discomfort. AB - Introduction: Binging is the consumption of larger amounts of food in a briefer period of time than would normally be consumed under similar circumstances. Binging requires palatable food (PF) to trigger abnormal eating, probably reflecting gene * environment interactions. In this study we examined the impact of trait binge eating (BE) and its compulsive nature on the conflict between hedonic eating of PF and anticipation of a delayed aversive effect. We used female rats as an animal model similar to other models of BE. A novel aspect of this model in this paper is the use of a delayed internal aversive effect produced by lactose ingestion. Establishing this model will allow us to better understand the nature of the conflict between immediate reward and its delayed aversive implications. We hypothesized that BE prone (BEP) rats will demonstrate maladaptive decision making, presenting higher motivation toward PF even when this is associated with delayed discomfort. Method: (Phase 1) 52 female adult Wistar rats were divided to two eating profiles: resistant and prone binge eaters (BER/BEP) based on intake of liquid PF (Ensure). Next, all subjects underwent a Lactose Conditioning Protocol (LCP) that included 4 h tests, one baseline and 3 conditioning days (Phase 2), in which solid PF (Oreo cookies) was paired with glucose (control-no internal aversive effect) or lactose, dissolved in liquid PF. Index for PF motivation was PF consumption during the 4 h LCP. To test for memory of lactose conditioning, we performed another LCP with glucose only (anticipation, but no actual lactose-induced discomfort), a week after the last conditioning session. Results: Lactose conditioned BEP showed higher motivation toward PF compared to lactose conditioned BER faced with delayed aversive effects. Only lactose conditioned BER rats devaluated the PF over LCP days, indicating an association between PF and abdominal discomfort. In addition, only lactose conditioned BER presented an adaptive dynamic behavior, by varying PF intake according to consequences. Furthermore, solid PF consumption was predicted by binge size of liquid PF, only for lactose conditioned rats. Conclusions: We established an animal model for a common eating conflict in humans using delayed internal aversive unconditional stimuli. PMID- 28725178 TI - Different Forms of AMPA Receptor Mediated LTP and Their Correlation to the Spatial Working Memory Formation. AB - Spatial working memory (SWM) and the classical, tetanus-induced long-term potentiation (LTP) at hippocampal CA3/CA1 synapses are dependent on L-alpha-amino 3-hydroxy-5-methylisoxazole-4-propionate receptors (AMPARs) containing GluA1 subunits as demonstrated by knockout mice lacking GluA1. In GluA1 knockout mice LTP and SWM deficits could be partially recovered by transgenic re-installation of full-length GluA1 in principle forebrain neurons. Here we partially restored hippocampal LTP in GluA1-deficient mice by forebrain-specific depletion of the GluA2 gene, by the activation of a hypomorphic GluA2(Q) allele and by transgenic expression of PDZ-site truncated GFP-GluA1(TG). In none of these three mouse lines, the partial LTP recovery improved the SWM performance of GluA1-deficient mice suggesting a specific function of intact GluA1/2 receptors and the GluA1 intracellular carboxyl-terminus in SWM and its associated behavior. PMID- 28725177 TI - Characterization of Lgr5+ Progenitor Cell Transcriptomes after Neomycin Injury in the Neonatal Mouse Cochlea. AB - Lgr5+ supporting cells (SCs) are enriched hair cell (HC) progenitors in the cochlea. Both in vitro and in vivo studies have shown that HC injury can spontaneously activate Lgr5+ progenitors to regenerate HCs in the neonatal mouse cochlea. Promoting HC regeneration requires the understanding of the mechanism of HC regeneration, and this requires knowledge of the key genes involved in HC injury-induced self-repair responses that promote the proliferation and differentiation of Lgr5+ progenitors. Here, as expected, we found that neomycin treated Lgr5+ progenitors (NLPs) had significantly greater HC regeneration ability, and greater but not significant proliferation ability compared to untreated Lgr5+ progenitors (ULPs) in response to neomycin exposure. Next, we used RNA-seq analysis to determine the differences in the gene-expression profiles between the transcriptomes of NLPs and ULPs from the neonatal mouse cochlea. We first analyzed the genes that were enriched and differentially expressed in NLPs and ULPs and then analyzed the cell cycle genes, the transcription factors, and the signaling pathway genes that might regulate the proliferation and differentiation of Lgr5+ progenitors. We found 9 cell cycle genes, 88 transcription factors, 8 microRNAs, and 16 cell-signaling pathway genes that were significantly upregulated or downregulated after neomycin injury in NLPs. Lastly, we constructed a protein-protein interaction network to show the interaction and connections of genes that are differentially expressed in NLPs and ULPs. This study has identified the genes that might regulate the proliferation and HC regeneration of Lgr5+ progenitors after neomycin injury, and investigations into the roles and mechanisms of these genes in the cochlea should be performed in the future to identify potential therapeutic targets for HC regeneration. PMID- 28725179 TI - Fine-Tuning ER Stress Signal Transducers to Treat Amyotrophic Lateral Sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motoneurons and paralysis. The mechanisms underlying neuronal degeneration in ALS are starting to be elucidated, highlighting disturbances in motoneuron proteostasis. Endoplasmic reticulum (ER) stress has emerged as an early pathogenic event underlying motoneuron vulnerability and denervation in ALS. Maintenance of ER proteostasis is controlled by a dynamic signaling network known as the unfolded protein response (UPR). Inositol-requiring enzyme 1 (IRE1) is an ER-located kinase and endoribonuclease that operates as a major ER stress transducer, mediating the establishment of adaptive and pro-apoptotic programs. Here we discuss current evidence supporting the role of ER stress in motoneuron demise in ALS and build the rational to target IRE1 to ameliorate neurodegeneration. PMID- 28725180 TI - Endothelial Nitric Oxide Synthase Is Present in Dendritic Spines of Neurons in Primary Cultures. AB - Nitric oxide exerts important regulatory functions in various brain processes. Its synthesis in neurons has been most commonly ascribed to the neuronal nitric oxide synthase (nNOS) isoform. However, the endothelial isoform (eNOS), which is significantly associated with caveolae in different cell types, has been implicated in synaptic plasticity and is enriched in the dendrites of CA1 hippocampal neurons. Using high resolution microscopy and co-distribution analysis of eNOS with synaptic and raft proteins, we now show for the first time in primary cortical and hippocampal neuronal cultures, virtually devoid of endothelial cells, that eNOS is present in neurons and is localized in dendritic spines. Moreover, eNOS is present in a postsynaptic density-enriched biochemical fraction isolated from these neuronal cultures. In addition, qPCR analysis reveals that both the nNOS as well as the eNOS transcripts are present in neuronal cultures. Moreover, eNOS inhibition in cortical cells has a negative impact on cell survival after excitotoxic stimulation with N-methyl-D-aspartate (NMDA). Consistent with previous results that indicated nitric oxide production in response to the neurotrophin BDNF, we could detect eNOS in immunoprecipitates of the BDNF receptor TrkB while nNOS could not be detected. Taken together, our results show that eNOS is located at excitatory synapses where it could represent a source for NO production and thus, the contribution of eNOS-derived nitric oxide to the regulation of neuronal survival and function deserves further investigations. PMID- 28725181 TI - Impact of Proestrus on Gene Expression in the Medial Preoptic Area of Mice. AB - The antero-ventral periventricular zone (AVPV) and medial preoptic area (MPOA) have been recognized as gonadal hormone receptive regions of the rodent brain that-via wiring to gonadotropin-releasing hormone (GnRH) neurons-contribute to orchestration of the preovulatory GnRH surge. We hypothesized that neural genes regulating the induction of GnRH surge show altered expression in proestrus. Therefore, we compared the expression of 48 genes obtained from intact proestrous and metestrous mice, respectively, by quantitative real-time PCR (qPCR) method. Differential expression of 24 genes reached significance (p < 0.05). Genes upregulated in proestrus encoded neuropeptides (kisspeptin (KP), galanin (GAL), neurotensin (NT), cholecystokinin (CCK)), hormone receptors (growth hormone secretagogue receptor, MU-opioid receptor), gonadal steroid receptors (estrogen receptor alpha (ERalpha), progesterone receptor (PR), androgen receptor (AR)), solute carrier family proteins (vesicular glutamate transporter 2, vesicular monoamine transporter 2), proteins of transmitter synthesis (tyrosine hydroxylase (TH)) and transmitter receptor subunit (AMPA4), and other proteins (uncoupling protein 2, nuclear receptor related 1 protein). Proestrus evoked a marked downregulation of genes coding for adenosine A2a receptor, vesicular gamma aminobutyric acid (GABA) transporter, 4-aminobutyrate aminotransferase, tachykinin precursor 1, NT receptor 3, arginine vasopressin receptor 1A, cannabinoid receptor 1, ephrin receptor A3 and aldehyde dehydrogenase 1 family, member L1. Immunocytochemistry was used to visualize the proteins encoded by Kiss1, Gal, Cck and Th genes in neuronal subsets of the AVPV/MPOA of the proestrous mice. The results indicate that gene expression of the AVPV/MPOA is significantly modified at late proestrus including genes that code for neuropeptides, gonadal steroid hormone receptors and synaptic vesicle transporters. These events support cellular and neuronal network requirements of the positive estradiol feedback action and contribute to preparation of the GnRH neuron system for the pre-ovulatory surge release. PMID- 28725182 TI - Canonical and Novel Non-Canonical Cholinergic Agonists Inhibit ATP-Induced Release of Monocytic Interleukin-1beta via Different Combinations of Nicotinic Acetylcholine Receptor Subunits alpha7, alpha9 and alpha10. AB - Recently, we discovered a cholinergic mechanism that inhibits the adenosine triphosphate (ATP)-dependent release of interleukin-1beta (IL-1beta) by human monocytes via nicotinic acetylcholine receptors (nAChRs) composed of alpha7, alpha9 and/or alpha10 subunits. Furthermore, we identified phosphocholine (PC) and dipalmitoylphosphatidylcholine (DPPC) as novel nicotinic agonists that elicit metabotropic activity at monocytic nAChR. Interestingly, PC does not provoke ion channel responses at conventional nAChRs composed of subunits alpha9 and alpha10. The purpose of this study is to determine the composition of nAChRs necessary for nicotinic signaling in monocytic cells and to test the hypothesis that common metabolites of phosphatidylcholines, lysophosphatidylcholine (LPC) and glycerophosphocholine (G-PC), function as nAChR agonists. In peripheral blood mononuclear cells from nAChR gene-deficient mice, we demonstrated that inhibition of ATP-dependent release of IL-1beta by acetylcholine (ACh), nicotine and PC depends on subunits alpha7, alpha9 and alpha10. Using a panel of nAChR antagonists and siRNA technology, we confirmed the involvement of these subunits in the control of IL-1beta release in the human monocytic cell line U937. Furthermore, we showed that LPC (C16:0) and G-PC efficiently inhibit ATP dependent release of IL-1beta. Of note, the inhibitory effects mediated by LPC and G-PC depend on nAChR subunits alpha9 and alpha10, but only to a small degree on alpha7. In Xenopuslaevis oocytes heterologously expressing different combinations of human alpha7, alpha9 or alpha10 subunits, ACh induced canonical ion channel activity, whereas LPC, G-PC and PC did not. In conclusion, we demonstrate that canonical nicotinic agonists and PC elicit metabotropic nAChR activity in monocytes via interaction of nAChR subunits alpha7, alpha9 and alpha10. For the metabotropic signaling of LPC and G-PC, nAChR subunits alpha9 and alpha10 are needed, whereas alpha7 is virtually dispensable. Furthermore, molecules bearing a PC group in general seem to regulate immune functions without perturbing canonical ion channel functions of nAChR. PMID- 28725183 TI - Bile Acid-Mediated Sphingosine-1-Phosphate Receptor 2 Signaling Promotes Neuroinflammation during Hepatic Encephalopathy in Mice. AB - Hepatic encephalopathy (HE) is a neuropsychiatric complication that occurs due to deteriorating hepatic function and this syndrome influences patient quality of life, clinical management strategies and survival. During acute liver failure, circulating bile acids increase due to a disruption of the enterohepatic circulation. We previously identified that bile acid-mediated signaling occurs in the brain during HE and contributes to cognitive impairment. However, the influences of bile acids and their downstream signaling pathways on HE-induced neuroinflammation have not been assessed. Conjugated bile acids, such as taurocholic acid (TCA), can activate sphingosine-1-phosphate receptor 2 (S1PR2), which has been shown to promote immune cell infiltration and inflammation in other models. The current study aimed to assess the role of bile-acid mediated S1PR2 signaling in neuroinflammation and disease progression during azoxymethane (AOM)-induced HE in mice. Our findings demonstrate a temporal increase of bile acids in the cortex during AOM-induced HE and identified that cortical bile acids were elevated as an early event in this model. In order to classify the specific bile acids that were elevated during HE, a metabolic screen was performed and this assay identified that TCA was increased in the serum and cortex during AOM induced HE. To reduce bile acid concentrations in the brain, mice were fed a diet supplemented with cholestyramine, which alleviated neuroinflammation by reducing proinflammatory cytokine expression in the cortex compared to the control diet fed AOM-treated mice. S1PR2 was expressed primarily in neurons and TCA treatment increased chemokine ligand 2 mRNA expression in these cells. The infusion of JTE 013, a S1PR2 antagonist, into the lateral ventricle prior to AOM injection protected against neurological decline and reduced neuroinflammation compared to DMSO-infused AOM-treated mice. Together, this identifies that reducing bile acid levels or S1PR2 signaling are potential therapeutic strategies for the management of HE. PMID- 28725184 TI - Sevoflurane Induces Coherent Slow-Delta Oscillations in Rats. AB - Although general anesthetics are routinely administered to surgical patients to induce loss of consciousness, the mechanisms underlying anesthetic-induced unconsciousness are not fully understood. In rats, we characterized changes in the extradural EEG and intracranial local field potentials (LFPs) within the prefrontal cortex (PFC), parietal cortex (PC), and central thalamus (CT) in response to progressively higher doses of the inhaled anesthetic sevoflurane. During induction with a low dose of sevoflurane, beta/low gamma (12-40 Hz) power increased in the frontal EEG and PFC, PC and CT LFPs, and PFC-CT and PFC-PFC LFP beta/low gamma coherence increased. Loss of movement (LOM) coincided with an abrupt decrease in beta/low gamma PFC-CT LFP coherence. Following LOM, cortically coherent slow-delta (0.1-4 Hz) oscillations were observed in the frontal EEG and PFC, PC and CT LFPs. At higher doses of sevoflurane sufficient to induce loss of the righting reflex, coherent slow-delta oscillations were dominant in the frontal EEG and PFC, PC and CT LFPs. Dynamics similar to those observed during induction were observed as animals emerged from sevoflurane anesthesia. We conclude that the rat is a useful animal model for sevoflurane-induced EEG oscillations in humans, and that coherent slow-delta oscillations are a correlate of sevoflurane-induced behavioral arrest and loss of righting in rats. PMID- 28725186 TI - Foxb1 Regulates Negatively the Proliferation of Oligodendrocyte Progenitors. AB - Oligodendrocyte precursor cells (OPC), neurons and astrocytes share a neural progenitor cell (NPC) in the early ventricular zone (VZ) of the embryonic neuroepithelium. Both switch to produce either of the three cell types and the generation of the right number of them undergo complex genetic regulation. The components of these regulatory cascades vary between brain regions giving rise to the unique morphological and functional heterogeneity of this organ. Forkhead b1 (Foxb1) is a transcription factor gene expressed by NPCs in specific regions of the embryonic neuroepithelium. We used the mutant mouse line Foxb1-Cre to analyze the cell types derived from Fobx1-expressing NPCs (the Foxb1 cell lineage) from two restricted regions, the medulla oblongata (MO; hindbrain) and the thalamus (forebrain), of normal and Foxb1-deficient mice. Foxb1 cell lineage derivatives appear as clusters in restricted regions, including the MO (hindbrain) and the thalamus (forebrain). Foxb1-expressing NPCs produce mostly oligodendrocytes (OL), some neurons and few astrocytes. Foxb1-deficient NPCs generate mostly OPC and immature OL to the detriment of neurons, astrocytes and mature OL. The axonal G ratio however is not changed. We reveal Foxb1 as a novel modulator of neuronal and OL generation in certain restricted CNS regions. Foxb1 biases NPCs towards neuronal generation and inhibits OPC proliferation while promoting their differentiation. PMID- 28725185 TI - Reticular Formation and Pain: The Past and the Future. AB - The involvement of the reticular formation (RF) in the transmission and modulation of nociceptive information has been extensively studied. The brainstem RF contains several areas which are targeted by spinal cord afferents conveying nociceptive input. The arrival of nociceptive input to the RF may trigger alert reactions which generate a protective/defense reaction to pain. RF neurons located at the medulla oblongata and targeted by ascending nociceptive information are also involved in the control of vital functions that can be affected by pain, namely cardiovascular control. The RF contains centers that belong to the pain modulatory system, namely areas involved in bidirectional balance (decrease or enhancement) of pain responses. It is currently accepted that the imbalance of pain modulation towards pain facilitation accounts for chronic pain. The medullary RF has the peculiarity of harboring areas involved in bidirectional pain control namely by the existence of specific neuronal populations involved in antinociceptive or pronociceptive behavioral responses, namely at the rostroventromedial medulla (RVM) and the caudal ventrolateral medulla (VLM). Furthermore the dorsal reticular nucleus (also known as subnucleus reticularis dorsalis; DRt) may enhance nociceptive responses, through a reverberative circuit established with spinal lamina I neurons and inhibit wide dynamic range (WDR) neurons of the deep dorsal horn. The components of the triad RVM-VLM-DRt are reciprocally connected and represent a key gateway for top-down pain modulation. The RVM-VLM-DRt triad also represents the neurobiological substrate for the emotional and cognitive modulation of pain, through pathways that involve the periaqueductal gray (PAG)-RVM connection. Collectively, we propose that the RVM-VLM-DRt triad represents a key component of the "dynamic pain connectome" with special features to provide integrated and rapid responses in situations which are life-threatening and involve pain. The new available techniques in neurobiological studies both in animal and human studies are producing new and fascinating data which allow to understand the complex role of the RF in pain modulation and its integration with several body functions and also how the RF accounts for chronic pain. PMID- 28725187 TI - Lack of Associations between Female Hormone Levels and Visuospatial Working Memory, Divided Attention and Cognitive Bias across Two Consecutive Menstrual Cycles. AB - Background: Interpretation of observational studies on associations between prefrontal cognitive functioning and hormone levels across the female menstrual cycle is complicated due to small sample sizes and poor replicability. Methods: This observational multisite study comprised data of n = 88 menstruating women from Hannover, Germany, and Zurich, Switzerland, assessed during a first cycle and n = 68 re-assessed during a second cycle to rule out practice effects and false-positive chance findings. We assessed visuospatial working memory, attention, cognitive bias and hormone levels at four consecutive time-points across both cycles. In addition to inter-individual differences we examined intra individual change over time (i.e., within-subject effects). Results: Estrogen, progesterone and testosterone did not relate to inter-individual differences in cognitive functioning. There was a significant negative association between intra individual change in progesterone and change in working memory from pre-ovulatory to mid-luteal phase during the first cycle, but that association did not replicate in the second cycle. Intra-individual change in testosterone related negatively to change in cognitive bias from menstrual to pre-ovulatory as well as from pre-ovulatory to mid-luteal phase in the first cycle, but these associations did not replicate in the second cycle. Conclusions: There is no consistent association between women's hormone levels, in particular estrogen and progesterone, and attention, working memory and cognitive bias. That is, anecdotal findings observed during the first cycle did not replicate in the second cycle, suggesting that these are false-positives attributable to random variation and systematic biases such as practice effects. Due to methodological limitations, positive findings in the published literature must be interpreted with reservation. PMID- 28725188 TI - Using Virtual Reality to Assess Ethical Decisions in Road Traffic Scenarios: Applicability of Value-of-Life-Based Models and Influences of Time Pressure. AB - Self-driving cars are posing a new challenge to our ethics. By using algorithms to make decisions in situations where harming humans is possible, probable, or even unavoidable, a self-driving car's ethical behavior comes pre-defined. Ad hoc decisions are made in milliseconds, but can be based on extensive research and debates. The same algorithms are also likely to be used in millions of cars at a time, increasing the impact of any inherent biases, and increasing the importance of getting it right. Previous research has shown that moral judgment and behavior are highly context-dependent, and comprehensive and nuanced models of the underlying cognitive processes are out of reach to date. Models of ethics for self-driving cars should thus aim to match human decisions made in the same context. We employed immersive virtual reality to assess ethical behavior in simulated road traffic scenarios, and used the collected data to train and evaluate a range of decision models. In the study, participants controlled a virtual car and had to choose which of two given obstacles they would sacrifice in order to spare the other. We randomly sampled obstacles from a variety of inanimate objects, animals and humans. Our model comparison shows that simple models based on one-dimensional value-of-life scales are suited to describe human ethical behavior in these situations. Furthermore, we examined the influence of severe time pressure on the decision-making process. We found that it decreases consistency in the decision patterns, thus providing an argument for algorithmic decision-making in road traffic. This study demonstrates the suitability of virtual reality for the assessment of ethical behavior in humans, delivering consistent results across subjects, while closely matching the experimental settings to the real world scenarios in question. PMID- 28725189 TI - Inversion Reveals Perceptual Asymmetries in the Configural Processing of Human Body. AB - Ambiguous human bodies performing unimanual/unipedal actions are perceived more frequently as right-handed/footed rather than left-handed/footed, which suggests a perceptual and attentional bias toward the right side of others' body. A bias toward the right arm of human bodies could be adaptive in social life, most social interactions occurring with right-handed individuals, and the implicit knowledge that the dominant hand of humans is usually placed on their right side might also be included in body configural information. Given that inversion disrupts configural processing for human bodies, we investigated whether inversion reduces the bias toward the right side of human bodies. Consistent with our hypothesis, when presented with ambiguous stimuli depicting humans performing lateralized actions or movements, participants perceived a greater proportion of right-handed figures when the stimuli were shown upright than when the stimuli were shown inverted. The present findings seem to confirm our hypothesis that body configural information may include some form of knowledge about the probable handedness of other individuals, although alternative accounts involving the role of experience cannot be ruled out. PMID- 28725192 TI - Commentary: Proceedings of the First Workshop on Peripheral Machine Interfaces: Going beyond Traditional Surface Electromyography. PMID- 28725191 TI - Bilateral Reflex Fluctuations during Rhythmic Movement of Remote Limb Pairs. AB - The modulation of spinal cord excitability during rhythmic limb movement reflects the neuronal coordination underlying actions of the arms and legs. Integration of network activity in the spinal cord can be assessed by reflex variability between the limbs, an approach so far very little studied. The present work addresses this question by eliciting Hoffmann (H-) reflexes in both limbs to assess if common drive onto bilateral pools of motoneurons influence spinal cord excitability simultaneously or with a delay between sides. A cross-covariance (CCV) sequence between reflexes in both arms or legs was evaluated under conditions providing common drive bilaterally through voluntary muscle contraction and/or rhythmic movement of the remote limbs. For H-reflexes in the flexor carpi radialis (FCR) muscle, either contraction of the FCR or leg cycling induced significant reduction in the amplitude of the peak at the zero lag in the CCV sequence, indicating independent variations in spinal excitability between both sides. In contrast, for H-reflexes in the soleus (SO) muscle, arm cycling revealed no reduction in the amplitude of the peak in the CCV sequence at the zero lag. This suggests a more independent control of the arms compared with the legs. These results provide new insights into the organization of human limb control in rhythmic activity and the behavior of bilateral reflex fluctuations under different motor tasks. From a functional standpoint, changes in the co variability might reflect dynamic adjustments in reflex excitability that are subsumed under more global control features during locomotion. PMID- 28725190 TI - Reliability of EEG Interactions Differs between Measures and Is Specific for Neurological Diseases. AB - Alterations of interaction (connectivity) of the EEG reflect pathological processes in patients with neurologic disorders. Nevertheless, it is questionable whether these patterns are reliable over time in different measures of interaction and whether this reliability of the measures is the same across different patient populations. In order to address this topic we examined 22 patients with mild cognitive impairment, five patients with subjective cognitive complaints, six patients with right-lateralized temporal lobe epilepsy, seven patients with left lateralized temporal lobe epilepsy, and 20 healthy controls. We calculated 14 measures of interaction from two EEG-recordings separated by 2 weeks. In order to characterize test-retest reliability, we correlated these measures for each group and compared the correlations between measures and between groups. We found that both measures of interaction as well as groups differed from each other in terms of reliability. The strongest correlation coefficients were found for spectrum, coherence, and full frequency directed transfer function (average rho > 0.9). In the delta (2-4 Hz) range, reliability was lower for mild cognitive impairment compared to healthy controls and left lateralized temporal lobe epilepsy. In the beta (13-30 Hz), gamma (31-80 Hz), and high gamma (81-125 Hz) frequency ranges we found decreased reliability in subjective cognitive complaints compared to mild cognitive impairment. In the gamma and high gamma range we found increased reliability in left lateralized temporal lobe epilepsy patients compared to healthy controls. Our results emphasize the importance of documenting reliability of measures of interaction, which may vary considerably between measures, but also between patient populations. We suggest that studies claiming clinical usefulness of measures of interaction should provide information on the reliability of the results. In addition, differences between patient groups in reliability of interactions in the EEG indicate the potential of reliability to serve as a new biomarker for pathological memory decline as well as for epilepsy. While the brain concert of information flow is generally variable, high reliability, and thus, low variability may reflect abnormal firing patterns. PMID- 28725193 TI - Annual Meeting of the International Society of Cancer Metabolism (ISCaM): Metabolic Networks in Cancer. AB - Cancers are metabolic entities wherein cancer cells adapt their metabolism to their oncogenic agenda and microenvironmental influences. Metabolically different cancer cell subpopulations collaborate to optimize nutrient delivery with respect to immediate bioenergetic and biosynthetic needs. They can also metabolically exploit host cells. These metabolic networks are directly linked with cancer progression, treatment resistance and relapse. Conversely, metabolic alterations in cancer are exploited for anticancer therapy, imaging and personalized medicine. These topics were addressed at the 3rd annual meeting of the International Society of Cancer Metabolism (ISCaM) in Brussels, Belgium, on 26-29 October 2016. PMID- 28725194 TI - Sophisticated Cloning, Fermentation, and Purification Technologies for an Enhanced Therapeutic Protein Production: A Review. AB - The protein productions strategies are crucial towards the development of application based research and elucidating the novel purification strategies for industrial production. Currently, there are few innovative avenues are studies for cloning, upstream, and purification through efficient bioprocess development. Such strategies are beneficial for industries as well as proven to be vital for effectual therapeutic protein development. Though, these techniques are well documented, but, there is scope of addition to current knowledge with novel and new approaches and it will pave new avenues in production of recombinant microbial and non-microbial proteins including secondary metabolites. In this review, we have focussed on the recent development in clone selection, various modern fermentation and purification technologies and future directions in these emerging areas. Moreover, we have also highlighted notable perspectives and challenges involved in the bioengineering of such proteins, including quality by design, gene editing and pioneering ideas. The biopharmaceutical industries continue to shift towards more flexible, automated platforms and economical product development, which in turn can help in developing the cost effective processes and affordable drug development for a large community. PMID- 28725195 TI - Vitamin E As a Potential Interventional Treatment for Metabolic Syndrome: Evidence from Animal and Human Studies. AB - A constellation of medical conditions inclusive of central obesity, hyperglycemia, hypertension, and dyslipidemia is known as metabolic syndrome (MetS). The safest option in curtailing the progression of MetS is through maintaining a healthy lifestyle, which by itself, is a long-term commitment entailing much determination. A combination of pharmacological and non pharmacological approach, as well as lifestyle modification is a more holistic alternative in the management of MetS. Vitamin E has been revealed to possess anti-oxidative, anti-inflammatory, anti-obesity, anti-hyperglycemic, anti hypertensive and anti-hypercholesterolemic properties. The pathways regulated by vitamin E are critical in the development of MetS and its components. Therefore, we postulate that vitamin E may exert some health benefits on MetS patients. This review intends to summarize the evidence in animal and human studies on the effects of vitamin E and articulate the contrasting potential of tocopherol (TF) and tocotrienol (T3) in preventing the medical conditions associated with MetS. As a conclusion, this review suggests that vitamin E may be a promising agent for attenuating MetS. PMID- 28725196 TI - Synergistic Effect of Doripenem and Cefotaxime to Inhibit CTX-M-15 Type beta Lactamases: Biophysical and Microbiological Views. AB - CTX-M-15 type beta-lactamase has the ability to hydrolyse cefotaxime, a third generation cephalosporin. The infections caused by multidrug resistant strains, especially CTX-M-15 producing strains are being treated with carbapenem group of beta-lactam antibiotics. The objective of the study was to know if cefotaxime in combination with doripenem (carbapemen antibiotic) at very low concentration, inhibits the CTX-M-15 producing bacterial strains. blaCTX-M-15 gene was cloned to express CTX-M-15 enzyme and construct CTX-M-15 producing strain. The clone carrying CTX-M-15 was found susceptible to doripenem. Doripenem and CTX-M-15 binding was an endothermic and spontaneous process leading to change in polarity in the micro-environment and conformational changes of enzyme as shown by fluorescence, UV and CD spectroscopic study. The catalytic efficiency of CTX-M-15 enzyme was reduced to about 15.86% when it was treated with doripenem along with cefotaxime (in 5 times molar ratio each of doripenem and cefotaxime w.r.t CTX-M 15), as compared to the studies where enzyme's efficiency was increased by 33% when treated with cefotaxime alone. Hence, doripenem in combination with cefotaxime reduces enzyme's efficiency to hydrolyse cefotaxime by about 48%. FIC study showed that doripenem paired with cefotaxime showed synergistic effect against CTX-M-15 producing bacterial strain. The study concludes that doripenem at very low concentration (25 nM), induces such a structural changes in CTX-M-15 which reduced enzyme's activity to hydrolyse cefotaxime. Hence, the synergistic use of doripenem and cefotaxime plays a significant role in inhibiting the efficiency of CTX-M-15 type beta-lactamase, and may provide an alternative approach to reduce the resistance against the cephalosporin type antibiotics. PMID- 28725198 TI - 3D Reconstruction of the Digestive System in Octopus vulgaris Cuvier, 1797 Embryos and Paralarvae during the First Month of Life. AB - Octopus vulgaris aquaculture is limited due to poor biological knowledge of the paralarval stages (e.g., digestive system functionality), their nutritional requirements (e.g., adequate live diet) and standardization of rearing techniques. These factors are important in explaining the high mortality rate observed in this developmental stage under culture conditions. For a better understanding of nutrition biology of this species, we investigated the 3D microanatomy of the digestive tract of the embryo and paralarvae during the first month of life. O. vulgaris paralarvae digestive system is similar to that in the adult. The "descending branch" has a dorsal position and is formed by the buccal mass, oesophagus and crop. Ventrally, the "ascending branch" is formed by the intestine and the anus. The digestive gland, the posterior salivary glands and the inner yolk sac (in the case of the embryo and hatched paralarvae) are located between the "ascending" and "descending" branches. In the curve of the U-shaped digestive tract, a caecum and the stomach can be found. The reconstructions reveal that anatomically the digestive system is already complete when the paralarvae hatch. The reconstruction of the buccal mass at different post hatching days has demonstrated that all the necessary structures for food intake are present. However, the radula surface in contact with the pharynx is very small on the first day of life. Although the digestive system has all the structures to feed, the digestive gland and radula take longer to reach full functionality. We have established four development periods: embryonic, early post-hatching, late post-hatching and juvenile-adult. The differentiation between these periods was done by type of feeding (endogenous or exogenous), the state of maturation and hence functionality of the digestive gland, type of growth (linear, no net, or exponential), and measurement of the arm lengths with respect to the mantle length. 3D reconstruction represents a new tool to study the morphology and functionality of the cephalopod digestive system during the first days of life. PMID- 28725197 TI - Skeletal Muscle Remodeling in Response to Eccentric vs. Concentric Loading: Morphological, Molecular, and Metabolic Adaptations. AB - Skeletal muscle contracts either by shortening or lengthening (concentrically or eccentrically, respectively); however, the two contractions substantially differ from one another in terms of mechanisms of force generation, maximum force production and energy cost. It is generally known that eccentric actions generate greater force than isometric and concentric contractions and at a lower metabolic cost. Hence, by virtue of the greater mechanical loading involved in active lengthening, eccentric resistance training (ECC RT) is assumed to produce greater hypertrophy than concentric resistance training (CON RT). Nonetheless, prevalence of either ECC RT or CON RT in inducing gains in muscle mass is still an open issue, with some studies reporting greater hypertrophy with eccentric, some with concentric and some with similar hypertrophy within both training modes. Recent observations suggest that such hypertrophic responses to lengthening vs. shortening contractions are achieved by different adaptations in muscle architecture. Whilst the changes in muscle protein synthesis in response to acute and chronic concentric and eccentric exercise bouts seem very similar, the molecular mechanisms regulating the myogenic adaptations to the two distinct loading stimuli are still incompletely understood. Thus, the present review aims to, (a) critically discuss the literature on the contribution of eccentric vs. concentric loading to muscular hypertrophy and structural remodeling, and, (b) clarify the molecular mechanisms that may regulate such adaptations. We conclude that, when matched for either maximum load or work, similar increase in muscle size is found between ECC and CON RT. However, such hypertrophic changes appear to be achieved through distinct structural adaptations, which may be regulated by different myogenic and molecular responses observed between lengthening and shortening contractions. PMID- 28725199 TI - Heart Performance Determination by Visualization in Larval Fishes: Influence of Alternative Models for Heart Shape and Volume. AB - Understanding cardiac function in developing larval fishes is crucial for assessing their physiological condition and overall health. Cardiac output measurements in transparent fish larvae and other vertebrates have long been made by analyzing videos of the beating heart, and modeling this structure using a conventional simple prolate spheroid shape model. However, the larval fish heart changes shape during early development and subsequent maturation, but no consideration has been made of the effect of different heart geometries on cardiac output estimation. The present study assessed the validity of three different heart models (the "standard" prolate spheroid model as well as a cylinder and cone tip + cylinder model) applied to digital images of complete cardiac cycles in larval mahi-mahi and red drum. The inherent error of each model was determined to allow for more precise calculation of stroke volume and cardiac output. The conventional prolate spheroid and cone tip + cylinder models yielded significantly different stroke volume values at 56 hpf in red drum and from 56 to 104 hpf in mahi. End-diastolic and stroke volumes modeled by just a simple cylinder shape were 30-50% higher compared to the conventional prolate spheroid. However, when these values of stroke volume multiplied by heart rate to calculate cardiac output, no significant differences between models emerged because of considerable variability in heart rate. Essentially, the conventional prolate spheroid shape model provides the simplest measurement with lowest variability of stroke volume and cardiac output. However, assessment of heart function especially if stroke volume is the focus of the study-should consider larval heart shape, with different models being applied on a species-by-species and developmental stage-by-stage basis for best estimation of cardiac output. PMID- 28725200 TI - Acoustic Features Influence Musical Choices Across Multiple Genres. AB - Based on a large behavioral dataset of music downloads, two analyses investigate whether the acoustic features of listeners' preferred musical genres influence their choice of tracks within non-preferred, secondary musical styles. Analysis 1 identifies feature distributions for pairs of genre-defined subgroups that are distinct. Using correlation analysis, these distributions are used to test the degree of similarity between subgroups' main genres and the other music within their download collections. Analysis 2 explores the issue of main-to-secondary genre influence through the production of 10 feature-influence matrices, one per acoustic feature, in which cell values indicate the percentage change in features for genres and subgroups compared to overall population averages. In total, 10 acoustic features and 10 genre-defined subgroups are explored within the two analyses. Results strongly indicate that the acoustic features of people's main genres influence the tracks they download within non-preferred, secondary musical styles. The nature of this influence and its possible actuating mechanisms are discussed with respect to research on musical preference, personality, and statistical learning. PMID- 28725201 TI - Nature and Specificity of Gestural Disorder in Children with Developmental Coordination Disorder: A Multiple Case Study. AB - Aim: Praxis assessment in children with developmental coordination disorder (DCD) is usually based on tests of adult apraxia, by comparing across types of gestures and input modalities. However, the cognitive models of adult praxis processing are rarely used in a comprehensive and critical interpretation. These models generally involve two systems: a conceptual system and a production system. Heterogeneity of deficits is consistently reported in DCD, involving other cognitive skills such as executive or visual-perceptual and visuospatial functions. Surprisingly, few researches examined the impact of these functions in gestural production. Our study aimed at discussing the nature and specificity of the gestural deficit in DCD using a multiple case study approach. Method: Tasks were selected and adapted from protocols proposed in adult apraxia, in order to enable a comprehensive assessment of gestures. This included conceptual tasks (knowledge about tool functions and actions; recognition of gestures), representational (transitive, intransitive), and non-representational gestures (imitation of meaningless postures). We realized an additional assessment of constructional abilities and other cognitive domains (executive functions, visual perceptual and visuospatial functions). Data from 27 patients diagnosed with DCD were collected. Neuropsychological profiles were classified using an inferential clinical analysis based on the modified t-test, by comparison with 100 typically developing children divided into five age groups (from 7 to 13 years old). Results: Among the 27 DCD patients, we first classified profiles that are characterized by impairment in tasks assessing perceptual visual or visuospatial skills (n = 8). Patients with a weakness in executive functions (n = 6) were then identified, followed by those with an impaired performance in conceptual knowledge tasks (n = 4). Among the nine remaining patients, six could be classified as having a visual spatial/visual constructional dyspraxia. Gestural production deficits were variable between and within profiles. Discussion: This study confirmed the heterogeneity of gestural production deficit among children with a diagnosis of DCD, at both intra- and inter-individual levels. The contribution of other cognitive deficits in most of the profiles allows discussing the specificity of gestural difficulties. This argues in favor of the necessity to distinguish gestural problems with other deficits made apparent through gesture. PMID- 28725202 TI - Emotional Picture Perception: Repetition Effects in Free-Viewing and during an Explicit Categorization Task. AB - Several studies have found that, despite a decrease in the overall amplitude of the late positive potential (LPP) with repeated presentation of the same picture, emotional stimuli continue to elicit a larger LPP than neutral ones. These findings seem to support the hypothesis that the affective modulation of the LPP reflects a mandatory process and does not rely on stimulus novelty. However, in these studies participants were asked to merely look at the pictures, without carrying out any additional task (free-viewing), making picture emotionality the most salient aspect of the stimulus, despite its repetition. The current study aimed to examine the impact of an explicit categorization task on the emotional processing of repeated pictures. To this purpose, ERPs to novel and repeated pictures were measured during free-viewing as well as during an explicit categorization task, where the emotional content of the pictures was task irrelevant. The within-subject comparison between the free-viewing and task context revealed that the overall LPP habituated more rapidly in the free-viewing condition, but, more importantly, the LPP affective modulation was unaffected by task requirements during both novel and repeated presentations. These results suggest that the affective modulation of the LPP reflects an automatic engagement of cortico-limbic motivational systems, which continues to take place regardless of stimulus novelty and task context. PMID- 28725203 TI - Retrieval and Monitoring Processes during Visual Working Memory: An ERP Study of the Benefit of Visual Semantics. AB - In this study, we examined electrophysiological indices of episodic remembering whilst participants recalled novel shapes, with and without semantic content, within a visual working memory paradigm. The components of interest were the parietal episodic (PE; 400-800 ms) and late posterior negativity (LPN; 500-900 ms), as these have previously been identified as reliable markers of recollection and post-retrieval monitoring, respectively. Fifteen young adults completed a visual matrix patterns task, assessing memory for low and high semantic visual representations. Matrices with either low semantic or high semantic content (containing familiar visual forms) were briefly presented to participants for study (1500 ms), followed by a retention interval (6000 ms) and finally a same/different recognition phase. The event-related potentials of interest were tracked from the onset of the recognition test stimuli. Analyses revealed equivalent amplitude for the earlier PE effect for the processing of both low and high semantic stimulus types. However, the LPN was more negative-going for the processing of the low semantic stimuli. These data are discussed in terms of relatively 'pure' and complete retrieval of high semantic items, where support can readily be recruited from semantic memory. However, for the low semantic items additional executive resources, as indexed by the LPN, are recruited when memory monitoring and uncertainty exist in order to recall previously studied items more effectively. PMID- 28725205 TI - School Functioning of a Particularly Vulnerable Group: Children and Young People in Residential Child Care. AB - A large proportion of the children and young people in residential child care in Spain are there as a consequence of abuse and neglect in their birth families. Research has shown that these types of adverse circumstances in childhood are risk factors for emotional and behavioral problems, as well as difficulties in adapting to different contexts. School achievement is related to this and represents one of the most affected areas. Children in residential child care exhibit extremely poor performance and difficulties in school functioning which affects their transition to adulthood and into the labor market. The main aim of this study is to describe the school functioning of a sample of 1,216 children aged between 8 and 18 living in residential child care in Spain. The specific needs of children with intellectual disability and unaccompanied migrant children were also analyzed. Relationships with other variables such as gender, age, mental health needs, and other risk factors were also explored. In order to analyze school functioning in this vulnerable group, the sample was divided into different groups depending on school level and educational needs. In the vast majority of cases, children were in primary or compulsory secondary education (up to age 16), this group included a significant proportion of cases in special education centers. The rest of the sample were in vocational training or post compulsory secondary school. Results have important implications for the design of socio-educative intervention strategies in both education and child care systems in order to promote better school achievement and better educational qualifications in this vulnerable group. PMID- 28725204 TI - History of Childhood Maltreatment and College Academic Outcomes: Indirect Effects of Hot Execution Function. AB - College students who report a history of childhood maltreatment may be at risk for poor outcomes. In the current study, we conducted an exploratory analysis to examine potential models that statistically mediate associations between aspects of maltreatment and aspects of academic outcome, with a particular focus on executive functions (EF). Consistent with contemporary EF research, we distinguished between relatively "cool" EF tasks (i.e., performed in a context relatively free of emotional or motivational valence) and "hot" EF tasks that emphasize performance under more emotionally arousing conditions. Sixty-one male and female college undergraduates self-reported childhood maltreatment history (emotional abuse and neglect, physical abuse and neglect, and sexual abuse) on the Childhood Trauma Questionnaire (CTQ), and were given two EF measures: (1) Go No-Go (GNG) test that included a Color Condition (cool); Neutral Face Condition (warm); and Emotion Face condition (hot), and (2) Iowa Gambling Task (IGT), a measure of risky decision making that reflects hot EF. Academic outcomes were: (1) grade point average (GPA: first-semester, cumulative, and semester concurrent with testing), and (2) Student Adaptation to College Questionnaire (SACQ). Correlational patterns suggested two EF scores as potential mediators: GNG reaction time (RT) in the Neutral Face condition, and IGT Block 2 adaptive responding. Indirect effects analyses indicated that IGT Block 2 adaptive responding has an indirect effect on the relationship between CTQ Total score and 1st semester GPA, and between CTQ Emotional Abuse and concurrent GPA. Regarding college adaptation, we identified a consistent indirect effect of GNG Neutral Face RT on the relationship between CTQ Emotional Neglect and SACQ total, academic, social, and personal-emotional adaption scores. Our results demonstrate that higher scores on a child maltreatment history self-report negatively predict college academic outcomes as assessed by GPA and by self-reported adaptation. Further, relatively "hot" EF task performance on the IGT and GNG tasks serves as a link between child maltreatment experiences and college achievement and adaptation, suggesting that hot EF skills may be a fruitful direction for future intervention efforts to improve academic outcomes for this population. PMID- 28725206 TI - Physiological Signal Analysis for Evaluating Flow during Playing of Computer Games of Varying Difficulty. AB - Flow is the experience of effortless attention, reduced self-consciousness, and a deep sense of control that typically occurs during the optimal performance of challenging tasks. On the basis of the person-artifact-task model, we selected computer games (tasks) with varying levels of difficulty (difficult, medium, and easy) and shyness (personality) as flow precursors to study the physiological activity of users in a flow state. Cardiac and respiratory activity and mean changes in skin conductance (SC) were measured continuously while the participants (n = 40) played the games. Moreover, the associations between self reported psychological flow and physiological measures were investigated through a series of repeated-measures analyses. The results showed that the flow experience is related to a faster respiratory rate, deeper respiration, moderate heart rate (HR), moderate HR variability, and moderate SC. The main effect of shyness was non-significant, whereas the interaction of shyness and difficulty influenced the flow experience. These findings are discussed in relation to current models of arousal and valence. The results indicate that the flow state is a state of moderate mental effort that arises through the increased parasympathetic modulation of sympathetic activity. PMID- 28725207 TI - Predictors of Biased Self-perception in Individuals with High Social Anxiety: The Effect of Self-consciousness in the Private and Public Self Domains. AB - "Biased self-perception," the tendency to perceive one's social performance as more negative than observers do, is characteristic of socially anxious individuals. Self-attention processes are hypothesised to underlie biased self perception, however, different models emphasise different aspects of self attention, with attention to the public aspects of the self being prominent. The current study aimed to investigate the relative contribution of two types of dispositional self-attention; public- and private self-consciousness to biased self-perception in a high (n = 48) versus a low (n = 48) social anxiety group undergoing an interaction task. The main finding was that private self consciousness explained substantial and unique variance in biased negative self perception in individuals with high social anxiety, while public self consciousness did not. This relationship was independent of increments in state anxiety. Private self-consciousness appeared to have a specific association with bias related to overestimation of negative social performance rather than underestimation of positive social performance. The implication of this finding is that current treatment models of Social anxiety disorder might include broader aspects of self-focused attention, especially in the context of formulating self evaluation biases. PMID- 28725208 TI - Aldo van Eyck's Playgrounds: Aesthetics, Affordances, and Creativity. AB - After World War II, the Dutch architect Aldo van Eyck developed hundreds of playgrounds in the city of Amsterdam. These public playgrounds were located in parks, squares, and derelict sites, and consisted of minimalistic aesthetic play equipment that was supposed to stimulate the creativity of children. Over the last decades, these playgrounds have been studied by sociologists, theorists of art and architecture, and psychologists. Adopting an ecological approach to the human environment, it is argued that the abstract forms of van Eyck's play sculptures indeed stimulate the creativity of the child. Whereas a slide or a swing almost dictates what a child is supposed to do, van Eyck's play equipment invites the child to actively explore the numerous affordances (action possibilities) it provided. However, it is argued that the standardization (e.g., equal distances between blocks or bars) that tends to characterize van Eyck' play equipment has negative effects on the playability. This standardization, which was arguably the result of the aesthetic motives of the designer, might be appealing to children when simply looking at the equipment, but it is not of overriding importance to them when playing in it. Indeed, a recent study indicates that the affordances provided by messy structures appear to have a greater appeal to playing children. PMID- 28725209 TI - A National Early Intervention System as a Strategy to Promote Inclusion and Academic Achievement in Portugal. AB - Early intervention with children at risk or facing developmental problems is a practice defined by three fundamental characteristics: being family-centered, being based on the community and on the child's life context, and being conducted by a team with transdisciplinary practice. In this paper we wish to present how the SNIPI-National System of Early Intervention, implemented in Portugal over the past 15 years, contributes to promote maximum development and the full inclusion of children up to 6 years of age and works to prevent school failure. The SNIPI covers the entire territory and intends to respond to the needs of children with developmental disorders or those in at risk situations. This community-based early intervention model is linked to the health, education and social care systems, involving the three responsible Ministries. In the present community case study, we present the implementation of this program in the Alentejo region, involving 31 local teams and almost 2500 children. Through the regional structure's reports and the responses of parents and professionals in impact studies, we demonstrate how the system is established and how it tackles school failure and improves the educational inclusion of these children. The impact of this Early Intervention model has been significant not only on children's developmental outcomes, but also for the health, education and social care professionals who work in a transdisciplinary perspective, as well as for the families who became more skilled at evaluating the children's needs and the support provided. This approach to implementing a family-centered Early Intervention program can contribute to full inclusion. It facilitates the transition to schooling based on a non-discriminatory approach and educational achievement by aiding development and an adapted contextualization in pre-school education. This program system introduces significant innovation within the framework of existing educational policies that promote development and inclusion, and has therefore earned the interest of the scientific community and policy-makers alike. It has been possible to implement some of principles already studied but it had never been tested. The Early Intervention program in Alentejo, as part of the SNIPI, can be an example of good practices, with its own characteristics that allowed to create a network of integrated and comprehensive responses to the needs of the population in this region. PMID- 28725210 TI - Multicenter Analytical Validation of Abeta40 Immunoassays. AB - BACKGROUND: Before implementation in clinical practice, biomarker assays need to be thoroughly analytically validated. There is currently a strong interest in implementation of the ratio of amyloid-beta peptide 1-42 and 1-40 (Abeta42/Abeta40) in clinical routine. Therefore, in this study, we compared the analytical performance of six assays detecting Abeta40 in cerebrospinal fluid (CSF) in six laboratories according to a recently standard operating procedure (SOP) developed for implementation of ELISA assays for clinical routine. METHODS: Abeta40 assays of six vendors were validated in up to three centers per assay according to recently proposed international consensus validation protocols. The performance parameters included sensitivity, precision, dilutional linearity, recovery, and parallelism. Inter-laboratory variation was determined using a set of 20 CSF samples. In addition, test results were used to critically evaluate the SOPs that were used to validate the assays. RESULTS: Most performance parameters of the different Abeta40 assays were similar between labs and within the predefined acceptance criteria. The only exceptions were the out-of-range results of recovery for the majority of experiments and of parallelism by three laboratories. Additionally, experiments to define the dilutional linearity and hook-effect were not executed correctly in part of the centers. The inter laboratory variation showed acceptable low levels for all assays. Absolute concentrations measured by the assays varied by a factor up to 4.7 for the extremes. CONCLUSION: All validated Abeta40 assays appeared to be of good technical quality and performed generally well according to predefined criteria. A novel version of the validation SOP is developed based on these findings, to further facilitate implementation of novel immunoassays in clinical practice. PMID- 28725212 TI - Neurochemical Systems of the Retina Involved in the Control of Movement. AB - Recent studies have revealed that the retina may exert control over deep brain function and may be importantly involved in the etiology, progression, and treatment of disorders such as Parkinson's disease (PD). While such a concept is uncharted territory and even less is known about the mechanism by which this might be achieved, this study was undertaken to determine how retinal dopamine (DA), serotonin (5-HT), and melatonin (MEL) neurotransmitter systems might be involved in the control of movement in their own right. To explore these further, intravitreal (IVIT) injections of DA, 5-HT, and MEL were made 0.5 or 3 h prior to testing horizontal and vertical movement in the open field as well as assessment on three motor tests used routinely to evaluate movement as a preclinical model of PD. The doses of DA (2 ul of 25 and 75 ug/ul), 5-HT (2 ul of 5 and 15 ug/ul), and MEL (2 ul of 5 ug/ul) were chosen because of previous work demonstrating an anatomically precise effect of these transmitters after they were injected directly into the brain. The postinjection times of testing were also chosen on the basis of previous intracerebral and IVIT work intimating the importance of the circadian cycle in determining the efficacy of such effects. 0.5 h after IVIT injection of DA at the 25 and 75 ug/ul doses, significant inhibition of motor function was observed. While IVIT injection of 10 or 30 ug of 5-HT also inhibited motor performance, this was significantly less than that seen with DA. In fact, IVIT injection increases motor performance compared to vehicle injection on some parameters. The IVIT injection of 10 ug of MEL facilitated motor function on many parameters compared to DA, 5-HT, and vehicle injection. When rats were tested 3 h after IVIT injection, the inhibition of vertical movement was also observed compared to controls. The present results illustrate that specific retinal neurotransmitter systems participate in the normal control of bodily motor function. The possible involvement of these systems in movement disorders such as PD is the subject of ongoing research. PMID- 28725211 TI - Critical Evaluation of the Lund Concept for Treatment of Severe Traumatic Head Injury, 25 Years after Its Introduction. AB - When introduced in 1992, the Lund concept (LC) was the first complete guideline for treatment of severe traumatic brain injury (s-TBI). It was a theoretical approach, based mainly on general physiological principles-i.e., of brain volume control and optimization of brain perfusion and oxygenation of the penumbra zone. The concept gave relatively strict outlines for cerebral perfusion pressure, fluid therapy, ventilation, sedation, nutrition, the use of vasopressors, and osmotherapy. The LC strives for treatment of the pathophysiological mechanisms behind symptoms rather than just treating the symptoms. The treatment is standardized, with less need for individualization. Alternative guidelines published a few years later (e.g., the Brain Trauma Foundation guidelines and European guidelines) were mainly based on meta-analytic approaches from clinical outcome studies and to some extent from systematic reviews. When introduced, they differed extensively from the LC. We still lack any large randomized outcome study comparing the whole concept of BTF guidelines with other guidelines including the LC. From that point of view, there is limited clinical evidence favoring any of the s-TBI guidelines used today. In principle, the LC has not been changed since its introduction. Some components of the alternative guidelines have approached those in the LC. In this review, I discuss some important principles of brain hemodynamics that have been lodestars during formulation of the LC. Aspects of ventilation, nutrition, and temperature control are also discussed. I critically evaluate the most important components of the LC 25 years after its introduction, based on hemodynamic principles and on the results of own an others experimental and human studies that have been published since then. PMID- 28725213 TI - Can Brain Natriuretic Peptides and Osteoprotegerin Serve As Biochemical Markers for the Detection of Aortic Pathology in Children and Adolescents with Turner Syndrome? AB - Turner syndrome (TS) is a chromosomal disorder that affects 1:2,000 females. It results from either the complete or partial loss of the X chromosome as well as other aberrations. Clinical features of TS include short stature, delayed puberty, and congenital cardiac malformations. TS children also have an increased prevalence of cardiometabolic risk factors, which predisposes them to complications like coronary artery disease, cerebrovascular-related deaths, and aortic dissection. Early cardiac imaging, such as echocardiography and cardiac magnetic resonance imaging, are recommended to detect underlying aortic pathology. However, these modalities are limited by cost, accessibility, and are operator dependent. In view of these shortcomings, alternative methods, like vascular biomarkers, are currently being explored. There are only a few studies that have examined the relationship between B-type natriuretic peptide (BNP), N terminal pro BNP (NT pro-BNP), and osteoprotegerin (OPG) and aortic disease in TS, and thus the data are only in proof-of-concept stages. Further meticulous longitudinal studies are required before BNP, NT pro-BNP, and OPG are used as vascular biomarkers for the detection of aortic disease in childhood and adolescent TS. PMID- 28725214 TI - Is There a Therapeutic Window for Metabolism-Based Cancer Therapies? PMID- 28725215 TI - Prolyl Hydroxylase Domain-2 Inhibition Improves Skeletal Muscle Regeneration in a Male Murine Model of Obesity. AB - Obesity leads to a loss of muscle mass and impaired muscle regeneration. In obese individuals, pathologically elevated levels of prolyl hydroxylase domain enzyme 2 (PHD2) limit skeletal muscle hypoxia-inducible factor-1 alpha and vascular endothelial growth factor (VEGF) expression. Loss of local VEGF may further impair skeletal muscle regeneration. We hypothesized that PHD2 inhibition would restore vigorous muscle regeneration in a murine model of obesity. Adult (22-week old) male mice were fed either a high-fat diet (HFD), with 60% of calories derived from fat, or a regular diet (RD), with 10% of calories derived from fat, for 16 weeks. On day 5 following cryoinjury to the tibialis anterior muscle, newly regenerated muscle fiber cross-sectional areas were significantly smaller in mice fed an HFD as compared to RD, indicating an impaired regenerative response. Cryoinjured gastrocnemius muscles of HFD mice also showed elevated PHD2 levels (twofold higher) and reduced VEGF levels (twofold lower) as compared to RD. Dimethyloxalylglycine, a cell permeable competitive inhibitor of PHD2, restored VEGF levels and significantly improved regenerating myofiber size in cryoinjured mice fed an HFD. We conclude that pathologically increased PHD2 in the obese state drives impairments in muscle regeneration, in part by blunting VEGF production. Inhibition of PHD2 over activity in the obese state normalizes VEGF levels and restores muscle regenerative potential. PMID- 28725216 TI - Survey of Antibiotic-producing Bacteria Associated with the Epidermal Mucus Layers of Rays and Skates. AB - Elasmobranchs represent a distinct group of cartilaginous fishes that harbor a remarkable ability to heal wounds rapidly and without infection. To date very little work has addressed this phenomenon although it is suggested that antibiotic capabilities associated with epidermal surfaces may be a factor. The study of benefits derived from mutualistic interactions between unicellular and multicellular organisms is a rapidly growing area of research. Here we survey and identify bacterial associates of three ray and one skate species in order to assess the potential for antibiotic production from elasmobranch associated bacteria as a novel source for new antibiotics. PMID- 28725218 TI - All New Faces of Diatoms: Potential Source of Nanomaterials and Beyond. AB - Nature's silicon marvel, the diatoms have lately astounded the scientific community with its intricate designs and lasting durability. Diatoms are a major group of phytoplanktons involved in the biogeochemical cycling of silica and are virtually inherent in every environment ranging from water to ice to soil. The usage of diatoms has proved prudently cost effective and its handling neither requires costly materials nor sophisticated instruments. Diatoms can easily be acquired from the environment, their culture requires ambient condition and does not involve any costly media or expensive instruments, besides, they can be transported in small quantities and proliferated to a desirable confluence from that scratch, thus are excellent cost effective industrial raw material. Naturally occurring diatom frustules are a source of nanomaterials. Their silica bio-shells have raised curiosity among nanotechnologists who hope that diatoms will facilitate tailoring minuscule structures which are beyond the capabilities of material scientists. Additionally, there is a colossal diversity in the dimensions of diatoms as the frustule shape differs from species to species; this provides a scope for the choice of a particular species of diatom to be tailored to an exacting requisite, thus paving the way to create desired three dimensional nanocomposites. The present article explores the use of diatoms in various arenas of science, may it be in nanotechnology, biotechnology, environmental science, biophysics or biochemistry and summarizes facets of diatom biology under one umbrella. Special emphasis has been given to biosilicification, biomineralization and use of diatoms as nanomaterials', drug delivery vehicles, optical and immune biosensors, filters, immunodiagnostics, aquaculture feeds, lab-on-a-chip, metabolites, and biofuels. PMID- 28725217 TI - Metagenomics: The Next Culture-Independent Game Changer. AB - A trend towards the abandonment of obtaining pure culture isolates in frontline laboratories is at a crossroads with the ability of public health agencies to perform their basic mandate of foodborne disease surveillance and response. The implementation of culture-independent diagnostic tests (CIDTs) including nucleic acid and antigen-based assays for acute gastroenteritis is leaving public health agencies without laboratory evidence to link clinical cases to each other and to food or environmental substances. This limits the efficacy of public health epidemiology and surveillance as well as outbreak detection and investigation. Foodborne outbreaks have the potential to remain undetected or have insufficient evidence to support source attribution and may inadvertently increase the incidence of foodborne diseases. Next-generation sequencing of pure culture isolates in clinical microbiology laboratories has the potential to revolutionize the fields of food safety and public health. Metagenomics and other 'omics' disciplines could provide the solution to a cultureless future in clinical microbiology, food safety and public health. Data mining of information obtained from metagenomics assays can be particularly useful for the identification of clinical causative agents or foodborne contamination, detection of AMR and/or virulence factors, in addition to providing high-resolution subtyping data. Thus, metagenomics assays may provide a universal test for clinical diagnostics, foodborne pathogen detection, subtyping and investigation. This information has the potential to reform the field of enteric disease diagnostics and surveillance and also infectious diseases as a whole. The aim of this review will be to present the current state of CIDTs in diagnostic and public health laboratories as they relate to foodborne illness and food safety. Moreover, we will also discuss the diagnostic and subtyping utility and concomitant bias limitations of metagenomics and comparable detection techniques in clinical microbiology, food and public health laboratories. Early advances in the discipline of metagenomics, however, have indicated noteworthy challenges. Through forthcoming improvements in sequencing technology and analytical pipelines among others, we anticipate that within the next decade, detection and characterization of pathogens via metagenomics-based workflows will be implemented in routine usage in diagnostic and public health laboratories. PMID- 28725219 TI - Gut Microbiota Co-microevolution with Selection for Host Humoral Immunity. AB - To explore coevolution between the gut microbiota and the humoral immune system of the host, we used chickens as the model organism. The host populations were two lines (HAS and LAS) developed from a common founder that had undergone 40 generations of divergent selection for antibody titers to sheep red blood cells (SRBC) and two relaxed sublines (HAR and LAR). Analysis revealed that microevolution of host humoral immunity contributed to the composition of gut microbiota at the taxa level. Relaxing selection enriched some microorganisms whose functions were opposite to host immunity. Particularly, Ruminococcaceae and Oscillospira enriched in high antibody relaxed (HAR) and contributed to reduction in antibody response, while Lactobacillus increased in low antibody relaxed (LAR) and elevated the antibody response. Microbial functional analysis showed that alterations were involved in pathways relating to the immune system and infectious diseases. Our findings demonstrated co-microevolution relationships of host-microbiota and that gut microorganisms influenced host immunity. PMID- 28725220 TI - A Novel Derivative of (-)mycousnine Produced by the Endophytic Fungus Mycosphaerella nawae, Exhibits High and Selective Immunosuppressive Activity on T Cells. AB - An endophytic fungus, Mycosphaerella nawae ZJLQ129, was isolated from the leaves of the traditional Chinese medicine Smilax china. From the fermentation broth and mycelium, a dibenzofurane compound (-)mycousnine (1) was isolated. Chemical modification of it to the amide derivative (-)mycousnine enamine (2), which is new to science, was found to have high and selective immunosuppressive activity: similar to cyclosporin A, (-)mycousnine enamine (2) selectively inhibited T cell proliferation, suppressed the expression of the surface activation antigens CD25 and CD69 and the formation and expression of the cytokines interleukin-2 as well as interferon gamma in activated T cells, but did not show any effect on the proliferation of B cells and cancer cells (PANC-1 and A549) and the activation of macrophages. Furthermore, the cytotoxicity of (-)mycousnine enamine was lower than that of cyclosporin A, and its therapeutic index (TC50/EC50) was 4,463.5, which is five-fold higher than that of cyclosporin A. We conclude that ( )mycousnine enamine (2), the semi-synthestic product prepared from the native product (-)mycousnine (1) of the endophyte M. nawae is a novel effective immunosuppressant showing low toxicity and high selectivity. PMID- 28725221 TI - Cell Surface Glycosylation Is Required for Efficient Mating of Haloferax volcanii. AB - Halophilic archaea use a fusion-based mating system for lateral gene transfer across cells, yet the molecular mechanisms involved remain unknown. Previous work implied that cell fusion involves cell-cell recognition since fusion occurs more efficiently between cells from the same species. Long believed to be restricted only to Eukarya, it is now known that cells of all three domains of life perform N-glycosylation, the covalent attachment of glycans to select target asparagine residues in proteins, and that this post-translational modification is common for archaeal cell surface proteins. Here, we show that differences in glycosylation of the Haloferax volcanii surface-layer glycoprotein, brought about either by changing medium salinity or by knocking out key glycosylation genes, reduced mating success. Thus, different glycosylation patterns are likely to underlie mating preference in halophilic archaea, contributing to speciation processes. PMID- 28725222 TI - Neuronal Surface Autoantibodies in Neuropsychiatric Disorders: Are There Implications for Depression? AB - Autoimmune diseases are affecting around 7.6-9.4% of the general population. A number of central nervous system disorders, including encephalitis and severe psychiatric disorders, have been demonstrated to associate with specific neuronal surface autoantibodies (NSAbs). It has become clear that specific autoantibodies targeting neuronal surface antigens and ion channels could cause severe mental disturbances. A number of studies have focused or are currently investigating the presence of autoantibodies in specific mental conditions such as schizophrenia and bipolar disorders. However, less is known about other conditions such as depression. Depression is a psychiatric disorder with complex etiology and pathogenesis. The diagnosis criteria of depression are largely based on symptoms but not on the origin of the disease. The question which arises is whether in a subgroup of patients with depression, the symptoms might be caused by autoantibodies targeting membrane-associated antigens. Here, we describe how autoantibodies targeting membrane proteins and ion channels cause pathological effects. We discuss the physiology of these antigens and their role in relation to depression. Finally, we summarize a number of studies detecting NSAbs with a special focus on cohorts that include depression diagnosis and/or show depressive symptoms. PMID- 28725223 TI - Gas Exchange Disturbances Regulate Alveolar Fluid Clearance during Acute Lung Injury. AB - Disruption of the alveolar-capillary barrier and accumulation of pulmonary edema, if not resolved, result in poor alveolar gas exchange leading to hypoxia and hypercapnia, which are hallmarks of acute lung injury and the acute respiratory distress syndrome (ARDS). Alveolar fluid clearance (AFC) is a major function of the alveolar epithelium and is mediated by the concerted action of apically located Na+ channels [epithelial Na+ channel (ENaC)] and the basolateral Na,K ATPase driving vectorial Na+ transport. Importantly, those patients with ARDS who cannot clear alveolar edema efficiently have worse outcomes. While hypoxia can be improved in most cases by O2 supplementation and mechanical ventilation, the use of lung protective ventilation settings can lead to further CO2 retention. Whether the increase in CO2 concentrations has deleterious or beneficial effects have been a topic of significant controversy. Of note, both low O2 and elevated CO2 levels are sensed by the alveolar epithelium and by distinct and specific molecular mechanisms impair the function of the Na,K-ATPase and ENaC thereby inhibiting AFC and leading to persistence of alveolar edema. This review discusses recent discoveries on the sensing and signaling events initiated by hypoxia and hypercapnia and the relevance of these results in identification of potential novel therapeutic targets in the treatment of ARDS. PMID- 28725224 TI - Nanobody Technology: A Versatile Toolkit for Microscopic Imaging, Protein-Protein Interaction Analysis, and Protein Function Exploration. AB - Over the last two decades, nanobodies or single-domain antibodies have found their way in research, diagnostics, and therapy. These antigen-binding fragments, derived from Camelid heavy chain only antibodies, possess remarkable characteristics that favor their use over conventional antibodies or fragments thereof, in selected areas of research. In this review, we assess the current status of nanobodies as research tools in diverse aspects of fundamental research. We discuss the use of nanobodies as detection reagents in fluorescence microscopy and focus on recent advances in super-resolution microscopy. Second, application of nanobody technology in investigating protein-protein interactions is reviewed, with emphasis on possible uses in mass spectrometry. Finally, we discuss the potential value of nanobodies in studying protein function, and we focus on their recently reported application in targeted protein degradation. Throughout the review, we highlight state-of-the-art engineering strategies that could expand nanobody versatility and we suggest future applications of the technology in the selected areas of fundamental research. PMID- 28725226 TI - JNK Pathway-Associated Phosphatase/DUSP22 Suppresses CD4+ T-Cell Activation and Th1/Th17-Cell Differentiation and Negatively Correlates with Clinical Activity in Inflammatory Bowel Disease. AB - This study aimed to investigate the role of JNK pathway-associated phosphatase (JKAP) in inflammatory bowel disease (IBD). JKAP expression was analyzed in the intestinal mucosa of 81 IBD patients and 25 healthy controls (HCs) by qPCR and immunoblotting. The correlations of JKAP with clinical activity and inflammatory cytokines were performed. JKAP expression before and after infliximab treatment was also measured. CD4+ T cells were isolated from peripheral blood in active IBD patient and HCs and transduced with lentivirus-encoding JKAP (LV-JKAP), anti-JKAP (LV-anti-JKAP), or empty vector (LV-scramble), and JKAP functions on IBD CD4+ T cells were subsequently investigated. JKAP expression was decreased in inflamed mucosa of active IBD patients and was negatively correlated with disease activity [Crohn's disease activity index (CDAI), Mayo index, C-reactive protein, and erythrocyte sedimentation rate], interleukin-17, and tumor necrosis factor (TNF) alpha levels. Anti-TNF-alpha treatment up-regulated JKAP expression in CD patients, and baseline JKAP expression was elevated in response patients than in failure patients. Transduction of LV-JKAP into CD4+ T cells inhibited the percentages of CD25+ and CD69+ cells and proliferation. Moreover, inhibition of JKAP promotes Th1/Th17 cell differentiation. Our data indicated that the decreased expression of JKAP in intestinal mucosa contributed to the pathogenesis of IBD, through facilitating CD4+ T-cell activation, proliferation, and Th1/Th17 cell differentiation. PMID- 28725227 TI - Foliar delta13C Showed No Altitudinal Trend in an Arid Region and Atmospheric Pressure Exerted a Negative Effect on Plant delta13C. AB - Previous studies have suggested foliar delta13C generally increases with altitude. However, some observations reported no changes or even decreased trends in foliar delta13C. We noted that all the studies in which delta13C increased with elevation were conducted in the human regions, whereas those investigations in which delta13C did not vary or decreased were conducted in areas with water stress. Thus, we proposed that the pattern of increasing delta13C with elevation is not a general one, and that delta13C may remain unchanged or decrease in plants grown in arid environments. To test the hypothesis, we sampled plants along altitude gradients on the shady and sunny slopes of Mount Tianshan characterized by arid and semiarid climates. The measurements of foliar delta13C showed no altitudinal trends for the plants grown on either of the slopes. Therefore, this study supported our hypothesis. In addition, the present study addressed the effect of atmospheric pressure on plant delta13C by accounting for the effects of temperature and precipitation on delta13C. This study found that the residual foliar delta13C increased with increasing altitude, suggesting that atmospheric pressure played a negative role in foliar delta13C. PMID- 28725225 TI - Antiviral Functions of Human Immunodeficiency Virus Type 1 (HIV-1)-Specific IgG Antibodies: Effects of Antiretroviral Therapy and Implications for Therapeutic HIV-1 Vaccine Design. AB - Contemporary antiretroviral therapy (ART) is effective and tolerable for long periods of time but cannot eradicate human immunodeficiency virus type 1 (HIV-1) infection by either elimination of viral reservoirs or enhancement of HIV-1 specific immune responses. Boosting "protective" HIV-1-specific immune responses by active or passive immunization will therefore be necessary to control or eradicate HIV-1 infection and is currently the topic of intense investigation. Recently reported studies conducted in HIV patients and non-human primate (NHP) models of HIV-1 infection suggest that HIV-1-specific IgG antibody responses may contribute to the control of HIV-1 infection. However, production of IgG antibodies with virus neutralizing activity by vaccination remains problematic and while vaccine-induced natural killer cell-activating IgG antibodies have been shown to prevent the acquisition of HIV-1 infection, they may not be sufficient to control or eradicate established HIV-1 infection. It is, therefore, important to consider other functional characteristics of IgG antibody responses. IgG antibodies to viruses also mediate opsonophagocytic antibody responses against virions and capsids that enhance the function of phagocytic cells playing critical roles in antiviral immune responses, particularly conventional dendritic cells and plasmacytoid dendritic cells. Emerging evidence suggests that these antibody functions might contribute to the control of HIV-1 infection. In addition, IgG antibodies contribute to the intracellular degradation of viruses via binding to the cytosolic fragment crystallizable (Fc) receptor tripartite motif containing-21 (TRIM21). The functional activity of an IgG antibody response is influenced by the IgG subclass content, which affects binding to antigens and to Fcgamma receptors on phagocytic cells and to TRIM21. The IgG subclass content and avidity of IgG antibodies is determined by germinal center (GC) reactions in follicles of lymphoid tissue. As HIV-1 infects cells in GCs and induces GC dysfunction, which may persist during ART, strategies for boosting HIV-1-specific IgG antibody responses should include early commencement of ART and possibly the use of particular antiretroviral drugs to optimize drug levels in lymphoid follicles. Finally, enhancing particular functions of HIV-1-specific IgG antibody responses by using adjuvants or cytokines to modulate the IgG subclass content of the antibody response might be investigated in NHP models of HIV-1 infection and during trials of therapeutic vaccines in HIV patients. PMID- 28725228 TI - Unraveling the Photoprotective Response of Lichenized and Free-Living Green Algae (Trebouxiophyceae, Chlorophyta) to Photochilling Stress. AB - Lichens and free-living terrestrial algae are widespread across many habitats and develop successfully in ecosystems where a cold winter limits survival. With the goal of comparing photoprotective responses in free-living and lichenized algae, the physiological responses to chilling and photochilling conditions were studied in three lichens and their isolated algal photobionts together as well as in a fourth free-living algal species. We specifically addressed the following questions: (i) Are there general patterns of acclimation in green algae under chilling and photochilling stresses? (ii) Do free-living algae exhibit a similar pattern of responses as their lichenized counterparts? (iii) Are these responses influenced by the selection pressure of environmental conditions or by the phylogenetic position of each species? To answer these questions, photosynthetic fluorescence measurements as well as pigment and low molecular weight carbohydrate pool analyses were performed under controlled laboratory conditions. In general, photochemical efficiency in all free-living algae decreased with increasing duration of the stress, while the majority of lichens maintained an unchanged photochemical activity. Nevertheless, these patterns cannot be generalized because the alga Trebouxia arboricola and the lichen Ramalina pollinaria (associated with Trebouxia photobionts) both showed a similar decrease in photochemical efficiency. In contrast, in the couple Elliptochloris bilobata Baeomyces rufus, only the algal partner exhibited a broad physiological performance under stress. This study also highlights the importance of the xanthophyll cycle in response to the studied lichens and algae to photochilling stress, while the accumulation of sugars was not related to cold acclimation, except in the alga E. bilobata. The differences in response patterns detected among species can be mainly explained by their geographic origin, although the phylogenetic position should also be considered, especially in some species. PMID- 28725229 TI - The Synergistic Priming Effect of Exogenous Salicylic Acid and H2O2 on Chilling Tolerance Enhancement during Maize (Zea mays L.) Seed Germination. AB - Chilling stress is an important constraint for maize seedling establishment in the field. To examine the role of salicylic acid (SA) and hydrogen peroxide (H2O2) in response to chilling stress, we investigated the effects of seed priming with SA, H2O2, and SA+H2O2 combination on maize resistance under chilling stress (13 degrees C). Priming with SA, H2O2, and especially SA+H2O2 shortened seed germination time and enhanced seed vigor and seedling growth as compared with hydropriming and non-priming treatments under low temperature. Meanwhile, SA+H2O2 priming notably increased the endogenous H2O2 and SA content, antioxidant enzymes activities and their corresponding genes ZmPAL, ZmSOD4, ZmAPX2, ZmCAT2, and ZmGR expression levels. The alpha-amylase activity was enhanced to mobilize starch to supply metabolites such as soluble sugar and energy for seed germination under chilling stress. In addition, the SA+H2O2 combination positively up-regulated expressions of gibberellic acid (GA) biosynthesis genes ZmGA20ox1 and ZmGA3ox2, and down-regulated GA catabolism gene ZmGA2ox1 expression; while it promoted GA signaling transduction genes expressions of ZmGID1 and ZmGID2 and decreased the level of seed germination inhibitor gene ZmRGL2. The abscisic acid (ABA) catabolism gene ZmCYP707A2 and the expressions of ZmCPK11 and ZmSnRK2.1 encoding response receptors in ABA signaling pathway were all up-regulated. These results strongly suggested that priming with SA and H2O2 synergistically promoted hormones metabolism and signal transduction, and enhanced energy supply and antioxidant enzymes activities under chilling stress, which were closely relevant with chilling injury alleviation and chilling tolerance improvement in maize seed. Highlights:Seed germination and seedling growth were significantly improved under chilling stress by priming with SA+H2O2 combination, which was closely relevant with the change of reactive oxygen species, metabolites and energy supply, hormones metabolism and regulation. PMID- 28725230 TI - Genetics and Genomics of Cotton Leaf Curl Disease, Its Viral Causal Agents and Whitefly Vector: A Way Forward to Sustain Cotton Fiber Security. AB - Cotton leaf curl disease (CLCuD) after its first epidemic in 1912 in Nigeria, has spread to different cotton growing countries including United States, Pakistan, India, and China. The disease is of viral origin-transmitted by the whitefly Bemisia tabaci, which is difficult to control because of the prevalence of multiple virulent viral strains or related species. The problem is further complicated as the CLCuD causing virus complex has a higher recombination rate. The availability of alternate host crops like tomato, okra, etc., and practicing mixed type farming system have further exaggerated the situation by adding synergy to the evolution of new viral strains and vectors. Efforts to control this disease using host plant resistance remained successful using two gene based resistance that was broken by the evolution of new resistance breaking strain called Burewala virus. Development of transgenic cotton using both pathogen and non-pathogenic derived approaches are in progress. In future, screening for new forms of host resistance, use of DNA markers for the rapid incorporation of resistance into adapted cultivars overlaid with transgenics and using genome editing by CRISPR/Cas system would be instrumental in adding multiple layers of defense to control the disease-thus cotton fiber production will be sustained. PMID- 28725232 TI - Transcriptome-Wide Identification of Differentially Expressed Genes in Solanum lycopersicon L. in Response to an Alfalfa-Protein Hydrolysate Using Microarrays. AB - An alfalfa-based protein hydrolysate (EM) has been tested in tomato (Solanum lycopersicon L.) plants at two different concentrations (0.1 and 1 mL L-1) to get insight on its efficacy as biostimulant in this species and to unravel possible metabolic targets and molecular mechanisms that may shed light on its mode of action. EM was efficient in promoting the fresh biomass and content in chlorophyll and soluble sugars of tomato plants, especially when it was applied at the concentration of 1 mL L-1. This effect on plant productivity was likely related to the EM-dependent up-regulation of genes identified via microarray and involved in primary carbon and nitrogen metabolism, photosynthesis, nutrient uptake and developmental processes. EM also up-regulated a number of genes implied in the secondary metabolism that leads to the synthesis of compounds (phenols and terpenes) functioning in plant development and interaction with the environment. Concomitantly, phenol content was enhanced in EM-treated plants. Several new genes have been identified in tomato as potential targets of EM action, like those involved in detoxification processes from reactive oxygen species and xenobiotic (particularly glutathione/ascorbate cycle-related and ABC transporters), and defense against abiotic and biotic stress. The model hypothesized is that elicitors present in the EM formulation like auxins, phenolics, and amino acids, may trigger a signal transduction pathway via modulation of the intracellular levels of the hormones ethylene, jasmonic acid and abscissic acid, which then further prompt the activation of a cascade events requiring the presence and activity of many kinases and transcription factors to activate stress-related genes. The genes identified suggest these kinases and transcription factors as players involved in a complex crosstalk between biotic and abiotic stress signaling pathways. We conclude that EM acts as a biostimulant in tomato due to its capacity to stimulate plant productivity and up-regulate stress-related responses. Its use in agricultural practices may reduce the need of inorganic fertilizers and pesticides, thereby reducing the environmental impact of productive agriculture. PMID- 28725231 TI - Chloroplast Redox Status Modulates Genome-Wide Plant Responses during the Non host Interaction of Tobacco with the Hemibiotrophic Bacterium Xanthomonas campestris pv. vesicatoria. AB - Non-host resistance is the most ample and durable form of plant resistance against pathogen infection. It includes induction of defense-associated genes, massive metabolic reprogramming, and in many instances, a form of localized cell death (LCD) at the site of infection, purportedly designed to limit the spread of biotrophic and hemibiotrophic microorganisms. Reactive oxygen species (ROS) have been proposed to act as signals for LCD orchestration. They are produced in various cellular compartments including chloroplasts, mitochondria and apoplast. We have previously reported that down-regulation of ROS build-up in chloroplasts by expression of a plastid-targeted flavodoxin (Fld) suppressed LCD in tobacco leaves inoculated with the non-host bacterium Xanthomonas campestris pv. vesicatoria (Xcv), while other defensive responses were unaffected, suggesting that chloroplast ROS and/or redox status play a major role in the progress of LCD. To better understand these effects, we compare here the transcriptomic alterations caused by Xcv inoculation on leaves of Fld-expressing tobacco plants and their wild-type siblings. About 29% of leaf-expressed genes were affected by Xcv and/or Fld. Surprisingly, 5.8% of them (1,111 genes) were regulated by Fld in the absence of infection, presumably representing pathways responsive to chloroplast ROS production and/or redox status during normal growth conditions. While the majority (~75%) of pathogen-responsive genes were not affected by Fld, many Xcv responses were exacerbated, attenuated, or regulated in opposite direction by expression of this protein. Particularly interesting was a group of 384 genes displaying Xcv responses that were already triggered by Fld in the absence of infection, suggesting that the transgenic plants had a larger and more diversified suite of constitutive defenses against the attacking microorganism compared to the wild type. Fld modulated many genes involved in pathogenesis, signal transduction, transcriptional regulation and hormone-based pathways. Remarkable interactions with proteasomal protein degradation were observed. The results provide the first genome-wide, comprehensive picture illustrating the relevance of chloroplast redox status in biotic stress responses. PMID- 28725233 TI - G Quadruplex in Plants: A Ubiquitous Regulatory Element and Its Biological Relevance. AB - G quadruplexes (G4) are higher-order DNA and RNA secondary structures formed by G rich sequences that are built around tetrads of hydrogen-bonded guanine bases. Potential G4 quadruplex sequences have been identified in G-rich eukaryotic non telomeric and telomeric genomic regions. Upon function, G4 formation is known to involve in chromatin remodeling, gene regulation and has been associated with genomic instability, genetic diseases and cancer progression. The natural role and biological validation of G4 structures is starting to be explored, and is of particular interest for the therapeutic interventions for human diseases. However, the existence and physiological role of G4 DNA and G4 RNA in plants species have not been much investigated yet and therefore, is of great interest for the development of improved crop varieties for sustainable agriculture. In this context, several recent studies suggests that these highly diverse G4 structures in plants can be employed to regulate expression of genes involved in several pathophysiological conditions including stress response to biotic and abiotic stresses as well as DNA damage. In the current review, we summarize the recent findings regarding the emerging functional significance of G4 structures in plants and discuss their potential value in the development of improved crop varieties. PMID- 28725234 TI - Major Novel QTL for Resistance to Cassava Bacterial Blight Identified through a Multi-Environmental Analysis. AB - Cassava, Manihot esculenta Crantz, has been positioned as one of the most promising crops world-wide representing the staple security for more than one billion people mainly in poor countries. Cassava production is constantly threatened by several diseases, including cassava bacterial blight (CBB) caused by Xanthomonas axonopodis pv. manihotis (Xam), it is the most destructive disease causing heavy yield losses. Here, we report the detection and localization on the genetic map of cassava QTL (Quantitative Trait Loci) conferring resistance to CBB. An F1 mapping population of 117 full sibs was tested for resistance to two Xam strains (Xam318 and Xam681) at two locations in Colombia: La Vega, Cundinamarca and Arauca. The evaluation was conducted in rainy and dry seasons and additional tests were carried out under controlled greenhouse conditions. The phenotypic evaluation of the response to Xam revealed continuous variation. Based on composite interval mapping analysis, 5 strain-specific QTL for resistance to Xam explaining between 15.8 and 22.1% of phenotypic variance, were detected and localized on a high resolution SNP-based genetic map of cassava. Four of them show stability among the two evaluated seasons. Genotype by environment analysis detected three QTL by environment interactions and the broad sense heritability for Xam318 and Xam681 were 20 and 53%, respectively. DNA sequence analysis of the QTL intervals revealed 29 candidate defense-related genes (CDRGs), and two of them contain domains related to plant immunity proteins, such as NB-ARC-LRR and WRKY. PMID- 28725235 TI - Gateway-Compatible CRISPR-Cas9 Vectors and a Rapid Detection by High-Resolution Melting Curve Analysis. AB - CRISPR-Cas9 system rapidly became an indispensable tool in plant biology to perform targeted mutagenesis. A CRISPR-Cas9-mediated double strand break followed by non-homologous end joining (NHEJ) repair most frequently results in a single base pair deletion or insertions (indels), which is hard to detect using methods based on enzymes that detect heteroduplex DNA. In addition, somatic tissues of the T1 generation inevitably contain a mosaic population, in which the portion of cells carrying the mutation can be too small to be detected by the enzyme-based methods. Here we report an optimized experimental protocol for detecting Arabidopsis mutants carrying a CRISPR-Cas9 mediated mutation, using high resolution melting (HRM) curve analysis. Single-base pair insertion or deletion (indel) can be easily detected using this method. We have also examined the detection limit for the template containing a one bp indel compared to the WT genome. Our results show that <5% of mutant DNA containing one bp indel can be detected using this method. The vector developed in this study can be used with a Gateway technology-compatible derivative of pCUT vectors, with which off-target mutations could not be detected even by a whole genome sequencing. PMID- 28725236 TI - The Seed Semipermeable Layer and Its Relation to Seed Quality Assessment in Four Grass Species. AB - The existence of a semipermeable layer in grass seeds has been extensively reported, yet knowledge of its influence on tests for seed viability and vigor that depend upon measurement of electrical conductivity (EC) is limited. This study determined the presence and location of the semipermeable layer, and its relation to seed viability and vigor assessment, in seeds of four important grass species-Elymus nutans Griseb., Lolium perenne L., Leymus chinensis (Trin.) Tzvel., and Avena sativa L. Intact seeds of E. nutans, Lolium perenne, and Leymus chinensis exhibited little staining with triphenyl tetrazolium chloride (TTC), and there were no differences in EC between seeds with different germination percentage (GP) (P > 0.05). After piercing the seed coat, however, all three species displayed positive staining with TTC, along with a significant negative correlation between EC and GP (E. nutans: R2 = 0.7708; Lolium perenne: R2= 0.8414; Leymus chinensis: R2 = 0.859; P < 0.01). In contrast, both intact and pierced seeds of A. sativa possessed a permeable seed coat that showed positive staining with TTC and EC values that were significantly negatively correlated with GP [R2 = 0.9071 (intact) and 0.9597 (pierced); P < 0.01]. In commercial seed lots of A. sativa, a field emergence test indicated that EC showed a significant negative correlation with field emergence at two sowing dates (R2= 0.6069, P < 0.01 and 0.5316, P < 0.05). Analysis of seed coat permeability revealed the presence of a semipermeable layer located in the seed coat adjacent to the endosperm in E. nutans, Lolium perenne, and Leymus chinensis; however, no semipermeable layer was observed in A. sativa. This is the first report of the absence of a semipermeable layer in a grass species. The existence of a semipermeable layer is one of the most important factors affecting seed viability and vigor testing (based on EC measurement) in E. nutans, Lolium perenne, and Leymus chinensis. Increasing the permeability of the semipermeable layer, e.g., by piercing the seed coat, may permit the use of EC measurement to assess seed vigor in species that possess such a layer. PMID- 28725237 TI - A Novel Soybean Dirigent Gene GmDIR22 Contributes to Promotion of Lignan Biosynthesis and Enhances Resistance to Phytophthora sojae. AB - Phytophthora root and stem rot caused by the oomycete pathogen Phytophthora sojae is a destructive disease of soybean worldwide. Plant dirigent proteins (DIR) are proposed to have roles in biosynthesis of either lignan or lignin-like molecules, and are important for defense responses, secondary metabolism, and pathogen resistance. In the present work, a novel DIR gene expressed sequence tag is identified as up-regulated in the highly resistant soybean cultivar 'Suinong 10' inoculated with P. sojae. The full length cDNA is isolated using rapid amplification of cDNA ends, and designated GmDIR22 (GenBank accession no. HQ_993047). The full length GmDIR22 is 789 bp and contains a 567 bp open reading frame encoding a polypeptide of 188 amino acids. The sequence analysis indicated that GmDIR22 contains a conserved dirigent domain at amino acid residues 43-187. The quantitative real-time reverse transcription PCR demonstrated that soybean GmDIR22 mRNA is expressed most highly in stems, followed by roots and leaves. The treatments with stresses demonstrated that GmDIR22 is significantly induced by P. sojae and gibberellic acid (GA3), and also responds to salicylic acid, methyl jasmonic acid, and abscisic acid. The GmDIR22 is targeted to the cytomembrane when transiently expressed in Arabidopsis protoplasts. Moreover, The GmDIR22 recombinant protein purified from Escherichia coli could effectively direct E coniferyl alcohol coupling into lignan (+)-pinoresinol. Accordingly, the overexpression of GmDIR22 in transgenic soybean increased total lignan accumulation. Moreover, the lignan extracts from GmDIR22 transgenic plants effectively inhibits P. sojae hyphal growth. Furthermore, the transgenic overexpression of GmDIR22 in the susceptible soybean cultivar 'Dongnong 50' enhances its resistance to P. sojae. Collectively, these data suggested that the primary role of GmDIR22 is probably involved in the regulation of lignan biosynthesis, and which contributes to resistance to P. sojae. PMID- 28725238 TI - A Non-targeted Metabolomics Approach Unravels the VOCs Associated with the Tomato Immune Response against Pseudomonas syringae. AB - Volatile organic compounds (VOCs) emitted by plants are secondary metabolites that mediate the plant interaction with pathogens and herbivores. These compounds may perform direct defensive functions, i.e., acting as antioxidant, antibacterial, or antifungal agents, or indirectly by signaling the activation of the plant's defensive responses. Using a non-targeted GC-MS metabolomics approach, we identified the profile of the VOCs associated with the differential immune response of the Rio Grande tomato leaves infected with either virulent or avirulent strains of Pseudomonas syringae DC3000 pv. tomato. The VOC profile of the tomato leaves infected with avirulent bacteria is characterized by esters of (Z)-3-hexenol with acetic, propionic, isobutyric or butyric acids, and several hydroxylated monoterpenes, e.g., linalool, alpha-terpineol, and 4-terpineol, which defines the profile of an immunized plant response. In contrast, the same tomato cultivar infected with the virulent bacteria strain produced a VOC profile characterized by monoterpenes and SA derivatives. Interestingly, the differential VOCs emission correlated statistically with the induction of the genes involved in their biosynthetic pathway. Our results extend plant defense system knowledge and suggest the possibility for generating plants engineered to over-produce these VOCs as a complementary strategy for resistance. PMID- 28725240 TI - Appraisal of testicular volumes: volumes matching ultrasound values referenced to stages of genital development. AB - BACKGROUND: Testicular volumes obtained with orchidometers or external linear measurements in the scrotum (centimeter ruler or calipers) grossly over-estimate ultrasound volumes, have much variability and may not be accurate or reproducible. The reference of the values obtained by orchidometers or US, to age or Tanner stages is not useful to determine the normal values for stages of puberty, because overlapping of ages and values. Pubertal development is determined by two events, genital and pubic hair development, that should be analyzed independently because one could be out of step with the other. The ultrasound (US) measurement of testicular volumes is the gold standard but is somewhat inconvenient, because it requires another procedure and, mainly, is costly. The solution of the problems would be to determine testicular volumes matching US values, from the width of the testis obtained in the scrotum with a centimeter ruler, by formulas recently described, and to reference them to the stages of genital development. METHODS: The width and length of the testes in the scrotum with a centimeter ruler were obtained in 159 study subjects, in different stages of genital development and adults, for a total of 318 testicular determinations, from the age of 3 to 34 years. The width obtained in the scrotum was corrected by subtracting the values of the double scrotal skin (ss). The formulas were then applied and the testicular volumes matching US values were calculated. The volumes and the range of ages for different stages of genital development were determined. Penile measurements were obtained in 145 subjects and pubic and other hair recorded. Paired and unpaired 2 tail student t-test was used to compare the means of the different groups expressed as means and SD and, in addition the Wilcoxon rank sum test and Bootstrap methods for the testicular volume groups. A p value of 0.05 or less was considered significant. The Institutional Review Board (IRB) of Nationwide Children's Hospital determined that this study did not require IRB approval. RESULTS: With a simple measurement of the width of the testis in the scrotum, with a centimeter ruler, testicular volumes matching US values were calculated and normative values for each stage of genital development were determined. CONCLUSION: This information should solve present problems. PMID- 28725239 TI - An Overview of Judgment and Decision Making Research Through the Lens of Fuzzy Trace Theory. AB - We present the basic tenets of fuzzy trace theory, a comprehensive theory of memory, judgment, and decision making that is grounded in research on how information is stored as knowledge, mentally represented, retrieved from storage, and processed. In doing so, we highlight how it is distinguished from traditional models of decision making in that gist reasoning plays a central role. The theory also distinguishes advanced intuition from primitive impulsivity. It predicts that different sorts of errors occur with respect to each component of judgment and decision making: background knowledge, representation, retrieval, and processing. Classic errors in the judgment and decision making literature, such as risky-choice framing and the conjunction fallacy, are accounted for by fuzzy trace theory and new results generated by the theory contradict traditional approaches. We also describe how developmental changes in brain and behavior offer crucial insight into adult cognitive processing. Research investigating brain and behavior in developing and special populations supports fuzzy trace theory's predictions about reliance on gist processing. PMID- 28725241 TI - miR-378 suppresses the proliferation, migration and invasion of colon cancer cells by inhibiting SDAD1. AB - BACKGROUND: MicroRNAs (miRNAs) play important roles in the growth and metastasis of colon cancer. It is known that one set of miRNAs are dysregulated in colon cancer cells, but the mechanism of their role in cancer development is still largely unknown. Our study focuses on the role of miR-378 in colon cancer cells. METHODS: Human colon cancer tissues and adjacent non-tumor tissues were collected from patients diagnosed in pathological examinations. In addition, human colon cancer cell lines LoVo, CaCo2, SW1116, SW480 and HCT-116, and a normal colonic mucosa cell line NCM460 were included. Quantitative RT-PCR was used to detect the miR-378 level in the clinical tissues and cell lines. In SW480 and HCT-116, miR 378 was artificially overexpressed or suppressed. Cell viability and proliferation were measured using MTT and colony formation assays, and apoptosis was detected via annexin V-PI staining and flow cytometry analysis. The transwell technique was applied to detect the migration and invasion of the colon cancer cells, and their epithelial-mesenchymal transition (EMT) was evaluated by detecting EMT-associated markers using Western blotting. Bioinformatics methods were used to predict the potential targets of miR-378, and luciferase reporter assays were performed to conform the direct binding between miR-378 and its target mRNA. The activity of the Wnt/beta-catenin pathway was evaluated by detecting the key factors through Western blotting. RESULTS: We found that miR 378 expression was low in colon cancer tissues and cell lines. Overexpression of miR-378 not only inhibits the proliferation of colon cancer cells in vitro by inducing apoptosis, but also inhibits migration and invasion by inhibiting the EMT of colon cancer cells. SDAD1 is a direct target gene of miR-378, and knockdown of SDAD1 suppresses the proliferation, migration and invasion of colon cancer cells. We also confirmed that miR-378 alleviated the malignant phenotypes of colon cancer cells by inhibiting the Wnt/beta-catenin pathway. CONCLUSION: miR 378 inhibits the proliferation, migration and invasion of colon cancer cells by targeting SDAD1, defining miR-378 as a potential target for the diagnosis and treatment of colon cancer. PMID- 28725242 TI - Focal application of low-dose-rate brachytherapy for prostate cancer: a pilot study. AB - PURPOSE: To evaluate the feasibility and to report the early outcomes of focal treatment of prostate cancer using low-dose-rate brachytherapy (LDR-PB). MATERIAL AND METHODS: Seventeen patients were screened with multi-parametric magnetic resonance imaging (mpMRI), 14 of whom proceeded to receive trans-perineal template mapping biopsy (TTMB). Focal LDR-PB was performed on five eligible patients using dual air kerma strength treatment plans based on planning target volumes derived from cancer locations and determined by TTMB. Patient follow-up includes prostate specific antigen (PSA) measurements, urinary and sexual function questionnaires, repeated imaging and TTMB at specific intervals post treatment. RESULTS: Feasibility of focal LDR-PB was shown and short-term outcomes are promising. While the detection rate of tumors, a majority of which were low grade GS 3 + 3, was found to be low on mpMRI (sensitivity of 37.5%), our results suggest the potential of mpMRI in detecting the presence of higher grade (GS >= 3 + 4), and bilateral disease indicating its usefulness as a screening tool for focal LDR-PB. CONCLUSIONS: Low-dose-rate brachytherapy is a favorable ablation option for focal treatment of prostate cancer, requiring minimal modification to the standard (whole gland) LDR-PB treatment, and appears to have a more favorable side effect profile. Further investigation, in the form of a larger study, is needed to assess the methods used and the long-term outcomes of focal LDR-PB. PMID- 28725243 TI - Outcomes of salvage high-dose-rate brachytherapy with or without external beam radiotherapy for isolated vaginal recurrence of endometrial cancer. AB - PURPOSE: This study was designed to retrospectively analyze outcomes of high-dose rate (HDR) brachytherapy, with or without external beam radiotherapy (EBRT), in patients with vaginal recurrence of endometrial carcinoma, and to identify factors prognostic of patient outcomes. MATERIAL AND METHODS: The medical records of all patients who underwent HDR brachytherapy for initial recurrence in the vagina of endometrial cancer after definitive surgery between 1992 and 2014 were retrospectively reviewed. All patients underwent either intracavitary brachytherapy (ICBT) or interstitial brachytherapy (ISBT) with or without EBRT. Late toxicity was graded using the EORTC (LENT/SOMA) scale, revised in 1995. RESULTS: Thirty-seven patients were identified. The median follow-up time was 48 months (range: 6-225 months). Of these 37 patients, 23 underwent ICBT, 14 underwent ISBT, and 26 underwent EBRT. Tumor size at first examination of initial relapse was significantly larger in the ISBT than in the ICBT group. The 4-year respective overall survival (OS), local control (LC), and progression-free survival (PFS) rates in the entire cohort were 81.0%, 77.9%, and 56.8%, respectively. The interval between diagnosis of first recurrence and radiotherapy (< 3 months, >= 3 months) was a significant predictor of LC and PFS. OS and LC rates did not differ significantly in the ICBT and ISBT groups. Two patients experienced grade 2 rectal bleeding, and four experienced grade 2 hematuria. No grade 3 or higher late complications were observed. CONCLUSIONS: Salvage HDR brachytherapy is an optimal for treating vaginal recurrence of endometrial carcinoma with acceptable morbidity. Early radiotherapy, including brachytherapy, should be considered for women who experience vaginal recurrence of endometrial cancer. PMID- 28725244 TI - Optimal perioperative anesthesia management for gynecologic interstitial brachytherapy. AB - PURPOSE: To propose an optimal perioperative pain management clinical care pathway for interstitial brachytherapy for gynecologic cancer based on our interdepartmental experience. MATERIAL AND METHODS: We conducted a retrospective review of 23 women who underwent 32 interstitial brachytherapy procedures for gynecological cancers, analyzing patient demographics, type of anesthetic, medications, postoperative pain scores, adverse events, and delays in discharge. We measured the association of postoperative nausea and/or vomiting (PONV) with hydromorphone use, and postoperative pain scores and total narcotic administration with type of anesthesia. RESULTS: In 91% of patients postoperative pain was managed with an epidural infusion plus, as needed (PRN), IV or patient controlled analgesia (PCA) narcotics. The most common postoperative adverse event was PONV (53%), followed by delirium (22%). Hospital discharge was delayed, at least by one night, in 26% of patients. Use of a basal rate on the PCA was associated with all cases of delayed discharge from over-sedation and PONV. The use of 5 mg or more of intravenous (IV) hydromorphone during the first 24-hours postoperatively was associated with PONV (p = 0.01). Use of a basal PCA was associated with delirium (p = 0.03). Postoperative pain scores were not significantly associated with the type of anesthesia. CONCLUSIONS: Interstitial gynecologic brachytherapy requires a multidisciplinary effort for optimal perioperative management. Our study outlines the appropriate preoperative, intraoperative, and postoperative anesthesia clinical care pathway. Decreased narcotic use during hospitalization and utilization of a patient-directed infusion may decrease side effects and allow for a more efficient hospital discharge. PMID- 28725245 TI - The usefulness of fleet rectal enemas on high-dose-rate intracavitary cervical cancer brachytherapy. A prospective trial. AB - PURPOSE: To evaluate the effects of rectal enemas on rectal doses during radical high-dose-rate (HDR) intracavitary cervical brachytherapy (BT). MATERIAL AND METHODS: Twenty patients suffering from cervical cancer and treated with external beam radiotherapy and HDR-BT were included in a prospective trial. The first brachytherapy fraction was considered the basal status, and patients were instructed to self-administer two rectal cleansing enemas before the second fraction. Dose-volume histogram (DVH) values were generated for the rectum and correlated with rectal volume variation. Brachytherapy was carried out with a Fletcher or Utrecht applicator. RESULTS: No significant rectal volume differences were observed between fractions with or without rectal enemas (without, 52.64 +/- 15.92 cc; with, 53.16 +/- 19.28 cc). There was a significant correlation between both rectal volumes (r = 0.722, p = 0.001). No significant differences were observed in analyzed DVH parameters (median values: DeltaD0.1cc, 4.17 vs. 3.61 Gy; DeltaD1cc, 3.23 vs. 2.87 Gy; DeltaD2cc, 2.9 vs. 2.54 Gy; DeltaD5cc, 2.35 vs. 2.05 Gy, for no enema and enema fraction, respectively). No significant rectal volume differences nor DVH parameter differences were observed according the applicator type. CONCLUSIONS: Our rectal enemas protocol prior to HDR-BT was ineffective in significantly modifying rectal DVH parameters. No differences were observed according to the type of applicator used. PMID- 28725246 TI - Effects of vaginal cylinder position on dose distribution in patients with endometrial carcinoma in treatment of vaginal cuff brachytherapy. AB - PURPOSE: To investigate the impact of different cylinder positions on dosimetry of critical structures in patients with endometrial carcinoma undergoing three dimensional image-based vaginal cuff brachytherapy (VCB). MATERIAL AND METHODS: We delivered VCB at a dose of 4 Gy to a depth of 5 mm in the vaginal cuff of 15 patients using three different cylinder positions (neutral [N], parallel [P], and angled [A]) according to the longitudinal axis of the patient. We analyzed the dose-volume distribution and volumetric variability of the rectum and bladder. We converted the total doses to equivalent doses in 2 Gy (EQD2) using a linear quadratic model (a/b = 3 Gy). RESULTS: The mean rectum volume for the N, P, and A positions was 68.2 +/- 22.7 cc, 79.3 +/- 33.7 cc, and 74.2 +/- 29.6 cc, respectively. The mean rectum volume for the P position was significantly larger than that for the N position (p = 0.03). Relative to the N position, the A position resulted in a lower total EQD2 in the highest irradiated 2 cc (D2cc; p = 0.001), 1 cc (D1cc; p = 0.004), and 0.1 cc (D0.1cc; p = 0.047) of the rectum. Similarly, the P position resulted in a lower EQD2 in the D2cc (p = 0.018) and D1cc (p = 0.024) of the rectum relative to the N position. In the bladder, the P position resulted in a higher EQD2 in the D2cc relative to the N position (p = 0.02). There was no dosimetric difference between the P and A positions in either the rectum or the bladder. CONCLUSIONS: Vaginal cuff brachytherapy in the P and A positions is significantly superior to that in the N position in terms of rectum dosimetry. The bladder dose in the N position is considerably lower than that in the other positions. PMID- 28725247 TI - Novel anesthetic technique for combined intracavitary and interstitial brachytherapy for cervix cancer in an outpatient setting. AB - PURPOSE: To determine the feasibility and safety of outpatient combined intracavitary and interstitial brachytherapy for cervix cancer with sedation and local anesthesia. MATERIAL AND METHODS: We included patients diagnosed with non metastatic cervix cancer and have completed brachytherapy between December 2015 and December 2016. Moderate to deep sedation was achieved using intravenous midazolam, propofol, fentanyl, and oxycodone. Local anesthesia was achieved with 2% lignocaine gel and a paracervical block containing a mixture of 1% ropivacaine, 2% lignocaine, and 1 : 1,000 adrenaline. Ceftriaxone and ondansetron were given prophylactically. Physiologic monitoring was performed throughout and pain scores were recorded using the Numeric Rating Scale. Follow-up was conducted at 8 weeks from the last fraction of brachytherapy. The feasibility and safety endpoints were a post-anesthesia discharge score (PADS) of 9 or above, and no grade 3 or above adverse events, respectively. RESULTS: A total of thirty-five brachytherapy insertions were carried out on nine patients. The median age of the patients was 56 years (range, 40-65). Eight patients had American Society of Anesthesiologists' physical status of I or II, and one had a status of III. The mean duration of the insertion was 39 minutes (standard deviation [SD] = 14), during which no adverse events occurred. There was no significant nausea or vomiting post-sedation. The median pain scores post-insertion and during recovery were 0 (range, 0-6) and 0 (range, 0-7), respectively. At discharge, all patients had pain scores of 0 and maximum PADS of 10. The mean time to discharge was 4.1 hours (SD = 0.95). There were no brachytherapy-related admissions or complications. CONCLUSIONS: Outpatient combined intracavitary and interstitial brachytherapy for cervix cancer with sedation and local anesthesia is feasible and safe. This could potentially lead to significant cost savings. PMID- 28725248 TI - Clinical outcomes with high-dose-rate surface mould brachytherapy for intra-oral and skin malignancies involving head and neck region. AB - PURPOSE: The literature and experience of high-dose-rate (HDR) surface mould brachytherapy (SMB) in head and neck cancer is sparse. We report our institutional experience of SMB for such tumours. MATERIAL AND METHODS: Thirty five patients with malignant localized early T1/T2, N0 (21 intra-oral and 14 skin) tumours treated with SMB during 2008-2014 were analyzed. Treatment was delivered using HDR 192Ir source to a median dose of 49 Gy (range, 38.5-52.5 Gy) as radical brachytherapy and 18 Gy (range, 15.5-30 Gy) as boost with 3-4 Gy/fraction twice daily using customized surface mould. RESULTS: Median follow-up was 52 months (range, 6 to 98 months). Local control (LC) for skin tumours and intra-oral malignancies at 5 years were 92% and 76%, respectively. Five-year cause specific survival was 92%. For T1 and T2 tumours, 5 year LC was 94.2% and 68.2%, respectively. T stage (p < 0.04) and dose/fractions (p < 0.003) were the only significant prognostic factors for LC on univariate analysis. CONCLUSIONS: Surface mould brachytherapy results in excellent LC rates for skin tumours and T1 intraoral tumours when considered as radical treatment, and preferable to consider it as a boost for T2 intraoral tumours. Surface mould brachytherapy results in excellent organ and function preservation. PMID- 28725249 TI - Two years results of electronic brachytherapy for basal cell carcinoma. AB - PURPOSE: The use of radiation therapy (RT) for non-melanoma skin cancer (NMSC) has been changing throughout the last century. Over the last decades, the use of radiotherapy has surged with the development of new techniques, applicators, and devices. In recent years, electronic brachytherapy (eBT) devices that use small x ray sources have been introduced as alternative to radionuclide dependence. Nowadays, several devices have been incorporated, with a few series reported, and with a short follow-up, due to the recent introduction of these systems. The purpose of this work is to describe the clinical results of our series after two years follow-up with a specific eBT system. MATERIAL AND METHODS: This is a prospective single-center, non-randomized pilot study, to assess clinical results of electronic brachytherapy in basal cell carcinoma using the Esteya(r) system. In 2014, 40 patients with 60 lesions were treated. Patient follow-up on a regular basis was performed for a period of two years. RESULTS: Twenty-six patients with 44 lesions achieved two years follow-up. A complete response was documented in 95.5% of cases. Toxicity was mild (G1 or G2) in all cases, caused by erythema, erosion, or alopecia. Cosmesis was excellent in 88.6% of cases, and good in the rest. Change in pigmentation was the most frequent cosmetic alteration. CONCLUSIONS: This work is special, since the equipment's treatment voltage was 69.5 kV, and this is the first prospective study with long term follow-up with Esteya(r). These preliminary report show excellent results with less toxicity and excellent cosmesis. While surgery has been the treatment of choice, certain patients might benefit from eBT treatment. These are elderly patients with comorbidities or undergoing anticoagulant treatment as well as those who simply refuse surgery or might have other contraindications. PMID- 28725250 TI - Adjuvant radiotherapy with brachytherapy boost in soft tissue sarcomas. AB - PURPOSE: The standard primary treatment for soft tissue sarcoma (STS) is a wide surgical resection, preceded or followed by radiotherapy. Purpose of this retrospective study was to assess the efficacy of perioperative brachytherapy (BRT) plus postoperative external beam radiation therapy (EBRT) in patients with intermediate-high risk STS. MATERIAL AND METHODS: BRT delivered dose was 20 Gy. External beam radiation therapy was delivered with 3D-technique using multiple beams. The prescribed dose was 46 Gy to the PTV. Neoadjuvant and adjuvant chemotherapy (CHT) was used in patients with potentially chemosensitive histological subtypes. The primary aim of the study was to analyze overall survival (OS) and local control (LC) in a large patient population treated with surgery, perioperative BRT, and adjuvant EBRT +/- CHT. Secondary objective was to identify prognostic factors for patients outcome in terms of LC, disease-free survival (DFS), and OS. RESULTS: From 2000 to 2011, 107 patients presenting 2-3 grade (FNLCC) primary or recurrent STS were treated with surgery, perioperative BRT, and adjuvant EBRT +/- CHT. Five-year LC and OS were 80.9% and 87.4%, respectively. At univariate analysis, a higher LC was recorded in primary vs. recurrent tumors (p = 0.015), and in lower limb tumors vs. other sites (p = 0.027). An improved DFS was recorded in patients with lower limb tumors vs. other sites (p = 0.034). CONCLUSIONS: The combination of BRT and EBRT was able to achieve satisfactory results even in a patients population with intermediate-high risk STS. Patients with recurrent or other than lower limb sited tumors show a worse LC. PMID- 28725251 TI - Custom-made micro applicators for high-dose-rate brachytherapy treatment of chronic psoriasis. AB - PURPOSE: In this study, we present the treatment of the psoriatic nail beds of patients refractory to standard therapies using high-dose-rate (HDR) brachytherapy. The custom-made micro applicators (CMMA) were designed and constructed for radiation dose delivery to small curvy targets with complicated topology. The role of the HDR brachytherapy treatment was to stimulate the T cells for an increased immune response. MATERIAL AND METHODS: The patient diagnosed with psoriatic nail beds refractory to standard therapies received monthly subunguinal injections that caused significant pain and discomfort in both hands. The clinical target was defined as the length from the fingertip to the distal interphalangeal joint. For the accurate and reproducible setup in the multi-fractional treatment delivery, the CMMAs were designed. Five needles were embedded into the dense plastic mesh and covered with 5 mm bolus material for each micro applicator. Five CMMAs were designed, resulting in the usage of 25 catheters in total. RESULTS: The prescription dose was planned to the depth of the anterior surface of the distal phalanx, allowing for the sparing of the surrounding tissue. The total number of the active dwell positions was 145 with step size of 5 mm. The total treatment time was 115 seconds with a 7.36 Ci activity of the 192Ir source. The treatment resulted in good pain control. The patient did not require further injections to the nail bed. After this initial treatment, additional two patients with similar symptoms received HDR brachytherapy. The treatment outcome was favorable in all cases. CONCLUSIONS: The first HDR brachytherapy treatment of psoriasis of the nail bed is presented. The initial experience revealed that brachytherapy treatment was well-tolerated and resulted in adequate control of the disease. A larger cohort of patients will be required for additional conclusions related to the long-term clinical benefits. PMID- 28725252 TI - Individualized 3D scanning and printing for non-melanoma skin cancer brachytherapy: a financial study for its integration into clinical workflow. AB - PURPOSE: Skin cancer is the most common tumor in the population. There are different therapeutic modalities. Brachytherapy is one of the techniques used, in which it is necessary to build customized moulds for some patients. Currently, these moulds are made by hand using rudimentary techniques. We present a new procedure based on 3D printing and the analysis of the clinical workflow. MATERIAL AND METHODS: Moulds can be made either by hand or by automated 3D printing. For making moulds by hand, a patient's alginate negative is created and, from that, the gypsum cast and customized moulds are made by hand from the patient's negative template. The new process is based on 3D printing. The first step is to take a 3D scan of the surface of the patient and then, 3D modelling software is used to obtain an accurate anatomical reconstruction of the treatment area. We present the clinical workflow using 3D scanning and printing technology, comparing its costs with the usual custom handmade mould protocol. RESULTS: The time spent for the new process is 6.25 hours, in contrast to the time spent for the conventional process, which is 9.5 hours. We found a 34% reduction in time required to create a mould for brachytherapy treatment. The labor cost of the conventional process is 211.5 vs. 152.5 hours, so the reduction is 59 hours. There is also a 49.5% reduction in the financial costs, mostly due to lack of need of a computed tomography (CT) scan of the gypsum and the mould. 3D scanning and printing offers financial benefits and reduces the clinical workload. CONCLUSIONS: As the present project demonstrates, through the application of 3D printing technologies, the costs and time spent during the process in the clinical workload in brachytherapy treatment are reduced. Overall, 3D printing is a promising technique for brachytherapy that might be well received in the community. PMID- 28725253 TI - Computed tomography-based treatment planning for high-dose-rate brachytherapy using the tandem and ring applicator: influence of applicator choice on organ dose and inter-fraction adaptive planning. AB - Three dimensional planning for high-dose-rate (HDR) brachytherapy in cervical cancer has been highly recommended by consensus guidelines such as the American Brachytherapy Society (ABS) and the Groupe Europeen de Curietherapie - European Society for Radiotherapy and Oncology (GEC-ESTRO). In this document, we describe our experience with computed tomography (CT)-based planning using the tandem/ring applicator. We discuss the influence of applicator geometry on doses to organs at risk (OARs), namely the bladder, rectum, and sigmoid. Through example cases with dose prescribed to point A, we demonstrate how adaptive planning can help achieve constraints to the OARs as per guidelines. PMID- 28725254 TI - INTERACTS (INTErventional Radiotherapy ACtive Teaching School) guidelines for quality assurance in choroidal melanoma interventional radiotherapy (brachytherapy) procedures. AB - Eye plaque brachytherapy represents a safe and effective therapeutic approach for choroidal melanoma, combining clinical outcomes with an eye and visual preservation. As it represents a complex procedure, a specific quality assurance program is strongly suggested to improve patients and operators safety, and to reduce possible complications linked to surgical procedure and radiation exposure. The aim of this paper is to describe the INTERACTS (Interventional Radiotherapy Active Teaching School) guidelines for quality assurance in choroidal melanoma interventional radiotherapy (brachytherapy) used in our institution. PMID- 28725256 TI - The effect of high-intensity breastfeeding on postpartum glucose tolerance in women with recent gestational diabetes. AB - BACKGROUND: Although breastfeeding is expected to reduce the incidence of diabetes in women with gestational diabetes, the effect has not been clearly confirmed. We examined whether or not high-intensity breastfeeding reduces the incidence of abnormal glucose tolerance and investigated the effect of high intensity breastfeeding on insulin resistance during the first year postpartum in Japanese women with current gestational diabetes. METHODS: In this retrospective study, we included women with gestational diabetes who underwent postpartum 75 g oral glucose tolerance test during the first year (12-14 months) postpartum from 2009 to 2011 at a single tertiary perinatal care center in Japan. High-intensity breastfeeding was defined as the condition in which infants were fed by breastfeeding alone or 80% or more of the volume. We investigated the effect of high-intensity breastfeeding on the prevalence of postpartum abnormal glucose tolerance and the postpartum homeostasis model of assessment of insulin resistance (HOMA-IR), after controlling for confounders, including prepregnancy obesity and weight changes during pregnancy and postpartum. RESULTS: Among 88 women with gestational diabetes, 46 (52%) had abnormal glucose tolerance during the postpartum period. High-intensity breastfeeding women (n = 70) were significantly less likely to have abnormal glucose tolerance than non-high intensity breastfeeding women (n = 18) (46% vs. 78%, p = 0.015). High-intensity breastfeeding was also associated with a lower HOMA-IR at 12-14 months postpartum than non-high-intensity breastfeeding (1.41 +/- 1.02 vs. 2.28 +/- 1.05, p = 0.035). Those associations remained significant after controlling for confounders. At least six months of high-intensity breastfeeding had a significant effect on lowering both the abnormal glucose tolerance prevalence and HOMA-IR compared with non-high-intensity breastfeeding. CONCLUSIONS: In Japanese women with gestational diabetes, high-intensity breastfeeding >=6 months had a protective effect against the development of abnormal glucose tolerance during the first year postpartum through improving insulin resistance, independent of obesity and postpartum weight change. PMID- 28725257 TI - Study protocol: An investigation of mother-infant signalling during breastfeeding using a randomised trial to test the effectiveness of breastfeeding relaxation therapy on maternal psychological state, breast milk production and infant behaviour and growth. AB - BACKGROUND: The physiological and psychological signalling between mother and infant during lactation is one of the prominent mother-infant factors that may influence breastfeeding outcomes. The infant can 'signal' his needs through vocalisation, and the mother can respond by allowing or restricting nipple access, which might alter the breast milk composition or volume. This may lead to parent-offspring conflict during the lactation period. Challenging infant behaviour has also been associated with maternal psychological distress, which might affect breastfeeding performance. Most attempts to improve breastfeeding rates focus on providing additional support, yet many aspects of the breastfeeding process are poorly understood. Thus, our objective is to investigate mother-infant signalling during breastfeeding by manipulating maternal psychological state using a relaxation therapy intervention. The study will test the hypothesis that mothers who listen to the therapy will be more relaxed/less stressed and this will favourably alter breast milk composition and/or affect milk volume and hence influence infant outcomes. METHODS: A randomised controlled trial will be conducted in first-time breastfeeding mothers and their new-born infants. Pregnant mothers will be recruited at antenatal clinics in Selangor, Malaysia, and four home visits will be carried out at 2, 6, 12 and 14 weeks postnatally. Participants will be randomised into a control and an intervention group in the early post-partum period. Mothers from the intervention group will be asked to listen daily to an audio recording with relaxation therapy during breastfeeding. Maternal psychological state, breastfeeding practices and infant behaviour will be assessed using validated questionnaires. Milk volume will be measured using stable isotopes. Breast milk samples will be collected to measure macronutrient content and hormone levels. Anthropometric measurements (weight, length and head circumference) will be performed during all home visits, including body composition at week 14. DISCUSSION: The main outcomes will be the effect of the intervention on maternal psychological state, milk production, cortisol levels, and infant behaviour and growth. Secondary outcomes will be associations between breast milk composition and infant appetite and growth. This study aims to provide a greater understanding of maternal-infant factors which influence breastfeeding outcomes and which may be useful targets for future interventions. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01971216. PMID- 28725258 TI - A meta-analysis of resuscitative endovascular balloon occlusion of the aorta (REBOA) or open aortic cross-clamping by resuscitative thoracotomy in non compressible torso hemorrhage patients. AB - BACKGROUND: The objective of this systematic review and meta-analysis was to determine the effect of REBOA, compared to resuscitative thoracotomy, on mortality and among non-compressible torso hemorrhage trauma patients. METHODS: Relevant articles were identified by a literature search in MEDLINE and EMBASE. We included studies involving trauma patients suffering non-compressible torso hemorrhage. Studies were eligible if they evaluated REBOA and compared it to resuscitative thoracotomy. Two investigators independently assessed articles for inclusion and exclusion criteria and selected studies for final analysis. We conducted meta-analysis using random effect models. RESULTS: We included three studies in our systematic review. These studies included a total of 1276 patients. An initial analysis found that although lower in REBOA-treated patients, the odds of mortality did not differ between the compared groups (OR 0.42; 95% CI 0.17-1.03). Sensitivity analysis showed that the risk of mortality was significantly lower among patients who underwent REBOA, compared to those who underwent resuscitative thoracotomy (RT) (RR 0.81; 95% CI 0.68-0.97). CONCLUSION: Our meta-analysis, mainly from observational data, suggests a positive effect of REBOA on mortality among non-compressible torso hemorrhage patients. However, these results deserve further investigation. PMID- 28725259 TI - Cardiovascular disease risk and prevention amongst Syrian refugees: mixed methods study of Medecins Sans Frontieres programme in Jordan. AB - BACKGROUND: The growing burden of non-communicable diseases (NCDs) presented new challenges for medical humanitarian aid and little was known about primary health care approaches for these diseases in humanitarian response. We aimed to evaluate Medecins Sans Frontieres (MSF's) use of total CVD risk based prevention strategies amongst Syrian refugees in northern Jordan to identify opportunities to improve total CVD risk based guidance for humanitarian settings. METHODS: We evaluated CVD risk assessment and management in two outpatient NCD clinics in the Irbid governorate of Jordan using a mixed methods design with qualitative and quantitative strands of equal priority, integrated during data collection and interpretation. World Health Organisation/International Society of Hypertension (WHO/ISH) CVD risk charts requiring measured cholesterol were used in the clinics and in our analysis. An electronic database of routine clinical information was used to determine the CVD risk profile of the clinic population, the pattern and concordance of lipid-lowering treatment prescriptions, and the prevalence and accuracy of documented CVD risk scores. This was combined with semi-structured interviews with MSF health workers, which were recorded, transcribed verbatim, and analysed thematically. RESULTS: We reviewed the clinical records of 2907 patients. One fifth (20.9%; 95% CI 19.5, 22.4) of patients had a history of CVD while 56.8% (95% CI 54.9, 58.6) of patients had a WHO/ISH risk of <10%. Only 23.3% (95% CI 21.9, 25.0) of patients had a documented WHO/ISH risk score of which 65% were correct. 60.4% (95% CI 58.6, 62.2) of patients were eligible for lipid-lowering treatment and 48.3% (95% CI 45.9, 50.6) of these patients were prescribed it. Analysis of interviews with sixteen MSF staff identified nine explanatory themes. Providers had confusion about when and how to use the risk charts, tended to favour lifestyle intervention over drug treatment, and had uncertainty about the role of lipid-lowering treatment in primary but not secondary prevention. Patients were reluctant to start, stop, or change medication and were less able to modify risk factors and benefit from health education because of their social and economic context. CONCLUSIONS: Four priority areas to improve CVD risk-based guidance for prevention in humanitarian settings include: practical training for health workers on total CVD risk assessment and associated guidance; supporting the use of CVD risk charts as a communication tool and task sharing; contextualising risk scoring in a broader, single consultation, total CVD risk-based algorithm; and targeting popular health myths amongst the community. PMID- 28725260 TI - Help seeking and suicidality among people with epilepsy in a rural low income country setting: cross-sectional survey. AB - BACKGROUNDS: Epilepsy is a serious neurological disorder associated with a high level of psychiatric comorbidity. Suicidality is a recognised complication of epilepsy. As part of developing an integrated service for people with epilepsy (PWE) and priority psychiatric disorders within primary care, a cross-sectional study was conducted in a rural district in Ethiopia to investigate patterns of help-seeking, suicidality and the association with duration of untreated epilepsy (DUE) among PWE. METHODS: Cases were identified through community key informants and diagnosis was confirmed by trained primary care clinicians. Severity of epilepsy, depression and suicidality were assessed using standardised methods. Multivariable regression analysis was used to test the hypothesis that suicidality was associated with DUE. RESULTS: The majority of PWE sought help from both religious and biomedical healing centres. The lifetime treatment gap for biomedical care was 26.9%, with a 12 month treatment gap of 56.7%. Close to one-third (29.9%) of participants reported using traditional and cultural healing practices. Nearly one-third (30.2%) of participants reported suicidality (suicidal ideation, plan or attempt) in the previous 1 year. The median (IQR) DUE was 24 months (4-72). There was no association between DUE and suicidality. In the multivariable model, being married [odds ratio (OR) 2.81, 95% CI 1.22, 6.46], increased depressive symptoms (OR 1.17, 95% CI 1.10, 1.26) and perceived poorer wealth relative to others (OR 2.67, 95% CI 1.07, 6.68) were associated independently with suicidality. CONCLUSION: In this study, PWE sought help from both biomedical and religious healing centres. Suicidality and depression have a high prevalence in PWE in this setting. Integrated mental and neurological health care within primary care is needed for improved holistic management of epilepsy. PMID- 28725261 TI - Health risk behavior among chronically ill adolescents: a systematic review of assessment tools. AB - BACKGROUND: Adolescents living with chronic illnesses engage in health risk behaviors (HRB) which pose challenges for optimizing care and management of their ill health. Frequent monitoring of HRB is recommended, however little is known about which are the most useful tools to detect HRB among chronically ill adolescents. AIMS: This systematic review was conducted to address important knowledge gaps on the assessment of HRB among chronically ill adolescents. Its specific aims were to: identify HRB assessment tools, the geographical location of the studies, their means of administration, the psychometric properties of the tools and the commonest forms of HRB assessed among adolescents living with chronic illnesses globally. METHODS: We searched in four bibliographic databases of PubMed, Embase, PsycINFO and Applied Social Sciences Index and Abstracts for empirical studies published until April 2017 on HRB among chronically ill adolescents aged 10-17 years. RESULTS: This review indicates a major dearth of research on HRB among chronically ill adolescents especially in low income settings. The Youth Risk Behavior Surveillance System and Health Behavior in School-aged Children were the commonest HRB assessment tools. Only 21% of the eligible studies reported psychometric properties of the HRB tools or items. Internal consistency was good and varied from 0.73 to 0.98 whereas test-retest reliability varied from unacceptable (0.58) to good (0.85). Numerous methods of tool administration were also identified. Alcohol, tobacco and other drug use and physical inactivity are the commonest forms of HRB assessed. CONCLUSION: Evidence on the suitability of the majority of the HRB assessment tools has so far been documented in high income settings where most of them have been developed. The utility of such tools in low resource settings is often hampered by the cultural and contextual variations across regions. The psychometric qualities were good but only reported in a minority of studies from high income settings. This result points to the need for more resources and capacity building for tool adaptation and validation, so as to enhance research on HRB among chronically ill adolescents in low resource settings. PMID- 28725262 TI - Comparison of four glycosyl residue composition methods for effectiveness in detecting sugars from cell walls of dicot and grass tissues. AB - BACKGROUND: The effective use of plant biomass for biofuel and bioproduct production requires a comprehensive glycosyl residue composition analysis to understand the different cell wall polysaccharides present in the different biomass sources. Here we compared four methods side-by-side for their ability to measure the neutral and acidic sugar composition of cell walls from herbaceous, grass, and woody model plants and bioenergy feedstocks. RESULTS: Arabidopsis, Populus, rice, and switchgrass leaf cell walls, as well as cell walls from Populus wood, rice stems, and switchgrass tillers, were analyzed by (1) gas chromatography-mass spectrometry (GC-MS) of alditol acetates combined with a total uronic acid assay; (2) carbodiimide reduction of uronic acids followed by GC-MS of alditol acetates; (3) GC-MS of trimethylsilyl (TMS) derivatives; and (4) high-pressure, anion-exchange chromatography (HPAEC). All four methods gave comparable abundance ranking of the seven neutral sugars, and three of the methods were able to quantify unique acidic sugars. The TMS, HPAEC, and carbodiimide methods provided comparable quantitative results for the specific neutral and acidic sugar content of the biomass, with the TMS method providing slightly greater yield of specific acidic sugars and high total sugar yields. The alditol acetate method, while providing comparable information on the major neutral sugars, did not provide the requisite quantitative information on the specific acidic sugars in plant biomass. Thus, the alditol acetate method is the least informative of the four methods. CONCLUSIONS: This work provides a side-by side comparison of the efficacy of four different established glycosyl residue composition analysis methods in the analysis of the glycosyl residue composition of cell walls from both dicot (Arabidopsis and Populus) and grass (rice and switchgrass) species. Both primary wall-enriched leaf tissues and secondary wall enriched wood/stem tissues were analyzed for mol% and mass yield of the non cellulosic sugars. The TMS, HPAEC, and carbodiimide methods were shown to provide comparable quantitative data on the nine neutral and acidic sugars present in all plant cell walls. PMID- 28725263 TI - Modeling and simulation of the redox regulation of the metabolism in Escherichia coli at different oxygen concentrations. AB - BACKGROUND: Microbial production of biofuels and biochemicals from renewable feedstocks has received considerable recent attention from environmental protection and energy production perspectives. Many biofuels and biochemicals are produced by fermentation under oxygen-limited conditions following initiation of aerobic cultivation to enhance the cell growth rate. Thus, it is of significant interest to investigate the effect of dissolved oxygen concentration on redox regulation in Escherichia coli, a particularly popular cellular factory due to its high growth rate and well-characterized physiology. For this, the systems biology approach such as modeling is powerful for the analysis of the metabolism and for the design of microbial cellular factories. RESULTS: Here, we developed a kinetic model that describes the dynamics of fermentation by taking into account transcription factors such as ArcA/B and Fnr, respiratory chain reactions and fermentative pathways, and catabolite regulation. The hallmark of the kinetic model is its ability to predict the dynamics of metabolism at different dissolved oxygen levels and facilitate the rational design of cultivation methods. The kinetic model was verified based on the experimental data for a wild-type E. coli strain. The model reasonably predicted the metabolic characteristics and molecular mechanisms of fnr and arcA gene-knockout mutants. Moreover, an aerobic microaerobic dual-phase cultivation method for lactate production in a pfl knockout mutant exhibited promising yield and productivity. CONCLUSIONS: It is quite important to understand metabolic regulation mechanisms from both scientific and engineering points of view. In particular, redox regulation in response to oxygen limitation is critically important in the practical production of biofuel and biochemical compounds. The developed model can thus be used as a platform for designing microbial factories to produce a variety of biofuels and biochemicals. PMID- 28725264 TI - Identification of developmental stage and anatomical fraction contributions to cell wall recalcitrance in switchgrass. AB - BACKGROUND: Heterogeneity within herbaceous biomass can present important challenges for processing feedstocks to cellulosic biofuels. Alterations to cell wall composition and organization during plant growth represent major contributions to heterogeneity within a single species or cultivar. To address this challenge, the focus of this study was to characterize the relationship between composition and properties of the plant cell wall and cell wall response to deconstruction by NaOH pretreatment and enzymatic hydrolysis for anatomical fractions (stem internodes, leaf sheaths, and leaf blades) within switchgrass at various tissue maturities as assessed by differing internode. RESULTS: Substantial differences in both cell wall composition and response to deconstruction were observed as a function of anatomical fraction and tissue maturity. Notably, lignin content increased with tissue maturity concurrently with decreasing ferulate content across all three anatomical fractions. Stem internodes exhibited the highest lignin content as well as the lowest hydrolysis yields, which were inversely correlated to lignin content. Confocal microscopy was used to demonstrate that removal of cell wall aromatics (i.e., lignins and hydroxycinnamates) by NaOH pretreatment was non-uniform across diverse cell types. Non-cellulosic polysaccharides were linked to differences in cell wall response to deconstruction in lower lignin fractions. Specifically, leaf sheath and leaf blade were found to have higher contents of substituted glucuronoarabinoxylans and pectic polysaccharides. Glycome profiling demonstrated that xylan and pectic polysaccharide extractability varied with stem internode maturity, with more mature internodes requiring harsher chemical extractions to remove comparable glycan abundances relative to less mature internodes. While enzymatic hydrolysis was performed on extractives-free biomass, extractible sugars (i.e., starch and sucrose) comprised a significant portion of total dry weight particularly in stem internodes, and may provide an opportunity for recovery during processing. CONCLUSIONS: Cell wall structural differences within a single plant can play a significant role in feedstock properties and have the potential to be exploited for improving biomass processability during a biorefining process. The results from this work demonstrate that cell wall lignin content, while generally exhibiting a negative correlation with enzymatic hydrolysis yields, is not the sole contributor to cell wall recalcitrance across diverse anatomical fractions within switchgrass. PMID- 28725265 TI - Two bifunctional enzymes from the marine protist Thraustochytrium roseum: biochemical characterization of wax ester synthase/acyl-CoA:diacylglycerol acyltransferase activity catalyzing wax ester and triacylglycerol synthesis. AB - BACKGROUND: Triacylglycerols (TAGs) and wax esters (WEs) are important neutral lipids which serve as energy reservoir in some plants and microorganisms. In recent years, these biologically produced neutral lipids have been regarded as potential alternative energy sources for biofuel production because of the increased interest on developing renewable and environmentally benign alternatives for fossil fuels. In bacteria, the final step in TAG and WE biosynthetic pathway is catalyzed by wax ester synthase/acyl coenzyme A (acyl CoA):diacylglycerol acyltransferase (WS/DGAT). This bifunctional WS/DGAT enzyme is also a key enzyme in biotechnological production of liquid WE via engineering of plants and microorganisms. To date, knowledge about this class of biologically and biotechnologically important enzymes is mainly from biochemical characterization of WS/DGATs from Arabidopsis, jojoba and some bacteria that can synthesize both TAGs and WEs intracellularly, whereas little is known about WS/DGATs from eukaryotic microorganisms. RESULTS: Here, we report the identification and characterization of two bifunctional WS/DGAT enzymes (designated TrWSD4 and TrWSD5) from the marine protist Thraustochytrium roseum. Both TrWSD4 and TrWSD5 comprise a WS-like acyl-CoA acyltransferase domain and the recombinant proteins purified from Escherichia coli Rosetta (DE3) have substantial WS and lower DGAT activity. They exhibit WS activity towards various chain-length saturated and polyunsaturated acyl-CoAs and fatty alcohols ranging from C10 to C18. TrWSD4 displays WS activity with the lowest Km value of 0.14 MUM and the highest kcat/Km value of 1.46 * 105 M-1 s-1 for lauroyl-CoA (C12:0) in the presence of 100 MUM hexadecanol, while TrWSD5 exhibits WS activity with the lowest Km value of 0.96 MUM and the highest kcat/Km value of 9.83 * 104 M-1 s-1 for decanoyl-CoA (C10:0) under the same reaction condition. Both WS/DGAT enzymes have the highest WS activity at 37 and 47 degrees C, and WS activity was greatly decreased when temperature exceeds 47 degrees C. TrWSD4 and TrWSD5 are insensitive to ionic strength and reduced WS activity was observed when salt concentration exceeded 800 mM. The potential of T. roseum WS/DGATs to establish novel process for biotechnological production of WEs was demonstrated by heterologous expression in recombinant yeast. Expression of either TrWSD4 or TrWSD5 in Saccharomyces cerevisiae quadruple mutant H1246, which is devoid of storage lipids, resulted in the accumulation of WEs, but not any detectable TAGs, indicating a predominant WS activity in yeast. CONCLUSIONS: This study demonstrates both in vitro WS and DGAT activity of two T. roseum WS/DGATs, which were characterized as unspecific acyltransferases accepting a broad range of acyl CoAs and fatty alcohols as substrates for WS activity but displaying substrate preference for medium-chain acyl-CoAs. In vivo characterization shows that these two WS/DGATs predominantly function as wax synthase and presents the feasibility for production of WEs by heterologous hosts. PMID- 28725266 TI - Highly efficient methane generation from untreated microalgae biomass. AB - BACKGROUND: The fact that microalgae perform very efficiently photosynthetic conversion of sunlight into chemical energy has moved them into the focus of regenerative fuel research. Especially, biogas generation via anaerobic digestion is economically attractive due to the comparably simple apparative process technology and the theoretical possibility of converting the entire algal biomass to biogas/methane. In the last 60 years, intensive research on biogas production from microalgae biomass has revealed the microalgae as a rather challenging substrate for anaerobic digestion due to its high cell wall recalcitrance and unfavorable protein content, which requires additional pretreatment and co fermentation strategies for sufficient fermentation. However, sustainable fuel generation requires the avoidance of cost/energy intensive biomass pretreatments to achieve positive net-energy process balance. RESULTS: Cultivation of microalgae in replete and limited nitrogen culture media conditions has led to the formation of protein-rich and low protein biomass, respectively, with the last being especially optimal for continuous fermentation. Anaerobic digestion of nitrogen limited biomass (low-N BM) was characterized by a stable process with low levels of inhibitory substances and resulted in extraordinary high biogas, and subsequently methane productivity [750 +/- 15 and 462 +/- 9 mLN g-1 volatile solids (VS) day-1, respectively], thus corresponding to biomass-to-methane energy conversion efficiency of up to 84%. The microbial community structure within this highly efficient digester revealed a clear predominance of the phyla Bacteroidetes and the family Methanosaetaceae among the Bacteria and Archaea, respectively. The fermentation of replete nitrogen biomass (replete-N BM), on the contrary, was demonstrated to be less productive (131 +/- 33 mLN CH4 g-1VS day-1) and failed completely due to acidosis, caused through high ammonia/ammonium concentrations. The organization of the microbial community of the failed (replete-N) digester differed greatly compared to the stable low-N digester, presenting a clear shift to the phyla Firmicutes and Thermotogae, and the archaeal population shifted from acetoclastic to hydrogenotrophic methanogenesis. CONCLUSIONS: The present study underlines the importance of cultivation conditions and shows the practicability of microalgae biomass usage as mono substrate for highly efficient continuous fermentation to methane without any pretreatment with almost maximum practically achievable energy conversion efficiency (biomass to methane).Graphical abstractGrowth condition dependence of anaerobic conversion efficiency of microalgae biomass to methane. PMID- 28725267 TI - Heterologous co-expression of a yeast diacylglycerol acyltransferase (ScDGA1) and a plant oleosin (AtOLEO3) as an efficient tool for enhancing triacylglycerol accumulation in the marine diatom Phaeodactylum tricornutum. AB - BACKGROUND: Microalgae are promising alternate and renewable sources for producing valuable products such as biofuel and essential fatty acids. Although this is the case, there are still challenges impeding on the effective commercial production of microalgal products. For instance, their product yield is still too low. Therefore, this study was oriented towards enhancing triacylglycerol (TAG) accumulation in the diatom Phaeodactylum tricornutum (strain Pt4). To achieve this, a type 2 acyl-CoA:diacylglycerol acyltransferase from yeast (ScDGA1) and the lipid droplet (LD) stabilizing oleosin protein 3 from Arabidopsis thaliana (AtOLEO3) were expressed in Pt4. RESULTS: The individual expression of ScDGA1 and AtOLEO3 in Pt4 resulted in a 2.3- and 1.4-fold increase in TAG levels, respectively, in comparison to the wild type. The co-expression of both, ScDGA1 and AtOLEO3, was accompanied by a 3.6-fold increase in TAG content. On the cellular level, the lines co-expressing ScDGA1 and AtOLEO3 showed the presence of the larger and increased numbers of lipid droplets when compared to transformants expressing single genes and an empty vector. Under nitrogen stress, TAG productivity was further increased twofold in comparison to nitrogen-replete conditions. While TAG accumulation was enhanced in the analyzed transformants, the fatty acid composition remained unchanged neither in the total lipid nor in the TAG profile. CONCLUSIONS: The co-expression of two genes was shown to be a more effective strategy for enhancing TAG accumulation in P. tricornutum strain Pt4 than a single gene strategy. For the first time in a diatom, a LD protein from a vascular plant, oleosin, was shown to have an impact on TAG accumulation and on LD organization. PMID- 28725268 TI - Towards microalgal triglycerides in the commodity markets. AB - BACKGROUND: Microalgal triglycerides (TAGs) hold great promise as sustainable feedstock for commodity industries. However, to determine research priorities and support business decisions, solid techno-economic studies are essential. Here, we present a techno-economic analysis of two-step TAG production (growth reactors are operated in continuous mode such that multiple batch-operated stress reactors are inoculated and harvested sequentially) for a 100-ha plant in southern Spain using vertically stacked tubular photobioreactors. The base case is established with outdoor pilot-scale data and based on current process technology. RESULTS: For the base case, production costs of 6.7 ? per kg of biomass containing 24% TAG (w/w) were found. Several scenarios with reduced production costs were then presented based on the latest biological and technological advances. For instance, much effort should focus on increasing the photosynthetic efficiency during the stress and growth phases, as this is the most influential parameter on production costs (30 and 14% cost reduction from base case). Next, biological and technological solutions should be implemented for a reduction in cooling requirements (10 and 4.5% cost reduction from base case when active cooling is avoided and cooling setpoint is increased, respectively). When implementing all the suggested improvements, production costs can be decreased to 3.3 ? per kg of biomass containing 60% TAG (w/w) within the next 8 years. CONCLUSIONS: With our techno-economic analysis, we indicated a roadmap for a substantial cost reduction. However, microalgal TAGs are not yet cost efficient when compared to their present market value. Cost-competiveness strictly relies on the valorization of the whole biomass components and on cheaper PBR designs (e.g. plastic film flat panels). In particular, further research should focus on the development and commercialization of PBRs where active cooling is avoided and stable operating temperatures are maintained by the water basin in which the reactor is placed. PMID- 28725269 TI - Musculoskeletal Echinococcus infection as a rare first presentation of hydatid disease: case report. AB - BACKGROUND: Hydatid disease (HD) is a cosmopolitan parasitosis caused by Echinococcus granulosus that can potentially affect any part of the human body. Liver and lungs are the most frequent localizations. Primary musculoskeletal hydatidosis are seldom reported in literature and their incidence is unknown. CASE PRESENTATION: We deem interesting to report a case of a primary hydatid cyst in a 25-year-old patient who presented with a painful swelling of the right elbow. Meticulous examination and preoperative imaging did not reveal other localizations. Patient was admitted for surgery where total excision of cyst was done without intraoperative spillage and a cutaneous skin flap was subsequently required to make up for soft tissue loss. CONCLUSION: Primary hydatid cysts are sometimes difficult to diagnose preoperatively. It should be considered in the differential diagnosis of subcutaneous cystic lesions in regions where hydatid cysts are endemic. Currently, surgical excision is deemed first choice treatment for solitary cysts and antihelminthic treatment should be initiated preoperatively in the case of risk of rupture or in the event of complications. PMID- 28725270 TI - Inter-segmental motions of the foot: differences between younger and older healthy adult females. AB - BACKGROUND: Although accumulative evidence exists that support the applicability of multi-segmental foot models (MFMs) in evaluating foot motion in various pathologic conditions, little is known of the effect of aging on inter-segmental foot motion. The objective of this study was to evaluate differences in inter segmental motion of the foot between older and younger adult healthy females during gait using a MFM with 15-marker set. METHODS: One hundred symptom-free females, who had no radiographic evidence of osteoarthritis, were evaluated using MFM with 15-marker set. They were divided into young (n = 50, 20-35 years old) and old (n = 50, 60-69 years old) groups. Coefficients of multiple correlations were evaluated to assess the similarity of kinematic curve. Inter-segmental angles (hindfoot, forefoot, and hallux) were calculated at each gait phase. To evaluate the effect of gait speed on intersegmental foot motion, subgroup analysis was performed according to the similar speed of walking. RESULTS: Kinematic curves showed good or excellent similarity in most parameters. Range of motion in the sagittal (p < 0.001) and transverse (p = 0.001) plane of the hallux, and sagittal (p = 0.023) plane of the forefoot was lower in older females. The dorsiflexion (p = 0.001) of the hallux at terminal stance and pre swing phases was significantly lower in older females. When we compared young and older females with similar speed, these differences remained. CONCLUSIONS: Although the overall kinematic pattern was similar between young and older females, reduced range of inter-segmental motion was observed in the older group. Our results suggest that age-related changes need to be considered in studies evaluating inter-segmental motion of the foot. PMID- 28725271 TI - Normal foot loading parameters and repeatability of the Footscan(r) platform system. AB - BACKGROUND: The Footscan(r) platform system is one of the most commonly used clinical tools for the measurement of the foot pressure. The present study was designed to assess the repeatability of the system and identify the range of loading parameters observed in the normal foot. METHODS: Measurements were collected from 32 healthy participants, 15 females and 17 males, twice at an interval of 1 week. Peak pressure (PP), contact time (CT), contact area (CA), pressure-time integral (PTI), and maximum force (MaF) were recorded; these parameters were investigated in 10 areas of the foot: medial heel, lateral heel, midfoot, first to fifth metatarsals, hallux, and toes 2-5. The intra-session repeatability was evaluated by calculating the intraclass correlation coefficients (ICCs) and coefficients of variation (CVs) across the three repeated trials within the same session. The inter-session repeatability was assessed using the average of the three trials in each session to determine the ICCs and CVs. RESULTS: The ICCs showed moderate to good repeatability for every variable of interest, and the CVs were all <28%. The highest zones of PP were found under the second and third metatarsals, followed by the medial heel. The CT was 68.5 82.8% of the total stance time under the metatarsal heads. CA was highest under the midfoot, PTI was highest under the second metatarsal, and MaF was highest under the medial heel. CONCLUSIONS: Footscan(r) platform system was found to be repeatable. Thus, it can be used as a valuable tool in the assessment of plantar pressure distribution, and the normal values of the foot loading parameters identified in this study can be employed to provide a reference range for the gait analysis performed by the Footscan(r) system. PMID- 28725273 TI - A randomized controlled trial comparing the effects of dapagliflozin and DPP-4 inhibitors on glucose variability and metabolic parameters in patients with type 2 diabetes mellitus on insulin. AB - BACKGROUND: Dipeptidyl peptidase-4 (DPP-4) inhibitors and sodium-glucose co transporter 2 (SGLT2) inhibitors improve hyperglycemia, and the usefulness of co administration of DPP-4 inhibitors and insulin therapy has been well established. However, it has been still uncertain whether combination therapy of SGLT2 inhibitors and insulin is superior to that of DPP-4 inhibitors and the latter. Therefore, we investigated the superiority of dapagliflozin on glucose fluctuation compared with DPP-4 inhibitors in patients with type 2 diabetes mellitus (T2DM) on insulin using a continuous glucose monitoring (CGM) system. METHODS: In this prospective, randomized, open-label controlled trial, 36 patients with T2DM and treated with DPP-4 inhibitors and insulin therapy, were enrolled and allocated into two groups. The patients either switched their DPP-4 inhibitors to dapagliflozin 5 mg for 12 weeks, or continued their DPP-4 inhibitors for the same period. CGM analyses and metabolic markers were assessed before and after treatment periods. RESULTS: In total, data from 29 patients were analyzed. There were no significant differences in the mean amplitude of glycemic excursions and other CGM profiles in either group after treatment. Within the dapagliflozin treatment group, significant reductions of body mass index and albuminuria, and increases of HbA1c, hemoglobin and hematocrit were observed, but improvement of albuminuria was not significant if compared with the DPP-4 continuation group. CONCLUSIONS: Combination therapy of dapagliflozin and insulin was not superior in glucose fluctuation to DPP-4 inhibitors on insulin. However, dapagliflozin may in part provide favorable effects on metabolism in patients with T2DM treated with insulin therapy. Trial registration UMIN-CTR: UMIN000015033. Registered 2 September 2014. PMID- 28725275 TI - ASH Meeting 2016: developments in hemostaseology. AB - During the annual meeting of the American Society of Hematology (ASH) in San Diego/California, novel developments in the field of hemostaseology were presented. Alternative treatment strategies besides factor replacement were discussed for patients with hemophilia. One of the highlights of the meeting in this year's plenary session was the presentation of successful adeno-associated virus mediated gene transfer in patients with hemophilia B leading to sustained elevation of factor IX:C (FIX:c). Other alternative treatment approaches in patients with hemophilia A may include bispecific antibodies mimicking factor VIIIa (FVIIIa) activity or disrupting anticoagulant proteins. Focusing on anticoagulation, data on the use of direct oral anticoagulants (DOACs) in cancer patients with atrial fibrillation as well as treatment of superficial vein thrombosis with rivaroxaban were presented. In this short review, we try to highlight the most important presentations during the ASH meeting 2016. PMID- 28725274 TI - News in AL Amyloidosis ASH 2016: A rapidly evolving field of investigation. AB - Amyloidosis is a rare but life-threatening protein misfolding disease. The early diagnosis and enrollment of patients into multicentre trials is of great importance, as is the need for intensive collaboration between multiple medical departments and experienced specialists. In the following review, the most interesting abstracts from the annual American Society of Hematology (ASH) meeting in 2016 are presented. The topics include the limitations of established biomarkers in risk assessment and response evaluation, the introduction of a new biomarker, the comparison of different treatment sequences and the efficacy of a multiple drug regimen in light-chain (AL) amyloidosis. PMID- 28725276 TI - Early stage breast cancer treatment and prognostic factors: Post San Antonio Breast Cancer Symposium 2016. AB - Developments in early breast cancer presented at the 2016 San Antonio Breast Cancer Symposium included important studies on extending adjuvant endocrine therapy with aromatase inhibitors, the role of bisphosphonates, and evidence for molecular prognostic factors and circulating tumor cells in early stage breast cancer patients. PMID- 28725277 TI - SABCS 2016: systemic therapy for metastatic breast cancer. AB - At the 2016 San Antonio Breast Cancer Symposium, several interesting phase II and phase III studies investigating systemic therapies for metastatic breast cancer were presented. The PrEGOC 0102 trial demonstrated that the combination of fulvestrant plus everolimus is safe and effective and could be an alternative to exemestane plus everolimus for selected patients with hormone-receptor positive, HER2-negative disease. The pan-PI3K inhibitor buparlisib showed some activity in combination with fulvestrant after failure of everolimus in the BELLE-3 trial. PIK3CA mutation detected in circulating tumor DNA (ctDNA) was predictive for a buparlisib efficacy. Unfortunately, the unfavorable toxicity profile precludes further development of this drug. Nonetheless, PI3K seems to be a valid target in tumors resistant to mTOR inhibition. The BROCADE phase II trial failed to show a statistically significant benefit by the addition of the PARP inhibitor veliparib to carboplatin and paclitaxel in patients with BRCA1/2 germline mutation. The overall response rate, however, was statistically significant higher in the veliparib arm compared to the placebo arm. Data from the phase III trial BROCADE 3 are awaited. Finally, the TNT trial did not identify further biomarkers, in addition to BRCA1/2 germline mutation, for carboplatin benefit in patients with metastatic triple-negative breast cancer. PMID- 28725278 TI - ASCO 2016 - update colorectal liver metastases. AB - This short review summarizes the most relevant data on colorectal liver metastases (CLM) presented at the 2016 Annual Meeting of the American Society of Clinical Oncology (ASCO). For this update, congress abstracts were grouped into three clinically relevant scenarios: CLM that are deemed upfront resectable, borderline resectable, and primarily unresectable. According to a large registry study, small, upfront resectable, solitary CLM should be resected using a parenchymal sparing technique. A prospective noninterventional study suggested that chemotherapy plus the anti-VEGF (vascular endothelial growth factor) antibody bevacizumab is effective and well tolerated in patients with borderline resectable CLM. In the setting of CLM deemed initially unresectable, a phase 2 study reported superior outcomes in terms of liver metastases resection rates as well as overall survival (OS) in patients receiving a chemotherapy triplet (FOLFIRINOX) plus a targeted agent as compared to FOLFIRI or FOLFOX4 with the same targeted therapy. Finally, a study suggested that tailoring first-line chemotherapy according to TYMS-3'UTR and ERCC1-118 polymorphism status results in higher response rates and longer progression-free survival (PFS) as well as OS. PMID- 28725272 TI - Brazilian guidelines on prevention of cardiovascular disease in patients with diabetes: a position statement from the Brazilian Diabetes Society (SBD), the Brazilian Cardiology Society (SBC) and the Brazilian Endocrinology and Metabolism Society (SBEM). AB - BACKGROUND: Since the first position statement on diabetes and cardiovascular prevention published in 2014 by the Brazilian Diabetes Society, the current view on primary and secondary prevention in diabetes has evolved as a result of new approaches on cardiovascular risk stratification, new cholesterol lowering drugs, and new anti-hyperglycemic drugs. Importantly, a pattern of risk heterogeneity has emerged, showing that not all diabetic patients are at high or very high risk. In fact, most younger patients who have no overt cardiovascular risk factors may be more adequately classified as being at intermediate or even low cardiovascular risk. Thus, there is a need for cardiovascular risk stratification in patients with diabetes. The present panel reviews the best current evidence and proposes a practical risk-based approach on treatment for patients with diabetes. MAIN BODY: The Brazilian Diabetes Society, the Brazilian Society of Cardiology, and the Brazilian Endocrinology and Metabolism Society gathered to form an expert panel including 28 cardiologists and endocrinologists to review the best available evidence and to draft up-to-date an evidence-based guideline with practical recommendations for risk stratification and prevention of cardiovascular disease in diabetes. The guideline includes 59 recommendations covering: (1) the impact of new anti-hyperglycemic drugs and new lipid lowering drugs on cardiovascular risk; (2) a guide to statin use, including new definitions of LDL-cholesterol and in non-HDL-cholesterol targets; (3) evaluation of silent myocardial ischemia and subclinical atherosclerosis in patients with diabetes; (4) hypertension treatment; and (5) the use of antiplatelet therapy. CONCLUSIONS: Diabetes is a heterogeneous disease. Although cardiovascular risk is increased in most patients, those without risk factors or evidence of sub clinical atherosclerosis are at a lower risk. Optimal management must rely on an approach that will cover both cardiovascular disease prevention in individuals in the highest risk as well as protection from overtreatment in those at lower risk. Thus, cardiovascular prevention strategies should be individualized according to cardiovascular risk while intensification of treatment should focus on those at higher risk. PMID- 28725279 TI - Erratum to: Delta rhythmicity is a reliable EEG biomarker in Angelman syndrome: a parallel mouse and human analysis. AB - [This corrects the article DOI: 10.1186/s11689-017-9195-8.]. PMID- 28725281 TI - Introduction: Testing and Refining Marc Lewis's Critique of the Brain Disease Model of Addiction. AB - In this introduction we set out some salient themes that will help structure understanding of a complex set of intersecting issues discussed in this special issue on the work of Marc Lewis: (1) conceptual foundations of the disease model, (2) tolerating the disease model given socio-political environments, and (3) A third wave: refining conceptualization of addiction in the light of Lewis's model. PMID- 28725280 TI - Single-molecule quantification of 5-hydroxymethylcytosine for diagnosis of blood and colon cancers. AB - BACKGROUND: The DNA modification 5-hydroxymethylcytosine (5hmC) is now referred to as the sixth base of DNA with evidence of tissue-specific patterns and correlation with gene regulation and expression. This epigenetic mark was recently reported as a potential biomarker for multiple types of cancer, but its application in the clinic is limited by the utility of recent 5hmC quantification assays. We use a recently developed, ultra-sensitive, fluorescence-based single molecule method for global quantification of 5hmC in genomic DNA. The high sensitivity of the method gives access to precise quantification of extremely low 5hmC levels common in many cancers. METHODS: We assessed 5hmC levels in DNA extracted from a set of colon and blood cancer samples and compared 5hmC levels with healthy controls, in a single-molecule approach. RESULTS: Using our method, we observed a significantly reduced level of 5hmC in blood and colon cancers and could distinguish between colon tumor and colon tissue adjacent to the tumor based on the global levels of this molecular biomarker. CONCLUSIONS: Single molecule detection of 5hmC allows distinguishing between malignant and healthy tissue in clinically relevant and accessible tissue such as blood and colon. The presented method outperforms current commercially available quantification kits and may potentially be developed into a widely used, 5hmC quantification assay for research and clinical diagnostics. Furthermore, using this method, we confirm that 5hmC is a good molecular biomarker for diagnosing colon and various types of blood cancer. PMID- 28725282 TI - Addiction and the Brain: Development, Not Disease. AB - I review the brain disease model of addiction promoted by medical, scientific, and clinical authorities in the US and elsewhere. I then show that the disease model is flawed because brain changes in addiction are similar to those generally observed when recurrent, highly motivated goal seeking results in the development of deep habits, Pavlovian learning, and prefrontal disengagement. This analysis relies on concepts of self-organization, neuroplasticity, personality development, and delay discounting. It also highlights neural and behavioral parallels between substance addictions, behavioral addictions, normative compulsive behaviors, and falling in love. I note that the short duration of addictive rewards leads to negative emotions that accelerate the learning cycle, but cortical reconfiguration in recovery should also inform our understanding of addiction. I end by showing that the ethos of the disease model makes it difficult to reconcile with a developmental-learning orientation. PMID- 28725283 TI - Q: Is Addiction a Brain Disease or a Moral Failing? A: Neither. AB - This article uses Marc Lewis' work as a springboard to discuss the socio political context of the brain disease model of addiction (BDMA). The claim that promotion of the BDMA is the only way the general public can be persuaded to withhold blame and punishment from addicts is critically examined. After a discussion of public understandings of the disease concept of addiction, it is pointed out that it is possible to develop a scientific account of addiction which is neither a disease nor a moral model but which the public could understand. Evidence is reviewed to suggest that public acceptance of the disease concept is largely lip-service and that the claim the BDMA removes stigma among the public and professionals is unsupported by evidence. Further, there is good evidence that biogenetic explanations of mental/behavioural disorders in general have been counterproductive in the attempt to ally stigma. A model of addiction as a disorder of choice may attract special problems in public-facing communications and risks being misunderstood. However, ways of presenting this model to the public are suggested that may avoid such risks. Lastly, the claim that the BDMA is the only way of ensuring access to treatment and of maintaining research funding for addiction is disputed and a way in which these benefits can be retained under a disorder-of-choice model proposed. The article concludes by enthusiastically endorsing Lewis' call for a third stage in the governing image of addiction. PMID- 28725284 TI - Addiction and Moralization: the Role of the Underlying Model of Addiction. AB - Addiction appears to be a deeply moralized concept. To understand the entwinement of addiction and morality, we briefly discuss the disease model and its alternatives in order to address the following questions: Is the disease model the only path towards a 'de-moralized' discourse of addiction? While it is tempting to think that medical language surrounding addiction provides liberation from the moralized language, evidence suggests that this is not necessarily the case. On the other hand non-disease models of addiction may seem to resuscitate problematic forms of the moralization of addiction, including, invoking blame, shame, and the wholesale rejection of addicts as people who have deep character flaws, while ignoring the complex biological and social context of addiction. This is also not necessarily the case. We argue that a deficit in reasons responsiveness as basis for attribution of moral responsibility can be realized by multiple different causes, disease being one, but it also seems likely that alternative accounts of addiction as developed by Flanagan, Lewis, and Levy, may also involve mechanisms, psychological, social, and neurobiological that can diminish reasons responsiveness. It thus seems to us that nondisease models of addiction do not necessarily involve moralization. Hence, a non-stigmatizing approach to recovery can be realized in ways that are consistent with both the disease model and alternative models of addiction. PMID- 28725285 TI - Free Will, Black Swans and Addiction. AB - The current dominant perspective on addiction as a brain disease has been challenged recently by Marc Lewis, who argued that the brain-changes related to addiction are similar to everyday changes of the brain. From this alternative perspective, addictions are bad habits that can be broken, provided that people are motivated to change. In that case, autonomous choice or "free will" can overcome bad influences from genes and or environments and brain-changes related to addiction. Even though we concur with Lewis that there are issues with the brain disease perspective, we also argue that pointing to black swans can be important, that is: there can be severe cases where addiction indeed tips over into the category of brain disease, but obviously that does not prove that every case of addiction falls into the disease category, that all swans are black. We argue that, for example, people suffering from Korsakoff's syndrome, can be described as having a brain disease, often caused by alcohol addiction. Moreover, the brain changes occurring with addiction are related to choice-behaviour (and the related notions of willed action), habit formation and insight, hence essential mental abilities to break the addiction. We argue for a more graded perspective, where both black swans (severe brain disease which makes recovery virtually impossible) and white swans (unaffected brain) are rare, and most cases of addiction come as geese in different shades of gray. PMID- 28725286 TI - Responsibility without Blame for Addiction. AB - Drug use and drug addiction are severely stigmatised around the world. Marc Lewis does not frame his learning model of addiction as a choice model out of concern that to do so further encourages stigma and blame. Yet the evidence in support of a choice model is increasingly strong as well as consonant with core elements of his learning model. I offer a responsibility without blame framework that derives from reflection on forms of clinical practice that support change and recovery in patients who cause harm to themselves and others. This framework can be used to interrogate our own attitudes and responses, so that we can better see how to acknowledge the truth about choice and agency in addiction, while avoiding stigma and blame, and instead maintaining care and compassion alongside a commitment to working for social justice and good. PMID- 28725287 TI - How to Recover from a Brain Disease: Is Addiction a Disease, or Is there a Disease-like Stage in Addiction? AB - People struggling with addiction are neither powerless over their addiction, nor are they fully in control. Lewis vigorously objects to the brain disease model of addiction (BDMA), because it makes people lose belief in their self-efficacy, and hence hinders their recovery. Although he acknowledges that there is a compulsive state in addiction, he objects to the claim that this compulsion is carved in stone. Lewis argues that the BDMA underestimates the agency of addicted people, and hence hinder their recovery. Lewis's work offers us a very much to be welcomed neurobiology of recovery. It offers addicted people a hopeful and respectful narrative for their recovery that treats them as agents rather than as damaged brains. However, I argue that overestimating people's agency can also result in people losing belief in their self-efficacy. Lewis's strong focus on the agency of addicted people might not match their experiences of struggle, hence reinforcing their feelings of guilt when they fail to control their use. I propose to replace the notion of addiction as a disease with a notion of a disease-like stage in addiction. I call this stage the duress stage in addiction, in which the addictive behaviour is largely impervious to the agent's values and to available techniques of self-control. However, the agent can overcome this stage by developing new techniques of self-control, by building on their self concept and belief in self-efficacy, by changing their environments and habits, and by engaging in projects that are meaningful to the agent. PMID- 28725288 TI - Views of Caregivers on the Ethics of Assistive Technology Used for Home Surveillance of People Living with Dementia. AB - This paper examines the ethics of using assistive technology such as video surveillance in the homes of people living with dementia. Ideation and concept elaboration around the introduction of a camera-based surveillance service in the homes of people with dementia, typically living alone, is explored. The paper reviews relevant literature on surveillance of people living with dementia, and summarises the findings from ideation and concept elaboration workshops, designed to capture the views of those involved in the care of people living with dementia at home. The research question relates to the ethical considerations of using assistive technologies that include video surveillance in the homes of people living with dementia, and the implications for a person living with dementia whenever video surveillance is used in their home and access to the camera is given to the person's family. The review of related work indicated that such video surveillance may result in loss of autonomy or freedom for the person with dementia. The workshops reflected the findings from the related work, and revealed useful information to inform the service design, in particular in fine tuning the service to find the best relationship between privacy and usefulness. Those who took part in the workshops supported the concept of the use of camera in the homes of people living with dementia, with some significant caveats around privacy. The research carried out in this work is small in scale but points towards an acceptance by many caregivers of people living with dementia of surveillance technologies. This paper indicates that those who care for people living with dementia at home are willing to make use of camera technology and therefore the value of this work is to help shed light on the direction for future research. PMID- 28725289 TI - Amnestic MCI Patients' Perspectives toward Disclosure of Amyloid PET Results in a Research Context. AB - BACKGROUND: Researchers currently are not obligated to share individual research results (IRR) with participants. This non-disclosure policy has been challenged on the basis of participants' rights to be aware and in control of their personal medical information. Here, we determined how patients view disclosure of research PET results of brain amyloid and why they believe it is advantageous or disadvantageous to disclose. METHOD: As a part of a larger diagnostic trial, we conducted semi-structured interviews with patients with amnestic Mild Cognitive Impairment (aMCI). Participants had the option to receive their brain amyloid PET scan result (i.e., their IRR). Interviews were conducted before they received their IRR. RESULTS: A total of 38 aMCI patients (100% of study participants) wanted to know their IRR. The two most frequently mentioned reasons for choosing IRR disclosure were to better understand their brain health status and to be better able to make informed decisions about future personal arrangements (e.g., inheritance tax, moving into a smaller house, end-of-life decisions, etc.). Emotional risk was mentioned as the primary disadvantage of knowing one's IRR. On the other hand, non-disclosure was considered to be emotionally difficult also, as patients would be uncertain about their future health condition. CONCLUSIONS: Many patients diagnosed clinically with aMCI want to know their brain amyloid test results, even though this knowledge may be disadvantageous to them. Knowing what is going on with their health and the ability to make informed decisions about their future were the two principal advantages mentioned for obtaining their amyloid PET results. Because of the overwhelming consensus of aMCI patients was to disclose their brain amyloid PET scan results, researchers should strongly consider releasing this information to research subjects. PMID- 28725291 TI - Relationship between normal tension glaucoma and Flammer syndrome. AB - BACKGROUND: Besides intraocular pressure, vascular factors play a role in the pathogenesis of glaucomatous optic neuropathy. One of these potential vascular factors is Flammer syndrome. The purpose of the present study was to determine in a Korean population whether signs and symptoms of Flammer syndrome occur more often in normal tension glaucoma patients than in control subjects. METHODS: Two hundred forty-six normal tension glaucoma patients and 1116 control subjects responded to a multiple-choice questionnaire asking about 15 signs and symptoms of Flammer syndrome. RESULTS: Seven of the 15 signs and symptoms of Flammer syndrome (increased drug sensitivity, good smell perception, reversible skin blotches, tinnitus, long sleep onset time, tendency to perfectionism, and cold hands/feet) were significantly more often positive in normal tension glaucoma patients than in controls. Six additional signs and symptoms (migraines, low blood pressure, headaches, dizziness, increased pain sensation, and feeling cold) also occurred more often, but did not reach statistical significance. Only two items (low body weight and reduced feeling of thirst) were more frequently (not significant) positive in the controls. CONCLUSION: There is an association between normal tension glaucoma and Flammer syndrome. If future studies confirm this relationship, treatment of Flammer syndrome may help to prevent normal tension glaucoma or to slow down its progression. PMID- 28725292 TI - "Pre-metastatic niches" in breast cancer: are they created by or prior to the tumour onset? "Flammer Syndrome" relevance to address the question. AB - Breast cancer (BC) epidemic in the twenty-first century is characterised by around half a million deaths and 1.7 million new cases registered annually worldwide. Metastatic disease is the major cause of death in BC patient cohorts. Current statistics are much alarming from the viewpoint of the early mortality amongst BC patients with de novo metastatic disease. A new paradigm of so-called "pre-metastatic niches" may sufficiently promote our knowledge regarding potential pathomechanisms, individual predisposition and prognosis in development and progression of the metastatic disease. However, the crucial question remains unaddressed, whether hypoxic pre-metastatic niches in BC are created by or prior to the tumour onset. So far, the current interpretation of the "Seed and Soil" theory of metastasis proposing that the pre-metastatic niches are formed by primary tumours which "induce and guide" the process is incomplete, since it does not provide satisfactory explanations towards several facts overviewed in the article. The overall results of this study clearly support the working hypothesis presented by the authors proposing that the epi/genetic predisposition of individuals at risk to form the systemic hypoxic pre-metastatic niches can be established a long time before breast malignancy is clinically manifested. "Flammer Syndrome" (FS) phenotype may strongly contribute to particularly poor outcomes of metastatic breast cancer. Significance and relevance of individual FS symptoms for breast cancer metastatic disease are discussed in extenso. PMID- 28725293 TI - Traditional medicine as a potential treatment for Flammer syndrome. PMID- 28725295 TI - Team Reasoning and Collective Intentionality. AB - Different versions of the idea that individualism about agency is the root of standard game theoretical puzzles have been defended by Regan 1980, Bacharach (Research in Economics 53: 117-147, 1999), Hurley (Behavioral and Brain Sciences 26: 264-265, 2003), Sugden (Philosophical Explorations 6(3):165-181, 2003), and Tuomela 2013, among others. While collectivistic game theorists like Michael Bacharach provide formal frameworks designed to avert some of the standard dilemmas, philosophers of collective action like Raimo Tuomela aim at substantive accounts of collective action that may explain how agents overcoming such social dilemmas would be motivated. This paper focuses on the conditions on collective action and intention that need to be fulfilled for Bacharach's "team reasoning" to occur. Two influential approaches to collective action are related to the idea of team reasoning: Michael Bratman's theory of shared intention and Raimo Tuomela's theory of a we-mode of intending. I argue that neither captures the "agency transformation" that team reasoning requires. That might be an acceptable conclusion for Bratman but more problematic for Tuomela, who claims that Bacharach's results support his theory. I sketch an alternative framework in which the perspectival element that is required for team reasoning - the 'we perspective' - can be understood and functionally characterized in relation to the traditional distinction between mode and content of intentional states. I claim that the latter understanding of a collective perspective provides the right kind of philosophical background for team reasoning, and I discuss some implications in relation to Tuomela's assumption that switching between individual and collective perspectives can be a matter of rational choice. PMID- 28725294 TI - Acupuncture benefits for Flammer syndrome in individuals with inherited diseases of the retina. AB - BACKGROUND: Patients with inherited diseases of the retina (IRD) often exhibit signs and symptoms of Flammer syndrome (FS). Acupuncture treatment has shown its positive effect on visual function in patients with IRD. The aim of the present study is to examine the effect of acupuncture on signs and symptoms of FS in a cohort of patients suffering simultaneously FS and IRD. PATIENTS AND METHODS: A prospective pilot study was performed on 17 patients with FS and IRD: rod-cone dystrophy, Nr: 12 (RCD); cone-rod dystrophy, Nr: 3 (CRD) and inherited macular dystrophy, Nr: 2 (IMD; 12?, 5?; mean age: 44.19 y; SD +/-17.09 y). Acupuncture treatment was done applying needle acupuncture of the body and the ears. The treatment was scheduled at 10 half-hour sessions over 5 weeks. Primary outcome was evaluation of the post-acupuncture effect on the signs and symptoms of FS in IRD patients using multiple-choice questionnaires. RESULTS: Following acupuncture, we found improvement in signs and symptoms of FS in patients suffering simultaneously IRD, as for instance (Nr. patients: improvement/suffering/total): a reduced tiredness (10/11/17), shorter sleep onset time (10/11/17), warmer feet and hands (10/10/17) and reduced frequency of headache attacks (9/11/17). Surprisingly, in four RCD patients and in one IMD patient, a reduction of macular edema was documented. CONCLUSIONS: The applied acupuncture protocol for FS in IRD patients showed improvement in FS signs and symptoms and was tolerated well. Nevertheless, the objective evaluation of this complementary therapy on FS in IRD patients remains to be elucidated. PMID- 28725290 TI - The discovery of the Flammer syndrome: a historical and personal perspective. AB - This review describes the clinical and basic research that led to the description of Flammer syndrome. It is narrated from a personal perspective. This research was initiated by the observation of an increased long-term fluctuation of visual fields in a subgroup of glaucoma patients. As these patients had strikingly cold hands, peripheral blood flow was tested with a capillary microscopy, and vasospastic syndrome (VS) was diagnosed. Further studies on these patients revealed frequently weakened autoregulation of ocular blood flow and increased flow resistivity in retroocular vessels. Their retinal vessels were more rigid and irregular and responded less to flickering light. Holistic investigation demonstrated low blood pressure, silent myocardial ischaemia, altered beat-to beat variation, altered gene expression in the lymphocytes, slightly increased plasma endothelin level and increased systemic oxidative stress. This combination of signs and symptoms was better described by the term primary vascular dysregulation (PVD) than by VS. Subsequent studies showed additional symptoms frequently related to PVD, such as low body mass index, cold extremities combined with slightly increased core temperature, prolonged sleep onset time, reduced feelings of thirst, increased sensitivity to smell and also for certain drugs and increased retinal venous pressure. To better characterise this entire syndrome, the term Flammer syndrome (FS) was introduced. Most subjects with FS were healthy. Nevertheless, FS seemed to increase the risk for certain eye diseases, particularly in younger patients. This included normal-tension glaucoma, anterior ischaemic optic neuropathy, retinal vein occlusions, Susac syndrome and central serous chorioretinopathy. Hereditary diseases, such as Leber's optic neuropathy or retinitis pigmentosa, were also associated with FS, and FS symptoms and sings occurred more frequent in patients with multiple sclerosis or with acute hearing loss. Further research should lead to a more concise definition of FS, a precise diagnosis and tools for recognizing people at risk for associated diseases. This may ultimately lead to more efficient and more personalised treatment. PMID- 28725296 TI - Revisiting Folk Moral Realism. AB - Moral realists believe that there are objective moral truths. According to one of the most prominent arguments in favour of this view, ordinary people experience morality as realist-seeming, and we have therefore prima facie reason to believe that realism is true. Some proponents of this argument have claimed that the hypothesis that ordinary people experience morality as realist-seeming is supported by psychological research on folk metaethics. While most recent research has been thought to contradict this claim, four prominent earlier studies (by Goodwin and Darley, Wainryb et al., Nichols, and Nichols and Folds Bennett) indeed seem to suggest a tendency towards realism. My aim in this paper is to provide a detailed internal critique of these four studies. I argue that, once interpreted properly, all of them turn out in line with recent research. They suggest that most ordinary people experience morality as "pluralist-" rather than realist-seeming, i.e., that ordinary people have the intuition that realism is true with regard to some moral issues, but variants of anti-realism are true with regard to others. This result means that moral realism may be less well justified than commonly assumed. PMID- 28725297 TI - Therapeutic strategies with oral fluoropyrimidine anticancer agent, S-1 against oral cancer. AB - Oral cancer has been recognized as a tumor with low sensitivity to anticancer agents. However, introduction of S-1, an oral cancer agent is improving treatment outcome for patients with oral cancer. In addition, S-1, as a main drug for oral cancer treatment in Japan can be easily available for outpatients. In fact, S-1 exerts high therapeutic effects with acceptable side effects. Moreover, combined chemotherapy with S-1 shows higher efficacy than S-1 alone, and combined chemo radiotherapy with S-1 exerts remarkable therapeutic effects. Furthermore, we should consider the combined therapy of S-1 and molecular targeting agents right now as these combinations were reportedly useful for oral cancer treatment. Here, we describe our findings related to S-1 that were obtained experimentally and clinically, and favorable therapeutic strategies with S-1 against oral cancer with bibliographic considerations. PMID- 28725298 TI - Thirst sensation and oral dryness following alcohol intake. AB - Substantial acute and chronic intakes of alcohol or ethanol (EtOH) severely influence oral sensations, such as thirst and oral dryness (dry mouth, xerostomia). Thirst sensation and oral dryness are primarily caused by the activation of neurons in brain regions, including the circumventricular organs and hypothalamus, which are referred to as the dipsogenic center, and by a decrease in salivary secretion, respectively. The sensation of thirst experienced after heavy-alcohol drinking is widely regarded as a consequence of EtOH-induced diuresis; however, EtOH in high doses induces anti-diuresis. Recently, it has been proposed that the ethanol metabolite acetaldehyde induces thirst via two distinct processes in the central nervous system from EtOH-induced diuresis, based on the results of animal experiments. The present review describes new insights regarding the induction mechanism of thirst sensation and oral dryness after drinking alcohol. PMID- 28725299 TI - Role of Streptococcus mutans two-component systems in antimicrobial peptide resistance in the oral cavity. AB - Approximately 100 trillion microorganisms exist in the oral cavity. For the commensal bacteria of the oral cavity, it is important to adapt to environmental stimuli, including human- or bacteria-derived antimicrobial agents. Recently, bacterial-specific signal transduction regulatory systems, called two-component systems (TCSs), which appear to be focused on sensing and adapting to the environment, were discovered. Streptococcus mutans is an oral commensal bacteria and is also known as a cariogenic bacteria. Although the virulence factors of S. mutans have been well demonstrated, the mechanism underlying the adaptation of the species to the oral cavity is poorly understood. S. mutans UA159 has 15 sets of TCSs. Among them, several have been demonstrated to be involved in acid tolerance, competence and biofilm formation. Recently, together with our findings, it was demonstrated that 5 TCSs were involved in resistance to antimicrobial agents. Furthermore, another TCS was associated with the production of bacteriocin. Six of 15 TCSs are associated with antimicrobial agents, implying that S. mutans can survive in the oral cavity by resisting various antimicrobial peptides. In this review, we highlight the role of antimicrobial peptides in the oral cavity. PMID- 28725301 TI - Review of Infectious Etiology of Acute Pancreatitis. AB - While gallstones and alcoholism are widely known to be the most common causative agents of acute pancreatitis, about 10% of cases are thought to be caused by infectious microorganisms. These microorganisms include viruses (e.g. mumps, Coxsackie B, and hepatitis), bacteria (e.g. Mycoplasma pneumoniae and leptospirosis), and parasites (e.g. Ascaris lumbricoides, Fasciola hepatica, and hydatid disease). Each organism causes acute pancreatitis through diverse mechanisms. The review is primarily conducted in an attempt to provide a better understanding of the possibility of acute pancreatitis presenting as a complication relating to these organisms, and the aim is to guide future diagnoses, management, and predictions of complications. PMID- 28725302 TI - The Trend of Tranexamic Use in Upper Gastrointestinal Bleeding Ulcers. AB - BACKGROUND: Bleeding ulcer is a common condition, especially among the elderly population. Tranexamic acid (TXA) has been successfully used for many bleeding conditions. Its use in patients with bleeding ulcer is inclusive yet. The aim of this study was to provide an overview of the prescription of TXA. METHODS: This retrospective cohort study was performed as a review of medical records at the Surgery Department, University Hospital in Linkoping. Patients with complete esophagogastroduodenoscopy and ulcer disease were included and divided on the basis of treatment with TXA or not. Differences between the groups were statistically analyzed. RESULTS: The main part of the prescription of TXA, 65%, occurred during 2010 and 2011, and 35% between 2012 and 2013 (P < 0.05). In the group treated with TXA, 84% needed blood transfusion, compared to 64% in the control group (P = 0.039). Of the patients treated with TXA, 18% were re-bleeding compared to 14% of the controls (P = 0.594). Median value for days at hospital was 5 in the tranexamic group and 3 in the control group (P = 0.005). CONCLUSION: The prescription of TXA has declined between 2010 and 2013. TXA was more often prescribed to patients with more severe gastrointestinal (GI) bleeding ulcer disease. Further investigation is needed to conclude the significance of tranexamic acid in patients with GI bleeding ulcer disease. PMID- 28725300 TI - Epstein-Barr virus (EBV)-associated epithelial and non-epithelial lesions of the oral cavity. AB - Epstein-Barr virus (EBV) is known to be associated with the development of malignant lymphoma and lymphoproliferative disorders (LPDs) in immunocompromised patients. EBV, a B-lymphotropic gamma-herpesvirus, causes infectious mononucleosis and oral hairy leukoplakia, as well as various pathological types of lymphoid malignancy. Furthermore, EBV is associated with epithelial malignancies such as nasopharyngeal carcinoma (NPC), salivary gland tumor, gastric carcinoma and breast carcinoma. In terms of oral disease, there have been several reports of EBV-related oral squamous cell carcinoma (OSCC) worldwide. However, the role of EBV in tumorigenesis of human oral epithelial or lymphoid tissue is unclear. This review summarizes EBV-related epithelial and non epithelial tumors or tumor-like lesions of the oral cavity. In addition, we describe EBV latent genes and their expression in normal epithelium, inflamed gingiva, epithelial dysplasia and SCC, as well as considering LPDs (MTX- and age related) and DLBCLs of the oral cavity. PMID- 28725303 TI - Evaluation of Esophageal Functions by Manometry in Iron Deficiency Anemia Patients. AB - BACKGROUND: The aim of this study was to investigate whether any esophageal motor dysfunction exists in patients with iron deficiency anemia (IDA). METHODS: The study included 39 patients (34 women, mean age: 44.17 +/- 14.21 years) who met WHO diagnostic criteria for IDA. An additional 30 functional dyspepsia patients were also included as a control group. Esophageal motility testing was performed; esophagus contraction amplitude, peak velocity, contraction time, lower esophageal sphincter (LES) resting pressure, LES relaxation, and LES relaxation duration were assessed. RESULTS: A majority (76.4%) of patients had at least one IDA symptom, such as reflux, chest pain, or dysphagia. Manometric findings in IDA patients vs. controls were as follows: mean LES resting pressure (mm Hg): 25.41 +/- 11.67 vs. 19.96 +/- 6.58 (P = 0.025); mean esophageal contraction amplitude (mm Hg): 61.61 +/- 24.21 vs. 63.23 +/- 18.86 (P = 0.764); mean LES relaxation duration (s, x +/- SD): 5.33 +/- 1.61 vs. 8.75 +/- 1.86 (P = 0.000); mean LES relaxation (%): 93.30 +/- 9.88 vs. 95.53 +/- 5.81 (P = 0.278); mean peak velocity (cm/s): 12.67 +/- 37.95 vs. 3.50 +/- 1.63 (P = 0.191). Esophageal dysmotility was found in 11 (28.2%) IDA patients. Non-specific esophageal motor disorder was found in three patients, hypomotility of the esophagus was found in three patients, achalasia was found in two patients, hypertensive LES was found in two patients, and hypotensive LES was found in one patient. CONCLUSION: LES resting pressure was higher and LES relaxation duration was shorter in patients with IDA. Esophageal dysmotility was present in 28.2% of the patients with IDA A little more than half of patients had dysphagia symptoms. IDA may contribute to esophageal motility dysfunction and esophageal symptoms. PMID- 28725304 TI - High C-Reactive Protein and Low Albumin Levels Predict High 30-Day Mortality in Patients Undergoing Percutaneous Endoscopic Gastrotomy. AB - BACKGROUND: Percutaneous endoscopic gastrotomy (PEG) enables long-term enteral feeding. The aim of this study was to identify biomarkers that may guide the decision of whether to perform the elective procedure of PEG. METHODS: The medical records of all patients who underwent PEG in our hospital from 2010 to 2016 were screened retrospectively. Patients with mortality within a 30-day follow-up period and those without were compared using the Chi-square test, and continuous variables were compared with the Kruskal-Wallis and Mann-Whitney U tests. Receiver operating characteristic (ROC) curve analysis was used to demonstrate the ability of biomarkers to predict mortality; a cut-off point was determined and its sensitivity, specificity, and positive and negative predictive values were calculated. The Youden index was used to determine the cut-off point. Kaplan-Meier analysis was used to identify PEG-related mortality risk factors and a Cox regression model was applied for risk characterization. RESULTS: A total of 120 patients who underwent PEG were evaluated in the study. The mean age was 67.00 +/- 18.00 years. The most common indication for PEG was cerebrovascular disease, in 69 (57.5%) of the patients. Infection of the PEG site was most common within 14 days after PEG tube placement, occurring in 13 patients (10.3%). The mortality rate among patients with post-PEG infection was 68.2%, significantly higher than in patients without infection (P = 0.012). Thirty-four patients (28.3%) died within 30 days of undergoing PEG. CRP values >= 78.31 mg/L increased mortality by 8.756-fold, and albumin levels < 2.71 g/dL increased mortality by 2.255-fold. CONCLUSION: Our results indicate that the presence of both high CRP level and low albumin level were associated with significantly higher rate of mortality (73.1%) in patients who underwent PEG. PMID- 28725305 TI - International Normalized Ratio Does Not Predict Gastrointestinal Bleeding After Endoscopic Retrograde Cholangiopancreatography in Patients With Cirrhosis. AB - BACKGROUND: Cirrhosis is often accompanied by an elevated international normalized ratio (INR) due to a decrease in pro-coagulant factors. An elevated INR in cirrhosis is often interpreted as an increased risk of bleeding. There are a paucity of data in the literature on the use of INR to predict risk of gastrointestinal bleeding (GIB) following endoscopic retrograde cholangiopancreatography (ERCP) in patients with cirrhosis. The aims of the study were to determine if there is a correlation between INR and GIB following ERCP in patients with cirrhosis, and to determine if there is a difference in frequency of post-ERCP complications in patients with and without cirrhosis. METHODS: A retrospective review of all ERCP procedures was performed at a tertiary care institution between 2012 and 2015. We identified ERCPs performed in patients with cirrhosis and compared them to a randomly selected group without liver cirrhosis. Univariate analysis was performed using Chi-square and ANOVA tests. A multivariable logistic regression model using generalized estimating equations was used to examine the association between INR and GIB. RESULTS: There were a total of 1,610 ERCPs performed from 2012 to 2015 with 129 performed in 56 patients with cirrhosis compared with 392 ERCPs performed in 310 patients without cirrhosis. There was no difference in the frequency of GIB following ERCP in both groups (P = 0.117). However, there was a difference in overall complications between both groups (P = 0.007), but no difference observed amongst Child Turcotte-Pugh classes (P = NS). In a multivariable analysis, sphincterotomy during ERCP (odds ratio (OR) = 3.22; 95% confidence interval (CI): 1.05 - 9.94; P = 0.042) and cirrhosis (OR = 3.58; 95% CI: 1.22 - 10.47; P = 0.02) were significant for predicting GIB. Anti-coagulation (OR = 2.90; 95% CI: 0.82 - 10.23; P = 0.097) and INR were not significant in the multivariable model (OR = 2.09; 95% CI: 0.85 - 5.12; P = 0.10). CONCLUSION: There was a statistical difference in overall complications between patients with and without cirrhosis but no difference was observed amongst Child-Turcotte-Pugh classes. Overall, INR was not a significant factor in predicting risk of bleeding in patients after ERCP. PMID- 28725306 TI - Histology and Glutamine Synthetase Immunoreactivity in Liver Biopsies From Patients With Congestive Heart Failure. AB - BACKGROUND: Long-standing congestive heart failure can induce a constellation of histopathology changes in the liver that can range from mild sinusoidal dilation to advanced fibrosis and loss of normal perivenular expression of glutamine synthetase (GS). Liver biopsies might be performed to assess the perioperative risk of these patients or to determine the need of synchronous liver transplant. We aimed to assess interobserver agreement in recognizing these liver histologic features in patients undergoing evaluation for heart transplantation and to examine whether immunohistochemistry of GS will aid the diagnosis of cardiac hepatopathy (CH). METHODS: Hematoxylin-eosin and trichrome-stained slides from 36 liver biopsies from patients undergoing evaluation for heart transplantation were reviewed by four liver pathologists. Histologic features of CH were reviewed and an overall fibrosis (stage) was assessed according to a recently proposed congestive hepatic fibrosis score (CHFS). In addition, 24 liver biopsies with a consensus diagnosis of CH and eight liver biopsies with no significant pathological changes were subjected to immunohistochemistry for GS. The Fleiss' kappa coefficient (K) analysis was performed to determine the interobserver agreement. Further, histologic features of CH were correlated with the staining pattern of GS. RESULTS: Sinusoidal dilation, centrilobular hepatocyte atrophy, centrilobular fibrosis and hemorrhage were the most common findings in this cohort with a substantial-to-fair level of interobserver agreement among four reviewers. The overall agreement on the diagnosis of CH and CHFS was moderate (K = 0.55, 95% confidence interval (CI): 0.32 - 0.73) and fair (K = 0.35, 95% CI: 0.24 - 0.49), respectively. Twelve (of 24, 50%) cases of CH showed loss of the normal perivenular GS staining, while the remaining 12 cases of CH and all eight controls showed retained GS expression. Histologic features of CH (presence of sinusoidal dilation, centrilobular hepatocyte atrophy, hemorrhage, and centrilobular fibrosis) and the stage of fibrosis (CHFS) were not correlated with the loss of GS staining. CONCLUSION: Most common features of CH can be interpreted with fair-to-substantial level of agreement by liver pathologists, with an overall moderate level agreement for the diagnosis and fair agreement for CHFS. Loss of normal perivenular expression of GS only occurs in 50% CH and thus is not a sensitive marker for CH. PMID- 28725307 TI - Acute Pancreatitis Secondary to Severe Hypertriglyceridemia: Management of Severe Hypertriglyceridemia in Emergency Setting. AB - Hypertriglyceridemia (HTG) is the third most common cause of acute pancreatitis (AP). The incidence of AP is around 10-20% with levels > 2,000 mg/dL. We present here a case of a 44-year-old male with history of uncontrolled diabetes mellitus and HTG admitted with severe abdominal pain. Labs revealed elevated lipase and amylase. CT of abdomen with contrast showed AP. He was found to have a triglyceride (TG) level of 6,672 mg/dL. Besides conventional treatment for AP with intravenous (IV) hydration, he was started on IV regular insulin along with dextrose saline. He had marked improvement in his TG level the next day. He was continued on insulin and dextrose saline with hourly glucose monitoring until TG was < 500 mg/dL. He was discharged on statins and fenofibrate. The goal of management of AP secondary to severe HTG in emergency setting is to lower the TG levels to less than 500 as quickly as possible as lower levels are associated with good clinical outcomes. Apheresis and IV insulin are both helpful in lowering TG levels with no randomized controlled trials showing greater efficacy of one over other. Further episodes of AP can be prevented by lifestyle modification and lipid lowering drugs to keep TG levels below 500 mg/dL. Fibrates are first-line drugs to lower TG and used either alone or in conjunction with statins. Periodic plasmapheresis can also be considered in some non-compliant patients with recurrent episodes of pancreatitis. PMID- 28725308 TI - A Case With Vitamin D Deficiency-Induced Cytomegalovirus Enteritis Presenting as Bowel Pseudo-Obstruction. AB - Cytomegalovirus (CMV) infection in small intestines has rarely been reported. We report a 67-year-old woman with abdominal pain for 2 weeks. Abdominal computed tomography (CT) revealed wall-thickening of the segmental small bowel. Enteroscopy disclosed discrete ulcers at the jejunum, and biopsy histopathology showed positive CMV immunoreactivity. Laboratory tests showed positive blood CMV with a viral load of 9,400 DNA copies/mL and high IgG titer and low vitamin D level. After antiviral therapy and oral vitamin D supply, her symptoms improved. Follow-up CT and enterology showed resolved enteritis. PMID- 28725309 TI - Cronkhite-Canada Syndrome: A Rare Cause of Chronic Diarrhea. AB - Cronkhite-Canada syndrome (CCS) is a rare non-hereditary disease characterized by chronic diarrhea, diffuse intestinal polyposis and onychodystrophy. We present here a case of a middle-aged female who presented with chronic intermittent bloody diarrhea associated alopecia and loss of finger and toe nails. Labs were remarkable for microcytic anemia and severe hypoalbuminemia. Endoscopy showed numerous polyps scattered throughout the colon. She was treated with nutritional support and corticosteroid with complete resolution of her symptoms and endoscopic findings. CCS is associated with high mortality and gastrointestinal malignancies. Clinicians should consider CCS in a patient with unexplained chronic diarrhea and ectodermal abnormalities. PMID- 28725310 TI - Refractory Celiac Disease Successfully Treated With Azathioprine. AB - Refractory celiac disease (CD) is a clinical diagnosis defined by the persistence of signs/symptoms, laboratory abnormalities or villous atrophy typical of CD despite strict adherence to a gluten-free diet for at least 6 - 12 months. It should be suspected when patients with CD fail to respond primarily or secondarily to a gluten-free diet, especially if there is significant weight loss. Differentiation between types is important both for management and predicting prognosis. Type I can be managed with mild immunosuppression with nutritional support. Type II requires strong immunosuppression like azathioprine. Recently, autologous stem cell transplantation has also been used to treat type II. PMID- 28725311 TI - Nafcillin-Induced Allergic Eosinophilic Cholestatic Hepatitis. AB - A 71-year-old female with no history of liver disease or antibiotic allergy developed jaundice with elevated liver enzymes and eosinophilia following treatment with nafcillin for septic arthritis. Further workup demonstrated hepatocellular dysfunction and liver biopsy showed expansion of portal tracts by lymphocytes and eosinophils consistent with a hypersensitivity reaction. Nafcillin and related antibiotics were withdrawn, and her symptoms resolved 3 months later. We searched PubMed using terms of "nafcillin cholestasis" and "nafcillin hepatitis", and a review of the literature showed other reports of nafcillin-induced hepatitis and cholestasis. Avoidance and on occasion the guarded use of glucocorticoids can lead to recovery from the insult. This case report shows that while rare, nafcillin can cause cholestatic hepatitis through a likely eosinophil-mediated hypersensitivity reaction. Further studies are needed to elucidate the mechanism of this reaction. PMID- 28725312 TI - Two Cases of Pneumatosis Cystoides Intestinalis With Intraperitoneal Free Air. AB - Intraperitoneal free air (IFA) is sometimes accompanied by pneumatosis cystoides intestinalis (PCI); therefore, proper diagnosis is essential for PCI management. We report two cases of PCI with IFA. A 70-year-old female taking anti-psychotic medication for schizophrenia presented with repeated vomiting and high-grade fever. Computed tomography revealed small, linear gaseous cysts in the intestinal wall along with IFA. Although there was no sign of peritoneal irritation, intestinal perforation was not excluded. Thus, exploratory laparotomy was performed; it revealed no ascites or perforated sites in the intestine, and revealed numerous small air bubbles in the intestinal wall and mesentery. Thus, a diagnosis of PCI was made, and ileostomy was performed to relieve intestinal pressure. The postoperative course was uneventful. A 79-year-old male with pulmonary emphysema presented with dyspnea due to abdominal distention. Cyanosis was evident, and arterial blood gas analysis revealed metabolic acidosis. CT revealed massive IFA along with multiple, small bubbly cysts under the intestinal serosa. He was intubated because of worsening respiratory conditions, and a 12 French drain was inserted to relieve the intraperitoneal pressure. There was no evidence of peritonitis, and IFA was conservatively observed. PMID- 28725313 TI - The Influence of Motivational Interviewing on Patients With Inflammatory Bowel Disease: A Systematic Review of the Literature. AB - Inflammatory bowel disease (IBD) is a condition accompanied by several physical and often psychological symptoms (e.g., depression). Treatments generally involve dietary modifications and prescription medications. Of concern, non-adherence rates with prescription medications for this population have been reported to be between 30% and 45%. In order to examine an intervention that has shown promise in improving adherence, researchers systematically reviewed the literature in order to determine the impact of a motivational interviewing (MI) intervention on outcomes for individuals diagnosed with IBD. The outcomes assessed were broad and included, among others, the target behaviors of medication adherence and advice seeking, and also patient-perceived provider empathy. Results suggest that MI can be effective in improving outcomes for individuals with IBD since patients experienced improved adherence rates, displayed greater advice-seeking behavior, and perceived providers as having more empathy and better communication skills. Further research is required since the pool of retained studies is small, evidencing a paucity of literature focusing on this evidence-based health behavior intervention for the behaviors needed to optimally manage IBD. Further, only adults were examined in these studies, so generalizations to children and adolescents are limited. PMID- 28725314 TI - Actions of the Biceps Brachii at the Shoulder: A Review. AB - Bi-articular muscles cross more than one joint and contribute to motion at both joints, and the extremities of the human body contain several such muscles. Actions produced by all muscles are determined, to a large extent, by joint moment arms and muscle length. These are transient factors which change as joint angles are altered. Measuring muscle moments while manipulating both joints will produce a better understanding of the actions of bi-articular muscles. This review summarizes investigations which have explored the actions of the biceps brachii as shoulder and elbow joints are moved into various angle combinations. Clinical implications of the findings are discussed. PMID- 28725315 TI - Oligoclonal Pattern/Abnormal Protein Bands in Post-Treatment Plasma Cell Myeloma Patients: Implications for Protein Electrophoresis and Serum Free Light Chain Assay Results. AB - BACKGROUND: The impact of autologous stem cell transplantation (ASCT) in plasma cell myeloma patients on the frequency, quality, and timing of oligoclonal pattern in serum protein electrophoresis/immunofixation electrophoresis (SPEP/SIFE) and serum free light chain assay (SFLCA) was evaluated. METHODS: Laboratory results and clinical data for 251 patients with plasma cell myeloma, who had SPEP/SIFE and/or SFLCA performed between January 2010 and December 2016 were reviewed. The results for SPEP/SIFE and SFLCA were compared in patients with ASCT to those without ASCT. The implications of oligoclonal pattern in interpretation of SPEP/SIFE and SFLCA - kappa/lambda ratio were addressed. RESULTS: In 251 patients, a total of 3,134 observations, of either SPEP/SIFE and/or SFLCA, were reviewed. One hundred fifty-nine patients received ASCT. The incidence of oligoclonal patterns was significantly higher after ASCT. More than half of the oligoclonal patterns developed in the first year after transplantation. In 13 of the 84 patients with lambda chain restricted plasma cell myeloma, the kappa/lambda ratio was kappa dominant in the presence of oligoclonal pattern. There was no reversal of kappa/lambda ratio in patients with kappa chain restricted plasma cell myelomas. CONCLUSIONS: ASCT is associated with significantly higher incidence of oligoclonal patterns than with chemotherapy alone. The presence of oligoclonal patterns has the potential to interfere with the interpretation of SPEP/SIFE and ascertainment of complete remission. At a minimum, the oligoclonal pattern caused an incorrect kappa dominant kappa/lambda ratio in 15.5% of patients with lambda chain restricted plasma cell myeloma. If a similar rate were to be applied to the 167 kappa chain myeloma patients, about 26 of these would have displayed an erroneous kappa chain dominant kappa/lambda ratio. The presence of oligoclonal pattern further degrades the performance of already dubious SFLCA. The need for recording the location of monoclonal spike in SPEP/SIFE and higher resolution protein electrophoresis methods are highlighted. PMID- 28725316 TI - Post-Prandial Plasma Glucose Less Than or Equal to 70 mg/dL Is Not Uncommon in Young Japanese Women. AB - BACKGROUND: Post-breakfast/post-challenge plasma glucose (PG) concentrations were studied less in young normal weight Japanese women. We addressed these issues. METHODS: Two separate groups of female collegiate athletes and female untrained students underwent either a standardized meal test or a standard 75-g oral glucose tolerance test, but not both. Frequency of women whose post breakfast/post-load PG fell to 70 mg/dL or lower (termed as low glycemia) was compared between athletes and non-athletes, who also underwent measurements of serum adipokines, markers of insulin resistance and inflammation and dual-energy X-ray absorptiometry. Insulin secretion, insulin sensitivity/resistance and serum adipokines were compared between women with and without post-breakfast low glycemia. The same comparison was done between women whose post-breakfast PG returned to levels below the fasting PG and women whose post-breakfast PG never fell below the fasting PG. RESULTS: There was no difference between athletes and non-athletes in frequency of post-breakfast low glycemia (47% (8/17) and 44% (8/18)) and post-challenge low glycemia (24% (12/50) and 23% (27/118)). As compared to seven women whose post-breakfast PG never fell below the fasting PG, 28 women whose post-breakfast PG returned to levels below the fasting PG had higher meal-induced insulin responses (283 +/- 366 vs. 89 +/- 36 uU/mg, P = 0.014). However, two groups did not differ in body composition, markers of insulin resistance and serum adiponectin. No significant difference was also observed in any of these variables between women with and without post-breakfast low glycemia. CONCLUSION: Post-prandial PG <= 70 mg/dL is not uncommon in young normal weight Japanese women and may not be a pathological condition. The underlying mechanisms for this finding need further exploration. PMID- 28725317 TI - Prevalence of Metabolic Syndrome Among the End-Stage Renal Disease Patients on Hemodialysis. AB - BACKGROUND: Patients with metabolic syndrome (MetS) have a 2.6-fold greater risk of incident chronic kidney disease (CKD). The primary goal of this study was to assess the prevalence of MetS in patients with end-stage renal disease (ESRD) who are on hemodialysis (HD) and the impact of MetS presence on HD-related outcomes. METHODS: This is a cross-sectional study conducted in the Dialysis Center, King Abdulaziz Specialist Hospital, Taif, Saudi Arabia. It was conducted among ESRD patients that attended the Dialysis Center between August 2013 and September 2016. We excluded patients on peritoneal dialysis and those < 18 years old. We used the International Diabetes Federation (IDF) criteria to identify patients with MetS. RESULTS: A total of 241 patients with ESRD on HD were found, with a mean age of 48.8 (SD 16) years, mean body mass index (BMI) of 25.6 (SD 8.7) kg/m2, and mean waist circumference (WC) of 92.0 (SD 23.5) cm. The mean duration of the HD was 69.3 (SD 65.6) months with arteriovenous fistula (AVF) as the most common access for HD. Of the patients, 38.2% had MetS. Compared to those without MetS, those with MetS were more likely to be older (P < 0.001), be female (P < 0.001), be married (P < 0.001), have higher BMI (P < 0.001), have larger WC (P < 0.001), have T2D and hypertension (HTN) (P < 0.001), have shorter HD duration (P < 0.001), have a longer duration since the AVF was placed (P = 0.026), and have high post-HD creatinine levels (P = 0.010) and were less likely to have adequate HD (P = 0.004) and have parathyroid hormone (PTH) at goal (P = 0.046). CONCLUSION: MetS is common among ESRD and MetS was associated with more comorbidity, worse anthropometric measures at baseline, and worse HD-related outcomes. The limitations were small sample size and single center. PMID- 28725318 TI - Detection of Apolipoprotein E Gene Polymorphism and Blood Lipid Level in Hemodialysis Patients. AB - BACKGROUND: The aim was to investigate the clinical characteristics of lipid metabolism and the effect of apolipoprotein E (ApoE) gene polymorphism on lipid metabolism in hemodialysis patients. METHODS: The serum levels of total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDLC), low-density lipoprotein cholesterol (LDLC), ApoA1, ApoB, ApoE and lipoprotein Lp(a) were detected by polymerase chain reaction-restriction fragment length (PCR RFLP). RESULTS: The level of serum TG was significantly increased and the level of HDLC was significantly decreased in hemodialysis patients. Serum TG level was 33% higher than normal, and HDLC was 10.4% less than normal. The correlation analysis showed that TG level was significantly correlated with serum albumin level and extracorporeal circulation blood flow during dialysis. HDLC was significantly correlated with KT/V. The incidence of hypertension in hemodialysis patients was 73.6% and cardiovascular disease was 25%. The level of TG in the cardiovascular disease group was significantly higher than that in the non cardiovascular disease group, and there was no significant difference between the hypertensive group and the non-hypertensive group. ApoE gene polymorphism test showed that the frequency of ApoE genotype epsilon3/3 and allele epsilon3 was the highest in hemodialysis patients, and the levels of TC, TG and LDLC were higher in ApoE genotype epsilon3/4 + epsilon4/4. CONCLUSION: The levels of serum TG and ApoB were significantly increased in patients with hemodialysis, and HDLC and other indexes were significantly decreased. The level of TG in patients with cardiovascular complications was significantly higher than in patients without complications. TG level was significantly correlated with serum albumin level and extracorporeal circulation blood flow during dialysis. HDLC was significantly correlated with KT/V. Hemodialysis patients who had ApoE allele epsilon4 are prone to lipid metabolism disorders. PMID- 28725319 TI - Autologous Stromal Vascular Fraction in the Intravenous Treatment of End-Stage Chronic Obstructive Pulmonary Disease: A Phase I Trial of Safety and Tolerability. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a consistently progressive, ultimately fatal disease for which no treatment exists capable of either reversing or even interrupting its course. It afflicts more than 5% of the population in many countries, and it accordingly represents the third most frequent cause of death in the US, where it accounts for more than 600 billion in health care costs, morbidity, and mortality. Adipose tissue contains within its stromal compartment a high abundance of adipose stem/stromal cells (ASCs), which can be readily separated from the adipocyte population by methods which require less than 2 h of processing time and yield a concentrated cellular preparation termed the stromal vascular fraction (SVF). The SVF contains all cellular elements of fat, excluding adipocytes. Recent clinical studies have begun to explore the feasibility and safety of the local injection or intravascular delivery of SVF or more purified populations of ASCs derived by culture protocols. Several pre-clinical studies have demonstrated a remarkable ability of ASC to nearly fully ameliorate the progress of emphysema due to cigarette smoke exposure as well as other causes. However, no prior clinical studies have evaluated the safety of administration of either ASC or SVF in subjects with COPD. We hypothesized that harvest, isolation, and immediate intravenous infusion of autologous SVF would be feasible and safe in subjects with COPD; and that such an approach, if ultimately determined to be efficacious as well as safe, would provide a highly practical method for treatment of COPD. METHODS: In this study, an initial phase I trial evaluating the early and delayed safety of SVF infusion was performed. Twelve subjects were enrolled in the study, in which adipose tissue was harvested using standard liposuction techniques, followed by SVF isolation and intravenous infusion of 150 - 300 million cells. Standardized questionnaires were administered to study feasibility as well as immediate and delayed outcomes and adverse events as primary endpoints. Secondary endpoints included subjective wellness and attitudes towards the procedure, as well as willingness to undergo the procedure a second time. The follow-up time ranged from 3 to 12 months, averaging 12 months. RESULTS: Of the 12 subjects, only one experienced an immediate adverse event, related to bruising from the liposuction. No observed pulmonary or cardiac issues were observed as related to the procedure. There were no deaths over the 12-month study period, and none identified in the subsequent telephonic follow-up. Attitudes toward the procedure were predominantly positive, and 92% of the study subjects expressed a desire to undergo the procedure a second time. CONCLUSIONS: This study is the first to demonstrate safety of SVF infusion in humans with serious pulmonary disease. Specifically, the use of intravenous infusion as a route to achieve pulmonary cellular targeting did not lead to clinical pulmonary compromise. The intravenous administration of SVF should be further explored as a potentially feasible and safe method for delivery leading to possible therapeutic benefit. PMID- 28725320 TI - Splice Site Variants in the KCNQ1 and SCN5A Genes: Transcript Analysis as a Tool in Supporting Pathogenicity. AB - BACKGROUND: Approximately 75% of clinically definite long QT syndrome (LQTS) cases are caused by mutations in the KCNQ1, KCNH2 and SCN5A genes. Of these mutations, a small proportion (3.2-9.2%) are predicted to affect splicing. These mutations present a particular challenge in ascribing pathogenicity. METHODS: Here we report an analysis of the transcriptional consequences of two mutations, one in the KCNQ1 gene (c.781_782delinsTC) and one in the SCN5A gene (c.2437 5C>A), which are predicted to affect splicing. We isolated RNA from lymphocytes and used a directed PCR amplification strategy of cDNA to show mis-spliced transcripts in mutation-positive patients. RESULTS: The loss of an exon in each mis-spliced transcript had no deduced effect on the translational reading frame. The clinical phenotype corresponded closely with genotypic status in family members carrying the KCNQ1 splice variant, but not in family members with the SCN5A splice variant. These results are put in the context of a literature review, where only 20% of all splice variants reported in the KCNQ1, KCNH2 and SCN5A gene entries in the HGMDPro 2015.4 database have been evaluated using transcriptional assays. CONCLUSIONS: Prediction programmes play a strong role in most diagnostic laboratories in classifying variants located at splice sites; however, transcriptional analysis should be considered critical to confirm mis splicing. Critically, this study shows that genuine mis- splicing may not always imply clinical significance, and genotype/phenotype cosegregation remains important even when mis-splicing is confirmed. PMID- 28725321 TI - Effect of Switching From an Anti-Diabetic Loose Dose Combination to a Fixed Dose Combination Regimen at Equivalent Dosage for 6 Months on Glycemic Control in Japanese Patients With Type 2 Diabetes: A Pilot Study. AB - BACKGROUND: Patients with type 2 diabetes mellitus often take multiple anti diabetic drugs for a long period. Fixed dose combination (FDC) therapy is expected to improve drug adherence for patients with diabetes. The effect of switching from a loose dose combination (LDC) regimen to an FDC regimen at equivalent dosage on glycemic control has not been evaluated fully. Therefore, we investigated the effect of switching from LDC to FDC at equivalent dosage for 6 months on glycemic control in Japanese patients with type 2 diabetes. METHODS: Thirty-eight Japanese patients with type 2 diabetes who were taking anti-diabetic drugs including pioglitazone + metformin, pioglitazone + alogliptin, or pioglitazone + glimepiride were enrolled. These drugs were switched to an FDC of Metact(r), Liobel(r) or Sonias(r), respectively, at equivalent dosage. Other anti diabetic drugs and units of insulin were not changed during the study if possible. HbA1c and body weight were measured 0, 2, 4 and 6 months after switching from an LDC to FDC. We also conducted a questionnaire survey 2 months after the start of the FDC regimen. RESULTS: HbA1c levels at 2, 4, and 6 months were not significantly changed compared with prior to switching from an LDC to FDC regimen. Moreover, 74.2% of patients considered decreasing the number of drugs to be "very good" or "good". CONCLUSION: HbA1c levels did not differ between patients receiving LDC and FDC therapy at equivalent dosage in this study. PMID- 28725322 TI - Recurrent Body Rash Warranted Second Desensitization With Acyclovir in a Myeloma Patient: A Case Report. AB - A 75-year-old woman developed a moderately severe rash about a week and a half after the start of bortezomib (Btb)-based chemotherapy for IgG lambda multiple myeloma; at the time, she was also receiving acyclovir as antiviral prophylaxis in addition to herpes zoster (HZ) vaccination. HZ reactivation rate is high in Btb recipients; therefore, the timing of antiviral prevention is critical in relation to Btb. Attempts were made to identify the offending agent based on the timing of drugs administered and the appearance of skin lesions in relation to other drugs. Both Btb and acyclovir were potential culprits. However, the timing of rash presented on days 9 - 10 revealed the offending agent when the corticosteroid was weaned off while acyclovir continued. A decision was made to administer acyclovir rapid desensitization program (RDP) for our patient. PMID- 28725323 TI - The Elevation of Cardio-Ankle Vascular Index in a Patient With Malignant Lymphoma Treated With a Combination Therapy of Rituximab and Cyclophosphamide, Doxorubicin, Vincristine, and Prednisolone. AB - An increased risk of arteriosclerosis has been noted in cancer survivors. Currently, there are only a few reports available that consider the risk of arteriosclerosis in patients treated with chemotherapy. Patients with an advanced stage B-cell malignant lymphoma are typically treated with a combination therapy of rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisolone (R CHOP). Complications such as diabetes mellitus (DM), hyperlipidemia (HL), and osteoporosis due to prednisolone and cardiotoxicity due to anthracyclines are well known. However, there are no studies that have investigated the link between R-CHOP therapy and arteriosclerosis. We discussed a patient with follicular lymphoma who was evaluated using cardio-ankle vascular index (CAVI) as an arterial stiffness parameter during R-CHOP therapy in this report. She achived complete remission after the eighth course therapy without complications such as hypertension (HT), HL, DM, and infection. This patient showed elevated CAVI with new plaque formation in the carotid arteries after the end of chemotherapy. These data indicate that R-CHOP therapy may progress the arteriosclerosis. PMID- 28725324 TI - Cardiorenal Syndrome: Role of Arginine Vasopressin and Vaptans in Heart Failure. AB - Heart and kidney failure continued to be of increasing prevalence in today's society, and their comorbidity has synergistic effect on the morbidity and mortality of patients. Cardiorenal syndrome (CRS) is a complex disease with multifactorial pathophysiology. Better understanding of this pathophysiological network is crucial for the successful intervention to prevent advancement of the disease process. One of the major factors in this process is neurohormonal activation, predominantly involving renin-angiotensin-aldosterone system (RAAS) and arginine vasopressin (AVP). Heart failure causes reduced cardiac output/cardiac index (CO/CI) and fall in renal perfusion pressures resulting in activation of baroreceptors and RAAS, respectively. Activated baroreceptors and RAAS stimulate the release of AVP (non-osmotic pathway), which acts on V2 receptors located in the renal collecting ducts, causing fluid retention and deterioration of heart failure. Effective blockade of AVP action on V2 receptors has emerged as a potential treatment option in volume overload conditions especially in the setting of hyponatremia. Vasopressin receptor antagonists (VRAs), such as vaptans, are potent aquaretics causing electrolyte-free water diuresis without significant electrolyte abnormalities. Vaptans are useful in hypervolemic hyponatremic conditions like heart failure and liver cirrhosis, and euvolemic hyponatremic conditions like syndrome of inappropriate anti-diuretic hormone secretion. Tolvaptan and conivaptan are pharmaceutical agents that are available for the treatment of these conditions. PMID- 28725325 TI - Left Atrial Appendage Volume and Plasma Docosahexaenoic Acid Levels Are Associated With Atrial Fibrillation Recurrence After Catheter Ablation. AB - BACKGROUND: Risk factors for atrial fibrillation (AF) recurrence in patients who have undergone AF catheter ablation have not been fully clarified. The objective of this study was to assess whether the left atrium (LA) and LA appendage (LAA) volumes, and cardio-metabolic markers such as polyunsaturated fatty acids (PUFAs) levels were associated with AF recurrence. METHODS: Seventy-seven consecutive patients with AF (mean age, 59 +/- 8 years; male, 81%; paroxysmal AF, 64%) undergoing catheter ablation were enrolled. Using contrast-enhanced cardiac multi detector computed tomography (MDCT) scan, the LA and LAA volume and orifice area were assessed. Radiofrequency ablation was performed by an irrigation catheter, initially targeting the pulmonary veins with a wide area circumferential ablation. RESULTS: Patients with AF recurrence (36%) exhibited both larger LAA volumes and an LAA orifice area than those without AF recurrence, whereas the LA diameter and LA volumes were not significantly different. Notably, AF recurrence occurred in all patients with a large LAA (>= 25 mL), and the LAA volume was significantly and negatively associated with docosahexaenoic acid (DHA) levels (beta = -0.33, P = 0.003). A multiple regression analysis revealed that the log N terminal proB-type natriuretic peptide and plasma DHA levels were independent factors for the LAA volume when adjusted for age, AF detected age, left ventricular (LV) ejection fraction, end-systolic LV diameter. CONCLUSIONS: These results suggest that the association between LAA volume and low plasma DHA levels may be an important factor for post-ablation AF recurrence. PMID- 28725326 TI - Comparison of Clopidogrel With Prasugrel and Ticagrelor in Patients With Acute Coronary Syndrome: Clinical Outcomes From the National Cardiovascular Database ACTION Registry. AB - BACKGROUND: We aimed to compare the clinical outcomes of clopidogrel, prasugrel, and ticagrelor in clinical practice using the National Cardiovascular Database ACTION Registry(r). Treatment guidelines for patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention recommend dual antiplatelet therapy (DAPT) for 12 months. Few clinical trials have compared the safety and efficacy of clopidogrel with that of newer antiplatelet therapies. METHODS: A retrospective study of patients hospitalized for ACS at Cleveland Clinic Akron General was conducted. Data elements included detailed medical history and clinical outcomes during hospital stay. The primary outcome was a composite of major clinical events (cardiogenic shock, atrial fibrillation, ventricular fibrillation, ventricular tachycardia, heart failure, bleeding, and mechanical ventilation). The independent variable was the type of DAPT. Statistical analyses were performed using Chi-square and Mann-Whitney U tests. A post-hoc analysis was performed to compare between the antiplatelet drugs head-to head. RESULTS: Subjects (n = 1,388) admitted between January 2011 and March 2016 with ACS and treated with clopidogrel, prasugrel, or ticagrelor were included in the study. Mean age was 65 +/- 14 years and 46% had ST-segment elevation myocardial infarction. Prasugrel administration within 24 h was associated with a lower incidence of the composite outcome (P = 0.049), bleeding (P = 0.028), and heart failure (P = 0.002). CONCLUSION: There was a significant difference between the type of antiplatelet drug and clinical outcomes in ACS patients who were treated with DAPT. Observations from current study may provide important information for prescribers in clinical decision-making. PMID- 28725327 TI - Prevalence of Undiagnosed Cardiovascular Risk Factors in Adults Aged 20 - 40: A Cross-Sectional Study in 2016 in Jeddah, Saudi Arabia. AB - BACKGROUND: Cardiovascular diseases (CVDs) are the first leading cause of death worldwide. In Saudi Arabia, CVDs are the major killers with a mortality rate of 46%. CVD risk factors are not exclusive to old populations. Thus, the purpose of this study was to approximately find the prevalence of these risk factors, particularly high blood pressure (HBP), high blood glucose (HBG), obesity, and smoking. METHODS: This cross-sectional was conducted in May 2016 and took place in the Ambulatory Care Center of King Abdulaziz Medical City, Jeddah. We used a non-probability convenience sampling technique where only individuals aged 20 - 40 who were free of medical illnesses were included. We excluded pregnant women and people on medications that might interfere with our measurements. We obtained a brief history and measured blood pressure, blood glucose, height and weight. Data analysis was done in form of frequencies. Chi-square test was utilized to compare qualitative variables. P < 0.05 was used to determine statistical significance. RESULTS: A total of 507 participants were included (76.3% males and 23.7% females). All participants were between 20 and 40 with a mean age of 31.6 +/- 6.06 SD. We found the prevalence of undiagnosed HBP to be 8.3% and males showed a significantly higher percentage (P < 0.001) when compared to females. HBG prevalence was only 0.6%. Regarding body mass index, the prevalence of overweight and obesity together was 66.3% and males showed significantly higher percentage in falling in this category (P < 0.001). Smoking prevalence was 37.9% with a significantly higher percentage among males (P < 0.001). CONCLUSION: CVD risk factors are apparently quite common in young adults. Efforts must be made to increase the public awareness regarding these risk factors. CVDs are not exclusive to old people. Thus, the public should appreciate this fact in order to prevent these risk factors by establishing healthy life-styles. PMID- 28725328 TI - Heterozygous Familial Hypercholesterolemia With APOE Haplotype: A Prospective Harbinger of a Catastrophic Cardiovascular Event. AB - We report a very young man with heterozygous familial hypercholesterolemia (FH) with APOE haplotype and a significant cardiac family history who underwent cardiac catheterization for intermittent episodes of exertional dyspnea and was noted to have a severe triple vessel coronary artery disease (CAD). He underwent coronary artery bypass graft (CABG) surgery which was uneventful. He was discharged on antiplatelet, beta blocker, nitrate, and statin. On routine health maintenance evaluation, he had no cardiac complaints and had been tolerating well his activities of daily living. PMID- 28725329 TI - Ticagrelor-Associated Conduction Disorder: A Case Report and Review of the Literature. AB - A 47-year-old female presented to emergency clinic due to non-ST-elevation myocardial infarction (NSTEMI). After receiving acetylsalicylic acid, a loading dose of ticagrelor 180 mg and intravenous unfractionated heparin, she underwent successful placement of drug eluting stent on the distal part of non-dominant left circumflex artery. The patient had no pre-existing atrioventricular (AV) block and did not use AV blocking agent. Approximately 10 h after taking a loading dose of ticagrelor, baseline normal rhythm degenerated to the first and then complete AV block, with mild dizziness. Following cessation of ticagrelor, cardiac rhythm returned to normal level within 2 days. The close monitoring of patients after starting ticagrelor is imperative, so ticagrelor may result in advanced conduction disorders. Here, we report a patient who developed various types of AV block associated with the ticagrelor taken during successful percutaneous coronary intervention for NSTEMI. We also reviewed the literature on the association between ticagrelor use and conduction abnormalities. PMID- 28725330 TI - Atrial Myxoma Mimicking Mitral Stenosis. AB - Myxoma is the most common primary cardiac tumor and is usually located in the left atrium. Clinical manifestation relies in large part on the size, location, and architecture of the tumor. There are many reports in the literature of cardiac myxomas causing syncope, embolism, even myocardial infarction. We present a rare case of a patient who underwent urgent surgical resection of a large left atrial myxoma mimicking mitral stenosis. The postoperative course of the patient was uncomplicated. One year after surgery, the patient is asymptomatic and disease-free. PMID- 28725331 TI - A Very Late Presentation of a Right Coronary Artery Occlusion After Transcatheter Aortic Valve Replacement. AB - Involvement of the coronary ostia is a rare complication after transcatheter aortic valve replacement (TAVR). This complication has been more commonly described immediately after valve deployment. This is the first reported case of delayed coronary obstruction caused by TAVR 6 months after the procedure. PMID- 28725332 TI - Thyrotoxic Valvulopathy: Case Report and Review of the Literature. AB - We report a 42-year-old female who was admitted for abdominal pain, and also endorsed dyspnea, fatigue and chronic palpitations. Past medical history included asthma, patent ductus arteriosus repaired in childhood and ill-defined thyroid disease. Physical examination revealed blood pressure of 136/88 mm Hg and heart rate of 149 beats per minute. Cardiovascular exam revealed an irregularly irregular rhythm, and pulmonary exam revealed mild expiratory wheezing. Abdomen was tender. Electrocardiogram revealed atrial fibrillation with rapid ventricular response which responded to intravenous diltiazem. Labs revealed TSH of < 0.1 mU/L and free T4 of 2.82 ng/dL, a positive TSH-receptor and thyroid peroxidase antibodies suggesting Grave's thyrotoxicosis. A transthoracic echocardiogram reported an ejection fraction of 55-60%, with mild to moderate mitral regurgitation (MR) and moderate to severe tricuspid regurgitation (TR) and dilated right heart chambers. Pulmonary artery systolic pressure was 52 mm Hg. Transesophageal echocardiogram revealed a myxomatous tricuspid valve with thickening and malcoaptation of the leaflets and moderate to severe TR, mild to moderate MR with mild thickening of the mitral valve leaflets. Abdominal ultrasound revealed wall thickening of the gall bladder concerning for acute cholecystitis. She underwent laparoscopic cholecystectomy and was discharged in stable condition on methimazole for her thyroid disease, and on oral diltiazem for rate control and anticoagulation for atrial fibrillation. Follow-up visit with her cardiologist few months later documented absence of cardiac symptoms, and no murmurs were reported on physical examination. This case underscores the importance of maintaining a high index of suspicion for hyperthyroidism when faced with significant newly diagnosed pulmonary hypertension and TR, as treatment of the thyroid abnormalities can reverse these cardiac findings. PMID- 28725333 TI - A Protective Association between SNAP Participation and Educational Outcomes Among Children of Economically Strained Households. AB - With the recent cuts to the Supplemental Nutrition Assistance Program (SNAP), more information is needed to assess the impact these policies have on vulnerable children. As such, this study assesses the potential moderating effect of SNAP participation on the association between material deprivation and educational outcomes among children living in poverty (n = 10 971, and n = 14 928). SNAP participation was found to moderate the association between material deprivation and grade retention, indicating that SNAP may be contributing to grade retention among children living in poverty, which can have positive lifelong consequences. PMID- 28725334 TI - Bloch Surface Wave-Coupled Emission at Ultra-Violet Wavelengths. AB - The interaction of fluorophores with nearby metallic structures is now an active area of research. Dielectric photonic structures offer some advantages over plasmonic structures, namely small energy losses and less quenching. We describe a dielectric one-dimensional photonic crystal (1DPC), which supports Bloch surface waves (BSWs) from 280 to 440 nm. This BSW structure is a quartz slide coated with alternating layers of SiO2 and Si3N4. We show that this structure displays BSWs and that the near-UV fluorophore, 2-aminopurine (2-AP), on the top surface of the structure couples with the BSWs. Fluorophores do not have to be inside the structure for coupling and show a narrow angular distribution, with an angular separation of wavelengths. The Bloch wave-coupled emission (BWCE) radiates through the dielectric layer. These BSW structures, with useful wavelength range for detection of intrinsic protein and cofactor fluorescence, provide opportunities for novel optical configurations for bioassays with surface localized biomolecules and for optical imaging using the coupled emission. PMID- 28725335 TI - Is peanut causing food allergy in Cuba? Preliminary assessment of allergic sensitization and IgE specificity profile to peanut allergens in Cuban allergic patients. AB - BACKGROUND: Peanut allergy is increasing at an alarming pace in developed countries. Peanut (Arachis hypogaea) is a common food in Cuba. Nevertheless, reported values of sensitization and symptom severity are usually low. As our objective, we carried out an evaluation of allergic sensitivity to perform an assessment of allergic sensitization and IgE specificity profile to peanut allergens in Cuban allergic patients. METHODS: The Skin Prick Test (SPT) was performed for each patient, using two glycerinated allergenic extracts, prepared from raw or roasted peanuts. Overall, 316 food allergic patients (159 adults and 157 children) attending allergy services at four hospitals in Havana were included, as well as 303 adult non- allergic volunteers. The IgE binding profile of 26 selected SPT positive patients was further analyzed by immunoblotting. RESULTS: The prevalence of sensitization to peanut was 4.6% in general adult population, whereas in adult food-allergic patients it was 18.6%. Prevalence rates were even greater in food allergic children achieving 25.8%. Sensitization frequencies were apparently greater for roasted, as compared to raw peanuts, although the difference was not significant (p> 0.05, Mc Nemar's). IgE binding was shown mostly by the 15 and 17 kDa bands, tentatively identified as the major allergens Ara h 2 and Ara h 6. The IgG4 binding profile was similar to IgE, although with more prominence of the bands at 37 and 28 KDa, corresponding to an Ara h 3 fragment and Peanut Agglutinin. DISCUSSION: The study estimated a relatively high prevalence of peanut sensitization in population. Data reported here suggest that IgE sensitization in Cuban patients is focused mostly on MW bands corresponding to the major allergens Ara h 6 and Ara h 2. CONCLUSIONS: Sensitization to peanut allergen is indeed relatively frequent in Cuba. The IgE profile is congruent to a sensitization pattern by ingestion of roasted peanuts and is directed to well-known major allergens. PMID- 28725336 TI - High-quality draft genome sequence of a biofilm forming lignocellulolytic Aspergillus niger strain ATCC 10864. AB - Filamentous fungus Aspergillus niger has high industrial value due to their lignocellulolytic enzyme activities and ATCC 10864 is one of the few type strains of A. niger which has a unique biofilm forming capability. Here we report the first draft genome sequence of A. niger ATCC 10864 strain. The genome of A. niger ATCC 10864 is 36,172,237 bp long and comprise of 310 scaffolds with 49.5% average GC content. A total of 10,804 protein-coding genes were predicted among which 10,761 genes were with putative functions. A. niger ATCC 10864 genome coded for 709 putative carbohydrate active enzyme families distributed in six functional categories and among them glycoside hydrolases (GHs) represent the most number of families (279). Genes that include pepA, brlA, exgA, LaeA, rodA, GCN have also been identified in this study, which may play a role in biofilm formation. This high-quality draft genome sequence will facilitate our understanding of the mechanisms behind fungal biofilm formation and higher lignocellulolytic enzyme production. PMID- 28725337 TI - Complete genome sequence of Leuconostoc suionicum DSM 20241T provides insights into its functional and metabolic features. AB - The genome of Leuconostoc suionicum DSM 20241T (=ATCC 9135T = LMG 8159T = NCIMB 6992T) was completely sequenced and its fermentative metabolic pathways were reconstructed to investigate the fermentative properties and metabolites of strain DSM 20241T during fermentation. The genome of L. suionicum DSM 20241T consists of a circular chromosome (2026.8 Kb) and a circular plasmid (21.9 Kb) with 37.58% G + C content, encoding 997 proteins, 12 rRNAs, and 72 tRNAs. Analysis of the metabolic pathways of L. suionicum DSM 20241T revealed that strain DSM 20241T performs heterolactic acid fermentation and can metabolize diverse organic compounds including glucose, fructose, galactose, cellobiose, mannose, sucrose, trehalose, arbutin, salcin, xylose, arabinose and ribose. PMID- 28725338 TI - US-color Doppler early diagnosis of uterine rupture with protrusion of umbilical cord. AB - OBJECTIVE: to analyze a case of uterine rupture in a pregnant woman that had a previous laparoscopic myomectomy. METHODS: pregnant woman at 34 weeks gestation came to our emergency room for abdominal pain. She had undergone a previous laparoscopic multiple myomectomy. Patient was evaluated in our Department, that is a tertiary center, by a team of experienced ultrasonographers. RESULTS: at a first clinical examination, the findings were a deep abdominal pain, dysuria and a positive Giordano's sign on the right. 2D ultrasound showed an alive intrauterine foetus, normal anterior fundal placenta and mild reduction of amniotic fluid. It revealed also a maternal right pyelectasis. A further meticulous ultrasound evaluation plus color Doppler revealed on the left side of the uterus the presence of a small vascularised area with venous and arterial flow that seemed to be in continuity with umbilical cord and that had its ultrasound characteristics. Emergency laparotomy was performed and confirmed the hypothesis of uterine rupture. DISCUSSION: uterine rupture seems to occur more frequently as a consequence of a laparoscopic myomectomy and the classic signs and symptoms are fetal distress, loss of uterine contractility, abdominal pain, hemorrhage and shock, so the early US suspect of uterine rupture was extremely important in the decision to perform an emergency caesarean section. CONCLUSION: the correlation between clinical examination and ultrasound-Doppler findings has been essential to recognise an obstetrical emergency and to perform prompt surgery. PMID- 28725339 TI - Congenital high airway obstruction syndrome (CHAOS): discussing the role and limits of prenatal diagnosis starting from a single-center case series. AB - OBJECTIVES: we aimed to report our experience about congenital high airway obstruction syndrome (CHAOS) that is a rare and fatal congenital anomaly; laryngeal atresia is the most frequent cause. Sonographic findings are enlarged echogenic lungs, dilated trachea, and ascites. METHODS: we performed a single center case series analysis collecting antenatally through ultrasound examination, and some of them confirmed by autopsy. RESULTS: we report six cases of CHAOS diagnosed by antenatal ultrasonography between 2007 and 2013. CONCLUSION: to date literature provides very few individual case reports. This work describes typical sonographic findings of this syndrome and it underlines the importance of early prenatal diagnosis to improve prognosis thought an ex utero intrapartum treatment, that seems to be the only chance of survival for the affected fetus. PMID- 28725341 TI - Fetal-MRI prenatal diagnosis of severe bilateral lung hypoplasia: alveolar capillary dysplasia case report. AB - Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a rare and lethal developmental disorder of the lung that affect both acinar structure and the intrinsic pulmonary vasculature. We report prenatal and postnatal imaging with histopathological findings of this rare condition. We, first, describe MR imaging features and discuss its role in prenatal imaging. PMID- 28725340 TI - Management, prognosis and reproductive outcomes of borderline ovarian tumor relapse during pregnancy: from diagnosis to potential treatment options. AB - BACKGROUND: fertility sparing surgery is the first option for treatment of childbearing age women affected by borderline ovarian tumor (BOT). This review put in evidence the benefits and the risks of conservative surgery procedure. Moreover, the literature review is aimed to analyze the possibility of fertility sparing surgery in BOTs and to define a standard treatment in the management of this pathology during pregnancy. METHODS: systematic analysis of the relevant literature for fertility sparing during pregnancy for BOT, accessed through MEDLINE (1982-2015), bibliographies, and interactions with investigators. The data were assimilated into a rigorous and objective contemporary description, enriched by prospective, controlled, and evidence-based studies. RESULTS: there are not many studies about BOT during pregnancy. It can reasonably assumed that after the diagnosis of a suspected BOT during the third trimester of pregnancy, an attitude of close surveillance could be adopted. To the best of our knowledge, we report the only case in literature focused about the treatment and management of borderline ovarian tumor relapse detected during pregnancy. CONCLUSION: basing on our experience and on literature reported, the conservative management of BOT during gestation up to delivery could be considered feasible. The conservative debulking surgery should be performed at the time of cesarean section in a third referral center for gynecologic oncology. PMID- 28725342 TI - A case of polimalformed fetus with a microdeletion of CTNNA3 gene. AB - We report a case of a male fetus of 20 weeks of gestation with plurimalformed observed by transonic scan and confirmed by MR. The karyotype was 46, XY. Molecular analysis showed a microdeletion of about 100 kb in the CTNNA3 gene. PMID- 28725343 TI - Predictive value of procalcitonin or c-reactive protein for subclinical intrauterine infection in patients with premature rupture of membranes (PROM). AB - INTRODUCTION: to evaluate the diagnostic value of procalcitonin (PCT) and C reactive protein (CRP) for the prediction of subclinical intrauterine infection in patients with premature rupture of membranes (PROM). METHODS: a retrospective analysis was performed based on patients with PROM admitted into our hospital between January 2011 and January 2016. Using the pathological diagnosis of placenta as the gold standard, the sensitivities, specificities, positive predictive values, and negative predictive values of PCT and CRP for the diagnosis of subclinical intrauterine infection at different gestational weeks were analyzed. Further, the diagnostic accuracies were compared according to their receiver operating characteristic (ROC) curves. RESULTS: 276 cases were included. The area under the ROC curve of CRP is 0.632, and it is significantly better than PCT. The sensitivity, specificity, positive predictive value, and negative predictive value of CRP are 0.686, 0.958, 0.501, and 0.765, which are all better than those of PCT. The group analysis according to different gestational weeks demonstrated that for the group of 28-33+6 weeks pregnant women, the area under the ROC curve of CRP and PCT is 0.869, and 0.787. The both test have satisfactory accuracy. But the sensitivity and specificity of PCT is 0.830, and 0.950, respectively. That are significantly better than CRP. CONCLUSION: both PCT and CRP have good application potential for the diagnostic prediction of subclinical intrauterine infection in <34 gestational weeks pregnant women with PROM, and PCT is more applicable to 28-33+6 gestational weeks pregnant women with PROM. PMID- 28725344 TI - Complete response of mediastinal clear cell sarcoma to pembrolizumab with radiotherapy. AB - BACKGROUND: Clear cell sarcoma (CCS) is a rare, aggressive soft tissue sarcoma thought to derive from neural crest and characterized by a 12;22 translocation. The resulting fusion protein directly activates expression of the melanocyte master transcription factor and drives the same down-stream pathways in CCS and melanoma leading to significant clinical parallels between these malignancies. Striking success of immune checkpoint blockade in melanoma has promoted interest in immunotherapy of CCS. CASE PRESENTATION: We report the first complete clinical response of a bulky chest wall recurrence of mediastinal CCS in a young woman to anti-PD1 checkpoint blockade with pembrolizumab combined with standard fractionation radiotherapy to enhance regional control and potentially boost the systemic immune response. The treatment was well tolerated with grade 2 skin toxicity within the range expected with radiation alone. Significant reduction in tumor bulk occurred after only 2 radiation fractions and complete response was achieved at 50 Gray. CONCLUSION: The complete clinical response observed in our patient suggests synergy between concurrent radiotherapy and PD1 blockade in CCS. This case and the striking parallels between CCS and melanoma indicate the need for prospective trials of immune checkpoint blockade combined with radiotherapy in this rare malignancy. PMID- 28725345 TI - Genome editing is revolutionizing biology. PMID- 28725346 TI - Diagnosing allergic sensitizations in the third millennium: why clinicians should know allergen molecule structures. AB - Diagnostic tests to detect allergic sensitization were introduced at the end of the nineteenth century but only in the late 1990s did the advent of molecular allergology revolutionize the approach to the allergic patient. Personalized Medicine, a medical procedure that separates patients into different groups with different medical decisions, practices and interventions has sanctioned this change. In fact, in the last few years molecular allergology and the observation that not every patient has the same allergic profile, even when allergic to the same allergenic source, has originated the concept "one size does not fit all". This new approach requires the identification of still unknown allergens, but also the more detailed investigation of those already known. In depth studies of the structure-function relationships in allergenic molecules can reveal the structural determinants involved in the IgE-binding. Then, the knowledge of the epitope profile of each allergen and of the environmental/experimental conditions affecting the exposure of IgE-binding epitopes can provide important contributions to the understanding of cross-reaction processes and to the improvement of diagnosis, immunotherapy and the overall patient treatment. The evolution of diagnostic systems cannot ignore these new needs in this field. PMID- 28725347 TI - Comparison of treatment outcomes in neck pain patients depending on the sex of the chiropractor: a prospective outcome study. AB - BACKGROUND: The high percentage of female chiropractic students in Switzerland suggests a future sex shift in the chiropractic profession in Switzerland. Thus the purpose of this study is to determine if male and female chiropractors achieve the same treatment outcomes in neck pain patients. METHODS: Included in this prospective outcomes study were 849 patients with neck pain of any duration. Prior to the first treatment, baseline demographic data, the Bournemouth Questionnaire (BQ) and the numerical rating scale (NRS) for neck and arm pain were completed. At the follow-up time points of 1 week, 1, 3, 6 and 12 months, the Patient's Global Impression of Change (PGIC) scale to categorize the actual 'improvement' and the BQ and the NRS for neck pain were completed. The Chi-square test compared the proportion of patients reporting 'improvement' between male and female chiropractors for each time point. The unpaired Student's t-test compared the BQ and the NRS actual and change scores between patients of male and female chiropractors at all time points. Demographic factors were compared between the sexes using the Chi-square test. RESULTS: Proportionally more patients of female chiropractors reported 'improvement' at 1 month (p = 0.035) and significantly more pain reduction at 3 months (p = 0.040). Patients of male chiropractors presented with significant older age (p = 0.0001), higher levels of baseline neck pain (p = 0.012), a lower proportion with radiculopathy (p = 0.014) and less pain medication use (p = 0.046). CONCLUSIONS: Female chiropractors achieve at least equally satisfying treatment results for neck pain patients compared to male chiropractors. Female chiropractors also have a higher proportion of female patients compared to male chiropractors and patients presenting with radiculopathy and using pain medications. TRIAL REGISTRATION: Not applicable for this type of study. PMID- 28725348 TI - Genetic structure of Micromeria (Lamiaceae) in Tenerife, the imprint of geological history and hybridization on within-island diversification. AB - Geological history of oceanic islands can have a profound effect on the evolutionary history of insular flora, especially in complex islands such as Tenerife in the Canary Islands. Tenerife results from the secondary connection of three paleo-islands by a central volcano, and other geological events that further shaped it. This geological history has been shown to influence the phylogenetic history of several taxa, including genus Micromeria (Lamiaceae). Screening 15 microsatellite markers in 289 individuals representing the eight species of Micromeria present in Tenerife, this study aims to assess the genetic diversity and structure of these species and its relation with the geological events on the island. In addition, we evaluate the extent of hybridization among species and discuss its influence on the speciation process. We found that the species restricted to the paleo-islands present lower levels of genetic diversity but the highest levels of genetic differentiation suggesting that their ranges might have contracted over time. The two most widespread species in the island, M. hyssopifolia and M. varia, present the highest genetic diversity levels and a genetic structure that seems correlated with the geological composition of the island. Samples from M. hyssopifolia from the oldest paleo-island, Adeje, appear as distinct while samples from M. varia segregate into two main clusters corresponding to the paleo-islands of Anaga and Teno. Evidence of hybridization and intraspecific migration between species was found. We argue that species boundaries would be retained despite hybridization in response to the habitat's specific conditions causing postzygotic isolation and preserving morphological differentiation. PMID- 28725349 TI - The relative importance of reproduction and survival for the conservation of two dolphin populations. AB - It has been proposed that in slow-growing vertebrate populations survival generally has a greater influence on population growth than reproduction. Despite many studies cautioning against such generalizations for conservation, wildlife management for slow-growing populations still often focuses on perturbing survival without careful evaluation as to whether those changes are likely or feasible. Here, we evaluate the relative importance of reproduction and survival for the conservation of two bottlenose dolphin (Tursiops cf aduncus) populations: a large, apparently stable population and a smaller one that is forecast to decline. We also assessed the feasibility and effectiveness of wildlife management objectives aimed at boosting either reproduction or survival. Consistent with other analytically based elasticity studies, survival had the greatest effect on population trajectories when altering vital rates by equal proportions. However, the findings of our alternative analytical approaches are in stark contrast to commonly used proportional sensitivity analyses and suggest that reproduction is considerably more important. We show that in the stable population reproductive output is higher, and adult survival is lower;the difference in viability between the two populations is due to the difference in reproduction;reproductive rates are variable, whereas survival rates are relatively constant over time;perturbations on the basis of observed, temporal variation indicate that population dynamics are much more influenced by reproduction than by adult survival;for the apparently declining population, raising reproductive rates would be an effective and feasible tool to reverse the forecast population decline; increasing survival would be ineffective. Our findings highlight the importance of reproduction - even in slow-growing populations - and the need to assess the effect of natural variation in vital rates on population viability. We echo others in cautioning against generalizations based on life-history traits and recommend that population modeling for conservation should also take into account the magnitude of vital rate changes that could be attained under alternative management scenarios. PMID- 28725350 TI - Quantifying the effects of drought on abrupt growth decreases of major tree species in Switzerland. AB - Drought entails important effects on tree physiology, which may result in short- to long-term radial growth decreases. While the majority of studies have focused on annual drought-related variability of growth, relatively little is known about sustained growth decreases following drought years. We apply a statistical framework to identify climatic factors that induce abrupt growth decreases and may eventually result in tree mortality. We used tree-ring data from almost 500 standing dead trees and 200 living trees in eight sites of the Swiss network of strict forest reserves, including four of the most important Central European tree species (Abies alba, Picea abies, Fagus sylvatica and Quercus spp.). First, to assess short-term growth responses to drought under various climate and site conditions, we calculated correlations and linear mixed-effects models between ring-width indices (RWIs) and drought based on the Standardized Precipitation Evapotranspiration Index (SPEI). Second, to quantify drought effects on abrupt growth decreases, we applied distributed lag nonlinear models (DLNMs), which account for both delayed effects and the nonlinear relationship between the SPEI and the occurrence of abrupt growth decreases. Positive correlations between RWIs and the SPEI indicated short-term growth responses of all species, particularly at arid sites. Results of the DLNMs revealed species-specific growth responses to drought. For Quercus spp., abrupt growth decreases were more likely to occur several years following severe drought, whereas for P. abies, A. alba, and F. sylvatica abrupt growth decreases started frequently immediately in the drought year. We conclude that the statistical framework allows for quantifying the effects of drought intensity on the probability of abrupt growth decreases, which ultimately contributes to an improved understanding of climate impacts on forest community dynamics. PMID- 28725351 TI - Comparative population structure of two dominant species, Shinkaia crosnieri (Munidopsidae: Shinkaia) and Bathymodiolus platifrons (Mytilidae: Bathymodiolus), inhabiting both deep-sea vent and cold seep inferred from mitochondrial multi genes. AB - Deep-sea hydrothermal vents and cold seeps, limited environments without sunlight, are two types of extreme habitat for marine organisms. The differences between vents and cold seeps may facilitate genetic isolation and produce population heterogeneity. However, information on such chemosynthetic fauna taxa is rare, especially regarding the population diversity of species inhabiting both vents and cold seeps. In this study, three mitochondrial DNA fragments (the cytochrome c oxidase submit I (COI), cytochrome b gene (Cytb), and 16S) were concatenated as a mitochondrial concatenated dataset (MCD) to examine the genetic diversity, population structure, and demographic history of Shinkaia crosnieri and Bathymodiolus platifrons. The genetic diversity differences between vent and seep populations were statistically significant for S. crosnieri but not for B. platifrons. S. crosnieri showed less gene flow and higher levels of genetic differentiation between the vent and seep populations than B. platifrons. In addition, the results suggest that all the B. platifrons populations, but only the S. crosnieri vent populations, passed through a recent expansion or bottleneck. Therefore, different population distribution patterns for the two dominant species were detected; a pattern of population differentiation for S. crosnieri and a homogeneity pattern for B. platifrons. These different population distribution patterns were related to both extrinsic restrictive factors and intrinsic factors. Based on the fact that the two species were collected in almost identical or adjacent sampling sites, we speculated that the primary factors underlying the differences in the population distribution patterns were intrinsic. The historical demographics, dispersal ability, and the tolerance level of environmental heterogeneity are most likely responsible for the different distribution patterns. PMID- 28725352 TI - Management adaptation of invertebrate fisheries to an extreme marine heat wave event at a global warming hot spot. AB - An extreme marine heat wave which affected 2000 km of the midwest coast of Australia occurred in the 2010/11 austral summer, with sea-surface temperature (SST) anomalies of 2-5 degrees C above normal climatology. The heat wave was influenced by a strong Leeuwin Current during an extreme La Nina event at a global warming hot spot in the Indian Ocean. This event had a significant effect on the marine ecosystem with changes to seagrass/algae and coral habitats, as well as fish kills and southern extension of the range of some tropical species. The effect has been exacerbated by above-average SST in the following two summers, 2011/12 and 2012/13. This study examined the major impact the event had on invertebrate fisheries and the management adaption applied. A 99% mortality of Roei abalone (Haliotis roei) and major reductions in recruitment of scallops (Amusium balloti), king (Penaeus latisulcatus) and tiger (P. esculentus) prawns, and blue swimmer crabs were detected with management adapting with effort reductions or spatial/temporal closures to protect the spawning stock and restocking being evaluated. This study illustrates that fisheries management under extreme temperature events requires an early identification of temperature hot spots, early detection of abundance changes (preferably using pre-recruit surveys), and flexible harvest strategies which allow a quick response to minimize the effect of heavy fishing on poor recruitment to enable protection of the spawning stock. This has required researchers, managers, and industry to adapt to fish stocks affected by an extreme environmental event that may become more frequent due to climate change. PMID- 28725353 TI - Novel distribution pattern between coexisting sexual and obligate asexual variants of the true estuarine macroalga Ulva prolifera. AB - Where sexual and asexual forms coexist within a species, the asexuals are often found to be prevalent in marginal habitats. This asexual distribution pattern has received evolutionary attention linked to the paradox of sex. In many marine species, there is a distributional trend of asexual modes being more common in lower salinity waters regarded as the ecogeographic marginal, being explained by negative effects of low salinities on sexual reproductive success. However, the distribution pattern of estuarine species recently adapted to low salinity waters has remained unknown. The brackish macroalga Ulva prolifera being a major benthic component of estuarine ecosystems includes a sexual variant and obligate asexual variants by means of motile spores. We examined the sexual-asexual distribution pattern of this alga along a salinity gradient in river estuaries. Surprisingly, opposite to the distributional trend of marine organisms, the results clearly showed the persistent predominance of sexuals in the lower salinity reaches than the asexuals. In addition, a frequent alternating of dioecious gametophytes and sporophytes in the sexual population was observed, suggesting the sexual reproductive process would be robustly performed in the low salinity waters. Considering U. prolifera had evolved from the ancestral marine species to become a true estuarine species of which the core habitat is the low salinity reaches, in a broad sense its sexual-asexual distribution pattern would be involved in asexual marginal occupations of the species range previously reported in other organisms. Based on the frozen niche variation model, we can give a concise explanation for the evolutionary process of this pattern; multiple asexuals with frozen genotypic variation had arisen from sexual ancestors undergoing low salinity adaptation and share the estuarine habitat with the sexuals at present. PMID- 28725354 TI - Maternal effects as drivers of sibling competition in a parent-offspring conflict context? An experimental test. AB - Maternal effects occur when the mother's phenotype influences her offspring's phenotype. In birds, differential allocation in egg yolk components can allow mothers to compensate for the competitive disadvantage of junior chicks. We hypothesize that the parent-older chick conflict peaks at intermediate conditions: parents benefit from the younger chick(s) survival, but its death benefits the older chick in terms of growth and survival. We thus expect maternal compensation to follow a bell-shaped pattern in relation to environmental conditions. We studied a black-legged kittiwake (Rissa tridactyla) population where previous results revealed increased allocation of yolk testosterone in younger as compared to older chicks in intermediate conditions, in line with our theoretical framework. We therefore predicted a maternally induced increase in aggressiveness, growth, and survival for younger chicks born in intermediate environmental conditions. Controlling for parental effects and chick sex, we manipulated food availability before egg laying to create a situation with intermediate (Unfed group) and good (Fed group) environmental conditions. Within each feeding treatment, we further created experimental broods where the natural hatching order was reversed to maximize our chances to observe an effect of feeding treatment on the younger chicks' aggressiveness. As predicted, we found that chick aggressiveness was higher in younger chicks born from the Unfed group (i.e., in intermediate environmental conditions), but only when they were put in a senior position, in reversed broods. Predictions on growth and survival were not confirmed. Mothers thus seem to favor the competitiveness of their younger chick in intermediate conditions via egg yolk components, but our study also suggests that hatching asynchrony need to be small for maternal compensation to be efficient. We emphasize the need for further studies investigating other chick behaviors (e.g., begging) and focusing on the relative role of different yolk components in shaping parent-offspring conflict over sibling competition. PMID- 28725355 TI - The population genomic basis of geographic differentiation in North American common ragweed (Ambrosia artemisiifolia L.). AB - Common ragweed (Ambrosia artemisiifolia L.) is an invasive, wind-pollinated plant nearly ubiquitous in disturbed sites in its eastern North American native range and present across growing portions of Europe, Africa, Asia, and Australia. Phenotypic divergence between European and native-range populations has been described as rapid evolution. However, a recent study demonstrated major human mediated shifts in ragweed genetic structure before introduction to Europe and suggested that native-range genetic structure and local adaptation might fully explain accelerated growth and other invasive characteristics of introduced populations. Genomic differentiation that potentially influenced this structure has not yet been investigated, and it remains unclear whether substantial admixture during historical disturbance of the native range contributed to the development of invasiveness in introduced European ragweed populations. To investigate fine-scale population genetic structure across the species' native range, we characterized diallelic SNP loci via a reduced-representation genotyping-by-sequencing (GBS) approach. We corroborate phylogeographic domains previously discovered using traditional sequencing methods, while demonstrating increased power to resolve weak genetic structure in this highly admixed plant species. By identifying exome polymorphisms underlying genetic differentiation, we suggest that geographic differentiation of this important invasive species has occurred more often within pathways that regulate growth and response to defense and stress, which may be associated with survival in North America's diverse climatic regions. PMID- 28725356 TI - Adaptional evolution of trichome in Caragana korshinskii to natural drought stress on the Loess Plateau, China. AB - Caragana korshinskii is commonly employed to improve drought ecosystems on the Loess Plateau, although the molecular mechanism at work is poorly understood, particularly in terms of the plant's ability to tolerate drought stress. Water is the most severe limiting factor for plant growth on the Loess Plateau. The trichome is known to play an efficient role in reducing water loss through decreasing the rate of transpiration, so in this study, we focused on the trichome-related gene expression of ecological adaptation in C. korshinskii under low precipitation conditions. In order to explore the responses of trichomes to drought, we selected two experimental sites from wet to dry along the Loess Plateau latitude gradient for observation. Micro-phenomena through which trichomes grew denser and larger under reduced precipitation were observed using a scanning electron microscope; de novo transcriptomes and quantitative PCR were then used to explore and verify gene expression patterns of C. korshinskii trichomes. Results showed that GIS2,TTG1, and GL2 were upregulated (as key positive-regulated genes on trichome development), while CPC was downregulated (negative-regulated gene). Taken together, our data indicate that downstream genes of gibberellin and cytokinin signaling pathways, alongside several cytoskeleton-related genes, contribute to modulating trichome development to enhance transpiration resistance ability and increase the resistance to drought stress in C. korshinskii. PMID- 28725358 TI - Grandparentage assignments identify unexpected adfluvial life history tactic contributing offspring to a reintroduced population. AB - Diversity in life history tactics contributes to the persistence of a population because it helps to protect against stochastic environments by varying individuals in space and time. However, some life history tactics may not be accounted for when assessing the demographic viability of a population. One important factor in demographic viability assessments is cohort replacement rate (CRR), which is defined as the number of future adults produced by an adult. We assessed if precocial resident males (500 leaves per species. We then scanned 30 leaves per species that had approximately the same length as the median leaf length for that species. The leaf-shape data from scanned profiles were fitted to the simplified Gielis equation. Results confirmed that the equation fits the leaf-shape data extremely well, with the coefficients of determination being 0.995 on average. We further demonstrated the bilateral symmetry of bamboo leaves, with a clearly defined leaf-shape parameter of all 42 bamboo species investigated ranging from 0.02 to 0.1. This results in a simple and reliable tool for precise determination of bamboo species, with applications in forestry, ecology, and taxonomy. PMID- 28725361 TI - Spatial heterogeneity distribution of soil total nitrogen and total phosphorus in the Yaoxiang watershed in a hilly area of northern China based on geographic information system and geostatistics. AB - Soil total nitrogen (STN) and total phosphorus (STP) are important indicators of soil nutrients and the important indexes of soil fertility and soil quality evaluation. Using geographic information system (GIS) and geostatistics, the spatial heterogeneity distribution of STN and STP in the Yaoxiang watershed in a hilly area of northern China was studied. The results showed that: (1) The STN and STP contents showed a declining trend with the increase in soil depth; the variation coefficients (Cv) of STN and STP in the 0- to 10-cm soil layer (42.25% and 14.77%, respectively) were higher than in the 10- to 30-cm soil layer (28.77% and 11.60%, respectively). Moreover, the Cv of STN was higher than that of STP. (2) The maximum C0/(C0 + C1) of STN and STP in the soil layers was less than 25%, this indicated that a strong spatial distribution autocorrelation existed for STN and STP; and the STP showed higher intensity and more stable variation than the STN. (3) From the correlation analysis, we concluded that the topographic indexes such as elevation and slope direction all influenced the spatial distribution of STN and STP (correlation coefficients were 0.688 and 0.518, respectively). (4) The overall distribution of STN and STP in the Yaoxiang watershed decreased from the northwest to the southeast. This variation trend was similar to the watershed DEM trend and was significantly influenced by vegetation and topographic factors. These results revealed the spatial heterogeneity distribution of STN and STP, and addressed the influences of forest vegetation coverage, elevation, and other topographic factors on the spatial distribution of STN and STP at the watershed scale. PMID- 28725362 TI - Negative correlation between altitudes and oxygen isotope ratios of seeds: exploring its applicability to assess vertical seed dispersal. AB - Vertical seed dispersal, which plays a key role in plant escape and/or expansion under climate change, was recently evaluated for the first time using negative correlation between altitudes and oxygen isotope ratio of seeds. Although this method is innovative, its applicability to other plants is unknown. To explore the applicability of the method, we regressed altitudes on delta18O of seeds of five woody species constituting three families in temperate forests in central Japan. Because climatic factors, including temperature and precipitation that influence delta18O of plant materials, demonstrate intensive seasonal fluctuation in the temperate zone, we also evaluated the effect of fruiting season of each species on delta18O of seeds using generalized linear mixed models (GLMM). Negative correlation between altitudes and delta18O of seeds was found in four of five species tested. The slope of regression lines tended to be lower in late fruiting species. The GLMM analysis revealed that altitudes and date of fruiting peak negatively affected delta18O of seeds. These results indicate that the estimation of vertical seed dispersal using delta18O of seeds can be applicable for various species, not just confined to specific taxa, by identifying the altitudes of plants that produced seeds. The results also suggest that the regression line between altitudes and delta18O of seeds is rather species specific and that vertical seed dispersal in late-fruiting species is estimated at a low resolution due to their small regression slopes. A future study on the identification of environmental factors and plant traits that cause a difference in delta18O of seeds, combined with an improvement of analysis, will lead to effective evaluation of vertical seed dispersal in various species and thereby promote our understanding about the mechanism and ecological functions of vertical seed dispersal. PMID- 28725363 TI - Bridging two scholarly islands enriches both: COI DNA barcodes for species identification versus human mitochondrial variation for the study of migrations and pathologies. AB - DNA barcodes for species identification and the analysis of human mitochondrial variation have developed as independent fields even though both are based on sequences from animal mitochondria. This study finds questions within each field that can be addressed by reference to the other. DNA barcodes are based on a 648 bp segment of the mitochondrially encoded cytochrome oxidase I. From most species, this segment is the only sequence available. It is impossible to know whether it fairly represents overall mitochondrial variation. For modern humans, the entire mitochondrial genome is available from thousands of healthy individuals. SNPs in the human mitochondrial genome are evenly distributed across all protein-encoding regions arguing that COI DNA barcode is representative. Barcode variation among related species is largely based on synonymous codons. Data on human mitochondrial variation support the interpretation that most - possibly all - synonymous substitutions in mitochondria are selectively neutral. DNA barcodes confirm reports of a low variance in modern humans compared to nonhuman primates. In addition, DNA barcodes allow the comparison of modern human variance to many other extant animal species. Birds are a well-curated group in which DNA barcodes are coupled with census and geographic data. Putting modern human variation in the context of intraspecies variation among birds shows humans to be a single breeding population of average variance. PMID- 28725364 TI - Interspecific variation in persistence of buried weed seeds follows trade-offs among physiological, chemical, and physical seed defenses. AB - Soil seedbanks drive infestations of annual weeds, yet weed management focuses largely on seedling mortality. As weed seedbanks increasingly become reservoirs of herbicide resistance, species-specific seedbank management approaches will be essential to weed control. However, the development of seedbank management strategies can only develop from an understanding of how seed traits affect persistence.We quantified interspecific trade-offs among physiological, chemical, and physical traits of weed seeds and their persistence in the soil seedbank in a common garden study. Seeds of 11 annual weed species were buried in Savoy, IL, from 2007 through 2012. Seedling recruitment was measured weekly and seed viability measured annually. Seed physiological (dormancy), chemical (phenolic compound diversity and concentration; invertebrate toxicity), and physical traits (seed coat mass, thickness, and rupture resistance) were measured.Seed half-life in the soil (t0.5) showed strong interspecific variation (F10,30 = 15, p < .0001), ranging from 0.25 years (Bassia scoparia) to 2.22 years (Abutilon theophrasti). Modeling covariances among seed traits and seedbank persistence quantified support for two putative defense syndromes (physiological-chemical and physical-chemical) and highlighted the central role of seed dormancy in controlling seed persistence.A quantitative comparison between our results and other published work indicated that weed seed dormancy and seedbank persistence are linked across diverse environments and agroecosystems. Moreover, among seedbank-forming early successional plant species, relative investment in chemical and physical seed defense varies with seedbank persistence. Synthesis and applications. Strong covariance among weed seed traits and persistence in the soil seedbank indicates potential for seedbank management practices tailored to specific weed species. In particular, species with high t0.5 values tend to invest less in chemical defenses. This makes them highly vulnerable to physical harvest weed seed control strategies, with small amounts of damage resulting in their full decay. PMID- 28725365 TI - The clonal root system of balsam poplar in upland sites of Quebec and Alberta. AB - Balsam poplar seeds are short-lived and require moist seedbeds soon after they are released to germinate. In addition to sexual reproduction, balsam poplar stands can regenerate clonally by root suckering. The origin of stands will in turn affect their genetic structure and root system architecture, which are poorly understood for upland forest stands. Three stands were hydraulically excavated in Quebec (moist) and Alberta (dry) to determine the origin of trees and to characterize root systems with respect to presence of parental roots and root grafts connections. Clones were identified using single-nucleotide polymorphism (SNPs), and all stems, roots and root grafts were aged using dendrochronology techniques. All 82 excavated trees were of sucker origin, and four of the six stands contained a single clone. Parental root connections were found between 22% and 25% of excavated trees, and 53% and 48% of trees were linked with a root graft between the same or different clones, in Alberta and Quebec, respectively. Mean distance between trees connected by parental root was significantly lower than the distance between unconnected trees (0.47 +/- 0.25 m vs. 3.14 +/- 0.15 m and 1.55 +/- 0.27 m vs. 4.25 +/- 0.13 m) in Alberta and in Quebec, respectively. The excavations also revealed many dead stumps with live roots, maintained through root connections with live trees. This research highlights that balsam poplar growing in upland stands is a clonal species that can maintain relatively high genotypic diversity, with frequent root connections between trees at maturity. Maintaining an extensive root system through root connections increases the chances of a clone surviving when the above ground tree is dead and may also enhance the resilience of balsam poplar stands after disturbance. PMID- 28725366 TI - Vegetation structure and photosynthesis respond rapidly to restoration in young coastal fens. AB - Young coastal fens are rare ecosystems in the first stages of peatland succession. Their drainage compromises their successional development toward future carbon (C) reservoirs. We present the first study on the success of hydrological restoration of young fens. We carried out vegetation surveys at six young fens that represent undrained, drained, and restored management categories in the Finnish land uplift coast before and after restoration. We measured plant level carbon dioxide (CO2) assimilation and chlorophyll fluorescence (Fv/Fm) from 17 most common plant species present at the sites. Within 5 years of restoration, the vegetation composition of restored sites had started to move toward the undrained baseline. The cover of sedges increased the most in response to restoration, while the cover of deciduous shrubs decreased the most. The rapid response indicates high resilience and low resistance of young fen ecosystems toward changes in hydrology. Forbs had higher photosynthetic and respiration rates than sedges, deciduous shrubs, and grasses, whereas rates were lowest for evergreen shrubs and mosses. The impact of management category on CO2 assimilation was an indirect consequence that occurred through changes in plant species composition: Increase in sedge cover following restoration also increased the potential photosynthetic capacity of the ecosystem. Synthesis and applications. Restoration of forestry drained young fens is a promising method for safeguarding them and bringing back their function as C reservoirs. However, their low resistance to water table draw down introduces a risk that regeneration may be partially hindered by the heavy drainage in the surrounding landscape. Therefore, restoration success is best safeguarded by managing the whole catchments instead of carrying out small-scale projects. PMID- 28725367 TI - The effect of seed traits on geographic variation in body size and sexual size dimorphism of the seed-feeding beetle Acanthoscelides macrophthalmus. AB - Explaining large-scale patterns of variation in body size has been considered a central question in ecology and evolutionary biology because several life-history traits are directly linked to body size. For ectothermic organisms, little is known about what processes influence geographic variation in body size. Changes in body size and sexual size dimorphism (SSD) have been associated with environmental variables, particularly for Bruchinae insects, which feed exclusively on seeds during the larval stage. However, the effect of important seed traits on body size variation has rarely been investigated, and whether SSD varies substantially among populations within bruchine species is poorly known. Using the seed-feeding beetle Acanthoscelides macrophthalmus infesting its host plant Leucaena leucocephala, we investigated whether specific seed traits (hardness, size, water content, carbon/nitrogen ratio, and phenolic content) were determinant in generating geographic variation in body size and SSD of A. macrophthalmus. We also examined the relationships between body size and SSD with latitude and altitude. The body size of both sexes combined was not related to latitude, altitude, and any of the physical and chemical seed traits. However, the female body size tended to vary more in size than the males, generating significant variation in SSD in relation to latitude and altitude. The females were the larger sex at higher latitudes and at lower altitudes, precisely where seed water content was greater. Therefore, our results suggest that water content was the most important seed trait, most severely affecting the females, promoting geographic variation in SSD of A. macrophthalmus. PMID- 28725368 TI - Prospects of herbivore egg-killing plant defenses for sustainable crop protection. AB - Due to a growing demand of food production worldwide, new strategies are suggested to allow for sustainable production of food with minimal effects on natural resources. A promising alternative to the application of chemical pesticides is the implementation of crops resistant to insect pests. Plants produce compounds that are harmful to a wide range of attackers, including insect pests; thus, exploitation of their natural defense system can be the key for the development of pest-resistant crops. Interestingly, some plants possess a unique first line of defense that eliminates the enemy before it becomes destructive: egg-killing. Insect eggs can trigger (1) direct defenses, mostly including plant cell tissue growth or cell death that lead to eggs desiccating, being crushed or falling off the plant or (2) indirect defenses, plant chemical cues recruiting natural enemies that kill the egg or hatching larvae (parasitoids). The consequences of plant responses to eggs are that insect larvae do not hatch or that they are impeded in development, and damage to the plant is reduced. Here, we provide an overview on the ubiquity and evolutionary history of egg-killing traits within the plant kingdom including crops. Up to now, little is known on the mechanisms and on the genetic basis of egg-killing traits. Making use of egg killing defense traits in crops is a promising new way to sustainably reduce losses of crop yield. We provide suggestions for new breeding strategies to grow egg-killing crops and improve biological control. PMID- 28725369 TI - Adding energy gradients and long-distance dispersal to a neutral model improves predictions of Madagascan bird diversity. AB - Macroecological patterns are likely the result of both stochastically neutral mechanisms and deterministic differences between species. In Madagascar, the simplest stochastically neutral hypothesis - the mid-domain effects (MDE) hypothesis - has already been rejected. However, rejecting the MDE hypothesis does not necessarily refute the existence of all other neutral mechanisms. Here, we test whether adding complexity to a basic neutral model improves predictions of biodiversity patterns. The simplest MDE model assumes that: (1) species' ranges are continuous and unfragmented, (2) are randomly located throughout the landscape, and (3) can be stacked independently and indefinitely. We designed a simulation based on neutral theory that allowed us to weaken each of these assumptions incrementally by adjusting the habitat capacity as well as the likelihood of short- and long-distance dispersal. Simulated outputs were compared to four empirical patterns of bird diversity: the frequency distributions of species richness and range size, the within-island latitudinal diversity gradient, and the distance-decay of species compositional similarity. Neutral models emulated empirical diversity patterns for Madagascan birds accurately. The frequency distribution of range size, latitudinal diversity gradient, and the distance-decay of species compositional similarity could be attributed to stochastic long-distance migration events and zero-sum population dynamics. However, heterogenous environmental gradients improved predictions of the frequency distribution of species richness. Patterns of bird diversity in Madagascar can broadly be attributed to stochastic long-distance migration events and zero-sum population dynamics. This implies that rejecting simple hypotheses, such as MDE, does not serve as evidence against stochastic processes in general. However, environmental gradients were necessary to explain patterns of species richness and deterministic differences between species are probably important for explaining the distributions of narrow-range and endemic species. PMID- 28725370 TI - Emlen funnel experiments revisited: methods update for studying compass orientation in songbirds. AB - Migratory songbirds carry an inherited capacity to migrate several thousand kilometers each year crossing continental landmasses and barriers between distant breeding sites and wintering areas. How individual songbirds manage with extreme precision to find their way is still largely unknown. The functional characteristics of biological compasses used by songbird migrants has mainly been investigated by recording the birds directed migratory activity in circular cages, so-called Emlen funnels. This method is 50 years old and has not received major updates over the past decades. The aim of this work was to compare the results from newly developed digital methods with the established manual methods to evaluate songbird migratory activity and orientation in circular cages.We performed orientation experiments using the European robin (Erithacus rubecula) using modified Emlen funnels equipped with thermal paper and simultaneously recorded the songbird movements from above. We evaluated and compared the results obtained with five different methods. Two methods have been commonly used in songbirds' orientation experiments; the other three methods were developed for this study and were based either on evaluation of the thermal paper using automated image analysis, or on the analysis of videos recorded during the experiment.The methods used to evaluate scratches produced by the claws of birds on the thermal papers presented some differences compared with the video analyses. These differences were caused mainly by differences in scatter, as any movement of the bird along the sloping walls of the funnel was recorded on the thermal paper, whereas video evaluations allowed us to detect single takeoff attempts by the birds and to consider only this behavior in the orientation analyses. Using computer vision, we were also able to identify and separately evaluate different behaviors that were impossible to record by the thermal paper.The traditional Emlen funnel is still the most used method to investigate compass orientation in songbirds under controlled conditions. However, new numerical image analysis techniques provide a much higher level of detail of songbirds' migratory behavior and will provide an increasing number of possibilities to evaluate and quantify specific behaviors as new algorithms will be developed. PMID- 28725371 TI - The role of novel forest ecosystems in the conservation of wood-inhabiting fungi in boreal broadleaved forests. AB - The increasing human impact on the earth's biosphere is inflicting changes at all spatial scales. As well as deterioration and fragmentation of natural biological systems, these changes also led to other, unprecedented effects and emergence of novel habitats. In boreal zone, intensive forest management has negatively impacted a multitude of deadwood-associated species. This is especially alarming given the important role wood-inhabiting fungi have in the natural decay processes. In the boreal zone, natural broad-leaved-dominated, herb-rich forests are threatened habitats which have high wood-inhabiting fungal species richness. Fungal diversity in other broadleaved forest habitat types is poorly known. Traditional wood pastures and man-made afforested fields are novel habitats that could potentially be important for wood-inhabiting fungi. This study compares species richness and fungal community composition across the aforementioned habitat types, based on data collected for wood-inhabiting fungi occupying all deadwood diameter fractions. Corticioid and polyporoid fungi were surveyed from 67 130 deadwood particles in four natural herb-rich forests, four birch-dominated wood pastures, and four birch-dominated afforested field sites in central Finland. As predicted, natural herb-rich forests were the most species-rich habitat. However, afforested fields also had considerably higher overall species richness than wood pastures. Many rare or rarely collected species were detected in each forest type. Finally, fungal community composition showed some divergence not only among the different habitat types, but also among deadwood diameter fractions. Synthesis and applications: In order to maintain biodiversity at both local and regional scales, conserving threatened natural habitat types and managing traditional landscapes is essential. Man-made secondary woody habitats could provide the necessary resources and serve as surrogate habitats for many broadleaved deadwood-associated species, and thus complement the existing conservation network of natural forests. PMID- 28725372 TI - Experimental warming increases herbivory by leaf-chewing insects in an alpine plant community. AB - Climate warming is predicted to affect species and trophic interactions worldwide, and alpine ecosystems are expected to be especially sensitive to changes. In this study, we used two ongoing climate warming (open-top chambers) experiments at Finse, southern Norway, to examine whether warming had an effect on herbivory by leaf-chewing insects in an alpine Dryas heath community. We recorded feeding marks on the most common vascular plant species in warmed and control plots at two experimental sites at different elevations and carried out a brief inventory of insect herbivores. Experimental warming increased herbivory on Dryas octopetala and Bistorta vivipara. Dryas octopetala also experienced increased herbivory at the lower and warmer site, indicating an overall positive effect of warming, whereas B. vivipara experienced an increased herbivory at the colder and higher site indicating a mixed effect of warming. The Lepidoptera Zygaena exulans and Sympistis nigrita were the two most common leaf-chewing insects in the Dryas heath. Based on the observed patterns of herbivory, the insects life cycles and feeding preferences, we argue that Z. exulans is the most important herbivore on B. vivipara, and S. nigrita the most important herbivore on D. octopetala. We conclude that if the degree of insect herbivory increases in a warmer world, as suggested by this study and others, complex interactions between plants, insects, and site-specific conditions make it hard to predict overall effects on plant communities. PMID- 28725373 TI - High-resolution photo-mosaic time-series imagery for monitoring human use of an artificial reef. AB - Successful marine management relies on understanding patterns of human use. However, obtaining data can be difficult and expensive given the widespread and variable nature of activities conducted. Remote camera systems are increasingly used to overcome cost limitations of conventional labour-intensive methods. Still, most systems face trade-offs between the spatial extent and resolution over which data are obtained, limiting their application. We trialed a novel methodology, CSIRO Ruggedized Autonomous Gigapixel System (CRAGS), for time series of high-resolution photo-mosaic (HRPM) imagery to estimate fine-scale metrics of human activity at an artificial reef located 1.3 km from shore. We compared estimates obtained using the novel system to those produced with a web camera that concurrently monitored the site. We evaluated the effect of day type (weekday/weekend) and time of day on each of the systems and compared to estimates obtained from binocular observations. In general, both systems delivered similar estimates for the number of boats observed and to those obtained by binocular counts; these results were also unaffected by the type of day (weekend vs. weekday). CRAGS was able to determine additional information about the user type and party size that was not possible with the lower resolution webcam system. However, there was an effect of time of day as CRAGS suffered from poor image quality in early morning conditions as a result of fixed camera settings. Our field study provides proof of concept of use of this new cost-effective monitoring tool for the remote collection of high-resolution large extent data on patterns of human use at high temporal frequency. PMID- 28725374 TI - Snowbeds are more affected than other subalpine-alpine plant communities by climate change in the Swiss Alps. AB - While the upward shift of plant species has been observed on many alpine and nival summits, the reaction of the subalpine and lower alpine plant communities to the current warming and lower snow precipitation has been little investigated so far. To this aim, 63 old, exhaustive plant inventories, distributed along a subalpine-alpine elevation gradient of the Swiss Alps and covering different plant community types (acidic and calcareous grasslands; windy ridges; snowbeds), were revisited after 25-50 years. Old and recent inventories were compared in terms of species diversity with Simpson diversity and Bray-Curtis dissimilarity indices, and in terms of community composition with principal component analysis. Changes in ecological conditions were inferred from the ecological indicator values. The alpha-diversity increased in every plant community, likely because of the arrival of new species. As observed on mountain summits, the new species led to a homogenization of community compositions. The grasslands were quite stable in terms of species composition, whatever the bedrock type. Indeed, the newly arrived species were part of the typical species pool of the colonized community. In contrast, snowbed communities showed pronounced vegetation changes and a clear shift toward dryer conditions and shorter snow cover, evidenced by their colonization by species from surrounding grasslands. Longer growing seasons allow alpine grassland species, which are taller and hence more competitive, to colonize the snowbeds. This study showed that subalpine-alpine plant communities reacted differently to the ongoing climate changes. Lower snow/rain ratio and longer growing seasons seem to have a higher impact than warming, at least on plant communities dependent on long snow cover. Consequently, they are the most vulnerable to climate change and their persistence in the near future is seriously threatened. Subalpine and alpine grasslands are more stable, and, until now, they do not seem to be affected by a warmer climate. PMID- 28725375 TI - Scale dependent drivers of wild bee diversity in tropical heterogeneous agricultural landscapes. AB - Factors associated with agricultural intensification, for example, loss of seminatural vegetation and pesticide use has been shown to adversely affect the bee community. These factors may impact the bee community differently at different landscape scales. The scale dependency is expected to be more pronounced in heterogeneous landscapes. However, the scale-dependent response of the bee community to drivers of its decline is relatively understudied, especially in the tropics where the agricultural landscape is often heterogeneous. This study looked at effects of agricultural intensification on bee diversity at patch and landscape scales in a tropical agricultural landscape. Wild bees were sampled using 12 permanent pan trap stations. Patch and landscape characteristics were measured within a 100 m (patch scale) and a 500 m (landscape scale) radius of pan trap stations. Information on pesticide input was obtained from farmer surveys. Data on vegetation cover, productivity, and percentage of agricultural and fallow land (FL) were collected using satellite imagery. Intensive areas in a bee-site network were less specialized in terms of resources to attract rare bee species while the less intensive areas, which supported more rare species, were more vulnerable to disturbance. A combination of patch quality and diversity as well as pesticide use regulates species diversity at the landscape scale (500 m), whereas pesticide quantity drove diversity at the patch scale (100 m). At the landscape scale, specialization of each site in terms of resources for bees increased with increasing patch diversity and FL while at the patch scale specialization declined with increased pesticide use. Bee functional groups responded differentially to landscape characteristics as well as pesticide use. Wood nesting bees were negatively affected by the number of pesticides used but other bee functional groups were not sensitive to pesticides. Synthesis and Applications: Different factors affect wild bee diversity at the scale of landscape and patch in heterogeneous tropical agricultural systems. The differential response of bee functional groups to agricultural intensification underpins the need for guild-specific management strategies for wild bee conservation. Less intensively farmed areas support more rare species and are vulnerable to disturbance; consequently, these areas should be prioritized for conservation to maintain heterogeneity in the landscape. It is important to conserve and restore seminatural habitats to maintain complexity in the landscapes through participatory processes and to regulate synthetic chemical pesticides in farm operations to conserve the species and functional diversity of wild bees. PMID- 28725376 TI - Moving south: effects of water temperatures on the larval development of invasive cane toads (Rhinella marina) in cool-temperate Australia. AB - The distributional limits of many ectothermic species are set by thermal tolerances of early-developmental stages in the life history; embryos and larvae often are less able to buffer environmental variation than are conspecific adults. In pond-breeding amphibians, for example, cold water may constrain viability of eggs and larvae, even if adults can find suitable thermal conditions in terrestrial niches. Invasive species provide robust model systems for exploring these questions, because we can quantify thermal challenges at the expanding range edge (from field surveys) and larval responses to thermal conditions (in the laboratory). Our studies on invasive cane toads (Rhinella marina) at the southern (cool-climate) edge of their expanding range in Australia show that available ponds often average around 20 degrees C during the breeding period, 10 degrees C lower than in many areas of the toads' native range, or in the Australian tropics. Our laboratory experiments showed that cane toad eggs and larvae cannot develop successfully at 16 degrees C, but hatching success and larval survival rates were higher at 20 degrees C than in warmer conditions. Lower temperatures slowed growth rates, increasing the duration of tadpole life, but also increased metamorph body mass. Water temperature also influenced metamorph body shape (high temperatures reduced relative limb length, head width, and body mass) and locomotor performance (increased speed from intermediate temperatures, longer hops from high temperatures). In combination with previous studies, our data suggest that lower water temperatures may enhance rather than reduce recruitment of cane toads, at least in areas where pond temperatures reach or exceed 20 degrees C. That condition is fulfilled over a wide area of southern Australia, suggesting that the continuing expansion of this invasive species is unlikely to be curtailed by the impacts of relatively low water temperatures on the viability of early life-history stages. PMID- 28725377 TI - Environmental variability and population dynamics: do European and North American ducks play by the same rules? AB - Density dependence, population regulation, and variability in population size are fundamental population processes, the manifestation and interrelationships of which are affected by environmental variability. However, there are surprisingly few empirical studies that distinguish the effect of environmental variability from the effects of population processes. We took advantage of a unique system, in which populations of the same duck species or close ecological counterparts live in highly variable (north American prairies) and in stable (north European lakes) environments, to distinguish the relative contributions of environmental variability (measured as between-year fluctuations in wetland numbers) and intraspecific interactions (density dependence) in driving population dynamics. We tested whether populations living in stable environments (in northern Europe) were more strongly governed by density dependence than populations living in variable environments (in North America). We also addressed whether relative population dynamical responses to environmental variability versus density corresponded to differences in life history strategies between dabbling (relatively "fast species" and governed by environmental variability) and diving (relatively "slow species" and governed by density) ducks. As expected, the variance component of population fluctuations caused by changes in breeding environments was greater in North America than in Europe. Contrary to expectations, however, populations in more stable environments were not less variable nor clearly more strongly density dependent than populations in highly variable environments. Also, contrary to expectations, populations of diving ducks were neither more stable nor stronger density dependent than populations of dabbling ducks, and the effect of environmental variability on population dynamics was greater in diving than in dabbling ducks. In general, irrespective of continent and species life history, environmental variability contributed more to variation in species abundances than did density. Our findings underscore the need for more studies on populations of the same species in different environments to verify the generality of current explanations about population dynamics and its association with species life history. PMID- 28725378 TI - Ecological role of vertebrate scavengers in urban ecosystems in the UK. AB - Recent research has demonstrated how scavenging, the act of consuming dead animals, plays a key role in ecosystem structure, functioning, and stability. A growing number of studies suggest that vertebrate scavengers also provide key ecosystem services, the benefits humans gain from the natural world, particularly in the removal of carcasses from the environment. An increasing proportion of the human population is now residing in cities and towns, many of which, despite being highly altered environments, contain significant wildlife populations, and so animal carcasses. Indeed, non-predation fatalities may be higher within urban than natural environments. Despite this, the fate of carcasses in urban environments and the role vertebrate scavengers play in their removal have not been determined. In this study, we quantify the role of vertebrate scavengers in urban environments in three towns in the UK. Using experimentally deployed rat carcasses and rapid fire motion-triggered cameras, we determined which species were scavenging and how removal of carcass biomass was partitioned between them. Of the 63 experimental carcasses deployed, vertebrate scavenger activity was detected at 67%. There was a significantly greater depletion in carcass biomass in the presence (mean loss of 194 g) than absence (mean loss of 14 g) of scavengers. Scavenger activity was restricted to three species, Carrion crows Corvus corone, Eurasian magpies Pica pica, and European red foxes Vulpes vulpes. From behavioral analysis, we estimated that a maximum of 73% of the carcass biomass was removed by vertebrate scavengers. Despite having low species richness, the urban scavenger community in our urban study system removed a similar proportion of carcasses to those reported in more pristine environments. Vertebrate scavengers are providing a key urban ecosystem service in terms of carcass removal. This service is, however, often overlooked, and the species that provide it are among some of the most disliked and persecuted. PMID- 28725379 TI - Field estimates of parentage reveal sexually antagonistic selection on body size in a population of Anolis lizards. AB - Sexual dimorphism evolves when selection favors different phenotypic optima between the sexes. Such sexually antagonistic selection creates intralocus sexual conflict when traits are genetically correlated between the sexes and have sex specific optima. Brown anoles are highly sexually dimorphic: Males are on average 30% longer than females and 150% heavier in our study population. Viability selection on body size is known to be sexually antagonistic, and directional selection favors large male size whereas stabilizing selection constrains females to remain small. We build on previous studies of viability selection by measuring sexually antagonistic selection using reproductive components of fitness over three generations in a natural population of brown anoles. We estimated the number of offspring produced by an individual that survived to sexual maturity (termed RSV), a measure of individual fitness that includes aspects of both individual reproductive success and offspring survival. We found directional selection on male body size, consistent with previous studies of viability selection. However, selection on female body size varied among years, and included periods of positive directional selection, quadratic stabilizing selection, and no selection. Selection acts differently in the sexes based on both survival and reproduction and sexual conflict appears to be a persistent force in this species. PMID- 28725380 TI - From the ground up: biotic and abiotic features that set the course from genes to ecosystems. AB - Spatial variation in cone serotiny in Rocky Mountain lodgepole pine (Pinus contorta ssp. latifolia) across Yellowstone National Park influences initial pine recruitment after stand-replacing fire with tremendous population, community, and ecosystem consequences. A previous study showed that much of the spatial variation in serotiny results from the balance of selection arising from high frequencies of fire favoring serotiny countered by opposing selection exerted by American red squirrels (Tamiasciurus hudsonicus) as seed predators. This earlier study, however, assumed stable local red squirrel densities over multiple generations of pines. Here, we examine environmental properties that might contribute to long-term stability in the densities of red squirrels among sites. We found that the amount of clay in the soil, an indicator of plant and fungal growth-the latter an important food resource for red squirrels-and the coefficient of variation (CV) in diameter at breast height (DBH) of forest trees together account for a substantial amount of variation in red squirrel density. Soil development occurs over very long time scales, and thus, intersite variation in the amount of clay is unlikely to shift across pine generations. However, CV of DBH and squirrel density increase with stand age, which acts to amplify selection against serotiny with increasing interfire interval. Regardless, much of the variation in the CV of DBH is accounted for by soil bulk density, mean annual temperature, and surface curvature, which are unlikely to vary in their relative differences among sites over time. Consequently, these soil and abiotic attributes could contribute to consistent spatial patterns of red squirrel densities from one pine generation to the next, resulting in consistent local and spatial variation in selection exerted by red squirrels against serotiny. PMID- 28725381 TI - Extending bioacoustic monitoring of birds aloft through flight call localization with a three-dimensional microphone array. AB - Bioacoustic localization of bird vocalizations provides unattended observations of the location of calling individuals in many field applications. While this technique has been successful in monitoring terrestrial distributions of calling birds, no published study has applied these methods to migrating birds in flight. The value of nocturnal flight call recordings can increase with the addition of three-dimensional position retrievals, which can be achieved with adjustments to existing localization techniques. Using the time difference of arrival method, we have developed a proof-of-concept acoustic microphone array that allows the three dimensional positioning of calls within the airspace. Our array consists of six microphones, mounted in pairs at the top and bottom of three 10-m poles, arranged in an equilateral triangle with sides of 20 m. The microphone array was designed using readily available components and costs less than $2,000 USD to build and deploy. We validate this technique using a kite-lofted GPS and speaker package, and obtain 60.1% of vertical retrievals within the accuracy of the GPS measurements (+/-5 m) and 80.4% of vertical retrievals within +/-10 m. The mean Euclidian distance between the acoustic retrievals of flight calls and the GPS truth was 9.6 m. Identification and localization of nocturnal flight calls have the potential to provide species-specific spatial characterizations of bird migration within the airspace. Even with the inexpensive equipment used in this trial, low-altitude applications such as surveillance around wind farms or oil platforms can benefit from the three-dimensional retrievals provided by this technique. PMID- 28725382 TI - Spatial modeling of data with excessive zeros applied to reindeer pellet-group counts. AB - We analyze a real data set pertaining to reindeer fecal pellet-group counts obtained from a survey conducted in a forest area in northern Sweden. In the data set, over 70% of counts are zeros, and there is high spatial correlation. We use conditionally autoregressive random effects for modeling of spatial correlation in a Poisson generalized linear mixed model (GLMM), quasi-Poisson hierarchical generalized linear model (HGLM), zero-inflated Poisson (ZIP), and hurdle models. The quasi-Poisson HGLM allows for both under- and overdispersion with excessive zeros, while the ZIP and hurdle models allow only for overdispersion. In analyzing the real data set, we see that the quasi-Poisson HGLMs can perform better than the other commonly used models, for example, ordinary Poisson HGLMs, spatial ZIP, and spatial hurdle models, and that the underdispersed Poisson HGLMs with spatial correlation fit the reindeer data best. We develop R codes for fitting these models using a unified algorithm for the HGLMs. Spatial count response with an extremely high proportion of zeros, and underdispersion can be successfully modeled using the quasi-Poisson HGLM with spatial random effects. PMID- 28725383 TI - Sexual selection impacts brain anatomy in frogs and toads. AB - Natural selection is a major force in the evolution of vertebrate brain size, but the role of sexual selection in brain size evolution remains enigmatic. At least two opposing schools of thought predict a relationship between sexual selection and brain size. Sexual selection should facilitate the evolution of larger brains because better cognitive abilities may aid the competition for mates. However, it may also restrict brain size evolution due to energetic trade-offs between brain tissue and sexually selected traits. Here, we examined the patterns of selection on brain size and brain anatomy in male anurans (frogs and toads), a group where the strength of sexual selection differs markedly among species, using a phylogenetically controlled generalized least-squared (PGLS) regression analyses. The analysis revealed that in 43 Chinese anuran species, neither mating system, nor type of courtship, or testes mass was significantly associated with relative brain size. While none of those factors related to the relative size of olfactory nerves, optic tecta, telencephalon, and cerebellum, the olfactory bulbs were relatively larger in monogamous species and those using calls during courtship. Our findings support the mosaic model of brain evolution and suggest that while the investigated aspects of sexual selection do not seem to play a prominent role in the evolution of brain size of anurans, they do impact their brain anatomy. PMID- 28725384 TI - Emissions of methane from northern peatlands: a review of management impacts and implications for future management options. AB - Northern peatlands constitute a significant source of atmospheric methane (CH 4). However, management of undisturbed peatlands, as well as the restoration of disturbed peatlands, will alter the exchange of CH 4 with the atmosphere. The aim of this systematic review and meta-analysis was to collate and analyze published studies to improve our understanding of the factors that control CH 4 emissions and the impacts of management on the gas flux from northern (latitude 40 degrees to 70 degrees N) peatlands. The analysis includes a total of 87 studies reporting measurements of CH 4 emissions taken at 186 sites covering different countries, peatland types, and management systems. Results show that CH 4 emissions from natural northern peatlands are highly variable with a 95% CI of 7.6-15.7 g C m-2 year-1 for the mean and 3.3-6.3 g C m-2 year-1 for the median. The overall annual average (mean +/- SD) is 12 +/- 21 g C m-2 year-1 with the highest emissions from fen ecosystems. Methane emissions from natural peatlands are mainly controlled by water table (WT) depth, plant community composition, and soil pH. Although mean annual air temperature is not a good predictor of CH 4 emissions by itself, the interaction between temperature, plant community cover, WT depth, and soil pH is important. According to short-term forecasts of climate change, these complex interactions will be the main determinant of CH 4 emissions from northern peatlands. Drainage significantly (p < .05) reduces CH 4 emissions to the atmosphere, on average by 84%. Restoration of drained peatlands by rewetting or vegetation/rewetting increases CH 4 emissions on average by 46% compared to the original premanagement CH 4 fluxes. However, to fully evaluate the net effect of management practice on the greenhouse gas balance from high latitude peatlands, both net ecosystem exchange (NEE) and carbon exports need to be considered. PMID- 28725385 TI - Do movement behaviors identify reproductive habitat sampling for wild turkeys? AB - Selection of habitats has regularly been suggested to influence species demography at both local and broad scales. The expectation is that selection behaviors have positive benefits via greater fitness or increased survival. The current paradigm of habitat selection theory suggests a hierarchical process, where an individual first selects where they choose to live (e.g., range) and then searches and selects locations within this range meeting life history needs. Using high-frequency GPS data collected from reproductively active Rio Grande (n = 21) and Eastern (n = 23) wild turkeys, we evaluated a long-standing theory for ground-nesting galliformes, in that movements during the prenesting period are behaviorally focused on sampling available habitats to optimize the selection of nesting sites. Contrary to expectations, we found no evidence that reproductively active females engage in habitat sampling activities. Although most nest sites (>80% for both subspecies) fell within the prenesting range, the average minimum daily distance from nest sites for Rio Grande and Eastern wild turkey females was large [1636.04 m (SE = 1523.96) and 1937.42 m (SE = 1267.84), respectively] whereas the average absolute minimum distance from the nest site for both Rio Grande and Eastern wild turkey females was 166.46 m (SE = 299.34) and 235.01 m (SE = 337.90), respectively, and showed no clear temporal reduction as laying approached. Overall, predicted probability that any female movements before laying were initiated intersected with her nesting range (area used during incubation) was <0.25, indicating little evidence of habitat sampling. Our results suggest that the long-standing assumption of hierarchical habitat selection by wild turkeys to identify nest sites may be incorrect. As such, habitat selection may not be the proximate driver of nest success and hence population-level fitness. Rather, based on our results, we suggest that wild turkeys and other ground-nesting species may be fairly plastic with regard to the selection of reproductive habitats, which is appropriate given the stochasticity of the environments they inhabit. PMID- 28725386 TI - The coevolution of sexual imprinting by males and females. AB - Sexual imprinting is the learning of a mate preference by direct observation of the phenotype of another member of the population. Sexual imprinting can be paternal, maternal, or oblique if individuals learn to prefer the phenotypes of their fathers, mothers, or other members of the population, respectively. Which phenotypes are learned can affect trait evolution and speciation rates. "Good genes" models of polygynous systems predict that females should evolve to imprint on their fathers, because paternal imprinting helps females to choose mates that will produce offspring that are both viable and sexy. Sexual imprinting by males has been observed in nature, but a theory for the evolution of sexual imprinting by males does not exist. We developed a good genes model to study the conditions under which sexual imprinting by males or by both sexes can evolve and to ask which sexual imprinting strategies maximize the fitness of the choosy sex. We found that when only males imprint, maternal imprinting is the most advantageous strategy. When both sexes imprint, it is most advantageous for both sexes to use paternal imprinting. Previous theory suggests that, in a given population, either males or females but not both will evolve choosiness in mating. We show how environmental change can lead to the evolution of sexual imprinting behavior by both sexes in the same population. PMID- 28725388 TI - Swimming with the giant: coexistence patterns of a new redfin minnow Pseudobarbus skeltoni from a global biodiversity hot spot. AB - Ecological niche theory predicts that coexistence is facilitated by resource partitioning mechanisms that are influenced by abiotic and biotic interactions. Alternative hypotheses suggest that under certain conditions, species may become phenotypically similar and functionally equivalent, which invokes the possibility of other mechanisms, such as habitat filtering processes. To test these hypotheses, we examined the coexistence of the giant redfin Pseudobarbus skeltoni, a newly described freshwater fish, together with its congener Pseudobabus burchelli and an anabantid Sandelia capensis by assessing their scenopoetic and bionomic patterns. We found high habitat and isotope niche overlaps between the two redfins, rendering niche partitioning a less plausible sole mechanism that drives their coexistence. By comparison, environment-trait relationships revealed differences in species-environment relationships, making habitat filtering and functional equivalence less likely alternatives. Based on P. skeltoni's high habitat niche overlap with other species, and its large isotope niche width, we inferred the likelihood of differential resource utilization at trophic level as an alternative mechanism that distinguished it from its congener. In comparison, its congener P. burchelli appeared to have a relatively small trophic niche, suggesting that its trophic niche was more conserved despite being the most abundant species. By contrast, S. capensis was distinguished by occupying a higher trophic position and by having a trophic niche that had a low probability of overlapping onto those of redfins. Therefore, trophic niche partitioning appeared to influence the coexistence between S. capensis and redfins. This study suggests that coexistence of these fishes appears to be promoted by their differences in niche adaptation mechanisms that are probably shaped by historic evolutionary and ecological processes. PMID- 28725387 TI - Origins of two hemiclonal hybrids among three Hexagrammos species (Teleostei: Hexagrammidae): genetic diversification through host switching. AB - Two natural, hemiclonal hybrid strains were discovered in three Hexagrammos species. The natural hybrids, all of which were females that produced haploid eggs containing only the Hexagrammos octogrammus genome (maternal ancestor; hereafter Hoc), generated F1 hybrid-type offspring by fertilization with haploid sperm of Hexagrammos agrammus or Hexagrammos otakii (paternal species; Hag and Hot, respectively). This study was performed to clarify the extent of diversification between the two hybrids and the maternal ancestor. Genealogical analysis using mtDNA revealed that all 38 Hoc/Hot hybrids formed a branch (Branch I) with 18 of the 33 Hoc/Hag hybrids. No haplotype sharing was observed with the maternal ancestor. Further, microsatellite DNA analysis suggested that the members of Branch I shared the same hemiclonal genome set. The results suggested that Hoc/Hot hybrids originated by anomalous hybridization, or "host switching," between Hoc/Hag and Hot, and not from interspecific hybridization between Hoc and Hot. The remaining 9 of 11 Hoc/Hag haplotypes and all of the 27 Hoc haplotypes were mixed within the genealogical tree, as if they had originated from multiple mutations. However, Hoc/Hag could also mate with Hoc. Although offspring from this host switch (Backcross-Hoc) have the same genome as normal Hoc, a part of their genome retains genetic factors capable of producing hemiclones. Consequently, when a descendant of a BC-Hoc hybrid mates with Hag males, a new hemiclone lineage will arise. Multiple haplotype revival through host switching from a single mutation in hybrids is another possible hypothesis for the observed mixing of Hoc/Hag haplotypes within the mtDNA genealogical tree. PMID- 28725389 TI - Quality versus quantity: Foraging decisions in the honeybee (Apis mellifera scutellata) feeding on wildflower nectar and fruit juice. AB - Foraging animals must often decide among resources which vary in quality and quantity. Nectar is a resource that exists along a continuum of quality in terms of sugar concentration and is the primary energy source for bees. Alternative sugar sources exist, including fruit juice, which generally has lower energetic value than nectar. We observed many honeybees (Apis mellifera scutellata) foraging on juice from fallen guava (Psidium guajava) fruit near others foraging on nectar. To investigate whether fruit and nectar offered contrasting benefits of quality and quantity, we compared honeybee foraging performance on P. guajava fruit versus two wildflowers growing within 50 m, Richardia brasiliensis and Tridax procumbens. Bees gained weight significantly faster on fruit, 2.72 mg/min, than on either flower (0.17 and 0.12 mg/min, respectively). However, the crop sugar concentration of fruit foragers was significantly lower than for either flower (12.4% vs. 37.0% and 22.7%, respectively). Fruit foragers also spent the most time handling and the least time flying, suggesting that fruit juice was energetically inexpensive to collect. We interpret honeybee foraging decisions in the context of existing foraging models and consider how nest-patch distance may be a key factor for central place foragers choosing between resources of contrasting quality and quantity. We also discuss how dilute solutions, such as fruit juice, can help maintain colony sugar-water balance. These results show the benefits of feeding on resources with contrasting quality and quantity and that even low-quality resources have value. PMID- 28725390 TI - Grazed wet meadows are sink habitats for the southern dunlin (Calidris alpina schinzii) due to nest trampling by cattle. AB - The effect of habitat management is commonly evaluated by measuring population growth, which does not distinguish changes in reproductive success from changes in survival or the effects of immigration or emigration. Management has rarely been evaluated considering complete life cycle of the target organisms, including also possible negative impacts from management. We evaluated the effectiveness of cattle grazing in the restoration of coastal meadows as a breeding habitat for small and medium-sized ground-nesting birds by examining the size and demography of a southern dunlin (Calidris alpina schinzii) breeding population. Using a stochastic renesting model that includes within-season variation in breeding parameters, we evaluated the effect of grazing time and stocking rates on reproduction. The census data indicated that the population was stable when nest trampling was prevented, but detailed demographic models showed that the population on managed meadows was a sink that persisted by attracting immigrants. Even small reductions in reproductive success caused by trampling were detrimental to long-term viability. We suggest that the best management strategy is to postpone grazing to after the 19th of June, which is about three weeks later than what is optimal from the farmer's point of view. The differing results from the two evaluation approaches warn against planning and evaluating management only based on census population size and highlight the need to consider target-specific life history characteristics and demography. Even though grazing management is crucial for creating and maintaining suitable habitats, we found that it was insufficient in maintaining a viable population without additional measures that increase nest success. In the presently studied case and in populations with similar breeding cycles, impacts from nest trampling can be avoided by starting grazing when about 70% of the breeding season has past. PMID- 28725391 TI - Explaining naturalization and invasiveness: new insights from historical ornamental plant catalogs. AB - We identified plant attributes associated with naturalization and invasiveness using century-old ornamental plant catalogs from Quebec (Canada). We tested the hypothesis that naturalization is determined by fewer factors than invasiveness, as the latter also requires dispersal, which introduces additional complexity. The approach we used took into account not only plant attributes as explanatory factors, but also propagule pressure, while accounting for phylogenetic relationships among species. Museum collections were used, in combination with scientific journal databases, to assess invasiveness. Particular attention was given to species that never escaped from gardens and thus represent cases of "failed" invasions. Naturalization in cold-temperate environments is determined by fewer factors than invasion, but only if phylogenetic links between species are taken into account, highlighting the importance of phylogenetic tools for analyzing species pools not resulting from a random selection of taxa. Hardiness is the main factor explaining naturalization in Quebec. Invasion requires dispersal, as shown by three significant variables associated with the spread of diaspores in the invasiveness model (seed weight, hydrochory, number of seed dispersal modes). Plants that are not cold-hardy are likely to disappear from the market or nature, but the disappearance phenomenon is more complex, involving also seed dispersal abilities and propagule pressure. Factors contributing to naturalization or invasiveness may differ greatly between regions. Differences are due in part to the plant traits used in the models and the methodology. However, this study, conducted in a cold-temperate region, sheds new light on what is likely a context (climatic)-dependant phenomenon. PMID- 28725392 TI - Beyond connectedness: why pairwise metrics cannot capture community stability. AB - The connectedness of species in a trophic web has long been a key structural characteristic for both theoreticians and empiricists in their understanding of community stability. In the past decades, there has been a shift from focussing on determining the number of interactions to taking into account their relative strengths. The question is: How do the strengths of the interactions determine the stability of a community? Recently, a metric has been proposed which compares the stability of observed communities in terms of the strength of three- and two link feedback loops (cycles of interaction strengths). However, it has also been suggested that we do not need to go beyond the pairwise structure of interactions to capture stability. Here, we directly compare the performance of the feedback and pairwise metrics. Using observed food-web structures, we show that the pairwise metric does not work as a comparator of stability and is many orders of magnitude away from the actual stability values. We argue that metrics based on pairwise-strength information cannot capture the complex organization of strong and weak links in a community, which is essential for system stability. PMID- 28725393 TI - Water mold infection but not paternity induces selective filial cannibalism in a goby. AB - Many animals heavily invest in parental care but still reject at least some of their offspring. Although seemingly paradoxical, selection can favor parents to neglect offspring of particularly low reproductive value, for example, because of small survival chances. We here assess whether filial cannibalism (FC), where parents routinely eat some of their own young, is selective in response to individual offspring reproductive value. We performed two independent laboratory experiments in the common goby (Pomatoschistus microps) to test whether caring fathers preferentially cannibalize eggs of a given infection history and paternity. While males did not discriminate kin from nonkin eggs, they consumed significantly more eggs previously exposed to water mold compared to uninfected eggs. Our findings clearly show that parents differentiate between eggs based on differences in egg condition, and thus complement the prevailing view that FC arises for energetic reasons. By preventing the spread of microbial infections, the removal of molded eggs can constitute an important component of parental care and may represent a key driver of selective FC in a wide array of parental fish. PMID- 28725394 TI - Support for the elevational Rapoport's rule among seed plants in Nepal depends on biogeographical affinities and boundary effects. AB - As one of the most important hypotheses on biogeographical distribution, Rapoport's rule has attracted attention around the world. However, it is unclear whether the applicability of the elevational Rapoport's Rule differs between organisms from different biogeographical regions. We used Stevens' method, which uses species diversity and the averaged range sizes of all species within each (100 m) elevational band to explore diversity-elevation, range-elevation, and diversity-range relationships. We compared support for the elevational Rapoport's rule between tropical and temperate species of seed plants in Nepal. Neither tropical nor temperate species supported the predictions of the elevational Rapoport's rule along the elevation gradient of 100-6,000 m a.s.l. for any of the studied relationships. However, along the smaller 1,000-5,000 m a.s.l. gradient (4,300 m a.s.l. for range-elevation relationships) which is thought to be less influenced by boundary effects, we observed consistent support for the rule by tropical species, although temperate species did not show consistent support. The degree of support for the elevational Rapoport's rule may not only be influenced by hard boundary effects, but also by the biogeographical affinities of the focal taxa. With ongoing global warming and increasing variability of temperature in high-elevation regions, tropical taxa may shift upward into higher elevations and expand their elevational ranges, causing the loss of temperate taxa diversity. Relevant studies on the elevational Rapoport's rule with regard to biogeographical affinities may be a promising avenue to further our understanding of this rule. PMID- 28725395 TI - Reduced aboveground tree growth associated with higher arbuscular mycorrhizal fungal diversity in tropical forest restoration. AB - Establishing diverse mycorrhizal fungal communities is considered important for forest recovery, yet mycorrhizae may have complex effects on tree growth depending on the composition of fungal species present. In an effort to understand the role of mycorrhizal fungi community in forest restoration in southern Costa Rica, we sampled the arbuscular mycorrhizal fungal (AMF) community across eight sites that were planted with the same species (Inga edulis, Erythrina poeppigiana, Terminalia amazonia, and Vochysia guatemalensis) but varied twofold to fourfold in overall tree growth rates. The AMF community was measured in multiple ways: as percent colonization of host tree roots, by DNA isolation of the fungal species associated with the roots, and through spore density, volume, and identity in both the wet and dry seasons. Consistent with prior tropical restoration research, the majority of fungal species belonged to the genus Glomus and genus Acaulospora, accounting for more than half of the species and relative abundance found on trees roots and over 95% of spore density across all sites. Greater AMF diversity correlated with lower soil organic matter, carbon, and nitrogen concentrations and longer durations of prior pasture use across sites. Contrary to previous literature findings, AMF species diversity and spore densities were inversely related to tree growth, which may have arisen from trees facultatively increasing their associations with AMF in lower soil fertility sites. Changes to AMF community composition also may have led to variation in disturbance susceptibility, host tree nutrient acquisition, and tree growth. These results highlight the potential importance of fungal-tree-soil interactions in forest recovery and suggest that fungal community dynamics could have important implications for tree growth in disturbed soils. PMID- 28725396 TI - American trees shift their niches when invading Western Europe: evaluating invasion risks in a changing climate. AB - Four North American trees are becoming invasive species in Western Europe: Acer negundo, Prunus serotina, Quercus rubra, and Robinia pseudoacacia. However, their present and future potential risks of invasion have not been yet evaluated. Here, we assess niche shifts between the native and invasive ranges and the potential invasion risk of these four trees in Western Europe. We estimated niche conservatism in a multidimensional climate space using niche overlap Schoener's D, niche equivalence, and niche similarity tests. Niche unfilling and expansion were also estimated in analogous and nonanalogous climates. The capacity for predicting the opposite range between the native and invasive areas (transferability) was estimated by calibrating species distribution models (SDMs) on each range separately. Invasion risk was estimated using SDMs calibrated on both ranges and projected for 2050 climatic conditions. Our results showed that native and invasive niches were not equivalent with low niche overlap for all species. However, significant similarity was found between the invasive and native ranges of Q. rubra and R. pseudoacacia. Niche expansion was lower than 15% for all species, whereas unfilling ranged from 7 to 56% when it was measured using the entire climatic space and between 5 and 38% when it was measured using analogous climate only. Transferability was low for all species. SDMs calibrated over both ranges projected high habitat suitability in Western Europe under current and future climates. Thus, the North American and Western European ranges are not interchangeable irrespective of the studied species, suggesting that other environmental and/or biological characteristics are shaping their invasive niches. The current climatic risk of invasion is especially high for R. pseudoacacia and A. negundo. In the future, the highest risks of invasion for all species are located in Central and Northern Europe, whereas the risk is likely to decrease in the Mediterranean basin. PMID- 28725397 TI - Genetic diversity and phylogeography of Siberian roe deer, Caproulus pygargus, in central and peripheral populations. AB - Current understanding of phylogeographical structure and genetic diversity of Siberian roe deer remains limited mainly due to small sample size and/or low geographical coverage in previous studies. Published data suggest at least two phylogroups: western (Ural Mountains and Western Siberia) and eastern (east from lake Baikal, including the Korean peninsula), but their phylogenetic relationship remains unclear. Combined sequences of cytochrome b (1140 bp) and the mtDNA control region (963 bp) were analyzed from 219 Siberian roe deer from 12 locations in Russia, Mongolia, and South Korea, which cover a large part of its range, to assess genetic diversity and phylogeographical status. Special emphasis was placed on the demographic history and genetic features of central, peripheral, and isolated populations. Results of median-joining network and phylogenetic tree analyses indicate that Siberian roe deer from the Urals to the Pacific Ocean are genetically diverse and that geographical distribution and composition of haplogroups coincide with previously described ranges of the subspecies Capreolus pygargus pygargus and Capreolus pygargus tianschanicus. We found that peripheral populations in the northwestern parts of the species range (Urals), as well as the isolated population from Jeju Island, are genetically distinct from those in the core part of the range, both in terms of genetic diversity and quantitative composition of haplogroups. We also found that northwestern (Urals) and northern (Yakutia) peripheral populations share the same haplogroup and fall into the same phylogenetic clade with the isolated population from Jeju Island. This finding sheds light on the taxonomic status of the Jeju Island population and leads to hypotheses about the discordance of morphological and genetic evolution in isolated populations and specific genetic features of peripheral populations. PMID- 28725398 TI - Phenological asynchrony between host plant and gypsy moth reduces insect gut microbiota and susceptibility to Bacillus thuringiensis. AB - The phenological synchrony between the emergence of overwintering herbivorous insects and the budding of host plants is considered a crucial factor in the population dynamics of herbivores. However, the mechanisms driving the interactions between the host plant, herbivores, and their pathogens are often obscure. In the current study, an artificially induced phenological asynchrony was used to investigate how the asynchrony between silver birch Betula pendula and gypsy moth Lymantria dispar affects the immunity of the insect to bacteria, its susceptibility to the entomopathogenic bacteria Bacillus thuringiensis, and the diversity in its midgut microbiota. The lysozyme-like activity in both the midgut and hemolymph plasma and the nonspecific esterase activity and antimicrobial peptide gene expression in the midgut were studied in both noninfected and B. thuringiensis-infected larvae. Our results provide the first evidence that phenologically asynchronous larvae are less susceptible to B. thuringiensis infection than phenologically synchronous larvae, and our results show that these effects are related to the high basic levels and B. thuringiensis induced levels of lysozyme-like activities. Moreover, a 16S rRNA analysis revealed that dramatic decreases in the diversity of the larval gut bacterial consortia occurred under the effect of asynchrony. Larvae infected with B. thuringiensis presented decreased microbiota diversity if the larvae were reared synchronously with the host plant but not if they were reared asynchronously. Our study demonstrates the significant effect of phenological asynchrony on innate immunity-mediated interactions between herbivores and entomopathogenic bacteria and highlights the role of nonpathogenic gut bacteria in these interactions. PMID- 28725399 TI - Optimizing performance of nonparametric species richness estimators under constrained sampling. AB - Understanding the functional relationship between the sample size and the performance of species richness estimators is necessary to optimize limited sampling resources against estimation error. Nonparametric estimators such as Chao and Jackknife demonstrate strong performances, but consensus is lacking as to which estimator performs better under constrained sampling. We explore a method to improve the estimators under such scenario. The method we propose involves randomly splitting species-abundance data from a single sample into two equally sized samples, and using an appropriate incidence-based estimator to estimate richness. To test this method, we assume a lognormal species-abundance distribution (SAD) with varying coefficients of variation (CV), generate samples using MCMC simulations, and use the expected mean-squared error as the performance criterion of the estimators. We test this method for Chao, Jackknife, ICE, and ACE estimators. Between abundance-based estimators with the single sample, and incidence-based estimators with the split-in-two samples, Chao2 performed the best when CV < 0.65, and incidence-based Jackknife performed the best when CV > 0.65, given that the ratio of sample size to observed species richness is greater than a critical value given by a power function of CV with respect to abundance of the sampled population. The proposed method increases the performance of the estimators substantially and is more effective when more rare species are in an assemblage. We also show that the splitting method works qualitatively similarly well when the SADs are log series, geometric series, and negative binomial. We demonstrate an application of the proposed method by estimating richness of zooplankton communities in samples of ballast water. The proposed splitting method is an alternative to sampling a large number of individuals to increase the accuracy of richness estimations; therefore, it is appropriate for a wide range of resource-limited sampling scenarios in ecology. PMID- 28725400 TI - Dealing with paralogy in RADseq data: in silico detection and single nucleotide polymorphism validation in Robinia pseudoacacia L. AB - The RADseq technology allows researchers to efficiently develop thousands of polymorphic loci across multiple individuals with little or no prior information on the genome. However, many questions remain about the biases inherent to this technology. Notably, sequence misalignments arising from paralogy may affect the development of single nucleotide polymorphism (SNP) markers and the estimation of genetic diversity. We evaluated the impact of putative paralog loci on genetic diversity estimation during the development of SNPs from a RADseq dataset for the nonmodel tree species Robinia pseudoacacia L. We sequenced nine genotypes and analyzed the frequency of putative paralogous RAD loci as a function of both the depth of coverage and the mismatch threshold allowed between loci. Putative paralogy was detected in a very variable number of loci, from 1% to more than 20%, with the depth of coverage having a major influence on the result. Putative paralogy artificially increased the observed degree of polymorphism and resulting estimates of diversity. The choice of the depth of coverage also affected diversity estimation and SNP validation: A low threshold decreased the chances of detecting minor alleles while a high threshold increased allelic dropout. SNP validation was better for the low threshold (4*) than for the high threshold (18*) we tested. Using the strategy developed here, we were able to validate more than 80% of the SNPs tested by means of individual genotyping, resulting in a readily usable set of 330 SNPs, suitable for use in population genetics applications. PMID- 28725401 TI - Sky island bird populations isolated by ancient genetic barriers are characterized by different song traits than those isolated by recent deforestation. AB - Various mechanisms of isolation can structure populations and result in cultural and genetic differentiation. Similar to genetic markers, for songbirds, culturally transmitted sexual signals such as breeding song can be used as a measure of differentiation as songs can also be impacted by geographic isolation resulting in population-level differences in song structure. Several studies have found differences in song structure either across ancient geographic barriers or across contemporary habitat barriers owing to deforestation. However, very few studies have examined the effect of both ancient barriers and recent deforestation in the same system. In this study, we examined the geographic variation in song structure across six populations of the White-bellied Shortwing, a threatened and endemic songbird species complex found on isolated mountaintops or "sky islands" of the Western Ghats. While some sky islands in the system are isolated by ancient valleys, others are separated by deforestation. We examined 14 frequency and temporal spectral traits and two syntax traits from 835 songs of 38 individuals across the six populations. We identified three major song clusters based on a discriminant model of spectral traits, degree of similarity of syntax features, as well as responses of birds to opportunistic playback. However, some traits like complex vocal mechanisms (CVM), relating to the use of syrinxes, clearly differentiated both ancient and recently fragmented populations. We suggest that CVMs may have a cultural basis and can be used to identify culturally isolated populations that cannot be differentiated using genetic markers or commonly used frequency-based song traits. Our results demonstrate the use of bird songs to reconstruct phylogenetic groups and impacts of habitat fragmentation even in complex scenarios of historic and contemporary isolation. PMID- 28725402 TI - What does body size mean, from the "plant's eye view"? AB - Alternative metrics exist for representing variation in plant body size, but the vast majority of previous research for herbaceous plants has focused on dry mass. Dry mass provides a reasonably accurate and easily measured estimate for comparing relative capacity to convert solar energy into stored carbon. However, from a "plant's eye view", its experience of its local biotic environment of immediate neighbors (especially when crowded) may be more accurately represented by measures of "space occupancy" (S-O) recorded in situ-rather than dry mass measured after storage in a drying oven. This study investigated relationships between dry mass and alternative metrics of S-O body size for resident plants sampled from natural populations of herbaceous species found in Eastern Ontario. Plant height, maximum lateral canopy extent, and estimated canopy area and volume were recorded in situ (in the field)-and both fresh and dry mass were recorded in the laboratory-for 138 species ranging widely in body size and for 20 plants ranging widely in body size within each of 10 focal species. Dry mass and fresh mass were highly correlated (r2 > .95) and isometric, suggesting that for some studies, between-species (or between-plant) variation in water content may be unimportant and fresh mass can therefore substitute for dry mass. However, several relationships between dry mass and other S-O body size metrics showed allometry-that is, plants with smaller S-O body size had disproportionately less dry mass. In other words, they have higher "body mass density" (BMD) - more dry mass per unit S-O body size. These results have practical importance for experimental design and methodology as well as implications for the interpretation of "reproductive economy"-the capacity to produce offspring at small body sizes-because fecundity and dry mass (produced in the same growing season) typically have a positive, isometric relationship. Accordingly, the allometry between dry mass and S-O body size reported here suggests that plants with smaller S-O body size-because of higher BMD-may produce fewer offspring, but less than proportionately so; in other words, they may produce more offspring per unit of body size space occupancy. PMID- 28725404 TI - Age-dependent male mating tactics in a spider mite-A life-history perspective. AB - Males often fight with rival males for access to females. However, some males display nonfighting tactics such as sneaking, satellite behavior, or female mimicking. When these mating tactics comprise a conditional strategy, they are often thought to be explained by resource holding potential (RHP), that is, nonfighting tactics are displayed by less competitive males who are more likely to lose a fight. The alternative mating tactics, however, can also be explained by life-history theory, which predicts that young males avoid fighting, regardless of their RHP, if it pays off to wait for future reproduction. Here, we test whether the sneaking tactic displayed by young males of the two-spotted spider mite can be explained by life-history theory. We tested whether young sneaker males survive longer than young fighter males after a bout of mild or strong competition with old fighter males. We also investigated whether old males have a more protective outer skin-a possible proxy for RHP-by measuring cuticle hardness and elasticity using nanoindentation. We found that young sneaker males survived longer than young fighter males after mild male competition. This difference was not found after strong male competition, which suggests that induction of sneaking tactic is affected by male density. Hardness and elasticity of the skin did not vary with male age. Given that earlier work could also not detect morphometric differences between fighter and sneaker males, we conclude that there is no apparent increase in RHP with age in the mite and age-dependent male mating tactics in the mite can be explained only by life-history theory. Because it is likely that fighting incurs a survival cost, age-dependent alternative mating tactics may be explained by life-history theory in many species when reproduction of old males is a significant factor in fitness. PMID- 28725403 TI - Potential and limitations of inferring ecosystem photosynthetic capacity from leaf functional traits. AB - The aim of this study was to systematically analyze the potential and limitations of using plant functional trait observations from global databases versus in situ data to improve our understanding of vegetation impacts on ecosystem functional properties (EFPs). Using ecosystem photosynthetic capacity as an example, we first provide an objective approach to derive robust EFP estimates from gross primary productivity (GPP) obtained from eddy covariance flux measurements. Second, we investigate the impact of synchronizing EFPs and plant functional traits in time and space to evaluate their relationships, and the extent to which we can benefit from global plant trait databases to explain the variability of ecosystem photosynthetic capacity. Finally, we identify a set of plant functional traits controlling ecosystem photosynthetic capacity at selected sites. Suitable estimates of the ecosystem photosynthetic capacity can be derived from light response curve of GPP responding to radiation (photosynthetically active radiation or absorbed photosynthetically active radiation). Although the effect of climate is minimized in these calculations, the estimates indicate substantial interannual variation of the photosynthetic capacity, even after removing site years with confounding factors like disturbance such as fire events. The relationships between foliar nitrogen concentration and ecosystem photosynthetic capacity are tighter when both of the measurements are synchronized in space and time. When using multiple plant traits simultaneously as predictors for ecosystem photosynthetic capacity variation, the combination of leaf carbon to nitrogen ratio with leaf phosphorus content explains the variance of ecosystem photosynthetic capacity best (adjusted R2 = 0.55). Overall, this study provides an objective approach to identify links between leaf level traits and canopy level processes and highlights the relevance of the dynamic nature of ecosystems. Synchronizing measurements of eddy covariance fluxes and plant traits in time and space is shown to be highly relevant to better understand the importance of intra and interspecific trait variation on ecosystem functioning. PMID- 28725405 TI - Effects of food abundance and early clutch predation on reproductive timing in a high Arctic shorebird exposed to advancements in arthropod abundance. AB - Climate change may influence the phenology of organisms unequally across trophic levels and thus lead to phenological mismatches between predators and prey. In cases where prey availability peaks before reproducing predators reach maximal prey demand, any negative fitness consequences would selectively favor resynchronization by earlier starts of the reproductive activities of the predators. At a study site in northeast Greenland, over a period of 17 years, the median emergence of the invertebrate prey of Sanderling Calidris alba advanced with 1.27 days per year. Yet, over the same period Sanderling did not advance hatching date. Thus, Sanderlings increasingly hatched after their prey was maximally abundant. Surprisingly, the phenological mismatches did not affect chick growth, but the interaction of the annual width and height of the peak in food abundance did. Chicks grew especially better in years when the food peak was broad. Sanderling clutches were most likely to be depredated early in the season, which should delay reproduction. We propose that high early clutch predation may favor a later reproductive timing. Additionally, our data suggest that in most years food was still abundant after the median date of emergence, which may explain why Sanderlings did not advance breeding along with the advances in arthropod phenology. PMID- 28725406 TI - Root exudate cocktails: the link between plant diversity and soil microorganisms? AB - Higher plant diversity is often associated with higher soil microbial biomass and diversity, which is assumed to be partly due to elevated root exudate diversity. However, there is little experimental evidence that diversity of root exudates shapes soil microbial communities. We tested whether higher root exudate diversity enhances soil microbial biomass and diversity in a plant diversity gradient, thereby negating significant plant diversity effects on soil microbial properties. We set up plant monocultures and two- and three-species mixtures in microcosms using functionally dissimilar plants and soil of a grassland biodiversity experiment in Germany. Artificial exudate cocktails were added by combining the most common sugars, organic acids, and amino acids found in root exudates. We applied four different exudate cocktails: two exudate diversity levels (low- and high-diversity) and two nutrient-enriched levels (carbon- and nitrogen-enriched), and a control with water only. Soil microorganisms were more carbon- than nitrogen-limited. Cultivation-independent fingerprinting analysis revealed significantly different soil microbial communities among exudate diversity treatments. Most notably and according to our hypothesis, adding diverse exudate cocktails negated the significant plant diversity effect on soil microbial properties. Our findings provide the first experimental evidence that root exudate diversity is a crucial link between plant diversity and soil microorganisms. PMID- 28725407 TI - The contribution of marine aggregate-associated bacteria to the accumulation of pathogenic bacteria in oysters: an agent-based model. AB - Bivalves process large volumes of water, leading to their accumulation of bacteria, including potential human pathogens (e.g., vibrios). These bacteria are captured at low efficiencies when freely suspended in the water column, but they also attach to marine aggregates, which are captured with near 100% efficiency. For this reason, and because they are often enriched with heterotrophic bacteria, marine aggregates have been hypothesized to function as important transporters of bacteria into bivalves. The relative contribution of aggregates and unattached bacteria to the accumulation of these cells, however, is unknown. We developed an agent-based model to simulate accumulation of vibrio-type bacteria in oysters. Simulations were conducted over a realistic range of concentrations of bacteria and aggregates and incorporated the dependence of pseudofeces production on particulate matter. The model shows that the contribution of aggregate-attached bacteria depends strongly on the unattached bacteria, which form the colonization pool for aggregates and are directly captured by the simulated oysters. The concentration of aggregates is also important, but its effect depends on the concentration of unattached bacteria. At high bacterial concentrations, aggregates contribute the majority of bacteria in the oysters. At low concentrations of unattached bacteria, aggregates have a neutral or even a slightly negative effect on bacterial accumulation. These results provide the first evidence suggesting that the concentration of aggregates could influence uptake of pathogenic bacteria in bivalves and show that the tendency of a bacterial species to remain attached to aggregates is a key factor for understanding species-specific accumulation. PMID- 28725408 TI - Landscape composition and configuration in the central highlands of Ethiopia. AB - Landscape dynamics are common phenomenon in the human-dominated environments whereby it can be observed that the composition and configuration between landscape elements change over time. This dynamism brings about habitat loss and fragmentation that can greatly alter ecosystem services at patch, class, and landscape levels. We conducted a study to examine composition and configuration of forested landscape in the central highlands of Ethiopia using satellite images of over a period of four decades, and FRAGSTAT raster dataset was used to analyze fragmentation. Our result showed five land use/land cover (LULC) types in the study area. Cultivated land and settlement land increased at the expense of forestland, shrubland, and grassland. Fragmentation analysis showed the number of patches increased for all LULC types, indicating the level of fragmentation and interspersion. Juxtaposition increased for shrubland, grassland, and cultivated lands and decreased for settlement and forestland resulting in the fragmentation and isolation of patches. The study of LULC along with fragmentation at the landscape level can help improve our understanding of the pace at which conversion of landscape elements is happening and the impacts on ecosystem services as studies of LULC are courser in nature and would not show how each land use is reducing in size, proximity and shape among other things that determine ecosystem services. Such type of studies in rural landscapes are very vital to consider appropriate land management policies for the landscape level by taking into account the interaction between each element for sustainable development. We recommend land managers, conservationists, and land owners for observing the roles of each patch in the matrix to maximize the benefits than focusing on a single element. PMID- 28725409 TI - Development of methane conversion factor models for Zebu beef cattle fed low quality crop residues and by-products in tropical regions. AB - The enteric methane conversion factor (Ym) is an important country-specific value for the provision of precise enteric methane emissions inventory reports. The objectives of this meta-analysis were to develop and evaluate the empirical Ym models for the national level and the farm level for tropical developing countries according to the IPCC's categorization. We used datasets derived from 18 in vivo feeding experiments from 1999 to 2015 of Zebu beef cattle breeds fed low-quality crop residues and by-products. We found that the observed Ym value was 8.2% gross energy (GE) intake (~120 g methane emission head-1 day-1) and ranged from 4.8% to 13.7% GE intake. The IPCC default model (tier 2, Ym = 6.5% +/ 1.0% GE intake) underestimated the Ym values by up to 26.1% compared with its refinement of 8.4% +/- 0.4% GE intake for the national-level estimate. Both the IPCC default model and the refined model performed worse in predicting Ym trends at the farm level (root mean square prediction error [MSPE] = 15.1%-23.1%, concordance correlation coefficient [CCC] = 0.16-0.18, R2 = .32). Seven of the extant Ym models based on a linear regression approach also showed inaccurately estimated Ym values (root MSPE = 16.2%-36.0%, CCC = 0.02-0.27, R2 < .37). However, one of the developed models, which related to the complexity of the energy use efficiencies of the diet consumed to Ym, showed adequate accuracy at the farm level (root MSPE = 9.1%, CCC = 0.75, R2 = .67). Our results thus suggest a new Ym model and future challenges for estimating Zebu beef cattle production in tropical developing countries. PMID- 28725410 TI - Aegean wall lizards switch foraging modes, diet, and morphology in a human-built environment. AB - Foraging mode is a functional trait with cascading impacts on ecological communities. The foraging syndrome hypothesis posits a suite of concurrent traits that vary with foraging mode; however, comparative studies testing this hypothesis are typically interspecific. While foraging modes are often considered typological for a species when predicting foraging-related traits or mode specific cascading impacts, intraspecific mode switching has been documented in some lizards. Mode-switching lizards provide an opportunity to test foraging syndromes and explore how intraspecific variability in foraging mode might affect local ecological communities.Because lizard natural history is intimately tied to habitat use and structure, I tested for mode switching between populations of the Aegean wall lizard, Podarcis erhardii, inhabiting undisturbed habitat and human built rock walls on the Greek island of Naxos. I observed foraging behavior among 10 populations and tested lizard morphological and performance predictions at each site. Furthermore, I investigated the diet of lizards at each site relative to the available invertebrate community.I found that lizards living on rock walls were significantly more sedentary-sit and wait-than lizards at nonwall sites. I also found that head width increased in females and the ratio of hindlimbs to forelimbs in both sexes increased as predicted. Diet also changed, with nonwall lizards consuming a higher proportion of sedentary prey. Lizard bite force also varied significantly between sites; however, the pattern observed was opposite to that predicted, suggesting that bite force in these lizards may more closely relate to intraspecific competition than to diet.This study demonstrates microgeographic variability in lizard foraging mode as a result of human land use. In addition, these results demonstrate that foraging mode syndromes can shift intraspecifically with potential cascading effects on local ecological communities. PMID- 28725411 TI - Choosing a mate in a high predation environment: Female preference in the fiddler crab Uca terpsichores. AB - The interplay between a receiver's sensory system and a sender's courtship signals is fundamental to the operation of sexual selection. Male courtship signals that match a female receiver's preexisting perceptual biases can be favored yet the message they communicate is not always clear. Do they simply beacon the male's location or also indicate his quality? We explored this question in a species of fiddler crab Uca terpsichores that courts under elevated predation risk and that mates and breeds underground in the safety of males' burrows. Sexually receptive females leave their own burrows and are thereby exposed to avian predators as they sequentially approach several courting males before they choose one. Males court by waving their single greatly enlarge claw and sometimes by building a sand hood next to their burrow entrance. Hoods are attractive because they elicit a risk-reducing orientation behavior in females, and it has been suggested that claw waving may also serve primarily to orient the female to the male. If the wave communicates male quality, then females should discriminate mates on the basis of variation in elements of the wave, as has been shown for other fiddler crabs. Alternatively, variation in elements of the claw waving display may have little effect on the display's utility as a beacon of the location of the male and his burrow. We filmed courting males and females under natural conditions as females responded to claw waving and chose mates. Analysis of the fine-scale courtship elements between the males that females rejected and those they chose revealed no differences. When predation risk during courtship is high, males' courtship displays may serve primarily to guide females to safe mating and breeding sites and not as indicators of male quality apart from their roles as beacons. PMID- 28725412 TI - Corticosterone: a costly mediator of signal honesty in sand lizards. AB - The mechanisms underlying honest signal expression remain elusive and may involve the integration of social and physiological costs. Corticosterone is a socially modulated metabolic hormone that mediates energy investment and behavior and may therefore function to deter dishonest signal expression. We examined the relationship between corticosterone and green badge coloration in male sand lizards (Lacerta agilis), hypothesizing that physiological and behavioral costs resulting from elevated baseline glucocorticoids function in maintenance of honest signal expression. We found that large-badged males had higher corticosterone titer, with this relationship apparent at the end of the season and absent early in the season. Large-badged males also suffered higher ectoparasite load (number of tick nymphs), despite being in better condition than small-badged males. Ectoparasite load was positively related to corticosterone titer early in the season at the time of badge formation. High-condition individuals had lower corticosterone and lower numbers of ectoparasites than low condition individuals, suggestive of conditional variation in ability to withstand costs of corticosterone. We found an opposing negative relationship between corticosterone titer and endoparasite load. Corticosterone titer was also negatively associated with male mobility, a fitness-determining behavior in this species. Because badge size is involved in mediating agonistic social interactions in this species, our results suggest that badge-dependent variation in corticosterone is likely reflective of variation in social conditions experienced over the course of the season. Our results implicate corticosterone in maintenance of signal honesty, both early in the season through enforcement of physiological costs (ectoparasite load) and during the season through behavioral costs (male mobility). We propose that socially modulated variation in corticosterone critically functions in mediation of signal honesty without requiring a direct role for corticosterone in trait expression. PMID- 28725413 TI - Prothonotary warbler nestling growth and condition in response to variation in aquatic and terrestrial prey availability. AB - Aquatic prey subsidies entering terrestrial habitats are well documented, but little is known about the degree to which these resources provide fitness benefits to riparian consumers. Riparian species take advantage of seasonal pulses of both terrestrial and aquatic prey, although aquatic resources are often overlooked in studies of how diet influences the reproductive ecology of these organisms. Ideally, the timing of resource pulses should occur at the time of highest reproductive demand. This study investigates the availability of aquatic (mayfly) and terrestrial (caterpillar) prey resources as well as the nestling diet of the prothonotary warbler (Protonotaria citrea) at two sites along the lower James River in Virginia during the 2014 breeding season. We found large differences in availability of prey items between the two sites, with one having significantly higher mayfly availability. Nestling diet was generally reflective of prey availability, and nestlings had faster mean growth rates at the site with higher aquatic prey availability. Terrestrial prey were fed more readily at the site with lower aquatic prey availability, and at this site, nestlings fed mayflies had higher mean growth rates than nestlings fed only terrestrial prey. Our results suggest that aquatic subsidies are an important resource for nestling birds and are crucial to understanding the breeding ecology of riparian species. PMID- 28725415 TI - Seed production areas for the global restoration challenge. AB - Wild-collected seed can no longer meet global demand in restoration. Dedicated Seed Production Areas (SPA) for restoration are needed and these require application of ecological, economic, and population-genetic science. SPA design and construction must embrace the ecological sustainability principles of restoration. PMID- 28725414 TI - SNPs across time and space: population genomic signatures of founder events and epizootics in the House Finch (Haemorhous mexicanus). AB - Identifying genomic signatures of natural selection can be challenging against a background of demographic changes such as bottlenecks and population expansions. Here, we disentangle the effects of demography from selection in the House Finch (Haemorhous mexicanus) using samples collected before and after a pathogen induced selection event. Using ddRADseq, we genotyped over 18,000 SNPs across the genome in native pre-epizootic western US birds, introduced birds from Hawaii and the eastern United States, post-epizootic eastern birds, and western birds sampled across a similar time span. We found 14% and 7% reductions in nucleotide diversity, respectively, in Hawaiian and pre-epizootic eastern birds relative to pre-epizootic western birds, as well as elevated levels of linkage disequilibrium and other signatures of founder events. Despite finding numerous significant frequency shifts (outlier loci) between pre-epizootic native and introduced populations, we found no signal of reduced genetic diversity, elevated linkage disequilibrium, or outlier loci as a result of the epizootic. Simulations demonstrate that the proportion of outliers associated with founder events could be explained by genetic drift. This rare view of genetic evolution across time in an invasive species provides direct evidence that demographic shifts like founder events have genetic consequences more widespread across the genome than natural selection. PMID- 28725416 TI - Contrasting patterns of selection between MHC I and II across populations of Humboldt and Magellanic penguins. AB - The evolutionary and adaptive potential of populations or species facing an emerging infectious disease depends on their genetic diversity in genes, such as the major histocompatibility complex (MHC). In birds, MHC class I deals predominantly with intracellular infections (e.g., viruses) and MHC class II with extracellular infections (e.g., bacteria). Therefore, patterns of MHC I and II diversity may differ between species and across populations of species depending on the relative effect of local and global environmental selective pressures, genetic drift, and gene flow. We hypothesize that high gene flow among populations of Humboldt and Magellanic penguins limits local adaptation in MHC I and MHC II, and signatures of selection differ between markers, locations, and species. We evaluated the MHC I and II diversity using 454 next-generation sequencing of 100 Humboldt and 75 Magellanic penguins from seven different breeding colonies. Higher genetic diversity was observed in MHC I than MHC II for both species, explained by more than one MHC I loci identified. Large population sizes, high gene flow, and/or similar selection pressures maintain diversity but limit local adaptation in MHC I. A pattern of isolation by distance was observed for MHC II for Humboldt penguin suggesting local adaptation, mainly on the northernmost studied locality. Furthermore, trans-species alleles were found due to a recent speciation for the genus or convergent evolution. High MHC I and MHC II gene diversity described is extremely advantageous for the long-term survival of the species. PMID- 28725417 TI - Reduced inflammation in expanding populations of a neotropical bird species. AB - The loss of regulating agents such as parasites is among the most important changes in biotic interactions experienced by populations established in newly colonized areas. Under a relaxed parasite pressure, individuals investing less in costly immune mechanisms might experience a selective advantage and become successful colonizers as they re-allocate resources to other fitness-related traits. Accordingly, a refinement of the evolution of increased competitive ability (EICA) hypothesis proposed that immunity of invasive populations has evolved toward a reduced investment in innate immunity, the most costly component of immunity, and an increased humoral immunity that is less costly. Biogeographical approaches comparing populations between native and expansion ranges are particularly relevant in exploring this issue, but remain very scarce. We conducted a biogeographical comparison between populations of Spectacled Thrush (Turdus nudigenis) from the native area (South America) and from the expansion range (Caribbean islands). First, we compared haemosporidian prevalence and circulating haptoglobin (an acute-phase protein produced during inflammation). Second, we challenged captive birds from both ranges with Escherichia coli lipopolysaccharides (LPS) and measured postchallenge haptoglobin production and body mass change. Birds from the expansion range showed lower haemosporidian prevalence and lower levels of haptoglobin than birds from the native range. In addition, the inflammation elicited by LPS injection and its associated cost in terms of body mass loss were lower in birds from the expansion range than in birds from the native range. In accordance with the enemy release hypothesis, our results suggest that range expansion is associated with a reduced infection risk. Our study also supports the hypothesis that individuals from newly established populations have evolved mechanisms to dampen the inflammatory response and are in accordance with one prediction of the refined EICA hypothesis, proposed to understand biological invasions. PMID- 28725418 TI - Development of an automated method of detecting stereotyped feeding events in multisensor data from tagged rorqual whales. AB - The introduction of animal-borne, multisensor tags has opened up many opportunities for ecological research, making previously inaccessible species and behaviors observable. The advancement of tag technology and the increasingly widespread use of bio-logging tags are leading to large volumes of sometimes extremely detailed data. With the increasing quantity and duration of tag deployments, a set of tools needs to be developed to aid in facilitating and standardizing the analysis of movement sensor data. Here, we developed an observation-based decision tree method to detect feeding events in data from multisensor movement tags attached to fin whales (Balaenoptera physalus). Fin whales exhibit an energetically costly and kinematically complex foraging behavior called lunge feeding, an intermittent ram filtration mechanism. Using this automated system, we identified feeding lunges in 19 fin whales tagged with multisensor tags, during a total of over 100 h of continuously sampled data. Using movement sensor and hydrophone data, the automated lunge detector correctly identified an average of 92.8% of all lunges, with a false-positive rate of 9.5%. The strong performance of our automated feeding detector demonstrates an effective, straightforward method of activity identification in animal-borne movement tag data. Our method employs a detection algorithm that utilizes a hierarchy of simple thresholds based on knowledge of observed features of feeding behavior, a technique that is readily modifiable to fit a variety of species and behaviors. Using automated methods to detect behavioral events in tag records will significantly decrease data analysis time and aid in standardizing analysis methods, crucial objectives with the rapidly increasing quantity and variety of on-animal tag data. Furthermore, our results have implications for next generation tag design, especially long-term tags that can be outfitted with on board processing algorithms that automatically detect kinematic events and transmit ethograms via acoustic or satellite telemetry. PMID- 28725419 TI - Tree species diversity promotes aboveground carbon storage through functional diversity and functional dominance. AB - The relationship between biodiversity and ecosystem function has increasingly been debated as the cornerstone of the processes behind ecosystem services delivery. Experimental and natural field-based studies have come up with nonconsistent patterns of biodiversity-ecosystem function, supporting either niche complementarity or selection effects hypothesis. Here, we used aboveground carbon (AGC) storage as proxy for ecosystem function in a South African mistbelt forest, and analyzed its relationship with species diversity, through functional diversity and functional dominance. We hypothesized that (1) diversity influences AGC through functional diversity and functional dominance effects; and (2) effects of diversity on AGC would be greater for functional dominance than for functional diversity. Community weight mean (CWM) of functional traits (wood density, specific leaf area, and maximum plant height) were calculated to assess functional dominance (selection effects). As for functional diversity (complementarity effects), multitrait functional diversity indices were computed. The first hypothesis was tested using structural equation modeling. For the second hypothesis, effects of environmental variables such as slope and altitude were tested first, and separate linear mixed-effects models were fitted afterward for functional diversity, functional dominance, and both. Results showed that AGC varied significantly along the slope gradient, with lower values at steeper sites. Species diversity (richness) had positive relationship with AGC, even when slope effects were considered. As predicted, diversity effects on AGC were mediated through functional diversity and functional dominance, suggesting that both the niche complementarity and the selection effects are not exclusively affecting carbon storage. However, the effects were greater for functional diversity than for functional dominance. Furthermore, functional dominance effects were strongly transmitted by CWM of maximum plant height, reflecting the importance of forest vertical stratification for diversity-carbon relationship. We therefore argue for stronger complementary effects that would be induced also by complementary light-use efficiency of tree and species growing in the understory layer. PMID- 28725421 TI - Antimicrobial use and antimicrobial susceptibility in Escherichia coli on small- and medium-scale pig farms in north-eastern Thailand. AB - BACKGROUND: Intensification of livestock production seen in many low- and middle income countries is often believed to be associated with increased use of antimicrobials, and may hence contribute to the emergence of antimicrobial resistance. The aim of this study was to map antimicrobial use on small- (n = 25) and medium-scale (n = 27) pig farms in north-eastern Thailand, and to compare antimicrobial susceptibility of commensal Escherichia coli isolated from sows on these farms. METHODS: Information regarding pig husbandry and antimicrobial treatment regimens was obtained by the use of semi-structured questionnaires. Faecal samples were collected from three healthy sows at each farm, and Escherichia coli was cultured and analysed for antimicrobial susceptibility using the broth microdilution method. Multilevel regression models were used to compare antimicrobial susceptibility between isolates from small- and medium-scale farms. RESULTS: All farms included in the study administered antimicrobials to their sows. Small-scale farmers most commonly (64%) decided themselves when to give antimicrobials and the majority (60%) bought the medicines at the local store or pharmacy, whereas farmers on medium-scale farms always discussed antimicrobial treatment with a veterinarian. Medium-scale farms used a greater diversity of antimicrobials than small-scale farms and did also administer antimicrobials in feed to a higher extent. High levels of antimicrobial resistance to several critically important antimicrobials for human medicine (including ciprofloxacin, streptomycin and ampicillin) were found in isolates from both small- and medium scale farms. Resistance levels were significantly (P < 0.05) higher in isolates from medium-scale farms for several of the antimicrobials tested, as well as the level of multidrug-resistance (P = 0.026). CONCLUSION: The routines regarding access and administration of antimicrobials differed between the small- and medium-scale farms. Although the level of antimicrobial resistance, as well as multidrug-resistance, was higher in isolates from medium-scale farms, it cannot be concluded if this increase is a consequence of a more abundant use of antimicrobials, or a result of differences in administration routines. PMID- 28725420 TI - A Click Chemistry Approach to Identify Protein Targets of Cancer Chemopreventive Phenethyl Isothiocyanate. AB - Here we report the identification of protein targets of chemopreventive phenethyl isothiocyanate (PEITC) via "click" chemistry in the A549 human lung cancer cell line, using a novel alkyne-tagged PEITC which was also found to show potent in vitro anticancer activity. PMID- 28725422 TI - Lesson learnt from a migrated drain: A case report. AB - INTRODUCTION: Though surgical drainage is used as a safety measure, it's not without complications. Migration of various drains has been described, but very little literature refers to the migration of peritoneal drain. PRESENTATION OF CASE: A 55-year male underwent anterior Gastro-Jejunostomy for inoperable metastatic carcinoma of the Gastric Pylorus. We found the peritoneal drain missing on the third post-operative day. On further evaluation, we found it to have migrated into the peritoneal cavity. We opened the operative wound for a partial length and retrieved the drain. DISCUSSION: We did research to find why drain migrates and searched literature on migration of peritoneal drains. The possible etiologies for drain migration are (1) Drain hasn't been fixed properly (2) Cutting through of suture material (3) Relatively low abdominal pressure (4) Pressure over the drain by patient's body weight when he lies on the same side as drain. CONCLUSION: Every use of drain should be weighed for its needs and risks. Proper precautions during drain placement avoid unnecessary complications, morbidity and prolonged hospital stay. PMID- 28725423 TI - Dysphagia caused by giant schwannoma of the supraglottic oropharynx: A case report and review of the literature. AB - BACKGROUND: Schwannomas are benign, encapsulated, peripheral nerve tumours that arise from the Schwann cell. Approximately 25%-45% of schwannomas occur in the head and neck. The most common site is the parapharyngeal space of the neck. However, schwannoma of the supraglottic oropharynx is rare. CASE PRESENTATION: We report on a 35-year-old female who complained of progressive dysphagia, from whom a large schwannoma in the supraglottic oropharynx was excised through a transoral approach. No recurrence was seen after one year follow-up. CONCLUSION: Although rare, schwannomas do occasionally occur in the supraglottic oropharynx. When dysphagia is present, a thorough diagnostic procedure should be performed to evaluate the morphology and function of the upper aerodigestive tract. MRI is sensitive and specific in the diagnosis of schwannoma. And the best treatment of choice is complete excision with preservation of functions. PMID- 28725424 TI - Implementation of GOLD consensus report in real life: results from the Velletri Lariano (VELA) cohort. AB - BACKGROUND: COPD is one of the leading causes of morbidity and mortality. Pharmacotherapy improves quality of life and reduces exacerbations although low adherence with prescribed treatments may represent a barrier to optimal disease management. The first objective of this paper is to report the distribution of COPD patients according to GOLD categories, in a sample of patients from a cohort study in an area of the Latium region in Italy. The second objective is to evaluate the agreement between the distributions of severity obtained from the HCPs and the experts included in the study board (Board). METHODS: COPD patients were given a card to collect demographic and clinical data at baseline. Information in those cards was independently evaluated by HCPs and Board to include each patient into one of the four GOLD categories. RESULTS: In a sample of 187 stable COPD patients, 59% male, mean age 70 year, the distribution of GOLD categories according to the Board was: 6% A, 34% B, 2% C, and 58% D. A discrepancy in GOLD classification was observed between the study board and field based HCPs, regarding more than 50% of the patients, with a clear trend to underestimate the frequency of patients in D level (21%) and to overestimate the frequency in C level (21%). CONCLUSIONS: These results describe for the first time the distribution of COPD patients in an Italian cohort according to the GOLD categories, with the highest frequencies in levels B and D. The misclassification from HCPs may impact the therapeutic approach and the clinical outcomes. PMID- 28725425 TI - Letter to the editor: health professionals' attitudes toward individuals with eating disorders: who do we think they are? AB - Health professionals are not immune to stigmatizing attitudes and stereotypes found in society-at-large. Along with patients and their loved ones, treatment providers are important stakeholders - and gatekeepers - in the successful delivery of mental healthcare. Prevailing attitudes among professionals can facilitate timely recognition, enable access to care and uptake of evidence-based practices, or undermine help-seeking and therapeutic engagement. At an interactive activity at the 2016 Nordic Eating Disorders Society (NEDS) meeting, we asked health professionals to describe individuals with eating disorders. The most common descriptive term used was "anxiety" followed by "thin", "sad", "control", "female", and "suffering/pain". Further research on professionals' attitudes toward individuals with eating disorders is necessary to inform education, awareness, and advocacy efforts following the diagnostic revisions in the DSM-5. PMID- 28725435 TI - Biogeophysical and physiological processes drive movement patterns in a marine predator. AB - BACKGROUND: Blue sharks (Prionace glauca) are among the most abundant and widely distributed of oceanic elasmobranchs. Millions are taken annually in pelagic longline fisheries and comprise the highest component of auctioned fin weight in the international shark fin trade. Though studies of blue sharks outnumber those of other large pelagic sharks, the species' complicated and sexually segregated life history still confound current understanding of Atlantic movement patterns. Lack of detailed information regarding movement and vertical behavior continues to limit management efforts that require such data for stock assessment and sustainable catch modeling. Therefore, this study aims to describe behavioral and ecological patterns distinct to aggregating and migrating blue sharks, and compare the findings to existing Atlantic movement models. RESULTS: Data collected from 23 blue sharks instrumented with pop-up satellite archival tags were used in statistical predictive regression models to investigate habitat use during a localized aggregation in the northwest Atlantic, while undergoing seasonal migrations, and with respect to environmental variables. Deployment durations ranged from 4 to 273 days, with sharks inhabiting both productive coastal waters and the open ocean, and exhibiting long-distance seasonal movements exceeding 3700 km. While aggregating on the continental shelf of the northwest Atlantic, blue sharks displayed consistent depth use independent of sex and life stage, and exhibited varied response to environmental (temperature and chlorophyll a) factors. As sharks dispersed from the aggregation site, depth use was influenced by bathymetry, latitude, demography, and presence in the Gulf Stream. Mature females were not observed at the New England tagging site, however, two mature females with recent mating wounds were captured and tagged opportunistically in The Bahamas, one of which migrated to the Mid-Atlantic Ridge. CONCLUSIONS: Vertical behaviors displayed by blue sharks varied greatly among locales; depth use off the continental shelf was significantly greater, and individuals exhibited a greater frequency of deep-diving behavior, compared to periods of aggregation on the continental shelf. Sexual segregation was evident, suggesting mature and immature males, and immature females may be subjected to high levels of anthropogenic exploitation in this region during periods of aggregation. Analysis of the spatio-temporal tracks revealed that nine individuals traveled beyond the United States EEZ, including a mature female captured in The Bahamas that migrated to the Mid-Atlantic Ridge. These results reflect and augment existing Atlantic migration models, and highlight the complex, synergistic nature of factors affecting blue shark ecology and the need for a cooperative management approach in the North Atlantic. PMID- 28725436 TI - Factors associated with increased pancreatic enzymes in septic patients: a prospective study. AB - BACKGROUND: The perfusion of splanchnic organs is deeply altered in patients with septic shock. The aim of the study is to identify the predictive factors of septic shock-induced increase of serum lipase and amylase and to assess and evaluate its prognostic impact. METHODS: We conducted a prospective observational study. All adult patients admitted with septic shock were eligible for our study. Serum lipase and amylase were measured on admission. Patients with and those without increased pancreatic enzymes were compared. Predictive factors of pancreatic insult identified by the univariate analysis were integrated in a stepwise multivariate analysis. Odds ratios (OR) with the 95% confidence interval (CI) were calculated accordingly. Second, the sensitivity and the specificity of amylase and lipase to predict intensive care unit (ICU) mortality were identified through the Receiver Operator Curve. RESULTS: Fifty patients were included. Median [quartiles] age was 68.5 [58-81] years. The APACHE II score was 26 [20 31]. Twenty-three patients (46%) had increased serum amylase and/or serum lipase. Diabetes mellitus (OR = 16; 95% CI [1.7-153.5]; p = 0.016), increased blood urea nitrogen (OR = 1.12; 95% CI [1.02-1.20], p = 0.016), and decreased C-reactive protein (OR = 0.97; 95% CI [0.96-0.99]; p = 0.027) were identified as independent factors predicting increased pancreatic enzymes. Twenty patients (40%) died in the ICU. Neither serum amylase level nor serum lipase level was significantly different between survivors and non-survivors (respectively 49 [27.7-106] versus 85.1 [20.1-165] UI/L; p = 0.7 and 165 [88-316] versus 120 [65.5-592] UI/L; p = 0.952). CONCLUSION: Increase of pancreatic enzymes is common in patients with septic shock. Diabetes and impaired renal function are predictive of increased pancreatic enzymes. Such finding does not carry any negative prognostic value. PMID- 28725437 TI - Towards evidence based strength training: a comparison of muscle forces during deadlifts, goodmornings and split squats. AB - BACKGROUND: To ensure an efficient and targeted adaptation with low injury risk during strength exercises, knowledge of the participant specific internal loading conditions is essential. The goal of this study was to calculate the lower limb muscles forces during the strength exercises deadlifts, goodmornings and splits squats by means of musculoskeletal simulation. METHODS: 11 participants were assessed performing 10 different variations of split squats by varying the step length as well as the maximal frontal tibia angle, and 13 participants were measured performing deadlift and goodmorning exercises. Using individualised musculoskeletal models, forces of the Quadriceps (four parts), Hamstrings (four parts) and m. gluteus maximus (three parts) were computed. RESULTS: Deadlifts resulted highest loading for the Quadriceps, especially for the vasti (18-34 N/kg), but not for the rectus femoris (8-10 N/kg), which exhibited its greatest loading during split squats (13-27 N/kg) in the rear limb. Hamstrings were loaded isometrically during goodmornings but dynamically during deadlifts. For the m. gluteus maximus, the highest loading was observed during split squats in the front limb (up to 25 N/kg), while deadlifts produced increasingly, large loading over large ranges of motion in hip and knee. CONCLUSIONS: Acting muscle forces vary between exercises, execution form and joint angle. For all examined muscles, deadlifts produced considerable loading over large ranges of motion, while split squats seem to be highly dependent upon exercise variation. This study provides key information to design strength-training programs with respect to loading conditions and ranges of motion of lower extremity muscles. PMID- 28725438 TI - Nickel-resistant bacteria isolated in human microbiome. AB - Nickel-resistant bacteria have been isolated so far only in contaminated soils and wastewaters polluted with different industrial sources. The aim of our study was to determine if nickel-resistant bacteria could also be isolated from human samples. In this brief communication, we describe how we were able to isolate human bacterial strains that grew without oxygen and in the presence of high concentrations of nickel. The identification was made by phenotypic and genetic techniques. The bacterial sequences have been deposited in the NCBI database repository. Our finding shows that there are several different heavy-metal tolerant bacteria in humans that should be considered for further studies. PMID- 28725439 TI - Characterization of Pontibacter altruii, sp. nov., isolated from a human blood culture. AB - The genus Pontibacter is a recent addition to the family Cytophagaceae, phylum Bacteroidetes. Previous reports of its cultivation and molecular detection are from a variety of environmental sources, including marine and desert habitats. We report the first description of a Pontibacter sp., which was initially identified as Elizabethkingia meningoseptica, isolated from a human clinical specimen. On the basis of 16S rRNA gene sequence, unique mass spectral profile and phenotypic characterization, this isolate represents a novel species within the genus Pontibacter that has been named Pontibacter altruii, sp. nov., strain Grand Forks. PMID- 28725440 TI - Description of 'Beduinibacterium massiliense' gen. nov., sp. nov., 'Massilimaliae massiliensis' gen. nov., sp. nov., 'Provencibacterium massiliense' gen. nov., sp. nov. and 'Oscilibacter massiliensis' sp. nov., isolated from a faecal specimen of a 19-year-old healthy Saudi Arabian Bedouin by culturomics. AB - We report here the main characteristics of 'Beduinibacterium massiliense' strain Marseille-P3337T gen. nov., sp. nov., 'Massilimaliae massiliensis' Marseille P2963T gen. nov., sp. nov., 'Provencibacterium massiliense' Marseille-P2780T gen. nov., sp. nov. and 'Oscilibacter massiliensis' Marseille-P2778T sp. nov., all isolated from the stool of a Bedouin from Saudi Arabia. We used a bacterial culturomics approach combined with taxonogenomics. PMID- 28725441 TI - Taking the lead from our colleagues in medical education: the use of images of the in-vivo setting in teaching concepts of pharmaceutical science. AB - Despite pharmaceutical sciences being a core component of pharmacy curricula, few published studies have focussed on innovative methodologies to teach the content. This commentary identifies imaging techniques which can visualise oral dosage forms in-vivo and observe formulation disintegration in order to achieve a better understanding of in-vivo performance. Images formed through these techniques can provide students with a deeper appreciation of the fate of oral formulations in the body compared to standard disintegration and dissolution testing, which is conducted in-vitro. Such images which represent the in-vivo setting can be used in teaching to give context to both theory and experimental work, thereby increasing student understanding and enabling teaching of pharmaceutical sciences supporting students to correlate in-vitro and in-vivo processes. PMID- 28725442 TI - Identification of dust storm origin in South -West of Iran. AB - BACKGROUND: Deserts are the main sources of emitted dust, and are highly responsive to wind erosion. Low content of soil moisture and lack of vegetation cover lead to fine particle's release. One of the semi-arid bare lands in Iran, located in the South-West of Iran in Khoozestan province, was selected to investigate Sand and Dust storm potential. METHODS: This paper focused on the metrological parameters of the sampling site, their changes and the relationship between these changes and dust storm occurrence, estimation of Reconaissance Drought Index, the Atterberg limits of soil samples and their relation with soil erosion ability, the chemical composition, size distribution of soil and airborne dust samples, and estimation of vertical mass flux by COMSALT through considering the effect of saffman force and interparticle cohesion forces during warm period (April-September) in 2010. The chemical compositions are measured with X-ray fluorescence, Atomic absorption spectrophotometer and X-ray diffraction. The particle size distribution analysis was conducted by using Laser particle size and sieve techniques. RESULTS: There was a strong negative correlation between dust storm occurrence and annual and seasonal rainfall and relative humidity. Positive strong correlation between annual and seasonal maximum temperature and dust storm frequency was seen. Estimation of RDIst in the studied period showed an extremely dry condition. Using the results of particle size distribution and soil consistency, the weak structure of soil was represented. X-ray diffraction analyses of soil and dust samples showed that soil mineralogy was dominated mainly by Quartz and calcite. X-ray fluorescence analyses of samples indicated that the most important major oxide compositions of the soil and airborne dust samples were SiO2, Al2O3, CaO, MgO, Na2O, and Fe2O3, demonstrating similar percentages for soil and dust samples. Estimation of Enrichment Factors for all studied trace elements in soil samples showed Br, Cl, Mo, S, Zn, and Hg with EF values higher than 10. CONCLUSION: The findings, showed the possible correlation between the degree of anthropogenic soil pollutants, and the remains of Iraq-Iran war. The results expressed sand and dust storm emission potential in this area, was illustrated with measured vertical mass fluxes by COMSALT. PMID- 28725443 TI - Associations of short-term exposure to air pollution with respiratory hospital admissions in Arak, Iran. AB - BACKGROUND: Ambient air pollution, is one of the most frequently stated environmental problems. Many epidemiological studies have documented adverse health effects for ambient air pollution. This study aimed to investigate the association between ambient air pollution and respiratory hospital admissions. METHODS: In this ecological time series study data about air pollutant concentrations including CO, NO2, O3, PM2.5, PM10 and SO2 and, respiratory hospital admissions in the urban population of Arak, from January 1st 2010 to December 31st 2015; were inquired, from the Arak Department of Environment, and two major hospitals, respectively. Meteorological data were inquired for the same period as well. Time-series regression analysis with a distributed lag model, controlled for seasonality long-time trends, weather and day of the week, was used for data analysis. RESULTS: Every 10 MUg/m3 increase in NO2, and PM10 and every 1 mg/m3 increase in CO at lag 0 corresponded to a RR = 1.032 (95%CI, 1.003 1.06), RR = 1.01 (95%CI, 1.004-1.017) and RR = 1.09 (95%CI, 1.04-1.14), increase in respiratory disease hospitalizations, respectively. Males and the elderly were found to be more susceptible than females and other age groups to air pollutants in regard to respiratory disease admissions. CONCLUSIONS: The results of this study showed that outdoor air pollutants significantly increase respiratory hospital admissions; especially among the men and elders in Arak. PMID- 28725444 TI - Post-tuberculous fibrosing mediastinitis: a review of the literature. AB - Fibrosing mediastinitis (FM) is a rare disease where there is thickening of the fibrous tissue in the mediastinum. While histoplasmosis is the the most common recognised cause, the link with tuberculosis (TB) has been rarely documented. We review the link between TB and FM, and describe a case of probable TB-related FM.Our case is of a 74-year-old man who presented with breathlessness 3 years after fully treated TB. Scans revealed a calcified soft tissue mass within the mediastinum, and a diagnosis of fibrosing mediastinitis resulting in pulmonary hypertension was made. Tests for histoplasmosis and IgG4 staining were negative. Surgical intervention was not felt to be beneficial, and he was treated with prednisolone and mycophenolate mofetil.In the review, we highlight the two forms of mediastinitis-granulomatous versus fibrous, and how these two entities may be on a spectrum of disease progression. We also explore the prevalence, clinical presentation, pathogenesis, imaging techniques and treatment options of TB related FM. PMID- 28725445 TI - Manual ventilation and open suction procedures contribute to negative pressures in a mechanical lung model. AB - INTRODUCTION: Removal of pulmonary secretions in mechanically ventilated patients usually requires suction with closed catheter systems or flexible bronchoscopes. Manual ventilation is occasionally performed during such procedures if clinicians suspect inadequate ventilation. Suctioning can also be performed with the ventilator entirely disconnected from the endotracheal tube (ETT). The aim of this study was to investigate if these two procedures generate negative airway pressures, which may contribute to atelectasis. METHODS: The effects of device insertion and suctioning in ETTs were examined in a mechanical lung model with a pressure transducer inserted distal to ETTs of 9 mm, 8 mm and 7 mm internal diameter (ID). A 16 Fr bronchoscope and 12, 14 and 16 Fr suction catheters were used at two different vacuum levels during manual ventilation and with the ETTs disconnected. RESULTS: During manual ventilation with ETTs of 9 mm, 8 mm and 7 mm ID, and bronchoscopic suctioning at moderate suction level, peak pressure (PPEAK) dropped from 23, 22 and 24.5 cm H2O to 16, 16 and 15 cm H2O, respectively. Maximum suction reduced PPEAK to 20, 17 and 11 cm H2O, respectively, and the end expiratory pressure fell from 5, 5.5 and 4.5 cm H2O to -2, -6 and -17 cm H2O. Suctioning through disconnected ETTs (open suction procedure) gave negative model airway pressures throughout the duration of the procedures. CONCLUSIONS: Manual ventilation and open suction procedures induce negative end-expiratory pressure during endotracheal suctioning, which may have clinical implications in patients who need high PEEP (positive end-expiratory pressure). PMID- 28725446 TI - Sound: a non-invasive measure of cough intensity. AB - INTRODUCTION: Cough intensity is an important determinant of cough severity reported by patients. Cough sound analysis has been widely validated for the measurement of cough frequency but few studies have validated its use in the assessment of cough strength. We investigated the relationship between cough sound and physiological measures of cough strength. METHODS: 32 patients with chronic cough and controls underwent contemporaneous measurements of voluntary cough sound, flow and oesophageal pressure. Sound power, peak energy, rise-time, duration, peak-frequency, bandwidth and centroid-frequency were assessed and compared with physiological measures. The relationship between sound and subjective cough strength Visual Analogue Score (VAS), the repeatability of cough sounds and the effect of microphone position were also assessed. RESULTS: Sound power and energy correlated strongly with cough flow (median Spearman's r=0.87 0.88) and oesophageal pressure (median Spearman's r=0.89). Sound power and energy correlated strongly with cough strength VAS (median Spearman's r=0.84-0.86) and were highly repeatable (intraclass correlation coefficient=0.93-0.94) but both were affected by change in microphone position. CONCLUSIONS: Cough sound power and energy correlate strongly with physiological measures and subjective perception of cough strength. Power and energy are highly repeatable measures but the microphone position should be standardised. Our findings support the use of cough sound as an index of cough strength. PMID- 28725447 TI - Anti-Saccharomyces cerevisiae antibodies (ASCA) are associated with body fat mass and systemic inflammation, but not with dietary yeast consumption: a cross sectional study. AB - BACKGROUND: Baker's/brewer's yeast, Saccharomyces cerevisiae, has been used as an alternative to antibiotic growth promoters to improve growth performance in animals. In humans, Saccharomyces cerevisiae is among the most commonly detected fungi in fecal samples and likely originates from food. Recently, an association between anti-Saccharomyces cerevisiae antibodies (ASCA) and obesity in humans was suggested, but the cause of the elevated ASCA levels is not clear. Our aim was to study ASCA in morbidly obese subjects and explore potential associations with anthropometrics, diet, co-morbidities and biomarkers of inflammation and gut permeability. METHODS: Subjects with morbid obesity referred to a specialized hospital unit were included. Diet and clinical data were recorded with self administered questionnaires. Main dietary sources of baker's/brewer's yeast (e.g. bread and beer) were used as a proxy for the intake of yeast. Laboratory analyses included ASCA, serum zonulin (reflecting gut permeability), C-reactive protein and a routine haematological and biochemical screening. RESULTS: One-hundred-and forty subjects; 109 (78%) female, 98 with dietary records, mean age 43 years and BMI 42 kg/m2 were included. The number of ASCA positive subjects was 31 (22%) for IgG, 4 (2.9%) for IgA and 3 (2.1%) for IgM. Age, body fat mass and C-reactive protein were significantly higher in IgG-positive compared to IgG-negative subjects (P < 0.05). A borderline significant association was found between elevated zonulin and ASCA IgG-positivity (P = 0.06). No association was found between yeast-containing food and ASCA IgG-positivity, or between yeast containing food and fat mass. CONCLUSIONS: The findings indicate that ASCA IgG positivity may be linked to the generalized inflammation commonly seen with increased adiposity, but not to dietary yeast intake. Other potential causes for the raised ASCA IgG concentrations, such as genetic predisposition, deviations in the gut microbiota and cross-reactivity of ASCA with other antigens, were not explored. PMID- 28725448 TI - Differential prevalence and associations of overweight and obesity by gender and population group among school learners in South Africa: a cross-sectional study. AB - BACKGROUND: Factors influencing the increasing prevalence of overweight/obesity among children and adolescents in sub-Saharan Africa remain unclear. We assessed the prevalence and determinants of overweight and obesity and effects on cardio metabolic profile in school learners in the Western Cape, South Africa. METHODS: Cross-sectional data were collected from 7 to 18-year-old South African school learners attending 14 schools, randomly selected from 107 government schools in the areas. The learners were selected through stratified random sampling techniques. Logistic regressions were used to assess the determinants of overweight/obesity and its association with cardio-metabolic profile. RESULTS: Among the 1559 participants, the overall prevalence of overweight/obesity was 22.9%. Being a girl (Odds ratio 2.51, 95% CI: 1.92-3.29), or Black African (1.35, 1.04-.75) was associated with increased odds of being overweight/obese. The identified health consequences among the overweight/obese learners differed between the ethnic groups. Overweight/obese coloured (mixed ancestry) learners were more likely to have hypertension (3.27, 1.18-9.08), hypertriglyceridemia (1.94, 0.99-3.78) and low high-density lipoprotein cholesterol (HDL-C) (3.65, 2.33-5.72), overweight/obese Black African learners had higher odds for hypertension (3.62, 1.31-10.04) and low HDL-C (1.56, 1.01-2.40) and overweight/obese White learners were prone to low HDL-C (5.04, 1.35-18.80). CONCLUSIONS: Overweight/obesity is highly prevalent among school learners in Western Cape (South Africa), with being female or Black African increasing the odds. That overweight/obesity is also associated with adverse cardio-metabolic risk profile aggravates the problem and suggests worse cardiovascular outcomes in South African young adults in the future. PMID- 28725449 TI - Therapeutic options for treatment of human papillomavirus-associated cancers - novel immunologic vaccines: ADXS11-001. AB - Survival of patients with advanced, recurrent, or metastatic human papillomavirus (HPV)-associated cancer is suboptimal despite the availability of various treatment modalities. The recently developed bacterial vector Listeria monocytogenes (Lm) activates innate and adaptive immune responses and is expected to offer immunologic advantages. Axalimogene filolisbac (AXAL or ADXS11-001) is a novel immunotherapeutic based on the live, irreversibly attenuated Lm fused to the nonhemolytic fragment of listeriolysin O (Lm-LLO) and secretes the Lm-LLO-HPV E7 fusion protein targeting HPV-positive tumors. Herein are reported the development and recent results of various clinical trials in patients with HPV associated cervical, head and neck, and anal cancers. PMID- 28725450 TI - Various levels of copra meal supplementation with beta-Mannanase on growth performance, blood profile, nutrient digestibility, pork quality and economical analysis in growing-finishing pigs. AB - BACKGROUND: To reduce use of main feed ingredient like corn, soy bean meal (SBM) and wheat, alternative ingredients has been studied like copra meal (CM). Production amount of CM which has been high makes CM to be an alternative feed stuff. However, low digestibility on AA and low energy content by high fiber content can be an obstacle for using CM. This experiment was conducted to evaluate the effects of CM supplementation with beta-mannanase on growth performance, blood profile, nutrient digestibility, pork quality and economic analysis in growing-finishing pigs. METHODS: A total of 100 growing pigs ([Yorkshire * Landrace] * Duroc) averaging 31.22 +/- 2.04 kg body weight were allotted to 5 different treatments by weight and sex in a randomized complete block (RCB) design in 5 replicate with 4 pigs per pen. Treatments were 1) Control (corn-SBM based diet + 0.1% of beta-mannanase (800 IU)), 2) CM10 (10% copra meal + 0.1% beta-mannanase (800 IU)), 3) CM15 (15% copra meal + 0.1% beta-mannanase (800 IU)), 4) CM20 (20% copra meal + 0.1% beta-mannanase (800 IU)) and 5) CM25 (25% copra meal + 0.1% beta-mannanase (800 IU)). Four phase feeding program was used: growing I (week 1-3), growing II (week 4-6), finishing I (week 7-9) and finishing II (week 10-12). RESULTS: In growth performance, there was no significant difference among treatments during whole experimental period. In growingI phase, G:F ratio tended to increase when CM was increased (P = 0.05), but ADG and ADFI tended to decrease in finishingII phase (linear, P = 0.08). Also, increasing CM reduced ADG (linear, P = 0.02) and feed efficiency (linear, P = 0.08) during the whole finishing period. In blood profiles, BUN was linearly increased as CM increased (linear, P = 0.02) at growingII period. In digestibility trial, there was no significant difference in dry matter, crude fat, crude ash and nitrogen digestibility. However, crude protein digestibility was decreased linearly (linear, P = 0.02). In economic analysis, feed cost per weight gain and total feed cost per pig were reduced in overall period when CM was provided by 25% (linear, P = 0.02). CONCLUSION: CM with 0.1% of beta mannanase (800 IU) could be supplemented instead of corn and SBM up to 25% without detrimental effects on growth performance and pork quality of growing finishing pigs. PMID- 28725451 TI - Feasibility of the trial procedures for a randomized controlled trial of a community-based peer-led wheelchair training program for older adults. AB - BACKGROUND: A novel peer-led manual wheelchair (MWC) training program may support the training needs of older adults, but establishing program feasibility is a pragmatic first step. The purpose of this study was to evaluate the feasibility of a peer-led Wheelchair training Self-Efficacy Enhanced for Use (WheelSeeU) program. METHODS: Forty MWC users (mean age 65 years) were randomly assigned to the experimental (WheelSeeU) or control group. Feasibility indicators of process, resources, management, and safety were collected throughout the study. RESULTS: The consent rate was 49%. Participant retention rate was 90% post-intervention and 87.5% at follow-up (6 months). All participants reported perceived benefits from WheelSeeU. Participants and trainers adhered to the study protocol (>90%), and fidelity of the WheelSeeU intervention was attained (>90%). There were no adverse events. CONCLUSIONS: WheelSeeU is an innovative and feasible approach for providing MWC training to older adults that is accessible beyond initial rehabilitation without increased clinician burden. With minor modifications, it is feasible that WheelSeeU can be administered to older adults living in the community. TRIAL REGISTRATION: NCT01838135. PMID- 28725452 TI - MapMySmoke: feasibility of a new quit cigarette smoking mobile phone application using integrated geo-positioning technology, and motivational messaging within a primary care setting. AB - BACKGROUND: Approximately 11,000 people die in Scotland each year as a result of smoking-related causes. Quitting smoking is relatively easy; maintaining a quit attempt is a very difficult task with success rates for unaided quit attempts stubbornly remaining in the single digits. Pharmaceutical treatment can improve these rates by lowering the overall reward factor of nicotine. However, these and related nicotine replacement therapies do not operate on, or address, the spatial and contextual aspects of smoking behaviour. With the ubiquity of smartphones that can log spatial, quantitative and qualitative data related to smoking behaviour, there exists a person-centred clinical opportunity to support smokers attempting to quit by first understanding their smoking behaviour and subsequently sending them dynamic messages to encourage health behaviour change within a situational context. METHODS: We have built a smartphone app-MapMySmoke that works on Android and iOS platforms. The deployment of this app within a clinical National Health Service (NHS) setting has two distinct phases: (1) a 2 week logging phase where pre-quit patients log all of their smoking and craving events; and (2) a post-quit phase where users receive dynamic support messages and can continue to log craving events, and should they occur, relapse events. Following the initial logging phase, patients consult with their general practitioner (GP) or healthcare provider to review their smoking patterns and to outline a precise, individualised quit attempt plan. Our feasibility study consists of assessment of an initial app version during and after use by eight patients recruited from an NHS Fife GP practice. In addition to evaluation of the app as a potential smoking cessation aid, we have assessed the user experience, technological requirements and security of the data flow. RESULTS: In an initial feasibility study, we have deployed the app for a small number of patients within one GP practice in NHS Fife. We recruited eight patients within one surgery, four of whom actively logged information about their smoking behaviour. Initial feedback was very positive, and users indicated a willingness to log their craving and smoking events. In addition, two out of three patients who completed follow-up interviews noted that the app helped them reduce the number of cigarettes they smoked per day, while the third indicated that it had helped them quit. The study highlighted the use of pushed notifications as a potential technology for maintaining quit attempts, and the security of collection of data was audited. These initial results influenced the design of a planned second larger study, comprised of 100 patients, the primary objectives of which are to use statistical modelling to identify times and places of probable switches into smoking states, and to target these times with dynamic health behaviour messaging. CONCLUSIONS: While the health benefits of quitting smoking are unequivocal, such behaviour change is very difficult to achieve. Many factors are likely to contribute to maintaining smoking behaviour, yet the precise role of cues derived from the spatial environment remains unclear. The rise of smartphones, therefore, allows clinicians the opportunity to better understand the spatial aspects of smoking behaviour and affords them the opportunity to push targeted individualised health support messages at vulnerable times and places. TRIAL REGISTRATION: ClinicalTrial.gov, NCT02932917. PMID- 28725453 TI - Development of an implementation intention-based intervention to change children's and parent-carers' behaviour. AB - BACKGROUND: Implementation intentions enable individuals to translate good intentions into action. Parents and children can find maintaining oral health difficult, as evidenced by the presence of tooth decay. This is a common condition in children in spite of being preventable through the use of regular tooth brushing, fluoride protection and avoiding sugar intake. Even when parents and children are positive about looking after the teeth, they can face challenges in maintaining consistent habits. The aim of this paper is to describe the design of a video animation to teach parents and children how to use implementation intentions to establish new habits to improve oral health, applied in this case, to parents and children with cleft lip and/or palate (CLP). METHODS: Evidence from a qualitative study of parents' and children's knowledge, beliefs and behaviour informed the design of an animation forming part of an intervention for children and parents using implementation intentions. The user views generated a set of guiding principles to determine the style and content of a teaching video, whilst an animation designer translated the key messages of implementation intention into images and characters appealing and meaningful to the target audience of children and parents. RESULTS: A team of researchers, an animation designer and a script writer designed a 2-min video as a teaching tool for children and parents. The team drafted and iteratively refined the content and visuals, with guidance from an advisory group and informal discussions with children in the target age group and their parents. Planning, consulting, designing and production of the animation spanned a total of 20 weeks. The video explains how to formulate 'if-then' plans using the voices of a boy and his mother in a conversation, with examples from oral health to illustrate how to enact intentions. It is available via digital media and designed to be delivered by dental care practitioners. The effectiveness of the intervention will be evaluated as part of a feasibility study. CONCLUSION: The current study describes the development of an intervention mediated through an animation tutorial that enables children and parents to devise 'if-then' plans to improve oral health as a collaborative endeavour between parents and children. The animation uses examples from oral health, but we believe there is scope for exploring application of the intervention to other areas of behaviour. PMID- 28725454 TI - Successful percutaneous trans-catheter treatment of left ventricular assist device outflow graft stenosis with a covered stent. AB - Left ventricular assist devices improve survival in patients with advanced heart failure but can be associated with significant complication including infection, pump thrombosis, and de novo severe aortic insufficiency. Outflow graft stenosis is a much more rare complication, but one with significant hemodynamic consequences. Surgical repair is often necessary, but many patients are too high risk for further surgical intervention. We describe the first case of left ventricular assist device outflow graft stenosis treated with percutaneous trans catheter placement of a covered stent. PMID- 28725455 TI - Effect of respiratory pattern on automated clinical blood pressure measurement: an observational study with normotensive subjects. AB - BACKGROUND: It has been reported that deep breathing could reduce blood pressures (BP) in general. It is also known that BP is decreased during inhalation and increased during exhalation. Therefore, the measured BPs could be potentially different during deep breathing with different lengths of inhalation and exhalation. This study aimed to quantitatively investigate the effect of different respiratory patterns on BPs. METHODS: Forty healthy subjects (20 males and 20 females, aged from 18 to 60 years) were recruited. Systolic and diastolic BPs (SBP and DBP) were measured using a clinically validated automated BP device. There were two repeated measurement sessions for each subject. Within each session, eight BP measurements were performed, including 4 measurements during deep breathing with different respiratory patterns (Pattern 1: 4.5 s vs 4.5 s; Patter 2: 6 s vs 2 s; Pattern 3: 2 s vs 6 s; and Pattern 4: 1.5 s vs 1.5 s, respectively for the durations of inhalation and exhalation) and additional 4 measurements from 1 min after the four different respiratory patterns. At the beginning and end of the two repeated measurement sessions, there were two baseline BP measurements under resting condition. RESULTS: The key experimental results showed that overall automated SBP significantly decreased by 3.7 +/- 5.7 mmHg, 3.9 +/- 5.2 mmHg, 1.7 +/- 5.9 mmHg and 3.3 +/- 5.3 mmHg during deep breathing, respectively for Patterns 1, 2, 3 and 4 (all p < 0.001 except p < 0.05 for Pattern 3). Similarly, the automated DBPs during deep breathing in pattern 1, 2 and 4 decreased by 3.7 +/- 5.0 mmHg, 3.7 +/- 4.9 mmHg and 4.6 +/- 3.9 mmHg respectively (all p < 0.001, except in Pattern 3 with a decrease of 1.0 +/- 4.3 mmHg, p = 0.14). Correspondingly, after deep breathing, automated BPs recovered back to normal with no significant difference in comparison with baseline BP (all p > 0.05, except for SBP in Pattern 4). CONCLUSIONS: In summary, this study has quantitatively demonstrated that the measured automated BPs decreased by different amounts with all the four deep breathing patterns, which recovered back quickly after these single short-term interventions, providing evidence of short term BP decrease with deep breathing and that BP measurements should be performed under normal breathing condition. PMID- 28725456 TI - Growing up with chronic arthritis: the confusing matter of classification. PMID- 28725457 TI - Genome-wide perturbations by miRNAs map onto functional cellular pathways, identifying regulators of chromatin modifiers. AB - BACKGROUND: Regulation of gene expression by microRNAs (miRNAs) is critical for determining cellular fate and function. Dysregulation of miRNA expression contributes to the development and progression of multiple diseases. miRNA can target multiple mRNAs, making deconvolution of the effects of miRNA challenging and the complexity of regulation of cellular pathways by miRNAs at the functional protein level remains to be elucidated. Therefore, we sought to determine the effects of expression of miRNAs in breast and ovarian cancer cells on cellular pathways by measuring systems-wide miRNA perturbations to protein and phosphoproteins. METHODS: We measure protein level changes by reverse-phase protein array (RPPA) in MDA-MB-231, SKOV3.ip1 and HEYA8 cancer cell lines transfected by a library of 879 human miRNA mimics. RESULTS: The effects of multiple miRNAs-protein networks converged in five broad functional clusters of miRNA, suggesting a broad overlap of miRNA action on cellular pathways. Detailed analysis of miRNA clusters revealed novel miRNA/cell cycle protein networks, which we functionally validated. De novo phosphoprotein network estimation using Gaussian graphical modeling, using no priors, revealed known and novel protein interplay, which we also observed in patient ovarian tumor proteomic data. We identified several miRNAs that have pluripotent activities across multiple cellular pathways. In particular we studied miR-365a whose expression is associated with poor survival across several cancer types and demonstrated that anti-miR-365 significantly reduced tumor formation in animal models. CONCLUSIONS: Mapping of miRNA-induced protein and phosphoprotein changes onto pathways revealed new miRNA-cellular pathway connectivity, paving the way for targeting of dysregulated pathways with potential miRNA-based therapeutics. PMID- 28725458 TI - Elucidation of the molecular mechanisms underlying adverse reactions associated with a kinase inhibitor using systems toxicology. AB - BACKGROUND/OBJECTIVES: Targeted kinase inhibitors are an important class of agents in anticancer therapeutics, but their limited tolerability hampers their clinical performance. Identification of the molecular mechanisms underlying the development of adverse reactions will be helpful in establishing a rational method for the management of clinically adverse reactions. Here, we selected sunitinib as a model and demonstrated that the molecular mechanisms underlying the adverse reactions associated with kinase inhibitors can efficiently be identified using a systems toxicological approach. METHODS: First, toxicological target candidates were short-listed by comparing the human kinase occupancy profiles of sunitinib and sorafenib, and the molecular mechanisms underlying adverse reactions were predicted by sequential simulations using publicly available mathematical models. Next, to evaluate the probability of these predictions, a clinical observation study was conducted in six patients treated with sunitinib. Finally, mouse experiments were performed for detailed confirmation of the hypothesized molecular mechanisms and to evaluate the efficacy of a proposed countermeasure against adverse reactions to sunitinib. RESULTS: In silico simulations indicated the possibility that sunitinib-mediated off-target inhibition of phosphorylase kinase leads to the generation of oxidative stress in various tissues. Clinical observations of patients and mouse experiments confirmed the validity of this prediction. The simulation further suggested that concomitant use of an antioxidant may prevent sunitinib-mediated adverse reactions, which was confirmed in mouse experiments. CONCLUSIONS: A systems toxicological approach successfully predicted the molecular mechanisms underlying clinically adverse reactions associated with sunitinib and was used to plan a rational method for the management of these adverse reactions. PMID- 28725460 TI - Accelerating systems biology research and its real world deployment. PMID- 28725459 TI - Network reconstruction and validation of the Snf1/AMPK pathway in baker's yeast based on a comprehensive literature review. AB - BACKGROUND/OBJECTIVES: The SNF1/AMPK protein kinase has a central role in energy homeostasis in eukaryotic cells. It is activated by energy depletion and stimulates processes leading to the production of ATP while it downregulates ATP consuming processes. The yeast SNF1 complex is best known for its role in glucose derepression. METHODS: We performed a network reconstruction of the Snf1 pathway based on a comprehensive literature review. The network was formalised in the rxncon language, and we used the rxncon toolbox for model validation and gap filling. RESULTS: We present a machine-readable network definition that summarises the mechanistic knowledge of the Snf1 pathway. Furthermore, we used the known input/output relationships in the network to identify and fill gaps in the information transfer through the pathway, to produce a functional network model. Finally, we convert the functional network model into a rule-based model as a proof-of-principle. CONCLUSIONS: The workflow presented here enables large scale reconstruction, validation and gap filling of signal transduction networks. It is analogous to but distinct from that established for metabolic networks. We demonstrate the workflow capabilities, and the direct link between the reconstruction and dynamic modelling, with the Snf1 network. This network is a distillation of the knowledge from all previous publications on the Snf1/AMPK pathway. The network is a knowledge resource for modellers and experimentalists alike, and a template for similar efforts in higher eukaryotes. Finally, we envisage the workflow as an instrumental tool for reconstruction of large signalling networks across Eukaryota. PMID- 28725461 TI - Cross-species gene expression analysis identifies a novel set of genes implicated in human insulin sensitivity. AB - OBJECTIVE: Insulin resistance (IR) is one of the earliest predictors of type 2 diabetes. However, diagnosis of IR is limited. High fat fed mouse models provide key insights into IR. We hypothesized that early features of IR are associated with persistent changes in gene expression (GE) and endeavored to (a) develop novel methods for improving signal:noise in analysis of human GE using mouse models; (b) identify a GE motif that accurately diagnoses IR in humans; and (c) identify novel biology associated with IR in humans. METHODS: We integrated human muscle GE data with longitudinal mouse GE data and developed an unbiased three level cross-species analysis platform (single gene, gene set, and networks) to generate a gene expression motif (GEM) indicative of IR. A logistic regression classification model validated GEM in three independent human data sets (n=115). RESULTS: This GEM of 93 genes substantially improved diagnosis of IR compared with routine clinical measures across multiple independent data sets. Individuals misclassified by GEM possessed other metabolic features raising the possibility that they represent a separate metabolic subclass. The GEM was enriched in pathways previously implicated in insulin action and revealed novel associations between beta-catenin and Jak1 and IR. Functional analyses using small molecule inhibitors showed an important role for these proteins in insulin action. CONCLUSIONS: This study shows that systems approaches for identifying molecular signatures provides a powerful way to stratify individuals into discrete metabolic groups. Moreover, we speculate that the beta-catenin pathway may represent a novel biomarker for IR in humans that warrant future investigation. PMID- 28725462 TI - A differential network analysis approach for lineage specifier prediction in stem cell subpopulations. AB - BACKGROUND: Stem cell differentiation is a complex biological process. Cellular heterogeneity, such as the co-existence of different cell subpopulations within a population, partly hampers our understanding of this process. The modern single cell gene expression technologies, such as single-cell RT-PCR and RNA-seq, have enabled us to elucidate such heterogeneous cell subpopulations. However, the identification of a transcriptional regulatory network (TRN) for each cell subpopulation within a population and genes determining specific cell fates (lineage specifiers) remains a challenge due to the slower development of appropriate computational and experimental workflows. Here, we propose a computational differential network analysis approach for predicting lineage specifiers in binary-fate differentiation events. METHODS: The proposed method is based on a model that considers each stem cell subpopulation being in a stable state maintained by its specific TRN stability core, and cell differentiation involves changes in these stability cores between parental and daughter cell subpopulations. The method first reconstructs topologically different cell subpopulation specific TRNs from single-cell gene expression data, literature knowledge and transcription factor (TF)-DNA binding-site prediction. Then, it systematically predicts lineage specifiers by identifying genes in the TRN stability cores in both parental and daughter cell subpopulations. RESULTS: Application of this method to different stem cell differentiation systems was able to predict known and putative novel lineage specifiers. These examples include the differentiation of inner cell mass into either primitive endoderm or epiblast, different progenitor cells in the hematopoietic system, and the lung alveolar bipotential progenitor into either alveolar type 1 or alveolar type 2. CONCLUSIONS: The method is generally applicable to any binary-fate differentiation system, for which single-cell gene expression data are available. Therefore, it should aid in understanding stem cell lineage specification, and in the development of experimental strategies for regenerative medicine. PMID- 28725463 TI - Combinatorial interventions inhibit TGFbeta-driven epithelial-to-mesenchymal transition and support hybrid cellular phenotypes. AB - Epithelial-to-mesenchymal transition (EMT) is a developmental process hijacked by cancer cells to leave the primary tumor site, invade surrounding tissue and establish distant metastases. A hallmark of EMT is the loss of E-cadherin expression, and one major signal for the induction of EMT is transforming growth factor beta (TGFbeta), which is dysregulated in up to 40% of hepatocellular carcinoma (HCC). We aim to identify network perturbations that suppress TGFbeta driven EMT, with the goal of suppressing invasive properties of cancer cells. We use a systems-level Boolean dynamic model of EMT to systematically screen individual and combination perturbations (inhibition or constitutive activation of up to four nodes). We use a recently developed network control approach to understand the mechanism through which the combinatorial interventions suppress EMT. We test the results of our in silico analysis using siRNA. Our model predicts that targeting key elements of feedback loops in combination with the SMAD complex is more effective than suppressing the SMAD complex alone. We demonstrate experimentally that expression of a majority of these elements is enriched in mesenchymal relative to epithelial phenotype HCC cell lines. An siRNA screen of the predicted combinations confirms that many targeting strategies suppress TGFbeta-driven EMT measured by E-cadherin expression and cell migration. Our analysis reveals that some perturbations give rise to hybrid states intermediate to the epithelial and mesenchymal states. Our results indicate that EMT is driven by an interconnected signaling network and many apparently successful single interventions may lead to steady states that are in-between epithelial and mesenchymal states. As these putative hybrid or partial EMT states may retain invasive properties, our results suggest that combinatorial therapies are necessary to fully suppress invasive properties of tumor cells. PMID- 28725464 TI - From START to FINISH: computational analysis of cell cycle control in budding yeast. AB - In the cell division cycle of budding yeast, START refers to a set of tightly linked events that prepare a cell for budding and DNA replication, and FINISH denotes the interrelated events by which the cell exits from mitosis and divides into mother and daughter cells. On the basis of recent progress made by molecular biologists in characterizing the genes and proteins that control START and FINISH, we crafted a new mathematical model of cell cycle progression in yeast. Our model exploits a natural separation of time scales in the cell cycle control network to construct a system of differential-algebraic equations for protein synthesis and degradation, post-translational modifications, and rapid formation and dissociation of multimeric complexes. The model provides a unified account of the observed phenotypes of 257 mutant yeast strains (98% of the 263 strains in the data set used to constrain the model). We then use the model to predict the phenotypes of 30 novel combinations of mutant alleles. Our comprehensive model of the molecular events controlling cell cycle progression in budding yeast has both explanatory and predictive power. Future experimental tests of the model's predictions will be useful to refine the underlying molecular mechanism, to constrain the adjustable parameters of the model, and to provide new insights into how the cell division cycle is regulated in budding yeast. PMID- 28725465 TI - Network analyses based on comprehensive molecular interaction maps reveal robust control structures in yeast stress response pathways. AB - Cellular stress responses require exquisite coordination between intracellular signaling molecules to integrate multiple stimuli and actuate specific cellular behaviors. Deciphering the web of complex interactions underlying stress responses is a key challenge in understanding robust biological systems and has the potential to lead to the discovery of targeted therapeutics for diseases triggered by dysregulation of stress response pathways. We constructed large scale molecular interaction maps of six major stress response pathways in Saccharomyces cerevisiae (baker's or budding yeast). Biological findings from over 900 publications were converted into standardized graphical formats and integrated into a common framework. The maps are posted at http://www.yeast maps.org/yeast-stress-response/ for browse and curation by the research community. On the basis of these maps, we undertook systematic analyses to unravel the underlying architecture of the networks. A series of network analyses revealed that yeast stress response pathways are organized in bow-tie structures, which have been proposed as universal sub-systems for robust biological regulation. Furthermore, we demonstrated a potential role for complexes in stabilizing the conserved core molecules of bow-tie structures. Specifically, complex-mediated reversible reactions, identified by network motif analyses, appeared to have an important role in buffering the concentration and activity of these core molecules. We propose complex-mediated reactions as a key mechanism mediating robust regulation of the yeast stress response. Thus, our comprehensive molecular interaction maps provide not only an integrated knowledge base, but also a platform for systematic network analyses to elucidate the underlying architecture in complex biological systems. PMID- 28725466 TI - Not just a colourful metaphor: modelling the landscape of cellular development using Hopfield networks. AB - The epigenetic landscape was introduced by Conrad Waddington as a metaphor of cellular development. Like a ball rolling down a hillside is channelled through a succession of valleys until it reaches the bottom, cells follow specific trajectories from a pluripotent state to a committed state. Transcription factors (TFs) interacting as a network (the gene regulatory network (GRN)) orchestrate this developmental process within each cell. Here, we quantitatively model the epigenetic landscape using a kind of artificial neural network called the Hopfield network (HN). An HN is composed of nodes (genes/TFs) and weighted undirected edges, resulting in a weight matrix (W) that stores interactions among the nodes over the entire network. We used gene co-expression to compute the edge weights. Through W, we then associate an energy score (E) to each input pattern (pattern of co-expression for a specific developmental stage) such that each pattern has a specific E. We propose that, based on the co-expression values stored in W, HN associates lower E values to stable phenotypic states and higher E to transient states. We validate our model using time course gene-expression data sets representing stages of development across 12 biological processes including differentiation of human embryonic stem cells into specialized cells, differentiation of THP1 monocytes to macrophages during immune response and trans differentiation of epithelial to mesenchymal cells in cancer. We observe that transient states have higher energy than the stable phenotypic states, yielding an arc-shaped trajectory. This relationship was confirmed by perturbation analysis. HNs offer an attractive framework for quantitative modelling of cell differentiation (as a landscape) from empirical data. Using HNs, we identify genes and TFs that drive cell-fate transitions, and gain insight into the global dynamics of GRNs. PMID- 28725467 TI - Pathways on demand: automated reconstruction of human signaling networks. AB - Signaling pathways are a cornerstone of systems biology. Several databases store high-quality representations of these pathways that are amenable for automated analyses. Despite painstaking and manual curation, these databases remain incomplete. We present PATHLINKER, a new computational method to reconstruct the interactions in a signaling pathway of interest. PATHLINKER efficiently computes multiple short paths from the receptors to transcriptional regulators (TRs) in a pathway within a background protein interaction network. We use PATHLINKER to accurately reconstruct a comprehensive set of signaling pathways from the NetPath and KEGG databases. We show that PATHLINKER has higher precision and recall than several state-of-the-art algorithms, while also ensuring that the resulting network connects receptor proteins to TRs. PATHLINKER's reconstruction of the Wnt pathway identified CFTR, an ABC class chloride ion channel transporter, as a novel intermediary that facilitates the signaling of Ryk to Dab2, which are known components of Wnt/beta-catenin signaling. In HEK293 cells, we show that the Ryk CFTR-Dab2 path is a novel amplifier of beta-catenin signaling specifically in response to Wnt 1, 2, 3, and 3a of the 11 Wnts tested. PATHLINKER captures the structure of signaling pathways as represented in pathway databases better than existing methods. PATHLINKER's success in reconstructing pathways from NetPath and KEGG databases point to its applicability for complementing manual curation of these databases. PATHLINKER may serve as a promising approach for prioritizing proteins and interactions for experimental study, as illustrated by its discovery of a novel pathway in Wnt/beta-catenin signaling. Our supplementary website at http://bioinformatics.cs.vt.edu/~murali/supplements/2016-sys-bio-applications pathlinker/ provides links to the PATHLINKER software, input datasets, PATHLINKER reconstructions of NetPath pathways, and links to interactive visualizations of these reconstructions on GraphSpace. PMID- 28725468 TI - Regulation of amino-acid metabolism controls flux to lipid accumulation in Yarrowia lipolytica. AB - Yarrowia lipolytica is a promising microbial cell factory for the production of lipids to be used as fuels and chemicals, but there are few studies on regulation of its metabolism. Here we performed the first integrated data analysis of Y. lipolytica grown in carbon and nitrogen limited chemostat cultures. We first reconstructed a genome-scale metabolic model and used this for integrative analysis of multilevel omics data. Metabolite profiling and lipidomics was used to quantify the cellular physiology, while regulatory changes were measured using RNAseq. Analysis of the data showed that lipid accumulation in Y. lipolytica does not involve transcriptional regulation of lipid metabolism but is associated with regulation of amino-acid biosynthesis, resulting in redirection of carbon flux during nitrogen limitation from amino acids to lipids. Lipid accumulation in Y. lipolytica at nitrogen limitation is similar to the overflow metabolism observed in many other microorganisms, e.g. ethanol production by Sacchromyces cerevisiae at nitrogen limitation. PMID- 28725469 TI - Dynamic models of the complex microbial metapopulation of lake mendota. AB - Like many other environments, Lake Mendota, WI, USA, is populated by many thousand microbial species. Only about 1,000 of these constitute between 80 and 99% of the total microbial community, depending on the season, whereas the remaining species are rare. The functioning and resilience of the lake ecosystem depend on these microorganisms, and it is therefore important to understand their dynamics throughout the year. We propose a two-layered set of dynamic mathematical models that capture and interpret the yearly abundance patterns of the species within the metapopulation. The first layer analyzes the interactions between 14 subcommunities (SCs) that peak at different times of the year and together contain all species whereas the second layer focuses on interactions between individual species and SCs. Each SC contains species from numerous families, genera, and phyla in strikingly different abundances. The dynamic models quantify the importance of environmental factors in shaping the dynamics of the lake's metapopulation and reveal positive or negative interactions between species and SCs. Three environmental factors, namely temperature, ammonia/phosphorus, and nitrate+nitrite, positively affect almost all SCs, whereas by far the most interactions between SCs are inhibitory. As far as the interactions can be independently validated, they are supported by literature information. The models are quite robust and permit predictions of species abundances over many years both, under the assumption that conditions do not change drastically, or in response to environmental perturbations. PMID- 28725472 TI - Model-based dietary optimization for late-stage, levodopa-treated, Parkinson's disease patients. AB - Levodopa has been the gold standard for Parkinson's disease treatment for more than 40 years. Its bioavailability is hindered by dietary amino acids, leading to fluctuations in the motor response particularly in late-stage (stage 3 and 4 on Hoehn and Yahr scale) patients. The routine dietary intervention consists of low protein (<0.8 g/kg) diets or the redistribution of daily protein allowance to the last meal. Computational modeling was used to examine the fluctuation of gastrointestinal levodopa absorption under consideration of the diet by (i) identifying the group of patients that could benefit from dietary interventions, (ii) comparing existing diet recommendations for their impact on levodopa bioavailability, and (iii) suggesting a mechanism-based dietary intervention. We developed a multiscale computational model consisting of an ordinary differential equations-based advanced compartmentalized absorption and transit (ACAT) gut model and metabolic genome-scale small intestine epithelial cell model. We used this model to investigate complex spatiotemporal relationship between dietary amino acids and levodopa absorption. Our model predicted an improvement in bioavailability, as reflected by blood concentrations of levodopa with protein redistribution diet by 34% compared with a low-protein diet and by 11% compared with the ante cibum (a.c.) administration. These results are consistent with the reported better outcome in late-stage patients. A systematic analysis of the effect of different amino acids in the diet suggested that a serine-rich diet could improve the bioavailability by 22% compared with the a.c. administration. In addition, the slower gastric emptying rate in PD patients exacerbates the loss of levodopa due to competition. Optimizing dietary recommendations in quantity, composition, and intake time holds the promise to improve levodopa efficiency and patient's quality of life based on highly detailed, mechanistic models of gut physiology endowed with improved extrapolative properties, thus paving the way for precision medical treatment. PMID- 28725470 TI - Synthetic and systems biology for microbial production of commodity chemicals. AB - The combination of synthetic and systems biology is a powerful framework to study fundamental questions in biology and produce chemicals of immediate practical application such as biofuels, polymers, or therapeutics. However, we cannot yet engineer biological systems as easily and precisely as we engineer physical systems. In this review, we describe the path from the choice of target molecule to scaling production up to commercial volumes. We present and explain some of the current challenges and gaps in our knowledge that must be overcome in order to bring our bioengineering capabilities to the level of other engineering disciplines. Challenges start at molecule selection, where a difficult balance between economic potential and biological feasibility must be struck. Pathway design and construction have recently been revolutionized by next-generation sequencing and exponentially improving DNA synthesis capabilities. Although pathway optimization can be significantly aided by enzyme expression characterization through proteomics, choosing optimal relative protein expression levels for maximum production is still the subject of heuristic, non-systematic approaches. Toxic metabolic intermediates and proteins can significantly affect production, and dynamic pathway regulation emerges as a powerful but yet immature tool to prevent it. Host engineering arises as a much needed complement to pathway engineering for high bioproduct yields; and systems biology approaches such as stoichiometric modeling or growth coupling strategies are required. A final, and often underestimated, challenge is the successful scale up of processes to commercial volumes. Sustained efforts in improving reproducibility and predictability are needed for further development of bioengineering. PMID- 28725471 TI - Strategies for structuring interdisciplinary education in Systems Biology: an European perspective. AB - Systems Biology is an approach to biology and medicine that has the potential to lead to a better understanding of how biological properties emerge from the interaction of genes, proteins, molecules, cells and organisms. The approach aims at elucidating how these interactions govern biological function by employing experimental data, mathematical models and computational simulations. As Systems Biology is inherently multidisciplinary, education within this field meets numerous hurdles including departmental barriers, availability of all required expertise locally, appropriate teaching material and example curricula. As university education at the Bachelor's level is traditionally built upon disciplinary degrees, we believe that the most effective way to implement education in Systems Biology would be at the Master's level, as it offers a more flexible framework. Our team of experts and active performers of Systems Biology education suggest here (i) a definition of the skills that students should acquire within a Master's programme in Systems Biology, (ii) a possible basic educational curriculum with flexibility to adjust to different application areas and local research strengths, (iii) a description of possible career paths for students who undergo such an education, (iv) conditions that should improve the recruitment of students to such programmes and (v) mechanisms for collaboration and excellence spreading among education professionals. With the growing interest of industry in applying Systems Biology approaches in their fields, a concerted action between academia and industry is needed to build this expertise. Here we present a reflection of the European situation and expertise, where most of the challenges we discuss are universal, anticipating that our suggestions will be useful internationally. We believe that one of the overriding goals of any Systems Biology education should be a student's ability to phrase and communicate research questions in such a manner that they can be solved by the integration of experiments and modelling, as well as to communicate and collaborate productively across different experimental and theoretical disciplines in research and development. PMID- 28725473 TI - Integrating highly quantitative proteomics and genome-scale metabolic modeling to study pH adaptation in the human pathogen Enterococcus faecalis. AB - Genome-scale metabolic models represent the entirety of metabolic reactions of an organism based on the annotation of the respective genome. These models commonly allow all reactions to proceed concurrently, disregarding the fact that at no point all proteins will be present in a cell. The metabolic reaction space can be constrained to a more physiological state using experimentally obtained information on enzyme abundances. However, high-quality, genome-wide protein measurements have been challenging and typically transcript abundances have been used as a surrogate for protein measurements. With recent developments in mass spectrometry-based proteomics, exemplified by SWATH-MS, the acquisition of highly quantitative proteome-wide data at reasonable throughput has come within reach. Here we present methodology to integrate such proteome-wide data into genome scale models. We applied this methodology to study cellular changes in Enterococcus faecalis during adaptation to low pH. Our results indicate reduced proton production in the central metabolism and decreased membrane permeability for protons due to different membrane composition. We conclude that proteomic data constrain genome-scale models to a physiological state and, in return, genome-scale models are useful tools to contextualize proteomic data. PMID- 28725475 TI - MINERVA-a platform for visualization and curation of molecular interaction networks. AB - Our growing knowledge about various molecular mechanisms is becoming increasingly more structured and accessible. Different repositories of molecular interactions and available literature enable construction of focused and high-quality molecular interaction networks. Novel tools for curation and exploration of such networks are needed, in order to foster the development of a systems biology environment. In particular, solutions for visualization, annotation and data cross-linking will facilitate usage of network-encoded knowledge in biomedical research. To this end we developed the MINERVA (Molecular Interaction NEtwoRks VisuAlization) platform, a standalone webservice supporting curation, annotation and visualization of molecular interaction networks in Systems Biology Graphical Notation (SBGN)-compliant format. MINERVA provides automated content annotation and verification for improved quality control. The end users can explore and interact with hosted networks, and provide direct feedback to content curators. MINERVA enables mapping drug targets or overlaying experimental data on the visualized networks. Extensive export functions enable downloading areas of the visualized networks as SBGN-compliant models for efficient reuse of hosted networks. The software is available under Affero GPL 3.0 as a Virtual Machine snapshot, Debian package and Docker instance at http://r3lab.uni.lu/web/minerva website/. We believe that MINERVA is an important contribution to systems biology community, as its architecture enables set-up of locally or globally accessible SBGN-oriented repositories of molecular interaction networks. Its functionalities allow overlay of multiple information layers, facilitating exploration of content and interpretation of data. Moreover, annotation and verification workflows of MINERVA improve the efficiency of curation of networks, allowing life-science researchers to better engage in development and use of biomedical knowledge repositories. PMID- 28725474 TI - The NAD World 2.0: the importance of the inter-tissue communication mediated by NAMPT/NAD+/SIRT1 in mammalian aging and longevity control. AB - The original concept of the NAD World was proposed in 2009, providing a comprehensive framework to investigate critical issues of biological robustness and trade-offs in mammalian aging and longevity control. Significant progress has been made over the past 7 years, advancing our understanding of the mechanisms by which biological robustness is maintained, and providing extensive support to the concept of the NAD World. Three key organs and tissues have been identified as basic elements in this control system for mammalian aging and longevity: the hypothalamus as the control center of aging, skeletal muscle as an effector, and adipose tissue as a modulator. While the hypothalamus sends a signal to skeletal muscle through the sympathetic nervous system, adipose tissue remotely regulates hypothalamic function by coordinating NAD+ biosynthesis at a systemic level. Skeletal muscle might also communicate with other organs and tissues by secreting various myokines. The mammalian NAD+-dependent protein deacetylase SIRT1 and the key NAD+ biosynthetic enzyme NAMPT mediate these inter-tissue communications. In this review, the function of each organ or tissue and their inter-tissue communications will be discussed in terms of understanding mammalian aging and longevity control. With such an emphasis on the system architecture, the concept is now reformulated as the NAD World 2.0, providing several important predictions. The concept of the NAD World 2.0 will provide a new foundation to understand a control system for mammalian aging and longevity and accelerate the development of an effective anti-aging intervention for humans. PMID- 28725477 TI - Molecular mechanisms involved in the side effects of fatty acid amide hydrolase inhibitors: a structural phenomics approach to proteome-wide cellular off-target deconvolution and disease association. AB - Fatty acid amide hydrolase (FAAH) is a promising therapeutic target for the treatment of pain and CNS disorders. However, the development of potent and safe FAAH inhibitors is hindered by their off-target mediated side effect that leads to brain cell death. Its physiological off-targets and their associations with phenotypes may not be characterized using existing experimental and computational techniques as these methods fail to have sufficient proteome coverage and/or ignore native biological assemblies (BAs; i.e., protein quaternary structures). To understand the mechanisms of the side effects from FAAH inhibitors and other drugs, we develop a novel structural phenomics approach to identifying the physiological off-targets binding profile in the cellular context and on a structural proteome scale, and investigate the roles of these off-targets in impacting human physiology and pathology using text mining-based phenomics analysis. Using this integrative approach, we discover that FAAH inhibitors may bind to the dimerization interface of NMDA receptor (NMDAR) and several other BAs, and thus disrupt their cellular functions. Specifically, the malfunction of the NMDAR is associated with a wide spectrum of brain disorders that are directly related to the observed side effects of FAAH inhibitors. This finding is consistent with the existing literature, and provides testable hypotheses for investigating the molecular origin of the side effects of FAAH inhibitors. Thus, the in silico method proposed here, which can for the first time predict proteome wide drug interactions with cellular BAs and link BA-ligand interaction with clinical outcomes, can be valuable in off-target screening. The development and application of such methods will accelerate the development of more safe and effective therapeutics. PMID- 28725476 TI - Food allergen detection by mass spectrometry: the role of systems biology. AB - Food allergy prevalence is rising worldwide, motivating the development of assays that can sensitively and reliably detect trace amounts of allergens in manufactured food. Mass spectrometry (MS) is a promising alternative to commonly employed antibody-based assays owing to its ability to quantify multiple proteins in complex matrices with high sensitivity. In this review, we discuss a targeted MS workflow for the quantitation of allergenic protein in food products that employs selected reaction monitoring (SRM). We highlight the aspects of SRM method development unique to allergen quantitation and identify opportunities for simplifying the process. One promising avenue identified through a comprehensive survey of published MS literature is the use of proteotypic peptides, which are peptides whose presence appears robust to variations in food matrix, sample preparation protocol, and MS instrumentation. We conclude that proteotypic peptides exist for a subset of allergenic milk, egg, and peanut proteins. For less studied allergens such as soy, wheat, fish, shellfish, and tree nuts, we offer guidance and tools for peptide selection and specificity verification as part of an interactive web database, the Allergen Peptide Browser (http://www.AllergenPeptideBrowser.org). With ongoing improvements in MS instrumentation, analysis software, and strategies for targeted quantitation, we expect an increasing role of MS as an analytical tool for ensuring regulatory compliance. PMID- 28725478 TI - Oscillation dynamics underlie functional switching of NF-kappaB for B-cell activation. AB - Transcription factor nuclear factor kappa B (NF-kappaB) shows cooperative switch like activation followed by prolonged oscillatory nuclear translocation in response to extracellular stimuli. These dynamics are important for activation of the NF-kappaB transcriptional machinery, however, NF-kappaB activity regulated by coordinated actions of these dynamics has not been elucidated at the system level. Using a variety of B cells with artificially rewired NF-kappaB signaling networks, we show that oscillations and switch-like activation of NF-kappaB can be dissected and that, under some conditions, these two behaviors are separated upon antigen receptor activation. Comprehensive quantitative experiments and mathematical analysis showed that the functional role of switch activation in the NF-kappaB system is to overcome transient IKK (IkappaB kinase) activity to amplify nuclear translocation of NF-kappaB, thereby inducing the prolonged NF kappaB oscillatory behavior necessary for target gene expression and B-cell activation. PMID- 28725479 TI - A time-resolved molecular map of the macrophage response to VSV infection. AB - Studying the relationship between virus infection and cellular response is paradigmatic for our understanding of how perturbation changes biological systems. Immune response, in this context is a complex yet evolutionarily adapted and robust cellular change, and is experimentally amenable to molecular analysis. To visualize the full cellular response to virus infection, we performed temporal transcriptomics, proteomics, and phosphoproteomics analysis of vesicular stomatitis virus (VSV)-infected mouse macrophages. This enabled the understanding of how infection-induced changes in host gene and protein expression are coordinated with post-translational modifications by cells in time to best measure and control the infection process. The vast and complex molecular changes measured could be decomposed in a limited number of clusters within each category (transcripts, proteins, and protein phosphorylation) each with own kinetic parameter and characteristic pathways/processes, suggesting multiple regulatory options in the overall sensing and homeostatic program. Altogether, the data underscored a prevalent executive function to phosphorylation. Resolution of the molecular events affecting the RIG-I pathway, central to viral recognition, reveals that phosphorylation of the key innate immunity adaptor mitochondrial antiviral-signaling protein (MAVS) on S328/S330 is necessary for activation of type-I interferon and nuclear factor kappa B (NFkappaB) pathways. To further understand the hierarchical relationships, we analyzed kinase-substrate relationships and found RAF1 and, to a lesser extent, ARAF to be inhibiting VSV replication and necessary for NFkappaB activation, and AKT2, but not AKT1, to be supporting VSV replication. Integrated analysis using the omics data revealed co regulation of transmembrane transporters including SLC7A11, which was subsequently validated as a host factor in the VSV replication. The data sets are predicted to greatly empower future studies on the functional organization of the response of macrophages to viral challenges. PMID- 28725481 TI - Identifying biological mechanisms for favorable cancer prognosis using non hypothesis-driven iterative survival analysis. AB - Survival analyses based on the Kaplan-Meier estimate have been pervasively used to support or validate the relevance of biological mechanisms in cancer research. Recently, with the appearance of gene expression high-throughput technologies, this kind of analysis has been applied to tumor transcriptomics data. In a 'bottom-up' approach, gene-expression profiles that are associated with a deregulated pathway hypothetically involved in cancer progression are first identified and then subsequently correlated with a survival effect, which statistically supports or requires the rejection of such a hypothesis. In this work, we propose a 'top-down' approach, in which the clinical outcome (survival) is the starting point that guides the identification of deregulated biological mechanisms in cancer by a non-hypothesis-driven iterative survival analysis. We show that the application of our novel method to a population of ~2,000 breast cancer patients of the METABRIC consortium allows the identification of several well-known cancer mechanisms, such as ERBB4, HNF3A and TGFB pathways, and the investigation of their paradoxical dual effect. In addition, several novel biological mechanisms are proposed as potentially involved in cancer progression. The proposed exploratory methodology can be considered both alternative and complementary to classical 'bottom-up' approaches for validation of biological hypotheses. We propose that our method may be used to better characterize cancer, and may therefore impact the future design of therapies that are truly molecularly tailored to individual patients. The method, named SURCOMED, was implemented as a web-based tool, which is publicly available at http://surcomed.vital-it.ch. R scripts are also available at http://surcomed.sourceforge.net). PMID- 28725480 TI - MUFINS: multi-formalism interaction network simulator. AB - Systems Biology has established numerous approaches for mechanistic modeling of molecular networks in the cell and a legacy of models. The current frontier is the integration of models expressed in different formalisms to address the multi scale biological system organization challenge. We present MUFINS (MUlti Formalism Interaction Network Simulator) software, implementing a unique set of approaches for multi-formalism simulation of interaction networks. We extend the constraint-based modeling (CBM) framework by incorporation of linear inhibition constraints, enabling for the first time linear modeling of networks simultaneously describing gene regulation, signaling and whole-cell metabolism at steady state. We present a use case where a logical hypergraph model of a regulatory network is expressed by linear constraints and integrated with a Genome-Scale Metabolic Network (GSMN) of mouse macrophage. We experimentally validate predictions, demonstrating application of our software in an iterative cycle of hypothesis generation, validation and model refinement. MUFINS incorporates an extended version of our Quasi-Steady State Petri Net approach to integrate dynamic models with CBM, which we demonstrate through a dynamic model of cortisol signaling integrated with the human Recon2 GSMN and a model of nutrient dynamics in physiological compartments. Finally, we implement a number of methods for deriving metabolic states from ~omics data, including our new variant of the iMAT congruency approach. We compare our approach with iMAT through the analysis of 262 individual tumor transcriptomes, recovering features of metabolic reprogramming in cancer. The software provides graphics user interface with network visualization, which facilitates use by researchers who are not experienced in coding and mathematical modeling environments. PMID- 28725482 TI - Systems biology driving drug development: from design to the clinical testing of the anti-ErbB3 antibody seribantumab (MM-121). AB - The ErbB family of receptor tyrosine kinases comprises four members: epidermal growth factor receptor (EGFR/ErbB1), human EGFR 2 (HER2/ErbB2), ErbB3/HER3, and ErbB4/HER4. The first two members of this family, EGFR and HER2, have been implicated in tumorigenesis and cancer progression for several decades, and numerous drugs have now been approved that target these two proteins. Less attention, however, has been paid to the role of this family in mediating cancer cell survival and drug tolerance. To better understand the complex signal transduction network triggered by the ErbB receptor family, we built a computational model that quantitatively captures the dynamics of ErbB signaling. Sensitivity analysis identified ErbB3 as the most critical activator of phosphoinositide 3-kinase (PI3K) and Akt signaling, a key pro-survival pathway in cancer cells. Based on this insight, we designed a fully human monoclonal antibody, seribantumab (MM-121), that binds to ErbB3 and blocks signaling induced by the extracellular growth factors heregulin (HRG) and betacellulin (BTC). In this article, we present some of the key preclinical simulations and experimental data that formed the scientific foundation for three Phase 2 clinical trials in metastatic cancer. These trials were designed to determine if patients with advanced malignancies would derive benefit from the addition of seribantumab to standard-of-care drugs in platinum-resistant/refractory ovarian cancer, hormone receptor-positive HER2-negative breast cancer, and EGFR wild-type non-small cell lung cancer (NSCLC). From preclinical studies we learned that basal levels of ErbB3 phosphorylation correlate with response to seribantumab monotherapy in mouse xenograft models. As ErbB3 is rapidly dephosphorylated and hence difficult to measure clinically, we used the computational model to identify a set of five surrogate biomarkers that most directly affect the levels of p-ErbB3: HRG, BTC, EGFR, HER2, and ErbB3. Preclinically, the combined information from these five markers was sufficient to accurately predict which xenograft models would respond to seribantumab, and the single-most accurate predictor was HRG. When tested clinically in ovarian, breast and lung cancer, HRG mRNA expression was found to be both potentially prognostic of insensitivity to standard therapy and potentially predictive of benefit from the addition of seribantumab to standard of care therapy in all three indications. In addition, it was found that seribantumab was most active in cancers with low levels of HER2, consistent with preclinical predictions. Overall, our clinical studies and studies of others suggest that HRG expression defines a drug-tolerant cancer cell phenotype that persists in most solid tumor indications and may contribute to rapid clinical progression. To our knowledge, this is the first example of a drug designed and clinically tested using the principles of Systems Biology. PMID- 28725483 TI - Engineering glucose metabolism of Escherichia coli under nitrogen starvation. AB - A major aspect of microbial metabolic engineering is the development of chassis hosts that have favorable global metabolic phenotypes, and can be further engineered to produce a variety of compounds. In this work, we focus on the problem of decoupling growth and production in the model bacterium Escherichia coli, and in particular on the maintenance of active metabolism during nitrogen limited stationary phase. We find that by overexpressing the enzyme PtsI, a component of the glucose uptake system that is inhibited by alpha-ketoglutarate during nitrogen limitation, we are able to achieve a fourfold increase in metabolic rates. Alternative systems were also tested: chimeric PtsI proteins hypothesized to be insensitive to alpha-ketoglutarate did not improve metabolic rates under the conditions tested, whereas systems based on the galactose permease GalP suffered from energy stress and extreme sensitivity to expression level. Overexpression of PtsI is likely to be a useful arrow in the metabolic engineer's quiver as productivity of engineered pathways becomes limited by central metabolic rates during stationary phase production processes. PMID- 28725484 TI - Logarithmic sensing in Bacillus subtilis aerotaxis. AB - Aerotaxis, the directed migration along oxygen gradients, allows many microorganisms to locate favorable oxygen concentrations. Despite oxygen's fundamental role for life, even key aspects of aerotaxis remain poorly understood. In Bacillus subtilis, for example, there is conflicting evidence of whether migration occurs to the maximal oxygen concentration available or to an optimal intermediate one, and how aerotaxis can be maintained over a broad range of conditions. Using precisely controlled oxygen gradients in a microfluidic device, spanning the full spectrum of conditions from quasi-anoxic to oxic (60 n mol/l-1 m mol/l), we resolved B. subtilis' 'oxygen preference conundrum' by demonstrating consistent migration towards maximum oxygen concentrations ('monotonic aerotaxis'). Surprisingly, the strength of aerotaxis was largely unchanged over three decades in oxygen concentration (131 n mol/l-196 MU mol/l). We discovered that in this range B. subtilis responds to the logarithm of the oxygen concentration gradient, a rescaling strategy called 'log-sensing' that affords organisms high sensitivity over a wide range of conditions. In these experiments, high-throughput single-cell imaging yielded the best signal-to-noise ratio of any microbial taxis study to date, enabling the robust identification of the first mathematical model for aerotaxis among a broad class of alternative models. The model passed the stringent test of predicting the transient aerotactic response despite being developed on steady-state data, and quantitatively captures both monotonic aerotaxis and log-sensing. Taken together, these results shed new light on the oxygen-seeking capabilities of B. subtilis and provide a blueprint for the quantitative investigation of the many other forms of microbial taxis. PMID- 28725485 TI - Segmentation errors in macular ganglion cell analysis as determined by optical coherence tomography in eyes with macular pathology. AB - BACKGROUND: To evaluate artifacts in macular ganglion cell inner plexiform layer (GCIPL) thickness measurement in eyes with retinal pathology using spectral domain optical coherence tomography (SD OCT). METHODS: Retrospective analysis of color-coded maps, infrared images and 128 horizontal B-scans (acquired in the macular ganglion cell inner plexiform layer scans), using the Cirrus HD-OCT (Carl Zeiss Meditec, Dublin, CA). The study population included 105 eyes with various macular conditions compared to 30 eyes of 30 age-matched healthy volunteers. The overall frequency of image artifacts and the relative frequency of artifacts were stratified by macular disease. RESULTS: Scan errors and artifacts were found in 55.1% of the 13,440 B-scans in eyes with macular pathology and 26.8% of the 3840 scans in normal eyes. Segmentation errors were the most common scan error in both groups, with more common involvement of both segmentation borders in diseased eyes and anterior segmentation border in normal eyes. CONCLUSION: Segmentation errors and artifacts in SD OCT GCA are common in conditions involving the macula. These findings should be considered when assessing macular GCIPL thickness and careful assessment of scans is suggested. PMID- 28725486 TI - Consequences of traumatic spinal cord injury during pregnancy in Pakistan. AB - INTRODUCTION: Traumatic spinal cord injury (SCI) is one of the major causes for poor outcomes of pregnancy. Injury during pregnancy is uncommon; therefore, outcome data are scarce. This case series presents outcomes of pregnancy in five women who sustained SCI during their pregnancies. CASE PRESENTATION: Five women who sustained SCIs during pregnancy (age range: 24-38 years) were identified and included in this case series. The causes of SCI in this population were fall from heights (cases 1 and 2), road traffic accidents (cases 3 and 4) and firearm injury (case 5). Two of the females were managed conservatively (cases 1 and 5) and the rest underwent surgical procedures for fixing their spine. Out of these patients, four patients delivered normal healthy babies, while the baby of one patient died within 1 hour after delivery. DISCUSSION: Limited data about the outcomes of pregnancy in women who sustained SCIs during pregnancy are available in the literature. The outcomes of pregnancy in women who sustained SCIs during the first trimester are not satisfactory, and special attention may be needed to improve the expected outcomes. Data from our study show similar findings to developed countries. PMID- 28725487 TI - Expectations of persons with paraplegia regarding their care in India: a qualitative study. AB - STUDY DESIGN: A qualitative study. OBJECTIVE: The aim of this study was to understand expectations of persons with paraplegia in India regarding their care. SETTING: India. METHODS: This study used a qualitative methodology to have a focus group interview of persons with paraplegia in India. Focus group consisted of two to four participants with paraplegia. Adults with level T6 and below, complete injury, duration of at least 6 months post injury and those living in the community were included. Online focus group interviews were conducted using ZOOM online software for online discussions/meetings. Data were collected till data saturation. Recorded videos were transcribed into texts, and the transcribed documents were analysed using the ATLASti.8 software for qualitative data analysis. RESULTS: Forty-eight codes were retrieved under fourteen code groups. These code groups were acceptance, accessibility, advanced technology, assistive devices, basic skills, employment, expectations, experiences, functional independence, government policies, knowledge, psychological make-up, physiotherapy and rural area. CONCLUSION: Because of lack of awareness, knowledge and education provided to persons with paraplegia, their expectations were often unrealistic. Patient education and education of the health professionals are two of the most important aspects in spinal cord injury rehabilitation that must be taken into consideration in India. PMID- 28725488 TI - Generation and analysis of spheroids from human primary skin myofibroblasts: an experimental system to study myofibroblasts deactivation. AB - Myofibroblasts are activated fibroblasts involved in tissue repair and cancer. They are characterized by de novo expression of alpha-smooth muscle actin (alpha SMA), immunoregulatory phenotype and paracrine interaction with normal and tumorigenic cells leading to cell proliferation. At the end of wound-healing myofibroblasts undergo apoptotic cell death, whereas in vitro-activated fibroblasts are also subjected to a programmed necrosis-like cell death, termed nemosis, associated with cyclooxygenase-2 (COX-2) expression induction and inflammatory response. Furthermore, myofibroblasts form clusters during wound healing, fibrotic states and tumorigenesis. In this study, we generated and analysed clusters such as spheroids from human primary cutaneous myofibroblasts, which represent a part of stromal microenvironment better than established cell lines. Therefore, we evaluated apoptotic or necrotic cell death, inflammation and activation markers during myofibroblasts clustering. The spheroids formation did not trigger apoptosis, necrotic cell death and COX-2 protein induction. The significant decrease of alpha-SMA in protein extracts of spheroids, the cytostatic effect exerted by spheroids conditioned medium on both normal and cancer cell lines and the absence of proliferation marker Ki-67 after 72 h of three-dimensional culture indicated that myofibroblasts have undergone a deactivation process within spheroids. The cells of spheroids reverted to adhesion growth preserved their proliferation capability and can re-acquire a myofibroblastic phenotype. Moreover, the spontaneous formation of clusters on plastic and glass substrates suggests that aggregates formation could be a physiological feature of cutaneous myofibroblasts. This study represents an experimental model to analyse myofibroblasts deactivation and suggests that fibroblast clusters could be a cell reservoir regulating tissues turnover. PMID- 28725489 TI - BMP-2 induces EMT and breast cancer stemness through Rb and CD44. AB - Bone morphogenetic protein 2 (BMP-2) has been reported to facilitate epithelial to-mesenchymal transition (EMT) and bone metastasis in breast cancer xenograft models. To investigate the role of BMP-2 in the development of breast cancer stem cells (BCSCs), and to further elucidate the mechanisms underlying its influence on breast cancer metastasis, we conducted a comprehensive molecular study using breast cancer cell lines and clinical samples. Our results showed that downregulation of Rb by BMP-2 was associated with ubiquitin-mediated degradation activated by phosphorylation of Rb via the PI3K/AKT signal pathway. In addition, the Smad signaling pathways are implicated in upregulation of CD44 protein expression by BMP-2. It was suggested that cross-talk exists between Rb and CD44 signaling pathways, as recombinant human BMP-2 (rhBMP-2) was found to regulate CD44 expression partly through Rb signals. In clinical tissues, BMP-2 was positively and negatively correlated with CD44 and Rb expression, respectively. Based on the in vitro and in vivo results, we have established an integrated mechanism by which rhBMP-2 induces EMT and stemness of breast cancer cells via the Rb and CD44 signaling pathways, which then contribute to breast cancer metastasis. These findings may be helpful for developing new strategies for the treatment and prognosis of advanced breast cancer. PMID- 28725490 TI - MUC1 O-glycosylation contributes to anoikis resistance in epithelial cancer cells. AB - Anoikis is a fundamental cellular process for maintaining tissue homeostasis. Resistance to anoikis is a hallmark of oncogenic epithelial-mesenchymal transition and is a pre-requisite for metastasis. Previous studies have revealed that the heavily glycosylated mucin protein MUC1, which is overexpressed in all types of epithelial cancer cells, prevents anoikis initiation in response to loss of adhesion. This effect of MUC1 is largely attributed to its extracellular domain that provides cell surface anoikis-initiating molecules with a 'homing' microenvironment. The present study investigated the influence of O-glycosylation on MUC1 extracellular domain on MUC1-mediated cell resistance to anoikis. It shows that stable suppression of the Core 1Gal-transferase (C1GT) by shRNA substantially reduces O-glycosylation in MUC1-positively transfected human colon cancer HCT116 cells and in high MUC1-expressing SW620 cells. Suppression of C1GT significantly increased anoikis of the MUC1-positive, but not MUC1-negative, cells in response to suspended culture. This effect was shown to be associated with increased ligand accessibility to cell surface anoikis-initiating molecules such as E-cadherin, integrinbeta1 and Fas. These results indicate that the extensive O-glycosylation on MUC1 extracellular domain contributes to MUC1 mediated cell resistance to anoikis by facilitating MUC1-mediated prohibition of activation of the cell surface anoikis-initiating molecules in response to loss of cell adhesion. This provides insight into the molecular mechanism of anoikis regulation and highlights the importance of cellular glycosylation in cancer progression and metastasis. PMID- 28725491 TI - DS16570511 is a small-molecule inhibitor of the mitochondrial calcium uniporter. AB - In cardiac myocytes, regulation of mitochondrial Ca2+ is important for cellular signaling and cardiac contraction. Ca2+ entry into the mitochondria is mediated by a highly selective Ca2+ channel called the mitochondrial calcium uniporter, which consists of a pore-forming subunit MCU and regulatory subunits such as MICU1. Although pharmacological regulation of the mitochondrial Ca2+ influx is a promising approach to controlling the cellular functions, a cell-permeable and specific inhibitor of the mitochondrial calcium uniporter has not yet been developed. Here, we identify a novel cell-permeable inhibitor of the uniporter by a high-throughput screening of 120 000 small-molecule compounds. In our study, DS16570511 dose-dependently inhibited serum-induced mitochondrial Ca2+ influx in HEK293A cells with an IC50 of 7 MUM. DS16570511 inhibited Ca2+ uptake of isolated mitochondria from human cells, rat heart and pig heart. Overexpression of hMCU or hMICU1 in HEK293A cells increased mitochondrial Ca2+ influx, and the increases were completely suppressed by the pretreatment with DS16570511. DS16570511 also blocks mitochondrial Ca2+ overload in a Langendorff perfused beating rat heart. Interestingly, DS16570511 increased cardiac contractility without affecting heart rate in the perfused heart. These results show that DS16570511 is a novel cell permeable inhibitor of the mitochondrial calcium uniporter and applicable for control of the cardiac functions. PMID- 28725492 TI - ROLE OF SPOUSAL INVOLVEMENT IN CONTINUOUS POSITIVE AIRWAY PRESSURE (CPAP) ADHERENCE IN PATIENTS WITH OBSTRUCTIVE SLEEP APNEA (OSA). AB - INTRODUCTION: Little is known about the impact of spousal involvement on continuous positive airway pressure (CPAP) adherence. The aim of this study was to determine whether spouse involvement affects adherence with CPAP therapy, and how this association varies with gender. METHODS: 194 subjects recruited from Apnea Positive Pressure Long Term Efficacy Study (APPLES) completed the Dyadic Adjustment Scale (DAS). The majority of participants were Caucasian (83%), and males (73%), with mean age of 56 years, mean BMI of 31 kg/m2. & 62% had severe OSA. The DAS is a validated 32-item self-report instrument measuring dyadic consensus, satisfaction, cohesion, and affectional expression. A high score in the DAS is indicative of a person's adjustment to the marriage. Additionally, questions related to spouse involvement with general health and CPAP use were asked. CPAP use was downloaded from the device and self-report, and compliance was defined as usage >= 4 h per night. RESULTS: There were no significant differences in overall marital quality between the compliant and noncompliant subjects. However, level of spousal involvement was associated with increased CPAP adherence at 6 months (p=0.01). After stratifying for gender these results were significant only among males (p=0.03). Three years after completing APPLES, level of spousal involvement was not associated with CPAP compliance even after gender stratification. CONCLUSION: Spousal involvement is important in determining CPAP compliance in males in the 1st 6 months after initiation of therapy but is not predictive of longer-term adherence. Involvement of the spouse should be considered an integral part of CPAP initiation procedures. SUPPORT: HL068060. PMID- 28725494 TI - Apixaban for treatment of confirmed heparin-induced thrombocytopenia: a case report and review of literature. AB - BACKGROUND: Heparin-induced thrombocytopenia (HIT) is a life and limb-threatening condition caused by the binding of platelet-activating antibodies (IgG) to multimolecular platelet factor 4 (PF4)/heparin complexes because of heparin exposure. The by-product of this interaction is thrombin formation which substantially increases the risk of venous and/or arterial thromboembolism. Currently, only one anticoagulant, argatroban, is United States Food and Drug Administration-approved for management of HIT; however, this agent is expensive and can only be given by intravenous infusion. Recently, several retrospective case-series, case reports, and one prospective study suggest that direct oral anticoagulants (DOACs) are also efficacious for treating HIT. We further review the literature regarding current diagnosis and clinical management of HIT. CASE PRESENTATION: A 66-year-old male patient developed HIT beginning on day 5 post cardiovascular surgery; the platelet count nadir on day 10 measured 16 * 109/L. Both the PF4-dependent ELISA and Serotonin-release assay were strongly positive. Despite initial anticoagulation with argatroban (day 6), the patient developed symptomatic Doppler ultrasound-documented bilateral lower extremity deep vein thrombosis on day 14 post-surgery. The patient was transitioned to the DOAC, apixaban, while still thrombocytopenic (platelet count 108) and discharged to home, with platelet count recovery and no further thrombosis at 3-month follow up. CONCLUSIONS: We report a patient with serologically confirmed HIT who developed symptomatic bilateral lower limb deep vein thrombosis despite anticoagulation with argatroban. The patient was switched to oral apixaban and made a complete recovery. Our patient case adds to the emerging literature suggesting that DOAC therapy is safe and efficacious for management of proven HIT. PMID- 28725495 TI - Anatomy of the Wrist. PMID- 28725493 TI - Interferon-alpha-based immunotherapies in the treatment of B cell-derived hematologic neoplasms in today's treat-to-target era. AB - B cell lymphoma and multiple myeloma (MM) are the most common hematological malignancies which benefit from therapeutic monoclonal antibodies (mAbs)-based immunotherapies. Despite significant improvement on patient outcome following the use of novel therapies for the past decades, curative treatment is unavailable for the majority of patients. For example, the 5-year survival of MM is currently less than 50%. In the 1980s, interferon-alpha was used as monotherapy in newly diagnosed or previously treated MM with an overall response rate of 15-20%. Noticeably, a small subset of patients who responded to long-term interferon alpha further achieved sustained complete remission. Since 1990, interferon-alpha containing regimens have been used as a central maintenance strategy for patients with MM. However, the systemic administration of interferon-alpha was ultimately limited by its pronounced toxicity. To address this, the selective mAb-mediated delivery of interferon-alpha has been developed to enhance specific killing of MM and B-cell malignant cells. As such, targeted interferon-alpha therapy may improve therapeutic window and sustain responses, while further overcoming suppressive microenvironment. This review aims to reinforce the role of interferon-alpha by consolidating our current understanding of targeting interferon-alpha with tumor-specific mAbs for B cell lymphoma and myeloma. PMID- 28725496 TI - Volar Distal Radius Anatomy Applied to the Treatment of Distal Radius Fracture. AB - Volar locking plate (VLP) fixation has become the standard surgical treatment for distal radius fractures. However, flexor tendon rupture is one of the major complications following volar plating. This detailed review on the anatomy and morphology of the volar distal radius might facilitate appropriate placement of the volar plate and thereby avoid flexor tendon rupture. We introduce safe and secure VLP fixation along standard surgical procedures to avoid complications based on anatomy of the volar surface of the distal radius. PMID- 28725497 TI - Effect of Screw Perpendicularity on Compression in Scaphoid Waist Fractures. AB - Background Central and perpendicular (PERP) screw orientations have each been described for scaphoid fracture fixation. It is unclear, however, which orientation produces greater compression. Questions/Purposes This study compares compression in scaphoid waist fractures with screw fixation in both PERP and pole to-pole (PTP) configurations. PERP orientation was hypothesized to produce greater compression than PTP orientation. Methods Ten preoperative computed tomography scans of scaphoid waist fractures were classified by fracture type and orientation in the coronal and sagittal planes. Three-dimensional models of each scaphoid and fracture plane were created. Simulated Acutrak 2 (Acumed, Hillsboro, OR) screws were placed into the models in both PERP and PTP orientations. Engagement length and screw angle relative to the fracture were measured. Compression strength was calculated from the shear area, average density, and angle acuity. Results The PTP angle between screw and fracture ranged from 36 to 84 degrees. By definition, the PERP screw-to-fracture angle was 90 degrees. Perpendicularity of the PTP screw to the fracture was positively correlated to compression strength. PERP screws had greater compression than PTP screws when the PTP screw-to-fracture angle was < 80 degrees (106 vs. 80 N), but there was no difference in compression when the PTP screw-to-fracture angle was > 80 degrees, approximating the PERP screw. Conclusion Increasing screw perpendicularity resulted in higher compression when the screw-to-fracture angle of the PTP screw was < 80 degrees. Maximum compression was obtained with a screw PERP to the fracture. The increased compression gained from PERP screw placement offsets the decreased engagement length. Clinical Relevance These results provide guidelines for optimal screw placement in scaphoid waist fractures. PMID- 28725498 TI - Percutaneous, Transtrapezial Fixation without Bone Graft Leads to Consolidation in Selected Cases of Delayed Union of the Scaphoid Waist. AB - Purpose We evaluated clinical and radiographic outcome of percutaneous transtrapezial fixation of the scaphoid delayed union or nonunion using a headless bone screw without bone grafting. Methods Sixteen patients with delayed union or nonunion of the scaphoid were included in this retrospective study between 2006 and 2011. All patients had a delayed presentation of scaphoid fracture, and none of them was treated conservatively elsewhere. Patients with bone graft, sclerotic bone debridement, or displacement of the fragment at the nonunion site were excluded. A percutaneous transtrapezial fixation technique was used in all cases. Patients were reviewed until clinical and radiographic union was observed. At the final follow-up, DASH (Disabilities of the Arm, Shoulder and Hand) and PRWHE (Patient-Rated Wrist and Hand Evaluation) outcome scores were completed. Results Radiographic union was obtained in 15 out of 16 patients (94%) at an average follow-up of 36 months (range: 12-98 months). No complications from the percutaneous technique were noted. The average DASH score was 6 (range: 0-39) and the average PRWHE score was 10 (range: 0-56). No statistical significant difference in range of motion and grip strength was found between the operated side and the contralateral side. Conclusion Percutaneous transtrapezial screw fixation for delayed or nonunion of selected scaphoid fractures without bone grafting is promising. At a mean of 4 months, 94% union was obtained with good functional results when there was no sclerosis, minimal osteolysis, and no displacement at the scaphoid nonunion site. Type of Study Therapeutic study. Level of Evidence IV. PMID- 28725499 TI - The Effect of Metacarpophalangeal Joint Hyperextension on Outcomes in the Surgical Treatment of Carpometacarpal Joint Arthritis. AB - Purpose In the surgical treatment of thumb carpometacarpal (CMC) joint arthritis, the effect of mild preoperative metacarpophalangeal (MCP) hyperextension on postoperative functional outcomes is unknown. We sought to examine outcomes after surgical treatment of CMC arthritis in patients with and without mild preexisting MCP deformity. Methods A retrospective review was conducted to analyze the functional outcomes of patients treated for CMC arthritis at a single institution from March 1998 to May 2009. All patients were treated with one of two standard CMC arthroplasty procedures-either ligament reconstruction tendon interposition (LRTI) or a Weilby procedure-and none had additional procedures to address MCP hyperextension. Pre- and postoperative assessments included pinch and grip strength, degree of MCP hyperextension, and thumb radial and palmar abduction. A t -test was used to assume unequal variances. Results A total of 203 patients were followed for an average of 27.3 months. Patients were divided into two groups: (1) patients without preoperative MCP hyperextension (167 patients) and (2) patients with mild but untreated preoperative MCP hyperextension (<= 30 degrees; 36 patients). All patients underwent either a Weilby procedure (118 patients) or an LRTI; 85 patients). The main difference between techniques was the use of the abductor pollicis longus tendon as a post to secure the flexor carpi radialis (Weilby) or the use of a bone tunnel in the first metacarpal (LRTI). Analysis of the preoperative data showed no difference in the baseline parameters among both the groups, with the exception of MCP hyperextension. Postoperatively, neither the type of CMC procedure nor the presence of MCP hyperextension demonstrated any significant differences in key pinch, tip pinch, grip strength, and radial or palmar abduction of the thumb between the groups. Conclusion There were no statistically significant differences in improvement of functional outcomes after surgery when comparing patients without preoperative MCP hyperextension to patients with untreated MCP hyperextension of less than 30 degrees. Level of Evidence Level III, retrospective comparative study. PMID- 28725500 TI - Volar Plate Fixation in Patients Older Than 70 Years with AO Type C Distal Radial Fractures: Clinical and Radiologic Outcomes. AB - Introduction Treatment of unstable distal radial fractures (DRFs) in elderly patients is controversial, and considering the increasing life expectancy, their appropriate treatment is of growing importance. Our aim was to analyze the clinical and radiologic outcomes in the elderly patients with AO type C DRF treated with volar locking plate (VLP). Materials and Methods Between 2007 and 2011, 572 DRFs were operated on in our hospital with open reduction and internal fixation with VLP. Of these, only 64 patients (66 DRFs) met the selection criteria (AO type C DRF, age > 70 years, minimum 12-month follow-up). Mean follow up was 28 months. Outcome assessment included range of motion, grip strength, VAS pain, Mayo Clinic Score, and DASH score. Analysis of pre- and postoperative radiographs was performed. Complications were recorded. Statistical analysis was performed comparing the results with the contralateral side. Results Mean postoperative range of motion of the injured wrist compared with the control contralateral side was 86% for flexion ( p < 0.001), 92% for extension ( p < 0.001). The average DASH was 12. Mayo Clinic Wrist Score showed 43 excellent results, 15 good, 4 satisfactory, and 4 poor. Articular step-offs were reduced in 34 of 38 wrists. Five (7%) patients required plate removal. Conclusion The treatment of articular DRF (AO type C) with VLP in the elderly patients achieved greater than 90% of the wrist range of motion and grip strength with no residual pain in greater than 90% of the patients. Level of Evidence Therapeutic IV, case series. PMID- 28725501 TI - Functional Outcomes of 24-Hour Thumb Immobilization in Healthy Volunteers: Prospective Comparative Study. AB - Background Immobilization is often needed for the treatment of wrist and hand injuries. The current best method of immobilization for several types of injuries has yet to be elucidated with little being reported on the functional differences of each type of immobilization. Purpose The purpose of this study is to compare the functional outcome between healthy young volunteers with a 24-hour short arm cast (SAC) versus thumb spica cast (TSC) immobilization. Methods A total of 50 healthy volunteers completed a baseline typing assessment and a Patient-Reported Outcomes Measurement Information System (PROMIS) upper extremity functional scoring assessment. Participants in group 1 were randomly initially assigned to a TSC of their dominant hand followed by an SAC, whereas participants in group 2 were randomly initially assigned to a TSC of their nondominant hand followed by an SAC. The volunteers completed the typing assessment and PROMIS assessment at the end of the 24-hour casting period. Results A total of 50 participants were enrolled in the study with 25 in group 1 and 25 in group 2. There was a 24.3 point difference between the average PROMIS score for participants with SAC compared with participants with TSC (93 vs. 68.7; p = 0.0001). There was a significant difference between the typing speed and accuracy of participants with SAC compared with participants with TSC ( p = 0.0001). Conclusion There is a significant difference in functionality of a TSC immobilization versus an SAC immobilization according to the PROMIS functional outcome score and typing speed in a 24-hour casting period. SAC immobilization should be considered to have a possible similar effect in pathologic conditions instead of TSC immobilization given these findings even though a 24-hour period is not enough to provide adequate long-term conclusions. Level of Evidence I, prospective comparative study. PMID- 28725502 TI - Universal 2 Wrist Arthroplasty in Rheumatoid Arthritis. AB - Purpose The aim of this study was to evaluate the mid- to long-term outcomes and complications in patients affected by rheumatic diseases treated with the Universal 2 (U2) total wrist arthroplasty (TWA). Methods We reviewed, in a retrospective, noncontrolled cohort study, 22 patients affected by rheumatoid arthritis (RA), who underwent U2 total wrist replacement between March 2003 and January 2014 for the treatment of 23 rheumatoid wrists with the aim of obtaining the remission of pain and a range of motion (ROM) useful for daily activities, according to the patients' demands, as an alternative to total wrist arthrodesis. The cohort of patients included 20 females and 2 males, with a mean age of 54.9 years. Residual pain, preoperative ROM, postoperative ROM increases, grip strength, radiographic changes, long-term complications, and reasons for revision or failures were evaluated. Results In this study, 22 patients were evaluated at a mean follow-up of 82.3 months (range: 2-12 years). All patients had good or complete pain relief, the mean visual analogue scale pain score was 0.82. The mean grip strength improved and postoperatively was 11 kg (Jamar). The mean total ROM of flexion-extension was 72.3 degrees; radial-ulnar deviation 24.9 degrees. The mean QuickDASH score of 49 and patient rate wrist/hand evaluation of 41.7 a revision surgical procedure in six cases (26%): in two cases, a carpal component revision procedure and in four cases, total implant failures requiring either conversion to a Swanson spacer or wrist joint fusion. Conclusion TWA provides pain relief, preserves motion, and improves function in severe degenerative RA. Our results at a mid- to long-term follow-up with the U2 prosthesis were encouraging and represent, when indicated, a valid alternative to fusion which is less appealing for RA patients. Level of Evidence Level of evidence is therapeutic IV. PMID- 28725503 TI - Patient-Rated Wrist Evaluation: Spanish Version and Evaluation of Its Psychometric Properties in Patients with Acute Distal Radius Fracture. AB - Purpose The purpose of this paper is to validate a Spanish version of patient rated wrist evaluation (PRWE) and evaluate its psychometric attributes in a population of patients with distal radius fracture. Material and Methods A translation and cross-cultural adaptation of the PRWE to Spanish (PRWE-S) was performed according to standardized guidelines. A total of 50 patients with a distal radius fracture were included during the different steps of the study. The reliability of the new instrument was assessed in terms of construct validity with the Quick DASH (Disability of the Arm, Shoulder, and Hand). Internal consistency and test-retest stability were also examined. Results The Spearman's correlation test for analysis of the criterion validity (0.75) indicates a strong positive correlation between the PRWE-S and the Quick DASH. The internal consistency according to Cronbach's alpha was 0.96, and the intraclass correlation coefficient was moderate (0.46). Conclusion A Spanish version of the PRWE indicated good validity and reliability in distal radius fracture patients. This valuable tool can be used in Spanish-speaking countries to evaluate various aspects as pain and function in patients with injuries of the wrist. PMID- 28725504 TI - Patients at Increased Risk of Major Adverse Events Following Operative Treatment of Distal Radius Fractures: Inpatient versus Outpatient. AB - Purpose The purpose of this study was to compare complication rates following inpatient versus outpatient distal radius fracture ORIF and identify specific complications that occur at increased rates among inpatients. Methods Using the 2005-2013 ACS-NSQIP, we collected patient demographics, comorbidities, surgical characteristics, and 30-day postoperative complications following isolated ORIF of distal radius fractures. A propensity score matched design using an 8-to-1 "greedy" matching algorithm in a 1:4 ratio of inpatients to outpatients was utilized. Rates of minor, major, and total complications were compared. A multinomial logistic regression model was then used to assess the odds of complications following inpatient surgery. Results Total 4,016 patients were identified, 776 (19.3%) of whom underwent inpatient surgery and 3,240 (80.3%) underwent outpatient surgery. The propensity score matching algorithm yielded a cohort of 629 inpatients who were matched with 2,516 outpatients (1:4 ratio). After propensity score matching, inpatient treatment was associated with increased rates of major and total complications but not with minor complications. There was an increased odds of major complications and total complications following inpatient surgery compared with outpatient surgery. There was no difference in odds of minor complications between groups. Conclusion Inpatient operative treatment of distal radius fractures is associated with significantly increased rates of major and total complications compared with operative treatment as an outpatient. Odds of a major complication are six times higher and odds of total complications are two and a half times higher following inpatient distal radius ORIF compared with outpatient. Quality improvement measures should be specifically targeted to patients undergoing distal radius fracture ORIF in the inpatient setting. PMID- 28725505 TI - Long Volar Plating for Metadiaphyseal Fractures of Distal Radius: Study Comparing Minimally Invasive Plate Osteosynthesis versus Conventional Approach. AB - Background Minimally invasive plate osteosynthesis (MIPO) has been used in wrist surgery for several years. The purpose of this retrospective study was to compare clinical and radiologic outcomes of MIPO technique with those of a conventional approach in the treatment of metadiaphyseal distal radius fracture by long volar plating. Materials and Methods Our series consisted of 32 fractures in 31 patients, mean age 63.9 years, including 16 men and 15 women. MIPO technique was used in 15 wrists (group 1) and conventional approach (> 60 mm of skin incision) in 17 wrists (group 2). In group 1, a long volar plate was inserted under pronator quadratus through a 15- to 30-mm distal incision then fixed to the epiphysis of the distal radius. Then, through a 15- to 30-mm proximal incision, the plate was fixed to the diaphysis of the radius, thus reducing the fracture. Results In group 1, mean distal incision size was 23.5 and 16.9 mm for proximal one. Mean total scar size (sum of both distal and proximal incisions) was 40.0 mm in group 1 and 84.1 mm in group 2. Mean tourniquet time was 58.4 minutes in group 1 and 68.9 minutes in group 2. At latest follow-up, no significant difference was noted in both the groups concerning pain, quick-DASH score, grip strength, ROM, and radiologic data. One extensor pollicis longus rupture treated by tendon transfer was done in group 1. Conclusion The MIPO technique for metadiaphyseal fractures of the distal radius by long volar plating has cosmetic and economic advantages compared with the conventional approach. Conversion to conventional approach is possible at any time in case of technical difficulties. Level of Evidence III. PMID- 28725506 TI - An Aberrant Abductor Digiti Minimi Muscle Crossing Guyon's Canal. AB - Anomalous hypothenar muscles in the wrist are relatively common with 47% prevalence, and their possible consequences associated with Guyon's canal are well known. The accessory of the abductor digiti minimi muscle (ADM) is known to be one of the causes of ulnar tunnel syndrome or ulnar artery thrombosis. A unique ADM was found in the volar wrist region of an 87-year-old male cadaver passing through Guyon's canal. PMID- 28725507 TI - Giant Cell Tumor of the Capitate Treated with Excision and Midcarpal Fusion. AB - Background Giant cell tumor (GCT) of bone is rare in the carpus, and only 11 cases have been reported in the capitate bone. The problem with this location is the high recurrence rate due to easy extension to the adjacent joint spaces and bones. We describe a case of GCT on the capitate bone and the treatment in comparison with the previously reported cases. Case Description The case report concerns a 48-year-old woman with a GCT of the capitate diagnosed on curettage. The treatment consisted of large resection with the lunatum and third metacarpal arthrodesis, with a successful union at 2 years follow-up, no recurrence, and an improved function of the wrist. Literature Review When treated by curettage (alone or with adjuvant procedures), the GCT of the capitate recurred in four out of five cases. All tumors treated with large resection did not recur. Clinical Relevance Recommended treatment of GCT of the capitate is resection with carpometacarpal arthrodesis. PMID- 28725508 TI - The Anatomy of the Dorsal Capsulo-Scapholunate Septum: A Cadaveric Study. AB - Background Tears of the dorsal radiocarpal capsule at the level of the scapholunate interosseous ligament (SLIL) have recently been described in association with predynamic scapholunate instability. Purpose The aim of this anatomical study of the dorsal capsulo-scapholunate septum (DCSS) was to examine the connection of the dorsal capsule on the SLIL and dorsal intercarpal ligament (DICL). Methods Fourteen fresh frozen wrists from seven adult cadavers were dissected through a dorsal approach. Any dorsal attachment of the DICL on the dorsal surface of the SLIL, that is, the DCSS, was identified and measured (height and width). Results The DCSS was consistently found connecting the DICL, the dorsal radiocarpal capsule, and the dorsal aspect of the SLIL. It was formed by the confluence of three arches like intersecting ribs in gothic architecture. The mean dimensions of the DCSS were 5.8 mm in height and 4.0 mm in maximum width. Conclusion The DCSS that connects the SLIL with the dorsal capsule and DICL could be a constant structure of dorsal wrist. Further investigation is required to study the histology of the DCSS and its biomechanical properties in isolation to know whether the DCSS can be considered a secondary stabilizer of the scapholunate ligament complex. Clinical Relevance A better anatomical knowledge of scapholunate ligament complex could help understand and manage instability of the wrist. PMID- 28725509 TI - Saving Tendons on Distal Radius Fractures: A Simple Surgical Pearl to Prevent FPL Tendon Conflict with Volar Locking Plates. AB - Injury to the flexor pollicis longus (FPL) tendon is one of the most frequent complications when fixing distal radius fractures with the volar locking plates. The author proposed a simple surgical technique providing a reliable soft tissue protection to prevent friction on the FPL with the volar locking plate, using a flap of the FCR sheath sutured to attachments of the volar capsule on the lunate buttress facet of the distal radius. PMID- 28725510 TI - A Critical Appraisal of Vascularized Bone Grafting for Scaphoid Nonunion. AB - Background Vascularized bone grafting (VBG) has the potential to yield reliable results in scaphoid nonunion; however, results across studies have been highly variable. This study critically evaluates surgical techniques, fracture location, and patient selection in relation to radiographic, clinical, and patient-centered outcomes after VBG for scaphoid nonunion. Methods We conducted a systematic review of the literature for the use of VBG in scaphoid nonunion. Physical examination, radiographic, and patient-centered outcomes were assessed. Four substratifications were performed: the location of scaphoid nonunion, pedicled versus free technique, Kirschner wire (K-wire) versus screw fixation, and VBG done as a primary versus revision procedure. Results A total of 41 publications were included in final analysis. VBG had an 84.7% union rate at 13 weeks after surgery. On an average, 89% of patients returned to preinjury activity levels by 18 weeks after surgery and 91% of patients reported satisfaction with the procedure. Proximal pole nonunions demonstrated similar union rates but lower functionality scores compared with nonunions across all regions of the scaphoid. Pedicled techniques demonstrated slightly improved range of motion compared with free technique. K-wire versus screw fixation demonstrated significantly higher union rates and faster union times. There were no differences in outcomes for VBG done as a primary versus revision procedure. Conclusion VBG serves as a viable option for the treatment of scaphoid nonunion, with consistent union rates in addition to significantly improved postoperative patient functionality. The fixation of these vascularized bone grafts with K-wires versus screw fixation may result in superior radiologic outcomes. Level of Evidence Therapeutic, Level III, systematic review. PMID- 28725511 TI - Erratum: The PARC Lesion: A Posterior Avulsion of the Radiocarpal Capsule. AB - [This corrects the article DOI: 10.1055/s-0036-1584162.]. PMID- 28725512 TI - Strengthening STEM Education through Community Partnerships. AB - California State University San Marcos (CSUSM) and San Marcos Elementary Schools have established a partnership to offer a large-scale community service learning opportunity to enrich science curriculum for K-5 students. It provides an opportunity for science, technology, engineering, and math (STEM) majors to give back to the community, allowing them to experience teaching in an elementary classroom setting, in schools that lack the resources and science instructor specialization needed to instill consistent science curricula. CSUSM responded to this need for more STEM education by mobilizing its large STEM student body to design hands-on, interactive science lessons based on Next Generation Science Standards (NGSS). Since 2012, the program has reached out to over four thousand K 5 students, and assessment data have indicated an increase in STEM academic performance and interest. PMID- 28725513 TI - Facial Nerve Schwannomas Mimicking as Vestibular Schwannomas. AB - Objective The objective of this study was to identify preoperative and intraoperative findings that may aid in distinguishing facial nerve schwannomas (FNS) from vestibular schwannomas (VSs), particularly in cases limited to the internal auditory canal (IAC) and cerebellopontine angle (CPA). Study Design This was a retrospective study. Setting This study was set at a Tertiary Referral Center. Patients Seventeen cases from October 2002 to July 2015 with an IAC/CPA mass presumed to be a VS who were found to have a FNS intraoperatively. Main Outcome Measures The main outcome measures included preoperative presentation, intraoperative findings, and subsequent intervention. Results Preoperative hearing loss and imbalance were seen in 70.5 and 64.7%, respectively. Suspicious intraoperative findings included: facial nerve incorporated intimately with the tumor capsule in 12 cases; spontaneous action potentials noted while drilling the bony IAC in 3 cases; and action potentials noted on stimulation of the entire tumor capsule in 10 cases. The mean long-term facial function was House-Brackmann grade II and the mean length of follow-up was 4.86 years. Conclusion FNSs are rare and may be difficult to distinguish from VS preoperatively. Surgical findings that should raise concern include spontaneous action potentials during drilling the bony IAC, absence of a plane of dissection between the facial nerve and tumor, or stimulation of the tumor capsule. PMID- 28725514 TI - Gamma Knife Stereotactic Radiosurgery for Grade 2 Meningiomas. AB - Purpose This study aims to report long-term clinical outcomes after Gamma Knife radiosurgery (GKRS) for intracranial grade 2 meningiomas. Methods In this Institutional Review Board approved study, we reviewed records of all patients with grade 2 meningiomas treated with GKRS between 1998 and 2014. Results A total of 97 postoperative histopathologically confirmed grade 2 meningiomas in 75 patients were treated and are included in this study. After a mean follow-up of 41 months, 28 meningiomas had local recurrence (29.79%). Median time to local recurrence was 89 months (mean: 69, range: 47-168). The 3- and 5-year actuarial local control (LC) rates were 68.9 and 55.7%, respectively. The 3- and 5-year overall survival rates were 88.6 and 81.1%, respectively. There was a trend toward worse LC with tumors treated with radiation doses <= 13 versus > 13 Gy. There was no radiation necrosis or second malignant tumors noted in our series. Conclusion This report, one of the largest GKRS series for grade 2 meningiomas, demonstrates that GKRS is a safe and effective treatment modality for patients with grade 2 meningiomas with durable tumor control and minimal toxicity. Adjuvant GKRS could be considered as a reasonable treatment approach for patients with grade 2 meningiomas. PMID- 28725515 TI - Quantitative Anterior and Posterior Clinoidectomy Analysis and Mobilization of the Oculomotor Nerve during Surgical Exposure of the Basilar Apex Using Frameless Stereotaxis. AB - Background Anterior and posterior clinoidectomies have been proposed to augment exposure of the basilar apex. A sequential quantitative benefit analysis offered by these maneuvers has not been reported. Methods Fourteen datasets from eight cadaveric specimens were analyzed. A modified orbitozygomatic frontotemporal craniotomy was performed. The extent of proximal control of the basilar artery was determined through the exposed opticocarotid and carotidoculomotor triangles before and after clinoidectomies and mobilization of the third nerve at the porous oculomotarius. Results Removal of the anterior and posterior clinoids significantly improved proximal basilar artery access ( p < 0.012) and increased the opticocarotid triangle and carotidoculomotor triangle areas ( p < 0.017). Surgical freedom increased inferosuperiorally in the opticocarotid triangle following anterior clinoidectomy ( p < 0.047) and in carotidoculomotor triangle following posterior clinoidectomy ( p < 0.047). Mobilization of the third nerve increased surgical freedom in the mediolateral projection of the carotidoculomotor triangle ( p < 0.047). Conclusion Anterior and posterior clinoidectomies significantly improved the area of exposure of the opticocarotid triangle, carotidoculomotor triangle, and the exposed length of the basilar artery available for proximal control. This improvement is extremely important for large or giant aneurysms of the upper basilar artery or aneurysms hidden by the posterior clinoid. PMID- 28725516 TI - How I Do It: The Role of Flexible Hand-held 2MU-Thulium Laser Fiber in Microsurgical Removal of Acoustic Neuromas. AB - Aims We performed a retrospective nonrandomized study to analyze the results of microsurgery of acoustic neuromas (AN) using 2MU-thulium flexible hand-held laser fiber (Revolix jr). Methods From September 2010 to September 2015, 89 patients suffering from AN have been operated on with microsurgical technique via retrosigmoid approach. In 37 cases, tumor resection was performed with the assistance of 2MU-thulium flexible hand-held laser fiber (L-group). Eight cases operated on with the assistance of CO 2 hand-held flexible laser fiber were excluded from this study. A total of 44 patients, operated on without laser assistance during the same period, were used as comparison group (C-group) (matched pair technique). Facial nerve function was assessed with the House Brackmann (HB) scale preoperatively, and 1 week and 6 months postoperatively. Results Overall time from incision to skin suture changed in relation to size of tumor (165-575 minutes) and was not affected by the use of laser. In 7 out of 81 cases, a preoperative facial nerve palsy HB2 and in 1 case, HB4 (permanent) were observed. In the remaining 80 cases, at 6-month follow-up, facial nerve preservation rate (HB1) was 92.5%. Hearing preservation rate (AAO-HNS A/B classes) was 68.2% (26 out of 36). Adopting a 0 to 3 scale, the mean surgeon satisfaction rate of usefulness of laser fiber was 2.7. Conclusion The use of 2MU-thulium hand-held flexible laser fiber in AN microsurgery seems to be safe and subjectively facilitates tumor resection especially in "difficult" conditions (e.g., highly vascularized and hard tumors). In this limited retrospective trial, the good functional outcome following conventional microsurgery had not further improved, nor the surgical time reduced by laser. Focusing its use on "difficult" (large and vascularized) cases may lead to different results in future. PMID- 28725517 TI - Preoperative Embolization for Skull Base Meningiomas. AB - The results of preoperative embolization for skull base meningiomas were retrospectively evaluated to confirm the efficacy of this procedure. Skull base meningiomas that were treated with preoperative embolization were evaluated in 20 patients. The occluded arteries, embolic materials, treatment time, excision rate, neurologic manifestations, and complications were analyzed. The embolic material was 80% liquid, 30% coils, and 15% particles. The surgery was normally completed within 3 to 5 hours. Blood loss was normally approximately 250 mL, excluding four patients having the following conditions: malignant meningioma, a large tumor located on the medial side of the sphenoidal ridge, the petroclival tumor, and infiltrated tumor into the sigmoid sinus. The mean excision rate was 90%, achieving a Simpson grade III, but 10% were graded as Simpson grade IV. No permanent complications due to the preoperative embolization occurred. No neurologic symptoms occurred after excision. Current cerebral endovascular treatment is sophisticated, and the complication rate has markedly decreased. Although it was impossible to compare directly with or without operative embolization, preoperative embolization should be actively used as part of the treatment for this benign tumor, with better understanding of dangerous anastomosis. PMID- 28725518 TI - Preferences and Utilities for Health States after Treatment of Olfactory Groove Meningioma: Endoscopic versus Open. AB - Objectives The purpose of this study is to report health utility scores for patients with olfactory groove meningiomas (OGM) treated with either the standard transcranial approach, or the expanded endonasal endoscopic approach. Design The time trade-off technique was used to derive health utility scores. Setting Healthy individuals without skull base tumors were surveyed. Main Outcome Measures Participants reviewed and rated scenarios describing treatment (endoscopic, open, stereotactic radiation, watchful waiting), remission, recurrence, and complications associated with the management of OGMs. Results There were 51 participants. The endoscopic approach was associated with higher utility scores compared with an open craniotomy approach (0.88 vs. 0.74; p < 0.001) and watchful waiting (0.88 vs.0.74; p = 0.002). If recurrence occurred, revision endoscopic resection continued to have a higher utility score compared with revision open craniotomy (0.68; p = 0.008). On multivariate analysis, older individuals were more likely to opt for watchful waiting ( p = 0.001), whereas participants from higher income brackets were more likely to rate stereotactic radiosurgery with higher utility scores ( p = 0.017). Conclusion The endoscopic approach was associated with higher utility scores than craniotomy for primary and revision cases. The present utilities can be used for future cost-utility analyses. PMID- 28725519 TI - Intracranial Hemangiopericytomas: Recurrence, Metastasis, and Radiotherapy. AB - Background Intracranial hemangiopericytomas (HPCs) are characterized by high recurrence rates and extracranial metastases. Radiotherapy provides an adjunct to surgery, but the timing of therapy and the patients most likely to benefit remain unclear. Methods A retrospective review of 20 patients with HPC treated at the University of Texas Southwestern Medical Center between 1985 and 2014 was conducted. Recurrence and metastasis rates along with overall survival (OS) were characterized based on therapeutic approach and tumor pathology using Kaplan Meier and Cox regression analyses. Results The mean age was 45.6 years (range: 19-77). Gross total resection (GTR) was achieved in 13 patients, whereas 5 patients underwent subtotal resection. Median follow-up was 91.5 months (range: 8 357). The 5-, 10-, and 15-year recurrence-free survival (RFS) rates were 61, 41, and 20%, respectively. Six patients developed metastases at an average of 113 months (range: 42-231). OS at last follow-up was 80%. Importantly, immediate postoperative adjuvant radiotherapy (IRT) did not influence RFS compared with surgery alone or OS compared with delayed radiotherapy at the time of recurrence. Conclusion HPCs have high recurrence rates necessitating close follow-up. Surgery remains an important first step, but the timing of radiotherapy for optimal control and OS remains uncertain. PMID- 28725520 TI - Mucosal Thickening Occurs in Contralateral Paranasal Sinuses following Sinonasal Malignancy Treatment. AB - Objective To investigate the incidence and degree of contralateral sinus disease following treatment of sinonasal malignancy (SNM) using radiological findings as an outcome measure. Study Design Retrospective case series. Setting Tertiary referral academic center. Participants Patients with SNM treated with surgical and adjuvant radiotherapy with or without concurrent chemotherapy. Main Outcome Measures Pre- and posttreatment computed tomography and magnetic resonance imaging scans, Lund-Mackay (LM) score, date of diagnosis, chemotherapy, and dosage of radiation therapy (RT). Results There was a significant difference between pre- and posttreatment LM scores ( p < 0.001) of the contralateral paranasal sinuses. There was no statistical significance between the change in pre- and posttreatment LM scores and patient age, gender, chemotherapy, RT dosage, and time lapse between diagnosis and when we performed this study in the univariate and the multivariable analyses. Conclusions Following treatment of SNM with surgical resection and RT, there was a significant increase in incidence and degree of mucosal thickening of the contralateral sinus by LM grading that persisted after the completion of treatment. This indicates the need for long term follow-up to monitor for chronic rhinosinusitis as a delayed complication following treatment of SNM. PMID- 28725521 TI - Naso- or Orbitocutaneous Fistulas after Free Flap Reconstruction of Orbital Exenteration Defects: Retrospective Study, Systematic Review, and Meta-Analysis. AB - Objective Naso- or orbitocutaneous fistula (NOF) is a challenging complication of orbital exenteration, and it often requires surgical repair. We sought to identify the incidence and risk factors for NOF after orbital exenteration. Study Design Retrospective chart review, systematic review, meta-analysis. Setting Tertiary care center. Participants Patients undergoing free flap reconstruction following orbital exenteration. Records were reviewed for clinicopathologic data, operative details, and outcomes. Main Outcome Measures Univariate analysis was used to assess risk factors for incidence of postoperative NOF. PubMed and Cochrane databases were searched for published reports on NOF after orbital exenteration. Rates of fistula and odds ratios for predictive factors were compared in a meta-analysis. Results Total 7 of 77 patients (9.1%) developed NOF; fistula formation was associated with ethmoid sinus involvement ( p < 0.05) and minor wound break down ( p < 0.05). On meta-analysis, pooled rates of fistula formation were 5.8% for free flap patients and 12.5% for patients receiving no reconstruction. Conclusion Immediate postoperative wound complications and medial orbital wall resection increased the risk for NOF. On review and meta-analysis, reconstruction of orbital exenteration defects decreased the risk for fistula formation, but published series did not demonstrate a significant decrease in risk with free flaps compared with other methods of reconstruction. PMID- 28725522 TI - Pathogenetic Analysis of Sinonasal Teratocarcinosarcomas Reveal Actionable beta catenin Overexpression and a beta-catenin Mutation. AB - Objective Sinonasal teratocarcinosarcomas are rare, aggressive tumors of the skull base. Treatment options are limited and outcomes are poor. Little is known in regard to the genetic factors regulating these tumors. Characterization of actionable molecular alterations in these tumors could provide potentially successful therapeutic options. Methods We performed targeted exome sequencing on an index sinonasal teratocarcinosarcoma specimen to identify potential driver mutations. We performed immunohistochemical stains for beta-catenin on paraffin embedded tissue on the index tumor and a subsequent teratocarcinosarcoma. Online databases of cancer mutations (Catalogue of Somatic Mutations in Cancer and The Cancer Genome Atlas) were accessed. Results We identified an activating p.S45F mutation in beta-catenin in our index sinonasal teratocarcinosarcoma. This mutation results in constitutive signaling in the Wnt/beta-catenin pathway. We confirmed beta-catenin overexpression and nuclear localization via immunohistochemistry in the index tumor and a second patient. The p.S45F activating mutation was found in a variety of solid tumors, and accounts for 3.3 to 10.4% of all known beta-catenin mutations. Conclusion We identified a potential driver mutation in beta-catenin in a sinonasal teratocarcinosarcoma, resulting in beta-catenin overexpression. These findings suggest a role for the Wnt/beta-catenin pathway in sinonasal teratocarcinosarcoma tumorigenesis and a role for anti-beta-catenin targeted therapy. PMID- 28725523 TI - A Method of Locating the Dehiscence during Middle Fossa Approach for Superior Semicircular Canal Dehiscence Surgery. AB - Objectives Superior semicircular canal dehiscence (SSCD) results from a defect in the middle cranial fossa floor. One challenge during SSCD repair is the lack of a consistent landmark. This study proposes a reference point above the external auditory canal at the level of the zygoma as the inferior craniectomy edge during surgery. Design This is a retrospective review of patients with SSCD. Setting/Participants A total of 72 cases of SSCD in 60 patients were repaired via a middle fossa approach at a single institution. Main Outcome Measures The distance from the proposed reference point to the dehiscence was statistically analyzed using Shapiro-Wilk's goodness-of-fit test and Student's t test. Results Average distance for all patients was 28.84 +/- 2.22 mm (range: 22.96-33.43). Average distance for females was 29.08 mm (range: 24.56-33.43) versus 28.26 mm (range: 22.96-32.36) for males. There was no difference in distance by sex ( p = 0.174). The distance measurements followed a normal distribution with 95% of the patients between 24.49 and 33.10 mm. Conclusion This study analyzed a potential reference point during a middle fossa approach for SSCD surgery. The distance from this reference point to the SSCD was found to be consistent and may serve as a readily identifiable landmark in localizing the dehiscence. PMID- 28725524 TI - Spin-polarized scanning tunneling microscopy with quantitative insights into magnetic probes. AB - Spin-polarized scanning tunneling microscopy and spectroscopy (spin-STM/S) have been successfully applied to magnetic characterizations of individual nanostructures. Spin-STM/S is often performed in magnetic fields of up to some Tesla, which may strongly influence the tip state. In spite of the pivotal role of the tip in spin-STM/S, the contribution of the tip to the differential conductance dI/dV signal in an external field has rarely been investigated in detail. In this review, an advanced analysis of spin-STM/S data measured on magnetic nanoislands, which relies on a quantitative magnetic characterization of tips, is discussed. Taking advantage of the uniaxial out-of-plane magnetic anisotropy of Co bilayer nanoisland on Cu(111), in-field spin-STM on this system has enabled a quantitative determination, and thereby, a categorization of the magnetic states of the tips. The resulting in-depth and conclusive analysis of magnetic characterization of the tip opens new venues for a clear-cut sub nanometer scale spin ordering and spin-dependent electronic structure of the non collinear magnetic state in bilayer high Fe nanoislands on Cu(111). PMID- 28725525 TI - Microbial degradation of petrochemical waste-polycyclic aromatic hydrocarbons. AB - BACKGROUND: Petrochemical industry is one of the fastest growing industries. This industry has immense importance in the growth of economy and manufacture of large varieties of chemicals. The petrochemical industry is a hazardous group of industry generating hazardous waste containing organic and inorganic compounds. In spite of the present treatment process, the hazardous waste compounds are found untreated to the acceptable level and found discharged at soil-water environment resulting into the persistent organic-inorganic pollutant into the environment. The bioremediation will be the innovative techniques to remove the persistent pollutants in the environment. RESULT: Petrochemical contaminated site was found to be a rich source of microbial consortium degrading polycyclic aromatic hydrocarbons. Indigenous microbial consortiums were identified and used for bioremediation of polycyclic aromatic hydrocarbons (naphthalene and anthracene) at the concentrations of 250, 500, and 750 ppm. The potential microorganism was also identified for naphthalene and anthracene, and their bioremediation was studied at varying concentrations. The bioremediation with consortium was found to be comparatively more effective than the potential microorganism used for bioremediation of each compound. Pseudomonas aeruginosa a potential organism was identified by 16S rRNA and further studied for the gene responsible for the PAH compounds. CONCLUSION: Indigenous microorganism as a consortium has been found effective and efficient source for remediation of organic compound-Polycyclic aromatic hydrocarbon and this will also be applicable to remediate the toxic compounds to clean up the environment. PMID- 28725526 TI - The Strong Light-Emission Materials in the Aggregated State: What Happens from a Single Molecule to the Collective Group. AB - The strong light emission of organic luminogens in the aggregated state is essential to their applications as optoelectronic materials with good performance. In this review, with respect to the aggregation-induced emission and room-temperature phosphorescence luminogens, the important role of molecular packing modes is highlighted. As demonstrated in the selected examples, the molecular packing status in the aggregate state is affected by many factors, including the molecular configurations, the inherent electronic properties, the special functional groups, and so on. With the consideration of all these parameters, the strong fluorescence and phosphorescence in the aggregated state could be achieved in the rationally designed organic luminogens, providing some guidance for the further development. PMID- 28725527 TI - Taking Electrons out of Bioelectronics: From Bioprotonic Transistors to Ion Channels. AB - From cell-to-cell communication to metabolic reactions, ions and protons (H+) play a central role in many biological processes. Examples of H+ in action include oxidative phosphorylation, acid sensitive ion channels, and pH dependent enzymatic reactions. To monitor and control biological reactions in biology and medicine, it is desirable to have electronic devices with ionic and protonic currents. Here, we summarize our latest efforts on bioprotonic devices that monitor and control a current of H+ in physiological conditions, and discuss future potential applications. Specifically, we describe the integration of these devices with enzymatic logic gates, bioluminescent reactions, and ion channels. PMID- 28725528 TI - Battery-Supercapacitor Hybrid Devices: Recent Progress and Future Prospects. AB - Design and fabrication of electrochemical energy storage systems with both high energy and power densities as well as long cycling life is of great importance. As one of these systems, Battery-supercapacitor hybrid device (BSH) is typically constructed with a high-capacity battery-type electrode and a high-rate capacitive electrode, which has attracted enormous attention due to its potential applications in future electric vehicles, smart electric grids, and even miniaturized electronic/optoelectronic devices, etc. With proper design, BSH will provide unique advantages such as high performance, cheapness, safety, and environmental friendliness. This review first addresses the fundamental scientific principle, structure, and possible classification of BSHs, and then reviews the recent advances on various existing and emerging BSHs such as Li-/Na ion BSHs, acidic/alkaline BSHs, BSH with redox electrolytes, and BSH with pseudocapacitive electrode, with the focus on materials and electrochemical performances. Furthermore, recent progresses in BSH devices with specific functionalities of flexibility and transparency, etc. will be highlighted. Finally, the future developing trends and directions as well as the challenges will also be discussed; especially, two conceptual BSHs with aqueous high voltage window and integrated 3D electrode/electrolyte architecture will be proposed. PMID- 28725530 TI - Smart Fluid Systems: The Advent of Autonomous Liquid Robotics. AB - Organic, inorganic or hybrid devices in the liquid state, kept in a fixed volume by surface tension or by a confining membrane that protects them from a harsh environment, could be used as biologically inspired autonomous robotic systems with unique capabilities. They could change shape according to a specific exogenous command or by means of a fully integrated adaptive system, and provide an innovative solution for many future applications, such as space exploration in extreme or otherwise challenging environments, post-disaster search and rescue in ground applications, compliant wearable devices, and even in the medical field for in vivo applications. This perspective provides an initial assessment of existing capabilities that could be leveraged to pursue the topic of "Smart Fluid Systems" or "Liquid Engineered Systems". PMID- 28725529 TI - Recent Progress on Piezoelectric and Triboelectric Energy Harvesters in Biomedical Systems. AB - Implantable medical devices (IMDs) have become indispensable medical tools for improving the quality of life and prolonging the patient's lifespan. The minimization and extension of lifetime are main challenges for the development of IMDs. Current innovative research on this topic is focused on internal charging using the energy generated by the physiological environment or natural body activity. To harvest biomechanical energy efficiently, piezoelectric and triboelectric energy harvesters with sophisticated structural and material design have been developed. Energy from body movement, muscle contraction/relaxation, cardiac/lung motions, and blood circulation is captured and used for powering medical devices. Other recent progress in this field includes using PENGs and TENGs for our cognition of the biological processes by biological pressure/strain sensing, or direct intervention of them for some special self-powered treatments. Future opportunities lie in the fabrication of intelligent, flexible, stretchable, and/or fully biodegradable self-powered medical systems for monitoring biological signals and treatment of various diseases in vitro and in vivo. PMID- 28725531 TI - Computational Insights into Materials and Interfaces for Capacitive Energy Storage. AB - Supercapacitors such as electric double-layer capacitors (EDLCs) and pseudocapacitors are becoming increasingly important in the field of electrical energy storage. Theoretical study of energy storage in EDLCs focuses on solving for the electric double-layer structure in different electrode geometries and electrolyte components, which can be achieved by molecular simulations such as classical molecular dynamics (MD), classical density functional theory (classical DFT), and Monte-Carlo (MC) methods. In recent years, combining first-principles and classical simulations to investigate the carbon-based EDLCs has shed light on the importance of quantum capacitance in graphene-like 2D systems. More recently, the development of joint density functional theory (JDFT) enables self-consistent electronic-structure calculation for an electrode being solvated by an electrolyte. In contrast with the large amount of theoretical and computational effort on EDLCs, theoretical understanding of pseudocapacitance is very limited. In this review, we first introduce popular modeling methods and then focus on several important aspects of EDLCs including nanoconfinement, quantum capacitance, dielectric screening, and novel 2D electrode design; we also briefly touch upon pseudocapactive mechanism in RuO2. We summarize and conclude with an outlook for the future of materials simulation and design for capacitive energy storage. PMID- 28725532 TI - Paper-Based Electrodes for Flexible Energy Storage Devices. AB - Paper-based materials are emerging as a new category of advanced electrodes for flexible energy storage devices, including supercapacitors, Li-ion batteries, Li S batteries, Li-oxygen batteries. This review summarizes recent advances in the synthesis of paper-based electrodes, including paper-supported electrodes and paper-like electrodes. Their structural features, electrochemical performances and implementation as electrodes for flexible energy storage devices including supercapacitors and batteries are highlighted and compared. Finally, we also discuss the challenges and opportunity of paper-based electrodes and energy storage devices. PMID- 28725535 TI - High Impact of Advanced Science. PMID- 28725533 TI - Controllable Photodynamic Therapy Implemented by Regulating Singlet Oxygen Efficiency. AB - With singlet oxygen (1O2) as the active agent, photodynamic therapy (PDT) is a promising technique for the treatment of various tumors and cancers. But it is hampered by the poor selectivity of most traditional photosensitizers (PS). In this review, we present a summary of controllable PDT implemented by regulating singlet oxygen efficiency. Herein, various controllable PDT strategies based on different initiating conditions (such as pH, light, H2O2 and so on) have been summarized and introduced. More importantly, the action mechanisms of controllable PDT strategies, such as photoinduced electron transfer (PET), fluorescence resonance energy transfer (FRET), intramolecular charge transfer (ICT) and some physical/chemical means (e.g. captivity and release), are described as a key point in the article. This review provide a general overview of designing novel PS or strategies for effective and controllable PDT. PMID- 28725534 TI - Photoinitiated Polymerization-Induced Self-Assembly (Photo-PISA): New Insights and Opportunities. AB - The polymerization-induced self-assembly (PISA) process is a useful synthetic tool for the efficient synthesis of polymeric nanoparticles of different morphologies. Recently, studies on visible light initiated PISA processes have offered a number of key research opportunities that are not readily accessible using traditional thermally initiated systems. For example, visible light mediated PISA (Photo-PISA) enables a high degree of control over the dispersion polymerization process by manipulation of the wavelength and intensity of incident light. In some cases, the final nanoparticle morphology of a single formulation can be modulated by simple manipulation of these externally controlled parameters. In addition, temporal (and in principle spatial) control over the Photo-PISA process can be achieved in most cases. Exploitation of the mild room temperature polymerizations conditions can enable the encapsulation of thermally sensitive therapeutics to occur without compromising the polymerization rate and their activities. Finally, the Photo-PISA process can enable further mechanistic insights into the morphological evolution of nanoparticle formation such as the effects of temperature on the self-assembly process. The purpose of this mini-review is therefore to examine some of these recent advances that have been made in Photo-PISA processes, particularly in light of the specific advantages that may exist in comparison with conventional thermally initiated systems. PMID- 28725536 TI - Choosing Cell Fate Through a Dynamic Cell Cycle. AB - A close relationship between proliferation and cell fate specification has been well documented in many developmental systems. In addition to the gradual cell fate changes accompanying normal development and tissue homeostasis, it is now commonly appreciated that cell fate could also undergo drastic changes, as illustrated by the induction of pluripotency from many differentiated somatic cell types during the process of Yamanaka reprogramming. Strikingly, the drastic cell fate change induced by Yamanaka factors (Oct4, Sox2, Klf4, and c-Myc) is preceded by extensive cell cycle acceleration. Prompted by our recent discovery that progression toward pluripotency from rare somatic cells could bypass the stochastic phase of reprogramming and that a key feature of these somatic cells is an ultrafast cell cycle (~8 h/cycle), we assess whether cell cycle dynamics could provide a general framework for controlling cell fate. Several potential mechanisms on how cell cycle dynamics may impact cell fate determination by regulating chromatin, key transcription factor concentration, or their interactions are discussed. Specific challenges and implications for studying and manipulating cell fate are considered. PMID- 28725537 TI - The Emerging Role of Histone Demethylases in Renal Cell Carcinoma. AB - Renal cell carcinoma (RCC), the most common kidney cancer, is responsible for more than 100,000 deaths per year worldwide. The molecular mechanism of RCC is poorly understood. Many studies have indicated that epigenetic changes such as DNA methylation, noncoding RNAs, and histone modifications are central to the pathogenesis of cancer. Histone demethylases (KDMs) play a central role in histone modifications. There is emerging evidence that KDMs such as KDM3A, KDM5C, KDM6A, and KDM6B play important roles in RCC. The available literature suggests that KDMs could promote RCC development and progression via hypoxia-mediated angiogenesis pathways. Small-molecule inhibitors of KDMs are being developed and used in preclinical studies; however, their clinical relevance is yet to be established. In this mini review, we summarize our current knowledge on the putative role of histone demethylases in RCC. PMID- 28725538 TI - A Rare Case of Solitary Kidney Metastasis Following Primary Laryngeal Squamous Cell Carcinoma. AB - Laryngeal cancer is the 14th most common malignancy worldwide, and its common subtype squamous cell carcinoma (SCC) is highly associated with tobacco use and long-term alcohol consumption. The incidence of distant metastasis from a primary laryngeal cancer has been reported to be very low, between 6.5% and 8.5%, according to published tumour registry data. Distant metastases of laryngeal SCC most commonly involve the lung, liver, bone and mediastinum, seldom involving the kidney. Renal metastasis has been well established in many other cancers such as lymphoma, lung, breast and gastric carcinoma. This report discusses the rare case of a solitary renal metastasis following a primary laryngeal SCC. PMID- 28725540 TI - The Pathology and Molecular Genetics of Sarcomatoid Renal Cell Carcinoma: A Mini Review. AB - Sarcomatoid renal cell carcinoma is a highly aggressive tumor. It is not a distinct histologic entity as it can be found in any subtypes of renal cell carcinoma. Recent molecular and genetic evidence suggest that sarcomatoid component is transformed from a common progenitor of the associated renal cell carcinoma, and the TP53 gene plays a pivotal role in this process. The presence of sarcomatoid carcinoma indicates poor prognosis, which also correlates with the amount of the sarcomatoid component. Therefore, the presence and quantity of sarcomatoid component should be reflected in pathology reports. However, pathology reporting seems to vary among laboratories prompting the need for a unified reporting system. We propose a pathology reporting system similar to that of transformed follicular lymphoma that is consistent with the molecular pathogenesis to ensure uniform reporting. PMID- 28725539 TI - The Evolving Treatment Landscape of Advanced Renal Cell Carcinoma in Patients Progressing after VEGF Inhibition. AB - Despite significant changes in the therapeutic landscape of renal cell carcinoma, the majority of patients with metastatic disease eventually progress after first line treatment with vascular endothelial growth factor receptors (VEGFR) tyrosine kinase inhibitor (TKI) therapy. Understanding existing data on subsequent therapies is crucial to define an optimal treatment sequence following first-line failure. This review examines the data supporting currently approved agents in this setting and provides a framework for decision-making regarding treatment sequencing beyond first-line therapy with VEGFR TKIs. PMID- 28725541 TI - Delayed Intervention of Small Renal Masses on Active Surveillance. AB - Although surgical excision is the standard of therapy for small renal masses (SRMs), there is a growing recognition of active surveillance as an option in select patients who are poor surgical candidates or who have shorter life expectancy. A number of patients on expectant management, however, subsequently advance to definitive therapy. In this study, we systematically reviewed the literature and performed a pooled analysis of active surveillance series to evaluate the rate and indications for definitive treatment after initiating a period of active surveillance. Fourteen clinical series (1245 patients; 1364 lesions) met our selection criteria. Mean lesion size at presentation was 2.30 +/ 0.40 cm with a mean follow-up of 33.6 +/- 16.9 months. Collectively, 34.0% of patients underwent delayed intervention, which ranged in individual series from 3.6% to 70.3%. Of patients undergoing delayed intervention, the average time on active surveillance prior to definitive treatment was 27.8 +/- 10.6 months. A pooled analysis revealed that 41.0% of patients underwent therapy secondary to tumor growth rate and 51.9% secondary to patient or physician preference in the absence of clinical progression. Overall, 1.1% of all patients progressed to metastatic disease during the average follow-up period. Thus, active surveillance may be an appropriate option for carefully selected patients with SRMs. However, delayed treatment is pursued in a significant percentage of patients within 3 years. Prospective registries and clinical trials with standardized indications for delayed intervention are needed to establish true rates of disease progressions and recommendations for delayed intervention. PMID- 28725542 TI - Self-reported health and behavioral factors are associated with metabolic syndrome in Americans aged 40 and over. AB - To determine whether behavioral factors differ among metabolic conditions and self-reported health, and to determine whether self-reported health is a valid predictor of metabolic syndrome (MetS). A total of 2997 individuals (>= 40 years old) were selected from four biennial U.S. National Health and Nutrition Examination Surveys (2007-2014). A set of weighted logistic regression models were used to estimate the odds ratios (ORs) and 95% confidence intervals (CIs)Individuals with light physical activity are more likely to have MetS and report poor health than those with vigorous physical activity with OR = 3.22 (95% CI: 2.23, 4.66) and 4.52 (95% CI: 2.78, 7.33), respectively. Individuals eating poor diet have greater odds of developing MetS and reporting poor health with OR = 1.32 (95% CI: 1.05, 1.66) and 3.13 (95% CI: 2.46, 3.98). The aforementioned relationships remained significant after adjustment for demographic and socio economic status. A potential intervention strategy will be needed to encourage individuals to aggressively improve their lifestyle to reduce MetS and improve quality of life. Despite the significant association between self-reported health with MetS, a low sensitivity indicated that better screening tools for MetS, diabetes and cardiovascular disease are essential. PMID- 28725543 TI - Exploring parents' screen-viewing behaviours and sedentary time in association with their attitudes toward their young child's screen-viewing. AB - Sedentary time and screen-viewing (SV) are associated with chronic disease risk in adults. Parent and child sedentary time and SV are associated. Parents influence children's SV through parenting styles and role modelling. Understanding whether parents' attitudes toward child SV are associated with their own SV and sedentary time will aid development of family interventions to reduce sedentary behaviours. Cross-sectional data with 809 parents from Bristol, UK were collected in 2012-2013 and analysed in 2016. Parental total sedentary time was derived from accelerometer data. Parents self-reported daily television viewing, use of computers, games consoles, and smartphone/tablets (none, 1-59 min, 1-2 h, > 2 h) and attitudes toward child SV. Adjusted linear and logistic regression models were used to examine associations, separately for weekdays and weekend days. Having negative attitudes toward child SV was associated with lower weekend sedentary time (Coeff: - 6.41 [95% CI: - 12.37 to - 0.45] min/day). Limiting behaviours and having negative attitudes toward child SV were associated with lower weekday television viewing (OR: 0.72 [0.57-0.90] and 0.57 [0.47-0.70] respectively), weekend television viewing (0.75 [0.59-0.95] and 0.61 [0.50 0.75]), and weekend computer use (0.73 [0.58-0.92] and 0.80 [0.66-0.97]). Negative attitudes were also associated with lower smartphone use on weekdays (0.70 [0.57-0.85]) and weekends (0.70 [0.58-0.86]). Parent self-efficacy for limiting child SV and setting SV rules were not associated with sedentary time or SV. Reporting negative attitudes toward child SV was associated with lower accelerometer-assessed weekend total sedentary time and self-reported SV behaviours, while limiting child SV was also associated with lower self-reported SV. PMID- 28725544 TI - Successful haploidentical stem cell transplantation with prophylactic administration of liposomal amphotericin B after invasive pulmonary zygomycosis. AB - A 54-year-old woman with acute myeloid leukemia (AML) achieved complete remission by induction chemotherapy, but developed zygomycosis after consolidation therapy. As zygomycosis could not be cured by liposomal amphotericin B and micafungin, left lower lobectomy was performed. As AML relapsed 7 months after onset, she received haploidentical stem cell transplantation under administration of liposomal amphotericin B. Despite experiencing severe acute graft-versus-host disease, she remains alive with no relapse of either zygomycosis or AML. PMID- 28725545 TI - A severe transmissible Majocchi's granuloma in an immunocompetent returned traveler. AB - Severe dermatophyte infection is rare in immunocompetent adults. Recently cases have been described in travelers returning from South East Asia (Luchsinger et al., 2015) [1]. These may be sexually transmitted and can have permanent sequelae. We describe the first reported case of Majocchi's granuloma (MG) in an Australian returned traveler and its subsequent transmission via sexual contact. Both patients were successfully treated with systemic antifungals. MG should be considered in patients with severe rash after travel to South East Asia. PMID- 28725546 TI - Pulmonary involvement in adult Still's disease: Case report and brief review of literature. AB - BACKGROUND: Adult onset Still disease (AOSD) is a rare condition characterized by elevated fever along with arthritic symptoms, elevated polymorphonuclear neutrophil count, evanescent rash, and hyperferritinemia. Diagnosis can be made only after have ruled out more frequent conditions, and Yamagouchi or Fautrel criteria should be applied. Parenchimal lung involvement (PLI) is present in less than 5% of AOSD cases and ranges from aspecific reticular interstitial opacities to life threatening conditions, such as acute respiratory distress syndrome (ARDS). CASE: We report the case of a 59 years old man who was referred to our ward because of high fever treated as a pneumonia with antibiotic but not responding to medical treatment, and findings suggestive of interstitial lung disease prevalent in the lower zone on high resolution computed tomography (HRCT). AOSD was diagnosed when the diagnostic Yamaguchi criteria were fulfilled and our suspect was confirmed by the rheumatologist; the patient was then successfully treated with corticosteroids. CONCLUSIONS: PLI in AOSD is very rare but must be considered among differential diagnosis in patients with high fever and aspecific interstial parenchimal lung involvement. PMID- 28725547 TI - Spatial working memory in neurofibromatosis 1: Altered neural activity and functional connectivity. AB - BACKGROUND: Neurofibromatosis Type 1 (NF1) is a genetic disorder that disrupts central nervous system development and neuronal function. Cognitively, NF1 is characterized by difficulties with executive control and visuospatial abilities. Little is known about the neural substrates underlying these deficits. The current study utilized Blood-Oxygen-Level-Dependent (BOLD) functional MRI (fMRI) to explore the neural correlates of spatial working memory (WM) deficits in patients with NF1. METHODS: BOLD images were acquired from 23 adults with NF1 (age M = 32.69; 61% male) and 25 matched healthy controls (age M = 33.08; 64% male) during an in-scanner visuo-spatial WM task. Whole brain functional and psycho-physiological interaction analyses were utilized to investigate neural activity and functional connectivity, respectively, during visuo-spatial WM performance. Participants also completed behavioral measures of spatial reasoning and verbal WM. RESULTS: Relative to healthy controls, participants with NF1 showed reduced recruitment of key components of WM circuitry, the left dorsolateral prefrontal cortex and right parietal cortex. In addition, healthy controls exhibited greater simultaneous deactivation between the posterior cingulate cortex (PCC) and temporal regions than NF1 patients. In contrast, NF1 patients showed greater PCC and bilateral parietal connectivity with visual cortices as well as between the PCC and the cerebellum. In NF1 participants, increased functional coupling of the PCC with frontal and parietal regions was associated with better spatial reasoning and WM performance, respectively; these relationships were not observed in controls. CONCLUSIONS: Dysfunctional engagement of WM circuitry, and aberrant functional connectivity of 'task negative' regions in NF1 patients may underlie spatial WM difficulties characteristic of the disorder. PMID- 28725548 TI - Age-dependent, lasting effects of methylphenidate on the GABAergic system of ADHD patients. AB - Stimulants are the main pharmacological treatment for patients with attention deficit/hyperactivity disorder (ADHD). Their current prescription rates are rising, both in children, adolescents and adults. Related to the impulse control phenotype, both preclinical and clinical studies have demonstrated lower gamma amino butyric acid (GABA) levels in prefrontal brain regions in ADHD. Whereas stimulant treatment increases GABA levels, preclinical studies have suggested that stimulant treatment effects may be age-dependent. As the long-term consequences of stimulant use in ADHD children and adolescents have so far been poorly studied, we used magnetic resonance spectroscopy to assess GABA+ and glutamate + glutamine (Glx) levels in the medial prefrontal cortex (mPFC) of adult ADHD patients, both before and after an oral methylphenidate (MPH) challenge. Three groups were studied: 1) ADHD patients who were first treated with stimulants before 16 years of age, i.e. during periods of ongoing brain development (early-stimulant-treated, EST); 2) patients first treated with stimulants in adulthood (i.e. > 23 years) (late-stimulant-treated, LST), and 3) stimulant-treatment-naive (STN) ADHD patients. Reduced basal GABA+ levels were found in EST compared to LST patients (p = 0.04), while after an MPH challenge, only the EST patients showed significant increases in GABA+ (p = 0.01). For Glx, no differences were found at baseline, nor after an MPH challenge. First stimulant exposure at a young age is thus associated with lower baseline levels of GABA+ and increased responsivity in adulthood. This effect could not be found in patients that started treatment at an adult age. Hence, while adult stimulant treatment seems to exert no major effects on GABA+ levels in the mPFC, MPH may induce long-lasting alterations in the adult mPFC GABAergic system when treatment was started at a young age. PMID- 28725549 TI - Performance of unscented Kalman filter tractography in edema: Analysis of the two tensor model. AB - Diffusion MRI tractography is increasingly used in pre-operative neurosurgical planning to visualize critical fiber tracts. However, a major challenge for conventional tractography, especially in patients with brain tumors, is tracing fiber tracts that are affected by vasogenic edema, which increases water content in the tissue and lowers diffusion anisotropy. One strategy for improving fiber tracking is to use a tractography method that is more sensitive than the traditional single-tensor streamline tractography. We performed experiments to assess the performance of two-tensor unscented Kalman filter (UKF) tractography in edema. UKF tractography fits a diffusion model to the data during fiber tracking, taking advantage of prior information from the previous step along the fiber. We studied UKF performance in a synthetic diffusion MRI digital phantom with simulated edema and in retrospective data from two neurosurgical patients with edema affecting the arcuate fasciculus and corticospinal tracts. We compared the performance of several tractography methods including traditional streamline, UKF single-tensor, and UKF two-tensor. To provide practical guidance on how the UKF method could be employed, we evaluated the impact of using various seed regions both inside and outside the edematous regions, as well as the impact of parameter settings on the tractography sensitivity. We quantified the sensitivity of different methods by measuring the percentage of the patient-specific fMRI activation that was reached by the tractography. We expected that diffusion anisotropy threshold parameters, as well as the inclusion of a free water model, would significantly influence the reconstruction of edematous WM fiber tracts, because edema increases water content in the tissue and lowers anisotropy. Contrary to our initial expectations, varying the fractional anisotropy threshold and including a free water model did not affect the UKF two-tensor tractography output appreciably in these two patient datasets. The most effective parameter for increasing tracking sensitivity was the generalized anisotropy (GA) threshold, which increased the length of tracked fibers when reduced to 0.075. In addition, the most effective seeding strategy was seeding in the whole brain or in a large region outside of the edema. Overall, the main contribution of this study is to provide insight into how UKF tractography can work, using a two tensor model, to begin to address the challenge of fiber tract reconstruction in edematous regions near brain tumors. PMID- 28725551 TI - Cervical cord myelin water imaging shows degenerative changes over one year in multiple sclerosis but not neuromyelitis optica spectrum disorder. AB - Spinal cord pathology is a feature of both neuromyelitis optica spectrum disorder (NMOSD) and relapsing-remitting multiple sclerosis (MS). While subclinical disease activity has been described in MS using quantitative magnetic resonance imaging measures, current evidence suggests that neurodegeneration is absent between relapses in NMOSD, although most evidence comes from brain studies. We aimed to assess cross-sectional differences and longitudinal changes in myelin integrity in relapse-free MS and NMOSD subjects over one year. 15 NMOSD, 15 MS subjects, and 17 healthy controls were scanned at 3 T using a cervical cord mcDESPOT protocol. A subset of 8 NMOSD, 11 MS subjects and 14 controls completed follow-up. Measures of the myelin water fraction (fM) within lesioned and non lesioned cord segments were collected. At baseline, fM in lesioned and non lesioned segments was significantly reduced in MS (lesioned: p = 0.002; non lesioned: p = 0.03) and NMOSD (lesioned: p = 0.0007; non-lesioned: p = 0.002) compared to controls. Longitudinally, fM decreased within non-lesioned cord segments in the MS group (- 7.3%, p = 0.02), but not in NMOSD (+ 5.8%, p = 0.1), while change in lesioned segments fM did not differ from controls' in either patient group. These results suggest that degenerative changes outside of lesioned areas can be observed over a short time frame in MS, but not NMOSD, and support the use of longitudinal myelin water imaging for the assessment of pathological changes in the cervical cord in demyelinating diseases. PMID- 28725552 TI - Repeated inoculations with the lung and heartworm nematode Angiostrongylus vasorum result in increasing larval excretion and worm burden in the red fox (Vulpes vulpes). AB - The French heartworm Angiostongylus vasorum is found in European red fox (Vulpes vulpes) and dog populations, where it appears to be spreading geographically. Once introduced into new areas, it establishes in local fox populations, typically to over 50% prevalence in a few years. High susceptibility and constant excretion of first stage larvae (L1) by the definitive hosts are prerequisites for sustaining high parasite biomass in a particular habitat. The present study explores the hypothesis that repeated ingestion of gastropods in nature will result in accumulation of adult worms and elevated excretion of L1 in feces. Experimentally infected foxes were subsequently inoculated via stomach tube once (9 weeks post initial inoculation) or twice (9 and 13 weeks post inoculation (wpi)) with 100 third stage A. vasorum larvae (L3) previously isolated from aquatic snails infected with L1 from a naturally infected dog. Despite large variation in fecal larval excretion for the individual animals within the groups, excretion of L1 was significantly higher in foxes twice inoculated as compared to foxes inoculated only once. With an outlier in the once inoculated group removed, excretion became significantly higher in the three times inoculated group. Establishment of adult worms varied and only a trend to higher worm burdens was found in the group of foxes inoculated three times. However, this became significant with the same single outlier removed. Overall, it appears that protective immunity to A. vasorum does not appear to occur in V. vulpes with animals exhibiting high infection intensities without obvious clinical signs. The increasing larval excretion in foxes being repeatedly exposed to A. vasorum L3 support the hypothesis that foxes under natural conditions may repeatedly ingest infected gastropods and remain a source of environmental contamination for several months, potentially contributing to the establishment of endemic foci through increasing L1 excretion. PMID- 28725553 TI - Behavioral, physiological and morphological correlates of parasite intensity in the wild Cururu toad (Rhinella icterica). AB - Large numbers of parasites are found in various organs of anuran amphibians, with parasite intensities thought to modulate the host's Darwinian fitness traits. Interaction between the anuran hosts and their multiple parasites should modulate the host's phenotypic characteristic, such as those associated with high energetic demand (such as calling effort and locomotor performance), energy balance (standard metabolic rate), and morphological plasticity (as indicated by organ masses). The present study investigated the impact of parasite intensities on the behavioral, physiological, and morphological traits of wild adult male Rhinella icterica (Anura: Bufonidae). We tested as to whether individuals with higher parasite intensities would present: 1) lower vocal calling effort in the field, as well as poorer locomotor performance and body-condition index; and 2) higher standard metabolic rates and internal organ masses. Measurements included: calling effort in the field; standard metabolic rate; locomotor performance; parasite intensity; internal organ masses (heart, liver, kidneys, intestines, stomach, lungs, hind limb muscle, and spleen); and the body-condition index. Results showed a negative association of parasite intensities with locomotor performance, and standard metabolic rate of R. icterica. A positive association between parasite intensities and relative organ masses (heart, intestines and kidneys) was also evident. Toads with higher pulmonary and intestinal parasites intensities also showed higher total parasite intensities. PMID- 28725550 TI - DTI measures identify mild and moderate TBI cases among patients with complex health problems: A receiver operating characteristic analysis of U.S. veterans. AB - Standard MRI methods are often inadequate for identifying mild traumatic brain injury (TBI). Advances in diffusion tensor imaging now provide potential biomarkers of TBI among white matter fascicles (tracts). However, it is still unclear which tracts are most pertinent to TBI diagnosis. This study ranked fiber tracts on their ability to discriminate patients with and without TBI. We acquired diffusion tensor imaging data from military veterans admitted to a polytrauma clinic (Overall n = 109; Age: M = 47.2, SD = 11.3; Male: 88%; TBI: 67%). TBI diagnosis was based on self-report and neurological examination. Fiber tractography analysis produced 20 fiber tracts per patient. Each tract yielded four clinically relevant measures (fractional anisotropy, mean diffusivity, radial diffusivity, and axial diffusivity). We applied receiver operating characteristic (ROC) analyses to identify the most diagnostic tract for each measure. The analyses produced an optimal cutpoint for each tract. We then used kappa coefficients to rate the agreement of each cutpoint with the neurologist's diagnosis. The tract with the highest kappa was most diagnostic. As a check on the ROC results, we performed a stepwise logistic regression on each measure using all 20 tracts as predictors. We also bootstrapped the ROC analyses to compute the 95% confidence intervals for sensitivity, specificity, and the highest kappa coefficients. The ROC analyses identified two fiber tracts as most diagnostic of TBI: the left cingulum (LCG) and the left inferior fronto-occipital fasciculus (LIF). Like ROC, logistic regression identified LCG as most predictive for the FA measure but identified the right anterior thalamic tract (RAT) for the MD, RD, and AD measures. These findings are potentially relevant to the development of TBI biomarkers. Our methods also demonstrate how ROC analysis may be used to identify clinically relevant variables in the TBI population. PMID- 28725554 TI - Successful surgical management of New Onset Refractory Status Epilepticus (NORSE) presenting with gelastic seizures in a 3 year old girl. AB - Gelastic seizures (GS) are typically associated with hypothalamic hamartomas and present during childhood. However it is now known that GS can be found in focal epilepsies arising from other regions in the brain, including mesial and neocortical frontal, temporal and parietal regions. GS have rarely been described as the presenting manifestation of New Onset Refractory Status Epilepticus (NORSE). In this article we describe a previously healthy 3-year-old who presented with an explosive onset of GS that were refractory to multiple anti seizure medications. These seizures arose from the right frontal region. An extensive metabolic and immunological evaluation was negative. Her brain magnetic resonance imaging (MRI) was negative, however the Positron Emission Tomography (PET) scan showed a hypermetabolic region in the right frontal inferior gyrus. She underwent a depth electrode evaluation that revealed a widespread irritative zone involving the PET "lesion" as well as mesial and neocortical regions in the right frontal lobe. The seizure onset zone was widespread and non-localizable. However the GS were associated with a clear ictal epileptiform discharge on invasive EEG arising from the depth of the superior frontal gyrus, which was not overlapping with the PET hypermetabolic region. She underwent a right frontal lobectomy sparing the primary motor region in the pre-central gyrus. She has remained seizure free for 15 months since. The pathological analysis showed focal cortical dysplasia type II in the region of the PET scan hypermetabolism. This case expands the clinical spectrum of GS to include cases of NORSE. Additionally the case highlights the role of resective surgery in GS presenting as NORSE and the potentially excellent outcome that can be achieved by early intervention. PMID- 28725555 TI - Genome sequence of the type strain CLIB 1764T (= CBS 14374T) of the yeast species Kazachstania saulgeensis isolated from French organic sourdough. AB - Kazachstania saulgeensis is a recently described species isolated from French organic sourdough. Here, we report the high quality genome sequence of a monosporic segregant of the type strain of this species, CLIB 1764T (= CBS 14374T). The genome has a total length of 12.9 Mb and contains 5326 putative protein-coding genes, excluding pseudogenes and transposons. The nucleotide sequences were deposited into the European Nucleotide Archive under the genome assembly accession numbers FXLY01000001-FXLY01000017. PMID- 28725556 TI - De novo transcriptome assembly for the lung of the ornamented pygmy frog (Microhyla fissipes). AB - Microhyla fissipes, belonging to Neobatrachia, is a new model organism to study developmental biology, adaptive mechanisms from aquatic to terrestrial life, environmental toxicology, and human disease. M. fissipes use of lungs soon after hatching makes it extremely valuable for the study of lung function and development mechanisms. However, our knowledge of genes and pathways associated with lung development in M. fissipes is very limited. In this study, we conducted de novo transcriptome assembly for the lung of M. fissipes using the Illumina HiSeq4000 platform. We obtained approximately 9.0 GB clean data from the lung of the stage 28 tadpole with lung inflation (NCBI accession numbers: SRP107055). De novo transcriptome assembly identified 209,358 transcripts and 93,813 unigenes. In addition, BLASTX against NR, NT, KO, SwissProt, PFAM, GO and KOG databases were used to annotate all the 93,813 unigenes. This study provides the transcriptome and functional annotation of genes in M. fissipes lung development, which will be useful for comparative transcriptome analyses and promote research into mechanism of lung development in anuran. PMID- 28725557 TI - Genome assembly of Chryseobacterium sp. strain IHBB 10212 from glacier top surface soil in the Indian trans-Himalayas with potential for hydrolytic enzymes. AB - The cold-active esterases are gaining importance due to their catalytic activities finding applications in chemical industry, food processes and detergent industry as additives, and organic synthesis of unstable compounds as catalysts. In the present study, the complete genome sequence of 4,843,645 bp with an average 34.08% G + C content and 4260 protein-coding genes are reported for the low temperature-active esterase-producing novel strain of Chrysobacterium isolated from the top-surface soil of a glacier in the cold deserts of the Indian trans-Himalayas. The genome contained two plasmids of 16,553 and 11,450 bp with 40.54 and 40.37% G + C contents, respectively. Several genes encoding the hydrolysis of ester linkages of triglycerides into fatty acids and glycerol were predicted in the genome. The annotation also predicted the genes encoding proteases, lipases, amylases, beta-glucosidases, endoglucanases and xylanases involved in biotechnological processes. The complete genome sequence of Chryseobacterium sp. strain IHBB 10212 and two plasmids have been deposited vide accession numbers CP015199, CP015200 and CP015201 at DDBJ/EMBL/GenBank. PMID- 28725558 TI - Temperature-dependent optoacoustic response and transient through zero Gruneisen parameter in optically contrasted media. AB - Non-invasive optoacoustic mapping of temperature in tissues with low blood content can be enabled by administering external contrast agents. Some important clinical applications of such approach include temperature mapping during thermal therapies in a prostate or a mammary gland. However, the technique would require a calibration that establishes functional relationship between the measured normalized optoacoustic response and local tissue temperature. In this work, we investigate how a key calibration parameter - the temperature of zero optoacoustic response (T0 ) - behaves in different environments simulating biological tissues augmented with either dissolved or particulate (nanoparticles) contrast agents. The observed behavior of T0 in ionic and molecular solutions suggests that in-vivo temperature mapping is feasible for contrast agents of this type, but requires knowledge of local concentrations. Oppositely, particulate contrast agents (plasmonic or carbon nanoparticles) demonstrated concentration independent thermal behavior of optoacoustic response with T0 defined by the thermoelastic properties of the local environment. PMID- 28725559 TI - A case of Klebsiella oxytoca endocarditis in an intravenous drug user. AB - Non-HACEK Gram-negative bacilli account for only a small percentage of infective endocarditis cases globally. Among those, Klebsiella species account for only about 10% of cases and are most often health-care acquired. We present a rare case of Klebsiella oxytoca endocarditis in a young intravenous drug user. PMID- 28725560 TI - Haemophilus influenzae serotype f endocarditis and septic arthritis. AB - Haemophilus influenzae represents gram-negative coccobacilli which can cause endocarditis, meningitis, septicemia, pneumonia, septic arthritis. H.influenzae exists as encapsulated and unencapsulated (non-typeable) strains. Non-typeable H.influenzae are emerging pathogens especially in elderly population. We report a case of a 73 year old woman with bacteremia, endocarditis and septic arthritis due to H.influenzae serotype f. This case emphasizes the clinical features and the key elements of diagnosis and management of infections caused by non-typeable strains of H.influenzae. PMID- 28725561 TI - Bronchopleural and pleurocutaneous fistula in HIV patient with pulmonary tuberculosis. AB - We present a 37-year-old man intravenous drug user, with HIV/HCV/HBV co infection, lymph node tuberculosis 10 years before (completed 12 months of treatment), and left lobar pneumonia 4 years earlier complicated by empyema (treated with left lower lobectomy with a persistent bronchopleural fistula) who was admitted to the emergency department with caseous-purulent drainage and exteriorization of air from an orifice in the chest wall. Acid-fast bacilli were identified in this drainage. A pleurocutaneous fistula was evident on the chest computed tomography scan. He was admitted to the Infectious Diseases Unit and started on antituberculous therapy with a favorable outcome. PMID- 28725562 TI - Pleural empyema and streptococcal toxic shock syndrome due to Streptococcus pyogenes in a healthy Spanish traveler in Japan. AB - Group A Streptococcus (GAS, Streptococcus pyogenes) causes invasive infections including streptococcal toxic shock syndrome (STSS) and local infections. To our knowledge, this is the first report of a case of an invasive GAS infection with pneumonia and pleural empyema (PE) followed by STSS (disseminated intravascular coagulation [DIC] and acute renal insufficiency) in a healthy male adult. He received combined supportive therapies of PE drainage, anti-DIC agent, hemodialysis, and antimicrobials and eventually made a clinical recovery. GAS isolated from PE was found to have emm1/speA genes, suggestive of a pathogenic strain. Clinicians should be aware of the possibility of this disease entity (pneumonia, PE, and STSS) in healthy male adults as well as children and adult women. PMID- 28725563 TI - Atypical hemolytic uremic syndrome triggered by varicella infection. AB - Varicella Zoster Virus (VZV) is a well-known virus that belongs to the Herpesviridae family which induces a self-limited disease except in specific cases in particular among stem cell transplant patients. This virus is not known however to trigger atypical Hemolytic Uremic Syndrome (aHUS). Here we report the case of a six-year-old boy who was hospitalized with fever and abdominal pains associated to pruritic and vesicular rash, thrombocytopenia and acute renal failure. He was diagnosed with aHUS precipitated by varicella virus. He was treated by an association of antimicrobials against potential superinfections, plasmapheresis and eculizumab for curative aHUS treatment. This was effective but after 6 months the kidney function remained poor. The current case describes an aHUS associated to varicella infection as demonstrated by the simultaneous occurrence of the viral infection and aHUS manifestations. Apart from typical Hemolytic Uremic Syndrome which is triggered by bacteria mostly Shiga toxin producing Echerichia coli and Streptococcus pneumoniae or Shigella, aHUS may be linked to viral infections such as HIV, EBV and enteroviruses, but very rarely by varicella. This case highlights a possible even rare complication of varicella infection a very common childhood disease. This complication could be avoided by to anti-VZV vaccination. PMID- 28725564 TI - Post-partum streptococcal toxic shock syndrome associated with necrotizing fasciitis. AB - We report a fatal case of post-partum streptococcal toxic shock syndrome in a patient who was previously healthy and had presented to the emergency department with an extensive blistering ecchymotic lesions over her right buttock and thigh associated with severe pain. The pregnancy had been uncomplicated, and the mode of delivery had been spontaneous vaginal delivery with an episiotomy. She was found to have septicemic shock requiring high inotropic support. Subsequently, she was treated for necrotizing fasciitis, complicated by septicemic shock and multiple organ failures. A consensus was reached for extensive wound debridement to remove the source of infection; however, this approach was abandoned due to the patient's hemodynamic instability and the extremely high risks of surgery. Both the high vaginal swab and blister fluid culture revealed Group A beta hemolytic streptococcus infection. Intravenous carbapenem in combination with clindamycin was given. Other strategies attempted for streptococcal toxic removal included continuous veno-venous hemofiltration and administration of intravenous immunoglobulin. Unfortunately, the patient's condition worsened, and she succumbed to death on day 7 of hospitalization. PMID- 28725565 TI - Facial rash in a renal transplant patient. PMID- 28725566 TI - Concomitant crystal-induced and septic arthritis. PMID- 28725567 TI - Response to Gelb et al.: "Comparison of tandem mass spectrometry to fluorimetry for newborn screening of LSDs". PMID- 28725568 TI - A compound heterozygote case of isolated sulfite oxidase deficiency. AB - We report an isolated sulfite oxidase deficiency in the first child boy of a non consanguineous Caucasian family. He's a compound heterozygote for the sulfite oxidase gene, presenting low cystine, undetectable homocysteine and normal uric acid blood concentrations and undetectable sulfite oxidase activity in his cultured fibroblasts. Both mutations are not reported yet. The clinical presentation was typical and severe, with generalized status epilepticus and premature death. PMID- 28725569 TI - Psychiatric adult-onset of urea cycle disorders: A case-series. AB - Adult onset urea cycle disorders (UCD) may present with psychiatric symptoms, occasionally as the initial presentation. We aimed to describe the characteristics of patients presenting with a psychiatric adult-onset of UCDs, to discuss which signs could suggest this diagnosis in such a situation, and to determine which tests should be conducted. A survey of psychiatric symptoms occurring in teenagers or adults with UCD was conducted in 2010 among clinicians involved in the French society for the study of inborn errors of metabolism (SFEIM). Fourteen patients from 14 to 57 years old were reported. Agitation was reported in 10 cases, perseveration in 5, delirium in 4, and disinhibition in 3 cases. Three patients had pre-existing psychiatric symptoms. All patients had neurological symptoms associated with psychiatric symptoms, such as ataxia or dysmetria, psychomotor slowing, seizures, or hallucinations. Fluctuations of consciousness and coma were reported in 9 cases. Digestive symptoms were reported in 7 cases. 9 patients had a personal history suggestive of UCD. The differential diagnoses most frequently considered were exogenous intoxication, non-convulsive status epilepticus, and meningoencephalitis. Hyperammonemia (180-600 MUmol/L) was found in all patients. The outcome was severe: mechanical ventilation was required in 10 patients, 5 patients died, and only 4 patients survived without sequelae. Adult onset UCDs can present with predominant psychiatric symptoms, associated with neurological involvement. These patients, as well as patients presenting with a suspicion of intoxication, must have UCD considered and ammonia measured without delay. PMID- 28725570 TI - Enzyme activities of alpha-glucosidase in Japanese neonates with pseudodeficiency alleles. AB - Lysosomal storage disorders (LSDs) are caused by defective enzyme activities in lysosomes, characterized by the accumulation of sphingolipids, glycolipids, oligosaccharides, mucopolysaccharides, the oxidation products of cholesterol, and other biological substances. A growing number of clinical studies have suggested the enhanced efficacy of existing therapies, including enzyme replacement therapy, which is effective when it is initiated during the presymptomatic period. Thus, the identification of disease-affected individuals by newborn screening has been considered an effective platform. Previous studies have suggested that the discrimination of infantile-onset Pompe disease (IOPD) requires multi-step examination of GAA enzyme activity using the fluorometric technique. In sharp contrast, the MS/MS-based technique can identify the population of IOPD and the pseudodeficiency alleles of the GAA enzyme [Liao HC et al. Clin Chem (2017) in press; doi: http://dx.doi.org/10.1373/clinchem.2016.269027]. To determine whether MS/MS-based assay can identify these two populations in Japanese neonates, we first performed a validation study of this assay using flow-injection analysis (FIA)-MS/MS and liquid chromatography (LC)-MS/MS followed by examination of GAA enzyme activity in our population. By minimizing the effect of substrate-derived in-source decomposition products, the activities of 6 LSD enzymes were quantified in FIA MS/MS and LC-MS/MS. The mean value of GAA activity with IOPD, pseudodeficiency alleles, and healthy controls by FIA-MS/MS were 1.0 +/- 0.3 MUmol/h/L (max, 1.3; min, 0.7; median, 1.2; n = 3), 2.7 +/- 0.7 MUmol/h/L (max, 4.5; min, 1.5; median, 2.5; n = 19), and 12.9 +/- 5.4 MUmol/h/L (max, 29.6; min, 2.5; median, 11.0; n = 83), respectively. These results suggest that the population of GAA with pseudodeficiency alleles has approximately 20% of GAA enzyme activity compared to controls, providing the preliminary evidence to estimate the cut-off values in the Japanese population using this technique. PMID- 28725571 TI - Application of a diagnostic methodology by quantification of 26:0 lysophosphatidylcholine in dried blood spots for Japanese newborn screening of X linked adrenoleukodystrophy. AB - X-linked adrenoleukodystrophy (X-ALD) is a rare inherited metabolic disease that results in the accumulation of very long chain fatty acids (VLCFA) in plasma and all tissues. Recent studies regarding cerebral X-ALD (CALD) treatment emphasize the importance of its early diagnosis. 26:0 lysophosphatidylcholine (LysoPC) is a sensitive biomarker for newborn screening of X-ALD, while its application for Japanese DBS is unclear. Therefore, we evaluated the feasibility of 20:0 LysoPC and 24:0 LysoPC along with 26:0 LysoPC for diagnosing X-ALD in a cohort of newborns (n = 604), healthy adults (n = 50) and patients (n = 4). Results indicated that 26:0 LysoPC had strong significance for discrimination of patients by the amounts of 2.0 to 4.0 and 0.1 to 1.9 pmol/punch for patients and newborns/healthy adults, respectively. Based on these values, we recommend that further diagnostic confirmation is essential if the amount of 26:0 LysoPC in DBS is above 1.7 pmol/punch. PMID- 28725573 TI - Determination of nitrogen balance in agroecosystems. AB - Nitrogen balance in agroecosystems provides a quantitative framework of N inputs and outputs and retention in the soil that examines the sustainability of agricultural productivity and soil and environmental quality. Nitrogen inputs include N additions from manures and fertilizers, atmospheric depositions including wet and dry depositions, irrigation water, and biological N fixation. Nitrogen outputs include N removal in crop grain and biomass and N losses through leaching, denitrification, volatilization, surface runoff, erosion, gas emissions, and plant senescence. Nitrogen balance, which is the difference between N inputs and outputs, can be reflected in changes in soil total (organic + inorganic) N during the course of the experiment duration due to N immobilization and mineralization. While increased soil N retention and mineralization can enhance crop yields and decrease N fertilization rate, reduced N losses through N leaching and gas emissions (primarily NH4 and NOx emissions, out of which N2O is a potent greenhouse gas) can improve water and air quality. *This paper discusses measurements and estimations (for non-measurable parameters due to complexity) of all inputs and outputs of N as well as changes in soil N storage during the course of the experiment to calculate N balance.*The method shows N flows, retention in the soil, and losses to the environment from agroecosystems.*The method can be used to measure agroecosystem performance and soil and environmental quality from agricultural practices. PMID- 28725574 TI - Sugar, acid and furfural quantification in a sulphite pulp mill: Feedstock, product and hydrolysate analysis by HPLC/RID. AB - Waste from pulp and paper mills consist of sugar-rich fractions comprising hemicellulose derivatives and cellulose by-products. A complete characterisation of the waste streams is necessary to study the possibilities of an existing mill. In this work, four chromatographic methods have been developed to obtain the most suitable chromatographic method conditions for measuring woody feedstocks, lignocellulosic hydrolysates and cellulose pulp in sulphite pulping processes. The analysis of major and minor monosaccharides, aliphatic carboxylic acids and furfurals has been optimised. An important drawback of the spent liquors generated after sulphite pulping is their acidic nature, high viscosity and adhesive properties that interfere in the column lifetime. This work recommends both a CHO-782Pb column for the sugar analysis and an SH-1011 resin-based cross linked gel column to separate low-molecular-weight chain acids, alcohols and furfurals. Such columns resulted in a good separation with long lifetime, wide pH operating range and low fouling issues. PMID- 28725572 TI - Novel panel of protein biomarkers to predict response to bortezomib-containing induction regimens in multiple myeloma patients. AB - BACKGROUND: Multiple myeloma (MM) is a complex heterogeneous disease. Various risk stratification models have been recommended including cytogenetic and FISH analysis to identify high-risk patients who may benefit from novel treatments, but such facilities are not widely available. The International Scoring System (ISS) using beta-2-microglobulin and albumin remains a widely used prognostic scoring system in many clinical practices; however it is not useful in predicting response to treatment in MM. The aim of this study is to identify clinically useful biomarkers to predict response to treatment containing bortezomib. METHODS: 17 MM patient serum samples (9 responders/8 non-responders) were used for the discovery phase (label-free mass spectrometry) and an additional 20 MM patient serum samples were used for the ELISA-based validation phase (14 responders/6 non-responders). RESULTS: CLU and ANG mean levels were higher in the responders group, while Complement C1q had lower concentrations. The combination of all standard biomarkers (albumin, beta-2-microglobulin (beta2M), paraprotein and kappa/lambda (K/L) ratio) had an AUC value of 0.71 with 65% correct classification, while an overall combination of new candidate protein biomarkers with standard biomarkers had an AUC value of 0.89 with 85.3% correct classification. CONCLUSIONS: A combination of new and standard biomarkers consisting of CLU, ANG, C1Q, albumin, beta2M, paraprotein and K/L ratio may have potential as a novel panel of biomarkers to predict MM response to treatment containing bortezomib. GENERAL SIGNIFICANCE: Use of this biomarker panel could facilitate a more personalized therapy approach and to minimize unnecessary side effects from ineffective drugs. PMID- 28725575 TI - Magnetic resonance imaging in prostate cancer. PMID- 28725577 TI - Standards for MRI reporting-the evolution to PI-RADS v 2.0. AB - Prostate cancer (PCa) remains a leading cause of death in the United States, but the vast majority of men diagnosed with PCa will die from other causes. While historically the capability of assessing the risk of life-threatening versus indolent PCa has relied heavily on serum prostate-specific antigen (PSA) and transrectal ultrasound (TRUS), multiparametric magnetic resonance imaging (mpMRI) has emerged as the leading tool for detection and characterization of clinically significant PCa. However, wide variations and lack of standardization of mpMRI data acquisition, interpretation, and reporting have hampered its progress. The development of a set of consensus guidelines, initially called Prostate Imaging and Reporting and Data System (PI-RADS) and eventually updated to a document called PI-RADS v2 has attempted to solve these shortcomings. As it stands, PI RADS v2 currently represents the most up-to-date information on how to acquire, interpret, and report mpMRI of the prostate. PMID- 28725576 TI - Cost consideration in utilization of multiparametric magnetic resonance imaging in prostate cancer. AB - The screening, evaluation and management of prostate cancer changed significantly in the last decade. The recommendations regarding prostate cancer screening continue to evolve with new revelations about existing data sets and longer followup of landmark trials. Robotics has gained the vast majority of the marketplace for surgically managed prostate cancer in rapid fashion. The need for intervention in low risk prostate cancer has been closely examined and more men are being expectantly managed than ever before. Amidst all these changes, prostate magnetic resonance imaging (MRI) has emerged as a disruptive technology. Through the use of dynamic contrast-enhanced and diffusion weighted series, prostate tumors that were previously not visible have become identifiable and quantifiable. The ability of MRI to improve staging and identification of clinically significant disease has resulted in increased utilization for different aspects of prostate cancer care. The best studied use is in men with a prior negative transrectal ultrasound guided (TRUS) prostate biopsy and the performance characteristics in this role match well with the clinical question raised. The role for MRI in initial biopsy, in pre-surgical planning before prostatectomy and in men on active surveillance is less well defined. A primary concern in the use of MRI is that of cost. MRI units are expensive, both in initial outlay and ongoing use. The availability of MRI varies widely between countries and even within regions of the same country. Different healthcare models have different approaches for allocating the use of expensive resources, including MRI, in times when they are scarce. Prostate MRI can be used at multiple points in the management algorithm of prostate cancer and each implies different cost concerns. In this review we present an overview of current research in cost and cost efficacy for the use of MRI in the management of prostate cancer. By examining what is known and highlighting areas of ongoing research we hope to provide the reader with a solid foundation for understanding these complex, ever-changing issues. PMID- 28725578 TI - Transperineal vs. transrectal biopsy in MRI targeting. AB - Prostate biopsy is typically performed via either the transrectal or transperineal approach. MRI-targeted biopsy, whether using any of the three options of cognitive fusion, MRI-ultrasound fusion software, or in-bore MRI guided biopsy, can also be performed via either transrectal or transperineal approaches. As an extension of traditional random prostate biopsy, the transrectal approach is far more commonly used for MRI-targeted biopsy due to its convenience. However, in the context of today's increasing multi-drug resistance of rectal flora, the transperineal approach is being used more often due to its lack of septic complications. In addition, only a first-generation cephalosporin, not a fluoroquinolone, is required as antibiotic prophylaxis. Evidence shows excellent detection rates of significant prostate cancer using magnetic resonance imaging (MRI)-targeted and/or systematic transperineal biopsy (TPB). However, there are no head-to-head studies comparing the different MRI-targeted methods within TPB. To provide truly patient-centred care, the biopsy technique using the safest method with the highest detection rate of significant cancer should be used. Depending on healthcare context and hospital resource utilization, MRI targeted TPB is an excellent option and should be performed wherever available and feasible. Whilst building capacity for TPB in one's practice, the routine use of rectal culture swabs prior to any transrectal biopsies is strongly encouraged. Independent of biopsy route, the addition of systematic cores needs to be discussed with the patient weighing maximal detection of significant cancer against increased detection of insignificant lesions. PMID- 28725579 TI - Multiparametric magnetic resonance imaging of the prostate-a basic tutorial. AB - Prostate cancer is the second most common cause of cancer related death in the United States and the most commonly diagnosed malignancy in men. In general, prostate cancer is slow growing, though there is a broad spectrum of disease that may be indolent, or aggressive and rapidly progressive. Screening for prostate is controversial and complicated by lack of specificity and over diagnosis of clinically insignificant cancer. Imaging has played a role in diagnosis of prostate cancer, primarily through systemic transrectal ultrasound (TRUS) guided biopsy. While TRUS guided biopsy radically changed prostate cancer diagnosis, it still remains limited by low resolution, poor tissue characterization, relatively low sensitivity and positive predictive value. Advances in multiparametric magnetic resonance imaging (mpMRI) have allowed more accurate detection, localization, and staging as well as aiding in the role of active surveillance (AS). The use of mpMRI for the evaluation of prostate cancer has increased dramatically and this trend is likely to continue as the technique is rapidly improving and its applications expand. The purpose of this article is to review the basic principles of mpMRI of the prostate and its clinical applications, which will be reviewed in greater detail in subsequent chapters of this issue. PMID- 28725580 TI - Pre-biopsy MRI as an adjunct for cancer detection in men with elevated PSA and no previous biopsy. AB - The role of magnetic resonance imaging (MRI) prior to biopsy in the diagnosis of prostate cancer in biopsy-naive patients has been strengthened by recent developments such as the PIRADS V2 criteria, which cover acquisition, interpretation, and reporting for clinical practice and data collection for research. Important questions on the role of prostate MRI remain: can MRI be used as a triage test before first biopsy series? Can it be used to avoid the use of systematic biopsies (SB) and instead use only targeted biopsies (TB) to MRI suspicious lesions? Studies to evaluate image guided TB compared to SB have started to accumulate. Objectives of these studies should be to reduce the detection of clinically insignificant disease, to maximize the detection of clinically significant cancer (CSC), to better assess disease size, grade and location. Accurate diagnosis will allow the choice of the most appropriate treatments options, minimising side effects and reducing overtreatment. Study results on MRI-TB detection rates are promising however some limitations should be considered. The majority of published and ongoing studies have been performed at expert centres, in order to demonstrate the optimal performance of MRI. Then, the validation of this strategy in less specialised institutions will be necessary before incorporating recommendations in international guidelines. It necessitates training for radiologists and urologists to perform and read MRI and MRI-targeted biopsy through education programs and standardization tools. All these advances will be consolidated with expected genetic screening tools to improve the detection of aggressive cancer. PMID- 28725581 TI - Direct magnetic resonance imaging-guided biopsy of the prostate: lessons learned in establishing a regional referral center. AB - MRI-targeted biopsy of the prostate appears to have the potential to reduce the high rates of underdiagnosis and overdiagnosis associated with the current diagnostic standard of transrectal ultrasound guided systematic biopsy. Direct or "in bore" MRI-guided biopsy is one of the three methods for MRI-targeted core needle sampling of suspicious, generally Pi-RADS 4 or 5, foci within the prostate, and our early experience suggests the approach demonstrates substantial utility and promise in the care of patients with prostate cancer. We performed direct MRI-guided biopsies in 50 patients within 19 months of establishing the first referral center for this service in our region. Our preliminary results indicate the service can be easily grown due to unmet demand, primarily in patients with a negative traditional systematic biopsy but with a concerning focus at MRI (30 of 50; 60%). Other applications include evaluation of patients who are on active surveillance (n=14; ten upgraded to higher Gleason score at MRI guided biopsy), who are biopsy naive (n=5; all positive at MRI-guided biopsy), or post focal therapy (n=1; positive for recurrent tumor at MRI-guided biopsy). With careful patient selection and technique, we have achieved a favorable overall positive biopsy rate of 73% (37 of 50), with 84% (31 of 37) positive biopsies demonstrating Gleason score 7 or greater disease. Large multicenter comparative trials will be required to determine the relative accuracy and appropriate utilization of direct MRI guided biopsy in the care pathway of patients with known or suspected prostate cancer. PMID- 28725582 TI - Co-registration of MRI and ultrasound: accuracy of targeting based on radiology pathology correlation. AB - We reviewed the role of multiparametric magnetic resonance imaging (MP-MRI) and methods of MRI guided biopsy including in-bore, cognitive fusion, and software based fusion. MP-MRI has been developed, optimized, and studied as a means of improving prostate cancer detection beyond the standard evaluation that utilizes digital rectal examinations and serum prostate specific antigen (PSA). MP-MRI has been proven to be an excellent diagnostic imaging modality that improves prostate cancer detection and risk stratification by guiding biopsy samples. The co registration between MRI and ultrasound has allowed for software-based fusion which enables office-based biopsy procedures while still benefiting from the detailed prostate characterization of MRI. MP-MRI/ultrasound fusion guided biopsy has been studied in detail as this technology has been developed, tested, and validated in the past decade. The imaging to pathology correlation supporting the use of MP-MRI/ultrasound fusion is well documented in the literature. As the indication for the use of prostate MP-MRI becomes more widespread, it is important to continue to evaluate the correlation between imaging and pathologic findings. PMID- 28725583 TI - Positron emission tomography (PET) in primary prostate cancer staging and risk assessment. AB - Prostate cancer (PCa) is one of the few neoplasms that are not well served by 18F Fluorodeoxyglucose (FDG) positron emission tomography (PET). As a result, a number of PET tracers have been developed to target particular biological features of PCa. Such agents can be used for diagnosis, staging, identification of biochemical recurrence (BCR) and evaluation of metastatic disease. Here, we focus on primary disease and local staging. To date, magnetic resonance imaging (MRI) has proven superior to PET in the imaging of primary PCa. However, some PET agents have shown remarkable promise in staging high-risk PCa (defined as any combination of a clinical T3, a PSA score >20 ng/mL, or a Gleason score of 8-10), as well as biochemical relapse after definitive therapy and metastatic PCa. PET agents can be divided into those that interrogate tumor metabolism (18F-FDG, 11C Choline, 18F-Choline, 11C-Acetate, 18F-FACBC), hormone receptors (18F-FDHT), and other targets such as prostate specific membrane antigen (PSMA) (68Ga-PSMA, 18F DCFBC, 18F-DCFPyl) or gastric releasing peptide (18F-GRP or 18F-Bombesin). In this review, we compare the available PCa targeted PET tracers utilized in staging of high risk tumors. PMID- 28725584 TI - Magnetic resonance imaging detection of prostate cancer in men with previous negative prostate biopsy. AB - Use of transrectal ultrasound guided systematic prostate biopsy has poor diagnostic accuracy for prostate cancer (PCa) detection. Recently multiparametric MRI (mpMRI) of the prostate and MR/US fusion biopsy has been gaining popularity for men who have previously undergone a negative biopsy. We performed PubMed(r) and Web of Science(r) searches to identify studies on this subject, particularly focusing on studies consisting of patients who have had at least one previously negative biopsy. Across the literature, when a suspicious lesion is found on mpMRI, MR/US fusion biopsy has consistently demonstrated higher detection rate for any PCa and clinically significant PCa (csPCa) compared to the traditional repeat systematic biopsy (SB) approach. Furthermore, anteriorly located tumors are frequently identified using MR targeted biopsy (TB), suggesting that an MR guided approach allows for increased accuracy for detecting tumors commonly missed by systematic biopsies. We conclude that men with a prior negative biopsy and continued suspicion of PCa should strongly be encouraged to get a prostate mpMRI prior to a repeat biopsy. PMID- 28725585 TI - A critical comparison of techniques for MRI-targeted biopsy of the prostate. AB - MRI-targeted biopsy is a promising technique that offers an improved detection of clinically significant prostate cancer over standard non-targeted biopsy. It is established that prostate MRI is of use in both the primary and repeat biopsy setting for the detection of significant prostate cancer. There are three approaches to targeting biopsies to areas of interest seen on prostate MRI. They each rely on the acquisition and reporting of a diagnostic quality multi parametric MRI scan used to identify areas of interest, and the subsequent use of those diagnostic quality images in combination with real-time images of the prostate during the biopsy procedure. The three techniques are: visual registration of the MRI images with a real-time ultrasound image; software assisted fusion of the MRI images and the real-time ultrasound images, and in bore biopsy, which requires registration of a diagnostic quality MRI scan with a real time interventional MRI image. In this paper we compare the three techniques and evaluate those studies where there is a direct comparison of more than one MRI-targeting technique. PubMed was searched from inception to November 2016 using the search terms (cognitive registration OR visual registration OR fusion biopsy OR in-bore biopsy OR targeted biopsy) AND (prostate cancer OR prostate adenocarcinoma OR prostate carcinoma OR prostatic carcinoma OR prostatic adenocarcinoma) AND (MRI OR NMR OR magnetic resonance imaging OR mpMRI OR multiparametric MRI). The initial search included 731 abstracts. Eleven full text papers directly compared two or more techniques of MRI-targeting, and were selected for inclusion. The detection of clinically significant prostate cancer varied from 0% to 93.3% for visual registration, 23.2% to 100% for software assisted registration and 29% to 80% for in-bore biopsy. Detection rates for clinically significant cancer are dependent on the prevalence of cancer within the population biopsied, which in turn is determined by the selection criteria [biopsy naive, previous negative biopsy, prostate specific antigen (PSA) selection criteria, presence of a lesion on MRI]. Cancer detection rates varied more between study populations than between biopsy approaches. Currently there is no consensus on which type of MRI-targeted biopsy performs better in a given setting. Although there have been studies supporting each of the three techniques, substantial differences in methodology and reporting the findings make it difficult to reliably compare their outcomes. PMID- 28725586 TI - Role of prostate magnetic resonance imaging in active surveillance. AB - Active surveillance (AS) has emerged as a beneficial strategy for management of low risk prostate cancer (PCa) and prevention of overtreatment of indolent disease. However, selection of patients for AS using traditional 12-core transrectal prostate biopsy is prone to sampling error and presents a challenge for accurate risk stratification. In fact, around a third of men are upgraded on repeat biopsy which disqualifies them as appropriate AS candidates. This uncertainty affects adoption of AS among patients and physicians, leading to current AS protocols involving repetitive prostate biopsies and unclear triggers for progression to definitive treatment. Prostate magnetic resonance imaging (MRI) has the potential to overcome some of these limitations through localization of significant tumors in the prostate. In conjunction with MRI targeted prostate biopsy, improved sampling and detection of clinically significant PCa can help streamline the process of selecting suitable men for AS and early exclusion of men who require definitive treatment. MRI can also help minimize the invasive nature of monitoring for disease progression while on AS. Men with stable MRI findings have high negative predictive value for Gleason upgrade on subsequently biopsy, suggesting that men may potentially be monitored by serial MRI examinations with biopsy reserved for significant changes on imaging. Targeted biopsy on AS also allows for specific sampling of concerning lesions, although further data is necessary to evaluate the relative contribution of systematic and targeted biopsy in detecting the 25-30% of men who progress on AS. Further research is also warranted to better understand the nature of clinically significant cancers that are missed on MRI and why certain men have progression of disease that is not visible on prostate MRI. Consensus is also needed over what constitutes progression on MRI, when prostate biopsy can be safely avoided, and how to best utilize this additional information in current AS protocols. Despite these challenges, prostate MRI, either alone or in conjunction with MRI-targeted prostate biopsy, has the potential to significantly improve our current AS paradigm and rates of AS adoption among patients moving forward. PMID- 28725587 TI - Multi-parametric MRI imaging of the prostate-implications for focal therapy. AB - The primary goal of a focal therapy treatment paradigm is to achieve cancer control through targeted tissue destruction while simultaneously limiting deleterious effects on peri-prostatic structures. Focal therapy approaches are employed in several oncologic treatment protocols, and have been shown to provide equivalent cancer control for malignancies such as breast cancer and renal cell carcinoma. Efforts to develop a focal therapy approach for prostate cancer have been challenged by several concepts including the multifocal nature of the disease and limited capability of prostate ultrasound and systematic biopsy to reliably localize the site(s) and aggressiveness of disease. Multi-parametric MRI (mpMRI) of the prostate has significantly improved disease localization, spatial demarcation and risk stratification of cancer detected within the prostate. The accuracy of this imaging modality has further enabled the urologist to improve biopsy approaches using targeted biopsy via MRI-ultrasound fusion. From this foundation, an improved delineation of the location of disease has become possible, providing a critical foundation to the development of a focal therapy strategy. This chapter reviews the accuracy of mpMRI for detection of "aggressive" disease, the accuracy of mpMRI in determining the tumor volume, and the ability of mpMRI to accurately identify the index lesion. While mpMRI provides a critical, first step in developing a strategy for focal therapy, considerable questions remain regarding the relationship between MR identified tumor volume and pathologic tumor volume, the accuracy and utility of mpMRI for treatment surveillance and the optimal role and timing of follow-up mpMRI. PMID- 28725588 TI - Role of mpMRI of the prostate in screening for prostate cancer. AB - Prostate cancer screening offers the opportunity to significantly reduce morbidity and mortality from this disease. Currently, serum prostate-specific antigen (PSA) testing is the most widely used screening modality. However, PSA testing continues to have low positive and negative predictive value leading to unnecessary invasive prostate biopsy while missing patients with aggressive forms of the disease. Magnetic resonance imaging (MRI) has been gaining an increasingly large role in the management of patients with early stage prostate cancer including diagnosis in patients with abnormal PSA levels, monitoring of patients on active surveillance, and staging prior to definitive interventions. MRI-based prostate cancer risk assessment has been shown to better distinguish between clinically-significant and insignificant tumors than PSA testing alone or from nomograms. Preliminary data indicate that, among unselected patients, MRI outperforms PSA in the identification of patients with clinically significant prostate cancer. Further work is needed to examine the role of mpMRI in prostate cancer screening. PMID- 28725589 TI - Multi-parametric magnetic resonance imaging as a management decision tool. AB - The ability to image the prostate accurately and better characterize cancerous lesions makes multiparametric magnetic resonance imaging (mpMRI) an invaluable tool to improve management of localized prostate cancer (PCa). Improved risk stratification is warranted given the evidence of significant overtreatment of indolent PCa. mpMRI can more accurately rule out clinically significant PCa in men deciding between surveillance and definitive treatment to reduce overtreatment. mpMRI improves detection of clinically significant PCa, which helps minimize sampling error, a major limitation of the traditional diagnostic paradigm. Aside from helping determine candidacy for initial surveillance vs. treatment, mpMRI is a useful tool for following men on active surveillance (AS) with the potential to reduce the need for serial biopsies. When definitive treatment is warranted, mpMRI can be used to determine the local extent of disease. This provides information that is useful in the treatment decision, counseling about outcomes, and surgical planning. While mpMRI is a significant step forward in PCa management, it is necessary to understand its limitations. mpMRI and MRI-guided fusion biopsy techniques still do not detect all clinically significant tumors. The utility of current mpMRI techniques is limited by the multifocal nature of PCa with poor detection of non-index lesions, inaccurate estimation of tumor size and geometry, and the need for interpretation by specialized radiologists. The role of mpMRI will continue to expand as improvements in technology and experience help overcome these limitations. PMID- 28725590 TI - MRI-fusion biopsy: the contemporary experience. AB - Advancements in magnetic resonance imaging (MRI) and MRI-ultrasound (US)-fusion targeted biopsy have resulted in a paradigm shift in the diagnosis of prostate cancer by overcoming the limitations of systematic biopsy. Prebiopsy MRI and MRI US-fusion biopsy results in an increased detection of clinically significant disease, reduction in the detection of indolent disease, and allows for tumor localization during targeted biopsy. With these advantages, we have adopted a prebiopsy MRI and MRI-US-fusion biopsy diagnostic care pathway for all men at risk for prostate cancer and have performed more than 1900 biopsies to date. Herein we present our institutional development of MRI-US-fusion biopsy and highlight our results in those men who have had a previous negative biopsy, no prior biopsy, and those with a prior cancer diagnosis who may be candidate for active surveillance. Risk stratification with biomarkers and nomograms may allow for further counseling on the need for biopsy and the risk of harboring clinically significant disease. PMID- 28725591 TI - Diffusion weighted imaging of the prostate-principles, application, and advances. AB - This review article aims to provide an overview on the principles of diffusion weighted magnetic resonance imaging (DW-MRI) and its applications in the imaging of the prostate. DW-MRI with regards to different applications for prostate cancer (PCa) detection and characterization, local staging as well as for active surveillance (AS) and tumor recurrence after radical prostatectomy (RP) will be discussed. Furthermore, advances in DW-MRI techniques like diffusion kurtosis imaging (DKI) will be presented. PMID- 28725592 TI - Is contrast enhancement needed for diagnostic prostate MRI? AB - Prostate Imaging Reporting and Data System version 2 (PI-RADS v2) provides clinical guidelines for multiparametric magnetic resonance imaging (mpMRI) [T2 weighted imaging (T2WI), diffusion-weighted imaging (DWI) and dynamic contrast enhanced magnetic resonance imaging (DCE-MRI)] of prostate. However, DCE-MRI seems to show a limited contribution in prostate cancer (PCa) detection and management. In our experience, DCE-MRI, did not show significant change in diagnostic performance in addition to DWI and T2WI [biparametric MRI (bpMRI)] which represent the predominant sequences to detect suspected lesions in peripheral and transitional zone (TZ). In this article we reviewed the role of DCE-MRI also indicating the potential contribute of bpMRI approach (T2WI and DWI) and lesion volume evaluation in the diagnosis and management of suspected PCa. PMID- 28725593 TI - Buccal mucosal graft urethroplasty in men-risk factors for recurrence and complications: a third referral centre experience in anterior urethroplasty using buccal mucosal graft. AB - BACKGROUND: Urethral stricture disease is a challenging condition to treat and several approaches including direct visual internal urethrotomy (DVIU) and anastomotic or augmentation urethroplasties based on the use of flaps and graft have been reported. The aim of this study is to determine risk factors for stricture recurrence and complications in patients having buccal mucosal graft (BMG) urethroplasty for anterior urethral stricture under a single surgeon in a third referral centre in UK. METHODS: We conducted a retrospective review of a prospectively gathered database of 128 patients having various forms of BMG urethroplasty between 2001 and 2015. Success and failure in terms of stricture recurrence, patient demographics, stricture aetiology and anatomy, and the adverse outcomes of: post-micturition dribbling (PMD), erectile dysfunction (ED) >12 months and complications were recorded in order to determine risk factors for recurrent stricture and complications. RESULTS: The mean age of all patients was 42.8 years (range, 16-74 years). Average follow-up was 45 months (range, 3-159 months). The total re-stricture rate was 19% (24 men). PMD was reported in 16% (n=20) and ED in 12.5% (n=16). All ED was none organic and responded to oral PDE5 inhibitor treatment. Post-operative complications were reported in 16 patients (12.5%). The most frequent complications recorded were urinary fistula (n=4; 3.1%), graft contracture (n=4; 3.1%) and graft failure (n=4; 3.1%), all reported after penile urethroplasty. Univariate analysis indicated that age at surgery, stricture length, site and aetiology were all significant risk factors for stricture recurrence. On multivariate analysis penile site was the only significant independent variable for restricture. CONCLUSIONS: BMG urethroplasty represents a reliable therapeutic option for patient with urethral strictures with a success rate of 81% at 45 months of follow-up. Complications are more common in complex stricture of the penile urethra. On multivariate analysis penile site was the only significant independent variable for re-stricture. PMID- 28725594 TI - Weekly ascorbic acid infusion in castration-resistant prostate cancer patients: a single-arm phase II trial. AB - BACKGROUND: Ascorbic acid (AA) has in vivo cytotoxic properties at concentrations that can only be achieved through intravenous (IV) administration in humans. Treatment with intravenous AA is widely and increasingly used in complementary medicine despite a lack of clinical evidence for the efficacy of this treatment. METHODS: This non-comparative, single-center, phase II trial included patients with chemotherapy-naive, metastatic castration-resistant prostate cancer (mCRPC) from an outpatient clinic to evaluate the efficacy and safety of IV AA therapy. Patients received weekly infusions of AA (week 1, 5 g; week 2, 30 g; and weeks 3 12, 60 g) followed by efficacy evaluation at 12 weeks. The primary endpoint for efficacy was a 50% reduction in the prostate-specific antigen (PSA) level. The secondary endpoints included changes in health-related quality of life (HRQoL), biomarkers of bone metabolism, inflammation and bone scans. Clinicaltrials.gov identifier: NCT01080352. RESULTS: Twenty-three patients were enrolled in this study, and 20 completed the efficacy evaluation at 12 weeks. The mean baseline PSA level was 43 ug/L. No patient achieved a 50% PSA reduction; instead, a median increase in PSA of 17 ug/L was recorded at week 12. Among the secondary endpoints, no signs of disease remission were observed. In total, 53 adverse events (AEs) were recorded. Eleven were graded as "serious". Three AEs were directly related to AA, and all of which were related to fluid load. CONCLUSIONS: Infusion with 60 g of AA did not result in disease remission. This study does not support the use of intravenous AA outside clinical trials. PMID- 28725595 TI - A prospective evaluation of penile measures and glans penis sensory changes after penile prosthetic surgery. AB - BACKGROUND: With better designed devices and lower infection rates, satisfaction with inflatable penile prosthesis (IPP) placement is increasingly high. However, dissatisfaction is still present and there is disagreement regarding length and sensation changes after the IPP placement. The aim of this study was to evaluate changes in penile length, girth and sensitivity after IPP placement. METHODS: From August 2012 to January 2013 all patients undergoing "de novo" IPP surgery were invited to participate in this study. Eighty six patients met inclusion criteria while 62 agreed to participate in this observational study. A week before surgery, penile length and circumference, and glans/elbow biothesiometer readings were recorded 15 minutes after Trimix induced erection. Same measures were taken at postoperative week 6 and month 6. RESULTS: Amperage from Glans biothesiometer readings showed statistically significant shorter readings than elbow biothesiometer preoperatively, 6 weeks and 6 months after surgery (P<0.001 each). No significant sensory difference in the glans penis after IPP was noted. However, compared to preoperative Trimix induced erections, penile length and circumference were greater after IPP placement (P=0.04 and P=0.001, respectively). CONCLUSIONS: We observed statistically significant increase in penile length and girth after IPP placement without significant changes in sensory conduction. PMID- 28725596 TI - Utility of trigger point injection as an adjunct to physical therapy in men with chronic prostatitis/chronic pelvic pain syndrome. AB - BACKGROUND: Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is often associated with pelvic floor muscle spasm. While pelvic floor physical therapy (PFPT) is effective, some men are unable to resolve their symptoms and have residual trigger points (TPs). TP injection has been used for treatment in several neuromuscular pain syndromes. The objective of this study was to examine the efficacy and side effects of TP injection in men with CP/CPPS and pelvic floor spasm refractory to PT. METHODS: Using an IRB approved Men's Health Registry we reviewed the records of all men with a diagnosis of CP/CPPS who received at least 1 TP injection. Patients were phenotyped with UPOINT (all had the "T" domain for tenderness of muscle) and symptoms measured with the NIH Chronic Prostatitis Symptom Index (CPSI). Response was measured by a 5-point Global Response Assessment (GRA) and change in CPSI (paired t-test). For pelvic TPs, a pudendal block was done in lithotomy position and then each TP was identified transrectally by palpation. A nerve block needle was passed through the perineum into the TP confirmed by palpation. Between 0.5-1 cc was injected into each TP of a local anesthetic mixture (30:70 of 2% lidocaine and 0.25% bupivacaine). For anterior TPs, an ultrasound guided ilioinguinal block was done first and then each TP injected by direct palpation through the abdominal skin. Men were offered up to three sets of injections separated by 6 weeks each. RESULTS: We identified 37 patients who had a total of 68 procedures. Three men had no follow-up after their first injection and were included for side effects but not included for outcome. The indication was failure to progress on PT in 33, recurrent symptoms in 1 and refusal to do PT in 3. Mean age was 43.7 years (range 21-70 years) and median UPOINT domains was 3 (range 1-5). Initial CPSI was pain 13.7+/-3.4, urinary 5.3+/-2.2, quality of life 9.8+/-2.1 and total 28.8+/-6.0. 16 men had 1 injection, 11 had 2 and 10 had 3. All had pelvic TPs injected and 9 also had anterior TPs. By GRA, 12 had significant improvement (35.3%), 10 had some improvement (29.4%), 11 had no change (32.3%) and 1 was worse (2.9%). Mean CPSI dropped from 28.8+/-6.0 to 21.8+/-7.2 (P<0.0001). 18 men had a drop of 6 or more points in CPSI (53%). Of note, none of 3 men who were noncompliant with PT had benefit. 3 men had temporary numbness in the lateral thigh after the injection (4.4%) and 1 had difficulty weight bearing on 1 leg for about 30 minutes. CONCLUSIONS: TP injection in CP/CPPS patients as an adjunct to PT is well tolerated and leads to symptom improvement in about half. Durability and long term results are yet to be determined. PMID- 28725597 TI - Canine prostate models in preclinical studies of minimally invasive interventions: part I, canine prostate anatomy and prostate cancer models. AB - The high prevalence of prostate cancer (PCa) in elderly men and technical advances in early detection of localized PCa have led to continued efforts to develop new therapeutic options of minimally invasive nature in current urologic oncology community. Increasing newly emerging therapies are undergoing preclinical tests on the technical feasibility, efficacy and safety in animal experiments. The dog is an ideal large animal because of its similar anatomy to human and the capability allowing the use of the same medical devices applied in future clinical trials. Awareness of the local anatomy, microvascular structure, and histological features of the prostate in dogs is essential to experimental design and performance of the tested procedures and techniques. Although dogs with spontaneous PCa may be used in preclinical investigation, the low incidence and pathological features limit its utility. Alternatively, canine orthotopic PCa models have a great potential in preclinical research for this purpose. The goal of this review is to provide detailed anatomic and histological information of the canine prostate, outline the pathological and clinical characteristics of spontaneous PCa in dogs and discuss the current status of canine orthotopic PCa models. PMID- 28725598 TI - Canine prostate models in preclinical studies of minimally invasive interventions: part II, benign prostatic hyperplasia models. AB - Canine prostate is widely used as animal model in the preclinical evaluation of emerging therapeutic interventions. Spontaneous benign prostatic hyperplasia (BPH) is common in adult intact male dogs with two distinct pathological types: glandular and complex form of prostatic hyperplasia. The complex form of prostatic hyperplasia, usually occurring in older dogs, represents an ideal model because of its unique pathologic feature, including not only glandular hyperplasia but also an increase in prostate stromal components. The limited commercial availability of adult dogs with spontaneous BPH motivates experimentally induced BPH in young dogs. Hormone-induced canine BPH model has been well established with various hormonal treatment regimens and administration approaches. The goal of this review is to provide the veterinary background in spontaneous BPH in dogs, summarize the techniques in hormonal induction of canine BPH, and highlight the pathological and clinical limitations of the canine models that may lead to distinct therapeutic responses compared to clinical trials in humans. PMID- 28725599 TI - Effects of metformin on endothelial health and erectile dysfunction. AB - Erectile dysfunction (ED) affects approximately 18 million American men. ED may be attributed to several etiologies, including arteriogenic, psychogenic, neurogenic, hormonal, drug-induced, and systemic disease or aging related factors. Specific to arteriogenic ED, three major mechanisms have been identified: (I) endothelium-dependent vasodilatory impairment; (II) sympathetic nerve activity elevation; (III) atherosclerotic luminal narrowing. Additionally, these insults have been linked to the insulin resistant state, which in turn is comorbid with obesity, dyslipidemia, diabetes, and hypertension. In this review, we summarize the evidence regarding the impact of metformin-an insulin sensitizer on the three mechanisms of arteriogenic ED. We report that metformin treatment positively affects two of three pathways, specifically through enhanced endothelium-dependent vasodilation and sympathetic nerve activity attenuation, but does not seem to have a significant impact on hypertension regulation. Given the encouraging data found in both animal and clinical studies, we advocate for further studies on metformin use in ED. PMID- 28725600 TI - Endogenous and exogenous testosterone and prostate cancer: decreased-, increased- or null-risk? AB - For more than 70 years, the contention that high levels of testosterone or that the use of testosterone therapy (TTh) increases the development and progression of prostate cancer (PCa) has been widely accepted and practiced. Yet, the increasing and emerging evidence on testosterone research seems to challenge that contention. To review literature on the associations of endogenous and exogenous testosterone with decreased-, increased-, or null-risk of PCa, and to further evaluate only those studies that reported magnitude of associations from multivariable modeling as it minimizes confounding effects. We conducted a literature search to identify studies that investigated the association of endogenous total testosterone [continuous (per 1 unit increment and 5 nmol/L increment) and categorical (high vs. low)] and use of TTh with PCa events [1990 2016]. Emphasis was given to studies/analyses that reported magnitude of associations [odds ratio (OR), relative risk (RR) and hazard ratios (HRs)] from multivariable analyses to determine risk of PCa and their statistical significance. Most identified studies/analyses included observational and randomized placebo-controlled trials. This review was organized in three parts: (I) association of endogenous total testosterone (per 1 unit increment and 5 nmol/L increment) with PCa; (II) relationship of endogenous total testosterone (categorical high vs. low) with PCa; and (III) association of use of TTh with PCa in meta-analyses of randomized placebo-controlled trials. The first part included 31 observational studies [20 prospective (per 5 nmol/L increment) and 11 prospective and retrospective cohort studies (per 1 unit increment)]. None of the 20 prospective studies found a significant association between total testosterone (5 nmol/L increment) and increased- or decreased-risk of PCa. Two out of the 11 studies/analyses showed a significant decreased-risk of PCa for total testosterone per 1 unit increment, but also two other studies showed a significant increased-risk of PCa. Remaining studies reported null-risks values. Second part: eight of out of 25 studies reported an increased-risk of PCa for men with high levels of testosterone compared to low, but only four were statistically significant. However, 17 studies showed a decreased-risk of PCa after comparing high vs. low levels of testosterone, but 11 studies/analyses were statistically significant. Third part: two meta-analyses of randomized placebo controlled trials (n=8 and n=11, each) that investigated use of TTh with PCa reported not significant decreased-risks of PCa. The contention that high levels of testosterone or that the use of TTh increases the risk of PCa doesn't seem to be supported from the literature. Yet, we still need a study with the adequate power, follow-up data, epidemiological, pathological and clinical data that can support the safety and beneficial effects of high levels of endogenous testosterone or use of TTh in the natural history of PCa and in men's health. PMID- 28725601 TI - Penile fracture: role of ultrasound. AB - Penile fracture is a rare surgical emergency which requires prompt diagnosis and immediate surgical repair. In most cases the diagnosis is clinical however, in equivocal cases ultrasound examination can help in establishing the diagnosis by demonstrating the site and extent of tunica albuginea disruption. In this article, we are presenting sonographic findings in two cases of penile fractures. PMID- 28725602 TI - Transrectal ultrasound-guided extraction of impacted prostatic urethral calculi: a simple alternative to endoscopy. AB - Urethral stones can become impacted in the posterior urethra, typically presenting with varying degrees of acute urinary retention and lower urinary tract symptoms. These are traditionally treated in the inpatient setting, with external urethrotomy or endoscopic push-back of the calculus into the urinary bladder followed by cystolitholapaxy or cystolithotripsy. However, these methods are invasive, involve general anesthesia, and require radiation. In this report, we describe a simple, minimally invasive, and safe alternative technique to visualize and remove impacted prostatic urethral stones under the real-time guidance of transrectal ultrasonography (TRUS). The urologist can accomplish this procedure in the office, avoiding radiation exposure to the patient and hospital admission. PMID- 28725603 TI - Emerging role of liquid biopsy of cell-free tumor DNA for bladder cancer surveillance. PMID- 28725604 TI - Early or delayed radiotherapy after prostatectomy-who really benefits? PMID- 28725605 TI - Bridging the gap: use of scaffolding tissue bio-grafts to bolster vesicourethral anastomosis during salvage robot-assisted prostatectomy reduced leak rates and catheter times. PMID- 28725607 TI - Long-term adherence to clinical therapy of overactive bladder. PMID- 28725606 TI - Drugs for the overactive bladder: are there differences in persistence and compliance? PMID- 28725608 TI - From PROMIS to PRO-MRI in primary prostate cancer diagnosis. PMID- 28725609 TI - Chronic orchialgia. PMID- 28725610 TI - Extirpative surgery for chronic orchialgia: is there a role? AB - Chronic orchialgia is a difficult and frustrating condition for both the patient and clinician. Determining appropriate course of therapy should require extensive conservative measures and consideration of alternative surgical options prior to concluding an orchiectomy is warranted. This manuscript aims to provide the clinician with the information currently available to determine if the anticipated success rate is warranted to consider extirpative surgery for idiopathic chronic orchialgia. PMID- 28725611 TI - Robot-assisted microsurgery for chronic orchialgia. AB - Chronic orchialgia is one of the most common complaints seen in the urologists office and has traditionally been considered a very difficult diagnostic and therapeutic challenge for the clinician. First line management of chronic orchialgia is conservative treatment; however, in men who fail conservative therapy, surgical intervention may be indicated. Microsurgery has been the mainstay for surgical treatment of chronic orchialgia, but the implementation of robotics to microsurgery lends itself particularly to surgical treatment of chronic orchialgia. PubMed was used to perform a current literature search on chronic orchialgia with robotic microsurgery, robotic spermatic cord denervation, robotic varicocelectomy, and robotic vasectomy reversal. Although conservative therapy is considered the first line treatment for chronic orchialgia, reported outcomes are moderate to poor, with the need to proceed to surgical intervention in select cases. Current surgical therapies in which robot assistance have been applied to microsurgery include microsurgical denervation of the spermatic cord, varicocelectomy, and vasectomy reversal. As further studies have assisted in the understanding of surgical treatment of chronic orchialgia, the application of robot assistance to this level of microsurgery has been shown to be feasible and safe with comparable outcomes to traditional microsurgery and may provide potential advantages. PMID- 28725612 TI - Vasectomy reversal for post-vasectomy pain syndrome. AB - Post-vasectomy pain syndrome (PVPS) is a rare, but devastating outcome following vasectomy. Given the widespread utilization of vasectomy for permanent contraception, with more than 500,000 procedures performed annually in the United States, it can be a significant challenge for both patients and providers. Vasectomy reversal is a surgical option for men who fail conservative or medical management. Despite improvements in technique, vasectomy carries some inherent risks making pre-procedure counseling regarding the risks of PVPS paramount. Chronic post-operative pain, or PVPS, occurs in 1-2% of men undergoing the procedure. This review will examine the utility of vasectomy reversal as a means of addressing PVPS. PMID- 28725613 TI - Psychological perspectives in the patient with chronic orchialgia. AB - Chronic orchialgia is a challenging problem to both the practitioner and unhappy patient and may be a poorly understood manifestation of a potential variety of different discrete causes. Treatment options can be wide ranging and include conservative measures, medical therapy, in office treatments and surgical procedures. Research has primarily focused on these more concrete treatment options with little focus on the either co-morbid or causative psychological issues. By at least considering the potential psychological co-morbidities and stressors that may be associated with chronic orchialgia, physicians can better utilize a multi-modal approach to this vexing problem. PMID- 28725614 TI - A review of varicocele repair for pain. AB - A dilation of the pampiniform venous plexus in the scrotum above the testicle, called a varicocele, affects approximately 15% of the general male population. While the majority is asymptomatic, pain results in up to 10% of cases of varicoceles. The pain associated with varicoceles is typically mild and is described as heavy, achy, or dull-and is usually isolated to the testicle or spermatic cord. Guidelines clearly recommend varicocele repair in males with varicoceles, infertility, and an abnormal semen analysis. While chronic, severe pain is an additional indication for repair, a careful evaluation to rule out other etiologies in addition to a period of conservative management are necessary prior to surgical treatment because of the high incidental prevalence of varicoceles in the general population. Several techniques for varicocele repair have been described, including retroperitoneal, laparoscopic, inguinal, and subinguinal. Additionally, recent adjuncts to improve visualization and identification of critical structures including the operating microscope and microvascular Doppler ultrasound have improved success and complication rates. With careful patient selection, outcomes of varicocele repair with regard to pain are excellent, with over 90% of patients experiencing symptomatic relief. After failure of conservative treatments, a varicocele associated with pain should be considered for repair, and the microsurgical subinguinal approach is the gold standard surgical treatment, offering excellent outcomes while minimizing risk of complications. PMID- 28725615 TI - Chronic scrotal pain and microsurgical spermatic cord denervation: tricks of the trade. AB - Every practicing urologist encounters patients complaining of chronic scrotal content pain (CSCP). This condition can be equally frustrating for both patients and clinicians as there are no clear treatment guidelines, or pathways, for urologists to follow. As a result, most patients typically seek out multiple providers without improvements in their symptoms. Fortunately, microsurgical spermatic cord denervation (MSCD) is becoming an accepted, reliable and reproducible technique for definitively addressing CSCP in select patients. This manuscript reviews the background, effectiveness and current practice guidelines for scrotal pain in general, and MSCD in particular. Technical insights into how this technique can be performed both safely, and efficaciously, are provided. Finally, the manuscript presents a simple, yet detailed, easy to follow treatment algorithm to aid all urologists in the management of patients presenting with chronic pain. PMID- 28725616 TI - Chronic orchialgia: epidemiology, diagnosis and evaluation. AB - Chronic orchialgia is a vexing condition defined as chronic or intermittent scrotal pain lasting at least three months that significantly interferes with daily activities. There are currently no guidelines regarding the diagnosis and management of this condition despite it being the cause of 2.5-4.8% of urologic clinic visits. Men often present with chronic orchialgia in their mid to late 30s, although the condition can present at any age. A broad differential diagnosis of chronic orchialgia includes epididymitis, testicular torsion, tumors, obstruction, varicocele, epididymal cysts, hydrocele, iatrogenic injury following vasectomy or hernia repair, and referred pain from a variety of sources including mid-ureteral stone, indirect inguinal hernia, aortic or common iliac artery aneurysms, lower back disorders, interstitial cystitis, and nerve entrapment due to perineural fibrosis; approximately 25-50% of chronic orchialgia is idiopathic in nature. In such cases, it is reasonable to consider psychological and psychosocial factors that may be contributing to chronic pain. Invasive testing is not recommended in the work-up of chronic orchialgia. PMID- 28725617 TI - Post-vasectomy pain syndrome: diagnosis, management and treatment options. AB - Vasectomy is the most effective form of sterilization for men. With approximately 500,000 vasectomies performed each year in the United States, 1-2% of these patients will experience chronic testicular pain for greater than three months after the procedure. Post-vasectomy pain syndrome (PVPS) is diagnosis of exclusion, and may be caused by direct damage to spermatic cord structures, compression of nerves in the spermatic cord via inflammation, back pressure from epididymal congestion, and perineural fibrosis. Treatment should begin with the most noninvasive options and progress towards surgical management if symptoms persist. Noninvasive therapies include acupuncture, pelvic floor therapy and pharmacologic options. Ultimately, management of PVPS requires a multimodal approach. Thorough understanding of the potential etiologies of PVPS along with the therapeutic options currently available is important to improve quality of life. PMID- 28725618 TI - Medical management of chronic orchialgia. AB - Chronic idiopathic orchialgia is a urologic disease process that is as frustrating as it is common. While no consensus exists on management for otherwise-unexplained testicular pain, most providers would agree that once other treatable organic causes are ruled out, initial management should be symptom focused, and should be medical rather than surgical. This chapter presents a review of the evidence available for a variety of pharmacotherapies commonly employed in the treatment of idiopathic chronic orchialgia. PMID- 28725619 TI - Anatomy and physiology of chronic scrotal pain. AB - This article reviews the anatomy and physiology of the scrotum and its contents as it pertains to chronic scrotal pain. Physiology of chronic pain is reviewed, as well as the pathophysiology involved in the development of chronic pain. PMID- 28725620 TI - Attenuation of diabetic nephropathy in streptozotocin-induced diabetic rats by Punica granatum Linn. leaves extract. AB - With an objective to develop Complementary and Alternative Medicine for the treatment of diabetic nephropathy, the present study investigated the protective effects of methanolic extract of Punica granatum leaves (MPGL) in streptozotocin induced diabetic nephropathy. Diabetic nephropathy has become a leading cause of end stage renal failure worldwide. P. granatum, due to its anti-diabetic, anti inflammatory and antioxidant activities may retard the progression of diabetic nephropathy. In this study, diabetes was induced by a single injection of streptozotocin (STZ, 45 mg/kg, i.p.) in rats. STZ-diabetic rats were treated with oral doses of MPGL (100, 200 and 400 mg/kg) for 8 weeks. At the end of the experimental period, body and kidney weight and blood glucose levels were determined. Serum and urine parameters were investigated. Antioxidant enzymes and lipid peroxide levels were determined in the kidney along with histopathological examination of the same. MPGL significantly increased body weight, lowered blood glucose levels and ameliorated kidney hypertrophy index in the STZ-diabetic rats. The extract also decreased the levels of creatinine, blood urea nitrogen, total cholesterol, triglycerides, advanced glycation end products and albumin in serum and urine, respectively. MPGL significantly increased the antioxidant parameters in the kidney. Histological evaluation revealed that MPGL treated STZ-diabetic rats demonstrated reduced vacuolar degeneration of tubules; periodic acid Schiff base (PAS) positivity staining intensity in glomeruli and basement membrane thickening. Present findings provide experimental evidence that MPGL has potential antioxidant, antihyperglycemic and anti-glycation activities which might be helpful in slowing the progression of diabetic nephropathy. PMID- 28725621 TI - Chemical composition, acute toxicity, antioxidant and anti-inflammatory activities of Moroccan Tetraclinis articulata L. AB - Hydro-distilled essential oil (EO) from the leaves of the western Mediterranean and Moroccan endemic plant Tetraclinis articulata was analyzed by GC/MS and examined for its acute toxicity on mice, in order to establish the safe doses. Furthermore, the anti-Inflammatory activity was evaluated based on carrageenan and trauma induced rats paw edema and the antioxidant potential has been investigated using different methods including DPPH radical-scavenging assay, Trolox equivalent antioxidant capacity (TEAC) and Ferric-reducing antioxidant power assay (FRAP). The major identified compounds in GC/MS analysis were bornyl acetate (26.81%), camphor (22.40%) and alpha-pinene (7.16%), with 25 other minor constituents. No mortalities in acute toxicity were observed, indicating that the LD50 of T. articulata essential oil is highest than 5 g/kg. In the anti inflammatory test based on chemical and mechanical induced trauma, the EO demonstrated an effective reduce swelling by 64.71 +/- 9.38% and 69.09 +/- 6.02% respectively obtained 6 h after administration at the dose of 200 mg/kg when compared to the control groups. Moreover in the antioxidant testing battery, T. articulata essential oil showed a promising scavenging effect measured by DPPH, TEAC and ferric-reducing power assays with IC50 values of 12.05 +/- 0.24 mg/mL, 8.90 +/- 0.17 mg/mL and 0.15 +/- 0.01 mg/mL respectively. These results suggest that, the EO from the leaves of T. articulata constitutes a valuable source of anti-inflammatory and antioxidant metabolites. These findings argue for the possible integration of this oil in pharmaceutical, cosmetic and food industries. PMID- 28725622 TI - Authentication of Piper betle L. folium and quantification of their antifungal activity. AB - The TLC profiles of intra- and inter-day precision for Piper betle L. (PBL) folium methanol extract was studied for their peak marker recognition and identification. The Numerical chromatographic parameters (NCPs) of the peak markers, the hierarchical clustering analysis (HCA) and the principal component analysis (PCA) were applied to authenticate the PBL. folium extract from other Piper species folium extract and to ensure the antifungal activity quality of the PBL essential oil. The spotted extract was developed with the mobile phase of toluene: ethyl acetate; 93:7, (v/v). The eluted plate was viewed with the TLC Visualizer, scanned under absorption and fluorescent mode detection, and on each sample the in-situ UV spectra were recorded between 190 to 400 nm. The NCPs profiles of intra- and inter-day precision results offered multi-dimensional chromatogram fingerprints for better marker peak pattern recognition and identification. Using the r-value fingerprints data series generated with this method allowed more precise discrimination the PBL. from other Piper species compared to the marker peak area fingerprint method. The cosine pair comparison was a simple method for authentication of two different fingerprints. The ward linkage clustering and the pair cross-correlation comparison were better chemometric methods to determine the consistency peak area ratio between fingerprints. The first component PCA-loading values of peak marker area fingerprints were correlated linearly to both the bio-marker concentration as well as the antifungal activity. This relationship could be used to control the quality and pharmacological potency. This simple method was developed for the authentication and quantification of herbal medicine. PMID- 28725623 TI - Isolation and characterization of antimicrobial compound from the stem-bark of the traditionally used medicinal plant Adenium obesum. AB - BACKGROUND: Medicinal plants constitute a natural reservoir for medicines worldwide. They serve mainstream therapeutics and are central in folklore medicine. In case of Adenium obesum (Lav, Apocynaceae), indigenous people of Oman use it for the treatment of venereal diseases, wounds, skin diseases, headaches, muscle pain as well as joint pain; yet, the active ingredients have not been classified. To screened the antioxidant and antimicrobial activities of an identified compound that we isolated from the highest active chloroform extract. METHODS: The antioxidant and antimicrobial activities of the extracts and the isolated compound were determined by diphenyl-1-picrylhydrazyl (DPPH) and disc diffusion methods. To characterize the compound, we used TLC, column, 1H-NMR, 13C NMR, 2D-NMR, IR and MS. RESULTS: The highest antioxidant activity was found in chloroform extract with EC50 value of 28.32 MUg/ml followed by water, methanol, butanol, ethyl acetate and hexane extracts, their IC50 being 29.95, 39.17, 42.40, 43.20 and 57.00 MUg/ml respectively. All crude extracts and pure compound displayed moderate antimicrobial activity against one Gram positive Staphylococcus aureus and three Gram negative Escherichia coli, Pseudomonas aeruginosa and Proteus vulgaris within growth inhibition range of 0-13 mm. The active metabolite was identified as 3,4-dihydroxycinnamic acid (R)-1-carboxy-2 (3,4-dihydroxyphenyl) ethyl ester which is a common plant ingredient known as rosmarinic acid. CONCLUSION: The results indicate that walnut chloroform fraction may contain effective compounds with a broad spectrum of curative applications. This is the first report on isolation and characterization of a compound from chloroform crude extract of A. obesum. PMID- 28725624 TI - Incretin effect of Urena lobata leaves extract on structure and function of rats islet beta-cells. AB - This study aims to determine the incretin effects of Urena lobata leaves extract on the structure and function of rats islet beta-cells. This study utilizes male Sprague-Dawley rats divided into 2 control group and 3 test group (n = 5). Diabetic rats were induced with High Fructose Diet (HFD) and single dose intraperitoneal streptozotocin 25 mg/kg bw. Aqueous leaves extract of U. lobata was prepared by decoction methods and administrated orally with doses of 250, 500, and 1000 mg/kg bw for 4 weeks then incretin effect was evaluated by measuring serum GLP-1, insulin, and blood glucose levels. Histology of islet beta cells was evaluated using photomicroscopy by analyzing size, shape, and number. Data were analyzed using ANOVA test followed by LSD test and p <= 0.05 is considered significant. Oral administration of aqueous extract U. lobata leaves at doses of 250, 500, and 1000 mg/kg body weight were able to prolong GLP-1 bioavailability by 3-fold, 5-fold, and 7-fold respectively when compared to the diabetic group whereas blood glucose level were decreased about 30%, 35%, and 40% respectively (p < 0.05). Extract at doses of 500 and 1000 mg/kg bw also increased insulin level by 4-fold and 8-fold respectively compared to the diabetic group and the islet beta-cells were repaired. The active compound in U. lobata leaves extract are suggested to prevent degradation of GLP-1 by inhibition of DPP-4 activity. Aqueous extract of U. lobata also improved the structure and function of islet beta-cells by increasing of GLP-1 bioavailability. PMID- 28725625 TI - Evaluation of effect of alcoholic extract of heartwood of Pterocarpus marsupium on in vitro antioxidant, anti-glycation, sorbitol accumulation and inhibition of aldose reductase activity. AB - Rising popularity of phytomedicines in various diseased conditions have strengthened the significance of plant-research and evaluation of phytoextracts in clinical manifestations. Pterocarpus marsupium Roxb., a medicinal plant, known for its anti-oxidant and anti-diabetic activity is a rich source of phytochemicals with antihyperglycemic and antihyperlipidemic activities. However, its possible role in diabetic complications is not evaluated yet. The present study explores the possible role of alcoholic extract of heartwood of P. marsupium in the treatment of long-term diabetic complications. The alcoholic extract of P. marsupium was evaluated for advanced glycation-end-products formation, erythrocyte sorbitol accumulation and rat kidney aldose reductase enzyme inhibition at the concentration of 25-400 MUg/ml using in-vitro bioassays. Also the phytoextract at the concentration of 10-320 MUg/ml was evaluated for its antioxidant potential by in-vitro antioxidant assays which includes, determination of total phenol content; reducing power assay; nitric oxide scavenging activity; superoxide radical scavenging activity; total antioxidant capacity; total flavonoid content; DPPH scavenging activity; and hydrogen peroxide scavenging activity. The alcoholic extract of P. marsupium across varying concentrations showed inhibitory effect as evident by IC50 on advanced glycation-end-products formation (55.39 MUg/ml), sorbitol accumulation (151.00 MUg/ml) and rat kidney aldose reductase (195.88 MUg/ml). The phytoextract also exhibited high phenolic and flavonoid contents with promising antioxidant potential against the antioxidant assays evaluated. The present investigation suggests that the phytoextract showed prominent antioxidant, antiglycation property and, inhibited accumulation of sorbitol and ALR enzyme, thus promising a beneficial role in reducing/delaying diabetic complications. PMID- 28725626 TI - Evaluation of anticancer activity of Cordia dichotoma leaves against a human prostate carcinoma cell line, PC3. AB - Mechanisms of antioxidant and apoptosis induction may be involved in the management of cancer by medicinal plants. Aim of the study was designed to evaluate anticancer activity of the methanolic extract of Cordia dichotoma leaves (MECD) against a human prostate carcinoma cell line, PC3. Flavonoid content was determined by colorimetric principle and antioxidant activity by various in vitro assays. MTT, DCFH-DA and DAPI staining assays were performed for the evaluation of cytotoxicity, analysis of induction of apoptosis and intracellular reactive oxygen species (ROS) activity level by MECD against human prostate carcinoma cell line, PC3. Flavonoid content was found to be 160 mg QE/g extract. IC50 values for MECD treatment in various assays based on scavenging of 2,2-diphenyl-1 picrylhydrazyl, 2,2-azinobis(3-ethylenebenzothiazoline-6-sulfonic acid), nitric oxide, peroxy radical, superoxide anion, hydroxy radical were found to be 315.5, 38, 476, 523, 197, 82 MUg/ml respectively. MECD exposure to PC3 cells significantly increased the cell death (p < 0.001, IC50 = 74.5 MUg/ml), nuclear condensation, apoptosis (p < 0.001) and induced production of ROS (p < 0.001) initiating apoptotic cascade in a dose dependent manner. This study confirms that MECD possesses antioxidant property and can prevent carcinogenesis by reducing oxidative stress. MECD possesses anticancer activity and lead to PC3 cell death via induction of apoptosis mediated through excessive ROS generation. Flavonoids in MECD may be responsible for these activities due to dual antioxidant and pro oxidant properties. PMID- 28725627 TI - Effect of yoga training on lipid metabolism in industrial workers with reference to body constitution (Prakriti). AB - INTRODUCTION: The progressive increase in dyslipidemia and physical inactivity are considered to be major risk factors for the onset of non communicable diseases. Awareness of body constitution plays a vital role to regularise optimum health. The present study was planned to evaluate the effect of yoga practices on lipid metabolism with reference to specific body constitution (Prakriti). METHODS: A self-as-control study was conducted on 36 male healthy volunteers between age group of 30-58 years. Their prakriti analysis was done using standardized, validated questionnaire and were divided into Vata-Pitta (n = 16) and Pitta-Kapha (n = 20) groups. The assessment of lipid profile was done in fasting blood samples before and after 12 weeks of yoga training. Data were analyzed using paired t-test and independent t-test. RESULTS: After yoga intervention, the result of within group comparison revealed that in Vata-Pitta (V-P) group, significant decrease in the levels of TC, LDL (p < 0.001) and significant increase in HDL (p < 0.01) was observed. While, Pitta-Kapha (P-K) group showed significant decrease in TC (p < 0.001), TG (p < 0.01), LDL (p < 0.001) and VLDL (p < 0.05) levels. Further, the results between groups revealed that P-K group has significantly higher baseline levels of TC, TG and VLDL as compared to V-P group (p < 0.05). CONCLUSION: The study concludes that yoga practices can effectively regulate lipid metabolism and total body energy expenditure with reference to specific constitutional type (Prakriti) that may act as a tool to assess magnitude of metabolic functions. PMID- 28725628 TI - Perspectives on reflexology: A qualitative approach. AB - INTRODUCTION: Reflexology is the systematic practice of applying some pressure to particular points on the feet and hands to impact on health of related parts of the body. OBJECTIVE: To explore the practitioners' perspectives of reflexology in Malaysia. METHODS: Data was collected using face-to-face semi-structured interviews with practitioners in Malaysia. The interviews were conducted in the Malay language and recorded. Interview conversations were translated and transcribed verbatim. Responses relating to different themes were identified in each of the interviews and a coding frame was developed. For each theme, the relevant data enabled a description of the range of views and experiences. Data collection and analysis were conducted concurrently and recruitment was stopped when saturation had been reached. All respondents gave written consent for their participation. RESULTS: The findings show that reflexology treatment nowadays has been accepted as one of the ways to maintain general health. Practitioners believe that reflexology is able to detect some problems in to the body, which can make patients aware of a health condition and seek further treatment. However, if reflexology is not performed correctly, it may cause negative effects such as pain and bruises. Some practitioners voiced concern that illegal activities are taking place in unethical reflexology centers. CONCLUSIONS: Empowering the practitioner as a professional would help gain the public's trust and confidence in their treatment. Strict enforcement of regulation related to illegal conduct in reflexology centers will improve people's perception of the practice. PMID- 28725629 TI - Evaluation the effect of 50 and 100 mg doses of Cuminum cyminum essential oil on glycemic indices, insulin resistance and serum inflammatory factors on patients with diabetes type II: A double-blind randomized placebo-controlled clinical trial. AB - AIM: The purpose of this study was to evaluate the effect of 50 and 100 mg doses of green cumin essential oil on glycemic and inflammatory indices in patients with diabetes type II. METHOD: In this randomized double-blind placebo-controlled clinical trial, subjects were divided into three groups after selecting them randomly according to the inclusion criteria: 1 - Cuminum cyminum capsule (100 mg/day,n = 33), 2 - C. cyminum capsule (50 mg/day, n = 33), and 3 - placebo (n = 33). Before and after 8 weeks of intervention, a blood sample was taken. FINDINGS: The findings demonstrated that the mean of the FBS, glycosylated hemoglobin (HgA1c) and the serum levels of insulin were significantly decreased and insulin sensitivity (HOMA-IR) was significantly increased in the groups receiving the 100 mg supplement (P < 0.001) and 50 mg supplement, but these indices were increased in the placebo group. The mean serum levels of TNF-alpha and hsCRP were significantly decreased, and serum levels of adiponectin was significantly increased at the end of the study in the groups receiving 100 mg (P < 0.001) and 50 mg (P = 0.008) supplement as well as in the group who received the placebo. There were no significant change in HOMA-B and QUICKI as insulin resistance parameters. DISCUSSION AND CONCLUSION: Administering C. cyminum supplement in patients with diabetes type II may decrease the serum levels of insulin, FBS, and glycosylated hemoglobin and also the inflammatory indices of TNF-alpha and hsCRP and increased the serum levels of adiponectin. In addition it may control the complications of diabetes type II in these patients. PMID- 28725630 TI - Curcumin: An age-old anti-inflammatory and anti-neoplastic agent. AB - Curcumin is a natural anti-inflammatory agent that has been used for treating medical conditions for many years. Several experimental and pharmacologic trials have demonstrated its efficacy in the role as an anti-inflammatory agent. Curcumin has been shown to be effective in treating chronic conditions like rheumatoid arthritis, inflammatory bowel disease, Alzheimer's and common malignancies like colon, stomach, lung, breast, and skin cancers. As treatments in medicine become more and more complex, the answer may be something simpler. This is a review article written with the objective to systematically analyze the wealth of information regarding the medical use of curcumin, the "curry spice", and to understand the existent gaps which have prevented its widespread application in the medical community. PMID- 28725631 TI - Biological activities and medicinal properties of Asafoetida: A review. AB - Ferula asafoetida Linn. is a main source of asafoetida, a strong, tenacious and sulfurous odor, and oleo-gum resin of medicinal and nutritional importance. Asafoetida has been consumed as a spice and a folk medicine for centuries. Recent studies have shown several promising activities particularly relaxant, neuroprotective, memory enhancing, digestive enzyme, antioxidant, antispasmodic, hypotensive, hepatoprotective, antimicrobial, anticarcinogenic, anticancer, anticytotoxicity, antiobesity, anthelmintic and antagonistic effect. This review effectively deals with phytochemistry and various pharmacological and clinical studies of asafoetida. PMID- 28725632 TI - Medicinal importance, pharmacological activities, and analytical aspects of hispidulin: A concise report. AB - Herbal medicines have been played an important role in the human civilization since very ancient time as a food, cloth, medicine and other aspects. Some of the important drugs in the modern medicine were derived from the natural sources such as aspirin, digitalis, quinine, vincristine, vinblastine etc. Hispidulin (4', 5, 7-trihydroxy-6-methoxyflavone) is a flavones derivative found in plant such as Grindelia argentina, Arrabidaea chica, Saussurea involucrate, Crossostephium chinense, Artemisia and Salvia species. Hispidulin have antioxidant, antifungal, anti-inflammatory, antimutagenic, and antineoplastic properties. So far, various analytical methods have been investigated and developed for detection of hispidulin in the plant materials. Productions of hispidulin through different tissue culture techniques have been also investigated. Present review summarized medicinal uses, pharmacological activities and analytical aspects of hispidulin. From the above mentioned aspects, we can conclude that, this review will be helpful to the researcher in the field of natural product for the development of novel molecule for the treatment of different disorders. PMID- 28725633 TI - Exploiting leech saliva to treat osteoarthritis: A provocative perspective. AB - Plant and animal-derived products are crucial components in complementary and alternative medicine. Although modern medicine has provided numerous innovations and advancements, these often fail to reveal new and dependable, inexpensive treatments nor real cures that are relatively free of adverse side effects. We present evidence that hirudotherapy, which utilizes leeches, improves certain diseases, including osteoarthritis. Osteoarthritis, a disease in joints, could benefit from use of medicinal peptides found in leech saliva, components of its immune system. PMID- 28725635 TI - Implications of MicroRNAs in Oncolytic Virotherapy. AB - MicroRNAs (miRNAs) are an abundant class of small non-coding RNA molecules (~22 nt) that can repress gene expression. Deregulation of certain miRNAs is widely recognized as a robust biomarker for many neoplasms, as well as an important player in tumorigenesis and the establishment of tumoral microenvironments. The downregulation of specific miRNAs in tumors has been exploited as a mechanism to provide selectivity to oncolytic viruses or gene-based therapies. miRNA response elements recognizing miRNAs expressed in specific tissues, but downregulated in tumors, have been inserted into the 3'UTR of viral genes to promote the degradation of these viral mRNAs in healthy tissue, but not in tumor cells. Consequently, oncolytic virotherapy-associated toxicities were diminished, while therapeutic activity in tumor cells was preserved. However, viral infections themselves can modulate the miRNome of the host cell, and such miRNA changes under infection impact the normal viral lifecycle. Thus, there is a miRNA mediated interplay between virus and host cell, affecting both viral and cellular activities. Moreover, the outcome of such interactions may be cell type or condition specific, suggesting that the impact on normal and tumoral cells may differ. Here, we provide an insight into the latest developments in miRNA-based viral engineering for cancer therapy, following the most recent discoveries in miRNA biology. Furthermore, we report on the relevance of miRNAs in virus-host cell interaction, and how such knowledge can be exploited to improve the control of viral activity in tumor cells. PMID- 28725634 TI - IP3 Receptor-Mediated Calcium Signaling and Its Role in Autophagy in Cancer. AB - Calcium ions (Ca2+) play a complex role in orchestrating diverse cellular processes, including cell death and survival. To trigger signaling cascades, intracellular Ca2+ is shuffled between the cytoplasm and the major Ca2+ stores, the endoplasmic reticulum (ER), the mitochondria, and the lysosomes. A key role in the control of Ca2+ signals is attributed to the inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs), the main Ca2+-release channels in the ER. IP3Rs can transfer Ca2+ to the mitochondria, thereby not only stimulating core metabolic pathways but also increasing apoptosis sensitivity and inhibiting basal autophagy. On the other hand, IP3-induced Ca2+ release enhances autophagy flux by providing cytosolic Ca2+ required to execute autophagy upon various cellular stresses, including nutrient starvation, chemical mechanistic target of rapamycin inhibition, or drug treatment. Similarly, IP3Rs are able to amplify Ca2+ signals from the lysosomes and, therefore, impact autophagic flux in response to lysosomal channels activation. Furthermore, indirect modulation of Ca2+ release through IP3Rs may also be achieved by controlling the sarco/endoplasmic reticulum Ca2+ ATPases Ca2+ pumps of the ER. Considering the complex role of autophagy in cancer development and progression as well as in response to anticancer therapies, it becomes clear that it is important to fully understand the role of the IP3R and its cellular context in this disease. In cancer cells addicted to ER mitochondrial Ca2+ fueling, IP3R inhibition leads to cancer cell death via mechanisms involving enhanced autophagy or mitotic catastrophe. Moreover, IP3Rs are the targets of several oncogenes and tumor suppressors and the functional loss of these genes, as occurring in many cancer types, can result in modified Ca2+ transport to the mitochondria and in modulation of the level of autophagic flux. Similarly, IP3R-mediated upregulation of autophagy can protect some cancer cells against natural killer cells-induced killing. The involvement of IP3Rs in the regulation of both autophagy and apoptosis, therefore, directly impact cancer cell biology and contribute to the molecular basis of tumor pathology. PMID- 28725636 TI - Epithelial-to-Mesenchymal Transition in the Female Reproductive Tract: From Normal Functioning to Disease Pathology. AB - Epithelial-to-mesenchymal transition (EMT) is a physiological process that is vital throughout the human lifespan. In addition to contributing to the development of various tissues within the growing embryo, EMT is also responsible for wound healing and tissue regeneration later in adulthood. In this review, we highlight the importance of EMT in the development and normal functioning of the female reproductive organs (the ovaries and the uterus) and describe how dysregulation of EMT can lead to pathological conditions, such as endometriosis, adenomyosis, and carcinogenesis. We also summarize the current literature relating to EMT in the context of ovarian and endometrial carcinomas, with a particular focus on how molecular mechanisms and the tumor microenvironment can govern cancer cell plasticity, therapy resistance, and metastasis. PMID- 28725637 TI - Opportunistic Pathogen Porphyromonas gingivalis Modulates Danger Signal ATP Mediated Antibacterial NOX2 Pathways in Primary Epithelial Cells. AB - Porphyromonas gingivalis, a major opportunistic pathogen in the etiology of chronic periodontitis, successfully survives in human gingival epithelial cells (GECs). P. gingivalis abrogates the effects of a host danger molecule, extracellular ATP (eATP)/P2X7 signaling, such as the generation of reactive oxygen species (ROS) via the mitochondria and NADPH oxidases (NOX) from primary GECs. However, antimicrobial functions of ROS production are thoroughly investigated in myeloid-lineage immune cells and have not been well-understood in epithelial cells. Therefore, this study characterizes antibacterial NOX2 generated ROS and host downstream effects in P. gingivalis infected human primary GECs. We examined the expression of NOX isoforms in the GECs and demonstrate eATP stimulation increased the mRNA expression of NOX2 (p < 0.05). Specific peptide inhibition of NOX2 significantly reduced eATP-mediated ROS as detected by DCFDA probe. The results also showed P. gingivalis infection can temporally modulate NOX2 pathway by reorganizing the localization and activation of cytosolic molecules (p47phox, p67phox, and Rac1) during 24 h of infection. Investigation into downstream biocidal factors of NOX2 revealed an eATP-induced increase in hypochlorous acid (HOCl) in GECs detected by R19-S fluorescent probe, which is significantly reduced by a myeloperoxidase (MPO) inhibitor. MPO activity of the host cells was assayed and found to be positively affected by eATP treatment and/or infection. However, P. gingivalis significantly reduced the MPO product, bactericidal HOCl, in early times of infection upon eATP stimulation. Analysis of the intracellular levels of a major host-antioxidant, glutathione during early infection revealed a substantial decrease (p < 0.05) in reduced glutathione indicative of scavenging of HOCl by P. gingivalis infection and eATP treatment. Examination of the mRNA expression of key enzymes in the glutathione synthesis pathway displayed a marked increase (p < 0.05) in glutamate cysteine ligase (GCL) subunits GCLc and GCLm, glutathione synthetase, and glutathione reductase during the infection. These suggest P. gingivalis modulates the danger signal eATP induced NOX2 signaling and also induces host glutathione synthesis to likely avoid HOCl mediated clearance. Thus, we characterize for the first time in epithelial cells, an eATP/NOX2-ROS-antibacterial pathway and demonstrate P. gingivalis can circumvent this important antimicrobial defense system potentially for successful persistence in human epithelial tissues. PMID- 28725638 TI - Isolation of F. novicida-Containing Phagosome from Infected Human Monocyte Derived Macrophages. AB - Francisella is a gram-negative bacterial pathogen, which causes tularemia in humans and animals. A crucial step of Francisella infection is its invasion of macrophage cells. Biogenesis of the Francisella-containing phagosome (FCP) is arrested for ~15 min at the endosomal stage, followed by gradual bacterial escape into the cytosol, where the microbe proliferates. The crucial step in pathogenesis of tularemia is short and transient presence of the bacterium within phagosome. Isolation of FCPs for further studies has been challenging due to the short period of time of bacterial residence in it and the characteristics of the FCP. Here, we will for the first time present the method for isolation of the FCPs from infected human monocytes-derived macrophages (hMDMs). For elimination of lysosomal compartment these organelles were pre-loaded with dextran coated colloidal iron particles prior infection and eliminated by magnetic separation of the post-nuclear supernatant (PNS). We encountered the challenge that mitochondria has similar density to the FCP. To separate the FCP in the PNS from mitochondria, we utilized iodophenylnitrophenyltetrazolium, which is converted by the mitochondrial succinate dehydrogenase into formazan, leading to increased density of the mitochondria and allowing separation by the discontinuous sucrose density gradient ultracentrifugation. The purity of the FCP preparation and its acquisition of early endosomal markers was confirmed by Western blots, confocal and transmission electron microscopy. Our strategy to isolate highly pure FCPs from macrophages should facilitate studies on the FCP and its biogenesis. PMID- 28725640 TI - Risk factors for impaired fasting glucose or diabetes among HIV infected patients on ART in the Copperbelt Province of Zambia. AB - BACKGROUND: Africa has a high prevalence of both Human Immunodeficiency Virus and Non Communicable Diseases (NCDs) but in Zambia there are few data on co-morbid NCDs like Diabetes Mellitus (DM) among HIV-infected individuals. We aimed to identify risk factors for impaired fasting glucose or diabetes among HIV-infected Zambians on long-term Combined Antiretroviral Treatment (cART). METHODS: This was a cross sectional study of adult HIV patients in five health facilities of Copperbelt Province in Zambia. HIV/AIDS patients aged 18 years and above, enrolled in care at those health facilities and had been on cART for more than 2 years were included. All patients known to have Diabetes mellitus were excluded from the study. Participants underwent assessment of random blood sugar levels at enrolment and returned the following morning for fasting glucose measured by glucometers. The primary outcome was proportion with impaired fasting glucose or DM. Multivariable logistic regression was used to examine if demographics, time on ART, type of ART regimen, body mass index and baseline CD4 count were predictors of impaired fasting glucose. RESULTS: Overall (n = 270) there were 186 females (69%) and 84 males (31%). The prevalence of impaired fasting blood sugar or diabetes after 8 h of fasting was 15% (95%CI: 11.1, 20.0). Ten percent (26/270) had impaired fasting glucose and 5 % (14/270) had diabetes. Impaired fasting glucose was higher in males than females [AOR = 3.26, (95% CI: 1.15-9.25; p-value = 0.03)]; as well as among patients on second line treatment than those on first line [AOR = 3.87 (95% CI 1.16-12.9); p-value = 0.03]. In contrast those with less likelihood of impaired fasting glucose included patients with a normal BMI (18.5-24.9) than overweight or obese patients [AOR = 0.09 (95% CI 0.03-0.31; p-value < 0.001)]; and participants who had less than 4 diabetes symptoms than those with more than 4 diabetes symptoms [AOR = 0.04 (95% CI 0.02-0.12); p-value < 0.001]. CONCLUSION: We have found high levels of impaired fasting glucose or diabetes among ART patients compared to what is reported in the general population suggesting missed care and support opportunities associated with metabolic imbalance management. There is thus a need to re-package HIV programming to include integration of diabetes screening as part of the overall care and support strategy. PMID- 28725642 TI - Medicaid Adult Dental Benefit Impact on Dental Utilization: A University Clinic Setting. AB - INTRODUCTION: In 2014, the state of Colorado initiated new dental coverage benefits for adults in the Colorado Medicaid program. The goal of this study was to investigate the utilization and impact of this new dental coverage at the University of Colorado School of Dental Medicine. The utilization of dental services delivered and the numbers of patients in this program were compared before and after the implementation of the benefit. MATERIALS AND METHODS: This retrospective study compared the utilization of services provided 2 years prior and 2 years after the Medicaid adult benefit was made available. Through the University of Colorado School of Dental Medicine (CU-SODM) electronic dental record, all adult Medicaid dental patients' (ages 21+) charts were extracted for zip code, CDT dental procedure codes, with a focus on tooth extraction compared to tooth saving procedures. Graphical analysis and Pearson's chi-squared tests were applied to assess the statistical significance of procedure utilization changes over time. RESULTS: After implementation of the Medicaid adult benefit, the number of patients seen at the school under this program increased by a factor of 4.5. The geographic range (zip code) increased with some patients coming from further distances to receive dental care. The number of patients from local zip codes increased by as much as 235%. There was a 51% increase in tooth saving procedures, which was statistically significant (P = 0.0013). Additionally, there was a 22% decrease in extractions, while not statistically significant (P = 0.0992), a downward trend was clear. DISCUSSION: The focus was on the utilization of Medicaid adult benefits at the dental school, which was only a small proportion of the state-wide Medicaid population. Therefore, these data are not generalizable for statewide assessments of the program. However, based on the findings at the school clinics, more adult patients utilized the benefits; and chose to receive more tooth saving procedures and less extractions after implementation of the Medicaid adult benefit. This Medicaid study conducted at the CU-SODM 2 years after the adult dental coverage can be used as a baseline for future studies. PMID- 28725639 TI - Anaplasma phagocytophilum MSP4 and HSP70 Proteins Are Involved in Interactions with Host Cells during Pathogen Infection. AB - Anaplasma phagocytophilum transmembrane and surface proteins play a role during infection and multiplication in host neutrophils and tick vector cells. Recently, A. phagocytophilum Major surface protein 4 (MSP4) and Heat shock protein 70 (HSP70) were shown to be localized on the bacterial membrane, with a possible role during pathogen infection in ticks. In this study, we hypothesized that A. phagocytophilum MSP4 and HSP70 have similar functions in tick-pathogen and host pathogen interactions. To address this hypothesis, herein we characterized the role of these bacterial proteins in interaction and infection of vertebrate host cells. The results showed that A. phagocytophilum MSP4 and HSP70 are involved in host-pathogen interactions, with a role for HSP70 during pathogen infection. The analysis of the potential protective capacity of MSP4 and MSP4-HSP70 antigens in immunized sheep showed that MSP4-HSP70 was only partially protective against pathogen infection. This limited protection may be associated with several factors, including the recognition of non-protective epitopes by IgG in immunized lambs. Nevertheless, these antigens may be combined with other candidate protective antigens for the development of vaccines for the control of human and animal granulocytic anaplasmosis. Focusing on the characterization of host protective immune mechanisms and protein-protein interactions at the host pathogen interface may lead to the discovery and design of new effective protective antigens. PMID- 28725643 TI - Crisis Team Management in a Scarce Resource Setting: Angkor Hospital for Children in Siem Reap, Cambodia. AB - INTRODUCTION: A crisis team management (CTM) simulation course was developed by volunteers from Health Volunteers Overseas for physicians and nurses at Angkor Hospital for Children (AHC) in Siem Reap, Cambodia. The framework for the course was adapted from crisis resource management (1, 2), crisis team training (3), and TeamSTEPPs(c) models (4). The CTM course focused on teaching physicians and nurses on the development of team performance knowledge, skills, and attitudes. Challenges to providing this course at AHC included availability of simulation equipment, cultural differences in learning, and language barriers. The purpose of this project was to evaluate the impact of a CTM simulation course at AHC on attitudes and perceptions of participants on concepts related to team performance. METHODS: Each of the CTM courses consisted of three lectures, including team performance concepts, communication, and debriefing followed by rotation through four simulation scenarios. The evaluation instrument used to evaluate the AHC CTM course was developed for Cambodian staff at AHC based on TeamSTEPPs(c) instruments evaluating attitude and perceptions of team performance (5). CTM team performance concepts included in lectures, debriefing sessions, and the evaluation instrument were: team structure, leadership, situation monitoring, mutual support, and communication. The Wilcoxon signed-rank test was used to analyze pre- and post-test paired data from participants in the course. RESULTS: Of the 54 participants completing the three CTM courses at AHC, 27 were nurses, 6 were anesthetists, and 21 were physicians. Attitude and perception scores were found to significantly improve (p < 0.05) for team structure, leadership, situation monitoring, and communication. Team performance areas that improved the most were: discussion of team performance, communication, and exchange of information. CONCLUSION: Teaching of non-technical skills can be effective in a setting with scarce resources in a Southeastern Asian country. PMID- 28725641 TI - Mechanisms Mediating Pediatric Severe Asthma and Potential Novel Therapies. AB - Although a rare disease, severe therapy-resistant asthma in children is a cause of significant morbidity and results in utilization of approximately 50% of health-care resources for asthma. Improving control for children with severe asthma is, therefore, an urgent unmet clinical need. As a group, children with severe asthma have severe and multiple allergies, steroid resistant airway eosinophilia, and significant structural changes of the airway wall (airway remodeling). Omalizumab is currently the only add-on therapy that is licensed for use in children with severe asthma. However, limitations of its use include ineligibility for approximately one-third of patients because of serum IgE levels outside the recommended range and lack of clinical efficacy in a further one third. Pediatric severe asthma is thus markedly heterogeneous, but our current understanding of the different mechanisms underpinning various phenotypes is very limited. We know that there are distinctions between the factors that drive pediatric and adult disease since pediatric disease develops in the context of a maturing immune system and during lung growth and development. This review summarizes the current data that give insight into the pathophysiology of pediatric severe asthma and will highlight potential targets for novel therapies. It is apparent that in order to identify novel treatments for pediatric severe asthma, the challenge of undertaking mechanistic studies using age appropriate experimental models and airway samples from children needs to be accepted to allow a targeted approach of personalized medicine to be achieved. PMID- 28725644 TI - Pesticides Curbing Soil Fertility: Effect of Complexation of Free Metal Ions. AB - Researchers have suggested that the reason behind infertility is pernicious effect of broad spectrum pesticides on non target, beneficial microorganism of soil. Here, studying the chelating effect of selective organophosphate and carbamate pesticides with essential metal ions, at all possible combinations of three different pH (4 +/- 0.05, 7 +/- 0.05 and 9 +/- 0.05) and three different temperatures (15 +/- 0.5 degrees C, 30 +/- 0.5 degrees C and 45 +/- 0.5 degrees C), shows very fast rate of reaction which further increases with increase of pH and temperature. Carbonyl oxygen of carbamate and phosphate oxygen of organophosphate were found to be common ligating sites among all the complexes. Formed metal complexes were found to be highly stable and water insoluble on interaction with essential metal ions in solvent medium as well as over silica. Density functional theory (DFT) calculations not only reinforced the experimental observations, but, after a wide computational conformational analysis, unraveled the nature of the high stable undesired species that consist of pesticides complexed by metal ions from the soil. All in all, apart from the direct toxicity of pesticides, the indirect effect by means of complexation of free metal ions impoverishes the soil. PMID- 28725645 TI - Imaging Bronchopulmonary Dysplasia-A Multimodality Update. AB - Bronchopulmonary dysplasia is the most common form of infantile chronic lung disease and results in significant health-care expenditure. The roles of chest radiography and computed tomography (CT) are well documented but numerous recent advances in imaging technology have paved the way for newer imaging techniques including structural pulmonary assessment via lung magnetic resonance imaging (MRI), functional assessment via ventilation, and perfusion MRI and quantitative imaging techniques using both CT and MRI. New applications for ultrasound have also been suggested. With the increasing array of complex technologies available, it is becoming increasingly important to have a deeper knowledge of the technological advances of the past 5-10 years and particularly the limitations of some newer techniques currently undergoing intense research. This review article aims to cover the most salient advances relevant to BPD imaging, particularly advances within CT technology, postprocessing and quantitative CT; structural MRI assessment, ventilation and perfusion imaging using gas contrast agents and Fourier decomposition techniques and lung ultrasound. PMID- 28725646 TI - Histone chaperone in regulation of cellular metabolism dictating stem cell fate? PMID- 28725647 TI - Retraction: Regulatory factors of induced pluripotency: current status. AB - [This retracts the article on p. 15 in vol. 1, PMID: 27358861.]. PMID- 28725648 TI - Deletion with 25 nucleotides of TCRzeta gene in T cells from a case with chronic myeloid leukemia. PMID- 28725649 TI - Inducible pluripotent stem cells and pulmonary arterial hypertension: the future is now! PMID- 28725650 TI - X-chromosome activity in naive human pluripotent stem cells-are we there yet? PMID- 28725651 TI - Human acute leukemia induced pluripotent stem cells: a unique model for investigating disease development and pathogenesis. PMID- 28725652 TI - Rescuing BMPR2-driven endothelial dysfunction in PAH: a novel treatment strategy for the future? PMID- 28725653 TI - CALR-positive myeloproliferative disorder in a patient with Ph-positive chronic myeloid leukemia in durable treatment-free remission: a case report. AB - Current diagnostic criteria for Philadelphia-negative myeloproliferative neoplasia (MPN) have been redefined by the discovery of Janus kinase 2 (JAK2), myeloproliferative leukemia (MPL) and calreticulin (CALR) genetic alterations. Only few cases of coexistence of CALR-mutated MPN and Philadelphia-positive chronic myeloid leukemia (CML) have been described so far. Here we report the case of a patient with CML diagnosed in 2001, treated with imatinib and pegylated interferon (IFN) frontline. She reached complete molecular remission (CMR) and discontinued imatinib, maintaining treatment free remission. Due to persistent thrombocytosis, we repeated bone marrow (BM) analysis and diagnosed CARL-mutated essential thrombocythemia (ET). A CALR-positive clone was found to be present since 2001, and was unaffected by imatinib treatment, possibly representing a molecular abnormality arising at stem cell level. PMID- 28725654 TI - Stem cells from human hair follicles: first mechanical isolation for immediate autologous clinical use in androgenetic alopecia and hair loss. AB - BACKGROUND: Hair follicles are known to contain a well-characterized niche for adult stem cells: the bulge, which contains epithelial and melanocytic stem cells. Stem cells in the hair bulge, a clearly demarcated structure within the lower permanent portion of hair follicles, can generate the interfollicular epidermis, hair follicle structures, and sebaceous glands. The bulge epithelial stem cells can also reconstitute in an artificial in vivo system to a new hair follicle. METHODS: In this study, we have developed a new method to isolate human adult stem cells by mechanical centrifugation of punch biopsy from human hair follicles without culture condition. Here, we used human follicle stem cells (HFSCs), to improve the hair density in 11 patients (38 to 61 years old) affected by AGA in stage 3-5 as determined by the Norwood-Hamilton classification scale. RESULTS: The primary outcomes were microscopic identification and counting of HFSCs. The secondary outcomes were clinical preliminary results and safety and feasibility in HFSCs-treated scalp. Each scalp tissue suspension contained about 3,728.5+/-664.5 cells. The percentage of hair follicle-derived mesenchymal stem cells CD44+ [from dermal papilla (DP)] was about 5%+0.7% whereas the percentage of hair follicle epithelial stem cells CD200+ (from the bulge) was about 2.6%+0.3%. In total, 23 weeks after the last treatment with HFSCs mean hair count and hair density increases over baseline values. In particular, a 29%+/-5% increase in hair density for the treated area and less than a 1% increase in hair density for the placebo area. CONCLUSIONS: We have shown that the isolated cells are capable to improve the hair density in patients affected by androgenetic alopecia (AGA). These cells appear to be located in the bulge area of human. PMID- 28725656 TI - Expression of vox and vent mRNAs and encoded proteins in zebrafish embryos. AB - In Danio rerio (zebrafish), members of the vent gene-family (vox/vega1, vent/vega2) are considered as ventralizing factors. We investigated not only the expression of their mRNAs by in situ hybridization at different stages of embryonic development, but also the spatial distribution of the encoded proteins by whole-mount immunostaining. We showed vox mRNA to be available in embryos since early cleavage and later on. Vent mRNA appeared after zygotic genome activation only. The vox and vent proteins were revealed at stage of eight blastomeres. At blastula and gastrula the vox and vent protein staining areas completely overlapped those of the mRNAs. They were expressed uniformly throughout the embryo except for a small region of clearing on the dorsal side. From the bud stage throughout somitogenesis, the vox and vent proteins staining progressively covered the embryos except for dorsal side: at the bud stage it resembled that of mRNA and at the beginning of somitogenesis it was clearly seen along the axis structures. At the pharyngula period stages the proteins were located in neural crest zone, but their mRNAs appeared to be in the tail tips. Thus during embryogenesis, the spatial distributions of a protein and its mRNA may not always quite coincide. We observed such mismatches in embryos at the cleavage stage and in the pharyngula period. PMID- 28725657 TI - Empirical and computational findings converge in support of the Hierarchical State Feedback Control theory. PMID- 28725655 TI - Cell replacement therapy is the remedial solution for treating Parkinson's disease. AB - The selective degeneration of dopaminergic (DA) neurons in Parkinson's disease (PD) has made an idol target for cell replacement therapies and other emerging surgical treatments. Certainly, by transplantation method, the therapeutic regimens such as human fetal ventral midbrain (hfVM) cells, human embryonic stem cells (hESCs), human neural stem/precursor/ progenitor cells (hNSCs/hNPCs), human mesenchymal stem cells (hMSCs), human induced neural stem cells (hiNSCs), and human induced pluripotent stem cells (hiPSCs) have been used into DA deficient striatum. In recent decades, surgical methods such as deep brain stimulation (DBS) and gene therapies have been used with the aim of treating PD. Though the technology has improved and many treating options arise, the permanent source for curing PD has not been identified yet. In this review, we examine how stem cell therapies have made advancement as a therapeutic source for PD when compared with surgical treatments. PMID- 28725658 TI - Mesenchymal Stem Cells Overexpressing Interleukin-10 Promote Neuroprotection in Experimental Acute Ischemic Stroke. AB - Interleukin (IL)-10 is a contributing factor to neuroprotection of mesenchymal stem cell (MSC) transplantation after ischemic stroke. Our aim was to increase therapeutic effects by combining MSCs and ex vivo IL-10 gene transfer with an adeno-associated virus (AAV) vector using a rat transient middle cerebral artery occlusion (MCAO) model. Sprague-Dawley rats underwent 90 min MCAO followed by intravenous administration of MSCs alone or IL-10 gene-transferred MSCs (MSC/IL 10) at 0 or 3 hr after ischemia reperfusion. Infarct lesions, neurological deficits, and immunological analyses were performed within 7 days after MCAO. 0 hr transplantation of MSCs alone and MSC/IL-10 significantly reduced infarct volumes and improved motor function. Conversely, 3-hr transplantation of MSC/IL 10, but not MSCs alone, significantly reduced infarct volumes (p < 0.01) and improved motor function (p < 0.01) compared with vehicle groups at 72 hr and 7 days after MCAO. Immunological analysis showed that MSC/IL-10 transplantation significantly inhibits microglial activation and pro-inflammatory cytokine expression compared with MSCs alone. Moreover, overexpressing IL-10 suppressed neuronal degeneration and improved survival of engrafted MSCs in the ischemic hemisphere. These results suggest that overexpressing IL-10 enhances the neuroprotective effects of MSC transplantation by anti-inflammatory modulation and thereby supports neuronal survival during the acute ischemic phase. PMID- 28725659 TI - Explant Methodology for Analyzing Neuroblast Migration. AB - The subventricular zone (SVZ) in the mammalian forebrain contains stem/progenitor cells that migrate through the rostral migratory stream (RMS) to the olfactory bulb throughout adulthood. SVZ-derived explant cultures provide a convenient method to assess factors regulating the intermediary stage of neural stem/progenitor cell migration. Here, we describe the isolation of SVZ-derived RMS explants from the neonatal mouse brain, and the conditions required to culture and evaluate their migration. PMID- 28725660 TI - Perceived Advantages and Disadvantages of Using Pre-Exposure Prophylaxis (PrEP) among Sexually Active Black Women: An Exploratory Study. AB - Knowledge of pre-exposure prophylaxis (PrEP) continues to remain scarce among Black women who are disproportionally affected by HIV in the United States. A thematic analysis of open-ended questions from a sample of Black women (n=119) who completed a mix-methods, online, e-health study was conducted to examine the perceived advantages and disadvantages of using PrEP. Being a female controlled method, empowerment, option for women with risky sex partners, and serodiscordant couples were advantages described. Disadvantages of PrEP were identified as the complexity of the choice, encouragement of sex with risky partners, increased burden, promotion of unprotected sex, and newness of the drug. PMID- 28725662 TI - Life satisfaction data in a developing country: CaliBRANDO measurement system. AB - This paper describes one large multi-annual research project-CaliBRANDO-about subjective wellbeing in a developing country. CaliBRANDO is a life satisfaction measurement system implemented in Cali, the third largest city in Colombia, South America. Data have been collected annually since 2014 and aim at collecting comprehensive temporal information about individual-level subjective wellbeing and its relationship with government performance. CaliBRANDO is the only study in Colombia that measures subjective wellbeing in a large city in this way. This paper presents the methodology followed in the study and discusses the relevance of the data collected. PMID- 28725661 TI - Assessment of stereotactic radiosurgery treatment response for brain metastases using MRI based diffusion index. AB - INTRODUCTION: To investigate the clinical predictive values of the apparent diffusion coefficient (ADC) as a biomarker in radiation response of brain metastases. METHOD: Forty-one patients with brain metastases treated with stereotactic radiosurgery (SRS) were imaged at baseline, one month post SRS, and six months post SRS using diffusion weighted MRI. The mean of ADC for metastases and tumor volume was calculated. A diffusion index (DI) was generated using the sum of 1/ADC among all the voxels in a tumor. Tumor response status was determined by lesion volume measured at six month post-SRS, or the last available follow-up MRI. Logistic regression analysis was used to account for factors associated with tumor response at baseline and one month post SRS. RESULTS: A higher ADC mean distinguished responders from non-responders only at six month post SRS (p < 0.05). However, a lower DI distinguished a responder from non responders on the baseline, one month post SRS and six months post SRS, indicating better diagnostic performance of the DI with regard to a non-invasive biomarker in monitoring SRS treatment response. A multivariate logistic regression analysis identified the DI as a predictor of tumor response at baseline and one month post SRS (p = 0.002 and p = 0.001, respectively). However, logistic regression analysis identified the ADC mean as a predictor of tumor response only at six months post SRS (p = 0.019). CONCLUSION: Our results support the hypothesis that ADC and tumor volume generated DT at baseline, one month and six months post SRS may be a promising biomarker predicting brain metastases' response. Specifically, a lower DI at baseline and one month distinguished responders from non-responders. PMID- 28725663 TI - Data for Sochi 2014 Olympics discussion on social media. AB - Presented data is related to the research article "Sochi 2014 Olympics on Twitter: Perspectives of Hosts and Guests" [2]. The data were collected through regular API Twitter search for five months windowing 2014 Sochi Olympic Games and further used for cluster analysis and analysis of the sentiment on the Games. The main dataset contains 616 thousand tweets, rigorously cleaned and filtered to remove irrelevant content. To comply with the Twitter API user agreement, the dataset presented in this article includes only generalized daily data with all information contained in individual tweets removed. The proposed use of the dataset is academic research of changing discussion on the topics related to Mega events in conjunction with political events. PMID- 28725664 TI - Morphotypes and pigment profiles of halophilic bacteria: Practical data useful for novelty, taxonomic categorization and for describing novel species or new taxa. AB - Halophilic bacteria were isolated from oil spill samples collected from West coast of Goa. Bacteria were isolated from oil studded soil, salt marsh and offshore samples (A, A7, CSM, CB and CM) collected along the West coastline in Goa (India) i.e. Arambol beach, Calanguate beach, Candolim beach and Colva beach on Zobell Marine agar, R2A agar, Mannitol salt agar and Blood agar at temperature 22 to 24 degrees C. Isolates showed growth in the presence of hydrocarbons (1% phenanthrene and 2% bitumen). Diverse profiles of pigments were observed on different nutrient medium. Color of pigments produced on agar media recorded as per standard color chart. All isolates showed different growth pattern. Isolate no 11 (GOACSMMS-11) showed three different morphological features/growth patterns on Zobell Marine Agar and R2A medium in the presence of hydrocarbons. Results obtained yield new information which gives a clear idea about morphological features and pigmented profiles of hydrocarbon resistant morphotypes in the presence different media compositions. The presented datasets will be useful for studies on bacterial species showing high sequence similarity. Hence, generated data serves as a benchmark for to distinguish between genetically similar bacteria and for further research in phenotype based microbial diversity, microbial ecology of microorganisms and microbial systematics and taxonomy in addition to genotype data. PMID- 28725665 TI - Data on haplotype-supported immunoglobulin germline gene inference. AB - Data that defines IGHV (immunoglobulin heavy chain variable) germline gene inference using sequences of IgM-encoding transcriptomes obtained by Illumina MiSeq sequencing technology are described. Such inference is used to establish personalized germline gene sets for in-depth antibody repertoire studies and to detect new antibody germline genes from widely available immunoglobulin-encoding transcriptome data sets. Specifically, the data has been used to validate (Parallel antibody germline gene and haplotype analyses support the validity of immunoglobulin germline gene inference and discovery (DOI: 10.1016/j.molimm.2017.03.012) (Kirik et al., 2017) [1]) the inference process. This was accomplished based on analysis of the inferred germline genes' association to the donors' different haplotypes as defined by their different, expressed IGHJ alleles and/or IGHD genes/alleles. The data is important for development of validated germline gene databases containing entries inferred from immunoglobulin-encoding transcriptome sequencing data sets, and for generation of valid, personalized antibody germline gene repertoires. PMID- 28725666 TI - Training and performance measures for novices to the area of fingerprint analysis. AB - The data accessible here represents the training tool used with novice students prior to an assessment of their performance in a fingerprint matching task (Stevenage and Pitfield, 2016; Stevenage and Bennett, in preparation) [1,2]. The training tool was compiled following semi-structured interviews with practicing fingerprint experts within the UK (Stevenage and Pitfield, 2016) [1], and has been verified as being a useful summary document by a subset of these experts. Also provided are the performance data of trained student participants on a fingerprint matching task. This was undertaken under biased and unbiased contextual conditions, and under control conditions in which no contextual information was provided. These resources are provided here to enable the interested reader to extend analysis in this area through studying the performance of non-naive participants, and to complete a meta-analysis across relevant studies. PMID- 28725667 TI - Data on Lipocalin 2 and phosphatidylinositol 3-kinase signaling in a methionine- and choline-deficient model of non-alcoholic steatohepatitis. AB - The data presented in this brief report support the research article "Altered mitochondrial and peroxisomal integrity in lipocalin-2-deficient mice with hepatic steatosis" [1, doi: 10.1016/j.bbadis.2017.04.006]. We tested whether the absence of Lipocalin-2 (LCN2) could dysregulate the phosphatidylinositol 3 kinase/protein kinase B (PI3K-PKB) pathway and hepatic homeostasis in Non Alcoholic-Steatohepatitis (NASH). The article highlights the role of LCN2 in hepatic homeostasis. PMID- 28725668 TI - Data on MyoD reduction by autophagy in C2C12 cells. AB - Autophagy is a highly regulated physiologic mechanism in which cells maintain homeostasis by degrading excessive or unnecessary proteins and damaged or aged organelles through the lysosomal machinery (Yorimitsu and Klionsky, 2005) [1]. MyoD is basic helix-loop-helix (bHLH) transcription factors that regulate myoblast proliferation and myogenic differentiation. MyoD is expressed in adult skeletal muscle (Megeney et al., 1996) [2] and adult fibers (Brack et al., 2005) [3]. MyoD is mainly degraded by the ubiquitin-proteasome system (Floyd et al., 2001) [4] and partly by autophagy (Kim et al., 2012) [5]. Data showed that autophagy decreased MyoD protein in C2C12 cells by Western blotting analysis. PMID- 28725669 TI - Data concerning the impact of mental fatigue on vigor as measured with the Brunel Mood Scale (BRUMS) in both physically active and trained subjects: A mini meta analysis. AB - The aim of the present mini meta-analysis was to compute the overall effect of mental fatigue induced by two cognitive tasks (namely, AX-continuous performance test or AX-CPT and incongruent Stroop test) on mood state, particularly on vigor, assessed using the Brunel Mood Scale (BRUMS), in both physically active and trained subjects. Search strategy was taken from a systematic review recently carried out by Van Cutsem and collaborators [1], as well as the quality assessment of the included studies. Mental fatigue was not found to impact on vigor score (n=62, effect size=0.12, -0.22-0.46, p=0.500, Q=0.18, I2=0.00, T2=0.00, p=0.996). However, an evidence of publication bias was found. PMID- 28725670 TI - Fatty acid and lipidomic data in normal and tumor colon tissues of rats fed diets with and without fish oil. AB - Data is provided to show the detailed fatty acid and lipidomic composition of normal and tumor rat colon tissues. Rats were fed either a Western fat diet or a fish oil diet, and half the rats from each diet group were treated with chemical carcinogens that induce colon cancer (azoxymethane and dextran sodium sulfate). The data show total fatty acid profiles of sera and of all the colon tissues, namely normal tissue from control rats and both normal and tumor tissues from carcinogen-treated rats, as obtained by gas chromatography with mass spectral detection. Data from lipidomic analyses of a representative subset of the colon tissue samples is also shown in heat maps generated from hierarchical cluster analysis. These data display the utility lipidomic analyses to enhance the interpretation of dietary feeding studies aimed at cancer prevention and support the findings published in the companion paper (Effects of fish oil supplementation on prostaglandins in normal and tumor colon tissue: modulation by the lipogenic phenotype of colon tumors, Djuric et al., 2017 [1]). PMID- 28725671 TI - Data on the no-load performance analysis of a tomato postharvest storage system. AB - In this present investigation, an original and detailed empirical data on the transfer of heat in a tomato postharvest storage system was presented. No-load tests were performed for a period of 96 h. The heat distribution at different locations, namely the top, middle and bottom of the system was acquired, at a time interval of 30 min for the test period. The humidity inside the system was taken into consideration. Thus, No-load tests with or without introduction of humidity were carried out and data showing the effect of a rise in humidity level, on temperature distribution were acquired. The temperatures at the external mechanical cooling components were acquired and could be used for showing the performance analysis of the storage system. PMID- 28725672 TI - Duplication of subtelomeric regions in an adult with acute monocytic leukemia with an acquired jumping translocation involving 3q13.31-qter. AB - A jumping translocation (JT) involves a single donor chromosome and two or more recipient chromosomes in which a similar chromosomal region is translocated to various recipient chromosomes in different cell lines of a single individual. JTs are often associated with telomeric regions. Only 21 acquired JTs have previously been described in myeloid malignancies. Three of these cases involved the 3q13.31 qter region of which all were associated with a dismal outcome. In our recent publication, "Characterization of an acquired jumping translocation involving 3q13.31-qter in a patient with de novo acute monocytic leukemia" [1], we characterized the breakpoint region 3q13.31 by oligo-based array comparative genomic hybridization analysis. The present article provides data on copy number aberrations observed in the subtelomeric regions of this patient. Copy number alterations in the subtelomeric region have not been addressed previously in patients with JT. PMID- 28725673 TI - Efficiency data of intracellular recombinant protein delivery using cationic lipid coated silk fibroin particle. AB - This article presents data related to the research article "Fibroin particle supported cationic lipid layers for highly efficient intracellular protein delivery" and focuses on the delivery efficiency aspects of the fibroin particle cationic lipid complex (Fibroplex), including its fabrication and the intracellular delivery to the mouse skin tissue. We introduced a stable lipid particle complex called "Fibroplex", formed by loading cargo protein onto a silk fibroin spherical particle core complexed with cationic liposomes to address the intracellular recombinant protein delivery. This system exhibits cationic charge, which is advantageous for cellular uptake. The particle core is loaded with the cargo protein with high efficiency and shows long-term release in serum environment. Fibroplex can be formed simply by mixing the particle core and cationic liposome, and this spontaneous interaction does not cause any detrimental effects on the function of cargo proteins. Lipid-particle complex structure is stable over 10 days in the serum at 37 degrees C. Fibroplex was delivered at high efficiency to a wide variety of cells, including cancer cells and primary cell-lines. Also, Fibroplex loaded with two types of cargo successfully introduced them into the cytoplasm. Furthermore, Fibroplex shows successful intracellular delivery when injected with various cargo proteins such as GFP, HRP and Tyrosinase into mouse skin tissue as well as in vitro. The highlights of this article include: (1) Data for fabrication procedure of Fibroplex, (2) loading capacity, surface charge changes of Fibroplex, and (3) Intracellular delivery aspects of Fibroin in vitro and vivo. PMID- 28725674 TI - Study of infectious diseases in archaeological bone material - A dataset. AB - Bones of human and ground sloth remains were analyzed for presence of Trypanosoma cruzi by conventional PCR using primers TC, TC1 and TC2. Sequence results amplified a fragment with the same product size as the primers (300 and 350pb). Amplified PCR product was sequenced and analyzed on GenBank, using Blast. Although these sequences did not match with these parasites they showed high amplification with species of bacteria. This article presents the methodology used and the alignment of the sequences. The display of this dataset will allow further analysis of our results and discussion presented in the manuscript "Finding the unexpected: a critical view on molecular diagnosis of infectious diseases in archaeological samples" (Pucu et al. 2017) [1]. PMID- 28725675 TI - Comparisons of ELISA and Western blot assays for detection of autophagy flux. AB - We analyzed autophagy/mitophagy flux in vitro (C2C12 myotubes) and in vivo (mouse skeletal muscle) following the treatments of autophagy inducers (starvation, rapamycin) and a mitophagy inducer (carbonyl cyanide m-chlorophenylhydrazone, CCCP) using two immunodetection methods, ELISA and Western blotting, and compared their working range, accuracy, and reliability. The ELISAs showed a broader working range than that of the LC3 Western blots (Table 1). Table 2 showed that data value distribution was tighter and the average standard error from the ELISA was much smaller than those of the Western blot, directly relating to the accuracy of the assay. Test-retest reliability analysis showed good reliability for three individual ELISAs (interclass correlation, >= 0.7), but poor reliability for three individual Western blots (interclass correlation, <= 0.4) (Table 3). PMID- 28725676 TI - Challenges to cervical cancer treatment in Bangladesh: The development of a women's cancer ward at Dhaka Medical College Hospital. AB - Cervical cancer is the second most common cause of female cancer mortality worldwide. Concurrent chemoradiotherapy represents the standard of care for patients with stages IB2 to IVa cervical cancer. Unfortunately radiation therapy capacity is severely limited to non-existent in many Low and Middle-Income Countries. One solution has been to use chemotherapy to reduce tumor size to allow for radical surgery or in the case of inoperable cancers, as a placeholder until radiation is available. In Bangladesh, there has been the progressive development of resources for the treatment of women with gynecologic cancers. However, radiation therapy resources are limited with a six-month waiting period to receive radiation. Neoadjuvant chemotherapy (NACT) remains the main primary treatment intervention for women with advanced cervical cancer in Bangladesh. This implementation study summarizes of the experience and challenges to caring for women in a new gynae-oncology ward at Dhaka Medical College Hospital, a 2600 bed government hospital in Dhaka, Bangladesh. PMID- 28725677 TI - A population-based study of cervical cytology findings and human papillomavirus infection in a suburban area of Thailand. AB - Despite the high incidence of cervical cancer in Thailand, large population-based studies on cervical cytology and HPV prevalence and genotype distribution are rare. This study aimed to determine cervical cytology results and the prevalence and distribution of HPV among Thai females in Bangkhayaeng subdistrict, Pathumthani province, Thailand. Of 4681 female inhabitants, aged 20-70 years, 1523 women finally participated in the study. Cervical samples using liquid-based cytology were collected during February-August 2013 and analyzed for HPV genotype by the LINEAR ARRAY(r) HPV Genotyping Test (Roche, USA). All participants with abnormal cytology or HPV positivity underwent colposcopy and biopsy. Of 1523 eligible women, 4.1% had abnormal cytology including ASC-US (2.4%), LSIL (1.0%), and HSIL (0.5%). The HPV infection rate was 13.7%. The prevalences of high-risk, probable high-risk, and low-risk HPV types were 5.6%, 3.5%, and 6.8%, respectively. The most common high-risk HPV types detected were HPV-16 (1.31%), HPV-51 (1.25%), and HPV-52 (1.25%). The most common probable high-risk and low risk HPV types detected were HPV-72 (1.51%), HPV-62 (1.38%), and HPV-70 (1.18%). The rates of CIN2-3 and cancer in this cohort were 1.4% and 0.3%, respectively. In conclusion, HPV prevalence in this study was lower than reported in studies conducted in Western countries or other Asia countries, despite the high prevalence of CIN2 + and cancer. HPV type screening results of the general population in Bangkhayaeng subdistrict were similar to those reported in other countries, with HPV-16 the most common type. However, higher frequencies of HPV 51 and HPV-52 were observed. Despite the availability of a free screening program in this area, the participation rate remains low. PMID- 28725678 TI - Hands-on experience can lead to systematic mistakes: A study on adults' understanding of sinking objects. AB - In line with theories of embodied cognition, hands-on experience is typically assumed to support learning. In the current paper, we explored this issue within the science domain of sinking objects. Adults had to make a guess about which of two objects in a pair would sink faster. The crucial manipulation was whether participants were handed real-life objects (real-objects condition) or were shown static images of objects (static-images condition). Results of Experiment 1 revealed more systematic mistakes in the real-objects than the static-images condition. Experiment 2 investigated this result further, namely by having adults make predictions about sinking objects after an initial training. Again, we found that adults made more mistakes in the real-objects than the static-images condition. Experiment 3 showed that the negative effect of hands-on experiences did not influence later performance. Thus, the negative effects of hands-on experiences were short-lived. Even so, our results call into question an undifferentiated use of manipulatives to convey science concepts. Based on our findings, we suggest that a nuanced theory of embodied cognition is needed, especially as it applies to science learning. PMID- 28725680 TI - Introducing a new journal on Parkinson's disease. PMID- 28725679 TI - Abnormal connectivity between the default mode and the visual system underlies the manifestation of visual hallucinations in Parkinson's disease: a task-based fMRI study. AB - BACKGROUND: The neural substrates of visual hallucinations remain an enigma, due primarily to the difficulties associated with directly interrogating the brain during hallucinatory episodes. AIMS: To delineate the functional patterns of brain network activity and connectivity underlying visual hallucinations in Parkinson's disease. METHODS: In this study, we combined functional magnetic resonance imaging (MRI) with a behavioral task capable of eliciting visual misperceptions, a confirmed surrogate for visual hallucinations, in 35 patients with idiopathic Parkinson's disease. We then applied an independent component analysis to extract time series information for large-scale neuronal networks that have been previously implicated in the pathophysiology of visual hallucinations. These data were subjected to a task-based functional connectivity analysis, thus providing the first objective description of the neural activity and connectivity during visual hallucinations in patients with Parkinson's disease. RESULTS: Correct performance of the task was associated with increased activity in primary visual regions; however, during visual misperceptions, this same visual network became actively coupled with the default mode network (DMN). Further, the frequency of misperception errors on the task was positively correlated with the strength of connectivity between these two systems, as well as with decreased activity in the dorsal attention network (DAN), and with impaired connectivity between the DAN and the DMNs, and ventral attention networks. Finally, each of the network abnormalities identified in our analysis were significantly correlated with two independent clinical measures of hallucination severity. CONCLUSIONS: Together, these results provide evidence that visual hallucinations are due to increased engagement of the DMN with the primary visual system, and emphasize the role of dysfunctional engagement of attentional networks in the pathophysiology of hallucinations. PMID- 28725681 TI - Comparison of clinical features in pathologically confirmed PSP and MSA patients followed at a tertiary center. AB - BACKGROUND/OBJECTIVES: The clinical diagnosis of progressive supranuclear palsy (PSP) and multiple system atrophy (MSA) remains challenging due to heterogeneity of the diseases. AIMS: Here we compared the clinical features of PSP and MSA to gain insight into their diagnosis and prognosis, particularly the prognostic value of down-gaze palsy latency in PSP progression. METHODS: We reviewed clinical features of pathologically confirmed 10 PSP and 13 MSA patients, incidentally matched in age-at-onset, gender, and disease duration, followed at Columbia University Medical Center during 1994-2009. RESULTS: The final antemortem diagnosis was incorrect in 30% of PSP (all lacking down-gaze palsy) and 23% of MSA patients. Falls in the first year of the disease, pyramidal involvement and freezing of gait during the course were similar between PSP and MSA. Ataxia and apraxia were in 50% of the PSP patients. Parkinsonism responsive to levodopa treatment was in 30% of the PSP (all with resting tremor) and 50% of the MSA patients. Dysautonomia in MSA could occur as early as 3 years preceding the motor symptoms, with 46% within the first year of the motor onset, but 15% did not have dysautonomia in life. The latency of down-gaze palsy and urogenital dysfunction and MMSE scores at first visit in PSP, and the latency of falls and wheelchair confinement in MSA were all associated with the disease progression. CONCLUSIONS: We confirmed most of the previously published characterizations, and identified for the first time the prognostic value of down-gaze palsy latency in PSP progression. PMID- 28725683 TI - Why is there motor deterioration in Parkinson's disease during systemic infections-a hypothetical view. AB - Clinicians are well aware of the fact that patients with Parkinson's disease may significantly deteriorate following a systemic infection or, in its most severe case, may even develop an akinetic crisis. Although this phenomenon is widely observed and has a major impact on the patients' condition, the knowledge about the underlying mechanisms behind is still sparse. Possible explanations encompass changes in the pharmacodynamics of the dopaminergic drugs, altered dopamine metabolism in the brain, alterations in the dopaminergic transmission in the striatum or an enhancement of neurodegeneration due to remote effects of peripheral inflammatory processes or circulating bacterial toxins. This article provides possible explanatory concepts and may hence support formulating hypothesis for future studies in this field. PMID- 28725682 TI - The range and nature of non-motor symptoms in drug-naive Parkinson's disease patients: a state-of-the-art systematic review. AB - Non-motor symptoms (NMS) are a key component of Parkinson's disease (PD). A range of NMS, most notably impaired sense of smell, sleep dysfunction, and dysautonomia are present from the 'pre-motor' phase to the final palliative stage. Theories as to the pathogenesis of PD such as those proposed by Braak and others also support the occurrence of NMS in PD years before motor symptoms start. However, research addressing the range and nature of NMS in PD has been confounded by the fact that many NMS arise as part of drug-related side effects. Thus, drug-naive PD (DNPD) patients provide an ideal population to study the differences in the presentation of NMS. The aim of this paper is therefore to systematically review all the available studies of NMS in DNPD patients. We believe this is the first review of its kind. The current review confirms the increasing research being conducted into NMS in DNPD patients as well as the necessity for further investigation into less-studied NMS, such as pain. Moreover, the data confirms non-motor heterogeneity among PD patients, and, therefore, further research into the concept of non-motor subtyping is encouraged. The review suggests that the clinical assessment of NMS should be integral to any assessment of PD in clinical and research settings. PMID- 28725685 TI - G-Force PD: a global initiative in coordinating stem cell-based dopamine treatments for Parkinson's disease. AB - Translating new cell-based therapies to the clinic for patients with neurodegenerative disorders is complex. It involves pre-clinical testing of the cellular product and discussions with several regulatory agencies, as well as ethical debates. In an attempt to support efforts around the world, we set up a global consortium that brings together the major funded teams working on developing a stem cell-derived neural transplantation therapy for Parkinson's disease (PD). This consortium, G-Force PD, involves teams from Europe, USA, and Japan, and has already met on two occasions to discuss common problems, solutions, and the roadmap to the clinic. In this short review, we lay out the brief history and rationale for this initiative and discuss some of the issues that arose in our most recent meeting (May 2015) as we consider undertaking first in-human clinical trials with stem cell-derived neurons for PD. PMID- 28725684 TI - The relationships between mild cognitive impairment and phenotype in Parkinson's disease. AB - BACKGROUND: The concept of differing clinical phenotypes within Parkinson's disease (PD) is well represented in the literature. However, there is no consensus as to whether any particular disease phenotype is associated with an increased risk of mild cognitive impairment (MCI) using the newly proposed Movement Disorders Society diagnostic criteria for this feature. AIMS: To explore the expression of PD-MCI in relation to the heterogeneity of idiopathic PD. METHODS: A cluster analysis incorporating a range of specific demographic, clinical and cognitive variables was performed on 209 patients in the early stages of PD (between Hoehn and Yahr stages I-III). Post hoc analyses exploring variables not included in the clustering solution were performed to interrogate the veracity of the subgroups generated. RESULTS: This study identified four distinct PD cohorts: a younger disease-onset subgroup, a tremor dominant subgroup, a non-tremor dominant subgroup, and a subgroup with rapid disease progression. The present study identified a differential expression of PD-MCI across these subgroups, with the highest frequency observed in the non-tremor dominant cluster. The non-tremor dominant subgroup was also associated with a higher prevalence of freezing of gait, hallucinations, daytime somnolence, and rapid eye movement sleep behavior disorder compared with other subgroups. CONCLUSIONS: This study confirms the existence of heterogeneity within the early clinical stages of PD and for the first time highlights the differential expression of PD-MCI using the newly defined diagnostic criteria for this feature. An improved understanding of PD-MCI and its clinical relationships may lead to an improved understanding of the pathophysiology underlying heterogeneity in PD. PMID- 28725686 TI - Classification of symptom-side predominance in idiopathic Parkinson's disease. AB - Asymmetry of symptom onset in Parkinson's disease (PD) is strongly linked to differential diagnosis, progression of disease, and clinical manifestation, suggesting its importance in terms of specifying a therapeutic strategy for each individual patient. To scrutinize the predictive value of this consequential clinical phenomenon as a neuromarker supporting a personalized therapeutic approach, we modeled symptom-side predominance at disease onset based on brain morphology assessed with magnetic resonance (MR) images by utilizing machine learning classification. The integration of multimodal MR imaging data into a multivariate statistical model led to predict left- and right-sided symptom onset with an above-chance accuracy of 96%. By absolute numbers, all but one patient were correctly classified. Interestingly, mainly hippocampal morphology supports this prediction. Considering a different disease formation of this single outlier and the strikingly high classification, this approach proves a reliable predictive model for symptom-side diagnostics in PD. In brief, this work hints toward individualized disease-modifying therapies rather than symptom-alleviating treatments. PMID- 28725687 TI - Brain activation underlying turning in Parkinson's disease patients with and without freezing of gait: a virtual reality fMRI study. AB - BACKGROUND: Freezing of gait is a debilitating symptom affecting many patients with Parkinson's disease (PD), causing severe immobility and decreased quality of life. Turning is known to be the most common trigger for freezing and also causes the highest rates of falls. However, the pathophysiological basis for these effects is not well understood. METHODS: This study used a virtual reality paradigm in combination with functional magnetic resonance imaging to explore the neural correlates underlying turning in 17 PD patients with freezing of gait (FOG) and 10 PD patients without FOG while off their dopaminergic medication. Participants used foot pedals to navigate a virtual environment, which allowed for blood oxygen level-dependent (BOLD) responses and footstep latencies to be compared between periods of straight "walking" and periods of turning through 90 degrees . BOLD data were then analyzed using a mixed effects analysis. RESULTS: Within group similarities revealed that overall, PD patients with freezing relied heavily on cortical control to enable effective stepping with increased visual cortex activation during turning. Between groups differences showed that when turning, patients with freezing preferentially activated inferior frontal regions that have been implicated in the recruitment of a putative stopping network. In addition, freezers failed to activate premotor and superior parietal cortices. Finally, increased task-based functional connectivity was found in subcortical regions associated with gait and stopping within the freezers group during turning. CONCLUSIONS: These findings suggest that an increased propensity towards stopping in combination with reduced sensorimotor integration may underlie the neurobiology of freezing of gait during turning. PMID- 28725688 TI - Delaying aging is neuroprotective in Parkinson's disease: a genetic analysis in C. elegans models. AB - Aging is the greatest risk factor for the development of Parkinson's disease (PD). However, the role of aging in the pathogenesis of PD is not known and it is currently uncertain why the symptoms take many decades to develop when inherited mutations that cause the disease can be present from birth. We hypothesize that there are specific changes that take place during the aging process that make cells susceptible to disease-causing mutations that are well-tolerated at younger ages. If so, then interventions that increase lifespan should be beneficial in the treatment of PD. To test this hypothesis, we used the powerful genetics of C. elegans, as this worm has been used extensively in aging research. We crossed transgenic worm models of PD expressing either human mutant alpha-synuclein (A53T) or LRRK2 (G2019S) with the long-lived insulin-IGF1 receptor mutant, daf-2. The daf-2 mutation increased the lifespan of both PD mutants. The increase in lifespan resulting from the daf-2 mutation rescued the degeneration of dopamine neurons in both worm models of PD and importantly rescued deficits in dopamine dependent behaviors including basal slowing, ethanol avoidance, and area restricted searching. Increasing lifespan through daf-2 mutation also delayed the formation of small aggregates in a worm model of PD expressing alpha-synuclein in the body wall muscle and rescued deficits in resistance to different stresses that were present in the PD mutant worms. Overall, this work suggests that slowing down the aging process may provide an effective treatment for PD. PMID- 28725689 TI - Single injection of small-molecule amyloid accelerator results in cell death of nigral dopamine neurons in mice. AB - The assembly process of alpha-synuclein toward amyloid fibers is linked to neurodegeneration in Parkinson's disease. In the present study, we capitalized on the in vitro discovery of a small-molecule accelerator of alpha-synuclein amyloid formation and assessed its effects when injected in brains of normal mice. An accelerator and an inhibitor of alpha-synuclein amyloid formation, as well as vehicle only, were injected into the striatum of normal mice and followed by behavioral evaluation, immunohistochemistry, and metabolomics up to six months later. The effects of molecules injected into the substantia nigra of normal and alpha-synuclein knock-out mice were also analyzed. When accelerator or inhibitor was injected into the brain of normal mice no acute compound toxicity was found. However, 6 months after single striatal injection of accelerator, mice sensorimotor functions were impaired, whereas mice injected with inhibitor had no dysfunctions. Injection of accelerator (but not inhibitor or vehicle) into the substantia nigra revealed significant loss of tyrosine hydroxylase (TH)-positive neurons after 3 months. No loss of TH-positive neurons was found in alpha synuclein knock-out mice injected with accelerator into the substantia nigra. Metabolic serum profiles from accelerator-injected normal mice matched those of newly diagnosed Parkinson's disease patients, whereas the profiles from inhibitor injected normal mice matched controls. Single inoculation of a small-molecule amyloid accelerator may be a new approach for studies of early events during dopamine neurodegeneration in mice. PMID- 28725690 TI - Different PD-MCI criteria and risk of dementia in Parkinson's disease: 4-year longitudinal study. AB - The Movement Disorder Society Task Force (MDS-TF) has proposed diagnostic criteria for mild cognitive impairment in Parkinson's disease (PD-MCI). We hypothesized that the risk of dementia (PDD) varies across the different cutoff schemes allowed. A longitudinal study followed 121 non-demented PD patients for up to 4.5 years. In Part One, unique groups of patients were identified as PD-MCI at baseline using the MDS-TF requirement of two impaired cognitive test scores, with both scores classified as impaired at either (i) 2 s.d., (ii) 1.5 s.d. or (iii) 1 s.d. below normative data; relative risk (RR) of PDD was assessed at each criterion. In Part Two, the whole sample was reassessed and (i) RR of PDD determined when two impairments at 1.5 s.d. existed within a single cognitive domain, followed by (ii) RR of PDD in the unique group whose two impairments at 1.5 s.d. did not exist within a single domain (i.e., only across two domains). Twenty-one percent of patients converted to PDD. Part One showed that the 1.5 s.d. criterion at baseline is optimal to maximize progression to PDD over 4 years. Part Two, however, showed that the 1.5 s.d. cutoff produced a high RR of PDD only when two impairments were identified within a single cognitive domain (7.2, 95% confidence interval (CI)=3.4-16.6, P<0.0001; 51% converted). The RR when the 1.5 s.d. impairments occurred only across two different domains, was nonsignificant (1.7, CI=0.5-7.4, P=0.13; 11% converted) and similar to using a 1 s.d. criterion (1.9, CI=0.3-4.3, P=0.13; 8% converted). If the intent of a PD-MCI diagnosis is to detect increased risk of PDD in the next 4 years, optimal criteria should identify at least two impairments at 1.5 s.d. within a single cognitive domain. PMID- 28725691 TI - Hippocampal subfield atrophy in relation to cerebrospinal fluid biomarkers and cognition in early Parkinson's disease: a cross-sectional study. AB - Cognition is often affected early in Parkinson's disease (PD). Lewy body and amyloid beta (Abeta) pathology and cortical atrophy may be involved. The aim of this study was to examine whether medial temporal lobe structural changes may be linked to cerebrospinal fluid (CSF) biomarker levels and cognition in early PD. PD patients had smaller volumes of total hippocampus, presubiculum, subiculum, CA2-3, CA4-DG, and hippocampal tail compared with normal controls (NCs). In the PD group, lower CSF Abeta38 and 42 were significant predictors for thinner perirhinal cortex. Lower Abeta42 and smaller presubiculum and subiculum predicted poorer verbal learning and delayed verbal recall. Smaller total hippocampus, presubiculum and subiculum predicted poorer visuospatial copying. Lower Abeta38 and 40 and thinner perirhinal cortex predicted poorer delayed visual reproduction. In conclusion, smaller volumes of hippocampal subfields and subhippocampal cortex thickness linked to lower CSF Abeta levels may contribute to cognitive impairment in early PD. Thirty-three early PD patients (13 without, 5 with subjective, and 15 with mild cognitive impairment) and NC had 3 T magnetic resonance imaging (MRI) scans. The MRI scans were post processed for volumes of hippocampal subfields and entorhinal and perirhinal cortical thickness. Lumbar puncture for CSF biomarkers Abeta38, 40, 42, total tau, phosphorylated tau (Innogenetics), and total alpha-synuclein (Meso Scale Diagnostics) were performed. Multiple regression analyses were used for between-group comparisons of the MRI measurements in the NC and PD groups and for assessment of CSF biomarkers and neuropsychological tests in relation to morphometry in the PD group. PMID- 28725692 TI - Deficits in cholinergic neurotransmission and their clinical correlates in Parkinson's disease. AB - In view of its ability to explain the most frequent motor symptoms of Parkinson's Disease (PD), degeneration of dopaminergic neurons has been considered one of the disease's main pathophysiological features. Several studies have shown that neurodegeneration also affects noradrenergic, serotoninergic, cholinergic and other monoaminergic neuronal populations. In this work, the characteristics of cholinergic deficits in PD and their clinical correlates are reviewed. Important neurophysiological processes at the root of several motor and cognitive functions remit to cholinergic neurotransmission at the synaptic, pathway, and circuital levels. The bulk of evidence highlights the link between cholinergic alterations and PD motor symptoms, gait dysfunction, levodopa-induced dyskinesias, cognitive deterioration, psychosis, sleep abnormalities, autonomic dysfunction, and altered olfactory function. The pathophysiology of these symptoms is related to alteration of the cholinergic tone in the striatum and/or to degeneration of cholinergic nuclei, most importantly the nucleus basalis magnocellularis and the pedunculopontine nucleus. Several results suggest the clinical usefulness of antimuscarinic drugs for treating PD motor symptoms and of inhibitors of the enzyme acetylcholinesterase for the treatment of dementia. Data also suggest that these inhibitors and pedunculopontine nucleus deep-brain stimulation might also be effective in preventing falls. Finally, several drugs acting on nicotinic receptors have proved efficacious for treating levodopa-induced dyskinesias and cognitive impairment and as neuroprotective agents in PD animal models. Results in human patients are still lacking. PMID- 28725694 TI - Smartphones as new tools in the management and understanding of Parkinson's disease. PMID- 28725693 TI - Central nervous system uptake of intranasal glutathione in Parkinson's disease. AB - Glutathione (GSH) is depleted early in the course of Parkinson's disease (PD), and deficiency has been shown to perpetuate oxidative stress, mitochondrial dysfunction, impaired autophagy, and cell death. GSH repletion has been proposed as a therapeutic intervention. The objective of this study was to evaluate whether intranasally administered reduced GSH, (in)GSH, is capable of augmenting central nervous system GSH concentrations, as determined by magnetic resonance spectroscopy in 15 participants with mid-stage PD. After baseline GSH measurement, 200 mg (in)GSH was self-administered inside the scanner without repositioning, then serial GSH levels were obtained over ~1 h. Statistical significance was determined by one-way repeated measures analysis of variance. Overall, (in)GSH increased brain GSH relative to baseline (P<0.001). There was no increase in GSH 8 min after administration, although it was significantly higher than baseline at all of the remaining time points (P<0.01). This study is the first to demonstrate that intranasal administration of GSH elevates brain GSH levels. This increase persists at least 1 h in subjects with PD. Further dose response and steady-state administration studies will be required to optimize the dosing schedule for future trials to evaluate therapeutic efficacy. PMID- 28725695 TI - Analysis of four scales for global severity evaluation in Parkinson's disease. AB - Global evaluations of Parkinson's disease (PD) severity are available, but their concordance and accuracy have not been previously tested. The present international, cross-sectional study was aimed at determining the agreement level among four global scales for PD (Hoehn and Yahr, HY; Clinical Global Impression of Severity, CGIS; Clinical Impression of Severity Index, CISI-PD; and Patient Global Impression of Severity, PGIS) and identifying which of them better correlates with itemized PD assessments. Assessments included additional scales for evaluation of the movement impairment, disability, affective disorders, and quality of life. Spearman correlation coefficients, weighted and generalized kappa, and Kendall's concordance coefficient were used. Four hundred thirty three PD patients, 66% in HY stages 2 or 3, mean disease duration 8.8 years, were analyzed. Correlation between the global scales ranged from 0.60 (HY with PGIS) to 0.91 (CGIS with CISI-PD). Kendall's coefficient of concordance resulted 0.76 (P<0.0001). HY and CISI-PD showed the highest association with age, disease duration, and levodopa-equivalent daily dose, and CISI-PD with measures of PD manifestations, disability, and quality of life. PGIS and CISI-PD correlated similarly with anxiety and depression scores. The lowest agreement in classifying patients as mild, moderate, or severe was observed between PGIS and HY or CISI-PD (58%) and the highest between CGIS and CISI-PD (84.3%). The four PD global severity scales agree moderately to strongly among them; clinician-based ratings estimate PD severity, as established by other measures, better than PGIS; and the CISI-PD showed the highest association with measures of impairment, disability, and quality of life. PMID- 28725697 TI - Cytoarchitectural changes in the olfactory bulb of Parkinson's disease patients. AB - Olfactory dysfunction is associated with nearly all the cases of Parkinson's disease (PD) and typically manifests years before motor symptoms are detected. The cellular mechanisms underlying this dysfunction, however, are not understood. In this study, olfactory bulbs (OBs) from male control and PD subjects were examined by histology for changes in cytoarchitecture. These studies found that the general OB laminar organization and the number of interneurons expressing tyrosine hydroxylase were unaltered. In contrast, the number of mitral/tufted projection neurons and interneurons expressing Calretinin were significantly decreased in PD subjects. This study reveals changes in OB cytoarchitecture mediated by PD and provides valuable insight into identifying specific OB neuronal populations vulnerable to PD-related neurodegeneration. PMID- 28725696 TI - Creation of a library of induced pluripotent stem cells from Parkinsonian patients. AB - Induced pluripotent stem cells (iPSCs) are becoming an important source of pre clinical models for research focusing on neurodegeneration. They offer the possibility for better understanding of common and divergent pathogenic mechanisms of brain diseases. Moreover, iPSCs provide a unique opportunity to develop personalized therapeutic strategies, as well as explore early pathogenic mechanisms, since they rely on the use of patients' own cells that are otherwise accessible only post-mortem, when neuronal death-related cellular pathways and processes are advanced and adaptive. Neurodegenerative diseases are in majority of unknown cause, but mutations in specific genes can lead to familial forms of these diseases. For example, mutations in the superoxide dismutase 1 gene lead to the motor neuron disease amyotrophic lateral sclerosis (ALS), while mutations in the SNCA gene encoding for alpha-synuclein protein lead to familial Parkinson's disease (PD). The generations of libraries of familial human ALS iPSC lines have been described, and the iPSCs rapidly became useful models for studying cell autonomous and non-cell autonomous mechanisms of the disease. Here we report the generation of a comprehensive library of iPSC lines of familial PD and an associated synucleinopathy, multiple system atrophy (MSA). In addition, we provide examples of relevant neural cell types these iPSC can be differentiated into, and which could be used to further explore early disease mechanisms. These human cellular models will be a valuable resource for identifying common and divergent mechanisms leading to neurodegeneration in PD and MSA. PMID- 28725698 TI - Effect of levodopa-carbidopa intestinal gel on resting tremors in patients with advanced Parkinson's disease. AB - Resting tremors occur in more than 70% of patients with advanced Parkinson's disease (PD). PD patients with resting tremors are typically treated with oral dopaminergic therapy or non-dopaminergic agents. However, treatment response with these medications is inconsistent and often unsatisfactory. Levodopa-carbidopa intestinal gel (LCIG, also known in the United States as carbidopa-levodopa enteral suspension (CLES)), administered continuously by a portable pump via a percutaneous endoscopic gastrojejunostomy (PEG-J) tube, significantly improves motor complications in patients with advanced PD. This was a post hoc analysis of a large phase 3, 12-month, open-label study evaluating long-term safety and efficacy of LCIG via PEG-J tube (NCT00335153). Unified Parkinson's Disease Rating Scale Part III Question 20 total scores at baseline, measuring resting tremors, were used to stratify patients into three subgroups (none, mild, or significant baseline resting tremors). Out of 354 enrolled patients, 286 had baseline and post-PEG-J assessments of resting tremors and were included in this analysis. At baseline the majority of patients (69%) had no resting tremors, whereas 13% had mild resting tremors, and 18% had significant resting tremors. A complete resolution in resting tremors after 12 months of LCIG treatment was reported for 78% and 70% of patients with mild and significant baseline resting tremors, respectively. Improvements in motor complications and quality of life occurred regardless of degree of baseline resting tremors. LCIG may provide more consistent and sustained improvements in resting tremors that were not well controlled with optimized oral medication among patients with advanced PD. PMID- 28725700 TI - Beyond patient-centered care: person-centered care for Parkinson's disease. AB - Interest has grown in centering Parkinson's disease (PD) care provision on the welfare of the patient with PD. By putting the welfare of patients first, this patient-centric focus tends to subordinate the welfare of others including clinicians and carers. A possible solution is person-centered care. Rather than remove the spotlight from the patients, it widens that light to illuminate moral interests of all healthcare participants as persons whose welfare is interdependent. It assumes that unwellness among clinicians, for example, can impact the quality of the PD care they provide, such that caring for clinicians may also optimize the welfare of persons with PD. For PD, we suggest how the two models differ and why these differences are important to understand and act on to optimize benefit for participating stakeholders. PMID- 28725701 TI - Efficacy and safety of levodopa-carbidopa intestinal gel from a study in Japanese, Taiwanese, and Korean advanced Parkinson's disease patients. AB - In a previous multinational, randomized, double-blind, double-dummy study, levodopa-carbidopa intestinal gel (LCIG) was tolerable and significantly improved 'off' time in advanced Parkinson's disease (PD) patients. However, efficacy and safety in the Asian population has not yet been demonstrated. In this open-label study, efficacy and safety of LCIG were assessed in Japanese, Korean, and Taiwanese advanced PD patients with motor complications not adequately controlled by available PD medication. The patients were treated with LCIG monotherapy for 12 weeks. The primary end point was the mean change from baseline to week 12 in 'off' time, as reported in the PD Symptom Diary, normalized to a 16 h waking day and analyzed by a mixed-model repeated-measures analysis. Adverse events (AEs) were recorded. Thirty-one patients were enrolled (23 Japanese, 4 Taiwanese, 4 Korean) and 28 (90%) completed the study. For those who completed the study, the mean (s.d.) total daily levodopa dose from LCIG was 1,206.3 (493.6) mg/day at final visit (n=28); last observation carried forward (n=30) was 1,227.6 (482.8) mg/day. There was a significant mean change (s.d.) of -4.6 (3.0) hours of 'off' time from baseline (mean (s.d.)=7.4 (2.3)) to week 12 (n=29), P<0.001. All the patients had an AE, with the most frequently reported being incision site pain (42%); 1 (3.2%) discontinued treatment because of an AE and later died because of sepsis, which the investigator considered unrelated to LCIG treatment. These results suggest that LCIG is efficacious and tolerable in Japanese, Taiwanese, and Korean advanced PD patients. PMID- 28725699 TI - Cognitive decline in Parkinson's disease: the complex picture. AB - Mild cognitive impairment (PD-MCI) and dementia (PDD) are among the most frequent non-motor symptoms in Parkinson's disease (PD). PD-MCI is six times more likely than age-matched controls to develop dementia and the PDD prevalence is 80% after 15-20 years of disease. Therefore, research has focused on the identification of early dementia biomarkers including specific cognitive at-risk profiles hoping to implement therapeutic interventions when they are most likely to be efficacious. However, given the heterogeneous neuropathological, neurochemical, and neuropsychological nature of cognitive deficits, definition of a comprehensive cognitive model of PDD is a challenge. Evidence from neuroimaging studies using different methods and techniques suggests that in addition to degeneration of the dopaminergic system, other mechanisms have a role including beta-amyloid and tau deposition, and that specific cognitive scales could help identifying a malignant profile. Prospective studies combining neuroimaging techniques and specific cognitive tests are required to define the interplay between the various neurodegenerative processes and the contribution of structural disconnection in brain functional networks, heralding the development of dementia in PD. PMID- 28725702 TI - Defining a role for hemoglobin in Parkinson's disease. AB - Hemoglobin (Hb) has been shown to be expressed within dopaminergic neurons and to have a role in maintaining iron and mitochondrial homeostasis. In Parkinson's disease tissues, Hb has been localized to the mitochondrion. Though heme synthesis occurs within the mitochondria, the localization of Hb to this organelle has only recently been described. It is now important to understand whether Hb expression is protective or is a part of the neurodegenerative process. It is possible that the accumulation of neuronal or mitochondrial Hb is initially protective, but over many decades causes pathology. Studying Hb in neurons can give insight into the iron accumulation seen in the brain and the potential role of alpha-synuclein as a ferrireductase. In this review, we discuss the interactions of neuronal and mitochondrial Hb with other proteins and its possible role in pathways relevant to Parkinson's disease. PMID- 28725703 TI - Living with chronic illness scale: international validation of a new self-report measure in Parkinson's disease. AB - Understanding how a person lives with a chronic illness, such as Parkinson's disease (PD), is necessary to provide individualized care and professionals role in person-centered care at clinical and community levels is paramount. The present study was aimed to analyze the psychometric properties of the Living with Chronic Illness-PD Scale (EC-PC) in a wide Spanish-speaking population with PD. International cross-sectional study with retest was carried out with 324 patients from four Latin American countries and Spain. Feasibility, acceptability, scaling assumptions, reliability, precision, and construct validity were tested. The study included 324 patients, with age (mean+/-s.d.) 66.67+/-10.68 years. None of the EC-PC items had missing values and all acceptability parameters fulfilled the standard criteria. Around two-third of the items (61.54%) met scaling assumptions standards. Concerning internal consistency, Cronbach's alpha values were 0.68 0.88; item-total correlation was >0.30, except for two items; item homogeneity index was >0.30, and inter-item correlation values 0.14-0.76. Intraclass correlation coefficient for EC-PC stability was 0.76 and standard error of measurement (s.e.m.) for precision was 8.60 (for a EC-PC s.d.=18.57). EC-PC presented strong correlation with social support (rS=0.61) and moderate correlation with life satisfaction (rS=0.46). Weak and negligible correlations were found with the other scales. Internal validity correlations ranged from 0.46 to 0.78. EC-PC total scores were significantly different for each severity level based on Hoehn and Yahr and Clinical Impression of Severity Index, but not for Patient Global Impression of Severity. The EC-PC has satisfactory acceptability, reliability, precision, and validity to evaluate living with PD. PMID- 28725704 TI - Non-oral dopaminergic therapies for Parkinson's disease: current treatments and the future. AB - Dysfunction of the gastrointestinal tract has now been recognized to affect all stages of Parkinson's disease (PD). The consequences lead to problems with absorption of oral medication, erratic treatment response, as well as silent aspiration, which is one of the key risk factors in developing pneumonia. The issue is further complicated by other gut abnormalities, such as small intestinal bacterial overgrowth (SIBO) and an altered gut microbiota, which occur in PD with variable frequency. Clinically, these gastrointestinal abnormalities might be associated with symptoms such as nausea, early-morning "off", and frequent motor and non-motor fluctuations. Therefore, non-oral therapies that avoid the gastrointestinal system seem a rational option to overcome the problems of oral therapies in PD. Hence, several non-oral strategies have now been actively investigated and developed. The transdermal rotigotine patch, infusion therapies with apomorphine, intrajejunal levodopa, and the apomorphine pen strategy are currently in clinical use with a few others in development. In this review, we discuss and summarize the most recent developments in this field with a focus on non-oral dopaminergic strategies (excluding surgical interventions such as deep brain stimulation) in development or to be licensed for management of PD. PMID- 28725707 TI - The economics of microgravity research. AB - In this introduction to the economics of microgravity research, DiFrancesco and Olson explore the existing landscape and begin to define the requirements for a robust, well-funded microgravity research environment. This work chronicles the history, the opportunities, and how the decisions made today will shape the future. The past 60 years have seen tremendous growth in the capabilities and resources available to conduct microgravity science. However, we are now at an inflection point for the future of humanity in space. A confluence of factors including the rise of commercialization, a shifting funding landscape, and a growing international presence in space exploration, and terrestrial research platforms are shaping the conditions for full-scale microgravity research programs. In this first discussion, the authors focus on the concepts of markets, tangible and intangible value, research pathways and their implications for investments in research projects, and the collateral platforms needed. The opportunities and implications for adopting new approaches to funding and market making illuminate how decisions made today will affect the speed of advances the community will be able to achieve in the future. PMID- 28725706 TI - The effect of deep brain stimulation on the non-motor symptoms of Parkinson's disease: a critical review of the current evidence. AB - The benefit of deep brain stimulation (DBS) in controlling the motor symptoms of Parkinson's disease is well established, however, the impact on the non-motor symptoms (NMS) remains to be elucidated, although the growing investigative efforts are promising. This article reviews the reported data and considers the level of evidence available with regard to the effect of DBS on NMS total burden and on the cognitive, neuropsychiatric, sleep, pain, dysautonomic, and weight domains. Multiple case series suggest that DBS improves the burden of NMS by reducing prevalence, intensity, and non-motor fluctuations. There is level I evidence on the effect of DBS on cognition and mood. Slight cognitive decline has been reported in most class I studies, although the functional effect is probably minimal. Two randomized prospective studies reported no change in depression while improvement of anxiety has been reported by a class I trial. Prospective cohort studies point to improvement of hyperdopaminergic behaviors, such as impulse control disorders, while others report that hypodopaminergic states, like apathy, can appear after DBS. There is only class III evidence supporting the benefit of DBS on other NMS such as nocturnal sleep, pain, dysautonomia (urinary, gastrointestinal, cardiovascular, and sweating), and weight loss. Although preliminary results are promising, randomized prospectively controlled trials with NMS as primary end points are necessary to further explore the effect of DBS on these often invalidating symptoms and offer conclusions about efficacy. PMID- 28725708 TI - Skin physiology in microgravity: a 3-month stay aboard ISS induces dermal atrophy and affects cutaneous muscle and hair follicles cycling in mice. AB - AIMS: The Mice Drawer System (MDS) Tissue Sharing program was the longest rodent space mission ever performed. It provided 20 research teams with organs and tissues collected from mice having spent 3 months on the International Space Station (ISS). Our participation to this experiment aimed at investigating the impact of such prolonged exposure to extreme space conditions on mouse skin physiology. METHODS: Mice were maintained in the MDS for 91 days aboard ISS (space group (S)). Skin specimens were collected shortly after landing for morphometric, biochemical, and transcriptomic analyses. An exact replicate of the experiment in the MDS was performed on ground (ground group (G)). RESULTS: A significant reduction of dermal thickness (-15%, P=0.05) was observed in S mice accompanied by an increased newly synthetized procollagen (+42%, P=0.03), likely reflecting an increased collagen turnover. Transcriptomic data suggested that the dermal atrophy might be related to an early degradation of defective newly formed procollagen molecules. Interestingly, numerous hair follicles in growing anagen phase were observed in the three S mice, validated by a high expression of specific hair follicles genes, while only one mouse in the G controls showed growing hairs. By microarray analysis of whole thickness skin, we observed a significant modulation of 434 genes in S versus G mice. A large proportion of the upregulated transcripts encoded proteins related to striated muscle homeostasis. CONCLUSIONS: These data suggest that a prolonged exposure to space conditions may induce skin atrophy, deregulate hair follicle cycle, and markedly affect the transcriptomic repertoire of the cutaneous striated muscle panniculus carnosus. PMID- 28725709 TI - Microgravity metal processing: from undercooled liquids to bulk metallic glasses. AB - Bulk metallic glasses (BMGs) are a novel class of metal alloys that are poised for widespread commercialization. Over 30 years of NASA and ESA (as well as other space agency) funding for both ground-based and microgravity experiments has resulted in fundamental science data that have enabled commercial production. This review focuses on the history of microgravity BMG research, which includes experiments on the space shuttle, the ISS, ground-based experiments, commercial fabrication and currently funded efforts. PMID- 28725705 TI - Parkinson's disease as a system-level disorder. AB - Traditionally, the basal ganglia have been considered the main brain region implicated in Parkinson's disease. This single area perspective gives a restricted clinical picture and limits therapeutic approaches because it ignores the influence of altered interactions between the basal ganglia and other cerebral components on Parkinsonian symptoms. In particular, the basal ganglia work closely in concert with cortex and cerebellum to support motor and cognitive functions. This article proposes a theoretical framework for understanding Parkinson's disease as caused by the dysfunction of the entire basal ganglia cortex-cerebellum system rather than by the basal ganglia in isolation. In particular, building on recent evidence, we propose that the three key symptoms of tremor, freezing, and impairments in action sequencing may be explained by considering partially overlapping neural circuits including basal ganglia, cortical and cerebellar areas. Studying the involvement of this system in Parkinson's disease is a crucial step for devising innovative therapeutic approaches targeting it rather than only the basal ganglia. Possible future therapies based on this different view of the disease are discussed. PMID- 28725711 TI - Welcome statement-npj Microgravity. PMID- 28725710 TI - How antifoams act: a microgravity study. AB - Antifoams are widely used to control or to avoid foam production. In order to work, antifoam particles need to break foam films efficiently, which many antifoams do very well. However, once they have broken a film, to continue to be effective they need to be transported to the next film. We show, for the first time, that buoyancy has an important part in the transport of the antifoam particles. In microgravity, where buoyancy and gravitational drainage are strongly slowed down, diffusion leads to poor antifoam performance. The foam is stable for the duration of the experiment, whereas on Earth the foam starts to disappear immediately. Indeed, microgravity renders highly efficient antifoam practically useless. PMID- 28725712 TI - Effects of angular frequency during clinorotation on mesenchymal stem cell morphology and migration. AB - AIMS: To determine the short-term effects of simulated microgravity on mesenchymal stem cell behaviors-as a function of clinorotation speed-using time lapse microscopy. BACKGROUND: Ground-based microgravity simulation can reproduce the apparent effects of weightlessness in spaceflight using clinostats that continuously reorient the gravity vector on a specimen, creating a time-averaged nullification of gravity. In this work, we investigated the effects of clinorotation speed on the morphology, cytoarchitecture, and migration behavior of human mesenchymal stem cells (hMSCs). METHODS: We compared cell responses at clinorotation speeds of 0, 30, 60, and 75 rpm over 8 h in a recently developed lab-on-chip-based clinostat system. Time-lapse light microscopy was used to visualize changes in cell morphology during and after cessation of clinorotation. Cytoarchitecture was assessed by actin and vinculin staining, and chemotaxis was examined using time-lapse light microscopy of cells in NGF (100 ng/ml) gradients. RESULTS: Among clinorotated groups, cell area distributions indicated a greater inhibition of cell spreading with higher angular frequency (P<0.005), though average cell area at 30 rpm after 8 h became statistically similar to control (P=0.794). Cells at 75 rpm clinorotation remained viable and were able to re spread after clinorotation. In chemotaxis chambers, clinorotation did not alter migration patterns in elongated cells, but most clinorotated cells exhibited cell retraction, which strongly compromised motility. CONCLUSIONS: These results indicate that hMSCs respond to clinorotation by adopting more rounded, less spread morphologies. The angular frequency-dependence suggests that a cell's ability to sense the changing gravity vector is governed by the rate of perturbation. For migration studies, cells cultured in clinorotated chemotaxis chambers were generally less motile and exhibited retraction instead of migration. PMID- 28725713 TI - Observational study: microgravity testing of a phase-change reference on the International Space Station. AB - BACKGROUND: Orbital sensors to monitor global climate change during the next decade require low-drift rates for onboard thermometry, which is currently unattainable without on-orbit recalibration. Phase-change materials (PCMs), such as those that make up the ITS-90 standard, are seen as the most reliable references on the ground and could be good candidates for orbital recalibration. Space Dynamics Lab (SDL) has been developing miniaturized phase-change references capable of deployment on an orbital blackbody for nearly a decade. AIMS: Improvement of orbital temperature measurements for long duration earth observing and remote sensing. METHODS: To determine whether and how microgravity will affect the phase transitions, SDL conducted experiments with ITS-90 standard material (gallium, Ga) on the International Space Station (ISS) and compared the phase-change temperature with earth-based measurements. The miniature on-orbit thermal reference (MOTR) experiment launched to the ISS in November 2013 on Soyuz TMA-11M with the Expedition 38 crew and returned to Kazakhstan in March 2014 on the Soyuz TMA-10 spacecraft. RESULTS: MOTR tested melts and freezes of Ga using repeated 6-h cycles. Melt cycles obtained on the ground before and after launch were compared with those obtained on the ISS. CONCLUSIONS: To within a few mK uncertainty, no significant difference between the melt temperature of Ga at 1 g and in microgravity was observed. PMID- 28725714 TI - Microgravity protein crystallization. AB - Over the past 20 years a variety of technological advances in X-ray crystallography have shortened the time required to determine the structures of large macromolecules (i.e., proteins and nucleic acids) from several years to several weeks or days. However, one of the remaining challenges is the ability to produce diffraction-quality crystals suitable for a detailed structural analysis. Although the development of automated crystallization systems combined with protein engineering (site-directed mutagenesis to enhance protein solubility and crystallization) have improved crystallization success rates, there remain hundreds of proteins that either cannot be crystallized or yield crystals of insufficient quality to support X-ray structure determination. In an attempt to address this bottleneck, an international group of scientists has explored use of a microgravity environment to crystallize macromolecules. This paper summarizes the history of this international initiative along with a description of some of the flight hardware systems and crystallization results. PMID- 28725715 TI - Growth of In x Ga1-x Sb alloy semiconductor at the International Space Station (ISS) and comparison with terrestrial experiments. AB - BACKGROUND: In x Ga1-x Sb is an important material that has tunable properties in the infrared (IR) region and is suitable for IR-device applications. Since the quality of crystals relies on growth conditions, the growth process of alloy semiconductors can be examined better under microgravity (MUG) conditions where convection is suppressed. AIMS: To investigate the dissolution and growth process of In x Ga1-x Sb alloy semiconductors via a sandwiched structure of GaSb(seed)/InSb/GaSb(feed) under normal and MUG conditions. METHODS: In x Ga1-x Sb crystals were grown at the International Space Station (ISS) under MUG conditions, and a similar experiment was conducted under terrestrial conditions (1G) using the vertical gradient freezing (VGF) method. The grown crystals were cut along the growth direction and its growth properties were studied. The indium composition and growth rate of grown crystals were calculated. RESULTS: The shape of the growth interface was nearly flat under MUG, whereas under 1G, it was highly concave with the initial seed interface being nearly flat and having facets at the peripheries. The quality of the MUG crystals was better than that of the 1G samples, as the etch pit density was low in the MUG sample. The growth rate was higher under MUG compared with 1G. Moreover, the growth started at the peripheries under 1G, whereas it started throughout the seed interface under MUG. CONCLUSIONS: Kinetics played a dominant role under 1G. The suppressed convection under MUG affected the dissolution and growth process of the In x Ga1-x Sb alloy semiconductor. PMID- 28725716 TI - Alterations in adaptive immunity persist during long-duration spaceflight. AB - BACKGROUND: It is currently unknown whether immune system alterations persist during long-duration spaceflight. In this study various adaptive immune parameters were assessed in astronauts at three intervals during 6-month spaceflight on board the International Space Station (ISS). AIMS: To assess phenotypic and functional immune system alterations in astronauts participating in 6-month orbital spaceflight. METHODS: Blood was collected before, during, and after flight from 23 astronauts participating in 6-month ISS expeditions. In flight samples were returned to Earth within 48 h of collection for immediate analysis. Assays included peripheral leukocyte distribution, T-cell function, virus-specific immunity, and mitogen-stimulated cytokine production profiles. RESULTS: Redistribution of leukocyte subsets occurred during flight, including an elevated white blood cell (WBC) count and alterations in CD8+ T-cell maturation. A reduction in general T-cell function (both CD4+ and CD8+) persisted for the duration of the 6-month spaceflights, with differential responses between mitogens suggesting an activation threshold shift. The percentage of CD4+ T cells capable of producing IL-2 was depressed after landing. Significant reductions in mitogen-stimulated production of IFNgamma, IL-10, IL-5, TNFalpha, and IL-6 persisted during spaceflight. Following lipopolysaccharide (LPS) stimulation, production of IL-10 was reduced, whereas IL-8 production was increased during flight. CONCLUSIONS: The data indicated that immune alterations persist during long-duration spaceflight. This phenomenon, in the absence of appropriate countermeasures, has the potential to increase specific clinical risks for crewmembers during exploration-class deep space missions. PMID- 28725717 TI - The influence of simulated microgravity on the proteome of Daphnia magna. AB - BACKGROUND: The waterflea Daphnia is an interesting candidate for bioregenerative life support systems (BLSS). These animals are particularly promising because of their central role in the limnic food web and its mode of reproduction. However, the response of Daphnia to altered gravity conditions has to be investigated, especially on the molecular level, to evaluate the suitability of Daphnia for BLSS in space. METHODS: In this study, we applied a proteomic approach to identify key proteins and pathways involved in the response of Daphnia to simulated microgravity generated by a two-dimensional (2D) clinostat. We analyzed five biological replicates using 2D-difference gel electrophoresis proteomic analysis. RESULTS: We identified 109 protein spots differing in intensity (P<0.05). Substantial fractions of these proteins are involved in actin microfilament organization, indicating the disruption of cytoskeletal structures during clinorotation. Furthermore, proteins involved in protein folding were identified, suggesting altered gravity induced breakdown of protein structures in general. In addition, simulated microgravity increased the abundance of energy metabolism-related proteins, indicating an enhanced energy demand of Daphnia. CONCLUSIONS: The affected biological processes were also described in other studies using different organisms and systems either aiming to simulate microgravity conditions or providing real microgravity conditions. Moreover, most of the Daphnia protein sequences are well-conserved throughout taxa, indicating that the response to altered gravity conditions in Daphnia follows a general concept. Data are available via ProteomeXchange with identifier PXD002096. PMID- 28725718 TI - Intrinsic cardiovascular autonomic regulatory system of astronauts exposed long term to microgravity in space: observational study. AB - The fractal scaling of the long-term heart rate variability (HRV) reflects the 'intrinsic' autonomic regulatory system. Herein, we examine how microgravity on the ISS affected the power-law scaling beta (beta) of astronauts during a long duration (about 6 months) spaceflight. Ambulatory electrocardiographic (ECG) monitoring was performed on seven healthy astronauts (5 men, 52.0+/-4.2 years of age) five times: before launch, 24+/-5 (F01) and 73+/-5 (F02) days after launch, 15+/-5 days before return (F03), and after return to Earth. The power-law scaling beta was calculated as the slope of the regression line of the power density of the MEM spectrum versus frequency plotted on a log10-log10 scale in the range of 0.0001-0.01 Hz (corresponding to periods of 2.8 h to 1.6 min). beta was less negative in space (-0.949+/-0.061) than on Earth (-1.163+/-0.075; P<0.025). The difference was more pronounced during the awake than during the rest/sleep span. The circadian amplitude and acrophase (phase of maximum) of beta did not differ in space as compared with Earth. An effect of microgravity was detected within 1 month (F01) in space and continued throughout the spaceflight. The intrinsic autonomic regulatory system that protects life under serious environmental conditions on Earth is altered in the microgravity environment, with no change over the 6-month spaceflight. It is thus important to find a way to improve conditions in space and/or in terms of human physiology, not to compromise the intrinsic autonomic regulatory system now that plans are being made to inhabit another planet in the near future. PMID- 28725719 TI - Circadian misalignment affects sleep and medication use before and during spaceflight. AB - Sleep deficiency and the use of sleep-promoting medication are prevalent during spaceflight. Operations frequently dictate work during the biological night and sleep during the biological day, which contribute to circadian misalignment. We investigated whether circadian misalignment was associated with adverse sleep outcomes before (preflight) and during spaceflight missions aboard the International Space Station (ISS). Actigraphy and photometry data for 21 astronauts were collected over 3,248 days of long-duration spaceflight on the ISS and 11 days prior to launch (n=231 days). Sleep logs, collected one out of every 3 weeks in flight and daily on Earth, were used to determine medication use and subjective ratings of sleep quality. Actigraphy and photometry data were processed using Circadian Performance Simulation Software to calculate the estimated endogenous circadian temperature minimum. Sleep episodes were classified as aligned or misaligned relative to the estimated endogenous circadian temperature minimum. Mixed-effects regression models accounting for repeated measures were computed by data collection interval (preflight, flight) and circadian alignment status. The estimated endogenous circadian temperature minimum occurred outside sleep episodes on 13% of sleep episodes during preflight and on 19% of sleep episodes during spaceflight. The mean sleep duration in low Earth orbit on the ISS was 6.4+/-1.2 h during aligned and 5.4+/-1.4 h (P<0.01) during misaligned sleep episodes. During aligned sleep episodes, astronauts rated their sleep quality as significantly better than during misaligned sleep episodes (66.8+/-17.7 vs. 60.2+/-21.0, P<0.01). Sleep-promoting medication use was significantly higher during misaligned (24%) compared with aligned (11%) sleep episodes (P<0.01). Use of any medication was significantly higher on days when sleep episodes were misaligned (63%) compared with when sleep episodes were aligned (49%; P<0.01). Circadian misalignment is associated with sleep deficiency and increased medication use during spaceflight. These findings suggest that there is an immediate need to deploy and assess effective countermeasures to minimize circadian misalignment and consequent adverse sleep outcomes both before and during spaceflight. PMID- 28725720 TI - Microgravity elicits reproducible alterations in cytoskeletal and metabolic gene and protein expression in space-flown Caenorhabditis elegans. AB - Although muscle atrophy is a serious problem during spaceflight, little is known about the sequence of molecular events leading to atrophy in response to microgravity. We carried out a spaceflight experiment using Caenorhabditis elegans onboard the Japanese Experiment Module of the International Space Station. Worms were synchronously cultured in liquid media with bacterial food for 4 days under microgravity or on a 1-G centrifuge. Worms were visually observed for health and movement and then frozen. Upon return, we analyzed global gene and protein expression using DNA microarrays and mass spectrometry. Body length and fat accumulation were also analyzed. We found that in worms grown from the L1 larval stage to adulthood under microgravity, both gene and protein expression levels for muscular thick filaments, cytoskeletal elements, and mitochondrial metabolic enzymes decreased relative to parallel cultures on the 1 G centrifuge (95% confidence interval (P?0.05)). In addition, altered movement and decreased body length and fat accumulation were observed in the microgravity cultured worms relative to the 1-G cultured worms. These results suggest protein expression changes that may account for the progressive muscular atrophy observed in astronauts. PMID- 28725721 TI - The effect of spaceflight on the gravity-sensing auxin gradient of roots: GFP reporter gene microscopy on orbit. AB - Our primary aim was to determine whether gravity has a direct role in establishing the auxin-mediated gravity-sensing system in primary roots. Major plant architectures have long been thought to be guided by gravity, including the directional growth of the primary root via auxin gradients that are then disturbed when roots deviate from the vertical as a gravity sensor. However, experiments on the International Space Station (ISS) now allow physical clarity with regard to any assumptions regarding the role of gravity in establishing fundamental root auxin distributions. We examined the spaceflight green fluorescent protein (GFP)-reporter gene expression in roots of transgenic lines of Arabidopsis thaliana: pDR5r::GFP, pTAA1::TAA1-GFP, pSCR::SCR-GFP to monitor auxin and pARR5::GFP to monitor cytokinin. Plants on the ISS were imaged live with the Light Microscopy Module (LMM), and compared with control plants imaged on the ground. Preserved spaceflight and ground control plants were examined post flight with confocal microscopy. Plants on orbit, growing in the absence of any physical reference to the terrestrial gravity vector, displayed typically "vertical" distribution of auxin in the primary root. This confirms that the establishment of the auxin-gradient system, the primary guide for gravity signaling in the root, is gravity independent. The cytokinin distribution in the root tip differs between spaceflight and the ground controls, suggesting spaceflight-induced features of root growth may be cytokinin related. The distribution of auxin in the gravity-sensing portion of the root is not dependent on gravity. Spaceflight appears benign to auxin and its role in the development of the primary root tip, whereas spaceflight may influence cytokinin-associated processes. PMID- 28725722 TI - Evaluation of rodent spaceflight in the NASA animal enclosure module for an extended operational period (up to 35 days). AB - The National Aeronautics and Space Administration Animal Enclosure Module (AEM) was developed as a self-contained rodent habitat for shuttle flight missions that provides inhabitants with living space, food, water, ventilation, and lighting, and this study reports whether, after minimal hardware modification, the AEM could support an extended term up to 35 days for Sprague-Dawley rats and C57BL/6 female mice for use on the International Space Station. Success was evaluated based on comparison of AEM housed animals to that of vivarium housed and to normal biological ranges through various measures of animal health and well being, including animal health evaluations, animal growth and body masses, organ masses, rodent food bar consumption, water consumption, and analysis of blood contents. The results of this study confirmed that the AEMs could support 12 adult female C57BL/6 mice for up to 35 days with self-contained RFB and water, and the AEMs could also support 5 adult male Sprague-Dawley rats for 35 days with external replenishment of diet and water. This study has demonstrated the capability and flexibility of the AEM to operate for up to 35 days with minor hardware modification. Therefore, with modifications, it is possible to utilize this hardware on the International Space Station or other operational platforms to extend the space life science research use of mice and rats. PMID- 28725723 TI - Microlayered flow structure around an acoustically levitated droplet under a phase-change process. AB - The acoustic levitation method (ALM) has found extensive applications in the fields of materials science, analytical chemistry, and biomedicine. This paper describes an experimental investigation of a levitated droplet in a 19.4-kHz single-axis acoustic levitator. We used water, ethanol, water/ethanol mixture, and hexane as test samples to investigate the effect of saturated vapor pressure on the flow field and evaporation process using a high-speed camera. In the case of ethanol, water/ethanol mixtures with initial ethanol fractions of 50 and 70 wt%, and hexane droplets, microlayered toroidal vortexes are generated in the vicinity of the droplet interface. Experimental results indicate the presence of two stages in the evaporation process of ethanol and binary mixture droplets for ethanol content >10%. The internal and external flow fields of the acoustically levitated droplet of pure and binary mixtures are clearly observed. The binary mixture of the levitated droplet shows the interaction between the configurations of the internal and external flow fields of the droplet and the concentration of the volatile fluid. Our findings can contribute to the further development of existing theoretical prediction. PMID- 28725724 TI - Fluid dynamics alter Caenorhabditis elegans body length via TGF-beta/DBL-1 neuromuscular signaling. AB - Skeletal muscle wasting is a major obstacle for long-term space exploration. Similar to astronauts, the nematode Caenorhabditis elegans displays negative muscular and physical effects when in microgravity in space. It remains unclear what signaling molecules and behavior(s) cause these negative alterations. Here we studied key signaling molecules involved in alterations of C. elegans physique in response to fluid dynamics in ground-based experiments. Placing worms in space on a 1G accelerator increased a myosin heavy chain, myo-3, and a transforming growth factor-beta (TGF-beta), dbl-1, gene expression. These changes also occurred when the fluid dynamic parameters viscosity/drag resistance or depth of liquid culture were increased on the ground. In addition, body length increased in wild type and body wall cuticle collagen mutants, rol-6 and dpy-5, grown in liquid culture. In contrast, body length did not increase in TGF-beta, dbl-1, or downstream signaling pathway, sma-4/Smad, mutants. Similarly, a D1-like dopamine receptor, DOP-4, and a mechanosensory channel, UNC-8, were required for increased dbl-1 expression and altered physique in liquid culture. As C. elegans contraction rates are much higher when swimming in liquid than when crawling on an agar surface, we also examined the relationship between body length enhancement and rate of contraction. Mutants with significantly reduced contraction rates were typically smaller. However, in dop-4, dbl-1, and sma-4 mutants, contraction rates still increased in liquid. These results suggest that neuromuscular signaling via TGF-beta/DBL-1 acts to alter body physique in response to environmental conditions including fluid dynamics. PMID- 28725725 TI - Four-year bacterial monitoring in the International Space Station-Japanese Experiment Module "Kibo" with culture-independent approach. AB - Studies on the relationships between humans and microbes in space habitation environments are critical for success in long-duration space missions, to reduce potential hazards to the crew and the spacecraft infrastructure. We performed microbial monitoring in the Japanese Experiment Module "Kibo", a part of the International Space Station, for 4 years after its completion, and analyzed samples with modern molecular microbiological techniques. Sampling was performed in September 2009, February 2011, and October 2012. The surface of the incubator, inside the door of the incubator, an air intake, air diffuser, and handrail were selected as sampling sites. Sampling was performed using the optimized swabbing method. Abundance and phylogenetic affiliation of bacteria on the interior surfaces of Kibo were determined by quantitative PCR and pyrosequencing, respectively. Bacteria in the phyla Proteobacteria (gamma-subclass) and Firmicutes were frequently detected on the interior surfaces in Kibo. Families Staphylococcaceae and Enterobacteriaceae were dominant. Most bacteria detected belonged to the human microbiota; thus, we suggest that bacterial cells are transferred to the surfaces in Kibo from the astronauts. Environmental bacteria such as Legionella spp. were also detected. From the data on bacterial abundance and phylogenetic affiliation, Kibo has been microbiologically well maintained; however, the microbial community structure in Kibo may change with prolonged stay of astronauts. Continuous monitoring is required to obtain information on changes in the microbial community structure in Kibo. PMID- 28725726 TI - Medically induced amenorrhea in female astronauts. AB - Medically induced amenorrhea can be achieved through alterations in the normal regulatory hormones via the adoption of a therapeutic agent, which prevents menstrual flow. Spaceflight-related advantages for medically induced amenorrhea differ according to the time point in the astronaut's training schedule. Pregnancy is contraindicated for many pre-flight training activities as well as spaceflight, therefore effective contraception is essential. In addition, the practicalities of menstruating during pre-flight training or spaceflight can be challenging. During long-duration missions, female astronauts have often continuously taken the combined oral contraceptive pill to induce amenorrhea. Long-acting reversible contraceptives (LARCs) are safe and reliable methods used to medically induce amenorrhea terrestrially but as of yet, not extensively used by female astronauts. If LARCs were used, daily compliance with an oral pill is not required and no upmass or trash would need disposal. Military studies have shown that high proportions of female personnel desire amenorrhea during deployment; better education has been recommended at recruitment to improve uptake and autonomous decision-making. Astronauts are exposed to similar austere conditions as military personnel and parallels can be drawn with these results. Offering female astronauts up-to-date, evidence-based, comprehensive education, in view of the environment in which they work, would empower them to make informed decisions regarding menstrual suppression while respecting their autonomy. PMID- 28725727 TI - Effects of microgravity simulation on zebrafish transcriptomes and bone physiology-exposure starting at 5 days post fertilization. AB - Physiological modifications in near weightlessness, as experienced by astronauts during space flight, have been the subject of numerous studies. Various animal models have been used on space missions or in microgravity simulation on ground to understand the effects of gravity on living animals. Here, we used the zebrafish larvae as a model to study the effect of microgravity simulation on bone formation and whole genome gene expression. To simulate microgravity (sim MUg), we used two-dimensional (2D) clinorotation starting at 5 days post fertilization to assess skeletal formation after 5 days of treatment. To assess early, regulatory effects on gene expression, a single day clinorotation was performed. Clinorotation for 5 days caused a significant decrease of bone formation, as shown by staining for cartilage and bone structures. This effect was not due to stress, as assessed by measuring cortisol levels in treated larvae. Gene expression results indicate that 1-day simulated microgravity affected musculoskeletal, cardiovascular, and nuclear receptor systems. With free swimming model organisms such as zebrafish larvae, the 2D clinorotation setup appears to be a very appropriate approach to sim-MUg. We provide evidence for alterations in bone formation and other important biological functions; in addition several affected genes and pathways involved in bone, muscle or cardiovascular development are identified. PMID- 28725728 TI - Protection against neurodegenerative disease on Earth and in space. AB - All living organisms have evolutionarily adapted themselves to the Earth's gravity, and failure to adapt to gravity changes may lead to pathological conditions. This perspective may also apply to abnormal aging observed in bedridden elderly patients with aging-associated diseases such as osteoporosis and sarcopenia. Given that bedridden elderly patients are partially analogous to astronauts in that both cannot experience the beneficial effects of gravity on the skeletal system and may suffer from bone loss and muscle weakness, one may wonder whether there are gravity-related mechanisms underlying diseases among the elderly. In contrast to numerous studies of the relevance of microgravity in skeletal disorders, little attention has been paid to neurodegenerative diseases. Therefore, the objective of this paper is to discuss the possible relevance of microgravity in these diseases. We particularly noted a proteomics paper showing that levels of hippocampal proteins, including beta-synuclein and carboxyl terminal ubiquitin hydrolase L1, which have been linked to familial neurodegenerative diseases, were significantly decreased in the hippocampus of mice subjected to hindlimb suspension, a model of microgravity. We suggest that microgravity-induced neurodegeneration may be further exacerbated by diabetes and other factors. On the basis of this view, prevention of neurodegenerative diseases through 'anti-diabetes' and 'hypergravity' approaches may be important as a common therapeutic approach on Earth and in space. Collectively, neurodegenerative diseases and space medicine may be linked to each other more strongly than previously thought. PMID- 28725729 TI - High dietary iron increases oxidative stress and radiosensitivity in the rat retina and vasculature after exposure to fractionated gamma radiation. AB - Radiation exposure in combination with other space environmental factors including microgravity, nutritional status, and deconditioning is a concern for long-duration space exploration missions. Astronauts experience altered iron homeostasis due to adaptations to microgravity and an iron-rich food system. Iron intake reaches three to six times the recommended daily allowance due to the use of fortified foods on the International Space Station. Iron is associated with certain optic neuropathies and can potentiate oxidative stress. This study examined the response of eye and vascular tissue to gamma radiation exposure (3 Gy fractionated at 37.5 cGy per day every other day for 8 fractions) in rats fed an adequate-iron diet or a high-iron diet. Twelve-week-old Sprague-Dawley rats were assigned to one of four experimental groups: adequate-iron diet/no radiation (CON), high-iron diet/no radiation (IRON), adequate-iron diet/radiation (RAD), and high-iron diet/radiation (IRON+RAD). Animals were maintained on the corresponding iron diet for 2 weeks before radiation exposure. As previously published, the high-iron diet resulted in elevated blood and liver iron levels. Dietary iron overload altered the radiation response observed in serum analytes, as evidenced by a significant increase in catalase levels and smaller decrease in glutathione peroxidase and total antioxidant capacity levels. 8-OHdG immunostaining, showed increased intensity in the retina after radiation exposure. Gene expression profiles of retinal and aortic vascular samples suggested an interaction between the response to radiation and high dietary iron. This study suggests that the combination of gamma radiation and high dietary iron has deleterious effects on retinal and vascular health and physiology. PMID- 28725730 TI - Spaceflight-induced vertebral bone loss in ovariectomized rats is associated with increased bone marrow adiposity and no change in bone formation. AB - There is often a reciprocal relationship between bone marrow adipocytes and osteoblasts, suggesting that marrow adipose tissue (MAT) antagonizes osteoblast differentiation. MAT is increased in rodents during spaceflight but a causal relationship between MAT and bone loss remains unclear. In the present study, we evaluated the effects of a 14-day spaceflight on bone mass, bone resorption, bone formation, and MAT in lumbar vertebrae of ovariectomized (OVX) rats. Twelve-week old OVX Fischer 344 rats were randomly assigned to a ground control or flight group. Following flight, histological sections of the second lumbar vertebrae (n=11/group) were stained using a technique that allowed simultaneous quantification of cells and preflight fluorochrome label. Compared with ground controls, rats flown in space had 32% lower cancellous bone area and 306% higher MAT. The increased adiposity was due to an increase in adipocyte number (224%) and size (26%). Mineral apposition rate and osteoblast turnover were unchanged during spaceflight. In contrast, resorption of a preflight fluorochrome and osteoclast-lined bone perimeter were increased (16% and 229%, respectively). The present findings indicate that cancellous bone loss in rat lumbar vertebrae during spaceflight is accompanied by increased bone resorption and MAT but no change in bone formation. These findings do not support the hypothesis that increased MAT during spaceflight reduces osteoblast activity or lifespan. However, in the context of ovarian hormone deficiency, bone formation during spaceflight was insufficient to balance increased resorption, indicating defective coupling. The results are therefore consistent with the hypothesis that during spaceflight mesenchymal stem cells are diverted to adipocytes at the expense of forming osteoblasts. PMID- 28725731 TI - Long-term effects of simulated microgravity and/or chronic exposure to low-dose gamma radiation on behavior and blood-brain barrier integrity. AB - Astronauts on lengthy voyages will be exposed to an environment of microgravity and ionizing radiation that may have adverse effects on physical abilities, mood, and cognitive functioning. However, little is known about the long-term effects of combined microgravity and low-dose radiation. We exposed mice to gamma radiation using a cobalt-57 plate (0.01 cGy/h for a total dose of 0.04 Gy), hindlimb unloading to simulate microgravity, or a combination of both for 3 weeks. Mice then underwent a behavioral test battery after 1 week, 1 month, 4 months, and 8 months to assess sensorimotor coordination/balance (rotarod), activity levels (open field), learned helplessness/depression-like behavior (tail suspension test), risk-taking (elevated zero maze), and spatial learning/memory (water maze). Aquaporin-4 (AQP4) expression was assessed in the brain after behavioral testing to determine blood-brain barrier (BBB) integrity. Mice that received unloading spent significantly more time in the exposed portions of the elevated zero maze, were hypoactive in the open field, and spent less time struggling on the tail suspension test than mice that did not receive unloading. Mice in the combination group expressed more AQP4 immunoactivity than controls. Elevated zero maze and AQP4 data were correlated. No differences were seen on the water maze or rotarod, and no radiation-only effects were observed. These results suggest that microgravity may lead to changes in exploratory/risk-taking behaviors in the absence of other sensorimotor or cognitive deficits and that combined microgravity and a chronic, low dose of gamma radiation may lead to BBB dysfunction. PMID- 28725732 TI - Physiological fluid shear alters the virulence potential of invasive multidrug resistant non-typhoidal Salmonella Typhimurium D23580. AB - Salmonella enterica serovar Typhimurium strains belonging to sequence type ST313 are a major cause of fatal bacteremia among HIV-infected adults and children in sub-Saharan Africa. Unlike "classical" non-typhoidal Salmonella (NTS), gastroenteritis is often absent during ST313 infections and isolates are most commonly recovered from blood, rather than from stool. This is consistent with observations in animals, in which ST313 strains displayed lower levels of intestinal colonization and higher recovery from deeper tissues relative to classic NTS isolates. A better understanding of the key environmental factors regulating these systemic infections is urgently needed. Our previous studies using dynamic Rotating Wall Vessel (RWV) bioreactor technology demonstrated that physiological levels of fluid shear regulate virulence, gene expression, and stress response profiles of classic S. Typhimurium. Here we provide the first demonstration that fluid shear alters the virulence potential and pathogenesis related stress responses of ST313 strain D23580 in a manner that differs from classic NTS. PMID- 28725733 TI - Treadmill exercise within lower-body negative pressure attenuates simulated spaceflight-induced reductions of balance abilities in men but not women. AB - Spaceflight causes sensorimotor adaptations that result in balance deficiencies on return to a gravitational environment. Treadmill exercise within lower-body negative pressure (LBNP) helps protect physiological function during microgravity as simulated by bed rest. Therefore, we hypothesized that treadmill exercise within LBNP would prevent balance losses in both male and female identical twins during 30 days of 6 degrees head-down tilt bed rest. Fifteen (seven female and eight male) identical twin sets participated in this simulation of microgravity. Within each twin pair, one twin was randomly assigned to an exercise group that performed 40 min of supine treadmill exercise within LBNP set to generate 1.0-1.2 body weight, followed by 5 min of static feet-supported LBNP, 6 days per week. Their identical sibling was assigned to a non-exercise control group with all other bed rest conditions equivalent. Before and immediately after bed rest, subjects completed standing and walking rail balance tests with eyes open and eyes closed. In control subjects, standing rail balance times (men: -42%, women: 40%), rail walk distances (men: -44%, women: -32%) and rail walk times (men: 34%, women: -31%) significantly decreased after bed rest. Compared with controls, treadmill exercise within LBNP significantly attenuated losses of standing rail balance time by 63% in men, but the 41% attenuation in women was not significant. Treadmill exercise within LBNP did not affect rail walk abilities in men or women. Treadmill exercise within LBNP during simulated spaceflight attenuates loss of balance control in men but not in women. PMID- 28725735 TI - Evaluation of techniques for performing cellular isolation and preservation during microgravity conditions. AB - Genomic and epigenomic studies require the precise transfer of microliter volumes among different types of tubes in order to purify DNA, RNA, or protein from biological samples and subsequently perform analyses of DNA methylation, RNA expression, and chromatin modifications on a genome-wide scale. Epigenomic and transcriptional analyses of human blood cells, for example, require separation of purified cell types to avoid confounding contributions of altered cellular proportions, and long-term preservation of these cells requires their isolation and transfer into appropriate freezing media. There are currently no protocols for these cellular isolation procedures on the International Space Station (ISS). Currently human blood samples are either frozen as mixed cell populations (within the CPT collection tubes) with poor yield of viable cells required for cell-type isolations, or returned under ambient conditions, which requires timing with Soyuz missions. Here we evaluate the feasibility of translating terrestrial cell purification techniques to the ISS. Our evaluations were performed in microgravity conditions during parabolic atmospheric flight. The pipetting of open liquids in microgravity was evaluated using analog-blood fluids and several types of pipette hardware. The best-performing pipettors were used to evaluate the pipetting steps required for peripheral blood mononuclear cell (PBMC) isolation following terrestrial density-gradient centrifugation. Evaluation of actual blood products was performed for both the overlay of diluted blood, and the transfer of isolated PBMCs. We also validated magnetic purification of cells. We found that positive-displacement pipettors avoided air bubbles, and the tips allowed the strong surface tension of water, glycerol, and blood to maintain a patent meniscus and withstand robust pipetting in microgravity. These procedures will greatly increase the breadth of research that can be performed on board the ISS, and allow improvised experimentation by astronauts on extraterrestrial missions. PMID- 28725734 TI - Towards human exploration of space: the THESEUS review series on neurophysiology research priorities. AB - The THESEUS project (Towards Human Exploration of Space: a European Strategy), initiated within the seventh Framework Programme by the European Commission, aimed at providing a cross-cutting, life-science-based roadmap for Europe's strategy towards human exploration of long space missions, and its relevance to applications on Earth. This topic was investigated by experts in the field, in the framework of the THESEUS project whose aim was to develop an integrated life sciences research roadmap regarding human space exploration. In particular, decades of research have shown that altered gravity impairs neurological responses at large, such as perception, sleep, motor control, and cognitive factors. International experts established a list of key issues that should be addressed in that context and provided several recommendations such as a maximal exploitation of currently available resources on Earth and in space. PMID- 28725736 TI - Investigation of directionally solidified InGaSb ternary alloys from Ga and Sb faces of GaSb(111) under prolonged microgravity at the International Space Station. AB - InGaSb ternary alloys were grown from GaSb (111)A and B faces (Ga and Sb faces) under microgravity conditions on board the International Space Station by a vertical gradient freezing method. The dissolution process of the Ga and Sb faces of GaSb and orientation-dependent growth properties of InGaSb were analysed. The dissolution of GaSb(111)B was greater than that of (111)A, which was found from the remaining undissolved seed and feed crystals. The higher dissolution of the Sb face was explained based on the number of atoms at that face, and its bonding with the next atomic layer. The growth interface shape was almost flat in both cases. The indium composition in both InGaSb samples was uniform in the radial direction and it gradually decreased along the growth direction because of segregation. The growth rate of InGaSb from GaSb (111)B was found to be higher than that of GaSb (111)A because of the higher dissolution of GaSb (111)B. PMID- 28725737 TI - Towards human exploration of space: The THESEUS review series on nutrition and metabolism research priorities. AB - Nutrition has multiple roles during space flight from providing sufficient nutrients to meet the metabolic needs of the body and to maintain good health, to the beneficial psychosocial aspects related to the meals. Nutrition is central to the functioning of the body; poor nutrition compromises all the physiological systems. Nutrition is therefore likely to have a key role in counteracting the negative effects of space flight (e.g., radiation, immune deficits, oxidative stress, and bone and muscle loss). As missions increase in duration, any dietary/nutritional deficiencies will become progressively more detrimental. Moreover, it has been recognized that the human diet contains, in addition to essential macronutrients, a complex array of naturally occurring bioactive micronutrients that may confer significant long-term health benefits. It is therefore critical that astronauts be adequately nourished during missions. Problems of nutritional origin are often treatable by simply providing the appropriate nutrients and adequate recommendations. This review highlights six key issues that have been identified as space research priorities in nutrition field: in-flight energy balance; altered feeding behavior; development of metabolic stress; micronutrient deficiency; alteration of gut microflora; and altered fluid and electrolytes balance. For each of these topics, relevance for space exploration, knowledge gaps and proposed investigations are described. Finally, the nutritional questions related to bioastronautics research are very relevant to multiple ground-based-related health issues. The potential spin-offs are both interesting scientifically and potentially of great clinical importance. PMID- 28725738 TI - The gravity-induced re-localization of auxin efflux carrier CsPIN1 in cucumber seedlings: spaceflight experiments for immunohistochemical microscopy. AB - Reorientation of cucumber seedlings induces re-localization of CsPIN1 auxin efflux carriers in endodermal cells of the transition zone between hypocotyl and roots. This study examined whether the re-localization of CsPIN1 was due to the graviresponse. Immunohistochemical analysis indicated that, when cucumber seedlings were grown entirely under microgravity conditions in space, CsPIN1 in endodermal cells was mainly localized to the cell side parallel to the minor axis of the elliptic cross-section of the transition zone. However, when cucumber seeds were germinated in microgravity for 24 h and then exposed to 1g centrifugation in a direction crosswise to the seedling axis for 2 h in space, CsPIN1 was re-localized to the bottom of endodermal cells of the transition zone. These results reveal that the localization of CsPIN1 in endodermal cells changes in response to gravity. Furthermore, our results suggest that the endodermal cell layer becomes a canal by which auxin is laterally transported from the upper to the lower flank in response to gravity. The graviresponse-regulated re localization of CsPIN1 could be responsible for the decrease in auxin level, and thus for the suppression of peg formation, on the upper side of the transition zone in horizontally placed seedlings of cucumber. PMID- 28725740 TI - The effect of reduced gravity on cryogenic nitrogen boiling and pipe chilldown. AB - Manned deep space exploration will require cryogenic in-space propulsion. Yet, accurate prediction of cryogenic pipe flow boiling heat transfer is lacking, due to the absence of a cohesive reduced gravity data set covering the expected flow and thermodynamic parameter ranges needed to validate cryogenic two-phase heat transfer models. This work provides a wide range of cryogenic chilldown data aboard an aircraft flying parabolic trajectories to simulate reduced gravity. Liquid nitrogen is used to quench a 1.27 cm diameter tube from room temperature. The pressure, temperature, flow rate, and inlet conditions are reported from 10 tests covering liquid Reynolds number from 2,000 to 80,000 and pressures from 80 to 810 kPa. Corresponding terrestrial gravity tests were performed in upward, downward, and horizontal flow configurations to identify gravity and flow direction effects on chilldown. Film boiling heat transfer was lessened by up to 25% in reduced gravity, resulting in longer time and more liquid to quench the pipe to liquid temperatures. Heat transfer was enhanced by increasing the flow rate, and differences between reduced and terrestrial gravity diminished at high flow rates. The new data set will enable the development of accurate and robust heat transfer models of cryogenic pipe chilldown in reduced gravity. PMID- 28725739 TI - Towards human exploration of space: the THESEUS review series on cardiovascular, respiratory, and renal research priorities. PMID- 28725741 TI - THESEUS: The European research priorities for human exploration of space. PMID- 28725742 TI - Nanopore sequencing in microgravity. AB - Rapid DNA sequencing and analysis has been a long-sought goal in remote research and point-of-care medicine. In microgravity, DNA sequencing can facilitate novel astrobiological research and close monitoring of crew health, but spaceflight places stringent restrictions on the mass and volume of instruments, crew operation time, and instrument functionality. The recent emergence of portable, nanopore-based tools with streamlined sample preparation protocols finally enables DNA sequencing on missions in microgravity. As a first step toward sequencing in space and aboard the International Space Station (ISS), we tested the Oxford Nanopore Technologies MinION during a parabolic flight to understand the effects of variable gravity on the instrument and data. In a successful proof of-principle experiment, we found that the instrument generated DNA reads over the course of the flight, including the first ever sequenced in microgravity, and additional reads measured after the flight concluded its parabolas. Here we detail modifications to the sample-loading procedures to facilitate nanopore sequencing aboard the ISS and in other microgravity environments. We also evaluate existing analysis methods and outline two new approaches, the first based on a wave-fingerprint method and the second on entropy signal mapping. Computationally light analysis methods offer the potential for in situ species identification, but are limited by the error profiles (stays, skips, and mismatches) of older nanopore data. Higher accuracies attainable with modified sample processing methods and the latest version of flow cells will further enable the use of nanopore sequencers for diagnostics and research in space. PMID- 28725743 TI - Exposure of Mycobacterium marinum to low-shear modeled microgravity: effect on growth, the transcriptome and survival under stress. AB - Waterborne pathogenic mycobacteria can form biofilms, and certain species can cause hard-to-treat human lung infections. Astronaut health could therefore be compromised if the spacecraft environment or water becomes contaminated with pathogenic mycobacteria. This work uses Mycobacterium marinum to determine the physiological changes in a pathogenic mycobacteria grown under low-shear modeled microgravity (LSMMG). M. marinum were grown in high aspect ratio vessels (HARVs) using a rotary cell culture system subjected to LSMMG or the control orientation (normal gravity, NG) and the cultures used to determine bacterial growth, bacterium size, transcriptome changes, and resistance to stress. Two exposure times to LSMMG and NG were examined: bacteria were grown for ~40 h (short), or 4 days followed by re-dilution and growth for ~35 h (long). M. marinum exposed to LSMMG transitioned from exponential phase earlier than the NG culture. They were more sensitive to hydrogen peroxide but showed no change in resistance to gamma radiation or pH 3.5. RNA-Seq detected significantly altered transcript levels for 562 and 328 genes under LSMMG after short and long exposure times, respectively. Results suggest that LSMMG induced a reduction in translation, a downregulation of metabolism, an increase in lipid degradation, and increased chaperone and mycobactin expression. Sigma factor H (sigH) was the only sigma factor transcript induced by LSMMG after both short and long exposure times. In summary, transcriptome studies suggest that LSMMG may simulate a nutrient-deprived environment similar to that found within macrophage during infection. SigH is also implicated in the M. marinum LSMMG transcriptome response. PMID- 28725744 TI - Spaceflight modulates gene expression in the whole blood of astronauts. AB - Astronauts are exposed to a unique combination of stressors during spaceflight, which leads to alterations in their physiology and potentially increases their susceptibility to disease, including infectious diseases. To evaluate the potential impact of the spaceflight environment on the regulation of molecular pathways mediating cellular stress responses, we performed a first-of-its-kind pilot study to assess spaceflight-related gene-expression changes in the whole blood of astronauts. Using an array comprised of 234 well-characterized stress response genes, we profiled transcriptomic changes in six astronauts (four men and two women) from blood preserved before and immediately following the spaceflight. Differentially regulated transcripts included those important for DNA repair, oxidative stress, and protein folding/degradation, including HSP90AB1, HSP27, GPX1, XRCC1, BAG-1, HHR23A, FAP48, and C-FOS. No gender-specific differences or relationship to number of missions flown was observed. This study provides a first assessment of transcriptomic changes occurring in the whole blood of astronauts in response to spaceflight. PMID- 28725746 TI - Academic Pathology: A New Journal. PMID- 28725745 TI - Towards human exploration of space: The THESEUS review series on immunology research priorities. AB - Dysregulation of the immune system occurs during spaceflight and may represent a crew health risk during exploration missions because astronauts are challenged by many stressors. Therefore, it is crucial to understand the biology of immune modulation under spaceflight conditions in order to be able to maintain immune homeostasis under such challenges. In the framework of the THESEUS project whose aim was to develop an integrated life sciences research roadmap regarding human space exploration, experts working in the field of space immunology, and related disciplines, established a questionnaire sent to scientists around the world. From the review of collected answers, they deduced a list of key issues and provided several recommendations such as a maximal exploitation of currently available resources on Earth and in space, and to increase increments duration for some ISS crew members to 12 months or longer. These recommendations should contribute to improve our knowledge about spaceflight effects on the immune system and the development of countermeasures that, beyond astronauts, could have a societal impact. PMID- 28725747 TI - Assessment and Management of Professionalism Issues in Pathology Residency Training: Results From Surveys and a Workshop by the Graduate Medical Education Committee of the College of American Pathologists. AB - Professionalism issues are common in residency training and can be very difficult to recognize and manage. Almost one-third of the milestones for pathology recently instituted by the Accreditation Council for Graduate Medical Education encompass aspects of professionalism. Program directors are often unsure of how and when to remediate residents for unprofessional behavior. We used a case-based educational approach in a workshop setting to assist program directors in the management of unprofessional behavior in residents. Eight case scenarios highlighting various aspects of unprofessional behavior by pathology residents were developed and presented in an open workshop forum at the annual pathology program director's meeting. Prior to the workshop, 2 surveys were conducted: (1) to collect data on program directors' experience with identifying, assessing, and managing unprofessional behavior in their residents and (2) to get feedback from workshop registrants on how they would manage each of the 8 case scenarios. A wide range of unprofessional behaviors have been observed by pathology program directors. Although there is occasionally general agreement on how to manage specific behaviors, there remains wide variation in how to manage many of the presented unprofessional behaviors. Remediation for unprofessional behavior in pathology residents remains a difficult and challenging process. Additional education and research in this area are warranted. PMID- 28725748 TI - The Pathology Resident Wiki: A Valuable Resource for Residents to Use on Call. AB - Situations encountered on-call often bring some of the most unique and educationally rich questions to a pathology resident's attention which can be difficult to incorporate into institutional memory. A searchable online site (wiki) provides an easily accessible platform by which to do this and could serve as a valuable after-hour resident resource. Therefore, we evaluated a wiki's usefulness by creating a wiki using Campuspack for residents to catalog uncommon questions/situations encountered on call or rotations. After 41 months in use, analytic software embedded in the site was queried for usage statistics and one year's cohort of residents was surveyed to assess the wiki's value. Since the sites inception, over 7200 individual interactions with the site were recorded, with June through August being the most active period each year. Of the 15 residents surveyed, 60% utilized the site to answer a clinical question at least monthly and the majority (93%) considered the wiki a valuable on call resource. These findings suggest that an on-call wiki is a convenient tool for capturing the unique situations that pathology residents encounter. The majority of residents find the site a valuable resource and utilize it to answer clinical questions. PMID- 28725749 TI - Academic Mentorship Builds a Pathology Community. AB - Since academic mentorship focuses on developing and supporting the next generation of pathologists as well as the existing faculty, it plays a vital role in creating a successful academic pathology department whose faculty deliver quality teaching, research, and clinical care. The central feature is the mentor mentee relationship which is built on mutual respect, transparency, and a genuine interest from the mentor in the success of the mentee. This relationship is a platform for career development, academic guidance, informed professional choices, and problem solving. Departments of pathology must embrace a culture of effective mentorship so that trainees and faculty members are well mentored. Mentorship should become an academic activity that is valued and rewarded. Departments should create and support formal educational programs that train mentors in mentorship. Effective models of formal mentorship need to be created and evaluated in order to strengthen academic pathology. A successful mentorship culture will provide for a sustainable community of academic pathologists that transmits their best practices to the next generation. PMID- 28725750 TI - Consensus Guidelines for Practical Competencies in Anatomic Pathology and Laboratory Medicine for the Undifferentiated Graduating Medical Student. AB - The practice of pathology is not generally addressed in the undergraduate medical school curriculum. It is desirable to develop practical pathology competencies in the fields of anatomic pathology and laboratory medicine for every graduating medical student to facilitate (1) instruction in effective utilization of these services for optimal patient care, (2) recognition of the role of pathologists and laboratory scientists as consultants, and (3) exposure to the field of pathology as a possible career choice. A national committee was formed, including experts in anatomic pathology and/or laboratory medicine and in medical education. Suggested practical pathology competencies were developed in 9 subspecialty domains based on literature review and committee deliberations. The competencies were distributed in the form of a survey in late 2012 through the first half of 2013 to the medical education community for feedback, which was subjected to quantitative and qualitative analysis. An approval rate of >=80% constituted consensus for adoption of a competency, with additional inclusions/modifications considered following committee review of comments. The survey included 79 proposed competencies. There were 265 respondents, the majority being pathologists. Seventy-two percent (57 of 79) of the competencies were approved by >=80% of respondents. Numerous comments (N = 503) provided a robust resource for qualitative analysis. Following committee review, 71 competencies (including 27 modified and 3 new competencies) were considered to be essential for undifferentiated graduating medical students. Guidelines for practical pathology competencies have been developed, with the hope that they will be implemented in undergraduate medical school curricula. PMID- 28725751 TI - An Innovative Interactive Modeling Tool to Analyze Scenario-Based Physician Workforce Supply and Demand. AB - Effective physician workforce management requires that the various organizations comprising the House of Medicine be able to assess their current and future workforce supply. This information has direct relevance to funding of graduate medical education. We describe a dynamic modeling tool that examines how individual factors and practice variables can be used to measure and forecast the supply and demand for existing and new physician services. The system we describe, while built to analyze the pathologist workforce, is sufficiently broad and robust for use in any medical specialty. Our design provides a computer-based software model populated with data from surveys and best estimates by specialty experts about current and new activities in the scope of practice. The model describes the steps needed and data required for analysis of supply and demand. Our modeling tool allows educators and policy makers, in addition to physician specialty organizations, to assess how various factors may affect demand (and supply) of current and emerging services. Examples of factors evaluated include types of professional services (3 categories with 16 subcategories), service locations, elements related to the Patient Protection and Affordable Care Act, new technologies, aging population, and changing roles in capitated, value-based, and team-based systems of care. The model also helps identify where physicians in a given specialty will likely need to assume new roles, develop new expertise, and become more efficient in practice to accommodate new value-based payment models. PMID- 28725752 TI - Pathology Milestones: Assessing Clinical Competency by Committee. AB - All Accreditation Council for Graduate Medical Education accredited pathology residency training programs are now required to evaluate residents using the new Pathology Milestones assessment tool. Similar to implementation of the 6 Accreditation Council for Graduate Medical Education competencies a decade ago, there have been challenges in implementation of the new milestones for many residency programs. The pathology department at the University of Iowa has implemented a process that divides the labor of the task in rating residents while also maintaining consistency in the process. The process is described in detail, and some initial trends in milestone evaluation are described and discussed. Our experience indicates that thoughtful implementation of the Pathology Milestones can provide programs with valuable information that can inform curricular changes. PMID- 28725753 TI - Fibroblasts in Head and Neck Squamous Cell Carcinoma Associated With Perineural Invasion Have High-Level Nuclear Yes-Associated Protein (YAP) Expression. AB - We retrospectively studied the expression of Yes-associated protein (YAP) using immunohistochemical staining in 10 cases of head and neck squamous cell carcinoma with associated perineural invasion. We find that fibroblasts in areas associated with perineural invasion show higher levels of nuclear YAP compared to fibroblasts in the stroma of normal mucosa, with a median cell count of 35.4 per high-power field in the former and 3.9 in the latter. No differences were observed between the expression of YAP phosphorylated at Ser127 in the tumoral stroma compared to that in the normal mucosa, with a median cell count expression of 4.9 in the former versus 5.0 in the latter. Therefore, a strong and increased nuclear YAP expression in fibroblasts associated with perineural invasion in head and neck squamous cell carcinoma suggests that YAP-mediated transcription programs in these fibroblasts may contribute to perineural invasion. PMID- 28725754 TI - Calgary Laboratory Services: A Unique Canadian Model for an Academic Department of Pathology and Laboratory Medicine Succeeding in the Face of Provincial Integration of Public, Private, and Academic Laboratories. AB - Calgary Laboratory Services provides global hospital and community laboratory services for Calgary and surrounding areas (population 1.4 million) and global academic support for the University of Calgary Cumming School of Medicine. It developed rapidly after the Alberta Provincial Government implemented an austerity program to address rising health care costs and to address Alberta's debt and deficit in 1994. Over roughly the next year, all hospital and community laboratory test funding within the province was put into a single budget, fee codes for fee-for-service test billing were closed, roughly 40% of the provincial laboratory budget was cut, and roughly 40% of the pathologists left the province of Alberta. In Calgary, in the face of these abrupt changes in the laboratory environment, private laboratories, publicly funded hospital laboratories and the medical school department precipitously and reluctantly merged in 1996. The origin of Calgary Laboratory Services was likened to an "unhappy shotgun marriage" by all parties. Although such a structure could save money by eliminating duplicated services and excess capacity and could provide excellent city-wide clinical service by increasing standardization, it was less clear whether it could provide strong academic support for a medical school. Over the past decade, iterations of the Calgary Laboratory Services model have been implemented or are being considered in other Canadian jurisdictions. This case study analyzes the evolution of Calgary Laboratory Services, provides a metric based review of academic performance over time, and demonstrates that this model, essentially arising as an unplanned experiment, has merit within a Canadian health care context. PMID- 28725755 TI - Examination of the Residency Interview Process for Academic Pathology Departments: How to Make the Most of a Resource-Heavy Process. AB - Annual resident recruitment is a complex undertaking that requires many departmental resources of faculty time and effort and in many cases financial investment for meals and lodging. The applicants represent the future of the profession as well as the providers of patient care in the respective training programs. Although we understand the importance of this process, as we become more and more distracted by financial, administrative, and academic duties, the demands of recruitment have not decreased and continue annually. In an attempt to find the best practices for the improvement in our methods of recruitment, a review of the literature on the employment interviews with a specific eye to pathology residency relevant information was conducted. This article reviews some of the factors proven to be important to the applicants as well as an examination of the structure of the interview and the postinterview applicant evaluation process. PMID- 28725756 TI - Black Males in Medicine: My View. PMID- 28725757 TI - The Role of Compensation Criteria to Minimize Face-Time Bias and Support Faculty Career Flexibility: An Approach to Enhance Career Satisfaction in Academic Pathology. AB - Work-life balance is important to recruitment and retention of the younger generation of medical faculty, but medical school flexibility policies have not been fully effective. We have reported that our school's policies are underutilized due to faculty concerns about looking uncommitted to career or team. Since policies include leaves and accommodations that reduce physical presence, faculty may fear "face-time bias," which negatively affects evaluation of those not "seen" at work. Face-time bias is reported to negatively affect salary and career progress. We explored face-time bias on a leadership level and described development of compensation criteria intended to mitigate face-time bias, raise visibility, and reward commitment and contribution to team/group goals. Leaders from 6 partner departments participated in standardized interviews and group meetings. Ten compensation plans were analyzed, and published literature was reviewed. Leaders did not perceive face-time issues but saw team pressure and perception of availability as performance motivators. Compensation plans were multifactor productivity based with many quantifiable criteria; few addressed team contributions. Using these findings, novel compensation criteria were developed based on a published model to mitigate face-time bias associated with team perceptions. Criteria for organizational citizenship to raise visibility and reward group outcomes were included. We conclude that team pressure and perception of availability have the potential to lead to bias and may contribute to underuse of flexibility policies. Recognizing organizational citizenship and cooperative effort via specific criteria in a compensation plan may enhance a culture of flexibility. These novel criteria have been effective in one pilot department. PMID- 28725758 TI - Physician Scientist Research Pathway Leading to Certification by the American Board of Pathology. AB - In 2014, the American Board of Pathology, in response to the pathology community, approved a physician scientist research pathway. This brief report summarizes the history of and objectives for creating the physician scientist research pathway and the requirements of the American Board of Pathology for the certification of physician scientist research pathway trainees. PMID- 28725759 TI - Opportunity: Newly Created Physician-Scientist Research Pathway by the American Board of Pathology. PMID- 28725761 TI - Insufficient Teaching of Laboratory Medicine in US Medical Schools. PMID- 28725760 TI - Interventions to Educate Family Physicians to Change Test Ordering: Systematic Review of Randomized Controlled Trials. AB - The purpose is to systematically review randomised controlled trials (RCTs) to change family physicians' laboratory test-ordering. We searched 15 electronic databases (no language/date limitations). We identified 29 RCTs (4,111 physicians, 175,563 patients). Six studies specifically focused on reducing unnecessary tests, 23 on increasing screening tests. Using Cochrane methodology 48.5% of studies were low risk-of-bias for randomisation, 7% concealment of randomisation, 17% blinding of participants/personnel, 21% blinding outcome assessors, 27.5% attrition, 93% selective reporting. Only six studies were low risk for both randomisation and attrition. Twelve studies performed a power computation, three an intention-to-treat analysis and 13 statistically controlled clustering. Unweighted averages were computed to compare intervention/control groups for tests assessed by >5 studies. The results were that fourteen studies assessed lipids (average 10% more tests than control), 14 diabetes (average 8% > control), 5 cervical smears, 2 INR, one each thyroid, fecal occult-blood, cotinine, throat-swabs, testing after prescribing, and urine-cultures. Six studies aimed to decrease test groups (average decrease 18%), and two to increase test groups. Intervention strategies: one study used education (no change): two feedback (one 5% increase, one 27% desired decrease); eight education + feedback (average increase in desired direction >control 4.9%), ten system change (average increase 14.9%), one system change + feedback (increases 5-44%), three education + system change (average increase 6%), three education + system change + feedback (average 7.7% increase), one delayed testing. The conclusions are that only six RCTs were assessed at low risk of bias from both randomisation and attrition. Nevertheless, despite methodological shortcomings studies that found large changes (e.g. >20%) probably obtained real change. PMID- 28725762 TI - Flexner 3.0-Democratization of Medical Knowledge for the 21st Century: Teaching Medical Science Using K-12 General Pathology as a Gateway Course. AB - A medical school general pathology course has been reformatted into a K-12 general pathology course. This new course has been implemented at a series of 7 to 12 grade levels and the student outcomes compared. Typically, topics covered mirrored those in a medical school general pathology course serving as an introduction to the mechanisms of diseases. Assessment of student performance was based on their score on a multiple-choice final examination modeled after an examination given to medical students. Two Tucson area schools, in a charter school network, participated in the study. Statistical analysis of examination performances showed that there were no significant differences as a function of school (F = 0.258, P = .6128), with students at school A having an average test scores of 87.03 (standard deviation = 8.99) and school B 86.00 (standard deviation = 8.18; F = 0.258, P = .6128). Analysis of variance was also conducted on the test scores as a function of gender and class grade. There were no significant differences as a function of gender (F = 0.608, P = .4382), with females having an average score of 87.18 (standard deviation = 7.24) and males 85.61 (standard deviation = 9.85). There were also no significant differences as a function of grade level (F = 0.627, P = .6003), with 7th graders having an average of 85.10 (standard deviation = 8.90), 8th graders 86.00 (standard deviation = 9.95), 9th graders 89.67 (standard deviation = 5.52), and 12th graders 86.90 (standard deviation = 7.52). The results demonstrated that middle and upper school students performed equally well in K-12 general pathology. Student course evaluations showed that the course met the student's expectations. One class voted K-12 general pathology their "elective course-of-the-year." PMID- 28725763 TI - Onboarding for Pathology Residency Programs-The Montefiore Experience. AB - Onboarding is a system frequently used in the corporate world as a means of orienting incoming employees to their duties and inculcating the workplace values. The program aims to facilitate transition into new work roles and improve employee retention rates. At Montefiore, we have instituted an onboarding curriculum that is given to new anatomic and clinical pathology residents about a month prior to the start of residency. The program includes an introductory video series of basic histology and a series of anatomic and clinical case studies illustrating basic laboratory principles. This didactic content is tagged to learning objectives and short self-assessment modules. In addition, content related to the work ethos at Montefiore and the role of the core competencies and milestones in residency education are included. Finally, a broader component of the onboarding gives the incoming residents a social welcome to our area, including key information about living in the area surrounding Montefiore. The program has been well received by our residents for whom the content has helped to boost confidence when starting. We feel that the program is helpful in ensuring that all incoming residents start having received the same baseline didactic content. Transmitting this didactic content via onboarding allows our residents to begin the work of learning pathology immediately, rather than spending the first weeks of residency covering remedial content such as basic histology. Such a program may be useful to other pathology residencies, most of whom have residents from a range of backgrounds and whose prior exposure to pathology may be limited. PMID- 28725764 TI - Identifying the Challenges of "Small" Pathology Residency Programs and Creating Collaborative Solutions. AB - The majority of pathology residency training programs in the United States are considered to be small training programs. Small training programs, regardless of specialty, encounter unique challenges that have been documented in the literature. With the implementation of the Next Accreditation System (NAS), and other Accreditation Council for Graduate Medical Education (ACGME) Common Program Requirements, adequate personnel and other resources are necessary. An online survey was conducted on the pathology program directors' section listserv to help identify characteristics and challenges of small pathology residency training programs. A discussion group on small pathology residency programs was held at the 2015 Association of Pathology Chairs/Program Directors annual meeting, where the results of the survey were discussed and small breakout groups followed the discussion of the survey. The results of the online survey and discussion groups are discussed in this paper. PMID- 28725765 TI - Changes in Resident Graduate Characteristics in a Large Pathology Training Program, 1994 to 2013. AB - The field of pathology has changed dramatically over the recent decades and has become more complex with emphasis toward subspecialization. These changes potentially influence resident training as programs and trainees search for cutting-edge skills in the evolving field. Over the last 20 years, our institution's residency education was modified profoundly to emphasize subspecialty practice. Furthermore, efforts were made to search for and recruit candidates who desired such training. In this study, we examined a 20-year time period to determine how these changes may have influenced the characteristics of our resident graduates. For each trainee who graduated from our pathology residency program (1994-2013), the following parameters were evaluated: highest academic degree, gender, graduating medical school, type of training, number of publications during residency, enrollment in fellowships, and type of career position. The data collected were divided into 4 time periods. Fisher exact test and 2-tailed t test were used for statistical analyses comparing the first half (1994-2003) to the latter half (2004-2013) of the study. In the second half, there were more graduates who pursued single track pathology training-anatomic pathology or clinical pathology versus combined anatomic/clinical pathology training (P = .035), more first author and total publications per graduate during residency (P < .001), more graduates who enrolled in fellowships (P < .001), and a greater tendency toward an academic career position than all other types combined (P = .034). In parallel to the subspecialization trends in our department, we witnessed changes in the characteristics of our resident graduates whose interests and career choices have become more focused. PMID- 28725766 TI - A Required Rotation in Clinical Laboratory Management for Pathology Residents: Five-Year Experience at Hofstra Northwell School of Medicine. AB - Leadership and management training during pathology residency have been identified repeatedly by employers as insufficient. A 1-month rotation in clinical laboratory management (CLM) was created for third-year pathology residents. We report on our experience and assess the value of this rotation. The rotation was one-half observational and one-half active. The observational component involved being a member of department and laboratory service line leadership, both at the departmental and institutional level. Observational participation enabled learning of both the content and principles of leadership and management activities. The active half of the rotation was performance of a project intended to advance the strategic trajectory of the department and laboratory service line. In our program that matriculates 4 residents per year, 20 residents participated from April 2010 through December 2015. Their projects either activated a new priority area or helped propel an existing strategic priority forward. Of the 16 resident graduates who had obtained their first employment or a fellowship position, 9 responded to an assessment survey. The majority of respondents (5/9) felt that the rotation significantly contributed to their ability to compete for a fellowship or their first employment position. The top reported benefits of the rotation included people management; communication with staff, departmental, and institutional leadership; and involvement in department and institutional meetings and task groups. Our 5-year experience demonstrates both the successful principles by which the CLM rotation can be established and the high value of this rotation to residency graduates. PMID- 28725767 TI - The Pathologist Pipeline: Implications of Changes for Programs and Post-Sophomore Fellowships-Program Directors' Section Perspective. AB - A shortage of physicians in the United States has been long projected. Because of predictions of retirement among the aging pathology workforce, there is an anticipated shortage of pathologist as well. To address the pathology workforce shortage among pathologists, the Association of Pathology Chairs assembled a subcommittee of the Association of Pathology Chairs Advocacy Committee to explore ways to identify the strengths, weaknesses, opportunities, and threats to the pathology workforce. One opportunity to encourage strong candidates to pursue pathology as a career is to explore possibility to revisit advanced credit for the post-sophomore fellowship. A survey that was designed to understand the post sophomore fellowship training better was distributed on the listserv of the Program Directors Section of the Association of Pathology Chairs. A review of the literature on post-sophomore fellowship programs is presented in light of the findings from this survey. Many post-sophomore fellowship programs are run similar to a first-year resident experience, although programs show great diversity in curriculum, including some programs that focus on research. Post sophomore fellowships attract medical students to the area of pathology and tend to end up in academic and research positions. A second survey of program directors served as an opinion poll of challenging issues that affect residency training. From the second opinion poll, most program directors feel that residents can use additional training to improve the outcome of our future pathologists. PMID- 28725768 TI - Strengths of the Northwell Health Laboratory Service Line: Maintaining Performance During Threatened Interruptions in Service. AB - From 2009 to 2015, the laboratories of the 19-hospital North Shore-LIJ Health System experienced 5 threatened interruptions in service and supported 2 regional health-care providers with threatened interruptions in their laboratory service. We report our strategies to maintain laboratory performance during these events, drawing upon the strengths of our integrated laboratory service line. Established in 2009, the laboratory service line has unified medical and administrative leadership and system-wide divisional structure, quality management, and standardization of operations and procedures. Among many benefits, this governance structure enabled the laboratories to respond to a series of unexpected events. Specifically, at our various service sites, the laboratories dealt with pandemic (2009), 2 floods (2010, 2012), 2 fires (2010, 2015), and laboratory floor subsidence (2013). We were also asked to provide support for a regional physician network facing abrupt loss of testing services from closure of another regional clinical laboratory (2010) and to intervene for a non-health system hospital threatened with closure owing to noncompliance of laboratory operations (2012). In all but a single instance, patient care was served without interruption in service. In the last instance, fire interrupted laboratory services for 30 minutes. We conclude that in a large integrated health system, threats to continuous laboratory operations are not infrequent when measured on an annual basis. While most threats are from external physical circumstances, some emanate from unexpected administrative events. A strong laboratory governance mechanism that includes unified medical and administrative leadership across the entirety of the laboratory service line enables successful responses to these threats. PMID- 28725769 TI - Opportunities for Academic Pathology: The Thoughts and Perspectives of a Legal Observer. AB - As American health care undergoes great change, academic pathology is uniquely positioned to establish pathologists as key to the new health-care environment. Pathologists are at the forefront of major innovations in health care and are specialists who interact with all other medical specialists and essentially the entire range of health-care services. Academic pathologists benefit from being subspecialist experts who provide care to patients referred from large geographic areas, who can attain high academic stature over the course of their careers, and who serve as mentors for learners across virtually all medical specialties. Academic medical centers, in turn, have excellent credibility in the community, strong information technology infrastructure with the ability for data accrual and analysis not available in community health-care settings, and strong liaisons with civic authorities and policy makers. However, pathologists have to overcome their own tendencies toward modesty and lack of assertiveness, in order to help counter the significant trends in the health-care marketplace that disempower health-care providers and place health industry decision-making in the hands of nonmedical stakeholders. Specifically, academic pathologists need to proactively play a major role in institutional efforts to improve performance in quality, patient safety, efficiency, and coordinated care delivery and become leaders in the delivery of effective and efficient patient care. They need to play an essential role in utilization management, including molecular testing. They need to develop their value propositions for payers and seek to gain access to payers in order to represent these value statements. They should gain visibility directly to patients seeking expertise for second opinions and pursue opportunities for outreach programs in the community well beyond the academic medical center. Absent such efforts by academic pathologists, pathology is at risk of continued commoditization by nonpathologists, with weakening of the value proposition that pathology might bring forward. PMID- 28725770 TI - Strategies for a Successful Anatomic Pathology Subspecialty Workgroup: The 26 Year Collaboration of "The Elves". AB - From 1990 to present, 14 liver pathologists and 2 clinical hepatologists from 9 countries have met annually to hold thematic 2.5-day meetings centered on case based discussion. The goal of these meetings has been to identify gaps in knowledge in our field and fuel scholarly effort to address these gaps. The founding principles were worldwide representation, good representation of women, compatibility of participants, commitment to stable membership and regular attendance, mutual education and friendship, and free exchange of ideas. A summary report of the 2.5-day meeting constituted an enduring document that captured the free flow of ideas discussed. These ideas were open to all participants for the pursuit of scholarship back at their home institutions. However, any idea borne out of an Elves meeting merits open invitation for other Elves to participate in, using established standards for meaningful coauthorship. Over 26 consecutive meetings (1990-2015), themes covered the breadth of liver pathology. With retirement of 2 individuals, resignation of 3, and death of 1, six new members were nominated and voted into membership. Over these same 26 years, active members published 2025 articles indexed in PubMEd Central under the topic "liver;" 3% of these articles represented collaborations between members. This international group represents a successful model in a subspecialty of anatomic pathology for open exchange of ideas, mutual education, and generation of topics worthy of scholarly investigation. We conclude that a self-selected group of subspecialty pathologists can meet successfully over 26 years, maintain a high state of engagement through each annual meeting, self-renew as a result of retirement or resignation, and provide a creative stimulus for highly productive academic careers. PMID- 28725771 TI - The Ethics of Ambiguity: Rethinking the Role and Importance of Uncertainty in Medical Education and Practice. AB - Understanding and embracing uncertainty are critical for effective teacher learner relationships as well as for shared decision-making in the physician patient relationship. However, ambiguity has not been given serious consideration in either the undergraduate or graduate medical curricula or in the role it plays in patient-centered care. In this article, the author examines the ethics of ambiguity and argues for a pedagogy that includes education in the importance of, and tolerance of, ambiguity that is inherent in medical education and practice. Common threads running through the ethics of ambiguity are the virtue of respect, and the development of a culture of respect is required for the successful understanding and implementation of a pedagogy of ambiguity. PMID- 28725772 TI - Pathology Informatics Essentials for Residents: A Flexible Informatics Curriculum Linked to Accreditation Council for Graduate Medical Education Milestones (a secondary publication). AB - CONTEXT: Recognition of the importance of informatics to the practice of pathology has surged. Training residents in pathology informatics has been a daunting task for most residency programs in the United States because faculty often lacks experience and training resources. Nevertheless, developing resident competence in informatics is essential for the future of pathology as a specialty. OBJECTIVE: To develop and deliver a pathology informatics curriculum and instructional framework that guides pathology residency programs in training residents in critical pathology informatics knowledge and skills, and meets Accreditation Council for Graduate Medical Education Informatics Milestones. DESIGN: The College of American Pathologists, Association of Pathology Chairs, and Association for Pathology Informatics formed a partnership and expert work group to identify critical pathology informatics training outcomes and to create a highly adaptable curriculum and instructional approach, supported by a multiyear change management strategy. RESULTS: Pathology Informatics Essentials for Residents (PIER) is a rigorous approach for educating all pathology residents in important pathology informatics knowledge and skills. PIER includes an instructional resource guide and toolkit for incorporating informatics training into residency programs that vary in needs, size, settings, and resources. PIER is available at http://www.apcprods.org/PIER (accessed April 6, 2016). CONCLUSIONS: PIER is an important contribution to informatics training in pathology residency programs. PIER introduces pathology trainees to broadly useful informatics concepts and tools that are relevant to practice. PIER provides residency program directors with a means to implement a standardized informatics training curriculum, to adapt the approach to local program needs, and to evaluate resident performance and progress over time. PMID- 28725773 TI - The Pathologist as Poet. AB - The role of the humanities (eg, philosophy, bioethics, literature, music, theater, religion, anthropology) in medical education has been argued long and hard for decades. It is argued that the study of subjects included in the humanities can enhance critical thinking skills, foster a deeper level of learning and understanding, and help to enhance one's level of compassion, empathy, and moral/ethical reasoning. It is the author's contention that writing and reading poetry (as an example of a personal pursuit in the humanities) can help achieve these goals not only in our contact with patients but also in our contact with other humans and cultures in the world at large. PMID- 28725774 TI - Communicating Uncertainty in Surgical Pathology Reports: A Survey of Staff Physicians and Residents at an Academic Medical Center. AB - In order to document perceptions of text comments appearing in surgical pathology reports, questionnaires were distributed to 4 groups of caregivers: university staff pathologists, resident pathologists, faculty clinicians (other than pathologists), and resident clinicians at a teaching hospital. Results of this pilot study showed a wide degree of variability existed within each group of surgical pathology report users, with respect to percent confidence assigned to various phrases, commonly used to express diagnostic uncertainty, appearing often as free-text comments in surgical pathology reports. The unavailability of immunohistochemistry tests, or ambiguous immunohistochemistry test results, was especially problematic. With respect to modes of communication between the surgical pathology laboratory and its service users, clinicians indicated they preferred to use tumor boards/interdisciplinary conferences, face-to-face meetings, and phone calls to clarify their interpretations of a pathologist's diagnoses, as compared with simply reading free-text comments. On the other hand, surgical pathologists rely heavily on their use of the comment portion of a surgical pathology report to clarify, modify, or expand on the diagnoses they render. The majority of clinicians stated that they "always" read the free-text comment portion of a surgical pathology report, whereas some acknowledged they do not always read it. Pathology residents had significantly less confidence in the ability of a free-text comment on a surgical pathology report to clarify a diagnosis (chi2 = 46.36, P < .0001). Pathology departments should consider standardizing definitions and weighting the words and phrases they use in their free-text comment sections of surgical pathology reports. PMID- 28725775 TI - Pathology: A Satisfying Medical Profession. AB - Medical students are often unsure about the viability of a career as a physician in pathology. In particular, they are concerned that pathologists may not have a gratifying lifestyle or be well compensated. These worries may cause angst among medical students considering pathology and among junior pathology residents wondering if they made the correct career choice. A 2016 survey of nearly 20 000 physicians including nearly 400 pathologists provides reassuring data about compensation and career choice. This survey showed that 52% of pathologists are satisfied with their career choice and 63% are satisfied with their compensation. Among the 26 specialties that were surveyed, pathologists ranked 2 in believing that they were fairly compensated. Moreover, 66% of pathologists find that making diagnostic decisions, a core aspect of our discipline, is the most rewarding aspect of their career. Pathologists also ranked among the highest groups of physicians in reporting happiness at work and among the lowest groups reporting burnout. Overall, these 2016 surveys show that the majority of pathologists find deep satisfaction in their careers as pathologists. PMID- 28725776 TI - Training Pathology Residents to Practice 21st Century Medicine: A Proposal. AB - Scientific advances, open information access, and evolving health-care economics are disrupting extant models of health-care delivery. Physicians increasingly practice as team members, accountable to payers and patients, with improved efficiency, value, and quality. This change along with a greater focus on population health affects how systems of care are structured and delivered. Pathologists are not immune to these disruptors and, in fact, may be one of the most affected medical specialties. In the coming decades, it is likely that the number of practicing pathologists will decline, requiring each pathologist to serve more and often sicker patients. The demand for increasingly sophisticated yet broader diagnostic skills will continue to grow. This will require pathologists to acquire appropriate professional training and interpersonal skills. Today's pathology training programs are ill designed to prepare such practitioners. The time to practice for most pathology trainees is typically 5 to 6 years. Yet, trainees often lack sufficient experience to practice independently and effectively. Many studies have recognized these challenges suggesting that more effective training for this new century can be implemented. Building on the strengths of existing programs, we propose a redesign of pathology residency training that will meet (and encourage) a continuing evolution of American Board of Pathology and Accreditation Council for Graduate Medical Education requirements, reduce the time to readiness for practice, and produce more effective, interactive, and adaptable pathologists. The essence of this new model is clear definition and acquisition of core knowledge and practice skills that span the anatomic and clinical pathology continuum during the first 2 years, assessed by competency-based metrics with emphasis on critical thinking and skill acquisition, followed by individualized modular training with intensively progressive responsibility during the final years of training. We anticipate that implementing some or all aspects of this model will enable residents to attain a higher level of competency within the current time-based constraints of residency training. PMID- 28725777 TI - Benchmarking Academic Anatomic Pathologists: The Association of Pathology Chairs Survey. AB - The most common benchmarks for faculty productivity are derived from Medical Group Management Association (MGMA) or Vizient-AAMC Faculty Practice Solutions Center(r) (FPSC) databases. The Association of Pathology Chairs has also collected similar survey data for several years. We examined the Association of Pathology Chairs annual faculty productivity data and compared it with MGMA and FPSC data to understand the value, inherent flaws, and limitations of benchmarking data. We hypothesized that the variability in calculated faculty productivity is due to the type of practice model and clinical effort allocation. Data from the Association of Pathology Chairs survey on 629 surgical pathologists and/or anatomic pathologists from 51 programs were analyzed. From review of service assignments, we were able to assign each pathologist to a specific practice model: general anatomic pathologists/surgical pathologists, 1 or more subspecialties, or a hybrid of the 2 models. There were statistically significant differences among academic ranks and practice types. When we analyzed our data using each organization's methods, the median results for the anatomic pathologists/surgical pathologists general practice model compared to MGMA and FPSC results for anatomic and/or surgical pathology were quite close. Both MGMA and FPSC data exclude a significant proportion of academic pathologists with clinical duties. We used the more inclusive FPSC definition of clinical "full time faculty" (0.60 clinical full-time equivalent and above). The correlation between clinical full-time equivalent effort allocation, annual days on service, and annual work relative value unit productivity was poor. This study demonstrates that effort allocations are variable across academic departments of pathology and do not correlate well with either work relative value unit effort or reported days on service. Although the Association of Pathology Chairs reported median work relative value unit productivity approximated MGMA and FPSC benchmark data, we conclude that more rigorous standardization of academic faculty effort assignment will be needed to improve the value of work relative value unit measurements of faculty productivity. PMID- 28725778 TI - Professionalism in Residency Training: A Compilation of Desirable Behaviors and a Case-Based Comparison Between Pathologists in Training and Practice. AB - Professionalism is one of the most important competencies for physicians but is also the most difficult to teach, assess, and manage. To better understand professionalism in pathology, we surveyed practicing pathologists and pathology residents and fellows in training. We identified 12 key desirable attributes of professionalism. In addition, 8 case scenarios highlighting unprofessional behavior were presented, and results between pathologists in practice and in training were compared. No significant differences between attending pathologists and residents were identified in how these cases should be managed. Our study demonstrated remarkable concordance between practicing pathologists and residents as to what constitutes professionalism and how to manage unprofessional behavior. Our case-based approach can be a useful technique to teach professionalism to both pathologists in practice and in training. PMID- 28725779 TI - Evolution of the Pathology Residency Curriculum: Preparing for a Positive Future. AB - The required medical knowledge and skill set for the pathologist of 2020 are different than in 2005. Pathology residency training curriculum must accordingly change to fulfill the needs of these ever-changing requirements. In order to make rational curricular adjustments, it is important for us to know the current trajectory of resident training in pathology-where we have been, what our actual current training curriculum is now-to understand how that might change in anticipation of meeting the needs of a changing patient and provider population and to fit within the evolving future biomedical and socioeconomic health-care setting. In 2013, there were 143 Accreditation Council for Graduate Medical Education-accredited pathology residency training programs in the United States, with approximately 2400 residents. There is diversity among residency training programs not only with respect to the number of residents but also in training venue(s). To characterize this diversity among pathology residency training programs, a curriculum survey was conducted of pathology residency program directors in 2013 and compared with a similar survey taken almost 9 years previously in 2005 to identify trends in pathology residency curriculum. Clinical pathology has not changed significantly in the number of rotations over 9 years; however, anatomic pathology has changed dramatically, with an increase in the number of surgical pathology rotations coupled with a decline in stand-alone autopsy rotations. With ever-expanding medical knowledge that the graduating pathology resident must know, it is necessary to (1) reflect upon what are the critical need subjects, (2) identify areas that have become of lesser importance, and then (3) prioritize training accordingly. PMID- 28725780 TI - Life After Being a Pathology Department Chair: Issues and Opportunities. AB - Although there is a considerable literature on transition of faculty members to the position of department chair, there is a dearth of publications about transitioning from the chair to other activities including retirement. The Association of Pathology Chairs senior fellows (all of whom are former chairs of academic departments of pathology) made this topic a focus of discussion at the Association of Pathology Chairs 2016 Annual Meeting. Of the 33 senior fellows engaged in this discussion, following their time as chairs, a small majority (18) transitioned to other administrative posts within or outside the university, while the others either returned to the active faculty (7) or retired (8). The motivating factors and influences for transitioning from the chair were probed along with the processes used in executing the transition, such as the development of transition plans. The reasons for selecting the specific type of postchair activity were also investigated. There was extraordinary diversity in the type of post-chair activities pursued. To our knowledge, no other medical specialty has examined these issues, which may be potentially relevant for the career planning of active chairs. PMID- 28725781 TI - Teaching Laboratory Management Principles and Practices Through Mentorship and Graduated Responsibility: The Assistant Medical Directorship. AB - With the changing landscape of medicine in general, and pathology in particular, a greater emphasis is being placed on laboratory management as a means of controlling spiraling medical costs and improving health-care efficiency. To meet this challenge, pathology residency programs have begun to incorporate formal laboratory management training into their curricula, using institutional curricula and/or online laboratory management courses offered by professional organizations. At the University of Utah, and its affiliated national reference laboratory, ARUP Laboratories, Inc, interested residents are able to supplement the departmental lecture-based and online laboratory management curriculum by participating in assistant medical directorship programs in one of several pathology subspecialty disciplines. The goals of many of the assistant medical directorship positions include the development of laboratory management skills and competencies. A survey of current and recent assistant medical directorship participants revealed that the assistant medical directorship program serves as an excellent means of improving laboratory management skills, as well as improving performance as a fellow and practicing pathologist. PMID- 28725782 TI - Use of Pathology Data to Improve High-Value Treatment of Cervical Neoplasia. AB - We investigated the influence of pathology data to improve patient outcomes in the treatment of high-grade cervical neoplasia in a joint pathology and gynecology collaboration. Two of us (B.S.D. and M.D.) reviewed all cytology, colposcopy and surgical pathology results, patient history, and pregnancy outcomes from all patients with loop electrosurgical excision procedure specimens for a 33-month period (January 2011-September 2013). We used this to determine compliance to 2006 consensus guidelines for the performance of loop electrosurgical excision procedure and shared this information in 2 interprofessional and interdisciplinary educational interventions with Obstetrics/Gynecology and Pathology faculty at the end of September 2013. We simultaneously emphasized the new 2013 guidelines. During the postintervention period, we continued to provide follow-up using the parameters previously collected. Our postintervention data include 90 cases from a 27-month period (October 2013-December 2015). Our preintervention data include 331 cases in 33 months (average 10.0 per month) with 76% adherence to guidelines. Postintervention, there were 90 cases in 27 months (average 3.4 per month) and 96% adherence to the 2013 (more conservative) guidelines (P < .0001, chi2 test). Preintervention, the rate of high-grade squamous intraepithelial lesion in loop electrosurgical excision procedures was 44%, whereas postintervention, there was a 60% high-grade squamous intraepithelial lesion rate on loop electrosurgical excision procedure (P < .0087 by 2-tailed Fisher exact test). The duration between diagnosis of low-grade squamous intraepithelial lesion and loop electrosurgical excision procedure also increased significantly from a median 25.5 months preintervention to 54 months postintervention (P < .0073; Wilcoxon Kruskal-Wallis test). Postintervention, there was a marked decrease of loop electrosurgical excision procedure cases as well as better patient outcomes. We infer improved patient safety, and higher value can be achieved by providing performance-based pathologic data. PMID- 28725783 TI - Flexner 2.0-Longitudinal Study of Student Participation in a Campus-Wide General Pathology Course for Graduate Students at The University of Arizona. AB - Faculty members from the Department of Pathology at The University of Arizona College of Medicine-Tucson have offered a 4-credit course on enhanced general pathology for graduate students since 1996. The course is titled, "Mechanisms of Human Disease." Between 1997 and 2016, 270 graduate students completed Mechanisms of Human Disease. The students came from 21 programs of study. Analysis of Variance, using course grade as the dependent and degree, program, gender, and year (1997-2016) as independent variables, indicated that there was no significant difference in final grade (F = 0.112; P = .8856) as a function of degree (doctorate: mean = 89.60, standard deviation = 5.75; master's: mean = 89.34, standard deviation = 6.00; certificate program: mean = 88.64, standard deviation = 8.25), specific type of degree program (F = 2.066, P = .1316; life sciences: mean = 89.95, standard deviation = 6.40; pharmaceutical sciences: mean = 90.71, standard deviation = 4.57; physical sciences: mean = 87.79, standard deviation = 5.17), or as a function of gender (F = 2.96, P = .0865; males: mean = 88.09, standard deviation = 8.36; females: mean = 89.58, standard deviation = 5.82). Students in the physical and life sciences performed equally well. Mechanisms of Human Disease is a popular course that provides students enrolled in a variety of graduate programs with a medical school-based course on mechanisms of diseases. The addition of 2 new medically oriented Master of Science degree programs has nearly tripled enrollment. This graduate level course also potentially expands the interdisciplinary diversity of participants in our interprofessional education and collaborative practice exercises. PMID- 28725784 TI - Medical School Anatomy and Pathology Workshops for High School Students Enhance Learning and Provide Inspiration for Careers in Medicine. AB - "Anatomy and Pathology Workshop" is a cadaver-based outreach program that models medical education to large groups of high school students. This study was designed to evaluate the impact of this program on students' knowledge of anatomy and interest in biomedical science. A total of 144 high school students participated in the workshop in 2015. Preworkshop and postworkshop assessments were administered to assess students' learning. A postworkshop survey was conducted to solicit students' reflections and feedback. It was found that student performance in the postworkshop examination (mean 78%) had significantly improved when compared to the performance in the preexamination (mean 54%), indicating that this program enhances learning. Students were also inspired to consider opportunities in medicine and allied health professions-97% indicated that they had a better understanding of medical education; 95% agreed that they had better understanding of the human body; 84% thought anatomy was interesting and exciting; and 62% of the students indicated that they looked forward to studying medicine or another health profession. Students rated the instructors highly-95% agreed that the instructors were professional and served as role models. Medical/graduate student instructors were also highly regarded by the high school students-96% thought it was valuable to have student instructors and 94% thought that student instructors were caring and enthusiastic about teaching. In summary, this study demonstrates that outreach programs provided by medical schools help young adults during their formative years by modeling professionalism, providing role models, enhancing learning, and encouraging many to consider opportunities in the health professions. PMID- 28725785 TI - Pathology Course Director Perspectives of a Recent LCME Experience: Preparation in an Integrated Curriculum With the Revised Standards. AB - Preparation for a Liaison Committee of Medical Education (LCME) accreditation site visit is a daunting task for any medical school, particularly for medical schools that have adopted integrated curricula. The LCME accreditation is the standard that all US and Canadian allopathic medical schools must meet in order for the school to award the degree of medical doctor. The Uniformed Services University of the Health Sciences (USU) recently underwent a full-scale LCME accreditation visit that was conducted under the newly revised LCME standards and elements. The site visit occurred just 5 years after our school began implementing a totally revised, organ system-based curriculum. Preparing for a critical, high-stakes site visit shortly after transitioning to a totally revised, integrated module-based preclerkship curriculum presented an array of new challenges that required a major modification to the type of preparation, communication, and collaboration that traditionally occurs between course directors and departmental chairs. These included the need to ensure accurate, timely communication of curricular details to different levels of the academic administration, particularly as it related to the execution of self-directed learning (SDL). Preparation for our site visit, did, however, provide a novel opportunity to highlight the unique educational experiences associated with the study of pathology, as pathology traverses both clinical and basic sciences. Sharing these experiences may be useful to other programs that are either undergoing or who are preparing to undergo an accreditation visit and may also aid in a broader communication of the highlights or initiatives of educational activities. PMID- 28725786 TI - Structured Annual Faculty Review Program Accelerates Professional Development and Promotion: Long-Term Experience of the Duke University Medical Center's Pathology Department. AB - This retrospective observational study on faculty development analyzes the Duke University Pathology Department's 18-year experience with a structured mentoring program involving 51 junior faculty members. The majority had MD degrees only (55%). The percentage of young women faculty hires before 1998 was 25%, increasing to 72% after 2005. Diversity also broadened from 9% with varied heritages before 1998 to 37% since then. The mentoring process pivoted on an annual review process. The reviews generally helped candidates focus much earlier, identified impediments they individually felt, and provided new avenues to gain a national reputation for academic excellence. National committee membership effectively helped gain national exposure. Thirty-eight percent of the mentees served on College of American Pathologists (CAP) committees, exponential multiples of any other national society. Some used CAP resources to develop major programs, some becoming nationally and internationally recognized for their academic activities. Several faculty gained national recognition as thought leaders for publishing about work initiated to serve administrative needs in the Department. The review process identified the need for more protected time for research, issues with time constraints, and avoiding exploitation when collaborating with other departments. This review identified a rigorous faculty mentoring and review process that included annual career counseling, goal oriented academic careers, monitored advancement to promotion, higher salaries, and national recognition. All contributed to high faculty satisfaction and low faculty turnover. We conclude that a rigorous annual faculty review program and its natural sequence, promotion, can greatly foster faculty satisfaction. PMID- 28725787 TI - NDER: A Novel Web Application for Teaching Histology to Medical Students. AB - Medical students require a strong foundation in normal histology. However, current trends in medical school curricula have diminished time devoted to histology. Thus, there is a need for more efficient methods of teaching histology. We have developed a novel software program (Novel Diagnostic Educational Resource; https://pcs webtest0.pathology.washington.edu/academics/pattern/) that uses annotated whole slide images to teach normal histology. Whole slide images of a wide variety of tissues were annotated by a trainee and validated by an experienced pathologist. Still images were extracted and transferred to the Novel Diagnostic Educational Resource web application. In Novel Diagnostic Educational Resource, an image was displayed briefly and the user was forced to identify the tissue type. The display time changed inversely based on cumulative accuracy to challenge the user and maintain engagement. A total of 129 second-year medical students completed the 30-minute Novel Diagnostic Educational Resource module. Surveys showed an increase in confidence from premodule (0% extremely confident, 4% very, 47% somewhat, and 49% not) to postmodule (9% extremely confident, 57% very, 32% somewhat, and 2% not), P < .0001. Accuracy increased from 72.6% pretest to 95.7% posttest, P < .002. The effect size (Cohen d = 2.30) was very large, where 0.2 is a small effect, 0.5 moderate, and 0.8 large. Ninety-six percent of students would recommend Novel Diagnostic Educational Resource to other medical students, and 98% would use Novel Diagnostic Educational Resource to further enhance their histology knowledge. Novel Diagnostic Educational Resource drastically improved medical student accuracy in classifying normal histology and improved confidence. Additional study is needed to determine knowledge retention, but Novel Diagnostic Educational Resource has great potential for efficient teaching of histology given the curriculum time constraints in medical education. PMID- 28725788 TI - Pathology Residents Comprise Inspection Team for a CAP Self-Inspection. AB - We report our experience at the University of Florida in which residents and fellows served as the inspection team for a College of American Pathologists (CAP) self-inspection. We aimed to determine whether the CAP self-inspection could serve as a learning opportunity for pathology residents and fellows. To prepare for the inspection, we provided a series of 4 lunchtime seminars covering numerous laboratory management topics relating to inspections and laboratory quality. Preparation for the inspection began approximately 4 months prior to the date of the inspection. The intent was to simulate a CAP peer inspection, with the exception that the date was announced. The associate residency program director served as the team leader. All residents and fellows completed inspector training provided by CAP, and the team leader completed the team leader training. A 20 question pre- and posttest was administered; additionally, an anonymous survey was given after the inspection. The residents' and fellows' posttest scores were an average of 15% higher than on the pretest (P < .01). The surveys as well as subjective comments were overwhelmingly positive. In conclusion, the resident's and fellow's experience as an inspector during a CAP self-inspection was a useful tool to learn accreditation and laboratory management. PMID- 28725789 TI - Improving American Healthcare Through "Clinical Lab 2.0": A Project Santa Fe Report. AB - Project Santa Fe was established both to provide thought leadership and to help develop the evidence base for the valuation of clinical laboratory services in the next era of American healthcare. The participants in Project Santa Fe represent major regional health systems that can operationalize laboratory-driven innovations and test their valuation in diverse regional marketplaces in the United States. We provide recommendations from the inaugural March 2016 meeting of Project Santa Fe. Specifically, in the transition from volume-based to value based health care, clinical laboratories are called upon to provide programmatic leadership in reducing total cost of care through optimization of time-to diagnosis and time-to-effective therapeutics, optimization of care coordination, and programmatic support of wellness care, screening, and monitoring. This call to action is more than working with industry stakeholders on the basis of our expertise; it is providing leadership in creating the programs that accomplish these objectives. In so doing, clinical laboratories can be effectors in identifying patients at risk for escalation in care, closing gaps in care, and optimizing outcomes of health care innovation. We also hope that, through such activities, the evidence base will be created for the new value propositions of integrated laboratory networks. In the very simplest sense, this effort to create "Clinical Lab 2.0" will establish the impact of laboratory diagnostics on the full 100% spend in American healthcare, not just the 2.5% spend attributed to in vitro diagnostics. In so doing, our aim is to empower regional and local laboratories to thrive under new models of payment in the next era of American health care delivery. PMID- 28725790 TI - Biobanking-Budgets and the Role of Pathology Biobanks in Precision Medicine. AB - Biobanks have become an important component of the routine practice of pathology. At the 2016 meeting of the Association of Pathology Chairs, a series of presentations covered several important aspects of biobanking. An often overlooked aspect of biobanking is the fiscal considerations. A biobank budget must address the costs of consenting, procuring, processing, and preserving high quality biospecimens. Multiple revenue streams will frequently be necessary to create a sustainable biobank; partnering with other key stakeholders has been shown to be successful at academic institutions which may serve as a model. Biobanking needs to be a deeply science-driven and innovating process so that specimens help transform patient-centered clinical and basic research (ie, fulfill the promise of precision medicine). Pathology's role must be at the center of the biobanking process. This ensures that optimal research samples are collected while guaranteeing that clinical diagnostics are never impaired. Biobanks will continue to grow as important components in the mission of pathology, especially in the era of precision medicine. PMID- 28725793 TI - From the Editor. PMID- 28725791 TI - Quality Improvement Intervention for Reduction of Redundant Testing. AB - Laboratory data are critical to analyzing and improving clinical quality. In the setting of residual use of creatine kinase M and B isoenzyme testing for myocardial infarction, we assessed disease outcomes of discordant creatine kinase M and B isoenzyme +/troponin I (-) test pairs in order to address anticipated clinician concerns about potential loss of case-finding sensitivity following proposed discontinuation of routine creatine kinase and creatine kinase M and B isoenzyme testing. Time-sequenced interventions were introduced. The main outcome was the percentage of cardiac marker studies performed within guidelines. Nonguideline orders dominated at baseline. Creatine kinase M and B isoenzyme testing in 7496 order sets failed to detect additional myocardial infarctions but was associated with 42 potentially preventable admissions/quarter. Interruptive computerized soft stops improved guideline compliance from 32.3% to 58% (P < .001) in services not receiving peer leader intervention and to >80% (P < .001) with peer leadership that featured dashboard feedback about test order performance. This successful experience was recapitulated in interrupted time series within 2 additional services within facility 1 and then in 2 external hospitals (including a critical access facility). Improvements have been sustained postintervention. Laboratory cost savings at the academic facility were estimated to be >=US$635 000 per year. National collaborative data indicated that facility 1 improved its order patterns from fourth to first quartile compared to peer norms and imply that nonguideline orders persist elsewhere. This example illustrates how pathologists can provide leadership in assisting clinicians in changing laboratory ordering practices. We found that clinicians respond to local laboratory data about their own test performance and that evidence suggesting harm is more compelling to clinicians than evidence of cost savings. Our experience indicates that interventions done at an academic facility can be readily instituted by private practitioners at external facilities. The intervention data also supplement existing literature that electronic order interruptions are more successful when combined with modalities that rely on peer education combined with dashboard feedback about laboratory order performance. The findings may have implications for the role of the pathology laboratory in the ongoing pivot from quantity-based to value-based health care. PMID- 28725792 TI - Entrustable Professional Activities for Pathology: Recommendations From the College of American Pathologists Graduate Medical Education Committee. AB - Competency-based medical education has evolved over the past decades to include the Accreditation Council for Graduate Medical Education Accreditation System of resident evaluation based on the Milestones project. Entrustable professional activities represent another means to determine learner proficiency and evaluate educational outcomes in the workplace and training environment. The objective of this project was to develop entrustable professional activities for pathology graduate medical education encompassing primary anatomic and clinical pathology residency training. The Graduate Medical Education Committee of the College of American Pathologists met over the course of 2 years to identify and define entrustable professional activities for pathology graduate medical education. Nineteen entrustable professional activities were developed, including 7 for anatomic pathology, 4 for clinical pathology, and 8 that apply to both disciplines with 5 of these concerning laboratory management. The content defined for each entrustable professional activity includes the entrustable professional activity title, a description of the knowledge and skills required for competent performance, mapping to relevant Accreditation Council for Graduate Medical Education Milestone subcompetencies, and general assessment methods. Many critical activities that define the practice of pathology fit well within the entrustable professional activity model. The entrustable professional activities outlined by the Graduate Medical Education Committee are meant to provide an initial framework for the development of entrustable professional activity related assessment and curricular tools for pathology residency training. PMID- 28725794 TI - Family Nonpresence during Stabilization in the ER: The Front and the Back. PMID- 28725795 TI - The REDE Model of Healthcare Communication: Optimizing Relationship as a Therapeutic Agent. AB - The REDE model is a conceptual framework for teaching relationship-centered healthcare communication. Based on the premise that genuine relationships are a vital therapeutic agent, use of the framework has the potential to positively influence both patient and provider. The REDE model applies effective communication skills to optimize personal connections in three primary phases of Relationship: Establishment, Development and Engagement (REDE). This paper describes the REDE model and its application to a typical provider-patient interaction. PMID- 28725797 TI - Analytical Insights from Patient Narratives: The Next Step for Better Patient Experience. PMID- 28725798 TI - Finding the Heart of [Hospital]ity: Patient Satisfaction and the Healthcare Experience. PMID- 28725796 TI - Enhancing the Empathic Connection: Using Action Methods to Understand Conflicts in End-of-Life Care. AB - Empathy is a core feature of patient-centered care. It enables practitioners to better understand the patient and family concerns that are key to patient and family satisfaction, prevention of anxiety and depression, and provider empowerment. Current methods of teaching communication skills do not specifically focus on enhancing the ability to "stand in the patient's shoes" as a way of connecting with the patient and/or family experience and understanding feelings that may be a source of conflict with providers. In this paper, we present a model for deepening empathic understanding based upon action methods (role reversal and doubling) derived from psychodrama and sociodrama. We describe these techniques and illustrate how they can be used to identify hidden emotions and attitudes and reveal that which the patient and family member may be thinking or feeling but be afraid to say. Finally, we present data showing that these methods were valuable to participants in enhancing their professional experience and skills. PMID- 28725799 TI - Caring Behaviors: Perceptions of Acute Care Nurses and Hospitalized Patients with Diabetes. AB - CARING BEHAVIORS: Perceptions of acute care nurses and hospitalized patients with diabetes. PURPOSE: The purpose of this study was to examine the perceptions of caring behaviors that influence the patient experience in acute care nurses and hospitalized patients with diabetes. BACKGROUND: Nurses are the caregivers who render most of the direct care patients receive while they are hospitalized. Understanding what patients perceive as caring behaviors is essential in tailoring nursing interventions to meet patient needs. DATA SOURCES: Data collection occurred at a 1,200 bed, nonprofit academic medical center located in the Midwest. DESCRIPTION: Sixty-four nurses and 54 patients with diabetes were queried about their experience with diabetes caring behaviors. CONCLUSION: Nurses consistently reported providing caring behaviors more frequently than patients reported receiving them. IMPLICATIONS: This study has implications for understanding the patient experience in the hospital setting specifically related to patient education. Providing patient education is an important caring intervention that directly affects the patient experience. However, none of the patients in this study identified this as a caring behavior used by nurses. PMID- 28725800 TI - Medicafka. PMID- 28725801 TI - From the Editor. PMID- 28725802 TI - Not Telling and Not Knowing: Comfort at the End of Life? PMID- 28725804 TI - HCAHPS Survey Results: Impact of Severity of Illness on Hospitals' Performance on HCAHPS Survey Results. AB - BACKGROUND: The Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) survey is used by the Centers of Medicare and Medicaid (CMS) to assess inpatient satisfaction. HCAHPS survey results are publicly reported, and performance began to affect CMS reimbursement to hospitals as of FY2013. However, the impact of severity of illness on patients' self-reported inpatient satisfaction as measured by HCAHPS survey scores remains unknown. OBJECTIVE: To determine the impact of severity of illness on patients' self-reported inpatient satisfaction. DESIGN: The All Patient-Refined, Diagnosis Related Group (APR-DRG) classifies every patient into one of four levels of severity of illness. We evaluated the impact of APR-DRG severity of illness on five HCAHPS domains, two reputation and two environmental questions, using linear regression analysis. SETTING: Adult inpatients discharged from a large, academic, tertiary care hospital. PATIENTS: 37,223 patients' HCAHPS survey data were combined with their APR-DRG severity of illness rating over a 39-month period between April 2008 and June 2011. MEASUREMENTS: HCAHPS scores. RESULTS: Higher severity of illness was consistently and inversely associated with lower patients' self-reported perception of inpatient hospital satisfaction as measured by HCAHPS scores. For each one-unit increase in severity of illness, the average HCHAPS scores across all five domains were approximately 3 percent lower. CONCLUSIONS: Hospitals treating patients with a higher severity of illness will have lower HCAHPS scores, potentially leading these hospitals to receive lower reimbursement from CMS. Conversely, hospitals with lower severity of illness will receive greater reimbursement. Failure to adequately adjust for severity of illness is a serious flaw in the current HCAHPS reporting system that should be corrected. PMID- 28725803 TI - Seven Guiding Commitments: Making the U.S. Healthcare System More Compassionate. AB - Despite the current focus on patient centeredness, healthcare professionals face numerous challenges that impede their ability to provide compassionate care that ameliorates concerns, distress, or suffering. These include fragmentation and discontinuity of care, technologies that both help and hinder communication and relationship-building, burgeoning operational and administrative requirements, inadequate communication skills training, alarming rates of burnout, and increased cost and market pressures. A compassionate healthcare system begins with compassionate people, but the organizations in which they train and work must reliably enable them to express and act on their compassion rather than impede it. We present a set of guiding commitments and recommendations to foster a more compassionate healthcare system. We urge healthcare organizations to adopt these commitments and take action to embed compassionate care in all aspects of training, research, patient care and organizational life. PMID- 28725806 TI - Workshops that Work: Physician Involvement in Service Training. AB - Physician involvement in service training initiatives can have a significant impact on the patient experience. This paper highlights some of the key components of what makes physician involvement in training engagements successful and includes anecdotes and data to support the findings. Our service training program emerged from a desire to help clinic sections improve the patient experience. Our workshops contained customized materials that addressed service priority areas, as identified by patient satisfaction survey results, for individual clinic sections and included opportunities to practice the concepts introduced in each session. However, we were missing one key ingredient in the recipe for a successful training program - physician involvement. This paper focuses on a best practice in which two physicians took an active role in creating, customizing and delivering service training for their clinic section and made a tremendous impact on their overall patient satisfaction scores and section morale. PMID- 28725805 TI - Help-Seeking Experiences of Youth with Suicidal Ideations. AB - Approximately 28 percent of Canadians begin to experience a mental health issue during their youth. In this article, we explore patients' perceptions of their mental healthcare experiences within a sample of youth who reported anxiety or depressive symptoms and past suicidal ideations. The study data is taken from in depth interviews with 23 youth in British Columbia. Interview topics included support systems, help-seeking behavior and healthcare experiences. Our findings indicate that participant experiences were most positive when experiences were neither dismissive nor stigmatizing. Important factors for participants were respect, acknowledgement, information and choice. Our results generated the concept that treatment perceptions for youth with suicidal behaviours can be placed on a theoretical spectrum, which may be a useful tool for self reflection for those who support individuals with mental health conditions professionally or personally. PMID- 28725807 TI - Small Blessings: World-Class Care for the World's Tiniest of Babies. PMID- 28725808 TI - From the Editor. PMID- 28725809 TI - Financial versus Non-Financial Incentives for Improving Patient Experience. AB - Delivering compassionate and coordinated care is a goal for all health care providers. Humans are not always consistent, though, both individually and collectively, and this is why everyone needs incentives to be at their best and to try to always be improving. The endlessly interesting question in patient experience is, what should those incentives look like? Should they be financial or nonfinancial? Dr. Thomas H. Lee explores what is most effective in regard to engaging and motivating physicians. While different approaches will work in different organizational cultures, financial incentives have their role in performance improvement. Compassionate coordinated care should be a social norm and be pursued by all health care organizations. PMID- 28725810 TI - Who is Taking Care of the Caregiver? AB - In neurology practices, the patient's caregiver is often overlooked, but it is essential to understand the importance of the caregiver in the management of a chronic neurological condition. Caring for a loved one with a chronic condition can often be profoundly fulfilling, as many times individuals move closer together when challenges arise; however it can also become overwhelming, physically and emotionally challenging, and isolating. At times, it can be thought of as a burden. Caregivers must learn to take care of themselves physically and emotionally. The multidisciplinary care model used in the treatment of chronic medical conditions is important not only for the patient or care recipient, but also for the caregiver. This care model allows for several practitioners to interact with the caregiver to assess and determine the optional interventions. The purpose of this article is to review common caregiver challenges and to determine how, as providers, we can address and help caregivers more effectively care for themselves while maintaining their responsibility to the patient or care recipient. PMID- 28725811 TI - Do I Buy It? How AIDETTM Training Changes Residents' Values about Patient Care. AB - OBJECTIVES: Acquiring communication and interpersonal skills is an important part of providing patient-centered care and improving patient satisfaction. This study explores whether residents' own values about patient communication can be influenced by training. METHODS: As part of service excellence, a three-hour communication skills training in AIDETTM (Acknowledge, Introduce, Duration, Explanation, Thank You) was delivered to first and second Post-Graduate Year (PGY) residents (n = 123). A survey was designed to measure the value of patient communication and administered pre/post communication skills training. RESULTS: Residents' scores about communication values improved significantly for all areas pre- to post-training for patient communication skills (p<0.04). After training, there was little difference by medical specialty, other than surgical specialties, which showed the greatest increase in valuing requesting permission (p=0.034). Gender was also not associated with differences in values, except men showed a greater increase in valuing sitting down (p=0.021) and introductions (p=0.005) than women who already valued these specific behaviors prior to training. CONCLUSIONS: Residents value communication, and AIDETTM training is a useful tool to increase the values of good communication and interpersonal skills to enhance service excellence. PMID- 28725812 TI - Puppy Love, Adolescence, and Chronic Illness: The Importance of Pets for Youth with Type 1 Diabetes. AB - The benefits of animal-companion ties to well-being are consistently documented, yet few studies use patient-centered methodologies to examine how youth living with chronic illnesses rely on domestic pets for support. Youth with type 1 diabetes (T1D) aged 12 to 19 years (N=40) completed surveys involving a prompt to take five photos of "what diabetes means to you," with an accompanying narrative. Content analysis was conducted for photos/narratives and numeric variables analyzed including socio-economic status (SES: measured by total household income and years of parental education) and HbA1C. More than half of the youth participants took pictures of coping mechanisms, including pictures of their pets. In fact, pictures of pets outnumbered pictures of people three to one. Pet depictions were captured by youth from all SES levels. Youth with T1D identify pets as an important source of support. More research is needed to understand how pets may offset disease burden for youth with T1D. PMID- 28725813 TI - Patient-Centered Care Transition for Patients Admitted through the ED: Improving Patient and Employee Experience. AB - With increasing wait times in emergency departments (ED) across America, there is a need to streamline the inpatient admission process in order to decrease wait times and more important, to increase patient and employee satisfaction. One inpatient unit at New York-Presbyterian Weill Cornell Medical Center initiated a program to help expedite the inpatient admission process from the ED. The goal of the ED Bridge program is to ease the patient's transition from the ED to an inpatient unit by visiting the patient in the ED and introducing and setting expectations for the inpatient environment (i.e. telemetry alarms, roommates, hourly comfort rounds). Along with improving the patient experience, this program intends to improve the collaboration between ED nurses and inpatient nurses. With the continued support of our nurse management, hospital administrators and most important, our staff, this concept is aimed to increase patient satisfaction scores and subsequently employee satisfaction. PMID- 28725814 TI - Empathic Failures from the Patient Perspective: Validation in the Acute Setting. PMID- 28725815 TI - From the Editor. PMID- 28725816 TI - I've Had Cancer for 45 Years. PMID- 28725817 TI - Integration of Behavioral Health and Medical Services: Using Patient Experience as a Guide. AB - OBJECTIVES: This study aimed to assess patient satisfaction with behavioral health consultation in a primary and specialty care setting and to gauge patient interest in other behavioral health services. METHODS: We surveyed patients with type 2 diabetes mellitus (N = 65), following a brief behavioral health consultation about their satisfaction with the experience and their interest in various behavioral health services. Doctoral students with master's degrees in clinical psychology provided the consultations. RESULTS: Patients were highly satisfied with behavioral health consultations and expressed moderate to high interest in various potential behavioral health services. Patients with more diabetes-related concerns were less satisfied with brief behavioral health consultations but reported greater interest in other behavioral health services. CONCLUSIONS: Results were used to build stakeholder support and guide expansion of integrated behavioral health services. Examining patient experience can help identify patients who need more extensive services and ensure that services are patient centered. PMID- 28725818 TI - Implementing Patient Family-Centered Care Grand Rounds Using Patient/Family Advisor Narratives. AB - With the emerging trend of patient family-centered care in health care, it is essential that physicians be exposed to patient and family perspectives of care during medical education and training. Grand Rounds provides an ideal format for physicians to learn about patient family-centered care. At Brigham and Women's Hospital, we sought to bring the voice of the patient to Patient Family-Centered Grand Rounds in order to expose clinicians to rich narratives describing the medical care received by patients/families and to ultimately change physician practice to reflect patient family-centered principles. We conducted a clinician survey and found promising results indicating that patient/family narratives can be effective at educating physicians about patient family-centered care. PMID- 28725819 TI - Proportional Distribution of Patient Satisfaction Scores by Clinical Service: The PRIME Model. AB - The Proportional Responsibility for Integrated Metrics by Encounter (PRIME) model is a novel means of allocating patient experience scores based on the proportion of each physician's involvement in care. Secondary analysis was performed on Hospital Consumer Assessment of Healthcare Providers and Systems surveys from a tertiary care academic institution. The PRIME model was used to calculate specialty-level scores based on encounters during a hospitalization. Standard and PRIME scores for services with the most inpatient encounters were calculated. Hospital medicine had the most discharges and encounters. The standard model generated a score of 74.6, while the PRIME model yielded a score of 74.9. The standard model could not generate a score for anesthesiology due to the lack of returned surveys, but the PRIME model yielded a score of 84.2. The PRIME model provides a more equitable method for distributing satisfaction scores and can generate scores for specialties that the standard model cannot. PMID- 28725820 TI - Results From a Patient Experience Study in Pediatric Gastrointestinal Endoscopy. AB - OBJECTIVE: Gastrointestinal endoscopy in children has become a standard diagnostic and therapeutic modality. The aim of our study was to characterize the most memorable elements of the patient experience from the parent's and patient's perspective and determine ways to improve the overall quality of their experience. METHODS: Using a structured questionnaire, we conducted 47 phone interviews with families who had recently undergone gastrointestinal endoscopic procedures. RESULTS: Our study showed clear communication and mutual agreement on care decisions contributed to positive experiences. Inadequate communication of information regarding alternatives to the procedure and risk of complications during the informed consent discussion contributed to negative patient experiences. Standardization of postprocedure follow-up and timely communication of pathology findings also had potential for improvement. CONCLUSION: Our study revealed 2 areas for quality improvement interventions: The need to ensure that alternatives and complications are thoroughly discussed and the need for standardization of postprocedure follow-up. PMID- 28725821 TI - Correlation of Inpatient Experience Survey Items and Domains With Overall Hospital Rating. AB - OBJECTIVE: To determine which individual patient experience questions and domains were most correlated with overall inpatient hospital experience. METHODS: Within 42 days of discharge, 27 639 patients completed a telephone survey based upon the Hospital-Consumer Assessment of Healthcare Systems and Processes instrument. Patients rated their overall experience on a scale of 0 (worst care) to 10 (best care). Correlation coefficients were calculated to assess the relationships between individual survey questions and domains with overall experience. RESULTS: Questions on provider coordination and nursing care were most correlated with overall experience. Hospital cleanliness, quietness, and discharge information questions showed poor correlation. Correlation with overall experience was strongest for the "communication with nurses" domain. CONCLUSIONS: Our individual question results are novel, while the domain-based findings replicate those of US based providers, results which had not yet been reported in the Canadian context one with universal health care coverage. Our results suggest that our large health care organization may attain initial inpatient experience improvements by focusing upon personnel-based initiatives, rather than physical attributes of our hospitals. PMID- 28725822 TI - Could Values and Social Structures in Singapore Facilitate Attainment of Patient Focused, Cultural, and Linguistic Competency Standards in a Patient-Centered Medical Home Pilot? AB - Primary care practices in the United States are transforming into patient centered medical homes (PCMHs) at a rapid pace. Newer PCMH standards have emphasized culturally and linguistically appropriate services (CLAS), but at this time, only some states in the United States have proposed or passed cultural competency training for health care professionals. Other countries are moving to PCMH models. Singapore, a small, ethnically diverse island nation, has national values and social structures that emphasize cultural and linguistic cohesion. In this piece, we examine Singapore's first PCMH pilot with a national academic center and primary care practice group. Features such as common shared values, self-reliance, racial and religious harmony, patient experience surveillance, and incorporation of CLAS standards in routine health care transactions may predict success for the PCMH in Singapore, with some implications for the United States. PMID- 28725823 TI - From the Editor. PMID- 28725824 TI - How I Combined Perseverance and Knowledge to Acquire My Cure for Hepatitis C and Beyond: A Patient Perspective. PMID- 28725825 TI - Association Between Medicare Summary Star Ratings for Patient Experience and Clinical Outcomes in US Hospitals. AB - OBJECTIVE: In 2015, the Centers for Medicare and Medicaid Services (CMS) released new summary star ratings for US hospitals based on patient experience. We aimed to test the association between CMS patient experience star ratings and clinical outcomes. METHODS: We analyzed risk-adjusted data for more than 3000 US hospitals from CMS Hospital Compare using linear regression. RESULTS: We found that better patient experience was associated with favorable clinical outcomes. Specifically, a higher number of stars for patient experience had a statistically significant association with lower rates of many in-hospital complications. A higher patient experience star rating also had a statistically significant association with lower rates of unplanned readmissions to the hospital within 30 days. CONCLUSION: Better patient experience according to the CMS star ratings is associated with favorable clinical outcomes. These results support the inclusion of patient experience data in the framework of how hospitals are paid for services. PMID- 28725827 TI - Evaluations of Neurologists by Their Patients and Residents Are Inversely Correlated. AB - OBJECTIVE AND BACKGROUND: We hypothesized that evaluation scores for attending neurologists by patients and residents would parallel one another. Additionally, we hypothesized that provider productivity would be also be associated with performance evaluations by patients and residents. METHODS: In a university neurology department, we collected individual Clinician and Group Consumer Assessment of Healthcare Providers and Systems patient satisfaction scores and standardized resident evaluation scores (n = 22 faculty members). We performed bivariate analysis of doctor-patient satisfaction versus resident evaluation scores. RESULTS: Attending neurologists with higher patient satisfaction received lower resident evaluation scores (P < .05). There seem to be disproportionate neurologists with low evaluations not meeting clinical productivity targets. CONCLUSION: Finding a significant inverse correlation was surprising. Perhaps what is valued by patients in their physician is not what residents value in teachers. That deserves further study. Maybe attending physicians who spend their energy on the patient experience do not have sufficient time to devote to teaching and vice versa. That neurologists with low evaluation scores appear more likely to not meet productivity targets supports this idea. PMID- 28725826 TI - Physician and Parent Perspectives on Psychosocial and Emotional Data Entry in the Electronic Medical Record in a Pediatric Setting. AB - OBJECTIVE: This pilot study was conducted to evaluate physician and patient preferences for documentation of emotional and psychosocial information in the electronic medical record (EMR). METHODS: Pediatricians from an academic medical center and parents of patients in an academic pediatric rheumatology practice were surveyed on 10 different elements using Likert-type scale items (1 = not at all important, 10 = extremely important). The importance of the proposed categories was evaluated by means testing and pairwise comparisons of the responses. RESULTS: Responses were obtained from 45 physicians and 35 parents. The overall mean scores for physicians and parents were 7.70 and 7.44, respectively. Scores on personality, friends, and school differed between physicians and parents, but those differences were not significant after adjustment for multiple comparisons (P = .13, .17, and .26, respectively). Fears, special requests, and special needs were in the high-score group for both physicians and parents. CONCLUSION: Physicians and parents reported that the incorporation of emotional and psychosocial information into the EMR added value to the health care of children. PMID- 28725828 TI - Transitions of Care Model Inclusive of Unplanned Care Improves the Patient Experience. AB - A major emphasis in health care is creating an experience whereby patients receive the right care at the right time from the right provider in the right setting at the right cost. Over the past several decades, there has been considerable effort in the area of medical management, with prior authorization, gatekeeper utilization management regimens, and other techniques designed to guide patients and caregivers into desired treatment pathways. Alternatively, the concept of demand management may be employed to achieve these desired outcomes by giving patients meaningful, expanded choices beyond traditional acute-care settings. The implementation of a novel, patient-centered, unplanned care delivery model is described along with illustrative case studies. PMID- 28725830 TI - Quiet Lessons. PMID- 28725829 TI - Student Perspectives With a High-Utilizing Patient. PMID- 28725831 TI - From the Editor. PMID- 28725832 TI - Dear ICU Nurse: The Letter I Wanted to Send. PMID- 28725833 TI - The "Face" of Diabetes: Insight Into Youths' Experiences as Expressed Through Drawing. AB - OBJECTIVE: The purpose of this descriptive pilot study was to assess the ability of youth to create a meaningful drawing related to living with type 1 diabetes and explore the benefits of expressing emotion through drawing in future interventional work. METHODS: Youth aged 4 to 19 years (N = 242) with type I diabetes attending routine follow-up appointments within a pediatric specialty clinic were asked to draw: "If diabetes had a face what would it look like?" RESULTS: Drawings reflected many emotions and ranged from simple to complex in detail. Drawings reflected multiple experiences of living with diabetes including emotions, tools used for management, and effects of self-care. CONCLUSIONS: Youth were able to create drawings reflecting their experience of living with diabetes. Youth conveyed a variety of emotions, attitudes, and experiences in drawing the "face" of diabetes. Drawing during clinic visits provides opportunity to explore the unspoken experiences of living with a chronic health condition, which may not be obtained during routine clinical information gathering. Deeper understanding of patient's lived experience may assist providers in therapeutic management. PMID- 28725834 TI - The Influence of Wait Time on Patient Satisfaction in the Orthopedic Clinic. AB - INTRODUCTION: Patient satisfaction is of increasing importance in the delivery of quality healthcare and may influence provider reimbursement. The purpose of this study is to examine how patient wait time relates to their level of satisfaction and likelihood to recommend an orthopedic clinic to others. METHODS: A retrospective analysis was performed on standardized new patient survey data collected at a single orthopedic clinic from June 2011 through October 2014. RESULTS: A total of 3125 and 3151 responses were collected for satisfaction and likelihood to recommend the practice. The mean wait time was 27.3 +/- 11.3 minutes. The likelihood of obtaining an "excellent" (odds ratio [OR]: 0.86, P = .01081) or "excellent/very good" (OR: 0.82, P = .0199) satisfaction demonstrated significant correlation with wait time in 15-minute intervals. The likelihood of obtaining an "agree" (OR: 0.9, P = .10575) and "strongly agree/agree" (OR: 0.85, P = .139) response to recommend the practice demonstrated no correlation during the same interval. CONCLUSION: Minimizing wait times in the orthopedic clinic may improve patient satisfaction but may not affect their likelihood of recommending the practice to others. PMID- 28725835 TI - Relationship Between Physicians' Active Participation in Maintenance of Certification and Patients' Perspective of Care Surveys. AB - OBJECTIVE: Medical specialty boards have a Maintenance of Certification (MOC) paradigm whose intention is to ensure high-quality patient care. How the patient experience is affected by physician MOC enrollment/participation is unknown. Our goal was to determine if patient experience is associated with physician board certification and MOC status. METHODS: We analyzed physician experience and MOC databases to determine the relationships among physicians' patient experience national percentile rankings and board certification status and MOC enrollment and activity status. RESULTS: Board-certified physicians enrolled in MOC did not have statistically significant different patient experience scores compared to board-certified physicians not enrolled in MOC. Mid-career physicians enrolled in MOC had patients more likely to recommend them and reported higher confidence in them. Patients did not perceive physicians participating in MOC patient safety modules as more cautious in providing patient care. CONCLUSION: Although most analyses did not demonstrate significant differences in patient experience scores for physicians actively participating in MOC compared to those not, some differences were noted. Higher provider-specific patient experience scores were noted, particularly for mid-career physicians. PMID- 28725837 TI - I'll Be Back. PMID- 28725836 TI - Supporting Client and Family Engagement in Care Through the Planning and Implementation of an Online Consumer Health Portal. AB - Web-based portals and electronic health records are making it easier for clients and families to access health information. This improved transparency and access to information has the potential to promote activation and improve outcomes, but to realize these benefits, the information needs to be valuable, meaningful, and understandable. Engagement of the end users in the planning and implementation will ensure that the product meets the needs of the consumers. The purpose of this case study is to describe the client and family engagement strategies that were employed to support the process of planning and implementing an online consumer health portal at a pediatric rehabilitation hospital to support the successful launch of this new information-sharing technology platform. PMID- 28725838 TI - From the Editor. PMID- 28725839 TI - Nursing Strategies for Engaging Families of Older Immigrants Hospitalized for End of-Life Care: An Australian Study. AB - BACKGROUND: Engaging with families of older non-English-speaking background (NESB) immigrants hospitalized for end-of-life (EOL) care can be challenging, especially when their cultures, lifeways, and family decision-making processes are unfamiliar to the nurses caring for them. Despite the recognized importance of family engagement when providing EOL care, the issue of ethnic minority family engagement has received little attention in the field. AIM: To explore and describe the strategies nurses use to facilitate engagement with families of older immigrant NESB patients hospitalized for EOL care. METHODS: A qualitative descriptive approach was used. Data were collected via in-depth interviews conducted with 22 registered nurses recruited from 4 Australian health services. FINDINGS: Using thematic analysis processes, 5 key strategies were identified: listening and understanding families, encouraging family members to speak first, dealing with angst, redressing naive views about the dying process, and managing intergenerational differences. Underpinning these strategies was a profound "will to engage" with the families and their cultural worldviews. CONCLUSION: Further cross-cultural comparative research is required to inform evidence-based policies, practice, and education on this issue. PMID- 28725840 TI - The Impact of Revised Discharge Instructions on Patient Satisfaction. AB - INTRODUCTION: The impact of discharge instructions on a patient's experience is not fully understood. This research explored whether nurse- and physician generated discharge instructions had a positive effect on patient perceptions regarding their discharge experience. METHODS: We compared Press Ganey discharge related patient satisfaction scores for the year prior to and the year subsequent to implementing revised discharge instructions for all patients admitted to a 180 bed community-based hospital. RESULTS: Following the implementation of our revised discharge instructions, patient satisfaction significantly improved (84.7% vs 83%, P < .01). Patients responded that they felt ready for discharge (86.6% vs 84.9%, P = .01) and were satisfied with instructions for home care (87.8% vs 85.3%, P < .01). DISCUSSION: This study finds that a novel discharge instruction set produced by both the nursing and physician staff may improve patient perceptions with the discharge process. PMID- 28725841 TI - Findings and Predictors of Patient-Reported Experience of Primary Health Care in Nigeria. AB - OBJECTIVE: The study reports findings and patients' characteristics that predict their experiences of primary health care (PHC) in Nigeria. METHODS: A cross sectional survey of 1680 patients attending 24 primary health centers in 6 states from the 6 geopolitical subdivisions in Nigeria. The patient evaluation scale was used for exit survey of patients' experiences with PHC. Categorical findings and mean ratings on experiences of PHC were analyzed using both descriptive and inferential statistics. RESULTS: The mean response rate was 98%, and most respondents were female (73%) and married (72%). A higher proportion of patients gave positive feedback on their relationships with staff (84%) than they did available space in the waiting area (60%). Higher self-rated health status and nonpayment for care at the point of receipt were consistent predictors of positive patient experiences from the multilevel analysis. CONCLUSION: Study reported findings and drivers of patient experiences with PHC. Aspects of PHC showing less positive patient experiences and some patients' factors associated with these are amenable to change and can form the focus of quality improvement actions. PMID- 28725842 TI - Understanding Patients' Process to Use Medical Marijuana: A Southern New Jersey Community Engagement Project. AB - Given the necessity to better understand the process patients need to go through in order to seek treatment via medical marijuana, this study investigates this process to better understand this phenomenon. Specifically, Compassion Care Foundation (CCF) and Stockton University worked together to identify a solution to this problem. Specifically, 240 new patients at CCF were asked to complete a 1 page survey regarding various aspects associated with their experience prior to their use of medicinal marijuana-diagnosis, what prompted them to seek treatment, level of satisfaction with specific stages in the process, total length of time the process took, and patient's level of pain. Results reveal numerous patient diagnoses for which medical marijuana is being prescribed; the top 4 most common are intractable skeletal spasticity, chronic and severe pain, multiple sclerosis, and inflammatory bowel disease. Next, results indicate a little over half of the patients were first prompted to seek alternative treatment from their physicians, while the remaining patients indicated that other sources such as written information along with friends, relatives, media, and the Internet persuaded them to seek treatment. These data indicate that a variety of sources play a role in prompting patients to seek alternative treatment and is a critical first step in this process. Additional results posit that once patients began the process of qualifying to receive medical marijuana as treatment, the process seemed more positive even though it takes patients on average almost 6 months to obtain their first treatment after they started the process. Finally, results indicate that patients are reporting a moderately high level of pain prior to treatment. Implication of these results highlights several important elements in the patients' initial steps toward seeking medical marijuana, along with the quality and quantity of the process patients must engage in prior to obtaining treatment. In addition, identifying patients' level of pain and better understanding the possible therapeutic value of medical marijuana are essential to patients and health practitioners. PMID- 28725843 TI - Identifying and Understanding the Health Information Experiences and Preferences of Individuals With TBI, SCI, and Burn Injuries. AB - INTRODUCTION: Traumatic brain injury, spinal cord injury, and burn injury can cause lifelong disability and changes in quality of life. In order to meet the challenges of postinjury life, various types of health information are needed. We sought to identify preferred sources of health information and services for persons with these injuries and discover how accessibility could be improved. METHODS: Thirty-three persons with injury participated in semistructured interviews. Responses to interview questions were coded using NVivo. RESULTS: Participants' difficulties accessing health information varied by injury type and individually. The majority of respondents found information via the Internet and advocated its use when asked to describe their ideal health information system. Nearly all participants supported the development of a comprehensive care website. When searching for health information, participants sought doctor and support group networks, long-term health outcomes, and treatments specific to their injury. CONCLUSION: To optimize the quality of health information resources, Internet-based health-care platforms should add or highlight access points to connect patients to medical professionals and support networks while aggregating specialized, injury-specific research and treatment information. PMID- 28725844 TI - Teaching About Better Family-Clinician Partnerships in High-Risk Pediatric Asthma Care. AB - Family-clinician partnership including communication, trust, respect, and power leveling is essential in pediatrics. Our case study illustrates elements supporting/hindering partnership in a high-risk urban pediatric asthma clinic. Data from observation of a 100-minute visit were qualitatively analyzed by applying codes to themes, using family-centered principles. Three key categories emerged from examining interactions and their sequencing: (1) partnership supported, (2) partnership missed, and (3) partnership hindered. Practitioners must become more sensitive to families' lives and skilled in family-centered care delivery. Clinician education about partnership can help with negotiating workable treatment strategies for complex conditions such as asthma and reduce health disparities. PMID- 28725845 TI - From the Editor. PMID- 28725846 TI - Living With "Man's Fate" Away From Home. AB - Edward Nilges is a former software consultant who came from Chicago to Hong Kong in 2005, and has since worked as a teacher. Having been residing in Hong Kong for all these years, Edward fell ill with cancer and its complications. He choose to receive medical treatment in Hong Kong, where both the dominant culture and medical system were foreign to him. Here, he gives an account of his physical, psychological, social and existential experience, in quest of meaning away from home, while his physician discusses the clinician's perspective. PMID- 28725847 TI - The Process and Impact of Stakeholder Engagement in Developing a Pediatric Intensive Care Unit Communication and Decision-Making Intervention. AB - Stakeholder-developed interventions are needed to support pediatric intensive care unit (PICU) communication and decision-making. Few publications delineate methods and outcomes of stakeholder engagement in research. We describe the process and impact of stakeholder engagement on developing a PICU communication and decision-making support intervention. We also describe the resultant intervention. Stakeholders included parents of PICU patients, healthcare team members (HTMs), and research experts. Through a year-long iterative process, we involved 96 stakeholders in 25 meetings and 26 focus groups or interviews. Stakeholders adapted an adult navigator model by identifying core intervention elements and then determining how to operationalize those core elements in pediatrics. The stakeholder input led to PICU-specific refinements, such as supporting transitions after PICU discharge and including ancillary tools. The resultant intervention includes navigator involvement with parents and HTMs and navigator-guided use of ancillary tools. Subsequent research will test the feasibility and efficacy of our intervention. PMID- 28725848 TI - Exploring Inpatients' Experiences of Healing and Healing Spaces: A Mixed Methods Study. AB - In order to understand a patient's healing experience it is essential to understand the elements that they, the patient, believes contributed to their healing. Previous research has focused on symptom reducers or contributors through environment such as stress. A person's experience of healing happens over time not instantaneous. Therefore, in this study, the interviews with patients happened after forty-eight hours of hospitalization. This mixed methods study describes the experiences of seventeen inpatients from two healthcare systems using a phenomenological approach combined with evidence based design evaluation methods to document the setting. The qualitative data was analyzed first for reoccurring themes then further explored and defined through quantitative environmental observations. The seventeen patients defined healing as "getting better/well." Seventy three statements were recorded about contributors and detractors to healing in the physical environment. Three primary themes emerged from the data as positive influencers of a healing experience: being cared for, being comfortable and experiencing something familiar or like home. These results demonstrate that patients perceive their inpatient healing experience through a supported environment. PMID- 28725849 TI - The Role of Oncofertility Clinics in Facilitating Access to Reproductive Specialists. AB - PURPOSE: To determine the impact of the establishment of a dedicated oncofertility clinic on the frequency of patient referrals for fertility preservation (FP) consultation and the time from patient referral to consultation. METHODS: A retrospective chart review of all women aged 21 to 44 years with an active cancer diagnosis who were referred for FP consultation from 2011 to 2015. RESULTS: A total of 6895 female patients eligible for FP were seen at the Massachusetts General Hospital (MGH) Cancer Center. Of those eligible, a total of 209 patients were referred for FP consultation with 150 included in the final analysis. Since the establishment of the oncofertility clinic, the mean time to nonemergent consultation with a reproductive endocrinologist decreased by 27%, from 10.4 to 7.6 days (P = .03). Furthermore, the proportion of reproductive aged females seen at the MGH Cancer Center referred for FP consultation increased from 1.7% to 3.0% (P < .01). CONCLUSION: A dedicated oncofertility clinic increases physician referrals for FP and decreases the mean time to consultation, improving access to FP consultation for reproductive-aged women with cancer. PMID- 28725850 TI - How Can Home Care Patients and Their Caregivers Better Manage Fall Risks by Leveraging Information Technology? AB - OBJECTIVES: From the perspectives of home care patients and caregivers, this study aimed to (a) identify the challenges for better fall-risk management during home care episodes and (b) explore the opportunities for them to leverage health information technology (IT) solutions to improve fall-risk management during home care episodes. METHODS: Twelve in-depth semistructured interviews with the patients and caregivers were conducted within a descriptive single case study design in 1 home health agency (HHA) in the mid-Atlantic region of the United States. RESULTS: Patients and caregivers faced challenges to manage fall risks such as unmanaged expectations, deteriorating cognitive abilities, and poor care coordination between the HHA and physician practices. Opportunities to leverage health IT solutions included patient portals, telehealth, and medication reminder apps on smartphones. CONCLUSION: Effectively leveraging health IT could further empower patients and caregivers to reduce fall risks by acquiring the necessary information and following clinical advice and recommendations. The HHAs could improve the quality of care by adopting IT solutions that show more promise of improving the experiences of patients and caregivers in fall-risk management. PMID- 28725851 TI - Different Combining Process Between Male and Female Patients to Reach Their Overall Satisfaction. AB - Patient satisfaction and how it is measured is an important field of study in healthcare. Consequently, there have been many patient satisfaction studies. However, there is a lack of studies that focused on how male and female patients perceive, or weigh, their overall satisfaction. Determining the weights of these attributes by gender is an important outcome to determine overall patient satisfaction and quality of care. Data were collected by applying the Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) survey instrument to record regular patient experience at 70 United States hospitals. The data were collected between July 1, 2011 and June 30, 2012, and there are 43,938 cases in the data set. This study found that all five of the attributes (Nursing Care, Physician Care, Staff Care, Room, and Help) had an association with patient satisfaction. Among them, nursing Care had the largest influence on patient satisfaction of all of the five attributes. This study also showed a statistically significant interaction effect by gender for the interaction between Nursing care x Gender, Physician care x Gender, and Help x Gender. Female patients rated their relationship with their nurses as being more important to their overall satisfaction, while male patients rated their relationship with their doctor as being more important to overall satisfaction. Male patients also rated their relationship with help as being more important to overall satisfaction when compared with the results from female patients. Suggestions to healthcare managers are also discussed. PMID- 28725853 TI - From the Editor. PMID- 28725852 TI - Developing An Analytic Approach to Understanding the Patient Care Experience. AB - The amount of data available to health-care institutions regarding the patient care experience has grown tremendously. Purposeful approaches to condensing, interpreting, and disseminating these data are becoming necessary to further understand how clinical and operational constructs relate to patient satisfaction with their care, identify areas for improvement, and accurately measure the impact of initiatives designed to improve the patient experience. We set out to develop an analytic reporting tool deeply rooted in the patient voice that would compile patient experience data obtained throughout the medical center. PMID- 28725854 TI - Improving the Patient Experience by Implementing an ICU Diary for Those at Risk of Post-intensive Care Syndrome. AB - The critical care literature in the US has recently brought attention to the impact an ICU experience can have long after the patient survives critical illness, particularly if delirium was present. Current recommendations to mitigate post-intensive care syndrome (PICS) are embedded in patient and family centered care and aim to promote family presence in the ICU, provide support for decision-making, and enhance communication with the health-care team. Evidence based interventions are few in number but include use of an ICU diary to minimize the psychological and emotional sequelae affecting patients and family members in the months following the ICU stay. In this paper we describe our efforts to implement an ICU diary and solicit feedback on its role in fostering teamwork and communication between patients, family members, and ICU staff. Next steps will involve a PICS follow-up clinic where trained staff will coordinate specialty referrals and perform long-term monitoring of mental health and other quality of life outcomes. PMID- 28725855 TI - Introduction of a Surgical Navigator in the Perioperative Process Improves Patient Satisfaction. AB - BACKGROUND: Patients who had received surgical services at Bellin Hospital reported anxiety with the surgical flow. This study tested the hypothesis that the introduction of a surgical navigator, someone who guided the patient and their accompanying others throughout the surgical process, would improve patient satisfaction. METHODS: Ambulatory surgical patients were randomized to control and study groups. The study group patients were assigned a surgical navigator. Prior to discharge from the hospital, patients were asked to complete a patient satisfaction survey. RESULTS: The study group had significantly higher mean scores (P value <= 0.026), top box scores (P value <= 0.021), and positive comments. CONCLUSION: The addition of a surgical navigator to the perioperative process significantly enhanced patient satisfaction in ambulatory surgical patients. PMID- 28725856 TI - Association Between Medicare Star Ratings for Patient Experience and Medicare Spending per Beneficiary for US Hospitals. AB - OBJECTIVE: To test the association between patient experience and Centers for Medicare and Medicaid Services (CMS) spending at the hospital level. METHODS: Using CMS Hospital Compare data set, we analyzed 2014 data for CMS patient experience star ratings and the hospital Medicare Spending per Beneficiary (MSPB) Measure, which assesses price-standardized, risk-adjusted payments for services provided to Medicare beneficiaries for an episode of care from 3 days before hospital admission to 30 days following discharge. We tested the association using linear regression, adjusting for complexity of care using hospital Case Mix Index (CMI) and for socioeconomic status of the hospital patient population using Disproportionate Share Hospital (DSH) status. RESULTS: The MSPB decreased with increasing hospital patient experience ratings. After adjustment for CMI and DSH, better hospital patient experience was associated with lower spending per episode (5.6% decrease from the lowest to highest patient experience star rating). CONCLUSION: We found that better hospital patient experience was associated with lower health-care spending. Further research is needed to define what specific elements and phases of the episode of care are driving the association. PMID- 28725857 TI - Bedside Interprofessional Rounding: The View From the Patient's Side of the Bed. AB - BACKGROUND: Bedside interprofessional rounding is gaining ground as a means to improve collaboration and patient outcomes, yet little is known regarding patients' perceptions of the practice. METHODS: This descriptive study used individual patient interviews to elicit views on interprofessional rounding from 35 patients at a large, urban hospital. RESULTS: The findings identified three major categories: 1) about the rounding process; 2) clinical information; and 3) the impact/value of bedside inter-professional rounding. DISCUSSION: Intentionally eliciting and responding to our patients' views of interprofessional rounding may help us design methods that are patient centered and effective. PMID- 28725858 TI - CAHPS and Comments: How Closed-Ended Survey Questions and Narrative Accounts Interact in the Assessment of Patient Experience. AB - OBJECTIVES: To investigate whether content from patient narratives explains variation in patients' primary care provider (PCP) ratings beyond information from the closed-ended questions of the Consumer Assessment of Healthcare Providers and Systems (CAHPS) Clinician and Group Survey and whether the relative placement of closed- and open-ended survey questions affects either the content of narratives or the CAHPS composite scores. METHODS: Members of a standing Internet panel (N = 332) were randomly assigned to complete a CAHPS survey that was either preceded or followed by a set of open-ended questions about how well their PCP meets their expectations and how they relate to their PCP. RESULTS: Narrative content from healthier patients explained only an additional 2% beyond the variation in provider ratings explained by CAHPS composite measures. Among sicker patients, narrative content explained an additional 10% of the variation. The relative placement of closed- and open-ended questions had little impact on narratives or CAHPS scores. CONCLUSION: Incorporating a protocol for eliciting narratives into a patient experience survey results in minimal distortion of patient feedback. Narratives from sicker patients help explain variation in provider ratings. PMID- 28725859 TI - Is Telehealth Right for Your Practice and Your Patients With Asthma? AB - INTRODUCTION: Telehealth services are becoming increasingly used to provide care to patients living in rural areas. Little is known about the patient satisfaction with the provision of these services. METHODS: A prospective cohort pilot study was developed to evaluate the use of telehealth for the delivery of asthma education services in the rural, medically underserved community of Oakes, North Dakota. A certified asthma educator used real-time, audio-visual telehealth technology to meet with patients the local community pharmacy. Patients met with the educator monthly for the first three months of the study, and once every three months thereafter. Patient satisfaction was measured using a five item survey. RESULTS: Eighteen patients completed the study (90 percent completion rate). Patient satisfaction scores were relatively high, typically between 4 and 5 on a 5-point scale. CONCLUSIONS: Participants in a rural, medically underserved community found the community pharmacy location and the telehealth technology a convenient means to access a specialty provider for asthma education. PMID- 28725860 TI - The Many Faces of Empathy: Biological, Psychological, and Interactional Perspectives. PMID- 28725861 TI - Pursuing Humanistic Medicine in a Technological Age. AB - The humanistic practice of medicine requires that the practitioner have sufficient time and appropriate focus. Both elements, however, are under assault by the high-speed, distraction-filled environment within which primary care is delivered today. Despite or perhaps because of modern medicine's technological advances, the potentially healing bond between doctor and patient is being frayed and the quality of care consequently degraded. PMID- 28725862 TI - What's in A Word? My Journey Toward Empathy Education and Practice at the Cleveland Clinic. PMID- 28725863 TI - Empathy in the Clinician-Patient Relationship: The Role of Reciprocal Adjustments and Processes of Synchrony. AB - The clinician-patient relationship is asymmetric in the sense that clinicians and patients have different roles in the medical consultation. Yet, there are qualities of reciprocity and mutuality in many clinician-patient encounters, and we suggest that such reciprocity may be related to the phenomenon of empathy. Empathy is often defined as the capacity to place oneself in another's position, but empathy may also be understood as a sequence of reciprocal turns-of talk, starting with the patient's expression of emotion, followed by the perception, vicarious experience, and empathic response by the clinician. These patterns of reciprocity may also include the patient's experience of and response to the clinician's emotions. Researchers in different fields of research have studied how informal human interaction often is characterized by mutuality of lexical alignment and reciprocal adjustments, vocal synchrony, as well as synchrony of movements and psychophysiological processes. A number of studies have linked these measures of reciprocity and synchrony in clinical encounters to the subjective experience of empathy. PMID- 28725864 TI - Dying From Cancer: Communication, Empathy, and the Clinical Imagination. AB - Medical oncologists and patients with advanced cancer struggle to discuss prognosis, goals, options, and values in a timely fashion. As a consequence, many patients die receiving aggressive treatment potentially inconsistent with their fully informed preferences and experience increased symptom burden and distress. The goals of patient - oncologist communication include exchanging information, building relationship, and engaging in shared decisions. Empathy is perhaps especially essential to effective patient - oncologist communication when the end of life is approaching. We speculate that, in addition to being a skilled response to a patient's negative emotions, empathy is an emergent property of the relationship that allows the patient and oncologist to imagine what it will be like to navigate the transition from living with to dying from cancer; and to prepare for the transition. We propose that effective empathy: 1) requires an attentive, curious and imaginative physician; 2) acknowledges the complex and shifting goals as the end of life approaches; and 3) begins with a willingness of physicians to check in and find out what she may have misunderstood or misperceived. Empathy in end of life conversations cultivates the shared experiences necessary to co-create the new goals of care that underlie excellent end of life care. PMID- 28725865 TI - The Science of Empathy. AB - Empathy plays a critical interpersonal and societal role, enabling sharing of experiences, needs, and desires between individuals and providing an emotional bridge that promotes pro-social behavior. This capacity requires an exquisite interplay of neural networks and enables us to perceive the emotions of others, resonate with them emotionally and cognitively, to take in the perspective of others, and to distinguish between our own and others' emotions. Studies show empathy declines during medical training. Without targeted interventions, uncompassionate care and treatment devoid of empathy, results in patients who are dissatisfied. They are then much less likely to follow through with treatment recommendations, resulting in poorer health outcomes and damaged trust in health providers. Cognitive empathy must play a role when a lack of emotional empathy exists because of racial, ethnic, religious, or physical differences. Healthcare settings are no exception to conscious and unconscious biases, and there is no place for discrimination or unequal care afforded to patients who differ from the majority culture or the majority culture of healthcare providers. Much work lies ahead to make healthcare equitable for givers and receivers of healthcare from all cultures. Self- and other-empathy leads to replenishment and renewal of a vital human capacity. If we are to move in the direction of a more empathic society and a more compassionate world, it is clear that working to enhance our native capacities to empathize is critical to strengthening individual, community, national, and international bonds. PMID- 28725866 TI - Patient Perceptions of Clinician's Empathy: Measurement and Psychometrics. AB - The prominence of reciprocal understanding in patient-doctor empathic engagement implies that patient perception of clinician's empathy has an important role in the assessment of the patient-clinician relationship. In response to a need for an assessment tool to measure patient's views of clinician empathy, we developed a brief (5-item) instrument, the Jefferson Scale of Patient Perceptions of Physician Empathy (JSPPPE). This review article reports evidence in support of the validity and reliability of the JSPPPE. PMID- 28725868 TI - Physico-mechanical, thermal and morphological properties of furfuryl alcohol/2 ethylhexyl methacrylate/halloysite nanoclay wood polymer nanocomposites (WPNCs). AB - In this study, the physical, morphological, mechanical and thermal properties of furfuryl alcohol/2-ethylhexyl methacrylate/halloysite nanoclay wood polymer nanocomposites (FA-co-EHMA-HNC WPNCs) were investigated. FA-co-EHMA-HNC WPNCs were prepared via an impregnation method and the properties of the nanocomposites were characterized through the weight percent gain, Fourier transform infrared (FT-IR) spectroscopy, scanning electron microscopy (SEM), three-point flexural test, dynamic mechanical thermal analysis (DMTA), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) analysis and moisture absorption test. The weight percent gain in the 50:50 FA-co-EHMA-HNC WPNC was the highest compared with the raw wood (RW) and other WPNCs. The FT-IR results confirmed that polymerization took place in the nanocomposites, especially 50:50 FA-co-EHMA-HNC WPNC, which had a reduced amount of hydroxyl groups. The SEM results revealed that the 50:50 FA-co-EHMA-HNC WPNC had the smoothest and most uniform surface among all of the nanocomposites. The 50:50 FA-co-EHMA-HNC WPNC showed the highest flexural strength and modulus of elasticity. The results revealed that the storage modulus and loss modulus of the FA-co-EHMA-HNC WPNCs were higher and the tan delta of FA-co-EHMA-HNC WNPCs was lower compared with the RW. The FA-co-EHMA HNC WPNCs exhibited the higher thermal stability in the TGA and DSC analysis. The 50:50 FA-co-EHMA-HNC WPNC exhibited remarkably lower moisture absorption compared with the RW. Overall, this study proved that the ratio 50:50 FA-co-EHMA ratio was the most suitable for introduction in the in the RW. PMID- 28725867 TI - Revisiting the psychometric properties of the Scoliosis Research Society-22 (SRS 22) French version. AB - BACKGROUND: Adolescent idiopathic scoliosis (AIS) is among the most common spinal deformities affecting adolescents. The Scoliosis Research Society-22 questionnaire is commonly used to assess health-related quality of life in AIS patients, including pain. The objective of this study is to verify the psychometric properties of the Scoliosis Research Society-22 French version (SRS 22fv) questionnaire. METHODS: A prospective methodological design was used to verify the psychometric properties of the French version of the SRS-22fv. Participants were initially recruited from the orthopaedic scoliosis department at Sainte-Justine Hospital (Montreal, Canada) and completed the SRS-22fv and the SF-12 questionnaire. The SRS-22fv's structure was evaluated through principal component analysis (PCA). Linear regression was used to assess convergent validity between the SRS-22fv and the SF-12. RESULTS: Data was available from 352 participants with AIS. Most participants were female (87%, n = 307), and the average age was 14.3 (SD = 1.8) years. The mean thoracic and lumbar Cobb angles were 27.9 degrees (SD = 3.3) and 23.6 degrees (SD = 9.4), respectively. Overall, 71.4% (n = 252) of the participants presented with spinal pain. About one-third (29%) reported thoracic pain, and almost half (44%) experienced lumbar pain. The PCA identified four redundant items, which resulted in a modified 18 item questionnaire. In comparison to the original questionnaire, the modified version showed higher levels of internal consistency for four of the five factors, explained a greater proportion of the total variance (63.3%), and generated higher inter-item total correlations. CONCLUSION: We propose a shorter version of the SRS-22fv, thus the Canadian SRS-18fv, which showed an improved internal consistency and scale structure compared to the original SRS-22fv. We believe that this modified version would be better suited to assess the quality of life of adolescents with idiopathic scoliosis. PMID- 28725869 TI - Automated approach to detecting behavioral states using EEG-DABS. AB - Electrocorticographic (ECoG) signals represent cortical electrical dipoles generated by synchronous local field potentials that result from simultaneous firing of neurons at distinct frequencies (brain waves). Since different brain waves correlate to different behavioral states, ECoG signals presents a novel strategy to detect complex behaviors. We developed a program, EEG Detection Analysis for Behavioral States (EEG-DABS) that advances Fast Fourier Transforms through ECoG signals time series, separating it into (user defined) frequency bands and normalizes them to reduce variability. EEG-DABS determines events if segments of an experimental ECoG record have significantly different power bands than a selected control pattern of EEG. Events are identified at every epoch and frequency band and then are displayed as output graphs by the program. Certain patterns of events correspond to specific behaviors. Once a predetermined pattern was selected for a behavioral state, EEG-DABS correctly identified the desired behavioral event. The selection of frequency band combinations for detection of the behavior affects accuracy of the method. All instances of certain behaviors, such as freezing, were correctly identified from the event patterns generated with EEG-DABS. Detecting behaviors is typically achieved by visually discerning unique animal phenotypes, a process that is time consuming, unreliable, and subjective. EEG-DABS removes variability by using defined parameters of EEG/ECoG for a desired behavior over chronic recordings. EEG-DABS presents a simple and automated approach to quantify different behavioral states from ECoG signals. PMID- 28725870 TI - Human factors in cybersecurity; examining the link between Internet addiction, impulsivity, attitudes towards cybersecurity, and risky cybersecurity behaviours. AB - The present study explored the relationship between risky cybersecurity behaviours, attitudes towards cybersecurity in a business environment, Internet addiction, and impulsivity. 538 participants in part-time or full-time employment in the UK completed an online questionnaire, with responses from 515 being used in the data analysis. The survey included an attitude towards cybercrime and cybersecurity in business scale, a measure of impulsivity, Internet addiction and a 'risky' cybersecurity behaviours scale. The results demonstrated that Internet addiction was a significant predictor for risky cybersecurity behaviours. A positive attitude towards cybersecurity in business was negatively related to risky cybersecurity behaviours. Finally, the measure of impulsivity revealed that both attentional and motor impulsivity were both significant positive predictors of risky cybersecurity behaviours, with non-planning being a significant negative predictor. The results present a further step in understanding the individual differences that may govern good cybersecurity practices, highlighting the need to focus directly on more effective training and awareness mechanisms. PMID- 28725871 TI - New anthrarobin acyl derivatives as butyrylcholinesterase inhibitors: synthesis, in vitro and in silico studies. AB - To treat Alzheimer's disease (AD), the available candidates are effective only against mild AD or have side effects. So, a study was planned to synthesis new candidates that may have good potential to treat AD. A series of new anthrarobin acyl derivatives (2-8) were synthesized by the reaction of anthrarobin (1) and acetic anhydride/acyl chlorides. The product were characterized by 1H NMR and EI MS, and evaluated for butyrylcholinesterase (BuChE) inhibition activity. Compounds 5 and 4 showed notable BuChE inhibitory potential with IC50 5.3 +/- 1.23 and 17.2 +/- 0.47 MUM, respectively when compared with the standard eserine (IC50 7.8 +/- 0.27 MUM), compound 5 showed potent BuChE inhibition potential than the standard eserine. The active compounds 5 and 4 have acyl groups at 2-OH and 10-OH positions which may be responsible for inhibitory potential as this orientation is absent in other products. In silico studies of 5 and 4 products revealed the high inhibitory potential due to stable binding of ligand with the BuChE active sites with docking energy score -18.8779 kcal/mol and -23.1159 kcal/mol, respectively. Subsequently, compound 5 that have potent BuChE inhibitory activity could be the potential candidate for drug development for Alzheimer's disease. PMID- 28725872 TI - Antioxidant and lipoxygenase activities of polyphenol extracts from oat brans treated with polysaccharide degrading enzymes. AB - This study used polysaccharide degrading enzymes and protein precipitation to extract polyphenols from oats and to determine their bioactivity. Duplicate oat brans were treated with viscozyme (Vis), cellulase (Cel) or no enzyme (control, CTL) then, proteins were removed in one set (Vis1, Cel1, CTL1) and not in the other (Vis2, Cel2, CTL2). HPLC analyses showed that for cellulase treated brans, precipitation of proteins increased phenolic acids and avenanthramides by 14%. Meanwhile, a decreased of 67% and 20% respectively was found for viscozyme and control brans. The effect of protein precipitation on soluble polyphenols is therefore dependent of the carbohydrase, as proteins with different compositions will interact differently with other molecules. Radical scavenging data showed that Cel1 and Vis1 had higher quenching effects on ROO* radicals with activities of 22.1 +/- 0.8 and 23.5 +/- 1.2 MUM Trolox Equivalents/g defatted brans. Meanwhile, CTL2 had the highest HO* radicals inhibition (49.4 +/- 2.8%) compared to 10.8-32.3% for others. Samples that highly inhibited lipoxygenase (LOX), an enzyme involved in lipid oxidation were Cel1 (23.4 +/- 2.3%) and CTL1 (18 +/- 0.4%). PMID- 28725873 TI - Genetic characterization of human immunodeficiency virus type 1 transmission in the Middle East and North Africa. AB - BACKGROUND: The HIV-1 spread in the Middle East and North Africa (MENA) has not been previously characterised using the phylogenetic approach. The aim of the current study was to investigate the genetic diversity and domestic transmission of HIV-1 in the MENA. METHODS: A total of 2036 HIV-1 sequences available in Genbank and collected in the MENA during 1988-2016 were used together with 715 HIV-1 reference sequences that were retrieved from Genbank based on genetic similarity with the MENA sequences. The REGA and COMET tools were used to determine HIV-1 subtypes and circulating recombinant forms. Maximum Likelihood and Bayesian phylogenetic analyses were used to identify and date HIV-1 transmission clusters. RESULTS: At least 21 HIV-1 subtypes and recombinant forms were prevalent in the MENA. Subtype B was the most common variant (39%), followed by CRF35_AD (19%) and CRF02_AG (14%). The most common genetic region was pol, and 675 partial pol sequences (average of 1005 bp) were eligible for detailed phylogenetic analysis. Fifty-four percent of the MENA sequences formed HIV-1 transmission clusters. Whereas numerous clusters were country-specific, some clusters indicated transmission links between countries for subtypes B, C and CRF02_AG. This was more common in North Africa compared with the Middle East (p < 0.001). Recombinant forms had a larger proportion of clustering compared to pure subtypes (p < 0.001). The largest MENA clusters dated back to 1991 (an Algerian CRF06_cpx cluster of 43 sequences) and 2002 (a Tunisian CRF02_AG cluster of 48 sequences). CONCLUSIONS: We found an extensive HIV-1 diversity in the MENA and a high proportion of sequences in transmission clusters. This study highlights the need for preventive measures in the MENA to limit HIV-1 spread in this region. PMID- 28725874 TI - Metabolites of alectinib in human: their identification and pharmacological activity. AB - Two metabolites (M4 and M1b) in plasma and four metabolites (M4, M6, M1a and M1b) in faeces were detected through the human ADME study following a single oral administration of [14C]alectinib, a small-molecule anaplastic lymphoma kinase inhibitor, to healthy subjects. In the present study, M1a and M1b, which chemical structures had not been identified prior to the human ADME study, were identified as isomers of a carboxylate metabolite oxidatively cleaved at the morpholine ring. In faeces, M4 and M1b were the main metabolites, which shows that the biotransformation to M4 and M1b represents two main metabolic pathways for alectinib. In plasma, M4 was a major metabolite and M1b was a minor metabolite. The contribution to in vivo pharmacological activity of these circulating metabolites was assessed from their in vitro pharmacological activity and plasma protein binding. M4 had a similar cancer cell growth inhibitory activity and plasma protein binding to that of alectinib, suggesting its contribution to the antitumor activity of alectinib, whereas the pharmacological activity of M1b was insignificant. PMID- 28725875 TI - Vape Shop Employees: Public Health Advocates? AB - INTRODUCTION: E-cigarettes have increased in popularity and given rise to a new type of sales outlet-the vape shop. Expanding on work examining vape shop employee e-cigarette and tobacco attitudes and behaviors1, this study examined key messages that vape shop employees communicate to customers. METHODS: Using informal interviews, observations, and a cross-sectional survey, we examined vape shop employees' (n=16) perceptions and e-cigarette use. Data were collected in nine vape shops in Louisville, Kentucky. We used open coding to analyze the qualitative interviews, observation notes, and open-ended survey responses. Descriptive statistics were used to analyze survey data. RESULTS: The findings revealed that nearly all employees were former smokers (93.8%), who now only use e-cigarettes. Over one-third of the employees (37.5%) began using e-cigarettes as a replacement for traditional cigarettes, and 93.8% reported better health (e.g., easier breathing, less coughing) since starting to use e-cigarettes. Although most employees believed e-cigarettes should be regulated, 56.3% thought regulations should be different from those governing traditional cigarettes. Analysis of qualitative data revealed that employees see themselves as health advocates who: 1) provide instructions on vaping and promote a vape community, 2) encourage cessation of traditional cigarettes, and 3) support some regulations. CONCLUSIONS: The findings reveal that vape shop employees regard e-cigarettes as viable smoking cessation tools and relish their role in assisting others in taking what employees view as positive health actions. Future research addressing communication between vape shop employees and customers, especially related to smoking cessation and health, is needed. PMID- 28725876 TI - Clean, cheap, convenient: promotion of Electronic cigarettes on YouTube. AB - INTRODUCTION: Videos promoting electronic cigarettes (e-cigarettes) can be easily accessed on YouTube. Marketing claims present in YouTube videos may help shape the public's opinion of e-cigarettes. Thus, it is important to understand the most frequent marketing claims and video sources. METHODS: The objectives of this study were to 1) identify marketing claims in YouTube videos that are commonly made on e-cigarette retail websites and 2) compare the frequency of marketing claims in user-generated and professional YouTube videos. Through content analysis, this study evaluated six marketing claims and descriptive information about YouTube videos (n = 50) related to "electronic cigarettes" and "vape". RESULTS: Overall, the most frequent marketing claim promoted e-cigarette use as better than traditional tobacco use (52%). Approximately 65% of videos appeared to be user-generated and 35% were professionally-produced. Compared to user generated videos, significantly more professional videos made claims that e cigarettes are cleaner (p < 0.001) and cheaper (p = 0.04) than traditional cigarettes. Additionally, more professional videos had claims promoting e cigarettes as better than traditional cigarettes because of their convenience-the user can smoke anywhere (p < 0.0001) and the products do not produce secondhand smoke (p < 0.001). The most frequent claim in user-generated videos was related to recreation (53%). CONCLUSIONS: Videos on YouTube promote e-cigarettes as safer than other tobacco products. Videos appearing to be user-generated contained different marketing claims compared to professional videos. Further research is necessary to assess how the perceived source of the video impacts the ways these marketing claims shape public perception and influence use. PMID- 28725877 TI - GLISTRboost: Combining Multimodal MRI Segmentation, Registration, and Biophysical Tumor Growth Modeling with Gradient Boosting Machines for Glioma Segmentation. AB - We present an approach for segmenting low- and high-grade gliomas in multimodal magnetic resonance imaging volumes. The proposed approach is based on a hybrid generative-discriminative model. Firstly, a generative approach based on an Expectation-Maximization framework that incorporates a glioma growth model is used to segment the brain scans into tumor, as well as healthy tissue labels. Secondly, a gradient boosting multi-class classification scheme is used to refine tumor labels based on information from multiple patients. Lastly, a probabilistic Bayesian strategy is employed to further refine and finalize the tumor segmentation based on patient-specific intensity statistics from the multiple modalities. We evaluated our approach in 186 cases during the training phase of the BRAin Tumor Segmentation (BRATS) 2015 challenge and report promising results. During the testing phase, the algorithm was additionally evaluated in 53 unseen cases, achieving the best performance among the competing methods. PMID- 28725878 TI - Segmentation of Gliomas in Pre-operative and Post-operative Multimodal Magnetic Resonance Imaging Volumes Based on a Hybrid Generative-Discriminative Framework. AB - We present an approach for segmenting both low- and high-grade gliomas in multimodal magnetic resonance imaging volumes. The proposed framework is an extension of our previous work [6,7], with an additional component for segmenting post-operative scans. The proposed approach is based on a hybrid generative discriminative model. Firstly, a generative model based on a joint segmentation registration framework is used to segment the brain scans into cancerous and healthy tissues. Secondly, a gradient boosting classification scheme is used to refine tumor segmentation based on information from multiple patients. We evaluated our approach in 218 cases during the training phase of the BRAin Tumor Segmentation (BRATS) 2016 challenge and report promising results. During the testing phase, the proposed approach was ranked among the top performing methods, after being additionally evaluated in 191 unseen cases. PMID- 28725879 TI - Using Closure Tables to Enable Cross-Querying of Ontologies in Database-Driven Applications. AB - We demonstrate that closure tables are an effective data structure for developing database-driven applications that query biomedical ontologies and that require cross-querying between multiple ontologies. A closure table stores all available paths within a tree, even those without a direct parent-child relationship; additionally, a node can have multiple ancestors which gives the foundation for supporting linkages between controlled ontologies. We augment the meta-data structure of the ICD9 and ICD10 ontologies included in i2b2, an open source query tool for identifying patient cohorts, to utilize a closure table. We describe our experiences in incorporating existing mappings between ontologies to enable clinical and health researchers to identify patient populations using the ontology that best matches their preference and expertise. PMID- 28725880 TI - Role of Intrinsic Factors in the Growth of Transplanted Organs Following Transplantation. AB - Shortages in the availability of transplantable organs have forced the transplant community to seek alternative methods to increase the supply of available organs. In our recent study following alpha-1,3-galactocyltransferase knockout (GalT-KO) pig-to-baboon kidney xenotransplantation, we found that certain recipients developed increased serum creatinine, possibly due to the rapid growth of orthotopic pig grafts in smaller baboon recipients. To test our hypothesis, we assessed whether the growth of outbred (Yorkshire) organ transplants (kidney and lung) in miniature swine was regulated by intrinsic (graft) factors. Yorkshire kidneys reached 3.7* their initial volume over 3 months vs. 1.2* for miniature swine kidneys over a similar time period. A similar pattern was seen in porcine lung allografts as well. Following xenotransplantation, a review of our results suggests that there is a threshold for kidney graft volume of 25 cm3/kg of recipient body weight at which cortical ischemia is induced in transplanted GalT KO kidneys in baboons. These results suggest that intrinsic factors are in part responsible for the growth of donor organs and this should be taken into consideration for growth-curve-mismatched transplants. PMID- 28725882 TI - Group-Based Active Learning of Classification Models. AB - Learning of classification models from real-world data often requires additional human expert effort to annotate the data. However, this process can be rather costly and finding ways of reducing the human annotation effort is critical for this task. The objective of this paper is to develop and study new ways of providing human feedback for efficient learning of classification models by labeling groups of examples. Briefly, unlike traditional active learning methods that seek feedback on individual examples, we develop a new group-based active learning framework that solicits label information on groups of multiple examples. In order to describe groups in a user-friendly way, conjunctive patterns are used to compactly represent groups. Our empirical study on 12 UCI data sets demonstrates the advantages and superiority of our approach over both classic instance-based active learning work, as well as existing group-based active-learning methods. PMID- 28725881 TI - Gold Nanoparticles for Radiation Enhancement in Vivo. AB - Enhancing the effect of radiation on tumors would be a significant improvement in radiation therapy. With radiation enhancement, less radiation could be used to achieve the same goals, lessening damage to healthy tissue and lessening side effects. Gold nanoparticles are a promising method for achieving this enhancement, particularly when the gold nanoparticles are targeted to cancer. This literature review discusses the properties of gold nanoparticles as well as existing in vivo radiation enhancement results using both targeted and non targeted gold nanoparticles. PMID- 28725883 TI - Efficient Learning of Classification Models from Soft-label Information by Binning and Ranking. AB - Construction of classification models from data in practice often requires additional human effort to annotate (label) observed data instances. However, this annotation effort may often be too costly and only a limited number of data instances may be feasibly labeled. The challenge is to find methods that let us reduce the number of the labeled instances but at the same time preserve the quality of the learned models. In this paper we study the idea of learning classification from soft label information in which each instance is associated with a soft-label further refining its class label. One caveat of applying this idea is that soft-labels based on human assessment are often noisy. To address this problem, we develop and test a new classification model learning algorithm that relies on soft-label binning to limit the effect of soft-label noise. We show this approach is able to learn classification models more rapidly and with a smaller number of labeled instances than (1) existing soft label learning methods, as well as, (2) methods that learn from class-label information. PMID- 28725884 TI - An enzyme-mediated competitive colorimetric sensor based on Au@Ag bimetallic nanoparticles for highly sensitive detection of disease biomarkers. AB - We developed a competitive colorimetric nanosensor based on Au@Ag bimetallic nanoparticles for the detection of interleukin-6 (IL-6) in clinical samples. Antibody-conjugated magnetic nanoparticles (MNPs) and polystyrene (PS) microparticles conjugated with both catalase and a secondary antibody can form sandwich structures that enable one-step target enrichment and separation. The catalase on the surface of the PS can catalyze the hydrolysis of hydrogen peroxide (H2O2) to regulate the deposition of Ag+ on the surface of gold nanoparticles (AuNPs), and forms different sizes and amounts of Au@Ag bimetallic nanoparticles (Au@AgNPs) which produce a distinct color signal for readout with the naked eye. Our sensor features high sensitivity, selectivity, reproducibility and anti-interference property as a result of comprehensive parameter optimization. The limit of detection of IL-6 can reach 11 pg mL-1 with the naked eye and 1.2 pg mL-1 by quantitative instrumental analysis. The whole analysis can be finished within 1 h. More importantly, we successfully apply our platform or the detection of IL-6 in clinical samples with better accuracy than conventional enzyme-linked immunosorbent assay (ELISA). PMID- 28725885 TI - An axis-specific rotational rainbow in the direct scatter of formaldehyde from Au(111) and its influence on trapping probability. AB - The conversion of translational to rotational motion often plays a major role in the trapping of small molecules at surfaces, a crucial first step for a wide variety chemical processes that occur at gas-surface interfaces. However, to date most quantum-state resolved surface scattering experiments have been performed on diatomic molecules, and little detailed information is available about how the structure of nonlinear polyatomic molecules influences the mechanisms for energy exchange with surfaces. In the current work, we employ a new rotationally resolved 1 + 1' resonance-enhanced multiphoton ionization (REMPI) scheme to measure the rotational distribution in formaldehyde molecules directly scattered from the Au(111) surface at incidence kinetic energies in the range 0.3-1.2 eV. The results indicate a pronounced propensity to excite a-axis rotation (twirling) rather than b- or c-axis rotation (tumbling or cartwheeling), and are consistent with a rotational rainbow scattering model. Classical trajectory calculations suggest that the effect arises-to zeroth order-from the three-dimensional shape of the molecule (steric effects). Analysis suggests that the high degree of rotational excitation has a substantial influence on the trapping probability of formaldehyde at incidence translational energies above 0.5 eV. PMID- 28725886 TI - Dependence of homogeneous crystal nucleation in water droplets on their radii and its implication for modeling the formation of ice particles in cirrus clouds. AB - We propose an approximation for the total ice nucleation rate J = J(T,R) in supercooled water droplets as a function of both droplet radius R and temperature T, taking into account both volume-based and surface-stimulated nucleation modes. Its crucial idea is that even in the surface-stimulated mode crystal nuclei initially emerge (as sub-critical clusters) homogeneously in the sub-surface layer, not "pseudo-heterogeneously" at the surface. This mode is negligible in large droplets, but becomes increasingly important with decreasing droplet size and is dominant in small droplets. The crossover droplet radius for the transition of homogeneous ice nucleation from the volume-based mode to the surface-stimulated mode nonmonotonically depends on T from 233 K to 239.5 K, ranging there from ~2 MUm to ~100 MUm. Using experimental data on ice nucleation rates in small droplets, we determine that the ice-air interfacial tension of basal facets of ice crystals monotonically increases from ~89 dyn cm-1 at T = 234.8 K to ~91 dyn cm-1 at T = 236.2 K. PMID- 28725887 TI - Photoresponsive ionic liquid crystals assembled via halogen bond: en route towards light-controllable ion transporters. AB - We demonstrate that halogen bonding (XB) can offer a novel approach for the construction of photoresponsive ionic liquid crystals. In particular, we assembled two new supramolecular complexes based on 1-ethyl-3-methylimidazolium iodides and azobenzene derivatives containing an iodotetrafluoro-benzene ring as XB donor, where the iodide anion acted as an XB acceptor. DSC and X-ray diffraction analyses revealed that the preferred stoichiometry between the XB donors and acceptors is 2 : 1, and that the iodide anions act as bidentate XB acceptors, binding two azobenzene derivatives. Due to the high directionality of the XB, calamitic superanions are obtained, while the segregation occurring between the charged and uncharged parts of the molecules gives rise to a layered structure in the crystal lattice. Despite the fact that the starting materials are non-mesomorphic, the halogen-bonded supramolecular complexes exhibited monotropic lamellar liquid-crystalline phases over broad temperature ranges, as confirmed with polarized optical microscopy. Due to the presence of the azobenzene moieties, the LCs were photoresponsive, and a LC-to-isotropic phase transition could be obtained by irradiation with UV light. We envisage that the light-induced phase transition, in combination with the ionic nature of the LC, provides a route towards light-induced control over ion transport and conductance in these supramolecular complexes. PMID- 28725889 TI - Cholesterol lowering by Pediococcus acidilactici LAB4 and Lactobacillus plantarum LAB12 in adult zebrafish is associated with improved memory and involves an interplay between npc1l1 and abca1. AB - This study assessed the cholesterol lowering effect of Pediococcus acidilactici LAB4 and Lactobacillus plantarum LAB12 using adult zebrafish. Animals were fed with a high cholesterol diet (HCD) with/without LAB for seven weeks. Serum and liver cholesterol was quantified using colorimetric and dye staining methods. Expressions of npc1l1 and abca1 in the liver and intestine and appa in the brain were quantified using RT-PCR. Serum and liver cholesterol was significantly lowered in LAB4- and LAB12-fed zebrafish (<=64% and <=71%, respectively), with reduced liver cholesterol deposition. The cholesterol lowering effect was accompanied by down-regulation of npc1l1 in intestines (<=28.7%), up-regulation of abca1 in the liver (>=30.5%) and down-regulation of appa in the brain (<=24.5%). A moderately strong positive Pearson correlation (r = 0.617, p < 0.01) was found between appa and serum cholesterol. LAB-fed zebrafish exhibited improved spatial learning and memory. LAB4 and LAB12 can be potentially used in preventing hypercholesterolaemia and Alzheimer's diseases. PMID- 28725890 TI - One-step synthesis of novel Cu@polymer nanocomposites through a self-activated route and their application as nonenzymatic glucose sensors. AB - In this study, we developed a one-step self-activated route for synthesizing novel core-shell Cu@polymer nanocomposites. Under solvothermal conditions, Cu2+ was reduced to metal copper by formaldehyde and salicylaldehyde and the newly generated copper crystals acted as the catalysts to activate the condensation polymerization between formaldehyde and salicylaldehyde, resulting in the formation of core-shell Cu@polymer nanocomposites with Cu nanoparticles as the cores and polymer as the shells. The Cu@polymer nanocomposites can be applied as a nonenzymatic sensor for glucose detection. The as-prepared Cu@polymer nanocomposite modified electrode shows good linear dependence in a wide range from 0.01 mM to 1 mM, a low detection limit, high sensitivity up to 1417.1 MUA cm 2 mM-1 and great selectivity to glucose concentration change. PMID- 28725891 TI - Fecal excretion of Maillard reaction products and the gut microbiota composition of rats fed with bread crust or bread crumb. AB - A comparison between the impacts of advanced (Nepsilon-carboxymethyllysine - CML) and terminal (melanoidins) Maillard reaction products from bread on gut microbiota was carried out in this study. Gut microbiota composition as well as fecal excretion of CML from both bread crust and bread crumb, and of melanoidins from bread crust were assessed on a rodent model. Rats were fed with pellets supplemented or not with 13% of bread crust, bread crumb, a fiber-free bread crust model (glucose, starch and gluten heated together) or a fiber-free melanoidin-free bread model (glucose-starch and gluten heated separately) for four weeks. These model systems were developed to limit the presence of wheat native dietary fibers such as cellulose, hemicelluloses and lignin. CML and melanoidins in pellets and feces were evaluated by LC/MS-MS and HPLC/fluorescence respectively, and gut microbiota composition was determined by cultivation and molecular approaches. Diets supplemented with crumb or the fiber-free-melanoidin free model contained respectively 17% and 64% less melanoidins than their respective controls. A higher excretion of melanoidins was observed for rats fed with crust or bread crust model compared to their controls, confirming that melanoidins are in contact with gut microbiota. No impact of diets was observed on Firmicutes, Bacteroidetes and lactic flora. A decrease of enterobacteria was only observed for rats fed with the diet supplemented with the fiber-free bread crust model. Moreover, a significant increase of bifidobacteria numbers in the presence of crust, crumb and both bread models was observed, showing that this bifidogenic effect of bread is not due to the presence of melanoidins or wheat native dietary fibers. PMID- 28725894 TI - Quantifying spontaneous metastasis in a syngeneic mouse melanoma model using real time PCR. AB - Modeling metastasis in vivo with animals is a priority for both revealing mechanisms of tumor dissemination and developing therapeutic methods. While conventional intravenous injection of tumor cells provides an efficient and consistent system for studying tumor cell extravasation and colonization, studying spontaneous metastasis derived from orthotopic tumor sites has the advantage of modeling more aspects of the metastatic cascade, but is challenging as it is difficult to detect small numbers of metastatic cells. In this work, we developed an approach for quantifying spontaneous metastasis in the syngeneic mouse B16 system using real time PCR. We first transduced B16 cells with lentivirus expressing firefly luciferase Luc2 gene for bioluminescence imaging. Next, we developed a real time quantitative PCR (qPCR) method for the detection of luciferase-expressing, metastatic tumor cells in mouse lungs and other organs. To illustrate the approach, we quantified lung metastasis in both spontaneous and experimental scenarios using B16F0 and B16F10 cells in C57BL/6Ncrl and NOD-Scid Gamma (NSG) mice. We tracked B16 melanoma metastasis with both bioluminescence imaging and qPCR, which were found to be self-consistent. Using this assay, we can quantitatively detect one Luc2 positive tumor cell out of 104 tissue cells, which corresponds to a metastatic burden of 1.8 * 104 metastatic cells per whole mouse lung. More importantly, the qPCR method was at least a factor of 10 more sensitive in detecting metastatic cell dissemination and should be combined with bioluminescence imaging as a high-resolution, end-point method for final metastatic cell quantitation. Given the rapid growth of primary tumors in many mouse models, assays with improved sensitivity can provide better insight into biological mechanisms that underpin tumor metastasis. PMID- 28725895 TI - Co-Doped Zn1-xCdxS nanocrystals from metal-organic framework precursors: porous microstructure and efficient photocatalytic hydrogen evolution. AB - Nanoporous Co-doped Zn1-xCdxS were facilely fabricated via adopting ZIFs as templates, and Cd(NO3)2 and thiourea as precursors. The highly porous microstructure and uniform Co-doping of the photocatalyst afford a high H2 production rate (45.2 and 422.2 times larger than those of Zn0.5Cd0.5S and CdS), providing an effective way for the development of high performance nanoporous photocatalysts. PMID- 28725897 TI - Integration and application of optical chemical sensors in microbioreactors. AB - The quantification of key variables such as oxygen, pH, carbon dioxide, glucose, and temperature provides essential information for biological and biotechnological applications and their development. Microfluidic devices offer an opportunity to accelerate research and development in these areas due to their small scale, and the fine control over the microenvironment, provided that these key variables can be measured. Optical sensors are well-suited for this task. They offer non-invasive and non-destructive monitoring of the mentioned variables, and the establishment of time-course profiles without the need for sampling from the microfluidic devices. They can also be implemented in larger systems, facilitating cross-scale comparison of analytical data. This tutorial review presents an overview of the optical sensors and their technology, with a view to support current and potential new users in microfluidics and biotechnology in the implementation of such sensors. It introduces the benefits and challenges of sensor integration, including, their application for microbioreactors. Sensor formats, integration methods, device bonding options, and monitoring options are explained. Luminescent sensors for oxygen, pH, carbon dioxide, glucose and temperature are showcased. Areas where further development is needed are highlighted with the intent to guide future development efforts towards analytes for which reliable, stable, or easily integrated detection methods are not yet available. PMID- 28725898 TI - The effect of selected food phytochemicals on breast cancer metastasis based on in vivo capture of circulating tumor cells. AB - The number of circulating tumor cells (CTCs) in a mouse tumor model fed with different dietary factors was first evaluated by in vivo CTC capture at different time points of cancer progression. The results showed that the number of CTCs reflected the degree of cancer progression. A new assessment method of dietary factor effects on cancer metastasis was established. PMID- 28725900 TI - Luminescence properties and warm white LED application of a ternary-alkaline fluoride red phosphor K2NaAlF6:Mn4+ . AB - Herein, a Mn4+ ion doped complex ternary-alkaline fluoride red phosphor K2NaAlF6:Mn4+ has been synthesized through a facile two-step co-precipitation method at room temperature. The crystal structure, morphological properties and influence of the dopant concentration, temperature and humidity on luminescence properties as well as the performance of the as-synthesized phosphor used in white light emitting diodes (WLEDs) were investigated carefully. Intense absorption in the blue region (~460 nm) and bright narrow-band red emission (~630 nm) with high color purity were observed from this resultant powder. Temperature dependent investigation and reliability examination in a HTHH environment (85 degrees C high temperature and 85% high humidity) indicate that the obtained ternary-alkaline fluoride phosphor K2NaAlF6:Mn4+ presents more exceptional thermal quenching behavior and longevity compared to some other binary-alkaline fluorides. Moreover, using K2NaAlF6:Mn4+ as a red light component, a warm WLED with a preferable color rendering index (Ra = 85.5) and luminous efficacy (LE = 91.2 lm W-1) as well as a low corresponding color temperature (CCT = 3650 K) is easily achieved, further revealing the great potential of the as-prepared ternary alkaline fluoride red phosphor K2NaAlF6:Mn4+ for WLED applications. PMID- 28725901 TI - Zinc binding sites in Pra1, a zincophore from Candida albicans. AB - The aim of this work is to understand the interactions of Zn(ii) with Pra1, a zincophore from Candida albicans, one of the most common causes of serious fungal infections in humans. Pra1 is a 299 amino acid protein, secreted from the fungus to specifically bind Zn(ii) and deliver it to a transmembrane zinc transporter, Zrt1. We take the first step towards understanding the bioinorganic chemistry of this process, by pointing out the Zn(ii) binding sites in Pra1 and understanding the thermodynamics of such interactions. Our approach involves working on model systems (unstructured parts of proteins) in order to identify those regions in Pra1, to which zinc binds with the highest affinity. Mass spectrometry shows the stoichiometry of Zn(ii)-peptide complex formation and potentiometric studies give us the partial and overall stability constants for all the formed zinc complexes. NMR clarifies binding sites in the case of doubts. A detailed comparison of these results shows that the C-terminal region of Pra1 binds Zn(ii) with the highest affinity, indicating that this region of the zincophore is responsible for the binding of zinc. Such knowledge is an input to the basic bioinorganic chemistry of zinc; it allows us to understand the inorganic biochemistry of zincophores, and it might be a stepping stone towards finding new, fungus specific treatments based on parts of zincophores coupled with antifungal drugs. PMID- 28725902 TI - Impact of grape pomace consumption on the blood lipid profile and liver genes associated with lipid metabolism of young rats. AB - Herein, we investigated the effects of grape pomace (GP) in diet on body weight, blood lipid profile, and expression of liver genes associated with lipid metabolism using a young rat model. In this study, twenty female Sprague-Dawley rats at 7 weeks of age were randomly divided into 4 groups, which were fed modified AIN-93G diets containing 0% (control), 6.9%, 13.8%, and 20.7% of GP for 10 weeks. Feed consumption and body weight were weekly determined. Blood samples were obtained at the beginning and end of the feeding period for cholesterol, alanine aminotransferase (ALT), and glucose analysis. At the end of the feeding period, all rats were fasted overnight and euthanized. Heart, kidney, and liver samples were obtained and weighed. Liver tissues were used for gene expression analysis. GP-containing diet did not influence the body weight of the rats. As GP content increased, blood triglyceride and very low density lipoprotein (VLDL) decreased (P < 0.05), high density lipoprotein (HDL) slightly increased but was not statistically significant, total cholesterol (TC) and low density lipoprotein (LDL) significantly increased (P < 0.05), blood glucose decreased, and ALT level slightly increased. The expressions of liver genes associated with fatty acid synthesis and lipid hydrolysis/metabolism were moderately downregulated by the GP diet. The study suggests that regular consumption of a diet containing appropriate amount of GP may help in the reduction of body fat accumulation and prevention of obesity. This is the first study revealing the change in gene expression caused by long-term consumption of GP-containing diet. PMID- 28725903 TI - Suppressive effects of dietary EPA-rich fish oil on the degradation of elastin fibers in the aortic wall in nicotine-administered mice. AB - Abdominal aortic aneurysm (AAA) is a vascular disease involving gradual dilation of the abdominal aorta. Recent studies suggest that nicotine, which is a primary component in cigarette smoke, is closely associated with the development and rupture of an AAA. Nicotine accelerates AAA development through the weakening of the vascular wall by increasing oxidative stress and matrix metalloproteinase (MMP)-2 expression. However, little is known about preventing the AAA induced by nicotine. A non-surgical means of preventing the weakening of the vascular wall before the onset of AAA by functional food factors would be a valuable option over surgery. Fish oil is a functional food that is rich in n-3 polyunsaturated fatty acids that have an anti-inflammatory effect. In this study, we evaluated the effect of dietary fish oil on the weakening of the aortic wall due to nicotine administration in a mouse model. Histological analysis showed that the dietary fish oil suppressed the degradation of elastin fibers in the nicotine administered mice. Additionally, the dietary fish oil suppressed the protein level of MMP-12, macrophage infiltration, and the oxidative stress in the vascular wall. These results suggest that fish oil could suppress the weakening of the vascular wall by suppressing the elastin fiber degradation caused by nicotine. By suppressing the nicotine induced weakening of the vascular wall, fish oil might help prevent the development of AAA. PMID- 28725904 TI - Cellular antioxidant, methylglyoxal trapping, and anti-inflammatory activities of cocoa tea (Camellia ptilophylla Chang). AB - Cocoa tea (Camellia ptilophylla Chang) is a naturally low caffeine-containing but gallocatechin gallate (GCG)-rich tea cultivar, though its biological activities have not been extensively explored. Herein, we evaluated the in vitro cellular antioxidant, methylglyoxal trapping, and anti-inflammatory activities of water extract of green tea from cocoa tea (CWE) and Yunnan Daye tea (Camellia sinensis) (YWE), and their predominant bioactive components GCG and epigallocatechin gallate (EGCG) for comparative purposes. Primarily, CWE exhibited a higher cellular antioxidant potential than YWE via a cellular antioxidant activity assay, while no significant difference was observed between GCG and EGCG. Moreover, CWE was more potent than YWE in the inhibitory effect on inflammatory responses in lipopolysaccharide-induced RAW 264.7 macrophages, including nitric oxide and interleukin-6 productions. Additionally, CWE showed comparable MGO trapping ability to YWE, although EGCG was more reactive with MGO than with GCG. This study suggested that cocoa tea would be a promising and potential functional beverage as a dietary antioxidant, methylglyoxal trapping, and anti-inflammatory agent. PMID- 28725905 TI - Schizosaccharomyces pombe Grx4 regulates the transcriptional repressor Php4 via [2Fe-2S] cluster binding. AB - The fission yeast Schizosaccharomyces pombe expresses the CCAAT-binding factor Php4 in response to iron deprivation. Php4 forms a transcription complex with Php2, Php3, and Php5 to repress the expression of iron proteins as a means to economize iron usage. Previous in vivo results demonstrate that the function and location of Php4 are regulated in an iron-dependent manner by the cytosolic CGFS type glutaredoxin Grx4. In this study, we aimed to biochemically define these protein-protein and protein-metal interactions. Grx4 was found to bind a [2Fe-2S] cluster with spectroscopic features similar to other CGFS glutaredoxins. Grx4 and Php4 also copurify as a complex with a [2Fe-2S] cluster that is spectroscopically distinct from the cluster on Grx4 alone. In vitro titration experiments suggest that these Fe-S complexes may not be interconvertible in the absence of additional factors. Furthermore, conserved cysteines in Grx4 (Cys172) and Php4 (Cys221 and Cys227) are necessary for Fe-S cluster binding and stable complex formation. Together, these results show that Grx4 controls Php4 function through binding of a bridging [2Fe-2S] cluster. PMID- 28725906 TI - Covalent bonding-assisted nanotransfer lithography for the fabrication of plasmonic nano-optical elements. AB - Many high-resolution patterning techniques have been developed to realize nano- and microscale applications of electric devices, sensors, and transistors. However, conventional patterning methods based on photo or e-beam lithography are not employed to fabricate optical elements of high aspect ratio and a sub-100 nm scale due to the limit of resolution, high costs and low throughput. In this study, covalent bonding-assisted nanotransfer lithography (CBNL) was proposed to fabricate various structures of high resolution and high aspect ratio at low cost by a robust and fast chemical reaction. The proposed process is based on the formation of covalent bonds between silicon of adhesive layers on a substrate and oxygen of the deposited material on the polymer stamp. The covalent bond is strong enough to detach multiple layers from the stamp for a large area without defects. The obtained nanostructures can be used for direct application or as a hard mask for etching. Two nano-optical applications were demonstrated in this study, i.e., a meta-surface and a wire-grid polarizer. A perfect absorption meta surface was generated by transferring subwavelength hole arrays onto a substrate without any post-processing procedures. In addition, a wire-grid polarizer with high aspect ratio (1 : 3) and 50 nm line width was prepared by the nano-transfer of materials, which were used as a hard mask for etching. Therefore, CBNL provides a means of achieving large-area nano-optical elements with a simple roll to-plate process at low cost. PMID- 28725907 TI - Development of a New Immunoassay for Human Cathepsin K-Generated Periostin Fragments as a Serum Biomarker for Cortical Bone. AB - Periostin is a matricellular protein mainly expressed by periosteal cells and osteocytes in bone, but is also present in several other tissues. Available immunoassays use antibodies of unclear specificity. The aim of the study was to develop a bone-specific periostin ELISA based on the detection of fragments generated by the osteoclastic and osteocytic protease cathepsin K. In vitro digestion of human recombinant intact periostin by cathepsin K leads to the generation of multiple fragments. Using LS-MS/MS, it was found that the GSLQPIIK peptide was the most efficiently and abundantly generated periostin fragment. A rabbit polyclonal antibody directed against the synthetic GSLQPIIK sequence was produced. Immunohistochemistry experiments of the tibia showed that the GSLQPIIK fragments localized at the periosteal surface and within the osteocytes. Using the same antibody, we developed an ELISA for the measurement of GSLQPIIK in the serum. This ELISA demonstrated intra- and interassay variability below 14% with a sensitivity allowing accurate determinations in the serum of healthy individuals. Serum GSLQPIIK was measured in 160 healthy postmenopausal women (mean age 65 year) participating in the Geneva Retiree Cohort. Serum GSLQPIIK levels did not correlate with total periostin, hip BMD, and the bone markers PINP and CTX. However, GSLQPIIK was negatively correlated (p values ranging from 0.007 to 0.03) with Hr-pQCT measures of tibia and radius cortical bone, but not with trabecular parameters. We have developed the first assay for the detection of periostin fragments generated by cathepsin K. Because serum levels of this new marker significantly correlated with cortical bone measurements in postmenopausal women, it may prove to be useful for the clinical investigation of patients with osteoporosis. PMID- 28725908 TI - Cyst-Like Lesions at Chondro-Osseous Junction. AB - This study described and histologically characterized a cyst-like lesion (CLL) at the chondro-osseous junction. Rat knees (n = 12), with or without excessive running-induced osteoarthritis (OA), were used for counting the incidence, morphological measurements, immunohistochemistry of the CLL. A typical CLL, appearing as a void space in the matrix, was located on the tidemark at the chondro-osseous junction. The content of the CLL included types II and VI collagen, proteoglycans but not intact chondrocytes. At least one CLL was found in 5/6 osteoarthritic knees and only 2/6 in the non-osteoarthritic knees. The margin of the CLL was depleted of proteoglycans. The chondrocytes around the lesion were deformed and occasionally apoptotic. Matrix metalloproteinase 13 and vascular endothelial growth factor receptor were not detected in and around the CLL. CLLs disrupt the integrity of cartilage at a mechanically critical location the chondro-osseous junction. The significance of the CLL in cartilage biology and its potential role in OA pathogenesis warrant further investigation. PMID- 28725909 TI - Skeletal Fluorosis Due to Fluorocarbon Inhalation from an Air Dust Cleaner. AB - Skeletal fluorosis (SF) is an osteosclerotic metabolic bone disorder caused by excessive ingestion or inhalation of fluoride. SF is extremely rare in developed countries. We report a case of SF due to inhalational abuse from a fluoride containing air dust cleaner. A 33-year-old man with no past medical history presented with progressively worsening low back pain for 2 years. Physical examination was notable for loss of lumbar lordosis and tenderness over the lumbar spine. Radiographs were notable for uniform generalized osteosclerosis in the long bones, entire spine, rib cage, and pelvic bones, and loss of the normal lumbar curvature. DXA scan showed Z-scores of +10.7 at the lumbar spine, +6.5 at the total hip, and +1.0 at the 1/3 radius. Laboratory studies were notable for elevated serum alkaline phosphatase (334 U/L, ref: 40-129 U/L) compared to a normal value 3 years prior, suggesting acquired osteosclerosis. Serum fluoride concentration returned elevated (2.8 mg/L, ref: 0.0-0.2 mg/L). Initially, the source of fluoride excess could not be identified. At a follow-up visit, he was found inhaling from a can of an air duster hidden in an inner pocket. He admitted "huffing" 2-7 cans weekly from a fluorocarbon-containing air dust cleaner for the past 3 years to achieve a euphoric feeling, explaining the source of his SF. Fluoride inhalation can be a potential source for SF, and should be suspected in patients with acquired osteosclerosis, as inhalant abuse is increasingly practiced in many countries. PMID- 28725910 TI - Preoperative quality of life questionnaires are an adequate tool to select women with genital prolapse for laparoscopic sacrocolpopexy. AB - INTRODUCTION AND HYPOTHESIS: No clear consensus exists on the selection of patients with pelvic organ prolapse (POP) for surgery. There is a need to preoperatively identify candidates who will benefit from surgery as there is no strict correlation between POP anatomical abnormalities and changes in symptoms and quality of life (QOL) after surgical treatment. Therefore, our objectives were to evaluate the changes in QOL after laparoscopic sacrocolpopexy (LSC) for POP using validated questionnaires and to assess their relevance in selecting women for surgery. METHODS: This was a prospective study of 48 women with advanced stages of POP treated by LSC from March 2005 to January 2015. We developed a recursive partitioning model from QOL PFDI-20 and PFIQ-7 questionnaire scores to determine a preoperative cut-off score for predicting improvement after surgery. The model was then validated in 84 consecutive women. RESULTS: Optimal anatomical results were obtained in 129 of the 132 women (97.7%). Both questionnaires revealed a significant improvement after LSC (p < 0.01). The probability of improvement after surgery was 0% in women with a preoperative PFIQ-7 score of <45.25, and 84% in women with a PFIQ-7 score of >=45.25. The probability of improvement after surgery was 0% in women with a preoperative PFDI-20 score of <52.15, 88.2% in those with a PFDI-20 score of >= 98.45, and 42.9% in those with a PFDI-20 score between 52.15 and 98.45. In the validation set, the discriminatory accuracies of the model were 0.96 (95% CI 0.925-0.998) and 0.75 (95% CI 0.64-0.85) for the PFIQ-7 and PFDI-20 questionnaires, respectively. The performance was accurate with a significant difference between observed outcome frequencies and predicted probabilities (p = 1). CONCLUSIONS: Our results support the use QOL questionnaires to select women for LSC. PMID- 28725911 TI - Autoantibody binding in liquid phase to IL-2 in human sera is not type 1 diabetes specific. PMID- 28725913 TI - Normoalbuminuric chronic kidney disease in type 1 diabetes: is it real and is it serious? PMID- 28725912 TI - SGLT2 inhibitors and risk of cancer in type 2 diabetes: a systematic review and meta-analysis of randomised controlled trials. AB - AIMS/HYPOTHESIS: The association between sodium-glucose cotransporter 2 (SGLT2) inhibitors and the risk of cancer in individuals with type 2 diabetes remains uncertain. This study aimed to evaluate the risk of cancer associated with SGLT2 inhibitor treatment of type 2 diabetes. METHODS: We systematically searched PubMed, EMBASE, Cochrane Central Register of Controlled Trials and ClinicalTrials.gov from inception to 15 February 2017 to identify eligible randomised controlled trials (RCTs) that report cancer events in individuals with type 2 diabetes treated with SGLT2 inhibitors for at least 24 weeks. We performed pairwise and network meta-analyses as well as a cumulative meta-analysis to calculate ORs and 95% CIs. RESULTS: In total, 580 incidences of cancer among 34,569 individuals were identified from 46 independent RCTs with a mean trial duration of 61 weeks. When compared with comparators (placebo or other active glucose-lowering treatments), SGLT2 inhibitors were not significantly associated with an increased risk of overall cancer (OR 1.14 [95% CI 0.96, 1.36]). For pre specified cancer types, the risk of bladder cancer might be increased with SGLT2 inhibitors (OR 3.87 [95% CI 1.48, 10.08]), especially empagliflozin (OR 4.49 [95% CI 1.21, 16.73]). Interestingly, canagliflozin might be protective against gastrointestinal cancers (OR 0.15 [95% CI 0.04, 0.60]). CONCLUSIONS/INTERPRETATION: Current evidence from short-term RCTs did not indicate a significantly increased risk of overall cancer among individuals with type 2 diabetes using SGLT2 inhibitors. Given the short-term trial durations and uncertainty of evidence, future long-term prospective studies and post-marketing surveillance studies are warranted. PMID- 28725914 TI - Vascular complications in diabetes: old messages, new thoughts. AB - In parallel with the growing diabetes pandemic, there is an increasing burden of micro- and macrovascular complications, occurring in the majority of patients. The identification of a number of synergistic accelerators of disease, providing therapeutic pathways, has stabilised the incidence of complications in most western nations. However, the primary instigators of diabetic complications and, thus, prevention strategies, remain elusive. This has necessitated a refocus on natural history studies, where tissue and plasma samples are sequentially taken to determine when and how disease initiates. In addition, recent Phase III trials, wherein the pleiotropic effects of compounds were arguably as beneficial as their glucose-lowering capacity in slowing the progression of complications, have identified knowledge gaps. Recently the influence of other widely recognised pathological pathways, such as mitochondrial production of reactive oxygen species, has been challenged, highlighting the need for a diverse and robust global research effort to ascertain viable therapeutic targets. Technological advances, such as -omics, high-resolution imaging and computational modelling, are providing opportunities for strengthening and re-evaluating research findings. Newer areas such as epigenetics, energetics and the increasing scrutiny of our synergistic inhabitants, the microbiota, also offer novel targets as biomarkers. Ultimately, however, this field requires concerted lobbying to support all facets of diabetes research. PMID- 28725916 TI - Cervical extraforaminal ligaments: an anatomical study. AB - PURPOSE: The purpose of this study was to elucidate the anatomy and clinical importance of extraforaminal ligaments in the cervical region. METHODS: This study was performed on eight embalmed cadavers. The existence and types of extraforaminal ligaments were identified. The morphology, quantity, origin, insertion, and orientation of the extraforaminal ligaments in the cervical region were observed. RESULTS: Extraforaminal ligaments could be divided into two types: transforaminal ligaments and radiating ligaments. It was observed that during their course, transforaminal ligaments cross the intervertebral foramen ventrally. They usually originate from the anteroinferior margin of the anterior tubercle of the cranial transverse process and insert into the superior margin of the anterior tubercle of the caudal transverse process. The dorsal aspect of the transforaminal ligaments adhere loosely to the spinal nerve sheath. The length, width and thickness of these ligaments increased from the cranial to the caudal direction. A single intervertebral foramen contained at least one transforaminal ligament. A total of 98 ligaments in 96 intervertebral foramina were found. The spinal nerves were extraforaminally attached to neighboring anterior and posterior tubercle of the cervical transverse process by the radiating ligaments. The radiating ligaments consisted of the ventral superior, ventral, ventral inferior, dorsal superior and dorsal inferior radiating ligaments. Radiating ligaments originated from the adjacent transverse processes and inserted into the nerve root sheath. The spinal nerve was held like the hub of a wheel by a series of radiating ligaments. The dorsal ligaments were the thickest. From C2-3 to C6-7 at the cervical spine, radiating ligaments were observed. They developed particularly at the level of the C5-C6 intervertebral foramen. CONCLUSIONS: This anatomic study may provide a better understanding of the relationship of the extraforaminal ligaments to the cervical nerve root. PMID- 28725915 TI - IKKbeta inhibition prevents fat-induced beta cell dysfunction in vitro and in vivo in rodents. AB - AIMS/HYPOTHESIS: We have previously shown that oxidative stress plays a causal role in beta cell dysfunction induced by fat. Here, we address whether the proinflammatory kinase inhibitor of (nuclear factor) kappaB kinase beta (IKKbeta), which is activated by oxidative stress, is also implicated. METHODS: Fat (oleate or olive oil) was infused intravenously in Wistar rats for 48 h with or without the IKKbeta inhibitor salicylate. Thereafter, beta cell function was evaluated in vivo using hyperglycaemic clamps or ex vivo in islets isolated from fat-treated rats. We also exposed rat islets to oleate in culture, with or without salicylate and 4(2'-aminoethyl)amino-1,8-dimethylimidazo(1,2 a)quinoxaline; BMS-345541 (BMS, another inhibitor of IKKbeta) and evaluated beta cell function in vitro. Furthermore, oleate was infused in mice treated with BMS and in beta cell-specific Ikkb-null mice. RESULTS: 48 h infusion of fat impaired beta-cell function in vivo, assessed using the disposition index (DI), in rats (saline: 1.41 +/- 0.13; oleate: 0.95 +/- 0.11; olive oil [OLO]: 0.87 +/- 0.15; p < 0.01 for both fats vs saline) and in mice (saline: 2.51 +/- 0.39; oleate: 1.20 +/- 0.19; p < 0.01 vs saline) and ex vivo (i.e., insulin secretion, units are pmol insulin islet-1 h-1) in rat islets (saline: 1.51 +/- 0.13; oleate: 1.03 +/- 0.10; OLO: 0.91 +/- 0.13; p < 0.001 for both fats vs saline) and the dysfunction was prevented by co-infusion of salicylate in rats (oleate + salicylate: 1.30 +/- 0.09; OLO + salicylate: 1.33 +/- 0.23) or BMS in mice (oleate + BMS: 2.25 +/- 0.42) in vivo and by salicylate in rat islets ex vivo (oleate + salicylate: 1.74 +/- 0.31; OLO + salicylate: 1.54 +/- 0.29). In cultured islets, 48 h exposure to oleate impaired beta-cell function ([in pmol insulin islet-1 h-1] control: 0.66 +/- 0.12; oleate: 0.23 +/- 0.03; p < 0.01 vs saline), an effect prevented by both inhibitors (oleate + salicylate: 0.98 +/- 0.08; oleate + BMS: 0.50 +/- 0.02). Genetic inhibition of IKKbeta also prevented fat-induced beta-cell dysfunction ex vivo ([in pmol insulin islet-1 h-1] control saline: 0.16 +/- 0.02; control oleate: 0.10 +/- 0.02; knockout oleate: 0.17 +/- 0.04; p < 0.05 control saline vs. control oleate) and in vivo (DI: control saline: 3.86 +/- 0.40; control oleate: 1.95 +/- 0.29; knockout oleate: 2.96 +/- 0.24; p < 0.01 control saline vs control oleate). CONCLUSIONS/INTERPRETATION: Our results demonstrate a causal role for IKKbeta in fat-induced beta cell dysfunction in vitro, ex vivo and in vivo. PMID- 28725917 TI - Double inter-internal carotid artery communication through intercavernous anastomosis and posterior communicating artery associated with multiple intracranial artery segmental agenesis/aplasia. AB - Segmental internal carotid artery (ICA) and basilar artery (BA) agenesis/aplasia are rare vascular anomalies. We report an extremely rare case of combined ICA, BA, and A1 segmental absence presenting with double inter-ICA collateral communication through the intercavernous anastomosis and posterior communicating arteries. The patient presented with diplopia and transient ischemic attack. The pathogenesis of the anatomic anomalies and clinical symptoms are discussed. PMID- 28725918 TI - A comprehensive review of motor innervation of the hand: variations and clinical significance. AB - PURPOSE: The objective of the present review is to assemble the recognized anatomical variations, classifications, and clinical evidence with regard to innervation of the hand and discuss the clinical significance of these variations. METHODS: The material for this review was obtained by exploring PubMed and Google Scholar (search terms: hand innervation, variations of ulnar nerve, variations of median nerve, variations of radial nerve) as well as from standard anatomy texts. This initial search returned approximately 300 articles, which was reduced by abstract or title review. Reviewing the reference lists of significant papers uncovered further studies missed in the initial search. A few standard anatomy texts were also consulted for normal anatomy. RESULTS: The median and ulnar nerves frequently display a number of significant deviations from the traditionally taught branching patterns. The traditionally taught innervation of the hand is also found to be highly variable. This is especially evident with regard to the motor innervation of thenar muscles. These variations may be explained by the often under-recognized anastomoses that exist in the hand, such as the motor Riche-Cannieu Anastomosis. Some of these variations are associated significant clinical consequences. CONCLUSIONS: The median and ulnar nerves display many anatomical variations, often with significant clinical implications. Awareness about these variations is clinically important when interpreting clinical examination findings, electrophysiological and radiological investigation as well as during management of patients in terms of surgical and anesthetic procedures. PMID- 28725919 TI - Accurate guide wire of lag screw placement in the intertrochanteric fractures: a technical note. AB - Cephalomedullary fixations are commonly used in the treatment of intertrochanteric fractures. In clinical practice, one of the difficulties is when we exit the guide wire in a wrong position of femoral neck and insert near the hole again, the guide wire often flow into the previous track. This study develops a surgical technique to direct the guide wire to slip away the previous track and slip into a right position. When guide wire is exited to the cortex of femoral, we let the wire in and out at the cortical layer for several times to enlarge the entry hole. After that, electric drill is inverted, rubbed and entered slowly at a right angle. When guide wire encountered new resistance, the electric drill is turned back instantly. This technique can help trauma and orthopedic surgeons to obtain precision placement of the lag screw after the first try is failed. PMID- 28725920 TI - Pre-papillary vitreous opacities associated with Behcet's disease: a case series and review of the literature. AB - PURPOSE: To present pre-papillary vitreous opacity as an uncommon manifestation of inflammation in Behcet's disease that may be specific to this uveitic entity. METHODS: We retrospectively reviewed the charts of 67 patients with Behcet's disease examined at our clinic between 2005 and 2016. Behcet's disease was diagnosed based on established clinical criteria of inflammation involving the eyes, mucocutaneous junctions, and skin. Patients with Behcet's disease who presented with papillitis and a pre-papillary vitreous opacity were identified. Response to anti-inflammatory treatment on examination and optical coherence tomography imaging were evaluated. PubMed searches were performed for (1) other cases with pre-papillary vitreous opacities in uveitic entities and (2) reports of optic nerve involvement specifically in Behcet's disease. RESULTS: We identified three patients with Behcet's disease who presented with unilateral papillitis and a pre-papillary vitreous opacity. The pre-papillary vitreous opacity had a funnel-shaped appearance on optical coherence tomography. All patients were initially treated with steroids, which led to resolution of the opacity clinically and on imaging. We identified one previous report of such a pre-papillary opacity in a patient with Behcet's disease, and no reports of this finding in other uveitic entities. CONCLUSION: This study expands the number of Behcet's disease cases presenting with a pre-papillary vitreous opacity and demonstrates novel optical coherence imaging of this finding. This finding may be specific to Behcet's disease as it was not identified in other uveitic entities in a review of the existing literature. PMID- 28725921 TI - [Parkinson's disease in the elderly]. AB - Due to the increasing life expectancy and a higher incidence in the elderly, the number of elderly patients with idiopathic Parkinson's disease will increase in the coming years. Since the burden of comorbidities is higher and medication side effects are more likely in the elderly, particularly in the light of frequently occurring polypharmacy, increased awareness and therapeutic knowledge is necessary. Besides the therapy of motor symptoms, non-motor symptoms, e. g. neuropsychiatric and autonomic disorders, also need to be addressed as they can also greatly impair the quality of life. In more advanced stages of the disease, non-pharmacological treatment, medical aids and caregiving become more important. A close integration in the social environment is of great importance for the implementation. PMID- 28725922 TI - Genetic Testing Protocol Reduces Costs and Increases Rate of Genetic Diagnosis in Infants with Congenital Heart Disease. AB - Genetic testing is routinely performed on infants with critical congenital heart disease (CHD). This project reviewed the effect of implementing a genetic testing protocol in this population. Charts of infants with critical CHD were reviewed for genetic testing and results across two time periods: the time before implementation of a genetic testing protocol (pre-protocol) and the time after implementation (post-protocol). The use of karyotype, 22q11.2 Deletion testing, and chromosomal microarray were compared across these two time periods. Records of 891 infants were reviewed. 562 (63%) had at least one of the target genetic tests completed. During the pre-protocol time period, 66% of patients who had genetic testing underwent multiple tests versus 24% during the post-protocol time period (p < 0.01). The rate of patients who underwent genetic testing increased from 60% in the pre-protocol time period to 77% in the post-protocol time period (p < 0.01). The rate of diagnosis of genetic conditions during the pre-protocol period was 26% versus 36% during the post-protocol period (p = 0.01). There was a reduction in cost to patients by $5105.59 per diagnosis during the post-protocol period. Patients with critical CHD in the post-protocol period were less likely to undergo multiple genetic tests and more likely to have a diagnosis of genetic disease. In addition there was a significant reduction in cost per diagnosis during the post-protocol time period. Genetic testing protocols for infants with critical CHD promoted more efficient use of genetic testing and increased the rate of diagnosis of genetic conditions in this population. PMID- 28725923 TI - Assessing 3D T2 FSE sequence for identification of the normal appendix: working toward a single-sequence MR appendicitis protocol. AB - PURPOSES: To assess the ability of a single isotropic 3D T2 FSE sequence to identify the normal appendix in children with potential implication as alternative second-line modality in pediatric appendicitis. MATERIALS AND METHODS: Retrospective review of MR abdomino-pelvis or pelvis in children from Oct 2014-Dec 2016 was done. Only exams with 3D T2 FSE sequence performed on a single scanner type were selected. Patients with history of post appendectomy, studies in which field of view did not include ileocecal valve, with technical and protocol errors, or with fat-saturated acquisition were excluded. All images were blindly reviewed by three radiologists. The following questions were asked: (1) Is the appendix visualized?, (2) What is the most clearly demonstrable plane?, (3) Where is the appendix located?, (4) Are there any findings indicating appendicitis? Average pairwise percentage and Fleiss Kappa were used to assess the inter-rater agreement on the visualization and location of the appendix. RESULTS: A total of 22 MRI studies were reviewed (F = 13:M = 9, Mean age = 11.45 yrs. [SD = 4.3]). Total MRI scan time was estimated at 6 mins. Readers saw appendix in 72.7-81.8%, and saw with high confidence in 12 cases (54.5%), low confidence in 4-6 case (18.2-27.3%), and did not see in 4-6 cases(18.2-27.3%). The average pairwise percentage agreement was 71.2%. Fleiss Kappa of overall rating of visualization was 0.52 (p < 0.001). Fleiss Kappa of high confidence of visualization was 0.76 (p < 0.001). Reader 1 and reader 2 saw the appendix best on the axial plane. Reader 3 saw the appendix best on the coronal plane. For location, deep pelvis was the most common identified location. The average pairwise percentage agreement was 68.2% and Fleiss Kappa was 0.76 (p < 0.001). There is no findings indicating appendicitis. CONCLUSION: A single 3D T2 FSE sequence had good ability to detect normal appendices and also allowed multiplanar reconstructions, which may use as a single-sequence protocol in cases of suspected appendicitis in children when ultrasound is inconclusive. PMID- 28725924 TI - Effect of training status on beta-range corticomuscular coherence in agonist vs. antagonist muscles during isometric knee contractions. AB - Antagonist muscle co-activation is thought to be partially regulated by cortical influences, but direct motor cortex involvement is not fully understood. Corticomuscular coherence (CMC) measures direct functional coupling of the motor cortex and muscles. As antagonist co-activation differs according to training status, comparison of CMC in agonist and antagonist muscles and in strength trained and endurance-trained individuals may provide in-depth knowledge of cortical implication in antagonist muscle co-activation. Electroencephalographic and electromyographic signals were recorded, while 10 strength-trained and 11 endurance-trained participants performed isometric knee contractions in flexion and extension at various torque levels. CMC magnitude in 13-21 and 21-31 Hz frequency bands was quantified by CMC analysis between Cz electroencephalographic electrode activity and all electromyographic signals. CMC was significant in both 13-21 and 21-31 Hz frequency bands in flexor and extensor muscles regardless of participant group, torque level, and direction of contraction. CMC magnitude decreased more in antagonist than in agonist muscles as torque level increased. Finally, CMC magnitude was higher in strength-trained than in endurance-trained participants. These findings provide experimental evidence that the motor cortex directly regulates both agonist and antagonist muscles. Nevertheless, the mechanisms underlying muscle activation may be specific to their function. Between-group modulation of corticomuscular coherence may result from training induced adaptation, re-emphasizing that corticomuscular coherence analysis may be efficient in characterizing corticospinal adaptations after long-term muscle specialization. PMID- 28725925 TI - Characterisation of Peptide5 systemic administration for treating traumatic spinal cord injured rats. AB - Systemic administration of a Connexin43 mimetic peptide, Peptide5, has been shown to reduce secondary tissue damage and improve functional recovery after spinal cord injury (SCI). This study investigated safety measures and potential off target effects of Peptide5 systemic administration. Rats were subjected to a mild contusion SCI using the New York University impactor. One cohort was injected intraperitoneally with a single dose of fluorescently labelled Peptide5 and euthanised at 2 or 4 h post-injury for peptide distribution analysis. A second cohort received intraperitoneal injections of Peptide5 or a scrambled peptide and was culled at 8 or 24 h post-injury for the analysis of connexin proteins and systemic cytokine profile. We found that Peptide5 did not cross the blood-spinal cord barrier in control animals, but reached the lesion area in the spinal cord injured animals without entering non-injured tissue. There was no evidence that the systemic administration of Peptide5 modulates Connexin43 protein expression or hemichannel closure in the heart and lung tissue of SCI animals. The expression levels of other major connexin proteins including Connexin30 in astrocytes, Connexin36 in neurons and Connexin47 in oligodendrocytes were also unaltered by systemic delivery of Peptide5 in either the injured or non-injured spinal cords. In addition, systemic delivery of Peptide5 had no significant effect on the plasma levels of cytokines, chemokines or growth factors. These data indicate that the systemic delivery of Peptide5 is unlikely to cause any off target or adverse effects and may thus be a safe treatment option for traumatic SCI. PMID- 28725927 TI - qEEG by neurointensivists: research agenda and implications for training. PMID- 28725928 TI - Structural modification of cuminaldehyde thiosemicarbazone increases inhibition specificity toward aflatoxin biosynthesis and sclerotia development in Aspergillus flavus. AB - Aspergillus flavus is an opportunistic mold that represents a serious threat for human and animal health due to its ability to synthesize and release, on food and feed commodities, different toxic secondary metabolites. Among them, aflatoxin B1 is one of the most dangerous since it is provided with a strong cancerogenic and mutagenic activity. Controlling fungal contamination on the different crops that may host A. flavus is considered a priority by sanitary authorities of an increasing number of countries due also to the fact that, owing to global temperature increase, the geographic areas that are expected to be prone to experience sudden A. flavus outbreaks are widening. Among the different pre- and post-harvest strategies that may be put forward in order to prevent fungal and/or mycotoxin contamination, fungicides are still considered a prominent weapon. We have here analyzed different structural modifications of a natural-derived compound (cuminaldehyde thiosemicarbazone) for their fungistatic and anti aflatoxigenic activity. In particular, we have focused our attention on one of the compound that presented a prominent anti-aflatoxin specificity, and performed a set of physiological and molecular analyses, taking also advantage of yeast (Saccharomyces cerevisiae) cell as an experimental model. PMID- 28725926 TI - The Intensive Care Medicine research agenda on critically ill oncology and hematology patients. AB - Over the coming years, accelerating progress against cancer will be associated with an increased number of patients who require life-sustaining therapies for infectious or toxic chemotherapy-related events. Major changes include increased number of cancer patients admitted to the ICU with full-code status or for time limited trials, increased survival and quality of life in ICU survivors, changing prognostic factors, early ICU admission for optimal monitoring, and use of noninvasive diagnostic and therapeutic strategies. In this review, experts in the management of critically ill cancer patients highlight recent changes in the use and the results of intensive care in patients with malignancies. They seek to put forward a standard of care for the management of these patients and highlight important updates that are required to care for them. The research agenda they suggest includes important studies to be conducted in the next few years to increase our understanding of organ dysfunction in this population and to improve our ability to appropriately use life-saving therapies or select new therapeutic approaches that are likely to improve outcomes. This review aims to provide more guidance for the daily management of patients with cancer, in whom outcomes are constantly improving, as is our global ability to fight against what is becoming the leading cause of mortality in industrialized and non-industrialized countries. PMID- 28725929 TI - Inverse correlation between galectin-4 and TTF-1 in lung adenocarcinoma. AB - We have previously shown that galectin-4 expression is an independent predictor for lymph node metastasis and serves as an adverse prognostic indicator in patients with acinar adenocarcinoma of the lung. In contrast, thyroid transcription factor-1 (TTF-1) expression in non-small cell lung carcinoma has been shown to be associated with a favorable prognosis. In the present study, 208 cases of acinar adenocarcinoma of the lung and 36 cases with distant metastatic lesions of lung adenocarcinoma were immunohistochemically examined for expression of galectin-4 and TTF-1 to elucidate their correlation with clinicopathological factors. TTF-1 expression was observed in 145 cases (69.7%) and associated with smaller tumor size, infrequent pleural invasion, and lower TNM stage. Galectin-4 expression was observed in 86 cases (41.3%). Furthermore, galectin-4-positive carcinoma cells and TTF-1-positive carcinoma cells existed exclusively within the same lesion. Expressions of TTF-1 and galectin-4 were favorable and adverse prognostic factors, respectively. Approximately 40% (15/36 cases) of lung adenocarcinoma at the distant metastatic sites were immunohistochemically negative for TTF-1. Four out of five galectin-4-positive metastatic lesions were negative for TTF-1. We found an inverse correlation between galectin-4 and TTF-1 expressions in acinar adenocarcinoma, and this phenomenon was also found to be present in metastatic sites. These findings suggest that we should not exclude the possibility of metastatic adenocarcinoma of the lung, even if the tumor cells are immunohistochemically negative for TTF-1 in the primary unknown tumor, because aggressive lung adenocarcinomas often lack TTF-1 expression. PMID- 28725930 TI - Infant Positioning, Baby Gear Use, and Cranial Asymmetry. AB - Objectives This study aimed to identify predictors of cranial asymmetry. We hypothesize that among infants diagnosed with cranial asymmetry in the sampled region, there is an association between exposure to more time in baby gear and less awake time in prone and side-lying than in infants who do not present with this condition. Methods The study employed a cross sectional survey of caregivers of typically developing infants and infants diagnosed with cranial asymmetry. Results A mutivariable model reveals that caregivers of children who are diagnosed with cranial asymmetry report their children spending significantly less time in prone play than those children without a diagnosis of cranial asymmetry. Side-lying and time spent in baby gear did not attain statistical significance. Conclusions for Practice Occupational therapists, physical therapists, pediatricians, nurses and other health care professionals must provide parents with early education about the importance of varying positions and prone play in infancy and address fears and concerns that may serve as barriers to providing prone playtime. PMID- 28725931 TI - Seasonal Trend of PAHs Concentrations in Farmed Mussels from the Coastal Areas of the Naples, Italy. AB - This paper reports on the results about the chemical pollution pressure in the Gulf of Naples and nearby coastal areas. Farmed mussels were analysed for the presence of polycyclic aromatic hydrocarbons (PAHs). The results documented a decreasing trend in the PAHs levels respect to the past years. The Bay of Pozzuoli remains as the most contaminated site within the Lucrino area with the highest reported number of samples exceeding the benzo(a)pyrene and PAHs sum limits. All the samples with concentrations above the European regulatory limit were collected in the winter period illustrating a seasonal trend of PAHs distribution in mussels during the 4 years investigated. PMID- 28725933 TI - [Callus distraction and bone transport in the treatment of bone defects]. AB - BACKGROUND: The method of "callus distraction" is the only technique which spontaneously produces vascularized bone within the surrounding soft tissues during lengthening reconstructive procedures. Remodeling of the regenerate bone to specific mechanical load can be influenced by the surgeon. In principle, there is no limit to the amount of new bone formation which can be created; this vascularized bone is both resistant to infection and can be created to replace resected infected bone. This is an important prerequisite for the successful treatment of large bone defects. TECHNIQUE: The ring fixator is still a standard tool if no radiological control is available in the operating theater, or in other less sophisticated environments. Over the last 30 years, however, the development of motorized, external and fully implantable systems has made it possible to achieve a significant increase in device implementation, which goes far beyond the standard. RESULTS: High-performance, reliable, custom-made external and fully implantable systems are cost intensive and require special surgical skills, which can only be ensured at specialized centers. However, the complication-free treatment results justify the effort both for the patient and, ultimately, for the cost bearers. PMID- 28725932 TI - DNA methylation in ELOVL2 and C1orf132 correctly predicted chronological age of individuals from three disease groups. AB - Improving accuracy of the available predictive DNA methods is important for their wider use in routine forensic work. Information on age in the process of identification of an unknown individual may provide important hints that can speed up the process of investigation. DNA methylation markers have been demonstrated to provide accurate age estimation in forensics, but there is growing evidence that DNA methylation can be modified by various factors including diseases. We analyzed DNA methylation profile in five markers from five different genes (ELOVL2, C1orf132, KLF14, FHL2, and TRIM59) used for forensic age prediction in three groups of individuals with diagnosed medical conditions. The obtained results showed that the selected age-related CpG sites have unchanged age prediction capacity in the group of late onset Alzheimer's disease patients. Aberrant hypermethylation and decreased prediction accuracy were found for TRIM59 and KLF14 markers in the group of early onset Alzheimer's disease suggesting accelerated aging of patients. In the Graves' disease patients, altered DNA methylation profile and modified age prediction accuracy were noted for TRIM59 and FHL2 with aberrant hypermethylation observed for the former and aberrant hypomethylation for the latter. Our work emphasizes high utility of the ELOVL2 and C1orf132 markers for prediction of chronological age in forensics by showing unchanged prediction accuracy in individuals affected by three diseases. The study also demonstrates that artificial neural networks could be a convenient alternative for the forensic predictive DNA analyses. PMID- 28725934 TI - [Scaffold-based Bone Tissue Engineering]. AB - Tissue engineering provides the possibility of regenerating damaged or lost osseous structures without the need for permanent implants. Within this context, biodegradable and bioresorbable scaffolds can provide structural and biomechanical stability until the body's own tissue can take over their function. Additive biomanufacturing makes it possible to design the scaffold's architectural characteristics to specifically guide tissue formation and regeneration. Its nano-, micro-, and macro-architectural properties can be tailored to ensure vascularization, oxygenation, nutrient supply, waste exchange, and eventually ossification not only in its periphery but also in its center, which is not in direct contact with osteogenic elements of the surrounding healthy tissue. In this article we provide an overview about our conceptual design and process of the clinical translation of scaffold-based bone tissue engineering applications. PMID- 28725935 TI - Erratum to: the role of Blastocystis sp. and Dientamoeba fragilis in irritable bowel syndrome: a systematic review and meta-analysis. PMID- 28725936 TI - Ultrastructural characters of the spermatozoon of the liver fluke Opisthorchis viverrini (Poirier, 1886) (Opisthorchiidae). AB - The present study records the ultrastructural organization of the mature spermatozoon of Opisthorchis viverrini by means of transmission electron microscopy. The spermatozoon of O. viverrini is a filiform cell, tapered at both extremities. It exhibits the characteristics of type IV spermatozoon of digeneans, namely with two axonemes of the 9+'1' trepaxonematan pattern, external ornamentation of the plasma membrane associated with cortical microtubules that are in the posterior part of the anterior region of the sperm cell, and with two mitochondria. The maximal number of cortical microtubules is in the anterior part of the spermatozoon and arranged into two bundles. Other characteristics are spine-like bodies and a posterior extremity with only the second axoneme. Ultrastructural characters of the spermatozoon of O. viverrini are compared with those of other known digeneans belonging to the Opisthorchioidea, with particular emphasis on representatives of the family Opisthorchiidae. The main differences between O. viverrini and its congener Opisthorchis felineus are the spine-like bodies (present and absent, respectively) and the posterior spermatozoon character (axoneme and nucleus, respectively). PMID- 28725937 TI - Aspirin use and head and neck cancer survival: an observational study of 11,623 person-years follow-up. AB - BACKGROUND: Acetylsalicylic acid (aspirin) and non-steroidal anti-inflammatory drugs (NSAIDs) have been associated with reduced risks for certain human cancers. However, the effects of aspirin and NSAIDs on head and neck squamous cell carcinoma (HNSCC) remain controversial, and the prognostic effects of these drugs in patients with HNSCC are largely unknown. This study examined the clinical impact of aspirin and NSAIDs on disease recurrence and survival in patients with HNSCC. METHODS: This study analysed a cohort of 1392 consecutive patients who received definitive treatment for previously untreated HNSCC at our tertiary referral center. Aspirin or NSAID use was considered positive if the patients were receiving aspirin or NSAID medication from HNSCC diagnosis to at least 1 year after treatment initiation. Cox proportional hazard models were utilised to determine the association of aspirin and/or NSAID use with recurrence, survival, and second primary cancer occurrence. RESULTS: Of 1392 patients, 81 (5.8%) and 89 (6.4%) received post-diagnosis treatment with aspirin and NSAIDs, respectively. After controlling for clinical factors, aspirin and NSAIDs were not significantly associated with recurrence, survival, or second cancer occurrence (P > 0.05). The cumulative dose of aspirin or NSAIDs did not alter survival outcomes (P > 0.05). CONCLUSION: Our data illustrated that the use of aspirin or NSAIDs has no effect on survival or recurrence in patients with HNSCC. PMID- 28725938 TI - Declining radiation dose of coronary computed tomography angiography: German cardiac CT registry experience 2009-2014. AB - BACKGROUND: Coronary computed tomography angiography (CTA) is increasingly used as a test to rule out coronary artery disease (CAD) in patients with a low to intermediate pre-test probability of the disease. We used the database of the German CT registry, collected between 2009 and 2014 in a broad patient population, to analyze contemporary radiation dose associated with coronary CTA in clinical practice. PATIENTS AND METHODS: The prospective observational registry included a total of 7061 patients >=18 years, referred to 12 participating centers for a clinically indicated cardiac CT examination. All centers were cardiology units well experienced in CTA and used multi-slice CT scanners with at least 64 rows. Coronary CTA was performed in a subset of 5001 patients, 59.6 +/- 11.8 years, body mass index (BMI) 26.9 +/- 4.5 kg/m2, 38% females. Three time periods with approximately equal numbers of patients were created (01/09-03/10, 04/10-03/11, 04/11-07/14). The dose-length product of all examinations and derived effective dose in mSv (conversion factor k = 0.014) as well as the influence of patient characteristics on dose were compared for the three time periods. RESULTS: BMI and proportion of female patients remained stable over time, and mean heart rate decreased from 60.3 +/- 9.0 to 58.5 +/- 9.3 bpm from the first to the last time period (p < 0.001). Overall, the mean effective dose of coronary CTA was 3.6 mSv (Q1 1.8 mSv, Q3 7.4 mSv). Within the three time periods, it declined from 5.6 (2.7, 8.6) mSv during the first to 4.8 (2.1, 8.2) mSv during the second and 2.5 (1.3, 4.6) mSv during the last time period (p < 0.001). Paralleling the decline in radiation dose over time, the proportion of prospectively ECG-triggered examinations increased (68, 79, 83%; p < 0.001), and the proportion of examinations with retrospective gating and no tube current modulation decreased (5.3, 4.0, 1.6%; p < 0.001). Tube current (mAs) and voltage (kV) both decreased over time. In multivariable analysis, besides earlier time period, further independent predictors of an increased radiation dose were older age, higher heart rate, and higher BMI as well as the technical factors higher mAs, higher kV, and retrospective gating. At three sites, CT scanners with improved technology were installed during the last time period. CONCLUSIONS: In current clinical practice among German cardiology units with specific expertise in cross-sectional cardiovascular imaging, overall radiation dose of coronary CTA was comparably low. Over time, a decline in radiation dose was demonstrated, probably due to a combination of improvements in data acquisition protocols and patient preparation as well as installation of new CT scanners with advanced technology. PMID- 28725939 TI - Escalated cocaine "binges" in rats: enduring effects of social defeat stress or intra-VTA CRF. AB - RATIONALE: Exposure to intermittent social defeat stress elicits corticotropin releasing factor (CRF) release into the VTA and induces long-term modulation of mesocorticolimbic dopamine activity in rats. These adaptations are associated with an intense cocaine-taking phenotype, which is prevented by CRF receptor antagonists. OBJECTIVE: The present studies examine whether infusion of CRF into the VTA is sufficient to escalate cocaine-taking behavior, in the absence of social defeat experience. Additionally, we aimed to characterize changes in cocaine valuation that may promote binge-like cocaine intake. METHODS: Male Long Evans rats were microinjected into the VTA with CRF (50 or 500 ng/side), vehicle, or subjected to social defeat stress, intermittently over 10 days. Animals were then trained to self-administer IV cocaine (FR5). Economic demand for cocaine was evaluated using a within-session behavioral-economics threshold procedure, which was followed by a 24-h extended access "binge." RESULTS: Rats that experienced social defeat or received intra-VTA CRF microinfusions (50 ng) both took significantly more cocaine than controls over the 24-h binge but showed distinct patterns of intake. Behavioral economic analysis revealed that individual demand for cocaine strongly predicts binge-like consumption, and demand elasticity (i.e. alpha) is augmented by intra-VTA CRF, but not by social defeat. The effects of CRF on cocaine-taking were also prevented by intra-VTA pretreatment with CP376395, but not Astressin-2B. CONCLUSIONS: Repeated infusion of CRF into the VTA persistently alters cocaine valuation and intensifies binge-like drug intake in a CRF-R1-dependent manner. Conversely, the persistent pattern of cocaine bingeing induced by social defeat stress may suggest impaired inhibitory control, independent of reward valuation. PMID- 28725940 TI - Construction of the First High-Density Genetic Linkage Map and Analysis of Quantitative Trait Loci for Growth-Related Traits in Sinonovacula constricta. AB - The razor clam (Sinonovacula constricta) is an important aquaculture species, for which a high-density genetic linkage map would play an important role in marker assisted selection (MAS). In this study, we constructed a high-density genetic map and detected quantitative trait loci (QTLs) for Sinonovacula constricta with an F1 cross population by using the specific locus amplified fragment sequencing (SLAF-seq) method. A total of 315,553 SLAF markers out of 467.71 Mreads were developed. The final linkage map was composed of 7516 SLAFs (156.60-fold in the parents and 20.80-fold in each F1 population on average). The total distance of the linkage map was 2383.85 cM, covering 19 linkage groups with an average inter marker distance of 0.32 cM. The proportion of gaps less than 5.0 cM was on average 96.90%. A total of 16 suggestive QTLs for five growth-related traits (five QTLs for shell height, six QTLs for shell length, three QTLs for shell width, one QTL for total body weight, and one QTL for soft body weight) were identified. These QTLs were distributed on five linkage groups, and the regions showed overlapping on LG9 and LG13. In conclusion, the high-density genetic map and QTLs for S. constricta provide a valuable genetic resource and a basis for MAS. PMID- 28725941 TI - Endoscopic Stents for the Biliary Tree and Pancreas. AB - OPINION STATEMENT: PURPOSE OF REVIEW: To review the recently published literature on biliary and pancreatic stents. RECENT FINDINGS: Covered self-expanding metal stents (SEMS) are increasingly being used in the endoscopic management of benign biliary strictures. Given the costs associated with SEMS, plastic stents are still the most commonly used stents. In this setting, SEMS are preferred over plastic stents for palliation of malignant biliary strictures due to superior patency and have a role in preoperative management of malignant biliary strictures. While plastic stents are predominantly used for management of pancreatic strictures, newer endoscopic ultrasound (EUS)-guided lumen-apposing SEMS have been increasingly used in management of pancreatic fluid collections. EUS-guided SEMS also enable safe transmural drainage of gall bladder and bile ducts in benign and malignant conditions. Endoscopic management is the first line treatment for multiple pancreatobiliary disorders. EUS-guided interventions have widened the scope of endoscopic management and decreased the need for surgical intervention. Further studies are needed to determine the safety and cost effectiveness of SEMS in benign pancreatic disorders. PMID- 28725943 TI - Let's not forget about the vagus and other updates on recent autonomic research. PMID- 28725942 TI - L-Arginine supplementation prevents allodynia and hyperalgesia in painful diabetic neuropathic rats by normalizing plasma nitric oxide concentration and increasing plasma agmatine concentration. AB - PURPOSE: Neuropathic pain is a common diabetic complication. It is characterized by symptoms of spontaneous and stimulus-evoked pain including hyperalgesia and allodynia. L-Arginine is a common precursor of many metabolites of biological interest, in particular, nitric oxide (NO), ornithine, and hence polyamines. In central nervous system, NO, glutamate, and polyamines share an N-methyl-D aspartate (NMDA) receptor-mediated effect. We hypothesized that a variation in arginine metabolism caused by diabetes may contribute to development and maintenance of neuropathic pain and to the worsening of clinical and biological signs of diabetes. METHODS: We examined whether oral L-arginine supplementation (2.58 +/- 0.13 g/l in drinking water for 3 weeks) could improve the development of neuropathic pain and the clinical, biological, and metabolic complications of diabetes in streptozocin (STZ)-induced diabetic (D) rats. RESULTS: STZ administration induced classical symptoms of type 1 diabetes. Diabetic rats also displayed mechanical hypersensitivity, tactile, and thermal allodynia. Plasma citrulline and NO levels were increased in diabetic hyperalgesic/allodynic rats. L-Arginine supplementation failed to reduce hyperglycaemia, polyphagia, and weight loss. Moreover, it abolished hyperalgesia and allodynia by normalizing NO plasma concentration and increasing plasma agmatine concentration. CONCLUSIONS: L Arginine supplementation prevented the development of mechanical hyperalgesia, tactile, and thermal allodynia in painful diabetic neuropathy with concomitant reduction of NO and increased agmatine production, offering new therapeutic opportunities for the management of diabetic neuropathic pain. PMID- 28725944 TI - Skin Bacterial Community Reorganization Following Metamorphosis of the Fire Bellied Toad (Bombina orientalis). AB - In organisms with complex life histories, dramatic changes in microbial community structure may occur with host development and immune system maturation. Amphibian host susceptibility to diseases such as chytridiomycosis may be affected by the reorganization of skin microbial community structure that occurs during metamorphosis. We tracked changes in the bacterial communities inhabiting skin of Korean fire-bellied toads (Bombina orientalis) that we infected as tadpoles with different strains of Batrachochytrium dendrobatidis (Bd), the pathogenic fungus that causes chytridiomycosis. We found that B. orientalis undergoes a major change in skin bacterial community composition between 5 and 15 days following metamorphosis. Richness indices and phylogenetic diversity measures began to diverge earlier, between aquatic and terrestrial stages. Our results further reveal differences in skin bacterial community composition among infection groups, suggesting that the effect of Bd infection on skin microbiome composition may differ by Bd strain. Additional studies are needed to further investigate the structural and temporal dynamics of microbiome shifts during metamorphosis in wild and captive amphibian populations. Analyses of the ontogeny of microbiome shifts may contribute to an understanding of why amphibians vary in their susceptibility to chytridiomycosis. PMID- 28725945 TI - Genetic Characteristics of Coronaviruses from Korean Bats in 2016. AB - Bats have increasingly been recognized as the natural reservoir of severe acute respiratory syndrome (SARS), coronavirus, and other coronaviruses found in mammals. However, little research has been conducted on bat coronaviruses in South Korea. In this study, bat samples (332 oral swabs, 245 fecal samples, 38 urine samples, and 57 bat carcasses) were collected at 33 natural bat habitat sites in South Korea. RT-PCR and sequencing were performed for specific coronavirus genes to identify the bat coronaviruses in different bat samples. Coronaviruses were detected in 2.7% (18/672) of the samples: 13 oral swabs from one species of the family Rhinolophidae, and four fecal samples and one carcass (intestine) from three species of the family Vespertiliodae. To determine the genetic relationships of the 18 sequences obtained in this study and previously known coronaviruses, the nucleotide sequences of a 392-nt region of the RNA dependent RNA polymerase (RdRp) gene were analyzed phylogenetically. Thirteen sequences belonging to SARS-like betacoronaviruses showed the highest nucleotide identity (97.1-99.7%) with Bat-CoV-JTMC15 reported in China. The other five sequences were most similar to MERS-like betacoronaviruses. Four nucleotide sequences displayed the highest identity (94.1-95.1%) with Bat-CoV-HKU5 from Hong Kong. The one sequence from a carcass showed the highest nucleotide identity (99%) with Bat-CoV-SC2013 from China. These results suggest that careful surveillance of coronaviruses from bats should be continued, because animal and human infections may result from the genetic variants present in bat coronavirus reservoirs. PMID- 28725946 TI - Validation and characterization of a QTL for adult plant resistance to stripe rust on wheat chromosome arm 6BS (Yr78). AB - KEY MESSAGE: This study validated one QTL for adult plant resistance to stripe rust, identified donor lines of the resistance allele, and demonstrated that it is different from previously named Yr genes. The spread of more virulent and aggressive races of Puccinia striiformis f. sp. tritici (Pst, causal pathogen of stripe rust) after the year 2000 has caused substantial yield losses worldwide. To find new sources of resistance, we previously performed a genome-wide association study and identified a strong QTL for adult plant resistance on the short arm of chromosome 6B (QYr.ucw-6B). In this study, we validated QYr.ucw-6B in ten biparental populations, and mapped it 0.6 cM proximal to IWA7257 and 3.9 cM distal to IWA4408. We showed that QYr.ucw-6B is located approximately 15 cM proximal to the all-stage resistance gene Yr35 and that none of the resistant lines carries the previously cloned Yr36 gene. Based on these results, QYr.ucw-6B was assigned the name Yr78. This gene was not effective against Pst at the seedling stage, suggesting that it is an adult plant resistance gene. Yr78 has been effective against Pst races present in field experiments performed in the Western USA between 2011 and 2016. Since this gene is predicted to be present at low frequency in wheat germplasm from this region, it can provide a useful tool to diversify the sources of resistance against this devastating pathogen. PMID- 28725947 TI - Clinical heterogeneity of SAPHO syndrome: challenging diagnose and treatment. AB - Synovitis, acne, pustulosis, hyperostosis and osteitis (SAPHO) syndrome is a rare disease which is often misdiagnosed and under-recognized, because of its peculiar and heterogeneous clinical presentation. Its main features consist of cutaneous and osteoarticular manifestations, the latter affecting more often the anterior chest wall and having typical radiologic findings. There are no validated diagnostic criteria for SAPHO and no guidelines for treatment, due mainly to its rarity; as a consequence, therapy is empirical and aimed to control pain and modifying inflammatory process. To date, the use of anti-TNF agents has been proved to be a valid alternative for patients unresponsive to conventional treatments, such as NSAIDs, corticosteroids, DMARDs and biphosphonates. The clinical heterogeneity of the disease, possibly due to differences in pathogenic mechanism of different manifestations, is challenging for both diagnosis and treatment, which should aim to control both skin and bone involvement in different clinical subsets. Here, we summarize the current status of knowledge about the SAPHO syndrome and present two cases of patients with very different disease manifestations, suggesting the need for personalized treatment. PMID- 28725948 TI - Genomics and epigenomics in rheumatic diseases: what do they provide in terms of diagnosis and disease management? AB - Most rheumatic diseases are complex or multifactorial entities with pathogeneses that interact with both multiple genetic factors and a high number of diverse environmental factors. Knowledge of the human genome sequence and its diversity among populations has provided a crucial step forward in our understanding of genetic diseases, identifying many genetic loci or genes associated with diverse phenotypes. In general, susceptibility to autoimmunity is associated with multiple risk factors, but the mechanism of the environmental component influence is poorly understood. Studies in twins have demonstrated that genetics do not explain the totality of the pathogenesis of rheumatic diseases. One method of modulating gene expression through environmental effects is via epigenetic modifications. These techniques open a new field for identifying useful new biomarkers and therapeutic targets. In this context, the development of "-omics" techniques is an opportunity to progress in our knowledge of complex diseases, impacting the discovery of new potential biomarkers suitable for their introduction into clinical practice. In this review, we focus on the recent advances in the fields of genomics and epigenomics in rheumatic diseases and their potential to be useful for the diagnosis, follow-up, and treatment of these diseases. The ultimate aim of genomic studies in any human disease is to understand its pathogenesis, thereby enabling the prediction of the evolution of the disease to establish new treatments and address the development of personalized therapies. PMID- 28725949 TI - Tubulointerstitial nephritis-induced hypophosphatemic osteomalacia in Sjogren's syndrome: a case report and review of the literature. AB - Sjogren's syndrome (SS) is a chronic autoimmune inflammatory disease that typically affects the salivary and lacrimal glands. Renal involvement is relatively uncommon and may precede other complaints. Tubulointestitial nephritis (TIN) is the most common renal involvement in SS. Osteomalacia occurring as the first manifestation of renal tubular disorder due to SS is very rare. We report a 39-year-old male who presented with polydipsia, polyuria, and multiple bone pain. Bone density test showed severe osteoporosis, and laboratory findings suggested hypokalemia, hypophosphatemia, and vitamin D deficiency, which supported the diagnosis of hypophosphatemic osteomalacia. He had nephrogenic loss of phosphate and potassium, tubular acidification, and concentration dysfunction. And, the diagnosis of chronic TIN was subsequently confirmed by renal biopsy. The patient reported dry mouth and physical examination showed multiple dental caries. Xerophthalmia, abnormal morphology, and function of the salivary glands by sonography and scintigraphy, together with positive anti-SSA and anti-SSB, confirmed the diagnosis of SS. The TIN indicated SS as the underlying cause of osteomalacia. After taking supplements of potassium, phosphate, vitamin D, and sodium bicarbonate for 1 month, bone pain was alleviated and serological potassium and phosphorus were also back to normal. In conclusion, renal involvement in SS may be latent and precede the typical sicca symptoms. Osteomalacia can be the first manifestation of renal disorder due to SS. Therefore, autoantibody investigations as well as the lacrimal and salivary gland examinations for SS should be considered and performed for suspected patients. PMID- 28725950 TI - Genome editing and assisted reproduction: curing embryos, society or prospective parents? AB - This paper explores the ethics of introducing genome-editing technologies as a new reproductive option. In particular, it focuses on whether genome editing can be considered a morally valuable alternative to preimplantation genetic diagnosis (PGD). Two arguments against the use of genome editing in reproduction are analysed, namely safety concerns and germline modification. These arguments are then contrasted with arguments in favour of genome editing, in particular with the argument of the child's welfare and the argument of parental reproductive autonomy. In addition to these two arguments, genome editing could be considered as a worthy alternative to PGD as it may not be subjected to some of the moral critiques moved against this technology. Even if these arguments offer sound reasons in favour of introducing genome editing as a new reproductive option, I conclude that these benefits should be balanced against other considerations. More specifically, I maintain that concerns regarding the equality of access to assisted reproduction and the allocation of scarce resources should be addressed prior to the adoption of genome editing as a new reproductive option. PMID- 28725951 TI - New aspects of the vulnerability stress model in general, its relevance in schizophrenic psychoses and the place of antipsychotics. PMID- 28725952 TI - Spirituality, Distress and Posttraumatic Growth in Breast Cancer Patients. AB - Breast cancer is the most common type of cancer for women and is associated with increased distress. Spirituality and posttraumatic growth (PTG) have been associated with illness adjustment, but the relationship between these variables is still not well understood. A sample of 100 breast cancer patients completed a demographic and clinical questionnaire, the Posttraumatic Growth Inventory, Spiritual and Religious Attitudes in Dealing with Illness, and the Hospital Anxiety and Depression Scale. Results showed an association between PTG, spirituality and distress. Women with a longer diagnosis and recurrence showed more distress. Younger age, recurrent cancer and spirituality predicted higher PTG. Patients' spirituality should be part of intervention with breast cancer patients since it seems to be related to greater growth and adjustment to the illness. PMID- 28725953 TI - Prognostic Significance of Low Systolic Blood Pressure at Discharge in Patients with Heart Failure and Preserved Ejection Fraction. AB - INTRODUCTION: Systolic blood pressure (SBP) is emerging as a predictor of outcome in chronic heart failure and low SBP has been shown to be related to higher mortality. AIM: To investigate the relationship between low SBP and long-term outcome in patients with heart failure with preserved ejection fraction (HFpEF). METHODS: We use prospectively collected data and recruited 297 patients with chronic HFpEF to investigate the relationship between low SBP at discharge and long-term outcome. SBP was recorded at discharge and analysed in a Cox regression model. The endpoint of interest was death from any cause. RESULTS: In follow-up period, the mortality rates were 61.4% for SBP <100 mmHg, and the survival rates decreased in SBP <100 mmHg as compared with the other SBP strata by using Kaplan Meier analysis (chi 2 = 22.95, log rank P < 0.001). Compared to SBP 140-159 mmHg (reference category), the unadjusted hazard ratios for mortality were 3.29 (95% CI 1.45-7.47, P = 0.004) for SBP <100 mmHg. On multivariate analysis, adjustment for all variables, there still was an inverse relation between SBP and all cause mortality with a threshold at 100 mmHg (P = 0.002) and the adjusted hazard ratios were 3.16 (95% CI 1.15-8.68, P = 0.026) for SBP <100 mmHg. CONCLUSIONS: SBP at discharge is an independent predictor of long-term outcome and affects all-cause mortality, and SBP <100 mmHg at discharge is associated with excess long-term mortality in HFpEF. PMID- 28725954 TI - Proteasome Stress Triggers Death of SH-SY5Y and T98G Cells via Different Cellular Mechanisms. AB - Overload or dysfunction of ubiquitin-proteasome system (UPS) is implicated in mechanisms of neurodegeneration associated with neurodegenerative diseases, e.g. Parkinson and Alzheimer disease, and ischemia-reperfusion injury. The aim of this study was to investigate the possible association between viability of neuroblastoma SH-SY5Y and glioblastoma T98G cells treated with bortezomib, inhibitor of 26S proteasome, and accumulation of ubiquitin-conjugated proteins with respect to direct cytotoxicity of aggregates of ubiquitin-conjugated proteins. Bortezomib-induced death of SH-SY5Y cells was documented after 24 h of treatment while death of T98G cells was delayed up to 48 h. Already after 4 h of treatment of both SH-SY5Y and T98G cells with bortezomib, increased levels of both ubiquitin-conjugated proteins with molecular mass more than 150 kDa and Hsp70 were observed whereas Hsp90 was elevated in T98G cells and decreased in SH SY5Y cells. With respect to the cell death mechanism, we have documented bortezomib-induced activation of caspase 3 in SH-SY5Y cells that was probably a result of increased expression of pro-apoptotic proteins, PUMA and Noxa. In T98G cells, bortezomib-induced expression of caspase 4, documented after 24 h of treatment, with further activation of caspase 3, observed after 48 h of treatment. The delay in activation of caspase 3 correlated well with the delay of death of T98G cells. Our results do not support the possibility about direct cytotoxicity of aggregates of ubiquitin-conjugated proteins. They are more consistent with a view that proteasome inhibition is associated with both transcription-dependent and -independent changes in expression of pro-apoptotic proteins and consequent cell death initiation associated with caspase 3 activation. PMID- 28725955 TI - Biologics in juvenile idiopathic arthritis: a narrative review. AB - : In the past years, pediatric rheumatology has seen a revolution in the treatments for rheumatic diseases, particularly juvenile idiopathic arthritis. Even if nonsteroidal anti-inflammatory drugs (NSAID), intra-articular corticosteroids (IAC) injections, and methotrexate remain the mainstay of the treatment for JIA patients, in aggressive disease, these treatments may be not sufficient to reach disease remission and to prevent long-term disability. Comprehension of immunological mechanisms involved in the pathogenesis of the diseases allowed to conceive new drugs targeting specific steps of the immune response. Several cytokines, like TNF alpha and IL-1, represent a very interesting target for biologic therapies. Due to the efficacy of these therapies, nowadays, "disease remission" in pediatric rheumatology is more and more frequent, especially in juvenile idiopathic arthritis patients, and the long term outcomes have been significantly improved. Crucial to these advancements have been multicenter controlled clinical trials and long-term safety monitoring. CONCLUSIONS: Research in pediatric rheumatology has resulted in dramatic advances in diseases management. Biologic treatments have improved physical and functional outcomes and quality of life of patients with rheumatic disease. What is Known: * NSAID, intra-articular injection of corticoids, and methotrexate are the mainstay in treatment of JIA. * In aggressive JIA, these treatments may be not sufficient to reach disease remission and to prevent long term disability. What is New: * In recent years, management of JIA has significantly improved with the development of biologic therapies that allowed children with arthritis to reach a normal growth and to achieve a good long-term functional outcome. PMID- 28725956 TI - Non-Suicidal Self-Injury in Pediatric Bipolar Disorder: Clinical Correlates and Impact on Psychosocial Treatment Outcomes. AB - Non-suicidal self-injury (NSSI) in childhood is not well documented, especially among youth with pediatric bipolar disorder (PBD). The current study evaluated prevalence and correlates of NSSI, and its impact on intervention response, in a randomized trial of Child- and Family-Focused Cognitive-Behavioral Therapy (CFF CBT) versus Treatment As Usual (TAU), adjunctive to pharmacotherapy. This study included 72 children ages 7-13 (58% male) with PBD. NSSI and correlates were assessed at baseline; mood and psychiatric severity were measured longitudinally. NSSI was common: 31% endorsed NSSI behaviors; 10% reported thoughts of NSSI, in the absence of behaviors. Children engaging in NSSI reported higher depression, psychosis, suicidality, and hopelessness; lower self-esteem; and reduced family help-seeking in univariate analyses. In a multivariate logistic regression, high child depression and psychosis, and low family help-seeking, remained significantly associated with baseline NSSI. In mixed-effects regression models, presence of NSSI at baseline did not influence the response of depressive symptoms to treatment. Children who endorsed NSSI experienced steeper response trajectories for psychiatric severity, regardless of treatment group. Youth who denied NSSI showed poorer response to TAU for manic symptoms; mania trajectories in CFF-CBT were similar across youth. Thus, NSSI in PBD is common and associated with impairment. As children might engage in NSSI for different reasons, the function of NSSI should be considered in treatment. Since children without NSSI fared worse in TAU, it may be important to ensure that youth with PBD receive structured, intensive interventions. CFF-CBT was efficacious regardless of NSSI, and thus shows promise for high-risk children with PBD. PMID- 28725957 TI - Not the Last Word: Viscosupplementation, Opioid Overuse, and the Excesses of Empathy. PMID- 28725958 TI - Immune Surveillance Plays a Role in Locally Aggressive Giant Cell Lesions of Bone. AB - BACKGROUND: Giant cell lesions are locally aggressive intraosseous neoplasms with capacity to metastasize. The role of immune surveillance in the pathophysiology of giant cell lesions is poorly understood, and understanding what role the immune system plays in giant cell lesions may lead to the development of more effective treatment. The aim of this study was to explore the role of immune surveillance in giant cell lesions by examining the expression of the HLA class I and class II antigens and tumor infiltrating lymphocytes. In addition, we examined the role of the immune modulating surface antigen B7-H3, which belongs to the B7 superfamily, a group of molecules that modulates T-cell responses. QUESTIONS/PURPOSES: (1) Is an immune response elicited by giant cell lesions? (2) Do clinically relevant human leukocyte antigen (HLA) defects exist in giant cell lesions? (3) Is B7-H3 a clinically relevant immune modulator? METHODS: The study sample was derived from the population of patients presenting to the Massachusetts General Hospital for evaluation and management of giant cell lesions from 1993 to 2008. We included patients with histologically confirmed giant cell lesions with a minimum followup of 6 months. Patients with systemic diseases (n = 4 [3%]), syndromes associated with giant cell lesions (n = 4 [3%]), and those without sufficient followup (n = 26 [19%]), inadequate records (n = 7 [5%]), or inadequate tissue available (n = 2 [1%]) were excluded. Tissue microarray, containing 288 tissue cores for 93 patients, was carefully constructed. This contained tissue from 45 patients with maxillofacial lesions, 38 with aggressive and seven with nonaggressive lesions, and 48 patients with axial and appendicular lesions, 30 with aggressive lesions and 18 with nonaggressive lesions. The population mean age was 28 +/- 12 years and the duration of followup was 4 +/- 3 years. The tissue microarray was immunohistochemically stained with monoclonal antibodies specific for HLA classes I and II and B7-H3 antigens and analyzed for tumor infiltrating lymphocytes. Antigen expression was examined in multinucleated giant cells and mononuclear stromal cells. The results were correlated with local invasion and tumor aggressiveness, which is based on accepted staging criteria. RESULTS: Tumor infiltrating lymphocytes were detected in all the tumors. The mean number of CD8+ T cell infiltration was lower in aggressive tumors (median, 4.8; interquartile range [IQR], 0.4-13.4), when compared with nonaggressive tumors (median, 15.8; IQR, 4.3-46.3; p = 0.007). HLA class I antigens were highly expressed by multinucleated giant cells in all tumors, but were lightly expressed on mononuclear stromal cells in 53% (45 of 84) to 73% (56 of 77) of tumors. HLA class I antigen low expression in mononuclear stromal cells was associated with tumor aggressiveness (odds ratio [OR], 4.3; p = 0.005). Low HLA class I expression combined with low CD8+ T cell infiltration was most highly associated with tumor aggressiveness (OR, 7.81; p = 0.011). B7-H3 antigen was expressed in 36.9% mononuclear stroma cells and also was associated with local tumor invasion (OR, 1.36; p < 0.001). Similarly, giant cell lesions with high B7-H3 expression and low CD8+ tumor infiltrating lymphocytes were associated with increased tumor aggressiveness (OR, 8.89; p = 0.0491). CONCLUSIONS: Locally aggressive giant cell lesions are associated with low HLA class 1 antigen expression, low CD8+T cell infiltration, and high expression of the immune modulator B7-H3. CLINICAL RELEVANCE: Failure of immune surveillance implies that there may be an opportunity to target aspects of the immune surveillance machinery to treat giant cell lesions. PMID- 28725959 TI - Linked color imaging improves the visibility of various featured colorectal polyps in an endoscopist's visibility and color difference value. AB - PURPOSE: Linked color imaging (LCI) by laser endoscopy is a novel narrow band light observation. In this study, we analyzed the efficacy of LCI for improving the various featured colorectal polyp's visibility utilizing a subjective endoscopist's visibility scoring and objective color difference (CD) value. METHODS: We retrospectively reviewed two pictures both with white light (WL) and LCI for 54 consecutive neoplastic polyps 2-20 mm in size. All pictures were evaluated by four endoscopists according to a published polyp visibility score from four (excellent visibility) to one (poor visibility). Additionally, we calculated CD value between each polyp and surrounding mucosa in LCI and WL using an original software. RESULTS: The mean polyp visibility scores of LCI (3.11 +/- 1.05) were significantly higher than those of WL (2.50 +/- 1.09, P < 0.001). The ratio of an endoscopist's poor visibility (polyp visibility scores 1 and 2) was significantly lower in LCI (27.9%) than WL (55.6%, P < 0.001). With respect to the CD analysis, the CD value of LCI was significantly higher than that of WL (33.3 +/- 13.9 vs. 20.7 +/- 13.6, P < 0.001). In a subgroup analysis, the polyp visibility scores and CD values of LCI about 24 diminutive polyps (<=5 mm) were higher than those of WL (3.29 +/- 0.99 vs. 2.12 +/- 0.99, P < 0.001; 31.6 +/- 12.8 vs. 14.7 +/- 7.6, P < 0.001). Additionally, the polyp visibility scores and CD values of LCI for polyps with any location, size, histology, and morphology were significantly higher than those of WL. CONCLUSIONS: LCI improved the various featured polyp's visibility compared to WL in both polyp visibility scores and CD value. PMID- 28725960 TI - Topic infliximab injection for refractory rectal stenosis in Crohn's disease: long-term follow-up in two patients. AB - PURPOSE: TNF blockers are approved for intravenous or subcutaneous systemic therapy of many chronic inflammatory diseases. As it is not possible to achieve a sufficient local clinical improvement through systemic therapy in every patient, diverse approaches of topical therapy using TNF blockers have been investigated in recent years. METHODS: In this paper, we report on long-term clinical results of originator infliximab (IFX) injections into symptomatic combined scarring and inflammatory stenoses of the rectum in two patients with Crohn's disease. Aiming at high tissue IFX levels, 25 mg of IFX was injected into each quadrant of the stenosis after endoscopic balloon dilatation. This off-label treatment was repeated as necessary, depending on the clinical success. RESULTS: Topic IFX injection after balloon dilation reduced imperative stool pressure, isolated episodes of incontinence and incomplete emptying. Improvement lasted between 4 and 14 weeks in one patient and the treatment was repeated 13 times in the following 6.6 years. In the other patient, the technique was necessary only twice with no symptom recurrence in the subsequent 5.3 years. CONCLUSION: Our experience suggests that topic application of a systemically approved anti-TNF substance may be a successful individualized therapy for refractory stenosis of the rectum in patients with Crohn's disease. PMID- 28725962 TI - Optimal Positioning of the Nipple-Areola Complex in Men Using the Mohrenheim Estimated-Tangential-Tracking-Line (METT-Line): An Intuitive Approach. AB - INTRODUCTION: The reconstruction of the body shape after post-bariatric surgery or high-grade gynecomastia involves, besides skin tightening, the repositioning of anatomical, apparent landmarks. The surgeon usually defines these during the preoperative planning. In particular, the positions of the nipple-areola complexes (NAC) should contribute to the gender-appropriate appearance. While in the female breast numerous methods have been developed to determine the optimal position of the NACs, there are only a few, metric and often impractical algorithms for positioning the nipples and areoles in the male. With this study, we show the accuracy of the intuitive positioning of the nipple-areola complex in men. MATERIAL AND METHODS: From a pre-examined and measured quantity of 10 young and healthy men, six subjects were selected, which corresponded, on the basis of their chest and trunk dimensions, to the average of known data from the literature. The photographed frontal views were retouched in two steps. Initially, only the NACs were removed and the chest contours were left. In a second step, all contours and the navel were blurred. These pictures were submitted to resident and consultant plastic surgeons, who were asked to draw the missing NACs without any tools. The original positions of the nipples were compared with the inscriptions. Furthermore, the results were compared between the contoured and completely retouched pictures and between the residents and consultants. RESULTS: A total of 8 consultants and 7 residents were included. In the contoured and completely retouched images, a significant deviation of the marked positions of the missing features was found. The height of the NAC was determined somewhat more precisely than the vertical position. There was no significant difference between the contoured and completely retouched images, with a discretely more accurate tendency on the contoured images. In comparison with the professional experience, the consultants were tangentially more precise, but without a statistically significant impact. DISCUSSION: The intuitive determination of the NACs is a challenge for the plastic surgeon. In this study, a statistically significant deviation was seen in almost all dimensions, although the clinical relevance cannot be conclusively assessed. We found a positional relationship of the NAC to the infraclavicular groove ("Mohrenheim pit") in the vertical and 4-4.5 cm above the submammary fold. The position of the NAC can be satisfactorily determined by a combination of plastic surgical intuition, patient wishes and practical metric methods using the Mohrenheim-Estimated-Tangential Tracking-Line (METT-Line). LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 28725961 TI - The plasma membrane proteome of Medicago truncatula roots as modified by arbuscular mycorrhizal symbiosis. AB - In arbuscular mycorrhizal (AM) roots, the plasma membrane (PM) of the host plant is involved in all developmental stages of the symbiotic interaction, from initial recognition to intracellular accommodation of intra-radical hyphae and arbuscules. Although the role of the PM as the agent for cellular morphogenesis and nutrient exchange is especially accentuated in endosymbiosis, very little is known regarding the PM protein composition of mycorrhizal roots. To obtain a global overview at the proteome level of the host PM proteins as modified by symbiosis, we performed a comparative protein profiling of PM fractions from Medicago truncatula roots either inoculated or not with the AM fungus Rhizophagus irregularis. PM proteins were isolated from root microsomes using an optimized discontinuous sucrose gradient; their subsequent analysis by liquid chromatography followed by mass spectrometry (MS) identified 674 proteins. Cross species sequence homology searches combined with MS-based quantification clearly confirmed enrichment in PM-associated proteins and depletion of major microsomal contaminants. Changes in protein amounts between the PM proteomes of mycorrhizal and non-mycorrhizal roots were monitored further by spectral counting. This workflow identified a set of 82 mycorrhiza-responsive proteins that provided insights into the plant PM response to mycorrhizal symbiosis. Among them, the association of one third of the mycorrhiza-responsive proteins with detergent resistant membranes pointed at partitioning to PM microdomains. The PM-associated proteins responsive to mycorrhization also supported host plant control of sugar uptake to limit fungal colonization, and lipid turnover events in the PM fraction of symbiotic roots. Because of the depletion upon symbiosis of proteins mediating the replacement of phospholipids by phosphorus-free lipids in the plasmalemma, we propose a role of phosphate nutrition in the PM composition of mycorrhizal roots. PMID- 28725963 TI - Robot-Assisted Surgery for Mandibular Angle Split Osteotomy Using Augmented Reality: Preliminary Results on Clinical Animal Experiment. AB - : Mandibular angle split osteotomy (MASO) is a procedure widely used for prominent mandibular angles. However, conventional mandibular plastic surgery is invasive and high risk. It may induce postoperative neurosensory disturbance of the inferior alveolar nerve, fractures and infection due to the complexity of the anatomical structure and the narrow surgical field of view. The success rate of MASO surgery usually depends on the clinical experience and skills of the surgeon. To evaluate the performance of inexperienced plastic surgeons conducting this surgery, a self-developed and constructed robot system based on augmented reality is used. This robot system provides for sufficient accuracy and safety within the clinical environment. To evaluate the accuracy and safety of MASO surgery, an animal study using this robot was performed in the clinical room, and the results were then evaluated. Four osteotomy planes were successfully performed on two dogs; that is, twenty tunnels (each dog drilled on bilaterally) were drilled in the dogs' mandible bones. Errors at entrance and target points were 1.04 +/- 0.19 and 1.22 +/- 0.24 mm, respectively. The angular error between the planned and drilled tunnels was 6.69 degrees +/- 1.05 degrees . None of the dogs experienced severe complications. Therefore, this technique can be regarded as a useful approach for training inexperienced plastic surgeons on the various aspects of plastic surgery. NO LEVEL ASSIGNED: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 28725964 TI - Toward early detection of Helicobacter pylori-associated gastric cancer. AB - BACKGROUND: Gastric cancer is typically diagnosed at a late stage, leading to poor prognoses. Helicobacter pylori is responsible for 70% of gastric cancers globally, and patients with this bacterial infection often present with early stages of the carcinogenic pathway such as inflammation or gastritis. Although many patients continue to progress to advanced-stage disease after antibacterial treatment, there are no follow-up screening protocols for patients with a history of H. pylori. METHODS: Several biomarkers (Lgr5, CD133, CD44) become upregulated during gastric carcinogenesis. A logistic regression model is developed using clinical data from 59 patients at different stages of the carcinogenic pathway to identify the likelihood of being at an advanced stage of disease for all combinations of age, sex, and marker positivity. Using these likelihood distributions and the observed rate of marker positivity increase, time to high likelihood (probability >0.8) of advanced disease for individual patients is predicted. RESULTS: A strong correlation between marker positivity and disease stage was found for all three markers. Disease stage was accurately classified by the respective regression models for more than 86% of retrospective patients. Highly patient-specific predictions of time to onset of dysplasia were made, allowing the classification of 17 patients initially diagnosed with intestinal metaplasia into high-, intermediate-, or low-risk categories. CONCLUSIONS: We present an approach designed to integrate pathology, mathematics, and statistics for detection of the earliest precancerous, treatable lesion. Given the simplicity and robustness of the framework, such technique has the potential to guide personalized screening schedules to minimize the risk of undetected malignant transformation. PMID- 28725965 TI - Medulloblastoma: experimental models and reality. AB - Medulloblastoma is the most frequent malignant brain tumor in childhood, but it may also affect infants, adolescents, and young adults. Recent advances in the understanding of the disease have shed light on molecular and clinical heterogeneity, which is now reflected in the updated WHO classification of brain tumors. At the same time, it is well accepted that preclinical research and clinical trials have to be subgroup-specific. Hence, valid models have to be generated specifically for every medulloblastoma subgroup to properly mimic molecular fingerprints, clinical features, and responsiveness to targeted therapies. This review summarizes the availability of experimental medulloblastoma models with a particular focus on how well these models reflect the actual disease subgroup. We further describe technical advantages and disadvantages of the models and finally point out how some models have successfully been used to introduce new drugs and why some medulloblastoma subgroups are extraordinary difficult to model. PMID- 28725966 TI - Childhood white matter disorders: much more than just diseases of myelin. PMID- 28725967 TI - alpha-Synuclein transfer between neurons and astrocytes indicates that astrocytes play a role in degradation rather than in spreading. AB - Recent evidence suggests that disease progression in Parkinson's disease (PD) could occur by the spreading of alpha-synuclein (alpha-syn) aggregates between neurons. Here we studied the role of astrocytes in the intercellular transfer and fate of alpha-syn fibrils, using in vitro and ex vivo models. alpha-Syn fibrils can be transferred to neighboring cells; however, the transfer efficiency changes depending on the cell types. We found that alpha-syn is efficiently transferred from astrocytes to astrocytes and from neurons to astrocytes, but less efficiently from astrocytes to neurons. Interestingly, alpha-syn puncta are mainly found inside the lysosomal compartments of the recipient cells. However, differently from neurons, astrocytes are able to efficiently degrade fibrillar alpha-syn, suggesting an active role for these cells in clearing alpha-syn deposits. Astrocytes co-cultured with organotypic brain slices are able to take up alpha-syn fibrils from the slices. Altogether our data support a role for astrocytes in trapping and clearing alpha-syn pathological deposits in PD. PMID- 28725970 TI - Ion release in ceramic bearings for total hip replacement: Results from an in vitro and an in vivo study. AB - INTRODUCTION: Literature on the potential release of trace elements following implantation of Zirconia-platelet toughened alumina (ZPTA) ceramic components is scant. The present study therefore analysed the in vitro and in vivo potential release of ions from ZPTA bearings. MATERIAL AND METHODS: An in vitro and in vivo study was conducted. The in vitro study compared leaching in bovine serum from two groups: ZPTA ceramic heads and Co-28Cr-6Mo alloy heads, both 28-mm diameter. A third group without implant served as reference group. An in vivo clinical study compared trace elements in the whole blood of patients with 36-mm diameter ZPTA ceramic-on-ceramic articulation after three and 12 months. A cohort of subjects without any prosthesis was used as control group. The release of ions was determined by high resolution-inductively coupled plasma-mass spectrometry. RESULTS: In the in vitro experiment, significant differences (p <= 0.01) in trace element release for chromium, cobalt and molybdenum were found, with increased levels of ion release in the Co-28Cr-6Mo metal group. The very low detection limit for yttrium allowed detection of a small yttrium release from the ZPTA heads, which was not confirmed by the in vivo study. No significant difference between the groups was found for strontium, aluminium, and zirconium. In the in vivo study, no relevant differences in ion levels between the reference group without any implant and the study group were found at the three and 12-month follow-up. CONCLUSION: This study supports that ZPTA ceramic articulation components are safe in terms of ion release, and may be an excellent alternative to bearings based on Co-28Cr-6Mo alloys. PMID- 28725971 TI - Colors. PMID- 28725969 TI - Mastocytosis: from a Molecular Point of View. AB - Mast cells (MCs) are physiologically activated by binding of stem cell factor (SCF) to the extracellular domains of the Kit receptor. This binding increases the proliferation and prolongs the survival of normal mature MCs, as well as intensifies the release of mediators. In mastocytosis, somatic mutations of the coding Kit gene cause autocrine dysregulation and lead to constitutive KIT activation even in the absence of its ligand SCF. Clinical symptoms are caused by MC-mediator release and/or infiltration of MCs into tissues. Aberrant KIT activation may result in increased production of MCs in the skin and extracutaneous organs. Depending on the affected organ(s), the disease can be divided into cutaneous mastocytosis (CM), systemic mastocytosis (SM), and localized MC tumors. The updated classification of WHO discriminates between several distinct subvariants of CM and SM. While the prognosis in CM and indolent SM (ISM) is excellent with (almost) normal life expectancy, the prognosis in aggressive SM (ASM) and MC leukemia (MCL) is dismal. The symptoms may comprise urticaria, angioedema, flush, pruritus, abdominal pain, diarrhea, hypotension, syncope, and musculoskeletal pain and are the results of MC infiltration and mediator release into target organs, i.e., the skin, gastrointestinal tract, liver, spleen, lymph nodes, and bone marrow. Mastocytosis differs from a lot of other hematological disorders because its pathology is not only based on the lack of normal function of a specific pathway or of a specific cell type but additionally is a proliferative disease. Currently available treatments of mastocytosis include symptomatic, antimediator and cytoreductive targeted therapies. PMID- 28725968 TI - Microglial-mediated PDGF-CC activation increases cerebrovascular permeability during ischemic stroke. AB - Treatment of acute ischemic stroke with the thrombolytic tissue plasminogen activator (tPA) can significantly improve neurological outcomes; however, thrombolytic therapy is associated with an increased risk of intra-cerebral hemorrhage (ICH). Previously, we demonstrated that during stroke tPA acting on the parenchymal side of the neurovascular unit (NVU) can increase blood-brain barrier (BBB) permeability and ICH through activation of latent platelet-derived growth factor-CC (PDGF-CC) and signaling by the PDGF receptor-alpha (PDGFRalpha). However, in vitro, activation of PDGF-CC by tPA is very inefficient and the mechanism of PDGF-CC activation in the NVU is not known. Here, we show that the integrin Mac-1, expressed on brain microglia/macrophages (denoted microglia throughout), acts together with the endocytic receptor LRP1 in the NVU to promote tPA-mediated activation of PDGF-CC. Mac-1-deficient mice (Mac-1-/-) are protected from tPA-induced BBB permeability but not from permeability induced by intracerebroventricular injection of active PDGF-CC. Immunofluorescence analysis demonstrates that Mac-1, LRP1, and the PDGFRalpha all localize to the NVU of arterioles, and following middle cerebral artery occlusion (MCAO) Mac-1-/- mice show significantly less PDGFRalpha phosphorylation, BBB permeability, and infarct volume compared to wild-type mice. Bone-marrow transplantation studies indicate that resident CD11b+ cells, but not bone-marrow-derived leukocytes, mediate the early activation of PDGF-CC by tPA after MCAO. Finally, using a model of thrombotic stroke with late thrombolysis, we show that wild-type mice have an increased incidence of spontaneous ICH following thrombolysis with tPA 5 h after MCAO, whereas Mac-1-/- mice are resistant to the development of ICH even with late tPA treatment. Together, these results indicate that Mac-1 and LRP1 act as co-factors for the activation of PDGF-CC by tPA in the NVU, and suggest a novel mechanism for tightly regulating PDGFRalpha signaling in the NVU and controlling BBB permeability. PMID- 28725972 TI - The versatility of N-alkyl-methoxyamine bi-functional linkers for the preparation of glycoconjugates. AB - The application of N-glycosyl-N-alkyl-methoxyamine bi-functional linkers for the synthesis of a variety of glycoconjugates is described. The linker contains a specific functional group, such as an amine, azide, thiol, or carboxylic acid, which can be used for conjugation methodologies that include amide ligation, sulfonylation, copper-mediated Huisgen cycloaddition or thiol-maleimide coupling. In this way, glycoconjugates equipped with biotin, a fluorescent reporter, or a protein were efficiently synthesised, thus demonstrating the versatility of this type of oxyamine linker for the construction of glycoconjugate probes. PMID- 28725973 TI - Erratum to: miRNAs: micro-managers of anticancer combination therapies. PMID- 28725974 TI - Carbofuran causes neuronal vulnerability to glutamate by decreasing GluA2 protein levels in rat primary cortical neurons. AB - Glutamate receptor 2 (GluA2/GluR2) is one of the four subunits of alpha-amino-3 hydroxy-5-methylisoxazole-4-propionic acid receptor (AMPAR); an increase in GluA2 lacking AMPARs contributes to neuronal vulnerability to excitotoxicity because of the receptor's high Ca2+ permeability. Carbofuran is a carbamate pesticide used in agricultural areas to increase crop productivity. Due to its broad-spectrum action, carbofuran has also been used as an insecticide, nematicide, and acaricide. In this study, we investigated the effect of carbofuran on GluA2 protein expression. The 9-day treatment of rat primary cortical neurons with 1 uM and 10 uM carbofuran decreased GluA2 protein expression, but not that of GluA1, GluA3, or GluA4 (i.e., other AMPAR subunits). Decreased GluA2 protein expression was also observed on the cell surface membrane of 10 uM carbofuran-treated neurons, and these neurons showed an increase in 25 uM glutamate-triggered Ca2+ influx. Treatment with 50 uM glutamate, which did not affect the viability of control neurons, significantly decreased the viability of 10 uM carbofuran treated neurons, and this effect was abolished by pre-treatment with 300 uM 1 naphthylacetylspermine, an antagonist of GluA2-lacking AMPAR. At a concentration of 100 uM, but not 1 or 10 uM, carbofuran significantly decreased acetylcholine esterase activity, a well-known target of this chemical. These results suggest that carbofuran decreases GluA2 protein expression and increases neuronal vulnerability to glutamate toxicity at concentrations that do not affect acetylcholine esterase activity. PMID- 28725976 TI - Target-mediated drug disposition model for drugs with two binding sites that bind to a target with one binding site. AB - The paper extended the TMDD model to drugs with two identical binding sites (2-1 TMDD). The quasi-steady-state (2-1 QSS), quasi-equilibrium (2-1 QE), irreversible binding (2-1 IB), and Michaelis-Menten (2-1 MM) approximations of the model were derived. Using simulations, the 2-1 QSS approximation was compared with the full 2-1 TMDD model. As expected and similarly to the standard TMDD for monoclonal antibodies (mAb), 2-1 QSS predictions were nearly identical to 2-1 TMDD predictions, except for times of fast changes following initiation of dosing, when equilibrium has not yet been reached. To illustrate properties of new equations and approximations, several variations of population PK data for mAbs with soluble (slow elimination of the complex) or membrane-bound (fast elimination of the complex) targets were simulated from a full 2-1 TMDD model and fitted to 2-1 TMDD models, to its approximations, and to the standard (1-1) QSS model. For a mAb with a soluble target, it was demonstrated that the 2-1 QSS model provided nearly identical description of the observed (simulated) free drug and total target concentrations, although there was some minor bias in predictions of unobserved free target concentrations. The standard QSS approximation also provided a good description of the observed data, but was not able to distinguish between free drug concentrations (with no target attached and both binding site free) and partially bound drug concentrations (with one of the binding sites occupied by the target). For a mAb with a membrane-bound target, the 2-1 MM approximation adequately described the data. The 2-1 QSS approximation converged 10 times faster than the full 2-1 TMDD, and its run time was comparable with the standard QSS model. PMID- 28725975 TI - Supporting sustainability initiatives through biometeorology education and training. AB - The International Society of Biometeorology (ISB) has covered significant breadth and depth addressing fundamental and applied societal and environmental challenges in the last 60 years. Biometeorology is an interdisciplinary science connecting living organisms to their environment, but there is very little understanding of the existence and placement of this discipline within formal educational systems and institutions. It is thus difficult to project the ability of members of the biometeorological community-especially the biometeorologists of the future-to help solve global challenges. In this paper, we ask: At present, how we are training people to understand and think about biometeorology? We also ask: What are the current tools and opportunities in which biometeorologists might address future challenges? Finally, we connect these two questions by asking: What type of new training and skill development is needed to better educate "biometeorologists of the future" to more effectively address the future challenges? To answer these questions, we provide quantitative and qualitative evidence from an educationally focused workshop attended by new professionals in biometeorology. We identify four common themes (thermal comfort and exposures, agricultural productivity, air quality, and urbanization) that biometeorologists are currently studying and that we expect to be important in the future based on their alignment with the United Nations Sustainable Development Goals. Review of recent literature within each of these thematic areas highlights a wide array of skill sets and perspectives that biometeorologists are already using. Current and new professionals within the ISB have noted highly varying and largely improvised educational pathways into the field. While variability and improvisation may be assets in promoting flexibility, adaptation, and interdisciplinarity, the lack of formal training in biometeorology raises concerns about the extent to which continuing generations of scholars will identify and engage with the community of scholarship that the ISB has developed over its 60-year history. PMID- 28725977 TI - The effect of vitamin D and calcium supplementation in pediatric steroid sensitive nephrotic syndrome. AB - BACKGROUND: Low serum levels of total 25-hydroxycholecalciferol (25(OH)D) occur in nephrotic syndrome (NS). We aimed to assess the effects of vitamin D3 and calcium supplementation on 25(OH)D levels, bone mineralization, and NS relapse rate in children with steroid-sensitive NS. METHODS: A randomized controlled trial (RCT) was performed in children with steroid-sensitive NS. The treatment group received vitamin D3 (60,000 IU orally, weekly for 4 weeks) and calcium supplements (500 to 1,000 mg/day for 3 months) after achieving NS remission. Blood samples for bone biochemistry were taken during relapse (T0), after 6 weeks (T1) and 6 months (T2) of randomization, whereas a lumbar DXA scan was performed at T0 and T2. Renal ultrasound was performed after study completion in the treatment group and in all patients with hypercalciuria. RESULTS: Of the 48 initial recruits, 43 patients completed the study. Post-intervention, 25(OH)D levels showed significant improvements in the treatment group compared with controls at T1 (p < 0.001) and T2 (p < 0.001). However, this was not associated with differences in bone mineral content (BMC) (p = 0.44) or bone mineral density (BMD) (p = 0.64) between the groups. Additionally, there was no reduction in relapse number in treated patients (p = 0.54). Documented hypercalciuria occurred in 52% of patients in the treatment group, but was not associated with nephrocalcinosis. CONCLUSIONS: Although supplementation with calcium and vitamin D improved 25(OH)D levels significantly, there was no effect on BMC, BMD or relapse rate over a 6-month follow-up. Occurrence of hypercalciuria mandates caution and appropriate monitoring if using such therapy. Appropriate dosage of vitamin D3 remains uncertain and studies examining biologically active vitamin D may provide answers. PMID- 28725978 TI - Strategies and methods for the detection and identification of viral vectors. AB - The production and application of viral vectors are frequently performed genetic engineering operations. HIV-1-based lentiviral vectors, AAV2-based, and adenoviral vectors are amongst the most abundant viral vectors utilized for gene delivery. They are generally classified into risk group 1 or 2 (according to EU directive 2000/54/EC on the protection of workers from risks related to exposure to biological agents at work). PMID- 28725979 TI - Effect of Weight Loss after Bariatric Surgery on Thyroid-Stimulating Hormone Levels in Patients with Morbid Obesity and Normal Thyroid Function. AB - BACKGROUND: Several studies have reported that morbid obesity is associated with increased thyroid-stimulating hormone (TSH) levels. However, it is not clear what is the impact of bariatric surgery on postoperative thyroid function. The aim of this study was to evaluate the effect of weight loss after bariatric surgery on TSH levels in euthyroid patients with morbid obesity. METHODS: We performed a retrospective observational study of 949 euthyroid patients (86.1% female; age 42.0 +/- 10.3 years, BMI 44.3 +/- 5.7 kg/m2) with morbid obesity submitted to bariatric surgery (laparoscopic adjustable gastric band, Roux-en-Y gastric bypass, or sleeve gastrectomy). Patients were subdivided in two groups: normal TSH group (TSH <2.5 mU/L) and high-normal TSH group (TSH >=2.5 mU/L). The impact of anthropometric parameters, comorbidities, TSH, free thyroxine (FT4), free triiodothyronine (FT3), type of surgery, and excessive body weight loss (EBWL) on TSH variation 12 months after surgery was evaluated. RESULTS: The high-normal TSH group (24.3% of patients) included more women, presented a higher BMI, higher systolic blood pressure, and higher FT3 levels. There was a significant decrease of TSH 12 months after surgery that was more marked in the high-normal TSH group (normal TSH group: 1.57 +/- 0.49 to 1.53 +/- 0.69 mIU/L, p = 0.063; high-normal TSH group: 3.23 +/- 0.59 to 2.38 +/- 0.86 mIU/L, p < 0.001). In a multivariate analysis, after adjusting for relevant covariates, EBWL, baseline BMI, and baseline FT3 were significantly associated with TSH decrease 12 months after bariatric surgery. CONCLUSION: Bariatric surgery promotes a decrease of TSH that is significantly greater in patients with high-normal TSH and is independently associated with EBWL after surgery. PMID- 28725980 TI - Prenatal diagnosis of premature constriction of the ductus arteriosus with tricuspid papillary muscle rupture: a case report. AB - We describe the case of a neonate who was prenatally diagnosed at a gestational age of 36 weeks with premature constriction of the ductus arteriosus. Blood from the thin ductus arteriosus flowed toward the pulmonary artery. Severe tricuspid regurgitation was also observed. We subsequently confirmed rupture of the tricuspid papillary muscle after birth. Cardiotonic drugs and nitric oxide were administered immediately at birth for pulmonary hypertension, and this therapy was continued until the seventh postnatal day. Emergency tricuspid valve repair was unnecessary, because there were no signs of severe circulatory insufficiency. This case suggests a relationship between prenatally diagnosed premature constriction of the ductus arteriosus and tricuspid papillary muscle rupture in neonates. PMID- 28725981 TI - Certolizumab pegol was effective for treating residual synovitis after total knee arthroplasty in a patient with rheumatoid arthritis: therapeutic monitoring by ultrasound. AB - We present the case of a 59-year-old female who developed rheumatoid arthritis in 2007. Right total knee arthroplasty (TKA) was performed in 2008. Although she was treated with methotrexate (MTX) after the operation, this treatment was insufficient. Infliximab (IFX) was introduced in 2001, and she achieved clinical remission. Left TKA was performed in October 2014. Because active synovitis was not detected by ultrasound after the operation, IFX was discontinued. She had been treated with MTX 8 mg weekly. However, arthralgia of the bilateral knees developed in March 2015. Ultrasound showed synovial hypertrophy with vascular signals representing postoperative residual synovitis. She was given certolizumab pegol. According to ultrasound, the synovitis had improved after 3 months. PMID- 28725982 TI - Analysis of risk factors influencing the outcome of the Epley maneuver. AB - Benign paroxysmal positional vertigo (BPPV) is the most frequent type of vertigo. The treatment of canalithiasis of the posterior semicircular canal consists in performing a particle-repositioning maneuver, such as the Epley maneuver (EM). However, the EM is not effective in all cases. The objective of this study is to identify risk factors, which predict the EM failure, among the clinical variables recorded in anamnesis and patient examination. This is an observational prospective multicentric study. All patients presenting with BPPV were recruited and applied the EM and appointed for a follow-up visit 7 days later. The following variables were recorded: sex, age, arterial hypertension, diabetes, hyperlipidemia, smoking habit, alcohol consumption, migraine, osteoporosis, diseases of the inner ear, previous ipsilateral BPPV, previous traumatic brain injury, previous sudden head deceleration, time of evolution, sulpiride or betahistine treatment, experienced symptoms, outcome of the Halmagyi maneuver, laterality, cephalic hyperextension of the neck, intensity of nystagmus, intensity of vertigo, duration of nystagmus, occurrence of orthotropic nystagmus, symptoms immediately after the EM, postural restrictions, and symptoms 7 days after the EM. Significant differences in the rate of loss of nystagmus were found for six variables: hyperlipidemia, previous ipsilateral BPPV, intensity of nystagmus, duration of nystagmus, post-maneuver sweating, and subjective status. The most useful significant variables in the clinical practice to predict the success of the EM are previous BPPV and intensity of nystagmus. In the other significant variables, no physiopathological hypothesis can be formulated or differences between groups are too small. PMID- 28725983 TI - Dabigatran and vitamin K antagonists' use in naive patients with non-valvular atrial fibrillation: a cross-sectional study of primary care-based electronic health records. AB - PURPOSE: The purpose of this study was to characterize the profile of patients with non-valvular atrial fibrillation who start an anticoagulant treatment after diagnosis with dabigatran and compare it with those who start with vitamin K antagonists (VKAs). METHODS: We analysed primary health care-based electronic health records data from 15,075 people with new diagnosis of atrial fibrillation who initiated treatment with dabigatran or VKA spanning 2011-2013. Logistic regression analysis for determination of factors associated with initiation of dabigatran was performed. RESULTS: We identified 14,266 (94.6%) people who initiated VKA and 809 (5.4%) who initiated dabigatran. Mean age of people treated with dabigatran was lower than in VKA patients (73.7 vs 75.5 years, p < 0.001). People (90.5%) in VKA group and 83.6% in the dabigatran group had a high risk of stroke, according to CHA2DS2VASc score. There was higher proportion of people with hypertension, diabetes mellitus, dyslipidaemia, and chronic kidney disease among people treated with VKA. The proportion of people with a history of cerebral haemorrhage and stroke was higher among dabigatran patients compared with VKA patients (1.4 vs 0.6%, p = 0.015 and 14.0% vs 10.8%, p = 0.006, respectively). Multivariable logistic model showed that treatment with dabigatran was associated with male sex, history of stroke and Mortalidad en areas pequenas Espanolas y Desigualdades Socioeconomicas index. CONCLUSIONS: Most patients recently diagnosed with non-valvular atrial fibrillation initiated treatment with VKA. Primary healthcare patients with non-valvular atrial fibrillation initiating dabigatran are younger, had a lower risk of stroke or bleeding, fewer comorbidity and more history of stroke and intracranial haemorrhage compared to those who were initiated on VKA. PMID- 28725984 TI - Cytokine expression and barrier disruption in human corneal epithelial cells induced by alarmin released from necrotic cells. AB - PURPOSE: Dying cells release endogenous molecules known as alarmins that signal danger to surrounding tissue. We investigated the effects of necrotic cell derived alarmins on cytokine expression and barrier function in human corneal epithelial cells. METHODS: The release of interleukin (IL)-6 and IL-8 from immortalized human corneal epithelial (HCE) cells in culture was measured with enzyme-linked immunosorbent assays. The abundance of IL-6 and 8 mRNAs was quantitated by reverse transcription and real-time polymerase chain reaction analysis. Barrier function of HCE cells was evaluated by measurement of transepithelial electrical resistance (TER). The subcellular localization of the p65 subunit of the transcription factor NF-kappaB was determined by immunofluorescence analysis, and phosphorylation of the endogenous NF-kappaB inhibitor IkappaBalpha was examined by immunoblot analysis. RESULTS: A necrotic cell supernatant prepared from HCE cells induced the up-regulation of IL-6 and 8 expression at both mRNA and protein levels as well as reduced TER in intact HCE cells. Among alarmins tested, only IL-1alpha (not IL-33 or HMGB1) mimicked these effects of the necrotic cell supernatant. Furthermore, IL-1 receptor antagonist (IL-1RA) and neutralizing antibodies to IL-1alpha (but not those to IL-1beta) each attenuated the effects of the necrotic cell supernatant. Exposure of HCE cells to the necrotic cell supernatant also induced the phosphorylation and degradation of IkappaBalpha as well as translocation of the p65 subunit of NF kappaB to the nucleus. CONCLUSION: IL-1alpha released from necrotic corneal epithelial cells may trigger inflammatory responses at the ocular surface, including cytokine production and barrier disruption. PMID- 28725985 TI - Diversity in fall characteristics hampers effective prevention: the precipitants, the environment, the fall and the injury. AB - : Falls among the elderly are common and characteristics may differ between injurious and non-injurious falls. Among 887 older Australian women followed for 1.6 years, 32% fell annually. Only 8.5% resulted in fracture and/or hospital admission. The characteristics of those falls are indistinguishable from those not coming to medical attention. INTRODUCTION: The precipitants and environment of all falls occurring among a large cohort of older Caucasian women were categorised by injury status to determine if the characteristics differed between injurious and non-injurious falls. METHODS: Among 887 Australian women (70+ years), falls were ascertained using monthly postcard calendars and a questionnaire was administered for each fall. Hospital admissions and fractures were independently confirmed. RESULTS: All falls were reported for a mean observation time of 577 (IQR 546-607) days per participant, equating to a total 1400 person-years. Thirty-two percent fell at least once per year. The most common features of a fall were that the faller was walking (61%) at home (61%) during the day (88%) and lost balance (32%). Only 12% of all falls occurred at night. Despite no difference in the type of injury between day and night, the likelihood of being hospitalised from a fall at night was 4.5 times greater than that of a daytime fall with adjustment for injury type and participant age (OR 4.5, 95% CI 2.1, 9.5; p < 0.001). Of all falls, approximately one third were associated with no injury to the faller (31%), one third reported a single injury (37%) and one third reported more than one injury (32%). In 95% of falls, the faller was not admitted to hospital. Only 5% of falls resulted in fracture(s). CONCLUSIONS: Our findings demonstrate the significant diversity of precipitants and environment where falls commonly occur among older community-dwelling women. Falls resulting in fracture and/or hospital admission collectively represent 8.5% of all falls and their characteristics are indistinguishable from falls not coming to medical attention and incurring no apparent cost to the health system. PMID- 28725986 TI - Patterns of alcohol consumption and risk of falls in older adults: a prospective cohort study. AB - : Falls are a major health problem in older adults, but their relationship with alcohol consumption in this population remains unclear. In a cohort with 2170 older adults followed up for 3.3 years, both moderate drinking and the Mediterranean drinking pattern were associated with a lower risk of falls and injurious falls. INTRODUCTION: This study aims to examine the association between certain patterns of alcohol consumption, including the Mediterranean drinking pattern (MDP), and the risk of falls in older adults. METHODS: A prospective cohort with 2170 community-dwelling individuals aged >=60 years was recruited in Spain in 2008-2010 and followed up through 2012. At baseline, participants reported alcohol consumption and, at the end of follow-up, their falls during the previous year. The MDP was defined as moderate alcohol consumption (threshold between moderate and heavy intake was 40 g/day for men and 24 g/day for women) with preference for wine and drinking only with meals. Analyses were conducted with negative binomial or logistic regression, as appropriate, and adjusted for the main confounders. RESULTS: Compared with never drinkers, the number of falls was lower in moderate drinkers (incidence rate ratio (95% confidence interval), 0.79 (0.63-0.99)) and drinkers with MDP (0.73 (0.56-0.96)). Also, moderate drinkers and those with MDP showed a lower risk of >=2 falls (odds ratio (95% confidence interval), 0.58 (0.38-0.88) and 0.56 (0.34-0.93), respectively) and of falls requiring medical care (0.67 (0.46-0.96) and 0.61 (0.39-0.96), respectively). CONCLUSION: Both moderate drinking and the MDP were associated with a lower risk of falls and injurious falls in older adults. However, sound advice on alcohol consumption should balance risks and benefits. PMID- 28725987 TI - Gene mutation spectrum and genotype-phenotype correlation in a cohort of Chinese osteogenesis imperfecta patients revealed by targeted next generation sequencing. AB - : The achievement of more accurate diagnosis would greatly benefit the management of patients with osteogenesis imperfecta (OI). In this study, we present the largest OI sample in China as screened by next generation sequencing. In particular, we successfully identified 81 variants, which included 45 novel variants. We further did a genotype-phenotype analysis, which helps make a better understanding of OI. INTRODUCTION: This study aims to reveal the gene mutation spectrum and the genotype-phenotype relationship among Chinese OI patients by next generation sequencing (NGS). METHODS: We developed a NGS-based panel for targeted sequencing of all exons of 14 genes related to OI, and performed diagnostic gene sequencing for a cohort of 103 Chinese OI patients from 101 unrelated families. Mutations identified by NGS were further confirmed by Sanger sequencing and co-segregation analysis. RESULTS: Of the 103 patients from 101 unrelated OI families, we identified 79 mutations, including 43 novel mutations (11 frameshift, 17 missense, 5 nonsense, 9 splice site, and 1 chromosome translocation) in 90 patients (87.4%). Mutations in genes encoding type I collagen, COL1A1 (n = 37), and COL1A2 (n = 29) accounts for 73.3% of all molecularly diagnosed patients, followed by IFITM5 (n = 9, 10%), SERPINF1 (n = 4, 4.4%), WNT1 (n = 4, 4.4%), FKBP10 (n = 3, 3.3%), TMEM38B (n = 3, 3.3%), and PLOD2 (n = 1, 1.1%). This corresponds to 75 autosomal dominant inherited (AD) OI patients and 15 autosomal recessive (AR) inherited patients. Compared with AD inherited OI patients, AR inherited patients had lower bone mineral density (BMD) at spine (P = 0.05) and less frequent blue sclera (P = 0.001). Patients with type I collagen qualitative defects had lower femoral neck BMD Z-score (P = 0.034) and were shorter compared with patients with type I collagen quantitative defects (P = 0.022). CONCLUSION: We revealed the gene mutation spectrum in Chinese OI patients, and novel mutations identified here expanded the mutation catalog and genotype and phenotype relationships among OI patients. PMID- 28725988 TI - Interim 18F-FGD PET/CT may not predict the outcome in primary central nervous system lymphoma patients treated with sequential treatment with methotrexate and cytarabine. AB - 18F-fluoro-2-dexoy-D-glucose-positron emission tomography (PET)/computed tomography (CT) is a useful imaging technique for monitoring the treatment response in lymphoma cases. We investigated the value of interim brain PET/CT (I PET/CT) for monitoring the response to intensive methotrexate-based chemotherapy in primary central nervous system lymphoma (PCNSL) patients with diffuse large B cell lymphoma (DLBCL). Of the 76 PCNSL patients treated with intensive methotrexate and cytarabine chemotherapy between September 2006 and December 2012, 66 patients with DLBCL were included in this study. The patient cohort of 66 individuals comprised 43 men and 23 women with a median age of 59 years (range, 17-75 years). During chemotherapy, 36 patients (54.5%) showed a negative metabolism on I-PET/CT, and 47 (71.2%) were negative on final (F) PET/CT. The baseline characteristics were similar between I-PET/CT-negative (n = 36) and I PET/CT-positive patients (n = 30) except ECOG performance status. After a median follow-up of 27.5 months, there was no difference in the progression-free survival (PFS; P = 0.701) or overall survival (OS; P = 0.620) between the I PET/CT-negative and I-PET/CT-positive groups. However, PFS in the F-PET/CT negative group was significantly longer than that in the F-PET/CT-positive group (P < 0.001) without a significant difference in OS (P = 0.892). I-PET/CT may not predict the survival outcome of PCNSL patients with DLBCL treated with intensive methotrexate and cytarabine chemotherapy. Prospective trials are required to fully evaluate the role of I-PET/CT. PMID- 28725989 TI - Imatinib in myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRB in chronic or blast phase. AB - We evaluated clinical characteristics and outcome on imatinib of 22 patients with myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRB. Median age was 49 years (range 20-80), 91% were male. Fifteen different PDGFRB fusion genes were identified. Eosinophilia was absent in 4/19 (21%) cases and only 11/19 (58%) cases had eosinophils >=1.5*109/L. On imatinib, 17/17 (100%) patients in chronic phase achieved complete hematologic remission after median 2 months (range 0-13). Complete cytogenetic remission and/or complete molecular remission by RT-PCR were achieved in 12/13 (92%) and 12/14 patients (86%) after median 10 (range 3-34) and 19 months (range 7-110), respectively. In patients with blast phase (myeloid, n = 2; lymphoid, n = 3), treatment included combinations of imatinib (n = 5), intensive chemotherapy (n = 3), and/or allogeneic stem cell transplantation (n = 3). All 3 transplanted patients (complex karyotype, n = 2) experienced early relapse. Initially, patients were treated with imatinib 400 mg/day (n = 15) or 100 mg/day (n = 7), the dose was reduced from 400 mg/day to 100 mg/day during follow-up in 9 patients. After a median treatment of 71 months (range 1-135), the 5-year survival rate was 83%; 4/22 (18%) patients died (chronic phase; n = 2; blast phase, n = 2) due to progression (n = 3) or comorbidity while in remission (n = 1). Of note, 3/4 patients had a complex karyotype. In summary, the most important characteristics of myeloid/lymphoid neoplasms with rearrangement of PDGFRB include (a) male predominance, (b) frequent lack of hypereosinophilia, PMID- 28725990 TI - Molecular Characterization of the Indigenous Stingless Bees (Tetragonula spp. Complex) Using ISSR Marker from Southern Peninsular India. AB - India is a country bestowed enormously with stingless bees, but genetic information about them is extremely minimal. This study focused to tap the geographic allocation, genetic variability, and differentiation among Tetragonula species complexes from natural and semi-urban habitats. Genetic analyses were assessed among 36 contrasting genotypes utilizing 20 ISSR primers. The dual combination exquisitely and productively amplified 245 DNA fragments at the loci, of which 240 bands were polymorphic (97.95%). Low to moderate level of genetic differentiation was detected from different estimators (Ht 0.29, G' STest 0.16, D est 0.072, F ST 0.14, and Nm 2.68). Hierarchical clustering analysis aided to partition the individual genotypes into its respective five species group formed, aided by substantial bootstrap support values, but differing under morphological identification. It also provided valuable insight into the moderate eco-genetic diversity (H 0.39) prevailing from geographically scattered inhabitants. Potential exploitation of hyper-variable ISSR marker turned out fairly as a promising technique for finding valid polymorphisms and infers relevant variations. This baseline information enhances our understanding of the genetic status of the indigenous species from the country. PMID- 28725991 TI - Preventive Effect Heterogeneity: Causal Inference in Personalized Prevention. AB - This paper employs a causal inference framework to explore two logically distinct forms of preventive effect heterogeneity relevant for studying variation in preventive effect as a basis for developing more personalized interventions. Following VanderWeele (2015), I begin with a discussion of causal interaction involving manipulable moderators that combine to yield more complex nonadditive effects. This is contrasted with effect heterogeneity, which involves variation in causal structure indexed by stable characteristics of populations or contexts. The paper then discusses one particularly promising approach, the baseline target moderated mediation (BTMM) design, which uses theoretically informed baseline target moderators to strengthen causal inference, suggesting methods for using BTMM designs to develop targeting strategies for personalized prevention. It presents examples of recent intervention trials that apply these different forms of moderation, and discusses causal inference and the problem of moderation confounding, reviewing methods for minimizing its impact, including recent advances in the use of propensity score matching. PMID- 28725992 TI - Social Profile of Middle School-Aged Adolescents Who Use Electronic Cigarettes: Implications for Primary Prevention. AB - Electronic cigarette (EC) use continues to increase among adolescents. From a primary prevention point of view, an important gap in our knowledge includes determining whether young smokers that use EC maintain a distinct social profile from kids who use combustible cigarettes (CC). Survey data from middle school students in West Virginia, USA were collected between September and November of 2015 (N = 6547, response rate 84.7%) as part of a state wide school-based mental health intervention program. Data was analyzed using multinomial logistic regression for categorical data. The results show that compared to never smokers, EC-only users possessed a weaker social support and parental monitoring profile and performed worse in school. Additionally, EC-only users were more likely to feel alienated from school, to associate with delinquent peers, to spend time outside late at night, and to engage in unsupervised gatherings with their friends. In 11 of 13 statistical models no difference was observed between EC only users compared with CC-only users. However, dual users (that had used both EC and CC in their lifetime) demonstrated a significantly greater risk profile compared with EC-only users. We conclude that middle school-aged kids that use EC share a similar risk profile as kids of the same age that use CC. Similar to traditional cigarette smoking, EC use in young adolescents is likely to be a social marker of a pathway to further delinquency and should therefore be subject to primary prevention approaches. PMID- 28725993 TI - Are young children able to learn exploratory strategies by observation? AB - New competencies may be learned through active experience (experiential learning or learning by doing) or observation of others' experiences (learning by observation). Observing another person performing a complex action facilitates the observer's acquisition of the same action. The present research is aimed at analyzing if the observation of specific explorative strategies adopted in a constrained environment, such as the Radial Arm Maze (RAM), could help young children to explore the maze and to build a cognitive spatial map of the explored environment. To this aim young children were randomly assigned to three groups: children who performed the RAM task following the observation of an actor solving the same maze by putting into action a highly structured exploratory strategy; children who performed the RAM task following the observation of the actor solving the same maze by putting into action a less structured exploratory strategy; children who directly performed the RAM task without any observation. The main result of the present research is that the children who observed the highly structured and correct exploratory strategy spent less time, made fewer errors, exhibited a longer spatial span, and thus they explored the maze more efficiently than the children who directly performed the RAM task without any observation. This finding indicates that when the observed explorative procedure is structured, sequential and repetitive the action understanding and information storage processes are more effective. Importantly, the observation of specific spatial strategies helped the children to build the cognitive spatial map of the explored environment and consequently to acquire/enrich the declarative knowledge of the environment. PMID- 28725994 TI - Evaluation of the effects of photobiomodulation on vertebras in two rat models of experimental osteoporosis. AB - The aim of this study was to evaluate the effects of photobiomodulation (PBM) on cancellous bone in rat models of ovariectomized induced osteoporosis (OVX-D) and glucocorticoid-induced osteoporosis (GIOP). The experiment comprised of nine groups. A group of healthy rats was used for baseline evaluations. The OVX-D rats were further divided into groups as follows: control rats with osteoporosis, OVX D rats that received alendronate (1 mg/kg 60 days), OVX-D rats treated with pulsed wave laser (890 nm, 80 Hz, 900 s, 0.0061 W/cm2, 5.5 J/cm2, three times a week, 60 days), and OVX-D rats treated with alendronate + pulsed laser. Dexamethasone was administered to the remaining rats that were split into four groups: control, alendronate-treated rats, laser-treated rats, and GIOP rats treated with alendronate + laser. T12, L1, L2, and L3 vertebrae were subjected to laser. Results of the current study demonstrated that OVX-D and GIOP significantly decreased some stereological parameters, and type 1 collagen gene expression compared to the healthy group. There was a significant increase in osteoclast number in both OVX-D and glucocorticoid administration compared to the healthy group. However, the detrimental effect of the OVX-D procedure on bone was more serious than glucocorticoid administration. Results showed that laser alone had a detrimental effect on trabecular bone volume, and cortical bone volume in groups GIOP and OVX-D compared to those in the healthy group. Alendronate significantly improved total vertebral bone volume, trabecular bone volume, and cortical bone volume, in GIOP and OVX-D groups compared to the laser-treated groups. Furthermore, the alendronate + laser in OVX-D rats and GIOP rats produced significantly increased osteoblast number and type 1 collagen gene expression and caused a significant decrease in osteoclast number compared to the controls. PMID- 28725995 TI - Intra-aortic balloon pumping and thrombocytopenia in patients with acute coronary syndrome : Incidence, risk factors, and prognosis. AB - BACKGROUND: Thrombocytopenia is a frequently encountered phenomenon during intra aortic balloon pumping (IABP), which may limit its prolonged utilization. The aim of the study was to explore the risk factors and clinical implications of IABP associated thrombocytopenia in patients with acute coronary syndrome (ACS). METHODS: We retrospectively analyzed the data of 222 patients with ACS undergoing invasive treatment strategy supported by IABP. The incidence and risk factors of IABP-associated thrombocytopenia, and the association between thrombocytopenia and relevant clinical endpoints (in-hospital death, bleeding according to the TIMI scale, and thromboembolic events), were analyzed. RESULTS: IABP-associated thrombocytopenia was observed in 54.5% (121/222) of the patients. The incidence of thrombocytopenia was higher and the magnitude of reduction in platelet count was greater in the Arrow balloon group (n = 89) compared with the Datascope balloon group (n = 133; 68.5% vs. 45.1%, p = 0.001; 48.7% vs. 33.2%, p < 0.001; respectively). Independent predictors of thrombocytopenia included older age and Arrow balloon utilization (odds ratio [OR]: 1.054; 95% confidence interval [CI]: 1.028-1.080; p<0.001; OR: 2.468; 95%CI: 1.375-4.431; p = 0.002; respectively). The incidence of in-hospital death was higher in patients who developed thrombocytopenia than those who did not (9.1% vs. 2.0%, p = 0.041), and thrombocytopenia was correlated with in-hospital death (OR: 5.932; 95%CI: 1.221 28.822; p = 0.027). However, the rates of TIMI bleeding and thromboembolic events were similar between the two groups (5.8% vs. 5.0%, p = 1.000; 3.2% vs. 6.0%, p = 0.518; respectively), and thrombocytopenia was not associated with TIMI bleeding or thromboembolic events (OR: 0.940; 95%CI: 0.267-3.307; p = 0.923; OR: 0.541, 95%CI: 0.148-1.974, p = 0.352; respectively). CONCLUSION: IABP-associated thrombocytopenia occurred in 54.5% of patients with ACS undergoing an invasive strategy and it was correlated with increased in-hospital mortality. Older age and use of the Arrow balloon may predict IABP-associated thrombocytopenia. PMID- 28725996 TI - Improvement of tricuspid regurgitation after transcatheter ASD closure in older patients. AB - BACKGROUND: Adult patients with undiagnosed atrial septal defect (ASD) may have right heart cavity enlargement and functional tricuspid valve insufficiency. Moderate or more severe tricuspid regurgitation has been associated with a worse prognosis, and more serious complications are typically seen in older patients. This study aimed to evaluate the improvement in functional tricuspid regurgitation and heart geometry after transcatheter ASD closure in older patients. PATIENTS AND METHODS: The data of 111 patients over 60 years of age with moderate or severe tricuspid regurgitation before ASD closure were analyzed. RESULTS: At the 1-month and 6-month follow-up after closure, both tricuspid regurgitation jet area and right atrial volume decreased significantly. Right ventricular volume decreased 1 month after closure, showing a further decrease at the end of the 6-month follow-up. However, 24 patients (21.6%) still had persistent severe tricuspid regurgitation after the procedure. Multivariate analysis revealed that patient age at ASD closure and pulmonary artery systolic pressure determined by echocardiography before closure were predictors of persistent tricuspid regurgitation after closure. CONCLUSION: Transcatheter ASD closure in older patients could significantly decrease tricuspid regurgitation and improve right heart geometry. PMID- 28726000 TI - Announcement (Issue 8), August 2017. PMID- 28725998 TI - Membrane phase transition during heating and cooling: molecular insight into reversible melting. AB - With increasing temperature, lipid bilayers undergo a gel-fluid phase transition, which plays an essential role in many physiological phenomena. In the present work, this first-order phase transition was investigated for variable heating and cooling rates for a dipalmitoylphosphatidylcholine (DPPC) lipid bilayer by means of atomistic molecular dynamics simulations. Alternative methods to track the melting temperature [Formula: see text] are compared. The resulting [Formula: see text] is shown to be independent of the scan rate for small heating rates (0.05 0.3 K/ns) implying reversible melting, and increases for larger heating (0.3-4 K/ns) or cooling rates (2-0.1 K/ns). The reported dependency of the melting temperature on the heating rate is in perfect agreement with a two-state kinetic rate model as suggested previously. Expansion and shrinkage, as well as the dynamics of melting seeds is described. The simulations further exhibit a relative shift between melting seeds in opposing membrane leaflets as predicted from continuum elastic theory. PMID- 28725997 TI - Mitotic spindle: kinetochore fibers hold on tight to interpolar bundles. AB - When a cell starts to divide, it forms a spindle, a micro-machine made of microtubules, which separates the duplicated chromosomes. The attachment of microtubules to chromosomes is mediated by kinetochores, protein complexes on the chromosome. Spindle microtubules can be divided into three major classes: kinetochore microtubules, which form k-fibers ending at the kinetochore; interpolar microtubules, which extend from the opposite sides of the spindle and interact in the middle; and astral microtubules, which extend towards the cell cortex. Recent work in human cells has shown a close relationship between interpolar and kinetochore microtubules, where interpolar bundles are attached laterally to kinetochore fibers almost all along their length, acting as a bridge between sister k-fibers. Most of the interpolar bundles are attached to a pair of sister kinetochore fibers and vice versa. Thus, the spindle is made of modules consisting of a pair of sister kinetochore fibers and a bundle of interpolar microtubules that connects them. These interpolar bundles, termed bridging fibers, balance the forces acting at kinetochores and support the rounded shape of the spindle during metaphase. This review discusses the structure, function, and formation of kinetochore fibers and interpolar bundles, with an emphasis on how they interact. Their connections have an impact on the force balance in the spindle and on chromosome movement during mitosis because the forces in interpolar bundles are transmitted to kinetochore fibers and hence to kinetochores through these connections. PMID- 28725999 TI - Surgical Anti-Reflux Options Beyond Fundoplication. AB - PURPOSE OF REVIEW: This paper provides an overview of current and future surgical interventions available for the management of gastroesophageal reflux disease (GERD) beyond the well established and recognized fundoplication. Review the current indications and outcomes of these surgical procedures. RECENT FINDINGS: Fundoplication has been a cornerstone of the surgical management of GERD. However, other effective surgical options exist and can be considered based on prior interventions as well as patient, anatomical or other factors. These options are intended to address some of the shortcomings or potential complications of fundoplication such as symptom recurrence, dysphagia, or gas bloating, for example. Alternative procedures to fundoplication include magnetic sphincter augmentation, electrical stimulation and Roux-en-Y gastric bypass. The indication for surgical management remains failure of or inability to tolerate medical therapy. PMID- 28726001 TI - Wound Healing Failure Following Venous Access Chest Port Placement Associated with Ramucirumab Therapy. PMID- 28726002 TI - Ultrasound-Guided Radiofrequency Ablation Using a New Electrode with an Electromagnetic Position Sensor for Hepatic Tumors Difficult to Place an Electrode: A Preliminary Clinical Study. AB - PURPOSE: To evaluate whether a new electrode embedded with an electromagnetic position sensor (EMPS) improves the technical feasibility of percutaneous radiofrequency ablation (RFA) in patients with hepatic tumors difficult to place an electrode under ultrasonography (US) guidance and to assess short-term therapeutic efficacy and safety. MATERIALS AND METHODS: This prospective study was approved by the institutional review board, and written informed consent was obtained from all patients. Between January 2015 and December 2016, 10 patients (7 men and 3 women; age range 52-75 years) with a single hepatic tumor (median 1.4 cm; range 1.1-1.8 cm) difficult to place an electrode under US guidance were enrolled. The technical feasibility of targeting and overlapping ablation during the RFA procedure was graded using a four-point scale and analyzed using the Wilcoxon signed rank test according to the use of EMPS. In addition, the rates of technical success, local tumor progression (LTP), and major complications were assessed. RESULTS: The use of the new RF electrode with EMPS significantly improved the technical feasibility of targeting and overlapping ablation (p = 0.002 and p = 0.003, respectively). After treatment, the technical success rate was 100%. LTP was not found in any patient during the follow-up period (median 8 months; range 4-22 months). No major procedure-related complications occurred. CONCLUSIONS: The technical feasibility of percutaneous RFA improves with the use of this RF electrode embedded with an EMPS. Short-term therapeutic efficacy and safety after RFA using the electrode were promising in patients with hepatic tumors difficult to place an electrode under US guidance. PMID- 28726003 TI - Chitooligosaccharides Modified Reduction-Sensitive Liposomes: Enhanced Cytoplasmic Drug Delivery and Osteosarcomas-Tumor Inhibition in Animal Models. AB - PURPOSE: To investigate the potential of a reduction-sensitive and fusogenic liposomes, enabled by surface-coating with chotooligosaccharides (COS) via a disulfide linker, for tumor-targeted cytoplasmic drug delivery. METHODS: COS (MW2000-5000) were chemically tethered onto the liposomes through a disulfide linker (-SS-) to cholesterol (Chol). Doxorubicin (DOX) was actively loaded in the liposomes. Their reduction-sensitivities, cellular uptake, cytotoxicity, pharmacokinetics and antitumor efficacy were investigated. RESULTS: The Chol-SS COS/DOX liposomes (100 nm) had zeta potential of 33.9 mV and high drug loading (13% w/w). The liposomes were stable with minimal drug leakage under physiological conditions but destabilized in the presence of reducing agents, dithiothreitol (DTT) or glutathione (GSH) at 10 mM, the cytosolic level. MTT assay revealed that the cationic Chol-SS-COS/DOX liposomes had higher cytotoxicity to MG63-osteosarcoma cells than non-reduction sensitive liposome (Chol-COS/DOX). Flow cytometry and confocal microscopy revealed that Chol-SS COS/DOX internalized more efficiently than Chol-COS/DOX with more content to cytoplasm whereas Chol-COS/DOX located around the cell membrane. Chol-SS-COS/DOX preferentially internalized into MG63 cancer cell over LO2 normal liver cells. In rats both liposomes produced a prolonged half-life of DOX by 4 - 5.5 fold (p < 0.001) compared with the DOX solution. Chol-SS-COS/DOX exhibited strong inhibitory effect on tumor growth in MG63 cell-bearing nude mice (n = 6), and extended animal survival rate. CONCLUSIONS: Reduction-responsive Chol-SS-COS liposomes may be an excellent platform for cytoplasmic delivery of anticancer drugs. Conjugation of liposomes with COS enhanced tumor cell uptake, antitumor effect and survival rate in animal models. PMID- 28726004 TI - Change in skin properties over the first 10 years of life: a cross-sectional study. AB - This study investigated skin characteristics in healthy Chinese children aged from 1 to 10 years and compared these findings with similar measures from the child's mothers. Children aged 1, 2, 3, 4, 5, and 10 years (n = 29-30 per age group) and the child's mothers were enrolled in a single-visit cross-sectional study. Clinical parameters evaluated on the face, ventral forearm, and calf were softness, smoothness, erythema, edema, rash, dryness, and scaling. Instrumental evaluations included transepidermal water loss, moisture content, and water holding capacity. The clinical evaluations indicated a general decrease in softness, smoothness, and overall skin condition with increased child age. In general, the child's clinical scores were better than in adults. Children had a more permeable skin barrier that matured to adult values by approximately 5 years of age. Mothers had greater skin moisture than children. Clinical and instrumental measures were consistent with skin being softer and smoother and in better overall condition in younger children. As the skin matured with age, higher scores were observed. Instrumental measures demonstrated a more permeable skin barrier in younger children compared with older children and with adults. PMID- 28726005 TI - The role of sleep in pemphigus: a review of mechanisms and perspectives. AB - Pemphigus is an autoimmune bullous disease that causes the development of blisters and erosions on the skin and/or mucosa. Its inflammatory process is mediated by cytokines, which interact with sleep in a bidirectional manner. Pain, a frequent symptom due to pemphigus lesions, is well known to impair sleep quality. Depression is also associated with pemphigus and pro-inflammatory cytokines and may impair sleep. Additionally, a common relationship among other dermatological diseases and sleep has increasingly been described. Poor sleep quality is associated with an increased risk for autoimmune diseases, and insomnia is a comorbidity that has recently been associated with pemphigus. Thus, this review will explore the evidence supporting the likely bidirectional relationship between pemphigus and sleep quality and its possible mechanisms involved. This approach covering both pemphigus and sleep will open a research avenue for future studies focusing on the efficacy of the sleep disorders treatment in patients with pemphigus. In the long term, this may provide relevant information to dermatologists regarding new strategies for the management of pemphigus clinical condition, allowing possibly a better quality of life for the patients. PMID- 28726007 TI - Sharing mutations: are biobanks still required in the post-CRISPR/Cas9 era? AB - Cryopreservation is seen as a key aspect of good colony management which supports the drive towards improvements in animal care and the implementation of the 3Rs. However, following the advent of gene editing technologies, the generation of new mouse models is quicker and cheaper than ever before. This has led some to question the future value of biobanks around the world. In the following commentary, we argue that the need to cryopreserve mouse strains and distribute them from well-funded repositories is as strong as it has ever been. Repositories are not simply archives for unwanted mouse strains. Biobanks distribute identical QC verified mouse strains to the community and eliminate the need to recreate mice. They provide a check point in the development of mouse strains that minimises genetic drift and breeding failures. What is more, cryopreservation makes resource sharing easier, cheaper and improves animal care by eliminating the need for live animal shipments. PMID- 28726008 TI - The trouble with collective nouns for genome editing. AB - We should start as we mean to go on and try to avoid the confusion most of us experience when bombarded with acronyms with overstated significations. You will be familiar with the situation, you are in a seminar or a meeting and someone who has been using a set of acronyms for years, includes them in sentence after sentence that has you lost because you don't know what some or most of them stand for. Even worse when scientists start making verbs out of them, CRISPR seems to have fallen into this category; how many of us have heard someone asking if a mutation can be CRISPRed! Does it matter though? We are all familiar with informal language in scientific talks and discussions which is replaced by more formal dialect when research is published or presented to the general public. However, when an ill-defined acronym slips outside of laboratory chatter and is widely recognised by the general public, we need to proceed with caution to avoid misinterpretation and misunderstandings. PMID- 28726006 TI - MicroRNA-21 in Skin Fibrosis: Potential for Diagnosis and Treatment. AB - Skin fibrosis is a common pathological process characterized by fibroblast proliferation and excessive deposition of extracellular matrix. However, the pathogenesis of the disease is still not clear. Previous studies have shown that microRNA-21 may play pivotal roles in the regulation of a variety of skin fibrosis, including keloid, scleroderma, and hypertrophic scar. In this review, we outline the structure, expression, and regulation of microRNA-21 and its role in fibrotic skin diseases. In future, it may be useful as a prognostic or diagnostic marker. However, there is a significant amount of work required to increase our current understanding of the role of microRNA-21 in skin fibrosis. PMID- 28726010 TI - Robot guidance for percutaneous minimally invasive placement of pedicle screws for pyogenic spondylodiscitis is associated with lower rates of wound breakdown compared to conventional fluoroscopy-guided instrumentation. AB - Postoperative wound healing can pose a problem in patients undergoing instrumented surgery for pyogenic spondylodiscitis. Robotic guidance allows the minimally invasive placement of pedicle screws in the thoracolumbar spine. We assessed whether using this technique to perform minimally invasive surgery had an impact on wound healing in patients with pyogenic spondylodiscitis when compared to conventional open fluoroscopy-guided surgery. We reviewed charts of 206 consecutive patients who underwent instrumentation for pyogenic spondylodiscitis. The need for wound revision was the primary outcome measure. Patient variables and comorbidities as well as surgical technique (robotic versus fluoroscopy-guided) were analyzed. We also compared fluoroscopy times between the two groups. Multivariate regression analysis was performed to identify predictors of wound breakdown. A total of 206 patients underwent surgery for spondylodiscitis. Robotic surgical assistance was used for percutaneous instrumentation in 47.6% of cases (n = 98). Wound healing problems requiring revision occurred in 30 out of 206 patients (14.6%). Univariate analysis revealed a potential association of wound breakdown with (1) robotic technique, (2) age > 70 years, and (3) the presence of methicillin-resistant Staphylococcus aureus. After multivariate correction however, only robotic technique retained significance with an odds ratio of 0.39 (CI 95% 0.16-0.94; p = 0.035). Wound revision was required in eight out of 98 patients (8.1%) in the robot group and 22/108 (20%) in the conventional surgery group. Fluoroscopy times were significantly lower in the robot group with a mean of 123 +/- 86 s in comparison with a mean of 157 +/- 99 s in the conventional group (p = 0.014). While initially designed to improve the accuracy of pedicle screw placement, robot assisted minimally invasive technique had a tangible effect on both radiation exposure and the rate of wound breakdown in patients with pyogenic spondylodiscitis in our large single-center study. PMID- 28726011 TI - Thermal, structural and acetylation behavior of snail and periwinkle shells chitin. AB - This article reports a successful removal of CaCO3 from snail and periwinkle shells for the purpose of producing high quality chitin for possible application as bio-fillers in bone fixation materials. Experiment was designed with varying concentrations of acid and alkali for demineralization, deproteinization and deacetylation of the samples. Thermal characteristics, morphology, degree of de acetylation, crystalline structure and hydrogen bonding characteristics of the extracted chitin were examined. Infra-red spectra, thermogravimetric analysis and X-ray diffraction patterns show that demineralization with 1.7 M HCl led to a successful removal of CaCO3. Subsequent deproteinization and deacetylation with 1.2 M NaOH led to a development of chitosan having a degree of deacetylation of 77 and 60% for periwinkle and snail shells, respectively. Generally, all results show that different treatments led to different chitin structure and consequently different properties. PMID- 28726012 TI - Acute kidney injury after cardiac surgery: a preventable event? PMID- 28726013 TI - [Hans Killian - surgical protagonist of German anesthesia]. PMID- 28726014 TI - A Study of the Therapeutic Effects of Resveratrol on Blunt Chest Trauma-Induced Acute Lung Injury in Rats and the Potential Role of Endocan as a Biomarker of Inflammation. AB - The present study focused on the therapeutic effects of resveratrol in a rat model of blunt chest trauma-induced acute lung injury and the potential role of endocan as a biomarker of inflammation. They were randomly divided into the following four groups (n = 7 in each group): control group (no treatment or trauma); trauma group (trauma-induced group); resveratrol group (resveratrol [0.3 mg/kg] administered via the i.p. route group); and resveratrol + trauma group (resveratrol [0.3 mg/kg] administered via the i.p. route 1 h prior to the induction of trauma At the end of the 24 h, all the experimental rats were sacrificed. Lung lobe and blood samples were collected for biochemical, histopathological, and immunohistochemical investigations. Serum endocan levels were found to be significantly higher in the travma, resveratrol, and resveratrol + trauma groups than in the control group (p < 0.001, p < 0.001, p < 0.001). Moreover, in resveratrol + trauma group, endocan showed a significant increase compared to trauma and resveratrol group (p < 0.001, p < 0.001). Serum MDA level was significantly higher in the trauma group than in the control group (p = 0.017). SOD showed a significant increase in resveratrol and resveratrol + trauma groups compared to control group (p < 0.001, p < 0.001). The present study suggested that resveratrol exerted antioxidant properties in a rat model of lung injury after blunt chest trauma. Thus, it may have therapeutic potential in cases of blunt chest trauma-induced lung injury. Serum levels of endocan were not correlated with the inflammation response. The clinical use of endocan as a biomarker of inflammation in lung injury caused by blunt chest trauma is not recommended. PMID- 28726015 TI - Community Perceptions of Hospitals and Shared Physical Space: A Qualitative Study. AB - In addition to providing critical medical services to communities, hospitals are also forces of broader change when seen from the perspective of neighborhood development. Over the past few decades the obligation on the part of U.S. nonprofit hospitals to positively impact the communities in which they are located has become entrenched in both U.S. tax law and the practices of many hospitals. This article presents findings from a grounded theory qualitative study of the relationship between a non-profit children's hospital in Columbus, Ohio, and the neighborhood in which it is located. Based on in-depth interviews with local residents and community leaders, findings suggest that community members often interpret distance, safety, and transportation in different, and often counter-intuitive ways. Drawing upon literature from medical geography and sociology, the authors argue that hospitals may benefit from working closely with community members to determine how space is understood and constructed when planning community health interventions. PMID- 28726016 TI - Amyloid-beta Derived from the Brain of the Alzheimer's Disease Transgenic Mouse Is Resistant to Proteolytic Digestion Due to Its Conformation. AB - The main pathological feature of Alzheimer's disease (AD) is the formation of abundant amyloid-beta (Abeta) plaques in the human brain. Studies have reported that Abeta from the AD brain is resistant to proteolytic digestion, which may explain why Abeta cannot be readily eliminated from this organ. However, there are only a few studies that address this important question. We used the AD transgenic mouse (APP/PS1) model to show that Abeta derived from the brain of the old mouse is resistant to proteolytic digestion. This was in contrast to the proteinase K-sensitive human Abeta peptide, whose amino acid sequence was identical to that of AD mouse-derived Abeta but whose conformation was different (i.e., the native protein, but not the peptide, folded into a three-dimensional conformation). To address this question, we denatured AD mouse-derived Abeta with urea and found that Abeta became proteinase K-sensitive. This phenomenon was concentration-dependent, and these results were confirmed by another protein denaturant, guanidinium hydrochloride. We recovered the conformation of the denatured AD mouse-derived Abeta by eliminating urea and adding the human Abeta peptide, and we found that human Abeta was converted to the proteinase K resistant form in the presence of partially undenatured AD mouse-derived Abeta. However, upon the addition of the rat Abeta peptide, there were no Abeta proteinase K-resistant fragments. Our results show that the resistance of AD mouse-derived Abeta to proteolytic digestion is dependent on the three dimensional conformation of Abeta. In summary, this study provides new insights on why Abeta plaques fail to be degraded in the human brain. PMID- 28726017 TI - Retrosternal Reconstruction Can be a Risk Factor for Upper Extremity Deep Vein Thrombosis After Esophagectomy. AB - BACKGROUND: Upper extremity deep vein thrombosis (UEDVT) is a rare but important complication because it can cause pulmonary embolism. The aim of this study was to investigate the incidence of UEDVT after esophagectomy and the risk factors related to UEDVT. METHODS: This study included 88 patients who underwent esophagectomy with retrosternal or posterior mediastinal reconstruction using gastric tube. The incidence of UEDVT and the diameter of left brachiocephalic vein were measured using postoperative contrast-enhanced computed tomography (CT). (a) The distance from sternum to brachiocephalic artery and (b) the distance from sternum to vertebra were measured by preoperative CT, and the ratio of (a) to (b) was defined as the width of the retrosternal space. RESULTS: Among the patients, 14 (15.9%) suffered from UEDVT. All UEDVTs were found in left-side upper extremity deep veins. Twelve of the 14 patients (85.7%) underwent retrosternal reconstruction. In a multivariate analysis, retrosternal reconstruction was an independent risk factor for UEDVT (odds ratio 5.48). The diameter of the left brachiocephalic vein in patients with retrosternal reconstruction was significantly smaller than that in patients with posterior mediastinal reconstruction (4.3 vs 6.9 mm; P < 0.001) due to compression of left brachiocephalic vein by the gastric tube. Among patients with retrosternal reconstruction, the width of the retrosternal space in patients with UEDVT was significantly smaller than that in patients without UEDVT (0.21 vs 0.27; P = 0.001). CONCLUSION: Retrosternal reconstruction can be a risk factor for UEDVT. In patients with small width of the retrosternal space, retrosternal reconstruction might be inappropriate. PMID- 28726018 TI - Association of Vagotomy and Decreased Risk of Subsequent Ischemic Stroke in Complicated Peptic Ulcer Patients: an Asian Population Study. AB - OBJECTIVES: The primary management of peptic ulcers is medical treatment. Persistent exacerbation of a peptic ulcer may lead to complications (perforation and/or bleeding). There has been a trend toward the use of a less invasive surgical simple suture, simple local suture or non-operative (endoscopic/angiography) hemostasis rather than acid-reducing vagotomy (i.e., vagus nerve severance) for treating complicated peptic ulcers. Other studies have shown the relationship between high vagus nerve activity and survival in cancer patients via reduced levels of inflammation, indicating the essential role of the vagus nerve. We were interested in the role of the vagus nerve and attempted to assess the long-term systemic effects after vagus nerve severance. Complicated peptic ulcer patients who underwent truncal vagotomy may represent an appropriate study population for investigating the association between vagus nerve severance and long-term effects. Therefore, we assessed the risks of subsequent ischemic stroke using different treatment methods in complicated peptic ulcer patients who underwent simple suture/hemostasis or truncal vagotomy/pyloroplasty. METHODS: We selected 299,742 peptic ulcer patients without a history of stroke and Helicobacter pylori infection and an additional 299,742 matched controls without ulcer, stroke, and Helicobacter pylori infection from the National Health Insurance database. The controls were frequency matched for age, gender, Charlson comorbidity index (CCI) score, hypertension, hyperlipidemia history, and index year. Then, we measured the incidence of overall ischemic stroke in the two cohorts. The hazard ratio (HR) and the 95% confidence intervals (CIs) were estimated by Cox proportional hazard regression. RESULTS: Compared to the controls, peptic ulcer patients had a 1.86-fold higher risk of ischemic stroke. There were similar results in gender, age, CCI, hypertension, and hyperlipidemia stratified analyses. In complicated peptic ulcer patients, those who received truncal vagotomy and pyloroplasty had a lower risk of ischemic stroke than patients who received simple suture/hemostasis (HR = 0.70, 95% CI = 0.60-0.81). CONCLUSIONS: Our findings suggest that patients with peptic ulcers have an elevated risk of subsequent ischemic stroke. Moreover, there were associations between vagotomy and a decreased risk of subsequent ischemic stroke in complicated peptic ulcer patients. PMID- 28726019 TI - Arabic translation, cultural adaptation, and validation study of Knee Outcome Survey: Activities of Daily Living Scale (KOS-ADLS). AB - Knee complaints and their accompanying functional impairments are frequent problems encountered by healthcare practitioners worldwide. Plenty of functional scoring systems were developed and validated to give a relative estimation about the knee function. Despite the wide geographic distribution of Arabic language in the Middle East and North Africa, it is rare to find a validated knee function scale in Arabic. The present study is aimed to translate, validate, and culturally adjust the Knee Outcome Survey: Activities of Daily Living Scale (KOS ADLS) into Arabic language for future use among Arabic-speaking patients. Permission for translation was obtained from the copyrights holder. Two different teams of high-level clinical and linguistic expertise conducted translation process blindly. Forward-backward translation technique was implemented to ensure preservation of the main conceptual content. Main study consisted of 280 subjects. Reliability was examined by test-retest pilot study. Visual Analogue Scale (VAS), Get Up and Go (GUG) Test, Ascending/Descending Stairs (A/D Stairs), and Subjective Assessment of Function (SAF) were conducted concurrently to show the validity of Arabic KOS-ADLS statistically in relation to these scales. Final translated version showed no significant discrepancies. Minor adaptive adjustment was required to fit Arabian cultural background. Internal consistency was favourable (Cronbach's alpha 0.90). Patients' scoring on Arabic KOS-ADLS appeared relatively consistent with their scoring on VAS, GUG, A/D Stairs, and SAF. A significant linear relationship was demonstrated between SAF and total KOS-ADLS scores on regression analysis (adj. R 2 = 0.548). Arabic KOS-ADLS, as its English counterpart, was found to be a simple, valid, and useful instrument for knee function evaluation. Arabic version of KOS-ADLS represents a promising candidate for unconditional use among Arabic-speaking patients with knee complaints. PMID- 28726020 TI - Patterns of circulatory and peripheral blood mononuclear cytokines in rheumatoid arthritis. AB - An imbalance in pro- and anti-inflammatory cytokines is suggested to contribute to tissue damage in rheumatoid arthritis (RA). This study was aimed at investigating profiles of cytokines in circulation and cytokines produced by mitogen-stimulated peripheral blood mononuclear cells (PBMC) in RA patients and healthy controls, and to explore correlations of cytokines with disease activity. Our aim was to identify patterns of cytokine expression as possible indicators of disease activity. Levels of plasma cytokines and PBMC-secreted cytokines were estimated in 26 female RA patients and 28 controls. Five pro-inflammatory cytokines (IFN-gamma, TNF-alpha, IL-6, IL-17, IL-12) and three anti-inflammatory cytokines (IL-4, IL-10, IL-13) were assayed in a multiplex ELISA. RA patients had significantly higher plasma levels of TNF-alpha, IL-12, and IL-4 compared to healthy controls. On the other hand, mitogen-activated PBMC secreted significantly higher levels of the pro-inflammatory cytokines TNF-alpha, IFN gamma, IL-17, and IL-12, but lower levels of the anti-inflammatory cytokine IL-10 in RA compared to healthy subjects. The ratios TNF-alpha/IL-10, IFN-gamma/IL-10, IL-17/IL-10, IL-12/IL-10, and IFN-gamma/IL-13 were significantly higher in RA patients compared to healthy controls. The range and expression of cytokines were higher in PBMC than in the plasma in all the groups studied. Multivariate pattern analysis of eight cytokines revealed a prediction accuracy of 69% in differentiating RA patients from healthy controls, and of 73% in classifying patients as in remission or active RA. Our data suggest that it is worthwhile to explore ratios of pro- to anti-inflammatory cytokines produced by mitogen stimulated PBMC in RA, and the use of multivariate cytokine pattern and algorithms for better delineation of this condition. PMID- 28726021 TI - How Fast Does Darwin's Elephant Population Grow? AB - In "The Origin of Species," Darwin describes a hypothetical example illustrating that large, slowly reproducing mammals such as the elephant can reach very large numbers if population growth is not affected by regulating factors. The elephant example has since been cited in various forms in a wide variety of books, ranging from educational material to encyclopedias. However, Darwin's text was changed over the six editions of the book, although some errors in the mathematics persisted throughout. In addition, full details of the problem remained hidden in his correspondence with readers of the Origin. As a result, Darwin's example is very often misinterpreted, misunderstood or presented as if it were a fact. We show that the population growth of Darwin's elephant population can be modeled by the Leslie matrix method, which we generalize here to males as well. Darwin's most often cited figure, about 19 million elephants after 750 years is not a typical outcome, actually a very unlikely result under more realistic, although still hypothetical situations. We provide a recursion formula suggesting that Darwin's original model corresponds to a tribonacci series, a proof showing that sex ratio is constant over all age classes, and a derivation of a generating function of the sequence. PMID- 28726024 TI - Thermal physiology of three sympatric and syntopic Liolaemidae lizards in cold and arid environments of Patagonia (Argentina). AB - The thermal physiology determines the whole biology of ectotherm organisms, by limiting their acquisition and allocation of resources. Herein, we aim to add knowledge on how different species use the thermal resources when they coexist in a habitat, studying the thermal physiology of three sympatric and syntopic liolaemid lizards, Phymaturus querque, Phymaturus zapalensis, and Liolaemus elongatus during the summer season. We measured the body temperatures at capture places, the operative microenvironmental temperatures in the field, and the preferred body temperature in an experimental thermal gradient in the laboratory. We found that the three species are thermoregulators, selecting cooler thermal microenvironments than the ones expected by chance, and even cooler than the temperatures they selected in a laboratory environment. Liolaemus elongatus is a more efficient thermoregulator (E = 0.671) than the two Phymaturus species, P. querque (E = 0.441) and P. zapalensis (E = 0.471), which are moderate thermoregulators and, apparently, specialists in finding specific types of shelters, since they seem to select certain types of rock crevices. Herein, we found that during the summer season, although individuals have access to warm microenvironments, they spend time on cool refuges, probably to prevent overheating. This highlights the importance of an adequate spatial distribution of operative temperatures (T e), more than just a mere availability of appropriate temperatures. PMID- 28726023 TI - Benefits and Risks of Non-Approved Injection Regimens for Botulinum Toxins in Spasticity. AB - Spasticity with muscle paresis and loss of dexterity is a common feature of upper motor neuron syndrome due to injuries or the pyramidal tract in several neurological conditions. Botulinum toxin type A has been considered the gold standard treatment for spasticity and movement disorders, with efficacy, reversibility, and low prevalence of complications. During the last 30 years, thousands of studies of its use have been performed, but few guidelines are available. Therefore, there is great variability in both the doses and intervals of administration and the approaches taken by clinicians with considerable experience in spasticity and movement disorder treatment. In the present review article, we provide a short overview of the benefits and risks of non-approved injection regimens and doses for botulinum toxins, focusing on the treatment of post-stroke spasticity, where there is great interest in the potential for increasing the number of treatment/years and the dose of botulinum toxin treatment for subjects with upper and lower limb spasticity. However, many doubts exist regarding antibody development and possible adverse effects. PMID- 28726022 TI - Quantification of Hand Motor Symptoms in Parkinson's Disease: A Proof-of Principle Study Using Inertial and Force Sensors. AB - This proof-of-principle study describes the methodology and explores and demonstrates the applicability of a system, existing of miniature inertial sensors on the hand and a separate force sensor, to objectively quantify hand motor symptoms in patients with Parkinson's disease (PD) in a clinical setting (off- and on-medication condition). Four PD patients were measured in off- and on dopaminergic medication condition. Finger tapping, rapid hand opening/closing, hand pro/supination, tremor during rest, mental task and kinetic task, and wrist rigidity movements were measured with the system (called the PowerGlove). To demonstrate applicability, various outcome parameters of measured hand motor symptoms of the patients in off- vs. on-medication condition are presented. The methodology described and results presented show applicability of the PowerGlove in a clinical research setting, to objectively quantify hand bradykinesia, tremor and rigidity in PD patients, using a single system. The PowerGlove measured a difference in off- vs. on-medication condition in all tasks in the presented patients with most of its outcome parameters. Further study into the validity and reliability of the outcome parameters is required in a larger cohort of patients, to arrive at an optimal set of parameters that can assist in clinical evaluation and decision-making. PMID- 28726025 TI - Synthesis of new tricyclic imidazotriazepine derivatives condensed with various heterocycles. AB - Previously synthesized 9-aryl-5H-imidazo[2,1-d][1,2,5]triazepin-6(7H)-ones have been used as starting materials for the synthesis of three new tricyclic ring systems, where an imidazotriazepine is condensed with an imidazole, triazole or tetrazole ring. These novel compounds could be potential drug candidates for central nervous system diseases because of their closely related structure to known tricyclic derivatives with anticonvulsant activity. PMID- 28726026 TI - Euthanasia: Global Scenario and Its Status in India. AB - The legal and moral validity of euthanasia has been questioned in different situations. In India, the status of euthanasia is no different. It was the Aruna Ramachandra Shanbaug case that got significant public attention and led the Supreme Court of India to initiate detailed deliberations on the long ignored issue of euthanasia. Realising the importance of this issue and considering the ongoing and pending litigation before the different courts in this regard, the Ministry of Health and Family Welfare, Government of India issued a public notice on May 2016 that invited opinions from the citizens and the concerned stakeholders on the proposed draft bill entitled The Medical Treatment of Terminally Ill Patients (Protection of Patients and Medical Practitioners) Bill. Globally, only a few countries have legislation with discreet and unambiguous guidelines on euthanasia. The ongoing developments have raised a hope of India getting a discreet law on euthanasia in the future. PMID- 28726027 TI - How Accused Scientists Deal with Scientific Fraud: View from a Different Culture. PMID- 28726028 TI - Should We All be Scientists? Re-thinking Laboratory Research as a Calling. AB - In recent years there have been major shifts in how the role of science-and scientists-are understood. The critical examination of scientific expertise within the field of Science and Technology Studies (STS) are increasingly eroding notions of the "otherness" of scientists. It would seem to suggest that anyone can be a scientist-when provided with the appropriate training and access to data. In contrast, however, ethnographic evidence from the scientific community tells a different story. Scientists are quick to recognize that not everyone can or should-be a scientist. Appealing to notions such as "good hands" or "gut feelings", scientists narrate a distinction between good and bad scientists that cannot be reduced to education, access, or opportunity. The key to good science requires scientists to express an intuitive feeling for their discipline, but also that individuals derive considerable personal satisfaction from their work. Discussing this personal joy in-and "fittingness" of-scientific occupations using the fields of STS, ethics and science policy is highly problematic. In this paper we turn to theology discourse to analyze the notion of "callings" as a means of understanding this issue. Callings highlight the identification and examination of individual talents to determine fit occupations for specific persons. Framing science as a calling represents a novel view of research that places the talents and dispositions of individuals and their relationship to the community at the center of flourishing practices. PMID- 28726029 TI - Ammonia exposure and subsequent recovery trigger oxidative stress responses in juveniles of Brazilian flounder Paralichthys orbignyanus. AB - The effects of ammonia exposure and recovery on oxidative stress parameters and histology of juvenile Brazilian flounder Paralichthys orbignyanus were evaluated. The fish were exposed to 0.12, 0.28 and 0.57 mg NH3-N L-1, plus a control, for 10 days followed by the same recovery time in ammonia-free water. Gill, liver and muscle samples (n = 9) were collected after 1, 5 and 10 days of exposure and after recovery for oxidative stress analysis (antioxidant capacity against peroxyl radicals (ACAP); glutathione S-transferase (GST) activity; lipoperoxidation levels measured through thiobarbituric acid reactive substances (TBARS) content). For histological assessment, gill, liver and brain samples were collected. Exposure to all NH3-N concentrations induced different time- and dose dependent changes in oxidative stress parameters. Reduced antioxidant capacity of the liver and muscle and enhanced TBARS levels in the gills and liver were demonstrated. Differently, a high ammonia concentration elicited lower hepatic TBARS levels. Enhanced GST activity in all organs and increased antioxidant capacity of the gills were also observed. No ammonia-induced histopathological effects were demonstrated. After recovery, most parameters (liver ACAP, GST activity in the muscle and liver and TBARS in the gills) returned to baseline levels. However, liver TBARS and gill GST activity remained altered 0.57 mg NH3-N L-1 treatment. The recovery period also led to a decrease in gill antioxidant capacity and an increase in muscle antioxidant capacity. In conclusion, a concentration of 0.12 mg NH3-N L-1 induces oxidative stress and antioxidant responses in juvenile Brazilian flounder. Moreover, a 10-day recovery period is not sufficient to restore fish homeostasis. PMID- 28726030 TI - Intravascular large B-cell lymphoma presenting clinically as rapidly progressive dementia. AB - BACKGROUND: In patients presenting with rapidly progressive dementia, prion disease may enter the differential diagnosis. The commonest malignancies masquerading as prion disease are primary CNS lymphoma and intravascular large B cell lymphoma, both rare and difficult to diagnose without brain biopsy. CASE PRESENTATION: This 82-year-old lady with a past history of hypertension, presented with rapidly progressive cognitive impairment and ataxia. The possibility of sCJD was raised. Brain biopsy was carried out. Western blot for prion protein was negative. Brain biopsy showed intravascular large B-cell lymphoma. She died shortly afterwards. CONCLUSION: The clinical presentation of intravascular large B-cell lymphoma is diverse. Patients may present as in this case with dementia, seizures, and myoclonus leading to a clinical diagnosis of sCJD. The diagnosis here was made at biopsy but is made at autopsy in over 50% of cases. PMID- 28726031 TI - The natural history of Leydig cell testicular tumours: an analysis of the National Cancer Registry. AB - BACKGROUND: Leydig cell tumour (LCT) of the testis is a rare histological subtype of stromal tumours, accounting for 1 to 3% of testicular neoplasms. The natural history of LCT is poorly understood. AIMS: The aim of this study was to assess the incidence and natural history of Leydig cell tumours (LCT) of the testes. METHODS: A search of the National Cancer Registry of Ireland database was performed regarding Leydig cell testicular tumours. Recurrence free survival (RFS) and disease-specific survival (DSS) were analysed. RESULTS: Between 1994 and 2013, 2755 new cases of testicular cancer were diagnosed in Ireland. Of these, 22 (0.79%) were Leydig cell tumours. Nineteen were invasive (stage T1) and three were in situ (stage Tis). One patient developed a local recurrence following an organ preserving procedure and underwent a completion orchidectomy 107 days after initial diagnosis. No further treatment was required. There have been no disease-specific deaths. The 1-, 3- and 5-year overall survival (OS) rates were 95.5, 88.2 and 73.3%, respectively. The 5-year disease-specific survival (DSS) was 100% and the 5-year recurrence free survival (RFS) was 93.3%. CONCLUSION: From the National Cancer Registry, LCT has been shown to be a rare subtype of testicular tumour. Due to the relatively favourable natural history, it may be possible to tailor less aggressive surveillance regimens in these patients. PMID- 28726032 TI - Comparison of abdominal, vaginal, and laparoscopic hysterectomies in a tertiary care hospital in Turkey. AB - AIM: The aim of this retrospective study was to assess and compare the clinical results of three hysterectomy techniques: abdominal hysterectomy (AH), vaginal hysterectomy (VH), and laparoscopic hysterectomy (LH). METHODS: A total of 2163 patients having undergone AH (n = 1226), VH (n = 426), and LH (n = 511) procedures were analyzed. The mean age, body mass index (BMI), parity, uterus weight, operation time, blood loss, duration of hospitalization, analgesic needs, intra- and postoperative complications, and indications for hysterectomy were analyzed and compared. RESULTS: There were no differences between the groups with respect to the BMI, parity, and intra- or postoperative major and minor complications. The operation time was significantly shorter in the VH group than in the other two groups (p < 0.001), and the blood loss was significantly lower in the LH group than in the others (p < 0.001). The duration of hospitalization and analgesic needs were the shortest in the LH group (p < 0.001), while the uterus weight and previous intra-abdominal surgery rate were the lowest in the VH group (p < 0.001). CONCLUSION(S): Despite the fact that the LH exhibited a longer operation time than the VH, the LH was considered to be a safe and effective surgical procedure due to the lesser blood loss, hospital stay, and analgesic needs. PMID- 28726033 TI - Recommendations for the inclusion of Fabry disease as a rare febrile condition in existing algorithms for fever of unknown origin. AB - Fever of unknown origin (FUO) is a rather rare clinical syndrome representing a major diagnostic challenge. The occurrence of more than three febrile attacks with fever-free intervals of variable duration during 6 months of observation has recently been proposed as a subcategory of FUO, Recurrent FUO (RFUO). A substantial number of patients with RFUO have auto-inflammatory genetic fevers, but many patients remain undiagnosed. We hypothesize that this undiagnosed subgroup may be comprised of, at least in part, a number of rare genetic febrile diseases such as Fabry disease. We aimed to identify key features or potential diagnostic clues for Fabry disease as a model of rare genetic febrile diseases causing RFUO, and to develop diagnostic guidelines for RFUO, using Fabry disease as an example of inserting other rare diseases in the existing FUO algorithms. An international panel of specialists in recurrent fevers and rare diseases, including internists, infectious disease specialists, rheumatologists, gastroenterologists, nephrologists, and medical geneticists convened to review the existing diagnostic algorithms, and to suggest recommendations for arriving at accurate diagnoses on the basis of available literature and clinical experience. By combining specific features of rare diseases with other diagnostic considerations, guidelines have been designed to raise awareness and identify rare diseases among other causes of FUO. The proposed guidelines may be useful for the inclusion of rare diseases in the diagnostic algorithms for FUO. A wide spectrum of patients will be needed to validate the algorithm in different clinical settings. PMID- 28726034 TI - Mentally stimulating activities associate with better cognitive performance in Parkinson disease. AB - Subjects at risk of dementia benefit from participation in mentally stimulating activities, but no prior studies have investigated similar associations in Parkinson disease (PD). The aim of this study was to investigate the relationship between times spent engaging in mentally stimulating activities and cognitive functions in PD while accounting for the degree of primary neurodegenerations. PD patients (N = 41, 33 males; age 68.5 +/- 7.2; Hoehn and Yahr stage 2.6 +/- 0.6) completed the Community Health Activities Model Program for Seniors questionnaire, mini-mental state examination (MMSE), and [11C]dihydrotetrabenazine dopaminergic and [11C]piperidinyl propionate acetylcholinesterase PET imaging. The subset of mentally stimulating activity items of the Community Health Activities Model Program for Seniors questionnaire was used to develop a rating scale as primary outcome variable in this study. Findings showed that mean rating scale score of time spent in mentally stimulating activities over a 4-week timespan was 20.0 +/- 8.3 h and mean MMSE score was 28.4 +/- 1.9. Regression analysis showed that duration of participation in mentally stimulating activities was a significant predictor of MMSE scores (standardized beta = 0.39, t = 2.8, p = 0.009; total model: F (6,34) = 3.5, p = 0.005) independent from significant effects for cortical cholinergic activity (beta = 0.35, t = 2.4, p = 0.024). Caudate nucleus dopaminergic activity, age, education, or duration of disease were not significant regressors. Post hoc analysis did not show significant effects of motor disease severity or level of physical activities. We conclude that engagement in mentally stimulating activities is associated with better cognitive abilities in PD, independent of education, severity of motor disease, nigrostriatal dopaminergic and cortical cholinergic degenerations. PMID- 28726035 TI - Evaluation of physical activity in sarcopenic conditions of kidney transplantation recipients. AB - INTRODUCTION: Sarcopenia is an involuntary decline in skeletal muscle mass, strength, and function that normally proceed with aging but may develop faster under some chronic disease conditions. In this study, we compared the physical activity between sarcopenia and non-sarcopenia subgroups in kidney transplant recipients. METHODS: Fifty-eight recipients (42 males and 16 females) were enrolled in this study. Mean age of the recipients was 46.6 +/- 12.7 years. Mean duration of dialysis was 2.8 +/- 4.0 years. Diagnostic criteria for sarcopenia referred to those of the Asia Working Group for Sarcopenia. The physical activity was assessed using the International Physical Activity Questionnaire, and the intensity of physical activity was expressed in metabolic equivalents (MET). RESULTS: Based on the skeletal muscle mass index (SMI) as well as functional index (HGS, walking speed), the participants were classified into the three subgroups: 12 patients (20.7%) with sarcopenia (Group 1), 25 (43.1%) with presarcopenia (Group 2), and 21 (36.2%) non-sarcopenia (Group 3). Analysis with ANOVA and pairwise comparisons showed that physical activity measured as total MET-min/week was significantly greater in Group 2 (1292 +/- 633) than in Group (1484 +/- 262). Moreover, physical activity of Group 3 (2461 +/- 1339)-min/week was significantly greater than those of Groups 1 and 2. CONCLUSIONS: Our data indicate that physical activity is restricted under presarcopenia and sarcopenia after kidney transplantation. Considering that the recipient age is now increasing, proper management of sarcopenia may become more crucial to improve the kidney survival and lifetime prognosis of the kidney transplant recipients. PMID- 28726036 TI - Proteolytic effects of gingipains on trefoil factor family peptides. AB - OBJECTIVES: The present study was aimed to determine whether trefoil factor family (TFF) peptides which were generally considered to be resistant to proteolysis could be digested by gingipains, a major proteinases produced by Porphyromonas gingivalis. MATERIALS AND METHODS: Recombinant human TFF1, TFF2, and TFF3 peptides were used as substrates. Gingipains including arginine gingipain (RgpB) and lysine gingipain (Kgp) were used as enzymes. Trypsin was used as a control protease. Matrix-assisted laser desorption/ionization with time of-flight / time-of-flight (MALDI-TOF/TOF) and liquid chromatography mass spectrometry (LC-MS) were used for analyzing peptide mass signals and amino acid sequences of digested TFF peptides. RESULTS: MALDI-TOF/TOF analyses demonstrated that Kgp, RgpB, and trypsin were able to cleave TFF1 and TFF2 peptides, resulting in different patterns of digested fragments. However, impurity in recombinant TFF3 peptide substrates affected the interpretations of enzymatic reaction by MALDI-TOF/TOF. LC-MS analyses demonstrated that identified fragments of TFF1, TFF2, and TFF3 from digestion by gingipains were similar to those by trypsin. CONCLUSIONS: Using MALDI-TOF/TOF and LC-MS, the present study provides new information that gingipains containing trypsin-like activities are able to digest TFF peptides. CLINICAL RELEVANCE: The proteolytic effects of gingipains on TFF peptides may be responsible for reduction of salivary TFF peptides in chronic periodontitis patients. Further investigations to determine the pathological effects of gingipains on TFF peptides in saliva and periodontal tissues of patients with chronic periodontitis would be of interest. PMID- 28726037 TI - Can a collaborative subspecialty antimicrobial stewardship intervention have lasting effects? AB - OBJECTIVE: We previously demonstrated the benefit of direct, daily collaboration between infectious disease (ID) and critical care practitioners (CCP) on guideline adherence and antibiotic use in the medical intensive care unit (MICU). In this post-intervention review, we sought to establish whether the effect on antibiotic use and guideline adherence was sustainable. DESIGN: A retrospective review of 87 patients, admitted to the 24-bed MICU, was done 3 (n = 45) and 6 months (n = 42) after the intervention. MEASUREMENTS: Data included demographics, severity indicators, admitting pathology, infectious diagnosis, clinical outcomes [mechanical ventilation days (MVD) and MICU length of stay (LOS), antibiotic days of therapy (DOT), in-hospital mortality], and antibiotic appropriateness based on current guidelines. RESULTS: In the 3-month (3-PI) and 6-month post-intervention (6-PI), there were no significant differences in the APACHE II score, MVD, LOS, DOT, or total antibiotic use at 3 (p = 0.59) and 6-PI (p = 0.87). There was no change in the mean use of extended-spectrum penicillins, cephalosporin, and carbapenems. While there were significant differences in vancomycin usage at 3-PI [3.1 DOT vs. 4.3 DOT (p = 0.007)], this finding was not seen after 6 months [3.1 DOT vs. 3.4 DOT (p = 0.08)]. When compared to the intervention period, the inappropriateness of antibiotic use at 3 (p = 1.00) and 6-PI (p = 0.30) did not change significantly. CONCLUSIONS: There were no significant differences in either total antibiotic use or inappropriate antibiotic use at the 6-PI time period. Continuous, daily, direct collaboration between ID and CCP, once implemented, can have lasting effects even at 6 months after the interaction has been discontinued. PMID- 28726038 TI - Subjective cognitive decline and fall risk in community-dwelling older adults with or without objective cognitive decline. AB - BACKGROUND: The association between subjective cognitive decline and falls has not been clearly determined. AIMS: Our aim was to explore the effect of subjective cognitive decline on falls in community-dwelling older adults with or without objective cognitive decline. METHODS: We included 470 older adults (mean age 73.6 +/- 5.2; 329 women) living in the community and obtained data on fall history directly from the participants. Subjective cognitive decline was assessed using a self-administered question. Objective cognitive function was measured using the Mini-Mental State Examination. Statistical analyses were carried out separately for participants with objective cognitive decline and those without. RESULTS: A multiple logistic regression analysis showed that, among participants without objective cognitive decline, subjective cognitive decline was positively associated with falls [OR 1.91; 95% confidence interval (CI) 1.17-3.12; p = 0.01). Conversely, among participants with objective cognitive decline, subjective cognitive decline was negatively associated with falls (OR 0.07; 95% CI 0.01-0.85, p = 0.04). DISCUSSION: The result suggests that the objective subjective disparity may affect falls in community-dwelling older adults. CONCLUSIONS: The presence of subjective cognitive decline was significantly positively associated with falls among cognitively intact older adults. However, among their cognitively impaired peers, the absence of subjective cognitive decline was positively associated with falls. PMID- 28726039 TI - TBC1D24 gene mRNA expression in a boy with early infantile epileptic encephalopathy-16. PMID- 28726040 TI - Assessing predicted age-specific breast cancer mortality rates in 27 European countries by 2020. AB - BACKGROUND: We assessed differences in predicted breast cancer (BC) mortality rates, across Europe, by 2020, taking into account changes in the time trends of BC mortality rates during the period 2000-2010. METHODS: BC mortality data, for 27 European Union (EU) countries, were extracted from the World Health Organization mortality database. First, we compared BC mortality data between time periods 2000-2004 and 2006-2010 through standardized mortality ratios (SMRs) and carrying out a graphical assessment of the age-specific rates. Second, making use of the base period 2006-2012, we predicted BC mortality rates by 2020. Finally, making use of the SMRs and the predicted data, we identified a clustering of countries, assessing differences in the time trends between the areas defined in this clustering. RESULTS: The clustering approach identified two clusters of countries: the first cluster were countries where BC predicted mortality rates, in 2020, might slightly increase among women aged 69 and older compared with 2010 [Greece (SMR 1.01), Croatia (SMR 1.02), Latvia (SMR 1.15), Poland (SMR 1.14), Estonia (SMR 1.16), Bulgaria (SMR 1.13), Lithuania (SMR 1.03), Romania (SMR 1.13) and Slovakia (SMR 1.06)]. The second cluster was those countries where BC mortality rates level off or decrease in all age groups (remaining countries). However, BC mortality rates between these clusters might diminish and converge to similar figures by 2020. CONCLUSIONS: For the year 2020, our predictions have shown a converging pattern of BC mortality rates between European regions. Reducing disparities, in access to screening and treatment, could have a substantial effect in countries where a non-decreasing trend in age specific BC mortality rates has been predicted. PMID- 28726041 TI - Alcohol Use, HIV Treatment Adherence, and Sexual Risk Among People with a History of Injecting Drug Use in Vietnam. AB - Alcohol use can limit the effectiveness of antiretroviral therapy (ART) for people living with HIV (PLH) who have a history of injecting drug use. This study described the patterns of alcohol use among PLH with a history of injecting drug use in Vietnam and examined the relationships between alcohol use, adherence to ART, and sexual risks. We utilized cross-sectional data of 109 PLH on ART collected from a randomized controlled intervention trial in Vietnam. Approximately 30 and 46% of the participants were frequent and occasional drinkers, respectively. Frequent drinkers reported the highest number of missed medication days. About 61% of frequent drinkers reported having sex after using alcohol. Additionally, 23, 34, and 24% of nondrinkers, occasional drinkers, and frequent drinkers, respectively, reported inconsistent condom use during sex. Future intervention programs should address the issues of alcohol use and sexual risks to maximize the effectiveness of HIV treatment programs in Vietnam. PMID- 28726042 TI - Reproductive Desires and Considerations of HIV-Positive Men in Heterosexual Relationships in New York City. AB - The reproductive desires of HIV-positive men have been investigated far less than those of HIV-positive women, especially in the US. This qualitative study of a sample of 94 HIV-positive men in New York City who were in a relationship with a woman of reproductive age examined their reasons for wanting a child as well as the conditions under which they would feel ready to attempt conception. Participants felt a child would make them feel normal, give meaning to their lives, or make others in their life happy. Although they reported HIV-related concerns (i.e., horizontal or vertical transmission, reinfection, or shortened life expectancy), participants mostly discussed factors unrelated to HIV (e.g., finances, housing, incarceration, substance abuse, or relationships) as deterrents to acting on their desire to having a child. When providing information on safer conception, healthcare providers should be aware of the broad desires and factors informing HIV-positive men's reproductive goals. PMID- 28726043 TI - Injection Drug Use, Unemployment, and Severe Food Insecurity Among HIV-HCV Co Infected Individuals: A Mediation Analysis. AB - Severe food insecurity (FI), which indicates reduced food intake, is common among HIV-hepatitis C virus (HCV) co-infected individuals. Given the importance of unemployment as a proximal risk factor for FI, this mediation analysis examines a potential mechanism through which injection drug use (IDU) is associated with severe FI. We used biannual data from the Canadian Co-infection Cohort (N = 429 with 3 study visits, 2012-2015). IDU in the past 6 months (exposure) and current unemployment (mediator) were self-reported. Severe FI in the following 6 months (outcome) was measured using the Household Food Security Survey Module. An overall association and a controlled direct effect were estimated using marginal structural models. Among participants, 32% engaged in IDU, 78% were unemployed, and 29% experienced severe FI. After adjustment for confounding and addressing censoring through weighting, the overall association (through all potential pathways) between IDU and severe FI was: risk ratio (RR) = 1.69 (95% confidence interval [CI] = 1.15-2.48). The controlled direct effect (the association through all potential pathways except that of unemployment) was: RR = 1.65 (95% CI = 1.08 2.53). We found evidence of an overall association between IDU and severe FI and estimated a controlled direct effect that is suggestive of pathways from IDU to severe FI that are not mediated by unemployment. Specifically, an overall association and a controlled direct effect that are similar in magnitude suggests that the potential impact of IDU on unemployment is not the primary mechanism through which IDU is associated with severe FI. Therefore, while further research is required to understand the mechanisms linking IDU and severe FI, the strong overall association suggests that reductions in IDU may mitigate severe FI in this vulnerable subset of the HIV-positive population. PMID- 28726044 TI - Computed tomographic characteristics for patients with unresectable gastric cancer harboring low-volume peritoneal carcinomatosis. AB - Although current staging workups could differentiate most patients with operable from inoperable advanced gastric cancers, there are still some patients with low volume peritoneal carcinomatosis, defined as only metastasis with multiple subcentimeter lesions in peritoneum, receiving unnecessary open-close procedures. The computed tomography (CT) of the patients with unresectable advanced gastric cancer harboring low-volume peritoneal carcinomatosis was retrospectively identified and then thoroughly reviewed by two independent radiologists unaware of the peritoneal carcinomatosis status. Of the 798 patients with newly diagnosed gastric cancer between January 2007 and December 2010, 52 patients harboring advanced gastric cancer with low-volume peritoneal carcinomatosis receiving surgery with curative intent were identified. Descriptive statistic was used for the radiologic characteristics. The most common radiologic characteristic of CT was omental fat stranding (57.7%), followed by omental clustered subcentimeter nodules (53.8%), distant enlarged lymph node (40.4%), distant grouping of small lymph nodes (36.5%), peritoneal nodules or thickening (34.6%), minimal loculated ascites (21.2%), intestinal wall thickening or irregularity (9.6%), and hydronephrosis or hydroureter without stone or urothelial lesion (5.8%). Comprehensively reviewing the radiologic characteristics of CT may identify the patients harboring advanced gastric cancer with low-volume peritoneal carcinomatosis. PMID- 28726045 TI - The use of psychological supportive care services and psychotropic drugs in patients with early-stage breast cancer: a comparison between two institutions on two continents. AB - The aim of this study was to evaluate the mental health consumption among patients with early-stage breast cancer in two radiation oncology departments in two countries (USA and Italy). Data were extracted from the medical records of consecutive patients treated between 2014 and 2015 in two centers. Extracted data included patient's demographics, treatment, referral to psychological supportive care programs, and prescribed psychotropic drugs. Data from the two centers were compared using Student's t, Wilcoxon, Fisher's exact, and Jonckheere-Terpstra tests. Adjusted relative risks (RR) were estimated using Poisson regression. A total of 231 (Italy = 110, USA = 121) patients were included, with a mean age of 60 years. The crude rate of psychological supportive care visits was similar in the US versus the Italian cohort (28.9 vs. 21.8%, p = 0.23). The crude rate of prescribed psychotropic drug was higher in the US cohort versus Italian cohort (43.8 vs. 18.2%, p < 0.0001). These differences remained significant after adjusting for breast cancer subtype, stage, and treatment (RR 1.8, 95 CI 1.17 2.76). Between 20 and 30% of patients receive psychological supportive care during treatment for breast cancer. The use of psychotropic medication was higher in the US cohort than the cohort from Italy. The reasons for these differences might be related to social and cultural differences and the method of prescribing medication. PMID- 28726046 TI - Spectrophotometric photodynamic detection involving extracorporeal treatment with hexaminolevulinate for bladder cancer cells in voided urine. AB - PURPOSE: To evaluate the feasibility of hexaminolevulinate (HAL) for the photodynamic detection of cancer cells in voided urine. METHODS: This study included 50 patients with bladder cancer that was confirmed histologically after transurethral resection (bladder cancer group) and 50 outpatients without a history of urothelial carcinoma or cancer-related findings (no malignancy group). One third of the voided urine samples were incubated with aminolevulinic acid (ALA-treated samples), one third were incubated with HAL (HAL-treated samples), and the remaining samples were incubated without treatment (untreated samples). For detecting cellular protoporphyrin IX levels, the intensity of the samples at the excitation wavelength of 405 nm was measured using a spectrophotometer. The difference between the intensity of the ALA-treated or HAL-treated samples and the untreated samples at 635 nm was calculated. RESULTS: HAL-induced fluorescence cytology (HFC) showed that the difference was significantly higher in patients with high-grade tumors than in those with low-grade tumors (p = 0.0003) and the difference was significantly higher in patients with low-grade tumors than in those without a history of urothelial carcinoma or cancer-related findings (p = 0.021). The areas under the receiver operating characteristic curves of ALA induced fluorescence cytology (AFC) and HFC were 0.77 and 0.81, respectively. The AUC of HFC was significantly higher than that of AFC (p < 0.0001). The overall sensitivity values for conventional cytology, AFC, and HFC were 49, 74, and 74%, respectively. The overall specificity values for AFC and HFC were 70 and 94%, respectively. CONCLUSIONS: Spectrophotometric photodynamic detection involving extracorporeal treatment with HAL for bladder cancer cells in voided urine showed high accuracy. This bladder cancer detection method is easy and cost-effective, and has the potential for clinical use. PMID- 28726047 TI - Dietary acrylamide exposure was associated with increased cancer mortality in Chinese elderly men and women: a 11-year prospective study of Mr. and Ms. OS Hong Kong. AB - AIM: Our study aims to investigate the association between dietary acrylamide exposure and cancer mortality among Chinese elderly. METHODS: A prospective cohort of 4000 elderly men and women aged 65 years and above (Mr. and Ms. OS Hong Kong study) was recruited from local communities from 2001 to 2003. Dietary exposure to acrylamide was evaluated at baseline based on a validated food frequency questionnaire and an acrylamide database from the 1st Hong Kong Total Diet Study. Data on mortality statistics through March 2014 were obtained from the Death Registry of the Department of Health of Hong Kong with a median follow up of 11.1 years. Cox proportional hazards models were used to examine the association between the acrylamide exposure and cancer mortality. Sex hormones were assessed in men. RESULTS: During a median follow-up of 11.1 years (39,271 person-years), we ascertained 330 cancer deaths. Vegetables (43.7%) and cereals (28.9%) products were the major contributors to dietary acrylamide. Compared with the lowest quartile of acrylamide intake (<9.9 ug/day), the multivariable hazard ratios for the highest quartile (>17.1 ug/day) were 1.9 (95% CI 1.3-2.8; P trend < 0.01), 1.9 (95% CI 1.0-3.6; P trend = 0.05), and 2.0 (95% CI 1.0-4.0; P trend = 0.06) for the cancer mortality from overall, digestive and respiratory system, respectively. The associations were attenuated to null after further adjustment for circulating free estradiol in men. No statistically significant interactions were observed between acrylamide exposure and sex, obesity and overall lifestyle pattern scores. CONCLUSIONS: The longitudinal data provided evidence that dietary acrylamide, in amounts that Chinese elderly are typically exposed to, was associated with increased cancer mortality. Circulating free estradiol may mediate the association in men. PMID- 28726048 TI - Is CT perfusion helpful in the treatment allocation of patients with acute ischemic stroke? An expert-opinion analysis. AB - BACKGROUND: Intravenous tPA is the standard treatment for acute ischemic stroke within 4.5 hours of symptom onset. Neuroradiological selection is currently based upon non-contrast- brain CT scan (NCCT). AIMS: To verify, in an "expert-opinion setting", the possible usefulness of CT perfusion (CTP) in decision-making toward i.v. thrombolysis. PATIENTS AND METHOD: One hundred and three consecutive patients with acute ischemic stroke who underwent NCCT and CTP were re-evaluated by an expert in cerebrovascular disease, to verify if adding CTP information would have changed expert's opinion. RESULTS: After CTP, a definitive decision was made for 20 more patients, changing the proportion of patients candidate to i.v. tPA from 44% to 51%, and reducing uncertainty from 29% to 10%. CTP results were useful inmilder stroke (p = 0.01). CONCLUSIONS: In a "real world" setting, CT perfusion could be useful for clinical decision, in particular for milder stroke. PMID- 28726049 TI - Quarterly repeat cycles of onabotulinumtoxinA in chronic migraine patients: the benefits of the prolonged treatment on the continuous responders and quality-of life conversion rate in a real-life setting. AB - OnabotulinumtoxinA was approved for treatment of chronic migraine (CM) after publication of Phase 3 Research Evaluating Migraine Prophylaxis Therapy (PREEMPT) trials. However, the PREEMPT trials lasted only up to 1 year. The main aim of our retrospective study was to evaluate whether a prolonged treatment of onabotulinumtoxinA (18 months, six quarterly cycles) will sustain or further improve the efficacy results and the quality of life achieved at 6 and 12 months. Patients were adults with CM with or without overuse of drugs, with at least six regularly repeat onabotulinumtoxinA treatments, administered according to the PREEMPT protocol. The outcomes were investigated after 6, 12, and 18 months of treatment with respect to baseline and with respect to each previous study time point. Headache days and hours, and dosage of headache medication taken with latency period, were collected from the patients daily. Quality of life was evaluated by means of the Migraine Disability Assessment (MIDAS) questionnaire. At each study time point, the proportion of responder patients with respect to baseline was evaluated. For all measures, the baseline data were referred to the previous month before starting. Forty-seven patients were evaluated. Our data show a decrease in the monthly headache days and hours, at each study evaluation, with respect to the previous one. They showed that beyond the first year, a statistically significant difference in the monthly days of headache compared at 18 vs. 12 months is observed. A significantly higher proportion of patients (with a response greater than 75% decrease from baseline in the frequency of headache days and hours) was observed at month 18 compared to month 12. The proportion of patients in MIDAS grade I increased over time, and a statistically significant improvement in MIDAS I score was obtained from month 12 to month 18. A positive modification in the consumption of analgesics over time was observed (p for trend <0.001). The mean acute drug latency strongly decreased over time. Our study confirmed that onabotulinumtoxinA is an effective treatment to reduce headache related disability and improve patients' quality of life, highlighting that upon repeated administration, the therapy efficacy increases significantly and a progressive trend of "first-time response" is observed for the entire period under consideration. PMID- 28726050 TI - A single center study: Abeta42/p-Tau181 CSF ratio to discriminate AD from FTD in clinical setting. AB - Abnormal levels of beta amyloid (Abeta42) and tau protein concentrations in the cerebral spinal fluid (CSF) have been largely described in Alzheimer's disease (AD). Thus, CSF analysis of these biomarkers has been incorporated in recent AD diagnostic criteria, and it is increasingly performed for neurodegenerative dementia diagnostic workout in clinical setting. Nevertheless, the precise biomarkers CSF features in neurodegenerative dementia, either AD or Frontotemporal dementia (FTD), are still not fully clear today. This is mainly due to lack of CSF clear cutoff values due to a well-known intersite (but even intrasite) variability of CSF procedures, ranging from collection to analysis. Applying CSF biomarker ratios, rather than their single values could represent a useful tool, especially for the differential diagnosis of different forms of dementia. We explored clinical values of six CSF ratios (by combining Abeta42 and tau) in order to better discriminate between AD and FTD; we identified Abeta42/p Tau181 ratio as a potential good candidate for helping differentiating AD from FTD in the clinical practice. PMID- 28726051 TI - Serum methylmalonic acid correlates with neuropathic pain in idiopathic Parkinson's disease. AB - Recent studies have shown a relatively higher prevalence of peripheral neuropathy in idiopathic Parkinson's disease (IPD). The hypothesis is that prolonged levodopa exposure causes vitamin B12 deficiency, which leads to peripheral neuropathy. The aim of our study was to find the relationship between vitamin B12 and its precursor methylmalonic acid (MMA) in IPD patients with neuropathic pain. We performed a cross-sectional study by enrolling consecutive 43 patients who were clinically tested positive for F-18 FP-CIT PET and 15 patients were diagnosed with peripheral neuropathy according to the Toronto clinical scoring system (TCSS). The severity of neuropathic pain was evaluated using total neuropathy scale, revised (TNSr), and Korean Neuropathic Pain Questionnaire (KNPQ). The correlations between age, IPD duration, levodopa equivalent dose (LED), UPDRS III, vitamin B12, MMA, and homocysteine levels were assessed. The prevalence rate of peripheral neuropathy in IPD patients was 35%. Among the serums assessed, MMA levels showed a positive correlation to TNSr and KNPQ in the IPD patients with peripheral neuropathy (TNSr r = 0.882, p < 0.001, KNPQ r = 0.710, p = 0.004), while Vitamin B12 and homocysteine showed no statistically significant correlation. Our study showed a prevalence of peripheral neuropathy in 35% of Korean IPD patients. The serum MMA positively correlated with the severity of neuropathic pain and this can be used as a useful marker in assessment of peripheral neuropathy in Parkinson's disease. PMID- 28726052 TI - Transcranial sonography image characteristics in different Parkinson's disease subtypes. AB - Recently, Parkinson's disease (PD) has been classified into three subtypes: postural instability gait difficulty (PIGD), tremor dominate (TD), and indeterminate PD. Transcranial sonography (TCS) is considered to be an important tool to diagnose PD. However, it is uncertain that whether there are differences in TCS image characteristics in different PD subtypes, so 373 idiopathic PD (188 PIGD, 108 TD, 77 indeterminate PD) were registered and received TCS in our investigation; also, the association between clinical characteristics and TCS results in different PD subtypes was analyzed. In accordance with several previous studies, we detected substantia nigra (SN) by TCS in 85.4% of patients with idiopathic PD; we concluded that PIGD patients had more serious disease than TD and indeterminate PD group (p < 0.05). They always had larger SN hyperechogenicity areas on TCS (p < 0.05), and we found that there was no correlation between SN hyperechogenicity and disease duration or severity (p > 0.05). Similarly, abnormal brainstem raphe signal was also more often in PIGD group than in TD and indeterminate PD group (p < 0.05), which might imply that PIGD group was vulnerable to suffer from depression in the future. PMID- 28726053 TI - The effect of different ankle and knee supports on balance in early ambulation of post-stroke hemiplegic patients. AB - The purpose of this study was to compare the effects of different ankle and knee supports on balance in early ambulation of post-stroke hemiplegic patients. This is a randomized experimental study. The study sample included 20 hemiplegic patients who were able to stand with support and who had been diagnosed with a cerebrovascular accident within the last month. A knee immobilization brace (KIB) was first placed on each individual (first application), followed by placement of knee immobilizer brace and Foot Lifter Orthosis (r) (FLO) (second application), and lastly, placement of KIB and rigid taping (RT) (third application). The balance parameters of the patients were evaluated using the Korebalance system. The mean age of the patients was 65.1 +/- 4.7 years, and the mean number of days that had passed since stroke occurred was 14.6 +/- 4.97. In calculating the front/left balance scores of the applications, statistically significant differences were observed in the comparisons of all three supports and first second applications performed (p = 0.041 and p = 0.021, respectively). Regarding the total scores between the applications, statistically significant differences were determined in balance in the comparisons on all three supports, in comparisons between the first and second applications, and in the comparisons between the second and third applications (p = 0.004, p = 0.007, and p = 0.001, respectively). Based on the findings from this study, it is recommended that the use of a knee immobilizer brace in combination with a foot lifter orthosis for post-stroke hemiplegic patients in early ambulation can lead to considerably improved standing balance. PMID- 28726054 TI - Reply to: "the complex interrelations between two paroxysmal disorders: headache and epilepsy". PMID- 28726055 TI - An IGRT margin concept for pelvic lymph nodes in high-risk prostate cancer. AB - PURPOSE: Gold-marker-based image-guided radiation therapy (IGRT) of the prostate allows to correct for inter- and intrafraction motion and therefore to safely reduce margins for the prostate planning target volume (PTV). However, pelvic PTVs, when coadministered in a single plan (registered to gold markers [GM]), require reassessment of the margin concept since prostate movement is independent from the pelvic bony anatomy to which the lymphatics are usually referenced to. METHODS: We have therefore revisited prostate translational movement relative to the bony anatomy to obtain adequate margins for the pelvic PTVs compensating mismatch resulting from referencing pelvic target volumes to GMs in the prostate. Prostate movement was analyzed in a set of 28 patients (25 fractions each, totaling in 684 fractions) and the required margins calculated for the pelvic PTVs according to Van Herk's margin formula [Formula: see text]. RESULTS: The overall mean prostate movement relative to bony anatomy was 0.9 +/- 3.1, 0.6 +/- 3.4, and 0.0 +/- 0.7 mm in anterior/posterior (A/P), inferior/superior (I/S) and left/right (L/R) direction, respectively. Calculated margins to compensate for the resulting mismatch to bony anatomy were 9/9/2 mm in A/P, I/S, and L/R direction and 10/11/6 mm if an additional residual error of 2 mm was assumed. CONCLUSION: GM-based IGRT for pelvic PTVs is feasible if margins are adapted accordingly. Margins could be reduced further if systematic errors which are introduced during the planning CT were eliminated. PMID- 28726056 TI - Interobserver variability of patient positioning using four different CT datasets for image registration in lung stereotactic body radiotherapy. AB - PURPOSE: To assess the impact of different reference CT datasets on manual image registration with free-breathing three-dimensional (3D) cone beam CTs (FB-CBCT) for patient positioning by several observers. METHODS: For 48 patients with lung lesions, manual image registration with FB-CBCTs was performed by four observers. A slow planning CT (PCT), average intensity projection (AIP), maximum intensity projection (MIP), and midventilation CT (MidV) were used as reference images. Couch shift differences between the four reference CT datasets for each observer as well as shift differences between the observers for the same reference CT dataset were determined. Statistical analyses were performed and correlations between the registration differences and the 3D tumor motion and the CBCT score were calculated. RESULTS: The mean 3D shift difference between different reference CT datasets was the smallest for AIPvsMIP (range 1.1-2.2 mm) and the largest for MidVvsPCT (2.8-3.5 mm) with differences >10 mm. The 3D shifts showed partially significant correlations to 3D tumor motion and CBCT score. The interobserver comparison for the same reference CTs resulted in the smallest ?3D mean differences and mean ?3D standard deviation for ?AIP (1.5 +/- 0.7 mm, 0.7 +/ 0.4 mm). The maximal 3D shift difference between observers was 10.4 mm (?MidV). Both 3D tumor motion and mean CBCT score correlated with the shift differences (Rs = 0.336-0.740). CONCLUSION: The applied reference CT dataset impacts image registration and causes interobserver variabilities. The 3D tumor motion and CBCT quality affect shift differences. The smallest differences were found for AIP which might be the most appropriate CT dataset for image registration with FB CBCT. PMID- 28726058 TI - [Rational diagnosis and treatment of male infertility]. AB - Male infertility can be diagnosed by evaluation of the (female and) male history with respect to risk factors, and includes scrotal sonography, hormone and semen measurements. In severe male factor infertility, genetic testing is indicated. Treatment options vary between preventive, medical or surgical strategies depending on the underlying diagnosis. Assisted reproductive techniques may be applied as a consequence of the couple's infertility profile. PMID- 28726057 TI - Macrophage migration inhibitory factor (MIF) modulates trophic signaling through interaction with serine protease HTRA1. AB - Macrophage migration inhibitory factor (MIF), a small conserved protein, is abundant in the immune- and central nervous system (CNS). MIF has several receptors and binding partners that can modulate its action on a cellular level. It is upregulated in neurodegenerative diseases and cancer although its function is far from clear. Here, we report the finding of a new binding partner to MIF, the serine protease HTRA1. This enzyme cleaves several growth factors, extracellular matrix molecules and is implicated in some of the same diseases as MIF. We show that the function of the binding between MIF and HTRA1 is to inhibit the proteolytic activity of HTRA1, modulating the availability of molecules that can change cell growth and differentiation. MIF is therefore the first endogenous inhibitor ever found for HTRA1. It was found that both molecules were present in astrocytes and that the functional binding has the ability to modulate astrocytic activities important in development and disease of the CNS. PMID- 28726059 TI - Professional Ethics for Digital Age Psychiatry: Boundaries, Privacy, and Communication. AB - PURPOSE OF REVIEW: Internet and social media use continue to expand rapidly. Many patients and psychiatrists are bringing digital technologies into the treatment process, but relatively little attention has been paid to the ethical challenges in doing this. This review presents ethical guidelines for psychiatry in the digital age. RECENT FINDINGS: Surveys demonstrate that patients are eager to make digital technologies part of their treatment. Substantial numbers search for professional and personal information about their therapists. Attitudes among psychiatrists about using digital technologies with patients range from dread to enthusiastic adoption. Digital technologies create four major ethical challenges for psychiatry: managing clinical boundaries; maintaining privacy and confidentiality; establishing realistic expectations regarding digital communications; and upholding professional ideals. Traditional ethical expectations are valid for the evolving digital arena, but guidance must be adapted for actual application in practice. PMID- 28726060 TI - Psychosocial Issues in Patients with Head and Neck Cancer: an Updated Review with a Focus on Clinical Interventions. AB - PURPOSE OF REVIEW: There are frequent and diverse psychosocial issues that afflict patients with head and neck cancer (HNC) across the illness trajectory, prompting a focus on clinical interventions to prevent and mitigate psychosocial distress. We sought to characterize current understanding on the cause, effects, and interplay of various psychosocial factors in HNC and summarize updated, evidence-based interventions. RECENT FINDINGS: The psychosocial experience of patients with HNC is characterized by a disproportionately high incidence of depression, suicide, continued substance dependence/abuse, and distress related to relationship conflict, social isolation, disfigurement, and damage to self image. As we move towards a more thorough understanding and greater appreciation of the relationship between HNC and patient quality of life (QoL), future research focuses on implementation of effective, accessible clinical interventions to alleviate psychosocial distress in this population. PMID- 28726061 TI - Advances in Psychotherapy for Depressed Older Adults. AB - PURPOSE OF REVIEW: We review recent advances in psychotherapies for depressed older adults, in particular those developed for special populations characterized by chronic medical illness, acute medical illness, cognitive impairment, and suicide risk factors. We review adaptations for psychotherapy to overcome barriers to its accessibility in non-specialty settings such as primary care, homebound or hard-to-reach older adults, and social service settings. RECENT FINDINGS: Recent evidence supports the effectiveness of psychotherapies that target late-life depression in the context of specific comorbid conditions including COPD, heart failure, Parkinson's disease, stroke and other acute conditions, cognitive impairment, and suicide risk. Growing evidence supports the feasibility, acceptability, and effectiveness of psychotherapy modified for a variety of health care and social service settings. Research supports the benefits of selecting the type of psychotherapy based on a comprehensive assessment of the older adult's psychiatric, medical, functional, and cognitive status, and tailoring psychotherapy to the settings in which older depressed adults are most likely to present. PMID- 28726062 TI - Valproic Acid in Women and Girls of Childbearing Age. AB - PURPOSE OF REVIEW: The aim of this paper is to evaluate recent literature on valproic acid (VPA) in women and girls of childbearing age and to emphasize new findings. RECENT FINDINGS: Recent research confirms VPAs teratogenicity and risk of hormone disruption. VPA exposure in utero increases the risk for a variety of major congenital malformations (MCMs), reduced IQ and behavioral problems. In girls and women, VPA increases the risk of hormone abnormalities, obesity, and polycystic ovarian syndrome (PCOS). Despite guidelines recommending caution, VPA use continues to be prescribed to reproductive-aged women and girls. Despite significant and well-documented risk, adherence to guidelines in VPA use in reproductive-aged girls and women remains low. PMID- 28726063 TI - Gaze-Based Assessments of Vigilance and Avoidance in Social Anxiety: a Review. AB - PURPOSE OF REVIEW: A broad base of research has sought to identify the biases in selective attention which characterize social anxiety, with the emergent use of eye tracking-based methods. This article seeks to provide a review of eye tracking studies examining selective attention biases in social anxiety. RECENT FINDINGS: Across a number of contexts, social anxiety may be associated with a mix of both vigilant and avoidant patterns of attention with respect to the processing of emotional social stimuli. Socially anxious individuals may additionally avoid maintaining eye contact and may exhibit a generalized vigilance via hyperscanning of their environment. The findings highlight the utility of eye tracking methods for increasing understanding of the gaze-based biases which characterize social anxiety disorder, with promising avenues for future research. PMID- 28726064 TI - Research Debate on 'Older Carers and Work' in Sub-Saharan Africa? Current Gaps and Future Frames. AB - Scientific debate on the interface of work and caregiving responsibilities among older adults is intensifying, yet it has had little resonance in African aging discourses thus far. In this commentary we explore the nature and possible reasons for the gap, and highlight a possible frame, and potential avenues for redressing it as part of an emergent research and policy endeavor on long-term care for older persons. PMID- 28726065 TI - Automatic referral to standardize palliative care access: an international Delphi survey. AB - PURPOSE: Palliative care referral is primarily based on clinician judgment, contributing to highly variable access. Standardized criteria to trigger automatic referral have been proposed, but it remains unclear how best to apply them in practice. We conducted a Delphi study of international experts to identify a consensus for the use of standardized criteria to trigger automatic referral. METHODS: Sixty international experts stated their level of agreement for 14 statements regarding the use of clinician-based referral and automatic referral over two Delphi rounds. A consensus was defined as an agreement of >=70% a priori. RESULTS: The response rate was 59/60 (98%) for the first round and 56/60 (93%) for the second round. Twenty-six (43%), 19 (32%), and 11 (18%) respondents were from North America, Asia/Australia, and Europe, respectively. The panel reached consensus that outpatient palliative care referral should be based on both automatic referral and clinician-based referral (agreement = 86%). Only 18% felt that referral should be clinician-based alone, and only 7% agreed that referral should be based on automatic referral only. There was consensus that automatic referral criteria may increase the number of referrals (agreement = 98%), facilitate earlier palliative care access, and help administrators to set benchmarks for quality improvement (agreement = 86%). CONCLUSIONS: Our panelists favored the combination of automatic referral to augment clinician-based referral. This integrated referral framework may inform policy and program development. PMID- 28726066 TI - Palliative care needs in hospitalized cancer patients: a 5-year follow-up study. AB - PURPOSE: The aims of this study were to describe and compare diagnoses, symptoms, and care needs in palliative cancer patients in two medium-sized hospitals in a county council with no specialized palliative care available 24/7; to analyze the relationships between diagnosis and symptoms/care needs; and to compare results and trends from two datasets (from 2007 and 2012). METHODS: The study was population-based with a cross-sectional design and was conducted at two acute care hospitals. We performed 142 one-day inventories (n = 2972) in 2007 and 139 in 2012 (n = 2843) to register symptoms, care needs, and diagnosis based on a questionnaire. Multiple logistic regression models were used in the analysis. RESULTS: During 2007 and 2012 combined, 10% (n = 589) of hospitalized patients were assessed as having cancer in a palliative phase. Prostate (12%) and colorectal (12%) cancers were most common. Pain (42%) and deterioration (42%) were the most prevalent symptoms and were associated with pancreas cancer in our regression models (p = 0.003 and p = 0.019, respectively). Other cancers had different associations: hematologic malignancies were associated with infections and blood transfusions (p < 0.001), breast cancer with pleurocentesis (p = 0.002), and stomach/esophagus cancer with nausea (p < 0.001). Nausea was more common in women than in men (p < 0.01). The mean number of symptoms/care needs was 2.9; patients with stomach/esophagus cancer had the highest number of symptoms/care needs (3.5). CONCLUSIONS: Acute care hospitals still play an important role for patients requiring palliative care. Symptoms and care needs were not strongly associated with specific diagnoses. Therefore, symptoms, rather than the specific cancer diagnoses, should be the focus of care. PMID- 28726067 TI - Lifestyle advice provision to teenage and young adult cancer patients: the perspective of health professionals in the UK. AB - PURPOSE: Health professionals are an important source of information for teenage and young adult (TYA) cancer patients. However, little is known about health professionals' provision of lifestyle advice to young people with cancer who are in their care. METHODS: An online survey was distributed to health professionals within the UK who identified themselves as working with TYA cancer patients. Health professional awareness of lifestyle guidance, provision of lifestyle advice to young people and views on lifestyle information format and delivery were explored. RESULTS: Ninety-five health professionals (44% nurses; 28% allied health professionals; 17% physicians) completed the survey. The majority (72%) of respondents were aware of some lifestyle guidance for cancer patients. However, less than half of TYA health professionals (46%) were able to successfully recall the source of the guidelines and less than a third reported proving specific advice to the majority of their patients on weight management, smoking, alcohol consumption and sun safety. Many health professionals (38%) felt that they were not the right person to provide advice and cited lack of resources as a key barrier to advice provision. The majority (95%) reported being interested in a resource containing relevant lifestyle information that could be given to young people with cancer. CONCLUSIONS: TYA health professionals' awareness of lifestyle guidance and provision of advice regarding health behaviour is sub-optimal. Clear and comprehensive guidance written specifically for TYA health professionals could overcome the reported barriers and improve professionals' confidence in addressing and providing advice on lifestyle to young people with cancer. PMID- 28726069 TI - Loss of sirtuin 4 leads to elevated glucose- and leucine-stimulated insulin levels and accelerated age-induced insulin resistance in multiple murine genetic backgrounds. AB - Several inherited metabolic disorders are associated with an accumulation of reactive acyl-CoA metabolites that can non-enzymatically react with lysine residues to modify proteins. While the role of acetylation is well-studied, the pathophysiological relevance of more recently discovered acyl modifications, including those found in inherited metabolic disorders, warrants further investigation. We recently showed that sirtuin 4 (SIRT4) removes glutaryl, 3 hydroxy-3-methylglutaryl, 3-methylglutaryl, and 3-methylglutaconyl modifications from lysine residues. Thus, we used SIRT4 knockout mice, which can accumulate these novel post-translational modifications, as a model to investigate their physiological relevance. Since SIRT4 is localized to mitochondria and previous reports have shown SIRT4 influences metabolism, we thoroughly characterized glucose and lipid metabolism in male and female SIRT4KO mice across different genetic backgrounds. While only minor perturbations in overall lipid metabolism were observed, we found SIRT4KO mice consistently had elevated glucose- and leucine-stimulated insulin levels in vivo and developed accelerated age-induced insulin resistance. Importantly, elevated leucine-stimulated insulin levels in SIRT4KO mice were dependent upon genetic background since SIRT4KO mice on a C57BL/6NJ genetic background had elevated leucine-stimulated insulin levels but not SIRT4KO mice on the C57BL/6J background. Taken together, the data suggest that accumulation of acyl modifications on proteins in inherited metabolic disorders may contribute to the overall metabolic dysfunction seen in these patients. PMID- 28726068 TI - Cardiac complications of congenital disorders of glycosylation (CDG): a systematic review of the literature. AB - Congenital disorders of glycosylation (CDG) are inborn errors of metabolism due to protein and lipid hypoglycosylation. This rapidly growing family of genetic diseases comprises 103 CDG types, with a broad phenotypic diversity ranging from mild to severe poly-organ -system dysfunction. This literature review summarizes cardiac involvement, reported in 20% of CDG. CDG with cardiac involvement were divided according to the associated type of glycosylation: N-glycosylation, O glycosylation, dolichol synthesis, glycosylphosphatidylinositol (GPI)-anchor biosynthesis, COG complex, V-ATPase complex, and other glycosylation pathways. The aim of this review was to document and interpret the incidence of heart disease in CDG patients. Heart disorders were grouped into cardiomyopathies, structural defects, and arrhythmogenic disorders. This work may contribute to improved early management of cardiac complications in CDG. PMID- 28726070 TI - [Flow density measurements using optical coherence tomography angiography : Impact of age and gender]. AB - BACKGROUND: This article presents the normative data for flow density measured using optical coherence tomography (OCT) angiography and the impact of age and gender is evaluated. METHODS: In this study 58 eyes from 58 healthy volunteers with no history of any ocular disease or ocular surgery were included. The OCT angiography imaging was performed using the RTVue XR Avanti with the AngioVue (Optovue, Fremont, CA). The macula was imaged using a 3 * 3 mm scan, and the flow density data in the superficial retinal OCT angiogram and deep retinal OCT angiogram were extracted and analyzed. The groups were compared using the Mann Whitney U-test and the degree of correlation between two variables was expressed as the Spearman's correlation coefficient (rSp.) RESULTS: The mean subject age was 38.3 +/- 14.6 years. The flow density (whole en face) in the deep retinal OCT angiogram was significantly higher compared to the flow density in the superficial retinal OCT angiogram (p < 0.001). There was no significant difference in the mean flow density in superficial and deep OCT angiograms of the macula between males (n = 27) and females (n = 31). There was a significant correlation between the flow density in the deep retinal OCT angiogram and age (rSp. = -0.41, p = 0.001). CONCLUSION: Whereas gender has no impact on the flow density measured using OCT angiography, there was a significant correlation between the flow density in the deep retinal OCT angiogram and age. PMID- 28726071 TI - The legend of Medusa with snake hair in Didymaion, in Didyma, Turkey. PMID- 28726072 TI - Concentration of Thyrotropic Hormone in Persons Occupationally Exposed to Lead, Cadmium and Arsenic. AB - Thyroid hormones are essential for body homeostasis. The scientific literature contains restricted proofs for effects of environmental chemical factors on thyroid function. The present study aimed at evaluating the relationship between toxicological parameters and concentration of thyrotropic hormone in persons occupationally exposed to lead, cadmium and arsenic. The studies were conducted on 102 consecutive workers occupationally exposed to lead, cadmium and arsenic (mean age 45.08 +/- 9.87 years). The estimated parameters characterizing occupational exposure to metals included blood cadmium concentration (Cd-B), blood lead concentration (Pb-B), blood zinc protoporphyrin concentration (ZnPP) and urine arsenic concentration (As-U). Thyroid function was evaluated using the parameter employed in screening studies, the blood thyrotropic hormone concentration (TSH). No differences were disclosed in mean values of toxicological parameters between the subgroup of persons occupationally exposed to lead, cadmium and arsenic with TSH in and out of the accepted normal values. Logistic regression demonstrated that higher blood total bilirubin concentrations (ORu = 4.101; p = 0.025) and higher Cd-B (ORu = 1.532; p = 0.027) represented independent risk factors of abnormal values of TSH in this group. In conclusion, in the group of workers exposed to lead, cadmium and arsenic, higher blood cadmium concentration seems to augment the risk of abnormal hormonal thyroid function. PMID- 28726073 TI - Investigation of Heavy Metal Level and Mineral Nutrient Status in Widely Used Medicinal Plants' Leaves in Turkey: Insights into Health Implications. AB - The use of plants in treatments has been as old as humanity and it has preserved its popularity for centuries til now because of their availability, affordability and safeness. However, despite their widespread use, safety and quality issues have been major concerns in the world due to industrial- and anthropogenic-based heavy metal contamination risks. Thus, this study was attempted to analyze the heavy metal levels and mineral nutrient status of widely used medicinal plants in Turkey to have insights about their health implications on humans. The plant concentrations of B, Ca, Cd, Cr, Cu, Fe, K, Mg, Mn, Na, Ni, Pb and Zn were analyzed by ICP-OES in the leaves of 44 medical plants purchased from herbal markets of three different districts of Istanbul/Turkey. The measured lowest to highest concentrations were 0.065-79.749 mg kg-1 B, 921.802-12,854.410 mg kg-1 Ca, 0.020-0.558 mg kg-1 Cd, 0.015-4.978 mg kg-1 Cr, 0.042-8.489 mg kg-1 Cu, 34.356-858.446 mg kg-1 Fe, 791.323-15,569.349 mg kg-1 K, 102.236-2837.836 mg kg-1 Mg, 4.915-91.519 mg kg-1 Mn, 10.224-3213.703 mg kg-1 Na, 0.001-5.589 mg kg-1 Ni, 0.003-3.636 mg kg-1 Pb and 2.601-36.102 mg kg-1 Zn. Those levels in plants were in acceptable limits though some elements in some plants have high limits which were not harmful. Variations (above acceptable limits) in element concentrations also indicated that these plants could be contaminated with other metals and that genetic variations may influence accumulation of these elements at different contents. Overall, analyzed medicinal plants are expected not to pose any serious threat to human health. PMID- 28726074 TI - Error performances of a model-based biplane fluoroscopic system for tracking knee prosthesis during treadmill gait task. AB - Roentgen stereophotogrammetry analysis technique allows an accurate measurement of knee joint prosthesis position and orientation using two X-ray images. Although this technique is used generally during static procedure, it is possible to use it with a biplane fluoroscopic system to measure the prosthesis kinematics during functional tasks (e.g., gait, squat, jump) performed in a laboratory environment. However, the performance of the system in terms of errors for the measurements and the model-based matching algorithm are not well known for dynamic tasks such as walking. The goal of this study was to estimate the static and dynamic errors of a model-based biplane fluoroscopic system for a treadmill gait task and analyze the error performance according to the speed and location of the knee joint prosthesis relative to X-ray sources. The results show a static maximum error (RMSE) of 0.13 degrees for orientation and 0.06 mm for position for prosthesis components. The dynamic errors were different for each axis of the acquisition system and each prosthesis component. The largest dynamic error was along the vertical axis for the position (RMSE = 2.42 mm) and along the medio lateral axis (perpendicular to movement) for the orientation (RMSE = 0.95 degrees ). As expected, the error depends on the distance between the prosthesis and the source in the acquisition system as well as the linear and angular velocity of the movement. The most accurate dynamic measure was around the centroid of the acquisition system, while kinematics measurements close to the X-rays detectors gave the worst errors. PMID- 28726075 TI - Effectiveness, Adverse Effects and Drug Compliance of Long-Acting Injectable Risperidone in Children and Adolescents. AB - BACKGROUND AND OBJECTIVES: Although the use of oral risperidone in children and adolescents has been well studied, there is little information on the intramuscular use of long-acting injectable risperidone (LAIR). The aims of this study were to investigate the effectiveness and adverse effects of LAIR in children and adolescents with conduct disorder, bipolar disorder, and schizophrenia. METHODS: In total, 42 patients (age range 12-17 years) who were non-adherent to oral antipsychotic drugs, received 25 mg of LAIR intramuscularly every 2 weeks. The drug was administered at least four times and up to 66 times (median drug use: 9.50 times). The effectiveness and adverse effects of the treatment were examined. RESULTS: There was an improvement in 13 (92.8%) of the 14 patients diagnosed with bipolar disorder, in 25 (78.1%) of 32 patients diagnosed with conduct disorder and in one (50%) of two patients diagnosed with schizophrenia. Six patients had comorbid conduct disorder and bipolar disorder. Totally, 81% of the patients improved with LAIR. Weight-gain, daytime somnolence, muscle stiffness and spasms, impaired concentration, and fatigue were the most common side effects through the whole sample. Menstrual problems were common in girls. In the study, 57.1% of the patients continued to receive their injections regularly until the end of the treatment, under physician control. A total of 16.7% discontinued the treatment due to non-adherence. The LAIR treatment was terminated in 26.2% of the patients, due to weight-gain, dystonia, and galactorrhea. CONCLUSIONS: In children and adolescents with conduct disorder, bipolar disorder and schizophrenia who show noncompliance with oral drugs, LAIR may improve treatment compliance. LAIR is a reliable treatment in terms of its effectiveness. Weight-gain, dystonia, and galactorrhea were the adverse effects that were responsible for LAIR treatment cessation. PMID- 28726076 TI - Ejection fraction in myocardial perfusion imaging assessed with a dynamic phantom: comparison between IQ-SPECT and LEHR. AB - BACKGROUND: Developments in single photon emission tomography instrumentation and reconstruction methods present a potential for decreasing acquisition times. One of such recent options for myocardial perfusion imaging (MPI) is IQ-SPECT. This study was motivated by the inconsistency in the reported ejection fraction (EF) and left ventricular (LV) volume results between IQ-SPECT and more conventional low-energy high-resolution (LEHR) collimation protocols. IQ-SPECT and LEHR quantitative results were compared while the equivalent number of iterations (EI) was varied. The end-diastolic (EDV) and end-systolic volumes (ESV) and the derived EF values were investigated. A dynamic heart phantom was used to produce repeatable ESVs, EDVs and EFs. Phantom performance was verified by comparing the set EF values to those measured from a gated multi-slice X-ray computed tomography (CT) scan (EFTrue). The phantom with an EF setting of 45, 55, 65 and 70% was imaged with both IQ-SPECT and LEHR protocols. The data were reconstructed with different EI, and two commonly used clinical myocardium delineation software were used to evaluate the LV volumes. RESULTS: The CT verification showed that the phantom EF settings were repeatable and accurate with the EFTrue being within 1% point from the manufacture's nominal value. Depending on EI both MPI protocols can be made to produce correct EF estimates, but IQ-SPECT protocol produced on average 41 and 42% smaller EDV and ESV when compared to the phantom's volumes, while LEHR protocol underestimated volumes by 24 and 21%, respectively. The volume results were largely similar between the delineation methods used. CONCLUSIONS: The reconstruction parameters can greatly affect the volume estimates obtained from perfusion studies. IQ-SPECT produces systematically smaller LV volumes than the conventional LEHR MPI protocol. The volume estimates are also software dependent. PMID- 28726077 TI - Bioscore: A Staging System for Breast Cancer Patients that Reflects the Prognostic Significance of Underlying Tumor Biology. AB - BACKGROUND: Biologic factors guide treatment decisions and have a significant impact on prognosis for breast cancer patients. This study was undertaken to develop a staging system incorporating biologic factors in addition to standard anatomic factors in the American Joint Committee on Cancer (AJCC) pathologic stage (PS) to assess disease-specific survival (DSS). METHODS: Overall, 3327 patients treated with surgery as an initial intervention at MD Anderson Cancer Center from 2007 to 2013 were identified. Multivariate analyses of factors, including PS, T stage (T), nodal stage (N), grade (G), estrogen receptor (ER) status (E) and human epidermal growth factor receptor (HER2) status (H) were performed to identify associations with DSS. A score of 0-4 was assigned for each factor by considering the hazard ratio magnitude. Multiple staging system models were then constructed: PS, PS + G, PS + G + E, PS + G + E + H, T + N, T + N + G, T + N + G + E, and T + N + G + E + H. Model performance was quantified using Harrell's concordance index, and the Akaike Information Criterion (AIC) was used to compare model fits. Comparable cases from California (n = 67,944) were used for validation. RESULTS: Median follow-up was 5.0 years (range 0.1-8.8) and 5 year DSS was 97.9% (95% confidence interval 97.3-98.4). Models incorporating grade, ER status, and HER2 status were most precise with identical C-index (0.81) and comparable AIC (994.9 for PS + G + E + H and 987.8 for T + N + G + E + H). Both models were externally validated. CONCLUSIONS: These results confirm the importance of biologic factors in determining prognosis for breast cancer patients. We propose the Bioscore, which incorporates grade, ER and HER2 status with AJCC PS, to provide more refined stratification of breast cancer patients undergoing surgery as an initial intervention with respect to DSS. PMID- 28726078 TI - Peritoneal Lavage CEA mRNA Levels Predict Conversion Gastrectomy Outcomes after Induction Chemotherapy with Intraperitoneal Paclitaxel in Gastric Cancer Patients with Peritoneal Metastasis. AB - BACKGROUND: The outcome of gastric cancer patients with peritoneal metastasis remains poor. We treated these patients with intraperitoneal and intravenous paclitaxel plus oral S-1 (tegafur/gimeracil/oteracil), followed by gastrectomy in responders. We evaluated the clinical significance of peritoneal lavage carcinoembryonic antigen (CEA) messenger RNA (mRNA) levels as a biomarker for indication of conversion gastrectomy. METHODS: The peritoneal lavage of 68 patients who received the above regimen as induction chemotherapy was repeatedly collected via intraperitoneal access ports. Gastrectomy was considered when improvement of peritoneal metastasis was confirmed by a second laparoscopic examination with negative peritoneal cytology. CEA and porphobilinogen deaminase mRNAs were chronologically quantified using the transcription reverse transcription concerted reaction method. The CEA mRNA index (CmRI) was calculated as CEA mRNA/porphobilinogen deaminase mRNA * 10,000. RESULTS: Thirty-nine patients underwent gastrectomy and 29 patients did not (median survival time, 27.8 vs. 10.7 months, respectively; P < 0.001). In gastrectomy-positive patients, the outcome largely differed according to CmRI values immediately prior to surgery. Patients with a preoperative CmRI value <100 (n = 20) were associated with a significantly longer survival than those with a preoperative CmRI value >100 (n = 19) (41.8 vs. 20.1 months, respectively; P < 0.001). A preoperative CmRI value <100 was confirmed as an independent predictor of survival for gastrectomy-positive patients in the multivariate analysis. CONCLUSIONS: The CmRI reflects the response of peritoneal metastases to induction intraperitoneal chemotherapy. It may be a useful biomarker for indicating gastrectomy in gastric cancer patients with peritoneal metastasis. PMID- 28726079 TI - Bilirubin enzyme biosensor: potentiality and recent advances towards clinical bioanalysis. AB - Bilirubin detection plays a major role in healthcare. Its high concentration in human serum is lethal and must be determined accurately. Clinically, it is vital for assessing patients with deleterious health conditions such as jaundice or icterus, hepatitis, mental disorders, cerebral palsy and brain damage especially in the case of neonates. In evaluating the drawbacks regarding the conventional methodology of bilirubin detection, there is need for a superior analytical tool. Bilirubin oxidase (BOx)-based sensors have been designed for the ultrasensitive analysis of bilirubin and quality deliverance of treatment and this review highlights the different mechanisms of bilirubin detection using different modified electrodes. Further, it also addresses the exploitation of highly attractive electrocatalytic properties of elite nanoparticles such as gold and zirconia- coated silica nanoparticles in enhancing the reproducibility and specificity of bilirubin biosensors. PMID- 28726080 TI - Proteomic approach to address low seed germination in Cyclobalnopsis gilva. AB - Seeds play essential roles in plant life cycle and germination is a complex process which is associated with different phases of water imbibition. Upon imbibition, seeds begin utilization of storage substances coupled with metabolic activity and biosynthesis of new proteins. Regeneration of organelles and emergence of radicals lead to the establishment of seedlings. All these activities are regulated in coordinated manners. Translation is the requirement of germination of seeds via involvements of several proteins like beta-amylase, starch phosphorylase. Some important proteins involved in seed germination are discussed in this review. In the past decade, several proteomic studies regarding seed germination of various species such as rice, Arabidopsis have been conducted. We face A paucity of proteomic data with respect to woody plants e.g. Fagus, Pheonix etc. With particular reference to Cyclobalnopsis gilva, a woody plant having low seed germination rate, no proteomic studies have been conducted. The review aims to reveal the complex seed germination mechanisms from woody and herbaceous plants that will help in understanding different seed germination phases and the involved proteins in C. gilva. PMID- 28726081 TI - Psoas muscle volume as a predictor of peripheral neurotoxicity induced by primary chemotherapy in ovarian cancers. AB - PURPOSE: Low skeletal muscle mass (sarcopenia) has been reported to have an influence on survival and toxicities of chemotherapy in several solid tumors. The impact of sarcopenia on the treatment of ovarian cancers has not been determined. The present study aimed to evaluate correlation between sarcopenia and toxicities of chemotherapy in ovarian cancers. METHODS: Medical charts of the ovarian cancer patients that received chemotherapy with paclitaxel and carboplatin at our hospital between 2010 and 2015 were retrospectively reviewed. Muscle areas of bilateral psoas major muscles at the fifth lumbar vertebra were measured using images obtained by computed tomography. The volume of muscle and clinicopathological factors were evaluated for toxicities of chemotherapy. The protocol of the present study was approved by the institutional review board of our institution. RESULTS: A total of 76 patients with ovarian cancers were identified, and enrolled in the present study. Median psoas index (PI, the psoas muscle major cross-sectional area divided by the height squared) was 583 mm2/m2 (range 326-999). The patients with low PI developed peripheral neuropathy more frequently compared with those with high PI (32 vs. 11%; P = 0.047). PI value was not associated with other toxicities such as neutropenia and thrombocytopenia. PI value was associated with grade 2 or higher peripheral neuropathy in univariate analysis (OR = 3.92; 95% CI 1.21-15.32; P = 0.02) and multivariate analysis (OR = 3.93; 95% CI 1.17-15.87; P = 0.03). CONCLUSIONS: PI value was significantly associated with peripheral neuropathy induced by combination therapy with paclitaxel and carboplatin in ovarian cancer patients. Although further studies are needed to confirm the results, the volume of skeletal muscle mass could be a potential biomarker to predict toxicities in ovarian cancer patients. PMID- 28726082 TI - Undergraduate Minor in Health Disparities in Society: a Magnet for Under represented Pre-professional Students. AB - Increasing the diversity of tomorrow's healthcare work force remains a challenge despite many thoughtful published reports and recommendations. As part of an effort to grow a more diverse pre-professional health population, we created an undergraduate minor, Health Disparities in Society, at the University of Florida. Most courses for the minor were identified from existing offerings, and we created only two new courses, an introduction course and a capstone service learning course. The new minor quickly became the most popular in the College of Liberal Arts and Sciences (which has approximately 12,000 total undergraduate students), and importantly, students selecting the minor were more likely to be under-represented minorities than would be expected given undergraduate demographics. Pre-professional students choosing this minor reflect the desired diversity of the healthcare workforce of tomorrow. PMID- 28726083 TI - Exploring Factors Associated with Declining HIV Diagnoses Among African American Females. AB - HIV diagnoses among females in the USA declined 40% during 2005-2014 with the largest decline (42%) among Black/African Americans. African American females remain disproportionately affected. We explored contributions of STD rates and sexual risk behaviors among African American females, HIV diagnoses among potential male partners, and sexual risk behaviors and viral suppression rates among HIV-positive potential male partners to declining rates of HIV diagnoses among African American females. Results suggest temporal trends in the factors that increase HIV infectiousness and transmissibility within sexual networks, i.e., decreases in rates of other sexually transmitted infections among African American females, decreases in HIV diagnoses among potential male partners, and increases in viral suppression among heterosexual and bisexual HIV-positive potential male partners in care, may explain the decline. Findings highlight a need for future research that provides context to the sexual risk behaviors and sexual network factors in order to continue progress. PMID- 28726084 TI - ACMT Recommends Against Use of Post-Chelator Challenge Urinary Metal Testing. PMID- 28726086 TI - Factor Structure and Sensitivity to Change of the Recovery Assessment Scale. AB - The focus on recovery, not just symptom reduction, in mental health care brings a need for psychometrically sound measures of recovery. This study examined the factor structure and sensitivity to change of a common measure of mental health recovery, the Recovery Assessment Scale (RAS). We conducted a secondary data analysis from a randomized clinical trial of self-management for depression (n = 302). We tested both bifactor and the previously found five-factor model. Sensitivity to change was examined three ways: (1) between the intervention and control group; (2) across time in the intervention group; and (3) in those whose depression remitted. The previous five-factor model was supported. One subscale, no domination by symptoms, was particularly sensitive to change and showed sensitivity to change whereas the subscale reliance on others did not show change in any of the comparisons. Results suggest that the subscales of the RAS should be examined separately in future studies of recovery. PMID- 28726087 TI - Population specific analysis of Yakut exomes. AB - We studied the genetic diversity of the Yakut population using exome sequencing. We performed comparative analysis of the Yakut population and the populations that are included in the "1000 Genomes" project and we identified the alleles specific to the Yakut population. We showed, that the Yakuts population is a separate cluster between Europeans and East Asians. PMID- 28726085 TI - MicroRNAs in mucosal inflammation. AB - Of the total human body's surface, the majority is internal surface, belonging to the lungs (100 m2) and intestinal tract (400 m2). In comparison, the external surface area, belonging to the skin, comprises less than 1% (2 m2). Continuous exposure of the mucosal surface to external factors (e.g., pathogens, food particles) requires tight regulation to maintain homeostasis. MicroRNAs (miRNAs) have gained noticeable attention as playing important roles in maintaining the steady-state of tissues by modulating immune functions and inflammatory responses. Accordingly, associations have been found between miRNA expression levels and human health conditions and diseases. These findings have important implications in inflammatory diseases involving pulmonary and intestinal mucosa, such as acute lung injury or inflammatory bowel disease. In this review, we highlight the known biology of miRNAs and discuss the role of miRNAs in modulating mucosal defense and homeostasis. Additionally, we discuss miRNAs serving as potential therapeutic targets to treat immunological conditions, particularly mucosal inflammation. PMID- 28726088 TI - Involvement of two-pore channels in hydrogen peroxide-induced increase in the level of calcium ions in the cytoplasm of human umbilical vein endothelial cells. AB - Hydrogen peroxide at concentrations below cytotoxic ones causes an increase in the cytoplasmic calcium concentration in human umbilical vein endothelial cells as a result of calcium release from intracellular stores. Two-pore calcium channel blocker trans-NED19 partially suppresses the increase in the level of calcium ions in the cells in response to the addition of hydrogen peroxide. The staining of endothelial cells with the fluorescent stereoisomer cis-NED19 and LysoTracker confirmed the localization of two-pore calcium channels in lysosomes and endolysosomal vesicles. PMID- 28726089 TI - Oxidation-induced modification of the fibrinogen polypeptide chains. AB - By using the mass-spectrometry method, the oxidative modifications of the fibrinogen Aalpha, Bbeta, and gamma polypeptide chains induced by its oxidation have been studied. The alphaC-region has been proven to be the most vulnerable target for the oxidizer (ozone) as compared with the other structural elements of the Aalpha chain. The Bbeta chain mapping shows that the oxidative sites are localized within all the structural elements of the chain in which the beta nodule exhibits high susceptibility to oxidation. The gamma chains are the least vulnerable to the oxidizer action. The results obtained demonstrate convincingly that the self-assembly centers dealing with interactions of knob "A": hole "a" are not involved in oxidative modification. It is concluded that the numerous oxidative sites revealed are mainly responsible for inhibiting lateral aggregation of protofibrils. The part of amino acid residues subjected to oxidation is supposed to carry out the antioxidant function. PMID- 28726090 TI - Flavoprotein miniSOG BRET-induced cytotoxicity depends on its intracellular localization. AB - It is proposed to use the bioluminescent resonance energy transfer to solve the problem of creating the internal light sources in photodynamic therapy of cancer. Energy donor in the developed system is the oxidized form of the luciferase NanoLuc substrate furimamide, and acceptor is the phototoxic fluorescent protein miniSOG. It is shown that, in the proposed system, the photoinduced cytotoxicity of flavoprotein miniSOG in vitro depends on the intracellular localization, and the cytotoxic effect is 48% for the cytoplasmic localization of the fusion protein, 65% for the mitochondrial localization, and 69% for the membrane localization. The obtained data indicate that, for maximization of the photodynamic effect in vivo, it is appropriate to use the NanoLuc-miniSOG fusion protein in the membrane localization. PMID- 28726091 TI - Modification of human serum albumin under induced oxidation. AB - For the first time, by using the complex of physicochemical methods (mass spectrometry, differential scanning calorimetry, spectrofluorimetry, method of spectral and fluorescent probes, dynamic light scattering, and UV spectrophotometry), the oxidation-mediated modification of chemical and spatial structure of albumin has been studied. All albumin structural regions are subjected to oxidation, methionine and aromatic amino acids primarily involved in oxidation. The albumin melting shows a decrease in thermal stabilization of the structure and changing of aggregation upon oxidation. The change in physical and chemical properties of albumin under different quantity of the oxidizer has been analyzed. PMID- 28726092 TI - Homeotic MADS-box genes encoding LeMADS-MC orthologues in wild tomato species (genus Solanum). AB - New full-length genes encoding the LeMADS-MC transcription factor orthologues were identified and functionally characterized in wild tomato species S. cheesmaniae and S. habrochaites. A comparative analysis of the encoded proteins and LeMADS-MC of the cultivated tomato species S. lycopersicum revealed two major amino acid residues substitutions: V155E in the K-domain of ShaMADS-MC (S. habrochaites) and S80L in the I-region of SchMADS-MC (S. cheesmaniae). Structural differences of the C-terminal regions of MC and the canonical euAP1 proteins indicate possible chromosomal rearrangements in the Solanoideae subfamily, which, however, did not change the main known conserved euAP1 functions. PMID- 28726093 TI - The fluorescence lifetime of lipofuscin granule fluorophores contained in the retinal pigment epithelium cells from human cadaver eyes in normal state and in the case of visualized pathology. AB - A comparative analysis of fluorescence lifetime of lipofuscin granule fluorophores contained in the retinal pigment epithelium cells from human cadaver eyes in normal state and in the case of visualized pathology was carried out. Measurements of fluorescence lifetimes of bis-retinoids and their photooxidation and photodegradation products were carried out using the method of counting time correlated photons. Comparative analysis showed that, in the case of visualized pathology, the contribution of photooxidation and photodegradation products of bis-retinoids to the total fluorescence of the retinal pigment epithelium cell suspension increases in comparison with the norm. PMID- 28726094 TI - Gene expression and content of enzymes of noradrenaline synthesis in the rat organ of Zuckerkandl at the critical period of morphogenesis. AB - Gene expression and content of the key enzymes involved in the synthesis of noradrenaline-tyrosine hydroxylase and dopamine beta-hydroxylase-was evaluated in the organ of Zuckerkandl of rats in the critical period of morphogenesis. High levels of mRNA and protein of both enzymes in the perinatal period of development and their sharp decline on day 30 of postnatal development were detected. These data indicate that the synthesis of noradrenaline in the organ of Zuckerkandl is maximum during the critical period of morphogenesis and decreases during the involution of this paraganglion. PMID- 28726095 TI - Fatty acid composition of fish species with different feeding habits from an Arctic Lake. AB - We compared the composition and content of fatty acids (FAs) in fish with different feeding habits (sardine (least) cisco Coregonus sardinella, goggle-eyed charr (pucheglazka) form of Salvelinus alpinus complex, humpback whitefish Coregonus pidschian, broad whitefish Coregonus nasus, boganid charr Salvelinus boganidae, and northern pike Esox lucius from an Arctic Lake. Feeding habits of the studied fish (planktivore, benthivore, or piscivore) significantly affected the composition of biomarker fatty acids and the ratio of stable isotopes of carbon and nitrogen in their biomass. The hypothesis on a higher content of eicosapentaenoic and docosahexaenoic acids in the fish of higher trophic level (piscivores) when compared within the same taxonomic group (order Salmoniformes) was confirmed. PMID- 28726096 TI - Identification and characterization of the flower meristem identity gene MhyLFY in mycoheterotrophic plant Monotropa hypopitys. AB - The gene encoding the transcription factor LEAFY was identified in the genome of the mycoheterotrophic plant, pinesap Monotropa hypopitys. In the transcriptomes of roots, bracts, and flowers of flowering pinesaps, the MhyLFY gene expression was absent. These data suggest the conservativeness of the LFY-dependent mechanism of flower meristem identity and flower formation in heterotrophic species with some differences associated to the specificity of development and the structure of such plants. The pinesap flowering under the control of the transcription factor MhyLFY may be initiated either in an embryonic inflorescence during spring dormancy release of adventitious root buds or in an inflorescence of a growing reproductive stem after photoperiodic induction. PMID- 28726097 TI - Kinetics of DNA elongation. AB - A mathematical model of the DNA elongation stage is proposed, and a formula for calculating the characteristic time of doubling a DNA strand consisting of a large numbers of nucleotides was derived. It is shown that, when the number of nucleotides is greater than 50, it is fair to use a linear dependence of the elongation time on the number of nucleotides. Calculations of the DNA elongation time for a number of organisms are given. PMID- 28726098 TI - Magnetic-dependent ATP pool in Escherichia coli. AB - The ATP pool in Escherichia coli is a magnetic-dependent characteristic of microorganism vital activity. It depends on the values of the external static magnetic field and the existence of magnetic moment of magnesium isotopes nuclei added to the growth nutrient medium. The combined effects of the magnetic field 70-95 mT and magnesium magnetic isotope 25Mg on E. coli bacteria leads to increase intracellular concentration of ATP. Magnetic-field effects in the range of 0.8-16 mT, registered for all bacteria regardless of the magnesium-isotopic enrichment of nutrient medium, evidence about the sensitivity of intracellular processes to weak magnetic fields. PMID- 28726099 TI - Lipoxygenases modulate the effect of glutoxim on Na+ transport in the frog skin epithelium. AB - Using voltage-clamp technique, the involvement of lipoxygenases in the effect of immunomodulatory drug glutoxim on Na+ transport in frog skin was investigated. It was shown for the first time that preincubation of the skin with lipoxygenase inhibitors caffeic acid, baicalein, and nordihydroguaiaretic acid significantly decreases the stimulatory effect of glutoxim on Na+ transport. The data suggest the involvement of lipoxygenase oxidation pathway of arachidonic acid metabolism in the glutoxim effect on Na+ transport in frog skin epithelium. PMID- 28726100 TI - MicroRNA in hormonal mechanisms of regulation of NK cell function. AB - We investigated the effect of human chorionic gonadotropin, estriol, leptin, ghrelin, and kisspeptin on the microRNA expression in separated NK cells. All of these hormones are able to effectively modulate the expression of microRNAs both stimulating and suppressing the cytotoxic potential of NK cells and thereby indirectly regulate the functions of these lymphocytes. PMID- 28726101 TI - Eukaryotic elongation factor 2 kinase activation in M. soleus under 14-day hindlimb unloading of rats. AB - Functional unloading of m. soleus of male Wistar rats was found to cause a reduction in protein synthesis. The level of phosphorylation of the translation elongation factor 2 (eEF2) and the eEF2 kinase (eEF2k) activity in m. soleus after 14 days of unloading were assessed. Rats were divided into the control group (C) and the group with hindlimb unloading for 14 days (HU14). The level of eEF2 phosphorylation in group HU14 was 80%, whereas in the control is was 40%. The indices of eEF2k expression and protein content in group HU14 increased compared to group C. PMID- 28726102 TI - Stereoselective biotransformation of phenylglycine nitrile by heterogeneous biocatalyst based on immobilized bacterial cells and enzyme preparation. AB - We studied the effect of a heterogeneous environment on the stereoselectivity of transformation of racemic phenylglycine nitrile. Immobilized biocatalysts were prepared by adhesion of Pseudomonas fluorescens C2 cells on carbon-containing supports and covalent crosslinking of nitrile hydratase and amidase of Rhodococcus rhodochrous 4-1 to activated chitosan as well as by the method of cross-linked aggregates. At a reaction duration of 20 h, the ratio of phenylglycine stereoisomers changes depending on the presence of support in medium. The highest optical purity of the product (enantiomeric excess of L phenylglycine solution, 98%) is achieved when enzyme aggregates of nitrile hydratase and amidase cross-linked with 0.1% glutaraldehyde are used as a biocatalyst. PMID- 28726103 TI - The effect of chlorpromazine on intracellular Ca2+ concentration in macrophages. AB - Using Fura-2AM microfluorimetry, it was shown for the first time that neuroleptic chlorpromazine causes intracellular Ca2+ concentration increase in macrophages due to Ca2+ mobilization from intracellular Ca2+ stores and subsequent Ca2+ entry from the external medium. Chlorpromazine-induced Ca2+ entry is inhibited by La3+ and 2-aminoethoxydiphenyl borate and is associated with Ca2+ store depletion. PMID- 28726104 TI - N-acyl dopamines induce apoptosis in PC12 cell line via the GPR55 receptor activation. AB - Dopamine amides of arachidonic, docosahexaenoic, and oleic acids were found to induce apoptosis in PC12 cells, which was blocked exclusively by antagonists and preincubation agonists of the receptor GPR55, belonging to the group of non CB1/CB2 receptors. PMID- 28726105 TI - Changes in levels of metabolic pathway gene expression under conditions of clear cell renal carcinoma. AB - A whole-transcriptome analysis of gene expression in six samples of clear cell renal cancer was performed. Using bioinformatics methods, we established a relationship between gene expression data and changes in activity of metabolic pathways: in this cancer type, the expression of genes involved in the metabolism of carbohydrates, lipids, and amino acids as well as in energy metabolism changed most significantly. PMID- 28726106 TI - Arginine derivatives of dicarboxylic acids from the parotid gland secretions of common toad Bufo bufo-New agonists of ionotropic gamma-aminobutyric acid receptors. AB - Compounds activating gamma-aminobutyric acid type A receptor were isolated from the toad Bufo bufo venom as a result of chromatographic separation. Analysis of the structure of these compounds by mass spectrometry and nuclear magnetic resonance showed that they are arginine derivatives of dicarboxylic acids and represent suberylarginine, pimeloylarginine, and adipoylarginine. PMID- 28726107 TI - Studying a novel ecdysone-dependent enhancer. AB - Earlier [4], we developed a two-stage scheme of the activation of expression of the ecdysone cascade gene ftz-f1 in Drosophila melanogaster S2 cells. In the first intron of the ftz-f1 gene, we found a binding site for the transcription activator DHR3. In this work, we studied the properties of this genomic element: the change in the histone modification level at different stages of transcription activation were analyzed, and data indicating the interaction of the intron element with the promoter were obtained. Taken together, the results of this study indicate that the studied genomic element exhibits the properties of an enhancer and functions at the stage of active gene transcription. PMID- 28726108 TI - Why does the bioluminescent fungus Armillaria mellea have luminous mycelium but nonluminous fruiting body? AB - By determining the components involved in the bioluminescence process in luminous and nonluminous organs of the honey fungus Armillaria mellea, we have established causes of partial luminescence of this fungus. The complete set of enzymes and substrates required for bioluminescence is formed only in the mycelium and only under the conditions of free oxygen access. Since the synthesis of luciferin precursor (hispidin) and 3-hydroxyhispidin hydroxylase in the fruiting bodies is blocked, the formation of luciferin-the key component of fungal bioluminescent system-was not observed. That is why the fruiting body of Armillaria mellea is nonluminous despite the presence of luciferase, the enzyme that catalyzes the oxidation of luciferin with a photon emission. PMID- 28726109 TI - The study of immunogenicity of the antigenic protein of high risk oncogenic type of the human papillomavirus HPV16 L1 produced in the plant expression system on the base of transgenic tomato. AB - The immunogenicity of plant-made peroral vaccine against cervical cancer was studied in mice during 342 days after vaccination with the material of tomato fruits genetically transformed with HPV16 L1 Omega 5'UTR TMV. The immune response was found on day 4 after vaccination in blood serum of vaccinated mice. On days 90-100, the rise to maximum value of the level of antibodies to HPV16 L1 was in the range of 500 ng of the standard antibodies to HPV16 L1 (Santa Cruz Biotechnology, United States). This level of antibodies was retained until the end of the study. PMID- 28726110 TI - Supplementation of selenium, vitamin E, chromium and betaine above recommended levels improves lactating performance of sows over summer. AB - Heat stress (HS) exacerbates the body weight loss of lactating sows and reduces litter weight gain. Selenium (Se), vitamin E (VE), chromium (Cr) and betaine have been shown to ameliorate symptoms of HS, and yeast nucleotides and mannan oligosaccharides have been reported to improve lactational performance and immune response in pigs. Therefore, a combination of these nutrients may improve lactational performance of sows in summer. The effects of two nutritionally enhanced diets on lactational performance of sows in summer were investigated in two experiments. In experiment 1, we compared the effects of a nutritionally fortified diet (0.4 ppm Se, 95 IU/kg VE, 0.4 ppm Cr and 0.2% betaine; named as SVCB diet) with the NRC 2012 standard diet (0.15 ppm Se, 44 IU/kg VE) on lactational performance of sows in summer. Results showed that the SVCB diet reduced body weight loss (P = 0.039) and tended to reduce backfat loss (P = 0.075) of sows without affecting feed intake, while litter weight gain was not influenced. In experiment 2, we further enhanced the nutrients in the SVCB diet (0.8 ppm Se, 1% yeast nucleotides, and 0.1% mannan oligosaccharides; named as SNM diet). Results showed that the SNM diet did not improve feed intake of sows, farrowing performance, or litter weight gain compared with the SVCB diet, but increased body weight loss of the third parity sows (P = 0.037). Overall, a combined supplementation of Se, VE, Cr, and betaine above the NRC recommended levels can reduce mobilisation of body reserve of lactating sows in summer. PMID- 28726111 TI - Glucokinase mutations in pediatric patients with impaired fasting glucose. AB - AIMS: Our aim was to detect the frequency of glucokinase (GCK) gene mutations in a cohort of patients with impaired fasting glucose and to describe the clinical manifestations of identified variants. We also aimed at predicting the effect of the novel missense mutations by computational approach. METHODS: Overall 100 unrelated Italian families with impaired fasting glucose were enrolled and subdivided into two cohorts according to strict and to mild criteria for diagnosis of maturity-onset diabetes of the young (MODY). GCK gene sequencing was performed in all participants. RESULTS: Fifty-three Italian families with 44 different mutations affecting the GCK and co-segregating with the clinical phenotype of GCK/MODY were identified. All mutations were in heterozygous state. In Sample 1, GCK defects were found in 32/36 (88.9%) subjects selected with strict MODY diagnostic criteria, while in Sample 2 GCK defects were found in 21/64 (32.8%) subjects selected with mild MODY diagnostic criteria. CONCLUSIONS: Our study enlarged the wide spectrum of GCK defects by adding 9 novel variants. The application of strict recruitment criteria resulted in 88.9% incidence of GCK/MODY, which confirmed it as the commonest form of MODY in the Italian population. In order to avoid misdiagnosis of GCK/MODY, it could be useful to perform molecular screening even if one or more clinical parameters for the diagnosis of MODY are missing. Computational analysis is useful to understand the effect of GCK defect on protein functionality, especially when the novel identified variant is a missense mutation and/or parents' DNA is not available. PMID- 28726112 TI - Mortality risk among older Australians hospitalised with hip fracture: a population-based matched cohort study. AB - : With an ageing population, the burden of hip fractures is expected to increase in the coming decades. Older individuals with hip fracture are more than 3.5 times more likely to die within 12 months compared to non-injured individuals. The main priority for reducing mortality should be prevention of hip fracture. PURPOSE: The aim of this study is to quantify and describe the 12-month mortality of older persons presenting to hospitals in Australia with a hip fracture. METHODS: Population-based matched cohort study using linked hospital and mortality data from four Australian states (New South Wales, Queensland, South Australia, and Tasmania). Individuals aged 65 years and older who had a hospital admission with a primary diagnosis of hip fracture in 2009 (n = 9748) and a matched comparison cohort of non-injured individual were selected from the electoral roll (n = 9748). The comparison group was matched 1:1 on age, sex, and postcode of residence. Adjusted mortality rate ratios (MRR) and attributable risk percent were calculated. Cox proportional hazard regression was used to examine the effect of risk factors on survival. RESULTS: The hip fracture cohort experienced significantly worse survival at the 12-month post-fracture hospitalisation (P < 0.0001). Individuals with hip fracture were more than 3.5 times more likely to die within 12 months compared to their non-injured counterparts (MRR 3.62 [95%CI 3.23-4.05]). Hip fracture was likely to be a contributory factor in 72% of mortality within 12 months after the index hospital admission. Excess mortality risk at 12 months was higher in males than that in females and in the 65-74-year age group. CONCLUSIONS: With an ageing population in Australia, the burden of hip fractures is expected to increase in the coming decades. Because incident hip fracture is the main predictor of subsequent mortality, the main priority for reducing excess mortality after hip fracture is primary and secondary prevention of hip fracture. PMID- 28726113 TI - Glucocorticoid sparing effect of zoledronic acid in sarcoid hypercalcemia. AB - INTRODUCTION: Glucocorticoids are regarded as first-line therapy in the management of hypercalcemia associated with sarcoidosis. However, prolonged glucocorticoid therapy leads to metabolic abnormalities, Cushingoid habitus, and impairment of bone health. This study demonstrates the efficacy and glucocorticoid-sparing effect of zoledronic acid in sarcoid hypercalcemia. METHODS: We present three patients with sarcoid hypercalcemia. They were successfully managed with oral glucocorticoids for many months. However, all patients developed adverse effects of glucocorticoids. When tapering of glucocorticoids was attempted, hypercalcemia recurred. Zoledronic acid was administered in order to control hypercalcemia and to allow tapering of glucocorticoids. RESULTS: Following zoledronic acid administration, serum calcium level normalised and glucocorticoids could be discontinued in all the three patients. Normocalcemia was maintained for an average of 18 months after a single infusion. Sarcoidosis remained in remission in all the three patients. CONCLUSION: Zoledronic acid should be studied as a potential first-line agent for sarcoid hypercalcemia. Furthermore, disease-modifying effects of zoledronic acid in sarcoidosis should be investigated. PMID- 28726114 TI - Sex-related differences in serum matrix metalloproteinase-9 screening non calcified and mixed coronary atherosclerotic plaques in outpatients with chest pain. AB - The objective of this study is to evaluate the clinical feasibility of serum matrix metalloproteinase-9 (MMP-9) for screening plaque composition as assessed by coronary computed tomography angiography (CCTA) in outpatients with chest pain,and the effects of sex on this feasibility. Eight hundred and sixty-two consecutive outpatients with chest pain were divided into three groups according to the results of CCTA: non-plaque (NP, n = 474), calcified plaques (CPs, n = 179), non-calcified and mixed plaques (NCPs and MPs, n = 209). We found that serum MMP-9 levels were significantly higher in patients with NCPs and MPs compared to those with either NP or CPs, especially in women (649.7 +/- 279.8 vs. 485.7 +/- 231.6 ng/mL or 515.7 +/- 274.5 ng/mL, P < 0.001). MMP-9 showed better identification of NCPs and MPs than other related factors and was an independent predictor for NCPs and MPs both in women and men. The receiver operating characteristic analysis indicated a substantial superiority in women with area under the curve of 0.75 (95% CI 0.69-0.82, P < 0.01), compared with men of 0.59 (95% CI 0.53-0.65, z = 3.71, P < 0.01). The diagnostic tests revealed a moderate risk of the presence of NCPs and MPs with MMP-9 >=531.6 ng/mL in female patients. PMID- 28726115 TI - The impact of coronary calcification on angiographic and 3-year clinical outcomes of everolimus-eluting stents: results of a XIENCE V/PROMUS post-marketing surveillance study. AB - Coronary calcification (CCA) is one of the independent predictors for major adverse cardiac events (MACEs) in coronary intervention. Post-marketing surveillance study Japan is a prospective registry designed to evaluate the safety and efficacy of the everolimus-eluting stent (EES, XIENCE V/PROMUS Stent) in routine clinical practice at 47 centers. In this study, 1848 lesions (1546 patients) were assessed using quantitative coronary angiography. In these 1546 patients, renal function data were unknown in 26 patients. Three patients in 70 patients with dialysis and 56 patients in 1450 patients with no dialysis were excluded, because they had multiple lesions with mixed calcification lesions. We evaluated the effects of CCA on 8-month angiographic and 3-year clinical outcomes in dialysis and non-dialysis patients. Moderate-to-severe (Ca group) and none-to mild CCA (non-Ca group) were observed in 33 lesions (30 patients) and 48 lesions (37 patients) in dialysis patients, and these were observed in 306 lesions (286 patients) and 1303 lesions (1108 patients) in non-dialysis patients, respectively. In non-dialysis patients, the ischemic-driven target lesion revascularization (ID-TLR) and MACE rate over the 3 years were significantly higher in the Ca group than in the non-Ca group (5.8 vs. 3.1%, p = 0.025 and 10.0 vs. 5.0%, p = 0.0011). In dialysis patients, ID-TLR and MACE rates were high in both groups (14.3 vs. 17.9%, p = 0.85 and 17.5 vs. 36.1%, p = 0.16). In non dialysis patients, 8-month angiographic and 3-year clinical outcomes were worse in the Ca group. However, in dialysis patients, both outcomes were worse regardless of CCA.Clinical Trial registration https://clinicaltrials.gov/ct2/show/NCT01086228 . PMID- 28726116 TI - A computationally efficient method for hand-eye calibration. AB - PURPOSE: Surgical robots with cooperative control and semiautonomous features have shown increasing clinical potential, particularly for repetitive tasks under imaging and vision guidance. Effective performance of an autonomous task requires accurate hand-eye calibration so that the transformation between the robot coordinate frame and the camera coordinates is well defined. In practice, due to changes in surgical instruments, online hand-eye calibration must be performed regularly. In order to ensure seamless execution of the surgical procedure without affecting the normal surgical workflow, it is important to derive fast and efficient hand-eye calibration methods. METHODS: We present a computationally efficient iterative method for hand-eye calibration. In this method, dual quaternion is introduced to represent the rigid transformation, and a two-step iterative method is proposed to recover the real and dual parts of the dual quaternion simultaneously, and thus the estimation of rotation and translation of the transformation. RESULTS: The proposed method was applied to determine the rigid transformation between the stereo laparoscope and the robot manipulator. Promising experimental and simulation results have shown significant convergence speed improvement to 3 iterations from larger than 30 with regard to standard optimization method, which illustrates the effectiveness and efficiency of the proposed method. PMID- 28726117 TI - Applying a new bilateral mammographic density segmentation method to improve accuracy of breast cancer risk prediction. AB - PURPOSE: How to optimally detect bilateral mammographic asymmetry and improve risk prediction accuracy remains a difficult and unsolved issue. Our aim was to find an effective mammographic density segmentation method to improve accuracy of breast cancer risk prediction. METHODS: A dataset including 168 negative mammography screening cases was used. We applied a mutual threshold to bilateral mammograms of left and right breasts to segment the dense breast regions. The mutual threshold was determined by the median grayscale value of all pixels in both left and right breast regions. For each case, we then computed three types of image features representing asymmetry, mean and the maximum of the image features, respectively. A two-stage classification scheme was developed to fuse the three types of features. The risk prediction performance was tested using a leave-one-case-out cross-validation method. RESULTS: By using the new density segmentation method, the computed area under the receiver operating characteristic curve was 0.830 +/- 0.033 and overall prediction accuracy was 81.0%, significantly higher than those of 0.633 +/- 0.043 and 57.1% achieved by using the previous density segmentation method ([Formula: see text], t-test). CONCLUSIONS: A new mammographic density segmentation method based on a bilateral mutual threshold can be used to more effectively detect bilateral mammographic density asymmetry and help significantly improve accuracy of near-term breast cancer risk prediction. PMID- 28726118 TI - Epidural steroid injection-related events requiring hospitalisation or emergency room visits among 52,935 procedures performed at a single centre. AB - OBJECTIVES: To analyse the incidence and type of epidural steroid injection (ESI) related adverse events, including procedure-related complications and drug related systemic effects requiring hospitalisation or emergency room (ER) visits. METHODS: This study included 52,935 ESI procedures performed in 22,059 patients in our department from March 2004 to February 2016. Of these, we retrospectively reviewed the cases of 1570 patients (1713 procedures) who were hospitalised or visited the ER within 1 month after ESI. ESI-related events were classified as procedure-related complications, drug-related systemic effects, or of uncertain relationship. Descriptive data are provided; no statistical analysis was performed. RESULTS: There were 244 ESI-related events in 235 patients (males:females = 102:133; mean age: 65.7 years; range: 20-93 years). The incidence of ESI-related events was 0.46% per procedure, including 14 procedure related complications, 56 drug-related systemic effects, and 174 events of uncertain cause. Of the 52,935 patients, 6 (0.011%) experienced major complications (two spine haematomas and four infections), 1 patient died, and 1 experienced neurological sequelae. CONCLUSIONS: Although major procedure-related complications and drug-related systemic effects of ESI requiring hospitalisation are very rare, infection and haematoma can occur, resulting in serious outcomes. Hence, ESI should be carefully considered in high-risk patients. KEY POINTS: * The incidence of ESI-related events requiring hospitalisation was 0.46%. * The incidence of procedure-related complications was 0.026%. * The incidence of drug related systemic effects was 0.11%. * The incidence of major complication of ESI was 0.011%. * The major complications were spine infection, haematoma, and sepsis. PMID- 28726119 TI - A cost-effectiveness analysis of the diagnostic strategies for differentiating focal nodular hyperplasia from hepatocellular adenoma. AB - OBJECTIVES: We evaluated the cost-effectiveness of a gadoxetic acid-enhanced MRI (EOB-MRI) strategy compared with conventional MRI strategy and biopsy to differentiate focal nodular hyperplasia (FNH) from hepatocellular adenoma (HCA). METHODS: A decision tree model was constructed to compare the cost-effectiveness of EOB-MRI, conventional MRI with extracellular contrast agents, and biopsy as the initial diagnostic modality in patients with incidentally detected focal liver lesions suspected of being FNH or HCA. We analysed the cost and effectiveness, i.e. probability of successful diagnosis of each strategy. Costs were based on utilisation rates and Medicare reimbursements in the USA and South Korea. RESULTS: In the base case analysis of our decision tree model, the effectiveness of the three strategies was similar. The cost of the EOB-MRI strategy ($1283 in USA, $813 in South Korea) was lowest compared with the biopsy strategy ($1725 in USA, $847 in South Korea) and the conventional MRI strategy ($1750 in USA, $962 in South Korea). One-way, two-way and probabilistic sensitivity analysis showed unchanged results over an acceptable range. CONCLUSIONS: EOB-MRI strategy is the most cost-effective strategy for differentiating FNH from HCA in patients with incidentally detected focal liver lesions in a non-cirrhotic liver. KEY POINTS: * The effectiveness of the three strategies was similar. * The cost of the EOB-MRI strategy was lowest. * EOB-MRI strategy is the most cost-effective for differentiating FNH from HCA. PMID- 28726120 TI - Magnetic resonance imaging for detection of parametrial invasion in cervical cancer: An updated systematic review and meta-analysis of the literature between 2012 and 2016. AB - OBJECTIVE: To review the diagnostic performance of MRI for detection of parametrial invasion (PMI) in cervical cancer patients. METHODS: MEDLINE and EMBASE databases were searched for studies providing diagnostic performance of MRI for detecting PMI in patients with cervical cancer. Studies published between 2012 and 2016 using surgico-pathological results as reference standard were included. Study quality was evaluated using QUADAS-2. Sensitivity and specificity of all studies were calculated. Results were pooled and plotted in a hierarchical summary receiver operating characteristic plot. Meta-regression and subgroup analyses were performed. RESULTS: Fourteen studies (1,028 patients) were included. Study quality was generally moderate. Pooled sensitivity was 0.76 (95% CI 0.67-0.84) and specificity was 0.94 (95% CI 0.91-0.95). The possibility of heterogeneity was considered low: Cochran's Q-test (p = 0.471), Tau2 (0.240), Higgins I2 (0%). With meta-regression analysis, magnet strength, use of DWI, and antispasmodic drugs were significant factors affecting heterogeneity (p < 0.01). Subgroup analysis for studies solely using radical hysterectomy as reference standard yielded pooled sensitivity and specificity of 0.73 (95% CI 0.60-0.83) and 0.93 (95% CI 0.90-0.95), respectively. CONCLUSIONS: MRI shows good performance for detection of PMI in cervical cancer. Using 3-T scanners and DWI may improve diagnostic performance. KEY POINTS: * MRI shows good performance for detection of parametrial invasion in cervical cancer. * Subgroup of studies using only radical hysterectomy showed consistent results. * Using 3-Tesla scanners and diffusion-weighted imaging may improve diagnostic performance. PMID- 28726121 TI - Bone marrow oedema predicts bone collapse in paediatric and adolescent leukaemia patients with corticosteroid-induced osteonecrosis. AB - OBJECTIVES: Corticosteroid treatment of paediatric leukaemia patients can lead to osteonecrosis (ON). We determined whether bone marrow oedema (BME) is an early sign of progressive ON and eventual bone collapse. METHODS: In a retrospective study, two radiologists reviewed MR imaging characteristics of 47 early stage epiphyseal ON in 15 paediatric and adolescent leukaemia patients. Associations between BME on initial imaging studies and subchondral fracture, disease progression and bone collapse were assessed by Cochran-Mantel-Haenszel tests. Differences in time to progression and bone collapse between lesions with and without oedema were assessed by log rank tests. RESULTS: Forty-seven occurrences of ON were located in weight bearing joints, with 77% occurring in the femur. Seventeen lesions progressed to collapse, two lesions worsened without collapse, and 28 remained stable or improved. BME was significantly associated with subchondral fracture (p = 0.0014), disease progression (p = 0.0015), and bone collapse (p < 0.001), with a sensitivity and specificity of 94% and 77%, respectively, for bone collapse. Time to progression for ON with oedema was 2.7 years (95% CI: 1.7-3.4); while the majority of no-oedema ON were stable (p = 0.0011). CONCLUSIONS: BME is an early sign of progressive ON and eventual bone collapse in paediatric and adolescent leukaemia patients. KEY POINTS: * Bone marrow oedema in corticosteroid-induced osteonecrosis predicts progression to bone collapse. * Bone marrow oedema is associated with subchondral fractures in corticosteroid-induced osteonecrosis. * Bone marrow oedema can be used to stratify patients to joint-preserving interventions. * Absence of bone marrow oedema can justify a "wait and watch" approach. PMID- 28726122 TI - Beta-Ketothiolase Deficiency Presenting with Metabolic Stroke After a Normal Newborn Screen in Two Individuals. AB - Beta-ketothiolase (mitochondrial acetoacetyl-CoA thiolase) deficiency is a genetic disorder characterized by impaired isoleucine catabolism and ketone body utilization that predisposes to episodic ketoacidosis. It results from biallelic pathogenic variants in the ACAT1 gene, encoding mitochondrial beta-ketothiolase. We report two cases of beta-ketothiolase deficiency presenting with acute ketoacidosis and "metabolic stroke." The first patient presented at 28 months of age with metabolic acidosis and pallidal stroke in the setting of a febrile gastrointestinal illness. Although 2-methyl-3-hydroxybutyric acid and trace quantities of tiglylglycine were present in urine, a diagnosis of glutaric acidemia type I was initially suspected due to the presence of glutaric and 3 hydroxyglutaric acids. A diagnosis of beta-ketothiolase deficiency was ultimately made through whole exome sequencing which revealed compound heterozygous variants in ACAT1. Fibroblast studies for beta-ketothiolase enzyme activity were confirmatory. The second patient presented at 6 months of age with ketoacidosis, and was found to have elevations of urinary 2-methyl-3-hydroxybutyric acid, 2 methylacetoacetic acid, and tiglylglycine. Sequencing of ACAT1 demonstrated compound heterozygous presumed causative variants. The patient exhibited choreoathethosis 2 months after the acute metabolic decompensation. These cases highlight that, similar to a number of other organic acidemias and mitochondrial disorders, beta-ketothiolase deficiency can present with metabolic stroke. They also illustrate the variability in clinical presentation, imaging, and biochemical evaluation that make screening for and diagnosis of this rare disorder challenging, and further demonstrate the value of whole exome sequencing in the diagnosis of metabolic disorders. PMID- 28726123 TI - Rapidly Progressive White Matter Involvement in Early Childhood: The Expanding Phenotype of Infantile Onset Pompe? AB - Glycogen accumulation in the central nervous system of patients with classical infantile onset Pompe disease (IOPD) has been a consistent finding on the few post-mortems performed. While delays in myelination and a possible reduction in processing speed have previously been noted, it has only been recently that the potential for clinically significant progressive white matter disease has been noted. The limited reports thus far published infer that in some IOPD patients, this manifests as intellectual decline in the second decade of life. We present a CRIM negative patient, immunomodulated with rituximab and methotrexate at birth, who despite an initial good clinical response to ERT, at the age of just under 4 years, presented with evolving spasticity in the lower limbs. The investigation of which revealed progressive central nervous system involvement. Given both the earlier onset of the symptoms and consanguineous familial pedigree, extensive biochemical and genetic investigation was undertaken to ensure no alternative pathology was elucidated. In light of these findings, we review the radiology and post-mortems of previous cases and discuss the potential mechanisms that may underlie this presentation. PMID- 28726125 TI - Nitrogen assimilation in denitrifier Bacillus azotoformans LMG 9581T. AB - Until recently, it has not been generally known that some bacteria can contain the gene inventory for both denitrification and dissimilatory nitrate (NO3 )/nitrite (NO2-) reduction to ammonium (NH4+) (DNRA). Detailed studies of these microorganisms could shed light on the differentiating environmental drivers of both processes without interference of organism-specific variation. Genome analysis of Bacillus azotoformans LMG 9581T shows a remarkable redundancy of dissimilatory nitrogen reduction, with multiple copies of each denitrification gene as well as DNRA genes nrfAH, but a reduced capacity for nitrogen assimilation, with no nas operon nor amtB gene. Here, we explored nitrogen assimilation in detail using growth experiments in media with different organic and inorganic nitrogen sources at different concentrations. Monitoring of growth, NO3- NO2-, NH4+ concentration and N2O production revealed that B. azotoformans LMG 9581T could not grow with NH4+ as sole nitrogen source and confirmed the hypothesis of reduced nitrogen assimilation pathways. However, NH4+ could be assimilated and contributed up to 50% of biomass if yeast extract was also provided. NH4+ also had a significant but concentration-dependent influence on growth rate. The mechanisms behind these observations remain to be resolved but hypotheses for this deficiency in nitrogen assimilation are discussed. In addition, in all growth conditions tested a denitrification phenotype was observed, with all supplied NO3- converted to nitrous oxide (N2O). PMID- 28726124 TI - Diversity of culturable filamentous Ascomycetes in the eastern South Pacific Ocean off Chile. AB - Our study reports the diversity of culturable mycoplankton in the eastern South Pacific Ocean off Chile to contribute with novel knowledge on taxonomy of filamentous fungi isolated from distinct physicochemical and biological marine environments. We characterized spatial distribution of isolates, evaluated their viability and assessed the influence of organic substrate availability on fungal development. Thirty-nine Operational Taxonomic Units were identified from 99 fungal strains isolated from coastal and oceanic waters by using Automatic Barcode Gap Discovery. All Operational Taxonomic Units belonged to phylum Ascomycota and orders Eurotiales, Dothideales, Sordariales and Hypocreales, mainly Penicillium sp. (82%); 11 sequences did not match existing species in GenBank, suggesting occurrence of novel fungal taxa. Our results suggest that fungal communities in the South Pacific Ocean off Chile appear to thrive in a wide range of environmental conditions in the ocean and that substrate availability may be a factor influencing fungal viability in the ocean. PMID- 28726126 TI - Characterization of a cold-adapted DNA photolyase from C. psychrerythraea 34H. AB - The phrB gene encoding a putative cold-adapted DNA photolyase was cloned from the bacterial genomic DNA of Colwellia psychrerythraea 34H, a psychrophilic bacterium. Recombinant DNA photolyase, rCpPL, was overexpressed and purified from three different vectors. rCpPL binds its DNA substrate by flipping a cyclobutane pyrimidine dimer (CPD) into its active site and repairs CPD-containing DNA in vitro. rCpPL contains one catalytic flavin adenine dinucleotide (FAD) cofactor, but displays promiscuity in cofactor binding, in which either a flavin mononucleotide (FMN) or a methenyltetrahydrofolate (MTHF) molecule is bound as an antenna molecule and found in sub-stoichiometric amounts. The UV/Vis spectrum of oxidized rCpPL shows that the FADOX absorption maximum is the most red-shifted reported for a PL, suggesting a unique cavity electrostatic environment. Modest FAD vibronic structure suggests that the binding pocket is more flexible than warmer PLs, corroborating the hypothesis that psychrophilic proteins must be highly flexible to function at low temperatures. Fluorescence excitation data show that the freshly purified flavin cofactor is in its fully reduced state (FADH-). A homology analysis of PL protein structures spanning 70 degrees C in growth temperature supports the data that the structure of CpPL is quite different from its warmer cousins. PMID- 28726127 TI - CLIPPERS. AB - PURPOSE OF REVIEW: Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a recently described treatable, inflammatory, brainstem predominant encephalomyelitis. The diagnosis of CLIPPERS is challenging without a specific biomarker, and thus it is important to consider if both the clinical and radiographic features are consistent with the diagnosis, or rather a disease mimicker. RECENT FINDINGS: Many patients with CLIPPERS-like lesions have been described in the literature with follow-up revealing a range of alternative diagnoses, such as malignancies, vasculitis, and other specific inflammatory diseases. As a result, some have proposed that CLIPPERS might represent a pre-malignancy state or simply an initial clinical syndrome of a variety of possible etiologies. We describe the typical clinical, radiographic, and pathological features of CLIPPERS and emphasize consideration for alternative diagnoses when findings are not classic. A recommended diagnostic evaluation and initial treatment plan is provided. PMID- 28726128 TI - On the response of the Baltic proper to changes of the total phosphorus supply. AB - Using a time-dependent phosphorus (P) budget model for the Baltic proper, describing sources and sinks at the external borders of the water column, one may compute the e-folding time T of the adjustment of the winter surface water P concentration c 1 to abruptly changed total P supply. The restoration time TR = 3T is introduced as a practical measure of the time it takes to achieve 95% of the change of c 1 towards the final, equilibrium, state c 1e. The P budget model, including an internal source emanating from deep anoxic bottoms, also shows that c 1e is proportional to the total P supply to the water column. About 70% of present time total P supply to the Baltic proper comes from deep anoxic bottoms. If deep bottoms were kept oxygenated, this internal P supply would be turned off and the equilibrium concentration c1e would be reduced by about 70%. This should imply that the Baltic proper may be restored to a state determined by the external P supplies from land-based and oceanic sources. According to the model, restoration would take 10-15 years. Thereafter most of the equipment used for oxygenation may be shut off since also the deepwater oxygen demand by decomposition of fresh organic matter, would have decreased by about 70% implying that the deepwater would be kept oxic by the natural vertical circulation. The model presented in this paper provides a new science-based solution of the eutrophication problem of the Baltic proper, which is of great interest from a management point of view. PMID- 28726129 TI - Immunological aspects of rabies: a literature review. AB - Rabies is a lethal disease caused by the neurotropic virus rabies virus (RABV), and it remains an important public health problem globally. It is known that the host immune response is important for control of viral infection and promoting viral clearance. In this context, it is well documented that, in addition to RABV neutralizing antibody, interferons and cell-mediated immunity also have an important role in preventing the establishment of disease. On the other hand, RABV suppresses host immunity through different mechanisms, for example, direct inhibition of host gene expression, sequestration of pathogen-associated molecular patterns, or modification of cytokine signalling pathways, which hinder the protective host immune responses to RABV infection. Here, we review the immunological aspects of rabies, highlighting innate and adaptive immunity, as well as the host evasion immune mechanisms used by the virus. Finally, we briefly discuss how this knowledge can direct new research and be harnessed for future therapeutic strategies. PMID- 28726130 TI - Transmission network characteristics based on env and gag sequences from MSM during acute HIV-1 infection in Beijing, China. AB - Molecular epidemiology can be used to identify human immunodeficiency virus (HIV) transmission clusters, usually using pol sequence for analysis. In the present study, we explored appropriate parameters to construct a simple network using HIV env and gag sequences instead of pol sequences for constructing a phylogenetic tree and a genetic transmission subnetwork, which were used to identify individuals with many potential transmission links and to explore the evolutionary dynamics of the virus among men who have sex with men (MSM) in Beijing. We investigated 70 acute HIV-1 infections, which consisted of HIV-1 subtype B (15.71%), the circulating recombinant forms CRF01_AE (47.14%), CRF07_BC (21.43%), CRF55_01B (1.43%), and CRF65_cpx (4.29%), and an unknown subtype (10.00%). By exploring the similarities and differences among HIV env, gag and pol sequences in describing the dynamics of the HIV-1 CRF01_AE transmission subnetwork among Beijing MSM, we found that four key points of the env sequences (strains E-2011_BJ.CY_16014, E-2011_BJ.FT_16017, E-2011_BJ.TZ_16064, and E 2011_BJ.XW_16035) contained more transmission information than gag sequences (three key points: strains G-2011_BJ.CY_16014, G-2011_BJ.FT_16017, and G 2011_BJ.XW_16035) and pol sequences (two key points: strains P-2011_BJ.CY_16014 and P-2011_BJ.XW_16035). Although the env and gag sequence results were similar to pol sequences in describing the dynamics of the HIV-1 CRF01_AE transmission subnetwork, we were able to obtain more precise information, allowing identification of key points of subnetwork expansion, based on HIV env and gag sequences instead of pol sequences. Taken together, the key points we found will improve our current understanding of how HIV spreads between MSM populations in Beijing and help to better target preventative interventions for promoting public health. PMID- 28726131 TI - Detection of Enzyme Activity and Inhibition during Studies in Solution, In Vitro and In Vivo with CatalyCEST MRI. AB - PURPOSE: The detection of enzyme activities and evaluation of enzyme inhibitors have been challenging with magnetic resonance imaging (MRI). To address this need, we have developed a diamagnetic, nonmetallic contrast agent and a protocol known as catalyCEST MRI that uses chemical exchange saturation transfer (CEST) to detect enzyme activity as well as enzyme inhibition. PROCEDURES: We synthesized a diamagnetic MRI contrast agent that has enzyme responsive and enzyme unresponsive CEST signals. We tested the ability of this agent to detect the activity of kallikrein 6 (KLK6) in biochemical solutions, in vitro and in vivo, with and without a KLK6 inhibitor. RESULTS: The agent detected KLK6 activity in solution and also detected KLK6 inhibition by antithrombin III. KLK6 activity was detected during in vitro studies with HCT116 colon cancer cells, relative to the detection of almost no activity in a KLK6-knockdown HCT116 cell line and HCT116 cells treated with antithrombin III inhibitor. Finally, strong enzyme activity was detected within an in vivo HCT116 tumor model, while lower enzyme activity was detected in a KLK6 knockdown tumor model and in the HCT116 tumor model treated with antithrombin III inhibitor. In all cases, comparisons of the enzyme responsive and enzyme unresponsive CEST signals were critical for the detection of enzyme activity. CONCLUSIONS: This study has established that catalyCEST MRI with an exogenous diaCEST agent can evaluate enzyme activity and inhibition in solution, in vitro and in vivo. PMID- 28726132 TI - Phase I dose escalation study of NMS-1286937, an orally available Polo-Like Kinase 1 inhibitor, in patients with advanced or metastatic solid tumors. AB - Background Pharmacological inhibition of polo-like kinase 1 (PLK1) represents a new approach for the treatment of solid tumors. This study was aimed at determining the first cycle dose-limiting toxicities (DLTs) and related maximum tolerated dose (MTD) of NMS-1286937, a selective ATP-competitive PLK1-specific inhibitor. Secondary objectives included evaluation of its safety and pharmacokinetic (PK) profile in plasma, its antitumor activity, and its ability to modulate intracellular targets in biopsied tissue. Methods This was a Phase I, open-label, dose-escalation trial in patients with advanced/metastatic solid tumors. A treatment cycle comprised 5 days of oral administration followed by 16 days of rest, for a total of 21 days (3-week cycle). Results Nineteen of 21 enrolled patients with confirmed metastatic disease received study medication. No DLTs occurred at the first 3 dose levels (6, 12, and 24 mg/m2/day). At the subsequent dose level (48 mg/m2/day), 2 of 3 patients developed DLTs. An intermediate level of 36 mg/m2/day was therefore investigated. Four patients were treated and two DLTs were observed. After further cohort expansion, the MTD and recommended phase II dose (RP2D) were determined to be 24 mg/m2/day. Disease stabilization, observed in several patients, was the best treatment response observed. Hematological toxicity (mostly thrombocytopenia and neutropenia) was the major DLT. Systemic exposure to NMS-1286937 increased with dose and was comparable between two cycles of treatment following oral administration of the drug. Conclusions This study successfully identified the MTD and DLTs for NMS 1286937 and characterized its safety profile. PMID- 28726133 TI - Iron protects porcine plasma coagulation kinetics from degradation by Crotalus atrox venom. AB - While the administration of antivenom to treat hemotoxic snake bite injury remains the gold standard of therapy, we have demonstrated that modifying human fibrinogen with iron and carbon monoxide renders it resistant to fibrinogenolytic snake venom enzymes. In order to translate these findings into a possible biometal-based therapy complementary to antivenom administration, a preclinical model that possesses fibrinogen that closely mimics the human molecule in response to iron and carbon monoxide needed to be identified. The goal of this investigation was to determine if a swine model could serve in this capacity by assessing the thrombelastographic response of porcine plasma to iron and carbon monoxide exposure, without or with further exposure to the fibrinogenolytic venom of the viper Crotalus atrox. Using plasma obtained from eight swine, it was determined that their plasma responded to iron and carbon monoxide in a manner similar to that of human plasma by displaying enhanced coagulation kinetics. However, in sharp contrast to the response seen with human plasma, only iron significantly protected porcine plasma coagulation kinetics from C. atrox venom degradation. Therefore the pig is an animal beyond humans that could derive benefit from the biometal-focused therapy of iron infusion to protect against venom mediated compromise of coagulation. Thus, future investigation to assess the effects of iron administration to attenuate the effects of fibrinogenolytic envenomation with a pig model is justified. PMID- 28726134 TI - Non-functioning parathyroid carcinoma: a case report. AB - BACKGROUND: Non-functioning parathyroid carcinoma is a rare disease that is difficult to distinguish from other diseases based on the lack of hyperparathyroidism. This is a report of non-functioning parathyroid carcinoma diagnosed by reverse transcription polymerase chain reaction (RT-PCR) targeting parathyroid hormone (PTH) messenger RNA. CASE PRESENTATION: The patient is a 67 year-old male who visited our hospital for the chief complaint of hoarseness. A 5 cm mass was observed in the right lobe of the thyroid gland, and poorly differentiated thyroid carcinoma was suspected according to the fine-needle biopsy results. The laboratory data for thyroid functions, thyroglobulin, anti thyroglobulin antibodies, calcium, phosphorus, and intact-PTH were all within the normal range. Right recurrent nerve paralysis was observed preoperatively. The patient was diagnosed with poorly differentiated thyroid carcinoma, and total thyroidectomy and central node dissection with partial resection of the right recurrent nerve and esophageal muscle were performed. The pathological findings revealed atypical cells containing clear cells in solid and alveolar structures with broad fibrosis. Mitosis, focal coagulative necrosis, and vascular and capsular invasions were observed. A slightly positive PTH immunohistochemical stain was noted, whereas the RT-PCR results were positive. We finally diagnosed this tumor as non-functioning PTC. No distant metastasis occurred, and the patient is still alive. CONCLUSIONS: This is a report of a patient with non functioning parathyroid carcinoma, which is clinically very rare. We diagnosed this tumor as non-functioning parathyroid carcinoma using RT-PCR for PTH mRNA. PMID- 28726135 TI - Increasing bile duct injury and decreasing utilization of intraoperative cholangiogram and common bile duct exploration over 14 years: an analysis of outcomes in New York State. AB - INTRODUCTION: During laparoscopic cholecystectomy (LC), common bile duct (CBD) visualization either directly or with cholangiography (IOC) is less routine. Cholangiography can be used to identify and possibly prevent bile duct injury (BDI), which is a dreaded complication of cholecystectomy. The purpose of our study was to evaluate the trend of IOC/CBD exploration and BDI during LC for benign disease. METHODS: A state-wide database (SPARCS) was used to identify all LC for benign biliary non-obstructive and obstructive disease between 2000 and 2014 in the state of New York. ICD-9 and CPT codes were used to identify IOC/CBD exploration and BDI. Multivariable logistic regression models were used in examining the linear trend in the risk of complication, 30-day readmission, 30 day ED visits, and BDI among all cholangiogram patients after controlling for possible confounding factors. RESULTS: During 2000-2014, 391,945 patients underwent laparoscopic cholecystectomy. The trend of IOC/CBD exploration performed significantly decreased for LC overall (12.37-10.44%, relative risk = 0.98, p <.0001) and particularly, in the outpatient setting (10.77-7.52%, relative risk = 0.96, p value <.0001). Among patients with IOC, overall complication rate, 30-day readmission rate, and 30-day ED visit rates increased. When looking at overall complication rate, there was an increase by about 4% per year (relative risk = 1.04, p value <.0001). After controlling for confounding factors, the complication risk and 30-day ED visit risk increased through years, while the 30-day readmission risk did not have significant change. Risk of BDI also increased significantly (p = 0.03). CONCLUSION: In an era of laparoscopy, the rate of IOC/CBD exploration during LC has significantly decreased, while BDI significantly increased. PMID- 28726136 TI - Robotic versus laparoscopic stapling during robotic Roux-en-Y gastric bypass surgery: a case-matched analysis of costs and clinical outcomes. AB - BACKGROUND: The purpose of this analysis is to compare the robotic EndoWrist Stapling System (EWSS) 45 mm (Intuitive Surgical Inc. Sunnyvale, CA, USA) and the ECHELON FLEXTM ENDOPATH(r) Staplers (EFES) 60 mm (Ethicon, Cincinnati, OH, USA) for gastric pouch formation during robotic gastric bypass surgery. METHODS: Patients who underwent robotic gastric bypass surgery with stapling using EWSS were matched with patients who underwent the same procedure with the EFES. Demographic, intra- and postoperative, and cost data were collected and analyzed. RESULTS: A total of 49 patients were identified who had undergone robotic gastric bypass surgery using EWSS. They were matched with 49 patients who underwent the equivalent procedure using EFES. With similar demographic parameters, corrected operating room time without cholecystectomy took longer for the patients that underwent surgery with EWSS (+22 min, p = 0.1042). Stapler clamping was unsuccessful in 19.0% of all recorded attempts with EWSS. Two intra-operative complications unrelated to stapling and one complication due to stapling were observed in the EWSS cohort, while none was observed for the EFES group. Significantly, more recharges were needed with EWSS to complete the gastric pouch (4.9 vs. 4.1, p = 0.0048) and overall stapling costs for the procedure were significantly higher (2212.2 vs. 1787.4 USD, p = 0.0001). CONCLUSION: Gastric pouch formation using EWSS during robotic gastric bypass surgery is feasible. Due to the shorter length of EWSS compared to EFES, more stapling recharges are required to complete gastric pouch formation and the stapling costs for gastric bypass surgery are higher. Further systematic research should be conducted to precisely determine the value of the robotic EWSS for gastric bypass surgery. PMID- 28726137 TI - Long- and short-term outcomes of laparoscopic gastrectomy versus open gastrectomy in patients with clinically and pathological locally advanced gastric cancer: a propensity-score matching analysis. AB - BACKGROUND: Laparoscopic (laparoscopy-assisted) gastrectomy (LG) has several short-term benefits as compared with open distal gastrectomy (OG) in patients with advanced gastric cancer (AGC). Survival rates did not differ significantly between LG and OG in retrospective studies of AGC, although some studies included unmatched groups of patients or patients with AGC who had a preoperative diagnosis of early gastric cancer. The aim of present study was to compare the short- and long-term outcomes of patients with AGC who underwent LG with those of patients with AGC who underwent OG using a propensity-score matching analysis. METHODS: The study group comprised patients with a preoperative and pathologically confirmed diagnosis of AGC who underwent LG or OG with lymphadenectomy between January 2001 and December 2012 in our hospital. To minimize bias between the LG and OG groups, propensity scores were calculated using a logistic regression model and the following variables: sex, age, body mass index, American Society of Anesthesiologists physical status class, type of gastrectomy, and clinical and pathological tumor stage. After propensity-score matching, 104 patients (52 who underwent LG and 52 who underwent OG) were studied. RESULTS: LG was associated with significantly earlier initiation of food intake (p <0.01) and a significantly shorter period of postoperative hospitalization (p <0.01). The incidence of all-grade overall, surgical, and medical complications did not differ significantly between the LG group and OG group (p = 0.24, p = 0.12, and p >0.99). Overall and relapse-free survival also did not differ between the LG group and OG group (p = 0.96, p = 0.91). In each tumor stage, overall and relapse-free survival did not differ significantly between the LG group and OG group. CONCLUSION: LG can be a feasible treatment that is beneficial in terms of earlier recovery after operation and can be expected to result in similar survival as OG in patients with AGC. PMID- 28726138 TI - Trainee-associated outcomes in laparoscopic colectomy for cancer: propensity score analysis accounting for operative time, procedure complexity and patient comorbidity. AB - BACKGROUND: Surgical trainee association with operative outcomes is controversial. Studies are conflicting, possibly due to insufficient control of confounding variables such as operative time, case complexity, and heterogeneous patient populations. As operative complications worsen long-term outcomes in oncologic patients, understanding effect of trainee involvement during laparoscopic colectomy for cancer is of utmost importance. Here, we hypothesized that resident involvement was associated with worsened 30-day mortality and 30 day overall morbidity in this patient population. METHODS: Patients undergoing laparoscopic colectomy for oncologic diagnosis from 2005 to 2012 were assessed using the American College of Surgeons National Surgical Quality Improvement Program dataset. Propensity score matching accounted for demographics, comorbidities, case complexity, and operative time. Attending only cases were compared to junior, middle, chief resident, and fellow level cohorts to assess primary outcomes of 30-day mortality and 30-day overall morbidity. RESULTS: A total of 13,211 patients met inclusion criteria, with 4075 (30.8%) cases lacking trainee involvement and 9136 (69.2%) involving a trainee. Following propensity matching, junior (PGY 1-2) and middle level (PGY 3-4) resident involvement was not associated with worsened outcomes. Chief (PGY 5) resident involvement was associated with worsened 30-day overall morbidity (15.5 vs. 18.6%, p = 0.01). Fellow (PGY > 5) involvement was associated with worsened 30-day overall morbidity (16.0 vs. 21.0%, p < 0.001), serious morbidity (9.3 vs. 13.5%, p < 0.001), minor morbidity (9.8 vs. 13.1%, p = 0.002), and surgical site infection (7.9 vs. 10.5%, p = 0.006). No differences were seen in 30-day mortality for any resident level. CONCLUSION: Following propensity-matched analysis of cancer patients undergoing laparoscopic colectomy, chief residents, and fellows were associated with worsened operative outcomes compared to attending along cases, while junior and mid-level resident outcomes were no different. Further study is necessary to determine what effect the PGY surgical trainee level has on post operative morbidity in cancer patients undergoing laparoscopic colectomy in the context of multiple collinear factors. PMID- 28726139 TI - Assessing trends in laparoscopic colostomy reversal and evaluating outcomes when compared to open procedures. AB - BACKGROUND: Laparoscopic colostomy reversal has emerged as a viable option for Hartmann's reversal but the trends in national adoption and postoperative complications are unknown. This study evaluates the practice trends for laparoscopic colostomy and compares complications, length of stay, and operative times between laparoscopic and open colostomy reversal. METHODS: All patients who had open or laparoscopic colostomy reversal surgery (current procedure codes: 44227 and 44626) between 2005 and 2014 were identified from the American College of Surgeons National Surgical Quality Improvement Program. Data collected included patient demographics, comorbid conditions, postsurgical diagnosis, and estimated probabilities of morbidity and mortality. Univariate and multivariate unconditional logistic regression models and linear regression models were employed to evaluate the associations between various outcomes and surgical specialties. RESULTS: The reported volume of both open and laparoscopic colostomy reversal surgeries increased over time, but the percentage of open reversal surgery decreased from 100% in 2005 to 74.2% in 2014. The average annual increase in percentage of laparoscopic colostomy reversal surgery was 2.87%. The complication rates of open colostomy reversal surgery were significantly higher than the rates of laparoscopic colostomy reversal surgery (P < 0.0001). Although there were fluctuations, the complication rates remained constant over the 9-year study period for both open and laparoscopic colostomy reversal surgeries. The total hospital length of stay among patients who had laparoscopic colostomy reversal surgery was shorter compared to patients who had open colostomy reversal surgery [mean change (MC) = -1.77 days, P < 0.0001]. Similarly, a shorter operation time was also observed for patients who had laparoscopic colostomy reversal surgery (MC = -26.48 min, P < 0.0001). CONCLUSION: Based on the NSQIP database, laparoscopic colostomy reversal is increasing steadily year over year from 2005 to 2014 in NSQIP participating hospitals. Overall complication rates and length of stay are significantly lower and sustained throughout the study period for laparoscopic reversal. PMID- 28726140 TI - Outcomes following laparoscopic versus open major hepatectomy for hepatocellular carcinoma in patients with cirrhosis: a propensity score-matched analysis. AB - BACKGROUND: Laparoscopic major hepatectomy (LMH) for hepatocellular carcinoma (HCC) in patients with cirrhosis remains controversial due to limited reports in the literature. This study analyzed the perioperative and oncological outcomes of LMH for HCC with cirrhosis compared with open major hepatectomy (OMH). METHODS: A retrospective analysis of patients with cirrhosis who underwent major hepatectomy for HCC between January 2015 and January 2017 was performed. Patients were divided into the LMH group and the OMH group. Short-term and oncological outcomes were compared before and after 1:1 propensity score matching (PSM). RESULTS: A total of 103 HCC patients who received major liver resection were enrolled. There were 36 (35.0%) patients in the LMH group and 67 (65.0%) patients in the OMH group. After 1:1 PSM, well-matched 32 patients in each group were evaluated. Significant differences were observed in operative time (median, 255 vs. 200 min, p < 0.001) and Pringle time (median, 50 vs. 30 min, p < 0.001) between two groups. The blood loss and transfusion requirement were comparable in two groups. The rate of overall postoperative complications did not differ between two groups, while the incidence of ascites in the LMH group was significantly less than OMH group (9.4 vs. 31.3%, p = 0.030). The oncological outcomes between the two groups were comparable with regard to 2-year overall survival (85.7 vs. 86.7%, p = 0.694) and disease-free survival (72.9 vs. 81.5%, p = 0.990), respectively. CONCLUSIONS: LMH for HCC patients with liver cirrhosis showed comparable results in terms of postoperative morbidity and oncological outcomes compared with traditional open procedure. LMH may serve as a safe and feasible alternative for selected HCC patients with cirrhosis. PMID- 28726141 TI - Transoral robotic thyroidectomy: lessons learned from an initial consecutive series of 24 patients. AB - BACKGROUND: Transoral thyroid surgery is an ideal method for minimally invasive thyroidectomy, as there is less flap dissection during the procedure and no postoperative scars. Nonetheless, technical obstacles have precluded the wide dissemination of this procedure. We present the surgical procedures and outcomes of transoral robotic thyroidectomy (TORT). METHODS: From September 2012 to June 2016, we performed TORT at Korea University Hospital. We used three intraoral ports and a single axillary port for the system's four robotic arms. The surgical outcomes were retrospectively reviewed. RESULTS: Twenty-four female patients (mean age 39.6 +/- 11.6 years; mean tumor size 1.0 +/- 1.3 cm) underwent unilateral thyroid lobectomies with or without ipsilateral central neck dissection. Twenty patients had papillary thyroid carcinomas (PTC), three had benign nodules, and one had a follicular thyroid carcinoma. The mean surgical time was 232 +/- 41 min; the mean hospital stay was 3.3 +/- 0.8 days. The number of retrieved central lymph nodes in the PTC patients was 4.7 +/- 3.2. There were no reports of transient or permanent vocal cord palsy, recurrence, or mortality during the median follow-up period of 16.8 months. Paresthesia of the lower lip and the chin due to mental nerve injury was observed in nine of the first 12 patients (six transient, three permanent), but no further reports of paresthesia were recorded after patient 12, when the locations of the intraoral incisions were modified. CONCLUSIONS: TORT is feasible and safe for selected patients after technical refinements, and can be a potential alternative approach for scarless thyroid surgery. PMID- 28726142 TI - Single-incision surgery trocar-site hernia: an updated systematic review meta analysis with trial sequential analysis by the Minimally Invasive Surgery Synthesis of Interventions Outcomes Network (MISSION). AB - BACKGROUND: Single-incision laparoscopic surgery (SILS) is a new technique that aims to minimize abdominal wall trauma and improve cosmesis. Concerns have been raised about the risk of trocar-site hernia following SILS. This study aims to assess the risk of trocar-site hernia following SILS compared to conventional laparoscopic surgery, and investigate whether current evidence is conclusive. METHODS: We performed a systematic search of MEDLINE, AMED, CINAHL, CENTRAL, and OpenGrey. We considered randomized clinical trials comparing the risk of trocar site hernia with SILS and conventional laparoscopic surgery. Pooled odds ratios with 95% confidence intervals (CI) were calculated using the Mantel-Haenszel method. Trial sequential analysis using the Land and DeMets method was performed to assess the possibility of type I error and compute the information size. RESULTS: Twenty-three articles reporting a total of 2471 patients were included. SILS was associated with higher odds of trocar-site hernia compared to conventional laparoscopic surgery (odds ratio 2.37, 95% CI 1.25-4.50, p = 0.008). There was no evidence of between-study heterogeneity or small-study effects. The information size was calculated at 1687 patients and the Z-curve crossed the O'Brien-Fleming alpha-spending boundaries at 1137 patients, suggesting that the evidence of higher risk of trocar-site hernia with SILS compared to conventional laparoscopic surgery can be considered conclusive. CONCLUSIONS: Single-incision laparoscopic procedures through the umbilicus are associated with a higher risk of trocar-site hernia compared to conventional laparoscopic surgery. PMID- 28726143 TI - Endoscopic management of post-laparoscopic sleeve gastrectomy stenosis. AB - BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) is the most popular bariatric surgery worldwide. Gastric sleeve stenosis is the most common postoperative complication, occurring in up to 3.9% of the cases. Current treatment options include endoscopic treatments, such as dilatations and stent placement as well as surgical revisions such as laparoscopic Roux-en-Y gastric bypass (LRYGB), wedge gastrectomy or seromyotomy. METHODS: A retrospective analysis of our prospectively collected therapeutical endoscopy database was performed between January 2014 and February 2017. We included all cases of axial deviation or stenosis post LSG, which were treated endoscopically. Patients with concomitant sleeve leaks were excluded. Endoscopic interventions were performed under general anaesthesia and fluoroscopic assistance when needed. Sequential treatment with CRE balloons, achalasia balloons (30-40 mm) and fully covered stent placement for refractory cases was performed. RESULTS: A total of 1332 LSG were performed. Overall, 27/1332 patients (2%) developed a gastric stenosis. All patients presented an axial deviation at the incisura angularis and 26% had a concomitant proximal stenosis. Successful endoscopic treatments were performed in 56% (15/27) of patients, 73% of the successful patients underwent a single dilatation procedure. All successful cases had a maximum of 3 interventions. The unsuccessful cases (44%) underwent LRYGB. Mean time between the primary surgery and the diagnosis of the stenosis was 10.3 months. Mean follow-up after the endoscopic treatment was 11.5 months. A stent migration was the only complication (3.7%) recorded. CONCLUSIONS: Endoscopic treatment appears to be effective in 56% of patients with post-LSG stenosis. Only one session of achalasia balloon dilatation is necessary in 73% of successful cases. Pneumatic balloon dilatation seems to be a safe procedure in this patient population. Surgical revision into a LRYGB offers good outcomes in patients that have failed three consecutive endoscopic treatments. PMID- 28726144 TI - Anastomotic stricture after ultralow anterior resection or intersphincteric resection for very low-lying rectal cancer. AB - BACKGROUND: Anastomotic stricture following colorectal cancer surgery is not a rare complication, but proper management of anastomotic stricture located close to the anal verge is uncertain. This study aimed to investigate risk factors and management strategies for anastomotic stricture after ultralow anterior resection (ULAR). METHODS: We retrospectively reviewed a database of patients with rectal cancer who underwent surgery between January 2007 and June 2015, and included patients with an anastomosis within 4 cm from the anal verge. Clinical outcomes and risk factors for anastomotic stricture were investigated. RESULTS: Among the 586 patients included, 46 (7.8%) were diagnosed as having anastomotic stricture. Multivariable logistic regression analysis revealed that intersphincteric resection (ISR) with hand-sewn anastomosis (odds ratio [OR] = 3.070; 95% confidence interval [CI] 1.247-7.557) and postoperative radiotherapy (OR 6.237; 95% CI 1.961-19.841) were independent risk factors of anastomotic stricture. Forty-one (89.1%) underwent anastomotic dilatation with a Hegar dilator; while three patients (6.5%) underwent endoscopic balloon dilatation and two (4.3%) underwent surgery initially. Among the patients with initial nonoperative management (n = 44), 21 (47.7%) were completely cured with nonoperative management alone, 12 (27.3%) experienced complications, such as bowel perforation, anastomotic rupture, and perirectal abscess; and 21 (47.7%) underwent further surgical management. Fifteen patients (32.6%) eventually had permanent stoma. CONCLUSION: ISR with a hand-sewn coloanal anastomosis, compared to ULAR with double-stapling anastomosis, and postoperative radiotherapy were independent risk factors of anastomotic stricture after surgery for very low lying rectal cancer. Nonoperative anastomotic dilatation showed poor clinical outcome, with high complication rates, and subsequent surgical management. Therefore, nonoperative management of such patients should be carefully selected. PMID- 28726145 TI - Robotic gastric bypass may lead to fewer complications compared with laparoscopy. AB - BACKGROUND: Robotic technology leads to improved visualization and precision over laparoscopy but also higher cost of care. The benefits of this technology to patient outcomes are controversial. Our objective was to assess whether the application of robotic surgery to Roux-en-Y gastric bypass (RYGB) would lead to improved patient outcomes. METHODS: A prospectively collected database at a bariatric center of excellence was reviewed for all RYGB procedures performed by one surgeon between 2007 and 2015. Procedures performed laparoscopically (transoral circular stapling technique) versus robotically (hand-sewn anastomosis) were compared; the transition in technique occurred in 2011. Patient demographics, baseline weight, BMI, operation duration, estimated blood loss (EBL), length of hospital stay (LOS), morbidity and mortality, and percent excess weight loss (%EWL) at 1-year follow-up were compared between groups. Morbidity up to 1-year postop was assessed using the Clavien-Dindo classification. RESULTS: Of 246 patients, 125 underwent robotic and 121 laparoscopic RYGB. Patients in the robotic group were older and heavier but achieved similar %EWL to the laparoscopic group. The operative duration was longer but the mean patient LOS was shorter with the robotic approach. There were no leaks and no mortality. Based on the Clavien-Dindo classification, fewer overall and fewer severe complications occurred in the robotic compared with the laparoscopic approach. CONCLUSION: In our experience, the use of robotic technology for the creation of gastric bypass led to longer operative times, similar %EWL but decreased LOS and number and severity of complications compared with the laparoscopic approach. Since our findings may have been influenced by the type of anastomotic technique used with each approach they need confirmation by a controlled trial. PMID- 28726146 TI - An Odyssey of complications from band, to sleeve, to bypass; definitive laparoscopic completion gastrectomy with distal esophagectomy and esophagojejunostomy for persistent leak. AB - INTRODUCTION: Anastomotic leaks are uncommon yet potentially devastating complications after bariatric surgery. While the initial management includes resuscitation and sepsis control, the definitive management often requires endoscopic or surgical interventions. Surgical revision of the initial surgery may be necessary for chronic non-healing fistula. PATIENTS AND METHODS: The patient is a 45-year-old female with history of laparoscopic adjustable gastric banding who underwent band removal and conversion to a sleeve gastrectomy (SG) due to her failed weight loss, which resulted in a leak at gastroesophageal junction. She underwent multiple attempted endoluminal treatments without success and then SG was converted to Roux-en-Y gastric bypass (RYGB). However, this failed and the persistent leak led to a gastro-pleural fistula requiring left chest decortication. After addressing nutritional deficiencies, she underwent laparoscopic completion gastrectomy and Roux-en-Y esophagojejunostomy reconstruction. RESULTS: Five ports and a liver retractor were placed. Dissection was carried down posteriorly to free up the Roux limb and then to the right crus. There was an abscess cavity around the left crus. The esophagus was circumferentially mobilized and the abscess cavity was debrided. The proximal Roux limb was disconnected with a linear stapler. Upper endoscopy was used to identify the leak. The healthy tissue was confirmed above the leak and the distal esophagus was transected. Esophageal stump was mobilized up into the middle mediastinum. Esophagojejunostomy was completed with 25 mm circular stapler. A linear stapler was used to close the candy cane. The procedure took 2 h and 40 min. Estimated blood loss was 100 ml. Her postoperative course was uncomplicated. CONCLUSION: We present a video of the complex surgical revision of a leak after through the gamut of bariatric surgery: band to sleeve, failed endoluminal therapy and conversion of SG to RYGB. Durable success was achieved by a completion gastrectomy, distal esophagectomy with Roux-en-Y esophagojejunostomy. PMID- 28726147 TI - Stent migration following endoscopic suture fixation of esophageal self expandable metal stents: a systematic review and meta-analysis. AB - BACKGROUND: Covered self-expandable metal stents (SEMS) are utilized for the management of benign and malignant esophageal conditions; however, covered SEMS are prone to migration. Endoscopic suture fixation may mitigate the migration risk of covered esophageal SEMS. Hence, we conducted a systematic review and meta analysis to evaluate the effectiveness and safety of endoscopic suture fixation for covered esophageal SEMS. METHODS: Following PRISMA guidelines, we performed a systematic review from 2011 to 2016 to identify studies (case control/case series) reporting the technical success and migration rate of covered esophageal SEMS following endoscopic suture fixation. We searched multiple electronic databases and conference proceedings. We calculated pooled rates (and 95% confidence intervals [CI]) of technical success and stent migration using a random effects model. RESULTS: We identified 14 studies (212 patients) describing covered esophageal SEMS placement with endoscopic suture fixation. When reported, SEMS indications included leak/fistula (n = 75), stricture (n = 65), perforation (n = 10), and achalasia (n = 4). The pooled technical success rate was 96.7% (95% CI 92.3-98.6), without heterogeneity (I 2 = 0%). We identified 29 SEMS migrations at rate of 15.9% (95% CI 11.4-21.6), without heterogeneity (I 2 = 0%). Publication bias was observed, and using the trim-and-fill method, a more conservative estimate for stent migration was 17.0%. Suture-related adverse events were estimated to occur in 3.7% (95% CI 1.6-8.2) of cases. CONCLUSIONS: Endoscopic suture fixation of covered esophageal SEMS appears to reduce stent migration when compared to published rates of non-anchored SEMS. However, SEMS migration still occurs in approximately 1 out of 6 cases despite excellent immediate technical success and low risk of suture-related adverse events. PMID- 28726148 TI - First human use of hybrid synthetic/biologic mesh in ventral hernia repair: a multicenter trial. AB - BACKGROUND: Mesh options for reinforcement of ventral/incisional hernia (VIH) repair include synthetic or biologic materials. While each material has known advantages and disadvantages, little is understood about outcomes when these materials are used in combination. This multicenter study reports on the first human use of a novel synthetic/biologic hybrid mesh (Zenapro(r) Hybrid Hernia Repair Device) for VIH repair. METHODS: This prospective, multicenter post-market clinical trial enrolled consecutive adults who underwent elective VIH repair with hybrid mesh placed in the intraperitoneal or retromuscular/preperitoneal position. Patients were classified as Ventral Hernia Working Group (VHWG) grades 1-3 and had clean or clean-contaminated wounds. Outcomes of ventral and incisional hernia were compared using appropriate parametric tests. RESULTS: In all, 63 patients underwent VIH repair with hybrid mesh. Most were females (54.0%), had a mean age of 54.8 +/- 10.9 years and mean body mass index of 34.5 +/- 7.8 kg/m2, and classified as VHWG grade 2 (87.3%). Most defects were midline (92.1%) with a mean area of 106 +/- 155 cm2. Cases were commonly classified as clean (92.1%) and were performed laparoscopically (60.3%). Primary fascial closure was achieved in 82.5% with 28.2% requiring component separation. Mesh location was frequently intraperitoneal (69.8%). Overall, 39% of patients available for follow-up at 12 months suffered surgical site events, which were generally more frequent after incisional hernia repair. Of these, seroma (23.7%) was most common, but few (8.5%) required procedural intervention. Other surgical site events that required procedural intervention included hematoma (1.7%), wound dehiscence (1.7%), and surgical site infection (3.4%). Recurrence rate was 6.8% (95% CI 2.2-16.6%) at 12-months postoperatively. CONCLUSION: Zenapro(r) Hybrid Hernia Repair Device is safe and effective in VHWG grade 1-2 patients with clean wounds out to 12 months. Short-term outcomes and recurrence rate are acceptable. This hybrid mesh represents a novel option for reinforcement during VIH repair. PMID- 28726149 TI - Cardiopulmonary exercise testing and SPECT myocardial perfusion imaging: Pre-test probability is the key. PMID- 28726150 TI - Inhibition mechanism of CDK-2 and GSK-3beta by a sulfamoylphenyl derivative of indoline-a molecular dynamics study. AB - A good understanding of the inhibition mechanism of enzymes exhibiting high levels of similarity is the first step to the discovery of new drugs with selective potential. Examples of such proteins include glycogen synthase kinase-3 (GSK-3beta) and cyclin-dependent kinase 2 (CDK-2). This article reports the mechanism of such enzyme inhibition as analyzed by an indoline sulfamylophenyl derivative (CHEMBL410072). Previous work has shown that such compounds exhibit selective properties towards their biological targets. This study used a combined procedure involving docking and molecular dynamics simulations, which allowed identification of interactions responsible for stabilization of complexes, and analysis of the dynamic stability of the systems obtained. The initial data obtained during the molecular docking stage show that the ligand molecule exhibits a similar affinity towards both active sites, which was confirmed by quantification of identified interactions and energy values. However, the data do not cover dynamic aspects of the considered systems. Molecular dynamics simulations realized for both complexes indicate significant dissimilarities in dynamics properties of both side chains of the considered ligands, especially in the case of the part containing the sulfamide group. Such increased mobility of the analyzed systems disrupts the stability of binding in the stabilized complex with GSK-3beta protein, which finally affects also the binding affinity of the ligand molecule towards this enzyme. PMID- 28726151 TI - Aromaticity of graphene nanoflakes in a new way: fragment analysis by combination of the nucleus-independent chemical shifts and the anisotropy of current induced density. AB - A graphene nanoflake (GNF) is a polycyclic aromatic hydrocarbon (PAH) with a huge two-dimensional pi-conjugated carbon material in which a central benzene ring is surrounded by identical benzene-type rings through infinite alternant method. In this paper, we explore the structure-aromaticity relationship of the GNFs and the GNFs with hollow sites (GNFHs) by combining the nucleus-independent chemical shifts (NICS) with the anisotropy of the current induced density (ACID). Firstly, the benzene is a typical aromatic molecule (NICS = -9.671 ppm), GNFs 1-6 is darned with benzene and the corresponding GNFHs 1'-6'. Secondly, the NICS values of GNFs 1-6 alternately vary: -1.214 (1) > -13.847 (2) < -2.662 (3) > -14.530 (4) < -3.932 (5) > -13.978 (6) ppm, the GNFs (2, 4, 6) with even fragments of annulene have larger aromaticity than that of GNFs (1, 3, 5) with odd fragments of annulene. Significantly, the NICS values of GNFs 1-6 can also be fragment analyzed by the NICS values and ACID of benzene and corresponding GNFHs 1'-6'. The NICS values for GNFs (2, 4, 6) can be roughly estimated by the NICS value of benzene minus the NICS value of the GNFHs (2', 4', 6'), respectively. The NICS values for GNFs (1, 3, 5) can be roughly estimated by the NICS value of the GNFHs (1', 3', 5') minus the NICS value of benzene, respectively. We hope that the present work can provide a simple and reliable method for the rational design of the GNF with aromaticity, which may be used to understand the origin of the graphene nanoflake aromatic properties. PMID- 28726152 TI - Cardiovascular Outcome Trial Update in Diabetes: New Evidence, Remaining Questions. AB - PURPOSE OF REVIEW: Seven trials of new agents to treat type 2 diabetes (T2DM) have been performed to assess cardiovascular (CV) safety. A significant amount of information regarding the effects of drugs in three classes is available, with new data from multiple other trials expected shortly. This article provides a summary of recently completed trials. RECENT FINDINGS: The dipeptidyl peptidase-4 inhibitors studied thus far do not alter the risk of major adverse CV events (MACE). Glucagon like peptide-1 receptor agonists liraglutide and semaglutide, and the sodium glucose cotransporter-2 inhibitor empagliflozin, significantly reduced the risk of MACE. Empagliflozin also decreased the risk of hospitalization for heart failure. Agents demonstrating a CV outcome benefit also improved parameters of renal function. Several newer antihyperglycemic agents have been found to reduce the risk of important CV complications in high-risk patients with T2DM. Future trials are needed to assess the effects of additional drugs and the impact of therapy in lower risk patients and provide additional information regarding non-CV safety outcomes. PMID- 28726153 TI - Immunological Issues After Stem Cell-Based beta Cell Replacement. AB - PURPOSE OF REVIEW: Islet and pancreas transplantation prove that beta cell replacement can cure the glycemic derangements in type 1 diabetes (T1D). Induced pluripotent stem cells (iPSCs) can differentiate into functional insulin producing cells, able to restore normoglycemia in diabetic animal models. iPSCs in particular can be derived from the somatic cells of a person with T1D. This review aims to clarify if it is possible to transplant autologous iPSC-derived beta cells without immunosuppression or which are the alternative approaches. RECENT FINDINGS: Several lines of evidence show that autologous iPSC and their derivatives can be immune rejected, and this immunogenicity depends on the reprogramming, the type of cells generated, the transplantation site, and the genetic/epigenetic modifications induced by reprogramming and differentiation. Besides, cell replacement in T1D should keep in consideration also the possibility of autoimmune reaction against autologous stem cell-derived beta cells. Autologous iPSC-derived beta cells could be immunogenic upon transplantation, eliciting both auto and allogeneic immune response. A strategy to protect cells from immune rejection is still needed. This strategy should be efficacious in protecting the grafted cells, but also avoid toxicity and the risk of tumor formation. PMID- 28726154 TI - Use of Continuous Glucose Monitoring in Youth-Onset Type 2 Diabetes. AB - PURPOSE OF REVIEW: Continuous glucose monitoring (CGM) technology has long been accepted as a tool for managing glycemia in type 1 diabetes (T1D) and is receiving increased attention as a tool for monitoring glucose patterns in patients with other forms of diabetes, in particular type 2 diabetes (T2D). Recent studies in adults with T2D have shown benefits of CGM in the investigation of glycemic variability, as well as utility as a tool for improving glycemic control. The literature on CGM use in youth-onset T2D, however, is sparse. This paper reviews the various roles for CGM in T2D, with a focus on published reports of CGM use in youth-onset T2D. The gaps in knowledge are highlighted, along with a discussion regarding need for future studies of potential applications for CGM in this younger population. RECENT FINDINGS: CGM systems provide insight into glycemic abnormalities in obese youth with and at risk for T2D. This technology has enabled examination of the relationship between free-living glycemic profiles and traditional diabetes screening tests, as well as markers of cardiometabolic risk in this high-risk population. Investigators are incorporating CGM technology into the study of T2D in youth, but interventional studies of CGM as a tool for glycemic control in youth-onset T2D are limited. Youth with T2D face a more aggressive disease than adults with T2D, and further studies utilizing advances in glucose monitoring technology to improve outcomes in this population are needed. PMID- 28726155 TI - Initial Weight Loss Response as an Indicator for Providing Early Rescue Efforts to Improve Long-term Treatment Outcomes. AB - PURPOSE OF REVIEW: There is a large variability in response to behavioral weight loss (WL) programs. Reducing rates of obesity and diabetes may require more individuals to achieve clinically significant WL post-treatment. Given that WL within the first 1-2 months of a WL program is associated with long-term WL, it may be possible to improve treatment outcomes by identifying and providing additional intervention to those with poor initial success (i.e., "early non responders"). We review the current literature regarding early non-response to WL programs and discuss how adaptive interventions can be leveraged as a strategy to "rescue" early non-responders. RECENT FINDINGS: Preliminary findings suggest that adaptive interventions, specifically stepped care approaches, offer promise for improving outcomes among early non-responders. Future studies need to determine the optimal time point and threshold for intervening and the type of early intervention to employ. Clinicians and researchers should consider the discussed factors when making treatment decisions. PMID- 28726156 TI - Remote Monitoring and Consultation of Inpatient Populations with Diabetes. AB - PURPOSE OF REVIEW: Inpatient hyperglycemia is common and is linked to increased morbidity and mortality. We review current and innovative ways diabetes specialists consult in the management of inpatient diabetes. RECENT FINDINGS: With electronic medical records (EMRs), remote monitoring and intervention may improve the management of inpatient hyperglycemia. Automated reports allow monitoring of glucose levels and allow diabetes teams to intervene through formal or remote consultation. Following a 2-year transition of our complex paper-based insulin order sets to be EMR based, we leveraged this change by developing new daily glycemic reports and a virtual glucose management service (vGMS). Based on a daily report identifying patients with two or more glucoses over 225 mg/dl and/or a glucose <70 mg/dl in the past 24 h, a vGMS note with management recommendations was placed in the chart. Following the introduction of the vGMS, the proportion of hyperglycemic patients decreased 39% from a baseline of 6.5 per 100 patient-days to 4.0 per 100 patient-days The hypoglycemia proportion decreased by 36%. Ninety-nine percent of surveyed medical and surgical residents said the vGMS was both important and helpful. PMID- 28726158 TI - Free boundary models for mosquito range movement driven by climate warming. AB - As vectors, mosquitoes transmit numerous mosquito-borne diseases. Among the many factors affecting the distribution and density of mosquitoes, climate change and warming have been increasingly recognized as major ones. In this paper, we make use of three diffusive logistic models with free boundary in one space dimension to explore the impact of climate warming on the movement of mosquito range. First, a general model incorporating temperature change with location and time is introduced. In order to gain insights of the model, a simplified version of the model with the change of temperature depending only on location is analyzed theoretically, for which the dynamical behavior is completely determined and presented. The general model can be modified into a more realistic one of seasonal succession type, to take into account of the seasonal changes of mosquito movements during each year, where the general model applies only for the time period of the warm seasons of the year, and during the cold season, the mosquito range is fixed and the population is assumed to be in a hibernating status. For both the general model and the seasonal succession model, our numerical simulations indicate that the long-time dynamical behavior is qualitatively similar to the simplified model, and the effect of climate warming on the movement of mosquitoes can be easily captured. Moreover, our analysis reveals that hibernating enhances the chances of survival and successful spreading of the mosquitoes, but it slows down the spreading speed. PMID- 28726157 TI - Anodal transcranial direct current stimulation over the left temporal pole restores normal visual evoked potential habituation in interictal migraineurs. AB - BACKGROUND: Neuroimaging data has implicated the temporal pole (TP) in migraine pathophysiology; the density and functional activity of the TP were reported to fluctuate in accordance with the migraine cycle. Yet, the exact link between TP morpho-functional abnormalities and migraine is unknown. Here, we examined whether non-invasive anodal transcranial direct current stimulation (tDCS) ameliorates abnormal interictal multimodal sensory processing in patients with migraine. METHODS: We examined the habituation of visual evoked potentials and median nerve somatosensory evoked potentials (SSEP) before and immediately after 20-min anodal tDCS (2 mA) or sham stimulation delivered over the left TP in interictal migraineurs. RESULTS: Prior to tDCS, interictal migraineurs did not exhibit habituation in response to repetitive visual or somatosensory stimulation. After anodal tDCS but not sham stimulation, migraineurs exhibited normal habituation responses to visual stimulation; however, tDCS had no effect on SSEP habituation in migraineurs. CONCLUSION: Our study shows for the first time that enhancing excitability of the TP with anodal tDCS normalizes abnormal interictal visual information processing in migraineurs. This finding has implications for the role of the TP in migraine, and specifically highlights the ventral stream of the visual pathway as a pathophysiological neural substrate for abnormal visual processing in migraine. PMID- 28726159 TI - Diagnosis and treatment delays among elderly breast cancer patients with pre existing mental illness. AB - PURPOSE: This study aimed to compare diagnosis and treatment delays in elderly breast cancer patients with and without pre-existing mental illness. METHODS: A retrospective cohort study was conducted using the Surveillance, Epidemiology and End Results-Medicare data including 16,636 women 68+ years, who were diagnosed with stage I-IIIa breast cancer in the United States from 2005 to 2007. Mental illness was identified using International Classification of Diseases, Ninth Revision, Clinical Modification codes recorded on inpatient and outpatient claims during the 3 years prior to breast cancer diagnosis. Patients were classified as having no mental illness, anxiety, depression, anxiety and depression, or severe mental illness (bipolar disorder, schizophrenia, and other psychotic disorder). Multivariable binomial regression was used to assess the association between mental illness and delays of >=60 and >=90 days after adjustment for confounders. RESULTS: Patients with comorbid anxiety and depression had an increased risk for diagnosis delay of >=90 days from symptom recognition (RR 1.11; 95% CI 1.00, 1.23), and those with severe mental illness had an increased risk for initial treatment delay of >=60 days from diagnosis (RR 1.36; 95% CI 1.06, 1.74). Patients with any mental illness experienced an increased risk for adjuvant chemotherapy delay of >=90 days from last operation (RR 1.13; 95% CI 1.01, 1.26) and each category of mental illness, except depression, showed a non-significant trend for this association. CONCLUSION: Breast cancer patients with mental illness should be closely managed by a cross-functional care team, including a psychiatrist, a primary care physician, and an oncologist, to ensure adequate care is received within an appropriate timeframe. PMID- 28726160 TI - Complete canine spinal cord transection model: a large animal model for the translational research of spinal cord regeneration. PMID- 28726161 TI - Celastrol specifically inhibits the activation of NLRP3 inflammasome. PMID- 28726162 TI - Complete chloroplast genome sequences of Schisandra chinensis: genome structure, comparative analysis, and phylogenetic relationship of basal angiosperms. PMID- 28726163 TI - Phosphoenolpyruvate:glucose phosphotransferase system modification increases the conversion rate during L-tryptophan production in Escherichia coli. AB - Escherichia coli FB-04(pta1), a recombinant L-tryptophan production strain, was constructed in our laboratory. However, the conversion rate (L-tryptophan yield per glucose) of this strain is somewhat low. In this study, additional genes have been deleted in an effort to increase the conversion rate of E. coli FB-04(pta1). Initially, the pykF gene, which encodes pyruvate kinase I (PYKI), was inactivated to increase the accumulation of phosphoenolpyruvate, a key L-tryptophan precursor. The resulting strain, E. coli FB-04(pta1)DeltapykF, showed a slightly higher L-tryptophan yield and a higher conversion rate in fermentation processes. To further improve the conversion rate, the phosphoenolpyruvate:glucose phosphotransferase system (PTS) was disrupted by deleting the ptsH gene, which encodes the phosphocarrier protein (HPr). The levels of biomass, L-tryptophan yield, and conversion rate of this strain, E. coli FB-04(pta1)DeltapykF/ptsH, were especially low during fed-batch fermentation process, even though it achieved a significant increase in conversion rate during shake-flask fermentation. To resolve this issue, four HPr mutations (N12S, N12A, S46A, and S46N) were introduced into the genomic background of E. coli FB 04(pta1)DeltapykF/ptsH, respectively. Among them, the strain harboring the N12S mutation (E. coli FB-04(pta1)DeltapykF-ptsHN12S) showed a prominently increased conversion rate of 0.178 g g-1 during fed-batch fermentation; an increase of 38.0% compared with parent strain E. coli FB-04(pta1). Thus, mutation of the genomic of ptsH gene provided an alternative method to weaken the PTS and improve the efficiency of carbon source utilization. PMID- 28726164 TI - One-day nasogastric tube decompression after distal gastrectomy: a prospective randomized study. PMID- 28726165 TI - Long-term outcomes of laparoscopic versus open splenectomy for immune thrombocytopenia. AB - PURPOSE: Splenectomy is the standard therapy for medically refractory immune thrombocytopenia (ITP). Laparoscopic splenectomy (LS) has gained wide acceptance; however, the long-term outcomes of LS versus open splenectomy (OS) for patients with ITP remain unclear. METHODS: We analyzed, retrospectively, 32 patients who underwent splenectomy, as LS in 22 and OS in 10, for refractory ITP at our institute. Data were evaluated based on the American Society of Hematology 2011 evidence-based practice guidelines for ITP. RESULTS: Although the operation time was significantly longer in the LS group (p < 0.01), LS was associated with less blood loss (p < 0.01), infrequent blood transfusion during surgery (p < 0.01), quicker resumption of oral intake (p < 0.01), and shorter hospital stay (p < 0.01) than OS. Positive responses, including complete and partial remission, were achieved in 90% of the OS group patients and 77% of the LS group patients. The mean follow-up periods were 183 and 92 months, respectively. Relapse-free survival rates, 15 years after the operation were 63% in the OS group and 94% in the LS group. CONCLUSIONS: LS can provide better short-term results and comparable long-term results to those of OS for ITP. PMID- 28726166 TI - Safety of laparoscopic distal gastrectomy for gastric cancer when performed by trainee surgeons with little experience in performing open gastrectomy. AB - PURPOSE: This study aimed to evaluate the surgical outcomes and clinical safety of laparoscopic distal gastrectomy (LDG) when performed by trainee surgeons with little prior experience in performing open gastrectomy, under the guidance of trainer surgeons. METHODS: From January 2008 until March 2015, 17 trainee surgeons and 5 trainer surgeons performed LDGs to treat 371 patients with clinical stage T1-T3 gastric cancer. Of these patients, 140 and 231 underwent LDG performed by trainee surgeons and trainer surgeons, respectively. We retrospectively analyzed the surgical outcomes of the two groups. RESULTS: Trainee surgeons required significantly longer operation times than the trainer surgeons, with respective mean operation times of 262 and 223 min (p < 0.001). However, the mean blood loss volumes, average numbers of retrieved lymph nodes, postoperative complications, and postoperative hospital stay lengths did not differ significantly between LDGs performed by trainee surgeons and trainer surgeons. CONCLUSIONS: The study findings suggest that, under the guidance of trainer surgeons, trainee surgeons with little experience with open gastrectomy and even without prior experience with LDG can perform radical surgeries safely. PMID- 28726167 TI - Early Increased Bradykinin 1 Receptor Contributes to Hemorrhagic Transformation After Ischemic Stroke in Type 1 Diabetic Rats. AB - Hemorrhagic transformation (HT) is a major complication of ischemic stroke and further deteriorates neurological outcomes. Bradykinin 1 receptor (B1R) has been proven to mediate vasculo-toxicity in various experimental models. However, its role in the development of HT after stroke remains unclear. We detected the B1R expression in brain tissues with or without HT in a rat model of cerebral ischemia/reperfusion (I/R) with type 1 diabetes, showing higher B1R expression in the hemorrhagic areas than the ischemic tissues. Then, B1R agonist or antagonist was administrated intravenously just before reperfusion to investigate its effect on HT and the underlying molecular mechanism. Administration of low (300 nmol/kg) or high (1 MUmol/kg) dose of B1R antagonist mitigated hemorrhage, improved neurobehavioral deficits, and preserved blood-brain-barrier (BBB) integrity after reperfusion for 8 h whereas the 300 nmol/kg of B1R agonist aggravated these outcomes, though only the high does of B1R antagonist affected the infarction volume. Extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation was increased by B1R activation but decreased by B1R inhibition, which mediated B1R toxicity on BBB disruption and ischemia-related HT. Furthermore, B1R activation facilitated the mRNA and protein expressions of MMP-9 in the hemorrhagic tissues, and these increases were blocked by both ERK inhibitor U0126 and NF-kappaB inhibitor PDTC. U0126 also remarkably decreased the B1R-induced NF-kappaB/p65 activation. We concluded that upregulated B1R may contribute to early HT after I/R in type 1 diabetic rats via ERK1/2/NF-kappaB/MMP-9 pathway. B1R inhibition could be an encouraging therapeutic strategy to withstand HT after ischemic stroke in diabetic patients. PMID- 28726169 TI - Comparison of the Systemic and Local Pharmacokinetics of Clonidine Mucoadhesive Buccal Tablets with Reference Clonidine Oral Tablets in Healthy Volunteers: An Open-Label Randomised Cross-Over Trial. AB - INTRODUCTION: The clonidine mucoadhesive buccal tablet (MBT) is a novel delivery system resulting in high and sustained concentrations of clonidine in the oral cavity. In a phase II clinical trial, clonidine MBT reduced the incidence of severe oral mucositis (OM) compared to placebo in head and neck cancer patients undergoing chemoradiation. This study compared the pharmacokinetics (PK), safety and tolerability of clonidine MBT with a reference oral tablet (OT). METHODS: This was a randomised, three-period, single-dose crossover study in 36 healthy subjects aged 18-50 years. Eligibility was assessed within 14 days of the first dose. IMP was administered in the fasted state on day 1 of each treatment period. PK samples were collected up to 24 h (saliva)/96 h (blood) for measurement of the clonidine concentration. Safety and tolerability were evaluated at specified times throughout the study. A washout period of at least 7 days was observed between administrations. RESULTS: Clonidine MBT (50 and 100 ug) applied to the upper gum resulted in a dose-proportional increase in saliva (C max and AUC0-t ) and plasma (Cmax and AUC0-inf) clonidine levels. Clonidine MBT was considered to mimic a continuous release of clonidine in plasma, significantly decreasing the C max and AUC and increasing the T max when compared with the reference clonidine HCl tablets. Clonidine MBT exhibited high and prolonged concentrations in saliva where concentrations with the clonidine HCl tablet were negligible. Clonidine MBT exhibited a favourable safety profile with significantly fewer subjects reporting AEs (dry mouth and fatigue) and a reduction in blood pressure when compared to the reference clonidine HCl tablets. CONCLUSION: Clonidine MBT is well tolerated and exhibits proportional saliva and plasma PK over the 50-100-ug dose level. The MBT results in higher saliva concentrations and lower systemic exposure than OT, which was associated with a trend towards fewer adverse events and less dry mouth, fatigue and hypotensive effect. FUNDING: Onxeo SA. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02548806. PMID- 28726168 TI - Cognitive Interventions for Cognitively Healthy, Mildly Impaired, and Mixed Samples of Older Adults: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. AB - Cognitive interventions may improve cognition, delay age-related cognitive declines, and improve quality of life for older adults. The current meta-analysis was conducted to update and expand previous work on the efficacy of cognitive interventions for older adults and to examine the impact of key demographic and methodological variables. EBSCOhost and Embase online databases and reference lists were searched to identify relevant randomized-controlled trials (RCTs) of cognitive interventions for cognitively healthy or mildly impaired (MCI) older adults (60+ years). Interventions trained a single cognitive domain (e.g., memory) or were multi-domain training, and outcomes were assessed immediately post-intervention using standard neuropsychological tests. In total, 279 effects from 97 studies were pooled based on a random-effects model and expressed as Hedges' g (unbiased). Overall, results indicated that cognitive interventions produce a small, but significant, improvement in the cognitive functioning of older adults, relative to active and passive control groups (g = 0.298, p < .001, 95% CI = 0.248-0.347). These results were confirmed using multi-level analyses adjusting for nesting of effect sizes within studies (g = 0.362, p < .001, 95% CI = 0.275, 0.449). Age, education, and cognitive status (healthy vs. MCI) were not significant moderators. Working memory interventions proved most effective (g = 0.479), though memory, processing speed, and multi-domain interventions also significantly improved cognition. Effects were larger for directly trained outcomes but were also significant for non-trained outcomes (i.e., "transfer effects"). Implications for future research and clinical practice are discussed. This project was pre-registered with PROSPERO (#42016038386). PMID- 28726170 TI - Prescribing Trends in a Glaucoma Clinic and Adherence to EGS Guidelines: A Retrospective, Non-Interventional, Single-Center UK Study. AB - INTRODUCTION: The purpose of this study was to determine prescribing trends in a specialist glaucoma clinic in the UK. Specifically, the aims were to determine which drugs were prescribed as first-, second-, and third-line treatment, the persistence of first-, second-, and third-line treatment regimens, and the proportion of treatment decisions conforming to the European Glaucoma Society (EGS) guidelines. METHODS: A retrospective, non-interventional, single-center, case-note review was performed on a cohort of consecutive patients presenting to a specialist glaucoma clinic for follow-up. Inclusion criteria for the study were (1) a diagnosis of primary open-angle glaucoma or ocular hypertension, (2) glaucoma management entirely within the unit, and (3) minimum of 2 years of follow-up. RESULTS: A total of 114 case notes met the inclusion criteria. Mean age was 71 years (range 40-95 years). Mean length of follow-up was 56 months (range 24-180 months). Prostaglandin analogues (PGA) were the most popular first line treatment in 73% of patients. As second-line treatment, PGA were again the predominant class, prescribed in 87% of cases, whereas beta-blockers (BB) were prescribed in 70% of cases. Carbonic anhydrase inhibitors (CAI) and alpha-2 agonists (AA) were more popular in third-line regimens. Second-line treatment was introduced at a mean of 28.0 months after first-line treatment (range 1-120 months, 95% CI 22.1-33.9 months). Third-line treatment was introduced at a mean of 22.9 months after second-line treatment (range 1-96 months, 95% CI 17.1-28.8 months). Breaches to EGS guidelines were most common for third-line treatment and included duplication of drug classes. DISCUSSION: There was a clear hierarchy of PGA as first-line, BB as second-line, while CAI and AA were considered third-line choices. First-line choices were generally in line with EGS guidelines. There was a tendency to breach guidelines by escalating treatment in dual steps rather than single steps (especially in third-line treatment). Combination drops were popular. In third-line treatment there was an increased incidence of prescribing errors. This data is important in terms of informing patients of the expected treatment course, to remind clinicians about best practice, and also to guide comparisons of cost-effectiveness with other treatment modalities. PMID- 28726171 TI - QSAR modeling, docking and ADMET studies for exploration of potential anti malarial compounds against Plasmodium falciparum. AB - Development of resistance in the Plasmodium falciparum to Artemisinin, the most effective anti-malarial compound, threatens malaria elimination tactics. To gain more efficacious Artemisinin derivatives, QSAR modeling and docking was performed. In the present study, 2D-QSAR model and molecular docking were used to evaluate the Artemisinin compounds and to reveal their binding modes and structural basis of inhibitory activity. Moreover, ADMET-related descriptors have been calculated to predict the pharmacokinetic properties of the effective compounds. The correlation expressed as coefficient of determination (r2) and prediction accuracy expressed in the form of cross-validated r2 (q2) of QSAR model are found 0.9687 and 0.9586, respectively. Total 239 descriptors have been included in the study as independent variables. The four chemical descriptors, namely radius of gyration, mominertia Z, SssNH count and SK Average have been found to be well correlated with anti-malarial activities. The model was statistically robust and has good predictive power which could be employed for virtual screening of proposed anti-malarial compounds. QSAR and docking results revealed that studied compounds exhibit good anti-malarial activities and binding affinities. The outcomes could be useful for the design and development of the potent inhibitors which after optimization can be potential therapeutics for malaria. PMID- 28726172 TI - Combined treatment for non-small cell lung cancer and breast cancer patients with brain metastases with whole brain radiotherapy and temozolomide: a systematic review and meta-analysis. AB - Brain metastasis is the leading cause of death among advanced non-small cell lung cancer (NSCLC) and breast cancer patients. The standard treatment for brain metastases is radiotherapy. The combination of radiotherapy and chemotherapy has been tested. However, the management of brain metastases has yet to be successful. Here, we aimed to determine the efficacy and safety of whole brain radiotherapy (WBRT) alone or in combination with temozolomide (TMZ) in NSCLC and breast cancer patients with brain metastases. A systematic review of PubMed, CNKI (China National Knowledge Infrastructure) and WANFANG (WANGFANG data) involving 870 patients were conducted. Fourteen randomized controlled trials (RCTs) were independently identified by two reviewers. The primary outcome measures were objective response rate (ORR), overall survival (OS), progression-free survival (PFS) and toxicity. The ORR was better with combination therapy of WBRT and TMZ than with WBRT alone (RR = 1.34, p < 0.00001) and subgroup analysis showed a significantly superior ORR in NSCLC patients (RR = 1.38, p < 0.00001), but not in breast cancer patients (RR = 1.03, p = 0.86). OS and PFS did not significantly differ between combination therapy and WBRT alone. A higher rate of toxicity was observed in combination therapy than in WBRT alone (RR = 1.83, p = 0.0006). No advantages of concurrent WBRT and TMZ were observed in breast cancer patients with brain metastases. Combination therapy was associated with improved ORR in NSCLC patients, especially in Chinese patients. As a "surrogate endpoint" for OS, ORR may allow a conclusion to be made about the management of NSCLC with brain metastases with the combination of WBRT and TMZ. However, it needs to be validated to show that improved ORR predicts the treatment effects on the clinical benefit. The ORR may be valid for a particular indication such as status of MGMT promoter methylation. PMID- 28726174 TI - Comparative study of the effects of a small-scale trout farm on the macrozoobenthos, potamoplankton, and epilithic diatom communities. AB - Trout farms are one of the major sources of pollution of highland streams and rivers, which are very sensitive ecosystems otherwise scarcely influenced by human activities. A trout farm with low annual production was chosen for comparative monitoring of its effects on the macrozoobenthos, epilithic diatom, and potamoplankton communities in the receiving stream. Research was conducted every 2 months during a period of 1 year (one control point and three localities downstream from the farm). The fish farm discharge induced moderate alteration of environmental factors in the receiving watercourse, viz., significant increase of the ionized and un-ionized ammonia fraction, dissolved oxygen concentration, and biological oxygen demand. Species richness and Simpson's diversity index did not change in any of the communities. Correspondent analysis of potamoplankton community composition clearly showed trout farm effects, thereby indicating the need for reevaluation of saprobic valence values for potamoplankton species. The complete lack of influence of the trout farm discharge on the epilithic diatom community is probably due to absence of significant changes of phosphorus concentration in the receiving stream. Effects of the trout farm on the macrozoobenthos community were further characterized by 14 additional indices. The percentages of Chironomidae larvae, shredders, and total collectors; ratio of shredders to collectors; and the family biotic index are suggested as candidates for future multimetric index for measuring of trout farm influence. PMID- 28726173 TI - Recurrent glioblastomas in the elderly after maximal first-line treatment: does preserved overall condition warrant a maximal second-line treatment? AB - A growing literature supports maximal safe resection followed by standard combined chemoradiotherapy (i.e. maximal first-line therapy) for selected elderly glioblastoma patients. To assess the prognostic factors from recurrence in elderly glioblastoma patients treated by maximal safe resection followed by standard combined chemoradiotherapy as first-line therapy. Multicentric retrospective analysis comparing the prognosis and optimal oncological management of recurrent glioblastomas between 660 adult patients aged of < 70 years (standard group) and 117 patients aged of >=70 years (elderly group) harboring a supratentorial glioblastoma treated by maximal first-line therapy. From recurrence, both groups did not significantly differ regarding Karnofsky performance status (KPS) (p = 0.482). Oncological treatments from recurrence significantly differed: patients of the elderly group received less frequently oncological treatment from recurrence (p < 0.001), including surgical resection (p < 0.001), Bevacizumab therapy (p < 0.001), and second line chemotherapy other than Temozolomide (p < 0.001). In multivariate analysis, Age >=70 years was not an independent predictor of overall survival from recurrence (p = 0.602), RTOG RPA classes 5-6 (p = 0.050) and KPS at recurrence <70 (p < 0.001), available in all cases, were independent significant predictors of shorter overall survival from recurrence. Initial removal of >= 90% of enhancing tumor (p = 0.004), initial completion of the standard combined chemoradiotherapy (p = 0.007), oncological treatment from recurrence (p < 0.001), and particularly surgical resection (p < 0.001), Temozolomide (p = 0.046), and Bevacizumab therapy (p = 0.041) were all significant independent predictors of longer overall survival from recurrence. Elderly patients had substandard care from recurrence whereas age did not impact overall survival from recurrence contrary to KPS at recurrence <70. Treatment options from recurrence should include repeat surgery, second line chemotherapy and anti-angiogenic agents. PMID- 28726175 TI - Using ensemble forecasting to examine how climate change promotes worldwide invasion of the golden apple snail (Pomacea canaliculata). AB - The golden apple snail, Pomacea canaliculata, is one of the world's 100 most notorious invasive alien species. Knowledge about the critical climate variables that limit the global distribution range of the snail, as well as predictions of future species distributions under climate change, is very helpful for management of snail. In this study, the climatically suitable habitats for this kind of snail under current climate conditions were modeled by biomod2 and projected to eight future climate scenarios (2 time periods [2050s, 2080s] * 2 Representative Concentration Pathways [RCPs; RCP2.6, RCP8.5] * 2 atmospheric General Circulation Models [GCMs; Canadian Centre for Climate Modelling and Analysis (CCCMA), Commonwealth Scientific and Industrial Research Organisation (CSIRO)]). The results suggest that the lowest temperature of coldest month is the critical climate variable to restrict the global distribution range of P. canaliculata. It is predicted that the climatically suitable habitats for P. canaliculata will increase by an average of 3.3% in 2050s and 3.8% in 2080s for the RCP2.6 scenario, while they increase by an average of 8.7% in 2050s and 10.3% in 2080s for the RCP8.5 scenario. In general, climate change in the future may promote the global invasion of the invasive species. Therefore, it is necessary to take proactive measures to monitor and preclude the invasion of this species. PMID- 28726176 TI - Quality assessment and public health status of harvested rainwater in a peri urban community in Edo State of Nigeria. AB - The harvested rainwater is an alternative water source in communities where there is limited or scarcity of water distribution system. However, contamination of roof-harvested rainwater is of immense concern to the general public health. Therefore, this study was initiated to assess the levels of physicochemical quality and heavy metal concentrations in the harvested rainwater from Oluku communities in Benin City, Edo State, Nigeria. The roof-harvested rainwater samples were collected from 20 independent different residential households in Oluku communities, between April 2015 and September 2015. Physicochemical analyses were carried out using standard analytical methods, and heavy metal concentrations were determined using atomic absorption spectrophotometry. The evaluation of the rainwater harvesting shows that 60% (12/20) of the roofs were made of corrugated iron sheets; aluminum sheets, 20% (4/20); asbestos, 10% (2/20); and open space was 10% (2/20). Also, the storage systems used for the storage of harvested rainwater were as follows: PVC tanks, 20% (4/20); drums, 30% (6/20); buckets, 25% (5/20); and wells, 25% (5/20). The physicochemical indicators investigated (temperature, nitrate, chlorine content, electrical conductivity, phosphate, total dissolved solids, and sulfate) were within World Health Organization (WHO) guidelines. However, some pH levels of the roof harvested rainwater were acidic and below the WHO standard. Furthermore, a high value of turbidity was observed in some locations and exceeded the WHO guidelines. Though some heavy metal indicators (Zn, Na, K, and Ca) in this study were within the WHO guidelines, some locations revealed heavy metal (Cu, Fe, and Cd) concentrations slightly above the WHO guidelines. There is need for proper rainwater harvesting system and continuous monitoring of harvested rainwater for potable uses. PMID- 28726178 TI - Being of "two minds": Assessing vacillating and simultaneous ambivalence with the density matrix. AB - Ambivalence is a common experience that permeates a broad range of research. Unfortunately, quantifying ambivalence has proven a daunting task, with researchers limited to studying vacillating ambivalence, VA (i.e., temporal oscillations between favor/disfavor evaluations of an attitude object). Here, we demonstrate the use of the density matrix to measure both VA and what we term "simultaneous ambivalence" (SA): ambivalence that manifests itself as "in the moment" concurrent favor/disfavor evaluations. In a methodological study we gave participants the option of either single-responding or double-responding to questionnaire items regarding a controversial topic (i.e., affirmative action). Since standard statistical procedures provide no means for analyzing double responses, such data are routinely treated as "bad." As demonstrated here, the density matrix provides an unambiguous and relatively easy means of accounting for double responses, which is our indicator of SA. Our data are well explained by a mixture model, with participants divided into two nearly equal groups of SA and non-SA participants, and provide evidence that the general phenomenon of SA transcends differences of gender and ethnicity. Further, the density matrix data are consistent with viewing SA and VA as distinct ambivalence constructs. PMID- 28726177 TI - The reliability paradox: Why robust cognitive tasks do not produce reliable individual differences. AB - Individual differences in cognitive paradigms are increasingly employed to relate cognition to brain structure, chemistry, and function. However, such efforts are often unfruitful, even with the most well established tasks. Here we offer an explanation for failures in the application of robust cognitive paradigms to the study of individual differences. Experimental effects become well established - and thus those tasks become popular - when between-subject variability is low. However, low between-subject variability causes low reliability for individual differences, destroying replicable correlations with other factors and potentially undermining published conclusions drawn from correlational relationships. Though these statistical issues have a long history in psychology, they are widely overlooked in cognitive psychology and neuroscience today. In three studies, we assessed test-retest reliability of seven classic tasks: Eriksen Flanker, Stroop, stop-signal, go/no-go, Posner cueing, Navon, and Spatial Numerical Association of Response Code (SNARC). Reliabilities ranged from 0 to .82, being surprisingly low for most tasks given their common use. As we predicted, this emerged from low variance between individuals rather than high measurement variance. In other words, the very reason such tasks produce robust and easily replicable experimental effects - low between-participant variability makes their use as correlational tools problematic. We demonstrate that taking such reliability estimates into account has the potential to qualitatively change theoretical conclusions. The implications of our findings are that well established approaches in experimental psychology and neuropsychology may not directly translate to the study of individual differences in brain structure, chemistry, and function, and alternative metrics may be required. PMID- 28726179 TI - Methionine and/or Methionine Sulfoxide Alter Ectoenzymes Activities in Lymphocytes and Inflammatory Parameters in Serum from Young Rats: Acute and Chronic Effects. AB - In this study we investigated the effect of acute and chronic treatment with Met and/or methionine sulfoxide (MetO) on ectonucleotidases and cholinesterases activities from lymphocytes and purine derivatives compounds, C-protein reactive, interleukin-10, interleukin-6, and tumor necrosis factor-alpha levels in serum of young rats. Adenosine triphosphate hydrolysis was decreased in lymphocytes 1 h after treatment by MetO and Met + MetO. However, adenosine triphosphate and adenosine diphosphate hydrolysis in lymphocytes was increased in the groups MetO and Met + MetO and adenosine deaminase activity was increased in MetO 3 h after the treatment. Acetylcholinesterase activity was increased in lymphocytes after 3 h and 21 days of treatment by MetO and Met + MetO, while serum butyrycholinesterase activity was decreased after 1 h and 21 days of treatment in the same groups. In chronic treatment, interleukin-6 and tumor necrosis factor alpha level were increased, while that interleukin-10 level was decreased by Met, MetO, and Met + MetO when compared to control group. C-protein reactive level was increased by MetO and Met + MetO. Adenosine triphosphate and adenosine monophosphate levels were reduced in all amino acids treated groups, while adenosine diphosphate and hypoxanthine were enhanced by MetO and Met + MetO. Adenosine and xanthine were reduced in the MetO group, whereas inosine levels were decreased in the MetO and Met + MetO groups. These findings help to understand the inflammatory alterations observed in hypermethioninemia. PMID- 28726180 TI - EPR Characterization of Dinitrosyl Iron Complexes with Thiol-Containing Ligands as an Approach to Their Identification in Biological Objects: An Overview. AB - The overview demonstrates how the use of only one physico-chemical approach, viz., the electron paramagnetic resonance method, allowed detection and identification of dinitrosyl iron complexes with thiol-containing ligands in various animal and bacterial cells. These complexes are formed in biological objects in the paramagnetic (electron paramagnetic resonance-active) mononuclear and diamagnetic (electron paramagnetic resonance-silent) binuclear forms and control the activity of nitrogen monoxide, one of the most universal regulators of metabolic processes in the organism. The analysis of electronic and spatial structures of dinitrosyl iron complex sheds additional light on the mechanism whereby dinitrosyl iron complex with thiol-containing ligands function in human and animal cells as donors of nitrogen monoxide and its ionized form, viz., nitrosonium ions (NO+). PMID- 28726181 TI - KI-67 heterogeneity in well differentiated gastro-entero-pancreatic neuroendocrine tumors: when is biopsy reliable for grade assessment? AB - PURPOSE: Ki-67 heterogeneity can impact on gastroenteropancreatic neuroendocrine tumor grade assignment, especially when tissue is scarce. This work is aimed at devising adequacy criteria for grade assessment in biopsy specimens. METHOD: To analyze the impact of biopsy size on reliability, 360 virtual biopsies of different thickness and lengths were constructed. Furthermore, to estimate the mean amount of non-neoplastic tissue component present in biopsies, 28 real biopsies were collected, the non-neoplastic components (fibrosis and inflammation) quantified and the effective area of neoplastic tissue calculated for each biopsy. RESULTS: Heterogeneity of Ki-67 distribution, G2 tumors and biopsy size all play an important role in reducing the reliability of biopsy samples in Ki-67-based grade assignment. In particular in G2 cases, 59.9% of virtual biopsies downgraded the tumor and the smaller the biopsy, the more frequent downgrading occurs. In real biopsies the presence of non-neoplastic tissue reduced the available total area by a mean of 20%. CONCLUSIONS: By coupling the results from these two different approaches we show that both biopsy size and non-neoplastic component must be taken into account for biopsy adequacy. In particular, we can speculate that if the minimum biopsy area, necessary to confidently (80% concordance) grade gastro-entero-pancreatic neuroendocrine tumors on virtual biopsies ranges between 15 and 30 mm2, and if real biopsies are on average composed of only 80% of neoplastic tissue, then biopsies with a surface area not <12 mm2 should be performed; using 18G needles, this corresponds to a minimum total length of 15 mm. PMID- 28726182 TI - Autoimmune hypothyroidism is three times more frequent in female prolactinoma patients compared to healthy women: data from a cross-sectional case-control study. AB - BACKGROUND: The potent immunomodulatory action of prolactin has been demonstrated in many experimental in vitro studies. In accordance with these data, our retrospective analyses revealed higher prevalence of autoimmune thyroid diseases in prolactinoma patients compared to general population. PURPOSE: A cross sectional case-control study was carried out in a single tertiary referral centre. The main aim was to assess the frequency of newly diagnosed autoimmune thyroid diseases in female patients with prolactinomas. METHODS: The study population consisted of 260 females (154 patients and 106 sex-matched, ethnicity matched, and age-matched healthy controls) enroled in a prospective manner. Physical exam, thyroid ultrasound, and laboratory testing (measurement of antibodies to thyroglobulin, thyroid peroxidase, TSH-receptor, serum TSH and FT4 levels) were performed in all study participants. RESULTS: Autoimmune thyroid diseases were diagnosed in 29.9% of the patients and 10.4% of the healthy subjects (p = 0.0002). Subclinical hypothyroidism was found in 9.7% of the patients versus 2.8% of the controls (p = 0.044). Autoimmune hyperthyroidism was observed in 1.3% of all patients. CONCLUSIONS: The prevalence of newly diagnosed autoimmune thyroid diseases, and especially the subclinical hypothyroidism, was significantly higher in our female prolactinoma patients in comparison to age matched healthy women. Based on our results, we suggest routine screening for autoimmune thyroid diseases (thyroid function, immunology and ultrasound examination) in all female patients with prolactinoma at the time of diagnosis. We also recommend a close follow-up of thyroid function in these women in case of pregnancy and after delivery. PMID- 28726183 TI - Escalated-dose somatostatin analogues for antiproliferative effect in GEPNETS: a systematic review. AB - BACKGROUND/PURPOSE: Somatostatin analogues are the cornerstone of systemic therapy for metastatic well-differentiated gastroenteropancreatic neuroendocrine tumours for both hormonal control and antiproliferative effect. Dose escalation of somatostatin analogues is often utilized in clinical practice, but small studies have yielded mixed results. The aim of this study was to systematically determine the efficacy and safety of escalated-dose somatostatin analogues in the above setting. METHODS: Eligible trials (using more than 30 mg octreotide or 120 mg lanreotide/28 days) were identified from MEDLINE, EMBASE, other databases and conference proceedings. Demographics, disease control rate, objective response rate, biochemical response, improvement in symptoms and toxicity were abstracted. Trials were synthesized qualitatively. RESULTS: Eighteen studies (1002 patients) were identified. The risk of bias was moderate for objective response outcomes, but high for the outcomes of symptom control and toxicity due to open-label trial designs. Disease control rates ranged from 30 to 100%, but response rates were modest (at 0-14%). Rates of biochemical improvement (27-100%) and symptom improvement (23-100%) ranged widely depending on the population studied and the definition of response. The most common toxicities were fatigue, diarrhoea, abdominal discomfort and cholelithiasis, with no severe or unexpected toxicities compared to standard-dose somatostatin analogues. CONCLUSIONS: The current evidence indicates that escalated-dose somatostatin analogues are well-tolerated in patients with gastroenteropancreatic neuroendocrine tumours, with significant rates of disease control but low rates of tumour response. It was difficult to judge the exact rate of biochemical response or symptomatic improvement. There is a need for large, prospective studies investigating the role of escalated-dose somatostatin analogues in the treatment of metastatic gastroenteropancreatic neuroendocrine tumours. PMID- 28726184 TI - Hormetic effect of triiodothyronine in metabolically healthy obese persons. AB - PURPOSE: Metabolically healthy obese is the designation for a subgroup of obese individuals with normal metabolic features. However, metabolically healthy obese individuals are prone to developing metabolic syndrome. Serum triiodothyronine (T3) levels are associated with various metabolic risk factors including obesity. Therefore, this longitudinal study aimed to explore the possible correlation between serum T3 concentration and the onset of MetS in metabolically healthy obese persons. METHODS: A retrospective analysis of 992 euthyroid metabolically healthy obese subjects who underwent yearly health checkups over 6 years was performed. The risk of developing MetS was analyzed according to baseline T3 concentration, as both tertiles and continuous values, using Cox regression analysis. Serum T3 concentration at the end of the study was further analyzed according to the final metabolic phenotype. RESULTS: The incidence of MetS was 464 cases (46.8%) during a median 3.3 years of follow-up (3168.2 person-years). The hazard ratio for incident MetS enhanced with increasing T3 concentration in both the crude and adjusted models. Higher baseline serum T3 levels were associated with unfavorable metabolic parameters. However, over the course of the study, serum T3 concentration significantly increased in subjects who sustained metabolically healthy phenotypes compared to baseline value, while it significantly decreased in the subjects who developed MetS. CONCLUSIONS: Serum T3 concentrations exhibit distinct associations with development of metabolic syndrome in euthyroid metabolically healthy obese persons, but its increment during follow-up maintained metabolically healthy state. These findings suggest that serum T3 modulation might be an adaptive process to protect against metabolic deterioration. PMID- 28726186 TI - Erratum to: Prostaglandin actions in established insect cell lines. PMID- 28726187 TI - Best practices for media selection for mammalian cells. AB - Cell culture medium is a complex mixture of nutrients and growth factors that, along with the physical environment, can either help or destroy your experiment or production run. Nutritional requirements differ with different cell types and functions, as do optimal pH and osmolality. As cell growth proceeds, different cells will utilize amino acids and other components at different rates. By controlling for ammonia, free radicals, heavy metal toxicity, pH shifts, fluctuations in osmolality, nutrient depletion, and chemical and biological contaminants, you will optimize the chances of success. The contribution of each component of the medium is essential for the maintenance of the cell type of interest. While some cell types, such as established human cancer cell lines, may be quite able to tolerate a range of media and supplements, many normal cells and stems cells are not. Optimization of each component may be required to successfully maintain the latter cell types. The procedures for selecting and optimizing cell culture media and supplements are presented. PMID- 28726185 TI - Raising awareness on the therapeutic role of cholecalciferol in CKD: a multidisciplinary-based opinion. AB - Vitamin D is recognized to play an essential role in health and disease. In kidney disease, vitamin D analogs have gained recognition for their involvement and potential therapeutic importance. Nephrologists are aware of the use of oral native vitamin D supplementation, however, uncertainty still exists with regard to the use of this treatment option in chronic kidney disease as well as clinical settings related to chronic kidney disease, where vitamin D supplementation may be an appropriate therapeutic choice. Two consecutive meetings were held in Florence in July and November 2016 comprising six experts in kidney disease (N = 3) and bone mineral metabolism (N = 3) to discuss a range of unresolved issues related to the use of cholecalciferol in chronic kidney disease. The panel focused on the following six key areas where issues relating to the use of oral vitamin D remain controversial: (1) vitamin D and parathyroid hormone levels in the general population, (2) cholecalciferol in chronic kidney disease, (3) vitamin D in cardiovascular disease, (4) vitamin D and renal bone disease, (5) vitamin D in rheumatological diseases affecting the kidney, (6) vitamin D and kidney transplantation. PMID- 28726188 TI - A lncRNA promotes myoblast proliferation by up-regulating GH1. AB - Long noncoding RNAs (lncRNAs) are key regulatory factors for gene expression in a variety of biological processes; however, the role of lncRNAs in muscle formation and development is poorly understood, particularly in cattle. Here, we identified a highly expressed lncRNA in muscle, lncYYW, by high-throughput sequencing in bovine longissimus, scapular, intercostal, and gluteus muscles. The expression of lncYYW increased gradually during myoblast differentiation. Overexpression of lncYYW increased the number of cells in the DNA synthesis (S) stage of the cell cycle and upregulated the expression of two well-established myogenic markers, myogenin and myosin heavy chain. A microarray analysis showed that lncYYW positively regulates the expression of growth hormone 1 and its downstream genes, AKT1 and PIK3CD, in bovine myoblasts. This discovery provides a good foundation for further study of the mechanism of action of lncYYW during bovine myoblast development. Taken together, our results reveal a novel lncRNA associated with bovine myoblast proliferation and differentiation. This lncRNA will play a crucial and critical role in future studies of bovine muscle development. PMID- 28726189 TI - Changing the Properties of Multipotent Mesenchymal Stromal Cells by IFNgamma Administration. AB - We studied changes in the population of human multipotent mesenchymal stromal cells activated by IFNgamma. The cells were cultured under standard conditions; IFNgamma was added in various concentrations for 4 h or over 2 passages. It was shown that the total cell production significantly decreased after long-term culturing with IFNgamma, but 4-h exposure did not affect this parameter. After 4 h culturing, the expression levels of IDO1, CSF1, and IL-6 increased by 300, 7, and 2.4 times, respectively, and this increase persisted 1 and 2 days after removal of IFNgamma from the culture medium. The expression of class I and II MHC (HLA) on cell surface practically did not change immediately after exposure to IFNgamma, but during further culturing, HLA-ABC (MHC I) and HLA-DR (MHC II) expression significantly increased, which abolished the immune privilege in these cells, the property allowing clinical use of allogenic multipotent mesenchymal stromal cells. Multipotent mesenchymal stromal cells can suppress proliferation of lymphocytes. The degree of this suppression depends on individual properties of multipotent mesenchymal stromal cell donor. Treatment with IFNgamma did not significantly affect the intensity of inhibition of lymphocyte proliferation by these cells. PMID- 28726190 TI - Effect of Peripheral MU-, delta-, and kappa-Opioid Ligands on the Development of Tolerance to Ethanol-Induced Analgesia. AB - We studied the rate of development of tolerance to the ethanol-induced analgesia under the effect of MU-, delta-, and kappa-opioid agonists and antagonists not crossing the blood-brain barrier and rapidly inactivated by gastric and duodenal proteolytic enzymes. Activation of gastric kappa-opioid receptors eliminated the analgesic effect of ethanol and accelerated the development of tolerance to ethanol-induced analgesia. In contrast, activation of gastric MU-opioid receptors decelerated the development of this tolerance. Activation of gastric delta-opioid receptors produced no effect on examined tolerance. MU-Opioid receptor antagonist decelerated and delta-opioid receptor antagonist accelerated the development of tolerance to ethanol-induced analgesia. Thus, the state of gastric opioid receptors affects the manifestation of ethanol-induced analgesia and the development of tolerance to this effect. PMID- 28726191 TI - Virtual Experimental Validation of Dynamic Osteosynthesis in the Treatment of Fractures of the Proximal Femur. AB - Volume model of transtrochanteric fracture of the femoral bone fixed by Targon PF dynamic fixator was studied by the finite element analysis. The following parameters were measured: magnitude and direction of displacement of system elements, pressure between fragments, and von Mises stress distribution in the fixator depending on support screw plunging into the sleeve. The results indicate that stability of the bone-nail system increases during fracture union and 10-mm shortening of the femoral neck axis, which is seen from a decrease in system deformation under load by 16.8%, stress in the implant by 20.2%, and pressure in the zone of fragments contact by 19.8%. PMID- 28726192 TI - Study of Proliferative Activity of Vaginal Epithelium in Women with Stress Urinary Incontinence Treated by Er:YAG Laser. AB - The expression of Ki-67 proliferation marker was studied in vaginal biopsy specimens from women with stress urinary incontinence treated using a Fotona nonablative erbium laser. Cells expressing Ki-67 were located in all cases in the parabasal and basal levels of stratified squamous epithelium, the index of labeled nuclei before Er:YAG laser exposure was 19.05+/-2.86%. After 1-2 months of laser therapy, the index of labeled nuclei in the epithelium increased significantly and reached 31.79+/-2.25%. These changes were interpreted as a result of epithelial-stromal interactions. Presumably, the increase in proliferative activity of the vaginal epithelium after exposure to Er:YAG laser was due to the presence of an appreciable level of synthetically active fibroblasts in the subepithelial stroma. PMID- 28726193 TI - Regenerative Potential of Spermatogonial Stem Cells, Endothelial Progenitor Cells, and Epithelial Progenitor Cells of C57Bl/6 Male Mice with Metabolic Disorders. AB - The properties of spermatogonial stem cells, endothelial progenitor cells, and the epithelial progenitors of C57Bl/6 mice under conditions of metabolic disorders were studied using the model of busulfan-induced suppression of spermatogenesis and in vitro culture technique. Spermatogonial stem cells CD117 CD90+ and epithelial progenitors CD45-CD31-Sca-1+CD49f+ derived from the testes of mice with metabolic disturbances demonstrated 17- and 28-fold increase in the respective cell mass and generated cell colonies in vitro. In contrast, spermatogonial stem cells with immune phenotype CD51-CD24+CD52+ had reduced selfrenewal capacity. Spermatogonial stem cells CD117-CD90+ and CD117+CD90+ as well as endothelial progenitors CD45-CD31+ derived from the testes of donor mice with metabolic disorders demonstrated high transplantation capacity in C57Bl/6 mouse testes damaged by cytostatic busulfan. PMID- 28726194 TI - Association between the Prevalence of Somatic Mutations in PIK3CA Gene in Tumors and Clinical and Morphological Characteristics of Breast Cancer Patients. AB - The presence of activating somatic mutations in codons 542 and 545 of exon 9 (p.E542K c.1624G>A and p.E545K c.1633G>A) and in codon 1047 of exon 20 (p.H1047R c.3140A>G and p.H1047L c.3140A>T) of PIK3CA gene encoding catalytic p110alpha subunit of phosphatidylinositol-3-kinase was studied in tumors of 473 breast cancer patients by multiplex allele-specific real-time PCR. Fifty-eight (12.3%) different mutations were found. An increase in the frequency of PIK3CA gene mutations with disease progression (from 2.4 to 28.7% with tumor progression from I-IIa to III-IV stage; p=0.0001) and a trend towards its increase in the tumors with unfavorable prognostic characteristics (high histological grade, triple negative phenotype) were demonstrated. The presence of the studied PIK3CA gene mutations in tumors significantly reduces relapse-free survival in the total group and in stage III cancer patients. PMID- 28726195 TI - Effects of Secondary Metabolites of Permafrost Bacillus sp. on Cytokine Synthesis by Human Peripheral Blood Mononuclear Cells. AB - We studied the effects of secondary metabolites of Bacillus sp. isolated from late Neogene permafrost on secretion of proinflammatory (TNF-alpha, IL-1beta, IL 8, IL-2, and IFNgamma) and antiinflammatory (IL-4 and IL-10) cytokines by human peripheral blood mononuclear cells. It was found that metabolites of Bacillus sp. produced more potent effect on cytokine secretion than mitogen phytohemagglutinin and metabolites of Bacillus cereus, medicinal strain IP5832. Activity of metabolites depended on the temperature of bacteria incubation. "Cold" metabolites of Bacillus sp. (isolated at -5 degrees C) primarily induced Th1 mediated secretion of IFNgamma, while "warm" metabolites (obtained at 37 degrees C) induced Th2-mediated secretion of IL-4. The results suggest that Bacillus sp. metabolites are promising material for the development of immunomodulating drugs. PMID- 28726196 TI - Mechanisms of Sensitivity of Soft Tissue Sarcoma Cells to Temozolomide. AB - We studied the mechanisms of sensitivity of soft tissue sarcoma cells to alkylating agent temozolomide. The mechanisms of tumor cell sensitivity to temozolomide are complex and are determined by not only the level of O6 methylguanine-DNA-methyltransferase (MGTM) expression, but also activity of oncosuppressor protein p53. A-673 Ewing's sarcoma cells were found to be the most sensitive to temozolomide, whereas temozolomide-treated SK-LMS-1 leiomyosarcoma cells exhibited signs of cell aging. PMID- 28726197 TI - Effect of Phenibut and Glufimet, a Novel Glutamic Acid Derivative, on Respiration of Heart and Brain Mitochondria from Animals Exposed to Stress against the Background of Inducible NO-Synthase Blockade. AB - Increased oxygen consumption by heart and brain mitochondria in the absence of ADP and reduced mitochondrial respiration in the presence of ADP were observed in rats exposed to stress simulated by suspension by the dorsal neck skin fold for 24 h, which attests to uncoupling of substrate oxidation and ATP synthesis and can cause electron drain from the respiratory chain, formation of ROS, and oxidative damage to cell structures. Blockade of inducible NO synthase with aminoguanidine (single intraperitoneal dose of 50 mg/kg before stress exposure) increased coupling of respiration and oxidative phosphorylation in heart and brain mitochondria of rats exposed to immobilization-painful stress, which was especially pronounced in cardiomyocytes. The test compounds glufimet (single intraperitoneal dose of 29 mg/kg before stress exposure) and phenibut (single intraperitoneal dose of 50 mg/kg before stress exposure) limited stress-induced mitochondrial damage against the background of inducible NO synthase blockade and without it, which was seen from increased respiratory control ratio in comparison with that in untreated rats exposed to stress (control). PMID- 28726198 TI - Anti-Inflammatory and Analgesic Activities of the Complex of Flavonoids from Lychnis chalcedonica L. AB - Anti-inflammatory and analgesic activities of the complex of flavonoids from Lychnis chalcedonica L. were studied in the models of acute aseptic inflammation induced by carrageenan, histamine, and serotonin and acetic acid-induced painful chemical stimulation. It is demonstrated that course treatment with flavonoids derived from Lychnis chalcedonica L. produced a stable pharmacological effect comparable with that of the reference anti-inflammatory drug diclofenac. PMID- 28726199 TI - A Study of the Protective Properties of an Antibody-Based Antidote Metabolizing Organophosphorus Pesticide Paraoxon. AB - A catalytic antibody A17 and its mutants highly efficiently interact with organophosphorus pesticide paraoxon. In this work, we studied the protective properties of antibody A17-K47 in paraoxon poisoning using a mouse model. The optimal paraoxon dose simulating the acute toxic effect of organophosphorus compounds was 550 MUg/kg. The pharmacokinetic parameters of A17-K47 antibody were t1/2distr =7.2+/-1.4 min, t1/2el =330+/-20 min. The antibody did not cause toxic effects when administered at a ten-fold calculated therapeutic dose (610 mg/kg). The drug did not reduce mortality from acute paraoxon poisoning; however, the absence of drug toxicity opens up prospects for its use in symptomatic treatment of chronic paraoxon poisoning. PMID- 28726200 TI - Intranasal Insulin Restores Metabolic Parameters and Insulin Sensitivity in Rats with Metabolic Syndrome. AB - We studied the effect of 10-week treatment with intranasal insulin (0.5 IU/day) on glucose tolerance, glucose utilization, lipid metabolism, functions of pancreatic beta cells, and insulin system in the liver of rats with cafeteria diet-induced metabolic syndrome. The therapy reduced body weight and blood levels of insulin, triglycerides, and atherogenic cholesterol that are typically increased in metabolic syndrome, normalized glucose tolerance and its utilization, and increased activity of insulin signaling system in the liver, thus reducing insulin resistance. The therapy did not affect the number of pancreatic islets and beta cells. The study demonstrates prospects of using intranasal insulin for correction of metabolic parameters and reduction of insulin resistance in metabolic syndrome. PMID- 28726201 TI - Delayed Results of Experimental Afobazole Therapy in Rats after Acute Myocardial Infarction. AB - Delayed cardioprotective effects of anxiolytic Afobazole (15 mg/kg, intraperitoneally for 14 days) were evaluated using dynamic echocardiographic recordings on days 2, 15, 56, and 98 after experimental myocardial infarction modeling (rat model of acute myocardial ischemia). The cardiotropic activity of Afobazole is assumed to be related to its agonistic effects on sigma1 receptor of cardiomyocytes. It was found that animals treated with Afobazole had no signs of heart failure by the end of observation, as evidenced by left ventricular ejection fraction. PMID- 28726202 TI - Experimental Assessment of the Effect of Kagocel on Reproductive Function in Pubertal Male Rats. AB - We studied possible toxic effects of antiviral drug Kagocel on reproductive function in pubertal male rats. The drug was administered in therapeutic and 10 fold higher doses throughout the spermatogenesis cycle (48 days). Kagocel did not reduce mating and fertilizing capacities, did not suppress spermatogenesis, and had no toxic effects on the offspring. The results characterize Kagocel as a drug with a broad reproductive safety profile and demonstrate that the age limits for using Kagocel in pediatric practice can be extended. PMID- 28726203 TI - Cysteine-Containing Peptides Stimulate Monocyte Migration through NADPH-Oxidase Activation. AB - We analyzed migration of monocytes under the effect of apocinin (NADPH inhibitor) and PD98059 (blocker of extracellular MEK/ERK kinase involved in Nox4 oxidase mediated migration of monocytes). Migration of monocytes stimulated by cysteine containing peptides (fragments of chemokines with free thiol group MCP-1 and fractalkine) was completely inhibited by apocinin and MEK/ERK blocker. It is assumed that the stimulating effect of cysteine-containing peptides on monocyte migration is mediated by the NADPH-oxidase system, in particular, Nox4. PMID- 28726204 TI - Association of Level of Proprotein Convertase Subtilisin/Kexin Type 9 with Intima Media Thickness in Patients with Familial Hypercholesterolemia. AB - We studied association of PCSK9 protein with the carotid artery intima-media thickness in patients with familial hypercholesterolemia (N=53; age 49.9+/-6.9 years) treated with statins. Blood level of PCSK9 protein was measured by ELISA; ultrasonography of the carotid arteries with measurement of the thickness of the intima-media complex of the common carotid arteries in the distal segment for 10 mm from the bifurcation on the far wall of the vessel was performed in on-line mode. The mean values were calculated for both sides, the maximum mean value was included in the analysis. It was shown that PCSK9 levels positively correlate with carotid artery intima-media thickness in patients with familial hypercholesterolemia. PMID- 28726205 TI - Dipeptidyl Peptidase 4 Inhibitors Diprotin A and Sitagliptin Administered on Weeks 2-3 of Postnatal Development Modulate Monoamine Metabolism in the Striatum of Adult Rats. AB - The levels of monoamines and their metabolites in brain structures of adult (3 month-old) rats with emotional and motivational disorders induced by inhibitors of dipeptidyl peptidase 4 (DPP-4; EC 3.4.14.5) diprotin A and sitagliptin on weeks 2-3 of postnatal development (postnatal days 5-18) were studied by HPLC with electrochemical detection. A significant decrease in the level of serotonin metabolite, 5-hydroxyindoleacetic acid, and a pronounced tendency towards reduced serotonin level were detected in the striatum of rats in both study groups. In adult rats treated with diprotin A during the neonatal period, a tendency towards activation of dopamine metabolism was observed (judging from DOPAC/DA ratio). The levels of monoamines and their metabolites in the frontal cortex, hypothalamus, and amygdala remained unchanged. The findings suggest that administration of DPP 4 inhibitors during the neonatal period induces long-term dysfunction of the serotonergic and dopaminergic systems of the brain. PMID- 28726206 TI - Preparation of Recombinant Serpin from Red King Crab Paralithodes samtschaticus for Biomedical Research Purposes. AB - Genetic constructs with different leader sequences for intra- and extracellular expression of the target protein were generated and an original method for effective selection of clones with maximum expression was developed. For intracellular expression in the Pichia pastoris system, seprin content in cells was 6 mg/liter. PMID- 28726207 TI - Approaches to Controlled Co-Amplification of Genes for Production of Biopharmaceuticals: Study of the Insertion and Amplification Dynamics of Genetic Cassettes in the Genome of Chinese Hamster Ovary Cells during Co-Expression of Compatible Pair of Plasmids. AB - Plasmid vector family p1.1 based on non-coding regions of Chinese hamster housekeeping gene EEF1A and concatemer of Epstein-Barr virus terminal repeat increases the frequency of genome integration and provides rapid amplification of the target genes in the genome. For a pair of fluorescent proteins eGFP and mCherry it was shown that p1.1 vectors bearing dihydrofolate reductase and glutamine synthetase selection markers upon co-transfection into CHO DG44 cell line allow obtaining a polyclonal cell population in which ~70% of cells express both genes. The subsequent one-step gene amplification of the genome-integrated genetic cassettes under the selective pressure of increased concentrations of methotrexate can increase the expression of both integrated genes up to 8.2% eGFP and 9.9% mCherry of total protein. This approach can be used for the development of cell lines for the production of functional heterodimeric proteins, e.g. polypeptide hormones and therapeutic antibodies. PMID- 28726208 TI - Immunolocation of Heme Oxygenases in the Walls of Cerebral Arteries of Various Diameters in Rats. AB - The distribution of two enzymes involved in the formation of carbon monoxide, heme oxygenases 1 and 2, in the pial branches of orders I-V of the middle cerebral artery basin and in intracerebral vessels was studied in adult Wistar rats. Immunohistochemical studies detected hemeoxygenase-2 in the endothelium of the small pial and intracerebral arterioles and in myocytes of pial branches I III. Heme oxygenase 1, an inducible form of the enzyme, is normally not expressed in the cerebral vessels, but the enzyme is expressed in response to sodium metaarsenite. In this case, heme oxygenase markers are detected in myocytes of pial arteries I-II and in the endothelium of small pial and intracerebral vessels. Sodium meta-arsenite is inessential for immunolocation and quantitative distribution of heme oxygenase 2 in the vessels. PMID- 28726209 TI - Characteristics of Mel Ibr Melanoma Line Subclone after Treatment with Chicken Embryo Extract. AB - We continue analysis of the phenotype of human melanoma cell Mel Ibr subclone obtained previously by treatment of the parental cell line by chicken embryo extract. The present study is focused on detection of markers of epithelial mesenchymal transition that determine enhanced metastatic and invasive potential of malignant tumors of various locations. Analysis of the expression of E cadherin and vimentin genes in the subclone and parental cells detected activation of epithelial-mesenchymal transition in the subclone. Immunological markers CD90, CD271, and CD95 were present in the parental population, but were not detected on the subclone cells. In contrast to the parental line, cells of the analyzed subclone retain viability in serum-free medium and formed vessel like structures characteristic of vasculogenic mimicry. PMID- 28726210 TI - Sodium Dodecyl Sulfate Cytotoxicity towards HaCaT Keratinocytes: Comparative Analysis of Methods for Evaluation of Cell Viability. AB - Viability of keratinocytes of HaCaT immortalized line incubated with sodium dodecyl sulfate for 3 min, 1 and 48 h, was studied by light microscopy, MTT test, and neutral red absorption test. The IC50 values were determined for each of the studied lengths of exposure. HaCaT cells exhibited a dose-dependent decrease of viability under the effect of sodium dodecyl sulfate, proportional to the length of exposure. The values measured by different methods (MTT test and neutral red absorption test) varied, the differences were determined by the duration of exposure to sodium dodecyl sulfate. The dispersion of values for 1 and 48 h exposure, obtained by MTT method, was greater than of the values obtained by neutral red absorption test. PMID- 28726211 TI - Genetic Engineering of Native Chain Combinations of B-Cell Repertoires on the Surface of Methylotrophic Yeasts Pichia pastoris. AB - We designed genetic constructs for exposing Fab-fragment library of natively paired single cell B-cell receptors on the surface of Pichia pastoris yeast cells. We have previously obtained the A17 antibody in our laboratory [6]. In this study we showed that the newly designed genetic constructs provide a compatible level of A17 antibody Fab fragment on the surface of yeast cells as well as in the case of vectors containing DNA fragments corresponding to each chain of the antibody. The data suggest that the developed approach for constructing immunoglobulin gene libraries is adequate and fully convenient for studying properties of the real human B-lymphocyte repertoire. PMID- 28726213 TI - How mechanisms explain interfield cooperation: biological-chemical study of plant growth hormones in Utrecht and Pasadena, 1930-1938. AB - This article examines to what extent a particular case of cross-disciplinary research in the 1930s was structured by mechanistic reasoning. For this purpose, it identifies the interfield theories that allowed biologists and chemists to use each other's techniques and findings, and that provided the basis for the experiments performed to identify plant growth hormones and to learn more about their role in the mechanism of plant growth. In 1930, chemists and biologists in Utrecht and Pasadena began to cooperatively study plant growth. I will argue that these researchers decided to join forces because they believed to rely on each other's findings and methods to solve their research problems adequately. In the course of the cooperation, organic chemists arrived at isolating plant growth hormones by using a test method developed in plant physiology. This achievement, in turn, facilitated biologists' investigation of the mechanism of plant growth. Researchers eventually believed to have the means to study the relation between a substance's molecular structure and its physiological activity. The way they conceptualized the problem of identifying hormones and unraveling the mechanism of plant growth, as well as their actual research actions are compatible with the new mechanists' account of mechanism research. The study illustrates that focusing on researchers' mechanistic reasoning can contribute considerably to explaining the structure of cross-disciplinary research projects. PMID- 28726214 TI - Goitrous Countrymen Andrea Fantoni (1659-1734). PMID- 28726212 TI - Melasma: an Up-to-Date Comprehensive Review. AB - Melasma is a common acquired condition of symmetric hyperpigmentation, typically occurring on the face, with higher prevalence in females and darker skin types. Multiple etiologies, including light exposure, hormonal influences, and family history, have been implicated in the pathogenesis of this disorder. Overall prevalence ranges widely at 1-50%, since values are typically calculated within a specific ethnic population within a geographic region. Histologically, melasma can display increased epidermal and/or dermal pigmentation, enlarged melanocytes, increased melanosomes, solar elastosis, dermal blood vessels, and, occasionally, perivascular lymphohistiocytic infiltrates. Various topical, oral, and procedural therapies have been successfully used to treat melasma. Traditional topical therapies including hydroquinone, tretinoin, corticosteroids, and triple combination creams; however, other synthetic and natural topical compounds have also shown varying efficacies. Promising oral therapies for melasma include tranexamic acid, Polypodium leucotomos, and glutathione. Procedures, including chemical peels, microneedling, radiofrequency, and lasers, are also often used as primary or adjunctive treatments for melasma. Notably, combination therapies within or across treatment modalities generally result in better efficacies than monotherapies. This review serves as a comprehensive update on the current understanding of the epidemiology, pathogenesis, clinical and histologic features of melasma, as well as treatments for this common, yet therapeutically challenging, condition. PMID- 28726216 TI - Dr Leonard David Kohn (1935-2012). PMID- 28726215 TI - Growth hormone, prolactin, and sexuality. AB - GH and PRL, although not considered as 'classi cal' sexual hormones, could play a role in the endocrine control of sexual function both in men and women. Physiologically, PRL seems to be involved in the central control of sexual behavior and activity, by modulating mainly the effects of dopaminergic and serotoninergic systems on sexual function. Indeed, circulating PRL levels increase after orgasm and may potentially play a role in the acute regulation of further sexual arousal following orgasm both in men and women. On the other hand, either short-term or long-term PRL in crease can modulate central nervous system areas involved in the control of sexual function and, peripherally, can directly influence mechanisms of penile erection in men, and presently only as an hypothesis, mechanisms related to the sexual response of genitalia in women. Furthermore, chronic hyperprolactinemia is classically associated with hypogonadotropic hypogonadism and sexual dysfunction in both sexes. Successful treatment of chronic hyperprolactinemia generally restores normal sexual function both in men and women although this effect is not only related to relapse of gonadal function. Hypoprolactinemia is recently recognised as a possible risk factor of arteriogenic erectile dysfunction while a possible role on female sexual function is not known. The physiological role of GH on sexual function is not fully elucidated. GH is an important regulator of hypothalamus-pituitary gonadal axis and seems to participate in the regulation of the sexual response of genitalia in men, and potentially also in women. Sexual function in men and women with GH deficiency (GHD) and GH excess, particularly in acromegaly, is scantily studied and GH- or IGF-I-dependent effects are difficult to quantify. Nevertheless, a decrease of desire and arousability both in men and women, together with an impairment of erectile function in men, have been described both in patients with GHD and acromegaly, although it is not clear whether they are dependent directly on the hormone defect or excess or they are consequence of the hypogonadism or the different clinical complications or the physical disfigurement and psychological imbalance, which are associated with the diseases, and are potentially affecting sexual function. Data on beneficial effects of GH replacement therapy and specific surgical or pharmacological approach for acromegaly are far to be fully elucidated although restoring normal GH/IGF-I levels have been associated to improvement of sexual function. PMID- 28726217 TI - Vitamin D receptor gene polymorphisms and sex steroid secretion in girls with precocious pubarche in Southern Brazil: A pilot study. AB - BACKGROUND: Evidence suggests that precocious pubarche (PP) girls may have higher risk of developing polycystic ovary syndrome (PCOS) at later ages. Vitamin D receptor (VDR) gene polymorphisms have been implicated in the risk of diabetes and PCOS, but little is known about the role of VDR in PP. AIM: To assess the frequencies of VDR gene ApaI, TaqI, BsmI, and FokI polymorphisms and to determine whether these variants are associated with sex hormone concentrations in patients with PP and controls from southern Brazil. SUBJECTS AND METHODS: Blood was collected from 36 girls with PP and 197 controls for genotyping of BsmI and FokI polymorphisms using real-time PCR and of ApaI e TaqI polymorphisms using restriction fragment length polymorphism. Hormone levels were also determined. RESULTS: Genotype GG of the ApaI single nucleotide polymorphism (SNP) was more frequent in PP (30.6%) than in controls (16.2%) [odds ratio (OR): 2.269; confidence interval 95% (95%CI): 1.015-5.076; p=0.042]. This genotype was also associated with lower estradiol [35.30 (14.80-50.48) pg/ml vs 12.22 (6.49-23.69) pg/ml; p=0.025] and total testosterone levels (0.52 (0.39-0.84) ng/ml vs 0.20 (0.11-0.47) ng/ml; p=0.005) as compared with the TT + TG genotypes in girls with PP. The distribution of TaqI, BsmI, and Fokl SNP was similar in PP and controls, and no association was found between these polymorphisms and sex steroid levels. CONCLUSIONS: The ApaI SNP of the VDR gene was associated with PP in the studied population and may modulate ovarian steroid secretion in these girls. PMID- 28726218 TI - Process optimization of biogas energy production from cow dung with alkali pre treated coffee pulp. AB - Biogas production from cow dung with co-substrate agricultural waste is one of the most demanding technologies for generating energy in a sustainable approach considering eco-friendly. In the present study, coffee pulp (CP) was pre-treated with 1% NaOH and combined with various proportions of cow dung (CD) to explore its biogas producing potentiality. The optimization of the process was studied using Response surface methodology. Statistics based on 3-D plots were generated to evaluate the changes in the response surface and to understand the relationship between the biogas yield and other parameters. The highest methane production (144 mL/kg) was achieved after 90 h of incubation with 1:3 of CP and CD at 40 degrees C. Gas chromatography analyzes the chemical compositions of the generated biogas and its post combustion emissions. The chemical composition of the substrates before digestion and after fermentation (biogas spent sludge) were measured in terms of fiber content and the values were noted as, total solids (0.53%), ash content (9.2%), volatile fatty acid (100 mg/L), organic carbon (46%) and a total carbohydrate (179 mg/g). The results of the optimization of biogas production presented in this work found to have significance with the process parameters. The outcome of the study has supported the fact of conventional combustion technology that has to be upgraded to prevent these hazardous emissions into the atmosphere. PMID- 28726219 TI - Erratum to: Petrol filling workers as biomonitor of PAH exposure and functional health capacity in resource-limited settings of city Rawalpindi, Pakistan. PMID- 28726220 TI - Effect of operational factors on bioregeneration of binary phenol and 4 chlorophenol-loaded granular activated carbon using PVA-immobilized biomass cryogels. AB - The effects of dry biomass density in cryogel beads, shaking speed and initial concentration ratio of phenol to 4-chlorophenol (4-CP) on the bioregeneration efficiencies of binary phenol and 4-CP-loaded granular activated carbon (GAC) for phenol and 4-CP, respectively, were investigated under the simultaneous adsorption and biodegradation approach. The results revealed higher bioregeneration efficiencies of binary-loaded GAC for phenol and 4-CP at higher dry biomass density but moderate shaking speed. The optimum dry biomass density in cryogel beads and shaking speed for use in bioregeneration were found to be 0.01 g/mL and 250 rpm, respectively. With respect to the initial phenol to 4-CP concentration ratio, the bioregeneration efficiencies were lower under increasing phenol and 4-CP initial concentrations, respectively, with the effect being more conspicuous under increasing 4-CP concentration. Higher bioregeneration efficiencies were achieved with the use of immobilized rather than suspended biomasses. PMID- 28726221 TI - Redox properties of humic substances under different environmental conditions. AB - Humic substances (HS) are one of the most important parts of dissolved organic matter which are ubiquitous in environments playing an important role in many (bio)geochemical processes. In order to define the effects of environmental conditions on the biological transformation of compounds in the presence of HS, microbial reduction rates of ferrihydrite under different HS concentrations, environmental temperature, and pH values were determined. The results showed that increasing the concentration of standard humic substances (Pahokee peat standard humic acids (PPHA) or Pahokee peat standard fulvic acids (PPFA)) purchased from the International Humic Substances Society could compensate for the certain gap of reduction rates between low temperature (10 degrees C) and high temperature (35 degrees C). Furthermore, PPHA showed a greater stimulation of Fe(III) reduction than PPFA in common groundwater temperature (10-25 degrees C). The reduction rates decreased significantly when pH values were greater than 7.7 with total organic carbon (TOC) contents above 5 mg C/L, and protein-like fluorophore was detected here. When pH values were lower than 7.7, the PPHA fluorescence characteristic primarily showed humic-like fluorophore composed of quinone-like fluorophore, which corresponds to a high microbial reduction rate. The finding of this study is that fluorophore characteristics of HS linked to the microbial reduction rate under different environment conditions are able to provide a potential development for in-suit remediation process prediction. PMID- 28726222 TI - Loss of crop yields in India due to surface ozone: an estimation based on a network of observations. AB - Surface ozone is mainly produced by photochemical reactions involving various anthropogenic pollutants, whose emissions are increasing rapidly in India due to fast-growing anthropogenic activities. This study estimates the losses of wheat and rice crop yields using surface ozone observations from a group of 17 sites, for the first time, covering different parts of India. We used the mean ozone for 7 h during the day (M7) and accumulated ozone over a threshold of 40 ppbv (AOT40) metrics for the calculation of crop losses for the northern, eastern, western and southern regions of India. Our estimates show the highest annual loss of wheat (about 9 million ton) in the northern India, one of the most polluted regions in India, and that of rice (about 2.6 million ton) in the eastern region. The total all India annual loss of 4.0-14.2 million ton (4.2-15.0%) for wheat and 0.3-6.7 million ton (0.3-6.3%) for rice are estimated. The results show lower crop loss for rice than that of wheat mainly due to lower surface ozone levels during the cropping season after the Indian summer monsoon. These estimates based on a network of observation sites show lower losses than earlier estimates based on limited observations and much lower losses compared to global model estimates. However, these losses are slightly higher compared to a regional model estimate. Further, the results show large differences in the loss rates of both the two crops using the M7 and AOT40 metrics. This study also confirms that AOT40 cannot be fit with a linear relation over the Indian region and suggests for the need of new metrics that are based on factors suitable for this region. PMID- 28726223 TI - Comprehensive study on parameter sensitivity for flow and nutrient modeling in the Hydrological Simulation Program Fortran model. AB - Numerous parameters are used to construct the HSPF (Hydrological Simulation Program Fortran) model, which results in significant difficulty in calibrating the model. Parameter sensitivity analysis is an efficient method to identify important model parameters. Through this method, a model's calibration process can be simplified on the basis of understanding the model's structure. This study investigated the sensitivity of the flow and nutrient parameters of HSPF using the DSA (differential sensitivity analysis) method in the Xitiaoxi watershed, China. The results showed that flow was mostly affected by parameters related to groundwater and evapotranspiration, including DEEPFR (fraction of groundwater inflow to deep recharge), LZETP (lower-zone evapotranspiration parameter), and AGWRC (base groundwater recession), and most of the sensitive parameters had negative and nonlinear effects on flow. Additionally, nutrient components were commonly affected by parameters from land processes, including MON-SQOLIM (monthly values limiting storage of water quality in overland flow), MON-ACCUM (monthly values of accumulation), MON-IFLW-CONC (monthly concentration of water quality in interflow), and MON-GRND-CONC (monthly concentration of water quality in active groundwater). Besides, parameters from river systems, KATM20 (unit oxidation rate of total ammonia at 20 degrees C) had a negative and almost linear effect on ammonia concentration and MALGR (maximal unit algal growth rate for phytoplankton) had a negative and nonlinear effect on ammonia and orthophosphate concentrations. After calibrating these sensitive parameters, our model performed well for simulating flow and nutrient outputs, with R 2 and ENS (Nash-Sutcliffe efficiency) both greater than 0.75 for flow and greater than 0.5 for nutrient components. This study is expected to serve as a valuable complement to the documentation of the HSPF model to help users identify key parameters and provide a reference for performing sensitivity analyses on other models. PMID- 28726224 TI - Spatial scale and seasonal dependence of land use impacts on riverine water quality in the Huai River basin, China. AB - Land use pattern is an effective reflection of anthropic activities, which are primarily responsible for water quality deterioration. A detailed understanding of relationship between water quality and land use is critical for effective land use management to improve water quality. Linear mixed effects and multiple regression models were applied to water quality data collected from 2003 to 2010 from 36 stations in the Huai River basin together with topography and climate data, to characterize the land use impacts on water quality and their spatial scale and seasonal dependence. The results indicated that the influence of land use categories on specific water quality parameter was multiple and varied with spatial scales and seasons. Land use exhibited strongest association with dissolved oxygen (DO) and ammonia nitrogen (NH3-N) concentrations at entire watershed scale and with total phosphorus (TP) and fluoride concentrations at finer scales. However, the spatial scale, at which land use exerted strongest influence on instream chemical oxygen demand (COD) and biochemical oxygen demand (BOD) levels, varied with seasons. In addition, land use composition was responsible for the seasonal pattern observed in contaminant concentrations. COD, NH3-N, and fluoride generally peaked during dry seasons in highly urbanized regions and during rainy seasons in less urbanized regions. High proportion of agricultural and rural areas was associated with high nutrient contamination risk during spring. The results highlight the spatial scale and seasonal dependence of land use impacts on water quality and can provide scientific basis for scale specific land management and seasonal contamination control. PMID- 28726225 TI - The principle and effect of transfer agent for the removal of PCE during in situ chemical oxidation. AB - Viscosity remedial technology, which uses a water-soluble polymer mixed with remedial fluids, has been introduced in recent years to improve the removal efficacy of perchloroethylene/tetrachloroethylene (PCE) by improving oxidant coverage (i.e. sweep efficiency). Xanthan gum and hydrolysed polyacrylamide (HPAM) are relatively stable with time and temperature and possess salt and oxidation resistance, indicating that they may be good flooding agents (the former is better than the latter in this work). In this work, we quantified the polymer directly improved oxidation of PCE during transport by using a two dimensional flow tank. Using a low pore volume (<=3.0), the removal rate of the PCE increased with the polymer concentration before stabilizing at approximately 93.00 and 88.30% for xanthan and HPAM, respectively. In this work, over 80% of PCE was removed via less than 3.0 PV of the SDS solution, whereas complete removal (100%) was achieved with less than 3.0 PV of SDS foam. Furthermore, the new experimental discoveries demonstrate that xanthan is better than HPAM and SDS foam is a better remediation agent than the SDS solution for removing PCE. Graphical abstract (Reaction device, A - inlet device (pump 1#), B - 2D tank, C - outflow device (pump 2#), D - data recording and processing device, E - microscopic expression, E (a) - KMnO4 flushing, E (b) - polymer solution flushing). PMID- 28726226 TI - Factors influencing silver recovery and power generation in bio-electrochemical reactors. AB - The recovery of silver from Ag+ solution coupled with power generation was investigated in bio-electrochemical system (BES). In this system, chemical energy existing in the organic matter in the anode chamber can be converted biologically to electrical energy which can be used for the reduction of Ag+ ions in the cathode chamber. Results showed that type of substrate influenced the metabolic pathway and affected the cell voltage progression, and columbic efficiency. Silver recovery was not affected by increasing initial pH (2.0 to 7.0) and Ag+ concentration (100 to 1000 mg/L) in the catholyte, whereas power generation was improved. A maximum power density of 8258 mW/m3 and a columbic efficiency of 21.61% could be achieved with 1000 mg/L of Ag+. Ag+ ions were reduced to form metallic deposits as Ag0 crystals on the cathode surface, which were then confirmed by scanning electron microscope (SEM) image and energy dispersive X-ray (EDX) spectrum. The BES reactor had high silver removal (i.e., >96%) after 24 h of operation. When considering the crossover of Ag+ ions through the cation exchange membrane, the removal was in the range of 83.73-92.51%. This crossover was not considerable as compared to the Ag+ initial concentration. At higher initial Ag+ concentration (2000 mg/L), the silver removal decreased to 88.61% and the maximum power density decreased to 5396 mW/m3. This study clearly showed that BES can be employed for silver recovery, wastewater treatment, and also electricity generation. PMID- 28726227 TI - Modelling the effects of water diversion and combined sewer overflow on urban inland river quality. AB - In order to assist and optimize the operation of a clean water diversion project for the medium-sized inland rivers in Chaohu, China, an integrated hydrodynamic and water quality model was used in this study. Sixteen diversion scenarios and five sewage interception scenarios were defined to assess the improvement of water quality parameters including ammonia nitrogen (NH3-N), total phosphorus (TP) and chemical oxygen demand (COD) under different diverted water flows, diverting times, diverting points, diverting routines and sewage interception proportions. An index of pollutant removal rate per unit diverted water flow (PRUWF) was proposed to evaluate the effect of the clean water diversion. Results show that operating conditions played important roles in water quality improvement of medium-sized inland rivers. The optimal clean water diversion was operated under the conditions of a flow rate of 5 m3/s for 48 h with an additional constructed bridge sluice. A global sensitivity analysis using the Latin Hypercube One-Factor-at-a-Time (LH-OAT) method was conducted to distinguish the contributions of various driving forces to inland river water restoration. Results show that sewage interception was more important than diverted water flow and diverting time with respect to water quality improvement, especially for COD. PMID- 28726228 TI - Microwave irradiation and citric acid assisted seed germination and phytoextraction of nickel (Ni) by Brassica napus L.: morpho-physiological and biochemical alterations under Ni stress. AB - The complex bio-geochemistry of soil allows pollutant to persist for a longer period of time which further decreased the fertility and natural composition of land. Nickel, an inorganic pollutant, coming from a wide range of industrial and manufacturing units possesses serious threat to soil degradation and crop productivity around the world. The present study was carried to evaluate the combined role of microwave irradiation (MR) and citric acid (CA) on the phytoextraction potential of Brassica napus L. under Ni stress. An initial seed germination test was conducted to select effective time scale of MR exposure. Highest seed germination was observed at exposure of 2.45 GHz frequency for 30 s. Healthy seeds of B. napus L. genotype Faisal Canola (RBN-03060) treated with MR at 2.45 GHz for 30 s were sown in plastic pots filled with 5 kg of soil. Nickel and CA applied exogenously in solution form with different combinations to both MR-treated and untreated B. napus plants. The MR-treated plants showed higher growth, biomass, photosynthetic pigments (Chl a, b, total, and carotenoids) and activities of antioxidant enzymes (SOD, POD, APX, CAT) as compared to untreated plants who showed higher reactive oxygen species (MDA, H2O2) and electrolyte leakage. Increasing Ni concentration significantly decreased the physiological and biochemical attributes of B. napus both in MR-treated and untreated plants. The addition of CA alleviated Ni-induced toxic effects in both MR-treated and untreated plants by improving antioxidant defense system. The degree of Ni stress mitigation was higher in MR-treated plants. The Ni concentration was higher in root, stem, and leaves of MR-treated plants under CA application as compared to untreated plants. The present study concluded that seeds treated with MR before sowing showed higher accumulation and concentration of Ni from soil, and this phenomenon boosted with the application of CA. PMID- 28726229 TI - Monitoring and modeling 4-chlorophenol biodegradation kinetics by phenol acclimated activated sludge by using open respirometry. AB - The aim of this study was to analyze the mechanisms, stoichiometry, and stability of 4-chlorophenol (4CP) biodegradation kinetics by phenol-acclimated activated sludge using open respirometry. While the removal of 4CP was higher than 98%, the removal of chemical oxygen demand (COD) ranged between 69 and 79% due to the accumulation of an intermediate metabolite. The value obtained from respirometric profiles for the stoichiometric ratio of O2 to 4CP (YO2/4CP) was 1.95 +/- 0.04 mol of oxygen consumed per mol of 4CP removed. This YO2/4CP value reflected the action of the oxygenases responsible for the first steps of the aerobic oxidation of 4CP. The 4CP degradation activity decreased noticeably when successive pulses of 4CP were added to the respirometer. A mathematical model was developed to represent the aerobic biodegradation of 4CP. The fitted model adequately predicted the oxygen consumption rate, total phenols, and soluble COD concentrations as a function of time. The results presented could help to predict the dynamic of biodegradation of chlorophenols in a biological wastewater treatment system. PMID- 28726231 TI - [Emotional facial recognition difficulties as primary deficit in children with attention deficit hyperactivity disorder: a systematic review]. AB - INTRODUCTION: It has recently been warned that children with attention deficit hyperactivity disorder (ADHD) show a deficit in emotional competence and emotional intelligence, specifically in their ability to emotional recognition. PATIENTS AND METHODS: A systematic review of the scientific literature in reference to the emotional recognition of facial expressions in children with ADHD is presented in order to establish or rule the existence of emotional deficits as primary dysfunction in this disorder and, where appropriate, the effect size of the differences against normal development or neurotypical children. RESULTS: The results reveal the recent interest in the issue and the lack of information. Although there is no complete agreement, most of the studies show that emotional recognition of facial expressions is affected in children with ADHD, showing them significantly less accurate than children from control groups in recognizing emotions communicated through facial expressions. A part of these studies make comparisons on the recognition of different discrete emotions; having observed that children with ADHD tend to a greater difficulty recognizing negative emotions, especially anger, fear, and disgust. CONCLUSIONS: These results have direct implications for the educational and clinical diagnosis of ADHD; and for the educational intervention for children with ADHD, emotional education might entail an advantageous aid. PMID- 28726230 TI - Health, wealth and behavioural change: an exploration of role responsibilities in the wake of epigenetics. AB - The field of epigenetics is leading to new conceptualizations of the role of environmental factors in health and genetic disease. Although more evidence is required, epigenetic mechanisms are being implicated in the link between low socioeconomic status and poor health status. Epigenetic phenomena work in a number of ways: they can be established early in development, transmitted from previous generations and/or responsive to environmental factors. Knowledge about these types of epigenetic traits might therefore allow us to move away from a genetic deterministic perspective, and provide individuals with the opportunity to change their health status. Although this could be equated with patient empowerment, it could also lead to stigmatization and discrimination where individuals are deemed responsible for their health, even if they are not in social situations where they are able to enact change that would alter their health status. In this paper, we will explore the responsibilities of different actors in the healthcare sphere in relation to epigenetics across four different contexts: (1) genetic research, (2) clinical practice, (3) prenatal care and (4) the workplace. Within this exploration of role responsibilities, we will also discuss the potential constraints that might prevent the patient, mother-to-be, research participant or employee, from enacting any necessary steps in order to increase their health status in response to epigenetic information. PMID- 28726232 TI - [Frequent episodic migraine and calcitonin gene-related peptide. Influence of treatment with topiramate and zonisamide on levels of the peptide]. AB - INTRODUCTION: The pathophysiology of pain in migraine is related to the activation of the trigeminovascular system by releasing vasoactive neuropeptides, the most important of which is calcitonin gene-related peptide (CGRP), which causes a neurogenic inflammation in the leptomeningeal vessels. AIM: To study whether CGRP is increased in frequent episodic migraine and whether preventive treatment with topiramate or zonisamide modifies its levels. SUBJECTS AND METHODS: We studied 28 patients with episodic migraine with or without aura, in accordance with the International Headache Society criteria, with a frequency of 4-14 days/month. Plasma levels of CGRP were determined in all the patients during an interictal period (> 72 hours without pain). Patients were divided at random into two treatment groups, one with 50 mg/day of topiramate and the other with 50 mg/day of zonisamide, for three months. At the end of the active period the CGRP level was analysed again. The control group consisted of nine healthy subjects. RESULTS: CGRP was significantly higher in the episodic migraine group than in the control group (50.61 +/- 22.5 pg/mL versus 34.96 +/- 17.03 pg/mL; p = 0.037). After treatment with neuromodulators no significant differences were found in the level of CGRP (46.11 +/- 24.2 pg/mL basal versus 47.5 +/- 24.88 pg/mL post treatment). Neither were any differences found on analysing the topiramate and zonisamide groups individually. CONCLUSIONS: The plasma level of CGRP is increased in episodic migraine, and its levels are not modified by treatment with low doses of topiramate or zonisamide. PMID- 28726233 TI - [Cannabidiol: its use in refractory epilepsies]. AB - INTRODUCTION: Some epileptic syndromes are characterised by seizures that are difficult to control and are associated to delayed neuropsychomotor development, which results in a deterioration in the patient's quality of life as well as in that of his or her family. AIM: To evaluate the use of cannabidiol as adjuvant therapy in patients with refractory epilepsies. PATIENTS AND METHODS: An observational study was conducted by means of a survey addressed to the patient's caregiver. Data collected included information about the patient and the caregiver, changes observed in the seizures, neuropsychological effects, side effects and the family's overall perception following the use of cannabidiol. RESULTS: The evaluation examined 15 patients with refractory epilepsies, who received cannabidiol over a period ranging from one month to one year. The frequency of seizures decreased in 40% of the patients, 60% of the patients were seen to have control over 50% of their seizures and in 27% of them the seizures disappeared completely. Neurocognitive changes were also reported: behaviour improved in 73%; 60% reported an improvement in language; in 50% sleep improved; 43% reported improvements in eating habits; and 100% said their mood had improved. The overall perception of the illness was that there had been improvements in 73% of respondents. The most common side effects were drowsiness and fatigue. CONCLUSIONS: These results suggest a possible beneficial effect of cannabidiol on the control of seizures and on the improvement of certain neurocognitive aspects in patients with refractory epilepsies. PMID- 28726234 TI - [Current status of congenital myasthenic syndromes]. AB - Since Engel reported the first case of congenital myasthenia in 1977 and the first pathogenic gene was found in 1995, knowledge about congenital myasthenic syndromes has continued to grow. Over the years, the pathogenic basis, its clinical features, the phenotype-genotype correlations that have been established and its therapeutic management have all been described. In this group of diseases the safety margin of neuromuscular transmission is altered by different mechanisms: in the synthesis or storage of acetylcholine quanta in the synaptic vesicles, in the calcium-mediated release of acetylcholine in the nerve terminal or in the efficiency of the quantum released to generate a post-synaptic depolarisation. Increased knowledge about them has enabled a number of different therapeutic strategies to be established. In this review the main updates on these syndromes are reported, including: the genes described as classifying 50% of cases, their current classification based on the localisation of the proteins that alter neuromuscular transmission, including a new group of congenital myasthenias, glycosylation disorders, the main key diagnoses and the therapeutic management of this group of under-diagnosed patients. PMID- 28726235 TI - [54.a Reunion Anual de la Sociedad Espanola de Neurofisiologia Clinica. Meeting with the British Society for Clinical Neurophysiology. Communications (II)]. PMID- 28726236 TI - Cross-Cultural Validation of the Patient Perception of Integrated Care Survey. AB - OBJECTIVE: To test the cross-cultural validity of the U.S. Patient Perception of Integrated Care (PPIC) Survey in a Dutch sample using a standardized procedure. DATA SOURCES: Primary data collected from patients of five primary care centers in the south of the Netherlands, through survey research from 2014 to 2015. STUDY DESIGN: Cross-sectional data collected from patients who saw multiple health care providers during 6 months preceding data collection. DATA COLLECTION: The PPIC survey includes 59 questions that measure patient perceived care integration across providers, settings, and time. Data analysis followed a standardized procedure guiding data preparation, psychometric analysis, and included invariance testing with the U.S. dataset. PRINCIPAL FINDINGS: Latent scale structures of the Dutch and U.S. survey were highly comparable. Factor "Integration with specialist" had lower reliability scores and noninvariance. For the remaining factors, internal consistency and invariance estimates were strong. CONCLUSIONS: The standardized cross-cultural validation procedure produced strong support for comparable psychometric characteristics of the Dutch and U.S. surveys. Future research should examine the usability of the proposed procedure for contexts with greater cultural differences. PMID- 28726237 TI - Facial annular elastolytic giant cell granuloma treated with pulsed dye laser and intralesional polydeoxyribonucleotide. PMID- 28726238 TI - A "Patch" to the NYU Emergency Department Visit Algorithm. AB - OBJECTIVE: To document erosion in the New York University Emergency Department (ED) visit algorithm's capability to classify ED visits and to provide a "patch" to the algorithm. DATA SOURCES: The Nationwide Emergency Department Sample. STUDY DESIGN: We used bivariate models to assess whether the percentage of visits unclassifiable by the algorithm increased due to annual changes to ICD-9 diagnosis codes. We updated the algorithm with ICD-9 and ICD-10 codes added since 2001. PRINCIPAL FINDINGS: The percentage of unclassifiable visits increased from 11.2 percent in 2006 to 15.5 percent in 2012 (p < .01), because of new diagnosis codes. Our update improves the classification rate by 43 percent in 2012 (p < .01). CONCLUSIONS: Our patch significantly improves the precision and usefulness of the most commonly used ED visit classification system in health services research. PMID- 28726239 TI - Updating the Emergency Department Algorithm: One Patch Is Not Enough. PMID- 28726240 TI - Questioning reliability of observational study. PMID- 28726241 TI - Investigating the role of the IGF axis as a predictor of biochemical recurrence in prostate cancer patients post-surgery. AB - BACKGROUND: Between 20% and 35% of prostate cancer (PCa) patients who undergo treatment with curative intent (ie, surgery or radiation therapy) for localized disease will experience biochemical recurrence (BCR). Alterations in the insulin like growth factor (IGF) axis and PTEN expression have been implicated in the development and progression of several human tumors including PCa. We examined the expression of the insulin receptor (INSR), IGF-1 receptor (IGF-1R), PTEN, and AKT in radical prostatectomy tissue of patients who developed BCR post-surgery. METHODS: Tissue microarrays (TMA) of 130 patients post-radical prostatectomy (65 = BCR, 65 = non-BCR) were stained by immunohistochemistry for INSR, IGF-1R, PTEN, and AKT using optimized antibody protocols. INSR, IGF1-R, PTEN, and AKT expression between benign and cancerous tissue, and different Gleason grades was assessed. Kaplan-Meier survival curves were used to examine the relationship between proteins expression and BCR. RESULTS: INSR (P < 0.001), IGF-1R (P < 0.001), and AKT (P < 0.05) expression was significantly increased and PTEN (P < 0.001) was significantly decreased in cancerous versus benign tissue. There was no significant difference in INSR, IGF-1R, or AKT expression in the cancerous tissue of non-BCR versus BCR patients (P = 0.149, P = 0.990, P = 0.399, respectively). There was a significant decrease in PTEN expression in the malignant tissue of BCR versus non-BCR patients (P = 0.011). Combinational analysis of the tissue proteins identified a combination of decreased PTEN and increased AKT or increased INSR was associated with worst outcome. We found that in each case, our hypothesized worst group was most likely to experience BCR and this was significant for combinations of PTEN+INSR and PTEN+AKT but not PTEN+IGF 1R (P = 0.023, P = 0.028, P = 0.078, respectively). CONCLUSIONS: Low PTEN is associated with BCR and this association is strongly modified by high INSR and high AKT expression. Measurement of these proteins could help inform appropriate patient selection for postoperative adjuvant therapy and prevent BCR. PMID- 28726242 TI - Noncentrosomal microtubules regulate autophagosome transport through CAMSAP2-EB1 cross-talk. AB - Microtubules (MTs) play essential roles in many steps of autophagy, an important degradation pathway in the maintenance of cellular homoeostasis. In many cells, MT networks are comprised of centrosomal MTs and noncentrosomal MTs. However, it is unknown whether noncentrosomal MTs and its binding proteins are involved in autophagy. Here, we show in HeLa cells that calmodulin-regulated spectrin associated protein 2 (CAMSAP2), a noncentrosomal MT minus-end stabilizing protein, regulates retrograde transport of autophagosomes through MT dynamics. CAMSAP2 cooperates with EB1 to regulate end-binding protein 1 (EB1) behaviour at MT plus ends, MT growth directions and autophagosome transport. An association between CAMSAP2 and EB1 in the cytosol may modulate EB1 binding to MT plus ends. Collectively, our data indicate that noncentrosomal MTs regulate autophagy through a cross-talk between CAMSAP2 and EB1. PMID- 28726243 TI - The effect of near-peer tutoring on medical students' performance in anatomical and physiological sciences. AB - Healthcare professional schools across the world are implementing near-peer tutoring (NPT) programs owing to numerous benefits to both tutors and tutees. This study determined whether higher attendance at NPT sessions led to improvements in course grades for high and low performing students. Fourth-year medical students used the USMLE Step 1 question format to tutor first-year medical students during the second half of the Structure and Function (SF) module, i.e., SF2. Attendance was recorded and students were accordingly divided into three groups: high, moderate, and low-no attendance. Students' performances in SF1 and SF2 were compared using Student's t-test. Differences among the three groups were analyzed using ANOVA and Scheffe post hoc test (P< 0.05). Students who earned 70-79% (C) in SF1 were further examined on the basis of their attendance rate and performance in SF2. Those who attended three or more sessions completed a survey evaluating the NPT program. Course grades were significantly higher in SF2 than SF1 for all students, regardless of attendance rate. However, students who received a C grade in SF1 and had high or moderate attendance improved significantly in their SF2 course grade. Most students agreed that the NPT program was valuable and they evaluated the tutors highly. They also agreed that NPT prepared them for course exams and Step 1, but did not reduce anxiety and stress about Step 1. The positive effect of the NPT program resulted in its expansion to include all first-year modules. Clin. Anat. 30:922-928, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28726244 TI - Computed tomographic morphometry of tympanic bulla shape and position in brachycephalic and mesaticephalic dog breeds. AB - Anatomic variations in skull morphology have been previously described for brachycephalic dogs; however there is little published information on interbreed variations in tympanic bulla morphology. This retrospective observational study aimed to (1) provide detailed descriptions of the computed tomographic (CT) morphology of tympanic bullae in a sample of dogs representing four brachycephalic breeds (Pugs, French Bulldogs, English Bulldog, and Cavalier King Charles Spaniels) versus two mesaticephalic breeds (Labrador retrievers and Jack Russell Terriers); and (2) test associations between tympanic bulla morphology and presence of middle ear effusion. Archived head CT scans for the above dog breeds were retrieved and a single observer measured tympanic bulla shape (width:height ratio), wall thickness, position relative to the temporomandibular joint, and relative volume (volume:body weight ratio). A total of 127 dogs were sampled. Cavalier King Charles Spaniels had significantly flatter tympanic bullae (greater width:height ratios) versus Pugs, English Bulldogs, Labrador retrievers, and Jack Russell terriers. French Bulldogs and Pugs had significantly more overlap between tympanic bullae and temporomandibular joints versus other breeds. All brachycephalic breeds had significantly lower tympanic bulla volume:weight ratios versus Labrador retrievers. Soft tissue attenuating material (middle ear effusion) was present in the middle ear of 48/100 (48%) of brachycephalic breeds, but no significant association was found between tympanic bulla CT measurements and presence of this material. Findings indicated that there are significant interbreed variations in tympanic bulla morphology, however no significant relationship between tympanic bulla morphology and presence of middle ear effusion could be identified. PMID- 28726245 TI - Opioid Use and Abuse and Neonatal Abstinence Syndrome. PMID- 28726246 TI - Cryo-electron tomography-the cell biology that came in from the cold. AB - Cryo-electron tomography (cryo-ET) provides high-resolution 3D views into cells pristinely preserved by vitrification. Recent technical advances such as direct electron detectors, the Volta phase plate and cryo-focused ion beam milling have dramatically pushed image quality and expanded the range of cryo-ET applications. Cryo-ET not only allows mapping the positions and interactions of macromolecules within their intact cellular context, but can also reveal their in situ structure at increasing resolution. Here, we review how recent work using cutting-edge cryo ET technologies is starting to provide fresh views into different aspects of cellular biology at an unprecedented level of detail. We anticipate that these developments will soon make cryo-ET a fundamental technique in cell biology. PMID- 28726247 TI - Women's attitudes to safe-induced abortion in Iran: Findings from a pilot survey. AB - AIM: To explore attitudes to safe-induced abortion among pregnant women in Iran. BACKGROUND: In Islamic teachings, abortion is generally forbidden. However in specific circumstances, abortion may be permitted and currently, in Iran, the law allows termination of pregnancy only if three specialist physicians confirm that the pregnancy outcome may be harmful for the mother during pregnancy or after birth. DESIGN: Pilot, descriptive survey. METHODS: A 15-item structured questionnaire focusing on attitudes to safe-induced abortion was developed and pilot tested. Participants were pregnant women who were referred to the Legal Medical Centre (July-December 2015) to obtain permission for abortion. On obtaining their informed consent, the women were asked to respond to each item if they agreed (Yes) or disagreed (No). Only their age, education, employment, marital status and religion were obtained. RESULTS: Of the 80 survey participants referred for a safe-induced abortion, 90% were carrying foetuses with a diagnosed congenital malformation and 10% were experiencing complications of pregnancy that endangered their health. The majority of women (85%) perceived abortion to be dangerous to health; 86% indicated that partners should be involved in decision making about abortion, while 83% believed that public health officials should have complete control of abortion law. CONCLUSIONS: There is a need to improve women's and couples' awareness and practice of effective contraceptive methods. Further research is needed to better understand the complex issues that lead to unintended pregnancies and abortions considering religious beliefs and cultural and legal contexts. PMID- 28726248 TI - Finding sacral: Developmental evolution of the axial skeleton of odontocetes (Cetacea). AB - Axial morphology was dramatically transformed during the transition from terrestrial to aquatic environments by archaeocete cetaceans, and again during the subsequent odontocete radiation. Here, we reconstruct the sequence of developmental events that underlie these phenotypic transitions. Archaeocete innovations include the loss of primaxial/abaxial interaction at the sacral/pelvic articulation and the modular dissociation of the fluke from the remainder of the tail. Odontocetes subsequently integrated lumbar, sacral, and anterior caudal vertebrae into a single torso module, and underwent multiple series-specific changes in vertebral count. The conservation of regional proportions despite regional fluctuations in count strongly argues that rates of somitogenesis can vary along the column and that segmentation was dissociated from regionalization during odontocete evolution. Conserved regional proportions also allow the prediction of the location and count of sacral homologs within the torso module. These predictions are tested with the analysis of comparative pudendal nerve root location and geometric morphometrics. We conclude that the proportion of the column represented by the sacral series has been conserved, and that its vertebrae have changed in count and relative centrum length in parallel with other torso vertebrae. Although the sacral series of odontocetes is de differentiated, it is not de-regionalized. PMID- 28726249 TI - ZmMYB14 is an important transcription factor involved in the regulation of the activity of the ZmBT1 promoter in starch biosynthesis in maize. AB - The biosynthesis of starch is a complex process that depends on the regulatory mechanisms of different functional enzymes, and transcriptional regulation plays an important role in this process. Brittle 1, encoded by BT1, is a transporter of adenosine diphosphate-glucose, which plays an important role in the biosynthesis of starch in the endosperm of cereals. Here, we report that the promoter (pZmBT1) of the maize BT1 homolog, ZmBT1, contains an MBSI site (TAACTG), which is important for its activity. Moreover, high expression level of the gene for ZmMYB14 transcription factor was observed in the maize endosperm; its expression pattern was similar to those of the starch synthesis-related genes in maize seeds. ZmMYB14 is a typical 2R-MYB transcription factor localized in the nucleus and possessed transcriptional activation activity. ZmMYB14 could bind to the region of pZmBT1 from -280 to -151 bp and promote its activity through the TAACTG site. It was also observed to promote the activity of pZmSh2, pZmBt2, pZmGBSSI, pZmSSI, and pZmSBE1 in the maize endosperm in transient gene overexpression assays. Furthermore, ZmMYB14 was also shown to bind directly to the promoters of six starch-synthesizing genes, ZmGBSSI, ZmSSI, ZmSSIIa, ZmSBE1, ZmISA1, and ZmISA2 in yeast. These findings indicate that ZmMYB14 functions as a key regulator of ZmBT1 and is closely related to the biosynthesis of starch. Our results provide crucial information related to the regulation of starch biosynthesis in maize and would be helpful in devising strategies for modulating starch production in maize endosperm. PMID- 28726250 TI - Too Big, Too Small, or Just Right? Cost-Efficiency of Environmental Inspection Services in Connecticut. AB - OBJECTIVE: To assess optimal activity size/mix of Connecticut local public health jurisdictions, through estimating economies of scale/scope/specialization for environmental inspections/services. DATA SOURCES/STUDY SETTING: Connecticut's 74 local health jurisdictions (LHJs) must provide environmental health services, but their efficiency or reasons for wide cost variation are unknown. The public health system is decentralized, with variation in organizational structure/size. We develop/compile a longitudinal dataset covering all 74 LHJs, annually from 2005 to 2012. STUDY DESIGN: We estimate a public health services/inspections cost function, where inputs are translated into outputs. We consider separate estimates of economies of scale/scope/specialization for four mandated inspection types. DATA COLLECTION/EXTRACTION METHODS: We obtain data from Connecticut Department of Public Health databases, reports, and other publicly available sources. There has been no known previous utilization of this combined dataset. PRINCIPAL FINDINGS: On average, regional districts, municipal departments, and part-time LHJs are performing fewer than the efficient number of inspections. The full-time municipal departments and regional districts are more efficient but still not at the minimum efficient scale. The regional districts' elasticities of scale are larger, implying they are more efficient than municipal health departments. CONCLUSIONS: Local health jurisdictions may enhance efficiency by increasing inspections and/or sharing some services. PMID- 28726251 TI - Effect of radical prostatectomy on levels of cancer related epitopes in circulating macrophages of patients with clinically localized prostate cancer. AB - OBJECTIVE: Epitopes of the apoptosis related protein DNaseX (Apo10) and the pentose-phosphate-pathway associated protein transketolase-like 1 (TKTL1) have been shown to be increased in circulating macrophages of patients with different cancer types including prostate cancer (PC). So far, the effect of cancer specific therapies on the levels of these markers in blood samples of patients with PC has not been evaluated yet. The aim of the present study was to prospectively assess the effect of surgical removal of the prostate on levels of Apo10 and TKTL1 in blood macrophages using Epitope Detection In Monocytes (EDIM). METHODS: We prospectively enrolled 174 patients with clinically localized PC undergoing radical prostatectomy. Peripheral blood was collected preoperatively in all patients and postoperatively in a subgroup of 72 patients. We separately assessed the proportion of CD14/CD16-positive monocytes expressing Apo10 and TKTL1 using flow cytometry. The proportion of positive cells was multiplied by ten to generate a score for Apo10 and TKTL1, separately. Pre- and postoperative scores of Apo10 and TKTL1 were compared. Moreover, results were correlated with clinicopathologic parameters. RESULTS: In the total cohort, Median preoperative Apo10 and TKTL1 scores were 136 (Range 101-254) and 139 (102-216). In patients who underwent blood collection and testing either pre- and postoperatively (n = 72), median pre- versus postoperative scores were 132 (101-215) versus 103 (70 156) for Apo10 (P < 0.0001) and 140 (102-212) versus 115 (84-187) (P < 0.0001) for TKTL1. Following radical prostatectomy, 56 (77.7%) and 59 (81.9%) patients in the cohort of patients with blood collection before and after prostatectomy showed a decrease of Apo10 and TKTL1 expressing monocytes. TKTL1 and Apo10 did not show any correlation with known histopathologic and clinical risk parameters. CONCLUSIONS: The present study demonstrates that surgical removal of the primary tumor leads to a significant decrease of Apo10 and TKTL1 expressing macrophages. This observation further encourages studies assessing the optimal clinical utility of EDIM-based detection of Apo10 and TKTL1 in patients with PC. PMID- 28726252 TI - Central amygdala relaxin-3/relaxin family peptide receptor 3 signalling modulates alcohol seeking in rats. AB - BACKGROUND AND PURPOSE: Alcohol use disorders are a leading cause of preventable deaths worldwide, and stress is a major trigger of relapse. The neuropeptide relaxin-3 and its cognate receptor, relaxin family peptide receptor 3 (RXFP3), modulate stress-induced relapse to alcohol seeking in rats, and while the bed nucleus of the stria terminalis has been implicated in this regard, the central nucleus of the amygdala (CeA) also receives a relaxin-3 innervation and CeA neurons densely express RXFP3 mRNA. Moreover, the CeA is consistently implicated in both stress and addictive disorders. Yohimbine precipitates relapse-like behaviour in rodents, although exactly how yohimbine induces relapse is unknown, possibly by increasing stress levels and inducing heightened cue reactivity. EXPERIMENTAL APPROACH: In the current study, we examined the effects of yohimbine (1 mg.kg-1 , i.p.) on anxiety-like behaviour in alcohol-experienced rats. Furthermore, we assessed CeA neuronal activation following yohimbine-induced reinstatement of alcohol seeking and the role of the relaxin-3/RXFP3 signalling within the CeA in yohimbine-induced reinstatement to alcohol seeking. KEY RESULTS: Low-dose yohimbine was anxiogenic in rats with a history of alcohol use. Furthermore, yohimbine-induced reinstatement of alcohol seeking increased Fos activation in CeA corticotrophin-releasing factor, dynorphin and GABA neurons compared with naive and vehicle controls. Bilateral intra-CeA injections of the selective RXFP3 antagonist, R3(B1-22)R, attenuated yohimbine-induced reinstatement of alcohol seeking. CONCLUSIONS: Collectively, these data suggest that the CeA is a node where yohimbine acts to induce reinstatement of alcohol seeking and implicate the relaxin-3/RXFP3 system within the CeA in this process. PMID- 28726254 TI - The Bobath concept. A guru-led set of teachings unsupported by emerging evidence. A response to Vaughan-Graham and Cott. (J Eval Clin Pract. 2016. doi: 10.1111/jep.12751). PMID- 28726253 TI - alpha9- and alpha7-containing receptors mediate the pro-proliferative effects of nicotine in the A549 adenocarcinoma cell line. AB - BACKGROUND AND PURPOSE: Tobacco smoke contains many classes of carcinogens and although nicotine is unable to initiate tumourigenesis in humans and rodents, it promotes tumour growth and metastasis in lung tumours by acting on neuronal nicotinic ACh receptors (nAChRs). The aim of this study was to identify molecularly, biochemically and pharmacologically which nAChR subtypes are expressed and functionally activated by nicotine in lung cancer cell lines. EXPERIMENTAL APPROACH: We used A549 and H1975 adenocarcinoma cell lines derived from lung tumours to test the in vitro effects of nicotine, and nAChR subtype specific peptides and compounds. KEY RESULTS: The two adenocarcinoma cell lines express distinctive nAChR subtypes, and this affects their nicotine-induced proliferation. In A549 cells, nAChRs containing the alpha7 or alpha9 subunits not only regulate nicotine-induced cell proliferation but also the activation of the Akt and ERK pathways. Blocking these nAChRs by means of subtype-specific peptides, or silencing their expression by means of subunit-specific siRNAs, abolishes nicotine-induced proliferation and signalling. Moreover, we found that the alpha7 antagonist MG624 also acts on alpha9-alpha10 nAChRs, blocks the effects of nicotine on A549 cells and has dose-dependent cytotoxic activity. CONCLUSIONS AND IMPLICATIONS: These results highlight the pathophysiological role of alpha7- and alpha9-containing receptors in promoting non-small cell lung carcinoma cell growth and intracellular signalling and provide a framework for the development of new drugs that specifically target the receptors expressed in lung tumours. LINKED ARTICLES: This article is part of a themed section on Nicotinic Acetylcholine Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.11/issuetoc. PMID- 28726255 TI - Creatine supplementation on cardiac autonomic functions. PMID- 28726256 TI - Injectable loop recorder (ILR): How to, where to, who to. PMID- 28726257 TI - Recommendations for analysis of repeated-measures designs: testing and correcting for sphericity and use of manova and mixed model analysis. AB - PURPOSE: A common experimental design in ophthalmic research is the repeated measures design in which at least one variable is a within-subject factor. This design is vulnerable to lack of 'sphericity' which assumes that the variances of the differences among all possible pairs of within-subject means are equal. Traditionally, this design has been analysed using a repeated-measures analysis of variance (RM-anova) but increasingly more complex methods such as multivariate anova (manova) and mixed model analysis (MMA) are being used. This article surveys current practice in the analysis of designs incorporating different factors in research articles published in three optometric journals, namely Ophthalmic and Physiological Optics (OPO), Optometry and Vision Science (OVS), and Clinical and Experimental Optometry (CXO), and provides advice to authors regarding the analysis of repeated-measures designs. RECENT FINDINGS: Of the total sample of articles, 66% used a repeated-measures design. Of those articles using a repeated-measures design, 59% and 8% analysed the data using RM-anova or manova respectively and 33% used MMA. The use of MMA relative to RM-anova has increased significantly since 2009/10. A further search using terms to select those papers testing and correcting for sphericity ('Mauchly's test', 'Greenhouse Geisser', 'Huynh and Feld') identified 66 articles, 62% of which were published from 2012 to the present. SUMMARY: If the design is balanced without missing data then manova should be used rather than RM-anova as it gives better protection against lack of sphericity. If the design is unbalanced or with missing data then MMA is the method of choice. However, MMA is a more complex analysis and can be difficult to set up and run, and care should be taken first, to define appropriate models to be tested and second, to ensure that sample sizes are adequate. PMID- 28726258 TI - Correlation between Z score, fetal fraction, and sequencing reads in non-invasive prenatal testing. PMID- 28726259 TI - Characterization of adenoviral transduction profile in prostate cancer cells and normal prostate tissue. AB - BACKGROUND: Prostate diseases are common in males worldwide with high morbidity. Gene therapy is an attractive therapeutic strategy for prostate diseases, however, it is currently underdeveloped. As well known, adeno virus (Ad) is the most widely used gene therapy vector. The aims of this study are to explore transduction efficiency of Ad in prostate cancer cells and normal prostate tissue, thus further providing guidance for future prostate pathophysiological studies and therapeutic development of prostate diseases. METHODS: We produced Ad expressing enhanced green fluorescence protein (EGFP), and characterized the transduction efficiency of Ad in both human and mouse prostate cancer cell lines in vitro, as well as prostate tumor xenograft, and wild-type mouse prostate tissue in vivo. Ad transduction efficiency was determined by EGFP fluorescence using microscopy and flow cytometry. Cell type-specific transduction was examined by immunofluorescence staining of cell markers. RESULTS: Our data showed that Ad efficiently transduced human and mouse prostate cancer cells in vitro in a dose dependent manner. Following intratumoral and intraprostate injection, Ad could efficiently transduce prostate tumor xenograft and the major prostatic cell types in vivo, respectively. CONCLUSIONS: Our findings suggest that Ad can efficiently transduce prostate tumor cells in vitro as well as xenograft and normal prostate tissue in vivo, and further indicate that Ad could be a potentially powerful toolbox for future gene therapy of prostate diseases. PMID- 28726260 TI - Three-year experience with interventional neuroradiology for management of cerebral aneurysms at a single Australian centre. AB - INTRODUCTION: Over the last decade interventional neuroradiology (NR) has become the mainstay of managing cerebral aneurysms. The aim of our study was to review our growing experiences with interventional NR and quantify morbidity and mortality associated with these procedures. METHODS: The electronic medical records of all patients admitted to the Gold Coast (University) Hospital Intensive Care Unit following subarachnoid haemorrhage (SAH) or elective interventional NR management of cerebral aneurysms between January 2012 and December 2014 were retrieved. Primary outcomes of interest were death, thromboembolic and haemorrhagic events during hospital admission. RESULTS: One hundred and fifty-two patients underwent interventional NR procedures for cerebral aneurysms. This consisted of 92 (60.5%) elective cases and 60 (39.5%) emergency cases following SAH. The all-cause mortality rate and the rate of thromboembolic and haemorrhagic events for the entire cohort were 5.9%, 11.2% and 7.2% respectively. Intra-procedural complications occurred in 6.6% of the entire cohort. Median length of follow-up was 448 days, with 91.6% of the entire cohort followed up. At follow-up, 64.1% of patients had no neurological deficits, 29% had mild non-specific deficits and 6.9% had significant disability. CONCLUSIONS: Interventional NR represents the primary treatment modality for all patients presenting to our service with cerebral aneurysm. Our results are encouraging and are comparable to published data in the international literature. Reducing the burden of thromboembolism in patients undergoing endovascular treatment of their aneurysmal disease is our main research focus currently, and we aim to improve outcomes for this patient group. PMID- 28726261 TI - Origin and prevalence of the accessory phrenic nerve: A meta-analysis and clinical appraisal. AB - The accessory phrenic nerve (APN) is a common anatomical variant with differing reports of prevalence in the literature. It can be injured during operative procedures to the neck and thorax or by regional anesthetic techniques in its vicinity. Our aim was to provide a comprehensive evidence-based assessment of the prevalence and origins of the APN. The databases PubMed, China National Knowledge Infrastructure, ScienceDirect, EMBASE, BIOSIS, SciELO, and Web of Science were searched comprehensively, followed by assessment of eligibility and extraction of data concerning the APN. The data were pooled into a meta-analysis. A total of 17 studies were included in the meta-analysis. Fourteen studies (n = 1,941 hemi necks) reported data on APN prevalence resulting in an overall pooled prevalence estimate of 36.5%. Nine studies (n = 941 APNs) reported data on the origin of the APN. Most commonly the APN originated from the ansa cervicalis (16.5%) followed by the nerve to the subclavius (15.8%). Subgroup analysis on the basis of laterality and geographic region revealed no statistically significant findings. The APN is a highly variable anatomical structure present in over one third of the population, most often originating from the ansa cervicalis or the nerve to the subclavius. Clinicians need to be aware of the varying constellation of symptoms that can arise from APN injury. Ultimately, knowledge of APN variation could provide for better outcomes and reduction of iatrogenic injuries, particularly in high-risk patients prone to long-term complications from diaphragmatic dysfunction. Clin. Anat. 30:1077-1082, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28726262 TI - Double aortic arch anomalies in Children: A Systematic 20-Year Single Center Study. AB - Aortic arch anomalies underlie numerous congenital disorders. Effectively diagnosing and treating them requires close understanding of cardiovascular embryology. As our Center serves the entire pediatric population of our country, we performed a comprehensive retrospective analysis of all aortic arch anomalies diagnosed at our Center over the past 20 years. We analyzed 40 children with aortic arch anomalies, distinguishing two defect types: Group 1 displayed ring forming anomalies, and Group 2 other types of aortic arch anomalies that did not form a vascular ring. We performed detailed morphological analyses using echocardiography, angiography, computed tomography, or magnetic resonance imaging and generated a catalog of all aortic arch anomalies present. Group 1 was represented by 25 patients; 40% with persistent both aortic arches, and 60% with various forms of right aortic arch and an incomplete left aortic arch. Group 2 was represented by 15 patients with complex heart defects. On the basis of our dataset, the incidence of all aortic arch anomalies was 0.033%, and of ring forming pathologies 0.021%. Although aortic arch anomalies are rare, it is important to diagnose them correctly. It is critical to distinguish ring-forming types. Although in complex defects the aortic arch anomaly represents only an additive diagnosis, its correct definition could be crucial for further management. Cumulatively, this unique, long-term study provides a systematic patient registry and offers critical epidemiological data to aid the study of rare congenital cardiovascular defects. Clin. Anat. 30:929-939, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28726263 TI - Developing a medical picture book for reducing venipuncture distress in preschool aged children. AB - AIM: Distress associated with needle-related procedures is a major concern in preschool-aged children nursing. This study developed a medical picture book for supporting preschool-aged children facing a venipuncture and determined the effectiveness of such a book intervention in decreasing behavioural distress. METHODS: The picture book was designed in 3 stages: developing stories on medical situations, penning the text, and drafting the book. We conducted a quasiexperimental study to examine the effectiveness of the book. The behavioural distress of the control and picture book groups were assessed before, during, and after the intervention by using the Observational Scale of Behavioral Distress Revised (OSBD-R). RESULTS: We created a 12-page picture book, Sick Rui-Rui Bear, in which cartoon characters were depicted undergoing venipunctures, as a guide for vein injection and for facilitating positive venipuncture outcomes in preschool-aged children. Over time, the OSBD-R scores of the picture book group were significantly lower than those of the control group (P < .001). CONCLUSION: We recommend the picture book be routinely read and used during venipunctures to decrease procedural distress in preschool-aged children. PMID- 28726264 TI - Differential protein expression in exosomal samples taken from trauma patients. PMID- 28726265 TI - How to harvest the greatest length of tibialis posterior tendon for tendon transfer: A cadaveric study. AB - : In anterior transfer of the tibialis posterior tendon, the tendon was harvested using two incisions, the first at its attachment point on the navicular bone and second on the medial side of the leg above the medial malleolus. To provide the maximum tendon length, the second incision needs to be as proximal as possible but injury to the muscle origin must be avoided. The purpose of this study is to establish the location of the second incision that yields the greatest tendon length. Forty-five unpaired embalmed cadaveric legs were dissected. Demographic data, gender, age, and side of specimen were recorded. The distance between the tip of the medial malleolus and the muscle origin was measured. Mobile tendon length, muscle origin, foot length, tibial length, and position of ankle were also noted. The mean mobile tendon length was 11.1 (range 10.7-11.4) cm and the distance between the tip of the medial malleolus and the muscle origin was 6.8 (range 6.5-7.0) cm. The mean foot length was 22.2 cm (range 21.7-22.7), tibial length was 31.5 cm (range 30.8-32.2), and muscle origin was 23.7 cm (range 21.0 26.3). The mean angle position was 46 degrees plantar flexion (range 43-49). In subgroup analysis by gender, the mobile tendon length, distance between the tip of the medial malleolus and the muscle origin, and tibial length, were significantly greater in males than females. In conclusion, for anterior transfer of the tibialis posterior tendon, an incision 7.1 cm above the medial malleolus in the male and 6.4 cm above it in the female provides the longest mobile tendon without injury to its origin. Clin. Anat. 30:1083-1086, 2017. (c) 2017 Wiley Periodicals, Inc. LEVEL OF EVIDENCE: V, Cadaveric descriptive study. PMID- 28726267 TI - Day length constrains the time budget of aphid predators. AB - Phenology shifts and range expansions cause organisms to experience novel day length - temperature correlations. Depending on the temporal niche, organisms may benefit or suffer from changes in day length, thus potentially affecting phenological adaptation. We assessed the impact of day length changes on larvae of Chrysoperla carnea (Stephens) and Episyrphus balteatus (De Geer), both of which prey on aphids. Larvae of E. balteatus are night-active, whereas those of C. carnea appear to be crepuscular. We subjected both species in climate chambers to day lengths of 16 : 8 L : D and, to circumvent diapause responses, 20 : 4 L : D. We recorded development times and predation rates of both species. E. balteatus grew 13% faster in the 16 : 8 L : D treatment and preyed on significantly more aphids. In contrast, C. carnea grew 13% faster in the 20 : 4 L : D treatment and higher predation rates in 20 : 4 L : D were marginally significant. Our results show that day length affects development and predation, but that the direction depends on species. Such differences in the use of day length may alter the efficiency of biocontrol agents in a changing climate. PMID- 28726266 TI - Survival among children with "Lethal" congenital contracture syndrome 11 caused by novel mutations in the gliomedin gene (GLDN). AB - Biallelic GLDN mutations have recently been identified among infants with lethal congenital contracture syndrome 11 (LCCS11). GLDN encodes gliomedin, a protein required for the formation of the nodes of Ranvier and development of the human peripheral nervous system. We report six infants and children from four unrelated families with biallelic GLDN mutations, four of whom survived beyond the neonatal period into infancy, childhood, and late adolescence with intensive care and chronic respiratory and nutritional support. Our findings expand the genotypic and phenotypic spectrum of LCCS11 and demonstrate that the condition may not necessarily be lethal in the neonatal period. PMID- 28726268 TI - Being similar while judging right and wrong: The effects of personal and situational similarity on moral judgements. AB - This study investigated the effects of similarity with the transgressor and the victim on the perceived immorality of the transgression. Participants read two stories describing a person that cheated on their partner and a police officer that mistreated somebody. In the first story we manipulated participants' personal similarity to the transgressor and in the second their personal similarity to the victim. In each story, participants' past situational similarity to the target character was assessed according to their previous experiences of being in the same position. Results show that both personal and past situational similarity to the transgressor determine less severe moral judgements, while personal and past situational similarity with the victim have the opposite effect. We also tested several potential mediators of these effects, derived from competing theoretical accounts of the influence of similarity on perceived responsibility. Empathy emerged as mediating most of the effects of similarity on moral judgements, except those induced by past situational similarity with the victim. The foreseen probability of being in a similar situation mediated only the effects of similarity to the transgressor, and not those of similarity to the victim. Overall, results highlight the complex mechanisms of the influences of similarity on moral judgements. PMID- 28726270 TI - Equimolar mixture of nitroux oxyde and oxygen during post-operative physiotherapy in patients with cerebral palsy: A randomized, double-blind, placebo-controlled study. AB - BACKGROUND: The administration of an equimolar mixture of nitrous oxide and oxygen (N2O) is recommended during painful procedures. However, the evaluation of its use during physiotherapy after surgery has not been reported, although pain may hamper physiotherapy efficiency. This study investigated whether the use of N2O improves the efficacy of post-operative physiotherapy after multilevel surgery in patients with cerebral palsy. METHOD: It was a randomized 1:1, double blind, placebo-controlled study. All patients had post-operative physiotherapy starting the day after surgery. Patients received either N2O or placebo gas during the rehabilitation sessions. All patients had post-operative pain management protocol, including pain medication as needed for acute pain. The primary objective was to reach angles of knee flexion of 110 degrees combined with hip extension of 10 degrees , with the patient lying prone, within six or less physiotherapy sessions. Secondary evaluation criteria were the number of sessions required to reach the targeted angles, the session-related pain intensity and the analgesics consumption for managing post-operative pain. RESULTS: Sixty-four patients were enrolled. Targeted angles were achieved more often in the N2O group (23 of 32, 72%, vs. Placebo: 13/ of 32, 41%; p = 0.01). CONCLUSION: The administration of N2O during post-operative physiotherapy can help to achieve more quickly an improved range of motion, and, although not significant in our study, to alleviate the need for pain medication. Further studies evaluating the administration of N2O in various settings are warranted. SIGNIFICANCE: During this randomized placebo-controlled double-blind study, children receiving nitrous oxide and oxygen (N2O) achieved more often the targeted range of motion during physiotherapy sessions after multilevel surgery. Compared to placebo, nitrous oxide and oxygen (N2O) enabled a better management of acute pain related to physiotherapy procedures. PMID- 28726271 TI - Survey of Australian dermatologists' perceptions and experiences with isotretinoin-induced depression and suicide. PMID- 28726272 TI - Does Maternity Care Coordination Influence Perinatal Health Care Utilization? Evidence from North Carolina. AB - OBJECTIVE: To examine effects of maternity care coordination (MCC) on perinatal health care utilization among low-income women. DATA SOURCES: North Carolina Center for Health Statistics Baby Love files that include birth certificates, maternity care coordination records, WIC records, and Medicaid claims. STUDY DESIGN: Causal effects of MCC participation on health care outcomes were estimated in a sample of 7,124 singleton Medicaid-covered births using multiple linear regressions with inverse probability of treatment weighting (IPTW). PRINCIPAL FINDINGS: Maternity care coordination recipients were more likely to receive first-trimester prenatal care (p < .01) and averaged three more prenatal visits and two additional primary care visits during pregnancy; they were also more likely to participate in WIC and to receive postpartum family planning services (p < .01). Medicaid expenditures were greater among mothers receiving MCC. CONCLUSIONS: Maternity care coordination facilitates access to health care and supportive services among Medicaid-covered women. Increased maternal service utilization may increase expenditures in the short run; however, improved newborn health may reduce the need for costly neonatal care, and by implication the need for early intervention and other supports for at-risk children. PMID- 28726269 TI - Previous physical exercise alters the hepatic profile of oxidative-inflammatory status and limits the secondary brain damage induced by severe traumatic brain injury in rats. AB - KEY POINTS: An early inflammatory response and oxidative stress are implicated in the signal transduction that alters both hepatic redox status and mitochondrial function after traumatic brain injury (TBI). Peripheral oxidative/inflammatory responses contribute to neuronal dysfunction after TBI Exercise training alters the profile of oxidative-inflammatory status in liver and protects against acute hyperglycaemia and a cerebral inflammatory response after TBI. Approaches such as exercise training, which attenuates neuronal damage after TBI, may have therapeutic potential through modulation of responses by metabolic organs. The vulnerability of the body to oxidative/inflammatory in TBI is significantly enhanced in sedentary compared to physically active counterparts. ABSTRACT: Although systemic responses have been described after traumatic brain injury (TBI), little is known regarding potential interactions between brain and peripheral organs after neuronal injury. Accordingly, we aimed to investigate whether a peripheral oxidative/inflammatory response contributes to neuronal dysfunction after TBI, as well as the prophylactic role of exercise training. Animals were submitted to fluid percussion injury after 6 weeks of swimming training. Previous exercise training increased mRNA expression of X receptor alpha and ATP-binding cassette transporter, and decreased inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 expression per se in liver. Interestingly, exercise training protected against hepatic inflammation (COX-2, iNOS, TNF-alpha and IL-6), oxidative stress (decreases in non-protein sulfhydryl and glutathione, as well as increases in 2',7'-dichlorofluorescein diacetate oxidation and protein carbonyl), which altered hepatic redox status (increases in myeloperoxidase and superoxide dismutase activity, as well as inhibition of catalase activity) mitochondrial function (decreases in methyl-tetrazolium and Deltapsi, as well as inhibition of citrate synthase activity) and ion gradient homeostasis (inhibition of Na+ ,K+ ATPase activity inhibition) when analysed 24 h after TBI. Previous exercise training also protected against dysglycaemia, impaired hepatic signalling (increase in phosphorylated c-Jun NH2-terminal kinase, phosphorylated decreases in insulin receptor substrate and phosphorylated AKT expression), high levels of circulating and neuronal cytokines, the opening of the blood-brain barrier, neutrophil infiltration and Na+ ,K+ -ATPase activity inhibition in the ipsilateral cortex after TBI. Moreover, the impairment of protein function, neurobehavioural (neuromotor dysfunction and spatial learning) disability and hippocampal cell damage in sedentary rats suggests that exercise training also modulates peripheral oxidative/inflammatory pathways in TBI, which corroborates the ever increasing evidence regarding health-related outcomes with respect to a physically active lifestyle. PMID- 28726273 TI - Epigallocatechin gallate enhances treatment efficacy of oral nifedipine against pregnancy-induced severe pre-eclampsia: A double-blind, randomized and placebo controlled clinical study. AB - WHAT IS KNOWN AND OBJECTIVE: Oral nifedipine is commonly used to treat pre eclampsia, one of the most severe complications during pregnancy, but its clinical efficacy is less than ideal. Epigallocatechin gallate (EGCG), a natural compound from green tea, could benefit cardiovascular health especially hypertension. We investigated the clinical efficacy of EGCG, when complemented with oral nifedipine, in treating pre-eclampsia. METHODS: A total of 350 pregnant women with severe pre-eclampsia were recruited and randomized to receive oral nifedipine, together with placebo (NIF+placebo) or EGCG (NIF+EGCG). The primary treatment outcome was the time needed to control blood pressure and interval time before a new hypertensive crisis, whereas the secondary treatment outcome was the number of treatment doses to effectively control blood pressure, maternal adverse effects and neonatal complications. RESULTS AND DISCUSSION: Comparing NIF+EGCG group to NIF+placebo group, the time needed to control blood pressure was significantly shorter (NIF+EGCG 31.2+/-16.7 minutes, NIF+placebo 45.3+/-21.9 minutes; 95% CI 9.7-18.5 minutes), whereas interval time before a new hypertensive crisis was significantly prolonged (NIF+EGCG 7.2+/-2.9 hours, NIF+placebo 4.1+/-3.7 hours; 95% CI 2.3-3.9 hours), and the number of treatment dosages needed to effectively control blood pressure was also lower. Between the two treatment groups, no differences in incidence rates of maternal adverse effects or neonatal complications were observed. WHAT IS NEW AND CONCLUSIONS: EGCG is both safe and effective in enhancing treatment efficacy of oral nifedipine against pregnancy-induced severe pre-eclampsia, but formal validation is required prior to its recommendation for use outside of clinical trials. PMID- 28726274 TI - Resilience and the rehabilitation of adult spinal cord injury survivors: A qualitative systematic review. AB - AIM: To synthesize the qualitative research evidence that explored how survivors of adult spinal cord injury experience and make sense of resilience. BACKGROUND: Spinal cord injury is often a sudden and unexpected life-changing event requiring complex and long-term rehabilitation. The development of resilience is essential in determining how spinal cord injury survivors negotiate this injury and rehabilitation. DESIGN: A qualitative systematic review and thematic synthesis of the research evidence. DATA SOURCES: CINAHL, PubMed, Embase, Scopus and PsycINFO were searched, no restriction dates were used. REVIEW METHODS: Methodological quality was assessed using the Critical Appraisal Skills Programme checklist. Thematic synthesis focused on how survivors of adult spinal cord injury experience and make sense of resilience. RESULTS: Six qualitative research articles reported the experiences of 84 spinal cord injury survivors. Themes identified were: uncertainty and regaining independence; prior experiences of resilience; adopting resilient thinking; and strengthening resilience through supports. CONCLUSION: Recovery and rehabilitation following spinal cord survivors is influenced by the individual's capacity for resilience. Resilience may be influenced by previous life experiences and enhanced by supportive nursing staff encouraging self-efficacy. Survivors identified the need for active involvement in decision-making about their care to enable a sense of regaining control of their lives. This has the potential to have a significant impact on their self efficacy and in turn health outcomes. PMID- 28726276 TI - The colonic groove of the plains viscacha (Lagostomus maximus): Histochemical evidence of an abrupt change in the glycosylation pattern of goblet cells. AB - The ascending colon of most rodent species shows a longitudinal colonic groove that works as a retrograde transport pathway for a mixture of bacteria and mucus toward the cecum. We describe the morphology and glycosylation pattern of the colonic groove of Lagostomus maximus to analyze the role of mucins in this anatomical feature. We also studied the distribution pattern of the interstitial cells of Cajal (ICC) to evaluate their regulatory influence on gut motility. The groove originated near the cecocolic junction and extended along the mesenteric side of the ascending colon, limited at both ends by nonpapillated ridges. These ridges divided the lumen of the ascending colon into two compartments: a narrow channel and a large channel, called the groove lumen and the main lumen, respectively. The histochemical analysis showed differences in the glycosylation pattern of the goblet cells inside and outside the groove. Unlike the mucosa lining the main lumen of the colon, the groove was rich in goblet cells that secrete sulfomucins. The PA/Bh/KOH/PAS technique evidenced an abrupt change in the histochemical profile of goblet cells, which presented a negative reaction in the groove and a strongly positive one in the rest of the colonic mucosa. The anti-c-kit immunohistochemical analysis showed different ICC subpopulations in the ascending colon of L. maximus. Of all types identified, the ICC-SM were the only cells located solely within the colonic groove. PMID- 28726275 TI - cPKCgamma-mediated down-regulation of UCHL1 alleviates ischaemic neuronal injuries by decreasing autophagy via ERK-mTOR pathway. AB - Stroke is one of the leading causes of death in the world, but its underlying mechanisms remain unclear. Both conventional protein kinase C (cPKC)gamma and ubiquitin C-terminal hydrolase L1 (UCHL1) are neuron-specific proteins. In the models of 1-hr middle cerebral artery occlusion (MCAO)/24-hr reperfusion in mice and 1-hr oxygen-glucose deprivation (OGD)/24-hr reoxygenation in cortical neurons, we found that cPKCgamma gene knockout remarkably aggravated ischaemic injuries and simultaneously increased the levels of cleaved (Cl)-caspase-3 and LC3-I proteolysis product LC3-II, and the ratio of TUNEL-positive cells to total neurons. Moreover, cPKCgamma gene knockout could increase UCHL1 protein expression via elevating its mRNA level regulated by the nuclear factor kappaB inhibitor alpha (IkappaB-alpha)/nuclear factor kappaB (NF-kappaB) pathway in cortical neurons. Both inhibitor and shRNA of UCHL1 significantly reduced the ratio of LC3-II/total LC3, which contributed to neuronal survival after ischaemic stroke, but did not alter the level of Cl-caspase-3. In addition, UCHL1 shRNA reversed the effect of cPKCgamma on the phosphorylation levels of mTOR and ERK rather than that of AMPK and GSK-3beta. In conclusion, our results suggest that cPKCgamma activation alleviates ischaemic injuries of mice and cortical neurons through inhibiting UCHL1 expression, which may negatively regulate autophagy through ERK-mTOR pathway. PMID- 28726277 TI - Aged garlic extract suppresses inflammation in apolipoprotein E-knockout mice. AB - SCOPE: Chronic inflammation plays a major role in the formation and progression of atherosclerotic plaques. To clarify the mode of action of aged garlic extract (AGE) to retard atherosclerosis, we investigated whether AGE suppresses the inflammation in apolipoprotein E-knockout (ApoE-KO) mice. METHODS AND RESULTS: ApoE-KO mice were fed standard diet with or without 3% AGE for 12 wk. AGE feeding inhibited the progression of atherosclerotic lesion by 27% and reduced the level of C-reactive protein (CRP) and thromboxane B2 (TXB2 ), a marker of platelet activation, in serum by 39 and 33%, respectively, compared to ApoE-KO mice without AGE treatment. AGE treatment also decreased the level of tumor necrosis factor alpha (TNF-alpha), a major stimulus inducing CRP production, in the liver by 35%. AGE decreased the level of interleukin-1 receptor-associated kinase 4 (IRAK4) by 60% and almost doubled the level of phospho-AMP-activated protein kinase (p-AMPK) in the liver. CONCLUSION: The anti-atherosclerotic effect of AGE involves the suppression of inflammation by reducing the serum level of CRP and TXB2 , and the protein level of TNF-alpha and IRAK4, and increasing AMPK activity in liver. PMID- 28726278 TI - Color Doppler Sonography of Merkel Cell Carcinoma. AB - We illustrate the color Doppler sonographic findings in primary cutaneous Merkel cell carcinoma. Eight cases (4 female and 4 male; mean age, 75.4 years) were collected. The most common affected regions were the face (63%) and the hip/buttock (25%). The mean transverse diameter and thickness were 21 and 14 mm, respectively. Fifty percent were oval, and 50% were dome shaped. All lesions were hypoechoic, with variable degrees of heterogeneity. All but 2 lesions were poorly defined. An acoustic reinforcement artifact was present in 3 and epidermal thickening in 2. All tumors had prominent and chaotic hypervascularity with arterial vessels (mean peak velocity, 11 cm/s; mean resistive index, 0.57). PMID- 28726279 TI - Localised longitudinal erythronychia caused by subungual capillary hemangioma. PMID- 28726280 TI - An efficient study design to test parent-of-origin effects in family trios. AB - Increasing evidence has shown that genes may cause prenatal, neonatal, and pediatric diseases depending on their parental origins. Statistical models that incorporate parent-of-origin effects (POEs) can improve the power of detecting disease-associated genes and help explain the missing heritability of diseases. In many studies, children have been sequenced for genome-wide association testing. But it may become unaffordable to sequence their parents and evaluate POEs. Motivated by the reality, we proposed a budget-friendly study design of sequencing children and only genotyping their parents through single nucleotide polymorphism array. We developed a powerful likelihood-based method, which takes into account both sequence reads and linkage disequilibrium to infer the parental origins of children's alleles and estimate their POEs on the outcome. We evaluated the performance of our proposed method and compared it with an existing method using only genotypes, through extensive simulations. Our method showed higher power than the genotype-based method. When either the mean read depth or the pair-end length was reasonably large, our method achieved ideal power. When single parents' genotypes were unavailable or parental genotypes at the testing locus were not typed, both methods lost power compared with when complete data were available; but the power loss from our method was smaller than the genotype based method. We also extended our method to accommodate mixed genotype, low-, and high-coverage sequence data from children and their parents. At presence of sequence errors, low-coverage parental sequence data may lead to lower power than parental genotype data. PMID- 28726281 TI - Validity and reliability of the Turkish Adherence to Refills and Medications Scale. AB - AIMS: The aim of the study was to create a Turkish version of the Adherence to Refills and Medications Scale (ARMS-7) and to examine its validity and reliability. METHODS: The sample of this methodological type study consisted of 100 Turkish patients with chronic disease. In the evaluation of data, the content validity index, Cronbach alpha, test-retest, item total score correlation, exploratory and confirmatory factor analyses, and adherence statistics were used. RESULTS: The scale's content validity index was 0.94, its Kendal W goodness-of fit test was 0.188 (P = .246), its Cronbach alpha coefficient was 0.75, and its item total score correlation was between 0.32 and 0.59 (P < .001). The test retest reliability was also satisfactory with interclass correlation coefficients higher than 0.75. CONCLUSION: The Turkish version of the ARMS-7 is a reliable and valid instrument that can be used in the evaluation of attitudes to adherence to medications and refills based on self-reporting by the chronically ill. PMID- 28726282 TI - Dermoscopy of pigmented invasive ductal carcinoma mimicking basal cell carcinoma. PMID- 28726283 TI - Vocal and gestural productions of 24-month-old children with sex chromosome trisomies. AB - BACKGROUND: Children with sex chromosome trisomies (SCT) frequently show problems in language development. However, a clear description of the communicative patterns of these children is still lacking. AIMS: To describe the first stages of language development in children with SCT in comparison with those in typically developing (TD) children. The purpose was to verify the existence of possible differences in communicative skills (in both vocal and gestural modality) and identify the presence of possible early predictors (i.e., low vocabulary size and low gesture production) of later language impairment in children with SCT. METHODS & PROCEDURES: Fifteen 24-month-old children with SCT (eight males with Klinefelter syndrome (KS) and seven females with triple X syndrome (TX)) and fifteen 24-month-old TD children (eight males and seven females) participated in the study. Their spontaneous communicative productions were assessed during a semi-structured play session in interaction with a parent. In addition, their vocabulary size was assessed using a parental report (the Italian version of the MacArthur Communicative Development Inventories). OUTCOMES & RESULTS: With regards to their vocabulary size, 60% of children with SCT (75% of children with KS and 43% of children with TX) were at risk for language impairments (i.e., they had a vocabulary size smaller than 50 words). In addition, TD children showed better lexical and syntactic skills than children with SCT in their spontaneous communicative productions. However, the production of communicative gestures was higher in children with SCT than in TD children. Boys with KS appeared to differ from TD males in more aspects of communication than girls with TX differed from TD females. CONCLUSIONS & IMPLICATIONS: The study showed the importance of early detection of language risk factors in children with SCT, while also considering the use of compensatory strategies (e.g., the use of communicative gestures). PMID- 28726284 TI - Alexithymia among Jordanian university students: Its prevalence and correlates with depression, anxiety, stress, and demographics. AB - PURPOSE: The aim of the article is to identify the prevalence, levels, and associated factors of alexithymia among Jordanian university students. DESIGN AND METHODS: Using stratified cluster random sampling, data were collected from 492 students using Toronto Alexithymia Scale (TAS-20), and Depression, Anxiety, and Stress Scale (DASS-21). FINDINGS: The prevalence of alexithymia, depression, anxiety, and stress were 24.6, 28.5, 38.4, and 22.6%, respectively, and were all higher among females. Alexithymia correlated with five factors: depression, anxiety, stress, female gender, and satisfaction with life. PRACTICAL IMPLICATIONS: There is a need for screening and interventional programs that prevent or alleviate the symptoms of alexithymia, depression, anxiety, and stress among university students. PMID- 28726285 TI - A cross-sectional analysis of executive function in Down syndrome from 2 to 35 years. AB - BACKGROUND: Previous research has indicated a unique profile of executive function (EF) in children and adolescents with Down syndrome (DS). However, there is a paucity of research on EF in adults with DS. This study aimed to gain a broader understanding of strengths and weaknesses in EF in DS from 2 to 35 years. METHOD: Parents of 112 individuals with DS between 2 and 35 years participated in this study. Parents either completed the Behaviour Rating Inventory of Executive Function - for individuals 6+ years - or the Behaviour Rating Inventory of Executive Function Preschool Version - for children 2-5 years. RESULTS: Results suggest not only overall difficulties but also patterns of strength and weakness within EF for individuals with DS. For the 2 to 5-year-old group, emotional control and shift were relative strengths, planning/organisation and inhibit were intermediate skills, and working memory was a relative weakness. For the 6 to 18 year-old group, emotional control and organisation of materials were relative strengths, inhibit and initiate were intermediate skills, and working memory, monitor, planning/organisation, and shift were relative weaknesses. Most abilities were consistent from 2 to 18 years, except shift, which decreased in preadolescence before beginning to recover in adolescence. Across the full age range (2-35 years), composite scores indicated quadratic trends in inhibit, working memory, and planning/organisation, and a cubic trend in shift, with EF abilities generally declining in middle childhood before recovering in adulthood. CONCLUSIONS: This study extends previous research on EF in DS by providing an initial description of EF profiles across the lifespan. More longitudinal and behavioural research is needed to further characterise the development of EF in DS. PMID- 28726286 TI - A new sample preparation and separation combination for the precise, accurate, and simultaneous determination of uracil and dihydrouracil in human plasma by reversed-phase HPLC. AB - We have developed an efficient procedure and detection method using reversed phase high-performance liquid chromatography for the simultaneous measurement of uracil and dihydrouracil in human plasma. The procedure, including chromatographic conditions and sample preparation, was optimized and validated. Optimization of the sample preparation included deproteinization, extraction, and cleanup. A new sample preparation method which resulted in an improved extraction yield of analytes and significantly reduced interference at low-wavelength UV detection was developed. The developed method was validated for specificity, linearity, limits of detection and quantitation, precision, and accuracy. All calibration curves showed excellent linear regression (R2 > 0.9990) within the testing range. The limit of detection for uracil and dihydrouracil was 2.5 and 5.0 ng/mL, respectively. The extraction yields were >94% for uracil and 91% for dihydrouracil. Intra- and interassay precision and accuracy for uracil and dihydrouracil were lower than 8% at all tested concentrations. The proposed method was successfully applied to measure plasma concentrations of uracil and dihydrouracil in colorectal cancer patients scheduled to receive fluoropyrimidine based chemotherapy. PMID- 28726288 TI - Hot dogs: High ambient temperatures impact reproductive success in a tropical carnivore. AB - Climate change imposes an urgent need to recognise and conserve the species likely to be worst affected. However, while ecologists have mostly explored indirect effects of rising ambient temperatures on temperate and polar species, physiologists have predicted direct impacts on tropical species. The African wild dog (Lycaon pictus), a tropical species, exhibits few of the traits typically used to predict climate change vulnerability. Nevertheless, we predicted that wild dog populations might be sensitive to weather conditions, because the species shows strongly seasonal reproduction across most of its geographical range. We explored associations between weather conditions, reproductive costs, and reproductive success, drawing on long-term wild dog monitoring data from sites in Botswana (20 degrees S, 24 years), Kenya (0 degrees N, 12 years), and Zimbabwe (20 degrees S, 6 years). High ambient temperatures were associated with reduced foraging time, especially during the energetically costly pup-rearing period. Across all three sites, packs which reared pups at high ambient temperatures produced fewer recruits than did those rearing pups in cooler weather; at the non-seasonal Kenya site such packs also had longer inter-birth intervals. Over time, rising ambient temperatures at the (longest-monitored) Botswana site coincided with falling wild dog recruitment. Our findings suggest a direct impact of high ambient temperatures on African wild dog demography, indicating that this species, which is already globally endangered, may be highly vulnerable to climate change. This vulnerability would have been missed by simplistic trait-based assessments, highlighting the limitations of such assessments. Seasonal reproduction, which is less common at low latitudes than at higher latitudes, might be a useful indicator of climate change vulnerability among tropical species. PMID- 28726287 TI - The sound and the fury: Late positive potential is sensitive to sound affect. AB - Emotion is an emergent construct of multiple distinct neural processes. EEG is uniquely sensitive to real-time neural computations, and thus is a promising tool to study the construction of emotion. This series of studies aimed to probe the mechanistic contribution of the late positive potential (LPP) to multimodal emotion perception. Experiment 1 revealed that LPP amplitudes for visual images, sounds, and visual images paired with sounds were larger for negatively rated stimuli than for neutrally rated stimuli. Experiment 2 manipulated this audiovisual enhancement by altering the valence pairings with congruent (e.g., positive audio + positive visual) or conflicting emotional pairs (e.g., positive audio + negative visual). Negative visual stimuli evoked larger early LPP amplitudes than positive visual stimuli, regardless of sound pairing. However, time frequency analyses revealed significant midfrontal theta-band power differences for conflicting over congruent stimuli pairs, suggesting very early (~500 ms) realization of thematic fidelity violations. Interestingly, late LPP modulations were reflective of the opposite pattern of congruency, whereby congruent over conflicting pairs had larger LPP amplitudes. Together, these findings suggest that enhanced parietal activity for affective valence is modality independent and sensitive to complex affective processes. Furthermore, these findings suggest that altered neural activities for affective visual stimuli are enhanced by concurrent affective sounds, paving the way toward an understanding of the construction of multimodal affective experience. PMID- 28726289 TI - In this August issue. PMID- 28726292 TI - (In)Visibility Online: The Benefits of Online Patient Forums for People with a Hidden Illness: The Case of Multiple Chemical Sensitivity (MCS). AB - Sufferers of medically unexplained conditions that are not observable in the clinic can experience multiple layers of invisibility: a lack of biomedical diagnosis; legal skepticism; political disinterest; and a loss of their prior social identity. For those with environmental sensitivities, this is compounded by literal hiddenness due to often being housebound. Drawing on an online survey of people with multiple chemical sensitivity, this article examines how the everyday experience of invisibility is mitigated by engaging with other patients online. Respondents used online forums to undertake various forms of "visibility work," including attempts to crystallize their suffering into something recognizable medically, legally, and politically, and to reconstruct an identity considered valid and deserving-although the therapeutic potential of online support was contingent on intra-group politics. This study demonstrates that online forums allow biomedicine's "invisible others" to struggle for alternative forms of recognition beyond the clinical gaze. PMID- 28726293 TI - In support of diversity in doctoral nursing education. PMID- 28726291 TI - High-dose Humanin analogue applied during ischemia exerts cardioprotection against ischemia/reperfusion injury by reducing mitochondrial dysfunction. AB - AIM: Although the gold standard treatment for acute myocardial infarction is reperfusion therapy, reperfusion itself can cause myocardial damage via induction of cardiac mitochondrial dysfunction. This can lead to increased myocardial infarct size, arrhythmias, and left ventricular (LV) dysfunction. Recently, a newly discovered peptide, Humanin, has been shown to exert several beneficial effects including antioxidative and antiapoptosis effects. We recently reported that a Humanin analogue (HNG, 84 MUg/kg) given prior to cardiac ischemia exerted cardioprotection against I/R injury, but failed to do so when it was given after ischemia was induced. However, in a clinical setting, patients can only be treated after the onset of ischemia. In this study, we investigated the potential benefit of various doses of HNG therapy (84, 168, 252 MUg/kg) against myocardial I/R injury when applied during ischemia on cardiac arrhythmia, myocardial infarct size, cardiac mitochondrial function, and LV function. METHODS: Myocardial I/R injury was induced in rats by 30-minute left anterior descending coronary artery occlusion, followed by 120-minute of reperfusion. HNG at the different doses were given intravenously at 15 minutes after ischemic onset and also at the onset of reperfusion. RESULTS: HNG (252 MUg/kg) applied during the ischemic period not only increased HN levels in the damaged myocardium, but also significantly decreased cardiac arrhythmia, myocardial infarct size, cardiac mitochondrial dysfunction, and left ventricular dysfunction. These benefits were mediated through the attenuation of cardiac mitochondrial dysfunction. CONCLUSIONS: High dose HN applied during ischemia in rats could exert cardioprotection against I/R injury-induced mitochondrial dysfunction. PMID- 28726294 TI - Screening and structural and functional investigation of a novel ferritin from Phascolosoma esculenta. AB - Ferritins are primary iron storage proteins and play a crucial role in iron storage and detoxification. Yeast two-hybrid method was employed to screen the cDNA library of Phascolosoma esculenta. Sequence of positive colony FER147 was analyzed. The higher similarity and conserved motifs for ferritin indicated that it belonged to a new member of ferritin family. The interaction between Ferritin and Fer147 was further confirmed through co-immunoprecipitation. The pET-28a FER147 prokaryotic expression vector was constructed. The expressed recombinant Fer147 was then isolated, purified, and refolded. When ferritins were treated by different heavy metals, several detection methods, including scanning electron microscopy (SEM), circular dichroism (CD), and inductively coupled plasma-mass spectrometry (ICP-MS) were applied to examine the structures and functions of the new protein Fer147, recombinant P. esculenta ferritin (Rferritin), and natural horse-spleen ferritin (Hferritin). SEM revealed that the three ferritin aggregates changed obviously after different heavy metals treatment, meanwhile, a little different in aggregates were detected when the ferritins were trapped by the same heavy metal. Hence, changes in aggregation structure of the three proteins are related to the nature of the different heavy metals and the interaction between the heavy metals and the three ferritins. CD data suggested that the secondary structure of the three ferritins hardly changed after different heavy metals were trapped. ICP-MS revealed that the ferritins exhibit different enrichment capacities for various heavy metals. In particular, the enrichment capacity of the recombinant Fer147 and Rferritin is much higher than that of hferritin. PMID- 28726296 TI - Mohs micrographic surgery using paraffin sections for the treatment of dermatofibroma of the face: A preliminary case series. PMID- 28726295 TI - Antioxidant defense and oxidative damage vary widely among high-altitude residents. AB - OBJECTIVES: People living at high altitude experience unavoidable low oxygen levels (hypoxia). While acute hypoxia causes an increase in oxidative stress and damage despite higher antioxidant activity, the consequences of chronic hypoxia are poorly understood. The aim of the present study is to assess antioxidant activity and oxidative damage in high-altitude natives and upward migrants. METHODS: Individuals from two indigenous high-altitude populations (Amhara, n = 39), (Sherpa, n = 34), one multigenerational high-altitude population (Oromo, n = 42), one upward migrant population (Nepali, n = 12), and two low-altitude reference populations (Amhara, n = 29; Oromo, n = 18) provided plasma for measurement of superoxide dismutase (SOD) activity as a marker of antioxidant capacity, and urine for measurement of 8-hydroxy-2'-deoxyguanosine (8-OHdG) as a marker of DNA oxidative damage. RESULTS: High-altitude Amhara and Sherpa had the highest SOD activity, while highland Oromo and Nepalis had the lowest among high altitude populations. High-altitude Amhara had the lowest DNA damage, Sherpa intermediate levels, and high-altitude Oromo had the highest. CONCLUSIONS: High altitude residence alone does not associate with high antioxidant defenses; residence length appears to be influential. The single-generation upward migrant sample had the lowest defense and nearly the highest DNA damage. The two high altitude resident samples with millennia of residence had higher defenses than the two with multiple or single generations of residence. PMID- 28726297 TI - Iodine-Promoted Semmler-Wolff Reactions: Step-Economic Access to meta-Substituted Primary Anilines via Aromatization. AB - An atom- and step-economic access to an array of unprotected meta-substituted primary anilines was disclosed using the Semmler-Wolff reaction, promoted by molecular iodine. Therein, noble metal catalysts and inert atmosphere are unnecessary while the forcing reaction conditions and the lengthy synthesis can be avoided. The synthetic utility of this approach is evident in the de novo syntheses of three bioactive molecules with good total yields. PMID- 28726298 TI - FAAH, but not MAGL, inhibition modulates acute TLR3-induced neuroimmune signaling in the rat, independent of sex. AB - Toll-like receptor (TLR)3 is a key component of the innate immune response to viral infection. The present study firstly examined whether sex differences exist in TLR3-induced inflammatory, endocrine, and sickness responses. The data revealed that TLR3-induced expression of interferon- or NFkB-inducible genes (IFN alpha/beta, IP-10, or TNF-alpha), either peripherally (spleen) or centrally (hypothalamus), did not differ between male and female rats, with the exception of TLR3-induced IFN-alpha expression in the spleen of female, but not male, rats 8 hr post TLR3 activation. Furthermore, TLR3 activation increased plasma corticosterone levels, induced fever, and reduced locomotor activity and body weight - effects independent of sex. Thus, the acute-phase inflammatory, endocrine, and sickness responses to TLR3 activation exhibit minimal sex-related differences. A further aim of this study was to examine whether enhancing endocannabinoid tone - namely, 2-arachidonylglycerol (2-AG) or N arachidonoylethanolamine (AEA), exhibited similar effects on TLR3-induced inflammatory responses in male versus female rats. Systemic administration of the monoacylglycerol lipase (MAGL) inhibitor MJN110 and subsequent increases in 2-AG levels did not alter the TLR3-induced increase in IP-10, IRF7, or TNF-alpha expression in the spleen or the hypothalamus of male or female rats. In contrast, the fatty acid amide hydrolase (FAAH) inhibitor URB597 increased levels of AEA and related N-acylethanolamines, an effect associated with the attenuation of TLR3-induced inflammatory responses in the hypothalamus, but not the spleen, of male and female rats. These data support a role for FAAH, but not MAGL, substrates in the modulation of TLR3-induced neuroinflammatory responses, effects independent of sex. PMID- 28726299 TI - ISPAD Guidelines. Managing diabetes in preschool children. PMID- 28726300 TI - Colossal Stability of Gas-Phase Trianions: Super-Pnictogens. AB - Multiply charged negative ions are ubiquitous in nature. They are stable as crystals because of charge compensating cations; while in solutions, solvent molecules protect them. However, they are rarely stable in the gas phase because of strong electrostatic repulsion between the extra electrons. Therefore, understanding their stability without the influence of the environment has been of great interest to scientists for decades. While much of the past work has focused on dianions, work on triply charged negative ions is sparse and the search for the smallest trianion that is stable against spontaneous electron emission or fragmentation continues. Stability of BeB11 (X)123- (X=CN, SCN, BO) trianions is demonstrated in the gas phase, with BeB11 (CN)123- exhibiting colossal stability against electron emission by 2.65 eV and against its neutral adduct by 15.85 eV. The unusual stability of these trianions opens the door to a new class of super-pnictogens with potential applications in aluminum-ion batteries. PMID- 28726301 TI - A rapid 3D fat-water decomposition method using globally optimal surface estimation (R-GOOSE). AB - PURPOSE: To improve the graph model of our previous work GOOSE for fat-water decomposition with higher computational efficiency and quantitative accuracy. METHODS: A modification of the GOOSE fat water decomposition algorithm is introduced while the global convergence guarantees of GOOSE are still inherited to minimize fat-water swaps and phase wraps. In this paper, two non-equidistant graph optimization frameworks are proposed as a single-step framework termed as rapid GOOSE (R-GOOSE), and a multi-step framework termed as multi-scale R-GOOSE (mR-GOOSE). Both frameworks contain considerably less graph connectivity than GOOSE, resulting in a great computation reduction thus making it readily applicable to multidimensional fat water applications. The quantitative accuracy and computational time of the novel frameworks are compared with GOOSE on the 2012 ISMRM Challenge datasets to demonstrate the improvement in performance. RESULTS: Both frameworks accomplish the same level of high accuracy as GOOSE among all datasets. Compared to 100 layers in GOOSE, only 8 layers were used in the new graph model. Computational time is lowered by an order of magnitude to around 5 s for each dataset in (mR-GOOSE), R-GOOSE achieves an average run-time of 8 s. CONCLUSION: The proposed method provides fat-water decomposition results with a lower run-time and higher accuracy compared to the previously proposed GOOSE algorithm. Magn Reson Med 79:2401-2407, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28726302 TI - A multicenter study to evaluate oxidative stress by oxidation-reduction potential, a reliable and reproducible method. AB - Seminal oxidative stress (OS) is well-known to affect male fertility status. The discrepancy in OS measurement has hindered its clinical use as a quality indicator for semen. Some tests measured single markers of oxidants or reductants, leading to lack of standardization of results. Oxidation-reduction potential (ORP) is a better representative for OS as it provides an overall measure of the activity of both oxidants and reductants. ORP assessment by MiOXSYS has been introduced as a measure of OS with high specificity in differentiating fertile from infertile semen samples. This is a retrospective study comparing data from semen analysis and ORP measurements between two andrology laboratories in the USA and Qatar over a period of 12 months. The same protocol was followed by both laboratories. The USA dataset contained 194 patients and 51 fertile donors, while the Qatar dataset contained 400 patients and 50 fertile donors. In both datasets and in the combined dataset, the infertile group had significantly lower sperm concentration, total and progressive motility, and normal morphology as well as higher ORP levels compared to fertile men (p < 0.05). When comparing data from both centers, the infertile group showed significant difference between both datasets regarding progressive motility and morphology (p < 0.001). Also, the percentage of patients with abnormal semen volume, sperm count, total and progressive motility were significantly different between both datasets (p < 0.05). ORP levels showed no significant difference between both datasets (p < 0.08). ROC analysis indicated that ORP cutoff value of 1.42 mV/106 /mL in the USA group, Qatar group, and combined dataset can accurately differentiate fertile from infertile semen groups. Although other semen parameters showed significant differences between the two centers, ORP remained consistent in both datasets individually or in combined data. This proves its reproducibility and reliability. PMID- 28726303 TI - The ecology of white-handed and pileated gibbons in a zone of overlap and hybridization in Thailand. AB - OBJECTIVES: The study of related species in contact zones can elucidate what factors mediate species coexistence and geographical distributions. We investigated niche overlap and group interactions of two gibbon species and their hybrids co-occurring in a zone of overlap and hybridization. METHODS: The location, composition and behavior of white-handed, pileated, and mixed-species gibbon groups were studied by following them during 31 consecutive months in a relatively large part of the contact zone. RESULTS: Twenty groups of white-handed gibbon were mapped followed by nine groups of pileated gibbons and five mixed species groups. White-handed, pileated and mixed-species groups had similar sizes and composition, ate a high proportion of fruits, shared a large number of species in their diets, and presented similar habitat preferences. Group home range sizes did not differ between species and overlapped little with neighboring groups irrespective of species, and intraspecific and interspecific encounter rates were similar. DISCUSSION: Ecological similarities support that competition between the gibbon species exists and takes the form of interspecific territoriality. However, we could not find any clear mechanism of niche partitioning favoring coexistence between species. Our findings suggest that the contact zone is unstable and is maintained by dispersal inward from groups of the parental species. The relatively low numbers of mixed-species groups and hybrids found suggests a high degree of premating reproductive isolation, perhaps mediated by interspecific miscommunication. The existence of hybrids and backcrosses potentially undetectable from phenotypic characters alone raises the possibility of more widespread introgression than has been evident. Hence, while interspecific territoriality should reduce the rate of gene transfer, it would not necessarily present a barrier to introgression into contiguous populations of the opposite species. PMID- 28726304 TI - Retardation of Antigen Release from DNA Hydrogel Using Cholesterol-Modified DNA for Increased Antigen-Specific Immune Response. AB - Our previous study indicates that cationization of an antigen is effective for sustained release of both immunostimulatory DNA containing unmethylated cytosine phosphate-guanine (CpG) dinucleotides, or CpG DNA, and antigen from a DNA hydrogel. Another approach to sustained antigen release would increase the applicability and versatility of the system. In this study, a hydrophobic interaction-based sustained release system of ovalbumin (OVA), a model antigen, from immunostimulatory CpG DNA hydrogel is developed by the use of cholesterol modified DNA and urea-denatured OVA (udOVA). Cholesterol-modified DNA forms a hydrogel, Dgel(chol), and induces IL-6 mRNA expression in mouse skin after intradermal injection, as DNA without cholesterol does. Cholesterol-modified DNA associated with OVA and denaturation of OVA using urea increases the interaction. The release of udOVA from Dgel(chol) is significantly slower than that from DNA hydrogel with no cholesterol, Dgel. Moreover, intratumoral injections of udOVA/Dgel(chol) significantly inhibit the growth of EG7-OVA tumors in mice. These results indicate that sustained release of antigen from Dgel can be achieved by the combination of urea denaturation and cholesterol modification, and retardation of antigen release is effective to induce antigen-specific cancer immunity. PMID- 28726306 TI - Asymmetric Synthesis of Chiral Cyclopentanes Bearing an All-Carbon Quaternary Stereocenter by Zirconium-Catalyzed Double Carboalumination. AB - Herein, we report a zirconium-catalyzed enantio- and diastereoselective inter/intramolecular double carboalumination of unactivated 2-substituted 1,5 dienes, which provides efficient and direct access to chiral cyclopentanes through the generation of two stereocenters, including one all-carbon quaternary stereocenter, generally with excellent diastereo- and high enantioselectivity. This tandem carboalumination process creates two new C-C bonds as well as one C Al bond, which can be oxidized in situ with O2 or hydrolyzed. Furthermore, the obtained chiral cyclopentanes can be readily functionalized to provide various chiral compounds. PMID- 28726305 TI - MYB30 transcription factor regulates oxidative and heat stress responses through ANNEXIN-mediated cytosolic calcium signaling in Arabidopsis. AB - Cytosolic calcium signaling is critical for regulating downstream responses in plants encountering unfavorable environmental conditions. In a genetic screen for Arabidopsis thaliana mutants defective in stress-induced cytosolic free Ca2+ ([Ca2+ ]cyt ) elevations, we identified the R2R3-MYB transcription factor MYB30 as a regulator of [Ca2+ ]cyt in response to H2 O2 and heat stresses. Plants lacking MYB30 protein exhibited greater elevation of [Ca2+ ]cyt in response to oxidative and heat stimuli. Real-time reverse transcription-polymerase chain reaction (RT-PCR) results indicated that the expression of a number of ANNEXIN (ANN) genes, which encode Ca2+ -regulated membrane-binding proteins modulating cytosolic calcium signatures, were upregulated in myb30 mutants. Further analysis showed that MYB30 bound to the promoters of ANN1 and ANN4 and repressed their expression. myb30 mutants were sensitive to methyl viologen (MV) and heat stresses. The H2 O2 - and heat-induced abnormal [Ca2+ ]cyt in myb30 was dependent on the function of ANN proteins. Moreover, the MV and heat sensitivity of myb30 was suppressed in mutants lacking ANN function or by application of LaCl3 , a calcium channel blocker. These results indicate that MYB30 regulates oxidative and heat stress responses through calcium signaling, which is at least partially mediated by ANN1 and ANN4. PMID- 28726307 TI - Naturally occurring circadian rhythm and sleep duration are related to executive functions in early adulthood. AB - Experimental sleep deprivation studies suggest that insufficient sleep and circadian misalignment associates with poorer executive function. It is not known whether this association translates to naturally occurring sleep patterns. A total of 512 of full-term-born members of the Arvo Ylppo Longitudinal Study [mean age = 25.3, standard deviation (SD) = 0.65] (44.3% men) wore actigraphs to define sleep duration, its irregularity and circadian rhythm (sleep mid-point) during a 1-week period (mean 6.9 nights, SD = 1.7). Performance-based executive function was assessed with the Trail-Making Test, Conners' Continuous Performance Test and Stroop. The self-rated adult version of Behavior Rating Inventory of Executive Function was used to assess trait-like executive function. We found that performance-based and self-reported trait-like executive function correlated only modestly (all correlations <=0.17). Shorter sleep duration associated with more commission errors. Later circadian rhythm associated with poorer trait-like executive function, as indicated by the Brief Metacognitive Index and the Behavior Regulation Index. Those belonging to the group with the most irregular sleep duration performed slower than others in the Trail-Making Test Part A. All associations were adjusted for sex, age, socioeconomic status and body mass index. In conclusion, naturally occurring insufficient sleep and later circadian rhythm showed modest associations with poorer executive function. Shorter habitual sleep duration was associated with lower scores of performance-based tests of executive function, and later circadian rhythm was associated mainly with poorer trait-like executive function characteristics. Our findings suggest additionally that sleep duration and circadian rhythm associate with different domains of executive function, and there are no additive effects between the two. PMID- 28726308 TI - The collateral venous system in late pregnancy: A systematic review of the literature. AB - Recent literature has reported an association between maternal supine sleep position and stillbirth during late pregnancy. In this position the gravid uterus almost completely obstructs the inferior vena cava. A small number of women experience supine hypotension, thought to be due in part to inadequate collateral venous circulation. The aim of this paper is to review the literature describing the anatomy of the collateral venous system and in particular the azygos system, the abdominal portion of which has not been well studied. A systematic review was conducted using the electronic databases: Medline, Embase, Scopus, and Google Scholar. Relevant anatomical and radiological literature concerning the azygos system in particular was reviewed. The search was limited to adult human studies only. The collateral venous system can be divided into superficial, intermediate and deep systems. The azygos system in particular provides immediate collateral venous circulation in the event of acute inferior vena caval obstruction. The abdominal portion of this pathway, including the ascending lumbar vein, has not been well studied and there are certain variations that can render it ineffective. In conclusion, the collateral venous system provides an alternative route for blood to flow back to the systemic circulation when acute occlusion of the inferior vena cava occurs in the supine position during late pregnancy. However, certain anatomical variations can render this pathway ineffective, and this could have implications for the development of supine hypotension and stillbirth in late pregnancy. Clin. Anat. 30:1087-1095, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28726309 TI - Religion, Sexual Orientation, and Suicide Attempts Among a Sample of Suicidal Adolescents. AB - Despite condemnation of same-sex attraction by certain religious groups, few studies have explored the relationship between religion, same-sex attraction, and suicidality. This study examined the moderating effect of same-sex attraction on the relationship between parent/adolescent religiosity and suicide ideation/attempts in a suicidal adolescent sample (N = 129). Linear and negative binomial regressions tested the effects of a two-way dichotomous (same-sex attraction, yes/no) by continuous (religiosity) interaction on ideation and attempts, respectively. The interaction was not significant for ideation. However, high religiosity was associated with more attempts in youth reporting same-sex attraction but fewer attempts in those reporting opposite-sex attraction only. PMID- 28726310 TI - Full-length sequencing of the HLA region identified a novel allele, HLA-B*52:70. AB - One nucleotide substitution at position 276 of HLA-B*52:01:01 results in a novel allele, HLA-B*52:70. PMID- 28726311 TI - GABA-, histamine-, and FMRFamide-immunoreactivity in the visual, vestibular and central nervous systems of Hermissenda crassicornis. AB - Hermissenda crassicornis is a model for studying the molecular and cellular basis for classical conditioning, based on its ability to associate light with vestibular stimulation. We used confocal microscopy to map histamine (HA), FMRF amide, and gamma-aminobutyric acid (GABA) immunoreactivity in the central nervous system (CNS), eyes, optic ganglia and statocysts of the nudibranchs. For HA immunoreactivity, we documented both consistently and variably labeled CNS structures across individuals. We also noted minor differences in GABA immunoreactivity in the CNS compared to previous work on Hermissenda. Contrary to expectations, we found no evidence for GABA inside the visual or vestibular systems. Instead, we found only FMRFamide- and HA immunoreactivity (FMRFamide: 4 optic ganglion cells, 4-5 hair cells; HA: 3 optic ganglion cells, 8 hair cells). Overall, our results can act as basis for comparisons of nervous systems across nudibranchs, and suggest further exploration of intraspecific plasticity versus evolutionary changes in gastropod nervous systems. PMID- 28726313 TI - Selectivity enhancements in gel-based DNA-nanoparticle assays by membrane-induced isotachophoresis: thermodynamics versus kinetics. AB - Selectivity against mutant nontargets with a few mismatches remains challenging in nucleic acid sensing. Sensitivity enhancement by analyte concentration does not improve selectivity because it affects targets and nontargets equally. Hydrodynamic or electrical shear enhanced selectivity is often accompanied by substantial losses in target signals, thereby leading to poor limits of detection. We introduce a platform based on depletion isotachophoresis in agarose gel generated by an ion-selective membrane that allows both selectivity and sensitivity enhancement with a two-step assay involving concentration polarization at an ion-selective membrane. By concentrating both the targets and probe-functionalized nanoparticles by ion enrichment at the membrane, the effective thermodynamic dissociation constant is lowered from 40 nM to below 500 pM, and the detection limit is 10 pM as reported previously. A dynamically optimized ion depletion front is then generated from the membrane with a high electrical shear force to selectively and irreversibly dehybridize nontargets. The optimized selectivity against a two-mismatch nontarget (in a 35-base pairing sequence) is shown to be better than the thermodynamic equilibrium selectivity by more than a hundred-fold, such that there is no detectable signal from the two mismatch nontarget. We offer empirical evidence that irreversible cooperative dehybridization plays an important role in this kinetic selectivity enhancement and that mismatch location controls the optimum selectivity even when there is little change in the corresponding thermodynamic dissociation constant. PMID- 28726314 TI - Dermoscopy is useful for the diagnosis of milia-like idiopathic calcinosis cutis. PMID- 28726312 TI - Spinal Cord Stimulator Related Infections: Findings From a Multicenter Retrospective Analysis of 2737 Implants. AB - INTRODUCTION: Surgical site infection is a potential complication of spinal cord stimulator (SCS) implantation. Current understanding of the epidemiology, diagnosis, and treatment of these infections is based largely on small clinical studies, many of which are outdated. Evidence-based guidelines for management of SCS-related infections thus rely instead on expert opinion, case reports, and case series. In this study, we aim to provide a large scale retrospective study of infection management techniques specifically for SCS implantation. METHODS: A multicenter retrospective study of SCS implants performed over a seven-year period at 11 unique academic and non-academic institutions in the United States. All infections and related complications in this cohort were analyzed. RESULTS: Within our study of 2737 SCS implant procedures, we identified all procedures complicated by infection (2.45%). Localized incisional pain and wound erythema were the most common presenting signs. Laboratory studies were performed in the majority of patients, but an imaging study was performed in less than half of these patients. The most common causative organism was Staphylococcus aureus and the IPG pocket was the most common site of an SCS-related infection. Explantation was ultimately performed in 52 of the 67 patients (77.6%). Non-explantation salvage therapy was attempted in 24 patients and was successful in resolving the infection in 15 patients without removal of SCS hardware components. DISCUSSION: This study provides current data regarding SCS related infections, including incidence, diagnosis, and treatment. PMID- 28726315 TI - Biomineralization of gold by Mucor plumbeus: The progress in understanding the mechanism of nanoparticles' formation. AB - This contribution describes the deposition of gold nanoparticles by microbial reduction of Au(III) ions using the mycelium of Mucor plumbeus. Biosorption as the major mechanism of Au(III) ions binding by the fungal cells and the reduction of them to the form of Au(0) on/in the cell wall, followed by the transportation of the synthesized gold nanoparticles to the cytoplasm, is postulated. The probable mechanism behind the reduction of Au(III) ions is discussed, leading to the conclusion that this process is nonenzymatic one. Chitosan of the fungal cell wall is most likely to be the major molecule involved in biomineralization of gold by the mycelium of M. plumbeus. Separation of gold nanoparticles from the cells has been carried out by the ultrasonic disintegration and the obtained nanostructures were characterized by UV-vis spectroscopy and transmission electron micrograph analysis. (c) 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:1381-1392, 2017. PMID- 28726316 TI - Deprotonation states of the two active site water molecules regulate the binding of protein phosphatase 5 with its substrate: A molecular dynamics study. AB - Protein phosphatase 5 (PP5), mainly localized in human brain, can dephosphorylate tau protein whose high level of phosphorylation is related to Alzheimer's disease. Similar to other protein phosphatases, PP5 has a conserved motif in the catalytic domain that contains two binding sites for manganese (Mn2+ ) ions. Structural data indicate that two active site water molecules, one bridging the two Mn2+ ions and the other terminally coordinated with one of the Mn2+ ions (Mn1), are involved in catalysis. Recently, a density functional theory study revealed that the two water molecules can be both deprotonated to keep a neutral active site for catalysis. The theoretical study gives us an insight into the catalytic mechanism of PP5, but the knowledge of how the deprotonation states of the two water molecules affect the binding of PP5 with its substrate is still lacking. To approach this problem, molecular dynamics simulations were performed to model the four possible deprotonation states. Through structural, dynamical and energetic analyses, the results demonstrate that the deprotonation states of the two water molecules affect the structure of the active site including the distance between the two Mn2+ ions and their coordination, impact the interaction energy of residues R275, R400 and H304 which directly interact with the substrate phosphoserine, and mediate the dynamics of helix alphaJ which is involved in regulation of the enzyme's activity. Furthermore, the deprotonation state that is preferable for PP5 binding of its substrate has been identified. These findings could provide new design strategy for PP5 inhibitor. PMID- 28726318 TI - Corrigendum for Koons et al. (2016) DOI: 10.1111/ele.12628. PMID- 28726317 TI - Should mothers provision their offspring equally? A manipulative field test. AB - Within-brood variation in offspring size is universal, but its causes are unclear. Theoretical explanations for within-brood variation commonly invoke bet hedging, although alternatives consider the role of sibling competition. Despite abundant theory, empirical manipulations of within-brood variation in offspring size are rare. Using a field experiment, we investigate the consequences of unequal maternal provisioning for both maternal and offspring fitness in a marine invertebrate. We create experimental broods of siblings with identical mean, but different variance, in offspring size, and different sibling densities. Overall, more-variable broods had higher mean performance than less-variable broods, suggesting benefits of unequal provisioning that arise independently of bet hedging. Complementarity effects drove these benefits, apparently because offspring-size variation promotes resource partitioning. We suggest that when siblings compete for the same resources, and offspring size affects niche usage, the production of more-variable broods can provide greater fitness returns given the same maternal investment; a process unanticipated by the current theory. PMID- 28726319 TI - Ultrastructure of Lingual Papillae in Common Chimpanzee (Pan troglodytes) Foetus, Newborn and Adult Specimens. AB - Among primates, the two recognized species of chimpanzees (common chimpanzee, Pan troglodytes; pygmy chimpanzee, Pan paniscus) are considered to be the most similar to humans. Importantly, in mammals, the food intake behaviour largely determines the tongue morphology, including the type, proportion and distribution of gustatory and non-gustatory tongue papillae. The lingual papillae form during its development and mature in post-natal life depending on the different feeding. In this study, we have used scanning electron microscopy to analyse the age related changes in the lingual papillae of foetal, newborn and adult P. troglodytes. Four main types of lingual papillae, denominated filiform, fungiform, foliate and vallate, and one subtype of filiform papillae called conical papillae, were found. The main age-related changes observed in all kinds of papillae were a progressive keratinization and morphological complexity along the lifespan. During the foetal period, there was scarce keratinization, which progressively increases in young animals to adulthood. The number of filiform increased with ageing, and both filiform and fungiform papillae in adult tongues are divided into pseudopapillae. On the other hand, the vallate papillae vary from smooth simple surfaces in foetal tongues to irregular surfaces with grooves and pseudopapillae (microscopic papilla-shaped formations within the papilla itself) in adults. These results describe for the first time the age-related variations in the three-dimensional aspect of lingual papillae of the chimpanzee tongue and provide new data to characterize more precisely these structures in the human closest specie. PMID- 28726320 TI - Assessing neurodevelopmental effects of arsenolipids in pre-differentiated human neurons. AB - SCOPE: In the general population exposure to arsenic occurs mainly via diet. Highest arsenic concentrations are found in seafood, where arsenic is present predominantly in its organic forms including arsenolipids. Since recent studies have provided evidence that arsenolipids could reach the brain of an organism and exert toxicity in fully differentiated human neurons, this work aims to assess the neurodevelopmental toxicity of arsenolipids. METHODS AND RESULTS: Neurodevelopmental effects of three arsenic-containing hydrocarbons (AsHC), two arsenic-containing fatty acids (AsFA), arsenite and dimethylarsinic acid (DMAV ) were characterized in pre-differentiated human neurons. AsHCs and arsenite caused substantial cytotoxicity in a similar, low concentration range, whereas AsFAs and DMAV were less toxic. AsHCs were highly accessible for cells and exerted pronounced neurodevelopmental effects, with neurite outgrowth and the mitochondrial membrane potential being sensitive endpoints; arsenite did not substantially decrease those two endpoints. In fully differentiated neurons, arsenite and AsHCs caused neurite toxicity. CONCLUSION: These results indicate for a neurodevelopmental potential of AsHCs. Taken into account the possibility that AsHCs might easily reach the developing brain when exposed during early life, neurotoxicity and neurodevelopmental toxicity cannot be excluded. Further studies are needed in order to progress the urgently needed risk assessment. PMID- 28726321 TI - The prevalence of transpancreatic common hepatic artery and coexisting variant anatomy. AB - We studied the prevalence of the transpancreatic common hepatic artery (tp-CHA) and coexisting variant anatomy. The study group comprised 788 consecutive liver transplant donor candidates who had undergone thin-section multidetector-row computed tomography (MDCT) studies to investigate vascular anatomy. Multiplanar reformatted (MPR) images obtained from the arterial phase were retrospectively reviewed to assess the presence/absence of the tp-CHA. Five cases of tp-CHA with pancreaticobiliary tumors were also included in an investigation of the presence/absence of variant hepatic arteries, celiac stenosis, and circumportal pancreas. Three of the 788 (0.38%) donor candidates had a tp-CHA. Overall, eight tp-CHA cases were assessed for coexisting variant anatomy. Seven of these eight cases had a hepatomesenteric trunk, six had celiac stenosis, and two had a circumportal pancreas. The prevalence of the tp-CHA was 0.38% (approx. one in 260 in normal populations). A tp-CHA can commonly be associated with a hepatomesenteric trunk and celiac stenosis. A circumportal pancreas can also coexist with a tp-CHA. Clin. Anat. 31:598-604, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 28726322 TI - Screening and prevention of preterm birth: what is a clinician to do? PMID- 28726323 TI - Characterization of a cathepsin D protease from CHO cell-free medium and mitigation of its impact on the stability of a recombinant therapeutic protein. AB - During purification process development of a recombinant therapeutic protein, an endoproteolytic activity endogenous to the Chinese hamster ovary (CHO) cells and leading to degradation at particular hydrophobic amino acid residues (e.g., Phe and Trp) was observed when processing at acidic pH. The presence of residual levels of protease activity in purified protein batches affected the inherent activity of the product when stored as a solution. To develop a robust purification strategy to minimize this undesirable impact, identification and characterization of this protease was essential to ultimately ensure that a solution formulation was stable for many years. A protease was isolated from CHO cell-free medium (CFM) using a combination of immobilized pepstatin-A agarose chromatography and size exclusion chromatography (SEC). The isolated protease has significant proteolytic activity at pH ~ 3 to neutral pH and was identified as cathepsin D by mass spectrometry. Analytical SEC, chip-based capillary gel electrophoresis, imaged capillary isoelectric focusing (cIEF), and circular dichroism (CD) spectropolarimetry analyses were performed for additional characterization of the protease. The identification and characterization of this protease enabled the development of a robust purification process by implementation of a controlled temperature inactivation unit operation (heat inactivation) that enabled essentially complete inactivation of the protease, resulting in the production of a stable drug product that had not been possible using column chromatography alone. (c) 2017 American Institute of Chemical Engineers Biotechnol. Prog., 34:120-129, 2018. PMID- 28726324 TI - Eczema exacerbation caused by Coxsackie virus A6. PMID- 28726326 TI - Speechless. PMID- 28726325 TI - Subacute cutaneous lupus erythematosus induced by nivolumab. PMID- 28726327 TI - Changing Metrics of Organ Procurement Organization Performance in Order to Increase Organ Donation Rates in the United States. AB - The shortage of deceased-donor organs is compounded by donation metrics that fail to account for the total pool of possible donors, leading to ambiguous donor statistics. We sought to assess potential metrics of organ procurement organizations (OPOs) utilizing data from the Nationwide Inpatient Sample (NIS) from 2009-2012 and State Inpatient Databases (SIDs) from 2008-2014. A possible donor was defined as a ventilated inpatient death <=75 years of age, without multi-organ system failure, sepsis, or cancer, whose cause of death was consistent with organ donation. These estimates were compared to patient-level data from chart review from two large OPOs. Among 2,907,658 inpatient deaths from 2009-2012, 96,028 (3.3%) were a "possible deceased-organ donor." The two proposed metrics of OPO performance were: (1) donation percentage (percentage of possible deceased-donors who become actual donors; range: 20.0-57.0%); and (2) organs transplanted per possible donor (range: 0.52-1.74). These metrics allow for comparisons of OPO performance and geographic-level donation rates, and identify areas in greatest need of interventions to improve donation rates. We demonstrate that administrative data can be used to identify possible deceased donors in the US and could be a data source for CMS to implement new OPO performance metrics in a standardized fashion. PMID- 28726328 TI - Dante's 'Two Suns': Reflections on the psychological sources of the Divine Comedy. AB - The power of Dante's Divine Comedy is unmistakable, but surprising in view of its theological structure and assumptions that are no longer current among most modern readers. This paper suggests that its power derives from the deep psychological truthfulness with which Dante deals with the painful personal crisis that underlies the poem and is his starting point. It attempts to clarify what may have constituted that crisis, and why the structure of the Comedy, and in particular its use of two guides, Virgil and Beatrice, who might be thought a somewhat incompatible pairing, point significantly to the nature of the solution Dante arrived at. In particular it suggests that the puzzling fictions to do with Statius in the Purgatorio are a clue to Dante's own difficulties in bridging the classical and Christian traditions, and that his highly original solution to these difficulties, by no means conforming to conventional Christian orthodoxy in the 13th/14th century, was needed with special urgency in a time of pervasive civil conflict. PMID- 28726329 TI - Sorafenib-induced erythema annulare centrifugum with spontaneous resolution after skin biopsy. PMID- 28726330 TI - Synthetic Analogues of Nitrogenase Metallocofactors: Challenges and Developments. AB - Nitrogenase is the only known biological system capable of reducing N2 to NH3 , which is a critical component of bioavailable nitrogen fixation. Since the discovery of discrete iron-sulfur metalloclusters within the nitrogenase MoFe protein, synthetic inorganic chemists have sought to reproduce the structural features of these clusters in order to understand how they facilitate the binding, activation and hydrogenation of N2 . Through the decades following the initial identification of these clusters, significant progress has been made to synthetically replicate certain compositional and functional aspects of the biogenic clusters. Although much work remains to generate synthetic iron-sulfur clusters that can reduce N2 to NH3 , the insights borne from past and recent developments are discussed in this concept article. PMID- 28726331 TI - Novel fluid shear-based dissociation device for improved single cell dissociation of spheroids and cell aggregates. AB - Biological industries commonly rely on bioreactor systems for the large-scale production of cells. Cell aggregation, clumping, and spheroid morphology of certain suspension cells make their large-scale culture challenging. Growing stem cells as spheroids is indispensable to retain their stemness, but large spheroids (>500 um diameter) suffer from poor oxygen and nutrient diffusion, ultimately resulting in premature cell death in the centers of the spheroids. Despite this, most large-scale bioprocesses do not have an efficient method for dissociating cells into single cells, but rely on costly enzymatic dissociation techniques. Therefore, we tested a proof-of-concept fluid shear-based mechanical dissociator that was designed to dissociate stem cell spheroids and aggregates. Our prototype was able to dissociate cells while retaining high viability and low levels of apoptosis. The dissociator also did not impact long-term cell growth or spheroid formation. Thus, the dissociator introduced here has the potential to replace traditional dissociation methods. (c) 2017 American Institute of Chemical Engineers Biotechnol. Prog., 34:293-298, 2018. PMID- 28726332 TI - Hospitalized patients' vs. nurses' assessments of pain intensity and barriers to pain management. AB - AIMS: The aim of the study was to identify if nurses and patients equally assessed pain intensity and patient-related barriers to pain management in hospitalized patients. BACKGROUND: Several studies reported poor to moderate agreement between patient- and nurse-reported pain assessment. Many of these studies focused on a specific patient group. So far, no study studied the level of agreement in the assessment of patient-related barriers between patients and nurses. DESIGN: A cross-sectional study was performed in two hospitals. PARTICIPANTS: Inclusion criteria for patients were: (1) being at least 18 years; (2) understanding the Dutch language; and (3) giving informed consent. All nurses responsible for the participating patients and present at the time of the survey were invited to participate. METHODS: Data were collected between October 2012 - April 2013. Patients and nurses completed the Numeric Rating Scale to measure pain intensity. Patient-related barriers to pain management were measured using the barriers to pain assessment and management scale developed by Elcigil et al. (Journal of Pediatric Hematology Oncology 2011, 33:S33). RESULTS: A moderate agreement between patients and nurses was found for the assessment of pain intensity. Multiple logistic regressions showed a significant association between pain intensity reported by patients and the under-, over- and adequate estimation of pain by nurses. Nurses significantly underrated the belief patients had about pain management. CONCLUSIONS: Nurses should be educated about these beliefs and should be encouraged to actively explore patient-related barriers to pain management with their individual patients. Routine pain assessments should also be encouraged and should be explained to patients. PMID- 28726333 TI - The auditory oddball paradigm revised to improve bedside detection of consciousness in behaviorally unresponsive patients. AB - Active paradigms requiring subjects to engage in a mental task on request have been developed to detect consciousness in behaviorally unresponsive patients. Using auditory ERPs, the active condition consists in orienting patient's attention toward oddball stimuli. In comparison with passive listening, larger P300 in the active condition identifies voluntary processes. However, contrast between these two conditions is usually too weak to be detected at the individual level. To improve test sensitivity, we propose as a control condition to actively divert the subject's attention from the auditory stimuli with a mental imagery task that has been demonstrated to be within the grasp of the targeted patients: navigate in one's home. Twenty healthy subjects were presented with a two-tone oddball paradigm in the three following condition: (a) passive listening, (b) mental imagery, (c) silent counting of deviant stimuli. Mental imagery proved to be more efficient than passive listening to lessen P300 response to deviant tones as compared with the active counting condition. An effect of attention manipulation (oriented vs. diverted) was observed in 19/20 subjects, of whom 18 showed the expected P300 effect and 1 showed an effect restricted to the N2 component. The only subject showing no effect also proved insufficient engagement in the tasks. Our study demonstrated the efficiency of diverting attention using mental imagery to improve the sensitivity of the active oddball paradigm. Using recorded instructions and requiring a small number of electrodes, the test was designed to be conveniently and economically used at the patient's bedside. PMID- 28726334 TI - Insulin sensitivity across the lifespan from obese adolescents to obese adults with impaired glucose tolerance: Who is worse off? AB - OBJECTIVE: Youth type 2 diabetes mellitus (T2DM) occurs decades earlier than adult T2DM and is characterized by high therapeutic failure rates and decreased response to insulin sensitizers suggesting a more severe disease process than in adults. To explain these observations, we hypothesized that insulin resistance is worse in obese youth than adults with impaired glucose tolerance (IGT), a state of high-risk for T2DM. As proof-of-concept, we compared insulin sensitivity between BMI-, sex-, and race-matched obese youth vs adults with IGT. METHODS: This retrospective analysis of IGT youth and adults included 34 obese adolescents matched (2:1) for BMI, sex, and race to 17 adults. Hepatic and peripheral insulin sensitivity were measured by [6,6-2 H2 ]glucose and hyperinsulinemic-euglycemic clamp. Body composition (DEXA) and serum lipid profile were examined. RESULTS: Despite similar percent body fat, obese adolescents had 2-fold higher fasting insulin concentration, lower hepatic (~53%) and peripheral (~42%) insulin sensitivity and lower HDL compared with adults (all P < .01). Surrogate estimate of insulin sensitivity, 1/fasting insulin was lower and HOMA-IR was higher in adolescents vs adults. Adults had a more atherogenic lipid profile with higher total-, LDL-, and non-HDL cholesterol. CONCLUSIONS: Obese youth and adults with IGT differ in that youth are more insulin resistant than adults in spite of similar adiposity. This could potentially explain the earlier onset of T2DM in youth through an early and amplified burden on a beta-cell destined to decompensate, and explicate their lower therapeutic response to insulin sensitizers. PMID- 28726335 TI - Preperitoneal fat as a non-invasive marker of increased risk of severe non alcoholic fatty liver disease in patients with type 2 diabetes. AB - BACKGROUND AND AIM: Fat distribution may have prognostic value in the evaluation of non-alcoholic fatty liver disease. This study was conducted to evaluate associations of magnetic resonance imaging-measured abdominal fat areas with steatosis, steatohepatitis, and fibrosis, assessed histopathologically, in patients with type 2 diabetes. METHODS: This prospective study included 66 patients with type 2 diabetes (12 males, 54 females, age 26-68 years), without chronic liver disease of other causes. Axial dual-echo magnetic resonance images were acquired. Visceral, subcutaneous, and preperitoneal fat areas were measured using Osirix software. Liver biopsy specimens were obtained from all patients and examined histopathologically to evaluate steatosis, steatohepatitis, and fibrosis. Linear (for steatosis) and logistic (for steatohepatitis and fibrosis) regression models were fitted for the outcomes. R2 was used as a measure of how much model variance the predictors explained and to compare different predictors of the same outcome. RESULTS: Visceral and preperitoneal fat areas correlated well with histopathologically determined liver steatosis grade (both P = 0.004) and liver fibrosis (P = 0.008 and P = 0.037, respectively). All fat areas correlated well with steatohepatitis (P <= 0.002). Preperitoneal and visceral fat areas were the best predictors of steatohepatitis (R2 = 0.379) and fibrosis (R2 = 0.181), respectively. CONCLUSIONS: Visceral fat area was the best predictor of fibrosis in patients with type 2 diabetes. Preperitoneal fat area was the best predictor of steatohepatitis and is a potential new non-invasive marker for use in the screening of these patients to detect more aggressive forms of non alcoholic fatty liver disease. PMID- 28726336 TI - Mass Killings in the United States from 2006 to 2013: Social Contagion or Random Clusters? AB - In line with previous research on suicide and social contagion, there has been widespread speculation that mass killings-which often involve suicidal offenders are socially contagious for up to 14 days. This study tested these claims by making comparisons (i) between observed chronological clusters of mass killings in the United States from 2006 to 2013 and clusters in 500 simulations containing 116,000 randomly generated dates, and then (ii) between observed mass killings receiving varying levels of public attention. No evidence of short-term contagion was found, although longer term copycat effects may exist. Further scholarly and policy implications are discussed. PMID- 28726337 TI - Fixed drug eruption probably induced by azithromycin. PMID- 28726338 TI - Household fear of deportation in Mexican-origin families: Relation to body mass index percentiles and salivary uric acid. AB - OBJECTIVE: Fear of deportation (FOD) is a prevalent concern among mixed-status families. Yet, our understanding of how FOD shapes human health and development is in its infancy. To begin to address this knowledge gap, we examined the relationship between household FOD, body mass index (BMI) percentiles and salivary uric acid (sUA), a biomarker related to oxidative stress/hypertension/metabolic syndrome, among 111 individuals living in Mexican origin families. METHODS: Participants were 65 children (2 months-17 years, 49% female) and 46 adults (20-58 years, 71% female) living in 30 Mexican-origin families with at least one immigrant parent in Phoenix, AZ. We recruited families using cluster probability sampling of 30 randomly selected census tracts with a high proportion of Hispanic/Latino immigrants. The head of household completed a survey containing demographic, FOD, and psychosocial measures. All family members provided saliva (later assayed for sUA) and anthropometric measures. Relationships between household FOD, BMI percentile, and sUA levels were estimated using multilevel models. RESULTS: Higher levels of household FOD were associated with lower BMI percentiles and lower sUA levels between families, after controlling for social support and socioeconomic proxies. CONCLUSION: Key features of the social ecology in which mixed-status families are embedded are associated with individual differences in biological processes linked to increased risk for chronic disease. PMID- 28726339 TI - Dielectric screening effect of electronic polarization and intramolecular hydrogen bonding. AB - Recent site-resolved hydrogen exchange measurements have uncovered significant discrepancies between simulations and experimental data during protein folding, including the excessive intramolecular hydrogen bonds in simulations. This finding indicates a possibility that intramolecular charge-charge interactions have not included sufficient dielectric screening effect of the electronic polarization. Scaling down peptide atomic charges according to the optical dielectric constant is tested in this study. As a result, the number of intramolecular hydrogen bonds is lower than using unscaled atomic charges while reaching the same levels of helical contents or beta-hairpin backbone hydrogen bonds, because van der Waals interactions contribute substantially to peptide folding in water. Reducing intramolecular charge-charge interactions and hydrogen bonding increases conformational search efficiency. In particular, it reduces the equilibrium helical content in simulations using AMBER force field and the energy barrier in folding simulations using CHARMM force field. PMID- 28726340 TI - Factors influencing property selection for conservation revolving funds. AB - Finding sustainable ways to increase the amount of private land protected for biodiversity is challenging for many conservation organizations. In some countries, organizations use revolving-fund programs, whereby land is purchased and then sold to conservation-minded owners under condition they enter into a conservation covenant or easement. The sale proceeds are used to purchase, protect, and sell additional properties, incrementally increasing the amount of protected private land. Because the effectiveness of this approach relies on selecting appropriate properties, we explored factors currently considered by practitioners and how these are integrated into decision making. We conducted exploratory, semistructured interviews with managers from each of the 5 major revolving funds in Australia. Responses indicated although conservation factors are important, financial and social factors are also highly influential. A major determinant was whether the property could be resold within a reasonable period at a price that replenishes the fund. To facilitate resale, often selected properties include the potential for the construction of a dwelling. Practitioners face with clear trade-offs between conservation, financial, amenity, and other factors in selecting properties and 3 main challenges: recovering the costs of acquisition, protection, and resale; reselling the property; and meeting conservation goals. Our findings suggest the complexity of these decisions may constrain revolving-fund effectiveness. Drawing from participant responses, we identified potential strategies to mitigate these risks, such as providing adequate recreational space without jeopardizing ecological assets. We suggest managers could benefit from a shared-learning and adaptive approach to property selection given the commonalities between programs. Understanding how practitioners deal with complex decisions in the implementation of revolving funds helps identify future research to improve the performance of this conservation tool. PMID- 28726341 TI - The wandering intraocular lens: an unusual suspect. PMID- 28726342 TI - Social workers' perceptions of barriers to interpersonal therapy implementation for treating postpartum depression in a primary care setting in Israel. AB - Research on evidence-based practice (EBP) implementation in social work often neglects to include evaluation of application barriers. This qualitative study examined social workers' perspectives of provider- and organisational-related barriers to implementing a brief eight-session interpersonal therapy (IPT) intervention, a time-limited EBP that addresses reducing depressive symptoms and improving interpersonal functioning. Implementation took place in a primary care setting in Israel and was aimed at treating women who have postpartum depression (PPD) symptoms. Using purposeful sampling, 25 primary care licensed social workers were interviewed between IPT training and implementation regarding their perceived barriers to implementing IPT in practice. Data analysis was facilitated using a phenomenological approach, which entails identifying the shared themes and shared experiences of research participants regarding barriers to implementing IPT. Three themes emerged from the analysis of interviews: Perceived lack of flexibility of IPT intervention in comparison with more familiar methods social workers previously applied, specifically regarding the number of sessions and therapeutic topics included in the IPT protocol; insecurity and hesitance to gain experience with a new method of intervention; and organisational barriers, including difficulties with referrals, the perception of HMOs as health facilities not suitable for therapy, and time constraints. Addressing perceived barriers of social workers toward implementing EBPs, such as IPT for postpartum depression, during the training phase is crucial for enabling appropriate implementation. Future training should include examining practitioners' attitudes toward implementation of EBPs, as part of standardised training protocols. PMID- 28726343 TI - Cultural misconceptions and public stigma against mental illness among Lebanese university students. AB - PURPOSE: The purpose of this study was to examine cultural misconceptions about mental illness and how they are associated with the public stigma against mental illness among Lebanese university students. METHODS: A sample of 203 participants completed the study. Data about cultural misconceptions, attitudes about mental illness, and public stigma of mental illness were obtained. The researchers examined the mean difference in public stigma according to cultural beliefs about mental illness. RESULTS: The majority of students believe that mental health professionals have inadequate knowledge and expertise to treat mental disorders. Various cultural misconceptions about mental illness were reported. Public stigma significantly differed based on these cultural misconceptions. CONCLUSION: Psychiatric nurses should play a vital role in reshaping the inappropriate cultural view about mental illness. PMID- 28726344 TI - Barriers to using electronic evidence based literature in nursing practice: a systematised review. AB - BACKGROUND: Nurses' use of electronic literature has remained limited. OBJECTIVES: The aim of this study was to identify barriers concerning application of electronic literature on evidence based practice in nursing. METHODS: Six bibliographic databases were searched using the following keywords: challenges, barriers, obstacles, evidence based practice, EBP, information seeking, online databases, electronic literature, bibliographic databases and nurs*. Results were filtered to peer reviewed empirical studies, written in English or Persian and published from 2010 to 2017. Studies were selected based on specified inclusion criteria, and quality of the included studies was assessed. The approved articles (n = 21) were extracted and synthesised. DISCUSSION: There are different types of barriers in using electronic evidence based literature in nursing demonstrating the issue as a multi-faceted problem. Not having enough time to conduct a search was the first major barrier noted by almost 81% (n = 17) of the reviewed studies followed by lack of knowledge on searching skills (66%; n = 14) and access requirements (38%; n = 8). CONCLUSIONS: There appears to be an important role for hospital management in providing nurses with enough time and access to online information while at work and also for health care librarians together with nursing leaders in providing the required training on using electronic evidence based literature. PMID- 28726345 TI - Enantioselective Construction of Trifluoromethoxylated Stereogenic Centers by a Nickel-Catalyzed Asymmetric Suzuki-Miyaura Coupling of Secondary Benzyl Bromides. AB - Trifluoromethoxy-substituted stereogenic centers can be constructed with high enantioselectivity by a nickel-catalyzed Suzuki-Miyaura coupling of readily available alpha-bromobenzyl trifluoromethyl ethers with a variety of aryl pinacol boronates. The coupling proceeds under mild reaction conditions, and a variety of common functional groups, such as fluoride, chloride, bromide, ester, enolizable ketone, nitro, cyano, amino, and vinyl moieties, were well tolerated. Furthermore, the reaction can be easily scaled up to gram quantities without a decrease in enantioselectivity. PMID- 28726346 TI - Imaging characteristics and treatment of a penetrating brain injury caused by an oropharyngeal foreign body in a dog. AB - A 4-year-old Border collie was presented with one episode of collapse, altered mentation, and a suspected pharyngeal stick injury. Magnetic resonance imaging (MRI) and computed tomography showed a linear foreign body penetrating the right oropharynx, through the foramen ovale and the brain parenchyma. The foreign body was surgically removed and medical treatment initiated. Complete resolution of clinical signs was noted at recheck 8 weeks later. Repeat MRI showed chronic secondary changes in the brain parenchyma. To the authors' knowledge, this is the first report of the advanced imaging findings and successful treatment of a penetrating oropharyngeal intracranial foreign body in a dog. PMID- 28726347 TI - MD2 Blockage Protects Obesity-Induced Vascular Remodeling via Activating AMPK/Nrf2. AB - OBJECTIVE: Obesity and increased free fatty acid (FFA) levels are tightly linked with vascular oxidative stress and remodeling. Myeloid differentiation 2 (MD2), an important protein in innate immunity, is requisite for endotoxin lipopolysaccharide responsiveness. This study shows that palmitic acid (PA) also bonds to MD2, initiating cardiac inflammatory injury. However, it is not clear whether MD2 plays a role in noninflammatory systems such as obesity- and FFA related oxidative stress involved in vascular remodeling and injury. The aim of this study is to examine whether MD2 participates in reactive oxygen species increase and vascular remodeling. METHODS: Male MD2-/- mice and wild-type littermates with a C57BL/6 background were fed a high-fat diet (HFD) to establish obesity-induced vascular remodeling. Rat aortic endothelial cells (RAECs) and vascular smooth muscle cells (VSMCs) were treated with PA to induce oxidative stress and injury. RESULTS: In vivo, MD2 deficiency significantly reduced HFD induced vascular oxidative stress, fibrosis, and remodeling, accompanied with AMP activated kinase (AMPK) activation and nuclear factor erythroid (Nrf2) upregulation. In VSMCs and RAECs, inhibition of MD2 by neutralizing monoclonal antibody to MD2 or small interfering RNA knockdown significantly activated the AMPK/Nrf2-signaling pathway and reduced PA-induced oxidative stress and cell injury. CONCLUSIONS: It was demonstrated that the deletion or inhibition of MD2 protects against HFD/FFA-induced vascular oxidative stress and remodeling by activating the AMPK/Nrf2-signaling pathway. PMID- 28726348 TI - State insurance mandates and off-label use of chemotherapy. AB - Access to cancer drugs used off-label is important to cancer patients but may drive up healthcare costs with little evidence of clinical benefit. We hypothesized that state health insurance mandates for private insurers to provide coverage for off-label use of cancer drugs cause higher rates of off-label use. We used Truven MarketScan data from 1999 to 2007 on utilization of 35 infused chemotherapy drugs in private health plans in the United States, covering the period when eight states implemented off-label coverage laws. We studied trends in off-label use of drugs, distinguishing between appropriate and inappropriate off-label use according to drug compendia, and estimated difference-in-difference regressions of the effect of state laws on off-label use. We estimate 41% of utilization was off-label, including 17% of use conservatively defined as inappropriate. Trends show gradual declines in off-label use over time. We also find no discernable effect of state laws mandating coverage of off-label use of cancer drugs on utilization patterns under multiple empirical specifications. Our conclusion is that policymakers should consider shifting away from mandating coverage as a way to ensure access to drugs off-label and towards incentivizing adherence to clinical practice guidelines to improve the quality and value of off label use. PMID- 28726349 TI - Aspherical, Nanostructured Microparticles for Targeted Gene Delivery to Alveolar Macrophages. AB - Introducing novel shapes to particulate carrier systems adds unique features to modern drug and gene delivery. Depending on the route of administration, particle geometry can influence deposition and fate within biological environments. In this work, a template-assisted engineering technique is applied, providing full control of size and shape in the preparation of aspherical, nanostructured microparticles. Based on the interconnection of nanoparticles, stabilized by a functional layer-by-layer (LbL) coating, the resulting cylindrical micrometer architecture is especially qualified for pulmonary delivery. Designed as gene delivery system, plasmid-DNA (pCMV-luciferase) and branched polyethylenimine are used to reach both structural integrity of the carrier system and delivery of genes into the cells of interest. Due to their size, particles are exclusively taken up by phagocytes, which also adds a targeting effect to the introduced system. The luciferase expression is demonstrated in macrophages showing increasing levels over a time period of at least 7 d. Furthermore, it is shown for the first time that the expression is depending on the LbL design. From in vivo experiments, corresponding luciferase expression is observed in mice alveolar macrophages. Combining site specific transport with the possibility of genetically engineering immunocompetent phagocytes, the presented system offers promising potential to improve applications for cell-based immunotherapy. PMID- 28726350 TI - What is distressing about auditory verbal hallucinations? The contribution of goal interference and goal facilitation. AB - OBJECTIVES: Distressing and pleasant/positive voices (auditory verbal hallucinations) are common in both clinical and non-clinical voice-hearers. Identifying factors that contribute to emotional reactions to voices is essential for developing effective psychological interventions. Several theories propose that facilitation and interference with personal goals are important predictors of distress and well-being. This study examined whether voice-related distress is related to the degree to which voices interfere with personal goals, and whether pleasantness of voices is influenced by the extent to which they facilitate goals. DESIGN: Cross-sectional with clinical and non-clinical voice-hearers. METHOD: Twenty-two clinical and 18 non-clinical voice-hearers completed interviews and self-report measures assessing (1) personal goals, (2) content, characteristics, and affective reactions to voices, and (3) ratings of the extent to which voices facilitated and/or interfered with achievement of important personal goals. RESULTS: Affective reactions were strongly correlated with measures of goal interference and goal facilitation. Regression analyses revealed that these associations remained significant when controlling for important covariates (e.g., participant grouping; content, frequency and duration of voices). Goal interference was specifically associated with distress, whereas goal facilitation specifically predicted perceived pleasantness of voices. CONCLUSIONS: This study provides a novel perspective on the factors that might contribute to distress in people who hear voices. The findings suggest that perceived impact of voices on valued personal goals may be an important contributor of voice-related distress. We propose that clinical assessments, formulations, and interventions could benefit from the careful analysis of the perceived impact of voices on goals. PRACTITIONER POINTS: These findings suggest that variability in voice-related distress is closely linked to the perceived impact of voices on personal goals. These strong effects observed highlight the importance of considering the role of personal goals in future research on the psychological mechanisms leading to distress associated with voice hearing. Psychological assessments may benefit from the careful exploration of the impact of voice hearing on valued goals, and interventions promoting control over personal goals may be explored as treatment options for clients with distressing voices. PMID- 28726351 TI - Correction of horizontal neck lines: Our preliminary experience with hyaluronic acid fillers. AB - BACKGROUND: There is an increasing trend shifting the esthetic focus downward from the face with a significant number of new treatments aimed at the aging neck. Hyaluronic acid (HA) filler injection is widely performed into the horizontal neck lines in Korea, but there are few reports assessing its effectiveness. OBJECTIVE: We aimed to evaluate the efficacy and safety of HA filler injection in the treatment of horizontal neck lines. PATIENTS AND METHODS: A retrospective chart review was performed on cases of horizontal neck lines treated with HA fillers. A total of 28 neck halves from 14 patients with Fitzpatrick skin types IV-V were included. All participants underwent a single treatment session with a 0.3 cc insulin syringe (31G*8 mm needle). Wrinkle assessment was conducted at baseline and 2 months after treatment. Two blinded physicians evaluated the improvement using a 5-point Global Aesthetic Improvement Scale (GAIS) (5-very much improved, 4-much improved, 3-improved, 2-no change, 1 worse) by comparing the pretreatment and post-treatment photographs. A questionnaire was used to evaluate patient satisfaction and the incidence of adverse reactions. RESULTS: Among the 28 neck halves, 35.7% were treated with the linear threading technique (LTT) and 64.3% were treated with the vertical technique (VT). The average amount of filler injection per side was 1.01+/-0.13 cc. The GAIS score of the horizontal neck lines measured at the 2-month follow-up after filler injection was 4.04+/-0.79 (overall); the GAIS score of the horizontal neck lines was 3.60+/-0.70 with the LTT and 4.27+/-0.75 with the VT (P=.027). Complications, such as skin irregularity and accentuation of neck lines, were observed, but they were transient. CONCLUSION: Our preliminary study results indicate that HA filler injection with a 0.3 cc insulin syringe could be a safe and effective treatment option for horizontal neck lines. PMID- 28726353 TI - Spin-singlet Quantum Ground State in Zigzag Spin Ladder Cu(CF3 COO)2. AB - The copper salt of trifluoroacetic acid, Cu(CF3 COO)2 , offers a new platform to investigate the quantum ground states of low-dimensional magnets. In practice, it realizes the ideal case of a solid hosting essentially isolated magnetic monolayers. These entities are constituted by well-separated two-leg half-integer spin ladders organized in a zigzag fashion. The ladders are comprised of dimeric units of edge-sharing tetragonal pyramids coupled through carbon ions. The spin gap state in this compound was revealed by static and dynamic magnetic measurements. No indications of long range magnetic ordering down to liquid helium temperature were obtained in specific heat measurements. First principles calculations allow estimation of the main exchange interaction parameters, J? =176 K and J? =12 K, consistent with the weakly interacting dimers model. PMID- 28726352 TI - Computational design of a specific heavy chain/kappa light chain interface for expressing fully IgG bispecific antibodies. AB - The use of bispecific antibodies (BsAbs) to treat human diseases is on the rise. Increasingly complex and powerful therapeutic mechanisms made possible by BsAbs are spurring innovation of novel BsAb formats and methods for their production. The long-lived in vivo pharmacokinetics, optimal biophysical properties and potential effector functions of natural IgG monoclonal (and monospecific) antibodies has resulted in a push to generate fully IgG BsAb formats with the same quaternary structure as monoclonal IgGs. The production of fully IgG BsAbs is challenging because of the highly heterogeneous pairing of heavy chains (HCs) and light chains (LCs) when produced in mammalian cells with two IgG HCs and two LCs. A solution to the HC heterodimerization aspect of IgG BsAb production was first discovered two decades ago; however, addressing the LC mispairing issue has remained intractable until recently. Here, we use computational and rational engineering to develop novel designs to the HC/LC pairing issue, and particularly for kappa LCs. Crystal structures of these designs highlight the interactions that provide HC/LC specificity. We produce and characterize multiple fully IgG BsAbs using these novel designs. We demonstrate the importance of specificity engineering in both the variable and constant domains to achieve robust HC/LC specificity within all the BsAbs. These solutions facilitate the production of fully IgG BsAbs for clinical use. PMID- 28726354 TI - High-performance of Agaricus blazei fungus for the biological pretreatment of elephant grass. AB - Biological pre-treatment seems to be promising being an eco-friendly process, with no inhibitor generated during the process. The potential for elephant grass pre-treatment with white degradation fungi Pleurotus ostreatus, Agaricus blazei, Lentinula edodes, Pleurotus citrinopileatus, and Pleurotus djamor, in isolated or mixed cultures of these strains, was evaluated. The highest activities of enzymes involved in the degradation of lignocellulosic biomass (laccases, endoglucanases, xylanases, and beta-glucosidases) were observed for A. blazei, L. edodes and the combination of P. ostreatus and A. blazei. In the enzymatic hydrolysis, there was greater release of reducing sugars in the pre-treated elephant grass samples by A. blazei during 10 days (338.91 +/- 7.39 mg g-1 of biomass). For this sample, higher lignin reductions, 24.81 and 57.45%, after 15 and 35 days of incubation, respectively, were also verified. These data indicate the potential of macromycetes such as A. blazei to perform biological pre-treatments. (c) 2017 American Institute of Chemical Engineers Biotechnol. Prog., 34:42-50, 2018. PMID- 28726355 TI - Combined Cataract/DSEK/DMEK: Changing Expectations. AB - Endothelial keratoplasty (EK) has revolutionized corneal transplant surgery by providing rapid visual recovery and improved visual outcomes. In parts of the world with Fuchs endothelial dystrophy, many patients may present with both cataracts and corneal degeneration requiring surgery. Other forms of endothelial decompensation may also present with cataracts. The staging or combination of transplant surgery and cataract surgery depend on both the abilities of the surgeon and the surgical techniques being considered. We currently use phacoemulsification to remove cataracts and routinely perform both cataract surgery and EK with topical anesthesia. The decision to perform either combined or staged cataract and transplant surgery depends upon the examination of the eye including assessment of the anterior chamber depth and the status of the anterior surface of the cornea, which affects the ability to reliably assess keratometry. Additional considerations include the type of lens implant to use, the desired refractive outcome, and the patient's preference about whether to undergo 1 or 2 surgical procedures per eye. PMID- 28726356 TI - Intrascleral IOL Fixation. AB - Intrascleral sutureless intraocular lens (IOL) fixation utilizes direct haptic fixation within the sclera in eyes with deficient capsular support. This has advantages of long-term stability, good control of tilt and decentration, and lesser pseudophakodonesis. This review summarizes various techniques for intrascleral haptic fixation, results, complications, adaptations in special situations, modifications of the technique, combination surgeries, and intrascleral capsular bag fixation techniques (glued capsular hook). PMID- 28726357 TI - The Complexities of Negative Dysphotopsia. AB - The appearance of a dark shadow in the temporal periphery, otherwise known as negative dysphotopsia, continues to be a problem for some patients after routine uncomplicated cataract surgery. Etiologies include type and design of intraocular lens (IOL), anatomical features and dimensions of the eye, pupil size, angle kappa, relationship of the optic to the anterior capsule, and the position of the optic/haptic junction of the IOL. Although the primary etiology remains controversial, it is clear that the cause is multifactorial. All of the factors should be considered when attempting to prevent or treat this phenomenon. PMID- 28726359 TI - Earplugs during the first night after cardiothoracic surgery may improve a fast track protocol. AB - BACKGROUND: Sleep deprivation after major surgery is common and associated with worse outcome. Noise is one important reason for sleep fragmentation, which contributes to enhanced morbidity. The purpose of this work was to evaluate the impact of earplugs on patients' sleep quality during their first night after cardiothoracic surgery to eventually improve an existing fast-track concept. METHODS: Sixty-three patients undergoing cardiothoracic surgery eligible for a postoperative fast-track regimen on our cardiothoracic post anesthesia care unit (C-PACU) were prospectively included. They were randomized to either sleep with or without earplugs. Quality of sleep was measured using questionnaires for patients and nurses. Required pain medications, pain intensity, and length of hospital stay were secondary outcome variables. RESULTS: Twenty-seven patients were randomized to the intervention group (earplugs) and 36 to the control group. Mean (SD) age was 61 (12) years. Self-reported quality of sleep was better in the intervention group (median, IQR [range]: 3, 2-4 [1-5] vs. 4, 3-5 [1-5]; scale: 1, "excellent," to 5, "very poor"; P=0.025). Patients of the intervention group also experienced less severe pain (P=0.047) despite similar dosages of administered analgesics and expressed improved satisfaction regarding their C-PACU stay (P=0.032). CONCLUSIONS: Implementation of the use of earplugs in a fast-track concept following cardiothoracic surgery is efficient and easy. Earplugs improved the quality of sleep as well as patient satisfaction and attenuated pain intensity. They may thereby contribute to a faster recovery, less morbidity, and reduced costs. PMID- 28726358 TI - Colorectal cancer and inflammatory bowel diseases: effects of diet and antioxidants. AB - It is well established that oxidative stress is common in inflammatory bowel diseases (IBDs). Accordingly, antioxidants are recommended for treatment. The aim of this study is to compare the effects of antioxidants contained in the various types of tea on symptoms and evolution of IBD and colorectal cancer (CRC). Analysis of the literature revealed that the theaflavin-3, 30-digallate (TFDG) contained in black tea, and epigallocatechin-3-O-gallate (EGCG) contained in green tea have protective effects against oxidative stress. Moreover, these substances are involved in many biochemical processes responsible for inflammation and proliferation of cancer cells. It is documented that both TFDG and EGCG are able to reduce inflammatory phenomena and symptoms associated with IBD, as well as to reduce the proliferation of CRC cells. Most studies are performed in vitro or in experimental animal models. It is, therefore, advisable to formulate studies that could be carried out on humans or human samples, in order to develop the appropriate therapeutic strategies. PMID- 28726360 TI - Machine perfusion in liver transplantation: an essential treatment or just an expensive toy? AB - This review focuses on recent developments in preservation techniques in liver transplantation. First, we discuss mechanisms of organ injury when using high risk organs, including donation after circulatory death and steatotic grafts and we summarize pathways of ischemia reperfusion injury together with their link to the immune response. Second, we report on improvement strategies of marginal liver grafts by different machine perfusion concepts and summarize perfusion approaches with recent clinical implementation. PMID- 28726361 TI - Risk of spontaneous fungal peritonitis in hospitalized cirrhotic patients with ascites: a systematic review of observational studies and meta-analysis. AB - INTRODUCTION: Spontaneous fungal peritonitis (SFP) is an infection of ascitic fluid occurring in cirrhotic patients. SFP prevalence varies from 0% to 41% of patients with spontaneous peritonitis (SP) and a positive ascitic fluid culture. Cirrhotic patients with SFP who fail to show improvement with empirical antibiotic therapy, before the identification of the fungal pathogen, have high mortality (89.5-100%). Although the weight of the disease is so dramatic, more recent guidelines on infections in cirrhosis do not consider SFP management. The aim of this meta-analysis was to investigate the association between hospitalization (at least 48-72 hours after admission) and risk of SFP. EVIDENCE ACQUISITION: A literature search was performed on PubMed, Scopus and Web of Science to identify relevant studies published up to March 2, 2017. Only observational studies that specify the etiology of SP were included. Data were pooled using risk difference as a summary measure and corresponding 95% confidence interval (CI). EVIDENCE SYNTHESIS: Thirteen cohort studies were included in the meta-analysis (12 retrospective and one prospective). A pooled risk difference, using a random effects model, of nosocomial versus non nosocomial SFP was 2.9% (95% CI, 0.4% to 5.3%, P=0.024) with a no significant heterogeneity among studies (P=0.090, I2=37%). CONCLUSIONS: This meta-analysis suggests that hospitalization is related to a significant increase of SFP risk. PMID- 28726362 TI - Early hypertension after vasopressor weaning during septic shock: associated factors and prognostic significance. AB - BACKGROUND: During septic shock, early development of hypertension after vasopressors weaning seems paradoxical. The aim of this study was to authenticate this empirical observation, identify associated factors and document its prognostic significance. METHODS: We conducted a descriptive, retrospective study in a medical ICU of a teaching hospital among adult patients with septic shock. RESULTS: From January 1st, 2013 to December 31st, 2014, 262 consecutive patients over 18 years of age were admitted because of septic shock; 195 of them were successfully weaned from vasopressors. Early hypertension within the 24 hours following vasopressors weaning occurred in 22% of patients (N.=43) who did not differ in terms of past history of hypertension or chronic renal insufficiency, severity scores, vasopressor doses or duration, volume resuscitation or fluid balance. In multivariate analysis, predictive factors for developing early hypertension were past history of ischemic heart disease (OR=4.25; 95% CI: 1.74 10.35, P=0.001) and invasive mechanical ventilation (OR=2.86; 95% CI: 1.26-6.51, P=0.01). Occurrence of early hypertension was independently associated with a better survival (OR=0.03; 95% CI: 0.001-0.73, P=0.03). CONCLUSIONS: Development of hypertension within 24 hours of vasopressor support cessation is a frequent event affecting almost a quarter of the patients who survived the initial phase of septic shock resuscitation and is independently associated with a better outcome. PMID- 28726363 TI - Does dexmedetomidine offer brain protection? PMID- 28726364 TI - New frontiers: art and innovation for intraoperative ventilatory management. PMID- 28726365 TI - Labor epidural failure: a serious concern! PMID- 28726366 TI - "I am in pain": is it really the magic formula to open the door of opioid abuse? PMID- 28726367 TI - Systematic Approach to the Development of Microfabricated Biosensors: Relationship between Gold Surface Pretreatment and Thiolated Molecule Binding. AB - Despite the increasing popularity of microfabricated biosensors due to advances in technologic and surface functionalization strategies, their successful implementation is partially inhibited by the lack of consistency in their analytical characteristics. One of the main causes for the discrepancies is the absence of a systematic and comprehensive approach to surface functionalization. In this article microfabricated gold electrodes aimed at biosensor development have been systematically characterized in terms of surface pretreatment, thiolated molecule binding, and reproducibility by means of X-ray photoelectron scattering (XPS) and cyclic voltammetry (CV). It has been shown that after SU-8 photolithography gold surfaces were markedly contaminated, which decreased the effective surface area and surface coverage of a model molecule mercaptohexanol (MCH). Three surface pretreatment methods compatible with microfabricated devices were compared. The investigated methods were (i) cyclic voltammetry in dilute H2SO4, (ii) gentle basic piranha followed by linear sweep voltammetry in dilute KOH, and (iii) oxygen plasma treatment followed by incubation in ethanol. It was shown that all three methods significantly decreased the contamination and increased MCH surface coverage. Most importantly, it was also revealed that surface pretreatments may induce structural changes to the gold surfaces. Accordingly, these alterations influence the characteristics of MCH functionalization. PMID- 28726368 TI - Mussel-Inspired Polydopamine-Coated Lanthanide Nanoparticles for NIR-II/CT Dual Imaging and Photothermal Therapy. AB - Nanomedicine has attracted substantial attention for the accurate diagnosis or treatment of carcinoma in recent years. Nd3+-doped lanthanide nanophosphor-based near-infrared-II (NIR-II) optical imaging is widely used for deep penetration tissue imaging while X-ray computed tomography (CT) is well-suited for in vivo imaging. Polymer-coated lanthanide nanophosphors are increasingly used in both diagnostics and therapies for tumor in vivo. However, the biocompatibility of nanocomposites and the efficiency of tumor ablation should be taken into consideration when constructing a nanotheranostic probe. In this article, we have fabricated polydopamine (PDA)-coated NaYF4:Nd3+@NaLuF4 nanocomposites using the reverse microemulsion approach. The thickness of the PDA shell can be precisely modulated from ~1.5 to ~18 nm, endowing the obtained NaYF4:Nd3+@NaLuF4@PDA with an excellent colloidal stability and considerable biocompatibility. The photothermal conversion efficiency of the resultant nanocomposites was optimized and maximized by the increase of the PDA shell thickness. Because of the remarkable photothermal conversion efficiency, the mice xenograft tumors were completely eradicated after NIR irradiation. Given the considerable photoluminescence and X-ray attenuation efficiency, the performance of NaYF4:Nd3+@NaLuF4@PDA for NIR-II optical imaging and X-ray CT dual imaging of the tumor in vivo was evaluated. All of the results above highlight the great potential of PDA-based NaYF4:Nd3+@NaLuF4 nanocomposites as a novel multifunctional nanotheranostic agent. PMID- 28726370 TI - Ultrastretchable Analog/Digital Signal Transmission Line with Carbon Nanotube Sheets. AB - Stretchable conductors can be used in various applications depending on their own characteristics. Here, we demonstrate simple and robust elastomeric conductors that are optimized for stretchable electrical signal transmission line. They can withstand strains up to 600% without any substantial change in their resistance (<=10% as is and <=1% with passivation), and exhibit suppressed charge fluctuations in the medium. The inherent elasticity of a polymeric rubber and the high conductivity of flexible, highly oriented carbon nanotube sheets were combined synergistically, without losing both properties. The nanoscopic strong adhesion between aligned carbon nanotube arrays and strained elastomeric polymers induces conductive wavy folds with microscopic bending of radii on the scale of a few micrometers. Such features enable practical applications such as in elastomeric length-changeable electrical digital and analog signal transmission lines at above MHz frequencies. In addition to reporting basic direct current, alternating current, and noise characterizations of the elastomeric conductors, various examples as a stretchable signal transmission line up to 600% strains are presented by confirming the capability of transmitting audio and video signals, as well as low-frequency medical signals without information distortion. PMID- 28726369 TI - Comprehensive Study of Sol-Gel versus Hydrolysis-Condensation Methods To Prepare ZnO Films: Electron Transport Layers in Perovskite Solar Cells. AB - Owing to the high charge mobility and low processing temperature, ZnO is regarded as an ideal candidate for electron transport layer (ETL) material in thin-film solar cells. For the film preparation, the presently dominated sol-gel (SG) and hydrolysis-condensation (HC) methods show great potential; however, the effect of these two methods on the performance of the resulting devices has not been investigated in the same frame. In this study, the ZnO films made through SG and HC methods were applied in perovskite solar cells (Pero-SCs), and the performances of corresponding devices were compared under parallel conditions. We found that the surface morphologies and the conductivities of the films prepared by SG and HC methods showed great differences. The HC-ZnO films with higher conductivity led to relatively higher device performance, and the best power conversion efficiencie (PCE) of 12.9% was obtained; meanwhile, for Pero-SCs based on SG-ZnO, the best PCE achieved was 10.9%. The better device performance of Pero SCs based on HC-ZnO should be attributed to the better charge extraction and transportation ability of HC-ZnO film. Moreover, to further enhance the performance of Pero-SCs, a thin layer of pristine C60 was introduced between HC ZnO and perovskite layers. By doing so, the quality of perovskite films was improved, and the PCE was elevated to 14.1%. The preparation of HC-ZnO film involves relatively lower-temperature (maximum 100 degrees C) processing; the films showed better charge extraction and transportation properties and can be a more promising ETL material in Pero-SCs. PMID- 28726371 TI - Multilayer Regulation of Atomic Boron Nitride Films to Improve Oxidation and Corrosion Resistance of Cu. AB - The boron nitride (BN) monolayer (1L) with high impermeability and resistivity seems to hold promise as a long-term corrosion barrier for Cu under ambient condition, which is supported by recent researches. Here, we perform a complete study of the alternating temperature tests (the sample is exposed in air for 30 days and subsequently heated at 200 degrees C for 2 h) and electrochemical measurements on 1L and multilayer BN-coated Cu foils. Results imply that the BN coated Cu foils are less oxidized than uncoated Cu foils after alternating temperature tests, regardless of the layers of BN. Particularly, the oxidation process proceeds slowly in multilayers because most of the underlying defects are covered with BN layers to suppress the oxygen diffusion in the vertical direction and the oxidation mainly occurs on the wrinkled region of BN films. Electrochemical analyses reveal that the BN layers provide an effective physical barrier against the corrosive medium and inhibit the electron diffusion because of their high electrical insulating behavior and the corrosion resistance of the samples increases with increasing BN layers. These findings indicate that BN films with adequate layers are good candidates for oxidation and corrosion protection at the atomic level, which is vital to many industrial and academic applications. PMID- 28726372 TI - Influence of Relativistic Effects on Assembled Structures of V-Shaped Bispyridine Molecules on M(111) Surfaces Where M = Cu, Ag, Au. AB - The self-assembly behavior of a V-shaped bispyridine, 1,3-bi(4-pyridyl)benzene (BPyB), was studied by scanning tunneling microscopy on the (111) surfaces of Cu, Ag, and Au. BPyB molecules coordinately bonded with active Cu adatoms on Cu(111) in the form of complete polygonal rings at low coverages. On Ag(111), BPyB molecules aggregated into two-dimensional islands by relatively weak intermolecular hydrogen bonds. The coexistence of hydrogen bonds and coordination interaction was observed on the BPyB-covered Au(111) substrate. Density functional theory calculations of the metal-molecule binding energy and Monte Carlo simulations were performed to help understand the forming mechanism of molecular superstructures on the surfaces. In particular, the comprehensive orbital composition analysis interprets the observed metal-organic complexes and reveals the importance of relativistic effects for the extraordinary activity of gold adatoms. The relativistic effects cause the energy stability of the Au 6s atomic orbital and decrease the energy separation between the Au 6s and 5d orbitals. The enhanced sd hybridization strengthens the N-Au-N bond in BPyB-Au BPyB complexes. PMID- 28726373 TI - Ultrasensitive Homogeneous Electrochemical Detection of Transcription Factor by Coupled Isothermal Cleavage Reaction and Cycling Amplification Based on Exonuclease III. AB - The assay and monitoring of transcription factors (TFs) has attracted extensive attention due to their important roles in regulation of gene expressions. Herein, a simple, low cost, rapid, and highly sensitive homogeneous electrochemical method utilizing the coupled isothermal cleavage reaction and cycling amplification based on exonuclease III (Exo III) was explored for the analysis of transcription factor NF-kappaB p50 in aqueous solution. In the assay, a 3' methylene blue (MB)-labeled hairpin probe is designed, which can be opened up by the single stranded DNA (ssDNA) protected by NF-kappaB p50 from the Exo III cleavage, to trigger the subsequent Exo III-assisted digestion, thus a large amount of MB-labeled mononucleotides are liberated to result in the greatly amplified electrochemical signal. By virtue of this Exo III-assisted target recycling, the present assay allows the detection of NF-kappaB p50 at the picomolar level, which is an exciting level for TFs detection. Furthermore, this detection possesses excellent selectivity, demonstrating high application potential in biological system and convenient TFs' inhibitors screening. Comparing with the other reported strategies for TFs detection, this Exo III assisted homogeneous electrochemical detection platform was just composed of one kind of enzyme and two DNA probes, offered a really simple and low-cost electrochemical detection for TFs assay. PMID- 28726374 TI - Impact of Thermal Annealing on Organic Photovoltaic Cells Using Regioisomeric Donor-Acceptor-Acceptor Molecules. AB - We report a promising set of donor-acceptor-acceptor (D-A-A) electron-donor materials based on coplanar thieno[3,2-b]/[2,3-b]indole, benzo[c][1,2,5]thiadiazole, and dicyanovinylene, which are found to show broadband absorption with high extinction coefficients. The role of the regioisomeric electron-donating thienoindole moiety on the physical and structural properties is examined. Bulk heterojunction (BHJ) organic photovoltaic cells (OPVs) based on the thieno[2,3-b]indole-based electron donor NTU-2, using C70 as an electron acceptor, show a champion power conversion efficiency of 5.2% under AM 1.5G solar simulated illumination. This efficiency is limited by a low fill factor (FF), as has previously been the case in D-A-A systems. In order to identify the origin of the limited FF, further insight into donor layer charge transport behavior is realized by examining planar heterojunction OPVs, with emphasis on the evolution of film morphology with thermal annealing. Compared to as-deposited OPVs that exhibit insufficient donor crystallinity, crystalline OPVs based on annealed thin films show an increase in the short-circuit current density, FF, and power conversion efficiency. These results suggest that that the crystallization of D-A-A molecules might not be realized spontaneously at room temperature and that further processing is needed to realize efficient charge transport in these materials. PMID- 28726375 TI - Nanoscale Hydrodynamic Film for Diffusive Mass Transport Control in Compartmentalized Microfluidic Chambers. AB - A compartmentalized microfluidic chamber array that offers not only separate cell culture environments but also independent control of the diffusion of small molecules provides an extremely useful platform for cell cultivations and versatile cellular assays. However, it is challenging to incorporate both cell compartmentalization and active diffusion control in real-time and precise manners. Here, we present a novel nanoscale hydrodynamic film (NHF) that is formed between a solid substrate and a polydimethylsiloxane (PDMS) surface. The thickness of the NHF can be adjusted by varying the pressure applied between them so that the mass transfer through the NHF can also be controlled. These novel phenomena are characterized and applied to develop a compartmentalized microchamber array with diffusion-tunable and solution-switchable chemostat-like versatile bacterial assays. The NHF-based compartmentalization technique is ideal for not only continuous bacterial cultivation by consistently refreshing various nutrient sources but also various diffusion-based microbial assays such as chemical induction of synthetically engineered bacterial cells and selective growth of a specific bacterial strain with respect to chemical environments. In addition, we show that tight compartmentalization protects cells in the chambers, while biofilm formation and nutrient contamination are eliminated by loading a lysis buffer, which typically hinders long-term continuous cultures and accurate microbial assays on a chip. Therefore, we ensure that the NHF-based compartmentalization platform proposed in this work will facilitate not only fundamental studies in microbiology but also various practical applications of microbes for production of valuable metabolites and byproducts in a high throughput and highly efficient format. PMID- 28726376 TI - Dentritic CuPtPd Catalyst for Enhanced Electrochemical Oxidation of Methanol. AB - The CuPtPd catalyst is designed and synthesized successfully via directly reducing metal ions. The composition, morphology, and structure of the as prepared CuPtPd nanohybrids are characterized by scanning electron microscopy and transmission electron microscopy, energy-dispersive spectrometry, selected-area electron diffraction, X-ray diffraction, and inductively coupled plasma atomic emission spectrometry. By comparison of the electrocatalytic properties of the ternary CuPtPd catalyst with bimetallic catalysts, we find that ternary nanocomposites perform better electrocatalytic and antipoisoning activity toward oxidation of methanol. The catalytic mass activity of the CuPtPd nanoparticles is 5.51-fold of commercial Pd black and 12.1-fold of Pt black. PMID- 28726377 TI - Targeted Mass Spectrometry Approach Enabled Discovery of O-Glycosylated Insulin and Related Signaling Peptides in Mouse and Human Pancreatic Islets. AB - O-Linked glycosylation often involves the covalent attachment of sugar moieties to the hydroxyl group of serine or threonine on proteins/peptides. Despite growing interest in glycoproteins, little attention has been directed to glycosylated signaling peptides, largely due to lack of enabling analytical tools. Here we explore the occurrence of naturally O-linked glycosylation on the signaling peptides extracted from mouse and human pancreatic islets using mass spectrometry (MS). A novel targeted MS-based method is developed to increase the likelihood of capturing these modified signaling peptides and to provide improved sequence coverage and accurate glycosite localization, enabling the first large scale discovery of O-glycosylation on signaling peptides. Several glycosylated signaling peptides with multiple glycoforms are identified, including the first report of glycosylated insulin-B chain and insulin-C peptide and BigLEN. This discovery may reveal potential novel functions as glycosylation could influence their conformation and biostability. Given the importance of insulin and its related peptide hormones and previous studies of glycosylated insulin analogues, this natural glycosylation may provide important insights into diabetes research and therapeutic treatments. PMID- 28726378 TI - PtNPs as Scaffolds to Regulate Interenzyme Distance for Construction of Efficient Enzyme Cascade Amplification for Ultrasensitive Electrochemical Detection of MMP 2. AB - The high catalytic efficiency of enzyme cascade reaction mainly depends on optimal interenzyme distance regulated by the special scaffolds. In this work, the rigid PtNPs with different sizes were employed as scaffolds to regulate interenzyme distance for efficient enzyme cascade amplification to construct electrochemical biosensor for sensitive detection of matrix metalloproteinases-2 (MMP-2), which overcame the drawbacks of instable construction and sophisticated preparation induced by conventional scaffolds such as metal-organic frameworks (MOFs), DNA nanostructures. Here, cucurbit[7]uril functionalized PtNPs (CB[7]@PtNPs) was utilized to load ferrocene (Fc)-labeled horseradish peroxidase (HRP) and glucose oxidase (GOx) via host-guest interaction between Fc and CB[7], respectively, resulting in the formation of a stable three-dimensional netlike structure containing amounts of enzymes. Interestingly, the enzyme cascade reaction regulated by 10 nm PtNPs as scaffold showed highly catalytic efficiency. Meanwhile, the PtNPs could also serve as catalyst to accelerate the enzyme cascade reaction with further enhanced catalytic efficiency. As a result, the proposed biosensor exhibited excellent sensitivity with a wide linear range of 0.1 pg.mL-1 to 20 ng.mL-1 and a detection limit of 0.03 pg.mL-1 for MMP-2. Such a strategy opened a new avenue for adopting metal nanoparticles to regulate interenzyme distance for efficient enzyme cascade amplification, thus providing a universal and easy operating method for sensitively detecting various targets such as DNA, metal ion, and protein. PMID- 28726380 TI - Assessment of the Stability and Operability of Cobalt Phosphide Electrocatalyst for Hydrogen Evolution. AB - Transition metal phosphides have been investigated heavily as hydrogen evolution reaction (HER) catalysts. One of the most active transition metal phosphides, CoP, has been tested for its stability and operability under mild conditions that it may be exposed to in its applications (photoelectrochemistry and artificial photosynthesis). Surface-interrogation scanning electrochemical microscopy (SI SECM) revealed that CoP HER catalyst is vulnerable to oxidation (by oxygen and chemical oxidants). The degradation mechanism was shown to be surface oxidation by dioxygen, followed by acid etching of the oxidized layer. The compositional integrity (unity ratio of cobalt and phosphorus) was maintained throughout the film decomposition progress. PMID- 28726379 TI - Topological Dissection of the Membrane Transport Protein Mhp1 Derived from Cysteine Accessibility and Mass Spectrometry. AB - Cys accessibility and quantitative intact mass spectrometry (MS) analyses have been devised to study the topological transitions of Mhp1, the membrane protein for sodium-linked transport of hydantoins from Microbacterium liquefaciens. Mhp1 has been crystallized in three forms (outward-facing open, outward-facing occluded with substrate bound, and inward-facing open). We show that one natural cysteine residue, Cys327, out of three, has an enhanced solvent accessibility in the inward-facing (relative to the outward-facing) form. Reaction of the purified protein, in detergent, with the thiol-reactive N-ethylmalemide (NEM), results in modification of Cys327, suggesting that Mhp1 adopts predominantly inward-facing conformations. Addition of either sodium ions or the substrate 5-benzyl-l hydantoin (L-BH) does not shift this conformational equilibrium, but systematic co-addition of the two results in an attenuation of labeling, indicating a shift toward outward-facing conformations that can be interpreted using conventional enzyme kinetic analyses. Such measurements can afford the Km for each ligand as well as the stoichiometry of ion-substrate-coupled conformational changes. Mutations that perturb the substrate binding site either result in the protein being unable to adopt outward-facing conformations or in a global destabilization of structure. The methodology combines covalent labeling, mass spectrometry, and kinetic analyses in a straightforward workflow applicable to a range of systems, enabling the interrogation of changes in a protein's conformation required for function at varied concentrations of substrates, and the consequences of mutations on these conformational transitions. PMID- 28726381 TI - Impact of the Metallic Crystalline Structure on the Properties of Nanocrystals and Their Mesoscopic Assemblies. AB - The spontaneous assembly of uniform-sized globular entities into ordered arrays is a universal phenomenon observed for objects with diameters spanning a broad range of length scales. These extend from the atomic scale (10-8 cm), through molecular and macromolecular scales with proteins, synthetic low polymers, and colloidal crystals (~10-6 cm), to the wavelength of visible light (~10-5 cm). The associated concepts of sphere packing have had an influence in diverse fields ranging from pure geometrical analysis to architectural models or ideals. Self assembly of atoms, supramolecules, or nanocrystals into ordered functional superstructures is a universal process and prevalent topic in science. About five billion years ago in the early solar system, highly uniform magnetite particles of a few hundred nanometers in size were assembled in 3D arrays.1 Thirty million years ago, silicate particles with submicrometer size were self-organized in the form of opal.2 Opal is colorless when composed of disordered silicate microparticles whereas it shows specific reflectivity when particles order in arrays. Nowadays, nanocrystals, characterized by a narrow size distribution and coated with alkyl chains to maintain their integrity, self-assemble to form crystallographic orders called supracrystals. Nanocrystals and supracrystals are arrangements of highly ordered atoms and nanocrystals, respectively. The morphologies of nanocrystals, supracrystals, and minerals are similar at various scales from nanometer to millimeter scale.3,4 Such suprastructures, which enable the design of novel materials, are expected to become one of the main driving forces in material research for the 21st century.5,6 Nanocrystals vibrate coherently in a supracrystal as atoms in a nanocrystal. Longitudinal acoustic phonons are detected in supracrystals as with atomic crystals, where longitudinal acoustic phonons propagate through coherent movements of atoms of the lattice out of their equilibrium positions. These vibrational properties show a full analogy with atomic crystals: In supracrystals, atoms are replaced by (uncompressible) nanocrystals and atomic bonds by coating agents (carbon chains), which act like mechanical springs holding together the nanocrystals. Electronic properties of very thick (more than a few micrometers) supracrystals reveal homogeneous conductance with the fingerprint of the isolated nanocrystal. Triangular single crystals formed by heat-induced (50 degrees C) coalescence of thin supracrystals deposited on a substrate as epitaxial growth of metal particles on a substrate with specific orientation produced by ultrahigh vacuum (UHV). Here we demonstrate that marked changes can occur in the chemical and physical properties of nanocrystals differing by their nanocrystallinity, that is, their crystalline structure. Furthermore, the properties (mechanical, growth processes) of supracrystals also change with the nanocrystallinity of the nanoparticles used as building blocks. PMID- 28726382 TI - Interparticle Reactions: An Emerging Direction in Nanomaterials Chemistry. AB - Nanoparticles exhibit a rich variety in terms of structure, composition, and properties. However, reactions between them remain largely unexplored. In this Account, we discuss an emerging aspect of nanomaterials chemistry, namely, interparticle reactions in solution phase, similar to reactions between molecules, involving atomically precise noble metal clusters. A brief historical account of the developments, starting from the bare, gas phase clusters, which led to the synthesis of atomically precise monolayer protected clusters in solution, is presented first. Then a reaction between two thiolate-protected, atomically precise noble metal clusters, [Au25(PET)18]- and [Ag44(FTP)30]4- (PET = 2-phenylethanethiol, FTP = 4-fluorothiophenol), is presented wherein these clusters spontaneously exchange metal atoms, ligands, and metal-ligand fragments between them under ambient conditions. The number of exchanged species could be controlled by varying the initial compositions of the reactant clusters. Next, a reaction of [Au25(PET)18]- with its structural analogue [Ag25(DMBT)18]- (DMBT = 2,4-dimethylbenzenethiol) is presented, which shows that atom-exchange reactions happen with structures conserved. We detected a transient dianionic adduct, [Ag25Au25(DMBT)18(PET)18]2-, formed between the two clusters indicating that this adduct could be a possible intermediate of the reaction. A reaction involving a dithiolate-protected cluster, [Ag29(BDT)12]3- (BDT = 1,3-benzenedithiol), is also presented wherein metal atom exchange alone occurs, but with no ligand and fragment exchanges. These examples demonstrate that the nature of the metal thiolate interface, that is, its bonding network and dynamics, play crucial roles in dictating the type of exchange processes and overall rates. We also discuss a recently proposed structural model of these clusters, namely, the Borromean ring model, to understand the dynamics of the metal-ligand interfaces and to address the site specificity and selectivity in these reactions. In the subsequent sections, reactions involving atomically precise noble metal clusters and one- and two-dimensional nanosystems are presented. We show that highly protected, stable clusters such as [Au25(PET)18]- undergo chemical transformation on graphenic surfaces to form a bigger cluster, Au135(PET)57. Finally, we present the transformation of tellurium nanowires (Te NWs) to Ag-Te-Ag dumbbell nanostructures through a reaction with an atomically precise silver cluster, Ag32(SG)19 (SG = glutathione thiolate). The starting materials and the products were characterized using high resolution electrospray ionization mass spectrometry, matrix assisted laser desorption ionization mass spectrometry, UV/vis absorption, luminescence spectroscopies, etc. We have analyzed principally mass spectrometric data to understand these reactions. In summary, we present the emergence of a new branch of chemistry involving the reactions of atomically precise cluster systems, which are prototypical nanoparticles. We demonstrate that such interparticle chemistry is not limited to metal clusters; it occurs across zero-, one-, and two-dimensional nanosystems leading to specific transformations. We conclude this Account with a discussion of the limitations in understanding of these reactions and future directions in this area of nanomaterials chemistry. PMID- 28726383 TI - Marangoni Convection Assisted Single Molecule Detection with Nanojet Surface Enhanced Raman Spectroscopy. AB - Many single-molecule (SM) label-free techniques such as scanning probe microscopies (SPM) and magnetic force spectroscopies (MFS) provide high resolution surface topography information, but lack chemical information. Typical surface enhanced Raman spectroscopy (SERS) systems provide chemical information on the analytes, but lack spatial resolution. In addition, a challenge in SERS sensors is to bring analytes into the so-called "hot spots" (locations where the enhancement of electromagnetic field amplitude is larger than 103). Previously described methods of fluid transport around hot spots like thermophoresis, thermodiffusion/Soret effect, and electrothermoplasmonic flow are either too weak or detrimental in bringing new molecules to hot spots. Herein, we combined the resonant plasmonic enhancement and photonic nanojet enhancemnet of local electric field on nonplanar SERS structures, to construct a stable, high-resolution, and below diffraction limit platform for single molecule label-free detection. In addition, we utilize Marangoni convection (mass transfer due to surface tension gradient) to bring new analytes into the hotspot. An enhancement factor of ~3.6 * 1010 was obtained in the proposed system. Rhodamine-6G (R6G) detection of up to a concentration of 10-12 M, an improvement of two orders of magnitude, was achieved using the nanojet effect. The proposed system could provide a simple, high throughput SERS system for single molecule analysis at high spatial resolution. PMID- 28726384 TI - Lightweight, Room-Temperature CO2 Gas Sensor Based on Rare-Earth Metal-Free Composites-An Impedance Study. AB - We report a light, flexible, and low-power poly(ionic liquid)/alumina composite CO2 sensor. We monitor the direct-current resistance changes as a function of CO2 concentration and relative humidity and demonstrate fast and reversible sensing kinetics. Moreover, on the basis of the alternating-current impedance measurements we propose a sensing mechanism related to proton conduction and gas diffusion. The findings presented herein will promote the development of organic/inorganic composite CO2 gas sensors. In the future, such sensors will be useful for numerous practical applications ranging from indoor air quality control to the monitoring of manufacturing processes. PMID- 28726385 TI - Low-Temperature Postfunctionalization of Highly Conductive Oxide Thin-Films toward Solution-Based Large-Scale Electronics. AB - Although transparent conducting oxides (TCOs) have played a key role in a wide range of solid-state electronics from conventional optoelectronics to emerging electronic systems, the processing temperature and conductivity of solution processed materials seem to be far exceeding the thermal limitations of soft materials and insufficient for high-perfomance large-area systems, respectively. Here, we report a strategy to form highly conductive and scalable solution processed oxide materials and their successful translation into large-area electronic applications, which is enabled by photoassisted postfunctionalization at low temperature. The low-temperature fabrication of indium-tin-oxide (ITO) thin films was achieved by using photoignited combustion synthesis combined with photoassisted reduction process under hydrogen atmosphere. It was noteworthy that the photochemically activated hydrogens on ITO surface could be triggered to facilitate highly crystalline oxygen deficient structure allowing significant increase of carrier concentration and mobility through film microstructure modifications. The low-temperature postfunctionalized ITO films demonstrated conductivity of >1607 S/cm and sheet resistance of <104 Omega/? under the process temperature of less than 300 degrees C, which are comparable to those of vacuum deposited and high-temperature annealed ITO films. Based on the photoassisted postfunctionalization route, all-solution-processed transparent metal-oxide thin film-transistors and large-area integrated circuits with the ITO bus lines were demonstrated, showing field-effect mobilities of >6.5 cm2 V-1 s-1 with relatively good operational stability and oscillation frequency of more than 1 MHz in 7 stage ring oscillators, respectively. PMID- 28726386 TI - Smart Biointerface with Photoswitched Functions between Bactericidal Activity and Bacteria-Releasing Ability. AB - Smart biointerfaces with capability to regulate cell-surface interactions in response to external stimuli are of great interest for both fundamental research and practical applications. Smart surfaces with "ON/OFF" switchability for a single function such as cell attachment/detachment are well-known and useful, but the ability to switch between two different functions may be seen as the next level of "smart". In this work reported, a smart supramolecular surface capable of switching functions reversibly between bactericidal activity and bacteria releasing ability in response to UV-visible light is developed. This platform is composed of surface-containing azobenzene (Azo) groups and a biocidal beta cyclodextrin derivative conjugated with seven quaternary ammonium salt groups (CD QAS). The surface-immobilized Azo groups in trans form can specially incorporate CD-QAS to achieve a strongly bactericidal surface that kill more than 90% attached bacteria. On irradiation with UV light, the Azo groups switch to cis form, resulting in the dissociation of the Azo/CD-QAS inclusion complex and release of dead bacteria from the surface. After the kill-and-release cycle, the surface can be easily regenerated for reuse by irradiation with visible light and reincorporation of fresh CD-QAS. The use of supramolecular chemistry represents a promising approach to the realization of smart, multifunctional surfaces, and has the potential to be applied to diverse materials and devices in the biomedical field. PMID- 28726387 TI - Aryl-Substituted Ruthenium(II) Complexes: A Strategy for Enhanced Photocleavage and Efficient DNA Binding. AB - Ruthenium polypyridine complexes have shown promise as agents for photodynamic therapy (PDT) and tools for molecular biology (chromophore-assisted light inactivation). To accomplish these tasks, it is important to have at least target selectivity and great reactive oxygen species (ROS) photogeneration: two properties that are not easily found in the same molecule. To prepare such new agents, we synthesized two new ruthenium complexes that combine an efficient DNA binding moiety (dppz ligand) together with naphthyl-modified (1) and anthracenyl modified (2) bipyridine as a strong ROS generator bound to a ruthenium complex. The compounds were fully characterized and their photophysical and photochemical properties investigated. Compound 2 showed one of the highest quantum yields for singlet oxygen production ever reported (PhiDelta= 0.96), along with very high DNA binding (log Kb = 6.78). Such photochemical behavior could be ascribed to the lower triplet state involving the anthracenyl-modified bipyridine, which is associated with easier oxygen quenching. In addition, the compounds exhibited moderate selectivity toward G-quadruplex DNA and binding to the minor groove of DNA, most likely driven by the pendant ligands. Interestingly, they also showed DNA photocleavage activity even upon exposure to a yellow light-emitting diode (LED). Regarding their biological activity, the compounds exhibited an exciting antibacterial action, particularly against Gram-positive bacteria, which was enhanced upon blue LED irradiation. Altogether, these results showed that our strategy succeeded in producing light-triggered DNA binding agents with pharmacological and biotechnological potential. PMID- 28726388 TI - Detection of Pesticide Residues in Food Using Surface-Enhanced Raman Spectroscopy: A Review. AB - Pesticides directly pollute the environment and contaminate foods ultimately being absorbed by the human body. Their residues contain highly toxic substances that have been found to cause serious problems to human health even at very low concentrations. The gold standard method, gas/liquid chromatography combined with mass spectroscopy, has been widely used for the detection of pesticide residues. However, these methods have some drawbacks such as complicated pretreatment and cleanup steps. Recent technological advancements of surface-enhanced Raman spectroscopy (SERS) have promoted the creation of alternative detection techniques. SERS is a useful detection tool with ultrasensitivity and simpler protocols. Present SERS-based pesticide residue detection often uses standard solutions of target analytes in conjunction with theoretical Raman spectra calculated by density functional theory (DFT) and actual Raman spectra detected by SERS. SERS is quite a promising technique for the direct detection of pesticides at trace levels in liquid samples or on the surface of solid samples following simple extraction to increase the concentration of analytes. In this review, we highlight recent studies on SERS-based pesticide detection, including SERS for pesticide standard solution detection and for pesticides in/on food samples. Moreover, in-depth analysis of pesticide chemical structures, structural alteration during food processing, interaction with SERS substrates, and selection of SERS-active substrates is involved. PMID- 28726389 TI - Antimelanogenic Effect of Urolithin A and Urolithin B, the Colonic Metabolites of Ellagic Acid, in B16 Melanoma Cells. AB - Antimelanogenic agents from natural sources have been widely investigated. Urolithin A (UA) and B (UB), the main gut microflora metabolites of dietary ellagic acid derivatives, have various bioactivities such as anti-inflammatory and antiaging effects. In this study, the metabolites were found to possess depigmentation efficacy by suppressing tyrosinase activity. Both UA and UB could attenuate melanogenesis in B16 melanoma cells to 55.1 +/- 3.8 and 76.4 +/- 17.4% of control at noncytotoxic dosage, 10 MUM, respectively. UA showed comparable efficacy to positive control, 5 MUM of kojic acid treatment (51.2 +/- 7.8). RT PCR results revealed that UA and UB inhibited melanin formation by affecting the catalytic activity of tyrosinase rather than its mRNA expression. Kinetics for UA and UB on tyrosinase activity revealed that their inhibition behavior toward cellular tyrosinase involved competitive inhibition. UA and UB may be potent tyrosinase inhibitors and they possess significant antimelanogenesis ability as novel skin-whitening ingredients. PMID- 28726390 TI - Glycolipid Biosurfactants Activate, Dimerize, and Stabilize Thermomyces lanuginosus Lipase in a pH-Dependent Fashion. AB - We present a study of the interactions between the lipase from Thermomyces lanuginosus (TlL) and the two microbially produced biosurfactants (BSs), rhamnolipid (RL) and sophorolipid (SL). Both RL and SL are glycolipids; however, RL is anionic, while SL is a mixture of anionic and non-ionic species. We investigate the interactions of RL and SL with TlL at pH 6 and 8 and observe different effects at the two pH values. At pH 8, neither RL nor SL had any major effect on TlL stability or activity. At pH 6, in contrast, both surfactants increase TlL's thermal stability and fluorescence and activity measurements indicate interfacial activation of TlL, resulting in 3- and 6-fold improved activity in SL and RL, respectively. Nevertheless, isothermal titration calorimetry reveals binding of only a few BS molecules per lipase. Size-exclusion chromatography and small-angle X-ray scattering suggest formation of TlL dimers with binding of small amounts of either RL or SL at the dimeric interface, forming an elongated complex. We conclude that RL and SL are compatible with TlL and constitute promising green alternatives to traditional surfactants. PMID- 28726391 TI - Tumor-Associated Mutations in Caspase-6 Negatively Impact Catalytic Efficiency. AB - Unregulated, particularly suppressed programmed cell death is one of the distinguishing features of many cancer cells. The cysteine protease caspase-6, one of the executioners of apoptotic cell death, plays a crucial role in regulation of apoptosis. Several somatic mutations in the CASP6 gene in tumor tissues have been reported. This work explores the effect of CASP6 tumor associated mutations on the catalytic efficiency and structure of caspase-6. In general, these mutations showed decreased overall rates of catalytic turnover. Mutations within 8 A of the substrate-binding pocket of caspase-6 were found to be the most catalytically deactivating. Notably, the R259H substitution decreased activity by 457-fold. This substitution disrupts the cation-pi stacking interaction between Arg-259 and Trp-227, which is indispensable for proper assembly of the substrate-binding loops in caspase-6. Sequence conservation analysis at the homologous position across the caspase family suggests a role for this cation-pi stacking in the catalytic function of caspases generally. These data suggest that caspase-6 deactivating mutations may contribute to multifactorial carcinogenic transformations. PMID- 28726392 TI - Characterization of Naphthenic Acids and Other Dissolved Organics in Natural Water from the Athabasca Oil Sands Region, Canada. AB - With growth of the Canadian oil sands industry, concerns have been raised about possible seepage of toxic oil sands process-affected water (OSPW) into the Athabasca River (AR). A sampling campaign in fall 2015 was undertaken to monitor for anthropogenic seepage while also considering natural sources. Naphthenic acids (NAs) and thousands of bitumen-derived organics were characterized in surface water, groundwater, and OSPW using a highly sensitive online solid phase extraction-HPLC-Orbitrap method. Elevated NA concentrations and bitumen-derived organics were detected in McLean Creek (30.1 MUg/L) and Beaver Creek (190 MUg/L), two tributaries that are physically impacted by tailings structures. This was suggestive of OSPW seepage, but conclusive differentiation of anthropogenic and natural sources remained difficult. High NA concentrations and bitumen-derived organics were also observed in natural water located far north of the industry, including exceedingly high concentrations in AR groundwater (A5w-GW, 2000 MUg/L) and elevated concentration in a tributary river (Pierre River, 34.7 MUg/L). Despite these evidence for both natural and anthropogenic seepage, no evidence of any bitumen-derived organics was detected at any location in AR mainstem surface water. The chemical significance of any bitumen-derived seepage to the AR was therefore minimal, and focused monitoring in tributaries will be valuable in the future. PMID- 28726393 TI - Bioreducible Peptide-Dendrimeric Nanogels with Abundant Expanded Voids for Efficient Drug Entrapment and Delivery. AB - Dendrimer-based nanoplatforms have exhibited wide prospects in the field of nanomedicine for drug delivery, without great success due to many predicaments of cytotoxicity, high cost, and low yield. In this work, we report a feasible strategy on dynamic cross-linkings of low-generation peptide dendrimers into bioreducible nanogels for efficient drug controlled release. With a facile fabrication, the disulfide cross-linking of biocompatible peptide dendrimers successfully possess well-defined and stable nanostructures with abundant expanded voids for efficient molecular encapsulation. More importantly, high reducing condition is capable of triggering the cleavage of disulfide bonds, the disintegration of peptide-dendrimeric nanogels, and stimuli-responsive release of guest molecules. The bioreducible nanogels improve antitumor drug internalization, contribute to endosomal escape, and realize intracellular drug controlled release. The doxorubicin-loaded nanogels afford high antitumor efficiency and reduce the side effects to BALB/c mice bearing 4T1 tumor. Therefore, dynamic cross-linkings of low-generation dendrimers into smart nanogels will be an alternative and promising strategy to resolve the dilemmas of current dendrimer-based nanocarriers as well as develop innovative nanoplatforms. PMID- 28726394 TI - Human CST Prefers G-Rich but Not Necessarily Telomeric Sequences. AB - The human CST (CTC1-STN1-TEN1) heterotrimeric complex plays roles in both telomere maintenance and DNA replication through its ability to interact with single-stranded DNA (ssDNA) of a variety of sequences. The precise sequence specificity required to execute these functions is unknown. Telomere-binding proteins have been shown to specifically recognize key telomeric sequence motifs within ssDNA while accommodating nonspecifically recognized sequences through conformationally plastic interfaces. To better understand the role CST plays in these processes, we have produced a highly purified heterotrimer and elucidated the sequence requirements for CST recognition of ssDNA in vitro. CST discriminates against random sequence and binds a minimal ssDNA comprised of three repeats of telomeric sequence. Replacement of individual nucleotides with their complement reveals that guanines are specifically recognized in a largely additive fashion and that specificity is distributed uniformly throughout the ligand. Unexpectedly, adenosines are also well tolerated at these sites, but cytosines are disfavored. Furthermore, sequences unrelated to the telomere repeat, yet still G-rich, bind CST well. Thus, CST is not inherently telomere specific, but rather is a G-rich sequence binder. This biochemical activity is reminiscent of the yeast t-RPA and Tetrahymena thermophila CST complexes and is consistent with roles at G-rich sites throughout the genome. PMID- 28726395 TI - Synthesis and Mechanism of Formation of Hydride-Sulfide Complexes of Iron. AB - Iron-sulfide complexes with hydride ligands provide an experimental precedent for spectroscopically detected hydride species on the iron-sulfur MoFe7S9C cofactor of nitrogenase. In this contribution, we expand upon our recent synthesis of the first iron sulfide hydride complex from an iron hydride and a sodium thiolate ( Arnet, N. A.; Dugan, T. R.; Menges, F. S.; Mercado, B. Q.; Brennessel, W. W.; Bill, E.; Johnson, M. A.; Holland, P. L., J. Am. Chem. Soc. 2015 , 137 , 13220 - 13223 ). First, we describe the isolation of an analogous iron sulfide hydride with a smaller diketiminate supporting ligand, which benefits from easier preparation of the hydride precursor and easier isolation of the product. Second, we describe mechanistic studies on the C-S bond cleavage through which the iron sulfide hydride product is formed. In a key experiment, use of cyclopropylmethanethiolate as the sulfur precursor leads to products from cyclopropane ring opening, implicating an alkyl radical as an intermediate. Combined with the results of isotopic labeling studies, the data are consistent with a mechanism in which homolytic C-S bond cleavage is followed by rebound of the alkyl radical to abstract a hydrogen atom from iron to give the observed alkane and iron-sulfide products. PMID- 28726396 TI - Potent Anti-Inflammatory and Antiadipogenic Properties of Bamboo (Sasa coreana Nakai) Leaves Extract and Its Major Constituent Flavonoids. AB - The pro-inflammatory response and recruitment of macrophages into adipose tissue contribute to metabolic dysfunction. Here, we reported the anti-inflammatory and antiadipogenic effects of the methanol (MeOH) extract and ethyl acetate (EtOAc) fraction of bamboo leaf and its molecular mechanism in RAW264.7 cells and 3T3-L1 adipocytes, respectively. Functional macrophage migration assays also were performed. Surprisingly, the EtOAc fraction of MeOH extracts from native Korean plant species Sasa coreana Nakai (SCN) has shown potent anti-inflammatory properties; SCN pretreatment inhibited nitric oxide (NO) production (p < 0.01) and inducible nitric oxide synthase (iNOS) expression in lipopolysaccharide (LPS) stimulated macrophages. Inflammatory genes induced by LPS, including TNFalpha, IL 1beta, and IL-6, were significantly attenuated by SCN (p < 0.01). Pretreatment with SCN antagonized NF-kappaB nuclear translocation and the simultaneous degradation of inhibitory kappaB protein. Furthermore, SCN selectively inhibited the LPS-induced phosphorylation of JNK (p < 0.01) and p38 (p < 0.05) but not ERK (p > 0.05). Similar to leaf extracts of other bamboo species, we identified that SCN contained several flavonoids including orientin, isoorientin, and vitexin; these compounds inhibited LPS-induced NO production (p < 0.05) and iNOS expression. In addition, SCN inhibited adipocyte differentiation in a dose dependent manner, as demonstrated by Oil Red O staining and the protein expression of mature adipogenic marker genes. Treatment with the major flavonoids of SCN also inhibited adipogenesis. Furthermore, conditioned medium obtained from adipocytes stimulated macrophage chemotaxis, whereas medium from adipocytes treated with SCN significantly inhibited macrophage migration. Therefore, SCN is a potential therapeutic agent for the prevention of inflammation and obesity. PMID- 28726397 TI - Potential Releases of 129I, 236U, and Pu Isotopes from the Fukushima Dai-ichi Nuclear Power Plants to the Ocean from 2013 to 2015. AB - After the Fukushima Dai-ichi nuclear accident, many efforts were put into the determination of the presence of 137Cs, 134Cs, 131I, and other gamma-emitting radionuclides in the ocean, but minor work was done regarding the monitoring of less volatile radionuclides, pure beta-ray emitters or simply radionuclides with very long half-lives. In this study we document the temporal evolution of 129I, 236U, and Pu isotopes (239Pu and 240Pu) in seawater sampled during four different cruises performed 2, 3, and 4 years after the accident, and we compare the results to 137Cs collected at the same stations and depths. Our results show that concentrations of 129I are systematically above the nuclear weapon test levels at stations located close to the FDNPP, with a maximum value of 790 * 107 at.kg-1, that exceeds all previously reported 129I concentrations in the Pacific Ocean. Yet, the total amount of 129I released after the accident in the time 2011-2015 was calculated from the 129I/137Cs ratio of the ongoing 137Cs releases and estimated to be about 100 g (which adds to the 1 kg released during the accident in 2011). No clear evidence of Fukushima-derived 236U and Pu isotopes has been found in this study, although further monitoring is encouraged to elucidate the origin of the highest 240Pu/239Pu atom ratio of 0.293 +/- 0.028 we found close to FDNPP. PMID- 28726398 TI - A Cyclopeptide and a Tetrahydroisoquinoline Alkaloid from Ophiorrhiza nutans. AB - A new cyclopeptide, ophiorrhisine A (1), a new tetrahydroisoquinoline alkaloid, 7',10-dide-O-methylcephaeline (2), two known beta-carboline alkaloids, and four known tetrahydroisoquinoline alkaloids were isolated from Ophiorrhiza nutans (Rubiaceae). Compound 1 is a tetrapeptide possessing a 14-membered paracyclophane ring and a novel N,N,N-trimethyltyrosine residue in the side chain. The stereochemistry at the aryl-alkyl ether bond was different from that of other known 14-membered paracyclophanes. The structure of 2 was established by spectroscopic analysis and semisynthesis. PMID- 28726399 TI - Finding the Next Deep-Ultraviolet Nonlinear Optical Material: NH4B4O6F. AB - Nonlinear optical materials are essential for the development of solid-state lasers. KBe2BO3F2 (KBBF) is a unique nonlinear optical material for generation of deep-ultraviolet coherent light; however, its industrial application is limited. Here, we report a new material NH4B4O6F, which exhibits a wide deep-ultraviolet transparent range and suitable birefringence that enables frequency doubling below 200 nm. NH4B4O6F possesses large nonlinear coefficients about 2.5 times that of KBBF. In addition, it is easy to grow bulk crystals and does not contain toxic elements. PMID- 28726400 TI - Quinoliniumolate and 2H-1,2,3-Triazole Derivatives from the Stems of Paramignya trimera and Their alpha-Glucosidase Inhibitory Activities: In Vitro and in Silico Studies. AB - From a CHCl3-soluble extract of the stems of Paramignya trimera, two new alkaloids, (E)-2-(prop-1-enyl)-N-methylquinolinium-4-olate (1) and (R)-2 ethylhexyl 2H-1,2,3-triazole-4-carboxylate (2), were isolated. Their structures were elucidated based on the spectroscopic data interpretation. Compound 2 possesses alpha-glucosidase inhibitory activity, with an IC50 value of 137.9 MUM. Molecular docking studies of 1 and 2 with human maltase-glucoamylase (MGAM) were performed for the first time; thus, the 2,3-diH+-1H-1,2,3-triazolium cation (2i) showed good interactions with both MGAM-N (2QMJ) and -C (3TOP) terminal subunits. PMID- 28726401 TI - Amidoalkylindoles as Potent and Selective Cannabinoid Type 2 Receptor Agonists with in Vivo Efficacy in a Mouse Model of Multiple Sclerosis. AB - Selective CB2 agonists represent an attractive therapeutic strategy for the treatment of a variety of diseases without psychiatric side effects mediated by the CB1 receptor. We carried out a rational optimization of a black market designer drug SDB-001 that led to the identification of potent and selective CB2 agonists. A 7-methoxy or 7-methylthio substitution at the 3-amidoalkylindoles resulted in potent CB2 antagonists (27 or 28, IC50 = 16-28 nM). Replacement of the amidoalkyls from 3-position to the 2-position of the indole ring dramatically increased the agonist selectivity on the CB2 over CB1 receptor. Particularly, compound 57 displayed a potent agonist activity on the CB2 receptor (EC50 = 114 142 nM) without observable agonist or antagonist activity on the CB1 receptor. Furthermore, 57 significantly alleviated the clinical symptoms and protected the murine central nervous system from immune damage in an experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis. PMID- 28726402 TI - Opioid Receptor Modulators with a Cinnamyl Group. AB - To obtain selective and potent opioid receptor ligands, we synthesized dehydro derivatives of alvimopan and found compound (28f), a selective but modest affinity MOR antagonist weaker than alvimopan (1). We replaced the arylpiperidine unit by an arylpiperazine to obtain the 1-(alpha-carboxycinnamyl)-4 arylpiperazines like 13h, which to our surprise had no MOR or DOR activity but was a KOR agonist with moderate affinity. In contrast, literature examples of arylpiperazines 4 and 5 were reported to be pan opioid receptor antagonists, while 6 was a MOR agonist. Two compounds (13l and 11b) showed analgesic response in tail flick test which was blocked by pretreatment with norbinaltorphimine (norBNI). Among 10 1-(alpha-carboxycinnamyl)-4-arylpiperidines, compound 28g and five others were specific MOR antagonists. Interestingly, compound 26b of this series was found to be more potent than naloxone but weaker than 1. Docking studies have explained differential activities of the above piperazines and piperidines. PMID- 28726403 TI - Molecular Mobility of an Amorphous Chiral Pharmaceutical Compound: Impact of Chirality and Chemical Purity. AB - A dielectric relaxation spectroscopy (DRS) study was performed to investigate the molecular mobility of amorphous chiral diprophylline (DPL). For this purpose, both racemic DPL and a single enantiomer of DPL were considered. After fast cooling from the melt at very low temperature (-140 degrees C), progressive heating below and above the glass transition (Tg ~ 37 degrees C) induces two secondary relaxations (gamma- and delta-) and primary relaxations (alpha-) for both enantiomeric compositions. After chemical purification of our samples by means of cooling recrystallization, no gamma-process could be detected by DRS. Hence, it was highlighted that the molecular mobility in the glassy state is influenced by the presence of theophylline (TPH), the main impurity in DPL samples. We also proved that the dynamic behavior of a single enantiomer and the racemic mixture of the same purified compound are quasi-identical. This study demonstrates that the relative stability and the molecular mobility of chiral amorphous drugs are strongly sensitive to chemical purity. PMID- 28726404 TI - Predicting Optimal DEER Label Positions to Study Protein Conformational Heterogeneity. AB - Double electron-electron resonance (DEER) spectroscopy is a powerful experimental technique for understanding the conformational heterogeneity of proteins. It involves attaching nitroxide spin labels to two residues in the protein to obtain a distance distribution between them. However, the choice of residue pairs to label in the protein requires careful thought, as experimentalists must pick label positions from a large set of all possible residue-pair combinations in the protein. In this article, we address the problem of the choice of DEER spin-label positions in a protein. For this purpose, we utilize all-atom molecular dynamics simulations of protein dynamics, to rank the sets of labeled residue pairs in terms of their ability to capture the conformational dynamics of the protein. Our design methodology is based on the following two criteria: (1) An ideal set of DEER spin-label positions should capture the slowest conformational-change processes observed in the protein dynamics, and (2) any two sets of residue pairs should describe orthogonal conformational-change processes to maximize the overall information gain and reduce the number of labeled residue pairs. We utilize Markov state models of protein dynamics to identify slow dynamical processes and a genetic-algorithm-based approach to predict the optimal choices of residue pairs with limited computational time requirements. We predict the optimal residue pairs for DEER spectroscopy in beta2 adrenergic receptor, the C terminal domain of calmodulin, and peptide transporter PepTSo. We find that our choices were ranked higher than those used to perform DEER experiments on the proteins investigated in this study. Hence, the predicted choices of DEER residue pairs determined by our method provide maximum insight into the conformational heterogeneity of the protein while using the minimum number of labeled residues. PMID- 28726405 TI - Fluorescence Enhancement of Unconstrained GFP Chromophore Analogues Based on the Push-Pull Substituent Effect. AB - Unlike the high fluorescence quantum yield of the naturally occurring green fluorescence protein (GFP, Phif ~ 0.8), the GFP chromophore, a benzylidenedimethylimidazolinone (BDI) dye, is nearly nonfluorescent (Phif < 0.001) in common solutions at room temperature. While many efforts have been devoted into the BDI chromophore engineering for fluorescence recovery, limited success has been achieved for structurally unconstrained GFP chromophore analogues (uGFPc). Herein we report a rational design of uGFPc toward an unprecedentedly high fluorescence quantum efficiency of 0.60 in hexane. This is achieved by a combined ortho-CN and meta-dimethylamino substituent electronic effect that largely suppresses the Z -> E photoisomerization (the tau torsion) reaction, which is the major nonradiative decay channel of uGFPc. The structural design relied on the assumptions that the tau torsion of the meta-amino substituted BDI systems leads to a zwitterionic twisted intermediate state (1p*) and that destabilizing the 1p* state by an electron-withdrawing CN substituent at the ortho or para position could slow down the tau torsion. The observed CN position effect conforms to the design concept. The push-pull substitution of BDI also leads to sensitive fluorescence-quenching responses to electron donors such as trimethylamine and to H-bond donors such as methanol. PMID- 28726406 TI - Regioselective Bromination of Thieno[2',3':4,5]pyrrolo[1,2-d][1,2,4]triazin-8(7H) one and Sequential Suzuki Couplings. AB - Regioselective bromination of thieno[2',3':4,5]pyrrolo[1,2-d][1,2,4]triazin-8(7H) one at the 2- or 9-position was achieved by modulating the basicity of the reaction conditions. An anion-directed site-specific bromination mechanism was proposed. In addition, a one-pot bromination-Suzuki coupling protocol was developed for quick access of analogues at the 9-position. PMID- 28726408 TI - A Computational Study on the Addition of HONO to Alkynes toward the Synthesis of Isoxazoles; a Bifurcation, Pseudopericyclic Pathways and a Barrierless Reaction on the Potential Energy Surface. AB - Homopropargyl alcohols react with t-BuONO to form acyloximes which can be oxidatively cyclized to yield ioxazoles. The mechanism for the initial reaction of HONO with alkynes to form acyloximes (e.g., 13c) has been explored at the B3LYP/6-31G(d,p) + ZPVE level of theory. The observed chemoselectivity and regioselectivity are explained via an acid-catalyzed mechanism. Furthermore, the potential energy surface revealed numerous surprising features. The addition of HONO (8) to protonated 1-phenylpropyne (18) is calculated to follow a reaction pathway involving sequential transition states (TS6 and TS8), for which reaction dynamics likely play a role. This reaction pathway can bypass the expected addition product 21 as well as transition state TS8, directly forming the rearranged product 23. Nevertheless, TS8 is key to understanding the potential energy surface; there is a low barrier for the pseudopericylic [1,3]-NO shift, calculated to be only 8.4 kcal/mol above 21. This places TS8 well below TS6, making the valley-ridge inflection point (VRI or bifurcation) and direct formation of 23 possible. The final tautomerization step to the acyloxime can be considered to be a [1,5]-proton shift. However, the rearrangement in the case of 17h to 13c is calculated to be barrierless, arguably because the pathway is pseudopericyclic and exothermic. PMID- 28726407 TI - Residue Specific Interaction of an Unfolded Protein with Solvents in Mixed Water Ethanol Solutions: A Combined Molecular Dynamics and ONIOM Study. AB - The molecular mechanism of ethanol governed unfolding of an enzymatic protein, chymotrypsin inhibitor 2 (CI2), in water-ethanol mixed solutions has been studied by using combined molecular dynamics simulations and ONIOM study. The residue specific solvation of the unfolded protein and the interactions between the individual amino acid residues of the protein with ethanol as well as water have been investigated. The results are compared with that obtained from the folded state of the protein. Further, emphasis has been given to explore the residue's preferential site of attraction toward the nature of the solvents. The heterogeneous structuring of water and ethanol around the hydrophobic and hydrophilic surfaces of the protein is found to correlate well with their available surface areas to the solvents. Both hydrophobic and hydrophilic interactions are found to have important contributions in rupturing protein's secondary structural segments. Further, residue-water as well as residue-ethanol binding energies show significant involvement of the hydrogen bonding environment in the unfolding process; particularly, residue-water hydrogen bonds are found to play an indispensable role. PMID- 28726409 TI - Observation of Steady Shear-Induced Nematic Ordering of Selenium Chain Moieties in Arsenic Selenide Liquids. AB - Structural anisotropy induced by steady shear and its mechanistic relation with shear thinning are investigated in AsxSe100-x glasses (5 <= x <= 30) quenched from parent liquids subjected to shear rates ranging between 0 and 104 s-1 using polarized Raman spectroscopy and two-dimensional X-ray diffraction. When taken together, the results demonstrate significant shear-induced partial alignment of Se-Se-Se- chain moieties in the flow direction of the extruded fibers. This alignment is reminiscent of nematic liquid crystals where orientational order exists without positional order. The degree of this structural alignment in quenched glasses appears to be practically independent of the shear rate, although the parent liquids undergo shear thinning at the highest shear rates. It is conjectured that any causal relationship between structural alignment and shear thinning in the liquid may be masked in the glassy state by the postextrusion structural relaxation of the parent liquid. PMID- 28726411 TI - Temperature-Dependent Partitioning of C152 in Binary Phosphatidylcholine Membranes and Mixed Phosphatidylcholine/Phosphatidylethanolamine Membranes. AB - Time-resolved fluorescence and differential scanning calorimetry were used to determine the partitioning of coumarin 152 (C152) into large unilamellar vesicles composed of binary mixtures of two phosphatidylcholines (12:0/12:0 DLPC and 14:0/14:0 DMPC) and vesicles composed of binary mixtures of a phosphatidylcholine and a phosphatidylethanolamine (14:0/14:0 DMPC and 14:0/14:0 DMPE). Differential scanning calorimetry showed that both DLPC/DMPC and DMPC/DMPE are miscible in lipid vesicles. Time-resolved fluorescence indicated that C152 partitioning into DLPC/DMPC mixtures showed nearly ideal behavior that was described with weighted contributions from C152 partitioning into pure DLPC and pure DMPC vesicles. In contrast, C152 partitioning into DMPC/DMPE mixtures was distinctly nonideal. For DMPC/DMPE lipid vesicles having DMPC mole fractions between 10 and 80%, C152 partitioning into the bilayer was measurably enhanced near the melting temperature, relative to expectations based simply on weighted contributions from C152 partitioning into vesicles comprised of pure lipids. The origin of this behavior remains uncertain. For vesicles comprised of pure DMPE, C152 shows almost no partitioning into the membrane, with >=80% of the solute remaining in the buffer solution at temperatures between 10 and 50 degrees C. PMID- 28726410 TI - Structural Insights into the Yersinia pestis Outer Membrane Protein Ail in Lipid Bilayers. AB - Yersinia pestis the causative agent of plague, is highly pathogenic and poses very high risk to public health. The outer membrane protein Ail (Adhesion invasion locus) is one of the most highly expressed proteins on the cell surface of Y. pestis, and a major target for the development of medical countermeasures. Ail is essential for microbial virulence and is critical for promoting the survival of Y. pestis in serum. Structures of Ail have been determined by X-ray diffraction and solution NMR spectroscopy, but the protein's activity is influenced by the detergents in these samples, underscoring the importance of the surrounding environment for structure-activity studies. Here we describe the backbone structure of Ail, determined in lipid bilayer nanodiscs, using solution NMR spectroscopy. We also present solid-state NMR data obtained for Ail in membranes containing lipopolysaccharide (LPS), a major component of the bacterial outer membranes. The protein in lipid bilayers, adopts the same eight-stranded beta-barrel fold observed in the crystalline and micellar states. The membrane composition, however, appears to have a marked effect on protein dynamics, with LPS enhancing conformational order and slowing down the 15N transverse relaxation rate. The results provide information about the way in which an outer membrane protein inserts and functions in the bacterial membrane. PMID- 28726412 TI - Fe(II)-Catalyzed Isomerization of 4-Vinylisoxazoles into Pyrroles. AB - The first synthesis of pyrroles by Fe(II)-catalyzed isomerization of 4 vinylisoxazoles is reported. 5-Alkoxy, amino, and N,N-dialkylamino-3-aryl/alkyl-4 (2-R-vinyl)isoxazoles afford 2-aryl/alkyl-5-aryl/alkyl/methoxycarbonyl-1H-pyrrol 3-carboxylic acid derivatives typically under mild conditions with cheap and available FeCl2.4H2O as a catalyst. The isomerization of 5-alkoxy/amino-3 arylisoxazoles, bearing unsaturated carbo and heterocyclic substituents at the position 4, gives the corresponding fused pyrrolecarboxylic acid derivatives in high yields. DFT calculations were used to elucidate a probable mechanism of the isomerization and explain the influence of steric congestion of the vinyl moiety on the isomerization pathway. PMID- 28726413 TI - Catalytic Asymmetric Electrophilic Cyanation of 3-Substituted Oxindoles. AB - The first example of catalytic asymmetric electrophilic cyanation of 3 substituted oxindoles has been achieved using readily accessible 4-acetylphenyl cyanate as the cyano source. Thus, a series of all-carbon quaternary center 3 aryl-3-cyano oxindoles were prepared using a zinc complex of a chiral pincer ligand as the catalyst in high yields (up to 95%) and excellent enantioselectivities (up to >99% ee) in the presence of 4 A MS and 2,6-lutidine in THF at 0 degrees C. PMID- 28726414 TI - Citrifurans A-D, Four Dimeric Aromatic Polyketides with New Carbon Skeletons from the Fungus Aspergillus sp. AB - Citrifurans A-D (1-4), metabolized by an Aspergillus sp., are unusual dimers of azaphilone and furanone derivatives. Michael addition was thought to be the pivotal procedure in their biosynthesis, and different addition sites generated two new different carbon skeletons. Their structures were elucidated on the basis of spectroscopic methods, single-crystal X-ray diffraction, chemical conversion, and electronic circular dichroism analyses. Compounds 1-3 showed moderate inhibitory activities against LPS-induced NO production in RAW 264.7 macrophages with IC50 values of 18.3, 22.6, and 25.3 MUM, respectively. PMID- 28726415 TI - Enhanced Diffusion of Passive Tracers in Active Enzyme Solutions. AB - Colloidal suspensions containing microscopic swimmers have been the focus of recent studies aimed at understanding the principles of energy transfer in fluidic media at low Reynolds number conditions. Going down in scale, active enzymes have been shown to be force-generating, nonequilibrium systems, thus offering opportunity to examine energy transfer at the ultralow Reynolds number regime. By monitoring the change of diffusion of inert tracers dispersed in active enzyme solutions, we demonstrate that the nature of energy transfer in these systems is similar to that reported for larger microscopic active systems, despite the large differences in scale, modes of energy transduction, and propulsion. Additionally, even an enzyme that catalyzes an endothermic reaction behaves analogously, suggesting that heat generation is not the primary factor for the observed enhanced tracer diffusion. Our results provide new insights into the mechanism of energy transfer at the molecular level. PMID- 28726416 TI - Atropisomeric Chiral Diiododienes (Z,Z)-2,3-Di(1-iodoalkylidene)tetralins: Synthesis, Enantiomeric Resolution, and Application in Asymmetric Catalysis. AB - The C2-symmetric tetralin-fused 1,4-diiodo-1,3-butadiene derivatives, (Z,Z)-2,3 di(1-iodoalkylidene)tetralin 1a-c, are atropisomeric and can be resolved into the two persistent axially chiral enantiomers by HPLC on a chiral stationary phase. The enantiomerically pure compounds can serve as chiral organocatalysts for dearomatizing spirolactonization to show good performance in up to 73% ee. PMID- 28726417 TI - Large Reverse Saturable Absorption at the Sunlight Power Level Using the Ultralong Lifetime of Triplet Excitons. AB - Large reverse saturable absorption (RSA) at the sunlight power level was observed from a host-guest amorphous material composed of d12-coronene as a guest and beta estradiol as a rigid amorphous host. The large highly symmetric two-dimensional (2D) aromatic structure of d12-coronene doped into the rigid host causes ultralong triplet lifetime as well as high triplet yield, serving efficient accumulation of the triplet excitons of d12-coronene under weak excitation light. The high absorption coefficient of the triplet state (sigma34) compared with that of the ground state (sigma01) for d12-coronene is also caused by the highly symmetric 2D aromatic structure. The efficient accumulation of the triplet excitons and high sigma34 - sigma01 led to an onset of the RSA characteristics under irradiance below 10-1 mW cm-2. A film of the amorphous material showed a large decrease of transmittance from 66% at 0.02 mW cm-2 to 24% at 50 mW cm-2 for continuous light at 405 nm. PMID- 28726419 TI - Hitoyol A and B, Two Norsesquiterpenoids from the Basidiomycete Coprinopsis cinerea. AB - Hitoyol A (1), an unprecedented norsesquiterpenoid with an exo tricyclo[5.2.1.02,6]decane skeleton, was isolated from the culture broth of Basidiomycete Coprinopsis cinerea along with a novel skeletal hitoyol B (2) containing 4-cyclopentene-1,3-dione. Their structures and absolute configurations were analyzed by single-crystal X-ray diffraction and electronic circular dichroism spectroscopic methods. Compound 1 is possibly biosynthesized through decarboxylation-induced cyclization of lagopodin B, a known cuparene-type sesquiterpenoid. Compound 2 showed weak antimalarial activity with an IC50 of 59 MUM. PMID- 28726418 TI - Quantitative Assessment of the Effects of Trypsin Digestion Methods on Affinity Purification-Mass Spectrometry-based Protein-Protein Interaction Analysis. AB - Affinity purification-mass spectrometry (AP-MS) has become the method of choice for discovering protein-protein interactions (PPIs) under native conditions. The success of AP-MS depends on the efficiency of trypsin digestion and the recovery of the tryptic peptides for MS analysis. Several different protocols have been used for trypsin digestion of protein complexes in AP-MS studies, but no systematic studies have been conducted on the impact of trypsin digestion conditions on the identification of PPIs. Here, we used NFkappaB/RelA and Bromodomain-containing protein 4 (BRD4) as baits and test five distinct trypsin digestion methods (two using "on-beads," three using "elution-digestion" protocols). Although the performance of the trypsin digestion protocols change slightly depending on the different baits, antibodies and cell lines used, we found that elution-digestion methods consistently outperformed on-beads digestion methods. The high-abundance interactors can be identified universally by all five methods, but the identification of low-abundance RelA interactors is significantly affected by the choice of trypsin digestion method. We also found that different digestion protocols influence the selected reaction monitoring (SRM)-MS quantification of PPIs, suggesting that optimization of trypsin digestion conditions may be required for robust targeted analysis of PPIs. PMID- 28726420 TI - Stereoselective Access to Alkylidenecyclobutanes through gamma-Selective Cross Coupling Strategies. AB - Alkylidenecyclobutanes (ACBs) containing all-carbon quaternary stereocenters were simply and efficiently synthesized by combining boron-homologation and gamma selective cross-coupling strategies. This unique sequence led to excellent regio- and diastereoselectivities in the generation of targeted four-membered rings with up to 99% enantiomeric excess using chiral substrates. In addition to the original synthesis of ACBs, the first asymmetric catalytic formation of quaternary stereocenters based on gamma-selective cross-coupling reactions is finally shown. PMID- 28726421 TI - Introduction of Trifluoroethylamine as Amide Isostere by C-H Functionalization of Heteroarenes. AB - A direct and efficient introduction of a trifluoroethylamine motif into various heteroaromatic structures, using a readily available xanthate S-[1-(N acetylamino)-2,2,2-trifluoroethyl]-O-ethyl dithiocarbonate (5), is reported. Medicinally relevant trifluoroethylaminated heteroarenes containing a wide range of functional groups were successfully synthesized under mild conditions. This amide isostere could be introduced into both electron-rich and -poor heteroarenes to give the desired products in one step. The beneficial effect of camphorsulfonic acid (CSA) was also demonstrated with electron-deficient heteroarenes. PMID- 28726422 TI - BF3-Promoted Divergent Reactions between Tryptophols and Propargylic Alcohols. AB - Trifluoroboron-promoted cascade reactions between tryptophols and propagylic alcohols furnished three types of skeletons, including carbazoles, cyclopenta[b]furo[2,3-b]indoles, and allenyl furo[2,3-b]indoles, with excellent selectivity based on the substrate structure. Tryptophols without a substituent on the 2-position of the indole ring reacted with 1,1,3-triphenylprop-2-yn-1-ol and 9-(phenylethynyl)-9H-fluoren-9-ol to give carbazoles and cyclopenta[b]furo[2,3-b]indoles, respectively, while the reaction of 2 substituted tryptophols afforded allenylfuro[2,3-b]indoles. PMID- 28726423 TI - Radical Difluoromethylation of Thiols with (Difluoromethyl)triphenylphosphonium Bromide. AB - A method for facile difluoromethylation of various thiols using (difluoromethyl)triphenylphosphonium bromide under mild reaction conditions is presented. The transformation proceeds in the absence of any transition metal using a bench-stable and readily accessible phosphonium salt. Deuterium labeling experiments and cyclic voltammetry measurements reveal that the difluoromethylation occurs via a SRN1-type mechanism. Substrate scope is broad, and various functional groups are tolerated (OH, NH2, amide, ester). PMID- 28726425 TI - Ruthenium(II)-Catalyzed Hydroarylation of Maleimides Using Carboxylic Acids as a Traceless Directing Group. AB - An efficient Ru(II)-catalyzed hydroarylation of maleimides with ready-stock aryl carboxylic acids has been developed based on weak carboxylate-directed ortho-C-H alkylation and concomitant decarboxylation processes, fabricating 3-aryl succinimides, a recurrent scaffold in drug molecules, in high yields (up to 97%). The protocol features operational simplicity, avoids the need for precious metal additives/oxidants, and offers broad substrate scope with formal meta- and para selectivities. It represents the first example of Ru(II)-catalyzed direct arylation of maleimides with unbiased benzoic acids. PMID- 28726426 TI - Catalytic and Enantioselective Diels-Alder Reactions of (E)-4-Oxopent-2-enoates. AB - Novel oxazaborolidines activated by the strong acid triflimide or AlBr3 form cationic chiral catalysts. These are effective catalysts for highly regio- and enantioselective Diels-Alder reactions using substituted (E)-4-oxopent-2-enoates as dienophiles. PMID- 28726424 TI - Self-encapsulating Poly(lactic-co-glycolic acid) (PLGA) Microspheres for Intranasal Vaccine Delivery. AB - Herein we describe a formulation of self-encapsulating poly(lactic-co-glycolic acid) (PLGA) microspheres for vaccine delivery. Self-healing encapsulation is a novel encapsulation method developed by our group that enables the aqueous loading of large molecules into premade PLGA microspheres. Calcium phosphate (CaHPO4) adjuvant gel was incorporated into the microspheres as a protein trapping agent for improved encapsulation of antigen. Microspheres were found to have a median size of 7.05 +/- 0.31 MUm, with a w/w loading of 0.60 +/- 0.05% of ovalbumin (OVA) model antigen. The formulation demonstrated continuous release of OVA over a 49-day period. Released OVA maintained its antigenicity over the measured period of >21 days of release. C57BL/6 mice were immunized via the intranasal route with prime and booster doses of OVA (10 MUg) loaded into microspheres or coadministered with cholera toxin B (CTB), the gold standard of mucosal adjuvants. Microspheres generated a Th2-type response in both serum and local mucosa, with IgG antibody responses approaching those generated by CTB. The results suggest that this formulation of self-encapsulating microspheres shows promise for further study as a vaccine delivery system. PMID- 28726427 TI - Rh(III)-Catalyzed C-H Activation/Cyclization of Benzamides and Diazonaphthalen 2(1H)-ones for Synthesis of Lactones. AB - A Rh(III)-catalyzed C-H activation/cyclization of benzamides and diazonaphthalen 2(1H)-ones for synthesis of lactones has been developed. In the presence of Rh(III) catalysis, the benzamides would form rhodacycle species and could be trapped by diazonaphthalen-2(1H)-ones for arylation, and the following intramolecular lactonization would rapidly furnish the products. Thus, the diazonaphthalen-2(1H)-ones were first revealed as a lactonization component in Rh(III)-catalysis, while the kinetic isotope effect study was conducted and a plausible reaction mechanism was proposed. PMID- 28726428 TI - [A present view on ivabradine in the therapy of cardiovascular diseases]. AB - Cardiovascular illnesses belong to diseases with the highest prevalence. They are also the most predominant reason of death in the vast majority of European countries. Hence, the offer of effective treatment of these dis-eases is absolutely crucial. This text focuses on the current therapeutical use of ivabradine in its approved indications - chronic stable angina pectoris and chronic heart failure - in the context of so far published relevant clinical trials.Key words: angina pectoris - bradines - heart failure - If current - ischemic heart disease - ivabradine. PMID- 28726429 TI - [Osteoprotective therapy with bisphosphonates or denosumab in patients with multiple myeloma: benefit and risks]. AB - Bisphosphonates have been used during the complete treatment of multiple myeloma for more than twenty years. They slow osteolysis and thereby contribute to the improvement of quality of life. Their long-term use, however, is related to 2 serious, usually later appearing complications: osteonecrosis of the jaw, occurring in 6-9 % of patients, and rarer atypical bone fractures. Both these complications are very difficult to heal, and all the more emphasis is therefore laid on prevention. This first of all includes discussion about the risk with the patient, followed by a dental checkup before the commencement of therapy and then repeated during its course, as well as reduced use of these drugs for a necessary period of time. However osteonecrosis of the jaw does not only develop as a consequence of bisphosphonate therapy. The complication is also caused by some new drugs (denosumab and others) used in cancer therapies. The text includes an overview of the drugs currently used in cancer treatment, which also increase the risk of appearance of osteonecrosis of the jaw. For patients with multiple myeloma, who achieve the complete or very good partial remission after chemotherapy, it is recommended to administer these drugs for more than 1 year after achieving the positive treatment response, but not longer than for 2 years. Only regarding those who do not reach the good treatment response, bisphosphonates are administered over the long term, as long as osteolytic activity of the disease lasts.Key words: atypical bone fractures - bisphosphonates - drug induced osteonecrosis of the jaw - multiple myeloma. PMID- 28726430 TI - [Thoughts about valvular abnormalities yesterday and today]. AB - The article deals with the problems of acquired valvular disorders. It mainly focuses on the new findings regarding ethiopathogenesis, diagnostics, evaluation and treatment, especially catheterization. In advanced countries, post-rheumatic abnormalities have almost disappeared, their current etiology has substantially changed (mitral stenosis). The earlier relatively rare degenerative changes now predominate, mainly affecting older patients (aortic stenosis). Also the treatment methods for acquired abnormalities have substantially changed - currently catheterization approaches are used more frequently in their correction.Key words: aortic regurgitation - aortic stenosis - echocardiography for valvular abnormalities - magnetic resonance abnormalities - mitral regurgitation - mitral stenosis - valve replacement. PMID- 28726431 TI - [What has the GLAGOV clinical study shown?] AB - If we want to favorably influence the cardiovascular atherosclerotic disease, it is necessary to significantly lower LDL-C blood levels. PCSK9 inhibitors can significantly reduce LDL-cholesterol levels, being administered together with statins. However we focus on establishing whether this plays a role in influencing coronary atherosclerosis. The GLAGOV study is a multicentric, double blinded and placebo-controlled study which during a 76-week period followed an impact of the treatment with evolocumab (PCSK9i) together with statin on the status of coronary atherosclerosis in patients with ischemic heart disease, and in comparison with the statin treatment. 968 patients at an average age of 60 have reached a significant decline in the levels of serum LDL-cholesterol (from 2.39 to 0.95 mmol/l) in the branch of the combined therapy, which led to a considerable reduction of percent atheroma volume in the coronary artery by 0.95% (in the branch of the statin-only therapy, the percent atheroma volume increased by 0.05%). The therapy was safe. As shown by the results, evolocumab can through additional reduction of blood levels of LDL-C favorably influence (reduce) coronary atherosclerosis.Key words: evolocumab - regression of coronary atherosclerosis - LDL-C blood levels. PMID- 28726432 TI - [News in the treatment of hypertension and dyslipidemia]. AB - These review article presents the results of major recent studies in cardiovascular prevention. HOPE-3 study showed that people with medium cardiovascular risk who have not experienced a cardiovascular event, and have normal blood pressure, benefit from deploying a statin, and in the presence of hypertension benefit from deploying a combination of a statin and antihypertensive drugs. Studies evaluating genetic predisposition brought new evidence that both LDL cholesterol and systolic blood pressure are independent and multiplicative causal risk factors for cardiovascular events. A mild long term reduction in blood pressure and LDL cholesterol has the potential to significantly reduce the lifetime risk of cardiovascular events. In the final section the article discusses options for improving patient adherence to antihypertensive and lipid treatment and the new available fixed combinations for these diseases.Key words: arterial hypertension - cardiovascular prevention - dyslipidemia - fixed combinations - treatment. PMID- 28726433 TI - Gastric antral vascular ectasia and solitary rectal ulcer syndrome - two rare diagnoses as the cause of anemia in a single patient: case report. AB - Gastric antral vascular ectasia (GAVE) and solitary rectal ulcer syndrome (SRUS) are both mentioned in the literature as rare causes of iron deficiency anemia and gastrointestinal (GI) bleeding. GAVE accounts for up to 4 % of upper non-variceal GI bleeding; SRUS is a rare benign disorder that presents with rectal bleeding. We present the case of a 75-year-old patient who was admitted to our facility with anemia. In the same patient, we encountered chronic bleeding from GAVE and SRUS. Both diagnoses were treated endoscopically: GAVE by argon plasma coagulation and a subsequent treatment with proton pump inhibitors and SRUS by adrenaline injection and clipping, consecutively treated with mesalazine enemas. The patient was successfully cured, resulting in a stable level of hemoglobin and no recurrent GI bleeding. We report a unique case of chronic GI bleeding caused by two uncommon diagnoses. The co-occurrence of GAVE and SRUS has not been previously described or published.Key words: anemia - endoscopy - gastric antral vascular ectasia (GAVE) - gastrointestinal bleeding - solitary rectal ulcer syndrome (SRUS). PMID- 28726434 TI - [Salvation of the diabetic foot through a comprehensive individualized treatment of the patient with type 2 diabetes: case study]. AB - This is a case of men with type 2 diabetes mellitus and diabetic foot. The patient was in danger of limb amputation. After improvement of diabetes, hypertension and dyslipidemia therapies a comprehensive treatment of diabetic foot including angioplasty, antibiotics and local maggot therapy was used for diabetic foot management. Therapy result was very satisfying for the patient. Despite of amputation of the 2nd digit due to advanced gangrene, the whole foot function was saved.Key words: diabetes foot - maggot therapies - type 2 diabetes mellitus. PMID- 28726435 TI - [Acute lymphoblastic leukemia of adults - a case of prolonged hip pain diagnostics with a surprising conclusion: case report]. AB - Though acute lymphoblastic leukemia (ALL) is the most common malignancy of childhood age, it is a rare diagnosis in adults. This disease often manifests with common and nonspecific symptoms, so it can easily escape an early diagnostics without a proper blood count examination. We present a case of an adult ALL patient suffering only from severe hips and thighs pain, without any significant blood count abnormities leading to the diagnostics. In the second part of the article, we summarize current highlights regarding this disease.Key words: acute lymphoblastic leukemia - adult - biological treatment - bone pain - CAR T-cells - osteolysis - symptoms. PMID- 28726436 TI - Is it intestinal tuberculosis again? Case report. AB - This case report focuses on an immigrant admitted to the Department of Respiratory Diseases, University Hospital Brno due to suspicion of relapsing intestinal tuberculosis. The patient presented with fever, night sweat, weight loss, diarrhea, and a history of several tuberculosis attacks in the last few years. None of the examinations confirmed the presence of active tuberculosis but raised suspicion of hematological malignancy. Pancytopenia was present in the peripheral blood. However, bone marrow examination and flowcytometry excluded the presence of a hematological malignancy. The results pointed to the possibility of vitamin B12 or folate deficiency that were both confirmed consequently by serum biochemical tests. Cobalamin and folate deficiency were caused by short bowel syndrome that developed after a major intestinal resection that the patient underwent in his past. Combined treatment including vitamins, pancreatic enzymes substitution, antidiarrhoics and spasmolytics was administered. The general health status of the patient improved rapidly with restitution of hematopoiesis, weight gain, and a decrease by 80% in daily number of stools. Clinical appearance of intestinal tuberculosis, short bowel syndrome and of cobalamin and folate deficiency as well as pathophysiology, diagnosis and treatment of these uncommon or even rare diseases are discussed in this case report.Key words: intestinal tuberculosis - pancytopenia - short bowel syndrome - vitamin B12 deficiency. PMID- 28726437 TI - Anti-profit beliefs: How people neglect the societal benefits of profit. AB - Profit-seeking firms are stereotypically depicted as immoral and harmful to society. At the same time, profit-driven enterprise has contributed immensely to human prosperity. Though scholars agree that profit can incentivize societally beneficial behaviors, people may neglect this possibility. In 7 studies, we show that people see business profit as necessarily in conflict with social good, a view we call anti-profit beliefs. Studies 1 and 2 demonstrate that U.S. participants hold anti-profit views of real U.S. firms and industries. Study 3 shows that hypothetical organizations are seen as doing more harm when they are labeled "for-profit" rather than "non-profit," while Study 4 shows that increasing harm to society is viewed as a strategy for increasing a hypothetical firm's long-run profitability. Studies 5-7 demonstrate that carefully prompting subjects to consider the long run incentives of profit can attenuate anti-profit beliefs, while prompting short run thinking does nothing relative to a control. Together, these results suggest that the default view of profits is zero-sum. While people readily grasp how profit can incentivize firms to engage in practices that harm others, they neglect how it can incentivize firms to engage in practices that benefit others. Accordingly, people's stereotypes of profit seeking firms are excessively negative. Even in one of the most market-oriented societies in history, people doubt the contributions of profit-seeking industry to societal progress. (PsycINFO Database Record PMID- 28726438 TI - Superior pattern detectors efficiently learn, activate, apply, and update social stereotypes. AB - Superior cognitive abilities are generally associated with positive outcomes such as academic achievement and social mobility. Here, we explore the darker side of cognitive ability, highlighting robust links between pattern detection and stereotyping. Across 6 studies, we find that superior pattern detectors efficiently learn and use stereotypes about social groups. This pattern holds across explicit (Studies 1 and 2), implicit (Studies 2 and 4), and behavioral measures of stereotyping (Study 3). We also find that superior pattern detectors readily update their stereotypes when confronted with new information (Study 5), making them particularly susceptible to counterstereotype training (Study 6). Pattern detection skills therefore equip people to act as naive empiricists who calibrate their stereotypes to match incoming information. These findings highlight novel effects of individual aptitudes on social-cognitive processes. (PsycINFO Database Record PMID- 28726439 TI - A stability bias effect among deceivers. AB - Research examining how truth tellers' and liars' verbal behavior is attenuated as a function of delay is largely absent from the literature, despite its important applied value. We examined this factor across 2 studies in which we examined the effects of a hypothetical delay (Experiment 1) or actual delay (Experiment 2) on liars' accounts. In Experiment 1-an insurance claim interview setting-claimants either genuinely experienced a (staged) loss of a tablet device (n = 40) or pretended to have experienced the same loss (n = 40). Truth tellers were interviewed either immediately after the loss (n = 20) or 3 weeks after the loss (n = 20), whereas liars had to either pretend the loss occurred either immediately before (n = 20) or 3 weeks before (n = 20) the interview (i.e., hypothetical delay for liars). In Experiment 2-a Human Intelligence gathering setting-sources had to either lie (n = 50) or tell the truth (n = 50) about a secret video they had seen concerning the placing of a spy device. Half of the truth tellers and liars where interviewed immediately after watching the video (n = 50), and half where interviewed 3-weeks later (n = 50; i.e., real delay for liars). Across both experiments, truth tellers interviewed after a delay reported fewer details than truth tellers interviewed immediately after the to-be remembered event. In both studies, liars failed to simulate this pattern of forgetting and reported similar amounts of detail when interviewed without or after a delay, demonstrating a stability bias in reporting. (PsycINFO Database Record PMID- 28726441 TI - Framing psychology as a discipline (1950-1999): A large-scale term co-occurrence analysis of scientific literature in psychology. AB - This study investigated the structure of psychological literature as represented by a corpus of 676,393 articles in the period from 1950 to 1999. The corpus was extracted from 1,269 journals indexed by PsycINFO. The data in our analysis consisted of the relevant terms mined from the titles and abstracts of all of the articles in the corpus. Based on the co-occurrences of these terms, we developed a series of chronological visualizations using a bibliometric software tool called VOSviewer. These visualizations produced a stable structure through the 5 decades under analysis, and this structure was analyzed as a data-mined proxy for the disciplinary formation of scientific psychology in the second part of the 20th century. Considering the stable structure uncovered by our term co occurrence analysis and its visualization, we discuss it in the context of Lee Cronbach's "Two Disciplines of Scientific Psychology" (1957) and conventional history of 20th-century psychology's disciplinary formation and history of methods. Our aim was to provide a comprehensive digital humanities perspective on the large-scale structural development of research in English-language psychology from 1950 to 1999. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 28726440 TI - PTSD symptoms predict outcome in trauma-informed treatment of intimate partner aggression. AB - OBJECTIVE: This study sought to extend findings from a randomized controlled trial of the Strength at Home Men's Program (SAH-M) for intimate partner aggression (IPA) in military veterans by examining the impact of pretreatment posttraumatic stress disorder (PTSD) symptoms on treatment efficacy, and by examining new data on postintervention follow-up for individuals who received SAH M after completing the enhanced treatment as usual (ETAU) wait-list control condition. METHOD: Using data from 125 male veterans who attended the SAH-M program immediately after an intake assessment or after waiting 6-month in the ETAU condition, this study used generalized linear modeling to examine predictors of physical and psychological IPA over a 9-month period of time. RESULTS: PTSD symptoms at intake significantly predicted both physical and psychological IPA use, even after accounting for the effects of treatment condition, time, and number of sessions attended. PTSD had a strong association with both physical and psychological IPA. An interaction between PTSD and SAH-M was observed for psychological IPA but not physical IPA, and the magnitude of the effect was not clinically significant. There was a significant effect of SAH-M in reducing IPA in the full sample, including previously unanalyzed outcome data from the ETAU condition. CONCLUSION: The study results suggest that while SAH-M does not need to be modified to address the interaction between PTSD and treatment, outcomes could be enhanced through additional direct treatment of PTSD symptoms. Results extend prior analyses by demonstrating the effectiveness of SAH-M in reducing use of IPA in both the treatment and ETAU conditions. (PsycINFO Database Record PMID- 28726442 TI - PTSD and autism spectrum disorder: Co-morbidity, gaps in research, and potential shared mechanisms. AB - BACKGROUND: While autism and trauma were often linked in psychoanalytic theory, very few scientific attempts have been made to explore the associations and comorbidity between the two. Instead, each area has grown separately, yielding large bodies of theoretical and clinical knowledge. THEORETICAL FRAMEWORK: In this article, we suggest several possible pathways that may link trauma and autism. First, autism spectrum disorder (ASD) may serve as a vulnerability marker for posttraumatic stress disorder (PTSD), specifically by increasing the risk for exposure to traumatic events. Second, PTSD, once it has appeared, may exacerbate certain ASD symptoms, for example, through maladaptive coping strategies and reduced help-seeking. Third, there may be shared underlying mechanisms for PTSD and ASD, including neurological abnormalities associated with both disorders, as well as cognitive and behavioral mechanisms, such as increased rumination, cognitive rigidity, avoidance, anger, and aggression. In addition, the unique characteristics of ASD may determine which events are experienced as particularly traumatic (e.g., social insults and degradation, sensory overstimulation, abrupt changes in known routines) and affect both the manifestation and severity of posttraumatic sequelae among diagnosed individuals. CONCLUSIONS AND RECOMMENDATIONS: Research conducted separately in the areas of PTSD and ASD strongly suggests several potential pathways connecting both disorders. We conclude that there is a pressing need for more PTSD-ASD research, focusing not only on the prevalence of traumatic stress in individuals with autism, but also on their potentially unique perception of traumatic events, particularly from the social sphere. Such research may carry important clinical implications. (PsycINFO Database Record PMID- 28726443 TI - Contextualizing risk and protection: Perceptions of Bedouin mothers from unrecognized villages in the Naqab. AB - This qualitative study utilizes ecological theory, a context-informed perspective, and an interactive model to study minority children, while considering structural factors, oppression, segregation, power dynamics, and awareness of the political context. It examines perceptions of risk and protection using "snowball" sampling of 33 Bedouin mothers, citizens of Israel, from the unrecognized villages (UVs) in the Naqab in Southern Israel. Data were collected via in-depth, semistructured interviews during 2011 to 2013. The interviews were thematically analyzed and then arranged according to the 5 contextual levels of the ecological systems theory. The findings demonstrate a wide range of risks to child development including immediate physical environment, lack of supervision, child characteristics, relationships in the child's life, difficult life conditions, sociopolitical risks, and risks related to the entry of technology. Despite these numerous risk factors, Bedouin families cope by trying to prevent risks, utilizing the mothers' constant investment in their children, family and tribal support, spirituality and religious beliefs, the positive use of technology, formal education, and cultural identity. Our findings suggest that marginalization and political discrimination affect child development on different contextual levels. Moreover, the findings highlight the need to include parental voices in discourse on risk and protection and the contribution of a context-informed perspective that includes awareness of historical and political effects. (PsycINFO Database Record PMID- 28726444 TI - Local fit evaluation of structural equation models using graphical criteria. AB - Evaluation of model fit is critically important for every structural equation model (SEM), and sophisticated methods have been developed for this task. Among them are the chi2 goodness-of-fit test, decomposition of the chi2, derived measures like the popular root mean square error of approximation (RMSEA) or comparative fit index (CFI), or inspection of residuals or modification indices. Many of these methods provide a global approach to model fit evaluation: A single index is computed that quantifies the fit of the entire SEM to the data. In contrast, graphical criteria like d-separation or trek-separation allow derivation of implications that can be used for local fit evaluation, an approach that is hardly ever applied. We provide an overview of local fit evaluation from the viewpoint of SEM practitioners. In the presence of model misfit, local fit evaluation can potentially help in pinpointing where the problem with the model lies. For models that do fit the data, local tests can identify the parts of the model that are corroborated by the data. Local tests can also be conducted before a model is fitted at all, and they can be used even for models that are globally underidentified. We discuss appropriate statistical local tests, and provide applied examples. We also present novel software in R that automates this type of local fit evaluation. (PsycINFO Database Record PMID- 28726445 TI - The Hebb repetition effect as a laboratory analogue of language acquisition: Learning three lists at no cost. AB - The Hebb repetition effect (i.e., the enhanced recall performance for a sequence of items that is repeated during a serial recall experiment) is considered an experimental analogue to language learning. However, although language learning occurs in a context in which multiple verbal sequences are repeated concurrently, the effect of increasing the number of repeated sequences in the Hebb repetition paradigm has received little attention, and previous studies have used tasks that depart considerably from the natural language learning experience. In the present study, we manipulated the number of repeated sequences in a Hebb repetition paradigm that is a close experimental analogue of language learning. Participants were asked to orally recall sequences of 7 nonsense syllables that were aurally presented. The paradigm included 1 or 3 sequences that were repeated every 4th trial. The results showed that participants could learn 3 sequences simultaneously and they could do so as easily as they would learn a single sequence. The results provide additional evidence to models relating the Hebb repetition effect to word-form learning. (PsycINFO Database Record PMID- 28726446 TI - Gold Medal Award for Life Achievement in the Application of Psychology: Robert J. Gatchel. AB - The American Psychological Foundation (APF) Gold Medal Awards recognize distinguished and engaging records of accomplishment in 4 areas of psychology. The 2017 Recipient of the Gold Medal Award for Life Achievement in the Application of Psychology is Robert J. Gatchel, PhD, ABPP. Terence M. Keane, PhD, president of the APF, will present the APF Gold Medal Awards at the 125th Annual Convention of the American Psychological Association on August 4, 2017, at 4:00 p.m. Members of the 2017 APF Board of Trustees are Terence M. Keane, PhD, president; Melba J. T. Vasquez, PhD, vice president/interim secretary; Richard C. McCarty, PhD, treasurer; Elisabeth R. Straus, executive vice president/executive director; Camilla Benbow, EdD; Rosie Phillips Bingham, PhD; Connie S. Chan; Arthur C. Evans Jr., PhD; Linda M. Forrest, PhD; Douglas C. Haldeman, PhD; Anthony W. Jackson, PhD; Archie L. Turner; W. Bruce Walsh, PhD; and Stewart E. Cooper, PhD, APA Board of Directors liaison. (PsycINFO Database Record PMID- 28726447 TI - Gold Medal Award for Life Achievement in the Practice of Psychology: Rodney R. Baker. AB - The American Psychological Foundation (APF) Gold Medal Awards recognize distinguished and engaging records of accomplishment in 4 areas of psychology. The 2017 recipient of the Gold Medal Award for Life Achievement in the Practice of Psychology is Rodney R. Baker, PhD. Terence M. Keane, PhD, president of the APF, will present the APF Gold Medal Awards at the 125th Annual Convention of the American Psychological Association on August 4, 2017, at 4:00 p.m. Members of the 2017 APF Board of Trustees are: Terence M. Keane, PhD, president; Melba J. T. Vasquez, PhD, vice president/interim secretary; Richard C. McCarty, PhD, treasurer; Elisabeth R. Straus, executive vice president/executive director; Camilla Benbow, EdD; Rosie Phillips Bingham, PhD; Connie S. Chan; Arthur C. Evans, Jr., PhD; Linda M. Forrest, PhD; Douglas C. Haldeman, PhD; Anthony W. Jackson, PhD; Archie L. Turner; W. Bruce Walsh, PhD; and Stewart E. Cooper, PhD, APA Board of Directors liaison. (PsycINFO Database Record PMID- 28726448 TI - Gold Medal Award for Life Achievement in Psychology in the Public Interest: Joseph Everett Trimble. AB - The American Psychological Foundation (APF) Gold Medal Awards recognize distinguished and engaging records of accomplishment in 4 areas of psychology. The 2017 recipient of the Gold Medal Award for Life Achievement in Psychology in Public Interest is Joseph Everett Trimble, PhD. Terence M. Keane, PhD, president of the APF, will present the APF Gold Medal Awards at the 125th Annual Convention of the American Psychological Association on August 4, 2017, at 4:00 p.m. Members of the 2017 APF Board of Trustees are: Terence M. Keane, PhD, president; Melba J.T. Vasquez, PhD, vice president/interim secretary; Richard C. McCarty, PhD, treasurer; Elisabeth R. Straus, executive vice president/executive director; Camilla Benbow, EdD; Rosie Phillips Bingham, PhD; Connie S. Chan; Arthur C. Evans, Jr., PhD; Linda M. Forrest, PhD; Douglas C. Haldeman, PhD; Anthony W. Jackson, PhD; Archie L. Turner; W. Bruce Walsh, PhD; and Stewart E. Cooper, PhD, APA Board of Directors liaison. (PsycINFO Database Record PMID- 28726449 TI - Gold Medal Award for Life Achievement in the Science of Psychology: Lynn Nadel. AB - The American Psychological Foundation (APF) Gold Medal Awards recognize distinguished and engaging records of accomplishment in 4 areas of psychology. The 2017 recipient of the Gold Medal Award for Life Achievement in the Science of Psychology is Lynn Nadel, PhD. Terence M. Keane, PhD, president of the APF, will present the APF Gold Medal Awards at the 125th Annual Convention of the American Psychological Association on August 4, 2017, at 4:00 p.m. Members of the 2017 APF Board of Trustees are Terence M. Keane, PhD, president; Melba J. T. Vasquez, PhD, vice president-interim secretary; Richard C. McCarty, PhD, treasurer; Elisabeth R. Straus, executive vice president-executive director; Camilla Benbow, EdD; Rosie Phillips Bingham, PhD; Connie S. Chan; Arthur C. Evans, Jr., PhD; Linda M. Forrest, PhD; Douglas C. Haldeman, PhD; Anthony W. Jackson, PhD; Archie L. Turner; W. Bruce Walsh, PhD; and Stewart E. Cooper, PhD, APA Board of Directors liaison. (PsycINFO Database Record PMID- 28726450 TI - Charles L. Brewer Award for Distinguished Teaching of Psychology: Regan A. R. Gurung. AB - The American Psychological Foundation (APF) Charles L. Brewer Award for Distinguished Teaching of Psychology recognizes exemplary career contributions to the teaching of psychology. The 2017 recipient of the Charles L. Brewer Award for Distinguished Teaching of Psychology is Regan A. R. Gurung, PhD. Terence M. Keane, PhD, president of the APF, will present the APF Charles L. Brewer Award for Distinguished Teaching of Psychology at the 125th Annual Convention of the American Psychological Association on August 4, 2017, at 4:00 p.m. Members of the 2017 APF Board of Trustees are Terence M. Keane, PhD, president; Melba J. T. Vasquez, PhD, vice president/interim secretary; Richard C. McCarty, PhD, treasurer; Elisabeth R. Straus, executive vice president/executive director; Camilla Benbow, EdD; Rosie Phillips Bingham, PhD; Connie S. Chan; Arthur C. Evans, Jr., PhD; Linda M. Forrest, PhD; Douglas C. Haldeman, PhD; Anthony W. Jackson, PhD; Archie L. Turner; W. Bruce Walsh, PhD; and Stewart E. Cooper, PhD, APA Board of Directors liaison. (PsycINFO Database Record PMID- 28726451 TI - Integrating psychobiography into psychology's mainstream: Introduction to the special section. AB - Psychobiography, the intense study of a particular person, has long existed at the fringes of mainstream psychology. This special section is comprised of two articles that take important steps to integrate psychobiography into the mainstream of psychology. Schultz and Lawrence (2017) do so by reviewing recent examples of how contemporary psychobiographers have used empirically supported methods and theories to reach conclusions about the individuals under study. Ponterotto and Reynolds (2017) do so by articulating important ethical issues relevant to the practice of psychobiography, a topic on which the American Psychological Association's current ethical code provides little guidance (American Psychological Association, 2017). This introduction closes by proposing that mainstream psychology might better appreciate how psychobiography contributes to psychological knowledge and practice if psychobiographers also clearly articulated their criteria for "good science," better explained how psychobiographical methods complement more mainstream methodological approaches, and empirically tested whether training in psychobiography helps clinicians better understand and treat their clients. (PsycINFO Database Record PMID- 28726452 TI - Psychobiography: Theory and method. AB - Psychobiography is best understood as a branch of applied personality science in which experimental findings are used to explore the lives and personalities of public figures, from artists to politicians. This article introduces the field, addresses questions commonly raised about it, and explores, among other subjects, what psychobiographical research might offer to the field of psychology. Two recent model psychobiographies are described in detail-McAdams's (2010) profile of George W. Bush and Kasser's (2013) analysis of John Lennon-both of which are oriented scientifically and rooted in experimentally derived concepts. Lastly, criteria for evaluating psychobiographical studies are summarized, as well as attributes of effective psychobiography that tend to include the components of fact, fit, and function. (PsycINFO Database Record PMID- 28726453 TI - Ethical and legal considerations in psychobiography. AB - Despite psychobiography's long-standing history in the field of psychology, there has been relatively little discussion of ethical issues and guidelines in psychobiographical research. The Ethics Code of the American Psychological Association (APA) does not address psychobiography. The present article highlights the value of psychobiography to psychology, reviews the history and current status of psychobiography in the field, examines the relevance of existing APA General Principles and Ethical Standards to psychobiographical research, and introduces a best practice ethical decision-making model to assist psychologists working in psychobiography. Given the potential impact of psychologists' evaluative judgments on other professionals and the lay public, it is emphasized that psychologists and other mental health professionals have a high standard of ethical vigilance in conducting and reporting psychobiography. (PsycINFO Database Record PMID- 28726454 TI - Attitude roots and Jiu Jitsu persuasion: Understanding and overcoming the motivated rejection of science. AB - There is a worryingly large chasm between scientific consensus and popular opinion. Roughly one third of Americans are skeptical that humans are primarily responsible for climate change; rates of some infectious diseases are climbing in the face of anti-immunization beliefs; and significant numbers of the population worldwide are antievolution creationists. It is easy to assume that resistance to an evidence-based message is a result of ignorance or failure to grasp evidence (the "deficit model" of science communication). But increasingly, theorists understand there are limits to this approach, and that if people are motivated to reject science, then repeating evidence will have little impact. In an effort to create a transtheoretical language for describing these underlying motivations, we introduce the notion of "attitude roots." Attitude roots are the underlying fears, ideologies, worldviews, and identity needs that sustain and motivate specific "surface" attitudes like climate skepticism and creationism. It is the antiscience attitude that people hear and see, but it is the attitude root-what lies under the surface-that allows the surface attitudes to survive even when they are challenged by evidence. We group these attitude roots within 6 themes worldviews, conspiratorial ideation, vested interests, personal identity expression, social identity needs, and fears and phobias-and review literature relevant to them. We then use these insights to develop a "jiu jitsu" model of persuasion that places emphasis on creating change by aligning with (rather than competing with) these attitude roots. (PsycINFO Database Record PMID- 28726455 TI - A developmental perspective on the link between parents' employment and children's obesity. AB - Despite public concerns about the negative implications of the increased labor force participation of mothers for child development, decades of research have revealed few risks and some benefits. One potential risk-a consistently observed association between maternal employment and childhood obesity-offers a window into how some dimensions of family health may be undermined by work in an economic and policy context that is not family friendly. The purpose of this article is to identify ways that a developmental perspective can enrich the literature on how children's weight may be related to the work experiences of both mothers and fathers across diverse populations, a literature that heretofore has been dominated by economic and demographic perspectives, focused almost solely on women, and largely ignored racial/ethnic variation. After reviewing the extant literature, we put forward a conceptual model that uses ecological and developmental insights to identify the mechanisms by which parents' employment might matter to children's weight and discuss this model in the context of the contemporary landscape of family policy. (PsycINFO Database Record PMID- 28726456 TI - Reconsidering what is vital about vital signs in electronic health records: Comment on Matthews et al. (2016). AB - The inclusion of psychosocial variables into electronic health records provides a unique opportunity for the translation of findings from social, psychological, and behavioral domains into patient care. This commentary is a response to the recommendations of a committee convened by the Institute of Medicine to address this opportunity (Matthews, Adler, Forrest, & Stead, 2016). We concur with the committee that the inclusion of psychosocial variables in electronic health records will broadly benefit researchers, practitioners, and patients and that there is clear need for a recommended panel of psychosocial measures that is ready for implementation in clinical settings. In fact, it seems likely that these recommendations will have lasting consequences. Given this, our response highlights several concerns about the recommendations and criteria. We suggest further clarification of the audience for these recommendations, reconsideration of the overly restrictive inclusion criteria, and more extensive engagement of psychosocial researchers to achieve broader consensus. (PsycINFO Database Record PMID- 28726457 TI - Optimal standard measures: Comment on Matthews et al. (2016). AB - Matthews, Adler, Forrest, and Stead (2016) implied that measures of mental health constructs such as depression can be made interchangeable by standardizing their scores. The present author contends that content differences in the measures a priori prevent their equivalence and that, instead, we need to agree on a standard definition of the construct and then use only a definition-fitting optimal standard measure. (PsycINFO Database Record PMID- 28726458 TI - Getting started: Reply to Condon et al. (2017) and Rossiter (2017). AB - Condon, Weston, and Hill (2017) and Rossiter (2017) expressed concerns about the recommended panel of psychosocial vital signs that should be included in electronic health records (EHRs). Condon et al. (2017) would prefer a broader array of measures and Rossiter (2017) a set of optimal measures based on consensus. Our task was to identify a core set of measures to be used now in all EHRs based on usefulness and low burden. We anticipate that with new evidence, changing needs, and greater input from stakeholders, the recommended measures will be elaborated or modified. (PsycINFO Database Record PMID- 28726459 TI - Leonard D. Goodstein (1927-2016). AB - Presents an obituary for Leonard D. Goodstein, who died in Scottsdale, Arizona, on July 20, 2016, at the age of 89. Goodstein was CEO of APA at a crucial time in its history when it faced both crippling financial difficulties and intramural conflict regarding the purpose of the organization. His efforts yielded important financial results and lasting structural changes to the organization. (PsycINFO Database Record PMID- 28726460 TI - Eugene Cullen Kennedy (1928-2015). AB - Presents an obituary for Eugene Cullen Kennedy, who died at age 86 on June 3, 2015, from heart and lung failure. Kennedy was trained as a counseling psychologist, but his impact went far beyond psychology, spanning 50 years and satisfying the intellectual tastes of a diversity of enthusiasts. (PsycINFO Database Record PMID- 28726461 TI - Laverne (Vern) C. Johnson (1925-2016). AB - Presents an obituary for Laverne (Vern) C. Johnson, who died at his home in La Mesa, California on October 1, 2016. Vern was a clinical psychologist who for two decades focused on a major program of research on sleep and biological rhythms, with particular emphasis on the relation of sleep loss and recovery to human performance, a matter of particular relevance to military service operations, in which variable work shift schedules and sustained performance over extended time periods are common. His publications attest to a core value he advanced throughout his career, namely, that scientific research at its best is a collaborative, team endeavor. (PsycINFO Database Record PMID- 28726462 TI - Allan Urho Paivio (1925-2016). AB - Presents an obituary for Allan Urho Paivio, who passed away on June 19, 2016. One of his many accomplishments was the development of a dual-coding theory. Dual coding theory, while very influential, has, unfortunately, been discussed all too often as a theory of mental imagery, and not within its larger context wherein mental imagery and verbal processes are separable but interconnected representational systems, an academic battle in clarification that Paivio waged much of his life. He published prodigiously, even in the decades after retirement. Among his many honors, he served as president of the Canadian Psychological Association (1975) and was appointed a fellow of the Royal Society of Canada (1978). (PsycINFO Database Record PMID- 28726463 TI - Steven (Steve) Walfish (1953-2016). AB - Presents an obituary for Steven (Steve) Walfish, who passed away in Atlanta, Georgia, on April 27, 2016. Walfish was a passionate clinical scholar and educator for independent practitioners. Well respected for his evaluations and consultations (presurgical weight loss, substance abuse, psychiatric issues), he became the go-to person for referrals for evidence-based practice with adults and couples. His untimely death to cancer deeply saddened the innumerable clients whose lives he touched and his diverse professional collaborators. (PsycINFO Database Record PMID- 28726464 TI - Summary Report of Journal Operations, 2016. AB - Presents a summary report of journal operations compiled from the 2016 annual reports of the Council of Editors and from Central Office records. Also includes a summary report of division journal operations compiled from the 2016 annual reports of the division journal editors. (PsycINFO Database Record PMID- 28726465 TI - Supplement to listing of accredited doctoral, internship, and postdoctoral training programs in health service psychology. AB - Provides an announcement from the Commission on Accreditation for the following status changes for accredited doctoral (clinical, counseling, school, or a combination there of and developed practice area), doctoral internship, and postdoctoral residency programs in health service psychology as of April 2, 2017. (PsycINFO Database Record PMID- 28726466 TI - Correction to "Summary Report of Journal Operations, 2014". AB - Reports an error in "Summary report of journal operations, 2014" by (American Psychologist, 2015[Jul-Aug], Vol 70[5], 455-456). In the report on p. 455 the columns displaying average publication lag time for online first and print articles were reversed. In addition, the reported number of accepted manuscripts for the Journal of Personality and Social Psychology should be 118, not 65, and the rejection rate should be 86% rather than 91%. (The following abstract of the original article appeared in record 2015-33530-012.) [Correction Notice: An Erratum for this article was reported in Vol 71(9) of American Psychologist (see record 2016-61507-015). In the report, the reported number of manuscripts received, accepted, and pending along with their accompanying rejection rates had errors in the following journals: Journal of Abnormal Psychology; Journal of Applied Psychology; Journal of Consulting and Clinical Psychology; Journal of Counseling Psychology; Journal of Experimental Psychology: General; Journal of Family Psychology; Journal of Personality and Social Psychology; Psychological Assessment; Psychological Methods; Psychological Review; Psychology and Aging; Psychology of Addictive Behaviors; Psychology, Public Policy, and Law; and Analyses of Social Issues and Public Policy. The online version of this report has been corrected.] Presents the American Psychological Association's summary report of its journal operations and division journal operations for 2014. (PsycINFO Database Record PMID- 28726467 TI - The importance of the neighborhood in the 2014 Ebola outbreak in the United States: Distress, worry, and functioning. AB - OBJECTIVE: Ebola media coverage directed public attention to potential disease carriers: residents or travelers from West Africa. We investigated the role of neighborhood population factors (i.e., the concentration of West African foreigners, non-West African foreigners, non-Hispanic Blacks) on individual responses to the Ebola outbreak in the United States. The role of these community level factors in emotional responses to this public health crisis is poorly understood. METHOD: Demographic factors, mental health, and stressful event history, collected as part of an ongoing longitudinal study of residents from 2 metropolitan communities (New York City and Boston, total N = 1,346), were combined with neighborhood data from the U.S. Census. Multilevel models estimated the effects of individual and neighborhood factors on individual psychological distress, functional impairment, and Ebola-related worry. RESULTS: Individuals living in neighborhoods with more West African-born foreigners or non-West African foreigners reported more somatization and anxiety symptoms, functioning difficulties, and/or Ebola-related worry than individuals living in neighborhoods with fewer foreign residents (p < .05). Individuals residing in neighborhoods with more non-Hispanic Blacks also reported more somatization symptoms than their residential counterparts (p < .05). CONCLUSION: Neighborhood demography is important to study during a public health outbreak like Ebola in which media and policy target specific people or regions. Findings suggest research and policies should not only assist at-risk individuals but also at-risk neighborhoods during and after an infectious disease crisis. (PsycINFO Database Record PMID- 28726468 TI - Longitudinal trajectories of benefit finding in adolescents with Type 1 diabetes. AB - OBJECTIVES: Benefit finding, which refers to perceiving positive life changes resulting from adversity, has been associated with better psychosocial well-being in different chronic illnesses. However, little research to date has examined how benefit finding develops in the context of Type 1 diabetes (T1D). The present study aimed to identify trajectories of benefit finding across adolescence and to investigate prospective associations with depressive symptoms, self-care, and metabolic control. METHOD: Adolescents with T1D aged 10 to 14 (Mage = 12.49 years, 54% girls) participated in a 4-wave longitudinal study spanning 1.5 years (N = 252 at Time 1). Adolescents filled out questionnaires on benefit finding, self-care, depressive symptoms, and illness perceptions. HbA1c values were obtained through point of care assays. We used latent growth curve modeling (LGCM) and latent class growth analysis (LCGA) to examine the development of benefit finding. Cross-lagged path analysis and multi-group LGCM were used to examine prospective associations among the study variables. RESULTS: Adolescents reported moderate levels of benefit finding which decreased over time. Three benefit finding trajectory classes were identified: low and decreasing, moderate and decreasing, and high and stable. These trajectory classes differed in terms of self-care, perceived personal and treatment control, and perceptions of illness cyclicality. Higher levels of benefit finding predicted relative increases in self-care 6 months later. Benefit finding was not prospectively related to depressive symptoms and metabolic control. CONCLUSIONS: Benefit finding may serve as a protective factor for adolescents with Type 1 diabetes and may motivate these adolescents to more closely follow their treatment regimen. (PsycINFO Database Record PMID- 28726469 TI - The unintended effects of providing risk information about drinking and driving. AB - OBJECTIVE: Alcohol-impaired driving remains a serious public health concern despite the fact that drinking and driving risks are widely disseminated and well understood by the public. This research examines the motivational conditions under which providing risk information can exacerbate rather than decrease potential drinking drivers' willingness to drive while impaired. METHOD: In a hypothetical drinking and driving scenario, 3 studies investigated participants' self-reported likelihood of drinking and driving as a function of (a) accessibility of information regarding risk associated with drinking and driving, (b) motivation to drive, and (c) need for cognitive closure (NFC). RESULTS: Across the 3 studies, participants self-reported a higher likelihood of driving when exposed to high-risk information (vs. low-risk information) if they were high in NFC. Risk information did decrease self-reported likelihood of driving among low-NFC participants (Studies 1-3). Furthermore, this effect was exacerbated when the relevant motivation (to get home conveniently) was high (Study 3). CONCLUSIONS: These findings have important implications for impaired driving prevention efforts. They suggest that at least under some circumstances, risk information can have unintended negative effects on drinking and driving decisions. The results are consistent with the motivated cognition literature, which suggests that people process and use information in a manner that supports their most accessible and important motivation despite potentially negative consequences. (PsycINFO Database Record PMID- 28726470 TI - Child sun safety: Application of an Integrated Behavior Change model. AB - OBJECTIVE: Childhood sun exposure increases risk of skin cancer in later life. Parents of young children play an important role in minimizing childhood sun exposure. The aim of the current study was to identify the motivational, volitional, and implicit antecedents of parents' sun-protective behaviors based on an Integrated Behavior Change model. METHOD: Parents (N = 373) of 2- to 5-year old children self-reported their intentions, attitudes, subjective norm, perceived behavioral control, autonomous and controlled motivation, action plans, habit, and past behaviors with respect to sun-protective behaviors for their children. Two weeks later (n = 273), the parents self-reported their participation in sun-protective behaviors for their child. RESULTS: Data were analyzed using variance-based structural equation modeling. Results showed significant direct effects of attitudes, subjective norm, perceived behavioral control, and past behavior on intentions, and significant direct effects of autonomous motivation, perceived behavioral control, intentions, action planning, habit, and past behavior on parents' participation in sun-protective behaviors for their child. There were also significant total indirect effects of autonomous motivation on intentions mediated by attitudes and subjective norm. CONCLUSIONS: Current results indicate that parents' sun-protective behaviors toward their children are a function of motivational (autonomous motivation, intentions), volitional (action planning), and implicit (habit) factors. The findings from the current study provide formative data to inform the development of behavior change interventions to increase parents' participation in sun-protective behaviors for their children. (PsycINFO Database Record PMID- 28726471 TI - The impact of medication nonadherence on the relationship between mortality risk and depression in heart failure. AB - OBJECTIVE: Heart failure affects more than 5 million U.S. adults, and approximately 20% of individuals with heart failure experience depressive symptoms. Depression is detrimental to prognosis in heart failure, conferring approximately a 2-fold increase in mortality risk. Medication nonadherence may help explain this relationship because depressed patients are less likely to adhere to the medication regimen. METHOD: Depression, electronically monitored medication adherence, and mortality were measured in a sample of 308 patients with heart failure participating in a study of self-management behavior. Cardiovascular and all-cause mortality data were obtained from the Centers for Disease Control and Prevention's National Death Index (median 2.9-year follow up). Cox proportional hazards regression was used to assess the relationship between depression and mortality, with and without adjustment for age, gender, disease severity, and medication nonadherence. RESULTS: In adjusted analyses, depression was associated with an increased all-cause mortality risk (hazard ratio 1.87; 95% confidence interval 1.04-3.37). Depression was not related to cardiovascular mortality, potentially because of a low number of cardiac-related deaths. When medication nonadherence was added to the model, nonadherence (hazard ratio 1.01; 95% confidence interval 1.004-1.02), but not depression, predicted all-cause mortality risk. CONCLUSIONS: Depressive symptoms confer increased all cause mortality risk in heart failure, and medication nonadherence contributes to this relationship. Depression and nonadherence represent potentially modifiable risk factors for poor prognosis. Future research is needed to understand whether interventions that concomitantly target these factors can improve outcomes. (PsycINFO Database Record PMID- 28726473 TI - The effects of temporal perspective on college students' energy drink consumption. AB - OBJECTIVE: Consideration of future consequences (CFC) describes the extent to which individuals consider potential future outcomes of their present behaviors. This personality trait has been found to predict repetitive health behaviors. Research is yet to explore the role of health beliefs, which may mediate the relationship between CFC and self-directed health behaviors. Thus, this study examined how CFC affects energy drink-related health beliefs and consumption behavior. DESIGN: A cross-sectional correlational online survey with 1,050 college students was conducted. Key measures include the CFC Scale, health belief measures, and current energy drink consumption pattern. RESULTS: CFC was associated with energy drink consumption as well as several health beliefs. CFC had indirect effects on energy drink consumption through health beliefs, including perceived severity of consuming energy drinks (indirect effect estimate = -.191, 95% confidence interval [CI] [-.271, -.122]), perceived benefits of avoiding energy drinks (indirect effect estimate = -.108, 95% CI [-.174, -.050]), and perceived barriers in abstaining from energy drinks (energy level-related barriers, indirect effect estimate = -.274, 95% CI [-.387, -.181]; and socialization-related barriers, indirect effect estimate = .152, 95% CI [.078, .249]). CONCLUSION: As the first study to examine CFC's indirect effects on a self-directed health behavior through health beliefs, this study extended CFC's applicability by examining its role in the context of college students' energy drink consumption. (PsycINFO Database Record PMID- 28726472 TI - The influence of pain memories on children's and adolescents' post-surgical pain experience: A longitudinal dyadic analysis. AB - OBJECTIVE: Although children's pain memories have been shown to be a powerful predictor of subsequent pain experiences in acute procedural and experimental pain settings, little is known about the influence of children's and parents' pain memories on children's future pain experiences in other painful contexts. This study used a dyadic approach to examine the roles of children's and parents' memories of pain on their subsequent reporting of postsurgical pain several months after the child underwent a major surgical procedure. METHOD: The sample included 66 parent-child dyads (Mage youth = 14.73 years, SD = 2.01) recruited from 2 tertiary level pediatric hospitals. At baseline, children and parents reported on their catastrophic thinking about the child's pain. Parent and child reports of child pain were collected at approximately 1 month and 5 months postsurgery. At 2-4 months postsurgery, children's and parents' memories for postsurgical pain were assessed. RESULTS: Results revealed that children's, but not parents', pain memories were a strong predictor of subsequent pain experienced at 5 months postsurgery. Children's and parents' memories for pain did not influence each others' subsequent pain reporting. CONCLUSIONS: Findings suggest that children's pain memories influence their continued recovery from postsurgical pain and may contribute to pain persistence. Implications for intervention and prevention are discussed. (PsycINFO Database Record PMID- 28726475 TI - Perceived physical activity and mortality: Evidence from three nationally representative U.S. samples. AB - OBJECTIVE: This research sought to examine the relationship of individuals' perceptions about their level of physical activity with mortality outcomes at the population level. METHOD: This study used 3 nationally representative samples with a total sample size of 61,141 U.S. adults (weighted N = 476 million). Data from the 1990 National Health Interview Survey (NHIS) and the 1999-2002/2003-2006 National Health and Nutrition Examination Survey (NHANES) were linked to prospective National Death Index mortality data through 2011, yielding follow-up periods of up to 21 years. Cox proportional hazards models were used to determine the association between respondents' perceptions of their relative level of physical activity (compared with other people their age) and all-cause mortality, adjusting for actual levels of physical activity, health status and behavior, and sociodemographic variables. RESULTS: Perceived physical activity relative to peers was associated with mortality risk. Individuals who perceived themselves as less active than others were up to 71% more likely to die in the follow-up period than those who perceived themselves as more active. This finding held across 3 samples and after adjusting for actual levels of physical activity and other covariates. CONCLUSIONS: Individuals' perceptions about their level of physical activity strongly predicted mortality, even after accounting for the effects of actual physical activity and other known determinants of mortality. This suggests that perceptions about health behaviors may play an important role in shaping health outcomes. (PsycINFO Database Record PMID- 28726474 TI - Is subjective social status a unique correlate of physical health? A meta analysis. AB - OBJECTIVE: Both social stratification (e.g., social rank) as well as economic resources (e.g., income) are thought to contribute to socioeconomic health disparities. It has been proposed that subjective socioeconomic status (an individual's perception of his or her hierarchical rank) provides increased predictive utility for physical health over and above more traditional, well researched socioeconomic constructs such as education, occupation, and income. METHOD: PsycINFO and PubMed databases were systematically searched for studies examining the association of subjective socioeconomic status (SES) and physical health adjusting for at least 1 measure of objective SES. The final sample included 31 studies and 99 unique effects. Meta-analyses were performed to: (a) estimate the overlap among subjective and objective indicators of SES and (b) estimate the cumulative association of subjective SES with physical health adjusting for objective SES. Potential moderators such as race and type of health indicator assessed (global self-reports vs. more specific and biologically based indicators) were also examined. RESULTS: Across samples, subjective SES shows moderate overlap with objective indicators of SES, but associations are much stronger in Whites than Blacks. Subjective SES evidenced a unique cumulative association with physical health in adults, above and beyond traditional objective indicators of SES (Z = .07, SE = .01, p < .05). This association was stronger for self-rated health than for biologically based and symptom-specific measures of health. Almost all available data were cross-sectional and do not allow for strong causal inference. CONCLUSIONS: Subjective SES may provide unique information relevant to understanding disparities in health, especially self rated health. (PsycINFO Database Record PMID- 28726476 TI - Spouses' daily feelings of appreciation and self-reported well-being. AB - OBJECTIVE: Research shows that active support provision is associated with greater well-being for spouses of individuals with chronic conditions. However, not all instances of support may be equally beneficial for spouses' well-being. The theory of communal responsiveness suggests that because spouses' well-being is interdependent, spouses benefit most from providing support when they believe their support increases their partner's happiness and is appreciated. Two studies tested this hypothesis. METHOD: Study 1 was a 7-day ecological momentary assessment (EMA) study of 73 spouses of persons with dementia (74%) and other conditions. In Study 1, spouses self-reported active help, perceptions of how happy the help made the partner and how much the help improved the partner's well being, and spouses' positive and negative affect at EMA time points. Study 2 was a 7-day daily assessment study of 43 spouses of persons with chronic pain in which spouses reported their emotional support provision, perceived partner appreciation, and their own physical symptoms. RESULTS: Study 1 showed that active help was associated with more positive affect for spouses when they perceived the help increased their partner's happiness and improved their partner's well-being. Study 2 showed that emotional support provision was associated with fewer spouse reported physical symptoms when perceptions of partner appreciation were high. CONCLUSION: Results suggest that interventions for spouses of individuals with chronic conditions take into account spouses' perceptions of their partners' positive emotional responses. Highlighting the positive consequences of helping may increase spouses' well-being. (PsycINFO Database Record PMID- 28726477 TI - South Asian ethnicity, socioeconomic status, and psychological mediators of faecal occult blood colorectal screening participation: A prospective test of a process model. AB - OBJECTIVE: Although ethnicity and socioeconomic status (SES) correlate with health inequality, efforts to explain variance in health behavior attributable to these factors are limited by difficulties in population sampling. We used ethnicity identification software to test effects of psychological beliefs about screening as mediators of ethnicity and SES on faecal occult blood colorectal screening behavior in a no-cost health care context. METHOD: Adults aged 50-67 years (N = 1,678), of whom 28% were from minority South Asian religiolinguistic ethnic groups (Hindu-Gujarati/Hindi, Muslim-Urdu and Sikh-Punjabi), participated in a prospective survey study. Subsequent screening participation was determined from medical records. RESULTS: Screening nonparticipation in the most deprived SES quintile was 1.6 times that of the least deprived quintile. Nonparticipation was 1.6 times higher in South Asians compared with non-Asians. A process model in which psychological variables mediated effects of ethnicity and SES on uptake was tested using structural equation modeling. Self-efficacy and perceived psychological costs of screening were, respectively, positive and negative direct predictors of uptake. Paths from Hindu, Muslim, and Sikh ethnicity, and SES on uptake were fully mediated by lower self-efficacy and higher perceived psychological costs. Paths from South Asian ethnicity to participation via self efficacy and psychological costs were direct, and indirect via SES. CONCLUSION: SES is implicated, but does not fully account for low colorectal screening uptake among South Asians. Targeting increased self-efficacy and reduced perceived psychological costs may minimize health inequality effects. Future research should test independent effects of SES and ethnicity on lower self-efficacy and higher psychological costs. (PsycINFO Database Record PMID- 28726478 TI - The association of positive emotion and first smoking lapse: An ecological momentary assessment study. AB - OBJECTIVE: Individuals attempting to quit smoking typically have poor success rates, and the majority fail to maintain long-term abstinence. Although a large body of evidence documents the impact of negative affect on reducing abstinence, there is a much smaller body of research on positive emotions, which could be an important mechanism that is associated with successful cessation. As such, this study examined positive emotions in real-time via ecological momentary assessment (EMA) to determine whether discrete positive emotions were uniquely related to 2 cessation milestones: quit day lapse and first lapse. METHOD: Participants were 391 smokers who received tobacco cessation treatment. EMAs were completed pre- and postquit, and positive emotion was assessed with 3 items (enthusiastic, happy, and relaxed) rated on 5-point Likert scales. Analyses examined the associations of the means and slopes of each emotion on the current day with the likelihood of lapse on the following day. RESULTS: When controlling for relevant covariates, prequit positive emotions were not related to quit day lapse. However, postquit positive emotions were associated with first lapse. Specifically, high levels of happiness and relaxation, as well as increasing levels of enthusiasm, happiness, and relaxation were related to a lower likelihood of next day lapse. CONCLUSIONS: These are some of the first real-time, real-world data to demonstrate that distinct positive emotions are associated with a lower risk of lapse during the postquit period among smokers attempting to quit. (PsycINFO Database Record PMID- 28726479 TI - Motivational interviewing and the clinical science of Carl Rogers. AB - The clinical method of motivational interviewing (MI) evolved from the person centered approach of Carl Rogers, maintaining his pioneering commitment to the scientific study of therapeutic processes and outcomes. The development of MI pertains to all 3 of the 125th anniversary themes explored in this special issue. Applications of MI have spread far beyond clinical psychology into fields including health care, rehabilitation, public health, social work, dentistry, corrections, coaching, and education, directly impacting the lives of many people. The public relevance and impact of clinical psychology are illustrated in the similarity of MI processes and outcomes across such diverse fields and the inseparability of human services from the person who provides them, in that both relational and technical elements of MI predict client outcomes. Within the history of clinical psychology MI is a clear product of clinical science, arising from the seminal work of Carl Rogers whose own research grounded clinical practice in empirical science. As with Rogers' work 70 years ago, MI began as an inductive empirical approach, observing clinical practice to develop and test hypotheses about what actually promotes change. Research on MI bridges the current divide between evidence-based practice and the well-established importance of therapeutic relationship. Research on training and learning of MI further questions the current model of continuing professional education through self-study and workshops as a way of improving practice behavior and client outcomes. (PsycINFO Database Record PMID- 28726480 TI - From efficacy to effectiveness to broad implementation: Evolution of the Body Project. AB - OBJECTIVE: At the turn of the millennium, eating disorders (EDs) prevention was largely nonexistent. No program had reduced future onset of EDs in even a single trial, and most had not reduced ED symptoms. Sixteen years later, the ED prevention field has translated basic risk factor research into interventions, with demonstrated efficacy and effectiveness in reducing ED risk factors and symptoms, as well as future ED onset in some trials. This article reviews the aforementioned progress focusing on a model intervention (i.e., the Body Project [BP]). METHOD: The article is a qualitative review of the existing BP literature. RESULTS: Although clinical psychology has struggled with bridging the research practice gap and translating efficacy and effectiveness research into clinical implementation, researchers, clinicians, and community stakeholders working with the BP have made significant progress in addressing barriers to scalability, large-scale implementation, and sustainability, reaching 3.5 million girls and young women in 125 countries. CONCLUSION: The successful evolution of the BP from basic research to traversing the efficacy-to-effectiveness-to dissemination/implementation continuum has yielded significant public health impact and is thus a fitting case for this special issue commemorating the 125th anniversary of the American Psychological Association. The BP example may help others broadly implement efficacious interventions for other mental health problems. (PsycINFO Database Record PMID- 28726482 TI - "Great powers and great responsibilities": A brief comment on "A brief mobile app reduces nonsuicidal and suicidal self-injury: Evidence from three randomized controlled trials" (Franklin et al., 2016). AB - Online and mobile mental health applications (apps) herald exciting new opportunities for the treatment and prevention of self-injurious thoughts and behaviors (SITBs). With such rapid technological advances, it is paramount that health care innovation not be achieved to the detriment of intervention quality. Franklin et al.'s (2016) therapeutic evaluative conditioning (TEC) app is a novel and timely addition to the mobile health landscape; uncommonly for such apps, it is evidence based. There are, however, several crucial challenges to be surmounted for TEC to be successful; arguably, interventions ought to build lasting skills that can be subsequently and consciously recruited to manage distress beyond the intervention period. Furthermore, SITBs are a coping mechanism (albeit maladaptive); thus, extinguishing SITBs via TEC must be bolstered by the development of alternative coping strategies, particularly if the psychological distress that underlies SITBs is not addressed therapeutically. Stigma exacerbates the psychological distress of those engaging in SITBs; therefore, we question whether the types of stimuli employed in TEC may further add to this stigma, potentially affecting future help seeking. One solution may be to explore a positive-only TEC; enhancing positive self-worth may provide a more sustainable and meaningful treatment target, particularly when used as an adjunct to therapy or as a waiting list intervention. Mobile interventions for SITBs bring unique ethical challenges, including individuals' right to be fully informed about potentially distressing stimuli. This commentary aims to highlight the methodological and ethical challenges faced by TEC and encourage further discussion around this topic. (PsycINFO Database Record PMID- 28726481 TI - A randomized controlled trial of an online, modular, active learning training program for behavioral activation for depression. AB - OBJECTIVE: This randomized-controlled trial assessed the efficacy of a trainer led, active-learning, modular, online behavioral activation (BA) training program compared with a self-paced online BA training with the same modular content. METHOD: Seventy-seven graduate students (M = 30.3 years, SD = 6.09; 76.6% female) in mental health training programs were randomly assigned to receive either the trainer-led or self-paced BA training. Both trainings consisted of 4 weekly sessions covering 4 core BA strategies. Primary outcomes were changes in BA skills as measured by an objective role-play assessment and self-reported use of BA strategies. Assessments were conducted at pre-, post-, and 6-weeks after training. A series of longitudinal mixed effect models assessed changes in BA skills and a longitudinal model implemented with generalized estimating equations assessed BA use over time. RESULTS: Significantly greater increases in total BA skills were found in the trainer-led training condition. The trainer-led training condition also showed greater increases in all core BA skills either at posttraining, follow-up, or both. Reported use of BA strategies with actual clients increased significantly from pre- to posttraining and maintained at follow-up in both training conditions. CONCLUSIONS: This trial adds to the literature on the efficacy of online training as a method to disseminate BA. Online training with an active learning, modular approach may be a promising and accessible implementation strategy. Additional strategies may need to be paired with the online BA training to assure the long-term implementation and sustainability of BA in clinical practice. (PsycINFO Database Record PMID- 28726483 TI - Understanding the context of novel interventions for self-injurious thoughts and behaviors: A reply to Nielsen et al. AB - In this response to the commentary by Nielsen, Kirtley, & Townsend (in press), the authors note several points of agreement related to further testing of therapeutic evaluative conditioning (TEC) for self-injurious thoughts and behaviors (SITBs), navigating logistical and ethical issues surrounding mobile interventions, and integrating such interventions into traditional practice. They also note a common mission held by Nielsen et al., themselves, and the SITB research community more broadly: the large-scale reduction of SITBs. Given that national rates of SITBs have never declined appreciably and have been on the rise in recent decades, there is an urgent need for progress toward this goal. However, they also highlight several unsupported or inaccurate assumptions and specific points made by Nielsen et al. that are important to correct for the sake of accuracy and progress in the prediction and prevention of SITBs. These include an overly narrow conceptualization of what constitutes an intervention; an unsupported model of the causes of SITBs and how to best prevent them; an erroneous belief about the iatrogenic effects of SITB stimulus exposure; and inaccuracies in their description of the development, testing, and release of TEC. The authors hope that this brief discussion of the evidence will facilitate progress toward the mission of large-scale reductions in SITBs. (PsycINFO Database Record PMID- 28726484 TI - Experience with newer central nervous system autoantibodies. AB - In the last decade, a large number of neuronal cell-surface antibodies have been described which are responsible for a range of neuroimmunological central nervous system disorders. Unlike the paraneoplastic antibodies which target intracellular antigens, these antibodies appear to be pathogenic and hence identification and prompt treatment can make a substantial impact on clinical outcomes of these patients. We review the common antibodies against the ionotropic glutamate receptors (NMDAR, AMPAR), metabotropic glutamate receptors (mGluR1 and mGluR5), voltage-gated potassium channel-complex proteins (LGI1, CASPR2), and other antibodies targeted against glycine receptor, glutamic acid decarboxylase, gamma amino butyric acid B, dopamine-2-receptor and dipeptidyl-peptidase-like protein 6. PMID- 28726485 TI - 20alpha- and 20beta-dihydrocortisone may interfere in LC-MS/MS determination of cortisol in saliva and urine. AB - Background LC-MS/MS methods offer high selectivity in cortisol determinations. However, endogenous steroid metabolites may still interfere and compromise the results, for example in the diagnosis of Cushing's syndrome. Erroneously elevated cortisol may, in particular, be misleading at the low concentrations found in salivary samples obtained at late night and after dexamethasone suppression. Methods Interferences in our LC-MS/MS method used for determination of cortisol in saliva and urine were identified by comparing their retention times and mass spectra with those of pure candidate substances. The chromatographic conditions used in our LC-MS/MS method, including column and mobile phase gradient, were varied in order to separate the target compound from the interferences. Results Two interferences, which were co-eluting or eluting close to cortisol in our original method, were successfully separated from cortisol by adjustment of the chromatographic conditions. These interferences were found in both urine and saliva and were identified as the two endogenous cortisol isomers 20alpha- and 20beta-dihydrocortisone. The isomers share molecular mass and mass spectrometric fragmentation pattern with cortisol using electrospray ionization in the positive ion mode. Both give rise to the transitions m/z 363.1>121.1, 363.1>115.1 and 363.1>97.1. In our original LC-MS/MS setup, the 20beta-dihydrocortisone co-eluted with cortisol in the chromatography step resulting in false high determinations. Conclusions Cortisol determination by LC-MS/MS may suffer from erroneously elevated results unless 20alpha- and 20beta-dihydrocortisone are chromatographically separated from cortisol. PMID- 28726486 TI - Reply to Voelkel: Cigarette Smoke Is an Endothelial Cell Toxin. PMID- 28726487 TI - Sensitive Windows for In Utero Exposures and Asthma Development. Layers of Complexity. PMID- 28726488 TI - Use of an Electrostatic Spraying System or the Sprayed Lethality in Container Method To Deliver Antimicrobial Agents onto the Surface of Beef Subprimals To Control Shiga Toxin-Producing Escherichia coli. AB - The efficacy of an electrostatic spraying system (ESS) and/or the sprayed lethality in container (SLIC) method to deliver antimicrobial agents onto the surface of beef subprimals to reduce levels of Shiga toxin-producing Escherichia coli (STEC) was evaluated. Beef subprimals were surface inoculated (lean side; ca. 5.8 log CFU per subprimal) with 2 mL of an eight-strain cocktail comprising single strains of rifampin-resistant (100 MUg/mL) STEC (O26:H11, O45:H2, O103:H2, O104:H4, O111:H-, O121:H19, O145:NM, and O157:H7). Next, inoculated subprimals were surface treated with lauric arginate (LAE; 1%), peroxyacetic acid (PAA; 0.025%), or cetylpyridinium chloride (CPC; 0.4%) by passing each subprimal, with the inoculated lean side facing upward, through an ESS cabinet or via SLIC. Subprimals were then vacuum packaged and stored at 4 degrees C. One set of subprimals was sampled after an additional 2 h, 3 days, or 7 days of refrigerated storage, whereas another set was retreated via SLIC after 3 days of storage with a different one of the three antimicrobial agents (e.g., a subprimal treated with LAE on day 0 was then treated with PAA or CPE on day 3). Retreated subprimals were sampled after 2 h or 4 days of additional storage at 4 degrees C. A single initial application of LAE, PAA, or CPC via ESS or SLIC resulted in STEC reductions of ca. 0.3 to 1.3 log CFU per subprimal after 7 days of storage. However, when subprimals were initially treated with LAE, PAA, or CPC via ESS or SLIC and then separately retreated with a different one of these antimicrobial agents via SLIC on day 3, additional STEC reductions of 0.4 to 1.0 log CFU per subprimal were observed after an additional 4 days of storage. Application of LAE, PAA, or CPC, either alone or in combination, via ESS or SLIC is effective for reducing low levels (ca. 0.3 to 1.6 log CFU) of STEC that may be naturally present on the surface of beef subprimals. PMID- 28726489 TI - Healthfulness, Modernity, and Availability of Food and Beverages: Adolescents' Perceptions in Southern India. AB - This study uses freelists to document perceptions of healthfulness, modernity, and availability of foods and beverages among adolescents ages 13-18 years (n = 26) in urbanizing India. Among the 10 foods and beverages adolescents perceived as "new," half were also seen as modern and unhealthy, 4 as traditional and unhealthy, and 3 as modern and healthy. Of those 10 "new" foods, 4 were reported as available only in supermarkets, 4 only in kiraana (local) stores, and 6 in both. Adolescents ascribed healthfulness and modernity to food and beverage items and were aware of their availability across stores. PMID- 28726490 TI - Psychotropic drug prescription for nursing home residents with dementia: prevalence and associations with non-resident-related factors. AB - OBJECTIVES: To determine psychotropic drug prescription rates in nursing home residents with dementia and to identify associations with the so far understudied psychosocial non-resident-related factors. METHOD: A cross-sectional, observational, exploratory design as part of PROPER I (PRescription Optimization of Psychotropic drugs in Elderly nuRsing home patients with dementia). Participants were 559 nursing home residents with dementia, 25 physicians, and 112 nurses in the Netherlands. Psychotropic drug prescription, non-resident related and known resident-related variables were measured to operationalize the themes of our previous qualitative analysis. RESULTS: Fifty-six percent of residents were prescribed any psychotropic drug, 25% antipsychotics, 29% antidepressants, 15% anxiolytics, and 13% hypnotics, with large differences between the units. Multivariate multilevel regression analyses revealed that antipsychotic prescription was less likely with higher physicians' availability (odds ratio 0.96, 95% confidence interval 0.93-1.00) and that antidepressant prescription was more likely with higher satisfaction of nurses on resident contact (odds ratio 1.50, 95% confidence interval 1.00-2.25). Resident-related factors explained 6%-15% of the variance, resident- and non-resident-related factors together 8%-17%. CONCLUSION: Prescription rates for antipsychotics are similar compared to other countries, and relatively low for antidepressants, anxiolytics, and hypnotics. Our findings indicate that improvement of prescribing could provisionally best be targeted at resident-related factors. PMID- 28726491 TI - Interview with Thomas Powles: The use of durvalumab in urothelial cancer - the latest strides in immuno-oncology. AB - Thomas Powles speaks to Sebastian Dennis-Beron, Commissioning Editor: Dr. Thomas Powles is a clinical professor of genitourinary oncology and the lead for solid tumor research at Barts Cancer Institute in London. His main research interests are in genital and urinary cancers, in which he leads a spectrum of clinical studies from Phase I to randomized Phase III investigating novel targeted and immune therapies. His research also focuses on correlation of novel biomarkers and aims to define markers with prognostic value that may predict response or resistance to therapy. Dr. Powles is the author of more than 100 publications, on the editorial board of a number of journals, and part of the faculty for multiple global oncology meetings. He qualified from St Bartholomew's Medical School and received his MD from the University of London. PMID- 28726492 TI - Does cognition-specific computer training have better clinical outcomes than non specific computer training? A single-blind, randomized controlled trial. AB - OBJECTIVE: The purpose of this study was to investigate differences between non specific computer training (NCT) and cognition-specific computer training (CCT). DESIGN: Randomized controlled experimental study. SETTING: Local community welfare center. SUBJECTS: A total of 78 subjects with mild cognitive impairment (MCI) were randomly assigned to the NCT ( n = 39) or CCT group ( n = 39). INTERVENTION: The NCT group underwent NCT using Nintendo Wii for improving functional performance, while the CCT group underwent CCT using CoTras for improving function of the cognitive domain specifically. Subjects in both groups received 30-minute intervention three times a week for 10 weeks. MAIN MEASURES: To identify effects on cognitive function, the Wechsler Adult Intelligence Scale (WAIS) digit span subtests, Rey Auditory Verbal Learning Test (RAVLT), Trail Making Test-Part B (TMT-B), Rey-Osterrieth Complex Figure Test, and Modified Taylor Complex Figure (MTCF) were used. Health-related quality of life (HRQoL) was assessed using the Short-Form 36-item questionnaire. RESULTS: After 10 weeks, the WAIS subtests (digit span forward: 0.48 +/- 0.08 vs. 0.12 +/- 0.04; digit span backward: 0.46 +/- 0.09 vs. 0.11 +/- 0.04) and HRQoL (vitality: 9.05 +/- 1.17 vs. 2.69 +/- 1.67; role-emotional: 8.31 +/- 1.20 vs. 4.15 +/- 0.71; mental health: 11.62 +/- 1.63 vs. 6.95 +/- 1.75; bodily pain: 4.21 +/- 2.17 vs. 0.10 +/- 0.38) were significantly higher in the NCT group ( P < 0.05). CONCLUSION: NCT was superior to CCT for improving cognitive function and HRQoL of elderly adults with MCI. PMID- 28726493 TI - Chemical profile and antihyperlipidemic effect of Portulaca oleracea L. seeds in streptozotocin-induced diabetic rats. AB - Hypolipidemic effect of Portulaca oleracea L. seed extract and its fractions have been studied on streptozotocin (STZ) at dose 75 mg/kg b.wt. After fractionation of the alcoholic extract; petroleum ether fraction was the most active fraction that decreased different hyperlipidemia biochemical parameters. After chromatographic analysis; oleamide, ethylpalmitate, beta-amyrin, stigmasterol and beta-sitosterol were identified. The GLC analysis of unsaponifiable matter revealed the presence of; lignoceric acid as a major constituent in the most bioactive fraction. In conclusion, petroleum ether fraction possessed a hypolipidemic effect in STZ-induced diabetic rats, which may be attributed to its phytosterols, fatty acid and amide compounds. The finding of the present investigation strongly demonstrates the potential of non-polar fraction of P. oleracea L. seed in combating hyperlipidemia in diabetic condition. So the petroleum ether fractions and its constituents can be used as hypolipdemic supplement in the developing countries towards the development of new therapeutic agents. PMID- 28726494 TI - Roccellatol, a new beta-orcinol based metabolite from the lichen Roccella montagnei. AB - Roccellatol, a new (2'R,3'S)-erythrityl-2,6-dihydroxy-4-methylbenzoate was isolated along with nine known compounds from the fruticose lichen, Roccella montagnei Bel. em. D.D. Awasthi. The structure of the new compound was elucidated by detailed spectroscopic analysis (1H, 13C, DEPT and HRMS). The present isolation of roccellatol (10) assumes significance as the esters of p-orcellinic acid are rare in lichens. Interestingly, among the known compounds, (+) montagnetol (9) was now isolated in very large quantity (4.66%). PMID- 28726495 TI - Use of Adeno-Associated Virus Vector for Cardiac Gene Delivery in Large-Animal Surgical Models of Heart Failure. AB - The advancement of gene therapy-based approaches to treat heart disease represents a need for clinically relevant animal models with characteristics equivalent to human pathologies. Rodent models of cardiac disease do not precisely reproduce heart failure phenotype and molecular defects. This has motivated researchers to use large animals whose heart size and physiological processes more similar and comparable to those of humans. Today, adeno-associated viruses (AAV)-based vectors are undoubtedly among the most promising DNA delivery vehicles. Here, AAV biology and technology are reviewed and discussed in the context of their use and efficacy for cardiac gene delivery in large-animal models of heart failure, using different surgical approaches. The remaining challenges and opportunities for the use of AAV-based vector delivery for gene therapy applications in the clinic are also highlighted. PMID- 28726497 TI - Prognosis Prediction for Postoperative Esophageal Cancer Patients Using Onodera's Prognostic Nutritional Index. AB - PURPOSE: Preoperative nutritional status may impact surgical outcome and prognosis. We evaluated the predictive value of Onodera's prognostic nutritional index (O's-PNI) of surgical outcome following esophagectomy in esophageal cancer patients. PATIENTS AND METHODS: In total, 144 patients undergoing esophagectomy for esophageal cancer from April 2010 to May 2015 were evaluated, retrospectively. Eighty-four patients were enrolled in this study. O's-PNIs were calculated before surgery, discharge, and 1, 2, and 6 mo after discharge. The relationship between O's-PNI and occurrence of complications as classified by the Clavien-Dindo (C-D) classification, length of hospital stay, and survival time was investigated. RESULTS: The mean O's-PNI for patients with complications of more than Grade 2 by the C-D classification was 37.4, which was significantly lower than that for Grades 0 or 1 (40.5, P = 0.0094). A negative correlation was obtained between O's-PNI and hospital stay length (P = 0.0006), whereas a positive correlation was obtained for O's-PNI at 6 mo postsurgery and overall survival (P = 0.0171, P = 0.0201). CONCLUSION: O's-PNI may represent a useful indicator of the occurrence of complications and length of hospital stay, and may influence overall survival at 6 mo postsurgery. Nutritional management during the perioperative period could therefore contribute to satisfactory outcomes following esophagectomy in esophageal cancer patients. PMID- 28726496 TI - A Preclinical Study in Rhesus Macaques for Cystic Fibrosis to Assess Gene Transfer and Transduction by AAV1 and AAV5 with a Dual-Luciferase Reporter System. AB - Cystic fibrosis (CF) is an autosomal recessive disease that is potentially treatable by gene therapy. Since the identification of the gene encoding CF transmembrane conductance regulator, a number of preclinical and clinical trials have been conducted using the first generation of adeno-associated virus, AAV2. All these studies showed that AAV gene therapy for CF is safe, but clinical benefit was not clearly demonstrated. Thus, a new generation of AAV vectors based on other serotypes is needed to move the field forward. This study tested two AAV serotypes (AAV1 and AAV5) using a dual-luciferase reporter system with firefly and Renilla luciferase genes packaged into AAV1 or AAV5, respectively. Two male and two female Rhesus macaques were each instilled in their lungs with both serotypes using a Penn-Century microsprayer. Both AAV1 and AAV5 vector genomes were detected in all the lung samples when measured at the time of necropsy, 45 days after instillation. However, the vector genome number for AAV1 was at least 10-fold higher than for AAV5. Likewise, luciferase activity was also detected in the same samples at 45 days. AAV1-derived activity was not statistically greater than that derived from AAV5. These data suggest that gene transfer is greater for AAV1 than for AAV5 in macaque lungs. Serum neutralizing antibodies were increased dramatically against both serotypes but were less abundant with AAV1 than with AAV5. No adverse events were noted, again indicating that AAV gene therapy is safe. These results suggest that with more lung-tropic serotypes such as AAV1, new clinical studies of gene therapy using AAV are warranted. PMID- 28726498 TI - Antibacterial activity of extract and fractions from branches of Protium spruceanum and cytotoxicity on fibroblasts. AB - The crude ethanol extract (CEE) and fractions from branches of Protium spruceanum were subjected to antibacterial and cytotoxicity assays. Compounds of the most active fraction were identified by GC-MS and LC-MS. CEE was active against 19 bacteria and the ethyl acetate fraction (EAF) showed the lowest minimum bactericidal concentration (MBC 0.3-80.0 mg/mL). Through time-kill assay was observed that EAF induced rapid bactericidal effect against Staphylococcus saprophyticus. The cytotoxicity tests against L929 fibroblasts showed great potential of EAF on the treatment of infections caused by five bacteria (MBC < IC50). The results provide in vitro scientific support to the possible application of branches of P. spruceanum as antimicrobial agent that may contribute for treatment of infections. PMID- 28726499 TI - An In Vitro Study of a New Device: Evaluation of Novel Wide-Angle Lens Flexible Cystoscope Using Phantom Bladder Model. AB - INTRODUCTION: The features and usefulness of a novel wide-angle lens flexible cystoscope were assessed with a view to its practical application. MATERIALS AND METHODS: A phantom bladder model, on which a total of 12 markers that resemble lesions were arranged, was created for this study. Twenty-six urologists at three institutions observed this phantom bladder model using a conventional flexible cystoscope and a novel wide-angle lens flexible cystoscope, and they compared the observation time, marker detection rate, number of misidentified marker locations, overlooked locations, and misidentified location sites of both devices. Specific observation procedures that make use of the features of a wide angle lens flexible cystoscope were also investigated. RESULTS: The observation time tended to be shorter with the wide-angle lens cystoscope than with a conventional cystoscope (104.9 seconds vs 113.6 seconds, p = 0.123). The marker detection rate was higher with the wide-angle lens cystoscope (90.2% vs 85.1%, p = 0.005). The number of marker location misidentifications did not differ between the two devices. Using a specifically designed observation procedure with the wide-angle lens cystoscope tended to further improve the marker detection rate (91.4% vs 88.1%, p = 0.157). CONCLUSION: Compared with a conventional cystoscope, a wide-angle lens cystoscope improved the lesion detection rate and has the potential to reduce observation time. The novel wide-angle lens flexible cystoscope is regarded as a useful device that offers advantages not available with a conventional cystoscope. PMID- 28726500 TI - Chemical constituents from Curcuma longa L. and their inhibitory effects of nitric oxide production. AB - A new bisabolane-type sesquiterpenoid, turmerone Q (1), along with six known compounds (2-7), were isolated from the rhizomes of Curcuma longa L. The structural elucidation of the new compound was conducted using 1H NMR, 13C NMR, HSQC, HMBC and NOESY spectroscopic analyses. The absolute configuration of 1 was elucidated by comparison of the experimental and calculated ECD spectra. The anti inflammatory effects of 1-7 were evaluated through lipopolysaccharide-induced nitric oxide (NO) production in RAW 264.7 macrophages assays, and compounds 6 and 7 showed potent inhibitory activity against NO production. PMID- 28726501 TI - Cigarette Smoke Is an Endothelial Cell Toxin. PMID- 28726502 TI - Spatial reorientation decline in aging: the combination of geometry and landmarks. AB - OBJECTIVES: The study is focused on the assessment of reorientation skills in a sample of community-dwelling elderly people, manipulating landmarks and geometric (layout) information. METHOD: A neuropsychological assessment was administered to 286 elderly participants, divided into six groups (healthy controls, HC; four subgroups of participants with mild cognitive impairment, MCI; participants with probable dementia, Prob_D) and tested with the Virtual Reorientation Test (VReoT). VReoT manipulated different spatial cues: geometry and landmarks (proximal and distal). RESULT: Compared with HC, participants with MCI and Prob_D showed to be impaired in tasks involving geometry, landmarks and a combination of them. Both single and multiple domain impairment in MCI had an impact on reorientation performance. Moreover, VReoT was marginally able to discriminate between amnesic and non-amnesic MCI. The occurrence of getting lost events seemed to be associated to learning of geometric information. CONCLUSION: The associative strength between landmark and target plays an important role in affecting spatial orientation performance of cognitively impaired participants. Geometry significantly supports landmark information and becomes helpful with the increase of cognitive impairment which is linked to a decrement in landmark encoding. VReoT seems to represent a reliable evaluation supplement for spatial orientation deficits in prodromal stages of dementia. PMID- 28726503 TI - Online Portals: Gateway to Patient-Centered Radiology. AB - OBJECTIVE: Online portals typically allow access to radiology reports, causing a shift in the communication. This article evaluates the studies available in the literature about patient portals and the use of patient portals in radiology. Patient and physician preferences and the impact on radiology reporting are presented. CONCLUSION: Patient portals provide an opportunity for radiologists to engage with their patients via a new method of communication. Radiologist collaboration with referring physicians is important in providing care in accordance with patient preferences. PMID- 28726504 TI - JOURNAL CLUB: Informal Consultations Between Radiologists and Referring Physicians, as Identified Through an Electronic Medical Record Search. AB - OBJECTIVE: The purpose of this study is to assess informal consultations between radiologists and referring physicians as identified through an electronic medical record (EMR) search. MATERIALS AND METHODS: The EMR was searched for physician notes containing either the term "radiologist" or "radiology" in combination with any of the following: "second opinion," "second-opinion," "2nd opinion," "2nd opinion," "rereview," "re-review," "reread," "re-read," "overread," "over-read," "spoke with," "discussed with," or "reviewed with." A sample of 300 notes describing a consultation by a referring physician with a diagnostic radiologist was identified. RESULTS: Of the consultations, 73.3% were related to a specific previously interpreted imaging study, and 26.7% were related to other general management issues, including patient safety. Only 18.7% of the physicians' notes indicated the name of the consulted radiologist; a fraction of these consultations were with a radiologist other than the one who originally interpreted the study or with a radiologist at an outside institution. Of consultations with a local radiologist regarding a specific prior examination, 33.9% resulted in a new finding, a change in severity of a previously detected finding, or a change in management recommendation. Of consultations with a change from the initial report, 24.6% were documented by the radiologist via an addendum; 92.9% of these addenda agreed with the referring physicians' notes. CONCLUSION: Radiologists may be unaware of how their consultations are captured within physician notes that may be incomplete or misrepresent the communication. Radiology practices should consider developing policies requiring radiologists to document informal consultations potentially affecting patient management, while developing solutions to facilitate such documentation when it is not readily achieved through report addenda (e.g., through direct documentation by the radiologist in the EMR). PMID- 28726505 TI - Renal Angiomyolipoma: Radiologic Classification and Imaging Features According to the Amount of Fat. AB - OBJECTIVE: The purposes of this article are to introduce the radiologic classifications of renal angiomyolipoma (AML) and the clinical implications, to show the imaging features of each type of AML, and to describe which types of AML should be biopsied. CONCLUSION: Renal AML can be classified according to amount of fat as fat rich, fat poor, or fat invisible. To detect fat, one needs to thoroughly evaluate the entire AML by controlling the size and shape of the ROI. Fat-invisible AML should be biopsied, and fat-poor AML requires further investigation to determine whether biopsy is necessary to differentiate it from renal cell carcinoma. If differentiation between AML and renal cell carcinoma is not clear with CT and MRI, percutaneous biopsy may be performed. PMID- 28726506 TI - Maximizing Value Through Innovations in Radiologist-Driven Communications in Breast Imaging. AB - OBJECTIVE: The purposes of this article are to provide an overview of current and emerging practices in radiologist communications with both referring physicians and patients across the breast cancer care continuum; to highlight areas in which radiologist-driven communications can improve value in breast cancer screening, diagnosis, and treatment; and describe how the integrative reporting and consultative practices of breast imagers can serve as models of higher-value patient-centered care in other radiology subspecialties. CONCLUSION: The traditional radiology report will eventually no longer be viewed as the sole consultation by radiologists but instead act as a starting point for more detailed communications between radiologists and both patients and physicians. The value-creating practices of breast imagers can be used as a road map for similar practices across other radiologic specialties, similar to the use of BI RADS as a road map for structured breast imaging reporting. PMID- 28726507 TI - Qualitative and Quantitative Assessment of Abdominal and Pelvic CT Image Quality Using Iopromide With Different Concentrations of Iodine (300 and 370 mg I/mL). AB - OBJECTIVE: The purpose of this study was to analyze the quality of MDCT images obtained using iopromide with two different concentrations of iodine (300 and 370 mg I/mL) in daily clinical settings. SUBJECTS AND METHODS: Patients from 38 hospitals in China undergoing abdominal or pelvic CT with iopromide were prospectively recruited. MDCT was performed using iopromide with an iodine concentration of 300 or 370 mg I/mL. CT quality image was graded as excellent, good, adequate, and poor. Objective indicators were the contrast-to-noise ratio (CNR) and signal-to-noise ratio (SNR). Outcomes were compared according to organ studied, tumor type (benign vs malignant), saline usage, and type of MDCT (16 MDCT vs 64-MDCT). RESULTS: A total of 4506 patients (63.7% men) with a mean (+/- SD) age of 56.3 +/- 14.1 years and mean body mass index (weight in kilograms divided by the square of height in meters) of 23.2 +/- 3.3 were included. Iopromide with 300 mg I/mL was used for 3042 patients (67.5%), and 370 mg I/mL was used for 1464 patients (32.2%). A total of 1847 scans (41.0%) had excellent image quality, 2454 (54.5%) had good quality, 176 (3.9%) had adequate quality, and 29 (0.6%) had poor quality. No differences were noted between CT scans that did or did not use saline, 16-MDCT versus 64-MDCT scans, and 300 versus 370 mg I/mL iopromide. Variations in the CNR and SNR were noted between the two iodine concentrations with respect to other parameters examined. CONCLUSION: Iopromide with both concentrations of iodine provided acceptable image quality, though according to CNR and SNR, one or the other may provide better quality in different situations. PMID- 28726508 TI - Optimizing MRI Logistics: Prospective Analysis of Performance, Efficiency, and Patient Throughput. AB - OBJECTIVE: The objective of this study is to optimize MRI logistics through evaluation of MRI workflow and analysis of performance, efficiency, and patient throughput in a tertiary care academic center. SUBJECTS AND METHODS: For 2 weeks, workflow data from two outpatient MRI scanners were prospectively collected and stratified by value added to the process (i.e., value-added time, business value added time, or non-value-added time). Two separate time cycles were measured: the actual MRI process cycle as well as the complete length of patient stay in the department. In addition, the impact and frequency of delays across all observations were measured. RESULTS: A total of 305 MRI examinations were evaluated, including body (34.1%), neurologic (28.9%), musculoskeletal (21.0%), and breast examinations (16.1%). The MRI process cycle lasted a mean of 50.97 +/- 24.4 (SD) minutes per examination; the mean non-value-added time was 13.21 +/- 18.77 minutes (25.87% of the total process cycle time). The mean length-of-stay cycle was 83.51 +/- 33.63 minutes; the mean non-value-added time was 24.33 +/- 24.84 minutes (29.14% of the total patient stay). The delay with the highest frequency (5.57%) was IV or port placement, which had a mean delay of 22.82 minutes. The delay with the greatest impact on time was MRI arthrography for which joint injection of contrast medium was necessary but was not accounted for in the schedule (mean delay, 42.2 minutes; frequency, 1.64%). Of 305 patients, 34 (11.15%) did not arrive at or before their scheduled time. CONCLUSION: Non-value added time represents approximately one-third of the total MRI process cycle and patient length of stay. Identifying specific delays may expedite the application of targeted improvement strategies, potentially increasing revenue, efficiency, and overall patient satisfaction. PMID- 28726509 TI - Soymilk fermentation by Enterococcus faecalis VB43 leads to reduction in the immunoreactivity of allergenic proteins beta-conglycinin (7S) and glycinin (11S). AB - Food allergies represent a serious problem affecting human health and soy proteins rank among the most allergenic proteins from food origin. The proteolytic enzymes produced by lactic acid bacteria (LAB) can hydrolyse the major allergens present in soybean, reducing their immunoreactivity. Many studies have reported the ability of LAB to ferment soy-based products; while the majority of them focus on the improvement of the sensory characteristics and functionality of soy proteins, a lack of information about the role of lactic fermentation in the reduction of immunoreactivity of these proteins exists. The aim of the present study was to evaluate the capability of the proteolytic strain Enterococcus faecalis VB43 to hydrolyse the main allergenic proteins present in soymilk and to determine the immunoreactivity of the obtained hydrolysates. Sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) results of fermented soymilk demonstrated complete hydrolysis of the beta-subunit from beta conglycinin and the acidic polypeptide from glycinin. Reversed phase high performance liquid chromatography (RP-HPLC) analysis of the peptides released after hydrolysis revealed the appearance of new peptides and the disappearance of non-hydrolysed proteins, indicating extensive hydrolysis of the substrate. Results from competitive enzyme-linked immunosorbent assay (ELISA) tests clearly indicated a reduction in the immunoreactivity (more than one logarithmic unit) in the fermented sample as compared to the non-fermented control. Our results suggest that the soymilk fermented by E. faecalis VB43 may induce lower allergic responses in sensitive individuals. The strain E. faecalis VB43 may be considered as an excellent candidate to efficiently reduce the immunoreactivity of soymilk proteins. PMID- 28726510 TI - The effect of probiotic Lactobacillus casei Shirota on knee osteoarthritis: a randomised double-blind, placebo-controlled clinical trial. AB - Knee osteoarthritis (OA) treatment is challenging due to inefficacy and adverse effects of current medications. Probiotic treatment has been shown to promote bone metabolism, reduce pain and inflammatory responses of age-related musculoskeletal disorders, including OA. We aimed to investigate the effect of probiotic Lactobacillus casei Shirota (LcS) on patients with knee OA. 537 patients with knee OA were enrolled in this double-blind, placebo-controlled trial, who were randomised to receive skimmed milk containing either LcS or placebo daily for 6 months. Primary outcome was defined as changes in WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index) and VAS (visual analog scale) scores. Secondary outcome was defined as changes in serum levels of high sensitivity C-reactive protein (hs-CRP). After 6 months of treatment, both WOMAC and VAS scores were significantly improved in the LcS groups of patients compared to the placebo group. Serum levels of hs-CRP were also significantly lower in patients receiving LcS than placebo. Strong linear correlations were observed between serum hs-CRP levels and WOMAC and VAS scores. LcS consumption could serve as a novel therapeutic option in the clinical management of knee OA, improving treatment outcome likely through reducing serum hs-CRP levels. PMID- 28726511 TI - How do probiotics and prebiotics function at distant sites? AB - The realisation that microbes regarded as beneficial to the host can impart effects at sites distant from their habitat, has raised many possibilities for treatment of diseases. The objective of a workshop hosted in Turku, Finland, by the International Scientific Association for Probiotics and Prebiotics, was to assess the evidence for these effects and the extent to which early life microbiome programming influences how the gut microbiota communicates with distant sites. In addition, we examined how probiotics and prebiotics might affect the skin, airways, heart, brain and metabolism. The growing levels of scientific and clinical evidence showing how microbes influence the physiology of many body sites, leads us to call for more funding to advance a potentially exciting avenue for novel therapies for many chronic diseases. PMID- 28726512 TI - Human milk oligosaccharide categories define the microbiota composition in human colostrum. AB - Human milk oligosaccharides (HMOs) are structurally diverse unconjugated glycans with a composition unique to each lactating mother. While HMOs have been shown to have an impact on the development of infant gut microbiota, it is not well known if HMOs also already affect milk microbial composition. To address this question, we analysed eleven colostrum samples for HMO content by high-pressure liquid chromatography and microbiota composition by quantitative PCR. Higher total HMO concentration was associated with higher counts of Bifidobacterium spp. (rho=0.63, P=0.036). A distinctive effect was seen when comparing different HMO groups: positive correlations were observed between sialylated HMOs and Bifidobacterium breve (rho=0.84, P=0.001), and non-fucosylated/non-sialylated HMOs and Bifidobacterium longum group (rho=0.65, P=0.030). In addition to associations between HMOs and bifidobacteria, positive correlations were observed between fucosylated HMOs and Akkermansia muciniphila (rho=0.70, P=0.017), and between fucosylated/sialylated HMOs and Staphylococcus aureus (rho=0.75, P=0.007). Our results suggest that the characterised HMOs have an effect on specific microbial groups in human milk. Both oligosaccharides and microbes provide a concise inoculum for the compositional development of the infant gut microbiota. PMID- 28726513 TI - Effects of depression and past-year binge drinking on cognitive control processes during a flanker task in college-aged adults. AB - BACKGROUND: Recent but largely separate literatures have examined neurocognitive alterations related to both depression and binge drinking, suggesting similar patterns of impairments in attention control and decisional processes. However, depression and problematic alcohol use tend to co-occur, and few studies have examined whether cognitive processing effects of depression and binge drinking are independent or interacting. OBJECTIVE: The current study examined joint effects of depressive symptoms and past-year binge drinking on cognitive processing (measured via EEG assessment). METHODS: University students aged 18 and over (N = 46; 63.4% female) were recruited based on self-reported depressive symptoms and also provided reports of alcohol use (51% reported significant depression; 46% reported at-least one past-year binge-drinking episode). Participants completed a computerized flanker task, assessing cognitive control processes. Forty-one participants providing useable data were included in analyses. RESULTS: Past-year binge drinking was associated with slower and more accurate behavioral responding. The interaction of binge-drinking and depressive symptoms was related to the magnitude of early attentional components (N1 and N2), with individuals reporting high depressive symptoms and a history of binge drinking exhibiting attenuated early attentional engagement (e.g., less negative N1) coupled with enhanced attention control processing (e.g., more negative N2). Depressive symptoms also predicted a lack of discriminated P3 amplitudes on congruent versus incongruent trials. CONCLUSION: The data suggest that depression and binge drinking in the past-year jointly interact to predict early attentional processing, with the pattern of responding consistent with a compensatory response process. Results highlight the importance of future work on binge drinking accounting for co-occurring depression. PMID- 28726514 TI - Increased blood 8-hydroxy-2-deoxyguanosine levels in methamphetamine users during early abstinence. AB - BACKGROUND: Reactive oxygen species (ROS) are thought to play a role in the adverse physical and mental consequences of methamphetamine usage. The oxidative DNA adduct 8-hydroxy-2'-deoxyguanosine (8-OHdG) is a well-known biomarker of ROS induced DNA damage. Currently, there is insufficient clinical information about methamphetamine-induced oxidative DNA damage. OBJECTIVES: This study examined differences in blood levels of 8-OHdG between methamphetamine users and non-users as well as alterations in 8-OHdG levels after 2 weeks of methamphetamine abstinence. METHODS: We recruited 182 methamphetamine users (78.6% of male) and 71 healthy controls (95.8% of male). Baseline serum 8-OHdG levels were measured in both groups using a competitive enzyme-linked immunosorbent assay. In methamphetamine users, 8-OHdG levels were measured again 2 weeks after baseline measurement. RESULTS: The results showed that methamphetamine users had significantly higher 8-OHdG levels (0.34 +/- 0.13 ng/mL) than healthy controls (0.30 +/- 0.08 ng/mL) (p < 0.001). The 8-OHdG levels did not alter after 2 weeks of methamphetamine abstinence (0.32 +/- 0.12 ng/mL, p = 0.051 compared to baseline measurement; p = 0.12 compared to healthy controls). No significant correlations were observed between baseline 8-OHdG levels in methamphetamine users and post-abstinence interval, age of the first methamphetamine use, duration of methamphetamine use, or history of frequent methamphetamine use. CONCLUSION: Our findings suggest that methamphetamine users had an enhanced level of oxidative damage, which did not normalize during early abstinence. Future studies are required to determine the effects of long-term methamphetamine abstinence and potential confounders on 8-OHdG levels in methamphetamine users. PMID- 28726515 TI - Estimate of the cost of multiple sclerosis in Spain by literature review. AB - INTRODUCTION: Multiple Sclerosis (MS) is a progressive disease leading to increasing disability and costs. A literature review was carried out to identify MS costs and to estimate its economic burden in Spain. Areas Covered: The public electronic databases PubMed, ScienceDirect and IBECS were consulted and a manual review of communications presented at related congresses was carried out. A total of 225 references were obtained, of which 43 were finally included in the study. Expert Commentary: Three major cost groups were identified: direct healthcare costs, direct non-healthcare costs and indirect costs. There is a direct relationship between disease progression and increased costs, mainly direct non healthcare costs (greater need for informal care) and indirect costs (greater loss of productivity). The total cost associated with MS in Spain is ?1,395 million per year, and that the mean annual cost per patient is ?30,050. Beyond costs, a large impact on the quality of life of patients, with an annual loss of up to 13,000 quality-adjusted life years was also estimated. MS has a large economic impact on Spanish society and a significant impact on the quality of life of patients. PMID- 28726516 TI - Targeting NSG Mice Engrafting Cells with a Clinically Applicable Lentiviral Vector Corrects Osteoclasts in Infantile Malignant Osteopetrosis. AB - Infantile malignant osteopetrosis (IMO) is a rare, lethal, autosomal recessive disorder characterized by nonfunctional osteoclasts. More than 50% of the patients have mutations in the TCIRG1 gene, encoding for a subunit of the osteoclast proton pump. The aim of this study was to develop a clinically applicable lentiviral vector expressing TCIRG1 to correct osteoclast function in IMO. Two mammalian promoters were compared: elongation factor 1alpha short (EFS) promoter and chimeric myeloid promoter (ChimP). EFS promoter was chosen for continued experiments, as it performed better. IMO osteoclasts corrected in vitro by a TCIRG1-expressing lentiviral vector driven by EFS (EFS-T) restored Ca2+ release to 92% and the levels of the bone degradation product CTX-I to 95% in the media compared to control osteoclasts. IMO CD34+ cells from five patients transduced with EFS-T were transplanted into NSG mice. Bone marrow was harvested 9-19 weeks after transplantation, and human CD34+ cells were selected, expanded, and seeded on bone slices. Vector-corrected IMO osteoclasts had completely restored Ca2+ release. CTX-I levels in the media were 33% compared to normal osteoclasts. Thus, in summary, evidence is provided that transduction of IMO CD34+ cells with the clinically applicable EFS-T vector leads to full rescue of osteoclasts in vitro and partial rescue of osteoclasts generated from NSG mice engrafting hematopoietic cells. This supports the continued clinical development of gene therapy for IMO. PMID- 28726517 TI - Robot assisted tumor resection devices. AB - INTRODUCTION: In Japan, colorectal endoscopic submucosal dissection (ESD) is being conducted safely and effectively as shown by the increased number of the cases, however, it is still regarded as a complicated and challenging procedure. Therefore, piecemeal endoscopic mucosal resection (p-EMR) is still regarded as an appropriate treatment, rather than ESD for large colorectal tumors, especially in Western countries. Areas covered: There are several factors those are responsible for colorectal ESD difficulty. Firstly, there is no adequate traction or counter traction in colorectal ESD. Secondly, it is challenging to handle the colonoscope in a redundant and narrow colonic lumen. Thirdly, the risk of perforation is estimated to be relatively higher compared to the stomach or esophagus Expert commentary: To overcome these difficulties, various traction and counter-traction methods have been reported and finally, the new concept of the Master and Slave Transluminal Endoscopic Robot (MASTER) has been developed and is soon to be available for clinical use. The authors have reviewed the history of colorectal ESD and MASTER in this paper. PMID- 28726518 TI - Differential responses of mesenteric arterial bed to vasoactive substances in L NAME-induced preeclampsia: Role of oxidative stress and endothelial dysfunction. AB - To investigate the systemic and placental oxidant status as well as vascular function in experimental preeclampsia (PE) induced by nitro-L-arginine methyl ester (L-NAME). Fetal parameters and maternal blood pressure, proteinuria, mesenteric arterial bed (MAB) reactivity, and systemic and placental oxidative stress were compared between four groups: pregnant rats receiving L-NAME (60 mg/kg/day, orally) (P + L-NAME) or vehicle (P) from days 13 to 20 of pregnancy and nonpregnant rats receiving L-NAME (NP + L-NAME) or vehicle (NP) during 7 days. L-NAME administration during pregnancy induced some hallmarks of PE, such as hypertension and proteinuria. The P + L-NAME group presented lower weight gain and placental mass as well as reduced number and weight of live fetuses than P group. The vasodilator effect induced by acetylcholine (ACh) and angiotensin II (Ang II) was lower in the perfused MAB from NP + L-NAME and P + L-NAME than in control groups. Otherwise, the nitroglycerine-induced vasodilation and the phenylephrine- and Ang II-induced vasoconstriction were higher in MAB from NP + L NAME and P + L-NAME groups than in the respective controls. Systemic and placental oxidative damage, assessed by malondialdehyde and carbonyl levels, was increased and activities of the antioxidant enzymes superoxide dismutase and glutathione peroxidase were reduced in P + L-NAME and NP + L-NAME groups compared to controls. The present data suggest that the oxidative stress and reduced bioavailability of nitric oxide may contribute to attenuation of vasodilator responses to ACh and Ang II, and hyperreactivity to Ang II in the mesentery of preeclamptic rat, which may contribute to the increased peripheral vascular resistance and BP, as well as intrauterine growth restriction in L-NAME-induced PE. PMID- 28726520 TI - Rural and urban substance use differences: Effects of the transition to college. AB - BACKGROUND: With approximately 20% of Americans residing in rural communities, substance use differences is an important topic for appropriate use of resources, policy decisions, and the development of prevention and intervention programs. OBJECTIVES: The current study examined differences in alcohol, tobacco, and marijuana use among students from rural and urban backgrounds across the transition to college. METHODS: Participants were 431 (48% male) undergraduate students from a large, public southeastern university who provided yearly alcohol, tobacco, and marijuana use data during freshman, sophomore, and junior years. RESULTS: Prevalence of alcohol, tobacco, and marijuana use was lower during early college years, and females were less likely to use tobacco and marijuana. Results indicated that rural individuals were less likely to use alcohol and marijuana than their urban counterparts as freshmen, but rose to meet the rates of urban students by junior year. In contrast, no rural/urban differences in tobacco were noted, although rural minorities were more likely to endorse tobacco use across all years. Finally, perceived peer use of each substance was a significant predictor of future use of that substance for all years. CONCLUSION: This is the first study to explore rural/urban, gender, and racial differences in substance use across the college transition. Results suggest that there are subgroups of individuals at specific risk who may benefit not only from feedback regarding the influence of perceived peer use in college, but also from a deeper understanding of how cultural norms maintain their substance use behaviors over time. PMID- 28726519 TI - Cancer stem cells CD133 inhibition and cytotoxicity of certain 3 phenylthiazolo[3,2-a]benzimidazoles: design, direct synthesis, crystal study and in vitro biological evaluation. AB - Cancer stem cells (CSCs) have been objects of intensive study since their identification in 1994. Adopting a structural rigidification approach, a novel series of 3-phenylthiazolo[3,2-a]benzimidazoles 4a-d was designed and synthesised, in an attempt to develop potent anticancer agent that can target the bulk of tumour cells and CSCs. The anti-proliferative activity of the synthesised compounds was evaluated against two cell lines, namely; colon cancer HT-29 and triple negative breast cancer MDA-MB-468 cell lines. Also, their inhibitory activity against the cell surface expression of CD133 was examined. In particular, compound 4b emerged as a promising hit molecule as it manifested good antineoplastic potency against both tested cell lines (IC50 = 9 and 12 MUM, respectively), beside its ability to inhibit the cell surface expression of CD133 by 50% suggesting a promising potential of effectively controlling the tumour by eradicating the tumour bulk and inhibiting the proliferation of the CSCs. Moreover, compounds 4a and 4c showed moderate activity against HT-29 (IC50 = 21 and 29 MUM, respectively) and MDA-MB-468 (IC50 = 23 and 24 MUM, respectively) cell lines, while they inhibited the CD133 expression by 14% and 48%, respectively. Finally, a single crystal X-ray diffraction was recorded for compound 4d. PMID- 28726521 TI - Polymer donors of nitric oxide improve the treatment of experimental solid tumours with nanosized polymer therapeutics. AB - Polymer carriers based on N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers with incorporated organic nitrates as nitric oxide (NO) donors were designed with the aim to localise NO generation in solid tumours, thus highly increasing the enhanced permeability and retention (EPR) effect. The NO donors were coupled to the polymer carrier either through a stable bond or through a hydrolytically degradable, pH sensitive, bond. In vivo, the co-administration of the polymer NO donor and HPMA copolymer-bound cytotoxic drug (doxorubicin; Dox) resulted in an improvement in the treatment of murine EL4 T-cell lymphoma. The polymer NO donors neither potentiated the in vitro toxicity of the cytotoxic drug nor exerted any effect on in vivo model without the EPR effect, such as BCL1 leukaemia. Thus, an increase in passive accumulation of the nanomedicine carrying cytotoxic drug via NO-enhanced EPR effect was the operative mechanism of action. The most significant improvement in the therapy was observed in a combination treatment with such a polymer conjugate of Dox, which is characterised by increased circulation in the blood and efficient accumulation in solid tumours. Notably, the combination treatment enabled the development of an anti-tumour immune response, which was previously demonstrated as an important feature of HPMA-based polymer cytotoxic drugs. PMID- 28726522 TI - Steerable Induction of the Thymosin beta4/MRTF-A Pathway via AAV-Based Overexpression Induces Therapeutic Neovascularization. AB - Viral vectors have been frequently used in a variety of preclinical animal models to deliver genetic constructs into tissues. Among the vectors used, adeno associated viral vectors (AAVs) may be targeted to specific tissues, depending on the serotype used. Moreover, they show robust expression for prolonged periods of time and have a low immunogenic potential. Furthermore, AAVs, unlike other vector systems, only display a low rate of genomic integration. However, to ensure efficient transgene production, expression is typically driven by constitutively active promoters, such as the cytomegalovirus (CMV) promoter. Tetracyclin responsive promoters represent a promising alternative to unregulated promoters. The present study compares AAVs encoding either constitutively active CMV or tet off promoter regions in the preclinical models of hindlimb and chronic myocardial ischemia. Therapeutically, mediators regulating vessel maturation, specifically thymosin beta 4 (Tbeta4) and the downstream signaling molecule myocardin-related transcription factor A (MRTF-A) as well as the endothelial activator angiopoietin 2 (Ang2) were overexpressed via AAVs using both promotors. In the model of rabbit hindlimb ischemia, temporary (tet-off) expression of Tbeta4 improved capillary density, collateralization, and perfusion in the ischemic hindlimb, with no detectable difference to constitutive Tbeta4 overexpression. Similarly, constitutive overexpression of MRTF-A alone was able to improve capillarization, collateralization and perfusion. Temporary expression of Ang2 for 7 days further increased capillary density and pericyte coverage compared with MRTF-A alone, without further improving collateralization or perfusion. In the pig model of chronic myocardial ischemia constitutive expression of Tbeta4 for 4 weeks induced capillary and collateral growth similarly to a pulsed expression (2 day expression per week for 3 weeks). Taken together these findings demonstrate for two models of preclinical interventions that temporary gene expression may lead to similar results as constitutive expression, highlighting the potential of controlled temporary gene expression for induction of vascular growth as a therapeutic approach. PMID- 28726523 TI - Investigational therapies for the treatment of narcolepsy. AB - INTRODUCTION: Narcolepsy is a chronic sleep disorder characterized by a pentad of excessive daytime sleepiness (EDS), cataplexy, sleep paralysis, hypnagogic/hypnopompic hallucinations, and disturbed nocturnal sleep. While non pharmacological treatments are sometimes helpful, more than 90% of narcoleptic patients require a pharmacological treatment. Areas covered: The present review is based on an extensive Internet and PubMed search from 1994 to 2017. It is focused on drugs currently in development for the treatment of narcolepsy. Expert opinion: Currently there is no cure for narcolepsy, with treatment focusing on symptoms control. However, these symptomatic treatments are often unsatisfactory. The research is leading to a better understanding of narcolepsy and its symptoms. New classes of compounds with possible applications in the development of novel stimulant/anticataplectic medications are described. H3 receptor antagonists represent a new therapeutic option for EDS in narcolepsy. JZP-110, with its distinct mechanism of action, would be a new therapeutic option for the treatment of EDS in the coming years. In the future, hypocretin-based therapies and immune based therapies, could modify the clinical course of the disease. However, more information would be necessary to completely understand the autoimmune process and also how this process can be altered for therapeutic benefits. PMID- 28726524 TI - Subnanomolar indazole-5-carboxamide inhibitors of monoamine oxidase B (MAO-B) continued: indications of iron binding, experimental evidence for optimised solubility and brain penetration. AB - Pharmacological and physicochemical studies of N-unsubstituted indazole-5 carboxamides (subclass I) and their structurally optimised N1-methylated analogues (subclass II), initially developed as drug and radioligand candidates for the treatment and diagnosis of Parkinson's disease (PD), are presented. The compounds are highly brain permeable, selective, reversible, and competitive monoamine oxidase B (MAO-B) inhibitors with improved water-solubility and subnanomolar potency (pIC50 >8.8). Using a well-validated, combined X ray/modelling technology platform, we performed a semi-quantitative analysis of the binding modes of all compounds and investigated the role of the indazole N1 position for their MAO-B inhibitory activity. Moreover, compounds NTZ-1006, 1032, and 1441 were investigated for their ability to bind Fe2+ and Fe3+ ions using UV visible spectroscopy. PMID- 28726525 TI - Working memory capacity and addiction treatment outcomes in adolescents. AB - BACKGROUND: Brief addiction treatments including motivational interviewing (MI) have shown promise with adolescents, but the factors that influence treatment efficacy in this population remain unknown. One candidate is working memory, the ability to hold a fact or thought in mind. This is relevant, as in therapy, a client must maintain and manipulate ideas while working with a clinician. Working memory depends upon brain structures and functions that change markedly during neurodevelopment and that can be negatively impacted by substance use. OBJECTIVES: In a secondary analysis of data from a clinical trial for adolescent substance use comparing alcohol/marijuana education and MI, we evaluated the relationship between working memory and three-month treatment-outcomes with the hypothesis that the relationship between intervention conditions and outcome would be moderated by working memory. METHODS: With a diverse sample of adolescents currently using alcohol and/or marijuana (N = 153, 64.7% male, 70.6% Hispanic), we examined the relationship between baseline measures of working memory and alcohol and cannabis-related problem scores measured at the three month follow-up. RESULTS: The results showed that lower working memory scores were associated with poorer treatment response only for alcohol use, and only within the education group. No relationship was found between working memory and treatment outcomes in the MI group. CONCLUSION: The results suggest that issues with working memory capacity may interfere with adolescents' ability to process and implement didactic alcohol and marijuana content in standard education interventions. These results also suggest that MI can be implemented equally effectively across the range of working memory functioning in youth. PMID- 28726526 TI - Integrated care coordination by an interprofessional team reduces emergency department visits and hospitalisations at an academic health centre. AB - People with chronic behavioural and physical health conditions have higher healthcare costs and mortality rates than patients with chronic physical conditions alone. As a result, there has been promotion of integrated care for this group. It is important to train primary care residents to practice in integrated models of care with interprofessional teams and to evaluate the effectiveness of integrated care models to promote high-quality care for this at risk group. We implemented an integrated, interprofessional care management programme for adults with chronic mental and physical health needs as part of a curriculum for family medicine and family medicine psychiatry residents. We then evaluated the clinical effectiveness of this programme by describing participants' healthcare utilisation patterns pre- and post-enrolment. Patients enrolled in the programme were approximately 60-70% less likely to utilise the emergency room and 50% less likely to be admitted to the hospital after enrolment in the programme compared to before enrolment. The odds of individual attendance at outpatient primary care and mental health visits improved after enrolment. In the context of the implementation of integrated behavioural and physical healthcare in primary care, this interprofessional care management programme reduced emergency department utilisation and hospitalisations while improving utilisation of primary care and psychiatry outpatient care. Further studies should focus on replication of this model to further discern the model's cost savings and health promotion effects. PMID- 28726527 TI - The Comparison and Estimation of the Prognostic Value of Lipid Profiles in Patients With Prostate Cancer Depends on Cancer Stage Advancement. AB - Lipid profiles and prostate cancer have a controversial relationship, and the predictive ability of lipids in determining cancer risk estimation is still questionable. This study demonstrates a significance assessment of the plasma lipid profiles of subjects with prostate cancer. Locoregional subjects irradiated with external beam therapy were compared to prostate cancer subjects with bone metastases. The histopathologic diagnosis of 103 subjects (71 locoregional [Group 1] and 32 palliative [Group 2]) were analyzed and compared using their blood samples, total cholesterol (CHL), triglycerides (TG), high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein (LDL) cholesterol. The HDL/CHL, LDL/CHL, and TG/HDL ratios were used for better fit and comparison. Subjects were grouped according to their cancer stages and assessed using statins in both groups. In this study, serum HDL/CHL was significantly increased in Group 1 compared to Group 2 ( p = .02), and time-statin factor in relation was statistically significant ( p = .02). For Group 2, this index decreased with each day after radiotherapy ( p = .07), which means the CHL was increased. Negative effects were noticed at the time of observation of the LDL/HDL ratio with an approximate increase of 0.0025 each day in palliative subjects. This ratio showed a statically significant elevation ( p = .04). There was not a statistically significant difference in the value of the TG/HDL ratio between both groups. As the survival of cancer subjects increases, frequent control of the lipid profile gains importance. PMID- 28726528 TI - The predictive value of the product of contrast medium volume and urinary albumin/creatinine ratio in contrast-induced acute kidney injury. AB - Preexisting renal impairment and the amount of contrast media are the most important risk factors for contrast-induced acute kidney injury (CI-AKI). We aimed to investigate whether the product of contrast medium volume and urinary albumin/creatinine ratio (CMV * UACR) would be a better predictor of CI-AKI in patients undergoing nonemergency coronary interventions. This was a prospective single-center observational study, and 912 consecutive patients who were exposed to contrast media during coronary interventions were investigated prospectively. CI-AKI is defined as a 44.2 MUmol/L rise in serum creatinine or a 25% increase, assessed within 48 h after administration of contrast media in the absence of other causes. Fifty patients (5.48%) developed CI-AKI. The urinary albumin/creatinine ratio (UACR) (OR = 1.002, 95% CI = 1.000-1.003, p = .012) and contrast medium volume (CMV) (OR = 1.008, 95% CI = 1.001-1.014, p = .017) were independent risk factors for the development of CI-AKI. The area under the ROC curve of CMV, UACR and CMV * UACR were 0.662 (95% CI = 0.584-0.741, p < .001), 0.761 (95% CI = 0.674-0.847, p < .001) and 0.808 (95% CI = 0.747-0.896, p < .001), respectively. The cutoff value of CMV * UACR to predict CI-AKI was 1186.2, with 80.0% sensitivity and 62.2% specificity. The product of CMV and UACR (CMV * UACR) might be a predictor of CI-AKI in patients undergoing nonemergency coronary interventions, which was superior to CMV or UACR alone. PMID- 28726530 TI - Incremental net monetary benefit of ocrelizumab relative to subcutaneous interferon beta-1a. AB - AIM: Disease-modifying therapies (DMTs) impact the natural history of relapsing forms of multiple sclerosis (RRMS) by reducing annual relapse rates and slowing disability progression. The effect of DMTs on indirect costs has not been consistently explored in cost-effectiveness studies thus far. The value to patients of an emerging DMT, ocrelizumab, was quantified in comparison to subcutaneous interferon beta-1a (IFNbetaSC) for the prevalent RRMS population with mild-to-moderate disability in the US, based on two Phase 3 trials, OPERA I and OPERA II, of ocrelizumab vs IFNbetaSC in RRMS. MATERIALS AND METHODS: A Markov model was developed to compare disability progression as measured by Expanded Disability Status Scale (EDSS) and relapse outcomes over a 30-year horizon for ocrelizumab vs IFNbetaSC. Direct, indirect, and informal costs (2016 US dollars) and utilities for EDSS health states were obtained from the literature. Hazard ratios for disability progression and relapse rates were estimated from clinical trials. Value was assessed by calculating the net monetary benefit (NMB), defined as the monetary value of discounted quality adjusted life years (QALYs) minus total costs, where the value of a QALY was $150,000. One-way sensitivity analyses were conducted. RESULTS: Ocrelizumab was associated with an incremental gain of 0.84 QALYs and cost savings of $287,713 relative to IFNbetaSC, resulting in an incremental NMB (INMB) of $413,611 per person over 30 years. The INMB increased by $151,763 for those initiating ocrelizumab at EDSS level 1 vs level 4. Influential parameters were QALY value, treatment costs, and disability progression; however, all sensitivity analyses indicated that the INMB for ocrelizumab relative to IFNbetaSC was >=$300,000 per person. CONCLUSIONS: Ocrelizumab provides greater value to RRMS patients compared with IFNbetaSC. Initiating ocrelizumab at lower EDSS levels leads to a greater cumulative value due to slower disability progression, which extends years with higher quality-of-life. PMID- 28726529 TI - Factors associated with the elevated percentage of CD4CD69 T cells in maintained hemodialysis patients. AB - BACKGROUND: CD4 T-cell abnormality, influencing the outcome of the maintained hemodialysis (MHD), is common in patients on dialysis. We try to find out factors associated with the activated CD4 T cells, CD4CD69 T cells, to improve the dialysis quality. METHODS: A cross-sectional study was conducted to evaluate the change of CD4CD69 in MHD patients and healthy controls in our hospital from September 2015 to May 2016. A total of 164 MHD patients and 24 healthy controls were included according to the criteria. Univariate and multivariate logistic regression models after correlation analysis were executed to discover the related factors of CD4CD69 T-cell posterior to the division of the CD4CD69 T cell according to its median. RESULTS: The lymphocytes were lower, but the percentage of CD4CD69 T cells was higher in MHD patients compared with healthy controls, even after the propensity score matching based on age and sex. The percentage of CD4 T cells showed no significant difference between the two groups. Further multivariate logistic regression models revealed that CD4CD69 T cell was independently associated with serum total protein (OR 95%CI: 0.830[0.696, 0.990], p = .038), transferrin (OR 95%CI: 3.072[1.131, 8.342], p = .028) and magnesium (OR 95%CI: 16.960[1.030, 279.275], p = .048). CONCLUSION: The percentage of CD4CD69 T cells, activated CD4 T cells, elevated in hemodialysis patients despite the decrease in lymphocytes. The elevated CD4CD69 T cells were independently associated with serum total protein negatively, but transferrin and magnesium positively. Strengthening nutrition, reducing the concentration of transferrin and magnesium might be beneficial to reduce the activation of CD4 T cells and improve the outcome of MHD patients. PMID- 28726531 TI - Looking Forward and Looking Back: Older Adults' Views of the Impacts of Stopping Driving. AB - This project aimed to identify the impact of driving cessation from the perspectives of older drivers and former drivers. Participants included 17 adults aged 65-88 years residing in a city in Northwestern Ontario, Canada. Using a semi structured interview guide (with questions regarding mobility, personal impact, impact on others, engagement with life, and finances), two focus groups were held with nine current drivers, and one-on-one interviews were held with six former drivers and two current drivers. Two themes emerged concerning stopping driving. The first theme included discussions on experiencing lifestyle changes, relationship impacts, and emotional impacts. The second, the adjustment to stopping driving, included practical adaptations, and emotional responses such as appreciation, resistance, acceptance, and being positive. Although the impacts of stopping driving were substantial, there were few discrepancies between what was anticipated and what was experienced. This information could assist with developing interventions to ease the transition to former-driver status. PMID- 28726532 TI - Local to global: Working together to meet the needs of vulnerable communities. AB - Since 2012, the University of Wisconsin-Milwaukee (UWM) faculty from nursing and physical therapy (PT) have been working together towards a common goal: to meet the healthcare needs of vulnerable populations in Malawi and Milwaukee. Sharing valuable knowledge and understanding one another's professions have allowed us to develop interprofessional education (IPE) learning experiences for students to help identify how quality of life could be improved or enhanced for children and their families across two different geographic spaces, one in rural Malawi and the other in urban Milwaukee. IPE learning modules were implemented in UWM's community health-focused short-term study abroad programmes to Malawi. IPE learning modules were also piloted at one of UWM's nurse-managed community health centres, located in a low-income, African American community in the inner city of Milwaukee, Wisconsin. Based on survey data collected from 10 participating IPE students in Milwaukee, from nursing, occupational therapy, PT, and speech and language pathology, a pilot study yielded a statistically significant change in a positive direction for increased understanding of three interprofessional collaborative practice core competencies: values and ethics, roles and responsibilities, and teams and teamwork. In this article, we discuss the processes used to develop, implement, and evaluate IPE experiences for UWM students, which may enable other professionals to envision the various projects they can embark upon from an interprofessional perspective. PMID- 28726533 TI - Ophthalmic findings in patients with arterial tortuosity syndrome and carriers: A case series. AB - INTRODUCTION: Arterial tortuosity syndrome (ATS) is a rare autosomal recessive disease hallmarked by tortuosity, stenosis, and aneurysm development of large- and medium-sized arteries. Mutations in SLC2A10, a gene that encodes the facilitative glucose transporter GLUT10, cause ATS. Several case reports have noted associated ophthalmic findings such as keratoconus, keratoglobus, and myopia without detailed descriptions or standardized examinations. We report the ophthalmic findings in a cohort of compound heterozygous ATS patients and heterozygous carriers of SLC2A10 mutations. METHODS: Five ATS patients and three carriers were identified through an ATS specialty clinic at the Arkansas Children's Hospital in Little Rock, Arkansas. Patients underwent complete eye examinations, including corneal pachymetry, topography, and optical coherence tomography when indicated. RESULTS: All five patients with ATS had myopia and thin corneas with an average central corneal thickness of 426 um, and three had corneal ectasia, two with early keratoconus and one with keratoglobus and deep stromal corneal opacities. One patient had bilateral high irregular astigmatism, and one had unilateral high regular astigmatism. All carriers had myopia, one had corneal thinning, and one developed keratectasia in one eye many years after laser-assisted in situ keratomileusis (LASIK) surgery. CONCLUSION: We document a spectrum of ophthalmic manifestations of ATS with universal findings of myopia, corneal thinning, and a propensity for corneal ectasia leading to keratoconus or keratoglobus. Heterozygous carriers may develop keratectasia after corneal refractive surgery. Our data support regular eye examinations for all patients carrying SLC2A10 mutations with follow-up tailored to clinical findings. PMID- 28726534 TI - An Occupational Therapy and Teaching Partnership: Applying a Scholarship of Practice Model. AB - Occupational therapists must generate knowledge and evidence that relates specifically to their practice context especially when there is a paucity of literature for emerging areas of practice. This paper describes the process of adopting a scholarship of practice approach with other professionals to generate evidence for practice in mainstream post primary school settings with students with social, emotional and behavioral difficulties (SEBD). Scholarship of practice and clinical reasoning are closely intertwined as therapists generate evidence on their practice to make informed decisions and judgments. In this paper, there are a number of important concepts needing to be highlighted for their meaning in this specific context. PMID- 28726535 TI - Mismatch repair deficient metastatic colon cancer and urothelial cancer: A case report of sequential immune checkpoint therapy. AB - A major recent advance in cancer therapy involves the use of immune checkpoint therapy for tumors with mismatch repair deficiency, as they have a high tumor mutation load and neoantigen burden. Approximately 4% of advanced colorectal cancer harbors a mismatch repair deficiency. When mismatch repair deficiency exists in the germline, there is increased susceptibility to a variety of cancers including colorectal cancer, uterine cancer, urothelial carcinoma, and skin cancer. Herein we report the case of a 62-year-old man with mismatch repair deficient metastatic colorectal adenocarcinoma, urothelial carcinoma and a history of sebaceous carcinomas. As the patient in 2016 was ineligible for clinical trials he received immune checkpoint anti-PD-1 therapy with pembrolizumab (200 mg every 3 weeks), on compassionate use basis, after the failure of second-line treatment. The patient's CEA initially responded to pembrolizumab for 4 months and then kept rising for 5 months before mildly declining again. His treatment was then switched to anti-PD-L1 therapy with atezolizumab as it was approved for urothelial carcinoma at that time, and his CEA declined again. This case raises interesting questions about caring for patients with mismatch repair deficient colorectal cancer, including the role of PD-L1 therapy, sequencing of immunotherapy, relying on CEA trends and determining future therapies after progression on pembrolizumab. PMID- 28726536 TI - Supraglottic stenosis in a case of Behcet's disease. PMID- 28726537 TI - A case of inclusion body myositis complicated by microscopic polyangiitis. PMID- 28726538 TI - Marked bleeding diathesis in patients with platelet dysfunction due to a novel mutation in RASGRP2, encoding CalDAG-GEFI (p.Gly305Asp). AB - Congenital platelet function disorders are often the result of defects in critical signal transduction pathways required for platelet adhesion and clot formation. Mutations affecting RASGRP2, the gene encoding the Rap GTPase activator, CalDAG-GEFI, give rise to a novel, and rare, group of platelet signal transduction abnormalities. We here report platelet function studies for two brothers (P1 and P2) expressing a novel variant of RASGRP2, CalDAG GEFI(p.Gly305Asp). P1 and P2 have a lifelong history of bleeding with severe epistaxis successfully treated with platelet transfusions or rFVIIa. Other bleedings include extended hemorrhage from minor wounds. Platelet counts and plasma coagulation were normal, as was alphaIIbbeta3 and GPIb expression on the platelet surface. Aggregation of patients' platelets was significantly impaired in response to select agonists including ADP, epinephrine, collagen, and calcium ionophore A23187. Integrin alphaIIbbeta3 activation and granule release were also impaired. CalDAG-GEFI protein expression was markedly reduced but not absent. Homology modeling places the Gly305Asp substitution at the GEF-Rap1 interface, suggesting that the mutant protein has very limited catalytic activity. In summary, we here describe a novel mutation in RASGRP2 that affects both expression and function of CalDAG-GEFI and that causes impaired platelet adhesive function and significant bleeding in humans. PMID- 28726539 TI - Rethinking transitions of care: An interprofessional transfer triage protocol in post-acute care. AB - Readmissions to hospitals from post-acute care (PAC) units within long-term care settings have been rapidly increasing over the past decade, and are drivers of increased healthcare costs. With an average of $11,000 per admission, there is a need for strategies to reduce 30-day preventable hospital readmission rates. In 2018, incentives and penalties will be instituted for long-term care facilities failing to meet all-cause, all-condition hospital readmission rate performance measures. An interprofessional team (IPT) developed and implemented a Transfer Triage Protocol used in conjunction with the INTERACT programme to enhance clinical decision-making and assess the potential to reduce the facility's 30-day preventable hospital readmission rates by 10% within 6 weeks of implementation. Results from quantitative analysis demonstrated an overall 35.2% reduction in the 30-day preventable hospital readmission rate. Qualitative analysis revealed the need for additional staff education, improved screening and communication upon admission and prior to hospital transfer, and the need for more IPT on-site availability. This pilot study demonstrates the benefits and implications for practice of an IPT to improve the quality of care within PAC and decrease 30-day preventable hospital readmissions. PMID- 28726540 TI - Mechanisms of the analgesic effect of calcitonin on chronic pain by alteration of receptor or channel expression. AB - The polypeptide hormone calcitonin is well known clinically for its ability to relieve osteoporotic back pain and neuropathic pain such as spinal canal stenosis, diabetic neuropathy, chemotherapy-induced neuropathy, and complex regional pain syndrome. Because the analgesic effects of calcitonin have a broad range, the underlying mechanisms of pain relief by calcitonin are largely unknown. However, recent studies using several types of chronic pain models combined with various methods have been gradually clarifying the mechanism. Here, we review the mechanisms of the analgesic action of calcitonin on ovariectomy induced osteoporotic and neuropathic pain. The analgesic action of calcitonin may be mediated by restoration of serotonin receptors that control selective glutamate release from C-afferent fibers in ovariectomized rats and by normalization of sodium channel expression in damaged peripheral nerves. Serotonin receptors are reduced or eliminated by the relatively rapid reduction in estrogen during the postmenopausal period, and damaged nerves exhibit hyperexcitability due to abnormal expression of Na+ channel subtypes. In addition, in chemotherapy-induced peripheral neuropathy, inhibition of signals related to transient receptor potential ankyrin-1 and melastatin-8 is proposed to participate in the anti-allodynic action of calcitonin. Further, an unknown calcitonin-dependent signal appears to be present in peripheral nervous tissues and may be activated by nerve injury, resulting in regulation of the excitability of primary afferents by control of sodium channel transcription in dorsal root ganglion neurons. The calcitonin signal in normal conditions may be non functional because no target is present, and ovariectomy or nerve injury may induce a target. Moreover, it has been reported that calcitonin reduces serotonin transporter but increases serotonin receptor expression in the thalamus in ovariectomized rats. These data suggest that calcitonin could alleviate lower back pain in patients with osteoporosis or neuropathic pain by the alteration in receptor or channel expression. PMID- 28726541 TI - Characterization of postsynaptic calcium signals in the pyramidal neurons of anterior cingulate cortex. AB - Calcium signaling is critical for synaptic transmission and plasticity. N-methyl D-aspartic acid (NMDA) receptors play a key role in synaptic potentiation in the anterior cingulate cortex. Most previous studies of calcium signaling focus on hippocampal neurons, little is known about the activity-induced calcium signals in the anterior cingulate cortex. In the present study, we show that NMDA receptor-mediated postsynaptic calcium signals induced by different synaptic stimulation in anterior cingulate cortex pyramidal neurons. Single and multi action potentials evoked significant suprathreshold Ca2+ increases in somas and spines. Both NMDA receptors and voltage-gated calcium channels contributed to this increase. Postsynaptic Ca2+signals were induced by puff-application of glutamate, and a NMDA receptor antagonist AP5 blocked these signals in both somas and spines. Finally, long-term potentiation inducing protocols triggered postsynaptic Ca2+ influx, and these influx were NMDA receptor dependent. Our results provide the first study of calcium signals in the anterior cingulate cortex and demonstrate that NMDA receptors play important roles in postsynaptic calcium signals in anterior cingulate cortex pyramidal neurons. PMID- 28726542 TI - Generation and functional characterization of anti-human and anti-mouse IL-36R antagonist monoclonal antibodies. AB - Deficiency of interleukin (IL)-36 receptor antagonist (DITRA) syndrome is a rare autosomal recessive disease caused by mutations in IL36RN. IL-36R is a cell surface receptor and a member of the IL1R family that is involved in inflammatory responses triggered in skin and other epithelial tissues. Accumulating evidence suggests that IL-36R signaling may play a role in the pathogenesis of psoriasis. Therapeutic intervention of IL-36R signaling offers an innovative treatment paradigm for targeting epithelial cell-mediated inflammatory diseases such as the life-threatening psoriasis variant called generalized pustular psoriasis (GPP). We report the discovery and characterization of MAB92, a potent, high affinity anti-human IL-36 receptor antagonistic antibody that blocks human IL-36 ligand (alpha, beta and gamma)-mediated signaling. In vitro treatment with MAB92 directly inhibits human IL-36R-mediated signaling and inflammatory cytokine production in primary human keratinocytes and dermal fibroblasts. MAB92 shows exquisite species specificity toward human IL-36R and does not cross react to murine IL-36R. To enable in vivo pharmacology studies, we developed a mouse cross reactive antibody, MAB04, which exhibits overlapping binding and pharmacological activity as MAB92. Epitope mapping indicates that MAB92 and MAB04 bind primarily to domain-2 of the human and mouse IL-36R proteins, respectively. Treatment with MAB04 abrogates imiquimod and IL-36-mediated skin inflammation in the mouse, further supporting an important role for IL-36R signaling in epithelial cell mediated inflammation. PMID- 28726543 TI - Differences in Brain Architecture in Remote Mild Traumatic Brain Injury. AB - Mild traumatic brain injury (mTBI) is brain trauma from an external impact with a loss of consciousness less than 30 min. Mild TBI results in several biopsychosocial impairments, with pronounced cognitive deficits thought to resolve within 3 months of injury. Previous research suggests that these impairments are due to a temporary inability to appropriately allocate neural resources in response to cognitive demands. Our study questioned this assumption and instead hypothesized that mTBI was associated with long-term neural disruptions and compromised brain structure integrity. By extension, we investigated the likelihood that functional restitution and cognitive resolution following mTBI may be due to some form of neurofunctional reorganization. To this end, we examined abnormalities in resting state functional connectivity and structure (volume, thickness, and fractional anisotropy) in two groups of mTBI those with 1-10 years time post-injury (mTBI1-10), and those with 20-65 years time post-injury, relative to age-, sex-, and education-matched controls. We observed abnormalities in brain architecture only in the mTBI1-10 group, characterized by functional hypo-activation in the right frontal pole, smaller frontal pole volume, and lesser fractional anisotropy in the genu of the corpus callosum that extended near the right frontal pole. This frontal region is laterally specialized to regulate function specific to socio-emotional processes. Collectively, neural disruptions and structural insult in mTBI may persist up to 10 years following injury, but injury-related pathology may resolve with longer recovery time. Disruption to frontal-dependent function that supports socio emotional processes also may interfere with cognitive functioning, as in the case of chronic mTBI. PMID- 28726544 TI - Evaluating WAIS-IV structure through a different psychometric lens: structural causal model discovery as an alternative to confirmatory factor analysis. AB - OBJECTIVE: Since the publication of the WAIS-IV in the U.S. in 2008, efforts have been made to explore the structural validity by applying factor analysis to various samples. This study aims to achieve a more fine-grained understanding of the structure of the Dutch language version of the WAIS-IV (WAIS-IV-NL) by applying an alternative analysis based on causal modeling in addition to confirmatory factor analysis (CFA). The Bayesian Constraint-based Causal Discovery (BCCD) algorithm learns underlying network structures directly from data and assesses more complex structures than is possible with factor analysis. METHOD: WAIS-IV-NL profiles of two clinical samples of 202 patients (i.e. patients with temporal lobe epilepsy and a mixed psychiatric outpatient group) were analyzed and contrasted with a matched control group (N = 202) selected from the Dutch standardization sample of the WAIS-IV-NL to investigate internal structure by means of CFA and BCCD. RESULTS: With CFA, the four-factor structure as proposed by Wechsler demonstrates acceptable fit in all three subsamples. However, BCCD revealed three consistent clusters (verbal comprehension, visual processing, and processing speed) in all three subsamples. The combination of Arithmetic and Digit Span as a coherent working memory factor could not be verified, and Matrix Reasoning appeared to be isolated. CONCLUSIONS: With BCCD, some discrepancies from the proposed four-factor structure are exemplified. Furthermore, these results fit CHC theory of intelligence more clearly. Consistent clustering patterns indicate these results are robust. The structural causal discovery approach may be helpful in better interpreting existing tests, the development of new tests, and aid in diagnostic instruments. PMID- 28726546 TI - Nanotopographic Influence on the In Vitro Behavior of Induced Pluripotent Stem Cells. AB - While the influence of nanotopography on stem cell behavior has been extensively investigated on adult stem cells, far fewer studies have investigated the interaction of induced pluripotent stem cells (iPSCs) with various nanotopographical patterns. The purpose of this study was to identify nanopatterns that can influence the stemness and proliferation, as well as the adhesive properties in iPSCs, and thereby explore the feasibility of applying these nano-features for regenerative medicine. Three kinds of nanopatterns were fabricated from polydimethylsiloxane membranes, irregular patterned membrane (IPM), groove patterned membrane (GPM), and postpatterned membrane (PPM), in addition to flat patterned membrane (FPM) which did not have any nanotopographic features and was used as the control pattern. On the surfaces of GPM or PPM, iPSCs showed tendency for aggregation and did not spread out well at passage 1. However, with continued passaging (P6, P10), the tendency to form aggregates was greatly reduced. While iPSCs cultured on GPM and PPM had low population doubling time values compared with FPM and IPM at P1, the differences disappeared in later passages. The expression of the cell proliferation marker Ki67 in iPSCs gradually decreased with continued passaging in cells cultured on FPM and IPM, but not in those cultured on GPM and PPM. The expression of Oct3/4 and Nanog, marker of stemness, was significantly higher on GPM and PPM than on FPM at P6 and P10. At P5, numerous filopodia were demonstrated in the peripheral attachments of iPSC colonies on FPM and IPM, while GPM and PPM generally had globular appearance. The expression of the focal adhesion (FA) molecules alpha-actinin, vinculin, phalloidin, or FA kinase was significantly greater on GPM and PPM than on FPM and IPM at P6 or P10. In conclusion, continued passaging on regular nanopatterns, including groove- and post-forms, was effective in maintaining an undifferentiated state and proliferation of iPSCs and also in increasing the expression of FA molecules. PMID- 28726545 TI - The t6A modification acts as a positive determinant for the anticodon nuclease PrrC, and is distinctively nonessential in Streptococcus mutans. AB - Endoribonuclease toxins (ribotoxins) are produced by bacteria and fungi to respond to stress, eliminate non-self competitor species, or interdict virus infection. PrrC is a bacterial ribotoxin that targets and cleaves tRNALysUUU in the anticodon loop. In vitro studies suggested that the post-transcriptional modification threonylcarbamoyl adenosine (t6A) is required for PrrC activity but this prediction had never been validated in vivo. Here, by using t6A-deficient yeast derivatives, it is shown that t6A is a positive determinant for PrrC proteins from various bacterial species. Streptococcus mutans is one of the few bacteria where the t6A synthesis gene tsaE (brpB) is dispensable and its genome encodes a PrrC toxin. We had previously shown using an HPLC-based assay that the S. mutans tsaE mutant was devoid of t6A. However, we describe here a novel and a more sensitive hybridization-based t6A detection method (compared to HPLC) that showed t6A was still present in the S. mutans DeltatsaE, albeit at greatly reduced levels (93% reduced compared with WT). Moreover, mutants in 2 other S. mutans t6A synthesis genes (tsaB and tsaC) were shown to be totally devoid of the modification thus confirming its dispensability in this organism. Furthermore, analysis of t6A modification ratios and of t6A synthesis genes mRNA levels in S. mutans suggest they may be regulated by growth phase. PMID- 28726547 TI - Three-Dimensional Bioprinting of Hepatic Structures with Directly Converted Hepatocyte-Like Cells. AB - Three-dimensional (3D) bioprinting technology is a promising new technology in the field of bioartificial organ generation with regard to overcoming the limitations of organ supply. The cell source for bioprinting is very important. Here, we generated 3D hepatic scaffold with mouse-induced hepatocyte-like cells (miHeps), and investigated whether their function was improved after transplantation in vivo. To generate miHeps, mouse embryonic fibroblasts (MEFs) were transformed with pMX retroviruses individually expressing hepatic transcription factors Hnf4a and Foxa3. After 8-10 days, MEFs formed rapidly growing hepatocyte-like colonies. For 3D bioprinting, miHeps were mixed with a 3% alginate hydrogel and extruded by nozzle pressure. After 7 days, they were transplanted into the omentum of Jo2-treated NOD Scid gamma (NSG) mice as a liver damage model. Real-time polymerase chain reaction and immunofluorescence analyses were conducted to evaluate hepatic function. The 3D bioprinted hepatic scaffold (25 * 25 mm) expressed Albumin, and ASGR1 and HNF4a expression gradually increased for 28 days in vitro. When transplanted in vivo, the cells in the hepatic scaffold grew more and exhibited higher Albumin expression than in vitro scaffold. Therefore, combining 3D bioprinting with direct conversion technology appears to be an effective option for liver therapy. PMID- 28726548 TI - Wnt/Yes-Associated Protein Interactions During Neural Tissue Patterning of Human Induced Pluripotent Stem Cells. AB - Human induced pluripotent stem cells (hiPSCs) have special ability to self assemble into neural spheroids or mini-brain-like structures. During the self assembly process, Wnt signaling plays an important role in regional patterning and establishing positional identity of hiPSC-derived neural progenitors. Recently, the role of Wnt signaling in regulating Yes-associated protein (YAP) expression (nuclear or cytoplasmic), the pivotal regulator during organ growth and tissue generation, has attracted increasing interests. However, the interactions between Wnt and YAP expression for neural lineage commitment of hiPSCs remain poorly explored. The objective of this study is to investigate the effects of Wnt signaling and YAP expression on the cellular population in three dimensional (3D) neural spheroids derived from hiPSCs. In this study, Wnt signaling was activated using CHIR99021 for 3D neural spheroids derived from human iPSK3 cells through embryoid body formation. Our results indicate that Wnt activation induces nuclear localization of YAP and upregulates the expression of HOXB4, the marker for hindbrain/spinal cord. By contrast, the cells exhibit more rostral forebrain neural identity (expression of TBR1) without Wnt activation. Cytochalasin D was then used to induce cytoplasmic YAP and the results showed the decreased HOXB4 expression. In addition, the incorporation of microparticles in the neural spheroids was investigated for the perturbation of neural patterning. This study may indicate the bidirectional interactions of Wnt signaling and YAP expression during neural tissue patterning, which have the significance in neurological disease modeling, drug screening, and neural tissue regeneration. PMID- 28726549 TI - Homeless veterans' experiences with substance use, recovery, and treatment through photo elicitation. AB - BACKGROUND: Homeless veterans often have addictions and comorbidities that complicate utilization of longitudinal health care services, such as primary care. An understanding of experiences of veterans enrolled in a Homeless Patient Aligned Care Team (H-PACT) may improve addiction treatment engagement in these settings. The authors aimed to describe H-PACT veterans' experiences with substance use (SU), substance use recovery (SUR), and substance use treatment (SUT). METHODS: Homeless veterans were recruited from a veteran primary care medical home clinic between September 2014 and March 2015. Twenty veterans were given digital cameras and prompts for taking photographs about their health and health care and participated in 2 photo elicitation interviews. For this secondary analysis, transcripts from the audio-recorded interviews were analyzed by 2 coders using qualitative content analysis. RESULTS: The majority of participants (75%, n = 15) discussed SU, SUR, and/or SUT in regards to their health and health care utilization. SU themes centered on disclosure of addiction or dependency; substances used; repercussions of SU; SU as a coping mechanism; and association of SU with military service. SUR themes included disclosure of length of sobriety; perceived facilitators of SUR in health, beliefs, social, environmental, financial, and creative pursuit domains; and perceived barriers to SUR in beliefs, social, and environmental domains. SUT themes focused on perceived facilitators of SUT in access to Department of Veterans Affairs (VA) and non-VA services and social domains and perceived barriers to SUT in the social domain. CONCLUSIONS: Providers seeking to elicit addiction-related clinical history and facilitate SUR and SUT might look to the current findings for guidance. Provider training in motivational interviewing may be warranted, which allows for an exploration of health-related consequences of SU and supports patients' self-efficacy. PMID- 28726550 TI - Exploring the impact of high intensity interval training on adolescents' objectively measured physical activity: Findings from a randomized controlled trial. AB - High Intensity Interval Training (HIIT) may be effective for accumulating VPA. However, the contribution of HIIT to overall physical activity is unknown. Our primary aim was to explore the impact of school-based HIIT on physical activity. The secondary aim was to explore within-individual changes in physical activity after participating in HIIT. Participants [n = 65; 15.8(0.6)years] were randomized to a HIIT or control group. Intervention groups participated in three HIIT sessions/week. GENEActiv accelerometers assessed objective physical activity at baseline and week-one, to detect changes in MPA and VPA. Intervention effects were examined using linear mixed models and evidence of a change in physical activity (i.e., compensation) were examined using multilevel linear regression models. The group-by-time interaction effects for MPA and VPA were small and moderate, respectively. Adjusted difference between groups for VPA was 1.70 min/day, 95%CI -1.96 to 5.36; p = 0.354; d = 0.55). Embedding HIIT within the school-day had a moderate effect on VPA compared to controls. Compensation analyses (i.e., individual level) suggested that adolescents were more active on days when they participated in HIIT. Further studies are needed to test the effects of HIIT on adolescents' physical activity over extended time periods. PMID- 28726552 TI - On the sources of forgetting in working memory: The test of competing hypotheses. AB - Whether forgetting from working memory (WM) is only due to interference or is also caused by temporal decay is still a matter of debate. In the present study, this question was examined using complex span tasks in which each memory item was followed by a series of processing episodes, the duration and number of which were varied. It is known that recall performance in these tasks depends on the cognitive load ( CL) of concurrent processing conceived as the ratio between processing time and free time, higher CL resulting in lower spans. The decay-and refresh hypothesis accounts for this effect by assuming that memory traces decay during processing but are refreshed during free time. This hypothesis predicts lower recall performance with longer processing episodes, but no effect of their number as long as CL remains constant. The interference-only hypothesis supposes that free time is used to alleviate the interference created by processing distractors. This hypothesis is potentially compatible with an effect of the duration of processing episodes through increased interference, but predicts a detrimental effect of their number. In three experiments, the recall pattern fitted the predictions of the decay-and-refresh hypothesis for verbal WM, but that of the interference-only hypothesis for visuospatial WM. Although the entire pattern of data is more easily accommodated by the decay-and-refresh hypothesis than by its interference-only contender, our results suggest that it is unwise to aim at identifying a unique source to a complex phenomenon like WM forgetting. PMID- 28726551 TI - Extracellular Matrix and Integrin Expression Profiles in Fuchs Endothelial Corneal Dystrophy Cells and Tissue Model. AB - Primary corneal endothelial cell (CEC) cultures and 3D-engineered tissue models were used to study the aberrant deposition of extracellular matrix (ECM) in a vision impairing pathology known as Fuchs endothelial corneal dystrophy (FECD). CECs were isolated from excised Descemet membranes of patients with end-stage FECD. CECs isolated from healthy corneas served as controls. Microarray gene profiling was performed on postconfluent cultures of healthy and FECD cells. Protein expression analyses were conducted on tissue models that were engineered by seeding an endothelium on previously devitalized human stromal carriers. The engineered endothelia were kept in culture for 1-3 weeks to reform the endothelial monolayer. Protein expression of integrin subunits alpha4, alpha6, alphav, and beta1, as well as laminin, type IV collagen, fibronectin, clusterin, and transforming growth factor beta-induced protein (TGFbetaIp) was then assessed by immunofluorescence. Microarray analysis showed nonstatistical twofold downregulation of collagen-coding genes (COL4A4, COL8A2, and COL21A1) and a twofold upregulation of the COL6A1, laminin alpha3 gene LAMA3, and integrin subunit alpha10 gene ITGA10 in FECD cells. Fibronectin type III domain containing 4 (FNDC4) and integrin beta5 (ITGB5) genes was significantly upregulated in FECD cells. Immunostainings demonstrated that the protein expression of the integrin subunits alpha4, alpha6, alphav, and beta1, type IV collagen, as well as laminin remained similar between native and engineered endothelia. TGFbetaIp expression was found on the stromal side of both FECD and healthy Descemet's membrane, and only one out of three FECD specimens was positive for the clusterin protein. Interestingly, the ECM protein fibronectin was also found to have a stronger presence on engineered FECD tissues, a result consistent with the native FECD specimens. To conclude, this study allowed to identify fibronectin deposition as one of the first steps in the pathogenesis of FECD, as defined by our engineered tissue model. This opens the way to an entirely new perspective for in vitro pharmacological testing of new therapies for FECD, the leading indication for corneal transplantation in North America. PMID- 28726554 TI - Navigational range lights: effect of stimulus configuration on alignment accuracy. AB - The use of range lights in nautical navigation involves the visual determination of the vertical alignment of two points of light, in order to indicate the centre of the channel. In two experiments it is shown that this vernier alignment task is more accurate if illuminated linear stimuli are used as range lights. Experiment 1 involved a laboratory simulation and experiment 2 involved a field test with full sized range lights. The average reduction of error through the use of linear stimuli over the standard point stimuli, for navigational alignments at a distance of one-half nautical mile from the range lights, was 69-4%. This suggests that a marked safety advantage might accrue from the use of linear range lights for nautical navigation purposes. PMID- 28726558 TI - Epidemiology and clinical relevance of Staphylococcus aureus intestinal carriage: a systematic review and meta-analysis. AB - INTRODUCTION: Recent data highlight the importance of screening more than one site for improving the detection of S. aureus colonization. Intestinal carriage is frequently under-investigated and its clinical impact ought to be defined a better way. Areas covered: This review and meta-analysis provide an updated overview of prevalence, characteristics and clinical significance of S. aureus intestinal carriage in different populations, both for methicillin-susceptible and -resistant S. aureus strains. Expert commentary: Intestinal S. aureus carriage is documented with higher prevalence in children and in patients with S. aureus skin and soft tissue infections. This site of colonization was shown to be associated with a high risk of dissemination in the environment and with S. aureus infection. Intestinal carriage is frequently retrieved in nasal carriers, reflecting probably an association with a high bacterial load. Exclusive intestinal carriage present in one third of intestinal carriers can be associated with infection. Comparative genotyping analysis of different strains from nasal and extra-nasal sites of carriage, including the intestinal ones, in the same individuals, would allow a better comprehension of the pathophysiology of S. aureus endogenous infection. It could also permit to improve the prevention of these infections by decolonization of sites implicated in infection genesis. PMID- 28726559 TI - Supercritical Carbon Dioxide-Assisted Decellularization of Aorta and Cornea. AB - Tissue engineering approaches utilize both natural and synthetic materials in the repair and regeneration processes. A naturally sourced material for this purpose is required to be free from any antigenic matter such as cells or cellular components. Decellularization of tissues may be achieved through chemical or physical removal agents. Supercritical carbon dioxide (sc-CO2) has been used on the purpose of removing bioburden from tissues and offers an alternative to the traditionally used treatment methods. In addition to many advantages it offers with regard to the successful decellularization of tissues, it is known to have a sterilization effect. This study provides an insight into sc-CO2-assisted decellularization trials of corneal and aortic tissues. Results showed that high pressure of the fluid bursts the cells during the treatment and rapid depressurization was found to be effective in the removal of the cells from the tissues. sc-CO2 decellularization offers significantly reduced treatment times, complete decellularization, and preserved extracellular matrix structure. PMID- 28726560 TI - Bayesian methods for addressing long-standing problems in associative learning: The case of PREE. AB - Most associative models typically assume that learning can be understood as a gradual change in associative strength that captures the situation into one single parameter, or representational state. We will call this view single-state learning. However, there is ample evidence showing that under many circumstances different relationships that share features can be learned independently, and animals can quickly switch between expressing one or another. We will call this multiple-state learning. Theoretically, it is understudied because it needs a different data analysis approach from those usually employed. In this article, we present a Bayesian model of the Partial Reinforcement Extinction Effect (PREE) that can test the predictions of the multiple-state view. This implies estimating the moment of change in the responses (from the acquisition to the extinction performance), both at the individual and group levels. We used this model to analyze data from a PREE experiment with three levels of reinforcement during acquisition (100%, 75% and 50%). We found differences in the estimated moment of switch between states during extinction, so that it was delayed after leaner partial reinforcement schedules. The finding is compatible with the multiple state view. It is the first time, to our knowledge, that the predictions from the multiple-state view are tested directly. The article also aims to show the benefits that Bayesian methods can bring to the associative learning field. PMID- 28726561 TI - Characteristics of the microwave pyrolysis and microwave CO2-assisted gasification of dewatered sewage sludge. AB - Microwave drying-pyrolysis or drying-gasification characteristics were examined to convert sewage sludge into energy and resources. The gasification was carried out with carbon dioxide as a gasifying agent. The examination results were compared with those of the conventional heating-type electric furnace to compare both product characteristics. Through the pyrolysis or gasification, gas, tar, and char were generated as products. The produced gas was the largest component of each process, followed by the sludge char and the tar. During the pyrolysis process, the main components of the produced gas were hydrogen and carbon monoxide, with a small amount of hydrocarbons such as methane and ethylene. In the gasification process, however, the amount of carbon monoxide was greater than the amount of hydrogen. In microwave gasification, a large amount of heavy tar was produced. The largest amount of benzene in light tar was generated from the pyrolysis or gasification. Ammonia and hydrogen cyanide, which are precursors of NOx, were also generated. In the microwave heating method, the sludge char produced by pyrolysis and gasification had pores in the mesopore range. This could be explained that the gas obtained from the microwave pyrolysis or gasification of the wet sewage sludge can be used as an alternative fuel, but the tar and NOx precursors in the produced gas should be treated. Sludge char can be used as a biomass solid fuel or as a tar removal adsorbent if necessary. PMID- 28726562 TI - Gene therapy for age-related macular degeneration. AB - INTRODUCTION: In neovascular age related macular degeneration (nAMD), gene therapy to chronically express anti-vascular endothelial growth factor (VEGF) proteins could ameliorate the treatment burden of chronic intravitreal therapy and improve limited visual outcomes associated with 'real world' undertreatment. Areas covered: In this review, the authors assess the evolution of gene therapy for AMD. Adeno-associated virus (AAV) vectors can transduce retinal pigment epithelium; one such early application was a phase I trial of AAV2-delivered pigment epithelium derived factor gene in advanced nAMD. Subsequently, gene therapy for AMD shifted to the investigation of soluble fms-like tyrosine kinase 1 (sFLT-1), an endogenously expressed VEGF inhibitor, binding and neutralizing VEGF-A. After some disappointing results, research has centered on novel vectors, including optimized AAV2, AAV8 and lentivirus, as well as genes encoding other anti-angiogenic proteins, including ranibizumab, aflibercept, angiostatin and endostatin. Also, gene therapy targeting the complement system is being investigated for geographic atrophy due to non-neovascular AMD. Expert opinion: The success of gene therapy for AMD will depend on the selection of the most appropriate therapeutic protein and its level of chronic expression. Future investigations will center on optimizing vector, promoter and delivery methods, and evaluating the risks of the chronic expression of anti-angiogenic or anti complement proteins. PMID- 28726563 TI - Mechanically strong and pH-responsive carboxymethyl chitosan/graphene oxide/polyacrylamide nanocomposite hydrogels with fast recoverability. AB - The biocompatible, quickly recoverable, mechanically strong and tough polymer hydrogels have great potential for biomedical applications. A novel carboxymethyl chitosan (CMCTs)/graphene oxide (GO)/polyacrylamide (PAM) nanocomposite (NC) hydrogel with excellent mechanical performance was synthesized through a facile, one-pot free radical polymerization, using GO nanosheets as the crosslink centers instead of toxic organic molecules. The content of GO nanosheets and CMCTs has great influence on the mechanical properties of CMCTs/GO/PAM NC hydrogels. When the amount of GO nanosheets is 0.118 wt % and CMCTs is 1.5 wt % (to the total weight of CMCTs and acrylamide), CMCTs/GO/PAM hydrogel displays a compressive stress as high as 5.8 MPa at the breaking deformation of 87.5% and a tensile strength of 223.6 kPa at the failure strain of 631%. Besides, with nearly complete recovery in 1 min at the room temperature after unloading, the CMCTs/GO/PAM hydrogels exhibit excellent fast recoverability. Additionally, the CMCTs/GO/PAM hydrogels also have an obvious pH-responsive property. PMID- 28726565 TI - NYSCHP Annual Assembly 2016 Poster Abstracts. PMID- 28726564 TI - NYSCHP Residency Research & Practice Forum 2017: Platform Presentation Abstracts. PMID- 28726566 TI - College of Psychiatric and Neurologic Pharmacists Abstracts. PMID- 28726567 TI - Possible mechanisms involved in the anti-nociceptive effects of hydro-ethanolic leaf extract of Ziziphus abyssinica. AB - CONTEXT: Various parts of Ziziphus abyssinica Hochst ex. A. Rich (Rhamnaceae) have been used in Ghanaian and African traditional medicine as an analgesic. However, there are little scientific data to support the anti-nociceptive effects of the hydro-ethanolic leaf extract of Ziziphus abyssinica (EthE) as well as the possible mechanisms involved in its anti-nociceptive effects. PURPOSE: To predict possible nociceptive pathways involved in the anti-nociceptive effects of EthE. MATERIALS AND METHODS: The effect of EthE (30, 100 and 300 mg/kg) on intraplantar injection of pain mediators such as interleukin-1beta, tumour necrosis factor alpha, prostaglandin E2 and bradykinin was evaluated in male Sprague Dawley rats using Randall-Selitto test for 5 h. The effect of specific antagonists to the opioidergic, adenosinergic, ATP-sensitive K+ channels, nitric oxide, serotonergic, muscarinic, adrenergic and voltage-gated calcium channel on the anti-nociceptive effect of EthE (100 mg/kg) was evaluated using the formalin test in male imprinting control region (ICR) mice for 1 h. RESULTS: Pretreatment of the rats with EthE significantly reversed the hypernociception induced by intraplantar injection of TNF-alpha (F4,120 = 10.86, p < 0.0001), IL-1beta (F4,120 = 14.71, p < 0.0001), bradykinin (F4,80 = 12.52, p < 0.0001) and prostaglandin E2 (F5,144 = 6.165, p = 0.0001). The anti-nociceptive effect exhibited by EthE in the formalin test was reversed by systemic administration of NG-l-nitro-arginine methyl ester, naloxone, theophylline and glibenclamide. CONCLUSIONS: EthE inhibits hypernociception induced by TNF-alpha, IL-1beta, bradykinin and prostaglandin E2. EthE exhibited anti-nociceptive effects possibly mediated through opioidergic, adenosinergic, ATP-sensitive potassium channels and nitric oxide cyclic GMP pathways. PMID- 28726569 TI - Founder Ashkenazi Jewish mutations of large deletion in the inherited retinal dystrophy genes. PMID- 28726568 TI - Double hyperautofluorescent ring on fundus autofluorescence in ABCA4. AB - We report an unusual phenotype in a child with a clinical diagnosis of recessive Stargardt disease (STGD1) and two pathogenic variants in the ABCA4 gene. Typically, the diagnosis of early-onset STGD1 is challenging because children may present with a variety of fundus changes and a variable rate of progression. At the time of his initial visit, the 6-year-old boy presented with 20/200 OD (right eye) and 20/150 OS (left eye), symmetrical mild foveal atrophy without flecks on fundus exam, and foveal hypoautofluorescence surrounded by a homogeneous hyperautofluorescent background on wide-field fundus autofluorescence. Over 4 years of follow-up, the retinal atrophy continued to progress, resulting in two well-defined and concentric hyperautofluorescent rings: one ring located at the posterior pole and the other located around the peripapillary region. Visual acuity also deteriorated to counting fingers at 4ft OD and 20/500 OS. To the best of our knowledge, this phenotype has not been previously described with the ABCA4 gene. PMID- 28726570 TI - Potential biomarkers for predicting hemorrhagic transformation of ischemic stroke. AB - Reperfusion therapy contributes to better clinical outcomes in patients with acute ischemic stroke but carries a more significant risk of hemorrhagic transformation (HT) compared to supportive care. Once HT occurs, the outcome is usually poor and this causes a dilemma in the treatment of ischemic stroke. Consequently, early prediction of HT would be extremely helpful for guiding precise treatment of ischemic stroke. In this review, we focus on summarizing biomarkers of HT and elucidating possible mechanisms so as to identify potential biomarkers for predicting HT. PMID- 28726571 TI - Primary Blast Causes Delayed Effects without Cell Death in Shell-Encased Brain Cell Aggregates. AB - Previous work in this laboratory used underwater explosive exposures to isolate the effects of shock-induced principle stress without shear on rat brain aggregate cultures. The current study has utilized simulated air blast to expose aggregates in suspension and enclosed within a spherical shell, enabling the examination of a much more complex biomechanical insult. Culture medium-filled spheres were exposed to single pulse overpressures of 15-30 psi (~6-7 msec duration) and measurements within the sphere at defined sites showed complex and spatially dependent pressure changes. When brain aggregates were exposed to similar conditions, no cell death was observed and no changes in several commonly used biomarkers of traumatic brain injury (TBI) were noted. However, similarly to underwater blast, immediate and transient increases in the protein kinase B signaling pathway were observed at early time-points (3 days). In contrast, the oligodendrocyte marker 2',3'-cyclic nucleotide 3'-phosphodiesterase, as well as vascular endothelial growth factor, both displayed markedly delayed (14-28 days) and pressure-dependent responses. The imposition of a spherical shell between the single pulse shock wave and the target brain tissue introduces greatly increased complexity to the insult. This work shows that brain tissue can not only discriminate the nature of the pressure changes it experiences, but that a portion of its response is significantly delayed. These results have mechanistic implications for the study of primary blast-induced TBI and also highlight the importance of rigorously characterizing the actual pressure variations experienced by target tissue in primary blast studies. PMID- 28726572 TI - Successful forearm prosthesis fitting in a patient with epidermolysis bullosa dystrophica: Case report. AB - BACKGROUND: Epidermolysis bullosa dystrophica is a rare dermatological disease characterized by extreme skin fragility and elevated risk of developing a squamous cell carcinoma. In some cases, amputation of a limb is necessary. Case description and methods: A 37-year-old man with recessive, severe generalized epidermolysis bullosa dystrophica developed a squamous cell carcinoma on the right forearm requiring a below-elbow amputation. Preoperative advice concerning indication and level of amputation was given. Due to potential skin problems, a conventional prosthesis was not feasible. Findings and outcomes: A custom designed adaptive prosthesis with an upper arm cuff was trialed and was well tolerated. Multiple working tools, attached with a rotation and inclination system, allowed independence and return to work. CONCLUSION: Despite multiple potential skin problems of the stump, the patient was successfully fitted with a custom-designed adaptive prosthesis. Preparation for this fitting was done by a comprehensive multidisciplinary patient-centered approach. Clinical relevance Despite severe skin fragility, a patient with epidermolysis bullosa dystrophica was successfully fitted with a custom-designed adaptive upper limb prosthesis allowing good functional outcome. This required a multidisciplinary and patient centered approach. PMID- 28726573 TI - Investigating variations of fluorescent dissolved organic matter in wastewater treatment using synchronous fluorescence spectroscopy combined with principal component analysis and two-dimensional correlation. AB - Synchronous fluorescence spectroscopy (SFS) combined with principal component analysis (PCA) and two-dimensional (2D) correlation was applied to investigate removal efficiencies and variations of dissolved organic matter (DOM) fractions in the wastewater treatment plant (WWTP) with an A2O craft. A decreasing order of total removal efficiencies was tyrosine-like fluorescence component (89.58%) > humic-like fluorescence (HLF) component (39.83%) > tryptophan-like fluorescence component (36.89%) > microbial humic-like fluorescence (HLF) component (12.47%) > fulvic-like fluorescence component (6.37%). The tyrosine-like, tryptophan-like and HLF components were deeply decomposed by anaerobic bacteria in the anaerobic zone. The tyrosine-like component was the preponderant fraction of DOM in the raw water and primary sediment tank. The tyrosine-like component was the dominant component of DOM too in the anaerobic and anoxic zones, but its proportion was slightly more than the tryptophan-like component. The tryptophan-like component was the dominant component in the facultative zone, the oxic zone and the secondary sediment tank. Based on the changing band order of 279 -> 304 -> 490 -> 330 -> 380 -> 430 nm, the decreasing variation order was tyrosine-like > tryptophan-like > humic-like > microbial humic-like > fulvic-like component. Therefore, the SFS combined with PCA and 2D correlation is an effective tool for not only monitoring the removal of DOM components but also characterizing variations of DOM fractions in the WWTP. PMID- 28726575 TI - Bioprinting Pattern-Dependent Electrical/Mechanical Behavior of Cardiac Alginate Implants: Characterization and Ex Vivo Phase-Contrast Microtomography Assessment. AB - Three-dimensional (3D)-bioprinting techniques may be used to modulate electrical/mechanical properties and porosity of hydrogel constructs for fabrication of suitable cardiac implants. Notably, characterization of these properties after implantation remains a challenge, raising the need for the development of novel quantitative imaging techniques for monitoring hydrogel implant behavior in situ. This study aims at (i) assessing the influence of hydrogel bioprinting patterns on electrical/mechanical behavior of cardiac implants based on a 3D-printing technique and (ii) investigating the potential of synchrotron X-ray phase-contrast imaging computed tomography (PCI-CT) for estimating elastic modulus/impedance/porosity and microstructural features of 3D printed cardiac implants in situ via an ex vivo study. Alginate laden with human coronary artery endothelial cells was bioprinted layer by layer, forming cardiac constructs with varying architectures. The elastic modulus, impedance, porosity, and other structural features, along with the cell viability and degradation of printed implants were examined in vitro over 25 days. Two selected cardiac constructs were surgically implanted onto the myocardium of rats and 10 days later, the rat hearts with implants were imaged ex vivo by means of PCI-CT at varying X-ray energies and CT-scan times. The elastic modulus/impedance, porosity, and structural features of the implant were inferred from the PCI-CT images by using statistical models and compared with measured values. The printing patterns had significant effects on implant porosity, elastic modulus, and impedance. A particular 3D-printing pattern with an interstrand distance of 900 MUm and strand alignment angle of 0/45/90/135 degrees provided relatively higher stiffness and electrical conductivity with a suitable porosity, maintaining high cell viability over 7 days. The X-ray photon energy of 30-33 keV utilizing a CT-scan time of 1-1.2 h resulted in a low-dose PCI-CT, which provided a good visibility of the low-X-ray absorbent alginate implants. After 10 days postimplantation, the PCI-CT provided a reasonably accurate estimation of implant strand thickness and alignment, pore size and interconnectivity, porosity, elastic modulus, and impedance, which were consistent with our measurements. Findings from this study suggest that 3D-printing patterns can be used to modulate electrical/mechanical behavior of alginate implants, and PCI-CT can be potentially used as a 3D quantitative imaging tool for assessing structural and electrical/mechanical behavior of hydrogel cardiac implants in small animal models. PMID- 28726576 TI - Recent Developments in Thiolated Polymeric Hydrogels for Tissue Engineering Applications. AB - This review focuses on the recent strategy in the preparation of thiolated polymers and fabrication of their hydrogel matrices. The mechanism involved in the synthesis of thiolated polymers and fabrication of thiolated polymer hydrogels is exemplified with suitable schematic representations reported in the recent literature. The 2-iminothiolane namely "Traut's reagent" has been widely used for effectively thiolating the natural polymers such as collagen and gelatin, which contain free amino group in their backbone. The free carboxylic acid group containing polymers such as hyaluronic acid and heparin have been thiolated by using the bifunctional molecules such as cysteamine and L-cysteine via N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide/N-hydroxysuccinimide (EDC/NHS) coupling reaction. The degree of thiolation in the polymer chain has been widely determined by using Ellman's assay method. The thiolated polymer hydrogels are prepared by disulfide bond formation (or) thiol-ene reaction (or) Michael-type addition reaction. The thiolated polymers such as thiolated gelatin are reacted with polyethylene glycol diacrylate for obtaining interpenetrating polymer network hydrogel scaffolds. Several in vitro cell culture experiments indicate that the developed thiolated polymer hydrogels exhibited biocompatibility and cellular mimicking properties. The developed hydrogel scaffolds efficiently support proliferation and differentiation of various cell types. In the present review article, the thiol-functionalized protein-based biopolymers, carbohydrate based polymers, and some synthetic polymers have been covered with recently published research articles. In addition, the usage of new thiolated nanomaterials as a crosslinking agent for the preparation of three-dimensional tissue-engineered hydrogels is highlighted. PMID- 28726574 TI - Rise of the Pigs: Utilization of the Porcine Model to Study Musculoskeletal Biomechanics and Tissue Engineering During Skeletal Growth. AB - Large animal models play an essential role in the study of tissue engineering and regenerative medicine (TERM), as well as biomechanics. The porcine model has been increasingly used to study the musculoskeletal system, including specific joints, such as the knee and temporomandibular joints, and tissues, such as bone, cartilage, and ligaments. In particular, pigs have been utilized to evaluate the role of skeletal growth on the biomechanics and engineered replacements of these joints and tissues. In this review, we explore the publication history of the use of pig models in biomechanics and TERM discuss interspecies comparative studies, highlight studies on the effect of skeletal growth and other biological considerations in the porcine model, and present challenges and emerging opportunities for using this model to study functional TERM. PMID- 28726577 TI - Will optogenetics be used to treat chronic pain patients? AB - Chronic pain affects a third of the population and current treatments produce limited relief and severe side effects. An alternative strategy to decrease pain would be to directly modulate somatosensory pathways using optogenetics. Optogenetics involves the use of genetically encoded and optically active proteins, namely opsins, to control neuronal circuits. In preclinical animal models, optical silencing of peripheral nociceptors has been shown to alleviate both inflammatory and neuropathic pain. An opsin-based gene therapy to treat chronic pain patients is not ready yet, but encouraging advances have been made in optical and viral technology. In view of the increasing burden of chronic pain in our aging society, innovative analgesic approaches based on optogenetics are definitely worth exploring. PMID- 28726578 TI - A Framework for Optimizing Phytosanitary Thresholds in Seed Systems. AB - Seedborne pathogens and pests limit production in many agricultural systems. Quarantine programs help prevent the introduction of exotic pathogens into a country, but few regulations directly apply to reducing the reintroduction and spread of endemic pathogens. Use of phytosanitary thresholds helps limit the movement of pathogen inoculum through seed, but the costs associated with rejected seed lots can be prohibitive for voluntary implementation of phytosanitary thresholds. In this paper, we outline a framework to optimize thresholds for seedborne pathogens, balancing the cost of rejected seed lots and benefit of reduced inoculum levels. The method requires relatively small amounts of data, and the accuracy and robustness of the analysis improves over time as data accumulate from seed testing. We demonstrate the method first and illustrate it with a case study of seedborne oospores of Peronospora effusa, the causal agent of spinach downy mildew. A seed lot threshold of 0.23 oospores per seed could reduce the overall number of oospores entering the production system by 90% while removing 8% of seed lots destined for distribution. Alternative mitigation strategies may result in lower economic losses to seed producers, but have uncertain efficacy. We discuss future challenges and prospects for implementing this approach. PMID- 28726579 TI - The Immunomodulatory Role of BMP-2 on Macrophages to Accelerate Osteogenesis. AB - Bone morphogenetic protein-2 (BMP-2) is one of the most frequently used osteogenic factors for osteogenesis. Macrophages, acting as both immune cells and osteoclast precursors, have an indispensable functional input during multiple stages of bone healing. This study aims to investigate the immunoregulatory role of BMP-2 on macrophages and the subsequent effects on osteogenesis. In the subcutaneous implantation study, gelatin sponge incorporated with 20 MUg/mL BMP-2 rendered significantly enhanced macrophage infiltration compared with the gelatin sponge control. Further in vitro study using murine macrophage cell line has shown that BMP-2 could function as a potent attractant for macrophage recruitment. The supplementation of BMP-2 dramatically diminished the expression of M1 phenotypic markers, including interleukin (IL)-1beta, IL-6, and iNOS in M1 polarized macrophages, indicating a positive immunoregulatory role of BMP-2 under inflammatory status. In addition, BMP-2 alone could robustly activate macrophages through pSmad1/5/8 signaling pathway and generate a positive feedback loop by increasing the expression of angiogenic factors. Conditioned medium collected from BMP2-stimulated macrophages accelerated the osteogenic differentiation of bone marrow stromal cells. Our finding suggests that BMP-2-induced osteogenesis may also involve the regulation of the local osteoimmune environment. The positive effect of BMP-2 on regulating immune response makes it possible to utilize the immunomodulatory properties of BMP-2 to manipulate the osteoimmune environment for favorable bone regeneration. PMID- 28726581 TI - Phenomenological modeling of reactive dye adsorption onto fish scales surface in the presence of electrolyte and surfactant mixtures. AB - The aim of this work was an experimental and theoretical investigation of the influence of electrolyte (NaCl) and surfactant (SP), as textile auxiliary agents (TAAs), onto reactive blue 5G (RB5G) dye removal by applying untreated fish scales (FS) in batch system. Kinetic and equilibrium studies were performed, aiming at the comprehension of the mass transfer mechanisms through phenomenological modeling. The biosorbent was texturally characterized, to investigate the adsorbent's characteristics and to support the models' assumptions. Hence, a 'physically meaningful' modeling to assess different systems containing dye-TAA mixtures was employed. The experimental results indicated that despite the FS nonporous characteristics, it showed remarkable adsorption capacities (~291 mg g-1), which may be ascribed to the adsorbent adsorbate affinity and to dye-aggregates adsorption onto the FS surface. Those results evidence a potential use of FS as an alternative biosorbent material. The mathematical model was able to identify the rate-limiting step of the process; to predict the adsorption kinetics and equilibrium condition, comprising the description of aggregates formation; and to successfully predict kinetic behavior of independent data in simulated real effluent. Those results indicate that the model can be used to simulate operating conditions and, therefore, support the design, optimization, and scale-up of adsorption processes. PMID- 28726580 TI - High-intensity and simultaneous alcohol and marijuana use among high school seniors in the United States. AB - BACKGROUND: Simultaneous alcohol and marijuana (SAM) use poses threats to health, particularly among adolescents. These risks would be exacerbated to the extent that high-intensity drinking (e.g., 10+ drinks in a row) and marijuana use (e.g., 1+ joints per day) are associated with a higher likelihood of SAM use. The current study examines the extent to which the intensity of alcohol use and of marijuana use are associated with adolescent SAM use prevalence, and whether associations remain after controlling for key covariates known to associate with both alcohol and marijuana use; it identifies alcohol and marijuana use intensity levels associated with the highest risk of adolescent SAM use. METHODS: Data come from nationally representative samples of US 12th graders who participated in the Monitoring the Future study from 2005 to 2014 (N = 24,203 respondents; 48.4% boys, 51.6% girls). RESULTS: SAM use during the past year was reported by 20% of 12th graders overall. SAM use prevalence was strongly and positively associated with alcohol and marijuana use intensity even after controlling for covariates. High school seniors at highest risk for engaging in SAM use were those who reported 10+ drinks and those smoking at least 1 joint/day. Approximately 60% of those who had 10-14 or 15+ drinks in a row during the past 2 weeks and 76%-80% of those who had 1 or 2+ joints per day on average during the past 30 days reported SAM use. CONCLUSIONS: Results suggest that high school seniors who consume high quantities of alcohol and marijuana are very likely to consume these substances so that their effects overlap. PMID- 28726582 TI - Expanding the Sphere of School Nursing Influence. PMID- 28726583 TI - President's Inaugural Address: Finding My Voice. PMID- 28726584 TI - Competency-Based Framework and Continuing Education for Preparing a Skilled School Health Workforce for Asthma Care: The Colorado Experience. AB - School health teams commonly address the needs of students with asthma, which requires specific knowledge and skills. To develop a skilled school health team, a competency-based framework for managing asthma in schools was developed. A modified Delphi with 31 panelists was completed. Consensus (>=80% agreement) was reached for all 148 items regarding the appropriateness as a minimum competency for asthma care in schools. The resultant Colorado Competency Framework for Asthma Care in Schools guided the development and pilot testing of a continuing education curriculum for school nurses. Pre- and postassessments demonstrated significant improvements in knowledge and self-confidence related to asthma care in schools and inhaler technique skills. This work is the first to use a consensus process to identify a framework of minimum competencies for providing asthma care in schools. This framework informed a continuing education curriculum that resulted in improved knowledge, confidence, and skills for school nurses. PMID- 28726585 TI - Student Bedtimes, Academic Performance, and Health in a Residential High School. AB - Inadequate sleep among adolescents is considered an epidemic in the United States. Late night bedtimes could be an important factor in academic performance and health with consequences continuing throughout adulthood. The purpose of this study was to explore the relationships between late night bedtimes, academic performance (grade point average [GPA]), and utilization of health care (school nurse visits) in a residential high school. The data were collected from archival records for one academic semester. The statistical analysis employed the nonparametric Pearson's correlation coefficient ( r) with the standard level of significance (alpha = .05). Positive and inverse linear relationships were found between bedtime and school nurse visits ( p < .00001) and bedtime and GPA ( p = .007). The findings suggest students' late night bedtimes may be related to increased school nurse visits and lower academic performance. Adolescent late night bedtimes may be an important consideration for academic success and maintaining health in residential high schools. PMID- 28726586 TI - Application of ureterorenoscope and flexible ureterorenoscope lithotripsy in removing calculus from extracorporeal living donor renal graft: a single-center experience. AB - Here, we reported our clinical application of ureterorenoscope (URS) and flexible URS lithotripsy in stone removal on 10 cases of excised living donor kidney graft. After the extraction of donor kidney by retroperitoneal laparoscopy, the donor graft was perfused with 4 degrees C HCA solution. Calculus between 2-4 mm were removed intact with lithotomy forceps under direct vision of URS. Larger calculi of >4 mm were fractured with flexible URS combining holmium laser lithotripsy. Fragments of the calculus were extracted with basket extractor and lithotomy forceps. All operations were successful. The operation time was 14-31 min (average 21.2 +/- 6.3 min). The kidneys were then transplanted to the recipients using routine procedure. The transplanted kidneys functioned well after transplantation. Gross hematuria resolved 1-4 d after operation (average 2.6 +/- 0.9 d). The transplanted kidneys functioned well without early complications such as functional recovery delay and acute graft rejection. The donors and recipients were followed for 12 months. The size of the transplanted kidneys was normal and new stones or urinary obstruction was not seen upon urinary color Doppler ultrasound examination. In conclusion, we believe it is feasible, safe and effective to use URS or flexible URS combining holmium laser lithotripsy on extracorporeal living donor kidney. PMID- 28726587 TI - Repair of Tympanic Membrane Perforations with Customized Bioprinted Ear Grafts Using Chinchilla Models. AB - The goal of this work is to develop an innovative method that combines bioprinting and endoscopic imaging to repair tympanic membrane perforations (TMPs). TMPs are a serious health issue because they can lead to both conductive hearing loss and repeated otitis media. TMPs occur in 3-5% of cases after ear tube placement, as well as in cases of acute otitis media (the second most common infection in pediatrics), chronic otitis media with or without cholesteatoma, or as a result of barotrauma to the ear. About 55,000 tympanoplasties, the surgery performed to reconstruct TMPs, are performed every year, and the commonly used cartilage grafting technique has a success rate between 43% and 100%. This wide variability in successful tympanoplasty indicates that the current approach relies heavily on the skill of the surgeon to carve the shield graft into the shape of the TMP, which can be extremely difficult because of the perforation's irregular shape. To this end, we hypothesized that patient specific acellular grafts can be bioprinted to repair TMPs. In vitro data demonstrated that our approach resulted in excellent wound healing responses (e.g., cell invasion and proliferations) using our bioprinted gelatin methacrylate constructs. Based on these results, we then bioprinted customized acellular grafts to treat TMP based on endoscopic imaging of the perforation and demonstrated improved TMP healing in a chinchilla study. These ear graft techniques could transform clinical practice by eliminating the need for hand-carved grafts. To our knowledge, this is the first proof of concept of using bioprinting and endoscopic imaging to fabricate customized grafts to treat tissue perforations. This technology could be transferred to other medical pathologies and be used to rapidly scan internal organs such as intestines for microperforations, brain covering (Dura mater) for determination of sites of potential cerebrospinal fluid leaks, and vascular systems to determine arterial wall damage before aneurysm rupture in strokes. PMID- 28726588 TI - Reconstituting Mouse Lungs with Conditionally Reprogrammed Human Bronchial Epithelial Cells. AB - We developed methods for conditionally reprogramming (CR) primary human bronchial epithelial cells (HBECs) to extend their functional lifespan and permit their differentiation into both upper and lower airway lung epithelium. We also developed a bioreactor to support vascular perfusion and rhythmic breathing of decellularized mouse lungs reconstituted with CR HBECs isolated from patients with and without cystic fibrosis (CF). While conditionally reprogrammed cells only differentiate into an upper airway epithelium after 35 days at the air liquid interface, in reconstituted lungs these cells differentiate into upper airway bronchial epithelium and lower airway alveolar structures after 12 days. Rapid scale-up and the ability to obtain clonal derivatives of primary patient derived HBECs without the need for genetic manipulation may permit rapid reconstitution of the lung epithelium; facilitating the study of lung disease in tissue-engineered models. PMID- 28726589 TI - Proteomic Study of SUMOylation During Solanum tuberosum-Phytophthora infestans Interactions. AB - Invasive plant pathogens have developed the ability to modify the metabolism of their host, promoting metabolic processes that facilitate the growth of the pathogen at the general expense of the host. The particular enzymatic process SUMOylation, which performs posttranslational modification of target proteins, leading to changes in many aspects of protein activity and, hence, metabolism, has been demonstrated to be active in many eukaryotic organisms, both animals and plants. Here, we provide experimental evidence that indicates that, in leaves of Solanum tuberosum that have been infected by Phytophthora infestans, the SUMO (small ubiquitin-like modifier) pathway enzymes of the host are partially under transcriptional control exerted by the oomycete. Using a recently developed approach that employs three-dimensional gels, we show that, during the infection process, the abundances of most of the known SUMO conjugates of S. tuberosum change significantly, some decreasing, but many increasing in abundance. The new proteomic approach has the potential to greatly facilitate investigation of the molecular events that take place during the invasion by a pathogen of its host plant. PMID- 28726590 TI - A Method of Managing Severe Traumatic Brain Injury in the Absence of Intracranial Pressure Monitoring: The Imaging and Clinical Examination Protocol. AB - The imaging and clinical examination (ICE) algorithm used in the Benchmark Evidence from South American Trials: Treatment of Intracranial Pressure (BEST TRIP) randomized controlled trial is the only prospectively investigated clinical protocol for traumatic brain injury management without intracranial pressure (ICP) monitoring. As the default literature standard, it warrants careful evaluation. We present the ICE protocol in detail and analyze the demographics, outcome, treatment intensity, frequency of intervention usage, and related adverse events in the ICE-protocol cohort. The 167 ICE protocol patients were young (median 29 years) with a median Glasgow Coma Scale motor score of 4 but with anisocoria or abnormal pupillary reactivity in 40%. This protocol produced outcomes not significantly different from those randomized to the monitor-based protocol (favorable 6-month extended Glasgow Outcome Score in 39%; 41% mortality rate). Agents commonly employed to treat suspected intracranial hypertension included low-/moderate-dose hypertonic saline (72%) and mannitol (57%), mild hyperventilation (adjusted partial pressure of carbon dioxide 30-35 mm Hg in 73%), and pressors to maintain cerebral perfusion (62%). High-dose hyperosmotics or barbiturates were uncommonly used. Adverse event incidence was low and comparable to the BEST TRIP monitored group. Although this protocol should produce similar/acceptable results under circumstances comparable to those in the trial, influences such as longer pre-hospital times and non-specialist transport personnel, plus an intensive care unit model of aggressive physician-intensive care by small groups of neurotrauma-focused intensivists, which differs from most high-resource models, support caution in expecting the same results in dissimilar settings. Finally, this protocol's ICP-titration approach to suspected intracranial hypertension (vs. crisis management for monitored ICP) warrants further study. PMID- 28726591 TI - Adolescents' trajectory through peer loss after a road traffic accident. AB - This mixed method study investigated the short- and long-term effects of peer loss on eight adolescents after a fatal school bus accident. Phenomenological analysis of their retrospective narratives revealed three patterns (living in despair, collecting my pieces, remembering, and moving on). Quantitative findings indicate progressive decrease in post-traumatic stress symptoms severity across time; increase in positive changes in perceptions of self, others, and life between 18 and 34 months; and stable continuing bond with the deceased peers. PMID- 28726592 TI - Effect of extreme adaptive frequency compression in bimodal listeners on sound localization and speech perception. AB - OBJECTIVES: This study aimed to improve access to high-frequency interaural level differences (ILD), by applying extreme frequency compression (FC) in the hearing aid (HA) of 13 bimodal listeners, using a cochlear implant (CI) and conventional HA in opposite ears. DESIGN: An experimental signal-adaptive frequency-lowering algorithm was tested, compressing frequencies above 160 Hz into the individual audible range of residual hearing, but only for consonants (adaptive FC), thus protecting vowel formants, with the aim to preserve speech perception. In a cross over design with at least 5 weeks of acclimatization between sessions, bimodal performance with and without adaptive FC was compared for horizontal sound localization, speech understanding in quiet and in noise, and vowel, consonant and voice-pitch perception. RESULTS: On average, adaptive FC did not significantly affect any of the test results. Yet, two subjects who were fitted with a relatively weak frequency compression ratio, showed improved horizontal sound localization. After the study, four subjects preferred adaptive FC, four preferred standard frequency mapping, and four had no preference. Noteworthy, the subjects preferring adaptive FC were those with best performance on all tasks, both with and without adaptive FC. CONCLUSION: On a group level, extreme adaptive FC did not change sound localization and speech understanding in bimodal listeners. Possible reasons are too strong compression ratios, insufficient residual hearing or that the adaptive switching, although preserving vowel perception, may have been ineffective to produce consistent ILD cues. Individual results suggested that two subjects were able to integrate the frequency compressed HA input with that of the CI, and benefitted from enhanced binaural cues for horizontal sound localization. PMID- 28726593 TI - Validation and Normalization of the Tower of London-Drexel University Test 2nd Edition in an Adult Population with Intellectual Disability. AB - Despite how important it is to assess executive functioning in persons with Intellectual Disability (ID), instruments adapted and validated for this population are scarce. This study's primary goal was to find evidence for the validity of the ID version of the Tower of London (TOLDXtm) test in persons with mild (IDMi) and moderate (IDMo) levels of ID with Down Syndrome (DS). A multicenter study was carried out. Subjects (n = 63, >= 39 years old) had DS with mild (n = 39) or moderate ID (n = 24) with no minor neurocognitive disorder or Alzheimer's disease. Assessment protocol: TOLDXtm for ID, Kaufman Brief Intelligence Test Second Edition (K-BIT II), Cambridge Examination for Mental Disorders of Older People with Down's Syndrome and Others with Intellectual Disabilities (CAMDEX-DS), Weigl's Color-Form Sorting Test (WCFST), Barcelona Test for Intellectual Disability (BT-ID), and the Behavior Rating Inventory of Executive Function (BRIEF-P). The internal consistency (IDMi and IDMo), factor structure of the different subscales, and relationship between TOLDXtm subscales and other cognitive measures (BT-ID, WCFST, and BRIEF-P) were analyzed. A normative data table with ID population quartiles is provided. TOLDXtm for ID showed a robust one factor structure and coherentassociations with other, related neuropsychological instruments. Significant differences between IDMi and IDMo on movement-related variables like Correct (Corr; p = .002) and Moves (Mov; p = .042) were observed, along with good internal consistency values, Corr (alpha = .75), Mov (alpha = .52). Regarding internal consistency, no between-groups differences were observed (all p-value > 0.05). The TOLDXtm for ID is thus an instrument, supported by good validity evidence, to evaluate problem-solving and planning in ID. It distinguishes between individuals with mild and moderate ID, and is highly associated with other measures of executive functioning. PMID- 28726594 TI - Crowding, Karenina, and Complexity: Patient Flow in Evolving Health Care Ecosystems. PMID- 28726596 TI - Getting the message across. An August bank holiday long ago. PMID- 28726595 TI - Co-circulation and co-infections of all dengue virus serotypes in Hyderabad, India 2014. AB - The burden of dengue virus infections increased globally during recent years. Though India is considered as dengue hyper-endemic country, limited data are available on disease epidemiology. The present study includes molecular characterization of dengue virus strains occurred in Hyderabad, India, during the year 2014. A total of 120 febrile cases were recruited for this study, which includes only children and 41 were serologically confirmed for dengue positive infections using non-structural (NS1) and/or IgG/IgM ELISA tests. RT-PCR, nucleotide sequencing and evolutionary analyses were carried out to identify the circulating serotypes/genotypes. The data indicated a high percent of severe dengue (63%) in primary infections. Simultaneous circulation of all four serotypes and co-infections were observed for the first time in Hyderabad, India. In total, 15 patients were co-infected with more than one dengue serotype and 12 (80%) of them had severe dengue. One of the striking findings of the present study is the identification of serotype Den-1 as the first report from this region and this strain showed close relatedness to the Thailand 1980 strains but not to any of the strains reported from India until now. Phylogenetically, all four strains of the present study showed close relatedness to the strains, which are reported to be high virulent. PMID- 28726597 TI - Serological and molecular diagnostic tests for canine visceral leishmaniasis in Brazilian endemic area: one out of five seronegative dogs are infected. AB - Euthanasia of infected dogs is one of the measures adopted in Brazil to control visceral leishmaniasis (VL) in endemic areas. To detect infected dogs, animals are screened with the rapid test DPP(r) Visceral Canine Leishmaniasis for detection of antibodies against K26/K39 fusion antigens of amastigotes (DPP). DPP positives are confirmed with an immunoenzymatic assay probing soluble antigens of promastigotes (ELISA), while DPP-negatives are considered free of infection. Here, 975 dogs from an endemic region were surveyed by using DPP, ELISA and real time PCR (qPCR) for the diagnosis of VL. When DPP-negative dogs were tested by qPCR applied in blood and lymph node aspirates, 174/887 (19.6%) were positive in at least one sample. In a second sampling using 115 cases, the DPP-negative dogs were tested by qPCR in blood, lymph node and conjunctival swab samples, and 36/79 (45.6%) were positive in at least one sample. Low-to-moderate pairwise agreement was observed between all possible pair of tests. In conclusion, the official diagnosis of VL in dogs in Brazilian endemic areas failed to accuse an expressive number of infected animals and the impact of the low accuracy of serological tests in the success of euthanasia-based measure for VL control need to be assessed. PMID- 28726598 TI - Pandemic-related health behavior: repeat episodes of influenza-like illness related to the 2009 H1N1 influenza pandemic. AB - The Houston Health Department (HHD) in Texas tracks influenza-like illness (ILI) in the community through its Influenza Sentinel Surveillance Program, which began in 2008. After the influenza A(H1N1) pandemic (pH1N1) in 2009, investigators sought to assess the feasibility of this program as a non-traditional data source for tracking and monitoring care-seeking activities. Through the process of characterizing and describing patients who had 'return visits', or who were considered the heaviest ILI-related care-utilizers, the investigators sought to understand the strengths and limitations of this data source. Data used for this study were obtained from a multispecialty clinic in Houston, Texas between August 2008 and January 2011 across three phases: pre-pH1N1, pH1N1, and post-pH1N1. The data, which comprised of 4047 patient visits, yielded 150 return visits. We found an increase in the number of visits for ILI and proportion of return visits during the pandemic phase (pH1N1), as well as differences in the likelihood of a return visit between genders and age groups. More broadly, the findings of this study provide important considerations for future research and expose important gaps in using surveillance data to assess sick-role behaviors. PMID- 28726600 TI - Age- and Sex-associated Differences in Phenotypic and Functional Characteristics of Peripheral Blood Lymphocytes in Chimpanzees (Pan troglodytes). AB - Chimpanzees are the closest phylogenetic relatives to humans, sharing more than 98% genetic sequence identity. Thesegenetic similarities prompted the belief that chimpanzees can serve as an ideal model for human disease conditions andvaccine development. However, in light of the recent NIH decision to phase out biomedical research in chimpanzees and retire NIH-supported chimpanzees, data from the present study will continue to provide value for the care of aged and sick chimpanzees located in zoos, sanctuaries, and primate centers. Surprisingly little information has been published regarding the normal chimpanzee immune system, and most extant studies have been based on small numbers of animals. In the current study, we provide a better understanding of the chimpanzee immune system with regard to age and sex. We examined immune parameters of chimpanzees (n = 94; 51 female, 43 male; age, 6 to 47 y) by using flow cytometry, immune function analysis, and cytokine analysis. Because lymphocytes are key mediators of cellular immune responses, particularly to intracellular pathogens such as viruses, we surveyed the phenotypic and functional attributes of T and B lymphocytes in this healthy and age-stratified population of chimpanzees. We noted a significantly higher percentage of CD16+T cells in male compared with female chimpanzees but no significant changes in percentages of CD3+, CD4+, CD8+, or CD4+CD8+ T cells with age or sex. In addition, aging was associated with decreased proliferative responses to mitogens in both sexes. Sex-specific differences also were present in the percentage of NK cells but not in their cytotoxic activity and in circulating cytokine levels in plasma. Going forward, the data presented here regarding immune cell changes associated with aging in healthy chimpanzees will serve to enhance the care of geriatric and ill animals. PMID- 28726599 TI - Improving patient experiences of mental health inpatient care: a randomised controlled trial. AB - BACKGROUND: Poorer patient views of mental health inpatient treatment predict both further admissions and, for those admitted involuntarily, longer admissions. As advocated in the UK Francis report, we investigated the hypothesis that improving staff training improves patients' views of ward care. METHOD: Cluster randomised trial with stepped wedge design in 16 acute mental health wards randomised (using the ralloc procedure in Stata) by an independent statistician in three waves to staff training. A psychologist trained ward staff on evidence based group interventions and then supported their introduction to each ward. The main outcome was blind self-report of perceptions of care (VOICE) before or up to 2 years after staff training between November 2008 and January 2013. RESULTS: In total, 1108 inpatients took part (616 admitted involuntarily under the English Mental Health Act). On average 51.6 staff training sessions were provided per ward. Involuntary patient's perceptions of, and satisfaction with, mental health wards improved after staff training (N582, standardised effect -0.35, 95% CI 0.57 to -0.12, p = 0.002; interaction p value 0.006) but no benefit to those admitted voluntarily (N469, -0.01, 95% CI -0.23 to 0.22, p = 0.955) and no strong evidence of an overall effect (N1058, standardised effect -0.18 s.d., 95% CI 0.38 to 0.01, p = 0.062). The training costs around L10 per patient per week. Resource allocation changed towards patient perceived meaningful contacts by an average of L12 (95% CI -L76 to L98, p = 0.774). CONCLUSION: Staff training improved the perceptions of the therapeutic environment in those least likely to want an inpatient admission, those formally detained. This change might enhance future engagement with all mental health services and prevent the more costly admissions. PMID- 28726601 TI - Zika Virus Infection in Patient with No Known Risk Factors, Utah, USA, 2016. AB - In 2016, Zika virus disease developed in a man (patient A) who had no known risk factors beyond caring for a relative who died of this disease (index patient). We investigated the source of infection for patient A by surveying other family contacts, healthcare personnel, and community members, and testing samples for Zika virus. We identified 19 family contacts who had similar exposures to the index patient; 86 healthcare personnel had contact with the index patient, including 57 (66%) who had contact with body fluids. Of 218 community members interviewed, 28 (13%) reported signs/symptoms and 132 (61%) provided a sample. Except for patient A, no other persons tested had laboratory evidence of recent Zika virus infection. Of 5,875 mosquitoes collected, none were known vectors of Zika virus and all were negative for Zika virus. The mechanism of transmission to patient A remains unknown but was likely person-to-person contact with the index patient. PMID- 28726603 TI - Clinical Laboratory Values as Early Indicators of Ebola Virus Infection in Nonhuman Primates. AB - The Ebola virus (EBOV) outbreak in West Africa during 2013-2016 demonstrated the need to improve Ebola virus disease (EVD) diagnostics and standards of care. This retrospective study compared laboratory values and clinical features of 3 nonhuman primate models of lethal EVD to assess associations with improved survival time. In addition, the study identified laboratory values useful as predictors of survival, surrogates for EBOV viral loads, and triggers for initiation of therapeutic interventions in these nonhuman primate models. Furthermore, the data support that, in nonhuman primates, the Makona strain of EBOV may be less virulent than the Kikwit strain of EBOV. The applicability of these findings as potential diagnostic and management tools for EVD in humans warrants further investigation. PMID- 28726602 TI - Maguari Virus Associated with Human Disease. AB - Despite the lack of evidence for symptomatic human infection with Maguari virus (MAGV), its close relation to Cache Valley virus (CVV), which does infect humans, remains a concern. We sequenced the complete genome of a MAGV-like isolate (OBS6657) obtained from a febrile patient in Pucallpa, Ucayali, Peru, in 1998. To facilitate its classification, we generated additional full-length sequences for the MAGV prototype strain, 3 additional MAGV-like isolates, and the closely related CVV (7 strains), Tlacotalpan (1 strain), Playas (3 strains), and Fort Sherman (1 strain) viruses. The OBS6657 isolate is similar to the MAGV prototype, whereas 2 of the other MAGV-like isolates are located on a distinct branch and most likely warrant classification as a separate virus species and 1 is, in fact, a misclassified CVV strain. Our findings provide clear evidence that MAGV can cause human disease. PMID- 28726604 TI - Scrub Typhus Outbreak in a Remote Primary School, Bhutan, 2014. AB - Scrub typhus in Bhutan was first reported in 2009. We investigated an outbreak of scrub typhus in a remote primary school during August-October 2014. Delay in recognition and treatment resulted in 2 deaths from meningoencephalitis. Scrub typhus warrants urgent public health interventions in Bhutan. PMID- 28726605 TI - Detection of Elizabethkingia spp. in Culicoides Biting Midges, Australia. AB - The bacterial pathogen Elizabethkingia is known to exist in certain species of mosquito but was unknown in other arthropods. We report the detection and identification of Elizabethkingia in species of Culicoides biting midge in Australia, raising the possibility of bacterial transmission via this species. PMID- 28726606 TI - Opiate Injection-Associated Skin, Soft Tissue, and Vascular Infections, England, UK, 1997-2016. AB - In England, UK, hospital admissions caused by bacterial infections associated with opioid use have increased annually since 2012, after 9 years of decline, mirroring trends in overdose deaths. The increase occurred among persons of both sexes and in all age groups and suggests preventive measures need reviewing. PMID- 28726607 TI - Acute Febrile Illness and Complications Due to Murine Typhus, Texas, USA1,2. AB - Murine typhus occurs relatively commonly in southern Texas, as well as in California. We reviewed records of 90 adults and children in whom murine typhus was diagnosed during a 3-year period in 2 hospitals in southern Texas, USA. Most patients lacked notable comorbidities; all were immunocompetent. Initial signs and symptoms included fever (99%), malaise (82%), headache (77%), fatigue (70%), myalgias (68%), and rash (39%). Complications, often severe, in 28% of patients included bronchiolitis, pneumonia, meningitis, septic shock, cholecystitis, pancreatitis, myositis, and rhabdomyolysis; the last 3 are previously unreported in murine typhus. Low serum albumin and elevated procalcitonin, consistent with bacterial sepsis, were observed in >70% of cases. Rash was more common in children; thrombocytopenia, hyponatremia, elevated hepatic transaminases, and complications were more frequent in adults. Murine typhus should be considered as a diagnostic possibility in cases of acute febrile illness in southern and even in more northern US states. PMID- 28726608 TI - Density-Dependent Prevalence of Francisella tularensis in Fluctuating Vole Populations, Northwestern Spain. AB - Tularemia in humans in northwestern Spain is associated with increases in vole populations. Prevalence of infection with Francisella tularensis in common voles increased to 33% during a vole population fluctuation. This finding confirms that voles are spillover agents for zoonotic outbreaks. Ecologic interactions associated with tularemia prevention should be considered. PMID- 28726609 TI - Influenza D Virus in Animal Species in Guangdong Province, Southern China. AB - Molecular tests revealed influenza D viruses of D/OK lineage widely circulating in farmed animal species in Guangdong Province, southern China. In particular, we found high levels of influenza D virus infection in goats and pigs. We also detected viral RNA in serum specimens and feces of animals with certain severe diseases. PMID- 28726610 TI - Serologic Evidence of Powassan Virus Infection in Patients with Suspected Lyme Disease1. AB - Powassan virus (POWV) lineage II is an emerging tickborne flavivirus with an unknown seroprevalence in humans. In a Lyme disease-endemic area, we examined the seroreactivity to POWV in 2 patient cohorts and described the clinical features of the POWV-seroreactive patients. POWV disease might be less neuroinvasive than previously thought. PMID- 28726612 TI - Seroprevalence of Baylisascaris procyonis Infection among Humans, Santa Barbara County, California, USA, 2014-2016. AB - Baylisascaris procyonis (raccoon roundworm) infection is common in raccoons and can cause devastating pathology in other animals, including humans. Limited information is available on the frequency of asymptomatic human infection. We tested 150 adults from California, USA, for B. procyonis antibodies; 11 were seropositive, suggesting that subclinical infection does occur. PMID- 28726611 TI - Added Value of Next-Generation Sequencing for Multilocus Sequence Typing Analysis of a Pneumocystis jirovecii Pneumonia Outbreak1. AB - Pneumocystis jirovecii is a major threat for immunocompromised patients, and clusters of pneumocystis pneumonia (PCP) have been increasingly described in transplant units during the past decade. Exploring an outbreak transmission network requires complementary spatiotemporal and strain-typing approaches. We analyzed a PCP outbreak and demonstrated the added value of next-generation sequencing (NGS) for the multilocus sequence typing (MLST) study of P. jirovecii strains. Thirty-two PCP patients were included. Among the 12 solid organ transplant patients, 5 shared a major and unique genotype that was also found as a minor strain in a sixth patient. A transmission map analysis strengthened the suspicion of nosocomial acquisition of this strain for the 6 patients. NGS-MLST enables accurate determination of subpopulation, which allowed excluding other patients from the transmission network. NGS-MLST genotyping approach was essential to deciphering this outbreak. This innovative approach brings new insights for future epidemiologic studies on this uncultivable opportunistic fungus. PMID- 28726613 TI - Human Metapneumovirus and Other Respiratory Viral Infections during Pregnancy and Birth, Nepal. AB - Human metapneumovirus (HMPV) is a respiratory virus that can cause severe lower respiratory tract disease and even death, primarily in young children. The incidence and characteristics of HMPV have not been well described in pregnant women. As part of a trial of maternal influenza immunization in rural southern Nepal, we conducted prospective, longitudinal, home-based active surveillance for febrile respiratory illness during pregnancy through 6 months postpartum. During 2011-2014, HMPV was detected in 55 of 3,693 women (16.4 cases/1,000 person years). Twenty-five women were infected with HMPV during pregnancy, compared with 98 pregnant women who contracted rhinovirus and 7 who contracted respiratory syncytial virus. Women with HMPV during pregnancy had an increased risk of giving birth to infants who were small for gestational age. An intervention to reduce HMPV febrile respiratory illness in pregnant women may have the potential to decrease risk of adverse birth outcomes in developing countries. PMID- 28726614 TI - Occupational Exposures to Ebola Virus in Ebola Treatment Center, Conakry, Guinea. AB - We report 77 cases of occupational exposures for 57 healthcare workers at the Ebola Treatment Center in Conakry, Guinea, during the Ebola virus disease outbreak in 2014-2015. Despite the high incidence of 3.5 occupational exposures/healthcare worker/year, only 18% of workers were at high risk for transmission, and no infections occurred. PMID- 28726615 TI - West Nile Virus Outbreak in Houston and Harris County, Texas, USA, 2014. AB - Since 2002, West Nile virus (WNV) has been detected every year in Houston and the surrounding Harris County, Texas. In 2014, the largest WNV outbreak to date occurred, comprising 139 cases and causing 2 deaths. Additionally, 1,286 WNV positive mosquito pools were confirmed, the most reported in a single mosquito season. PMID- 28726616 TI - Molecular Characterization of Corynebacterium diphtheriae Outbreak Isolates, South Africa, March-June 2015. AB - In 2015, a cluster of respiratory diphtheria cases was reported from KwaZulu Natal Province in South Africa. By using whole-genome analysis, we characterized 21 Corynebacterium diphtheriae isolates collected from 20 patients and contacts during the outbreak (1 patient was infected with 2 variants of C. diphtheriae). In addition, we included 1 cutaneous isolate, 2 endocarditis isolates, and 2 archived clinical isolates (ca. 1980) for comparison. Two novel lineages were identified, namely, toxigenic sequence type (ST) ST-378 (n = 17) and nontoxigenic ST-395 (n = 3). One archived isolate and the cutaneous isolate were ST-395, suggesting ongoing circulation of this lineage for >30 years. The absence of preexisting molecular sequence data limits drawing conclusions pertaining to the origin of these strains; however, these findings provide baseline genotypic data for future cases and outbreaks. Neither ST has been reported in any other country; this ST appears to be endemic only in South Africa. PMID- 28726617 TI - Scrub Typhus as a Cause of Acute Encephalitis Syndrome, Gorakhpur, Uttar Pradesh, India. AB - Outbreaks of acute encephalitis syndrome (AES) have been occurring in Gorakhpur Division, Uttar Pradesh, India, for several years. In 2016, we conducted a case control study. Our findings revealed a high proportion of AES cases with Orientia tsutsugamushi IgM and IgG, indicating that scrub typhus is a cause of AES. PMID- 28726618 TI - Global Spread of Norovirus GII.17 Kawasaki 308, 2014-2016. AB - Analysis of complete capsid sequences of the emerging norovirus GII.17 Kawasaki 308 from 13 countries demonstrated that they originated from a single haplotype since the initial emergence in China in late 2014. Global spread of a sublineage SL2 was identified. A new sublineage SL3 emerged in China in 2016. PMID- 28726620 TI - Acute Encephalitis Syndrome and Scrub Typhus in India. PMID- 28726619 TI - Serologic Evidence of Scrub Typhus in the Peruvian Amazon. AB - Using a large, passive, febrile surveillance program in Iquitos, Peru, we retrospectively tested human blood specimens for scrub typhus group orientiae by ELISA, immunofluorescence assay, and PCR. Of 1,124 participants, 60 (5.3%) were seropositive, and 1 showed evidence of recent active infection. Our serologic data indicate that scrub typhus is present in the Peruvian Amazon. PMID- 28726621 TI - Characterization of Fitzroy River Virus and Serologic Evidence of Human and Animal Infection. AB - In northern Western Australia in 2011 and 2012, surveillance detected a novel arbovirus in mosquitoes. Genetic and phenotypic analyses confirmed that the new flavivirus, named Fitzroy River virus, is related to Sepik virus and Wesselsbron virus, in the yellow fever virus group. Most (81%) isolates came from Aedes normanensis mosquitoes, providing circumstantial evidence of the probable vector. In cell culture, Fitzroy River virus replicated in mosquito (C6/36), mammalian (Vero, PSEK, and BSR), and avian (DF-1) cells. It also infected intraperitoneally inoculated weanling mice and caused mild clinical disease in 3 intracranially inoculated mice. Specific neutralizing antibodies were detected in sentinel horses (12.6%), cattle (6.6%), and chickens (0.5%) in the Northern Territory of Australia and in a subset of humans (0.8%) from northern Western Australia. PMID- 28726622 TI - mcr-1 and blaKPC-3 in Escherichia coli Sequence Type 744 after Meropenem and Colistin Therapy, Portugal. AB - Escherichia coli Ec36 was recovered from a patient in Portugal after treatment with meropenem and colistin. Besides an IncF plasmid with Tn1441d-blaKPC-3, already reported in clinical strains in this country, E. coli Ec36 co-harbored an IncX4::mcr-1 gene. Results highlight emerging co-resistance to carbapenems and polymyxins after therapy with drugs from both classes. PMID- 28726623 TI - Candidatus Dirofilaria hongkongensis as Causative Agent of Human Ocular Filariosis after Travel to India. AB - We report a human case of ocular Dirofilaria infection in a traveler returning to Austria from India. Analysis of mitochondrial sequences identified the worm as Candidatus Dirofilaria hongkongensis, a close relative of Dirofilaria repens, which was only recently described in Hong Kong and proposed as a new species. PMID- 28726624 TI - Lyme Borreliosis in Finland, 1995-2014. AB - We investigated the epidemiology of Lyme borreliosis (LB) in Finland for the period 1995-2014 by using data from 3 different healthcare registers. We reviewed data on disseminated LB cases from the National Infectious Diseases Register (21,051 cases) and the National Hospital Discharge Register (10,402 cases) and data on primary LB (erythema migrans) cases from the Register for Primary Health Care Visits (11,793 cases). Incidence of microbiologically confirmed disseminated LB cases increased from 7/100,000 population in 1995 to 31/100,000 in 2014. Incidence of primary LB cases increased from 44/100,000 in 2011 to 61/100,000 in 2014. Overall, cases occurred predominantly in women, and we observed a bimodal age distribution in all 3 registers. Our results clearly demonstrate that the geographic distribution of LB has expanded in Finland and underscore the importance of LB as an increasing public health concern in Finland and in northern Europe in general. PMID- 28726625 TI - Risk for Death among Children with Pneumonia, Afghanistan. AB - In Afghanistan, childhood deaths from pneumonia are high. Among 639 children at 1 hospital, the case-fatality rate was 12.1%, and 46.8% of pneumococcal serotypes detected were covered by the 13-valent vaccine. Most deaths occurred within 2 days of hospitalization; newborns and malnourished children were at risk. Vaccination could reduce pneumonia and deaths. PMID- 28726626 TI - Human Infection with Burkholderia thailandensis, China, 2013. AB - Burkholderia thailandensis infection in humans is uncommon. We describe a case of B. thailandensis infection in a person in China, a location heretofore unknown for B. thailandensis. We identified the specific virulence factors of B. thailandensis, which may indicate a transition to a new virulent form. PMID- 28726627 TI - Mucus-Activatable Shiga Toxin Genotype stx2d in Escherichia coli O157:H7. AB - We identified the mucus-activatable Shiga toxin genotype stx2d in the most common hemolytic uremic syndrome-associated Escherichia coli serotype, O157:H7. stx2d was detected in a strain isolated from a 2-year-old boy with bloody diarrhea in Spain, and whole-genome sequencing was used to confirm and fully characterize the strain. PMID- 28726628 TI - California Serogroup Virus Infection Associated with Encephalitis and Cognitive Decline, Canada, 2015. AB - California serogroup (CSG) viruses, such as Jamestown Canyon and snowshoe hare viruses, are mosquitoborne pathogens that cause febrile illness and neurologic disease. Human exposures have been described across Canada, but infections are likely underdiagnosed. We describe a case of neuroinvasive illness in a New Brunswick, Canada, patient infected with a CSG virus. PMID- 28726629 TI - Effects of Influenza Strain Label on Worry and Behavioral Intentions. AB - Persons who read information about a hypothetical influenza strain with scientific (H11N3 influenza) or exotic-sounding (Yarraman flu) name reported higher worry and vaccination intentions than did those who read about strains named after an animal reservoir (horse flu). These findings suggest that terms used for influenza in public communications can influence reactions. PMID- 28726630 TI - Dissection of specific binding of HIV-1 Gag to the 'packaging signal' in viral RNA. AB - Selective packaging of HIV-1 genomic RNA (gRNA) requires the presence of a cis acting RNA element called the 'packaging signal' (Psi). However, the mechanism by which Psi promotes selective packaging of the gRNA is not well understood. We used fluorescence correlation spectroscopy and quenching data to monitor the binding of recombinant HIV-1 Gag protein to Cy5-tagged 190-base RNAs. At physiological ionic strength, Gag binds with very similar, nanomolar affinities to both Psi-containing and control RNAs. We challenged these interactions by adding excess competing tRNA; introducing mutations in Gag; or raising the ionic strength. These modifications all revealed high specificity for Psi. This specificity is evidently obscured in physiological salt by non-specific, predominantly electrostatic interactions. This nonspecific activity was attenuated by mutations in the MA, CA, and NC domains, including CA mutations disrupting Gag-Gag interaction. We propose that gRNA is selectively packaged because binding to Psi nucleates virion assembly with particular efficiency. PMID- 28726631 TI - Lipid transfer from plants to arbuscular mycorrhiza fungi. AB - Arbuscular mycorrhiza (AM) symbioses contribute to global carbon cycles as plant hosts divert up to 20% of photosynthate to the obligate biotrophic fungi. Previous studies suggested carbohydrates as the only form of carbon transferred to the fungi. However, de novo fatty acid (FA) synthesis has not been observed in AM fungi in absence of the plant. In a forward genetic approach, we identified two Lotus japonicus mutants defective in AM-specific paralogs of lipid biosynthesis genes (KASI and GPAT6). These mutants perturb fungal development and accumulation of emblematic fungal 16:1omega5 FAs. Using isotopolog profiling we demonstrate that 13C patterns of fungal FAs recapitulate those of wild-type hosts, indicating cross-kingdom lipid transfer from plants to fungi. This transfer of labelled FAs was not observed for the AM-specific lipid biosynthesis mutants. Thus, growth and development of beneficial AM fungi is not only fueled by sugars but depends on lipid transfer from plant hosts. PMID- 28726634 TI - Birth and death of a protein. AB - The ways in which recombination sites are determined during meiosis are becoming clearer following a phylogenomic analysis for 225 different species. PMID- 28726633 TI - Bmal1 function in skeletal muscle regulates sleep. AB - Sleep loss can severely impair the ability to perform, yet the ability to recover from sleep loss is not well understood. Sleep regulatory processes are assumed to lie exclusively within the brain mainly due to the strong behavioral manifestations of sleep. Whole-body knockout of the circadian clock gene Bmal1 in mice affects several aspects of sleep, however, the cells/tissues responsible are unknown. We found that restoring Bmal1 expression in the brains of Bmal1-knockout mice did not rescue Bmal1-dependent sleep phenotypes. Surprisingly, most sleep amount, but not sleep-timing, phenotypes could be reproduced or rescued by knocking out or restoring BMAL1 exclusively in skeletal muscle, respectively. We also found that overexpression of skeletal-muscle Bmal1 reduced the recovery response to sleep loss. Together, these findings demonstrate that Bmal1 expression in skeletal muscle is both necessary and sufficient to regulate total sleep amount and reveal that critical components of normal sleep regulation occur in muscle. PMID- 28726632 TI - Dynamics of genomic innovation in the unicellular ancestry of animals. AB - Which genomic innovations underpinned the origin of multicellular animals is still an open debate. Here, we investigate this question by reconstructing the genome architecture and gene family diversity of ancestral premetazoans, aiming to date the emergence of animal-like traits. Our comparative analysis involves genomes from animals and their closest unicellular relatives (the Holozoa), including four new genomes: three Ichthyosporea and Corallochytrium limacisporum. Here, we show that the earliest animals were shaped by dynamic changes in genome architecture before the emergence of multicellularity: an early burst of gene diversity in the ancestor of Holozoa, enriched in transcription factors and cell adhesion machinery, was followed by multiple and differently-timed episodes of synteny disruption, intron gain and genome expansions. Thus, the foundations of animal genome architecture were laid before the origin of complex multicellularity - highlighting the necessity of a unicellular perspective to understand early animal evolution. PMID- 28726636 TI - Live-cell visualization of gasdermin D-driven pyroptotic cell death. AB - Pyroptosis is a form of cell death important in defenses against pathogens that can also result in a potent and sometimes pathological inflammatory response. During pyroptosis, GSDMD (gasdermin D), the pore-forming effector protein, is cleaved, forms oligomers, and inserts into the membranes of the cell, resulting in rapid cell death. However, the potent cell death induction caused by GSDMD has complicated our ability to understand the biology of this protein. Studies aimed at visualizing GSDMD have relied on expression of GSDMD fragments in epithelial cell lines that naturally lack GSDMD expression and also lack the proteases necessary to cleave GSDMD. In this work, we performed mutagenesis and molecular modeling to strategically place tags and fluorescent proteins within GSDMD that support native pyroptosis and facilitate live-cell imaging of pyroptotic cell death. Here, we demonstrate that these fusion proteins are cleaved by caspases-1 and -11 at Asp-276. Mutations that disrupted the predicted p30-p20 autoinhibitory interface resulted in GSDMD aggregation, supporting the oligomerizing activity of these mutations. Furthermore, we show that these novel GSDMD fusions execute inflammasome-dependent pyroptotic cell death in response to multiple stimuli and allow for visualization of the morphological changes associated with pyroptotic cell death in real time. This work therefore provides new tools that not only expand the molecular understanding of pyroptosis but also enable its direct visualization. PMID- 28726637 TI - MicroRNA-101 attenuates pulmonary fibrosis by inhibiting fibroblast proliferation and activation. AB - Aberrant proliferation and activation of lung fibroblasts contribute to the initiation and progression of idiopathic pulmonary fibrosis (IPF). However, the mechanisms responsible for the proliferation and activation of fibroblasts are not fully understood. The objective of this study was to investigate the role of miR-101 in the proliferation and activation of lung fibroblasts. miR-101 expression was determined in lung tissues from patients with IPF and mice with bleomycin-induced pulmonary fibrosis. The regulation of miR-101 and cellular signaling was investigated in pulmonary fibroblasts in vitro The role of miR-101 in pulmonary fibrosis in vivo was studied using adenovirus-mediated gene transfer in mice. The expression of miR-101 was down-regulated in fibrotic lungs from patients with IPF and bleomycin-treated mice. The down-regulation of miR-101 occurred via the E26 transformation-specific (ETS) transcription factor. miR-101 suppressed the WNT5a-induced proliferation of lung fibroblasts by inhibiting NFATc2 signaling via targeting Frizzled receptor 4/6 and the TGF-beta-induced activation of lung fibroblasts by inhibition of SMAD2/3 signaling via targeting the TGF-beta receptor 1. Adenovirus-mediated miR-101 gene transfer in the mouse lung attenuated bleomycin-induced lung fibrosis and improved lung function. Our data suggest that miR-101 is an anti-fibrotic microRNA and a potential therapeutic target for pulmonary fibrosis. PMID- 28726638 TI - Understanding inhibitor resistance in Mps1 kinase through novel biophysical assays and structures. AB - Monopolar spindle 1 (Mps1/TTK) is a protein kinase essential in mitotic checkpoint signaling, preventing anaphase until all chromosomes are properly attached to spindle microtubules. Mps1 has emerged as a potential target for cancer therapy, and a variety of compounds have been developed to inhibit its kinase activity. Mutations in the catalytic domain of Mps1 that give rise to inhibitor resistance, but retain catalytic activity and do not display cross resistance to other Mps1 inhibitors, have been described. Here we characterize the interactions of two such mutants, Mps1 C604Y and C604W, which raise resistance to two closely related compounds, NMS-P715 and its derivative Cpd-5, but not to the well characterized Mps1 inhibitor, reversine. We show that estimates of the IC50 (employing a novel specific and efficient assay that utilizes a fluorescently labeled substrate) and the binding affinity (KD ) indicate that, in both mutants, Cpd-5 should be better tolerated than the closely related NMS-P715. To gain further insight, we determined the crystal structure of the Mps1 kinase mutants bound to Cpd-5 and NMS-P715 and compared the binding modes of Cpd-5, NMS-P715, and reversine. The difference in steric hindrance between Tyr/Trp604 and the trifluoromethoxy moiety of NMS-P715, the methoxy moiety of Cpd-5, and complete absence of such a group in reversine, account for differences we observe in vitro Our analysis enforces the notion that inhibitors targeting Mps1 drug-resistant mutations can emerge as a feasible intervention strategy based on existing scaffolds, if the clinical need arises. PMID- 28726639 TI - Mitochondrial calcium uniporter in Drosophila transfers calcium between the endoplasmic reticulum and mitochondria in oxidative stress-induced cell death. AB - Mitochondrial calcium plays critical roles in diverse cellular processes ranging from energy metabolism to cell death. Previous studies have demonstrated that mitochondrial calcium uptake is mainly mediated by the mitochondrial calcium uniporter (MCU) complex. However, the roles of the MCU complex in calcium transport, signaling, and dysregulation by oxidative stress still remain unclear. Here, we confirmed that Drosophila MCU contains evolutionarily conserved structures and requires essential MCU regulator (EMRE) for its calcium channel activities. We generated Drosophila MCU loss-of-function mutants, which lacked mitochondrial calcium uptake in response to caffeine stimulation. Basal metabolic activities were not significantly affected in these MCU mutants, as observed in examinations of body weight, food intake, body sugar level, and starvation induced autophagy. However, oxidative stress-induced increases in mitochondrial calcium, mitochondrial membrane potential depolarization, and cell death were prevented in these mutants. We also found that inositol 1,4,5-trisphosphate receptor genetically interacts with Drosophila MCU and effectively modulates mitochondrial calcium uptake upon oxidative stress. Taken together, these results support the idea that Drosophila MCU is responsible for endoplasmic reticulum-to mitochondrial calcium transfer and for cell death due to mitochondrial dysfunction under oxidative stress. PMID- 28726640 TI - C1q/TNF-related protein 6 (CTRP6) links obesity to adipose tissue inflammation and insulin resistance. AB - Obesity is associated with chronic low-grade inflammation, and metabolic regulators linking obesity to inflammation have therefore received much attention. Secreted C1q/TNF-related proteins (CTRPs) are one such group of regulators that regulate glucose and fat metabolism in peripheral tissues and modulate inflammation in adipose tissue. We have previously shown that expression of CTRP6 is up-regulated in leptin-deficient mice and, conversely, down-regulated by the anti-diabetic drug rosiglitazone. Here, we provide evidence for a novel role of CTRP6 in modulating both inflammation and insulin sensitivity. We found that in obese and diabetic humans and mouse models, CTRP6 expression was markedly up-regulated in adipose tissue and that stromal vascular cells, such as macrophages, are a major CTRP6 source. Overexpressing mouse or human CTRP6 impaired glucose disposal in peripheral tissues in response to glucose and insulin challenge in wild-type mice. Conversely, Ctrp6 gene deletion improved insulin action and increased metabolic rate and energy expenditure in diet induced obese mice. Mechanistically, CTRP6 regulates local inflammation and glucose metabolism by targeting macrophages and adipocytes, respectively. In cultured macrophages, recombinant CTRP6 dose-dependently up-regulated the expression and production of TNF-alpha. Conversely, CTRP6 deficiency reduced circulating inflammatory cytokines and pro-inflammatory macrophages in adipose tissue. CTRP6-overexpressing mice or CTRP6-treated adipocytes had reduced insulin stimulated Akt phosphorylation and glucose uptake. In contrast, loss of CTRP6 enhanced insulin-stimulated Akt activation in adipose tissue. Together, these results establish CTRP6 as a novel metabolic/immune regulator linking obesity to adipose tissue inflammation and insulin resistance. PMID- 28726641 TI - A plant/fungal-type phosphoenolpyruvate carboxykinase located in the parasite mitochondrion ensures glucose-independent survival of Toxoplasma gondii. AB - Toxoplasma gondii is considered to be one of the most successful intracellular pathogens, because it can reproduce in varied nutritional milieus, encountered in diverse host cell types of essentially any warm-blooded organism. Our earlier work demonstrated that the acute (tachyzoite) stage of T. gondii depends on cooperativity of glucose and glutamine catabolism to meet biosynthetic demands. Either of these two nutrients can sustain the parasite survival; however, what determines the metabolic plasticity has not yet been resolved. Here, we reveal two discrete phosphoenolpyruvate carboxykinase (PEPCK) enzymes in the parasite, one of which resides in the mitochondrion (TgPEPCKmt), whereas the other protein is not expressed in tachyzoites (TgPEPCKnet). Parasites with an intact glycolysis can tolerate genetic deletions of TgPEPCKmt as well as of TgPEPCKnet, indicating their nonessential roles for tachyzoite survival. TgPEPCKnet can also be ablated in a glycolysis-deficient mutant, while TgPEPCKmt is refractory to deletion. Consistent with this, the lytic cycle of a conditional mutant of TgPEPCKmt in the glycolysis-impaired strain was aborted upon induced repression of the mitochondrial isoform, demonstrating its essential role for the glucose independent survival of parasites. Isotope-resolved metabolomics of the conditional mutant revealed defective flux of glutamine-derived carbon into RNA bound ribose sugar as well as metabolites associated with gluconeogenesis, entailing a critical nodal role of PEPCKmt in linking catabolism of glucose and glutamine with anabolic pathways. Our data also suggest a homeostatic function ofTgPEPCKmt in cohesive operation of glycolysis and the tricarboxylic acid cycle in a normal glucose-replete milieu. Conversely, we found that the otherwise integrative enzyme pyruvate carboxylase (TgPyC) is dispensable not only in glycolysis-competent but also in glycolysis-deficient tachyzoites despite a mitochondrial localization. Last but not least, the observed physiology of T. gondii tachyzoites appears to phenocopy cancer cells, which holds promise for developing common therapeutics against both threats. PMID- 28726645 TI - CHRONIC MYELOID LEUKEMIA EXPECTED RELAPSE'S CLINICAL-LABORATORY INDEXES. AB - Today Chronic Myeloid Leukemia (CML) relapse's final assessment and monitoring in the whole world is implemented by BCR-ABL gene quantitative detection - during the polymerase chain reaction (by PSR means). Implementation of this monitoring materially and technically is not often available and remission during years is being assessed using monthly clinical-laboratory data. Proceeding from this, the goal of our work was to find the clinical-laboratory features, indicating the expected relapse and require the urgent molecular research carry out. In order to find the clinical-hematologic indicators of the Chronic Myeloid Leukemia expected relapse, BCR-ABL gene quantitative determination using the PSR method after the Imatinib treatment was done in 64 patients with CML who had remission (duration 0,5-14 years). The retrospective analyses of clinical-laboratory data was also held before the research. According to the molecular research results, we have set the risk groups of the patients - low, moderate and high risk groups. In the groups we have found the clinical-laboratory changes, existed before the research. We have held the comparative analyses of the molecular research in groups and the clinical-laboratory changes in them. As a result, we have established, that moderate anemia (expressed often during the whole remission period among the patients of all three risk groups) does not indicate the expected relapse and that in the Chronic Myeloid Leukemia remission period the expected relapse indicator could be the patient's Imatinib irregular intakes, non systemic treatment and high, inexplicable progressive thrombocytosis in peripheral blood. These factors indicate the necessity to hold the urgent molecular research in order to define the post-treatment tactics. PMID- 28726643 TI - Reconstructed ancestral enzymes reveal that negative selection drove the evolution of substrate specificity in ADP-dependent kinases. AB - One central goal in molecular evolution is to pinpoint the mechanisms and evolutionary forces that cause an enzyme to change its substrate specificity; however, these processes remain largely unexplored. Using the glycolytic ADP dependent kinases of archaea, including the orders Thermococcales, Methanosarcinales, and Methanococcales, as a model and employing an approach involving paleoenzymology, evolutionary statistics, and protein structural analysis, we could track changes in substrate specificity during ADP-dependent kinase evolution along with the structural determinants of these changes. To do so, we studied five key resurrected ancestral enzymes as well as their extant counterparts. We found that a major shift in function from a bifunctional ancestor that could phosphorylate either glucose or fructose 6-phosphate (fructose-6-P) as a substrate to a fructose 6-P-specific enzyme was started by a single amino acid substitution resulting in negative selection with a ground state mode against glucose and a subsequent 1,600-fold change in specificity of the ancestral protein. This change rendered the residual phosphorylation of glucose a promiscuous and physiologically irrelevant activity, highlighting how promiscuity may be an evolutionary vestige of ancestral enzyme activities, which have been eliminated over time. We also could reconstruct the evolutionary history of substrate utilization by using an evolutionary model of discrete binary characters, indicating that substrate uses can be discretely lost or acquired during enzyme evolution. These findings exemplify how negative selection and subtle enzyme changes can lead to major evolutionary shifts in function, which can subsequently generate important adaptive advantages, for example, in improving glycolytic efficiency in Thermococcales. PMID- 28726642 TI - Coordinated transcriptional control of adipocyte triglyceride lipase (Atgl) by transcription factors Sp1 and peroxisome proliferator-activated receptor gamma (PPARgamma) during adipocyte differentiation. AB - The breakdown of stored fat deposits into its components is a highly regulated process that maintains plasma levels of free fatty acids to supply energy to cells. Insulin-mediated transcription of Atgl, the enzyme that mediates the rate limiting step in lipolysis, is a key point of this regulation. Under conditions such as obesity or insulin resistance, Atgl transcription is often misregulated, which can contribute to overall disease progression. The mechanisms by which Atgl is induced during adipogenesis are not fully understood. We utilized computational approaches to identify putative transcriptional regulatory elements in Atgl and then tested the effect of these elements and the transcription factors that bind to them in cultured preadipocytes and mature adipocytes. Here we report that Atgl is down-regulated by the basal transcription factor Sp1 in preadipocytes and that the magnitude of down-regulation depends on interactions between Sp1 and peroxisome proliferator-activated receptor gamma (PPARgamma). In mature adipocytes, when PPARgamma is abundant, PPARgamma abrogated transcriptional repression by Sp1 at the Atgl promoter and up-regulated Atgl mRNA expression. Targeting the PPARgamma-Sp1 interaction could be a potential therapeutic strategy to restore insulin sensitivity by modulating Atgl levels in adipocytes. PMID- 28726644 TI - Arabidopsis calmodulin-like protein CML36 is a calcium (Ca2+) sensor that interacts with the plasma membrane Ca2+-ATPase isoform ACA8 and stimulates its activity. AB - Calmodulin-like (CML) proteins are major EF-hand-containing, calcium (Ca2+) binding proteins with crucial roles in plant development and in coordinating plant stress tolerance. Given their abundance in plants, the properties of Ca2+ sensors and identification of novel target proteins of CMLs deserve special attention. To this end, we recombinantly produced and biochemically characterized CML36 from Arabidopsis thaliana We analyzed Ca2+ and Mg2+ binding to the individual EF-hands, observed metal-induced conformational changes, and identified a physiologically relevant target. CML36 possesses two high-affinity Ca2+/Mg2+ mixed binding sites and two low-affinity Ca2+-specific sites. Binding of Ca2+ induced an increase in the alpha-helical content and a conformational change that lead to the exposure of hydrophobic regions responsible for target protein recognition. Cation binding, either Ca2+ or Mg2+, stabilized the secondary and tertiary structures of CML36, guiding a large structural transition from a molten globule apo-state to a compact holoconformation. Importantly, through in vitro binding and activity assays, we showed that CML36 interacts directly with the regulative N terminus of the Arabidopsis plasma membrane Ca2+ ATPase isoform 8 (ACA8) and that this interaction stimulates ACA8 activity. Gene expression analysis revealed that CML36 and ACA8 are co-expressed mainly in inflorescences. Collectively, our results support a role for CML36 as a Ca2+ sensor that binds to and modulates ACA8, uncovering a possible involvement of the CML protein family in the modulation of plant-autoinhibited Ca2+ pumps. PMID- 28726647 TI - RESULTS OF MINIMAL INVASIVE TREATMENT IN LOCALIZED ACQUIRED CUTIS LAXA TYPE 1 AND TYPE 2 - CASE REPORT AND DISCUSSION. AB - Cutis laxa is a disease of premature ageing. While the congenital type is characterized by mutations of genes involved in extracellular matrix turnover, acquired cutis laxa is a rare disease that can be induced by a variety of exogenous factors. We present a case of acquired type 2 cutis laxa of the neck due to excessive exposure to natural sunlight and a type 1 facial acquired cutis laxa, both significantly improved by minor invasive procedures. The etiology, prevention and treatment options are discussed. PMID- 28726646 TI - THE PROGNOSTIC SIGNIFICANCE OF COMBAIND EXPRESSION OF ZAP-70 AND CD38 IN CHRONIC LYMPHOCYTIC LEUKEMIA. AB - Our aim was to assess the inter links of the markers CD38 and ZAP-70 based on our materials, the attitude according to the disease stage, and to document which of them had leading meaning for prognosis and treatmend of the disease. In our study we have used flow cytometry for detection CD38 and ZAP-70+ markers expression. (58 patients to assessments their prognostic value in shronic lymphocytic leukemia (CLL), Correlation to Rai stages and relationships between this markers and outcome of therapy). We divided all patients in two groups based on level of ZAP-70+ cell and CD38+cells,(I group-patients) ZAP-70+ cells <20% CD38+<30% and ZAP-70+ cells >20% and CD38>30%,(II group) becaus our in investigation shows, that ZAP -70+ is very importance independent prognoctic marker as why in ZAP-70+ cases when its number was <20%, patients had favorable prognosis - the big part of them (13(40.6%) didn't need treatment during a long period, but which need the treatment was effective and this patients life expectancy was long (62 mounts). When ZAP-70 cells were>20% (II group n=26) prognosis was unfavorable, patients treatment was not effective and accordingly life expectancy was shorter (39 mounts). Despite CD38 positive or negative cells number. During research where compared were ZAP-70+ and ZAP-70- cases events treatment results and the research was held on the minimal residual disease existence, in ZAP-70+ positive cases treatment the remission obtained was always incomplete, and on the contrary, where the ZAP-70+ was negative - complete. In our study we didn,t reveal the importance of CD38 as a prognostic independent marker and there were not correlation between CD38+ and CD38- cells numbers in CLL prognosis. Because our study data confirm that ZAP-70 marker is more importance marker then CD38 and it has seriously prognostic significance, we think that information about ZAP-70 marker expression. Because our study data confirm that ZAP-70 marker has the advantageous prognostic meaning, we reckon the information on CLL disease debut on ZAP-70 market expression can be used not only for defining the aggressive process of the disease, but also in greater part, to define the refracterity towards the modern chemotherapy regimens. PMID- 28726648 TI - [CONE BEAM COMPUTED TOMOGRAPHY IN DIAGNOSTICS OF ODONTOGENIC MAXILLARY SINUSITIS (CASE REPORTS)]. AB - Diagnostic studies performed by cone beam computed tomography Morita 3D made possible to obtain high resolution images of hard tissues of upper jawbone and maxillary sinus, to detect bony tissue defects, such as odontogenic cysts, cystogranulomas and granulomas. High-resolution and three dimensional tomographic image reconstructions allowed for optimal and prompt determination of the scope of surgical treatment and planning of effective conservative treatment regimen. Interactive diagnostics helped to estimate cosmetic and functional results of surgical treatment, to prevent the occurrence of surgical complications, and to evaluate the efficacy of conservative treatment. The obtained data contributed to determination of particular applications of cone beam computed tomography in the diagnosis of odontogenic maxillary sinusitis, detection of specific defects with cone beam tomography as the most informative method of diagnosis; as well as to determination of weak and strong sides, and helped to offer mechanisms of x-ray diagnostics to dental surgeons and ENT specialists. PMID- 28726649 TI - LIPOPROTEIN ASSOCIATED PHOSPHOLIPASE A2 AS A MARKER OF VULNERABLE ATHEROSCLEROTIC PLAQUE IN PATIENTS WITH INTERNAL CAROTID ARTERY STENOSIS. AB - The aim of this study was to compare the concentration of inflammatory vascular markers and morphological structure of atherosclerotic plaque in symptomatic and asymptomatic patients with the stenosis of internal carotid artery (ICA). The research was carried out in 70 patients with hemodynamically significant stenosis of ICA out of which 40 (57%) were asymptomatic patients and 30 (43%) were symptomatic patients, of which 20 patients (66%) have had a stroke, or transient ischemic attack (TIA), 10 patients (33%). All the patients were indicated to carotid endarterectomy as a surgical prevention of stroke. All the patients were taken their blood for biochemical testing (T-Chol, LDL, HDL, TG, Fibrinogen, CRP and specific markers IL-4 and Lp-PLA2) early morning prior to surgery. The highest concentrations of T-Chol, LDL, HDL, CRP and Fibrinogen were measured in symptomatic patients, however, these did not feature a significant difference compared with the group of asymptomatic patients (P>0.05). Significant difference was found in IL-4 (P<0.001) and in Lp-PLA2 (P<0.001). When evaluating concentration of tracked parameters in patients with soft atherosclerotic plaque and patients with calcified atherosclerotic plaque, significant differences were found in these markers: TG (P<0.05), CRP (P<0.01), IL-4 (P<0.001) and Lp-PLA2 (P<0.001). The paper deals with higher concentrations of Lp-PLA2 in patients with a soft atherosclerotic plaque. Higher concentration of Lp-PLA2 and systemic inflammatory markers (CRP, IL-4) could be used along with ultrasonography to detect mainly asymptomatic patients who are in urgent need of surgical or endovascular treatment as a prevention of stroke. PMID- 28726650 TI - [MODIFIED SYSTEM OF THROMBOPROPHYLAXIS IN PATIENTS WITH SURGICAL PROFILE]. AB - The aim of the study was to reduce the incidence of postoperative thrombosis in the veins of the inferior vena cava basin under planned surgical interventions by using a modified thromboprophylaxis method. Two groups of patients were studied in a total of 698 patients who underwent a risk assessment of postoperative venous thromboembolism (PVTE) using the J. Caprini scale (2012). According to the patients indicated in determining the degree of risk of HTHP development according to the J. Caprini scale, the level of surgical stress was simultaneously determined. The level of the latter was established by the content of glucose and cortisol in the blood in the preoperative period, during the traumatic stage of surgical intervention and in the early postoperative period. Introduction to the J. Caprini system of the degree of surgical stress objectifies the system for determining the risk of postoperative venous thrombosis. Inclusion of UFH (the prevailing influence on factor II) in the system of thromboprophylaxis of LMWH (predominant influence on Xa factor) with planned surgical interventions made it possible to reduce the incidence of postoperative thrombosis of the veins in the NIP basin by 1.8 (p<0.001) times. PMID- 28726651 TI - FACTORS ASSOCIATED WITH POST-STROKE FATIGUE WITHIN THE FIRST 3 MONTH AFTER STROKE. AB - Aim - identify socio-demographic, personal and psychological factors associated with certain post-stroke fatigue (PSF) domains within first 3 months after stroke. There were examined patients consequently in definite time points after ischemic or hemorrhagic strokes: at hospital stay (234 patients), in 1 month (203 patients) and in 3 months (176 patients). Global PSF and certain PSF domains were measured by multidimensional fatigue inventory-20 (MFI-20) scale. In multivariate logistic regression analysis the majority of variables (gender, marital status, education level, smoking status, level of alcohol consumption, apathetic impairments, arterial hypertension, atrial fibrillation, ischemic heart disease, diabetes mellitus, body mass index, waist circumference) were not significantly associated with any PSF domain risk at any time point after stroke. On the other hand, it had been found reliable associations between risk of global PSF and employing status before stroke, pre-stroke fatigue, anxiety symptoms, excessive daytime sleepiness, pain. Majority of risk factors for specific PSF domains (physical, mental, activity-related, motivational) are the same as for global PSF. The exception is mild cognitive impairments for mental PSF and depression signs for motivational PSF. Management of modifiable risk factors (anxiety and depression signs, excessive daytime sleepiness, chronic pain) probably may be helpful for PSF prevention within first 3 months after stroke. PMID- 28726652 TI - INVESTIGATION OF BONE MINERALIZATION IN PATIENTS WITH CORONARY HEART DISEASE COMPLICATED BY CHRONIC HEART FAILURE, STAGE II-A. AB - The majority of the studies have shown that individuals with cardiovascular diseases have a higher risk of experiencing bone loss and thus greater predisposition to risk of fracture. On the other hand there is growing evidence that individuals with low bone mass have higher mortality for cardiovascular events compared to patients with cardiovascular disease with normal bone mass. This research aims to investigate bone mineralization in patients with coronary heart disease complicated by stage II-A chronic heart failure. The study involved 33 men with coronary heart disease complicated by Stage II-A chronic heart failure. Bone mineral density was measured using dual energy x-ray densitometry of lumbar region of spine. Structural and functional changes of bone tissue of the lumbar spine have been found in 49,2% patients with coronary heart disease complicated by Stage II-A chronic heart failure, in particular, I stage of osteopenia - in 44,6%, II stage of osteopenia - in 27,7%, III stage of osteopenia - in 10,8% and osteoporosis - in 16,9%. It was established the same type of downward trend for BMD decreasing in L1 of patients with different stages of osteopenia, but in case of osteoporosis mineralization decreased equally in all vertebrae. PMID- 28726653 TI - RETROSPECTIVE STUDY OF EVALUATION OF PATIENTS WITH ST ELEVATION MYOCARDIAL INFARCTION AND INTACT CORONARY ARTERIES. EVALUATION OF TREATMENT APPROACHES; OUTCOME AND PROGNOSIS. AB - Myocardial infarction with normal coronary arteries is a well known pathology. It may or may not be associated with left ventricle wall motion abnormalities. Data was reviewed retrospectively for patients with ST elevation myocardial infarction who underwent cardiac catheterization. From the total number of patients evaluated 10.3% (17) patients had Myocardial Infarction with normal coronary arteries. Females were more likely to present with MINCA then males. Coronary flow was normal in 11 from 17 patients with MINCA. In 6 cases slow coronary flow was detected. Myocardial segments with slow coronary flow did not correlate with wall motion abnormalities detected by echocardiography and ventriculography. In 8 females, Takotsubo cardiomyopathy was suspected. Data were analyzed retrospectively and we were not able to obtain full coagulation panel for all evaluated patients. Myocardial biopsy was not performed in either of patients under observation. Spontaneous thrombolysis was suspected in number of cases. Most angiography investigations were done within three hours after symptoms start. Prognosis of patients with ST-elevation Myocardial Infarction (STEMI) and normal coronary arteries was good. No fatal or non-fatal complications during hospitalization. During 6 month, follow up one male patient was re-hospitalized due to Acute Coronary Syndrome (ACS) in 5.5 month after initial event. Repeated coronary angiography did not reveal the abnormalities. Our study is first attempt for collecting retrospectively different data for patients with STEMI and NCA. Important is that no correlation was found between wall motion abnormalities and coronary flow limitations (if present). Compared to other studies we found higher incidences of wall motion abnormalities detected by echocardiography and/or ventriculography. Future prospective design studies in STEMI and NCA are warranted to understand the pathophysiology and define right treatment approaches. Stress may be considered as prominent factor, but future studies are needed with psychological evaluation; autonomous nerves system testing and catecholamine levels determination to verify its role in this pathology. PMID- 28726654 TI - THE SAFETY AND EFFICACY OF AMIODARONE AND CARVEDILOL COMBINATION IN TREATMENT OF PATIENTS WITH SEVERE CARDIAC RHYTHM DISORDERS. AB - Different arrhythmias are cause of sudden death in many patients with heart failure. Amiodarone is usually used for prevent this arrhythmias, but it is not drug of choice for treatment the patients with heart failure. We retrospectively analyzed 142 patients with moderate and severe heart failure and history of myocardial infarction. These patients have received amiodarone, carvedilol or combination of these two medications together with standard therapy. In our retrospective analysis, the combination therapy with Amiodarone and Carvedilol had highly significant decrease arrhythmic death compare with carvedilol and amiodarone groups. This therapy is more effective in recovering of sinus rhythm in patients with atrial fibrillation and for control ventricular arrhythmias. The effects of carvedilol on left ventricular remodeling, systolic function and symptomatic status are not affected adversly by concurrent treatment with amiodarone. Carvedilol is an effective additional therapy for the patients with chronic heart failure already receiving Amiodarone. Carvedilol can be added to Amiodarone in patients with severe ventricular rhythm disorders and increased risk of sudden death without expecting of increase adverse events (than either drug alone) or loss of clinical efficacy. PMID- 28726655 TI - INFLUENCE OF BETA-BLOCKERS AND IVABRADINE ON LONG-TERM PROGNOSIS OF PATIENTS WITH STABLE ANGINA. AB - The purpose of the study was to evaluate the influence of beta-blockers and ivabradine on long-term prognosis of patients with stable angina. 90 patients with stable angina that have been involved in present study along with nitrates, antiplatelet agents and statins received bisoprolol (Group I), carvedilol (Group II) and ivabradine (Group III). We analyzed the following indicators: patient adherence to treatment, cases of myocardial infarction and circulatory decompensation, which resulted in necessity of patient's hospitalization during the year of observation, calculating the probability of achieving a key prognostic endpoint by patient using the concept of the odds ratio and determination of important components in the progression of the disease. We concluded that in compared patients groups developed cardiovascular death and unstable angina with almost equal frequency. As for cases of myocardial infarction and the need for revascularization, their number was smaller in patients who in addition to standard treatment received ivabradine. Prognosis of patients with stable angina after 12 months of treatment primarily depends on their adherence to treatment, age, heart rate, presence of harmful habits, and markers of endothelial dysfunction, including endothelin-1 and homocysteine. PMID- 28726656 TI - ANXIETY LEVELS IN PATIENTS WITH PAROXY-SMAL SUPRAVENTRICULAR TACHYCARDIA IN RELATION WITH THE PATIENT DEMOGRAPHICS, TYPE OF SUPRAVENTRICULAR TACHYCARDIA AND THEIR PERSONALITY TYPE. AB - The aim of the study was to evaluate the incidence of different personality types and state and trait anxiety levels in patients with paroxysmal supraventricular tachycardia and their association with patients age, gender and the mechanism of the paroxysmal SVT. 62 patients with documented paroxysmal supraventricular tachycardia who underwent endocardial eletrophysiological study and catheter ablation of the paroxysmal SVT were included in the study. The patients were asked to fill out the Myers-Brigss Type Indicator and State-Trait Anxiety Inventory questionnaires and the results were analyzed and correlated with the arrhythmia mechanism determined during electrophysiological study and catheter ablation procedure, and the patients' demographics (age and gender). There was no significant difference in State (mean 41.53+/-13.51, p=0.893) or Trait (mean 44.70+/-12.62, p=0.315) anxiety scores according to gender although higher scores were found in females. Older patients (>=50 years old compared to <50 years old) had higher anxiety scores but with no statistical significance (p=0.344 for state anxiety and p=0.100 for trait anxiety). The patients with AVNRT had significantly higher Trait anxiety scores (mean 46.82+/-10.52) than the patients with AVRT or AT (mean 40.59+/-10.91) (p=0.032). State anxiety score was not significantly different between patients with different SVT types (p=0.706). Anxiety is an important factor to be considered in patients with paroxysmal supraventricular tachycardia. It doesn't seem to be associated with different personality types. Female and older patients tend to show higher anxiety levels. The atrioventricular Nodal Reentrant Tachycardia (AVNRT) is associated with significantly higher trait anxiety levels compared to other types of paroxysmal supraventricular tachycardia. PMID- 28726657 TI - ECHOCARDIOGRAPHIC CHARACTERISTICS OF DIFFERENT WHO/ISH CARDIOVASCULAR DISEASE RISK GROUPS. AB - The objective of the study was to analyze association of echocardiographic TOD variables with the CVD risk groups defined by WHO/ISH. A cross-sectional study was conducted between (September 2008 - December 2010) Consecutive sample of 146 participants were enrolled in the study, 97 (66.4 %) women and (49) 33,6 % men, mean age. Study population was categorized in three groups according to WHO/ISH risk categories: Group 1 included population with risk less than 10% according to WHO/ISH, in Group 2 there were united two WHO/ISH risk categories (10-10.9% and 20-29.9%) and Group 3 represented population of 30-39.9% and more than 40% of CVD risk. Routine Echocardiography was conducted. The data was analyzed using SPSS, version 21. The distribution of echocardiography characteristics in WHO/ISH groups was statistically different for LA, PSP and EF (P<0.05). In groups I and II LA were only mildly dilated, while in group III was revealed moderate LA enlargement. The mean PSP was in normal range in groups I and II and mildly to moderate elevated in group III. The mean EF was in normal range for all the groups with tendency of reduction from group I to group III. Unlike this we have not found statistically significant differences in other echocardiographic variables, as IVS, PWT, LVD and LVEDV and they were in normal range for all risk groups. According to the findings of our study and considering that our study population is without any clinical presentation of cardiovascular disease and still have statistically significant tendency toward increase in LA and PSP we argue that those variables can be considered as early predictors of cardiovascular disease. Furthermore, it is recommended to include echocardiographic examination as part of the CVD risk evaluation protocol in selected population. PMID- 28726658 TI - [OPTIMIZATION OF DIAGNOSTICS OF EXUDATIVE PLEURITIS OF UNKNOWN ORIGIN]. AB - The article describes 143 cases of exudative pleuritis of unknown origin in patients who were diagnosed and treated with any minimally invasive surgical procedures: pleural puncture (PP), video-assisted thoracoscopy (VATS) with biopsy of the pleura. A different diagnostic methods (cytological, microbiological, histological) used in various diagnostic surgical procedures are analyzed in detail and calculated diagnostic sensitivity, specificity, and accuracy of each method. Based on the analysis of cytological, histological and microbiological studies in the performance of VATS concluded relatively high, comparable with the method of open pleural biopsy, diagnostic efficiency, the sensitivity of this method in the scheme of the diagnostic algorithm of EP of unknown origin. PMID- 28726659 TI - FACTORS AFFECTING SURVIVAL OF WOMEN DIAGNOSED WITH BREAST CANCER IN GEORGIA. AB - Breast cancer is the most frequently diagnosed cancer in women worldwide with nearly 2.4 million new cases diagnosed in 2015, In Georgia survival from breast cancer is lower than in many developing countries. The goal of the study was to identify predictors for low survival of disease in the country. Data from population-based cancer registry was used in order to estimate 1-year and 5-years relative survival rates for breast cancer. To identify predictors for low survival time, was performed bivariate analysis. Statistical analyses looked at correlations between possible predictors and survival period. From the cancer registry database 190 breast cancer cases, whose diagnosis were conformed histologically and died in 2015 were included in a statistical analysis. All analyses were performed using Epi Info version 7. According to population-based cancer registry, breast cancer is the most common form of cancer among women in Georgia. In 2015 1838 breast cancer new cases were detected in the country, incidence rate composed 94.7 per 100000 population. Based on 190 breast cancer patients' data, that died during 2015, one-year and 5-year survival rate composed 69% and 26% in accordance. The results of bivariate analysis, show that late stage at diagnosis (OR=1.89, 95%CI=0.74-4.68), a young age of patients at diagnosis (OR=1.89, 95%CI=0.50-7.17), highly differentiated histological grade (OR=1.21, 95%CI= 0.44 - 3.54), is positively correlated with low survival period (less than 5 years), while having mastectomy (OR=0.52, 95%CI=0.27-0.89), adjuvant chemotherapy (OR=0.38, 95%CI=0.20-0.74), and a radiotherapy (OR=0.62, 95%CI=0.31 1.25), have statistically significant positive association with high (more than 5 years), survival period. A young age of patients at diagnosis, highly differentiated histological grade and late stage at diagnosis were possible predictors for low survival time (less than 5 years) in Georgia. Breast cancer survival can be extended by using complex methods of treatment and implementation of standardized approaches to management of diseases throughout the country. PMID- 28726661 TI - [HEART RATE VARIABILITY IN CHILDREN WITH FALSE CHORDS IN THE LEFT CARDIAC VENTRICULAR]. AB - We examined 64 children with false tendons in the left cardiac ventricular. The research included evaluation of time and frequency domain parameters of the heart rhythm with cardiointervalography. The parameter changes were noted. Thus, sympathetic vegetative system (VS) part prevalence was present in boys and characterized by decreasing of SDNN when compared with control data (85,4+/-5,8 i 158,2 +/-25,6, r<0,05). rMSSD and PNN50%, which are responsible for parasympathetic VS part have the tendency to increasing in girls. Nevertheless, frequency domain analysis showed an increasing of the total spectrum power (TP) in both subgroups with statistically significant result (4734,2+/-319,4 and 3520+/-381 - boys, r<0,05 when compared with control; 4961,7+/-413,7 and 3520+/ 381, r<0,05 - girls, respectively). That was proved by other parameters. VLF were also increased when compared with control group (4188,4+/-413,1 and 1717+/-154, r<0,05 - boys; 3050,5+/-468,1 and 1433+/-811 - girls, r<0,05, respectively), which characterizes sympathetic VS part prevalence in both subgroups. Other frequency domain parameters statistically were not changed but they had tendency as to increasing as to decreasing. All previously noted shows the sympathicotonia in children with FT. These children should be under observation of pediatricians and child cardiologists. PMID- 28726662 TI - CYTOKINES AS THE PREDICTORS OF SEVERE MYCOPLASMA PNEUMONIAE PNEUMONIA IN CHILDREN (REVIEW). AB - In spite of many attempts to differentiate bacterial from viral disease and predict severity and outcome, the etiologic diagnosis of paediatric community acquired pneumonia and the estimation of potential outcomes remain unsolved problems in most cases. Mycoplasma pneumoniae is one of the major pathogens causing CAP in children. Although MP infection was traditionally thought to be a self-limited process, more and more severe cases even fatal cases of MP infections were reported in recent years. So it is essential for pediatricians to recognize severe or refractory or severe MP early, treat it promptly and prevent the progress of the disease. In recent years, several new biomarkers have been tested in children with CAP. Some of the biomarkers used for etiologic diagnosis in children with CAP and they also have been used the MP infection severity. Among traditional biomarkers, several cytokines appears to be effective both in selection of bacterial cases and in evaluation of severity. However, a precise cut-off level able to separate bacterial from viral cases and mild from severe cases has not been defined. Further studies enrolled with a large number of children with Mycoplasma pneumoniae is needed to be carried out to identify the potential utility of different cytokines as the good predictors. PMID- 28726663 TI - [PECULIARITIES OF COMMUNITY-ACQUIRED PNEUMONIA IN CHILDREN WITH NEUROLOGICAL PATHOLOGY]. AB - Neurological disorders in children highly affect the course of pneumonia, its outcome and the development of possible complications. The aim of the study was to reveal clinical and paraclinical features of community-acquired pneumonia in younger children with neurologic pathology infantile cerebral palsy. Under observation were 37 children with community-acquired pneumonia aged 1 to 3 years that suffered from spastic forms of infantile cerebral palsy. The comparison group consisted of 30 children with community-acquired pneumonia without any concomitant neurological pathology. The age of the children in the comparison and study groups was the same. The results of the study show that the presence of infantile cerebral palsy allow to relate the child to the risk group of respiratory pathology development. The course of community-acquired pneumonia in children affected by infantile cerebral palsy is characterized by rapid progression of symptoms and severity of the condition, and the clinical picture also has a number of characteristic features. Thus, cough, local physical data, classical laboratory signs of inflammation in the form of leukocytosis with neutrophil shift were noticed significantly less often in children with infantile cerebral palsy. The debut of the disease was often accompanied by bronchial obstruction, the inflammatory process was localized in the lower parts of the lungs and often matched the side of the neurologically affected part of the body. Children with cerebral palsy required a longer hospital-stay and a prolonged course of antibiotic therapy. Therefore, the risk of pneumonia in children with infantile cerebral palsy should be taken into account at the primary stage of medical care for the creation of preventive programs. PMID- 28726664 TI - EXPANDED PHENOTYPE OF TMEM67 GENE MUTATION (CASE REPORT). AB - Human ciliopathies are a class of multi-organ genetic disorders caused by defects of proteins expressed at the primary cilium, an organelle present on the cell surface of almost all cell types. Thus far, dozens of causative genes for ciliopathies have been identified and many of them are known to cause allelic disease. Of particular interest is the TMEM67 gene, encoding the transmembrane protein meckelin. The involvement of the mutant TMEM67 gene is known to be associated with a broad range of clinical presentations, namely Joubert syndrome 6 (JBTS6), nephronophthisis 11 (NPHP11), Bardet-Biedel syndrome (BBS), COACH syndrome, and lethal Meckel syndrome type 3 (MKS3). Here we present a case of a 3 year-old boy with compound heterozygous missense mutations in the TMEM67 gene manifesting features of both JBTS and NPHP syndromes, with neonatal onset of end stage renal disease (ESRD) and associated microcephaly. Such a phenotype has not been reported to date, thus highlighting the diversity of ciliopathies and expanding the phenotype of the TMEM67 gene. PMID- 28726665 TI - [ABOUT THE ROLE OF DIGESTIVE TRACT DECOMPRESSION IN PATIENTS WITH ACUTE BOWEL OBSTRUCTION. MISTAKES, COMPLICATIONS AND THEIR PREVENTION]. AB - The purpose of the work is improvement in treatment of patients with acute small bowel obstruction by justification for gastrointestinal decompression and different methods of small intestine intubation for effective evacuation of itscontents. We conducted morphological and morphometric study of the small intestine in 53 white rats. It was established that acute small bowel obstruction causes expansion of all parts of small bowel microvasculature with significant lesions of venous structures. We revealed thinning of intestinal muscular layer 2.15 timesand increase of submucosallayer 1.65 times. Changesin nuclear/cytoplasmic ratioof these structures showed tension and instability in structural homeostasis at cellular level. These changes lead to malabsorption and require evacuation of intestinal pathological contents. We analyzed 30 medical records of patients who died from acute small bowel obstruction. Decompression was performed only in 60.71% ofall cases and in 50.0% of re-laparotomy cases. The cause of death in 80.0% was syndrome of multiple organ failure due to progressiveintoxication caused by functional obstruction of the small intestine. 196 patients were operated. In 50% of cases nasointestinal intubation was used for small bowel decompression, in 11.22% - intraoperative one-stage evacuation of intestinal contents and in 3.57% - "open" methods of intestinal drainage. We drew attention to problems and errorsin performingsmall bowel intubation. We offered some variants of intubation using different probes according to the operating situation and aim of intubation. Design of probe for intubation and method of enterostomy was suggested. We also offered an algorithm for selectionof small intestinal decompression method in patients with acute small bowel obstruction depending on the operating situation. We emphasizethat intestinal decompression in patients with acute small bowel obstruction improves the results of surgery. PMID- 28726666 TI - [PATHOMORPHOLOGICAL CHANGES UNDER LATENT MASTOIDITIS]. AB - In our opinion it is caused by incomplete awareness of the distribution of pathological process and the character of morphological changes in the patients. In this regard, we studied structural changes in the soft and bone tissue taken from various cavities of the middle ear system. Operating material was formed in paraffin after the fixation and proper processing. We proceed with decalcification of bone tissues in 15-20% nitric acid. We painted 5-6 mm thick peels prepared on the rotating microtome with hematoxylin and eosin. The microscopic examination revealed inflammatory-destructive changes in the mucous membrane as well as in the bone tissues, also serous inflammation-fibrin inflammation, and well-expressed edema. The inflammatory infiltration demonstrated the presence of lymphocytes, macrophages, plasmocytes and also predominantly dislocated leukocytes. There were also revealed various amount of glandular structures. The bone tissues - along with the inflammatory infiltration - revealed destructive cells, which contained osteoclast, epithelial cells and fibroblasts. The mentioned structural changes should be assessed as demonstration of an osteitis and osteomyelitis. Based on the above mentioned, we believe that treatment of latent mastoiditis requires surgical method and it is necessary the complete sanitization of not only the granulating tissue but the damaged bone masses. Otherwise, the remaining inflammatory nidus may cause a relapse. The correct treatment of latent mastoiditis in turn will reduce the mortality rate and the percentage of disability. PMID- 28726667 TI - CLINICAL AND GENETIC PECULIARITIES OF VASCULAR MANIFESTATIONS OF ANTIPHOSPHOLIPID SYNDROME (CASE REPORT). AB - Pathogenetic mechanisms of the development of antiphospholipid syndrome (APS) are considered in the article, which is the basis for the development of clinical manifestations and laboratory markers of APS. The modern literature data are analyzed, according to which the presence of antiphospholipid antibodies is a hypercoagulable background, and the formation of thrombi occurs under the influence of other allowing procoagulation factors. The classification of the main types of hereditary thrombophilia is given, which is the primary disorder, against the background of which an autoimmune thrombosis APS develops. A clinical observation of a young age patient is given, whose heterozygous carriage of mutations in the genes responsible for blood coagulation (F7, PAI-1 and ITGB3 beta-integrin), as well as homozygous carriage of a mutation in the MTRR gene associated with a violation of homocysteine methylation, APS was developed, which led to the processes of thrombosis. Timely diagnosis and individually developed pathogenetic therapy allow avoiding life-threatening complications of APS and improving the patients' quality of life. A conclusion about the need for APS and hereditary thrombophilias' examination to all patients of young age with unprovoked thrombosis of deep veins of lower extremities and PE was made. PMID- 28726668 TI - FORMULATION AND TECHNOLOGY DEVELOPMENT OF HERBAL PHENOLIC BIOPOLYMER-CONTAINING FILMS FOR BURN TREATMENT. AB - Application of phytofilms based on biosolublepolymers is considered as a prospectivemethod for burn treatment . Herbal remedies contain biologically active substances, that are relatively less toxic, do not cause skin irritation or allergic reactions and, importantly, affectstrains of the microorganisms and viruses resistant to antibiotics and synthetic drugs. Nowadays, the advantages are given to such burn healing drugs, which along with high specific efficacy, have analgesic, anti-inflammatory and antimicrobial effects, and don't irritate the tissues. The mentioned peculiarities are characteristic for a new herbal phenolic biopolymer poly[3-(3,4-dihydroxyphenyl) glyceric acid](PDGA), isolated from the roots and stems of different comfrey species . The aim of the study was the development of the formulation and technology of biosoluble films for burn treatment on the basis of PDGA. The optimal content of phytofilm for burn healing was selected on the basis of the biopharmaceutical study results. The impact of the film-former on the quality, adhesion and moisture absorption of the phytofilmhas been studied. The optimal degree of the phytofilm moisture, determining its high adhesive properties,was established. The film prepared on the basis of sodium alginate, with 30.4% humidity, demonstrated the greatest adhesion strength. After investigation of the PDGA release it was found, that the hydrophilic bases such as: sodium carboxymethyl-cellulose (69.2%) andsodium alginate (78,65%) appeared to be optimal among the others. At the same time, taking into consideration the disadvantages of sodium carboxymethyl-cellulose (tautening effect on burnt surface, relatively low stability), a film based on sodium alginate has been chosen. The manufacturing technology for obtaining PDGA containing phytofilm by casting is proposed. Theshelf-lifeofproposedPDGA containingphytofilmis 2 years. PMID- 28726669 TI - Spectral performance of a whole-body research photon counting detector CT: quantitative accuracy in derived image sets. AB - Photon-counting computed tomography (PCCT) uses a photon counting detector to count individual photons and allocate them to specific energy bins by comparing photon energy to preset thresholds. This enables simultaneous multi-energy CT with a single source and detector. Phantom studies were performed to assess the spectral performance of a research PCCT scanner by assessing the accuracy of derived images sets. Specifically, we assessed the accuracy of iodine quantification in iodine map images and of CT number accuracy in virtual monoenergetic images (VMI). Vials containing iodine with five known concentrations were scanned on the PCCT scanner after being placed in phantoms representing the attenuation of different size patients. For comparison, the same vials and phantoms were also scanned on 2nd and 3rd generation dual-source, dual energy scanners. After material decomposition, iodine maps were generated, from which iodine concentration was measured for each vial and phantom size and compared with the known concentration. Additionally, VMIs were generated and CT number accuracy was compared to the reference standard, which was calculated based on known iodine concentration and attenuation coefficients at each keV obtained from the U.S. National Institute of Standards and Technology (NIST). Results showed accurate iodine quantification (root mean square error of 0.5 mgI/cc) and accurate CT number of VMIs (percentage error of 8.9%) using the PCCT scanner. The overall performance of the PCCT scanner, in terms of iodine quantification and VMI CT number accuracy, was comparable to that of EID-based dual-source, dual-energy scanners. PMID- 28726670 TI - Solid-state nanopore based biomimetic voltage gated ion channels. AB - Voltage gating is essential to the computational ability of neurons. We show this effect can be mimicked in a solid-state nanopore by functionalizing the pore interior with a redox active molecule. We study the integration of an active biological molecule-a quinone-into a solid state nanopore, and its subsequent induced voltage gating. We show that the voltage gating effect mimics biological gating systems in its classic sigmoidal voltage response, unlike previous synthetic voltage gating systems. Initially, the quinone undergoes a reduction due to radicals in the bulk solution, and is converted to the hydroquinone state. Upon deprontonation the hydroquinone then acts as a charged nanomechanical arm, which opens the channel under the applied potential. We establish that the quinone gains a single net charge when the pH inside of the nanopore reaches its pKa value, and explore factors that influence the net pH in the middle of the pore. Using a combination of theory, experiment and simulation, we conclude that concentration polarization and a shift of the pH inside of the channel is the main cause of this gating effect. PMID- 28726671 TI - In situ decoration of plasmonic Au nanoparticles on graphene quantum dots graphitic carbon nitride hybrid and evaluation of its visible light photocatalytic performance. AB - This work spotlights the development of a plasmonic photocatalyst showing surface plasmon induced enhanced visible light photocatalytic (PC) performance. Plasmonic Au nanoparticles (NPs) are decorated over the hybrid nanosystem of graphitic carbon nitride (GCN) and graphene quantum dots (GQD) by citrate reduction method. Surface plasmon resonance (SPR) induced enhancement of Raman G and 2D band intensity is encountered on excitation of the Plasmonic hybrid at 514.5 nm, which is near to the 532 nm absorption band of Au NPs. Time-resolved photoluminescence and XPS studies show charge transfer interaction between GQD-GCN and Au NPs. Plasmonic hybrid exhibits an enhanced PC activity over the other catalysts in the photodegradation of methylene blue (MB) under visible light illumination. Plasmonic photocatalyst displays more than 6 fold enhancement in the photodecomposition rate of MB over GQD and nearly 2 fold improvement over GCN and GQD-GCN. GQD-GCN absorbs mostly in the near visible region and can be photoexcited by visible light of wavelength ([Formula: see text]) < 460 nm. Plasmon activation in Au NPs decorated GQD-GCN could exploit the entire UV visible light for photocatalysis. Furthermore, plasmonic Au act as antennas for accumulation and enhancement of localized electromagnetic field at the interface with GQD-GCN, and thereby promotes photogeneration of large numbers of carriers on GQD-GCN. The carriers are separated by charge transfer migration from hybrid to Au NPs. Finally, the carriers on the plasmonic Au nanostructures initiate MB degradation under visible light. Our results have shown that plasmon decoration is a suitable strategy to design a carbon based hybrid photocatalyst for solar energy conversion. PMID- 28726672 TI - The influence of surface potential on the optical switching of spiropyran self assembled monolayers. AB - Surfaces whose macroscopic properties can be switched by light are potentially useful in a wide variety of applications. One such promising application is electrochemical sensors that can be gated by optically switching the electrode on or off. One way to make such a switchable electrode is by depositing a self assembled monolayer (SAM) of bistable, optically switchable molecules onto an electrode surface. Quantitative application of any such sensor requires understanding how changes in interfacial field affect the composition of photostationary states, i.e. how does electrode potential affect the extent to which the electrode is on or off when irradiated, and the structure of the SAM. Here we address these questions for a SAM of a 6-nitro-substituted spiro[2H-1 benzopyran-2,2'-indoline] covalently attached through a dithiolane linker to an Au electrode immersed in a 0.1 M solution of Tetramethylammonium hexafluorophosphate in Acetonitrile using interface-specific vibrational spectroscopy. We find that in the absence of irradiation, when the SAM is dominated by the closed spiropyran form, variations in potential of 1 V have little effect on spiropyran relative stability. In contrast, under UV irradiation small changes in potential can have dramatic effects: changes in potential of 0.2 V can completely destabilize the open merocyanine form of the SAM relative to the spiropyran and dramatically change the chromophore orientation. Quantitatively accounting for these effects is necessary to employ this, or any other optically switchable bistable chromophore, in electrochemical applications. PMID- 28726673 TI - Off-on fluorescence monitoring of intracellular Ag+ in single living cells using an Ag+-responsive probe. AB - Detection of silver ions (Ag+) in living cells has becoming more and more attractive due to the important biological impact of Ag+ on cellular functions. Here, we put forward a new approach to realize the in situ fluorescence imaging and detection of Ag+ in single cells via an ultrasensitive Ag+-responsive probe, 3',6'-bis (diethylamino)-2-(2-iodoethyl) spiro[isoindoline-1,9'-xanthen]-3-one (BDISIX). In the presence of Ag+, the fluorescence of the probe can be turned 'on', generating strong red fluorescence. Using breast cancer cells (MCF-7) as the example, we successfully realize the imaging of intracellular Ag+ through one step incubation of the probe, which is especially convenient and fast for the in situ intact detection of Ag+ in living cells. PMID- 28726674 TI - Graphene gas sensing using a non-contact microwave method. AB - We report a non-contact CVD graphene gas sensing method that utilises a high Q microwave dielectric resonator perturbation technique. A graphene sample is coupled to the evanescent field of a dielectric resonator whereupon nitrogen dioxide (NO2), a p-doping gas, is detected by monitoring the change in the linewidth and frequency of the resonant mode. The resonant peak shape is dependent on the number of carriers in the graphene sheet. Therefore, the linewidth perturbation can be converted to a measurement of the graphene sheet resistance. To demonstrate the strength of this technique, sensor response curves for NO2 at different concentrations and temperatures are measured showing sub ppm sensitivity. This technique eliminates interactions between the trace gas and metal contacts that otherwise effect the sensor response of the graphene device. PMID- 28726675 TI - Sensitivity of magnetic properties to chemical pressure in lanthanide garnets Ln 3 A 2 X 3O12, Ln = Gd, Tb, Dy, Ho, A = Ga, Sc, In, Te, X = Ga, Al, Li. AB - A systematic study of the structural and magnetic properties of three dimensionally frustrated lanthanide garnets Ln 3 A 2 X 3O12, Ln = Gd, Tb, Dy, Ho, A = Ga, Sc, In, Te, X = Ga, Al, Li is presented. Garnets with Ln = Gd show magnetic behaviour consistent with isotropic Gd3+ spins; no magnetic ordering is observed for T ? 0.4 K. Magnetic ordering features are seen for garnets with Ln = Tb, Dy, Ho in the temperature range 0.4 < T < 2.5 K, however the nature of the magnetic ordering varies for the different Ln as well as for different combinations of A and X. The magnetic behaviour can be explained by tuning of the magnetic interactions and changes in the single-ion anisotropy. The change in magnetic entropy is evaluated from isothermal magnetisation measurements to characterise the magnetocaloric effect in these materials. Among the Gd garnets, the maximum change in magnetic entropy per mole (15.45 J K-1 [Formula: see text]) is observed for Gd3Sc2Ga3O12 at 2 K, in a field of 9 T. The performance of Dy3Ga5O12 as a magnetocaloric material surpasses the other garnets with Ln = Tb, Dy, Ho. PMID- 28726676 TI - A biokinetic and dosimetric model for ionic indium in humans. AB - This paper reviews biokinetic data for ionic indium, and proposes a biokinetic model for systemic indium in adult humans. The development of parameter values focuses on human data and indium in the form of ionic indium(III), as indium chloride and indium arsenide. The model presented for systemic indium is defined by five different pools: plasma, bone marrow, liver, kidneys and other soft tissues. The model is based on two subsystems: one corresponding to indium bound to transferrin and one where indium is transported back to the plasma, binds to red blood cell transferrin and is then excreted through the kidneys to the urinary bladder. Absorbed doses to several organs and the effective dose are calculated for 111In- and 113mIn-ions. The proposed biokinetic model is compared with previously published biokinetic indium models published by the ICRP. The absorbed doses are calculated using the ICRP/ICRU adult reference phantoms and the effective dose is estimated according to ICRP Publication 103. The effective doses for 111In and 113mIn are 0.25 mSv MBq-1 and 0.013 mSv MBq-1 respectively. The updated biokinetic and dosimetric models presented in this paper take into account human data and new animal data, which represent more detailed and presumably more accurate dosimetric data than that underlying previous models for indium. PMID- 28726677 TI - Branched poly(ethyleneimine): a versatile scaffold for patterning polymer brushes by means of remote photocatalytic lithography. AB - Patterning of functional surfaces is one of the cornerstones of nanotechnology as it allows the fabrication of sensors and lab-on-a-chip devices. Here, the patterning of self-assembled monolayers of branched poly(ethyleneimine) (bPEI) on silica was achieved by means of remote photocatalytic lithography. Moreover, when 2-bromoisobutyryl-modified bPEI was used, the resulting pattern could be amplified by grafting polymer brushes by means of surface-initiated atom transfer radical polymerization. In contrast to previous reports for the patterning of bPEI, the present approach can be conducted in minutes instead of hours, reducing the exposure time to UV radiation and enhancing the overall efficiency. Furthermore, our approach is much more user-friendly, allowing a facile fabrication of patterned initiator-modified surfaces and the use of inexpensive instrumentation such as a low-power UV source and a simple photomask. Considering the versatility of bPEI as a scaffold for the development of biosensors, patterning by means of remote photocatalytic lithography will open new opportunities in a broad field of applications. PMID- 28726678 TI - Collateral contamination concomitant to the polonium-210 poisoning of Mr Alexander Litvinenko. AB - Mr Litvinenko died on 23 November 2006, having been poisoned with polonium-210 on 1 November, with evidence of a previous poisoning attempt during October 2006. Measurements of 210Po in urine samples were made for a large number of people to determine whether they may have been contaminated. In the majority of cases, measured levels were attributable to the presence of 210Po from normal dietary sources. For a small number of cases, elevated levels provided evidence of direct contamination associated with the poisonings. For one individual, while estimated doses were below thresholds for irreversible organ damage, a notably increased risk of cancer can be inferred. The use of the chelating agent, unithiol, to increase 210Po excretion in this case was only moderately effective in reducing doses received. PMID- 28726679 TI - Accuracy of Rhenium-188 SPECT/CT activity quantification for applications in radionuclide therapy using clinical reconstruction methods. AB - The main applications of 188Re in radionuclide therapies include trans-arterial liver radioembolization and palliation of painful bone-metastases. In order to optimize 188Re therapies, the accurate determination of radiation dose delivered to tumors and organs at risk is required. Single photon emission computed tomography (SPECT) can be used to perform such dosimetry calculations. However, the accuracy of dosimetry estimates strongly depends on the accuracy of activity quantification in 188Re images. In this study, we performed a series of phantom experiments aiming to investigate the accuracy of activity quantification for 188Re SPECT using high-energy and medium-energy collimators. Objects of different shapes and sizes were scanned in Air, non-radioactive water (Cold-water) and water with activity (Hot-water). The ordered subset expectation maximization algorithm with clinically available corrections (CT-based attenuation, triple energy window (TEW) scatter and resolution recovery was used). For high activities, the dead-time corrections were applied. The accuracy of activity quantification was evaluated using the ratio of the reconstructed activity in each object to this object's true activity. Each object's activity was determined with three segmentation methods: a 1% fixed threshold (for cold background), a 40% fixed threshold and a CT-based segmentation. Additionally, the activity recovered in the entire phantom, as well as the average activity concentration of the phantom background were compared to their true values. Finally, Monte-Carlo simulations of a commercial [Formula: see text]-camera were performed to investigate the accuracy of the TEW method. Good quantification accuracy (errors <10%) was achieved for the entire phantom, the hot-background activity concentration and for objects in cold background segmented with a 1% threshold. However, the accuracy of activity quantification for objects segmented with 40% threshold or CT-based methods decreased (errors >15%), mostly due to partial volume effects. The Monte-Carlo simulations confirmed that TEW-scatter correction applied to 188Re, although practical, yields only approximate estimates of the true scatter. PMID- 28726680 TI - Towards 4D printed scaffolds for tissue engineering: exploiting 3D shape memory polymers to deliver time-controlled stimulus on cultured cells. AB - Tissue engineering needs innovative solutions to better fit the requirements of a minimally invasive approach, providing at the same time instructive cues to cells. The use of shape memory polyurethane has been investigated by producing 4D scaffolds via additive manufacturing technology. Scaffolds with two different pore network configurations (0/90 degrees and 0/45 degrees ) were characterized by dynamic-mechanical analysis. The thermo-mechanical analysis showed a Tg at about 32 degrees C (Tg = T trans), indicating no influence of the fabrication process on the transition temperature. In addition, shape recovery tests showed a good recovery of the permanent shape for both scaffold configurations. When cells were seeded onto the scaffolds in the temporary shape and the permanent shape was recovered, cells were significantly more elongated after shape recovery. Thus, the mechanical stimulus imparted by shape recovery is able to influence the shape of cells and nuclei. The obtained results indicate that a single mechanical stimulus is sufficient to initiate changes in the morphology of adherent cells. PMID- 28726681 TI - A novel cylindrical microwell featuring inverted-pyramidal opening for efficient cell spheroid formation without cell loss. AB - Spheroid cultures have been often used to simulate and understand in situ biological occurrences with potential to be further applied to therapeutic approaches, such as cell transplantation. However, traditional lab-scale techniques hardly reached the needed large scale production of cell spheroids, thus limiting their versatility in many biomedical fields. Microscale technologies have rapidly improved in the last decade, and contributed to the large scale production of cell spheroids with high controllability and reproducibility. Nonetheless, the existing microwell culture platforms are problematic due to unwanted cellular adhesion to the substrate as well as due to substantial amounts of cell loss. In this study, we have developed a novel configuration of cylindrical type polyethylene glycol (PEG) hydrogel microwells featuring inverted-pyramidal openings (iPO). Highly refined microstructures of our novel microwell could be fabricated by our optimized micro-electro mechanical system protocols consisting of a silicon (Si) wet/dry etching, Si-to polydimethylsiloxane substrate bonding, and the established soft-lithography techniques. The iPO, the PEG hydrogel, and the cylindrical geometry of our microwell successfully (1) avoided inefficient washing steps after cell seeding, (2) achieved the complete resistance to cellular adhesion on the microwell substrate, and (3) made all seeded cells readily gathered and jam-packed to form cell spheroids with uniform size, respectively. The maximal sizes of cell spheroids were confined to below 200 MUm according to the size of microwells used in this study. The efficiency testing for cell spheroid formation was conducted in comparison with other types of microwells that have been often used in the fields. The results showed that our novel microwell platform effectively reached almost zero percent of cell loss while mass-producing human mesenchymal stem cell spheroids with highly precise control over spheroid's size and cell number. We believe that this study could deliver an effective method to extend the practical usability of cell spheroids in a variety of biomedical applications. PMID- 28726682 TI - Broadband non-contact characterization of epitaxial graphene by near-field microwave microscopy. AB - In this paper, a broadband non-destructive and non-contact local characterization of graphene fabricated by epitaxial method on silicon carbide is demonstrated by using an interferometer-based near-field microwave microscope. First, a method has been proposed to extract the dielectric properties of silicon carbide, and finally, the graphene flake has been characterized as a resistance (~20 kOmega) and a small inductance (360 pH) in the frequency band (2-18 GHz). The advantage of the proposed method is that there is no need to fabricate electrodes on the sample surface for the characterization. The instrument proposed is a good candidate for the local characterization of 2D materials. PMID- 28726683 TI - Canonical-ensemble extended Lagrangian Born-Oppenheimer molecular dynamics for the linear scaling density functional theory. AB - We discuss the development and implementation of a constant temperature (NVT) molecular dynamics scheme that combines the Nose-Hoover chain thermostat with the extended Lagrangian Born-Oppenheimer molecular dynamics (BOMD) scheme, using a linear scaling density functional theory (DFT) approach. An integration scheme for this canonical-ensemble extended Lagrangian BOMD is developed and discussed in the context of the Liouville operator formulation. Linear scaling DFT canonical-ensemble extended Lagrangian BOMD simulations are tested on bulk silicon and silicon carbide systems to evaluate our integration scheme. The results show that the conserved quantity remains stable with no systematic drift even in the presence of the thermostat. PMID- 28726684 TI - Low-dose 4D cone-beam CT via joint spatiotemporal regularization of tensor framelet and nonlocal total variation. AB - Excessive radiation exposure is still a major concern in 4D cone-beam computed tomography (4D-CBCT) due to its prolonged scanning duration. Radiation dose can be effectively reduced by either under-sampling the x-ray projections or reducing the x-ray flux. However, 4D-CBCT reconstruction under such low-dose protocols is prone to image artifacts and noise. In this work, we propose a novel joint regularization-based iterative reconstruction method for low-dose 4D-CBCT. To tackle the under-sampling problem, we employ spatiotemporal tensor framelet (STF) regularization to take advantage of the spatiotemporal coherence of the patient anatomy in 4D images. To simultaneously suppress the image noise caused by photon starvation, we also incorporate spatiotemporal nonlocal total variation (SNTV) regularization to make use of the nonlocal self-recursiveness of anatomical structures in the spatial and temporal domains. Under the joint STF-SNTV regularization, the proposed iterative reconstruction approach is evaluated first using two digital phantoms and then using physical experiment data in the low dose context of both under-sampled and noisy projections. Compared with existing approaches via either STF or SNTV regularization alone, the presented hybrid approach achieves improved image quality, and is particularly effective for the reconstruction of low-dose 4D-CBCT data that are not only sparse but noisy. PMID- 28726685 TI - Enhanced thermoelectric performance of Bi2Te3 through uniform dispersion of single wall carbon nanotubes. AB - The advancement in nanostructured powder processing has attracted great interest as a cost effective and scalable strategy for high performance thermoelectric bulk materials. However, the level of technical breakthrough realized in quantum dot supperlattices/wires has not yet been demonstrated in these materials. Here, we report the first ever study on the uniform dispersion of single wall carbon nanotubes (SWCNTs) in nanostructured Bi2Te3 bulk, and their effect on thermoelectric parameters above room temperature. The Bi2Te3 based SWCNT composites were prepared through controlled powder processing, and their thermoelectric properties were finely tuned at the nanoscale by regulating various (0.5, 0.75, 1.0 and 1.5) vol% of SWCNTs in the matrix. The flexible ropes of SWCNT, making an interconnected network through the inter/trans granular positions of Bi2Te3, thus substantially change the transport properties of the composites. The perfect one-dimensional (1D) conducting structure of SWCNTs acts as a source of electrical transport through a percolating network, with significantly suppressed lattice thermal conductivity, via intensified boundary scattering. The remarkable increase in power factor is ascribed to energy filtering effects and excellent electrical transport of 1D SWCNTs in the composites. Consequently, with a considerable reduction in thermal conductivity, the figure of merit culminates in a several-fold improvement, at 0.5 vol% of SWCNTs, over pristine bulk Bi2Te3. PMID- 28726686 TI - Dual mode operation, highly selective nanohole array-based plasmonic colour filters. AB - Taking advantage of nanostructured metal films as plasmonic colour filters (PCFs) has been evolved remarkably as an alternative to the conventional technologies of chemical colour filtering. However, most of the proposed PCFs depict a poor colour purity focusing on generating either the additive or subtractive colours. In this paper, we present dual mode operation PCFs employing an opaque aluminium film patterned with sub-wavelength holes. Subtractive colours like cyan, magenta, and yellow are the results of reflection mode of these filters yielding optical efficiencies as high as 70%-80% and full width at half maximum of the stop-bands up to 40-50 nm. The colour selectivity of the transmission mode for the additive colours is also significant due to their enhanced performance through the utilization of a relatively thick aluminium film in contact with a modified dielectric environment. These filters provide a simple design with one-step lithography in addition to compatibility with the conventional CMOS processes. Moreover, they are polarization insensitive due to their symmetric geometry. A complete palette of pure subtractive and additive colours has been realized with potential applications, such as multispectral imaging, CMOS image sensors, displays, and colour printing. PMID- 28726687 TI - A new sparse optimization scheme for simultaneous beam angle and fluence map optimization in radiotherapy planning. AB - [Formula: see text]-minimization-based sparse optimization was employed to solve the beam angle optimization (BAO) in intensity-modulated radiation therapy (IMRT) planning. The technique approximates the exact BAO formulation with efficiently computable convex surrogates, leading to plans that are inferior to those attainable with recently proposed gradient-based greedy schemes. In this paper, we alleviate/reduce the nontrivial inconsistencies between the [Formula: see text]-based formulations and the exact BAO model by proposing a new sparse optimization framework based on the most recent developments in group variable selection. We propose the incorporation of the group-folded concave penalty (gFCP) as a substitution to the [Formula: see text]-minimization framework. The new formulation is then solved by a variation of an existing gradient method. The performance of the proposed scheme is evaluated by both plan quality and the computational efficiency using three IMRT cases: a coplanar prostate case, a coplanar head-and-neck case, and a noncoplanar liver case. Involved in the evaluation are two alternative schemes: the [Formula: see text]-minimization approach and the gradient norm method (GNM). The gFCP-based scheme outperforms both counterpart approaches. In particular, gFCP generates better plans than those obtained using the [Formula: see text]-minimization for all three cases with a comparable computation time. As compared to the GNM, the gFCP improves both the plan quality and computational efficiency. The proposed gFCP-based scheme provides a promising framework for BAO and promises to improve both planning time and plan quality. PMID- 28726688 TI - Energy efficient and fast reversal of a fixed skyrmion two-terminal memory with spin current assisted by voltage controlled magnetic anisotropy. AB - Recent work (P-H Jang et al 2015 Appl. Phys. Lett. 107 202401, J. Sampaio et al 2016 Appl. Phys. Lett. 108 112403) suggests that ferromagnetic reversal with spin transfer torque (STT) requires more current in a system in the presence of Dzyaloshinskii-Moriya interaction (DMI) than switching a typical ferromagnet of the same dimensions and perpendicular magnetic anisotropy (PMA). However, DMI promotes the stabilization of skyrmions and we report that when perpendicular anisotropy is modulated (reduced) for both the skyrmion and ferromagnet, it takes a much smaller current to reverse the fixed skyrmion than to reverse the ferromagnet in the same amount of time, or the skyrmion reverses much faster than the ferromagnet at similar levels of current. We show with rigorous micromagnetic simulations that skyrmion switching proceeds along a different path at very low PMA, which results in a significant reduction in the spin current or time required for reversal. This can offer potential for memory applications where a relatively simple modification of the standard STT-RAM (to include a heavy metal adjacent to the soft magnetic layer and with appropriate design of the tunnel barrier) can lead to an energy efficient and fast magnetic memory device based on the reversal of fixed skyrmions. PMID- 28726689 TI - WSe2/MoS2 and MoTe2/SnSe2 van der Waals heterostructure transistors with different band alignment. AB - Heterostructure field-effect transistors (hetero-FETs) are experimentally demonstrated, consisting of van der Waals heterostructure channels based on a 2D semiconductor. By optimally selecting the band alignment of the heterostructure channels, different output characteristics of the hetero-FETs were achieved. In atomically thin WSe2/MoS2 hetero-FET with staggered energy band, the oscillating transfer characteristic and negative transconductance were realized. With near broken-gap alignment in the MoTe2/SnSe2 heterostructure channel, a superior reverse-biased current was obtained in the hetero-FETs, which can be analyzed as typical tunneling current. Our study on the hetero-FET-based atomically thin van der Waals heterostructure channel, provides significant inspiration and reference to novel heterostructure FETs. PMID- 28726690 TI - Tuning the morphologies of fluorine-doped tin oxides in the three-dimensional architecture of graphene for high-performance lithium-ion batteries. AB - The morphology of electrode materials plays an important role in determining the performance of lithium-ion batteries (LIBs). However, studies on determining the most favorable morphology for high-performance LIBs have rarely been reported. In this study, a series of F-doped SnO x (F-SnO2 and F-SnO) materials with various morphologies was synthesized using ethylenediamine as a structure-directing agent in a facile hydrothermal process. During the hydrothermal process, the F-SnO x was embedded in situ into the three-dimensional (3D) architecture of reduced graphene oxide (RGO) to form F-SnO x @RGO composites. The morphologies and nanostructures of F-SnO x , i.e., F-SnO2 nanocrystals, F-SnO nanosheets, and F SnO2 aggregated particles, were fully characterized using electron microscopy, x ray diffraction, and x-ray photoelectron spectroscopy. Electrochemical characterization indicated that the F-SnO2 nanocrystals uniformly distributed in the 3D RGO architecture exhibited higher specific capacity, better rate performance, and longer cycling stability than the F-SnO x with other morphologies. These excellent electrochemical performances were attributed to the uniform distribution of the F-SnO2 nanocrystals, which significantly alleviated the volume changes of the electrode material and shortened the Li ion diffusion path during lithiation/delithiation processes. The F-SnO2@RGO composite composed of uniformly distributed F-SnO2 nanocrystals also exhibited excellent rate performance, as the specific capacities were measured to be 1158 and 648 mA h g-1 at current densities of 0.1 and 5 A g-1, respectively. PMID- 28726691 TI - An exploratory study of the effects of stormwater pipeline materials on transported stormwater quality. AB - Implications of three sewer pipe materials (concrete, galvanized corrugated steel, and polyvinyl chloride (PVC)) for stormwater quality were explored in laboratory experiments, in which three types of stormwater, SW1-SW3, were circulated in 0.5 m long sewer pipe sections. SW1 and SW2 represented synthetic rainwater, without and with fine street sediment added (CTSS = 150 mg/L), respectively, and SW3 was actual stormwater with the same sediment addition as SW2. Following 20-min runs, with an equivalent distance of 500 m travelled by water particles, a number of statistically significant changes in the stormwater chemistry were observed: (i) pH of all the simulated stormwaters increased in the concrete pipe (from 7.0-7.3 to 8.1-9.3), (ii) turbidity decreased in two stormwaters with sediments (SW2 and SW3) in concrete and galvanized corrugated steel pipes (by 50 and 85%, respectively), (iii) the type of stormwater affected the observed copper (Cu) concentrations, with Cudiss concentrations as high as 25.3 MUg/L noted in SW3 passing through the PVC pipe, and (iv) zinc (Zn) concentrations sharply increased (Zntot = 759-1,406 MUg/L, Zndiss = 670-1,400 MUg/L) due to Zn elution from the galvanized steel pipe by all three stormwaters. Such levels exceeded the applicable environmental guidelines. PMID- 28726692 TI - Chemical speciation of trace metals in the industrial sludge of Dhaka City, Bangladesh. AB - The objective of this study was to assess total concentration and chemical fractionation of trace metals in the industrial wastewater and sludge collected from seven different types of industries in Dhaka City, Bangladesh. The sludge from industries is either dumped on landfills or reused as secondary resources in order to preserve natural resources. Metals were analyzed using inductively coupled plasma mass spectrometry (ICP-MS). The ranges of Cr, Ni, Cu, As, Cd, and Pb in the sludges were 1.4-9,470, 4.8-994, 12.8-444, 2.2-224, 1.9-46.0 and 1.3 87.0 mg/kg, respectively. As a whole, the average concentrations of trace metals in samples were in the decreasing order of Cr > Ni > Cu > As > Pb > Cd. The results of the Community Bureau of Reference (BCR) sequential extraction showed that the studied metals were predominantly associated with the residual fraction followed by the oxidizable fraction. The study revealed that the mobile fractions of trace metals are poorly predictable from the total content, and bioavailability of all fractions of elements tends to decrease. PMID- 28726693 TI - Nitrogen removal in a shallow maturation pond with sludge accumulated during 10 years of operation in Brazil. AB - Accumulated sludge in polishing (maturation) ponds reduces the hydraulic retention time (smaller useful volume), and this could potentially lead to a decrease in performance. However, settled biomass, present in the sediments, can contribute to nitrogen removal by different mechanisms such as nitrification and denitrification. This study investigated the influence of the bottom sludge present in a shallow maturation pond treating the effluent from an anaerobic reactor on the nitrification and denitrification processes. Nitrification and denitrification rates were determined in sediment cores by applying ammonia pulses. Environmental conditions in the medium were measured and bacteria detected and quantified by real-time polymerase chain reaction (real-time PCR). The pond showed daily cycles of mixing and stratification and most of the bacteria involved in nitrogen removal decreased in concentration from the upper to the lower part of the sludge layer. The results indicate that denitrifiers, nitrifiers and anammox bacteria coexisted in the sludge, and thus different metabolic pathways were involved in ammonium removal in the system. Therefore, the sediment contributed to nitrogen removal, even with a decrease in the hydraulic retention time in the pond due to the volume occupied by the sludge. PMID- 28726694 TI - Characteristic numbers of granular activated carbon for the elimination of micropollutants from effluents of municipal wastewater treatment plants. AB - Adsorption on granular activated carbon (GAC) is a promising step to extend existing treatment trains in municipal wastewater treatment plants (WWTPs) and, thus, to reduce the concentration of micropollutants (MPs) (e.g. pharmaceuticals) in wastewater. It is common practice to use characteristic numbers when choosing GAC for a specific application. In this study, characteristic numbers were correlated for five different GACs, with measured adsorption capacities of these carbons for three pharmaceutical MPs (carbamazepine, diclofenac and sulfamethoxazole) and dissolved organic carbon of a WWTP effluent. The adsorption capacities were measured using rapid small scale column tests. Density of GAC showed the highest correlation to adsorption of MP. All other characteristic numbers (iodine number, Brunauer-Emmett-Teller (BET) surface and methylene blue titre) are not suitable markers for choosing an appropriate activated carbon product for the elimination of MPs from municipal wastewater. PMID- 28726695 TI - A combined reed bed/freezing bed technology for septage treatment and reuse in cold climate regions. AB - A combined reed bed-freezing bed (RB-FB) technology was effective at treating septage under Canadian climatic conditions over a 5-year period with average loading rates of 82-104 kg TS/m2/y. Varying hydraulic and solid loading rates as well as the increasing sludge cake with time had little to no effect on treatment efficiency, with almost complete removal of organic matter, solids, heavy metals and nutrients. Filtrate concentrations varied significantly between the freeze thaw and growing seasons for many parameters, although the differences were not important from a treatment or reuse perspective with filtrate quality similar to a low to medium strength domestic wastewater. The potential to reuse the filtrate as a source of irrigation water will depend upon local regulations. The dewatered sludge cake consistently met biosolids land application standards in terms of pathogen and metals content, with Escherichia coli numbers declining with time as sludge cake depth increased. A combined RB-FB technology can provide a cost effective solution for septage management in northern rural communities with potential for beneficial reuse of both the filtrate and dewatered sludge cake. PMID- 28726696 TI - A novel freeze protection strategy for shallow buried sewer pipes: temperature modelling and field investigation. AB - The burial of sewer and water pipes below the maximum ground frost depth can be very costly and laborious in regions with cold winters. If a freeze protection measure is applied, the utility lines can be installed in a shallower trench to reduce the excavation needs. One freeze protection measure, so called heat tracing, consists of supplying heat along the pipes. In this work, the use of 4th generation district heating as a heat tracing solution was investigated at a pilot site in Kiruna, Sweden. The influence of the system on sewer and water pipe temperatures was studied at a snow-free and snow-covered cross section. To this end, five heat tracing temperatures were tested and the corresponding sewer and water pipe temperatures were measured. The field experiment was also simulated with a two dimensional finite volume model. The study showed that, under the climatic conditions of the experiment, a heat tracing temperature of 25 degrees C allowed prevention of freezing of the pipes while keeping drinking water pipes in a safe temperature range at both cross sections. The other main result was that the developed finite volume model of the sections showed a good fitting to the experimental data. PMID- 28726697 TI - Removing lead ions from aqueous solutions by the thiosemicarbazide grafted multi walled carbon nanotubes. AB - A novel multi-walled carbon nanotubes (MWCNTs) material functionalized with thiosemicarbazide was synthesized successfully and used to remove lead ions from aqueous solutions. The technologies of Fourier Transform Infrared Spectroscopy, scanning electron microscopy and thermal gravimetric analysis were used to characterize the structure and properties of thiosemicarbazide grafted MWCNTs. The adsorption conditions, such as pH, contact time and temperature, were investigated. The results showed pH affected the adsorption process greatly, and the adsorption process reached equilibrium within 60 min. The maximum adsorption capacity was 42.01 mg/g. The adsorption process fitted well with the pseudo second-order kinetic model and the Langmuir model. The thermodynamic parameters indicated the adsorption process was endothermic and spontaneous in nature. PMID- 28726698 TI - Experimental study and artificial neural network modeling of tartrazine removal by photocatalytic process under solar light. AB - This research focuses on the application of an artificial neural network (ANN) to predict the removal efficiency of tartrazine from simulated wastewater using a photocatalytic process under solar illumination. A program is developed in Matlab software to optimize the neural network architecture and select the suitable combination of training algorithm, activation function and hidden neurons number. The experimental results of a batch reactor operated under different conditions of pH, TiO2 concentration, initial organic pollutant concentration and solar radiation intensity are used to train, validate and test the networks. While negligible mineralization is demonstrated, the experimental results show that under sunlight irradiation, 85% of tartrazine is removed after 300 min using only 0.3 g/L of TiO2 powder. Therefore, irradiation time is prolonged and almost 66% of total organic carbon is reduced after 15 hours. ANN 5-8-1 with Bayesian regulation back-propagation algorithm and hyperbolic tangent sigmoid transfer function is found to be able to predict the response with high accuracy. In addition, the connection weights approach is used to assess the importance contribution of each input variable on the ANN model response. Among the five experimental parameters, the irradiation time has the greatest effect on the removal efficiency of tartrazine. PMID- 28726699 TI - Detoxification of photo-catalytically treated 2-chlorophenol: optimization through response surface methodology. AB - The present study was conducted to degrade and detoxify 2-chlorophenol (2-CP) under UV irradiation in the presence of titanium dioxide (TiO2) and hydrogen peroxide (H2O2). The treatment efficiency was evaluated on the basis of degradation and cytotoxicity reduction as well as biochemical oxygen demand (BOD), chemical oxygen demand (COD) and total organic carbon (TOC) removal. The process variables such as TiO2, pH, UV irradiation time and H2O2 were optimized. Central composite design in combination with response surface methodology was employed to optimize the process variables. A quadratic model was proposed to predict the treatment efficiency and analysis of variance was used to determine the significance of the variables. The correlation between the experimental and predicted degradation was confirmed by the F and P values (<0.05). The coefficient of determination (R2 = 0.99) were high enough to support the validity of developed model. At optimized conditions, up to 92% degradation of 2-CP was achieved with 3.5 * 10-4 s-1 rate constant. Significant reductions in BOD, COD and TOC values were also achieved. Cytotoxicity was evaluated using bioassays and it was observed that UV/TiO2/H2O2 reduced the cytotoxicity considerably. It is concluded that UV/TiO2/H2O2 could possibly be used to detoxify 2-CP in industrial wastewater. PMID- 28726700 TI - Adsorption studies of Orange II onto polyaniline/bentonite nanocomposite. AB - Modification of bentonite is essential for the adsorption of anionic dyes, as its negative surface charge. In this study, polyaniline/bentonite (PAni-Bent) nanocomposite was synthesized by in-situ intercalative polymerization technique and used to remove anionic dye Orange II (ORII) from synthetic wastewater. Its structure was confirmed by X-ray diffraction (XRD), scanning electron microscopy, Fourier-transform infrared spectra and Brunauer-Emmett-Teller specific surface area measurements. The adsorption behaviours of PAni-Bent towards ORII in the single anionic dye wastewater, the cationic/anionic mixture dye wastewater, with or without salt or surfactant, were investigated principally. The results show that cetyl trimethyl ammonium bromide have an obviously suppressing effect on dye removal in the MB/ORII mixture system. The Langmuir and Temkin isotherm models described the adsorption process better than Freundlich or Dubinin-Radushkevich (D-R) model, and the pseudo-second-order and Boyd kinetic models fit better with the experimental data. Considering all these unique characteristics, PAni-Bent can be considered as effective adsorbent material for potential removal of dye from aqueous solution in industry. PMID- 28726701 TI - Sewage sludge and waterworks sludge stabilization in sludge treatment reed bed systems. AB - In this study, results about sludge stabilization in sludge treatment reed bed (STRB) systems in two different systems, Hanningfield STRB 1 (England), treating waterworks sludge, and Stenlille STRB 2 (Denmark), treating surplus activated sludge, are presented. The study mainly focused on the effectiveness of the STRBs systems in stabilizing sludge organic matter; in fact, parameters correlated to biochemical and chemico-structural properties of organic sludge matter were determined. Dewatering and sludge stabilization were effective in both STRBs, as highlighted by total and volatile dry solids trend. beta-glucosidase, phosphatase, arylsulphatase, leucine amino-peptidase and butyrate esterase activities, enzymes related to C, P, S, N and overall microbial activity, respectively, significantly declined along the profile in both STRBs. The determination of humic carbon highlighted the formation of a stable nucleus of humified organic matter in both STRBs in the deepest layers, thus meaning the successful stabilization of sludge organic matter for both kind of sludges. Similar conclusions can be drawn from pyrolysis gas chromatography analysis (Py GC), which enables the characterization of soil organic matter quality from a chemical-structural point of view. The pyrolytic indices of mineralization and humification showed that in both STRBs the sludge organic matter is well stabilized. PMID- 28726702 TI - Photodegradation of the benzothiostrobin in solution and on soil and glass surface. AB - The photolytic characteristics of benzothiostrobin were investigated in solution and on soil and glass surface. The main influence factors such as initial concentration, organic solvent and the aqueous environmental substances, including NO2-, NO3-, Fe2+, Fe3+, H2O2 and turbidity were investigated. Three photodegradation products of benzothiostrobin were identified by ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The photodegradation rates of benzothiostrobin increased with decreasing initial concentration of benzothiostrobin. The degradation rates of benzothiostrobin in different organic solvent showed the following order: n-hexane > methanol > acetonitrile > acetone. The photodegradation of benzothiostrobin was promoted by Fe3+, NO2- and H2O2, and were inhibited by Fe2+ and turbidity. The presence of NO3- had no effect on photodegradation. Benzothiostrobin was photodegraded at a slower rate on soil surface and glass surface compared to its photolysis in aqueous solution. The presumed photodegradation pathway was proposed to be the cleavage of the thioether bond in benzothiostrobin. PMID- 28726703 TI - High-performance magnetic chicken bone-based biochar for efficient removal of rhodamine-B dye and tetracycline: competitive sorption analysis. AB - Magnetic chicken bone-based biochar (MCBB) was successfully prepared and efficiently adsorbed rhodamine-B (RB) dye and tetracycline (TC) in multi component systems. The magnetisation value, surface area, and pHpzc of the MCBB were found to be 66.5 emu/g, 328 m2/g, and 8.3, respectively. RB has higher saturation capacity (96.5 mg/g) and occupies more active sites on MCBB, thus limiting the sorption of TC with lower saturation capacity (63.3 mg/g). Langmuir isotherm suitably describes the sorption process in a single-component system; however, the multi-component system was well fitted to the Sheindorf-Rebhun Sheintuch model. The selectivity factor values confirmed that MCBB had higher adsorption affinity toward RB than TC. The intraparticle diffusion model played a significant role in the sorption process. The MCBB can be easily desorbed with base-spiked H2O and reused without loss in stability or structural integrity. PMID- 28726704 TI - Simultaneous heterotrophic nitrification and aerobic denitrification at high concentrations of NaCl and ammonia nitrogen by Halomonas bacteria. AB - To improve the efficiency of simultaneous heterotrophic nitrification and aerobic denitrification (SND) at high concentrations of NaCl and ammonia nitrogen (NH4+ N), we investigated the SND characteristics of Halomonas bacteria with the ability to synthesize the compatible solute ectoine. Halomonas sp. strain B01, which was isolated, screened and identified in this study, could simultaneously remove nitrogen (N) by SND and synthesize ectoine under high NaCl conditions. Gene cloning and sequencing analysis indicated that this bacterial genome contains ammonia monooxygenase (amoA) and nitrate reductase (narH) genes. Optimal conditions for N removal in a solution containing 600 mg/L NH4+-N were as follows: sodium succinate supplied as organic carbon (C) source at a C/N ratio of 5, pH 8 and shaking culture at 90 rpm. The N removal rate was 96.0% under these conditions. The SND by Halomonas sp. strain B01 was performed in N removal medium containing 60 g/L NaCl and 4,000 mg/L NH4+-N; after 180 h the residual total inorganic N concentration was 21.7 mg/L and the N removal rate was 99.2%. Halomonas sp. strain B01, with the ability to synthesize the compatible solute ectoine, could simultaneously tolerate high concentrations of NaCl and NH4+-N and efficiently perform N removal by SND. PMID- 28726705 TI - Spatiotemporal distribution of nitrogen and phosphorus in alpine lakes in the Sanjiangyuan Region of the Tibetan Plateau. AB - To provide a theoretical basis for alpine source lake protection, ten samples were taken from each lake annually from 2012 to 2015. Each year, the various species of nitrogen and phosphorus nutrients were measured. The average contents of nitrate nitrogen, ammonia nitrogen, nitrite nitrogen, total phosphorus, and total nitrogen in the four lakes are 0.195-0.0 mg/L, 0.038-0.143 mg/L, 0.004 0.168 mg/L, 0.006-0.740 mg/L, and 0.050-0.547 mg/L, respectively. The total phosphorus contents in Eling Lake, Longbao Lake and Sea Star were higher than Class I water quality standards, and the total nitrogen contents in Eling Lake, Sea Star and Zhaling Lake were higher than Class I water quality standards as well. The concentration contour maps of the nitrate nitrogen, ammonia nitrogen, nitrite nitrogen, total phosphorus and total nitrogen showed that the indicators of the four lakes in the east, the west, and the center of the lake did not have the same trend. From 2012 to 2015, each of the measured nutrients showed a rising trend year by year. The four lakes are polluted by both endogenous and exogenous pollution, and it is necessary to limit the exogenous pollution and protect the alpine lakes immediately. PMID- 28726706 TI - Cost assessment of different routes for phosphorus recovery from wastewater using data from pilot and production plants. AB - Phosphorus (P) recovery from wastewater has considerable potential to supplement limited fossil P reserves. Reliable cost data are essential for investor and policymaker decisions. In this study, investment and operational costs for nine P recovery processes were calculated from the investor's perspective, taking into account all relevant side effects on the sludge treatment or the wastewater treatment plant. The assessment was based on pilot and full-scale data which were thoroughly consolidated and standardized with technical and cost data from the German wastewater-sludge treatment train to enable direct comparison. The cost influence of precipitation processes on the current wastewater-sludge treatment train ranges from -0.14 (generating profit) to 0.23 EUR per population equivalent (PE) and year, while the cost influence of sludge leaching processes is around 2.50 EUR/(PE y). The cost influence of processes using dry sludge and mono incineration ash varies between 0.33 and 3.13 EUR/(PE y), depending on existing disposal pathways, mono-incineration, co-incineration or agricultural use of sludge. The specific costs per kg P recovered (-4 to 10 EUR/kg P) are in general higher than conventional fertilizer production (1.6 EUR/kg P). However, annual costs per PE represent less than 3% of the total costs for wastewater disposal. PMID- 28726707 TI - Three dimensional Eulerian-Eulerian simulation on hydrodynamics in dissolved air flotation tank with different turbulence models. AB - The Eulerian-Eulerian approach is used to simulate the two phase flow of air and water in a dissolved air flotation (DAF) tank. Unsteady simulation is adopted to obtain the quasi-steady result. The two dimensional model cannot capture the three dimensional feature of flow pattern in the tank. The three dimensional model reproduces the stratification structure observed in the experiment and obtains the satisfactory volume fraction of air bubbles in the separation zone. To account for the turbulence effect, four two-equation turbulence models are evaluated. Although all turbulence models capture the stratification structure in the separation zone, the re-normalization group theory (RNG) k-E model obtains the best agreement with the experimental data. The effect of bubble diameter on the performance of DAF tank is simulated. Small air bubbles can form a big range of high volume fraction of air bubbles, which helps to remove the suspended matters. PMID- 28726708 TI - Potential of integrated vertical and horizontal flow constructed wetland with native plants for sewage treatment under different hydraulic loading rates. AB - In this study, a pilot-scale integrated constructed wetland with vertical flow (VF) and horizontal flow (HF) in series was designed and investigated to evaluate sewage wastewater treatment capacity. The VF unit was planted with Canna indica and was 1.2 m long, 1.2 m wide, and 1.2 m high; whereas the HF unit contained Colocasia esculenta and was 3.0 m long, 1.0 m wide, and 1.0 m high. The system was operated under different hydraulic loading rates (HLRs) of 0.1, 0.2, and 0.15 m/d. The effluent concentrations differed as HLR changed, and the means were total suspended solids (TSS): 87 mg/L; biological oxygen demand (BOD5): 31 mg/L; chemical oxygen demand (CODCr): 59 mg/L; ammonium nitrogen (NH4-N): 5.3 mg/L; nitrate nitrogen NO3-N: 8.4 mg/L; total nitrogen (TN): 7.1 mg/L; phosphate (PO4 P): 0.9 mg/L; and total coliforms (TCol): 1,485 most probable number (MPN)/100 mL. The average removal efficiencies for TSS, BOD5, TN, NH4-N, PO4-P, and TCol were 28.3, 74.9, 79, 76.2, 3.6, and 82%, respectively. There were significant differences in the effluent concentrations among the three HLRs (P < 0.05), except for PO4-P. PMID- 28726709 TI - Impact of surface condition and roughness on sediment formation: an experimental sewer system operated with real wastewater. AB - Regular sewer cleaning in North Rhine-Westphalia (Germany) generates annual costs of around 50 million Euros. This leads to the question of whether and to what extent sewer cleaning is necessary. To determine the effect of roughness, sewer surface condition and discharge, experiments with real wastewater were performed, using a sewer test track with acrylic glass tubes (DN 300) prepared with abrasive paper and nature stone tiles at the wastewater treatment plant (WWTP) Bochum Olbachtal (Ruhrverband, Germany). A logarithmic relationship between deposit height and time was found to lead to maximum deposit heights of 5 to 60 mm. Surface structure analysis by texture measuring indicated that deposits within the first 28 days after cleaning are highly influenced by the surface condition of the sewer and not necessarily by roughness. Furthermore, under dry weather conditions deposit heights are nearly stable after this time, indicating the limiting effect of sewer cleaning. Deposit formation amounted to 1.75-1.80 mm/d at a roughness of ks = 0.10 mm (fine but catchy microstructure) and 0-0.1 mm/d at ks 1.25 mm (wavy microstructure) at steady state and transient discharge within the first 28 days after sewer cleaning. PMID- 28726710 TI - Using amine-functionalized magnetite hollow nanospheres (AMHNs) as adsorbents for heavy metal ions. AB - In this paper, the amine-functionalized magnetite hollow nanospheres (AMHNs), prepared through a facile one-pot synthesis, were used as heavy metal ion adsorbents, whose morphology and physicochemical features were exploring by transmission electron microscopy, vibrating sample magnetometer, X-ray diffraction and Fourier-transform infrared analyses. Its adsorption performances for Pb2+, Cu2+, Zn2+, Ni2+ and Cd2+ were studied in detail. The adsorption increased with the increase of initial pH value of the solution and could be obviously affected by ionic strength. Also, the adsorption kinetics and isotherms were studied. The adsorption processes for Pb2+, Cu2+, Zn2+, Ni2+ and Cd2+ could all reach equilibrium in 60 min and be described well by the Langmuir thermodynamics model. The saturated adsorption capacities for Pb2+, Cu2+, Zn2+, Ni2+ and Cd2+ were 0.66, 0.47, 0.45, 0.38 and 0.26 mmol/g, respectively. In addition, the competitive adsorption showed the AMHNs had higher affinity to Pb2+ than to other heavy metal ions. PMID- 28726711 TI - The use of constructed wetlands for the treatment and reuse of urban wastewater for the irrigation of two warm-season turfgrass species under Mediterranean climatic conditions. AB - Constructed wetlands (CWs) represent low-cost technology for the treatment and reuse of wastewater in urban areas. This study aimed to evaluate the pollutant removal efficiency of a CW system and to assess the effects of irrigation using treated urban wastewater on soil and on two warm-season turf species. The research was carried out in Sicily (Italy) on a pilot-scale horizontal subsurface flow system which was fed with treated urban wastewater following secondary treatment from an activated-sludge wastewater treatment plant. The pilot system was located in an open urban park and comprised two separate parallel planted units. Experimental fields of Cynodon dactylon (L.) Pers. and Paspalum vaginatum Sw. were set up close to the system and irrigated with both treated wastewater (TWW) and freshwater (FW). Irrigation with TWW did not result in a significant variation in soil pH and soil salinity in the topsoil. The turf species tolerated high sodium levels in the soil due to TWW irrigation. Savings in FW and mineral fertilizers were deemed significant. The results highlight the fact that use of CW systems for the treatment and reuse of wastewater can represent a sustainable way to obtain alternative water resources for turfgrass irrigation in urban areas. PMID- 28726712 TI - Constructed wetland integrated microbial fuel cell system: looking back, moving forward. AB - In the last 10 years, the microbial fuel cell (MFC) has been extensively studied worldwide to extract energy from wastewater via electricity generation. More recently, a merged technique of embedding MFC into a constructed wetland (CW) has been developed and appears to be increasingly investigated. The driving force to integrate these two technologies lies in the fact that CWs naturally possess a redox gradient (depending on flow direction and wetland depth), which is required by MFCs as anaerobic anode and aerobic cathode chambers. No doubt, the integration of MFC with a CW will upgrade the CW to allow it to be used for wastewater treatment and, simultaneously, electricity generation, making CWs more sustainable and environmentally friendly. Currently, published work shows that India, China, Ireland, Spain, Germany and Malaysia are involved in the development of this technology although it is in its infant stage and many technical issues are faced on system configuration, operation and maximisation of electricity production. This paper aims to provide an updated review and analysis of the CW-MFC development. Focuses are placed on the experience gained so far from different researchers in the literature and further research directions and proposals are discussed in great detail. PMID- 28726713 TI - A comprehensive study on adsorption behavior of some azo dyes from aqueous solution onto different adsorbents. AB - One of the major environmental problems is the existence of dye materials in water sources. This pollutant must be removed from water by appropriate methods. Although most of these methods are efficient for the treatment of waters contaminated with dye pollutants, they are very costly and commercially unattractive. Adsorption is one of the most popular methods for the removal of dye pollutants from water especially if the sorbent is inexpensive. Sorbents are classified as natural sorbents, commercial sorbents, and the sorbents obtained from industrial and agricultural wastes. Although commercial activated carbon is widely used in wastewater treatment applications, it is very expensive. In this study, usability of inexpensive materials - sepiolite as a natural adsorbent, and walnut shell and hazelnut shell as agricultural wastes - was investigated instead of commercial activated carbon to remove some azo dyes (methyl red, methyl orange and methyl yellow) from aqueous solution. Batch experiments were carried out to determine the effect of different adsorption parameters such as pH, initial dye concentration, contact time, adsorbent dose and temperature. The equilibrium of adsorptions was modeled using Langmuir and Freundlich isotherm models. This comprehensive study showed that these alternative adsorbents had sufficient binding capacity to remove these azo dyes from water. PMID- 28726714 TI - Performance of a novel recycling magnetic flocculation membrane filtration process for tetracycline-polluted surface water treatment. AB - A recycling magnetic flocculation membrane filtration (RMFMF) process integrating circulating coagulation, magnetic enhanced flocculation and membrane filtration was investigated for the treatment of surface water micro-polluted by tetracycline, a typical pharmaceutical and personal care product. A bench-scale experiment was conducted and several water quality parameters including turbidity, ultraviolet absorbance at 254 nm (UV254), total organic carbon and tetracycline concentration were evaluated, taking coagulation membrane filtration and magnetic flocculation membrane filtration processes as reference treatments. The experimental results showed that at the optimum doses of 20 mg.L-1 ferric chloride (FeCl3), 4 mg.L-1 magnetite (Fe3O4) and 6 mg.L-1 reclaimed magnetic flocs in RMFMF processes, removal efficiencies of above evaluated parameters ranged from 55.8% to 92.9%, which performed best. Simultaneously, the largest average particle size of 484.71 MUm and the highest fractal dimension of 1.37 of flocs were achieved, which did not only present the best coagulation effect helpful in enhancing the performance of removing multiple contaminants, but also lead to the generation of loose and porous cake layers favouring reduced permeate flux decline and membrane fouling. PMID- 28726715 TI - Overexpression of the OsIMP Gene Increases the Accumulation of Inositol and Confers Enhanced Cold Tolerance in Tobacco through Modulation of the Antioxidant Enzymes' Activities. AB - Inositol is a cyclic polyol that is involved in various physiological processes, including signal transduction and stress adaptation in plants. l-myo-inositol monophosphatase (IMPase) is one of the metal-dependent phosphatase family members and catalyzes the last reaction step of biosynthesis of inositol. Although increased IMPase activity induced by abiotic stress has been reported in chickpea plants, the role and regulation of the IMP gene in rice (Oryza sativa L.) remains poorly understood. In the present work, we obtained a full-length cDNA sequence coding IMPase in the cold tolerant rice landraces in Gaogonggui, which is named as OsIMP. Multiple alignment results have displayed that this sequence has characteristic signature motifs and conserved enzyme active sites of the phosphatase super family. Phylogenetic analysis showed that IMPase is most closely related to that of the wild rice Oryza brachyantha, while transcript analysis revealed that the expression of the OsIMP is significantly induced by cold stress and exogenous abscisic acid (ABA) treatment. Meanwhile, we cloned the 5' flanking promoter sequence of the OsIMP gene and identified several important cis-acting elements, such as LTR (low-temperature responsiveness), TCA-element (salicylic acid responsiveness), ABRE-element (abscisic acid responsiveness), GARE-motif (gibberellin responsive), MBS (MYB Binding Site) and other cis-acting elements related to defense and stress responsiveness. To further investigate the potential function of the OsIMP gene, we generated transgenic tobacco plants overexpressing the OsIMP gene and the cold tolerance test indicated that these transgenic tobacco plants exhibit improved cold tolerance. Furthermore, transgenic tobacco plants have a lower level of hydrogen peroxide (H2O2) and malondialdehyde (MDA), and a higher content of total chlorophyll as well as increased antioxidant enzyme activities of superoxide dismutase (SOD), catalase (CAT) and peroxidase (POD), when compared to wild type (WT) tobacco plants under normal and cold stress conditions. PMID- 28726717 TI - Mini Review of Controlled Cortical Impact: A Well-Suited Device for Concussion Research. AB - Mild traumatic brain injury (mTBI) is increasingly recognized as a significant public health problem which warrants additional research. Part of the effort to understand mTBI and concussion includes modeling in animals. Controlled cortical impact (CCI) is a commonly employed and well-characterized model of experimental TBI that has been utilized for three decades. Today, several commercially available pneumatic- and electromagnetic-CCI devices exist as do a variety of standard and custom injury induction tips. One of CCI's strengths is that it can be scaled to a number of common laboratory animals. Similarly, the CCI model can be used to produce graded TBI ranging from mild to severe. At the mild end of the injury spectrum, CCI has been applied in many ways, including to study open and closed head mTBI, repeated injuries, and the long-term deficits associated with mTBI and concussion. The purpose of this mini-review is to introduce the CCI model, discuss ways the model can be applied to study mTBI and concussion, and compare CCI to alternative pre-clinical TBI models. PMID- 28726716 TI - New Insights into the Role of Matrix Metalloproteinases in Preeclampsia. AB - Preeclampsia is a severe pregnancy complication globally, characterized by poor placentation triggering vascular dysfunction. Matrix metalloproteinases (MMPs) exhibit proteolytic activity implicated in the efficiency of trophoblast invasion to the uterine wall, and a dysregulation of these enzymes has been linked to preeclampsia. A decrease in MMP-2 and MMP-9 interferes with the normal remodeling of spiral arteries at early pregnancy stages, leading to the initial pathophysiological changes observed in preeclampsia. Later in pregnancy, an elevation in MMP-2 and MMP-9 induces abnormal release of vasoactive factors conditioning hypertension. Although these two enzymes lead the scene, other MMPs like MMP-1 and MMP-14 seem to have a role in this pathology. This review gathers published recent evidence about the implications of different MMPs in preeclampsia, and the potential use of these enzymes as emergent biomarkers and biological therapeutic targets, focusing on studies involving human subjects. PMID- 28726718 TI - Inhibitory Effects of Trapping Agents of Sulfur Drug Reactive Intermediates against Major Human Cytochrome P450 Isoforms. AB - In some cases, the formation of reactive species from the metabolism of xenobiotics has been linked to toxicity and therefore it is imperative to detect potential bioactivation for candidate drugs during drug discovery. Reactive species can covalently bind to trapping agents in in vitro incubations of compound with human liver microsomes (HLM) fortified with beta-nicotinamide adenine dinucleotide phosphate (NADPH), resulting in a stable conjugate of trapping agent and reactive species, thereby facilitating analytical detection and providing evidence of short-lived reactive metabolites. Since reactive metabolites are typically generated by cytochrome P450 (CYP) oxidation, it is important to ensure high concentrations of trapping agents are not inhibiting the activities of CYP isoforms. Here we assessed the inhibitory properties of fourteen trapping agents against the major human CYP isoforms (CYP1A2, 2C9, 2C19, 2D6 and 3A). Based on our findings, eleven trapping agents displayed inhibition, three of which had IC50 values less than 1 mM (2-mercaptoethanol, N methylmaleimide and N-ethylmaleimide (NEM)). Three trapping agents (dimedone, N acetyl-lysine and arsenite) did not inhibit CYP isoforms at concentrations tested. To illustrate effects of CYP inhibition by trapping agents on reactive intermediate trapping, an example drug (ticlopidine) and trapping agent (NEM) were chosen for further studies. For the same amount of ticlopidine (1 MUM), increasing concentrations of the trapping agent NEM (0.007-40 mM) resulted in a bell-shaped response curve of NEM-trapped ticlopidine S-oxide (TSO-NEM), due to CYP inhibition by NEM. Thus, trapping studies should be designed to include several concentrations of trapping agent to ensure optimal trapping of reactive metabolites. PMID- 28726719 TI - SiMa Cells for a Serotype Specific and Sensitive Cell-Based Neutralization Test for Botulinum Toxin A and E. AB - Botulinum toxins (BoNTs), of which there are seven serotypes, are among the most potent neurotoxins, with serotypes A, B and E causing human botulism. Antitoxins form the first line of treatment for botulism, and functional, highly sensitive in vitro methods for toxin neutralization are needed to replace the current in vivo methods used for determination of antitoxin potency. In this preliminary proof of concept study, we report the development of a neutralization test using the neuroblastoma SiMa cell line. The assay is serotype specific for either BoNT/A or BoNT/E, which both cleave unique sequences on SNAP-25 within SiMa cells. The end point is simple immunodetection of cleaved SNAP-25 from cell lysates with antibodies detecting only the newly exposed sequence on SNAP-25. Neutralizing antibodies prevent the toxin-induced cleavage of SNAP-25. The toxin neutralization assay, with an EC50 of ~2 mIU/mL determined with a standardized reference antiserum, is more sensitive than the mouse bioassays. Relevance was demonstrated with commercial and experimental antitoxins targeting different functional domains, and of known in vivo neutralizing activities. This is the first report describing a simple, specific, in vitro cell-based assay for the detection of neutralizing antibodies against BoNT/A and BoNT/E with a sensitivity exceeding that of the mouse bioassay. PMID- 28726720 TI - TGF-beta-Dependent Growth Arrest and Cell Migration in Benign and Malignant Breast Epithelial Cells Are Antagonistically Controlled by Rac1 and Rac1b. AB - Despite improvements in diagnosis and treatment, breast cancer is still the most common cancer type among non-smoking females. TGF-beta can inhibit breast cancer development by inducing cell cycle arrest in both, cancer cells and, as part of a senescence program in normal human mammary epithelial cells (HMEC). Moreover, TGF beta also drives cell migration and invasion, in part through the small GTPases Rac1 and Rac1b. Depletion of Rac1b or Rac1 and Rac1b in MDA-MB-231 or MDA-MB-435s breast cancer cells by RNA interference enhanced or suppressed, respectively, TGF beta1-induced migration/invasion. Rac1b depletion in MDA-MB-231 cells also increased TGF-beta-induced p21WAF1 expression and ERK1/2 phosphorylation. Senescent HMEC (P15/P16), when compared to their non-senescent counterparts (P11/P12), presented with dramatically increased migratory activity. These effects were paralleled by elevated expression of genes associated with TGF-beta signaling and metastasis, downregulated Rac1b, and upregulated Rac1. Our data suggest that acquisition of a motile phenotype in HMEC resulted from enhanced autocrine TGF-beta signaling, invasion/metastasis-associated gene expression, and a shift in the ratio of antimigratory Rac1b to promigratory Rac1. We conclude that although enhanced TGF-beta signaling is considered antioncogenic in HMEC by suppressing oncogene-induced transformation, this occurs at the expense of a higher migration and invasion potential. PMID- 28726721 TI - Identification and Validation of New Alleles of FALSIFLORA and COMPOUND INFLORESCENCE Genes Controlling the Number of Branches in Tomato Inflorescence. AB - The architecture of inflorescences shows extensive diversity in both branching frequency and flower number, which eventually, determines agricultural productivity. In this study, F2 (second filial) populations derived from a cross between Solanum lycopersicum 10AS111A (highly-branched inflorescence) and the S. pimpinellifolium PI124039 (inflorescence having a single branch) were used to decipher the genetic control of branch number (BN) of inflorescence in plants bearing small-sized tomato fruits. The segregation ratio of single- and moderately-branched types to the highly-branched type was significantly different from 3:1 but not different from 15:1 at p < 0.05, suggesting that more than one gene controls the branch number of the inflorescences. Through genome-wide comparison of single-nucleotide polymorphism (SNP) profiles between the highly branched type bulk and the single-branch type bulk constructed using the F2 plants, we identified a major quantitative trait locus (QTL) on chromosome 3 (58.75-61.4 Mb) and a minor QTL on chromosome 2 (32.95-37.1 Mb), which explained 15.7% and 6.1% of the BN variation, respectively. FALSIFLORA (FA) and COMPOUND INFLORESCENCE (S) genes, located in the QTL peak regions, caught our attention. Sequence comparison of the FA and S genes and their promoter regions from the two parental lines revealed that both contain missense mutations in the coding regions. Segregation analysis of FA and S alleles by high-resolution melting (HRM) method confirmed that alleles for both genes from 10AS111A significantly increased the BN and the size of inflorescence. In conclusion, we propose that SNPs in coding sequences might cause changes in the function of FA and S genes, which might be important determinants of BN. PMID- 28726722 TI - Comparison of the Results of Studies of Air Pollution Fungi Using the SAS Super 100, MAS 100, and Air IDEAL. AB - Although several air sampling devices for identifying and enumerating airborne microorganisms are commercially available, each poses some limitations. The aim of this study was to evaluate air pollution fungi using three such samplers: SAS Super 100, Microbiological Air Sampler (MAS) 100, and Air IDEAL. Mycological air was taken from the cellars of a 17th-century church in Siemiatycze, Poland, and the nearby outdoor environment. With samplers placed 1.5 m above the floor, microbial flora in air samples collected inside and outside the cellar were detected. The number of colony-forming units (CFU) of fungi obtained with the three samplers from the cellars and outdoor environment differed; the most CFU were obtained with the Air IDEAL and the least with the SAS Super 100. Significant differences emerged in CFUs collected from air samples with the MAS 100 and SAS Super 100, on the one hand, and the SAS Super 100 and Air IDEAL, on the other. Otherwise, results among the samplers were different. More Cladosporium species were collected with the MAS 100 sampler, whereas more Fusarium and Aspergillus species were collected with the Air IDEAL sampler. Significant differences among CFU/m3 values among the tested sites depended on the sampler used. PMID- 28726724 TI - Theoretical Studies on Two-Photon Fluorescent Hg2+ Probes Based on the Coumarin Rhodamine System. AB - The development of fluorescent sensors for Hg2+ has attracted much attention due to the well-known adverse effects of mercury on biological health. In the present work, the optical properties of two newly-synthesized Hg2+ chemosensors based on the coumarin-rhodamine system (named Pro1 and Pro2) were systematically investigated using time-dependent density functional theory. It is shown that Pro1 and Pro2 are effective ratiometric fluorescent Hg2+ probes, which recognize Hg2+ by Forster resonance energy transfer and through bond energy transfer mechanisms, respectively. To further understand the mechanisms of the two probes, we have developed an approach to predict the energy transfer rate between the donor and acceptor. Using this approach, it can be inferred that Pro1 has a six times higher energy transfer rate than Pro2. Thus the influence of spacer group between the donor and acceptor on the sensing performance of the probe is demonstrated. Specifically, two-photon absorption properties of these two probes are calculated. We have found that both probes show significant two-photon responses in the near-infrared light region. However, only the maximum two-photon absorption cross section of Pro1 is greatly enhanced with the presence of Hg2+, indicating that Pro1 can act as a potential two-photon excited fluorescent probe for Hg2+. The theoretical investigations would be helpful to build a relationship between the structure and the optical properties of the probes, providing information on the design of efficient two-photon fluorescent sensors that can be used for biological imaging of Hg2+ in vivo. PMID- 28726723 TI - Mertensene, a Halogenated Monoterpene, Induces G2/M Cell Cycle Arrest and Caspase Dependent Apoptosis of Human Colon Adenocarcinoma HT29 Cell Line through the Modulation of ERK-1/-2, AKT and NF-kappaB Signaling. AB - Conventional treatment of advanced colorectal cancer is associated with tumor resistance and toxicity towards normal tissues. Therefore, development of effective anticancer therapeutic alternatives is still urgently required. Nowadays, marine secondary metabolites have been extensively investigated due to the fact that they frequently exhibit anti-tumor properties. However, little attention has been given to terpenoids isolated from seaweeds. In this study, we isolated the halogenated monoterpene mertensene from the red alga Pterocladiella capillacea (S.G. Gmelin) Santelices and Hommersand and we highlight its inhibitory effect on the viability of two human colorectal adenocarcinoma cell lines HT29 and LS174. Interestingly, exposure of HT29 cells to different concentrations of mertensene correlated with the activation of MAPK ERK-1/-2, Akt and NF-kappaB pathways. Moreover, mertensene-induced G2/M cell cycle arrest was associated with a decrease in the phosphorylated forms of the anti-tumor transcription factor p53, retinoblastoma protein (Rb), cdc2 and chkp2. Indeed, a reduction of the cellular level of cyclin-dependent kinases CDK2 and CDK4 was observed in mertensene-treated cells. We also demonstrated that mertensene triggers a caspase-dependent apoptosis in HT29 cancer cells characterized by the activation of caspase-3 and the cleavage of poly (ADP-ribose) polymerase (PARP). Besides, the level of death receptor-associated protein TRADD increased significantly in a concentration-dependent manner. Taken together, these results demonstrate the potential of mertensene as a drug candidate for the treatment of colon cancer. PMID- 28726725 TI - A Cultural Conscience for Conservation. AB - On 2 July 2015, the killing of a lion nicknamed "Cecil" prompted the largest global reaction in the history of wildlife conservation. In response to this, it is propitious to consider the ways in which this moment can be developed into a financial movement to transform the conservation of species such as the lion that hold cultural significance and sentiment but whose numbers in the wild are dwindling dangerously. This provocative piece explores how a species royalty could be used effectively by drawing revenue from the heavy symbolic use of charismatic animals in affluent economies. This would, in turn, reduce strain on limited government funds in threatened animals' native homelands. Three potential areas of lucrative animal symbolism-fashion, sports mascots, and national animals provide examples of the kind of revenue that could be created from a species royalty. These examples also demonstrate how this royalty could prove to be a desirable means by which both corporations and consumers could positively develop their desired selves while simultaneously contributing to a relevant and urgent cause. These examples intend to ignite a multi-disciplinary conversation on the global cultural economy's use of endangered species symbols. An overhaul in perspective and practice is needed because time is running out for much of the wildlife and their ecosystems that embellish products and embody anthropocentric business identities. PMID- 28726726 TI - LEDs: Sources and Intrinsically Bandwidth-Limited Detectors. AB - The increasing demand for light emitting diodes (LEDs) is driven by a number of application categories, including display backlighting, communications, signage, and general illumination. Nowadays, they have also become attractive candidates as new photometric standards. In recent years, LEDs have started to be applied as wavelength-selective photo-detectors as well. Nevertheless, manufacturers' datasheets are limited about LEDs used as sources in terms of degradation with operating time (aging) or shifting of the emission spectrum as a function of the forward current. On the contrary, as far as detection is concerned, information about spectral responsivity of LEDs is missing. We investigated, mainly from a radiometric point of view, more than 50 commercial LEDs of a wide variety of wavelength bands, ranging from ultraviolet (UV) to near infrared (NIR). Originally, the final aim was to find which LEDs could better work together as detector-emitter pairs for the creation of self-calibrating ground-viewing LED radiometers; however, the findings that we are sharing here following, have a general validity that could be exploited in several sensing applications. PMID- 28726727 TI - In Vitro Quantified Determination of beta-Amyloid 42 Peptides, a Biomarker of Neuro-Degenerative Disorders, in PBS and Human Serum Using a Simple, Cost Effective Thin Gold Film Biosensor. AB - A simple in vitro biosensor for the detection of beta-amyloid 42 in phosphate buffered saline (PBS) and undiluted human serum was fabricated and tested based on our platform sensor technology. The bio-recognition mechanism of this biosensor was based on the effect of the interaction between antibody and antigen of beta-amyloid 42 to the redox couple probe of K4Fe(CN)6 and K3Fe(CN)6. Differential pulse voltammetry (DPV) served as the transduction mechanism measuring the current output derived from the redox coupling reaction. The biosensor was a three-electrode electrochemical system, and the working and counter electrodes were 50 nm thin gold film deposited by a sputtering technique. The reference electrode was a thick-film printed Ag/AgCl electrode. Laser ablation technique was used to define the size and structure of the biosensor. Cost-effective roll-to-roll manufacturing process was employed in the fabrication of the biosensor, making it simple and relatively inexpensive. Self-assembled monolayers (SAM) of 3-Mercaptopropionic acid (MPA) was employed to covalently immobilize the thiol group on the gold working electrode. A carbodiimide conjugation approach using N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) was undertaken for cross linking antibody of beta-amyloid 42 to the carboxylic groups on one end of the MPA. The antibody concentration of beta-amyloid 42 used was 18.75 ug/mL. The concentration range of beta-amyloid 42 in this study was from 0.0675 ug/mL to 0.5 ug/mL for both PBS and undiluted human serum. DPV measurements showed excellent response in this antigen concentration range. Interference study of this biosensor was carried out in the presence of Tau protein antigen. Excellent specificity of this beta-amyloid 42 biosensor was demonstrated without interference from other species, such as T-tau protein. PMID- 28726728 TI - A Novel Physical Sensing Principle for Liquid Characterization Using Paper-Based Hygro-Mechanical Systems (PB-HMS). AB - In recent years paper-based microfluidic systems have emerged as versatile tools for developing sensors in different areas. In this work; we report a novel physical sensing principle for the characterization of liquids using a paper based hygro-mechanical system (PB-HMS). The PB-HMS is formed by the interaction of liquid droplets and paper-based mini-structures such as cantilever beams. The proposed principle takes advantage of the hygroscopic properties of paper to produce hygro-mechanical motion. The dynamic response of the PB-HMS reveals information about the tested liquid that can be applied to characterize certain properties of liquids. A suggested method to characterize liquids by means of the proposed principle is introduced. The experimental results show the feasibility of such a method. It is expected that the proposed principle may be applied to sense properties of liquids in different applications where both disposability and portability are of extreme importance. PMID- 28726729 TI - Online Denoising Based on the Second-Order Adaptive Statistics Model. AB - Online denoising is motivated by real-time applications in the industrial process, where the data must be utilizable soon after it is collected. Since the noise in practical process is usually colored, it is quite a challenge for denoising techniques. In this paper, a novel online denoising method was proposed to achieve the processing of the practical measurement data with colored noise, and the characteristics of the colored noise were considered in the dynamic model via an adaptive parameter. The proposed method consists of two parts within a closed loop: the first one is to estimate the system state based on the second order adaptive statistics model and the other is to update the adaptive parameter in the model using the Yule-Walker algorithm. Specifically, the state estimation process was implemented via the Kalman filter in a recursive way, and the online purpose was therefore attained. Experimental data in a reinforced concrete structure test was used to verify the effectiveness of the proposed method. Results show the proposed method not only dealt with the signals with colored noise, but also achieved a tradeoff between efficiency and accuracy. PMID- 28726730 TI - Estimating the Availability of Potential Homes for Unwanted Horses in the United States. AB - There are approximately 200,000 unwanted horses annually in the United States. This study aimed to better understand the potential homes for horses that need to be re-homed. Using an independent survey company through an Omnibus telephone (land and cell) survey, we interviewed a nationally projectable sample of 3036 adults (using both landline and cellular phone numbers) to learn of their interest and capacity to adopt a horse. Potential adopters with interest in horses with medical and/or behavioral problems and self-assessed perceived capacity to adopt, constituted 0.92% of the total sample. Extrapolating the results of this survey using U.S. Census data, suggests there could be an estimated 1.25 million households who have both the self-reported and perceived resources and desire to house an unwanted horse. This number exceeds the estimated number of unwanted horses living each year in the United States. This study points to opportunities and need to increase communication and support between individuals and organizations that have unwanted horses to facilitate re homing with people in their community willing to adopt them. PMID- 28726731 TI - The Use of Imaging in the Prediction and Assessment of Cancer Treatment Toxicity. AB - Multimodal imaging is commonly used in the management of patients with cancer. Imaging plays pivotal roles in the diagnosis, initial staging, treatment response assessment, restaging after treatment and the prognosis of many cancers. Indeed, it is difficult to imagine modern precision cancer care without the use of multimodal molecular imaging, which is advancing at a rapid pace with innovative developments in imaging sciences and an improved understanding of the complex biology of cancer. Cancer therapy often leads to undesirable toxicity, which can range from an asymptomatic subclinical state to severe end organ damage and even death. Imaging is helpful in the portrayal of the unwanted effects of cancer therapy and may assist with optimal clinical decision-making, clinical management, and overall improvements in the outcomes and quality of life for patients. PMID- 28726732 TI - Characterization of the Dioscorin Gene Family in Dioscorea alata Reveals a Role in Tuber Development and Environmental Response. AB - Dioscorin is one of the major soluble proteins in yam tubers. Unlike other well known plant storage proteins, such as patatin and sporamin, dioscorin is argued for its function as storage proteins, and the molecular mechanisms underlying its expressional complexity are little understood. In this study, we isolated five dioscorin genes from Dioscorea alata L., comprising three class A (Da-dio1, -3 and -4) and two class B (Da-dio2 and -5) isoforms. Expressions of all dioscorin genes gradually decreased in mother tubers during yam sprouting and regrowth. On the other hand, all dioscorin genes accumulated transcripts progressively with tuber development in new tubers, with Da-dio5 being the most prominent isoform. In yam leaves, the expressions of Da-dio5 were up-regulated by the treatments of five phytohormones (gibberellic acid, salicylic acid, indole-3-acetic acid, abscisic acid, and ethylene), and three abiotic stresses (high-temperature, low temperature and drought). To further elucidate the regulatory mechanisms of Da dio5 expressions, transgenic Arabidopsis plants harboring the Da-dio5 promoter beta-glucuronidase (GUS) fusion were generated. GUS staining showed that expressions of the Da-dio5 promoter were detected mainly in the shoot apical meristem (SAM) and hypocotyls, and enhanced by the treatments of the five hormones, and the three abiotic stresses mentioned above. These results suggest diverse roles of Da-dio5 in yam sprouting, regrowth, and tuberization, as well as in response to enviromental cues. PMID- 28726734 TI - Ranging Behaviour of Commercial Free-Range Broiler Chickens 1: Factors Related to Flock Variability. AB - Little is known about the ranging behaviour of chickens. Understanding ranging behaviour is required to improve management and shed and range design to ensure optimal ranging opportunities. Using Radio Frequency Identification technology, we tracked 300 individual broiler chickens in each of four mixed sex ROSS 308 flocks on one commercial farm across two seasons. Ranging behaviour was tracked from the first day of range access (21 days of age) until 35 days of age in winter and 44 days of age in summer. Range use was higher than previously reported from scan sampling studies. More chickens accessed the range in summer (81%) than winter (32%; p < 0.05). On average, daily frequency and duration of range use was greater in summer flocks (4.4 +/- 0.1 visits for a total of 26.3 +/ 0.8 min/day) than winter flocks (3.2 +/- 0.2 visits for a total of 7.9 +/- 1.0 min/day). Seasonal differences were only marginally explained by weather conditions and may reflect the reduction in range exposure between seasons (number of days, hours per day, and time of day). Specific times of the day (p < 0.01) and pop-holes were favoured (p < 0.05). We provide evidence of relationships between ranging and external factors that may explain ranging preferences. PMID- 28726735 TI - Ranging Behaviour of Commercial Free-Range Broiler Chickens 2: Individual Variation. AB - Little is known about broiler chicken ranging behaviour. Previous studies have monitored ranging behaviour at flock level but whether individual ranging behaviour varies within a flock is unknown. Using Radio Frequency Identification technology, we tracked 1200 individual ROSS 308 broiler chickens across four mixed sex flocks in two seasons on one commercial farm. Ranging behaviour was tracked from first day of range access (21 days of age) until 35 days of age in winter flocks and 44 days of age in summer flocks. We identified groups of chickens that differed in frequency of range visits: chickens that never accessed the range (13 to 67% of tagged chickens), low ranging chickens (15 to 44% of tagged chickens) that accounted for <15% of all range visits and included chickens that used the range only once (6 to 12% of tagged chickens), and high ranging chickens (3 to 9% of tagged chickens) that accounted for 33 to 50% of all range visits. Males spent longer on the range than females in winter (p < 0.05). Identifying the causes of inter-individual variation in ranging behaviour may help optimise ranging opportunities in free-range systems and is important to elucidate the potential welfare implications of ranging. PMID- 28726733 TI - Interaction of Mitochondria with the Endoplasmic Reticulum and Plasma Membrane in Calcium Homeostasis, Lipid Trafficking and Mitochondrial Structure. AB - Studying organelles in isolation has been proven to be indispensable for deciphering the underlying mechanisms of molecular cell biology. However, observing organelles in intact cells with the use of microscopic techniques reveals a new set of different junctions and contact sites between them that contribute to the control and regulation of various cellular processes, such as calcium and lipid exchange or structural reorganization of the mitochondrial network. In recent years, many studies focused their attention on the structure and function of contacts between mitochondria and other organelles. From these studies, findings emerged showing that these contacts are involved in various processes, such as lipid synthesis and trafficking, modulation of mitochondrial morphology, endoplasmic reticulum (ER) stress, apoptosis, autophagy, inflammation and Ca 2 + handling. In this review, we focused on the physical interactions of mitochondria with the endoplasmic reticulum and plasma membrane and summarized present knowledge regarding the role of mitochondria-associated membranes in calcium homeostasis and lipid metabolism. PMID- 28726736 TI - ProtozoaDB 2.0: A Trypanosoma Brucei Case Study. AB - Over the last decade new species of Protozoa have been sequenced and deposited in GenBank. Analyzing large amounts of genomic data, especially using Next Generation Sequencing (NGS), is not a trivial task, considering that researchers used to deal or focus their studies on few genes or gene families or even small genomes. To facilitate the information extraction process from genomic data, we developed a database system called ProtozoaDB that included five genomes of Protozoa in its first version. In the present study, we present a new version of ProtozoaDB called ProtozoaDB 2.0, now with the genomes of 22 pathogenic Protozoa. The system has been fully remodeled to allow for new tools and a more expanded view of data, and now includes a number of analyses such as: (i) similarities with other databases (model organisms, the Conserved Domains Database, and the Protein Data Bank); (ii) visualization of KEGG metabolic pathways; (iii) the protein structure from PDB; (iv) homology inferences; (v) the search for related publications in PubMed; (vi) superfamily classification; and (vii) phenotype inferences based on comparisons with model organisms. ProtozoaDB 2.0 supports RESTful Web Services to make data access easier. Those services were written in Ruby language using Ruby on Rails (RoR). This new version also allows a more detailed analysis of the object of study, as well as expanding the number of genomes and proteomes available to the scientific community. In our case study, a group of prenyltransferase proteinsalready described in the literature was found to be a good drug target for Trypanosomatids. PMID- 28726737 TI - Respiratory Tract Infections and the Role of Biologically Active Polysaccharides in Their Management and Prevention. AB - Respiratory tract infections (RTIs) are the most common form of infections in every age category. Recurrent respiratory tract infections (RRTIs), a specific form of RTIs, represent a typical and common problem associated with early childhood, causing high indirect and direct costs on the healthcare system. They are usually the consequence of immature immunity in children and high exposure to various respiratory pathogens. Their rational management should aim at excluding other severe chronic diseases associated with increased morbidity (e.g., primary immunodeficiency syndromes, cystic fibrosis, and ciliary dyskinesia) and at supporting maturity of the mucosal immune system. However, RRTIs can also be observed in adults (e.g., during exhausting and stressful periods, chronic inflammatory diseases, secondary immunodeficiencies, or in elite athletes) and require greater attention. Biologically active polysaccharides (e.g., beta glucans) are one of the most studied natural immunomodulators with a pluripotent mode of action and biological activity. According to many studies, they possess immunomodulatory, anti-inflammatory, and anti-infectious activities and therefore could be suggested as an effective part of treating and preventing RTIs. Based on published studies, the application of beta-glucans was proven as a possible therapeutic and preventive approach in managing and preventing recurrent respiratory tract infections in children (especially beta-glucans from Pleurotus ostreatus), adults (mostly the studies with yeast-derived beta-glucans), and in elite athletes (studies with beta-glucans from Pleurotus ostreatus or yeast). PMID- 28726738 TI - Scheduling for Emergency Tasks in Industrial Wireless Sensor Networks. AB - Wireless sensor networks (WSNs) are widely applied in industrial manufacturing systems. By means of centralized control, the real-time requirement and reliability can be provided by WSNs in industrial production. Furthermore, many approaches reserve resources for situations in which the controller cannot perform centralized resource allocation. The controller assigns these resources as it becomes aware of when and where accidents have occurred. However, the reserved resources are limited, and such incidents are low-probability events. In addition, resource reservation may not be effective since the controller does not know when and where accidents will actually occur. To address this issue, we improve the reliability of scheduling for emergency tasks by proposing a method based on a stealing mechanism. In our method, an emergency task is transmitted by stealing resources allocated to regular flows. The challenges addressed in our work are as follows: (1) emergencies occur only occasionally, but the industrial system must deliver the corresponding flows within their deadlines when they occur; (2) we wish to minimize the impact of emergency flows by reducing the number of stolen flows. The contributions of this work are two-fold: (1) we first define intersections and blocking as new characteristics of flows; and (2) we propose a series of distributed routing algorithms to improve the schedulability and to reduce the impact of emergency flows. We demonstrate that our scheduling algorithm and analysis approach are better than the existing ones by extensive simulations. PMID- 28726739 TI - 5-aza-2',2'-Difluoro Deoxycytidine (NUC013): A Novel Nucleoside DNA Methyl Transferase Inhibitor and Ribonucleotide Reductase Inhibitor for the Treatment of Cancer. AB - Tumor suppressor genes can be silenced genetically as well as epigenetically. One approach to reversing epigenetic suppression of tumor suppressor genes is to inhibit DNA methyl transferase. 5-aza-2',2'-diflurorodeoxycytidine (NUC013) is a novel DNA methyl transferase and ribonucleotide reductase inhibitor that is a more potent inhibitor of growth than decitabine in the NCI 60 cancer cell line panel. NUC013 is more active than decitabine against p53-null/mutant cancer cell lines (p = 0.027) but is even more so against p53 wild-type (WT) cell lines (p = 0.0025). The maximum tolerated dose in mice of NUC013 is greater than 120 mg/kg administered intravenously for three consecutive days a week for three weeks. With this regimen and a dose of 20 mg/kg in a human leukemia HL-60 (p53-null) NCr nu/nu mouse xenograft model (n = 10/group), NUC013 demonstrated a survival benefit (saline median survival (MS) = 26.5 days, NUC013 MS = 32 days and hazard ratio (HR) = 0.26 (p = 0.032)). In a colon cancer LoVo (TP53 WT) xenograft, mice treated with decitabine at 5 mg/kg had worse survival than saline controls (decitabine MS = 31 days, saline MS > 60 days and HR = 26.89 (p < 0.0001)). At a dose of 20 mg/kg NUC013, mean tumor volume in the LoVo xenografts was lower than controls by 50.9% and at 40 mg/kg by 53.7% (both p < 0.0001). PMID- 28726740 TI - Cyclic Peptides as Novel Therapeutic Microbicides: Engineering of Human Defensin Mimetics. AB - Cyclic peptides are receiving significant attention thanks to their antimicrobial activity and high serum stability, which is useful to develop and design novel antimicrobial agents. Antimicrobial peptides appear to be key components of innate defences against bacteria, viruses, and fungi. Among the others, defensins possess a strong microbicidial activity. Defensins are cationic and amphipathic peptides with six cysteine residues connected by three disulfide bonds found in plants, insects, and mammals; they are divided in three families: alpha-, beta-, and theta-defensins. alpha-Defensins are contained in the primary granules of human neutrophils; beta-defensins are expressed in human epithelia; and theta defensins are pseudo-cyclic defensins not found in humans, but in rhesus macaques. The structural diversities among the three families are reflected in a different antimicrobial action as well as in serum stability. The engineering of these peptides is an exciting opportunity to obtain more functional antimicrobial molecules highlighting their potential as therapeutic agents. The present review reports the most recent advances in the field of cyclic peptides with a specific regard to defensin analogs. PMID- 28726741 TI - Magnolol, a Natural Polyphenol, Attenuates Dextran Sulfate Sodium-Induced Colitis in Mice. AB - Magnolol is a lignan with anti-inflammatory activity identified in Magnolia officinalis. Ulcerative colitis (UC), one of the types of inflammatory bowel disease (IBD), is a disease that causes inflammation and ulcers in the colon. To investigate the effect of magnolol in dextran sulfate sodium (DSS)-induced experimental UC model, male C57 mice were treated with 2% DSS drinking water for 5 consecutive days followed by intragastric administration with magnolol (5, 10 and 15 mg/kg) daily for 7 days. The results showed that magnolol significantly attenuated disease activity index, inhibited colonic shortening, reduced colonic lesions and suppressed myeloperoxidase (MPO) activity. Moreover, colonic pro inflammatory cytokines (TNF-alpha, IL-6, and IL-1beta) induced by colitis were dramatically decreased by magnolol. To further unveil the metabolic signatures upon magnolol treatment, mass spectrometry-based metabolomic analysis of the small molecular metabolites in mice serum were performed. Compared with controls, abnormality of serum metabolic phenotypes in DSS-treated mice were effectively reversed by different doses of magnolol. In particular, magnolol treatment effectively elevated the serum levels of tryptophan metabolites including kynurenic acid (KA), 5-hydroxyindoleacetic acid, indoleacetic acid (IAA), indolelactic acid and indoxylsulfuric acid, which are potential aryl hydrocarbon receptor (AHR) ligands to impact colitis. These findings suggest that magnolol exerts anti-inflammatory effect on DSS-induced colitis and its underlying mechanisms are associated with the restoring of tryptophan metabolites that inhibit the colonic inflammation. PMID- 28726742 TI - Special Issue: Adenosine Receptors. AB - Nearly 90 years ago, Drury and Szent-Gyorgyi revealed that adenosine produced profound hypotension and bradycardia, and it affected kidney function in mammals [1]. [...]. PMID- 28726743 TI - The Effect of N-Terminal Cyclization on the Function of the HIV Entry Inhibitor 5P12-RANTES. AB - Despite effective treatment for those living with Human Immunodeficiency Virus (HIV), there are still two million new infections each year. Protein-based HIV entry inhibitors, being highly effective and specific, could be used to protect people from initial infection. One of the most promising of these for clinical use is 5P12-RANTES, a variant of the chemokine RANTES/CCL5. The N-terminal amino acid of 5P12-RANTES is glutamine (Gln; called Q0), a residue that is prone to spontaneous cyclization when at the N-terminus of a protein. It is not known how this cyclization affects the potency of the inhibitor or whether cyclization is necessary for the function of the protein, although the N-terminal region of RANTES has been shown to be critical for receptor interactions, with even small changes having a large effect. We have studied the kinetics of cyclization of 5P12-RANTES as well as N-terminal variations of the protein that either produce an identical cyclized terminus (Glu0) or that cannot similarly cyclize (Asn0, Phe0, Ile0, and Leu0). We find that the half life for N-terminal cyclization of Gln is roughly 20 h at pH 7.3 at 37 degrees C. However, our results show that cyclization is not necessary for the potency of this protein and that several replacement terminal amino acids produce nearly-equally potent HIV inhibitors while remaining CC chemokine receptor 5 (CCR5) antagonists. This work has ramifications for the production of active 5P12-RANTES for use in the clinic, while also opening the possibility of developing other inhibitors by varying the N-terminus of the protein. PMID- 28726744 TI - Future Protein Supply and Demand: Strategies and Factors Influencing a Sustainable Equilibrium. AB - A growing global population, combined with factors such as changing socio demographics, will place increased pressure on the world's resources to provide not only more but also different types of food. Increased demand for animal-based protein in particular is expected to have a negative environmental impact, generating greenhouse gas emissions, requiring more water and more land. Addressing this "perfect storm" will necessitate more sustainable production of existing sources of protein as well as alternative sources for direct human consumption. This paper outlines some potential demand scenarios and provides an overview of selected existing and novel protein sources in terms of their potential to sustainably deliver protein for the future, considering drivers and challenges relating to nutritional, environmental, and technological and market/consumer domains. It concludes that different factors influence the potential of existing and novel sources. Existing protein sources are primarily hindered by their negative environmental impacts with some concerns around health. However, they offer social and economic benefits, and have a high level of consumer acceptance. Furthermore, recent research emphasizes the role of livestock as part of the solution to greenhouse gas emissions, and indicates that animal-based protein has an important role as part of a sustainable diet and as a contributor to food security. Novel proteins require the development of new value chains, and attention to issues such as production costs, food safety, scalability and consumer acceptance. Furthermore, positive environmental impacts cannot be assumed with novel protein sources and care must be taken to ensure that comparisons between novel and existing protein sources are valid. Greater alignment of political forces, and the involvement of wider stakeholders in a governance role, as well as development/commercialization role, is required to address both sources of protein and ensure food security. PMID- 28726745 TI - Dual-Source Linear Energy Prediction (LINE-P) Model in the Context of WSNs. AB - Energy harvesting technologies such as miniature power solar panels and micro wind turbines are increasingly used to help power wireless sensor network nodes. However, a major drawback of energy harvesting is its varying and intermittent characteristic, which can negatively affect the quality of service. This calls for careful design and operation of the nodes, possibly by means of, e.g., dynamic duty cycling and/or dynamic frequency and voltage scaling. In this context, various energy prediction models have been proposed in the literature; however, they are typically compute-intensive or only suitable for a single type of energy source. In this paper, we propose Linear Energy Prediction "LINE-P", a lightweight, yet relatively accurate model based on approximation and sampling theory; LINE-P is suitable for dual-source energy harvesting. Simulations and comparisons against existing similar models have been conducted with low and medium resolutions (i.e., 60 and 22 min intervals/24 h) for the solar energy source (low variations) and with high resolutions (15 min intervals/24 h) for the wind energy source. The results show that the accuracy of the solar-based and wind-based predictions is up to approximately 98% and 96%, respectively, while requiring a lower complexity and memory than the other models. For the cases where LINE-P's accuracy is lower than that of other approaches, it still has the advantage of lower computing requirements, making it more suitable for embedded implementation, e.g., in wireless sensor network coordinator nodes or gateways. PMID- 28726746 TI - Crack Detection in Concrete Tunnels Using a Gabor Filter Invariant to Rotation. AB - In this article, a system for the detection of cracks in concrete tunnel surfaces, based on image sensors, is presented. Both data acquisition and processing are covered. Linear cameras and proper lighting are used for data acquisition. The required resolution of the camera sensors and the number of cameras is discussed in terms of the crack size and the tunnel type. Data processing is done by applying a new method called Gabor filter invariant to rotation, allowing the detection of cracks in any direction. The parameter values of this filter are set by using a modified genetic algorithm based on the Differential Evolution optimization method. The detection of the pixels belonging to cracks is obtained to a balanced accuracy of 95.27%, thus improving the results of previous approaches. PMID- 28726747 TI - Sleep Duration and Quality in Pregnant Women: A Cross-Sectional Survey in China. AB - Objectives: Good maternal health and fetal development require sufficient and good quality of sleep during pregnancy. This study investigated sleep duration and quality in pregnant women, assessing factors with possibly influence on sleep. Method: A cross-sectional survey was conducted on pregnant women between June and August in 2015 in 16 hospitals in five provinces in China. A total of 2345 pregnant women aged 18 years and older were surveyed. Insufficient sleeping duration was defined as sleeping of less than 7 h per day. Excessive sleep duration was defined as sleeping of more than 9 h per day. Results: A total of 561 (23.9%) participants reported insufficient sleeping duration, whereas 485 (20.9%) claimed excessive sleep duration. A total of 358 (15.2%) of pregnant women reported problems regarding sleep quality. Compared to pregnant women with sufficient sleeping duration, those with insufficient sleeping duration were prone to have poor sleep quality, whereas those with excessive sleeping duration featured low possibility of poor sleep quality. High-risk groups of insufficient sleep duration include women of Han nationality, with siblings, in their first trimester of pregnancy, receiving care in low-capacity/quality hospital settings, and with daily or 1-3 days of secondhand smoke exposure. High-risk groups of excessive sleep duration include women living in rural areas, unemployed, in their third trimester of pregnancy, and receiving care in medium-capacity/quality hospital settings. High-risk groups of poor sleep quality include women of non Han nationality, low income level, in their third trimester of pregnancy, and with insufficient sleep duration. Conclusions: Insufficient/excessive sleep duration and poor sleep quality commonly occur during pregnancy in China. Findings provide a better understanding of the influencing factors of insufficient/excessive sleep duration and poor quality of sleep. These findings have some implications for future interventions on sleep among pregnant women. PMID- 28726748 TI - Effect of Air Pollution on Menstrual Cycle Length-A Prognostic Factor of Women's Reproductive Health. AB - Air pollution can influence women's reproductive health, specifically menstrual cycle characteristics, oocyte quality, and risk of miscarriage. The aim of the study was to assess whether air pollution can affect the length of the overall menstrual cycle and the length of its phases (follicular and luteal). Municipal ecological monitoring data was used to assess the air pollution exposure during the monitored menstrual cycle of each of 133 woman of reproductive age. Principal component analyses were used to group pollutants (PM10, SO2, CO, and NOx) to represent a source-related mixture. PM10 and SO2 assessed separately negatively affected the length of the luteal phase after standardization (b = -0.02; p = 0.03; b = -0.06; p = 0.02, respectively). Representing a fossil fuel combustion emission, they were also associated with luteal phase shortening (b = -0.32; p = 0.02). These pollutants did not affect the follicular phase length and overall cycle length, neither in single- nor in multi-pollutant models. CO and NOx assessed either separately or together as a traffic emission were not associated with overall cycle length or the length of cycle phases. Luteal phase shortening, a possible manifestation of luteal phase deficiency, can result from fossil fuel combustion. This suggests that air pollution may contribute to fertility problems in women. PMID- 28726750 TI - Properties of Cement Mortar and Ultra-High Strength Concrete Incorporating Graphene Oxide Nanosheets. AB - In this work, the effect of graphene oxide nanosheet (GONS) additives on the properties of cement mortar and ultra-high strength concrete (UHSC) is reported. The resulting GONS-cement composites were easy to prepare and exhibited excellent mechanical properties. However, their fluidity decreased with increasing GONS content. The UHSC specimens were prepared with various amounts of GONSs (0-0.03% by weight of cement). Results indicated that using 0.01% by weight of cement GONSs caused a 7.82% in compressive strength after 28 days of curing. Moreover, adding GONSs improved the flexural strength and deformation ability, with the increase in flexural strength more than that of compressive strength. Furthermore, field-emission scanning electron microscopy (FE-SEM) was used to observe the morphology of the hardened cement paste and UHSC samples. FE-SEM observations showed that the GONSs were well dispersed in the matrix and the bonding of the GONSs and the surrounding cement matrix was strong. Furthermore, FE-SEM observation indicated that the GONSs probably affected the shape of the cement hydration products. However, the growth space for hydrates also had an important effect on the morphology of hydrates. The true hydration mechanism of cement composites with GONSs needs further study. PMID- 28726751 TI - An Adaptive Feature Learning Model for Sequential Radar High Resolution Range Profile Recognition. AB - This paper proposes a new feature learning method for the recognition of radar high resolution range profile (HRRP) sequences. HRRPs from a period of continuous changing aspect angles are jointly modeled and discriminated by a single model named the discriminative infinite restricted Boltzmann machine (Dis-iRBM). Compared with the commonly used hidden Markov model (HMM)-based recognition method for HRRP sequences, which requires efficient preprocessing of the HRRP signal, the proposed method is an end-to-end method of which the input is the raw HRRP sequence, and the output is the label of the target. The proposed model can efficiently capture the global pattern in a sequence, while the HMM can only model local dynamics, which suffers from information loss. Last but not least, the proposed model learns the features of HRRP sequences adaptively according to the complexity of a single HRRP and the length of a HRRP sequence. Experimental results on the Moving and Stationary Target Acquisition and Recognition (MSTAR) database indicate that the proposed method is efficient and robust under various conditions. PMID- 28726752 TI - Health Impacts of Climate Change-Induced Subzero Temperature Fires. AB - General fire risk and the special risk related to cold climate cellulosic drying processes are outlined. Four recent subzero temperatures fires are studied with respect to health impacts: a wooden village fire, a single wood structure fire, a wildland urban interface (WUI) fire and a huge wildland fire. The health impacts range from stress related to loss of jobs, psychological effects of lost possessions, exposure to smoke and heat as well as immediate, or delayed, loss of lives. These four fires resulted in 32 fatalities, 385 persons hospitalized for shorter or longer periods, 104 structures lost and 1015 km2 of wildland burned north of, and just south of, the Arctic Circle. It is shown that the combination of subzero temperature dry weather, strong winds, changing agricultural activities and declining snowpack may lead to previously anticipated threats to people and the environment. There are reasons to believe that these fires are a result of the ongoing climate changes. Risk impacts are discussed. Rural districts and/or vulnerable populations seem to be most affected. Training methods to identify and better monitor critical fire risk parameters are suggested to mitigate the health impacts of a possibly increasing number of such fires. PMID- 28726749 TI - Ladder-Shaped Ion Channel Ligands: Current State of Knowledge. AB - Ciguatoxins (CTX) and brevetoxins (BTX) are polycyclic ethereal compounds biosynthesized by the worldwide distributed planktonic and epibenthic dinoflagellates of Gambierdiscus and Karenia genera, correspondingly. Ciguatera, evoked by CTXs, is a type of ichthyosarcotoxism, which involves a variety of gastrointestinal and neurological symptoms, while BTXs cause so-called neurotoxic shellfish poisoning. Both types of toxins are reviewed together because of similar mechanisms of their action. These are the only molecules known to activate voltage-sensitive Na+-channels in mammals through a specific interaction with site 5 of its alpha-subunit and may compete for it, which results in an increase in neuronal excitability, neurotransmitter release and impairment of synaptic vesicle recycling. Most marine ciguatoxins potentiate Nav channels, but a considerable number of them, such as gambierol and maitotoxin, have been shown to affect another ion channel. Although the extrinsic function of these toxins is probably associated with the function of a feeding deterrent, it was suggested that their intrinsic function is coupled with the regulation of photosynthesis via light-harvesting complex II and thioredoxin. Antagonistic effects of BTXs and brevenal may provide evidence of their participation as positive and negative regulators of this mechanism. PMID- 28726753 TI - Antimicrobial Properties of Selected Copper Alloys on Staphylococcus aureus and Escherichia coli in Different Simulations of Environmental Conditions: With vs. without Organic Contamination. AB - Background: Hospital equipment made from copper alloys can play an important role in complementing traditional methods of disinfection. Aims of the study: The aim of this study was to assess the dynamics of the antimicrobial properties of selected copper alloys in different simulations of environmental conditions (with organic contamination vs. without organic contamination), and to test alternatives to the currently used testing methods. Materials and Methods: A modification of Japanese standard JIS Z 2801 as well as Staphylococcus aureus (SA) and Escherichia coli (EC) suspended in NaCl vs. tryptic soy broth (TSB) were used in tests performed on seven commonly used copper alloys, copper, and stainless steel. Results: A much faster reduction of the bacterial suspension was observed for the inoculum prepared in NaCl than in TSB. A faster reduction for EC than for SA was observed in the inoculum prepared in NaCl. The opposite results were found for the inoculum based on TSB. A significant correlation between the copper concentration in the copper alloys and the time and degree of bacterial suspension reduction was only observed in the case of EC. Conclusions: This study confirmed the antimicrobial properties of copper alloys, and additionally showed that Staphylococcus aureus was more resistant than Escherichia coli in the variant of the experiment without organic contamination. However, even for SA, a total reduction of the bacterial inoculum's density took no longer than 2 h. Under conditions simulating organic contamination, all of the tested alloys were shown to have bactericidal or bacteriostatic properties, which was contrary to the results from stainless steel. PMID- 28726754 TI - Identification of Load Categories in Rotor System Based on Vibration Analysis. AB - Rotating machinery is often subjected to variable loads during operation. Thus, monitoring and identifying different load types is important. Here, five typical load types have been qualitatively studied for a rotor system. A novel load category identification method for rotor system based on vibration signals is proposed. This method is a combination of ensemble empirical mode decomposition (EEMD), energy feature extraction, and back propagation (BP) neural network. A dedicated load identification test bench for rotor system was developed. According to loads characteristics and test conditions, an experimental plan was formulated, and loading tests for five loads were conducted. Corresponding vibration signals of the rotor system were collected for each load condition via eddy current displacement sensor. Signals were reconstructed using EEMD, and then features were extracted followed by energy calculations. Finally, characteristics were input to the BP neural network, to identify different load types. Comparison and analysis of identifying data and test data revealed a general identification rate of 94.54%, achieving high identification accuracy and good robustness. This shows that the proposed method is feasible. Due to reliable and experimentally validated theoretical results, this method can be applied to load identification and fault diagnosis for rotor equipment used in engineering applications. PMID- 28726755 TI - Control Measurements of Crane Rails Performed by Terrestrial Laser Scanning. AB - This article presents a method for measuring the geometry of crane rails with terrestrial laser scanning (TLS). Two sets of crane rails were divided into segments, their planes were adjusted, and the characteristic rail lines were defined. We used their profiles to define the positional and altitude deviations of the rails, the span and height difference between the two rails, and we also verified that they complied with the Eurocode 3 standard. We tested the method on crane rails at the hydroelectric power plant in Krsko and the thermal power plant in Brestanica. We used two scanning techniques: "pure" TLS (Riegel VZ-400) and "hybrid" TLS (Leica MS50) scanning. This article's original contribution lies in the detailed presentation of the computations used to define the characteristic lines of the rails without using the numeric procedures from existing software packages. We also analysed the influence of segment length and point density on the rail geometry results, and compared the two laser scanning techniques. We also compared the results obtained by terrestrial laser scanning with the results obtained from the classic polar method, which served as a reference point for its precision. PMID- 28726756 TI - Functional Implications of MicroRNAs in Crohn's Disease Revealed by Integrating MicroRNA and Messenger RNA Expression Profiling. AB - Crohn's disease (CD) is a debilitating inflammatory bowel disease (IBD) that emerges due to the influence of genetic and environmental factors. microRNAs (miRNAs) have been identified in the tissue and sera of IBD patients and may play an important role in the induction of IBD. Our study aimed to identify differentially expressed miRNAs and miRNAs with the ability to alter transcriptome activity by comparing inflamed tissue samples with their non inflamed counterparts. We studied changes in miRNA-mRNA interactions associated with CD by examining their differential co-expression relative to normal mucosa from the same patients. Correlation changes between the two conditions were incorporated into scores of predefined gene sets to identify biological processes with altered miRNA-mediated control. Our study identified 28 miRNAs differentially expressed (p-values < 0.01), of which 14 are up-regulated. Notably, our differential co-expression analysis highlights microRNAs (i.e., miR 4284, miR-3194 and miR-21) that have known functional interactions with key mechanisms implicated in IBD. Most of these miRNAs cannot be detected by differential expression analysis that do not take into account miRNA-mRNA interactions. The identification of differential miRNA-mRNA co-expression patterns will facilitate the investigation of the miRNA-mediated molecular mechanisms underlying CD pathogenesis and could suggest novel drug targets for validation. PMID- 28726757 TI - Characterization of Essential Oil Composition in Different Basil Species and Pot Cultures by a GC-MS Method. AB - Basil (Ocimum L.) species are used as medicinal plants due to their essential oils exhibiting specific biological activity. The present work demonstrated that both the variety and season/conditions of cultivation had a significant effect on (i) the produced amount (extraction yield), (ii) qualitative, as well as (iii) quantitative profile of basil essential oil. Among studied basil varieties, a new variety, 'Manes', was characterized for the first time. Based on our quantitative evaluation of GC-MS profiles, the following chemotypes and average concentrations of a main component were detected in the studied basil varieties: 'Ohre', 'Lettuce Leaf', 'Purple Opaal', 'Dark Green' (linalool, 5.99, 2.49, 2.34, 2.01 mg/mL, respectively), and 'Mammolo Genovese', 'Manes', 'Red Rubin' (eucalyptol, 1.34, 0.96, 0.76 mg/mL, respectively). At the same time, when considering other compounds identified in GC-MS profiles, all the studied varieties, except from 'Lettuce Leaf', were methyl eugenol-rich with a strong dependence of the eugenol:methyl eugenol ratio on the seasonal changes (mainly solar irradiation, but also temperature and relative humidity). More complex and/or variable (depending on the season and cultivation) chemotypes were observed with 'Lettuce Leaf' (plus estragole, 2.27 mg/mL), 'Dark Green' (plus eucalyptol, 1.36 mg/mL), 'Mammolo Genovese' (plus eugenol, 1.19 mg/mL), 'Red Rubin' (plus linalool and eugenol, 0.46 and 0.56 mg/mL, respectively), and 'Manes' (plus linalool and eugenol, 0.58 and 0.40 mg/mL, respectively). When considering superior extraction yield (ca. 17 mL.kg-1, i.e., two to five times higher than other examined varieties) and consistent amounts (yields) of essential oil when comparing inter seasonal or inter-year data (RSD and inter-year difference in mean yield values ?2.5%), this new basil variety is very promising for use in the pharmaceutical, food, and cosmetic industries. PMID- 28726758 TI - The Consumption of Dietary Antioxidant Vitamins Modifies the Risk of Obesity among Korean Men with Short Sleep Duration. AB - Short sleep duration has been reported to be associated with various health problems. This study examined the influence of sleep duration on the odds of being obese in relation to the consumption of dietary antioxidant vitamins among 3941 Korean men between 40 and 69 years of age. After adjusting for age, education, household income, marital status, insomnia, smoking and drinking status, participants with short sleep duration (<6 h) had significantly higher body mass index (p = 0.005), body fat mass (p = 0.010), body fat percentage (p = 0.021), waist circumference (p = 0.029), as well as the odds ratio (OR) of risk of obesity [OR (95% CI) = 1.467 (1.282-1.678)], compared to participants with optimal sleep duration (>=7 h). Short sleepers with a low consumption of dietary antioxidant vitamins had a higher risk of obesity than those with a high consumption of dietary antioxidant vitamins; however, this relationship did not hold among those with optimal sleep duration. Although a causal relationship among sleep-related variables could not be definitively demonstrated because of this study's cross-sectional design, our results suggested that the increased risk of obesity associated with short sleep duration may be modified by the consumption of dietary antioxidant vitamins. PMID- 28726759 TI - High-Resolution Inhibition Profiling Combined with HPLC-HRMS-SPE-NMR for Identification of PTP1B Inhibitors from Vietnamese Plants. AB - Protein tyrosine phosphatase 1B (PTP1B) plays a key role as a negative regulator in insulin signal transduction by deactivating the insulin receptor. Thus, PTP1B inhibition has emerged as a potential therapeutic strategy for curing insulin resistance. In this study, 40 extracts from 18 different plant species were investigated for PTP1B inhibitory activity in vitro. The most promising one, the EtOAc extract of Ficus racemosa, was investigated by high-resolution PTP1B inhibition profiling combined with HPLC-HRMS-SPE-NMR analysis. This led to the identification of isoderrone (1), derrone (2), alpinumisoflavone (3) and mucusisoflavone B (4) as PTP1B inhibitors. IC50 of these compounds were 22.7 +/- 1.7, 12.6 +/- 1.6, 21.2 +/- 3.8 and 2.5 +/- 0.2 uM, respectively. Kinetics analysis revealed that these compounds inhibited PTP1B non-competitively with Ki values of 21.3 +/- 2.8, 7.9 +/- 1.9, 14.3 +/- 2.0, and 3.0 +/- 0.5 uM, respectively. These findings support the important role of F. racemosa as a novel source of new drugs and/or as a herbal remedy for treatment of type 2 diabetes. PMID- 28726760 TI - Synthesis, Antitumor Evaluation and Molecular Docking of New Morpholine Based Heterocycles. AB - A series of new morpholinylchalcones was prepared and then used as building blocks for constructing a series of 7-morpholino-2-thioxo-2,3-dihydropyrido[2,3 d]pyrimidin-4(1H)-ones via their reaction with 6-aminothiouracil. The latter thiones reacted with the appropriate hydrazonoyl chloride to give the corresponding pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidin-5(1H)-ones. The assigned structures for all the newly synthesized compounds were confirmed on the basis of elemental analyses and spectral data and the mechanisms of their formation were also discussed. Most of the synthesized compounds were tested for in vitro activity against human lung cancer (A-549) and human hepatocellular carcinoma (HepG-2) cell lines compared with the employed standard antitumor drug (cisplatin) and the results revealed that compounds 8, 4e and 7b have promising activities against the A-549 cell line (IC50 values of 2.78 +/- 0.86 MUg/mL, 5.37 +/- 0.95 MUg/mL and 5.70 +/- 0.91 MUg/mL, respectively) while compound 7b has promising activity against the HepG-2 cell lines (IC50 = 3.54 +/- 1.11 MUg/mL). Moreover, computational studies using MOE 2014.09 software supported the biological activity results. PMID- 28726761 TI - A Cell-Adhesive Plasma Polymerized Allylamine Coating Reduces the In Vivo Inflammatory Response Induced by Ti6Al4V Modified with Plasma Immersion Ion Implantation of Copper. AB - Copper (Cu) could be suitable to create anti-infective implants based on Titanium (Ti), for example by incorporating Cu into the implant surface using plasma immersion ion implantation (Cu-PIII). The cytotoxicity of Cu might be circumvented by an additional cell-adhesive plasma polymerized allylamine film (PPAAm). Thus, this study aimed to examine in vivo local inflammatory reactions for Ti6Al4V implants treated with Cu-PIII (Ti-Cu), alone or with an additional PPAAm film (Ti-Cu-PPAAm), compared to untreated implants (Ti). Successful Cu-PIII and PPAAm treatment was confirmed with X-ray Photoelectron Spectroscopy. Storage of Ti-Cu and Ti-Cu-PPAAm samples in double-distilled water for five days revealed a reduction of Cu release by PPAAm. Subsequently, Ti, Ti-Cu and Ti-Cu-PPAAm samples were simultaneously implanted into the neck musculature of 24 rats. After 7, 14 and 56 days, peri-implant tissue was retrieved from 8 rats/day for morphometric immunohistochemistry of different inflammatory cells. On day 56, Ti Cu induced significantly stronger reactions compared to Ti (tissue macrophages, antigen-presenting cells, T lymphocytes) and to Ti-Cu-PPAAm (tissue macrophages, T lymphocytes, mast cells). The response for Ti-Cu-PPAAm was comparable with Ti. In conclusion, PPAAm reduced the inflammatory reactions caused by Cu-PIII. Combining both plasma processes could be useful to create antibacterial and tissue compatible Ti-based implants. PMID- 28726762 TI - User Interaction Modeling and Profile Extraction in Interactive Systems: A Groupware Application Case Study. AB - A relevant goal in human-computer interaction is to produce applications that are easy to use and well-adjusted to their users' needs. To address this problem it is important to know how users interact with the system. This work constitutes a methodological contribution capable of identifying the context of use in which users perform interactions with a groupware application (synchronous or asynchronous) and provides, using machine learning techniques, generative models of how users behave. Additionally, these models are transformed into a text that describes in natural language the main characteristics of the interaction of the users with the system. PMID- 28726763 TI - Cloning and Characterization of ThSHRs and ThSCR Transcription Factors in Taxodium Hybrid 'Zhongshanshan 406'. AB - Among the GRAS family of transcription factors, SHORT ROOT (SHR) and SCARECROW (SCR) are key regulators of the formation of root tissues. In this study, we isolated and characterized two genes encoding SHR proteins and one gene encoding an SCR protein: ThSHR1 (Accession Number MF045148), ThSHR2 (Accession Number MF045149) and ThSCR (Accession Number MF045152) in the adventitious roots of Taxodium hybrid 'Zhongshanshan'. Gene structure analysis indicated that ThSHR1, ThSHR2 and ThSCR are all intron free. Multiple protein sequence alignments showed that each of the corresponding proteins, ThSHR1, ThSHR2 and ThSCR, contained five well-conserved domains: leucine heptad repeat I (LHRI), the VHIID motif, leucine heptad repeat II (LHR II), the PFYRE motif, and the SAW motif. The phylogenetic analysis indicated that ThSCR was positioned in the SCR clade with the SCR proteins from eight other species, while ThSHR1 and ThSHR2 were positioned in the SHR clade with the SHR proteins from six other species. Temporal expression patterns of these genes were profiled during the process of adventitious root development on stem cuttings. Whereas expression of both ThSHR2 and ThSCR increased up to primary root formation before declining, that of ThSHR1 increased steadily throughout adventitious root formation. Subcellular localization studies in transgenic poplar protoplasts revealed that ThSHR1, ThSHR2 and ThSCR were localized in the nucleus. Collectively, these results suggest that the three genes encode Taxodium GRAS family transcription factors, and the findings contribute to improving our understanding of the expression and function of SHR and SCR during adventitious root production, which may then be manipulated to achieve high rates of asexual propagation of valuable tree species. PMID- 28726764 TI - Fluorination of Naturally Occurring N6-Benzyladenosine Remarkably Increased Its Antiviral Activity and Selectivity. AB - Recently, we demonstrated that the natural cytokinin nucleosides N6 isopentenyladenosine (iPR) and N6-benzyladenosine (BAPR) exert a potent and selective antiviral effect on the replication of human enterovirus 71. In order to further characterize the antiviral profile of this class of compounds, we generated a series of fluorinated derivatives of BAPR and evaluated their activity on the replication of human enterovirus 71 in a cytopathic effect (CPE) reduction assay. The monofluorination of the BAPR-phenyl group changed the selectivity index (SI) slightly because of the concomitant high cell toxicity. Interestingly, the incorporation of a second fluorine atom resulted in a dramatic improvement of selectivity. Moreover, N6-trifluoromethylbenzyladenosines derivatives (9-11) exhibited also a very interesting profile, with low cytotoxicity observed. In particular, the analogue N6-(3-trifluoromethylbenzyl) adenosine (10) with a four-fold gain in potency as compared to BAPR and the best SI in the class represents a promising candidate for further development. PMID- 28726765 TI - Oleic Acid Uptake Reveals the Rescued Enterocyte Phenotype of Colon Cancer Caco-2 by HT29-MTX Cells in Co-Culture Mode. AB - Gastrointestinal epithelium is the unique route for nutrients and for many pharmaceuticals to enter the body. The present study aimed to analyze precisely whether co-culture of two colon cancer cell lines, mucus-producing cells HT29-MTX and enterocyte-like Caco-2 cells, ameliorate differentiation into an in vitro intestinal barrier model and the signaling pathways involved. Differentiated Caco 2 cells gene datasets were compared first to intestinal or cancer phenotypes and second to signaling pathway gene datasets. Experimental validations were performed in real-time experiments, immunochemistry, and gene expression analyses on Caco-2 versus co-cultures of Caco-2 and HT29-MTX (10%) cells. Partial maintenance of cancer-cell phenotype in differentiated Caco-2 cells was confirmed and fatty acids merged as potential regulators of cancer signaling pathways. HT29 MTX cells induced morphological changes in Caco-2 cells, slightly increased their proliferation rate and profoundly modified gene transcription of phenotype markers, fatty acid receptors, intracellular transporters, and lipid droplet components as well as functional responses to oleic acid. In vitro, enterocyte phenotype was rescued partially by co-culture of cancer cells with goblet cells and completed through oleic acid interaction with signaling pathways dysregulated in cancer cells. PMID- 28726766 TI - The Alternaria alternata Mycotoxin Alternariol Suppresses Lipopolysaccharide Induced Inflammation. AB - The Alternaria mycotoxins alternariol (AOH) and alternariol monomethyl ether (AME) have been shown to possess genotoxic and cytotoxic properties. In this study, the ability of AOH and AME to modulate innate immunity in the human bronchial epithelial cell line (BEAS-2B) and mouse macrophage cell line (RAW264.7) were investigated. During these studies, it was discovered that AOH and to a lesser extent AME potently suppressed lipopolysaccharide (LPS)-induced innate immune responses in a dose-dependent manner. Treatment of BEAS-2B cells with AOH resulted in morphological changes including a detached pattern of growth as well as elongated arms. AOH/AME-related immune suppression and morphological changes were linked to the ability of these mycotoxins to cause cell cycle arrest at the G2/M phase. This model was also used to investigate the AOH/AME mechanism of immune suppression in relation to aryl hydrocarbon receptor (AhR). AhR was not found to be important for the immunosuppressive properties of AOH/AME, but appeared important for the low levels of cell death observed in BEAS-2B cells. PMID- 28726767 TI - Fat Taste Sensitivity Is Associated with Short-Term and Habitual Fat Intake. AB - Evidence suggests individuals less sensitive to fat taste (high fat taste thresholds (FTT)) may be overweight or obese and consume greater amounts of dietary fat than more sensitive individuals. The aims of this study were to assess associations between FTT, anthropometric measurements, fat intake, and liking of fatty foods. FTT was assessed in 69 Australian females (mean age 41.3 (15.6) (SD) years and mean body mass index 26.3 (5.7) kg/m2) by a 3-alternate forced choice methodology and transformed to an ordinal scale (FT rank). Food liking was assessed by hedonic ratings of high-fat and reduced-fat foods, and a 24-h food recall and food frequency questionnaire was completed. Linear mixed regression models were fitted. FT rank was associated with dietary % energy from fat ( beta ^ = 0.110 [95% CI: 0.003, 0.216]), % energy from carbohydrate ( beta ^ = -0.112 [-0.188, -0.035]), and frequency of consumption of foods per day from food groups: high-fat dairy ( beta ^ = 1.091 [0.106, 2.242]), meat & meat alternatives ( beta ^ = 0.669 [0.168, 1.170]), and grain & cereals ( beta ^ = 0.771 [0.212, 1.329]) (adjusted for energy and age). There were no associations between FT rank and anthropometric measurements or hedonic ratings. Therefore, fat taste sensitivity appears to be associated with short-term fat intake, but not body size in this group of females. PMID- 28726768 TI - Characterization and Purification of Bergamottin from Citrus grandis (L.) Osbeck cv. Yongjiazaoxiangyou and Its Antiproliferative Activity and Effect on Glucose Consumption in HepG2 cells. AB - Bergamottin is a natural furanocoumarin compound with weak polarity. Characterization and quantification of bergamottin were carried out in different fruit tissues of various citrus cultivars. Among the four citrus tissues tested, i.e., flavedo, albedo, segment membrane (SM), and juice sacs (JS) in eight citrus cultivars, the highest bergamottin content was found in the flavedo of Citrus grandis (L.) Osbeck cv. Yongjiazaoxiangyou (YJZXY, 666.54 MUg.g-1 DW). A combination of silica gel column chromatography and high-speed counter-current chromatography (HSCCC) was established to efficiently purify bergamottin from the flavedo of YJZXY. Bergamottin showed significant antiproliferative activity on three cancer cell lines, i.e., human liver cancer HepG2, promyelocytic leukemia HL-60, and gastric cancer BGC-823 cells, which showed a marked inhibition effect on these cell lines in a dose-dependent manner. In addition, bergamottin significantly increased glucose consumption in HepG2 cells also in a dose dependent manner, which is the first report of its potential in anti-diabetes applications. PMID- 28726769 TI - Activity dependent feedback inhibition may maintain head direction signals in mouse presubiculum. AB - Orientation in space is represented in specialized brain circuits. Persistent head direction signals are transmitted from anterior thalamus to the presubiculum, but the identity of the presubicular target neurons, their connectivity and function in local microcircuits are unknown. Here, we examine how thalamic afferents recruit presubicular principal neurons and Martinotti interneurons, and the ensuing synaptic interactions between these cells. Pyramidal neuron activation of Martinotti cells in superficial layers is strongly facilitating such that high-frequency head directional stimulation efficiently unmutes synaptic excitation. Martinotti-cell feedback plays a dual role: precisely timed spikes may not inhibit the firing of in-tune head direction cells, while exerting lateral inhibition. Autonomous attractor dynamics emerge from a modelled network implementing wiring motifs and timing sensitive synaptic interactions in the pyramidal-Martinotti-cell feedback loop. This inhibitory microcircuit is therefore tuned to refine and maintain head direction information in the presubiculum. PMID- 28726770 TI - A model for the regulation of follicular dendritic cells predicts invariant reciprocal-time decay of post-vaccine antibody response. AB - Follicular dendritic cells (FDC) play a crucial role in the regulation of humoral immunity. They are believed to be responsible for long-term persistence of antibody, due to their role in antibody response induction and their ability to retain antigen in immunogenic form for long periods. In this article, a regulatory control model is proposed which links persistence of humoral immunity with cellular processes associated with FDCs. The argument comprises three elements. The first is a literature review of population-level studies of post vaccination antibody persistence. It is found that reciprocal-time (?1/t) decay of antibody levels is widely reported, over a range of ages, observation times and vaccine types. The second element is a mathematical control model for cell population decay for which reciprocal-time decay is a stable attractor. Additionally, control effectors are easily identified, leading to models of homeostatic control of the reciprocal-time decay rate. The final element is a literature review of FDC functionality. This reveals a striking concordance between cell properties required by the model and those widely observed of FDCs, some of which are unique to this cell type. The proposed model is able to unify a wide range of disparate observations of FDC function under one regulatory principle, and to characterize precisely forms of FDC regulation and dysregulation. Many infectious and immunological diseases are increasingly being linked to FDC regulation, therefore a precise understanding of the underlying mechanisms would be of significant benefit for the development of new therapies. PMID- 28726771 TI - Rapid elicitation of broadly neutralizing antibodies to HIV by immunization in cows. AB - No immunogen to date has reliably elicited broadly neutralizing antibodies to HIV in humans or animal models. Advances in the design of immunogens that antigenically mimic the HIV envelope glycoprotein (Env), such as the soluble cleaved trimer BG505 SOSIP, have improved the elicitation of potent isolate specific antibody responses in rabbits and macaques, but so far failed to induce broadly neutralizing antibodies. One possible reason for this failure is that the relevant antibody repertoires are poorly suited to target the conserved epitope regions on Env, which are somewhat occluded relative to the exposed variable epitopes. Here, to test this hypothesis, we immunized four cows with BG505 SOSIP. The antibody repertoire of cows contains long third heavy chain complementary determining regions (HCDR3) with an ultralong subset that can reach more than 70 amino acids in length. Remarkably, BG505 SOSIP immunization resulted in rapid elicitation of broad and potent serum antibody responses in all four cows. Longitudinal serum analysis for one cow showed the development of neutralization breadth (20%, n = 117 cross-clade isolates) in 42 days and 96% breadth (n = 117) at 381 days. A monoclonal antibody isolated from this cow harboured an ultralong HCDR3 of 60 amino acids and neutralized 72% of cross-clade isolates (n = 117) with a potent median IC50 of 0.028 MUg ml-1. Breadth was elicited with a single trimer immunogen and did not require additional envelope diversity. Immunization of cows may provide an avenue to rapidly generate antibody prophylactics and therapeutics to address disease agents that have evolved to avoid human antibody responses. PMID- 28726772 TI - Mice lacking NF-kappaB1 exhibit marked DNA damage responses and more severe gastric pathology in response to intraperitoneal tamoxifen administration. AB - Tamoxifen (TAM) has recently been shown to cause acute gastric atrophy and metaplasia in mice. We have previously demonstrated that the outcome of Helicobacter felis infection, which induces similar gastric lesions in mice, is altered by deletion of specific NF-kappaB subunits. Nfkb1-/- mice developed more severe gastric atrophy than wild-type (WT) mice 6 weeks after H. felis infection. In contrast, Nfkb2-/- mice were protected from this pathology. We therefore hypothesized that gastric lesions induced by TAM may be similarly regulated by signaling via NF-kappaB subunits. Groups of five female C57BL/6 (WT), Nfkb1-/-, Nfkb2-/- and c-Rel-/- mice were administered 150 mg/kg TAM by IP injection. Seventy-two hours later, gastric corpus tissues were taken for quantitative histological assessment. In addition, groups of six female WT and Nfkb1-/- mice were exposed to 12 Gy gamma-irradiation. Gastric epithelial apoptosis was quantified 6 and 48 h after irradiation. TAM induced gastric epithelial lesions in all strains of mice, but this was more severe in Nfkb1-/- mice than in WT mice. Nfkb1-/- mice exhibited more severe parietal cell loss than WT mice, had increased gastric epithelial expression of Ki67 and had an exaggerated gastric epithelial DNA damage response as quantified by gammaH2AX. To investigate whether the difference in gastric epithelial DNA damage response of Nfkb1-/- mice was unique to TAM-induced DNA damage or a generic consequence of DNA damage, we also assessed gastric epithelial apoptosis following gamma-irradiation. Six hours after gamma-irradiation, gastric epithelial apoptosis was increased in the gastric corpus and antrum of Nfkb1-/- mice. NF-kappaB1-mediated signaling regulates the development of gastric mucosal pathology following TAM administration. This is associated with an exaggerated gastric epithelial DNA damage response. This aberrant response appears to reflect a more generic sensitization of the gastric mucosa of Nfkb1-/- mice to DNA damage. PMID- 28726773 TI - T-cell autonomous death induced by regeneration of inert glucocorticoid metabolites. AB - Glucocorticoids (GC) are essential regulators of T-cell development and function. Activation of the immune system increases systemic adrenal-derived GC levels which downregulate immune activity as part of a negative feedback control system. Increasing evidence shows, however, that GC can also be derived from extra adrenal sources such as the thymus or intestine, thus providing local control of GC-mediated effects. The thymus reportedly produces GC, but whether thymic epithelial cells or thymocytes produce GC acting either in an autocrine or paracrine fashion is not clear. We studied the expression of two main enzymes involved in de novo GC synthesis, CYP11A1 and CYP11B1, as well as the expression and activity of HSD11B1, an enzyme catalyzing interconversion of inert GC metabolites with active GC. While we found no evidence of de novo GC synthesis in both thymocytes and peripheral T cells, abundant regeneration of GC from the inactive metabolite 11-dehydrocorticosterone was detectable. Irrespective of their maturation stage, T cells that produced GC in this manner undergo autonomous cell death as this was blocked when glucocorticoid receptor-deficient T cells were treated with GC metabolites. These results indicate that both immature and mature T cells possess the capacity to undergo apoptosis in response to intrinsically generated GC. Consequently, positive selection of thymocytes, as well as survival of peripheral T cells may depend on TCR-induced escape of otherwise HSD11B1-driven autonomous T-cell death. PMID- 28726774 TI - Interleukin-22 ameliorated renal injury and fibrosis in diabetic nephropathy through inhibition of NLRP3 inflammasome activation. AB - Diabetic nephropathy (DN) is one of the most lethal complications of diabetes mellitus with metabolic disorders and chronic inflammation. Although the cytokine IL-22 was initially implicated in the pathogenesis of chronic inflammatory diseases, recent studies suggested that IL-22 could suppress inflammatory responses and alleviate tissue injury. Herein, we examined the role of IL-22 in DN. We found that serum levels of IL-22 were significantly downregulated in both patients and mice with DN. The expression of IL-22 was further decreased with the progression of DN, whereas IL-22 gene therapy significantly ameliorated renal injury and mesangial matrix expansion in mice with established nephropathy. IL-22 could also markedly reduce high glucose-induced and TGF-beta1-induced overexpression of fibronectin and collagen IV in mouse renal glomerular mesangial cells in a dose-dependent manner, suggesting the potential role of IL-22 to inhibit the overproduction of ECM in vitro. Simultaneously, IL-22 gene therapy drastically alleviated renal fibrosis and proteinuria excretion in DN. In addition, IL-22 gene therapy markedly attenuated hyperglycemia and metabolic disorders in streptozotocin-induced experimental diabetic mice. Notably, IL-22 drastically reversed renal activation of NLRP3, cleavage of caspase-1, and the maturation of IL-1beta in DN, suggesting unexpected anti-inflammatory function of IL-22 via suppressing the activation of NLRP3 inflammasome in vivo. Moreover, IL 22 markedly downregulated high glucose-induced activation of NLRP3 inflammasome in renal mesangial cells in a dose-dependent manner, indicating that the effects of IL-22 on NLRP3 inflammasome activation was independent of improved glycemic control. These results suggested that nephroprotection by IL-22 in DN was most likely associated with reduced activation of NLRP3 inflammasome. In conclusion, our finding demonstrated that IL-22 could exert favorable effects on DN via simultaneously alleviating systemic metabolic syndrome and downregulating renal NLRP3/caspase-1/IL-1beta pathway, suggesting that IL-22 might have therapeutic potential for the treatment of DN. PMID- 28726775 TI - Oroxylin A activates PKM1/HNF4 alpha to induce hepatoma differentiation and block cancer progression. AB - Liver cancer is the second cause of death from cancer worldwide, without effective treatment. Traditional chemotherapy for liver cancer has big side effects for patients, whereas targeted drugs, such as sorafenib, commonly have drug resistance. Oroxylin A (OA) is the main bioactive flavonoids of Scutellariae radix, which has strong anti-hepatoma effect but low toxicity to normal tissue. To date, no differentiation-inducing agents have been reported to exert a curative effect on solid tumors. Here our results demonstrated that OA restrained the proliferation and induced differentiation of hepatoma both in vitro and in vivo, via inducing a high PKM1 (pyruvate kinase M1)/PKM2 (pyruvate kinase M2) ratio. In addition, inhibited expression of polypyrimidine tract-binding protein by OA was in charge of the decrease of PKM2 and increase of PKM1. Further studies demonstrated that increased PKM1 translocated into the nucleus and bound with HNF 4alpha (hepatocyte nuclear factor 4 alpha) directly, promoting the transcription of HNF-4alpha-targeted genes. This work suggested that OA increased PKM1/PKM2 ratio, resulting in HNF-4alpha activation and hepatoma differentiation. Especially, OA showed reliable anticancer effect on both human primary hepatocellular carcinoma cells and patient-derived tumor xenograft model for hepatoma, and slowed down the development of primary hepatoma, suggesting that OA could be developed into a novel differentiation inducer agent for hepatoma. PMID- 28726776 TI - Autophagosome maturation mediated by Rab7 contributes to neuroprotection of hypoxic preconditioning against global cerebral ischemia in rats. AB - Autophagy disruption leads to neuronal damage in hypoxic-ischemic brain injury. Rab7, a member of the Rab GTPase superfamily, has a unique role in the regulation of autophagy. Hypoxic preconditioning (HPC) provides neuroprotection against transient global cerebral ischemia (tGCI). However, the underlying mechanisms remain poorly understood. Thus, the current study explored the potential molecular mechanism of the neuroprotective effect of HPC by investigating how Rab7 mediates autophagosome (AP) maturation after tGCI in adult rats. We found that HPC attenuated AP accumulation in the hippocampal CA1 region after tGCI via restoration of autophagic flux. We also confirmed that this HPC-induced neuroprotection was not caused by the increase in lysosomes or the improvement of lysosomal function after tGCI. Electron microscopic analysis then revealed an increase in autolysosomes in CA1 neurons of HPC rats. Moreover, the inhibition of autophagosome-lysosome fusion by chloroquine significantly aggravated neuronal death in CA1, indicating that AP maturation contributes to HPC-induced neuroprotection against neuronal injury after tGCI. Furthermore, the activation of Rab7 was found to be involved in the neuroprotective effect of AP maturation after HPC. At last, the knockdown of ultraviolet radiation resistance-associated gene (UVRAG) in vivo disrupted the interaction between Vps16 and Rab7, attenuated the activation of Rab7, interrupted autophagic flux, and ultimately abrogated the HPC-induced neuroprotection against tGCI. Our results indicated that AP maturation was enhanced by the activation of Rab7 via UVRAG-Vps16 interaction, which further demonstrated the potential neuroprotective role of Rab7 in HPC against tGCI-induced neuronal injury in adult rats. PMID- 28726777 TI - Humanin G (HNG) protects age-related macular degeneration (AMD) transmitochondrial ARPE-19 cybrids from mitochondrial and cellular damage. AB - Age-related macular degeneration (AMD) ranks third among the leading causes of visual impairment with a blindness prevalence rate of 8.7%. Despite several treatment regimens, such as anti-angiogenic drugs, laser therapy, and vitamin supplementation, being available for wet AMD, to date there are no FDA-approved therapies for dry AMD. Substantial evidence implicates mitochondrial damage and retinal pigment epithelium (RPE) cell death in the pathogenesis of AMD. However, the effects of AMD mitochondria and Humanin G (HNG), a more potent variant of the mitochondrial-derived peptide (MDP) Humanin, on retinal cell survival have not been elucidated. In this study, we characterized mitochondrial and cellular damage in transmitochondrial cybrid cell lines that contain identical nuclei but possess mitochondria from either AMD or age-matched normal (Older-normal (NL)) subjects. AMD cybrids showed (1) reduced levels of cell viability, lower mtDNA copy numbers, and downregulation of mitochondrial replication/transcription genes and antioxidant enzyme genes; and (2) elevated levels of genes related to apoptosis, autophagy and ER-stress along with increased mtDNA fragmentation and higher susceptibility to amyloid-beta-induced toxicity compared to NL cybrids. In AMD cybrids, HNG protected the AMD mitochondria, reduced pro-apoptosis gene and protein levels, upregulated gp130 (a component of the HN receptor complex), and increased the protection against amyloid-beta-induced damage. In summary, in cybrids, damaged AMD mitochondria mediate cell death that can be reversed by HNG treatment. Our results also provide evidence of Humanin playing a pivotal role in protecting cells with AMD mitochondria. In the future, it may be possible that AMD patient's blood samples containing damaged mitochondria may be useful as biomarkers for this condition. In conclusion, HNG may be a potential therapeutic target for treatment of dry AMD, a debilitating eye disease that currently has no available treatment. Further studies are needed to establish HNG as a viable mitochondria-targeting therapy for dry AMD. PMID- 28726778 TI - Protection of Mcc950 against high-glucose-induced human retinal endothelial cell dysfunction. AB - Diabetic retinopathy (DR) is a well-known microvascular complication related to inflammation. Mcc950 is a potent and specific inhibitor of the NLRP3 inflammasome but its influence on DR has not been studied. Thus, we evaluated the anti inflammatory effects of Mcc950 on high-glucose-induced human retinal endothelial cells (HRECs) and the potential underlying mechanism. In surgical excised proliferative membranes from DR patients, high expression of NLRP3, caspase 1 and IL-1beta was observed and co-localization of NLRP3 and IL-1beta occurred in CD31+ labeled HRECs. Moreover, in high-glucose-stimulated HRECs, increased production of the NLRP3 inflammasome activation and severe apoptosis were rescued with Mcc950 treatment. Additionally, the inhibitory effect of Mcc950 was mimicked through downregulation of NEK7 by siRNA in high-glucose-induced HRECs and Mcc950 treatment remarkably inhibited Nek7 and NLRP3 interactions by co immunoprecipitation, suggesting that Mcc950 may be a potentially protective agent against inflammation, likely via downregulation of the Nek7-NLRP3 pathway. In conclusion, Mcc950 inhibited HREC dysfunction under high-glucose conditions and this research may offer insight for future pharmaceutical approaches for treating DR. PMID- 28726779 TI - Maml1 acts cooperatively with Gli proteins to regulate sonic hedgehog signaling pathway. AB - Sonic hedgehog (Shh) signaling is essential for proliferation of cerebellar granule cell progenitors (GCPs) and its misregulation is linked to various disorders, including cerebellar cancer medulloblastoma. The effects of Shh pathway are mediated by the Gli family of transcription factors, which controls the expression of a number of target genes, including Gli1. Here, we identify Mastermind-like 1 (Maml1) as a novel regulator of the Shh signaling since it interacts with Gli proteins, working as a potent transcriptional coactivator. Notably, Maml1 silencing results in a significant reduction of Gli target genes expression, with a negative impact on cell growth of NIH3T3 and Patched1-/- mouse embryonic fibroblasts (MEFs), bearing a constitutively active Shh signaling. Remarkably, Shh pathway activity results severely compromised both in MEFs and GCPs deriving from Maml1-/- mice with an impairment of GCPs proliferation and cerebellum development. Therefore Maml1-/- phenotype mimics aspects of Shh pathway deficiency, suggesting an intrinsic requirement for Maml1 in cerebellum development. The present study shows a new role for Maml1 as a component of Shh signaling, which plays a crucial role in both development and tumorigenesis. PMID- 28726780 TI - FOXQ1 regulates senescence-associated inflammation via activation of SIRT1 expression. AB - Cellular senescence is an initial barrier to tumor development that prevents the proliferation of premalignant cells. However, some of the features of senescent cells seem to promote tumor progression via senescence-associated secretory phenotype (SASP). Here, we demonstrated that the protein level of forkhead box Q1 (FOXQ1), which highly overexpresses in several kinds of tumors, was significantly downregulated during both replicative and oncogene-induced senescence. Moreover, overexpression of FOXQ1 delayed senescence, whereas FOXQ1 silence led to premature senescence in human fibroblasts. Furthermore, we identified that FOXQ1 upregulated SIRT1 expression through transcriptional regulation via directly binding to the SIRT1 promoter. Finally, we showed that FOXQ1 remarkably inhibited the replicative senescence through depressing the expression of the inflammatory cytokines interleukin-6 (IL-6) and IL-8 via modulation of SIRT1-NF-kappaB pathway. In addition, FOXQ1 overexpressed in human esophageal cancer cells and ablation of FOXQ1 restrained the tumourigenic ability of the esophageal cancer cells (EC109 and EC9706) in a mouse xenograft model in vivo. Taken together, these findings uncover a previously unidentified role of FOXQ1 regulating SASP and tumor development at same time. PMID- 28726781 TI - Autophagy inhibition reduces chemoresistance and tumorigenic potential of human ovarian cancer stem cells. AB - Epithelial ovarian cancer (EOC) is one of the most malignant gynecological tumors with a high mortality rate owing to tumor relapse after anticancer therapies. It is widely accepted that a rare tumor cell population, known as cancer stem cells (CSC), is responsible for tumor progression and relapse; intriguingly, these cells are able to survive nutrient starvation (such as in vitro culture in the absence of glucose) and chemotherapy treatment. Recent data also indicated that chemotherapy resistance is associated with autophagy activation. We thus decided to investigate both in vitro and in vivo the autophagic activity and the effects of the perturbation of this pathway in CSC isolated from EOC ascitic effusions. Ovarian CSC, identified according to their CD44/CD117 co-expression, presented a higher basal autophagy compared with the non-stem counterpart. Inhibition of this pathway, by in vitro chloroquine treatment or CRISPR/Cas9 ATG5 knockout, impaired canonical CSC properties, such as viability, the ability to form spheroidal structures in vitro, and in vivo tumorigenic potential. In addition, autophagy inhibition showed a synergistic effect with carboplatin administration on both in vitro CSC properties and in vivo tumorigenic activity. On the whole, these results indicate that the autophagy process has a key role in CSC maintenance; inhibition of this pathway in combination with other chemotherapeutic approaches could represent a novel effective strategy to overcome drug resistance and tumor recurrence. PMID- 28726782 TI - PKCzeta phosphorylates TRAF2 to protect against intestinal ischemia-reperfusion induced injury. AB - Intestinal ischemia-reperfusion (I/R) is a common clinical problem that occurs during various clinical pathological processes. Excessive apoptosis has an indispensable role in intestinal I/R injury. Tumor necrosis factor receptor associated factor 2 (TRAF2) and PKCzeta have an essential role in apoptosis. Here, we aimed to investigate the effects of PKCzeta and TRAF2 and to explore the correlation between PKCzeta and TRAF2 in intestinal I/R injury. Mice were subjected to intestinal I/R injury in vivo. In vitro experiments were conducted by treating Caco-2 cells with hypoxia/reoxygenation (H/R) stimulation to simulate intestinal I/R. Intestinal tissue samples and Caco-2 cells were examined using various approaches. Intestinal I/R induced the membrane translocation and phosphorylation of PKCzeta. Pretreatment with the PKCzeta activator phosphatidylcholine remarkably attenuated gut injury by suppressing apoptosis. H/R induced PKCzeta to combine with TRAF2, which was phosphorylated by PKCzeta at Ser55, but not at Ser11, under intestinal I/R or H/R conditions. In addition, TRAF2 Ser55 phosphorylation increased cell survival by inhibiting cell apoptosis in the H/R model. Mechanistically, TRAF2 Ser55 phosphorylation promoted NF-kappaB activation but suppressed c-Jun activation in Caco-2 cells under H/R conditions. The results of this study demonstrate that the PKCzeta/TRAF2 pathway represents a novel protective mechanism against intestinal I/R injury. Therefore, the PKCzeta/TRAF2 pathway is a novel target for potential treatments of intestinal I/R injury-related diseases. PMID- 28726784 TI - Binding of doxorubicin to Sorcin impairs cell death and increases drug resistance in cancer cells. AB - Sorcin is a calcium binding protein that plays an important role in multidrug resistance (MDR) in tumors, since its expression confers resistance to doxorubicin and to other chemotherapeutic drugs. In this study, we show that Sorcin is able to bind doxorubicin, vincristine, paclitaxel and cisplatin directly and with high affinity. The high affinity binding of doxorubicin to sorcin has been demonstrated with different techniques, that is, surface plasmon resonance, fluorescence titration and X-ray diffraction. Although the X-ray structure of sorcin in complex with doxorubicin has been solved at low resolution, it allows the identification of one of the two doxorubicin binding sites, placed at the interface between the EF5 loop the G helix and the EF4 loop. We show that Sorcin cellular localization changes upon doxorubicin treatment, an indication that the protein responds to doxorubicin and it presumably binds the drug also inside the cell, soon after drug entrance. We also demonstrate that Sorcin is able to limit the toxic effects of the chemotherapeutic agent in the cell. In addition, Sorcin silencing increases cell death upon treatment with doxorubicin, increases the accumulation of doxorubicin in cell nucleus, decreases the expression of MDR1 and doxorubicin efflux via MDR1. PMID- 28726783 TI - KMT2A promotes melanoma cell growth by targeting hTERT signaling pathway. AB - Melanoma is an aggressive cutaneous malignancy, illuminating the exact mechanisms and finding novel therapeutic targets are urgently needed. In this study, we identified KMT2A as a potential target, which promoted the growth of human melanoma cells. KMT2A knockdown significantly inhibited cell viability and cell migration and induced apoptosis, whereas KMT2A overexpression effectively promoted cell proliferation in various melanoma cell lines. Further study showed that KMT2A regulated melanoma cell growth by targeting the hTERT-dependent signal pathway. Knockdown of KMT2A markedly inhibited the promoter activity and expression of hTERT, and hTERT overexpression rescued the viability inhibition caused by KMT2A knockdown. Moreover, KMT2A knockdown suppressed tumorsphere formation and the expression of cancer stem cell markers, which was also reversed by hTERT overexpression. In addition, the results from a xenograft mouse model confirmed that KMT2A promoted melanoma growth via hTERT signaling. Finally, analyses of clinical samples demonstrated that the expression of KMT2A and hTERT were positively correlated in melanoma tumor tissues, and KMT2A high expression predicted poor prognosis in melanoma patients. Collectively, our results indicate that KMT2A promotes melanoma growth by activating the hTERT signaling, suggesting that the KMT2A/hTERT signaling pathway may be a potential therapeutic target for melanoma. PMID- 28726785 TI - JUN is important for ocular hypertension-induced retinal ganglion cell degeneration. AB - Ocular hypertension, a major risk factor for glaucoma, is thought to trigger glaucomatous neurodegeneration through injury to retinal ganglion cell (RGC) axons. The molecular signaling pathway leading from ocular hypertension to RGC degeneration, however, is not well defined. JNK signaling, a component of the mitogen-activated protein kinase (MAPK) family, and its canonical target, the transcription factor JUN, have been shown to regulate neurodegeneration in many different systems. JUN is expressed after glaucoma-relevant injuries and Jun deficiency protects RGCs after mechanical injury to the optic nerve. Here, we tested the importance of JNK-JUN signaling for RGC death after ocular hypertensive axonal injury in an age-related, mouse model of ocular hypertension. Immunohistochemistry was performed to evaluate JUN expression in ocular hypertensive DBA/2J mice. JUN was expressed in a temporal and spatial pattern consistent with a role in glaucomatous injury. To determine the importance of JUN in ocular hypertension-induced RGC death, a floxed allele of Jun and a retinal expressed cre recombinase (Six3-cre) were backcrossed onto the DBA/2J background. Intraocular pressure (IOP) and gross morphology of the retina and optic nerve head were assessed to determine whether removing Jun from the developing retina altered IOP elevation or retinal development. Jun deficiency in the retina did not alter DBA/2J IOP elevation or retinal development. Optic nerves and retinas were assessed at ages known to have glaucomatous damage in DBA/2J mice. Jun deficiency protected RGC somas from ocular hypertensive injury, but did not protect RGC axons from glaucomatous neurodegeneration. Jun is a major regulator of RGC somal degeneration after glaucomatous ocular hypertensive injury. These results suggest in glaucomatous neurodegeneration, JNK-JUN signaling has a major role as a pro-death signaling pathway between axonal injury and somal degeneration. PMID- 28726786 TI - Calcium-binding protein S100A14 induces differentiation and suppresses metastasis in gastric cancer. AB - S100A14 is a calcium-binding protein involved in cell proliferation and differentiation as well as the metastasis of human tumors. In this study, we characterized the regulation of S100A14 expression between biological signatures and clinical pathological features in gastric cancer (GC). Our data demonstrated that S100A14 induced the differentiation of GC by upregulating the expression of E-cadherin and PGII. Moreover, S100A14 expression negatively correlated with cell migration and invasion in in vitro and in vivo experimental models. Interestingly, S100A14 blocked the store-operated Ca2+ influx by suppressing Orai1 and STIM1 expression, leading to FAK expression activation, focal adhesion assembly and MMP downregulation. Taken together, our results indicate that S100A14 may have a role in the induction of differentiation and inhibition of cell metastasis in GC. PMID- 28726787 TI - ALKBH7 drives a tissue and sex-specific necrotic cell death response following alkylation-induced damage. AB - Regulated necrosis has emerged as a major cell death mechanism in response to different forms of physiological and pharmacological stress. The AlkB homolog 7 (ALKBH7) protein is required for regulated cellular necrosis in response to chemotherapeutic alkylating agents but its role within a whole organism is unknown. Here, we show that ALKBH7 modulates alkylation-induced cellular death through a tissue and sex-specific mechanism. At the whole-animal level, we find that ALKBH7 deficiency confers increased resistance to MMS-induced toxicity in male but not female mice. Moreover, ALKBH7-deficient mice exhibit protection against alkylation-mediated cytotoxicity in retinal photoreceptor and cerebellar granule cells, two cell types that undergo necrotic death through the initiation of the base excision repair pathway and hyperactivation of the PARP1/ARTD1 enzyme. Notably, the protection against alkylation-induced cerebellar degeneration is specific to ALKBH7-deficient male but not female mice. Our results uncover an in vivo role for ALKBH7 in mediating a sexually dimorphic tissue response to alkylation damage that could influence individual responses to chemotherapies based upon alkylating agents. PMID- 28726788 TI - Neuroprotection by eIF2alpha-CHOP inhibition and XBP-1 activation in EAE/optic neuritiss. AB - No therapies exist to prevent neuronal deficits in multiple sclerosis (MS), because the molecular mechanism responsible for the progressive neurodegeneration is unknown. We previously showed that axon injury-induced neuronal endoplasmic reticulum (ER) stress plays an important role in retinal ganglion cell (RGC) death and optic nerve degeneration in traumatic and glaucomatous optic neuropathies. Optic neuritis, one of the most common clinical manifestations of MS, is readily modeled by experimental autoimmune encephalomyelitis (EAE) in mouse. Using this in vivo model, we now show that ER stress is induced early in EAE and that modulation of ER stress by inhibition of eIF2alpha-CHOP and activation of XBP-1 in RGC specifically, protects RGC somata and axons and preserves visual function. This finding adds to the evidence that ER stress is a general upstream mechanism for neurodegeneration and suggests that targeting ER stress molecules is a promising therapeutic strategy for neuroprotection in MS. PMID- 28726789 TI - Predominant area of brain lesions in neonates with herpes simplex encephalitis. AB - OBJECTIVE: Nonspecific manifestations and a varied distribution of brain lesions can delay the diagnosis of herpes simplex encephalitis (HSE) in neonates. The aim of this study was to report predominant brain lesions in neonatal HSE, and then to investigate the association between pattern of predominant brain lesions, clinical variables and neurodevelopmental outcome. STUDY DESIGN: A multicenter retrospective study was performed in neonates diagnosed with HSE between 2009 and 2014. Magnetic resonance (MR) images, including diffusion-weighted images, were obtained in the acute and chronic phase. RESULTS: Three predominant areas of brain injury could be defined based on characteristic MRI findings in 10 of the 13 infants (77%). The inferior frontal/temporal pole area was involved in five (38%) patients. The watershed distribution was present in six (46%) patients. Four (31%) infants involved the corticospinal tract area. No significant association was found between any predominant distribution of brain lesion pattern and sex, country, viral type or viral load. However, the corticospinal tract involvement was significantly associated with motor impairment (P=0.045). CONCLUSION: Three predominant areas of brain lesion could be recognized in neonatal HSE. Recognition of those areas can improve prediction of neurodevelopmental outcome. PMID- 28726790 TI - Improvements in the delivery of resuscitation and newborn care after Helping Babies Breathe training. AB - BACKGROUND: To evaluate changes in neonatal resuscitation and postnatal care following Helping Babies Breathe (HBB) training at a community hospital in rural Honduras. We hypothesized that HBB training would improve resuscitation and essential newborn care interventions. METHODS: Direct observation and video recording of delivery room care spanned before and after an initial HBB workshop held in August 2013. Rates of essential newborn care interventions were compared in resuscitations performed by individuals who had and had not received HBB training, and run charts recording performance of newborn care practices over time were developed. RESULTS: Ten percent of deliveries (N=250) were observed over the study period, with 156 newborn resuscitations performed by individuals without HBB training, compared to 94 resuscitations performed by HBB trainees. After HBB training, significant improvements were seen in skin-to-skin care, breastfeeding within 60 min of age, and delayed cord clamping after 1 min (all P<0.01). More babies cared for by HBB trainees received basic neonatal resuscitation such as drying and stimulation. Run charts tracking these practices over time showed significant improvements after HBB training that were sustained during the study period, but remained below ideal goals. With improvement in drying/stimulation practices, fewer babies required bag/mask ventilation. CONCLUSION: In a rural Honduran community hospital, improvements in basic neonatal resuscitation and postnatal essential newborn care practices can be seen after HBB training. Further improvements in newborn care practices may require focused quality improvement initiatives for hospitals to sustain high quality care. PMID- 28726793 TI - Correction: Vitamin B12 deficiency. AB - This corrects the article DOI: 10.1038/nrdp.2017.40. PMID- 28726791 TI - Implementation of a multidisciplinary guideline improves preterm infant admission temperatures. AB - BACKGROUND: Hypothermia is a common problem in preterm infants immediately following delivery.Local problem:The rate of admission hypothermia in our neonatal intensive care unit (NICU) was above the rate of comparable NICUs in the Vermont Oxford Network. METHODS: To reduce the rate of preterm admission hypothermia, a quality improvement (QI) project was implemented, utilizing the plan-do-study-act (PDSA) methodology. A guideline for delivery room thermoregulation management in <35-week infants at the University of Virginia was created and put into practice by a multidisciplinary team. INTERVENTIONS: Clinical practice changes in the guideline included: increasing operating room temperatures, obtaining a 10-min axillary temperature, using an exothermic mattress for all infants <35 weeks, and using a polyethylene wrap for infants <32 weeks. RESULTS: The baseline rate of hypothermia (<36.5 degrees CC) was 63%. Three PDSA cycles data were completed on 168 consecutive preterm births. The post implementation rate of hypothermia (<36.5 degrees C) was reduced to 30% (P<0.001). The incidence of moderate hypothermia (< 36 degrees C) was reduced from a baseline of 29% to a rate of 9% (P<0.001). CONCLUSION: Use of a multidisciplinary guideline to increase preterm NICU admission temperatures resulted in a decrease in hypothermic infants. PMID- 28726794 TI - Biological iron-sulfur storage in a thioferrate-protein nanoparticle. AB - Iron-sulfur clusters are ubiquitous in biology and function in electron transfer and catalysis. They are assembled from iron and cysteine sulfur on protein scaffolds. Iron is typically stored as iron oxyhydroxide, ferrihydrite, encapsulated in 12 nm shells of ferritin, which buffers cellular iron availability. Here we have characterized IssA, a protein that stores iron and sulfur as thioferrate, an inorganic anionic polymer previously unknown in biology. IssA forms nanoparticles reaching 300 nm in diameter and is the largest natural metalloprotein complex known. It is a member of a widely distributed protein family that includes nitrogenase maturation factors, NifB and NifX. IssA nanoparticles are visible by electron microscopy as electron-dense bodies in the cytoplasm. Purified nanoparticles appear to be generated from 20 nm units containing ~6,400 Fe atoms and ~170 IssA monomers. In support of roles in both iron-sulfur storage and cluster biosynthesis, IssA reconstitutes the [4Fe-4S] cluster in ferredoxin in vitro. PMID- 28726795 TI - A retrospective analysis of hypertension screening at a mass gathering in India: implications for non-communicable disease control strategies. AB - Cardiovascular disease is the leading case of mortality from non-communicable diseases (NCD) in India. The government's National Programme for Prevention and Control of Cancer, Diabetes, Cardiovascular Diseases and Stroke seeks to increase capacity building, screening, referral and management of NCDs across India, and includes community-based outreach and screening programmes. The government in India routinely provides basic care at religious mass gatherings. However, in 2015, at the Kumbh Mela in Nashik and Trimbakeshwar, the state government extended its services to include a hypertension screening programme. We examine here the value and implications of such opportunistic screening at mass gatherings. At the Kumbh, 5760 persons voluntarily opted for hypertension screening, and received a single blood pressure measurement. In all, 1783 (33.6%) screened positive, of whom, 1580 were previously unaware of their diagnosis. Of the 303 that had previously known hypertension, 240 (79%) were prescribed medications, and 160 were compliant (that is, 52.8% under treatment). Fifty-five (18%) had normal blood pressure readings (BP under control). The data also demonstrated higher prevalence (39%) of hypertension among tobacco users compared to non-users (28%) (P<0.001). Poor recording of phone numbers (0.01%) precluded any phone-based follow-up. The low rates of hypertension awareness, treatment and control underscore the ongoing challenge of both hypertension screening and management in India. PMID- 28726796 TI - Three-year change in endothelin-1 and markers of vascular remodelling in a bi ethnic South African cohort: the SABPA study. AB - South Africans are at high risk for developing cardiovascular disease. Endothelin 1 is known for its vasoconstrictive properties and its ability to contribute to vascular structural changes. In this study we investigated the association of change in endothelin-1 levels and change in markers implicated in vascular remodelling after 3 years. Serum endothelin-1 levels and markers of vascular remodelling such as carotid intima-media thickness, carotid cross-sectional wall area (CSWA) and arterial compliance were measured. Participants were divided into two groups according to an increase (n=185) and a decrease (n=152) in plasma endothelin-1 levels after 3 years. In partial regression analysis, the extent of endothelin-1 increase correlated positively with a change in pulse pressure and inversely with the change in arterial compliance in the group with increased endothelin-1 levels after 3 years. In the group with decreased endothelin-1 levels, the extent of decreased endothelin-1 correlated inversely with a change in CSWA. In multiple regression analysis, after splitting for race, the increase in endothelin-1 levels associated positively with the change in pulse pressure (Adj. R2=0.092; beta=0.278; P=0.036) in the black participants only. In conclusion, with increased endothelin-1 levels after 3 years, the positive association between endothelin-1 and pulse pressure suggest subclinical haemodynamic changes with potential premature onset of cardiovascular disease in the black participants. PMID- 28726797 TI - Multiple myeloma. AB - Multiple myeloma is a malignancy of terminally differentiated plasma cells, and patients typically present with bone marrow infiltration of clonal plasma cells and monoclonal protein in the serum and/or urine. The diagnosis of multiple myeloma is made when clear end-organ damage attributable to the plasma cell proliferative disorder or when findings that suggest a high likelihood of their development are present. Distinguishing symptomatic multiple myeloma that requires treatment from the precursor stages of monoclonal gammopathy of undetermined significance and smouldering multiple myeloma is important, as observation is the standard for those conditions. Much progress has been made over the past decade in the understanding of disease biology and individualized treatment approaches. Several new classes of drugs, such as proteasome inhibitors and immunomodulatory drugs, have joined the traditional armamentarium (corticosteroids, alkylating agents and anthracyclines) and, along with high-dose therapy and autologous haemopoietic stem cell transplantation, have led to deeper and durable clinical responses. Indeed, an increasing proportion of patients are achieving lasting remissions, raising the possibility of cure for this disease. Success will probably depend on using combinations of effective agents and treating patients in the early stages of disease, such as patients with smouldering multiple myeloma. PMID- 28726798 TI - Gene therapy research in Asia. AB - Gene therapy has shown great potential for the treatment of diseases that previously were either untreatable or treatable but not curable with conventional schemes. Recent progress in clinical gene therapy trials has emerged in various severe diseases, including primary immunodeficiencies, leukodystrophies, Leber's congenital amaurosis, haemophilia, as well as retinal dystrophy. The clinical transformation and industrialization of gene therapy in Asia have been remarkable and continue making steady progress. A total of six gene therapy-based products have been approved worldwide, including two drugs from Asia. This review aims to highlight recent progress in gene therapy clinical trials and discuss the prospects for the future in China and wider Asia. PMID- 28726799 TI - The Insular Cortex Dynamically Maps Changes in Cardiorespiratory Interoception. AB - Palpitations and dyspnea are fundamental to the human experience of panic anxiety, but it remains unclear how the brain dynamically represents changes in these interoceptive sensations. We used isoproterenol, a rapidly acting peripheral beta-adrenergic agonist similar to adrenaline, to induce sensations of palpitation and dyspnea in healthy individuals (n=23) during arterial spin labeling functional magnetic resonance imaging (fMRI). We hypothesized that the right mid-insular cortex, a central recipient of viscerosensory input, would preferentially respond during the peak period of cardiorespiratory stimulation. Bolus infusions of saline and isoproterenol (1 or 2 MUg) were administered in a blinded manner while participants continuously rated the intensity of their cardiorespiratory sensation using a dial. Isoproterenol elicited dose-dependent increases in cardiorespiratory sensation, with all participants reporting palpitations and dyspnea at the 2 MUg dose. Consistent with our hypothesis, the right mid-insula was maximally responsive during the peak period of sympathetic arousal, heart rate increase, and cardiorespiratory sensation. Furthermore, a shift in insula activity occurred during the recovery period, after the heart rate had largely returned to baseline levels, with an expansion of activation into anterior and posterior sectors of the right insula, as well as bilateral regions of the mid-insula. These results confirm the right mid-insula is a key node in the interoceptive network, and inform computational models proposing specific processing roles for insula subregions during homeostatic inference. The combination of isoproterenol and fMRI offers a powerful approach for evaluating insula function, and could be a useful probe for examining interoceptive dysfunction in psychiatric disorders. PMID- 28726800 TI - Role of Nicotinamide N-Methyltransferase in Dorsal Striatum in Cocaine Place Preference. AB - Nicotinamide N-methyltransferase (NNMT) transfers the methyl from S-adenosyl-L methionine (SAM) to nicotinamide (NA) to produce S-adenosyl-L-homocysteine (SAH) and 1-methylnicotinamide (MeN). NNMT has been implicated in a variety of diseases; however, the role of NNMT in drug addiction is largely unknown. Here, we found that the expression of Nnmt was significantly upregulated in the dorsal striatum (DS) of cocaine-conditioned mice. Cocaine significantly decreased SAM/SAH ratio levels in the DS, which was accompanied with the decreased activities of Rac1 and RhoA. Lentivirus-mediated knockdown of Nnmt in the dorsomedial striatum (DMS) attenuated cocaine conditioned place preference (CPP) reward, but increased striatal SAM/SAH ratio levels as well as Rac1 and RhoA activities. In addition, pharmacological inhibition of NNMT through intra-DMS infusion of MeN attenuated cocaine CPP and the activities of Rac1 and RhoA, but increased SAM/SAH ratio. These results suggest that NNMT-dependent transmethylation is involved in the activation of Rac1 and RhoA, which utilize SAM as a methyl donor cofactor. Co-immunoprecipitation assay using a RhoGDIalpha antibody indirectly captured Rac1 or RhoA that were bound to RhoGDIalpha. The results showed that cocaine increased the association of RhoGDIalpha with Rac1 or RhoA, whereas such effect was inhibited by Nnmt knockdown. Collectively, our findings show that NNMT regulates cocaine CPP through SAM-mediated modification of Rac1 and RhoA. PMID- 28726801 TI - Accumbens Mechanisms for Cued Sucrose Seeking. AB - Many studies support a perspective that addictive drugs usurp brain circuits used by natural rewards, especially for the dopamine-dependent reinforcing qualities of both drugs and natural rewards. Reinstated drug seeking in animal models of relapse relies on glutamate spillover from cortical terminals synapsing in the nucleus accumbens core (NAcore) to stimulate metabotropic glutamate receptor5 (mGluR5) on neuronal nitric oxide synthase (nNOS) interneurons. Contrasting the release of dopamine that is shared by sucrose and drugs of abuse, reinstated sucrose seeking does not induce glutamate spillover. We hypothesized that pharmacologically promoting glutamate spillover in the NAcore would mimic cocaine induced adaptations and potentiate cued reinstatement of sucrose seeking. Inducing glutamate spillover by blocking astroglial glutamate transporters (GLT 1) had no effect on reinstated sucrose seeking. However, glutamate release probability is negatively regulated by presynaptic mGluR2/3, and sucrose reinstatement was potentiated following mGluR2/3 blockade. Potentiated sucrose reinstatement by mGluR2/3 blockade was reversed by antagonizing mGluR5, but reinstated sucrose seeking in the absence of mGluR2/3 blockade was not affected by blocking mGluR5. In cocaine-trained rodents mGluR5 stimulation reinstates drug seeking by activating nNOS, but activating mGluR5 did not promote reinstated sucrose seeking, nor was potentiated reinstatement after mGluR2/3 blockade reduced by blocking nNOS. However, chemogenetic activation of nNOS interneurons in the NAcore reinstated sucrose seeking. These data indicate that dysregulated presynaptic mGluR2/3 signaling is a possible site of shared signaling in drug seeking and potentiated reinstated sucrose seeking, but that downregulated glutamate transport and subsequent activation of nNOS by synaptic glutamate spillover is not shared. PMID- 28726802 TI - Strain-induced skeletal rearrangement of a polycyclic aromatic hydrocarbon on a copper surface. AB - Controlling the structural deformation of organic molecules can drive unique reactions that cannot be induced only by thermal, optical or electrochemical procedures. However, in conventional organic synthesis, including mechanochemical procedures, it is difficult to control skeletal rearrangement in polycyclic aromatic hydrocarbons (PAHs). Here, we demonstrate a reaction scheme for the skeletal rearrangement of PAHs on a metal surface using high-resolution noncontact atomic force microscopy. By a combination of organic synthesis and on surface cyclodehydrogenation, we produce a well-designed PAH-diazuleno[1,2,3 cd:1',2',3'-fg]pyrene-adsorbed flatly onto Cu(001), in which two azuleno moieties are highly strained by their mutual proximity. This local strain drives the rearrangement of one of the azuleno moieties into a fulvaleno moiety, which has never been reported so far. Our proposed thermally driven, strain-induced synthesis on surfaces will pave the way for the production of a new class of nanocarbon materials that conventional synthetic techniques cannot attain. PMID- 28726803 TI - Quality of life in men with Klinefelter syndrome: the impact of genotype, health, socioeconomics, and sexual function. AB - PurposeKlinefelter syndrome (KS) is associated with lower socioeconomic status and greater morbidity. However, relatively little is known about the quality of life for men with KS, or how KS and other factors combine to determine it.MethodsA total of 132 men with KS were recruited in clinics, and 313 matched controls were identified by Statistics Denmark. Demographics, socioeconomic status, health problems and behaviors, sexual function, medical follow-up, and mental and physical quality of life (MQoL and PQoL, respectively) were assessed for all participants through surveys.ResultsMen with KS reported significantly lower education attainment levels, income, physical activity, and both PQoL and MQoL, as well as more illness, medication, and sexual dysfunction. KS status was associated directly with lower PQoL, as well as indirectly through reduced income, physical activity, and sexual function, and increased body mass index. KS status and younger age were associated directly with lower MQoL, as well as indirectly through reduced income, physical activity, and partner status (for KS status), or through partner status (for age).ConclusionKS status is associated with lower PQoL and MQoL through both direct and indirect paths. These results suggest the need for more comprehensive research and clinical approaches to addressing quality of life for men with KS. PMID- 28726804 TI - Diagnostic cytogenetic testing following positive noninvasive prenatal screening results: a clinical laboratory practice resource of the American College of Medical Genetics and Genomics (ACMG). AB - Disclaimer: ACMG Clinical Laboratory Practice Resources are developed primarily as an educational tool for clinical laboratory geneticists to help them provide quality clinical laboratory genetic services. Adherence to these practice resources is voluntary and does not necessarily assure a successful medical outcome. This Clinical Laboratory Practice Resource should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, the clinical laboratory geneticist should apply his or her own professional judgment to the specific circumstances presented by the individual patient or specimen. Clinical laboratory geneticists are encouraged to document in the patient's record the rationale for the use of a particular procedure or test, whether or not it is in conformance with this Clinical Laboratory Practice Resource. They also are advised to take notice of the date any particular guideline was adopted, and to consider other relevant medical and scientific information that becomes available after that date. It also would be prudent to consider whether intellectual property interests may restrict the performance of certain tests and other procedures.Noninvasive prenatal screening (NIPS) using cell-free DNA has been rapidly adopted into prenatal care. Since NIPS is a screening test, diagnostic testing is recommended to confirm all cases of screen-positive NIPS results. For cytogenetics laboratories performing confirmatory testing on prenatal diagnostic samples, a standardized testing algorithm is needed to ensure that the appropriate testing takes place. This algorithm includes diagnostic testing by either chorionic villi sampling or amniocentesis samples and encompasses chromosome analysis, fluorescence in situ hybridization, and chromosomal microarray. PMID- 28726805 TI - PREPL deficiency: delineation of the phenotype and development of a functional blood assay. AB - PurposePREPL deficiency causes neonatal hypotonia, ptosis, neonatal feeding difficulties, childhood obesity, xerostomia, and growth hormone deficiency. Different recessive contiguous gene deletion syndromes involving PREPL and a variable combination of SLC3A1 (hypotonia-cystinuria syndrome), CAMKMT (atypical hypotonia-cystinuria syndrome), and PPM1B (2p21 deletion syndrome) have been described. In isolated PREPL deficiency, previously described only once, the absence of cystinuria complicates the diagnosis. Therefore, we developed a PREPL blood assay and further delineated the phenotype.MethodsClinical features of new subjects with PREPL deficiency were recorded. The presence of PREPL in lymphocytes and its reactivity with an activity-based probe were evaluated by western blot.ResultsFive subjects with isolated PREPL deficiency, three with hypotonia-cystinuria syndrome, and two with atypical hypotonia-cystinuria syndrome had nine novel alleles. Their IQs ranged from 64 to 112. Adult neuromuscular signs included ptosis, nasal dysarthria, facial weakness, and variable proximal and neck flexor weakness. Autonomic features are prevalent. PREPL protein and reactivity were absent in lymphocytes from subjects with PREPL deficiency, but normal in the clinically similar Prader-Willi syndrome.ConclusionPREPL deficiency causes neuromuscular, autonomic, cognitive, endocrine, and dysmorphic clinical features. PREPL is not deficient in Prader Willi syndrome. The novel blood test should facilitate the confirmation of PREPL deficiency. PMID- 28726807 TI - When genotype is not predictive of phenotype: implications for genetic counseling based on 21,594 chromosomal microarray analysis examinations. AB - PurposeTo compare the frequency of copy-number variants (CNVs) of variable penetrance in low-risk and high-risk prenatal samples and postnatal samples.MethodsTwo cohorts were categorized according to chromosomal microarray analysis (CMA) indication: group I, low-risk prenatal-women with uneventful pregnancy (control group); group II, high-risk prenatal-women whose fetuses had congenital malformations; and group III, postnatal-individuals with unexplained developmental delay/intellectual disability, autism spectrum disorders, or multiple congenital anomalies. CNVs were categorized based on clinical penetrance: (i) high (>40%), (ii) moderate (10-40%), and (iii) low (<10%).ResultsFrom 2013 to 2016, 21,594 CMAs were performed. The frequency of high-penetrance CNVs was 0.1% (21/15,215) in group I, 0.9% (26/2,791) in group II, and 2.6% (92/3,588) in group III. Moderate-penetrance CNV frequency was 0.3% (47/15,215), 0.6% (19/2,791), and 1.2% (46/3,588), respectively. These differences were statistically significant. The frequency of low-penetrance CNVs was not significantly different among groups: 0.6% (85/15,215), 0.9% (25/2,791), and 1.0% (35/3,588), respectively.ConclusionHigh-penetrance CNVs might be a major factor in the overall heritability of developmental, intellectual, and structural anomalies. Low-penetrance CNV alone does not seem to contribute to these anomalies. These data may assist pre- and posttest CMA counseling. PMID- 28726808 TI - Prevalence of germ-line mutations in cancer genes among pancreatic cancer patients with a positive family history. AB - PurposePanel-based genetic testing has identified increasing numbers of patients with pancreatic ductal adenocarcinoma (PDAC) who carry germ-line mutations. However, small sample sizes or number of genes evaluated limit prevalence estimates of these mutations. We estimated prevalence of mutations in PDAC patients with positive family history.MethodsWe sequenced 25 cancer susceptibility genes in lymphocyte DNA from 302 PDAC patients in the Mayo Clinic Biospecimen Resource for Pancreatic Research Registry. Kindreds containing at least two first-degree relatives with PDAC met criteria for familial pancreatic cancer (FPC), while the remaining were familial, but not FPC.ResultsThirty-six patients (12%) carried at least one deleterious mutation in one of 11 genes. Of FPC patients, 25/185 (14%) were carriers, while 11/117 (9%) non-FPC patients with family history were carriers. Deleterious mutations (n) identified in PDAC patients were BRCA2 (11), ATM (8), CDKN2A (4), CHEK2 (4), MUTYH/MYH (3 heterozygotes, not biallelic), BRCA1 (2), and 1 each in BARD1, MSH2, NBN, PALB2, and PMS2. Novel mutations were found in ATM, BARD1, and PMS2.ConclusionMultiple susceptibility gene testing in PDAC patients with family history of pancreatic cancer is warranted regardless of FPC status and will inform genetic risk counseling for families. PMID- 28726806 TI - Data sharing as a national quality improvement program: reporting on BRCA1 and BRCA2 variant-interpretation comparisons through the Canadian Open Genetics Repository (COGR). AB - PurposeThe purpose of this study was to develop a national program for Canadian diagnostic laboratories to compare DNA-variant interpretations and resolve discordant-variant classifications using the BRCA1 and BRCA2 genes as a case study.MethodsBRCA1 and BRCA2 variant data were uploaded and shared through the Canadian Open Genetics Repository (COGR; http://www.opengenetics.ca). A total of 5,554 variant observations were submitted; classification differences were identified and comparison reports were sent to participating laboratories. Each site had the opportunity to reclassify variants. The data were analyzed before and after the comparison report process to track concordant- or discordant variant classifications by three different models.ResultsVariant-discordance rates varied by classification model: 38.9% of variants were discordant when using a five-tier model, 26.7% with a three-tier model, and 5.0% with a two-tier model. After the comparison report process, the proportion of discordant variants dropped to 30.7% with the five-tier model, to 14.2% with the three-tier model, and to 0.9% using the two-tier model.ConclusionWe present a Canadian interinstitutional quality improvement program for DNA-variant interpretations. Sharing of variant knowledge by clinical diagnostic laboratories will allow clinicians and patients to make more informed decisions and lead to better patient outcomes. PMID- 28726809 TI - Genomic diagnostics within a medically underserved population: efficacy and implications. AB - PurposeWe integrated whole-exome sequencing (WES) and chromosomal microarray analysis (CMA) into a clinical workflow to serve an endogamous, uninsured, agrarian community.MethodsSeventy-nine probands (newborn to 49.8 years) who presented between 1998 and 2015 remained undiagnosed after biochemical and molecular investigations. We generated WES data for probands and family members and vetted variants through rephenotyping, segregation analyses, and population studies.ResultsThe most common presentation was neurological disease (64%). Seven (9%) probands were diagnosed by CMA. Family WES data were informative for 37 (51%) of the 72 remaining individuals, yielding a specific genetic diagnosis (n = 32) or revealing a novel molecular etiology (n = 5). For five (7%) additional subjects, negative WES decreased the likelihood of genetic disease. Compared to trio analysis, "family" WES (average seven exomes per proband) reduced filtered candidate variants from 22 +/- 6 to 5 +/- 3 per proband. Nineteen (51%) alleles were de novo and 17 (46%) inherited; the latter added to a population-based diagnostic panel. We found actionable secondary variants in 21 (4.2%) of 502 subjects, all of whom opted to be informed.ConclusionCMA and family-based WES streamline and economize diagnosis of rare genetic disorders, accelerate novel gene discovery, and create new opportunities for community-based screening and prevention in underserved populations. PMID- 28726810 TI - A randomized controlled trial of disclosing genetic risk information for Alzheimer disease via telephone. AB - PurposeTelephone disclosure of genetic test results can improve access to services. To date, studies of its impact have focused on return of Mendelian risk information, principally hereditary cancer syndromes.MethodsIn a multisite trial of Alzheimer disease genetic risk disclosure, asymptomatic adults were randomized to receive test results in person or via telephone. Primary analyses examined patient outcomes 12 months after disclosure.ResultsData from 257 participants showed that telephone disclosure occurred 7.4 days sooner and was 30% shorter, on average, than in-person disclosure (both P < 0.001). Anxiety and depression scores were well below cutoffs for clinical concern across protocols. Comparing telephone and in-person disclosure protocols, 99% confidence intervals of mean differences were within noninferiority margins on scales assessing anxiety, depression, and test-related distress, but inconclusive about positive impact. No differences were observed on measures of recall and subjective impact. Subanalyses supported noninferiority on all outcomes among apolipoprotein E (APOE) E4-negative participants. Subanalyses were inconclusive for APOE E4 positive participants, although mean anxiety and depression scores were still well below cutoffs for clinical concern.ConclusionTelephone disclosure of APOE results and risk for Alzheimer disease is generally safe and helps providers meet demands for services, even when results identify an increased risk for disease. PMID- 28726813 TI - Lung Cancer: Frontline nivolumab - CheckMate 026 ends in stalemate. PMID- 28726811 TI - Knowledge base and mini-expert platform for the diagnosis of inborn errors of metabolism. AB - PurposeRecognizing individuals with inherited diseases can be difficult because signs and symptoms often overlap those of common medical conditions. Focusing on inborn errors of metabolism (IEMs), we present a method that brings the knowledge of highly specialized experts to professionals involved in early diagnoses. We introduce IEMbase, an online expert-curated IEM knowledge base combined with a prototype diagnosis support (mini-expert) system.MethodsDisease-characterizing profiles of specific biochemical markers and clinical symptoms were extracted from an expert-compiled IEM database. A mini-expert system algorithm was developed using cosine similarity and semantic similarity. The system was evaluated using 190 retrospective cases with established diagnoses, collected from 15 different metabolic centers.ResultsIEMbase provides 530 well-defined IEM profiles and matches a user-provided phenotypic profile to a list of candidate diagnoses/genes. The mini-expert system matched 62% of the retrospective cases to the exact diagnosis and 86% of the cases to a correct diagnosis within the top five candidates. The use of biochemical features in IEM annotations resulted in 41% more exact phenotype matches than clinical features alone.ConclusionIEMbase offers a central IEM knowledge repository for many genetic diagnostic centers and clinical communities seeking support in the diagnosis of IEMs. PMID- 28726814 TI - WIN to avoid the valley of death. PMID- 28726812 TI - A patient with germ-line gain-of-function PDGFRB p.N666H mutation and marked clinical response to imatinib. AB - PurposeHeterozygous germ-line activating mutations in PDGFRB cause Kosaki and Penttinen syndromes and myofibromatosis. We describe a 10-year-old child with a germ-line PDGFRB p.N666H mutation who responded to the tyrosine kinase inhibitor imatinib by inhibition of PDGFRB.MethodsThe impact of p.N666H on PDGFRB function and sensitivity to imatinib was studied in cell culture.ResultsCells expressing the p.N666H mutation showed constitutive PDGFRB tyrosine phosphorylation. PDGF independent proliferation was abolished by imatinib at 1 MUM concentration. Patient fibroblasts showed constitutive receptor tyrosine phosphorylation that was also abrogated by imatinib with reduced proliferation of treated cells.This led to patient treatment with imatinib at 400 mg daily (340 mg/m2) for a year with objective improvement of debilitating hand and foot contractures, reduced facial coarseness, and significant improvement in quality of life. New small subcutaneous nodules developed, but remained stable. Transient leukopenia, neutropenia, and fatigue resolved without intervention; however, mildly decreased growth velocity resulted in reducing imatinib dose to 200 mg daily (170 mg/m2). The patient continues treatment with ongoing clinical response.ConclusionTo our knowledge, this is one of the first personalized treatments of a congenital disorder caused by a germ-line PDGF receptor mutation with a PDGFRB inhibitor. PMID- 28726816 TI - NASA: No cost crisis for space telescope. PMID- 28726818 TI - Topological quantum chemistry. AB - Since the discovery of topological insulators and semimetals, there has been much research into predicting and experimentally discovering distinct classes of these materials, in which the topology of electronic states leads to robust surface states and electromagnetic responses. This apparent success, however, masks a fundamental shortcoming: topological insulators represent only a few hundred of the 200,000 stoichiometric compounds in material databases. However, it is unclear whether this low number is indicative of the esoteric nature of topological insulators or of a fundamental problem with the current approaches to finding them. Here we propose a complete electronic band theory, which builds on the conventional band theory of electrons, highlighting the link between the topology and local chemical bonding. This theory of topological quantum chemistry provides a description of the universal (across materials), global properties of all possible band structures and (weakly correlated) materials, consisting of a graph-theoretic description of momentum (reciprocal) space and a complementary group-theoretic description in real space. For all 230 crystal symmetry groups, we classify the possible band structures that arise from local atomic orbitals, and show which are topologically non-trivial. Our electronic band theory sheds new light on known topological insulators, and can be used to predict many more. PMID- 28726820 TI - Africa: Restrict bush fires used in animal hunts. PMID- 28726822 TI - Ribosomes are optimized for autocatalytic production. AB - Many fine-scale features of ribosomes have been explained in terms of function, revealing a molecular machine that is optimized for error-correction, speed and control. Here we demonstrate mathematically that many less well understood, larger-scale features of ribosomes-such as why a few ribosomal RNA molecules dominate the mass and why the ribosomal protein content is divided into 55-80 small, similarly sized segments-speed up their autocatalytic production. PMID- 28726825 TI - Materials science: Chemistry and physics happily wed. PMID- 28726826 TI - Imaging techniques: X-rays used to watch spins in 3D. PMID- 28726827 TI - Nitrogen reduction and functionalization by a multimetallic uranium nitride complex. AB - Molecular nitrogen (N2) is cheap and widely available, but its unreactive nature is a challenge when attempting to functionalize it under mild conditions with other widely available substrates (such as carbon monoxide, CO) to produce value added compounds. Biological N2 fixation can do this, but the industrial Haber Bosch process for ammonia production operates under harsh conditions (450 degrees Celsius and 300 bar), even though both processes are thought to involve multimetallic catalytic sites. And although molecular complexes capable of binding and even reducing N2 under mild conditions are known, with co-operativity between metal centres considered crucial for the N2 reduction step, the multimetallic species involved are usually not well defined, and further transformation of N2-binding complexes to achieve N-H or N-C bond formation is rare. Haber noted, before an iron-based catalyst was adopted for the industrial Haber-Bosch process, that uranium and uranium nitride materials are very effective heterogeneous catalysts for ammonia production from N2. However, few examples of uranium complexes binding N2 are known, and soluble uranium complexes capable of transforming N2 into ammonia or organonitrogen compounds have not yet been identified. Here we report the four-electron reduction of N2 under ambient conditions by a fully characterized complex with two Uiii ions and three K+ centres held together by a nitride group and a flexible metalloligand framework. The addition of H2 and/or protons, or CO to the resulting complex results in the complete cleavage of N2 with concomitant N2 functionalization through N-H or N-C bond-forming reactions. These observations establish that a molecular uranium complex can promote the stoichiometric transformation of N2 into NH3 or cyanate, and that a flexible, electron-rich, multimetallic, nitride-bridged core unit is a promising starting point for the design of molecular complexes capable of cleaving and functionalizing N2 under mild conditions. PMID- 28726828 TI - Archaeology: Early signs of human presence in Australia. PMID- 28726821 TI - The whole-genome landscape of medulloblastoma subtypes. AB - Current therapies for medulloblastoma, a highly malignant childhood brain tumour, impose debilitating effects on the developing child, and highlight the need for molecularly targeted treatments with reduced toxicity. Previous studies have been unable to identify the full spectrum of driver genes and molecular processes that operate in medulloblastoma subgroups. Here we analyse the somatic landscape across 491 sequenced medulloblastoma samples and the molecular heterogeneity among 1,256 epigenetically analysed cases, and identify subgroup-specific driver alterations that include previously undiscovered actionable targets. Driver mutations were confidently assigned to most patients belonging to Group 3 and Group 4 medulloblastoma subgroups, greatly enhancing previous knowledge. New molecular subtypes were differentially enriched for specific driver events, including hotspot in-frame insertions that target KBTBD4 and 'enhancer hijacking' events that activate PRDM6. Thus, the application of integrative genomics to an extensive cohort of clinical samples derived from a single childhood cancer entity revealed a series of cancer genes and biologically relevant subtype diversity that represent attractive therapeutic targets for the treatment of patients with medulloblastoma. PMID- 28726829 TI - Experimental signatures of the mixed axial-gravitational anomaly in the Weyl semimetal NbP. AB - The conservation laws, such as those of charge, energy and momentum, have a central role in physics. In some special cases, classical conservation laws are broken at the quantum level by quantum fluctuations, in which case the theory is said to have quantum anomalies. One of the most prominent examples is the chiral anomaly, which involves massless chiral fermions. These particles have their spin, or internal angular momentum, aligned either parallel or antiparallel with their linear momentum, labelled as left and right chirality, respectively. In three spatial dimensions, the chiral anomaly is the breakdown (as a result of externally applied parallel electric and magnetic fields) of the classical conservation law that dictates that the number of massless fermions of each chirality are separately conserved. The current that measures the difference between left- and right-handed particles is called the axial current and is not conserved at the quantum level. In addition, an underlying curved space-time provides a distinct contribution to a chiral imbalance, an effect known as the mixed axial-gravitational anomaly, but this anomaly has yet to be confirmed experimentally. However, the presence of a mixed gauge-gravitational anomaly has recently been tied to thermoelectrical transport in a magnetic field, even in flat space-time, suggesting that such types of mixed anomaly could be experimentally probed in condensed matter systems known as Weyl semimetals. Here, using a temperature gradient, we observe experimentally a positive magneto thermoelectric conductance in the Weyl semimetal niobium phosphide (NbP) for collinear temperature gradients and magnetic fields that vanishes in the ultra quantum limit, when only a single Landau level is occupied. This observation is consistent with the presence of a mixed axial-gravitational anomaly, providing clear evidence for a theoretical concept that has so far eluded experimental detection. PMID- 28726830 TI - Gravitational waves: Stellar palaeontology. PMID- 28726831 TI - Second World War: Paris neurosurgeon's map outwitted Nazis. PMID- 28726832 TI - Three-dimensional magnetization structures revealed with X-ray vector nanotomography. AB - In soft ferromagnetic materials, the smoothly varying magnetization leads to the formation of fundamental patterns such as domains, vortices and domain walls. These have been studied extensively in thin films of thicknesses up to around 200 nanometres, in which the magnetization is accessible with current transmission imaging methods that make use of electrons or soft X-rays. In thicker samples, however, in which the magnetization structure varies throughout the thickness and is intrinsically three dimensional, determining the complex magnetic structure directly still represents a challenge. We have developed hard-X-ray vector nanotomography with which to determine the three-dimensional magnetic configuration at the nanoscale within micrometre-sized samples. We imaged the structure of the magnetization within a soft magnetic pillar of diameter 5 micrometres with a spatial resolution of 100 nanometres and, within the bulk, observed a complex magnetic configuration that consists of vortices and antivortices that form cross-tie walls and vortex walls along intersecting planes. At the intersections of these structures, magnetic singularities-Bloch points-occur. These were predicted more than fifty years ago but have so far not been directly observed. Here we image the three-dimensional magnetic structure in the vicinity of the Bloch points, which until now has been accessible only through micromagnetic simulations, and identify two possible magnetization configurations: a circulating magnetization structure and a twisted state that appears to correspond to an 'anti-Bloch point'. Our imaging method enables the nanoscale study of topological magnetic structures in systems with sizes of the order of tens of micrometres. Knowledge of internal nanomagnetic textures is critical for understanding macroscopic magnetic properties and for designing bulk magnets for technological applications. PMID- 28726834 TI - Ditching diesel won't clear the air. PMID- 28726835 TI - Female astronomers of colour face daunting discrimination. PMID- 28726833 TI - Human occupation of northern Australia by 65,000 years ago. AB - The time of arrival of people in Australia is an unresolved question. It is relevant to debates about when modern humans first dispersed out of Africa and when their descendants incorporated genetic material from Neanderthals, Denisovans and possibly other hominins. Humans have also been implicated in the extinction of Australia's megafauna. Here we report the results of new excavations conducted at Madjedbebe, a rock shelter in northern Australia. Artefacts in primary depositional context are concentrated in three dense bands, with the stratigraphic integrity of the deposit demonstrated by artefact refits and by optical dating and other analyses of the sediments. Human occupation began around 65,000 years ago, with a distinctive stone tool assemblage including grinding stones, ground ochres, reflective additives and ground-edge hatchet heads. This evidence sets a new minimum age for the arrival of humans in Australia, the dispersal of modern humans out of Africa, and the subsequent interactions of modern humans with Neanderthals and Denisovans. PMID- 28726836 TI - Engineered cell therapy for cancer gets thumbs up from FDA advisers. PMID- 28726837 TI - Solve Antarctica's sea-ice puzzle. PMID- 28726838 TI - US lawmakers seek $1.1-billion boost for the NIH. PMID- 28726839 TI - Satellite snafu masked true sea-level rise for decades. PMID- 28726840 TI - The strange topology that is reshaping physics. PMID- 28726841 TI - The DeepMind debacle demands dialogue on data. PMID- 28726842 TI - All shook up over topology. PMID- 28726844 TI - Maryam Mirzakhani, quantum teleportation and the Great Red Spot. PMID- 28726843 TI - New Antarctic iceberg echoes old problem. PMID- 28726845 TI - Climate scientists flock to France's call. PMID- 28726846 TI - European Commission urges logging ban in ancient Bialowieza Forest. PMID- 28726847 TI - Mapping genome-wide transcription-factor binding sites using DAP-seq. AB - To enable low-cost, high-throughput generation of cistrome and epicistrome maps for any organism, we developed DNA affinity purification sequencing (DAP-seq), a transcription factor (TF)-binding site (TFBS) discovery assay that couples affinity-purified TFs with next-generation sequencing of a genomic DNA library. The method is fast, inexpensive, and more easily scaled than chromatin immunoprecipitation sequencing (ChIP-seq). DNA libraries are constructed using native genomic DNA from any source of interest, preserving cell- and tissue specific chemical modifications that are known to affect TF binding (such as DNA methylation) and providing increased specificity as compared with in silico predictions based on motifs from methods such as protein-binding microarrays (PBMs) and systematic evolution of ligands by exponential enrichment (SELEX). The resulting DNA library is incubated with an affinity-tagged in vitro-expressed TF, and TF-DNA complexes are purified using magnetic separation of the affinity tag. Bound genomic DNA is eluted from the TF and sequenced using next-generation sequencing. Sequence reads are mapped to a reference genome, identifying genome wide binding locations for each TF assayed, from which sequence motifs can then be derived. A researcher with molecular biology experience should be able to follow this protocol, processing up to 400 samples per week. PMID- 28726848 TI - Patch-clamp technique to characterize ion channels in enlarged individual endolysosomes. AB - According to proteomics analyses, more than 70 different ion channels and transporters are harbored in membranes of intracellular compartments such as endosomes and lysosomes. Malfunctioning of these channels has been implicated in human diseases such as lysosomal storage disorders, neurodegenerative diseases and metabolic pathologies, as well as in the progression of certain infectious diseases. As a consequence, these channels have engendered very high interest as future drug targets. Detailed electrophysiological characterization of intracellular ion channels is lacking, mainly because standard methods to analyze plasma membrane ion channels, such as the patch-clamp technique, are not readily applicable to intracellular organelles. Here we present a protocol detailing how to implement a manual patch-clamp technique for endolysosomal compartments. In contrast to the alternatively used planar endolysosomal patch-clamp technique, this method is a visually controlled, direct patch-clamp technique similar to conventional patch-clamping. The protocol assumes basic knowledge and experience with patch-clamp methods. Implementation of the method requires up to 1 week, and material preparation takes ~2-4 d. An individual experiment (i.e., measurement of channel currents across the endolysosomal membrane), including control experiments, can be completed within 1 h. This excludes the time for endolysosome enlargement, which takes between 1 and 48 h, depending on the approach and cell type used. Data analysis requires an additional hour. PMID- 28726850 TI - Growth and development: Poly(A) tail-based regulation of cardiac hypertrophy. PMID- 28726851 TI - Autoimmune cardiac channelopathies: the heart of the matter. PMID- 28726849 TI - O2-controllable hydrogels for studying cellular responses to hypoxic gradients in three dimensions in vitro and in vivo. AB - Oxygen (O2) acts as a potent upstream regulator of cell function. In both physiological and pathophysiological microenvironments, the O2 concentration is not uniformly distributed but instead follows a gradient that depends on distance from oxygen-carrying blood vessels. Such gradients have a particularly important role in development, tissue regeneration, and tumor growth. In this protocol, we describe how to use our previously reported gelatin-based O2-controllable hydrogels that can provide hypoxic microenvironments in vitro. The hydrogel polymeric network is formed via a laccase-mediated cross-linking reaction. In this reaction, laccase catalyzes diferulic acid (diFA) formation to form hydrogels with an O2-consuming reaction. Cells, such as cancer or endothelial cells, as well as tumor/tissue grafts, can be encapsulated in the hydrogels during hydrogel formation and then analyzed for cellular responses to 3D hypoxic gradients and to elucidate the underlying mechanisms governing these responses. Importantly, oxygen gradients can be precisely controlled in standard cell/tissue culture conditions and in vivo. This platform has been applied to study vascular morphogenesis in response to hypoxia and to understand how oxygen gradients mediate cancer cell behavior. Herein, we describe the means to validate the assay from polymer synthesis and characterization-which take 1-2 weeks and include verification of ferulic acid (FA) conjugation, rheological measurements, and O2 monitoring-to the study of cellular responses and use in rodent models. Time courses for biological experiments using this hydrogel are variable, and thus they may range from hours to weeks, depending on the application and user end goal. PMID- 28726853 TI - Dyslipidaemia: Effect of hypercholesterolaemia on HDL particle remodelling. PMID- 28726852 TI - Autoimmune channelopathies: questions remain. PMID- 28726854 TI - Erratum: The gut microbiota: a major player in the toxicity of environmental pollutants? AB - [This corrects the article DOI: 10.1038/npjbiofilms.2016.3.]. PMID- 28726855 TI - Cyclodextrin-based biological stimuli-responsive carriers for smart and precision medicine. AB - Spurred on by recent progress in nanotechnology and precision medicine, smart drug carriers are entering an entirely new era. Smart drug carriers have been widely studied in recent years as a result of their ability to control drug release under different microenvironments (such as pH, redox, and enzyme) in vivo. Host-guest interactions based on cyclodextrins have proven to be an efficient tool for fabricating smart drug carriers. Because of the application of host-guest interactions, many kinds of biological molecules or supramolecular building blocks can combine into an organic whole at the molecular level. In this review, the features, mechanisms of action, and potent applications of biological stimuli-responsive drug carriers based on cyclodextrins are discussed. In addition, some personal perspectives on this field are presented. PMID- 28726856 TI - Manganese-catalyzed synthesis of monofluoroalkenes via C-H activation and C-F cleavage. AB - The manganese-catalyzed alpha-fluoroalkenylation of arenes via C-H activation and C-F cleavage has been described. This protocol provides a very useful method for the synthesis of monofluoroalkenes with predominant unconventional E-isomer selectivity which complements the existing strategies for the access to these molecular architectures. In addition, the selectivity of beta-defluorination in the catalytic cycle not only determines the configurations of the products but also obviates the use of external oxidants, providing a good example in the exploitation of manganese-catalyzed redox-neutral C-H transformations. PMID- 28726857 TI - Instrument-free visual detection of tetracycline on an autocatalytic DNA machine using a caged G-quadruplex as the signal reporter. AB - An instrument-free visual biosensor for the amplified detection of tetracycline has been successfully constructed using an autocatalytic DNA machine as the signal amplifier and a caged G-quadruplex as the signal reporter. The assay is ultrasensitive, enabling the visual detection of trace levels of tetracycline as low as 1 pM without instrumentation. PMID- 28726858 TI - Pumping and probing vibrational modulated coupled electronic coherence in HCN using short UV fs laser pulses: a 2D quantum nuclear dynamical study. AB - The coupled electronic-nuclear coherent dynamics induced by a short strong VUV fs pulse in the low excited electronic states of HCN is probed by transient absorption spectroscopy with a second weaker fs UV pulse. The nuclear time dependent Schrodinger equation is solved on a 2D nuclear grid with several electronic states with a Hamiltonian including the dipole coupling to the pump and the probe electric fields. The two internal nuclear coordinates describe the motion of the light H atom. There is a band of several excited electronic states at about 8 eV above the ground state (GS) that is transiently accessed by the pump pulse. We tailored the pump so as to selectively populate the lowest 1A'' electronic state thereby the pulse creates an electronic coherence with the GS. Our simulations show that this electronic coherence is modulated by the nuclear motion and persists all the way to dissociation on the 1A'' state. Transient absorption spectra computed as a function of the delay time between the pump and the probe pulses provide a detailed probe of the electronic amplitude and its phase, as well as of the modulation of the electronic coherence by the nuclear motion, both bound and dissociative. PMID- 28726859 TI - Surface hydration drives rapid water imbibition into strongly hydrophilic nanopores. AB - The imbibition of liquids into nanopores plays a critical role in numerous applications, and most prior studies focused on imbibition due to capillary flows. Here we report molecular simulations of the imbibition of water into single mica nanopores filled with pressurized gas. We show that, while capillary flow is suppressed by the high gas pressure, water is imbibed into the nanopore through surface hydration in the form of monolayer liquid films. As the imbibition front moves, the water film behind it gradually densifies. Interestingly, the propagation of the imbibition front follows a simple diffusive scaling law. The effective diffusion coefficient of the imbibition front, however, is more than ten times larger than the diffusion coefficient of the water molecules in the water film adsorbed on the pore walls. We clarify the mechanism for the rapid water imbibition observed here. PMID- 28726860 TI - Enhancing thermally activated delayed fluorescence characteristics by intramolecular B-N coordination in a phenylpyridine-containing donor-acceptor pi system. AB - An efficient thermally activated delayed fluorescence emitter based on an N heteroarene acceptor bearing an intramolecularly coordinated boryl group was developed. The impact of the B-N coordination on the optoelectronic properties and electroluminescence performance of devices was investigated. PMID- 28726861 TI - Collaborative enhancement from Pb2+ and F- in Pb2(NO3)2(H2O)F2 generates the largest second harmonic generation effect among nitrates. AB - The first metal nitrate fluoride nonlinear optical material, Pb2(NO3)2(H2O)F2, was synthesized with the largest second harmonic generation (SHG) effect (12 * KH2PO4) among nitrates. Theoretical calculations revealed the synergistic effect of [NO3]-, lone pair electrons in Pb2+, and F- for the SHG effect. The F- also promoted the blue-shift of the ultraviolet cut-off edge. PMID- 28726862 TI - A targeted delivery strategy for the development of potent trypanocides. AB - A new drug delivery strategy was investigated for the development of potent anti parasitic compounds against Trypanosoma brucei, the causative agent of African sleeping sickness. Thus, potent in vitro hexokinase inhibitors were rendered cytotoxic by appending a tripeptide peroxosomal targeting sequence that facilitated delivery of the molecular cargo to the appropriate organelle in the parasite. PMID- 28726863 TI - A near-infrared fluorescence off-on probe for sensitive imaging of hydrogen polysulfides in living cells and mice in vivo. AB - A new hemicyanine-based near-infrared fluorescence off-on probe with phenyl 2 (benzoylthio)benzoate as the recognition moiety to trap hydrogen polysulfides (H2Sn, n > 1) is developed, and is used for the sensitive imaging of H2Sn in cells and mice in vivo. PMID- 28726864 TI - BN nanoflake quantum-dot arrays: structural stability, and electronic and half metallic properties. AB - New one-dimensional (1D) crystals, 1D quantum-dot arrays(1D QDAs), are proposed and constructed by an ordered arrangement of zigzag-edged triangular h-BN nanoflakes. Their geometrical stability is confirmed by the calculated binding energy, phonon dispersion and molecular dynamics simulation. These 1D QDAs demonstrate different quantum confinement effects on electronic and half-metallic properties due to different linking modes. For example, in the nonmagnetic state, different 1D QDAs are predicted to be semiconductors or metals remarkably depending on their linking manner, whereas in the ferromagnetic state, they are found to be all prominent half-metals but with greatly different gaps from ~0.6 to 5.1 eV, reaching a difference almost as large as 10 times. In addition, the study on the electric-magnetic coupling effects suggests that the applied traversed electric field can significantly benefit the enhancement of 1D QDA half metallicity by further enlarging the gap. PMID- 28726865 TI - Recent advances in the ruthenium(ii)-catalyzed chelation-assisted C-H olefination of substituted aromatics, alkenes and heteroaromatics with alkenes via the deprotonation pathway. AB - The transition-metal-catalyzed chelation-assisted alkenylation at the inert C-H bond of aromatics with alkenes is one of the efficient methods to synthesize substituted vinylarenes in a highly regio- and stereoselective manner. Palladium, rhodium and ruthenium complexes are frequently used as catalysts for this type of transformation. The present review describes the recent advances in the ruthenium catalyzed chelation-assisted alkenylation at the C-H bond of aromatics, alkenes and heteroaromatics with alkenes via the deprotonation pathway. Several directing groups including 2-pyridyl, carbonyl, amidine, amide, amine, imidate, sulphonic acid, triazole, cyano, oxazolidinone and hydontoin are widely used in the reaction. The scope, limitation and mechanistic investigation of the alkenylation reactions are discussed elaborately. This feature article includes all the reported ruthenium-catalyzed alkenylation reactions via the deprotonation pathway until the end of March 2017. PMID- 28726866 TI - Acyclic cucurbit[n]uril conjugated dextran for drug encapsulation and bioimaging. AB - An acyclic cucurbit[n]uril (CB[n]) conjugated dextran is developed as a new biomaterial for drug delivery and bioimaging. This biomaterial retains the host guest recognition properties of acyclic CB[n]s. It is able to directly encapsulate anti-tumor drugs 5-fluorouracil and temozolomide. This polymeric material can form a supramolecular assembly with polyethyleneimine (PEI). Although there is no conventional chromophore in these supramolecular systems, they exhibit aggregation-induced emission (AIE) in water with a quantum yield of 10%. This supramolecular assembly is used for bioimaging in vitro with good biocompatibility. PMID- 28726867 TI - Fluorine-substituted benzothiadiazole-based hole transport materials for highly efficient planar perovskite solar cells with a FF exceeding 80. AB - Fluorine-substituted benzothiadiazole (BT) was introduced as a core structure to construct new hole transport materials. Planar perovskite solar cells with conventional materials (CH3NH3PbI3-xClx) were fabricated. The perovskite solar cells using monofluorinated BT exhibit a leading efficiency of 18.54% with a FF as high as 81%. PMID- 28726868 TI - Raman spectroscopy for cancer detection and cancer surgery guidance: translation to the clinics. AB - Oncological applications of Raman spectroscopy have been contemplated, pursued, and developed at academic level for at least 25 years. Published studies aim to detect pre-malignant lesions, detect cancer in less invasive stages, reduce the number of unnecessary biopsies and guide surgery towards the complete removal of the tumour with adequate tumour resection margins. This review summarizes actual clinical needs in oncology that can be addressed by spontaneous Raman spectroscopy and it provides an overview over the results that have been published between 2007 and 2017. An analysis is made of the current status of translation of these results into clinical practice. Despite many promising results, most of the applications addressed in scientific studies are still far from clinical adoption and commercialization. The main hurdles are identified, which need to be overcome to ensure that in the near future we will see the first Raman spectroscopy-based solutions being used in routine oncologic diagnostic and surgical procedures. PMID- 28726869 TI - One-step, green synthesis of a supramolecular organogelator based on mellitic triimide for the recognition of aromatic compounds. AB - Mellitic triimide derivatives with N-benzyl groups form conformations with concave cavities, that are capable of including aromatic molecules such as benzene, nitrobenzene, etc. In addition, they act as supramolecular gelators, which enable the detection of aromatic molecules as a gel-sol phase transition. PMID- 28726870 TI - Highly efficient photosensitizers with aggregation-induced emission characteristics obtained through precise molecular design. AB - We herein report a new strategy to obtain highly efficient photosensitizers (PSs) by reducing the singlet-triplet energy gap (DeltaEST) and blocking the non radiative decay pathways. Through precise molecular design, TP1-8 were synthesized to exhibit predictable properties including moderate to high photosensitizing efficacy, tunable absorption and emission wavelengths and aggregation-induced emission characteristics. PMID- 28726871 TI - Monitoring of "on-demand" drug release using dual tumor marker mediated DNA capped versatile mesoporous silica nanoparticles. AB - A versatile drug delivery system with dual specific capacity of controllable release and monitoring of the intracellular release process, which extremely maximize therapeutic efficacy on diseased cells while minimizing drug toxicity to healthy cells, was reported for the first time. PMID- 28726872 TI - Specific fluorescence labeling of target proteins by using a ligand-4 azidophthalimide conjugate. AB - We herein propose a simple affinity-labeling method using a ligand-4 azidophthalimide (AzPI) conjugate. As a proof of concept, we show that two different ligand-AzPI conjugates enabled highly specific fluorescence labeling of their individual target proteins even in crude cell lysates. This method was also applied to label endogenous target proteins inside living cells. PMID- 28726873 TI - Local decomposition of imaginary polarizabilities and dispersion coefficients. AB - We present a new way to compute the two-body contribution to the dispersion energy using ab initio theory. By combining the complex polarization propagator method and the LoProp transformation, local contributions to the Casimir-Polder interaction is obtained. The full dispersion energy in dimer systems consisting of pairs of molecules including H2, N2, CO, CH4, pyridine, and benzene is investigated, where anisotropic as well as isotropic models of dispersion are obtained using a decomposition scheme for the dipole-dipole polarizability. It is found that the local minima structure of the pi-cloud stacking of the benzene dimer is underestimated by the total molecular dispersion, but is alleviated by the inclusion of atomic interactions via the decomposition scheme. The dispersion energy in the T-shaped benzene dimer system is greatly underestimated by all dispersion models, as compared to high-level quantum calculations. The generalization of the decomposition scheme to higher order multipole polarizability interactions, representing higher order dispersion coefficients, is briefly discussed. It is argued that the incorporation of atomic C6 coefficients in new atomic force fields may have important ramifications in molecular dynamics studies of biomolecular systems. PMID- 28726874 TI - New mechanistic insights into intramolecular aromatic ligand hydroxylation and benzyl alcohol oxidation initiated by the well-defined (MU-peroxo)diiron(iii) complex. AB - A (MU-peroxo)diiron(iii) complex [Fe2(LPh4)(O2)(Ph3CCO2)]2+ (1-O2) with a dinucleating ligand (LPh4), generated from the reaction of a carboxylate bridged diiron(ii) complex [Fe2(LPh4)(Ph3CCO2)]2+ (1) with dioxygen in CH2Cl2, provides a diiron(iv)-oxo species as an active oxidant which is involved in either aromatic ligand hydroxylation or benzyl alcohol oxidation. PMID- 28726875 TI - Time-resolved spectroscopic analysis of the light-energy harvesting mechanism in carbazole-dendrimers with a blue-phosphorescent Ir-complex core. AB - In order to investigate the light-energy harvesting mechanism, a series of dendrimers with a heteroleptic iridium(iii) complex core, [Ir(dmb)2(pic-Czn)] (Gn: n = 1, 2, and 3), with 2,6-difluoro-3-(4-methylpyridin-2-yl)benzonitrile (dmb) as the cyclometallating ligand and 3-hydroxypicolinate (pic) as the ancillary ligand, connected to carbazole-based dendrons (Czn: n = 2, 4, and 8) was synthesized. The Ir centred complex [Ir(dmb)2(pic-OCH3), G0] shows a blue emission at <500 nm, which is assigned to metal-to-ligand charge-transfer (3MLCT) phosphorescence. This phosphorescence was enhanced with increasing generations due to the increase in the total absorbance of the Cz-dendron. The light harvesting efficiencies determined by various methods were approximately 160 (G1), 220 (G2), and 330% (G3). The energy transfer efficiencies for G1-G3 from the peripheral Cz-dendron to the Ir-core complex were above 97%, determined using the reduction in the lifetime of the excited 1Cz*-dendrons. G1-G3 showed a transient absorption (TA) band at 600 nm, which was attributed to the Sn <- S1 transition of the Cz-dendrons. The fast decay of these TA bands was consistent with the fast emission decay times. The time-resolved TA band correlated with the core Ir-complex was observed at 500 nm, though it overlapped and interfered with the intense TA band of the Cz-dendrons. Therefore, we attempted a global analysis by singular value decomposition (SVD). The determination of the absorption spectra of the individual species participating in the energy transfer process by SVD analysis can distinguish between different mechanistic models. The analysed rate constants were consistent with the results determined by the emission decays. PMID- 28726876 TI - Bioceramic nanocomposite thiol-acrylate polyHIPE scaffolds for enhanced osteoblastic cell culture in 3D. AB - Emulsion-templated (polyHIPE) scaffolds for bone tissue engineering were produced by photopolymerisation of a mixture of trimethylolpropane tris(3 mercaptopropionate) and dipentaerythritol penta-/hexa-acrylate in the presence of hydroxyapatite (HA) or strontium-modified hydroxyapatite (SrHA) nanoparticles. Porous and permeable polyHIPE materials were produced regardless of the type or incorporation level of the bioceramic, although higher loadings resulted in a larger average pore diameter. Inclusion of HA and SrHA into the scaffolds was confirmed by EDX-SEM, FTIR and XPS and quantified by thermogravimetry. Addition of HA to polyHIPE scaffolds significantly enhanced compressive strength (148-216 kPa) without affecting compressive modulus (2.34-2.58 MPa). The resulting materials were evaluated in vitro as scaffolds for the 3D culture of MG63 osteoblastic cells vs. a commercial 3D cell culture scaffold (Alvetex(r)). Cells were able to migrate throughout all scaffolds, achieving a high density by the end of the culture period (21 days). The presence of HA and in particular SrHA gave greatly enhanced cell proliferation, as determined by staining of histological sections and total protein assay (Bradford). Furthermore, Von Kossa and Alizarin Red staining demonstrated significant mineralisation from inclusion of bioceramics, even at the earliest time point (day 7). Production of alkaline phosphatase (ALP), an early osteogenic marker, was used to investigate the influence of HA and SrHA on cell function. ALP levels were significantly reduced on HA- and SrHA-modified scaffolds by day 7, which agrees with the observed early onset of mineralisation in the presence of the bioceramics. The presented data support our conclusions that HA and SrHA enhance osteoblastic cell proliferation on polyHIPE scaffolds and promote early mineralisation. PMID- 28726877 TI - Fluorescence recognition of chiral amino alcohols by using a novel ionic liquid sensor. AB - A novel task-specific ionic liquid derived from l-phenylalaninol was prepared as an enantioselective fluorescent sensor for the first time. Fluorescent chiral ionic liquid 1 (FCIL1) is found to exhibit highly enantioselective fluorescence enhancements toward both aromatic and non-aromatic chiral amino alcohols. When (S)-FCIL1 was treated with the enantiomers of phenylalaninol, a great fluorescence enhancement at 349 nm could be observed and the value of the enantiomeric fluorescence difference (ef) is 5.92. This demonstrated that the chiral sensor (S)-FCIL1 exhibited an excellent enantioselective response behaviour to d-phenylalaninol. Besides that, both the fluorescence intensity at 349 nm (I349) and the ratio of I349 to I282 depend linearly on the concentration of amino alcohols. Both the concentration and the enantiomeric composition could be determined by using the chiral ionic liquid. Differently, the sensor treated with the enantiomers of 2-amino-1-butanol showed an opposite result: the fluorescence intensity of the S-enantiomer is higher than that of the R enantiomer. Furthermore, the size of the substituents on the chiral carbon might be important for the enantioselective fluorescent response. PMID- 28726878 TI - Noninvasive photoacoustic measurement of glucose by data fusion. AB - We proposed a novel noninvasive method for glucose detection using a photoacoustic (PA) technique utilizing both the peak-to-peak value and peak arrival time delay information. Without increasing apparatus and system complexity, we demonstrated the accuracy enhancement of 29.5% and 33.63% for high (0-7 g dL-1) and low (0-350 mg dL-1) concentration of glucose solution, compared to conventional amplitude-based prediction. PMID- 28726879 TI - o-Phthalaldehyde catalyzed hydrolysis of organophosphinic amides and other P([double bond, length as m-dash]O)-NH containing compounds. AB - Over 50 years ago, Jencks and Gilchrist showed that formaldehyde catalyses the hydrolysis of phosphoramidate through electrophilic activation, induced by covalent attachment to its nitrogen atom. Given our interest in the use of aldehydes as catalysts, this work was revisited to identify a superior catalyst, o-phthalaldehyde, which facilitates hydrolyses of various organophosphorus compounds bearing P([double bond, length as m-dash]O)-NH subunits under mild conditions. Interestingly, chemoselective hydrolysis of the P([double bond, length as m-dash]O)-N bonds could be accomplished in the presence of P([double bond, length as m-dash]O)-OR bonds. PMID- 28726880 TI - Squishy nanotraps: hybrid cellulose nanocrystal-zirconium metallogels for controlled trapping of biomacromolecules. AB - A brick-and-mortar-like ultrasoft nanocomposite metallogel is formed by crosslinking cellulose nanocrystals (CNC) with ammonium zirconium carbonate (AZC) to trap and reconfigure dextran, a model biomacromolecule. The bricks (CNC) reinforce the metallogel, compete with dextran in reacting with AZC, and decouple long-time dextran dynamics from network formation, while the mortar (AZC) imparts bimodality to the dextran diffusion. PMID- 28726881 TI - Effects of CO2 adsorption on proton migration on a hydrated ZrO2 surface: an ab initio molecular dynamics study. AB - Hydration reactions on a carbonate-terminated cubic ZrO2(110) surface were analyzed using ab initio molecular dynamics (AIMD) simulations. After hydration reactions, carbonates were still present on the surface at 500 K. However, these carbonates are very weak conjugate bases and only act as steric hindrance in proton hopping processes between acidic chemisorbed H2O molecules (Zr-OH2) and monodentate hydroxyl groups (Zr-OH-). Similar to a carbonate-free hydrated surface, Zr-OH2, Zr-OH-, and polydentate hydroxyl groups ([double bond splayed left]OH+) were observed, while the ratio of acidic Zr-OH2 was significantly larger than that on the carbonate-free hydrated surface. A thermodynamic discussion and bond property analysis reveal that CO2 adsorption significantly decreases the basicity of surface oxide ions ([double bond splayed left]O), whereas the acidity of Zr-OH2 is not affected. As a result, protons released from [double bond splayed left]OH+ react with Zr-OH- to form Zr-OH2, leading to a deficiency of proton acceptor sites, which decreases the proton conductivity by the hopping mechanism. PMID- 28726882 TI - Trimethylsilyl hedgehogs - a novel class of super-efficient hydrocarbon surfactants. AB - Presented here are the results for a novel class of hydrocarbon surfactants, termed trimethylsilyl hedgehogs (TMS-hedgehogs), due to the presence of silicon in the tails. By comparing the surface properties of these hybrid hedgehogs to purely hydrocarbon equivalents, links between performance and the structure are made. Namely, by controlling the molecular volume of the surfactant fragments, improvements can be made in surface coverage, generating lower surface energy monolayers. Small-angle neutron scattering (SANS) data have been collected showing that these novel surfactants aggregate to form ellipsoidal micelles which grow with increasing concentration. This study highlights the sensitive relationship between surface tension and the surfactant chain, for designing new super-efficient surfactants close to the limit of the lowest surface tensions possible. PMID- 28726883 TI - Highly reducible pi-extended copper corroles. AB - Di- and octa-phenylethynyl (PE) substituted pi-extended copper corroles were synthesized and characterized as to their structural, electrochemical and spectroscopic properties. The addition of two or eight PE groups to the beta pyrrole positions of the corrole results in dramatic red shifts in the electronic absorption spectra and new reductions which are not seen for the parent compound lacking PE substituents. CuCor(PE)8 is reduced in four reversible one-electron transfer steps to give derivatives of [CuCor(PE)8]n- where n = 1, 2, 3 or 4. Variable temperature 1H NMR and EPR measurements were carried out and suggest that the octa- and di-PE substituted Cu-corroles can both be described as an antiferromagnetically coupled CuII corrole cation radical which is in equilibrium with a triplet state, possibly due to a lower singlet-triplet energy gap as compared to 1 and 2 at room temperature. The EPR spectra of one-electron oxidized and one electron reduced species exhibited the characteristics of Cu(ii) corroles. The products generated in the first two reductions of each pi-extended corrole were characterized by thin-layer spectroelectrochemistry, thus providing new insights into how UV-vis spectra of highly reduced corroles vary as a function of the number of PE groups and overall charge on the molecule. The singly reduced and singly oxidized copper corroles were also chemically generated in CH3CN and shown to have UV-visible spectra almost identical to the spectra obtained by electroreduction or electrooxidation in PhCN or THF containing 0.1 M tetrabutylammonium perchlorate. PMID- 28726884 TI - Lithium dendrite growth mechanisms in polymer electrolytes and prevention strategies. AB - Future lithium-ion batteries must use lithium metal anodes to fulfill the demands of high energy density applications with the potential to enable affordable electric cars with 350-mile range. However, dendrite growth during charging prevents the commercialization of this technology. It has been demonstrated that the presence of a compressive mechanical stress field around a dendritic protrusion prevents growth. Several techniques based on this concept, such as protective layers, externally applied pressure and solid electrolytes have been investigated by other researchers. Because of the low coulombic efficiencies associated with the stiff protective layers and high-pressure conditions, implementation of these techniques in commercial cells is complicated. Polymer based solid electrolytes demonstrate better efficiency and capacity retention capabilities. However, dendrite growth is still possible in polymer electrolytes at higher current densities. The simulations described in this article provide guidance on the conditions under which dendrite growth is possible in polymer cells and targets for material properties needed for dendrite prevention. Increasing the elastic modulus of the electrolyte prevents the growth of dendritic protrusions in two ways: (i) higher compressive mechanical stress leads to reduced exchange current density at the protrusion peak compared to the valley, and (ii) plastic deformation of lithium metal results in reduction of the height of the dendritic protrusion. A phase map is constructed, showing the range of operation (applied current) and design (electrolyte elastic modulus) parameters that corresponds to stable lithium deposition. It is found that increasing the yield strength of the polymer electrolyte plays a significant role in preventing dendrite growth in lithium metal anodes, providing a new avenue for further exploration. PMID- 28726885 TI - Simulation of the experimental imaging results for the OH + CHD3 reaction with a simple and accurate theoretical approach. AB - The OH + CHD3 reaction is among the largest one ever studied at the high resolution level permitted by imaging techniques [B. Zhang et al., J. Phys. Chem. A, 2005, 109, 8989]. This process involves eighteen configuration space coordinates, which are large enough to make exact quantum scattering calculations beyond reach. Moreover, freezing some degrees-of-freedom in order to render these calculations feasible may lead to unrealistic predictions. However, we have found it possible to reproduce for the first time the pair-correlated measurements of Zhang et al. at a nearly quantitative level by means of full-dimensional classical trajectory calculations in a quantum spirit on a recent ab initio potential energy surface. These calculations combine the classical description of the dynamics, well suited to polyatomic systems, with Bohr quantization of both reagent and product vibrational motions. While this pseudo-quantization is exactly imposed to the reagents, it is approximately imposed to the products in a first step through energy-based Gaussian binning (1GB). In a second step, we show that the original action-based Gaussian binning (GB), long thought to be inapplicable in practice to polyatomic reactions, yields in fact results comparable in accuracy and numerical cost to those obtained by means of 1GB, provided that Gaussian weights are properly widened. This new finding clearly extends the scope of GB in theoretical reactive scattering. PMID- 28726886 TI - Radiation-induced synthesis of nanoscale Co- and Ni-based electro-catalysts on carbon for the oxygen reduction reaction. AB - A facile synthesis of 3d-metal based electro-catalysts directly incorporated into a carbon support was carried out by gamma-radiation. Transition metals of period 4, i.e. Ni and Co, were precipitated and reduced from their respective salt solutions. The obtained materials were characterized by XRD, SEM, SQUID and the BET methods. Thereafter, the electrodes for fuel cells were fabricated out of synthesized material and their electrochemical performance for the oxygen reduction reaction in 6 M KOH was measured. Although the concentrations of Co and Ni in the electrode material were low (3.4% Co and 0.4% Ni) after reduction by irradiation, both the Ni and Co-based gas diffusion electrodes showed high catalytic activity for oxygen reduction both at room temperature and at 60 degrees C. PMID- 28726887 TI - Standard and rapid scan infrared spectroscopic studies of o-xylene transformations in terms of pore arrangement of 10-ring zeolites - 2D COS analysis. AB - This study attempts to offer an insight into o-xylene isomerization process in terms of steric constraints of 10-ring zeolites. The zeolites under investigation, i.e. ZSM-5, IM-5 and TNU-9, have purely microporous structures and crystals with the same shape and offer comparable protonic functionality, both in manner of amount and strength of Si(OH)Al groups. Under these conditions, micropore topology is recognised to deliver differentiated catalytic performance of each zeolitic structure. Moreover, 10-ring zeolites of reduced dimensionality, i.e. TNU-10 and ZSM-22, are chosen as reference materials. The 2D COS analysis of IR spectra reveal that interaction and catalytic activity in o-xylene isomerization process are strongly influenced by diffusion of reagents in rigid microporous environment and the formation of intermediate species is characterised by IR bands at 1485 and 1455 cm-1. With a prolonged time of the reaction (15 min), the formation of the latter species is observed for zeolite IM 5 characterised by limited 3-dimensionality. Rapid scan experiments show that in a shorter reaction time (4 min), these intermediate moieties are present for all the structure studied. The intermediate species are believed to originate from arenium ions such as methylbenzenium CH3-C6H5+-CH3 and/or methyl-substituted cycloheptatrienyl ions CH3-C7H7+. Their amount is strictly related to the rigidity of the microporous system: the most spacious environment for o-xylene transformation, e.g. TNU-9, is characterised by the lowest population of intermediates, whereas structures offering sufficiently tight geometry, e.g. TNU 10, can accommodate intermediate species in higher quantities, finally leading to the production of p-xylene with high selectivity. PMID- 28726888 TI - A gigantic polyoxozirconate with visible photoactivity. AB - We present a gigantic polyoxozirconate nanocluster (Zr18O21(MU2-OH)2(OOCPh)28), involving 6, 7 and 8-coordinated Zr atoms. It exhibits visible light driven photocatalytic activity for H2 evolution. The current results could represent a prelude of polyoxozirconate-based photocatalysis. PMID- 28726889 TI - Modeling electrochromic poly-dioxythiophene-containing materials through TDDFT. AB - A DFT/TDDFT model was developed to predict the chemical properties for three colored to nearly transmissive electrochromic polymers synthesized by the John Reynolds's group. Using a functional-basis set pairing of mPW1PBE/cc-PVDZ along with the conductor polarizable calculation model (CPCM), simulated neutral spectra showed a strong correlation to the experimental UV-Vis data where the largest absolute peak maximum difference was 14 nm. Frontier molecular orbitals, electronic transitions, and ground-state geometries of these systems were evaluated to provide further information about the oxidative process the polymers undergo. Here we report the first colorimetric model using this level of theory. PMID- 28726890 TI - Dynamics and resonances of the H(2S) + CH+(X1Sigma+) reaction in the electronic ground state: a detailed quantum wavepacket study. AB - Initial state-selected and energy resolved channel-specific reaction probabilities, integral cross sections and thermal rate constants of the H(2S) + CH+(X1Sigma+) reaction are calculated within the coupled states approximation by a time-dependent wave packet propagation method. The new ab initio global potential energy surface (PES) of the electronic ground state (1 2A') of the system, recently reported by Li et al. [J. Chem. Phys., 2015, 142, 124302], is employed for this purpose. All partial wave contributions up to the total angular momentum J = 60 are considered to obtain the converged integral reaction cross section up to a collision energy of 1.0 eV. Thermal rate constants are calculated by averaging the reaction cross sections over the Boltzmann distribution of energies and compared with the available theoretical and experimental results for the temperature range 10-1000 K. Investigation of the channel-specific reaction attributes shows that the H abstraction (CH+ destruction) channel is highly favored over the H exchange channel. The effect of rotational and vibrational excitations of the CH+ reagent on the dynamics is also studied. The resonances formed during the course of the reaction are also identified by calculating the transition state spectrum and characterized in terms of the eigenfunctions and lifetimes. More than 260 vibrational levels are obtained and their eigenfunctions are calculated, which are represented in terms of the nodal assignments and the eigenenergies. They reveal both the local and hyperspherical behavior for the bound and quasibound states of the CH2+ complex in the ground 1 2A' surface. The lifetime analysis of the quasibound states indicates that the CH2+ resonances survive for as long as ~400 fs at high energies (E ~ 2.0 eV) and are expected to decay faster with further increasing energy. Finally, the type of mechanism for the formation of the product (C+ + H2) is elucidated. PMID- 28726891 TI - Frontier orbitals of photosubstitutionally active ruthenium complexes: an experimental study of the spectator ligands' electronic properties influence on photoreactivity. AB - The synthesis and characterization of [Ru(tpy)(R2bpy)(L)](X)n complexes (tpy = 2,2':6',2''-terpyridine, R2bpy = 4,4'-dimethyl-2,2'-bipyridine (dmbpy), or 4,4' bis(trifluoromethyl)-2,2'-bipyridine (tfmbpy), X = Cl- or PF6-, and n = 1 or 2) are described. The dmbpy and tfmbpy bidentate ligands allow for investigating the effects of electron-donating and electron-withdrawing ligands, respectively, on the frontier orbital energetics as well as the photoreactivity of these ruthenium polypyridyl complexes for five prototypical monodentate ligands L = Cl-, H2O, CH3CN, 2-(methylthio)ethanol (Hmte), or pyridine. According to spectroscopic and electrochemical studies, the dmbpy analogues displayed a singlet metal-to-ligand charge transfer (1MLCT) transition at higher energy than the tfmbpy analogues. The shift of the 1MLCT to higher energy results from the lowest unoccupied molecular orbital (LUMO) for the dmbpy analogues being tpy-based, whereas for the tfmbpy analogues orbital inversion occurs resulting in a tfmbpy-based LUMO. The energy level of the highest occupied molecular orbital (HOMO) was considerably affected by the nature of the monodentate ligand. Visible light irradiation of the complexes demonstrated that the tfmbpy analogue increased the rate and quantum yields of photosubstitution reactions, compared to the dmbpy analogue, suggesting that the electron-withdrawing substituents allowed better thermal accessibility of the triplet metal-centered (3MC) state from the photochemically generated triplet metal-to-ligand charge transfer (3MLCT) excited state. A correlation between the photolability of the monodentate ligands and the electrochemical reversibility of the metal-based oxidation is also reported. PMID- 28726892 TI - On the microscopic mechanism behind the purely orientational disorder-disorder transition in the plastic phase of 1-chloroadamantane. AB - Globular molecules of 1-chloroadamantane form a plastic phase in which the molecules rotate in a restrained way, but with their centers of mass forming a crystalline ordered lattice. Plastic phases can be regarded as test cases for the study of disordered phases since, contrary to what happens in the liquid phase, there is a lack of stochastic translational degrees of freedom. When the temperature is increased, a hump in the specific heat curve is observed indicating a change in the energetic footprint of the dynamics of the molecules. This change takes place without a change in the symmetry of the crystalline lattice, i.e. no first-order transition is observed between temperatures below and above the calorimetric hump. This implies that subtle changes in the dynamics of the disordered plastic phase concerning purely orientational degrees of freedom should appear at the thermodynamic anomaly. Accordingly, we describe, for the first time, the microscopic mechanisms behind a disorder-disorder transition through the analysis of neutron diffraction and QENS experiments. The results evince a change in the molecular rotational dynamics accompanied by a continuous change in density. PMID- 28726893 TI - Diverse polarization bi-stability in ferroelectric tunnel junctions due to the effects of the electrode and strain: an ab initio study. AB - Both electrodes and substrates are factors of great significance for the performance of ferroelectric tunnel junctions (FTJs) in designing functional nanodevices. To provide a comprehensive view on the polarization stability in FTJs due to the effects of an electrode and a substrate misfit strain, in this work we calculated more than 1000 FTJ structures by utilizing an ab initio density functional theory (DFT) method, via changing the symmetry of the FTJ structure (i.e., both asymmetric and symmetric FTJs), electrodes (including Au, Ag, Cu, Pt, Co, Fe, and SrRuO3), barrier thickness (ranging from 2 to 10 unit cells), polarization direction (both positive and negative polarizations) and epitaxial strain (i.e., -3%, -2.5%, -2%, -1.5% and -1%) as variables. This shows that the FTJs can exhibit quite diverse polarization bi-stability due to the combined effect of the electrode and strain control, which indicates diverse performance of the FTJs modulated by the electrode and strain. In particular, the polarization-mediated electrostatic potential in the barriers with different electrodes forecasts an electrode-tailored tunnel electroresistance effect. Our study provides guidance on the practical applications of FTJs with regard to the selection of electrodes and substrates. PMID- 28726894 TI - Photocatalytic hydrogenation of furan to tetrahydrofuran in alcoholic suspensions of metal-loaded titanium(iv) oxide without addition of hydrogen gas. AB - The use of metal co-catalysts broadens the application of photocatalytic reduction without the use of dihydrogen (H2) gas. We examined photocatalytic hydrogenation of furan, a representative heterocyclic compound and a compound derived from biomass, in alcoholic suspensions of metal-loaded titanium(iv) oxide (TiO2) under a H2-free condition and we found that furan was almost quantitatively hydrogenated to tetrahydrofuran with a high apparent quantum efficiency of 37% at 360 nm when palladium was used as a co-catalyst. Effects of different metal co-catalysts, different amounts of the co-catalyst, the type of TiO2, the type of alcohol, light wavelength and reusability for furan hydrogenation were investigated. Based on the results, the functions of TiO2 and the co-catalyst and the reaction process are discussed. PMID- 28726895 TI - A fluorescence-electrochemical study of carbon nanodots (CNDs) in bio- and photoelectronic applications and energy gap investigation. AB - Carbon nanodots (CNDs) have attracted great attention due to their superior solubility, biocompatibility, tunable photoluminescence, and opto-electronic properties. This work describes a new fluorescence-based spectroelectrochemistry approach to simultaneously study the photoluminescence and wavelength dependent photocurrent of microwave synthesized CNDs. The fluorescence of CNDs shows selective quenching upon a reversible redox couple, ferricyanide/ferrocyanide, reaction during cyclic voltammetry. The CND modified gold slide electrode demonstrates wavelength dependent photocurrent generation during the fluorescence electrochemical study, suggesting the potential application of CNDs in photoelectronics. UV-Vis absorption and electrochemistry are used to quantify the energy gap of the CNDs, and then to calibrate a Huckel model for CNDs' electronic energy levels. The Huckel (or tight binding) model treatment of an individual CND as a molecule combines the conjugated pi states (C[double bond, length as m dash]C) with the functional groups (C[double bond, length as m-dash]O, C-O, and COOH) associated with the surface electronic states. This experimental and theoretical investigation of CNDs provides a new perspective on the optoelectronic properties of CNDs and should aid in their development for practical use in biomedicine, chemical sensing, and photoelectric devices. PMID- 28726897 TI - Ultrafast structural dynamics of photoexcited adenine. AB - We report deep UV initiated excited state dynamics of the canonical nucleobase adenine (Ade) through Resonance Raman (RR) intensity analysis. RR spectra of Ade at excitation wavelengths throughout the Bb absorption band in the 210-230 nm wavelength range are measured and subsequently converted to scattering cross sections. The time-dependent wave packet (TDWP) formalism has been employed for self-consistent simulations of the resulting wavelength dependent Raman excitation profiles (REP) and absorption spectrum of Ade. These simulations yield instantaneous nuclear dynamics of Ade within tens of femtoseconds (fs) of photoabsorption as structural distortions, linewidth broadening and solvation parameters. The instantaneous geometrical distortions of the purine ring following photoexcitation into the Bb state are analyzed vis-a-vis the low energy La state (~260 nm) of Ade. We find that while photoabsorption by the La state causes major distortions of the imidazole ring, pyrimidine ring suffers maximal changes following Bb excitation. Seven in-plane stretching vibrations out of fifteen resonantly enhanced modes of Ade are found to contribute 76% of the total internal reorganization energy (981 cm-1) in the Bb excited state. In addition, the inertial response of the solvation shell to photoexcitation is found to be of 1190 cm-1 in magnitude, and with a relaxation time of 26.5 fs. A parallel comparison is drawn between the UV-C initiated photodynamics of Ade (6 aminopurine) with that of two substituted purines, viz., 6-chloroguanine (6-ClG or 2-amino-6-chloropurine) and guanine (2-amino-6-oxo-purie) which were reported earlier. PMID- 28726898 TI - Probe-location dependent resonance energy transfer at lipid/water interfaces: comparison between the gel- and fluid-phase of lipid bilayer. AB - Despite significant interest in understanding the role of the local dielectric environment and lipid-bilayer fluidity/rigidity in resonance energy transfer between chromophores at lipid/water interfaces, a comprehensive approach to quantify such environmental dependence on energy transfer is missing - primarily because of the scarcity of suitable probes. Here we present the results on multi chromophoric Forster resonance energy transfer (FRET) from a series of 4 aminophthalimide-based molecules (4AP-Cn; n = 2-10, 12) of different lipophilicity (donors), which reside at different depths across the lipid/water interfaces, to rhodamine-6G (Rh6G; acceptor) molecules that stay in a water-rich region near the lipid headgroups. We apply steady-state and time-resolved fluorescence spectroscopy, and find that multi-chromophoric FRET from the series of 4AP-Cn donors to the Rh6G acceptor occurs in a peculiar stepwise fashion at the lipid/water interface of a gel-phase (Lbeta') DPPC (1,2-dipalmitoyl-sn glycero-3-phosphocholine) bilayer at room temperature. However, the same donor acceptor pairs show only subtle but continuous donor-depth-dependent FRET at the lipid/water interface of a fluid-phase (Lalpha) DOPC (1,2-dioleoyl-sn-glycero-3 phosphocholine) bilayer. These features were found to correlate with the lipid phase dependent local environmental polarity sensed by 4AP-Cn donors at the interfaces. Molecular dynamics (MD) simulations, combined with experimental results, show that relative depth (and angle) variation of the 4AP-Cn donors and Rh6G acceptor directly controls the FRET efficiencies through fine tuning of the emission and absorption spectra of the donors and acceptor, respectively. The results indicate that the 4AP-Cn probes are well-suited as donors for FRET studies, which allow the FRET parameters at lipid/water interfaces of gel- and fluid-phases of lipid-bilayers to be quantified and compared simultaneously. PMID- 28726899 TI - Enhanced interfacial activity of multi-arm poly(ethylene oxide) star polymers relative to linear poly(ethylene oxide) at fluid interfaces. AB - Interfacial tension reduction, dynamic dilatational elasticity and extent of adsorption were investigated for linear poly(ethylene oxide) (PEO) chains of varying molecular weight and for PEO star polymers with an average of 64 arms per star at air/water, xylene/water, and cyclohexane/water interfaces. Adsorption on planar interfaces was monitored by ellipsometry, while interfacial tension and dilatational elasticity were measured separately by pendant drop tensiometry. Previously reported to be efficient emulsifiers, PEO stars are shown here to also be more effective foaming agents than linear PEO. Accordingly, PEO stars adsorb to a greater extent and produce larger interfacial tension reduction and greater dynamic dilatational moduli than linear PEO. The more extensive adsorption and greater interfacial tension reduction for PEO stars are attributed to their compactness. More mass is introduced per unit area of interface, and more interfacial penetration is achieved, upon their adsorption than for adsorption of linear polymers that adopt the conformation of loops, trains and tails. Whereas cyclohexane is a non-solvent for PEO, xylene is a good solvent. Dispersing PEO stars in the xylene phase yields greater interfacial tension reduction at the xylene/water interface than occurs when initially dispersing PEO stars in the aqueous phase. In contrast, the interfacial tension for linear PEO shows no dependence on the phase from which it adsorbs. Ellipsometry confirms the path dependent extent of adsorption to the xylene/water interface, but also reveals additional complexity. When adsorbing from xylene, thick interfacial films result that likely contain dispersed water, as suggested by the observation of spontaneous water-in-xylene emulsification when PEO stars are initially dispersed in xylene. This is tentatively attributed to shear provided by Marangoni flow. Spontaneous emulsification occurs only when PEO stars are initially dispersed in the xylene phase. Linear PEO produces neither thick interfacial films nor spontaneous emulsification. PMID- 28726896 TI - Cycloaddition reactions of enoldiazo compounds. AB - Enoldiazo esters and amides have proven to be versatile reagents for cycloaddition reactions that allow highly efficient construction of various carbocycles and heterocycles. Their versatility is exemplified by (1) [2+n] cycloadditions (n = 3, 4) by the enol silyl ether units of enoldiazo compounds with retention of the diazo functionality to furnish alpha-cyclic-alpha-diazo compounds that are themselves subject to further transformations of the diazo functional group; (2) [3+n]-cycloadditions (n = 1-5) by metallo-enolcarbenes formed by catalytic dinitrogen extrusion from enoldiazo compounds; (3) [2+n] cycloadditions (n = 3, 4) by donor-acceptor cyclopropenes generated in situ from enoldiazo compounds that produce cyclopropane-fused ring systems. The role of dirhodium(ii) and the emergence of copper(i) catalysts are described, as are the different outcomes of reactions initiated with these catalysts. This comprehensive review on cycloaddition reactions of enoldiazo compounds, with emphasis on methodology development, mechanistic insight, and catalyst-controlled chemodivergence, aims to provide inspiration for future discoveries in the field and to catalyze the application of enoldiazo reagents by the wider synthetic community. PMID- 28726900 TI - Potential energy surface stationary points and dynamics of the F- + CH3I double inversion mechanism. AB - Direct dynamics simulations were performed to study the SN2 double inversion mechanism SN2-DI, with retention of configuration, for the F- + CH3I reaction. Previous simulations identified a transition state (TS) structure, i.e. TS0, for the SN2-DI mechanism, including a reaction path. However, intrinsic reaction coordinate (IRC) calculations from TS0 show it is a proton transfer (PT) TS connected to the F-HCH2I SN2 pre-reaction complex and the FHCH2I- proton transfer post-reaction complex. Inclusion of TS0 in the SN2-DI mechanism would thus involve non-IRC atomistic dynamics. Indeed, trajectories initiated at TS0, with random ensembles of energies as assumed by RRKM theory, preferentially form the SN2-DI products and ~70% follow the proposed SN2-DI pathway from TS0 to the products. In addition, the Sudden Vector Projection (SVP) method was used to identify which CH3I vibrational mode excitations promote access to TS0 and the SN2-DI mechanism. Results of F- + CH3I simulations, with SVP specified mode excitations, are disappointing. With the CH3 deformations of CH3I excited, the SN2 single inversion mechanism is the dominant pathway. If the CH stretch modes are also excited, proton transfer dominates the reaction. SN2-DI occurs, but with a very small probability of ~1%. The reasons behind these results are discussed. PMID- 28726901 TI - On the capacitance of narrow nanotubes. AB - The storage of ions in narrow nanotubes is investigated by grand-canonical Monte Carlo simulations. The interaction between the ions is screened by the image charge on the wall of the tube, but at close distances it is still much larger than the thermal energy. Depending on the electrochemical potential imposed by the contact with an electrolyte solution, two different regimes can be distinguished at the potential of zero charge: for low values corresponding to an ionophobic pore the tube is almost empty; for high values - ionophilic pore - a one dimensional salt is formed. The two regions are separated by a narrow transition zone marked by strong fluctuations. Depending on the regime and on the value assumed for the dielectric constant, the interfacial capacity shows four, two, or in rare cases three maxima. The results are compared to a reference system of non-interacting ions, and discussed with respect to recent calculations within classical density functional theory. PMID- 28726902 TI - Limiting the valence: advancements and new perspectives on patchy colloids, soft functionalized nanoparticles and biomolecules. AB - Limited bonding valence, usually accompanied by well-defined directional interactions and selective bonding mechanisms, is nowadays considered among the key ingredients to create complex structures with tailored properties: even though isotropically interacting units already guarantee access to a vast range of functional materials, anisotropic interactions can provide extra instructions to steer the assembly of specific architectures. The anisotropy of effective interactions gives rise to a wealth of self-assembled structures both in the realm of suitably synthesized nano- and micro-sized building blocks and in nature, where the isotropy of interactions is often a zero-th order description of the complicated reality. In this review, we span a vast range of systems characterized by limited bonding valence, from patchy colloids of new generation to polymer-based functionalized nanoparticles, DNA-based systems and proteins, and describe how the interaction patterns of the single building blocks can be designed to tailor the properties of the target final structures. PMID- 28726903 TI - Reversible trans?cis photoisomerizations of [Re(CO)3(ph2phen)(stpyCN)]+ towards molecular machines. AB - In our search for light powered molecular devices, a novel fac [Re(CO)3(ph2phen)(trans-stpyCN)]+ complex was synthesized to show switchable trans-cis configurations of the coordinated stpyCN ligand through efficient and reversible photoassisted isomerizations. Controlled photolyses of acetonitrile solutions led to spectral changes ascribed to reversible trans?cis photoisomerization processes. A remarkable quantum yield for the back cis-to trans isomerization was obtained, with the same magnitude of the trans-to-cis photoprocess, and curiously, both trans- and cis-isomers are emissive at room temperature. Photochemical and photophysical characterization studies for fac [Re(CO)3(ph2phen)(stpyCN)]+ provided insights into the isomerization and emissive light-driven pathways that are resulted from the interactions between the close lying intraligand and charge transfer states. The reversible cis-trans photoisomerization has potential to be exploited as light-powered molecular motors and geometry regulators in molecular machines. PMID- 28726904 TI - Vesicle aggregates as a model for primitive cellular assemblies. AB - Primitive cell models help to understand the role that compartmentalization plays in origin of life scenarios. Here we present a combined experimental and modeling approach towards the construction of simple model systems for primitive cellular assemblies. Charged lipid vesicles aggregate in the presence of oppositely charged biopolymers, such as nucleic acids or polypeptides. Based on zeta potential measurements, dynamic light scattering and cryo-transmission electron microscopy, we have characterized the behavior of empty and ferritin-filled large unilamellar POPC vesicles, doped with different amounts of cationic (DDAB, CTAB) and anionic (sodium oleate) surfactants, and their aggregation upon the addition of anionic (tRNA, poly-l-glutamic acid) and cationic (poly-l-arginine) biopolymers, respectively. The experimental results are rationalized by a phenomenological modeling approach that predicts the average size of the vesicle aggregates as function of the amount of added biopolymers. In addition, we discuss the mechanism of vesicle aggregation induced by oppositely charged biopolymers. Our study complements previous reports about the formation of giant vesicle clusters and thus provides a general vista on primitive cell systems, based on the association of vesicles into compartmentalized aggregates. PMID- 28726905 TI - The exemplary role of nanoconfinement in the proton transfer from acids to ammonia. AB - Proton transfer processes from mineral acids to bases (HX, where X = F, Cl, Br and I to ammonia) are normally feasible in solution and they cannot spontaneously occur in the gas phase. We demonstrate that this process can be feasible under nanoconfinement without using any solvent molecules. More interestingly, in contrast to the general observation, halide ions except fluoride behave like protons under high confinement, leading to the formation of NH3X instead of NH4 ions. The triggering transformation of hydrogen bonded to the proton transferred complex under nanoconfinement is explained based on the thermodynamic quantity, static pressure. PMID- 28726906 TI - Influence of local structure on photoluminescence properties of Eu3+ doped CeO2 red phosphors through induced oxygen vacancies by contrasting rare earth substitutions. AB - A new family of red phosphors, Ce0.9-xRExO2-delta:0.1Eu3+ (RE = Y and La; x = 0, 0.20, 0.40, 0.60, 0.80, and 0.90), was synthesized by a conventional solid-state route. The influence of contrasting rare earth substitutions (Y and La) in the system was investigated on the local structure and associated photoluminescence properties by various characterization techniques. Both trivalent ion substitutions lead to the same kind of variation during phase transformation from fluorite to the respective parent oxide structure (x >= 0.6). On the other hand, the substitutions have a distinct effect on local structure, absorption, luminescence and lifetimes. The smaller Y3+ ion substitution enables the ordering of oxygen vacancies in a lattice, inhibiting the defect formation of Ce3+ oxidation states. In contrast, the larger La3+ ion substitution liberates oxygen vacancies, allowing defect formation. Consequently, the concentration of Ce3+ is dependent on the ionic radius of the metal ions and it has a bearing on the band gap and luminescence properties of the system. Ce0.1Y0.8O2-delta:0.1Eu3+ phosphor exhibited maximum red emission intensity at 612 nm, which is 8 times higher than that of Ce0.9O2-delta:0.1Eu3+ and better than that of commercial Philips red phosphor, whereas La substitution yielded poor emission intensities with higher concentrations. The co-substitution of contrasting rare earth metals with Eu3+ allow the understanding of local structure and a smaller ion like Y3+ greatly functionalizes CeO2:Eu3+ phosphor. PMID- 28726907 TI - The first water coordination sphere of lanthanide(iii) motexafins (Ln-Motex2+, Ln = La, Gd, Lu) and its effects on structures, reduction potentials and UV-vis absorption spectra. Theoretical studies. AB - Density functional calculations have been performed to study selected hydrated lanthanide(iii) motexafins (Ln-Motex2+, Ln = La, Gd, Lu) by using energy consistent 4f-in-core lanthanide pseudopotentials to include the major relativistic effects due to the heavy metals. The maximum number (n) of water molecules bound strongly to [Ln-Motex]2+ (Ln = La, Gd, Lu) was determined to be 6 by calculating the change of the Gibbs energies for the reactions [Ln Motex(H2O)n]2+ + H2O -> [Ln-Motex(H2O)n+1]2+. The number of water molecules coordinated directly to Ln3+ was found to be 3 for La, and 2 for Gd and Lu. The explicit treatment of the tightly bound water molecules in [Ln-Motex(H2O)6]2+ in combination with the COSMO solvation model yielded calculated reduction potentials and UV-vis absorption spectra in good agreement with available experimental data. PMID- 28726908 TI - Mn4+,Li+ co-doped SrMgAl10O17 phosphor-in-glass: application in high-power warm w LEDs. AB - Currently, the shortage of red components and easy aging of organic silicone still remain challenges for high-power phosphor-converted warm white light emitting diodes (w-LEDs). Aiming to alleviate these issues, phosphor-in-glass (PiG), fabricated by co-sintering red- and yellow-emitting phosphors and low melting glass, has been regarded as a promising color converter for w-LEDs. In this study, a Li+,Mn4+ co-doped SrMgAl10O17 red phosphor was synthesized via a conventional solid-state reaction. The as-prepared phosphor exhibits a deep red emission, ascribed to Mn4+:2Eg->4A2g spin-forbidden transition in the range of 600-700 nm with a narrow-band full width at half maximum of 55 nm, and provides an ideal broadband excitation extending from 250 to 530 nm. Impressively, the Li+ additive used as charge compensation was beneficial to enhance the Mn4+ luminescence by allowing more Mn4+ to replace Al3+. Furthermore, the developed SrMgAl10O17:Mn4+,Li+ red phosphor and commercial YAG:Ce3+ yellow phosphor co doped inorganic PiG were successfully fabricated as color converters to substitute organic silicone. The w-LED was fabricated by combining an InGaN blue LED chip with a PiG plate. Importantly, the constructed w-LEDs exhibited superior optical performance and tuned chromaticity feature with the correlated color temperature evolved from bluish cool white (6903 K) to yellowish warm white (3717 K), and the color rendering index increased from 69.4 to 85.5, meeting the requirements for indoor lighting. PMID- 28726910 TI - The influence of heteroatoms on the aromatic character and the current pathways of B2N2-dibenzo[a,e]pentalenes. AB - Four polycyclic molecules have been investigated at the DFT B3LYP/def2-TZVP level of theory using calculated magnetically induced current densities as an indicator of their (anti)aromaticity. Complicated current pathways were found in dibenzo[a,e]pentalene and its three heterocyclic analogues each containing two boron and two nitrogen atoms. The antiaromatic character of the pentalene moiety is weaker in the hydrocarbon molecule and in 5,11 dihydrobenzo[d]benzo[4,5][1,2,3]azadiborolo[3,2-b][1,2,3]azadiborole as compared to the pentalene molecule. The antiaromatic character of the pentalene moiety is completely absent in the other two heterocyclic structures. In 6,12 dihydrobenzo[d]benzo[4,5][1,2,3]diazaborolo[2,1-a][1,2,3]diazaborole all four molecular rings are aromatic according to the ring-current criterion, and in 6,12 dihydrobenzo[d]benzo[3,4][1,2,5]azadiborolo[1,2-a][1,3,2]diazaborole, the diazaborole ring is aromatic, while the azadiborole ring is antiaromatic. In all four molecules the six-membered rings are aromatic sustaining a weaker ring current than benzene does. PMID- 28726909 TI - Lysine-based amino-functionalized lipids for gene transfection: the protonation state in monolayers at the air-liquid interface. AB - Cationic lipids are considered as non-viral carriers for genetic material used in gene therapy. They have no carcinogenic potential and cause low immune response compared to existing viral systems. The protonation degree of these cationic lipids is a crucial parameter for the binding behavior of polynucleotides (e.g., DNA). Newly synthesized peptide-mimic lysine-based amino-functionalized lipids have been investigated in 2D models as monolayers at the air-liquid interface. Standard surface pressure - area isotherms have been measured to prove the layer stability. Total reflection X-ray fluorescence (TRXF) has been used as a surface sensitive analytical method to estimate the amount of counterions at the head groups. Using a standard sample as a reference, the protonation degree of these cationic lipids can be quantified on buffers with different pH values. It is found that the protonation degree depends linearly on the packing density of the lipid monolayer. PMID- 28726911 TI - Feeding a sustainable chemical industry: do we have the bioproducts cart before the feedstocks horse? AB - A sustainable chemical industry cannot exist at scale without both sustainable feedstocks and feedstock supply chains to provide the raw materials. However, most current research focus is on producing the sustainable chemicals and materials. Little attention is given to how and by whom sustainable feedstocks will be supplied. In effect, we have put the bioproducts cart before the sustainable feedstocks horse. For example, bulky, unstable, non-commodity feedstocks such as crop residues probably cannot supply a large-scale sustainable industry. Likewise, those who manage land to produce feedstocks must benefit significantly from feedstock production, otherwise they will not participate in this industry and it will never grow. However, given real markets that properly reward farmers, demand for sustainable bioproducts and bioenergy can drive the adoption of more sustainable agricultural and forestry practices, providing many societal "win-win" opportunities. Three case studies are presented to show how this "win-win" process might unfold. PMID- 28726913 TI - Mechanistic insights into dioxygen activation, oxygen atom exchange and substrate epoxidation by AsqJ dioxygenase from quantum mechanical/molecular mechanical calculations. AB - Herein, we use in-protein quantum mechanical/molecular mechanical (QM/MM) calculations to elucidate the mechanism of dioxygen activation, oxygen atom exchange and substrate epoxidation processes by AsqJ, an FeII/alpha-ketoglutarate dependent dioxygenase (alpha-KGD) using a 2-His-1-Asp facial triad. Our results demonstrated that the whole reaction proceeds through a quintet surface. The dioxygen activation by AsqJ leads to a quintet penta-coordinated FeIV-oxo species, which has a square pyramidal geometry with the oxo group trans to His134. This penta-coordinated FeIV-oxo species is not the reactive one in the substrate epoxidation reaction since its oxo group is pointing away from the target C[double bond, length as m-dash]C bond. Instead, it can undergo the oxo group isomerization followed by water binding or the water binding followed by oxygen atom exchange to form the reactive hexa-coordinated FeIV-oxo species with the oxo group trans to His211. The calculated parameters of Mossbauer spectra for this hexa-coordinated FeIV-oxo intermediate are in excellent agreement with the experimental values, suggesting that it is most likely the experimentally trapped species. The calculated energetics indicated that the rate-limiting step is the substrate C[double bond, length as m-dash]C bond activation. This work improves our understanding of the dioxygen activation by alpha-KGD and provides important structural information about the reactive FeIV-oxo species. PMID- 28726912 TI - 3D material cytometry (3DMaC): a very high-replicate, high-throughput analytical method using microfabricated, shape-specific, cell-material niches. AB - Studying cell behavior within 3D material niches is key to understanding cell biology in health and diseases, and developing biomaterials for regenerative medicine applications. Current approaches to studying these cell-material niches have low throughput and can only analyze a few replicates per experiment resulting in reduced measurement assurance and analytical power. Here, we report 3D material cytometry (3DMaC), a novel high-throughput method based on microfabricated, shape-specific 3D cell-material niches and imaging cytometry. 3DMaC achieves rapid and highly multiplexed analyses of very high replicate numbers ("n" of 104-106) of 3D biomaterial constructs. 3DMaC overcomes current limitations of low "n", low-throughput, and "noisy" assays, to provide rapid and simultaneous analyses of potentially hundreds of parameters in 3D biomaterial cultures. The method is demonstrated here for a set of 85 000 events containing twelve distinct cell-biomaterial micro-niches along with robust, customized computational methods for high-throughput analytics with potentially unprecedented statistical power. PMID- 28726914 TI - 3D-printed smartphone-based point of care tool for fluorescence- and magnetophoresis-based cytometry. AB - In developing countries, there are often limited resources available to provide important medical diagnostics, which severely limits our ability to diagnose conditions and administer proper treatment, leading to high mortality rates for treatable conditions. Here, we propose a multiplex tool capable of density-based cell sorting via magnetic focusing in parallel with fluorescence imaging to provide highly specific clinical assays. While many cell sorting techniques and fluorescence microscopes generally are costly and require extensive user training, limiting accessibility and usability in developing countries, this device is compact, low-cost, and portable. The device can separate cells on the basis of density, which can be used to identify cell type and cell activity, and image the cells in either brightfield, darkfield, or fluorescent imaging modes using the built-in smartphone camera. The combination of these two powerful and versatile techniques - magnetic focusing and fluorescence imaging - will make this platform broadly applicable to a range of biomedical assays. Clinical applications include cell cytometry and immunocytochemistry-based assays in limited-resource settings, which can ultimately help to improve worldwide accessibility to medical diagnostics. PMID- 28726915 TI - Oleuropein represses the radiation resistance of ovarian cancer by inhibiting hypoxia and microRNA-299-targetted heparanase expression. AB - Radiotherapy in ovarian cancer frequently invokes resistance; this severely compromises its therapeutic effect and results in poor clinical prognosis. How to overcome the acquired resistance and re-sensitize tumors to radiation is the central question in this clinical setting. Cancer cell survival was evaluated using a clonogenic assay. The microRNA expression profile was analyzed using a microarray. Transcript expression was determined using real time PCR. The expression of protein was determined by immunoblotting. Transcription activation was measured using a luciferase reporter assay. Transcription factor binding was determined using ChIP-PCR. Xenograft model was established and exposed to radiation with the simultaneous administration of oleuropein. Tumor growth was monitored. We demonstrated that treatment of oleuropein-sensitized ovarian cells with radiation altered the microRNA expression profile. The endogenous expression of miR-299 was suppressed by a hypoxia inducible factor and relieved in response to oleuropein, which in turn suppressed HPSE1 expression and consequently led to increased sensitivity to radiation. Our data elucidates an unappreciated mechanism mediating radiotherapy resistance in ovarian cancer and exploits the potential synergistic effect of oleuropein with radiation, which warrants further clinical investigation. PMID- 28726916 TI - A novel 3-D bio-microfluidic system mimicking in vivo heterogeneous tumour microstructures reveals complex tumour-stroma interactions. AB - A 3-D microfluidic system consisting of microchamber arrays embedded in a collagen hydrogel with tuneable biochemical gradients that mimics the tumour microenvironment of mammary glands was constructed for the investigation on the interactions between invasive breast cancer cells and stromal cells. The hollow microchambers in collagen provide a very similar 3-D environment to that in vivo that regulates collective cellular dynamics and behaviour, while the microfluidic channels surrounding the collagen microchamber arrays allow one to impose complex concentration gradients of specific biological molecules or drugs. We found that breast epithelial cells (MCF-10A) seeded in the microchambers formed lumen-like structures similar to those in epithelial layers. When MCF-10A cells were co cultured with invasive breast cancer cells (MDA-MB-231), the formation of lumen like structures in the microchambers was inhibited, indicating the capability of cancer cells to disrupt the structures formed by surrounding cells for further invasion and metastasis. Subsequent mechanism studies showed that down regulation of E-cad expression due to MMPs produced by the cancer cells plays a dominant role in determining the cellular behaviour. Our microfluidic system offers a robust platform for high throughput studies that aim to understand combinatorial effects of multiple biochemical and microenvironmental factors. PMID- 28726917 TI - Engineering micromyocardium to delineate cellular and extracellular regulation of myocardial tissue contractility. AB - Cardiovascular diseases are a leading cause of death, in part due to limitations of existing models of the myocardium. Myocardium consists of aligned, contractile cardiac myocytes interspersed with fibroblasts that synthesize extracellular matrix (ECM). The cellular demographics and biochemical and mechanical properties of the ECM remodel in many different cardiac diseases. However, the impact of diverse cellular and extracellular remodeling on the contractile output of the myocardium are poorly understood. To address this, we micropatterned 13 kPa and 90 kPa polyacrylamide gels with aligned squares of fibronectin (FN) or laminin (LN). We seeded gels with two concentrations of primary neonatal rat ventricular myocytes, which naturally contain fibroblasts. Cells assembled into aligned "MUMyocardia" with fibroblast : myocyte ratios dependent on initial seeding concentration. Using traction force microscopy (TFM), we found that the peak systolic longitudinal cross-sectional force was similar across conditions, but the peak systolic work was significantly lower on 90 kPa gels. This indicates that ECM elasticity dominates over ECM ligand and cell demographics in regulating contractile output. Because our platform provides independent control over cell cell and cell-matrix interactions, it has many applications for cardiac disease modeling. PMID- 28726918 TI - Two hybrid lanthanide complexes exhibiting a large magnetocaloric effect and slow magnetic relaxation. AB - Two isostructural lanthanide (Ln) hybrid complexes co-bridged by organic oxalate and inorganic hypophosphite, [Ln(oxa)(H2PO2)(H2O)2] (oxa = oxalate; Ln = Gd (1), Dy (2)), were solvothermally prepared with the goal of elucidating the role of a hybrid framework in the generation of novel molecular magnetic materials. The title compounds feature a two dimensional (2D) hybrid layer. The LnIII ions are octa-coordinated with distorted square antiprism geometry. The adjacent LnIII ions are co-bridged by hypophosphite and one type of oxalate ligand to form 1D hybrid chains, which are further linked by a second type of oxalate ligand to generate the resulting 2D framework. Magnetic investigations reveal that compound 1 features a large magnetocaloric effect with -DeltaS = 46.60 J kg-1 K-1 (134.39 mJ cm-3 K-1), due to the combined advantages of organic oxalate and inorganic hypophosphite ligands, while compound 2 displays slow magnetic relaxation. PMID- 28726919 TI - Exploring the construction of multicompartmental micelles by halogen bonding of complementary macromolecules. AB - An approach to the construction of multicompartmental micelles, using halogen bonding between complementary macromolecules, is described. The design involves a sequential assembly protocol, in which the initial compartments are formed by interpolymer halogen bonding, followed by the collapse of a second, hydrophobic compartment upon transfer to aqueous solvent. Triblock terpolymers incorporating a halogen bond accepting segment have been synthesized. Transmission electron microscopy was used to characterize multicompartmental assemblies generated from these terpolymers in the presence of a halogen bond donor-functionalized polystyrene derivative. PMID- 28726920 TI - Pheomelanin molecular vibration is associated with mitochondrial ROS production in melanocytes and systemic oxidative stress and damage. AB - Vibrations in covalent bonds affect electron delocalization within molecules, as reported in polymers. If synthesized by living cells, the electron delocalization of polymers affects the stabilization of cellular free radicals, but biomolecular vibration has never been considered a potential source of cytotoxicity. Here we show that the vibrational characteristics of natural pheomelanin and eumelanin contribute to feather color expression in four poultry breeds with different melanin-based pigmentation patterns, but only the vibrational characteristics of pheomelanin are related to the production of reactive oxygen species (ROS) in the mitochondria of melanocytes and to systemic levels of cellular oxidative stress and damage. This association may be explained by the close physical contact existing between mitochondria and melanosomes, and reveals an unprecedented factor affecting the viability of organisms through their pigmentation. These findings open a new avenue for understanding the mechanism linking pheomelanin synthesis to human melanoma risk. PMID- 28726921 TI - Molecular dynamics simulations and in vitro analysis of the CRMP2 thiol switch. AB - The collapsin response mediator protein CRMP2 (gene: DPYSL2) is crucial for neuronal development. The homotetrameric CRMP2 complex is regulated via two mechanisms: first by phosphorylation and second by the reduction and oxidation of the Cys504 residues of two adjacent subunits. Here, we have analysed the effects of this redox switch on the protein in vitro combined with force field molecular dynamics (MD). Earlier X-ray data reveal the structure of the rigid body of the molecule but lack the flexible C-terminus with the important sites for phosphorylation and redox regulation. An in silico model for this part was established by replica exchange simulations and homology modelling, which is consistent with the CD spectroscopy results of the recombinant protein. Thermofluor data indicated that the protein aggregates at bivalent ion concentrations below 200 mM. In simulations the protein surface was covered under these conditions by a large number of ions, which most likely prevent aggregation. A tryptophan residue (Trp295) in close proximity to the forming disulphide allowed the measurement of the structural relaxation of the rigid body upon reduction by fluorescence quenching. We were also able to determine the second-order rate constant of CRMP2 oxidation by H2O2. The simulated solvent accessible surface of the hydroxyl group of Ser518 significantly increased upon reduction of the disulphide bond. Our results give the first detailed insight into the profound structural changes of the tetrameric CRMP2 due to oxidation and indicate a tightly connected regulation by phosphorylation and redox modification. PMID- 28726922 TI - Correction: Infrared nonlinear optical properties of lithium-containing diamond like semiconductors Li2ZnGeSe4 and Li2ZnSnSe4. AB - Correction for 'Infrared nonlinear optical properties of lithium-containing diamond-like semiconductors Li2ZnGeSe4 and Li2ZnSnSe4' by Jian-Han Zhang et al., Dalton Trans., 2015, 44, 11212-11222. PMID- 28726924 TI - Peculiarities of thermal denaturation of OmpF porin from Yersinia ruckeri. AB - Irreversible denaturation of membrane proteins in detergent solutions is similar to unfolding of water-soluble multidomain proteins and represents a complex, multistage process. Pore-forming proteins of Gram-negative bacteria are heat modifiable proteins, i.e., proteins altering their molecular forms (trimers or monomers), and accordingly, their electrophoretic mobilities depending upon denaturation conditions. There are still some contradictory data on the peculiarities of the conformational changes in the porin structure with temperature. Some authors demonstrated the loss of the porin trimeric structure only after unfolding of monomer subunits. Other researchers initially observed the dissociation of porin oligomers into the folded monomers. Using SDS-PAGE, spectroscopic methods and differential scanning calorimetry, a detailed study of thermally induced changes in the spatial structure of OmpF porin from the fish pathogen Yersinia ruckeri (Yr-OmpF) was carried out. The data obtained allowed us to conclude unambiguously that changes in the spatial structure of the monomers of Yr-OmpF precede the dissociation of the porin trimer. PMID- 28726925 TI - Prospects for 207Pb solid-state NMR studies of lead tetrel bonds. AB - The feasibility and value of 207Pb solid-state NMR experiments on compounds featuring lead tetrel bonds is explored. Although the definition remains to be formalized, lead tetrel bonds may be qualitatively described as existing when there is evidence of a net attractive interaction between an electrophilic region associated with lead in a molecular entity and a nucleophilic region in another, or the same, molecular entity. Unambiguous identification of lead tetrel bonds can be challenging due to the hypervalent tendency of lead. We report here a series of 207Pb solid-state NMR experiments on five metal-organic frameworks featuring lead coordinated to hydrazone-based ligands. Such frameworks may be held together in part by lead tetrel bonds. The acquisition of 207Pb solid-state NMR spectra for such materials is feasible and is readily accomplished using a combination of magic-angle spinning and Carr-Purcell-Meiboom-Gill methods in moderate to low applied magnetic fields. The lead centres are characterized by 207Pb isotropic chemical shifts ranging from -426 to -2591 ppm and chemical shift tensor spans ranging from 910 to 2681 ppm. Careful inspection of the structures of the compounds and the literature 207Pb NMR data may suggest that a tetrel bond to lead results in chemical shift parameters which are intermediate between those which are characteristic of holodirected and hemidirected lead coordination geometries. Challenges associated with DFT computations of the 207Pb NMR parameters are discussed. In summary, the 207Pb data for the compounds studied herein show a marked response to the presence of non-coordinating electron-rich moieties in close contact with the electrophilic surface of formally hemidirectionally coordinated lead compounds. PMID- 28726923 TI - Robust manufacturing of lipid-polymer nanoparticles through feedback control of parallelized swirling microvortices. AB - A variety of therapeutic and/or diagnostic nanoparticles (NPs), or nanomedicines, have been formulated for improved drug delivery and imaging applications. Microfluidic technology enables continuous and highly reproducible synthesis of NPs through controlled mixing processes at the micro- and nanoscale. Yet, the inherent low-throughput remains a critical roadblock, precluding the probable applications of new nanomedicines for clinical translation. Here we present robust manufacturing of lipid-polymer NPs (LPNPs) through feedback controlled operation of parallelized swirling microvortex reactors (SMRs). We demonstrate the capability of a single SMR to continuously produce multicomponent NPs and the high-throughput performance of parallelized SMRs for large-scale production (1.8 kg d-1) of LPNPs while maintaining the physicochemical properties. Finally, we present robust and reliable manufacturing of NPs by integrating the parallelized SMR platform with our custom high-precision feedback control system that addresses unpredictable disturbances during the production. Our approach may contribute to efficient development and optimization of a wide range of multicomponent NPs for medical imaging and drug delivery, ultimately facilitating good manufacturing practice (GMP) production and accelerating the clinical translation. PMID- 28726926 TI - Using one halogen bond to change the nature of a second bond in ternary complexes with PCl and FCl halogen bonds. AB - Ab initio MP2/aug'-cc-pVTZ calculations have been carried out to determine the effect of the presence of one halogen bond on the nature of the other in ternary complexes H2XP:ClF:ClH and H2XP:ClF:ClF, for X = F, Cl, H, NC, and CN. The PCl bonds remain chlorine-shared halogen bonds in the ternary complexes H2XP:ClF:ClH, although the degree of chlorine sharing increases relative to the corresponding binary complexes. The FCl bonds in the ternary complexes remain traditional halogen bonds. The binding energies of the complexes H2XP:ClF:ClH increase relative to the corresponding binary complexes, and nonadditivities of binding energies are synergistic. In contrast, the presence of two halogen bonds in the ternary complexes H2XP:ClF:ClF has a dramatic effect on the nature of these bonds in the four most strongly bound complexes. In these, chlorine transfer occurs across the PCl halogen bond to produce complexes represented as (H2XP-Cl)+: (F:ClF). In the ion-pair, the cation is also halogen bonded to the anion by a ClF halogen bond, while the anion is stabilized by an -FCl halogen bond. The central ClF molecule no longer exists as a molecule. The binding energies of the ternary H2XP:ClF:ClF complexes are significantly greater than the binding energies of the H2XP:ClF:ClH complexes, and nonadditivities exhibit large synergistic effects. The Wiberg bond indexes for the complexes H2XP:ClF, H2XP:ClF:ClH, and H2XP:ClF:ClF, and the cations (H2XP-Cl)+ reflect the changes in the P-Cl and Cl-F bonds. Similarly, EOM-CCSD spin-spin coupling constants are also consistent with the changes in these same bonds. In particular, 1xJ(P-Cl) in H2XP:ClF complexes becomes 1J(P-Cl) in the ternary complexes with chlorine-transferred halogen bonds. A plot of these coupling constants shows a change in the curvature of the trendline as chlorine-shared halogen bonds in H2XP:ClF:ClH become chlorine transferred halogen bonds in H2XP:ClF:ClF. 1xJ(F-Cl) coupling constants also reflect changes in the nature of FCl halogen bonds. PMID- 28726927 TI - Custom 3D printer and resin for 18 MUm * 20 MUm microfluidic flow channels. AB - While there is great interest in 3D printing for microfluidic device fabrication, to-date the achieved feature sizes have not been in the truly microfluidic regime (<100 MUm). In this paper we demonstrate that a custom digital light processor stereolithographic (DLP-SLA) 3D printer and a specifically-designed, low cost, custom resin can readily achieve flow channel cross sections as small as 18 MUm * 20 MUm. Our 3D printer has a projected image plane resolution of 7.6 MUm and uses a 385 nm LED, which dramatically increases the available selection of UV absorbers for resin formulation compared to 3D printers with 405 nm LEDs. Beginning with 20 candidate absorbers, we demonstrate the evaluation criteria and process flow required to develop a high-resolution resin. In doing so, we introduce a new mathematical model for characterizing the resin optical penetration depth based only on measurement of the absorber's molar absorptivity. Our final resin formulation uses 2-nitrophenyl phenyl sulfide (NPS) as the UV absorber. We also develop a novel channel narrowing technique that, together with the new resin and 3D printer resolution, enables small flow channel fabrication. We demonstrate the efficacy of our approach by fabricating 3D serpentine flow channels 41 mm long in a volume of only 0.12 mm3, and by printing high aspect ratio flow channels <25 MUm wide and 3 mm tall. These results indicate that 3D printing is finally positioned to challenge the pre-eminence of methods such as soft lithography for microfluidic device prototyping and fabrication. PMID- 28726928 TI - Comparative study of non-covalent interactions between cationic N-phenylviologens and halides by electrochemistry and NMR: the halogen bonding effect. AB - Five N-phenylviologen (PV2+) derivatives have been synthesized and their electrochemical behavior in the presence of halide anions has been studied. Further investigations were carried out by 1H and 19F NMR spectroscopy at different chloride concentrations. This is the first time a systematic study combines cyclic voltammetry and NMR spectroscopy in order to analyse the contribution of halogen bonding among the various non-covalent interactions between iodinated N-phenylviologens. The results show strong evidence for a significant "halogen bonding effect" in the interaction between halides and the iodo-tetrafluoro-phenylviologen PV2+-C6F4I. A significant influence of halogen bonding on reduction potentials of the novel halogen bond donor PV2+-C6F4I has been evidenced resulting in the first example of "inverse redox switching" of an XB-donor being partially deactivated upon reduction. Furthermore the particular binding properties of the perfluorinated derivative PV2+-C6F5 towards chloride are discussed considering a possible contribution of pi-anion interaction in solution. PMID- 28726929 TI - Sesamin prevents apoptosis and inflammation after experimental myocardial infarction by JNK and NF-kappaB pathways. AB - Myocardial infarction is a devastating event, especially when reperfusion is not performed. The inflammatory response has been associated with the pathogenesis of left ventricular remodeling after myocardial infarction. This study focused on the anti-apoptotic and anti-inflammatory effects of sesamin on ligation of the left anterior descending artery in an experimental mouse model and the potential mechanism underlying the activation of JNK and NF-kappaB pathways. Mice with MI induced by surgical left anterior descending coronary artery ligation were treated with sesamin by gavage for 1 week. Results showed that after treatment with sesamin, MI-induced cardiac damage was alleviated significantly, indicated by the histopathological examination. The myocardial apoptosis in the border zone was dramatically reduced by sesamin, resulting from the altered expression of apoptosis factors. Moreover, treatment with sesamin also mitigated the inflammatory response, decreased expression of cytokines and the inactivation of NF-kappaB (nuclear factor kappaB) signaling. Sesamin decreased the levels of p JNK protein, which in turn inactivated pro-apoptotic signaling events by restoring the balance between mitochondrial pro-apoptotic Bcl-2 and Bax proteins. Thus, our study suggests that sesamin could alleviate MI-induced cardiac dysfunction through decrease of myocardial apoptosis and inflammatory response. PMID- 28726930 TI - Competition and selectivity in supramolecular synthesis: structural landscape around 1-(pyridylmethyl)-2,2'-biimidazoles. AB - Three isomeric forms of 1-(pyridylmethyl)-2,2'-biimidazole, A1-A3, have been synthesized and subjected to systematic co-crystallizations with selected hydrogen- and halogen-bond donors in order to explore the impact of electrostatics and geometry on the resulting supramolecular architectures. The solid-state supramolecular behavior of A1-A3 is largely consistent in halogen bonded co-crystals. Only two types of primary interactions, the N-HN/NH-N homomeric hydrogen-bond interactions responsible for the pairing of biimidazole moieties and the IN(pyridine) halogen bonds responsible for the co-crystal formation and structure extension, are present in these systems. The co crystallizations with hydrogen-bond donors (carboxylic acids), however, lead to multiple possible structural outcomes because of the presence of the biimidazole acid N-HO[double bond, length as m-dash]C/NH-O heterosynthon that can compete with biimidazole-biimidazole N-HN/NH-N homosynthon. In addition, the somewhat unpredictable nature of proton transfer makes the hydrogen-bonded co-crystals structurally less consistent than their halogen-bonded counterparts. PMID- 28726931 TI - Electron-transfer reactions of halogenated electrophiles: a different look into the nature of halogen bonding. AB - The rates of oxidation of ferrocene derivatives by brominated molecules R-Br (CBr3CN, CBr4, CBr3NO2, CBr3COCBr3, CBr3CONH2, CBr3F, and CBr3H) were consistent with the predictions of the outer-sphere dissociative electron-transfer theory. The similar redox-reactions of the R-Br electrophiles with the typical halogen bond acceptors tetramethyl-p-phenylenediamine (TMPD) or iodide were much faster than calculated using the same model. The fast redox-processes in these systems were related to the involvement of the transient halogen-bonded [R-Br, TMPD] or [R-Br, I-] complexes in which barriers for electron transfer were lowered by the strong electronic coupling of reactants. The Mulliken-Hush treatment of the spectral and structural characteristics of the [R-Br, TMPD] or [R-Br, I-] complexes corroborated the values of coupling elements, Hab, of 0.2-0.5 eV implied by the kinetic data. The Natural Bond Orbital analysis of these complexes indicated a noticeable donor/acceptor charge transfer, Deltaq, of 0.03-0.09 e. The Hab and Deltaq values in the [R-Br, TMPD] and [R-Br, I-] complexes (which are similar to those in the traditional charge-transfer associates) indicate significant contribution of charge-transfer (weakly-covalent) interaction to halogen bonding. The decrease of the barrier for electron transfer between the halogen-bonded reactants demonstrated in the current work points out that halogen bonding should be taken into account in the mechanistic analysis of the reactions of halogenated species. PMID- 28726932 TI - Cationic all-halogen bonding rotaxanes for halide anion recognition. AB - A family of cationic halogen bonding [2]rotaxanes have been synthesised via an active-metal template synthetic strategy. 1H NMR spectroscopic anion titration investigations reveal these interlocked host systems recognize halides selectively over oxoanions in aqueous-organic solvent media. Furthermore, systematically modulating the rigidity and size of the rotaxanes' anion binding cavities via metal complexation, as well as by varying the number of halogen bond donor groups in the axle component, was found to dramatically influence halide anion selectivity. PMID- 28726933 TI - Comparison of halogen bonding networks with Ru(ii) complexes and analysis of the influence of the XB interactions on their reactivity. AB - Coordination compounds of formula [Ru(Cl)2(CNR)4] are interesting building blocks for the preparation of halogen bonding supramolecular networks, since the chloride ligand is a good XB acceptor. When using I2 as the XB donor, an unexpected reaction on the ruthenium coordination sphere happens where the chloride ligands are substituted by iodides. The isolation of several intermediates with different substitution degrees and showing XB interactions in a solid state network evidenced the clear influence of the XB species in this unusual reaction process. The extension of the studies to bromine gave the analogous result, i.e. the substitution of the chloride ligands by bromides. Furthermore, changing the organic substituent in the isocyanide ligands from alkyl to aryl does not affect the outcome of the reaction; however the process is faster when the alkyl substituents are present. In the course of the study of these reactions we have isolated a whole range of XB-based networks were interactions such as ClI-I, BrBr-Br, II-I and IBr-Br are present, a systematic comparison of the XB structural features for the different networks isolated and the influence in their reactivity has been performed. PMID- 28726934 TI - Clove extract functions as a natural fatty acid synthesis inhibitor and prevents obesity in a mouse model. AB - Numerous medicinal plants have been reported to prevent various chronic diseases. In this study, we screened a new FASN inhibitor-alcohol extract of clove (AEC) using a fast microplate method developed in our laboratory. The major components of AEC were: eugenol (42.27%), acetyl eugenol (29.12%), caryophyllene (15.40%), and humulene (3.22%). Fatty acid synthase (FASN) is a key enzyme for de novo lipogenesis, and it has been suggested as a potential therapeutic target in cancer and obesity. We have tested the ability of AEC to inhibit FASN in mammalian cells and tissues. Furthermore, we found that AEC as a FASN inhibitor could inhibit the S-phase DNA replication of HepG2 cells and adipocyte differentiation of OP9 cells. AEC also limited the development of high fat diet (HFD) induced obesity. AEC supplementation significantly reduced body weight and abdominal adipose tissue weight, lowered lipid accumulation in the liver and epididymal adipose tissue compared with the HFD control group. The serum lipid profiles showed that AEC could regulate the content of total triglyceride (TG), low-density lipoprotein cholesterol (LDL-C). Collectively, our data suggest that FASN inhibitor AEC is a potential therapeutic agent for obesity. PMID- 28726935 TI - Strength, character, and directionality of halogen bonds involving cationic halogen bond donors. AB - Halogen bonds involving cationic halogen bond donors and anionic halogen bond acceptors have recently been recognized as being important in stabilizing the crystal structures of many salts. Theoretical characterization of these types of interactions, most importantly in terms of their directionality, has been limited. Here we generate high-quality symmetry adapted perturbation theory potential energy curves of a H3N-C[triple bond, length as m-dash]C-Br+Cl- model system in order to characterize halogen bonds involving charged species, in terms of contributions from electrostatics, exchange, induction, and dispersion, with special emphasis on analyzing contributions that are most responsible for the directionality of these interactions. It is found that, as in the case of neutral halogen bonds, exchange forces are important contributors to the directionality of charged halogen bonds, however, it is also found that induction effects, which contribute little to the stability and directionality of neutral halogen bonds, play a large role in the directionality of halogen bonds involving charged species. Potential energy curves based on the omegaB97X-D/def2-TZVP/C-PCM method, which includes an implicit solvation model in order to mimic the effects of the crystal medium, are produced for both the H3N-C[triple bond, length as m-dash]C Br+Cl- model system and for the 4-bromoaniliniumCl- dimer, which is based on the real 4-bromoanilinium chloride salt, whose crystal structure has been determined experimentally. It is found that, within a crystal-like medium, charged halogen bond are significantly weaker than in the gas phase, having optimum interaction energies up to approximately -20 kcal mol-1. PMID- 28726936 TI - Dithiolato- and halogenido-bridged nickel-iron complexes related to the active site of [NiFe]-H2ases: preparation, structures, and electrocatalytic H2 production. AB - A new series of the structural and functional models for the active site of [NiFe]-H2ases has been prepared by a simple and convenient synthetic route. Thus, treatment of diphosphines RN(PPh2)2 (1a, R = p-MeC6H4CH2; 1b, R = EtO2CCH2) with an equimolar NiCl2.6H2O, NiBr2.3H2O, and NiI2 in refluxing CH2Cl2/MeOH or EtOH gave the mononuclear Ni complexes RN(PPh2)2NiX2 (2a, R = p-MeC6H4CH2, X = Cl; 2b, R = EtO2CCH2, X = Cl; 3a, R = p-MeC6H4CH2, X = Br; 3b, R = EtO2CCH2, X = Br; 4a, R = p-MeC6H4CH2, X = I; 4b, R = EtO2CCH2, X = I) in 67-97% yields. Further treatment of complexes 2a,b-4a,b with an equimolar mononuclear Fe complex (dppv)(CO)2Fe(pdt) and NaBF4 resulted in formation of the targeted model complexes [RN(PPh2)2Ni(MU-pdt)(MU-X)Fe(CO)(dppv)](BF4) (5a, R = p-MeC6H4CH2, X = Cl; 5b, R = EtO2CCH2, X = Cl; 6a, R = p-MeC6H4CH2, X = Br; 6b, R = EtO2CCH2, X = Br; 7a, R = p-MeC6H4CH2, X = I; 7b, R = EtO2CCH2, X = I) in 60-96% yields. All the new complexes 3a,b-4a,b and 5a,b-7a,b have been characterized by elemental analysis and spectroscopy, and particularly for some of them (3a,b/4a,b and 5b/6b) by X-ray crystallography. More interestingly, the electrochemical and electrocatalytic properties of such halogenido-bridged model complexes are first studied systematically and particularly they have been found to be pre-catalysts for proton reduction to H2 under CV conditions. PMID- 28726937 TI - Novel nanoparticles with Cr3+ substituted ferrite for self-regulating temperature hyperthermia. AB - For hyperthermia to be used under clinical conditions for cancer therapeutics the temperature regulation needs to be precise and accurately controllable. In the case of the metal nanoparticles used for such activities, a high coercivity is a prerequisite in order to couple more energy in a single heating cycle for efficient and faster differential heating. The chemically stable Co-Zn ferrite nanoparticles have typically not been used in such self-regulating hyperthermia temperature applications to date due to their low Curie temperature usually accompanied by a poor coercivity. The latter physical property limitation under clinically applied magnetic field conditions (frequency: 100 kHz, intensity: 200 Oe) restricts the transfer of a reasonable heat energy, and thus limits the hyperthermia efficiency. Here, we report a novel Cr3+ substituted Co-Zn ferrite (Zn0.54Co0.46Cr0.6Fe1.4O4), whose Curie temperature and coercivity values are 45.7 degrees C and 174 Oe, respectively. Under clinically acceptable magnetic field conditions, the temperature of these nanoparticle suspensions can be self regulated to 44.0 degrees C and, most importantly with a specific absorption rate (SAR) of 774 W kg-1, which is two-fold higher than the SAR standard for magnetic nanoparticles used in hyperthermia (300 W kg-1). The evaluation of the in vitro cytotoxicity of the nanoparticles reports a low toxicity, which points to a novel set of magnetic nanoparticles for use in self-regulating hyperthermia. PMID- 28726938 TI - Design and characterization of a plasmonic Doppler grating for azimuthal angle resolved surface plasmon resonances. AB - We present a two-dimensional plasmonic Doppler grating (PDG) for broadband and azimuthal angle-resolved nanophotonic applications. The PDG consists of a set of non-concentric circular rings mimicking the wavefronts of a moving point source that exhibits the Doppler effect and thereby offers a continuous azimuthal angle dependent lattice momentum for photon-plasmon coupling. The center and span of the working frequency window are fully designable for optimal performance in specific applications. We detail the design, fabrication and optical characterization of the PDG. The design of the Doppler grating provides a general platform for in-plane angle-resolved nanophotonic applications. PMID- 28726939 TI - A super flexible and custom-shaped graphene heater. AB - In this paper, we fabricate a graphene film heater through laser reduction on graphene oxide, which is a two-step process. The electrothermal performance of the graphene heater can be adjusted by the laser energy density. While the applied voltage is 18 V, the graphene heater reaches a steady-state temperature of 247.3 degrees C within 20 s. After the graphene heater is folded in half 100 times, its output temperature remains to be precisely controlled by the input power and the temperature distribution is uniform. In addition, the flexibility of the graphene heater is superior to a heater based on a commercial indium tin oxide film. It's worth noting that the graphene heater can be fabricated with desired shapes directly and easily, which is rare among the reported film heaters. In consideration of the high performance of the graphene film heater, we demonstrate its three application scenarios: portable warmers applied in medical infusion apparatus, flexible custom-shaped heaters for special requirements and displays. PMID- 28726940 TI - Measurement of specific heat and thermal conductivity of supported and suspended graphene by a comprehensive Raman optothermal method. AB - The last decade has seen the rapid growth of research on two-dimensional (2D) materials, represented by graphene, but research on their thermophysical properties is still far from sufficient owing to the experimental challenges. Herein, we report the first measurement of the specific heat of multilayer and monolayer graphene in both supported and suspended geometries. Their thermal conductivities were also simultaneously measured using a comprehensive Raman optothermal method without needing to know the laser absorption. Both continuous wave (CW) and pulsed lasers were used to heat the samples, based on consideration of the variable laser spot radius and pulse duration as well as the heat conduction within the substrate. The error from the laser absorption was eliminated by comparing the Raman-measured temperature rises for different spot radii and pulse durations. The thermal conductivity and specific heat were extracted by analytically fitting the temperature rise ratios as a function of spot size and pulse duration, respectively. The measured specific heat was about 700 J (kg K)-1 at room temperature, which is in accordance with theoretical predictions, and the measured thermal conductivities were in the range of 0.84 1.5 * 103 W (m K)-1. The measurement method demonstrated here can be used to investigate in situ and comprehensively the thermophysical properties of many other emerging 2D materials. PMID- 28726941 TI - Superlubricity of a graphene/MoS2 heterostructure: a combined experimental and DFT study. AB - Graphene and other two-dimensional materials have been proved to be able to offer low friction. Here we assembled van der Waals heterostructures with graphene and molybdenum disulphide monolayers. The Raman spectrum together with a modified linear chain model indicate a two-orders-of-magnitude decrease in the interlayer lateral force constant, as compared with their homogeneous bilayers, indicating a possible routine to achieve superlubricity. The decrease in the interlayer lateral force constant is consistent with the ultrasmall potential energy corrugation during sliding, which is derived from density functional theory calculations. The potential energy corrugation is found to be determined by the sliding-induced interfacial charge density fluctuation, suggesting a new perspective to understand the physical origin of the atomic scale friction of two dimensional materials. PMID- 28726942 TI - Conjugated polymer covalently modified graphene oxide quantum dots for ternary electronic memory devices. AB - Zero dimensional graphene oxide (GO) quantum dots (GOQDs) have been expected to play an important role in the development of new memory materials. When the size of GO was reduced to that of GOQDs, both the electron affinity and ionization potential of GO were found to be decreased, and this was followed by the elevation of lowest energy unoccupied molecular orbital (LUMO) energy level. This implies that the electron withdrawing ability of GOQDs is weaker than that of GO. In this work, a novel arylamine-based polyazomethine covalently functionalized graphene oxide quantum dots (TPAPAM-GOQDs), which was synthesized using an amidation reaction, was for the first time used to fabricate a ternary memory device with a configuration of gold/TPAPAM-GOQDs/indium tin oxide. The current ratio of OFF : ON-1 : ON-2 was found to be 1 : 60 : 3000. Its conductive nature was also revealed using an in situ conductive atomic force microscopy technique. This memory device could potentially increase the memory capacity of the device from the conventional 2n to 3n when compared to binary memory devices. PMID- 28726943 TI - Low-temperature atomic layer deposition delivers more active and stable Pt-based catalysts. AB - We tailored the size distribution of Pt nanoparticles (NPs) on graphene nanoplatelets at a given metal loading by using low-temperature atomic layer deposition carried out in a fluidized bed reactor operated at atmospheric pressure. The Pt NPs deposited at low temperature (100 degrees C) after 10 cycles were more active and stable towards the propene oxidation reaction than their high-temperature counterparts. Crucially, the gap in the catalytic performance was retained even after prolonged periods of time (>24 hours) at reaction temperatures as high as 450 degrees C. After exposure to such harsh conditions the Pt NPs deposited at 100 degrees C still retained a size distribution that is narrower than the one of the as-synthesized NPs obtained at 250 degrees C. The difference in performance correlated with the difference in the number of facet sites as estimated after the catalytic test. Our approach provides not only a viable route for the scalable synthesis of stable supported Pt NPs with tailored size distributions but also a tool for studying the structure-function relationship. PMID- 28726947 TI - On the critical role of the substrate: the adsorption behaviour of tetrabenzoporphyrins on different metal surfaces. AB - The adsorption behaviour of 2H-5,10,15,20-tetraphenyltetrabenzoporphyrin (2HTPTBP) on different metal surfaces, i.e., Ag(111), Cu(111), Cu(110), and Cu(110)-(2 * 1)O was investigated by scanning tunnelling microscopy at room temperature. The adsorption of 2HTPTBP on Ag(111) leads to the formation of a well-ordered two-dimensional (2D) island structure due to the mutual stabilization through the intermolecular pi-pi stacking and T-type-like interactions of phenyl and benzene substituents of neighboring molecules. For 2HTPTBP on Cu(111), the formed 2D supramolecular structures exhibit a coverage dependent behaviour, which can be understood from the interplay of molecule substrate and molecule-molecule interactions. In contrast, on Cu(110) the 2HTPTBP molecules form dispersed one-dimensional (1D) molecular chains along the [11[combining macron]0] direction of the substrate due to relatively strong attractive molecule-substrate interactions. Furthermore, we demonstrate that the reconstruction of the Cu(110) surface by oxygen atoms yields a change in dimensionality of the resulting nanostructures from 1D on Cu(110) to 2D on (2 * 1) oxygen-reconstructed Cu(110), induced by a decreased molecule-substrate interaction combined with attractive molecule-molecule interactions. This comprehensive study on these prototypical systems enables us to deepen the understanding of the particular role of the substrate concerning the adsorption behavior of organic molecules on metal surfaces and thus to tweak the ordering in functional molecular architectures. PMID- 28726948 TI - An expeditious method to synthesize difluoroboron complexes of beta-keto amides from beta-keto nitriles and BF3.OEt2. AB - A convenient and expeditious strategy to synthesize difluoroboron complexes of beta-keto amides has been developed from beta-keto nitriles and BF3.OEt2. BF3.OEt2 serves as both a BF2 source and a Lewis acid catalyst in the synthetic strategy. The formation mechanism of the difluoroboron complexes from beta-keto nitriles and BF3.OEt2 was proposed. The difluoroboron complexes can be further converted into beta-keto amides by treatment with sodium acetate. The strategy features advantages such as a wide substrate scope, non-metal catalysis, and easy operation. Some of the difluoroboron complexes display good fluorescence properties in the solid state and potential application in solid-state luminescent materials. PMID- 28726949 TI - Spin-reversal energy barriers of 305 K for Fe2+ d6 ions with linear ligand coordination. AB - A remarkably large magnetic anisotropy energy of 305 K is computed by quantum chemistry methods for divalent Fe2+ d6 substitutes at Li-ion sites with D6h point group symmetry within the solid-state matrix of Li3N. This is similar to values calculated by the same approach and confirmed experimentally for linearly coordinated monovalent Fe1+ d7 species, among the largest so far in the research area of single-molecule magnets. Our ab initio results therefore mark a new exciting exploration path in the search for superior single-molecule magnets, rooted in the configuration of d6 transition-metal ions with linear or quasilinear nearest-neighbor coordination. This d6 axial anisotropy may be kept robust even for symmetries lower than D6h, provided the ligand and farther neighbor environment is engineered such that the splitting remains large enough. PMID- 28726950 TI - One DNA strand homo-polymerizes into defined nanostructures. AB - We report a strategy for programmed DNA self-assembly that is favorable in terms of both thermodynamics and kinetics. In a previous study, it has been demonstrated that DNA self-assembly is primarily driven by thermodynamics and the assembly kinetics is not considered. To reach such stable states at equilibria, prolonged annealing duration is needed. In addition, there are cases where the desired structures could not compete with alternative structures. For example, a single-stranded DNA with a palindromic sequence quickly folds into a one-stranded hairpin instead of forming a two-stranded DNA duplex. Given that most of the DNA tiles are multi-stranded complexes, the kinetic trap represents a challenge to DNA self-assembly. To overcome this problem, we have developed a one-stranded motif that can intramolecularly and quickly fold from a single DNA strand and can be programmed to assemble into a range of nanostructures, including a one dimensional (1D) ladder, a 1D chain, a two-dimensional (2D) array, and a three dimensional (3D) triangular prism. All structures have been characterized by polyacrylamide gel electrophoresis (PAGE) and atomic force microscopy (AFM) imaging. PMID- 28726951 TI - Facile one-pot exfoliation and integration of 2D layered materials by dispersion in a photocurable polymer precursor. AB - Efficient exfoliation of graphene and related materials (GRM) and fast and inexpensive integration/assembly are crucial to fulfil their full potential. A high degree of exfoliation in organic media can be achieved with high boiling point liquids that usually leave residues after drying, which is a handicap for many applications. Here, the effective exfoliation and dispersion of GRM in a vinyl monomer, which is subsequently converted to a functional polymer by photopolymerization, is reported. Nanocomposite membranes and three-dimensional objects are produced by the photo-curing process and stereolithography 3D printing, respectively. PMID- 28726952 TI - Porphyra polysaccharide-derived carbon dots for non-viral co-delivery of different gene combinations and neuronal differentiation of ectodermal mesenchymal stem cells. AB - In this study, multifunctional fluorescent carbon dots (CDs) were synthesized using a one-pot hydrothermal carbonization reaction, with the naturally-occurring porphyra polysaccharide (PPS) serving as a single carbon source for the first time and ethylenediamine (Ed) acting as the surface passivation agent. The resulting CDs enjoyed a high quantum yield (56.3%), excitation-dependent fluorescence, small size (<10 nm), spherical shape, uniform distribution, positive surface charge, low cytotoxicity and excellent ability to condense macromolecular plasmid DNA. The synthesized CDs were employed for neuronal induction from ectodermal mesenchymal stem cells for the first time via highly efficient non-viral gene delivery. The optimal combination of factors (Ascl1 and Brn2) was selected from seven different combinations out of Ascl1, Brn2 and Sox2 according to the expression of neuronal markers (Tuj1, Map2 and Tau). The results of qRT-PCR demonstrated that the CDs possessed a significantly higher transfection efficiency than the commercially available transfection reagents PEI (25 kDa) and Lipofectamine2000. Moreover, the CDs/pDNA nanoparticles exhibited more efficient neuronal differentiation of the EMSCs than the AT-RA-containing induction medium. Furthermore, the CDs/pDNA nanoparticles could enter cells via both caveolae- and clathrin-mediated endocytosis. Taken together, the natural polysaccharide PPS-derived CDs enriched the current application of CDs by employing the CDs as a novel non-viral gene carrier for neuronal differentiation of adult stem cells, which held great promise in tissue engineering and bioimaging. PMID- 28726953 TI - 4,4'-Di-tert-butyl-6-(1H-tetrazol-5-yl)-2,2'-bipyridine: modification of a highly selective N-donor ligand for the separation of trivalent actinides from lanthanides. AB - In the present work, the complexation and extraction behaviour of 4,4'di-tert butyl-6-(1H-tetrazol-5-yl)-2,2'-bipyridine (HN4tbubipy) towards trivalent actinides (An(iii)) and lanthanides (Ln(iii)) is studied by spectroscopic methods, liquid-liquid extraction, and quantum chemical calculations. The ligand synthesis of HN4tbubipy as well as its application in coordination chemistry of the 4f elements is described. Reaction of HN4tbubipy with [Ln(NO3)3.6H2O] (Ln = Sm, Eu) results in [H2N4tbubipy]+[Ln(N4tbubipy)(NO3)3(H2O)]-. Both compounds have been characterized by single crystal X-ray diffraction. The solubility of the ligand in different organic solvents is determined, showing a high solubility in MeOH which decreases with the lipophilicity of the solvent. The pKa = 2.4 +/- 0.2 of HN4tbubipy in EtOH (4.4 vol% H2O) is determined by absorption spectrophotometry. The complexation of Cm(iii) and Eu(iii) with HN4tbubipy is studied by time resolved laser fluorescence spectroscopy (TRLFS). For both metal ions the formation of the complexes [M(N4tbubipy)n]3-n with n = 2, 3 (M = Cm(iii), Eu(iii)) is observed. Slightly higher conditional stability constants for Eu(iii) (log beta'2(Eu(N4tbubipy)2+) = 8.9 +/- 0.3, log beta'3(Eu(N4tbubipy)3) = 12.7 +/- 0.5), compared to Cm(iii) (log beta'2(Cm(N4tbubipy)2+) = 8.5 +/- 0.4 and log beta'3(Cm(N4tbubipy)3) = 12.4 +/- 0.6) are determined. Thus, the ligand has no preference for the complexation of An(iii) over Ln(iii). Additionally, no significant extraction of Am(iii) and Eu(iii) is observed in liquid-liquid extraction experiments due to protonation of the ligand at the experimental conditions. The experimental studies are supported by quantum chemical calculations of the free ligand and the [M(N4tbubipy)3] complexes (M = Cm(iii), Gd(iii)). The results are in excellent agreement with the experimental data and provide a deeper understanding of the complexation properties of HN4tbubipy. PMID- 28726954 TI - The interaction of amino acids with macrocyclic pH probes of pseudopeptidic nature. AB - The fluorescence quenching, by a series of amino acids, of pseudopeptidic compounds acting as probes for cellular acidity has been investigated. It has been found that amino acids containing electron-rich aromatic side chains like Trp or Tyr, as well as Met quench the emission of the probes mainly via a collisional mechanism, with Stern-Volmer constants in the 7-43 M-1 range, while other amino acids such as His, Val or Phe did not cause deactivation of the fluorescence. Only a minor contribution of a static quenching due to the formation of ground-state complexes has been found for Trp and Tyr, with association constants in the 9-24 M-1 range. For these ground-state complexes, a comparison between the macrocyclic probes and an open chain analogue reveals the existence of a moderate macrocyclic effect due to the preorganization of the probes in the more rigid structure. PMID- 28726956 TI - Concealing the taste of the Guinness World's most bitter substance by using a synthetic nanocontainer. AB - Upon supramolecular encapsulation by using a synthetic nanocontainer (cucurbit[7]uril), the taste of the Guinness World's most bitter substance, denatonium benzoate, was dramatically concealed during a two-bottle preference drinking test in a mammalian model, demonstrating the significant potential of cucurbit[7]uril as a taste-masking nanocontainer for the first time. PMID- 28726957 TI - Reductive amination catalyzed by iridium complexes using carbon monoxide as a reducing agent. AB - Development of novel, sustainable catalytic methodologies to provide access to amines represents a goal of fundamental importance. Herein we describe a systematic study for the construction of a variety of amines catalyzed by a well defined homogeneous iridium complex using carbon monoxide as a reducing agent. The methodology was shown to be compatible with functional groups prone to reduction by hydrogen or complex hydrides. PMID- 28726958 TI - Wasabia japonica is a potential functional food to prevent colitis via inhibiting the NF-kappaB signaling pathway. AB - Inflammatory bowel diseases (IBDs), including Crohn's disease (CD) and ulcerative colitis (UC), are prevalent and debilitating health problems worldwide. Many types of drugs are used to treat IBDs, but they exhibit adverse effects such as vomiting, nausea, abdominal pain, diarrhea, etc. In order to overcome the limitations of current therapeutic drugs, scientists have searched for functional foods from natural resources. In this study, we investigated the anti-colitic effects of Wasabia japonica extract in a DSS-induced colitis model. Wasabi japonica is a plant of the Brassicaceae family that has recently been reported to exhibit properties of detoxification, anti-inflammation, and induction of apoptosis in cancer cells. In this study, we generated wasabi ethanol extract (WK) and assessed its anti-colitic effect. In addition, in order to improve delivery of the extract to the colon, WK was coated with 5% Eudragit S100 (WKE), after which the anti-colitic effects of WKE were assessed. In conclusion, WK prevented development of colitis through inhibition of the NF-kB signaling pathway and recovery of epithelial tight junctions. In addition, the anti-colitic effect of WK was enhanced by improving its delivery to the colon by coating the WK with Eudragit S100. Therefore, we suggest that wasabi can be used as a new functional food to prevent IBDs due to its anti-colitic effect. PMID- 28726959 TI - Association of cultured myotubes and fasting plasma metabolite profiles with mitochondrial dysfunction in type 2 diabetes subjects. AB - Accumulating evidence implicates mitochondrial dysfunction-induced insulin resistance in skeletal muscle as the root cause for the greatest hallmarks of type 2 diabetes (T2D). However, the identification of specific metabolite-based markers linked to mitochondrial dysfunction in T2D has not been adequately addressed. Therefore, we sought to identify the markers-based metabolomics for mitochondrial dysfunction associated with T2D. First, a cellular disease model was established using human myotubes treated with antimycin A, an oxidative phosphorylation inhibitor. Non-targeted metabolomic profiling of intracellular defined metabolites on the cultured myotubes with mitochondrial dysfunction was then determined. Further, a targeted MS-based metabolic profiling of fasting blood plasma from normal (n = 32) and T2D (n = 37) subjects in a cross-sectional study was verified. Multinomial logical regression analyses for defining the top 5% of the metabolites within a 95% group were employed to determine the differentiating metabolites. The myotubes with mitochondrial dysfunction exhibited insulin resistance, oxidative stress and inflammation with impaired insulin signalling activities. Four metabolic pathways were found to be strongly associated with mitochondrial dysfunction in the cultured myotubes. Metabolites derived from these pathways were validated in an independent pilot investigation of the fasting blood plasma of healthy and diseased subjects. Targeted metabolic analysis of the fasting blood plasma with specific baseline adjustment revealed 245 significant features based on orthogonal partial least square discriminant analysis (PLS-DA) with a p-value < 0.05. Among these features, 20 significant metabolites comprised primarily of branched chain and aromatic amino acids, glutamine, aminobutyric acid, hydroxyisobutyric acid, pyroglutamic acid, acylcarnitine species (acetylcarnitine, propionylcarnitine, dodecenoylcarnitine, tetradecenoylcarnitine hexadecadienoylcarnitine and oleylcarnitine), free fatty acids (palmitate, arachidonate, stearate and linoleate) and sphingomyelin (d18:2/16:0) were identified as predictive markers for mitochondrial dysfunction in T2D subjects. The current study illustrates how cellular metabolites provide potential signatures associated with the biochemical changes in the dysregulated body metabolism of diseased subjects. Our finding yields additional insights into the identification of robust biomarkers for T2D associated with mitochondrial dysfunction in cultured myotubes. PMID- 28726960 TI - Robust triplet-triplet annihilation photon upconversion by efficient oxygen scavenging. AB - We hereby present a simple method for reducing the effect of oxygen quenching in Triplet-Triplet Annihilation Upconversion (TTA-UC) systems. A number of commercially available thioethers and one thiol have been tested as singlet oxygen scavengers. Recording of the upconverted emission from a well-studied PdOEP (sensitizer)-DPA (annihilator/emitter) couple has been made over time with steady-state excitation capturing the steady-state kinetics of the TTA-UC process as the solubilized oxygen is depleted by reaction with the scavengers. The efficiency of the TTA-UC process is compared between chemical oxygen scavenging and mechanical removal by inert gas purging or the freeze-pump-thaw method. Selected methods are combined to explore the highest attainable TTA-UC quantum yield. A maximum TTA-UC quantum yield of 21% with the shortest UC onset time was obtained with dimethylthiomethane (DMTM) as the scavenger in an air-saturated solvent and slightly higher quantum yields were obtained in combination with other deoxygenation techniques. Samples containing DMTM displayed little decrease in the quantum yield over four hours of continuous high intensity irradiation, which illustrates the robustness of applying chemical oxygen removal in TTA-UC instead of more time-consuming mechanical processes that usually require specialized equipment. PMID- 28726961 TI - Functional single-walled carbon nanotubes 'CAR' for targeting dopamine delivery into the brain of parkinsonian mice. AB - Current treatments for Parkinson's disease (PD) are limited, partly due to the difficulties posed by the blood brain barrier (BBB) when delivering drugs to the brain. Herein, we explore the feasibility and efficacy of functional single walled carbon nanotubes 'CAR' (SWCNT-PEGs-Lf) which carry and target-deliver dopamine (DA) to the brain in PD mice for treatment. SWCNTs can penetrate the cell-membrane remarkably, with the characteristics including high drug-loading and pH-dependent therapeutic unloading capacities. It has been reported that polyethylene glycol (PEG)-coated SWCNTs could increase the circulation time and thus prolong the concentration gradient of SWCNTs to the brain. Besides, an obvious lactoferrin-nanoparticle (Lf-NP) accumulation in the striatum, wherein the pharmacological target site of PD has been reported, a dual modification of PEG and Lf onto SWCNTs was applied and thus a specific 'CAR' to carry DA. The results from in vitro studies demonstrate that with 20 mol L-1 DA loaded onto SWCNT-polyethylene glycol (PEGs) in addition to 100 MUmol L-1 6-hydroxydopamine (6-OHDA), the activity of PC12 cells increases significantly (p < 0.05), and that the lactate dehydrogenase (LDH) levels and reactive oxygen species (ROS) content also significantly decrease (p < 0.01). Furthermore, the levels of oxidative stress, tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta are all reduced significantly in PD mice and the CAR-25 mg kg-1 DA group in comparison with that in 6-OHDA-lesioned mice with saline and 6-OHDA-lesioned mice, as well as the Tyrosine hydroxylase-immunoreactive (TH-ir) density increased (p < 0.01). The toxicity of CAR was in vitro and in vivo investigated, showing that the safe dose of SWCNT-PEG exposure to PC12 cells was 6.25 MUg MUl-1 or lower with a higher metabolic activity in comparison with that in the control group and the safe dose of CAR in the mice experiments was 3.25 mg kg-1 or less, given by intraperitoneal injection with a lower level of oxidative stress and inflammatory responses in comparison with that in the control group. This study suggests that 25 mg kg-1 DA loaded onto 3.25 mg kg-1 CAR can alleviate the oxidative stress and inflammatory responses in parkinsonian mice and increase the TH-ir density in the striatum. PMID- 28726962 TI - Recent advances in functional mesoporous graphitic carbon nitride (mpg-C3N4) polymers. AB - Mesoporous micro-/nanostructures acting as supports for catalysts or used directly in catalysis reactions generally show fascinating performances that could lead to great potential for application. In the past few decades, extensive efforts have been devoted to the exploration and enrichment of graphitic carbon nitride (g-C3N4) based research. Especially, mesoporous g-C3N4 (mpg-C3N4) with controllable porosity and electronic/atomic structure can bring to bear unique physicochemical properties and has been widely applied in the fields of photocatalysis, adsorbents, sensors and chemical templates. However, a comprehensive summary on mpg-C3N4 micro/nanostructures is less reported and there is an urgent need to further promote the development of function-oriented mpg C3N4-based materials. Herein, we will overview the significant advances in functional mpg-C3N4 polymers, including general synthesis strategies and growth mechanisms, modifications of electronic/atomic structures and interfacial properties (such as exfoliation, doping and hybridizing), as well as their current applications. Finally, several emerging issues and perspectives are also proposed. PMID- 28726963 TI - Comment on "An unexpected formation of the novel 7-oxa-2-azabicyclo[2.2.1]hept-5 ene skeleton during the reaction of furfurylamine with maleimides and their bioprospection using a zebrafish embryo model" by C. E. Puerto Galvis and V. V. Kouznetsov, Org. Biomol. Chem., 2013, 11, 407. AB - It has been proved that the reaction between furfuryl amines and N-R-maleimides leads to the formation of aza-Michael addition products - 3-(furylmethylamino)-N R-pyrrolidine-2,5-diones, instead of 7-oxa-2-azabicyclo[2.2.1]hept-5-enes, as this journal reported previously. PMID- 28726964 TI - A beta-galactosidase probe for the detection of cellular senescence by mass cytometry. AB - Mass cytometry (MC) is a powerful method that combines the cellular resolution of flow cytometry with the isotopic resolution of inductively coupled plasma mass spectrometry (ICP-MS). This combination theoretically allows for the simultaneous quantification of >80 different parameters at the single cell level, in turn allowing for the deep profiling of heterogeneous cell populations. The majority of available reagents for MC are antibodies labeled with heavy metal isotopes, allowing for the quantification of static biomarkers. To complement these reagents, we aim to develop small molecule reporters of cellular metabolism that are compatible with MC. Here we report a probe of beta-galactosidase activity capable of detecting cellular senescence. The galactoside probe contains a tellurophene reporter group and, when hydrolyzed, generates a quinone alkide. This reactive alkylating agent forms covalent tellurophene bearing conjugates with local nucleophiles, allowing for the quantification of beta-galactosidase activity in individual cells. Difluoromethyl and monofluoroethyl quinone alkide generating warheads were examined for their activities and compared in vitro and in vivo. We showed that the difluoromethyl derivative gave higher tellurium labelling in vitro and that the quinone methide was more reactive towards thiols than amines. In vivo the difluoromethyl derivative successfully labeled senescent cells with comparable selectivity to the commonly used fluorescent senescence probe C12FDG. PMID- 28726966 TI - Ab initio performance predictions of single-layer In-V tunnel field-effect transistors. AB - The device performances of both n-type and p-type tunnel field-effect transistors (TFETs) made of single-layer InX (X = N, P, As, Sb) are theoretically evaluated through density functional theory (DFT) and ab initio simulations in this paper. It is found that a promising steep subthreshold swing (SS) of [less-than-or-eq] 60 mV dec-1 can be obtained with gate length LG = 15.2 nm for all two-dimensional (2D) InX TFETs. In particular, an outstanding on-current of ~1058 MUA MUm-1 (or 880 MUA MUm-1) is estimated in a 2D p-type (or n-type) InSb device, which could barely satisfy the ITRS requirements for future high-performance (HP) applications. In addition, the 2D InAs p-type (or n-type) TFET containing a 15.2 nm gate length has great potential to be applied to the low-power (LP) devices with an ON-OFF ratio of ION/IOFF = 1.8 * 107 (or ION/IOFF = 1.9 * 107). However, the density-of-state bottleneck effect strongly influences the behavior of 2D InP and InN devices. Our results provide guidance for experimental synthesis and future designs of a single-layer material device with a steep inverse subthreshold slope, low OFF-, and high ON-current. PMID- 28726967 TI - Unprecedented ferromagnetic Gdnitronyl nitroxide coupling through a hydrogen bonding bridge. AB - A novel lanthanide(iii)-nitronyl nitroxide chain {[Gd(hfac)3(Nit-Ph-3,5 bIm)(H2O)].C4H10O}n (1) was prepared and characterized. Strikingly, an unexpected ferromagnetic coupling between the Gd(iii) ion and the nitroxide group mediated by hydrogen bonding has been observed for the first time. PMID- 28726969 TI - A fiber asymmetric supercapacitor based on FeOOH/PPy on carbon fibers as an anode electrode with high volumetric energy density for wearable applications. AB - Fiber supercapacitors are promising energy storage devices for wearable applications. However, the fiber supercapacitors are currently limited by the mediocre capacitance performances due to the use of typical carbon materials as the anode, sacrificing the volumetric energy density of the whole device. In addition, the inability to undergo washable cycles and poor self-discharge rate prevents the fiber-shaped supercapacitors from being a true energy textile and affects their practicability. Hence, the porous anode electrode FeOOH/PPy@CF has been firstly prepared with a high volumetric capacitance of 30.17 F cm-3, contributing to a high volumetric energy density of 2 mWh cm-3 (based on the whole encapsulated device) for a fiber asymmetric supercapacitor MnO2@CF//FeOOH/PPy@CF in PVA/LiCl. Good flexibility could be exhibited when it was woven into a glove. Desired working voltage and capacity output could be easily obtained when connecting devices in series and parallel. The encapsulated device could work stably even after it was dipped for multiple cycles in different solutions and with intensive stirring in water that simulates washing cycles. The self-discharge rate could be mitigated when an ionogel electrolyte ([EMIM][TFSI]/FS) was incorporated and this further enhanced the energy density to 3.7 mWh cm-3. The outstanding properties of our assembled asymmetric fiber supercapacitor device render it a good candidate for practical wearable energy storage devices. PMID- 28726968 TI - Evaluation of spectral photon counting computed tomography K-edge imaging for determination of gold nanoparticle biodistribution in vivo. AB - Spectral photon counting computed tomography (SPCCT) is an emerging medical imaging technology. SPCCT scanners record the energy of incident photons, which allows specific detection of contrast agents due to measurement of their characteristic X-ray attenuation profiles. This approach is known as K-edge imaging. Nanoparticles formed from elements such as gold, bismuth or ytterbium have been reported as potential contrast agents for SPCCT imaging. Furthermore, gold nanoparticles have many applications in medicine, such as adjuvants for radiotherapy and photothermal ablation. In particular, longitudinal imaging of the biodistribution of nanoparticles would be highly attractive for their clinical translation. We therefore studied the capabilities of a novel SPCCT scanner to quantify the biodistribution of gold nanoparticles in vivo. PEGylated gold nanoparticles were used. Phantom imaging showed that concentrations measured on gold images correlated well with known concentrations (slope = 0.94, intercept = 0.18, RMSE = 0.18, R2 = 0.99). The SPCCT system allowed repetitive and quick acquisitions in vivo, and follow-up of changes in the AuNP biodistribution over time. Measurements performed on gold images correlated with the inductively coupled plasma-optical emission spectrometry (ICP-OES) measurements in the organs of interest (slope = 0.77, intercept = 0.47, RMSE = 0.72, R2 = 0.93). TEM results were in agreement with the imaging and ICP-OES in that much higher concentrations of AuNPs were observed in the liver, spleen, bone marrow and lymph nodes (mainly in macrophages). In conclusion, we found that SPCCT can be used for repetitive and non-invasive determination of the biodistribution of gold nanoparticles in vivo. PMID- 28726970 TI - A homeotropic main-chain tolane-type liquid crystal elastomer film exhibiting high anisotropic thermal conductivity. AB - The development of pure polymeric films with anisotropic thermal conductivities for electronic device packaging applications has attracted intense scientific attention. In order to enhance the polymeric film's normal-direction thermal conductivity, homeotropic alignment of macromolecular chains is the primary concern. One of the promising preparation strategies is to perform in situ photopolymerization of homeotropic-oriented liquid crystal monomers. In this work, we design and synthesize a novel tolane-core thiol-ene-tailed liquid crystal monomer. Benefitting from the conjugated and extended tolane pi-system of the mesogenic core and length extension of the terminal aliphatic tails, the normal-to-plane thermal conductivity value and the thermal conductivity anisotropy value of the corresponding cross-linked main-chain end-on liquid crystal polymer (xMELCP) film reach 3.56 W m-1 K-1 and 15.0, respectively. Compared with the data of a previously reported ester-type thiol-ene xMELCP film, the two primary values of this novel tolane-type thiol-ene xMELCP material are increased dramatically by 46% and 29%, respectively. PMID- 28726971 TI - An Environment for Guideline-based Decision Support Systems for Outpatients Monitoring. AB - OBJECTIVES: We propose an architecture for monitoring outpatients that relies on mobile technologies for acquiring data. The goal is to better control the onset of possible side effects between the scheduled visits at the clinic. METHODS: We analyze the architectural components required to ensure a high level of abstraction from data. Clinical practice guidelines were formalized with Alium, an authoring tool based on the PROforma language, using SNOMED-CT as a terminology standard. The Alium engine is accessible through a set of APIs that may be leveraged for implementing an application based on standard web technologies to be used by doctors at the clinic. Data sent by patients using mobile devices need to be complemented with those already available in the Electronic Health Record to generate personalized recommendations. Thus a middleware pursuing data abstraction is required. To comply with current standards, we adopted the HL7 Virtual Medical Record for Clinical Decision Support Logical Model, Release 2. RESULTS: The developed architecture for monitoring outpatients includes: (1) a guideline-based Decision Support System accessible through a web application that helps the doctors with prevention, diagnosis and treatment of therapy side effects; (2) an application for mobile devices, which allows patients to regularly send data to the clinic. In order to tailor the monitoring procedures to the specific patient, the Decision Support System also helps physicians with the configuration of the mobile application, suggesting the data to be collected and the associated collection frequency that may change over time, according to the individual patient's conditions. A proof of concept has been developed with a system for monitoring the side effects of chemo-radiotherapy in head and neck cancer patients. CONCLUSIONS: Our environment introduces two main innovation elements with respect to similar works available in the literature. First, in order to meet the specific patients' needs, in our work the Decision Support System also helps the physicians in properly configuring the mobile application. Then the Decision Support System is also continuously fed by patient-reported outcomes. PMID- 28726972 TI - Consequences of warfarin suspension after major bleeding in very elderly patients with non valvular atrial fibrillation. PMID- 28726974 TI - Back on Track. PMID- 28726976 TI - Absence of transforming growth factor beta 1 in murine platelets reduces neointima formation without affecting arterial thrombosis. AB - Platelet degranulation at the site of vascular injury prevents bleeding and may affect the chronic vascular wound healing response. Transforming Growth Factor (TGF)-beta1 is a major component of platelet alpha-granules known to accumulating in thrombi. It was our aim to determine the role of TGFbeta1 released from activated platelets for neointima formation following arterial injury and thrombosis. Mice with platelet-specific deletion of TGFbeta1 (Plt.TGFbeta-KO) underwent carotid artery injury. Immunoassays confirmed the absence of active TGFbeta1 in platelet releasates and plasma of Plt.TGFbeta-KO mice. Whole blood analyses revealed similar haematological parameters, and tail cut assays excluded major bleeding defects. Platelet aggregation and the acute thrombotic response to injury in vivo did not differ between Plt.TGFbeta-KO and Plt.TGFbeta-WT mice. Morphometric analysis revealed that absence of TGFbeta1 in platelets resulted in a significant reduction of neointima formation with lower neointima area, intima to-media ratio, and lumen stenosis. On the other hand, the media area was enlarged in mice lacking TGFbeta1 in platelets and contained increased amounts of proteases involved in latent TGFbeta activation, including MMP2, MMP9 and thrombin. Significantly increased numbers of proliferating cells and cells expressing the mesenchymal markers platelet-derived growth factor receptor-beta or fibroblast-specific protein-1, and the macrophage antigen F4/80, were observed in the media of Plt.TGFbeta-KO mice, whereas the medial smooth muscle-actin immunopositive area and collagen content did not differ between genotypes. Our findings support an essential role for platelet-derived TGFbeta1 for the vascular remodelling response to arterial injury, apparently independent from the role of platelets in thrombosis or haemostasis. PMID- 28726977 TI - Added value of SPECT/spiral CT versus SPECT or CT alone in diagnosing solitary skeletal lesions. AB - AIM: The aim of this study was to investigate the added value of SPECT/spiral CT versus SPECT or CT alone in the differential diagnosis of solitary skeletal lesions. METHODS: This was a retrospective study on a total of 69 patients who had a solitary skeletal "hot spot" that could not be definitively diagnosed using planar scintigraphy. Thus, SPECT/spiral CT was performed on the indeterminate lesions. SPECT, CT and SPECT/spiral CT images were independently interpreted by two experienced doctors who have both identification of CT and nuclear medicine. Each lesion was graded on a 4-point diagnostic scale (1: benign, 2: likely benign, 3: likely malignant, 4: malignant). The final diagnosis of each lesion was based on pathological confirmation after surgery within 3 weeks of the bone scan. RESULTS: Final diagnoses based on the pathological results revealed that 43 of the 69 patients were diagnosed with malignancy, and the remaining 26 patients were diagnosed as having benign lesions. For SPECT and CT scans, both of the reviewers rated 55.1 % (38/69) and 37.7 % (26/69) of lesions as equivocal, with the help of SPECT/CT, 33.3 % (23/69) of lesions were rated as equivocal. The diagnostic accuracies of SPECT, CT alone and SPECT/CT were 66.7 % (46/69) ,82.6 % (57/69) and 85.5 %(59/69), respectively. The kappa scores for the degree of agreement between SPECT, CT alone or SPECT/CT with pathological results were 0.185 (p = 0.054) , 0.612 (p < 0.001) and 0.671 (p < 0.001), respectively. CONCLUSION: Compared with SPECT or imaging alone, SPECT/spiral CT imaging was more accurate and valuable in the differential diagnosis of solitary skeletal lesions and resulted in significantly fewer equivocal findings. PMID- 28726978 TI - Analysis of the substrate specificity of Factor VII activating protease (FSAP) and design of specific and sensitive peptide substrates. AB - Factor VII (FVII) activating protease (FSAP) is a circulating serine protease that is likely to be involved in a number of disease conditions such as stroke, atherosclerosis, liver fibrosis, thrombosis and cancer. To date, no systematic information is available about the substrate specificity of FSAP. Applying phage display and positional scanning substrate combinatorial library (PS-SCL) approaches we have characterised the specificity of FSAP towards small peptides. Results were evaluated in the context of known protein substrates as well as molecular modelling of the peptides in the active site of FSAP. The representative FSAP-cleaved sequence obtained from the phage display method was Val-Leu-Lys-Arg-Ser (P4-P1'). The sequence X-Lys/Arg-Nle-Lys/Arg (P4-P1) was derived from the PS-SCL method. These results show a predilection for cleavage at a cluster of basic amino acids on the nonprime side. Quenched fluorescent substrate (Ala-Lys-Nle-Arg-AMC) (amino methyl coumarin) and (Ala-Leu-Lys-Arg-AMC) had a higher selectivity for FSAP compared to other proteases from the hemostasis system. These substrates could be used to measure FSAP activity in a complex biological system such as plasma. In histone-treated plasma there was a specific activation of pro-FSAP as validated by the use of an FSAP inhibitory antibody, corn trypsin inhibitor to inhibit Factor XIIa and hirudin to inhibit thrombin, which may account for some of the haemostasis-related effects of histones. These results will aid the development of further selective FSAP activity probes as well as specific inhibitors that will help to increase the understanding of the functions of FSAP in vivo. PMID- 28726979 TI - Chronic Disease Registries - Trends and Challenges. AB - BACKGROUND: This accompanying editorial is an introduction to the focus theme of "chronic disease registries - trends and challenges". METHODS: A call for papers was announced on the website of Methods of Information in Medicine in April 2016 with submission deadline in September 2016. A peer review process was established to select the papers for the focus theme, managed by two guest editors. RESULTS: Three papers were selected to be included in the focus theme. Topics range from contributions to patient care through implementation of clinical decision support functionality in clinical registries; analysing similar-purposed acute coronary syndrome registries of two countries and their registry-to-SNOMED CT maps; and data extraction for speciality population registries from electronic health record data rather than manual abstraction. CONCLUSIONS: The focus theme gives insight into new developments related to disease registration. This applies to technical challenges such as data linkage and data as well as data structure abstraction, but also the utilisation for clinical decision making. PMID- 28726980 TI - Interdependence between osteoprotegerin and active von Willebrand factor in long term cardiovascular mortality prediction in patients undergoing percutaneous coronary intervention. AB - The interdependence of the predictive accuracy of serum osteoprotegerin (OPG) and von Willebrand factor (vWF) levels for long-term cardiovascular outcomes has not been investigated so far. This was a prospective observational cohort study in 361 patients with coronary artery disease undergoing percutaneous coronary intervention (PCI). Baseline levels of OPG, vWF, active vWF (act vWF) and ristocetin cofactor activity (vWF:RICO) were measured. Cardiovascular mortality was recorded over a median of five years. OPG concentrations >3.7 ug/ml emerged as the strongest predictor of cardiovascular (CV) death: 30 % of patients died during the five-year follow-up in this group, as compared to 10 % in patients with OPG <=3.7 ug/ml (p<0.001). Act vWF had a significant prognostic impact on CV mortality when OPG levels were low (<=3.7 ug/ml): patients with act vWF concentration >1 ug/ml died in 14 %, whereas those with act vWF values <=1 ug/ml had a mortality rate of 1 % (p=0.015). We stratified patients into three groups: high OPG, low OPG/high act vWF and low OPG/low act vWF. Patients with high OPG values had a 13-fold higher risk for CV death than those with low OPG/low act vWF concentrations (adj. HR: 12.6; 95 %CI: 1.7-94.7; p=0.014), and a two-fold higher risk as compared to those patients with low OPG/high act vWF concentrations (adj. HR: 2.0; 95 %CI: 1.1-3.7; p=0.03) in the adjusted Cox regression analysis. In conclusion, elevated OPG at the time of PCI was a strong independent predictor of five-years cardiovascular mortality, whereas act vWF had a significant prognostic impact on CV mortality when OPG levels were low. PMID- 28726981 TI - TRIENNIAL GROWTH AND DEVELOPMENT SYMPOSIUM: Factors influencing bovine intramuscular adipose tissue development and cellularity. AB - Appearance, distribution, and amount of intramuscular fat (IMF), often referred to as marbling, are highly variable and depend on environmental and genetic factors. On the molecular level, the concerted action of several drivers, including hormones, receptors, transcription factors, etc., determines where clusters of adipocytes arise. Therefore, the aim of future studies remains to identify such factors as biological markers of IMF to increase the ability to identify animals that deposit IMF early in age to increase efficiency of high quality meat production. In an attempt to unravel the cellular development of marbling, we investigated the abundance of markers for adipogenic differentiation during fattening of cattle and the transcriptome of muscle and dissected IMF. Markers of different stages of adipogenic differentiation are well known from cell culture experiments. They are usually transiently expressed, such as delta like homolog 1 (DLK1) that is abundant in preadipocytes and absent during differentiation to mature adipocytes. It is even a greater challenge to detect those markers in live animals. Within skeletal muscles, hyperplasia and hypertrophy of adipocytes can be observed throughout life. Therefore, development of marbling requires, on the cellular level, recruitment, proliferation, and differentiation of adipogenic cells to store excess energy in the form of lipids in new cells. In a recent study, we investigated the localization and abundance of early markers of adipogenic differentiation, such as DLK1, in bovine muscle tissue. An inverse relationship between IMF content and number of DLK1-positive cells in bovine muscle was demonstrated. Considering the cellular environment of differentiating adipocytes in muscle and the secretory action of adipocytes and myocytes, it becomes obvious that cross talk between cells via adipokines and myokines may be important for IMF development. Secreted proteins can act on other cells, inhibiting or stimulating their function via autocrine and paracrine actions. Such factors with potential influence on IMF, among them, agouti signaling protein and thrombospondin 4, were identified in transcriptome analyses and further investigated. Furthermore, results from transcriptome analysis indicate involvement of genes that are not directly related to adipogenesis and lipid metabolism, providing new candidates for future research. PMID- 28726982 TI - Effects of ractopamine hydrochloride on growth performance, carcass characteristics, and physiological response to different handling techniques. AB - Feedlot cattle ( = 128; BW = 549 +/- 60 kg) were used to evaluate the effects of ractopamine hydrochloride (RAC) on growth performance, physiological response to handling, and mobility during shipment for slaughter in a study utilizing a split plot design with a 2 * 2 factorial arrangement of treatments: 1) diet (CON [no beta-adrenergic agonist] vs. RAC [400 mg.animal.d ractopamine hydrochloride for 28 d]) and 2) handling intensity (HI; low-stress handling [LSH; cattle moved at a walking pace with no electric prod use] vs. high-stress handling [HSH; cattle moved at a minimum of a trot and an electric prod applied while in the alley for posthandling restraint and during loading for shipment to the abattoir]). Cattle fed RAC tended to have greater ADG and G:F ( = 0.06), and had greater HCW and LM area ( = 0.04). The HI treatments were applied on the day after the 28-d growth performance period. Blood samples were collected before HI treatment (baseline), after HI treatments (POSTHAND), after transport to the abattoir (POSTTRANS), and during exsanguination at slaughter. A diet * HI interaction ( = 0.01) was observed in the change in cortisol from baseline to POSTTRANS, and there tended ( <= 0.07) to be diet * HI interactions for the change in epinephrine from baseline to POSTHAND and for the change in creatine kinase (CK) from baseline to POSTTRANS. Feeding RAC and HSH both increased the change from baseline to POSTHAND in norepinephrine and pH ( <= 0.05). The HSH cattle also had greater changes from baseline to POSTHAND in blood HCO, base excess, partial pressure of CO, lactate, cortisol, and glucose ( <= 0.01). Ractopamine and HSH both produced greater increases in CK concentrations from baseline to slaughter ( < 0.01). Mobility was not affected by RAC at the feedlot or following an average 6-h lairage ( >= 0.43). This study confirms RAC improves growth performance and suggests metabolic acidosis, a precursor to fatigued cattle syndrome, develops in cattle allowed to trot without the use of a lead rider regardless of RAC administration. Cattle fed RAC displayed altered hormonal responses to handling and transport stress, and the overall proportion of cattle with compromised mobility appears to increase later in the marketing channel. These findings warrant additional research aimed at better understanding the physiological response to stress and protect the welfare of cattle during shipment for slaughter. PMID- 28726983 TI - Effect of space allowance and flooring on the behavior of pregnant ewes. AB - Space allowance recommendations for pregnant ewes vary considerably. The aim of this experiment was to investigate the effect of space allowance and floor type on activity, lying position, displacements, and aggressive interactions in pregnant ewes. A 3 * 2 factorial experiment was conducted with space allowance (0.75, 1.50, and 2.25 m/ewe) and type of flooring (straw bedding and expanded metal flooring) as the main factors. A total of 48 pregnant ewes were randomly assigned to 6 groups with 8 ewes in each group. All groups were exposed to each treatment for 7 d. The ewes were video recorded for 24 h at the end of each treatment period and general activity, lying position in the pen, and social lying position were scored every 15 min. Displacements and aggressive interactions were scored continuously from 1030 to 1430 h. Mean lying time ( < 0.0001) and time spent lying simultaneously ( < 0.0001) increased whereas time spent eating ( < 0.001) and standing ( < 0.001) decreased when space allowance increased from 0.75 to 1.50 m/ewe. Further increasing the space allowance to 2.25 m/ewe, however, had no effect on these parameters. Sitting was observed only in the 0.75 m/ewe treatment. Type of flooring had no significant effect on general activity. Ewes in the straw bedding treatment spent more time lying in the middle of the pen than ewes on expanded metal ( < 0.0001), but space allowance had no significant effect on this parameter. The proportion of time spent lying against side walls increased ( < 0.0001) whereas the proportion of time spent lying against the back wall decreased ( < 0.0001) when the space allowance was increased. In general, the distance between the ewes when lying significantly increased when space allowance increased from 0.75 to 1.50 m/ewe. Total number of displacements when lying ( < 0.0001) and aggressive interactions when active ( < 0.001) decreased when space allowance increased from 0.75 to 1.50 m/ewe and further slightly decreased, although the decrease was significant only for displacements when lying, when space allowance increased to 2.25 m/ewe. Low ranked ewes were not exposed to more aggressive behavior than high-ranked ewes. In conclusion, increasing space allowance from 0.75 to 1.50 m/ewe had positive effects on activity and behavior in pregnant ewes, but further increasing space allowance to 2.25 m/ewe had limited effects, as did type of flooring. Hence, recommended space allowance for pregnant ewes should not be lower than 1.50 m/ewe. PMID- 28726984 TI - PHYSIOLOGY AND ENDOCRINOLOGY SYMPOSIUM: Alterations in uteroplacental hemodynamics during melatonin supplementation in sheep and cattle. AB - Compromised placental function can result in fetal growth restriction which is associated with greater risk of neonatal morbidity and mortality. Large increases in transplacental nutrient and waste exchange, which support the exponential increase in fetal growth during the last half of gestation, are dependent primarily on the rapid growth and vascularization of the uteroplacenta. The amplitude of melatonin secretion has been associated with improved oxidative status and altered cardiovascular function in several mammalian species; however, melatonin mediated alterations of uteroplacental capacity in sheep and cattle are lacking. Therefore, our laboratories are examining uteroplacental blood flow and fetal development during maternal melatonin supplementation. Using a mid- to late gestation ovine model of intrauterine growth restriction, we examined uteroplacental blood flow and fetal growth during supplementation with 5 mg/d of dietary melatonin. Maternal nutrient restriction decreased uterine arterial blood flow, while melatonin supplementation increased umbilical arterial blood flow compared with non-supplemented controls. Although melatonin treatment did not rescue fetal weight in nutrient restricted ewes; we observed disproportionate fetal size and fetal organ development. Elevated fetal concentrations of melatonin may result in altered blood flow distribution during important time points of development. These melatonin specific responses on umbilical arterial hemodynamics and fetal development may be partially mediated through vascular melatonin receptors. Recently, we examined the effects of supplementing Holstein heifers with 20 mg/d of dietary melatonin during the last third of gestation. Uterine arterial blood flow was increased by 25% and total serum antioxidant capacity was increased by 43% in melatonin supplemented heifers vs. non supplemented controls. In addition, peripheral concentrations of progesterone were decreased in melatonin supplemented heifers vs. non-supplemented controls. Using an in vitro model, melatonin treatment increased the activity of cytochrome P450 2C, a progesterone inactivating enzyme, which was blocked by treatment with the melatonin receptor antagonist, luzindole. Elucidating the consequences of specific hormonal supplements on the continual plasticity of placental function will allow us to determine important endogenous mediators of offspring growth and development. PMID- 28726985 TI - Influence of dietary crude protein and phosphorus on ileal digestion of phosphorus and amino acids in growing pigs. AB - A study was conducted to investigate the effect of dietary CP levels on ileal P digestion in growing pigs. A total of 18 ileal-cannulated pigs (44.2 +/- 3.2 kg initial BW) were used in a duplicated 9 * 3 incomplete Latin square design, with 9 treatments and three 7-d experimental periods giving 6 replicates per treatment. The 9 treatments consisted of 1 N-free diet to estimate basal endogenous loss of AA and 8 corn-soybean meal-based diets in a 2 * 4 factorial arrangement, which included 2 CP levels (6.9 or 13.4%) and 4 apparent total tract digestible P (ATTDP) levels (0.09, 0.16, 0.24, or 0.32%). Soybean meal and monocalcium phosphate were used to adjust the CP level and ATTDP level, respectively. Limestone was included in diets to maintain a Ca:ATTDP ratio of 2.5 across treatments. Ileal digesta was continuously collected for 10 h on the last 2 d of each 7-d experimental period. The ileal digesta samples were lyophilized and analyzed to calculate ileal digested N and P. Data were analyzed using PROC MIXED of SAS (9.3) and contrasts were used to test the linear and quadratic effects of increasing levels of P within each CP level. In the low-CP group (6.9%), the ileal digested P was 0.71, 1.16, 1.64, and 2.03 g/kg DMI for diets that contained 0.09, 0.16, 0.24, and 0.32% ATTDP, respectively, and was 0.70, 1.54, 2.03, and 1.99 g/kg DMI, respectively, for their counterparts in the high CP group (13.4%). A low dietary CP level decreased ( < 0.05) ileal digested P (g/kg DMI). The ileal digested P (g/kg DMI) linearly increased ( < 0.01) with increasing ATTDP levels in the low-CP group, but the pattern was linear ( < 0.01) and quadratic ( < 0.01) in the high-CP group. In the low- and high-CP diets, the determined true ileal digestibility of P in monocalcium phosphate was 54.4 and 75.6%, respectively. In conclusion, this research indicated that the ileal digestion of P could be limited by protein deficiency. The dietary CP level should be considered in P digestibility-related studies. PMID- 28726986 TI - BOARD-INVITED REVIEW: Quantifying water use in ruminant production. AB - The depletion of water resources, in terms of both quantity and quality, has become a major concern both locally and globally. Ruminants, in particular, are under increased public scrutiny due to their relatively high water use per unit of meat or milk produced. Estimating the water footprint of livestock production is a relatively new field of research for which methods are still evolving. This review describes the approaches used to quantify water use in ruminant production systems as well as the methodological and conceptual issues associated with each approach. Water use estimates for the main products from ruminant production systems are also presented, along with possible management strategies to reduce water use. In the past, quantifying water withdrawal in ruminant production focused on the water demand for drinking or operational purposes. Recently, the recognition of water as a scarce resource has led to the development of several methodologies including water footprint assessment, life cycle assessment, and livestock water productivity to assess water use and its environmental impacts. These methods differ with respect to their target outcome (efficiency or environmental impacts), geographic focus (local or global), description of water sources (green, blue, and gray), handling of water quality concerns, the interpretation of environmental impacts, and the metric by which results are communicated (volumetric units or impact equivalents). Ruminant production is a complex activity where animals are often reared at different sites using a range of resources over their lifetime. Additional water use occurs during slaughter, product processing, and packaging. Estimating water use at the various stages of meat and milk production and communicating those estimates will help producers and other stakeholders identify hotspots and implement strategies to improve water use efficiency. Improvements in ruminant productivity (i.e., BW and milk production) and reproductive efficiency can also reduce the water footprint per unit product. However, given that feed production makes up the majority of water use by ruminants, research and development efforts should focus on this area. More research and clarity are needed to examine the validity of assumptions and possible trade-offs between ruminants' water use and other sustainability indicators. PMID- 28726987 TI - Effect of butyrate infusion into the rumen on butyrate flow to the duodenum, selected gene expression in the duodenum epithelium, and nutrient digestion in sheep. AB - The aim of the study was to determine the effect of butyrate infusion into the rumen on butyrate flow to the duodenum, expression of short-chain fatty acid (SCFA) transporters (monocarboxylate transporter-1, -2, and -4) and receptors (G protein coupled receptor-41 and -43) in the duodenal epithelium and nutrient digestion in sheep. Eight wethers (39.0 +/- 3.00 kg; mean +/- SD) with ruminal and T-shape duodenal cannulas were allocated to 4 * 4 replicated Latin square design with each experimental period lasting for 21 d (12 d of adaptation and 9 d for data and sample collection). Experimental treatments were: 1) distilled water infusion into the rumen (CONT); 2) 15 g/d of butyric acid infusion into the rumen (BUT15); 3) 30 g/d of butyric acid infusion into the rumen (BUT30); and 4) 45 g/d of butyric acid infusion into the rumen (BUT45). The daily dose of butyrate was infused into the rumen via the rumen cannula, with 200 mL of solution of butyric acid and distilled water, at a constant rate (0.1389 mL/min) throughout the day using a peristaltic pump. Correspondingly, 200 mL/d of distilled water was infused into the rumen of CONT. The wethers were fed daily 900 g of chopped meadow hay and 200 g of concentrate in two equal meals at 0600 and 1800 h. Butyrate infusion into the rumen did not affect total SCFA concentration in the rumen fluid ( > 0.11). Molar proportion of butyrate in total SCFA linearly increased, and molar proportion of acetate and isovalerate linearly decreased ( <= 0.02) with an increasing amount of butyrate infused into the rumen. The molar proportion of butyrate in total SCFA in the duodenal digesta linearly increased ( < 0.01), and butyrate flow to duodenum tended to linearly increase ( = 0.06) with an increasing dose of exogenous butyrate delivered to the rumen. Butyrate infusion into the rumen did not affect ( >= 0.14) the mRNA expression of monocarboxylate transporter-2 and -4 and G protein coupled receptor-43 in the duodenal epithelium. The G protein coupled receptor-41 and monocarboxylate transporter-1 mRNA expression in the duodenal epithelium was very low in many of the analyzed samples. Digestibility of organic matter, neutral detergent fiber, and acid detergent fiber in the stomach (forestomach and abomasum) decreased for BUT15 and BUT30 and then increased for BUT45 (quadratic, <= 0.04); however, neither digestibility in the intestine nor total tract digestibility differed between treatments ( >= 0.10). PMID- 28726988 TI - Erratum. PMID- 28726990 TI - CELL BIOLOGY SYMPOSIUM: Membrane trafficking and signal transduction. PMID- 28726989 TI - Economic selection index development for Beefmaster cattle II: General-purpose breeding objective. AB - An economic selection index was developed for Beefmaster cattle in a general purpose production system in which bulls are mated to a combination of heifers and mature cows, with resulting progeny retained as replacements or sold at weaning. National average prices from 2010 to 2014 were used to establish income and expenses for the system. Genetic parameters were obtained from the literature. Economic values were estimated by simulating 100,000 animals and approximating the partial derivatives of the profit function by perturbing traits 1 at a time, by 1 unit, while holding the other traits constant at their respective means. Relative economic values for the objective traits calving difficultly direct (CDd), calving difficulty maternal (CDm), weaning weight direct (WWd), weaning weight maternal (WWm), mature cow weight (MW), and heifer pregnancy (HP) were -2.11, -1.53, 18.49, 11.28, -33.46, and 1.19, respectively. Consequently, under the scenario assumed herein, the greatest improvements in profitability could be made by decreasing maintenance energy costs associated with MW followed by improvements in weaning weight. The accuracy of the index lies between 0.218 (phenotypic-based index selection) and 0.428 (breeding values known without error). Implementation of this index would facilitate genetic improvement and increase profitability of Beefmaster cattle operations with a general-purpose breeding objective when replacement females are retained and with weaned calves as the sale end point. PMID- 28726991 TI - High-sulfate water consumption determines intake and metabolic responses to protein supplementation in lambs consuming low-quality forage. AB - Twenty Hampshire lambs (31 +/- 4 kg BW) in individual metabolism cages were used in a 10-treatment by 2-period ( = 4) trial to evaluate the interaction between protein supplementation and sulfate water on intake and metabolic responses when lambs were fed low-quality grass hay (; 6.4% CP, 79.5% NDF). The treatment structure was a 2 * 5 factorial: 2 water qualities (WQ; low-sulfate [LS] and high sulfate [HS]; 442 and 8,358 mg/kg total dissolved solids, respectively) and 5 soybean meal levels (SBM; 0%, 0.25%, 0.50%, 0.75%, and 1.00% BW/d). After 15 d of adaptation, periods consisted of 5 d for determination of forage and water intake, nitrogen balance, and digestion measurements (d 16 to 20) and 1 d for blood sampling and determination of ruminal hydrogen sulfide (HS) concentration (d 21). Supplemental SBM * WQ interactions were significant for forage OM intake ( = 0.04) and total OM intake ( = 0.04), whereas a tendency was observed for total tract digestible OM intake ( = 0.07). Intake values of LS lambs were higher than those of HS lambs ( < 0.05) in only the first and second levels of SBM. Water intake increased linearly ( < 0.01) with SBM level but was not affected by WQ ( = 0.39). Water quality and SBM supplementation affected total tract OM digestibility (TTOMD; < 0.01); LS lambs had lower TTOMD than HS lambs ( < 0.01). Plasma urea N increased linearly in response to SBM ( < 0.01) but was not affected by WQ ( = 0.11). Nitrogen balance was not affected by SBM * WQ interaction ( > 0.12), except for N utilization (N retained/N intake ratio; < 0.01). Regardless of WQ, N intake ( > 0.01), N urine ( > 0.01), and N balance increased linearly ( > 0.01) with SBM level. Water quality adversely affected N intake and N balance, although at the highest level of SBM no differences in N balance were observed between LS and HS lambs ( = 0.85). No changes due to WQ were observed for either urea reabsorbed by kidneys ( = 0.63) or glomerular filtration rate ( = 0.30), but renal function was affected by SBM level ( < 0.01). There was a supplemental SBM * WQ interaction for ruminal HS concentration ( < 0.01) due mainly to a greater concentration from 0.25% BW SBM in HS than in LS lambs. In conclusion, these results confirmed the existence of an interaction between sulfate water and supplemental protein, which alters intake and metabolic responses when lambs are fed low-quality grass hay. PMID- 28726993 TI - Genetic parameters for wool traits, live weight, and ultrasound carcass traits in Merino sheep. AB - Genetic correlations between 29 wool production and quality traits and live weight and ultrasound fat depth (FAT) and eye muscle depth (EMD) traits were estimated from the Information Nucleus (IN). The IN comprised 8 genetically linked flocks managed across a range of Australian sheep production environments. The data were from a maximum of 9,135 progeny born over 5 yr from 184 Merino sires and 4,614 Merino dams. The wool traits included records for yearling and adult fleece weight, fiber diameter (FD), staple length (SL), fiber diameter CV (FDCV), scoured color, and visual scores for breech and body wrinkle. We found high heritability for the major yearling wool production traits and some wool quality traits, whereas other wool quality traits, wool color, and visual traits were moderately heritable. The estimates of heritability for live weight generally increased with age as maternal effects declined. Estimates of heritability for the ultrasound traits were also higher when measured at yearling age rather than at postweaning age. The genetic correlations for fleece weight with live weights were positive (favorable) and moderate (approximately 0.5 +/- 0.1), whereas those with FD were approximately 0.3 (unfavorable). The other wool traits had lower genetic correlations with the live weights. The genetic correlations for FAT and EMD with FD and SL were positive and low, with FDCV low to moderate negative, but variable with wool weight and negligible for the other wool traits. The genetic correlations for FAT and EMD with postweaning weight were positive and high (0.61 +/- 0.18 to 0.75 +/- 0.14) but were generally moderate with weights at other ages. Selection for increased live weight will result in a moderate correlated increase in wool weight as well as favorable reductions in breech cover and wrinkle, along with some unfavorable increases in FD and wool yellowness but little impact on other wool traits. The ultrasound meat traits, FAT and EMD, were highly positively genetically correlated (0.8), and selection to increase them would result in a small unfavorable correlated increase in FD, moderately favorable reductions in breech cover and wrinkle, but equivocal or negligible changes in other wool traits. The estimated parameters provide the basis for calculation of more accurate Australian Sheep Breeding Values and selection indexes that combine wool and meat objectives in Merino breeding programs. PMID- 28726994 TI - CELL BIOLOGY SYMPOSIUM: Practical application of the basic aspects of GLUT4 membrane trafficking and insulin signaling on issues related to animal agriculture. AB - Because of the relatively short lifespans of beef cattle, membrane trafficking in relation to inflammation is not considered important unless it overtly affects productivity. However, glucose uptake and utilization is important for adipose tissue development in beef cattle, and increasing glucose utilization in intramuscular adipose tissue can increase carcass quality. Research from the 1980s demonstrated a lack of insulin sensitivity in isolated bovine adipocytes and adipose tissue explants incubated in vitro. Insulin did not stimulate glucose or acetate incorporation into fatty acids, nor did it increase concentrations of glycolytic intermediates in bovine adipose tissue incubated with exogenous glucose. Specific binding of [I] iodoinsulin and insulin degradation in bovine isolated adipocytes was low to non-detectable. These early studies indicated that insulin-dependent receptor-mediated signaling was less important in bovine adipose tissue than in adipose tissues of humans, swine, or laboratory species. More recent research demonstrated that glucose transporter protein 4 (GLUT4) expression in muscle and adipose tissue declines markedly after birth in calves, indicating the development of insulin resistance as cattle transition from suckling to functional ruminants. Insulin resistance is important in dairy cattle, causing ketosis and fatty liver. Consistent with this, subcutaneous adipose tissue expression decreases 50% following parturition in dairy cattle, although expression of genes associated with insulin responsiveness (, , and ) is up-regulated by 21 d postpartum. Understanding the underlying mechanisms of insulin resistance in beef and dairy cattle would increase animal health and thereby improve productivity. PMID- 28726995 TI - Effects of transdermal flunixin meglumine on pain biomarkers at dehorning in calves. AB - The objective of this study was to evaluate the analgesic properties of transdermal flunixin meglumine when given at the time of dehorning on pain biomarkers. Twenty-four weaned male Holstein calves, 6 to 8 wk of age were enrolled into the study. The calves were randomly assigned to 1 of 3 treatment groups: 1) transdermal flunixin and dehorn (DH-FLU); 2) transdermal flunixin and sham dehorn (SHAM-FLU); and 3) placebo and dehorn (DH-PLBO). Transdermal flunixin at a label dose of 3.33 mg/kg (or placebo at an equivalent volume) was administered as a pour-on along the top-line of the calves in each treatment group concurrently with electrocautery dehorning or sham dehorning. Biomarker parameters collected and analyzed included: infrared thermography (IRT), mechanical nociception threshold (MNT), plasma cortisol, and substance P (SP). There were no differences in maximal temperatures detected for the IRT measurements of the medial canthus of the eye for the DH groups. Mean control point MNT measurements at 48 h were 3.14 kgF, 3.46 kgF, and 1.43 kgF for the DH FLU, Sham-FLU, and DH-PLBO groups, respectively (P = 0.0001). No other differences of MNT were detected between the dehorned groups for the other test sites and time points. Plasma cortisol reached peak concentration at 20 min postdehorning for the DH-FLU and DH-PLBO groups and 10 min for SHAM-FLU group. Peak plasma cortisol concentrations were 32.0 ng/mL, 12.7 ng/mL, and 28.8 ng/mL for the DH-FLU, SHAM-FLU, and DH-PLBO groups, respectively. Cortisol concentrations were lower for the DH-FLU group at 90 min postdehorning compared to the SHAM-FLU and DH-PLBO groups ( = 0.04). Area under the effect curve (AUEC) were similar for all groups ( = 0.93). No statistical differences in SP concentrations between groups were detected for any of the time points. In conclusion, transdermal flunixin meglumine given at the time of dehorning did not provide substantial analgesia based on the pain biomarkers investigated. Further investigation into its role as part of a multimodal analgesic plan is warranted. PMID- 28726996 TI - Direct multitrait selection realizes the highest genetic response for ratio traits. AB - For a number of traits the phenotype considered to be the goal trait is a combination of 2 or more traits, like methane (CH) emission (CH/kg of milk). Direct selection on CH4 emission defined as a ratio is problematic, because it is uncertain whether the improvement comes from an improvement in milk yield, a decrease in CH emission or both. The goal was to test different strategies on selecting for 2 antagonistic traits- improving milk yield while decreasing methane emissions. The hypothesis was that to maximize genetic gain for a ratio trait, the best approach is to select directly for the component traits rather than using a ratio trait or a trait where 1 trait is corrected for the other as the selection criteria. Stochastic simulation was used to mimic a dairy cattle population. Three scenarios were tested, which differed in selection criteria but all selecting for increased milk yield: 1) selection based on a multitrait approach using the correlation structure between the 2 traits, 2) the ratio of methane to milk and 3) gross methane phenotypically corrected for milk. Four correlation sets were tested in all scenarios, to access robustness of the results. An average genetic gain of 66 kg of milk per yr was obtained in all scenarios, but scenario 1 had the best response for decreased methane emissions, with a genetic gain of 24.8 l/yr, while scenarios 2 and 3 had genetic gains of 27.1 and 27.3 kg/yr. The results found were persistent across correlation sets. These results confirm the hypothesis that to obtain the highest genetic gain a multitrait selection is a better approach than selecting for the ratio directly. The results are exemplified for a methane and milk scenario but can be generalized to other situations where combined traits need to be improved. PMID- 28726997 TI - Body composition, protein and energy efficiencies, and requirements for growth of F1 Boer * Saanen goat kids. AB - We conducted a study in which body composition, energy and protein requirements, and efficiency of MP and ME were determined in F1 Boer * Saanen goat kids of 5 to 25 kg BW by using the comparative slaughter technique. Two experiments were performed: Exp. 1 estimated the maintenance requirements of kids from 15 to 25 kg BW, and Exp. 2 estimated the gain requirements of kids from 5 to 25 kg BW. In Exp. 1, 28 intact male F1 Boer * Saanen goat kids were utilized, with 7 kids slaughtered (BW of 15.0 +/- 0.35 kg) at the onset for estimation of initial body composition and the remaining 21 kids assigned to a randomized block design. Within each block, kids were subjected to 3 levels of feed intake treatments (ad libitum [100%] or restricted to 70% or 40% ad libitum). All kids in each block were slaughtered when the animals fed ad libitum reached 25 kg BW. The NE, ME for maintenance, and partial efficiency of use of ME for NE were 321.6 kJ/kg BW, 525.9 kJ/kg BW, and 0.61, respectively. The net protein and MP for maintenance were 2.43 g/kg of BW and 4.41 g/kg of BW, respectively; thus, the estimated partial efficiency of MP for maintenance was 0.55. In Exp. 2, 32 intact male F1 Boer * Saanen goat kids were distributed in a completely randomized design and slaughtered at 5.6 +/- 0.85 kg BW ( = 6), 10.0 +/- 0.35 kg BW ( = 6), 15.3 +/- 0.52 kg BW ( = 7), 20.4 +/- 0.66 kg BW ( = 6), and 25 +/- 0.46 kg BW ( = 7). Body composition was then fitted to allometric equations. Body fat composition increased from 37 to 114 g/kg empty BW (EBW; < 0.001), and body protein composition decreased by 10% (from 203.2 to 180.6 g/kg EBW; < 0.001) when kids grew from 5 to 25 kg BW. The NE increased by approximately 60% (from 7.2 to 11.5 MJ/kg of empty BW gain [EWG]; < 0.001), and the net protein for gain decreased by 10% (from 186 to 166 g/kg of EWG; < 0.001). The partial efficiency of the utilization of ME to NE for growth was 0.32 ( < 0.0001), and the partial efficiencies of the utilization of ME for the synthesis of protein and fat were 0.19 and 0.59 ( < 0.011), respectively. These results demonstrate that the protein and energy maintenance requirements in young crossbred goat kids are greater than values reported previously in feeding system studies. In addition, their requirements for gain depend on body composition and are driven by efficiencies of deposition. PMID- 28726998 TI - Potential for improving fiber digestion in the rumen of cattle (Bos taurus) through microbial inoculation from bison (Bison bison): In situ fiber degradation. AB - The objective of this experiment was to determine if partial replacement of cattle rumen contents with those from bison would increase in situ ruminal fiber degradation of various forages. The second objective was to examine individual variation among cattle in their ability to degrade forage and their responses to inoculation. In situ degradation of barley straw, canola straw, alfalfa hay, and timothy hay was measured in 16 ruminally cannulated heifers fed a barley straw based diet before and after inoculation with combined rumen contents from 32 bison (performed twice, 14 d apart). Each feed was incubated in the rumen of each heifer for 0, 4, 8, 12, 24, 48, 96, and 120 h, and the degradation parameters were determined as washout fraction (), potentially degradable fraction (), rate of digestion of fraction (), and total potentially degradable fraction (). The of barley straw decreased ( = 0.04) after inoculation, whereas fraction of NDF increased ( = 0.03) and fraction of NDF and ADF decreased ( <= 0.02) by inoculation. In contrast, of alfalfa hay NDF and ADF decreased ( = 0.002) after inoculation, but fraction of NDF and ADF ( <= 0.02) increased. There were no major effects ( > 0.06) of inoculation on the fiber degradation of timothy hay or canola straw. The differential response between barley straw and alfalfa hay may have occurred because the cattle were previously adapted to a barley straw diet, whereas the bison were fed barley silage and oats. Some animals consistently ranked higher or lower for or across at least 3 of the 4 feeds incubated, but the rankings changed after inoculation. In conclusion, inoculation of cattle with bison rumen contents failed to improve degradation of fiber from barley straw, canola straw, or timothy hay in cattle well adapted to a barley straw diet, although there were small improvements in the extent of degradation of fiber from alfalfa hay. Cattle varied both in their ability to degrade various forages and in their responses to inoculation with bison rumen contents. PMID- 28727000 TI - PRODUCTION, MANAGEMENT AND THE ENVIRONMENT SYMPOSIUM: Impacts of livestock production on environmental reactive nitrogen. PMID- 28726999 TI - The effects of instrumental color and extractable lipid content on sensory characteristics of pork loin chops cooked to a medium-rare degree of doneness. AB - Boneless loins ( = 286) were selected from a population of pigs of a common genetic line and management strategy to be used in an experiment to determine the effects of instrumental color and extractable lipid content on sensory traits of boneless pork chops cooked to an end point internal temperature of 63 degrees C. Loins were cut into 2.54-cm-thick chops and aged until 14 d postmortem. Chop L* values ranged from 57.60 (light) to 43.11 (dark) and extractable lipid ranged from 0.80 to 5.52%. Using these values, chops were assigned to 5 color and 6 marbling categories using National Pork Producers Council (NPPC) standards, resulting in a 5 * 6 factorial arrangement of treatments. Chops were also assigned a quality grade using a proposed grading system. Low-quality loins ( = 56) had marbling scores < 1.5, regardless of color, or had color scores <= 2.5 and marbling scores <= 2.0. Medium-quality loins ( = 180) had color scores of 2.0 to 3.5 and marbling scores >= 2.5 or loins with color scores of 3.0 through 3.5 and marbling scores >= 2.0. High-quality loins ( = 50) had color scores > 4.0 and marbling scores >= 2.0. Chops were cooked to a medium-rare degree of doneness (63 degrees C) and evaluated for tenderness, juiciness, and pork flavor by trained panelists. Slice shear force (SSF) and cooking loss were also evaluated. Data were analyzed using the MIXED procedure of SAS as a 1-way ANOVA with the fixed effect of quality grade and using the REG procedure of SAS. Individually, extractable lipid content and instrumental color accounted for no more than 2% ( <= 0.02) of the variation in tenderness, juiciness, or pork flavor. High-quality chops had 6.5 and 11.2% less SSF ( <= 0.04) than medium- and low-quality chops, respectively, and medium-quality chops had 5.6% less SSF ( < 0.04) than low quality chops. Trained sensory panelists did not detect differences in tenderness ( = 0.09) or juiciness ( = 0.48) among quality grades, but low- and medium quality chops were more flavorful ( < 0.01) than high-quality chops. Cooking loss tended ( = 0.06) to decrease from 16.57% to 15.32% as quality grade increased. Neither color nor marbling alone was predictive of sensory quality. But when these were used together, as they were in the proposed grading system, pork sensory flavor ratings were greater for low-quality chops than for high- and medium-quality chops. Also, the proposed grading system was able to discern differences in SSF but not sensory tenderness among the quality grades. PMID- 28727001 TI - Analysis of genetic diversity of Chinese dairy goats via microsatellite markers. AB - In this study, 15 polymorphic microsatellite markers were used to analyze the genetic structure and phylogenetic relationships of 6 dairy goat breeds in China, including 4 native developed breeds and 2 introduced breeds. The results showed that a total of 172 alleles were detected in 347 samples of the dairy goat breeds included in this study. The mean number of effective alleles per locus was 4.92. Except for BMS0812, all of the remaining microsatellite loci were highly polymorphic (polymorphism information content [PIC] > 0.5). The analysis of genetic diversity parameters, including the number of effective alleles, PIC, and heterozygosity, revealed that the native developed dairy goat breeds in China harbored a rich genetic diversity. However, these breeds showed a low breeding degree and a high population intermix degree, with a certain degree of inbreeding and within-subpopulation inbreeding coefficient ( > 0). The analysis of population genetic differentiation and phylogenetic tree topologies showed a moderate state of genetic differentiation among subpopulations of native developed breed dairy goats in China (0.05 < gene fixation coefficient [] < 0.15). The native developed breeds shared a common ancestor, namely, the Saanen dairy goat, originating from Europe. The results showed that there was a close genetic relationship between Wendeng and Laoshan dairy goats while the Guanzhong dairy goat and the Xinong Saanen dairy goat were also found to have a close genetic relationship, which were both in agreement with the formation history and geographical distribution of the breeds. This study revealed that adopting genetic management strategies, such as expanding pedigree source and strengthening multi-trait selection, is useful in maintaining the genetic diversity of native developed breeds and improving the population uniformity of dairy goats. PMID- 28727002 TI - Hourly methane production in finishing steers fed at different levels of dry matter intake. AB - Methane (CH) loss from finishing cattle is important as it represents an energy loss that could be used for maintenance and growth, and CH is a greenhouse gas with a global warming potential 21 to 25 times that of CO. Our objectives were to determine hourly CH production from growing cattle fed diets differing in corn processing method (dry rolling or steam flaking) and wet distillers grains with solubles (WDGS) inclusion rate. Eight steers (195 kg +/- 2.3 in Exp. 1 and 322 kg +/- 3.7 in Exp. 2) were fed the following diets: 1) steam-flaked corn (SFC)-based diet with 0% WDGS (SFC-0); 2) SFC-based diet with 15% WDGS (SFC-15); 3) SFC-based diet with 30% WDGS (SFC-30); 4) SFC-based diet with 45% WDGS (SFC-45); 5) Dry rolled corn DRC)-based diet with 0% WDGS (DRC-0); and 6) DRC-based diet with 30% WDGS (DRC-30). All hourly CH data were analyzed using the MIXED procedure of SAS. Individual animal was the experimental unit. The model included the fixed effect of h, diet, and the h * diet interaction. Hourly differences in CH were analyzed using repeated measures. There were numerous h * diet interactions and thus simple-effect means are presented. In steers fed DRC-0 or DRC-30 at 2-times maintenance, the greatest hourly CH emissions occur 6 h after feeding ( < 0.01) with a secondary peak between 10 and 11 h after feeding ( < 0.01). For cattle fed SFC-0, SFC-15, SFC-30, and SFC-45 at 2-times maintenance, all diets had peak CH emissions 5 and 6 h after feeding ( < 0.01), with a secondary CH peak for SFC-45 nine to 11 h after feeding ( < 0.01). Cattle fed all diets at a maintenance level of intake exhibited 1 peak in hourly CH production between 3 and 6 h after feeding ( < 0.01). All steers fed SFC-30 and SFC-45 had sustained CH production over several hours, irrespective of intake level. Steers fed SFC-45 produced more CH beginning 4 h after feeding ( < 0.01) and produced a greater amount of CH than any other treatment ( < 0.01). Methane production generally peaked 6 h after feeding irrespective of intake level or diet type. Additionally, when fed above a maintenance level of intake, a secondary peak in CH production was observed 9 to 11 h after feeding, and steers fed at a maintenance level of intake had only 1 peak in CH production in a 23-h period. PMID- 28727003 TI - TRIENNIAL GROWTH AND DEVELOPMENT SYMPOSIUM: Intramuscular fat deposition in ruminants and pigs: A transcriptomics perspective. AB - The genomics era has led to an explosion in the study of gene expression in production animals. Intramuscular fat (IMF) content (both high and low) and composition are major quality attributes of meat, and more than 90 transcriptomic studies of IMF deposition have been undertaken in the ruminants and pigs since 2001, with the majority since 2008. The studies have implicated many genes involved in the control of adipogenesis, lipogenesis, and deposition of IMF, but there is relatively little consistency between the different studies. However, the genes encoding the synthesis enzymes acetyl-CoA carboxylase alpha, fatty acid synthase, and stearoyl-CoA desaturase; the fatty acid binding protein 4; the potential signaling protein thyroid hormone responsive; and the regulators C/EBPalpha, PPARgamma, and sterol regulatory element binding transcription factor 1 are supported by 5 or more of the 90 studies. By combining the results of all the studies, complete pathways for long-chain fatty acid (LCFA) and triacylglyceride (TAG) synthesis are identified, as are a number of genes encoding proteins probably associated with the storage of TAG and genes encoding a number of known and potential adipokines. In contrast, support for the association of lipolytic pathways with IMF percentage is less strong. Differences in experimental design-in particular, the age of the animals, the rate of IMF deposition at sampling, the past nutritional history of the animals used, and the complexities of using a tissue with mixed cell types-have contributed to the differences in results and interpretation. Biomarkers predictive of future IMF percentage, facilitating reaching optimal IMF content at slaughter, may have industry utility, but to be useful in animal biopsy and postslaughter samples, where multiple cell types are present, genes must be carefully chosen to ensure that they are informative about the expected processes. Despite these problems, candidate biomarkers for estimation of de novo intramuscular adipocyte LCFA synthesis, LCFA uptake rate by intramuscular adipocytes, and IMF deposition rate have been identified and examples of their utility have been published. However, further work is required to demonstrate how best to apply the assays for the benefit of the relevant livestock production industries. PMID- 28727004 TI - PHYSIOLOGY AND ENDOCRINOLOGY SYMPOSIUM: Postnatal reproductive development and the lactocrine hypothesis. AB - Maternal effects on development can program cell fate and dictate offspring phenotype. Such effects do not end at birth, but extend into postnatal life through signals communicated from mother to offspring in first milk (colostrum). Transmission of bioactive factors from mother to offspring as a specific consequence of nursing defines a lactocrine mechanism. The female reproductive tract is not fully formed at birth (postnatal day = PND 0). Data for ungulates and mice indicate that disruption of development during neonatal life can have lasting effects on the form and function of uterine tissues. Uterine growth and histogenesis proceed in an ovary-independent manner shortly after birth, suggesting that extra-ovarian inputs are important in this process. Data for the pig indicate that lactocrine signals communicated within 12 to 48 h from birth constitute one source of such uterotrophic support. Disruption of lactocrine signaling, either naturally, by limited colostrum consumption, or experimentally, by milk replacer feeding, alters neonatal porcine uterine development and can have negative consequences for reproductive performance in adults. Substantial differences in endometrial and uterine gene expression between colostrum- and replacer-fed gilts were evident by PND 2, when RNA sequencing revealed over 800 differentially expressed, lactocrine-sensitive genes. Lactocrine-sensitive biological processes identified through transcriptomic studies and integrated microRNA-mRNA pathway analyses included those associated with both cell-cell and ESR1 signaling, and tissue development. Evidence for the pig indicates that colostrum consumption and lactocrine signaling are required to establish a normal uterine developmental program and optimal uterine developmental trajectory. PMID- 28727005 TI - RAPID COMMUNICATION: Generation of FGF5 knockout sheep via the CRISPR/Cas9 system. AB - Sheep are an important source of fiber production. Fibroblast growth factor 5 (FGF5) is a dominant inhibitor of length of the anagen phase of the hair cycle. Knockout or silencing of the gene results in a wooly coat in mice, donkeys, dogs, and rabbits. In sheep breeding, wool length is one of the most important wool quality traits. However, traditional breeding cannot accurately and efficiently mediate an advanced genotype into the sheep genome. In this study, we generated 3 knockout sheep via the 1-step clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 system. Sequencing analysis confirmed that mutations in the gene existed in all germ lines of 3 founders: besides the intact sequence, 3 kinds of deletions in the gene (including 5, 13, and 33 bp) were detected. The changes in the primary and senior structure of the FGF5 protein due to the 3 deletions in founders suggested that the FGF5 protein was dysfunctional. In addition, the expression level of intact mRNA in heterozygous individuals decreased compared with the wild types ( < 0.01). Functionally, we discovered that wool length in founders was significantly longer than in wild types ( < 0.05). Collectively, the knockout sheep with the longer wool length phenotype will provide an efficient way for fast genetic improvement of sheep breeding and promote the development of wool industry. PMID- 28727006 TI - Genetic analysis of semen production traits of Japanese Black and Holstein bulls: genome-wide marker-based estimation of genetic parameters and environmental effect trends. AB - The semen production traits of bulls from 2 major cattle breeds in Japan, Holstein and Japanese Black, were analyzed comprehensively using genome-wide markers. Weaker genetic correlations were observed between the 2 age groups (1 to 3 yr old and 4 to 6 yr old) regarding semen volume and sperm motility compared with those observed for sperm number and motility after freeze-thawing. The preselection of collected semen for freezing had a limited effect. Given the increasing importance of bull proofs at a young age because of genomic selection and the results from preliminary studies, we used a multiple-trait model that included motility after freeze-thawing with records collected at young ages. Based on variations in contemporary group effects, accounting for both seasonal and management factors, Holstein bulls may be more sensitive than Japanese Black bulls to seasonal environmental variations; however, the seasonal variations of contemporary group effects were smaller than those of overall contemporary group effects. The improvement of motilities, recorded immediately after collection and freeze-thawing, was observed in recent years; thus, good management and better freeze-thawing protocol may alleviate seasonal phenotypic differences. The detrimental effects of inbreeding were observed in all traits of both breeds; accordingly, the selection of candidate bulls with high inbreeding coefficients should be avoided per general recommendations. Semen production traits have never been considered for bull selection. However, negative genetic trends were observed. The magnitudes of the estimated h were comparable to those of other economically important traits. A single-step genomic BLUP will provide more accurate predictions of breeding values compared with BLUP; thus, marker genotype information is useful for estimating the genetic merits of bulls for semen production traits. The selection of these traits would improve sperm viability, a component related to breeding success, and alleviate negative genetic trends. PMID- 28727007 TI - Best management practices for newly weaned calves for improved health and well being. AB - Morbidity and mortality in newly weaned calves resulting from bovine respiratory disease (BRD) continue to be the most significant problems facing the beef industry. Morbidity attributed to BRD accounts for approximately 75% of total feedlot morbidity. Several experiments have documented the economic impacts of BRD. Direct costs attributable to BRD include death loss, treatment and labor costs, and prevention costs, while indirect costs associated with BRD include decreased growth performance and feed efficiency, increased days on feed, and decreased carcass merit and market value. In recent years, cattle treated for BRD have returned $50 to $250 less per head at harvest than cattle never treated for BRD. Best management practices for newly weaned calves vary depending on a multitude of factors including: season of year calves are purchased, calf genetics, length of time in the marketing and transport channels, previous management and vaccination programs, and other factors. In general, calves purchased directly from a ranch have fewer health problems than calves purchased through auction markets. The longer a calf is in the marketing chain, the more likely health problems will be encountered. Calves that have spent several days in the marketing chain may develop clinical BRD before or very soon after arrival, whereas cattle with less time in the marketing chain may get sick later (2 to 4 wk), due to the length of time it takes for BRD to develop. On or before arrival, calves should be given a risk score (high, medium, or low) that relates to the quantity and magnitude of stress they have encountered and the probability they will develop BRD. High-risk calves typically will have been recently weaned, received no vaccinations, not been castrated or dehorned, been commingled, and moved through an auction market. Low-risk calves will often originate from a single source and will have gone through a preconditioning program that includes vaccination, castration, dehorning, weaning, and potentially feed bunk adaptation. Variation exists within risk category, so the preliminary assessment should be combined with visual observation on arrival as additional health assessments and feed intake information becomes available. Cattle managers should adjust management strategies based on risk category to meet the perceived needs of individual lots of cattle to improve the health and well-being of newly weaned calves. PMID- 28727008 TI - 2016 TRIENNIAL GROWTH AND DEVELOPMENT SYMPOSIUM: New perspectives and insight on intramuscular adipose tissue. PMID- 28727009 TI - Effects of energy supplementation on energy losses and nitrogen balance of steers fed green-chopped wheat pasture I: Calorimetry. AB - Cattle grazing wheat pasture in the southern Great Plains are sometimes fed an energy supplement; however, the benefits of supplementation on nutrient balance, energy metabolism, and greenhouse gas emissions have not been elucidated. Therefore, we used 10 British crossbred steers (206 +/- 10.7 kg initial BW) in a respiration calorimetry study to evaluate the effects of energy supplementation on energy losses, N balance, and nutrient digestibility of steers fed green chopped wheat forage. The study design was an incomplete replicated 4 * 4 Latin square with treatments in a 2 * 2 factorial arrangement. Steers ( = 8) were assigned to 1 of 2 BW blocks (4 steers per block) with dietary factors consisting of 1) no supplementation (CON) or supplemented with a steam-flaked corn-based energy supplement (that also contained monensin sodium) at 0.5% of BW daily (SUP) and 2) NEm intakes of 1 times (1x) or 1.5 times (1.5x) maintenance. Wheat forage was harvested daily and continuously fed as green-chop to steers during the 56-d study. There were no differences ( >= 0.32) between CON and SUP for OM (78.3 vs. 80.7%, respectively) or NDF (68.3 vs. 64.8%, respectively) digestibility. At the 1.5x level of intake, there was no difference ( >= 0.16) in energy lost in feces (4.27 vs. 3.92 Mcal/d) or urine (0.58 vs. 0.55 Mcal/d), heat production (8.69 vs. 8.44 Mcal/d), or retained energy (3.10 vs. 3.46 Mcal/d) between supplementation treatments. Oxygen consumption (1,777 vs. 1,731 L/d; = 0.67) and CO production (1,704 vs. 1,627 L/d; = 0.56) of CON and SUP steers, respectively, were not different; however, SUP steers tended to have ( = 0.06) lower CH production (115 vs 130 L/d) than CON steers. Methane, as a proportion of GE intake, was similar for CON (6.87%) and SUP (6.07%; = 0.18), as was the ME:DE ratio ( = 0.24; 86.3% for CON and 87.9% for SUP). Fractional N excretion in urine and feces, as a proportion of total N excreted ( >= 0.84) or N intake ( >= 0.63), was not different between treatments. Calculated NEm and NEg values for CON were 1.76 and 1.37 Mcal/kg DM, respectively, whereas the NEm and NEg values for the SUP treatment were 2.32 and 1.61 Mcal/kg DM, respectively. Calculated NE values for steers fed additional energy were approximately 17.5% greater than the expected difference in energy content. This was probably the result of the inconsistent response at the 1x DMI level. Under these circumstances, energy supplementation did appear to enhance NEm and NEg value of the supplemented wheat forage diet. PMID- 28727010 TI - Effect of experimentally increased protein supply to postpartum dairy cows on plasma protein synthesis, rumen tissue proliferation, and immune homeostasis. AB - The effect of experimentally increasing the postpartum protein supply on plasma protein synthesis, rumen tissue proliferation, and immune homeostasis was studied using 8 periparturient Holstein cows in a complete randomized design. At calving, cows were assigned to abomasal infusion of water (CTRL) or casein (CAS) in addition to a lactation diet. Casein infusion was gradually decreased from 696 +/ 1 g/d at +2 d relative to calving (DRTC) to 212 +/- 10 g/d at +29 DRTC to avoid excessive supply. Synthesis rate of plasma proteins was measured at -14, +4, +15, and +29 DRTC by measuring [C]Phe isotopic enrichment in arterial plasma free Phe, total plasma proteins, and albumin after 3, 5, and 7 h of jugular ring[C]Phe infusion. Plasma volume was determined at +4 and +29 DRTC by dilution of a [I]BSA dose. Synthesis rate of tissue protein in biopsied rumen papillae was determined by measuring [C]Phe isotopic enrichment, and mRNA expression of selected genes was measured by real-time qPCR. Total and differential leukocyte counts were performed and immune responsiveness of monocytes was evaluated by tumor necrosis factor alpha (TNFalpha) concentration on ex vivo whole blood stimulation with Escherichia coli lipopolysaccharide (LPS) and responsiveness of T-lymphocytes by interferon gamma (IFNgamma) concentration on stimulation with Staphylococcus aureus enterotoxin beta (SEB). Further, ELISA plasma concentrations of IgM, IgA, and IgG were determined. The DRTC affected the majority of investigated parameters as expected. The CAS treatment increased milk protein yield (P = 0.04), and tended to lower TNFalpha (P = 0.06), and lowered IFNgamma (P = 0.03) responsiveness per monocyte and lymphocyte, respectively, compared with CTRL. Further, fractional synthesis rate of albumin was greater at +4 DRTC for CAS compared with CTRL but did not differ by +29 DRTC (interaction: P = 0.01). In rumen papillae, synthesis rate of tissue protein was greater for CAS compared with CTRL (P < 0.01) and mRNA expression of genes for cell proliferation tended to be or were greater for CAS compared with CTRL (P <= 0.07). In conclusion, increased postpartum protein supply seem to enhance vital body functions as interpreted from increased liver synthesis of albumin, increased rumen papillae proliferation, and stabilized the ex vivo inflammatory responsiveness of leukocytes. Further studies are needed to enlighten the importance of increased postpartum protein supply in periparturient cows. PMID- 28727011 TI - Effects of supplementing sow diets with Saccharomyces cerevisiae refermented sorghum dried distiller's grains with solubles from late gestation to weaning on the performance of sows and progeny. AB - We performed 2 experiments to study the effects of supplementing sow diets with refermented sorghum dried distiller's grains with solubles (SSDDGS) from late gestation to weaning on the performance of sows and their progeny. In Exp. 1, 24 sows at 85 d of gestation were allocated to the following 3 dietary treatments: 1) sows fed a basal diet from late gestation to weaning ( = 8), 2) sows fed a diet with 2% SSDDGS ( = 8), and 3) sows fed a diet with 4% SSDDGS ( = 8). The 4% SSDDGS treatment significantly improved the sows' ADFI, the litter weaning alive rate, and the individual piglet weaning weights and significantly reduced the litter stillbirth rate and the levels of urea N and somatic cell counts (SCC) in the milk. However, the 2% SSDDGS treatment did not alter the performance of the sows or progeny. Therefore, we considered the volume of 4% SSDDGS to be more efficient than 2% SSDDGS. To verify the results of Exp. 1, we performed Exp. 2, in which 60 sows at 85 d of gestation were allocated into the following 2 dietary treatments: 1) sows fed a basal gestation diet from 85 d of gestation to weaning ( = 30) and 2) sows fed a basal diet with 4% SSDDGS from 85 d of gestation to weaning ( = 30). The 4% SSDDGS supplementation tended to increase the sows' ADFI, litter weaning size, litter weight gain during lactation, and individual piglet weaning weight and weight gain during lactation, and it also increased the milk yield and the fat and DM contents of the milk. This treatment also decreased the levels of urea N and SCC in the milk. Therefore, the present study indicates that supplementing sow diets with 4% SSDDGS from late gestation to weaning has the potential to 1) increase sow ADFI, 2) promote progeny growth performance, 3) increase sow milk production and quality, and 4) improve the maternal health status as indicated by improved protein utilization and reduced potential inflammatory response. PMID- 28727012 TI - BEEF SPECIES SYMPOSIUM: Improving Welfare of Beef Cattle. PMID- 28727013 TI - Changes in the rumen bacterial microbiome of cattle exposed to ponderosa pine needles. AB - Consumption of ponderosa pine needles, as well as needles and bark from a number of other trees, can cause abortions in cattle. The abortifacient compounds in these trees are labdane resin acids, including isocupressic acid and agathic acid. Previous research has demonstrated that cattle conditioned to pine needles metabolize the labdane resin acids more quickly than naive cattle. The results from that study indicated that changes had occurred in the rumen of conditioned cattle. Therefore, in this study, the changes that occurred in the rumen bacterial microflora of cattle during exposure to ponderosa pine needles were evaluated. Cattle were dosed with ground pine needles twice daily for 7 d. Rumen samples were collected on d 0, 3, 7, and 14 (7 d after treatment stopped) and ruminal bacterial microbiome analyses were performed. There were 372 different genera of bacteria identified in the rumen samples. Principal coordinate analysis indicated that there was a significant difference in the rumen bacterial composition between the time points. There were 18 genera that increased in abundance from d 0 to d 7. Twenty three genera decreased in abundance from d 0 to d 7. The results from this study demonstrated that exposure of cattle to pine needles caused a clear shift in the rumen microbiome composition. In general, this shift lasted less than 1 wk post exposure, which indicates that any prophylactic treatment to manipulate the ruminal metabolism of the abortifacient compounds in pine needles would need to be continuously administered to maintain the necessary microbial composition in the rumen. PMID- 28727015 TI - TRIENNIAL GROWTH AND DEVELOPMENT SYMPOSIUM: Molecular mechanisms related to bovine intramuscular fat deposition in the longissimus muscle. AB - The intramuscular fat (IMF) content of the LM, also known as marbling, is particularly important in determining the price of beef in Korea, Japan, and the United States. Deposition of IMF is influenced by both genetic (e.g., breed, gender, and genotype) and nongenetic factors (e.g., castration, nutrition, stressors, animal weight, and age). Castration of bulls markedly increases deposition of IMF, resulting in improved beef quality. Here, we present a comparative gene expression approach between bulls and steers. Transcriptomic and proteomic studies have demonstrated that the combined effects of increases in lipogenesis, fatty acid uptake, and fatty acid esterification and decreased lipolysis are associated with increased IMF deposition in the LM. Several peripheral tissues (LM, adipose tissues, and the liver) are involved in lipid metabolism. Therefore, understanding the significance of the tissue network in lipid metabolism is important. Here, we demonstrate that lipid metabolism in LM tissues is crucial for IMF deposition, whereas lipid metabolism in the liver plays only a minor role. Metabolism of body fat and IMF deposition in bovine species has similarities with these processes in metabolic diseases, such as obesity in humans and rodents. Extensive studies on metabolic diseases using epigenome modification (DNA methylation, histone modification, and microRNA), microbial metagenomics, and metabolomics have been performed in humans and rodents, and new findings have been reported using these technologies. The importance of applying "omics" fields (epigenomics, metagenomics, and metabolomics) to the study of IMF deposition in cattle is described. New information on the molecular mechanisms of IMF deposition may be used to design nutritional or genetic methods to manipulate IMF deposition and to modify fatty acid composition in beef cattle. Applying nutrigenomics could maximize the expression of genetic potential of economically important traits (e.g., marbling) in animals. PMID- 28727014 TI - Further testing of Melatonin Receptor 1a for out-of-season reproduction in the Cornell flock and allelic frequencies compared with Romney sheep. AB - Sheep are seasonally polyestrous breeders, meaning they breed when day length shortens in the autumn. Ewes respond to changing day length through chemical pathways involving melatonin receptors. Some breeds, such as Dorset, are known to be less seasonal with many ewes able to breed and lamb year-round. The Melatonin Receptor 1a () gene was identified as a candidate gene controlling out-of-season lambing. The first studies in the Cornell STAR accelerated lambing flock found that a allele was associated with a shorter time to first lambing and a shorter period between lambings. The favorable allele was denoted the allele and the unfavorable allele, the allele. This study evaluated additional data for the effect of the polymorphism on sheep reproduction. Genotypic frequencies among the 320 sheep in this study differed between Romney and breeds selected for accelerated lambing ( < 0.02), but they did not deviate from Hardy-Weinberg equilibrium. Using 228 ewes from the Cornell University flock, we found no association ( > 0.05) between the allele and success for out-of-season lambing and no significant differences were observed in several production measures, such as number of lambs delivered per yr or number of lambs weaned ( > 0.05). With few ewes in the flock, these results may be due to the high level of selection for accelerated lambing. This study shows that the allele may not be a beneficial marker for use within flocks seeking to improve production and the ability to lamb out-of-season. These findings warrant additional research on the genetics of aseasonality in sheep. PMID- 28727016 TI - Genomewide association mapping and pathway analysis of meat tenderness in Polled Nellore cattle. AB - Brazil is one of the world's largest beef exporters, although the product has a low price due to quality issues. The meat exported by Brazil is considered medium and low quality by international buyers, mainly due to lack of tenderness. The predominant Zebu breeds (80% Nellore) are known for producing tougher beef than taurine breeds. Nonetheless, some studies have shown that there is substantial genetic variability for tenderness within the Nellore breed, although it is a difficult trait to improve by conventional selection methods. Therefore, the aim of this study was to perform a genomewide association study (GWAS) and a gene set enrichment analysis to identify genomic regions and biologically relevant pathways associated with meat tenderness in Polled Nellore cattle. Data consisted of Warner-Bratzler shear force values of LM from 427 Polled Nellore animals divided into 3 experimental slaughters (years 2005, 2008, and 2010). The animals were genotyped with either the Illumina BovineHD BeadChip (777k, on 61 samples) or the GGP Indicus HD chip (77k, on 366 samples). Single nucleotide polymorphisms were excluded when the call rate was <90%, the Hardy-Weinberg proportions -value was <1% (Fisher exact test, Bonferroni adjusted), and the minor allele frequency was <1%. Imputation from the GGP Indicus HD chip to the Illumina BovineHD BeadChip was performed using the FImput program. Genomewide association analysis was performed using the Efficient Mixed Model Association eXpedited (EMMAx) and the population parameters previously determined (P3D) methods. The GWAS was complemented with a gene set enrichment analysis performed using the FatiGO procedure. Significant markers ( < 0.0001) explaining a larger proportion of variation than other significant SNPs were located on chromosomes 3, 13, 17, 20, 21, and 25, indicating QTL associated with meat tenderness throughout the genome. Additionally, gene set analysis identified 22 Gene Ontology functional terms and 2 InterPro entries that showed significant enrichment of genes associated with tenderness. The functional categories included protein tyrosine and serine/threonine kinase activity, calcium ion binding, lipid metabolic process, and growth factors, among others. These results help to elucidate the genetic architecture and metabolic pathways underlying this trait, which is of extreme economic and social importance to Brazil, because Nellore is the dominant beef cattle breed in the country. PMID- 28727018 TI - Evaluation of electrical broad bandwidth impedance spectroscopy as a tool for body composition measurement in cows in comparison with body measurements and the deuterium oxide dilution method. AB - Body fatness and degree of body fat mobilization in cows vary enormously during their reproduction cycle and influence energy partitioning and metabolic adaptation. The objective of the study was to test bioelectrical impedance spectroscopy (BIS) as a method for predicting fat depot mass (FDM), in living cows. The FDM is defined as the sum of subcutaneous, omental, mesenteric, retroperitoneal, and carcass fat mass. Bioelectrical impedance spectroscopy is compared with the prediction of FDM from the deuterium oxide (DO) dilution method and from body conformation measurements. Charolais * Holstein Friesian (HF; = 18; 30 d in milk) crossbred cows and 2 HF (lactating and nonlactating) cows were assessed by body conformation measurements, BIS, and the DO dilution method. The BCS of cows was a mean of 3.68 (SE 0.64). For the DO dilution method, a bolus of 0.23 g/kg BW DO (60 atom%) was intravenously injected and deuterium (D) enrichment was analyzed in plasma and whey by stabile isotope mass spectrometry, and total body water content was calculated. Impedance measurement was performed using a 4-electrode interface and time domain-based measurement system consisting of a voltage/current converter for applying current stimulus and an amplifier for monitoring voltage across the sensor electrodes. For the BIS, we used complex impedances over three frequency decades that delivers information on intra- and extracellular water and capacity of cell membranes. Impedance data (resistance of extra- and intracellular space, cell membrane capacity, and phase angle) were extracted 1) by simple curve fit to extract the resistance at direct current and high frequency and 2) by using an electrical equivalent circuit. Cows were slaughtered 7 d after BIS and D enrichment measurements and dissected for the measurement of FDM. Multiple linear regression analyses were performed to predict FDM based on data obtained from body conformation measurements, BIS, and D enrichment, and applied methods were evaluated by cross-validation. The FDM varied widely between cows and was correlated to D enrichment in plasma ( = 0.91, < 0.05). Prediction of FDM by body size measurements was less precise ( = 0.84), but FDM prediction was more accurate using D enrichment in plasma ( = 0.90) and BIS ( = 0.99) data. Therefore, both BIS and D enrichment analysis resulted in similarly good predictions of FDM in cows, and we conclude that BIS could have the potential to predict FDM in dairy cows from 40 to 380 kg. PMID- 28727019 TI - TRIENNIAL GROWTH AND DEVELOPMENT SYMPOSIUM: Dedifferentiated fat cells: Potential and perspectives for their use in clinical and animal science purpose. AB - An increasing body of evidences has demonstrated the ability of the mature adipocyte to dedifferentiate into a population of proliferative-competent cells known as dedifferentiated fat (DFAT) cells. As early as the 1970s, in vitro studies showed that DFAT cells may be obtained by ceiling culture, which takes advantage of the buoyancy property of lipid-filled cells. It was documented that DFAT cells may acquire a phenotype similar to mesenchymal stem cells and yet may differentiate into multiple cell lineages, such as skeletal and smooth muscle cells, cardiomyocytes, osteoblasts, and adipocytes. Additionally, recent studies showed the ability of isolated mature adipocytes to dedifferentiate in vivo and the capacity of the progeny cells to redifferentiate into mature adipocytes, contributing to the increase of body fatness. These findings shed light on the potential for use of DFAT cells, not only for clinical purposes but also within the animal science field, because increasing intramuscular fat without excessive increase in other fat depots is a challenge in livestock production. Knowledge of the mechanisms underlying the dedifferentiation and redifferentiation of DFAT cells will allow the development of strategies for their use for clinical and animal science purposes. In this review, we highlight several aspects of DFAT cells, their potential for clinical purposes, and their contribution to adipose tissue mass in livestock. PMID- 28727020 TI - Interaction of dietary energy source and body weight gain during the juvenile period on metabolic endocrine status and age at puberty in beef heifers. AB - Using a previously established model for nutritional acceleration of puberty, beef heifers ( = 48; 1/2 Angus * 1/4 Hereford * 1/4 Brahman) were used in a replicated 2 * 2 factorial design to examine the effects of diet type (high forage [HF] vs. high concentrate [HC]) and rate of BW gain (low gain [LG], 0.45 kg/d, vs. high gain [HG], 0.91 kg/d) on key metabolic hormones and age at puberty. After weaning at 14 +/- 1 wk of age, heifers were assigned randomly to be fed HC-HG, HC-LG, HF-HG, or HF-LG ( = 12/group) beginning at 4 mo of age for 14 wk. Heifers were then switched to a common growth diet until puberty. Average daily gain was greater ( < 0.04) during the dietary treatment phase in HG heifers (0.81 +/- 0.06 kg/d) than in LG heifers (0.43 +/- 0.06 kg/d), and there was no diet type * rate of gain interaction. Puberty was achieved at a younger age (54.5 +/- 1.8 wk) in both HG groups than in LG groups (60.2 +/- 1.9 wk; < 0.04), but dietary energy source (HC vs. HF) did not influence this variable. Moreover, mean BW at puberty did not differ by diet type or rate of gain during the dietary treatment phase. Nonetheless, heifers fed HC-HG exhibited a striking increase ( < 0.0001) in serum leptin beginning at 26 +/- 1 wk of age and remained elevated ( < 0.01) throughout the remainder of the experimental feeding phase compared to all other treatments. However, serum leptin in HC-HG dropped precipitously when heifers were switched to the common growth diet and did not differ from that of other groups thereafter. Overall mean concentrations of serum glucose were greater ( < 0.006) in HG heifers than in LG during the dietary treatment phase, with serum insulin also greater ( < 0.04) in HG than in LG only during weeks 20, 22, and 30. Mean serum IGF-1 was not affected by dietary type or rate of BW gain. We speculate that failure of the marked increase in serum leptin observed in HC HG heifers during the dietary treatment phase to further accelerate puberty compared to HF-HG occurred because of its abrupt decline at the onset of the common growth phase, thus attenuating the temporal cue for activation of the reproductive neuroendocrine system. PMID- 28727021 TI - PHYSIOLOGY AND ENDOCRINOLOGY SYMPOSIUM:The effects of poor maternal nutrition during gestation on offspring postnatal growth and metabolism. AB - Poor maternal nutrition during gestation has been linked to poor growth and development, metabolic dysfunction, impaired health, and reduced productivity of offspring in many species. Poor maternal nutrition can be defined as an excess or restriction of overall nutrients or specific macro- or micronutrients in the diet of the mother during gestation. Interestingly, there are several reports that both restricted- and over-feeding during gestation negatively affect offspring postnatal growth with reduced muscle and bone deposition, increased adipose accumulation, and metabolic dysregulation through reduced leptin and insulin sensitivity. Our laboratory and others have used experimental models of restricted- and over-feeding during gestation to evaluate effects on early postnatal growth of offspring. Restricted- and over-feeding during gestation alters body size, circulating growth factors, and metabolic hormones in offspring postnatally. Both restricted- and over-feeding alter muscle growth, increase lipid content in the muscle, and cause changes in expression of myogenic factors. Although the negative effects of poor maternal nutrition on offspring growth have been well characterized in recent years, the mechanisms contributing to these changes are not well established. Our laboratory has focused on elucidating these mechanisms by evaluating changes in gene and protein expression, and stem cell function. Through RNA-Seq analysis, we observed changes in expression of genes involved in protein synthesis, metabolism, cell function, and signal transduction in muscle tissue. We recently reported that satellite cells, muscle stem cells, have altered expression of myogenic factors in offspring from restricted-fed mothers. Bone marrow derived mesenchymal stem cells, multipotent cells that contribute to development and maintenance of several tissues including bone, muscle, and adipose, have a 50% reduction in cell proliferation and altered metabolism in offspring from both restricted- and over-fed mothers. These findings indicate that poor maternal nutrition may alter offspring postnatal growth by programming stem cell populations. In conclusion, poor maternal nutrition during gestation negatively affects offspring postnatal growth, potentially through impaired stem and satellite cell function. Therefore, determining the mechanisms that contribute to fetal programming is critical to identifying effective management interventions for these offspring and improving efficiency of production. PMID- 28727022 TI - TRIENNIAL GROWTH AND DEVELOPMENT SYMPOSIUM: Genetics and breeding for intramuscular fat and oleic acid content in pigs. AB - The intramuscular fat (IMF) and oleic acid (OL) content have been favorably related to pork quality and human health. This influences the purchasing behavior of consumers and, therefore, also shifts the attention of breeding companies toward whether these traits are included into the breeding goal of the lines producing for high-valued markets. Because IMF and OL are unfavorably associated with lean content, a key economic trait, the real challenge for the industry is not simply to increase IMF and OL, but rather to come up with the right trade-off between them and lean content. In this paper we review the efforts performed to genetically improve IMF and OL, with particular reference to the research we conducted in a Duroc line aimed at producing high quality fresh and dry-cured pork products. Based on this research, we conclude that there are selection strategies that lead to response scenarios where IMF, OL, and lean content can be simultaneously improved. Such scenarios involve regular recording of IMF and OL, so that developing a cost-efficient phenotyping system for these traits is paramount. With the economic benefits of genomic selection needing further assessment in pigs, selection on a combination of pedigree-connected phenotypes and genotypes from a panel of selected genetic markers is presented as a suitable alternative. Evidence is provided supporting that at least a polymorphism in the leptin receptor and another in the stearoyl-CoA desaturase genes should be in that panel. Selection for IMF and OL results in an opportunity cost on lean growth. The extent to which it is affordable relies on the consumers' willingness to pay for premium products and on the cost to benefit ratio of alternative management strategies, such as specific dietary manipulations. How the genotype can influence the effect of the diet on IMF and OL remains a topic for further research. PMID- 28727023 TI - Rapid Communication: High-resolution quantitative trait loci analysis identifies LTBP2 encoding latent transforming growth factor beta binding protein 2 associated with thoracic vertebrae number in a large F2 intercross between Landrace and Korean native pigs. AB - Number of vertebrae is associated with body size and meat productivity in pigs. The aim of this study was to identify QTL and associated positional candidate genes affecting the number of thoracic vertebrae (THO). A genomewide association study was conducted in a large resource population derived from an F intercross between Landrace and Korean native pigs using the Porcine SNP 60K BeadChip and the genomewide complex trait analysis (GCTA) program based on a linear mixed effects model. A total of 38,385 SNP markers from 1,105 F progeny were analyzed for the THO trait after filtering for quality control. A total of 90 genomewide significant SNP markers ( < 1.30 * 10) on SSC 7 covering a 20-Mb region were identified for THO in this study. Several previous studies also mapped QTL for vertebral numbers in this region. The strongest association signals were detected at ASGA0035500 (-value = 4.46 * 10; 103,574,383 bp) and DIAS0000795 (-value = 4.46 * 10; 103,594,753 bp). The QTL region on SSC 7 for THO encompasses and , which are previously described candidate genes for vertebral number variation. To refine the QTL region, a haplotype-based linkage and linkage disequilibrium (LALD) analysis using the DualPHASE program was applied because subsequent conditional association and haplotype block analyses could not resolve the region that contains the 2 loci. The LALD analysis refined the critical region to a 533.9-kb region including ; was located outside the critical region. The gene encoding latent transforming growth factor beta binding protein 2 is involved in bone metabolisms. Based on these data, we propose as a positional candidate gene for THO in pigs. After further functional studies and verification of the association in other independent populations, these results could be useful for optimizing breeding programs that improve THO and other economically important traits in pigs. PMID- 28727024 TI - Factors affecting ewe performance in a crossbred dairy sheep research flock in the United States. AB - The Spooner Agricultural Research Station operated the only dairy sheep research flock in North America through 2016. The original nondairy ewe flock was "bred up" to a crossbred dairy flock through the use of rams and semen of the East Friesian (EF) and Lacaune (LA) dairy breeds. The objective of this study was to determine the environmental and nonadditive genetic effects that influence performance of dairy ewes. The traits analyzed were 180 d adjusted milk (180d MY), fat (180d FY), and protein (180d PY) yields, percentage fat (%F) and protein (%P) in milk, lactation average somatic cell score (LSCS), and number of lambs born per ewe lambing (NLB). The univariate repeatability models included the fixed effects of year of lambing, age, weaning system (except for the trait of NLB), individual breed composition, and individual retained heterosis along with the random additive genetic, permanent environmental, and residual effects. Estimates of heritability were moderate for 180d MY (0.32 +/- 0.04), 180d FY (0.26 +/- 0.04), and 180d PY (0.29 +/- 0.04), high for %F (0.54 +/- 0.04) and %P (0.61 +/- 0.04), and low for LSCS (0.12 +/- 0.03) and NLB (0.08 +/- 0.02). Ewes that reared their lambs had lower ( < 0.01) 180d MY, 180d FY, 180d PY, %F, and %P and higher ( < 0.001) LSCS than ewes that had their lambs removed shortly after parturition. Relative to nondairy breeding, EF and LA breeding had positive ( < 0.001) effects on 180d MY, 180d FY, and 180d PY, but a negative ( < 0.03) effect on %P. Purebred EF ewes were predicted to have lower ( < 0.001) %F than purebred LA or nondairy ewes. Purebred LA ewes were predicted to have a higher ( < 0.001) LSCS than purebred EF or nondairy ewes. Purebred EF ewes were expected to be more ( < 0.001) prolific than purebred LA or nondairy ewes. Individual retained heterosis had a favorable ( < 0.01) effect on 180d MY, 180d FY, 180d PY, and NLB. Knowledge of the factors affecting dairy ewe performance are important for dairy sheep producers to make more informed husbandry and breeding decisions. PMID- 28727025 TI - Effect of handling intensity at the time of transport for slaughter on physiological response and carcass characteristics in beef cattle fed ractopamine hydrochloride. AB - The effects of handling intensity on the physiological response and carcass characteristics of feedlot cattle fed ractopamine hydrochloride were evaluated at the time of transport to slaughter. Eighty steers (BW = 668 +/- 36 kg) representing 10 lots of similar breed, frame size, and degree of finish were blocked by lot, stratified by weight, and randomly assigned to 1 of 2 handling intensities (HI) over a 1,600 m dirt alley course: 1) low-stress handling (LSH) or 2) high-stress handling (HSH). For the LSH treatment, 4 penmates were kept at a walk with the use of a lead rider. For the HSH treatment, 4 penmates were kept at a minimum of a trot and received 2 applications of an electric prod (approximately 1 s per impulse) at 2 separate instances: first in the alley before post-handling sampling, and again during loading for transportation to the abattoir. Behavioral observations and physical indicators of stress were recorded a minimum of 1 h before handling (baseline), immediately after handling (POSTHAND), and while in lairage after a 200 km transport to the abattoir. Vital parameters were recorded at baseline and POSTHAND. Venous blood samples were collected via jugular venipuncture at baseline and POSTHAND, and mixed arterial and venous blood samples were collected during exsanguination at slaughter. Muscle tremors tended to be more prevalent in HSH cattle at POSTHAND ( = 0.10). The HSH cattle tended to have greater POSTHAND heart rate ( = 0.08); however, there was no effect of HI on POSTHAND respiration rate or rectal temperature ( 0.34). The HSH cattle had greater lactate, epinephrine, norepinephrine, cortisol, and glucose concentrations at POSTHAND ( <= 0.02). Additionally, HSH cattle had lower POSTHAND blood pH, bicarbonate, base excess, and partial pressure carbon dioxide ( < 0.0001). Bicarbonate concentrations were greater in HSH cattle at slaughter ( = 0.05); however, there were no differences between HI treatments for the remaining blood variables ( 0.11). Concentrations of stress hormones and CK were significantly greater at slaughter relative to baseline and POSTHAND for both LSH and HSH cattle ( < 0.001). These findings suggest cattle trotted without a lead rider develop metabolic acidosis, and illustrate the importance of low stress handling at the time of transport for slaughter. Further research is warranted to develop strategies to mitigate stress at the time of transport and ensure the welfare of beef cattle presented to abattoirs. PMID- 28727026 TI - Impact of alternative definitions of contemporary groups on genetic evaluations of traits recorded at lambing. AB - The objective of this study was to quantify the impact of alternative contemporary group definitions for lambing traits on genetic evaluations in the Irish multibreed sheep population. Three lambing traits were considered for analysis: lambing difficulty, birth weight, and survival. Eight alternative contemporary group definitions were investigated for each lambing trait; all contemporary groups were formed within flock of lambing and included (flock by) week of lambing, week of lambing by litter size (i.e., singles vs. multiples), 2 wk interval (i.e., fortnight) of lambing, fortnight of lambing by litter size, month of lambing, and month of lambing by litter size or were based on an optimized algorithm that creates contemporary groups based on animals from the same flock that are born in close proximity of date. Three alternative scenarios were modeled for each of the lambing traits using the contemporary group definitions: the first scenario (termed Current Scenario) represented the editing criteria currently employed in the Irish national genetic evaluations; the second scenario (No Restriction Scenario) removed any restriction on number of records per contemporary group, and the final scenario (Variation Scenario) included only data from contemporary groups with some variability in the dependent variable. Variance components and EBV for each of the 3 lambing traits were estimated using linear mixed models. The direct heritability estimates ranged from 0.09 +/- 0.02 to 0.29 +/- 0.02 for lambing difficulty, 0.11 +/- 0.01 to 0.24 +/- 0.01 for birth weight, and 0.05 +/- 0.02 to 0.10 +/- 0.02 for lamb survival. Irrespective of lambing trait, greater estimated accuracy of the sire EBV was achieved with the No Restriction Scenario. Results for the ability to predict future lambing characteristics, based on only the direct and maternal EBV, revealed that the area under the receiver operator characteristic curve for the dichotomized lambing assistance phenotype varied from 0.56 to 0.66; a lambing event predicted to be in the worst 10% risk category of a difficult lambing on the basis of genetic merit alone was 5.48 times (95% CI: 3.94 to 7.61; < 0.001) more likely to require assistance at lambing compared to a lambing event in the best 10%. Results show that the use of contemporary groups formed over short time periods, coupled with moderate editing of the data, yielded superior predictions for all lambing traits. PMID- 28727027 TI - PHYSIOLOGY AND ENDOCRINOLOGY SYMPOSIUM: Pre- and post-natal impacts on offspring performance. PMID- 28727028 TI - PRODUCTION, MANAGEMENT AND THE ENVIRONMENT SYMPOSIUM: Measurement and mitigation of reactive nitrogen species from swine and poultry production. AB - Reactive nitrogen (Nr) species include oxides of nitrogen [N; nitric oxide, nitrogen dioxide and nitrous oxide (NO)], anions (nitrate and nitrite), and amine derivatives [ammonia (NH), ammonium salts and urea]. Of the different Nr species, air emissions from swine and poultry facilities are predominantly NH followed by NO. Excreta emissions are NH, ammonium ions, and urea with trace amounts of nitrate and nitrite. Farm systems and practices that handle manure as a wet product without pH modification favor almost exclusive NH production. Systems and practices associated with dry manure handling and bedded systems emit more NH than NO. Results from a turkey grow-out study estimated that just under 1% of consumed N was emitted as NO from housing, compared with just under 11% emitted as NH. Despite generally less NO emissions from animal housing compared with crop field emissions, NO emissions from housing are often greater than estimated. Lagoon systems emit more NO than either slurry or deep pit swine systems. Deep pit swine buildings emit only one-third the NO that is emitted from deep bedded swine systems. Laying hen, broiler chicken, and turkey buildings emit over 4 times as much NO as swine housing, on a weight-adjusted basis. Critical control points for mitigation center on: 1) reducing the amount of N excreted and, therefore, excreted N available for loss to air or water during housing, manure storage, or following land application of manures; 2) capturing excreted N to prevent release of N-containing compounds to air, water, or soil resources; or 3) conversion or treatment of N-containing compounds to non-reactive N gas. PMID- 28727029 TI - Effects of graded levels of microbial phytase on apparent total tract digestibility of calcium and phosphorus and standardized total tract digestibility of phosphorus in four sources of canola meal and in soybean meal fed to growing pigs. AB - One hundred twenty pigs were used to determine effects of graded levels of microbial phytase on the apparent total tract digestibility (ATTD) of P and Ca and the standardized total tract digestibility (STTD) of P in 4 sources of canola meal and in 1 source of soybean meal (SBM) fed to growing pigs. The 4 sources of canola meal were produced from 1 source of high-protein canola seeds and 2 sources of conventional canola seeds with 1 of the conventional canola seeds being divided into 2 separate batches before crushing. Pigs (16.2 +/- 5.3 kg initial BW) were individually housed in metabolism crates and were randomly allotted to 1 of 20 diets in a 5 * 4 factorial arrangement of treatments with 5 ingredients and 4 levels of phytase. There were 6 replicate pigs per diet. Five basal diets based on high-protein canola meal (CM-HP), high-temperature processed canola meal (CM-HT), low-temperature processed canola meal (CM-LT), conventional canola meal (CM-CV), or SBM were formulated. The basal diets contained no phytase. Fifteen additional diets were prepared by adding approximately 500, 1,500, or 2,500 phytase units/kg to each of the 5 basal diets. Feces were quantitatively collected for 5 d based on the marker-to-marker approach after a 7 d adaptation period. Results indicated that supplementation of microbial phytase increased (linear, < 0.05) the ATTD of Ca in diets containing CM-HP, CM-HT, CM CV, and SBM but not in diets containing CM-LT. Microbial phytase also increased (linear and quadratic, < 0.05) the ATTD and STTD of P in all 5 ingredients. Compared with the CM-CV diets, the CM-HP diets had greater ( < 0.05) ATTD of Ca. The ATTD of Ca in the SBM diet was greater ( < 0.05) than in all canola meal diets, but no differences were observed in ATTD of Ca between CM-HT and CM-LT diets. The ATTD and the STTD of P were less ( < 0.05) in CM-HP, CM-HT, CM-LT, or CM-CV than in SBM if no microbial phytase was added, but no differences were observed in the ATTD and STTD of P in SBM, CM-HP, CM-HT, or CM-CV if the highest amount of phytase were added (interaction, < 0.05). Regression equations were developed to calculate the response to microbial phytase on the STTD of P in CM HP, CM-HT, CM-LT, CM-CV, and SBM. In conclusion, inclusion of graded levels of microbial phytase increased the ATTD and STTD of P in CM-HP, CM-HT, CM-LT, CM-CV, and SBM and the response to microbial phytase added to each ingredient can be predicted by regression equations. PMID- 28727030 TI - Apparent and true ileal and total tract digestibility of fat in canola press-cake or canola oil and effects of increasing dietary fat on amino acid and energy digestibility in growing pigs. AB - Digestibility of remaining oil in canola press-cake (CPC) may be lower than that of extracted, liquid canola oil (CO) because oil may be partly entrapped in the CPC matrix. To determine true digestibility of fat in ingredients, endogenous fat losses should be estimated. Dietary fat may interact with digestion of other dietary components. To test these hypotheses, 10 ileal-cannulated pigs (initial BW, 25.4 kg) were fed 10 diets for 8 periods in a 10 * 8 Youden square. A basal diet was formulated based on wheat, barley, and canola meal. The 4 CPC and 4 CO test diets were prepared by replacing identical portion of basal diet with 10%, 20%, 30%, or 40% CPC, or 1.5%, 3.0%, 4.5%, or 6.0% CO, respectively, to match the fat content of CPC diet with CO diet at each fat level. An N-free diet based on corn starch was prepared to measure basal endogenous losses of AA. Apparent total tract digestibility (ATTD) and apparent ileal digestibility (AID) of acid hydrolyzed ether extract (AEE) were calculated for each diet. True ileal digestibility (TID) and true total tract (TTTD) digestibility of AEE in CPC and CO, and total endogenous losses of AEE were estimated by regressing apparent digestible AEE (g/kg of DMI) against dietary AEE intake (g/kg of DM) at the total tract and distal ileum, respectively. The mean AID and ATTD of AEE in CPC diets were 78.9% and 61.5%, which were lower ( < 0.01) than 81.9% and 63.4% in CO diets. Apparent ileal and total tract digestible AEE content in CPC and CO diets increased linearly ( < 0.01) with increasing AEE intake. Endogenous losses of AEE were greater ( < 0.05) for the total tract than for the ileum (23.4 vs. 9.4 g/kg of DMI). Dietary fat source did not affect ( > 0.05) total tract or ileal endogenous losses of AEE. The TID and TTTD of AEE in CPC were 92.3% and 94.5%, respectively, lower ( < 0.01) than 96.5% and 100% in CO. Increasing dietary inclusion of CO linearly increased ( < 0.001) standardized ileal digestibility (SID) of CP, Lys, Met, Thr, and Trp, and quadratically increased ( < 0.001) the AID and ATTD of energy in the basal part of the test diets. In conclusion, CPC had lower TID and TTTD of AEE than CO. Dietary fat source did not affect endogenous losses of AEE. The lower digestibility of AEE in CPC than in CO indicates that fat digestibility of CPC should be considered to predict its nutritional value accurately. Dietary inclusion of CO may increase digestibility of CP and energy originating from the balance of the diet. PMID- 28727031 TI - Mammary nutrient uptake in multiparous sows fed supplementary arginine during gestation and lactation. AB - Arginine is the precursor for the synthesis of nitric oxide and may increase mammary plasma flow (MPF), which may in turn increase mammary nutrient uptake. Quantifying mammary nutrient uptake improves our understanding of mammary nutrient metabolism and may potentially allow identification of limiting nutrients for colostrum and milk production. Thus, the objectives of the present study were 1) to study the impact of 25 g/d of crystalline Arg (ARG) on MPF and uptake of nutrients by the mammary glands compared with an isonitrogenous supply of Ala (51 g/d; control [CON]) fed to a total of 8 sows from d 30 of gestation until weaning on d 28 of lactation and 2) to quantify mammary nutrient uptake in late gestation and in early and at peak lactation. Sows were surgically fitted with indwelling catheters on d 76 +/- 2 SEM of gestation. -amino hippuric acid (AH) was infused (3.0 mmol/h) in the infusion catheter inserted in the mammary vein, initiated 1 h before the first blood sample at -10, -3, 3, and 17 d in milk (DIM). Blood samples were simultaneously drawn from catheters inserted in the femoral artery and the mammary vein, and the samples were collected in hourly intervals from 0.5 h before to 6.5 h after feeding. Sow milk production was assessed at 3 and 17 DIM. Arterial plasma concentrations of Arg and Ala were increased in ARG and CON sows, respectively ( < 0.01), whereas we did not succeed in detecting a greater MPF in ARG sows ( = 0.30). Arterial-venous differences ( = 0.03) and net mammary flux ( = 0.01) of Ala were increased in CON sows, while the net flux of most other metabolites ( > 0.05) was unaffected by treatment. The mammary extraction of all essential AA was below 13% in late gestation. The average mammary extraction of essential AA at peak lactation was greatest for Leu (51%), while the preprandial extraction was greatest for Lys (57%). The mammary carbon balance (input-output) was negative (-39 +/- 12 mol C/d) in early lactation but almost balanced at peak lactation (-13 +/- 14 mol C/d), suggesting that mammary fat depots contributed to milk synthesis. In conclusion, we failed to observe an increased MPF and mammary uptake of AA and energy metabolites in ARG-supplemented sows. The mammary extraction rate of essential AA indicated that AA were not limiting for the mammary glands in late gestation, while Lys and Leu appeared to be the 2 most limiting essential AA for milk production at peak lactation. PMID- 28727032 TI - Probiotic supplementation protects weaned pigs against enterotoxigenic Escherichia coli K88 challenge and improves performance similar to antibiotics. AB - These studies evaluated the effects of probiotics (PB) as a potential substitute for antibiotics (AB) on diarrhea in relation to immune responses and intestinal health in weaned pigs challenged with enterotoxigenic (ETEC) K88 (Exp. 1) and the effects of PB on performance and nutrient digestibility in weaned pigs (Exp. 2). In Exp. 1, 24 weaned barrows (4.9 +/- 0.4 kg initial BW) were randomly assigned to 1 of 4 treatments. The treatments consisted of pigs fed an unsupplemented corn soybean meal basal diet and not challenged (NON-C) or challenged with ETEC K88 (CHA-C) on d 9 and pigs fed the same basal diet supplemented with AB (100 mg/kg zinc bacitracin, 50 mg/kg colistin sulfate, and 100 mg/kg olaquindox; CHA-AB) or 500 mg/kg PB ( and ; CHA-PB) and challenged with ETEC K88 on d 9. In Exp. 2, 108 weaned pigs (7.5 +/- 0.9 kg initial BW) not challenged with ETEC K88 were randomly assigned to 1 of 3 treatments, including an AB-free basal diet (CON) and the basal diet with AB (ABD) or 500 mg/kg PB supplementation (PBD). In Exp. 1, after challenge, CHA-C decreased ( < 0.05) ADG and ADFI, whereas CHA-AB and CHA PB revealed no significant change compared with NON-C. Compared with CHA-C, CHA AB and CHA-PB improved ( < 0.05) ADG and ADFI and decreased ( < 0.05) the diarrhea incidence in pigs. Mucosal secretory Ig A contents in the jejunum and ileum were greater in CHA-C than in NON-C ( < 0.05) and lower than in CHA-PB ( < 0.05). The diet containing PB alleviated the increase in the endotoxin and diamine oxidase concentration and cecal count ( < 0.05) and the decrease in intestinal villus height, cecal count, and jejunal mucosal occludin protein abundance ( < 0.05). In Exp. 2, dietary supplementation with AB and PB had positive effects on ADG and feed efficiency ( < 0.05). Compared with CON, apparent digestibility of nutrients in PBD was improved ( < 0.05). Collectively, PB supplementation protected the pigs against ETEC K88 infection by enhancing immune responses and attenuating intestinal damage and improved the performance and nutrient digestibility of weaned pigs. Therefore, PB could be a potential effective alternative to AB for ameliorating diarrhea and improving performance in weaned pigs. PMID- 28727033 TI - The effect of age and carbohydrate and protein sources on digestibility, fecal microbiota, fermentation products, fecal IgA, and immunological blood parameters in dogs. AB - The present study compared the effects of diets formulated with fibers of different fermentability and protein sources of animal or vegetable origins on old and adult dogs. The experiment was organized in a 3 (diets) * 2 (ages) factorial arrangement, totaling 6 treatments. Thirty-six Beagle dogs were used (18 old dogs [10.2 +/- 1.0 yr] and 18 young adult dogs [2.6 +/- 0.9 yr]), with 6 dogs per treatment. Three diets with similar compositions were used: a nonfermentable insoluble fiber source (sugarcane fiber) and chicken byproduct meal (nonfermentable fiber [NFF] diet), a fermentable fiber source (beet pulp) and chicken byproduct meal (fermentable fiber [FF] diet), and soybean meal as a protein and fiber source (soybean meal [SM] diet). Data were evaluated using the MIXED procedure and considering the effects and interactions of block, animal, diets, and age. Means were compared using Tukey's test ( < 0.05). Age * diet interactions were evaluated when < 0.1. Old dogs had a reduced coefficient of total tract apparent digestibility of DM, which was explained by the age and diet interaction of CP and fat digestibility that was lower for old than for adult dogs fed the FF diet ( < 0.05). The SM diet obtained higher DM, OM, CP, and fiber digestibility compared with the NFF diet ( < 0.05). The feces of dogs fed the NFF diet had increased DM content ( < 0.05). The short-chain fatty acids (SCFA) did not change by age group and were higher for dogs fed the FF and SM diets compared with dogs fed the NFF diet ( < 0.05). An age and diet interaction was observed for lactate and was increased in the feces of old dogs compared with adult dogs fed the FF diet ( < 0.05). Fecal putrescine, cadaverine, and spermine were increased for old dogs compared with adult dogs ( < 0.05), and the spermidine fecal concentration was increased for dogs fed the SM diet regardless of age ( < 0.05). Old dogs had reduced peripheral T and B lymphocytes ( < 0.05). An age and diet interaction was observed for fecal IgA ( < 0.001). Adult dogs fed the SM diet had increased IgA in feces compared with animals fed the NFF and FF diets ( < 0.05). However, for old dogs, both the FF and SM diets induced increased IgA compared with the NFF diet ( < 0.05). In conclusion, beet pulp may reduce digestibility and induce increased lactate in the feces of old dogs. The protein and oligosaccharides of soybean meal are digestible by dogs, induce the production of SCFA and spermidine, and increase fecal IgA. Old dogs had increased putrecine, cadaverine, and spermine fecal concentrations. PMID- 28727034 TI - Standardized ileal digestible amino acid contents of canola meal from Canadian crushing plants for growing pigs. AB - Studies have shown that there are variations in the chemical and nutritive composition of canola meal (CM) produced in Canada, some of which may result from differences among the canola seed crushing plants. Therefore, it is necessary to determine the variability in the nutritive value of CM as its end users desire increased meal consistency and more information on any potential variability in AA digestibility. Thus, 18 ileal cannulated barrows (average initial BW = 23.3 kg) were used to determine the apparent (AID) and standardized (SID) ileal digestibility of N and AA and standardized ileal digestible N and AA contents in CM from 6 processing plants in Canada. Two processing plants provided CM in both mash and pellet forms, whereas the other 4 provided it only in mash form, giving a total of 8 CM samples. The barrows were fed 9 cornstarch-based diets. The first 8 diets were formulated to contain the CM samples as the only source of AA. The ninth diet was a casein-cornstarch diet to determine ileal endogenous AA losses. All diets contained 0.3% titanium dioxide as an indigestible marker. Pigs were housed individually in pens and were fed the 9 diets in a completely randomized design for 3 periods to give 6 pigs per diet. Each experimental period lasted for 7 d, consisting of 5 d of adaptation and 2 d of ileal digesta collection at 2-h intervals from 0800 to 2000 h on d 6 and 7. There was an effect ( < 0.05) of CM source on 1) the AID of N, Met, Cys, Thr, Val, Gly, and Ser; 2) the SID of N, Met, and Cys; and 3) the standardized ileal digestible content of all AA. Pelleting reduced ( < 0.05) the standardized ileal digestible content of Arg, Ile, Glu, and Gly in 1 of the CM samples tested and of all AA except His in the other CM sample. The SID values for Arg, Lys, Met, and Thr averaged 87.2%, 78.2%, 84.5%, and 74.1%, respectively. The standardized ileal digestible contents of Arg, Lys, Met, and Thr averaged 2.10%, 1.71%, 0.50%, and 1.01%, respectively. In conclusion, there were variations in the AID, SID, and standardized ileal digestible AA contents of CM among crushing plants in Canada. PMID- 28727035 TI - Genetic analysis of feet and leg conformation traits in Nelore cattle. AB - Feet and leg conformation scores are important traits in beef cattle because they encompass a wide range of locomotion disorders that can lead to productive and reproductive losses. Thus, the study of feet and legs in beef cattle is essential for evaluating possible responses to selection focusing on minimizing economic losses caused by the occurrence of feet and leg problems. The aim of this study was to estimate variance components for feet and leg conformation traits in Nelore cattle. The data set contained records of approximately 300,000 animals that were born between 2000 and 2013. These animals belonged to the commercial beef cattle breeding program of the CRV Lagoa (). Feet and legs were evaluated by assigning visual scores at 2 different time points: feet and leg evaluated as a binary trait (FL1), measured at yearling (about 550 d of age) to identify whether (or not) an animal has feet and leg defects, and feet and leg score (FL2), ranging from 1 (less desirable) to 5 (more desirable) was assigned to the top 20% of animals according to the selection index adopted by the beef cattle breeding program, which was measured 2 to 5 mo after the yearling evaluation. The FL1 and FL2 traits were analyzed together with yearling weight (YW). The (co)variance components and breeding values were estimated by Bayesian inference using 2-trait animal models. The posterior means (standard errors) of the heritabilities for FL1, FL2, and YW were 0.18 (0.04), 0.39 (0.07), and 0.47 (0.01), respectively. The results indicate that the incidence of feet and leg problems in this population might be reduced by selection. The genetic correlation between FL1 and FL2 (-0.47) was moderate and negative as expected because the classification score that holds up each trait has opposite numerical values. The genetic trends estimated for FL1 and FL2 (-0.042 and 0.021 genetic standard deviations per year, respectively) were favorable and they indicate that the independent culling strategy for feet and leg problems promotes favorable changes and contributes to the genetic progress of these traits in the population under study. PMID- 28727036 TI - Supplementation of glycerol or fructose via drinking water to grazing lambs on tissue glycogen level and lipogenesis. AB - Lambs ( = 18; 40.1 +/- 7.4 kg BW) were used to assess supplementation of glycerol or fructose via drinking water on growth, tissue glycogen levels, postmortem glycolysis, and lipogenesis. Lambs were blocked by BW and allocated to alfalfa paddocks (2 lambs/paddock and 3 paddocks/treatment). Each paddock within a block was assigned randomly to drinking water treatments for 30 d: 1) control (CON), 2) 120 g fructose/L of drinking water (FRU), or 3) 120 g glycerol/L of drinking water (GLY). Lambs grazed alfalfa with free access to water treatments for 28 d and then were fasted in indoor pens for a final 2 d with access to only water treatments. Data were analyzed using the MIXED procedure of SAS with water treatment and time (when appropriate) in the model. During the 28-d grazing period, ADG was greater ( < 0.05) for GLY than for CON or FRU. During the 2-d fasting period, BW shrink was lower ( < 0.05) for GLY compared with CON or FRU. Hot carcass weight was greater ( < 0.05) for GLY than for FRU. The interaction for glycogen content * postmortem time was significant ( = 0.003) in LM and semitendinosus (ST) muscles. Glycogen content in the LM was greater ( < 0.05) for GLY at 2 and 3 h and for FRU at 1 h postmortem compared with CON. Glycogen content in ST did not differ between treatments ( > 0.05). Liver glycogen content was over 14-fold greater ( < 0.05) for GLY compared with FRU or CON. Liver free glucose was greater ( < 0.05) for GLY than for CON, whereas liver lipid content was higher ( < 0.05) for CON than for GLY. Supplementation with GLY increased ( < 0.05) odd-chain fatty acids in LM, subcutaneous fat (SQ), and the liver. Stearic acid (C18:0) concentrations were reduced in LM ( = 0.064) and subcutaneous adipose tissue (SQ; = 0.018), whereas oleic acid (C18:1 -9) concentration tended to be increased ( = 0.066) in SQ with FRU and GLY. Linolenic acid (C18:3 -3) was reduced ( = 0.031) and all long-chain -3 fatty acid (eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid) concentrations were increased ( < 0.05) with FRU and GLY compared with CON. Glycerol supplementation upregulated ( < 0.05) stearoyl-CoA desaturate () and fatty acid synthase () mRNA by over 40 fold in the SQ and 5-fold in the liver. Glycerol supplementation also upregulated ( < 0.05) glucose transporters and glycogen branching enzyme in the liver. Overall, glycerol supplementation improved growth, reduced BW shrink during fasting, increased glycogen content in muscle and the liver, and stimulated de novo lipogenesis. PMID- 28727037 TI - Assessment of objective measures of beef steak juiciness and their relationships to sensory panel juiciness ratings. AB - The objective of this study was to evaluate multiple instrumental measures of beef juiciness and determine their relationships with sensory panel juiciness ratings. Treatments were selected to maximize variation in juiciness and included 5 USDA quality grades (Prime, upper two-thirds Choice, lower one-third Choice, Select, and Standard) as well as 2 enhanced Select treatments (112 and 107% of the initial raw weight) and were prepared to 3 degrees of doneness (DOD; rare [66 degrees C], medium [71 degrees C], and well done [77 degrees C]). A total of 21 objective measures of raw samples were evaluated and included marbling level, CIE color values, pH, water activity, proximate composition, and multiple measures of water-holding capacity. Also, 17 objective measures were evaluated for cooked beef samples and included cooking loss, drip loss, and compression-based methods used to quantify expressible moisture. These measures were compared with results from a previous sensory study to evaluate the relationship between the various objective measures and sensory panel juiciness ratings. Differences ( < 0.05) were found among quality treatments for many of the measures evaluated, with the greatest differences occurring for many of the measures among samples cooked to different DOD. Of all the objective measures evaluated, protein percentage, cooking loss, and pressed juice percentage (PJP) were most closely associated ( < 0.05) with consumer juiciness ratings ( = -0.55, = -0.51, and = 0.45, respectively). Additionally, cooking loss and PJP were more closely associated ( < 0.05) with trained sensory panel initial and sustained juiciness ratings than all other measures evaluated. Regression analysis revealed that PJP explained ( < 0.05) 20, 48, and 45% of the variation in consumer, trained panel initial, and trained panel sustained juiciness scores, respectively. This was a greater percentage of the variation than slice shear force explained ( < 0.05) in trained sensory panel initial (39%) and sustained tenderness ratings (40%) and similar to the amount explained (26%) in consumer tenderness ratings. These results indicate PJP was a better predictor of sensory panel juiciness scores than all traits evaluated other than the cooking loss of steaks evaluated by sensory panelists. Pressed juice percentage explained a similar or greater amount of variation in sensory panel scores as slice shear force, indicating PJP as a potential industry standard for objective juiciness evaluation. PMID- 28727038 TI - Genetic correlations between wool traits and carcass traits in Merino sheep. AB - Genetic correlations between 29 wool production and quality traits and 14 whole carcass measures and carcass component traits were estimated from the Information Nucleus of 8 flocks managed across a range of Australian sheep production environments and genetically linked. Wool data were from over 5,000 Merino progeny born over 5 yr, whereas carcass data were from over 1,200 wether progeny of over 176 sires, slaughtered at about 21 kg carcass weight, on average. Wool traits included yearling and adult records for wool weight, fiber diameter, fiber diameter variation, staple strength, scoured color, and visual scores for breech and body wrinkle. Whole carcass measures included HCW, dressing percentage (DP), and various measures of fat depth and eye muscle dimensions. Carcass components were obtained by dissection, and lean meat yield (LMY) was predicted. Heritability estimates for whole carcass measures ranged from 0.12 +/- 0.08 to 0.35 +/- 0.10 and ranged from 0.17 +/- 0.10 to 0.46 +/- 0.10 for carcass dissection traits, with no evidence of important genotype * environment interactions. Genetic correlations indicated that selection for increased clean wool weight will result in reduced carcass fat (-0.17 to -0.34) and DP (-0.48 +/- 0.15), with little effect on carcass muscle. Selection for lower fiber diameter will reduce HCW (-0.48 +/- 0.15) as well as carcass fat (0.14 to 0.27) and muscle (0.21 to 0.50). There were high genetic correlations between live animal measures of fat and muscle depth and the carcass traits (generally greater than 0.5 in size). Selection to increase HCW (and DP) will result in sheep with fewer wrinkles on the body (-0.57 +/- 0.10) and barer breeches (-0.74 +/- 0.12, favorable), with minor deterioration in scoured wool color (reduced brightness and increased yellowness). Selection for reduced fat will also result in sheep with fewer body wrinkles (-0.42 to -0.79). Increasing LMY in Merinos through selection would result in a large reduction in carcass fat and DP (-0.66 to 0.84), with a smaller increase in carcass muscle and some increase in wool weight and wrinkles. Although no major antagonisms are apparent between the wool and carcass traits, developing selection indexes for dual-purpose wool and meat breeding objectives will require accurate estimates of genetic parameters to ensure that unfavorable relationships are suitably considered. The findings will aid development of dual-purpose wool and meat breeding objectives. PMID- 28727039 TI - Application of bioelectrical impedance analysis to assess rabbit's body composition from 25 to 77 days of age. AB - The aim of the study was to develop prediction equations for assessing, in vivo, the whole body composition of growing rabbits. The accuracy of the models obtained was externally validated with independent data sets. One hundred fifty rabbits grouped at 5 different ages (25, 35, 49, 63, and 77 d) were used. A body composition analyzer with 4 terminals was used to obtain resistance (Rs; Omega) and reactance (Xc; Omega) values. The distance between internal electrodes (D; cm), body length (Len; cm), and live BW (g) were also registered. Average values of Rs, Xc, impedance (Z), Len, D, and BW were 83.5 +/- 23.1 Omega, 18.2 +/- 3.8 Omega, 85.6 +/- 22.9 Omega, 30.6 +/- 6.9 cm, 10.8 +/- 3.1 cm, and 1,454 +/- 845 g, respectively. At each selected age, animals were slaughtered, ground, and frozen (-20 degrees C) for determining water, fat, CP, ash, and GE (70.5 +/- 3.36%, 27.7 +/- 7.61% DM, 54.9 +/- 5.41% DM, 11.1 +/- 1.55% DM, and 2,267 +/- 183 kJ/100 g DM, on average, respectively). Fat and GE contents increased with the age, whereas CP, ash, and water contents decreased. A multiple linear regression analysis was used to determine the prediction equations, using BW, Len, and Z data as independent variables. Equations obtained to estimate water (g), CP (g), fat (g), ash (g), and GE (MJ) had coefficient of determination () values of 0.99, 0.99, 0.97, 0.98, and 0.99, respectively, and the relative mean prediction error (RMPE) was 2.79, 6.15, 24.3, 15.2, and 10.6%, respectively. When water was expressed as a percentage, the and RMPE were 0.85 and 2.30%, respectively. When prediction of the content of protein (% DM), fat (% DM), ash (% DM), and energy (kJ/100 g DM) was done, values of 0.79, 0.83, 0.71, and 0.86, respectively, for and 5.04, 18.9, 12.0, and 3.19%, respectively, for RMPE were obtained. It could be concluded that bioelectrical impedance analysis is a good, noninvasive method to estimate, in vivo, whole body composition of growing rabbits from 25 to 77 d of age. PMID- 28727040 TI - Genome-wide association studies and meta-analysis reveal novel quantitative trait loci and pleiotropic loci for swine head-related traits. AB - The pig is an important domestic animal that provides a larger amount of meat and serves as a biomedical animal model for human. Head and facial features are closely linked to identity recognition in mammal communication. To uncover the genetic architecture of swine head and facial features, we constructed 5 experimental pig populations and accurately measured 10 traits related to head and facial features, for which genome-wide association studies and meta-analysis were later carried out. As a result, we identified a total of 24 loci harboring 437 SNP on 8 swine chromosomes (SSC) that surpassed suggestively significant levels, of which 17 loci on 6 chromosomes exceeded the 5% genome-wide significance thresholds. To our knowledge, this is the first report of QTL for the distance from the low corner of the eye to the snout end (DES) and to the mouth corner (DEM), the size of extra mouth cleft (EMC), lip thickness, head length, and tongue weight and length in pigs. Notably, 3 pleiotropic loci were detected, including the loci at 298.1 Mb on SSC1 for head length and DES, at about 80.0 Mb on SSC4 for head weight, tongue weight and length, and at 34.8 Mb on SSC7 for head weight, EMC, and lip thickness. Several positional candidate genes at the identified loci might play roles in craniofacial development or have been implicated in syndromes affecting human head and facial features, including glutamate metabotropic receptor 4 (), high mobility group AT-hook 1 (), high mobility group AT-hook 2 (), serum/glucocorticoid regulated kinase family member 3 (), pleiomorphic adenoma gene 1 (), proto-oncogene serine/threonine-protein kinase mos () and DENN (differentially expressed in normal and neoplastic cells) domain containing 1A (). These findings will contribute to further detection of the causal mutations underlying these QTL for head and facial features in pigs and provide insights into the genetic basis of head and facial characteristics in human or other mammals. PMID- 28727041 TI - Proteomic features linked to tenderness of aged pork loins. AB - There is considerable evidence that the protein component of fresh pork makes a major contribution to tenderness. In particular, the proteomic profile can be linked to postmortem events including pH decline, tissue oxidation, and protein degradation. The objectives for this study were to determine differences in sarcoplasmic proteomes that contribute to tenderness variation in aged pork longissimus dorsi muscles (LM). A defined set of pork loins selected to be similar in pH, color, and lipid yet different in tenderness were used. Pork loins were assigned to tenderness groups based on their star probe values; a high star probe group (HSP; n=12 mean star probe 7.75 kg) and low star probe group (LPS; n=12 star probe 4.95 kg) Samples were selected for proteomic experiments based on star probe values, and selected samples were within specified ranges for ultimate pH (5.54-5.86), marbling score (1.0-3.0), and percent total lipid (1.61-3.37%). Two-dimensional difference in gel electrophoresis (2D-DIGE) and mass spectrometry were used to examine sarcoplasmic protein abundance and potential modifications. Proteins spots that were significantly different across groups were selected for identification. Results from 2D-DIGE showed that HSP samples had significantly more abundant metabolic, stress response, and regulatory proteins in the sarcoplasmic fraction compared with LSP samples. The stress response protein peroxiredoxin-2 was more abundant in HSP samples as determined by 2D-DIGE ( <= 0.01; 2 spots) and western blot assay ( = 0.02). Low star probe samples showed significantly more degradation of the structural protein desmin in 2D-DIGE ( < 0.01) and western blot assay ( < 0.01). These results demonstrate that extreme proteolytic differences influenced measured tenderness of LSP and HSP samples and that soluble desmin and peroxiredoxin-2 may be used as biomarkers to differentiate between tough and tender aged pork products. PMID- 28727042 TI - Dietary supplementation with arginine and glutamic acid modifies growth performance, carcass traits, and meat quality in growing-finishing pigs. AB - Sixty Duroc * Large White * Landrace pigs with an average initial BW of 77.1 +/- 1.3 kg were used to investigate the effects of dietary supplementation with arginine and glutamic acid on growth performance, carcass traits, and meat quality in growing-finishing pigs. The animals were randomly assigned to 1 of 5 treatment groups (12 pigs/group, male:female ratio 1:1). The pigs in the control group were fed a basal diet (basal diet group), and those in the experimental groups were fed the basal diet supplemented with 2.05% -alanine (isonitrogenous group), 1.0% -arginine (Arg group), 1% glutamic acid + 1.44% -alanine (Glu group), or 1.0% -arginine + 1.0% glutamic acid (Arg+Glu group). After a 60-d period of supplementation, growth performance, carcass traits, and meat quality were evaluated. The results showed no significant differences ( > 0.05) in growth performance and carcass traits of the pigs in the Arg group relative to the basal diet group; however, the longissimus dorsi (LD) muscle and back fat showed a decrease ( < 0.05) in the percentage of SFA. In the Glu group, the final BW, phase 1 (d 1 to 30) and phase 2 (d 31 to 60) ADFI, and average back fat thickness of the pigs decreased ( < 0.05) by 7.14%, 23.43%, 8.03%, and 33.88%, respectively, when compared with the basal diet group. Dietary Arg+Glu supplementation had no effect ( > 0.05) on the final BW, phase 2 ADFI, and average daily weight gain in pigs but decreased ( < 0.05) their phase 1 ADFI, average back fat thickness, and percentage of SFA in the LD muscle and back fat, and increased ( < 0.05) the i.m. fat (IMF) content of the LD and biceps femoris muscles when compared with the basal diet group. Furthermore, a 16% decrease in yellowness (b* value; < 0.05) was observed in the Arg+Glu group pigs when compared with the isonitrogenous group. These findings suggest that dietary supplementation with both Arg and Glu beneficially increases the IMF deposition and improves the meat color and fatty acid composition without affecting growth performance and s.c. fat in pigs, providing a novel strategy to enhance meat quality in growing-finishing pigs. PMID- 28727043 TI - Effect of monensin withdrawal on intake, digestion, and ruminal fermentation parameters by Bos taurus indicus and Bos taurus taurus steers consuming bermudagrass hay. AB - Effects of monensin withdrawal and cattle subspecies on the utilization of bermudagrass hay (14.3% CP, 72.3% NDF, and 36.9% ADF) were evaluated using ruminally cannulated steers (5 [BI] and 5 [BT]). Subspecies were concurrently subjected to a 2-period, 2-treatment crossover design. Treatments consisted of either 0 mg.steer.d-1 monensin with no previous monensin feeding (CON) or withdrawal from 200 mg.steer.d-1 monensin (MON) fed individually in 0.91 kg dried distillers' grains with solubles for 42 d. Withdrawal was evaluated for a 28-d period. Ruminal fluid was collected 2 h after feeding on d 0, 1, 4, 7, 14, and 21 after withdrawal for determination of pH, VFA, ruminal NH-N (RAN), rate of NH production, and CH production rate. Hay, ort, and fecal grab samples were collected d 23 through 28 after withdrawal for determination of intake and digestion. No subspecies * monensin, subspecies * day, or subspecies * monensin * day interactions were observed ( >= 0.11). An effect of day after monensin withdrawal was observed ( < 0.01) for total VFA concentration, with an increase following withdrawal followed by a decrease and then stabilization. Monensin * day after monensin withdrawal interactions ( <= 0.01) were observed for the acetate:propionate (A:P) ratio and molar percent of acetate and propionate. There was a decrease in molar percent of propionate between d 1 and 4 from 19.1 to 18.0; however, it remained greater ( <= 0.10) for MON than CON through d 7. Withdrawal increased molar percent of acetate from 68.3 to 69.8 between d 0 and 4 for MON steers. The A:P ratio was less ( <= 0.01) on d 0 for MON than for CON (3.4 vs. 4.0), but by d 4, it increased to 3.8 and was not different ( = 0.14) from CON. By d 14, no differences ( >= 0.88) remained for acetate, propionate, or the A:P ratio. After monensin withdrawal, monensin reduced ( < 0.01) RAN by 12.3% (2.09 vs. 1.83 m for CON and MON, respectively). Monensin withdrawal and cattle subspecies had no effect ( >= 0.23) on rate of NH production or CH production rate. Monensin withdrawal had no effect ( >= 0.45) on intake or digestibility parameters. Greater forage OM intake ( = 0.09; 21.2 vs. 19.2 g/kg BW) and OM digestibility ( < 0.01; 72.4 vs. 63.0%) resulted in greater ( < 0.01) total digestible OM intake (16.8 vs. 13.2 g/kg BW) in BT steers than in BI steers. These results suggest that BT steers are better able to utilize bermudagrass hay than BI steers. Upon monensin withdrawal, steers previously fed monensin continue to have a reduced A:P ratio for at least 7 d. PMID- 28727044 TI - Muscle lipid metabolism in two rabbit lines divergently selected for intramuscular fat. AB - A divergent selection experiment for intramuscular fat (IMF) of LM at 9 wk of age was performed in rabbits. The objective of this work was to compare the lipid metabolism in muscles and fat tissues of the high-IMF and low-IMF lines. Lipogenic, catabolic, and lipolytic activities were studied in 2 muscles with different oxidative patterns (LM and semimembranosus proprius) and in the perirenal fat depot at 2 ages, 9 and 13 wk. In addition, adipocytes were characterized in perirenal fat. In the fifth generation, direct response to selection was 0.26 g IMF/100 g muscle. Lines showed differences in their lipogenic activities of muscles and fat tissues at 13 wk but not at 9 wk. The high-IMF line showed greater glucose-6-phosphate dehydrogenase (G6PDH), malic enzyme (EM), and fatty acid synthase (FAS) activities in LM than the low-IMF line, with probabilities = 1.00, 0.93, and 0.90, respectively. Differences between lines were particularly great for G6PDH activity, representing 1.13 SD. The high-IMF line also showed greater G6PDH and FAS activities in semimembranosus proprius (P = 0.98 for G6PDH and 0.95 for FAS) and perirenal fat (P = 0.91 for G6PDH and 0.96 for FAS). However, in perirenal fat, EM activity was greater in the low-IMF line (P = 0.90). No differences between lines were found in almost any catabolic or lipolytic activities of muscles. Regarding adipocyte characteristics, the high-IMF line showed larger adipocytes in perirenal fat depot tissue (P = 0.97) compared to the low-IMF line, but no differences between lines were observed in the number of adipocytes. This study sheds light on the metabolic activities involved in the genetic differentiation of lipid deposition in rabbits. This study shows that lipogenic activities in muscles and fat tissues, in particular G6PDH in LM, are involved in the lipid accumulation in muscle and adipose tissues. PMID- 28727045 TI - Technical note: Characterization of lipid constitution in Fourier transform infrared spectra and spectroscopic discrimination of animal-derived feedstuffs from different species. AB - The objective of the current work was to assess the capability of Fourier transform infrared (FT-IR) spectroscopy in combination with chemometric methods to discriminate animal-derived feedstuffs from different origins based on the lipid characteristics. A total of 82 lipid samples extracted from animal-derived feedstuffs, comprising porcine, poultry, bovine, ovine, and fish samples, were investigated by gas chromatography and FT-IR. The relationship between the lipid constitutions and the responding FT-IR spectral characteristics were explored. Results indicated that high correlations ( > 0.900) were found between the contents of MUFA and PUFA and FT-IR spectral data. In addition, the peak intensity at about 1,116 and 1,098 cm-1 showed a significant difference ( < 0.05) between ruminant and nonruminant animals; the change of peak ratio (1,116:1,098) was proved consistent with the degree of unsaturation of lipid from different animal species. Successful discrimination was further achieved among porcine, poultry, bovine, and ovine meat and bone meal (MBM) and fishmeal based on lipid characteristics by applying the FT-IR spectra coupled with chemometrics, for which the values of sensitivity and specificity were close to 1 and classification error were almost equal to 0. PMID- 28727046 TI - The ileal digestibility of most amino acids is greater in red dog than in wheat middlings when fed to growing pigs. AB - The objective of this experiment was to determine the apparent ileal digestibility (AID) and the standardized ileal digestibility (SID) of CP and AA in 10 sources of wheat middlings and in 1 source of red dog. Ten diets that each contained 1 of the 10 sources of wheat middlings and 1 diet that contained red dog as the only source of protein and AA were formulated. An N-free diet was used to determine basal endogenous losses of CP and AA. Chromic oxide (0.4%) was added to all diets as an indigestible marker. Twelve pigs (BW: 29.23 +/- 1.5 kg) were fitted with a T-cannula in the distal ileum. Pigs were allotted to a 12 * 8 Youden square design with 12 diets and eight 7-d periods. The initial 5 d of each period was the adaptation period, but ileal digesta were collected on the last 2 d of each period. Results indicated that the AID of CP in wheat middlings was 31.1 +/- 6.9%, but the AID of CP in red dog (47.0%) was greater ( < 0.05) than the average AID of CP for wheat middlings. The AID of indispensable AA in wheat middlings ranged from 30.1 +/- 5.4% for Lys to 67.7 +/- 2.2% for His, and the AID of indispensable AA in red dog ranged from 53.7% in Val to 86.2% for Met. The average SID of CP in wheat middlings was 61.5 +/- 5.1%, and there were no differences among the 10 sources of wheat middlings, but the SID of CP in red dog (78.5%) was greater ( < 0.05) than in wheat middlings. The SID of Arg, His, and Asp in wheat middlings was 81.4 +/- 2.7%, 77.7 +/- 2.1%, and 66.4 +/- 2.7%, respectively, and no differences among sources of wheat middlings were observed for these AA. The SID of Met (73.6 +/- 1.8%) and the SID of Ala (54.8 +/- 4.9%) tended ( = 0.071 and = 0.090, respectively) to be different among sources of wheat middlings, and the SID of all other AA was different ( < 0.05) among the 10 sources of wheat middlings. There were no differences between red dog and wheat middlings for the SID of Arg, His, and Ser, and the SID of Cys was less ( < 0.05) in red dog than in wheat middlings, but for all other AA, the SID in red dog was greater ( < 0.05) than in wheat middlings. In conclusion, wheat middlings and red dog contain approximately the same quantities of AA, but the AID and SID of CP and most AA in red dog are greater than in wheat middlings. PMID- 28727047 TI - A diet supplemented with n-3 polyunsaturated fatty acids influences the metabomscic and endocrine response of rabbit does and their offspring. AB - The aim of the present study was to evaluate the productive, endocrine, and metabomscic responses as well as oxidative stress of rabbit does and their offspring when fed a diet supplemented with -3 PUFA during their first productive cycle. To this aim, a total of 105 rabbit does were fed ad mscibitum from d 60 to 172 of age 2 isoenergetic and isoproteic diets differing in fatty acid composition. The control diet ( = 52 does) contained 45.9 g/kg of -3 of the total fatty acids and the enriched diet ( = 53 does) contained 149.2 g/kg of -3 of the total fatty acids. Both experimental groups had similar feed intake during rearing, pregnancy, and lactation. The enrichment of diet had no effect on ultrasonographic assessment of does on d 9 and 16 of pregnancy, with an embryonic vesicle number and fetus and placenta size similar between groups ( > 0.05). Even though there were no major effects ( > 0.05) on fertimscity, duration of gestation, and number born amscive and stillborn kits at parturition, mscive kits from enriched does were longer (71.6 +/- 2.42 vs. 79.5 +/- 2.13 mm; < 0.05) and tended to be heavier (42.5 +/- 3.94 vs. 50.8 +/- 3.47 g; = 0.07) than those from control does ( < 0.05). The 2 groups had similar milk production and mortamscity values during lactation; consequently, there were no differences between diets in ADG, mscitter weight, and number of weaned kits ( > 0.05). In enriched does, higher plasma leptin and estradiol concentrations than in control does ( < 0.05) were observed. In addition, enriched females also had lower total and high density mscipoprotein cholesterol (HDL-c) than control females during lactation ( < 0.05). Regarding offspring, the enrichment of diet with PUFA caused a hypermscipidemic status (greater values of plasma triglycerides, total cholesterol, and HDL-c; < 0.05) at 1 d postpartum (dpp), compared with the control group, that disappeared at 32 dpp. Supplemented does before parturition and their offspring at 1 dpp had greater oxidative stress than those in the control group. In conclusion, an increase of -3 PUFA concentration in the diet of rabbit does and, consequently, of their offspring during a productive cycle alters their mscipid profile and the indicators of oxidative stress, without major endocrine modifications or improvements in the productive variables. PMID- 28727048 TI - Nutrient composition, digestible and metabolizable energy content, and prediction of energy for animal protein byproducts in finishing pig diets. AB - An industry survey and animal experiment were conducted to evaluate compositional variability and DE and ME content of animal protein byproducts and to generate equations to predict DE and ME content based on chemical analysis. For the 220 samples collected, the greatest concentration of CP was observed in blood meal (BM) and the least in meat and bone meal (MBM) and the greatest concentration of ether extract was in meat meal and the least in BM, with ash content greatest in MBM and least in BM, with Ca and P levels being 36.1 and 16.3% of the ash content, respectively. For the balance experiment, a corn-soybean meal basal diet was used with test diets formulated by mixing 80% of the basal diet with 20% of the animal protein byproduct, except for BM, which was included at 10 and 20% of the test diets. Ten groups of 24 gilts (92.5 +/- 7.4 kg final BW) were randomly assigned to the test or basal diet within each group, resulting in 16 replications per animal protein byproduct or basal diet, except for BM determinations (20 replications). Gilts were placed in metabolism crates and offered 2.4 kg daily of their assigned diet for 13 d, with total collection of feces and urine during the last 4 d. Gross energy in the diets, feces, and urine was used to calculate the DE and ME content of each ingredient by the difference procedure, using DE and ME of the basal diet as a covariate among groups of pigs. The DE content of the animal protein byproducts ranged from 5,367 to 2,567 kcal DE/kg DM, and ME ranged from 4,783 to 2,340 kcal ME/kg DM. Using all animal protein byproducts, the best-fit equations were as follows: DE (kcal/kg DM) = 2,468 + (1.26 * GE, kcal/kg DM), with of 0.84, SE = 390, and < 0.01, and ME (kcal/kg DM) = -2,331 + (1.15 * GE, kcal/kg DM), with of 0.86, SE = 327, and < 0.01. The apparent total tract digestibility (ATTD) of Ca and P were also determined using the difference procedure, with the average ATTD of Ca and P for the animal protein byproducts, excluding BM and feather meal, being 27.1 and 39.1%, respectively. These data indicate that DE and ME substantially varied among the animal protein byproducts and sources and that a variety of nutritional components can be used to accurately predict DE and ME for finishing pigs. In addition, it appears that high dietary inclusion rates of animal protein byproducts may result in low ATTD estimates of Ca and P, which may be due to excessive concentrations of total Ca and P affecting digestibility. PMID- 28727049 TI - Association of udder traits with single nucleotide polymorphisms in crossbred Bos indicus-Bos taurus cows. AB - The size, support, and health of udders limit the productive life of beef cows, especially those with background, because, in general, such cows have a reputation for problems with udders. Genomic association studies of bovine udder traits have been conducted in dairy cattle and recently in Continental European beef breeds but not in cows with background. The objective of this study was to determine associations of SNP and udder support scores, teat length, and teat diameter in half (Nellore), half (Angus) cows. Udders of cows ( = 295) born from 2003 to 2007 were evaluated for udder support and teat length and diameter ( = 1,746 records) from 2005 through 2014. These included a subjective score representing udder support (values of 1 indicated poorly supported, pendulous udders and values of 9 indicated very well-supported udders) and lengths and diameters of individual teats in the 4 udder quarters as well as the average. Cows were in full-sibling or half-sibling families. Residuals for each trait were produced from repeated records models with cow age category nested within birth year of cows. Those residuals were averaged to become the dependent variables for genomewide association analyses. Regression analyses of those dependent variables included genotypic values as explanatory variables for 34,980 SNP from a commercially available array and included the genomic relationship matrix. Fifteen SNP loci on BTA 5 were associated (false discovery rate controlled at 0.05) with udder support score. One of those was also detected as associated with average teat diameter. Three of those 15 SNP were located within genes, including one each in (), (), and (). These are notable for their functional role in some aspect of mammary gland formation or health. Other candidate genes for these traits in the vicinity of the SNP loci include () and (). Because these were detected in Nellore-Angus crossbred cows, which typically have very well-formed udders with excellent support across their productive lives, similar efforts in other breeds should be completed, because that may facilitate further refinement of genomic regions responsible for variation in udder traits important in multiple breeds. PMID- 28727050 TI - Net energy of hemp hulls and processed hemp hull products fed to growing pigs and the comparison of net energy determined via indirect calorimetry and calculated from prediction equations. AB - An experiment was conducted to determine the NE of hemp hulls (HH), extruded HH (EHH), and a blended product of HH with pea (HHP) fed to growing pigs using indirect calorimetry (IC) and to determine effects of dietary fiber on heat production (HP) and fasting HP (FHP). Twenty-four growing barrows with an average initial BW of 22.9 +/- 1.75 kg were individually housed in adjustable metabolism crates. Pigs were randomly allotted to 1 of 4 dietary treatments with 6 replicates per treatment. A corn-soybean meal basal diet was prepared. Three additional diets were formulated to contain a constant ratio of corn and soybean meal and each of the test ingredients. Pigs were fed experimental diets for 16 d including 10 d for adaptation and 6 d for total collection of feces and urine to determine DE and ME of experimental diets. Pigs were then moved into IC chambers to determine HP and FHP. The apparent total tract digestibility (ATTD) of DM was greater ( < 0.01) in the HHP diet than in the HH and EHH diets but less ( < 0.01) than in the basal diet. Similarly, the ATTD of GE in the basal diet was greater ( < 0.01) compared with the HH, EHH, and HHP diets. The DE, ME, and NE of the basal diet were greater ( < 0.01) than those of the HH, EHH, and HHP diets. No significant differences were observed for the HP (on average, 1,904 kcal/kg DM) and FHP (on average, 1,320 kcal/kg DM) among treatments. However, the retained energy of pigs fed the basal diet (1,763 kcal/kg DM) was greater ( < 0.05) than for those fed the HH (1,501 kcal/kg DM) and HHP (1,482 kcal/kg DM) diets. The NE:ME ratio tended to be greater ( <= 0.10) for the basal diet (0.85) than for the HH (0.82), EHH (0.82), and HHP (0.83) diets. The NE of HH, EHH, and HHP determined by the IC method were 2,375, 2,320, and 2,399 kcal/kg DM, respectively, whereas values calculated using published prediction equations were 2,308, 2,161, and 2,278 kcal/kg DM, respectively. However there was no difference between determined and predicted values. In conclusion, the NE of HH, EHH, and HHP determined using the IC method were 2,375, 2,320, and 2,399 kcal/kg DM, respectively, and these values were 2.9, 7.1, and 5.2% greater, respectively, than the predicted values, although no difference was observed between determined and predicted values. However, the HP values observed for the basal diet and the diets containing high dietary fiber in the form of HH, EHH, or HHP were similar. PMID- 28727051 TI - Carotenoid intake and SCD genotype exert complementary effects over fat content and fatty acid composition in Duroc pigs. AB - Nutritional and genetic strategies are needed to enhance intramuscular fat (IMF) and MUFA content without altering carcass leanness. Dietary vitamin A restriction has been suggested to specifically promote IMF, whereas a polymorphism of the () gene has shown to specifically increase MUFA. The purpose of this study was to investigate the combined effects of provitamin A (PVA) carotenoid intake and genotype (>) on hepatic retinoid content and on the liver, muscle (LM and gluteus medius [GM]), and subcutaneous fat (SF) content and fatty acid composition. Following a split-plot design, 32 castrated Duroc pigs, half of each of the 2 homozygous genotypes (CC and TT), were subjected from 165 to 195 d of age to 2 finishing diets differing in the PVA carotenoid content (an enriched-carotene diet [C+] and a control diet [C-]). Both diets were identical except for the corn line used in the feed. The C+ was formulated with 20% of a carotenoid-fortified corn (M37W-Ph3) whereas the C- instead used 20% of its near isogenic M37W line, which did not contain PVA carotenoids. No vitamin A was added to the diets. The C was estimated to provide, at most, 1,300 IU of vitamin A/kg and the C+ to supply an extra amount of at least 800 IU vitamin A/kg. Compared with the pigs fed the C , pigs fed with C+ had 3-fold more retinoic acid ( < 0.01) and 4-fold more gene expression in the liver ( = 0.06). The diet did not affect performance traits and backfat thickness, but pigs fed the C+ had less fat (4.0 vs. 5.0%; = 0.07) and MUFA (18.3 vs. 22.5%; = 0.01) in the liver, less IMF (5.4 vs. 8.3%; = 0.04) in the GM, and more fat content (90.4 vs. 87.9%; = 0.09) and MUFA (48.0 vs. 46.6%; = 0.04) in SF. The TT genotype at the gene increased MUFA ( < 0.05) in all tissues (21.4 vs. 19.5% in the liver, 55.0 vs. 53.1% in the LM, 53.9 vs. 51.7% in the GM, and 48.0 vs. 46.7% in SF for TT and CC genotypes, respectively). Liver fat and MUFA content nonlinearly declined with liver all- retinoic acid, indicating a saturation point at relatively low all- retinoic acid content. The results obtained provide evidence for a complementary role between dietary PVA and genotype, in the sense that the TT pigs fed with a low-PVA diet are expected to show higher and more monounsaturated IMF without increasing total fat content. PMID- 28727053 TI - Erratum. PMID- 28727054 TI - Rapid Communication: MiR-92a as a housekeeping gene for analysis of bovine mastitis-related microRNA in milk. AB - Our aim was to identify a suitable microRNA housekeeping gene for real-time PCR analysis of bovine mastitis-related microRNA in milk. We identified , , and as housekeeping gene candidates on the basis of previous Solexa sequencing results. Threshold cycle (CT) values for , , and did not differ between milk from control cows and milk from mastitis-affected cows. NormFinder software identified as the most stable single housekeeping gene. We evaluated the suitability of the housekeeping gene candidates by using them to assess expression levels of the inflammation-related gene . Regardless of the housekeeping gene candidates used for normalization, relative expression levels of were significantly higher in mastitis-affected samples than in control samples. However, of all the housekeeping genes and gene combinations investigated, normalization with alone generated the difference in relative expression between mastitis-affected and control samples with the highest significance. These results suggest that is suitable for use as a housekeeping gene for analysis of bovine mastitis-related microRNA in milk. PMID- 28727052 TI - Rapid Communication: Subclinical bovine respiratory disease - loci and pathogens associated with lung lesions in feedlot cattle. AB - Bovine respiratory disease (BRD) is an economically important disease of feedlot cattle that is caused by viral and bacterial pathogen members of the BRD complex. Many cases of subclinical BRD go untreated and are not detected until slaughter, when lung lesions are identified. The objectives of this study were to identify which BRD pathogens were associated with the presence of lung lesions at harvest and to identify genomic loci that were associated with susceptibility to lung lesions as defined by consolidation of the lung and/or the presence of fibrin tissue. Steers from a Colorado feedlot ( = 920) were tested for the presence of viral and bacterial pathogens using deep pharyngeal and mid-nasal swabs collected on entry into the study. Pathogen profiles were compared between cattle with or without lung consolidation (LC), fibrin tissue in the lung (FT), a combination of LC and FT in the same lung (lung lesions [LL]), and hyperinflated lungs (HIF) at harvest. Genotyping was conducted using the Illumina BovineHD BeadChip. Genomewide association analyses (GWAA) were conducted using EMMAX (efficient mixed-model association eXpedited), and pseudoheritabilities were estimated. The pathogen profile comparisons revealed that LC ( = 0.01, odds ratio [OR] = 3.37) and LL cattle ( = 0.04, OR = 4.58) were more likely to be infected with bovine herpes virus-1 and that HIF cattle were more likely to be infected with spp. ( = 0.04, OR = 4.33). Pseudoheritability estimates were 0.25 for LC, 0.00 for FT, 0.28 for LL, and 0.13 for HIF. Because pseudoheritability for FT was estimated to be 0, GWAA results for FT were not reported. There were 4 QTL that were moderately associated ( < 1 * 10) with only LC, 2 that were associated with only LL, and 1 that was associated with LC and LL. Loci associated with HIF included 12 that were moderately associated and 3 that were strongly associated (uncorrected P < 5 * 10-7). A 24-kb region surrounding significant lead SNP was investigated to identify positional candidate genes. Many positional candidate genes underlying or flanking the detected QTL have been associated with signal transduction, cell adhesion, or gap junctions, which have functional relevance to the maintenance of lung health. The identification of pathogens and QTL associated with the presence of lung abnormalities in cattle exhibiting subclinical BRD allows the identification of loci that may not be detected through manifestation of clinical disease alone. PMID- 28727056 TI - Effects of protein and fat concentration in coproduct-based growing calf diets on adipogenic and lipogenic gene expression, blood metabolites, and carcass composition. AB - Crossbred calves ( = 30; age = 95 +/- 1.7 d; BW = 179 +/- 18 kg) were fed 1 of 5 growing diets: 1) corn-based control, 2) low-fat, low-protein coproduct blend, 3) high-fat, low-protein coproduct blend, 4) low-fat, high-protein coproduct blend, and 5) high-fat, high-protein coproduct blend for 112 d (growing phase) followed by a common corn-based finishing diet (additional 112 d; finishing phase). Calves were biopsied at 0, 112, and 224 d for transcriptional analysis via real-time quantitative PCR of 14 genes associated with adipogenesis and lipogenesis within the muscle. Serum was collected at d 0, 112, and 224 and analyzed for leptin, IGF 1, and GH concentration. Treatments were arranged in a 2 * 2 factorial. Data were analyzed using the MIXED procedures of SAS (SAS Inst. Inc., Cary, NC) to ascertain the effects of 2 protein levels, 2 fat levels, time, and any interactions. Increased protein and decreased fat in the growing diet resulted in a carryover effect that increased ( 0.01) gene expression of PPARgamma, insulin induced gene 1, thyroid hormone responsive SPOT14 protein, ATP citrate lyase, adiponectin, diacylglycerol O-acyltransferase homologue 2, fatty acid binding protein 4, fatty acid synthase, phosphoenolpyruvate carboxykinase 1, and stearoyl CoA desaturase as well as serum leptin concentrations between d 112 and 224. Expression of sterol regulatory element binding transcription factor 1 was increased ( 0.01) at d 112 in steers fed high-protein, high-fat diets compared to those fed high-protein, low-fat diets. A fat * day interaction ( 0.01) occurred for the expression of adiponectin receptor 2 and CCAAT/enhancer binding protein alpha, resulting in a carryover effect wherein low-fat diets fed during the growing phase increased expression of both genes at the end of the finishing phase (d 224). After slaughter, cattle fed the control during the growing phase tended ( 0.09) to have greater marbling scores, whereas other carcass parameters were not different ( >= 0.13). These data indicate that feeding differing levels of dietary fat and protein during the growing phase does affect i.m. adipogenesis at the transcriptional level, but differences in gene expression were not sufficient to affect carcass quality among cattle fed coproducts. PMID- 28727057 TI - Effects of feeding pregnant beef cows selenium-enriched alfalfa hay on selenium status and antibody titers in their newborn calves. AB - In newborn dairy calves, it has been demonstrated that supranutritional maternal and colostral Se supplementation using Se yeast or sodium selenite, respectively, improves passive transfer of IgG. In beef cattle, agronomic biofortification with Se is a more practical alternative for Se supplementation, whereby the Se concentration of hay is increased through the use of Se-containing fertilizer amendments. It has been previously demonstrated that agronomic Se biofortification is an effective strategy to improve immunity and performance in Se-replete weaned beef calves. The objective of this experiment was to determine the effects of feeding beef cows Se-enriched alfalfa () hay during the last 8 to 12 wk of gestation on passive transfer of antibodies to calves. At 10 wk +/- 16 d before calving, 45 cows were assigned to 1 of 3 treatment groups with 3 pens (5 cows/pen) per treatment: Control cows were fed non-Se-fortified alfalfa hay plus a mineral supplement containing 120 mg/kg Se from sodium selenite, Med-Se cows were fed alfalfa hay fertilized with 45.0 g Se/ha as sodium selenate, and High-Se cows were fed alfalfa hay fertilized with 89.9 g Se/ha as sodium selenate; both the Med-Se and the High-Se groups received mineral supplement without added Se. Colostrum and whole blood (WB) were collected from cows at calving, and WB was collected from calves within 2 h of calving and at 12, 24, 36, and 48 h of age. Concentrations of IgG1 and J-5 antibody in cow colostrum and calf serum were quantified using ELISA procedures. Selenium concentrations linearly increased in WB ( < 0.001) and colostrum ( < 0.001) of cows and in WB of newborn calves ( < 0.001) with increasing Se concentration in alfalfa hay. Colostrum concentrations of IgG1 ( = 0.03) were increased in cows fed Se-biofortified alfalfa hay, but J-5 antibody ( = 0.43) concentrations were not. Calf serum IgG1 ( = 0.43) and J-5 antibody ( = 0.44) concentrations during the first 48 h of age were not affected by prior Se treatment of cows. These data suggest that feeding Se-biofortified alfalfa hay promotes the accumulation of Se and antibodies in colostrum but does not affect short-term serum antibody concentrations in calves. PMID- 28727058 TI - Technical note: Recording rules for behavioral studies in growing heifers fed high-concentrate diets. AB - Continuous recording over 24 h is an accurate method for behavioral measurements in ruminants but is very time-consuming. The aim of this study was to compare different recording rules, in particular continuous recording (CR) with different time samplings (TS) methods, when the behavior of growing heifers housed individually and fed a high-concentrate diet is recorded. Behavior of 8 growing heifers was recorded on 6 non-consecutive days. Continuous recording over 24 h, considered the control treatment, was used to evaluate TS methods by recording all the behaviors that occurred for 60 s at intervals of 2 (S2), 5 (S5), 10 (S10), 15 (S15), 20 (S20) and 30 (S30) min. Three additional TS methods were considered: a sampling of the first 10 min of every h (FS10), and a sampling during 4 h (4PF) and 8 h post-feeding (8PF). Two procedures to assess the accuracy of the relationship between CR and TS methods were used: a) data analysis using the GLIMMIX procedure of SAS together with the Pearson correlation coefficient, and b) linear regression analysis. In this last case, 1-time sampling was considered to accurately reflect true values obtained with CR if the following 3 criteria were met: the coefficient of determination () was greater than 0.76, the intercept did not differ from 0 ( > 0.05), and the slope did not differ from 1 ( > 0.05). The results of the present study suggest that the latter approach provides a much more focused and reliable way of ensuring the accuracy of each TS method. The S5 TS method produced an accurate estimate for all the behavioral activities, except for drinking, social behavior and rummaging in wood shavings, where it would be necessary to consider the S2 TS method, and S10 for self-grooming. Ruminating and resting can be accurately estimated using the S20 and S30 TS methods, respectively. However, FS10, 4PF and 8PF were inadequate TS methods to measure all the activities studied in the present experiment. In conclusion, not all the TS methods tested are adequate for measuring the behaviors recorded. PMID- 28727059 TI - Dynamics of nitrogen retention at two feeding levels in gestating parity 2 and 3 sows. AB - Parity-2 ( = 39) and -3 ( = 28; same sows from parity-2 sows) Yorkshire sows were used to measure whole body protein deposition (Pd) during gestation (maternal and pregnancy-associated) at 2 feeding levels to test the hypothesis that the pattern of whole body and maternal Pd during gestation does not differ when feeding either 15% above or 15% below estimated ME requirements, both exceeding AA requirements. Initial BW and backfat (BF) at d 26 +/- 0.3 of gestation were 195.4 +/- 5.2 kg and 15.1 +/- 0.5 mm, and 223.1 +/- 5.3 kg and 16.0 +/- 0.6 mm for parity-2 and -3, respectively. Sows were assigned to 1 of 2 feeding levels (high and low; 15% above and 15% below estimated ME requirements, respectively) of the same diet (3.30 Mcal ME/kg, 17.8% CP, 0.82% SID Lys) from d 31 to 110 of each gestation cycle. Five N balances were conducted throughout each gestation starting at d 36, 51, 65, 85, and 106 +/- 0.5 during 4-d periods. Pregnancy associated Pd was model-derived for each sow and N balance period using the gestating sow model, based on actual litter size (including stillborn) and mean piglet birth weight. Maternal Pd was calculated as the difference between whole body and pregnancy-associated Pd. Whole body Pd and maternal Pd were greater ( 0.002) for sows on the high feeding level. Whole body Pd increased ( 0.001) with day of gestation and maternal Pd did not differ with day of gestation. Whole body and maternal Pd were greater ( <= 0.004) for parity-3 sows from d 51 to 54 and 85 to 88 of gestation only. Estimated efficiency of Lys retention for whole body Pd was not different between the 2 feeding levels, greater ( 0.016) for parity-3 sows, and increased quadratically ( 0.027) with day of gestation. During lactation (21.3 +/- 0.3 d), there was no effect on sow ADFI and minimal effect on litter performance due to gestation feeding level or parity. Sows on the high feeding level had greater ( 0.009) BW and BF loss during lactation and these parameters were not affected by parity. Feeding 15% above estimated ME requirements during gestation resulted in consistently greater whole body and maternal. Whole body and maternal Pd were particularly greater for parity-3 sows from d 51 to 54 and 85 to 88 of gestation. The pattern of maternal Pd, regardless of feeding level, was not affected by day of gestation and is in contrast to , where maternal Pd is expected to be greater in early gestation. PMID- 28727060 TI - Effect of monensin inclusion on intake, digestion, and ruminal fermentation parameters by Bos taurus indicus and Bos taurus taurus steers consuming bermudagrass hay. AB - Effects of monensin inclusion and cattle subspecies on utilization of bermudagrass hay (13.7% CP, 77.3% NDF, and 38.8% ADF) were evaluated using ruminally cannulated steers (5 [BI] and 5 [BT]; 398 kg BW). Subspecies were concurrently subjected to a 2-period, 2-treatment crossover design. Treatments were 0 (CON) or 200 mg.steer.d monensin (MON) in 0.91 kg dried distillers' grains with solubles. Periods were 70 d in length: 20 d of adaptation, 22 d of sample collection, and 28 d for withdrawal of treatment. Steers were group housed during adaptation and moved to individual covered pens for sampling. Hay, ort, and fecal grab samples were collected d 21 through 25 for determination of intake and digestion. Ruminal fluid was collected with a suction strainer 0, 2, 4, 8, and 12 h after feeding on d 42 for pH, VFA, and ruminal NH-N (RAN) analysis. Additionally, at h 2, ruminal fluid and contents were collected for determination of rate of NH production and CH production rate. No subspecies * monensin interactions were observed ( >= 0.12). Monensin had no effect ( >= 0.16) on intake or digestibility parameters. No subspecies effect ( >= 0.11) was observed for forage OM intake, total OM intake, or OM digestion. Total digestible OM intake tended to be greater ( = 0.06) for BT steers than for BI steers (14.0 vs. 12.2 g/kg BW). There was an effect of hour after feeding ( <= 0.01) on pH, total VFA, acetate:propionate ratio, and molar percent acetate and propionate. Total VFA concentration was greater ( = 0.01) in CON steers than in MON steers (66.5 vs. 62.0 m). Monensin decreased molar percent acetate ( = 0.02) from 72.5 to 71.2% and increased molar percent propionate ( < 0.01) from 16.9 to 18.7%, resulting in a reduced ( < 0.01) acetate:propionate ratio (from 4.34 to 3.85). Although not significantly ( = 0.19), monensin numerically reduced the CH production rate by 15.8%. Greater ( = 0.07) CH production rate tended to be observed in BI steers than in BT steers (21.4 vs. 16.6 MUmol CH.mL.h, respectively). Monensin had no effect ( >= 0.32) on pH, RAN, or rate of NH production. A subspecies * hour after feeding interaction was observed for RAN, with BT having greater RAN at h 0 and 4, whereas BI had greater RAN at h 2, 8, and 12. Overall, monensin decreased the acetate:propionate ratio and total VFA concentration but had no effect on forage utilization. steers consumed less digestible OM and had a greater CH production rate compared with BT steers, suggesting BT were better able to utilize the available forage resource than BI. PMID- 28727061 TI - Behavior of immunologically castrated barrows in comparison to gilts, physically castrated barrows, and intact male pigs. AB - The behavior of immunologically castrated barrows (IC; with Improvest; Zoetis, Parsippany, NJ) was compared with that of intact males (IM), physically castrated barrows (PC), and gilts (G). The study used 160 commercial crossbred pigs in a randomized complete block design (blocking factor was start date of study) and was performed over an 8-wk period from 16 wk of age (67.2 +/- 2.50 kg BW) to a final BW of 126.5 +/- 6.05 kg. The first Improvest dose was given to IC at the start of the study (d 0), and the second dose was given 28 d later. Pigs were housed in single-gender groups of 4 and had ad libitum access to feed and water. General, aggressive, and sexual behaviors were observed over a 12-h period from 0600 to 1800 h by the same trained investigators on d -1 (d prior to first dose), 13, 27 (day prior to second dose), 34, 41, and 55 of study (end of test). General behaviors (number of pigs lying, sitting, standing, at feeder, and at drinker) were recorded every 10 min in all pens (10 pens/gender), and aggressive (bites, head butts, and fights) and sexual (mounts) behaviors were recorded continuously over the 12-h period on a subsample of 4 pens/gender. There was no difference ( > 0.05) between the genders for lying, sitting, or drinker-related behavior. For the 4-wk period prior to second dose, a greater percentage of PC and G were at the feeder ( < 0.05) than IC or IM (8.0%, 7.4%, 10.2%, and 9.3% for IC, IM, PC, and G, respectively; SEM = 0.44). However, after the second dose, the percentage of pigs at the feeder was similar ( > 0.05) for IC, PC, and G and was greater ( < 0.05) for those genders than IM (10.1%, 7.1%, 10.0%, and 8.8%, respectively; SEM = 0.50). Prior to the second dose, the incidence of aggressive behaviors was generally greater for IC and IM compared with PC and G; however, after the second dose, the incidence of aggressive behaviors was similar for IC and PC and lower ( < 0.05) for those genders than for IM. The frequency of mounts for IC was greater ( < 0.05) than for PC before (25.5, 27.3, 2.5, and 1.5 total mounts/pen, respectively; SEM = 4.37) but not after ( > 0.05; 3.3, 33.3, 0.25, and 0.25 total mounts/pen, respectively; SEM = 1.15) the second dose. These results suggest that prior to the second Improvest dose, the behavior of IC was similar to that of IM and transitioned to become more similar to the behavior of PC after the second dose. PMID- 28727062 TI - Workload of official contests, net cost of transport, and metabolic power of Mangalarga Marchador horses of marcha batida or picada gaits. AB - This study aimed to characterize the maximum heart rate (HR) and the intensity of official marcha contests (OMC) and to compare the cost of transport (COT) and metabolic power (Pmet) of Mangalarga Marchador (MM) horses of marcha batida (MB) and marcha picada (MP) gaits. Twenty-two MM horses participated in this study. The experiment was conducted in 3 phases: 1) maximum effort test (MET), 2) OMC, and 3) standardized marcha test (SMT). To characterize the HR, 19 horses (14 MB and 5 MP) underwent a MET. Of those, 13 (9 MB and 4 MP) were monitored during the OMC, which consisted of 4 stages: marcha, walk, functional trial, and rest. The average heart rate (HR) in each stage of the OMC was related to the HR to determine their relative intensity. The SMT was performed with 14 horses (9 MB and 5 MP), of which 11 had already participated in the previous stages. The COT and Pmet were calculated from the HR values obtained during the SMT. Blood samples were collected to analyze plasma lactate concentration ([Lac]). One-way ANOVA or 1-way repeated-measures ANOVA followed by the Tukey's test ( < 0.05) were used to analyze the results. The average HR was 211 +/- 11 and 214 +/- 11 beats/min (bpm) for the MB and MP groups, respectively, with no difference ( = 0.7066) between them. The [Lac] increased as a result of the MET ( < 0.05), with no difference between groups ( > 0.05). This indicated that horses of both groups had the same physical fitness levels. The OMC stages defined in our study differed ( < 0.05) regarding the relative intensity of the HR, except for the walk and standing stages, which were similar ( = 0.0875). The MP group presented greater COT ( = 0.0247) and Pmet ( = 0.0193). It can be concluded that the mean HR of MM horses (MB and MP) is 212 +/- 11 bpm. The OMC of the MM breed can be characterized as an effort of intermittent and submaximal intensity. In addition, the locomotion of the MB horses is probably more energetically efficient than that of MP horses. PMID- 28727063 TI - Effect of dietary fiber and diet particle size on nutrient digestibility and gastrointestinal secretory function in growing pigs. AB - Reduction of diet particle size (PS) increases feed efficiency due to an increase in the apparent total tract (ATTD) of GE. However, other effects of PS on the gut secretory function are not known. Therefore, the objective of this experiment was to measure the effect of diet composition (DC) and PS on nutrient digestibility, gastrointestinal hormones, total bile acids (TBA), total cholesterol and glucose concentrations in plasma of finishing pigs ( = 8/diet). Pigs were fed finely (374 +/- 29 um) or coarsely (631 +/- 35 um) ground corn-soybean meal (CSB), CSB + 35% corn dried distillers' grains with solubles (DDGS), and CSB with 21% soybean hulls (SBH) diets for 49 d. Diet composition, nutrient digestibility, along with fasting plasma concentrations of gastrin, insulin, glucagon-like peptide-1 (GLP 1), glucose-dependent insulinotropic peptide (GIP), TBA, cholesterol, and glucose were measured. Fine ground diets had greater ( < 0.05) ATTD of GE as well as greater ( < 0.05) ME than coarse ground diets independent on the DC. Fine ground diets also had greater ( < 0.05) ATTD of DM, N, ether extract, and NDF, independent of DC. A decrease in PS also caused an increase ( < 0.05) in ATTD of N, K, and S, but it did not affect ATTD of Ca, P, or Na. The DC and PS affected plasma gastrin, insulin and TBA but not GIP, GLP-1, glucose, and cholesterol. Gastrin concentration was greater ( < 0.05) in pigs fed coarse DDGS compared with feeding coarse CSB and SBH diets. Insulin concentration of pigs fed CSB was greater ( < 0.01) in pigs fed fine compared with coarse DDGS, and was greater ( < 0.05) in coarse compared with fine SBH diets. Pigs fed DDGS had greater ( < 0.05) TBA than those fed SBH and fine CSB diets. Gastrin, insulin, TBA and cholesterol tended ( < 0.10), or correlated ( < 0.05) with P, K and Fe intake. Insulin, TBA, and cholesterol were correlated ( < 0.05) with Na and S intake. In conclusion, a decrease in diet PS increases the ATTD of nutrients independently of DC, while mineral intake affects gastrointestinal secretion of hormones with potential metabolic impacts. Plasma insulin and glucose concentrations were correlated with DM intake, and glucose was associated with lipid and protein intake. Diet energy, nutrient digestibility, and plasma gastrin, insulin and TBA concentrations were affected by DC and PS. PMID- 28727064 TI - Ileal starch digestibility of different cereal grains fed to growing pigs. AB - The objective of the present study was to determine, in growing pigs, the ileal starch digestibility and ileal digestible starch content of 8 different genotypes of barley, rye, triticale, and wheat each. Therefore, 4 experiments were conducted with 34 ileally cannulated growing pigs (initial BW of 24 to 32 kg) in total. The experimental diets were formulated to contain 1 of the 8 genotypes of each cereal grain at an inclusion level of 95%. Cereal grains were ground through a 2-mm sieve and were the sole dietary source of starch. All diets were supplemented with plant oil, minerals and vitamins, and titanium dioxide as an indigestible marker. The experiments were arranged either as a row-column design with 8 periods of 6 d each and 9 pigs (for barley and wheat) or according to an 8 * 8 Latin square design with 8 periods of 6 (rye) or 7 d (triticale) and 8 pigs. Experimental periods comprised 4 (barley, rye, and wheat) or 5 d (triticale) for adaptation followed by 2 d for ileal digesta collection. The daily feed intake amounted to 4% of pigs' average BW, corresponding to about 3 times the animals' energy requirement for maintenance (106 kcal of ME [as-fed basis]/kg of metabolic BW). Ileal starch digestibility was different ( < 0.05) within barley and triticale genotypes, with values ranging between 90.1 and 95.0% for barley and between 96.5 and 98.1% for triticale and tended to differ within rye genotypes ( < 0.1). Ileal digestible starch content was different ( < 0.05) within all cereal grains. On average, ileal starch digestibility amounted to 92.7, 95.0, 97.3, and 92.2% for barley, rye, triticale, and wheat, respectively, and was different among cereal grains ( < 0.001). Average ileal digestible starch content was greatest ( < 0.001) in triticale (68.3%, DM basis) followed by wheat (66.1%, DM basis), rye (61.1%, DM basis), and barley (57.6%, DM basis). Differences in ileal starch digestibility and ileal digestible starch content within and among grain genotypes may reflect variations in contents of several fiber fractions such as NDF, ADF, and nonstarch polysaccharides (NSP). For most cereal grains, ileal starch digestibility and ileal digestible starch content decreased ( < 0.05) with increasing contents of soluble, insoluble, and total NSP. In conclusion, in the present study, triticale is superior when compared with the other cereal grains due to its relatively low fiber and high starch content and its high ileal starch digestibility values. PMID- 28727065 TI - Effects of feeding camelina cake to weaned pigs on safety, growth performance, and fatty acid composition of pork. AB - Feeding cake with remaining oil contributes dietary energy (fat) in addition to protein (AA) and may provide an opportunity to enrich the n-3 fatty acid content of pork. Information regarding safety, growth performance, and efficacy of feeding camelina cake to pigs is limited. We therefore evaluated the effects of camelina cake inclusion in pig nursery diets. In total, 192 pigs (9.4 kg BW) were randomly allocated by sex to 48 pens, 2 heavy and 2 light pigs per pen. Pigs were fed 1 of 4 wheat-based diets including camelina cake (0%, 6%, 12%, or 18%; variety Celine) replacing soybean meal for 4 wk. Individual pigs, pen feed added, and orts were weighed weekly. Feces were collected on d 26 and 27. A blood sample was taken on d 29 from 24 pigs with the lowest BW/pen, which were then euthanized and necropsied. Gross pathological examination was conducted, and organ weights were measured. Samples of liver, back fat, belly fat, and jowl fat were collected for fatty acid analysis. Increasing dietary camelina cake inclusion linearly decreased ( 0.001) apparent total tract digestibility (ATTD) of DM, OM, GE and ash but did not affect ATTD of CP and P. For the entire trial (d 0 to 28), increasing camelina cake inclusion by 6% linearly decreased ( 0.001) ADFI by 74 g/d, ADG by 51 g/d, and BW by 0.8 kg but did not affect feed efficiency (G:F). Increasing camelina cake inclusion linearly increased ( 0.001) liver weight relative to BW, linearly decreased ( 0.050) kidney weight, but did not affect spleen, heart, and thyroid weights. Increasing camelina cake inclusion did not result in serological (large-animal standard panel, T3, and T4) or gross clinical (morphology) findings that might suggest toxicity. In liver, back fat, belly fat, and jowl fat, increasing dietary camelina cake inclusion linearly increased ( 0.050) total n-3 fatty acids and shorter-chain n-3 and n-6 fatty acids but did not increase docosahexaenoic acid (n-3) or arachidonic acid (n-6). In conclusion, feeding camelina cake to weaned pigs at up to 18% did not elicit clinical signs of toxicity and increased n-3 fatty acids in carcass fat depots. The decrease in ADFI as camelina cake inclusion increased resulted in pigs fed 18% weighing 5 kg less than controls at the end of the nursery period. PMID- 28727066 TI - Effect of replacing conventional soybean meal with low-oligosaccharide soybean meal on growth performance and carcass characteristics of wean-to-finish pigs1. AB - A trial was conducted to determine the effect of replacing conventional soybean meal (CSBM) with low-oligosaccharide soybean meal (LOSBM) on growth performance and carcass characteristics of wean-to-finish pigs. A total of 432 crossbred pigs (19 d and 6.6 +/- 1.2 kg BW) were blocked by sex and BW and assigned to 1 of 6 dietary treatments: 1) CSBM in all phases and fishmeal and spray-dried plasma protein (FM/SDPP) in phases 1 to 3, 2) CSBM in all phases but with no FM/SDPP, 3) LOSBM and FM/SDPP in phases 1 to 3 and CSBM in phases 4 to 6, 4) LOSBM in phases 1 to 3 and CSBM in phases 4 to 6, 5) LOSBM in phases 1 to 6 and FM/SDPP in phases 1 to 3, and 6) LOSBM in phases 1 to 6. The results showed that pig growth performance (ADG, ADFI, and G:F) during the overall period (phases 1 to 6) and carcass traits (HCW, dressing percentage, fat depth, loin depth, and lean percentage) were not affected ( > 0.05) by dietary treatments. Moreover, replacing CSBM with LOSBM in phases 1 to 3 did not affect early phase growth performance in the absence of FM/SDPP but reduced ( <= 0.05) ADFI and increased ( < 0.05) G:F during the nursery period (phases 1 and 2) in the presence of FM/SDPP. In phase 2, LOSBM increased ( < 0.05) blood urea nitrogen in comparison with CSBM. In conclusion, reduction of oligosaccharide by replacing CSBM with LOSBM in the early, late, or entire phase of the wean-to-finish period did not improve growth performance and carcass characteristics of pigs. PMID- 28727067 TI - Compositional mixed modeling of methane emissions and ruminal volatile fatty acids from individual cattle and multiple experiments. AB - The aim of the study was to investigate the association of methane (CH) yields (g/kg DMI) with rumen VFA molar proportions and animal and diet-related covariates from individual animals and multiple experiments. The dataset available consisted of 284 measurements of CH yields for beef cattle from 6 experiments measured in indirect respiration chambers. A compositional modeling approach was employed where VFA measurements were considered as a whole, instead of in isolation, emphasizing their multivariate relative scale. The analysis revealed expected close groupings of acetate and butyrate; propionate and valerate; iso-butyrate and iso-valerate. Linear mixed models were then fitted to examine relationships between CH yield and VFA, represented by meaningful log contrasts of components called compositional balances, while accounting for other animal and diet-related covariates and random variability between experiments. A compositional balance representing (acetate * butyrate)/propionate best explained the contribution of VFA to variation in CH yield. The covariates DMI, forage:concentrate proportion (expressed as a categorical variable diet type: high concentrate, mixed forage:concentrate or high forage), and diet ME were also statistically significant. These results provided new insights into the relative inter-relationships among VFA measurements and also between VFA and CH yield. In conclusion, VFA molar proportions as represented by compositional balances were a significant contributor to explaining variation in CH yields from individual cattle. PMID- 28727068 TI - The effects of molybdenum water concentration on feedlot performance, tissue mineral concentrations, and carcass quality of feedlot steers,. AB - Thirty cross-bred steers (initial BW 452.0 +/- 12.1 kg) were used to investigate the effects of Mo water concentration on performance, carcass characteristics, and mineral status of feedlot steers. The experimental design was a randomized complete block design. Steers were blocked by weight and then divided into 2 weight blocks each consisting of 15 steers. Steers were randomly assigned within block to one of 5 treatments (3 steers/treatment per block). Water treatments consisted of: 1) 0.0 ug/L, 2) 160 ug/L, 3) 320 ug/L, 4) 480 ug/L, and 5) 960 ug/L of supplemental Mo added as Na2MoO4 to the drinking water. Steers were housed in individual pens (steer = experimental unit) that contained individual 265 L water tanks for monitoring water intake. Steers were fed a growing diet for 28 d and then transitioned to a finishing diet. Block 1 steers were fed for a total of 151 d and block 2 steers were fed for a total of 112 d. Daily water intake was recorded for each steer. Steers were individually weighed on 2 consecutive days at the beginning and end of the experiment and interim weights and jugular blood samples were obtained every 28 d. Liver biopsies were obtained on d 0 and 84 from each steer within each block. Steers were transported to a commercial abattoir, slaughtered, and individual carcass data and liver samples were collected. Initial BW was used as a covariate for statistical analysis of data and significance was determined at P <= 0.05. No differences were observed for final BW (P > 0.98). Overall ADG (P > 0.91), DMI (P > 0.92), feed efficiency (P > 0.94), water intake (P > 0.40), hot carcass weight (P > 0.98), dressing percentage (P > 0.98), yield grade (P > 0.91), and marbling score (P > 0.29) did not differ across treatments. Lastly, no treatment differences were observed for liver concentrations of Cu (P > 0.93), Mo (P > 0.90) and Zn (P > 0.86) or plasma concentrations of Cu (P > 0.42), Mo (P > 0.43) and Zn (P > 0.62). These data indicate that water Mo concentration, within the range studied, had no impact on performance, mineral status, water intake, and carcass characteristics in feedlot steers. PMID- 28727069 TI - System dynamics modeling in designing breeding schemes: The case of Menz sheep in Ethiopian highlands. AB - A comprehensive dynamic simulation model was developed to describe a community based breeding program for the Menz sheep population of Ethiopia. Selection of male and female animals based on their own and maternal performance was simulated. The breeding goal traits were 6-mo weight, preweaning survival, and fertility rate. The model input data were obtained from the flock book, questionnaires, and references. The simulation model used a mix of deterministic and stochastic procedures to model the complex system. In the baseline scenario, the proportion of selected male and female animals varied between 20 and 30% and between 70 and 80%, respectively. A reasonable annual genetic gain was predicted for the breeding goal traits at the village level. For 6-mo weight and preweaning survival rate, the annual genetic gain varied from 0.213 to 0.214 kg and 0.255 to 0.256%, respectively. For fertility rate, an annual genetic gain of 0.063% was obtained. The predicted rate of inbreeding per year was between 0.094 and 0.116%. Furthermore, a scenario analysis was conducted by varying the proportions of selected animals. Annual genetic gains of 0.230 kg, 0.277%, and 0.069% were obtained for 6-mo weight, preweaning survival rate, and fertility rate, respectively, when the proportion of selected male and female animals decreased by 10%. The annual genetic gains decreased to 0.198 kg, 0.236%, and 0.059%, respectively, when the selection proportion of male and female animals increased by 10%. The lowest rate of inbreeding per year, ranging from 0.065 to 0.079%, was achieved when the selection proportion of selected male and female animals increased. The model is relevant for the step-by-step evaluation of more than one round of selection. It is flexible and usage driven. The model is a valuable tool to design different population structures and can be easily expanded to adopt different breeding strategies. Hence, the system dynamics modeling approach is a potential tool to describe complex breeding programs. PMID- 28727070 TI - Short-term heat stress causes altered intracellular signaling in oxidative skeletal muscle. AB - Heat stress (HS) causes morbidities and mortalities, in part by inducing organ specific injury and dysfunction. Further, HS markedly reduces farm animal productivity, and this is especially true for lean tissue accretion. The purpose of this investigation was to determine the extent to which short-term HS caused muscle dysfunction in skeletal muscle. We have previously found increased free radical injury in skeletal muscle following 24 h of HS. Thus, we hypothesized that HS would lead to apoptosis, autophagy, and decreased mitochondrial content in skeletal muscle. To test this hypothesis, crossbred gilts were divided into 3 groups ( = 8/group): thermal neutral (TN: 21 degrees C), HS (37 degrees C), and pair-fed thermal neutral (PFTN: feed intake matched with heat-stressed animals). Following 12 h of treatment, animals were euthanized and red (STR) and white (STW) portions of the semitendinosus were recovered. Heat stress did not alter intracellular signaling in STW. In STR, the oxidative stress marker malondialdehyde protein and concentration were increased in HS ( = 0.007) compared to TN and PFTN, which was matched by an inadequate antioxidant response, including an increase in superoxide dismutase (SOD) I ( = 0.03) and II relative protein abundance ( = 0.008) and total SOD activity ( = 0.02) but a reduction ( = 0.006) in catalase activity in HS compared to TN. Further, B-cell lymphoma 2 associated X protein ( = 0.02) and apoptotic protease activating factor 1 ( = 0.01) proteins were increased by HS compared to TN and PFTN. However, caspase 3 activity was similar between groups, indicating a lack of apoptotic execution. Despite increased initiation, autophagy appeared to be inhibited by HS as the microtubule-associated protein A/B light chain 3 II/I ratio and mitofusin-2 proteins were decreased ( < 0.03) and sequestosome 1(p62) protein abundance was increased ( = 0.001) in HS compared to TN and PFTN. Markers of mitochondrial content cytochrome c, cytochrome c oxidase IV, voltage-dependent anion channel, pyruvate dehydrogenase, and prohibitins 1 were increased ( < 0.05) in HS compared to TN, whereas mitochondrial biogenesis and mitophagy markers were similar between groups. These data demonstrate that HS caused aberrant intracellular signaling, which may contribute to HS-mediated muscle dysfunction. PMID- 28727071 TI - Feed efficiency phenotypes in lambs involve changes in ruminal, colonic, and small-intestine-located microbiota. AB - Several studies have revealed differences in rumen-located microbes between greatly efficient and inefficient animals; however, how the microbiota vary in the hind gastrointestinal tract (GIT) has only been sparsely explored and how they vary in the small intestine remains to be determined. We therefore sampled the microbiota of the duodenum, jejunum, ileum, colon, and colorectally-obtained feces, in addition to the rumen of 12 lambs that, in a residual feed intake trial, were found to be at either extreme of feed efficiency phenotypes. The 16S rRNA gene (V3-V4 region) profiles of all samples were analyzed and revealed unique microbiota in all GIT locations except the jejunum and ileum (ANOSIM > 0.2, < 0.001). Measures of beta-diversity revealed greater dissimilarity between more anatomically distant GIT locations (e.g., Rumen-Duodenum, ANOSIM = 0.365, < 0.001; Rumen-Colon, ANOSIM = 1, < 0.001) with the nearest distal region typically more similar than the nearest proximal location. The relative abundances of 13 operational taxonomic units (OTUs) from the duodenum, jejunum, colon, and feces, as well as the rumen, differed between efficient and inefficient animals (Bonferroni corrected, < 0.05), while another 2 OTUs trended toward significance. These OTUs were classified as taxa with known roles in fibrolysis (Fibrobacteres, Ruminococcaceae, and Saccharofermentans) and others that are commonly associated with health (Bifidobacteriaceae, and Christensenellaceae) and dysbiosis (Proteobacteria). Our findings show biospatial delineations of microbiota throughout the GIT and suggest that feed efficiency extends beyond the rumen, transcending these regions, and involves increases in both rumen- and colon located fibrolytic taxa, increases in bifidobacterial species in the small intestine, and reductions in small intestine and distal GIT-located Proteobacteria. PMID- 28727072 TI - The equine glucose-dependent insulinotropic polypeptide receptor: A potential therapeutic target for insulin dysregulation. AB - Metabolic disease is a significant problem that causes a range of species specific comorbidities. Recently, a better understanding of glucose-dependent insulinotropic polypeptide (GIP) biology has led to the suggestion that inhibiting its action may attenuate obesity in several species. In horses, antagonism of GIP may also reduce hyperinsulinemia, which leads to insulin associated laminitis, a painful comorbidity unique to this species. However, little is known about GIP in horses. The aims of this study were to examine the tissue distribution of equine GIP receptors (eGIPR), to determine whether eGIPR can be blocked using a GIP antagonist not tested previously in horses, and to establish whether there is any association between GIP concentrations and body mass in this species. Archived tissues from healthy horses were used to establish that eGIPR gene expression was strong in pancreas, heart, liver, kidney, and duodenum and absent in gluteal muscle. Pancreatic islets were isolated from fresh horse pancreas using collagenase digestion and layering through a density gradient. Islet viability was confirmed microscopically and by demonstrating that insulin production was stimulated by glucose in a concentration-dependent manner. Insulin release was also shown to be concentration-dependent with GIP up to 0.1uM, and the response to GIP was decreased ( = 0.037) by the antagonist (Pro3)GIP. As for the relationship between body mass and GIP in vivo postprandial GIP concentrations in archived plasma samples were positively correlated with body condition and cresty neck scores ( < 0.05). Thus, the eGIPR is a potential therapeutic target for insulin dysregulation and obesity in horses. PMID- 28727073 TI - Technical note: valuation of an enteric methane emissions measurement system for cattle. AB - Through the process of enteric fermentation, cattle produce methane (CH), a potent greenhouse gas (GHG). Growing public concern about climate change has increased the need for accurate methods of measuring CH emissions from cattle directly to improve emission inventories and evaluate emissions mitigation techniques. The present study evaluated a ventilated head box system capable of measuring CH and carbon dioxide (CO) emissions, and oxygen (O) consumption from cattle. Six Holstein heifers were used to measure CH and CO emissions and O consumption from 2 ad libitum intake measurement periods (ADAPT and ADLIB) and 1 measurement period (RESTRICT) with intake restricted to 2% of BW on a DM basis. Methane emissions during RESTRICT were significantly lower ( < 0.0001) than both ad libitum periods. Daily CH4 emission rates per animal were 235.0 +/- 6.19 L/d, 228.3 +/- 6.18 L/d, and 193.2 +/- 8.88 L/d for the periods ADAPT, ADLIB, and RESTRICT, respectively. Carbon dioxide emission rates were 3627 +/- 90.72 L/d, 3632 +/- 90.47, and 3184 +/- 104.79 L/d for the ADAPT, ADLIB, and RESTRICT periods, respectively. Oxygen consumption rates were 3391 +/- 99.77 L/d, 3454 +/- 99.57 L/d, and 3002 +/- 111.36 L/d for the periods ADAPT, ADLIB, and RESTRICT, respectively. The head box system evaluated provides an accurate method of measuring emissions from cattle and can provide information about daily variations and peaks in emissions. PMID- 28727075 TI - Amino acid digestibility by weanling pigs of processed ingredients originating from soybeans, 00-rapeseeds, or a fermented mixture of plant ingredients. AB - An experiment was conducted to determine the apparent ileal digestibility (AID) and the standardized ileal digestibility (SID) of CP and AA in 4 sources of processed soybean products, in conventional dehulled soybean meal (SBM-CV), in conventional 00-rapeseed expellers (RSE), and in a fermented coproduct mixture (FCM) that contained rapeseed meal, wheat, soy molasses, and potato peel fed to weanling pigs. The 4 processed soybean products included 2 sources of enzyme treated soybean meal (ESBM-1 and ESBM-2), extruded soybean meal, and soy protein concentrate (SPC). Twenty-seven weanling barrows (9.29 +/- 0.58 kg initial BW) were surgically equipped with a T-cannula in the distal ileum. Pigs were randomly allotted to three 9 * 5 Youden squares with 9 pigs and five 7-d periods in each square. Seven cornstarch-based diets were prepared using each of the protein sources as the sole source of CP and AA. A N-free diet was prepared to calculate basal endogenous losses of CP and AA, and this diet was fed to 2 groups of pigs, which resulted in a total of 9 dietary treatments. Results indicate that the SID of CP was greater ( < 0.05) in ESBM-1 than in SPC, RSE, or FCM. The SID of Arg, His, Ile, Leu, Met, and Phe were greater ( < 0.05) in ESBM-1 than in SPC, and the SID of Lys was greater ( < 0.05) in SBM-CV than in ESBM-2. The SID of Thr, Trp, Val, and total indispensable AA were not different among the soybean products, but the SID of total dispensable AA in ESBM-1 was greater ( < 0.05) than in SPC. Therefore, the SID of total AA was greater ( < 0.05) in ESBM-1 than in SPC, but no other differences were observed among soybean meal (SBM) products. The SID of most AA in RSE and the SID of all AA in FCM were less ( < 0.05) than in all the SBM products, but the SID of all AA in RSE were greater ( < 0.05) than in FCM. Results of this research indicate that although processing of SBM results in increased concentration of CP, processing may also reduce the digestibility of AA, which is likely due to heat damage during processing. There are, however, differences among processed soy products, with some products having greater SID of AA than others. Results also indicate that fermentation of a mixture of rapeseed meal, wheat, and relatively low quality coproducts does not result in SID values that are similar to those of unfermented 00-rapeseed expellers or soybean products. PMID- 28727076 TI - Effect of post-ethanol extraction sorghum silage as a forage source in growing and finishing diets on steer performance, carcass characteristics, and nutrient digestibility. AB - Two experiments evaluated the use of post-ethanol extraction sorghum silage as an alternative forage source in feedlot diets. Seventy-two crossbred steers (397 kg [SD 23]) were used to evaluate growth and carcass characteristics. Steers were blocked by BW into pens of 6 steers and randomly assigned to growing diets containing 40% (DM basis) sorghum silage (SS; 57.6% NDF) or grass hay (CON; 63.3% NDF) for 56 d ( = 6 pens per treatment). Within each treatment, steers transitioned to dry-rolled corn-based finishing diets (fed for 56 d) containing 6% effective NDF contributed by the forage source, resulting in forage inclusions of 16% for SS and 13.1% for CON, where forage replaced corn. A subsample of steers ( = 12 per treatment) housed in pens equipped with GrowSafe bunks were used for determination of growing phase diet total tract digestibility. From d 28 to 42, steers received titanium dioxide at approximately 10 g?steer?d, and fecal samples were collected on d 41 and 42. Fecal and total mixed ration samples were dried and ground for analysis of DM, OM, NDF, ADF, CP, ether extract (EE), and starch. Data were analyzed with the MIXED procedure of SAS, with fixed effects of treatment and block for performance and carcass data or treatment for digestibility data; significance was determined at <= 0.05 and tendencies at <= 0.10. Growing phase DMI and ADG did not differ due to treatment ( >= 0.19); however, SS-fed steers had improved G:F compared with CON-fed steers ( = 0.04). Finishing period ADG and G:F did not differ ( >= 0.15) between treatments, despite SS-fed steers having lesser ( = 0.008) DMI than CON-fed steers. No differences in DMI, ADG, or G:F over the whole trial were noted between treatments ( >= 0.12) nor were any carcass traits affected ( >= 0.23). During the digestibility assessment period, DMI was less ( = 0.003) in SS-fed steers. Growing phase total tract apparent digestibility of DM and starch did not differ ( >= 0.19) due to treatment; however, OM digestibility tended to be greater ( = 0.09) in SS-fed steers. Steers fed SS had greater ( <= 0.03) digestibility of EE, CP, NDF, and hemicellulose than CON-fed steers. However, CON-fed steers had greater ( < 0.0001) ADF digestibility than SS-fed steers. These data suggest that postextraction sorghum silage can be effectively used in feedlot diets as an alternative forage source. PMID- 28727077 TI - Excess of dietary montmorillonite impairs growth performance, liver function, and antioxidant capacity in starter pigs. AB - Montmorillonite (MMT) is widely used as a mycotoxin adsorbent in animal feeds, but its safety remains unclear. This study was conducted to investigate the safety of MMT supplementation in diets fed to starter pigs. A total of 120 32-d old piglets (initial weight, 8.0 +/- 0.9 kg) were randomly allotted into dietary treatments with graded MMT levels (0 [FS 0], 0.5% [FS 0.5], 1.0% [FS 1.0], 2.5% [FS 2.5], and 5.0% [FS 5.0]) with 6 replicate pens per treatment and 4 pigs per pen. All diets were fed for 28 d. As the MMT level increased, ADG and G:F changed in a linear and quadratic manner, while ADFI was linearly decreased ( > 0.05). Compared with FS 0, ADG, ADFI, and G:F of pigs in FS 1.0 increased ( < 0.05). However, the ADFI in pigs of FS 5.0 was lower than that in pigs of FS 0 ( < 0.05). The relative liver weight activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) changed in a linear and quadratic manner ( < 0.05). Compared with FS 0, pigs in FS 2.5 and FS 5.0 had a greater serum ALT ( < 0.05), while AST activity significantly increased in pigs of FS 5.0 ( < 0.05). Dietary MMT supplementation decreased serum Mg content in a linear and quadratic manner ( < 0.05), while Zn and Cu contents were linearly decreased ( < 0.05). Serum Zn and Cu contents of pigs in FS 0.5, FS 2.5, and FS 5.0 groups were lower than those in the control. Pigs fed with 2.5% and 5% MMT showed hepatic histopathological changes, including swelling, granular and vesicular degeneration, and apparent vacuolar degeneration. In addition, the content of serum total antioxidant capacity (T-AOC) and activity of glutathione peroxidase (GSH-PX) decreased in a linear and quadratic manner ( < 0.05). Compared to the control, 5.0% MMT significantly increased piglets' serum malondialdehyde (MDA) concentration and decreased GSH-PX activity ( < 0.05). T-AOC concentration in the pigs fed 2.5% and 5.0% MMT was lower than that in the control group ( < 0.05). Serum superoxide dismutase (SOD) activity changed in a quadratic manner ( < 0.05). Piglets in FS 1.0 showed a higher SOD activity when compared with the control ( < 0.05). These results indicate that supplementation of MMT higher than 1.0% can negatively affect liver structure and serum mineral content, and 5.0% MMT supplementation would also decrease feed intake, aggravate liver damage, and reduce the antioxidant capacity of starter pigs. Therefore, excess supplementation of MMT is not safe in starter pigs. PMID- 28727078 TI - Flaxseed meal and oat hulls supplementation modulates growth performance, blood lipids, intestinal fermentation, bile acids, and neutral sterols in growing pigs fed corn-soybean meal-based diets. AB - The present study was conducted to determine the effect of flaxseed meal and oat hulls supplementation on growth performance, apparent total tract digestibility (ATTD) of fat, serum lipids, and concentrations of VFA, bile acids (BA), and neutral sterols (NS) in digesta and feces in growing pigs. Forty-eight Genesus [(Duroc boar * Yorkshire-Landrace sows] barrows (25.0 +/- 0.32 kg initial BW) were housed in pairs. Pigs were assigned to 1 of the 3 corn-soybean meal-based diets-a basal corn-soybean meal-containing diet (control), a flaxseed meal containing diet (FM), or an oat hulls-containing diet (OH)-in a completely randomized design. All diets were formulated to be isoenergetic and to contain similar standardized ileal digestible AA contents and meet other nutrient requirements for growing pigs. The experiment lasted for 28 d. Average daily feed intake; ADG; G:F; ATTD of fat, serum lipids, and digesta; and fecal VFA, BA, and NS concentrations were determined. Pigs fed the control or OH had greater final BW ( < 0.001), ADFI ( = 0.005), and ADG ( < 0.001) than FM-fed pigs. The ATTD of fat in the FM was lowest at 70.1% followed by 79.2% in OH and was greatest at 92.4% in the control ( = 0.020). Total serum cholesterol content was 2.25 and 1.99 mmol/L and lower ( < 0.001) in pigs fed FM and OH, respectively, than the 2.36 mmol/L in pigs fed the control. Pigs fed the FM and OH had greater ileal and cecal total VFA ( < 0.001), ileal deoxycholic acid ( < 0.01), and cecal ( < 0.001) and fecal cholesterol ( = 0.002) concentrations than those fed the control. Pigs fed the FM excreted more fecal lithocholic acid ( = 0.002) and ursodeoxycholic acid ( = 0.001) compared with those that consumed the control and OH. The concentrations of coprostanol in cecal digesta ( < 0.001) and feces ( = 0.011) were higher in pigs fed the FM and OH than in pigs fed the control. In conclusion, feeding flaxseed meal and oat hulls induced intestinal fermentation; however, the former depressed growth performance whereas the latter did not have any effect. Addition of flaxseed meal and oat hulls in growing pig diets reduced fat digestibility and serum cholesterol and stimulated malabsorption of primary BA and excretion of secondary BA and NS. PMID- 28727079 TI - Detection of dietary DNA, protein, and glyphosate in meat, milk, and eggs. AB - Products such as meat, milk, and eggs from animals that have consumed genetically engineered (GE) feed are not currently subject to mandatory GE labeling requirements. Some voluntary "non-genetically modified organism" labeling has been associated with such products, indicating that the animals were not fed GE crops, as there are no commercialized GE food animals. This review summarizes the available scientific literature on the detection of dietary DNA and protein in animal products and briefly discusses the implications of mandatory GE labeling for products from animals that have consumed GE feed. Because glyphosate is used on some GE crops, the available studies on glyphosate residues in animal products are also reviewed. In GE crops, recombinant DNA (rDNA) makes up a small percentage of the plant's total DNA. The final amount of DNA in food/feed depends on many factors including the variable number and density of cells in the edible parts, the DNA-containing matrix, environmental conditions, and the specific transgenic event. Processing treatments and animals' digestive systems degrade DNA into small fragments. Available reports conclude that endogenous DNA and rDNA are processed in exactly the same way in the gastrointestinal tract and that they account for a very small proportion of food intake by weight. Small pieces of high copy number endogenous plant genes have occasionally been detected in meat and milk. Similarly sized pieces of rDNA have also been identified in meat, primarily fish, although detection is inconsistent. Dietary rDNA fragments have not been detected in chicken or quail eggs or in fresh milk from cows or goats. Collectively, studies have failed to identify full-length endogenous or rDNA transcripts or recombinant proteins in meat, milk, or eggs. Similarly, because mammals do not bioaccumulate glyphosate and it is rapidly excreted, negligible levels of glyphosate in cattle, pig and poultry meat, milk, and eggs have been reported. Despite consumer concern about the presence of trace concentrations of glyphosate that might have been applied to feed crops and/or the presence of rDNA or recombinant proteins in meat, milk, and eggs, the available data do not provide evidence to suggest that products from animals that have consumed approved GE feed crops differ in any distinguishable way from those derived from animals fed conventional feed or that products from animals fed GE feedstuffs pose novel health risks. PMID- 28727081 TI - Comparative Gut Physiology Symposium: The Microbe-Gut-Brain Axis. PMID- 28727080 TI - Management of native warm-season grasses for beef cattle and biomass production in the Mid-South USA. AB - Native grasses, such as switchgrass (SG; L.), big bluestem (BB; Vitman), indiangrass (IG; Nash), and eastern gamagrass (EG; [L.] L.) may be capable of providing desirable summer forage for cattle as well as a source of biomass for renewable energy. To evaluate that potential, experiments were conducted at 2 locations in Tennessee comparing weaned beef () steers (268 +/- 25 kg initial BW) during early-season grazing (Early; 30 d, typically corresponding to May, followed by postdormancy biomass harvest) and full-season grazing (Full, mean duration = 98 d). For Exp. 1, which compared SG, a blend of BB and IG (BBIG), and EG, ADG was greater ( < 0.05) for BBIG (1.02 kg/d) than SG (0.85 kg/d), and both were greater ( < 0.05) than EG (0.66 kg/d). Grazing days for SG and EG were similar (389 and 423 animal unit days [AUD]/ha, respectively) and exceeded ( < 0.05) that of BBIG (233 AUD/ha) during Full. In Exp. 2 (SG and BBIG only), rates of gain were comparable to that of Exp. 1, but AUD were 425 (SG) and 299 (BBIG) AUD/ha. Such rates of gain and grazing days indicate that these grasses can provide desirable summer forage for growing cattle. Early produced 211 to 324 kg BW gain/ha, depending on experiment and forage, followed by dormant-season harvests of 7.5 to 10.5 Mg/ha of biomass, indicating a potential for beef cattle forage and biomass production on the same land resource. Native grasses provided productive summer pasture and good rates of gain on growing cattle and could contribute to forage programs, especially where cool-season grasses currently predominate. PMID- 28727082 TI - Comparison of amino acid digestibility in full-fat soybean, two soybean meals, and peanut flour between broiler chickens and growing pigs. AB - The aim of this study was to determine the apparent ileal digestibility (AID) and the standardized ileal digestibility (SID) of CP and AA in full-fat soybean (FFSB), solvent-extracted soybean meal containing 430 g/kg CP (SBM-43), solvent extracted soybean meal containing 470 g/kg CP (SBM-47), and peanut flour (PNF) fed to broiler chickens and pigs and to compare the digestibility of CP and AA between broiler chickens and pigs. Four diets were prepared to contain FFSB, SBM 43, SBM-47, and PNF as the sole source of N. A N-free diet was formulated to estimate the basal ileal endogenous losses of CP and AA for broiler chickens and pigs. In Exp. 1, a total of four hundred sixteen 21-d-old male broiler chickens (922.1 +/- 79.9 g initial BW) were assigned to 5 experimental diets in a randomized complete block design with BW as a blocking factor. After 5 d of adaptation, ileal digesta samples were collected after birds were euthanized by CO asphyxiation. In Exp. 2, twenty barrows (62.0 +/- 6.9 kg initial BW) surgically fitted with T-cannulas at the distal ileum were allotted to 5 experimental diets with 2 consecutive 7-d experimental periods. After 5 d of adaptation, ileal digesta samples were collected at d 6 and 7. For statistical analysis, treatments were considered a 2 * 4 factorial arrangement with effects of species and experimental diets (Exp. 1 vs. Exp. 2). There were no interactions between species and diets for the digestibility of CP and AA except for Cys ( < 0.01). The AID of CP and indispensable AA in pigs were greater ( < 0.01) than in broiler chickens. In both broiler chickens and pigs, the AID of CP and indispensable AA in SBM-47 were greater ( < 0.05) than in FFSB, and the AID of Lys in PNF was the least ( < 0.05) among ingredients. The SID of CP and indispensable AA in pigs were greater ( < 0.05) than in broiler chickens except for Trp. In both broiler chickens and pigs, the SID of Lys in PNF was the least ( < 0.05) among ingredients. In broiler chickens, the SID of CP, Ile, Leu, Thr, Trp, and Val in FFSB were less ( < 0.05) than that in SBM-43, SBM-47, and PNF. In pigs, the SID of Arg, Ile, Leu, Met, Phe, and Val in FFSB were less ( < 0.05) than in SBM-43, SBM-47, and PNF. In conclusion, the digestibility of CP and most AA were less in broiler chickens than in pigs, but the pattern of differences in the AA digestibility among ingredients was similar between broiler chickens and pigs. PMID- 28727083 TI - Influence of feed efficiency classification and growing and finishing diet type on meat tenderness attributes of beef steers. AB - Enhancing feed efficiency (FE) in cattle continues to be an important goal in the beef industry. Previous research suggests improving FE may alter calpain system activity, potentially having negative effects on meat tenderness. The objective of this study was to assess the potential influence of beef cattle FE on postmortem meat tenderness. During the growing phase, 181 crossbred steers were fed for 76 d at the University of Missouri on a whole shell corn-based diet (MU Corn; = 90) or a roughage-based diet (MU-Rough; = 91). Within diet, steers were classified for FE based on residual feed intake (RFI) calculations. Within each growing phase diet, the 12 most feed efficient (HFE; average RFI -3.33 +/- 0.77) and 12 least feed efficient (LFE; average RFI 2.90 +/- 0.94) steers (48 steers total) were selected and shipped to Iowa State University for the finishing phase. Steers were fed in pens with GrowSafe bunks and equally assigned to a cracked corn-based finishing diet (ISU-Corn) or a byproduct-based finishing diet (ISU-Byp) for the 87-d finishing phase. After a 24-h chill, rib sections were collected from all carcasses and aged for 2 or 14 d prior to analysis of calpastatin activity and calpain 1 autolysis (d 2), troponin-T degradation (d 2 and 14), proximate composition (d 2), and Warner-Bratzler shear force (WBSF; d 14). Data were analyzed as a 2 * 2 * 2 factorial, with steer or steak as the experimental unit ( = 6 per treatment combination). There were no 3- or 2-way interactions ( >= 0.12) noted for any data, with the exception of steak lipid content, which tended ( = 0.08) to be affected by FE * Iowa State University diet. Steaks from LFE steers had greater lipid content compared with steaks from HFE steers within ISU-Byp, with no differences due to FE within ISU-Corn. Growing diet did not affect calpastatin activity, calpain 1 autolysis, or troponin T degradation ( >= 0.12); however, MU-Rough had greater WBSF than MU-Corn ( = 0.05). Day-2 calpastatin activity tended ( = 0.10) to be greater in steaks from HFE vs. LFE steers, although no differences due to FE classification were observed for calpain 1 protein, troponin-T degradation, or WBSF ( >= 0.13). Finishing diet did not affect calpastatin activity, calpain 1 autolysis, d-2 troponin-T degradation, or WBSF ( >= 0.24); however, d-14 troponin-T degradation was greater in ISU-Corn than in ISU-Byp ( = 0.005). In this study, using phenotypic extremes for FE revealed a tendency for greater calpastatin activity only in highly feed-efficient steers; however, these data indicate that high fiber diets may negatively impact meat tenderness, and further work is needed to clarify the influence of diet type on parameters of meat tenderness. PMID- 28727084 TI - Feed efficiency metrics in growing pigs. AB - The objective of the present study was to quantify the interrelationships between different feed efficiency measures in growing pigs and characterize pigs divergent for a selection of these measures. The data set included data from 311 growing pigs between 42 and 91 d of age from 3 separate batches. Growth-related metrics available included midtest metabolic BW (BW), energy intake (EI), and ADG. Ratio efficiency traits included energy conversion ratio (ECR), Kleiber ratio (ADG/BW), relative growth rate (RGR), residual EI (REI), and residual daily gain (RDG). Residual intake and gain (RIG; i.e., a dual index of both REI and RDG) and residual midtest metabolic weight (RMW) were also calculated. Simple Pearson correlations were estimated between the growth and feed efficiency metrics. In litters with at least 3 pigs of each sex, pigs were separately stratified on each residual trait as high, medium, and low rank. Considerable interanimal variability existed in all metrics evaluated. Male pigs were superior to females for all metrics ( < 0.001) except for both BW and EI, where no sex differences were evident. Feed efficiency metrics improved as birth BW increased ( < 0.05) except for RGR, where the contrary was observed. Correlations between most growth and feed efficiency metrics were strong to moderate ( < 0.05). Low REI pigs (i.e., more efficient) had lower EI and ECR and were superior for RIG ( < 0.001) compared with high- and medium-REI pigs. High-RDG pigs (i.e., more efficient) had greater BW gain and better ECR ( < 0.001) compared with medium- and low-RDG pigs. Residual EI and RIG were both superior ( < 0.001) in high-RDG pigs compared with medium- and low-RDG pigs. Energy conversion ratio, REI, and RIG were superior ( < 0.05) in high-RMW pigs (i.e., more efficient) compared with medium-RMW pigs. High-RIG pigs (i.e., more efficient) had lower EI ( < 0.01) and superior ECR for RDG and REI compared with medium- and low-RIG pigs. In general, most of the correlations among the feed efficiency traits investigated in this study were different from unity, indicating that each trait is depicting a different aspect of efficiency in pigs, although the moderate to strong correlations suggest that improvement in one trait would, on average, lead to improvements in the others. Pigs ranked as more efficient on residual traits such as REI consumed less energy for a similar BW gain, which would translate into an economic benefit for pig producers. PMID- 28727086 TI - 2017 ASAS Scholastic Achievement Awards. PMID- 28727085 TI - Impact of microbial efficiency to predict MP supply when estimating protein requirements of growing beef cattle from performance. AB - Data from 16 trials were compiled to calculate microbial CP (MCP) production and MP requirements of growing cattle on high-forage diets. All cattle were individually fed diets with 28% to 72% corn cobs in addition to either alfalfa, corn silage, or sorghum silage at 18% to 60% of the diet (DM basis). The remainder of the diet consisted of protein supplement. Source of protein within the supplement varied and included urea, blood meal, corn gluten meal, dry distillers grains, feather meal, meat and bone meal, poultry by-product meal, soybean meal, and wet distillers grains. All trials included a urea-only treatment. Intake of all cattle within an experiment was held constant, as a percentage of BW, established by the urea-supplemented group. In each trial the base diet (forage and urea supplement) was MP deficient. Treatments consisted of increasing amounts of test protein replacing the urea supplement. As protein in the diet increased, ADG plateaued. Among experiments, ADG ranged from 0.11 to 0.73 kg. Three methods of calculating microbial efficiency were used to determine MP supply. Gain was then regressed against calculated MP supply to determine MP requirement for maintenance and gain. Method 1 (based on a constant 13% microbial efficiency as used by the beef NRC model) predicted an MP maintenance requirement of 3.8 g/kg BW and 385 g MP/kg gain. Method 2 calculated microbial efficiency using low-quality forage diets and predicted MP requirements of 3.2 g/kg BW for maintenance and 448 g/kg for gain. Method 3 (based on an equation predicting MCP yield from TDN intake, proposed by the Beef Cattle Nutrient Requirements Model [BCNRM]) predicted MP requirements of 3.1 g/kg BW for maintenance and 342 g/kg for gain. The factorial method of calculating MP maintenance requirements accounts for scurf, endogenous urinary, and metabolic fecal protein losses and averaged 4.2 g/kg BW. Cattle performance data demonstrate formulating diets to meet the beef NRC model recommended MP maintenance requirement (3.8 g/kg S) works well when using 13% microbial efficiency. Therefore, a change in how microbial efficiency is calculated necessitates a change in the proposed MP maintenance requirement to not oversupply or undersupply RUP. Using the 2016 BCNRM to predict MCP production and formulate diets to meet MP requirements also requires changing the MP maintenance requirement to 3.1 g/kg BW. PMID- 28727087 TI - Effects of zilpaterol hydrochloride on methane production, total body oxygen consumption, and blood metabolites in finishing beef steers. AB - An indirect calorimetry experiment was conducted to determine the effects of feeding zilpaterol hydrochloride (ZH) for 20 d on total body oxygen consumption, respiratory quotient, methane production, and blood metabolites in finishing beef steers. Sixteen Angus steers (initial BW = 555 +/- 12.7 kg) were individually fed at ad libitum intake and used in a completely randomized design. The model included the fixed effects of dietary treatment, day, and treatment * day. Dry matter intake did not differ between the treatments ( = 0.89), but was greater on d 0 than any other day ( < 0.01). Oxygen consumption was not different between treatments ( = 0.79), but was different across day ( < 0.01) on d 7, 14, 21, and 28. Respiratory quotient was less for cattle fed ZH than control ( < 0.01), and also different across day ( < 0.01), being greater on d 7, 21, and 28 than d 3 or 21. Methane production (L/kg of DMI) was greater for steers fed the control vs. the ZH diet ( < 0.01), and it also differed by day ( < 0.01), being greater on d 21 and 28 than d 0, 3, 7, and 14. Nonesterified fatty acids were not different across treatments ( = 0.82), and there was no effect of treatment on beta hydroxybutyrate concentration ( = 0.45). Whole blood glucose concentrations were not affected by feeding ZH in this experiment ( = 0.76); however, lactate concentrations were reduced by feeding ZH ( = 0.03). Additionally, there was no treatment effect on alpha-amino-N, blood glutamate, or glutamine ( >= 0.16). Plasma NH was not affected by ZH ( = 0.07), but plasma urea nitrogen was reduced by ZH ( < 0.01). Urinary creatinine was increased by steers receiving ZH ( = 0.01), and urine 3-methylhistidine (3-MH) concentrations were normalized to creatinine, the 3-MH:creatinine ratio decreased from d 0 to d 3 in steers fed ZH, and remained less than control steers until d 28. These data provide insight into how beta-agonists alter nutrient partitioning and improve the efficiency of tissue accretion, mainly through decreased muscle protein turnover and altering the catabolic fuel for peripheral tissues. PMID- 28727088 TI - Ultraviolet irradiation of spray-dried porcine plasma does not affect the growth performance of nursery pigs when compared with nonirradiated bovine plasma. AB - Ultraviolet light irradiation of spray-dried porcine plasma (SDPP) decreases the risk of disease transmission, but it may decrease the activity of bioactive components in SDPP. Therefore, the objectives of this study were to determine growth performance, morbidity, and mortality responses of nursery pigs fed UV irradiated SDPP (UV-SDPP) compared with nonirradiated spray-dried bovine plasma (SDBP). Pigs ( = 480; 6.09 +/- 2.4 kg initial BW) were blocked by initial BW, and blocks were assigned to pens. the sex ratio was equalized within blocks and pens. Pens were randomly assigned to 1 of 5 dietary treatments (8 pigs/pen and 12 replicates/treatment) in a 3-phase feeding program (phase 1 = d 0 to 13, phase 2 = d 14 to 27, and phase 3 = d 28 to 55). Dietary treatments included a control diet without UV-SDPP or SDBP and diets containing 3% UV-SDPP, 3% SDBP, 6% UV SDPP, or 6% SDBP during phase 1. Diets were formulated to meet or exceed nutrient requirements and contained the same concentrations of standardized ileal digestible Lys and Lys:ME ratio within phases. Pigs were provided ad libitum access to diets throughout the 55-d experiment. Dietary inclusion rates during phase 2 were reduced to 1.5% UV-SDPP, 1.5% SDBP, 3% UV-SDPP, and 3% SDBP, and all pigs were fed a common diet without UV-SDPP or SDBP during phase 3. Growth performance data were analyzed as a 2 * 2 factorial arrangement of treatments with a control within a completely randomized block design to evaluate the main effects of plasma processing (UV irradiated vs. nonirradiated) and dietary inclusion level, and block, room, and pen were random effects. In phase 1, there were no differences in G:F among treatments, but pigs fed 6% UV-SDPP and 6% SDBP had greater ( < 0.01) ADG (0.11 vs. 0.08 kg/d) and ADFI (0.17 vs. 0.15 kg/d) than pigs fed the control, 3% SDBP, and 3% UV-SDPP diets. After phase 1 (d13), feeding UV-SDPP or SDBP increased ( = 0.02) the BW of pigs. In phases 2 and 3 and the overall feeding period (d 0 to 55), there were no differences in ADG, ADFI, and G:F among dietary treatments. There was a linear decrease ( < 0.01) in mortality of nursery pigs as dietary inclusion rate of SDBP and UV-SDPP increased. In conclusion, feeding SDBP or UV-SDPP diets improved ADG and ADFI during the first 2 wk after weaning due to improved feed consumption, and UV irradiation appeared to have no detrimental effects on the feeding value of SDPP. PMID- 28727089 TI - The use of oxidative stress biomarkers in live animals (in vivo) to predict meat quality deterioration postmortem (in vitro) caused by changes in muscle biochemical components. AB - This study was conducted to determine whether circulating concentrations of blood isoprostanes can be used as an effective biomarker in lambs to predict degradation of color and/or lipid stability in meat. Lambs ( = 84) were fed diets of either lucerne pasture, annual ryegrass pasture, a commercial feedlot pellet, or a combination of annual ryegrass and feedlot pellet for 8 wk, including a 2-wk adaptation period. Blood isoprostane concentration at wk 0, 4, 6 or 8 of feeding was determined. Blood isoprostane concentration for each animal was then correlated with muscle biochemical components that impact color and/or lipid oxidative status during retail display. This included lipid oxidation levels in muscle assessed by thiobarbituric acid reactive substances and meat redness determined by a HunterLab colorimetric spectrometer. Lambs that consumed the commercial feedlot pellet had a lower muscle vitamin E level (< 0.01) and a greater level of -6 PUFA ( < 0.001) compared with lambs finished on annual ryegrass or lucerne. Lipid oxidation levels were greatest for lambs finished on the feedlot ration, lowest in lambs finished on the ryegrass diet, and intermediate for lambs finished on lucerne and ryegrass-feedlot combination ( < 0.01). After 8 wk of feeding, blood isoprostane concentration was positively correlated with lipid oxidation of meat displayed for 72 h in simulated retail conditions ( < 0.01). There was a negative linear relationship between isoprostane concentration and muscle vitamin E concentration ( = 0.07), lipid oxidation and muscle vitamin E concentration ( < 0.01) but a positive linear relationship between isoprostane concentration and muscle -6 PUFA ( < 0.001) or lipid oxidation and muscle -6 PUFA concentration ( < 0.001). Blood isoprostane concentration and lipid oxidation in meat were influenced by muscle vitamin E and -6 PUFA but not by -3 PUFA. There was no significant relationship observed between blood isoprostane concentration at 0, 4, 6 or 8 wk feeding vs. overall meat color (redness of meat) at 0 and 72 h of display, stored under simulated retail conditions. The results indicate that circulating blood isoprostane concentration can be a useful tool to predict the oxidative status of postmortem meat. Future work will examine the impact of this relationship on meat flavor/aroma deterioration post farm. PMID- 28727090 TI - Effect of natural betaine and ractopamine HCl on whole-body and carcass growth in pigs housed under high ambient temperatures. AB - Betaine is an osmolyte that helps to maintain water homeostasis and cell integrity, which is essential during heat stress. We hypothesized that supplemental betaine can improve growth during heat stress and may further improve the response to ractopamine. Two studies were conducted to determine: 1) the effects of betaine in combination with ractopamine; and 2) the optimum betaine level for late finishing pigs during heat stress. Heat stress was imposed by gradually increasing temperatures over 10 d to the target high temperature of 32 degrees C. In Exp. 1, pigs ( = 1477, BW = 91.6 +/- 3 kg) were assigned within BW blocks and sex to 1 of 4 diets arranged in a 2 * 2 factorial RCB design (68 pens; 20 to 23 pigs/pen). Treatments consisted of diets without or with ractopamine (5 mg/kg for 21 d followed by 8.8 mg/kg to market) and each were supplemented with either 0 or 0.2% of betaine. Betaine reduced ( <= 0.05) BW (123.1 vs. 124.3 kg), ADG (0.780 vs. 0.833 kg/d), and ADFI (2.800 vs. 2.918 kg/d), but did not impact carcass characteristics. Ractopamine increased ( < 0.01) BW (125.5 vs. 121.9 kg), ADG (0.833 vs. 0.769 kg/d), G:F (0.295 vs. 0.265), HCW (94.1 vs. 90.0 kg), carcass yield (74.8 vs. 73.8%), loin depth (63.6 vs. 60.0 mm), and predicted lean percentage (53.2 vs. 51.7%) and reduced ADFI (2.822 vs. 2.896 kg/d, = 0.033) and backfat depth ( < 0.001; 20.2 vs. 22.5 mm). In Exp. 2, pigs ( = 2193, BW = 95.5 +/- 3.5 kg) were allocated within BW blocks and sex to 1 of 5 treatments in a RCB design (100 pens; 20 to 24 pigs/pen). Treatments consisted of diets with 0, 0.0625, 0.125, 0.1875% of betaine, and a positive control diet with ractopamine, but not betaine. Betaine tended to decrease carcass yield quadratically ( = 0.076; 74.1, 73.5, 73.8, and 73.9 for 0, 0.0625, 0.125, 0.1875% of betaine, respectively), but did not impact other responses. Ractopamine improved ( < 0.001) BW (121.6 vs. 118.5 kg), G:F (0.334 vs. 0.295), carcass yield (74.7 vs. 73.8%), loin depth (61.7 vs. 59.0 mm), and predicted lean percentage (53.2 vs. 52.6%), and reduced backfat (18.7 vs. 20.4 mm). Collectively, data indicate that under commercial conditions, betaine did not improve performance of pigs housed under high ambient temperatures, regardless of ractopamine inclusion. Ractopamine improved whole-body growth and especially carcass growth of pigs raised under high ambient temperatures. The ability of ractopamine to stimulate growth during heat stress makes it an important production technology. PMID- 28727091 TI - Endogenous fat loss and true total tract digestibility of poultry fat in adult dogs. AB - Fat plays an important role in the carnivore diet. It has high digestibility and high energy content and likely improves digestibility of the diet when present in greater amounts, suggesting that endogenous fat adversely affects the apparent digestibility of fat in low-fat diets. This study aimed to determine the endogenous fat loss (EFL) and true total tract digestibility (TTTD) of fat in dogs by using diets having different fat:carbohydrate ratios. Furthermore, the apparent total tract digestibility (ATTD) of macronutrients and energy, food intake, fecal output, and stool quality were evaluated. Twelve adult Beagle dogs were stratified into three 10-d periods in a 6 * 3 balanced incomplete Latin square design. Dietary treatments included a low-fat basal diet (3.4% fat) supplemented with 6 poultry fat levels (1, 4, 10, 12, 16, or 20%). The dogs were individually housed in metabolic cages and fed to meet the maintenance energy requirements. The ME intake was similar across the diets, despite the clearly low palatability of the 1 and 4% fat diets. Dietary ATTD of DM, OM, fat, and GE were improved after fat inclusion ( < 0.001). The ATTD of CP was not affected by dietary fat increase ( > 0.05). The amount of fecal output decreased with increasing level of fat in the diet, but the fecal score was not affected. The stool quality was close to ideal (2.4-2.8) and no different among diets. The EFL was estimated using 2 regression methods and was expressed as 155 mg?kg BW?d or 7.9 g/kg of DMI. The TTTD of poultry fat was the same irrespective of the dietary fat level. Poultry fat was 99.3% digestible for the dogs. The relation between EFL and fat intake was higher for the lower-fat diets, explaining the ATTD of fat increase according to the dietary fat inclusion. In conclusion, dietary fat is well digested by dogs irrespective of the level included, close to 100%. The ATTD of fat in low-fat diets is underestimated because the endogenous content is proportionally greater than that in high-fat diets. PMID- 28727092 TI - Effects of dried distiller's grains and lasalocid inclusion on feedlot lamb growth, carcass traits, nutrient digestibility, ruminal fluid volatile fatty acid concentrations, and ruminal hydrogen sulfide concentration. AB - Our hypothesis was that increasing the inclusion level of dried distiller's grains with solubles (DDGS) to feedlot lambs would increase growth and the inclusion of lasalocid (LAS; Bovatec, Alpharma, LLC, Bridgewater, NJ) would increase ADG and G:F, while not affecting digestibility, ruminal VFA concentration, and ruminal pH. Furthermore, we hypothesized that rations containing LAS and higher levels of DDGS would cause increased ruminal hydrogen sulfide gas (HS) concentrations. Two hundred forty crossbred (Suffolk * Rambouillet) lambs (31.9 +/- 5.87 kg BW; approximately 90 d of age) were allocated to 6 treatments in a completely randomized design with a 3 * 2 factorial arrangement of treatments. Lambs were placed into 24 feedlot pens (4 pens/treatment; 10 lambs/pen) for a 111 d finishing study. Main effects included concentration of DDGS (0, 15, or 30% DM basis) and inclusion of LAS (0 or 22.05 g/metric ton LAS) resulting in treatments of: 1) 0% DDGS without LAS (0DDGS-NL), 2) 0% DDGS with LAS (0DDGS-L), 3) 15% DDGS without LAS (15DDGS-NL), 4) 15% DDGS with LAS (15DDGS-L), 5) 30% DDGS without LAS (30DDGS-NL), and 6) 30% DDGS with LAS (30DDGS-L). Two-day weights were taken at the beginning and end of the experiment. Two-hundred-eighteen lambs (64.8 +/- 7.99 kg BW) were slaughtered on d 112 at a commercial abattoir and carcass data collected. The inclusion of LAS increased ( <= 0.02) final BW, ADG, G:F, and HCW. As DDGS in the ration increased to 30%, DMI decreased linearly ( = 0.03) while G:F increased linearly ( = 0.03). A second study was conducted utilizing the same treatments to evaluate N and S balance, ruminal VFA and H2S concentration, and ruminal pH in 24 crossbred wethers (Suffolk * Rambouillet; 41.2 +/- 12.23 kg BW). Daily urinary sulfur excretion and ruminal H2S concentration were linearly increased ( < 0.001) as DDGS increased in the ration. Total ruminal VFA concentration linearly decreased ( = 0.002) as DDGS increased in the ration. The inclusion of LAS increased ( = 0.02) ruminal pH. The results confirm our hypothesis that LAS increased overall growth and increasing DDGS increased ruminal HS concentration but did not influence growth. We reject the hypothesis that the combined effects of LAS and DDGS would have no effect on rumen pH and VFA concentrations. PMID- 28727093 TI - Effects of intravenous lipopolysaccharide administration on feed intake, ruminal forage degradability, and liquid parameters and physiological responses in beef cattle. AB - This experiment compared DMI, ruminal forage degradability, and liquid parameters as well as physiological responses in beef cattle receiving a lipopolysaccharide (LPS) challenge or not. Eight ruminally cannulated Angus * Hereford steers (485 +/- 16 kg BW) were housed in individual pens on d -7, ranked by BW, and allocated to 1 of 2 treatments administered on d 0: 1) an intravenous (i.v.) bolus dose (0.5 MUg/kg of BW, diluted in 5 mL of 0.9% sterile saline) of bacterial LPS ( 0111:B4) or 2) a 5-mL i.v. injection of 0.9% sterile saline (CON). Steers had free-choice access to mixed alfalfa-grass hay, water, and a commercial vitamin + mineral mix during the experiment (d -7 to 6). Hay DMI was evaluated daily from d -5 to 6. Immediately prior to treatment administration (h 0), polyester bags containing 4 g of ground dietary hay (DM basis) were immersed into the rumen of each steer and incubated for 0, 4, 8, 12, 24, 36, and 48 h for DM and NDF degradability evaluation. Steers were also intraruminally pulse-dosed with 5 g of Co-EDTA immediately prior to treatment administration, and rumen fluid samples were collected at 0, 2, 4, 6, 8, 12, 16, and 24 h for ruminal liquid volume and dilution rate calculations. Blood was collected every 2 h from -2 to 8 h, every 4 h from 8 to 16 h, every 12 h from 24 to 72 h, and every 24 h from 96 to 144 h relative to treatment administration. Values obtained before treatment administration were used as a covariate within each respective analysis. Steers receiving LPS had less ( <= 0.03) DMI on d 0 and 1 compared with CON steers. Steers receiving LPS had reduced ( <= 0.05) rumen liquid volume and dilution rate as well as ruminal disappearance rate and effective degradability of DM and NDF compared with CON steers. Steers receiving LPS had greater ( <= 0.05) plasma tumor necrosis factor alpha at 2 h, greater plasma haptoglobin from 24 to 72 h, greater plasma cortisol from 12 to 16 h, greater serum NEFA from 6 to 48 h, greater plasma insulin and glucose at 2 h, reduced plasma glucose from 4 to 12 h, greater plasma cholecystokinin at 16 h, and greater plasma leptin concentrations at 8, 12, 16, 36, 48, and 60 h after treatment administration compared with CON steers. Hence, LPS administration transiently reduced DMI in steers via physiological reactions that modulate gastrointestinal motility and satiety centers in the central nervous system, in addition to potential host-microbiome endocrine interactions that impaired ruminal hay DM and NDF degradability. PMID- 28727094 TI - Effects of adding minimally refined cottonseed oil or crude glycerol to diets containing 40% corn distiller's dried grains with solubles on growth performance, carcass characteristics, and pork fat firmness of growing-finishing pigs. AB - Diets containing more than 20% distiller's dried grains with solubles (DDGS) reduce fat firmness in pork, but supplementation of cottonseed oil or crude glycerol may improve fat firmness. The objective of this study was to assess the effect of feeding minimally refined cottonseed oil or crude glycerol on growth performance, carcass composition, and fat quality of growing-finishing pigs. Mixed sex pigs ( = 216; 24 +/- 4 kg initial BW) were blocked by BW and allotted to 1 of 3 dietary treatments: 1) a basal corn-soybean meal diet with 40% DDGS (CON), 2) CON diet plus 5% minimally refined cottonseed oil added throughout the experiment (COT), or 3) CON fed during the first 8 wk and CON + 8% crude glycerol fed during the last 6 wk of the experiment (GLY). Although diets were not isocaloric, total AA-to-ME ratios were calculated to be equal among diets. Carcass composition was estimated using real-time ultrasound 2 d before harvest. Gilts (16/treatment) closest to the mean BW of each pen were harvested (115 +/- 8 kg BW), and bellies were retrieved for in-depth analysis of fat quality. Belly fat was sampled and analyzed for fatty acid composition. Overall, ADFI of pigs fed COT (2.30 kg/d) was less ( < 0.01) than that of pigs fed CON or GLY (2.47 and 2.49 kg/d, respectively). Pigs fed COT (0.93 kg/d) had greater ( < 0.01) ADG compared with pigs fed CON or GLY (0.88 and 0.87 kg/d, respectively). Greater ( < 0.01) G:F was observed for pigs fed COT (0.41) than for pigs fed CON or GLY diets (0.36 and 0.35, respectively). Final BW of pigs fed COT (124.3 kg) was greater ( < 0.01) than that of pigs fed CON or GLY (118.9 and 118.6 kg, respectively). Pigs fed COT had greater ( < 0.01) HCW (94.9 kg) compared with pigs fed CON or GLY (89.9 and 89.2 kg, respectively). No differences were observed for dressing percentage (75.7, 76.3, and 75.3%), fat-free carcass lean percentage (50.5, 49.7, and 50.0%), and belly flop angle (6.21, 8.57, and 6.06 degrees ) for CON, COT, and GLY, respectively. Pigs assigned to COT had higher ( < 0.01) melting point of belly fat compared with pigs assigned to CON or GLY (30.4 vs. 26.3 and 25.3 degrees C, respectively). Pigs fed COT had increased ( < 0.05) SFA, PUFA, and iodine value (IV) compared with CON-fed pigs. Glycerol supplementation had no influence on SFA, MUFA, and PUFA concentrations or IV of belly, jowl, and back fat compared with CON. In conclusion, COT diets improved growth performance due to greater energy density, but carcass composition was not affected by treatments. In this experiment, feeding neither COT nor GLY improved fat firmness of pigs fed diets containing 40% DDGS. PMID- 28727095 TI - Bta-miR-130a regulates the biosynthesis of bovine milk fat by targeting peroxisome proliferator-activated receptor gamma. AB - Milk fat determines the quality of milk and is also a main targeted trait in dairy cow breeding. Recent studies have revealed important regulatory roles of microRNAs (miRNA) in milk fat synthesis in the mammary gland. However, the role of miRNA in bovine mammary epithelial cells (BMEC) remains largely unknown. In this study, we found that the overexpression of miR-130a significantly decreased cellular triacylglycerol (TAG) levels and suppressed lipid droplet formation, whereas the inhibition of miR-130a resulted in greater lipid droplet formation and TAG accumulation in BMEC. MiR-130a also significantly affected mRNA expression related to milk fat metabolism. Specifically, the overexpression of miR-130a reduced the mRNA expression of , , , and , whereas the downregulation of miR-130a increased the mRNA expression of , , , , , and . Furthermore, western blot analysis revealed the protein level of PPARG in miR-130a mimic and inhibitor transfection groups to be consistent with the mRNA expression response. Finally, luciferase reporter assays verified that PPARG was the direct target of miR-130a. This study provides the first experimental evidence that miR-130a directly affects TAG synthesis in BMEC by targeting PPARG, suggesting that miR-130a potentially could be used to improve beneficial milk components in dairy cows. PMID- 28727097 TI - Evaluating the impact of breed, pregnancy, and hair coat on body temperature and sweating rate of hair sheep ewes in the tropics. AB - The objective of this study was to evaluate the effect of pregnancy, breed, and hair coat on body temperature and sweating rate (SR) of hair sheep. St. Croix White (STX; = 9) and Dorper * STX (DRPX; = 9) ewes (3.6 yr of age) were evaluated over 4 d at 126 d of gestation (PREG) and over 4 d at 46 d postpartum (OPEN) in the shade and sun and in the morning (AM; 0900 to 1200 h) and afternoon (PM; 1300 to 1600 h) after a 20 min acclimation to each condition on each day. Data loggers recorded vaginal temperature (VT) at 10-min intervals for 96 h. Rectal temperature (RT) was measured using a digital veterinary thermometer, and respiration rate (RR) was measured as breaths per minute (bpm). Sweating rate was calculated from measured air properties passing over a shaved (300 cm) and unshaved area of the ewes' body using a portable calorimeter. Data were analyzed using GLM procedures of SAS (SAS Inst. Inc., Cary, NC) with breed, pregnancy status, sun exposure, and time of day as main effects. Mean temperature, relative humidity, temperature-humidity index, wind speed, and solar radiation on the days of data collection were 28.2 degrees C, 82.8%, 80.3, 4.2 km/h, and 237.5 W/m, respectively. There was no difference ( > 0.10) in RT, RR, and SR between DRPX and STX ewes. The PREG ewes had lower RT ( < 0.007) and SR ( < 0.0001) and higher RR ( < 0.007) than OPEN ewes (38.5 +/- 0.2 vs. 39.1 +/- 0.2 degrees C, 70.2 +/- 3.1 vs. 88.3 +/- 3.1 g?m?h, and 79.5 +/- 2.2 vs. 72.1 +/- 2.2 bpm, respectively). During the PM, RR, RT ( < 0.05), and SR ( < 0.006) were higher than in the AM. In the sun, RR ( < 0.001) and SR ( < 0.0001) were higher than in the shade, but there was no difference ( > 0.10) in RT. There was no difference in SR ( > 0.10) between the shaved and unshaved area of the ewe. The DRPX ewes had higher ( < 0.0001) VT than STX ewes. The PREG ewes had higher ( < 0.001) VT than OPEN ewes during the night time and lower VT than the OPEN ewes during the day time ( < 0.0001). The OPEN ewes had a greater ( < 0.009) daily range of VT than PREG ewes did (2.5 +/- 0.4 vs. 1.1 +/- 0.4 degrees C, respectively), but there was no breed difference ( > 0.10). Hair coat did not have an influence on the SR of the ewes, and PREG ewes appeared to use increased respiration as opposed to sweating to help control RT. The narrower range of body temperature, measured as VT, of PREG compared to OPEN ewes may be a protective mechanism for the developing fetus. PMID- 28727098 TI - Transport stress-induced cerebrum oxidative stress is not mitigated by activating the Nrf2 antioxidant defense response in newly hatched chicks. AB - Transportation of newly hatched chicks from the hatchery to the farm is inevitable, especially for parent stock and grandsire parent stock chicks. However, the possible effects of transport stress in the newly hatched chicks are poorly understood. The aim of this study was to determine the adaptive responses to transport stress by activing the nuclear factor-erythroid 2-related factor 2 (Nrf2)-induced antioxidant defense. One hundred twenty newly hatched chicks were divided into 3 groups (control group, transport group, and simulation transport group) for 2, 4, and 8 h of real or simulated transportation. Transport stress could cause oxidative stress in the cerebrum of newly hatched chicks by increasing lipid peroxidation and production of free radicals and decreasing the activities of antioxidant enzymes and the glutathione:oxidized glutathione ratio. Transport stress activated the Nrf2 signaling pathway and triggered the transcription of antioxidant parameters. However, transport stress-induced cerebrum oxidative stress was not mitigated by activating the Nrf2 antioxidant defense response in newly hatched chicks. PMID- 28727099 TI - Identification of differentially expressed proteins in testicular semen of sex reversed female (XX) and normal male (XY) rainbow trout. AB - Masculinized females, named sex-reversed females (SRF), have a male phenotype but retain the female genotype (XX) and all spermatozoa produced in their testes carry the X chromosome. Masculinization of females leads to incomplete testicular development and the production of lower-quality semen. The mechanism of masculinization is unknown at present. Therefore, the aim of our study was to identify differentially abundant proteins in testicular semen of normal males and SRF using a difference in-gel electrophoresis approach. Masculinization seemed to not lead to significant changes in the testicular seminal plasma proteome, but did have an impact on the proteome of SRF and normal male sperm. We identified 26 proteins enriched ( < 0.05) in testicular male spermatozoa compared to SRF. A total of 28 proteins were also found to be differentially expressed ( < 0.05) in testicular SRF sperm in comparison to normal males. Bioinformatic analysis highlighted pathways associated with energy production for normal male spermatozoa and pathways related to protein remodeling for SRF sperm. Normal male spermatozoa seemed to be equipped with proteins participating in diverse metabolic pathways, focusing on producing the energy required for sperm movement. On the other hand, SRF spermatozoa were characterized by the enhanced expression of proteins associated with cytoskeletal structures and those related to remodeling, which could indicate that spermatogenesis and spermiogenesis are not fully accomplished. These results can be the basis for further research on the molecular mechanisms of masculinization and toward the development of a method for separating X and Y fish sperm. PMID- 28727100 TI - Gestating sows have greater digestibility of energy in full fat rice bran and defatted rice bran than growing gilts regardless of level of feed intake. AB - The first objective of this experiment was to test the hypothesis that apparent total tract digestibility (ATTD) of GE and nutrients in full fat rice bran (FFRB) and defatted rice bran (DFRB) determined in gestating sows is greater if feed is provided at 1.5 * the ME required for maintenance than at 3.5 * the ME requirement. The second objective was to test the hypothesis that the ATTD of GE and nutrients and the concentrations of DE and ME in FFRB and DFRB is not different between growing gilts and gestating sows if both groups of animals are fed 3.5 * the maintenance requirement for ME. Forty eight gestating sows (parity 2 to 6) were allotted to 3 diets and 2 levels of feed intake (i.e., 1.5 or 3.5 * the maintenance requirement for ME) in a randomized complete block design, with 4 blocks of 12 sows and 2 replicate sows per block for a total of 8 replicate sows per diet. Twenty four growing gilts (51.53 +/- 3.1 kg BW) were randomly allotted to the same 3 diets, but all gilts were fed at 3.5 * the maintenance requirement for ME. A basal diet containing corn and soybean meal and 2 diets that consisted of 60% basal diet and 40% FFRB or DFRB were used. Results of the experiment indicated that there were no effects of level of feed intake of sows on ATTD of GE, DM, OM, or NDF, or on concentrations of DE and ME. However, concentrations of DE and ME were greater ( < 0.05) in FFRB than in DFRB regardless of feed intake level. The ATTD of GE, OM, DM, and NDF of diets containing FFRB or DFRB was less ( < 0.05) than in the basal diet, regardless of the physiological stage of the animals. However, the ATTD of GE, OM, and NDF of the basal diet and diets containing FFRB or DRFB was greater ( < 0.05) in gestating sows than in growing gilts. Concentrations of DE and ME in the diets were also greater ( < 0.05) if determined in gestating sows than in growing gilts. The ATTD of GE and the concentrations of DE and ME of FFRB were greater ( < 0.05) than in DFRB and these values were also greater ( < 0.05) in gestating sows than in growing gilts. In conclusion, the level of feed intake by gestating sows did not affect the digestibility of GE and nutrients or the concentrations of DE and ME in diets or in FFRB or DFRB, but the ATTD of GE and the concentration of DE and ME in diets and in FFRB and DFRB were greater in gestating sows than in growing gilts. PMID- 28727101 TI - The effect of frequency of supplementing rumen-protected unsaturated fatty acids on blood serum fatty acid profiles in beef heifers and lactating cows. AB - The objective of this study was to determine if supplementation frequency of rumen-protected fat (RPF) influences circulating serum concentrations of fatty acids (FA), NEFA, and urea nitrogen in beef heifers and lactating cows. In Exp. 1, 12 early gestation beef heifers were supplemented 0.5 kg of corn gluten feed (CGF) daily during a 2-wk adaptation period. During the last 3 d of adaptation, blood samples were collected immediately before supplementation and then 8 and 16 h postsupplementation daily. Each heifer was then randomly assigned to 1 of 3 supplementation frequency treatments of RPF (3, 5, or 7 d/wk) for 3 wk in a 3 * 3 Latin square design with 3 periods (4 heifers per treatment per period), with each treatment receiving the same amount of RPF and CGF per wk (1.0 and 2.7 kg as fed, respectively). Blood samples were collected during the final 3 d of each supplementation period as described in the adaptation period. In Exp. 2, 18 Angus crossbred cows in early lactation were supplemented with 4.54 kg (as fed) of CGF weekly either at 3, 5, or 7 d/wk during a 2-wk adaptation period. Blood samples were collected during the last 3 d of adaptation as in Exp. 1. For the subsequent 3 wk, RPF (530, 318, and 227 g/d when supplemented) was added to the CGF supplement so that each supplementation frequency received 1.59 kg as fed/wk of RPF. Blood samples were collected during the last 3 d of supplementation as in Exp. 1. Serum FA profiles on a random subsample of 9 heifers in Exp. 1 and all animals in Exp. 2 were determined via gas chromatograph (GC), and values were analyzed using the MIXED procedure of SAS. In Exp. 1, there were no differences ( >= 0.53) in serum FA profile across supplementation frequencies. There was a decrease in serum 18:2, 18:1 -9 and total FA during the sampling time (time effect, < 0.02). In Exp. 2, there was treatment * time effect ( <= 0.001) for both 18:2 and total FA measured. The 7 d/wk frequency had a greater concentration of C18:2 and total FA at 8 h of the sampling period when compared to the other 2 frequencies. These results demonstrate that supplementation of RPF at 3, 5 or 7 d/wk resulted in no changes in serum FA profiles in growing heifers. In early lactating beef cows, there were minor time point changes in serum FA due to supplementation frequency; however, the vast majority of time points were not different, indicating no substantial changes in serum FA profiles. PMID- 28727102 TI - Effects of lipid form and source on digestibility of fat and fatty acids in growing pigs. AB - The objective of this study was to compare the effect of source (corn DDGS, rice bran, or soybean) or form of oil (extracted or intact) on apparent total tract digestibility (ATTD) and true total tract digestibility (TTTD) of acid-hydrolyzed ether extract (AEE) and fatty acids. The study determined and compared the ATTD or TTTD of AEE and fatty acids in extracted corn oil, rice oil, and soybean oil with intact oil in corn DDGS, full-fat rice bran, and full-fat soybean. Seventy eight barrows (initial BW = 47.2 +/- 3.9 kg; Duroc * Landrace * Yorkshire) were allotted to 1 of 13 dietary treatments in a randomized complete block design with 6 barrows in each dietary treatment. The 13 experimental diets included 1 cornstarch-soybean meal basal diet (AEE, 0.56%) and 3 diets containing 6% extracted oils (corn oil, rice oil, and soybean oil) and 9 diets supplemented with 3 levels of corn DDGS (17%, 34%, and 51%), full-fat rice bran (14%, 28%, and 42%), and full-fat soybean (12%, 24%, and 36%). These diets provided about 2%, 4%, and 6% intact oil, respectively. The barrows were housed in individual metabolism crates and were fed the assigned test diets at 4% of initial BW per day. A 5-d total collection of feces followed a 7-d diet adaptation period. The ATTD of AEE were calculated for each diet. The endogenous flow of AEE associated with each ingredient and values for TTTD were calculated using regression methods. The ATTD of AEE were greater ( < 0.05) for extracted oil than for intact oil. Compared to extracted oil, intact oil had lower ( < 0.01) ATTD of palmitic acid (C16:0), stearic acid (C18:0), oleic acid (C18:1), linoleic acid (C18:2), and linolenic acid (C18:3). However, a source by form interaction ( < 0.01) was observed for ATTD of C18:0, C18:2, and C18:3. The ATTD of C18:0, C18:2, and C18:3 in extracted corn and rice oil were greater compared with intact corn DDGS and rice oil ( < 0.05), while there was no significant difference for the ATTD of C18:0, C18:2, and C18:3 between extracted soybean oil and intact oil in full-fat soybean. In conclusion, lipids that are extracted have a greater digestibility compared with intact lipids, and this is especially true regarding saturated fatty acids. The ATTD of AEE in 2 forms of rice oil (intact oil and extracted oil) was less than the values in corn oil and soybean oil. The TTTD of AEE in corn DDGS and full-fat soybeans were greater than in full-fat rice bran. PMID- 28727103 TI - Effects of dietary calcium fructoborate supplementation on joint comfort and flexibility and serum inflammatory markers in dogs with osteoarthritis. AB - Our objective was to evaluate the short-term effects of calcium fructoborate (CFB) on gait, joint range of motion, serum inflammatory markers, and owner perception of pain in client-owned dogs. We used 59 osteoarthritic dogs with impairment, with dogs being randomly assigned to 4 treatments: placebo (60 mg fructose; = 15), low dose (69 mg CFB; = 14), high dose (127 mg CFB; = 14), or combination (69 mg CFB, 500 mg glucosamine hydrochloride and 200 mg chondroitin sulfate; = 16). Dogs up to 22.9 kg received 1 capsule/d, while dogs weighing 23 to 50 kg received 2 capsules/d. A physical examination, radiographs, goniometry measurements, gait analysis, blood sample collection, and a canine brief pain inventory questionnaire were performed on d 0 and 28. Change from baseline values were statistically analyzed among groups. After 28 d, dogs fed the low and high doses had an improved ( < 0.05) ability to rise from a lying position compared to placebo. Dogs fed the high dose also had a greater ( = 0.05) increase in soluble receptor for advanced glycation end products concentration than dogs fed the placebo. Sub-analysis of only large dogs (> 23 kg) showed that dogs fed the low dose had decreased ( < 0.05) pain severity score and pain at its worst compared to dogs fed the placebo. Large dogs fed the low dose also were shown to improve ( < 0.05) in their ability to rise from a lying position compared to dogs fed the placebo. Overall, CFB supplementation was well-tolerated and may aid in mitigating joint discomfort in dogs. PMID- 28727104 TI - A major gene for host response to porcine reproductive and respiratory syndrome is not unfavorably associated with overall performance under nonchallenging conditions in commercial pig lines. AB - A QTL for host response to porcine reproductive and respiratory syndrome (PRRS) was identified in a previous study. The SNP WUR10000125 (WUR) is used as a tag SNP for this QTL. The favorable (B) allele at this SNP is in low frequency in commercial populations, possibly because this allele is unfavorably associated with an important trait under nonchallenging conditions and, therefore, may have been selected against. Therefore, objectives of this study were to estimate the effect of WUR on traits under selection in commercial lines under nonchallenging conditions and to estimate the effect of WUR genotype of parents on performance of crossbred progeny in a commercial-like environment. Data were collected on 4 purebred lines: a Landrace dam line (D1), a Large White dam line (D2), a synthetic sire line (S1), and a Pietrain sire line (S2). Traits analyzed included total number born, number stillborn, farrowing survival, lactation survival, litter mortality, daily feed intake (DFI), backfat, average test daily gain (TGR), average lifetime daily gain (LGR), and Topigs Norsvin selection index (TSI) value, indicative of overall economic value. Deregressed EBV were calculated for each trait (except TSI) and analyzed within line. In the S1 line, AB and BB pigs had significantly lower TGR ( = 0.002) and LGR ( = 0.001) than AA pigs but also lower DFI ( = 0.004). Conversely, AB and BB pigs had significantly higher DFI ( < 0.001) and AB pigs had significantly higher TGR ( = 0.03) than AA pigs in the S2 line. The effect of WUR on TSI was not significant for any line ( >= 0.15). Analyses of phenotypic records collected on crossbred progeny of S1 sires and D1 * D2 F females showed no significant effect of parent WUR genotype on DFI, backfat, TGR, or LGR ( >= 0.07). In conclusion, the effect of WUR was nonsignificant for most traits but the magnitude and direction of the effect differed by trait and by line. The favorable allele for host response to PRRS was associated with greater DFI and a tendency for greater TGR in the S2 line, but the opposite direction of effect was detected for the S1 line. Regardless of the effect on individual traits, no significant effect of WUR on TSI was detected for any line. Therefore, selecting for the B allele is expected to result in progeny with increased resistance to PRRS without compromising overall economic value under normal, nonchallenging conditions. PMID- 28727105 TI - Analysis of the gut bacterial communities in beef cattle and their association with feed intake, growth, and efficiency. AB - The impetus behind the global food security challenge is direct, with the necessity to feed almost 10 billion people by 2050. Developing a food-secure world, where people have access to a safe and sustainable food supply, is the principal goal of this challenge. To achieve this end, beef production enterprises must develop methods to produce more pounds of animal protein with less. Selection for feed-efficient beef cattle using genetic improvement technologies has helped to understand and improve the stayability and longevity of such traits within the herd. Yet genetic contributions to feed efficiency have been difficult to identify, and differing genetics, feed regimens, and environments among studies contribute to great variation and interpretation of results. With increasing evidence that hosts and their microbiomes interact in complex associations and networks, examining the gut microbial population variation in feed efficiency may lead to partially clarifying the considerable variation in the efficiency of feed utilization. The use of metagenomics and high throughput sequencing has greatly impacted the study of the ruminant gut. The ability to interrogate these systems at great depth has permitted a greater understanding of the microbiological and molecular mechanisms involved in ruminant nutrition and health. Although the microbial communities of the reticulorumen have been well documented to date, our understanding of the populations within the gastrointestinal tract as a whole is limited. The composition and phylogenetic diversity of the gut microbial community are critical to the overall well-being of the host and must be determined to fully understand the relationship between the microbiomes within segments of the cattle gastrointestinal tract and feed efficiency, ADG, and ADFI. This review addresses recent research regarding the bacterial communities along the gastrointestinal tract of beef cattle; their association with ADG, ADFI, and feed efficiency; and the potential implications for beef production. PMID- 28727106 TI - Increasing dietary inclusions of camelina cake fed to pigs from weaning to slaughter: Safety, growth performance, carcass traits, and n-3 enrichment of pork. AB - Feeding cake with remaining oil content not only provides additional dietary energy but may also enrich pork with -3 fatty acids. Limited information is available on feeding camelina cake to pigs relating to feeding safety (toxicity), growth performance, and efficacy of -3 enrichment of pork. Therefore, we evaluated the effects of feeding increasing camelina cake (12.2% crude fat) inclusions in diets for nursery and grower-finisher pigs. In total, 128 pigs (9.2 kg BW) were randomly allocated by sex to 32 nursery pens for 4 wk and were then moved and combined into 16 mixed-sex grower-finisher pens. Pigs were fed 1 of 4 wheat/barley-based diets including camelina variety 'Celine' cake (0%, 6%, 12%, or 18% in the nursery phase and 0%, 5%, 10%, or 15% in the grower-finisher phase) replacing soybean meal over 5 feeding phases (d 0 to 7, d 7 to 28, d 28 to 56, d 56 to 84, and d 84 to slaughter). Individual pigs and pen feed added were weighed. On d 106, a blood sample was collected from the pig with the lowest BW per pen, which was then euthanized. A pathologist conducted a gross clinical examination, and organs were weighed. Liver, back fat, and belly and jowl fat were sampled for fatty acid analysis. Pigs were slaughtered at approximately 125 kg BW. Increasing dietary camelina cake inclusion linearly decreased ( < 0.010) ADFI, ADG, BW, and G:F over the 105-d trial. Increasing dietary camelina cake inclusion linearly increased days to slaughter ( < 0.001) and carcass lean yield ( < 0.010) and linearly decreased farm ship weight ( < 0.010), carcass weight ( < 0.001), dressing percentage ( < 0.050), and back fat thickness ( < 0.010) but did not affect loin depth and index. Increasing camelina cake inclusion linearly increased liver and pancreas weight ( < 0.050) relative to BW but did not affect heart, thyroid, or kidney weights. Increasing camelina cake inclusion did not result in gross clinical or serological findings that would indicate toxicity. Increasing dietary camelina cake inclusion linearly increased ( < 0.050) -3 fatty acids, including docosahexaenoic acid, in back fat and belly and jowl fat. In conclusion, feeding camelina cake to pigs at up to 18% in the nursery phase and 15% in the grower, developer, and finisher phases did not result in clinical signs of toxicity and enriched carcass fat depots with -3 fatty acids. The observed decrease in ADFI and, consequently, ADG as camelina cake inclusion increased resulted in pigs fed 15% reaching slaughter weight 27 d later than controls. PMID- 28727107 TI - National Beef Quality Audit - 2016: Survey of carcass characteristics through instrument grading assessments. AB - The instrument grading assessment portion of the National Beef Quality Audit (NBQA) - 2016 allows the unique opportunity to evaluate beef carcass traits over the course of a year. One week of instrument grading data was collected each month from 5 beef processing corporations encompassing 18 facilities from January 2016 through December 2016 ( = 4,544,635 carcasses). Mean USDA yield grade (YG) was 3.1 with 1.37 cm fat thickness (FT), 88.9 cm LM area, 393.6 kg HCW, and 2.1% KPH. Frequency distribution of USDA YG was 9.5% YG 1, 34.6% YG 2, 38.8% YG 3, 14.6% YG 4, and 2.5% YG 5. Increases in HCW and FT since the NBQA-2011 were major contributors to differences in mean YG and the (numerically) increased frequency of YG 3, 4, and 5 carcasses found in the current audit. Mean marbling score was Small, and the distribution of USDA quality grades was 4.2% Prime, 71.4% Choice, 21.7% Select, and 2.7% other. Frequency of carcasses grading Prime on Monday (6.43%) was numerically higher than the average frequency of carcasses grading Prime overall (4.2%). Monthly HCW means were 397.6 kg in January, 397.2 kg in February, 396.5 kg in March, 389.3 kg in April, 384.8 kg in May, 385.0 kg in June, 386.1 kg in July, 394.1 kg in August, 399.1 kg in September, 403.9 kg in October, 406.5 kg in November, and 401.9 kg in December. Monthly mean marbling scores were Small in January, Small in February, Small in March, Small in April, Small in May, Small in June, Small in July, Small in August, Small in September, Small in October, Small in November, and Small in December. Both mean HCW and mean marbling score declined in the months of May and June. The month with the greatest numerical frequency of dark cutters was October (0.74%). Comparison of overall data from in-plant carcass and instrument grading assessments revealed close alignment of information, especially for YG (3.1 for in-plant assessment versus 3.1 for instrument grading) and marbling (Small for in-plant assessment versus Small for instrument grading). These findings allow the beef industry access to the greatest volume of beef value-determining characteristics for the U.S. fed steer and heifer population than ever reported, resulting in potentially more precise targeting of future quality and consistency efforts. PMID- 28727108 TI - Development of a Salmonella Typhimurium challenge model in weaned pigs to evaluate effects of water and feed interventions on fecal shedding and growth performance. AB - The aim of this study was to develop a Typhimurium (ST) challenge model in weaned pigs suitable to evaluate effects of water and feed interventions on fecal shedding and growth performance. Two studies were performed. In Exp. 1 weaned pigs were fed either a standard diet (CON) or a diet with a high buffer capacity (HB) and challenged for either 3 or 7 consecutive days in a Latin square design with 4 * 8 individually housed pigs. In Exp. 2, the CON 7-d challenge method was chosen for further model development and validation. Thirty-two individually housed weaned pigs were divided over 4 treatments: a nonchallenged control group (NCON), a challenged positive control group (PCON), a challenged intervention group with acidified water (WATER), and a challenged intervention group with acidified feed (FEED). Pigs were orally challenged once daily on d 7 to 9 or d 7 to 13 after weaning (d 0) with 1 *10 cfu ST. From d 0 to 28, rectal temperature and occurrence of diarrhea were recorded daily, and BW and feed intake were measured weekly. Fecal samples were collected on d 0, 2, 7, 9, 13, 16, 20, 23, and 27 in Exp. 1 and d 0, 2, 7, 8, 9, 13, 15, and 27 in Exp. 2 for quantification. The results of both experiments showed quantifiable fecal shedding (average peak shedding of approximately 3.5 log and 5.5 log cfu/g, respectively), accompanied by a transient 0.5 degrees C increase in rectal temperature and an increase in occurrence of diarrhea. In Exp. 2 during the week of challenge (i.e., d 7 to 14), a reduction in growth performance (ADG: -157 to 200 g/d and G:F: -0.22 to 0.25 g/d; < 0.01) in PCON and FEED was observed compared to NCON, with WATER showing an intermediate response. The WATER treatment also showed a numerically lower peak shedding (difference of -1.3 to 1.4 log cfu/g) compared to PCON and FEED. To conclude, we repeatedly infected weaned pigs successfully with 1 * 10 cfu of ST for 7 consecutive days, resulting in detectable and quantifiable fecal shedding. This ST challenge model may be suitable for evaluation of effects of water and feed interventions on peak fecal shedding and growth performance. PMID- 28727109 TI - National Beef Quality Audit-2016: In-plant survey of carcass characteristics related to quality, quantity, and value of fed steers and heifers. AB - The National Beef Quality Audit (NBQA)-2016 used in-plant cooler assessments to benchmark the current status of the fed steer and heifer beef industry in the United States. In-plant cooler assessments ( = 9,106 carcasses) were conducted at 30 facilities, where approximately 10% of a single day's production were evaluated for USDA quality grade (QG) and yield grade (YG) factors. Frequencies of evaluated traits were 66.5% steer and 33.4% heifer sex classes and 82.9% native, 15.9% dairy-type, and 1.2% estimated breed types. Mean USDA YG factors were 1.42 cm for adjusted fat thickness, 89.5 cm for LM area, 390.3 kg for HCW, and 1.9% for KPH. Mean USDA YG was 3.1, with a frequency distribution of 9.6% YG 1, 36.7% YG 2, 39.2% YG 3, 12.0% YG 4, and 2.5% YG 5. Mean USDA QG traits were Small for marbling score, A for overall maturity, A55 for lean maturity, and A for skeletal maturity. Mean USDA QG was Select with a frequency distribution of QG of 3.8% Prime, 67.3% Choice, 23.2% Select, and 5.6% lower score. Lower score included dark cutter (1.9%), blood splash (0.1%), and hard bone, which are USDA overall maturity scores of C or older (1.8%). Marbling score distributions were 0.85% Slightly Abundant or greater, 7.63% Moderate, 23.54% Modest, 39.63% Small, 23.62% Slight, and 0.83% Traces or less. Carcasses that were Choice or Select and USDA YG 2 or 3 accounted for 70.7% of the carcasses evaluated. Compared with the previous NBQA, we found a numerical increase in mean USDA YG, USDA QG, adjusted fat thickness, HCW, LM area, and marbling score with an increase in dairy-type carcasses and percentage of carcasses grading USDA Prime and Choice as well as frequency of USDA YG 4 and 5. The findings from this study will be used by all segments of the industry to understand and improve the quality of fed steer and heifer beef that is being produced. PMID- 28727110 TI - Calibration and validation of a carbon oxidation system and determination of the bicarbonate retention factor and the dietary phenylalanine requirement, in the presence of excess tyrosine, of adult, female, mixed-breed dogs,. AB - Carbon oxidation methods have been used as rapid and sensitive methods to determine whole-body AA requirements in multiple species. The objectives of the current studies were to validate complete CO recovery, determine the bicarbonate retention factor, and estimate the Phe requirement, in the presence of excess Tyr, in adult dogs using the direct oxidation technique. In this series of studies, 2 oxidation chambers were constructed and calibrated to ensure accurate collection of breath CO. First, 104.6 +/- 7.1% CO was recovered from chambers and suggests that the chambers were appropriately designed for complete and efficient CO recovery. Second, we determined bicarbonate retention in 5 dogs using repeated oral dosing of a bicarbonate tracer (NaHCO) with small meals. At isotopic and physiological steady state, 102.5 +/- 2.6% of the delivered NaHCO was recovered in breath. Third, the Phe requirement, when Tyr was supplied in excess, was determined by the rate of appearance of CO in the breath (CO). Dogs ( = 5) were fed test diets with different concentrations of Phe ranging from deficient to excessive for 2 d prior to conducting the tracer studies. The mean Phe requirement (when Tyr was supplied in excess) was 0.535% of diet (upper 95% confidence interval = 0.645% diet) on an as-fed basis or 0.575% of diet (upper 95% confidence interval = 0.694% of diet) on a DM basis and was based on a calculated (modified Atwater calculation) dietary ME density of 3.73 Mcal/kg DM. These data support the use of carbon oxidation methods and oral dosing of isotope to measure whole-body requirements of indispensable AA in adult dogs and suggest the current recommendations may be low. PMID- 28727111 TI - Phenotypic and genetic relationships of residual feed intake measures and their component traits with fatty acid composition in subcutaneous adipose of beef cattle. AB - Feed efficiency is of particular interest to the beef industry because feed is the largest variable cost in production and fatty acid composition is emerging as an important trait, both economically and socially, due to the potential implications of dietary fatty acids on human health. Quantifying correlations between feed efficiency and fatty acid composition will contribute to construction of optimal multiple-trait selection indexes to maximize beef production profitability. In the present study, we estimated phenotypic and genetic correlations of feed efficiency measures including residual feed intake (RFI), RFI adjusted for final ultrasound backfat thickness (RFIf); their component traits ADG, DMI, and metabolic BW; and final ultrasound backfat thickness measured at the end of feedlot test with 25 major fatty acids in the subcutaneous adipose tissues of 1,366 finishing steers and heifers using bivariate animal models. The phenotypic correlations of RFI and RFIf with the 25 individual and grouped fatty acid traits were generally low (<0.25 in magnitude). However, relatively stronger genetic correlation coefficients of RFI and RFIf with PUFA traits including the -6:-3 ratio (0.52 +/- 0.29 and 0.45 +/- 0.31, respectively), 18:2-6 (0.45 +/- 0.18 and 0.40 +/- 0.19, respectively), -6 (0.43 +/- 0.18 and 0.38 +/- 0.19, respectively), PUFA (0.42 +/- 0.18 and 0.36 +/- 0.20, respectively), and 9-16:1 (-0.43 +/- 0.20 and -0.33 +/- 0.22, respectively) were observed. Hence, selection for low-RFI or more efficient beef cattle will improve fatty acid profiles by lowering the content of -6 PUFA, thus reducing the ratio of -6 to -3 along with increasing the amount of 9-16:1. Moderate to moderately high genetic correlations were also observed for DMI with 9-14:1 (-0.32 +/- 0.17) and the sum of CLA analyzed (SumCLA; -0.45 +/- 0.21), suggesting that selection of beef cattle with lower DMI will lead to an increase amount of 9-14:1 and SumCLA in the subcutaneous adipose tissue. However, unfavorable genetic correlations were detected for ADG with 11-18:1 (-0.38 +/- 0.23) and SumCLA ( 0.73 +/- 0.26), implying that selection of beef cattle with a better growth rate will decrease the contents of healthy fatty acids 11-18:1 and SumCLA. Therefore, it is recommended that a multiple-trait selection index be used when genetic improvements of fatty acid composition, feed efficiency, feed intake, and growth are important in the breeding objective. PMID- 28727112 TI - Effect of in ovo feeding of l-arginine on the hatchability, growth performance, gastrointestinal hormones, and jejunal digestive and absorptive capacity of posthatch broilers. AB - This study was conducted to investigate the effects of in ovo feeding (IOF) of Arg solution on the hatchability, growth performance, gastrointestinal hormones, serum AA, activities of digestive enzymes, and mRNA expressions of sensing receptors and nutrient transporters in the jejunum of posthatch broilers. One thousand two hundred embryonated eggs with similar weight were randomly allocated to 5 groups consisting of 8 replicates of 40 eggs each. The 5 treatments were arranged as a noninjected control, a diluent-injected (0.75% NaCl solution) group, and Arg solution-injected groups with 0.5%, 1.0%, and 2.0% Arg, all dissolved in diluent. At 17.5 d of incubation, 0.6 mL of IOF solution was injected into the amniotic fluid of each egg of the injected groups. Results showed the hatchability of the 2% Arg group was lower (linear, = 0.025) than that of the other groups, and the BW of 21-d-old broilers increased (linear, = 0.008; quadratic, = 0.003) with increasing IOF concentration of Arg. The ADFI (linear, = 0.005; quadratic, = 0.001) and ADG (linear, = 0.010; quadratic, = 0.004) increased during d 1 to 21 with increasing IOF concentration of Arg. For 7- and 21-d-old broilers, the weights of digestive organs increased (linear, < 0.05) with increasing IOF concentrations of Arg; the greatest values were observed in the 1% Arg group. For 21-d-old broilers, IOF of the 1% Arg solution increased ( < 0.05) the concentrations of ghrelin and glucagon-like peptide 2; the activities of digestive enzymes, alkaline phosphatase, maltase, and sucrase in the jejunum; and the concentrations of serum AA of Val, Met, Ile, Leu, Arg, and Pro compared with those of the noninjected control and diluent-injected group. In ovo feeding of the 1% Arg solution also increased ( < 0.05) the mRNA expressions of jejunal sensing receptors of taste receptor type 1 members 1 and 3; the G protein-coupled receptor, class C, group 6, subtype A; nutrient transporters of solute carrier family 7, members 4, 6, and 7; sodium-glucose transporter 1; and fatty acid binding protein 1. In conclusion, the 1% Arg solution was the appropriate injection level. In ovo feeding of the 1% Arg solution did not affect the hatchability but facilitated the release of gastrointestinal hormones, increasing the digestive and absorptive capacity and finally improving the growth performance of 21-d-old broilers. Therefore, IOF of the appropriate Arg solution could be an effective technology for regulating early nutrition supply and subsequent growth development in the poultry industry. PMID- 28727113 TI - Feed withdrawal and transportation effects on Salmonella enterica levels in market-weight pigs. AB - Feed withdrawal and transport commonly occur together in pigs. Objectives of this study were to determine if these preslaughter stressors, feed withdrawal and transportation, affect the levels of , stress hormone concentrations, and immune functions in infected market pigs. A 2 * 2 factorial analysis of a randomized complete block design with feed withdrawal and transport as fixed effects was used. Sixty market-weight pigs were individually inoculated with serovar Typhimurium. The experiment was replicated 3 times (blocking factor) with 20 pigs per replicate. Three days after inoculation, the pigs were randomly assigned to 1 of 4 treatments (5 pigs per treatment in each/replicate), including 1) control (Control; or no stress), 2) feed withdrawal for 12 h (FW), 3) transportation for 2 h (T), and 4) feed withdrawal for 12 h followed by transportation for 2 h (FWT). Feed withdrawal by itself or followed by transportation caused an increase of levels in ileal contents ( < 0.05), whereas only FWT caused an increase of levels in cecal contents ( < 0.05). Rectal contents (feces) consistently contained very low levels of , with no difference among treatments ( > 0.10). Cortisol increased in pigs from all 3 stress treatments ( < 0.001), with T and FWT pigs having greater concentrations than Control pigs ( < 0.05), although total white blood cell counts were lower for FWT pigs compared with Controls ( > 0.03). Each granulocyte percentage (neutrophil, eosinophils, and basophils) increased ( < 0.05) following transport but was attenuated ( > 0.05) by feed withdrawal with transport. Lymphocytes were suppressed ( < 0.05) by all stressors, and the greatest suppression occurred when pigs were transported (T and FWT). However, monocytes were suppressed ( < 0.05) compared with Controls only by FWT. Expression of IL-1 (produced by monocytes/macrophages) from the spleen cells increased ( < 0.05) with FW compared with Controls, whereas its receptor antagonist was suppressed by FWT ( < 0.05). It is concluded that some typical preslaughter practices, such as feed withdrawal and transportation, lead to greater intestinal levels and gut-associated lymphoid tissue markers of inflammation in market pigs and, consequently, to an increased food safety risk. PMID- 28727114 TI - Rapid Communication: Ranking dairy cows for methane emissions measured using respiration chamber or GreenFeed techniques during early, peak, and late lactation. AB - Our objective was to compare the ranking of dairy cows according to their methane (CH) emissions as measured by a respiration chamber (RC) technique and the GreenFeed (GF) technique during 3 periods in second lactation. Two-day CH measurements in a RC performed in wk 3, 14, and 42 of lactation were flanked by GF measurements for 20 (period 1 [P1]), 35 (period 2 [P2]), and 35 (period 3 [P3]) days, respectively, before and after RC measurement. This gave the total duration of CH measurements using the GF system of 40, 70, and 70 d for P1, P2, and P3, respectively. Mean daily CH production (g/d) of the 8 dairy cows was 346, 439, and 430 using the RC technique and 338, 378, and 416 using the GF system during P1, P2, and P3, respectively. Average daily CH production determined by the GF technique was 2.4, 13.8, and 3.2% lower in P1, P2, and P3, respectively. Methane normalized to DMI continuously increased from P1 to P3 when measured in a RC, whereas it was lowest during P2 when measured by the GF method. Ranking of the cows according to CH production, CH/energy-corrected milk yield (ECM; CH/ECM), and CH/DMI differed between periods no matter which method was used. Cluster analysis including all 3 periods, however, identified the same cows with the highest and lowest CH production determined either by the RC technique or the GF system. In conclusion, multiple CH measurements at different stages of lactation are necessary for reliable discrimination of highest and lowest CH emitting cows and the GF system may be used to discriminate the extremes. PMID- 28727115 TI - The microbiota-gut-brain axis as a key regulator of neural function and the stress response: Implications for human and animal health. AB - The brain-gut-microbiota axis comprises an extensive communication network between the brain, the gut, and the microbiota residing there. Development of a diverse gut microbiota is vital for multiple features of behavior and physiology, as well as many fundamental aspects of brain structure and function. Appropriate early-life assembly of the gut microbiota is also believed to play a role in subsequent emotional and cognitive development. If the composition, diversity, or assembly of the gut microbiota is impaired, this impairment can have a negative impact on host health and lead to disorders such as obesity, diabetes, inflammatory diseases, and even potentially neuropsychiatric illnesses, including anxiety and depression. Therefore, much research effort in recent years has focused on understanding the potential of targeting the intestinal microbiota to prevent and treat such disorders. This review aims to explore the influence of the gut microbiota on host neural function and behavior, particularly those of relevance to stress-related disorders. The involvement of microbiota in diverse neural functions such as myelination, microglia function, neuronal morphology, and blood-brain barrier integrity across the life span, from early life to adolescence to old age, will also be discussed. Nurturing an optimal gut microbiome may also prove beneficial in animal science as a means to manage stressful situations and to increase productivity of farm animals. The implications of these observations are manifold, and researchers are hopeful that this promising body of preclinical work can be successfully translated to the clinic and beyond. PMID- 28727116 TI - Technical note: Development of a feed matrix as inoculum in Salmonella infection studies in piglets. AB - Current methods used for oral administration of pathogens to piglets are stressful for the animals because of fixation and use of inoculation methods such as oral gavage. In the present study an alternative way to challenge piglets with Typhimurium (ST) is investigated. The strategy was to incorporate the in a feed matrix, which is fed to the piglets and eaten voluntary. Different types of feed matrices were tested for their absorption capacity, handling properties, and palatability to piglets. Furthermore, the viability of ST in feed matrices was studied. The ST could be incorporated in ladyfinger biscuits; a 2-cm piece absorbs 1 mL of culture media. The ladyfinger biscuits were very well accepted by the piglets. After a short training period, the piglets consumed the incorporated biscuits out of the feeding trough. In this way the animals were infected in a more natural way and without stress. The safety of farm workers was also increased because the incorporated ST results in less spoilage and spreading of ST during the infections. Results indicated that the ST cell count was reduced by only 0.2 log unit to 8.7 log cfu per inoculum after 24 h at 4 degrees C incorporation of ST into the biscuits, which is sufficient for an infection study and indicates excellent viability of the . The viability was also indicated by increased fecal shedding of ST. Thus, it is concluded that ladyfinger biscuits are a suitable matrix to challenge piglets with ST. PMID- 28727117 TI - Relationship between ovulation rate and embryonic characteristics in gilts at 35 d of pregnancy. AB - This study investigated the relationship between ovulation rate (OR) and embryonic characteristics in gilts. Landrace ( = 86) and Yorkshire x Landrace ( = 212) gilts were inseminated with semen stored for 3 to 5 d (SS1, = 59), 6 to7 d (SS2, = 133), or 8 to 10 d (SS3, = 106), and slaughtered at 35 d of pregnancy. Ovulation rate was assessed by dissection of the corpora lutea on both ovaries. Embryos were classified as vital (VE) by visual appearance and individually weighed (VEg) and the SD of the weight calculated (SDVEg). Early embryonic mortality (EM) was estimated as the difference between OR and the number of vital plus nonvital embryos. Embryonic characteristics were analyzed with a model that included linear and quadratic terms of OR and fixed class effects of semen storage duration (SS) and genetic line (GL). Landrace gilts had a higher OR than Yorkshire x Landrace gilts (22.1 +/- 0.4 vs. 20.3 +/- 0.2, <= 0.05) and also a higher EM (6.1 +/- 0.4 vs. 3.5 +/- 0.3, <= 0.05). EM was also higher in gilts inseminated with semen stored for more than 8 d. Also, Yorkshire x Landrace gilts had a higher number of VE (16.9 +/- 0.7) than the Landrace gilts (13.3 +/- 0.8) when inseminations were done with semen stored for up to 5 d. Yorkshire x Landrace gilts had the highest VEg when inseminated with semen stored for 3 to 5 d (SS1: 4.9 +/- 0.2 g, SS2: 4.1 +/- 0.1 g, and SS3: 4.0 +/- 0.2 g; <= 0.05). VE and VEg did not differ within Landrace gilts between different SS classes. A quadratic relationship of OR ( <= 0.05) was found with VE: a maximum of 16.8 VE was observed at 26 ovulations [(2.5 (+/- 0.6)*OR- 0.05 (+/- 0.01)*OR]. A quadratic relationship of OR ( <= 0.05) was also found for EM: a minimum of 3.33 EM was observed at 15 ovulations [(-1.1 (+/- 0.6)*OR -0.03 (+/- 0.01)*OR]. VEg was not related with OR, but SDVEg had a positive linear relationship with OR [0.01 (+/- 0.003)*OR, <= 0.05]. Results show that Yorkshire x Landrace gilts perform better than Landrace when inseminated with fresh semen, but not with semen stored for longer time. Also, the VE increases with an increase in OR up to 26, but at a lower level at higher OR, which is likely related with the increase in EM. The higher EM at higher OR might arise from a higher variation in follicular/oocyte quality leading to a higher variation in embryonic quality and development, increasing mortality before uterine implantation and the variation in embryonic weight already at 35 d of pregnancy. PMID- 28727118 TI - Technical note: Assessment of an alternative technique for measuring body temperature in pigs. AB - Core body temperature (CBT) is one of the main vital signs that is used to evaluate the health status of pigs. The most common and feasible method for assessing CBT in pigs is rectal temperature (RT). Obtaining RT is stressful for animals, may generate inaccurate results, and has the risk of spreading disease. Infrared imaging (IR) thermography of the body of pigs may be a safer and less stressful alternative to RT. The objective of the current study was to evaluate the efficacy of using IR as an alternative for monitoring CBT in pigs. Twenty three gilts (30.5 +/- 5.62 kg BW) were housed in metabolism crates in an environmentally controlled facility and fed an 860 g/d grower diet. After 4 d of adaptation, the febrile response was induced by intramuscular injection of lipopolysaccharide (LPS; 25 ug/kg BW). Each pig's body temperature was recorded at 0, 2, 4, 6, 8, 10, and 24 h after LPS challenge using the following 3 methods: 1) RT, 2) IR of the eye and ear, and 3) CBT using an orally administered digital temperature sensor. Statistical analysis was performed in a completely randomized design in SAS using Mixed, Correlation, and Regression procedures. Relative to time 0 h, LPS increased the eye temperature, CBT, and RT by 0.92, 1.32, and 1.48 degrees C, respectively ( < 0.01), but had no significant effect on ear temperature. Eye temperature, RT, and CBT, but not ear temperature, were highly correlated ( >= 0.96) during the course of the study ( < 0.01). Estimated regression parameters (alpha and beta) for predicting CBT using eye temperature were -28.2 +/- 8.70 and 1.76 +/- 0.221, respectively, and for RT were -24.5 +/- 7.69 and 1.65 +/- 0.196, respectively ( >= 0.96; 95% confidence interval). Collectively, these results indicated a strong relationship between eye temperature, RT, and CBT in pigs. Therefore, IR of the eye can be used as a precise, noncontact alternative to RT measurements for monitoring CBT in swine. PMID- 28727119 TI - Nitrogen from ammonia is as efficient as that from free amino acids or protein for improving growth performance of pigs fed diets deficient in nonessential amino acid nitrogen. AB - Inclusion of NPN in diets may compensate the deficient supply of nonessential AA (NEAA) in very low CP levels. To assess this, 2 studies were conducted to determine the effect of supplementing NPN and specific NEAA to diets severely deficient in NEAA nitrogen (NEAA-N) on growth performance of pigs. In Exp. 1, 48 gilts (initial BW 15.2 +/- 1.3 kg; 2 pigs per pen; 6 pens per treatment) were randomly assigned to 1 of the 4 dietary treatments: 1) positive control (Pos Ctrl), not deficient in essential AA (EAA) and total N, with all N supplied from intact protein (casein and soybean meal) or crystalline EAA, (2) negative control (Neg Ctrl), supplying the same amount of potentially limiting EAA as Pos Ctrl but deficient in NEAA-N, 3) Neg Ctrl plus 1.45% CP from ammonia-N (low NPN), and 4) Neg Ctrl plus 2.90% CP from ammonia-N (high NPN), supplying the same amount of digestible N as the Pos Ctrl diet. Pigs were fed ad libitum, and ADG and ADFI were monitored weekly during a 3-wk period. Gain:feed improved linearly ( < 0.05) with supplementation of ammonia-N in diets. Gain:feed for high NPN was similar ( = 0.496) to that for Pos Crtl (0.51 and 0.52, respectively). In the Exp. 2, 72 individually housed barrows (initial BW 13.5 +/- 0.6 kg; 8 pigs per treatment) were assigned to 9 dietary treatments. A basal diet was formulated to be deficient in NEAA-N with a ratio of EAA-N to total N (EAA-N:TN) of 0.74. The basal diet was supplemented with 1 of 4 different N sources (urea, ammonia, glutamic acid, and a mixture of NEAA) at 2 levels each, decreasing the final EAA N:TN to 0.63 and 0.55, respectively. Pigs were fed at 3.0 times maintenance energy requirements during 9 d of adaptation and 3 wk of observations. Body weight was monitored weekly. At the end of the experiment, blood samples from the portal vein and abdominal aorta were collected to determine ammonia- and urea-N concentrations. Final BW, ADG, and G:F increased ( < 0.05) with supplemented ammonia, glutamate, and the NEAA mix but not (> 0.10) with urea. Final BW, ADG, and G:F were not different ( > 0.05) between pigs fed the ammonia, glutamate, and NEAA mix supplemented diets. Urea concentration in portal and arterial blood plasma increased linearly ( < 0.05) with urea intake. In conclusion, growing pigs can utilize N from ammonia as efficiently as intact protein or NEAA as a source of extra N when diets are severely deficient in NEAA-N. PMID- 28727120 TI - Economic selection indexes for Hereford and Braford cattle raised in southern Brazil. AB - Economic selection indexes (EI) are considered the best way to select the most profitable animals for specific production systems. Nevertheless, in Brazil, few genetic evaluation programs deliver such indexes to their breeders. The aims of this study were to determine the breeding goals (BG) and economic values (EV, in US$) for typical beef cattle production systems in southern Brazil, to propose EI aimed to maximize profitability, and to compare the proposed EI with the currently used empirical index. Bioeconomic models were developed to characterize 3 typical production systems, identifying traits of economic impact and their respective EV. The first was called the calf-crop system and included the birth rate (BR), direct weaning weight (WWd), and mature cow weight (MCW) as selection goals. The second system was called the full-cycle system, and its breeding goals were BR, WWd, MCW, and carcass weight (CW). Finally, the third was called the stocking and finishing system, which had WWd and CW as breeding goals. To generate the EI, we adopted the selection criteria currently measured and used in the empirical index of PampaPlus, which is the genetic evaluation program of the Brazilian Hereford and Braford Association. The comparison between the EI and the current PampaPlus index was made by the aggregated genetic-economic gain per generation (Delta). Therefore, for each production system an index was developed using the derived economic weights, and it was compared with the current empirical index. The relative importance (RI) for BR, WWd, and MCW for the calf crop system was 68.03%, 19.35%, and 12.62%, respectively. For the full-cycle system, the RI for BR, WWd, MCW, and CW were 69.63%, 7.31%, 5.01%, and 18.06%, respectively. For the stocking and finishing production system, the RI for WWd and CW was 34.20% and 65.80%, respectively. The Delta for the calf-crop system were US$6.12 and US$4.36, using the proposed economic and empirical indexes, respectively. Respective values were US$19.87 and US$18.22 for the full-cycle system and US$20.52 and US$18.52 in the stocking and finishing system. The efficiency of the proposed EI had low sensitivity to changes in the values of the economic and genetic parameters. The 3 EI generated higher Delta when using the proposed economic weight compared to the Delta provided by a PampaPlus index, suggesting the use of proposed EI to obtain greater economic profitability in relation to the current empirical PampaPlus index. PMID- 28727121 TI - Supplementing newborn intrauterine growth restricted piglets with a bolus of porcine colostrum raises rectal temperatures one degree Celsius. AB - Hyperprolific sows have increased litter sizes but also result in more piglets that have been exposed to intrauterine growth restriction (IUGR). These IUGR piglets are likely to have a low rectal temperature and lower blood glucose levels compared with normal piglets at birth. Therefore, we hypothesized that a colostrum bolus at birth and/or heat from an external source would have a positive effect on blood glucose levels, rectal temperatures, and growth up to 8 h postpartum. In addition, liver glycogen and blood values at 8 h were investigated. Eighty-four piglets were classified at birth (time = 0) as IUGR based on their head morphology and randomly allocated to 1 of 4 treatments ( = 21) in a 2 * 2 factorial arrangement: 1) with or without a porcine colostrum bolus (12 mL/kg BW at birth) and 2) with sow or isolated from sow with external heat. Piglets were removed from the sow before they had suckled and were numbered and dried, and initial whole-blood glucose, rectal temperature, and BW were recorded. Piglets in the 2 treatments isolated from sow were placed under a heating lamp (150 W) with a temperature range of 35 to 39 degrees C. Rectal temperatures, glucose, and BW were measured again at 1, 2, 4, 6, and 8 h after birth, and a final plasma sample and organs (liver and brain) were removed at 8 h. There was a time * colostrum bolus interaction ( = 0.026) and a time * sow interaction ( < 0.001) for whole-blood glucose. The piglets that were given a bolus had greater glucose levels after 1 h postpartum (time = 1 h) than piglets without a bolus at birth, but from time = 2 h and onward, there was no difference ( > 0.05). There was a time * colostrum bolus interaction ( < 0.001) and a time * sow interaction ( < 0.001) on rectal temperatures. One hour after birth, the piglets with a bolus had a greater rectal temperature compared with piglets without a bolus (37.5 vs. 36.6 degrees C; < 0.001) and the piglets that had been isolated from the sow had a greater rectal temperature compared with the 2 treatments with sows (37.8 vs. 36.3 degrees C; < 0.001). Four hours after birth, rectal temperature was not affected by treatments. In conclusion, both heat and a colostrum bolus increased rectal temperature by 1 degrees C an hour after birth. However, after 4 h, no differences were found between the treatments. Interventions to help IUGR piglets postpartum most likely need to be frequent to have any effect on whole-blood glucose, rectal temperatures, and BW over the first 8 h. PMID- 28727122 TI - Effect of increasing dietary canola meal inclusion on lactation performance, milk composition, and nutrient digestibility of lactating sows. AB - The aim was to determine the effects of increasing dietary canola meal in substitution for soybean meal in lactation sow diets. Forty-five sows with an average parity of 1.8 (SD = 0.83) were randomly assigned to 1 of 3 dietary treatments ( = 15) consisting of a corn-based control diet and 2 diets with 15% and 30% canola meal formulated by replacing soybean meal with canola meal. Diets were formulated to be similar in standardized ileal digestible AA content and NE value and to meet or exceed nutrient recommendations for lactating sows. Sows were moved to farrowing on d 111 of gestation and fed the experimental diets until weaning on d 21. Sows were fed 3.0 kg/d from d 111 of gestation until parturition. After farrowing, feed was gradually increased through d 6 after which the diets were offered on an ad libitum basis until weaning. Sows were weighed and backfat thickness measured on d 111 of gestation and also on d 0, 7, and 21 postfarrowing. Litters were weighed on d 0, 7, and 21. Weaning to estrus interval in sows was also recorded. Blood and milk samples were collected 2 h postfeeding from sows on d 0, 7, and 21 and analyzed for plasma urea nitrogen (PUN) and milk composition. Fecal samples were collected on d 10, 11, and 12 postfarrowing to determine energy and nutrient digestibility. There were no dietary effects on lactation feed intake, sow BW and backfat change, weaning to estrus interval, and milk fat, protein, lactose, and urea composition. Also, there were no dietary effects on piglet ADG ( 0.10). Sows fed diets containing 15% and 30% canola meal had lower (linear, < 0.05) PUN values compared with those fed the control diet on d 0, 7, and 21 postfarrowing. Apparent total tract digestibility of DM, GE, CP, and P were reduced linearly ( < 0.05) with increasing canola meal inclusion. In conclusion, up to 30% canola meal in lactation diet can support satisfactory sow and suckling piglet performance. PMID- 28727124 TI - Similar effects of lysine deficiency in muscle biochemical characteristics of fatty and lean piglets. AB - The main objective of this work was to investigate the effects of feeding Lys deficient diets on muscle biochemical characteristics, particularly intramuscular fat concentration and fatty acid profile, in a fatty (Iberian) and a conventional pig genotype (Landrace * Large White [LDW]) maintained in identical experimental conditions. Performance and plasma metabolite changes were also monitored. Twenty eight barrows of 10 kg initial BW, 14 of Iberian and 14 of LDW breed, were randomly assigned to each of 2 experimental diets in a 2 * 2 factorial arrangement (2 breeds * 2 diets). Seven pigs were allocated to each treatment combination. Diets (isonitrogenous and isoenergetic; 200 g CP/kg DM and 14.7 MJ ME) based on barley, corn, corn gluten meal, and soybean meal, with identical composition, except for their Lys content (10.9 g/kg for the diet adequate in Lys and 5.2 g/kg for the diet deficient in Lys), were assayed. Pigs were housed in individual 2 m pens and fed at 85% of ad libitum intake of the Iberian genotype, of greater intake capacity. Daily feed allowance was based on BW individually measured each week. At 25 kg BW, pigs were slaughtered by exsanguination after electrical stunning. Blood samples were taken and longissimus dorsi and biceps femoris muscles were rapidly dissected and stored frozen prior to analysis. Performance was reduced in both pig breeds when fed Lys-deficient diets, particularly in LDW pigs (breed * diet interaction, < 0.05). Intramuscular fat content increased in longissimus dorsi of Iberian ( < 0.05) and in biceps femoris of both pig genotypes ( < 0.01) when fed Lys-deficient diets. Oleic acid increased ( < 0.05) and PUFA acid decreased ( < 0.01) in longissiumus dorsi and biceps femoris of pigs of both genotypes fed Lys-deficient diets. The proportion of oxidative fibers ( < 0.001) and free carnitine content ( < 0.05) increased in longissimus dorsi of both pigs types fed Lys-deficient diets. Plasma creatinine was greater in LDW pigs compared with Iberian pigs ( < 0.01). Urea and total cholesterol increased in pigs consuming Lys-deficient diets ( < 0.01). The plasma free carnitine concentration was higher in Iberian pigs than in LDW pigs ( < 0.059). No changes in plasma carnitine status due to dietary Lys supply were detected. Feeding Lys-deficient diets could be a suitable strategy for increasing intramuscular fat content in fatty and lean pigs. PMID- 28727126 TI - The incidence of metabolic syndrome in adolescents with different phenotypes of PCOS. AB - OBJECTIVES: To evaluate the incidence of metabolic syndrome in Turkish adolescents with different phenotypes of polycystic ovary syndrome (PCOS). MATERIAL AND METHODS: This cross-sectional study was performed on the Youth Center clinic of a tertiary referral hospital in Turkey. Adolescents with PCOS (n = 144) were classified into four phenotype groups according to the presence of oligo/anovulation (O), hyperandrogenism (H), and polycystic ovarian morphology (P) as follows: Phenotype A (O + H + P), Phenotype B (H + O), Phenotype C (H + P), Phenotype D (O + P). The adolescents gave early follicular phase blood samples for endocrine and metabolic tests. The incidence and the presence of parameters of metabolic syndrome were assessed among the four groups. RESULTS: In total, 54.9% of the adolescents with PCOS were overweight and 25.7% had metabolic syndrome. The incidence of metabolic syndrome in Phenotypes A-D were as follows: 39.5%, 20.5%, 26.5%, and 15.2%, respectively. Although body mass index was higher in the Phenotype A group, insulin resistance was similar in all of the phenotype groups. The most common dyslipidemia was low HDL-C levels and this was present in more than half of the adolescents with PCOS. Both body mass index and total testosterone levels were significantly higher in adolescents with metabolic syndrome in comparison to those without metabolic syndrome. CONCLUSIONS: Although low HDL-C levels and insulin resistance are common PCOS findings in adolescents, the metabolic profile seems to be worse in Phenotype A than the other phenotypes. Therefore, screening programs should evaluate patients based on the known risk factors and phenotypes for adolescents with PCOS. PMID- 28727125 TI - Usefulness of saline infusion sonohysterography and feeding artery imaging in endometrial polyp diagnosis. AB - OBJECTIVES: The aim of this study was to assess the usefulness of sonohysterography with feeding artery visualization using transvaginal sonography to diagnose endometrial polyps. MATERIAL AND METHODS: We conducted an observational study of 60 perimenopausal patients referred to the Department of Fetal Medicine and Gynaecology, Medical University of Lodz with abnormal uterine bleeding or suspicion of endometrial pathology based on sonography scan. In all 60 patients transvaginal sonography scan showed a possibility of an endometrial polyp. Of these, 46 underwent saline infusion sonohysterography with sonography visualization of a feeding artery. Pathological examination was performed on material collected during hysteroscopy. RESULTS: Sonography detection of endometrial polyp based on feeding artery visualization had a 40% sensitivity, whereas sonohysterographic polyp detection had a sensitivity of 75% and a specificity of 100%. The positive and negative predictive values of saline infusion sonohysterography in diagnosing endometrial polyps were estimated at 75% and 72% (95% CI: 52-86%), respectively. The combination of sonohysterography and feeding artery imaging in transvaginal sonography was 84% sensitive and 95% specific in detecting endometrial polyps. The positive and negative predictive values were: PPV = 96% and NPV = 89%. CONCLUSION: Saline infusion sonohysterography with feeding artery visualization may become a standard method in the diagnostics of endometrial polyps in perimenopausal women. PMID- 28727127 TI - The assessment of overall survival (OS) after adjuvant chemotherapy for patients with malignant endometrial cancer in Poland. AB - OBJECTIVES: In 2013 malignant endometrial cancers have amounted to 7.3% of all cancers diagnosed among women in the report by the Polish National Cancer Registry Raw prevalence rate amounted to 28.7, whereas standardised prevalence rate 15.6 per 100 000 population. Among the causes of death, these cancers amounted to 3% and were ranked ninth on the list of the most common causes of oncologic mortality of women. In the year 2013 a total of 1243 women died of malignant endometrial cancers. A stable increase of malignant endometrial cancer incidence has been observed for 2 decades. Despite that fact, the increase of the mortality incidence is at a much lower level, which demonstrates the much higher effectiveness of the treatment of such cancers. The recording rate of the malignant endometrial cancer mortality amounts to 95%, so the presented absolute numbers are reliable. Examining the clinical stages of malignant endometrial cancers, we can establish that approx. 85% of them are diagnosed at stage I or II according to the FIGO classification. Patients with advanced stages of cancer represent less than 15%. MATERIAL AND METHODS: retrospective analysis of endometrial body cancer prevalence data for the entire population of Poland, assessment of malignant endometrial cancer prevalence in the years 2008-2015 and overall survival probability in the population of patients undergoing adjuvant chemotherapy. RESULTS: The number of patients with a diagnosed malignant endometrial cancer within the studied period in Poland remains on a stable level (2008 - 30.6 thousand patients, 2015 - 40.2 thousand patients). Among all listed patients with the indica-tion of C54 each year approx. 20% enters hospital treatment. System therapy with chemotherapy drugs was used in approx. 1-2% of patients treated in hospitals. The average age of the patients was 64.9 years, and the median age 65 years. The num-ber of observations was 2085, including 1088 censored observations. The average survival for the sample under study was 30.67 month (SD = +/- 0.6); median survival time was 23.93 month. The number of censored observations was 1088 (52.16%). Probable survival of 1 year is achieved by 67.57% of patients, 2 years by 49.73%, 3 years by 40.68%, above 5 years 30.77%. CONCLUSIONS: The incidence of endometrial cancer in Poland in the years 2008-2015 continues to grow at 5% upward trend (in Europe 3.4-5.9). In Poland in 2012, crude incidence rate for cancer of the uterus was 29.8 and did not differ significantly from the results in countries such as Finland, Slovakia, Sweden, Belgium and Bulgaria. The overall survival after adjuvant chemotherapy for patients with malignant endometrial cancer in Poland shows considerable differences depending on the region of the country. PMID- 28727128 TI - Transvaginal six-arm mesh OPUR in women with apical pelvic organ prolapse - analysis of short-term results, pelvic floor ultrasound evaluation. AB - OBJECTIVES: Analysis of feasibility, efficacy and short-term results after six arm transvaginal mesh OPUR implantation in women with apical prolapse. MATERIAL AND METHODS: The same surgeon operated all of 39 women using mesh OPUR. Preoperatively patients had a standardized interview and clinical examination. Intraoperative and postoperative complications were analyzed. Postoperative evaluation included standardized interview, clinical examination and standardized pelvic floor ultrasound performed with 2D transvaginal probe and 4D abdominal probe. RESULTS: There was no complication that needed operative intervention. Hematomas in 3 patients resolved spontaneously. Transient voiding difficulties which lasted less than 7 days were observed in 5 patients. No erosion was observed. Comparison of pre- and postoperative results in 34 women revealed that in all 3 compartments improvement in POP-Q scale was statistically significant (p < 0.0000). One patient with malposition and rolled up mesh needed re-operation. During PFS-TV in 94.1% of patients urethra was normobile or hypermobile. In all of the patients urethral end of the mesh was positioned far enough from the middle part of the urethra (ultrasound) to implant suburethral sling without risk of collision. Sexually active women did not inform of any important discomfort or pain during intercourse. CONCLUSIONS: It seems that six-arm OPUR mesh, if implanted under strict surgical rules, gives low risk of complications and high chance to successfully reduce POP symptoms in short term after the operation. It seems that OPUR mesh should not have negative influence on the results after anti incontinence suburethral sling. PMID- 28727129 TI - Potentialization of N-a-tosyl-L-phenylalanine chloromethyl ketone (TPCK) cytotoxic activity by 2-(1-adamantylamino)-6-methylpyridine (AdAMP) in human ovarian cancer cells. AB - OBJECTIVES: TNF is one of the key cytokines involved in cancer development. TNF signaling can result in both stimulating and inhibitory signals that can result in opposite biological effects in cancerogenesis. 2-(1-adamantylamino)-6 methylpyridine (AdAMP) enhances TNF secretion whereas N-a-tosyl-L-phenylalanine chloromethyl ketone (TPCK) is a NF-kappaB inhibitor potentially stimulating proapoptotic TNF signals. The aim of the study was to assess the effect of TPCK in combination with AdAMP on human ovarian cells. MATERIAL AND METHODS: CAOV-1 human ovarian cell line was incubated with TPCK and AdAMP for 24 hours. The cytotoxic effect was evaluated in a crystal violet assay. A monoclonal antibody against TNF, Infliximab, was added to examine the possible mechanism of interactions. RESULTS: Depending on concentration, AdAMP potentialized cytotoxic activity of TPCK or had a synergistic effect with TPCK. Infliximab did not reverse cytotoxicity of AdAMP and TPCK and in some cytotoxic and non-cytotoxic concentrations even enhanced their cytotoxicity. CONCLUSIONS: AdAMP and TPCK cytotoxicity seems to be dependent on TNF signaling, however, the exact mechanism of interactions remains unclear. PMID- 28727130 TI - The utility of maternal mean platelet volume levels for early onset neonatal sepsis prediction of term infants. AB - OBJECTIVES: This study is aimed to evaluate the role of maternal mean platelet volume (MPV) levels for antenatal prediction marker of early onset neonatal sepsis in term infants born to mothers who have low infection risk. MATERIAL AND METHODS: A total of 62 pregnant women who gave birth in our hospital and whose neonates were admitted to a third level Neonatal Intensive Care Unit due to confirmed neonatal sepsis between January 2010 and May 2016 were selected as a study group. Within the same period, 68 women who gave birth to healthy neonates were enrolled as a control group. We compared maternal MPV values which were evaluated before delivery. The receiver operating characteristic (ROC) curves were drawn to evaluate the values maternal MPV in the diagnosis of neonatal sepsis. RESULTS: MPV levels were detected statistically higher in the study group than the control group (8.27 +/- 1.85 vs. 8.98 +/- 1.16) (p = 0.001). CONCLUSION: The maternal serum MPV level is a clinically useful, non-invasive and reliable marker in antenatal prediction of EOS. PMID- 28727131 TI - Evaluation of the hematologic system as a marker of subclinical inflammation in hyperemesis gravidarum: a case control study. AB - OBJECTIVES: Current evidence suggests that subclinical inflammation plays a significant role in the development of hyperemesis gravidarum (HEG). Simple hematological markers, such as mean platelet volume (MPV), neutrophil-to lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR), have been shown to reflect inflammatory burden and disease activity in several disorders. This study aimed to determine the diagnostic value of these hematological parameters for HEG. MATERIAL AND METHODS: A total of 54 HEG patients and 58 age- and gestational-age-matched control subjects were studied. NLR, MPV, PLR, platelet distribution width (PDW), and red cell distribution width (RDW) values in all patients were calculated and recorded from complete blood cell counts. RESULTS: For HEG patients, the median NLR was 3.2 (1.6-7.1), and the median PLR was 143.7 (78.1-334.6); for control subjects, the values were 2.1 (1.0-4.7) and 93.1 (47.3 194.7), respectively. Although both the NLR and PLR of HEG patients were found to be significantly higher than in the controls, no significant difference was found between the study groups in terms of MPV, RDW, or PDW. Correlation analysis revealed a significant correlation between NLR and CRP (r = 0.872, p < 0.001). CONCLUSIONS: Our results show that peripheral blood NLR and PLR values can reflect inflammatory burden in HEG patients and can be used as markers for HEG. PMID- 28727132 TI - Analysis of intravaginal misoprostol 0.2 mg versus intracervical dinoprostone 0.5 mg doses for labor induction at term pregnancies. AB - OBJECTIVES: Labor-induction methods are used in about 23% of labors. Most commonly, pharmacological methods are used to pre-induct the labor with dinoprostone - a PGE2 analog, and misoprostol - a PGE1 analog. The aim of this study was to evaluate two pharmacological methods of labor induction with the use of prostaglandins applied via an intravagi-nal insert containing misoprostol at a dose of 0.2 mg and intracervical gel containing dinoprostone at a dose of 0.5 mg. MATERIAL AND METHODS: This retrospective study was conducted on a group of 50 adult patients qualified for the pre-induction of labor. Following data were recorded: the time from the drug administration to the beginning of regular contractile function, the time from administration to amniotic fluid rupture, the time from medicament administration to the vaginal labor or caesarean section, the duration of I, II and III stages of labor, the delivery method and in the event of caesarean section - the indications for surgery. RESULTS: In comparison to dinoprostone, the misoprostol application was found to shorten the time from drug administration to amniotic fluid rupture by 14.1 hours, the time to the beginning of the first stage of labor by 11.7 hours and from the drug administration to the delivery by 17.3 hours (p-value < 0.05). The duration of the first stage of labor in the misoprostol group was shorter by 1.2 hours than in dinoprostone group (p-value < 0.05). CONCLUSIONS: Application of intravaginal insert with misoprostol at a dose of 0.2 mg appears to be a more effective method of labor induction in comparison to intracervical gel with dinoprostone at a dose of 0.5mg. Thorough analysis of these methods requires further studies. PMID- 28727133 TI - Is unexplained elevated maternal serum alpha-fetoprotein still important predictor for adverse pregnancy outcome? AB - OBJECTIVES: The purpose of this study was to determined the predictive value of maternal serum alpha-fetoprotein (MSAFP) as a marker for adverse pregnancy outcomes. MATERIAL AND METHODS: This study was carried out at Dr. Zekai Tahir Burak Women's Health Education and Research Hospital between 2009 and 2010. This study included a total of 1,177 pregnant women, including 170 in the study group and 1,007 in the control group. Pregnancy outcomes and characteristics were analyzed with regard to the MSAFP value. RESULTS: Gestational week, birth weight and APGAR scores were significantly lower in the elevated MSAFP group (p < 0.001). Adverse pregnancy outcomes, such as preterm delivery, preterm premature rupture of membranes (PPROM), oligohydramnios and intrauterine growth restriction (IUGR) rates were increased in the elevated MSAFP group. CONCLUSIONS: Although ultrasound outweighs as a screening method for neural tube defects and non invasive prenatal testing outweighs for aneuploidy screening MSAFP level in the second trimester is still an important predictor for poor maternal/fetal outcomes. PMID- 28727134 TI - Biological markers with potential clinical value in endometrial cancer - review of the literature. AB - Endometrial carcinoma (EC) is the most common malignancy of the female genital tract encountered in western countries, making it the fourth most common cancer in women. The incidence of uterine cancer is on the rise throughout the developed world where diagnosis is increasingly observed among younger patients. With regard to this, attention has been focused on conducting more studies to achieve a better understanding of the molecular genetics related to endometrial carcinogenesis. Over the years, EC has been classified into two broad histopathological subtypes based on the mechanism of development, and we can therefore observe specific biomarkers related to the respective subtype. Based on this idea, more research has been carried out in the last decade, using biotechnological methods, with the aim to identify new potential tumor markers. By translating these findings into clinical use one may facilitate accurate diagnosis and prognostic prediction, and contribute to individualized treatment. Without a doubt, there is a demanding need to identify biomarkers that can be adopted in clinical practice in order to reduce the time needed to obtain diagnosis. Such markers may be of great value in improving patient outcome. However, a number of problems remain to be solved before this becomes a reality. This paper briefly reviews the current status of rising biomarkers in EC. PMID- 28727135 TI - The role of metalloproteinases in endometrial remodelling during menstrual cycle. AB - Endometrium is the only tissue in the human body subject to cyclic transformations under the influence of ovarian steroid hormones. As estradiol and progesterone balance throughout the physiological menstrual cycle changes, so does the expression of metalloproteinases (MMPs). These endopeptides are responsible for keeping the balance between the process of synthesis and degradation of extracellular matrix proteins. Thus, MMP's take part in sustaining physiological stability of the endometrium. A number of MMPs found in the endometrial tissue and their activity is related to menstrual cycle phase. This paper is an up-to-date review of literature of Medline database. The search was conducted for key words including "matrix metalloproteinases", "MMPs", "TIMPs" and "tissue inhibitors of metalloproteinases". Over 1092 publications regarding interdependence and interplay between ovarian hormones and the role of various MMPs and their inhibitors in normal endometrial remodelling and in pathological conditions were analysed and critically reviewed. PMID- 28727137 TI - National evaluation of multidisciplinary quality metrics for head and neck cancer. AB - BACKGROUND: The National Quality Forum has endorsed quality-improvement measures for multiple cancer types that are being developed into actionable tools to improve cancer care. No nationally endorsed quality metrics currently exist for head and neck cancer. METHODS: The authors identified patients with surgically treated, invasive, head and neck squamous cell carcinoma in the National Cancer Data Base from 2004 to 2014 and compared the rate of adherence to 5 different quality metrics and whether compliance with these quality metrics impacted overall survival. The metrics examined included negative surgical margins, neck dissection lymph node (LN) yield >= 18, appropriate adjuvant radiation, appropriate adjuvant chemoradiation, adjuvant therapy within 6 weeks, as well as overall quality. RESULTS: In total, 76,853 eligible patients were identified. There was substantial variability in patient-level adherence, which was 80% for negative surgical margins, 73.1% for neck dissection LN yield, 69% for adjuvant radiation, 42.6% for adjuvant chemoradiation, and 44.5% for adjuvant therapy within 6 weeks. Risk-adjusted Cox proportional-hazard models indicated that all metrics were associated with a reduced risk of death: negative margins (hazard ratio [HR] 0.73; 95% confidence interval [CI], 0.71-0.76), LN yield >= 18 (HR, 0.93; 95% CI, 0.89-0.96), adjuvant radiation (HR, 0.67; 95% CI, 0.64-0.70), adjuvant chemoradiation (HR, 0.84; 95% CI, 0.79-0.88), and adjuvant therapy <=6 weeks (HR, 0.92; 95% CI, 0.89-0.96). Patients who received high-quality care had a 19% reduced adjusted hazard of mortality (HR, 0.81; 95% CI, 0.79-0.83). CONCLUSIONS: Five head and neck cancer quality metrics were identified that have substantial variability in adherence and meaningfully impact overall survival. These metrics are appropriate candidates for national adoption. Cancer 2017;123:4372-81. (c) 2017 American Cancer Society. PMID- 28727136 TI - A multidimensional view of racial differences in access to prostate cancer care. AB - BACKGROUND: Racial disparities in prostate cancer treatment and outcomes are widespread and poorly understood. In the current study, the authors sought to determine whether access to care, measured across multiple dimensions, contributed to racial differences in prostate cancer. METHODS: The Philadelphia Area Prostate Cancer Access Study (P2 Access) included 2374 men diagnosed with localized prostate cancer between 2012 and 2014. Men were surveyed to assess their experiences accessing care (response rate of 51.1%). The authors determined appointment availability at 151 urology practices using simulated patient telephone calls and calculated travel distances using geospatial techniques. Multivariable logistic regression models were used to determine the association between 5 different domains of access (availability, accessibility, accommodation, affordability, and acceptability) and receipt of treatment, perceived quality of care, and physician-patient communication. RESULTS: There were 1907 non-Hispanic white and 394 black men in the study cohort. Overall, approximately 85% of the men received definitive treatment with no differences noted by race. Black men were less likely to report a high quality of care (69% vs 81%; P<.001) and good physician-patient communication (60% vs 71%; P<.001) compared with white men. In adjusted models, none of the 5 domains of access were found to be associated with definitive treatment overall or with radical prostatectomy. All access domains were associated with perceived quality of care and communication, although these domains did not mediate racial disparities. CONCLUSIONS: To the authors' knowledge, the current study presents the first comprehensive assessment of prostate cancer care access, treatment, and patient experience, demonstrating that although access was related to overall perceived quality of care and better physician-patient communication, it did not appear to explain observed racial differences. Cancer 2017;123:4449-57. (c) 2017 American Cancer Society. PMID- 28727138 TI - Partial diel migration: A facultative migration underpinned by long-term inter individual variation. AB - The variations in migration that comprise partial diel migrations, putatively occur entirely as a consequence of behavioural flexibility. However, seasonal partial migrations are increasingly recognised to be mediated by a combination of reversible plasticity in response to environmental variation and individual variation due to genetic and environmental effects. Here, we test the hypothesis that while partial diel migration heterogeneity occurs primarily due to short term within-individual flexibility in behaviour, long-term individual differences in migratory behaviour also underpin this migration variation. Specifically, we use a hierarchical behavioural reaction norm approach to partition within- and among-individual variation in depth use and diel plasticity in depth use, across short- and long-term time-scales, in a group of 47 burbot (Lota lota) tagged with depth-sensing acoustic telemetry transmitters. We found that within-individual variation at the among-dates-within-seasons and among-seasons scale, explained the dominant proportion of phenotypic variation. However, individuals also repeatedly differed in their expression of migration behaviour over the 2 year study duration. These results reveal that diel migration variation occurs primarily due to short-term within-individual flexibility in depth use and diel migration behaviour. However, repeatable individual differences also played a key role in mediating partial diel migration. These findings represent a significant advancement of our understanding of the mechanisms generating the important, yet poorly understood phenomena of partial diel migration. Moreover, given the pervasive occurrence of diel migrations across aquatic taxa, these findings indicate that individual differences have an important, yet previously unacknowledged role in structuring the temporal and vertical dynamics of aquatic ecosystems. PMID- 28727139 TI - Effect of solvent/detergent-treated pooled plasma on fibrinolysis in reconstituted whole blood. AB - BACKGROUND: Hyperfibrinolysis has been observed in patients heavily transfused with solvent/detergent-treated pooled plasma (S/D plasma). We compared coagulation and fibrinolytic variables in blood containing S/D plasma with blood containing fresh-frozen plasma (FFP), with and without alpha2-antiplasmin or tranexamic acid (TXA) supplementation. STUDY DESIGN AND METHODS: Whole blood samples were reconstituted from red blood cells, platelet (PLT) concentrates, and varying mixtures of FFP and S/D plasma. Hematocrit and PLT count of reconstituted whole blood samples were varied. For a subset of runs, alpha2-antiplasmin or TXA was added to S/D plasma whole blood samples. Thromboelastography (TEG) analysis was performed to assess 50% clot lysis time (CLT50% ), maximum amplitude (MA), and initial clotting time (R-time). RESULTS: The change in CLT50% of whole blood as the plasma compartment transitions from FFP to S/D plasma was -52% (95% confidence interval [CI], -60% to -45%; p < 0.001). PLT count strengthened the effect, leading to an additional change in CLT50% of -8% (95% CI, -14% to -2%; p = 0.012) as PLT count increased from 10 * 109 to 150 * 109 /L. MA and R-time were not associated with fraction of S/D plasma in whole blood. alpha2-Antiplasmin and TXA restored clot lysis time in S/D plasma whole blood. CONCLUSION: Whole blood with S/D plasma has shorter clot lysis times in vitro compared to whole blood with FFP. alpha2-Antiplasmin and TXA restore clot lysis time of S/D plasma whole blood to that of FFP whole blood. Clinicians should be aware of the decreased clot lysis time associated with S/D plasma transfusion. PMID- 28727140 TI - Respiratory sinus arrhythmia in the fourth decade of life depends on birth weight and the DRD4 gene: Implications for understanding the development of emotion regulation. AB - INTRODUCTION: The long allele of the DRD4 gene can confer different behavioral and emotional phenotypes depending upon environmental exposure, although the physiological changes underlying these phenotypes are not fully known. We sought to extend this work by assessing the interaction of the DRD4 gene and exposure to perinatal adversity (indexed by extremely low birth weight [ELBW]) on resting respiratory sinus arrhythmia (RSA), a neurophysiological measure of emotion regulation, in adulthood. METHODS: We examined the interaction between the DRD4 gene and perinatal adversity on RSA at age 30-35 in a longitudinal cohort of ELBW survivors (n = 49) and NBW controls (n = 63). Buccal DNA samples were genotyped for short and long carriers of the exon III DRD4 VNTR gene. Resting RSA was assessed by electrocardiogram. RESULTS: We report an interaction between birth weight status and DRD4 gene (F = 9.42, p = 0.003) in predicting RSA, such that DRD4 long carriers had the highest and lowest resting RSA depending on whether they were born NBW or ELBW, respectively. DRD4 short carriers were less sensitive to birth weight. Additionally, reduced RSA was correlated with a history of major depressive disorder, suggesting it was a reliable index of emotion dysregulation. DISCUSSION: These results suggest that the perinatal environment influences autonomic nervous system functioning in individuals with genotypes that confer additional sensitivity. Whether the long-term autonomic outcomes of this environmental sensitivity are beneficial or detrimental appears to depend on the quality of the early life environment, and may influence the development of emotion regulatory and psychiatric problems in adulthood. PMID- 28727141 TI - Etiologic and differential diagnostic significance of tumor location in the supraclavicular fossa. AB - OBJECTIVE: Patients presenting with a cervical mass are common for head and neck specialists and present a diagnostic challenge against the backdrop of a wide variety of etiologies. The objective of the present study was to evaluate the significance of a mass in the supraclavicular fossa for etiology, diagnostic procedure, and therapy. STUDY DESIGN: Individual retrospective cohort study. METHODS: We reviewed the data of 211 consecutive cases (116 male, 95 female) with excisional biopsy or tumor removal of a supraclavicular mass. RESULTS: In 202 of 211 cases, a biopsy was taken from a lymph node. In 182 biopsies, a malignant lymphadenopathy was found (117 metastases, 65 malignant lymphoma). The histologic findings of metastatic diseases were adenocarcinoma (48), followed by squamous cell carcinoma (22). The majority of primary carcinomas were located below the clavicle (94), in the lung (32), in the breast (29), and in the head and neck region (18). In the left supraclavicular fossa, only metastases of the genitourinary tract were significantly more frequent (16 of 17). In nonmalignant tumors (29), tuberculosis (11) was most prevalent. In 79% of biopsies, the neck mass was the first manifestation of the disease. CONCLUSION: The location of a cervical mass in the supraclavicular fossa provides a strong indication of malignancy. A biopsy is mandatory in the majority of patients presenting with a supraclavicular mass. In cases of metastatic disease, the location of a cervical mass helps identify the primary site. Histologic findings are essential for further diagnostic steps, therapy, and prognosis. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:646-650, 2018. PMID- 28727143 TI - Predator ontogeny affects expression of inducible defense morphology in rotifers. AB - Many prey organisms show induced morphological responses to predators including changes in protective spine length, such as in rotifers, although previous studies have mainly focused on how prey become larger than the predator gape-size optimum. Here we show that a large-sized predator makes prey rotifers escape below the gape-size optimum of the predator by reducing spine length. In experiments and field studies we show that during part of their ontogeny fish larvae feed intensively on the common rotifer Keratella cochlearis, and that larval fish predation reduces rotifer spine length both through induction of shorter spines and selective predation on long-spined individuals. We also describe a global scale pattern in spine length of K. cochlearis, showing an increasing variance in spine length with latitude. This pattern may be explained by differences in fish reproduction from once per year at high latitudes to several times per year at lower latitudes. That spine length is adaptively adjusted to the ontogeny of a dominant predator taxa provides a novel view on our understanding of factors affecting temporal and spatial variations in prey defense morphology. PMID- 28727142 TI - Genomic and transcriptomic heterogeneity of colorectal tumours arising in Lynch syndrome. AB - Colorectal cancer (CRC) arising in Lynch syndrome (LS) comprises tumours with constitutional mutations in DNA mismatch repair genes. There is still a lack of whole-genome and transcriptome studies of LS-CRC to address questions about similarities and differences in mutation and gene expression characteristics between LS-CRC and sporadic CRC, about the molecular heterogeneity of LS-CRC, and about specific mechanisms of LS-CRC genesis linked to dysfunctional mismatch repair in LS colonic mucosa and the possible role of immune editing. Here, we provide a first molecular characterization of LS tumours and of matched tumour distant reference colonic mucosa based on whole-genome DNA-sequencing and RNA sequencing analyses. Our data support two subgroups of LS-CRCs, G1 and G2, whereby G1 tumours show a higher number of somatic mutations, a higher amount of microsatellite slippage, and a different mutation spectrum. The gene expression phenotypes support this difference. Reference mucosa of G1 shows a strong immune response associated with the expression of HLA and immune checkpoint genes and the invasion of CD4+ T cells. Such an immune response is not observed in LS tumours, G2 reference and normal (non-Lynch) mucosa, and sporadic CRC. We hypothesize that G1 tumours are edited for escape from a highly immunogenic microenvironment via loss of HLA presentation and T-cell exhaustion. In contrast, G2 tumours seem to develop in a less immunogenic microenvironment where tumour promoting inflammation parallels tumourigenesis. Larger studies on non-neoplastic mucosa tissue of mutation carriers are required to better understand the early phases of emerging tumours. Copyright (c) 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 28727144 TI - Density-mediated indirect effects from active predators and narrow habitat domain prey. AB - The hunting-mode-habitat-domain-range framework suggests that the mechanism driving trophic cascades (i.e., trait-mediated indirect interactions [TMIIs] vs. density-mediated indirect interactions [DMIIs]) should depend upon the functional traits of predators and prey. For example, trophic cascades containing active, broad habitat domain range (BHDR) predators interacting with narrow habitat domain range (NHDR) prey are predicted to arise primarily via TMIIs, because these prey should reduce their conspicuous activity in the presence of these predators. Unfortunately, this hypothesis is difficult to test given the strong bias against studies assessing trophic cascades containing NHDR prey. Furthermore, this hypothesis ignores evidence that (1) active predators can have high consumption rates on prey, (2) continuously responding to active predators foraging across broad areas is energetically costly for prey, and (3) cues from active, BHDR predators may not influence prey density. We examined the TMIIs and total indirect interaction (TII) produced during interactions between an active, BHDR ladybeetle predator (Naemia seriata) and its NHDR prey (scale insects). We exposed scale insects to nonlethal and lethal ladybeetle predators in laboratory mesocosms for 15 weeks. We measured the growth of the scale insect's host plant (cordgrass) and the population density of scale insects. Contrary to theory, nonlethal ladybeetles did not induce TMIIs. However, lethal ladybeetles increased cordgrass total and root dry biomass by 36% and 44%, respectively, suggesting the presence of strong DMIIs. Additionally, both lethal and nonlethal ladybeetles reduced scale insect population density. Our findings suggest that DMIIs, rather than TMIIs, can result from interactions between active BHDR predators and NHDR prey. PMID- 28727145 TI - Transcriptional control of photosynthetic capacity: conservation and divergence from Arabidopsis to rice. AB - Contents 32 I. 32 II. 33 III. 36 IV. 41 43 References 43 SUMMARY: Photosynthesis is one of the most important biological processes on Earth. It provides the consumable energy upon which almost all organisms are dependent, and modulates the composition of the planet's atmosphere. To carry out photosynthesis, plants require a large cohort of genes. These genes encode proteins that capture light energy, store energy in sugars and build the subcellular structures required to facilitate this energy capture. Although the function of many of these genes is known, little is understood about the transcriptional networks that coordinate their expression. This review places our understanding of the transcriptional regulation of photosynthesis in Arabidopsis thaliana in an evolutionary context, to provide new insight into transcriptional regulatory networks that control photosynthesis gene expression in grasses. The similarities and differences between the rice and Arabidopsis networks are highlighted, revealing substantial disparity between the two systems. In addition, avenues are identified that may be exploited for photosynthesis engineering projects in the future. PMID- 28727146 TI - Antimicrobial Effects of Silver Nanoparticles Synthesized by Fatsia japonica Leaf Extracts for Preservation of Citrus Fruits. AB - Due to their potent antimicrobial activity, silver nanoparticles (AgNPs) synthesized by biomass might be promising in food preservation, whereas effects of AgNPs on Penicillium italicum-induced rot of Citrus fruits have not been investigated. In this study, a novel AgNPs biosynthesis method was developed based on Fatsia japonica leaf extracts. It was revealed that concentrations of leaf extracts, AgNO3 and NaCl affected AgNPs yields and particle sizes obviously. Under the optimized conditions (8 mg/mL extracts, 2 mM AgNO3 and 1 mM NaCl), AgNPs, synthesized within 80 min, showed potent preservative effect against P. italicum-induced rot of Citrus fruits. Furthermore, inhibition test and TEM analysis indicated that as-synthesized AgNPs caused cell deformation, cytoplasmic leakage, and thereupon cell death of P. italicum. Moreover, AgNPs had significant antibacterial activities against Escherichia coli and Staphylococcus aureus, which might be beneficial for Citrus fruits preservation. Altogether this study develops an efficient AgNPs synthesis method and a novel preservation method for Citrus fruits. PMID- 28727147 TI - The role of medical/nursing skills training in caregiver confidence and burden: A CanCORS study. AB - BACKGROUND: Informal cancer caregivers provide essential support to cancer patients, including performing direct medical/nursing tasks, assisting with activities of daily living, and offering social support. This study examined associations between the receipt of medical/nursing skills training and the caregiver burden as well as the mediation of caregiving confidence on this relationship in a sample of caregivers of lung and colorectal cancer patients. METHODS: Caregivers who had been identified by cancer patients in the Cancer Care Outcomes Research and Surveillance consortium completed a questionnaire assessing the care provided, the type of medical/nursing skills training received, the burden (measured with the modified short-form Zarit Burden Interview), and the confidence in caring for their patient's physical needs. Regression models that had been adjusted for sociodemographic, caregiver, and care recipient characteristics assessed the relationship between training received and burden, and a mediation analysis assessed the role of confidence in this relationship. RESULTS: Six hundred forty-one caregivers performed some type of medical/nursing task, with 59% (n = 377) reporting that they did not receive training for all the care provided. Caregivers reported moderate levels of burden (mean summary score, 32.07; standard deviation, 12.66; possible range, 14-70), and a lack of receipt of training was associated with greater levels of burden (b = 2.60; standard error, 0.98; P = .01). Confidence partially mediated the relation between training and burden (Sobel's t = 1.90; P = 0.03). CONCLUSIONS: As the number of cancer patients and caregivers increases, understanding how best to reduce the caregiver burden is necessary. Skills training is a potential area for interventions, but research on how best to provide training for caregivers (ie, the content, mode of delivery, and timing) is needed. Cancer 2017;123:4481-7. (c) 2017 American Cancer Society. PMID- 28727148 TI - Treatment of intrahepatic congenital portosystemic shunts in dogs: a systematic review. AB - The aim of this study was to establish the evidence base for the treatment of intrahepatic congenital portosystemic shunts in dogs through a systematic review of the pertinent literature. Studies were filtered for evidence to answer the question "Which of the treatment options for intrahepatic CPSS in dogs offers the best short- and long-term outcome?" Studies were assigned a level of evidence based on a system published by the Oxford Centre for Evidence-Based Medicine. Thirty-two studies were included in the review. Twenty-six provided level 4 evidence and six provided level 5 evidence. There were no level 1, 2 or 3 studies. One study compared surgical treatment with medical management and one study compared suture ligation with ameroid constrictor placement. The remaining studies were case series describing the outcome for one treatment method alone. Methods and timings of assessments of short- and long-term outcomes were highly varied, making direct comparisons challenging. The evidence regarding the treatment of intrahepatic congenital portosystemic shunts in dogs is weak, with only two studies directly comparing treatments. There is a lack of evidence regarding short- and long-term outcomes on which to base clinical decisions. PMID- 28727149 TI - Aortic microcalcification is associated with elastin fragmentation in Marfan syndrome. AB - Marfan syndrome (MFS) is a connective tissue disorder in which aortic rupture is the major cause of death. MFS patients with an aortic diameter below the advised limit for prophylactic surgery (<5 cm) may unexpectedly experience an aortic dissection or rupture, despite yearly monitoring. Hence, there is a clear need for improved prognostic markers to predict such aortic events. We hypothesize that elastin fragments play a causal role in aortic calcification in MFS, and that microcalcification serves as a marker for aortic disease severity. To address this hypothesis, we analysed MFS patient and mouse aortas. MFS patient aortic tissue showed enhanced microcalcification in areas with extensive elastic lamina fragmentation in the media. A causal relationship between medial injury and microcalcification was revealed by studies in vascular smooth muscle cells (SMCs); elastin peptides were shown to increase the activity of the calcification marker alkaline phosphatase (ALP) and reduce the expression of the calcification inhibitor matrix GLA protein in human SMCs. In murine Fbn1C1039G/+ MFS aortic SMCs, Alpl mRNA and activity were upregulated as compared with wild-type SMCs. The elastin peptide-induced ALP activity was prevented by incubation with lactose or a neuraminidase inhibitor, which inhibit the elastin receptor complex, and a mitogen-activated protein kinase kinase-1/2 inhibitor, indicating downstream involvement of extracellular signal-regulated kinase-1/2 (ERK1/2) phosphorylation. Histological analyses in MFS mice revealed macrocalcification in the aortic root, whereas the ascending aorta contained microcalcification, as identified with the near-infrared fluorescent bisphosphonate probe OsteoSense 800. Significantly, microcalcification correlated strongly with aortic diameter, distensibility, elastin breaks, and phosphorylated ERK1/2. In conclusion, microcalcification co-localizes with aortic elastin degradation in MFS aortas of humans and mice, where elastin-derived peptides induce a calcification process in SMCs via the elastin receptor complex and ERK1/2 activation. We propose microcalcification as a novel imaging marker to monitor local elastin degradation and thus predict aortic events in MFS patients. Copyright (c) 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 28727151 TI - Erratum. PMID- 28727150 TI - Generalized convulsive seizures are associated with ketamine anesthesia in a rhesus macaque (Macaca mulatta) undergoing urodynamic studies and transcutaneous spinal cord stimulation. AB - A female rhesus macaque developed two episodes of generalized convulsions during transcutaneous spinal cord stimulation (TSCS) and urodynamic studies under ketamine anesthesia. The seizures took place in the absence of active TSCS and bladder pressure elevation. Ketamine anesthesia remains the primary risk factor for the convulsions during these experimental procedures. PMID- 28727153 TI - Month of birth is associated with the subsequent diagnosis of autoimmune hypothyroidism. A nationwide Danish register-based study. AB - BACKGROUND: The triggering of thyroid autoimmunity in the genetically susceptible remains a conundrum. Environmental exposures during gestation and/or early postnatally have proponents, as suggested in diabetes mellitus, with a higher incidence of births during spring and summer. Whether the development of autoimmune hypothyroidism (AIT) is influenced by month or season of birth is less clear. METHOD: Nationwide cohort study of 111 565 individuals diagnosed with AIT and four euthyroid controls per case, matched according to age and sex, were identified from Danish health registers. Differences in month of birth across the year were evaluated by the Walter-Elwood test. The risk of patients with AIT being born in a certain month or season of the year was calculated using a Cox regression model. RESULTS: There was a significant difference in birth month between cases and controls, P<.001. Individuals with AIT had a significantly increased risk of being born in June (Hazard ratio 1.04; 95% Confidence interval (CI): 1.02-1.08) and in the summer (June-August; HR 1.02; 95%CI: 1.01-1.04). CONCLUSION: In this large-scale nationwide cohort study, we found a higher risk of AIT when born in the summer season or more specifically in June, supporting the hypothesis that seasonal variations in exposures-gestationally and/or early postnatally-may contribute to the development of AIT. PMID- 28727154 TI - Comments on "Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease: Systematic review and meta-analysis". PMID- 28727155 TI - Mucosal-associated Invariant Cells are Deficient in Systemic Sclerosis. AB - Systemic sclerosis (SSc) is an autoimmune disease, characterized by fibrosis of the skin and other organs, vascular impairment and deficient immune responses. Mucosal-associated invariant T cells (MAIT) have been involved in various inflammatory and autoimmune diseases. The aims of this study were to determine the frequencies of MAIT cells in the blood of patients with systemic sclerosis (SSc) and to compare their distribution in different types of SSc. Blood samples from patients with SSc and healthy controls were examined by flow cytometer to analyse the frequencies of MAIT and gammadelta T cells. We demonstrate that in SSc the frequencies and absolute numbers of MAIT and gammadelta T cells are significantly reduced in comparison with healthy controls. MAIT and gammadelta T cells did not correlate with C-reactive protein, BNP, pulmonary involvement or median skin fibrosis scale, steroid amount or disease duration. In addition, MAIT and gammadelta T cells decrease did not stratify with gender, interstitial lung disease or active digital ulcers. Functional studies are necessary to determine the signification of MAIT cells decrease in systemic sclerosis. PMID- 28727156 TI - Safety and effectiveness of a 6-French MRI conditional pacemaker lead: The INGEVITYTM clinical investigation study results. AB - BACKGROUND: The design of pacemaker leads has continued to evolve; ease of lead handling, improved electrical performance, and magnetic resonance imaging (MRI) conditional aspects have become more important, while safety remains critical. The INGEVITYTM family leads was designed to provide MRI conditional aspects, decreased diameter, and improved performance of pacemaker leads. The INGEVITY study is an investigational device exemption trial evaluating the acute and chronic safety and effectiveness of these leads. METHODS: Consecutive patients were included in 77 institutions worldwide, where 1,657 leads (846 right ventricular active fixation leads, 213 right ventricular passive fixation leads, 121 right atrial passive fixation preformed J-leads, and 477 right atrial active fixation leads) were implanted or attempted in 1,060 subjects. RESULTS: At 3 month follow-up, the electrical performance were: mean pacing threshold 0.67 V at 0.5-ms pulse width, pacing impedance 773 ohms, mean P-wave amplitude 4.8 mV, and R-wave amplitude 16.5 +/- 6.5 mV. Over a median follow-up of 31 months, 93 subjects died and 33 subjects reported lead-related complications. Lead-related complication-free rate from 0 to 3 months and 3 to 12 months for all leads was 98.4% and 99.7%, respectively. The hazard of lead-related complications was observed to be decelerating over the course of follow-up (Weibull shape = 0.23). The overall lead dislodgment rate observed in the study was 1.3%, the perforation rate was 0.0%, and the pericardial effusion rate was 0.3%. CONCLUSIONS: The clinical performance of the INGEVITY lead demonstrated a high lead-related complication-free rate over 12 months of follow-up and excellent electrical characteristics. PMID- 28727157 TI - Reply. PMID- 28727158 TI - HPLC fingerprinting approach for raw material assessment and unit operation tracking for IVIG production from Cohn I+II+III fraction. AB - The plasma-derived IgG used either for diagnostic purpose or intravenous application (in form of IVIG) in various medical therapies is certainly gaining more and more attention on annual basis. Different manufacturing processes are used to isolate immunoglobulins from human plasma. However, a quest for alternative paths in IgG isolation not only requires development of the most efficient isolation process, but also a rapid and reliable analytics to track the purification. Fast and reliable fingerprint-based method for characterization of IgG prepared from Cohn I+II+III paste is presented in this paper. The fingerprint method bases on partial separation of proteins in linear gradient on CIMacTM quaternary amine, strong anion exchange group (QA) 0.1 mL column. Partial separation of proteins does not allow simple quantitative analysis of the samples during the IgG isolation from Cohn I+II+III fraction paste, but very accurate qualitative information about the composition of the sample can be obtained in less than 5 min. From the differences in the chromatograms of various samples, the ratio between IgG and impurities in each sample can be easily assessed. The method is suitable for input material control, in-line monitoring of the downstream processing, final control of the products, as well as in stability studies and enables taking fast and accurate decisions during fractionation process. PMID- 28727159 TI - Children with Heavy Prenatal Alcohol Exposure Exhibit Atypical Gait Characteristics. AB - BACKGROUND: Impaired motor function in children with histories of prenatal exposure to alcohol has been previously reported but, to date, no studies using quantitatively based analyses have been performed to assess gait in these children. METHODS: Gait of children with (n = 18) or without (n = 26) prenatal alcohol exposure was assessed using an electronically instrumented walkway. Children completed blocks of trials traversing the walkway with different combinations of walking condition (increased, self-paced, and decreased cadence) and direction (forward and backward). Gait velocity, cadence, stride length, step width, foot angle, and double support time, as well as the variability of these temporal-spatial markers, were used to assess gait. RESULTS: Results indicated that, in comparison with typically developing children, alcohol-exposed children produced exaggerated foot angle and increased step width. Additionally, alcohol exposed children produced greater intrasubject variability of gait velocity and walking cadence while walking forward and backward, and greater variability in step width when walking backward and for all 3 walking conditions. CONCLUSIONS: The results indicate that selected gait markers are adversely affected by prenatal exposure to alcohol. Clinicians and front-line personnel (e.g., teachers) should provide movement enriched experiences to help ameliorate these alcohol-related deficits. PMID- 28727160 TI - The long-term effect of a zinc acetate and chlorhexidine diacetate containing mouth rinse on intra-oral halitosis-A randomized clinical trial. AB - AIM: To evaluate the long-term effects of a zinc acetate and chlorhexidine diacetate mouth rinse (Zn/CHX) on intra-oral halitosis. MATERIALS AND METHODS: Forty-six adults with intra-oral halitosis were randomized into a 6-month, double blind, placebo-controlled clinical study. The presence of intra-oral halitosis was evaluated at baseline, 3 and 6 months after treatment by assessment of organoleptic score (OLS) and by total volatile sulphur compounds (T-VSC), hydrogen sulphide (H2 S) and methyl mercaptan (MM) concentrations in exhaled air. RESULTS: A Zn/CHX mouth rinse provided significantly better control of intra-oral halitosis than a placebo mouth rinse. At 3 and 6 months, individuals rinsing with the Zn/CHX rinse presented with reductions of the OLS, T-VSC (p < .01, respectively), H2 S (p < .001), and MM (p < .01) in subjects' exhaled air. At 6 months, 68.2% of individuals using the Zn/CHX rinse experienced a 1 or 2 category improvement in OLS compared with 19.1% of placebo-treated subjects. 91% of subjects in the Zn/CHX group were categorized as being effectively treated for intra-oral halitosis (i.e. H2 S < 112 ppb), compared to 43% in the placebo group. CONCLUSION: Zn/CHX mouth rinse provides effective long-term efficacy against intra-oral halitosis, assessed both objectively and subjectively. With regular rinsing, the effect was sustained for 6 months. PMID- 28727161 TI - Reply. PMID- 28727162 TI - 'Will I want these stickers tomorrow?' Preschoolers' ability to predict current and future needs. AB - Between 3 and 5 years of age, children develop the ability to plan for their own and others' future needs; however, they have great difficulty predicting future needs that conflict with current ones. Importantly, this ability has only been tested in the domain of physiological states (e.g., thirst). Therefore, it is still an open question whether in a different context preschoolers can disengage from their current needs to secure a different future one. In a Resource Allocation task, 4- and 5-year-olds had to distribute three types of rewards between themselves and another child for either 'right now' or 'tomorrow'. Children's current needs were manipulated by providing them (or not) with their preferred reward at beginning of the task. Only 5-year-olds could predict future needs that conflict with their current ones and act accordingly. Younger children's performance is discussed in the context of temporal and social distance. Statement of contribution What is already known on this subject? By the age of 4, children can plan for their own and others' future needs. Seven-year old children still have difficulty predicting future physiological needs that conflict with their current ones. What does this study add? In a Resource Allocation task, preschoolers had to share rewards with another child for 'right now' or 'tomorrow'. Children's current needs were manipulated by providing them (or not) with their preferred reward. This study shows that 5-year-olds can predict future (non-physiological) needs that conflict with their current ones. PMID- 28727163 TI - Dental erosion among South Brazilian adolescents: A 2.5-year longitudinal study. AB - OBJECTIVES: This population-based longitudinal study investigated the incidence, progression and risk factors for dental erosion among South Brazilian adolescents. METHODS: Eight hundred and one schoolchildren attending 42 public and private schools were clinically examined at 12 years of age; clinical examinations were repeated after 2.5 years (SD=0.3). After tooth cleaning and drying, permanent incisors and first molars were classified using the Basic Erosive Wear Examination (BEWE) scoring criteria. Questionnaires were used to collect data on socio-demographic characteristics, dietary habits, toothbrushing frequency and general health. Poisson regression analysis was used to assess the association between dental erosion incidence and explanatory variables, with adjusted incidence risk ratios (IRR) and 95% CI estimated. RESULTS: Among those who did not have dental erosion at baseline, 49 of 680 schoolchildren (7.1%; 95% CI=5.2-9.1) developed erosive lesions over the follow-up period. Among schoolchildren who had dental erosion at baseline, 31 of 121 (25.4%; 95% CI=17.6 33.3) had new or more severe lesions. Boys were more likely to develop dental erosion than girls (IRR=1.88; 95% CI=1.06-3.32). CONCLUSIONS: A moderate incidence of dental erosion was observed among South Brazilian adolescents, with boys being at higher risk. The high progression rate of 25% observed here is very concerning, and it should be taken in consideration when designing preventive strategies for dental erosion. PMID- 28727164 TI - The innate host response in caries and periodontitis. AB - INTRODUCTION: Innate immunity rapidly defends the host against infectious insults. These reactions are of limited specificity and exhaust without providing long-term protection. Functional fluids and effector molecules contribute to the defence against infectious agents, drive the immune response, and direct the cellular players. AIM: To review the literature and present a summary of current knowledge about the function of tissues, cellular players and soluble mediators of innate immunity relevant to caries and periodontitis. METHODS: Historical and recent literature was critically reviewed based on publications in peer-reviewed scientific journals. RESULTS: The innate immune response is vital to resistance against caries and periodontitis and rapidly attempts to protect against infectious agents in the dental hard and soft tissues. Soluble mediators include specialized proteins and lipids. They function to signal to immune and inflammatory cells, provide antimicrobial resistance, and also induce mechanisms for potential repair of damaged tissues. CONCLUSIONS: Far less investigated than adaptive immunity, innate immune responses are an emerging scientific and therapeutic frontier. Soluble mediators of the innate response provide a network of signals to organize the near immediate molecular and cellular response to infection, including direct and immediate antimicrobial activity. Further studies in human disease and animal models are generally needed. PMID- 28727165 TI - Increased fibre and reduced trans fatty acid intake are primary predictors of metabolic improvement in overweight polycystic ovary syndrome-Substudy of randomized trial between diet, exercise and diet plus exercise for weight control. AB - OBJECTIVE: Polycystic ovary syndrome (PCOS) is commonly affected by obesity. PCOS phenotypes are prone to increased waist/hip ratio, insulin resistance and dyslipidaemia. This substudy was undertaken to evaluate the effects of lifestyle interventions on metabolic biomarkers in overweight/obese PCOS women and the interventional effects of dietary components related to metabolic outcomes. DESIGN: Randomized three-arm parallel study. PATIENTS: Fifty-seven PCOS women body mass index (BMI >27 kg/m2 , age 18-40) were randomly assigned to diet (D, n = 19), exercise (E, n = 19) or diet plus exercise (DE, n = 19) in three-arm fashion over 16 weeks. The D group received nutritional counselling by a dietician to reduce their energy intake by at least 600 kcal/d. The E group received an ambulatory exercise regimen from a physiotherapist. The DE group had both interventions. MEASUREMENTS: Self-reported food intake over 4 days, exercise pedometers, BMI, waist/hip ratio, blood pressure, body composition and oral glucose tolerance test were performed before and at the end of intervention. RESULTS: BMI, waist circumference and total cholesterol were significantly reduced in the D and DE groups, as well as low-density lipoprotein and Homeostasis Model of Assessment index in the D group. In the E group, exercise was increased along with a decrease in BMI and waist circumference. The strongest predictor of reduced BMI was increased fibre intake (-0.44, P = .03), while a decrease in trans fatty acid intake predicted reduced insulinogenic index (0.44, P < .01). CONCLUSIONS: Nutritional counselling with dieting is clearly effective to improve metabolic disturbances in overweight/obese women with PCOS. Increased fibre and reduced trans fatty acid intake are primary predictors of metabolic improvement and weight control. PMID- 28727166 TI - Hepatocytes contribute to residual glucose production in a mouse model for glycogen storage disease type Ia. AB - : It is a long-standing enigma how glycogen storage disease (GSD) type I patients retain a limited capacity for endogenous glucose production despite the loss of glucose-6-phosphatase activity. Insight into the source of residual endogenous glucose production is of clinical importance given the risk of sudden death in these patients, but so far contradictory mechanisms have been proposed. We investigated glucose-6-phosphatase-independent endogenous glucose production in hepatocytes isolated from a liver-specific GSD Ia mouse model (L-G6pc-/- mice) and performed real-time analysis of hepatic glucose fluxes and glycogen metabolism in L-G6pc-/- mice using state-of-the-art stable isotope methodologies. Here we show that G6pc-deficient hepatocytes are capable of producing glucose. In vivo analysis of hepatic glucose metabolism revealed that the hepatic glucokinase flux was decreased by 95% in L-G6pc-/- mice. It also showed increased glycogen phosphorylase flux in L-G6pc-/- mice, which is coupled to the release of free glucose through glycogen debranching. Although the ex vivo activities of debranching enzyme and lysosomal acid maltase, two major hepatic alpha glucosidases, were unaltered in L-G6pc-/- mice, pharmacological inhibition of alpha-glucosidase activity almost completely abolished residual glucose production by G6pc-deficient hepatocytes. CONCLUSION: Our data indicate that hepatocytes contribute to residual glucose production in GSD Ia. We show that alpha-glucosidase activity, i.e. glycogen debranching and/or lysosomal glycogen breakdown, contributes to residual glucose production by GSD Ia hepatocytes. A strong reduction in hepatic GCK flux in L-G6pc-/- mice furthermore limits the phosphorylation of free glucose synthesized by G6pc-deficient hepatocytes, allowing the release of glucose into the circulation. The almost complete abrogation of GCK flux in G6pc-deficient liver also explains the contradictory reports on residual glucose production in GSD Ia patients. (Hepatology 2017;66:2042-2054). PMID- 28727167 TI - Rediscussion on linearity between fibrosis stages and mortality risk in nonalcoholic fatty liver disease patients. PMID- 28727168 TI - The royal free hospital cirrhosis glomerular filtration rate: Validation in a danish cohort. PMID- 28727169 TI - A mediation analysis study: The influence of mothers' dental anxiety on children's dental utilization among low-income African Americans. AB - OBJECTIVES: The aim of this study was to test a hypothesized mediation model to explain associations between mothers' dental anxiety and children's dental utilization through the mothers' own dental utilization. METHODS: Two hundred and fourteen low-income African American mothers with young children (age 31-59 months) completed a study questionnaire which assessed (i) mothers' dental anxiety; (ii) mothers' dental utilization (seeing a dentist at least once a year) and (iii) children's dental utilization (at least one non-study-related dental visit during the 36-month study period). The hypothesized mediation model consisted of these three elements with both a direct path from mothers' dental anxiety to children's dental utilization and an indirect path from mothers' dental anxiety to children's dental utilization through mothers' dental utilization. Mediation analysis with bootstrapping was conducted to test the hypothesized model. RESULTS: The mediation analysis indicated significant total effect of mothers' dental anxiety on children's dental utilization. The standardized total effect of mothers' anxiety on children's dental utilization was -0.172 (SE=.084, P=.041), and the standardized indirect effect of mothers' anxiety on children's dental utilization mediated by mothers' dental utilization was -0.069 (SE=.039, P=.076). The direct effect from mothers' anxiety to children's dental utilization was not statistically significant (P=.261) after adjusting for the mothers' dental utilization. CONCLUSIONS: In this low-income African American sample, there was a trend for mothers' dental anxiety to be associated with children's dental utilization indirectly through mothers' own dental utilization, while the direct influence of mothers' dental anxiety on children's dental utilization was not seen. This suggests that mothers' dental utilization might explain how mothers' dental anxiety impacts children's early dental utilization. PMID- 28727170 TI - Entire papilla preservation technique in the regenerative treatment of deep intrabony defects: 1-Year results. AB - AIM: This study evaluates the clinical outcomes of a novel tunnel-like surgical technique in the treatment of isolated deep intrabony defects. MATERIAL AND METHODS: Twelve patients presenting with at least one isolated deep intrabony defect received regenerative periodontal treatment with "entire papilla preservation (EPP)" technique. Access to the intrabony defect for debridement was provided by a bevelled vertical releasing incision positioned in the buccal gingiva of the neighbouring inter-dental space. Following the elevation of a buccal flap, an inter-dental tunnel was prepared undermining the defect associated papilla. Granulation tissue was removed, root surfaces were carefully debrided and bone substitutes and enamel matrix derivative were applied. Microsurgical suturing technique was used for optimal wound closure. RESULTS: Early healing was uneventful in all cases, and 100% wound closure was maintained during the entire healing period. At 1-year, there was significant attachment gain of 6.83+/-2.51 mm (p<0.001). The 7+/-2.8 mm reduction in probing depth was also significant (p<0.001), which was associated with minimal increase in gingival recession (0.16+/-0.38 mm, p=0.166). CONCLUSIONS: Tunnel-like "EPP" technique may limit the risk of wound failure particularly in the early healing phase, thereby preventing exposure of regenerative biomaterials, possibly enhancing stabilization of blood clot in deep intrabony defects and leading to optimal clinical outcomes. PMID- 28727171 TI - Modeling chemical accumulation in sediment of small waterbodies accounting for sediment transport and water-sediment exchange processes over long periods. AB - In a recent scientific opinion of the European Food Safety Authority it is argued that the accumulation of plant protection products in sediments over long time periods may be an environmentally significant process. Therefore, the European Food Safety Authority proposed a calculation to account for plant protection product accumulation. This calculation, however, considers plant protection product degradation within sediment as the only dissipation route, and does not account for sediment dynamics or back-diffusion into the water column. The hydraulic model Hydrologic Engineering Center-River Analysis System (HEC-RAS; US Army Corps of Engineers) was parameterized to assess sediment transport and deposition dynamics within the FOrum for Co-ordination of pesticide fate models and their USe (FOCUS) scenarios in simulations spanning 20 yr. The results show that only 10 to 50% of incoming sediment would be deposited. The remaining portion of sediment particles is transported across the downstream boundary. For a generic plant protection product substance this resulted in deposition of only 20 to 50% of incoming plant protection product substance. In a separate analysis, the FOCUS TOXSWA model was utilized to examine the relative importance of degradation versus back-diffusion as loss processes from the sediment compartment for a diverse range of generic plant protection products. In simulations spanning 20 yr, it was shown that back-diffusion was generally the dominant dissipation process. The results of the present study show that sediment dynamics and back diffusion should be considered when calculating long-term plant protection product accumulation in sediment. Neglecting these may lead to a systematic overestimation of accumulation. Environ Toxicol Chem 2017;36:3223-3231. (c) 2017 SETAC. PMID- 28727172 TI - Immunohistochemical expression of MYB in salivary gland basal cell adenocarcinoma and basal cell adenoma. AB - BACKGROUND: Basal cell predominant salivary gland neoplasms can be difficult to separate histologically. One of the most aggressive of basaloid salivary gland neoplasms is adenoid cystic carcinoma. MYB expression by immunohistochemistry has been documented in adenoid cystic carcinoma. Some investigators have suggested that using this expression can help in establishing the diagnosis of adenoid cystic carcinoma. Utilizing tissue microarrays, we studied a group of basal cell adenocarcinomas and basal cell adenomas to determine: (i) whether either tumor expressed MYB and (ii) the frequency of any expression in either tumors. METHODS: Seventeen salivary gland basal cell adenocarcinomas and 30 salivary gland basal cell adenomas were used to construct microarrays. These tissue microarrays were used to assess for immunohistochemical MYB expression. RESULTS: Fifty-three percent (nine of 17) of salivary gland basal cell adenocarcinomas and 57% (17 of 30) of salivary gland basal cell adenomas showed MYB overexpression. For comparison, we studied 11 adenoid cystic carcinomas for MYB expression and found that 64% (seven of 11) overexpressed MYB. We found no relation to clinical course for basal adenomas or basal cell adenocarcinomas that overexpressed MYB vs those that did not. CONCLUSIONS: MYB expression does not help separate basal cell adenocarcinomas from basal cell adenomas, and our data suggest it does not differentiate between either of these neoplasms and adenoid cystic carcinoma. PMID- 28727173 TI - National data study showed that adolescents living in poorer households and with one parent were more likely to be bullied. AB - AIM: The aim of this study was to assess whether sociodemographic household characteristics were associated with which Swedish adolescents were more likely to be bullied. METHODS: The data were derived from the Swedish Living Conditions Survey and its child supplements from the survey years 2008-2011. The analyses included information on 3951 adolescents aged 10-18 years. Exposure to bullying was reported by adolescents, and information on sociodemographic household characteristics was reported by parents and obtained from official registers. Binary logistic regression was used to analyse the data. RESULTS: Adolescents were more likely to be bullied if they lived in households with no cash margin, defined as the ability to pay an unexpected bill of 8000 Swedish Kronor or about 800 Euros, and if they lived with just one custodial parent. In the unadjusted analyses, elevated risks were identified if adolescents lived in working class households and had unemployed and foreign-born parents. However, these associations were at least partly accounted for by other sociodemographic household characteristics, in particular the lack of a cash margin. CONCLUSION: This study showed that Swedish adolescents living in households with more limited financial resources had an increased risk of being bullied, supporting results from previous international research. PMID- 28727174 TI - Alkaline Phosphatase: Discovery and Naming of Our Favorite Enzyme. AB - Alkaline phosphatase can be considered "our favorite enzyme" for reasons apparent to those who diagnose and treat metabolic bone diseases or who study skeletal biology. Few might know, however, that alkaline phosphatase likely represents the most frequently assayed enzyme in all of medicine. Elevated activity in the circulation is universally recognized as a marker for skeletal or hepatobiliary disease. Nevertheless, the assay conditions in many ways are nonphysiological. The term alkaline phosphatase emerged when it became necessary to distinguish "bone phosphatase" from the phosphatase in the prostate that features an acidic pH optimum. Beginning in 1948, studies of the inborn-error-of-metabolism hypophosphatasia would identify the natural substrates and establish the physiological role of alkaline phosphatase, including in biomineralization. Here, we recount the discovery in 1923 and then eventual naming of this enzyme that remains paramount in our field. (c) 2017 American Society for Bone and Mineral Research. PMID- 28727175 TI - The cost of treating diabetic ketoacidosis in the UK: a national survey of hospital resource use. AB - AIM: Diabetic ketoacidosis is a commonly encountered metabolic emergency. In 2014, a national survey was conducted looking at the management of diabetic ketoacidosis in adult patients across the UK. The survey reported the clinical management of individual patients as well as institutional factors that teams felt were important in helping to deliver that care. However, the costs of treating diabetic ketoacidosis were not reported. METHODS: We used a 'bottom up' approach to cost analysis to determine the total expense associated with treating diabetic ketoacidosis in a mixed population sample. The data were derived from the source data from the national UK survey of 283 individual patients collected via questionnaires sent to hospitals across the country. RESULTS: Because the initial survey collection tool was not designed with a health economic model in mind, several assumptions were made when analysing the data. The mean and median time in hospital was 5.6 and 2.7 days respectively. Based on the individual patient data and using the Joint British Diabetes Societies Inpatient Care Group guidelines, the cost analysis shows that for this cohort, the average cost for an episode of diabetic ketoacidosis was L2064 per patient (95% confidence intervals: 1800, 2563). CONCLUSION: Despite relatively short stays in hospital, costs for managing episodes of diabetic ketoacidosis in adults were relatively high. Assumptions made in the calculations did not consider prolonged hospital stay due to comorbidities or costs incurred as a loss of productivity. Therefore, the actual costs to the healthcare system and society in general are likely to be substantially higher. PMID- 28727176 TI - Polygenic risk score analysis of pathologically confirmed Alzheimer disease. AB - Previous estimates of the utility of polygenic risk score analysis for the prediction of Alzheimer disease have given area under the curve (AUC) estimates of <80%. However, these have been based on the genetic analysis of clinical case control series. Here, we apply the same analytic approaches to a pathological case-control series and show a predictive AUC of 84%. We suggest that this analysis has clinical utility and that there is limited room for further improvement using genetic data. Ann Neurol 2017;82:311-314. PMID- 28727177 TI - Total Synthesis of the Marine Natural Product Hemiasterlin by Organocatalyzed alpha-Hydrazination. AB - An efficient synthesis of the potently cytotoxic marine peptide hemiasterlin is presented. The tetramethyltryptophan moiety is assembled by tert-prenylation of indole, followed by the high-yielding organocatalyzed alpha-hydrazination of a sterically congested aldehyde with excellent enantioselectivity. 2-Bromo-N ethylpyridinium tetrafluoroborate (BEP)-mediated peptide coupling completes the synthesis, being the first approach that does not employ chiral auxiliaries. A novel phenonium-type rearrangement of the indole system occurred when subjecting dihydroxylated 3-tert-prenylindole to Mitsunobu conditions. PMID- 28727178 TI - Tailored Band Gaps in Sulfur- and Nitrogen-Containing Porous Donor-Acceptor Polymers. AB - Donor-acceptor dyads hold the key to tuning of electrochemical properties and enhanced mobility of charge carriers, yet their incorporation into a heterogeneous polymer network proves difficulty owing to the fundamentally different chemistry of the donor and acceptor subunits. A family of sulfur- and nitrogen-containing porous polymers (SNPs) are obtained via Sonogashira-Hagihara cross-coupling and combine electron-withdrawing triazine (C3 N3 ) and electron donating, sulfur-containing linkers. Choice of building blocks and synthetic conditions determines the optical band gap (from 1.67 to 2.58 eV) and nanoscale ordering of these microporous materials with BET surface areas of up to 545 m2 g 1 and CO2 capacities up to 1.56 mmol g-1 . Our results highlight the advantages of the modular design of SNPs, and one of the highest photocatalytic hydrogen evolution rates for a cross-linked polymer without Pt co-catalyst is attained (194 MUmol h-1 g-1 ). PMID- 28727180 TI - Why was a local anaesthetic used before administering intranasal ketamine for paediatric injuries? PMID- 28727179 TI - Overexpression of GalphaS in Murine Osteoblasts In Vivo Leads to Increased Bone Mass and Decreased Bone Quality. AB - GalphaS is a heterotrimeric G protein that transduces signals from activated G protein-coupled receptors on the cell surface to stimulate adenylyl cyclase/cyclic adenosine monophosphate (AMP) signaling. GalphaS plays a central role in mediating numerous growth and maintenance processes including osteogenesis and bone turnover. Decreased GalphaS expression or activating mutations in GalphaS both affect bone, suggesting that modulating GalphaS protein levels may be important for bone health and development. To examine the effects of increased osteoblastic GalphaS expression on bone development in vivo, we generated transgenic mice with GalphaS overexpression in osteoblasts (HOM-Gs mice) driven by the 3.6-kilobase (kb) Col1A1 promoter. Both male and female HOM Gs mice exhibit increased bone turnover with overactive osteoblasts and osteoclasts, resulting in a high bone mass phenotype with significantly reduced bone quality. At 9 weeks of age, HOM-Gs mice have increased trabecular number, volumetric BMD (vBMD), and bone volume; however, the bone was woven and disorganized. There was also increased cortical bone volume despite an overall reduction in size in HOM-Gs mice along with increased cortical porosity and brittleness. The skeletal phenotype of HOM-Gs mice progressed into maturity at 26 weeks of age with further accrual of trabecular bone, whereas WT mice lost trabecular bone at this age. Although cortical bone volume and geometry were similar between mature HOM-Gs and WT mice, increased porosity persisted and the bone was weaker. At the cellular level, these alterations were mediated by an increase in bone resorption by osteoclasts and an overwhelmingly higher increase in bone formation by osteoblasts. In summary, our findings demonstrate that high osteoblastic GalphaS expression results in aberrant skeletal development in which bone production is favored at the cost of bone quality. (c) 2017 American Society for Bone and Mineral Research. PMID- 28727182 TI - Probing Anisotropic Thermal Conductivity of Transition Metal Dichalcogenides MX2 (M = Mo, W and X = S, Se) using Time-Domain Thermoreflectance. AB - Transition metal dichalcogenides (TMDs) are a group of layered 2D semiconductors that have shown many intriguing electrical and optical properties. However, the thermal transport properties in TMDs are not well understood due to the challenges in characterizing anisotropic thermal conductivity. Here, a variable spot-size time-domain thermoreflectance approach is developed to simultaneously measure both the in-plane and the through-plane thermal conductivity of four kinds of layered TMDs (MoS2 , WS2 , MoSe2 , and WSe2 ) over a wide temperature range, 80-300 K. Interestingly, it is found that both the through-plane thermal conductivity and the Al/TMD interface conductance depend on the modulation frequency of the pump beam for all these four compounds. The frequency-dependent thermal properties are attributed to the nonequilibrium thermal resistance between the different groups of phonons in the substrate. A two-channel thermal model is used to analyze the nonequilibrium phonon transport and to derive the intrinsic thermal conductivity at the thermal equilibrium limit. The measurements of the thermal conductivities of bulk TMDs serve as an important benchmark for understanding the thermal conductivity of single- and few-layer TMDs. PMID- 28727183 TI - A randomized controlled trial on a nurse-led smartphone-based self-management programme for people with poorly controlled type 2 diabetes: A study protocol. AB - AIM: To develop and compare a nurse-led smartphone-based self-management programme with an existing nurse-led diabetes service on health-related outcomes for people with poorly controlled type 2 diabetes in Singapore. BACKGROUND: Over the past decades, Asia has emerged as the "diabetes epicentre" in the world due to rapid economic development, urbanization and nutrition transition. There is an urgent need to develop more effective care management strategies in response to this rising diabetes epidemic. DESIGN: A randomized controlled trial with pre- and repeated posttests control group design. METHODOLOGY: A total of 128 adults with poorly controlled type 2 diabetes will be recruited from the diabetes clinic of a public acute hospital in Singapore through convenience sampling. Study participants will be randomly allocated either to the experimental group or the control group. Outcome measures will include the 10-item General Self-Efficacy Scale, 11-item Revised Summary of Diabetes Self-care Activities and 19-item Diabetes-Dependent Quality of Life. Data will be collected at three time points: baseline, 3 and 6 months from the baseline. DISCUSSION: It is expected that this programme will be an alternative offered to diabetes patients to master their self-care management skills, in addition to the existing diabetes service provided in diabetes clinics in Singapore hospitals. Furthermore, the self supporting and less resource-intensive nature of this programme, using a smartphone application as the mode of intervention delivery, will greatly reduce nurses' direct contact time with patients and allow more time to be allocated to those who require more attention. The study has been registered with ClinicalTrials.gov. The trial registration number is NCT03088475. PMID- 28727184 TI - Early warning systems and rapid response to the deteriorating patient in hospital: A systematic realist review. AB - AIM: To determine the Rapid Response System programme theory and investigate how the mechanisms of implementation and the characteristics of context combine to enable or constrain the implementation of Rapid Response Systems and the achievement of desired outcomes. BACKGROUND: Rapid Response Systems have been implemented internationally to improve the recognition and management of patient deterioration, reduce the need for cardiopulmonary resuscitation and improve patient outcomes. DESIGN: Realist review. DATA SOURCES: We searched DARE, CENTRAL, NHSEED, MEDLINE, Medline In Process, EMBASE, CINAHL, PubMed, Scopus, The Web of Science and PychInfo databases from 1997 - 2017 in addition to purposively searching the grey literature looking for articles supporting, refuting or explaining Rapid Response System programme theories. REVIEW METHODS: Included studies were critically appraised and graded using the Critical Appraisal Skills Programme tool. Data extraction and synthesis investigated the Rapid Response System theoretical propositions against the empirical evidence to refine Rapid Response System programme theories. RESULTS: The review found that the Rapid Response System programme theory achieved desired outcomes when there were sufficient skills mix of experienced staff, EWS protocols were used flexibly alongside clinical judgement and staff had access to ongoing, multiprofessional, competency-based education. However, ward cultures, hierarchical referral systems, workload and staffing resources had a negative impact on the implementation of the Rapid Response System. CONCLUSION: To improve the recognition and management of patient deterioration, policymakers need to address those cultural, educational and organizational factors that have an impact on the successful implementation of Rapid Response Systems in practice. PMID- 28727186 TI - Telephone monitoring and home visits significantly improved the quality of life, treatment adherence and lung function in children with cystic fibrosis. PMID- 28727185 TI - Automation of pattern recognition analysis of dynamic contrast-enhanced MRI data to characterize intratumoral vascular heterogeneity. AB - PURPOSE: To automate dynamic contrast-enhanced MRI (DCE-MRI) data analysis by unsupervised pattern recognition (PR) to enable spatial mapping of intratumoral vascular heterogeneity. METHODS: Three steps were automated. First, the arrival time of the contrast agent at the tumor was determined, including a calculation of the precontrast signal. Second, four criteria-based algorithms for the slice specific selection of number of patterns (NP) were validated using 109 tumor slices from subcutaneous flank tumors of five different tumor models. The criteria were: half area under the curve, standard deviation thresholding, percent signal enhancement, and signal-to-noise ratio (SNR). The performance of these criteria was assessed by comparing the calculated NP with the visually determined NP. Third, spatial assignment of single patterns and/or pattern mixtures was obtained by way of constrained nonnegative matrix factorization. RESULTS: The determination of the contrast agent arrival time at the tumor slice was successfully automated. For the determination of NP, the SNR-based approach outperformed other selection criteria by agreeing >97% with visual assessment. The spatial localization of single patterns and pattern mixtures, the latter inferring tumor vascular heterogeneity at subpixel spatial resolution, was established successfully by automated assignment from DCE-MRI signal-versus-time curves. CONCLUSION: The PR-based DCE-MRI analysis was successfully automated to spatially map intratumoral vascular heterogeneity. Magn Reson Med 79:1736-1744, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28727187 TI - A Computational Study of the Intermolecular [2+2+2] Cycloaddition of Acetylene and C60 Catalyzed by Wilkinson's Catalyst. AB - The functionalization of fullerenes helps to modulate their electronic and physicochemical properties, generating fullerene derivatives with promising features for practical applications. Herein, DFT is used to explore the attachment of a cyclohexadiene ring to C60 through a rhodium-catalyzed intermolecular [2+2+2] cycloaddition of C60 and acetylene. All potential reaction paths are analyzed and it can be concluded that the [2+2+2] cycloaddition of C60 and two acetylene molecules catalyzed by [RhCl(PPh3 )3 ], yielding a cyclohexadiene ring fused to a [6,6] bond of C60 , is energetically feasible. PMID- 28727188 TI - MiR-21: A key player in glioblastoma pathogenesis. AB - Glioblastoma multiform (GBM) is one of common cancers worldwide which has high rate among various populations. Despite serious efforts worldwide, GBM remains a deadly disease which is associated with poor prognosis. Multiple lines evidence indicated that deregulation of a variety of cellular and molecular pathways are related with GBM pathogenesis. Among of various targets involved in GBM pathogenesis, microRNAs (miRNAs) have been emerged as targets which deregulation of them are related with various stages of GBM. These molecules are small non coding RNAs which could affect on a variety of cellular and molecular pathways involved in GBM. It has been showed that deregulation of them are associated with initiation and progression of GBM. MiR-21 is one of important miRNAs involved in GBM pathogenesis. A large number studies indicated that this miRNA could affect on a variety of cellular and molecular pathways such as insulin-like growth factor (IGF)-binding protein-3 (IGFBP3), RECK, and TIMP3. Exosomes are one of important players in GBM pathogenesis. Among of various exosomes, exosomal miR-21 may has key roles in GBM pathogenesis. These findings indicated that miR-21 has critical roles in GBM pathogenesis and could be used as diagnostic and therapeutic biomarkers for GBM patients. Here, we summarized the roles of miR-21 and exosomal miR-21 in GBM pathogenesis. Moreover, we highlighted utilization of miR-21 as diagnostic and therapeutic biomarker for GBM patients. PMID- 28727189 TI - Inversion of cpADH5 Enantiopreference and Altered Chain Length Specificity for Methyl 3-Hydroxyalkanoates. AB - Expanding the substrate scope of enzymes opens up new routes for synthesis of valuable chemicals. Ketone-functionalized fatty acid derivatives and corresponding chiral alcohols are valuable building blocks for the synthesis of a variety of chemicals including pharmaceuticals. The alcohol dehydrogenase from Candida parapsilosis (cpADH5) catalyzes the reversible oxidations of chiral alcohols and has a broad substrate range; a challenge for cpADH5 is to convert alcohols with small substituents (methyl or ethyl) next to the oxidized alcohol moiety. Molecular docking studies revealed that W286 is located in the small binding pocket and limits the access to substrates that contain aliphatic chains longer than ethyl substituent. In the current manuscript, we report that positions L119 and W286 are key residues to boost oxidation of medium chain methyl 3-hydroxy fatty acids; interestingly the enantiopreference toward methyl 3 hydroxybutyrate was inverted. Kinetic characterization of W286A showed a 5.5 fold increase of Vmax and a 9.6 fold decrease of Km values toward methyl 3 hydroxyhexanoate (Vmax : 2.48 U mg- and Km : 4.76 mm). Simultaneous saturation at positions 119 and 286 library yielded a double mutant (L119M/W286S) with more than 30-fold improved activity toward methyl 3-hydroxyoctanoate (WT: no conversion; L119M/W286S: 30 %) and inverted enantiopreference (S-enantiomer >=99 % activity decrease and R-enantiomer >20-fold activity improvement) toward methyl 3-hydroxybutyrate. PMID- 28727190 TI - Tuning the Effects of Bacterial Membrane Permeability through Photo-Isomerization of Antimicrobial Cationic Amphiphiles. AB - Several important antimicrobial drugs act by permeabilizing cell membranes. In this study, we showed that the intensity of membrane permeability caused by antimicrobial cationic amphiphiles can be modified not only by their concentration but also through light-induced isomerization of their lipid segment. Two types of photo-isomerizable cationic amphiphiles were developed and the effects of photo-isomerization on bacterial growth and membrane permeability were evaluated. One photo-isomer inhibited cell growth and division, whereas the other photo-isomer led to a rapid and lethal bacterial membrane-disrupting effect. The switch from "on" to "off" can be obtained by either the cis- or trans isomer depending on the bacterial strain and the type of cationic amphiphile. These cationic amphiphiles offer a novel tool for research and industrial applications that require light-controlled bacterial membrane permeabilization. PMID- 28727191 TI - Anterior pericardial access to facilitate electrophysiology study and catheter ablation of ventricular arrhythmias: A single tertiary center experience. AB - INTRODUCTION: Epicardial ablation is becoming an important part of management in patients with ventricular tachycardia (VT). Posterior epicardial access via the Sosa or needle-in-needle (NIN) approach for epicardial VT ablation is considered to be the method of choice for most electrophysiologists. Anterior epicardial access as an alternative technique has recently been proposed, but there are limited data about its safety, efficacy, and the rate of immediate complications. In this study, we report our experience with anterior epicardial access between 2009 and 2016. METHODS: Between 2009 and June 2016, 100 consecutive patients underwent epicardial VT ablation using an anterior approach. The success rate, epicardial bleeding, and other complications related to the epicardial access in these patients were compared to the previously reported rate of complications in patients whom epicardial access was performed using the NIN or Sosa techniques. RESULTS: Anterior epicardial access was obtained successfully in 100% of patients in the first attempt. The success rate of the anterior approach was comparable with the reported success rate of the NIN technique (100% vs. 100%, P value not significant) but better than the Sosa technique (100% vs. 94%, P = 0.012). None of the patients in the anterior approach series suffered from significant pericardial bleeding (defined as greater than 80 mL of blood loss), RV puncture/damage, or need for an emergent cardiac surgery. CONCLUSION: An anterior epicardial approach is feasible and appears to have an acceptable safety profile in comparison with other epicardial approaches. PMID- 28727192 TI - Current evidence for endovascular therapy in stroke and remaining uncertainties. AB - Class 1 level A evidence now supports endovascular thrombectomy as best practice in the management of large vessel occlusion acute ischaemic stroke. However, significant questions pertaining to initial imaging, radiological assessment, patient selection and therapeutic limits remain unanswered. A specific cohort of patients who benefit from endovascular thrombectomy has been established, although current uncertainties regarding selection of those not meeting top-tier evidence criteria may potentially deny certain patients the benefit of intervention. This is of particular relevance in patients presenting in a delayed manner. Whilst superior outcomes are achieved with reduced time to endovascular reperfusion, denying patients intervention based on symptom duration alone may not be appropriate. Advanced understanding of ischaemic stroke pathophysiology supports an individualized approach to patient evaluation, given variance in the rate of ischaemic core progression and the extent of salvageable penumbra. Physiological imaging techniques may therefore be utilized to better inform patient selection for endovascular thrombectomy and evidence suggests that a transition from time-based to tissue-based therapeutic thresholds may be of greater value. Multiple ongoing randomized controlled trials aim to further define the benefit of endovascular thrombectomy and it is hoped that these results will advance, and possibly broaden, patient selection criteria to ensure that maximum benefit from the intervention may be achieved. PMID- 28727193 TI - Hydrogen-Bonded Polymer-Porphyrin Assemblies in Water: Supramolecular Structures for Light Energy Conversion. AB - In this study, a new type of functional, self-assembled nanostructure formed from porphyrins and polyamidoamine dendrimers based on hydrogen bonding in an aqueous solution is presented. As the aggregates formed are promising candidates for solar-energy conversion, their photocatalytic activity is tested using the model reaction of methyl viologen reduction. The self-assembled structures show significantly increased activity as compared to unassociated porphyrins. Details of interaction forces driving the supramolecular structure formation and regulating catalytic efficiency are fundamentally discussed. PMID- 28727194 TI - A wolf in sheep's clothing: An unusual cause of atrio-ventricular Wenckebach phenomenon. PMID- 28727195 TI - Patterns of divergence across the geographic and genomic landscape of a butterfly hybrid zone associated with a climatic gradient. AB - Hybrid zones are a valuable tool for studying the process of speciation and for identifying the genomic regions undergoing divergence and the ecological (extrinsic) and nonecological (intrinsic) factors involved. Here, we explored the genomic and geographic landscape of divergence in a hybrid zone between Papilio glaucus and Papilio canadensis. Using a genome scan of 28,417 ddRAD SNPs, we identified genomic regions under possible selection and examined their distribution in the context of previously identified candidate genes for ecological adaptations. We showed that differentiation was genomewide, including multiple candidate genes for ecological adaptations, particularly those involved in seasonal adaptation and host plant detoxification. The Z chromosome and four autosomes showed a disproportionate amount of differentiation, suggesting genes on these chromosomes play a potential role in reproductive isolation. Cline analyses of significantly differentiated genomic SNPs, and of species-diagnostic genetic markers, showed a high degree of geographic coincidence (81%) and concordance (80%) and were associated with the geographic distribution of a climate-mediated developmental threshold (length of the growing season). A relatively large proportion (1.3%) of the outliers for divergent selection were not associated with candidate genes for ecological adaptations and may reflect the presence of previously unrecognized intrinsic barriers between these species. These results suggest that exogenous (climate-mediated) and endogenous (unknown) clines may have become coupled and act together to reinforce reproductive isolation. This approach of assessing divergence across both the genomic and geographic landscape can provide insight about the interplay between the genetic architecture of reproductive isolation and endogenous and exogenous selection. PMID- 28727196 TI - Insulin regimens for newly diagnosed children with type 1 diabetes mellitus in Australia and New Zealand: A survey of current practice. AB - AIM: There is no consensus on the optimal insulin treatment for children newly diagnosed with type 1 diabetes mellitus (T1DM). The aims of this study were (i) to describe the insulin regimens used at diagnosis by patient age and geographical region and (ii) to explore differences between and within Australia (AU) and New Zealand (NZ) with regards to other aspects of patient management and education. METHODS: An online survey of medical professionals caring for children with T1DM in AU and NZ was undertaken. Questions included clinic demographics, insulin regimen/dosing choices and patient education. RESULTS: Of 110 clinicians identified, 100 responded (91%). The majority of those in AU (69%, P < 0.0001) favour multiple daily injections (MDI) for all ages. In NZ, for patients < 10 years old, (twice daily (BD)) BD therapy was favoured (75%, P < 0.0001), with MDI dominant for ages >= 10 years (82%, P < 0.0001). Insulin pump therapy was never considered at diagnosis in NZ, but 38% of clinicians in AU considered using pumps at diagnosis in patients <2 years, but rarely in patients aged 2 and over (16%). Differences in clinician choices were also seen in relation to starting insulin dose. CONCLUSION: This is the first study to examine current clinical practice with regards to children newly diagnosed with T1DM. Practice varies across Australasia by clinician and region. This lack of consensus is likely driven by ongoing debates in the current paediatric diabetes evidence base as well as by differences in clinician/centre preference, variations in resourcing and their interpretations of the influence of various patient factors. PMID- 28727198 TI - Morphology quiz: Mediastinal adenopathy cytology from endobronchial ultrasound transbronchial aspiration (EBUS-TBNA). PMID- 28727197 TI - Influence of weather on incidence of bronchiolitis in Australia and New Zealand. AB - AIM: We aimed to examine the impact of weather on hospital admissions with bronchiolitis in Australia and New Zealand. METHODS: We collected data for inpatient admissions of infants aged 2-12 months to seven hospitals in four cities in Australia and New Zealand from 2009 until 2011. Correlation of hospital admissions with minimum daily temperature, wind speed, relative humidity and rainfall was examined using linear, Poisson and negative binomial regression analyses as well as general estimated equation models. To account for possible lag between exposure to weather and admission to hospital, analyses were conducted for time lags of 0-4 weeks. RESULTS: During the study period, 3876 patients were admitted to the study hospitals. Hospital admissions showed strong seasonality with peaks in wintertime, onset in autumn and offset in spring. The onset of peak incidence was preceded by a drop in temperature. Minimum temperature was inversely correlated with hospital admissions, whereas wind speed was directly correlated. These correlations were sustained for time lags of up to 4 weeks. Standardised correlation coefficients ranged from -0.14 to -0.54 for minimum temperature and from 0.18 to 0.39 for wind speed. Relative humidity and rainfall showed no correlation with hospital admissions in our study. CONCLUSION: A decrease in temperature and increasing wind speed are associated with increasing incidence of bronchiolitis hospital admissions in Australia and New Zealand. PMID- 28727199 TI - Can the electrocardiogram distinguish foci from rotors during ventricular fibrillation? PMID- 28727200 TI - Landscape genetic analyses reveal fine-scale effects of forest fragmentation in an insular tropical bird. AB - Within the framework of landscape genetics, resistance surface modelling is particularly relevant to explicitly test competing hypotheses about landscape effects on gene flow. To investigate how fragmentation of tropical forest affects population connectivity in a forest specialist bird species, we optimized resistance surfaces without a priori specification, using least-cost (LCP) or resistance (IBR) distances. We implemented a two-step procedure in order (i) to objectively define the landscape thematic resolution (level of detail in classification scheme to describe landscape variables) and spatial extent (area within the landscape boundaries) and then (ii) to test the relative role of several landscape features (elevation, roads, land cover) in genetic differentiation in the Plumbeous Warbler (Setophaga plumbea). We detected a small scale reduction of gene flow mainly driven by land cover, with a negative impact of the nonforest matrix on landscape functional connectivity. However, matrix components did not equally constrain gene flow, as their conductivity increased with increasing structural similarity with forest habitat: urban areas and meadows had the highest resistance values whereas agricultural areas had intermediate resistance values. Our results revealed a higher performance of IBR compared to LCP in explaining gene flow, reflecting suboptimal movements across this human-modified landscape, challenging the common use of LCP to design habitat corridors and advocating for a broader use of circuit theory modelling. Finally, our results emphasize the need for an objective definition of landscape scales (landscape extent and thematic resolution) and highlight potential pitfalls associated with parameterization of resistance surfaces. PMID- 28727201 TI - Gene expression stasis and plasticity following migration into a foreign environment. AB - Selection against migrants is key to maintaining genetic differences between populations linked by dispersal. However, migrants may mitigate fitness costs by proactively choosing among available habitats, or by phenotypic plasticity. We previously reported that a reciprocal transplant of lake and stream stickleback (Gasterosteus aculeatus) found little support for divergent selection. Here, we revisit that experiment to test whether phenotypic plasticity in gene expression may have helped migrants adjust to unfamiliar habitats. We measured gene expression profiles in stickleback via TagSeq and tested whether migrants between lake and stream habitats exhibited a plastic response to their new environment that allowed them to converge on the expression profile of adapted natives. We report extensive gene expression differences between genetically divergent lake and stream stickleback, despite gene flow. But for many genes, expression was highly plastic. Fish transplanted into the adjoining habitat partially converged on the expression profile typical of natives from their new habitat. This suggests that expression plasticity may soften the impact of migration. Nonetheless, lake and stream fish differed in survival rates and parasite infection rates in our study, implying that expression plasticity is not fast or extensive enough to fully homogenize fish performance. PMID- 28727202 TI - Influence of the left atrial contact areas on fixed low-voltage zones during atrial fibrillation and sinus rhythm in persistent atrial fibrillation. AB - BACKGROUND: Atrial low-voltage zones (LVZ) are suggested as important factors for maintaining persistent atrial fibrillation (PsAF). The relationship between LVZs and left atrial (LA) contact areas (CoAs) is still unclear. OBJECTIVE: To assess whether CoA regions were involved in atrial substrate properties maintaining PsAF. METHODS: A total of 50 patients with PsAF (36 long-lasting) were analyzed. Three representative CoA detection areas (ascending aorta-anterior-LA, descending aorta-left pulmonary vein antrum, and vertebrae-posterior-LA) were registered on the mapping geometry. Electrograms during AF and sinus rhythm (SR) were acquired, and the fractionated electrograms (CFE; < 80milliseconds) and voltages were analyzed regarding the CoAs. RESULTS: After SR conversion, 76% (38/50) had a significant LVZ (>5% of the total LA surface area). Patients with long-lasting PsAF versus PsAF had larger CoA areas (7.7 +/- 3.0 vs. 4.5 +/- 2.5cm2 , P < 0.05) and overlapped-LVZs (8.2 [3.2-11.0] vs. 2.1 [0.7-3.7] cm2 , P = 0.0126) between the SR-LVZs (<0.5 mV) and AF-LVZs (<0.2 mV). Overlapped-LVZs were frequently observed in CoA regions (anterior 76.4%; LIPV antrum 78.8%, and vertebrae 39.2%), and those LVZs had smaller unipolar voltages than those distant from the CoA regions (0.64 +/- 0.16 vs. 2.5 +/- 1.5 mV, P < 0.0001). SR-LVZ targeted ablation, including of CoA regions, rendered AF termination (n = 8, 21%), and 88% of the sites were not located immediately above, but adjacent to, the overlapped-LVZs. Significant AF slowing (6.0 +/- 0.6 to 5.6 +/- 0.6 Hz; P < 0.05) accompanied by unintentional CFE elimination (9.8-1.8 cm2 ; P < .0001) was achieved in patients without termination. CONCLUSION: Our data suggested that external structures in contact with the LA are involved in the creation of localized diseased myocardium necessary for PsAF maintenance. PMID- 28727204 TI - Comparison of thyroid fine needle aspiration biopsy results before and after implementation of Bethesda classification. AB - OBJECTIVE: The Bethesda classification was introduced in 2008 to provide standardisation in the evaluation of thyroid fine needle aspiration cytology (FNAC). We compared the diagnostic value of pre-Bethesda and Bethesda classification systems in the differentiation of benign and malignant thyroid nodules. METHODS: Medical records of patients who underwent a thyroidectomy between June 2007 and June 2014 were reviewed retrospectively. Nodules evaluated with FNAC before March 2010 were classified as pre-Bethesda (non-diagnostic, benign, indeterminate, suspicious for malignancy and malignant), and those evaluated after March 2010 were considered Bethesda (non-diagnostic, benign, atypia of undetermined significance/follicular lesion of undetermined significance, follicular neoplasia/suspicious for follicular neoplasia, suspicious for malignancy and malignant). Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy of the two classification systems were calculated. RESULTS: There were 1810 nodules in the pre-Bethesda and 5115 nodules in the Bethesda group. The non-diagnostic rate was significantly higher, and benign and suspicious for malignancy rates were lower in Bethesda compared with the pre-Bethesda group (P<.001 for each). When benign cytology was considered negative, and indeterminate, follicular neoplasia/suspicious for follicular neoplasia, suspicious for malignancy and malignant cytologies were considered positive, results for pre-Bethesda and Bethesda were as follows: sensitivity, 78.9% and 78.5%; specificity, 86.6% and 97.0%; PPV, 42.8% and 72.6%; NPV, 97% and 97.8%; and accuracy, 85.7% and 95.3%, respectively. CONCLUSIONS: Among operated nodules, percentages of benign and suspicious for malignancy cytologies decreased, and percentages of non-diagnostic and uncertain cytologies increased with the implementation of Bethesda. The diagnostic value of FNAC seems to have increased with the use of Bethesda classification. PMID- 28727205 TI - Drivers of woody canopy water content responses to drought in a Mediterranean type ecosystem. AB - Severe droughts increase physiological stress in woody plant species, which can lead to mortality, fundamentally altering the composition, structure, and biogeography of forests in many regions. Little is known, however, about the factors determining the physiological response of woody plants to drought at landscape scales. Our objective was to understand woody plant species responses to ongoing changes in climate, using remotely sensed canopy water content (CWC) as an indicator of plant physiological and phenological status. We used fused imaging spectroscopy and light detection and ranging from the Carnegie Airborne Observatory to quantify the factors affecting species compositional changes in CWC in a diverse Mediterranean-type ecosystem (Jasper Ridge Biological Preserve, California, USA) between 2013 and 2015. Mapped CWC was spatially variable in both of the observation years, and proved to be most closely tied to species composition and distribution across the landscape. The secondary predictors of CWC were elevation and soil substrate. In contrast, we found that CWC change was much more related to environmental factors than to the species composition. We suggest that the effect of environment on CWC change is mediated through species resistance and resilience to drought. Monitoring CWC change with imaging spectroscopy is a powerful approach to identifying species-level responses to climatic events and long-term change, which may provide support for policy decisions and conservation at large spatial scales. PMID- 28727203 TI - The association between acute mental stress and abnormal left atrial electrophysiology. AB - BACKGROUND: Acute stress may trigger atrial fibrillation (AF), but the underlying mechanisms are unclear. We examined if acute mental stress results in abnormal left atrial electrophysiology as detected by more negative deflection of P-wave terminal force in lead V1 (PTFV1 ), a well-known marker of AF risk. METHODS AND RESULTS: We examined this hypothesis in 422 patients (mean age = 56 +/- 10 years; 61% men; 44% white) with stable coronary heart disease who underwent mental (speech task) stress testing. PTFV1 was defined as the duration (milliseconds) times the value of the depth (MUV) of the downward deflection (terminal portion) of the P-wave in lead V1 measured on digital electrocardiograms (ECG). Electrocardiographic left atrial abnormality was defined as PTFV1 <= -4000 MUV*ms. Mean PTFV1 values during stress and recovery were compared with rest. The percentage of participants who developed left atrial abnormality during stress and recovery was compared with the percentage at rest. Compared with rest, PTFV1 became more negative during mental stress (mean change = -348, 95% CI = [-515, 182]; P < 0.001) and no change was observed at recovery (mean change = 12, 95%CI = [-148, 172]; P = 0.89). A larger percentage of participants showed left atrial abnormality on ECGs obtained at stress (n = 163, 39%) and recovery (n = 142, 34%) compared with rest (n = 127, 30%). CONCLUSION: Acute mental stress alters left atrial electrophysiology, suggesting that stressful situations promote adverse transient electrical changes to provide the necessary substrate for AF. PMID- 28727206 TI - The mother-offspring dyad: microbial transmission, immune interactions and allergy development. AB - The increasing prevalence of allergy in affluent countries may be caused by reduced intensity and diversity of microbial stimulation, resulting in abnormal postnatal immune maturation. Most studies investigating the underlying immunomodulatory mechanisms have focused on postnatal microbial exposure, for example demonstrating that the gut microbiota differs in composition and diversity during the first months of life in children who later do or do not develop allergic disease. However, it is also becoming increasingly evident that the maternal microbial environment during pregnancy is important in childhood immune programming, and the first microbial encounters may occur already in utero. During pregnancy, there is a close immunological interaction between the mother and her offspring, which provides important opportunities for the maternal microbial environment to influence the immune development of the child. In support of this theory, combined pre- and postnatal supplementations seem to be crucial for the preventive effect of probiotics on infant eczema. Here, the influence of microbial and immune interactions within the mother-offspring dyad on childhood allergy development will be discussed. In addition, how perinatal transmission of microbes and immunomodulatory factors from mother to offspring may shape appropriate immune maturation during infancy and beyond, potentially via epigenetic mechanisms, will be examined. Deeper understanding of these interactions between the maternal and offspring microbiome and immunity is needed to identify efficacious preventive measures to combat the allergy epidemic. PMID- 28727207 TI - Palliative care physicians' experiences of end-of-life communication: A focus group study. AB - The aim of this study was to explore palliative home care physicians' experiences regarding end-of-life breakpoint communication (BPC). This is a qualitative study where focus group interviews were conducted and analysed using qualitative content analysis. The results show that the participants saw themselves as being responsible for accomplishing BPC, and they were convinced that it should be regarded as a process of communication initiated at an early stage, i.e. proactively. However, BPC was often conducted as a reaction to the patient's sudden deterioration or sometimes not at all. The barriers to achieving proactive BPC included physicians' uncertainty regarding the timing of BPC, primarily due to difficulties in prognostication in terms of time of death, and uncertainty as to what BPC should include and how it should best be approached. Furthermore, there was insufficient documentation regarding previous BPC, which impeded proactive BPC. Although our study shows that physicians are ambitious when it comes to the communication of information to patients and families, there is a need for further training in how to conduct BPC and when to initiate the BPC process. Furthermore, there should be documentation that different professionals can access as this would appear to facilitate a proactive BPC process. PMID- 28727208 TI - Differential expression of appetite-regulating genes in avian models of anorexia and obesity. AB - Chickens from lines that have been selected for low (LWS) or high (HWS) juvenile body weight for more than 57 generations provide a unique model by which to research appetite regulation. The LWS display different severities of anorexia, whereas all HWS become obese. In the present study, we measured mRNA abundance of various factors in appetite-associated nuclei in the hypothalamus. The lateral hypothalamus (LHA), paraventricular nucleus (PVN), ventromedial hypothalamus (VMH), dorsomedial nucleus (DMN) and arcuate nucleus (ARC) were collected from 5 day-old chicks that were fasted for 180 minutes or provided with continuous access to food. Fasting increased neuropeptide Y receptor subtype 1 (NPYR1) mRNA in the LHA and c-Fos in the VMH, at the same time as decreasing c-Fos in the LHA, neuropeptide Y receptor subtype 5 and ghrelin in the PVN, and neuropeptide Y receptor subtype 2 in the ARC. Fasting increased melanocortin receptor subtype 3 (MC3R) expression in the DMN and NPY in the ARC of LWS but not HWS chicks. Expression of NPY was greater in LWS than HWS in the DMN. neuropeptide Y receptor subtype 5 mRNA was greater in LWS than HWS in the LHA, PVN and ARC. Expression of orexin was greater in LWS than HWS in the LHA. There was greater expression of NPYR1, melanocortin receptor subtype 4 and cocaine- and amphetamine-regulated transcript in HWS than LWS and mesotocin in LWS than HWS in the PVN. In the ARC, agouti-related peptide and MC3R were greater in LWS than HWS and, in the VMH, orexin receptor 2 and leptin receptor were greater in LWS than HWS. Greater mesotocin in the PVN, orexin in the LHA and ORXR2 in the VMH of LWS may contribute to their increased sympathetic tone and anorexic phenotype. The results of the present study also suggest that an increased hypothalamic anorexigenic tone in the LWS over-rides orexigenic factors such as NPY and AgRP that were more highly expressed in LWS than HWS in several nuclei. PMID- 28727209 TI - A dual flip angle 3D bSSFP magnetization transfer-like method to differentiate between recent and old myocardial infarction. AB - BACKGROUND: Magnetic resonance imaging (MRI) tissue signal is modulated by magnetization transfer (MT) phenomena, intrinsically induced by balanced steady state free precession (bSSFP) imaging. PURPOSE: To investigate the possible value of such a MT-like bSSFP approach in two clinical settings involving focal myocardial lesions highligthed by late gadolinium enhancement (LGE+): edema induced by recent myocardial infarction (MI) and fibrotic scar related to chronic infarction. MATERIALS AND METHODS: Population: 48 LGE + patients were studied: 26 with recent MI, 22 with chronic MI. 20 LGE-normal subjects were considered the control group. Field strength/sequence: Navigator-based short axis 3D-bSSFP sequences with 20 degrees and 90 degrees excitation flip angles were acquired (1.5T). ASSESSMENT: Pixel-wise normalized MT Ratio (nMTR) parametric images were calculated according to: nMTR = 100*(S20 -S90 *k)/S20 , with S20 and S90 signal intensity in 20 degrees and 90 degrees flip angle images and k = Blood20 /Blood90 as a normalization ratio. Statistical tests: analysis of variance (ANOVA), receiver operating characteristic (ROC) analysis. RESULTS: Overall normal myocardial nMTR was 50.2 +/- 3.6%. In recent MI, nMTR values were significantly reduced in LGE + regions (-22.3 +/- 9.9%, P < 0.0001). In cases of chronic infarct, nMTR was significantly increased in LGE + regions (14.2 +/- 11.4%, P < 0.0001). Comparison between observed results and theoretical values obtained with the Freeman-Hill formula showed that most variations observed in MI are related to MT effects instead of relaxation effects. CONCLUSION: In contrast to LGE imaging, which may show a similar hyperenhancement in recent and old infarctions, nMTR imaging demonstrates an opposite pattern: decreased values for recent infarction and increased values for old infarction, thus allowing to discriminate between these two clinical conditions without gadolinium injection. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;47:798-808. PMID- 28727211 TI - Clinical presentation of nipple duct ectasia: A rare glimpse. PMID- 28727212 TI - Successful case of breast conservation radiotherapy in a patient with type III Ehlers-Danlos syndrome. PMID- 28727210 TI - Thermal affinity as the dominant factor changing Mediterranean fish abundances. AB - Recent decades have seen profound changes in species abundance and community composition. In the marine environment, the major anthropogenic drivers of change comprise exploitation, invasion by nonindigenous species, and climate change. However, the magnitude of these stressors has been widely debated and we lack empirical estimates of their relative importance. In this study, we focused on Eastern Mediterranean, a region exposed to an invasion of species of Red Sea origin, extreme climate change, and high fishing pressure. We estimated changes in fish abundance using two fish trawl surveys spanning a 20-year period, and correlated these changes with estimated sensitivity of species to the different stressors. We estimated sensitivity to invasion using the trait similarity between indigenous and nonindigenous species; sensitivity to fishing using a published composite index based on the species' life-history; and sensitivity to climate change using species climatic affinity based on occurrence data. Using both a meta-analytical method and random forest analysis, we found that for shallow-water species the most important driver of population size changes is sensitivity to climate change. Species with an affinity to warm climates increased in relative abundance and species with an affinity to cold climates decreased suggesting a strong response to warming local sea temperatures over recent decades. This decrease in the abundance of cold-water-associated species at the trailing "warm" end of their distribution has been rarely documented. Despite the immense biomass of nonindigenous species and the presumed high fishing pressure, these two latter factors seem to have only a minor role in explaining abundance changes. The decline in abundance of indigenous species of cold-water origin indicates a future major restructuring of fish communities in the Mediterranean in response to the ongoing warming, with unknown impacts on ecosystem function. PMID- 28727213 TI - Farming and incidence of motor neuron disease: French nationwide study. AB - BACKGROUND AND PURPOSE: The association of farming with motor neuron disease (MND) is unclear, with conflicting studies. We performed a French nationwide study of the association of farming with MND incidence, and compared findings with those for Parkinson's disease (PD), which has been shown to be more frequent in farmers. METHODS: We used the French national health insurance and hospital discharge databases to identify MND/PD incident cases. The Mutualite Sociale Agricole (MSA) guarantees health insurance for farmers and agricultural workers. We compared the incidence of MND (2010-2014) and PD (2011-2012) in MSA farmers, MSA workers and non-MSA affiliates, and estimated relative risks (RRs) and 95% confidence intervals (CIs). Probabilistic sensitivity analyses were used for external smoking adjustment. RESULTS: Analyses relied on 8931 MND (MSA, 9%) and 45 409 PD (MSA,11%) cases. There was a trend towards higher MND incidence in MSA farmers compared with non-MSA affiliates (RR,1.08; 95% CI,0.99-1.18) and MSA workers (RR, 1.13; 95% CI, 0.97-1.31) that strengthened after smoking adjustment (if associated with MND). PD incidence was higher in MSA farmers than non-MSA affiliates (RR, 1.13; 95% CI, 1.08-1.17) and MSA workers (RR, 1.10; 95% CI, 1.02 1.18); this association remained after smoking adjustment (RR, 1.09; 95% CI, 1.05 1.14). CONCLUSIONS: This French nationwide study suggested an association between farming and MND, and confirmed higher PD incidence in farmers in France, a country with high pesticide use. PMID- 28727214 TI - What plant functional traits can reduce nitrous oxide emissions from intensively managed grasslands? AB - Plant species exert a dominant control over the nitrogen (N) cycle of natural and managed grasslands. Although in intensively managed systems that receive large external N inputs the emission of the potent greenhouse gas nitrous oxide (N2 O) is a crucial component of this cycle, a mechanistic relationship between plant species and N2 O emissions has not yet been established. Here we use a plant functional trait approach to study the relation between plant species strategies and N2 O emissions from soils. Compared to species with conservative strategies, species with acquisitive strategies have higher N uptake when there is ample N in the soil, but also trigger N mineralization when soil N is limiting. Therefore, we hypothesized that (1) compared to conservative species, species with acquisitive traits reduce N2 O emissions after a high N addition; and (2) species with conservative traits have lower N2 O emissions than acquisitive plants if there is no high N addition. This was tested in a greenhouse experiment using monocultures of six grass species with differing above- and below-ground traits, growing across a gradient of soil N availability. We found that acquisitive species reduced N2 O emissions at all levels of N availability, produced higher biomass and showed larger N uptake. As such, acquisitive species had 87% lower N2 O emissions per unit of N uptake than conservative species (p < .05). Structural equation modelling revealed that specific leaf area and root length density were key traits regulating the effects of plants on N2 O emission and biomass productivity. These results provide the first framework to understand the mechanisms through which plants modulate N2 O emissions, pointing the way to develop productive grasslands that contribute optimally to climate change mitigation. PMID- 28727215 TI - Neutrophil extracellular traps coincide with a pro-coagulant status of microcirculatory endothelium in burn wounds. AB - Burn-induced tissue loss is partly related to secondary expansion of necrosis into vital dermis neighboring the initial burn injury. An important factor herein is the severe loss of perfusion of the burn wound, probably caused by microvascular damage induced by the intense local inflammatory responses as well as burn-induced hypercoagulation. We hypothesize that the formation of neutrophilic extracellular traps (NETs) play an important role in this. The purpose of this study was to investigate postburn intravascular thrombosis, NETs formation and the coagulant state in the microvasculature of burns in both animal models and patients. We used two in vivo burn wound models: rats and pigs. In rats, the entire wound was excised at day 14 postburn and in pigs burn wound biopsies were collected at different time points up to 60 days postburn. To confirm the data in patients, eschar from the burn wound was obtained from burn wound patients at different time points after wounding. The number of intravascular thrombi, the presence of intravascular NETs and the number of tissue factor (TF) positive blood vessels in the burn wound was determined. In rats, a significant increase in intravascular thrombi and TF expression was observed 14 days postburn, that in majority coincided with NETs. In pigs, a significant increase in intravascular thrombi and TF expression was found over time up to 60 days postburn, that in majority coincided with NETs too. Also in eschar of burn wound patients, a significant increase in intravascular thrombi was noted, that in majority coincided with NETs, already 0.5 days postburn and remained elevated up to 46 days postburn. This study shows the presence of NETosis in microcirculatory thrombosis of burn wounds and a switch in the microcirculatory endothelium toward a procoagulant phenotype. PMID- 28727216 TI - Digestibility of common reed (Pharagmites communis Trin.) silage as ruminant feed and effects of inclusion levels in the diet of breeding cows on feed intake, ruminal fermentation and blood metabolites. AB - To examine the digestibility of common reed (Pharagmites communis Trin.) silage and effects of inclusion levels in the diet of breeding cows on nutrient intakes, ruminal fermentation and nutrient status, two digestion trials using four sheep and cows, respectively, at the maintenance stage were conducted. In the trial using sheep, common reed silage contained 20% crude protein (CP) and 50% total digestible nutrients (TDN) on a dry matter basis. In the trial using cows, treatments were the control (92.4% Sudangrass hay and 7.6% soybean meal) and CS25, CS50 and CS80 (replacing 25%, 50%, and 80% of the control with silage, respectively). The intake and sufficiency rate of CP increased by increasing the silage level in the diet (P < 0.05), and the CP requirements of cows at maintenance was satisfied in CS80. In contrast, the sufficiency rate of TDN decreased in CS80, although it was 99.8%. Ruminal pH and NH3 -N concentration changed among the treatments (P < 0.05); however, the blood metabolites were not affected by silage. The results indicated that including common reed silage of up to 80% in the diet of breeding cows was possible and did not have adverse effects on the blood metabolites. PMID- 28727217 TI - Adaptation strategies to climate change in marine systems. AB - The world's oceans are highly impacted by climate change and other human pressures, with significant implications for marine ecosystems and the livelihoods that they support. Adaptation for both natural and human systems is increasingly important as a coping strategy due to the rate and scale of ongoing and potential future change. Here, we conduct a review of literature concerning specific case studies of adaptation in marine systems, and discuss associated characteristics and influencing factors, including drivers, strategy, timeline, costs, and limitations. We found ample evidence in the literature that shows that marine species are adapting to climate change through shifting distributions and timing of biological events, while evidence for adaptation through evolutionary processes is limited. For human systems, existing studies focus on frameworks and principles of adaptation planning, but examples of implemented adaptation actions and evaluation of outcomes are scarce. These findings highlight potentially useful strategies given specific social-ecological contexts, as well as key barriers and specific information gaps requiring further research and actions. PMID- 28727218 TI - Altered sediment biota and lagoon habitat carbonate dynamics due to sea cucumber bioturbation in a high-pCO2 environment. AB - The effects of global change on biological systems and functioning are already measurable, but how ecological interactions are being altered is poorly understood. Ecosystem resilience is strengthened by ecological functionality, which depends on trophic interactions between key species and resilience generated through biogenic buffering. Climate-driven alterations to coral reef metabolism, structural complexity and biodiversity are well documented, but the feedbacks between ocean change and trophic interactions of non-coral invertebrates are understudied. Sea cucumbers, some of the largest benthic inhabitants of tropical lagoon systems, can influence diel changes in reef carbonate dynamics. Whether they have the potential to exacerbate or buffer ocean acidification over diel cycles depends on their relative production of total alkalinity (AT ) through the dissolution of ingested calcium carbonate (CaCO3 ) sediments and release of dissolved inorganic carbon (CT ) through respiration and trophic interactions. In this study, the potential for the sea cucumber, Stichopus herrmanni, a beche-de-mer (fished) species listed as vulnerable to extinction, to buffer the impacts of ocean acidification on reef carbonate chemistry was investigated in lagoon sediment mesocosms across diel cycles. Stichopus herrmanni directly reduced the abundance of meiofauna and benthic primary producers through its deposit-feeding activity under present-day and near future pCO2 . These changes in benthic community structure, as well as AT (sediment dissolution) and CT (respiration) production by S. herrmanni, played a significant role in modifying seawater carbonate dynamics night and day. This previously unappreciated role of tropical sea cucumbers, in support of ecosystem resilience in the face of global change, is an important consideration with respect to the beche-de-mer trade to ensure sea cucumber populations are sustained in a future ocean. PMID- 28727219 TI - Fractal MTW Zeolite Crystals: Hidden Dimensions in Nanoporous Materials. AB - Screw dislocation structures in crystals are an origin of symmetry breaking in a wide range of dense-phase crystals. Preparation of such analogous structures in framework-phase crystals is of great importance in zeolites but is still a challenge. On the basis of crystal-structure solving and model building, it was found that the two specific intergrowths in MTW zeolite produce this complex fractal and spiral structure. With the structurally determined parameters (spiral pitch h, screw angle theta, and spatial angle psi) of Burgers circuit, the screw dislocation structure can be constructed by two different dimensional intergrowth sections. Thus the reported complexity of various dimensions in diverse crystals can be unified. PMID- 28727220 TI - Should resistance training be targeted to a specific subgroup of patients with non-small cell lung cancer? PMID- 28727221 TI - Scar formation following excisional and burn injuries in a red Duroc pig model. AB - Scar research is challenging because rodents do not naturally form excessive scars, and burn depth, size, and location cannot be controlled in human longitudinal studies. The female, red Duroc pig model has been shown to form robust scars with biological and anatomical similarities to human hypertrophic scars. To more closely mimic the mode of injury, recreate the complex chemical milieu of the burn wound environment and enhance scar development, an animal model of excessive burn-induced scarring was developed and compared with the more commonly used model, which involves excisional wounds created via dermatome. Standardized, full-thickness thermal wounds were created on the dorsum of female, red Duroc pigs. Wounds for the dermatome model were created using two different total dermatome settings: ~1.5 mm and >= 1.9 mm. Results from analysis over 150 days showed that burn wounds healed at much slower rate and contracted more significantly than dermatome wounds of both settings. The burn scars were hairless, had mixed pigmentation, and displayed fourfold and twofold greater excess erythema values, respectively, compared with ~1.5 mm and >= 1.9 mm deep dermatome injuries. Burn scars were less elastic, less pliable, and weaker than scars resulting from excisional injuries. Decorin and versican gene expression levels were elevated in the burn group at day 150 compared with both dermatome groups. In addition, transforming growth factor-beta 1 was significantly up regulated in the burn group vs. the ~1.5 mm deep dermatome group at all time points, and expression remained significantly elevated vs. both dermatome groups at day 150. Compared with scars from dermatome wounds, the burn scar model described here demonstrates greater similarity to human hypertrophic scar. Thus, this burn scar model may provide an improved platform for studying the pathophysiology of burn-related hypertrophic scarring, investigating current anti scar therapies, and development of new strategies with greater clinical benefit. PMID- 28727222 TI - Spatiotemporal pattern of gross primary productivity and its covariation with climate in China over the last thirty years. AB - The uncertainties of China's gross primary productivity (GPP) estimates by global data-oriented products and ecosystem models justify a development of high resolution data-oriented GPP dataset over China. We applied a machine learning algorithm developing a new GPP dataset for China with 0.1 degrees spatial resolution and monthly temporal frequency based on eddy flux measurements from 40 sites in China and surrounding countries, most of which have not been explored in previous global GPP datasets. According to our estimates, mean annual GPP over China is 6.62 +/- 0.23 PgC/year during 1982-2015 with a clear gradient from southeast to northwest. The trend of GPP estimated by this study (0.020 +/- 0.002 PgC/year2 from 1982 to 2015) is almost two times of that estimated by the previous global dataset. The GPP increment is widely spread with 60% area showing significant increasing trend (p < .05), except for Inner Mongolia. Most ecosystem models overestimated the GPP magnitudes but underestimated the temporal trend of GPP. The monsoon affected eastern China, in particular the area surrounding Qinling Mountain, seems having larger contribution to interannual variability (IAV) of China's GPP than the semiarid northwestern China and Tibetan Plateau. At country scale, temperature is the dominant climatic driver for IAV of GPP. The area where IAV of GPP dominated by temperature is about 42%, while precipitation and solar radiation dominate 31% and 27% respectively over semiarid area and cold wet area. Such spatial pattern was generally consistent with global GPP dataset, except over the Tibetan Plateau and northeastern forests, but not captured by most ecosystem models, highlighting future research needs to improve the modeling of ecosystem response to climate variations. PMID- 28727223 TI - Effect of abacus training on executive function development and underlying neural correlates in Chinese children. AB - Executive function (EF) refers to a set of cognitive abilities involved in self regulated behavior. Given the critical role of EF in cognition, strategies for improving EF have attracted intensive attention in recent years. Previous studies have explored the effects of abacus-based mental calculation (AMC) training on several cognitive abilities. However, it remains unclear whether AMC training affects EF and its neural correlates. In this study, participants were randomly assigned to AMC or control groups upon starting primary school. The AMC group received 2 h AMC training every week, while the control group did not have any abacus experience. Neural activity during an EF task was examined using functional MRI for both groups in their 4th and 6th grades. Our results showed that the AMC group performed better and faster than the control group in both grades. They also had lower activation in the frontoparietal reigons than the control group in the 6th grade. From the 4th to the 6th grade, the AMC group showed activation decreases in the frontoparietal regions, while the control group exhibited an opposite pattern. Furthermore, voxel-wise regression analyses revealed that better performance was associated with lower task-relevant brain activity in the AMC group but associated with greater task-relevant brain activity in the control group. These results suggest that long-term AMC training, with calculation ability as its original target, may improve EF and enhance neural efficiency of the frontoparietal regions during development. Hum Brain Mapp 38:5234-5249, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28727224 TI - A mixed-methods study to explore the supportive care needs of breast cancer survivors. AB - OBJECTIVE: Needs assessment is the essence of quality cancer survivorship care. The aim of this study was to explore the supportive care needs of breast cancer survivors (BCS) in the first 5 years post treatment. METHODS: A mixed-methods approach was employed. A quantitative study included a Supportive Care Needs Survey, which was completed by 250 BCS to identify the level of their needs for help. The quantitative data informed semistructured qualitative interviews undertaken with 60 BCS to explore in detail their posttreatment needs and experiences. RESULTS: 32.4% and 16.8% reported 1 to 5 and greater than or equal to 6 needs for help, respectively. The regression analyses revealed that women within 2 years posttreatment and with higher educational level had higher levels of Psychological and Health Care System/Information needs. The qualitative data revealed "continuity of care" and "lifestyle advice and self-management" as prominent survivorship concerns. It was shown that determination to continue normal life, social support, and feeling overwhelmed by information were all experienced as important influences on survivors' need for help. CONCLUSIONS: Posttreatment needs vary with BCS characteristics and to the domains concerned. The approach to posttreatment care needs to be personalized and viable. PMID- 28727225 TI - Intact blood-brain barrier during spontaneous attacks of migraine without aura: a 3T DCE-MRI study. AB - BACKGROUND AND PURPOSE: The integrity of the blood-brain barrier (BBB) has been questioned in migraine, but BBB permeability has never been investigated during spontaneous migraine attacks. In the present study, BBB permeability during spontaneous attacks of migraine without aura was investigated compared to an interictal state. METHODS: Seventy-four patients suffering from migraine without aura were recruited to participate in this cross-sectional dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) study. The patients were instructed to report at the hospital for DCE-MRI scan during and outside of a spontaneous migraine attack. The primary end-point was a difference in the BBB permeability (ml/100 g/min) between the attack and the headache-free days. The permeability was assessed in five different regions of interest (ROIs) located in the anterior, middle and posterior cerebral area, brain stem, posterior pons and whole brain. The paired samples t test was used to compare Ki (permeability) values between the attack and headache-free days. RESULTS: Nineteen patients completed the study. Median time from onset of migraine attack to scan was 6.5 h (range 4.0-15.5 h). No change in the mean BBB permeability (ml/100 g/min) was found between the attack and the headache-free days in any of the measured ROIs. No relationship between the pain side or intensity and BBB permeability was found in 15 patients with unilateral pain during the examined attack. CONCLUSIONS: It was demonstrated that the BBB permeability during spontaneous migraine attacks without aura was unchanged. PMID- 28727226 TI - Risk of malignant brain tumor as a second primary is significantly reduced after treatment of breast cancer. PMID- 28727227 TI - Long-term outcomes of simultaneous heart and kidney transplantation in pediatric recipients. AB - Pediatric sHKTx has become an effective therapy for patients with combined cardiac and renal failure. Often, these patients develop human leukocyte antigen antibodies from their previous allografts and are therefore more difficult to re transplant. We describe the largest case series of a predominantly sensitized pediatric sHKTx with emphasis on medical management and patient outcomes. Demographics, clinical characteristics, antibody, and biopsy data were retrospectively collected from University of California, Los Angeles database and correlated with short- and long-term patient and allograft outcomes of all sHKTx performed between 2002 and 2015. We identified seven pediatric patients who underwent sHKTx at our center. Mean age at time of sHKTx was 13.7 years and 85.7% were re-graft patients. 57.1% were sensitized with cPRA >50% and another 57.1% had preformed donor-specific antibody. Five-year renal allograft survival and patient survival was 85.7% for both end-points. The remaining six patients are all alive (mean follow-up 78.5 months) with good kidney and heart function. sHKTx in a population with increased immunological risk can be associated with good long-term outcomes and offers potential guidance to the pediatric transplant community where data are limited. PMID- 28727228 TI - Actin Gamma 1, a new skin cancer pathogenic gene, identified by the biological feature-based classification. AB - Skin cancer is the most common form of cancer that accounting for at least 40% of cancer cases around the world. This study aimed to identify skin cancer-related biological features and predict skin cancer candidate genes by employing machine learning based on biological features of known skin cancer genes. The known skin cancer-related genes were fetched from database and encoded by the enrichment scores of gene ontology and pathways. The optimal features of the skin cancer related genes were selected with a series of feature selection methods, such as mRMR, IFS, and Random Forest algorithm. Quantitative PCR (Q-PCR) was performed for the predicted genes. Effects on proliferation and metastasis of skin cancer cell line A431 were detected through MTT and transwell assay. The effects on myosin light chain (MLC) phosphorylation of Actin Gamma 1 (ACTG1) were detected by Western blot. A total of 1233 GO terms and 55 KEGG pathway terms were identified as the optimal features for the depiction of skin cancer. According to those terms, 1134 possible skin cancer-related genes were predicted. We further identified 16 new biomarkers in expression and the classification model can predict skin cancer cases with 100% accuracy. Among the 16 genes, ACTG1 had significantly high expression in skin cancer tissue. Our investigation suggested that ACTG1 can regulate the cell proliferation and migration through ROCK signaling pathway. PMID- 28727229 TI - Volatile organic compound detection as a potential means of diagnosing cutaneous wound infections. AB - Chronic cutaneous wound infections and surgical site infections (SSIs) present a huge burden on the healthcare system and can lead to increased morbidity and mortality. Current diagnostic methods of identifying and confirming infection involve culture-based and molecular methods. Both techniques are time-consuming and delays commonly lead to untargeted empirical treatment. An ideal diagnostic method would be noninvasive and highly sensitive and detect pathogenic organisms with a high degree of accuracy to allow targeted treatment. Volatile organic compounds (VOCs) are a diverse group of carbon-based molecules produced and released by humans and microorganisms. VOC detection has the potential in aiding cutaneous wound infection diagnostics using noninvasive and time-efficient methods. This review provides a comprehensive update on VOCs produced and emitted by bacteria commonly associated with chronic wounds and SSIs. VOC sampling has the advantage of being painless, time-efficient, noninvasive, and reproducible. VOCs emitted by these organisms are diverse. In vitro studies have identified potential signature volatile profiles, which can be used in detecting these microorganisms. Combining these profiles with volatile profiles emitted from acute, chronic and surgical wounds in vivo could potentially allow identification of bacterial-specific VOCs. VOC detection has the potential for a relatively inexpensive, portable, noninvasive, and reliable clinical diagnostic tool, which could be used in detecting cutaneous wound infections and guiding their optimal management. PMID- 28727230 TI - Urothelial cell carcinoma after BK polyomavirus infection in kidney transplant recipients: A cohort study of veterans. AB - BACKGROUND: BK polyomavirus (BKPyV) reactivation is a common clinical occurrence in kidney transplant recipients (KTR). Several other polyomaviruses have been implicated as pathogens with a direct role in the development of malignancies, raising the question of whether BKPyV might also be oncogenic. METHODS: This study is the first retrospective, multicenter cohort study evaluating the relative risk for urothelial cell carcinoma (UCC) associated with BKPyV infection among KTR, and was conducted among veterans who underwent transplantation between 2000 and 2009. BKPyV cases were defined as those veterans with any clinical evidence of BKPyV infection, including positive polymerase chain reaction testing of urine and/or serum for BKPyV or kidney biopsy showing BKPyV-associated nephropathy. RESULTS: Among the 646 veterans who met inclusion criteria for the study, 103 had clinical evidence of BKPyV infection (16%). The overall relative risk for developing any malignancy after BKPyV infection was 1.13 (95% confidence interval [CI] 0.89-1.44). The adjusted relative risk for malignancy after BKPyV infection was greatest with UCC (8.21, 95% CI 0.75-89.7) and with metastatic disease of unknown etiology (8.21, 95% CI 0.75-89.7). The screening prevalence for BKPyV infection increased from 18% for those veterans who underwent transplantation in 2000 to 86% for those veterans who underwent transplantation in 2009, during which time the measured prevalence of BKPyV infection increased from 7% to 24%. CONCLUSION: In this cohort of KTR veterans, no overall increased or decreased relative risk for malignancy was associated with evidence of prior BKPyV infection. A >8-fold increased risk of developing UCC after BKPyV infection was seen, although this risk was not found to be statistically significant. PMID- 28727231 TI - Nulliparity is associated with subtle adverse metabolic outcomes in overweight/obese mothers and their offspring. AB - BACKGROUND: We aimed to evaluate metabolic outcomes in overweight/obese nulliparous and multiparous women and their offspring. STUDY DESIGN: Seventy-two overweight and obese women who participated in a randomized controlled trial of exercise in pregnancy were included in the study, comparing 18 nulliparous and 54 multiparous women and their singleton offspring. Women were assessed at 19 and 36 weeks of gestation. Fetal growth was measured using standard obstetric ultrasound techniques. Cord blood was collected at birth. Maternal and offspring body composition was assessed using DXA ~2 weeks after delivery. RESULTS: Nulliparous women had higher HbA1c in the third trimester of pregnancy than multiparous women (5.48% vs 5.29%; P=.002) and were more insulin-resistant based on the surrogate marker sex hormone-binding globulin (354 vs 408 nmol/L; P=.047). Nulliparous women also had higher levels of the inflammatory marker tumour necrosis factor alpha (4.74 vs 3.62 pg/mL; P=.025). At birth, the offspring of nulliparous women were on average 340 g (P=.013) and 0.69 standard deviation scores (P=.026) lighter than those born of multiparous women. Cord blood data showed lower insulin-like growth factor-II (P=.026) and higher IGF binding protein-1 (P=.002) levels in the offspring of nulliparous women. In addition, a less favourable metabolic profile was observed in the offspring of nulliparous women, as indicated by higher triglyceride (P<.001) and interleukin-6 (P=.039) concentrations. CONCLUSIONS: Infants born of nulliparous overweight and obese women appear to be exposed to a less favourable metabolic environment in utero, with evidence of subtle adverse metabolic outcomes at birth compared to infants of overweight/obese multiparous women. PMID- 28727232 TI - Functional genomic analysis of corals from natural CO2 -seeps reveals core molecular responses involved in acclimatization to ocean acidification. AB - Little is known about the potential for acclimatization or adaptation of corals to ocean acidification and even less about the molecular mechanisms underpinning these processes. Here, we examine global gene expression patterns in corals and their intracellular algal symbionts from two replicate population pairs in Papua New Guinea that have undergone long-term acclimatization to natural variation in pCO2 . In the coral host, only 61 genes were differentially expressed in response to pCO2 environment, but the pattern of change was highly consistent between replicate populations, likely reflecting the core expression homeostasis response to ocean acidification. Functional annotations highlight lipid metabolism and a change in the stress response capacity of corals as key parts of this process. Specifically, constitutive downregulation of molecular chaperones was observed, which may impact response to combined climate change-related stressors. Elevated CO2 has been hypothesized to benefit photosynthetic organisms but expression changes of in hospite Symbiodinium in response to acidification were greater and less consistent among reef populations. This population-specific response suggests hosts may need to adapt not only to an acidified environment, but also to changes in their Symbiodinium populations that may not be consistent among environments, adding another challenging dimension to the physiological process of coping with climate change. PMID- 28727233 TI - Optimal Pessary Care: A Modified Delphi Consensus Study. AB - INTRODUCTION: Support pessaries are an important, low-risk treatment option for women with vaginal prolapse but evidence to inform optimal practice is lacking. Currently, gynecologists, urologists, and urogynecologists recommend silicone vaginal support pessaries as first-line treatment for symptomatic vaginal prolapse in women of all ages. It is unknown how many providers who are not physicians prescribe and care for women using pessaries. For this study we attempted to collect opinions of expert nurse providers who fit pessaries on topics related to pessary care and management in an effort to develop consensus to guide practice. METHODS: A 4-round modified Delphi technique was utilized and included one series of online surveys, 2 rounds of anonymous online questionnaires, and one series of face-to-face meetings at conferences. Respondents were invited to participate in all opportunities to provide opinion. For the first 3 rounds respondents were asked to rate statements on a 3-point scale, (agree, disagree, neutral) and provide written comments for those statements with which they did not agree. The goal of additional rounds was 80% agreement between participants, including no less than 6 nurse pessary experts. RESULTS: Greater than 80% consensus was achieved for 22 statements related to patient and provider education, terminology for documentation, pessary management, and follow-up care. Use of vaginal estrogen, antimicrobials, and prevention and management of mechanical injury were areas where no consensus was reached. DISCUSSION: Expert pessary providers were able to develop consensus recommendations to inform provider education and clinical care where the evidence base remains sparse. Areas where consensus was not achieved inform the future pessary-related research agenda needed to identify optimal cost-effective pessary care and educational methods for new pessary providers. PMID- 28727235 TI - Thermal imaging and dermoscopy for detecting inflammation in frontal fibrosing alopecia. AB - BACKGROUND: Frontal fibrosing alopecia (FFA) is an inflammatory condition of the scalp, which leads to scarring and slowly progressive recession of frontotemporal and/or frontoparietal hairline. Choice of FFA treatment is highly dependent on accurate assessment of disease phase, as medical treatments are effective only during the initial inflammatory stage. METHODS: To objectively quantify the activity of the inflammatory process in FFA, 22 female patients were examined by both infrared thermography and optical dermoscopy before tissue sampling. The presence of perifollicular erythema or scaling was considered to be strongly suggestive for appropriate scalp biopsy site. Skin temperature differences in dermoscopy-selected area >0.5 degrees C for temperature of the reference area (lower area of forehead) were considered abnormal. For evaluation of the inflammatory infiltrate, a grading scale was used. RESULTS: The scale classified 14 (64%) subjects as being in the active disease phase of FFA and eight (36%) as in the inactive one. Using the thermography findings, 17 (77%) patients were considered to have the active FFA and five (23%) patients had the inactive one. The clinical assessment of active FFA was most accurate using thermal imaging combined with dermoscopy, with a sensitivity of 64%, a specificity of 88%, a positive predictive value of 90%, and an negative predictive value of 58%. CONCLUSION: We believe that infrared thermography is a noninvasive and accessible imaging modality that may serve as a complementary tool in FFA diagnosis. PMID- 28727236 TI - Structural and Electronic Flexibility in Hydrides of Zintl Phases with Tetrel Hydrogen and Tetrel-Tetrel Bonds. AB - The hydrogenation of Zintl phases enables the formation of new structural entities with main-group-element-hydrogen bonds in the solid state. The hydrogenation of SrSi, BaSi, and BaGe yields the hydrides SrSiH5/3-x, BaSiH5/3-x and BaGeH5/3-x . The crystal structures show a sixfold superstructure compared to the parent Zintl phase and were solved by a combination of X-ray, neutron, and electron diffraction and the aid of DFT calculations. Layers of connected HSr4 (HBa4 ) tetrahedra containing hydride ions alternate with layers of infinite single- and double-chain polyanions, in which hydrogen atoms are covalently bound to silicon and germanium. The idealized formulae AeTtH5/3 (Ae=alkaline earth, Tt=tetrel) can be rationalized with the Zintl-Klemm concept according to (Ae2+ )3 (TtH- )(Tt2 H2- )(H- )3 , where all Tt atoms are three-binding. The non stoichiometry (SrSiH5/3-x , x=0.17(2); BaGeH5/3-x , x=0.10(3)) can be explained by additional pi-bonding of the Tt chains. PMID- 28727237 TI - Pre-hydrated sterile acellular dermal matrix allograft in breast reconstruction: review of a single unit's experience. AB - BACKGROUND: The acellular dermal matrix (Flex HD) (FHD) became available for use in Western Australia in 2014 to aid prosthetic breast reconstruction and this descriptive study aims to review and discuss a single institution's experience since its introduction. METHODS: By retrospective case note, review data were collected for all patients who underwent prosthetic breast reconstruction with the aid of FHD between January 2014 and August 2015 in our institution. Data on basic demographic parameters, risk factors, surgery-related factors, post operative factors and follow-up information were collected. All complications were recorded and described in detail. RESULTS: FHD was used in 42 breast reconstructions in 26 patients. Procedure-related complications were seen in 26% (n = 11) of cases. A major complication requiring return to theatre was seen in 11% (n = 5) of cases. Cellulitis of the reconstructed breast (red breast syndrome) was seen in 16.67% (n = 7) cases. Overall implant loss was 2.4% (n = 1). Of the six possible risk factors for any complication, only current smoking was found to increase the risk of complications (odds ratio = 9.667, 95% confidence interval = 1.429-65.377). CONCLUSION: FHD is associated with a relatively high overall complication rate. Use of this optional expensive material has to be carefully selected balancing its perceived advantages against this possible risk. The red breast syndrome merits further studies considering its frequent occurrence with FHD use. PMID- 28727234 TI - Kynurenine, a Tryptophan Metabolite That Accumulates With Age, Induces Bone Loss. AB - Age-dependent bone loss occurs in humans and in several animal species, including rodents. The underlying causal mechanisms are probably multifactorial, although an age-associated increase in the generation of reactive oxygen species has been frequently implicated. We previously reported that aromatic amino acids function as antioxidants, are anabolic for bone, and that they may potentially play a protective role in an aging environment. We hypothesized that upon oxidation the aromatic amino acids would not only lose their anabolic effects but also potentially become a catabolic byproduct. When measured in vivo in C57BL/6 mice, the tryptophan oxidation product and kynurenine precursor, N-formylkynurenine (NFK), was found to increase with age. We tested the direct effects of feeding kynurenine (kyn) on bone mass and also tested the short-term effects of intraperitoneal kyn injection on bone turnover in CD-1 mice. MUCT analyses showed kyn-induced bone loss. Levels of serum markers of osteoclastic activity (pyridinoline [PYD] and RANKL) increased significantly with kyn treatment. In addition, histological and histomorphometric studies showed an increase in osteoclastic activity in the kyn-treated groups in both dietary and injection based studies. Further, kyn treatment significantly increased bone marrow adiposity, and BMSCs isolated from the kyn-injected mice exhibited decreased mRNA expression of Hdac3 and its cofactor NCoR1 and increased expression of lipid storage genes Cidec and Plin1. A similar pattern of gene expression is observed with aging. In summary, our data show that increasing kyn levels results in accelerated skeletal aging by impairing osteoblastic differentiation and increasing osteoclastic resorption. These data would suggest that kyn could play a role in age-induced bone loss. (c) 2017 American Society for Bone and Mineral Research. PMID- 28727238 TI - Unified Total Synthesis of Polyoxins J, L, and Fluorinated Analogues on the Basis of Decarbonylative Radical Coupling Reactions. AB - Polyoxins J (1 a) and L (1 b) are important nucleoside antibiotics. The complex and densely functionalized dipeptide structures of 1 a and 1 b contain thymine and uracil nucleobases, respectively. Herein we report the unified total synthesis of 1 a, 1 b, and their artificial analogues 1 c and 1 d with trifluorothymine and fluorouracil structures. Decarbonylative radical coupling between alpha-alkoxyacyl tellurides and a chiral glyoxylic oxime ether led to chemo- and stereoselective construction of the ribonucleoside alpha-amino acid structures of 1 a-d without damaging the preinstalled nucleobases. The high applicability of the radical-based methodology was further demonstrated by preparation of the trihydroxynorvaline moiety of 1 a-d. The two amino acid fragments were connected and elaborated into 1 a-d (longest linear sequence: 11 steps). Compounds 1 a and 1 b assembled in this way exhibited potent activity against true fungi, while only 1 d was active against Gram-positive bacteria. PMID- 28727239 TI - How to differentiate congenital from noncongenital chronic neutropenia at the first medical examination? Proposal of score: A pilot study from the French Severe Chronic Neutropenia registry. AB - OBJECTIVES: We developed a diagnostic score to differentiate congenital from noncongenital neutropenia at the time of diagnosis using reliable data collected at the first visit of a patients with neutropenia. STUDY DESIGN: In a pilot retrospective study, we included 120 patients diagnosed with chronic neutropenia; 61 had congenital and 59 had noncongenital neutropenia. We reviewed patient medical charts and collected the initial complete blood count (CBC) and other reliable data. We used logistic regression to determine the probability that the neutropenia was congenital. RESULTS: On the initial CBC, the degree of neutropenia had no predictive value; only monocytosis >1.5 * 109 /l, hemoglobin <90 g/l, or mild thrombocytopenia <150 * 109 /l suggested congenital neutropenia. The most predictive factors for congenital neutropenia were a medical history (consanguinity and patient history of neutropenia), severe infections, and oral stomatitis or gingivitis at the time of diagnosis. The age at diagnosis had limited predictive value. CONCLUSION: A diagnosis of congenital neutropenia may be reliably suspected based only on information from the CBC, some basic information from patient and parent interviews, and a clinical examination. A pilot score with six factors that could be readily, reliably collected, should facilitate the diagnosis of congenital neutropenia. PMID- 28727240 TI - Development and Dissemination of the El Centro Health Disparities Measures Library. AB - PURPOSE: This report describes the development and dissemination of a library of English measures, with Spanish translations, on constructs relevant to social determinants of health and behavioral health outcomes. The El Centro Measures Library is a product of the Center of Excellence for Health Disparities Research: El Centro, a program funded by the National Institute on Minority Health and Health Disparities of the U.S. National Institutes of Health. The library is aimed at enhancing capacity for minority health and health disparities research, particularly for Hispanics living in the United States and abroad. DESIGN: The open-access library of measures (available through www.miami.edu/sonhs/measureslibrary) contains brief descriptions of each measure, scoring information (where available), links to related peer-reviewed articles, and measure items in both languages. Links to measure websites where commercially available measures can be purchased are included, as is contact information for measures that require author permission. Links to several other measures libraries are hosted on the library website. Other researchers may contribute to the library. METHODS: El Centro investigators began the library by electing to use a common set of measures across studies to assess demographic information, culture-related variables, proximal outcomes of interest, and major outcomes. The collection was expanded to include other health disparity research studies. In 2012, a formal process was developed to organize, expand, and centralize the library in preparation for a gradual process of dissemination to the national and international community of researchers. FINDINGS: The library currently contains 61 measures encompassing 12 categories of constructs. Thus far, the library has been accessed 8,883 times (unique page views as generated by Google Analytics), and responses from constituencies of users and measure authors have been favorable. CLINICAL RELEVANCE: With the paucity of availability and accessibility of translated measures, behavioral nursing research focused on reducing health disparities can benefit from repositories of research instruments such as the El Centro Measures Library. PMID- 28727241 TI - Aneurysmal fibrous histiocytoma - spindle cell tumour with pigment: A diagnostic dilemma on cytology. PMID- 28727242 TI - Examining trust in health professionals among family caregivers of nursing home residents with advanced dementia. AB - AIM: In a context of increasing emphasis on shared decision-making and palliative care in dementia, research on family caregivers' trust in health professionals in advanced dementia is surprisingly scant. The aim of the present study was to assess trust in nursing home health professionals of family caregivers of nursing home residents with advanced dementia, and possible correlates, such as family caregivers' satisfaction, involvement in care, care burden and patients' symptom burden. METHODS: A cross-sectional study was carried out using structured questionnaires administered through the telephone. Generalized estimating equation analyses with adjustment for nursing home clustering were applied to assess the most important associations with family caregivers' trust. RESULTS: A total of 214 family caregivers of persons with dementia residing in 25 nursing homes participated in the study. The majority of the participants (67%) were women and adult children (75%). The majority of the family caregivers trusted physicians, nurses and nurses' aides at a moderate-to-high level. Approximately half to one-third reported moderate-to-low levels of trust. Higher levels of trust were associated with more positive care outcomes, such as higher family satisfaction with care and more positive evaluations of physician-family communication. CONCLUSIONS: The present study showed the importance of family caregivers trusting nursing home health professionals for their experiences as caregivers. Although causation cannot be established, increased family caregivers' trust in nursing home health professionals by improving communication and exchange of information might provide a good basis for providing optimal palliative care in advanced dementia. Geriatr Gerontol Int 2017; 17: 2466-2471. PMID- 28727243 TI - Filamin A expression predicts early recurrence of hepatocellular carcinoma after hepatectomy. AB - BACKGROUND & AIMS: Recurrence of hepatocellular carcinoma (HCC) after hepatectomy is very high. A predictive marker of early recurrence (ER) capable of personalizing follow-up and developing a new target therapy would be beneficial. The overexpression of Filamin-A (FLNA), a cytoskeleton protein with scaffolding properties, has recently been associated with progression in tumours. The aim of this study was to test the expression of FLNA in a cohort of patients operated for HCC. METHODS: A retrospective cohort of patients who underwent hepatic resection at Humanitas Clinical and Research Center between January 2004 and December 2014 was analysed. FLNA was tested, using a tissue microarray, in the HCC and in the surrounding tissues. The endpoint was the role of FLNA expression in predicting ER of HCC after hepatectomy. Analyses were performed following the REMARK guidelines. RESULTS: A total of 113 patients were considered. FLNA was expressed only in the tumoral tissue. Several variables, including T stage, tumour number, tumour size, type of viral hepatitis, type of hepatectomy and intra and peritumoral immune-reactivity to FLNA were significantly associated with ER by univariate analysis. With multivariate analysis, only T stage (HR=2.108; P=.002), tumour number (HR=1.586; P=.023), intra-tumoral (HR=2.672; P<.001) and peritumoral immune-reactivity to FLNA (HR=2.569; P<.001), significantly correlated with ER. The logistic regression analysis revealed that advanced T stage (OR=2.985; P=.001), HCV-infection (OR=1.219; P=.008) and advanced tumour grading (OR=2.781; P=.002) were associated with intratumoral FLNA immune-reactivity. CONCLUSIONS: FLNA expression predicts recurrence of HCC after hepatectomy. This finding provides important insights that would help physicians to personalize follow-up strategies. PMID- 28727244 TI - From Where I Sit. PMID- 28727245 TI - Stereospecific Decarboxylative Nazarov Cyclization Mediated by Carbon Dioxide for the Preparation of Highly Substituted 2-Cyclopentenones. AB - Highly substituted 2-cyclopentenones were stereospecifically and regioselectively constructed with high catalytic efficiency through Lewis-acid catalyzed decarboxylative Nazarov cyclization of the cyclic carbonate derivative, which is prepared by reacting the propargyl alcohol with carbon dioxide in the presence of a silver catalyst. The stereochemistry of the 2-cyclopentenone is strictly controlled by the geometry of the alkene in the starting material. This method is applicable for various substrates. PMID- 28727246 TI - Recognition and Extraction of Cesium Hydroxide and Carbonate by Using a Neutral Multitopic Ion-Pair Receptor. AB - Current approaches to lowering the pH of basic media rely on the addition of a proton source. An alternative approach is described herein that involves the liquid-liquid extraction-based removal of cesium salts, specifically CsOH and Cs2 CO3 , from highly basic media. A multitopic ion-pair receptor (2) is used that can recognize and extract the hydroxide and carbonate anions as their cesium salts, as confirmed by 1 H NMR spectroscopic titrations, ICP-MS, single-crystal structural analyses, and theoretical calculations. A sharp increase in the pH and cesium concentrations in the receiving phase is observed when receptor 2 is employed as a carrier in U-tube experiments involving the transport of CsOH through an intervening chloroform layer. The pH of the source phase likewise decreases. PMID- 28727248 TI - Vascular anomaly cases for the pediatric hematologist oncologists-An interdisciplinary review. AB - Vascular anomalies (VAs) are classified as tumors or malformations depending on their clinical characteristics, pathological diagnosis, and genomic information. Diagnosis can be challenging because of the heterogeneity of clinical presentation; thus, the best diagnosis and care are provided by an interdisciplinary team of specialists. Over the past 10 years, an increasing number of pediatric hematologist/oncologists are caring for patients with VAs secondary to new medical therapy options and clinical trials. This paper focuses on complicated VA issues often seen by the pediatric hematologist/oncologist. The paper reviews clinical pearls on diagnosis, histology, radiology, and treatment options. PMID- 28727247 TI - Acceptability of a very-low-energy diet in Type 2 diabetes: patient experiences and behaviour regulation. AB - AIMS: To evaluate the acceptability of an 8-week very-low-energy diet for remission of Type 2 diabetes, and to identify barriers and facilitators of adherence and behaviour-regulation strategies used by participants in the Counterbalance study. METHODS: Eighteen of 30 participants in the Counterbalance study (ISRCTN88634530) took part in semi-structured interviews. Of these, 15 participants were interviewed before and after the 8-week very-low-energy diet intervention. Thematic analysis was used to analyse the narratives. RESULTS: The prospect of diabetes remission, considerable weight loss, and long-term health improvement provided participants with substantial initial motivation. This motivation was sustained through the experience of rapid weight loss, improvements in blood glucose levels, social support and increased physical and psychological well-being. Overall, adherence to the very-low-energy diet for 8 weeks was perceived as much easier than anticipated, but required personal effort. Participants addressed challenges by removing food from the environment, planning, avoidance of tempting situations or places, and self-distraction. Weight loss and improvements in blood glucose levels lead to a sense of achievement and improvements in physical and psychological wellbeing. CONCLUSIONS: Dietary treatment for reversal of Type 2 diabetes is acceptable and feasible in motivated participants, and the process is perceived as highly gratifying. Research outside of controlled trial settings is needed to gauge the generalisability of these findings. PMID- 28727249 TI - Dynamics of amino acid redistribution in the carnivorous Venus flytrap (Dionaea muscipula) after digestion of 13 C/15 N-labelled prey. AB - Amino acids represent an important component in the diet of the Venus flytrap (Dionaea muscipula), and supply plants with much needed nitrogen resources upon capture of insect prey. Little is known about the significance of prey-derived carbon backbones of amino acids for the success of Dionaea's carnivorous life style. The present study aimed at characterizing the metabolic fate of 15 N and 13 C in amino acids acquired from double-labeled insect powder. We tracked changes in plant amino acid pools and their delta13 C- and delta15 N-signatures over a period of five weeks after feeding, as affected by contrasting feeding intensity and tissue type (i.e., fed and non-fed traps and attached petioles of Dionaea). Isotope signatures (i.e., delta13 C and delta15 N) of plant amino acid pools were strongly correlated, explaining 60% of observed variation. Residual variation was related to contrasting effects of tissue type, feeding intensity and elapsed time since feeding. Synthesis of nitrogen-rich transport compounds (i.e., amides) during peak time of prey digestion increased 15 N- relative to 13 C- abundances in amino acid pools. After completion of prey digestion, 13 C in amino acid pools was progressively exchanged for newly fixed 12 C. The latter process was most evident for non-fed traps and attached petioles of plants that had received ample insect powder. We argue that prey-derived amino acids contribute to respiratory energy gain and loss of 13 CO2 during conversion into transport compounds (i.e., 2 days after feeding), and that amino-nitrogen helps boost photosynthetic carbon gain later on (i.e., 5 weeks after feeding). PMID- 28727250 TI - Lack of adjustment for confounding could lead to misleading conclusions. PMID- 28727251 TI - Degree of conversion and cross-link density within a resin-matrix composite. AB - The aims of this study were to profile light radiated from two light-curing units (LCUs) and evaluate profile relationship to polymerization patterns within a resin-matrix composite (RMC). Beam profiles of one multiple emission peak light emitting-diode and one quartz-tungsten-halogen curing-unit were measured using a beam profiler/spectrometer system. A camera-based profiler and an integrating sphere/spectrometer assembly were used to evaluate each LCU beam. Polymerization patterns within a nano-hybrid RMC were investigated using a mapping approach by assessing the degree of conversion utilizing micro-Raman spectroscopy and indirectly estimating cross-link-density by repeated microhardness testing before and after exposure to ethanol (%KH reduction, n = 3). The irradiance received on the top and bottom specimen surfaces from both LCUs was measured using a MARC-RC system. The investigated beam profile area from both LCUs was non-uniform and yielded localized discrepancies in DC (55.7-74.9%) and %KH reduction (26.7 54.1%). The LCU irradiance received at the bottom of the specimens was ~10% of the top value. This study demonstrated that LCU beam profiles were non-uniform in the area explored. Localized differences in DC and %KH reduction existed throughout the RMC specimens but did not follow a specific pattern. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1496 1504, 2018. PMID- 28727252 TI - Frapbot: An open-source application for FRAP data. AB - We introduce Frapbot, a free-of-charge open source software web application written in R, which provides manual and automated analyses of fluorescence recovery after photobleaching (FRAP) datasets. For automated operation, starting from data tables containing columns of time-dependent intensity values for various regions of interests within the images, a pattern recognition algorithm recognizes the relevant columns and identifies the presence or absence of prebleach values and the time point of photobleaching. Raw data, residuals, normalization, and boxplots indicating the distribution of half times of recovery (t1/2 ) of all uploaded files are visualized instantly in a batch-wise manner using a variety of user-definable fitting options. The fitted results are provided as .zip file, which contains .csv formatted output tables. Alternatively, the user can manually control any of the options described earlier. (c) 2017 International Society for Advancement of Cytometry. PMID- 28727253 TI - Systemic treatment for sarcoidosis was needed for 16% of 1810 Caucasian patients. AB - INTRODUCTION AND OBJECTIVE: Sarcoidosis is a systemic granulomatous disease predominantly affecting the lungs, although granulomas can also involve all other organs. Fortunately, it is often a self-limiting disease and aggressive treatment is not indicated in majority of cases. However, treatment is recommended when critical organs are affected or the disease is progressive. So far, there is lack of reliable information regarding the frequency of treatment in Caucasian population or data are discordant. The aim of this study was to evaluate the prevalence of systemic immune-modulating treatment in a large cohort of sarcoidosis patients. METHODS: We performed a retrospective analysis of patients discharged from our institution with the final diagnosis 'sarcoidosis' (ICD-10: D86) from January 2010 to December 2013. RESULTS: 1810 sarcoidosis patients were hospitalized during these four years, 47.6% were females, mean age was 43.5 +/- 12.2 years. The majority (80.6%) were discharged as pulmonary and/or lymph node sarcoidosis (D86.0, D86.1, D86.2). Only 281 (15.5%) patients were discharged with systemic treatment, 60.1% of them were men (OR 1.5; 95% CI: 1.1-1.9, P = .0047). The 44.8% of patients who had sarcoidosis also involving an organ other than the lungs (D86.8) were much more likely to be treated: OR 5.6; 95% CI: 4.2-7.4, P < .0001). Older age (>50) was also identified as a risk factor for treatment (odds ratio: 1.8; 95% CI: 1.5-2.4). CONCLUSIONS: Less than 16% sarcoidosis patients required systemic treatment. Older men with multiorgan sarcoidosis were more likely to be treated. PMID- 28727254 TI - Introduction to the Chinese society for reproductive immunology. PMID- 28727255 TI - Reproductive immunology in Asia: An international collaboration. AB - Percentage of global access to articles published in the AJRI by investigators in the USA and China. PMID- 28727256 TI - Localization of ventricular arrhythmias: The importance of evaluating the frontal axis. PMID- 28727257 TI - Routine surveillance imaging after end of therapy for pediatric extracranial tumors: A retrospective analysis. AB - Frequent surveillance imaging is routine practice for pediatric patients after cancer therapy. This retrospective study evaluated the follow-up of 301 children with extracranial tumors diagnosed between 2002 and 2012, at a tertiary pediatric cancer center in Beirut, Lebanon. Recurrence occurred in 15% of patients, at a median of 12 months after end of primary therapy. Outcome was not different comparing patients with recurrence detected via imaging surveillance versus clinically. False positive findings in 55 patients led to further interventions. These results raise important questions regarding benefit of current surveillance practices as standard care, especially in countries with limited resources. PMID- 28727258 TI - Changing Systems Through Effective Teams: A Role for Simulation. AB - Teams are the building blocks of the healthcare system, with growing evidence linking the quality of healthcare to team effectiveness, and team effectiveness to team training. Simulation has been identified as an effective modality for team training and assessment. Despite this, there are gaps in methodology, measurement, and implementation that prevent maximizing the impact of simulation modalities on team performance. As part of the 2017 Academic Emergency Medicine Consensus Conference "Catalyzing System Change Through Health Care Simulation: Systems, Competency, and Outcomes," we explored the impact of simulation on various aspects of team effectiveness. The consensus process included an extensive literature review, group discussions, and the conference "workshop" involving emergency medicine physicians, medical educators, and team science experts. The objectives of this work were to: 1) explore the antecedents and processes that support team effectiveness, 2) summarize the current role of simulation in developing and understanding team effectiveness, and 3) identify research targets to further improve team-based training and assessment, with the ultimate goal of improving healthcare systems. PMID- 28727259 TI - Developing an aftercare decision aid; assessing health professionals' and patients' preferences. AB - Personalising aftercare for curatively treated breast cancer patients is expected to improve patient satisfaction with care. A patient decision aid can support women in making decisions about their aftercare trajectory, but is currently not available. The aim of this study was to assess the needs of patients and health professionals with regard to an aftercare decision aid to systematically develop such a decision aid. Focus groups with patients and individual interviews with health professionals were digitally recorded and coded using the Framework analysis. Although most patients felt few aftercare options were available to them, health professionals reported to provide various options on the patients' request. Patients reported difficulty in expressing their need for options to their health professional. Although most patients were unfamiliar with decision aids, the majority preferred a paper-based patient decision aid, while most health professionals preferred an online tool. The practical implications for the intended patient decision aid are: that a digital tool with paper-based element should be developed, the patient decision aid should facilitate both rational and intuitive processes and should provide insight in patients' preferences concerning aftercare to discuss these explicitly. PMID- 28727260 TI - Gastric peroral endoscopic myotomy for pylorospasm: Case report and literature review. PMID- 28727261 TI - More than meets the eye: The barrier effect of the Yangtze River outflow. AB - The Yangtze (Changjiang) River enters the East China Sea with huge annual freshwater and sediment deposits. This outflow, known as the Changjiang diluted water (CDW), causes striking ecological gradients that potentially shape coastal species' distribution and differentiation. The CDW has long been rendered as a marine biogeographic boundary separating cold-temperature and warm-water faunas, but it remains unclear whether and to what extent it acts as an intraspecific barrier. Here, we synthesize published phylogeographic studies related to the CDW to address these issues. We find that the influence of the CDW on population differentiation is taxonomically variable, and even congeneric species may respond differently. In studies that claim the CDW is a phylogeographic barrier, the underlying assumptions explaining observed genetic breaks are sometimes incorrect, and some may have misinterpreted results due to conceptual confusion or insufficient geographic sampling. After excluding these studies, the remaining ones generally show shallow genetic divergence but significant population structure for coastal species across the CDW, suggesting that the CDW has not been a historically persistent barrier, but rather has acted as a filter within some species recently, probably after the last glacial maximum. PMID- 28727262 TI - Further improvement of antigen specific T cell detection. PMID- 28727263 TI - Hearing outcomes of incus-interposition vs titanium-partial ossicular replacement prostheses-Hearing outcomes in 115 patients. PMID- 28727265 TI - Comment on: Generation and optimization of the self-administered pediatric bleeding questionnaire and its validation as a screening tool for von Willebrand disease. PMID- 28727264 TI - Phosphorylated Polyacrylonitrile Fibers as an Efficient and Greener Acetalization Catalyst. AB - A novel solid acid catalyst (PANEAP F) is developed by immobilization of phosphoric acid on polyacrylonitrile fiber through covalent bonding. Various characterization techniques such as elemental analysis (EA), X-ray photoelectron spectroscopy (XPS), Fourier transform infrared spectroscopy (FTIR), etc. are utilized to confirm the successful grafting and the stability of the fiber catalysts during application. PANEAP F shows high catalytic activity in the acetalization of aldehydes owing to the high utilization efficiency of its functionalized acid sites. In addition, the strong polarity micro-environment in the surface layers of PANEAP F make it highly suitable for catalytic application in both water and alcohol. Furthermore, the fiber catalyst can be applied to the acetalization of aldehydes in a continuous-flow process at room temperature, and shows excellent reactivity and superior recyclability (over 20 times). The many advantages of PANEAP F such as simple preparation, convenient regulation of acid amount, high durability, and eco-friendly process make it very attractive for fixed-bed reactors in the chemical industry. PMID- 28727266 TI - Next-generation sequencing of cytologic preparations: An analysis of quality metrics. AB - BACKGROUND: Next-generation sequencing (NGS) fails for many small biopsies (BXs) because of a low overall DNA concentration or tumor percentage. Cytology smears and liquid-based preparations (LBPs), or smears/LBPs, often contain abundant tumor cells and may provide adequate material for molecular testing when other materials are insufficient. This study examined the performance of smears/LBPs on a clinical NGS assay. METHODS: This study retrospectively reviewed quality metrics from consecutive smear/LBP, core BX, and cell block (CB) cases run on a hybrid-capture NGS assay interrogating 309 cancer-related genes. The following quality metrics were compared: adequacy rate, initial DNA concentration, postshearing fragment size, post-library preparation fragment size, fragment size difference, insert size, total reads, passing-filter reads aligned, percent passing-filter unique reads aligned, mean target coverage, percentage of loci with >100* coverage, percent duplication rate, percent selected bases, and percent usable bases on bait. RESULTS: Twenty-three of 26 smears/LBPs (88%) were successfully sequenced, whereas 77 of 87 core BXs (89%) and 29 of 30 CBs (97%) were. The mean target coverage, median insert size, and percent usable bases were significantly higher in the smear/LBP category. The postshearing fragment size and the percent duplication were significantly lower for smears/LBPs. CONCLUSIONS: The adequacy rate of cytology smears/LBPs for NGS is comparable to that of core BXs or CBs. Increased values for the mean insert size, mean target coverage, and percent usable bases, along with a lower duplication rate, suggest that smears/LBPs provide higher quality DNA than formalin-fixed material. Cytology smears/LBPs can serve as a valuable source of material for molecular testing. Cancer Cytopathol 2017;125:786-94. (c) 2017 American Cancer Society. PMID- 28727267 TI - Distinguishing in-hospital and out-of-hospital status epilepticus: clinical implications from a 10-year cohort study. AB - BACKGROUND AND PURPOSE: The aim was to determine differences of clinical, treatment and outcome characteristics between patients with in-hospital and out of-hospital status epilepticus (SE). METHODS: From 2005 to 2014, clinical data were assessed in adults with SE treated in an academic medical care centre. Clinical characteristics, treatment and outcomes were compared between patients with in-hospital and out-of-hospital SE. RESULTS: Amongst 352 patients, 213 were admitted with SE and 139 developed in-hospital SE. Patients with in-hospital SE had more acute/fatal aetiologies (60% vs. 35%, P < 0.001), fewer previous seizures (33% vs. 50%, P = 0.002), a higher median Charlson Comorbidity Index (3 vs. 2, P < 0.001), longer median SE duration (1 vs. 0.5 days, P = 0.001), more refractory SE (52% vs. 39%, P = 0.022), less return to functional baseline (38% vs. 54%, P = 0.006) and increased mortality (29% vs. 19%, P = 0.001). Whilst in multivariable analyses an increasing Status Epilepticus Severity Score (STESS) was an independent predictor for death in both groups, increased Charlson Comorbidity Index and treatment refractory SE were associated with death only in patients with in-hospital SE. Continuous anaesthesia for refractory SE was associated with increased mortality only in patients with out-of-hospital SE. The area under the receiver operating curve was 0.717 for prediction of death by STESS in patients with in-hospital SE and 0.811 in patients with out-of-hospital SE. CONCLUSIONS: Patients with in-hospital SE had more fatal aetiologies and comorbidities, refractory SE, less return to functional baseline, and increased mortality compared to patients with out-of-hospital SE. Whilst the STESS was a robust predictor for death in both groups, the association between continuous anaesthesia and death was limited to out-of-hospital SE. PMID- 28727268 TI - Identification of a novel allele, HLA-C*02:02:33, by full-length genomic sequencing. AB - The HLA-C*02:02:33 allele differs by a single nucleotide at codon 215 compared with HLA-C*02:02:02:01. PMID- 28727269 TI - Discovery of a novel HLA-A*02 variant, HLA-A*02:684, in a Taiwanese individual. AB - One nucleotide replacement at residue 728 of HLA-A*02:03:01 results in a new allele, HLA-A*02:684. PMID- 28727271 TI - The effectiveness of an initial continuing education course in leadership for dentists. AB - PURPOSE/OBJECTIVES: The purpose of this study was to measure the effectiveness of a continuing education course in leadership presented to postdoctoral dentist leaders. METHODS: The authors developed a 3-day course on leadership and management with topics including self-awareness, leadership qualities, emotional intelligence, communication skills, social skills, conflict management, personal branding, quality improvement and team motivation. Twenty-two course participants with a median age of 37.5 years and an average of 13.7 years of professional experience were assessed using three different metrics: satisfaction with the course and presenters immediately following the course; pre-course and post course tests on knowledge of leadership topics; and self-assessments of leadership competency skills prior to the course, immediately following the course and then 6 months after the course. RESULTS: Participant satisfaction with both instructors' effectiveness and the overall course design was very high. A survey 6 months following the course showed that participants were very positive regarding the practical use of the leadership skills they acquired in the course. The average of all participants' scores on the objectively assessed leadership knowledge test showed a statistically significant (P<.001) difference between pre course and post-course scores. At 6-month follow-up, participant self-assessment of leadership competency significantly improved following the course. CONCLUSION: A well-designed course in leadership skills can have a positive impact on the leadership knowledge and competency of dentist-leaders. This unique leadership course was effective in increasing leadership knowledge and self-perceived leadership competency. The course and the skilled instructors were rated very highly by participants. PMID- 28727270 TI - Efficacy and safety of pregabalin for painful diabetic peripheral neuropathy in a population of Chinese patients: A randomized placebo-controlled trial. AB - BACKGROUND: Limited information exists regarding the efficacy of pregabalin in Chinese patients with painful diabetic peripheral neuropathy (pDPN). METHODS: An 11-week double-blind placebo-controlled trial was performed in Chinese pDPN patients randomized (1 : 1) to 300 mg/day pregabalin or placebo. The primary outcome was change from baseline to endpoint in mean pain score (MPS; 0, no pain; 10, worst possible pain; using the mean of the last seven daily pain scores). Secondary outcomes included weekly MPS and responder status (MPS reduced by >=30% or >=50% vs baseline). Subgroup analysis assessed patients with severe (>=7) baseline MPS. Adverse events (AEs) were reported. RESULTS: In all, 620 patients were randomized (pregabalin, n = 313; placebo, n = 307). Improvement in MPS with pregabalin versus placebo was not significant (P = 0.0559). Post hoc sensitivity analyses, excluding one patient/site due to Good Clinical Practice (GCP) non compliance, showed pregabalin significantly improved MPS when excluding the patient (P = 0.0448) or site (P = 0.0142). Pregabalin significantly improved weekly MPS (P = 0.0164) and >=50% responders at endpoint (P = 0.0384). Improvement in proportion of >=30% responders, impression of change, pain intensity, and sleep did not differ significantly between the treatment groups. In the severe pDPN subpopulation, pregabalin significantly improved MPS versus placebo (P = 0.0040). The most commonly reported AE was dizziness (9.6% vs 3.9% with placebo). CONCLUSIONS: Pregabalin did not significantly improve the primary measure of pain in the trial. Significant reductions in MPS were observed when excluding the GCP non-compliant patient/site and in the severe pDPN subpopulation. Pregabalin was well tolerated in Chinese pDPN patients. PMID- 28727272 TI - Performance of clinical prediction rules for diagnosis of pleural tuberculosis in a high-incidence setting. AB - OBJECTIVES: Diagnosis of pleural tuberculosis (PT) is still a challenge, particularly in resource-constrained settings. Alternative diagnostic tools are needed. We aimed at evaluating the utility of Clinical Prediction Rules (CPRs) for diagnosis of pleural tuberculosis in Peru. METHODS: We identified CPRs for diagnosis of PT through a structured literature search. CPRs using high complexity tests, as defined by the FDA, were excluded. We applied the identified CPRs to patients with pleural exudates attending two third-level hospitals in Lima, Peru, a setting with high incidence of tuberculosis. Besides pleural fluid analysis, patients underwent closed pleural biopsy for reaching a final diagnosis through combining microbiological and histopathological criteria. We evaluated the performance of the CPRs against this composite reference standard using classic indicators of diagnostic test validity. RESULTS: We found 15 eligible CPRs, of which 12 could be validated. Most included ADA, age, lymphocyte proportion and protein in pleural fluid as predictive findings. A total of 259 patients were included for their validation, of which 176 (67%) had PT and 50 (19%) malignant pleural effusion. The overall accuracy of the CPRs varied from 41% to 86%. Two had a positive likelihood ratio (LR) above 10, but none a negative LR below 0.1. ADA alone at a cut-off of >=40 IU attained 87% diagnostic accuracy and had a positive LR of 6.6 and a negative LR of 0.2. CONCLUSION: Many CPRs for PT are available. In addition to ADA alone, none of them contributes significantly to diagnosis of PT. PMID- 28727273 TI - Should resistance training be targeted to a specific subgroup of patients with non-small cell lung cancer? - Reply. PMID- 28727274 TI - The effect of depression and side effects of antiepileptic drugs on injuries in patients with epilepsy. AB - BACKGROUND AND PURPOSE: People with epilepsy are at increased risk of accidents and injuries but, despite several studies on this subject, data regarding preventable causes are still contradictory. The aim of this study was to investigate the relationship between injuries, side effects of antiepileptic drugs (AEDs) and depression. METHODS: Data from a consecutive sample of adult patients with epilepsy attending the outpatient clinics at St George's University Hospital in London were included. All patients were asked if they had had any injury since the last clinic appointment and completed the Liverpool Adverse Event Profile (LAEP) and Neurological Disorders Depression Inventory for Epilepsy. RESULTS: Among 407 patients (243 females, mean age 43.1 years), 71 (17.4%) reported injuries since the last appointment. A two-step cluster analysis revealed two clusters with the major cluster (53.5% of the injured group) showing a total score for LAEP >=45, a positive Neurological Disorders Depression Inventory for Epilepsy screening and presence of AED polytherapy. A total score for LAEP >=45 was the most important predictor. CONCLUSIONS: Antiepileptic drug treatment should be reviewed in patients reporting injuries in order to evaluate the potential contribution and burden of AED side effects. PMID- 28727275 TI - Corrigendum: Novel yeast isolated from broilers' feedstuff, gut and faeces as aflatoxin B1 adsorbents. PMID- 28727276 TI - Correlation between microRNA expression, clinicopathological characteristics, and prognosis in patients with Non-small cell Lung Cancer: A retrospective study. AB - BACKGROUND: Lung cancer prognosis is related to various factors; however, the comprehensive relationship between these factors, including microRNAs (miRNAs), and lung cancer prognosis has not been determined. Thus, the aim of this study was to identify the key factors associated with lung cancer prognosis. METHODS: We retrospectively analyzed prognosis and relevant factors in 216 non-small cell lung cancer (NSCLC) patients diagnosed from January 2008 to December 2014. Paraffin-embedded lung tissue samples were used to detect miRNA-21 and miRNA-155. Clinical information was collected, including tumor malignancy, tumor node metastasis (TNM) classification, pathological type, site of the original tumor, and lung involvement. The association between factors and overall survival was analyzed. A Cox proportional hazard model was used to perform univariate and multivariate analyses. RESULTS: Age at surgery (hazard ratio [HR] 1.021, 95% confidence interval [CI] 1.003-1.040), TNM stages II (HR 3.858, 95% CI 2.449 6.078) and III (HR 3.099, 95% CI 1.911-5.023), and miRNA-21 (HR 1.002, 95% CI 1.001-1.003) and miRNA-155 expression (HR 1.131, 95% CI 1.064-1.202) were independent prognostic factors in NSCLC patients. MiRNA-21 expression with TNM stages II (HR 1.282, 95% CI 1.197-1.372) and III (HR 1.247, 95% CI 1.149-1.354) interacted to affect prognosis in NSCLC patients. CONCLUSIONS: Older age, higher clinical TNM stage, and increased miRNA-21 and miRNA-155 expression in NSCLC tissue were independently associated with poor survival in NSCLC patients. MiRNA 21 expression and clinical TNM stage interacted to affect prognosis. PMID- 28727277 TI - High-dose palliative radiotherapy for malignant pleural mesothelioma. AB - INTRODUCTION: High-dose radiotherapy to the hemithorax for patients with malignant pleural mesothelioma is a controversial treatment. Between 2003 and 2013 our institution had a policy of giving hemithoracic radiotherapy to at least 45 Gy. This retrospective study reports survival, progression and toxicity associated with this policy. METHODS: Seventy-one patients with pleural mesothelioma were irradiated with doses of 45-60 Gy. Conformal radiotherapy (3D CRT) to the lower hemithorax was used for 17 and intensity-modulated radiotherapy (IMRT) to the whole hemithorax for 54 patients. All patients have been followed up for at least 2 years from commencement of radiotherapy. RESULTS: Sixty-four patients (90%) completed planned radiotherapy and seven stopped early, usually due to progressive disease. Median overall survival was 9.5 months (95% CI: 7.7 12.4) and median progression-free survival was 4.9 months (95% CI: 4.4-5.8). Eighty-seven per cent of patients progressed or died within 2 years: 25% in field, 49% outside the RT field and 13% died without progression. Severe toxicity (grade 3-5) was observed in 53% of 3D-CRT and 78% of IMRT patients, most commonly pulmonary fibrosis 27%, radiation dermatitis 18%, dyspnoea 11%, GGT increased 11%, pneumonitis 10%, pleuritic pain 8% and fatigue 8%. There were two, possibly three, treatment-related deaths. CONCLUSION: High-dose radiotherapy to the hemithorax caused significant toxicity to most patients with no improvement in survival. Lower doses of radiotherapy to limited volumes may be useful for palliative purposes. PMID- 28727278 TI - Phylogeny determines flower size-dependent sex allocation at flowering in a hermaphroditic family. AB - In animal-pollinated hermaphroditic plants, optimal floral allocation determines relative investment into sexes, which is ultimately dependent on flower size. Larger flowers disproportionally increase maleness whereas smaller and less rewarding flowers favour female function. Although floral traits are considered strongly conserved, phylogenetic relationships in the interspecific patterns of resource allocation to floral sex remain overlooked. We investigated these patterns in Cistaceae, a hermaphroditic family. We reconstructed phylogenetic relationships among Cistaceae species and quantified phylogenetic signal for flower size, dry mass and nutrient allocation to floral structures in 23 Mediterranean species using Blomberg's K-statistic. Lastly, phylogenetically controlled correlational and regression analyses were applied to examine flower size-based allometry in resource allocation to floral structures. Sepals received the highest dry mass allocation, followed by petals, whereas sexual structures increased nutrient allocation. Flower size and resource allocation to floral structures, except for carpels, showed a strong phylogenetic signal. Larger flowered species allometrically allocated more resources to maleness, by increasing allocation to corollas and stamens. Our results suggest a major role of phylogeny in determining interspecific changes in flower size and subsequent floral sex allocation. This implies that flower size balances the male-female function over the evolutionary history of Cistaceae. While allometric resource investment in maleness is inherited across species diversification, allocation to the female function seems a labile trait that varies among closely related species that have diversified into different ecological niches. PMID- 28727279 TI - Characterization of two homeodomain transcription factors with critical but distinct roles in virulence in the vascular pathogen Verticillium dahliae. AB - Vascular wilt caused by Verticillium dahliae is a destructive disease that represents a chronic economic problem for crop production worldwide. In this work, we characterized two new regulators of pathogenicity in this species. Vph1 (VDAG_06555) was identified in a candidate gene approach as a putative homologue of the transcription factor Ste12. Vhb1 (VDAG_08786), identified in a forward genetics approach, is similar to the homeobox transcription factor Htf1, reported as a regulator of conidiogenesis in several fungi. Deletion of vph1 did not affect vegetative growth, whereas deletion of vhb1 greatly reduced sporulation rates in liquid medium. Both mutants failed to induce Verticillium wilt symptoms. However, unlike Deltavph1, Deltavhb1 could be re-isolated from the vascular system of some asymptomatic plants. Confocal microscopy further indicated that Deltavph1 and Deltavhb1 differed in their behaviour in planta; Deltavph1 could not penetrate the root cortex, whereas Deltavhb1 was impaired in its ability to colonize the xylem. In agreement with these observations, only Deltavhb1 could penetrate cellophane paper. On cellophane, wild-type and Deltavhb1 strains produced numerous short branches with swollen tips, resembling the hyphopodia formed on root surfaces, contrasting with Deltavph1, which generated unbranched long filaments without swollen tips. A microarray analysis showed that these differences in growth were associated with differences in global transcription patterns, and allowed us to identify a large set of novel genes potentially involved in virulence in V. dahliae. Ste12 homologues are known regulators of invasive growth, but Vhb1 is the first putative Htf1 homologue identified with a critical role in virulence. PMID- 28727281 TI - Defaunation leads to interaction deficits, not interaction compensation, in an island seed dispersal network. AB - Following defaunation, the loss of interactions with mutualists such as pollinators or seed dispersers may be compensated through increased interactions with remaining mutualists, ameliorating the negative cascading impacts on biodiversity. Alternatively, remaining mutualists may respond to altered competition by reducing the breadth or intensity of their interactions, exacerbating negative impacts on biodiversity. Despite the importance of these responses for our understanding of the dynamics of mutualistic networks and their response to global change, the mechanism and magnitude of interaction compensation within real mutualistic networks remains largely unknown. We examined differences in mutualistic interactions between frugivores and fruiting plants in two island ecosystems possessing an intact or disrupted seed dispersal network. We determined how changes in the abundance and behavior of remaining seed dispersers either increased mutualistic interactions (contributing to "interaction compensation") or decreased interactions (causing an "interaction deficit") in the disrupted network. We found a "rich-get-richer" response in the disrupted network, where remaining frugivores favored the plant species with highest interaction frequency, a dynamic that worsened the interaction deficit among plant species with low interaction frequency. Only one of five plant species experienced compensation and the other four had significant interaction deficits, with interaction frequencies 56-95% lower in the disrupted network. These results do not provide support for the strong compensating mechanisms assumed in theoretical network models, suggesting that existing network models underestimate the prevalence of cascading mutualism disruption after defaunation. This work supports a mutualist biodiversity-ecosystem functioning relationship, highlighting the importance of mutualist diversity for sustaining diverse and resilient ecosystems. PMID- 28727282 TI - Imaging and pathological findings in a case of invasive squamous cell carcinoma of the breast. PMID- 28727280 TI - Two novel effectors of trafficking and maturation of the yeast plasma membrane H+ -ATPase. AB - The endoplasmic reticulum (ER) is the entry site of proteins into the endomembrane system. Proteins exit the ER via coat protein II (COPII) vesicles in a selective manner, mediated either by direct interaction with the COPII coat or aided by cargo receptors. Despite the fundamental role of such receptors in protein sorting, only a few have been identified. To further define the machinery that packages secretory cargo and targets proteins from the ER to Golgi membranes, we used multiple systematic approaches, which revealed 2 uncharacterized proteins that mediate the trafficking and maturation of Pma1, the essential yeast plasma membrane proton ATPase. Ydl121c (Exp1) is an ER protein that binds Pma1, is packaged into COPII vesicles, and whose deletion causes ER retention of Pma1. Ykl077w (Psg1) physically interacts with Exp1 and can be found in the Golgi and coat protein I (COPI) vesicles but does not directly bind Pma1. Loss of Psg1 causes enhanced degradation of Pma1 in the vacuole. Our findings suggest that Exp1 is a Pma1 cargo receptor and that Psg1 aids Pma1 maturation in the Golgi or affects its retrieval. More generally our work shows the utility of high content screens in the identification of novel trafficking components. PMID- 28727283 TI - Current Resources for Evidence-Based Practice, July/August 2017. PMID- 28727284 TI - Technical Note: Using k-means clustering to determine the number and position of isocenters in MLC-based multiple target intracranial radiosurgery. AB - PURPOSE: To present the k-means clustering algorithm as a tool to address treatment planning considerations characteristic of stereotactic radiosurgery using a single isocenter for multiple targets. METHODS: For 30 patients treated with stereotactic radiosurgery for multiple brain metastases, the geometric centroids and radii of each met were determined from the treatment planning system. In-house software used this as well as weighted and unweighted versions of the k-means clustering algorithm to group the targets to be treated with a single isocenter, and to position each isocenter. The algorithm results were evaluated using within-cluster sum of squares as well as a minimum target coverage metric that considered the effect of target size. Both versions of the algorithm were applied to an example patient to demonstrate the prospective determination of the appropriate number and location of isocenters. RESULTS: Both weighted and unweighted versions of the k-means algorithm were applied successfully to determine the number and position of isocenters. Comparing the two, both the within-cluster sum of squares metric and the minimum target coverage metric resulting from the unweighted version were less than those from the weighted version. The average magnitudes of the differences were small (-0.2 cm2 and 0.1% for the within cluster sum of squares and minimum target coverage, respectively) but statistically significant (Wilcoxon signed-rank test, P < 0.01). CONCLUSIONS: The differences between the versions of the k-means clustering algorithm represented an advantage of the unweighted version for the within-cluster sum of squares metric, and an advantage of the weighted version for the minimum target coverage metric. While additional treatment planning considerations have a large influence on the final treatment plan quality, both versions of the k-means algorithm provide automatic, consistent, quantitative, and objective solutions to the tasks associated with SRS treatment planning using a single isocenter for multiple targets. PMID- 28727285 TI - Adapting VMAT plans optimized for an HD120 MLC for delivery with a Millennium MLC. AB - Linac downtime invariably impacts delivery of patients' scheduled treatments. Transferring a patient's treatment to an available linac is a common practice. Transferring a Volumetric Modulated Arc Therapy (VMAT) plan from a linac equipped with a standard-definition MLC to one equipped with a higher definition MLC is practical and routine in clinics with multiple MLC-equipped linacs. However, the reverse transfer presents a challenge because the high-definition MLC aperture shapes must be adapted for delivery with the lower definition device. We have developed an efficient method to adapt VMAT plans originally designed for a high definition MLC to a standard-definition MLC. We present the dosimetric results of our adaptation method for head-and-neck, brain, lung, and prostate VMAT plans. The delivery of the adapted plans was verified using standard phantom measurements. PMID- 28727286 TI - Using cell nuclei features to detect colon cancer tissue in hematoxylin and eosin stained slides. AB - Currently, diagnosis of colon cancer is based on manual examination of histopathological images by a pathologist. This can be time consuming and interpretation of the images is subject to inter- and intra-observer variability. This may be improved by introducing a computer-aided diagnosis (CAD) system for automatic detection of cancer tissue within whole slide hematoxylin and eosin (H&E) stains. Cancer disrupts the normal control mechanisms of cell proliferation and differentiation, affecting the structure and appearance of the cells. Therefore, extracting features from segmented cell nuclei structures may provide useful information to detect cancer tissue. A framework for automatic classification of regions of interest (ROI) containing either benign or cancerous colon tissue extracted from whole slide H&E stained images using cell nuclei features was proposed. A total of 1,596 ROI's were extracted from 87 whole slide H&E stains (44 benign and 43 cancer). A cell nuclei segmentation algorithm consisting of color deconvolution, k-means clustering, local adaptive thresholding, and cell separation was performed within the ROI's to extract cell nuclei features. From the segmented cell nuclei structures a total of 750 texture and intensity-based features were extracted for classification of the ROI's. The nine most discriminative cell nuclei features were used in a random forest classifier to determine if the ROI's contained benign or cancer tissue. The ROI classification obtained an area under the curve (AUC) of 0.96, sensitivity of 0.88, specificity of 0.92, and accuracy of 0.91 using an optimized threshold. The developed framework showed promising results in using cell nuclei features to classify ROIs into containing benign or cancer tissue in H&E stained tissue samples. (c) 2017 International Society for Advancement of Cytometry. PMID- 28727287 TI - Weighing the risks: Morbid obesity and diabetes are associated with increased risk of death on the liver transplant waiting list. AB - BACKGROUND & AIMS: Obesity is a growing problem in liver transplant (LT) candidates, paralleling the US obesity epidemic and increase in LT for non alcoholic steatohepatitis (NASH). While post-LT survival appears to be similar in obese and non-obese patients, data are scarce regarding risk of waitlist dropout in patients with morbid obesity (BMI >= 40 kg/m2 ). We examined the impact of obesity on waitlist mortality and evaluated predictors of dropout in LT candidates with morbid obesity or NASH. METHODS: Competing risk analyses were performed in candidates listed between 3/2002-12/2013 to evaluate predictors of waitlist removal or death. Variables with P-value <.05 in univariable models or clinically relevant were included in multivariable models. RESULTS: Eighty-four thousand two hundred and fifty-four patients (34% female, median age 55, 15% Hispanic) were included. Compared to those with BMI 25-29.9 kg/m2 , candidates with BMI >= 40 kg/m2 were more likely to be female (46% vs 28%), diabetic (25% vs 18%) and have NASH (35% vs 13%); all P < .001. After adjusting for well recognized predictors of waitlist dropout, including ascites severity, morbid obesity (HR = 1.27, CI 1.20-1.36) and diabetes (HR = 1.14, CI 1.11-1.17) were independent predictors of dropout. Morbid obesity remained a predictor (HR = 1.27, CI 1.10-1.47) of dropout in patients without ascites (24%). In NASH patients, morbid obesity (HR = 1.21, CI 1.07-1.37) and diabetes (HR = 1.15, CI 1.06-1.23) were also associated with a higher dropout risk. In patients with morbid obesity, diabetes trended towards a higher dropout risk but was not significant (HR = 1.12, CI 0.995-1.26). CONCLUSIONS: Morbid obesity and diabetes are independent predictors of death in LT candidates. PMID- 28727288 TI - Complications preceding early deaths in Black and White children with acute myeloid leukemia. AB - Black patients have a twofold increased risk of induction mortality compared to White patients with acute myeloid leukemia (AML). We reviewed diagnosis and billing data from Pediatric Health Information System for 28 AML Induction I deaths to investigate conditions preceding death in White and Black patients. Half of deaths occurred within 10 days of initial diagnostic admission. Respiratory, cardiac, renal, and infectious complications were common prior to both White and Black deaths. Deaths in White patients were more commonly preceded by intracranial hemorrhage compared to deaths in Black patients. Future studies should assess management approaches of complications by race to identify modifiable processes that reduce mortality. PMID- 28727289 TI - Strategy for the separation of concentrated samples by capillary electrophoresis. AB - The use of concentrated samples is usually avoided during conventional separations since utilization of concentrated samples normally compromises the quality of separation. However, in case of the detection of low-abundance components, highly concentrated samples are necessary, which leads to an extremely high concentration for high-abundant components. This will make the separation difficult due to the serious longitudinal dispersion. Here, we developed a method to separate high concentration of components based on the modified capillary electrophoresis. The mechanism involves concentrated sample stretched into a wider zone in the higher electric field strength; the sample zone is fractionated into thin sections via a cutting effect; these thin sections are then separated. Based on this mechanism, we examined to separate an overloaded mixture of N,N'-diphenylguanidine and N,N'-di(o-tolyl)guanidine. Baseline separation was achieved due to much small longitudinal dispersion. The theoretical plate numbers of peaks were around 3.5 * 105 m-1 . The practicality of the new approach is demonstrated in the separation of a model protein mixture, containing lysozyme, bovine serum albumin, and ribonuclease A. PMID- 28727290 TI - Web alert: Radiation- and desiccation-resistant bacteria: An annotated selection of World Wide Web sites relevant to the topics in environmental microbiology. PMID- 28727291 TI - Proteomic analysis and bioluminescent reporter gene assays to investigate effects of simulated microgravity on Caco-2 cells. AB - Microgravity is one of the most important features in spaceflight. Previous evidence from in-vitro studies has shown that significant changes occur under simulated microgravity. For this reason, human colon adenocarcinoma Caco-2 cells were selected as cell model of intestinal epithelial barrier and their response to altered gravity conditions was investigated, especially on the protein level. In this study, we combined label-free shotgun proteomics and bioluminescent reporter gene assays to identify key proteins and pathways involved in the response of Caco-2 cells under reference and microgravity conditions. A two dimensional clinostat was modified with 3D-printed adaptors to hold conventional T25 culture flasks. The comparative proteome analysis led to identify 38 and 26 proteins differently regulated by simulated microgravity after 48 and 72 h, respectively. Substantial fractions of these proteins are involved in regulation, cellular and metabolic processes and localization. Bioluminescent reporter gene assays were carried out to investigate microgavity-induced alterations on the transcriptional regulation of key targets, such as NF-kB pathway and CYP27A1. While no significant difference was found in the basal transcription, a lower NF kB basal activation in simulated microgravity conditions was reported, corroborating the hypothesis of reduced immunity in microgravity conditions. PMID- 28727293 TI - Cytometry is expanding. PMID- 28727292 TI - Impact of Signal Peptides on Furin-2A Mediated Monoclonal Antibody Secretion in CHO Cells. AB - Studies had shown the benefits of using furin-2A peptides for high monoclonal antibody (mAb) expression in mammalian cells. How signal peptides affect furin-2A mediated mAb secretion has yet to be investigated. The impact of signal peptides on mAb secretion in furin-2A based tricistronic vectors in CHO cells is evaluated. In each tricistronic vector, heavy chain (HC) is arranged as the first cistron and followed by a furin recognition sequence, a 2A peptide, light chain (LC), an internal ribosome entry site (IRES), and dihydrofolate reductase (DHFR). Signal peptides for HC and LC are either removed or changed in different vectors. The vectors with signal peptides on both HC and LC genes gIve the highest mAb secretion levels. Changing to signal peptides with different strengths on either HC or LC do not change the mAb secretion level. IgG is still secreted when the signal peptide on the LC gene is removed but at a lower level compared to the vectors containing signal peptides on both HC and LC genes. Removing the HC signal peptide results in almost no IgG secretion regardless of whether the downstream LC carries any signal peptide. Removing the furin cleavage site does not affect mAb secretion levels while removing the 2A sequence results in low mAb secretion. The results present here will be beneficial for designing furin-2A based vectors for expressing mAb in mammalian cells. PMID- 28727296 TI - Chitosan-Fe (III) Complex as a Phosphate Chelator in Uraemic Rats: A Novel Treatment Option. AB - Phosphate retention and hyperphosphataemia are associated with increased mortality in patients with chronic kidney disease (CKD). We tested the use of cross-linked iron chitosan III (CH-FeCl) as a potential phosphate chelator in rats with CKD. We evaluated 96 animals, divided equally into four groups (control, CKD, CH-FeCl and CKD/CH-FeCl), over 7 weeks. We induced CKD by feeding animals an adenine-enriched diet (0.75% in the first 4 weeks and 0.1% in the following 3 weeks). We administered 30 mg/kg daily of the test polymer, by gavage, from the third week until the end of the study. All animals received a diet supplemented with 1% phosphorus. Uraemia was confirmed by the increase in serum creatinine in week 4 (36.24 +/- 18.56 versus 144.98 +/- 22.1 MUmol/L; p = 0.0001) and week 7 (41.55 +/- 22.1 versus 83.98 +/- 18.56 MUmol/L; p = 0.001) in CKD animals. Rats from the CKD group treated with CH-FeCl had a 54.5% reduction in serum phosphate (6.10 +/- 2.23 versus 2.78 +/- 0.55 mmol/L) compared to a reduction of 25.6% in the untreated CKD group (4.75 +/- 1.45 versus 3.52 +/- 0.74 mmol/L, p = 0.021), between week 4 and week 7. At week 7, renal function in both CKD groups was similar (serum creatinine: 83.98 +/- 18.56 versus 83.10 +/- 23.87 MUmol/L, p = 0.888); however, the CH-FeCl-treated rats had a reduction in phosphate overload measured by fractional phosphate excretion (FEPi) (0.71 +/- 0.2 versus 0.4 +/- 0.16, p = 0.006) compared to the untreated CKD group. Our study demonstrated that CH-FeCl had an efficient chelating action on phosphate. PMID- 28727297 TI - ParSel: Parallel Selection of Micro-RNAs for Survival Classification in Cancers. AB - It is known that tumor micro-RNAs (miRNA) can define patient survival and treatment response. We present a framework to identify miRNAs which are predictive of cancer survival. The framework attempts to rank the miRNAs by exploring their collaborative role in gene regulation. Our approach tests a significantly large number of combinatorial cases leveraging parallel computation. We carefully avoided parametric assumptions involved in evaluations of miRNA expressions but used rigorous statistical computation to assign an importance score to a miRNA. Experimental results on three cancer types namely, KIRC, OV and GBM verify that the top ranked miRNAs obtained using the proposed framework produce better classification accuracy as compared to some best practice variable selection methods. Some of these top ranked miRNA are also known to be associated with related diseases. PMID- 28727298 TI - Nine patients with chronic granulomatous disease having selective neck dissection for severe cervical lymphadenitis. PMID- 28727300 TI - Women and babies need protection from the dangers of normal birth ideology: AGAINST: Support for normal birth is crucial to safe high-quality maternity care. PMID- 28727299 TI - Re: An economic evaluation on outpatient versus inpatient polyp treatment for abnormal bleeding. PMID- 28727301 TI - Supervision, self care, rare events and rejection. PMID- 28727302 TI - Authors' reply re: Obstetric and neonatal complications in pregnancies conceived after oocyte donation: a systematic review and meta-analysis. PMID- 28727303 TI - Author's reply re: China's new two-child policy: maternity care in the new multiparous era. PMID- 28727304 TI - Re: Obstetric and neonatal complications in pregnancies conceived after oocyte donation: a systematic review and meta-analysis: Significance of advising women prior to fertility treatment. PMID- 28727305 TI - Re: China's new two-child policy: maternity care in the new multiparous era: China's two-child policy and reproductive ill-health. PMID- 28727306 TI - Women and babies need protection from the dangers of normal birth ideology: FOR: The recent maternity review risks making the situation even worse. PMID- 28727307 TI - Re: RCT evidence should not drive everything we do clinically: Trials and errors: Role of RCTs and EBM will be enhanced by discussion about limitations, avoidance of pitfalls and judicious application to clinical practice. PMID- 28727308 TI - Instrumental delivery: complex paternity and a fading art. PMID- 28727309 TI - Re: AGAINST: fetal scalp blood sampling in conjunction with electronic fetal monitoring reduces the risk of unnecessary operative delivery. PMID- 28727312 TI - UK Secretary of State for Health proposes new model for compensating the victims of adverse outcomes resulting from medical/midwifery errors during childbirth. PMID- 28727310 TI - Author's reply re: AGAINST: fetal scalp blood sampling in conjunction with electronic fetal monitoring reduces the risk of unnecessary operative delivery. PMID- 28727314 TI - Transperitoneal rectus sheath block and transversus abdominis plane block for laparoscopic inguinal hernia repair: A novel approach. AB - INTRODUCTION: A laparoscopic approach for inguinal hernia repair is now considered the gold standard. Laparoscopic surgery is associated with a significant reduction in postoperative pain. Epidural analgesia cannot be used in patients with perioperative anticoagulant therapy because of complications such as epidural hematoma. As such, regional anesthetic techniques, such as ultrasound guided rectus sheath block and transversus abdominis plane block, have become increasingly popular. However, even these anesthetic techniques have potential complications, such as rectus sheath hematoma, if vessels are damaged. We report the use of a transperitoneal laparoscopic approach for rectus sheath block and transversus abdominis plane block as a novel anesthetic procedure. MATERIAL AND SURGICAL TECHNIQUE: An 81-year-old woman with direct inguinal hernia underwent laparoscopic transabdominal preperitoneal inguinal repair. Epidural anesthesia was not performed because anticoagulant therapy was administered. A Peti-needleTM was delivered through the port, and levobupivacaine was injected though the peritoneum. Surgery was performed successfully, and the anesthetic technique did not affect completion of the operative procedure. The patient was discharged without any complications. DISCUSSION: This technique was feasible, and the procedure was performed safely. Our novel analgesia technique has potential use as a standard postoperative regimen in various laparoscopic surgeries. Additional prospective studies to compare it with other techniques are required. PMID- 28727315 TI - Robotic hernia surgery: An attractive perspective. PMID- 28727316 TI - Primary inguinal hernia: The open repair today pros and cons. AB - Open anterior repair for inguinal hernia offers several distinct advantages over endoscopic repair, especially when real-world effectiveness is taken into account. The learning curve for endoscopic techniques is long, whereas the Lichtenstein and other open tension-free techniques are easier to teach and replicate at all levels. The outcomes of Lichtenstein repairs for primary inguinal hernia as performed by non-experts and supervised residents are comparable to those of experts. Moreover, open tension-free repair does not require expensive instruments or dedicated equipment, other than the prosthetic mesh. As such, it is feasible in any operating room anywhere in the world with limited costs. In our opinion, the most important advantage offered by open tension-free repair is that it can be performed under local anesthesia. Nevertheless, local anesthesia has some disadvantages: it requires training, excellent knowledge of the anatomy and the necessary technique, patience, and gentle handling of the tissues. Open inguinal hernia repair is a procedure that every surgeon should know and be able to perform because it is necessary to treat two conditions, groin hernia recurrence after a posterior approach (both laparoscopic and open) and pubic inguinal pain syndrome. PMID- 28727317 TI - Laparoscopic transabdominal preperitoneal approach for umbilical hernia with rectus diastasis. AB - INTRODUCTION: Rectus diastasis, when coexistent with umbilical hernia, can benefit from mesh-based repair of the midline. Laparoscopic correction of an umbilical hernia involves the placement of a mesh in the peritoneal cavity, but this comes with the risk of bowel complications. However, newly developed dual sided composite meshes have helped to reduce this risk. MATERIALS AND SURGICAL TECHNIQUE: Four men and three women with umbilical hernia and rectus diastasis were treated with laparoscopic transabdominal preperitoneal repair. Composite mesh with a hydrophilic 3-D polyester textile on the parietal side and an absorbable collagen barrier on the peritoneal side were placed in the preperitoneal pocket after hernial sac reduction. Mean hernia size was 2.5 cm, and no recurrences were observed during the mean follow-up period of 9.2 months. DISCUSSION: The laparoscopic transabdominal preperitoneal approach for umbilical hernia and rectus diastasis may be a safe surgical option when trying to avoid potential complications related to intra-abdominal mesh positioning. PMID- 28727318 TI - Appropriate cyclic tensile strain promotes biological changes of cranial base synchondrosis chondrocytes. AB - OBJECTIVES: This study was designed to clarify biological changes of cranial base synchondrosis chondrocytes (CBSCs) upon cyclic tensile strain (CTS) loading which simulated orthopaedic mechanical protraction on cranial base synchondroses (CBS). MATERIAL AND METHODS: A two-step digestion method was used to isolate CBSCs obtained from 1-week-old Sprague Dawley rats. Immunohistochemical staining of type II collagen and Sox9 was conducted to identify chondrocytes. A CTS of 1 Hz and 10% elongation was applied to the second passage of CBSCs by FX-5000TM Tension System for 24 hours. The control group kept static at the same time. The expression levels of extracellular matrix (Acan, Col1a1, Col2a1 and Col10a1) and key regulatory factors (Sox9, Ihh and PTHrP) were detected by quantitative real time RT-PCR. RESULTS: Positive staining of type II collagen and Sox9 was detected in the isolated CBSCs. The relative expression level of Acan, Col2a1, Col10a1, Sox9 and Ihh in the CTS-loading group was 1.85-fold, 2.19-fold, 1.53-fold, 6.62 fold, and 1.39-fold, respectively, as much as that in the control group, which had statistical significance (P<.05). There was no statistical difference (P>.05) in the expression of Col1a1 and PTHrP. CONCLUSIONS: A CTS of 1 Hz and 10% elongation for 24 hours had positive effects on chondrocyte proliferation, phenotype maintenance and cartilage matrix synthesis. PMID- 28727319 TI - Novel evaluation and treatment techniques for white spot lesions. An in vitro study. AB - OBJECTIVE: White spot lesions (WSLs) are commonly seen during and after orthodontic treatment. Therefore, the objective of this in vitro study was to assess the effect of 45S5-bioglass in remineralizing WSLs using cross polarization optical coherence tomography (CP-OCT) and confirm the findings by micro-hardness test. METHODS: Ceramic orthodontic brackets were bonded to the buccal surface of 45 human premolars with Transbond XT primer followed by Transbond PLUS according to the manufacturer's instructions. Then, all specimens were varnished excluding the area of interest (AOI) around the bonded brackets, immersed in demineralizing solution and divided into three groups: BG, REM and CONT. In BG group, 15 specimens were treated with bioglass paste for 24 hours. REM group had 15 specimens stored in remineralization solution for 24 hours. CONT group had the remaining 15 specimens with no treatment. All specimens were examined under CP-OCT and tested using cross-sectional micro-hardness techniques. RESULTS: CP-OCT analysis showed that the maximum pixel value after bioglass application was significantly increased at AOI when compared to CONT and REM groups (P>.05), which was confirmed by the cross-sectional micro-hardness results (P>.05). CONCLUSION: Early enamel demineralization and remineralization can be easily and non-invasively monitored with CP-OCT. Bioglass is a potent remineralizing agent. PMID- 28727320 TI - Plasmonic Gold Nanostars Incorporated into High-Efficiency Perovskite Solar Cells. AB - Incorporating appropriate plasmonic nanostructures into photovoltaic (PV) systems is of great utility for enhancing photon absorption and thus improving device performance. Herein, the successful integration of plasmonic gold nanostars (AuNSs) into mesoporous TiO2 photoelectrodes for perovskite solar cells (PSCs) is reported. The PSCs fabricated with TiO2 -AuNSs photoelectrodes exhibited a device efficiency of up to 17.72 %, whereas the control cells without AuNSs showed a maximum efficiency of 15.19 %. We attribute the origin of increased device performance to enhanced light absorption and suppressed charge recombination. PMID- 28727321 TI - Micelle-Directing Synthesis of Ag-Doped WO3 and MoO3 Composites for Photocatalytic Water Oxidation and Organic-Dye Adsorption. AB - In this paper, an Ag-doped WO3 (and MoO3 ) composite has been prepared by following a simple micelle-directed method and high-temperature sintering route. The as-prepared samples were characterized by X-ray diffraction, inductively coupled plasma, transmission electron microscopy, X-ray photoelectron spectroscopy, UV/Vis diffuse reflectance spectroscopy, Brunauer-Emmett-Teller, photoluminescence spectroscopy, and electrochemical impedance spectroscopy techniques. The photocatalytic experiments reveal that their oxygen-production rates are up to 95.43 MUmol (75.45 MUmol) for Ag-doped WO3 (MoO3 ), which is 9.5 (7.3) times higher than that of pure WO3 : 9.012 MUmol (MoO3 : 9.00 MUmol) under visible-light illumination (lambda>=420 nm), respectively. The improvement of their photocatalytic activity is attributed to the enhancement of their visible light absorption and the separation efficiency of photogenerated carriers by Ag doping. Moreover, Ag-doped WO3 (MoO3 ) also shows excellent adsorption of rhodamine B (RhB) and methylene blue (MB) in aqueous solution, with maximum adsorption capacities towards RhB and MB of 822 and 820 mg g-1 for Ag-doped WO3 , and 642 and 805 mg g-1 for Ag-doped MoO3 , respectively. PMID- 28727322 TI - HFE gene polymorphism defined by sequence-based typing of the Brazilian population and a standardized nomenclature for HFE allele sequences. AB - The HFE molecule controls iron uptake from gut, and defects in the molecule have been associated with iron overload, particularly in hereditary hemochromatosis. The HFE gene including both coding and boundary intronic regions were sequenced in 304 Brazilian individuals, encompassing healthy individuals and patients exhibiting hereditary or acquired iron overload. Six sites of variation were detected: (1) H63D C>G in exon 2, (2) IVS2 (+4) T>C in intron 2, (3) a C>G transversion in intron 3, (4) C282Y G>A in exon 4, (5) IVS4 (-44) T>C in intron 4, and (6) a new guanine deletion (G>del) in intron 5, which were used for haplotype inference. Nine HFE alleles were detected and six of these were officially named on the basis of the HLA Nomenclature, defined by the World Health Organization (WHO) Nomenclature Committee for Factors of the HLA System, and published via the IPD-IMGT/HLA website. Four alleles, HFE*001, *002, *003, and *004 exhibited variation within their exon sequences. PMID- 28727323 TI - Indocyanine green near-infrared lymphangiography for evaluation of effectiveness of edema fluid flow under therapeutic compression. AB - The commonly used modalities for therapy of limb lymphedema are manual lymphatic drainage, manual devices moving edema fluid and intermittent pneumatic compression (IPC). What seems to be necessary for validation of the effect of the compression procedure is imaging of the mobilized moving edema fluid. Picture of edema fluid flow would allow the therapist to use force adjusted to the tissue volume and stiffness differing in various limb regions as well as identify sites of abundant accumulation of fluid requiring more compression. The purpose of the present study was to visualize tissue edema fluid flow during manual drainage, Linforoll massage, IPC and bandaging. To obtain data how high compression pressures should be used to mobilize indocyanine green (ICG)-stained fluid, concomitantly tissue fluid pressure measurements were performed. The following observations were obtained: (1) the possibility of real-time observation of edema fluid movement using various compression modalities, (2) the threshold pressures necessary to move edema fluid to be over 80 mm Hg in the compression device and over 40 mm Hg in the tissue fluid and (3) inefficacy of compression in some cases despite applying high compression force. These observations point to the need of ICG lymphangiography before compression therapy in each patient. The images observed during the compression procedure give an insight into the distribution of edema fluid, sites of its accumulation and efficacy of applied external force on fluid mobilization. PMID- 28727324 TI - Bacillus thuringiensis: An annotated selection of World Wide Web sites relevant to the topics in environmental microbiology. PMID- 28727325 TI - ? PMID- 28727326 TI - [Evaluation of an outpatient multidisciplinary Neuro-HIV clinic by the patients and referring doctors]. AB - The neurocognitive complaints among HIV infected patients remain frequent, and to establish their etiology can be challenging. We created in 2011 an outpatient Neuro-HIV clinical platform that takes advantage of a multidisciplinary approach with 5 specialists (neuropsychologist, neurologist, psychiatrist, infectiologist and neuroradiologist). In order to estimate its utility, we conducted two questionnaire-based interviews by phone calls with the patients and their referring physicians. Three quarters of both the patients and the physicians interviewed consider the platform useful or essential. Even though there is often no immediate treatment for cognitive disorders, the patients receive from this multidisciplinary approach a better understanding of their disease, which may help them to better cope with their anxieties in daily life. PMID- 28727327 TI - [Evaluation of psychosocial difficulties and needs of persons living with HIV in a nurse consultation]. AB - Despite the improvements in antiretroviral therapy, the psychosocial management of persons living with HIV remains complex and requires a multidisciplinary approach. An auto-evaluation scale of psychosocial difficulties and needs was used by a team of nurses working in an HIV outpatient clinic. After 3 years of experience, this well-accepted tool revealed a high prevalence of psychosocial difficulties within this population, including psychological health, financial situation and sexual life. This instrument also allowed implementing a number of targeted nurse interventions to improve the management of these patients. PMID- 28727328 TI - [How to use microbiological diagnostic tests in a hospital setting]. AB - Microbiological cultures provide essential information to guide the antibiotic therapy. However, their results might be misleading for physicians and drive useless treatment, sometimes harmful for patients. Recommendations highlight the importance of clinical signs in order to take into account the pre-test probability when interpreting the results. This combination will improve the predictive value of microbiological tests. The sampling strategy is also important to avoid an overuse of these tests but also misleading results through a reduction of contaminants. PMID- 28727329 TI - [Fever and rash in the adult patient]. AB - Fever with rash is a frequent reason for consultation. A detailed medical history and thorough physical examination are essential since laboratory tests often lack specificity. Certain infectious and non-infectious causes are considered medical emergencies and must always be investigated upon initial evaluation. In the case of a history of recent travel the differential diagnosis has to be broadened but it should not be forgotten that resurgent " childhood " viral diseases like measles can be acquired while traveling. PMID- 28727330 TI - [Lower urinary tract infections in men. Urethritis, cystitis and prostatitis]. AB - Recommendations for the treatment of lower non-catheter-related urinary tract infection (UTI) in men are rarely evidence-based. Their management requires the localization of the site of infection, whether it be the urethra, bladder or prostate, and includes antibiotic therapy and in most cases urological assessment. They are often associated with urinary tract procedures or anatomical or functional abnormalities. Nearly 80 % of male UTIs are caused by Enterobacteriaceae. The prevalence of broad-spectrum beta-lactamase-producing strains (ESBL) and quinolone-resistant strains is increasing. The aim of this article is to define three types of lower, non-catheter-related UTI in men - urethritis, cystitis and prostatitis - their microbiology and management in Switzerland. PMID- 28727331 TI - [Toxocariasis, a neglected disease in Switzerland ?] AB - Toxocariasis is a zoonotic disease that occurs when humans are infected by the parasites Toxocara canis or Toxocara cati. Toxocariasis is highly prevalent in tropical areas, but can also be found in industrialized countries, particularly in rural areas. Clinical presentation can range from asymptomatic infection to more severe disease. Diagnosis of toxocariasis is based on suggestive clinical findings, eosinophilia and a positive serological testing. Albendazole represents the first-line treatment, associated with corticosteroids in case of severe disease. Here we describe three clinical cases of toxocariasis in order to illustrate the clinical presentation, diagnosis and treatment of this unrecognized disease. PMID- 28727333 TI - ? PMID- 28727332 TI - [Inhibitors of PCSK9]. AB - Observational data show a consistent association between elevated low density lipoproteins (LDL-C) and cardiovascular disease (CVD). Reduction of LDL-C reduces the risk of CVD as has been shown by many trials. Statins are currently the most effective drugs for lowering LDL-C, but can present side effects which might limit the prescribed dosage and prevent patients from reaching the recommended LDL levels. Although treated with statins important residual cardiovascular event risk remains in patients in primary and secondary prevention for CVD. The discovery of protein convertase subtilisin kexin 9 antibodies is a very promising new hypolipidemic treatment and the aim of this review is to explain their mechanism of action and to discuss safety and efficacy results of some phase III studies. PMID- 28727334 TI - ? PMID- 28727335 TI - ? PMID- 28727336 TI - ? PMID- 28727337 TI - ? PMID- 28727338 TI - ? PMID- 28727339 TI - ? PMID- 28727340 TI - [Phosphocalcic anomalies and bone fragility keys for the general practitioner]. AB - How to recognize secondary causes of bone fragility in relation with an abnormal calcium and phosphate laboratory in general practice ? Through clinical cases presentations we will discuss the calcium and phosphate abnormalities which can be related to bone fragility and for which a-specific approach must be proposed. It can be abnormal results of calcium, phosphate or vitamin D. Some causes are frequent, others are iatrogenic, and others are related to a rare disease sometimes of genetic cause which consequences are more important than expected. PMID- 28727341 TI - [Use of Trabecular Bone Score as a complementary approach to DXA for fracture risk assessment in clinical practice]. AB - Physicians can assess the risk of fracture based on bone density (BMD) and several risk factors. Some of them and BMD are incorporated into FRAX, an assessment tool that estimates the 10-years probability of fracture. BMD didn't take into account the microarchitecture. TBS is a texture parameter related to bone microarchitecture. A low TBS is associated with a history of fracture and the incidence of new fracture independently of BMD, clinical risk factors and FRAX. TBS is yet integrated in the FRAX tool, and this effect is of greatest utility for individuals who are close to an intervention threshold. It is particularly useful for the evaluation of secondary osteoporosis, including type 2 diabetes, Gluco-corticoid induced osteoporosis. It responds to osteoporosis treatments and is not influenced by lumbar degenerative disorders. PMID- 28727342 TI - [Obesity, fat and bones: friends or foes ?] AB - Low fat mass is associated with an increased risk of fracture because of low bone mineral density (BMD) and altered bone micro-architecture. Conversely, overweight and obese patients also have an increased risk of fracture, particularly of the humerus and ankle, despite greater BMD. Visceral abdominal fat, which is the most metabolically active, may be associated with poorer quality of bone tissue properties, as suggested in diabetes. Other factors may contribute to higher fracture risk in overweight patients, notably higher frequency of falls and lower bioavailability of vitamin D stoked in fat. Thus, fat mass and its distribution should be taken into account beyond BMD and classical clinical risk factors in the assessment of fracture risk. PMID- 28727343 TI - [Hypophosphatasia]. AB - Hypophosphatasia (HPP) is an inborn metabolic bone disorder caused by loss-of function mutations in the gene encoding tissue nonspecific alkaline phosphatase (TNSALP). The adult form can be mistaken with common osteoporosis and/or present recurrent metatarsal fractures, skeletal and muscular pain. Subtrochanteric femoral pseudofractures resembling bisphosphonate-associated atypical femoral fractures can also be present, and Bps are therefore contraindicated in HPP. Early tooth loss and renal calcifications can orient towards the diagnosis. The diagnosis is based on low serum ALP levels (< 40 U/L) and high ALP substrate levels, such as vitamin B6 (pyridoxin), eventually on genetic testing. Recent development of an enzyme replacement therapy offers new therapeutic perspectives in severe cases. PMID- 28727344 TI - [To where and until when handle the osteoporosis?] AB - Estrogen replacement therapy, selective modulators of the estrogen receptor (SERMs), bisphophonates and denosumab are antiresorptive therapies which can be used for several years. Teriparatide is still the only bone forming agent available, its use is limited to 24 months. Except the absence of new fragility fractures, there is no well defined target in the treatment of osteoporosis. Nevertheless persistence of high fracture risk (prevalent fractures and/or low BMD) on therapy indicates to maintain or intensify the treatment. On the contrary, if fracture risk is low, a " therapeutic window " could be considered after treatment with bisphosphonates, whereas after denosumab a short course of another treatment may be necessary. PMID- 28727345 TI - [Denosumab in clinical practice : beware before, during and after]. AB - Denosumab is a very effective treatment of osteoporosis, easy to use and very well tolerated. Due to some associated risks, a close clinical follow-up is necessary. Before the first injection, it is necessary to correct hypocalcaemia or vitamin D deficiency when present. Calcemia has to be followed in case of renal insufficiency. Injections of denosumab should be done scrupulously every 6 months (+/- 3 weeks). Discontinuation of denosumab is associated with a severe rebound effect characterized by increased markers of bone remodeling, a rapid decrease of bone density values, and a risk of multiple spontaneous vertebral fractures. The administration of a potent bisphosphonate (zoledronate, alendronate) minimises or avoids this rebound effect. PMID- 28727346 TI - [Doctor, physical activity at my age ?] AB - Engaging in regular and appropriate physical activity confers health benefits at any age. For seniors, swapping the role of " sedentary " for " someone who's on the move " offers much more substantial benefits than any medication, and notably even starting at a dose of 10-15 minutes per day ! Any physician who cares for elderly patients must pursue the objective of encouraging physical activity that is integrated into daily life (e.g. walking, gardening, shopping). This article consists of a literature review concerning the evidence for the benefits of physical activity in seniors in terms of quality of life, longevity, maintenance of functional independence, and prevention of cognitive decline. PMID- 28727347 TI - ? PMID- 28727348 TI - ? PMID- 28727349 TI - ? PMID- 28727350 TI - ? PMID- 28727351 TI - ? PMID- 28727352 TI - ? PMID- 28727353 TI - ? PMID- 28727354 TI - [Endovascular treatment for acute ischemic stroke]. AB - The benefit of endovascular treatment (ET) after acute ischemic stroke has long been debated. Recent studies have demonstrated the clinical benefit of ET up to approximately 8 hours after stroke onset, mainly in association with intranenous thrombolysis. The positive effect is higher if ET is initiated early and performed by an experienced team. Current ET techniques include thrombectomy with clot removal using stentretriever technques or local thromboaspiration of the clot. ET seems to be so efficient that stroke care networks have to be organised to offer ET as quickly as possible in all patients who could benefit from this therapy. PMID- 28727355 TI - [Perfusion imaging of acute ischemic stroke]. AB - Multi-modal imaging in acute ischemic stroke includes structural imaging, perfusion imaging and angiographic assessment of brain arteries. Perfusion imaging discriminates brain tissue that is critically hypo-perfused but salvageable (ischemic penumbra) from irreversibly injured tissue (ischemic core). In acute reperfusion therapies (intravenous or endovascular), patients who have substantial penumbra and a small core (target mismatch pattern) are most likely to have a good clinical outcome. Patient selection based on multi-modal imaging is not proven mandatory for acute treatment in patients admitted within the established time-window. Multi-modal image-based patient selection may be promising tool to identify candidates for acute treatment beyond the established time-window. PMID- 28727356 TI - [Management of carotid artery stenosis]. AB - Carotid artery atherosclerosis remains one of the major causes of stroke. The efficacy of carotid artery recanalization has already been established and is considered significant for symptomatic stenosis >70% and moderate for stenosis between 50-69 %. Regarding asymptomatic stenosis, carotid artery recanalization should be reserved for carefully selected patients with a stenosis between 70-90 % and an estimated procedural risk at less than 3 %. Two therapeutic options are currently available : angioplasty with stent placement and endarterectomy. While the endovascular approach may be associated with a higher periprocedural complication rate of stroke, there remains a significant decrease in the rate of myocardial infarction and peripheral nerve palsy compared to surgery. As a result, each case should be reviewed with a multidisciplinary approach in order to propose the best therapeutic strategy. PMID- 28727357 TI - [Spontaneous carotid and vertebral dissections]. AB - Dissections of the cervical arteries account for approximately 15-20 % of all strokes in young patients. Clinically they present with laterocervical and/or hemicranial pain associated to a Horner syndrome in case of carotid dissection and a posterior cervical pain associated to headache in the occipital area in case of vertebral dissection. A multifactorial origin is often suggested, resulting from the combination of a weakness of the arterial wall, hereditary or not, of environmental factors such minor trauma or a previous infection and also of the presence of a certain number of vascular risk factors such as high blood pressure or migraines. The diagnosis is best established with MRI which shows specifically the intramural hematoma. Treatment includes anticoagulants or antiplatelets agents. PMID- 28727358 TI - [Antiplatelet therapy in secondary stroke prevention]. AB - New studies have refined the role of antiplatelet therapy in secondary prevention after noncardioembolic strokes. The first line antiplatelet therapy remains Aspirin. Clopidogrel and the combination aspirine plus dipyridamole are suitable alternatives with a slightly better protection. Ticagrelor, a reversible P2Y12 receptor inhibitor used in cardiology, has not demonstrated its superiority to Aspirin. Early after stroke, a double antiplatelet therapy combining Aspirin and clopidogrel is increasingly administered as a recent study demonstrated a decrease in the incidence of cerebrovascular events after a minor stroke or high risk TIA. This benefit is particularly high in patients with severe atherosclerotic disease. The duration of the double antiplatelet therapy should not exceed three months to reduce the haemorrhagic risk. PMID- 28727359 TI - [Stroke prevention in patients with atrial fibrillation]. AB - Oral anticoagulation with vitamin K antagonists (VKA) was the cornerstone of stroke prevention in atrial fibrillation (AF). This review article presents the state of the art, with regard to the treatment options developed over the past few years, the new oral anticoagulants (NOAC). A search in PubMed for relevant published studies has been performed. Dabigatran and apixaban were superior to warfarin to reduce stroke risk or systemic embolism ; dabigatran, rivaroxaban and edoxaban were non-inferior. All NOAC are globally non-inferior to warfarin for stroke prevention in non-valvular AF and they have a superior safety profile, with a reduced intracranial bleeding risk. They are now the first choice for treatment. PMID- 28727360 TI - [Musculoskeletal complications in diabetes mellitus]. AB - Musculoskeletal abnormalities are common and multiple in diabetic patients. They often result from pathologic changes in the microvasculature (microangiopathy), connective tissue, and peripheral nerves related to chronic hyperglycaemia. Their prevalence in patients with diabetes vary depending upon the diagnostic criteria, the study population and is generally correlated with poor glycaemic control and the occurrence of other complications of diabetes. These entities are important to recognize because they often respond to treatment, preventing pain and disability and improving quality of life. PMID- 28727361 TI - ? PMID- 28727362 TI - ? PMID- 28727363 TI - ? PMID- 28727364 TI - ? PMID- 28727365 TI - ? PMID- 28727366 TI - ? PMID- 28727367 TI - Prospective evaluation of vesicourethral anastomosis outcomes in robotic radical prostatectomy during early experience in a university hospital. AB - PURPOSE: Robotic assisted radical prostatectomy (RARP) presents challenges for the surgeon, especially during the initial learning curve. We aimed to evaluate early and mid-term functional outcomes and complications related to vesicourethral anastomosis (VUA), in patients who underwent RARP, during the initial experience in an academic hospital. We also assessed possible predictors of postoperative incontinence and compared these results with the literature. MATERIALS AND METHODS: We prospectively collected data from consecutive patients that underwent RARP. Patients with at least 6 months of follow-up were included in the analysis for the following outcomes: time to complete VUA, continence and complications related to anastomosis. Nerve-sparing status, age, BMI, EBL, pathological tumor staging, and prostate size were evaluated as possible factors predicting early and midterm continence. Results were compared with current literature. RESULTS: Data from 60 patients was assessed. Mean time to complete VUA was 34 minutes, and console time was 247 minutes. Continence in 6 months was 90%. Incidence of urinary leakage was 3.3%, no patients developed bladder neck contracture or postoperative urinary retention. On multivariate analysis, age and pathological staging was associated to 3-month continence status. CONCLUSION: Our data show that, during early experience with RARP in a public university hospital, it is possible to achieve good results regarding continence and other outcomes related to VUA. We also found that age and pathological staging was associated to early continence status. PMID- 28727368 TI - Medical ozone therapy reduces oxidative stress and testicular damage in an experimental model of testicular torsion in rats. AB - OBJECTIVE: Testicular torsion (TT) refers to rotation of the testis and twisting of the spermatic cord. TT results in ischemia-reperfusion (I/R) injury involving increased oxidative stress, inflammation and apoptosis, and can even lead to infertility. The aim of this study was to investigate the effect of ozone therapy on testicular damage due to I/R injury in an experimental torsion model. MATERIALS AND METHODS: 24 male Sprague-Dawley rats were divided into 3 groups; sham-operated, torsion/detorsion (T/D), and T/D+ozone. Ozone (1mg/kg) was injected intraperi-toneally 120 minutes before detorsion and for the following 24h. Blood and tissue samples were collected at the end of 24h. Johnsen score, ischemia modified albumin (IMA), total antioxidant status (TAS), total oxidant status (TOS), and oxidative stress index (OSI) levels were determined. RESULTS: Levels of IMA, TOS, OSI, and histopathological scores increased in the serum/tissue of the rats in the experimental T/D group. Serum IMA, TOS, and OSI levels and tissue histo-pathological scores were lower in the rats treated with ozone compared with the T/D group. CONCLUSION: Our study results suggest that ozone therapy may exhibit beneficial effects on both biochemical and histopathological findings. Clinical trials are now necessary to confirm this. PMID- 28727369 TI - Comparison of two different suture techniques in laparoscopic partial nephrectomy. AB - OBJECTIVE: To comparatively evaluate the traditional interrupted knot-tying and running suture renorrhaphy with Monocryl(r) in laparoscopic partial nephrectomy (LPN). MATERIALS AND METHODS: A retrospective analysis of 62 consecutive patients undergoing LPN using traditional interrupted knot-tying suture renorrhaphy (Group 1; n=31) or running suture technique renorrhaphy with 2-0 monofilament polyglecaprone (Monocryl(r), Ethicon) (Group 2; n=31) from December 2011 to October 2015 at the University. All patients underwent LPN performed by an experienced laparoscopic surgeon. The demographic, perioperative and postoperative parameters were compared between the groups, and the effect of both suture techniques on the warm ischemic time (WIT) and trifecta were evaluated. RESULTS: The running suture renorrhaphy with Monocryl(r) reduced WIT, estimated blood lost and length of hospitalization stay significantly without increasing postoperative complication rate during LPN in comparison with interrupted knot tying suture. CONCLUSION: The renorrhaphy using the running suture with Monocryl(r) is an effective and safe technique with the advantage of shortening WIT even in more challenging and larger tumors during LPN. PMID- 28727370 TI - Serum tissue factor as a biomarker for renal clear cell carcinoma. AB - PURPOSE: to determine the usefulness of serum TF as a potential marker for patients with clear cell RCC. MATERIALS AND METHODS: prospective study of 30 patients with clear cell RCC submitted to nephrectomy and 16 controls without clear cell RCC treated surgically for other conditions. TF is a endothelium marker that was correlated with worse prognosis in a variety of solid tumors including RCC. Serum TF was collected before surgery at the operating room and in the postoperative setting after at least four weeks. Serum samples were analyzed with a commercial ELISA kit for human TF (R&D Systems(r)). RESULTS: Mean preoperative serum TF levels in clear cell RCC patients and in controls were 66.8 pg/dL and 28.4 pg/dL, respectively (p<0.001). Mean postoperative serum TF levels in clear cell RCC patients were 26.3 pg/dL. In all patients with clear cell RCC postoperative serum levels of TF were lower, with a mean reduction of 41.6 pg/dL in the postoperative setting (p<0.001). Linear regression revealed that tumor size was correlated with the postoperative reduction of serum TF levels (p=0.037). CONCLUSIONS: We have shown a 3-fold reduction in the median preoperative serum levels of TF in patients with clear cell RCC after surgery. We have also shown a difference of the same magnitude in the serum levels of TF compared with those of a control group of patients with benign diseases. TF appears to be a useful serum marker for the presence of clear cell RCC. Further studies are needed to validate these findings. PMID- 28727371 TI - miR-483-5p promotes prostate cancer cell proliferation and invasion by targeting RBM5. AB - OBJECTIVE: miR-483-5p has been identified as a miRNA oncogene in certain cancers. However, its role in prostate cancer has not been sufficiently investigated. In this study, we investigated the role of miR-483-5p in prostate cancer and examined RBM5 regulation by miR-483-5p. MATERIAL AND METHODS: Expression levels of miR-483-5p were determined by quantitative real-time PCR. The effect of miR 483-5p on proliferation was evaluated by MTT assay, cell invasion was evaluated by trans-well invasion assays, and target protein expression was determined by western blotting in LNCaP, DU-145, and PC-3 cells. Luciferase reporter plasmids were constructed to confirm the action of miR-483-5p on downstream target gene RBM5 in HEK-293T cells. RESULTS: we observed that miR-483-5p was upregulated in prostate cancer cell lines and tissues. A miR-483-5p inhibitor inhibited prostate cancer cell growth and invasion in DU-145 and PC-3 cells. miR-483-5p directly bound to the 3' untranslated region (3'UTR) of RBM5 in HEK-293T cells. RBM5 overexpression inhibited prostate cancer cell growth and invasion in LNCaP cells. Enforced RBM5 expression alleviated miR- 483-5p promotion of prostate cancer cell growth and invasion in LNCaP cells. CONCLUSION: The present study describes a potential mechanism underlying a miR-483- 5p/RBM5 link that contributes to prostate cancer development. PMID- 28727372 TI - Fosfomycin: a good alternative drug for prostate biopsy prophylaxis the results of a prospective, randomized trial with respect to risk factors. AB - PURPOSE: To determine the risk factors and the efficiency of rectal swab samples to prevent infectious complications in prostate biopsy, and compare fosfomycin with ciprofloxacin use in prophylaxis. MATERIALS AND METHODS: Between May and October 2014, pre-biopsy risk factors and their effect in ciprofloxacin and fosfomycin prophylaxis were determined. Pre-biopsy urinalysis, urine culture and rectal swab samples were obtained from all of the patients. Rectal swabs were obtained upon admission, and biopsy was performed in the following 3-7 days. The place of rectal swab samples and efficiency of fosfomycin use was evaluated. RESULTS: Pre-biopsy rectal swabs were obtained from 110 patients who revealed 60.9% fluoroquinolone resistance (FQR), and 32.7% fluoroquinolone sensitivity (FQS). Fosfomycin resistance was present in 3 patients. Ciprofloxacin use in last 6 months was the only risk factor for FQR. Antibiotic prophylaxis was given to both groups with and without risk factors, according to swab results, and no infective complications were observed. Among the group where fosfomycin was used empirically, one patient had an infection needing hospitalization, however this constitutes no statistical difference between the Group that fosfomycin used empirically or according to swab results (p=0.164). CONCLUSIONS: In prostate biopsy prophylaxis, ciprofloxacin may be used liberally in patients without risk factors, but it should be given according to the rectal swab results in the patients with risk, and fosfomycin may be used independently of risk factors and rectal swab results. PMID- 28727373 TI - New concept for treating female stress urinary incontinence with radiofrequency. AB - PURPOSE: To evaluate the clinical response and adverse effects of radiofrequency on the urethral meatus in the treatment of stress urinary incontinence in women. MATERIALS AND METHODS: This phase one study included ten women with Stress Urinary Incontinence (SUI). The evaluation consisted of 1 hour Pad tests to quantify urine loss and to assess the degree of procedure satisfaction by using the Likert scale. To evaluate safety, we observed the number of referred side effects. RESULTS: Average age was 53.10 years+/-7.08 years. In assessing the final Pad Test, 70% showed a reduction and 30% a worsening of urinary loss. Using the Pad Test one month later, there was a reduction in all patients (p=0.028). The degree of satisfaction was 90% and no side effects have been observed. One patient reported burning sensation. CONCLUSION: The treatment of SUI with radiofrequency on the urethral meatus has no adverse effects, being a low risk method that reduces urinary loss in women. However, to increase the validity of the study, larger clinical trials are warranted. PMID- 28727375 TI - An unanswered question in pediatric urology: the post pubertal persistence of prepubertal congenital penile curvature correction by tunical plication. AB - OBJECTIVE: The aim of this study is to analyze post pubertal results of pre pubertal tunica albuginea plication with non-absorbable sutures in the correction of CPC. MATERIALS AND METHODS: The files of patients who underwent tunica albuginea plication without incision (dorsal/lateral) were retrospectively reviewed. Patients younger than 13 years of age at the time of operation and older than 14 years of age in November 2015 were included. Patients with a penile curvature of less than 30 degrees & more than 45 degrees and penile/urethral anomalies were excluded. All of the patients underwent surgery followed by circumcision. RESULTS: The mean age of patients at the time of the operation was 9.7 years (range, 6-13 years). The mean degree of ventral penile curvature measured during the operation was 39 degrees while it was 41 degrees in the lateral curvatures. All of the patients were curvature-free at the end of the operation. At the time of the follow-up examination, the mean age was 16.7 years (range, 14-25 years). Six patients had a straight (0-10 degrees) penis during erection and seven patients had recurrent penile curvatures ranging from 30 to 50 degrees. CONCLUSION: Pre pubertal tunica albuginea plication of congenital penile curvature (30-45 degrees) with non-absorbable sutures performed without incision is a minimal invasive method especially when performed during circumcision. However, recurrence might be observed in half of the patients after puberty. PMID- 28727374 TI - Dipyridamole reduces penile apoptosis in a rat model of post-prostatectomy erectile dysfunction. AB - PURPOSE: Despite the nerve-sparing technique, many patients suffer from erectile dysfunction after radical prostatectomy (RP) due to cavernous nerve injury. The aim of this study was to evaluate dipyridamole as a potential treatment agent of post-radical prostatectomy erectile dysfunction. MATERIAL AND METHODS: A total of 18 male Sprague-Dawley rats were randomized into three experimental Groups (SHAM+DMSO, BCNI+DMSO and BCNI+DIP). An animal model of bilateral cavernous nerve crush injury (BCNI) was established to mimic the partial nerve damage during nerve-sparing RP. After creating of BCNI, dimethyl sulphoxide (DMSO) was administered transperitoneally as a vehicle to SHAM+DMSO and BCNI+DMSO Groups. BCNI+DIP Group received dipyiridamole (10mg/kg/day) as a solution in DMSO for 15 days. Afterwards, rats were evaluated for in vivo erectile response to cavernous nerve stimulation. Penile tissues were also analyzed biochemically for transforming growth factor-beta1 (TGF-beta1) level. Penile corporal apoptosis was determined by TUNEL method. RESULTS: Erectile response was decreased in rats with BCNI and there was no significant improvement with dipyridamole treatment. TGF beta1 levels were increased in rats with BCNI and decreased with dipyridamole treatment. Dipyridamole led to reduced penile apoptosis in rats with BCNI and there was no significant difference when compared to sham operated rats. CONCLUSIONS: Although fifteen-day dipyridamole treatment has failed to improve erectile function in rats with BCNI, the decline in both TGF-beta1 levels and apoptotic indices with treatment may be helpful in protecting penile morphology after cavernous nerve injury. PMID- 28727376 TI - Inflammatory pseudotumor of kidney: a challenging diagnostic entity. PMID- 28727377 TI - Laparoscopic pectopexy: initial experience of single center with a new technique for apical prolapse surgery. AB - OBJECTIVE: To share our first experience with laparoscopic pectopexy, a new technique for apical prolapse surgery, and to evaluate the feasibility of this technique. MATERIALS AND METHODS: Seven patients with apical prolapse underwent surgery with laparoscopic pectopexy. The lateral parts of the iliopectineal ligament were used for a bilateral mesh fixation of the descended structures. The medical records of the patients were reviewed, and the short-term clinical outcomes were analyzed. RESULTS: The laparoscopic pectopexy procedures were successfully performed, without intraoperative and postoperative complications. De novo apical prolapse, de novo urgency, de novo constipation, stress urinary incontinence, anterior and lateral defect cystoceles, and rectoceles did not occur in any of the patients during a 6-month follow-up period. CONCLUSION: Although laparoscopic sacrocolpopexy has shown excellent anatomical and functional long-term results, laparoscopic pectopexy offers a feasible, safe, and comfortable alternative for apical prolapse surgery. Pectopexy may increase a surgeon's technical perspective for apical prolapse surgery. PMID- 28727378 TI - Anastomosing hemangioma simulating renal cell carcinoma. AB - The anastomosing hemangioma is a recent described rare variant, which histologically simulates an angiosarcoma and occurs primarily in the genitourinary tract. We present a case of renal anastomosing hemangioma from a radiologic perspective, describing its imaging features and reviewing its presentation and management. PMID- 28727379 TI - Adjuvant radiotherapy for the primary treatment of adrenocortical carcinoma: Are we offering the best? AB - PURPOSE: To evaluate the role of ARDT after surgical resection of ACC. MATERIALS AND METHODS: Records of patients from our institutional ACC database were retrospectively assessed. A paired comparison analysis was used to evaluate the oncological outcomes between patients treated with surgery followed by ARDT or surgery only (control). The endpoints were LRFS, RFS, and OS. A systematic review of the literature and meta-analysis was also performed to evaluate local recurrence of ACC when ARDT was used. RESULTS: Ten patients were included in each Group. The median follow-up times were 32 months and 35 months for the ARDT and control Groups, respectively. The results for LRFS (p=0.11), RFS (p=0.92), and OS (p=0.47) were similar among subsets. The mean time to present with local recurrence was significantly longer in the ARDT group compared with the control Group (419+/-206 days vs. 181+/-86 days, respectively; p=0.03). ARDT was well tolerated by the patients; there were no reports of late toxicity. The meta analysis, which included four retrospective series, revealed that ARDT had a protective effect on LRFS (HR=0.4; CI=0.17-0.94). CONCLUSIONS: ARDT may reduce the chance and prolong the time to ACC local recurrence. However, there were no benefits for disease recurrence control or overall survival for patients who underwent this complementary therapy. PMID- 28727380 TI - Re: Insufficient conclusions regarding the association between overactive bladder symptoms and degree of dementia. PMID- 28727381 TI - Nephrometry scores and perioperative outcomes following robotic partial nephrectomy. AB - OBJECTIVES: Based on imaging features, nephrometry scoring systems have been conceived to create a standardized and reproducible way to characterize renal tumor anatomy. However, less is known about which of these individual measures are important with regard to clinically relevant perioperative outcomes such as ischemia time (IT), estimated blood loss (EBL), length of hospital stay (LOS), and change in estimated glomerular filtration rate (eGFR) after robotic partial nephrectomy (PN). We aimed to assess the utility of the RENAL and PADUA scores, their subscales, and C-index for predicting these outcomes. MATERIALS AND METHODS: We analyzed imaging studies from 283 patients who underwent robotic PN between 2008 and 2014 to assign nephrometry scores (NS): PADUA, RENAL and C index. Univariate linear regression was used to assess whether the NS or any of their subscales were associated with EBL or IT. Multivariable linear regression and linear regression models were created to assess LOS and eGFR. RESULTS: The three NS were significantly associated with EBL, IT, LOS, and eGFR at 12 months after surgery. All subscales with the exception of anterior/posterior were significantly associated with EBL and IT. Collecting system, renal rim location, renal sinus, exophytic/endophytic, and nearness to collecting system were significant predictors for LOS. Only renal rim location, renal sinus invasion and polar location were significantly associated with eGFR at 12 months. CONCLUSIONS: Tumor size and depth are important characteristics for predicting robotic PN outcomes and thus could be used individually as a simplified way to report tumors features for research and patient counseling purposes. PMID- 28727382 TI - Can baseline serum creatinine and e-GFR predict renal function outcome after augmentation cystoplasty in children? AB - OBJECTIVE: To assess cut-off value of creatinine and glomerular filtration rate for augmentation cystoplasty (AC) in paediatric age-group. MATERIALS AND METHODS: Data of all paediatric-patients (<18 years) with small capacity bladder, in whom AC was advised between 2005-2015 were reviewed. All patients were divided in two groups, AC-group and control-group (without AC). Creatinine and e-GFR were assessed at the time of surgery, at 6 months and at last follow-up. Renal function deterioration was defined as increase in creatinine by >=25% from baseline value or new-onset stage-3 CKD or worsening of CKD stage with pre operative-CKD stage-3. ROCs were plotted using creatinine and e-GFR for AC. RESULTS: A total of 94 patients with mean-age 8.9 years were included. The mean creatinine and e-GFR were 1.33mg/dL and 57.68mL/min respectively. Out of 94 patients, AC was performed in 45 patients and in the remaining 49 patients AC was not done (control-group), as they were not willing for the same. Baseline patient's characteristics were comparable in both Groups. 22 underwent gastro cystoplasty (GC) and 25 underwent ileo-cystoplasty (IC). Decline in renal function was observed in 15 (33.3%) patients of AC-group and in 31 (63.3%) patients of control-group. Patients having creatinine >=1.54mg/dL (P=0.004, sensitivity (S) 63.6% and specificity (s) 90.5%) at baseline and e-GFR <=46mL/min (P=0.000, S=100% and s=85.7%) at the time of surgery had significantly increased probability of renal function deterioration on follow-up after AC. CONCLUSION: e GFR <=46mL/min and creatinine >=1.54mg/dL at time of surgery could serve as a predictor of renal function deterioration in AC in paediatric patients. PMID- 28727384 TI - A neural network - based algorithm for predicting stone - free status after ESWL therapy. AB - OBJECTIVE: The prototype artificial neural network (ANN) model was developed using data from patients with renal stone, in order to predict stone-free status and to help in planning treatment with Extracorporeal Shock Wave Lithotripsy (ESWL) for kidney stones. MATERIALS AND METHODS: Data were collected from the 203 patients including gender, single or multiple nature of the stone, location of the stone, infundibulopelvic angle primary or secondary nature of the stone, status of hydronephrosis, stone size after ESWL, age, size, skin to stone distance, stone density and creatinine, for eleven variables. Regression analysis and the ANN method were applied to predict treatment success using the same series of data. RESULTS: Subsequently, patients were divided into three groups by neural network software, in order to implement the ANN: training group (n=139), validation group (n=32), and the test group (n=32). ANN analysis demonstrated that the prediction accuracy of the stone-free rate was 99.25% in the training group, 85.48% in the validation group, and 88.70% in the test group. CONCLUSIONS: Successful results were obtained to predict the stone-free rate, with the help of the ANN model designed by using a series of data collected from real patients in whom ESWL was implemented to help in planning treatment for kidney stones. PMID- 28727383 TI - Outcomes of miniaturized percutaneous nephrolitotomy in infants: single centre experience. AB - OBJECTIVES: The present study was aim to evaluate the safety and efficacy of Mini PNL to treat kidney stones in patients aged <3 years. This is the one of the largest series in the literature in this age group of patients. MATERIAL AND METHODS: From May 2012 to April 2016, the medical records of 74 infant patients who underwent mini-PNL for renal stones were reviewed retrospectively. All infants were evaluated with the plain abdominal radiograph, urinary ultrasound, noncontrast computerized tomography and/or intravenous urogram. Pre-operative, intraoperative and post-operative data were analyzed. RESULTS: A total of 74 infant (42 male, 32 female) with a mean age 21.5+/-8.2 (10-36) months were included in this study. The mean size of the stones was 22.0+/-5.9 (14-45) mm. A 17 Fr rigid pediatric nephroscope with a pneumatic intracorporeal lithotripsy were used through 20-22 Fr access sheath. The stone-free rate was 84.7% at 1 month after the operation. Mean operative time was 74.0 (40-140) min. Mean fluoroscopy screening time was as 4.3(3.1-8.6) min. Average hospitalization time was 3.8 (2-9) day. Auxiliary procedures were performed to 11(15.3%) patients (7 extracorporeal shock wave lithotripsy, 3 re- percutaneous nephrolitotomy, 1 retrograde intrarenal surgery). No major complication classified as Clavien IV-V observed in study group. CONCLUSIONS: Mini-PNL with pneumatic intracorporeal lithotripsy can be performed safely and effectively to manage kidney stones in infants with high stone free rate and low complications. PMID- 28727385 TI - Abobotulinum - a toxin injection in patients with refractory idiopathic detrusor overactivity: injections in detrusor, trigone and bladder neck or prostatic urethra, versus detrusor - only injections. AB - PURPOSE: To evaluate if the injections of abobotulinum-A toxin in trigone and bladder neck/prostatic urethra in addition to detrusor provides better symptoms relief and urodynamic findings in patients with idiopathic detrusor overactivity (IDO) refractory to medical treatment. MATERIALS AND METHODS: A total of 74 patients with IDO refractory to anticholinergics received injections in detrusor, trigone and bladder neck/prostatic urethra (Group A, N=36) versus detrusor only injections (Group B, N=38) of abobotulinum-A toxin. All patients were evaluated by a standard overactive bladder symptom score (OABSS) questionnaire and cystometrography before and 6 weeks after the operation. OABSS questionnaire was also completed 20 weeks after the operation. RESULTS: The magnitude of OABSS reduction from baseline to 6 weeks after operation in groups A and B patients was 13.4+/-2.2 versus 11.7+/-2.1 (p=0.001). Cystometry results were similar in both groups except for higher volume at urgent desire to void in Group B patients (p <0.001). The mean+/-SD change in residual volume in Group A at 6 weeks after the operation was -4.8+/-28.6mL (p=0.33) compared to 21.3+/-16.9mL in Group B patients (p <0.001). CONCLUSIONS: In patients with IDO, adding trigone, and bladder neck/prostatic urethra as sites of abobotulinum- A toxin injection produces greater reductions in OABSS score and less residual urine volume but a lower volume at urgent desire to void in comparison with detrusor only injections. PMID- 28727386 TI - Retroperitoneal access for robotic renal surgery. AB - INTRODUCTION AND OBJECTIVE: Retroperitoneal access for robotic renal surgery is an effective alternative to the commonly used transperitoneal approach. We describe our contemporary experience and technique for attaining retroperitoneal access. MATERIALS AND METHODS: We outline our institutional approach to retroperitoneal access for the instruction of urologists at the beginning of the learning curve. The patient is placed in the lateral decubitus position. The first incision is made just inferior to the tip of the twelfth rib as described by Hsu, et al. After the lumbodorsal fascia is traversed, the retroperitoneal space is dilated with a round 10 millimeter AutoSutureTM (Covidien, Mansfield, MA) balloon access device. The following trocars are used: A 130 millimeter KiiR balloon trocar (Applied Medical, Rancho Santa Margarita, CA), three robotic, and one assistant. Key landmarks for the access and dissection are detailed. RESULTS: 177 patients underwent a retroperitoneal robotic procedure from 2007 to 2015. Procedures performed include 158 partial nephrectomies, 16 pyeloplasties, and three radical nephrectomies. The robotic fourth arm was utilized in all cases. When compared with the transperitoneal approach, the retroperitoneal approach was associated with shorter operative times and decreased length of stay (1). Selection bias and surgeon preference accounted for the higher proportion of patients who underwent partial nephrectomy off-camp via the retroperitoneal approach. CONCLUSIONS: Retroperitoneal robotic surgery may confer several advantages. In patients with previous abdominal surgery or intra-abdominal conditions, the retroperitoneum can be safely accessed while avoiding intraperitoneal injuries. The retroperitoneum also provides a confined space that may minimize the sequelae of potential complications including urine leak. Moreover, at our institution, retroperitoneal robotic surgery is associated with shorter operative times and a decreased length of stay when compared with the transperitoneal approach (2). In selected patients, the retroperitoneal approach is a viable alternative to the transperitoneal approach for a variety of renal procedures. PMID- 28727387 TI - Focal cryotherapy: step by step technique description. AB - INTRODUCTION AND OBJECTIVE: Focal cryotherapy emerged as an efficient option to treat favorable and localized prostate cancer (PCa). The purpose of this video is to describe the procedure step by step. MATERIALS AND METHODS: We present the case of a 68 year-old man with localized PCa in the anterior aspect of the prostate. RESULTS: The procedure is performed under general anesthesia, with the patient in lithotomy position. Briefly, the equipament utilized includes the cryotherapy console coupled with an ultrasound system, argon and helium gas bottles, cryoprobes, temperature probes and an urethral warming catheter. The procedure starts with a real-time trans-rectal prostate ultrasound, which is used to outline the prostate, the urethra and the rectal wall. The cryoprobes are pretested and placed in to the prostate through the perineum, following a grid template, along with the temperature sensors under ultrasound guidance. A cystoscopy confirms the right positioning of the needles and the urethral warming catheter is installed. Thereafter, the freeze sequence with argon gas is started, achieving extremely low temperatures (-40oC) to induce tumor cell lysis. Sequentially, the thawing cycle is performed using helium gas. This process is repeated one time. Results among several series showed a biochemical disease-free survival between 71-93% at 9-70 month- follow-up, incontinence rates between 0 3.6% and erectile dysfunction between 0-42% (1-5). CONCLUSIONS: Focal cryotherapy is a feasible procedure to treat anterior PCa that may offer minimal morbidity, allowing good cancer control and better functional outcomes when compared to whole-gland treatment. PMID- 28727388 TI - Lysozyme gene treatment in testosterone induced benign prostate hyperplasia rat model and comparasion of its' effectiveness with botulinum toxin injection. AB - OBJECTIVES: To compare the effects and histopathological changes of botulinum neurotoxin type A and lysozyme gene injections into prostate tissue within a testosterone induced benign prostate hyperplasia rat model. MATERIALS AND METHODS: 40 male Wistar rats were randomized into four Groups. Group-1: Control, Group-2: Testosterone replacement, Group-3: Testosterone+botulinum neurotoxin type A, Group-4: Testosterone+plazmid DNA/liposome complex. RESULTS: Estimated prostate volume of the testosterone injected Groups were higher than the control (p <0.05). Actual prostate weight of the testosterone injected Groups was higher than the control Group (p <0.05). Testosterone undecanoate increased the prostate weight by 39%. Botulinum neurotoxin type A treatment led to an estimated prostate volume and actual prostate weights decreased up to 32.5% in rats leading to prostate apoptosis. Lysozyme gene treatment led to an estimated prostate volume and actual prostate weights decrease up to 38.7%. CONCLUSION: Lysozyme gene and botulinum neurotoxin type A treatments for prostate volume decreasing effect have been verified in the present study that could be anew modality of treatment in prostatic benign hyperplasia that needs to be verified in large randomized human experimental studies. PMID- 28727389 TI - Schooling impacts on the overactive bladder diagnosis in women. AB - OBJECTIVE: To evaluate the overactive bladder (OAB) diagnosis using OAB-V8 and ICIQ-OAB questionnaires in women with different schooling and cultural levels. MATERIALS AND METHODS: Three hundred and eighty six healthy women answered a clinical questionnaire filling out information about schooling, demographic and gynecological data. The OAB-V8 and ICIQ-OAB questionnaires were used to evaluate OAB diagnosis and symptoms; and the QS-F questionnaire, to determine the sexual function. All questionnaires were validated in Portuguese. RESULTS: The mean age was 37.3 years-old. Regarding to schooling level, 23.1% had concluded primary education; 65.8%, secondary school; and 11.1% had higher education. Considering the OAB-V8 (score >=8), 51.8% of evaluated women had OAB diagnosis. There was a positive linear correlation between the OAB-V8 and ICIQ-OAB questionnaires in its sections "a" (r=0.812, p<0.001) and "b" (r=759, p<0.001). There was a positive linear correlation between age and the amount of time used to answer the OAB-V8, ICIQ-OAB and QS-F questionnaires (p<0.001). The ICIQ-OAB was the hardest to answer for all schooling levels when compared to the other questionnaires. Women who had concluded primary and secondary education significantly demanded more help to answer all questionnaires than those with higher education (p<0.05). Furthermore, women with higher education took significantly less time answering all questionnaires when compared to their less educated counterparts (primary and secondary schooling), since they were quicker to answer each individual question. CONCLUSION: Educational level and ageing had an impact on women response using different questionnaires for OAB and sexual function evaluations. PMID- 28727390 TI - Use of indocyanine green angiography in microsurgical subinguinal varicocelectomy - lessons learned from our initial experience. AB - Microsurgical subinguinal varicocelectomy (MSV) is generally considered the gold standard nowadays in view of the lower risk of complications and recurrence. To achieve complete ligation of veins while preserving testicular artery (TA) during the procedure remains challenging despite the application of high power optical magnification and micro-Doppler ultrasonography. The use of intraoperative indocyanine green angiography (ICGA) with infrared fluorescence operative micro scope in MSV potentially lowers the incidence of TA injury and shortens the learning curve of nov-ice surgeons. We present our initial experience in the application of the technique in nine patients and explore the potential of the new adjunct. PMID- 28727391 TI - Re: Preliminary assessment of neck circumference in benign prostatic hyperplasia in patients with metabolic syndrome. PMID- 28727392 TI - Re: Assessment of sexual functions in partners of women with complaints of urinary incontinence. PMID- 28727404 TI - Mortality and Cardiovascular Disease in Type 1 and Type 2 Diabetes. PMID- 28727405 TI - Incidence Trends of Type 1 and Type 2 Diabetes among Youths, 2002-2012. PMID- 28727406 TI - Heat-Stable Oral Rotavirus Vaccine. PMID- 28727407 TI - Sickle Cell Disease. PMID- 28727408 TI - Sickle Cell Disease. PMID- 28727409 TI - Plasmonic Nano-Oven by Concatenation of Multishell Photothermal Enhancement. AB - Metallodielectric multishell nanoparticles are capable of hosting collective plasmon oscillations distributed among different metallic layers, which result in large near-field enhancement at specific regions of the structure, where light absorption is maximized. We exploit this capability of multishell nanoparticles, combined with thermal boundary resistances and spatial tailoring of the optical near fields, to design plasmonic nano-ovens capable of achieving high temperatures at the core region using moderate illumination intensities. We find a large optical intensity enhancement of ~104 over a relatively broad core region with a simple design consisting of three metal layers. This provides an unusual thermal environment, which together with the high pressures of ~105 atm produced by concatenated curved layers holds great potential for exploring physical and chemical processes under extreme optical/thermal/pressure conditions in confined nanoscale spaces, while the outer surface of the nano-oven is close to ambient conditions. PMID- 28727411 TI - One-Step Synthesis of Antioxidative Graphene-Wrapped Copper Nanoparticles on Flexible Substrates for Electronic and Electrocatalytic Applications. AB - In this study, we report a novel, one-step synthesis method to fabricate multilayer graphene (MLG)-wrapped copper nanoparticles (CuNPs) directly on various substrates (e.g., polyimide film (PI), carbon cloth (CC), or Si wafer (Si)). The electrical resistivities of the pristine MLG-CuNPs/PI and MLG-CuNPs/Si were measured 1.7 * 10-6 and 1.4 * 10-6 Omega.m, respectively, of which both values are ~100-fold lower than earlier reports. The MLG shell could remarkably prevent the Cu nanocore from serious damages after MLG-CuNPs being exposed to various harsh conditions. Both MLG-CuNPs/PI and MLG-CuNPs/Si retained almost their conductivities after ambient annealing at 150 degrees C. Furthermore, the flexible MLG-CuNPs/PI exhibits excellent mechanical durability after 1000 bending cycles. We also demonstrate that the MLG-CuNPs/PI can be used as promising source drain electrodes in fabricating flexible graphene-based field-effect transistor (G-FET) devices. Finally, the MLG-CuNPs/CC was shown to possess high performance and durability toward hydrogen evolution reaction (HER). PMID- 28727410 TI - Exosomes Mediate Epithelium-Mesenchyme Crosstalk in Organ Development. AB - Organ development requires complex signaling by cells in different tissues. Epithelium and mesenchyme interactions are crucial for the development of skin, hair follicles, kidney, lungs, prostate, major glands, and teeth. Despite myriad literature on cell-cell interactions and ligand-receptor binding, the roles of extracellular vesicles in epithelium-mesenchyme interactions during organogenesis are poorly understood. Here, we discovered that ~100 nm exosomes were secreted by the epithelium and mesenchyme of a developing tooth organ and diffused through the basement membrane. Exosomes were entocytosed by epithelium or mesenchyme cells with preference by reciprocal cells rather than self-uptake. Exosomes reciprocally evoked cell differentiation and matrix synthesis: epithelium exosomes induce mesenchyme cells to produce dentin sialoprotein and undergo mineralization, whereas mesenchyme exosomes induce epithelium cells to produce basement membrane components, ameloblastin and amelogenenin. Attenuated exosomal secretion by Rab27a/b knockdown or GW4869 disrupted the basement membrane and reduced enamel and dentin production in organ culture and reduced matrix synthesis and the size of the cervical loop, which harbors epithelium stem cells, in Rab27aash/ash mutant mice. We then profiled exosomal constituents including miRNAs and peptides and further crossed all epithelium exosomal miRNAs with literature-known miRNA Wnt regulators. Epithelium exosome-derived miR135a activated Wnt/beta-catenin signaling and escalated mesenchymal production of dentin matrix proteins, partially reversible by Antago-miR135a attenuation. Our results suggest that exosomes may mediate epithelium-mesenchyme crosstalk in organ development, suggesting that these vesicles and/or the molecular contents they are transporting may be interventional targets for treatment of diseases or regeneration of tissues. PMID- 28727412 TI - Host-Guest Recognition-Assisted Electrochemical Release: Its Reusable Sensing Application Based on DNA Cross Configuration-Fueled Target Cycling and Strand Displacement Reaction Amplification. AB - In this work, an elegantly designed host-guest recognition-assisted electrochemical release was established and applied in a reusable electrochemical biosensor for the detection of microRNA-182-5p (miRNA-182-5p), a prostate cancer biomarker in prostate cancer, based on the DNA cross configuration-fueled target cycling and strand displacement reaction (SDR) amplification. With such a design, the single target miRNA input could be converted to large numbers of single stranded DNA (S1-Trp and S2-Trp) output, which could be trapped by cucurbit[8]uril methyl viologen (CB-8-MV2+) based on the host-guest recognition, significantly enhancing the sensitivity for miRNA detection. Moreover, the nucleic acids products obtained from the process of cycling amplification could be utilized sufficiently, avoiding the waste and saving the experiment cost. Impressively, by resetting a settled voltage, the proposed biosensor could release S1-Trp and S2-Trp from the electrode surface, attributing that the guest ion methyl viologen (MV2+) was reduced to MV+. under this settled voltage and formed a more-stable CB-8-MV+.-MV+. complex. Once O2 was introduced in this system, MV+. could be oxidized to MV2+, generating the complex of CB-8-MV2+ for capturing S1-Trp and S2-Trp again in only 5 min. As a result, the simple and fast regeneration of biosensor for target detection was realized on the base of electrochemical redox-driven assembly and release, overcoming the challenges of time-consuming, burdensome operations and expensive experimental cost in traditional reusable biosensors and updating the construction method for a reusable bisensor. Furthermore, the biosensor could be reused for more than 10 times with a regeneration rate of 93.20%-102.24%. After all, the conception of this work provides a novel thought for the construction of effective reusable biosensor to detect miRNA and other biomarkers and has great potential application in the area requiring the release of nucleic acids or proteins. PMID- 28727413 TI - Quantifying the Metabolome of Pseudomonas taiwanensis VLB120: Evaluation of Hot and Cold Combined Quenching/Extraction Approaches. AB - Absolute quantification of free intracellular metabolites is a valuable tool in both pathway discovery and metabolic engineering. In this study, we conducted a comprehensive examination of different hot and cold combined quenching/extraction approaches to extract and quantify intracellular metabolites of Pseudomonas taiwanensis (P. taiwanensis) VLB120 to provide a useful reference data set of absolute intracellular metabolite concentrations. The suitability of commonly used metabolomics tools including a pressure driven fast filtration system followed by combined quenching/extraction techniques (such as cold methanol/acetonitrile/water, hot water, and boiling ethanol/water, as well as cold ethanol/water) were tested and evaluated for P. taiwanensis VLB120 metabolome analysis. In total 94 out of 107 detected intracellular metabolites were quantified using an isotope-ratio-based approach. The quantified metabolites include amino acids, nucleotides, central carbon metabolism intermediates, redox cofactors, and others. The acquired data demonstrate that the pressure driven fast filtration approach followed by boiling ethanol quenching/extraction is the most adequate technique for P. taiwanensis VLB120 metabolome analysis based on quenching efficiency, extraction yields of metabolites, and experimental reproducibility. PMID- 28727414 TI - Graphene-Based Three-Dimensional Capacitive Touch Sensor for Wearable Electronics. AB - The development of input device technology in a conformal and stretchable format is important for the advancement of various wearable electronics. Herein, we report a capacitive touch sensor with good sensing capabilities in both contact and noncontact modes, enabled by the use of graphene and a thin device geometry. This device can be integrated with highly deformable areas of the human body, such as the forearms and palms. This touch sensor detects multiple touch signals in acute recordings and recognizes the distance and shape of the approaching objects before direct contact is made. This technology offers a convenient and immersive human-machine interface and additional potential utility as a multifunctional sensor for emerging wearable electronics and robotics. PMID- 28727415 TI - Hydrophobic Nanosized All-Silica Beta Zeolite: Efficient Synthesis and Adsorption Application. AB - All-silica beta zeolite, synthesized by conventional hydroxide route, usually possesses small crystal size of a few hundred nanometers but poor hydrophobicity, whereas the fluoride-mediated one exhibits to be highly hydrophobic but microsized. To obtain nanosized all-silica beta zeolite with excellent hydrophobicity, an innovative and efficient hydrothermal route via interzeolite transformation for synthesizing all-silica beta zeolite is proposed in present study. With the assistance of beta seeds and tetraethylammonium hydroxide as the structure-directing agent, siliceous beta zeolite is well-crystallized at a high solid yield via dissolution-recrystallization of all-silica ITQ-1 crystals at an extremely low water content (H2O/SiO2 molar ratio of 1). The obtained all-silica beta crystals are composed of 30-70 nm nanoparticles and highly hydrophobic just next to siliceous beta-F zeolite synthesized by environmentally unfriendly fluoride route, which is derived from relatively small amounts of internal defect sites. Thus, this beta zeolite is superior to other pure silica beta zeolites in the adsorption of large-sized volatile organic compounds (VOCs), which is mainly attributed to its high total pore volume and specific surface area as well as excellent hydrophobicity. PMID- 28727416 TI - In Situ Electrochemical Sensing and Real-Time Monitoring Live Cells Based on Freestanding Nanohybrid Paper Electrode Assembled from 3D Functionalized Graphene Framework. AB - In this work, we develop a new type of freestanding nanohybrid paper electrode assembled from 3D ionic liquid (IL) functionalized graphene framework (GF) decorated by gold nanoflowers (AuNFs), and explore its practical application in in situ electrochemical sensing of live breast cell samples by real-time tracking biomarker H2O2 released from cells. The AuNFs modified IL functionalized GF (AuNFs/IL-GF) was synthesized via a facile and efficient dopamine-assisted one pot self-assembly strategy. The as-obtained nanohybrid assembly exhibits a typical 3D hierarchical porous structure, where the highly active electrocatalyst AuNFs are well dispersed on IL-GF scaffold. And the graft of hydrophilic IL molecules (i.e., 1-butyl-3-methylimidazolium tetrafluoroborate, BMIMBF4) on graphene nanosheets not only avoids their agglomeration and disorder stacking during the self-assembly but also endows the integrated IL-GF monolithic material with unique hydrophilic properties, which enables it to be readily dispersed in aqueous solution and processed into freestanding paperlike material. Because of the unique structural properties and the combinational advantages of different components in the AuNFs/IL-GF composite, the resultant nanohybrid paper electrode exhibits good nonenzymatic electrochemical sensing performance toward H2O2. When used in real-time tracking H2O2 secreted from different breast cells attached to the paper electrode without or with radiotherapy treatment, the proposed electrochemical sensor based on freestanding AuNFs/IL-GF paper electrode can distinguish the normal breast cell HBL-100 from the cancer breast cells MDA-MB 231 and MCF-7 cells, and assess the radiotherapy effects to different breast cancer cells, which opens a new horizon in real-time monitoring cancer cells by electrochemical sensing platform. PMID- 28727417 TI - Oxygen-Dependent Lipid Profiles of Three-Dimensional Cultured Human Chondrocytes Revealed by MALDI-MSI. AB - Articular cartilage is exposed to a gradient of oxygen levels ranging from 5% at the surface to 1% in the deepest layers. While most cartilage research is performed in supraphysiological oxygen levels (19-21%), culturing chondrocytes under hypoxic oxygen levels (<=8%) promotes the chondrogenic phenotype. Exposure of cells to various oxygen levels alters their lipid metabolism, but detailed studies examining how hypoxia affects lipid metabolism in chondrocytes are lacking. To better understand the chondrocyte's behavior in response to oxygen, we cultured 3D pellets of human primary chondrocytes in normoxia (20% oxygen) and hypoxia (2.5% oxygen) and employed matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI) in order to characterize the lipid profiles and their spatial distribution. In this work we show that chondrocytes cultured in hypoxia and normoxia can be differentiated by their lipid profiles. Among other species, phosphatidylglycerol species were increased in normoxic pellets, whereas phosphatidylinositol species were the most prominent lipids in hypoxic pellets. Moreover, spatial mapping revealed that phospahtidylglyycerol species were less prominent in the center of pellets where the oxygen level is lower. Additional analysis revealed a higher abundance of the mitochondrial-specific lipids, cardiolipins, in normoxic conditions. In conclusion MALDI-MSI described specific lipid profiles that could be used as sensors of oxygen level changes and may especially be relevant for retaining the chondrogenic phenotype, which has important implications for the treatment of bone and cartilage diseases. PMID- 28727419 TI - Next-Generation Lipids in RNA Interference Therapeutics. AB - RNA is emerging as a potential therapeutic modality for the treatment of incurable diseases. Despite intense research, the advent to clinical utility remains compromised by numerous biological barriers, hence, there is a need for sophisticated delivery vehicles. In this aspect, lipid nanoparticles (LNPs) are the most advanced platform among nonviral vectors for gene delivery. In this review, we critically review the literature and the reasons for ineffective delivery beyond the liver. We discuss the toxicity issues associated with permanently charged cationic lipids and then turn our attention to next generation ionizable cationic lipids. These lipids exhibit reduced toxicity and immunogenicity and undergo ionization under the acidic environment of the endosome to release the encapsulated payload to their site of action in the cytosol. Finally, we summarize recent achievements in therapeutic nucleic acid delivery and report on the current status of clinical trials using LNP and the obstacles to clinical translation. PMID- 28727418 TI - Combining Time-of-Flight Secondary Ion Mass Spectrometry Imaging Mass Spectrometry and CARS Microspectroscopy Reveals Lipid Patterns Reminiscent of Gene Expression Patterns in the Wing Imaginal Disc of Drosophila melanogaster. AB - Using label-free ToF-SIMS imaging mass spectrometry, we generated a map of small molecules differentially expressed in the Drosophila wing imaginal disc. The distributions of these moieties were in line with gene expression patterns observed during wing imaginal disc development. Combining ToF-SIMS imaging and coherent anti-Stokes Raman spectroscopy (CARS) microspectroscopy allowed us to locally identify acylglycerols as the main constituents of the pattern differentiating the future body wall tissue from the wing blade tissue. The findings presented herein clearly demonstrate that lipid localization patterns are strongly correlated with a developmental gene expression. From this correlation, we hypothesize that lipids play a so far unrecognized role in organ development. PMID- 28727420 TI - Bioinspired Development of P(St-MAA)-Avermectin Nanoparticles with High Affinity for Foliage To Enhance Folia Retention. AB - Pesticides are chemical or biological substances to control pests and protect the crop yield. Most pesticides suffering from large amounts of losses in the environment lead to damage of ecological systems and food pollution. To reduce their losses and increase the utilization rate, we have developed bioinspired mussel avermectin nanoparticles [P(St-MAA)-Av-Cat] with strong adhesion to crop foliage by the emulsion-solvent evaporation method and chemical modification. They were near spheres with a diameter of around 120 nm. They displayed remarkable high avermectin content of more than 50% (w/w) and presented excellent storage stability as well as continuous sustained release. The photosensitive avermectins loaded were highly improved against ultraviolet light. Meanwhile, the retention rate of P(St-MAA)-Av-Cat on the crop foliage surfaces was significantly increased. As a result, the indoor toxicity of P(St-MAA)-Av-Cat was highly enhanced. The adhesive property strongly depended upon the functional groups on the nanoparticle surface. The multimodal binding mode of P(St-MAA)-Av-Cat to the crop foliage surface resulted in stronger adhesion and a longer retention time. PMID- 28727422 TI - Correction to Identification of Indole Diterpenes in Ipomoea asarifolia and Ipomoea muelleri, Plants Tremorgenic to Livestock. PMID- 28727421 TI - Shallow Representation Learning via Kernel PCA Improves QSAR Modelability. AB - Linear models offer a robust, flexible, and computationally efficient set of tools for modeling quantitative structure-activity relationships (QSARs) but have been eclipsed in performance by nonlinear methods. Support vector machines (SVMs) and neural networks are currently among the most popular and accurate QSAR methods because they learn new representations of the data that greatly improve modelability. In this work, we use shallow representation learning to improve the accuracy of L1 regularized logistic regression (LASSO) and meet the performance of Tanimoto SVM. We embedded chemical fingerprints in Euclidean space using Tanimoto (a.k.a. Jaccard) similarity kernel principal component analysis (KPCA) and compared the effects on LASSO and SVM model performance for predicting the binding activities of chemical compounds against 102 virtual screening targets. We observed similar performance and patterns of improvement for LASSO and SVM. We also empirically measured model training and cross-validation times to show that KPCA used in concert with LASSO classification is significantly faster than linear SVM over a wide range of training set sizes. Our work shows that powerful linear QSAR methods can match nonlinear methods and demonstrates a modular approach to nonlinear classification that greatly enhances QSAR model prototyping facility, flexibility, and transferability. PMID- 28727423 TI - Seasonal Variation of Terrigenous Polycyclic Aromatic Hydrocarbons along the Marginal Seas of China: Input, Phase Partitioning, and Ocean-Current Transport. AB - To study the spatial distributions and seasonal differences of concentrations, source identification, and phase partitioning of polycyclic aromatic hydrocarbons (PAHs) in surface water, intensive sampling was carried out along the marginal seas of China in four seasons. In the northern South China Sea (SCS), the highest PAH levels occurred in the summer (July to August) and autumn (October to November). In the East China Sea (ECS) and the Yellow Sea, the highest occurred in the summer (August) and winter (December). In all areas, the lowest PAH levels were found in the spring (May to June). The estimated mass inventory of PAHs in the surface water (0-5 m) of the northern SCS and ECS accounted for less than 8% of PAHs outflow into the offshore environment. That showed the consistent seasonal variation with PAHs levels. Land- and ocean-based emissions, surface runoff, and the open seawater dilution were the most important environmental factors influencing the seasonal heterogeneity and the spatial distributions of PAH in the surface water. The decline of observed organic carbon normalized partition coefficients in the four seasons was probably affected by the presence of submicrometer-sized soot particles accompanying the PAH outflow from China. PMID- 28727424 TI - Enantioselective Construction of Tertiary C-O Bond via Allylic Substitution of Vinylethylene Carbonates with Water and Alcohols. AB - An efficient method for the enantioselective construction of tertiary C-O bond via asymmetric allylic substitution of racemic vinylethylene carbonates with water and alcohols has been developed. Under the cooperative catalysis system of an in situ generated chiral palladium complex and boron reagent in mild conditions, the process allowed rapid access to valuable tertiary alcohols and ethers in high yields with complete regioselectivities and high enantioselectivities. This protocol represented the first example of direct enantioselective formation of a tertiary C-O bond with water as an oxygen donor. The synthetic utilities of the process have been demonstrated by the elaboration of the products into key intermediates of biologically relevant agents, and chiral tertiary cyclic ethers could also be provided through the sequential reactions of the allylic etherification and ring-closing metathesis. PMID- 28727425 TI - Database and Bioinformatics Studies of Probiotics. AB - Probiotics have been widely explored for health benefits, animal cares, and agricultural applications. Recent advances in microbiome, microbiota, and microbial dark matter research have fueled greater interests in and paved ways for the study of the mechanisms of probiotics and the discovery of new probiotics from uncharacterized microbial sources. A probiotics database named PROBIO was developed to facilitate these efforts and the need for the information on the known probiotics, which provides the comprehensive information about the probiotic functions of 448 marketed, 167 clinical trial/field trial, and 382 research probiotics for use or being studied for use in humans, animals, and plants. The potential applications of the probiotics data are illustrated by several literature-reported investigations, which have used the relevant information for probing the function and mechanism of the probiotics and for discovering new probiotics. PROBIO can be accessed free of charge at http://bidd2.nus.edu.sg/probio/homepage.htm . PMID- 28727426 TI - Fully Atomistic Abeta40 and Abeta42 Oligomers in Water: Observation of Porelike Conformations. AB - Oligomers formed by amyloid beta-protein (Abeta) are central to Alzheimer's disease (AD) pathology, yet their structure remains elusive. Of the two predominant Abeta alloforms, Abeta40 and Abeta42, the latter is more strongly associated with AD. Here, we structurally characterized Abeta40 and Abeta42 monomers through pentamers which were converted from previously derived coarse grained (DMD4B-HYDRA) simulations into all-atom conformations and subjected to explicit-solvent MD. Free energy landscapes revealed that structural differences between Abeta40 and Abeta42 conformations increase with oligomer order up to trimers. All conformations display high statistical coil and turn content (40 50%) with minor beta-strand and alpha-helical content (<10%). Abeta40 tetramers and pentamers exhibit significantly more elongated morphologies than the respective Abeta42 conformations. Unlike the initial DMD4B-HYDRA conformations, fully atomistic Abeta40 and Abeta42 trimers, tetramers, and pentamers form water permeable pores, whereby the tendency for pore formation sharply increased with oligomer order and is the highest for Abeta42 pentamers. Previous studies reported that Abeta oligomers form ion channels when embedded into a cellular membrane, which causes an abnormal ion flux and eventually leads to cell death. Our findings reveal an extraordinary ability of Abeta oligomers to form pores in pure water prior to their insertion into a membrane and thus provide support to the ion channel hypothesis of AD. PMID- 28727427 TI - High-Throughput Synthesis and Structure of Zeolite ZSM-43 with Two-Directional 8 Ring Channels. AB - The aluminosilicate zeolite ZSM-43 (where ZSM = Zeolite Socony Mobil) was first synthesized more than 3 decades ago, but its chemical structure remained unsolved because of its poor crystallinity and small crystal size. Here we present optimization of the ZSM-43 synthesis using a high-throughput approach and subsequent structure determination by the combination of electron crystallographic methods and powder X-ray diffraction. The synthesis required the use of a combination of both inorganic (Cs+ and K+) and organic (choline) structure-directing agents. High-throughput synthesis enabled a screening of the synthesis conditions, which made it possible to optimize the synthesis, despite its complexity, in order to obtain a material with significantly improved crystallinity. When both rotation electron diffraction and high-resolution transmission electron microscopy imaging techniques are applied, the structure of ZSM-43 could be determined. The structure of ZSM-43 is a new zeolite framework type and possesses a unique two-dimensional channel system limited by 8-ring channels. ZSM-43 is stable upon calcination, and sorption measurements show that the material is suitable for adsorption of carbon dioxide as well as methane. PMID- 28727428 TI - Correction to Potent Inhibitor of Drug-Resistant HIV-1 Strains Identified from the Medicinal Plant Justicia gendarussa. PMID- 28727429 TI - Elliptic Cylinder Airborne Sampling and Geostatistical Mass Balance Approach for Quantifying Local Greenhouse Gas Emissions. AB - In this study, we explore observational, experimental, methodological, and practical aspects of the flux quantification of greenhouse gases from local point sources by using in situ airborne observations, and suggest a series of conceptual changes to improve flux estimates. We address the major sources of uncertainty reported in previous studies by modifying (1) the shape of the typical flight path, (2) the modeling of covariance and anisotropy, and (3) the type of interpolation tools used. We show that a cylindrical flight profile offers considerable advantages compared to traditional profiles collected as curtains, although this new approach brings with it the need for a more comprehensive subsequent analysis. The proposed flight pattern design does not require prior knowledge of wind direction and allows for the derivation of an ad hoc empirical correction factor to partially alleviate errors resulting from interpolation and measurement inaccuracies. The modified approach is applied to a use-case for quantifying CH4 emission from an oil field south of San Ardo, CA, and compared to a bottom-up CH4 emission estimate. PMID- 28727430 TI - Renal Clearable Peptide Functionalized NaGdF4 Nanodots for High-Efficiency Tracking Orthotopic Colorectal Tumor in Mouse. AB - The effective delivery of bioimaging probes to a selected cancerous tissue has extensive significance for biological studies and clinical investigations. Herein, the peptide functionalized NaGdF4 nanodots (termed as, pPeptide-NaGdF4 nanodots) have been prepared for highly efficient magnetic resonance imaging (MRI) of tumor by formation of Gd-phosphonate coordinate bonds among hydrophobic NaGdF4 nanodots (4.2 nm in diameter) with mixed phosphorylated peptide ligands including a tumor targeting phosphopeptide and a cell penetrating phosphopeptide. The tumor targeting pPeptide-NaGdF4 nanodots have paramagnetic property with ultrasmall hydrodynamic diameter (HD, c.a., 7.3 nm) which greatly improves their MRI contrast ability of tumor and facilitates renal clearance. In detail, the capability of the pPeptide-NaGdF4 nanodots as high efficient contrast agent for in vivo MRI is evaluated successfully through tracking small drug induced orthotopic colorectal tumor (c.a., 195 mm3 in volume) in mouse. PMID- 28727431 TI - Pd-Catalyzed/Iodide-Promoted alpha-Arylation of Ketones for the Regioselective Synthesis of Isocoumarins. AB - A variety of isocoumarins have been synthesized directly from 2-halobenzoates and ketones through a palladium-catalyzed alpha-arylation step followed by an intramolecular cyclization process. The addition of iodide anions to the reaction mixture increased yields and selectivities especially when 2-bromobenzoates were employed. This phosphine-free one-pot synthesis features a high functional group tolerance and gives access to richly decorated isocoumarins. This general methodology was successful in the total synthesis of Xyridin A, an important natural product with antibacterial and antifungal activity. PMID- 28727432 TI - Controlled Functionalization of Gold Nanoparticles with Mixtures of Calix[4]arenes Revealed by Infrared Spectroscopy. AB - Labile ligands such as thiols and carboxylates are commonly used to functionalize AuNPs, though little control over the composition is possible when mixtures of ligands are used. It was shown recently that robustly functionalized AuNPs can be obtained through the reductive grafting of calix[4]arenes bearing diazonium groups on the large rim. Here, we report a calix[4]arene-tetradiazonium decorated by four oligo(ethylene glycol) chains on the small rim, which upon grafting gave AuNPs with excellent stability thanks to the C-Au bonds. Mixtures of this calixarene and one with four carboxylate groups were grafted on AuNPs. The resulting particles were analyzed by infrared spectroscopy, which revealed that the composition of the ligand shell clearly reflected the ratio of calixarenes that was present in solution. This strategy opens the way to robustly protected AuNPs with well-defined numbers of functional or postfunctionalizable groups. PMID- 28727433 TI - 53rd North American Chemical Residue Workshop. PMID- 28727434 TI - Ellipsometry of Colloidal Solutions: New Experimental Setup and Application to Metallic Colloids. AB - An ellipsometric cell is developed to simultaneously determine the shape distribution, the volume fraction, and the complex refractive index of gold and silver colloids. Simulation reveals that this cell drastically improves the detection limit of ellipsometry. Indeed, Ag and Au nanoparticles (NPs) are detected at the ppmv level. We demonstrate that the NPs shape distribution can be estimated from ellipsometric measurements by analyzing them with a shape distributed effective medium theory (SDEMT). The obtained distributions from ellipsometry are in agreement with those deduced from transmission electron microcopy (TEM). Contrary to TEM, ellipsometry probes a large number of NPs estimated at about 1011 NPs. Finally, we show that the complex refractive index of colloids as determined from ellipsometry is sensitive to the optical properties of the solvent and the plasmonic properties of NPs. PMID- 28727435 TI - Wettability Effect on Evaporation Dynamics and Crystalline Patterns of Sessile Saline Droplets. AB - The evaporative dynamics and crystalline patterns from sessile saline droplets on various substrates are experimentally investigated. On the silicon wafer and poly(methyl methacrylate) (PMMA) plate, the saline droplets exhibit unique evaporative dynamics such that the contact angle keeps increasing for a lasting period. Such an enlargement in contact angle is attenuated at a higher salt concentration. Interestingly, the onset of precipitation is almost overlapped with the end of contact angle enlargement when the contact angle reaches its apex. The lower wettability and the smaller pinning effect of silicon wafer and PMMA result in the morphology of crystalline cubes at the droplet center. On the soda lemon glass, the high wettability and lifetime pinning stage of the droplet lead to spherical profiles of precipitation. The crystalline deposit depends on the salt concentration on soda lemon glass such that it is comprised of exterior cracked layers of salt and interior separated small cubes for low salt concentrations, whereas large crystalline chunks stay near the droplet rim for high salt concentrations. PMID- 28727436 TI - Evidence for Ultralow-Energy Vibrations in Large Organic Molecules. AB - The quantum efficiency or the rate of conversion of incident photon to free electron in photosynthesis is known to be extremely high. It has long been thought that the origin of this efficiency are molecular vibrations leading to a very fast separation of electrons and holes within the involved molecules. However, molecular vibrations are commonly in the range above 100 meV, which is too high for excitations in an ambient environment. Here, we analyze experimental spectra of single organic molecules on metal surfaces at ~4 K, which often exhibit a pronounced dip. We show that measurements on iron(II) [tetra (pentafluorophenyl)]porphyrin resolve this single dip at 4 K into a series of step-shaped inelastic excitations at 0.4 K. Via extensive spectral maps under applied magnetic fields and corresponding theoretical analysis we find that the dip is due to ultralow-energy vibrations of the molecular frame, typically in the range below 20 meV. The result indicates that ultralow energy vibrations in organic molecules are much more common than currently thought and may be all pervasive for molecules above a certain size. PMID- 28727437 TI - A Modular Synthesis of 4-Aminoquinolines and [1,3] N-to-C Rearrangement to Quinolin-4-ylmethanesulfonamides. AB - A copper-catalyzed regiocontrolled three-component reaction afforded diversified 4-aminoquinolines using nitriles, diaryliodoniums, and ynamides. The C7 substituted regioisomers were formed regioselectively when meta-substituted phenyliodonium salts were used. [1,3] N-to-C rearrangement of the products to quinolin-4-ylmethanesulfonamides and simultaneous deprotection of benzyl and sulfonamide group were newly developed. Finally, antimalarial CK-2-68 was successfully prepared. PMID- 28727438 TI - A Wettability Metric for Characterization of Capillary Flow on Textured Superhydrophilic Surfaces. AB - Surface wettability is typically characterized by measuring the static contact angle of a sessile droplet placed on the surface. For extremely wetting surfaces on which liquid spontaneously spreads into a thin liquid film, the near-zero static contact angle is not amenable to measurement and does not fully describe the wetting behavior. There are unmet needs in microfluidics, boiling heat transfer enhancement, and antifogging applications for a metric to characterize highly wetting (i.e., superhydrophilic) textured surfaces based on their capillary-driven liquid pumping performance, as a supplement to the contact angle for this highly wetting regime. To describe the wetting behavior, the textured surface can be approximated as a thin porous layer through which the liquid spreads. An analytical model is developed for the volumetric flow in this layer, which reveals a single superhydrophilicity metric that captures the wetting behavior for a given liquid. A simple experimental approach is proposed to characterize this metric by measuring the volumetric liquid intake into the surface from a filled capillary tube. This approach is validated by characterizing micropillared superhydrophilic surfaces of known geometry; the predicted and measured wetting behaviors show good agreement. The metric proposed in this study offers a simple approach for accurately characterizing and differentiating highly wetting surfaces based on their liquid pumping ability. PMID- 28727439 TI - Solid-State NMR Study of the Cicada Wing. AB - Wings of flying insects are part of the cuticle which forms the exoskeleton. The primary molecular components of cuticle are protein, chitin, and lipid. How these components interact with one another to form the exoskeleton is not completely understood. The difficulty in characterizing the cuticle arises because it is insoluble and noncrystalline. These properties severely limit the experimental tools that can be used for molecular characterization. Solid-state nuclear magnetic resonance experiments have been used in the past to characterize the exoskeleton of beetles and have found that chitin and protein make comparable contributions to the molecular matrix. However, little work has been done to characterize the components of the wing, which includes vein and membrane. In this work, solid-state NMR was used to characterize the wing of the 17-year cycle cicada (Magicicada cassini) that appeared in northern West Virginia during the summer of 2016. The NMR results show noticeable differences between the molecular components of the vein and membrane. PMID- 28727440 TI - Sensitization of Nanocrystalline Metal Oxides with a Phosphonate-Functionalized Perylene Diimide for Photoelectrochemical Water Oxidation with a CoOx Catalyst. AB - A planar organic thin film composed of a perylene diimide dye (N,N' bis(phosphonomethyl)-3,4,9,10-perylenediimide, PMPDI) with photoelectrochemically deposited cobalt oxide (CoOx) catalyst was previously shown to photoelectrochemically oxidize water (DOI: 10.1021/am405598w). Herein, the same PMPDI dye is studied for the sensitization of different nanostructured metal oxide (nano-MOx) films in a dye-sensitized photoelectrochemical cell architecture. Dye adsorption kinetics and saturation decreases in the order TiO2 > SnO2 ? WO3. Despite highest initial dye loading on TiO2 films, photocurrent with hydroquinone (H2Q) sacrificial reductant in pH 7 aqueous solution is much higher on SnO2 films, likely due to a higher driving force for charge injection into the more positive conduction band energy of SnO2. Dyeing conditions and SnO2 film thickness were subsequently optimized to achieve light-harvesting efficiency >99% at the lambdamax of the dye, and absorbed photon-to-current efficiency of 13% with H2Q, a 2-fold improvement over the previous thin-film architecture. A CoOx water-oxidation catalyst was photoelectrochemically deposited, allowing for photoelectrochemical water oxidation with a faradaic efficiency of 31 +/- 7%, thus demonstrating the second example of a water-oxidizing, dye-sensitized photoelectrolysis cell composed entirely of earth-abundant materials. However, deposition of CoOx always results in lower photocurrent due to enhanced recombination between catalyst and photoinjected electrons in SnO2, as confirmed by open-circuit photovoltage measurements. Possible future studies to enhance photoanode performance are discussed, including alternative catalyst deposition strategies or structural derivatization of the perylene dye. PMID- 28727441 TI - Adsorption Induced Changes of Human Hemoglobin on Ferric Pyrophosphate Nanoparticle Surface Probed by Isotope Exchange Mass Spectrometry: An Implication on Structure-Function Correlation. AB - In general, proteins in the biological system interact with nanoparticles (NPs) via adsorption on the particle surface. Understanding the adsorption at the molecular level is crucial to explore NP-protein interactions. The increasing concerns about the risk to human health on NP exposure have been explored through the discovery of a handful protein biomarkers and biochemical analysis. However, detailed information on structural perturbation and associated functional changes of proteins on interaction with NPs is limited. Erythrocytes (red blood cells) are devoid of defense mechanism of protecting NP penetration through endocytosis. Therefore, it is important to investigate the interaction of erythrocyte proteins with NPs. Hemoglobin, the most abundant protein of human erythrocyte, is a tetrameric molecule consisting of alpha- and beta-globin chains in duplicate. In the present study, we have used hemoglobin as a model system to investigate NP protein interaction with ferric pyrophosphate NPs [NP-Fe4(P2O7)3]. We report the formation of a bioconjugate of hemoglobin upon adsorption to NP-Fe4(P2O7)3 surface. Analysis of the bioconjugate indicated that Fe3+ ion of NP-Fe4(P2O7)3 contributed in the bioconjugate formation. Using hydrogen/deuterium exchange based mass spectrometry, it was observed that the amino termini of alpha- and beta-globin chains of hemoglobin were involved in the adsorption on NP surface whereas the carboxy termini of both chains became more flexible in its conformation compared to the respective regions of the normal hemoglobin. Circular dichroism spectra of desorbed hemoglobin indicated an adsorption induced localized structural change in the protein molecule. The formation of bioconjugate led to functional alteration of hemoglobin, as probed by oxygen binding assay. Thus, we hypothesize that the large amount of energy released upon adsorption of hemoglobin to NP surface might be the fundamental cause of structural perturbation of human hemoglobin and subsequent formation of the bioconjugate with an altered function. PMID- 28727443 TI - Plasmonic Thermal Decomposition/Digestion of Proteins: A Rapid On-Surface Protein Digestion Technique for Mass Spectrometry Imaging. AB - A method based on plasmon surface resonance absorption and heating was developed to perform a rapid on-surface protein thermal decomposition and digestion suitable for imaging mass spectrometry (MS) and/or profiling. This photothermal process or plasmonic thermal decomposition/digestion (plasmonic-TDD) method incorporates a continuous wave (CW) laser excitation and gold nanoparticles (Au NPs) to induce known thermal decomposition reactions that cleave peptides and proteins specifically at the C-terminus of aspartic acid and at the N-terminus of cysteine. These thermal decomposition reactions are induced by heating a solid protein sample to temperatures between 200 and 270 degrees C for a short period of time (10-50 s per 200 MUm segment) and are reagentless and solventless, and thus are devoid of sample product delocalization. In the plasmonic-TDD setup the sample is coated with Au-NPs and irradiated with 532 nm laser radiation to induce thermoplasmonic heating and bring about site-specific thermal decomposition on solid peptide/protein samples. In this manner the Au-NPs act as nanoheaters that result in a highly localized thermal decomposition and digestion of the protein sample that is independent of the absorption properties of the protein, making the method universally applicable to all types of proteinaceous samples (e.g., tissues or protein arrays). Several experimental variables were optimized to maximize product yield, and they include heating time, laser intensity, size of Au-NPs, and surface coverage of Au-NPs. Using optimized parameters, proof-of principle experiments confirmed the ability of the plasmonic-TDD method to induce both C-cleavage and D-cleavage on several peptide standards and the protein lysozyme by detecting their thermal decomposition products with matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS). The high spatial specificity of the plasmonic-TDD method was demonstrated by using a mask to digest designated sections of the sample surface with the heating laser and MALDI MS imaging to map the resulting products. The solventless nature of the plasmonic TDD method enabled the nonenzymatic on-surface digestion of proteins to proceed with undetectable delocalization of the resulting products from their precursor protein location. The advantages of this novel plasmonic-TDD method include short reaction times (<30 s/200 MUm), compatibility with MALDI, universal sample compatibility, high spatial specificity, and localization of the digestion products. These advantages point to potential applications of this method for on tissue protein digestion and MS-imaging/profiling for the identification of proteins, high-fidelity MS imaging of high molecular weight (>30 kDa) proteins, and the rapid analysis of formalin-fixed paraffin-embedded (FFPE) tissue samples. PMID- 28727442 TI - Manipulating Semicrystalline Polymers in Confinement. AB - Because final properties of nanoscale polymeric structures are largely determined by the solid-state microstructure of the confined polymer, it is imperative not only to understand how the microstructure of polymers develops under nanoscale confinement but also to establish means to manipulate it. Here we present a series of processing strategies, adapted from methods used in bulk polymer processing, that allow us to control the solidification of polymer nanostructures. First, we show that supramolecular nucleating agents can be readily used to modify the crystallization kinetics of confined poly(vinylidene fluoride) (PVDF). In addition, we demonstrate that microstructural features that are not traditionally affected by nucleating agents, such as the orientation of crystals, can be tuned with the crystallization temperature applied. Interestingly, we also show that high crystallization temperatures and long annealing periods induce the formation of the gamma modification of PVDF, hence enabling the simple production of ferro/piezoelectric nanostructures. We anticipate that the approaches presented here can open up a plethora of new possibilities for the processing of polymer-based nanostructures with tailored properties and functionalities. PMID- 28727444 TI - Fosfomycin Biosynthesis via Transient Cytidylylation of 2-Hydroxyethylphosphonate by the Bifunctional Fom1 Enzyme. AB - Fosfomycin is a wide-spectrum phosphonate antibiotic that is used clinically to treat cystitis, tympanitis, etc. Its biosynthesis starts with the formation of a carbon-phosphorus bond catalyzed by the phosphoenolpyruvate phosphomutase Fom1. We identified an additional cytidylyltransferase (CyTase) domain at the Fom1 N terminus in addition to the phosphoenolpyruvate phosphomutase domain at the Fom1 C-terminus. Here, we demonstrate that Fom1 is bifunctional and that the Fom1 CyTase domain catalyzes the cytidylylation of the 2-hydroxyethylphosphonate (HEP) intermediate to produce cytidylyl-HEP. On the basis of this new function of Fom1, we propose a revised fosfomycin biosynthetic pathway that involves the transient CMP-conjugated intermediate. The identification of a biosynthetic mechanism via such transient cytidylylation of a biosynthetic intermediate fundamentally advances the understanding of phosphonate biosynthesis in nature. The crystal structure of the cytidylyl-HEP-bound CyTase domain provides a basis for the substrate specificity and reveals unique catalytic elements not found in other members of the CyTase family. PMID- 28727446 TI - Reductive Outer-Sphere Single Electron Transfer Is an Exception Rather than the Rule in Natural and Engineered Chlorinated Ethene Dehalogenation. AB - Chlorinated ethenes (CEs) such as perchloroethylene, trichloroethylene and dichloroethylene are notorious groundwater contaminants. Although reductive dehalogenation is key to their environmental and engineered degradation, underlying reaction mechanisms remain elusive. Outer-sphere reductive single electron transfer (OS-SET) has been proposed for such different processes as Vitamin B12-dependent biodegradation and zerovalent metal-mediated dehalogenation. Compound-specific isotope effect (13C/12C, 37Cl/35Cl) analysis offers a new opportunity to test these hypotheses. Defined OS-SET model reactants (CO2 radical anions, S2--doped graphene oxide in water) caused strong carbon (epsilonC = -7.90/00 to -11.90/00), but negligible chlorine isotope effects (epsilonCl = -0.120/00 to 0.040/00) in CEs. Greater chlorine isotope effects were observed in CHCl3 (epsilonC = -7.70/00, epsilonCl = -2.60/00), and in CEs when the exergonicity of C-Cl bond cleavage was reduced in an organic solvent (reaction with arene radical anions in glyme). Together, this points to dissociative OS-SET (SET to a sigma* orbital concerted with C-Cl breakage) in alkanes compared to stepwise OS-SET (SET to a pi* orbital followed by C-Cl cleavage) in ethenes. The nonexistent chlorine isotope effects of chlorinated ethenes in all aqueous OS-SET experiments contrast strongly with pronounced Cl isotope fractionation in all natural and engineered reductive dehalogenations reported to date suggesting that OS-SET is an exception rather than the rule in environmental transformations of chlorinated ethenes. PMID- 28727447 TI - Systematic Comparison between Half and Full Dielectric Barrier Discharges Based on the Low Temperature Plasma Probe (LTP) and Dielectric Barrier Discharge for Soft Ionization (DBDI) Configurations. AB - Dielectric barrier discharge (DBD)-based analytical applications have experienced rapid development in recent years. DBD designs and parameters and the application they are used for can vary considerably. This leads to a diverse field with many apparently unique systems that are all based on the same physical principle. The most significant changes among DBDs used for chemical analysis are in how the discharge electrodes are separated from the ignited discharge gas. While the official definition of a DBD states that at least one electrode has to be covered by a dielectric to be considered a DBD, configurations with both electrodes covered by dielectric layers can also be realized. The electrode surface plays a major role in several plasma-related technical fields, surface treatment or sputtering processes, for example, and has hence been studied in great detail. Analytical DBDs are often operated at low power and atmospheric pressure, making a direct transfer of insight and know-how gained from the aforementioned well studied fields complicated. This work focuses on comparing two DBD configurations: the low temperature plasma probe (LTP) and the dielectric barrier discharge for soft ionization (DBDI). The LTP is representative of a DBD with one covered electrode and the DBDI of a design in which both electrodes are covered. These two configurations are well suited for a systematic comparison due to their similar geometric designs based on a dielectric capillary. PMID- 28727445 TI - Antibiotic That Inhibits the ATPase Activity of an ATP-Binding Cassette Transporter by Binding to a Remote Extracellular Site. AB - Antibiotic-resistant strains of Staphylococcus aureus pose a major threat to human health and there is an ongoing need for new antibiotics to treat resistant infections. In a high throughput screen (HTS) of 230 000 small molecules designed to identify bioactive wall teichoic acid (WTA) inhibitors, we identified one hit, which was expanded through chemical synthesis into a small panel of potent compounds. We showed that these compounds target TarG, the transmembrane component of the two-component ATP-binding cassette (ABC) transporter TarGH, which exports WTA precursors to the cell surface for attachment to peptidoglycan. We purified, for the first time, a WTA transporter and have reconstituted ATPase activity in proteoliposomes. We showed that this new compound series inhibits TarH-catalyzed ATP hydrolysis even though the binding site maps to TarG near the opposite side of the membrane. These are the first ABC transporter inhibitors shown to block ATPase activity by binding to the transmembrane domain. The compounds have potential as therapeutic agents to treat S. aureus infections, and purification of the transmembrane transporter will enable further development. PMID- 28727448 TI - Extensive Survey of Antibody Invariant Positions for Efficient Chemical Conjugation Using Expanded Genetic Codes. AB - The site-specific chemical conjugation of proteins, following synthesis with an expanded genetic code, promises to advance antibody-based technologies, including antibody drug conjugation and the creation of bispecific Fab dimers. The incorporation of non-natural amino acids into antibodies not only guarantees site specificity but also allows the use of bio-orthogonal chemistry. However, the efficiency of amino acid incorporation fluctuates significantly among different sites, thereby hampering the identification of useful conjugation sites. In this study, we applied the codon reassignment technology to achieve the robust and efficient synthesis of chemically functionalized antibodies containing Nepsilon (o-azidobenzyloxycarbonyl)-l-lysine (o-Az-Z-Lys) at defined positions. This lysine derivative has a bio-orthogonally reactive group at the end of a long side chain, enabling identification of multiple new positions in Fab-constant domains, allowing chemical conjugation with high efficiency. An X-ray crystallographic study of a Fab variant with o-Az-Z-Lys revealed high-level exposure of the azido group to solvent, with six of the identified positions subsequently used to engineer "Variabodies", a novel antibody format allowing various connections between two Fab molecules. Our findings indicated that some of the created Variabodies exhibited agonistic activity in cultured cells as opposed to the antagonistic nature of antibodies. These results showed that our approach greatly enhanced the availability of antibodies for chemical conjugation and might aid in the development of new therapeutic antibodies. PMID- 28727449 TI - Use of MALDI-MS Combined with Differential Hydrogen-Deuterium Exchange for Semiautomated Protein Global Conformational Screening. AB - Matrix-assisted laser desorption/ionization (MALDI) coupled with a time-of-flight (TOF) mass-spectrometry (MS) detector is acknowledged to be very useful for analysis of biological molecules. At the same time, hydrogen-deuterium exchange (HDX) is a well-known technique for studying protein higher-order structure. However, coupling MALDI with HDX has been challenging because of undesired back exchange reactions during analysis. In this report, we survey an approach that utilizes MALDI coupled with an automated sample preparation to compare global conformational changes of proteins under different solution conditions using differential HDX. A nonaqueous matrix was proposed for MALDI sample preparation to minimize undesirable back-exchange. An automated experimental setup based on the use of a liquid-handling robot and automated data acquisition allowed for tracking protein conformational changes as a difference in the number of protons exchanged to deuterons at specified solution conditions. Experimental time points to study the deuteration-labeling kinetics were obtained in a fully automated manner. The use of a nonaqueous matrix solution allowed experimental error to be minimized to within 1% RSD. We applied this newly developed MALDI-HDX workflow to study the effect of several common excipients on insulin folding stability. The observed results were corroborated by literature data and were obtained in a high throughput and automated manner. The proposed MALDI-HDX approach can also be applied in a high-throughput manner for batch-to-batch higher-order structure comparison, as well as for the optimization of protein chemical modification reactions. PMID- 28727450 TI - Carbon Nanotube Reinforced Polymer-Stabilized Liquid Crystal Device: Lowered and Thermally Invariant Threshold with Accelerated Dynamics. AB - Polymer-stabilized liquid crystal (PSLC) devices comprise a polymer matrix in an otherwise continuous phase of liquid crystal. The fibrils of the polymer provide, even in the bulk, virtual surfaces with finite anchoring energy resulting in attractive electro-optic properties. Here, we describe a novel variation of the PSLC device fabricated by reinforcing the polymer matrix with polymer-capped single-walled carbon nanotubes (CNTs). The most important outcome of this strengthening of the polymer strands is that the threshold voltage associated with the electro-optic switching becomes essentially temperature independent in marked contrast to the significant thermal variation seen in the absence of the nanotubes. The reinforcement reduces the magnitude of the threshold voltage, and notably accelerates the switching dynamics and the effective splay elasticity. Each of these attributes is quite attractive from the device operation point of view, especially the circuit design of the required drivers. The amelioration is caused by the polymer decorating CNTs being structurally identical to that of the matrix. The resulting good compatibility between CNTs and the matrix prevents the CNTs from drifting away from the matrix polymer, a lacuna in previous attempts to have CNTs in PSLC systems. The difference in the morphology, perhaps the primary cause for the effects seen, is noted in the electron microscopy images of the films. PMID- 28727451 TI - Regular Fluorescence of 4-Fluoro-N,N-dimethylaniline: No Charge Transfer and No Twisting. AB - Recently, two contradicting experimental investigations have been published on the fluorescence behavior of 4-fluoro-N,N-dimethylaniline (FDMA). Motivated by the discrepancies between these studies, we have examined the deactivation pathways of photoexcited FDMA using high-level quantum chemical methods such as time-dependent density functional theory (TDDFT), coupled cluster (CC2) theory, and the algebraic diagrammatic construction scheme (ADC(2), ADC(3)) simulating solvation using continuum solvation models. Our results show the initial population of the bright S2 (pipi*) state of FDMA relax to a linear, almost planar S1 state minimum from which emission occurs. Our study further reveals that TDDFT/B3LYP erroneously predicts a planar twisted intramolecular charge transfer (TICT) S1 state minimum that vanishes when the amount of nonlocal Hartree-Fock exchange in the functional is increased. PMID- 28727452 TI - Catalytic Intermolecular Carboamination of Unactivated Alkenes via Directed Aminopalladation. AB - An intermolecular 1,2-carboamination of unactivated alkenes proceeding via a Pd(II)/Pd(IV) catalytic cycle has been developed. To realize this transformation, a cleavable bidentate directing group is used to control the regioselectivity of aminopalladation and stabilize the resulting organopalladium(II) intermediate, such that oxidative addition to a carbon electrophile outcompetes potential beta hydride elimination. Under the optimized reaction conditions, a broad range of nitrogen nucleophiles and carbon electrophiles are compatible coupling partners in this reaction, affording moderate to high yields. The products of this reaction can be easily converted to free gamma-amino acids and gamma-lactams, both of which are common structural motifs found in drug molecules and bioactive compounds. Reaction kinetics and DFT calculations shed light on the mechanism of the reaction and explain empirically observed reactivity trends. PMID- 28727454 TI - Route to Substituted Furan-2(5H)-ones from cyclo-Alkenecarboxylic Acids and Acrylates via C-H Activation. AB - Under rhodium(III) catalysis, four kinds of cycloalkenecarboxylic acids successfully reacted with acrylates via direct activation of the beta-alkenyl C-H bond. The present protocol provides the facile and highly efficient synthesis of substituted furan-2(5H)-ones from readily available starting materials with moderate to good yields. In addition, their possible reaction mechanisms were also discussed. PMID- 28727453 TI - Formation of Developmentally Toxic Phenanthrene Metabolite Mixtures by Mycobacterium sp. ELW1. AB - Mycobacterium sp. ELW1 co-metabolically degraded up to 1.8 MUmol of phenanthrene (PHE) in ~48 h, and hydroxyphenanthrene (OHPHE) metabolites, including 1 hydroxyphenanthrene (1-OHPHE), 3-hydroxyphenanthrene (3-OHPHE), 4 hydroxyphenanthrene (4-OHPHE), 9-hydroxyphenanthrene (9-OHPHE), 9,10 dihydroxyphenanthrene (1,9-OHPHE), and trans-9,10-dihydroxy-9,10 dihydrophenanthrene (trans-9,10-OHPHE), were identified and quantified over time. The monooxygenase responsible for co-metabolic transformation of PHE was inhibited by 1-octyne. First-order PHE transformation rates, kPHE, and half lives, t1/2, for PHE-exposed cells were 0.16-0.51 h-1 and 1.4-4.3 h, respectively, and the 1-octyne controls ranged from 0.015-0.10 h-1 to 7.0-47 h, respectively. While single compound standards of PHE and trans-9,10-OHPHE, the major OHPHE metabolite formed by ELW1, were not toxic to embryonic zebrafish (Danio rerio), single compound standards of minor OHPHE metabolites, 1-OHPHE, 3 OHPHE, 4-OHPHE, 9-OHPHE, and 1,9-OHPHE, were toxic, with effective concentrations (EC50's) ranging from 0.5 to 5.5 MUM. The metabolite mixtures formed by ELW1, and the reconstructed standard mixtures of the identified OHPHE metabolites, elicited a toxic response in zebrafish for the same three time points. EC50s for the metabolite mixtures formed by ELW1 were lower (more toxic) than those for the reconstructed standard mixtures of the identified OHPHE metabolites. Ten unidentified hydroxy PHE metabolites were measured in the derivatized mixtures formed by ELW1 and may explain the increased toxicity of the ELW1 metabolites mixture relative to the reconstructed standard mixtures of the identified OHPHE metabolites. PMID- 28727455 TI - Electron-Deficient Chiral Lactic Acid-Based Hypervalent Iodine Reagents. AB - Novel electron-deficient chiral hypervalent iodine reagents were prepared in good overall yields. The reactivity and stereoselectivity of these reagents in oxidative rearrangements of alkenes to alpha-aryl ketones were investigated. The results show that the new reagents have good reactivity and generate products with high enantiomeric excess. PMID- 28727457 TI - Enthalpy of Formation of N2H4 (Hydrazine) Revisited. AB - In order to address the accuracy of the long-standing experimental enthalpy of formation of gas-phase hydrazine, fully confirmed in earlier versions of Active Thermochemical Tables (ATcT), the provenance of that value is re-examined in light of new high-end calculations of the Feller-Peterson-Dixon (FPD) variety. An overly optimistic determination of the vaporization enthalpy of hydrazine, which created an unrealistically strong connection between the gas phase thermochemistry and the calorimetric results defining the thermochemistry of liquid hydrazine, was identified as the probable culprit. The new enthalpy of formation of gas-phase hydrazine, based on balancing all available knowledge, was determined to be 111.57 +/- 0.47 kJ/mol at 0 K (97.42 +/- 0.47 kJ/mol at 298.15 K). Close agreement was found between the ATcT (even excluding the latest theoretical result) and the FPD enthalpy. PMID- 28727456 TI - Constrained Mixed-Effect Models with Ensemble Learning for Prediction of Nitrogen Oxides Concentrations at High Spatiotemporal Resolution. AB - Spatiotemporal models to estimate ambient exposures at high spatiotemporal resolutions are crucial in large-scale air pollution epidemiological studies that follow participants over extended periods. Previous models typically rely on central-site monitoring data and/or covered short periods, limiting their applications to long-term cohort studies. Here we developed a spatiotemporal model that can reliably predict nitrogen oxide concentrations with a high spatiotemporal resolution over a long time span (>20 years). Leveraging the spatially extensive highly clustered exposure data from short-term measurement campaigns across 1-2 years and long-term central site monitoring in 1992-2013, we developed an integrated mixed-effect model with uncertainty estimates. Our statistical model incorporated nonlinear and spatial effects to reduce bias. Identified important predictors included temporal basis predictors, traffic indicators, population density, and subcounty-level mean pollutant concentrations. Substantial spatial autocorrelation (11-13%) was observed between neighboring communities. Ensemble learning and constrained optimization were used to enhance reliability of estimation over a large metropolitan area and a long period. The ensemble predictions of biweekly concentrations resulted in an R2 of 0.85 (RMSE: 4.7 ppb) for NO2 and 0.86 (RMSE: 13.4 ppb) for NOx. Ensemble learning and constrained optimization generated stable time series, which notably improved the results compared with those from initial mixed-effects models. PMID- 28727458 TI - Unraveling the High Open Circuit Voltage and High Performance of Integrated Perovskite/Organic Bulk-Heterojunction Solar Cells. AB - We have demonstrated high-performance integrated perovskite/bulk-heterojunction (BHJ) solar cells due to the low carrier recombination velocity, high open circuit voltage (VOC), and increased light absorption ability in near-infrared (NIR) region of integrated devices. In particular, we find that the VOC of the integrated devices is dominated by (or pinned to) the perovskite cells, not the organic photovoltaic cells. A Quasi-Fermi Level Pinning Model was proposed to understand the working mechanism and the origin of the VOC of the integrated perovskite/BHJ solar cell, which following that of the perovskite solar cell and is much higher than that of the low bandgap polymer based organic BHJ solar cell. Evidence for the model was enhanced by examining the charge carrier behavior and photovoltaic behavior of the integrated devices under illumination of monochromatic light-emitting diodes at different characteristic wavelength. This finding shall pave an interesting possibility for integrated photovoltaic devices to harvest low energy photons in NIR region and further improve the current density without sacrificing VOC, thus providing new opportunities and significant implications for future industry applications of this kind of integrated solar cells. PMID- 28727459 TI - Synthesis and Structure of a Functionalized [9]Cycloparaphenylene Bearing Three Indeno[2,1-a]fluorene-11,12-dione-2,9-diyl Units. AB - A synthetic pathway to a functionalized [9]cycloparaphenylene bearing three indeno[2,1-a]fluorene-11,12-dione-2,9-diyl units in the macrocyclic ring structure ([3]CIFO) has been developed. The 1H and 13C NMR spectra show that only the anti rotamer (anti-[3]CIFO) is produced. DFT calculations indicate that the anti rotamer is thermodynamically more stable than the syn rotamer by 4.3 kcal/mol, and the rotational barrier from the anti to syn rotamer is estimated to be 23.3 kcal/mol. The UV-vis and fluorescence spectra and cyclic voltammogram of anti-[3]CIFO were investigated. PMID- 28727460 TI - 2D Organic Superlattice Promoted via Combined Action of pi-pi Stacking and Dipole Dipole Interaction in Discotic Liquid Crystals. AB - A series of discotic liquid crystals based on hexapentyloxytriphenylene (HAT5) have been investigated where one out of the six ether side chains of a triphenylene core was replaced by an ester side chain and named for 5a-5h. During the process of studying these compounds, the characteristic straight line defect of ordered columnar structure was identified by polarizing optical microscopy (POM) and liquid crystal state over a wide temperature range was obtained by differential scanning calorimetry (DSC). Basic phase structure and molecular arrangement were assigned by one-dimensional wide-angle X-ray diffraction (1D WAXD), small-angle X-ray scattering (SAXS), two-dimensional wide-angle X-ray diffraction (2D WAXD), and transmission electron microscope (TEM). Combined with sharp and regular dots in 2D WAXD patterns and characteristic peaks at small angle in SAXS pattern which indicated the existence of superlattice, we proved that 2D superlattice formed from self-assembly of discotic molecules with a polar group via pi-pi stacking and dipole-dipole interaction. In order to verify the effect of orientation on charge carrier mobility, their electron and hole mobilities were measured by time-of-flight (TOF) device, among which the charge carrier mobility could achieve almost twice as that of HAT5. The formation of superlattice no doubt improved their electronic properties and made them more attractive in organic electronics. PMID- 28727461 TI - Risk Indicators and Prevention of Implant Soft-Tissue Complications: Interproximal Papillae Loss and Midfacial Implant Mucosal Recessions. AB - Achieving a long-term esthetic implant restoration in the maxillary anterior area is sometimes unpredictable. This article reviews several risk indicators of implant mucosal recession and loss of interproximal papillae, and how to prevent these risks. Results obtained from the literature suggest that the following factors are strongly related to implant soft-tissue complications: buccally positioned implant placement, a thin gingival biotype, lack of an adequate amount of keratinized mucosa, implant placement after ridge augmentation procedures, an increased distance of tooth bone peak to the contact point, and an inadequate horizontal implant-tooth distance. Factors that have been shown to favor longterm stability and improve implant esthetic outcomes include implant placement in an ideal 3-dimensional position, use of platform-switching implant/abutment designs, and performing soft-tissue grafting. Careful assessment of the above factors and adoption of suggested guidelines are critical to executing successful implant placement with favorable esthetic outcomes while minimizing soft-tissue complications. PMID- 28727462 TI - Tridimensional Reconstruction of a Complex Iatrogenic Defect Using Orthodontic Forced Eruption and Minimally Invasive Bone Grafting. AB - As the use of dental implants has become more common, so has the frequency of complications and unforeseen outcomes. This article describes the treatment of a complex iatrogenic defect secondary to a failed implant (No. 7) and multiple bone grafting attempts in the maxillary anterior region. The patient's revealing smile line and high-risk circumstances demanded the use of an interdisciplinary treatment approach with high potential for predictable esthetic results. Forced eruption was performed to restore the alveolar height deficit and develop the compromised hard and soft tissues around teeth Nos. 6 and 8. The subperiosteal minimally invasive (a)esthetic ridge-augmentation technique (SMART) was subsequently used to provide horizontal bone augmentation while preserving the soft-tissue architecture. After bone-graft integration, immediate postextraction implants were placed at Nos. 6 and 8 using a flapless approach, and a screwretained long-term polymethylmethacrylate provisional prosthesis was delivered during the same appointment. The synergy of these combined therapies resulted in a complete tridimensional reconstruction of the defect. Gingival and alveolar volumes and gingival margin levels were successfully restored. PMID- 28727463 TI - Angled Implant Design to Accommodate Screw-retained Implant-supported Prostheses. AB - Anatomical constraints at implant sites often precipitate a conflict between surgical and prosthodontic prerequisites for screw retention of implantsupported prostheses. This article discusses use of a dual-axis implant designed to help clinicians overcome these challenges by facilitating accuracy of surgical placement and prosthetic simplicity, as well as improving biomechanics and enhancing esthetics. PMID- 28727464 TI - Cutting-Edge Implant Rehabilitation Design and Management: A Tapered Abutment Approach. AB - Soft-tissue recession around an implant rehabilitation over time has been considered a physiologic phenomenon. The divergent profile of the abutment and the abutment's dis/reconnections are the most critical predisposing and precipitating factors regarding such gingival recession. Recent publications have discussed how tapered and marginless abutments that allow no disconnections and increase soft-tissue thickness could prevent implant rehabilitations from experiencing gingival recession. The objective of this article is to demonstrate the biologic rationale of tissue behavior surrounding tapered abutments and their clinical application. PMID- 28727465 TI - Clinical Management of Type 3 Recession Defects With Immediate Implant and Provisional Restoration Therapy: A Case Report. AB - Type 3 extraction sockets present a unique challenge in that they possess gingival recession indicative of facial hard- and soft-tissue loss. When teeth present with prior disease requiring removal and implant replacement, the treatment strategy incorporates palatal implant positioning as well as proper restorative contour management to compensate for the recession defect, thereby allowing the gingival tissues to heal in the correct 3-dimensional position. This article describes the case of a patient with a nonrestorable maxillary right central incisor with internal resorption. The case demonstrates the use of immediate implant and provisional restoration therapy in type 3 (recession) clinical situations. PMID- 28727466 TI - Ceramic Veneers With Gingiva-Shaded Porcelain to Replace Lost Interdental Papillae: A Case Report. AB - With implant-supported reconstructions, gingiva-shaded pink-colored restorative materials serve as an option for replacing both hard and soft tissues cosmetically. This article presents a case report describing restorative treatment for a patient who requested individual crowns and veneers after she had had multiple surgical interventions to replace a failing implant tooth No. 9. In addition to replacement of the implant prosthesis, this case involved restorative papillae reconstruction that was performed to treat interdental recession that had occurred after the surgeries. A beveled slip-joint concept was used whereby the flat plane approximating porcelain surfaces would not be visible from the frontal perspective, resulting in an esthetic-appearing restoration. PMID- 28727467 TI - Digital Imaging and Prosthetic-Driven Implant Planning: Efficient, Accurate, and Reliable Treatment. PMID- 28727469 TI - Bilateral Maxillary Paramolars in an Adolescent. AB - Paramolars are relatively uncommon supernumerary molars. Limited cases of bilateral maxillary or mandibular paramolars have been reported. This case report describes bilateral maxillary premolars and their management in a 15-year-old girl, whose chief complaint was food lodgment in these regions. After a diagnosis of bilateral maxillary premolars was made and confirmed by orthopantomogram, both of the paramolars were extracted. PMID- 28727468 TI - Effect of Finishing Procedures on the Surface Roughness of Resin-modified Glass Ionomer Materials. AB - This study examined the influence of finishing procedures on the surface roughness of different formulations of resin-modified glass ionomers (RMGIs) available in capsules compared with standard resin composites (RCs). Disc samples of three RMGIs and two RCs were fabricated using a metal mold (5 mm x 1.5 mm). Samples were randomly divided into seven groups (N = 10) and subjected to finishing and polishing procedures using a combination of carbide or diamond burs, followed by either rubber points or aluminum-oxide discs. Three different regions of each sample were analyzed using a contact profilometer to determine the average roughness (Ra). The main surface roughness was calculated using a two way analysis of variance (ANOVA) and the Bonferroni correction for multiple comparisons. A dual-stage combination of a fine carbide bur followed by the use of the finest two grits of aluminum-oxide discs was found to produce the smoothest finished and polished surface. the smoothest surfaces were found to be on the two RCs and one of the RMGIs. PMID- 28727470 TI - All-on-4(r) Treatment Concept in a Severely Resorbed Jaw Using Narrow-Platform Implants: A Case Report. AB - Although many approaches to the restoration of edentulous maxillae and mandibles have been developed, these treatments can be costly and time-consuming, and involve extensive grafting of the edentulous ridges. The All-on-4(r) treatment concept has been shown to be a viable alternative, with limited grafting required, using at least four regular-platform implants to support an acrylic, screw-retained provisional prosthesis before the fabrication of a definitive prosthesis. This case presentation will discuss the use of narrow-platform (3.5 mm) implants to provide a patient with a screw-retained acrylic provisional on the day of implant placement. PMID- 28727471 TI - Cutting-Edge Implant Rehabilitation Design and Management: A Tapered Abutment Approach. AB - Immediate implant placement can pose challenges surgically and, ultimately, restoratively. Yet immediate placement has become the standard when adequate bone is present to achieve primary stability and site infection is minimal. To avoid prosthetic complications and ensure the implant is encased in bone after healing, proper planning must consider that implant placement does not necessarily need to follow the trajectory of the root socket. As discussed in this article, maxillary anterior sites have potential issues related to the "triangle of bone" that are not encountered in molar sites and demand different approaches to ensure treatment success. Additionally, this article addresses decision-making on molar sites in regard to implant diameter, as well as the rationale for platform switching. PMID- 28727472 TI - Relieving Dry Mouth: Varying Levels of pH Found in Bottled Water. AB - It is estimated that 30% of people older than 60 years suffer from hyposalivation or dry mouth. Drinking water frequently has been recommended as a safe, non pharmacologic way to combat hyposalivation. The saliva in patients with dry mouth is acidic. Beverages consumed daily may have an erosive potential on teeth. The pH and the mineral content of the beverage determine its erosive potential. An acidic beverage, therefore, may have harmful effects on mineralized tooth structures, causing erosion of enamel, dentin, and cementum. Because bottled water is both convenient and easily available, the authors tested the pH of eight common brands of bottled water. (One brand included two different bottle types, for a total of nine bottled waters tested.) To standardize the pH electrode, pH buffers of 4.7 and 10 were used. The pH was measured using the Denver Instruments basic pH meter. Six recordings were used for each brand and then averaged to report the pH. Two of the bottled water samples tested were below the critical level of 5.2 pH to 5.5 pH, the level at which erosion of enamel occurs. Six of the samples tested were below the critical pH of 6.8, at which erosion of root dentin occurs. The authors conclude that both patients and clinicians incorrectly presume bottled water to be innocuous. Clinicians should be cognizant of the erosive potential of different brands of bottled water to both educate patients and to recommend water with neutral or alkaline pH for patients with symptoms of dry mouth to prevent further deterioration and demineralization of tooth structure. PMID- 28727473 TI - Delay in initiation of treatment after diagnosis of pulmonary tuberculosis in primary health care setting: eight year cohort analysis from district Faridabad, Haryana, North India. AB - INTRODUCTION: Delay in initiation of tuberculosis (TB) treatment may have a tremendous impact on disease transmission, development of drug resistance, poor outcome and overall survival of TB patients. The delay can occur at various levels. Delay in initiation of treatment after diagnosis is mostly due to health system failure and has immense programmatic implications. It has not been studied extensively in the Indian setting. METHODS: The authors did a cohort analysis of all TB patients initiated on treatment from two primary health centres (PHCs) at Ballabgarh Health and Demographic Surveillance System between January 2007 and December 2014. Diagnosis and treatment of TB in the study area was done as per the protocol envisaged in the national program. Information related to demography, details of diagnosis and treatment of TB and outcome of treatment were extracted from the TB register. Delay in initiation of treatment after diagnosis was considered if the gap between diagnosis and treatment was greater than 7 days. Bivariate and multivariate analyses were done to find the association of various factors with delay in initiation of treatment after diagnosis. RESULTS: Out of 885 patients, 662 patients started treatment for pulmonary TB. Mean time interval between diagnosis and initiation of treatment was 8.95 days. Only 57.7% of pulmonary TB patients were started on treatment within 7 days of diagnosis, and an additional 24.5% were started on treatment 8 14 days after diagnosis. Patients on retreatment regimens and those residing in villages without a PHC were more likely to have delayed initiation of treatment (odds ratio (OR)=1.82 (1.3-2.7, p=0.001) and OR=1.62 (1.1-2.5, p=0.01) respectively). Delay in initiation of treatment was also associated with unfavourable treatment outcome such as default, failure or death. CONCLUSIONS: There is a need to have healthcare changes related to TB care to enable initiation of treatment as early as possible. Pretreatment counselling especially for retreatment patients is of utmost importance. PMID- 28727474 TI - A primer on exocrine pancreatic insufficiency, fat malabsorption, and fatty acid abnormalities. AB - Exocrine pancreatic insufficiency (EPI) is characterized by a deficiency of exocrine pancreatic enzymes, resulting in deficits in digestion of all macronutrients, with deficiencies in digestion of fats being the most clinically relevant. The leading cause of EPI is chronic pancreatitis. However, many other causes and conditions may be implicated, including cystic fibrosis, pancreatic duct obstruction, gastric and pancreatic surgery, diabetes mellitus and other conditions. Physical and biochemical causes of EPI include decreased production and secretion of lipase, increased lipase destruction, pancreatic duct obstruction, decreased lipase stimulation and degradation, as well as gastrointestinal motility disorders. EPI is largely diagnosed clinically, and is often identified by symptoms such as steatorrhea, weight loss, abdominal discomfort, and abdominal bloating. Lifestyle modifications (eg, smoking cessation, limiting or avoiding alcoholic drinks, and reducing dietary fat intake) and exogenous pancreatic enzyme supplements are commonly used to help restore normal digestion and absorption of dietary nutrients in patients with EPI. PMID- 28727475 TI - Guidance for supplemental enteral nutrition across patient populations. AB - Enteral nutrition is preferred over parenteral nutrition as a result of the greater safety of enteral nutrition therapy and comparative convenience. A wide variety of enteral nutrition products have been developed, including disease specific products to help manage the nutritional needs of patients with kidney failure, liver failure, lung disease, diabetes, and other conditions. An assessment of each patient's nutritional needs and digestive function should be conducted prior to initiation of enteral nutrition therapy. Other considerations in determining the appropriate route and method of enteral nutrition administration include the time and nursing involvement required for administration, potential complications of medication administration, and concerns related to pancreatic dysfunction in certain groups. Tailored guidelines and treatment considerations are reviewed in this manuscript the application of enteral nutrition in various patient populations. PMID- 28727476 TI - Options for addressing exocrine pancreatic insufficiency in patients receiving enteral nutrition supplementation. AB - Patients with exocrine pancreatic insufficiency (EPI) have suboptimal secretion of pancreatic digestive enzymes and experience a range of clinical symptoms related to the malabsorption of fat. In patients with EPI unable to meet their nutritional requirements, enteral nutrition (EN) support is used to augment nutritional status. In addition to protein and carbohydrate, EN formulas contain fats as a calorie source, as well as vitamins and minerals to help prevent nutritional deficiencies related to malabsorption. Semielemental enteral nutrition formulas are advantageous as they contain hydrolyzed protein, shorter chain carbohydrates, and may contain medium chain triglycerides as a fat source. However, severely pancreatic insufficient patients may be unable to absorb complex long-chain triglycerides provided by EN formulas due to insufficient pancreatic lipase; replacement pancreatic enzyme products are recommended for these patients. Currently, none of the FDA-approved pancreatic enzyme replacement therapy (PERT) products are indicated for use in patients receiving enteral nutrition and administration of enzymes by mixing into enteral nutrition formula is not supported by guidelines as this route is associated with risks. RELiZORB (immobilized lipase) is a novel in-line digestive cartridge that has been designed to address the unmet need for PERT in patients receiving enteral nutrition. RELiZORB efficacy and compatibility with a range of commercially available polymeric and semielemental formulas with varying nutrient, caloric content, and triglyceride chain lengths have been demonstrated. In most formulas, RELiZORB efficiently hydrolyzed greater than 90% of fats within the formula into absorbable fatty acids and monoglycerides. PMID- 28727478 TI - Alloimmune hemolysis due to major RhE incompatibility after unrelated cord blood transplantation. PMID- 28727477 TI - National survey describing and quantifying students with communication needs. AB - PURPOSE: Research literature has yet to quantify and describe how students with complex communication needs are supported in the classroom and how special educators are being prepared to offer support. This study sought out special educators to complete a survey about their students with complex communication needs. METHOD: Over 4,000 teachers representing 50 states reported on the communicative and behavioral characteristics of 15,643 students. Teachers described the training they have received and instructional approaches they used. RESULTS: The majority of students were reported to use speech as their primary communication mode. Over half of students utilizing alternative and augmentative communication (AAC) were reported to have non-proficient communication. Teacher training varied across respondents as well as the supports they used to support these students in the classroom. CONCLUSION: The majority of students with disabilities using AAC when communicating across the nation are not proficiently communicating. Implications and recommendations will be discussed. PMID- 28727479 TI - Extracellular chloride is required for efficient platelet aggregation. AB - Anion channels perform a diverse range of functions and have been implicated in ATP release, volume regulation, and phosphatidylserine exposure. Platelets have been shown to express several anion channels but their function is incompletely understood. Due to a paucity of specific pharmacological blockers, we investigated the effect of extracellular chloride substitution on platelet activation using aggregometry and flow cytometry. In the absence of extracellular chloride, we observed a modest reduction of the maximum aggregation response to thrombin or collagen-related peptide. However, the rate of aggregation was substantially reduced in a manner that was dependent on the extracellular chloride concentration and aggregation in the absence of chloride was noticeably biphasic, indicative of impaired secondary signaling. This was further investigated by targeting secondary agonists with aspirin and apyrase or by blockade of the ADP receptor P2Y12. Under these conditions, the rates of aggregation were comparable to those recorded in the absence of extracellular chloride. Finally, we assessed platelet granule release by flow cytometry and report a chloride-dependent element of alpha, but not dense, granule secretion. Taken together these data support a role for anion channels in the efficient induction of platelet activation, likely via enhancement of secondary signaling pathways. PMID- 28727480 TI - Pilot study of propranolol premedication to reduce FDG uptake in brown adipose tissue on PET scans of adolescent and young adult oncology patients. AB - OBJECTIVE: Physiologic uptake of 18F-fluorodeoxyglucose (FDG) in brown adipose tissue (adipose tissue) of cancer patients may confound interpretation of positron emission tomography (PET) scans. Uptake in adipose tissue occurs in up to half of pediatric oncology patients undergoing PET scans, and is especially common in adolescents. adipose tissue is innervated by the sympathetic nervous system, and beta blockers such as propranolol have shown efficacy in reducing adipose tissue uptake on PET scans done in older adult oncology patients. PARTICIPANTS: Because propranolol may cause hypoglycemia or other side effects in fasting patients, we prospectively assessed the safety of a single dose of 20 mg propranolol in adolescent and young adult oncology patients undergoing FDG-PET imaging. METHODS: Ten patients (median age 18 years, range 14-24) received propranolol premedication prior to FDG-PET. RESULTS: No adverse effects or clinically significant changes in serum glucose, heart rate, or blood pressure were observed. Five of the 10 patients had adipose tissue identified on previous PET scans. However, following propranolol administration only, one patient had persistent uptake in adipose tissue. CONCLUSIONS: Propranolol was convenient and safe in fasting adolescent and young adult oncology patients undergoing PET scans. Larger studies are warranted to better define the effectiveness of this approach. PMID- 28727481 TI - Leucocyte- and platelet-rich fibrin (L-PRF) as a regenerative medicine strategy for the treatment of refractory leg ulcers: a prospective cohort study. AB - Chronic wounds (VLU: venous leg ulcer, DFU: diabetic foot ulcer, PU: pressure ulcer, or complex wounds) affect a significant proportion of the population. Despite appropriate standard wound care, such ulcers unfortunately may remain open for months or even years. The use of leukocyte- and platelet-rich fibrin (L PRF) to cure skin ulcers is a simple and inexpensive method, widely used in some countries but unknown or neglected in most others. This auto-controlled prospective cohort study explored and quantified accurately for the first time the adjunctive benefits of topical applications of L-PRF in the management of such refractory ulcers in a diverse group of patients. Forty-four consecutive patients with VLUs (n = 28, 32 wounds: 17 <= 10 cm2 and 15 > 10 cm2), DPUs (n = 9, 10 wounds), PUs (n = 5), or complex wounds (n = 2), all refractory to standard treatment for >=3 months, received a weekly application of L-PRF membranes. L-PRF was prepared following the original L-PRF method developed more than 15 years ago (400g, 12 minutes) using the Intra-Spin L-PRF centrifuge/system and the XPression box kit (Intra-Lock, Boca Raton, FL, USA; the only CE/FDA cleared system for the preparation of L-PRF). Changes in wound area were recorded longitudinally via digital planimetry. Adverse events and pain levels were also registered. All wounds showed significant improvements after the L-PRF therapy. All VLUs <= 10 cm2, all DFUs, as well as the two complex wounds showed full closure within a 3 month period. All wounds of patients with VLUs > 10 cm2 who continued therapy (10 wounds) could be closed, whereas in the five patients who discontinued therapy improvement of wound size was observed. Two out of the five PUs were closed, with improvement in the remaining three patients who again interrupted therapy (surface evolution from 7.35 +/- 4.31 cm2 to 5.78 +/- 3.81 cm2). No adverse events were observed. A topical application of L-PRF on chronic ulcers, recalcitrant to standard wound care, promotes healing and wound closure in all patients following the treatment. This new therapy is simple, safe and inexpensive, and should be considered a relevant therapeutic option for all refractory skin ulcers. PMID- 28727482 TI - Atypical preference for infant-directed speech as an early marker of autism spectrum disorders? A literature review and directions for further research. AB - Autism spectrum disorders (ASD) refer to a complex group of neurodevelopmental disorders causing difficulties with communication and interpersonal relationships, as well as restricted and repetitive behaviours and interests. As early identification, diagnosis, and intervention provide better long-term outcomes, early markers of ASD have gained increased research attention. This review examines evidence that auditory processing enhanced by social interest, in particular auditory preference of speech directed towards infants and young children (i.e. infant-directed speech - IDS), may be an early marker of risk for ASD. Although this review provides evidence for IDS preference as, indeed, a potential early marker of ASD, the explanation for differences in IDS processing among children with ASD versus other children remains unclear, as are the implications of these impairments for later social-communicative development. Therefore, it is crucial to explore atypicalities in IDS processing early on development and to understand whether preferential listening to specific types of speech sounds in the first years of life may help to predict the impairments in social and language development. PMID- 28727483 TI - Pharmacological treatment of tardive dyskinesia: recent developments. AB - INTRODUCTION: Tardive dyskinesia (TD) occurs in patients receiving antipsychotic treatment with dopamine receptor antagonists. Despite the prevalence of TD and its negative impact on patients' lives, there has been a lack of approved treatments and limited evidence from controlled trials of pharmacological treatment. Areas covered: PubMed was searched for English-language papers published during 2007-2016 using terms 'tardive dyskinesia' or 'drug-induced movement disorder', and 'treatment'. Studies evaluating pharmacological agents for the treatment of TD were selected. A total of 26 studies (five meta-analyses, twelve randomized controlled trials, and nine open-label observational studies) are reviewed. Expert commentary: Treatment of TD necessitates a stepwise approach. Optimization of antipsychotic therapy should be considered before initiation of antidyskinetic therapies. Data from some recent studies indicate possible improvements in TD after switching antipsychotics or with the use of amantadine, levetiracetam, piracetam, zonisamide, propranolol, vitamin B6, or certain unregulated herbal medicines; although significance of these improvements is unclear and require further investigation in randomized controlled trials. By contrast, recent evidence from Phase III trials of novel vesicular monoamine transporter-2 inhibitors demonstrates they could have a significant effect on TD symptom severity and suggests these agents may have the potential to transform treatment of TD in coming years. PMID- 28727485 TI - The longitudinal relationship between acceptance and anxiety and depression in people who have had a stroke. AB - OBJECTIVES: The role that acceptance may play in anxiety and depression has received little attention in stroke, unlike other chronic conditions. This study aimed to clarify whether acceptance of a stroke is related to anxiety and depression post-stroke when controlling for social support. DESIGN: A longitudinal design was employed with 35 participants completing measures at two time points: three-month and nine-month post-stroke. METHODS: Forty-one stroke patients, who were three-month post-stroke, were recruited from a stroke service register. Participants completed measures of anxiety, depression, social support and acceptance at two time points, six months apart. RESULTS: Acceptance was moderately and negatively correlated with anxiety and depression at three- and nine-month post-stroke. Acceptance showed a moderate and positive correlation with emotional and practical social support at Time 1 but not at Time 2. Acceptance at Time 1 was a stronger predictor of both anxiety and depression at Time 2 than emotional or practical social support. CONCLUSIONS: Acceptance is an important area to consider in relation to rehabilitation and adjustment following a stroke. PMID- 28727486 TI - Association of Physician Orders for Life-Sustaining Treatment Form Use With End of-Life Care Quality Metrics in Patients With Cancer. AB - PURPOSE: Many patients with advanced cancer receive aggressive treatment near the end of life. The Physician Orders for Life-Sustaining Treatment (POLST) form is an innovation that converts patient preferences into medical orders. We compared the end-of-life care of patients with advanced cancer who had completed POLST forms with that of patients who had advance directives (ADs). METHODS: We studied 2,159 West Virginians with ADs and/or POLST forms in the West Virginia e Directive Registry who died as a result of cancer between January 2011 and February 2016. Data from the Vital Registration Office (date, site, and cause of death) were merged with those from the registry (form type, completion date, and hospice admission). The primary outcome variables were out-of-hospital death (OHD) and hospice admission. RESULTS: The percentage of patients with OHD was 85.7% for patients with POLST forms compared with 72.0% for those with ADs ( P < .001). The odds of OHD for patients with POLST forms were 2.33 times those of patients with ADs. The percentage of patients admitted to hospice was 49.9% for those with POLST forms compared with 27.0% for those with ADs ( P < .001). The odds of being admitted to hospice for patients with POLST forms were 2.69 times those of patients with ADs. CONCLUSION: Advance care planning with completion of POLST forms compared with ADs in patients with advanced cancer was associated with two quality end-of-life care metrics: OHD and hospice admission. Our study suggests that goals-of-care discussions including POLST form completion may improve end-of-life care for patients with advanced cancer. PMID- 28727484 TI - Construction and analysis of circular RNA molecular regulatory networks in liver cancer. AB - Liver cancer is the sixth most prevalent cancer, and the third most frequent cause of cancer-related deaths. Circular RNAs (circRNAs), a kind of special endogenous ncRNAs, have been coming back to the forefront of cancer genomics research. In this study, we used a systems biology approach to construct and analyze the circRNA molecular regulatory networks in the context of liver cancer. We detected a total of 127 differentially expressed circRNAs and 3,235 differentially expressed mRNAs. We selected the top-5 upregulated circRNAs to construct a circRNA-miRNA-mRNA network. We enriched the pathways and gene ontology items and determined their participation in cancer-related pathways such as p53 signaling pathway and pathways involved in angiogenesis and cell cycle. Quantitative real-time PCR was performed to verify the top-five circRNAs. ROC analysis showed circZFR, circFUT8, circIPO11 could significantly distinguish the cancer samples, with an AUC of 0.7069, 0.7575, and 0.7103, respectively. Our results suggest the circRNA-miRNA-mRNA network may help us further understand the molecular mechanisms of tumor progression in liver cancer, and reveal novel biomarkers and therapeutic targets. PMID- 28727488 TI - Microsatellites mapping for non-model species with chromosomal rearrangement: a case study in the frog Quasipaa boulengeri (Anura: Dicroglossidae). AB - Gene mapping is an important resource for understanding the evolution of genes and cytogenetics. Model species with a known genetic map or genome sequence allow for the selection of genetic markers on a desired chromosome, while it is hard to locate these markers on chromosomes of non-model species without such references. A frog species, Quasipaa boulengeri, shows chromosomal rearrangement polymorphisms, making itself a fascinating model for chromosomal speciation mediated by suppressed recombination. However, no markers have been located on its rearranged chromosomes. We present a complete protocol to map microsatellites based on mechanical microdissection and chromosome amplification techniques. Following this protocol, we mapped 71 microsatellites of Q. boulengeri at the chromosome level. In total, eight loci were assigned to rearranged chromosomes, and the other 63 loci might attach to other chromosomes. These microsatellites could be used to compare the gene flow and verify the chromosomal suppressed recombination hypothesis in Q. boulengeri. This integrated protocol could be effectively used to map genes to chromosomes for non-model species. PMID- 28727487 TI - Improving Care With a Portfolio of Physician-Led Cancer Quality Measures at an Academic Center. AB - PURPOSE: Development and implementation of robust reporting processes to systematically provide quality data to care teams in a timely manner is challenging. National cancer quality measures are useful, but the manual data collection required is resource intensive, and reporting is delayed. We designed a largely automated measurement system with our multidisciplinary cancer care programs (CCPs) to identify, measure, and improve quality metrics that were meaningful to the care teams and their patients. METHODS: Each CCP physician leader collaborated with the cancer quality team to identify metrics, abiding by established guiding principles. Financial incentive was provided to the CCPs if performance at the end of the study period met predetermined targets. Reports were developed and provided to the CCP physician leaders on a monthly or quarterly basis, for dissemination to their CCP teams. RESULTS: A total of 15 distinct quality measures were collected in depth for the first time at this cancer center. Metrics spanned the patient care continuum, from diagnosis through end of life or survivorship care. All metrics improved over the study period, met their targets, and earned a financial incentive for their CCP. CONCLUSION: Our quality program had three essential elements that led to its success: (1) engaging physicians in choosing the quality measures and prespecifying goals, (2) using automated extraction methods for rapid and timely feedback on improvement and progress toward achieving goals, and (3) offering a financial team-based incentive if prespecified goals were met. PMID- 28727489 TI - Third person singular -s in typical development and specific language impairment: Input and neighbourhood density. AB - The purpose of this study was to examine factors promoting the use of third person singular -s by 23 children with specific language impairment (SLI) and 21 children with typical development (TD). Relative proportions of third person singular -s forms in the input (input proportion) were calculated for 25 verbs based on data from an American English corpus of child-directed speech. Neighbourhood density values were also collected for these verbs. With previously collected probes of third person singular -s use for each of these verbs, we found with logistic regression that input proportion was positively associated with the likelihood of third person singular -s use for both groups. For neighbourhood density, we found that children with SLI were more likely to inflect sparse verbs than dense verbs; density was not significantly related to inflection use for TD children. We argue that as a result of their verbs' poorly encoded phonological representations, children with SLI were less able to inflect dense verbs than sparse verbs. We recommend that clinicians be aware of the effects of input proportion and neighbourhood density to ensure that assessments are representative and that treatment success is optimal. PMID- 28727490 TI - Comparison of the release of microRNAs and extracellular vesicles from platelets in response to different agonists. AB - On activation platelets release microRNAs and extracellular vesicles (EV) into circulation. The release of EV from platelets has been shown to be dependent on the agonist; in this study, we investigated whether the microRNA profile or EV released from platelets was also agonist specific. Washed platelets from healthy subjects were maximally stimulated with agonists specific for the receptors for collagen (Glycoprotein VI (GPVI)), thrombin (PAR1/PAR4), or ADP (P2Y1/P2Y12) with/without inhibiting secondary mediators, using aspirin to block cyclooxygenase-1 and apyrase to remove ADP. The released microRNAs were profiled using TaqMan microRNA microarray cards. Platelet-derived EV (pdEV) were characterized by size (Nanoparticle Tracking Analysis, NTA), for procoagulant activity (Annexin-V binding and support of thrombin generation), and for the EV markers CD63 and HSP70. Platelet activation triggered the release of 57-79 different microRNAs, dependent upon agonist, with a core of 46 microRNAs observed with all agonists. There was a high level of correlation between agonists (r2 > 0.98; p < 0.0001 for all), and with the microRNA content of the parent platelets (r2 > 0.98; p < 0.0001). The 46 microRNAs seen in all samples are predicted to have significant effects on the translation of proteins involved in endocytosis, cell cycle control, and differentiation. MiR-223-3p was the most abundant in all samples and has previously been implicated in myeloid lineage development and demonstrated to have anti-inflammatory effects. Stimulation through GPVI produced a pdEV population with significantly more procoagulant activity than the other agonists. Apyrase significantly reduced microRNA and pdEV release, while aspirin had little effect. These data suggest that all tested agonists trigger the release of a similar microRNA profile while the procoagulant activity of the pdEV was agonist dependent. ADP was shown to play an important role in the release of both microRNAs and pdEV. PMID- 28727491 TI - Impact of Point-of-Care Xpert MTB/RIF on Tuberculosis Treatment Initiation. A Cluster-randomized Trial. AB - RATIONALE: Point-of-care (POC) diagnostics have the potential to reduce pretreatment loss to follow-up and delays to initiation of appropriate tuberculosis (TB) treatment. OBJECTIVES: To evaluate the effect of a POC diagnostic strategy on initiation of appropriate TB treatment. METHODS: We conducted a cluster-randomized trial of adults with cough who were HIV positive and/or at high risk of drug-resistant TB. Two-week time blocks were randomized to two strategies: (1) Xpert MTB/RIF test (Cepheid, Sunnyvale, CA) performed at a district hospital laboratory or (2) POC Xpert MTB/RIF test performed at a primary health care clinic. All participants provided two sputum specimens: one for the Xpert test and the other for culture as a reference standard. The primary outcome was the proportion of participants with culture-positive pulmonary tuberculosis (PTB) initiated on appropriate TB treatment within 30 days. MEASUREMENTS AND MAIN RESULTS: Between August 22, 2011, and March 1, 2013, 36 two-week blocks were randomized, and 1,297 individuals were enrolled (646 in the laboratory arm, 651 in the POC arm), 159 (12.4%) of whom had culture-positive PTB. The proportions of participants with culture-positive PTB initiated on appropriate TB treatment within 30 days were 76.5% in the laboratory arm and 79.5% in the POC arm (odds ratio, 1.13; 95% confidence interval, 0.51-2.53; P = 0.76; risk difference, 3.1%; 95% confidence interval, -16.2 to 10.1). The median time to initiation of appropriate treatment was 7 days (laboratory) versus 1 day (POC). CONCLUSIONS: POC positioning of the Xpert test led to more rapid initiation of appropriate TB treatment. Achieving one-stop diagnosis and treatment for all people with TB will require simpler, more sensitive diagnostics and broader strengthening of health systems. Clinical trial registered with www.isrctn.com (ISRCTN 18642314) and www.sanctr.gov.za (DOH-27-0711-3568). PMID- 28727493 TI - Sibilant production in Hebrew-speaking adults: Apical versus laminal. AB - The Hebrew IPA charts describe the sibilants /s, z/ as 'alveolar fricatives', where the place of articulation on the palate is the alveolar ridge. The point of constriction on the tongue is not defined - apical (tip) or laminal (blade). Usually, speech and language pathologists (SLPs) use the apical placement in Hebrew articulation therapy. Some researchers and SLPs suggested that acceptable /s, z/ could be also produced with the laminal placement (i.e. the tip of the tongue approximating the lower incisors). The present study focused at the clinical level, attempting to determine the prevalence of these alternative points of constriction on the tongue for /s/ and /z/ in three different samples of Hebrew-speaking young adults (total n = 242), with typical articulation. Around 60% of the participants reported using the laminal position, regardless of several speaker-related variables (e.g. tongue-thrust swallowing, gender). Laminal production was more common in /s/ (than /z/), coda (than onset) position of the sibilant, mono- (than di-) syllabic words, and with non-alveolar (than alveolar) adjacent consonants. Experiment 3 revealed no acoustical differences between apical and laminal productions of /s/ and of /z/. From a clinical perspective, we wish to raise the awareness of SLPs to the prevalence of the two placements when treating Hebrew speakers, noting that tongue placements were highly correlated across sibilants. Finally, we recommend adopting a client centred practice, where tongue placement is matched to the client. We further recommend selecting targets for intervention based on our findings, and separating between different prosodic positions in treatment. PMID- 28727492 TI - Chronic psychological stress seems associated with elements of the metabolic syndrome in patients with ischaemic heart disease. AB - BACKGROUND AND OBJECTIVES: Chronic psychological stress, the metabolic syndrome (MS) and ischaemic heart disease (IHD) seem closely connected. In this study, we evaluate the association between chronic stress and elements of MS in patients with stable IHD. DESIGN: Cross-sectional cohort study. METHODS: Three hundred and fifty patients with stable IHD were included. Chronic stress was evaluated by the two questionnaires, Major Depression Inventory (MDI) and the psychological wellbeing index WHO-5, as well as by Pressure Pain Sensitivity (PPS), a physiological measure of hyperalgesia at the sternum known to be associated to elements of the chronic stress syndrome. Elements of MS were evaluated by dual energy X-ray absorptiometry, body weight, HOMA-IR and blood lipids. RESULTS: Depressive symptoms were associated with a high percentage of body fat (beta = 0.179, p = .001), and high level of triglycerides (beta = 0.150, p = .007). Low psychological wellbeing was associated with a high percentage of body fat (beta = -0.165, p = .002) and low level of HDL cholesterol (beta = 0.128, p = .024). Chronic stress measured by PPS was associated with a high percentage body fat (beta = 0.327, p < .001), low body weight (beta = -0.218, p < .001) and low HDL cholesterol (beta = -0.137, p = .013). Adjusting for several life style factors did not change these results. CONCLUSIONS: In patients with stable IHD, different measures of chronic psychological stress seem associated with a high percentage of body fat and adverse blood lipids independent of several lifestyle factors. PMID- 28727495 TI - Localization of PP2A-B56 to centromeres in Drosophila. PMID- 28727494 TI - Efficacy of standard prophylaxis versus on-demand treatment with bayer's sucrose formulated recombinant FVIII (rFVIII-FS) in Chinese children with severe hemophilia A. AB - In China, care of patients with severe hemophilia primarily involves insufficient dosing of on-demand treatment and secondary low-dose prophylaxis (10 IU/kg 2* /wk). We sought to evaluate 3* /wk, standard-dose prophylaxis with sucrose formulated recombinant factor VIII (rFVIII-FS; Bayer) compared with on-demand treatment in Chinese children with severe hemophilia A. Children and adolescents aged 2-16 years with severe hemophilia A, no inhibitors, and no prophylaxis for >6 consecutive months before study entry were eligible for this 24-week, interventional, sequential-treatment study. Patients received rFVIII-FS on demand for 12 weeks followed by a 12-week prophylaxis period (25 IU/kg 3* /wk). The primary efficacy endpoint was comparison of the annualized bleeding rate (ABR) of all bleeds in the prophylaxis versus on-demand phase. Additional variables included ABR of joint bleeds, school attendance/activity, daily activity, and hemophilia Joint Health Score (HJHS). Thirty patients (median age, 12 years) were treated and analyzed. Compared with on-demand treatment, prophylaxis reduced median (quartile [Q1; Q3]) ABR of all bleeds (57.5 [44.5; 73.9] vs 0 [0; 4.0]) and joint bleeds (34.5 [26.1; 56.5] vs 0 [0; 4.0]). Median (range) total HJHS improved after both the prophylaxis and on-demand phases (8.0 [0-48.0] and 11.0 [0-55.0], respectively) compared with baseline (16.0 [0-56.0]). School attendance/activity and daily activity improved with prophylaxis versus on demand. No inhibitors or treatment-related adverse events were reported. In this first prospective, standard-dose, secondary prophylaxis study in China, rFVIII-FS prophylaxis reduced bleeding and improved health outcomes versus on-demand treatment in children with severe hemophilia A. PMID- 28727496 TI - Modulation of VEGF-induced migration and network formation by lymphatic endothelial cells: Roles of platelets and podoplanin. AB - Lymphatic endothelial cells (LEC) express the transmembrane receptor podoplanin whose only known endogenous ligand CLEC-2 is found on platelets. Both podoplanin and CLEC-2 are required for normal lymphangiogenesis as mice lacking either protein develop a blood-lymphatic mixing phenotype. We investigated the roles of podoplanin and its interaction with platelets in migration and tube formation by LEC. Addition of platelets or antibody-mediated crosslinking of podoplanin inhibited LEC migration induced by vascular endothelial growth factors (VEGF-A or VEGF-C), but did not modify basal migration or the response to basic fibroblast growth factor or epidermal growth factor. In addition, platelets and podoplanin crosslinking disrupted networks of LEC formed in co-culture with fibroblasts. Depletion of podoplanin in LEC using siRNA negated the pro-migratory effect of VEGF-A and VEGF-C. Inhibition of RhoA or Rho-kinase reduced LEC migration induced by VEGF-C, but had no further effect after crosslinking of podoplanin, suggesting that podoplanin is required for signaling downstream of VEGF-receptors but upstream of RhoA. Together, these data reveal for the first time that podoplanin is an intrinsic specific regulator of VEGF-mediated migration and network formation in LEC and identify crosslinking of podoplanin by platelets or antibodies as mechanisms to modulate this pathway. PMID- 28727497 TI - Rhythmic radiotherapy beats down TGF-beta. PMID- 28727499 TI - Delta133p53: A p53 isoform enriched in human pluripotent stem cells. PMID- 28727498 TI - New perspectives regarding the antiviral effect of vitamin A on norovirus using modulation of gut microbiota. AB - Gut microbiota has been revealed to play an important role in various health conditions, and recent studies have suggested the modulation of gut microbiota as a therapeutic strategy. There is no effective treatment of norovirus infection, though vitamin A has been suggested to have an antiviral effect in an epidemiological study. We demonstrated that vitamin A significantly inhibited murine norovirus replication. Vitamin A supplementation significantly increased the abundance of Lactobacillus sp. during norovirus infection, which played a crucial role in antiviral efficacy, inhibiting murine norovirus. Therefore, we elaborated the antiviral effect of vitamin A via modulation of gut microbiota. Furthermore, we suggest a novel strategy, using potential probiotics, as having a protective and therapeutic effect on noroviral infection. PMID- 28727500 TI - Risk Stratification of Adnexal Cysts and Cystic Masses: Clinical Performance of Society of Radiologists in Ultrasound Guidelines. AB - Purpose To evaluate the performance of the 2010 Society of Radiologists in Ultrasound (SRU) consensus guidelines in the risk stratification of symptomatic and asymptomatic adnexal cysts. Materials and Methods An institutional review board-approved retrospective review was performed, including adnexal cysts detected with ultrasonography (US) with surgical diagnosis or at least 2 years of imaging or clinical follow-up, from January to June 2011. SRU management recommendations were scored as 0, no follow-up; 1, US follow-up; 2, magnetic resonance (MR) imaging follow-up; and 3, surgical evaluation. Distribution of outcomes (nonneoplastic cyst, benign neoplasm, malignant neoplasm) was compared in each rating group by using the Cochran-Armitage trend test. Where SRU guidelines allow more than one management option, they were classified as being interpreted in either a "surgically focused" environment, with limited MR imaging availability, or an "MR-capable" center, where MR imaging is selected whenever it is an option. Predictors of neoplasms and malignancy were evaluated by using multivariate logistic regression. Results A total of 570 cysts in 500 women aged 18-90 years (mean, 42 years) were included. There were 475 (83.3%) nonneoplastic cysts, 77 (13.5%) benign neoplasms, and 18 (3.2%) malignant neoplasms. Of the 500 women, 161 (32.2%) were asymptomatic. In the surgically focused interpretation of guidelines, proportions of any neoplasm and malignant neoplasm, respectively, were 1% and 0% in SRU 0, 17% and 1% in SRU 1, 48% and 0% in SRU 2, and 48% and 16% in SRU 3 (P < .0001 for both trends). In the interpretation of SRU guidelines with MR imaging when it was an option, proportions of any neoplasm and malignant neoplasm, respectively, were 1% and 0% in SRU 0, 17% and 1% in SRU 1, 38% and 5% in SRU 2, and 81% and 52% in SRU 3 (P < .0001, both trends) and 82 (89.1%) fewer benign cysts would have gone directly to surgical evaluation. In multivariate regression, SRU rating predicted both any neoplasm (odds ratio, 2.58; P < .0001) and malignant neoplasm (odds ratio, 4.94; P = .005). Conclusion SRU consensus guidelines effectively stratified the risk of neoplasia and malignancy. Selecting MR imaging when it is an option in the guidelines would have reduced the number of benign cysts sent for surgical evaluation. (c) RSNA, 2017. PMID- 28727502 TI - Triage in psychiatric emergency services in Copenhagen: results from a descriptive 1-year evaluation study. AB - Inspired by the Australasian triage system, a regional psychiatric triage system was introduced in the psychiatric emergency units (PEUs) in Copenhagen in 2011. Our aim of the study is to determine the characteristics of the patient according to the defined triage criteria and check if this is in accordance with recommendations. A random 10% data sample was obtained throughout 2012 in three PEUs of Copenhagen. Triage category, demographic, social and clinically relevant variables were collected. A total of 929 contacts were registered. We found significant associations between triage category and several clinical parameters. Time of visit was correlated to diagnoses. The results indicate that use of the new triage system in emergency psychiatry has facilitated urgency categorization, reduced waiting time, and optimized clinical decisions. These goals are important clinical implications of the service in PEUs. The need for PEUs out-of-daytime (when all Community Mental Health Centers are closed) has also been demonstrated. PMID- 28727501 TI - Validation of the Dominant Sequence Paradigm and Role of Dynamic Contrast enhanced Imaging in PI-RADS Version 2. AB - Purpose To validate the dominant pulse sequence paradigm and limited role of dynamic contrast material-enhanced magnetic resonance (MR) imaging in the Prostate Imaging Reporting and Data System (PI-RADS) version 2 for prostate multiparametric MR imaging by using data from a multireader study. Materials and Methods This HIPAA-compliant retrospective interpretation of prospectively acquired data was approved by the local ethics committee. Patients were treatment naive with endorectal coil 3-T multiparametric MR imaging. A total of 163 patients were evaluated, 110 with prostatectomy after multiparametric MR imaging and 53 with negative multiparametric MR imaging and systematic biopsy findings. Nine radiologists participated in this study and interpreted images in 58 patients, on average (range, 56-60 patients). Lesions were detected with PI-RADS version 2 and were compared with whole-mount prostatectomy findings. Probability of cancer detection for overall, T2-weighted, and diffusion-weighted (DW) imaging PI-RADS scores was calculated in the peripheral zone (PZ) and transition zone (TZ) by using generalized estimating equations. To determine dominant pulse sequence and benefit of dynamic contrast-enhanced (DCE) imaging, odds ratios (ORs) were calculated as the ratio of odds of cancer of two consecutive scores by logistic regression. Results A total of 654 lesions (420 in the PZ) were detected. The probability of cancer detection for PI-RADS category 2, 3, 4, and 5 lesions was 15.7%, 33.1%, 70.5%, and 90.7%, respectively. DW imaging outperformed T2-weighted imaging in the PZ (OR, 3.49 vs 2.45; P = .008). T2-weighted imaging performed better but did not clearly outperform DW imaging in the TZ (OR, 4.79 vs 3.77; P = .494). Lesions classified as PI-RADS category 3 at DW MR imaging and as positive at DCE imaging in the PZ showed a higher probability of cancer detection than did DCE-negative PI-RADS category 3 lesions (67.8% vs 40.0%, P = .02). The addition of DCE imaging to DW imaging in the PZ was beneficial (OR, 2.0; P = .027), with an increase in the probability of cancer detection of 15.7%, 16.0%, and 9.2% for PI-RADS category 2, 3, and 4 lesions, respectively. Conclusion DW imaging outperforms T2-weighted imaging in the PZ; T2-weighted imaging did not show a significant difference when compared with DW imaging in the TZ by PI-RADS version 2 criteria. The addition of DCE imaging to DW imaging scores in the PZ yields meaningful improvements in probability of cancer detection. (c) RSNA, 2017 An earlier incorrect version of this article appeared online. This article was corrected on July 27, 2017. Online supplemental material is available for this article. PMID- 28727503 TI - First Freshwater Bothriocephalidean (Cestoda) from Tropical South America, Closely Related to African Taxa. AB - Regobothrium microhamulinum n. gen. and n. sp. (Bothriocephalidea: Bothriocephalidae) is proposed to accommodate a new cestode from flatfish Catathyridium jenynsii (Chabanaud, 1922) (Pleuronectiformes: Acharidae; type host) and another 3 freshwater fishes of the orders Characiformes, Cyprinodontiformes, and Siluriformes in the Neotropical Region. The new genus is placed in the Bothriocephalidae because it possesses medioventral uterine and mediodorsal genital pores and a follicular vitellarium. Regobothrium n. gen. is characterized by possessing a tiny, slightly subovate scolex narrower than the strobila, with an apical disc armed with 2 semicircles of 15-17 tiny hooks in each and an acraspedote strobila. Regobothrium n. gen. differs from all bothriocephalid cestodes that have a scolex armed with hooks by their small size (maximum length less than 20 MUm) and a triangular shape with the basal part (handle or basal plate) shorter than the distal coniform part (blade). In the other hooked bothriocephalids, hooks have a longer handle than a blade. Regobothrium microhamulinum n. gen. and n. sp. is the third bothriocephalidean cestode described from freshwater teleosts in South America but the first out of Patagonia. Molecular phylogenetics consider Regobothrium as a member of a lineage consisting of (up to now exclusively) freshwater bothriocephalids from the Ethiopian biogeographic region, thus indicating Gondwanan relationship. PMID- 28727504 TI - Lessons to be learned from early psychedelic therapy in Denmark. PMID- 28727505 TI - Opportunities and Benefits for Powerchair Users Through Power Soccer. AB - Power soccer (or powerchair football), the first competitive team sport for users of motorized wheelchairs, is receiving increased attention among people with disabilities, healthcare professionals, and academics. The present study provides a qualitative analysis of the experiences of 34 American power soccer athletes. Participant observation and in-depth interviews with 11 female and 23 male athletes were conducted between 2007 and 2013. Results indicate that involvement in power soccer provides participants with an increased sense of empowerment, acquisition of social capital, and psychosocial benefits, including a deep satisfaction of the desire to participate in competitive sports and an opportunity to be independent. Implications of these findings for improving the quality of life of people with physical disabilities and for future research are discussed. PMID- 28727506 TI - Nutritional Habits and Performance in Male Elite Wheelchair Basketball Players During a Precompetitive Period. AB - Physical condition and an optimized diet are relevant to enhance performance and recovery. The diet composition and meal frequency of eleven elite wheelchair basketball players were estimated using a 3-day food-weighing diary in two months during the precompetitive-period. Performance was determined through a 20 m sprint test. The players consumed 4.2 +/- 0.8 meals/day in May and 4.5 +/- 0.9 meals/day in June, resulting in total energy intakes of 2492 +/- 362 kcal/d and 2470 +/- 497 kcal/d, respectively. The macronutrient distribution was 3.8 +/- 1.3 g/kg carbohydrates, 1.7 +/- 0.6 g/kg protein, and 36 +/- 5% of energy derived from fat in May, and 4.2 +/- 1.9 g/kg carbohydrates, 1.5 +/- 0.5 g/kg protein and 32 +/- 5% of energy derived from fat in June. The maximum velocity of the sprint test improved from 4.77 +/- 0.31 m/s in May to 5.19 +/- 0.23 m/s in June. Our results revealed carbohydrate intake below and fat intake above recommendations, but improvements of dietary patterns. Further nutritional advice is necessary to ensure health and performance improvements. PMID- 28727508 TI - Collective Stories of Exercise: Making Sense of Gym Experiences With Disabled Peers. AB - Using a dialogical narrative approach, we explored how disabled people made sense of their gym experiences as part of a peer group. Interviews were conducted with 18 disabled people (10 men and 8 women, aged 23-60) who had experience exercising in the gym as part of a group. Data were rigorously analyzed using a dialogical narrative analysis. Within their peer group, participants crafted a collective story that they used to resist disablism in the gym. The dialogical components of the collective story functioned to (a) validate participants' experiences of oppression in the gym, (b) forge an unspoken understanding with peers, (c) craft a more affirmative identity, and (d) instill a sense of empowerment in participants so that they can tell their own story. This study extends knowledge in the field of exercise and disability by showing that despite the oppression disabled people experienced in the gym, they can create a collective story, which is useful for helping to promote and sustain exercise in this space. PMID- 28727509 TI - Music and On-task Behaviors in Preschool Children With Autism Spectrum Disorder. AB - The purpose of our study was to determine the effect of music (music with lyrics versus music with lyrics plus instruction) relative to on-task behaviors in preschool children with autism spectrum disorder (ASD) in a gross motor setting. Five preschool children (4 boys, 1 girl) diagnosed with ASD served as participants. A multiple baseline across participants in conjunction with an alternating-treatment design was used. For all participants, music with lyrics plus instruction increased on-task behaviors to a greater extent than did music with lyrics. The results of our study provide a better understanding of the role of music with regard to the behaviors of young children with ASD. PMID- 28727510 TI - Inclusion of Children With Disabilities in Physical Education: A Systematic Review of Literature From 2009 to 2015. AB - This systematic review examines research published from 2009 to 2015 on inclusion of children with disabilities in physical education according to the PRISMA guidelines. We have used a stakeholder approach as a framework for organizing and discussing the results. The searches yielded 535 studies, of which 112 were included. The systematic review outlines which stakeholder perspectives received the most attention, the main themes and findings, the methodological trends that governed the research contribution, and the country of data collection. The main findings indicated that perspectives of pre- and in-service teachers and studies of attitudes still dominate the research contributions. The strengths and limitations of the research conducted to date highlight that several other perspectives need to be discussed. Especially important is seeking information from children with disabilities themselves. Other barriers and facilitators perceived by those actively involved in the inclusion process need to be sought. PMID- 28727511 TI - Guest Editorial: How APAQ Was Born. PMID- 28727512 TI - Digest. PMID- 28727513 TI - Adapted Tango for Adults With Parkinson's Disease: A Qualitative Study. AB - The purpose of this qualitative study was to explore the experiences of 16 individuals with Parkinson's disease (PD) partaking in an adapted tango class and the perceived impact on participation and quality of life (QOL). The Ecology of Human Performance and the International Classification of Function were the theoretical frameworks for the study. Data collection involved focus groups conducted during the intervention and at a follow-up six months later. Data analysis followed inductive thematic analysis techniques. The themes addressed living with PD, the class structure and experiences, the participants' expectations for the class, and the multiple effects experienced by participants at both time periods. The results suggest that adapted tango, when offered in a structured environment with skilled instruction, may improve skills for participation in daily activities and contribute to increased QOL for persons with PD. PMID- 28727514 TI - Similarity in romantic couples' drinking motivations and drinking behaviors. AB - BACKGROUND: Research suggests that enhancement, conformity, social, coping-with anxiety, and coping-with-depression drinking motives are linked to specific drinking outcomes in a theoretically expected manner. Social learning theory suggests that people who spend more time together emulate each other's behavior to acquire reinforcing outcomes. The present study sought to integrate drinking motives theory and social learning theory to investigate similarity in drinking behaviors and drinking motives in romantic couples. We hypothesized that couples would be more similar than chance in their drinking behaviors and motives. We also hypothesized that demographics reflecting time around and interactions with romantic partners (e.g., days spent drinking together) would positively correlate with similarity in drinking behaviors and motivations. METHODS: The present study tested hypotheses in 203 romantic couples. Participants completed a Timeline Follow-Back measure and the Modified Drinking Motives Questionnaire-Revised to track their alcohol use and drinking motives. Similarity profiles were calculated using McCrae's (J Pers Assess. 2008;90:105-109) coefficient of profile agreement, rpa. RESULTS: Couples were more similar in their drinking behavioral and motivational profiles than could be explained by chance. Days spent drinking together and days with face-to-face contact predicted increased similarity in drinking behavior profiles, but not similarity in drinking motives profiles. CONCLUSIONS: Results are partially consistent with social learning theory and suggest that social influences within couples could be important intervention targets to prevent escalations in drinking. PMID- 28727516 TI - Serological Survey for West Nile Virus in Wild Artiodactyls, Southern Moravia (Czech Republic). AB - Antibodies to West Nile virus (WNV) were examined by plaque-reduction neutralization test in the blood sera of 1023 wild artiodactyls: 105 roe deer (Capreolus capreolus), 148 red deer (Cervus elaphus), 287 fallow deer (Dama dama), 71 mouflons (Ovis musimon), and 412 wild boars (Sus scrofa), sampled in South Moravian district of Breclav (Czech Republic) in the years 1990-2008. Neutralizing antibodies were detected in 5.9% of wild ruminants (4.8% roe deer, 4.1% red deer, 6.3% fallow deer, 9.9% mouflons) and 4.1% of wild boars, with titers ranging between 1:20 and 1:320. The results indicate that WNV has circulated in wild artiodactyls at a variable frequency during the years in the area. PMID- 28727515 TI - Brave New Worlds: The Expanding Universe of Lyme Disease. AB - Projections around the globe suggest an increase in tick-vectored disease incidence and distribution, and the potential for emergence of novel tick-borne pathogens. Lyme disease is the most common reported tick-borne illness in the Unites States and is prevalent throughout much of central Europe. In recent years, the worldwide burden of Lyme disease has increased and extended into regions and countries where the disease was not previously reported. In this review, we discuss the trends for increasing Lyme disease, and examine the factors driving Lyme disease expansion, including the effect of climate change on the spread of vector Ixodid ticks and reservoir hosts; and the impacts of increased awareness on disease reporting and diagnosis. To understand the growing threat of Lyme disease, we need to study the interplay between vector, reservoir, and pathogen. In addition, we need to understand the contributions of climate conditions to changes in disease risk. PMID- 28727517 TI - Comparative Toxicity and Effectiveness of Trastuzumab-Based Chemotherapy Regimens in Older Women With Early-Stage Breast Cancer. AB - Purpose The combination of chemotherapy and trastuzumab is the standard of care for adjuvant treatment of human epidermal growth factor receptor 2-positive breast cancer. Two regimens have been widely adopted in the United States: doxorubicin, cyclophosphamide, paclitaxel, and trastuzumab (ACTH) and docetaxel, carboplatin, and trastuzumab (TCH). No head-to-head comparison of these regimens has been conducted in a clinical trial, and existing trial data have limited generalizability to older patients. Methods We used SEER-Medicare data from 2005 to 2013 to compare outcomes of ACTH versus TCH among patients age older than 65 years. Propensity score matching was used to balance cohort characteristics between treatment arms. Outcomes included toxicity-related hospitalization, survival, and trastuzumab completion. Data from 1,077 patients receiving ACTH or TCH were analyzed, and the propensity-matched subsample included 416 women. Results There was a significant shift toward TCH over time, with 88% of patients receiving ACTH in 2005 compared with 15% by 2011. Among propensity score-matched patients, we found no difference between regimens in health care use overall or for chemotherapy-related adverse events (ACTH, 34% v TCH, 36.5%; P = .46). Patients receiving TCH were significantly more likely to complete trastuzumab (89% v 77%; P = .001). There was no difference in 5-year breast cancer-specific survival (ACTH, 92% v TCH, 96%; hazard ratio, 2.08; 95% CI, 0.90 to 4.82) or overall survival. Conclusion Among a matched sample of older patients, ACTH compared with TCH was not associated with a higher rate of serious adverse events or hospitalizations, but it was associated with less completion of adjuvant trastuzumab. We did not detect a difference in 5-year survival outcomes for ACTH compared with TCH. In the context of limited evidence in older patients, selection between these two regimens on the basis of concerns about differential toxicity or efficacy may not be appropriate. PMID- 28727519 TI - Obesity and Overweight in American Indian and Alaska Native Children, 2006-2015. AB - OBJECTIVES: To estimate obesity and overweight prevalence in American Indian and Alaska Native (AI/AN) children across genders, ages, and geographic regions in the Indian Health Service active clinical population. METHODS: We obtained data from the Indian Health Service National Data Warehouse. At least 184 000 AI/AN children aged 2 to 19 years had body mass index data for each year studied, 2006 to 2015. We calculated body mass index percentiles with the 2000 Centers for Disease Control and Prevention growth charts. RESULTS: In 2015, the prevalence of overweight and obesity in AI/AN children aged 2 to 19 years was 18.5% and 29.7%, respectively. Boys had higher obesity prevalence than girls (31.5% vs 27.9%). Children aged 12 to 19 years had a higher prevalence of overweight and obesity than younger children. The AI/AN children in our study had a higher prevalence of obesity than US children overall in the National Health and Nutrition Examination Survey. Results for 2006 through 2014 were similar. CONCLUSIONS: The prevalence of overweight and obesity among AI/AN children in this population may have stabilized, while remaining higher than prevalence for US children overall. PMID- 28727520 TI - Undocumented Immigration, Drug Problems, and Driving Under the Influence in the United States, 1990-2014. AB - OBJECTIVES: To examine the influence of undocumented immigration in the United States on 4 different metrics of drug and alcohol problems: drug arrests, drug overdose fatalities, driving under the influence (DUI) arrests, and DUI deaths. METHODS: We combined newly developed state-level estimates of the undocumented population between 1990 and 2014 from the Center for Migration Studies with arrest data from the Federal Bureau of Investigation Uniform Crime Reports and fatality information from the Fatality Analysis Reporting System and the Centers for Disease Control and Prevention Underlying Cause of Death database. We used fixed-effects regression models to examine the longitudinal association between increased undocumented immigration and drug problems and drunk driving. RESULTS: Increased undocumented immigration was significantly associated with reductions in drug arrests, drug overdose deaths, and DUI arrests, net of other factors. There was no significant relationship between increased undocumented immigration and DUI deaths. CONCLUSIONS: This study provides evidence that undocumented immigration has not increased the prevalence of drug or alcohol problems, but may be associated with reductions in these public health concerns. PMID- 28727521 TI - Ethical Guidance for Disaster Response, Specifically Around Crisis Standards of Care: A Systematic Review. AB - BACKGROUND: Terrorism, disease outbreaks, and other natural disasters and mass casualty events have pushed health care and public health systems to identify and refine emergency preparedness protocols for disaster response. Ethical guidance, alongside legal and medical frameworks, are increasingly common components of disaster response plans. OBJECTIVES: To systematically review the prevalence and content of ethical guidance offered for disaster response, specifically around crisis standards of care (CSCs). SEARCH METHODS: We systematically indexed academic literature from PubMed, Google Scholar, and ISI Web of Science from 2012 to 2016. SELECTION CRITERIA: We searched for peer-reviewed articles that substantively engaged in discussion of ethical guidance for CSCs. DATA COLLECTION AND ANALYSIS: Researchers screened potential articles for identification and discussion of ethical issues in CSC planning. We categorized and cataloged ethical concepts and principles. MAIN RESULTS: Of 580 peer-reviewed articles mentioning ethics and CSCs or disaster planning, 38 (6%) met selection criteria. The systematic review of the CSC ethics literature since 2012 showed that authors were primarily focused on the ethical justifications for CSC (n = 20) as well as a need for ethics guidelines for implementing CSCs; the ethical justifications for triage (n = 19), both as to which criteria to use and the appropriate processes by which to employ triage; and international issues (n = 17). In addition to these areas of focus, the scholarly literature included discussion of a number of other ethical issues, including duty to care (n = 11), concepts of a duty to plan (n = 8), utilitarianism (n = 5), moral distress (n = 4), professional norms (n = 3), reciprocity (n = 2), allocation criteria (n = 4), equity (n = 4), research ethics (n = 2), duty to steward resources (n = 2), social utility and social worth (n = 2), and a number of others (n = 20). Although public health preparedness efforts have paid increasing attention to CSCs in recent years, CSC plans have rarely been implemented within the United States to date, although some components are common (e.g., triage is used in US emergency departments regularly). Conversely, countries outside the United States more commonly implement CSCs within a natural disaster or humanitarian crisis response, and may offer significant insight into ethics and disaster response for US-based practitioners. CONCLUSIONS: This systematic review identifies the most oft-used and -discussed ethical concepts and principles used in disaster planning around CSCs. Although discussion of more nuanced issues (e.g., health equity) are present, the majority of items substantively engaging in ethical discussion around disaster planning do so regarding triage and why ethics is needed in disaster response generally. Public health implications. A significant evolution in disaster planning has occurred within the past decade; ethical theories and frameworks have been put to work. For ethical guidance to be useful, it must be practical and implementable. Although high-level, abstract frameworks were once prevalent in disaster planning-especially in the early days of pandemic planning concerns about the ethically difficult concept of CSCs pervade scholarly articles. Ethical norms must be clearly stated and justified and practical guidelines ought to follow from them. Ethical frameworks should guide clinical protocols, but this requires that ethical analysis clarifies what strategies to use to honor ethical commitments and achieve ethical objectives. Such implementation issues must be considered well ahead of a disaster. As governments and health care systems plan for mass casualty events, ethical guidance that is theoretically sound and practically useful can-and should-form an important foundation from which to build practical guidance for responding to disasters with morally appropriate means. PMID- 28727523 TI - From Lead Exposure in Early Childhood to Adolescent Health: A Chicago Birth Cohort. AB - OBJECTIVES: To assess the relationships between childhood lead exposure and 3 domains of later adolescent health: mental, physical, and behavioral. METHODS: We followed a random sample of birth cohort members from the Project on Human Development in Chicago Neighborhoods, recruited in 1995 to 1997, to age 17 years and matched to childhood blood test results from the Department of Public Health. We used ordinary least squares regression, coarsened exact matching, and instrumental variables to assess the relationship between average blood lead levels in childhood and impulsivity, anxiety or depression, and body mass index in adolescence. All models adjusted for relevant individual, household, and neighborhood characteristics. RESULTS: After adjustment, a 1 microgram per deciliter increase in average childhood blood lead level significantly predicts 0.06 (95% confidence interval [CI] = 0.01, 0.12) and 0.09 (95% CI = 0.03, 0.16) SD increases and a 0.37 (95% CI = 0.11, 0.64) point increase in adolescent impulsivity, anxiety or depression, and body mass index, respectively, following ordinary least squares regression. Results following matching and instrumental variable strategies are very similar. CONCLUSIONS: Childhood lead exposure undermines adolescent well-being, with implications for the persistence of racial and class inequalities, considering structural patterns of initial exposure. PMID- 28727518 TI - Therapeutic and Prognostic Implications of BRAF V600E in Pediatric Low-Grade Gliomas. AB - Purpose BRAF V600E is a potentially highly targetable mutation detected in a subset of pediatric low-grade gliomas (PLGGs). Its biologic and clinical effect within this diverse group of tumors remains unknown. Patients and Methods A combined clinical and genetic institutional study of patients with PLGGs with long-term follow-up was performed (N = 510). Clinical and treatment data of patients with BRAF V600E mutated PLGG (n = 99) were compared with a large international independent cohort of patients with BRAF V600E mutated-PLGG (n = 180). Results BRAF V600E mutation was detected in 69 of 405 patients (17%) with PLGG across a broad spectrum of histologies and sites, including midline locations, which are not often routinely biopsied in clinical practice. Patients with BRAF V600E PLGG exhibited poor outcomes after chemotherapy and radiation therapies that resulted in a 10-year progression-free survival of 27% (95% CI, 12.1% to 41.9%) and 60.2% (95% CI, 53.3% to 67.1%) for BRAF V600E and wild-type PLGG, respectively ( P < .001). Additional multivariable clinical and molecular stratification revealed that the extent of resection and CDKN2A deletion contributed independently to poor outcome in BRAF V600E PLGG. A similar independent role for CDKN2A and resection on outcome were observed in the independent cohort. Quantitative imaging analysis revealed progressive disease and a lack of response to conventional chemotherapy in most patients with BRAF V600E PLGG. Conclusion BRAF V600E PLGG constitutes a distinct entity with poor prognosis when treated with current adjuvant therapy. PMID- 28727524 TI - Development of a Research Agenda Focused on Academic Health Departments. AB - An academic health department (AHD) is a formal partnership between an academic institution and a governmental public health agency. Case studies have described the value of individual AHDs in the areas of student engagement, practice-based research, workforce development, and service. With growing interest in AHDs and the increasing importance of academic-practice linkages in both academic programs' and public health agencies' accreditation processes, articulating a research agenda focused on the AHD model can be useful for stimulating the research and practice fields to further develop the evidence base for AHDs. We provide a research agenda, developed through an iterative process involving academicians, practitioners, and others interested in academic-practice linkages. PMID- 28727522 TI - Excessive Gestational Weight Gain and Subsequent Maternal Obesity at Age 40: A Hypothetical Intervention. AB - OBJECTIVES: To model the hypothetical impact of preventing excessive gestational weight gain on midlife obesity and compare the estimated reduction with the US Healthy People 2020 goal of a 10% reduction of obesity prevalence in adults. METHODS: We analyzed 3917 women with 1 to 3 pregnancies in the prospective US National Longitudinal Survey of Youth, from 1979 to 2012. We compared the estimated obesity prevalence between 2 scenarios: gestational weight gain as reported and under the scenario of a hypothetical intervention that all women with excessive gestational weight gain instead gained as recommended by the Institute of Medicine (2009). RESULTS: A hypothetical intervention was associated with a significantly reduced estimated prevalence of obesity for first (3.3 percentage points; 95% confidence interval [CI] = 1.0, 5.6) and second (3.0 percentage points; 95% CI = 0.7, 5.2) births, and twice as high in Black as in White mothers, but not significant in Hispanics. The population attributable fraction was 10.7% (95% CI = 3.3%, 18.1%) in first and 9.3% (95% CI = 2.2%, 16.5%) in second births. CONCLUSIONS: Development of effective weight-management interventions for childbearing women could lead to meaningful reductions in long term obesity. PMID- 28727525 TI - Trends in Prescription Opioids Detected in Fatally Injured Drivers in 6 US States: 1995-2015. AB - OBJECTIVES: To assess the time trends in prescription opioids detected in fatally injured drivers. METHODS: We analyzed 1995 to 2015 Fatality Analysis Reporting System data from California, Hawaii, Illinois, New Hampshire, Rhode Island, and West Virginia of toxicological tests for drivers fatally injured within 1 hour of a crash (n = 36 729). We used the Cochran-Armitage test for trend to assess the statistical significance of changes in the prevalence of prescription opioids detected in these drivers over time. RESULTS: The prevalence of prescription opioids detected in fatally injured drivers increased from 1.0% (95% confidence interval [CI] = 0.5, 1.4) in 1995 to 7.2% (95% CI = 5.7, 8.8) in 2015 (Z = -9.04; P < .001). Prescription opioid prevalence was higher in female than in male drivers (4.4% vs 2.9%; P < .001). Of the drivers testing positive for prescription opioids, 30.0% had elevated blood alcohol concentrations (>= 0.01 g/dL), and 66.9% tested positive for other drugs. CONCLUSIONS: The prevalence of prescription opioids detected in fatally injured drivers has increased in the past 2 decades. The need to assess the effect of increased prescription opioid use on traffic safety is urgent. PMID- 28727526 TI - Zika and Reproductive Rights in Brazil: Challenge to the Right to Health. AB - The Zika virus epidemic rapidly spread across Brazil and Latin America, gaining international attention because of the causal relationship between Zika and birth defects. The high number of cases in Brazil has been attributed to a failure of the state to contain the epidemic and protect the affected people, especially women. Therefore, the public health crisis created by Zika exposed a stark conflict between Brazil's constitutional right to health and the long-standing violation of reproductive rights in the country. Although health is considered to be a right of all in Brazil, women struggle with barriers to reproductive services and lack of access to safe and legal abortions. In response to the epidemic, women's rights advocates have filed a lawsuit with Brazil's supreme court that requires the decriminalization of abortion upon the diagnosis of Zika virus. However, the selective decriminalization of abortion may lead to negative social consequences and further stigmatization of people with disabilities. A solution to the reproductive health crisis in Brazil must reconcile women's right to choose and the rights of people with disabilities. PMID- 28727527 TI - Television Watching and Telomere Length Among Adults in Southwest China. AB - OBJECTIVES: To explore the independent associations of sedentary behavior and physical activity with telomere length among Chinese adults. METHODS: Data on total time of sedentary behavior, screen-based sedentary behavior (including television watching and computer or phone use), moderate to vigorous physical activity, and dietary intake of 518 adults in Chengdu, Guizhou, and Xiamen in China (54.25% women) aged 20 to 70 years were obtained between 2013 and 2015 through questionnaires. Height, weight, and waist circumference were measured to calculate body mass index and percentage of body fat. Telomere length was measured through Southern blot technique. RESULTS: Television watching was inversely related to adjusted telomere length (-71.75 base pair; SE = 34.40; P = .04). Furthermore, a similar trend between telomere length and television watching was found in the group aged 20 to 40 years after adjusting for all covariates. Adults aged 20 to 40 years in the highest tertile of daily time spent on watching television had 4.0% shorter telomere length than adults in the lowest tertile (P = .03). CONCLUSIONS: Although the association is modest, television watching is inversely related to telomere length among Chinese adults, warranting further investigation in large prospective studies. PMID- 28727529 TI - "Ain't Necessarily So!": The Brake Industry's Impact on Asbestos Regulation in the 1970s. AB - Canada is proposing a ban on asbestos, and the US Environmental Protection Agency has listed it among the first 10 materials it is investigating under the new Toxic Substances Control Act revisions. However, this effort is currently running up against enormous industry and political opposition. Here, we detail the activities in the early 1970s of the Friction Materials Standards Institute, an industry trade association, to stifle earlier attempts to regulate asbestos use in brake linings, one of the oldest and most obvious sources of asbestos exposure to mechanics, among others. (Am J Public Health. 2017: 1395-1399. doi: 10.2105/AJPH.2017.303901). PMID- 28727528 TI - Racial/Ethnic and Socioeconomic Disparities in Hydration Status Among US Adults and the Role of Tap Water and Other Beverage Intake. AB - OBJECTIVES: To evaluate whether differences in tap water and other beverage intake explain differences in inadequate hydration among US adults by race/ethnicity and income. METHODS: We estimated the prevalence of inadequate hydration (urine osmolality >= 800 mOsm/kg) by race/ethnicity and income of 8258 participants aged 20 to 74 years in the 2009 to 2012 National Health and Nutrition Examination Survey. Using multivariable regression models, we estimated associations between demographic variables, tap water intake, and inadequate hydration. RESULTS: The prevalence of inadequate hydration among US adults was 29.5%. Non-Hispanic Blacks (adjusted odds ratio [AOR] = 1.44; 95% confidence interval [CI] = 1.17, 1.76) and Hispanics (AOR = 1.42; 95% CI = 1.21, 1.67) had a higher risk of inadequate hydration than did non-Hispanic Whites. Lower-income adults had a higher risk of inadequate hydration than did higher-income adults (AOR = 1.23; 95% CI = 1.04, 1.45). Differences in tap water intake partially attenuated racial/ethnic differences in hydration status. Differences in total beverage and other fluid intake further attenuated sociodemographic disparities. CONCLUSIONS: Racial/ethnic and socioeconomic disparities in inadequate hydration among US adults are related to differences in tap water and other beverage intake. Policy action is needed to ensure equitable access to healthy beverages. PMID- 28727530 TI - Homicide Rates of Transgender Individuals in the United States: 2010-2014. AB - OBJECTIVES: To estimate homicide rates of transgender US residents and relative risks (RRs) of homicide with respect to cisgender comparators intersected with age, gender, and race/ethnicity. METHODS: I estimated homicide rates for transgender residents and transfeminine, Black, Latin@, and young (aged 15-34 years) subpopulations during the period 2010 to 2014 using Transgender Day of Remembrance and National Coalition of Anti-Violence Programs transgender homicide data. I used estimated transgender prevalences to estimate RRs using cisgender comparators. I performed a sensitivity analysis to situate all results within assumptions about underreporting of transgender homicides and assumptions about the prevalence of transgender residents. RESULTS: The overall homicide rate of transgender individuals was likely to be less than that of cisgender individuals, with 8 of 12 RR estimates below 1.0. However, the homicide rates of young transfeminine Black and Latina residents were almost certainly higher than were those of cisfeminine comparators, with all RR estimates above 1.0 for Blacks and all above 1.0 for Latinas. CONCLUSIONS: Antiviolence public health programs should identify young and Black or Latina transfeminine women as an especially vulnerable population. PMID- 28727531 TI - Minimum Age of Sale for Tobacco Products and Electronic Cigarettes: Ethical Acceptability of US "Tobacco 21 Laws". AB - Several US jurisdictions have recently passed laws that raise the minimum age of sale for tobacco products and electronic cigarettes to 21 years (Tobacco 21 laws). Although these laws have been demonstrated to be an effective means to reduce youth smoking initiation, their passage and potential expansion have provoked controversy. Critics have objected to these laws, claiming that they unduly intrude on individual freedom and that they irrationally and paternalistically restrict the freedom of those aged 18 to 20 years, who were previously able to legally purchase tobacco products. We have examined the ethical acceptability of Tobacco 21 laws. First, we have described ethical support for such a restriction grounded in its public health benefit. We have then offered arguments that raise doubts about the soundness of critics' objections to these regulations and described an additional ethical justification arising from concern about preventing harm to others. On the basis of this analysis, we conclude that Tobacco 21 laws are ethically justifiable. PMID- 28727532 TI - Evacuation of Pets During Disasters: A Public Health Intervention to Increase Resilience. AB - During a disaster, many pet owners want to evacuate their pets with them, only to find that evacuation and sheltering options are limited or nonexistent. This disregard for companion animal welfare during a disaster can have public health consequences. Pet owners may be stranded at home, unwilling to leave their pets behind. Others refuse evacuation orders or attempt to reenter evacuation sites illegally to rescue their animals. Psychopathologies such as grief, depression, and posttraumatic stress disorder are associated with pet abandonment during an evacuation. Health care workers may refuse to work if their animals are in danger, leaving medical facilities understaffed during crises. Zoonotic disease risk increases when pets are abandoned or left to roam, where they are more likely to encounter infected wildlife or unowned animals than they would if they were safely sheltered with their owners. These sequelae are not unique to the United States, nor to wealthy countries. Emergency planning for companion animals during disasters is a global need in communities with a significant pet population, and will increase resilience and improve public health. PMID- 28727533 TI - Transit Rider Body Mass Index Before and After Completion of Street Light-Rail Line in Utah. AB - OBJECTIVES: To determine whether 2012 to 2015 (times 1-3) ridership changes correlated with body mass index (BMI) changes after transit line completion in Salt Lake City, Utah. METHODS: We used Global Positioning System/accelerometry measured transit ridership measures in 2012 to 2013 (times 1-2) to compare objective and self-reported ridership. Regression models related changes in objectively measured ridership (times 1-2) and self-reported ridership (times 1-2 and times 1-3) to BMI changes, adjusting for control variables. RESULTS: Objective and self-reported ridership measures were consistent. From time 1 to 2 (P = .021) or to 3 (P = .015), BMI increased among self-reported former riders and decreased among new riders (P = .09 for both times 1-2 and times 1-3), although the latter was nonsignificant. Time 3 attrition adjustment had no effect on results. Adjusting for baseline BMI, the nonsignificant effect for new riders remained nonsignificant, indicating no BMI change; the BMI increase after discontinuing transit remained significant. CONCLUSIONS: Observed BMI increases subsequent to stopping transit ridership persisted for more than 2 years (postintervention). These results suggest that transit ridership protects against BMI gains and support the need to provide convenient transit for public health. PMID- 28727534 TI - Patterns of Use of Smokeless Tobacco in US Adults, 2013-2014. AB - OBJECTIVES: To examine patterns of smokeless tobacco (SLT) use, by type, in wave 1 (2013-2014) of the Population Assessment of Tobacco and Health Study in the United States. METHODS: We analyzed data from 32 320 adults (aged >= 18 years) to assess the use of pouched snus and other SLT products (loose snus, moist snuff, dip, spit, and chewing tobacco). RESULTS: Overall, SLT use was most common among men, younger adults, non-Hispanic Whites, and nonurban respondents. Pouched snus users were more likely to report nondaily and polytobacco use than users of other SLT products. Respondents who used SLT some days were more likely to be current established cigarette smokers than those who used SLT every day (57.9% vs 20.2%). Furthermore, current established smokers who used SLT some days were more likely to smoke every day and had a higher median number of cigarettes smoked per day than smokers who used SLT every day. CONCLUSIONS: Polytobacco use, especially cigarette smoking, is common among SLT users. Pouched snus users are more likely to report nondaily snus use and polytobacco use than users of other SLT products. PMID- 28727535 TI - Civil Unrest in the Context of Chronic Community Violence: Impact on Maternal Depressive Symptoms. AB - OBJECTIVES: To examine changes in maternal-child health surrounding the April 2015 civil unrest in Baltimore, Maryland, following Freddie Gray's death while in police custody. METHODS: We conducted cross-sectional Children's HealthWatch surveys January 2014 through December 2015 in pediatric emergency departments and primary care clinics on maternal-child health and June 2015 through October 2015 on daily and community routines. We used trend analysis and piecewise logistic regression to examine effects of time, residential proximity moderation, and mediation analysis to assess proximity and maternal-child health relations via maternal concerns. RESULTS: Participants comprised 1095 mothers, 93% of whom were African American and 100% of whom had public or no insurance; 73% of participants' children were younger than 24 months. Following the unrest, prevalence of maternal depressive symptoms increased significantly in proximal, but not distal, neighborhoods (b = 0.41; 95% confidence interval [CI] = 0.03, 0.79; P = .03). Maternal concerns were elevated in proximal neighborhoods and associated with depressive symptoms; mediation through maternal concern was not significant. Five months after the unrest, depressive symptoms returned to previous levels. CONCLUSIONS: Civil unrest has an acute effect on maternal depressive symptoms in neighborhoods proximal to unrest. Public Health Implications. To mitigate depressive symptoms associated with civil unrest, maintain stability of community routines, screen for maternal depressive symptoms, and provide parent-child nurturing programs. PMID- 28727536 TI - 1918 Influenza Pandemic: In Utero Exposure in the United States and Long-Term Impact on Hospitalizations. AB - OBJECTIVES: To explore associations between in utero exposure to the 1918 influenza pandemic and hospitalization rates in old age (>= 70 years) in the United States. METHODS: We identified individuals exposed (mild and deadly waves) and unexposed in utero to the 1918 influenza pandemic (a natural experiment) by using birth dates from the Asset and Health Dynamics Among the Oldest Old survey. We analyzed differences in hospitalization rates by exposure status with multivariate linear regression. RESULTS: In utero exposure to the deadly wave of the 1918 influenza pandemic increased the number of hospital visits by 10.0 per 100 persons. For those exposed in utero to the deadliest wave of the influenza pandemic, high rates of functional limitations are shown to drive the higher rates of hospitalizations in old age. CONCLUSIONS: In utero exposure to the influenza pandemic increased functional limitations and hospitalization rates in old age. Public Health Implications. To determine investments in influenza pandemic prevention programs that protect fetal health, policymakers should include long-term reductions in hospitalizations in their cost-benefit evaluations. PMID- 28727537 TI - State Health Agency and Local Health Department Workforce: Identifying Top Development Needs. AB - OBJECTIVES: To identify occupations with high-priority workforce development needs at public health departments in the United States. METHODS: We surveyed 46 state health agencies (SHAs) and 112 local health departments (LHDs). We asked respondents to prioritize workforce needs for 29 occupations and identify whether more positions, more qualified candidates, more competitive salaries for recruitment or retention, or new or different staff skills were needed. RESULTS: Forty-one SHAs (89%) and 36 LHDs (32%) participated. The SHAs reported having high-priority workforce needs for epidemiologists and laboratory workers; LHDs for disease intervention specialists, nurses, and administrative support, management, and leadership positions. Overall, the most frequently reported SHA workforce needs were more qualified candidates and more competitive salaries. The LHDs most frequently reported a need for more positions across occupations and more competitive salaries. Workforce priorities for respondents included strengthening epidemiology workforce capacity, adding administrative positions, and improving compensation to recruit and retain qualified employees. CONCLUSIONS: Strategies for addressing workforce development concerns of health agencies include providing additional training and workforce development resources, and identifying best practices for recruitment and retention of qualified candidates. PMID- 28727538 TI - Per Diems in Polio Eradication: Perspectives From Community Health Workers and Officials. AB - Nearly all global health initiatives give per diems to community health workers (CHWs) in poor countries for short-term work on disease-specific programs. We interviewed CHWs, supervisors, and high-level officials (n = 95) in 6 study sites across sub-Saharan Africa and South Asia in early 2012 about the per diems given to them by the Global Polio Eradication Initiative. These per diems for CHWs ranged from $1.50 to $2.40 per day. International officials defended per diems for CHWs with an array of arguments, primarily that they were necessary to defray the expenses that workers incurred during campaigns. But high-level ministry of health officials in many countries were concerned that even small per diems were unsustainable. By contrast, CHWs saw per diems as a wage; the very small size of this wage led many to describe per diems as unjust. Per diem polio work existed in the larger context of limited and mostly exploitative options for female labor. Taking the perspectives of CHWs seriously would shift the international conversation about per diems toward questions of labor rights and justice in global health pay structures. PMID- 28727539 TI - State and Local Chronic Disease Surveillance Using Electronic Health Record Systems. AB - OBJECTIVES: To assess the feasibility of chronic disease surveillance using distributed analysis of electronic health records and to compare results with Behavioral Risk Factor Surveillance System (BRFSS) state and small-area estimates. METHODS: We queried the electronic health records of 3 independent Massachusetts-based practice groups using a distributed analysis tool called MDPHnet to measure the prevalence of diabetes, asthma, smoking, hypertension, and obesity in adults for the state and 13 cities. We adjusted observed rates for age, gender, and race/ethnicity relative to census data and compared them with BRFSS state and small-area estimates. RESULTS: The MDPHnet population under surveillance included 1 073 545 adults (21.8% of the state adult population). MDPHnet and BRFSS state-level estimates were similar: 9.4% versus 9.7% for diabetes, 10.0% versus 12.0% for asthma, 13.5% versus 14.7% for smoking, 26.3% versus 29.6% for hypertension, and 22.8% versus 23.8% for obesity. Correlation coefficients for MDPHnet versus BRFSS small-area estimates ranged from 0.890 for diabetes to 0.646 for obesity. CONCLUSIONS: Chronic disease surveillance using electronic health record data is feasible and generates estimates comparable with BRFSS state and small-area estimates. PMID- 28727541 TI - Postdischarge smoking cessation in subgroups of hospitalized smokers: A latent class analysis. AB - BACKGROUND: Hospitalization presents a window of opportunity to treat smoking, and hospital-initiated smoking treatment has demonstrated effectiveness. Despite effective interventions, not all smokers will discontinue use, highlighting the need to better understand which patients achieve cessation. Traditional regression methods may not capture the complexity of inpatient smoker subgroups. METHODS: Latent class analysis (LCA) was conducted with data from 397 hospitalized adult cigarette smokers enrolled in a randomized trial. Six categorical indicator variables known to impact cessation were selected to estimate subgroups: health conditions (smoking-related disease [SRD], depressive symptoms, positive screen for alcohol problems) and smoking-related variables (time to first cigarette, cigarettes/day, smoking indoors). The probability of achieving biologically verified 7-day tobacco cessation 6 months after discharged was estimated. RESULTS: A 3-class model best fit the trial data: a Light Smokers subgroup had lower probability for most indicators; a High Health Burden subgroup had high smoking behavior probabilities and similar health problems to the Light Smokers subgroup; and a Heavy Smoking Drinking Depressed subgroup had high nicotine dependence, depressive symptoms, and alcohol misuse probabilities. Probability of biologically verified cessation conditional on class membership was significantly higher (P < .001) for the High Health Burden and the Light Smokers subgroups compared with the Heavy Smoking Drinking Depressed subgroup. CONCLUSION: Results suggest that subgroups with lower probabilities of alcohol misuse and depression and higher probability of SRD had higher probability of successful cessation after hospital discharge. Hospitalized patients with nicotine dependence combined with behavioral and mental health problems have additional cessation barriers that may require intervention focus. PMID- 28727540 TI - Community-Based, Preclinical Patient Navigation for Colorectal Cancer Screening Among Older Black Men Recruited From Barbershops: The MISTER B Trial. AB - OBJECTIVES: To test the effectiveness of a preclinical, telephone-based patient navigation intervention to encourage colorectal cancer (CRC) screening among older Black men. METHODS: We conducted a 3-parallel-arm, randomized trial among 731 self-identified Black men recruited at barbershops between 2010 and 2013 in New York City. Participants had to be aged 50 years or older, not be up-to-date on CRC screening, have uncontrolled high blood pressure, and have a working telephone. We randomized participants to 1 of 3 groups: (1) patient navigation by a community health worker for CRC screening (PN), (2) motivational interviewing for blood pressure control by a trained counselor (MINT), or (3) both interventions (PLUS). We assessed CRC screening completion at 6-month follow-up. RESULTS: Intent-to-treat analysis revealed that participants in the navigation interventions were significantly more likely than those in the MINT-only group to be screened for CRC during the 6-month study period (17.5% of participants in PN, 17.8% in PLUS, 8.4% in MINT; P < .01). CONCLUSIONS: Telephone-based preclinical patient navigation has the potential to be effective for older Black men. Our results indicate the importance of community-based health interventions for improving health among minority men. PMID- 28727542 TI - Single-Session High-Intensity Focused Ultrasound Treatment for Persistent or Relapsed Graves Disease: Preliminary Experience in a Prospective Study. AB - Purpose To evaluate the safety and efficacy of ultrasonography (US)-guided high intensity focused ultrasound (HIFU) ablation as a treatment for medically refractory Graves disease (GD). Materials and Methods After ethics approval, a prospective trial (NCT02685514) was performed from November 2015 to February 2016. Thirty patients underwent ablation of the entire right and left thyroid lobes, with areas near the tracheal-esophageal groove and common carotid artery left unablated. Serum thyroid-stimulating hormone (TSH), free T4 (FT4), antithyroid autoantibodies, and TSH receptor (TSHR) antibody levels were evaluated afterward, and US color Doppler, US volumetry, and eye assessment were performed. The primary outcome was the 12-month relapse rate. Relapse referred to hyperthyroidism (FT4 > 23 pmol/L) afterward. Variables associated with relapse were analyzed by using binary logistic regression. Results The technical success rate was 96.7%. The cohort comprised entirely women, with a median age of 38.2 years (interquartile range, 29.5-49.0 years). After 12 months, eight patients (26.7%; 95% confidence interval [CI]: 14.19%, 44.95%) experienced relapse. One patient (3.3%; 95% CI: 0.59%, 16.67%) experienced vocal cord palsy, while two patients (6.7%; 95% CI: 1.85%, 21.33%) experienced Horner syndrome, but none of these conditions were permanent. No changes in gland volume, antithyroid autoantibody levels, and ophthalmic parameters were found at 12-month follow-up. Baseline TSHR was found to have decreased significantly at 6- and 12-month follow up (P < .001 for both). TSHR antibody (odds ratio [OR] = 1.414; 95% CI: 1.018, 1.965; P = .039) and gland volume (OR = 0.557; 95% CI: 0.353, 0.880; P = .012) were associated with 12-month relapse, with higher antibody levels conferring a higher likelihood and smaller gland volumes conferring a lower likelihood. Conclusion US-guided HIFU of the thyroid may be a safe and efficacious treatment in patients with persistent or relapsed GD. However, further study is warranted before it can become mainstream for this indication. (c) RSNA, 2017 Online supplemental material is available for this article. PMID- 28727544 TI - Abbreviated Biparametric Prostate MR Imaging in Men with Elevated Prostate specific Antigen. AB - Purpose To determine the diagnostic accuracy for clinically significant prostate cancer achieved with abbreviated biparametric prostate magnetic resonance (MR) imaging in comparison with full multiparametric contrast material-enhanced prostate MR imaging in men with elevated prostate-specific antigen (PSA) and negative transrectal ultrasonography (US)-guided biopsy findings; to determine the significant cancer detection rate of biparametric versus full multiparametric contrast-enhanced MR imaging and between-reader agreement for interpretation of biparametric MR imaging. Materials and Methods In this institutional review board approved retrospective review of prospectively acquired data, men with PSA greater than or equal to 3 ng/mL after negative transrectal US-guided biopsy findings underwent state-of-the-art, full multiparametric contrast-enhanced MR imaging at 3.0-T including high-spatial-resolution structural imaging in several planes, diffusion-weighted imaging at 0, 800, 1000, and 1400 mm2/sec, and dynamic contrast-enhanced MR imaging, obtained without endorectal coil within 34 minutes 19 seconds. One of four radiologists with different levels of expertise (1-9 years) first reviewed only a fraction of the full multiparametric contrast enhanced MR images, consisting of single-plane (axial) structural imaging (T2 weighted turbo spin-echo and diffusion-weighted imaging), acquired within 8 minutes 45 seconds (referred to as biparametric MR imaging), and established a diagnosis according to the Prostate Imaging Reporting and Data System (PI-RADS) version 2; only thereafter, the remaining full multiparametric contrast-enhanced MR images were read. Men with PI-RADS categories 3-5 underwent MR-guided targeted biopsy. Men with PI-RADS categories 1-2 remained in urologic follow-up for at least 2 years, with rebiopsy (transrectal US-guided or transperineal saturation) where appropriate. McNemar test was used to compare diagnostic accuracies. To investigate between-reader agreement, biparametric MR images of 100 patients were read independently by all three radiologists. Results A total of 542 men, aged 64.8 years +/- 8.2 (median PSA, 7 ng/mL), were included. Biparametric MR imaging helped detect clinically significant prostate cancer in 138 men. Full multiparametric contrast-enhanced MR imaging allowed detection of one additional clinically significant prostate cancer (a stage pT2a, intermediate-risk cancer with a Gleason score of 3+4) and caused 11 additional false-positive diagnoses. Diagnostic accuracy for detection of clinically significant cancer of biparametric MR imaging (89.1%, 483 of 542) was similar to that of full multiparametric contrast-enhanced MR imaging (87.2%, 473 of 542). Between-reader agreement of biparametric MR imaging interpretation was substantial (kappa = 0.81). Conclusion Biparametric MR imaging allows detection of clinically significant prostate cancer missed by transrectal US-guided biopsy. Biparametric prostate MR imaging takes less than 9 minutes examination time, works without contrast agent injection, and offers a diagnostic accuracy and cancer detection rate that are equivalent to those of conventional full multiparametric contrast enhanced MR imaging protocols. (c) RSNA, 2017. PMID- 28727543 TI - Non-Small Cell Lung Cancer Radiogenomics Map Identifies Relationships between Molecular and Imaging Phenotypes with Prognostic Implications. AB - Purpose To create a radiogenomic map linking computed tomographic (CT) image features and gene expression profiles generated by RNA sequencing for patients with non-small cell lung cancer (NSCLC). Materials and Methods A cohort of 113 patients with NSCLC diagnosed between April 2008 and September 2014 who had preoperative CT data and tumor tissue available was studied. For each tumor, a thoracic radiologist recorded 87 semantic image features, selected to reflect radiologic characteristics of nodule shape, margin, texture, tumor environment, and overall lung characteristics. Next, total RNA was extracted from the tissue and analyzed with RNA sequencing technology. Ten highly coexpressed gene clusters, termed metagenes, were identified, validated in publicly available gene expression cohorts, and correlated with prognosis. Next, a radiogenomics map was built that linked semantic image features to metagenes by using the t statistic and the Spearman correlation metric with multiple testing correction. Results RNA sequencing analysis resulted in 10 metagenes that capture a variety of molecular pathways, including the epidermal growth factor (EGF) pathway. A radiogenomic map was created with 32 statistically significant correlations between semantic image features and metagenes. For example, nodule attenuation and margins are associated with the late cell-cycle genes, and a metagene that represents the EGF pathway was significantly correlated with the presence of ground-glass opacity and irregular nodules or nodules with poorly defined margins. Conclusion Radiogenomic analysis of NSCLC showed multiple associations between semantic image features and metagenes that represented canonical molecular pathways, and it can result in noninvasive identification of molecular properties of NSCLC. Online supplemental material is available for this article. PMID- 28727545 TI - Role of Age and Acculturation in Diet Quality Among Mexican Americans - Findings From the National Health and Nutrition Examination Survey, 1999-2012. AB - Age and acculturation may play a role in diet quality among Mexican Americans. This study examined diet quality in Mexican Americans by age and whether acculturation influences diet quality across different age groups, using data from the National Health and Nutrition Examination Survey (NHANES). Diet quality, measured by the Healthy Eating Index 2010, improved with age except in categories of dairy, sodium, and refined grains. More acculturation was associated with lower scores in overall diet quality and categories of vegetables, fruits, and sodium and empty calories across almost all ages, but higher scores in grain categories, especially in younger groups. A diet rich in fruits and vegetables but low in fat and sodium should be promoted among more acculturated Mexican Americans, and whole-grain foods should be promoted among young but less acculturated Mexican Americans. PMID- 28727547 TI - Designing and Implementation of Stable Sinusoidal Rough-Neural Identifier. AB - A rough neuron is defined as a pair of conventional neurons that are called the upper and lower bound neurons. In this paper, the sinusoidal rough-neural networks (SR-NNs) are used to identify the discrete dynamic nonlinear systems (DDNSs) with or without noise in series-parallel configuration. In the identification of periodic nonlinear systems, sinusoidal activation functions provide more efficient neural networks than the sigmoidal activation functions. Based on the Lyapunov stability theory, an online learning algorithm is developed to train the SR-NNs. The asymptotically convergence of the identification error to zero and the boundedness of parameters as well as predictions are proved. SR NNs are used to identify some DDNSs and the cement rotary kiln (CRK). CRK is a complex nonlinear system in the cement factory, which produces the cement clinker. The experiments show that the SR-NNs in the identification of nonlinear systems have better performances than multilayer perceptrons (MLPs), sinusoidal neural networks, and rough MLPs, particularly in the presence of noise. PMID- 28727546 TI - A Formative Evaluation of a Diabetes Prevention Program Using the RE-AIM Framework in a Learning Health Care System, Utah, 2013-2015. AB - INTRODUCTION: Evaluation of interventions can help to close the gap between research and practice but seldom takes place during implementation. Using the RE AIM framework, we conducted a formative evaluation of the first year of the Intermountain Healthcare Diabetes Prevention Program (DPP). METHODS: Adult patients who met the criteria for prediabetes (HbA1c of 5.70%-6.49% or fasting plasma glucose of 100-125 mg/dL) were attributed to a primary care provider from August 1, 2013, through July 31, 2014. Physicians invited eligible patients to participate in the program during an office visit. We evaluated 1) reach, with data on patient eligibility, participation, and representativeness; 2) effectiveness, with data on attaining a 5% weight loss; 3) adoption, with data on providers and clinics that referred patients to the program; and 4) implementation, with data on patient encounters. We did not measure maintenance. RESULTS: Of the 6,862 prediabetes patients who had an in-person office visit with their provider, 8.4% of eligible patients enrolled. Likelihood of participation was higher among patients who were female, aged 70 years or older, or overweight; had depression and higher weight at study enrollment; or were prescribed metformin. DPP participants were more likely than nonparticipants to achieve a 5% weight loss (odds ratio, 1.70; 95% confidence interval, 1.29-2.25; P < .001). Providers from 7 of 8 regions referred patients to the DPP; 174 providers at 53 clinics enrolled patients. The mean number of DPP counseling encounters per patient was 2.3 (range, 1-16). CONCLUSION: The RE-AIM framework was useful for estimating the formative impact (ie, reach, effectiveness, adoption, and implementation fidelity) of a DPP-based lifestyle intervention deployed in a learning health care system. PMID- 28727548 TI - MR-NTD: Manifold Regularization Nonnegative Tucker Decomposition for Tensor Data Dimension Reduction and Representation. AB - With the advancement of data acquisition techniques, tensor (multidimensional data) objects are increasingly accumulated and generated, for example, multichannel electroencephalographies, multiview images, and videos. In these applications, the tensor objects are usually nonnegative, since the physical signals are recorded. As the dimensionality of tensor objects is often very high, a dimension reduction technique becomes an important research topic of tensor data. From the perspective of geometry, high-dimensional objects often reside in a low-dimensional submanifold of the ambient space. In this paper, we propose a new approach to perform the dimension reduction for nonnegative tensor objects. Our idea is to use nonnegative Tucker decomposition (NTD) to obtain a set of core tensors of smaller sizes by finding a common set of projection matrices for tensor objects. To preserve geometric information in tensor data, we employ a manifold regularization term for the core tensors constructed in the Tucker decomposition. An algorithm called manifold regularization NTD (MR-NTD) is developed to solve the common projection matrices and core tensors in an alternating least squares manner. The convergence of the proposed algorithm is shown, and the computational complexity of the proposed method scales linearly with respect to the number of tensor objects and the size of the tensor objects, respectively. These theoretical results show that the proposed algorithm can be efficient. Extensive experimental results have been provided to further demonstrate the effectiveness and efficiency of the proposed MR-NTD algorithm. PMID- 28727549 TI - Learning and Inferring "Dark Matter" and Predicting Human Intents and Trajectories in Videos. AB - This paper presents a method for localizing functional objects and predicting human intents and trajectories in surveillance videos of public spaces, under no supervision in training. People in public spaces are expected to intentionally take shortest paths (subject to obstacles) toward certain objects (e.g., vending machine, picnic table, dumpster etc.) where they can satisfy certain needs (e.g., quench thirst). Since these objects are typically very small or heavily occluded, they cannot be inferred by their visual appearance but indirectly by their influence on people's trajectories. Therefore, we call them "dark matter", by analogy to cosmology, since their presence can only be observed as attractive or repulsive "fields" in the public space. A person in the scene is modeled as an intelligent agent engaged in one of the "fields" selected depending his/her intent. An agent's trajectory is derived from an Agent-based Lagrangian Mechanics. The agents can change their intents in the middle of motion and thus alter the trajectory. For evaluation, we compiled and annotated a new dataset. The results demonstrate our effectiveness in predicting human intent behaviors and trajectories, and localizing and discovering distinct types of "dark matter" in wide public spaces. PMID- 28727550 TI - ISAR Imaging of High-Speed Maneuvering Target Using Gapped Stepped-Frequency Waveform and Compressive Sensing. AB - In the case of a stepped-frequency waveform (SFW) inverse synthetic aperture radar (ISAR) system, the translational motion (TM) of a target can be usually divided into two parts: 1) target motion within a pulse repetition interval, called the inter-pulse translational motion (IPTM) and 2) target motion between bursts, called the inter-burst translational motion (IBTM). The former induces severe blurring in the ISAR images as well as range-compressed data (i.e., range profile), and the latter also causes dramatic degradation of the ISAR image quality. In this paper, a novel framework for high-resolution gapped SFW (GSFW) ISAR imaging of high-speed maneuvering target is proposed. The main novelty of the proposed method is twofold: 1) accurate TM parameter estimation in conjunction with a compressive sensing theory using a newly devised cost function and particle swarm optimization and 2) compensation for both the IPTM and IBTM phase errors simultaneously even with the GSFW data set. Simulation results using ideal point scatterers show that the proposed method is capable of precise reconstruction of ISAR image and accurate TM parameter estimation. Experimental results using real measured data verify the robustness and the effectiveness of the proposed method. PMID- 28727551 TI - Inverse Rendering and Relighting From Multiple Color Plus Depth Images. AB - We propose a novel relighting approach that takes advantage of multiple color plus depth images acquired from a consumer camera. Assuming distant illumination and Lambertian reflectance, we model the reflected light field in terms of spherical harmonic coefficients of the bi-directional reflectance distribution function and lighting. We make use of the noisy depth information together with color images taken under different illumination conditions to refine surface normals inferred from depth. We first perform refinement on the surface normals using the first order spherical harmonics. We initialize this non-linear optimization with a linear approximation to greatly reduce computation time. With surface normals refined, we formulate the recovery of albedo and lighting in a matrix factorization setting, involving second order spherical harmonics. Albedo and lighting coefficients are recovered up to a global scaling ambiguity. We demonstrate our method on both simulated and real data, and show that it can successfully recover both illumination and albedo to produce realistic relighting results. PMID- 28727552 TI - Nonparametric Joint Shape and Feature Priors for Image Segmentation. AB - In many image segmentation problems involving limited and low-quality data, employing statistical prior information about the shapes of the objects to be segmented can significantly improve the segmentation result. However, defining probability densities in the space of shapes is an open and challenging problem, especially if the object to be segmented comes from a shape density involving multiple modes (classes). Existing techniques in the literature estimate the underlying shape distribution by extending Parzen density estimator to the space of shapes. In these methods, the evolving curve may converge to a shape from a wrong mode of the posterior density when the observed intensities provide very little information about the object boundaries. In such scenarios, employing both shape- and class-dependent discriminative feature priors can aid the segmentation process. Such features may involve, e.g., intensity-based, textural, or geometric information about the objects to be segmented. In this paper, we propose a segmentation algorithm that uses nonparametric joint shape and feature priors constructed by Parzen density estimation. We incorporate the learned joint shape and feature prior distribution into a maximum a posteriori estimation framework for segmentation. The resulting optimization problem is solved using active contours. We present experimental results on a variety of synthetic and real data sets from several fields involving multimodal shape densities. Experimental results demonstrate the potential of the proposed method. PMID- 28727553 TI - FlyCap: Markerless Motion Capture Using Multiple Autonomous Flying Cameras. AB - Aiming at automatic, convenient and non-instrusive motion capture, this paper presents a new generation markerless motion capture technique, the FlyCap system, to capture surface motions of moving characters using multiple autonomous flying cameras (autonomous unmanned aerial vehicles(UAVs) each integrated with an RGBD video camera). During data capture, three cooperative flying cameras automatically track and follow the moving target who performs large-scale motions in a wide space. We propose a novel non-rigid surface registration method to track and fuse the depth of the three flying cameras for surface motion tracking of the moving target, and simultaneously calculate the pose of each flying camera. We leverage the using of visual-odometry information provided by the UAV platform, and formulate the surface tracking problem in a non-linear objective function that can be linearized and effectively minimized through a Gaussian Newton method. Quantitative and qualitative experimental results demonstrate the plausible surface and motion reconstruction results. PMID- 28727554 TI - A Human-Humanoid Interaction Through the Use of BCI for Locked-In ALS Patients Using Neuro-Biological Feedback Fusion. AB - This paper illustrates a new architecture for a human-humanoid interaction based on EEG-brain computer interface (EEG-BCI) for patients affected by locked-in syndrome caused by Amyotrophic Lateral Sclerosis (ALS). The proposed architecture is able to recognise users' mental state accordingly to the biofeedback factor , based on users' attention, intention, and focus, that is used to elicit a robot to perform customised behaviours. Experiments have been conducted with a population of eight subjects: four ALS patients in a near locked-in status with normal ocular movement and four healthy control subjects enrolled for age, education, and computer expertise. The results showed as three ALS patients have completed the task with 96.67% success; the healthy controls with 100% success; the fourth ALS has been excluded from the results for his low general attention during the task; the analysis of factor highlights as ALS subjects have shown stronger (81.20%) than healthy controls (76.77%). Finally, a post-hoc analysis is provided to show how robotic feedback helps in maintaining focus on expected task. These preliminary data suggest that ALS patients could successfully control a humanoid robot through a BCI architecture, potentially enabling them to conduct some everyday tasks and extend their presence in the environment. PMID- 28727555 TI - TiD-Introducing and Benchmarking an Event-Delivery System for Brain-Computer Interfaces. AB - In this paper, we present and analyze an event distribution system for brain computer interfaces. Events are commonly used to mark and describe incidents during an experiment and are therefore critical for later data analysis or immediate real-time processing. The presented approach, called Tools for brain computer interaction interface D (TiD), delivers messages in XML format via a buslike system using transmission control protocol connections or shared memory. A dedicated server dispatches TiD messages to distributed or local clients. The TiD message is designed to be flexible and contains time stamps for event synchronization, whereas events describe incidents, which occur during an experiment. TiD was tested extensively toward stability and latency. The effect of an occurring event jitter was analyzed and benchmarked on a reference implementation under different conditions as gigabit and 100-Mb Ethernet or Wi-Fi with a different number of event receivers. A 3-dB signal attenuation, which occurs when averaging jitter influenced trials aligned by events, is starting to become visible at around 1-2 kHz in the case of a gigabit connection. Mean event distribution times across operating systems are ranging from 0.3 to 0.5ms for a gigabit network connection for 106 events. Results for other environmental conditions are available in this paper. References already using TiD for event distribution are provided showing the applicability of TiD for event delivery with distributed or local clients. PMID- 28727556 TI - Effective Screening and Classification of Cervical Precancer Biopsy Imagery. AB - Microscope images of biopsy samples of cervical precancers conventionally discriminated by histopathology, the current "gold standard" for cancer detection, showed that their correlation properties are segregated into different classes. The correlation domains clearly indicate increasing cellular clustering in different grades of precancer compared with their normal counterparts. This trend indicates the probability of pixel distribution of the corresponding tissue images. Because the cell density is not uniform in the higher grades, the skewness (asymmetry of a distribution), kurtosis (sharpness of a distribution), entropy (randomness), and standard deviation are affected. A combination of these parameters effectively improves the diagnosis and quantitatively classifies the normal and all the three grades of precancerous cervical tissue sections significantly. Thus, the statistical analysis of microscope images is a promising approach for early stage tumor detection and quantitative classification of precancerous grades; this can effectively supplement the qualitative analysis by the pathologist. PMID- 28727557 TI - Integrating Flexible Sensor and Virtual Self-Organizing DC Grid Model With Cloud Computing for Blood Leakage Detection During Hemodialysis. AB - Blood leakage and blood loss are serious complications during hemodialysis. From the hemodialysis survey reports, these life-threatening events occur to attract nephrology nurses and patients themselves. When the venous needle and blood line are disconnected, it takes only a few minutes for an adult patient to lose over 40% of his / her blood, which is a sufficient amount of blood loss to cause the patient to die. Therefore, we propose integrating a flexible sensor and self organizing algorithm to design a cloud computing-based warning device for blood leakage detection. The flexible sensor is fabricated via a screen-printing technique using metallic materials on a soft substrate in an array configuration. The self-organizing algorithm constructs a virtual direct current grid-based alarm unit in an embedded system. This warning device is employed to identify blood leakage levels via a wireless network and cloud computing. It has been validated experimentally, and the experimental results suggest specifications for its commercial designs. The proposed model can also be implemented in an embedded system. PMID- 28727558 TI - Understanding Robust Adaptation Dynamics of Gene Regulatory Network. AB - Robust adaptation is a critical attribute for gene regulatory network (GRN), understanding the relationship between adaptation and the GRN topology, and corresponding parameters is a challenging issue. The work in this paper includes: first, seven constraint multiobjective optimization algorithms are used to find sufficient solutions to get more reliable statistic rules. Meanwhile, the algorithms are compared to facilitate the future algorithm selection; second, a fuzzy c-mean algorithm is used to analyze solutions and to classify the solutions into different groups; third, the histogram analysis for all satisfactory solutions shows the preferred parameter range, i.e., parameter motif. The contributions of this paper includes: 1) Two new adaptation indices i.e., peak time and settle down time, are proposed for the first time to give more accurate description of the robust adaptation. Our conclusion is that some solutions even with satisfactory sensitivity and precision are not practically of robust adaptation because of too long time needed. 2) The relationship between topology, parameter set, and robust adaptation of GRN is discovered in the sense of both preferred topology and parameter motif. Our conclusion is that the robust adaptation depends more on the GRN topology than the model parameter set in two feasible topologies. PMID- 28727559 TI - A Microfluidic Cytometer for Complete Blood Count With a 3.2-Megapixel, 1.1- MUm Pitch Super-Resolution Image Sensor in 65-nm BSI CMOS. AB - Based on a 3.2-Megapixel 1.1- MUm-pitch super-resolution (SR) CMOS image sensor in a 65-nm backside-illumination process, a lens-free microfluidic cytometer for complete blood count (CBC) is demonstrated in this paper. Backside-illumination improves resolution and contrast at the device level with elimination of surface treatment when integrated with microfluidic channels. A single-frame machine learning-based SR processing is further realized at system level for resolution correction with minimum hardware resources. The demonstrated microfluidic cytometer can detect the platelet cells (< 2 MUm) required in CBC, hence is promising for point-of-care diagnostics. PMID- 28727560 TI - A Multimodal Framework Based on Integration of Cortical and Muscular Activities for Decoding Human Intentions About Lower Limb Motions. AB - In this study, a multimodal fusion framework based on three different modal biosignals is developed to recognize human intentions related to lower limb multi joint motions which commonly appear in daily life. Electroencephalogram (EEG), electromyogram (EMG) and mechanomyogram (MMG) signals were simultaneously recorded from twelve subjects while performing nine lower limb multi-joint motions. These multimodal data are used as the inputs of the fusion framework for identification of different motion intentions. Twelve fusion techniques are evaluated in this framework and a large number of comparative experiments are carried out. The results show that a support vector machine-based three-modal fusion scheme can achieve average accuracies of 98.61%, 97.78% and 96.85%, respectively, under three different data division forms. Furthermore, the relevant statistical tests reveal that this fusion scheme brings significant accuracy improvement in comparison with the cases of two-modal fusion or only a single modality. These promising results indicate the potential of the multimodal fusion framework for facilitating the future development of human-robot interaction for lower limb rehabilitation. PMID- 28727561 TI - A COTS-Based Microwave Imaging System for Breast-Cancer Detection. AB - Microwave imaging is an emerging breast cancer diagnostic technique, which aims at complementing already established methods like mammography, magnetic resonance imaging, and ultrasound. It offers two striking advantages: no-risk for the patient and potential low-cost for national health systems. So far, however, the prototypes developed for validation in labs and clinics used costly lab instruments such as a vector network analyzer (VNA). Moreover, the CPU time required by complex image reconstruction algorithms may not be compatible with the duration of a medical examination. In this paper, both these issues are tackled. Indeed, we present a prototype system based on low-cost and off-the shelf microwave components, custom-made antennas, and a small form-factor processing system with an embedded field-programmable gate array for accelerating the execution of the imaging algorithm. We show that our low-cost system can compete with an expensive VNA in terms of accuracy, and it is more than 20x faster than a high-performance server at image reconstruction. PMID- 28727562 TI - A Digitally Dynamic Power Supply Technique for 16-Channel 12 V-Tolerant Stimulator Realized in a 0.18- MUm 1.8-V/3.3-V Low-Voltage CMOS Process. AB - A new digitally dynamic power supply technique for 16-channel 12-V-tolerant stimulator is proposed and realized in a 0.18-MUm 1.8-V/3.3-V CMOS process. The proposed stimulator uses four stacked transistors as the pull-down switch and pull-up switch to withstand 4 times the nominal supply voltage (4 * V DD). With the dc input voltage of 3.3 V, the regulated three-stage charge pump, which is capable of providing 11.3-V voltage at 3-mA loading current, achieves dc conversion efficiency of up to 69% with 400-pF integrated capacitance. Power consumption is reduced by implementing the regulated charge pump to provide a dynamic dc output voltage with a 0.5-V step. The proposed digitally dynamic power supply technique, which is implemented by using a p-type metal oxide semiconductor (PMOS) inverter with pull-down current source and digital controller, greatly improves the power efficiency of a system. The silicon area of the stimulator is approximately 3.5 mm2 for a 16-channel implementation. The functionalities of the proposed stimulator have been successfully verified through animal test. PMID- 28727563 TI - A Low-Power High-Dynamic-Range Receiver System for In-Probe 3-D Ultrasonic Imaging. AB - In this paper, a dual-mode low-power, high dynamic-range receiver circuit is designed for the interface with a capacitive micromachined ultrasonic transducer. The proposed ultrasound receiver chip enables the development of an in-probe digital beamforming imaging system. The flexibility of having two operation modes offers a high dynamic range with minimum power sacrifice. A prototype of the chip containing one receive channel, with one variable transimpedance amplifier (TIA) and one analog to digital converter (ADC) circuit is implemented. Combining variable gain TIA functionality with ADC gain settings achieves an enhanced overall high dynamic range, while low power dissipation is maintained. The chip is designed and fabricated in a 65 nm standard CMOS process technology. The test chip occupies an area of 76[Formula: see text] 170 [Formula: see text]. A total average power range of 60-240 [Formula: see text] for a sampling frequency of 30 MHz, and a center frequency of 5 MHz is measured. An instantaneous dynamic range of 50.5 dB with an overall dynamic range of 72 dB is obtained from the receiver circuit. PMID- 28727564 TI - Causal Inference on Multidimensional Data Using Free Probability Theory. AB - In this paper, we deal with the problem of inferring causal relations for multidimensional data. Based on the postulate that the distribution of the cause and the conditional distribution of the effect given cause are generated independently, we show that the covariance matrix of the mean embedding of the cause in reproducing kernel Hilbert space (RKHS) is free independent with the covariance matrix of the conditional embedding of the effect given cause. This, called freeness condition, induces a cause-effect asymmetry that a designed measurement is 0 in the causal direction but smaller than 0 in the anticausal direction, and it uncovers the causal direction. One important novel aspect of this paper is that we interpret the independence as a freeness condition between covariance matrices of RKHS distribution embeddings, and it has a wide applicability. We show that our freeness condition-based inference method succeeds in scenarios like additive noise cases, where other methods fail, by theoretical analysis and experimental results. PMID- 28727565 TI - DANoC: An Efficient Algorithm and Hardware Codesign of Deep Neural Networks on Chip. AB - Deep neural networks (NNs) are the state-of-the-art models for understanding the content of images and videos. However, implementing deep NNs in embedded systems is a challenging task, e.g., a typical deep belief network could exhaust gigabytes of memory and result in bandwidth and computational bottlenecks. To address this challenge, this paper presents an algorithm and hardware codesign for efficient deep neural computation. A hardware-oriented deep learning algorithm, named the deep adaptive network, is proposed to explore the sparsity of neural connections. By adaptively removing the majority of neural connections and robustly representing the reserved connections using binary integers, the proposed algorithm could save up to 99.9% memory utility and computational resources without undermining classification accuracy. An efficient sparse mapping-memory-based hardware architecture is proposed to fully take advantage of the algorithmic optimization. Different from traditional Von Neumann architecture, the deep-adaptive network on chip (DANoC) brings communication and computation in close proximity to avoid power-hungry parameter transfers between on-board memory and on-chip computational units. Experiments over different image classification benchmarks show that the DANoC system achieves competitively high accuracy and efficiency comparing with the state-of-the-art approaches. PMID- 28727566 TI - Model-Free Adaptive Control for Unknown Nonlinear Zero-Sum Differential Game. AB - In this paper, we present a new model-free globalized dual heuristic dynamic programming (GDHP) approach for the discrete-time nonlinear zero-sum game problems. First, the online learning algorithm is proposed based on the GDHP method to solve the Hamilton-Jacobi-Isaacs equation associated with optimal regulation control problem. By setting backward one step of the definition of performance index, the requirement of system dynamics, or an identifier is relaxed in the proposed method. Then, three neural networks are established to approximate the optimal saddle point feedback control law, the disturbance law, and the performance index, respectively. The explicit updating rules for these three neural networks are provided based on the data generated during the online learning along the system trajectories. The stability analysis in terms of the neural network approximation errors is discussed based on the Lyapunov approach. Finally, two simulation examples are provided to show the effectiveness of the proposed method. PMID- 28727567 TI - Intuitionistic Multiplicative Group Analytic Hierarchy Process and Its Use in Multicriteria Group Decision-Making. AB - As an extension of multiplicative preference relations (MPRs), intuitionistic MPRs (IMPRs) reflect experts' hesitant quantitative judgments. This paper presents an intuitionistic multiplicative preference information-based group analytic hierarchy process (AHP) and develops an intuitionistic multiplicative group AHP (IMGAHP), which addresses multicriteria group decision-making (MCGDM) that uses IMPRs to capture experts' preference judgments. First, we introduce a consistency index to gauge the consistency of IMPRs and describe the concept of acceptably consistent IMPRs. Second, we propose an algorithm for repairing an inconsistent IMPR to an acceptable level. Third, we propose an aggregation operator to integrate acceptably consistent IMPRs into a collective IMPR with acceptable consistency. We also propose an approach to derive an intuitionistic multiplicative priority weight vector from an acceptably consistent IMPR. An IMGAHP method is then described as a means of solving an MCGDM process with IMPRs. Finally, a practical example and comparative analysis are presented. PMID- 28727568 TI - Atopy as a risk factor for subclinical hypothyroidism development in children. AB - BACKGROUND: Increased thyroid stimulating hormone (TSH) serum concentration can be a marker of subclinical hypothyroidism (SCH) or transient hyperthyrotropinemia. The aim of our study was to evaluate whether high serum TSH concentrations in allergic children could represent true SCH or isolated and transient hyperthyrotropinemia. METHODS: We enrolled 620 allergic children (1.11 12.8 years) consecutively attending to our department. They were classified as atopics and non-atopics on the basis of the atopy work-up and, at baseline, they were investigated for thyroid function and low-grade inflammation state. Further, TSH was evaluated after 6 (T1) and 12 (T2) months. RESULTS: Both atopics and non atopics showed higher SCH prevalence compared to controls (p=0.0055 and p=0.02, respectively), and a significant association between atopy and SCH (OR 10.11, 95% CI 1.36-75.12) was found. Both at T1 and T2, atopics had a significant risk of developing severe SCH compared to non-atopics (RR 1.8, 95% CI 1.39-2.34 and 1.61, 95% CI 1.21-2.14; respectively). CONCLUSIONS: Our data may suggest that hyperthyrotropinemia in atopic children could be used as a marker of true SCH. PMID- 28727569 TI - Comparing the performance of linear and nonlinear principal components in the context of high-dimensional genomic data integration. AB - Linear principal component analysis (PCA) is a widely used approach to reduce the dimension of gene or miRNA expression data sets. This method relies on the linearity assumption, which often fails to capture the patterns and relationships inherent in the data. Thus, a nonlinear approach such as kernel PCA might be optimal. We develop a copula-based simulation algorithm that takes into account the degree of dependence and nonlinearity observed in these data sets. Using this algorithm, we conduct an extensive simulation to compare the performance of linear and kernel principal component analysis methods towards data integration and death classification. We also compare these methods using a real data set with gene and miRNA expression of lung cancer patients. First few kernel principal components show poor performance compared to the linear principal components in this occasion. Reducing dimensions using linear PCA and a logistic regression model for classification seems to be adequate for this purpose. Integrating information from multiple data sets using either of these two approaches leads to an improved classification accuracy for the outcome. PMID- 28727575 TI - Surface energy-tunable iso decyl acrylate based molds for low pressure nanoimprint lithography. AB - We presented surface energy-tunable nanoscale molds for unconventional lithography. The mold is highly robust, transparent, has a minimized haze, does not contain additives, and is a non-fluorinated isodecyl acrylate and trimethylolpropane triacrylate based polymer. By changing the mixing ratio of the polymer components, the cross-linking density, mechanical modulus, and surface energy (crucial factors in low pressure ((1-2) * 105 N m-2) low pressure nanoimprint lithography (LP-NIL)), can be controlled. To verify these properties of the molds, we also characterized the surface energy by measuring the contact angles and calculating the work of adhesion among the wafer, polymer film, and mold for successful demolding in nanoscale structures. Moreover, the molds showed high optical clarity and precisely tunable mechanical and surface properties, capable of replicating sub-100 nm patterns by thermal LP-NIL and UV-NIL. PMID- 28727576 TI - Severe Respiratory Failure, Extracorporeal Membrane Oxygenation, and Intracranial Hemorrhage. AB - OBJECTIVES: For patients supported with veno-venous extracorporeal membrane oxygenation, the occurrence of intracranial hemorrhage is associated with a high mortality. It is unclear whether intracranial hemorrhage is a consequence of the extracorporeal intervention or of the underlying severe respiratory pathology. In a cohort of patients transferred to a regional severe respiratory failure center that routinely employs admission brain imaging, we sought 1) the prevalence of intracranial hemorrhage; 2) survival and neurologic outcomes; and 3) factors associated with intracranial hemorrhage. DESIGN: A single-center, retrospective, observational cohort study. SETTING: Tertiary referral severe respiratory failure center, university teaching hospital. PATIENTS: Patients admitted between December 2011 and February 2016. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: Three hundred forty-two patients were identified: 250 managed with extracorporeal support and 92 managed using conventional ventilation. The prevalence of intracranial hemorrhage was 16.4% in extracorporeal membrane oxygenation patients and 7.6% in conventionally managed patients (p = 0.04). Multivariate analysis revealed factors independently associated with intracranial hemorrhage to be duration of ventilation (d) (odds ratio, 1.13 [95% CI, 1.03 1.23]; p = 0.011) and admission fibrinogen (g/L) (odds ratio, 0.73 [0.57-0.91]; p = 0.009); extracorporeal membrane oxygenation was not an independent risk factor (odds ratio, 3.29 [0.96-15.99]; p = 0.088). In patients who received veno-venous extracorporeal membrane oxygenation, there was no significant difference in 6 month survival between patients with and without intracranial hemorrhage (68.3% vs 76.0%; p = 0.350). Good neurologic function was observed in 92%. CONCLUSIONS: We report a higher prevalence of intracranial hemorrhage than has previously been described with high level of neurologically intact survival. Duration of mechanical ventilation and admission fibrinogen, but not exposure to extracorporeal support, are independently associated with intracranial hemorrhage. PMID- 28727577 TI - Nurses Exploring the Spirituality of Their Patients With Cancer: Participant Observation on a Medical Oncology Ward. AB - BACKGROUND: Attention for spirituality should be an integral part of professionals' caregiving. Particularly, nurses caring for patients with cancer might have opportunities to give attention to this dimension. OBJECTIVE: The aim of this study was to gain insight in the way and extent to which nurses during daily caregiving observe and explore spiritual issues of hospitalized patients with cancer. METHODS: We performed an ethnographic study with participant observation. Data were collected in 2015 during 4 shifts at the medical oncology department of a university hospital. The researcher, a spiritual care provider (chaplain) wearing the same kind of uniform as the nurses, observed the nurses, participated in their actions, and interviewed them after the shift. RESULTS: Although the patients did send many implicit and explicit messages concerning spiritual issues, the nurses did not explore them. If noticed, 3 barriers for exploring spiritual issues were mentioned by the nurses: lack of time, conflict with their mindset, and being reserved to talk about such issues. CONCLUSIONS: During their daily caregiving to patients with a life-threatening illness, nurses have many opportunities to explore spiritual issues, but they do not often recognize them. If they do, they tend not to explore the spiritual issues. IMPLICATIONS FOR PRACTICE: Communication training for nurses is necessary to develop skills for exploring the spiritual dimension in patients with cancer. In such training, attention to the misconception that such a conversation requires a lot of time and for recognizing signals from patients inviting an exploration of their concerns is necessary. PMID- 28727579 TI - Enhanced anticancer efficacy of histone deacetyl inhibitor, suberoylanilide hydroxamic acid, in combination with a phosphodiesterase inhibitor, pentoxifylline, in human cancer cell lines and in-vivo tumor xenografts. AB - Vorinostat [suberoylanilide hydroxamic acid (SAHA)], a histone deacetylase inhibitor, shows limited clinical activity against solid tumors when used alone. The methyl xanthine drug, pentoxifylline (PENT), has been described to have antitumor properties. The aim of this study was to look for the enhanced anticancer activities of both agents when used in combination at doses lower than their respective efficacy dose when used alone. We investigated the antitumor potential of this novel combination in vitro and in vivo. The combination index was assessed for these two drugs to look for synergistic antiproliferative activity against a broad spectrum of human cancer cell lines. Consistent additive to synergistic interactions were observed in HCT116 cells when PENT was combined with SAHA at all drug tested concentrations. The combination of SAHA and PENT induces chromatin condensation and apoptosis downstream of the pan histone deacetylase inhibition and phosphodiesterase regulation, leading to subsequent cell cycle arrest at their lower tested concentrations. Further, the ability of this combination to inhibit angiogenesis, both in vitro and in vivo, was examined and a significant inhibition in tube formation in HUVEC cells and neovascularization of Matrigel plug was observed. A significant inhibition in tumor growth was observed in severe combined immunodeficient mice bearing HCT116 (colon) and PC3 (prostate) human xenografts treated with SAHA (30 mg/kg, intraperitoneal) in combination with PENT (60 mg/kg, intraperitoneal), with no loss in body weight and 100% survival. In conclusion, these findings indicate the enhanced anticancer activity of SAHA in combination with PENT both in vitro and in vivo. PMID- 28727578 TI - Physical Activity and Survival in Women With Advanced Breast Cancer. AB - BACKGROUND: Several empirical investigations have attempted to characterize the effect of physical activity on cancer mortality, but these investigations have rarely focused on patients with advanced breast cancer. OBJECTIVE: The current study examined the hypothesis that greater physical activity is associated with longer survival among women with advanced breast cancer. METHODS: We conducted a secondary data analysis of a prospective study of 103 patients with stage IV (n = 100) or locally recurrent (n = 3) breast cancer involved in a group psychotherapy trial. Physical activity was assessed at baseline using the Seven-Day Physical Activity Recall questionnaire, and patients were followed until April 1, 2016, at which time 93 of 103 had died. RESULTS: Greater physical activity level at baseline was significantly associated with longer subsequent survival time in a Cox proportional hazards model (hazard ratio [HR], 0.90; 95% confidence interval [CI], 0.84-0.97; P < .01). Engaging in 1 additional hour per day of moderate activity reduced the hazard of subsequent mortality by 23% (HR, 0.77; 95% CI, 0.65-0.92; P < .01). These results remained significant even after controlling for demographic, medical, cancer, depression, and cortisol variables (HR, 0.91; 95% CI, 0.84-0.99; P < .05). CONCLUSIONS: Women with advanced breast cancer who engaged in physical activity for 1 or more hours per day at baseline had an increased likelihood of survival compared with those who exercised less than 1 hour per day. IMPLICATIONS FOR PRACTICE: Nurses should consider recommending moderate physical activity for women with advanced breast cancer. Randomized trials of physical activity interventions for this population are needed. PMID- 28727580 TI - Increase in intracranial pressure by application of a rigid cervical collar: a pilot study in healthy volunteers. AB - OBJECTIVES: Rigid cervical collars are known to increase intracranial pressure (ICP) in severe traumatic brain injury (TBI). Cerebral blood flow might decrease according to the Kellie Monroe doctrine. For this reason, the use of the collar in patients with severe TBI has been abandoned from several trauma protocols in the Netherlands. There is no evidence on the effect of a rigid collar on ICP in patients with mild or moderate TBI or indeed patients with no TBI. As a first step we tested the effect in healthy volunteers with normal ICPs and intact autoregulation of the brain. METHODS: In this prospective blinded cross-over study, we evaluated the effect of application of a rigid cervical collar in 45 healthy volunteers by measuring their optical nerve sheath diameter (ONSD) by transocular sonography. Sonographic measurement of the ONSD behind the eye is an indirect noninvasive method to estimate ICP and pressure changes. RESULTS: We included 22 male and 23 female volunteers. In total 360 ONSD measurements were performed in these 45 volunteers. Application of a collar resulted in a significant increase in ONSD in both the left (beta=0.06, 95% confidence interval: 0.05-0.07, P<0.001) and the right eye (beta=0.01, 95% confidence interval: 0.00-0.02, P=0.027) CONCLUSION: Application of a rigid cervical collar significantly increases the ONSD in healthy volunteers with intact cerebral autoregulation. This suggests that ICP may increase after application of a collar. In healthy volunteers, this seems to be of minor importance. On the basis of our findings the effect of a collar on ONSD and ICP in patients with mild and moderate TBI needs to be determined. PMID- 28727582 TI - Rapidly growing coronary artery aneurysm associated with pericarditis. PMID- 28727581 TI - Perioperative Gabapentin Does Not Reduce Postoperative Delirium in Older Surgical Patients: A Randomized Clinical Trial. AB - BACKGROUND: Postoperative pain and opioid use are associated with postoperative delirium. We designed a single-center, randomized, placebo-controlled, parallel arm, double-blinded trial to determine whether perioperative administration of gabapentin reduced postoperative delirium after noncardiac surgery. METHODS: Patients were randomly assigned to receive placebo (N = 347) or gabapentin 900 mg (N = 350) administered preoperatively and for the first 3 postoperative days. The primary outcome was postoperative delirium as measured by the Confusion Assessment Method. Secondary outcomes were postoperative pain, opioid use, and length of hospital stay. RESULTS: Data for 697 patients were included, with a mean +/- SD age of 72 +/- 6 yr. The overall incidence of postoperative delirium in any of the first 3 days was 22.4% (24.0% in the gabapentin and 20.8% in the placebo groups; the difference was 3.20%; 95% CI, 3.22% to 9.72%; P = 0.30). The incidence of delirium did not differ between the two groups when stratified by surgery type, anesthesia type, or preoperative risk status. Gabapentin was shown to be opioid sparing, with lower doses for the intervention group versus the control group. For example, the morphine equivalents for the gabapentin-treated group, median 6.7 mg (25th, 75th quartiles: 1.3, 20.0 mg), versus control group, median 6.7 mg (25th, 75th quartiles: 2.7, 24.8 mg), differed on the first postoperative day (P = 0.04). CONCLUSIONS: Although postoperative opioid use was reduced, perioperative administration of gabapentin did not result in a reduction of postoperative delirium or hospital length of stay. PMID- 28727583 TI - Serum Bupivacaine Concentration After Periarticular Injection With a Mixture of Liposomal Bupivacaine and Bupivacaine HCl During Total Knee Arthroplasty. AB - BACKGROUND AND OBJECTIVES: A relatively new technique to reduce postoperative pain for total knee arthroplasty is to inject a mixture of 266 mg of liposomal bupivacaine and 125 mg of 0.25% bupivacaine HCl with epinephrine 1:300,000 around the knee joint at the time of surgery. Currently, no publications report serum bupivacaine concentrations over time after periarticular injection of liposomal mixed with free bupivacaine. This information is important to ensure safe serum bupivacaine concentrations are maintained especially when considering supplemental or rescue peripheral nerve blocks. METHODS: A total of 40 subjects scheduled for primary unilateral total knee arthroplasty with intraoperative periarticular injection of the liposomal bupivacaine and bupivacaine HCl mixture were included. Total serum bupivacaine concentrations were measured after the last injection at selected time points and calculated by gas chromatography. Quantile regression techniques were used to analyze the data over time. This study is registered with ClinicalTrials.gov (ID NCT02626559). RESULTS: Peak serum concentration ranged from 0.17 to 1.2 MUg/mL and occurred from 10 minutes to 48 hours. Across all time points, the 48-hour interval had the highest mean concentration of total serum bupivacaine at 0.55 MUg/mL (SD, 0.27). Quantile regression showed total serum bupivacaine concentrations increased over the 48 hours measured. None of the participants demonstrated signs or symptoms of local anesthetic toxicity. CONCLUSIONS: Total serum concentrations of bupivacaine after periarticular administration of liposomal bupivacaine mixed with bupivacaine HCl remained below the described toxicity threshold (2.5 MUg/mL) within the first 48 hours, and no patients demonstrated signs or symptoms of toxicity. However, peak serum concentration time was not achieved within the 48-hour interval. Additional studies are needed to describe the course of serum bupivacaine levels after 48 hours and to ascertain the risk of toxicity when combining this method of periarticular injection with peripheral nerve blocks. PMID- 28727584 TI - Thoracic Epidural Catheter Placement in a Preoperative Block Area Improves Operating Room Efficiency and Decreases Epidural Failure Rate. AB - BACKGROUND AND OBJECTIVES: The primary aim of this study was to review the impact of inserting thoracic epidural catheters in a preoperative block room setting on operating room efficiency. METHODS: We conducted a retrospective preintervention/postintervention review of thoracic epidurals inserted over a 12 month period. The review included 6 months of data prior to implementation of the regional anesthesia block room and 6 months of data following implementation. The primary outcome measure was anesthesia-controlled operating room time, defined as time from patient arrival to the operating room to time of surgical site sterile preparation. Secondary measures included operating room waiting time for the patient arrival, thoracic epidural failure rate, and number of epidural insertion attempts. RESULTS: Data from thoracic epidurals for 112 patients of preblock room and 142 patients of postblock room implementation were collected. Anesthesia controlled operating room time was reduced by an average of 22.9 minutes per patient (95% confidence interval, 19.3-26.3 minutes; P < 0.01). Average operating room waiting time for patient arrival increased by 3.8 minutes (95% confidence interval, 1.0-6.5 minutes; P < 0.01), resulting in net operating room time savings of 19.1 minutes per epidural. The epidural failure rate decreased from 16.0% to 5.6% (P < 0.01). There was no difference in the number of epidural insertion attempts made per patient. CONCLUSIONS: Insertion of thoracic epidural analgesia in a preoperative block room setting can significantly reduce anesthesia-controlled operating room time and epidural failure rates. PMID- 28727585 TI - Closed Continuous Irrigation With Lidocaine and Immediate Mobilization for Treatment of Pyogenic Tenosynovitis. AB - Pyogenic flexor tenosynovitis treatment consists of either closed continuous irrigation with sterile saline or antibiotic solution, or open debridement and irrigation. These treatment approaches serve to resolve the infection, but are extremely painful and residual stiffness can be devastating to the patient. We describe herein our approach to managing pyogenic flexor tenosynovitis. To provide continuous irrigation, a butterfly catheter with needle removed is utilized with irrigation holes cut into the tubing. The catheter is inserted into the tendon sheath at the level of the Al pulley and brought out at the level of the A5 pulley. A knot is tied in the end of the catheter for retention, eliminating the need for sutures. Immediately postoperative, continuous irrigation with sterile saline mixed with lidocaine is initiated and is titrated to achieve pain-free motion in the finger. Occupational therapy begins an aggressive course of active and passive range of motion exercises immediate postoperatively, which is continued for the remainder of hospitalization. Our approach of continuous infusion of a lidocaine solution allows for pain-free movement immediately postoperatively to mechanically debride tissue, as well as allow for early active range of motion. We have obtained excelleepaknt results with this technique in all of our cases. PMID- 28727586 TI - Moisture Balance the Tipping Point. PMID- 28727587 TI - The Scout Device's Reliability: Methodological Issues. PMID- 28727590 TI - Prepare Your Systems for the Social Security Number Removal Initiative. PMID- 28727591 TI - The Effectiveness of EMLA as a Primary Dressing on Painful Chronic Leg Ulcers: A Pilot Randomized Controlled Trial. AB - OBJECTIVE: To evaluate the effectiveness of the eutectic mixture of local anesthetics (EMLA; Aspen Pharmacare, St. Leonards, New South Wales, Australia) as a primary dressing on painful chronic leg ulcers. DESIGN: A pilot randomized controlled trial. SETTING: The study was conducted across 6 community nursing procedure clinics located in a community nursing service in New South Wales, Australia. PARTICIPANTS: Sixty participants with painful chronic leg ulcers of varied etiology were recruited into the study. INTERVENTION: Participants were randomly assigned to an intervention (daily EMLA use for 4 weeks as a primary dressing) or a standard wound care group. MAIN OUTCOME MEASURE: The effectiveness of EMLA on wound-related pain intensity before, during, and after dressing change. MAIN RESULTS: Mean pain scores were similar between the 2 groups at baseline (P = .84). During dressing change, mean pain scores across the 4-week intervention period were significantly lower in the intervention compared with the control group (intervention group: mean, 3.39 [SD, 2.16]; control group: mean, 4.82 [SD, 2.27]; P = .02). Mean pain scores after dressing change were also significantly lower for the intervention group over the 4-week intervention period (intervention group: mean, 2.71 [SD, 1.94]; control group: mean, 3.92 [SD, 2.03]; P = .03). CONCLUSIONS: Data from this pilot study suggest that EMLA as a primary dressing may be effective in reducing chronic leg ulcer pain during and after dressing change and warrant further evaluation. PMID- 28727592 TI - Nutrition, Exercise, and Skin Integrity among Frail Older Adults in Taiwan. AB - OBJECTIVE: The purpose was to determine the correlation between nutrition status and skin integrity in the frail older adult population. DESIGN AND SETTING: Participants (N = 94) in this cross-sectional study were recruited through convenience sampling from the neurology and geriatrics outpatient department at a regional teaching hospital in Northern Taiwan. Study tools included a Basic Participant Profile Fill-in Sheet, which assesses demographic and exercise habit; the Comorbidity Index; Skin Integrity Evaluation Chart; Mini-Nutritional Assessment-Short Form; and Taiwan International Physical Activity Questionnaire Form. Data were analyzed by independent-samples t tests, chi tests, linear regressions, and logistic regression analyses. RESULTS: Significant correlations were found among nutrition status, aging, and exercise habits, as well as between participants' demographics and their skin integrity. Logistic linear regression showed that the decline of skin integrity can be predicted by nutrition status. CONCLUSIONS: Exercise programs and a balanced diet should be planned for frail older adults, and their nutrition status should be monitored closely. Those with declining nutrition status should be provided with nutrition supplements. In addition, clinicians should evaluate the skin condition of frail older adults to prevent the development of pressure injuries. PMID- 28727593 TI - Understanding Moisture-Associated Skin Damage, Medical Adhesive-Related Skin Injuries, and Skin Tears. AB - GENERAL PURPOSE: To provide information on superficial skin issues related to moisture-associated skin damage, medical adhesive-related skin injury, and skin tears. TARGET AUDIENCE: This continuing education activity is intended for physicians, physician assistants, nurse practitioners, and nurses with an interest in skin and wound care. LEARNING OBJECTIVES/OUTCOMES: After participating in this educational activity, the participant should be better able to:1. Examine the anatomy of skin, including changes that occur from aging and chronic wounds.2. Identify issues related to moisture-associated skin damage, medical adhesive-related skin injury, and skin tears, including techniques for prevention. ABSTRACT: The purpose of this continuing education article is to examine the superficial skin issues related to moisture-associated damage, medical adhesive-related skin injury, and skin tears. Similarities, differences, prevention, and treatment will be described. PMID- 28727594 TI - Quality Payment Program and Quality Measure Benchmarks. PMID- 28727595 TI - Understanding Moisture-Associated Skin Damage, Medical Adhesive-Related Skin Injuries, and Skin Tears. PMID- 28727596 TI - Intraoperative Acute Multivessel Coronary Vasospasm in Cardiac Allograft: A Case Report. AB - We present a patient who developed acute intraoperative cardiac failure requiring open cardiac message immediately after uncomplicated heart transplantation. After successful resuscitation and establishment of extracorporeal membrane oxygenation, coronary angiography showed diffuse multivessel coronary vasospasm, which responded to intracoronary and IV administration of vasodilators. Cardiac function gradually improved and the patient was discharged home after a prolonged hospital course. Cardiac allograft dysfunction associated with coronary vasospasm immediately after heart transplantation has not previously been reported. PMID- 28727597 TI - Bilateral Continuous Erector Spinae Plane Block Contributes to Effective Postoperative Analgesia After Major Open Abdominal Surgery: A Case Report. AB - The erector spinae plane (ESP) block is a regional anesthetic technique involving local anesthetic injection in a paraspinal plane deep to the erector spinae muscle. Originally described for thoracic analgesia when performed at the T5 transverse process, the ESP block can provide abdominal analgesia if performed at lower thoracic levels because the erector spinae muscles extend to the lumbar spine. A catheter inserted into this plane can extend analgesic duration and can be an alternative to epidural analgesia. In this report, we describe using bilateral ESP catheters inserted at the T8 level to provide effective perioperative analgesia for major open lower abdominal surgery. PMID- 28727598 TI - Unusual Eruption on the Arm: Challenge. PMID- 28727599 TI - Refractory Intertrigo in the Right Inguinal Crease: Challenge. PMID- 28727600 TI - Nodular Lesion in Cheek With a Hair Tuft. PMID- 28727601 TI - Erythema Multiforme Following lines of Blaschko. PMID- 28727602 TI - Unusual Eruption on the Arm. PMID- 28727603 TI - Nodular Lesion in Cheek With a Hair Tuft. AB - Trichostasis spinulosa is a rarely diagnosed disorder of the pilosebaceous unit, characterized by retention of telogen hairs within the dilated follicles. A hair tuft can be seen protruding from the follicles. We present a case of trichostasis spinulosa associated with intradermal melanocytic nevi, where dermoscopy helps to identify this entity. PMID- 28727604 TI - Preclinical Development of EBI-005: An IL-1 Receptor-1 Inhibitor for the Topical Ocular Treatment of Ocular Surface Inflammatory Diseases. AB - OBJECTIVE: Topical interleukin (IL)-1 receptor (R)1 blockade is therapeutically active in reducing signs and symptoms of dry eye disease. Herein, we describe in vitro and in vivo nonclinical Investigational New Drug (IND)-enabling studies of EBI-005, a novel protein chimera of IL-1beta and IL-1 receptor antagonist (IL-1Ra or anakinra) that potently binds IL-1R1 and blocks signaling. These studies provide an assessment of receptor affinity, drug bioavailability, immunogenic response, safety, and tolerability in mice and rabbits. METHODS: In vitro and in silico along with Good Laboratory Practices (GLP) and non-GLP in vivo studies in mice and rabbits assessed the topical ocular and systemic immunogenicity and toxicology of EBI-005. Animals were treated with EBI-005 once daily subcutaneously or four times daily by topical ocular administration for up to 6 weeks (with 2-week recovery phase). RESULTS: EBI-005 has 500 times higher affinity than anakinra to IL-1R1. Predictive immunogenicity testing suggested that EBI-005 is not more immunogenic. Systemic bioavailability of EBI-005 is low (1.4% in mice and 0.2% in rabbits) after topical ocular administration. EBI-005 penetrated into the anterior ocular tissues within 15 min of topical ocular administration. However, it is low or undetectable after 4 hr and does not form a depot after repeated topical ocular administration. EBI-005 was safe and well tolerated, and exposure to drug was maintained despite an antidrug antibody response after systemic administration, based on IND-enabling toxicology and safety pharmacology studies. CONCLUSIONS: Ocular doses of EBI-005 at 50 mg/mL in mice and rabbits totaling 0.15 mg/eye in mice and 1.5 mg/eye in rabbits, administered 4 times daily, did not produce adverse effects, and demonstrated excellent bioavailability in target tissues with low systemic exposure. In addition, immunogenic response to the drug did not cause adverse effects or diminish the drug's activity in most cases. The results support drug administration of the highest anticipated human clinical study dose of a 20 mg/mL solution (40 MUL 3 times daily in each eye). PMID- 28727605 TI - In Vitro Compatibility of Contact Lenses With Corneal Epithelial Cells. AB - PURPOSE: To determine the interaction of contact lenses of different materials with corneal epithelial cells grown in tissue culture. METHODS: Two different corneal epithelial cell lines were grown to confluence in culture media. Two hydrogel contact lenses with and without polyvinylpyrrolidone (PVP) {1-DAY ACUVUE MOIST (1-Day ACUVUE [hydrogel lenses]) and a silicone hydrogel contact lens, AIR OPTIX NIGHT & DAY} were removed from their blister packs, washed in phosphate buffered saline, and applied to the cells. After exposure for 24 hr at 37 degrees C, lenses were removed, and the corneal cells and supernatants processed. Supernatants from the cell assays were used to quantify the amount of 17 different cytokines that were produced using a multiplex bead assay. Cells were stained to assess amount of cell death (apoptosis or necrosis) or stained to determine the level of mitochondrial activity. Stimulants of necrotic death (latex) or apoptotic death (sorbitol) were used as positive controls. RESULTS: Cells produced cytokines during normal growth. Exposure of cells to the hydrogel lenses resulted in only minimal changes to normal production of cytokines, but latex or sorbitol produced the most change. Exposure of the cells to all three lenses caused 4% to 23% reduction in mitochondrial activity, whereas exposure to the positive controls caused 71% to 98% reduction in mitochondrial activity. Exposure of the corneal epithelial cells to contact lenses produced minimal morphological changes, whereas exposure to latex or sorbitol produced significant changes to the human corneal epithelial cell line. CONCLUSIONS: Exposure of corneal epithelial cells to contact lenses had minimal impact on their physiology. There was no difference in epithelial cell responses to hydrogel with or without PVP compared with the silicone hydrogel contact lens. PMID- 28727606 TI - The Clinical Utility of Respiratory Variation in Inferior Vena Cava Diameter for Predicting Fluid Responsiveness in Spontaneously Ventilating Patients. PMID- 28727608 TI - Evaluation of Noninvasive Hemoglobin Monitoring in Trauma Patients with Low Hemoglobin Levels. AB - OBJECTIVE: Bleeding is a leading cause of death among trauma patients. Delayed assessment of blood hemoglobin level might result in either unnecessary blood transfusion in nonindicated patients or delayed blood transfusion in critically bleeding patients. In this study, we evaluate the precision of noninvasive hemoglobin monitoring in trauma patients with low hemoglobin levels. METHODS: We included trauma patients with low hemoglobin levels (less than 8 g/dL) scheduled for surgical intervention. Blood samples were obtained on admission and after each blood unit with concomitant measurement of serum hemoglobin using radical-7 Masimo device. The change in blood hemoglobin after every transfused blood unit was also assessed by both methods (change in noninvasive Masimo hemoglobin [Delta Sp-Hb] and change in laboratory hemoglobin [Delta-Lab-Hb]). The precision of Masimo hemoglobin level (Sp-Hb) compared with Laboratory hemoglobin level (Lab Hb) was determined using both Bland-Altman and Pearson correlation analyses. RESULTS: One hundred eighty-four time-matched samples were available for final analysis. Bland-Altman analysis showed excellent accuracy of Sp-Hb compared with Lab-Hb with mean bias of 0.12 g/dL and limits of agreement between -0.56 g/dL and 0.79 g/dL. Excellent correlation was reported between both measures with Pearson correlation coefficient of 0.872. Excellent agreement was also reported between both Delta-Sp-Hb and Delta-Lab-Hb with mean bias of -0.05 and limits of agreement from -0.62 to 0.51 CONCLUSIONS:: Sp-Hb showed accurate precision in both absolute values and trend values compared with Lab-Hb measurement in trauma patients with low hemoglobin levels. PMID- 28727607 TI - New-Onset Heart Failure and Mortality in Hospital Survivors of Sepsis-Related Left Ventricular Dysfunction. AB - BACKGROUND: The association between new-onset left ventricular (LV) dysfunction during sepsis with long-term heart failure outcomes is lesser understood. METHODS: Retrospective cohort study of all adult patients with severe sepsis and septic shock between 2007 and 2014 who underwent echocardiography within 72 h of admission to the intensive care unit. Patients with prior heart failure, LV dysfunction, and structural heart disease were excluded. LV systolic dysfunction was defined as LV ejection fraction <50% and LV diastolic dysfunction as >=grade II. Primary composite outcome included new hospitalization for acute decompensated heart failure and all-cause mortality at 2-year follow-up. Secondary outcomes included persistent LV dysfunction, and hospital mortality and length of stay. RESULTS: During this 8-year period, 434 patients with 206 (48%) patients having LV dysfunction were included. The two groups had similar baseline characteristics, but those with LV dysfunction had worse function as demonstrated by worse LV ejection fraction, cardiac index, and LV diastolic dysfunction. In the 331 hospital survivors, new-onset acute decompensated heart failure hospitalization did not differ between the two cohorts (15% vs. 11%). The primary composite outcome was comparable at 2-year follow-up between the groups with and without LV dysfunction (P = 0.24). Persistent LV dysfunction was noted in 28% hospital survivors on follow-up echocardiography. Other secondary outcomes were similar between the two groups. CONCLUSIONS: In patients with severe sepsis and septic shock, the presence of new-onset LV dysfunction did not increase the risk of long-term adverse heart failure outcomes. PMID- 28727609 TI - Atrial Natriuretic Peptide: A Potential Early Therapy for the Prevention of Multiple Organ Dysfunction Syndrome Following Severe Trauma. AB - Trauma remains a tremendous medical burden partly because of increased expenditure for the management of multiple organ dysfunction syndrome (MODS) developed during hospital stay. The intestinal barrier injury continues to be a second insult resulting in MODS which currently lacks efficient strategies for prevention. Recent studies have uncovered multi-organ protective benefits of atrial natriuretic peptide (ANP) in cardiovascular disease. However, the role of ANP in the prevention of MODS following severe trauma has not been understood. In our laboratory study, 1-h infusion of exogenous ANP during hemorrhagic shock following severe trauma induced high-level expression of endogenous serum ANP after 24 h, this effect was related to the improved level of functional biomarkers in multiple organs. Such phenomenon has not been found in other laboratories. A thorough literature review consequently was performed to uncover the potential mechanisms, to appraise therapy safety, and to propose uncertainties. In severe trauma, short-term exogenous ANP therapy during hemorrhagic shock may promote sustained endogenous expression of ANP from intestinal epithelium through activating a positive feedback loop mechanism involving phospholipase C-gamma1 and reactive oxygen species crosstalk. This feedback loop may prevent MODS through multiple signaling pathways. Administration of ANP during hemorrhagic shock is thought to be safe. Further studies are required to confirm our proposed mechanisms and to investigate the dose, duration, and timing of ANP therapy in severe trauma. PMID- 28727610 TI - The Metabolopathy of Tissue Injury, Hemorrhagic Shock, and Resuscitation in a Rat Model. AB - INTRODUCTION: The metabolic consequences of trauma induce significant clinical pathology. In this study, we evaluate the independent, metabolic contributions of tissue injury (TI) and combined tissue injury and hemorrhagic shock (TI/HS) using mass spectrometry (MS) metabolomics in a controlled animal model of critical injury. METHODS: Sprague-Dawley rats (n = 14) underwent TI alone or TI/HS, followed by resuscitation with normal saline and shed blood. Plasma was collected (baseline, post-laparotomy, post-HS, post-resuscitation) for ultra-high pressure liquid chromatography MS-metabolomics. Repeated-measures ANOVA with Tukey multiple column comparison test compared the fold change of metabolite concentration among the animal groups at corresponding time points. RESULTS: Four hundred forty metabolites were identified. TI alone did not change the metabolite levels versus baseline. TI/HS induced changes in metabolites from glycolysis, the tricarboxylic acid cycle, the pentose phosphate, fatty acid and glutathione homeostasis pathways, sulfur metabolism, and urea cycle versus TI alone. Following resuscitation many metabolites normalized to TI alone levels, including lactate, most tri-carboxylic acid metabolites, most urea cycle metabolites, glutathione disulfide, and some metabolites from both the pentose phosphate pathway and sulfur metabolism. CONCLUSIONS: Significant changes occur immediately following TI/HS versus TI alone. These metabolic changes are not explained by dilution as a number of metabolites remained unchanged or even increased following resuscitation. The differential metabolic changes resulting from TI alone and TI/HS provide foundation for future investigations severe injury in humans, where TI and HS are often concurrent. This investigation provides a foundation to evaluate metabolic-related outcomes and design-targeted resuscitation strategies. PMID- 28727611 TI - Formula Feeding as a Risk Factor for Attention-Deficit/Hyperactivity Disorder: Is Bisphenol A Exposure a Smoking Gun? AB - OBJECTIVE: Breastfeeding during infancy is associated with a lower risk of attention-deficit/hyperactivity disorder (ADHD). Although this is presumably due to breast milk's nutritional advantages, formula-fed infants have, until recently, also been exposed to bisphenol A (BPA), a neurotoxic chemical previously used to manufacture baby bottles and formula cans. Our goal was to examine the association between formula feeding and preschool ADHD in 2 comparable, serial cohorts of preschool children who differ in BPA exposure during infancy. METHODS: Cross-sectional analysis of the 2007 and 2011/12 National Survey of Children's Health (NSCH). Logistic regression was used to model preschool ADHD diagnoses as a function of breastfeeding, adjusting for 12 possible confounding variables using a propensity score. RESULTS: In the 2007 data set (weighted n = 9,644,405), formula-fed subjects had a 5-fold increased odds of ADHD compared with breastfed subjects (adjusted odds ratio [aOR]: 5.58, 95% confidence interval [CI], 2.16-14.41). In the 2011/12 data set (n = 9,732,865), there was no significant association between formula feeding and later ADHD (aOR: 1.05, 95% CI, 0.42-2.64). This is despite an increase in the prevalence of preschool ADHD in 2011 (0.88%) compared with 2007 (0.40%) (Rao Scott chi, p < .0075). CONCLUSION: Compared with breastfed infants, ADHD was more common among formula-fed infants in the 2007 but not the 2011/12 sample, where exposure to BPA was markedly reduced. These findings suggest that the reduced prevalence of ADHD among breastfed infants may not be due to the nutritional benefits of breast milk, but rather early exposure to BPA, a neurotoxic chemical previously found in infant formula. PMID- 28727612 TI - Commentary on "Formula Feeding as a Risk Factor for Attention Deficiency Hyperactivity Disorder: Is Bisphenol A Exposure a Smoking Gun?" PMID- 28727613 TI - Aberrometry Repeatability and Agreement with Autorefraction. AB - SIGNIFICANCE: Commercially available aberrometers are essential to clinical studies evaluating refractive error and image quality. The Discovery System (Innovative Visual Systems, Elmhurst, IL) is a promising clinical instrument that allows investigators to export aberration data for research and analysis purposes. An assessment of the Discovery System's performance is essential to the interpretation of the data obtained. PURPOSE: The aims of this study were to determine the between-visit repeatability of refractive error and higher-order aberration measurements with the Discovery System and to examine between instrument agreement of refractive error measurements with the Discovery System and Grand Seiko WAM-5500 open-field autorefractor (Grand Seiko Co., Hiroshima, Japan). METHODS: Cycloplegic refractive error values from the Discovery System (over a 3-mm pupil) and the Grand Seiko autorefractor were converted to power vectors (M, J0, and J45), and averaged. Zernike coefficients were also calculated by the Discovery System over a 6-mm pupil through the sixth radial order. Between visit repeatability and agreement were evaluated using Bland-Altman difference versus-mean plots. A t-test compared each mean difference (bias) to zero, and the 95% limits of agreement were calculated. RESULTS: Twenty-five young adults with a mean (+/-SD) cycloplegic spherical-equivalent refractive error of -2.91 +/- 1.85 diopters (D) (range, -6.96 to +0.74 D) were enrolled. There were no significant between-visit differences with the Discovery System for M, J0, J45, third- through sixth-order root mean square (RMS), higher-order RMS, or spherical aberration (all P > .30), and the repeatability for defocus and higher-order RMS were +/-0.31 D and +/-0.095 MUm, respectively, for a 6-mm pupil. At a 3-mm pupil, the Discovery System, on average, measured slightly more positive values than the Grand Seiko for M (0.28 D), J0 (0.11 D), and J45 (0.12 D; all P < .005). CONCLUSIONS: The Discovery System was very repeatable and would be an appropriate instrument to measure cycloplegic refractive error and higher-order aberration changes in adults. Small differences in refractive error were found between the Discovery System and Grand Seiko. PMID- 28727614 TI - A 5-Minute Interval between Two Dilating Eye Drops Increases Their Effect. AB - PURPOSE: Patients are usually advised to wait 5 minutes between eye drops. This delay supposedly allows the first drop not to be washed out by the second one, thereby increasing the combined effect. However, in the only experimental study conducted in humans on the concurrent administration of two different eye drops, the authors concluded that a 10-minute time interval between eye drops did not increase their combined effect. Our study was designed to address this puzzling observation. METHODS: Using digital photographs shot in photopic conditions in 40 eyes of 20 healthy volunteers, we compared relative pupil surface (i.e., pupil to iris surface area ratios) before and after the administration of one drop of 10% phenylephrine and one drop of 0.5% tropicamide either immediately or after a 5 minute time interval. RESULTS: Waiting 5 minutes yielded a 5.6% relative pupil surface gain (observer 1: P = .003, observer 2: P = .005) indicating an additional combined effect with a 5-minute time interval. CONCLUSIONS: These results show a detectable additive effect that is probably the result of methodological refinements including the challenging of the mydriasis by photopic conditions and the use of pupil and iris surface areas, which may show differences that would be undetectable in terms of diameter. PMID- 28727616 TI - Iterative Reconstruction May Improve Diagnosis of Gout: An Ex Vivo (Bio)Phantom Dual-Energy Computed Tomography Study. AB - OBJECTIVES: We hypothesize that, compared with filtered back projection (FBP), iterative reconstruction (IR) increases the detected volume of uric acid, which serves as a measure of the sensitivity of the method, and therefore allows examinations with lower radiation exposure. Thus, the aim of our study was to evaluate the role of IR in dual-energy computed tomography (DECT) for gout assessment and volumetry in an ex vivo gout model using an epoxy phantom and a biophantom. MATERIALS AND METHODS: We prepared specimens with different concentrations of monosodium uric acid in ultrasound gel (30%-50%) and inserted them into an epoxy-based phantom and a porcine foreleg. Computed tomography scanning was performed on a 320-row single-source DECT scanner in volume mode with an ascending order of tube currents. Image data sets were reconstructed using FBP and IR with 2 iteration levels (IR1 and IR2). Measurements in regions of interest (ROIs) and volumetric measurements were performed using either fixed parameters for the analysis software (epoxy phantom) or parameters specifically adapted for each data set (porcine phantom). Seven retrospectively identified clinical data sets were used for validation in patients. Rm-ANOVA was used for statistical analysis. No institutional review board approval was required. RESULTS: We found no differences in Hounsfield units between the different reconstruction algorithms (P = 0.09 and 0.05 for 80 and 135 kVp, respectively) and the calculated dual-energy gradient (P = 0.27). Filtered back projection detected less uric acid compared with IR (with fixed parameters: 6.0 +/- 0.3 cm for FBP and 6.1 +/- 0.2 for IR1 and IR2; with adapted thresholds: 1.2 +/- 0.3 cm for FBP and 1.8 +/- 0.1 and 2.0 +/- 0.1 for IR1 and IR2, respectively). The differences were significant for all measurements (P = 0.0003). Also in the test cases, FBP detected significantly fewer tophi (mean volume, 1.38 +/- 2.1 cm) compared with IR1 (1.86 +/- 2.9) and IR2 (2.07 +/- 3.1) (P = 0.04). CONCLUSIONS: Iterative reconstruction has the potential to improve the sensitivity of a DECT scan for gouty tophi, to decrease radiation exposure, or to combine both options. PMID- 28727615 TI - Multiplexing Prisms for Field Expansion. AB - PURPOSE: Prisms used for field expansion are limited by the optical scotoma at a prism apex (apical scotoma). For a patient with two functioning eyes, fitting prisms unilaterally allows the other eye to compensate for the apical scotoma. A monocular patient's field loss cannot be expanded with a conventional or Fresnel prism because of the apical scotoma. A newly invented optical device, the multiplexing prism (MxP), was developed to overcome the apical scotoma limitation in monocular field expansion. METHODS: A Fresnel-prism-like device with alternating prism and flat elements superimposes shifted and see-through views, thus creating the (monocular) visual confusion required for field expansion and eliminating the apical scotoma. Several implementations are demonstrated and preliminarily evaluated for different monocular conditions with visual field loss. The field expansion of the MxP is compared with the effect of conventional prisms using calculated and measured perimetry. RESULTS: Field expansion without apical scotomas is shown to be effective for monocular patients with hemianopia or constricted peripheral field. The MxPs are shown to increase the nasal field for a patient with only one eye and for patients with bitemporal hemianopia. The MxPs placed at the far temporal field are shown to expand the normal visual field. The ability to control the contrast ratio between the two images is verified. CONCLUSIONS: A novel optical device is demonstrated to have the potential for field expansion technology in a variety of conditions. The devices may be inexpensive and can be constructed in a cosmetically acceptable format. PMID- 28727618 TI - Clinical Study of Bone Regeneration by Conditioned Medium From Mesenchymal Stem Cells After Maxillary Sinus Floor Elevation. AB - OBJECTIVE: This clinical study was undertaken to evaluate the safety of use of the secretome of bone marrow-derived mesenchymal stem cells (MSC-CM) for maxillary sinus floor elevation (SFE). MATERIALS AND METHODS: MSC-CM was prepared from conditioned medium from human bone marrow-derived MSCs. Six partially edentulous patients were enrolled in the study. MSC-CM was mixed with porous beta tricalcium phosphate (beta-TCP) and implanted in 4 patients (experimental group), whereas only beta-TCP was implanted in the other 2 patients (control group). Six months after SFE, bone biopsies and histological assessments were performed. RESULTS: Bone formation was clinically confirmed in all cases. Although Hounsfield units in computed tomography images were not significantly different between the groups, histological analysis revealed a significant difference in newly formed bone area between the groups. In particular, bone volume in the center of the augmented area was significantly greater in the MSC-CM group. Newly formed bone consisted of lamellar bone in the MSC-CM group but woven bone in the beta-TCP group. CONCLUSION: The secretome of bone marrow-derived mesenchymal stem cells (MSC-CM) was used safely and has great osteogenic potential for regenerative medicine of bone. PMID- 28727617 TI - Granulosa Cell Tumors: Novel Predictors of Recurrence in Early-stage Patients. AB - Granulosa cell tumors (GCTs) comprise 2% to 5% of ovarian neoplasms, with unpredictable patterns of recurrence. The HER family, GATA4, and SMAD3 genes are reportedly involved in GCT proliferation and apoptosis and may serve as new predictors of recurrence. The aim of the study was to evaluate novel predictors of recurrence in GCT from a large single institution cohort. Patients diagnosed with GCTs (n=125) between 1975 and 2014 were identified. Clinicopathologic parameters were obtained and immunohistochemical evaluation was performed of calretinin, inhibin, HER2, CD56, SMAD3, and GATA4. Statistical analyses were conducted using Fisher exact test and Kaplan-Meier survival curves and Cox regression analysis. The median follow-up period was 120 months (range, 1-465 mo). Recurrence was noted in 12/125 (9.6%) patients. Kaplan-Meier analysis showed a shorter mean disease-free interval in whites versus blacks (P=0.001), stage III IV versus stage I-II (P=0.0001), patients treated with surgery+chemotherapy versus surgery (P=0.0001), mitotic rate >=4 (P=0.005), severe nuclear pleomorphism (P=0.013), high HER2 expression (P=0.001), high CD56 expression (P=0.001), and high SMAD3 expression (P=0.001). On Cox regression analysis, SMAD3 and type of treatment received were the only 2 independent prognostic factors for disease-free interval (P=0.03 and P=0.007, respectively). On subanalysis for early-stage (stage I) GCTs, the need for adjuvant chemotherapy and high expression of SMAD3 continued to be independent predictors of recurrence (HR=10.2, P=0.01 and HR=8.9, P=0.001, respectively). PMID- 28727619 TI - An Innovative Transitional Care Program Improves Community Health. AB - In this month's Magnet(r) Perspectives column, Barbara Richardson, MSN, RN-BC, CCRN, clinical nurse specialist at the Southwestern Vermont Medical Center, examines the ways in which a robust transitional care program improves community health, reduces readmissions and emergency department visits, and provides valuable social support for even the most complex patients. Richardson shares critical factors that impacted the program's success, including a Magnet(r) environment of innovation, a visionary hospital leadership team, strong community alliances, and collaborative solutions to previously intractable problems. Her efforts to build and implement a successful transitional care program earned Richardson the 2016 National Magnet(r) Nurse of the Year Award for Structural Empowerment. PMID- 28727620 TI - The Case for Focusing on Millennial Retention. AB - A concern for nurse leaders is rapid turnover of engaged, early-tenure millennial nurses. In this 1st article in a 2-part series, the authors describe why leaders should supplement their organization's current investments in engagement with retention strategies targeted at millennial nurses. PMID- 28727621 TI - How Information Drives Complexity. AB - As systems evolve over time, their natural tendency is to become increasingly more complex. Studies in the field of complex systems have generated new perspectives on the application of management strategies in health systems. This article is the 2nd in a series of articles that focuses on why technological complexity is increasing and strategies nurse administrators can use to successfully implement change in the face of it. PMID- 28727622 TI - An Innovative Academic/Service Partnership to Increase BSN-Prepared RNs in a Rural Hospital. AB - Developing innovative ways to increase BSN-prepared nurses in hospitals in rural regions is a struggle. A partnership between 1 hospital and a local university to support the associate-degree new graduates to progress toward their BSN is proving to be a success. PMID- 28727623 TI - Return on Investment: Evaluating the Evidence Regarding Financial Outcomes of Workplace Wellness Programs. AB - Workplace wellness programs are expected to reduce employee healthcare costs, increase productivity, and provide a positive return on investment. A review of the literature from 2000 to 2016 was conducted to determine whether workplace wellness programs deliver a positive economic impact. Individual financial metrics and results varied; 6 of 7 studies reported a positive economic impact. Additional study is recommended because of the high-degree variability and lack of longitudinal data. PMID- 28727625 TI - Decreasing Stress and Burnout in Nurses: Efficacy of Blended Learning With Stress Management and Resilience Training Program. AB - OBJECTIVE: The study's purpose was to assess efficacy of blended learning to decrease stress and burnout among nurses through use of the Stress Management and Resiliency Training (SMART) program. BACKGROUND: Job-related stress in nurses leads to high rates of burnout, compromises patient care, and costs US healthcare organizations billions of dollars annually. Many mindfulness and resiliency programs are taught in a format that limits nurses' attendance. METHODS: Consistent with blended learning, participants chose the format that met their learning styles and goals; Web-based, independent reading, facilitated discussions. The end points of mindfulness, resilience, anxiety, stress, happiness, and burnout were measured at baseline, postintervention, and 3-month follow-up to examine within-group differences. RESULTS: Findings showed statistically significant, clinically meaningful decreases in anxiety, stress, and burnout and increases in resilience, happiness, and mindfulness. CONCLUSIONS: Results support blended learning using SMART as a strategy to increase access to resiliency training for nursing staff. PMID- 28727624 TI - Longitudinal Outcomes of an Institutionally Developed Nurse Residency Program. AB - Nurse residency programs are widely implemented to enhance integration of new graduate nurses entering the workforce. This article presents a retrospective analysis of 10 years of residency data from an internally developed residency program that used the Casey-Fink Graduate Nurse Experience Survey. Outcomes of this program were similar to those from studies using commercially available products, suggesting that an internally developed residency curricula may be equally beneficial to the development of new graduate nurses. PMID- 28727626 TI - System-Level Shared Governance Structures and Processes in Healthcare Systems With Magnet(r)-Designated Hospitals: A Descriptive Study. AB - OBJECTIVE: The purpose was to identify and describe structures and processes of best practices for system-level shared governance in healthcare systems. BACKGROUND: Currently, more than 64.6% of US community hospitals are part of a system. System chief nurse executives (SCNEs) are challenged to establish leadership structures and processes that effectively and efficiently disseminate best practices for patients and staff across complex organizations, geographically dispersed locations, and populations. METHODS: Eleven US healthcare SCNEs from the American Nurses Credentialing Center's repository of Magnet(r)-designated facilities participated in a 35-multiquestion interview based on Kanter's Theory of Organizational Empowerment. RESULTS: Most SCNEs reported the presence of more than 50% of the empowerment structures and processes in system-level shared governance. CONCLUSIONS: Despite the difficulties and complexities of growing health systems, SCNEs have replicated empowerment characteristics of hospital shared governance structures and processes at the system level. PMID- 28727627 TI - Associations of Organizational Safety Practices and Culture With Physical Workload, Perceptions About Work, and Work-Related Injury and Symptoms Among Hospital Nurses. AB - OBJECTIVE: The study aim was to examine the relationships of organizational safety practices with nurses' perceptions about job and risk and experiences of work-related injury and symptoms. BACKGROUND: Nursing professions report high rates of work-related injuries. Organizational safety practices have been linked to workers' safety outcomes and perceptions about work. METHODS: This study analyzed data from a random sample of 280 California RNs in a cross-sectional statewide survey. Data were collected by both postal and online surveys. RESULTS: Higher perceptions of organizational safety practices (safety climate, ergonomic practices, people-oriented culture) were significantly associated with lower physical workload, lower job strain, higher job satisfaction, lower risk perception, and lower work-related injury and symptom experiences. Ergonomic practices and people-oriented culture were associated with less intention of leaving job. CONCLUSIONS: Organizational safety practices may play a pivotal role in improving positive perceptions about jobs, reducing injury risks, and promoting nurse retention. PMID- 28727628 TI - Replication confirms the association of loci in FOXE1, PDE8B, CAPZB and PDE10A with thyroid traits: a Genetics of Diabetes Audit and Research Tayside study (GoDARTS). AB - OBJECTIVE: Replication of associations in genome-wide association studies is desirable to ensure that such signals are potentially clinically meaningful. This study aimed to replicate associations of selected single-nucleotide polymorphisms (SNPs) with hypothyroidism and serum thyroid-stimulating hormone (TSH) using electronic medical records (EMRs). PATIENTS AND METHODS: A cross-sectional study was carried out among patients of European Caucasian ethnicity from the Genetics of Diabetes Audit and Research Tayside recruited in Tayside (Scotland, UK). EMRs (biochemistry, prescribing, hospital admissions and demographics) were used to ascertain patients with hypothyroidism and their controls as well as average serum TSH concentration, and linked to genetic biobank data. Genetic tests of association were performed using logistic and linear regression models. RESULTS: We analysed 1703 cases of hypothyroidism and 9457 controls. All four SNPs located on chromosome 9 at FOXE1 were associated with hypothyroidism with similar effect estimates (odds ratio=0.75-0.76, P<5e-08). Also, loci on chromosomes 1 (PTPN22), six (HLA-E/HLA-C) and 12 (SH2B3) were replicated. For serum TSH, we confirmed 12 SNPs previously reported at PDE8B, CAPZB, PDE10A, LOC105371356, NR3C2, VEGFA, IGFBP5, INSR, PRDM11, NFIA, ITPK1 and ABO. Overall, these SNPs accounted for 6.8% of the serum TSH variation (P<1e-04). CONCLUSION: EMRs linked to genomic data in large populations enable validation of genome-wide association studies discoveries without additional genotyping costs. Our replication confirmed at genome-wide significance the association of loci at FOXE1 with hypothyroidism, and PDE8B, CAPZB and PDE10A with serum TSH. A total of 12 SNPs seemed to explain nearly 7% of the serum TSH variation. PMID- 28727629 TI - An Automated Inpatient Split-dose Bowel Preparation System Improves Colonoscopy Quality and Reduces Repeat Procedures. AB - BACKGROUND/GOALS: Inpatient colonoscopy preparations are often inadequate, compromising patient safety and procedure quality, while resulting in greater hospital costs. The aims of this study were to: (1) design and implement an electronic inpatient split-dose bowel preparation order set; (2) assess the intervention's impact upon preparation adequacy, repeated colonoscopies, hospital days, and costs. STUDY: We conducted a single center prospective pragmatic quasiexperimental study of hospitalized adults undergoing colonoscopy. The experimental intervention was designed using DMAIC (define, measure, analyze, improve, and control) methodology. Prospective data collected over 12 months were compared with data from a historical preintervention cohort. The primary outcome was bowel preparation quality and secondary outcomes included number of repeated procedures, hospital days, and costs. RESULTS: On the basis of a Delphi method and DMAIC process, we created an electronic inpatient bowel preparation order set inclusive of a split-dose bowel preparation algorithm, automated orders for rescue medications, and nursing bowel preparation checks. The analysis data set included 969 patients, 445 (46%) in the postintervention group. The adequacy of bowel preparation significantly increased following intervention (86% vs. 43%; P<0.01) and proportion of repeated procedures decreased (2.0% vs. 4.6%; P=0.03). Mean hospital days from bowel preparation initiation to discharge decreased from 8.0 to 6.9 days (P=0.02). The intervention resulted in an estimated 1-year cost savings of $46,076 based on a reduction in excess hospital days associated with repeated and delayed procedures. CONCLUSIONS: Our interdisciplinary initiative targeting inpatient colonoscopy preparations significantly improved quality and reduced repeat procedures, and hospital days. Other institutions should consider utilizing this framework to improve inpatient colonoscopy value. PMID- 28727630 TI - Same-day Versus Split-dose Bowel Preparation Before Colonoscopy: A Meta-analysis. AB - BACKGROUND: Split-dose regimens (SpDs) were recommended as a first choice for bowel preparation, whereas same-day regimens (SaDs) were recommended as an alternative; however, randomized trials compared them with mixed results. The meta-analysis was aimed at clarifying efficacy level between the 2 regimens. MATERIALS AND METHODS: We used MEDLINE/PubMed, EMBASE, Scopus, CINAHL, Cochrane Library, and Web of Science to identify randomized trials published from 1990 to 2016, comparing SaDs to SpDs in adults. The pooled odds ratios (ORs) were calculated for preparation quality, cecal intubation rate (CIR), adenoma detection rate (ADR), and any other adverse effects. RESULTS: Fourteen trials were included. The proportion of individuals receiving SaDs and SpDs with adequate preparation in the pooled analysis were 79.4% and 81.7%, respectively, with no significant difference [OR=0.92; 95% confidence interval (CI), 0.62-1.36] in 11 trials. Subgroup analysis revealed that the odds of adequate preparation for SaDs with bisacodyl were 2.45 times that for SpDs without bisacodyl (95% CI, 1.45-4.51, in favor of SaDs with bisacodyl). Subjects received SaDs experienced better sleep. CONCLUSIONS: SaDs were comparable with SpDs in terms of bowel cleanliness, CIR, and ADR, and could also outperform SpDs in preparation quality with bisacodyl. SaDs also offered better sleep the previous night than SpDs did, which suggests that SaDs might serve as a superior alternative to SpDs. The heterogenous regimens and measurements likely account for the low rates of optimal bowl preparations in both arms. Further studies are needed to validate these results and determine the optimal purgatives and dosages. PMID- 28727631 TI - One year of baclofen in 100 patients with or without cirrhosis: a French real life experience. AB - BACKGROUND: Several studies have suggested the efficacy of baclofen in reducing alcohol consumption, leading to a temporary recommendation for use in France. AIM: Our aim was to report our experience in using baclofen in alcohol-dependant patients with or without liver cirrhosis. PATIENTS AND METHODS: Consecutive patients from two liver and alcohol units were recruited over a 3-year period and received increasing doses of baclofen associated with social, psychological, and medical care. RESULTS: One hundred patients were treated, of whom 65 were cirrhotic. After 1 year, 86 patients were still being followed up. At a mean dosage of 40 mg/day (extremes: 30-210), the median daily alcohol consumption reduced from 80 to 0 g/day (P<0.001). Twenty patients drank a small amount of alcohol of up to 30 g/day and 44 patients were completely abstinent. These declarative results were associated with a significant improvement in alcohol related biological markers in this 'low-consumption' group of 64 patients: the median gamma-glutamyl transferase decreased from 3.9 to 2.0 UNL (P<0.001), the mean aspartate transaminase decreased from 2.6 to 1.2 UNL (P<0.001), and the mean corpuscular volume decreased from 101 to 93 um (P<0.001). In cirrhotic patients, bilirubinemia decreased significantly from 22 to 11 umol/l (P=0.026), prothrombin time increased from 68 to 77% (P<0.001), and albuminemia increased from 34.1 to 37.4 g/l (P<0.001). Twenty patients reported grades 1-2 adverse events. No liver or renal function deterioration occurred in cirrhotic patients. CONCLUSION: In our cohort, baclofen associated with a global care was very well tolerated even in cirrhotic patients. The marked reduction in alcohol consumption in 64 patients translated into a significant improvement in biological markers and in liver function tests. Baclofen could be very useful, especially in cases of severe alcoholic liver disease. PMID- 28727632 TI - A Prospective Randomized Controlled Trial Comparing Quality of Life Following Endoscopic Totally Extraperitoneal (TEP) Versus Open Stoppa Inguinal Hernioplasty. AB - In inguinal hernia surgery, quality of life (QOL) has emerged as a striking issue. Evidence suggests better QOL of patients operated with laparoscopic procedure as compared with open anterior hernia repairs. However data are scarce with relation to open posterior repair in terms of QOL issues. A prospective randomized single-blind study from November 2014 to October 2015 including all patients who underwent elective primary endoscopic [totally extraperitoneal (TEP)] or open Stoppa inguinal hernia repair was undertaken. Mean operating time, intraoperative and postoperative complications, and QOL using short form-36 and Carolinas equation of QOL were analyzed. Physical functioning, mental health, bodily pain, and general health showed advantages of TEP over Stoppa repair in first month of postoperative period. Postoperative prediction of hernia discomfort after 1 year was found to be significantly more in Stoppa repair. Complications were slightly higher with open repair. To conclude TEP is associated with significant increased operative time, better QOL in early postoperative period, and less predicted discomfort after 1 year of surgery. PMID- 28727633 TI - Is the Use of a Robotic Camera Holder Economically Viable? A Cost Comparison of Surgical Assistant Versus the Use of a Robotic Camera Holder in Laparoscopic Liver Resections. AB - The laparoscopic approach has gained acceptance in the field of hepatopancreaticobiliary surgery. It offers several advantages including reduced blood loss, reduced postoperative pain, and shorter length of stay. However, long operating times can be associated with surgeon and assistant fatigue and image tremor. Robotic camera holders have been designed to overcome these drawbacks but may come with significant costs. The aim of this study was to economically evaluate their use compared with standard assistants using a single surgeon consecutive series of laparoscopic liver resections from January 2014 to May 2015. Only use of nurse assistants with no advanced training and postgraduate year 2 doctors were cheaper than utilization of the device. We suggest the use of a robotic camera holder is cost-beneficial and may have wider service and educational benefits. PMID- 28727634 TI - Is Single-incision Laparoscopic Cholecystectomy Feasible for Acute Cholecystitis? A Consecutive Study of 60 Cases. AB - The feasibility of single-incision laparoscopic cholecystectomy (SIL-C) for patients with acute cholecystitis were evaluated based on the timing of operation after onset of symptoms. Sixty patients with acute cholecystitis who underwent SIL-C were divided into 2 groups according to the timing of operation: group E included 23 patients who underwent SIL-C within 72 hours, and group O included 37 patients who underwent SIL-C later. There were no statistical differences between group E and group O in clinicopathologic characteristics. Group E demonstrated significantly shorter operating time and less blood loss than group O. Although the incidences of additional port(s) requirements were not significantly different, 8 patients in group O required open conversion, indicating significantly higher rate. As group E demonstrated favorable surgical outcomes compared with group O, SIL-C for acute cholecystitis seems to be a feasible therapeutic procedure when performed within 72 hours as updated Tokyo Guidelines recommended. PMID- 28727635 TI - Salvage Endoscopic Argon Plasma Coagulation After Chemoradiotherapy for Inoperable Esophageal Cancer. AB - PURPOSE: The purpose of this study is to evaluate the effectiveness of salvage endoscopic argon plasma coagulation (APC) therapy for local failure occurring after definitive chemoradiotherapy (CRT) in patients with inoperable esophageal cancer. PATIENTS AND METHODS: A total of 47 patients with esophageal squamous cell carcinoma received CRT from January 2009 through November 2011 in our hospital. Thirty-five of these patients were excluded because of long-term disease-free status or because they received salvage surgery, systemic chemotherapy, or best supportive care. The other 12 patients had local relapse (n=8) or residual lesions (n=4) after definitive CRT and received salvage APC therapy. Local failures after definitive CRT were divided into 2 groups: the superficial growth group (n=6) and the submucosal growth group (n=6). The primary endpoints were relapse-free survival and overall survival after 60 months of follow-up. RESULTS: Six patients in the superficial growth group and 1 patient in submucosal growth group had a complete response after salvage APC. The rates of both relapse-free survival and overall survival were higher in the superficial growth group than in the submucosal growth group. No complications occurred after APC. CONCLUSIONS: Salvage APC is a potentially curative treatment for patients who have local failure associated with superficial tumors after CRT for esophageal squamous cell carcinoma. PMID- 28727636 TI - A Comparison of Robotic Versus Laparoscopic Adrenalectomy in Patients With Primary Hyperaldosteronism. AB - BACKGROUND: Over the last decade, robotic approaches have been described for removing adrenal tumors. Although there are reports comparing robotic and laparoscopic techniques in general, there are limited data on outcomes in patients with primary hyperaldosteronism (PHA). The aim of this study is to compare the safety and efficacy of robotic adrenalectomy (RA) versus laparoscopic adrenalectomy (LA) for PHA. MATERIALS AND METHODS: The records of 20 patients who underwent RA for PHA were compared with 16 patients who underwent LA between 2000 and 2014. Data were retrospectively reviewed from a prospectively maintained, IRB approved adrenal database. Statistical analysis was performed using t test and the Fisher exact analysis. Continuous variables are reported as mean+/-SEM. RESULTS: Demographic and clinical parameters were similar between the groups. There were no conversions to open in either group. Estimated blood loss, length of stay, and complication rates were comparable. Operative time was shorter in the robotic versus laparoscopic group (130+/-8.94 vs. 159+/-11.1 min, P=0.0487). In follow-up, the improvement in patients' blood pressure after adrenalectomy, as assessed by the reduction in the number of antihypertensive medications, was similar between the 2 groups. However, 1 patient in the RA and 1 patient in the LA group were not cured, as determined by postoperative aldosterone:renin levels. The biochemical cure rate between the groups was similar (P=0.529). CONCLUSIONS: To our knowledge, this is the first study comparing robotic versus laparoscopic resection of PHA. Our results show that the robotic approach was similar to laparoscopic regarding safety and efficacy. Operative time was shorter with the robotic approach, which could be related to more efficient dissection with wristed instrumentation. PMID- 28727637 TI - Evaluation and Student Perceptions of an OB Boot Camp Simulation for Undergraduate Nursing Students: A Mixed-Method Approach. AB - Obstetrical nursing offers unique challenges as a specialty clinical area as the process of birth and the nature of the setting are unpredictable. Traditional undergraduate baccalaureate nursing students may not have experience with maternal/newborn care. An eight-hour OB Boot Camp was developed to prepare students for their first obstetrical clinical rotation. An explanatory sequential mixed-method research study was used to explore student perceptions and evaluate the experience. On the basis of the results of this research study, the OB Boot Camp was a valuable instructional method to prepare students for obstetrical clinical rotations and coursework. PMID- 28727638 TI - Exertional and CrossFit-Induced Rhabdomyolysis. AB - Few publications of exercise-induced rhabomyolysis currently exist in the medical literature besides case reports. However, this condition can be severe, resulting in hospitalization and IV fluid administration to prevent serious sequelae. This report describes a case of exercise-induced rhabdomyolysis caused by a CrossFit workout. A 31-year-old female presented with 2 days of bilateral upper extremity pain and soreness, which began 2 days after she completed a CrossFit workout. Workup revealed an elevated creatine phosphokinase (CPK) of 18 441 U/L, consistent with exercise-induced rhabdomyolysis, and elevated liver function tests and elevated D-dimer, although her renal function was normal. She was hospitalized for 2 days and treated with IV fluids. This case report demonstrates that CrossFit exercises can lead to rhabdomyolysis, highlighting a condition that may be underdiagnosed and underreported. PMID- 28727639 TI - Effects of 12-Week Resistance Exercise on Electroencephalogram Patterns and Cognitive Function in the Elderly With Mild Cognitive Impairment: A Randomized Controlled Trial. AB - OBJECTIVE: To investigate the effects of a 12-week resistance exercise program with an elastic band on electroencephalogram (EEG) patterns and cognitive function in elderly patients with mild cognitive impairment (MCI). DESIGN: Randomized controlled trial. SETTING: Community center. PARTICIPANTS: Twenty-two subjects with MCI and 25 healthy volunteer subjects were randomly assigned to 1 of 4 groups: subjects with MCI who undertook the exercise program (MCI-EX; n = 10), an MCI control group (MCI-Con; n = 12), a healthy volunteer exercise group (NG-EX; n = 12), and a healthy volunteer control group (NG-Con; n = 13). INTERVENTION: The exercise group engaged in a 15-repetition maximum (15RM; 65% of 1RM) resistance exercise program for 12 weeks. MAIN OUTCOME MEASURES: Electroencephalograms, neuropsychological tests, and Senior Fitness Test. RESULTS: The 12-week 15RM (65% of 1RM) resistance exercise program significantly improved variables related to the physical fitness of the elderly subjects. Furthermore, for the EEG test, the MCI and NG groups showed significant differences at baseline in relative beta waves on electrodes Fp1 (P < 0.05) and F3 (P < 0.05), as well as in relative beta2 waves on F3 (P < 0.05). In addition, after the 12-week exercise intervention, differences in a region that benefits from exercise were observed between (1) the MCI-EX group in the relative theta power on F3 (P < 0.05) and the relative alpha power on T3 (P < 0.05) and in (2) the NG-EX group in the relative theta power on P3 (P < 0.05) and P4 (P < 0.01). In addition, only the score of the digit span backward in the MCI-EX group changed significantly (P < 0.05). CONCLUSIONS: The 12-week resistance exercise with an elastic band had a positive effect on EEG patterns in elderly subjects with MCI, along with providing physical benefits and slight changes in cognitive function in MCI-EX group. SIGNIFICANCE: A 15RM resistance exercise program can be an effective treatment for delaying cognitive decline and improving physical fitness. PMID- 28727641 TI - Decreased Average Power of the Hip External Muscles as a Predictive Parameter for Lower Extremity Injury in Women: A Prospective Study. AB - OBJECTIVE: To prospectively identify hip strength associated risk factors contributing to the development of lower extremity (LE) injury. DESIGN: Data were prospectively collected on healthy female physical education students. SETTING: This study was conducted in the institution of the University of Ghent. PARTICIPANTS: Eighty-nine female physical education students aged 19.53 +/- 1.07 years. ASSESSMENT OF RISK FACTORS: Testing included isokinetic hip strength measurements of abductors, adductors, internal rotators, and external rotators (ERs). MAIN OUTCOME MEASURES: Follow-up of the participants was assessed using a weekly online questionnaire and a 3-month retrospective control questionnaire. Lower extremity injury was diagnosed by an experienced medical doctor. Cox regression was used to identify the potential risk factors for the development of an LE injury. RESULTS: Thirty-four participants were diagnosed with an LE injury during follow-up. This study identified that decreased average power (AP) (P = 0.031) on concentric ER strength was found to be a significant risk factor for LE injury. No other hip strength parameters were found to be significant contributors to the development of LE injury. CONCLUSIONS: Decreased AP of the hip ER muscles was identified as a significant predictor for LE injury, whereas no hip abduction weakness or peak torque parameters were found to be predictive. Because controlling LE extremity movements is an important function of the hip muscles, they might be more challenged in a dynamic measure such as AP than in a point measure such as peak torque. Concentric AP of hip ER muscles can therefore be seen as an interesting factor to include in LE injury screening protocols. PMID- 28727640 TI - No Seasonal Changes in Cognitive Functioning Among High School Football Athletes: Implementation of a Novel Electrophysiological Measure and Standard Clinical Measures. AB - OBJECTIVE: To evaluate neuroelectric and cognitive function relative to a season of football participation. Cognitive and neuroelectric function declines are hypothesized to be present in football athletes. DESIGN: Observational. SETTING: Athletic fields and research laboratory. PATIENTS (OR PARTICIPANTS): Seventy seven high school athletes (15.9 + 0.9 years, 178.6 + 7.2 cm, 74.4 + 14.7 kg, and 0.8 + 0.8 self-reported concussions) participating in football (n = 46) and noncontact sports (n = 31). INTERVENTIONS (OR ASSESSMENT OF RISK FACTORS): All athletes completed preseason, midseason, and postseason assessments of cognitive and neuroelectric function, self-reported symptoms, and quality of life. All athletes participated in their respective sports without intervention, while head impact exposure in football athletes was tracked using the Head Impact Telemetry System. MAIN OUTCOME MEASURES: Cognitive performance was based on Cogstate computerized cognitive assessment tool processing speed, attention, learning, working memory speed, and working memory accuracy scores. ElMindA brain network activation amplitude, synchronization, timing and connectivity brain network activation scores demarcated neuroelectric performance. Quality of life was assessed on the Health Behavior Inventory and Satisfaction with Life Scale and symptoms on the SCAT3 inventory. RESULTS: Football and control sport athletes did not show declines in cognitive or neuroelectric function, quality-of-life measures, or symptom reports across a season of sport participation. CONCLUSIONS: These findings refute the notion that routine football participation places athletes at risk for acute cognitive declines. The lack of impairment may be associated with no association with head impacts and cognitive function, increased physical activity offsetting any declines, and/or test sensitivity. How these findings are associated with long-term cognitive function is unknown. PMID- 28727642 TI - Injuries Among Recreational Football Players: Results of a Prospective Cohort Study. AB - OBJECTIVES: To establish the incidence and patterns of football injuries and associated consequences in daily life and labor loss, among public employees. DESIGN: Prospective cohort study. SETTING: Football tournament between public employees in Turkey. PARTICIPANTS: A total of 1821 recreational players from 78 teams. MAIN OUTCOME MEASURES: Injury rates (injuries per 1000 hours of football exposure) during tournament by age group, as well as prevalence, severity, and injury types were recorded. The data regarding the occurrence (eg, location, type, circumstances) and consequences (eg, absenteeism, medical treatment, labor loss) of injuries were collected. RESULTS: Of the 1821 football players registered for participation, 57% (n = 1038) were included in the study with the returned questionnaire forms. In total, 257 matches were played with a total exposure time of 5654 hours. A total of 218 injuries were recorded in 192 players (10.5%), resulting in a mean of 0.85 time-loss injuries per match (38.6 per 1000 hours). Severe injuries constituted 42.6% of all injuries, and 28.9% of all injuries caused the participants to be absent at least 1 day for the next working day. The total labor loss was 1196 days for all injuries. The rate of missing subsequent working day was significantly less for muscle injuries (P < 0.05). CONCLUSIONS: The risk of injury in recreational football players is relatively high causing significant labor loss. The results suggest that prevention programs should consider specific injury characteristics, as there is a greater incidence of muscle and anterior cruciate ligament injuries in this population. PMID- 28727643 TI - Improving Early Adolescent Girls' Motor Skill: A Cluster Randomized Controlled Trial. AB - BACKGROUND: Physical activity (PA) levels decline substantially during adolescence and are consistently lower in girls. Competency in a range of fundamental movement skills (FMSs) may serve as a protective factor for the decline in PA typically observed in adolescent girls; yet, girls' mastery in FMS is low. Although interventions can improve FMS, there is a lack of interventions targeting girls, and very few are conducted in high schools. In addition, interventions are usually conducted by researchers, not teachers, and thus have little chance of being embedded into curricula. PURPOSE: This study aimed to evaluate the effectiveness of a school-based intervention, delivered by teachers, in improving adolescent girls' FMS. METHODS: Four all-girls Australian secondary schools were recruited and randomized into intervention or control groups. In total, 190 year 7 girls (103 control/87 intervention; mean age, 12.4 +/- 0.3 yr) completed baseline and posttest measures at 12 wk. Six FMS (i.e., catch, throw, kick, jump, leap, and dodge) were measured using the Victorian FMS Assessment instrument. Mixed models with posttest skill (i.e., locomotor, object control, and total skill) as the outcome, adjusting for baseline skill, intervention and control status, and relevant covariates, as well as accounting for clustering at school and class level, were used to assess the intervention impact. RESULTS: There were significant intervention effects, and large effect sizes (Cohen d) noted in locomotor (P = 0.04, t = 5.15, d = 1.6), object control (P < 0.001, t = 11.06, d = 0.83), and total skill (P = 0.02, t = 7.22, d = 1.36). CONCLUSIONS: Teachers adequately trained in authentic assessment and student-centered instruction can significantly improve the FMS competency of early adolescent girls. Therefore, comprehensive teacher training should be viewed as an integral component of future school-based interventions. PMID- 28727644 TI - Cariprazine specificity profile in the treatment of acute schizophrenia: a meta analysis and meta-regression of randomized-controlled trials. AB - Cariprazine is a new dopamine D2 and D3 receptor partial agonist antipsychotic. Meta-analytic evidence of efficacy in acute schizophrenia and specific groups of patients is lacking. We carried out a meta-analysis in patients with acute schizophrenia to evaluate the efficacy of cariprazine over placebo and active comparators in overall symptoms, positive and negative symptoms and quality of life. Low and high (>=6 mg/day) doses were tested separately. The possible effect of clinical-demographic modulators was also tested. Four studies (2144 patients) were included. Both high and low cariprazine doses proved superior to placebo in all symptom domains. The standardized mean difference (SMD) to placebo showed a modest impact on overall symptoms compared with meta-analytic results for other antipsychotics (SMD was similar to lurasidone, asenapine, ziprasidone and aripiprazole, but lower than risperidone, quetiapine and olanzapine). The SMD to placebo on negative symptoms was superior to many antipsychotics including aripiprazole, with a slightly more relevant effect of cariprazine low doses. This effect was probably on secondary negative symptoms since the short-term follow-up of the studies included. Meta-regression data further refined the compound clinical profile, suggesting that cariprazine may be particularly useful in young patients with a relatively short duration of disease. PMID- 28727647 TI - Surgical Anatomy of the Uterosacral Ligament Colpopexy. AB - OBJECTIVE: The aim of this study was to describe the relationship of the uterosacral ligament (USL) to the ureter and rectum along a surgeon's target location for suture placement under conditions simulating live surgery. METHODS: Dissections were performed in 11 unembalmed female cadavers. Steps were taken to identify the USL simulating USL colpopexy. Pins were placed in the midportion of the USL at the level of the IS, and at 1-cm, 2-cm, and 3-cm increments traveling proximally toward the sacrum (Fig. 1). We measured minimum distances from the USL to the ureter and rectum at each target location. RESULTS: In general, the ureters range from 1.3 to 2.0 cm lateral to the USLs along the target length. The rectum ranges from 1.9 to 2.6 cm from the right USL and remains 1.5 cm from the left USL. The mean change in distance between the ureter and USL for every 1 cm advanced toward the sacrum is 0.2 cm (95% confidence interval [CI], 0.19-0.24) on the right and 0.2 cm (95% CI, 0.18-0.27) on the left. The mean change in distance between the rectum and USL for every 1 cm advanced toward the sacrum is 0.2 cm (95% CI, 0.19-0.24) on the right and 0.0 cm (95% CI, 0-0) on the left. CONCLUSIONS: For every centimeter traveled along the bilateral USLs from the IS toward the sacrum, the ureter moves 0.2 cm laterally away from the ligament, the rectum moves 0.2 cm medially away from the right USL, but maintains its position from the left USL. PMID- 28727648 TI - Is Something Missing From Antenatal Education? A Survey of Pregnant Women's Knowledge of Pelvic Floor Disorders. AB - OBJECTIVE: This study aimed to describe the knowledge on pelvic floor disorders among a cross section of pregnant women. STUDY DESIGN: This was an institutional review board-approved cross-sectional survey study of pregnant women with a gestational age of more than 18 weeks at a single tertiary care institution. Participants completed the validated 24-item Prolapse and Incontinence Knowledge Questionnaire, and responses were graded to determine a raw accuracy score (0 100%). Proficiency in the topic was defined as a score greater than 80% on the urinary scale and greater than 50% on the prolapse scale. RESULTS: Four hundred two women completed the survey. Mean +/- SD raw accuracy in urinary incontinence was 66% +/- 12%, and mean +/- SD raw accuracy in pelvic organ prolapse was 41% +/ 17%. These results were not significantly different among age or ethnic groups. Pregnant women were more likely to know that delivery could lead to incontinence (62%) than to pelvic organ prolapse (42%; P = 0.02), and 83% knew that pelvic floor exercises could prevent urinary incontinence. Proficiency was low among the population on both scales. CONCLUSIONS: Pregnant women have limited knowledge about pelvic floor dysfunction despite being at increased risk for these conditions during and after their pregnancies. This is an area where patient education and empowerment during routine prenatal care could improve. PMID- 28727649 TI - Variables Affecting Intra-abdominal Pressure During Lifting in the Early Postpartum Period. AB - OBJECTIVES: Intra-abdominal pressure (IAP) may contribute to pelvic floor health, although the direction and magnitude of such an effect, if any, are not yet known. Identifying individual characteristics, and in particular modifiable factors, associated with higher IAP during recovery from vaginal childbirth might serve to mitigate early pelvic floor dysfunction. The aim of this study was to identify characteristics associated with maximal IAP during lifting in postpartum primiparous women who delivered vaginally. METHODS: At 6 to 10 weeks postpartum, we measured maximal IAP, assessed via an upper vaginal sensor, as participants (enrolled in an ongoing cohort study) lifted a weighted car seat (12.5 kg). We evaluated whether the following independent variables were associated with maximal IAP: age, ethnicity, body mass index, height, abdominal circumference, weight gain during pregnancy, lifting time, breath holding during lifting, lifting technique, measures of muscular fitness, and days since delivery. RESULTS: In the 206 participants, weight, waist circumference, body mass index, and days since delivery were positively associated with mean maximal IAP during lifting, whereas IAP decreased as height increased. As the duration of the lifting task increased, mean maximal IAP during lifting also increased, but there were no associations between lifting technique or breath holding during lifting and IAP. Neither pelvic floor muscle strength nor abdominal muscle endurance was associated with IAP during lifting. CONCLUSIONS: Other than measures of body habitus and lifting duration, we did not identify modifiable factors that could mitigate maximal pressures experienced by the pelvic floor during the early postpartum period. PMID- 28727650 TI - Acquired External Auditory Canal Atresia: A Comparison of Acellular Dermal Matrix and Split-thickness Skin Grafting Techniques. AB - OBJECTIVE: To describe the use of acellular dermal matrix (ADM) in the repair of acquired external auditory canal atresia (AEACA), and compare surgical results to AEACA repair by split-thickness skin grafting (STSG). STUDY DESIGN: Retrospective chart review. SETTING: Neurotology clinical practice. PATIENTS AND INTERVENTION: From 2007 to 2015, 25 AEACA surgeries (8 ADM and 17 STSG) were identified meeting inclusion and exclusion criteria. Pre- and postoperative audiometric data with clinical follow-up were examined. OUTCOME MEASURES: Rate of external auditory canal restenosis, improvement of conductive hearing loss, and resolution of otorrhea. RESULTS: Both surgical groups had similar preoperative air bone gaps (ABG). Mean follow-up was 24 months. There was no significant difference in restenosis rates between the ADM (13%, n = 1/8) and STSG (12%, n = 2/17) groups. ABG improved from 28 dB to 11 dB in the ADM group and from 24 dB to 9 dB in the STSG group. ABG closure with surgery was statistically significant (p < 0.05), but there was no difference between the two groups. There was no significant reduction of otorrhea. CONCLUSION: Acellular dermal matrix grafting has not been previously reported for use in AEACA repair, and is a reasonable alternative to STSG with similar hearing, restenosis, and otorrhea outcomes. PMID- 28727651 TI - Visual Processing Recruits the Auditory Cortices in Prelingually Deaf Children and Influences Cochlear Implant Outcomes. AB - OBJECTIVE: Although visual processing recruitment of the auditory cortices has been reported previously in prelingually deaf children who have a rapidly developing brain and no auditory processing, the visual processing recruitment of auditory cortices might be different in processing different visual stimuli and may affect cochlear implant (CI) outcomes. METHODS: Ten prelingually deaf children, 4 to 6 years old, were recruited for the study. Twenty prelingually deaf subjects, 4 to 6 years old with CIs for 1 year, were also recruited; 10 with well-performing CIs, 10 with poorly performing CIs. Ten age and sex-matched normal-hearing children were recruited as controls. Visual ("sound" photo [photograph with imaginative sound] and "nonsound" photo [photograph without imaginative sound]) evoked potentials were measured in all subjects. P1 at Oz and N1 at the bilateral temporal-frontal areas (FC3 and FC4) were compared. RESULTS: N1 amplitudes were strongest in the deaf children, followed by those with poorly performing CIs, controls and those with well-performing CIs. There was no significant difference between controls and those with well-performing CIs. "Sound" photo stimuli evoked a stronger N1 than "nonsound" photo stimuli. Further analysis showed that only at FC4 in deaf subjects and those with poorly performing CIs were the N1 responses to "sound" photo stimuli stronger than those to "nonsound" photo stimuli. No significant difference was found for the FC3 and FC4 areas. No significant difference was found in N1 latencies and P1 amplitudes or latencies. CONCLUSION: The results indicate enhanced visual recruitment of the auditory cortices in prelingually deaf children. Additionally, the decrement in visual recruitment of auditory cortices was related to good CI outcomes. PMID- 28727653 TI - Rising Incidence of Paediatric Inflammatory Bowel Disease in Canterbury, New Zealand, 1996-2015. AB - BACKGROUND: The incidence of paediatric inflammatory bowel disease (IBD) around the world is increasing. Canterbury, New Zealand, has one of the highest Crohn disease (CD) incidence rates published. The present study aimed to document the incidence of paediatric IBD in Canterbury between 1996 and 2015. METHODS: All patients diagnosed with IBD in Canterbury, while younger than 16 years, between January 1, 1996 and December 31, 2015 were identified. Demographic and disease phenotypic details were collected and entered into a secure database. Age specific population data for Canterbury were obtained and annual incidence rates were then calculated. RESULTS: The mean annual incidence rate over the 20-year period was 7.18/100,000 (95% confidence interval 5.55-8.81) children. There was a 4-fold increase in the incidence of paediatric IBD in Canterbury between 1996 and 2015. The ratio of CD to ulcerative colitis (UC) diagnosed was 8.4:1. Disease phenotype of CD and UC, based on the Paris classification, were comparable with other studies. CONCLUSIONS: The incidence of paediatric IBD in Canterbury has increased dramatically during the last 2 decades. Some of the observed incidence rates are among the highest documented anywhere in the world. The preponderance of CD over UC in the present study is the highest published. PMID- 28727652 TI - Surgical Emphysema Following Canalplasty for Aural Exostoses. AB - OBJECTIVE: To describe the presentation and management of surgical emphysema involving the temporomandibular joint and deep neck following exostoses removal. PATIENT: A 60-year-old male surfer presented with hearing loss and recurrent infections in the right ear. An examination revealed obstructing bony exostoses in the right external auditory canal. He underwent right canalplasty using a postauricular approach. At 5 weeks after surgery, he presented with right otalgia, swelling of the right face and neck, and complaints of a squeaking noise in the right ear with mandibular excursions. An otomicroscopic examination demonstrated a focal area of prolapsing soft tissue along the anterior bony external auditory canal with mandibular movement. The examination also revealed palpable crepitus of the right face and neck. Computed tomography was obtained of the temporal bones and neck confirming a focal anterior canal wall defect allowing communication between the glenoid fossa and external auditory canal with subcutaneous emphysema tracking around the temporomandibular joint into the masticator, parotid, and parapharyngeal spaces. INTERVENTION: Maxillomandibular fixation for 2 weeks with revision canalplasty using a split tragal cartilage graft. RESULTS: At 6 weeks after revision surgery, the patient reported complete resolution of all symptoms. Repeat imaging demonstrated complete resolution of subcutaneous and deep neck emphysema, and the otomicroscopic examination revealed a fully epithelialized external auditory canal with no further evidence of soft tissue prolapse. CONCLUSION: Maxillomandibular fixation with autologous cartilage graft is an effective management strategy for complications of canalplasty resulting in exposure of the temporomandibular joint capsule and surgical emphysema. PMID- 28727655 TI - Preterm Infants With Biliary Atresia: A Nationwide Cohort Analysis From The Netherlands. AB - OBJECTIVES: Biliary atresia (BA) occurs in 0.54 of 10.000 of overall live births in the Netherlands. BA has an unfavorable prognosis: <40% of patients are cleared of jaundice after Kasai portoenterostomy (KPE), 4-year transplant-free survival rate is 46% and the 4-year survival rate is ~75%. Little is known on difficulties in diagnosis and the outcome of BA in preterm infants. We aimed to analyze the incidence and outcome of BA in preterm infants in the Netherlands. METHODS: Retrospective study including Dutch preterm infants treated for BA. Parameters included gestational age, congenital anomalies, age at KPE, days between first symptoms, and KPE and referral interval (first hospital to KPE). Outcome parameters were clearance of jaundice (COJ) and (transplant-free) survival. Data are presented as medians (ranges). RESULTS: Included 28 preterm infants (13 boys/15 girls) between March 1988 and December 2015. The incidence of BA was 1.06 of 10.000 preterm live births. Gestational age was 34.8 (27.3-36.9) weeks. Congenital anomalies were present in 11 of 28 (39%) infants. Time between first symptoms and KPE was 57 (9-138) days. Referral interval was 28 (8-86) days. Age at KPE was 70 (35-145) days. COJ was achieved in 23% of cases. Four-year transplant-free survival rate was 21%. Four-year overall survival was 61%. CONCLUSIONS: BA has a higher incidence in the preterm population compared to the overall BA population. The outcome of BA in preterm infants is poor, regarding COJ and (transplant-free) survival. We speculate that timely recognition of BA related signs and symptoms in preterm infants will improve prognosis. PMID- 28727654 TI - Growth and Nutritional Biomarkers of Preterm Infants Fed a New Powdered Human Milk Fortifier: A Randomized Trial. AB - OBJECTIVES: The aim of this study was to assess growth and nutritional biomarkers of preterm infants fed human milk (HM) supplemented with a new powdered HM fortifier (nHMF) or a control HM fortifier (cHMF). The nHMF provides similar energy content, 16% more protein (partially hydrolyzed whey), and higher micronutrient levels than the cHMF, along with medium-chain triglycerides and docosahexaenoic acid. METHODS: In this controlled, multicenter, double-blind study, a sample of preterm infants <=32 weeks or <=1500 g were randomized to receive nHMF (n = 77) or cHMF (n = 76) for a minimum of 21 days. Weight gain was evaluated for noninferiority (margin = -1 g/day) and superiority (margin = 0 g/day). Nutritional status and gut inflammation were assessed by blood, urine, and fecal biochemistries. Adverse events were monitored. RESULTS: Adjusted mean weight gain (analysis of covariance) was 2.3 g/day greater in nHMF versus cHMF; the lower limit of the 95% CI (0.4 g/day) exceeded both noninferiority (P < 0.001) and superiority margins (P = 0.01). Weight gain rate (unadjusted) was 18.3 (nHMF) and 16.8 g . kg . day (cHMF) between study days 1 and 21 (D1-D21). Length and head circumference (HC) gains between D1 and D21 were not different. Adjusted weight-for-age z score at D21 and HC-for-age z score at week 40 corrected age were greater in nHMF versus cHMF (P = 0.013, P = 0.003 respectively). nHMF had higher serum blood urea nitrogen, pre-albumin, alkaline phosphatase, and calcium (all within normal ranges; all P <= 0.019) at D21 versus cHMF. Both HMFs were well tolerated with similar incidence of gastrointestinal adverse events. CONCLUSIONS: nHMF providing more protein and fat compared to a control fortifier is safe, well-tolerated, and improves the weight gain of preterm infants. PMID- 28727656 TI - Potential Association of IL1B Polymorphism With Iron Deficiency Risk in Childhood Helicobacter pylori Infection. AB - OBJECTIVE: Helicobacter pylori infection occurs predominantly in childhood. Host immune response gene polymorphism is reported to affect the susceptibility to H pylori infection and the outcome of H pylori-related gastric cancer. Not all H pylori-infected patients, however, exhibit iron deficiency (ID). The relationship between host genetic polymorphisms and ID mediated by H pylori infection is not well understood. METHODS: Subjects (n = 644) from the general population of age 10 to 18 years were divided into 2 groups based on serology testing for anti-H pylori IgG: seropositive study group; and seronegative control group. Five single nucleotide polymorphisms (SNPs) in IL1B (rs1143627 and rs16944), IL8 (rs4073), IL10 (rs1800896), and ABO (rs505922), were genotyped and the iron status of the 2 groups was compared. RESULTS: The seroprevalence rate for H pylori was 10.7% in this study. Infected subjects were significantly older and had lower serum iron levels than uninfected subjects (P = 0.0195 and 0.0059, respectively). Multivariate analysis revealed a significantly higher frequency of the T allele of rs505922 (odds ratio [OR] = 6.128; P < 0.001) and lower frequency of the T allele of rs1143627 (OR = 0.846; P = 0.014) in seropositive subjects. Among 59 seropositive subjects, the T allele frequency of rs1143627 was significantly higher in those with ID (OR = 3.156; P = 0.043), compared with those without ID. CONCLUSIONS: ABO (rs505922) and IL1B (rs1143627) may affect H pylori infection susceptibility, and IL1B (rs1143627) may also influence ID risk in infected children. PMID- 28727657 TI - Cholic Acid to Treat HSD3B7 and AKR1D1 Deficiencies. PMID- 28727658 TI - White cell and marrow imaging: subtracting uncertainty. AB - A subtraction method for assessments of dual-isotope indium-111 (In)-labelled white cell and Tc-nanocoll was proposed, and following a pilot study was introduced in routine service to improve the confidence of reporters. This technical note describes a simple technique to produce subtraction images from routinely acquired images to investigate and exclude post joint replacement infection. Labelled leucocytes (with In) show areas of increased white cell accumulation, whereas Tc-nanocoll images show bone marrow distribution. Images resulting from the subtraction protocol highlight any areas of white cell activity which is not concurrent with the marrow distribution indicative of infection. Fusion images produced from these images sets also assists in localization of white cell accumulation(s). Key to the success of this technique is the use of simultaneous acquisition of both white cell and marrow images; thus removing any issues with patient movement and/or repositioning. Reporting clinicians convey a clear preference for the inclusion of the subtracted and fused images at clinical review. PMID- 28727659 TI - Patient release criteria following radioactive iodine-131 treatment in the light of international practice: where does South Africa fit in? AB - The release from hospital of patients treated with radioactive iodine-131 (I) remains a controversial issue as a result of the range of guidelines implemented by national regulatory bodies responsible for radiation protection in various countries worldwide. The aim of this study was to review and analyse the literature on patient release criteria (PRC) applied internationally in an attempt to achieve a justifiable approach to setting equivalent criteria in South Africa. In 2016, the South African Department of Health, Directorate: Radiation Control added conditions (numbers 50 and 90), to licences to use radioactive nuclides. These conditions state that patients must be hospitalized when the dose rate at 1 m is above 25 MUSv/h, or more than 555 MBq of iodine-131 was administered to the patient. However, these criteria do not consider patients' socioeconomic conditions. A literature survey was carried out of articles detailing PRC from high-income countries as well as those in the middle-income and lower-income groups. Socioeconomic conditions within countries were determined using the International Monetary Fund lists of gross domestic product. The results from the literature have shown that in setting PRC, several countries have considered the socioeconomic conditions prevailing in their countries to achieve harmony between public protection and cost associated with hospitalization. The South African authority conditions must be seen in the context of the approach followed by other countries. Considering the international context, a justifiable, and potentially implementable, guideline or policy for improving individualized and more caring patient management is advocated. PMID- 28727660 TI - Alcohol Use Disorder Moderates the Effect of Age on Heart Rate Variability in Veterans With Posttraumatic Stress Disorder. AB - Research on heart rate variability (HRV) in posttraumatic stress disorder (PTSD) and comorbid alcohol use disorder (AUD) is limited despite its use as a biomarker of both disorders. This study examined whether AUD comorbidity contributes an additive effect on HRV for veterans with PTSD. HRV was assessed in 70 male Operation Enduring Freedom/Operation Iraqi Freedom veterans with PTSD, including 32 with co-occurring AUD. Mean HRV values for both groups were below the mean for healthy adults, but additive effects of PTSD and AUD on HRV were not observed. Consistent with prior studies, hierarchical regressions showed that HRV decreased with age in the PTSD-only group. However, HRV increased slightly with age among veterans with both PTSD and AUD. This interaction remained significant after controlling for common HRV covariates. These findings support HRV as a biomarker of PTSD and extend research by demonstrating the complex relationship between PTSD and HRV in the context of co-occurring AUD. PMID- 28727661 TI - Comparison of Post-Cesarean Section Opioid Analgesic Requirements in Women With Opioid Use Disorder Treated With Methadone or Buprenorphine. AB - OBJECTIVE: Buprenorphine is a highly effective treatment for opioid use disorders, but its continuation in the perioperative setting remains controversial, unlike the accepted practice of perioperative methadone continuation. METHODS: We conducted a retrospective cohort study from 2006 to 2014 comparing post-cesarean section opioid analgesic requirements of women with opioid use disorders treated with methadone or buprenorphine. Preoperative, intraoperative, and postoperative opioid requirements (morphine equivalent dose [MED]), postoperative complications, and length of stay were compared between the methadone and buprenorphine groups. RESULTS: During the 9-year study period, there were 185 women treated with methadone (mean dose 93.7 mg, SD 2.6) and 88 women treated with buprenorphine (mean dose 16.1 mg, SD 7.8). There were no statistically significant differences in MED requirements in the methadone versus buprenorphine groups: preoperative MED (11.4 mg [SD 31.5] vs 20.0 mg [SD 15.1]; mean difference [MD] 8.6, 95% confidence interval [CI] -1.9, 19.1), intraoperative MED (3.5 mg [SD 6.6] vs 5.2 mg [SD 13.7]; MD 1.8, 95% CI -1.1, 4.6), and postoperative MED during hospitalization (97.7 mg [SD 65.6] vs 85.1 mg [SD 73.0]; MD -12.6, 95% CI -31.1, 5.8). There were no statistically significant differences in postoperative complications or length of stay. CONCLUSIONS: Our study suggests that buprenorphine treatment will not interfere more than methadone with pain management after a cesarean section with no significant differences in opioid analgesic requirements, postoperative complications, or length of hospital stay. Future studies should investigate the generalizability to other surgeries. PMID- 28727662 TI - Paraphilic Thoughts, Behaviors and Sex Addiction in a Sample of Persons Who Use Drugs: A Cross-Sectional Study. AB - OBJECTIVE: The aim of this study was to evaluate the prevalence of paraphilic thoughts/behaviors (including paraphilic disorders) with and without sexual addiction and sexual-related conditions in a sample of substance disorder patients. METHODS: This was a cross-sectional study of substance-dependent individuals who sought outpatient treatment in Sao Paulo, Brazil. Data included sociodemographic information, drug of choice, responses to questions about sexual behavior, and to the following standardized questionnaires: (a) Sexual Addiction Screening Test, and (b) Childhood Trauma Questionnaire. RESULTS: The sample comprised 134 persons who use drug, predominantly men (76.1%), 39.6% were aged between 18 and 29 years, and 54.9% were single. Most were persons who use polydrug, 73.9% were alcohol and cocaine users, 63.4% marijuana users, 81.1% tobacco users, and 5.2% steroid users. Prevalence of paraphilic thoughts/behaviors (including paraphilic disorders) with and without sexual addiction was 47%. The HPV/herpes and hepatitis B rates were 7.9% (P = 0.021) and 6.3% (P = 0.046) respectively. Paraphilic and nonparaphilic thoughts/behaviors were associated to the presence of childhood physical neglect (odds ratios [OR] = 4.7, 95% confidence interval [CI] 1.0 to 21.9), low educational level (OR = 7.2, 95% CI 1.4 to 36), heterosexuality (OR = 3.8, 95% CI 1.1 to 12.8) and youth (age 18 to 20 years) (OR = 5.6, 95% CI 1.4 to 11.8). CONCLUSIONS: The high prevalence of paraphilic thoughts/behaviors with or without sex addiction in persons who use drugs may be related to the experience of physical and emotional neglect during childhood and this possibility should routinely be investigated in clinical practice. PMID- 28727664 TI - Effect of Self-efficacy Intervention on Quality of Life of Patients With Intestinal Stoma. AB - Colorectal carcinoma is one of the most common malignancies worldwide and the most prevalent cause of cancer mortality in China. The Miles operation and permanent colostomy are effective treatment. However, these affect the quality of life of patients as they alter normal defecation. Self-efficacy is used to define an individuals' assessments of their ability to perform a specific behavior successfully. It is regarded as an important belief that can predict health behaviors. The aim of this study was to explore the effect of a self-efficacy intervention on the quality of life of patients with a permanent colostomy. Forty eight patients in treatment for permanent colostomy surgery were divided into the control and intervention groups. The control group received routine nursing; the intervention group was exposed to a 3-month self-efficacy intervention, as well as routine nursing. The two groups completed the Chinese version of a self efficacy questionnaire at 10 days, 1 month, and 3 months after surgery. Three months after surgery, the two groups also completed a quality-of-life questionnaire. There were significant differences in the quality of life between the two groups. The self-efficacy intervention nursing method improved self efficacy and the quality of life of patients with intestinal stoma and is worthy of clinical utilization and application. PMID- 28727663 TI - Mindfulness-based Relapse Prevention for Substance Use Disorders: A Systematic Review and Meta-analysis. AB - OBJECTIVES: Substance use disorder (SUD) is a prevalent health issue with serious personal and societal consequences. This review aims to estimate the effects and safety of Mindfulness-based Relapse Prevention (MBRP) for SUDs. METHODS: We searched electronic databases for randomized controlled trials evaluating MBRP for adult patients diagnosed with SUDs. Two reviewers independently assessed citations, extracted trial data, and assessed risks of bias. We conducted random effects meta-analyses and assessed quality of the body of evidence (QoE) using the Grading of Recommendations Assessment, Development, and Evaluation approach. RESULTS: We identified 9 randomized controlled trials comprising 901 participants. We did not detect statistically significant differences between MBRP and comparators on relapse (odds ratio [OR] 0.72, 95% confidence interval [CI] 0.46-1.13, low QoE), frequency of use (standardized mean difference [SMD] 0.02, 95% CI -0.40 to 0.44, low QoE), treatment dropout (OR 0.81, 95% CI 0.40 to 1.62, very low QoE), depressive symptoms (SMD -0.09, 95% CI -0.39 to 0.21, low QoE), anxiety symptoms (SMD -0.32, 95% CI -1.16 to 0.52, very low QoE), and mindfulness (SMD -0.28, 95% CI -0.72 to 0.16, very low QoE). We identified significant differences in favor of MBRP on withdrawal/craving symptoms (SMD 0.13, 95% CI -0.19 to -0.08, I = 0%, low QoE) and negative consequences of substance use (SMD -0.23, 95% CI -0.39 to -0.07, I = 0%, low QoE). We found negligible evidence of adverse events. CONCLUSIONS: We have limited confidence in estimates suggesting MBRP yields small effects on withdrawal/craving and negative consequences versus comparator interventions. We did not detect differences for any other outcome. Future trials should aim to minimize participant attrition to improve confidence in effect estimates. PMID- 28727665 TI - TETANY WITH HYPOMAGNESEMIA, HYPOKALEMIA, AND HYPOCALCEMIA AS INITIAL PRESENTATION OF CELIAC DISEASE. PMID- 28727666 TI - Arthropathies in Inflammatory Bowel Disease: A Review for Clinicians. AB - Inflammatory bowel disease (IBD) is a systemic, chronic autoimmune disease of the digestive tract. The etiology and pathophysiology of IBD is not fully understood, though it is believed to be due to a complex interaction among the patient's genotype, immune system, and environmental factors. Inflammatory bowel disease is frequently accompanied by extraintestinal manifestations that occur in almost half of all patients. The most common extraintestinal manifestation that occurs is joint disease, collectively termed the arthropathies of IBD. While epidemiological studies have estimated that the arthropathies of IBD occur in over 46% of the IBD population, there is a paucity of nursing literature concerning the extraintestinal manifestations of IBD and the role of nurses in patient care. Thus, the purpose of this article is to facilitate a greater understanding for nurses and nurse clinicians regarding the arthropathies associated with IBD including classifications, pathophysiology, diagnosis, and management. PMID- 28727667 TI - Sleep Apnea Screening Practices During Department of Transportation Medical Examinations. AB - OBJECTIVE: The aim of this study was to examine the practices of Michigan Occupational and Environmental Medicine Association (MOEMA) members regarding screening for sleep apnea during required driver medical examinations. METHODS: A 13-question survey on sleep apnea screening practices was emailed to the MOEMA member. Nonresponders received additional E-mails and calls. RESULTS: The survey response rate was 66%. Fifty-five percent of respondents performed driver examinations and 94% screened for sleep apnea. Variations in practice included differences in how many risk factors were used to determine the need for polysomnography, 13% never ordered polysomnography and 42% never denied medical certification because of sleep apnea. CONCLUSION: Although there was significant consensus that sleep apnea screening was important, there was a large variation in the indication for and frequency in which sleep studies were ordered and drivers were denied approval because of concern about sleep apnea. PMID- 28727668 TI - Comprehensive Cardiac Rehabilitation for Secondary Prevention After Transient Ischemic Attack or Mild Stroke: PSYCHOLOGICAL PROFILE AND OUTCOMES. AB - PURPOSE: Having previously reported that comprehensive cardiac rehabilitation (CCR) is effective for secondary prevention post-transient ischemic attack (TIA)/mild nondisabling stroke (MNDS), we present psychometric findings for the same sample that elucidate subacute TIA/MNDS psychological outcomes and test whether CCR would be independently associated with psychological improvements. METHODS: In this prospective cohort trial patients with >=1 risk factor, recruited from a stroke prevention clinic within 12 months (mean = 11.5 weeks) post-TIA/MNDS, entered CCR. RESULTS: Of the 110 recruited patients, 100 (mean age = 65.4 years; 46 females) entered CCR and 80 completed CCR (mean duration = 7.6 months). At CCR entry, 16.5% and 39.2% screened positively for depression and anxiety, decreasing nonsignificantly at exit to 4.2%, and significantly to 16.9% (P = .008), respectively. Age-corrected deficits occurred more frequently than expected (P <= .03); at entry, mental health status (13.3%), clock-drawing (31.6%), oral-verbal fluency (16.9%), word-list learning (11.2%), and recall (12.6%); at exit, clock-drawing (30.0%). Entry-to-exit, mean depression, anxiety, mental and physical health status, word-list learning, memory, digit-symbol coding, and oral-verbal fluency scores improved significantly (P <= .031). No reliable change indices were significant. Psychological service recipients improved significantly more than nonrecipients in depression (P = .049). Baseline North American Adult Reading Test score predicted exercise attendance (R = 0.275; P = .044); New York Heart Association (NYHA) class and depression score predicted exit physical health status (R = 0.770, P < .001); and depression score predicted exit mental health status (R = 0.523, P < .001). CONCLUSIONS: Anxiety and executive dysfunction persisted post-TIA/MNDS. Although promising for secondary prevention post-TIA/MNDS, CCR was not independently associated with psychological improvements. CCR psychological treatment may benefit depression. Subacute NYHA class and depression may later affect quality of life. PMID- 28727669 TI - Differential Pulmonary Rehabilitation Outcomes in Patients With and Without COPD: ROLE OF GENDER. AB - PURPOSE: Individuals with all forms of pulmonary disease are referred for pulmonary rehabilitation. This study examines pulmonary rehabilitation outcomes between individuals with chronic obstructive lung disease (COPD) and non-COPD disease and the impact of gender. METHODS: This is a retrospective study at a tertiary center. The primary endpoint was the difference in 6-min walk test distance. Secondary measurements included treadmill and NuStep minutes; biceps curls and front arm raises load; quality of life measured by the St George's Respiratory Questionnaire; and University of California San Diego-Shortness of Breath Questionnaire (UCSD-SOBQ) scores. RESULTS: Eighty patients were included: 38 men (23 COPD, 15 non-COPD) and 42 women (31 COPD, 11 non-COPD). There was a statistically significant improvement in 6-min walk test distances pre- to post pulmonary rehabilitation for all participants, P = .0003. Although both the COPD and non-COPD groups demonstrated overall improvement (P < .0004 and P = .02, respectively), subgroup analysis showed no statistically significant change in the non-COPD group when divided by gender. There was a significant statistical improvement in lower and upper extremity strength in all participants. Only women with COPD showed a statistically significant improvement with respect to overall quality of life as measured by St. George's Respiratory Questionnaire (P = .01). Women showed significant improvement in their depression score, as well as a trend toward improvement in the University of California San Diego-Shortness of Breath Questionnaire, while only men with COPD showed any improvement in their sleep quality measured by the Pittsburgh Sleep Quality Index. CONCLUSIONS: Pulmonary rehabilitation results in different but improved outcomes regardless of gender or disease state. PMID- 28727670 TI - Effect of Psychosocial and Vocational Interventions on Return-to-Work Rates Post Acute Myocardial Infarction: A SYSTEMATIC REVIEW. AB - PURPOSE: To examine whether the effects of psychosocial and vocational interventions delivered in the first 3 mo post-acute myocardial infarction (AMI) are effective for improving work outcomes compared with other interventions. METHODS: A search was completed for English language publications up to March 2016 across 4 electronic databases and gray literature. Inclusion criteria were (1) psychosocial and/or vocational interventions; (2) adults 18 years or older with an AMI who were within the first 3 mo post-AMI; (3) randomized or clinically controlled trials; and (4) reporting of at least 1 return-to-work (RTW) outcome: including return to paid/unpaid employment, either full-time or part-time, to the previous job role or on modified duties. Studies were independently screened by 2 reviewers and graded using the Cochrane Collaboration tool for assessing risk of bias. A narrative synthesis and meta-analysis of the included studies was undertaken. RESULTS: Eighteen studies of varying quality were analyzed. Individually delivered psychosocial and vocational interventions may improve work rates at 3 mo (relative risk = 1.17; P = .05) when compared with usual care but there was no difference at 6 or 12 mo. People receiving group or individual psychological/vocational counselling returned to work 6.11 d sooner than those who received usual care (95% CI, -6.95 to -5.26; P < .001). CONCLUSIONS: Although psychosocial and vocational interventions show promise in people within 3 mo of AMI, compelling evidence is still limited. There is a need for more detailed, high-quality studies with valid comparison groups and adequate follow-up. PMID- 28727671 TI - Phenotypes and Characterization of COPD: A PULMONARY REHABILITATION PERSPECTIVE. AB - Phenotyping and the characterization of chronic obstructive pulmonary disease (COPD) is currently an active area of interest. The perspectives gleaned from evaluating COPD in the context of exercise lend new insights into this endeavor. Pulmonary rehabilitation centers are uniquely positioned to generate such clinical observations and have enhanced an understanding of the disease processes that are involved in COPD. This review and commentary discusses the various patterns of exercise intolerance and characterizes COPD from the perspectives of clinicians caring for persons with COPD. PMID- 28727672 TI - Cardiac Rehabilitation in Patients With Left Ventricular Assist Device: A SYSTEMATIC REVIEW AND META-ANALYSIS. AB - PURPOSE: Exercise-based cardiac rehabilitation (EBCR) has been demonstrated to improve functional capacity in heart failure (HF). However, there are limited data on the effect of EBCR in patients with advanced HF and left ventricular assist devices (LVADs). This meta-analysis sought to evaluate the effects of EBCR on functional capacity in patients with LVAD. METHODS: PubMed, Web of Science, CINAHL, and Cochrane Library databases were searched for randomized studies assessing the impact of EBCR in patients following LVAD implantation compared with standard therapy (ST). Using pre-defined criteria, appropriate studies were identified and selected. Data from selected studies were extracted in a standardized fashion and a meta-analysis was performed using a random-effects model with DerSimonian Liard weighting. Analysis employed weighted mean difference (WMD) as the effect size and intention-to-treat (ITT) principle. Study quality, publication bias, and heterogeneity were assessed. RESULTS: Six trials with a total of 183 patients (EBCR: 125; ST: 58) were identified. Mean age was 51 years and 83% were males. The initiation of EBCR varied from LVAD implantation during the index hospitalization to 10 mo post-LVAD implantation. The median rehabilitation period ranged from 6 to 10 wk. Exercise-based cardiac rehabilitation was associated with improved peak oxygen uptake ((Equation is included in full-text article.)O2) in all trials. Quantitative analysis was performed on 3 randomized studies involving 61 patients (EBCR = 39, ST = 22). Exercise-based cardiac rehabilitation was associated with significantly greater peak (Equation is included in full-text article.)O2 (WMD: 3.00 mL/kg/min; 95% CI: 0.64-5.35, P = .001). Similarly, 6-minute walk distance (6MWD) showed significantly greater improvement in the EBCR group than in the ST group (WMD: 60.06 m; 95% CI, 22.61-97.50, P = .002). Heterogeneity was low among the included trials. Exclusion sensitivity and per-protocol analysis demonstrated results consistent with ITT analysis. None of the included studies reported serious adverse events related to EBCR, which supports the safety of EBCR after LVAD implantation. CONCLUSION: This systematic review and meta-analysis demonstrated that EBCR following LVAD implantation is associated with greater improvement in functional capacity compared with ST as reflected by improved peak (Equation is included in full-text article.)O2 and 6MWD. However, given the small number of patients, further research into the clinical impact of EBCR in LVAD patients is necessary. PMID- 28727673 TI - Exercise Training Improves Ventilatory Efficiency in Patients With a Small Abdominal Aortic Aneurysm: A RANDOMIZED CONTROLLED STUDY. AB - PURPOSE: To investigate the effects of exercise training on ventilatory efficiency and physiological responses to submaximal exercise in subjects with small abdominal aortic aneurysm (AAA). METHODS: Sixty-five male patients (72.3 +/ 7.0 years) were randomized to exercise training (n = 33) or usual care group (n = 32). Exercise subjects participated in a training groups for 3 mo. Cardiopulmonary exercise testing was performed before and after the study period and peak (Equation is included in full-text article.)O2, the ventilatory threshold (VT), the oxygen uptake efficiency slope (OUES), and the (Equation is included in full-text article.)E2/(Equation is included in full-text article.)CO2 slope were identified. Baseline work rates at VT were matched to examine cardiopulmonary responses after training. RESULTS: Significant interactions indicating improvements before and after training in the exercise group were noted for time (P < .01), (Equation is included in full-text article.)O2 (P < .01), and work rate (P < .01) at the VT. At peak effort, significant interactions were noted for time (P < .01) and work rate (P < .01), while borderline significance was noted for absolute (P = .07) and relative (P = .04) (Equation is included in full-text article.)O2. Significant interactions were observed for the OUES both when using all exercise data (P = .04) and when calculated up to the VT (P < .01). For the (Equation is included in full-text article.)E2/(Equation is included in full-text article.)CO2 slope, significance was noted only when calculated up to the VT (P = .04). After training, heart rate, (Equation is included in full-text article.)E, (Equation is included in full-text article.)O2 and respiratory exchange ratio were significantly attenuated for the same baseline work rate only in the exercise group (all P < .01). CONCLUSIONS: Exercise training improves ventilatory efficiency in patients with small AAA. In addition, patients who exercised exhibited less demanding cardiorespiratory responses to submaximal effort. PMID- 28727674 TI - The Community Balance and Mobility Scale: A VALID ASSESSMENT TOOL OF BALANCE IN CARDIAC REHABILITATION PATIENTS. AB - PURPOSE: Many patients participating in cardiac rehabilitation (CR) programs have decreased balance. This is a concern, as it may affect their ability to optimally perform physical exercise in CR and thus decrease CR efficacy. Despite this concern, balance is typically not assessed as part of CR intake. This may be attributable to the fact that a suitable balance assessment tool has not been identified for higher-functioning CR patients. A potential solution to this issue is using the Community Balance and Mobility Scale (CBMS), which has been used to assess balance in higher-functioning clinical populations; however, its use in a CR population has never been investigated. Therefore, the purpose of this study was to determine the reliability and validity of the CBMS for assessing balance in CR patients. METHODS: Fifty-three participants were recruited from local CR programs to perform the CBMS. Dynamic posturography was also measured in a subset of participants (n = 31) using the Limits of Stability (LOS) test. RESULTS: Analysis of CBMS scores revealed that the mean CBMS score was 61.9 +/- 16.2 (out of 96) and that no floor or ceiling effects were observed for any participants. CBMS scores were significantly correlated with the LOS results (0.41-0.53). Interrater reliability between novice and expert testers was strong (r = 0.95), with all differences falling within the 95% limits of agreement. CONCLUSION: Overall, these results suggest that the CBMS is a valid tool to measure balance in CR patients and can be reliably administered by health care professionals with minimal training. PMID- 28727675 TI - Type 1 diabetes mellitus caused by treatment with low-dose interferon-alpha in a melanoma patient. AB - Interferon-alpha (INF-alpha) is used as an adjuvant treatment for high-risk cutaneous melanoma. It has a large variety of potentially severe and irreversible side effects and can contribute toward the development of autoimmune disease. We report a case of a 59-year-old woman who developed type 1 diabetes following the use of low-dose IFN-alpha for the adjuvant treatment of stage IIB melanoma. Fifteen months after initiating IFN-alpha, she presented with blood glucose of 1126 mg/dl, hyponatremia, and microalbuminuria. Antibodies to glutamic acid decarboxylase and islet antigen-2 were negative and C-peptide was markedly reduced. There was no personal or family history of any autoimmune conditions. Reinforced insulin treatment and volume substitution with saline and glucose as a counter-regulation was started. To the best of our knowledge, this is the first reported case of low-dose IFN-alpha-induced type 1 diabetes. Clinicians should closely evaluate the pros and cons of IFN-alpha treatment in an adjuvant setting and remain mindful of the possibility of drug-induced autoimmune disease. PMID- 28727676 TI - Association Between Diabetes Mellitus and Outcomes of Patients with Sepsis: A Meta-Analysis. AB - BACKGROUND Diabetes mellitus (DM) is a critical medical problem that can make people more likely to develop infectious complications, even sepsis. However, the influence of DM on the outcomes of septic patients is still controversial. Thus, we conducted the present meta-analysis to investigate whether DM worsens outcomes of septic patients. MATERIAL AND METHODS We searched studies from PubMed, Embase, and Cochrane Library databases from 1966 to July 1, 2016. The primary outcome we chose was 28-day or 30-day mortality or in-hospital mortality. RESULTS Our meta analysis of 10 enrolled studies performed between 2000 and 2016 shows that the mortality rate of septic patients with DM was slightly lower than that of non diabetic patients (risk ratio [RR]=0.97, 95% confidence interval [CI]: 0.96 to 0.98, P<0.00001). On the other hand, septic patients with DM had a shorter hospital stay (weighted mean difference (WMD)=-2.27, 95% CI: -4.11 to -0.44, P=0.01), a higher incidence rate of AKI (RR=1.56, 95% CI: 1.25 to 1.95, P<0.001), and a similar incidence of respiratory dysfunction (RR=0.86, 95% CI: 0.71 to 1.04, P=0.11) compared with those without DM. CONCLUSIONS The results from the meta-analysis suggest that DM does not impair the outcome of patients with sepsis, and the incidence of acute kidney injury increases dramatically in septic patients with DM. Due to the limitations of the analysis, more well-designed trials are still necessary. PMID- 28727677 TI - Surveillance for Silicosis Deaths Among Persons Aged 15-44 Years - United States, 1999-2015. AB - Silicosis is usually a disease of long latency affecting mostly older workers; therefore, silicosis deaths in young adults (aged 15-44 years) suggests acute or accelerated disease.* To understand the circumstances surrounding silicosis deaths among young persons, CDC analyzed the underlying and contributing causes? of death using multiple cause-of-death data (1999-2015) and industry and occupation information abstracted from death certificates (1999-2013). During 1999-2015, among 55 pneumoconiosis deaths of young adults with International Classification of Diseases, Tenth Revision (ICD-10) code J62 (pneumoconiosis due to dust containing silica),S 38 (69%) had code J62.8 (pneumoconiosis due to other dust containing silica), and 17 (31%) had code J62.0 (pneumoconiosis due to talc dust) listed on their death certificate. Decedents whose cause of death code was J62.8 most frequently worked in the manufacturing and construction industries and production occupations where silica exposure is known to occur. Among the 17 decedents who had death certificates listing code J62.0 as cause of death, 13 had certificates with an underlying or a contributing cause of death code listed that indicated multiple drug use or drug overdose. In addition, 13 of the 17 death certificates listing code J62.0 as cause of death had information on decedent's industry and occupation; among the 13 decedents, none worked in talc exposure associated jobs, suggesting that their talc exposure was nonoccupational. Examining detailed information on causes of death (including external causes) and industry and occupation of decedents is essential for identifying silicosis deaths associated with occupational exposures and reducing misclassification of silicosis mortality. PMID- 28727678 TI - Progress Toward Measles Elimination - Bangladesh, 2000-2016. AB - In 2013, at the 66th session of the Regional Committee of the World Health Organization (WHO) South-East Asia Region (SEAR), a regional goal was established to eliminate measles and control rubella and congenital rubella syndrome* by 2020 (1). WHO-recommended measles elimination strategies in SEAR countries include 1) achieving and maintaining >=95% coverage with 2 doses of measles-containing vaccine (MCV) in every district, delivered through the routine immunization program or through supplementary immunization activities (SIAs)?; 2) developing and sustaining a sensitive and timely measles case-based surveillance system that meets targets for recommended performance indicators; and 3) developing and maintaining an accredited measles laboratory network (2). In 2014, Bangladesh, one of 11 countries in SEAR, adopted a national goal for measles elimination by 2018 (2,3). This report describes progress and challenges toward measles elimination in Bangladesh during 2000-2016. Estimated coverage with the first MCV dose (MCV1) increased from 74% in 2000 to 94% in 2016. The second MCV dose (MCV2) was introduced in 2012, and MCV2 coverage increased from 35% in 2013 to 93% in 2016. During 2000-2016, approximately 108.9 million children received MCV during three nationwide SIAs conducted in phases. During 2000-2016, reported confirmed measles incidence decreased 82%, from 34.2 to 6.1 per million population. However, in 2016, 56% of districts did not meet the surveillance performance target of >=2 discarded nonmeasles, nonrubella casesS per 100,000 population. Additional measures that include increasing MCV1 and MCV2 coverage to >=95% in all districts with additional strategies for hard-to-reach populations, increasing sensitivity of measles case-based surveillance, and ensuring timely transport of specimens to the national laboratory will help achieve measles elimination. PMID- 28727679 TI - Notes from the Field: Cronobacter sakazakii Infection Associated with Feeding Extrinsically Contaminated Expressed Human Milk to a Premature Infant - Pennsylvania, 2016. PMID- 28727680 TI - QuickStats: Percentage* of Office-Based Primary Care Physicians Accepting New Patients, by Source of Payment Accepted - National Electronic Health Records Survey, 2015. PMID- 28727681 TI - Notes from the Field: Cluster of Acute Flaccid Myelitis in Five Pediatric Patients - Maricopa County, Arizona, 2016. PMID- 28727682 TI - Racial and Ethnic Differences in Homicides of Adult Women and the Role of Intimate Partner Violence - United States, 2003-2014. AB - Homicide is one of the leading causes of death for women aged <=44 years.* In 2015, homicide caused the death of 3,519 girls and women in the United States. Rates of female homicide vary by race/ethnicity (1), and nearly half of victims are killed by a current or former male intimate partner (2). To inform homicide and intimate partner violence (IPV) prevention efforts, CDC analyzed homicide data from the National Violent Death Reporting System (NVDRS) among 10,018 women aged >=18 years in 18 states during 2003-2014. The frequency of homicide by race/ethnicity and precipitating circumstances of homicides associated with and without IPV were examined. Non-Hispanic black and American Indian/Alaska Native women experienced the highest rates of homicide (4.4 and 4.3 per 100,000 population, respectively). Over half of all homicides (55.3%) were IPV-related; 11.2% of victims of IPV-related homicide experienced some form of violence in the month preceding their deaths, and argument and jealousy were common precipitating circumstances. Targeted IPV prevention programs for populations at disproportionate risk and enhanced access to intervention services for persons experiencing IPV are needed to reduce homicides among women. PMID- 28727683 TI - Notes from the Field: Hospital Contact Investigation for a Patient Who Developed a Zoster Vaccine-Related Rash - Maryland, February 2015. PMID- 28727684 TI - Erratum: Vol. 66, No. 23. AB - In the report, "Tobacco Use Among Middle and High School Students - United States, 2011-2016," an error occurred in the Table. The prevalence estimate for cigar smoking among high school males should read "9.9 (8.6-11.2)." PMID- 28727685 TI - ErbB4 signaling in dopaminergic axonal projections increases extracellular dopamine levels and regulates spatial/working memory behaviors. AB - Genetic variants of Neuregulin 1 (NRG1) and its neuronal tyrosine kinase receptor ErbB4 are associated with risk for schizophrenia, a neurodevelopmental disorder characterized by excitatory/inhibitory imbalance and dopamine (DA) dysfunction. To date, most ErbB4 studies have focused on GABAergic interneurons in the hippocampus and neocortex, particularly fast-spiking parvalbumin-positive (PV+) basket cells. However, NRG has also been shown to modulate DA levels, suggesting a role for ErbB4 signaling in dopaminergic neuron function. Here we report that ErbB4 in midbrain DAergic axonal projections regulates extracellular DA levels and relevant behaviors. Mice lacking ErbB4 in tyrosine hydroxylase-positive (TH+) neurons, but not in PV+ GABAergic interneurons, exhibit different regional imbalances of basal DA levels and fail to increase DA in response to local NRG1 infusion into the dorsal hippocampus, medial prefrontal cortex and dorsal striatum measured by reverse microdialysis. Using Lund Human Mesencephalic (LUHMES) cells, we show that NRG/ErbB signaling increases extracellular DA levels, at least in part, by reducing DA transporter (DAT)-dependent uptake. Interestingly, TH-Cre;ErbB4f/f mice manifest deficits in learning, spatial and working memory-related behaviors, but not in numerous other behaviors altered in PV-Cre;ErbB4f/f mice. Importantly, microinjection of a Cre-inducible ErbB4 virus (AAV-ErbB4.DIO) into the mesencephalon of TH-Cre;ErbB4f/f mice, which selectively restores ErbB4 expression in DAergic neurons, rescues DA dysfunction and ameliorates behavioral deficits. Our results indicate that direct NRG/ErbB4 signaling in DAergic axonal projections modulates DA homeostasis, and that NRG/ErbB4 signaling in both GABAergic interneurons and DA neurons contribute to the modulation of behaviors relevant to psychiatric disorders.Molecular Psychiatry advance online publication, 20 July 2017; doi:10.1038/mp.2017.132. PMID- 28727686 TI - FBXW7 regulates DISC1 stability via the ubiquitin-proteosome system. AB - Disrupted in schizophrenia 1 (DISC1) is a multi-functional scaffolding protein that has been associated with neuropsychiatric disease. The role of DISC1 is to assemble protein complexes that promote neural development and signaling, hence tight control of the concentration of cellular DISC1 in neurons is vital to brain function. Using structural and biochemical techniques, we show for we believe the first time that not only is DISC1 turnover elicited by the ubiquitin proteasome system (UPS) but that it is orchestrated by the F-Box protein, FBXW7. We present the structure of FBXW7 bound to the DISC1 phosphodegron motif and exploit this information to prove that disruption of the FBXW7-DISC1 complex results in a stabilization of DISC1. This action can counteract DISC1 deficiencies observed in neural progenitor cells derived from induced pluripotent stem cells from schizophrenia patients with a DISC1 frameshift mutation. Thus manipulation of DISC1 levels via the UPS may provide a novel method to explore DISC1 function. PMID- 28727687 TI - Hippocampus-dependent memory and allele-specific gene expression in adult offspring of alcohol-consuming dams after neonatal treatment with thyroxin or metformin. AB - Fetal alcohol spectrum disorder (FASD), the result of fetal alcohol exposure (FAE), affects 2-11% of children worldwide, with no effective treatments. Hippocampus-based learning and memory deficits are key symptoms of FASD. Our previous studies show hypothyroxinemia and hyperglycemia of the alcohol-consuming pregnant rat, which likely affects fetal neurodevelopment. We administered vehicle, thyroxine (T4) or metformin to neonatal rats post FAE and rats were tested in the hippocampus-dependent contextual fear-conditioning paradigm in adulthood. Both T4 and metformin alleviated contextual fear memory deficit induced by FAE, and reversed the hippocampal expression changes in the thyroid hormone-inactivating enzyme, deiodinase-III (Dio3) and insulin-like growth factor 2 (Igf2), genes that are known to modulate memory processes. Neonatal T4 restored maternal allelic expressions of the imprinted Dio3 and Igf2 in the adult male hippocampus, while metformin restored FAE-caused changes in Igf2 expression only. The decreased hippocampal expression of DNA methyltransferase 1 (Dnmt1) that maintains the imprinting of Dio3 and Igf2 during development was normalized by both treatments. Administering Dnmt1 inhibitor to control neonates resulted in FAE-like deficits in fear memory and hippocampal allele-specific expression of Igf2, which were reversed by metformin. We propose that neonatal administration of T4 and metformin post FAE affect memory via elevating Dnmt1 and consequently normalizing hippocampal Dio3 and Igf2 expressions in the adult offspring. The present results indicate that T4 and metformin, administered during the neonatal period that is equivalent to the third trimester of human pregnancy, are potential treatments for FASD and conceivably for other neurodevelopmental disorders with cognitive deficits. PMID- 28727689 TI - Do robots get burnout? PMID- 28727690 TI - Demographic and psychological correlates of satisfaction with healthcare access in New Zealand. AB - AIMS: To explore the distribution of New Zealanders' satisfaction with their healthcare access and identify various demographic and psychological factors associated with this satisfaction. METHODS: 15,822 participants responded to the 2014/15 New Zealand Attitudes and Values Study (NZAVS) survey. This survey included questions on participants' demographic and psychological characteristics, and an item asking for their level of satisfaction with "your access to healthcare when you need it". RESULTS: The majority of participants were highly satisfied with their access to healthcare when needed (68.4%), while 25.3% were moderately satisfied and 6.1% expressed low satisfaction. Younger individuals, those of Maori, Pacific, or Asian ethnicity, and those with higher deprivation and lower income, exhibited lower satisfaction. Conversely, those with a partner, living in an urban area and non-parents showed greater satisfaction. These effects remained significant even after controlling for various psychological factors. In terms of personality, those high on Extraversion, Agreeableness, Conscientiousness and Honesty-Humility, but low on Neuroticism and Openness also expressed higher satisfaction. Lastly, higher self rated health was associated with greater satisfaction. CONCLUSION: The majority of New Zealanders are highly satisfied with their access to healthcare when needed, but a considerable number of people express some degree of dissatisfaction. This is broadly consistent with the New Zealand Health Survey (NZHS), and substantiates the finding that approximately 28-32% of New Zealanders experience low healthcare access. Our findings make a novel contribution to the literature by showing that the Big-Six personality traits are reliably associated with New Zealanders' satisfaction with their healthcare access. PMID- 28727688 TI - Diazepam actions in the VTA enhance social dominance and mitochondrial function in the nucleus accumbens by activation of dopamine D1 receptors. AB - Benzodiazepines can ameliorate social disturbances and increase social competition, particularly in high-anxious individuals. However, the neural circuits and mechanisms underlying benzodiazepines' effects in social competition are not understood. Converging evidence points to the mesolimbic system as a potential site of action for at least some benzodiazepine-mediated effects. Furthermore, mitochondrial function in the nucleus accumbens (NAc) has been causally implicated in the link between anxiety and social competitiveness. Here, we show that diazepam facilitates social dominance, ameliorating both the competitive disadvantage and low NAc mitochondrial function displayed by high anxious rats, and identify the ventral tegmental area (VTA) as a key site of action for direct diazepam effects. We also show that intra-VTA diazepam infusion increases accumbal dopamine and DOPAC, as well as activity of dopamine D1- but not D2-containing cells. In addition, intra-NAc infusion of a D1-, but not D2, receptor agonist facilitates social dominance and mitochondrial respiration. Conversely, intra-VTA diazepam actions on social dominance and NAc mitochondrial respiration are blocked by pharmacological NAc micro-infusion of a mitochondrial complex I inhibitor or an antagonist of D1 receptors. Our data support the view that diazepam disinhibits VTA dopaminergic neurons, leading to the release of dopamine into the NAc where activation of D1-signaling transiently facilitates mitochondrial function, that is, increased respiration and enhanced ATP levels, which ultimately enhances social competitive behavior. Therefore, our findings critically involve the mesolimbic system in the facilitating effects of diazepam on social competition and highlight mitochondrial function as a potential therapeutic target for anxiety-related social dysfunctions. PMID- 28727691 TI - Appendicitis presenting as the first manifestation of colorectal carcinoma: a 13 year retrospective study. AB - AIM: Appendicitis in older adults may present as the first sign of underlying colorectal cancer. We aim to determine whether there was a difference in the rate of diagnosis of colorectal carcinoma for patients >=45 years following a presentation with appendicitis, compared with New Zealand standardised rates. METHOD: Retrospective study of patients >=45 years with a confirmed diagnosis of appendicitis from 2003 to 2015 inclusive. The rate of colorectal carcinoma diagnosed during the 36-month follow-up period was calculated and compared to standardised rates, as per the New Zealand cancer registry. RESULTS: Six hundred and twenty-nine patients were included for analysis, 15 had a diagnosis of colorectal cancer in the follow-up period. Patients >=45 years had a 6.3-fold (CI 3.6-10.2) increased risk of colorectal carcinoma than predicted given the population demographics. Those patients aged between 45-60 years had a 17-fold (95% CI 8-32.2) increased standardised risk ratio. CONCLUSION: This is the first study of its kind conducted in Australasia. This study found patients >=45 years who present with appendicitis have significantly increased risk of underlying colorectal cancer. Until further research is conducted the authors recommend clinicians consider colonic investigation for older adults following a diagnosis of appendicitis. PMID- 28727692 TI - Short-term outcomes following cytoreductive surgery and heated intra-peritoneal chemotherapy at Waikato. AB - AIM: Pseudomyxoma peritonei is a rare disease that affects 1-2 per million population per year. Treatment with cytoreductive surgery with heated intraperitoneal chemotherapy (CRS with IPC) has been well described. The purpose of this study was to look at the short-term outcomes following CRS with IPC for all such patients treated in Waikato. METHOD: Records for all patients presenting to surgery for CRS with IPC were retrospectively reviewed. CRS with IPC was performed in accordance with the techniques described by Sugarbaker. Data recorded included patient characteristics, characteristics of surgical treatment and early post-operative outcomes. RESULTS: Sixty-eight patients underwent 72 procedures. Fourteen patients were deemed unresectable at surgery and were treated palliatively. The median age was 57 with the majority being female (59%). The median time, from the decision made for surgery to CRS with IPC, was three months. The median prior surgical score was 1 and the median peritoneal cancer index (PCI) was 19.5. The median operating time was 9.08 hours (5.43-15.20). The majority of patients (76%) had pseudomyxoma peritonei, while the remainder had a combination of other appendiceal, colorectal, ovarian, gastric and primary mesothelial primaries. The major complication rate was 24% and the 30-day mortality rate was 1.4%. The median hospital stay was 12 days. CONCLUSION: Short term outcomes following CRS with IPC at Waikato are comparable to those published in the literature. Further follow-up is anticipated for the publication of survival and recurrence data. PMID- 28727693 TI - A cross-disciplinary assessment of student loans debt, financial support for study and career preferences upon graduation. AB - AIM: To explore relationships between student loans debt, financial support and career preferences upon graduation for all healthcare disciplines offered at the Faculty of Medical and Health Sciences, University of Auckland. METHODS: The Faculty Tracking Project is a longitudinal study which invites students to complete a questionnaire at the beginning and end of their educational programmes, including questions on debt, financial support and career preference. Our analysis comprised three phases: (1) a descriptive analysis of data related to debt and financial support; (2) a principal component analysis in order to find related categories of career choice; and (3) logistic regression models to determine how career preference categories could be explained by either levels of student loans debt or financial support. RESULTS: Data from 2,405 participating students were included. Students in health sciences, nursing and pharmacy typically accrue levels of student loans debt of around $15,000 to $29,999, while optometry students accrue debt around $15,000 higher. Medical students show debt distributed around modes of $0 and $90,000 or more. All students typically access three sources of financial support during study. Career preferences at graduation reduced to four categories for all health disciplines. We found five significant effects, involving students in health sciences, medicine and pharmacy, relating the number of sources of financial support to the four categories of career preference. No significant effects were found related to level of student loans debt. CONCLUSIONS: Our results suggest that financial support is a more strongly determining factor in career choices than the level of student loans debt. The four-category framework for student career preferences appears to be a useful model for further research. PMID- 28727694 TI - 30-day mortality after percutaneous coronary intervention in New Zealand public hospitals (ANZACS-QI 18). AB - AIM: The aim of this report is to provide hospitals in New Zealand with data about their own outcomes for percutaneous coronary intervention (PCI) procedures and allow comparisons with other New Zealand units and with international data. METHODS: All PCI procedures (n=5,033) were identified in nine public hospital catheterisation laboratories between 1 October 2014 and 30 September 2015. Risk adjusted mortality rates were derived for each hospital and compared with the national rate. RESULTS: The overall 30-day mortality rate after PCI was 1.23%. The national 30-day mortality rates were 3.28% for the subgroup of patients treated for a ST segment elevation myocardial infarct and 0.66% for those treated for other acute coronary syndrome (ACS) or non-ACS indications. There were no statistically significant differences in outcomes between the different New Zealand public hospital catheterisation laboratories, either overall or for each patient subgroup. CONCLUSIONS: Mortality rates in the first 30 days after PCI are low and comparable across New Zealand public hospitals. The outcomes are comparable with international experience. PMID- 28727695 TI - Where to from here? Posthumous healthcare data, digital e(lectronic)-mortality and New Zealand's healthcare future. AB - Ongoing improvements in digital data acquisition and storage has led to the phenomenon of e(lectronic)-mortality, where digital data can now exist for a potentially infinite period. Globally, many countries are facilitating the acquisition and researcher-led access to large-scale, population-based digitised healthcare data sets. Their utilisation has led to numerous positive advances in healthcare. New Zealand's medical record system is becoming increasingly digitised, and as a consequence there will be an ever-increasing resource of posthumous healthcare data stored digitally, including genomic information. Such data could be utilised for research purposes, and developing such a consolidated resource could improve healthcare outcomes in our own nation and allow us to parallel global progress in healthcare research trends. This viewpoint article explores the issues surrounding, and potential for utilisation of, a national resource of posthumous digital healthcare data. Currently, there appear to be no legal barriers to the large-scale acquisition and utilisation of posthumous healthcare data in New Zealand, however, previous legislation may not have been developed with developments in technology or e-mortality in mind. Ethically, culturally and socially there are many challenges to address, including issues surrounding obtaining consent, respecting privacy, management of incidental findings, maintaining anonymity and ensuring community support for such a resource. Despite the potential for widespread health benefits that utilisation of posthumous healthcare data in this country may facilitate, wide and ongoing consultation is required to examine how such a precious resource can be enabled for the downstream benefit of all New Zealanders. PMID- 28727696 TI - The thumb sign. PMID- 28727697 TI - A villous adenoma of bladder/urachus origin located in the perineum. PMID- 28727698 TI - High Prevalence of Neuropathic Pain Component in Patients with Low Back Pain: Evidence from Meta-Analysis. AB - BACKGROUND: Low back pain (LBP) is a complex syndrome which includes a nociceptive (NcP) component, a neuropathic (NeP) component, or a mixture of components (mixed pain). The NeP component (NePC) in LBP is defined as the presence of NeP with or without an NcP. OBJECTIVE: This meta-analysis aimed at assessing the pooled prevalence of NePC in patients with LBP and at identifying the factors causing significant heterogeneity in reported prevalence. STUDY DESIGN: Meta-analysis. METHODS: A systematic literature search was carried out, with inclusion of all epidemiological studies describing the NeP prevalence levels in LBP patients while using standard diagnostic methods. The "pooled prevalence rate (PPR)" of NePC, either on its own or in combination with NcP, was calculated. A pre-specified subgroup analysis was carried out, considering LBP duration, presence of leg pain, diagnostic method(s), and questionnaire(s) used. RESULTS: The meta-analysis included 20 studies relating to a total of 14,269 LBP patients, of whom 7,969 patients (55.8%) were identified as presenting with NePC. The pooled PR (95% CI) of NePC in patients with LBP was 0.47 (0.40 - 0.54), while the pooled PR of NcP was 0.56 (0.48 - 0.63). Higher NePC pooled PR values were identified in LBP with leg pain as compared to uncomplicated LBP (respectively: 0.60; 0.47 - 0.73 vs 0.27; 0.23 - 0.31; Pinteraction < 0.01). LIMITATIONS: The quality of the included studies was assessed using ad-hoc criteria. Due to the limited number of available studies, one may need to be cautious in reaching conclusions about the impact of disease duration on NePC prevalence values. We pooled studies which used a range of different diagnostic methods, with putatively different sensitivity/specificity diagnosing levels. CONCLUSIONS: Overall, high NePC prevalence levels were here identified in LBP patients. As the pain is a subjective phenomenon and there is no gold standard for the diagnosis of NePC, there is the possibility that the pooled effect estimate may alter depending upon the diagnostic method used. KEY WORDS: Neuropathic pain, nociceptive pain, low back pain, symptom-based questionnaire, chronicity. PMID- 28727699 TI - Efficacy of Palmitoylethanolamide for Pain: A Meta-Analysis. AB - BACKGROUND: Palmitoylethanolamide (PEA) is a cannabimimetic compound that has been investigated as an analgesic agent in animal models and clinical trials. OBJECTIVES: We conducted a meta-analysis to examine the efficacy of PEA for treating pain in randomized, controlled trials. STUDY DESIGN: Systematic review and meta-analysis. SETTING: This meta-analysis examined all randomized, controlled trials involving the effect of PEA on pain score. METHODS: We searched PubMed and Embase for randomized, active or placebo-controlled trials of PEA for the treatment of acute or chronic pain. Our primary outcome was the weighted mean difference in visual analog pain scales of PEA treatment compared to inactive controls. RESULTS: We identified 10 studies including data from 786 patients who received PEA and 512 controls for inclusion in our systematic review. Eight trials included an inactive control group and were included in the meta-analysis. PEA was associated with significantly greater pain reduction compared to inactive control conditions (WMD = 2.03, 95% CI: 1.19 - 2.87, z = 4.75, P < 0.001). Use of placebo control, presence of blinding, allowance for concomitant treatments, and duration or dose of PEA treatment did not affect the measured efficacy of PEA. All-cause dropout was non-significantly reduced in the PEA group compared to inactive control conditions (RR = 0.36, 95% CI: 0.10 - 1.26, z = -1.60, P = 0.11). LIMITATIONS: This meta-analysis relied on a relatively small number of trials across a variety of conditions causing pain with differing trial designs. Overall quality of the underlying studies and assessment of side effects were often poor. CONCLUSIONS: PEA may be a useful treatment for pain and is generally well tolerated in research populations. Further, well-designed, randomized, placebo-controlled trials are needed to provide reliable estimates of its efficacy and to identify less serious adverse events associated with this compound. KEY WORDS: PEA, palmidrol, palmitoylethanolamide, efficacy, pain, pain management, meta-analysis. PMID- 28727700 TI - Therapeutic Role of Placebo: Evolution of a New Paradigm in Understanding Research and Clinical Practice. AB - Research into interventional techniques in managing chronic spinal pain continues to be challenging, mystifying, confusing, and biased. Insight, or lack thereof, into placebo and nocebo phenomena contributes mightily to these difficulties. Unfortunately, placebo-nocebo responses are the subject of numerous controversies and challenges from not only a research perspective, but also clinical perspective. While interventionalists consider the biggest threat to interventional pain management research is inappropriate and outdated interpretation of the data, a greater problem is the misuse of the placebo response in research, with the declaration that all and everything as a placebo effect: with a misinterpretation of the nature of the placebo the, associated conclusions can be inaccurate.Researchers have been aware of placebo and nocebo effects for decades, even though misunderstandings and misgivings continue to be seen in scientific studies. In simplistic terms, placebo and nocebo had been understood to indicate improving or worsening of symptoms that occur during treatment with placebo/nocebo drugs or modalities. However, research has demonstrated that such terminology does not necessarily reflect "true" placebo effect or nocebo response. These effects are based on numerous factors, including natural course of a disease, spontaneous remission, regression to the mean, and a multitude of other conceptual, explanatory, and moral challenges. In modern clinical research, a neutral substance called placebo has been mainly used as a comparison factor rather than being studied itself, while the nocebo response has only been minimally studied.A major misconception involves active placebo, a concept that has been extended beyond the administration of inert substances. The definition of active placebo of an active agent given to a patient, even though the pharmacologic action of the active agent is not known to be beneficial, has been converted to conveniently change many of the treatments which are effective on their own to be defined as placebos, often leading to conclusions that none of the interventions are effective. This review focuses on a multitude of controversies surrounding placebo and nocebo phenomena in research and clinical applications. The discussion includes a focus on unsolved, forgotten, and ignored features of placebo responses in medicine, and provides an appropriate understanding of placebo and nocebo phenomena in interventional pain management. To that effect, this review also describes therapeutic placebos, research with open placebos, and improvements in understanding clinical applications of present interventional pain management research. PMID- 28727701 TI - Randomized Placebo-Controlled Placebo Trial to Determine the Placebo Effect Size. AB - BACKGROUND: It is the gold standard to use a placebo treatment as the control group in prospective randomized controlled trials (RCTs). Although placebo controlled trials can reveal an effect of an active treatment, the pure effect of a placebo treatment alone has never been presented or evaluated. No evidence based, placebo-therapeutic options are currently available, and no placebo controlled trials have been performed to elucidate the pure placebo effect. OBJECTIVES: To analyze the pure placebo effect on clinical, chronic pain through a blinded RCT. STUDY DESIGN: A prospective, randomized, placebo-controlled trial. SETTING: Medical University centers. METHODS: One-hundred eighty-two patients suffering from chronic plantar heel pain for over 6 months,who failed to respond to conservative treatments, were screened and 106 of these patients were enrolled into this study. The patients were randomly assigned to receive either a blinded placebo shockwave treatment or an unblinded placebo shockwave treatment. The primary outcome measure was the differences in percentage change of visual analogue scale (VAS) scores 6 weeks after the intervention. The secondary outcome measure was the differences in Roles and Maudsley pain score (RMS) 6 weeks after intervention. As an exploratory outcome, 2-sided group comparisons for baseline characteristics between active treatment and controls were done using the Mann Whitney-U tests for group comparisons; treatment efficiency was calculated by the effect size coefficient and benchmarks for the Mann-Whitney estimator according to the t-test of 2 independent samples for quantitative data, as well as the Fisher's exact test for binary data. RESULTS: Patients from both groups did not differ with respect to heel pain ratings at baseline, for both the VAS (P = .476) and RMS (P = .810) scores. After 6 weeks, patients receiving the blinded placebo treatment reported less heel pain on both scales (VAS: P = .031; RMS: P = .004). Change scores of pain ratings were significantly higher in the blinded placebo group than in the un-blinded placebo group (VAS: P = .002; RMS: P = .002). LIMITATIONS: As the study represents the first to use an inverse placebo RCT (IPRCT), further conceptual and methodological issues need to be addressed to describe detailed, underlying mechanisms. Specific contextual, intrapersonal, and interpersonal factors modulating the placebo effects should be addressed in future IPRCTs. CONCLUSIONS: The present study indicated that true placebo effect sizes can be analyzed through a proper IPRCT design. Instead of treating high numbers of patients with placebos in a RCT, which increases the risk for subjects not receiving the active treatment, the IPRCT technique seems to be much more appropriate to analyze the effect sizes of any active treatment, in accordance with the Good Clinical Practice guidelines and Declarations of Helsinki. KEY WORDS: Pain, randomized controlled trial, RCT, placebo, effect size, inverse placebo, study, pain therapy. PMID- 28727703 TI - Intrathecal Morphine Improves Hemodynamic Parameters and Analgesia in Patients Undergoing Aortic Valve Replacement Surgery: A Prospective, Double-Blind, Randomized Trial. AB - BACKGROUND: Intrathecal morphine (ITM) has been used in hopes of providing good postoperative analgesia in cardiac surgery. Little is known about its use in isolated aortic valve replacement surgery. OBJECTIVES: To evaluate the effects of 7 u/kg ITM administration in aortic valve replacement in regards to hemodynamics, pain score, and postoperative complications when compared to general anesthesia alone. STUDY DESIGN: A randomized, double-blind trial. SETTING: Academic medical center. METHODS: Forty-four patients, who underwent aortic valve replacement, were randomly assigned to receive ITM, before the induction of general anesthesia (ITM group, n = 22) or no intrathecal injection i.e., general anesthesia alone (control group, n = 22). Induction of anesthesia was done with fentanyl, propofol, and isoflurane. Pain scores, determined by visual analog scale (VAS), were recorded immediately after extubation, at the first, sixth, twelfth, eighteenth, and twenty-fourth hour after extubation. Hemodynamics, heart rate, mean arterial pressure, central venous pressure, pulmonary capillary wedge pressure, and cardiac index were recorded intra-operatively and up to 24 hours post-operatively. RESULTS: VAS scores were lower in the ITM group at each measured time than control group (P < 0.01). The cumulative fentanyl consumption during the first 24 hours after extubation was significantly reduced by 35% in the ITM group (951 ug /first 24 hours) as compared to the control group (1463.6 ug /first 24 hours), (P < 0.001). The mean time to first request for rescue analgesia was significantly prolonged in the ITM group (20.11 +/- 4.24 hours, P < 0.001) compared with the control group (0.60 +/- 0.44 hours). The mean tramadol consumption dose was significantly reduced in the ITM group (279.33 +/- 61.35 mg), compared with the control group (895 +/- 106.42 mg), (P < 0.001). Hemodynamic parameters exhibited a significant decrease in HR and MAP in the ITM group, but no significant difference was found in regards to CVP, PCWP, and CI. Glyceryl trinitrate consumption in the first 24 hours was significantly reduced by 43% in the ITM group (28.3 mg /first 24 hours) when compared to the control group (145.5 mg /first 24 hours), (P < 0.001). Extubation time (4.5 +/- 7.5 vs. 5.3 +/- 1.0 hours, P < 0.05) and intensive care unit length of stay (3.7 +/- 1.0 vs. 5.6 +/- 1.6 days, P < 0.01) were shorter in the ITM group. LIMITATIONS: Small sample size. CONCLUSIONS: In valvular heart disease patients undergoing aortic replacement surgery, ITM is a good adjunct to general anesthesia as a safe and effective analgesic alternative. It provides better hemodynamic control, earlier tracheal extubation, and shorter ICU stay. KEY WORDS: Intrathecal, morphine, fentanyl, analgesia, aortic, cardiac, surgery. PMID- 28727702 TI - Subcutaneous Injection of Triamcinolone and Lidocaine to Prevent Postherpetic Neuralgia. AB - BACKGROUND: Herpes zoster (HZ) is associated with inflammation of the peripheral nerves, which is considered to be an important cause of postherpetic neuralgia (PHN). Interventions aimed at reducing this inflammation could prevent PHN. One option is the epidural administration of corticosteroid and local anesthetic. However, several authors have reported a risk of arachnoiditis with epidural corticosteroids. Subcutaneous injection in an outpatient setting is a safer option. However, there is limited evidence of the effectiveness of this alternative for preventing PHN. OBJECTIVES: The aim of this study was to assess the effectiveness of subcutaneous injection of triamcinolone and lidocaine for the prevention of PHN in elderly HZ patients. STUDY DESIGN: Randomized, single center, clinical trial. SETTING: Department of pain management of a teaching hospital in Beijing, China. METHODS: Patients with acute HZ with rash < 7 days (n = 100) were randomly assigned to receive either standard therapy (oral antivirals and analgesics) alone or standard therapy plus subcutaneous injection of triamcinolone and lidocaine. The severity of pain was assessed using a numeric rating scale (NRS) at enrollment and at one, 3, and 6 months after rash onset. Quality of life (QoL) was evaluated by the SF-36 before treatment and at 3 and 6 months after rash onset. The primary endpoint was the presence of zoster associated pain (ZAP) at 3 months after rash onset. RESULTS: At enrollment, all patients reported ZAP with average NRS scores of 6.64 +/- 1.44 and 7.16 +/- 1.22 in the standard group and subcutaneous group, respectively. At 3 and 6 months after rash onset, the pain had decreased in both groups, but the decrease was significantly greater in the subcutaneous injection group. At 3 months, 2 (4%) patients in the subcutaneous injection group vs. 10 (20%) patients in the standard group had ZAP with NRS > 3 (P = 0.014). Both groups showed significant improvement in QoL at 3 and 6 months. No patient had major adverse events related to the subcutaneous injection. LIMITATIONS: The main limitation of the study was the absence of a placebo subcutaneous injection in the standard group. CONCLUSION: Subcutaneous injection of triamcinolone and lidocaine in the acute phase of HZ can reduce ZAP more effectively than oral antivirals and analgesics alone, and may be a feasible method to prevent PHN. KEY WORDS: Subcutaneous injection, lidocaine, triamcinolone, postherpetic neuralgia, prevention. PMID- 28727704 TI - Evaluating the Adjuvant Effect of Dexamethasone to Ropivacaine in Transversus Abdominis Plane Block for Inguinal Hernia Repair and Spermatocelectomy: A Randomized Controlled Trial. AB - BACKGROUND: The transversus abdominis plane (TAP) block is a relatively straightforward regional technique used for postoperative analgesia in patients undergoing abdominal surgeries. Various adjuvants have been used in past to prolong the duration of action of analgesia in peripheral nerve blocks. Several studies investigating the analgesic efficacy of dexamethasone added to local anesthetic agents, such as bupivacaine, have shown promising results. However, there are few studies comparing the efficacy of dexamethasone with ropivacaine. OBJECTIVES: To determine if the addition of dexamethasone 8 mg to ropivacaine 0.2% in a TAP block would prolong the analgesic effect when compared with ropivacaine 0.2% alone after inguinal hernia repair and spermatocelectomy. STUDY DESIGN: A randomized, double blinded, placebo-controlled, prospective study. SETTING: Teaching hospital. METHODS: A total of 82 patients undergoing inguinal hernia repair or spermatocelectomy were enrolled in the study, of which 41 patients received TAP block with ropivacaine with saline, and the other 41 received ropivacaine with dexamethasone immediately following surgery. Both the proceduralist (resident) and the patient were blinded to the solution used. Visual analog pain scores (0 - 10) were obtained pre-block and immediately post block. Our primary endpoint was visual analog pain score at 12 hours, with 24 and 48-hour pain scores as the secondary endpoints. RESULTS: The averaged pre-block pain score was 7.6 +/- 1.7 in the saline group and 7.7 +/- 2.2 in the dexamethasone group. There was an improvement in the pain scores from the baseline, at 12 hours after the administration of the block in both the groups. Although the dexamethasone group had a greater change in pain score (-3.2) than the saline group (-2.2), the difference between the 2 groups was not statistically significant (0.08). We did not observe significant differences in change from baseline at 24 hours and 48 hours between the 2 groups (P value = 0.74 and 0.44, respectively). LIMITATIONS: We did not assess the total dose of analgesics used during the surgery with the assumption that the effect of intraoperative analgesics should wear off by the time we collect the 12-hour pain score. We did not control for the expertise of the provider that performed the block, as some of the providers may have been junior residents with limited experience and expertise in the area. Additionally, we were unable to include postoperative opioid consumption due to concerns of inconsistencies during patient reporting and data quality. CONCLUSIONS: In conclusion, we could not show a statistically significant prolongation of analgesia for TAP blocks with ropivacaine when dexamethasone was added, though there was a one point drop in pain score at 12 hours post block when dexamethasone was added to the block solution. This decrease in pain scores at 12 hours may still be beneficial to patient satisfaction given the low side effect profile of dexamethasone. As ropivacaine has a lower pH than other local anesthetic agents, further well designed studies are needed to investigate the combination of this drug with more alkaline drugs like corticosteroids. KEY WORDS: Regional anesthesia, transversus abdominis plane, dexamethasone, ropivacaine. PMID- 28727705 TI - Activation of the RAGE/STAT3 Pathway in the Dorsal Root Ganglion Contributes to the Persistent Pain Hypersensitivity Induced by Lumbar Disc Herniation. AB - BACKGROUND: Clinically, chronic low back pain and sciatica associated with lumbar disc herniation (LDH) is a common musculoskeletal disorder. Due to the unawareness of detailed mechanisms, it is difficult to get an effective therapy. OBJECTIVE: The aim of the present study was to identify the role of the RAGE/STAT3 pathway in the dorsal root ganglion (DRG) on the formation and development of persistent pain hypersensitivity induced by LDH. STUDY DESIGN: Controlled animal study. SETTING: University laboratory. METHODS: After LDH induced by implantation of autologous nucleus pulposus (NP, harvested from animal tail) on the left L5 nerve root was established, mechanical thresholds and electrophysiological tests were conducted at relevant time points during an observation period of 28 days. Protein levels and localization of RAGE and p STAT3 were performed by using Western blotting and immunohistochemistry, respectively. RESULTS: LDH induced persistent pain hypersensitivity, increased excitability of DRG neurons, and upregulated the expression of RAGE and p-STAT3 in the DRG. Consecutive injection of both RAGE antagonist FPS-ZM1 (i.t.) and STAT3 activity inhibitor S3I-201 (i.t.) inhibited the enhanced excitability of DRG neurons and mechanical allodynia induced by NP implantation. Furthermore, local knockdown of STAT3 by intrathecal injection of AAV-Cre-GFP into STAT3flox/flox mice markedly alleviated NP implantation-induced mechanical allodynia in mice. Importantly, the expression of p-STAT3 was colocalized with that of RAGE in the DRG and inhibition of RAGE with FPS-ZM1 prevented NP implantation-induced STAT3 activation. LIMITATIONS: More underlying mechanism(s) of the role of the RAGE/STAT3 pathway on the formation and development of persistent pain hypersensitivity induced by LDH will be needed to be explored in future research. CONCLUSIONS: These findings suggest activation of the RAGE/STAT3 pathway plays a critical role in persistent pain induced by LDH, and this pathway may represent novel therapeutic targets for the treatment of LDH-induced persistent pain. KEY WORDS: Lumbar disc herniation, persistent pain, RAGE, STAT3, DRG. PMID- 28727706 TI - Opioids for Ocular Pain - A Narrative Review. AB - BACKGROUND: Refractive surgery is a common procedure, but may be associated with severe post-operative pain. OBJECTIVES: To describe studies addressing the use of opioids for control of pain after ocular surgery, with an emphasis on refractive surgery. STUDY DESIGN: This is a narrative review of relevant articles on the physiology of corneal pain and the use of opioids for its treatment after surgery. SETTING: Single tertiary center. METHODS: A PubMed search was conducted for studies published from January 1985 to May 2015 on the physiopathology of corneal pain and opioid treatment of post-refractive surgical pain. Reviews, meta analyses, and randomized clinical trials were included. Inclusion criteria focused on photorefractive keratectomy (PRK) and laser in situ keratomileusis (LASIK). RESULTS: Authors found 109 articles through the search strategies. A total of 75 articles were included based on the inclusion criteria. DISCUSSION: Pain after ocular surgery is likely to be a multifactorial phenomenon. A combination of topical and systemic analgesics is used to treat post-operative pain after refractive surgery. Pain may be severe during the first 72 to 96 hours, depending on the surgical procedure. No studies were found that directly analyze the benefits of opioids after PRK, although they are routinely prescribed in some centers. LIMITATIONS: This is a narrative review in contrast to a systematic review and did not include studies indexed in databases other than PubMed. CONCLUSIONS: Although opioids are used for the short-term treatment of post-operative pain in refractive surgery, their benefits and risks should be properly evaluated in randomized clinical trials before their use can be safely advised. KEY WORDS: Photorefractive keratectomy, in situ keratomileusis, pain, analgesia, opioid, codeine, review. PMID- 28727707 TI - Continuing Anti-thrombotic Medication During Low-to-Intermediate Risk Spinal Procedures: A Retrospective Evaluation. AB - BACKGROUND: The current American Society of Regional Anesthesia (ASRA) guidelines recommend discontinuing anti-thrombotic therapy prior to any interventional spine procedures to decrease the incidence of bleeding complications. However, discontinuing anti-thrombotics may pose considerable danger in terms of cerebrovascular and cardiovascular events. Recent evidence suggests that some spinal interventions may still be performed safely with anti-thrombotics on board and some practitioners thus elect to continue certain anti-thrombotics for these procedures. OBJECTIVE: To assess the rate of adverse events in patients undergoing spine procedures that are currently classified by the ASRA guidelines as "low-to-intermediate bleeding risk," while being on continued anti-thrombotic therapy. STUDY DESIGN: Retrospective cohort study. SETTING: Interventional pain management practice. METHODS: A retrospective chart review was performed on patients who underwent low-to-intermediate risk spine procedures with variable anti-thrombotic medications continued throughout the course of treatment. RESULTS: Between October 2015 and May 2016, out of 2,204 patients who underwent low-to-intermediate risk spine procedures, we identified 490 patients on anti thrombotic medications. These included aspirin (N = 275), P2Y12 inhibitors (N = 129), warfarin (N = 62), heparin (N = 10), factor Xa inhibitors (N = 55), and dipyridamole (N = 1). Forty-two patients were on multiple anti-thrombotics. Anti thrombotics were continued throughout the procedure for 467 of 490 patients (88%). One bleeding complication (injection site bleeding) occurred in a patient that continued clopidogrel and aspirin during a lumbar radiofrequency ablation. We encountered no bleeding complications attributable to anti-thrombotics in the other 466 procedures in which anti-thrombotics were continued during lumbar (N = 260), thoracic (N = 18), and cervical (N = 40) medial branch injections, sacroiliac injections (N = 47), and during lumbar (N = 87) thoracic (N = 2), and cervical (N = 12) medial branch radiofrequency ablations. LIMITATIONS: The retrospective nature of the study and its reliance on electronic medical records are potential limitations. CONCLUSIONS: Continuing anti-thrombotic medication during medial branch and sacroiliac injections may be possible. KEY WORDS: Interventional pain management, thrombotic complications, hemostasis, anti coagulation, bleeding complications. PMID- 28727708 TI - Efficacy of Short-Term Spinal Cord Stimulation in Acute/Subacute Zoster-Related Pain: A Retrospective Study. AB - BACKGROUND: Postherpetic neuralgia (PHN) is a refractory condition that impairs the patient's quality of life (QoL), it develops secondary to herpes zoster infection. Therefore, it's important to prevent the transition of acute/subacute zoster-related pain to PHN. Despite of numerous studies, the optimal intervention that reduces PHN incidence is still unknown. OBJECTIVE: We evaluate the efficacy of short-term spinal cord stimulation (stSCS) in patients with refractory acute/subacute zoster-related pain. STUDY DESIGN: Retrospective study. SETTING: Tertiary referral center/teaching hospital. METHODS: A total of 46 patients who presented with acute/subacute zoster-related pain, and had previously failed conventional therapies, underwent stSCS treatment. Visual analog scale (VAS), Short Form Health Survey 12 items (SF-12), and analgesic consumptions were recorded before stSCS, post-stSCS, 2 weeks, and 1, 3, 6, 9, and 12 months after stimulation. RESULTS: The VAS scores at post-stSCS, 2 weeks, and 1, 3, 6, 9, and 12 months after stSCS treatment were significantly decreased compared with the baseline score (P < 0.001). Thirty-two patients (69.6%, 32/46) achieved the minimal clinically important difference (MCID), including 18 patients (39.1%, 18/46) who achieved complete pain relief (VASless than orequal to2). During the follow-up period, the efficacy of stSCS didn't decrease and VAS scores were declining. Similarly, SF-12 scores and analgesic consumptions improved after stSCS treatment. The efficacy of stSCS did not differ significantly among patients with different durations of acute/subacute zoster-related pain starting from the onset of rash. No serious adverse effects were observed in the entire follow-up period. LIMITATIONS: This study was not a randomized prospective controlled study. We did not compare the outcomes with patients presenting with mild or moderate pain, and did not compare the efficacy of stSCS treatment with conventional therapies. CONCLUSIONS: stSCS is a safe, effective, and less invasive analgesic method for patients with refractory acute/subacute zoster related pain. KEY WORDS: Herpes zoster, zoster-related pain, postherpetic neuralgia, spinal cord stimulation, VAS. PMID- 28727709 TI - Transforaminal Percutaneous Endoscopic Discectomy and Foraminoplasty after Lumbar Spinal Fusion Surgery. AB - BACKGROUND: The most common causes of pain following lumbar spinal fusions are residual herniation, or foraminal fibrosis and foraminal stenosis that is ignored, untreated, or undertreated. The original surgeon may advise his patient that nothing more can be done in his opinion that the nerve was visually decompressed by the original surgery. Post-operative imaging or electrophysiological assessment may be inadequate to explain all the reasons for residual or recurrent symptoms. Treatment of failed lumbar spinal fusions by repeat traditional open revision surgery usually incorporates more extensive decompression causing increased instability and back pain. The authors, having limited their practice to endoscopic surgery over the last 10 years, report on their experience gained during that period to relieve pain by transforaminal percutaneous endoscopic revision of lumbar spinal fusions. OBJECTIVE: To assess the effectiveness of transforaminal percutaneous endoscopic discectomy and foraminoplasty in patients with pain after lumbar spinal fusion. STUDY DESIGN: Retrospective study. SETTING: Inpatient surgery center. METHODS: Sixteen consecutive patients with pain after lumbar spinal fusions presenting with back and leg pain that had supporting imaging diagnosis of foraminal stenosis and/or residual/recurrent disc herniation, or whose pain complaint was supported by relief from diagnostic and therapeutic injections, were offered percutaneous transforaminal endoscopic discectomy and foraminoplasty over a repeat open procedure. Each patient sought consultation following a transient successful, partially successful or unsuccessful open lumbar spinal fusions treatment for disc herniation or spinal stenosis. Endoscopic foraminoplasty was also performed to either decompress the bony foramen in the case of foraminal stenosis, or to allow for endoscopic visual examination of the affected traversing and exiting nerve roots in the axilla. The average follow-up time was 30.3 months, minimum 12 months. Outcome data at each visit included MacNab criteria, visual analog scale (VAS), and Oswestry Disability Index (ODI). RESULTS: The average leg VAS improved from 9.1 +/- 2.0 to 2.0 +/- 0.8 (P < 0.005). Ten patients had excellent outcomes, 5 had good outcomes, one had a fair outcome, and none had poor outcomes, according to the MacNab criteria. Fifteen of 16 patients had excellent or good outcomes, for an overall success rate of 93.7%. No patients required reoperation. There were no incidental durotomies, infections, vascular, or visceral injuries. There was one complication, a case of leg numbness caused by dorsal root ganglion injury. The numbness improved after 2 weeks. After 3 months, physical exam showed that the total area of numbness in the legs had decreased. At last follow-up, the patient had no pain, and only a few areas with numbness remained that did not affect the patient's activities of daily living. The patient was relieved to be able to avoid open decompression. LIMITATIONS: This is a retrospective study. CONCLUSIONS: The transforaminal endoscopic approach is effective for patients with back or leg pain after lumbar spinal fusions due to residual/recurrent nucleus pulposus and foraminal stenosis. Failed initial index surgery may involve failure to recognize patho-anatomy in the axilla of the foramen housing the traversing and the exiting nerve. The transforaminal endoscopic approach effectively decompresses the foramen and does not further destabilize the spine needing stabilization. It also avoids going through the previous surgical site. KEY WORDS: Full-endoscopic, foraminal stenosis, recurrent herniation, surgical treatment, fusion. PMID- 28727710 TI - Management of Symptomatic Tarlov Cysts: A Retrospective Observational Study. AB - BACKGROUND: Symptomatic Tarlov cysts are a common cause of chronic pain. Many methods have been reported to treat this disease, with variable results. Most previous reports concerning the treatment methods of symptomatic Tarlov cysts were either sporadic case reports or series of limited cases. OBJECTIVE: This study aimed to further optimize the management for patients with symptomatic Tarlov cysts (TCs) by analyzing the results of 82 patients who were treated with different strategies. STUDY DESIGN: Three different strategies were applied to 82 patients with symptomatic TCs and their clinical effects were evaluated in 13 months to 12 years follow-up. SETTING: A pain management practice, a medical center, major metropolitan city, China. METHODS: From June 2003 to August 2015, a total number of 82 patients with symptomatic TCs were treated with 3 different methods (microsurgical cyst fenestration and imbrication, C-arm fluoroscopy guided percutaneous fibrin gel injection, and conservative management) in the first affiliated hospital of Chongqing Medical University. The pain severity was assessed according to visual analog scale (VAS), and imaging changes were evaluated by magnetic resonance imaging (MRI). Patient improvements in pain and neurologic function were evaluated during a follow-up the period of 13 months to 12 years. RESULTS: All the patients who underwent microsurgical cyst fenestration and imbrication had either complete (7 patients, 50%) or substantial (7 patients, 50%) resolution of their preoperative symptoms and neurological deficits. However, 3 patients (21%) had cerebrospinal fluid (CSF) leakage and 3 patients (21%) suffered from recurrent symptoms. In C-arm fluoroscopy guided percutaneous fibrin gel injection group, 34 patients (61%) had complete resolution and 22 patients had (39%) substantial resolution, and no CSF leakage or recurrence occurred. Only 3 patients (25%) got substantial resolution in the conservative management group, but 9 patients (75%) had aggravation. LIMITATIONS: An observational study with a relatively small sample size. CONCLUSIONS: C-arm fluoroscopy guided percutaneous fibrin gel injection therapy could be recommend as a better consideration for symptomatic TCs. KEY WORDS: Tarlov cysts, C-arm fluoroscopy guided, fibrin gel, microsurgical cyst fenestration, conservative management. PMID- 28727711 TI - High Body Mass Index Is a Potential Risk Factor for Persistent Postoperative Pain after Breast Cancer Treatment. AB - BACKGROUND: Risk factors associated with persistent pain after breast cancer treatment are needed to develop prevention and treatment strategies to improve the quality of life for patients with breast cancer. OBJECTIVES: To identify factors associated with persistent pain in women undergoing breast cancer treatments. STUDY DESIGN: Retrospective study. SETTING: Regional hospital in the Netherlands. METHODS: The primary outcome was pain associated with surgery at more than 6 months postoperatively and patients were stratified based on the associated visual analog" scale score they reported: reporting no pain as "no pain," pain 1 - 29 mm as "mild pain," and pain 30 - 100 mm as "moderate/severe pain." Secondary outcomes were function, symptom, and total quality of life scores. Predefined risk factors analyzed for association with outcomes included: age, smoking status, diabetes, body mass index (BMI), disease stage, surgery type, axillary lymph node dissection, reoperation, chemotherapy, radiotherapy, and hormone therapy. RESULTS: Of the 718 patients who were approached, 492 were included (follow-up 2.5 +/- 1.8 years). Thirty-five percent of patients developed persistent pain (n = 122 "mild pain," n = 53 "moderate/severe pain'"). Age, BMI, surgery type, axillary lymph node dissection, disease stage, reoperation, chemotherapy, and radiotherapy were identified as potential risk factors in univariate ordinal regression analyses (P < 0.10). Age (P < 0.01) and BMI (P = 0.04) remained independently predictive in the multivariate model. BMI and age were associated with odds ratios (ORs) of 1.04 (95% confidence intervals (CI): 1.00 - 1.08) and 0.97 (95% CI: 0.95 - 0.99), respectively per point and year increase. BMI was associated with a higher symptom score (r = 0.14, P < 0.01), a lower level of function (r = -0.11, P = 0.01), and lower total quality of life scores (r = -0.13, P < 0.01). LIMITATIONS: The retrospective nature of this study makes it prone to response and misclassification bias. CONCLUSIONS: BMI and age may be risk factors for persistent postoperative pain after breast cancer treatment. KEY WORDS: Persistent postsurgical pain, breast cancer treatment, BMI, age, chronic postoperative pain, breast cancer surgery. PMID- 28727712 TI - Intervertebral Foramen Injection of Ozone Relieves Mechanical Allodynia and Enhances Analgesic Effect of Gabapentin in Animal Model of Neuropathic Pain. AB - BACKGROUND: In a 5-year follow-up study in a hospital in southern China, it was shown that intervertebral foramen (IVF) injection of ozone at the involved segmental levels could significantly alleviate paroxysmal spontaneous pain and mechanical allodynia in patients with chronic, intractable postherpetic neuralgia (PHN) and improve the quality of life. However, so far no proof-of-concept studies in animals have been available. OBJECTIVE: This study was designed to investigate whether IVF ozone has an analgesic effect on animal models of neuropathic and inflammatory pain. STUDY DESIGN: Experimental trial in rats. SETTING: Institute for Biomedical Sciences of Pain. METHODS: By IVF injection, a volume of 50 ul containing 30 ug/mL ozone-oxygen mixture or 50 ul air was carried out on male Sprague-Dawley rats of naive, inflammatory pain states produced by injections of either bee venom or complete Freud's adjuvant, and neuropathic pain state produced by spared nerve injury, respectively. The effects of IVF ozone on pain-related behaviors were evaluated for 2 weeks or one month. Then combined use of gabapentin (100 mg/1 kg body weight) with IVF ozone was evaluated in rats with neuropathic pain by intraperitoneal administration 5 days after the ozone treatment. Finally, the analgesic effects of another 4 drugs, AMD3100 (a CXCR4 antagonist), A-803467 (a selective Nav1.8 blocker), rapamycin (the mTOR inhibitor), and MGCD0103 (a selective histone deacetylase inhibitor) were evaluated for long term through IVF injection, respectively. RESULTS: (1) IVF injection of ozone at L4-5 was only effective in suppression of mechanical allodynia in rats with neuropathic pain but not with inflammatory pain; (2) the analgesic effects of IVF ozone lasted much longer (> 14 days) than other selective molecular target drugs (< 48 hours) inhibiting or antagonizing at Nav1.8 (A-803467), CXCR4 (AMD3100), mTOR (rapamycin), and histone deacetylase (MGCD0103); (3) combined use of systemic gabapentin and IVF ozone produced a synergistic analgesic effect in rats with neuropathic pain. LIMITATIONS: Evaluation of the possible analgesic effects of the intraplantar injection of ozone was not performed. CONCLUSIONS: In the present study, we provided a line of evidence for the first time that IVF injection of ozone selectively relieved neuropathic pain but not inflammatory pain, and enhanced the analgesic effect of gabapentin. KEY WORDS: Chronic pain, neuropathic pain, inflammatory pain, ozone therapy, interventional therapy, gabapentin, spared nerve injury, bee venom, complete Freud's adjuvant. PMID- 28727713 TI - Local Brain Activity Differences Between Herpes Zoster and Postherpetic Neuralgia Patients: A Resting-State Functional MRI Study. AB - BACKGROUND: Herpes zoster (HZ) can develop into postherpetic neuralgia (PHN), both of which are painful diseases. PHN patients suffer chronic pain and emotional disorders. Previous studies showed that the PHN brain displayed abnormal activity and structural change, but the difference in brain activity between HZ and PHN is still not known. OBJECTIVES: To identify regional brain activity changes in HZ and PHN brains with resting-state functional magnetic resonance imaging (rs-fMRI) technique, and to observe the differences between HZ and PHN patients. STUDY DESIGN: Observational study. SETTING: University hospital. METHODS: Regional homogeneity (ReHo) and fractional aptitude of low frequency fluctuation (fALFF) methods were employed to analysis resting-state brain activity. Seventy-three age and gender matched patients (50 HZ, 23 PHN) and 55 healthy controls were enrolled. ReHo and fALFF changes were analyzed to detect the functional abnormality in HZ and PHN brains. RESULTS: Compared with healthy controls, HZ and PHN patients exhibited abnormal ReHo and fALFF values in classic pain-related brain regions (such as the frontal lobe, thalamus, insular, and cerebellum) as well as the brainstem, limbic lobe, and temporal lobe. When HZ developed to PHN, the activity in the vast area of the cerebellum significantly increased while that of some regions in the occipital lobe, temporal lobe, parietal lobe, and limbic lobe showed an apparent decrease. LIMITATIONS: (a) Relatively short pain duration (mean 12.2 months) and small sample size (n = 23) for PHN group. (b) Comparisons at different time points (with paired t-tests) for each patient may minimize individual differences. CONCLUSIONS: HZ and PHN induced local brain activity changed in the pain matrix, brainstem, and limbic system. HZ chronification induced functional change in the cerebellum, occipital lobe, temporal lobe, parietal lobe, and limbic lobe. These brain activity changes may be correlated with HZ-PHN transition. KEY WORDS: Herpes zoster, postherpetic neuralgia, resting-state fMRI (rs-fMRI), regional homogeneity (ReHo), fractional aptitude of low-frequency fluctuation (fALFF). PMID- 28727714 TI - 3D Morphometric Analysis of Normal Sacroiliac Joints: A New Classification of Surface Shape Variation and the Potential Implications in Pain Syndromes. AB - BACKGROUND: Normal sacroiliac (SI) joints vary widely in shape, and it is unclear whether SI joint morphology plays a role in the development of pain. To answer this question, we used 3D-CT surface rendering to image healthy study participants and used the resulting images to develop a classification system for SI joint morphology. In a case-control study comparing health research participants to patients with SI pain, we assessed whether the classification of SI joint morphology was associated with pain. OBJECTIVES: We aimed to define normal variation in area and shape of the synovialized SI joint. We also aimed to determine interactions between joint area and shape and SI pain in men and women. STUDY DESIGN: A retrospective cohort study. SETTING: University hospital tertiary care center. METHODS: We conducted a retrospective case-control study. We acquired 3D-CT surface rendered images of the SI joint in 223 normal controls and 34 patients with SI pain syndrome. We measured the sacral and iliac surface areas and performed morphologic 3D assessment of both articular surfaces. We classified SI joints into 3 types based on morphology (types one, 2, and 3). We used descriptive statistics to provide a reference standard for normal SI joints. We used multivariate models to assess whether articular surface area differed between study participants with and without SI pain. We also assessed the association between morphology type and the presence of pain. RESULTS: Sacral and iliac surface areas differ by participant gender. Sacral and iliac surface area was associated with SI joint pain in both men (P = 0.0007) and in women (P = 0.02). In women (P = 0.04), but not in men (P = 0.11), joint shape was associated with pain. LIMITATIONS: A retrospective study may create potential for misclassification bias if SI joint symptoms/histories were present but not well documented in the electronic medical record. A lack of clinical standardization in the pre-procedural assessment of SI joint pain via provocative maneuvers (FABER, etc.) is also a limitation. CONCLUSIONS: Our study provides insight into the association between shape and joint surface area and SI joint pain. Further, prospective studies will allow us to determine the role of joint shape and surface area in the patho-etiology of SI joint pain, and thus provide information for patients and physicians about prevention or treatment. KEY WORDS: Sacroiliac joint, spine pain, 3D reformation, SI joint area, SI joint shape, SI joint pain syndrome. PMID- 28727715 TI - A Pilot Cross-Sectional Study of Postpartum Wrist Pain in an Urban Chinese Population: Its Prevalence and Risk Factors. AB - BACKGROUND: Wrist pain after childbirth is commonly encountered in clinical practice. Little is known about the prevalence of this musculoskeletal disorder which is important to overall maternal health. OBJECTIVE: To examine the prevalence of and risk factors for de novo wrist pain in women after childbirth. STUDY DESIGN: A pilot cross-sectional survey. SETTING: A telephone interview was conducted 2 months after childbirth among women who delivered at a tertiary hospital in Hong Kong. METHODS: The prevalence of de novo wrist pain was recorded; its severity was rated using the numerical rating scale and Patient Rated Wrist Evaluation (PRWE) with pain and functional subscale scores. RESULTS: In total, 259 women aged 32.8 +/- 4.0 years participated; 149 women (57.5%) developed wrist pain after childbirth and 125 (84%) had persistent wrist pain 2 months postpartum. The majority had moderate (43.5%) to severe (21%) wrist pain. Bilateral involvement was common (56.8%), with most of the pain (59.3%) located on the radial side of the wrist. Primiparity was associated with wrist pain development (odds ratio 2.62, 95% confidence interval 1.33 - 5.16, P = 0.01); pain intensity was negatively correlated with the baby's birth weight (beta = 1.059, P = 0.013). Mean PRWE pain and function scores were 22.8 +/- 10.3 and 15.6 +/- 10.7, respectively. LIMITATIONS: Cross-sectional survey is prone to volunteer bias, though recent literature indicates that the bias may not substantially affect the internal validity of the study. CONCLUSIONS: Wrist pain is prevalent after childbirth; future studies may consider looking into its exact pathology, long-term consequences, and overall effect on maternal health. KEY WORDS: Wrist pain, DeQuervain disease, postpartum, childbirth, mothers, prevalence, cross sectional study, survey. PMID- 28727716 TI - The Relationship Between Body Mass Index and Fluoroscopy Time During Intraarticular Hip Injection: A Multicenter Cohort Study. AB - BACKGROUND: Higher body mass index (BMI) is associated with difficulty in obtaining imaging studies. While there is a small body of literature regarding the relationship between fluoroscopy time and BMI during injections for pain management, this has not been studied for intraarticular (IA) hip injections. Further, in academic training centers, trainee involvement may affect this relationship. OBJECTIVE: To determine the relationship between BMI and fluoroscopy time during IA hip injections, both with and without involvement of a trainee. STUDY DESIGN: Multicenter retrospective cohort study. SETTING: Three academic, outpatient musculoskeletal and pain medicine centers. METHODS: Patients who underwent fluoroscopically guided IA hip injections with encounter data regarding fluoroscopy time during the procedure and BMI were included. Mean and standard deviation fluoroscopy time were recorded. Comparisons were made between BMI categories of normal (18.5 - 24.9 kg/m2), overweight (25.0 - 29.9 kg/m2), and obese (greater than or equal to30.0 kg/m2). Statistical significance was set at P = 0.01 due to multiple comparisons. RESULTS: A total of 559 IA hip injections are represented in this cohort. Patients had a mean age of 58 (standard deviation [SD] 14) years and 63% were women. There was no significant difference in fluoroscopy time when comparing BMI categories (P = 0.02). However, when trainees were not involved in the injection, fluoroscopy times were significantly shorter with decreasing BMI category, with normal weight patients requiring the shortest fluoroscopy times (P = 0.01). LIMITATIONS: This study evaluated total fluoroscopy time, not radiation dose exposure per injection, which provides more direct and precise information with regard to provider and patient radiation exposure and overall safety. Future study of the impact of BMI on radiation dose during fluoroscopically guided IA hip injections is needed. CONCLUSIONS: Fluoroscopy times during IA hip injections increase with higher BMI categories in a statistically significant manner when performed by experienced clinicians but this relationship is not observed when injections are performed with a trainee in a teaching institution. This finding appears to be related to longer fluoroscopy time required to complete an IA hip injection in patients with lower BMI when a trainee is involved. KEY WORDS: Hip, injections, obesity, overweight, body mass index, fluoroscopy, radiation, pain. PMID- 28727717 TI - Percutaneous Vertebroplasty for Primary Non-Hodgkin's Lymphoma of the Thoracic Spine: Case Report and Review of the Literature. AB - : Primary non-Hodgkin's lymphoma of the vertebra is rare in the spine of the elderly. The clinical presentation and radiological features are unspecific, which make it more difficult for diagnosis. We report a case of a 79-year-old woman complaining of serious backache without any injury. The magnetic resonance imaging (MRI) showed invasion of the fifth thoracic vertebra with the posterior vertebral body wall defect. There was a high suspicion that the patient had a metastatic tumor of the vertebra. A percutaneous vertebroplasty was performed under fluoroscopic guidance, which was used to treat the osteoporotic vertebral compression fracture, vertebral metastases, verte-bral hemangioma, and multiple myeloma. The pain was rapidly and conspicuously relieved after the procedure. The visual analog scale (VAS) score decreased from 8 preoperatively to 2 postoperatively. The imaging examination postoperatively revealed a small amount cement leaking into the spinal canal, but there were no symptoms and no complications in our patient. During vertebroplasty, a biopsy was done by biopsy needle before injection of the cement (polymethyl methacrylate). The histopathological examination revealed a diffuse large B-cell lymphoma. No new evidence of any other lesion was found during a 6-month follow-up period. The patient was diagnosed with primary bone lymphoma finally. Due to the previous condition of the patient, R-miniCHOP chemotherapy was applied following the surgery in the department of hematology. Until the 9 months follow-up, the clinical result was still satisfactory. KEY WORDS: Vertebroplasty, polymethyl methacrylate, biopsy, spine, lymphoma, large B-cell, diffuse. PMID- 28727718 TI - Quantity of Disc Removal and Radiological Outcomes of Percutaneous Endoscopic Lumbar Discectomy. AB - BACKGROUND: Herniated intervertebral disc disease (HIVD) is a common cause of lower back and leg pain. Percutaneous endoscopic lumbar discectomy (PELD) is indicated when non-surgical treatments such as medication and interventions are intractable. Ruptured discs and loose fragments inside discs are removed during PELD. Nerve root decompression is usually assessed by visualizing the free movement of the traversing nerve root or epidural fat, the free passage of a probe into the epidural space, the depression of the annulus, and the removal of the expected ruptured discs and loose fragments based on preoperative magnetic resonance images (MRI). However, these criteria are subjective, and the quantity of the disc removal necessary for successful outcomes after PELD has not been investigated. OBJECTIVES: The present study investigates the amount of discectomy of PELD and its clinical and radiological outcomes. STUDY DESIGN: A retrospective case study (IRB Number H-1611-015-803). SETTING: University Medical Center, Seoul, Korea. METHODS: PELD was performed in 109 consecutive patients (M:F = 53:56; mean age, 37.4 years) using the transforaminal or interlaminar route. Ruptured disc fragments were first removed in all patients, and the graspable loose fragments under the disc were removed. After surgery, all removed disc fragments were placed into disposable syringes and manually compressed to measure their volume. The volume of herniated disc outside the disc boundary was calculated in MRI. The measured and calculated disc volumes were retrospectively compared. Clinical success was defined as an improvement in both the Oswestry Disability Index (ODI) and leg pain, as well as no recurrent symptoms. Radiological success was defined as the disappearance of herniated disc material outside the disc boundary based on postoperative MRI taken within one day after surgery. The follow-up period was 7.2 +/- 5.2 months. RESULTS: Successful clinical outcomes were obtained in 96/109 (88.1%) patients in a median time of 3 months. Re-operation was performed in 3 patients due to recurrent discs in 2 patients and a residual disc in one patient. Predictors of clinical success were not identified, and the quantity of the removed disc was not associated with the clinical outcome. Radiological success was achieved in 93/109 (85.3%) patients. Of 13 patients with radiological failure, 2 patients showed clinical failure. A logistic regression analysis showed that the relative volume of the removed disc (%) compared with the volume of preoperative herniated disc based on the MRI was the only significant predictor (P < 0.001; OR = 0.96). When 100% of the calculated disc amount was removed during the operation, the probability of residual disc was 30%. When 131% of the calculated disc amount was removed, the probability of residual disc was 10%. LIMITATIONS: This study employed a retrospective design, and its inherent selection bias and limited statistical power should be considered. CONCLUSIONS: The amount of disc removal during PELD was not a significant predictor of clinical success after the primary ruptured fragments were removed. The relative volume of the removed disc based on the preoperative MRI might predict the postoperative MRI. KEY WORDS: Disc, lumbar vertebra, discectomy, surgery, endoscopy, volume. PMID- 28727719 TI - Intercostal Neuralgia Occurring as a Complication of Splanchnic Nerve Radiofrequency Ablation in a Patient with Chronic Pancreatitis. AB - : Our intent is to report a case of intercostal neuralgia occuring as a complication of splanchnic radiofreqency ablation (RFA), due to a breach in the integrity of the insulating sheath of the RFA needle.A 48-year-old man presented to our pain clinic with upper abdominal pain due to chronic pancreatitis, recalcitrant to medical management. We decided to perform bilateral splanchnic nerve RFA in this patient. After confirmation of bilateral correct needle placement under fluoroscopic guidance and sensorimotor testing, RFA was performed on the right side uneventfully. However, during RFA on the left side, the patient experienced severe pain in the epigastric region. A bolus of fentanyl 50 ug was given intravenously in order to minimise discomfort, and RFA was performed. In the post-procedure period, the patient described severe pain in the left subcostal and epigastric region, with features suggestive of intercostal neuralgia of the left 11th intercostal nerve. We went back and analysed all the fluoroscopic images again. Convinced of correct needle placement, we examined the RFA needles which had been used for ablation in this patient. One of the needles was discovered to have a fine breach in its insulating sheath, at a distance of approximately 30 mm from the active tip. It is of utmost importance for all interventional pain physicians to perform a thorough pre-use check of the equipment prior to any RFA procedure, with special emphasis on ensuring the integrity of the insulating sheath of the needles which are to be used, in order to prevent injury of non target nerves. KEY WORDS: Splanchnic nerve block, radiofrequency ablation, intercostal neuralgia, radiofrequency ablation complications, radiofrequency equipment check, radiofrequency needle. PMID- 28727721 TI - Errata. PMID- 28727720 TI - Pulmonary Embolism: A Rare Complication of Neurolytic Alcohol Celiac Plexus Block. PMID- 28727723 TI - Analytical sensitivity and specificity of a loop-mediated isothermal amplification (LAMP) kit prototype for detection of Trypanosoma cruzi DNA in human blood samples. AB - This study aimed to assess analytical parameters of a prototype LAMP kit that was designed for detection of Trypanosoma cruzi DNA in human blood. The prototype is based on the amplification of the highly repetitive satellite sequence of T.cruzi in microtubes containing dried reagents on the inside of the caps. The reaction is carried out at 65 degrees C during 40 minutes. Calcein allows direct detection of amplified products with the naked eye. Inclusivity and selectivity were tested in purified DNA from Trypanosoma cruzi stocks belonging to the six discrete typing units (DTUs), in DNA from other protozoan parasites and in human DNA. Analytical sensitivity was estimated in serial dilutions of DNA samples from Sylvio X10 (Tc I) and CL Brener (Tc VI) stocks, as well as from EDTA-treated or heparinized blood samples spiked with known amounts of cultured epimastigotes (CL Brener). LAMP sensitivity was compared after DNA extraction using commercial fiberglass columns or after "Boil & Spin" rapid preparation. Moreover, the same DNA and EDTA-blood spiked samples were subjected to standardized qPCR based on the satellite DNA sequence for comparative purposes. A panel of peripheral blood specimens belonging to Chagas disease patients, including acute, congenital, chronic and reactivated cases (N = 23), as well as seronegative controls (N = 10) were evaluated by LAMP in comparison to qPCR. LAMP was able to amplify DNAs from T. cruzi stocks representative of the six DTUs, whereas it did not amplify DNAs from Leishmania sp, T. brucei sp, T. rangeli KPN+ and KPN-, P. falciparum and non infected human DNA. Analytical sensitivity was 1x10-2 fg/MUL of both CL Brener and Sylvio X10 DNAs, whereas qPCR detected up to 1x 10-1 fg/MUL of CL Brener DNA and 1 fg/MUl of Sylvio X10 DNA. LAMP detected 1x10-2 parasite equivalents/mL in spiked EDTA blood and 1x10-1 par.eq/mL in spiked heparinized blood using fiberglass columns for DNA extraction, whereas qPCR detected 1x10-2 par.eq./mL in EDTA blood. Boil & Spin extraction allowed detection of 1x10-2 par.eq /mL in spiked EDTA blood and 1 par.eq/ml in heparinized blood. LAMP was able to detect T.cruzi infection in peripheral blood samples collected from well-characterised seropositive patients, including acute, congenital, chronic and reactivated Chagas disease. To our knowledge, this is the first report of a prototype LAMP kit with appropriate analytical sensitivity for diagnosis of Chagas disease patients, and potentially useful for monitoring treatment response. PMID- 28727722 TI - An attenuated Shigella mutant lacking the RNA-binding protein Hfq provides cross protection against Shigella strains of broad serotype. AB - Few live attenuated vaccines protect against multiple serotypes of bacterial pathogen because host serotype-specific immune responses are limited to the serotype present in the vaccine strain. Here, immunization with a mutant of Shigella flexneri 2a protected guinea pigs against subsequent infection by S. dysenteriae type 1 and S. sonnei strains. This deletion mutant lacked the RNA binding protein Hfq leading to increased expression of the type III secretion system via loss of regulation, resulting in attenuation of cell viability through repression of stress response sigma factors. Such increased antigen production and simultaneous attenuation were expected to elicit protective immunity against Shigella strains of heterologous serotypes. Thus, the vaccine potential of this mutant was tested in two guinea pig models of shigellosis. Animals vaccinated in the left eye showed fewer symptoms upon subsequent challenge via the right eye, and even survived subsequent intestinal challenge. In addition, oral vaccination effectively induced production of immunoglobulins without severe side effects, again protecting all animals against subsequent intestinal challenge with S. dysenteriae type 1 or S. sonnei strains. Antibodies against common virulence proteins and the O-antigen of S. flexneri 2a were detected by immunofluorescence microscopy. Reaction of antibodies with various strains, including enteroinvasive Escherichia coli, suggested that common virulence proteins induced protective immunity against a range of serotypes. Therefore, vaccination is expected to cover not only the most prevalent serotypes of S. sonnei and S. flexneri 2a, but also various Shigella strains, including S. dysenteriae type 1, which produces Shiga toxin. PMID- 28727724 TI - Grandmothering and cognitive resources are required for the emergence of menopause and extensive post-reproductive lifespan. AB - Menopause, the permanent cessation of ovulation, occurs in humans well before the end of the expected lifespan, leading to an extensive post-reproductive period which remains a puzzle for evolutionary biologists. All human populations display this particularity; thus, it is difficult to empirically evaluate the conditions for its emergence. In this study, we used artificial neural networks to model the emergence and evolution of allocation decisions related to reproduction in simulated populations. When allocation decisions were allowed to freely evolve, both menopause and extensive post-reproductive life-span emerged under some ecological conditions. This result allowed us to test various hypotheses about the required conditions for the emergence of menopause and extensive post reproductive life-span. Our findings did not support the Maternal Hypothesis (menopause has evolved to avoid the risk of dying in childbirth, which is higher in older women). In contrast, results supported a shared prediction from the Grandmother Hypothesis and the Embodied Capital Model. Indeed, we found that extensive post-reproductive lifespan allows resource reallocation to increase fertility of the children and survival of the grandchildren. Furthermore, neural capital development and the skill intensiveness of the foraging niche, rather than strength, played a major role in shaping the age profile of somatic and cognitive senescence in our simulated populations. This result supports the Embodied Capital Model rather than the Grand-Mother Hypothesis. Finally, in simulated populations where menopause had already evolved, we found that reduced post-reproductive lifespan lead to reduced children's fertility and grandchildren's survival. The results are discussed in the context of the evolutionary emergence of menopause and extensive post-reproductive life-span. PMID- 28727725 TI - redGEM: Systematic reduction and analysis of genome-scale metabolic reconstructions for development of consistent core metabolic models. AB - Genome-scale metabolic reconstructions have proven to be valuable resources in enhancing our understanding of metabolic networks as they encapsulate all known metabolic capabilities of the organisms from genes to proteins to their functions. However the complexity of these large metabolic networks often hinders their utility in various practical applications. Although reduced models are commonly used for modeling and in integrating experimental data, they are often inconsistent across different studies and laboratories due to different criteria and detail, which can compromise transferability of the findings and also integration of experimental data from different groups. In this study, we have developed a systematic semi-automatic approach to reduce genome-scale models into core models in a consistent and logical manner focusing on the central metabolism or subsystems of interest. The method minimizes the loss of information using an approach that combines graph-based search and optimization methods. The resulting core models are shown to be able to capture key properties of the genome-scale models and preserve consistency in terms of biomass and by-product yields, flux and concentration variability and gene essentiality. The development of these "consistently-reduced" models will help to clarify and facilitate integration of different experimental data to draw new understanding that can be directly extendable to genome-scale models. PMID- 28727726 TI - A cross-sectional seroepidemiological survey of typhoid fever in Fiji. AB - Fiji, an upper-middle income state in the Pacific Ocean, has experienced an increase in confirmed case notifications of enteric fever caused by Salmonella enterica serovar Typhi (S. Typhi). To characterize the epidemiology of typhoid exposure, we conducted a cross-sectional sero-epidemiological survey measuring IgG against the Vi antigen of S. Typhi to estimate the effect of age, ethnicity, and other variables on seroprevalence. Epidemiologically relevant cut-off titres were established using a mixed model analysis of data from recovering culture confirmed typhoid cases. We enrolled and assayed plasma of 1787 participants for anti-Vi IgG; 1,531 of these were resident in mainland areas that had not been previously vaccinated against S. Typhi (seropositivity 32.3% (95%CI 28.2 to 36.3%)), 256 were resident on Taveuni island, which had been previously vaccinated (seropositivity 71.5% (95%CI 62.1 to 80.9%)). The seroprevalence on the Fijian mainland is one to two orders of magnitude higher than expected from confirmed case surveillance incidence, suggesting substantial subclinical or otherwise unreported typhoid. We found no significant differences in seropositivity prevalences by ethnicity, which is in contrast to disease surveillance data in which the indigenous iTaukei Fijian population are disproportionately affected. Using multivariable logistic regression, seropositivity was associated with increased age (odds ratio 1.3 (95% CI 1.2 to 1.4) per 10 years), the presence of a pit latrine (OR 1.6, 95%CI 1.1 to 2.3) as opposed to a septic tank or piped sewer, and residence in settlements rather than residential housing or villages (OR 1.6, 95% CI 1.0 to 2.7). Increasing seropositivity with age is suggestive of low-level endemic transmission in Fiji. Improved sanitation where pit latrines are used and addressing potential transmission routes in settlements may reduce exposure to S. Typhi. Widespread unreported infection suggests there may be a role for typhoid vaccination in Fiji, in addition to public health management of cases and outbreaks. PMID- 28727727 TI - A comparative study of patients' activities and interactions in a stroke unit before and after reconstruction-The significance of the built environment. AB - Early mobilization and rehabilitation, multidisciplinary stroke expertise and comprehensive therapies are fundamental in a stroke unit. To achieve effective and safe stroke care, the physical environment in modern stroke units should facilitate the delivery of evidence-based care. Therefore, the purpose of this study was to explore patients' activities and interactions in a stroke unit before the reconstruction of the physical environment, while in a temporary location and after reconstruction. This case study examined a stroke unit as an integrated whole. The data were collected using a behavioral mapping technique at three different time points: in the original unit, in the temporary unit and in the new unit. A total of 59 patients were included. The analysis included field notes from observations of the physical environment and examples from planning and design documents. The findings indicated that in the new unit, the patients spent more time in their rooms, were less active, and had fewer interactions with staff and family than the patients in the original unit. The reconstruction involved a change from a primarily multi-bed room design to single-room accommodations. In the new unit, the patients' lounge was located in a far corner of the unit with a smaller entrance than the patients' lounge in the old unit, which was located at the end of a corridor with a noticeable entrance. Changes in the design of the stroke unit may have influenced the patients' activities and interactions. This study raises the question of how the physical environment should be designed in the future to facilitate the delivery of health care and improve outcomes for stroke patients. This research is based on a case study, and although the results should be interpreted with caution, we strongly recommend that environmental considerations be included in future stroke guidelines. PMID- 28727728 TI - An integrative genomics approach identifies novel pathways that influence candidaemia susceptibility. AB - Candidaemia is a bloodstream infection caused by Candida species that primarily affects specific groups of at-risk patients. Because only small candidaemia patient cohorts are available, classical genome wide association cannot be used to identify Candida susceptibility genes. Therefore, we have applied an integrative genomics approach to identify novel susceptibility genes and pathways for candidaemia. Candida-induced transcriptome changes in human primary leukocytes were assessed by RNA sequencing. Genetic susceptibility to candidaemia was assessed using the Illumina immunochip platform for genotyping of a cohort of 217 patients. We then integrated genetics data with gene-expression profiles, Candida-induced cytokine production capacity, and circulating concentrations of cytokines. Based on the intersection of transcriptome pathways and genomic data, we prioritized 31 candidate genes for candidaemia susceptibility. This group of genes was enriched with genes involved in inflammation, innate immunity, complement, and hemostasis. We then validated the role of MAP3K8 in cytokine regulation in response to Candida stimulation. Here, we present a new framework for the identification of susceptibility genes for infectious diseases that uses an unbiased, hypothesis-free, systems genetics approach. By applying this approach to candidaemia, we identified novel susceptibility genes and pathways for candidaemia, and future studies should assess their potential as therapeutic targets. PMID- 28727729 TI - Induction of labor versus expectant management of large-for-gestational-age infants in nulliparous women. AB - BACKGROUND: There is no apparent consensus on obstetric management, i.e., induction of labor or expectant management of women with suspected large-for gestational-age (LGA)-fetuses. METHODS AND FINDINGS: To further examine the subject, a nationwide population-based cohort study from the Swedish Medical Birth Register in nulliparous non-diabetic women with singleton, vertex LGA (>90th centile) births, 1992-2013, was performed. Delivery of a live-born LGA infant induced at 38 completed weeks of gestation in non-preeclamptic pregnancies, was compared to those of expectant management, with delivery at 39, 40, 41, or 42 completed weeks of gestation and beyond, either by labor induction or via spontaneous labor. Primary outcome was mode of delivery. Secondary outcomes included obstetric anal sphincter injury, 5-minute Apgar<7 and birth injury. Multivariable logistic regression analysis was performed to control for potential confounding. We found that among the 722 women induced at week 38, there was a significantly increased risk of cesarean delivery (aOR = 1.44 95% CI:1.20-1.72), compared to those with expectant management (n = 44 081). There was no significant difference between the groups in regards to risk of instrumental vaginal delivery (aOR = 1.05, 95% CI:0.85-1.30), obstetric anal sphincter injury (aOR = 0.81, 95% CI:0.55-1.19), nor 5-minute Apgar<7 (aOR = 1.06, 95% CI:0.58-1.94) or birth injury (aOR = 0.82, 95% CI:0.49-1.38). Similar comparisons for induction of labor at 39, 40 or 41 weeks compared to expectant management with delivery at a later gestational age, showed increased rates of cesarean delivery for induced women. CONCLUSIONS: In women with LGA infants, induction of labor at 38 weeks gestation is associated with increased risk of cesarean delivery compared to expectant management, with no difference in neonatal morbidity. PMID- 28727730 TI - Do MZ twins have discordant experiences of friendship? A qualitative hypothesis generating MZ twin differences study. AB - Using a qualitative monozygotic (MZ) twin differences design we explored whether adolescent MZ twins report discordant peer relationships and, if so, whether they perceive them as causes, consequences or correlates of discordant behaviour. We gathered free-response questionnaire data from 497 families and conducted in depth telephone interviews with 97 of them. Within this dataset n = 112 families (23% of the sample) described discordant peer relationships. Six categories of discordance were identified (peer victimisation, peer rejection, fewer friends, different friends, different attitudes to friendship and dependence on co-twin). Participants described peer relationship discordance arising as a result of chance occurrences, enhanced vulnerability in one twin or discordant behaviour. Consequences of discordant peer relationships were seen as discordance in self confidence, future plans, social isolation, mental health and interests. In all cases the twin with worse peer experiences was seen as having a worse outcome. Specific hypotheses are presented. PMID- 28727731 TI - Pregnancy incidence and intention after HIV diagnosis among women living with HIV in Canada. AB - BACKGROUND: Pregnancy incidence rates among women living with HIV (WLWH) have increased over time due to longer life expectancy, improved health status, and improved access to and HIV prevention benefits of combination antiretroviral therapy (cART). However, it is unclear whether intended or unintended pregnancies are contributing to observed increases. METHODS: We analyzed retrospective data from the Canadian HIV Women's Sexual and Reproductive Health Cohort Study (CHIWOS). Kaplan-Meier methods and GEE Poisson models were used to measure cumulative incidence and incidence rate of pregnancy after HIV diagnosis overall, and by pregnancy intention. We used multivariable logistic regression models to examine independent correlates of unintended pregnancy among the most recent/current pregnancy. RESULTS: Of 1,165 WLWH included in this analysis, 278 (23.9%) women reported 492 pregnancies after HIV diagnosis, 60.8% of which were unintended. Unintended pregnancy incidence (24.6 per 1,000 Women-Years (WYs); 95% CI: 21.0, 28.7) was higher than intended pregnancy incidence (16.6 per 1,000 WYs; 95% CI: 13.8, 20.1) (Rate Ratio: 1.5, 95% CI: 1.2-1.8). Pregnancy incidence among WLWH who initiated cART before or during pregnancy (29.1 per 1000 WYs with 95% CI: 25.1, 33.8) was higher than among WLWH not on cART during pregnancy (11.9 per 1000 WYs; 95% CI: 9.5, 14.9) (Rate Ratio: 2.4, 95% CI: 2.0-3.0). Women with current or recent unintended pregnancy (vs. intended pregnancy) had higher adjusted odds of being single (AOR: 1.94; 95% CI: 1.10, 3.42), younger at time of conception (AOR: 0.95 per year increase, 95% CI: 0.90, 0.99), and being born in Canada (AOR: 2.76, 95% CI: 1.55, 4.92). CONCLUSION: Nearly one-quarter of women reported pregnancy after HIV diagnosis, with 61% of all pregnancies reported as unintended. Integrated HIV and reproductive health care programming is required to better support WLWH to optimize pregnancy planning and outcomes and to prevent unintended pregnancy. PMID- 28727732 TI - Incidence of thromboembolic events in asymptomatic carriers of IgA anti beta2 glycoprotein-I antibodies. AB - BACKGROUND: The antiphospholipid syndrome (APS) is defined by simultaneous presence of vascular clinical events and antiphospholipid antibodies (aPL). The aPL considered as diagnostics are lupus anticoagulant and antibodies anticardiolipin (aCL) and anti-beta2 glycoprotein-I (aB2GP1). During recent years, IgA aB2GP1 antibodies have been associated with thrombotic events both in patients positive, and mainly negative for other aPL, however its value as a pro thrombotic risk-factor in asymptomatic patients has not been well defined. OBJECTIVE: To test the role of IgA anti B2GP1 as a risk factor for the development of APS-events (thrombosis or pregnancy morbidity) in asymptomatic population with a 5-year follow-up. METHODS: 244 patients isolated positive for anti-beta2-glycoprotein I IgA (Group-1 study) and 221 negative patients (Group-2 control) were studied. All the patients were negative for IgG and IgM aCL. RESULTS: During the follow-up, 45 patients (9.7%) had APS-events, 38 positive for IgA-aB2GP1 and 7 negative (15.6% vs 3.2%, p<0.001). The incidence rate of APS events was 3.1% per year in IgA-aB2GP1 positive patients and 0.6% per year in the control group. Arterial thrombosis were the most frequent APS-events (N = 25, 55%) and were mainly observed in Group-1 patients (21 vs 4, p = 0.001). Multivariate analysis were shown as independent risk-factors for the development of APS-events, age, sex (men) and presence of IgA-aB2GP1 (odds ratio 5.25, 95% CI 2.24 to 12.32). CONCLUSION: The presence of IgA-aB2GP1 in people with no history of APS-events is the main independent risk factor for the development of these types of events, mainly arterial thrombosis. PMID- 28727733 TI - A new methodology for sampling blackflies for the entomological surveillance of onchocerciasis in Brazil. AB - The effectiveness of the MosqTent(r) trap was evaluated in endemic area to onchocerciasis in Brazil. This study seeks to provide subsidies for the monitoring of the onchocerciasis transmission in the country. The study was carried out at the Homoxi and Thirei villages, located in the Yanomami Indigenous Land, in the state of Roraima. This area presents hyperendemicity, high blackflies densities, large population migrations and mining activities. The Homoxi and Thirei villages are assisted by the Brazilian Ministry of Health. To conduct the present study, the village leader, health leaders and the Brazilian Ethics Committee were consulted. Blackflies captures were carried out simultaneously at the Homoxi and Thirei, using systematized methods to allow for comparisons between the traditional Human Landing Catch (HLC) and HLC protected by the MosqTent(r). The female blackflies were captured at two equidistant capture stations per locality, by two collectors per station, for five consecutive days. Individuals captured by interval/station/day were counted, identified and maintained at -20 degrees C. The underlying probability distributions and the differences between the methods for the independent sample data were verified in a comparative statistical analysis between the use of the MosqTent(r) and the HLC. A total of 10,855 antropophilic blackflies were captured by both methodologies. A total of 7,367 (67.87%) blackflies belonging to seven species were captured by MosqTent(r) -Simulium incrustatum s.l (99.06%); S. guianense s.l (0.74%), S. oyapockense s.l (0.01%), S. exiguum (0.10%), S. metallicum (0.05%), S. ochraceum (0.03%) and S. minusculum s.l (0.01%). Moreover, 3,488 (32.14%) blackflies belonging to four species were captured by HLC-S. incrustatum s.l (98.33%); S. guianense s.l (1.38%), S. oyapockense s.l (0.26%) and S. metallicum (0.03%). The MosqTent(r) was more effective and efficient when compared to HLC. When comparing total blackflies captured/day, the MosqTent(r) was more efficient than HLC (p = 0.031) with a means of 799.4 blackflies/day versus 217.6 blackflies/day by HLC. The results demonstrated improved performance and high reliability of the MosqTent(r) compared to the traditional HLC method. PMID- 28727734 TI - MicroRNA-200c inhibits epithelial-mesenchymal transition, invasion, and migration of lung cancer by targeting HMGB1. AB - MicroRNAs (miRs) play critical roles in cancer development, proliferation, epithelial-mesenchymal transition (EMT), invasion, and migration through regulating the expression of oncogenes and tumour suppressor genes. Previous studies have indicated that miR-200c acts as a tumour suppressor in various cancers by downregulating high-mobility group box 1 (HMGB1) and thereby suppressing EMT and metastasis. In addition, miR-200c was reported to be downregulated and correlated with poor outcomes in non-small cell lung cancer (NSCLC). However, its functional role in HMGB1 regulation in NSCLC is still unclear. This study aimed to clarify whether miR-200c acts as a tumour suppressor in NSCLC by downregulating HMGB1, which is associated with EMT, invasion, cytoskeleton rearrangement, and migration in vitro and in vivo. In order to demonstrate HMGB1 downregulation by miR-200c, the NSCLC cell line A549 was transfected with miR-200c mimic or inhibitor. The mimic significantly reduced HMGB1 expression and suppressed EMT, invasion, and migration, while the inhibitor generated the opposite effects. Additionally, using xenograft mouse models, we confirmed that HMGB1 overexpression increased tumour EMT. In summary, our results demonstrated that miR-200c could suppress EMT, invasion, and migration of NSCLC cells by downregulating HMGB1. PMID- 28727735 TI - We perceive a mind in a robot when we help it. AB - People sometimes perceive a mind in inorganic entities like robots. Psychological research has shown that mind perception correlates with moral judgments and that immoral behaviors (i.e., intentional harm) facilitate mind perception toward otherwise mindless victims. We conducted a vignette experiment (N = 129; Mage = 21.8 +/- 6.0 years) concerning human-robot interactions and extended previous research's results in two ways. First, mind perception toward the robot was facilitated when it received a benevolent behavior, although only when participants took the perspective of an actor. Second, imagining a benevolent interaction led to more positive attitudes toward the robot, and this effect was mediated by mind perception. These results help predict what people's reactions in future human-robot interactions would be like, and have implications for how to design future social rules about the treatment of robots. PMID- 28727737 TI - Improving deep convolutional neural networks with mixed maxout units. AB - Motivated by insights from the maxout-units-based deep Convolutional Neural Network (CNN) that "non-maximal features are unable to deliver" and "feature mapping subspace pooling is insufficient," we present a novel mixed variant of the recently introduced maxout unit called a mixout unit. Specifically, we do so by calculating the exponential probabilities of feature mappings gained by applying different convolutional transformations over the same input and then calculating the expected values according to their exponential probabilities. Moreover, we introduce the Bernoulli distribution to balance the maximum values with the expected values of the feature mappings subspace. Finally, we design a simple model to verify the pooling ability of mixout units and a Mixout-units based Network-in-Network (NiN) model to analyze the feature learning ability of the mixout models. We argue that our proposed units improve the pooling ability and that mixout models can achieve better feature learning and classification performance. PMID- 28727736 TI - Persistent damaged bases in DNA allow mutagenic break repair in Escherichia coli. AB - Bacteria, yeast and human cancer cells possess mechanisms of mutagenesis upregulated by stress responses. Stress-inducible mutagenesis potentially accelerates adaptation, and may provide important models for mutagenesis that drives cancers, host pathogen interactions, antibiotic resistance and possibly much of evolution generally. In Escherichia coli repair of double-strand breaks (DSBs) becomes mutagenic, using low-fidelity DNA polymerases under the control of the SOS DNA-damage response and RpoS general stress response, which upregulate and allow the action of error-prone DNA polymerases IV (DinB), II and V to make mutations during repair. Pol IV is implied to compete with and replace high fidelity DNA polymerases at the DSB-repair replisome, causing mutagenesis. We report that up-regulated Pol IV is not sufficient for mutagenic break repair (MBR); damaged bases in the DNA are also required, and that in starvation stressed cells, these are caused by reactive-oxygen species (ROS). First, MBR is reduced by either ROS-scavenging agents or constitutive activation of oxidative damage responses, both of which reduce cellular ROS levels. The ROS promote MBR other than by causing DSBs, saturating mismatch repair, oxidizing proteins, or inducing the SOS response or the general stress response. We find that ROS drive MBR through oxidized guanines (8-oxo-dG) in DNA, in that overproduction of a glycosylase that removes 8-oxo-dG from DNA prevents MBR. Further, other damaged DNA bases can substitute for 8-oxo-dG because ROS-scavenged cells resume MBR if either DNA pyrimidine dimers or alkylated bases are induced. We hypothesize that damaged bases in DNA pause the replisome and allow the critical switch from high fidelity to error-prone DNA polymerases in the DSB-repair replisome, thus allowing MBR. The data imply that in addition to the indirect stress-response controlled switch to MBR, a direct cis-acting switch to MBR occurs independently of DNA breakage, caused by ROS oxidation of DNA potentially regulated by ROS regulators. PMID- 28727738 TI - Propagation characteristics of pulverized coal and gas two-phase flow during an outburst. AB - Coal and gas outbursts are dynamic failures that can involve the ejection of thousands tons of pulverized coal, as well as considerable volumes of gas, into a limited working space within a short period. The two-phase flow of gas and pulverized coal that occurs during an outburst can lead to fatalities and destroy underground equipment. This article examines the interaction mechanism between pulverized coal and gas flow. Based on the role of gas expansion energy in the development stage of outbursts, a numerical simulation method is proposed for investigating the propagation characteristics of the two-phase flow. This simulation method was verified by a shock tube experiment involving pulverized coal and gas flow. The experimental and simulated results both demonstrate that the instantaneous ejection of pulverized coal and gas flow can form outburst shock waves. These are attenuated along the propagation direction, and the volume fraction of pulverized coal in the two-phase flow has significant influence on attenuation of the outburst shock wave. As a whole, pulverized coal flow has a negative impact on gas flow, which makes a great loss of large amounts of initial energy, blocking the propagation of gas flow. According to comparison of numerical results for different roadway types, the attenuation effect of T-type roadways is best. In the propagation of shock wave, reflection and diffraction of shock wave interact through the complex roadway types. PMID- 28727739 TI - Survival analysis of heart failure patients: A case study. AB - This study was focused on survival analysis of heart failure patients who were admitted to Institute of Cardiology and Allied hospital Faisalabad-Pakistan during April-December (2015). All the patients were aged 40 years or above, having left ventricular systolic dysfunction, belonging to NYHA class III and IV. Cox regression was used to model mortality considering age, ejection fraction, serum creatinine, serum sodium, anemia, platelets, creatinine phosphokinase, blood pressure, gender, diabetes and smoking status as potentially contributing for mortality. Kaplan Meier plot was used to study the general pattern of survival which showed high intensity of mortality in the initial days and then a gradual increase up to the end of study. Martingale residuals were used to assess functional form of variables. Results were validated computing calibration slope and discrimination ability of model via bootstrapping. For graphical prediction of survival probability, a nomogram was constructed. Age, renal dysfunction, blood pressure, ejection fraction and anemia were found as significant risk factors for mortality among heart failure patients. PMID- 28727741 TI - Antimicrobial resistance rates in gram-positive bacteria do not drive glycopeptides use. AB - Surveillance data are considered essential to appropriate empiric antibiotic therapy and stewardship. The objective of this study was to determine if a change in the rates of antibiotic resistance impacts antibiotic use in European hospitals. Glycopeptides use was selected to study the correlation between resistance rates and antibiotic use because of the restricted spectrum against resistant gram positive bacteria. PubMed, ECDC databases and national/regional surveillance systems were searched to identify glycopeptides' consumption in defined daily dose per 1000 inhabitant-days (DID) and rate of methicillin resistant Staphylococcus aureus (MRSA), methicillin-resistant coagulase negative staphylococci (MRCoNS), and vancomycin-resistant enterococci (VRE) in bloodstream infections (BSIs) in European countries between 1997 and 2015. Time trends were studied and associations between DID and BSI resistance rates were tested using multi-level mixed effect models. To account for the gap in the publication and dissemination of the yearly resistance data, a 2-year lag in the resistance rates was applied. Data on glycopeptides' DID and resistance rates of target microorganisms in blood cultures were identified among 31 countries over a 19 year period. Glycopeptides use significantly increased (p<0.0001) while rates of MRSA BSIs decreased in majority of the countries (p<0.0001) and MRCoNS and VRE BSIs remained stable. Variation in glycopeptides' DID was not associated with variation in BSIs due to MRSA (p = 0.136) and VRE (p = 0.613). After adjusting for MRCoNS and VRE resistance rates, among 21 countries, 11 (52%) had a concordant and 10 (48%) a discordant trend in yearly glycopeptides' DID and MRSA BSI rates. No correlation was found between resistance rates and DID data even among 8 countries with more than 5% decrease in MRSA rates over time. (RC -0.009, p = 0.059). Resistance rate of MRSA, MRCoNS, and VRE BSIs does not impact DID of glycopeptides in European hospitals. This finding is key to redefining the role and structure of antimicrobial surveillance and stewardship programmes. PMID- 28727740 TI - Genetically engineered suicide gene in mesenchymal stem cells using a Tet-On system for anaplastic thyroid cancer. AB - Anaplastic thyroid cancer (ATC) is the most aggressive malignancy of the thyroid, during which undifferentiated tumors arise from the thyroid follicular epithelium. ATC has a very poor prognosis due to its aggressive behavior and poor response to conventional therapies. Gene-directed enzyme/prodrug therapy using genetically engineered mesenchymal stromal cells (MSC) is a promising therapeutic strategy. The doxycycline (DOX)-controlled Tet inducible system is the most widely utilized regulatory system and could be a useful tool for therapeutic gene based therapies. For example, use a synthetic "tetracycline-on" switch system to control the expression of the therapeutic gene thymidine kinase, which converts prodrugs to active drugs. The aim of this study was to develop therapeutic MSCs, harboring an inducible suicide gene, and to validate therapeutic gene expression using optical molecular imaging of ATC. We designed the Tet-On system using a retroviral vector expressing herpes simplex virus thymidine kinase (HSV1-sr39TK) with dual reporters (eGFP-Fluc2). Mouse bone marrow-derived mesenchymal stromal cells (BM-MSC) were transduced using this system with (MSC-Tet-TK/Fluc2) or without (MSC-TK/Fluc) the Tet-On system. Transduced cells were screened and characterized. Engineered MSCs were co-cultured with ATC (CAL62/Rluc) cells in the presence of the prodrug ganciclovir (GCV) and stimulated with DOX. The efficiency of cell killing monitored by assessing Rluc (CAL62/Rluc) and Fluc (MSC Tet-TK/Fluc and MSC-TK/Fluc) activities using IVIS imaging. Fluc activity increased in MSC-Tet-TK/Fluc cells in a dose dependent manner following DOX treatment (R2 = 0.95), whereas no signal was observed in untreated cells. eGFP could also be visualized after induction with DOX, and the HSV1-TK protein could be detected by western blotting. In MSC-TK/Fluc cells, the Fluc activity increased with increasing cell number (R2 = 0.98), and eGFP could be visualized by fluorescence microscopy. The Fluc activity and cell viability of MSC-Tet TK/Fluc and MSC-TK/Fluc cells decreased significantly following GCV treatment. A bystander effect of the therapeutic cells confirmed in co-cultures of CAL62 cells, an anaplastic thyroid cancer cell line, with either MSC-Tet-TK/Fluc cells or MSC-TK/Fluc cells. The Rluc activity in MSC-Tet-TK/Fluc co-cultures, derived from the CAL62/Rluc cells, decreased significantly with GCV treatment of DOX treated cultures, whereas no significant changes were observed in untreated cultures. In addition, the Fluc activity of MSC-Tet-TK/Fluc cells also decreased significantly with DOX treatment whereas no signal was present in untreated cultures. A bystander effect also be demonstrated in co-cultures with MSC-TK/Fluc cells and CAL62/Rluc; both the Rluc activity and the Fluc activity were significantly decreased following GCV treatment. We have successfully developed a Tet-On system of gene-directed enzyme/prodrug delivery using MSCs. We confirmed the therapeutic bystander effect in CAL62/Rluc cells with respect to MSC-Tet TK/Fluc and MSC-TK/Fluc cells after GCV treatment with and without DOX. Our results confirm the therapeutic efficiency of a suicide gene, with or without the Tet-On system, for ATC therapy. In addition, our findings provide an innovative therapeutic approach for using the Tet-On system to eradicate tumors by simple, repeated administration of MSC-Tet-TK/Fluc cells with DOX and GCV. PMID- 28727742 TI - Physical structure and absorption properties of tailor-made porous starch granules produced by selected amylolytic enzymes. AB - Porous starch granules (PSGs) with various pores and cavity sizes were prepared by amylolysis enzymes. The greatest hydrolysis rate on corn starch granule was observed with alpha-amylase, followed by gluco- and beta-amylases. Temperature increase enhanced glucoamylase reaction rate more drastically than other enzyme treatments. Final hydrolysis level with glucoamylase reached to 66.9%, close to 67.5% of alpha-amylolysis. The alpha-amylase-treated PSGs displayed the greatest pore size and ratio of cavity-to-granule diameters. Gelatinization onset temperatures of PSGs increased to 72.1 (alpha-), 68.7 (beta-), and 68.1 degrees C (gluco-amylolysis) after 8 h; enthalpy changes of beta- and gluco-amylase-treated PSGs increased to 13.4, and 13.1 J/g but alpha-amylase-treated one showed slightly reduced value of 8.5 J/g. Water holding capacities of PSGs were 209.7 (alpha-), 94.6 (beta-), and 133.8% (gluco-amylolysis), and the untreated control had 89.1%; oil holding capacities of them showed 304.5, 182.7, and 211.5%, respectively, while the untreated control had 161.8%. Thus, enzyme types and their reaction conditions can be applied to generate desirable cavity and pore sizes in starch granules. This biocatalytic approach could contribute to develop tailor-made PSGs with distinct internal structure for specific uses in wide range of food, pharmaceutical and other industrial applications. PMID- 28727743 TI - Effect of depth information on multiple-object tracking in three dimensions: A probabilistic perspective. AB - Many daily situations require us to track multiple objects and people. This ability has traditionally been investigated in observers tracking objects in a plane. This simplification of reality does not address how observers track objects when targets move in three dimensions. Here, we study how observers track multiple objects in 2D and 3D while manipulating the average speed of the objects and the average distance between them. We show that performance declines as speed increases and distance decreases and that overall tracking accuracy is always higher in 3D than in 2D. The effects of distance and dimensionality interact to produce a more than additive improvement in performance during tracking in 3D compared to 2D. We propose an ideal observer model that uses the object dynamics and noisy observations to track the objects. This model provides a good fit to the data and explains the key findings of our experiment as originating from improved inference of object identity by adding the depth dimension. PMID- 28727744 TI - Climate change and sugarcane expansion increase Hantavirus infection risk. AB - Hantavirus Cardiopulmonary Syndrome (HCPS) is a disease caused by Hantavirus, which is highly virulent for humans. High temperatures and conversion of native vegetation to agriculture, particularly sugarcane cultivation can alter abundance of rodent generalist species that serve as the principal reservoir host for HCPS, but our understanding of the compound effects of land use and climate on HCPS incidence remains limited, particularly in tropical regions. Here we rely on a Bayesian model to fill this research gap and to predict the effects of sugarcane expansion and expected changes in temperature on Hantavirus infection risk in the state of Sao Paulo, Brazil. The sugarcane expansion scenario was based on historical data between 2000 and 2010 combined with an agro-environment zoning guideline for the sugar and ethanol industry. Future evolution of temperature anomalies was derived using 32 general circulation models from scenarios RCP4.5 and RCP8.5 (Representative greenhouse gases Concentration Pathways adopted by IPCC). Currently, the state of Sao Paulo has an average Hantavirus risk of 1.3%, with 6% of the 645 municipalities of the state being classified as high risk (HCPS risk >= 5%). Our results indicate that sugarcane expansion alone will increase average HCPS risk to 1.5%, placing 20% more people at HCPS risk. Temperature anomalies alone increase HCPS risk even more (1.6% for RCP4.5 and 1.7%, for RCP8.5), and place 31% and 34% more people at risk. Combined sugarcane and temperature increases led to the same predictions as scenarios that only included temperature. Our results demonstrate that climate change effects are likely to be more severe than those from sugarcane expansion. Forecasting disease is critical for the timely and efficient planning of operational control programs that can address the expected effects of sugarcane expansion and climate change on HCPS infection risk. The predicted spatial location of HCPS infection risks obtained here can be used to prioritize management actions and develop educational campaigns. PMID- 28727745 TI - Evaluation of tissue displacement and regional strain in the Achilles tendon using quantitative high-frequency ultrasound. AB - The Achilles tendon has a unique structure-function relationship thanks to its innate hierarchical architecture in combination with the rotational anatomy of the sub-tendons from the triceps surae muscles. Previous research has provided valuable insight in global Achilles tendon mechanics, but limitations with the technique used remain. Furthermore, given the global approach evaluating muscle tendon junction to insertion, regional differences in tendon mechanical properties might be overlooked. However, recent advancements in the field of ultrasound imaging in combination with speckle tracking have made an intratendinous evaluation possible. This study uses high-frequency ultrasound to allow for quantification of regional tendon deformation. Also, an interactive application was developed to improve clinical applicability. A dynamic ultrasound of both Achilles tendons of ten asymptomatic subjects was taken. The displacement and regional strain in the superficial, middle and deep layer were evaluated during passive elongation and isometric contraction. Building on previous research, results showed that the Achilles tendon displaces non-uniformly with a higher displacement found in the deep layer of the tendon. Adding to this, a non uniform regional strain behavior was found in the Achilles tendon during passive elongation, with the highest strain in the superficial layer. Further exploration of tendon mechanics will improve the knowledge on etiology of tendinopathy and provide options to optimize existing therapeutic loading programs. PMID- 28727747 TI - Plant species dispersed by Galapagos tortoises surf the wave of habitat suitability under anthropogenic climate change. AB - Native biodiversity on the Galapagos Archipelago is severely threatened by invasive alien species. On Santa Cruz Island, the abundance of introduced plant species is low in the arid lowlands of the Galapagos National Park, but increases with elevation into unprotected humid highlands. Two common alien plant species, guava (Psidium guajava) and passion fruit (Passiflora edulis) occur at higher elevations yet their seeds are dispersed into the lowlands by migrating Galapagos tortoises (Chelonoidis spp.). Tortoises transport large quantities of seeds over long distances into environments in which they have little or no chance of germination and survival under current climate conditions. However, climate change is projected to modify environmental conditions on Galapagos with unknown consequences for the distribution of native and introduced biodiversity. We quantified seed dispersal of guava and passion fruit in tortoise dung piles and the distribution of adult plants along two elevation gradients on Santa Cruz to assess current levels of 'wasted' seed dispersal. We computed species distribution models for both taxa under current and predicted future climate conditions. Assuming that tortoise migratory behaviour continues, current levels of "wasted" seed dispersal in lowlands were projected to decline dramatically in the future for guava but not for passion fruit. Tortoises will facilitate rapid range expansion for guava into lowland areas within the Galapagos National Park where this species is currently absent. Coupled with putative reduction in arid habitat for native species caused by climate change, tortoise driven guava invasion will pose a serious threat to local plant communities. PMID- 28727746 TI - Atorvastatin reduces beta-Adrenergic dysfunction in rats with diabetic cardiomyopathy. AB - BACKGROUND: In the diabetic heart the beta-adrenergic response is altered partly by down-regulation of the beta1-adrenoceptor, reducing its positive inotropic effect and up-regulation of the beta3-adrenoceptor, increasing its negative inotropic effect. Statins have clinical benefits on morbidity and mortality in diabetic patients which are attributed to their "pleiotropic" effects. The objective of our study was to investigate the role of statin treatment on beta adrenergic dysfunction in diabetic rat cardiomyocytes. METHODS: beta-adrenergic responses were investigated in vivo (echocardiography) and ex vivo (left ventricular papillary muscles) in healthy and streptozotocin-induced diabetic rats, who were pre-treated or not by oral atorvastatin over 15 days (50 mg.kg 1.day-1). Micro-array analysis and immunoblotting were performed in left ventricular homogenates. Data are presented as mean percentage of baseline +/- SD. RESULTS: Atorvastatin restored the impaired positive inotropic effect of beta adrenergic stimulation in diabetic hearts compared with healthy hearts both in vivo and ex vivo but did not suppress the diastolic dysfunction of diabetes. Atorvastatin changed the RNA expression of 9 genes in the beta-adrenergic pathway and corrected the protein expression of beta1-adrenoceptor and beta1/beta3 adrenoceptor ratio, and multidrug resistance protein 4 (MRP4). Nitric oxide synthase (NOS) inhibition abolished the beneficial effects of atorvastatin on the beta-adrenoceptor response. CONCLUSIONS: Atorvastatin restored the positive inotropic effect of the beta-adrenoceptor stimulation in diabetic cardiomyopathy. This effect is mediated by multiple modifications in expression of proteins in the beta-adrenergic signaling pathway, particularly through the NOS pathway. PMID- 28727748 TI - Wellbeing and chronic lung disease incidence: The Survey of Health, Ageing and Retirement in Europe. AB - BACKGROUND: Previous studies indicate that psychosocial factors can impact COPD prevalence. However, research into this association has predominantly focused on negative factors such as depression. The aim of this study was to examine whether high subjective wellbeing is associated with a lower risk of developing COPD. METHODS: The sample consisted of 12,246 participants aged >=50 years from the Survey of Health, Ageing and Retirement in Europe. We used Cox proportional hazards regression to examine the relationship between wellbeing (measured using the CASP-12) and incidence of COPD over a follow-up period of 9 years. RESULTS: There was a significant association between wellbeing and COPD risk. In age adjusted analyses, a standard deviation increase in CASP-12 score was associated with a reduced risk of COPD; hazard ratios (95% confidence intervals) for men and women were 0.67 (0.60-0.75) and 0.80 (0.73-0.87) respectively. After additional adjustment for demographic and health behaviour variables, this association remained significant for men but not for women: the fully-adjusted hazard ratios were 0.80 (0.70-0.91) and 0.91 (0.82-1.03) respectively. CONCLUSIONS: Greater wellbeing is associated with a reduced risk of COPD, particularly in men. Future research is needed to establish whether gender reliably moderates this association. PMID- 28727749 TI - Student perception of group dynamics predicts individual performance: Comfort and equity matter. AB - Active learning in college classes and participation in the workforce frequently hinge on small group work. However, group dynamics vary, ranging from equitable collaboration to dysfunctional groups dominated by one individual. To explore how group dynamics impact student learning, we asked students in a large-enrollment university biology class to self-report their experience during in-class group work. Specifically, we asked students whether there was a friend in their group, whether they were comfortable in their group, and whether someone dominated their group. Surveys were administered after students participated in two different types of intentionally constructed group activities: 1) a loosely-structured activity wherein students worked together for an entire class period (termed the 'single-group' activity), or 2) a highly-structured 'jigsaw' activity wherein students first independently mastered different subtopics, then formed new groups to peer-teach their respective subtopics. We measured content mastery by the change in score on identical pre-/post-tests. We then investigated whether activity type or student demographics predicted the likelihood of reporting working with a dominator, being comfortable in their group, or working with a friend. We found that students who more strongly agreed that they worked with a dominator were 17.8% less likely to answer an additional question correct on the 8-question post-test. Similarly, when students were comfortable in their group, content mastery increased by 27.5%. Working with a friend was the single biggest predictor of student comfort, although working with a friend did not impact performance. Finally, we found that students were 67% less likely to agree that someone dominated their group during the jigsaw activities than during the single group activities. We conclude that group activities that rely on positive interdependence, and include turn-taking and have explicit prompts for students to explain their reasoning, such as our jigsaw, can help reduce the negative impact of inequitable groups. PMID- 28727750 TI - Functional connectivity analysis in EEG source space: The choice of method. AB - Functional connectivity (FC) is among the most informative features derived from EEG. However, the most straightforward sensor-space analysis of FC is unreliable owing to volume conductance effects. An alternative-source-space analysis of FC is optimal for high- and mid-density EEG (hdEEG, mdEEG); however, it is questionable for widely used low-density EEG (ldEEG) because of inadequate surface sampling. Here, using simulations, we investigate the performance of the two source FC methods, the inverse-based source FC (ISFC) and the cortical partial coherence (CPC). To examine the effects of localization errors of the inverse method on the FC estimation, we simulated an oscillatory source with varying locations and SNRs. To compare the FC estimations by the two methods, we simulated two synchronized sources with varying between-source distance and SNR. The simulations were implemented for hdEEG, mdEEG, and ldEEG. We showed that the performance of both methods deteriorates for deep sources owing to their inaccurate localization and smoothing. The accuracy of both methods improves with the increasing between-source distance. The best ISFC performance was achieved using hd/mdEEG, while the best CPC performance was observed with ldEEG. In conclusion, with hdEEG, ISFC outperforms CPC and therefore should be the preferred method. In the studies based on ldEEG, the CPC is a method of choice. PMID- 28727751 TI - Oral health and cardiovascular care: Perceptions of people with cardiovascular disease. AB - MAIN OBJECTIVE: The aim of this study was to explore the perception of patients with cardiovascular disease towards oral health and the potential for cardiac care clinicians to promote oral health. METHOD: A needs assessment was undertaken with twelve patients with cardiovascular disease attending cardiac rehabilitation between 2015 and 2016, in three metropolitan hospitals in Sydney, Australia. These patients participated in face-to-face semi-structured interviews. Data was analysed using thematic analysis. RESULTS: Results suggested that while oral health was considered relevant there was high prevalence of poor oral health among participants, especially those from socioeconomic disadvantaged background. Awareness regarding the importance of oral health care its impact on cardiovascular outcomes was poor among participants. Oral health issues were rarely discussed in the cardiac setting. Main barriers deterring participants from seeking oral health care included lack of awareness, high cost of dental care and difficulties in accessing the public dental service. Findings also revealed that participants were interested in receiving further information about oral health and suggested various mediums for information delivery. The concept of cardiac care clinicians, especially nurses providing education, assessment and referrals to ongoing dental care was well received by participants who felt the post-acute period was the most appropriate time to receive oral health care advice. The issues of oral health training for non-dental clinicians and how to address existing barriers were highlighted by participants. RELEVANCE TO CLINICAL PRACTICE: The lack of oral health education being provided to patients with cardiovascular disease offers an opportunity to improve care and potentially, outcomes. In view of the evidence linking poor oral health with cardiovascular disease, cardiac care clinicians, especially nurses, should be appropriately trained to promote oral health in their practice. Affordable and accessible dental care services for people with cardiovascular disease should be considered and offered by health services in Australia. PMID- 28727752 TI - Atypical presentation of hepatic visceral larva migrans mimicking cancer and associated with ADAMTS13 deficiency-mediated thrombotic microangiopathy: A first report from Reunion Island. PMID- 28727753 TI - A prospective cohort study on risk factors of musculoskeletal complaints (pain and/or stiffness) in a general population. The Tromso study. AB - BACKGROUND: Female gender has been associated with musculoskeletal complaints (MSCs), but there are limited studies on how other factors may influence women and men differently. The aim of this prospective cohort study was to explore possible predictors of MSCs in women and men free of MSCs at baseline. METHODS: The present study included participants from the population-based Tromso study, with baseline data from 1994-1995 and follow-up data from 2007-2008. MSCs were defined as having pain and/or stiffness in muscles and joints for 3 consecutive months during the past year. Predictors of MSCs were examined through binary logistic regression analyses and presented as odds ratios with 95% confidence intervals. RESULTS: At baseline 4,496 participants reported no MSCs and among these 2,015 (44.8%) and 441 (9.8%) participants reported mild or severe MSCs, respectively, at follow-up. Female gender predicted MSCs in multivariable logistic regression analyses (odds ratio [OR] 1.46, 95% confidence interval [CI]: 1.29-1.66). Educational level of primary/secondary school (OR 1.73, 95% CI: 1.46 2.05) was the strongest predictor of MSCs, followed by poor self-perceived health (OR 1.62, 95% CI: 1.30-2.02). Other predictors were BMI >=30 kg/m2 (OR 1.39, 95% CI: 1.10-1.77) and smoking (OR 1.33, 95% CI: 1.16-1.52). Age and physical activity level were not significantly associated with MSCs. Gender-stratified analyses revealed that mental health complaints (i.e., depression and/or anxiety) predicted MSCs in men (OR 2.03, 95% CI: 1.18-3.50), but not in women. Current smoking (OR 1.43, 95% CI: 1.16-1.76) and poor self-perceived health (OR 1.90, 95% CI: 1.34-2.71) showed slightly higher odds ratios among women than men, but the gender differences were not significant. CONCLUSION: The present study demonstrates that several negative health determinants are predicting subsequent MSCs. However, the examined risk factors could not explain the higher prevalence of MSCs in women. PMID- 28727754 TI - Dysregulation of endothelial colony-forming cell function by a negative feedback loop of circulating miR-146a and -146b in cardiovascular disease patients. AB - Functional impairment of endothelial colony-forming cells (ECFCs), a specific cell lineage of endothelial progenitor cells (EPCs) is highly associated with the severity of coronary artery disease (CAD), the most common type of cardiovascular disease (CVD). Emerging evidence show that circulating microRNAs (miRNAs) in CAD patients' body fluid hold a great potential as biomarkers. However, our knowledge of the role of circulating miRNA in regulating the function of ECFCs and the progression of CAD is still in its infancy. We showed that when ECFCs from healthy volunteers were incubated with conditioned medium or purified exosomes of cultured CAD ECFCs, the secretory factors from CAD ECFCs dysregulated migration and tube formation ability of healthy ECFCs. It is known that exosomes influence the physiology of recipient cells by introducing RNAs including miRNAs. By using small RNA sequencing (smRNA-seq), we deciphered the circulating miRNome in the plasma of healthy individual and CAD patients, and found that the plasma miRNA spectrum from CAD patients was significantly different from that of healthy control. Interestingly, smRNA-seq of both healthy and CAD ECFCs showed that twelve miRNAs that had a higher expression in the plasma of CAD patients also showed higher expression in CAD ECFCs when compared with healthy control. This result suggests that these miRNAs may be involved in the regulation of ECFC functions. For identification of potential mRNA targets of the differentially expressed miRNA in CAD patients, cDNA microarray analysis was performed to identify the angiogenesis-related genes that were down-regulated in CAD ECFCs and Pearson's correlation were used to identify miRNAs that were negatively correlated with the identified angiogenesis-related genes. RT-qPCR analysis of the five miRNAs that negatively correlated with the down-regulated angiogenesis related genes in plasma and ECFC of CAD patients showed miR-146a-5p and miR-146b 5p up-regulation compared to healthy control. Knockdown of miR-146a-5p or miR 146b-5p in CAD ECFCs enhanced migration and tube formation activity in diseased ECFCs. Contrarily, overexpression of miR-146a-5p or miR-146b-5p in healthy ECFC repressed migration and tube formation in ECFCs. TargetScan analysis showed that miR-146a-5p and miR-146b-5p target many of the angiogenesis-related genes that were down-regulated in CAD ECFCs. Knockdown of miR-146a-5p or miR-146b-5p restores CAV1 and RHOJ levels in CAD ECFCs. Reporter assays confirmed the direct binding and repression of miR-146a-5p and miR-146b-5p to the 3'-UTR of mRNA of RHOJ, a positive regulator of angiogenic potential in endothelial cells. Consistently, RHOJ knockdown inhibited the migration and tube formation ability in ECFCs. Collectively, we discovered the dysregulation of miR-146a-5p/RHOJ and miR-146b-5p/RHOJ axis in the plasma and ECFCs of CAD patients that could be used as biomarkers or therapeutic targets for CAD and other angiogenesis-related diseases. PMID- 28727755 TI - No abatement of steroid injections for tennis elbow in Australian General Practice: A 15-year observational study with random general practitioner sampling. AB - OBJECTIVE: Evaluate general practitioner (GP) management of tennis elbow (TE) in Australia. METHODS: Data about the management of TE by GPs from 2000 to 2015 were extracted from the Bettering the Evaluation of Care of Health program database. Patient and GP characteristics and encounter management data were classified by the International Classification of Primary Care, version 2, and reported using descriptive statistics with point estimates and 95% confidence intervals. RESULTS: TE was managed by GPs 242,000 times per year on average. Patients were mainly female (52.3%), aged between 35 and 64 years (mean: 49.3 yrs), had higher relative risks of concomitant disorders (e.g. carpal tunnel syndrome and other tendonitis) and their TE was 10 times more likely to be work related than problems managed for patients who did not have TE. Use of diagnostic tests was low, implying a clinical examination based diagnosis of TE. Management was by procedural treatments (36 per 100 TE problems), advice, education or counselling (25 per 100), and referral to other health care providers (14 per 100, mainly to physiotherapy). The rate of local injection did not change over the 15 years and was performed at similar rates as physiotherapy referral. CONCLUSION: The high risk of comorbidities and work relatedness and no abatement in the reasonably high rate of local injections (which is contrary to the evidence from clinical trials) provides support for the development and dissemination of TE clinical guidelines for GPs. PMID- 28727756 TI - Dysregulation of microRNAs and renin-angiotensin system in high salt diet-induced cardiac dysfunction in uninephrectomized rats. AB - Uninephrectomy is not associated with major adverse events in cardiovascular and renal functions of live kidney donors. The effect of high salt diet on the quality of life of live kidney donors is largely unknown. Hence in this study, we aimed to determine the effect of high salt diet on the alterations of renin angiotensin system and microRNAs leading to CV and renal dysfunction in uninephrectomized rats. In order to mimic clinical scenario, uninephrectomized male Sprague Dawley rats were fed initially with normal pellet diet for 12 weeks and then for 20 weeks with high salt (10% w/w NaCl) diet. At the end of the study, biochemical, functional, histological and molecular parameters were measured. High salt diet feeding resulted in renal dysfunction & fibrosis, decreased baroreflex sensitivity, increased in vivo cardiovascular reactivity to angiotensin II owing to upregulation of angiotensin II type 1 receptors and L type calcium channels leading to cardiovascular dysfunction in uninephrectomized rats (UNX+HSD) worse than that of normal (binephric) rats fed with high salt diet (HSD). Protein expression of functional and hypertrophic protein markers revealed decreased SERCA, p-AMPK and increased p-AKT. Interestingly, levels of miR-25, miR 451 and miR-155 increased and miR-99 decreased in heart of uninephrectomized rats fed with high salt. However, circulating miR-25 and miR-451 levels decreased and miR-99b increased in these animals. Our study points out that since tissue and circulating levels of miRNAs are not similar, caution must be exercised during the usage of miRs as diagnostic or prognostic biomarkers. To our knowledge, we are the first to show that epigenetic alterations result in cardiac dysfunction in uninephrectomized rats fed with high salt diet. PMID- 28727757 TI - Development of organic fertilizers from food market waste and urban gardening by composting in Ecuador. AB - Currently, the management of urban waste streams in developing countries is not optimized yet, and in many cases these wastes are disposed untreated in open dumps. This fact causes serious environmental and health problems due to the presence of contaminants and pathogens. Frequently, the use of specific low-cost strategies reduces the total amount of wastes. These strategies are mainly associated to the identification, separate collection and composting of specific organic waste streams, such as vegetable and fruit refuses from food markets and urban gardening activities. Concretely, in the Chimborazo Region (Ecuador), more than 80% of municipal solid waste is dumped into environment due to the lack of an efficient waste management strategy. Therefore, the aim of this study was to develop a demonstration project at field scale in this region to evaluate the feasibility of implanting the composting technology not only for the management of the organic waste fluxes from food market and gardening activities to be scaled-up in other developing regions, but also to obtain an end-product with a commercial value as organic fertilizer. Three co-composting mixtures were prepared using market wastes mixed with pruning of trees and ornamental palms as bulking agents. Two piles were created using different proportions of market waste and prunings of trees and ornamental palms: pile 1 (50:33:17) with a C/N ratio 25; pile 2: (60:30:10) with C/N ratio 24 and pile 3 (75:0:25) with C/N ratio 33), prepared with market waste and prunings of ornamental palm. Throughout the process, the temperature of the mixtures was monitored and organic matter evolution was determined using thermogravimetric and chemical techniques. Additionally, physico-chemical, chemical and agronomic parameters were determined to evaluate compost quality. The results obtained indicated that all the piles showed a suitable development of the composting process, with a significant organic matter decomposition, reached in a shorter period of time in pile 3. At the end of the process, all the composts showed absence of phytotoxicity and suitable agronomic properties for their use as organic fertilizers. This reflects the viability of the proposed alternative to be scaled-up in developing areas, not only to manage and recycle urban waste fluxes, but also to obtain organic fertilizers, including added value in economic terms related to nutrient contents. PMID- 28727758 TI - Longevity effect of a polysaccharide from Chlorophytum borivilianum on Caenorhabditis elegans and Saccharomyces cerevisiae. AB - The traditional Indian medicine, Ayurveda, provides insights and practical solutions towards a healthy life style. Rasayana is a branch of Ayurveda known for preserving and promoting health, enhancing the quality of life and delaying the aging process. In the traditional knowledge, the Rasayana herb, Chlorophytum borivilianum (C. borivilanum) is regarded as a general health promoting tonic that delays aging and increases lifespan, cognitive function and physical strength. Aging is a complex and multifactorial physiological phenomenon that manifests itself over a wide range of biological systems, tissues, and functions. Longevity is an obvious marker of physiological aging. Simple model systems such as the single-cell budding yeast Saccharomyces cerevisiae (S. cerevisiae) and the nematode, Caenorhabditis elegans (C. elegans) are widely used to study the aging process and longevity. Here, we show that a polysaccharide fraction obtained from C. borivilianum increases the lifespan of S. cerevisiae and C. elegans, using an automated screening platform (ChronoscreenTM). Chemical analysis of this extract revealed a low molecular weight polysaccharide of 1000 Da, predominantly comprising Glu1->6Glu linkage. This polysaccharide showed significant dose dependent extension of the median lifespan of S. cerevisiae by up to 41% and of the median lifespan of C. elegans by up to 10%. Taking cue from these results and the traditionally described benefits of Rasayanas on skin rejuvenation, we tested in vitro the polysaccharide for potential skin benefits. In a keratinocyte culture, we observed that this polysaccharide increased cell proliferation significantly, and induced synthesis of hyaluronic acid (HA), a well-known extracellular matrix component. Furthermore, when added to culture medium of human reconstructed epidermis, we observed an enhanced production of epidermal markers, e.g. CD44 and HA that are otherwise diminished in aged skin. Together, these results suggest that in addition to life-span extension of S. cerevisiae and C. elegans, a polysaccharide from the Rasayana herb, C. borivilianum may have beneficial effects on skin aging parameters. PMID- 28727759 TI - Use of a microfluidic platform to uncover basic features of energy and environmental stress responses in individual cells of Bacillus subtilis. AB - Bacteria use a variety of stress-sensing systems to sense and respond to diverse stressors and to ensure their survival under adverse conditions. The gram positive bacterium Bacillus subtilis responds to energy stress (ATP depletion) and to environmental stressors using two distinct stress-sensing pathways that converge on the alternative sigma factor sigmaB to provoke a general stress response. Past efforts to study the sigmaB stress response in bulk culture and on agarose pads were unable to visualize the responses of individual cells under tightly controlled conditions for extended periods of time. Here we use a microfluidics-based strategy to discern the basic features of sigmaB activation in single cells in response to energy and environmental stress, both immediately upon stressor exposure and for tens of generations thereafter. Upon energy stress at various levels of stressor, cells exhibited fast, transient, and amplitude modulated responses but not frequency modulation as previously reported. Upon environmental stress, which is mediated by the stressosome complex, wild-type cells primarily exhibited a transient and amplitude-modulated response. However, mutant cells producing only one of the four paralogous RsbR stressosome proteins showed striking and previously unseen differences. Whereas RsbRA-only cells mimicked the wild type, RsbRC-only cells displayed a slower but sustained overall response composed of repeated activation events in single cells. PMID- 28727760 TI - Detection of titin fragments in urine in response to exercise-induced muscle damage. AB - Many studies have attempted to determine the associations between blood biomarkers and exercise-induced muscle damage. However, poor correlations between the changes in biomarker levels and the magnitude of muscle symptoms have been reported. Recent advances in proteomic tools offer a strategy for the comprehensive analysis of protein expression, which can be used to identify biomarkers. Here, we used a proteomic analysis to identify urinary proteins that appear in response to a calf-raise exercise, including repetitive eccentric muscle contractions, and found that a titin (also known as connectin) N-terminal fragment molecule appears in the urine after eccentric exercise. We measured the titin fragment in urine samples from nine individuals before and after eccentric exercise using a newly-established enzyme-linked immunosorbent assay and found that the titin fragment excretion rate increased 96 h after the exercise (5.1 to 77.6 pg/min, p <0.01). The changes in the titin fragment excretion rate were correlated strongly with blood markers of muscle damage and with muscle symptoms. These findings suggest that the urinary titin fragment is potentially a noninvasive biomarker of muscle damage. PMID- 28727762 TI - Sexual diversity in the United States: Results from a nationally representative probability sample of adult women and men. AB - In 2015, we conducted a cross-sectional, Internet-based, U.S. nationally representative probability survey of 2,021 adults (975 men, 1,046 women) focused on a broad range of sexual behaviors. Individuals invited to participate were from the GfK KnowledgePanel(r). The survey was titled the 2015 Sexual Exploration in America Study and survey completion took about 12 to 15 minutes. The survey was confidential and the researchers never had access to respondents' identifiers. Respondents reported on demographic items, lifetime and recent sexual behaviors, and the appeal of 50+ sexual behaviors. Most (>80%) reported lifetime masturbation, vaginal sex, and oral sex. Lifetime anal sex was reported by 43% of men (insertive) and 37% of women (receptive). Common lifetime sexual behaviors included wearing sexy lingerie/underwear (75% women, 26% men), sending/receiving digital nude/semi-nude photos (54% women, 65% men), reading erotic stories (57% of participants), public sex (>=43%), role-playing (>=22%), tying/being tied up (>=20%), spanking (>=30%), and watching sexually explicit videos/DVDs (60% women, 82% men). Having engaged in threesomes (10% women, 18% men) and playful whipping (>=13%) were less common. Lifetime group sex, sex parties, taking a sexuality class/workshop, and going to BDSM parties were uncommon (each <8%). More Americans identified behaviors as "appealing" than had engaged in them. Romantic/affectionate behaviors were among those most commonly identified as appealing for both men and women. The appeal of particular behaviors was associated with greater odds that the individual had ever engaged in the behavior. This study contributes to our understanding of more diverse adult sexual behaviors than has previously been captured in U.S. nationally representative probability surveys. Implications for sexuality educators, clinicians, and individuals in the general population are discussed. PMID- 28727761 TI - Genome-wide identification of the potato WRKY transcription factor family. AB - WRKY transcription factors play pivotal roles in regulation of stress responses. This study identified 79 WRKY genes in potato (Solanum tuberosum). Based on multiple sequence alignment and phylogenetic relationships, WRKY genes were classified into three major groups. The majority of WRKY genes belonged to Group II (52 StWRKYs), Group III had 14 and Group I consisted of 13. The phylogenetic tree further classified Group II into five sub-groups. All StWRKY genes except StWRKY79 were mapped on potato chromosomes, with eight tandem duplication gene pairs and seven segmental duplication gene pairs found from StWRKY family genes. The expression analysis of 22 StWRKYs showed their differential expression levels under various stress conditions. Cis-element prediction showed that a large number of elements related to drought, heat and salicylic acid were present in the promotor regions of StWRKY genes. The expression analysis indicated that seven StWRKYs seemed to respond to stress (heat, drought and salinity) and salicylic acid treatment. These genes are candidates for abiotic stress signaling for further research. PMID- 28727763 TI - Loss of receptor activity-modifying protein 2 in mice causes placental dysfunction and alters PTH1R regulation. AB - Receptor activity-modifying protein 2 (Ramp2) is a single-pass transmembrane protein that heterodimerizes with several family B G-protein coupled receptors to alter their function. Ramp2 has been primarily characterized in association with calcitonin receptor-like receptor (Calcrl, CLR), forming the canonical receptor complex for the endocrine peptide adrenomedullin (Adm, AM). However, we previously demonstrated that Ramp2+/- female mice display a constellation of endocrine-related phenotypes that are distinct from those of Adm+/- and Calcrl+/- mice, implying that RAMP2 has physiological functions beyond its canonical complex. Here, we localize Ramp2 expression in the mouse placenta, finding that Ramp2 is robustly expressed in the fetal labyrinth layer, and then characterize the effects of loss of Ramp2 on placental development. Consistent with the expression pattern of Ramp2 in the placenta, Ramp2-/- placentas have a thinner labyrinth layer with significantly fewer trophoblast cells secondary to a reduction in trophoblast proliferation. We also find that absence of Ramp2 leads to failed spiral artery remodeling unaccompanied by changes in the uterine natural killer cell population. Furthermore, we assess changes in gene expression of other RAMP2-associated G-protein coupled receptors (GPCRs), concluding that Ramp2 loss decreases parathyroid hormone 1 receptor (Pthr1) expression and causes a blunted response to systemic parathyroid hormone (PTH) administration in mice. Ultimately, these studies provide in vivo evidence of a role for RAMP2 in placental development distinct from the RAMP2-CLR/AM signaling paradigm and identify additional pathways underlying the endocrine and fertility defects of the previously characterized Ramp2 heterozygous adult females. PMID- 28727764 TI - Vaccinia virus and Cowpox virus are not susceptible to the interferon-induced antiviral protein MxA. AB - MxA protein is expressed in response to type I and type III Interferon and constitute an important antiviral factor with broad antiviral activity to diverse RNA viruses. In addition, some studies expand the range of MxA antiviral activity to include particular DNA viruses like Monkeypox virus (MPXV) and African Swine Fever virus (ASFV). However, a broad profile of activity of MxA to large DNA viruses has not been established to date. Here, we investigated if some well characterized DNA viruses belonging to the Poxviridae family are sensitive to human MxA. A cell line inducibly expressing MxA to inhibitory levels showed no anti-Vaccinia virus (VACV) virus activity, indicating either lack of susceptibility of the virus, or the existence of viral factors capable of counteracting MxA inhibition. To determine if VACV resistance to MxA was due to a virus-encoded anti-MxA activity, we performed coinfections of VACV and the MxA sensitive Vesicular Stomatitis virus (VSV), and show that VACV does not protect VSV from MxA inhibition in trans. Those results were extended to several VACV strains and two CPXV strains, thus confirming that those Orthopoxviruses do not block MxA action. Overall, these results point to a lack of susceptibility of the Poxviridae to MxA antiviral activity. PMID- 28727765 TI - Defining the target and the effect of imatinib on the filarial c-Abl homologue. AB - BACKGROUND: Previously we demonstrated the micro- and macrofilaricidal properties of imatinib in vitro. Here we use electron and multiphoton microscopy to define the target of imatinib in the adult and microfilarial stages of Brugia malayi and assess the effects of pharmacologically relevant levels of imatinib on the adult parasites. METHODS: After fixation of adult B. malayi males and females, sections were stained with polyclonal rabbit anti-c-Abl antibody (or isotype control) and imaged with multiphoton fluorescent microscopy. Microfilariae were fixed and labeled with rabbit anti-c-Abl IgG primary antibody followed by anti-rabbit gold conjugated secondary antibody and imaged using transmission electron microscopy (TEM; immunoEM). In addition, adult B. malayi males and females were exposed to 0 or 10MUM of imatinib for 7 days following which they were prepared for transmission electron microscopy (TEM) to assess the drug's effect on filarial ultrastructure. RESULTS: Fluorescent localization of anti-c-Abl antibody demonstrated widespread uptake in the adult filariae, but the most intense signal was seen in the reproductive organs, muscle, and intestine of both male and female worms. Fluorescence was significantly more intense in the early microfilarial stage (i.e. early morula) compared with later development stages (i.e. pretzel). Anti-c-Abl antibody in the microfilariae localized to the nuclei. Based on TEM assessment following imatinib exposure, imatinib appeared to be detrimental to embryogenesis in the adult female B. malayi. CONCLUSIONS: At pharmacologically achievable concentrations of imatinib, embryogenesis is impaired and possibly halted in adult filariae. Imatinib is likely a slow microfilaricide due to interference in intra-nuclear processes, which are slowly detrimental to the parasite and not immediately lethal, and thus may be used to lower the levels of L. loa microfilariae before they are treated within the context of conventional mass drug administration. PMID- 28727766 TI - Clinical implications of the novel cytokine IL-38 expressed in lung adenocarcinoma: Possible association with PD-L1 expression. AB - Interleukin (IL)-38, a novel member of the IL-1 cytokine family, is homologous to IL-1 receptor antagonist (IL-1Ra) and IL-36Ra, and has been reported to act as an antagonist. IL-38 expression is found in tonsil, placenta, and spleen, and recent studies suggest an association between IL-38 and autoimmune diseases. However, whether IL-38 plays a role in carcinogenesis or cancer growth is unclear. In the present study, we identified increases in IL-38 expression by immunohistochemistry in multiple types of cancer cells. In the examination of 417 surgically resected primary lung adenocarcinomas, Fisher's exact tests showed significant associations between high IL-38 expression and high tumor grades, an advanced T status, advanced N status, advanced stage, and the presence of pleural and vessel invasions. Survival analyses by the Kaplan-Meier method showed that patients with high expression of IL-38 had significantly shorter disease-free survival and shorter overall survival after surgery than patients with low expression of IL-38 (log-rank test: P = 0.0021 and P = 0.0035, respectively). Moreover, programmed cell death-ligand 1 (PD-L1)-positive cases showed higher expression of IL-38 than PD-L1-negative cases (Wilcoxon rank-sum test: P < 0.0001). In conclusion, IL-38 was expressed in tumor cells of various cancers, and IL-38 expression was associated with poor survival of lung adenocarcinoma patients. IL-38 may affect host immunity or the tumor microenvironment, and contribute to the progression of lung adenocarcinoma. PMID- 28727767 TI - Exploring the binding pathways of the 14-3-3zeta protein: Structural and free energy profiles revealed by Hamiltonian replica exchange molecular dynamics with distancefield distance restraints. AB - The 14-3-3 protein family performs regulatory functions in eukaryotic organisms by binding to a large number of phosphorylated protein partners. Whilst the binding mode of the phosphopeptides within the primary 14-3-3 binding site is well established based on the crystal structures of their complexes, little is known about the binding process itself. We present a computational study of the process by which phosphopeptides bind to the 14-3-3zeta protein. Applying a novel scheme combining Hamiltonian replica exchange molecular dynamics and distancefield restraints allowed us to map and compare the most likely phosphopeptide-binding pathways to the 14-3-3zeta protein. The most important structural changes to the protein and peptides involved in the binding process were identified. In order to bind phosphopeptides to the primary interaction site, the 14-3-3zeta adopted a newly found wide-opened conformation. Based on our findings we additionally propose a secondary interaction site on the inner surface of the 14-3-3zeta dimer, and a direct interference on the binding process by the flexible C-terminal tail. A minimalistic model was designed to allow for the efficient calculation of absolute binding affinities. Binding affinities calculated from the potential of mean force along the binding pathway are in line with the available experimental estimates for two of the studied systems. PMID- 28727768 TI - Benign and tumor parenchyma metabolomic profiles affect compensatory renal growth in renal cell carcinoma surgical patients. AB - BACKGROUND AND OBJECTIVES: Pre-operative kidney volume is an independent predictor of glomerular filtration rate in renal cell carcinoma patients. Compensatory renal growth (CRG) can ensue prior to nephrectomy in parallel to tumor growth and benign parenchyma loss. We aimed to test whether renal metabolite abundances significantly associate with CRG, suggesting a causative relationship. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: Tissue metabolomics data from 49 patients, with a median age of 60 years, were previously collected and the pre-operative fold-change of their contra to ipsi lateral benign kidney volume served as a surrogate for their CRG. Contra-lateral kidney volume fold-change within a 3.3 +/- 2.1 years follow-up interval was used as a surrogate for long-term CRG. Using a multivariable statistical model, we identified metabolites whose abundances significantly associate with CRG. RESULTS: Our analysis found 13 metabolites in the benign (e.g. L-urobilin, Variable Influence in Projection, VIP, score = 3.02, adjusted p = 0.017) and 163 metabolites in the malignant (e.g. 3-indoxyl-sulfate, VIP score = 1.3, adjusted p = 0.044) tissues that significantly associate with CRG. Benign/tumor fold change in metabolite abundances revealed three additional metabolites with that significantly positively associate with CRG (e.g. p-cresol sulfate, VIP score = 2.945, adjusted p = 0.033). At the pathway level, we show that fatty-acid oxidation is highly enriched with metabolites whose benign tissue abundances strongly positively associate with CRG, both pre-operatively and long term, whereas in the tumor tissue significant enrichment of dipeptides and benzoate (positive association), glycolysis/gluconeogenesis, lysolipid and nucleotide sugar pentose (negative associations) sub-pathways, were observed. CONCLUSION: These data suggest that specific biological processes in the benign as well as in the tumor parenchyma strongly influence compensatory renal growth. PMID- 28727770 TI - Cerebrospinal fluid humoral immunity in the differential diagnosis of multiple sclerosis. AB - BACKGROUND: The diagnostic accuracy of cerebrospinal fluid oligoclonal bands (CSF OCB) detected by isoelectric focusing (IEF) in patients with multiple sclerosis (MS) was evaluated in our study. METHODS: Three hundred and twenty-one patients with MS and other central nervous system (CNS) immune mediated disorders were assessed (CIMD). Cerebrospinal fluid and matched serum samples were examined for the presence of OCB by IEF-IB (isoelectric focusing with immunoblotting). RESULTS: Isolated oligoclonal bands (ISO-OCB) were the only predictor of MS diagnosis independent of age, gender and CSF-OCB. ISO-OCB >= 3.5 detected by IEF yielded a sensitivity of 98% and specificity of 87% in distinguishing MS from MS mimickers. CONCLUSIONS: For the neurologist, a score of >= 4 ISO-OCB supports the diagnosis of MS. On the other hand, ISO-OCB <=3 favors CIMD. Further studies with larger population samples are warranted to confirm these findings. PMID- 28727772 TI - Description of an establishment event by the invasive Asian longhorned beetle (Anoplophora glabripennis) in a suburban landscape in the northeastern United States. AB - The establishment of non-native species is commonly described as occurring in three phases: arrival, establishment, and dispersal. Both arrival and dispersal by the Asian longhorned beetle (Anoplophora glabripennis Motschulsky), a xylophagous Cerambycid native to China and the Korean peninsula, has been documented for multiple locations in both North America and Europe, however the transitional phase, establishment, is not well understood for this species due to the need to rapidly remove populations to prevent dispersal and assist eradication, and the evident variation in the behavior of populations. Here we describe the dynamics of an establishment event for the Asian longhorned beetle in a small, isolated population within the regulated quarantine zone near Worcester, Massachusetts, USA. These data were collected during an opportunity afforded by logistical limits on the Cooperative Asian Longhorned Beetle Eradication Program administered by state, federal, and local government partners. Seventy-one infested red maple (Acer rubrum) trees and 456 interspersed un-infested trees were surveyed in an isolated, recently established population within a ~0.29 ha stand in a suburban wetland conservation area in which nearly 90% of the trees were host species, and nearly 80% were Acer rubrum. Tree-ring analyses show that within this establishing population, Asian longhorned beetles initially infested one or two A. rubrum, before moving through the stand to infest additional A. rubrum based not on distance or direction, but on tree size, with infestation biased towards trees with larger trunk diameters. Survey data from the larger landscape suggest this population may have generated long distance dispersers (~1400 m), and that these dispersal events occurred before the originally infested host trees were fully exploited by the beetle. The distribution and intensity of damage documented in this population suggest dispersal here may have been spatially more rapid and diffuse than in other documented infestations. Dispersal at these larger spatial scales also implies that when beetles move beyond the closed canopy of the stand, the direction of dispersal may be linked to prevailing winds. PMID- 28727769 TI - Small subunit ribosomal metabarcoding reveals extraordinary trypanosomatid diversity in Brazilian bats. AB - BACKGROUND: Bats are a highly successful, globally dispersed order of mammals that occupy a wide array of ecological niches. They are also intensely parasitized and implicated in multiple viral, bacterial and parasitic zoonoses. Trypanosomes are thought to be especially abundant and diverse in bats. In this study, we used 18S ribosomal RNA metabarcoding to probe bat trypanosome diversity in unprecedented detail. METHODOLOGY/PRINCIPAL FINDINGS: Total DNA was extracted from the blood of 90 bat individuals (17 species) captured along Atlantic Forest fragments of Espirito Santo state, southeast Brazil. 18S ribosomal RNA was amplified by standard and/or nested PCR, then deep sequenced to recover and identify Operational Taxonomic Units (OTUs) for phylogenetic analysis. Blood samples from 34 bat individuals (13 species) tested positive for infection by 18S rRNA amplification. Amplicon sequences clustered to 14 OTUs, of which five were identified as Trypanosoma cruzi I, T. cruzi III/V, Trypanosoma cruzi marinkellei, Trypanosoma rangeli, and Trypanosoma dionisii, and seven were identified as novel genotypes monophyletic to basal T. cruzi clade types of the New World. Another OTU was identified as a trypanosome like those found in reptiles. Surprisingly, the remaining OTU was identified as Bodo saltans-closest non-parasitic relative of the trypanosomatid order. While three blood samples featured just one OTU (T. dionisii), all others resolved as mixed infections of up to eight OTUs. CONCLUSIONS/SIGNIFICANCE: This study demonstrates the utility of next-generation barcoding methods to screen parasite diversity in mammalian reservoir hosts. We exposed high rates of local bat parasitism by multiple trypanosome species, some known to cause fatal human disease, others non-pathogenic, novel or yet little understood. Our results highlight bats as a long-standing nexus among host parasite interactions of multiple niches, sustained in part by opportunistic and incidental infections of consequence to evolutionary theory as much as to public health. PMID- 28727771 TI - Randomized controlled trial on the effects of a supervised high intensity exercise program in patients with a hematologic malignancy treated with autologous stem cell transplantation: Results from the EXIST study. AB - BACKGROUND: This single blind, multicenter randomized controlled trial aimed to evaluate the effectiveness of a supervised high intensity exercise program on physical fitness and fatigue in patients with multiple myeloma or lymphoma recently treated with autologous stem cell transplantation. METHODS: 109 patients were randomly assigned to the 18-week exercise intervention or the usual care control group. The primary outcomes included physical fitness (VO2peak and Wpeak determined using a cardiopulmonary exercise test; grip strength and the 30s chair stand test) and fatigue (Multidimensional Fatigue Inventory) and were assessed prior to randomization and after completion of the intervention or at similar time points for the control group. Multivariable multilevel linear regression analyses were performed to assess intervention effects. RESULTS: Patients in the intervention group attended 86% of the prescribed exercise sessions. Of the patients in the control group, 47% reported >=10 physiotherapy sessions, which most likely included supervised exercise, suggesting a high rate of contamination. Median improvements in physical fitness ranged between 16 and 25% in the intervention group and between 12 and 19% in the control group. Fatigue decreased in both groups. There were no significant differences between the intervention and control group. CONCLUSION: We found no significant beneficial effects of the supervised high intensity exercise program on physical fitness and fatigue when compared to usual care. We hypothesized that the lack of significant intervention effects may relate to suboptimal timing of intervention delivery, contamination in the control group and/or suboptimal compliance to the prescribed exercise intervention. TRIAL REGISTRATION: Netherlands Trial Register-NTR2341. PMID- 28727773 TI - The tradition algorithm approach underestimates the prevalence of serodiagnosis of syphilis in HIV-infected individuals. AB - Currently, there are three algorithms for screening of syphilis: traditional algorithm, reverse algorithm and European Centre for Disease Prevention and Control (ECDC) algorithm. To date, there is not a generally recognized diagnostic algorithm. When syphilis meets HIV, the situation is even more complex. To evaluate their screening performance and impact on the seroprevalence of syphilis in HIV-infected individuals, we conducted a cross-sectional study included 865 serum samples from HIV-infected patients in a tertiary hospital. Every sample (one per patient) was tested with toluidine red unheated serum test (TRUST), T. pallidum particle agglutination assay (TPPA), and Treponema pallidum enzyme immunoassay (TP-EIA) according to the manufacturer's instructions. The results of syphilis serological testing were interpreted following different algorithms respectively. We directly compared the traditional syphilis screening algorithm with the reverse syphilis screening algorithm in this unique population. The reverse algorithm achieved remarkable higher seroprevalence of syphilis than the traditional algorithm (24.9% vs. 14.2%, p < 0.0001). Compared to the reverse algorithm, the traditional algorithm also had a missed serodiagnosis rate of 42.8%. The total percentages of agreement and corresponding kappa values of tradition and ECDC algorithm compared with those of reverse algorithm were as follows: 89.4%,0.668; 99.8%, 0.994. There was a very good strength of agreement between the reverse and the ECDC algorithm. Our results supported the reverse (or ECDC) algorithm in screening of syphilis in HIV-infected populations. In addition, our study demonstrated that screening of HIV-populations using different algorithms may result in a statistically different seroprevalence of syphilis. PMID- 28727774 TI - Inhibitors of Mycobacterium marinum virulence identified in a Dictyostelium discoideum host model. AB - Tuberculosis remains one of the major threats to public health worldwide. Given the prevalence of multi drug resistance (MDR) in Mycobacterium tuberculosis strains, there is a strong need to develop new anti-mycobacterial drugs with modes of action distinct from classical antibiotics. Inhibitors of mycobacterial virulence might target new molecular processes and may represent a potential new therapeutic alternative. In this study, we used a Dictyostelium discoideum host model to assess virulence of Mycobacterium marinum and to identify compounds inhibiting mycobacterial virulence. Among 9995 chemical compounds, we selected 12 inhibitors of mycobacterial virulence that do not inhibit mycobacterial growth in synthetic medium. Further analyses revealed that 8 of them perturbed functions requiring an intact mycobacterial cell wall such as sliding motility, bacterial aggregation or cell wall permeability. Chemical analogs of two compounds were analyzed. Chemical modifications altered concomitantly their effect on sliding motility and on mycobacterial virulence, suggesting that the alteration of the mycobacterial cell wall caused the loss of virulence. We characterized further one of the selected compounds and found that it inhibited the ability of mycobacteria to replicate in infected cells. Together these results identify new antimycobacterial compounds that represent new tools to unravel the molecular mechanisms controlling mycobacterial pathogenicity. The isolation of compounds with anti-virulence activity is the first step towards developing new antibacterial treatments. PMID- 28727775 TI - Adolescent health in rural Ghana: A cross-sectional study on the co-occurrence of infectious diseases, malnutrition and cardio-metabolic risk factors. AB - In sub-Saharan Africa, infectious diseases and malnutrition constitute the main health problems in children, while adolescents and adults are increasingly facing cardio-metabolic conditions. Among adolescents as the largest population group in this region, we investigated the co-occurrence of infectious diseases, malnutrition and cardio-metabolic risk factors (CRFs), and evaluated demographic, socio-economic and medical risk factors for these entities. In a cross-sectional study among 188 adolescents in rural Ghana, malarial infection, common infectious diseases and Body Mass Index were assessed. We measured ferritin, C-reactive protein, retinol, fasting glucose and blood pressure. Socio-demographic data were documented. We analyzed the proportions (95% confidence interval, CI) and the co occurrence of infectious diseases (malaria, other common diseases), malnutrition (underweight, stunting, iron deficiency, vitamin A deficiency [VAD]), and CRFs (overweight, obesity, impaired fasting glucose, hypertension). In logistic regression, odds ratios (OR) and 95% CIs were calculated for the associations with socio-demographic factors. In this Ghanaian population (age range, 14.4-15.5 years; males, 50%), the proportions were for infectious diseases 45% (95% CI: 38 52%), for malnutrition 50% (43-57%) and for CRFs 16% (11-21%). Infectious diseases and malnutrition frequently co-existed (28%; 21-34%). Specifically, VAD increased the odds of non-malarial infectious diseases 3-fold (95% CI: 1.03, 10.19). Overlap of CRFs with infectious diseases (6%; 2-9%) or with malnutrition (7%; 3-11%) was also present. Male gender and low socio-economic status increased the odds of infectious diseases and malnutrition, respectively. Malarial infection, chronic malnutrition and VAD remain the predominant health problems among these Ghanaian adolescents. Investigating the relationships with evolving CRFs is warranted. PMID- 28727776 TI - Language related differences of the sustained response evoked by natural speech sounds. AB - In tonal languages, such as Mandarin Chinese, the pitch contour of vowels discriminates lexical meaning, which is not the case in non-tonal languages such as German. Recent data provide evidence that pitch processing is influenced by language experience. However, there are still many open questions concerning the representation of such phonological and language-related differences at the level of the auditory cortex (AC). Using magnetoencephalography (MEG), we recorded transient and sustained auditory evoked fields (AEF) in native Chinese and German speakers to investigate language related phonological and semantic aspects in the processing of acoustic stimuli. AEF were elicited by spoken meaningful and meaningless syllables, by vowels, and by a French horn tone. Speech sounds were recorded from a native speaker and showed frequency-modulations according to the pitch-contours of Mandarin. The sustained field (SF) evoked by natural speech signals was significantly larger for Chinese than for German listeners. In contrast, the SF elicited by a horn tone was not significantly different between groups. Furthermore, the SF of Chinese subjects was larger when evoked by meaningful syllables compared to meaningless ones, but there was no significant difference regarding whether vowels were part of the Chinese phonological system or not. Moreover, the N100m gave subtle but clear evidence that for Chinese listeners other factors than purely physical properties play a role in processing meaningful signals. These findings show that the N100 and the SF generated in Heschl's gyrus are influenced by language experience, which suggests that AC activity related to specific pitch contours of vowels is influenced in a top-down fashion by higher, language related areas. Such interactions are in line with anatomical findings and neuroimaging data, as well as with the dual-stream model of language of Hickok and Poeppel that highlights the close and reciprocal interaction between superior temporal gyrus and sulcus. PMID- 28727778 TI - In vitro study of accuracy of subaxial cervical pedicle screw insertion using calipers based on the gravity line. AB - OBJECT: There is a high probability of iatrogenic perforation of the vertebral pedicle wall during the application of subaxial cervical pedicle screw (CPS). The goal of this study was to evaluate the accuracy of CPS insertion at C3-C7 in vitro using novel calipers based on the gravity line. METHODS: Nine cadaveric cervical spines underwent computed tomography scanning and preoperative design. A lateral fluoroscopic view was taken to measure the intra-operative sagittal angle by C-arm with hanging cross structured K-wires. By referring to the gravity line, caliper A was used to locate the entry point, while caliper B was employed to guide the screw insertion. Postoperative CT scans were performed to assess the accuracy of the screw placements, according to the Neo classification. RESULTS: Overall, 78 (88.6%) of the 88 pedicle screw placements were classified as grade 0 (correct position), 4 (4.5%) were grade 1 (non-critical perforation), 4 (4.5%) were grade 2 (critical perforation), and 2 (2.3%) were grade 3 (critical perforation). CONCLUSIONS: Using our novel calipers and referring to the gravity line was helpful for locating and guiding individual cervical pedicle screw insertions. PMID- 28727777 TI - 8-oxoguanine DNA glycosylase (OGG1) deficiency elicits coordinated changes in lipid and mitochondrial metabolism in muscle. AB - Oxidative stress resulting from endogenous and exogenous sources causes damage to cellular components, including genomic and mitochondrial DNA. Oxidative DNA damage is primarily repaired via the base excision repair pathway that is initiated by DNA glycosylases. 8-oxoguanine DNA glycosylase (OGG1) recognizes and cleaves oxidized and ring-fragmented purines, including 8-oxoguanine, the most commonly formed oxidative DNA lesion. Mice lacking the OGG1 gene product are prone to multiple features of the metabolic syndrome, including high-fat diet induced obesity, hepatic steatosis, and insulin resistance. Here, we report that OGG1-deficient mice also display skeletal muscle pathologies, including increased muscle lipid deposition and alterations in genes regulating lipid uptake and mitochondrial fission in skeletal muscle. In addition, expression of genes of the TCA cycle and of carbohydrate and lipid metabolism are also significantly altered in muscle of OGG1-deficient mice. These tissue changes are accompanied by marked reductions in markers of muscle function in OGG1-deficient animals, including decreased grip strength and treadmill endurance. Collectively, these data indicate a role for skeletal muscle OGG1 in the maintenance of optimal tissue function. PMID- 28727779 TI - Contemporary status of insecticide resistance in the major Aedes vectors of arboviruses infecting humans. AB - Both Aedes aegytpi and Ae. albopictus are major vectors of 5 important arboviruses (namely chikungunya virus, dengue virus, Rift Valley fever virus, yellow fever virus, and Zika virus), making these mosquitoes an important factor in the worldwide burden of infectious disease. Vector control using insecticides coupled with larval source reduction is critical to control the transmission of these viruses to humans but is threatened by the emergence of insecticide resistance. Here, we review the available evidence for the geographical distribution of insecticide resistance in these 2 major vectors worldwide and map the data collated for the 4 main classes of neurotoxic insecticide (carbamates, organochlorines, organophosphates, and pyrethroids). Emerging resistance to all 4 of these insecticide classes has been detected in the Americas, Africa, and Asia. Target-site mutations and increased insecticide detoxification have both been linked to resistance in Ae. aegypti and Ae. albopictus but more work is required to further elucidate metabolic mechanisms and develop robust diagnostic assays. Geographical distributions are provided for the mechanisms that have been shown to be important to date. Estimating insecticide resistance in unsampled locations is hampered by a lack of standardisation in the diagnostic tools used and by a lack of data in a number of regions for both resistance phenotypes and genotypes. The need for increased sampling using standard methods is critical to tackle the issue of emerging insecticide resistance threatening human health. Specifically, diagnostic doses and well-characterised susceptible strains are needed for the full range of insecticides used to control Ae. aegypti and Ae. albopictus to standardise measurement of the resistant phenotype, and calibrated diagnostic assays are needed for the major mechanisms of resistance. PMID- 28727780 TI - Comparative analysis of signature genes in PRRSV-infected porcine monocyte derived cells to different stimuli. AB - Monocyte-derived DCs (mDCs) are major target cells in porcine reproductive and respiratory syndrome virus (PRRSV) pathogenesis; however, the plasticity of mDCs in response to activation stimuli and PRRSV infection remains unstudied. In this study, we polarized mDCs, and applied genome-wide transcriptomic analysis and predicted protein-protein interaction networks to compare signature genes involved in mDCs activation and response to PRRSV infection. Porcine mDCs were polarized with mediators for 30 hours, then mock-infected, infected with PRRSV strain VR2332, or a highly pathogenic PRRSV strain (rJXwn06), for 5 h. Total RNA was extracted and used to construct sequencing libraries for RNA-Seq. Comparisons were made between each polarized and unpolarized group (i.e. mediator vs. PBS), and between PRRSV-infected and uninfected cells stimulated with the same mediator. Differentially expressed genes (DEG) from the comparisons were used for prediction of interaction networks affected by the viruses and mediators. The results showed that PRRSV infection inhibited M1-prone immune activity, downregulated genes, predicted network interactions related to cellular integrity, and inflammatory signaling in favor of M2 activity. Additionally, the number of DEG and predicted network interactions stimulated in HP-PRRSV infected mDCs was superior to the VR-2332 infected mDCs and conformed with HP-PRRSV pathogenicity. PMID- 28727781 TI - Escherichia coli mastitis strains: In vitro phenotypes and severity of infection in vivo. AB - Mastitis remains a major infection of dairy cows and an important issue for dairy farmers and the dairy industry, in particular infections due to Escherichia coli strains. So far, properties specific to E. coli causing mastitis remain ill defined. In an attempt to better understand the properties required for E. coli to trigger mastitis, we used a range of in vitro assays to phenotypically characterize four E. coli strains, including the prototypical E. coli mastitis strain P4, possessing different relative abilities to cause mastitis in a mouse model. Our results indicate that a certain level of serum resistance might be required for colonization of the mammary gland. Resistance to neutrophil killing is also likely to contribute to a slower clearance of bacteria and higher chances to colonize the udder. In addition, we show that the four different strains do induce a pro-inflammatory response by mammary epithelial cells but with different intensities. Interestingly, the prototypical mastitis strain P4 actually induces the less intense response while it is responsible for the most severe infections in vivo. Altogether, our results suggest that different strategies can be used by E. coli strains to colonize the mammary gland and cause mastitis. PMID- 28727782 TI - Detecting expression of 5T4 in CTCs and tumor samples from NSCLC patients. AB - The fetal oncogene 5T4 is a cell surface protein, with overexpression observed in a variety of cancers as compared to normal adult tissue. The ability to select patients with tumors that express high levels of 5T4 may enrich a clinical trial cohort with patients most likely to respond to 5T4 targeted therapy. To that end, we developed assays to measure 5T4 in both tumors and in circulating tumor cells (CTCs). We identified the presence of 5T4 in both adenocarcinoma and squamous cell carcinoma of lung, in all clinical stages and grades of disease. CTCs were identified in peripheral blood from the majority of patients with NSCLC, and 5T4 was detectable in most samples. Although 5T4 was present in both CTCs and tumors in most patients, there was no concordance between relative amount in either sample type. Clinical response rates of patients treated with the therapies directed against 5T4 in early stage clinical trials, as determined by these assays, may provide important insights into the biology of 5T4 in tumors and the mechanisms of action of 5T4-targeting therapy. PMID- 28727783 TI - The impact of local government investment on the carbon emissions reduction effect: An empirical analysis of panel data from 30 provinces and municipalities in China. AB - Among studies of the factors that influence carbon emissions and related regulations, economic aggregates, industrial structures, energy structures, population levels, and energy prices have been extensively explored, whereas studies from the perspective of fiscal leverage, particularly of local government investment (LGI), are rare. Of the limited number of studies on the effect of LGI on carbon emissions, most focus on its direct effect. Few studies consider regulatory effects, and there is a lack of emphasis on local areas. Using a cointegration test, a panel data model and clustering analysis based on Chinese data between 2000 and 2013, this study measures the direct role of LGI in carbon dioxide (CO2) emissions reduction. First, overall, within the sample time period, a 1% increase in LGI inhibits carbon emissions by 0.8906% and 0.5851% through its influence on the industrial structure and energy efficiency, respectively, with the industrial structure path playing a greater role than the efficiency path. Second, carbon emissions to some extent exhibit inertia. The previous year's carbon emissions impact the following year's carbon emissions by 0.5375%. Thus, if a reduction in carbon emissions in the previous year has a positive effect, then the carbon emissions reduction effect generated by LGI in the following year will be magnified. Third, LGI can effectively reduce carbon emissions, but there are significant regional differences in its impact. For example, in some provinces, such as Sichuan and Anhui, economic growth has not been decoupled from carbon emissions. Fourth, the carbon emissions reduction effect in the 30 provinces and municipalities sampled in this study can be classified into five categories-strong, relatively strong, medium, relatively weak and weak-based on the degree of local governments' regulation of carbon emissions. The carbon emissions reduction effect of LGI is significant in the western and central regions of China but not in the eastern and northeast regions. This study helps overcome the limitations of previous studies on the regulatory effects of LGI on carbon emissions, and the constructed model may more closely reflect actual economic conditions. Moreover, the current study can benefit countries similar to China that aim to objectively identify the impacts of their LGI on carbon emissions, and such countries can use it as a reference in the formulation of investment policies based on their economic and industrial characteristics. PMID- 28727784 TI - An NS5A single optimized method to determine genotype, subtype and resistance profiles of Hepatitis C strains. AB - The objective was to develop a method of HCV genome sequencing that allowed simultaneous genotyping and NS5A inhibitor resistance profiling. In order to validate the use of a unique RT-PCR for genotypes 1-5, 142 plasma samples from patients infected with HCV were analysed. The NS4B-NS5A partial region was successfully amplified and sequenced in all samples. In parallel, partial NS3 sequences were analyzed obtained for genotyping. Phylogenetic analysis showed concordance of genotypes and subtypes with a bootstrap >95% for each type cluster. NS5A resistance mutations were analyzed using the Geno2pheno [hcv] v0.92 tool and compared to the list of known Resistant Associated Substitutions recently published. In conclusion, this tool allows determination of HCV genotypes, subtypes and identification of NS5A resistance mutations. This single method can be used to detect pre-existing resistance mutations in NS5A before treatment and to check the emergence of resistant viruses while undergoing treatment in major HCV genotypes (G1-5) in the EU and the US. PMID- 28727785 TI - Novel CRISPR/Cas9 gene drive constructs reveal insights into mechanisms of resistance allele formation and drive efficiency in genetically diverse populations. AB - A functioning gene drive system could fundamentally change our strategies for the control of vector-borne diseases by facilitating rapid dissemination of transgenes that prevent pathogen transmission or reduce vector capacity. CRISPR/Cas9 gene drive promises such a mechanism, which works by converting cells that are heterozygous for the drive construct into homozygotes, thereby enabling super-Mendelian inheritance. Although CRISPR gene drive activity has already been demonstrated, a key obstacle for current systems is their propensity to generate resistance alleles, which cannot be converted to drive alleles. In this study, we developed two CRISPR gene drive constructs based on the nanos and vasa promoters that allowed us to illuminate the different mechanisms by which resistance alleles are formed in the model organism Drosophila melanogaster. We observed resistance allele formation at high rates both prior to fertilization in the germline and post-fertilization in the embryo due to maternally deposited Cas9. Assessment of drive activity in genetically diverse backgrounds further revealed substantial differences in conversion efficiency and resistance rates. Our results demonstrate that the evolution of resistance will likely impose a severe limitation to the effectiveness of current CRISPR gene drive approaches, especially when applied to diverse natural populations. PMID- 28727786 TI - Is there a relationship between geographic distance and uptake of HIV testing services? A representative population-based study of Chinese adults in Guangzhou, China. AB - Achieving high coverage of HIV testing services is critical in many health systems, especially where HIV testing services remain centralized and inconvenient for many. As a result, planning the optimal spatial distribution of HIV testing sites is increasingly important. We aimed to assess the relationship between geographic distance and uptake of HIV testing services among the general population in Guangzhou, China. Utilizing spatial epidemiological methods and stratified household random sampling, we studied 666 adults aged 18-59. Computer assisted interviews assessed self-reported HIV testing history. Spatial scan statistic assessed the clustering of participants who have ever been tested for HIV, and two-level logistic regression models assessed the association between uptake of HIV testing and the mean driving distance from the participant's residence to all HIV testing sites in the research sites. The percentage of participants who have ever been tested for HIV was 25.2% (168/666, 95%CI: 21.9%, 28.5%), and the majority (82.7%) of participants tested for HIV in Centres for Disease Control and Prevention, public hospitals or STIs clinics. None reported using self-testing. Spatial clustering analyses found a hotspot included 48 participants who have ever been tested for HIV and 25.8 expected cases (Rate Ratio = 1.86, P = 0.002). Adjusted two-level logistic regression found an inverse relationship between geographic distance (kilometers) and ever being tested for HIV (aOR = 0.90, 95%CI: 0.84, 0.96). Married or cohabiting participants (aOR = 2.14, 95%CI: 1.09, 4.20) and those with greater social support (aOR = 1.04, 95%CI: 1.01, 1.07) were more likely to be tested for HIV. Our findings underscore the importance of considering the geographical distribution of HIV testing sites to increase testing. In addition, expanding HIV testing coverage by introducing non-facility based HIV testing services and self-testing might be useful to achieve the goal that 90% of people living with HIV knowing their HIV status by the year 2020. PMID- 28727787 TI - Feasibility of a 3D-printed anthropomorphic patient-specific head phantom for patient-specific quality assurance of intensity-modulated radiotherapy. AB - This study evaluated the feasibility of utilizing a 3D-printed anthropomorphic patient-specific head phantom for patient-specific quality assurance (QA) in intensity-modulated radiotherapy (IMRT). Contoured left and right head phantoms were converted from DICOM to STL format. Fused deposition modeling (FDM) was used to construct an anthropomorphic patient-specific head phantom with a 3D printer. An established QA technique and the patient-specific head phantom were used to compare the calculated and measured doses. When the established technique was used to compare the calculated and measured doses, the gamma passing rate for gamma <= 1 was 97.28%, while the gamma failure rate for gamma > 1 was 2.72%. When the 3D-printed patient-specific head phantom was used, the gamma passing rate for gamma <= 1 was 95.97%, and the gamma failure rate for gamma > 1 was 4.03%. The 3D printed patient-specific head phantom was concluded to be highly feasible for patient-specific QA prior to complicated radiotherapy procedures such as IMRT. PMID- 28727788 TI - Oecomys catherinae (Sigmodontinae, Cricetidae): Evidence for chromosomal speciation? AB - Among the Oryzomyini (Sigmodontinae), Oecomys is the most speciose, with 17 species. This genus presents high karyotypic diversity (2n = 54 to 2n = 86) and many taxonomic issues at the species level because of the presence of cryptic species and the overlap of morphological characters. For these reasons the real number of species of Oecomys may be underestimated. With the aim of verifying if the taxon Oecomys catherinae is composed of more than one species, we made comparative studies on two populations from two regions of Brazil, one from the Amazon and another from the Atlantic Forest using both classical cytogenetics (G- and C-banding) and comparative genomic mapping with whole chromosome probes of Hylaeamys megacephalus (HME), molecular data (cytochrome b mitochondrial DNA) and morphology. Our results confirm that Oecomys catherinae occurs in the southeast Amazon, and reveal a new karyotype for the species (2n = 62, FNa = 62). The comparative genomic analysis with HME probes identified chromosomal homeologies between both populations and rearrangements that are responsible for the different karyotypes. We compared our results in Sigmodontinae genera with other studies that also used HME probes. These chromosomal differences together with the absence of consistent differentiation between the two populations on morphological and molecular analyses suggest that these populations may represent cryptic species. PMID- 28727789 TI - lumpGEM: Systematic generation of subnetworks and elementally balanced lumped reactions for the biosynthesis of target metabolites. AB - In the post-genomic era, Genome-scale metabolic networks (GEMs) have emerged as invaluable tools to understand metabolic capabilities of organisms. Different parts of these metabolic networks are defined as subsystems/pathways, which are sets of functional roles to implement a specific biological process or structural complex, such as glycolysis and TCA cycle. Subsystem/pathway definition is also employed to delineate the biosynthetic routes that produce biomass building blocks. In databases, such as MetaCyc and SEED, these representations are composed of linear routes from precursors to target biomass building blocks. However, this approach cannot capture the nested, complex nature of GEMs. Here we implemented an algorithm, lumpGEM, which generates biosynthetic subnetworks composed of reactions that can synthesize a target metabolite from a set of defined core precursor metabolites. lumpGEM captures balanced subnetworks, which account for the fate of all metabolites along the synthesis routes, thus encapsulating reactions from various subsystems/pathways to balance these metabolites in the metabolic network. Moreover, lumpGEM collapses these subnetworks into elementally balanced lumped reactions that specify the cost of all precursor metabolites and cofactors. It also generates alternative subnetworks and lumped reactions for the same metabolite, accounting for the flexibility of organisms. lumpGEM is applicable to any GEM and any target metabolite defined in the network. Lumped reactions generated by lumpGEM can be also used to generate properly balanced reduced core metabolic models. PMID- 28727790 TI - Correction: Hybrid Dysfunction Expressed as Elevated Metabolic Rate in Male Ficedula Flycatchers. AB - [This corrects the article DOI: 10.1371/journal.pone.0161547.]. PMID- 28727791 TI - Predisposition to insulin resistance and obesity due to staple consumption of rice: Amylose content versus germination status. AB - Type 2 diabetes is a metabolic disorder with established, well-defined precursors. Obesity and insulin resistance are amongst most important factors in predisposition to diabetes. Rice is a staple for about half the global population and its consumption has been strongly linked with diabetogenesis. We assert that tackling the prevalence of predisposing factors by modifying certain rice cultivars could reduce the global burden of obesity and insulin resistance, and by extension type 2 diabetes. Several rice cultivars with various properties were fed to nulliparous rats (five weeks old at the start of the experiment) for 90 days. They were then returned to a diet of standard pellets and mated with males raised on a standard diet. The resulting pups and dams were investigated for obesity and insulin resistance markers. We found that germination did more to reduce predisposition to obesity and insulin resistance than high amylose content. The combined reducing effect of germination and high amylose content on predisposition to obesity and insulin resistance was greater than the sum of their independent effects. Polished (white) rice with a low amylose content predisposed dams on a high-fat diet to markers of insulin resistance and obesity and this predisposition was inherited (in biochemical terms) by their F1 offspring. Overall, the results suggest that harnessing the beneficial properties of germination and amylose in rice would reduce the burden of obesity and insulin resistance, which are known to be key risk factors for development of type 2 diabetes. PMID- 28727793 TI - Effect of child marriage on girls' school dropout in Nepal: Analysis of data from the Multiple Indicator Cluster Survey 2014. AB - School dropout and child marriage are interrelated outcomes that have an enormous impact on adolescent girls. However, the literature reveals gaps in the empirical evidence on the link between child marriage and the dropout of girls from school. This study identifies the 'tipping point' school grades in Nepal when the risk of dropout due to marriage is highest, measures the effect of child marriage on girls' school dropout rates, and assesses associated risk factors. Weighted percentages were calculated to examine the grades at highest risk and the distribution of reasons for discontinuing school. Using the Nepal Multiple Indicator Cluster Survey (MICS) 2014 data, we estimated the effect of marriage on school attendance and dropout among girls aged 15-17 by constructing logistic regression models. A multivariate logistic regression model was used to assess risk factors of school dropout due to child marriage. It was found that early marriage is the most common reason given for leaving school. Overall, the risk of school dropout due to marriage heightens after girls complete the fifth or sixth grade. The risk of girls' dropping out peaks in the seventh and eighth grades and remains noteworthy in the ninth and tenth grades. Married girls in Nepal are 10 times more likely to drop out than their unmarried peers. Little or no education of the household head, belonging to the Kirat religion, and membership of a traditionally disadvantaged social class each elevate the risk of school dropout due to early marriage. The findings underscore the need to delay girl's marriage so as to reduce girls' school dropout in Nepal. School-based programmes aimed at preventing child marriage should target girls from the fifth grade because they are at increased risk of dropping out, as well as prioritizing girls from disadvantaged groups. PMID- 28727792 TI - Aging, working memory capacity and the proactive control of recollection: An event-related potential study. AB - The present study investigated the role of working memory capacity (WMC) in the control of recollection in young and older adults. We used electroencephalographic event-related potentials (ERPs) to examine the effects of age and of individual differences in WMC on the ability to prioritize recollection according to current goals. Targets in a recognition exclusion task were words encoded using two alternative decisions. The left parietal ERP old/new effect was used as an electrophysiological index of recollection, and the selectivity of recollection measured in terms of the difference in its magnitude according to whether recognized items were targets or non-targets. Young adults with higher WMC showed greater recollection selectivity than those with lower WMC, while older adults showed nonselective recollection which did not vary with WMC. The data suggest that aging impairs the ability to engage cognitive control effectively to prioritize what will be recollected. PMID- 28727794 TI - Lie construction affects information storage under high memory load condition. AB - Previous studies indicate that lying consumes cognitive resources, especially working memory (WM) resources. Considering the dual functions that WM might play in lying: holding the truth-related information and turning the truth into lies, the present study examined the relationship between the information storage and processing in the lie construction. To achieve that goal, a deception task based on the old/new recognition paradigm was designed, which could manipulate two levels of WM load (low-load task using 4 items and high-load task using 6 items) during the deception process. The analyses based on the amplitude of the contralateral delay activity (CDA), a proved index of the number of representations being held in WM, showed that the CDA amplitude was lower in the deception process than that in the truth telling process under the high-load condition. In contrast, under the low-load condition, no CDA difference was found between the deception and truth telling processes. Therefore, we deduced that the lie construction and information storage compete for WM resources; when the available WM resources cannot meet this cognitive demand, the WM resources occupied by the information storage would be consumed by the lie construction. PMID- 28727795 TI - Effect of therapy switch on time to second-line antiretroviral treatment failure in HIV-infected patients. AB - BACKGROUND: Switch from first line antiretroviral therapy (ART) to second-line ART is common in clinical practice. However, there is limited knowledge of to which extent different reason for therapy switch are associated with differences in long-term consequences and sustainability of the second line ART. MATERIAL AND METHODS: Data from 869 patients with 14601 clinical visits between 1999-2014 were derived from the national cohort database. Reason for therapy switch and viral load (VL) levels at first-line ART failure were compared with regard to outcome of second line ART. Using the Laplace regression model we analyzed the median, 10th, 20th, 30th and 40th percentile of time to viral failure (VF). RESULTS: Most patients (n = 495; 57.0%) switched from first-line to second-line ART without VF. Patients switching due to detectable VL with (n = 124; 14.2%) or without drug resistance mutations (DRM) (n = 250; 28.8%) experienced VF to their second line regimen sooner (median time, years: 3.43 (95% CI 2.90-3.96) and 3.20 (95% 2.65 3.75), respectively) compared with those who switched without VF (4.53 years). Furthermore level of VL at first-line ART failure had a significant impact on failure of second-line ART starting after 2.5 years of second-line ART. CONCLUSIONS: In the context of life-long therapy, a median time on second line ART of 4.53 years for these patients is short. To prolong time on second-line ART, further studies are needed on the reasons for therapy changes. Additionally patients with a high VL at first-line VF should be more frequently monitored the period after the therapy switch. PMID- 28727796 TI - Effects of health risk assessment and counselling on physical activity in older people: A pragmatic randomised trial. AB - BACKGROUND: Interventions to increase physical activity (PA) among older community-dwelling adults may be enhanced by using multidimensional health risk assessment (HRA) as a basis for PA counselling. METHODS: The study was conducted among nondisabled but mostly frail persons 65 years of age and older at an ambulatory geriatric clinic in Bucharest, Romania. From May to July 2014, 200 participants were randomly allocated to intervention and control groups. Intervention group participants completed an initial HRA questionnaire and then had monthly counselling sessions with a geriatrician over a period of six months that were aimed at increasing low or maintaining higher PA. Counselling also addressed the older persons' concomitant health risks and problems. The primary outcome was PA at six months (November 2014 to February 2015) evaluated with the International Physical Activity Questionnaire. RESULTS: At baseline, PA levels were similar in intervention and control groups (median 1089.0, and 1053.0 MET [metabolic equivalent of task] minutes per week, interquartile ranges 606.0 1401.7, and 544.5-1512.7 MET minutes per week, respectively). Persons in the intervention group had an average of 11.2 concomitant health problems and risks (e.g., pain, depressive mood, hypertension). At six months, PA increased in the intervention group by a median of 180.0 MET minutes per week (95% confidence interval (CI) 43.4-316.6, p = 0.01) to 1248.8 MET minutes per week. In the control group, PA decreased by a median of 346.5 MET minutes per week (95% CI 178.4-514.6, p<0.001) to 693.0 MET minutes per week due to a seasonal effect, resulting in a difference of 420.0 MET minutes per week (95% CI 212.7-627.3, p< 0.001) between groups. CONCLUSION: The use of HRA to inform individualized PA counselling is a promising method for achieving improvements in PA, and ultimately health and longevity among large groups of community-dwelling older persons. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number: ISRCTN11166046. PMID- 28727797 TI - Prophylactic supplementation of resveratrol is more effective than its therapeutic use against doxorubicin induced cardiotoxicity. AB - Resveratrol (RSV), a polyphenolic compound and naturally occurring phytoalexin, has been reported to exert cardio-protective effects in several animal studies. However, the outcome of initial clinical trials with RSV was less effective compared to pre-clinical studies. Therefore, RSV treatment protocols need to be optimized. In this study we evaluated prophylactic versus therapeutic effect of resveratrol (RSV) in mitigating doxorubicin (Dox)-induced cardiac toxicity in rats. To investigate prophylactic effects, RSV was supplemented for 2 weeks along with Dox administration. After 2 weeks, Dox treatment was stopped and RSV was continued for another 4 weeks. To study therapeutic effects, RSV treatment was initiated after 2 weeks of Dox administration and continued for 4 weeks. Both prophylactic and therapeutic use of RSV mitigated Dox induced deterioration of cardiac function as assessed by echocardiography. Also RSV treatment (prophylactic and therapeutic) prevented Dox induced myocardial damage as measured by cardiac enzymes (LDH and CK-MB) in serum. Which was associated with decrease in Dox induced myocardial apoptosis and fibrosis. Interestingly our study also reveals that prophylactic use of RSV was more effective than its therapeutic use in mitigating Dox induced apoptosis and fibrosis in the myocardium. Therefore, prophylactic use of resveratrol may be projected as a possible future adjuvant therapy to minimize cardiotoxic side effects of doxorubicin in cancer patients. PMID- 28727798 TI - Cloning and expression of genes encoding heat shock proteins in Liriomyza trifolii and comparison with two congener leafminer species. AB - The polyphagous agromyzid fly, Liriomyza trifolii, is a significant and important insect pest of ornamental and vegetable crops worldwide. The adaptation of insects to different environments is facilitated by heat shock proteins (HSPs), which play an important role in acclimation to thermal stress. In this study, we cloned and characterized five HSP-encoding genes of L. trifolii (Lthsp20, Lthsp40, Lthsp60, Lthsp70, and Lthsp90) and monitored their expression under different thermal stresses using real-time quantitative PCR. Pupae of L. trifolii were exposed to 19 different temperatures ranging from -20 to 45 degrees C. The results revealed that Lthsp20, Lthsp40, Lthsp70 and Lthsp90 were significantly upregulated in response to both heat and cold stress, while Lthsp60 was induced only by heat temperatures. The temperatures of the onset (Ton) and maximal (Tmax) expression of the five Lthsps were also determined and compared with published Ton and Tmax values of homologous genes in L. sativae and L. huidobrensis. Although L. trifolii occurs primarily in southern China, it has cold tolerance comparable with the other two Liriomyza species. Based on the heat shock proteins expression patterns, L. trifolii has the capacity to tolerate extreme temperatures and the potential to disseminate to northern regions of China. PMID- 28727800 TI - Demographic disequilibrium in living nautiloids (Nautilus and Allonautilus): Canary in the coal mines? AB - Averaged demographic data from previously unfished populations of Nautilus and Allonautilus (Cephalopoda) provide a baseline to determine if a population is undisturbed and in "equilibrium" or is in "disequilibrium" as a result of fishery pressure. Data are available for previously undisturbed local nautiloid populations in Papua New Guinea, Australia, Indonesia, Fiji, Palau, American Samoa, New Caledonia and Vanuatu (total n = 2,669 live-caught, tagged and released animals). The data show that unfished populations average ~75% males and ~74% mature animals. By contrast, unpublished, anecdotal and historical records since 1900 from the heavily fished central Philippines have shown a persistent decline in trap yields and a change in demographics of N. pompilius. By 1979, a sample of fished live-caught animals (n = 353) comprised only ~28% males and ~27% mature animals. Continued uncontrolled trapping caused collapse of the fishery and the shell industry has moved elsewhere, including Indonesia. In addition, we show that estimated rates of population decline are offered by unpublished tag release records in unfished Palau. These data show that patterns of trap yields and demographic differences between fished and unfished populations in relative age class and sex ratios can indicate disequilibria wrought by fisheries pressure that can render local populations inviable. Given adequate samples (n >=100 live caught animals), a threshold of <50% males and mature animals in fished populations should signal the need to initiate curative conservation initiatives. The current trajectory of uncontrolled nautiloid fisheries can only mean trouble and possibly extinction of local populations of this ancient, iconic molluscan lineage. PMID- 28727799 TI - Atlantic salmon cardiac primary cultures: An in vitro model to study viral host pathogen interactions and pathogenesis. AB - Development of Salmon Cardiac Primary Cultures (SCPCs) from Atlantic salmon pre hatch embryos and their application as in vitro model for cardiotropic viral infection research are described. Producing SCPCs requires plating of trypsin dissociated embryos with subsequent targeted harvest from 24h up to 3 weeks, of relevant tissues after visual identification. SCPCs are then transferred individually to chambered wells for culture in isolation, with incubation at 15 22 degrees . SCPCs production efficiency was not influenced by embryo's origin (0.75/ farmed or wild embryo), but mildly influenced by embryonic developmental stage (0.3 decline between 380 and 445 accumulated thermal units), and strongly influenced by time of harvest post-plating (0.6 decline if harvested after 72 hours). Beating rate was not significantly influenced by temperature (15-22 degrees ) or age (2-4 weeks), but was significantly lower on SCPCs originated from farmed embryos with a disease resistant genotype (F = 5.3, p<0.05). Two distinct morphologies suggestive of an ex vivo embryonic heart and a de novo formation were observed sub-grossly, histologically, ultra-structurally and with confocal microscopy. Both types contained cells consistent with cardiomyocytes, endothelium, and fibroblasts. Ageing of SCPCs in culture was observed with increased auto fluorescence in live imaging, and as myelin figures and cellular degeneration ultra-structurally. The SCPCs model was challenged with cardiotropic viruses and both the viral load and the mx gene expression were measurable along time by qPCR. In summary, SCPCs represent a step forward in salmon cardiac disease research as an in vitro model that partially incorporates the functional complexity of the fish heart. PMID- 28727801 TI - Proponent or collaborative: Physician perspectives and approaches to disease modifying therapies in sickle cell disease. AB - Sickle cell disease (SCD) is an inherited blood disorder that primarily affects African-American and other ethnic minority populations. There are three available disease-modifying therapies for sickle cell disease: hydroxyurea (HU), bone marrow transplantation (BMT), and chronic blood transfusion (CBT). Since these treatments vary in their therapeutic intent, efficacy in preventing progression of the disease, short and long-term adverse effects, costs and patient burden, the decision-making process regarding these therapies is complicated for both the patient and healthcare provider. While previous research has focused on the patient perspective of treatment-related decision making, there is a paucity of research investigating the physician perspective of treatment-related decision making. We conducted a qualitative study with physicians who were experts in the field of SCD. Interviews focused on physician perceptions of patient decisional needs as well as physicians' approach to decision making regarding disease modifying therapies in SCD. Thirty-six physician interviews were analyzed, with a focus on their perspectives regarding available treatment options and on how they approach decision making with patients. We identified two narrative approaches. The Collaborative approach (CA) was characterized by emphasizing the need to discuss all possible treatment options to ensure that the patient and/or family was equipped to make an informed decision. The Proponent approach (PA) was characterized by strongly advocating a pre-determined treatment plan and providing patients/families with information, with the objective of convincing them to accept the treatment. An interplay of patient-related and disease-related factors, decision type and physician-related factors, as well as institutional frameworks, influenced physician perspectives on treatment options and decision making regarding these therapies. These findings point to the potential value of developing systems to foster patient engagement as a way of facilitating shared decision making. PMID- 28727802 TI - Diagnostic accuracy of procalcitonin, neutrophil-lymphocyte count ratio, C reactive protein, and lactate in patients with suspected bacterial sepsis. AB - BACKGROUND: Early recognition is a key factor to achieve improved outcomes for septic patients. Combinations of biomarkers, as opposed to single ones, may improve timely diagnosis and survival. We investigated the performance characteristics of sepsis biomarkers, alone and in combination, for diagnosis of verified bacterial sepsis using Sepsis-2 and Sepsis-3 criteria, respectively. METHODS: Procalcitonin (PCT), neutrophil-lymphocyte count ratio (NLCR), C reactive protein (CRP), and lactate were determined in a total of 1,572 episodes of adult patients admitted to the emergency department on suspicion of sepsis. All sampling were performed prior to antibiotic administration. Discriminant analysis was used to construct two composite biomarkers consisting of linear combinations of the investigated biomarkers, one including three selected biomarkers (i.e., NLCR, CRP, and lactate), and another including all four (i.e., PCT, NLCR, CRP, and lactate). The diagnostic performances of the composite biomarkers as well as the individual biomarkers were compared using the area under the receiver operating characteristic curve (AUC). RESULTS: For diagnosis of bacterial sepsis based on Sepsis-3 criteria, the AUC for PCT (0.68; 95% CI 0.65-0.71) was comparable to the AUCs for the both composite biomarkers. Using the Sepsis-2 criteria for bacterial sepsis diagnosis, the AUC for the NLCR (0.68; 95% CI 0.65-0.71) but not for the other single biomarkers, was equal to the AUCs for the both composite biomarkers. For diagnosis of severe bacterial sepsis or septic shock based on the Sepsis-2 criteria, the AUCs for both composite biomarkers were significantly greater than those of the single biomarkers (0.85; 95% CI 0.82-0.88 for the composite three-biomarker, and 0.86; 95% CI 0.83-0.89 for the composite four-biomarker). CONCLUSIONS: Combinations of biomarkers can improve the diagnosis of verified bacterial sepsis in the most critically ill patients, but in less severe septic conditions either the NLCR or PCT alone exhibit equivalent performance. PMID- 28727803 TI - Role of fomites in SARS transmission during the largest hospital outbreak in Hong Kong. AB - The epidemic of severe acute respiratory syndrome (SARS) had a significant effect on global society in the early 2000s and the potential of its resurgence exists. Studies on the modes of transmission of SARS are limited though a number of outbreak studies have revealed the possible airborne route. To develop more specific and effective control strategies, we conducted a detailed mechanism based investigation that explored the role of fomite transmission in the well known Ward 8A outbreak. We considered three hypothetical transmission routes, i.e., the long-range airborne, fomite and combined routes, in 1,744 scenarios with combinations of some important parameters. A multi-agent model was used to predict the infection risk distributions of the three hypothetical routes. Model selection was carried out for different scenarios to compare the distributions of infection risk with that of the reported attack rates and select the hypotheses with the best fitness. Our results reveal that under the assumed conditions, the SARS coronavirus was most possible to have spread via the combined long-range airborne and fomite routes, and that the fomite route played a non-negligible role in the transmission. PMID- 28727804 TI - Effects of pre-surgical administration of prostaglandin analogs on the outcome of trabeculectomy. AB - For primary open angle glaucoma (POAG), laser treatment or surgery is used when the target intraocular pressure (IOP) cannot be achieved by pharmacological agents, such as prostaglandin (PG) analogs; these drugs also have varied effects. We retrospectively reviewed the medical records of 74 POAG patients (74 eyes) whose IOP was inadequately controlled by PG analogs (bimatoprost [13 eyes], latanoprost [34 eyes], tafluprost [11 eyes], and travoprost [16 eyes]) and underwent primary trabeculectomy. The proportion of patients with no recurrent IOP elevation within 24 months post-trabeculectomy was significantly (P < 0.001) lower in the bimatoprost group (31.3%) than in the latanoprost (83.2%), tafluprost (45.5%), or travoprost groups (65.6%). Deepening of the upper eyelid sulcus (DUES) was observed before trabeculectomy in 18 of 74 eyes (24.3%) treated with bimatoprost (9 eyes; 50.0%), latanoprost (3 eyes; 16.7%), tafluprost (1 eye; 5.5%) and travoprost (5 eyes; 27.8%). The proportion of patients with no recurrent IOP elevation up to 24 months post-trabeculectomy was significantly (P < 0.0001) lower in the DUES(+) group (34.7%) than in the DUES(-) group (74.3%). Multivariate stepwise logistic regression analysis, with no recurrent IOP elevation used as dependent variable, and bimatoprost, latanoprost, travoprost, tafluprost, beta-blocker, carbonic anhydrase inhibitor, brimonidine, gender, age, preoperative IOP, mean deviation, duration of PG analog use before surgery, and the number of ophthalmic solutions used as independent variables, identified only bimatoprost as a significant independent factor (P = 0.0368). Thus, the outcome of trabeculectomy varied depending on the PG analog used preoperatively, and bimatoprost use was associated with a high risk of recurrent IOP elevation up to 2 years post-trabeculectomy. This may indicate that the incidence of DUES differed with the PG analog used. Patients with glaucoma who are treated with bimatoprost should be monitored for DUES, and when these patients undergo trabeculectomy, the postoperative course of IOP should be followed carefully. PMID- 28727806 TI - GenoCore: A simple and fast algorithm for core subset selection from large genotype datasets. AB - Selecting core subsets from plant genotype datasets is important for enhancing cost-effectiveness and to shorten the time required for analyses of genome-wide association studies (GWAS), and genomics-assisted breeding of crop species, etc. Recently, a large number of genetic markers (>100,000 single nucleotide polymorphisms) have been identified from high-density single nucleotide polymorphism (SNP) arrays and next-generation sequencing (NGS) data. However, there is no software available for picking out the efficient and consistent core subset from such a huge dataset. It is necessary to develop software that can extract genetically important samples in a population with coherence. We here present a new program, GenoCore, which can find quickly and efficiently the core subset representing the entire population. We introduce simple measures of coverage and diversity scores, which reflect genotype errors and genetic variations, and can help to select a sample rapidly and accurately for crop genotype dataset. Comparison of our method to other core collection software using example datasets are performed to validate the performance according to genetic distance, diversity, coverage, required system resources, and the number of selected samples. GenoCore selects the smallest, most consistent, and most representative core collection from all samples, using less memory with more efficient scores, and shows greater genetic coverage compared to the other software tested. GenoCore was written in R language, and can be accessed online with an example dataset and test results at https://github.com/lovemun/Genocore. PMID- 28727805 TI - Turgor-responsive starch phosphorylation in Oryza sativa stems: A primary event of starch degradation associated with grain-filling ability. AB - Grain filling ability is mainly affected by the translocation of carbohydrates generated from temporarily stored stem starch in most field crops including rice (Oryza sativa L.). The partitioning of non-structural stem carbohydrates has been recognized as an important trait for raising the yield ceiling, yet we still do not fully understand how carbohydrate partitioning occurs in the stems. In this study, two rice subspecies that exhibit different patterns of non-structural stem carbohydrates partitioning, a japonica-dominant cultivar, Momiroman, and an indica-dominant cultivar, Hokuriku 193, were used as the model system to study the relationship between turgor pressure and metabolic regulation of non structural stem carbohydrates, by combining the water status measurement with gene expression analysis and a dynamic prefixed 13C tracer analysis using a mass spectrometer. Here, we report a clear varietal difference in turgor-associated starch phosphorylation occurred at the initiation of non-structural carbohydrate partitioning. The data indicated that starch degradation in Hokuriku 193 stems occurred at full-heading, 5 days earlier than in Momiroman, contributing to greater sink filling. Gene expression analysis revealed that expression pattern of the gene encoding alpha-glucan, water dikinase (GWD1) was similar between two varieties, and the maximum expression level in Hokuriku 193, reached at full heading (4 DAH), was greater than in Momiroman, leading to an earlier increase in a series of amylase-related gene expression in Hokuriku 193. In both varieties, peaks in turgor pressure preceded the increases in GWD1 expression, and changes in GWD1 expression was correlated with turgor pressure. Additionally, a threshold is likely to exist for GWD1 expression to facilitate starch degradation. Taken together, these results raise the possibility that turgor-associated starch phosphorylation in cells is responsible for the metabolism that leads to starch degradation. Because the two cultivars exhibited remarkable varietal differences in the pattern of non-structural carbohydrate partitioning, our findings propose that the observed difference in grain-filling ability originated from turgor associated regulation of starch phosphorylation in stem parenchyma cells. Further understanding of the molecular mechanism of turgor-regulation may provide a new selection criterion for breaking the yield barriers in crop production. PMID- 28727807 TI - Digoxin reveals a functional connection between HIV-1 integration preference and T-cell activation. AB - HIV-1 integrates more frequently into transcribed genes, however the biological significance of HIV-1 integration targeting has remained elusive. Using a selective high-throughput chemical screen, we discovered that the cardiac glycoside digoxin inhibits wild-type HIV-1 infection more potently than HIV-1 bearing a single point mutation (N74D) in the capsid protein. We confirmed that digoxin repressed viral gene expression by targeting the cellular Na+/K+ ATPase, but this did not explain its selectivity. Parallel RNAseq and integration mapping in infected cells demonstrated that digoxin inhibited expression of genes involved in T-cell activation and cell metabolism. Analysis of >400,000 unique integration sites showed that WT virus integrated more frequently than N74D mutant within or near genes susceptible to repression by digoxin and involved in T-cell activation and cell metabolism. Two main gene networks down-regulated by the drug were CD40L and CD38. Blocking CD40L by neutralizing antibodies selectively inhibited WT virus infection, phenocopying digoxin. Thus the selectivity of digoxin depends on a combination of integration targeting and repression of specific gene networks. The drug unmasked a functional connection between HIV-1 integration and T-cell activation. Our results suggest that HIV-1 evolved integration site selection to couple its early gene expression with the status of target CD4+ T-cells, which may affect latency and viral reactivation. PMID- 28727809 TI - Optical modelling of a supplementary tunable air-spaced goggle lens for rodent eye imaging. AB - Aberration variations severely degrade retinal imaging in small animal eyes. Previously, the approach of a goggle lens with a matching corneal index was proposed to overcome the on-axis resolution limit of static imaging systems, which allows the use of the full eye pupil. But this technique didn't address the problem of the large power variation, and the ensuing aberration on and off-axis, when dealing with small animal eyes. In this study, we present the concept of a tunable goggle lens, designed to compensate individual ocular aberration for different rodent eye powers. Ray tracing evidences that lens-fitted goggles permit, not only to adjust individual eyes power, but also to surpass conventional adaptive correction technique over large viewing angle, provided a minimum use of two spaced liquids. We believe that the overlooked advantage of the 3D lens function is a seminal finding for further technological advancements in widefield retinal imaging. PMID- 28727808 TI - Automatic mouse ultrasound detector (A-MUD): A new tool for processing rodent vocalizations. AB - House mice (Mus musculus) emit complex ultrasonic vocalizations (USVs) during social and sexual interactions, which have features similar to bird song (i.e., they are composed of several different types of syllables, uttered in succession over time to form a pattern of sequences). Manually processing complex vocalization data is time-consuming and potentially subjective, and therefore, we developed an algorithm that automatically detects mouse ultrasonic vocalizations (Automatic Mouse Ultrasound Detector or A-MUD). A-MUD is a script that runs on STx acoustic software (S_TOOLS-STx version 4.2.2), which is free for scientific use. This algorithm improved the efficiency of processing USV files, as it was 4 12 times faster than manual segmentation, depending upon the size of the file. We evaluated A-MUD error rates using manually segmented sound files as a 'gold standard' reference, and compared them to a commercially available program. A-MUD had lower error rates than the commercial software, as it detected significantly more correct positives, and fewer false positives and false negatives. The errors generated by A-MUD were mainly false negatives, rather than false positives. This study is the first to systematically compare error rates for automatic ultrasonic vocalization detection methods, and A-MUD and subsequent versions will be made available for the scientific community. PMID- 28727811 TI - Factors limiting sulfolane biodegradation in contaminated subarctic aquifer substrate. AB - Sulfolane, a water-soluble organosulfur compound, is used industrially worldwide and is associated with one of the largest contaminated groundwater plumes in the state of Alaska. Despite being widely used, little is understood about the degradation of sulfolane in the environment, especially in cold regions. We conducted aerobic and anaerobic microcosm studies to assess the biological and abiotic sulfolane degradation potential of contaminated subarctic aquifer groundwater and sediment from Interior Alaska. We also investigated the impacts of nutrient limitations and hydrocarbon co-contamination on sulfolane degradation. We found that sulfolane underwent biodegradation aerobically but not anaerobically under nitrate, sulfate, or iron-reducing conditions. No abiotic degradation activity was detectable under either oxic or anoxic conditions. Nutrient addition stimulated sulfolane biodegradation in sediment slurries at high sulfolane concentrations (100 mg L-1), but not at low sulfolane concentrations (500 MUg L-1), and nutrient amendments were necessary to stimulate sulfolane biodegradation in incubations containing groundwater only. Hydrocarbon co-contamination retarded aerobic sulfolane biodegradation rates by ~30%. Our study is the first to investigate the sulfolane biodegradation potential of subarctic aquifer substrate and identifies several important factors limiting biodegradation rates. We concluded that oxygen is an important factor limiting natural attenuation of this sulfolane plume, and that nutrient amendments are unlikely to accelerate biodegradation within in the plume, although they may biostimulate degradation in ex situ groundwater treatment applications. Future work should be directed at elucidating the identity of indigenous sulfolane degrading microorganisms and determining their distribution and potential activity in the environment. PMID- 28727810 TI - Cucumber mosaic virus coat protein modulates the accumulation of 2b protein and antiviral silencing that causes symptom recovery in planta. AB - Shoot apical meristems (SAM) are resistant to most plant viruses due to RNA silencing, which is restrained by viral suppressors of RNA silencing (VSRs) to facilitate transient viral invasion of the SAM. In many cases chronic symptoms and long-term virus recovery occur, but the underlying mechanisms are poorly understood. Here, we found that wild-type Cucumber mosaic virus (CMVWT) invaded the SAM transiently, but was subsequently eliminated from the meristems. Unexpectedly, a CMV mutant, designated CMVRA that harbors an alanine substitution in the N-terminal arginine-rich region of the coat protein (CP) persistently invaded the SAM and resulted in visible reductions in apical dominance. Notably, the CMVWT virus elicited more potent antiviral silencing than CMVRA in newly emerging leaves of infected plants. However, both viruses caused severe symptoms with minimal antiviral silencing effects in the Arabidopsis mutants lacking host RNA-DEPENDENT RNA POLYMERASE 6 (RDR6) or SUPPRESSOR OF GENE SILENCING 3 (SGS3), indicating that CMVWT induced host RDR6/SGS3-dependent antiviral silencing. We also showed that reduced accumulation of the 2b protein is elicited in the CMVWT infection and consequently rescues potent antiviral RNA silencing. Indeed, co infiltration assays showed that the suppression of posttranscriptional gene silencing mediated by 2b is more severely compromised by co-expression of CPWT than by CPRA. We further demonstrated that CPWT had high RNA binding activity leading to translation inhibition in wheat germ systems, and CPWT was associated with SGS3 into punctate granules in vivo. Thus, we propose that the RNAs bound and protected by CPWT possibly serve as templates of RDR6/SGS3 complexes for siRNA amplification. Together, these findings suggest that the CMV CP acts as a central hub that modulates antiviral silencing and VSRs activity, and mediates viral self-attenuation and long-term symptom recovery. PMID- 28727812 TI - Electrically controlled cloud of bulk nanobubbles in water solutions. AB - Using different experimental techniques we visualize a cloud of gas in water that is produced electrochemically by the alternating polarity process. Liquid enriched with gas does not contain bubbles strongly scattering visible light but its refractive index changes significantly near the electrodes. The change of the refractive index is a collective effect of bulk nanobubbles with a diameter smaller than 200 nm. Any alternative explanation fails to explain the magnitude of the effect. Spatial structure of the cloud is investigated with the optical lever method. Its dynamics is visualised observing optical distortion of the electrode images or using differential interference contrast method. The cloud covers concentric electrodes, in a steady state it is roughly hemispherical with a size two times larger than the size of the electrode structure. When the electrical pulses are switched off the cloud disappears in less than one second. The total concentration of gases can reach very high value estimated as 3.5 * 1020 cm-3 that corresponds to an effective supersaturation of 500 and 150 for hydrogen and oxygen, respectively. PMID- 28727813 TI - Label-free three-dimensional imaging of Caenorhabditis elegans with visible optical coherence microscopy. AB - Fast, label-free, high-resolution, three-dimensional imaging platforms are crucial for high-throughput in vivo time-lapse studies of the anatomy of Caenorhabditis elegans, one of the most commonly used model organisms in biomedical research. Despite the needs, methods combining all these characteristics have been lacking. Here, we present label-free imaging of live Caenorhabditis elegans with three-dimensional sub-micrometer resolution using visible optical coherence microscopy (visOCM). visOCM is a versatile optical imaging method which we introduced recently for tomography of cell cultures and tissue samples. Our method is based on Fourier domain optical coherence tomography, an interferometric technique that provides three-dimensional images with high sensitivity, high acquisition rate and micrometer-scale resolution. By operating in the visible wavelength range and using a high NA objective, visOCM attains lateral and axial resolutions below 1 MUm. Additionally, we use a Bessel illumination offering an extended depth of field of approximately 40 MUm. We demonstrate that visOCM's imaging properties allow rapid imaging of full sized living Caenorhabditis elegans down to the sub-cellular level. Our system opens the door to many applications such as the study of phenotypic changes related to developmental or ageing processes. PMID- 28727814 TI - Low PCSK9 levels are correlated with mortality in patients with end-stage liver disease. AB - INTRODUCTION: Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a key role in the cholesterol metabolism and is synthesized by the liver. It interacts with the LDL-receptor to promote its degradation. The model of end-stage liver disease (MELD) score is a well-established tool to estimate the risk of mortality in patients with end-stage chronic liver disease. The study aims to assess the associations between PCSK9, hypocholesterinemia, liver synthesis, cholestasis, MELD score and mortality in patients with end-stage liver disease. METHODS: Serum samples were obtained from 74 patients with severe liver disease. The study participants were aged between 23 and 70 y (mean: 55.8 y; 47 males [63.5%], 27 females [36.5%]). Samples were selected from those with a wide range of MELD scores (7 to 40). Patients that underwent liver transplantation (17 / 74) were censored at the time of transplantation for mortality analysis. RESULTS: PCSK9 values ranged from 31.47 ng/mL to 261.64 ng/mL. The median value was 106.39 ng/ml. PCSK9 was negatively correlated with markers of liver function and cholestasis (INR, bilirubin). Over a 90-d follow-up, 15 of 57 (26,3%) patients died within the 90-d follow-up without receiving liver transplantation. Thirteen of 31 (42%) patients with PCSK9 levels below the median died compared to 2/26 (8%) patients with higher PCSK9 levels (p = 0.006). In this cohort, there were no significant correlations between PCSK9, cholesterol, its precursors and several phytosterols. CONCLUSIONS: Low PCSK9 serum concentrations were associated with higher mortality in patients with end-stage liver disease. The mean PCSK9 levels in the study population were much lower than those found in normal or healthy populations. Further studies are required to acquire a more detailed understanding of the role of PCSK9 in liver-related mortality. PMID- 28727815 TI - Polymorphisms associated with everolimus pharmacokinetics, toxicity and survival in metastatic breast cancer. AB - PURPOSE: Metastatic breast cancer (MBC) progressing after endocrine therapy frequently activates PI3K/AKT/mTOR pathway. The BOLERO-2 trial showed that everolimus-exemestane achieves increased progression free survival (PFS) compared with exemestane. However, there is great inter-patient variability in toxicity and response to exemestane-everolimus treatment. The objective of this study was to perform an exploratory study analyzing the implication of single nucleotide polymorphisms (SNPs) on outcomes from this treatment through a pharmacogenetic analysis. PATIENTS AND METHODS: Blood was collected from 90 postmenopausal women with hormone receptor-positive, HER2-negative MBC treated with exemestane everolimus following progression after prior treatment with a non-steroidal aromatase inhibitor. Everolimus pharmacokinetics was measured in 37 patients. Twelve SNPs in genes involved in everolimus pharmacokinetics and pharmacodynamics were genotyped and associations assessed with drug plasma levels, clinically relevant toxicities (non-infectious pneumonitis, mucositis, hyperglycemia and hematological toxicities), dose reductions or treatment suspensions due to toxicity, progression free survival (PFS) and overall survival. RESULTS: We found that CYP3A4 rs35599367 variant (CYP3A4*22 allele) carriers had higher everolimus blood concentration compared to wild type patients (P = 0.019). ABCB1 rs1045642 was associated with risk of mucositis (P = 0.031), while PIK3R1 rs10515074 and RAPTOR rs9906827 were associated with hyperglycemia and non-infectious pneumonitis (P = 0.016 and 0.024, respectively). Furthermore, RAPTOR rs9906827 was associated with PFS (P = 0.006). CONCLUSIONS: CYP3A4*22 allele influenced plasma concentration of everolimus and several SNPs in PI3K/AKT/mTOR pathway genes were associated with treatment toxicities and prognosis. These results require replication, but suggest that germline variation could influence everolimus outcomes in MBC. PMID- 28727816 TI - High levels of FLT3-ligand in bone marrow and peripheral blood of patients with advanced multiple myeloma. AB - INTRODUCTION: Multiple myeloma (MM) is still incurable due to resistance against various therapies. Thus, the identification of biomarkers predicting progression is urgently needed. Here, we evaluated four biomarkers in bone marrow and peripheral blood of MM patients for their prognostic significance. MATERIALS & METHODS: Bone marrow- and peripheral blood plasma levels of FLT3-L, soluble TIE2, endostatin, and osteoactivin were determined in patients with monoclonal gammopathy of undetermined significance (MGUS, n = 14/n = 4), patients with newly diagnosed MM (NDMM, n = 42/n = 31) and patients with relapsed/refractory MM (RRMM, n = 27/n = 16) by sandwich ELISA. RESULTS: Median FLT3-L expression increased from MGUS (58.77 pg/ml in bone marrow; 80.40 pg/ml in peripheral blood) to NDMM (63.15 pg/ml in bone marrow; 85.05 pg/ml in peripheral blood) and was maximal in RRMM (122 pg/ml in bone marrow; 160.47 pg/ml in peripheral blood; NDMM vs. RRMM p<0.001). A cut-off value of FLT3-L >92 pg/ml in bone marrow and >121 pg/ml in peripheral blood was associated with relapse or refractoriness in MM patients. FLT3-L was found to be a high predictive marker for discrimination between NDMM and RRMM as well in bone marrow as in peripheral blood (AUC 0.75 in bone marrow; vs 0.84 in peripheral blood). CONCLUSION: High levels of FLT3-L in bone marrow and peripheral blood of MM patients identify patients with progressive disease and are associated with relapse or refractoriness in MM patients. FLT3-L could be useful as a marker to identify RRMM patients and should be evaluated as target for future therapies. PMID- 28727817 TI - Immunogenicity of a novel Clade B HIV-1 vaccine combination: Results of phase 1 randomized placebo controlled trial of an HIV-1 GM-CSF-expressing DNA prime with a modified vaccinia Ankara vaccine boost in healthy HIV-1 uninfected adults. AB - BACKGROUND: A phase 1 trial of a clade B HIV vaccine in HIV-uninfected adults evaluated the safety and immunogenicity of a DNA prime co-expressing GM-CSF (Dg) followed by different numbers and intervals of modified vaccinia Ankara Boosts (M). Both vaccines produce virus-like particles presenting membrane-bound Env. METHODS: Four US sites randomized 48 participants to receiving 1/10th the DNA dose as DgDgMMM given at 0, 2, 4, 6 and 8 months, or full dose DgDgM_M or DgDgMM_M regimens, given at 0, 2, 4, and 8 months, and 0, 2, 4, 6, and 10 months, respectively. Peak immunogenicity was measured 2 weeks post-last vaccination. RESULTS: All regimens were well tolerated and safe. Full dose DgDgM_M and DgDgMM_M regimens generated Env-specific IgG to HIV-1 Env in >90%, IgG3 in >80%, and IgA in <20% of participants. Responses to gp140 and gp41 targets were more common and of higher magnitude than to gp120 and V1V2. The gp41 antibody included reactivity to the conserved immunodominant region with specificities known to mediate virus capture and phagocytosis and did not cross-react with a panel of intestinal flora antigens. The 3rd dose of MVA increased the avidity of elicited antibody (7.5% to 39%), the ADCC response to Bal gp120 (14% to 64%), and the one year durability of the IgG3 responses to gp41 by 4-fold (13% vs. 3.5% retention of peak response). The co-expressed GM-CSF did not enhance responses over those in trials testing this vaccine without GM-CSF. CONCLUSION: This DNA/MVA prime boost regimen induced durable, functional humoral responses that included ADCC, high antibody avidity, and Env IgG1 and IgG3 binding responses to the immunodominant region of gp41. The third, spaced MVA boost improved the overall quality of the antibody response. These products without co-expressed GM-CSF but combined with protein boosts will be considered for efficacy evaluation. TRIAL REGISTRATION: ClinicalTrials.gov NCT01571960. PMID- 28727818 TI - PrEP in Italy: The time may be ripe but who's paying the bill? A nationwide survey on physicians' attitudes towards using antiretrovirals to prevent HIV infection. AB - Several studies have demonstrated the efficacy of the oral pre-exposure prophylaxis (PrEP) with tenofovir (with or without emtricitabine) on preventing HIV-negative partners of HIV infected patients to become infected through sexual contacts. PrEP is already available in the United States and now is approved by European Medicine Agency. In this setting we would like to gauge physicians' knowledge, acquaintance with and attitude to include PrEP in their clinical practice. A cross sectional survey was conducted among Italian physicians expert on antiretroviral therapy. Out of 146 physicians, 35% of participants declared to be familiar with PrEP but only 46% of them believed that, currently, there are not enough reasons to make it available in Italy. 51% of physicians have already been attracted to prescribe it and 63.4% have been openly asked about PrEP. The main concerns noticed were: the risk of acquire other sexual transmitted diseases (STDs) (70% of physicians feared that PrEP could favor STDs spread), the potential harmful of PrEP if not adequately implemented and, especially the risk of possible side effects if not properly used. Nevertheless, 55.9% of participants believed that Health Authorities face an ethical obligation to make PrEP available as part of the strategies to protect from HIV transmission and half of the respondents asked for further researches to better define the role for PrEP. Attitudes regarding PrEP impact on Italian National Health Organization were also very interesting: 57.5% of participants did not believe that investing in PrEP would be an appropriate use of healthcare resources, while 70.6% affirmed that PrEP's financial coverage should not be funded by the Italian National System of Health (SSN). This survey showed a high awareness of PrEP potential among Italian physicians coupled with a great deal of skepticism about how and if implementing it in clinical practice. PMID- 28727819 TI - The gene drive bubble: New realities. PMID- 28727821 TI - Advances in using Internet searches to track dengue. AB - Dengue is a mosquito-borne disease that threatens over half of the world's population. Despite being endemic to more than 100 countries, government-led efforts and tools for timely identification and tracking of new infections are still lacking in many affected areas. Multiple methodologies that leverage the use of Internet-based data sources have been proposed as a way to complement dengue surveillance efforts. Among these, dengue-related Google search trends have been shown to correlate with dengue activity. We extend a methodological framework, initially proposed and validated for flu surveillance, to produce near real-time estimates of dengue cases in five countries/states: Mexico, Brazil, Thailand, Singapore and Taiwan. Our result shows that our modeling framework can be used to improve the tracking of dengue activity in multiple locations around the world. PMID- 28727820 TI - Active hexose-correlated compound enhances extrinsic-pathway-mediated apoptosis of Acute Myeloid Leukemic cells. AB - Active Hexose Correlated Compound (AHCC) has been shown to have many immunostimulatory and anti-cancer activities in mice and in humans. As a natural product, AHCC has potential to create safer adjuvant therapies in cancer patients. Acute Myeloid Leukemia (AML) is the least curable and second-most common leukemia in adults. AML is especially terminal to those over 60 years old, where median survival is only 5 to 10 months, due to inability to receive intensive chemotherapy. Hence, the purpose of this study was to investigate the effects of AHCC on AML cells both in vitro and in vivo. Results showed that AHCC induced Caspase-3-dependent apoptosis in AML cell lines as well as in primary AML leukopheresis samples. Additionally, AHCC induced Caspase-8 cleavage as well as Fas and TRAIL upregulation, suggesting involvement of the extrinsic apoptotic pathway. In contrast, monocytes from healthy donors showed suppressed Caspase-3 cleavage and lower cell death. When tested in a murine engraftment model of AML, AHCC led to significantly increased survival time and decreased blast counts. These results uncover a mechanism by which AHCC leads to AML-cell specific death, and also lend support for the further investigation of AHCC as a potential adjuvant for the treatment of AML. PMID- 28727822 TI - DNA methylation of candidate genes in peripheral blood from patients with type 2 diabetes or the metabolic syndrome. AB - INTRODUCTION: The prevalence of type 2 diabetes (T2D) and the metabolic syndrome (MetS) is increasing and several studies suggested an involvement of DNA methylation in the development of these metabolic diseases. This study was designed to investigate if differential DNA methylation in blood can function as a biomarker for T2D and/or MetS. METHODS: Pyrosequencing analyses were performed for the candidate genes KCNJ11, PPARgamma, PDK4, KCNQ1, SCD1, PDX1, FTO and PEG3 in peripheral blood leukocytes (PBLs) from 25 patients diagnosed with only T2D, 9 patients diagnosed with T2D and MetS and 11 control subjects without any metabolic disorders. RESULTS: No significant differences in gene-specific methylation between patients and controls were observed, although a trend towards significance was observed for PEG3. Differential methylation was observed between the groups in 4 out of the 42 single CpG loci located in the promoters regions of the genes FTO, KCNJ11, PPARgamma and PDK4. A trend towards a positive correlation was observed for PEG3 methylation with HDL cholesterol levels. DISCUSSION: Altered levels of DNA methylation in PBLs of specific loci might serve as a biomarker for T2D or MetS, although further investigation is required. PMID- 28727823 TI - Structural instability of large-scale functional networks. AB - We study how large functional networks can grow stably under possible cascading overload failures and evaluated the maximum stable network size above which even a small-scale failure would cause a fatal breakdown of the network. Employing a model of cascading failures induced by temporally fluctuating loads, the maximum stable size nmax has been calculated as a function of the load reduction parameter r that characterizes how quickly the total load is reduced during the cascade. If we reduce the total load sufficiently fast (r >= rc), the network can grow infinitely. Otherwise, nmax is finite and increases with r. For a fixed r(< rc), nmax for a scale-free network is larger than that for an exponential network with the same average degree. We also discuss how one detects and avoids the crisis of a fatal breakdown of the network from the relation between the sizes of the initial network and the largest component after an ordinarily occurring cascading failure. PMID- 28727824 TI - Infiltrative tumor growth patterns on magnetic resonance imaging associated with systemic inflammation and oncological outcome in patients with high-grade soft tissue sarcoma. AB - OBJECTIVE: The aim of this study was to determine whether the tumor infiltrative growth pattern on magnetic resonance imaging (MRI) was associated with blood inflammatory markers (C-reactive protein; CRP and Neutrophil-lymphocyte ratio; NLR) and survival in patients with high-grade soft-tissue sarcoma (STS). METHODS: The cohort for this retrospective study included 81 patients with a mean age of 63 years. The tumor depth was superficial or deep in 15 and 66 patients, respectively. The mean CRP and NLR were 1.31 mg/dL and 2.81, respectively. The assessment of a peripheral growth pattern which divided into three patterns on MRI was based on the largest midsection of the tumor. RESULTS: On MRI scans, diffuse-type, focal-type, and pushing-type growth patterns were observed in 18, 33, and 30 patients, respectively. Superficial high-grade STS were prone to show a focal-type pattern on MRI. There were no correlations between growth pattern type and clinicopathological factors such as age, sex, tumor size, and histological grade. However, the incidence of infiltrative growth was significantly higher in patients with elevated CRP (p = 0.0002). In multivariate analysis, growth pattern and CRP were independent prognostic factors for disease specific survival, metastasis-free survival. Growth pattern was also related to local tumor control. CONCLUSIONS: There were significant associations between the tumor growth pattern and CRP levels in patients with high-grade soft-tissue sarcoma. An infiltrative growth pattern and elevated CRP may be associated with inferior disease-specific and metastasis-free survival rates in these patients. Therefore, careful post-treatment follow-up should be conducted in such patients. PMID- 28727825 TI - Differentially expressed genes in the head of the 2nd instar pre-molting larvae of the nm2 mutant of the silkworm, Bombyx mori. AB - Molting is an important physiological process in the larval stage of Bombyx mori and is controlled by various hormones and peptides. The silkworm mutant that exhibits the phenotype of non-molting in the 2nd instar (nm2) is incapable of molting in the 2nd instar and dies after seven or more days. The ecdysone titer in the nm2 mutant is lower than that in the wildtype, and the mutant can be rescued by feeding with 20E and cholesterol. The results of positional cloning indicated that structural alteration of BmCPG10 is responsible for the phenotype of the nm2 mutant. To explore the possible relationship between BmCPG10 and the ecdysone titer as well as the genes affected by BmCPG10, digital gene expression (DGE) profile analysis was conducted in the nm2 mutant, with the wildtype strain C603 serving as the control. The results revealed 1727 differentially expressed genes, among which 651 genes were upregulated and 1076 were downregulated in nm2. BLASTGO analysis showed that these differentially expressed genes were involved in various biological processes, cellular components and molecular functions. KEGG analysis indicated an enrichment of these differentially expressed genes in 240 pathways, including metabolic pathways, pancreatic secretion, protein digestion and absorption, fat digestion and absorption and glycerolipid metabolism. To verify the accuracy of the DGE results, quantitative reverse transcription PCR (qRT-PCR) was performed, focusing on key genes in several related pathways, and the results were highly consistent with the DGE results. Our findings indicated significant differences in cuticular protein genes, ecdysone biosynthesis genes and ecdysone-related nuclear receptors genes, but no significant difference in juvenile hormone and chitin biosynthesis genes was detected. Our research findings lay the foundation for further research on the formation mechanism of the nm2 mutant. PMID- 28727826 TI - Germline and reproductive tract effects intensify in male mice with successive generations of estrogenic exposure. AB - The hypothesis that developmental estrogenic exposure induces a constellation of male reproductive tract abnormalities is supported by experimental and human evidence. Experimental data also suggest that some induced effects persist in descendants of exposed males. These multi- and transgenerational effects are assumed to result from epigenetic changes to the germline, but few studies have directly analyzed germ cells. Typically, studies of transgenerational effects have involved exposing one generation and monitoring effects in subsequent unexposed generations. This approach, however, has limited human relevance, since both the number and volume of estrogenic contaminants has increased steadily over time, intensifying rather than reducing or eliminating exposure. Using an outbred CD-1 mouse model, and a sensitive and quantitative marker of germline development, meiotic recombination, we tested the effect of successive generations of exposure on the testis. We targeted the germline during a narrow, perinatal window using oral exposure to the synthetic estrogen, ethinyl estradiol. A complex three generation exposure protocol allowed us to compare the effects of individual, paternal, and grandpaternal (ancestral) exposure. Our data indicate that multiple generations of exposure not only exacerbate germ cell exposure effects, but also increase the incidence and severity of reproductive tract abnormalities. Taken together, our data suggest that male sensitivity to environmental estrogens is increased by successive generations of exposure. PMID- 28727828 TI - Spatial and temporal dynamics of shifting cultivation in the middle-Amazonas river: Expansion and intensification. AB - Shifting cultivation is the main land-use system transforming landscapes in riverine Amazonia. Increased concentration of the human population around villages and increasing market integration during the last decades may be causing agricultural intensification. Studies have shown that agricultural intensification, i.e. higher number of swidden-fallow cycles and shorter fallow periods, reduces crop productivity of swiddens and the regrowth capacity of fallows, undermining the resilience of the shifting cultivation system as a whole. We investigated the temporal and spatial dynamics of shifting cultivation in Brazilian Amazonia to test the hypotheses that (i) agriculture has become more intensive over time, and (ii) patterns of land-use intensity are related to land accessibility and human population density. We applied a breakpoint-detection algorithm to Landsat time-series spanning three decades (1984-2015) and retrieved the temporal dynamics of shifting cultivation fields, which go through alternating phases of crop production (swidden) and secondary forest regrowth (fallow). We found that fallow-period length has decreased from 6.4 to 5.1 years on average, and that expansion over old-growth forest has slowed down over time. Shorter fallow periods and higher frequency of slash and burn cycles are practiced closer to residences and around larger villages. Our results indicate that shifting cultivation in riverine Amazonia has gone through a process of agricultural intensification in the past three decades. The resulting landscape is predominantly covered by young secondary forests (<= 12 yrs old), and 20% of it have gone through intensive use. Reversing this trend and avoiding the negative consequences of agricultural intensification requires land use planning that accounts for the constraints of land use in riverine areas. PMID- 28727827 TI - Diversity and phylogenetic relationships among Bartonella strains from Thai bats. AB - Bartonellae are phylogenetically diverse, intracellular bacteria commonly found in mammals. Previous studies have demonstrated that bats have a high prevalence and diversity of Bartonella infections globally. Isolates (n = 42) were obtained from five bat species in four provinces of Thailand and analyzed using sequences of the citrate synthase gene (gltA). Sequences clustered into seven distinct genogroups; four of these genogroups displayed similarity with Bartonella spp. sequences from other bats in Southeast Asia, Africa, and Eastern Europe. Thirty of the isolates representing these seven genogroups were further characterized by sequencing four additional loci (ftsZ, nuoG, rpoB, and ITS) to clarify their evolutionary relationships with other Bartonella species and to assess patterns of diversity among strains. Among the seven genogroups, there were differences in the number of sequence variants, ranging from 1-5, and the amount of nucleotide divergence, ranging from 0.035-3.9%. Overall, these seven genogroups meet the criteria for distinction as novel Bartonella species, with sequence divergence among genogroups ranging from 6.4-15.8%. Evidence of intra- and intercontinental phylogenetic relationships and instances of homologous recombination among Bartonella genogroups in related bat species were found in Thai bats. PMID- 28727829 TI - Functional differentiation and spatial-temporal co-expression networks of the NBS encoding gene family in Jilin ginseng, Panax ginseng C.A. Meyer. AB - Ginseng, Panax ginseng C.A. Meyer, is one of the most important medicinal plants for human health and medicine. It has been documented that over 80% of genes conferring resistance to bacteria, viruses, fungi and nematodes are contributed by the nucleotide binding site (NBS)-encoding gene family. Therefore, identification and characterization of NBS genes expressed in ginseng are paramount to its genetic improvement and breeding. However, little is known about the NBS-encoding genes in ginseng. Here we report genome-wide identification and systems analysis of the NBS genes actively expressed in ginseng (PgNBS genes). Four hundred twelve PgNBS gene transcripts, derived from 284 gene models, were identified from the transcriptomes of 14 ginseng tissues. These genes were classified into eight types, including TNL, TN, CNL, CN, NL, N, RPW8-NL and RPW8 N. Seven conserved motifs were identified in both the Toll/interleukine-1 receptor (TIR) and coiled-coil (CC) typed genes whereas six were identified in the RPW8 typed genes. Phylogenetic analysis showed that the PgNBS gene family is an ancient family, with a vast majority of its genes originated before ginseng originated. In spite of their belonging to a family, the PgNBS genes have functionally dramatically differentiated and been categorized into numerous functional categories. The expressions of the across tissues, different aged roots and the roots of different genotypes. However, they are coordinating in expression, forming a single co-expression network. These results provide a deeper understanding of the origin, evolution and functional differentiation and expression dynamics of the NBS-encoding gene family in plants in general and in ginseng particularly, and a NBS gene toolkit useful for isolation and characterization of disease resistance genes and for enhanced disease resistance breeding in ginseng and related species. PMID- 28727830 TI - The receptor tyrosine kinase AXL promotes migration and invasion in colorectal cancer. AB - The receptor tyrosine kinases (RTKs) TYRO3, AXL and MERTK (TAM) have well described oncogenic functions in a number of cancers. Notwithstanding, TAM RTKs are also potent and indispensable inhibitors of inflammation. The combined deletion of Axl and Mertk in mice enhances chronic inflammation and autoimmunity, including increased inflammation in the gut and colitis-associated cancer. On the other hand, deletion of Tyro3 increases the risk of allergic responses. Therefore, the indiscriminate inhibition of these TAM RTKs could result in undesirable immunological diseases. Here we show that AXL, but not MERTK or TYRO3 expression is enhanced in late stage colorectal cancer (CRC) and AXL expression associates with a cell migration gene signature. Silencing AXL or the inhibition of AXL kinase activity significantly inhibits tumor cell migration and invasion. These results indicate that the selective inhibition of AXL alone might confer sufficient therapeutic benefit in CRC, while preserving at least some of the beneficial, anti-inflammatory effects of MERTK and TYRO3 RTKs. PMID- 28727831 TI - Follicle Stimulating Hormone is an accurate predictor of azoospermia in childhood cancer survivors. AB - The accuracy of Follicle Stimulating Hormone as a predictor of azoospermia in adult survivors of childhood cancer is unclear, with conflicting results in the published literature. A systematic review and post hoc analysis of combined data (n = 367) were performed on all published studies containing extractable data on both serum Follicle Stimulating Hormone concentration and semen concentration in survivors of childhood cancer. PubMed and Medline databases were searched up to March 2017 by two blind investigators. Articles were included if they contained both serum FSH concentration and semen concentration, used World Health Organisation certified methods for semen analysis, and the study participants were all childhood cancer survivors. There was no evidence for either publication bias or heterogeneity for the five studies. For the combined data (n = 367) the optimal Follicle Stimulating Hormone threshold was 10.4 IU/L with specificity 81% (95% CI 76%-86%) and sensitivity 83% (95% CI 76%-89%). The AUC was 0.89 (95%CI 0.86-0.93). A range of threshold FSH values for the diagnosis of azoospermia with their associated sensitivities and specificities were calculated. This study provides strong supporting evidence for the use of serum Follicle Stimulating Hormone as a surrogate biomarker for azoospermia in adult males who have been treated for childhood cancer. PMID- 28727832 TI - Neurosurgeon academic impact is associated with clinical outcomes after clipping of ruptured intracranial aneurysms. AB - BACKGROUND: Surgeon-dependent factors such as experience and volume are associated with patient outcomes. However, it is unknown whether a surgeon's research productivity could be related to outcomes. The main aim of this study is to investigate the association between the surgeon's academic productivity and clinical outcomes following neurosurgical clipping of ruptured aneurysms. METHODS: We performed a post-hoc analysis of 3567 patients who underwent clipping of ruptured intracranial aneurysms in the randomized trials of tirilazad mesylate from 1990 to 1997. These trials included 162 centers and 156 surgeons from 21 countries. Primary and secondary outcomes were: Glasgow outcome scale score and mortality, respectively. Total publications, H-index, and graduate degrees were used as academic indicators for each surgeon. The association between outcomes and academic factors were assessed using a hierarchical logistic regression analysis, adjusting for patient covariates. RESULTS: Academic profiles were available for 147 surgeons, treating a total of 3307 patients. Most surgeons were from the USA (62, 42%), Canada (18, 12%), and Germany (15, 10%). On univariate analysis, the H-index correlated with better functional outcomes and lower mortality rates. In the multivariate model, patients under the care of surgeons with higher H-indices demonstrated improved neurological outcomes (p = 0.01) compared to surgeons with lower H-indices, without any significant difference in mortality. None of the other academic indicators were significantly associated with outcomes. CONCLUSION: Although prognostication following surgery for ruptured intracranial aneurysms primarily depends on clinical and radiological factors, the academic impact of the operating neurosurgeon may explain some heterogeneity in surgical outcomes. PMID- 28727833 TI - Refugee and migrant women's engagement with sexual and reproductive health care in Australia: A socio-ecological analysis of health care professional perspectives. AB - BACKGROUND: In Australia only 2.2% of published health research has focused on multi-cultural health despite the increase of culturally and linguistically diverse populations. Research on the perceptions and experiences of health care professionals (HCPs) in engaging with refugee and migrant women is also lacking. Given the integral role of HCPs in providing sexual and reproductive health (SRH) care for these populations, an understanding of the challenges they experience is required. Therefore, this study sought to examine the perspectives and practices of Australian HCPs with regard to the provision of SRH care for refugee and migrant women. METHODS: Employing qualitative methods, twenty-one semi-structured interviews were conducted with HCPs representing various professions, work experiences, cultural backgrounds, age and healthcare sectors. The interviews were analysed using thematic analysis and the socio-ecological model was utilised to interpret the data. RESULTS: The complexities of HCP's engagement with refugee and migrant women were identified in three major themes: Being a Migrant; Gender Roles and SRH Decision-making; and Women in the Healthcare System. HCPs discussed the impact of accessing SRH care in women's country of origin and the influence of re-settlement contexts on their SRH knowledge, engagement with care and care provision. Perception of gender roles was integral to SRH decision-making with the need to involve male partners having an impact on the provision of women centred care. Barriers within the healthcare system included the lack of services to address sexual functioning and relationship issues, as well as lack of resources, time constraints, cost of services, and funding. CONCLUSION: Australian HCPs interviewed reported that migrant and refugee women do not have appropriate access to SRH care due to multifaceted challenges. These challenges are present across the entire socio-ecological arena, from individual to systemic levels. Multiple and multidimensional interventions are required to increase SRH utilisation and improve outcomes for refugee and migrant women. PMID- 28727834 TI - Systematic review: Outcome reporting bias is a problem in high impact factor neurology journals. AB - BACKGROUND: Selective outcome reporting is a significant methodological concern. Comparisons between the outcomes reported in clinical trial registrations and those later published allow investigators to understand the extent of selection bias among trialists. We examined the possibility of selective outcome reporting in randomized controlled trials (RCTs) published in neurology journals. METHODS: We searched PubMed for randomized controlled trials from Jan 1, 2010 -Dec 31, 2015 published in the top 3 impact factor neurology journals. These articles were screened according to specific inclusion criteria. Each author individually extracted data from trials following a standardized protocol. A second author verified each extracted element and discrepancies were resolved. Consistency between registered and published outcomes was evaluated and correlations between discrepancies and funding, journal, and temporal trends were examined. RESULTS: 180 trials were included for analysis. 10 (6%) primary outcomes were demoted, 38 (21%) primary outcomes were omitted from the publication, and 61 (34%) unregistered primary outcomes were added to the published report. There were 18 (10%) cases of secondary outcomes being upgraded to primary outcomes in the publication, and there were 53 (29%) changes in timing of assessment. Of 82 (46%) major discrepancies with reported p-values, 54 (66.0%) favored publication of statistically significant results. CONCLUSION: Across trials, we found 180 major discrepancies. 66% of major discrepancies with a reported p-value (n = 82) favored statistically significant results. These results suggest a need within neurology to provide more consistent and timely registration of outcomes. PMID- 28727836 TI - The disc damage likelihood scale: Diagnostic accuracy and correlations with cup to-disc ratio, structural tests and standard automated perimetry. AB - Our objective was to compare the diagnostic accuracies of and to determine the correlations between the disc damage likelihood scale (DDLS) and anatomical and functional tests used for glaucoma detection. A total of 54 healthy subjects (54 eyes) and 47 primary open-angle glaucoma patients (47 eyes) were included in this cross-sectional observational study. DDLS scores and cup-to-disc (C/D) ratios were evaluated. Subjects underwent standard automated perimetry (SAP), optic disc and retinal nerve fiber layer (RNFL) imaging with time and spectral-domain optical coherence tomography (TD and SD-OCT), Heidelberg Retina Tomograph (HRT II), and scanning laser polarimetry (GDx-VCC). Areas under the receiver operating characteristic curves (AROCs) for DDLS and diagnostic tests parameters were calculated. DDLS correlations (Spearman's rank) among these parameters were analyzed. Fifty-four eyes were healthy and 47 had glaucoma, including 16 preperimetric glaucoma. DDLS, vertical and horizontal C/D ratios had the largest AROCs (0.92, 0.94 and 0.91, respectively). DDLS diagnostic accuracy was better than the accuracies of HRT II parameters, TD and SD-OCT RNFL thicknesses, and SAP mean deviation (MD) index. There were no significant differences between the accuracies of the DDLS and the C/D ratios, TD-OCT vertical (0.89) and horizontal (0.86) C/D ratios, TD-OCT C/D area ratio (0.89), and GDx-VCC NFI (0.81). DDLS showed significant strong correlations with vertical (r = 0.79) and horizontal (0.74) C/D ratios, and with the parameters vertical C/D ratio and C/D area ratio from HRT II (both 0.77) and TD-OCT (0.75 and 0.72, respectively). DDLS had significant moderate correlations with most of the other structural measurements and SAP MD. The optic disc clinical evaluation with DDLS system and C/D ratio demonstrated excellent accuracy in distinguishing glaucomatous from healthy eyes. DDLS had moderate to strong correlations with most structural and functional parameters. These findings stress the importance of optic disc clinical examination to detect glaucoma in a clinical scenario. PMID- 28727835 TI - Conflicting relationship between age-dependent disorders, valvular heart disease and coronary artery disease by covariance structure analysis: Possible contribution of natriuretic peptide. AB - BACKGROUND: It is conceivable that contemporary valvular heart disease (VHD) is affected largely by an age-dependent atherosclerotic process, which is similar to that observed in coronary artery disease (CAD). However, a comorbid condition of VHD and CAD has not been precisely examined. The first objective of this study was to examine a possible comorbid condition. Provided that there is no comorbidity, the second objective was to search for the possible reasons by using conventional risk factors and plasma B-type natriuretic peptide (BNP) because BNP has a potentiality to suppress atherosclerotic development. METHODS: The study population consisted of 3,457 patients consecutively admitted to our institution. The possible comorbid condition of VHD and CAD and the factors that influence the comorbidity were examined by covariance structure analysis and multivariate analysis. RESULTS: The distribution of the patients with VHD and those with CAD in the histograms showed that the incidence of VHD and the severity of CAD rose with seniority in appearance. The real statistical analysis was planned by covariance structure analysis. The current path model revealed that aging was associated with VHD and CAD severity (P < 0.001 for each); however, as a notable result, there was an inverse association regarding the comorbid condition between VHD and CAD (Correlation coefficient [beta]: -0.121, P < 0.001). As the second objective, to clarify the factors leading to this inverse association, the contribution of conventional risk factors, such as age, gender, hypertension, smoking, diabetes, obesity and dyslipidemia, to VHD and CAD were examined by multivariate analysis. However, these factors did not exert an opposing effect on VHD and CAD, and the inverse association defied explanation. Since different pathological mechanisms may contribute to the formation of VHD and CAD, a differentially proposed path model using plasma BNP revealed that an increase in plasma BNP being drawn by VHD suppressed the progression of CAD (beta: -0.465, P < 0.001). CONCLUSIONS: The incidence of VHD and CAD showed a significant conflicting relationship. This result supported the likely presence of unknown diverse mechanisms on top of the common cascade of atherosclerosis. Among them, the continuous elevation of plasma BNP due to VHD might be one of the explicable factors suppressing the progression of CAD. PMID- 28727837 TI - Differing roles for short chain fatty acids and GPR43 agonism in the regulation of intestinal barrier function and immune responses. AB - Inflammatory bowel disease (IBD) is associated with a loss of intestinal barrier function and dysregulated immune responses. It has been shown that short chain fatty acids (SCFAs) are protective in IBD and that GPR43 mediates the protective effects of SCFAs. In this study, we investigated the effects of SCFAs in comparison to highly specific GPR43 agonists on human intestinal epithelial and immune cells. Our results confirm that SCFAs are enhancers of barrier function in intestinal epithelial cells. Additionally, SCFAs also displayed potent immunoregulatory properties based upon the ability to inhibit LPS-induced cytokine production in PBMC, and human T cell proliferation and cytokine production. Unexpectedly, and in contrast to the current belief, specific GPR43 agonists failed to exhibit similar barrier enhancing and anti-inflammatory properties. These findings demonstrate that SCFA possess broad protective functions in IBD and agonizing GPR43 alone is unlikely to be beneficial in patients. PMID- 28727838 TI - Prevalence and factors associated with recent intimate partner violence and relationships between disability and depression in post-partum women in one clinic in eThekwini Municipality, South Africa. AB - Intimate partner violence (IPV) experienced by pregnant and post-partum women has negative health effects for women, as well as the foetus, and the new-born child. In this study we sought to assess the prevalence and factors associated with recent IPV amongst post-partum women in one clinic in eThekwini Municipality, South Africa, and explore the relationship between IPV, depression and functional limitations/disabilities. Past 12 month IPV-victimisation was 10.55%. Logistic regression modelled relationships between IPV, functional limitations, depressive symptoms, socio-economic measures, and sexual relationship power. In logistic regression models, overall severity of functional limitations were not associated with IPV-victimisation when treated as a continuous overall score. In this model relationship power (aOR0.22, p = 0.001) and depressive symptoms (aOR1.26, p = 0.001) were significant. When the different functional limitations were separated out in a second model, significant factors were relationship power (aOR0.20, p = 0.001), depressive symptoms (aOR1.20, p = 0.011) and mobility limitations (aOR2.96, p = 0.024). The study emphasises that not all functional limitations are associated with IPV-experience, that depression and disability while overlapping can also be considered different drivers of vulnerability, and that women's experience of IPV is not dependent on pregnancy specific factors, but rather wider social factors that all women experience. PMID- 28727839 TI - Cardiac autonomic modulation induced by doxorubicin in a rodent model of colorectal cancer and the influence of fullerenol pretreatment. AB - The very effective anticancer drug doxorubicin (DOX) is known to have cardiotoxic side effects, which could be accompanied by autonomic modulation. Autonomic disbalance might even be an initiating mechanism underlying DOX-induced cardiotoxicity and can be studied noninvasively by the analysis of heart rate variability (HRV). A number of strategies have been assessed to predict chemotherapy-induced cardiac dysfunction while HRV, a potential detecting tool, has not yet been tested. Thus, we aimed to determine the effect of DOX treatment on HRV in a rat model of colorectal cancer. While pretreatment with fullerenol (Frl) acts protectively on DOX-induced cardiotoxicity, we aimed to test the effect of Frl pretreatment on DOX-induced HRV alterations. After the induction of colorectal cancer, adult male Wistar rats were treated with saline (n = 7), DOX (1.5 mg/kg per week, n = 7) or DOX after pretreatment with Frl (25 mg/kg per week, n = 7) for three weeks (cumulative DOX dose 4.5 mg/kg). One week after treatment rats were anaesthetized, standard ECG was measured and HRV was analyzed in time and frequency domain. During autopsy the intestines and hearts were gathered for biochemical analysis and histopathological examination. DOX treatment significantly decreased parasympathetically mediated high-frequency component (p<0.05) and increased the low-frequency component of HRV (p<0.05), resulting in an increased LF/HF ratio (p<0.05) in cancerous rats. When pretreated with Frl, DOX-induced HRV alterations were prevented: the high-frequency component of HRV increased (p<0.01), the low-frequency decreased (p<0.01), LF/HF ratio decreased consequently (p<0.01) compared to DOX only treatment. In all DOX treated animals, disbalance of oxidative status in heart tissue and early myocardial lesions were found and were significantly reduced in rats receiving Frl pretreatment. Autonomic modulation accompanied the development of DOX-induced cardiotoxicity in rat model of colorectal cancer and was prevented by Frl pretreatment. Our results demonstrated the positive prognostic power of HRV for the early detection of DOX-induced cardiotoxicity. PMID- 28727840 TI - Dual inhibition of Fes and Flt3 tyrosine kinases potently inhibits Flt3-ITD+ AML cell growth. AB - Acute myelogenous leukemia (AML) is often associated with activating mutations in the receptor tyrosine kinase, Flt3, including internal tandem duplications (ITDs) within the regulatory juxtamembrane region. Previous studies have linked Flt3-ITD to the activation of the Fes protein tyrosine kinase in AML, and RNAi-knockdown studies suggest that Fes may be required for Flt3 function. In this study, we tested Fes inhibitors from three different chemical classes for their growth suppressive activity against Flt3-ITD+ myeloid leukemia cell lines (MV4-11, MOLM 13 and MOLM-14) vs. myeloid cells with wild-type Flt3 (THP-1). All Fes inhibitors selectively inhibited the growth of Flt3-ITD+ AML cells, with IC50 values for diaminopyrimidine and pyrrolopyridine inhibitors ranging from 19 to 166 nM. In contrast, a pyrazolopyrimidine inhibitor was less potent in Flt3-ITD+ AML cells, with IC50 values in the 1.0 MUM range. In vitro kinase assays showed that the most potent inhibitors of Flt3-ITD+ AML cell proliferation blocked both Fes and Flt3-ITD kinase activity, while the pyrazolopyrimidine was more selective for Fes vs. Flt3-ITD. All three inhibitors induced significant apoptosis in Flt3-ITD+ AML cells, with potency equivalent to or greater than the established Flt3-ITD inhibitor, tandutinib. Transformation of TF-1 cells with Flt3-ITD resulted in constitutive activation of endogenous Fes, and rendered the cells highly sensitive to all three Fes inhibitors with IC50 values in the 30-500 nM range. The pyrrolopyridine compound also induced apoptotic responses in patient-derived Flt3-ITD+ AML bone marrow cells but not in normal bone marrow mononuclear cells. These results demonstrate that Fes kinase activity contributes to Flt3-ITD signaling in AML, and suggests that dual inhibition of both Flt3 and Fes may provide a therapeutic advantage for the treatment of Flt3-ITD+ AML. PMID- 28727842 TI - How issue frames shape beliefs about the importance of climate change policy across ideological and partisan groups. AB - We use an experiment to examine whether the way in which climate change is framed affects individuals' beliefs about its importance as a policy issue. We employ frames that emphasize national security, human rights, and environmental importance about the consequences of climate change. We find no evidence that issue frames have an overall effect on opinions about the importance of climate change policy. We do find some evidence that the effect of issue frames varies across ideological and partisan groups. Most notably, issue frames can lead Republicans and those on the political right to view climate change policy as less important. We conclude by discussing our findings relative to extant literature and considering the implications of our findings for those who seek to address the issue of climate change. PMID- 28727841 TI - River-specific macrogenomic diversity in Simulium guianense s. l. (Diptera: Simuliidae), a complex of tropical American vectors associated with human onchocerciasis. AB - Simulium guianense Wise is a Latin American vector complex of black flies associated with transmission of the causal agent of human onchocerciasis (river blindness). An analysis of the chromosomal banding patterns of 607 larvae of S. guianense s. l. revealed a high level of variation involving 83 macrogenomic rearrangements across 25 populations in Brazil, French Guiana, and Venezuela. The 25 populations were assigned to 13 cytoforms (A1, A2, B1-B4, C, D, E1-E4, and F), some of which are probably valid species. Based on geographical proximity, a member of the B group of cytoforms probably represents the name-bearing type specimen of S. guianense and the primary vector in the last-remaining onchocerciasis foci in the Western Hemisphere. Cytoform B3 in Amapa State is implicated as an anthropophilic simuliid in an area currently and historically free of onchocerciasis. Distributions of cytoforms are associated with geography, elevation, and drainage basin, and are largely congruent with ecoregions. Despite extraordinarily large larval populations of S. guianense s. l. in big rivers and consequent production of female flies for dispersal, the cytoforms maintain their chromosomal distinction within individual rivers, suggesting a high degree of fidelity to the specialized breeding habitats-rocky shoals-of the natal rivers. PMID- 28727843 TI - Atomistic modeling of alternating access of a mitochondrial ADP/ATP membrane transporter with molecular simulations. AB - The mitochondrial ADP/ATP carrier (AAC) is a membrane transporter that exchanges a cytosolic ADP for a matrix ATP. Atomic structures in an outward-facing (OF) form which binds an ADP from the intermembrane space have been solved by X-ray crystallography, and revealed their unique pseudo three-fold symmetry fold which is qualitatively different from pseudo two-fold symmetry of most transporters of which atomic structures have been solved. However, any atomic-level information on an inward-facing (IF) form, which binds an ATP from the matrix side and is fixed by binding of an inhibitor, bongkrekic acid (BA), is not available, and thus its alternating access mechanism for the transport process is unknown. Here, we report an atomic structure of the IF form predicted by atomic-level molecular dynamics (MD) simulations of the alternating access transition with a recently developed accelerating technique. We successfully obtained a significantly stable IF structure characterized by newly formed well-packed and -organized inter domain interactions through the accelerated simulations of unprecedentedly large conformational changes of the alternating access without a prior knowledge of the target protein structure. The simulation also shed light on an atomistic mechanism of the strict transport selectivity of adenosine nucleotides over guanosine and inosine ones. Furthermore, the IF structure was shown to bind ATP and BA, and thus revealed their binding mechanisms. The present study proposes a qualitatively novel view of the alternating access of transporters having the unique three-fold symmetry in atomic details and opens the way for rational drug design targeting the transporter in the dynamic functional cycle. PMID- 28727844 TI - Revisiting the concept of a cytopathic viral infection. PMID- 28727845 TI - Emergent multisystemic Enterococcus infection threatens endangered Christmas Island reptile populations. AB - Multisystemic infections with a morphologically unusual bacterium were first observed in captive critically endangered Lister's geckos (Lepidodactylus listeri) on Christmas Island in October 2014. Since then the infection was identified in another captive critically endangered lizard species, the blue tailed skink (Cryptoblepharus egeriae) and two species of invasive geckos; the four clawed gecko (Gehyra mutilata) and Asian house gecko (Hemidactylus frenatus), in a wide geographic range across the east side of the island. The Gram and periodic acid-Schiff positive cocci to diplococci have a propensity to form chains surrounded by a matrix, which ultrastructurally appears to be formed by fibrillar capsular projections. The bacterium was associated with severe and extensive replacement of tissues, but minimal host inflammatory response. Attempts to grow the organism in culture and in embryonated eggs were unsuccessful. Molecular characterisation of the organism placed it as a novel member of the genus Enterococcus. Disease Risk Analyses including this organism should now be factored into conservation management actions and island biosecurity. PMID- 28727847 TI - Outstanding micro-endemism in New Caledonia: More than one out of ten animal species have a very restricted distribution range. AB - New Caledonia is a biodiversity hotspot, with an extremely high number of endemic species with narrow distribution ranges that are at high risk of extinction due to open-cast nickel mining, invasive species and seasonal man-induced fires. Mentions of micro-endemism permeate the literature on the biota of this archipelago. However, so far there has been no research comparing distribution range in different animal groups. The aim of this study is to examine the implication of different sampling effort variables in order to distinguish micro endemicity from data deficiency, and evaluate the distribution range, frequency, and extent to which micro-endemism is common to several groups of organisms. We compiled a dataset derived from publications in Zoologia Neocaledonica, comprising 1,149 species, of which 86% are endemic to New Caledonia. We found that the sampling effort variables that were best correlated with distribution range were the number of sampling dates and the number of collectors per species. The median value of sampling dates was used to establish a cut-off point for defining adequately sampled species. We showed that, although only 52% of species were sampled adequately enough to determine their distribution range, the number of species with a very narrow distribution range was still high. Among endemics from New Caledonia, 12% (116 species) have ranges <=5.2km2 and 3.9% (38 species) have ranges between 23 and 100 km2. Surprisingly, a similar trend was observed in non-endemic species: 22% occurred in areas <= 5.2 km2, and 8% in areas 23-100 km2, suggesting that environmental dissimilarity may play an important role in the distribution of these species. Micro-endemic species were predominant in 18 out of 20 orders. These results will contribute to a re-assessment of the IUCN red list of species in this archipelago, indicating that at least 116 species are probably critically endangered. PMID- 28727846 TI - Effects of high-intensity interval versus mild-intensity endurance training on metabolic phenotype and corticosterone response in rats fed a high-fat or control diet. AB - The aim of the present study was to compare the effects of high-intensity interval training (HI) to mild-intensity endurance training (ME), combined with a high-fat diet (HFD) or control diet (CD) on metabolic phenotype and corticosterone levels in rats. Fifty-three rats were randomized to 6 groups according to diet and training regimen as follows: CD and sedentary (CS, n = 11), CD and ME (CME, n = 8), CD and HI (CHI, n = 8), HFD and sedentary (HS, n = 10), HFD and ME (HME, n = 8), and HFD and HI (HHI, n = 8). All exercise groups were trained for 10 weeks and had matched running distances. Dietary intake, body composition, blood metabolites, and corticosterone levels were measured. Histological lipid droplets were observed in the livers. The HFD led to hyperglycemia, hyperlipidemia and higher body fat (all, P < 0.01, eta2 > 0.06), as well as higher corticosterone levels (P < 0.01, eta2 = 0.09) compared with the CD groups. Exercise training improved fat weight, glucose, and lipid profiles, and reduced corticosterone levels (P < 0.01, eta2 = 0.123). Furthermore, body and fat weight, serum glucose and triglycerides, lipid content in the liver, and corticosterone levels (P < 0.05) were lower with HI training compared to ME training. Reductions in HFD-induced body weight gain, blood glucose and lipid profiles, and corticosterone levels, as well as improvements in QUICKI were better with HHI compared to HME. Correlation analyses revealed that corticosterone levels were significantly associated with phenotype variables (P < 0.01). Corticosterone level was inversely correlated with QUICKI (r = -0.38, P < 0.01). Altogether, these results indicate that HFD may elicit an exacerbated basal serum corticosterone level and thus producing a metabolic imbalance. Compared with ME training, HI training contributes to greater improvements in metabolic and corticosterone responses, leading to a greater reduction in susceptibility to HFD-induced disorders. PMID- 28727848 TI - The nuclear proteome of Trypanosoma brucei. AB - Trypanosoma brucei is a protozoan flagellate that is transmitted by tsetse flies into the mammalian bloodstream. The parasite has a huge impact on human health both directly by causing African sleeping sickness and indirectly, by infecting domestic cattle. The biology of trypanosomes involves some highly unusual, nuclear-localised processes. These include polycistronic transcription without classical promoters initiated from regions defined by histone variants, trans splicing of all transcripts to the exon of a spliced leader RNA, transcription of some very abundant proteins by RNA polymerase I and antigenic variation, a switch in expression of the cell surface protein variants that allows the parasite to resist the immune system of its mammalian host. Here, we provide the nuclear proteome of procyclic Trypanosoma brucei, the stage that resides within the tsetse fly midgut. We have performed quantitative label-free mass spectrometry to score 764 significantly nuclear enriched proteins in comparison to whole cell lysates. A comparison with proteomes of several experimentally characterised nuclear and non-nuclear structures and pathways confirmed the high quality of the dataset: the proteome contains about 80% of all nuclear proteins and less than 2% false positives. Using motif enrichment, we found the amino acid sequence KRxR present in a large number of nuclear proteins. KRxR is a sub-motif of a classical eukaryotic monopartite nuclear localisation signal and could be responsible for nuclear localization of proteins in Kinetoplastida species. As a proof of principle, we have confirmed the nuclear localisation of six proteins with previously unknown localisation by expressing eYFP fusion proteins. While proteome data of several T. brucei organelles have been published, our nuclear proteome closes an important gap in knowledge to study trypanosome biology, in particular nuclear-related processes. PMID- 28727849 TI - Associations between PPARG polymorphisms and the risk of essential hypertension. AB - BACKGROUND: Peroxisome proliferator-activated receptor gamma (PPARG) plays an important role in the pathogenesis and maintenance of essential hypertension (EH). It has been suggested that polymorphisms of PPARG are associated with the risk of EH. However, findings to date remain controversial. To elucidate the associations between the PPARG Pro12Ala and C161T polymorphisms and EH risk, a meta-analysis was carried out. METHODS: A comprehensive literature search of PubMed, Embase, CNKI (Chinese National Knowledge Infrastructure), VIP and Wanfang databases was conducted. The pooled odds ratios (ORs) and 95% confidence interval (CI) were calculated to estimate the size of the effect using the random-effects model. At the same time, the pooled standardized mean difference (SMD) with 95% CI was used for the meta-analysis of the PPARG Pro12Ala polymorphism and blood pressure. RESULTS: Finally, Fifteen papers (seventeen studies) including 4,151 cases and 4,997 controls to evaluate the association of the PPARGPro12Ala polymorphism and EH risk, were included in this study. Overall, the results suggested that Ala allele was associated with the decreased EH risk (for allelic model, OR = 0.757, 95%CI: 0.624-0.918, P = 0.005; for dominant model, OR = 0.771, 95%CI: 0.627-0.946, P = 0.013). The subgroup analysis stratified by ethnicity showed that the significant association between the PPARG Pro12Ala polymorphism and EH was only detected in the Asian subgroup. There was no difference in blood pressure values between Ala carriers and non-carriers. For the C161T polymorphism, only 5 studies comprising 1,118 cases and 1,357 controls met the inclusion criteria. The overall results showed that the PPARG C161T polymorphism was not associated with the risk of EH. But in the subgroup analysis, we found that the PPARG C161T polymorphism significantly associated with the risk of EH in the Asian subgroup (for allelic model, OR = 0.719, 95% CI: 0.537-0.963, P = 0.027; for dominant model, OR = 0.653, 95% CI: 0.439-0.972, P = 0.036). CONCLUSION: Our meta-analysis suggested that the PPARG polymorphisms might be associated with the risk of EH. PMID- 28727850 TI - Hybrid Cubature Kalman filtering for identifying nonlinear models from sampled recording: Estimation of neuronal dynamics. AB - Kalman filtering methods have long been regarded as efficient adaptive Bayesian techniques for estimating hidden states in models of linear dynamical systems under Gaussian uncertainty. Recent advents of the Cubature Kalman filter (CKF) have extended this efficient estimation property to nonlinear systems, and also to hybrid nonlinear problems where by the processes are continuous and the observations are discrete (continuous-discrete CD-CKF). Employing CKF techniques, therefore, carries high promise for modeling many biological phenomena where the underlying processes exhibit inherently nonlinear, continuous, and noisy dynamics and the associated measurements are uncertain and time-sampled. This paper investigates the performance of cubature filtering (CKF and CD-CKF) in two flagship problems arising in the field of neuroscience upon relating brain functionality to aggregate neurophysiological recordings: (i) estimation of the firing dynamics and the neural circuit model parameters from electric potentials (EP) observations, and (ii) estimation of the hemodynamic model parameters and the underlying neural drive from BOLD (fMRI) signals. First, in simulated neural circuit models, estimation accuracy was investigated under varying levels of observation noise (SNR), process noise structures, and observation sampling intervals (dt). When compared to the CKF, the CD-CKF consistently exhibited better accuracy for a given SNR, sharp accuracy increase with higher SNR, and persistent error reduction with smaller dt. Remarkably, CD-CKF accuracy shows only a mild deterioration for non-Gaussian process noise, specifically with Poisson noise, a commonly assumed form of background fluctuations in neuronal systems. Second, in simulated hemodynamic models, parametric estimates were consistently improved under CD-CKF. Critically, time-localization of the underlying neural drive, a determinant factor in fMRI-based functional connectivity studies, was significantly more accurate under CD-CKF. In conclusion, and with the CKF recently benchmarked against other advanced Bayesian techniques, the CD-CKF framework could provide significant gains in robustness and accuracy when estimating a variety of biological phenomena models where the underlying process dynamics unfold at time scales faster than those seen in collected measurements. PMID- 28727851 TI - Unintentional and self-poisoning mortalities in Mexico, 2000-2012. AB - INTRODUCTION: Poisoning remains a major worldwide public health problem. Mortality varies by country, region and ethnicity. The objective of this study is to analyze recent trends in poisoning mortality in the Mexican population. METHODS: Data regarding mortality induced by poisoning was obtained from a publicly available national database maintained by the National Institute of Statistics and Geography. RESULTS: During the period from 2000 to 2012, average mortality rates for unintentional and self-poisoning were 1.09 and 0.41 per 100000 population, respectively. The highest mortality rate for unintentional poisoning was in older individuals of both genders while the highest mortality for self-poisoning was in older men and young women. Additional studies are needed in Mexico, especially those that analyze risk factors in older individuals and young women. PMID- 28727852 TI - Ash dieback epidemic in Europe: How can molecular technologies help? PMID- 28727853 TI - Independent and joint effects of moderate alcohol consumption and smoking on the risks of non-alcoholic fatty liver disease in elderly Chinese men. AB - BACKGROUND: Whether cigarette smoking and moderate drinking are associated with non-alcoholic fatty liver disease (NAFLD)has not been fully described. This study investigated the separate and joint effects of smoking and moderate drinking on Chinese men with NAFLD. METHODS: Across-sectional assay from DFTJ Cohort study was performed with a size of 9432 elderly Chinese men excluding excessive alcohol consumption (<210g/week). Fatty liver was diagnosed by standardized ultrasonographic inspection. The odds ratio (OR) of alcohol consumption and smoking for the prevalence of NAFLD were analyzed using multiple logistic regression with multiple adjustments. RESULTS: The prevalence of NAFLD in current smokers (pack-year>=40) and drinkers (80~210g/week or drinking duration>=35years) was significantly higher than that in non-smokers and non-drinkers, respectively. The combination of current smoking (pack-year>=40) and drinking (80~210g/week) was associated with the highest risk of NAFLD (OR 1.85; 95% confidence interval [CI] 1.28-2.68;P<0.01). The similar combined effect was found in participants with pack-year>=40 and drinking duration>=35 years (OR 1.72; 95% CI 1.26 2.34;P<0.01). Moreover, an interaction was observed between current smoking and moderate drinking in NAFLD. CONCLUSIONS: In elderly Chinese men, cigarette smoking and moderate alcohol consumption exerts an evident joint effect and interaction on the prevalence of NAFLD, although both are significantly and independently associated with NAFLD prevalence. Such findings highlight particular significance of avoidance of cigarette and alcohol on NAFLD prevention. PMID- 28727854 TI - Toxoplasma gondii: Entry, association, and physiological influence on the central nervous system. AB - Toxoplasma gondii is one of the world's most successful parasites, in part because of its ability to infect and persist in most warm-blooded animals. A unique characteristic of T. gondii is its ability to persist in the central nervous system (CNS) of a variety of hosts, including humans and rodents. How, what, and why T. gondii encysts in the CNS has been the topic of study for decades. In this review, we will discuss recent work on how T. gondii is able to traverse the unique barrier surrounding the CNS, what cells of the CNS play host to T. gondii, and finally, how T. gondii infection may influence global and cellular physiology of the CNS. PMID- 28727855 TI - Association of APOE gene polymorphism with lipid profile and coronary artery disease in Afro-Caribbeans. AB - OBJECTIVES: Apolipoprotein E gene (APOE) polymorphism is associated with the lipid profile and cardio-vascular disease. However, these relationships vary between ethnic groups. We evaluated, for the first time in an Afro-Caribbean population, the distribution of APOE polymorphisms and their associations with coronary artery disease (CAD), the lipid profile and other cardio-metabolic risk factors. METHODS: We studied 712 Afro-Caribbean subjects including 220 with documented CAD and 492 healthy subjects. TaqMan assays were performed to genotype rs7412 and rs429358, the two variants that determine the APOE alleles epsilon2, epsilon3 and epsilon4. The association between APOE genotype and the lipid profile was analysed by comparing epsilon2 carriers, epsilon3 homozygotes and epsilon4 carriers. RESULTS: The frequencies of epsilon2, epsilon3 and epsilon4 in the overall sample were 8%, 70% and 22%, respectively. CAD was not associated with APOE polymorphism. The total cholesterol level was higher in epsilon4 carriers compared with epsilon2 carriers: 5.07 vs 4.59 mmol/L (P = 0.016). The LDL-cholesterol level was lower in APOE epsilon2 carriers compared with epsilon3 homozygotes and epsilon4 carriers: 2.65 vs 3.03 and 3.17 mmol/L, respectively (p = 0.002). The total cholesterol/HDL-cholesterol and LDL-cholesterol/HDL cholesterol ratios were similar in the three allelic groups. APOE polymorphism was not associated with diabetes, hypertension, waist circumference or body mass index. CONCLUSIONS: Our results indicate that APOE gene polymorphism is associated with the lipid profile but not with CAD in Afro-Caribbean people. This lack of association with CAD may be explained by the low atherogenic profile observed in epsilon4 carriers, which may warrant further investigation. PMID- 28727857 TI - An Unusual Laryngeal Foreign Body-A Bee Stinger in the Epiglottis. PMID- 28727856 TI - Systematic studies of the interactions between a model polyphenol compound and microbial beta-glucosidases. AB - Lignin is a major obstacle for cost-effective conversion of cellulose into fermentable sugars. Non-productive adsorption onto insoluble lignin fragments and interactions with soluble phenols are important inhibition mechanisms of cellulases, including beta-glucosidases. Here, we examined the inhibitory effect of tannic acid (TAN), a model polyphenolic compound, on beta-glucosidases from the bacterium Thermotoga petrophila (TpBGL1 and TpBGL3) and archaeon Pyrococcus furiosus (PfBGL1). The results revealed that the inhibition effects on beta glucosidases were TAN concentration-dependent. TpBGL1 and TpBGL3 were more tolerant to the presence of TAN when compared with PfBGL1, while TpBGL1 was less inhibited when compared with TpBGL3. In an attempt to better understand the inhibitory effect, the interaction between TAN and beta-glucosidases were analyzed by isothermal titration calorimetry (ITC). Furthermore, the exposed hydrophobic surface areas in beta-glucosidases were analyzed using a fluorescent probe and compared with the results of inhibition and ITC. The binding constants determined by ITC for the interactions between TAN and beta-glucosidases presented the same order of magnitude. However, the number of binding sites and exposed hydrophobic surface areas varied for the beta-glucosidases studied. The binding between TAN and beta-glucosidases were driven by enthalpic effects and with an unfavorable negative change in entropy upon binding. Furthermore, the data suggest that there is a high correlation between exposed hydrophobic surface areas and the number of binding sites on the inhibition of microbial beta glucosidases by TAN. These studies can be useful for biotechnological applications. PMID- 28727858 TI - Association of Velopharyngeal Insufficiency With Quality of Life and Patient Reported Outcomes After Speech Surgery. AB - Importance: Patients with cleft palate and other causes of velopharyngeal insufficiency (VPI) suffer adverse effects on social interactions and communication. Measurement of these patient-reported outcomes is needed to help guide surgical and nonsurgical care. Objectives: To further validate the VPI Effects on Life Outcomes (VELO) instrument, measure the change in quality of life (QOL) after speech surgery, and test the association of change in speech with change in QOL. Design, Setting, and Participants: Prospective descriptive cohort including children and young adults undergoing speech surgery for VPI in a tertiary academic center. Participants completed the validated VELO instrument before and after surgical treatment. Main Outcomes and Measures: The main outcome measures were preoperative and postoperative VELO scores and the perceptual speech assessment of speech intelligibility. The VELO scores are divided into subscale domains. Changes in VELO after surgery were analyzed using linear regression models. VELO scores were analyzed as a function of speech intelligibility adjusting for age and cleft type. The correlation between speech intelligibility rating and VELO scores was estimated using the polyserial correlation. Results: Twenty-nine patients (13 males and 16 females) were included. Mean (SD) age was 7.9 (4.1) years (range, 4-20 years). Pharyngeal flap was used in 14 (48%) cases, Furlow palatoplasty in 12 (41%), and sphincter pharyngoplasty in 1 (3%). The mean (SD) preoperative speech intelligibility rating was 1.71 (1.08), which decreased postoperatively to 0.79 (0.93) in 24 patients who completed protocol (P < .01). The VELO scores improved after surgery (P<.001) as did most subscale scores. Caregiver impact did not change after surgery (P = .36). Speech Intelligibility was correlated with preoperative and postoperative total VELO score (P < .01) and to preoperative subscale domains (situational difficulty [VELO-SiD, P = .005] and perception by others [VELO-PO, P = .05]) and postoperative subscale domains (VELO-SiD [P = .03], VELO-PO [P = .003]). Neither the VELO total nor subscale score change after surgery was correlated with change in speech intelligibility. Conclusions and Relevance: Speech surgery improves VPI-specific quality of life. We confirmed validation in a population of untreated patients with VPI and included pharyngeal flap surgery, which had not previously been included in validation studies. The VELO instrument provides patient-specific outcomes, which allows a broader understanding of the social, emotional, and physical effects of VPI. Level of Evidence: 2. PMID- 28727860 TI - Do Not Miss the Fourth Dimension of the Nasal Airway. PMID- 28727859 TI - Space Flight-Associated Neuro-ocular Syndrome. AB - New and unique physiologic and pathologic systemic and neuro-ocular responses have been documented in astronauts during and after long-duration space flight. Although the precise cause remains unknown, space flight-associated neuro-ocular syndrome (SANS) has been adopted as an appropriate descriptive term. The Space Medicine Operations Division of the US National Aeronautics and Space Administration (NASA) has documented the variable occurrence of SANS in astronauts returning from long-duration space flight on the International Space Station. These clinical findings have included unilateral and bilateral optic disc edema, globe flattening, choroidal and retinal folds, hyperopic refractive error shifts, and nerve fiber layer infarcts. The clinical findings of SANS have been correlated with structural changes on intraorbital and intracranial magnetic resonance imaging and in-flight and terrestrial ultrasonographic studies and ocular optical coherence tomography. Further study of SANS is ongoing for consideration of future manned missions to space, including a return trip to the moon or Mars. PMID- 28727861 TI - Patient Preference Research in Otolaryngology: What Do Patients Want? PMID- 28727862 TI - Misspelled Author Name. PMID- 28727863 TI - YAG Laser Vitreolysis-Is It as Clear as It Seems? PMID- 28727864 TI - Concerns About Methodology of a Trial Investigating Vaginal Health During Aromatase Inhibitor Therapy for Breast Cancer. PMID- 28727866 TI - Pediatric Posttonsillectomy Analgesia Before and After the Black Box Warning Against Codeine Use. PMID- 28727865 TI - Proton Beam Radiotherapy and Concurrent Chemotherapy for Unresectable Stage III Non-Small Cell Lung Cancer: Final Results of a Phase 2 Study. AB - Importance: Proton beam radiotherapy (PBT) has the potential to reduce toxic effects in the definitive management of locally advanced non-small cell lung cancer (NSCLC), but long-term prospective data are lacking. Objective: To report the final (5-year) results of a prospective study evaluating concurrent chemotherapy and high-dose PBT to treat unresectable stage III NSCLC. Design, Setting, and Participants: In this open-label, single-group assignment study, with median follow-up of 27.3 months for all patients and 79.6 months for survivors, 64 patients were enrolled and analyzed; inclusion criteria were unresectable IIIA/IIIB histologically confirmed NSCLC, Karnofsky performance status 70 to 100, and 6-month prediagnosis weight loss of no more than 10%. Staging used positron emission tomography and/or computed tomography. Induction chemotherapy was allowed. Interventions: Concurrent chemotherapy (carboplatin paclitaxel) and passively scattered PBT (74-Gy relative biological effectiveness) in all patients. Main Outcomes and Measures: Kaplan-Meier analysis of overall survival (OS), progression-free survival (PFS), actuarial distant metastasis, and locoregional recurrence. Patterns of treatment failure were categorized as local/regional or distant. Acute and late toxic effects were prospectively assigned using Common Terminology Criteria for Adverse Events, v3.0. Results: Of 64 patients (22 [34%] female; median [range] age, 70 [37-78] years; stage IIIA, 30 [47%]; IIIB, 34 [53%]), 17 (27%) were alive at last follow-up. Median OS was 26.5 months (5-year OS, 29%; 95% CI, 18%-41%). Five-year PFS was 22% (95% CI, 12% 32%); 5-year actuarial distant metastasis and locoregional recurrence were 54% (n = 36) and 28% (n = 22), respectively. Treatment failures were largely (31 [48%] patients) distant, with low rates of crude local (10 [16%]) and regional (9 [14%]) recurrences. Rates of grade 2 and 3 acute esophagitis were 18 (28%) and 5 (8%), respectively. Acute grade 2 pneumonitis occurred in 1 (2%) patient. Late toxic effects were uncommon: 1 (2%) patient developed an esophageal stricture (grade 2) and 1 (2%) grade 4 esophagitis. Late grades 2 and 3 pneumonitis occurred in 10 (16%) and 8 (12%), respectively. Two (3%) patients developed a bronchial stricture (grade 2), and 1 (2%) a grade 4 bronchial fistula. There were no acute or late grade 5 toxic effects. Conclusions and Relevance: Concurrent chemotherapy and PBT to treat unresectable NSCLC afford promising clinical outcomes and rates of toxic effects compared with historical photon therapy data. Further optimization of proton therapy, particularly intensity-modulated proton therapy, is still needed. PMID- 28727867 TI - Unintended Consequences of Machine Learning in Medicine. PMID- 28727868 TI - Morphologic three-dimensional scanning of fallopian tubes to assist ovarian cancer diagnosis. AB - The majority of high-grade serous ovarian cancers is now believed to originate in the fallopian tubes. Therefore, current practices include the pathological examination of excised fallopian tubes. Detection of tumors in the fallopian tubes using current clinical approaches remains difficult but is of critical importance to achieve accurate staging and diagnosis. Here, we present an intraoperative imaging system for the detection of human fallopian tube lesions. The system is based on optical coherence tomography (OCT) to access subepithelial tissue architecture. To demonstrate that OCT could identify lesions, we analyzed 180 OCT volumes taken from five different ovarian lesions and from healthy fallopian tubes, and compared them to standard pathological review. We demonstrated that qualitative features could be matched to pathological conditions. We then determined the feasibility of intraluminal imaging of intact human fallopian tubes by building a dedicated endoscopic single-fiber OCT probe to access the mucosal layer inside freshly excised specimens from five patients undergoing prophylactic surgeries. The probe insertion into the lumen acquired images over the entire length of the tubes without damaging the mucosa, providing the first OCT images of intact human fallopian tubes. PMID- 28727869 TI - Solid tissue simulating phantoms having absorption at 970 nm for diffuse optics. AB - Tissue simulating phantoms can provide a valuable platform for quantitative evaluation of the performance of diffuse optical devices. While solid phantoms have been developed for applications related to characterizing exogenous fluorescence and intrinsic chromophores such as hemoglobin and melanin, we report the development of a poly(dimethylsiloxane) (PDMS) tissue phantom that mimics the spectral characteristics of tissue water. We have developed these phantoms to mimic different water fractions in tissue, with the purpose of testing new devices within the context of clinical applications such as burn wound triage. Compared to liquid phantoms, cured PDMS phantoms are easier to transport and use and have a longer usable life than gelatin-based phantoms. As silicone is hydrophobic, 9606 dye was used to mimic the optical absorption feature of water in the vicinity of 970 nm. Scattering properties are determined by adding titanium dioxide, which yields a wavelength-dependent scattering coefficient similar to that observed in tissue in the near-infrared. Phantom properties were characterized and validated using the techniques of inverse adding-doubling and spatial frequency domain imaging. Results presented here demonstrate that we can fabricate solid phantoms that can be used to simulate different water fractions PMID- 28727870 TI - Concerns About Methodology of a Trial Investigating Vaginal Health During Aromatase Inhibitor Therapy for Breast Cancer. PMID- 28727871 TI - Biosimilars in Oncology in the United States: A Review. AB - Importance: Biosimilars are biological medicines that contain a highly similar version of the active substance of an already approved biologic reference product. The availability of biosimilars might provide an opportunity to lower health care expenditures as a result of the inherent price competition with their reference product. Understanding how biosimilar cancer drugs are regulated, approved, and paid for, as well as their impact in a value-based care environment, is essential for physicians and other stakeholders in oncology. Observations: Important structural and regulatory differences exist between biosimilar and generic medications. Minor differences in clinically inactive components with no clinically meaningful differences between biosimilars and their reference biologic are allowed. A biosimilar uses the same mechanism of action as the reference biologic, and its condition of use is the same as the approved indication, although extrapolation is permitted across indications under regulatory guidance. A biosimilar has to have a similar route of administration, dosage, and strength as the reference biologic. As patent expiration of multiple cancer biologics will occur in the next few years, more biosimilars might enter the market. Whether the approval and use of biosmilars as replacements for these heavily prescribed reference biologics will ultimately lead to cost savings is unknown and requires longer follow-up. Two biosimilars with an oncology supportive care indication are currently approved in the United States; both are myeloid growth factors. Conclusions and Relevance: The financial impact of generic drug competition can be dramatic, but significant differences in regulatory and development processes between generics and biosimilars limit such comparisons and likely present significant challenges for biosimilar approval and adoption in the US market. However, a value-based care environment and their cost savings potential make biosimilars an attractive option for the therapeutic arsenal. Oncologists' understanding of biosimilars is critical to moving forward. PMID- 28727872 TI - Fluid Leak Following Deep Midfacial Laceration. PMID- 28727873 TI - Potential of Prospective Particle Therapy Trials to Increase the Therapeutic Ratio for Locally Advanced Lung Cancer. PMID- 28727874 TI - Concerns About Methodology of a Trial Investigating Vaginal Health During Aromatase Inhibitor Therapy for Breast Cancer-Reply. PMID- 28727877 TI - Genetic Predisposition to Breast Cancer Due to Mutations Other Than BRCA1 and BRCA2 Founder Alleles Among Ashkenazi Jewish Women. AB - Importance: Among Ashkenazi Jewish women, 3 mutations in BRCA1 and BRCA2 severely increase the risk of breast and ovarian cancer. However, among Ashkenazi Jewish patients with breast cancer who do not carry one of these founder mutations, the likelihood of carrying another pathogenic mutation in BRCA1 or BRCA2 or another breast cancer gene is not known. This information would be valuable to the patient and family for cancer prevention and treatment. Objective: To determine the frequency of cancer-predisposing mutations other than the BRCA1 and BRCA2 founder alleles among patients of Ashkenazi Jewish ancestry with breast cancer. Design, Setting, and Participants: In this cohort study, genomic DNA of women from 12 major cancer centers with a first diagnosis of invasive breast cancer who identified themselves and all 4 grandparents as Ashkenazi Jewish and participated in the New York Breast Cancer Study (NYBCS) from 1996 to 2000 was sequenced for known and candidate breast cancer genes. Data analysis was performed from July 10, 2014, to March 10, 2017. Main Outcomes and Measures: Genomic DNA from all 1007 NYBCS probands was sequenced for 23 known and candidate breast cancer genes using BROCA, a targeted multiplexed gene panel. Results: Of the 1007 probands in the study, 903 probands had no founder mutations in BRCA1 or BRCA2; of these probands, 7 (0.8%) carried another pathogenic mutation in BRCA1 or BRCA2, and 31 (3.4%) carried a pathogenic mutation in another breast cancer gene (29 in CHEK2, and 1 each in BRIP1 and NBN). Of all inherited predispositions to breast cancer in the NYBCS, 73.8% (104 of 142) were due to a BRCA1 or BRCA2 founder allele, 4.9% (7 of 142) to another BRCA1 or BRCA2 mutation, and 21.8% (31 of 142) to a mutation in another gene. Overall, 14.1% (142 of 1007) of Ashkenazi Jewish patients with breast cancer in the NYBCS carried a germline mutation responsible for their disease: 11.0% (111 of 1007) in BRCA1 or BRCA2, and 3.1% (31 of 1007) in CHEK2 or another breast cancer gene. Of the 111 patients with BRCA1 or BRCA2 mutations, 57 (51.4%) had a mother or sister with breast or ovarian cancer and 54 patients (48.6%) did not. Conclusions and Relevance: Comprehensive sequencing would provide complete relevant genetic information for Ashkenazi Jewish patients with breast cancer. PMID- 28727878 TI - Concerns About Methodology of a Trial Investigating Vaginal Health During Aromatase Inhibitor Therapy for Breast Cancer. PMID- 28727879 TI - The United Kingdom Sets Limits on Experimental Treatments: The Case of Charlie Gard. PMID- 28727882 TI - Corneal Confocal Microscopy: An Imaging Endpoint for Axonal Degeneration in Multiple Sclerosis. AB - Purpose: To evaluate whether corneal confocal microscopy (CCM) detects axonal degeneration and whether this is associated with retinal nerve fiber degeneration and clinical disability in patients with multiple sclerosis (MS). Methods: Twenty five patients with MS and 25 healthy control subjects underwent CCM, optical coherence tomography (OCT), and assessment of neurological disability using the expanded disability status scale (EDSS) and MS severity score (MSSS). Results: In patients with MS compared with controls, there was a significant reduction in corneal nerve fiber density (CNFD), branch density (CNBD), and length (CNFL). There was no significant difference in CCM parameters between patients with optic neuritis (MS-ON) and without (MS-NON), or between relapsing-remitting (RRMS) and secondary-progressive MS (SPMS). There was significant thinning of the retinal nerve fiber layer (RNFL) in the global, temporal, temporal superior, and temporal inferior quadrants, with no difference between MS-ON and MS-NON. Patients with SPMS compared with RRMS had a significantly lower global, temporal superior, temporal inferior, nasal, and nasal superior RNFL. The EDSS and MSSS correlated significantly with CNBD, nasal, nasal superior, and nasal inferior RNFL and with CNBD and nasal inferior RNFL, respectively. Conclusions: CCM and OCT detect significant corneal and retinal nerve degeneration which relates to the severity of neurological deficits in patients with mild MS. PMID- 28727883 TI - Corneal Confocal Microscopy Is Emerging as a Powerful Diagnostic Tool for Assessing Systemic Neurologic Disease. PMID- 28727884 TI - OCT Angiography and Ellipsoid Zone Mapping of Macular Telangiectasia Type 2 From the AVATAR Study. AB - Purpose: To evaluate alterations on optical coherence tomography angiography (OCT A) and quantitatively assess alterations in the ellipsoid zone (EZ) in eyes with macular telangiectasia type 2 (MacTel type 2). Methods: The Observational Assessment of Visualizing and Analyzing Vessels With Optical Coherence Tomography Angiography in Retinal Diseases study is an institutional review board-approved prospective, observational study investigating OCT-A in macular disease. Patients underwent spectral-domain (SD)-OCT and OCT-A imaging at a single visit. SD-OCT data were analyzed using a novel OCT EZ-mapping software to obtain linear, area, and volumetric measurements of the EZ-retinal pigment epithelium (RPE) complex across the macular cube. OCT-A retinal capillary density was measured using the Optovue Avanti split-spectrum amplitude-decorrelation angiography algorithm. EZ RPE parameters were compared to age-matched, sex-matched controls. Results: Fourteen eyes of seven patients (mean age, 59 +/- 6.5 years) were analyzed. Mean visual acuity was 20/45 (range, 20/20-20/150). EZ-RPE central foveal mean thickness was 27.8 +/- 6.7 MUm, EZ-RPE central foveal thickness was 22.1 +/- 21.6 MUm, EZ-RPE central foveal area was 0.17 +/- 0.04 mm2, and EZ-RPE central subfield volume was 0.017 +/- 0.012 mm3. Each of these measurements was significantly inversely correlated with visual acuity (P < 0.02). In addition, all of these measurements were significantly reduced compared to controls (all P <= 0.005). OCT-A showed a reduced parafoveal vessel density of 50.8% temporally compared to 53.8% nasally (P = 0.01) in the superficial vascular plexus. In the deep vascular plexus, similar findings were noted with a parafoveal vessel density of 56.7% temporally and 58.8% nasally (P = 0.01). Conclusions: Abnormalities in EZ-RPE thickness, area, and volume are correlated with visual acuity in MacTel type 2, and may provide quantitative markers to measure disease progression and treatment response. OCT-A was a useful adjunct for determining disease severity. PMID- 28727885 TI - Sustained Activation of the Unfolded Protein Response Induces Cell Death in Fuchs' Endothelial Corneal Dystrophy. AB - Purpose: The unfolded protein response (UPR) is believed to play a role in the pathogenesis of Fuchs' endothelial corneal dystrophy (FECD). The purpose of this study was to investigate whether unfolded proteins accumulate in the corneal endothelium in FECD and if they are involved in triggering cell death. Methods: Descemet's membranes with corneal endothelial cells (CECs) were obtained during keratoplasty, and expression of aggresomes, type 1 collagen, fibronectin, and agrin was evaluated. Endoplasmic reticulum (ER) stress of immortalized human CECs from non-FECD subjects and from FECD patients (iHCEC and iFECD, respectively) were evaluated. The effect of MG132-mediated aggresome formation on the UPR and intrinsic pathway and the effect of mitochondrial damage on UPR were also examined. The effect of CHOP knockdown on the ER stress-mediated intrinsic pathway was also evaluated. Results: Aggresome formation was higher in iFECD than in iHCEC and was colocalized with type 1 collagen, fibronectin, and agrin. GRP78, phosphorylated IRE1, PERK, and CHOP showed higher activation in iFECD than in iHCEC. MG132-mediated aggresome formation upregulated ER stress sensors, the mitochondrial membrane potential drop, cytochrome c release to the cytoplasm, and activation of caspase-9 and -3. By contrast, staurosporine-mediated mitochondrial damage did not induce ER stress. Knockdown of CHOP attenuated the ER stress induced cleavage of caspase-9, which is caused by intrinsic pathway activation. Conclusions: Excessive synthesis of extracellular matrix proteins induced unfolded protein accumulation in FECD. Prolonged ER stress-mediated cell death, occurring via the intrinsic apoptotic signaling pathway, therefore might be associated with the pathogenesis of FECD. PMID- 28727887 TI - YAG Laser Vitreolysis vs Sham YAG Vitreolysis for Symptomatic Vitreous Floaters: A Randomized Clinical Trial. AB - Importance: Vitreous floaters are common and can worsen visual quality. YAG vitreolysis is an untested treatment for floaters. Objective: To evaluate YAG laser vitreolysis vs sham vitreolysis for symptomatic Weiss ring floaters from posterior vitreous detachment. Design, Setting, and Participants: This single center, masked, sham-controlled randomized clinical trial was performed from March 25, 2015, to August 3, 2016, in 52 eyes of 52 patients (36 cases and 16 controls) treated at a private ophthalmology practice. Interventions: Patients were randomly assigned to YAG laser vitreolysis or sham YAG (control). Main Outcomes and Measures: Primary 6-month outcomes were subjective change measured from 0% to 100% using a 10-point visual disturbance score, a 5-level qualitative scale, and National Eye Institute Visual Functioning Questionnaire 25 (NEI VFQ 25). Secondary outcomes included objective change assessed by masked grading of color fundus photography and Early Treatment Diabetic Retinopathy Study best corrected visual acuity. Results: Fifty-two patients (52 eyes; 17 men and 35 women; 51 white and 1 Asian) with symptomatic Weiss rings were enrolled in the study (mean [SD] age, 61.4 [8.0] years for the YAG laser group and 61.1 [6.6] years for the sham group). The YAG laser group reported greater symptomatic improvement (54%) than controls (9%) (difference, 45%; 95% CI, 25%-64%; P < .001). In the YAG laser group, the 10-point visual disturbance score improved by 3.2 vs 0.1 in the sham group (difference, -3.0; 95% CI, -4.3 to -1.7; P < .001). A total of 19 patients (53%) in the YAG laser group reported significantly or completely improved symptoms vs 0 individuals in the sham group (difference, 53%; 95% CI, 36%-69%, P < .001). Compared with sham, NEI VFQ-25 revealed improved general vision (difference, 16.3; 95% CI, 0.9-31.7; P = .04), peripheral vision (difference, 11.6; 95% CI, 0.8-22.4; P = .04), role difficulties (difference, 17.3; 95% CI, 8.0-26.6; P < .001), and dependency (difference, 5.6; 95% CI, 0.5 10.8; P = .03) among the YAG laser group. Best-corrected visual acuity changed by -0.2 letters in the YAG laser group and by -0.6 letters in sham group (difference, 0.4; 95% CI, -6.5 to 5.3; P = .94). No differences in adverse events between groups were identified. Conclusions and Relevance: YAG laser vitreolysis subjectively improved Weiss ring-related symptoms and objectively improved Weiss ring appearance. Greater confidence in these outcomes may result from larger confirmatory studies of longer duration. Trial Registration: clinicaltrials.gov NCT02897583. PMID- 28727888 TI - Association of Mental Health Status With Perception of Nasal Function. AB - Importance: Mental health issues are thought to be overrepresented among patients undergoing rhinoplasty and may be associated with patient presentation prior to surgery. Objective: To assess the association of poor mental health with perception of nasal function. Design, Setting, and Participants: A cross sectional study of patients presenting for airway assessment was performed from December 1, 2011, to October 31, 2015, at 2 tertiary rhinoplasty centers in Sydney, Australia. Mental health was independently defined preoperatively by the Mental Component Summary of the 36-item Short Form Health Survey version 2 (a score of <40 indicated poor mental well-being), the Rosenberg Self-Esteem Scale (a score of <15 indicated low self-esteem), and the Dysmorphic Concerns Questionnaire (a score of >11 indicated above-average dysmorphic concerns). Main Outcomes and Measures: Nasal function was assessed with patient-reported outcome measures, including the Nasal Obstruction Symptom Evaluation Scale, the 22-item Sinonasal Outcome Test, a visual analog scale to rate ease of breathing on the left and right sides, and Likert scales to assess overall function and nasal obstruction. Nasal airflow was assessed by nasal peak inspiratory flow, nasal airway resistance, and minimum cross-sectional area. Results: Among 495 patients in the study (302 women and 193 men; mean [SD] age, 36.5 [13.6] years), compared with patients with good mental health, those with poor mental health had poorer scores in all patient-reported outcome measures, including the visual analog scale for the left side (mean [SD], 51 [25] vs 42 [25]; P = .001), visual analog scale for the right side (mean [SD], 54 [24] vs 45 [26]; P < .001), Nasal Obstruction Symptom Evaluation Scale (mean [SD], 2.64 [0.95] vs 1.96 [1.04]; P < .001), 22-item Sinonasal Outcome Test (mean [SD], 2.14 [0.84] vs 1.33 [0.83]; P < .001), nasal obstruction (58 of 145 [40.2%] vs 83 of 350 [23.7%] with severe or worse obstruction; P < .001), and nasal function (72 of 145 [49.7%] vs 111 of 350 [31.8%] with poor or worse function; P < .001). Subclinical differences in nasal peak inspiratory flow could be demonstrated, but all other nasal airflow measures were similar. Low self-esteem produced a similar pattern, but dysmorphia did not. Conclusions and Relevance: Poor mental health status is associated with a poorer self-perception of nasal function compared with those who are mentally healthy with clinically similar nasal airflow. Clinicians should be aware that patients with poor mental health reporting obstructed airflow may in part be representing an extension of their negative emotions rather than true obstruction and may require further assessment prior to surgery. Level of Evidence: NA. PMID- 28727889 TI - Clinical assessment of uterine contractions. AB - The assessment of uterine contractions is important in clinical decision-making, but the precise role for appraising contractions remains controversial. Four clinical approaches to assessing contractions are available: manual palpation; intrauterine pressure determination; external tocodynamometry; and electrohysterography. Palpation is inexpensive and harmless but requires the constant bedside presence of a trained observer. Intrauterine pressure measurement is considered the most sensitive and specific technique, and has become the standard by which other methods are judged; however, its quantitative measurements are not always precise or reproducible. Moreover, the availability of intrauterine pressure measurements does not seem to improve maternal or neonatal outcomes in most situations. External tocodynamometry is the most widely used technique. It is easy to apply and provides reasonably accurate information about the frequency and duration of contractions, but not their amplitude. It can require frequent adjustment during labor and might not work well in patients who are obese. Electrohysterography is a recently available noninvasive technology that detects uterine electrical activity using electrodes placed on the mother's abdominal wall. This approach is at least as reliable and accurate as tocodynamometry. PMID- 28727890 TI - Surfactant concentration and type affects the removal of Escherichia coli from pig skin during a simulated hand wash. AB - : The effect of surfactant type and concentration on a bland soap formulation's ability to remove bacteria from hands remains largely unstudied. Several combinations of surfactants and water were combined to test bacterial removal efficacy using a hand-washing device (two pieces of pig skin and a mechanical motor) to simulate a hand wash. A nalidixic acid-resistant, nonpathogenic strain of Escherichia coli (ATCC 11229) was used. Two anionic surfactants, sodium lauryl sulphate and sodium stearoyl lactylate, and two nonionic surfactants, poloxamer 407 and sorbitan monostearate, each in concentrations of 2, 5 and 10% were studied. A slight positive (r2 = 0.17) but significant (P = 0.03) correlation was observed between hydrophile-lipophile balance value and mean log reduction. No correlation was observed between pH of the treatment solution and the mean log reduction (r2 = 0.05, P = 0.25). A 10% sodium lauryl sulphate mixture showed the highest log reduction (x- = 1.1 log CFU reduction, SD = 0.54), and was the only treatment significantly different from washing with water (P = 0.0005). There was a correlation between increasing surfactant concentrations above the critical micelle concentration, and mean microbial reduction (r2 = 0.62, P = 0.001). SIGNIFICANCE AND IMPACT OF THE STUDY: This study characterizes the role of surfactants in removing microbes during a hand wash. Numerous studies address how surfactants support antimicrobial effect in soap, or cause irritation of skin, but no published studies show which surfactants are best for removing microbes. We used pig skin as a model for human skin and a lathering device to simulate a hand wash. A 10% sodium lauryl sulphate mixture was the only treatment significantly different from a water wash. There was a strong correlation between increasing surfactant concentrations above the critical micelle concentration and mean microbial reduction. PMID- 28727891 TI - Prenatal diagnosis of Sotos syndrome characterized by fetal growth restriction. PMID- 28727892 TI - End-of-life experiences of family caregivers of deceased patients with cancer: A nation-wide survey. AB - OBJECTIVES: The purpose of this study was (a) to describe the end-of-life experience of family caregivers of cancer patients, (b) to describe talking about death and dying of the patient to minor children, and (c) to examine the association of family caregivers' experiences by their characteristics and talking about death and dying of the patient. METHODS: A cross-sectional nationwide survey of bereaved family caregivers was conducted. In total, 968 questionnaires were sent to bereaved family caregivers, and 711 were completed and returned. Fifty-three responses indicating patients had minor children were analyzed. Univariate analysis and principal component analysis were performed. RESULTS: Family caregivers' experiences were divided into 3 domains by principal component analysis: protect children from the patient's imminent death, little regard for the children, and worry and concern about the children's emotional reaction. Family caregivers' common experiences were as follows: "I wanted to know how the children felt," "I wanted to avoid making the children confused," and "I did not have much time to talk with and/or play with the children." About 30% of family caregivers reported that they "did not talk" about death and dying of patients to minor children. Spouses of patients and family caregivers who did not talk about death tended to experience distress and worry. CONCLUSIONS: Most family caregivers experienced worry and fear regarding minor children's emotional reaction; therefore, clinicians need to explain children's emotional and psychological reactions to family caregivers when a patient is at the end-of life. PMID- 28727893 TI - Outcome after prenatal and postnatal diagnosis of complex congenital heart defects and the influence of genetic anomalies. AB - OBJECTIVE: Determine prenatal detection rate, mortality and association with genetic abnormalities in patients with severe CHD. METHOD: Single center retrospective study in patients with severe CHD diagnosed prenatally or postnatally (2006 to 2014). RESULTS: A total of 567 patients were included, 176 (31%) after prenatal diagnosis, with large differences in prenatal detection rate among CHD types. Coarctation (24%), tetralogy of Fallot (21%) and univentricular heart (19%) were the most prevalent CHD. Overall mortality rate was 30% with important contributions of prenatal mortality including termination of pregnancy (40%) and postnatal compassionate care (15%). In the group requiring surgery, mortality rate was 12%. Genetic testing was available in 70%. A genetic cause was present in 140/394 patients tested (36%; 25% in the total group). Mortality was higher in the group with abnormal genetic testing compared with those with normal or no genetic testing (57/141 vs 112/423; p = 0,002). CONCLUSION: Only one third of severe CHD are detected; overall mortality remains high (30%) with major contributions of termination of pregnancy and compassionate care. A genetic cause was found in 36% and was associated with a decreased survival. Counseling must include the possibility of associated genetic pathology and its impact on survival. (c) 2017 John Wiley & Sons, Ltd. PMID- 28727894 TI - Enzymatic and Chemoenzymatic Three-Step Cascades for the Synthesis of Stereochemically Complementary Trisubstituted Tetrahydroisoquinolines. AB - Chemoenzymatic and enzymatic cascade reactions enable the synthesis of complex stereocomplementary 1,3,4-trisubstituted tetrahydroisoquinolines (THIQs) with three chiral centers in a step-efficient and selective manner without intermediate purification. The cascade employs inexpensive substrates (3 hydroxybenzaldehyde and pyruvate), and involves a carboligation step, a subsequent transamination, and finally a Pictet-Spengler reaction with a carbonyl cosubstrate. Appropriate selection of the carboligase and transaminase enzymes enabled the biocatalytic formation of (1R,2S)-metaraminol. Subsequent cyclization catalyzed either enzymatically by a norcoclaurine synthase or chemically by phosphate resulted in opposite stereoselectivities in the products at the C1 position, thus providing access to both orientations of the THIQ C1 substituent. This highlights the importance of selecting from both chemo- and biocatalysts for optimal results. PMID- 28727896 TI - ProSeal versus Classic laryngeal mask airway (LMA) for positive pressure ventilation in adults undergoing elective surgery. AB - BACKGROUND: The development of supraglottic airway devices has revolutionized airway management during general anaesthesia. Two devices are widely used in clinical practice to facilitate positive pressure ventilation: the ProSeal laryngeal mask airway (pLMA) and the Classic laryngeal mask airway (cLMA). It is not clear whether these devices have important clinical differences in terms of efficacy or complications. OBJECTIVES: To compare the effectiveness of the ProSeal laryngeal mask airway (pLMA) and the Classic LMA (cLMA) for positive pressure ventilation in adults undergoing elective surgery. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 3) in the Cochrane Library; MEDLINE (Ovid SP, 1997 to April 2017); Embase (Ovid SP, 1997 to April 2017); the Institute for Scientific Information (ISI) Web of Science (1946 to April 2017); and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) (EBSCO host, 1982 to April 2017).We searched trial registries for ongoing studies to April 2017.We did not impose language restrictions. We restricted our search to the time from 1997 to April 2017 because pLMA was introduced into clinical practice in the year 2000. SELECTION CRITERIA: We included randomized controlled trials (RCTs) that compared the effectiveness of pLMA and cLMA for positive pressure ventilation in adults undergoing elective surgery. We planned to include only data related to the first phase of cross-over RCTs. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by the Cochrane Collaboration. MAIN RESULTS: We included eight RCTs that involved a total of 829 participants (416 and 413 participants in the pLMA and cLMA groups, respectively). We identified six cross over studies that are awaiting classification; one is completed but has not been published, and data related to the first treatment period for the other five studies were not yet available. Seven included studies provided data related to the primary outcome, and eight studies provided data related to more than one secondary outcome.Our analysis was hampered by the fact that a large proportion of the included studies reported no events in either study arm. No studies reported significant differences between devices in relation to the primary review outcome: failure to adequately mechanically ventilate. We evaluated this outcome by assessing two variables: inadequate oxygenation (risk ratio (RR) 0.75, 95% confidence interval (CI) 0.17 to 3.31; four studies, N = 617) and inadequate ventilation (not estimable; one study, N = 80).More time was required to establish an effective airway using pLMA (mean difference (MD) 10.12 seconds, 95% CI 5.04 to 15.21; P < 0.0001; I2 = 73%; two studies, N = 434). Peak airway pressure during positive pressure ventilation was lower in cLMA participants (MD 0.84, 95% CI 0.02 to 1.67; P = 0.04; I2 = 0%; four studies, N = 259). Mean oropharyngeal leak (OPL) pressure was higher in pLMA participants (MD 6.93, 95% CI 4.23 to 9.62; P < 0.00001; I2 = 87%; six studies, N = 709).The quality of evidence for all outcomes, as assessed by GRADE score, is low mainly owing to issues related to blinding and imprecision.Data show no important differences between devices with regard to failure to insert the device, use of an alternate device, mucosal injury, sore throat, bronchospasm, gastric insufflation, regurgitation, coughing, and excessive leak. Data were insufficient to allow estimation of differences for obstruction related to the device. None of the studies reported postoperative nausea and vomiting as an outcome. AUTHORS' CONCLUSIONS: We are uncertain about the effects of either of the airway devices in terms of failure of oxygenation or ventilation because there were very few events. Results were uncertain in terms of differences for several complications. Low-quality evidence suggests that the ProSeal laryngeal mask airway makes a better seal and therefore may be more suitable than the Classic laryngeal mask airway for positive pressure ventilation. The Classic laryngeal mask airway may be quicker to insert, but this is unlikely to be clinically meaningful. PMID- 28727895 TI - How to become a killer, or is it all accidental? Virulence strategies in oral streptococci. AB - Streptococci are a diverse group of Gram-positive microorganisms sharing common virulence traits and similar strategies to escape the oral niche and establish an infection in other parts of the host organism. Invasive infection with oral streptococci is "a perfect storm" that requires the concerted action of multiple biotic and abiotic factors. Our understanding of streptococcal pathogenicity and infectivity should probably be less mechanistic and driven not only by the identification of novel virulence factors. The observed diversity of the genus, including the range of virulence and pathogenicity mechanisms, is most likely the result of interspecies interactions, a massive horizontal gene transfer between streptococci within a shared oral niche, recombination events, selection of specialized clones, and modification of regulatory circuits. Selective pressure by the host and bacterial communities is a driving force for the selection of virulence traits and shaping the streptococcal genome. Global regulatory events driving niche adaptation and interactions with bacterial communities and the host steer research interests towards attempts to define the oral interactome on the transcriptional level and define signal cross-feeding and co-expression and co regulation of virulence genes. PMID- 28727897 TI - The course of fear of cancer recurrence: Different patterns by age in breast cancer survivors. AB - OBJECTIVE: To examine the time course and predictors of fear of cancer recurrence (FCR) in breast cancer survivors over a period of 18 months after initial surgery. METHODS: Breast cancer patients (n = 267) were followed until 18 months after primary breast surgery. Shortly after surgery, participants completed the Life Orientation Test-Revised to measure optimism and the Concerns about Recurrence Scale to measure FCR. Mixed regression analysis was performed with age, optimism, marital status, education, type of surgery, with or without lymphectomy, chemotherapy, hormonal therapy, or radiotherapy, time since surgery, and all interactions with time as predictors of FCR. RESULTS: The final model included a significant interaction between age and time since surgery and a main effect for optimism. CONCLUSION: These results suggest that the course of FCR depends on the age of breast cancer survivors. Younger survivors showed an increase of fear during the first 1.5 years after breast surgery, whereas older survivors showed stable levels during the first 6 months after which it declined. Also, less optimistic survivors reported higher levels of FCR. Health care providers should pay (extra) attention to FCR in younger and less optimistic patients and offer psychological help when needed. PMID- 28727898 TI - Three-dimensional printing for patient counseling. PMID- 28727899 TI - Sacral neuromodulation for combined faecal and urinary incontinence following obstetric anal sphincter injury. AB - AIM: The aim of this study was to investigate the efficacy of sacral neuromodulation (SNM) in the treatment of faecal incontinence and concomitant urinary incontinence in women with a history of obstetric anal sphincter injury (OASIS). METHOD: In this prospective study, consecutive women with faecal incontinence following OASIS accepted for SNM were screened for concomitant urinary incontinence. The primary outcome was the change in urinary incontinence score on the International Consultation on Incontinence Questionnaire for Urinary Incontinence, Short Form (ICIQ-UI-SF), between baseline and 12 months. Secondary outcomes included the change in St Mark's score, sexual function and quality of life, change in grade of urinary incontinence and disappearance of urgency. RESULTS: From March 2012 to September 2014, 39 women with combined faecal incontinence and urinary incontinence received SNM. Thirty-seven women were available for analysis after 12 months. The mean reduction in the ICIQ-UI-SF score between the baseline and 12 months was 5.8 (95% CI 3.7-8.0, P < 0.001). ICIQ-UI-SF was reduced in 29 (78%) women, urinary incontinence resolved in 13/37 (35%, 95% CI 20%-50%) patients, and urgency disappeared in 14/33 (42%, 95% CI 26% 59%). The mean reduction in the St Mark's score was 10.6 (95% CI 8.6-12.7, P < 0.001). Disease-specific quality of life, Euroqual 5-dimension visual analogue scale (EQ-5D VAS) and several areas of sexual function changed significantly for the better. CONCLUSION: More than three-quarters of the women with combined faecal and urinary incontinence following OASIS reported a successful outcome with reduction in ICIQ-UI-SF at 12 months after SNM. PMID- 28727900 TI - Head midline position for preventing the occurrence or extension of germinal matrix-intraventricular hemorrhage in preterm infants. AB - BACKGROUND: Preterm birth is known to constitute the major risk factor for development of germinal matrix-intraventricular hemorrhage (GM-IVH). Head position may affect cerebral hemodynamics and thus may be involved indirectly in development of GM-IVH. Turning the head toward one side may functionally occlude jugular venous drainage on the ipsilateral side while increasing intracranial pressure and cerebral blood volume. Thus, it has been suggested that cerebral venous pressure is reduced and hydrostatic brain drainage improved if the patient is in supine midline position with the bed tilted 30 degrees . The midline position might be achieved in the supine position and, with the use of physical aids, in the lateral position as well. Midline position should be kept, at least when the incidence of GM-IVH is greatest, that is, during the first two to three days of life. OBJECTIVES: Primary objective To assess whether head midline position is more effective than any other head position for preventing or extending germinal matrix-intraventricular hemorrhage in infants born at <= 32 weeks' gestational age. Secondary objectives To perform subgroup analyses regarding gestational age, birth weight, intubated versus not intubated, and with or without GM-IVH at trial entry. SEARCH METHODS: We used the standard search strategy of the Cochrane Neonatal Review Group to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 8), MEDLINE via PubMed (1966 to September 19, 2016), Embase (1980 to September 19,.2016), and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1982 to September 19, 2016). We searched clinical trials databases, conference proceedings, and reference lists of retrieved articles for randomized controlled trials and quasi randomized trials. SELECTION CRITERIA: Randomized clinical controlled trials, quasi-randomized trials, and cluster-randomized controlled trials comparing placing very preterm infants in a head midline position versus placing them in a prone or lateral decubitus position, or undertaking a strategy of regular position change, or having no prespecified position. We included trials enrolling infants with existing GM-IVH and planned to assess extension of hemorrhage in a subgroup of infants. We planned to analyze horizontal (flat) versus head elevated positions separately for all body positions. DATA COLLECTION AND ANALYSIS: We used standard methods of the Cochrane Neonatal Review Group. For each of the included trials, two review authors independently extracted data (e.g., number of participants, birth weight, gestational age, initiation and duration of head midline position, co-intervention with horizontal vs head elevated position, use of physical aids to maintain head position) and assessed risk of bias (e.g., adequacy of randomization, blinding, completeness of follow-up). The primary outcomes considered in this review are GM-IVH , severe IVH, and neonatal death. MAIN RESULTS: Our search strategy yielded 2696 references. Two review authors independently assessed all references for inclusion. Two randomized controlled trials, for a total of 110 infants, met the inclusion criteria of this review. Both trials compared supine midline head position with the bed at 0 degrees versus supine head rotated 90 degrees with the bed at 0 degrees . We found no trials that compared supine versus prone midline head position, and no trials that compared effects of head tilting. We found no significant differences in rates of GM-IVH (typical risk ratio [RR] 1.14, 95% confidence interval [CI] 0.55 to 2.35; typical risk difference [RD] 0.03, 95% CI -0.13 to 0.18; two studies, 110 infants; I2 = 0% for RR and I2 = 0% for RD), severe IVH (typical RR 1.57, 95% CI 0.28 to 8.98; typical RD 0.02, 95% CI -0.06 to 0.10; two studies, 110 infants; I2 = 0% for RR and I2 = 0% for RD), and neonatal mortality (typical RR 0.52, 95% CI 0.16 to 1.65; typical RD -0.07, 95% CI -0.18 to 0.05; two studies, 110 infants; I2 = 28% for RR and I2 = 44% for RD). Among secondary outcomes, we found no significant differences in terms of cystic periventricular leukomalacia (one study; RR 3.25, 95% CI 0.14 to 76.01; RD 0.04, 95% CI -0.07 to 0.15), retinopathy of prematurity (one study; RR 2.27, 95% CI 0.85 to 6.11; RD 0.25, 95% CI -0.02 to 0.53), and severe retinopathy of prematurity (one study; RR 2.73, 95% CI 0.31 to 24.14; RD 0.09, 95% CI -0.09 to 0.26). None of the included trials reported on the other specified outcomes of this review (i.e., cerebellar hemorrhage, brain magnetic resonance imaging abnormalities, impairment in cerebral hemodynamics, long-term neurodevelopmental outcomes, and major neurodevelopmental disability). The quality of evidence supporting these findings is limited owing to the imprecision of the estimates. We identified no ongoing studies. AUTHORS' CONCLUSIONS: Given the imprecision of the estimate, results of this systematic review are consistent with beneficial or detrimental effects of a supine head midline position versus a lateral position and do not provide a definitive answer to the review question. PMID- 28727901 TI - Carbon-ion radiotherapy for isolated para-aortic lymph node recurrence from colorectal cancer. AB - BACKGROUND: The safety and effectiveness of carbon-ion radiotherapy (CIRT) for isolated para-aortic lymph node (PALN) metastasis was evaluated retrospectively. METHODS: CIRT for isolated PALN metastasis from CRC was performed in 34 cases from June 2006 to August 2015 in our institute. A median dose of 52.8 Gy(RBE) (range, 48-52.8 Gy(RBE)) was delivered with a median daily dose of 4.4 Gy(RBE) (range, 4.0-4.4 Gy(RBE)). RESULTS: The median follow-up duration for all patients was 24.4 months (range, 7-82.8 months). There were 13 cases (38.2%) who achieved complete response after treatment. The local control rates at 2 and 3 years were 70.1% and 70.1%, respectively. The overall survival rates at 2 and 3 years were 83.3% and 63.0%, respectively. The 3-year survival rates for Stage I-III were 68.7%, while those for Stage IV was 0%. The overall survival of cases with rectal cancer or with high CA19-9 values pre-CIRT tended to be worse. The median survival period was 41.7 months. Twelve of the 34 patients survived for more than 3 years. There were no adverse effects of Grade 3 or higher. CONCLUSIONS: CIRT for isolated PALN recurrence after curative resection for CRC appears effective and safe, and it is considered a promising therapy. PMID- 28727902 TI - Glucocorticoid assessment in the domestic horse: The impacts of time and climatic variables on sample integrity. AB - BACKGROUND: Assessment of faecal glucocorticoid metabolites (FGM) offers a noninvasive method of monitoring adrenal activity in domestic horses. Samples are collected on an opportunistic basis and, if they are not fresh or have been exposed to the elements before they are identified, may not accurately reflect FGM concentrations. OBJECTIVES: To explore the impact of a range of environmental conditions upon the integrity of FGM levels in equine faeces. STUDY DESIGN: In vitro experiment. METHOD: Equine faeces were exposed to six controlled environmental conditions intended to simulate a range of weather and seasonal patterns (temperate climate, high heat, high heat and rainfall, temperate climate and rainfall, high heat/temperate climate, freeze/thaw) over a period of 5 days. FGM were quantified using an enzyme-linked immunoassay. RESULTS: Faecal samples exposed to room temperature and high heat demonstrated significant increases in FGM levels over time. No changes in FGM levels were observed in the remaining treatments. MAIN LIMITATIONS: The study should be repeated in field conditions and with known high and low levels of FGM to further inform sampling regimes. CONCLUSIONS: Adrenal monitoring in the domestic horse should be performed with consideration of the impact of climate on the integrity of faecal samples in order to further inform sampling schedules and improve the reliability of results. PMID- 28727903 TI - Mechanochemistry Induced Using Force Exerted by a Functionalized Microscope Tip. AB - Atomic-scale mechanochemistry is realized from force exerted by a C60 functionalized scanning tunneling microscope tip. Two conformers of tin phthalocyanine can be prepared on coinage-metal surfaces. A transition between these conformers is induced on Cu(111) and Ag(100). Density-functional calculations reveal details of this reaction. Because of the large energy barrier of the reaction and the strong interaction of SnPc with Cu(111), the process cannot be achieved by electrical means. PMID- 28727904 TI - Electrophilic Amination with Nitroarenes. AB - An exceptionally general electrophilic amination, which directly transforms commercially available nitroarenes into alkylated aromatic aminoboranes with zinc organyl compounds was developed. The reaction starts with a two-step partial reduction of the nitro group to a nitrenoid, which is used in situ as the electrophilic amination reagent. To facilitate isolation, the resulting air- and moisture-sensitive aminoboranes were reacted with a range of electrophiles. The method not only represents a direct transformation of nitro compounds into electrophilic amination reagents but also provides an elegant alternative to dehydrocoupling methods for the generation of aminoboranes. PMID- 28727905 TI - Species richness and traits predict overyielding in stem growth in an early successional tree diversity experiment. AB - Over the last two decades, empirical work has established that higher biodiversity can lead to greater primary productivity; however, the importance of different aspects of biodiversity in contributing to such relationships is rarely elucidated. We assessed the relative importance of species richness, phylogenetic diversity, functional diversity, and identity of neighbors for stem growth 3 yr after seedling establishment in a tree diversity experiment in eastern Minnesota. Generally, we found that community-weighted means of key functional traits (including mycorrhizal association, leaf nitrogen and calcium, and waterlogging tolerance) as well as species richness were strong, independent predictors of stem biomass growth. More phylogenetically diverse communities did not consistently produce more biomass than expected, and the trait values or diversity of individual functional traits better predicted biomass production than did a multidimensional functional diversity metric. Furthermore, functional traits and species richness best predicted growth at the whole-plot level (12 m2 ), whereas neighborhood composition best predicted growth at the focal tree level (0.25 m2 ). The observed effects of biodiversity on growth appear strongly driven by positive complementary effects rather than by species-specific selection effects, suggesting that synergistic species' interactions rather than the influence of a few important species may drive overyielding. PMID- 28727906 TI - Potential of telmisartan in the treatment of benign prostatic hyperplasia. AB - Benign prostatic hyperplasia (BPH) is a common health problem in ageing men. This study was carried out to investigate the protective effect of telmisartan on testosterone-induced BPH in rats. Fifty-four male Wistar rats (200-250 g) were randomly divided into nine groups (n = 6) and orally treated for 28 consecutive days: group 1 - vehicle normal, olive oil (10 mL/kg); group 2 - BPH model control (10 mL/kg); groups 3-5 - telmisartan (5, 10 or 20 mg/kg, respectively); group 6 - pioglitazone (20 mg/kg); group 7 - celecoxib (20 mg/kg); group 8 - combination of telmisartan (5 mg/kg) and pioglitazone (20 mg/kg); group 9 - combination of telmisartan (5 mg/kg) and celecoxib (20 mg/kg). Animals in groups 2-9 were given testosterone propionate in olive oil (3 mg/kg) subcutaneously 15 min after pretreatments. On day 29, blood was collected for the estimation of serum testosterone and prostate-specific antigen (PSA). The prostates were excised, weighed and subjected to biochemical and histological studies. Testosterone injection induced significant increase in prostatic index, serum testosterone and PSA suggesting BPH as well as increased prostate oxidative stress which were ameliorated with the pretreatment of rats with telmisartan or co-administration of celecoxib and pioglitazone. Histological examination showed that testosterone disrupted the morphology of the prostate epithelial cells evidenced in the involution of the epithelial lining of the acini into the lumen indicating BPH which was reversed by telmisartan. Findings from this study showed that telmisartan alone or in combination with pioglitazone prevented the development of testosterone-induced prostatic hyperplasia. PMID- 28727907 TI - Novel role of surfactant protein A in bacterial sinusitis. AB - BACKGROUND: Chronic rhinosinusitis (CRS) is a common inflammatory disorder of the upper airway characterized by chronic inflammation and significant sinonasal remodeling. CRS is comprised of 2 major subgroups, based on whether polyps are present or absent. In some cases, it is characterized by colonization with opportunistic pathogens such as Pseudomonas aeruginosa (PA), Staphylococcus aureus, and other bacteria. The innate immune system of the sinonasal epithelium is the first line of defense against inhaled pathogens. Surfactant protein A (SP A) is a member of the collectin family secreted by the airway epithelia and plays a critical role in airway innate immunity, as it can aggregate bacteria. We hypothesized that SP-A plays a role in bacterial CRS. METHODS: Air-liquid interface (ALI) cultures of nasal epithelial cells were derived from human ex vivo healthy and CRS sinus tissues (n = 26) and challenged with PA. SP-A levels were measured with western blot and quantitative reverse transcript-polymerase chain reaction (qRT-PCR) in ALI and sinus tissues. RESULTS: We determined that SP A: (i) mRNA and protein levels are increased significantly in CRS tissues compared with healthy sinuses; (ii) although primarily expressed in the lung, it is also synthesized and expressed in sinonasal epithelia; (ii) is expressed in the sinuses of an SP-A humanized transgenic mouse but not in SP-A knockout mice; (iv) mRNA levels are upregulated significantly during PA challenge, but protein levels are downregulated 4 hours postchallenge and upregulated at 12 hours. CONCLUSION: Our data suggest that SP-A is expressed in the sinuses and that it plays a role in the sinus innate immune responses during bacterial infections. PMID- 28727908 TI - Leveraging a Clinical Phase Ib Proof-of-Concept Study for the GPR40 Agonist MK 8666 in Patients With Type 2 Diabetes for Model-Informed Phase II Dose Selection. AB - GPR40 mediates free fatty acid-induced insulin secretion in beta cells. We investigated the safety, pharmacokinetics, and glucose response of MK-8666, a partial GPR40 agonist, after once-daily multiple dosing in type 2 diabetes patients. This double-blind, multisite, parallel-group study randomized 63 patients (placebo, n = 18; 50 mg, n = 9; 150 mg, n = 18; 500 mg, n = 18) for 14 day treatment. The results showed no serious adverse effects or treatment-related hypoglycemia. One patient (150-mg group) showed mild-to-moderate transaminitis at the end of dosing. Median MK-8666 Tmax was 2.0-2.5 h and mean apparent terminal half-life was 22-32 h. On Day 15, MK-8666 reduced fasting plasma glucose by 54.1 mg/dL (500 mg), 36.0 mg/dL (150 mg), and 30.8 mg/dL (50 mg) more than placebo, consistent with translational pharmacokinetic/pharmacodynamic model predictions. Maximal efficacy for longer-term assessment is projected at 500 mg based on exposure-response analysis. In conclusion, MK-8666 was generally well tolerated with robust glucose-lowering efficacy. PMID- 28727909 TI - Positive allergen reaction in allergic and nonallergic rhinitis: a systematic review. AB - BACKGROUND: The diagnosis of allergic rhinitis (AR) is based on cutaneous and serological assessment to determine immunoglobulin E (IgE)-mediated disease. However, discrepancies between these tests and nasal provocation exist. Patients diagnosed as non-allergic rhinitis (NAR) but with positive nasal allergen provocation test (NAPT) may represent a local allergic condition or entopy, still suitable to allergy interventions. The objective of this study was to determine the frequency of nasal reactivity toward allergens among AR and NAR patients, and to describe the diagnostic characteristics of NAPT methodologies. METHODS: EMBASE (1947-) and Medline (1946-) were searched until December 8, 2015. A search strategy was used to identify studies on AR or NAR patients subjected to diagnostic local nasal provocation. All studies providing original NAPT data among the AR or NAR population were included. Meta-analysis of proportion data was presented as a weighted probability % (95% confidence interval [CI]). RESULTS: The search yielded 4504 studies and 46 were included. The probability of nasal allergen reactivity for the AR population was 86.3% (95% CI, 84.4 to 88.1) and in NAR was 24.7% (95% CI, 22.3 to 27.2). Reactivity was high with pollen for both AR 97.1% (95% CI, 94.2 to 99.2) and NAR 47.5% (95% CI, 34.8 to 60.4), and lowest with dust for both AR 79.1% (95% CI, 76.4 to 81.6) and NAR 12.2% (95% CI, 9.9 to 14.7). NAPT yielded high positivity when defined by subjective end-points: AR 91.0% (95% CI, 86.6 to 94.8) and NAR 30.2% (95% CI, 22.9 to 37.9); and lower with objective end-points: AR 80.8% (95% CI, 76.8 to 84.5) and NAR 14.1% (95% CI, 11.2 to 17.2). CONCLUSION: Local allergen reactivity is demonstrated in 26.5% of patients previously considered non-allergic. Similarly, AR, when defined by skin prick test (SPT) or serum specific IgE (sIgE), may lead to 13.7% of patients with inaccurate allergen sensitization or non-allergic etiologies. PMID- 28727910 TI - HLA-B*40:01:45, a novel variant of HLA-B*40:01, discovered in a Taiwanese hematopoitic stem cell donor. AB - Two nucleotide replacements within HLA-B*40:01:01 result in the novel allele, HLA B*40:01:45. PMID- 28727912 TI - Multivariate Analysis for Quantification of Plutonium(IV) in Nitric Acid Based on Absorption Spectra. AB - Development of more effective, reliable, and fast methods for monitoring process streams is a growing opportunity for analytical applications. Many fields can benefit from online monitoring, including the nuclear fuel cycle where improved methods for monitoring radioactive materials will facilitate maintenance of proper safeguards and ensure safe and efficient processing of materials. Online process monitoring with a focus on optical spectroscopy can provide a fast, nondestructive method for monitoring chemical species. However, identification and quantification of species can be hindered by the complexity of the solutions if bands overlap or show condition-dependent spectral features. Plutonium(IV) is one example of a species which displays significant spectral variation with changing nitric acid concentration. Single variate analysis (i.e., Beer's Law) is difficult to apply to the quantification of Pu(IV) unless the nitric acid concentration is known and separate calibration curves have been made for all possible acid strengths. Multivariate or chemometric analysis is an approach that allows for the accurate quantification of Pu(IV) without a priori knowledge of nitric acid concentration. PMID- 28727911 TI - Ultrasound processing of liquid system(s) and its antimicrobial mechanism of action. AB - : Ultrasound creates cavitation phenomena, resulting in the formation of several free radicals, namely OH and H, due to the breakdown of the H2 O molecule. These radicals affect the cellular integrity of the bacteria, causing the inactivation of several processes, and thus it is important to unravel the mechanism of action of this technology. This research looks into the application and mechanism of action of ultrasound technology as a means of disinfection by acoustic cavitation. Sterile water and synthetic waste water were inoculated with different mutants of Escherichia coli K12 strains containing deletions in genes affecting specific functional properties of E. coli. These were: dnak soxR, soxS, oxyR, rpoS, gadA/gadB, gadC and yneL. Escherichia coli K-12 DeltaoxyR appeared to be more resistant to the treatment together with gadW, gadX, gabT and gabD, whereas the mutant K-12 DeltadnaK was more sensitive with c. 2.5 log (CFU per ml) reduction in comparison to their isogenic wild-type E. coli K-12. This indicates that the dnaK gene participates in general stress response and more specifically to hyperosmotic stress. The other E. coli deleted genes tested (soxS, rpoS, gadB, gadC, yneL) did not appear to be involved in protection of microbial cells against ultrasound. SIGNIFICANCE AND IMPACT OF THE STUDY: This study looks at the mechanism of action of ultrasound technology for the disinfection of wastewater. Different mutants with deleted genes were used to study the respective sensitivity or resistance to this treatment. This is essential to characterize changes at the molecular level, which might be occurring during treatment, resulting in bacterial adaptation. PMID- 28727913 TI - Alpha-l-Fucosidase Immunoassay for Early Detection of Hepatocellular Carcinoma. AB - Detection of alpha-l-fucosidase has been shown to have relevance in diagnosing hepatocellular carcinoma. Few assays have been developed to measure this enzyme, with most relying on colorimetric techniques involving the enzyme's kinetics. While these assays are facile and quick, the sensitivity is not always sufficient for early tumor detection. To improve upon previous assays for alpha-l fucosidase, a fluorescence based immunoassay was produced implementing an alpha-l fucosidase specific antibody (FUCA2). The immobilization of the alpha-l fucosidase-specific antibody onto a quartz slide was investigated with several bioconjugation approaches and an immunoassay for detection of alpha-l-fucosidase was produced. The immunoassay was utilized to produce calibration curves for quantifying alpha-l-fucosidase concentrations in both PBS and human blood serum. A detection limit of 10 nM was found using human blood serum, which is well below the diagnostic cutoff point of 80 nM. PMID- 28727914 TI - eNORA2 Exact NOE Analysis Program. AB - We have recently developed an NMR protocol to extract exact distances between nuclei in proteins from an exact interpretation of NOESY buildup intensities (eNOEs). This enabled us to calculate multistate structural ensembles that exhibit realistic spatial sampling and long-range correlations. Our initial studies were laborious and required a deep understanding of the underlying spin dynamics. Here, we present a MatLab package that integrates all data processing steps required to convert intensities of assigned peaks in NOESY series into upper and lower distance limits for structure calculation. Those steps include organization of the data in object format, extraction of autorelaxation and cross relaxation rate constants by fitting of diagonal peak decays and cross peak buildups, validation of the data, correction for spin diffusion, graphical display of the results, and generation of distance limits in CYANA compatible format. The analysis may be carried out using a full relaxation matrix or a simplified "divide and conquer" approach that allows for partial deuteration of protons. As the program does not require expertise beyond that of standard resonance assignment/structure calculation, it is suitable for experts and nonexperts alike. PMID- 28727915 TI - Improving Accuracy, Diversity, and Speed with Prime Macrocycle Conformational Sampling. AB - A novel method for exploring macrocycle conformational space, Prime macrocycle conformational sampling (Prime-MCS), is introduced and evaluated in the context of other available algorithms (Molecular Dynamics, LowModeMD in MOE, and MacroModel Baseline Search). The algorithms were benchmarked on a data set of 208 macrocycles which was curated for diversity from the Cambridge Structural Database, the Protein Data Bank, and the Biologically Interesting Molecule Reference Dictionary. The algorithms were evaluated in terms of accuracy (ability to reproduce the crystal structure), diversity (coverage of conformational space), and computational speed. Prime-MCS most reliably reproduced crystallographic structures for RMSD thresholds >1.0 A, most often produced the most diverse conformational ensemble, and was most often the fastest algorithm. Detailed analysis and examination of both typical and outlier cases were performed to reveal characteristics, shortcomings, expected performance, and complementarity of the methods. PMID- 28727916 TI - Transient Catalytic Voltammetry of Sulfite Oxidase Reveals Rate Limiting Conformational Changes. AB - Sulfite oxidases are metalloenzymes that oxidize sulfite to sulfate at a molybdenum active site. In vertebrate sulfite oxidases, the electrons generated at the Mo center are transferred to an external electron acceptor via a heme domain, which can adopt two conformations: a "closed" conformation, suitable for internal electron transfer, and an "open" conformation suitable for intermolecular electron transfer. This conformational change is an integral part of the catalytic cycle. Sulfite oxidases have been wired to electrode surfaces, but their immobilization leads to a significant decrease in their catalytic activity, raising the question of the occurrence of the conformational change when the enzyme is on an electrode. We recorded and quantitatively modeled for the first time the transient response of the catalytic cycle of human sulfite oxidase immobilized on an electrode. We show that conformational changes still occur on the electrode, but at a lower rate than in solution, which is the reason for the decrease in activity of sulfite oxidases upon immobilization. PMID- 28727917 TI - A 3D-Printed, Portable, Optical-Sensing Platform for Smartphones Capable of Detecting the Herbicide 2,4-Dichlorophenoxyacetic Acid. AB - Onsite rapid detection of herbicides and herbicide residuals in environmental and biological specimens are important for agriculture, environmental concerns, food safety, and health care. The traditional method for herbicide detection requires expensive laboratory equipment and a long turnaround time. In this work, we developed a single-stripe microliter plate smartphone-based colorimetric device for rapid and low-cost in-field tests. This portable smartphone platform is capable of screening eight samples in a single-stripe microplate. The device combined the advantages of small size (50 * 100 * 160 mm3) and low cost ($10). The platform was calibrated by using two different dye solutions, i.e. methyl blue (MB) and rhodamine B, for the red and green channels. The results showed good correlation with results attained from a traditional laboratory reader. We demonstrated the application of this platform for detection of the herbicide 2,4 dichlorophenoxyacetic acid in the range of 1 to 80 ppb. Spiked samples of tap water, rat serum, plasma, and human serum were tested by our device. Recoveries obtained varied from 95.6% to 105.2% for all of the spiked samples using the microplate reader and from 93.7% to 106.9% for all of the samples using the smartphone device. This work validated that the smartphone optical-sensing platform is comparable to the commercial microplate reader; it is eligible for onsite, rapid, and low-cost detection of herbicides for environmental evaluation and biological monitoring. PMID- 28727918 TI - Sensitive and Quantitative Detection of Anti-Poly(ethylene glycol) (PEG) Antibodies by Methoxy-PEG-Coated Surface Plasmon Resonance Sensors. AB - Pre-existing and induced anti-poly(ethylene glycol) (PEG) antibodies (abs) have been shown to be related with limitation of therapeutic efficacy and reduction in tolerance of several therapeutic agents. However, the current methods to detect anti-PEG abs are tedious and usually lack quantification. A facile, rapid, sensitive, and reliable technique to detect anti-PEG abs is highly desired in both research and clinic settings. In this work, we have presented a surface plasmon resonance (SPR) biosensor technique for the detection of anti-PEG abs and compared three PEG surface chemistries. Methoxy-PEG (mPEG) 5k was found to have the best performance. The detection of anti-PEG abs directly from diluted blood serum was achieved within 40 min. Detection sensitivity is as good as or better than enzyme-linked immunosorbent assay (ELISA). Furthermore, different antibody isotypes can be quantitatively differentiated by adopting secondary antibodies. A pilot study has been performed to analyze clinical blood samples using this technology, demonstrating its potential as a convenient and powerful method to prescreen and monitor anti-PEG abs in the patients before or after they receive treatment with PEG-containing drugs. PMID- 28727919 TI - Comprehensive Multiphase (CMP) NMR Monitoring of the Structural Changes and Molecular Flux Within a Growing Seed. AB - A relatively recent technique termed comprehensive multiphase (CMP) NMR spectroscopy was used to investigate the growth and associated metabolomic changes of 13C-labeled wheat seeds and germinated seedlings. CMP-NMR enables the study of all phases in intact samples (i.e., liquid, gel-like, semisolid, and solid), by combining all required electronics into a single NMR probe, and can be used for investigating biological processes such as seed germination. All components, from the most liquid-like (i.e., dissolved metabolites) to the most rigid or solid-like (seed coat) were monitored in situ over 4 days. A wide range of metabolites were identified, and after 96 h of germination, the number of metabolites in the mobile phase more than doubled in comparison to 0 h (dry seed). This work represents the first application of CMP-NMR to follow biological processes in plants. PMID- 28727920 TI - Ballistic Penetration of Highly Charged Nanoaerosol Particles through a Lipid Monolayer. AB - To be used as a drug, inhaled nanoaerosol particles (NAPs) must first penetrate the lipid layer on top of the lung fluid before they will be able to reach the lung epithelium. We investigated how the penetration of NAPs through a model lipid monolayer (LM) depends upon their charging level and size. It was shown that deposition of NAPs 20-200 nm in diameter and charged to the Rayleigh limit gradually increased the surface tension of a dipalmitoylphosphatidylcholine monolayer (DPPC), indicating a loss of lipid molecules from the monolayer. This phenomenon was reproduced with a variety of NAPs produced from glucose, proteins, and polymers. Transfer of the lipid material into the subphase was documented by direct visualization of lipid nanoparticles in the subphase with atomic force microscopy after deposition of glucose NAPs on a DPPC monolayer, followed by collection of the lipid nanoparticles on a mica surface. Partial restoration of tension upon storage indicates that some of the lipid may return to the monolayer. Experiments with the deposition of highly charged calibrated polystyrene nanoparticles showed that the amount of lipid removed from the surface was roughly proportional to the overall surface area of the deposited NAPs. When the number of charges on the NAPs was reduced from their Rayleigh level of 103-104 units to 1-10 units, no notable changes in monolayer surface tension were observed even with prolonged deposition of such NAPs. It was therefore concluded that only highly charged NAPs of a certain size acquire sufficient speed from their attraction by mirror charges to enable ballistic penetration through a lipid monolayer. PMID- 28727921 TI - Effect of lysophosphatidylglycerol on intracellular free Ca2+ concentration in A10 vascular smooth muscle cells. AB - Although plasma levels of lysophosphatidylglycerol (LPG) are increased in hypertension, its role in the pathogenesis of vascular defects is not clear. In view of the importance of Ca2+ overload in causing vascular smooth muscle (VSM) dysfunction, the action of LPG on [Ca2+]i in cultured A10 VSM cell line was examined by using Fura 2-AM acetoxymethyl ester technique. LPG was found to induce a concentration-dependent increase in [Ca2+]i in VSM cells. This change was dependent both on the extracellular and intracellular Ca2+ sources, as it was reduced by 30% by EGTA, an extracellular Ca2+ chelator, and 70% by thapsigargin, a sarcoplasmic reticulum (SR) Ca2+-pump inhibitor. However the increase in [Ca2+]i due to LPG was not altered by caffeine or ryanodine, which affect Ca2+ release through the ryanodine receptors in the SR. On the other hand, LPG-induced change in [Ca2+]i was suppressed by 2-nitro-4-carboxyphenyl N,N diphenylcarbamate, a phospholipase C (PLC) inhibitor, as well as by xestospongin and 2-aminoethoxydiphenyl borate, two inositol trisphosphate (IP3) receptor inhibitors in the SR. These observations support the view that LPG-induced increase in [Ca2+]i in VSM cells is mainly a result of Ca2+ release from Ca2+ pool in the SR through PLC/IP3-sensitive signal transduction mechanism. Furthermore, it is suggested that the elevated level of LPG may induce intracellular Ca2+ overload and thus play a critical role in the development of vascular abnormalities. PMID- 28727922 TI - Considerations in physical therapy management of a non-responding patient with low back pain. AB - STUDY DESIGN: Case Study. BACKGROUND AND PURPOSE: Low back pain is a common condition managed by physical therapists (PT). Screening tools have been developed to assist the PT with medical screening of patients for serious disease. Sinister pathologies may present as musculoskeletal symptoms during the patient examination. It is important for the PT to frequently reevaluate their patient's response to therapeutic interventions and refer for further evaluation if they are not responding to conservative care. CASE DESCRIPTION: This case reports on the history and examination findings of a 36-year-old male presenting with recurrent low back pain. An emphasis is placed on the therapist's understanding and use of screening tools when interviewing patients and determining when medical referral may be indicated based on the patients history and examination findings. A review of the evidence on the diagnostic accuracy of screening strategies for malignancy in patients presenting with low back pain is presented. CONCLUSION: Sinister causes for low back pain are extremely rare. It is important that PTs be familiar with specific signs and symptoms that may indicate serious pathology when evaluating patients with low back pain. Identification of two red flags from this patient's history leads the clinician to refer the patient back to their primary care provider (PCP) for further investigation. They included: 1) the patient's inability to improve after one month and 2) clinicians' judgment. Use of "clinical judgment" may assist the PT in determining if their patient needs further investigation. PMID- 28727923 TI - Height Prediction From Ulna Length of Critically Ill Patients. AB - BACKGROUND: Ulna length (UL) has been used in mathematical formulas to predict the body height of healthy and sick individuals. However, the evaluation of its use with patients admitted to intensive care units (ICU) is scarce. The objective of this study was to develop a mathematical equation to estimate critically ill patients' height using the UL measure and to evaluate its agreement with measured standing height. METHODS: This cross-sectional study was performed at the ICU of a tertiary hospital in Brazil. A total of 100 patients aged >=18 years who had their body height measured before ICU admission were enrolled. The equation was developed through multiple linear regression, and its agreement was assessed through paired Student's t test and Bland-Altman plot. RESULTS: The following formula was obtained: height in cm = 153.492 - (7.97 * sex [sex: male = 1, female = 2]) + (0.974 * UL [in cm]). The difference between means of measured height (MH) and height estimated from UL was not significant (166.26 +/- 8.75 cm and 166.30 +/- 5.29 cm, respectively, P = .96), and a significant correlation (r = 0.624, P < .001) was detected. In the Bland-Altman analysis, UL was in agreement with MH; however, there was a significant bias (P < .001) suggesting that it may be disproportional and dependent on the average's height value. CONCLUSION: The mathematical equation for height estimation using UL developed in this study matched the MH of critically ill patients. However, we suggest more studies for its validation. PMID- 28727924 TI - Does early change predict long-term (6 months) improvements in subjects who receive manual therapy for low back pain? AB - Early change is commonly assessed for manual therapy interventions and has been used to determine treatment appropriateness. However, current studies have only explored the relationship of between or within-session changes and short-/medium term outcomes. The goal of this study was to determine whether pain changes after two weeks of pragmatic manual therapy could predict those participants with chronic low back pain who demonstrate continued improvements at 6-month follow up. This study was a retrospective observational design. Univariate logistic regression analyses were performed using a 33% and a 50% pain change to predict improvement. Those who experienced a >=33% pain reduction by 2 weeks had 6.98 (95% CI = 1.29, 37.53) times higher odds of 50% improvement on the GRoC and 4.74 (95% CI = 1.31, 17.17) times higher odds of 50% improvement on the ODI (at 6 months). Subjects who reported a >=50% pain reduction at 2 weeks had 5.98 (95% CI = 1.56, 22.88) times higher odds of a 50% improvement in the GRoC and 3.99 (95% CI = 1.23, 12.88) times higher odds of a 50% improvement in the ODI (at 6 months). Future studies may investigate whether a change in plan of care is beneficial for patients who are not showing early improvement predictive of a good long-term outcome. PMID- 28727925 TI - Investigating the Relationship Between Social and Economic Policy Views, Firearm Ownership, and Death by Firearm in a Sample of Suicide Decedents. AB - Extant literature provides evidence for the frequent use and lethality of firearms in suicide and the ability of means safety measures to prevent suicides; however, little evidence exists to provide an understanding of the characteristics that differentiate suicide decedents who die by firearm from those who die by other methods. In this study, we build on prior findings regarding the characteristics of those who die by firearms by examining the relationship between social and economic policy views and both firearm ownership and death by firearm in a sample of 160 American suicide decedents. We hypothesized that individuals with more conservative social and economic policy views would have higher rates of firearm ownership and would be more likely to die by firearm than would individuals with more liberal social and economic policy views. Furthermore, we hypothesized that differences in the likelihood of dying by a firearm would be accounted for by firearm ownership, providing preliminary evidence for a specific mechanism through which risk for death by firearm is conferred. As expected, suicide decedents with conservative social and economic policy views owned firearms at higher rates than did decedents with moderate or liberal views. The use of a firearm, the most common method across all decedents, was higher in individuals with conservative policy views. These results represent a novel angle from which to consider the importance of means safety efforts focused on firearm ownership and storage and limit concerns that firearm specific suicide research has relied too heavily on samples that are not representative of typical American suicide decedents. PMID- 28727927 TI - Technology Components as Adjuncts to Family-Based Pediatric Obesity Treatment in Low-Income Minority Youth. AB - BACKGROUND: Strategies to treat pediatric obesity are needed, especially among high-need populations. Technology is an innovative approach; however, data on technology as adjuncts to in-person treatment programs are limited. METHODS: A total of 64 children [body mass index (BMI) >=85th percentile, mean age = 9.6 +/- 3.1 years, 32.8% female, 84.4% Hispanic] were recruited to participate in one of three cohorts of a family-based behavioral group (FBBG) treatment program: FBBG only, TECH1, and TECH2. Rolling, nonrandomized recruitment was used to enroll participants into three cohorts from May 2014 to February 2015. FBBG began in May 2014 and received the standard, in-person 12-week treatment only (n = 21); TECH1 began in September 2014 and received FBBG plus a digital tablet equipped with a fitness app (FITNET) (n = 20); TECH2 began in February 2015 and received FBBG and FITNET, plus five individually tailored TeleMed health-coaching sessions delivered via Skype (n = 23). Child BMI z-score (BMI-z) was assessed at baseline and postintervention. Secondary aims examined weekly FBBG attendance, feasibility/acceptability of FITNET and Skype, and the effect of technology engagement on BMI-z. RESULTS: FBBG and TECH1 participants did not show significant reductions in BMI-z postintervention [FBBG: beta = -0.05(0.04), p = 0.25; TECH1: beta = -0.006(0.06), p = 0.92], but TECH2 participants did [beta = 0.09(0.02), p < 0.001] and TeleMed session participation was significantly associated with BMI-z reduction [beta = -0.04(0.01), p = 0.01]. FITNET use and FBBG attendance were not associated with BMI-z in any cohort. Overall, participants rated the technology as highly acceptable. CONCLUSIONS: Technology adjuncts are feasible, used by hard-to-reach participants, and show promise for improving child weight status in obesity treatment programs. PMID- 28727928 TI - Vascular senescence and ageing: a role for the MEOX proteins in promoting endothelial dysfunction. AB - In the vascular system, ageing is accompanied by the accrual of senescent cells and is associated with an increased risk of vascular disease. Endothelial cell (EC) dysfunction is a hallmark of vascular disease and is characterized by decreased angiogenic potential, reduced nitric oxide bioavailability, impaired vasodilation, increased production of ROS, and enhanced inflammation. In ECs, the major producer of nitric oxide is the endothelial nitric oxide synthase (eNOS) enzyme that is encoded by the NOS3 gene. NOS3/eNOS function is tightly regulated at both the transcriptional and post-transcriptional levels to maintain normal vascular function. A key transcriptional regulator of eNOS expression is p53, which has been shown to play a central role in mediating cellular senescence and thereby vascular dysfunction. Herein, we show that, in ECs, the MEOX homeodomain transcription factors decrease the expression of genes involved in angiogenesis, repress eNOS expression at the mRNA and protein levels, and increase the expression of p53. These findings support a role for the MEOX proteins in promoting endothelial dysfunction. PMID- 28727929 TI - Na+-H+ exchanger and proton channel in heart failure associated with Becker and Duchenne muscular dystrophies. AB - Cardiomyopathy is found in patients with Duchenne (DMD) and Becker (BMD) muscular dystrophies, which are linked muscle diseases caused by mutations in the dystrophin gene. Dystrophin defects are not limited to DMD but are also present in mild BMD. The hereditary cardiomyopathic hamster of the UM-X7.1 strain is a particular experimental model of heart failure (HF) leading to early death in muscular dystrophy (dystrophin deficiency and sarcoglycan mutation) and heart disease (delta-sarcoglycan deficiency and dystrophin mutation) in human DMD. Using this model, our previous work showed a defect in intracellular sodium homeostasis before the appearance of any apparent biochemical and histological defects. This was attributed to the continual presence of the fetal slow sodium channel, which was also found to be active in human DMD. Due to muscular intracellular acidosis, the intracellular sodium overload in DMD and BMD was also due to sodium influx through the sodium-hydrogen exchanger NHE-1. Lifetime treatment with an NHE-1 inhibitor prevented intracellular Na+ overload and early death due to HF. Our previous work also showed that another proton transporter, the voltage-gated proton channel (Hv1), exists in many cell types including heart cells and skeletal muscle fibers. The Hv1 could be indirectly implicated in the beneficial effect of blocking NHE-1. PMID- 28727930 TI - Visual Perception of British Women's Skin Color Distribution in Two Nonindustrialized Societies, the Maasai and the Tsimane'. AB - In women with lightly pigmented skin in particular, facial skin color homogeneity decreases with age, primarily due to chronic exposure to solar ultraviolet radiation (UVR), leading to a decrease in perceived health and attractiveness. Perception of female skin may be influenced by continuous exposure to, and thus familiarity with, age-related changes in visible skin condition in a given society. Men and women of two traditional societies, the Maasai (Tanzania) and the Tsimane' (Bolivia), unfamiliar with lighter colored skin, judged images of British women's facial skin for age, health, and attractiveness. In both samples, images with homogeneous skin color (from the cheeks of younger women) were judged to be younger and healthier and received a stronger preference than corresponding images with heterogeneous skin color (from older women). We suggest that (i) human sensitivity for quality-related information from facial skin color distribution is universal and independent of any known age-dependent variation in skin in a given population and (ii) skin discoloration is universally associated with less positive judgment. PMID- 28727931 TI - Pumping Milk Without Ever Feeding at the Breast in the Moms2Moms Study. AB - BACKGROUND: More than 85% of contemporary lactating women in the United States express their milk at least sometimes. Some produce milk exclusively through pumping. We characterized women who pumped but never fed at the breast and compared their infant feeding practices with those of women who fed at the breast with or without pumping. SUBJECTS AND METHODS: Study participants were those delivered at Ohio State University Wexner Medical Center in 2011 and completed a questionnaire at 12 months postpartum (n = 478). We used bivariate and multivariate approaches (survival analysis) to compare women who pumped but never fed at the breast with women who fed at the breast with or without pumping. RESULTS: Women (n = 33, 6.9%) who pumped but never fed at the breast comprised a diverse group but were more likely to have delivered preterm and were of lower socioeconomic status on average. They initiated pumping and formula feeding earlier (median = day 1 after delivery) and were more likely to report difficulty making enough milk compared with women who fed at the breast with or without pumping. They had much shorter total duration of milk production (adjusted hazard ratio = 3.3, 95% confidence interval: 2.1, 5.2) after controlling for clinical and sociodemographic confounders. CONCLUSIONS: Pumping without feeding at the breast is associated with shorter milk feeding duration and earlier introduction of formula compared with feeding at the breast with or without pumping. Establishing feeding at the breast, rather than exclusive pumping, may be important for achieving human milk feeding goals. PMID- 28727932 TI - Laboratory Studies of Methane and Its Relationship to Prebiotic Chemistry. AB - To examine how prebiotic chemical evolution took place on Earth prior to the emergence of life, laboratory experiments have been conducted since the 1950s. Methane has been one of the key molecules in these investigations. In earlier studies, strongly reducing gas mixtures containing methane and ammonia were used to simulate possible reactions in the primitive atmosphere of Earth, producing amino acids and other organic compounds. Since Earth's early atmosphere is now considered to be less reducing, the contribution of extraterrestrial organics to chemical evolution has taken on an important role. Such organic molecules may have come from molecular clouds and regions of star formation that created protoplanetary disks, planets, asteroids, and comets. The interstellar origin of organics has been examined both experimentally and theoretically, including laboratory investigations that simulate interstellar molecular reactions. Endogenous and exogenous organics could also have been supplied to the primitive ocean, making submarine hydrothermal systems plausible sites of the generation of life. Experiments that simulate such hydrothermal systems where methane played an important role have consequently been conducted. Processes that occur in other Solar System bodies offer clues to the prebiotic chemistry of Earth. Titan and other icy bodies, where methane plays significant roles, are especially good targets. In the case of Titan, methane is both in the atmosphere and in liquidospheres that are composed of methane and other hydrocarbons, and these have been studied in simulation experiments. Here, we review the wide range of experimental work in which these various terrestrial and extraterrestrial environments have been modeled, and we examine the possible role of methane in chemical evolution. Key Words: Methane-Interstellar environments-Submarine hydrothermal systems-Titan-Origin of life. Astrobiology 17, 786-812. PMID- 28727934 TI - Phylogenomics reveals a complex evolutionary history of lobed-leaf white oaks in western North America. AB - Species within the genus Quercus (oak) hybridize in complex patterns that have yet to be fully explored with phylogenomic data. Analyses to date have recovered reasonable divergent patterns, suggesting that the impact of introgression may not always be obvious in inferred oak phylogenies. We explore this phenomenon using RADseq data for 136 samples representing 54 oak species by conducting phylogenetic analyses designed to distinguish signals of lineage diversification and hybridization, focusing on the lobed-leaf species Quercus gambelii, Q. lobata, and Q. garryana in the context of a broad sampling of allied white oaks (Quercus section Quercus), and particularly the midwestern Q. macrocarpa. We demonstrate that historical introgressive hybridization between once sympatric species affects phylogeny estimation. Historical range expansion during periods of favorable climate likely explains our observations; analyses support genetic exchange between ancestral populations of Q. gambelii and Q. macrocarpa. We conclude that the genomic consequences of introgression caused the attraction of distant lineages in phylogenetic tree space, and that introgressive and divergent signals can be disentangled to produce a robust estimate of the phylogenetic history of the species. PMID- 28727933 TI - Genotype-specific acquisition, evolution and adaptation of characteristic mutations in hepatitis E virus. AB - Hepatitis E virus (HEV) infection is a major cause of acute hepatitis but also provokes chronic infection in immunocompromised patients. Although the pathogenesis and treatment outcome involve complex interplay between the virus and host, the nature of adaptive responses of HEV to the host immune system remain obscure at best. In this study, we used large-scale proteomic bioinformatics to profile characteristic mutations in human HEV isolates associated to ribavirin treatment failure, chronic hepatitis, hepatic failure or altered immunoreactivity. The prevalence of specific mutations was examined in a large number of protein sequences of ORF1 and ORF2 regions of the 3 major human derived HEV genotypes (1, 3 and 4). By analyzing potential B, CD4+ and CD8+ T cell epitopes, we found that many of these mutations overlap with the predicted epitopes and are frequently present among the 3 HEV genotypes. These overlapping mutations mediate reduced antigenicity. Finally, by delineation of diversification and evolution of the underlying epitopes, we observe that most of these variants apparently evolved earlier in genotype 1 when compared with genotypes 3 and 4. These results indicate that HEV is under substantial evolutionary pressure to develop mutations enabling evasion of the host immune response and resistance to antiviral treatment. This indicates the existence of an ongoing evolutionary arms race between human immunity, antiviral medication and HEV. PMID- 28727935 TI - Food Addiction: A Barrier for Effective Weight Management for Obese Adolescents. AB - BACKGROUND: Findings from studies of food addiction in adults suggest those with food addiction are less successful in weight-loss interventions. Little is known about food addiction in obesity treatment-seeking adolescents; therefore, the purpose of this study was to explore the prevalence of food addiction and correlates of food addiction symptoms in obese adolescents entering an outpatient, weight management program. METHODS: Obese adolescents (n = 26) were administered the Yale Food Addiction Scale for Children (YFAS-C), measures of appetitive responsiveness, and health-related quality of life (HRQOL) before and following a 12-week, outpatient, behavioral weight management program. Descriptive statistics and correlations between YFAS-C symptoms and study variables were performed and further examined with linear regression. Baseline differences were compared between those meeting criteria for food addiction to those who did not (independent t-tests) and pre-postweight management program changes were examined (paired t-tests). RESULTS: 30.7% met criteria for food addiction and 50% reported >=3 symptoms. Number of YFAS-C symptoms was correlated with appetitive responsiveness (r = 0.57, p < 0.05) and inversely correlated with all domains of HRQOL (r = 0.47-0.53, p < 0.05). Attrition rate was higher in adolescents with food addiction compared to those without (62.5% vs. 44.4%, p < 0.05). CONCLUSIONS: Adolescents with food addiction or with a higher number of food addiction symptoms may warrant additional resources to support adherence to and retention with a weight management program. Implementing screening measures for food addiction before enrolling in a weight management program may be an effective strategy to identify adolescents who may benefit from adjunct modalities. PMID- 28727936 TI - Helper T Cells and Cancer-Associated Inflammation: A New Direction for Immunotherapy? AB - CD4+ helper T cells are critical regulators in immunity and inflammation. Growing evidence has indicated their involvement in cancer, by shaping the tumor microenvironment. In this study, I summarize latest literature on Th2 and Th17 cells in cancer-associated inflammation and propose that they may be targeted for cancer immunotherapy. PMID- 28727937 TI - Preoperative Short Form Health Survey Score Is Predictive of Return to Play and Minimal Clinically Important Difference at a Minimum 2-Year Follow-up After Anterior Cruciate Ligament Reconstruction. AB - BACKGROUND: There is increased interest in understanding the preoperative determinants of postoperative outcomes. Return to play (RTP) and the patient reported minimal clinically important difference (MCID) are useful measures of postoperative outcomes after anterior cruciate ligament reconstruction (ACLR). PURPOSE: To define the MCID after ACLR and to investigate the role of preoperative outcome scores for predicting the MCID and RTP after ACLR. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: There were 294 active athletes enrolled as part of an institutional ACL registry with a minimum 2-year follow-up who were eligible for inclusion. A questionnaire was administered to elicit factors associated with RTP. Patient demographic and clinical data as well as patient-reported outcome measures were captured as part of the registry. Outcome measures included the International Knee Documentation Committee (IKDC) subjective knee evaluation form, Lysholm scale, and 12-Item Short Form Health Survey (SF-12) physical component summary (PCS) and mental component summary (MCS). Preoperative outcome score thresholds predictive of RTP were determined using a receiver operating characteristic (ROC) with area under the curve (AUC) analysis. The MCID was calculated using a distribution-based method. Multivariable logistic models were fitted to identify predictors for achieving the MCID and RTP. RESULTS: At a mean (+/-SD) follow-up of 3.7 +/- 0.7 years, 231 patients were included from a total 294 eligible patients. The mean age and body mass index were 26.7 +/- 12.5 years and 23.7 +/- 3.2 kg/m2, respectively. Of the 231 patients, 201 (87.0%) returned to play at a mean time of 10.1 months. Two year postoperative scores on all measures were significantly increased from preoperative scores (IKDC: 50.1 +/- 15.6 to 87.4 +/- 10.7; Lysholm: 61.2 +/- 18.1 to 89.5 +/- 10.4; SF-12 PCS: 41.5 +/- 9.0 to 54.7 +/- 4.6; SF-12 MCS: 53.6 +/- 8.1 to 55.7 +/- 5.7; P < .001 for all). The corresponding MCID values were 9.0 (IKDC), 10.0 (Lysholm), 5.1 (SF-12 PCS), and 4.3 (SF-12 MCS). Preoperative score thresholds predictive of RTP were the following: IKDC, 60.9; Lysholm, 57.0; SF-12 PCS, 42.3; and SF-12 MCS, 48.3. These thresholds were not independently predictive but achieved significance as part of the multivariable analysis. In the multivariable analysis for RTP, preoperative SF-12 PCS scores above 42.3 (odds ratio [OR], 2.73; 95% CI, 1.09-7.62) and SF-12 MCS scores above 48.3 (OR, 4.41; 95% CI, 1.80-10.98) were predictive for achieving RTP; an ACL allograft (OR, 0.26; 95% CI, 0.06-1.00) was negatively predictive of RTP. In the multivariable analysis for the MCID, patients with higher preoperative scores were less likely to achieve the MCID ( P < .0001); however, a higher preoperative SF-12 MCS score was predictive of achieving the MCID on the IKDC form (OR, 1.27; 95% CI, 1.11-1.52) and Lysholm scale (OR, 1.08; 95% CI, 1.00-1.16). Medial meniscal injuries, older age, and white race were also associated with a decreased likelihood for achieving the MCID. CONCLUSION: Preoperative SF-12 MCS and PCS scores were predictive of RTP after ACLR; patients scoring above 42.3 on the SF-12 PCS and 48.3 on the SF-12 MCS were more likely to achieve RTP. Additionally, we defined the MCID after ACLR and found that higher SF-12 MCS scores were predictive of achieving the MCID on knee-specific questionnaires. PMID- 28727938 TI - Difference in the response to angiotensin II between left and right ventricular endocardial endothelial cells. AB - Previous studies focused on the right ventricular endocardial endothelial cells (EECRs) and showed that angiotensin II (Ang II) induced increase in cytosolic and nuclear calcium via AT1 receptor activation. In the present study, we verified whether the response of left EECs (EECLs) to Ang II is different than that of EECRs. Our results showed that the EC50 of the Ang II-induced increase of cytosolic and nuclear calcium in EECLs was 10* higher (around 2 * 10-13 mol/L) than in EECRs (around 8 * 10-12 mol/L). The densities of both AT1 and AT2 receptors were also higher in EECLs than those previously reported in EECRs. The effect of Ang II was mediated in both cell types via the activation of AT1 receptors. Treatment with Ang II induced a significant increase of cytosolic and nuclear AT1 receptors in EECRs, whereas the opposite was found in EECLs. In both cell types, there was a transient increase of cytosolic and nuclear AT2 receptors following the Ang II treatment. In conclusion, our results showed that both AT1 and AT2 receptors densities are higher in both EECLs compared to what was reported in EECRs. The higher density of AT1 receptors in EECLs compared to REECs may explain, in part, the higher sensitivity of EECLs to Ang II. PMID- 28727939 TI - Phytohormone and genome variations in Vitis amurensis resistant to downy mildew. AB - Downy mildew (DM) resistance is a highly desirable agronomic trait in grape breeding. High variation in Plasmopara viticola resistance was found in Vitis cultivars. Some accessions show high P. viticola resistance even under conditions highly conducive to DM. Here, leaf disc inoculation experiments revealed that Vitis amurensis 'Zuoshaner' exhibited DM resistance with necrotic spots, whereas the V. amurensis * V. vinifera hybrid cultivar 'Zuoyouhong' was susceptible. Changes in plant hormones accumulation profiles differed between the cultivars. To investigate the genetic mechanisms related to DM resistance, we performed genome-wide sequencing of 'Zuoshaner' and 'Zuoyouhong' and identified cultivar specific single-nucleotide polymorphisms, insertions/deletions (indels), structural variations (SVs), and copy number variations (CNVs), identifying 5399 SVs and 191 CNVs specific for 'Zuoshaner'. Genes affected by these genetic variations were enriched in biological processes, including defense response and response to stress and stimulation, and were associated with sesquiterpenoid and triterpenoid biosynthesis, ABC transporters, and phenylalanine metabolism pathways. Additionally, indels and SVs were detected in six NBS-LRR disease resistance genes, and a CNV was mapped to the Rpv8 locus responsible for downy mildew resistance. These findings further our understanding of the genetic mechanisms underlying grape mildew resistance, and will facilitate genomic marker assisted breeding for improved V. amurensis cultivars. PMID- 28727940 TI - Intestinal Transit Time and Cortisol-Mediated Stress in Zebrafish. AB - Intestinal motility, the spontaneous and rhythmic smooth muscle contraction, is a complex process that is regulated by overlapping and redundant regulatory mechanisms. Primary regulators intrinsic to the gastrointestinal tract include interstitial cells of Cajal, enteric neurons, and smooth muscle cells. Extrinsic primary regulators include the autonomic nervous system, immune system, and the endocrine system. Due to this complexity, a reductionist approach may be inappropriate if the ultimate goal is to understand motility regulation in vivo. Motility can be directly visualized in intact zebrafish, with intact regulatory systems, because larvae are transparent. Intestinal motility can therefore be measured in a complete system. However, the intestinal tract may respond to external influences, such as handling, which may invoke a stress response and influence intestinal transit. We used SR4G transgenic zebrafish, which express green fluorescent protein following activation of glucocorticoid receptors, and showed that handling required for the intestinal motility assay induces stress. Separate experiments showed that exogenous application of hydrocortisone did not influence intestinal transit, suggesting that handling may not interfere with transit measurements in intact zebrafish larvae. These experiments contribute to further development of the zebrafish model for intestinal motility research. PMID- 28727941 TI - Mucin 1 is a novel glycoprotein involved in host defense against invasive pneumococcal disease. PMID- 28727942 TI - Dectin-1 embraces Candida glabrata. PMID- 28727943 TI - The Genetic Background of Metabolic Trait Clusters in Children and Adolescents. AB - BACKGROUND: It is well known that metabolic risk factors of cardiovascular diseases are correlated, but the background of this clustering in children is more poorly known than in adults. Thus, we studied the contribution of genetic and environmental factors to the clustering of metabolic traits in childhood and adolescence. DATA AND METHODS: Nine metabolic traits were measured in 214 complete twin pairs aged 3-18 years in the Autonomous Region of Madeira, Portugal, in 2007 and 2008. The variation of and covariations between the traits were decomposed into genetic and environmental components by using classical genetic twin modeling. RESULTS: A model, including additive genetic and environmental factors unique for each twin individual, explained the variation of metabolic factors well. Under this model, the heritability estimates varied from 0.47 (systolic blood pressure in children under 12 years of age) to 0.91 (high density lipoprotein [HDL] cholesterol in adolescents 12 years of age or older). The most systematic correlations were found between adiposity (body mass index and waist circumference) and blood lipids (HDL cholesterol, low-density lipoprotein cholesterol, and triglycerides), as well as blood pressure. These correlations were mainly explained by common genetic factors. CONCLUSIONS: Our results suggest that obesity, in particular, is behind the clustering of metabolic factors in children and adolescents. Both general and abdominal obesity partly share the same genetic background as blood lipids and blood pressure. Obesity prevention early in childhood is important in reducing the risk of metabolic diseases in adulthood. PMID- 28727944 TI - Computer-Based Case Simulations for Assessment in Health Care: A Literature Review of Validity Evidence. AB - Simulation for education and training in health-care professions has been widely applied. However, its value as an assessment tool for competence is not fully known. Logistical barriers of simulation-based assessments have led some health care organizations to utilize computer-based case simulations (CCSs) for assessment. This article provides a review of the literature on the identification of psychometrically sound, CCS instruments designed to measure decision-making competence in health-care professionals. CINAHL, MEDLINE, and Ovid databases identified 84 potentially relevant articles published between January 2000 and May 2017. A total of 12 articles met criteria for inclusion in this review. Findings of these 12 articles indicate that summative assessment in health care using CCSs in the form of clinical scenarios is utilized to assess higher order performance aspects of competence in the form of decision-making. Psychometric strength was validated in eight articles and supported by four replication studies. Two of the eight articles reported evidence of construct validity and support the need for evidence based on a theoretical framework. This literature review offers implications for further research on the use of CCS tools as a method for assessment of competence in health-care professionals and the need for psychometric evidence to support it. PMID- 28727945 TI - Micronutrient Alterations During Continuous Renal Replacement Therapy in Critically Ill Adults: A Retrospective Study. AB - BACKGROUND: Continuous renal replacement therapy (CRRT) is commonly used to provide renal replacement therapy in the intensive care unit. Limited published data suggest that CRRT may lead to depletion of water-soluble vitamins and trace elements. The goal of this study was to identify the incidence of trace element and vitamin deficiencies in critically ill patients during CRRT. MATERIALS AND METHODS: This study is based on a retrospective chart review of patients who were referred to Emory University Hospital's nutrition support services and had at least 1 serum micronutrient level measured during CRRT (thiamin, pyridoxine, ascorbic acid, folate, zinc, and copper) between April 1, 2009, and June 1, 2012. RESULTS: Seventy-five patients were included in the study. Nine of 56 patients (16%) had below-normal whole blood thiamin concentrations, and 38 of 57 patients (67%) had below-normal serum pyridoxine levels. Serum ascorbic acid and folate deficiencies were identified among 87% (13 of 15) and 33% (3 of 9) of the study patients, respectively. Nine of 24 patients had zinc deficiency (38%), and 41 of 68 patients had copper deficiency (60%). Of the 75 total subjects, 60 patients (80%) had below-normal levels of at least 1 of the micronutrients measured. CONCLUSIONS: The incidence of various micronutrient deficiencies in critically ill patients who required CRRT was higher than previously reported. Prospective studies are needed to determine the impact of CRRT on micronutrient status and the potential clinical and metabolic efficacy of supplementation in the intensive care unit setting. PMID- 28727946 TI - Confounding by Single Nucleotide Polymorphism rs117648444 (P70S) Affects the Association of Interferon Lambda Locus Variants with Response to Interferon-alpha Ribavirin Therapy in Patients with Chronic Genotype 3 Hepatitis C Virus Infection. AB - Genome-wide association studies discovered interferon lambda (IFNL or IFN-lambda) locus on chromosome 19 to be involved in clearance of chronic hepatitis C virus (HCV) infection in patients following interferon-alpha-ribavirin (IFN-RBV) therapy. Subsequent studies established a dinucleotide polymorphism rs368234815, as the prime causal variant behind this association. The DeltaG allele of this variant gives rise to a new IFNL gene, IFNL4, coding for IFN-lambda4 whose activity paradoxically associates with lesser viral clearance rates. A low frequency, nonsynonymous single nucleotide polymorphism (SNP) rs117648444 within the 2nd exon of IFNL4 changes the 70th amino acid from proline to serine resulting in lower activity of the functional IFN-lambda4 protein, thereby increasing HCV clearance rates. In the present study, we used a cohort of genotype 3 HCV-infected patients, drawn from different geographical regions of India who underwent IFN-RBV therapy, to examine the association of several important IFNL locus SNPs/variants with sustained virological response (SVR). Intriguingly, the causal variant rs368234815 did not show the best strength and significance of association with SVR, while further analysis revealed that a negative confounding effect of rs117648444 was responsible for this phenomenon. Our results indicate that IFNL locus SNPs are subject to either a positive or a negative confounding effect by rs117648444; the nature of confounding depends on the linkage of the IFNL SNPs with the low-activity IFN-lambda4-generating minor allele of rs117648444. Thus, our work demonstrates that the linkage disequilibrium structure of the IFNL region may confound the results of association studies. These results have implications for the design and understanding of future case-control studies involving IFNL locus SNPs/variants. PMID- 28727947 TI - Definitions and Clinical Guidance on the Enteral Dependence Component of the Avoidant/Restrictive Food Intake Disorder Diagnostic Criteria in Children. AB - The aim of the current article is to offer definitive guidance on weaning children who are reliant on nasogastric/gastrostomy feeding tubes. To date, no internationally recognized definitions or principles for interventions exist, and clinics have been reliant on creating their own unique intervention criteria. To achieve the aim, 2 goals are set out within the current article. The first goal was to definitively define the process of tube weaning. To achieve this, both tube dependency and oral eating also required definitions. It is necessary for these 2 additional definitions to fully understand the process of tube weaning and the transition that the child is making within these clinical interventions. The second goal of this article was to propose a set of minimum measurement criteria within a tube weaning protocol so that different clinical practices and perspectives may be measured accurately. This would then allow outcomes from different clinical services to be compared for efficacy. The culmination of this article is a set of 5 core principles that should govern clinics that adhere to the auspices of evidence-based practice. These principles, if adopted, will provide the basis of a set of internationally recognized criteria within this field of pediatric gastroenterology. PMID- 28727948 TI - A Collaborative, Network-Based Approach to Advance Women's Depression Research in the United States: Preliminary Findings. AB - OBJECTIVE: Translation of women's mental health research has yet to impact overall prevalence and burden of Mood Disorders in the United States. The lack of standard measures and methodological coordination across studies has contributed to the slow impact of research on outcomes. The primary aims of this project were to demonstrate the process by which multiple investigators, sites, and settings administered a standard women's mental health questionnaire within a new Women's Depression Network. Information on the prevalence of mental health and service use across sites is provided. METHODS: A standard women's mental health questionnaire was developed and administered across seven different women's health sites in the United States. Validated measures of depression and anxiety were included (Patient Health Questionnaire Depression Scale [PHQ-9] and Generalized Anxiety Disorder Scale [GAD-7]). Administration of the questionnaire was embedded into existing clinical or research activities at each site. RESULTS: Data from 1,316 women were collected from seven sites over 12 months. A total of 14% and 15% of the women scored at or above the cutoff on the PHQ-9 and GAD-7 respectively. Just over half of the women screening positive for either depression or anxiety reported current treatment use. CONCLUSIONS: Findings suggest that coordination and administration of a standard women's mental health questionnaire is feasible across multiple settings and sites. Results highlight a low percentage of treatment use across various settings. The infrastructure developed for this study sets the stage for hypothesis-driven studies that can facilitate coordinated, network-based research that has the potential to accelerate advances in the field. PMID- 28727949 TI - A Novel Intuitively Controlled Articulating Instrument for Reoperative Foregut Surgery: A Case Report. AB - The field of laparoscopic surgery has continued to grow exponentially over the years, prompting new innovative technologies. Despite substantial advancements, standard laparoscopic tools have undergone little design changes and fail to optimize mobility in limited spaces. Advancements in robotics have attempted to address this, allowing for increasing degrees of freedom and articulation of instruments. Even so, this system has proven to be cumbersome with questionable cost-effectiveness. In this study, we present the first use of a solely mechanical intuitively controlled articulating laparoscopic needle driver. The ability to naturally articulate allowed for ease during suturing and knot tying during the critical portions of the operation. The FlexDex surgical instrument demonstrates promise in the field of foregut surgery in addition to other areas of minimally invasive specialties. PMID- 28727950 TI - Sociodemographic Characteristics and Health Outcomes Among Lesbian, Gay, and Bisexual U.S. Adults Using Healthy People 2020 Leading Health Indicators. AB - PURPOSE: This study aimed to characterize the sociodemographic characteristics of sexual minority (i.e., gay, lesbian, bisexual) adults and compare sexual minority and heterosexual populations on nine Healthy People 2020 leading health indicators (LHIs). METHODS: Using a nationally representative, cross-sectional survey (National Health Interview Survey 2013-2015) of the civilian, noninstitutionalized population (228,893,944 adults), nine Healthy People 2020 LHIs addressing health behaviors and access to care, stratified using a composite variable of sex (female, male) and sexual orientation (gay or lesbian, bisexual, heterosexual), were analyzed individually and in aggregate. RESULTS: In 2013 2015, sexual minority adults represented 2.4% of the U.S. POPULATION: Compared to heterosexuals, sexual minorities were more likely to be younger and to have never married. Gays and lesbians were more likely to have earned a graduate degree. Gay males were more likely to have a usual primary care provider, but gay/lesbian females were less likely than heterosexuals to have a usual primary care provider and health insurance. Gay males received more colorectal cancer screening than heterosexual males. Gay males, gay/lesbian females, and bisexual females were more likely to be current smokers than their sex-matched, heterosexual counterparts. Binge drinking was more common in bisexuals compared to heterosexuals. Sexual minority females were more likely to be obese than heterosexual females; the converse was true for gay males. Sexual minorities underwent more HIV testing than their heterosexual peers, but bisexual males were less likely than gay males to be tested. Gay males were more likely to meet all eligible LHIs than heterosexual males. Overall, more sexual minority adults met all eligible LHIs compared to heterosexual adults. Similar results were found regardless of HIV testing LHI inclusion. CONCLUSION: Differences between sexual minorities and heterosexuals suggest the need for targeted health assessments and public health interventions aimed at reducing specific negative health behaviors. PMID- 28727951 TI - In Vitro Activity of Telavancin Against Clinically Important Gram-Positive Pathogens from 69 U.S. Medical Centers (2015): Potency Analysis by U.S. Census Divisions. AB - A total of 8,072 gram-positive isolates collected from 69 medical centers among all 9 U.S. Census Divisions during the 2015 SENTRY Antimicrobial Surveillance Program were included. Telavancin had minimal inhibitory concentration (MIC)50 and MIC90 values of 0.03/0.06 MUg/mL, respectively, against methicillin susceptible (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA). Similar activity was also observed among coagulase-negative staphylococci (MIC50/90, 0.03/0.06 MUg/ml; 100.0% inhibited by <=0.12 MUg/ml). Telavancin was active against vancomycin-susceptible Enterococcus faecalis (MIC50/90, 0.12/0.12 MUg/ml) and Enterococcus faecium (MIC50/90, 0.03/0.06 MUg/ml), but was less active against vancomycin-resistant E. faecium (MIC90, >2 MUg/ml) and E. faecalis (MIC90, >2 MUg/ml). Streptococci showed modal MIC results of 0.008 MUg/ml (Streptococcus pneumoniae) to 0.015 MUg/ml (beta-hemolytic streptococci and viridans group streptococci). Potency variations for telavancin within Census Divisions were not observed. Telavancin remains potent in vitro against indicated pathogens recovered from U.S. medical centers (2015). PMID- 28727952 TI - Time-Resolved Laser-Induced Fluorescence Spectroscopy as a Guidance Tool for Laser Lithotripsy of Gallbladder Stones. AB - BACKGROUND AND OBJECTIVES: Although laser lithotripsy for fragmentation of gallbladder stones has been applied successfully in many clinical situations, this approach has two major limitations: (1) the potential to damage or perforate the bile duct and (2) the efficiency can be affected by the chemical composition of the gallstones. The present study evaluated the use of time-resolved laser induced fluorescence spectroscopy to classify stone types and distinguish stone from tissue. MATERIALS AND METHODS: Ex vivo time-resolved laser-induced fluorescence analysis (excitation wavelength lambdaex = 400 nm and emission wavelength = 450-700 nm) of 54 gallbladder stones and seven gallbladder tissue samples was conducted. The spectral and temporal parameters were analyzed using linear discrimination analysis (LDA) to differentiate stone from tissue and to classify different stone types using two wavelength regions (lambda1 = 510-530 nm and lambda2 = 550-570 nm). RESULTS: Examination of 54 gallbladder stones and seven gallbladder tissue samples showed a significant difference in spectral- and temporal-derived parameters. The data were classified using LDA, and the overall accuracy was 94.88%, 84.39%, and 85.79% for both spectral and temporal parameters, only spectral parameters, and only temporal parameters, respectively. CONCLUSIONS: Our findings establish the feasibility of using time-resolved laser induced fluorescence spectroscopy as a tool to identify gallbladder stone types and as a stone-tissue detection system to improve the effectiveness of laser lithotripsy procedures and reduce the risk of damaging biliary tract tissues. PMID- 28727954 TI - Nutrition Screening vs Nutrition Assessment: What's the Difference? AB - Screening and assessment imply different processes, with the former indicating risk factors for a deprived nutrition condition and the latter providing the nutrition diagnosis. Both should be routinely performed at hospital admission according to recommended guidelines; however, this is not the reality worldwide, and undernutrition remains highly prevalent in the hospital setting. Therefore, the objective of the current review is to delve into the principles leading to nutrition status deficiencies and how they should be addressed by screening and assessment. A critical appraisal for the reasons associated with the misunderstanding between screening and assessing is proposed without further discussing the many available screening tools while approaching some of the assessment instruments. PMID- 28727953 TI - Fatty Acid Composition of Plasma Phosphatidylcholine Determines Body Fat Parameters in Subjects with Metabolic Syndrome-Related Traits. AB - BACKGROUND: This study examines the associations of fatty acids (FAs) in plasma phosphatidylcholine (PC) with the anthropometrical and biochemical characteristic of patients with metabolic syndrome (MetS)-related traits. METHODS: We analyzed the FA profiles of PC in 300 persons with MetS-related traits (152 M/148F, mean age 46.9 +/- 9.0 years) and in 70 healthy controls of the same age using a balanced men/women ratio and gas-liquid chromatography. Multivariate linear regression analysis was performed to determine the coefficients of determination (R2) using FA proportions of the mentioned proband characteristics. RESULTS: The FA composition of PC in patients with MetS traits was only associated with waist circumference (R2 = 0.27), waist-to-hip ratio (WHR; R2 = 0.41), body fat percentage (R2 = 0.62), and fat mass (R2 = 0.29). Positive associations were found for dihomo-gamma-linolenic (DGLA), palmitic, stearic (SA), alpha-linolenic (ALA), and eicosapentaenoic acids, whereas negative associations were found for linoleic (LA), oleic, and docosapentaenoic acids. Palmitoleic acid (POA) was positively associated with waist circumference but negatively with fat percentage. In controls, significant associations were found for waist circumference (R2 = 0.51), WHR (R2 = 0.53), body fat percentage (R2 = 0.60), and fat mass (R2 = 0.34). DGLA and saturated FA (SFA) were positively associated, whereas docosahexaenoic, adrenic, and cis-vaccenic acids were negatively associated. The study group differed from controls as follows: lower concentrations of LA and total n-6 FA, higher indices of delta-9-desaturase and delta-6 desaturase activity and higher proportions of POA, SA, ALA, DGLA, and SFA. CONCLUSIONS: We found significant associations (R2 >0.25) of FA in plasma PC with adiposity in middle-aged persons with MetS-related traits, but not with metabolic indices. PMID- 28727955 TI - Longitudinal child-oriented dietary intervention: Association with parental diet and cardio-metabolic risk factors. The Special Turku Coronary Risk Factor Intervention Project. AB - Background The child-oriented dietary intervention given in the prospective Special Turku Coronary Risk Factor Intervention Project (STRIP) has decreased the intake of saturated fat and lowered serum cholesterol concentration in children from infancy until early adulthood. In this study, we investigated whether the uniquely long-term child-oriented intervention has affected also secondarily parental diet and cardio-metabolic risk factors. Methods The STRIP study is a longitudinal, randomized infancy-onset atherosclerosis prevention trial continued from the child's age of 8 months to 20 years. The main aim was to modify the child's diet towards reduced intake of saturated fat. Parental dietary intake assessed by a one-day food record and cardio-metabolic risk factors were analysed between the child's ages of 9-19 years. Results Saturated fat intake of parents in the intervention group was lower [mothers: 12.0 versus 13.9 daily energy (E%), p < 0.0001; fathers: 12.5 versus 13.9 E%, p < 0.0001] and polyunsaturated fat intake was higher (mothers: 6.1 versus 5.4 E%, p < 0.0001; fathers: 6.3 versus 5.9 E%, p = 0.0003) compared with the control parents. Maternal total and low density lipoprotein cholesterol concentrations were lower in the intervention compared with the control group (mean +/- SE 5.02 +/- 0.04 versus 5.14 +/- 0.04 mmol/l, p = 0.04 and 3.19 +/- 0.04 versus 3.30 +/- 0.03 mmol/l, p = 0.03, respectively). Paternal cholesterol values did not differ between the intervention and control groups. Other cardio-metabolic risk factors were similar in the study groups. Conclusions Child-oriented dietary intervention shifted the dietary fat intakes of parents closer to the recommendations and tended to decrease total and low-density lipoprotein cholesterol in the intervention mothers. Dietary intervention directed to children benefits also parents. PMID- 28727956 TI - Increasing availability of benzodiazepines among people who inject drugs in a Canadian setting. AB - BACKGROUND: Benzodiazepine misuse is associated with mortality and is common among people who inject drugs (PWID). This study aimed to examine the temporal trends in the availability of benzodiazepines among PWID in a Canadian setting, and to identify factors associated with more immediate access to benzodiazepines. METHODS: Data were derived from 3 prospective cohorts of PWID in Vancouver, Canada, between June 2012 and May 2015. The primary outcome was the perceived availability of benzodiazepines, measured in 3 levels: not available, delayed availability (available in >=10 minutes), and immediate availability (available in <10 minutes). The authors used multivariable generalized estimating equations to identify factors associated with availability of benzodiazepines. RESULTS: In total, 1641 individuals were included in these analyses. In multivariable analyses, factors associated with immediate benzodiazepine availability included incarceration (adjusted odds ratio [AOR]: 1.42, 95% confidence interval [CI]: 1.06, 1.89) and participation in methadone maintenance therapy (MMT) (AOR: 1.35, 95% CI: 1.14, 1.60). Factors associated with delayed benzodiazepine availability included incarceration (AOR: 1.45, 95% CI: 1.02, 2.07) and participation in MMT (AOR: 1.77, 95% CI: 1.48, 2.12). Benzodiazepine availability increased throughout the study period for both immediate (AOR: 1.14, 95% CI: 1.10, 1.18 per 6-month follow-up period) and delayed (AOR: 1.17, 95% CI: 1.12, 1.22 per 6-month follow up period) availability. CONCLUSIONS: Among our sample of PWID, benzodiazepine availability is increasing and was associated with health and criminal justice system characteristics. Our findings indicate a need to examine prescribing practices and educate both PWID and health care providers about the risks associated with benzodiazepine use. PMID- 28727957 TI - Awareness of state legislation on naloxone accessibility associated with willingness to prescribe naloxone. AB - BACKGROUND: Increasing rates of opioid-related deaths, state naloxone legislation changes, and negativity prompted investigation of predictive factors associated with willingness to prescribe naloxone to populations at risk of overdose, including knowledge of risk factors, assessment of persons at risk, awareness of legislative changes, perceptions of professional responsibility, and confidence around naloxone prescribing and distribution. METHODS: Cross-sectional, Web based, anonymous, voluntary survey to prescribers of 2 regional health care systems serving urban and rural North Dakota, northern Minnesota, and northwestern Wisconsin. Human subject research was approved by university and health care systems' institutional review boards. RESULTS: Overall, 203 of 1586 prescribers responded; however, not all prescribers completed each survey item. A majority (89.4%, n = 127/142) of respondents had never prescribed naloxone for overdose prevention. Willingness to prescribe naloxone for 4 patient care scenarios involving substantial opioid overdose risk ranged from 43.4% to 70.5%. Knowledge mean score was 15.5 (SD = 2.9) out of 22 with median 15 (range: 5-22). Naloxone legislation awareness score was 8.8 (SD = 3.8) out of 15 with median 8 (range: 3-15). There was a statistically significant but modest correlation between willingness to prescribe naloxone and the other variables, including awareness of state naloxone-related legislation (r = 0.43, P < .0001), level of self-confidence about dosing, prescribing, and writing protocols for naloxone (r = 0.37, P < .0001), general knowledge (r = 0.24, P = .0032), and perception of professional responsibility (r = 0.19, P = .03). Multivariate regression analysis indicated willingness to prescribe naloxone was associated with statistically significant predictors, including awareness of the naloxone laws (P = .0016) and self-confidence about dosing, prescribing, and writing protocols (P = .0011). CONCLUSIONS: Prescribers who are more aware of state laws regarding naloxone and confident in their knowledge of dosing, administration, and writing protocols may be more willing to prescribe naloxone. PMID- 28727959 TI - Is Psychology Headed in the Right Direction? AB - Is psychology headed in the right direction? In this essay, I share my views on the answer to this question. I begin by describing how recent advances in technology, heightened levels of interdisciplinary collaboration, a renewed emphasis on considering the broader implications of basic psychological research, and field-wide efforts to encourage optimal research practices have combined to tilt psychology's trajectory upward. I then offer three suggestions for how to maintain the field's upward slanting course: (a) collaborate more to build cumulative knowledge, (b) improve the way we communicate contextual factors in psychological research, and (c) examine the psychological effects of technology. I conclude by offering a single piece of advice for new researchers and a few closing comments. PMID- 28727958 TI - Lipid Injectable Emulsion Survey With Gap Analysis. AB - BACKGROUND: Lipid injectable emulsion (ILE) is an integral part of parenteral nutrition (PN), providing energy and essential fatty acids. With recent consensus recommendations for PN, clinical guidelines for ordering and preparation of PN, the U.S. Food and Drug Administration approval of new ILE products, and revised ILE labeling to include a 1.2-micron filter, a gap in current practice knowledge was apparent. MATERIALS AND METHODS: The American Society for Parenteral and Enteral Nutrition PN Safety Committee surveyed clinicians on how ILE products are prescribed, prepared, and administered to patients from neonates to adults. RESULTS: The results of this survey conducted in late 2016 found a wide variation in practice, particularly across patient age groups. CONCLUSION: These findings demonstrate the need for ongoing dissemination and education on standardized safe practices for ILE use. PMID- 28727960 TI - Perspectives on Psychological Science: Right Way/Wrong Way Symposium. AB - In unpredictable times, it is perhaps even more important to contemplate the direction different fields of science are headed. In this article, I contemplate two directions of psychological science: the increasing integration of the study of psychology with other sciences and the concern of many sciences, including ours, with improving the reproducibility of our findings. Both of these are argued to be "right ways," but these directions also have challenges that, unless carefully addressed, could detract from our ability to move the science of psychology forward. I detail these challenges along with a consideration of how to chart our science through the unpredictable waters we face at this point in history. PMID- 28727961 TI - Psychology's Replication Crisis and the Grant Culture: Righting the Ship. AB - The past several years have been a time for soul searching in psychology, as we have gradually come to grips with the reality that some of our cherished findings are less robust than we had assumed. Nevertheless, the replication crisis highlights the operation of psychological science at its best, as it reflects our growing humility. At the same time, institutional variables, especially the growing emphasis on external funding as an expectation or de facto requirement for faculty tenure and promotion, pose largely unappreciated hazards for psychological science, including (a) incentives for engaging in questionable research practices, (b) a single-minded focus on programmatic research, (c) intellectual hyperspecialization, (d) disincentives for conducting direct replications, (e) stifling of creativity and intellectual risk taking, (f) researchers promising more than they can deliver, and (g) diminished time for thinking deeply. Preregistration should assist with (a), but will do little about (b) through (g). Psychology is beginning to right the ship, but it will need to confront the increasingly deleterious impact of the grant culture on scientific inquiry. PMID- 28727962 TI - A Website System for Communicating Psychological Science. AB - The peer review and journal system have shortcomings, and both computers and the Internet have made complementary or alternative systems attractive. In this article, I recommend that we implement a new platform for open communication of psychological science on a dedicated website to complement the current review and journal system, with reader reviews of the articles and with all behavioral scientists being eligible to publish and review articles. The judged merit of articles would be based on the citations and the ratings of the work by the whole scientific community. This online journal will be quicker, more democratic, and more informative than the current system. Although the details of the system should be debated and formulated by a committee of scientists, adding this online journal to the existing publications of a society such as the Association for Psychological Science has few risks and many possible gains. An online journal deserves to be tried and assessed. PMID- 28727963 TI - Going in Many Right Directions, All at Once. AB - When asked whether the field is going in the right direction, my answer is "yes, mostly." Policymakers' respect and the public's interest put us in the spotlight for our intrinsic strengths-but they also draw attention to our weaknesses as reflected by the replication crisis, about which reasonable opinions differ. Among other concerns, civility and mutual tolerance have sometimes been an issue in these debates. As an example of a constructive debate, our lab's recent experience with mutually respectful engagement has advanced solving one scientific puzzle. Principles facilitating this adversarial collaboration include using our respective tribes as secure bases for exploration, sharing agreed-upon rigorous standards, and establishing mutual trust. Finally, my own career path has perhaps oriented me to rely on perseverance, flexibility, tolerance, and optimism for the field. PMID- 28727964 TI - Psychological Science as a Complex System: Report Card. AB - Psychological science is increasingly diverse in the tools available for research and the questions it is able to ask. But this potential is seriously limited by a lack of diversity in study populations, in situations and contexts explored, and in the researchers themselves. The current situation is problematic and difficult to change because of niche construction processes that favor the status quo. Systems level changes are needed to support a healthy psychological science. PMID- 28727965 TI - Is Psychology Headed in the Right Direction? Yes, No, and Maybe. AB - In this piece, I first celebrate the growing contribution of psychology to the understanding and solution of pressing social issues. Then, despite these exciting developments, I worry about whether we have created a field that our students want to spend their lives in, and I suggest concerns that might fruitfully be addressed. Finally, I worry about the potential fragmentation of psychology and applaud programs of research that have shown the unique and important contributions to be made when the methods and perspectives of neuroscience, cognitive science, and computational modeling are integrated with those of social, personality, and developmental psychology. In sum, although this is an exciting time for our field, we can do more to ensure its vigor and its truly interdisciplinary nature as we move forward. PMID- 28727966 TI - Mountain Climbing in the Dark: Introduction to the Special Symposium on the Future Direction of Psychological Science. AB - This special symposium in Perspectives on Psychological Science answers the question, "Do you believe the field of psychological science is headed in the right direction?" Respondents are a sampling of Association for Psychological Science award winners over the past 5 years dating back from publication of this symposium. PMID- 28727967 TI - Whither Psychology. AB - Contemporary psychology is experiencing tremendous growth in neuroscience, and there is every indication that it will continue to gain in popularity notwithstanding the scarcity of academic positions for newly minted Ph.Ds. Despite the general perception that brain correlates "explain" or "cause" the mind and behavior, these correlates have not yet proven useful in understanding psychological processes, although they offer the possibility of early identification of some disorders. Other recent developments in psychology include increased emphasis on applications and more global representation among researchers and participants. In thinking about the way we want psychology to evolve, psychologists need to pay more than lip service to the idea that complex questions in psychology require multiple levels of analysis with contributions from biological (brain, hormones, and genetics), individual differences and social and cultural perspectives. Early career psychologists who can attain a breadth of knowledge will be well-positioned for a team approach to psychological inquiry. Finally, I offer the belief that an emphasis on enhancing critical thinking skills at all levels of education offers the best hope for the future. PMID- 28727968 TI - Do You Believe the Field of Psychological Science Is Headed in the Right Direction? AB - The state of psychological science is considered in terms of current issues and suggestions for the future. PMID- 28727969 TI - Fetal Dysmorphology-Still an Essential Art. Analysis of the Limitations of Microarray in a Fetal Population and a Look Toward the Genome Sequencing Era. AB - Cytogenomic microarray allows assessment of the genome at higher resolutions than traditional karyotyping. The objective of this study is to evaluate the utility of microarray in a routine fetal autopsy setting before the advent of routine fetal exome/genome sequencing and the issues these technologies may generate. A systematic review of fetal postmortems at 12-24 weeks gestation between January 2011 and December 2014 was undertaken. Cases where there was no consent for audit, research, or genetic testing were excluded as were cases referred to the Procurator Fiscal, stillbirths, and neonatal deaths. Copy number variations were detected in 16 cases. In addition, there was 1 case of uniparental disomy; not all of these were related to the phenotype. There were a number of cases with phenotypic abnormalities and normal array results. Five of these underwent directed mutation analysis-3 were positive. Genetic laboratory investigations such as microarray and Quantitative Fluorescent-Polymerase Chain Reaction may increase the diagnostic yield in the assessment of fetal dysmorphology. However, this study shows that genetic results not only require careful review given the potential uncertain significance but also require phenotypic assessment of the fetus by a competent fetal dysmorphologist to determine the likely causative effect of any detected anomaly. This best practice will also extend to next generation sequencing and interpretation of variants of unknown significance. Fetal medicine teams should ideally include specialists well versed in assessment of fetal anomaly to provide families with the best possible information about the cause of their pregnancy loss and their options for future pregnancies. PMID- 28727970 TI - Severe Fat Accumulation in Multiple Organs in Pediatric Autopsies: An Uncommon but Significant Finding. AB - Background The observation of fat accumulation in different organs at pediatric autopsy may help determine the cause of death. However, a comprehensive study on fat accumulation and related etiologies is still lacking. Aim To investigate the incidence of fat accumulation in different organs in pediatric autopsies and their relevance to the cause of death. Methods From February 2004 until March 2015, fat accumulation was assessed in 561 routinely performed pediatric autopsies in our center. Age at death ranged from 14 weeks of gestation for fetuses to 16 years. Samples of liver, heart, kidney, and muscle were stained with Oil-Red-O and scored for fat accumulation by one pediatric pathologist. Results Fat accumulation in >=1 organ(s) was present in 132 (39.8%) of 332 prenatal cases. Only 3 (0.9%) had fat accumulation in all 4 organs. For postnatal cases, fat accumulation in >=1 organ(s) was present in 106 (46.3%) of 229 postnatal cases. Only 12 (5.2%) had fat accumulation in all 4 organs. Fat accumulation was mostly seen in liver, both in prenatal and postnatal cases. Fatty acid oxidation disorders were the only cause of death associated with severe fat accumulation in all 4 organs. No other etiologies could be linked directly to distribution or severity of fat accumulation. Conclusion Severe fat accumulation in at least 4 organs is a rare finding in pediatric autopsies, whereas fat accumulation in only the liver is relatively common. Severe fat accumulation in both liver, muscle, kidney, and heart was only seen in cases with fatty acid oxidation disorders. PMID- 28727972 TI - PPS Annual meeting Lund, Sweden 2016. PMID- 28727971 TI - Congenital Extrahepatic Portosystemic Shunt (Abernethy Malformation Type Ib) With Associated Hepatocellular Carcinoma: Case Report and Literature Review. AB - Abernethy malformation, also termed congenital portosystemic shunt and congenital absence of portal vein is the result of malformation of the splanchnic venous system. Congenital portosystemic shunts are divided into extra- and intrahepatic shunts. Two shunts have been defined: Type I is characterized by the complete diversion of portal blood into the vena cava with an associated congenital absence of the portal vein. Type II is defined by an intact but diverted portal vein through a side-to-side, extrahepatic connection to the vena cava. The clinical manifestations of Abernethy malformation are diverse with a typical presentation consisting of hypoxia and hepto-pulmonary syndrome. Histologically, focal nodular hyperplasia, nodular regenerative hyperplasia, liver adenoma, hepatoblastoma, and hepatocellular carcinoma have all been reported. Herein, we report a case of Abernethy malformation, type Ib, in a 12-month-old male who was found to have a small hepatocellular carcinoma at the time of explant. The immunohistochemical characteristics in relation to the genetic aspects are discussed. To our knowledge, this is the first reported case of hepatocellular carcinoma developing in a patient who is under the age of 5 years with Abernethy malformation. PMID- 28727973 TI - Pediatric Xanthogranulomatous Cystitis: The First Described Case in a Pre pubertal Male and Review of the Literature. AB - Xanthogranulomatous cystitis (XC) is a rare condition affecting the bladder thought to be caused by chronic inflammation. Fewer than 30 cases have been reported in the literature since being first described in 1932. We present the first reported case of XC in a pre-pubertal male and review the literature. A 10 year-old boy presenting with dysuria subsequently developed frequency. After failure of conservative management, an ultrasound of the bladder revealed a mass. The patient underwent partial cystectomy. Pathology showed XC. At 10 months postoperatively, the patient remained asymptomatic and without evidence of recurrence. PMID- 28727974 TI - Autoamputation of the Appendix Presenting as a Calcified Abdominal Mass Following Necrotizing Enterocolitis. AB - Autoamputation of the appendix has previously been reported in the literature, but it is likely an unusual event. We report a 2-year-old male child who had previously undergone laparotomy and bowel resection for necrotizing enterocolitis. Two years later a calcified intra-abdominal mass was identified on abdominal radiography and ultrasonography. Eventual laparotomy revealed a densely calcified mass within the transverse mesocolon. The mass was uneventfully resected. Pathologic evaluation showed appendiceal tissue, consistent with prior autoamputation of the vermiform appendix. Autoamputation of the appendix has not to our knowledge previously been associated with a calcified mass nor been associated with a history of necrotizing enterocolitis, and these factors distinguish this case as noteworthy. PMID- 28727975 TI - Appendicular Biopsy in Total Colonic Aganglionosis: A Histologically Challenging and Inadvisable Practice. AB - Background The reliability of intraoperative evaluation of ganglion cells in the appendix as a guide to a diagnosis of total colonic aganglionosis is unclear. Objective To evaluate the diagnostic utility of appendicular innervation in colonic Hirschsprung disease (HD) and TCA. Methods Prospective, systematic study of ganglion cells and the neural plexii in appendices from cases (HD and TCA) and age matched controls with frozen and paraffin sections, rapid acetylcholinesterase (AChE) and immunohistochemistry. Results A total of 48 appendices (28 controls, 20 cases; 19 frozen) were evaluated. Of these 48, 30 were neonates. Ganglion cell clusters were smaller in controls (28) and HD (6) than those in the rectum, distorted at places and mimicked lymphocytes and endothelial cells, especially in neonates. Complete study of 13 appendices in TCA showed absence of ganglion cells, hypertrophic nerves, AChE activity, and calretinin staining. In 2/13 TCA, an erroneous frozen section identification of ganglia was later corrected based on AChE histochemistry and a panel of IHC stains. Ileal biopsies guided the placement of a ganglionic ileostomy in all. One case each of skip segment aganglionosis in a TCA and variable hypoganglionosis in long segment colonic HD is reported. Conclusion Intraoperative characterization of appendicular innervation as a guide to the diagnosis of TCA is unreliable, in part because of the possibility of skip segment disease/variable hypoganglionosis. We propose terminal ileal biopsies for diagnosis and leveling of aganglionosis. AChE on frozen/calretinin on paraffin tissue is the best approach to avoid diagnostic errors. PMID- 28727976 TI - Monozygotic Twins Discordant for Trisomy 13: A Case of Trisomic Rescue Supporting the Continued Need for First-Trimester Ultrasound. AB - Monozygotic twins with discordant karyotypes for trisomy 13 are rare. We report a case of a spontaneously conceived pregnancy who presented with first-trimester ultrasound finding of umbilical cord cyst and increased nuchal translucency in Twin A and no abnormalities in Twin B. Amniocentesis revealed 47,XY,+13 karyotype in Twin A and 46,XY karyotype in Twin B. Selective fetal reduction was performed for Twin A. Twin B was delivered at 32 weeks gestation with normal phenotype. Peripheral blood karyotype revealed 15% mosaicism for trisomy 13 and skin fibroblast revealed 46,XY karyotype. The surviving twin will be monitored for potential complication of uniparental disomy 13 and mosaic trisomy 13. This case reinforces the need for early ultrasound and nuchal translucency measurements, especially in twin gestations. PMID- 28727978 TI - Pulmonary Neuroendocrine Cell Hyperplasia in Hemoglobin Bart-induced Hydrops Fetalis: A model for Chronic Intrauterine Hypoxia. AB - The pulmonary neuroendocrine system includes pulmonary neuroendocrine cells (PNECs) and neuroepithelial bodies (NEBs) that are distributed throughout respiratory epithelium and regulate lung growth and maturation antenatally. Abnormalities in this system have been linked to many hypoxia-associated pediatric pulmonary disorders. Hemoglobin (Hb) Bart disease is a severe form of alpha-thalassemia resulting in marked intrauterine hypoxia with hydrops fetalis (HF) and usually death in utero. Affected fetuses can serve as a naturally occurring human model for the effects of intrauterine hypoxia, and we postulated that these effects should include changes in the pulmonary neuroendocrine system. Bombesin immunostaining was used to assess PNECs and NEBs in stillborn fetuses with Hb Bart HF ( n = 16) and with HF from other causes ( n = 14) in comparison to non-HF controls. Hb Bart HF showed a significant increase in the proportion of PNECs in respiratory epithelium ( P = .002), mean number of NEB nuclei ( P = .03), and mean size of NEBs ( P = .002), compared to normal non-HF controls. Significant differences were not observed between HF due to other causes and non HF controls with normal lungs. Non-HF controls with pulmonary hypoplasia showed significant increases in PNECs compared to HF cases not due to Hb Bart HF, implying HF alone does not cause such increases. In contrast, no significant differences were noted between non-HF controls with pulmonary hypoplasia and Hb Bart cases. Hb Bart HF may provide a useful model for studying the pulmonary neuroendocrine system under chronic intrauterine hypoxia. PMID- 28727977 TI - The Vanishing Twin Syndrome: Two Cases of Extreme Malformations Associated With Vanished Twins. AB - Two cases of devastating fetal malformations associated with vanished monochorionic twins were identified upon review of pathology files. A 35-year-old G1P0 woman and 36-year-old G3P1 woman were both diagnosed with an intrauterine twin gestation via transvaginal ultrasound at 10 weeks. The spectrum of fetal anomalies ranged from omphalocele, bilateral upper extremity, and unilateral lower extremity hypoplasia, to craniofacial malformation with diaphragmatic hernia. On histopathologic examination, the placentas demonstrated vascular anastomoses between the surviving co-twin and the "vanished" fetal sac. We propose anastomotic placental vasculature as a contributing factor to the observed fetal malformations. Additionally, genetic or teratogenic factors may have been attributed to the demise of the first twin and the anomalies seen in the other twin. While such instances are rare, they are important to consider when counseling patients regarding outcomes associated with a monochorionic vanished twin. PMID- 28727981 TI - Engaging Cold to Upregulate Cell Proliferation in Alginate-Encapsulated Liver Spheroids. AB - For many years, the impact of hyper- and hypothermia on mammalian cells has been examined. With the exception of short, low temperature storage, which has uses in areas such as preservation for transplantation or regenerative medicine, advantages for the use of low temperature treatment in hepatocytes have not been previously reported. We have observed that alginate-encapsulated HepG2 liver spheroids that are cryopreserved or experience a cold reduction in temperature (<=10 degrees C) for periods between 1 and 90 min display an enhanced cell proliferation during culture 7-16 days post-treatment compared with untreated samples. Following 8-12 days post-treatment, alginate-encapsulated liver spheroids experienced a cell density of 1.71 +/- 0.35 times that of control samples (p < 0.001). This effect occurred in samples with a variety of cold treatments. This low temperature treatment offers a simple method to rapidly increase cell proliferation rates for extended culture systems, such as bioartificial liver devices. This would allow the manufacture of required biomass more rapidly, and to a higher cell density, reducing final required biomass volume. This could enable bioartificial liver devices to be prepared more cheaply, making them a more cost effective treatment. PMID- 28727982 TI - Genome-wide DNA methylation profile of prepubertal porcine testis. AB - The biological structure and function of the mammalian testis undergo important developmental changes during prepuberty and DNA methylation is dynamically regulated during testis development. In this study, we generated the first genome wide DNA methylation profile of prepubertal porcine testis using methyl-DNA immunoprecipitation (MeDIP) combined with high-throughput sequencing (MeDIP-seq). Over 190 million high-quality reads were generated, containing 43642 CpG islands. There was an overall downtrend of methylation during development, which was clear in promoter regions but less so in gene-body regions. We also identified thousands of differentially methylated regions (DMRs) among the three prepubertal time points (1 month, T1; 2 months, T2; 3 months, T3), the majority of which showed decreasing methylation levels over time. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses revealed that many genes in the DMRs were linked with cell proliferation and some important pathways in porcine testis development. Our data suggest that DNA methylation plays an important role in prepubertal development of porcine testis, with an obvious downtrend of methylation levels from T1 to T3. Overall, our study provides a foundation for future studies and gives new insights into mammalian testis development. PMID- 28727979 TI - Hypercapnic acidosis attenuates pressure-dependent increase in whole-lung filtration coefficient (Kf). AB - Hypercapnic acidosis (HCA) has beneficial effects in experimental models of lung injury by attenuating inflammation and decreasing pulmonary edema. However, HCA increases pulmonary vascular pressure that will increase fluid filtration and worsen edema development. To reconcile these disparate effects, we tested the hypothesis that HCA inhibits endothelial mechanotransduction and protects against pressure-dependent increases in the whole lung filtration coefficient (Kf). Isolated perfused rat lung preparation was used to measure whole lung filtration coefficient (Kf) at two levels of left atrial pressure (PLA = 7.5 versus 15 cm H2O) and at low tidal volume (LVt) versus standard tidal volume (STVt) ventilation. The ratio of Kf2/Kf1 was used as the index of whole lung permeability. Double occlusion pressure, pulmonary artery pressure, pulmonary capillary pressures, and zonal characteristics (ZC) were measured to assess effects of HCA on hemodynamics and their relationship to Kf2/Kf1. An increase in PLA2 from 7.5 to 15 cm H2O resulted in a 4.9-fold increase in Kf2/Kf1 during LVt and a 4.8-fold increase during STVt. During LVt, HCA reduced Kf2/Kf1 by 2.7-fold and reduced STVt Kf2/Kf1 by 5.2-fold. Analysis of pulmonary hemodynamics revealed no significant differences in filtration forces in response to HCA. HCA interferes with lung vascular mechanotransduction and prevents pressure-dependent increases in whole lung filtration coefficient. These results contribute to a further understanding of the lung protective effects of HCA. PMID- 28727983 TI - Editorial Comment. PMID- 28727984 TI - GBA Analysis in Next-Generation Era: Pitfalls, Challenges, and Possible Solutions. AB - Mutations in the gene encoding the lysosomal enzyme acid beta-glucosidase (GBA) are responsible for Gaucher disease and represent the main genetic risk factor for developing Parkinson disease. In past years, next-generation sequencing (NGS) technology has been applied for the molecular analysis of the GBA gene, both as a single gene or as part of gene panels. However, the presence of complex gene pseudogene rearrangements, resulting from the presence of a highly homologous pseudogene (GBAP1) located downstream of the GBA gene, makes NGS analysis of GBA challenging. Therefore, adequate strategies should be adopted to avoid misdetection of GBA recombinant mutations. Here, we validated a strategy for the identification of GBA mutations using parallel massive sequencing and provide an overview of the major drawbacks encountered during GBA analysis by NGS. We implemented a NGS workflow, using a set of 38 patients with Gaucher disease carrying different GBA alleles identified previously by Sanger sequencing. As expected, the presence of the pseudogene significantly affected data output. However, the combination of specific procedures for the library preparation and data analysis resulted in maximal repeatability and reproducibility, and a robust performance with 97% sensitivity and 100% specificity. In conclusion, the pipeline described here represents a useful approach to deal with GBA sequencing using NGS technology. PMID- 28727986 TI - This Month in AJP. AB - The following highlights summarize research articles that are published in the current issue of The American Journal of Pathology. PMID- 28727985 TI - Comparative Study and Analytical Verification of PCR Methods for the Diagnosis of Congenital Chagas Disease. AB - Congenital infection is currently the first cause of new cases of Chagas disease in Argentina and nonendemic areas worldwide. Its diagnosis is of utmost importance to guarantee curative treatment. To improve such diagnosis, a transfer process of PCR tests to the national laboratory network has been initiated. We performed a comparative study of four PCR assays [two end-point PCR and two duplex real-time quantitative PCR (qPCR) procedures] to detect Trypanosoma cruzi DNA in blood samples. Because satellite DNA and kinetoplastid DNA qPCR methods showed the best performance and the use of two different molecular targets for confirmatory purposes has been recommended, these methods were selected to perform the transfer process and, in consequence, subjected to an analytical verification protocol based on international guidelines. The anticipated reportable range was verified between 0.25 and 105 parasite equivalents per milliliter of blood (par. eq./mL) for both qPCR methods, and the limit of detection was estimated to be 0.87 (95% CI, 0.62-1.24) and 0.43 (95% CI, 0.32 0.59) par. eq./mL for satellite DNA and kinetoplastid DNA qPCR methods, respectively. In addition, both qPCR methods showed trueness and verified precision in the highest and the lowest concentrations tested. This work provides critical knowledge of the technology transfer process planned to cover laboratories of the regional network with known installed facilities. PMID- 28727987 TI - Associations of Autoimmunity, Immunodeficiency, Lymphomagenesis, and Gut Microbiota in Mice with Knockins for a Pathogenic Autoantibody. AB - A number of mouse strains transgenic for B-cell receptors specific for nucleic acids or other autoantigens have been generated to understand how autoreactive B cells are regulated in normal and autoimmune mice. Previous studies of nonautoimmune C57BL/6 mice heterozygous for both the IgH and IgL knockins of the polyreactive autoantibody, 564, produced high levels of autoantibodies in a largely Toll-like receptor 7-dependent manner. Herein, we describe studies of mice homozygous for the knockins that also expressed high levels of autoantibodies but, unlike the heterozygotes, exhibited a high incidence of mature B-cell lymphomas and enhanced susceptibility to bacterial infections. Microarray analyses and serological studies suggested that lymphomagenesis might be related to chronic B-cell activation promoted by IL-21. Strikingly, mice treated continuously with antibiotic-supplemented water did not develop lymphomas or abscesses and exhibited less autoimmunity. This mouse model may help us understand the reasons for enhanced susceptibility to lymphoma development exhibited by humans with a variety of autoimmune diseases, such as Sjogren syndrome, systemic lupus erythematosus, and highly active rheumatoid arthritis. PMID- 28727989 TI - Oral Papillomatosis in Immunocompromised Patients: A Case Series of Kidney Transplant Recipients and Myelodysplastic Syndrome. AB - Solitary papilloma is a human papillomavirus (HPV)-induced benign indolent epithelial tumor with limited growth, whereas papillomatosis is an entirely different entity. Papillomatosis requires attention because of its aggressive and recurrent clinical progress with risks of dysplastic and malignant transformation. Recurrent respiratory papillomatosis (RRP) has a high prevalence of dysplasia and reports of transformation to carcinoma-ex-papillomatosis, especially when associated with low-risk HPV type 11. Although papillomatosis seldom occurs in the oral cavity, this report describes 3 cases of oral papillomatosis in immunocompromised patients, with 1 case identified as having HPV type 11. Two cases were kidney transplant recipients and the other case had a history of myelodysplastic syndrome followed by allogeneic bone marrow transplantation and graft-versus-host disease. Oral papillomatosis might be problematic, as in RRP, and periodic oral examination for persistent recurrences and malignant transformation can be beneficial to immunocompromised patients. PMID- 28727988 TI - Environmental exposures and pediatric kidney function and disease: A systematic review. AB - BACKGROUND: Environmental chemical exposures have been implicated in pediatric kidney disease. No appraisal of the available evidence has been conducted on this topic. METHODS: We performed a systematic review of the epidemiologic studies that assessed association of environmental exposures with measures of kidney function and disease in pediatric populations. The search period went through July 2016. RESULTS: We found 50 studies that met the search criteria and were included in this systematic review. Environmental exposures reviewed herein included lead, cadmium, mercury, arsenic, fluoride, aflatoxin, melamine, environmental tobacco, bisphenol A, dental procedures, phthalates, ferfluorooctanoic acid, triclosan, and thallium/uranium. Most studies assessed environmental chemical exposure via biomarkers but four studies assessed exposure via proximity to emission source. There was mixed evidence of association between metal exposures, and other non-metal environmental exposures and pediatric kidney disease and other kidney disease biomarkers. The evaluation of causality is hampered by the small numbers of studies for each type of environmental exposure, as well as lack of study quality and limited prospective evidence. CONCLUSION: There is a need for well-designed epidemiologic studies of environmental chemical exposures and kidney disease outcomes. PMID- 28727990 TI - New heterocyclic compounds from Ranunculus ternatus Thunb. AB - Five new heterocyclic compounds, 5-alpha-d-fructofuranosylmethyl-furfural (1), 5 beta-d-fructofuranosylmethyl-furfural (2), 5-beta-d-fructopyranosylmethyl furfural (3), 4-(2-((2S-2,3-dihydroxypropoxy)methyl)-5-formyl-1H-pyrrol-1 yl)butanoic acid (4), and 3S,4S-4,5,8-trihydroxy-3-(prop-1-en-2-yl)isochroman-1 one (5), were obtained from the root of Ranunculus ternatus Thunb., which is a traditional Chinese anti-tuberculosis medicine. Their structures were elucidated by UV, IR, HRESIMS, NMR data, and the comparison of experimental and calculated electronic circular dichroism (ECD) spectra. Notably, compounds 1-3 are rarely occurring furfural fructosides in natural sources. These heterocyclic compounds could be further studied for the synthetic chemists and pharmacologists due to the source and structural properties. PMID- 28727991 TI - How accurate are self-reported height and weight in the seriously mentally ill? AB - AIMS: (1) Determine the accuracy of self-reported height, weight, and body mass index (BMI) calculated from those values in a population suffering from both serious mental illness (SMI) and overweight/obesity; (2) identify any associations that may predict error in self-reported measurements. Data were collected from screening appointments for two clinical trials for adult patients with SMI and overweight/obesity (BMI > 28) who gained weight while on antipsychotic medications. Both studies were conducted at the same urban community mental health center. Differences in self-reported and measured height, weight, and BMI were calculated. Analysis included age, sex, race, psychiatric diagnosis, and level of education. BMI calculated from self-reported height and weight were significantly lower (-0.47kg/m2) than measured values. Height was significantly overestimated (1.04cm), while weight was underestimated (0.055kg). Men underestimated BMI more than women (0.55 vs. 0.41kg/m2). Increasing age correlated with lower accuracy of self-reported height and BMI. No differences due to psychiatric diagnosis, race, or education were found. BMI calculated from self-reported height and weight from patients with SMI and overweight/obesity is as accurate as the self-reported measurements collected from the general population and, while measurement is best, self-reports can be used as a tool for screening for obesity. PMID- 28727992 TI - How does emotional exhaustion influence work stress? Relationships between stressor appraisals, hedonic tone, and fatigue in nurses' daily tasks: A longitudinal cohort study. AB - BACKGROUND: Work-related stress is a prevalent condition in the nursing profession, and its influence may vary according to changeable individual and situational factors. It is, therefore, important to investigate the real-time momentary changes in these factors and their relationship to emotional exhaustion experienced by nurses. OBJECTIVES: We aim to analyse how their perceptions of demand, control, effort and reward change according to the task performed through real-time assessment and interact with the emotional exhaustion level of ward nurses. DESIGN: The research design was longitudinal. METHOD: A three-level hierarchical model with a repeated measures design was used to assess the momentary self-reports of 96 hospital ward nurses, completed using a smartphone programmed with random alarms. RESULTS: Findings show that demand, effort, and control appraisals depend on the task performed. The task appraised as most demanding, effortful, and controllable was direct care. Reward appraisal depends on the task performed and personal variables, i.e. emotional exhaustion. The situations perceived as more rewarding were rest and direct care. Momentary hedonic tone can be explained by the task performed, demand, reward, emotional exhaustion and by the interaction between emotional exhaustion and demand appraisal. Momentary fatigue can be explained by the task performed, demand, reward, and the emotional exhaustion. CONCLUSIONS: This study highlights the importance of using momentary measures to understand complex and changeable inter relationships. While also clarifying the targets of intervention programmes aimed at preventing burnout within the nursing profession. PMID- 28727993 TI - How do nurse practitioners work in primary health care settings? A scoping review. AB - OBJECTIVES: This scoping review explores the work of nurse practitioners in primary health care settings in developed countries and critiques their contribution to improved health outcomes. DESIGN: A scoping review design was employed and included development of a research question, identification of potentially relevant studies, selection of relevant studies, charting data, collating, summarising and reporting findings. An additional step was added to evaluate the methodological rigor of each study. DATA: Data sources included literature identified by a search of electronic databases conducted in September 2015 (CINAHL, Informit, Web of Science, Scopus and Medline) and repeated in July 2016. Additional studies were located through hand searching and authors' knowledge of other relevant studies. RESULTS: 74 articles from eight countries were identified, with the majority emanating from the United States of America. Nurse practitioners working in communities provided care mostly in primary care centres (n=42), but also in community centres (n=6), outpatient departments (n=6), homes (n=5), schools (n=3), child abuse clinics (n=1), via communication technologies (n=6), and through combined face-to-face and communication technologies (n=5). The scope of nurse practitioner work varied on a continuum from being targeted towards a specific disease process or managing individual health and wellbeing needs in a holistic manner. Enhanced skills included co ordination, collaboration, education, counselling, connecting clients with services and advocacy. Measures used to evaluate outcomes varied widely from physiological data (n=25), hospital admissions (n=10), use of health services (n=15), self-reported health (n=13), behavioural change (n=14), patient satisfaction (n=17), cost savings (n=3) and mortality/morbidity (n=5). CONCLUSIONS: The majority of nurse practitioners working in community settings did so within a selective model of primary health care with some examples of nurse practitioners contributing to comprehensive models of primary health care. Nurse practitioners predominantly worked with populations defined by an illness with structured protocols for curative and rehabilitative care. Nurse practitioner work that also incorporated promotive activities targeted improving social determinants of health for people rendered vulnerable due to ethnicity, Aboriginal identity, socioeconomic disadvantage, remote location, gender and aging. Interventions were at individual and community levels with outcomes including increased access to care, cost savings and salutogenic characteristics of empowerment for social change. PMID- 28727994 TI - Retrospective Evaluation of the Procedural Sedation Practices of Expert Nurses During Abortion Care. AB - OBJECTIVE: To evaluate the provision of procedural sedation during abortion by expert nurses and to describe the factors that are associated with time to discharge for women who receive this sedation. DESIGN: Retrospective chart review. METHODS: Descriptive statistics were generated to describe a retrospective cohort of women presenting for abortion under procedural sedation. Analysis of variance was used to determine significant characteristics that influenced time to discharge. SETTING: A single clinical site that employs seven expert nurses. PARTICIPANTS: A total of 194 medical records were available for this analysis. RESULTS: All women were discharged home with accompaniment, and no incidents of respiratory distress or other adverse complications occurred. Most women (n = 136) received at least 150 MUg fentanyl and 3 mg midazolam, and 71% of women in the first trimester and 83% of women in the second trimester entered the recovery area with no pain. Variables significantly associated with time spent in the recovery area were gestational age at time of abortion (t = -2.68, p = .008), pain at entry to recovery area (t = -0.254, p = .008), and pain at 15 minutes (t = 0.25, p = .038). CONCLUSION: Expert nurses can administer procedural sedation for pain control associated with abortion and are capable of monitoring women and helping them return to baseline status after the procedure. PMID- 28727995 TI - Physician perceptions about living organ donation in patients with Amyotrophic Lateral Sclerosis. AB - OBJECTIVES: Patients with Amyotrophic Lateral Sclerosis (ALS) have expressed desire to become living organ donors but are unable to do so with current organ donation policies. Our objective is to assess ALS patient's interest in organ donation, and perceived concerns of this practice by ALS neurologists. PATIENTS AND METHODS: An electronic survey was administered to ALS neurologists across the United States regarding living organ donation in ALS patients prior to respiratory failure. RESULTS: 52 complete responses were received from 121 invites. 67% (35/52) of neurologists expressed no concerns about living organ donation in ALS patients, and 33% had concerns. The concerns related to respiratory failure, anesthesia exposure and renal dysfunction. With their concerns addressed, 71% of neurologists reported that they would endorse living organ donation. 49% of neurologists reported being asked by a patient for information regarding living organ donation. ALS neurologists felt that 22.8% of ALS patients (median 19%) would be interested in learning more about organ donation, while only 6% of neurologists broach this subject with their patients. CONCLUSION: Our results indicate that 1 in every 4 ALS patients may be interested in exploring options for living organ donation, and this topic is not routinely addressed by ALS clinics. These results indicate an unexplored area of patient interest. To honor a patient's wishes to donate, the transplant community will have to accommodate living organ donation from terminally ill patients, and address neurologist concerns. Such a practice could benefit two groups of patients. PMID- 28727996 TI - Efficacy and safety of one-stage posterior hemivertebral resection for unbalanced multiple hemivertebrae: A more than 2-year follow-up. AB - OBJECTIVE: One-stage posterior hemivertebral resection has been proven to be an effective, reliable surgical option for treating congenital scoliosis due to a single hemivertebra. To date, however, no studies of treating unbalanced multiple hemivertebrae have appeared. This study evaluated the efficacy and safety of one stage posterior hemivertebral resection for unbalanced multiple hemivertebrae. PATIENTS AND METHODS: Altogether, we studied 15 patients with unbalanced multiple hemivertebrae who had undergone hemivertebral resection using the one-stage posterior approach with at least 2 years of follow-up. Clinical outcomes were assessed radiographically and with the Scoliosis Research Society-22 (SRS-22) score. Related complications were also recorded. RESULTS: The mean Cobb angle of the main curve was 62.4 degrees (46 degrees -98 degrees ) before surgery and 18.2 degrees (9 degrees -33 degrees ) at the most recent follow-up (average correction 73.3%). The compensatory cranial curve was corrected from 28.5 degrees (11 degrees -52 degrees ) to 9.1 degrees (0 degrees -30 degrees ) (average correction 70.0%). The compensatory caudal curve was corrected from 31.6 degrees (14 degrees -54 degrees ) to 6.9 degrees (0 degrees -19 degrees ) (average correction 79.1%). The segmental kyphosis/lordosis was corrected from 41.1 degrees (-40 degrees to 98 degrees ) to 12.3 degrees (-25 degrees to 41 degrees ) (average correction 65.5%). The mean growth rate of the T1-S1 length in immature patients was 9.8mm/year during the follow-up period. Health-related quality of life (SRS-22 score) had significantly improved. Complications include one wound infection and one developing deformity. CONCLUSION: One-stage posterior hemivertebral resection for unbalanced multiple hemivertebrae provides good radiographic and clinical outcomes with no severe complications when performed by an experienced surgeon. Longer follow-up to detect late complications is obligatory. PMID- 28727997 TI - Therapeutic intranasal instillation of allergen-loaded microbubbles suppresses experimental allergic asthma in mice. AB - Despite proven efficiency, subcutaneous immunotherapy for aeroallergens is impaired by the duration of the protocol, the repeated injections and potential side-effects associated with the doses of allergen administered. Intranasal delivery of immunotherapeutic agents may overcome several of these drawbacks, provided that an efficient allergen delivery vehicle can be identified. This study evaluates whether intranasally delivered gas-filled microbubble (MB) associated ovalbumin (OVA), used as a model allergen, can serve as a therapeutic treatment in a mouse model of established allergic asthma. Lung and systemic production of pro-tolerogenic markers, including Foxp3+ CD4 T cells, IL-10, and TGF-beta, as well as the Th1-type cytokine IFN-gamma, was observed after intranasal immunization with OVA-MB. Post-treatment, aerosol-sensitized mice exhibited the same pattern of markers. Moreover, decrease of eosinophils and neutrophils in BALs, lower frequencies of Th2 cytokine- and IL-17-producing CD4 T cells in lungs and reduced specific IgE in BALs and sera after allergen challenge were observed. Concomitantly, lung resistance and mucus production diminished in OVA-MB-treated animals. Thus, therapeutic intranasal administration of OVA-MBs in established experimental allergic asthma allows modulating pathology-associated immune and physiological parameters usually triggered after exposure to the allergen. PMID- 28727998 TI - Enrichment of endogenous fractalkine and anti-inflammatory cells via aptamer functionalized hydrogels. AB - Early recruitment of non-classical monocytes and their macrophage derivatives is associated with augmented tissue repair and improved integration of biomaterial constructs. A promising therapeutic approach to recruit these subpopulations is by elevating local concentrations of chemoattractants such as fractalkine (FKN, CX3CL1). However, delivering recombinant or purified proteins is not ideal due to their short half-lives, suboptimal efficacy, immunogenic potential, batch variabilities, and cost. Here we report an approach to enrich endogenous FKN, obviating the need for delivery of exogenous proteins. In this study, modified FKN-binding-aptamers are integrated with poly(ethylene glycol) diacrylate to form aptamer-functionalized hydrogels ("aptagels") that localize, dramatically enrich and passively release FKN in vitro for at least one week. Implantation in a mouse model of excisional skin injury demonstrates that aptagels enrich endogenous FKN and stimulate significant local increases in Ly6CloCX3CR1hi non-classical monocytes and CD206+ M2-like macrophages. The results demonstrate that orchestrators of inflammation can be manipulated without delivery of foreign proteins or cells and FKN-aptamer functionalized biomaterials may be a promising approach to recruit anti-inflammatory subpopulations to sites of injury. Aptagels are readily synthesized, highly customizable and could combine different aptamers to treat complex diseases in which regulation or enrichment of multiple proteins may be therapeutic. PMID- 28727999 TI - Drug/ion co-delivery multi-functional nanocarrier to regenerate infected tissue defect. AB - Regeneration of infected tissues is a globally challenging issue in medicine and dentistry. Common clinical therapies involving a complete removal of infected areas together with a treatment of antimicrobial drugs are often suboptimal. Biomaterials with anti-bacterial and pro-regenerative potential can offer a solution to this. Here we design a novel nanocarrier based on a mesoporous silicate-calcium glass by doping with Ag ions and simultaneously loading antimicrobial drugs onto mesopores. The nanocarriers could controllably release multiple ions (silver, calcium, and silicate) and drugs (tetracycline or chlorohexidine) to levels therapeutically relevant, and effectively internalize to human dental stem cells (~90%) with excellent viability, ultimately stimulating odontogenic differentiation. The release of Ag ions had profound effects on most oral bacteria species through a membrane rupture, and the antibiotic delivery complemented the antibacterial functions by inhibiting protein synthesis. Of note, the nanocarriers easily anchored to bacteria membrane helping the delivery of molecules to an intra-bacterial space. When administered to an infected dentin-pulp defect in rats, the therapeutic nanocarriers effectively regenerated tissues following a complete bacterial killing. This novel concept of multiple-delivering ions and drug can be extensively applied to other infectious tissues that require relayed biological functions (anti bacterial then pro-regenerative) for successful healing. PMID- 28728000 TI - Tailor-made purified human platelet lysate concentrated in neurotrophins for treatment of Parkinson's disease. AB - Human platelet lysates (PLs), which contain multiple neurotrophins, have been proposed for treating neurodegenerative disorders, including Parkinson's disease (PD). However, current PLs suspended in plasma have high protein content and contain fibrinogen/fibrin and, following activation, also proteolytic and thrombogenic enzymes. Upon brain administration, such PLs may saturate the cerebrospinal fluid and exert neurotoxicity. We assessed whether purified PLs, concentrated in neurotrophins, protected dopaminergic neurons in PD models. Platelet concentrates were collected by apheresis and centrifuged to eliminate plasma and recover the platelets. Platelets were lysed by freeze-thaw cycles, and the 10-fold concentrated platelet pellet lysates (PPLs) were heat-treated (at 56 degrees C for 30 min). The heat-treated PPLs were low in total proteins, depleted in both plasma and platelet fibrinogen, and devoid of thrombogenic and proteolytic activities. They exerted very high neuroprotective activity when non oncogenic, Lund human mesencephalic (LUHMES) cells that had differentiated into dopaminergic neurons were exposed to the MPP+ neurotoxin. Heat treatment improved the neuroprotection and inactivated the neurotoxic blood-borne hepatitis C virus. PPL did not induce inflammation in BV2 microglial cells and inhibited COX-2 expression upon lipopolysaccharide exposure. Intranasal administration in mice revealed (a) diffusion of neurotrophins in the striatum and cortex, and (b) MPTP intoxication neuroprotection in the substantia nigra and striatum and the absence of neuroinflammation. These dedicated heat-treated PPLs can be a safe and valuable candidate for a therapeutic strategy for PD. PMID- 28728001 TI - Modeling the effect of temperature-control curtain on the thermal structure in a deep stratified reservoir. AB - Temperature-control curtain (TCC) is an effective facility of selective withdrawal. Previous research has estimated the influence of TCC on the outflow temperature, but its effect on the thermal structure of a reservoir area is unknown, which is crucial to the reservoir ecology. For this purpose, taking the Sanbanxi Reservoir as a case study, a 2-D hydrodynamic and temperature model covering the whole reservoir was built and calibrated to simulate the flow and temperature fields under different TCC scenarios, and the change rules of thermal stability and outflow temperature are obtained. When the water-retaining proportion (Pr) of bottom-TCC increases, the temperature difference between inflow and outflow monotonously decreases, while the thermal stability first increases and later decreases. The maximum thermal stability exists at Pr = 62.5%; it goes against water quality improvement and should be avoided in practice. A bottom-TCC with Pr > 80% is practical for deep reservoirs such as Sanbanxi Reservoir to decrease the temperature difference between inflow and outflow without the increase of thermal stability. In terms of top-TCC, as Pr increases, the temperature difference between inflow and outflow monotonously increases and thermal stability decreases. The top-TCCs are recommended when a smaller thermal stability is more preferentially considered than outflow temperature, or a cool outflow in the summer is required for downstream coldwater fishes. In addition, the TCC cannot decrease or increase the outflow temperature all of the time throughout the whole year, and it primarily changes the phase and variation range of the outflow temperature. This study quantitatively estimates the potential effect of TCCs on the thermal structure and water environment management and provides a theoretical basis for the application of TCC. PMID- 28728002 TI - Development of an integrated generic model for multi-scale assessment of the impacts of agro-ecosystems on major ecosystem services in West Africa. AB - This paper presents an integrated model assessing the impacts of climate change, agro-ecosystem and demographic transition patterns on major ecosystem services in West-Africa along a partial overview of economic aspects (poverty reduction, food self-sufficiency and income generation). The model is based on an agent-based model associated with a soil model and multi-scale spatial model. The resulting Model for West-Africa Agro-Ecosystem Integrated Assessment (MOWASIA) is ecologically generic, meaning it is designed for all sudano-sahelian environments but may then be used as an experimentation facility for testing different scenarios combining ecological and socioeconomic dimensions. A case study in Burkina Faso is examined to assess the environmental and economic performances of semi-continuous and continuous farming systems. Results show that the semi continuous system using organic fertilizer and fallowing practices contribute better to environment preservation and food security than the more economically performant continuous system. In addition, this study showed that farmers heterogeneity could play an important role in agricultural policies planning and assessment. In addition, the results showed that MOWASIA is an effective tool for designing, analysing the impacts of agro-ecosystems. PMID- 28728003 TI - Evaluation of the effects of low energetic microwave irradiation on anaerobic digestion. AB - The present study investigates the effects of microwave irradiation on the performance of anaerobic digestion processes. A first set of experiments is performed to distinguish the upper limit of the applied energy levels. Secondly, the effects of these treatments on the performance of the digestion process are evaluated in 3 experimental setups: (i) monitoring the acetic acid degradation, (ii) performing a biological methane potential (BMP) assay and (iii) conducting a specific methanogenic activity (SMA) test. The solubilisation experiment reveals a limited degree of disintegration of anaerobic biomass up to a microwave treatment of 10000 kJ/kg TS. Above this threshold value the soluble COD level started to rise, with up to 350% at 30000 kJ/kg TS regardless of the microwave output power. Because solubilisation of the biomass increases the easily degradable content, this would lead to false observations regarding increased activity. Therefore, solubilisation is minimized by limiting the microwave treatment to a maximum of 6000 kJ/kg TS during the second part of the experiments. Monitoring the degradation of acetic acid after a low intensity microwave treatment, reveals that microwave irradiation shortens the lag phase, e.g., from 21 to 3 h after a microwave treatment of 1000 kJ/kg TS at 100 W. However most treatments also result in a decrease of the maximum degradation and of the degradation rate of acetic acid. BMP assays are performed to evaluate the activity and performance of the entire anaerobic community. Every treatment results in a decreased biogas production potential and decreased biogas production rate. Moreover, each treatment induced an increase of the lag phase. The SMA experiments show no influence of the microwave irradiation in terms of biogas or methane production. PMID- 28728004 TI - Effects of aspect ratio of multi-walled carbon nanotubes on coal washery waste water treatment. AB - The dependency of adsorption behaviour on the aspect ratio of multi-walled carbon nanotubes (MWCNTs) has been explored. In this study, effect of growth temperature on yield and aspect ratio of MWCNTs by catalytic chemical vapour deposition (CCVD) method is reported. The result revealed that yield and aspect ratio of synthesised MWCNTs strongly depend on the growth temperature during CCVD operation. The resulting MWCNTs were characterized by High Resolution Transmission Electron Microscope (HRTEM), Dynamic Light Scattering (DLS) and X ray diffraction (XRD) techniques to determine it diameter, hydrodynamic diameter and crystallinity respectively. Aspect ratio and length of the grown MWCNTs were determined from the HRTEM images with the hydrodynamic diameter using the modified Navier-Stokes and Stokes-Einstein equations. The effect of the prepared MWCNTs dosage were investigated on the Turbidity, Iron (Fe) and Lead (Pb) removal efficiency of coal washery effluent. The MWCNTs with higher length (58.17 MUm) and diameter (71 nm) tend to show high turbidity and Fe removal, while MWCNTs with lower length (38.87 MUm) and diameter (45 nm) tend to show high removal of Pb. Hence, the growth temperature during CCVD operation shows a great effluence on the aspect ratio of MWCNTs which determines it area of applications. PMID- 28728005 TI - Thermal destruction of organic waste hydrophobicity for agricultural soils application. AB - Use of organic amendments is a good strategy for combating the growing problem of soil degradation due to deterioration of organic matter content, particularly severe in semi-arid European Mediterranean regions, while at the same time providing an opportunity for recycling organic wastes. Olive mill pomace (OMP), the main by-product of the olive oil industry, is being used increasingly in olive grove soils for this purpose. Although the positive effects of OMP amendments have been widely studied, they also have some negative effects on soil. One of the most critical is that they increase water repellency (WR) due to the presence of poorly evolved, strongly aliphatic compounds. This detrimental effect has received very little attention, although it may impair plant water availability and infiltration rates, increase erosion and lower long-term soil quality. This study proposed, for the first time, thermal treatment as an effective way of reducing WR in organic amendments (i.e. mixtures of OMP, olive tree pruning, chicken manure and spent coffee grounds) prior to their application to soil. Thermal treatment at 275 degrees C proved effective in removing WR, while lower temperatures (175 or 225 degrees C) can even increase it. Changes by thermal treatment in the characteristics of the organic amendments studied with FTIR and UV-Vis spectroscopy and thermogravimetric analysis showed that it strongly reduced the aliphatic compounds mainly responsible for their hydrophobicity, concentrated aromatic compounds and increased thermostability. Heating also reduced phytotoxicity, making all of the organic amendments usable in the field (germination index over 100%). Therefore, heating at 275 degrees C could be an acceptable option for removing WR from organic amendments, enhancing their quality with more stable evolved characteristics. PMID- 28728006 TI - An electrochemical impedance biosensor for Hg2+ detection based on DNA hydrogel by coupling with DNAzyme-assisted target recycling and hybridization chain reaction. AB - In this work, an electrochemical impedance biosensor for high sensitive detection of Hg2+ was presented by coupling with Hg2+-induced activation of Mg2+-specific DNAzyme (Mg2+-DNAzyme) for target cycling and hybridization chain reaction (HCR) assembled DNA hydrogel for signal amplification. Firstly, we synthesized two different copolymer chains P1 and P2 by modifying hairpin DNA H3 and H4 with acrylamide polymer, respectively. Subsequently, Hg2+ was served as trigger to activate the Mg2+-DNAzyme for selectively cleavage ribonucleobase-modified substrate in the presence of Mg2+. The partial substrate strand could dissociate from DNAzyme structure, and hybridize with capture probe H1 to expose its concealed sequence for further hybridization. With the help of the exposed sequence, the HCR between hairpin DNA H3 and H4 in P1 and P2 was initiated, and assembled a layer of DNA cross-linked hydrogel on the electrode surface. The formed non-conductive DNA hydrogel film could greatly hinder the interfacial electronic transfer which provided a possibility for us to construct a high sensitive impedance biosensor for Hg2+ detection. Under the optimal conditions, the impedance biosensor showed an excellent sensitivity and selectivity toward Hg2+ in a concentration range of 0.1pM - 10nM with a detection limit of 0.042pM Moreover, the real sample analysis reveal that the proposed biosensor is capable of discriminating Hg2+ ions in reliable and quantitative manners, indicating this method has a promising potential for preliminary application in routine tests. PMID- 28728007 TI - Direct immune-detection of cortisol by chemiresistor graphene oxide sensor. AB - In this study, a biosensor to detect a stress biomarker of cortisol using cortisol monoclonal antibody (c-Mab) covalently immobilized on reduced graphene oxide (rGO) channel as electrical sensing element was demonstrated. Highly specific immune-recognition between the c-Mab and the cortisol was identified and characterized on a basis of resistance change at the rGO channel based chemiresistor sensor achieving the limit of detection of 10pg/mL (27.6 pM). In addition, cortisol concentrations of real human salivary sample and buffer solution of rat adrenal gland acute slices, which could secret the cortisol induced by adrenocorticotropic hormone (ACTH), were directly measured by the chemiresistor corresponding to the specific sensing of the cortisol. The rGO chemiresistor could selectively measure the cortisol levels in spite of diverse neuroendocrine's existence. The potential perspective of this study can be a protocol of new cortisol sensor development, which will be applicable to point-of care testing (POCT) targeted for salivary cortisol, in vitro psychobiological study on cortisol induction, and implantable sensor chip in the future. PMID- 28728008 TI - Pen-on-paper strategy for point-of-care testing: Rapid prototyping of fully written microfluidic biosensor. AB - Paper-based microfluidic biosensors have recently attracted increasing attentions in point-of-care testing (POCT) territories benefiting from their affordable, accessible and eco-friendly features, where technologies for fabricating such biosensors are preferred to be equipment free, easy-to-operate and capable of rapid prototyping. In this work, we developed a pen-on-paper (PoP) strategy based on two custom-made pens, i.e., a wax pen and a conductive-ink pen, to fully write paper-based microfluidic biosensors through directly writing both microfluidic channels and electrodes. Particularly, the proposed wax pen is competent to realize one-step fabrication of wax channels on paper, as the melted wax penetrates into paper during writing process without any post-treatments. The practical applications of the fabricated paper-based microfluidic biosensors are demonstrated by both colorimetric detection of Salmonella typhimurium DNA with detection limit of 1nM and electrochemical measurement of glucose with detection limit of 1mM. The developed PoP strategy for making microfluidic biosensors on paper characterized by true simplicity, prominent portability and excellent capability for rapid prototyping shows promising prospect in POCT applications. PMID- 28728009 TI - Bridged Rebar Graphene functionalized aptasensor for pathogenic E. coli O78:K80:H11 detection. AB - We report a novel fabrication method of functionalised Bridged Rebar Graphene (BRG) onto newly designed nanostructured aptasensor for label free impedimetric sensing of pathogenic bacteria E. coli O78:K80:H11. The chemical facilitated unscrolling of MWCNT and subsequent bridging with terephthalaldehyde (TPA) to form 3D-hierarchical BRG nanoconstruct exhibited synergistic effect by combining enhanced electrical properties and facile chemical functionality for stable bio interface. The bacteria-DNA interactions were captured on BRG nanostructured electrode by using specific anti-E.coli DNA aptamer (Kd~ 14nM), screened by new in-situ developed SELEX method using phenylboronic acid on microtitre plate. The developed nanostructured aptasensor demonstrated a low detection limit and sensitivity of ~ 101cfu/mL towards E. coli O78:K80:H11 with a dynamic response range from 101 to 106cfu/mL in water, juice and milk samples. PMID- 28728010 TI - Advances in point-of-care technologies for molecular diagnostics. AB - Advances in miniaturization, nanotechnology, and microfluidics, along with developments in cloud-connected point-of-care (POC) diagnostics technologies are pushing the frontiers of POC devices toward low-cost, user-friendly, and enhanced sensitivity molecular-level diagnostics. The combination of various bio-sensing platforms within smartphone-integrated electronic readers provides accurate on site and on-time diagnostics based on various types of chemical and biological targets. Further, 3D printing technology shows a huge potential toward fabrication and improving the performance of POC devices. Integration of skin like flexible sensors with wireless communication technology creates a unique opportunity for continuous, real-time monitoring of patients for both preventative healthcare and during disease outbreaks. Here, we review recent developments and advances in POC technologies and describe how these advances enhance the performance of POC platforms. Also, this review describes challenges, directions, and future trends on application of emerging technologies in POC diagnostics. PMID- 28728011 TI - Anti-inflammatory effect of sugar-amino acid Maillard reaction products on intestinal inflammation model in vitro and in vivo. AB - The Maillard reaction is a nonenzymatic reaction between an amino acid and a reducing sugar that usually occurs upon heating. This reaction occurs routinely in cooking, generates numerous products, which are collectively referred to as Maillard reaction products (MRPs) contributing to aroma and color features. Advanced glycation end-products (AGEs) transformed from MRPs are participated in many types of inflammation reaction. In this study, various sugar-amino acid MRPs were prepared from three different amino acids (lysine, arginine, and glycine) and sugars (glucose, fructose, and galactose) for 1 h with heating at 121 degrees C. Treatment of lipopolysaccharide-stimulated RAW264.7 macrophages with the MRPs decreased nitric oxide (NO) expression compared to control without MRPs treatment. MRPs derived from lysine and galactose (Lys-Gal MRPs) significantly inhibited NO expression. The retentate fraction of Lys-Gal MRPs with cut-off of molecular weight of 3-10 kDa (LGCM) suppressed NO expression more effectively than did Lys-Gal MRPs. The anti-inflammatory effect of LGCM was evaluated using a co-culture system consisting of Caco-2 (apical side) and RAW264.7 or THP-1 (basolateral side) cells to investigate the gut inflammation reaction by stimulated macrophage cells. In this system, LGCM prevented a decreased transepithelial electrical resistance, and decreased both tumor necrosis factor alpha production in macrophages and interleukin (IL)-8 and IL-1beta mRNA expression in Caco-2 cells. In co-culture and in vivo dextran sulfate sodium (DSS)-induced colitis model study, we also observed the anti-inflammatory activity of LGCM. PMID- 28728012 TI - Ovipositor setation in oldest insects (Insecta: Archaeognatha) revealed by SEM and He-ion microscopy. AB - Archaeognatha represent the oldest living lineage of true insects (=Ectognatha), which are remarkable, among others, for plesiomorphic genital morphology and complicated mating behaviour. I used scanning electron microscopy and He-ion microscopy to examine the ovipositor morphology of seven species, in order to describe the cuticle microsculpture. The species studied are characterised by different types of the ovipositor setation pattern, which are considered an important taxonomic feature for Archaeognatha. The common and well discernible elements of ovipositor setation in Archaeognatha are: (1) non-articulated terminal seta, (2) grooved type I basiconic sensillum with apical pore, (3) multiporous type II basiconic sensillum, (4) articulated setae of different length. Coeloconica-like sensilla and campaniform sensilla demonstrate a variety of transient morphology. Results of this study provide morphological evidence of presence of olfactory receptors on the ovipositor in Archaeognatha. The possible functions of the ovipositor setation in Archaeognatha are discussed. PMID- 28728013 TI - Dynamic and elastic shape transitions in curved ESCRT-III filaments. AB - The ESCRT-III complex is an evolutionary ancient and conserved complex that catalyzes fission of lipid membranes from the lumen of the neck in many, if not all processes requiring this specific fission reaction. The ESCRT-III membrane remodeling complex is unique as its molecular and polymeric structures do not intuitively suggests how it could deform and break lipid membranes. Here we review the common structural features of the ESCRT-III subunits, and the shape diversity of the various filamentous forms. We propose a simple geometry and elasticity framework that could help to isolate which features of the ESCRT-III filaments are common to all filamentous forms as well as to explain their diversity. We speculate on how these features could provide mechanistic insights into the many functions of the ESCRT-III complex. PMID- 28728014 TI - The Structured Observation of Motor Performance in Infants can detect cerebral palsy early in neonatal intensive care recipients. AB - BACKGROUND: The detection of motor problems in infancy requires a detailed assessment method that measures both the infants' level of motor development and movement quality. AIMS: To evaluate the ability of the Structured Observation of Motor Performance in Infants (SOMP-I) to detect cerebral palsy (CP) in neonatal intensive care recipients. STUDY DESIGN: Prospective cohort study analyzed retrospectively. SUBJECTS: 212 (girls: 96) neonatal intensive care recipients (mean gestational age 34weeks, range: 23-43). Twenty infants were diagnosed with CP. OUTCOME MEASURES: The infants were assessed using SOMP-I at 2, 4, 6 and 10months' corrected age. Accuracy measures were calculated for level of motor development, quality of motor performance and a combination of the two to detect CP at single and repeated assessments. RESULTS: At 2months, 17 of 20 infants with CP were detected, giving a sensitivity of 85% (95% CI 62-97%) and a specificity of 48% (95% CI 40-55%), while the negative likelihood ratio was 0.3 (95% CI 0.1 0.9) and the positive likelihood ratio was 1.6 (95% CI 1.3-2.0). At 6months all infants with CP were detected using SOMP-I, and all infants had repeatedly been assessed outside the cut-offs. Specificity was generally lower for all assessment ages, however, for repeated assessments sensitivity reached 90% (95% CI 68-99%) and specificity 85% (95% CI 79-90%). CONCLUSIONS: SOMP-I is sensitive for detecting CP early, but using the chosen cut-off can lead to false positives for CP. Assessing level and quality in combination and at repeated assessments improved predictive ability. PMID- 28728016 TI - Location, Location, Location: Microglia Are Where They Live. AB - A deep dive into microglia form and function reveals startling regional heterogeneity in number, morphology, activity, and transcriptomics in nuclei relevant to motor control and motivation (De Biase et al., 2017). Differences appear 2 weeks after birth, and depletion and recolonization in adulthood recapitulate the original phenotype, implicating local environment as mediators of microglial phenotype. PMID- 28728015 TI - Diagnostic yield of percutaneous biopsy for sclerotic bone lesions: Influence of mean Hounsfield units. AB - PURPOSE: To identify whether there was an association between Hounsfield units of sclerotic bone lesions and diagnostic yield of biopsy. METHOD: All core needle biopsies of sclerotic bone lesion were identified from a database. Pathology reports were reviewed to determine whether the biopsy was diagnostic or non diagnostic. RESULTS: 91 patients were included in the study group. The yield for lesions with mean HU>=500 was significantly lower than those with a mean HU<=500 (40% vs. 69.6%, p<0.05). CONCLUSION: Lesions with a mean HU>500 are more likely to have a non-diagnostic biopsy than a diagnostic biopsy. PMID- 28728017 TI - Oxytocin Mobilizes Midbrain Dopamine toward Sociality. AB - Oxytocin and dopamine possess significant overlap in the modulation of life essential behaviors. Here, Xiao et al. (2017) show that the activity of dopamine neurons of the ventral tegmental area and the substantia nigra is finely tuned by axonal release of oxytocin. PMID- 28728018 TI - Unbelievable: Neural Correlate of the Feedback Negativity in the Anterior Cingulate. AB - The feedback- or error-related negativity (FN) has been extensively documented in frontal EEG recordings in human participants. In this issue of Neuron, Hyman et al. (2017) have documented a single-cell correlate of the FN in the ACC of rodents. PMID- 28728019 TI - Unraveling the Complex Tapestry of Association Networks. AB - Prior group-level studies have described several large-scale distributed networks within association cortex. In this issue of Neuron, Braga and Buckner (2017) attend to the individual brain, revealing a challenging new portrait of its fine grained organization. PMID- 28728020 TI - Neuroscience-Inspired Artificial Intelligence. AB - The fields of neuroscience and artificial intelligence (AI) have a long and intertwined history. In more recent times, however, communication and collaboration between the two fields has become less commonplace. In this article, we argue that better understanding biological brains could play a vital role in building intelligent machines. We survey historical interactions between the AI and neuroscience fields and emphasize current advances in AI that have been inspired by the study of neural computation in humans and other animals. We conclude by highlighting shared themes that may be key for advancing future research in both fields. PMID- 28728022 TI - Loss of TMEM106B Ameliorates Lysosomal and Frontotemporal Dementia-Related Phenotypes in Progranulin-Deficient Mice. AB - Progranulin (GRN) and TMEM106B are associated with several common neurodegenerative disorders including frontotemporal lobar degeneration (FTLD). A TMEM106B variant modifies GRN-associated FTLD risk. However, their functional relationship in vivo and the mechanisms underlying the risk modification remain unclear. Here, using transcriptomic and proteomic analyses with Grn-/- and Tmem106b-/- mice, we show that, while multiple lysosomal enzymes are increased in Grn-/- brain at both transcriptional and protein levels, TMEM106B deficiency causes reduction in several lysosomal enzymes. Remarkably, Tmem106b deletion from Grn-/- mice normalizes lysosomal protein levels and rescues FTLD-related behavioral abnormalities and retinal degeneration without improving lipofuscin, C1q, and microglial accumulation. Mechanistically, TMEM106B binds vacuolar-ATPase accessory protein 1 (AP1). TMEM106B deficiency reduces vacuolar-ATPase AP1 and V0 subunits, impairing lysosomal acidification and normalizing lysosomal protein levels in Grn-/- neurons. Thus, Grn and Tmem106b genes have opposite effects on lysosomal enzyme levels, and their interaction determines the extent of neurodegeneration. PMID- 28728023 TI - Persistent Expression of VCAM1 in Radial Glial Cells Is Required for the Embryonic Origin of Postnatal Neural Stem Cells. AB - During development, neural stem cells (NSCs) undergo transitions from neuroepithelial cells to radial glial cells (RGCs), and later, a subpopulation of slowly dividing RGCs gives rise to the quiescent adult NSCs that populate the ventricular-subventricular zone (V-SVZ). Here we show that VCAM1, a transmembrane protein previously found in quiescent adult NSCs, is expressed by a subpopulation of embryonic RGCs, in a temporal and region-specific manner. Loss of VCAM1 reduced the number of active embryonic RGCs by stimulating their premature neuronal differentiation while preventing quiescence in the slowly dividing RGCs. This in turn diminished the embryonic origin of postnatal NSCs, resulting in loss of adult NSCs and defective V-SVZ regeneration. VCAM1 affects the NSC fate by signaling through its intracellular domain to regulate beta-catenin signaling in a context-dependent manner. Our findings provide new insight on how stem cells in the embryo are preserved to meet the need for growth and regeneration. PMID- 28728021 TI - Memory Takes Time. AB - Memory is an adaptation to particular temporal properties of past events, such as the frequency of occurrence of a stimulus or the coincidence of multiple stimuli. In neurons, this adaptation can be understood in terms of a hierarchical system of molecular and cellular time windows, which collectively retain information from the past. We propose that this system makes various timescales of past experience simultaneously available for future adjustment of behavior. More generally, we propose that the ability to detect and respond to temporally structured information underlies the nervous system's capacity to encode and store a memory at molecular, cellular, synaptic, and circuit levels. PMID- 28728024 TI - Origins of Cell-Type-Specific Olfactory Processing in the Drosophila Mushroom Body Circuit. AB - How cell-type-specific physiological properties shape neuronal functions in a circuit remains poorly understood. We addressed this issue in the Drosophila mushroom body (MB), a higher olfactory circuit, where neurons belonging to distinct glomeruli in the antennal lobe feed excitation to three types of intrinsic neurons, alpha/beta, alpha'/beta', and gamma Kenyon cells (KCs). Two photon optogenetics and intracellular recording revealed that whereas glomerular inputs add similarly in all KCs, spikes were generated most readily in alpha'/beta' KCs. This cell type was also the most competent in recruiting GABAergic inhibition fed back by anterior paired lateral neuron, which responded to odors either locally within a lobe or globally across all lobes depending on the strength of stimuli. Notably, as predicted from these physiological properties, alpha'/beta' KCs had the highest odor detection speed, sensitivity, and discriminability. This enhanced discrimination required proper GABAergic inhibition. These results link cell-type-specific mechanisms and functions in the MB circuit. PMID- 28728025 TI - A Neural Signature of Divisive Normalization at the Level of Multisensory Integration in Primate Cortex. AB - Studies of multisensory integration by single neurons have traditionally emphasized empirical principles that describe nonlinear interactions between inputs from two sensory modalities. We previously proposed that many of these empirical principles could be explained by a divisive normalization mechanism operating in brain regions where multisensory integration occurs. This normalization model makes a critical diagnostic prediction: a non-preferred sensory input from one modality, which activates the neuron on its own, should suppress the response to a preferred input from another modality. We tested this prediction by recording from neurons in macaque area MSTd that integrate visual and vestibular cues regarding self-motion. We show that many MSTd neurons exhibit the diagnostic form of cross-modal suppression, whereas unisensory neurons in area MT do not. The normalization model also fits population responses better than a model based on subtractive inhibition. These findings provide strong support for a divisive normalization mechanism in multisensory integration. PMID- 28728027 TI - Highly sensitive response of solution-processed bismuth sulfide nanobelts for room-temperature nitrogen dioxide detection. AB - Low dimensional nanomaterials have emerged as candidates for gas sensors owing to their unique size-dependent properties. In this paper, Bi2S3 nanobelts were synthesized via a facile solvothermal process and spin-coated onto alumina substrates at room temperature. The conductometric devices can even sensitively response to the relatively low concentrations of NO2 at room temperature, and their sensing performance can be effectively enhanced by the ligand exchange treatment with inorganic salts. The Pb(NO3)2-treated device exhibited superior sensing performance of 58.8 under 5ppm NO2 at room-temperature, with the response and recovery time of 28 and 106s. The competitive adsorption of NO2 against O2 on Bi2S3 nanobelts, with the enhancement both in gas adsorption and charge transfer caused by the porous network of the very thin Bi2S3 nanobelts, can be a reasonable explanation for the improved performance at room temperature. Their sensitive room-temperature response behaviors combined with the excellent solution processability, made Bi2S3 nanobelts very attractive for the construction of low-cost gas sensors with lower power consumption. PMID- 28728028 TI - Direct evidence of the photocatalytic generation of reactive oxygen species (ROS) in a Bi2W2O9 layered-structure. AB - In the present work, the Bi2W2O9 photocatalyst has been prepared by an easy and prompt co-precipitation route. From the structural characterization, we have stated that the formation of the Bi2W2O9 is accompanied by a small amount of the Bi2WO6 oxide, which gradually decreases by increasing the calcination temperature. The conduction and valence band edges of the Bi2W2O9 semiconductor were experimentally estimated for the first time using the X-ray photoelectron (XPS) and diffuse reflectance (DRS) spectroscopies. The best photocatalytic performance was attained for the sample calcined at 700 degrees C, which showed the highest production of hydroxyl radicals, superoxide ions as well as the highest photodegradation of the ciprofloxacin drug. In addition, by means of photoluminescence spectroscopy we propose that the effective separation of the photogenerated charge carriers in the sample calcined at 700 degrees C produces a higher production of reactive oxygen species and thus a higher photoactivity under solar-like irradiation conditions. PMID- 28728026 TI - Parallel Interdigitated Distributed Networks within the Individual Estimated by Intrinsic Functional Connectivity. AB - Certain organizational features of brain networks present in the individual are lost when central tendencies are examined in the group. Here we investigated the detailed network organization of four individuals each scanned 24 times using MRI. We discovered that the distributed network known as the default network is comprised of two separate networks possessing adjacent regions in eight or more cortical zones. A distinction between the networks is that one is coupled to the hippocampal formation while the other is not. Further exploration revealed that these two networks were juxtaposed with additional networks that themselves fractionate group-defined networks. The collective networks display a repeating spatial progression in multiple cortical zones, suggesting that they are embedded within a broad macroscale gradient. Regions contributing to the newly defined networks are spatially variable across individuals and adjacent to distinct networks, raising issues for network estimation in group-averaged data and applied endeavors, including targeted neuromodulation. PMID- 28728029 TI - Peroxidase mimetic activity of Fe3O4 nanoparticle prepared based on magnetic hydrogels for hydrogen peroxide and glucose detection. AB - Stimuli-response magnetic hydrogels were prepared in the mixtures of magnetic surfactants, (CnTAFB(C), n=12, 14, 16), and chiral amphiphiles, sodium cholate (SC). The gelation behavior of CnTAFB(C)/SC were studied in detail. The results proved that the hydrophobicity of surfactants and the hydration radius (Rh) of anions played a vital role in the gelation process. The microstructure of the hydrogels were determined to be three-dimensional network of fibrous aggregates. The formation of the hydrogel fibrils was considered to be mainly driven by a delicate balance of multiple non-covalent interactions including hydrophobic interaction, electrostatic interaction, hydrogen bonding, van der Waals force, and the steric effect of SC molecule. Rheological measurements demonstrated that the hydrogels are high mechanical strength materials (the yield stress exceeding 2000Pa). The mechanical strength of the hydrogels is dependent on the fiber density, which can be regulated by changing the proportion of the two compounds, the total concentration and the chain length of the surfactants. The magnetic hydrogels of C12TAFB/SC mixtures served as the precursors for preparing cubic Fe3O4 nanoparticles with the diameter of 7.2nm. The as-prepared Fe3O4 nanoparticles exhibit excellent ferromagnetic characteristic and high peroxidase like activity and can be used as biosensor for hydrogen peroxide (H2O2) and glucose detection. We developed a convenient and green method for preparing Fe3O4 nanoparticles, which can be used as a promising candidate biosensor for glucose detection. PMID- 28728030 TI - Enhanced visible light photocatalytic hydrogen evolution over porphyrin hybridized graphitic carbon nitride. AB - Tetra (4-carboxyphenyl) porphyrin (TCPP) was loaded on the surface of Pt/g-C3N4 via a simple adsorption process, and the microstructure and chemical structure of the composites were characterized by high resolution transmission electron microscopy, X-ray diffraction, X-ray photoelectron spectroscopy, Fourier transform infrared spectroscopy, UV-visible diffused reflectance spectroscopy and photoluminescence spectroscopy. Loading TCPP onto Pt/g-C3N4 enhanced the visible light-driven photocatalytic evolution of H2 from water. The TCPP/Pt/g-C3N4 composite with a TCPP loading of 1wt% had the highest photoactivity, which was 2.1 times higher than that of Pt/g-C3N4. This improvement is attributed to enhanced visible light utilization by the TCPP/Pt/g-C3N4 resulting from the strong visible light response of TCPP. In addition, the formed organic heterostructure between TCPP and g-C3N4 with overlapping bad gaps accelerates the electron transfer and inhibits the recombination of the photogenerated electrons and holes on g-C3N4. PMID- 28728031 TI - Applying a modified Donnan model to describe the surface complexation of chromate to iron oxyhydroxide agglomerates with heteromorphous pores. AB - In this study, a modified Donnan model (mDM) is incorporated into surface complexation model (SCM) to better understand the physicochemical processes for adsorption of hexavalent chromium, Cr(VI), on porous iron oxyhydroxide agglomerates (IOAs). The mDM includes a chemical potential term MUatt to account for ionic transport and electrostatic interaction in micropores (dmi<2nm) which is usually neglected in typical Donnan model (tDM). To estimate the parameters of mDM in a simple and accurate way, a rigorous protocol was presented. First, the prepared IOAs was characterized with a heteromorphous pore structure (i.e., co existing micropores and macropores, dma>2nm) demonstrating high Cr(VI) adsorption in a broad range of ionic strengths. The batch data was then fitted with Donnan model in PHREEQC to obtain Stern (psiS) and Donnan (psiD) potentials used for MUatt calculation. The decreasing MUatt values with ionic strength indicated obstructing effect of electrolyte ions on Cr(VI) uptake in micropores. Finally, the ionic activity coefficients and reaction constants were corrected using Pitzer model due to the high level electrolytes accumulated in the Donnan layer through osmotic and electrostatic attraction. Results of this study have captured the effects of inner structure of IOAs on Cr(VI) uptake and quantitatively discerned the contribution of micropores and macropores for adsorption reactions at different ionic strengths. PMID- 28728032 TI - Tunable fluorescence quenching near the graphene-aqueous interface. AB - With increased interest in graphene-based sensors for biomolecules and other targets, we investigated the impact of ionic strength on the steady-state emissions from fluorescein labels on proteins adsorbing on pristine CVD (chemical vapor deposited)-graphene on a silica support. Using the model system of fluorescein-tagged fibrinogen we demonstrated that, for fluorescein tags on adsorbed fibrinogen, emission intensity was very sensitive to the salt concentration. This behavior was not seen for fluorescein-tagged fibrinogen in solution. We demonstrated that fluorescein "quenching" in this system was a result of fluorescein's pH sensitivity: with changes in salt concentration, near surface fluorescein experiences either the neutral bulk pH or, with a negatively charged surface, an acidic environment. The findings carry the important implication that the aqueous environment near silica-supported graphene is substantially acidic as a result of near-surface negative charge. This further implies, because of the purity of the graphene in this study and its lack of oxidation, that negative charge arises from ion adsorption and/or from the underlying silica support, which may be hydrated and present dissociated surface silanols. That is, the electrostatic potential from silica beneath the graphene may pass through the graphene, much as van der Waals interactions have been proven to do. Results were semi-quantitatively consistent with calculations that employed a Guoy Chapman model of the interface and the established pKa of the fluorescein. While these findings were obtained with adsorbed proteins, similar fluorescence quenching would be expected for any fluorescein-tagged species in the vicinity of silica-supported graphene. Thus, because of the negative charge at the aqueous graphene interface, ionic strength can be exploited as means of creating a molecular ruler of fluorescein emissions, and the emissions can be assessed within different distances, corresponding to the Debye length, from the graphene interface. PMID- 28728033 TI - Deposition pattern and tracer particle motion of evaporating multi-component sessile droplets. AB - The understanding of near-wall motion, evaporation behavior and dry pattern of sessile nanofluid droplets is fundamental to a wide range of applications such as painting, spray drying, thin film coating, fuel injection and inkjet printing. However, a deep insight into the heat transfer, fluid flow, near-wall particle velocity and their effects on the resulting dry patterns is still much needed to take the full advantage of these nano-sized particles in the droplet. This work investigates the effect of direct absorptive silicon/silver (Si/Ag) hybrid nanofluids via two experiments. The first experiment identifies the motion of tracer particles near the triple line of a sessile nanofluid droplet on a super hydrophilic substrate under ambient conditions by the multilayer nanoparticle image velocimetry (MnPIV) technique. The second experiment reveals the effect of light-sensitive Si/Ag composite nanoparticles on the droplet evaporation rate and subsequent drying patterns under different radiation intensities. The results show that the presence of nanoparticle in a very small proportion significantly affects the motion of tracer particles, leading to different drying patterns and evaporation rates, which can be very important for the applications such as spray coating and inkjet printing. PMID- 28728034 TI - Construction of novel WO3/SnNb2O6 hybrid nanosheet heterojunctions as efficient Z scheme photocatalysts for pollutant degradation. AB - The artificially Z-scheme heterojunctions between WO3 nanosheet and SnNb2O6 nanosheet with strongly coupled heterointerfaces were successfully constructed via a simple hydrothermal coassembly method. Transmission electron microscopy (TEM) and high-resolution TEM proved that an intimate contact interface was formed. The synthesized heterojunctions exhibites enhanced photodegradation efficiency for Rhodamine B under irradiation of visible light, and the highest reaction rate over 30%-WO3/SnNb2O6 nanosheet heterojunctions is about 4.7-fold and 2-fold higher than that of pristine WO3 and SnNb2O6, respectively. Such a considerable improvement could be mainly attributed to the rapid migration of the photo-induced e-/h+ pairs through the nanosheets-coupled heterojunction interfaces. A possible directly Z-scheme charge transfer mechanism was proposed for the elimination of organic contaminants under irradiation of visible light. This work may furnish new insights into development of novel 2D/2D nanosheet heterojunctions with the enhanced photocatalytic activity. PMID- 28728035 TI - Modulatory roles of proinflammatory cytokines on the expression of cathelicidins in the lower regions of the oviduct of laying hens. AB - The current study aimed to confirm and examine the physiological roles of the proinflammatory cytokines IL1B and IL6 on the immune functions which mediated by cathelicidins (CATHs) in the uterus and vagina of laying hens. Snaps of the mucosal tissues of uterus and vagina were incubated in culture medium or chicken recombinant IL1B and IL6 for 1.5h or 3h before extraction of total RNA to be used for examination of IL1B and IL6, their receptors, and cathelicidins by semi quantitative PCR; and to examine the changes in cathelicidins expressions by real time PCR. PCR analysis confirmed that IL1B and IL6, their receptors, and CATH1-3 were expressed in the mucosal tissues of the uterus and vagina. In uterus tissue, IL1B did not affect the expression of CATH1 and -2 at different doses and incubation time, whereas CATH3 was significantly downregulated by incubation with IL1B for 1.5h. In the vaginal tissue, the expressed CATH1, -2 and -3 were significantly upregulated by incubation with IL1B for 1.5h in a dose-dependent manner. In uterus tissue, CATH1 expression was down-regulate by IL6 incubation for 1.5h, but not by 3h however, CATH3 expression was significantly increased by incubation with IL6 for 1.5h, but not for 3h. In the vaginal tissues, all CATHs expression was not affected significantly by incubation with IL6. These current observations suggest that CATH1, -2 and -3 in the vagina are upregulated by IL1B, and CATH3 in the uterus is also upregulated by IL6. IL1B and IL6 synthesized in response to infection by the microbes may enhance the defense system in the oviduct mucosal tissues by increasing the synthesis of CATHs. PMID- 28728036 TI - The relationship between brain volumes and intelligence in bipolar disorder. AB - OBJECTIVES: Bipolar disorder type-I (BD-I) patients show a lower Intelligence Quotient (IQ) and smaller brain volumes as compared with healthy controls. Considering that in healthy individuals lower IQ is related to smaller total brain volume, it is of interest to investigate whether IQ deficits in BD-I patients are related to smaller brain volumes and to what extent smaller brain volumes can explain differences between premorbid IQ estimates and IQ after a diagnosis of BD-I. METHODS: Magnetic resonance imaging brain scans, IQ and premorbid IQ scores were obtained from 195 BDI patients and 160 controls. We studied the relationship of (global, cortical and subcortical) brain volumes with IQ and IQ change. Additionally, we investigated the relationship between childhood trauma, lithium- and antipsychotic use and IQ. RESULTS: Total brain volume and IQ were positively correlated in the entire sample. This correlation did not differ between patients and controls. Although brain volumes mediated the relationship between BD-I and IQ in part, the direct relationship between the diagnosis and IQ remained significant. Childhood trauma and use of lithium and antipsychotic medication did not affect the relationship between brain volumes and IQ. However, current lithium use was related to lower IQ in patients. CONCLUSIONS: Our data suggest a similar relationship between brain volume and IQ in BD-I patients and controls. Smaller brain volumes only partially explain IQ deficits in patients. Therefore, our findings indicate that in addition to brain volumes and lithium use other disease factors play a role in IQ deficits in BD-I patients. PMID- 28728037 TI - Including the online feedback site, Patient Opinion, in the nursing curriculum: Exploratory study. AB - BACKGROUND: Globally, universities aim to involve people who use health services to enrich the nursing curriculum for students, but there can be barriers to this involvement. Many also want students to contribute to local communities. Online communication can help connect students to service users to achieve these aims. The online British patient feedback site, Patient Opinion, gathers comments from service users about services and encourages service responses to the comments. OBJECTIVES: To explore the feasibility and acceptability of five ways of including Patient Opinion in the undergraduate nursing curriculum. DESIGN: Five case studies using mixed data collection methods. SETTINGS: British University with nursing students across two campuses, accustomed to using webinars, video presentations and social media. PARTICIPANTS: Students from different years participated in the five approaches of making use of Patient Opinion in the curriculum; 18 students took part in an online forum to discuss Patient Opinion in the curriculum. METHODS: We trialled timetabled webinars, video-linked lectures, optional enhanced access for self-study, optional audit of service user comments for two local hospitals, and optional Twitter and Tweetchat. Students discussed the aims and approaches in an online forum. RESULTS: Of the five approaches trialled, webinars seemed effective in ensuring that all nursing students engaged with the topic. Video-linked lectures provided an alternative when timetabling did not allow webinars, but were less interactive. The three optional approaches (Tweetchats, audit exercise, self-directed study) provided opportunities for some students to enhance their learning but students needed guidance. Sending a summary of student reviews of patients' feedback to local hospitals illustrated how students might be agents of change in local health services. CONCLUSIONS: Experience from these case studies suggests that webinars followed by use of Patient Opinion preparing for placements may be a sustainable way of embedding feedback sites in the nursing curriculum. PMID- 28728038 TI - Predictors of smoking cessation group treatment engagement among veterans with serious mental illness. AB - High prevalence rates of tobacco use, particularly cigarettes, pose a serious health threat for individuals with serious mental illness (SMI), and research has demonstrated the effectiveness of pharmacotherapy and psychosocial interventions to reduce tobacco use in this group. However, few studies have considered predictors of tobacco cessation treatment engagement among individuals with SMI. The current study examined predictors of engagement in smoking cessation groups among veterans with SMI engaged in mental health services at three VA medical centers. All veterans were participating in a smoking cessation treatment study. Of 178 veterans who completed baseline assessments, 127 (83.6%) engaged in treatment, defined as attending at least three group sessions. Forty-one (N=41) predictors across five domains (demographics, psychiatric concerns, medical concerns, smoking history, and self-efficacy to quit smoking) were identified based on previous research and clinical expertise. Using backward elimination to determine a final multivariable logistic regression model, three predictors were found to be significantly related to treatment engagement: marital status (never married individuals more likely to engage); previous engagement in group smoking cessation services; and greater severity of positive symptoms on the Brief Psychiatric Rating Scale. When included in the multivariable logistic regression model, the full model discriminates between engagers and non-engagers reasonably well (c statistic=0.73). Major considerations based on these findings are: individuals with SMI appear to be interested in smoking cessation services; and serious psychiatric symptomatology should not discourage treatment providers from encouraging engagement in smoking cessation services. PMID- 28728039 TI - Cognitive restructuring of gambling-related thoughts: A systematic review. AB - Gamblers' thoughts have a fundamental influence on their gambling problem. Cognitive restructuring is the intervention of choice to correct those thoughts. However, certain difficulties are noted in the application of cognitive restructuring techniques and the comprehension of their guidelines. Furthermore, the increase of skill game players (e.g. poker) entering treatment creates a challenge for therapists, as these gamblers present with different thoughts than those of the gamblers usually encountered in treatment (e.g. chance-only games like electronic gambling machines). This systematic review aims to describe how cognitive restructuring is carried out with gamblers based on the evidence available in empirical studies that include cognitive interventions for gambling. Of the 2607 studies collected, 39 were retained. The results highlight exposure as the most frequently used technique to facilitate identification of gambling related thoughts (imaginal=28.2%; in vivo=10.3%). More than half of the studies (69.2%) clearly reported therapeutic techniques aimed to correct gamblers' thoughts, of which 37% involved visual support to challenge those thoughts (e.g. ABC log). Of the 39 studies retained, 48.7% included skill game players (i.e., poker, blackjack, sports betting) in their sample. However, none of these studies mentioned whether cognitive restructuring had been adapted for these gamblers. Several terms referring to gamblers' thoughts were used interchangeably (e.g. erroneous, dysfunctional or inadequate thoughts), although each of these terms could refer to specific content. Clinical implications of the results are discussed with regard to the needs of therapists. This review also suggests recommendations for future research. PMID- 28728041 TI - Multi-structure docking analysis of BACE1 crystal structures and non-peptidic ligands. AB - In order to design novel non-peptidic inhibitors of BACE1, many research groups have attempted using computational studies including docking analyses. Since there are too many 3D structures for BACE1 in the protein database, the selection of suitable crystal structures is a key prerequisite for the successful application of molecular docking. We employed a multi-structure docking protocol. In which 615 ligands' structures were docked into 150 BACE1 structures. The large number of the resultant docking scores were post-processed by different data analysis methods including exploratory data analysis, regression analysis and discriminant analysis. It was found that using one crystal structure for docking did not result in high accuracy for predicting activity of the BACE1 inhibitors. Instead, using of the multi-structural docking scores, post-processed by chemometrics methods arrived to highly accurate predictive models. In this regards, the PDB accession codes of 4B70, 4DVF and 2WEZ could discriminate between active and inactive compounds, with higher accuracy. Clustering of the BACE1 structures based on principal component analysis of the crystallographic structures the revealed that the discriminant structures are in the center of the clusters. Thus, these structures can be selected as predominant crystal structures for docking studies of non-peptidic BACE1 inhibitors. PMID- 28728040 TI - Measures and predictors of varenicline adherence in the treatment of nicotine dependence. AB - INTRODUCTION: While adherence to medication in smoking cessation clinical trials is strongly associated with clinical outcome, very few studies have evaluated the validity of pill count as a measure of adherence relative to a biological assay, and evaluated a broad range of correlates of adherence. METHODS: In a smoking cessation clinical trial of varenicline, we compared pill counts collected over 4 different time periods to varenicline salivary levels taken after 2weeks of treatment, as well as evaluated predictors of adherence to varenicline. RESULTS: Using a binary measure of adherence based on salivary varenicline levels, adherence was higher among older, white, and more educated participants. Relative to 3, 7, and 14-day pill count, 12-week pill count was the only significant measure able to discriminate adherence as defined by salivary varenicline levels (assessed by area under the receiver operating characteristic curve; AUC=0.59, p=0.004). Seventy-two percent of participants who indicated adherence on 12-week pill count were classified as adherent based on varenicline saliva levels (sensitivity=0.80; specificity=0.40). There was modest variability in the relationship between 12-week pill count and varenicline levels across race and rate of nicotine metabolism. Lastly, General Estimating Equation models demonstrated that longitudinal changes in withdrawal, craving, negative and positive affect, and side effect count and severity were not related to adherence based on salivary varenicline levels. CONCLUSIONS: These results indicate that 12 week pill count was the best, albeit a relatively weak, measure of varenicline adherence; additional factors associated with treatment adherence need to be identified. PMID- 28728042 TI - Pharmacological relationships and ligand discovery of G protein-coupled receptors revealed by simultaneous ligand and receptor clustering. AB - Conventional ligand and receptor similarity methods have been extensively used for exposing pharmacological relationships and drug lead discovery. They may in some cases neglect minor relationships useful for target hopping particularly against the remote family members. To complement the conventional methods for capturing these minor relationships, we developed a new method that uses a SLARC (Simultaneous Ligand And Receptor Clustering) 2D map to simultaneously characterize the ligand structural and receptor binding-site sequence relationships of a receptor family. The SLARC maps of the rhodopsin-like GPCR family comprehensively revealed scaffold hopping, target hopping, and multi target relationships for the ligands of both homologous and remote family members. Their usefulness in new ligand discovery was validated by guiding the prospective discovery of novel indole piperazinylpyrimidine dual-targeting adenosine A2A receptor antagonist and dopamine D2 agonist compounds. The SLARC approach is useful for revealing pharmacological relationships and discovering new ligands at target family levels. PMID- 28728043 TI - Autofocus on moving object in scanning electron microscope. AB - The sharpness of the images coming from a Scanning Electron Microscope (SEM) is a very important property for many computer vision applications at micro- and nanoscale. It represents how much object details are distinctive in the images: the object may be perceived sharp or blurred. Image sharpness highly depends on the value of focal distance, or working distance in the case of the SEM. Autofocus is the technique allowing to automatically adjust the working distance to maximize the sharpness. Most of the existing algorithms allows working only with a static object which is enough for the tasks of visualization, manual microanalysis or microcharacterization. These applications work with a low frame rate, less than 1 Hz, that guarantees a low level of noise. However, static autofocus can not be used for samples performing continuous 3D motion, which is the case of robotic applications where it is required to carry out a continuous 3D position measurement, e.g., nano-assembly or nanomanipulation. Moreover, in addition to constantly keeping object in focus while it is moving, it is required to perform the operation at high frame rate. The approach offering both these possibilities is presented in this paper and is referred as dynamic autofocus. The presented solution is based on stochastic optimization techniques. It allows tracking the maximum of the sharpness of the images without sweep and without training. It works under uncertainty conditions: presence of noise in images, unknown maximal sharpness and unknown 3D motion of the specimen. The experiments, that were performed with noisy images at high frame rate (5 Hz), were conducted on a Carl Zeiss Auriga 60 FE-SEM. They prove the robustness of the algorithm with respect to the variation of optimization parameters, object speed and magnification. Moreover, it is invariant to the object structure and its variation in time. PMID- 28728044 TI - Atomic force microscopy study of morphological modifications induced by different decontamination treatments on Escherichia coli. AB - In this paper we used atomic force microscopy (AFM) to investigate the surface morphology of Escherichia coli, after being subjected to decontamination treatments, at sub-MICs levels (minimal inhibitory concentrations), with different disinfectants used in hospitals, pharmaceutical, food industry and even in our home, as an essential means to prevent the spreading of microorganisms. This article focuses on different morphological modifications adopted by E. coli cells as responses to the different modes of action of these substances. For high resolution AFM images bacterial cells were immobilized on mica (Muscovite) disks. Each kind of treatment induces its distinct morphological changes, due to different mechanisms of action. PMID- 28728045 TI - Postdiagnosis neurological care for patients with psychogenic nonepileptic spells (PNES). AB - OBJECTIVE: This study investigated continuity of neurological care for patients discharged from the epilepsy monitoring unit (EMU) with a diagnosis of psychogenic nonepileptic spells (PNES). Because PNES are seizure-like episodes that cannot be explained by abnormal electrical brain activity, they are challenging for patients to understand and accept. Consequently, after diagnosis, patients commonly fail to start recommended psychotherapy and instead pursue redundant medical care. As consistent relationships with healthcare providers may help, we instituted standard follow-up for patients diagnosed with PNES. METHODS: We performed a retrospective observational cohort study of adults diagnosed with PNES in our EMU. In November 2013, we began routine scheduling of postdischarge follow-up neurology appointments. We compared preintervention (November 2010 October 2013) and postintervention (November 2013-May 2016) cohorts with regard to clinic attendance, understanding the diagnosis, compliance with recommendations, and event frequency. RESULTS: We identified 55 patients in the preintervention cohort and 123 patients in the postintervention cohort. We successfully implemented the intended practice changes; more patients had follow up scheduled by discharge (preintervention 2% vs. postintervention 36%, p<0.001), time to follow-up decreased (46days vs. 29, p=0.001), and providers more consistently queried understanding of diagnosis (38% vs. 67%, p=0.03). Explicit planning for continued care did not produce the anticipated patient-provider relationships, as follow-up in clinic was low (38% vs. 37%). For patients who attended clinic, the intervention did not improve establishment of psychiatric care, compliance with medication recommendations, understanding of diagnosis, or event frequency. The odds of reduced event frequency were nonsignificantly increased with understanding the diagnosis (OR 3.75, p=0.14). Recommending antiepileptic drug (AED) discontinuation was associated with increased odds of event freedom (OR 6.91, p<0.01). SIGNIFICANCE: Scheduling follow-up for patients diagnosed with PNES did not facilitate ongoing patient-provider relationships due to poor clinic attendance. As follow-up is unreliable, the inpatient visit is a critical window of opportunity for intervention. PMID- 28728046 TI - Advanced morphological neuroimaging study in lateral temporal lobe epilepsy: A multicentric study. AB - Lateral temporal lobe epilepsy (lTLE) is a rare condition characterized by auditory auras or receptive aphasia, negative MRI, and relatively benign evolution. With the low number of cases in the world, our objective was to analyze a cohort of sporadic cases with lTLE (slTLE), in order to investigate possible cerebral morphological alterations. Forty patients with lTLE (34.93+/ 12.08years of age) and 38 healthy controls (CTRL, 34.55+/-9.08years of age) were enrolled from four tertiary Italian epilepsy centers, which provided brain MRI T1 weighted images following a standard protocol for patients with epilepsy. We performed group comparison by following different approaches: voxel-based morphometry (VBM, SPM8), cortical thickness (CT), and local gyrification index (lGI) (FreeSurfer 5.3). At a more conservative threshold (p<0.05, FWE correction), no significant differences between groups survived, neither in VBM nor CT/lGI. Multicenter studies have more power than smaller studies in conducting sophisticated evaluations of rare diseases, and further investigations are required to develop a full picture of this rare phenotype. PMID- 28728048 TI - Accumulation and detoxification dynamics of Chromium and antioxidant responses in juvenile rare minnow, Gobiocypris rarus. AB - Hexavalent chromium (Cr6+) compounds are hazardous via all exposure routes. To explore the dynamics of Cr accumulation and elimination and to reveal the mechanisms underlying detoxification and antioxidation in juvenile Gobiocypris rarus, one-month old G. rarus larvae were exposed to 0.1mgL-1 Cr6+ for four weeks for accumulation and subsequently placed to clean water for another week for depuration. The contents of Cr were measured weekly in the whole body of G. rarus juveniles. The activities of catalase (CAT), glutathione peroxidase (GPx), superoxide dismutase (SOD), glutathione S-transferase (GST) and glutathione reductase (GR), and contents of glutathione (GSH) and malonaldehyde (MDA), and transcripts of cat, Cu/Zn-sod, Mn-sod, gpx1, gstpi, gr, mt1, nrf2 and uba52 were determined. The results indicated that G. rarus juveniles had a strong ability to resist the Cr accumulation by Cr6+ exposure and to remove Cr from the body in clean water. In addition, GST and MT proteins may be involved in the detoxification of Cr6+. Moreover, Cr6+-induced GST detoxification in G. rarus juveniles might be accomplished through the Nrf2-mediated regulation of gene expressions. The antioxidant enzyme systems exhibited a response mechanism of the protective enzymes in organisms when they are subjected to external environmental stress. Two weeks of Cr6+ treatments could have led to the damage and consecutive degradation of antioxidant enzymes via ubiquitination, and MT proteins could be involved in protecting the activity of these enzymes. The capability of antioxidant enzyme systems to recover from the Cr6+-induced damage was strong in G. rarus juveniles after Cr6+ was removed from the water. PMID- 28728049 TI - Application of forensic image analysis in accident investigations. AB - Forensic investigations are primarily meant to obtain objective answers that can be used for criminal prosecution. Accident analyses are usually performed to learn from incidents and to prevent similar events from occurring in the future. Although the primary goal may be different, the steps in which information is gathered, interpreted and weighed are similar in both types of investigations, implying that forensic techniques can be of use in accident investigations as well. The use in accident investigations usually means that more information can be obtained from the available information than when used in criminal investigations, since the latter require a higher evidence level. In this paper, we demonstrate the applicability of forensic techniques for accident investigations by presenting a number of cases from one specific field of expertise: image analysis. With the rapid spread of digital devices and new media, a wealth of image material and other digital information has become available for accident investigators. We show that much information can be distilled from footage by using forensic image analysis techniques. These applications show that image analysis provides information that is crucial for obtaining the sequence of events and the two- and three-dimensional geometry of an accident. Since accident investigation focuses primarily on learning from accidents and prevention of future accidents, and less on the blame that is crucial for criminal investigations, the field of application of these forensic tools may be broader than would be the case in purely legal sense. This is an important notion for future accident investigations. PMID- 28728047 TI - Early life co-exposures to a real-world PAH mixture and hypoxia result in later life and next generation consequences in medaka (Oryzias latipes). AB - Acute effects of individual and complex mixtures of polycyclic aromatic hydrocarbons (PAHs) are well documented in vertebrate species. Hypoxia in fish reduces metabolic rate and reproduction. However, less is known about the later life consequences stemming from early-life exposure to PAHs or hypoxia, particularly their co-exposure. To address this, medaka (Oryzias latipes) embryos were exposed to a complex PAH mixture sediment extract from the Elizabeth River, VA (ERSE) at concentrations of 0.1, 0.5, or 1.0% or to one of three different hypoxia scenarios: continuous, nocturnal, or late stage embryogenesis hypoxia. Co exposures with 0.1% ERSE and each of the hypoxia scenarios were conducted. Results included decreased survival with ERSE, hatching delays with hypoxia, and higher occurrences of deformities with each. The continuous hypoxia scenario caused the most significant changes in all endpoints. These early-life exposures altered later-life growth, impaired reproductive capacity, and reduced the quality of their offspring. ERSE alone resulted in a female-biased sex ratio while continuous or nocturnal hypoxia produced significantly greater numbers of males; and co-exposure produced an equal sex ratio. Exposure to a PAH mixture and hypoxia during early life stages has meaningful later-life and next generational consequences. PMID- 28728051 TI - Detailed mechanisms of 1H spin-lattice relaxation in ammonium dihydrogen phosphate confirmed by magic angle spinning. AB - Mechanisms of the 1H spin-lattice relaxation in NH4H2PO4 were studied in detail by use of the effect of magic angle spinning on the relaxation. The acid and the ammonium protons have different relaxation times at the spinning rates higher than 10 kHz due to suppression of spin diffusion between the two kinds of protons. The intrinsic relaxation times not affected by the spin diffusion and the spin-diffusion assisted relaxation times were evaluated separately, taking into consideration temperature dependence. Both mechanisms contribute to the 1H relaxation of the acid protons comparatively. The spin-diffusion assisted relaxation mechanism was suppressed to the level lower than the experimental errors at the spinning rate of 30 kHz. PMID- 28728050 TI - Topoisomerase expression and amplification in solid tumours: Analysis of 24,262 patients. AB - BACKGROUND: Topoisomerase I (TOPO1) and topoisomerase IIalpha (TOP2A) are specific targets of multiple chemotherapy drugs. Increased expression of TOPO1 protein and amplification of the TOP2A gene have been associated with treatment response in colorectal and breast cancers, respectively. TOPO1 and TOP2A may be potential therapeutic targets in other malignancies as well. SUMMARY OF METHODS: We analysed TOPO1 protein expression and TOP2A gene amplification in patients (n = 24,262 specimens) with diverse cancers. Since HER2 and TOP2A co-amplification have been investigated for predictive value regarding anthracycline benefit, we analysed specimens for HER2 amplification as well. RESULTS: Overexpressed TOPO1 protein was present in 51% of the tumours. Four percent of the tumours had TOP2A amplification, with gallbladder tumours and gastroesophageal/oesophageal tumours having rates over 10%. Overall, 4903 specimens were assessed for both TOP2A and HER2 amplification; 129 (2.6%) had co-amplification. High rates (>40%) of HER2 amplification were seen in patients with TOP2A amplification in breast, ovarian, gastroesophageal/oesophageal and pancreatic cancer. CONCLUSION: Our data indicate that increased TOPO1 expression and TOP2A amplification, as well as HER2 co alterations, are present in multiple malignancies. The implications of these observations regarding sensitivity to chemotherapy not traditionally administered to these tumour types merits investigation. PMID- 28728052 TI - The forgotten entity of cycloid psychosis. PMID- 28728053 TI - Cannabis and delusional zoopathy: A mole that ran amok. PMID- 28728054 TI - An artificial neural network system to identify alleles in reference electropherograms. AB - Electropherograms are produced in great numbers in forensic DNA laboratories as part of everyday criminal casework. Before the results of these electropherograms can be used they must be scrutinised by analysts to determine what the identified data tells them about the underlying DNA sequences and what is purely an artefact of the DNA profiling process. This process of interpreting the electropherograms can be time consuming and is prone to subjective differences between analysts. Recently it was demonstrated that artificial neural networks could be used to classify information within an electropherogram as allelic (i.e. representative of a DNA fragment present in the DNA extract) or as one of several different categories of artefactual fluorescence that arise as a result of generating an electropherogram. We extend that work here to demonstrate a series of algorithms and artificial neural networks that can be used to identify peaks on an electropherogram and classify them. We demonstrate the functioning of the system on several profiles and compare the results to a leading commercial DNA profile reading system. PMID- 28728055 TI - Investigation of length heteroplasmy in mitochondrial DNA control region by massively parallel sequencing. AB - Accurate sequencing of the control region of the mitochondrial genome is notoriously difficult due to the presence of polycytosine bases, termed C-tracts. The precise number of bases that constitute a C-tract and the bases beyond the poly cytosines may not be accurately defined when analyzing Sanger sequencing data separated by capillary electrophoresis. Massively parallel sequencing has the potential to resolve such poor definition and provides the opportunity to discover variants due to length heteroplasmy. In this study, the control region of mitochondrial genomes from 20 samples was sequenced using both standard Sanger methods with separation by capillary electrophoresis and also using massively parallel DNA sequencing technology. After comparison of the two sets of generated sequence, with the exception of the C-tracts where length heteroplasmy was observed, all sequences were concordant. Sequences of three segments 16184-16193, 303-315 and 568-573 with C-tracts in HVI, II and III can be clearly defined from the massively parallel sequencing data using the program SEQ Mapper. Multiple sequence variants were observed in the length of C-tracts longer than 7 bases. Our report illustrates the accurate designation of all the length variants leading to heteroplasmy in the control region of the mitochondrial genome that can be determined by SEQ Mapper based on data generated by massively parallel DNA sequencing. PMID- 28728056 TI - Sequence-based diversity of 23 autosomal STR loci in Koreans investigated using an in-house massively parallel sequencing panel. AB - As DNA databases continue to grow and international cooperation increases, forensic STR loci have expanded to increase the discriminatory power and inter database compatibility. Current capillary electrophoresis (CE) and/or massively parallel sequencing (MPS)-based commercial STR analysis systems reflect such changing trends of expanding STR loci. Due to the general gains of larger multiplexing and the detection of sequence variation, the application of MPS technology to STR analysis has further improved discrimination and is expected to aid in mixture interpretation by increasing the effective number of alleles. However, high-throughput analysis has rarely been reported for forensic DNA databasing. In this study, we present the sequencing results from 250 Korean samples at 23 commonly used STR loci (D1S1656, TPOX, D2S441, D2S1338, D3S1358, FGA, CSF1PO, D5S818, D6S1043, D7S820, D8S1179, D10S1248, TH01, vWA, D12S391, D13S317, Penta E, D16S539, D18S51, D19S433, D21S11, Penta D, and D22S1045) using an in-house assay designed for MPS. All amplicons in the multiplex exhibited a size range of 77 to 217 base pairs, and the barcoded library for the MPS run was easily prepared using a PCR-based library preparation method followed by sequencing on a MiSeq System (Illumina). We compared the STR genotyping results with those obtained using CE and scrutinized the sequence variations in both the targeted STR and flanking regions. MPS results of 23 autosomal STRs were 99.97% concordant with those of CE results. D12S391 and D21S11 exhibited, respectively, the highest number of alleles and genotypes by the MPS analysis. Single nucleotide polymorphisms and insertion and deletions (Indels) were observed in the flanking regions of D1S1656, D2S441, D5S818, D7S820, D13S317, D16S539, D21S11, and Penta D. Consequently, an MPS analysis of an expanded set of STRs, as demonstrated in the population statistics of a Korean population, will be of great practical use in forensic genetics. PMID- 28728057 TI - Integrating the microbiome as a resource in the forensics toolkit. AB - The introduction of DNA fingerprinting to forensic science rapidly expanded the available evidence that could be garnered from a crime scene and used in court cases. Next generation sequencing technologies increased available genetic data that could be used as evidence by orders of magnitude, and as such, significant additional genetic information is now available for use in forensic science. This includes DNA from the bacteria that live in and on humans, known as the human microbiome. Next generation sequencing of the human microbiome demonstrates that its bacterial DNA can be used to uniquely identify an individual, provide information about their life and behavioral patterns, determine the body site where a sample came from, and estimate postmortem intervals. Bacterial samples from the environment and objects can also be leveraged to address similar questions about the individual(s) who interacted with them. However, the applications of this new field in forensic sciences raises concerns on current methods used in sample processing, including sample collection, storage, and the statistical power of published studies. These areas of human microbiome research need to be fully addressed before microbiome data can become a regularly incorporated evidence type and routine procedure of the forensic toolkit. Here, we summarize information on the current status of microbiome research as applies to the forensic field, the mathematical models used to make predictions, and the possible legal and practical difficulties that can limit the application of microbiomes in forensic science. PMID- 28728058 TI - High prevalence of ESBLs in retail chicken meat despite reduced use of antimicrobials in chicken production, France. AB - Extended-spectrum cephalosporins (ESCs) are critically important antibiotics for humans and their use in animals poses a potential threat for public health. Chicken represents an increasing part of the human diet and has also been regarded as a source of ESC-resistant Enterobacteriaceae because of the worldwide off-label use of ceftiofur, a broad-spectrum cephalosporin. Thus, numerous studies pointed out chicken as a reservoir of ESBL/pAmpC genes, plasmids and/or clones at risk for humans. In France, late 2011, strong political pressure led to a drastic reduction of ceftiofur use and all other antibiotics in chicken production. Here, we ascertained the potential impact of those efforts on the prevalence of ESC-resistant E. coli in retail chicken. From October 2015 to January 2016, of 48 unrelated pieces of meat (chicken legs) belonging to four different brands, 44 (91.7%) were positive for ESC-resistant E. coli. The blaCTX M-1 gene was highly prevalent (68/74, 91.9%), mostly located on IncI1/ST3 plasmids (65/68, 95.6%). Other ESBL/pAmpC genes (blaTEM-52, blaSHV-12, blaCMY-2) were carried by IncX1, IncI1/ST36, IncI1/ST95, IncA/C or IncK plasmids. The positive isolates were non-clonal, suggesting a horizontal spread of the ESBL/pAmpC genes. Obviously, the strong decrease of antimicrobial use in chicken farms had no impact yet on the ESBL/pAmpC prevalence in retail chicken meat in France. A human source of these ESBL/pAmpC genes is unlikely as blaCTX-M-1 IncI1/ST3 plasmids are dominant in animals and rare in humans. Our data question the real impact of the decrease of antimicrobial use in chicken production on ESBL contamination of chicken meat and point out the risk of ESBL/AmpCs human transfer through the food chain. PMID- 28728059 TI - Iterative variational mode decomposition based automated detection of glaucoma using fundus images. AB - Glaucoma is one of the leading causes of permanent vision loss. It is an ocular disorder caused by increased fluid pressure within the eye. The clinical methods available for the diagnosis of glaucoma require skilled supervision. They are manual, time consuming, and out of reach of common people. Hence, there is a need for an automated glaucoma diagnosis system for mass screening. In this paper, we present a novel method for an automated diagnosis of glaucoma using digital fundus images. Variational mode decomposition (VMD) method is used in an iterative manner for image decomposition. Various features namely, Kapoor entropy, Renyi entropy, Yager entropy, and fractal dimensions are extracted from VMD components. ReliefF algorithm is used to select the discriminatory features and these features are then fed to the least squares support vector machine (LS SVM) for classification. Our proposed method achieved classification accuracies of 95.19% and 94.79% using three-fold and ten-fold cross-validation strategies, respectively. This system can aid the ophthalmologists in confirming their manual reading of classes (glaucoma or normal) using fundus images. PMID- 28728060 TI - Clinical neurophysiology of prolonged disorders of consciousness: From diagnostic stimulation to therapeutic neuromodulation. AB - The identification of signs of awareness in patients with prolonged disorders of consciousness (DoC) after severe brain injury is a challenging task for clinicians. Differentiating on behavioural examination the vegetative state (VS) from the minimally conscious state (MCS) can lead to a high misdiagnosis rate. Advanced neuroimaging and neurophysiological techniques can supplement clinical evaluation by providing physiological evidence of brain activity. However, an open issue remains whether these empirical results are directly or indirectly associated with covert consciousness and limitations emerge for their diagnostic application at the single-patient level. On the therapeutic side, the efficacy of both non-invasive and invasive brain stimulation/modulation trials is matter of debate. The present review provides an updated analysis of the diagnostic and prognostic impact that the different neurophysiological techniques of stimulation [including short-latency evoked potentials, long-latency event related potentials (ERPs), transcranial magnetic stimulation (TMS), TMS-EEG co-registration] offer in prolonged DoC. The results of the therapeutic stimulation techniques are also evaluated. It is concluded that TMS-EEG emerges as the most promising tool for differentiating VS from MCS whereas ERPs allow neurophysiologists to probe covert cognitive capacities of each patient. Significant behavioural improvements in prolonged DoC with brain stimulation techniques are still anecdotical and further treatment options are awaited. PMID- 28728061 TI - Qualifying information on deaths and serious injuries caused by road traffic in five Brazilian capitals using record linkage. AB - INTRODUCTION: Road traffic crashes (RTC) are an important public health problem, accounting for 1.2 million deaths per year worldwide. In Brazil, approximately 40,000 deaths caused by RTC occur every year, with different trends in the Federal Units. However, these figures may be even greater if health databases are linked to police records. In addition, the linkage procedure would make it possible to qualify information from the health and police databases, improving the quality of the data regarding underlying cause of death, cause of injury in hospital records, and injury severity. OBJECTIVE: This study linked different data sources to measure the numbers of deaths and serious injuries and to estimate the percentage of corrections regarding the underlying cause of death, cause of injury, and the severity injury in victims in matched pairs from record linkage in five representative state capitals of the five macro-regions of Brazil. METHODS: This cross-sectional, population-based study used data from the Hospital Information System (HIS), Mortality Information System (MIS), and Police Road Traffic database of Belo Horizonte, Campo Grande, Curitiba, Palmas, and Teresina, for the year 2013 for Teresina, and 2012 for the other capitals. RecLink III was used to perform probabilistic record linkage by identifying matched pairs to calculate the global correction percentage of the underlying cause of death, the circumstance that caused the road traffic injury, and the injury severity of the victims in the police database. RESULTS: There was a change in the cause of injury in the HIS, with an overall percentage of correction estimated at 24.4% for Belo Horizonte, 96.9% for Campo Grande, 100.0% for Palmas, and 33.2% for Teresina. The overall percentages of correction of the underlying cause of death in the MIS were 29.9%, 11.9%, 4.2%, and 33.5% for Belo Horizonte, Campo Grande, Curitiba, and Teresina, respectively. The correction of the classification of injury severity in police database were 100.0% for Belo Horizonte and Teresina, 48.0% for Campo Grande, and 51.4% for Palmas after linkage with hospital database. The linkage between mortality and police database found a percentage of correction of 29.5%, 52.3%, 4.4%, 74.3 and 72.9% for Belo Horizonte, Campo Grande, Palmas, Curitiba and Teresina, respectively in the police records. CONCLUSIONS: The results showed the importance of linking records of the health and police databases for estimating the quality of data on road traffic injuries and the victims in the five capital cities studied. The true causes of death and degrees of severity of the injuries caused by RTC are underestimated in the absence of integration of health and police databases. Thus, it is necessary to define national rules and standards of integration between health and traffic databases in national and state levels in Brazil. PMID- 28728062 TI - Investigation of factors affecting the injury severity of single-vehicle rollover crashes: A random-effects generalized ordered probit model. AB - Rollover crashes are responsible for a notable number of serious injuries and fatalities; hence, they are of great concern to transportation officials and safety researchers. However, only few published studies have analyzed the factors associated with severity outcomes of rollover crashes. This research has two objectives. The first objective is to investigate the effects of various factors, of which some have been rarely reported in the existing studies, on the injury severities of single-vehicle (SV) rollover crashes based on six-year crash data collected on the Malaysian federal roads. A random-effects generalized ordered probit (REGOP) model is employed in this study to analyze injury severity patterns caused by rollover crashes. The second objective is to examine the performance of the proposed approach, REGOP, for modeling rollover injury severity outcomes. To this end, a mixed logit (MXL) model is also fitted in this study because of its popularity in injury severity modeling. Regarding the effects of the explanatory variables on the injury severity of rollover crashes, the results reveal that factors including dark without supplemental lighting, rainy weather condition, light truck vehicles (e.g., sport utility vehicles, vans), heavy vehicles (e.g., bus, truck), improper overtaking, vehicle age, traffic volume and composition, number of travel lanes, speed limit, undulating terrain, presence of central median, and unsafe roadside conditions are positively associated with more severe SV rollover crashes. On the other hand, unpaved shoulder width, area type, driver occupation, and number of access points are found as the significant variables decreasing the probability of being killed or severely injured (i.e., KSI) in rollover crashes. Land use and side friction are significant and positively associated only with slight injury category. These findings provide valuable insights into the causes and factors affecting the injury severity patterns of rollover crashes, and thus can help develop effective countermeasures to reduce the severity of rollover crashes. The model comparison results show that the REGOP model is found to outperform the MXL model in terms of goodness-of-fit measures, and also is significantly superior to other extensions of ordered probit models, including generalized ordered probit and random-effects ordered probit (REOP) models. As a result, this research introduces REGOP as a promising tool for future research focusing on crash injury severity. PMID- 28728063 TI - Factors associated with non-return to work in the severely injured victims 3 years after a road accident: A prospective study. AB - Road accidents may impact victims' physical and/or mental health and socio occupational life, particularly the capacity to return to work. The purpose of our study is to assess modifiable medical and socio-occupational factors of non return to work in the severely injured 3 years after a road accident. Among1,168 road accidents casualties in the Rhone administrative Departement of France followed for five years, 141 of the 222 severely injured (Maximal Abbreviated Injury Scale >= 3) aged more than 16 years who were in work at the time of the accident, reported whether they had returned to work in the 3 years following the accident. The subgroups of those who had (n=113) and had not returned to work (n=28) were compared for socio-occupational (gender, age, educational level, marital status, socio-occupational group) accident-related medical factors (type of road user, type of journey, responsibility in the accident, initial care) and post-accident medical factors (pain intensity, post-traumatic stress disorder, physical sequelae, quality of life) by using standardized tools. Severity of initial head, face and lower-limb injury, intense persistent pain, post-traumatic stress disorder, poor self-assessed quality of life and health status at 3 years were associated with non-return to work on univariate analysis. On multivariate analysis, severity of initial head and lower-limb injury, intense persistent pain at 3 years and post-traumatic stress disorder were significantly associated with non-return to work 3 years following severe road-accident injury. Post-traumatic stress disorder and chronic pain were essential modifiable medical determinants of non-return to work in the severely injured after a road accident: early adapted management could promote return to work in the severely injured. Improve early adapted treatment of pain and PTSD in the rehabilitation team should help the severely injured return to work following a road accident. PMID- 28728064 TI - LDL subfractions are associated with incident cardiovascular disease in the Malmo Prevention Project Study. AB - BACKGROUND AND AIMS: After assessing the risk for cardiovascular disease (CVD) based on traditional risk factors, decisions concerning lipid lowering therapy might remain uncertain. To investigate whether lipoprotein subfraction levels could aid these decisions, we assessed the association between lipoprotein subfractions and CVD, after adjustment for traditional risk factors including standard lipids. METHODS: Using a case-cohort design, participants were randomly drawn from the Malmo Prevention Project (MPP), a population-based prospective study of 18,240 participants, and supplemented with additional incident CVD events (5764 participants, 1784 CVD events). RESULTS: Low density lipoprotein particle number (LDL-P) and individual subfractions ranging in size from very small to large were associated with CVD (continuous p value (pcont) < 0.001) while adjusting for age, sex, hypertension, smoking, and diabetes. After further adjustment for LDL-C, HDL-C, and triglycerides, very small LDL subfraction (b) (LDL-VS (b)) remained associated with CVD (HR = 1.23, 95% CI, 1.06 to 1.43 for top vs. bottom quartile, pcont = 0.03). Among participants with low/intermediate risk [without diabetes and with LDL-C <3.36 mmol/L (<130 mg/dL)], the fully adjusted HR for LDL-small (top vs. bottom quartile) was 1.48 (95% CI 1.02 to 2.17, pcont = 0.03). Among those with very-high risk (>20% 10-year risk of CVD), LDL-VS(a) and LDL-VS(b) were associated with CVD in fully adjusted models (HR = 1.37, 95% CI 1.12 to 1.67 and HR = 1.28, 95% CI 1.07 to 1.53, respectively, pcont<=0.03). CONCLUSIONS: Smaller LDL particles are associated with incident CVD independently of traditional risk factors, including standard lipids, in participants with low/intermediate and very-high risk, who might benefit from improved risk assessment. PMID- 28728065 TI - C-reactive protein in atherosclerosis - A risk marker but not a causal factor? A 13-year population-based longitudinal study: The Tromso study. AB - BACKGROUND AND AIMS: CRP predicts cardiovascular disease (CVD) in large epidemiologic studies. The aim of the present study was to elucidate the role of CRP in atherosclerosis formation and progression in a prospective population based study. METHODS: 6503 middle-aged subjects from The Tromso study had serum CRP, carotid ultrasound and complete covariate data collected at baseline in 1994. Of these, 4730 and 2917 attended follow-up surveys with repeated assessments in 2001 and 2007, respectively. The cross-sectional associations between CRP and subclinical carotid atherosclerosis, and the longitudinal associations between baseline CRP and novel plaque formation and plaque progression were assessed in generalized estimating equations and linear mixed models stratified by sex. RESULTS: At baseline, traditional risk factors and plaque prevalence increased by CRP risk categories (<1 mg/L, 1-3 mg/L, and >3 mg/L) in both sexes. In cross-sectional analyses, multivariable-adjusted CRP was associated with plaque prevalence and total plaque area (TPA) in men and women. Age-adjusted baseline CRP >3 mg/L compared to CRP <1 mg/L predicted novel plaque formation (OR 1.44, CI 1.08-1.92) and TPA progression (beta = 0.0.029 (CI, 0.003 0.056)) in men, but not in women. In neither men nor women was baseline CRP a predictor of TPA-progression or novel plaque formation when adjusted for traditional risk factors. CONCLUSIONS: CRP was associated with plaque presence and TPA in cross-sectional analyses, but was not an independent predictor of novel plaque formation or plaque progression. Our findings suggest that CRP may link to CVD by other mechanisms than promoting formation and progression of atherosclerotic plaques. PMID- 28728066 TI - Baseline serum phosphatidylcholine plasmalogen concentrations are inversely associated with incident myocardial infarction in patients with mixed peripheral artery disease presentations. AB - BACKGROUND AND AIMS: Despite current best care, patients with peripheral artery disease (PAD) remain at high risk of myocardial infarction, and biomarkers to more accurately assess cardiovascular risk are needed. This study assessed the relationship between the serum lipidome and incident myocardial infarction in a cohort of PAD patients. METHODS: 265 PAD patients were followed up for a median of 23 months, during which 18 people suffered a myocardial infarction. Fasting serum concentrations of 332 lipid species were measured via mass spectrometry and their association with incident myocardial infarction was assessed via Cox regression. Secondary analyses investigated prognostic potential of specific lipid species. RESULTS: Total serum concentrations of alkyl-phosphatidylcholine and alkenylphospatidylcholine (plasmalogen) lipids were inversely associated with incident myocardial infarction after adjusting for multiple testing (hazards ratio (95% confidence intervals): 0.43 (0.24-0.74); p = 0.032; and 0.28 (0.14 0.56), p = 0.010, respectively). Specifically, 10 alkenylphosphatidylcholine species and 6 alkyl-phosphatidylcholine species were negatively associated with incident myocardial infarction after adjusting for traditional risk factors and correcting for multiple testing (hazards ratios ranging from 0.07 to 0.51, p < 0.05). Incorporation of serum phosphatidylcholine plasmalogen species PC(P-40:6) concentration within analyses designed to determine subsequent myocardial infarction incidence led to an improvement in predictive accuracy compared to traditional risk factors alone. CONCLUSIONS: Serum concentrations of phosphatidylcholine plasmalogens and alkyl-phosphatidylcholines were negatively associated with incident myocardial infarction and have potential to act as novel prognostic markers in at-risk populations. PMID- 28728067 TI - An optimized HPLC-UV method for quantitatively determining sesquiterpenes in Nardostachyos Radix et Rhizoma. AB - Nardostachyos Radix et Rhizoma (NR), the root and rhizome from either Nardostachys jatamansi Batal or Nardostachys jatamansi DC, is known to have biological functions including neuro-protective and anti-pancreatitis activity. The main bioactive compounds within NR are all classified as sesquiterpenes, and include desoxo-narchinol A, nardosinonediol, and nardosinone. Although NR is a valuable herb that is widely used in many Asian countries, robust quality control protocols for NR are still in question, especially those that can analyze the three main active compounds. Current quantitative methods within the Chinese Pharmacopoeic use nardosinone as a marker compounds. One compound cannot represent a complicated matrix, and is thus insufficient to control the quality of this herbal medicine. Moreover, there are no high-performance liquid chromatography (HPLC) methods that can simultaneously analyze desoxo-narchinol A (DA), nardosinonediol (NE), and nardosinone (ND) within NR. This study aimed to establish an efficient quality control protocol by developing an analytical method that simultaneously detects the three sesquiterpenes with HPLC using response surface methodology (RSM) to optimize sample preparation. Optimized HPLC conditions included a mobile phase of 0.1% formic acid in water (A), and a 0.1% formic acid in acetonitrile (B) under an elution program of 20% B-80% B for 30min at 254nm. The method was well validated, demonstrating satisfactory linearity, accuracy, precision, recovery, repeatability, and stability. Optimized conditions for creating the analytical sample were predicted by RSM using a Box-Behnken design. These conditions included reflux at 70 degrees C for 3h using 24.98% ethanol as the extraction solvent (solvent: solid ratio=78.81mL/g). The relationship between the results between predicted and experimental conditions was well correlated, and varied between 96.48%-102.11%. Thus, our developed HPLC method, paired with optimized sample preparation conditions, accurately quantified all three sesquiterpenes, and may thus be a prospective means of controlling the quality of NR. PMID- 28728068 TI - Evaluation of several electrolyte mixture-cathode material combinations in electrodeposition of americium radioisotopes for alpha-spectrometric measurements. AB - Three different types of electrolytes, subsequently modified and adjusted, in combination with three cathode materials used as source backings were analysed for electrodeposition of americium isotopes for alpha-spectrometric measurements. The obtained results are discussed in terms of electrodeposition yield and source quality (source homogeneity and spectral resolution, FWHM). The optimal conditions for source preparation are provided. PMID- 28728069 TI - Development of separation techniques for analysis of Nb-94 in radwaste samples. AB - A chemical separation technique for removing interfering gamma-ray radionuclides by combined precipitation of Nb pentoxide and anion exchange was proposed, thereby allowing detection of trace 94Nb in low-level radwastes. The detection limit for 94Nb was improved by a factor of 10-103, and the scaling factor (94Nb/60Co) of the radwastes was estimated to be less than 10-5. This technique can be used for low-level radwaste classification and power reactor decommissioning. PMID- 28728070 TI - Feasibility study for wax deposition imaging in oil pipelines by PGNAA technique. AB - Wax deposition in pipelines is a crucial problem in the oil industry. A method based on the prompt gamma-ray neutron activation analysis technique was applied to reconstruct the image of wax deposition in oil pipelines. The 2.223MeV hydrogen capture gamma rays were used to reconstruct the wax deposition image. To validate the method, both MCNP simulation and experiments were performed for wax deposited with a maximum thickness of 20cm. The performance of the method was simulated using the MCNP code. The experiment was conducted with a 252Cf neutron source and a LaBr3: Ce detector. A good correspondence between the simulations and the experiments was observed. The results obtained indicate that the present approach is efficient for wax deposition imaging in oil pipelines. PMID- 28728071 TI - Effect of dienogest on pain and ovarian endometrioma occurrence after laparoscopic resection of uterosacral ligaments with deep infiltrating endometriosis. AB - OBJECTIVE: To evaluate the effect of dienogest (DNG) in preventing the occurrence of pain and endometriomas after laparoscopic resection of uterosacral ligaments (USLs) with deep infiltrating endometriosis (DIE). STUDY DESIGN: This retrospective analysis included 126 patients who underwent laparoscopic resection of USLs with DIE followed by postoperative administration of DNG or no medication. Every 6 months postoperatively, patients answered questions and underwent ultrasound examination to identify pain and/or endometrioma. RESULT: There were three (5.0%) cases of endometrioma in 59 patients from the DNG group and 21 (31.3%) cases in 67 patients from the no medication group (P=0.0002). Pain returned to preoperative levels in eight (11.9%) cases in the no medication group. No recurrence of pain occurred in the DNG group (P=0.0061). CONCLUSION: The administration of DNG after resection of USLs with DIE significantly reduces the occurrence rate of endometriosis-related pain and endometriomas. PMID- 28728072 TI - Postmortem diagnosis of sepsis: A preliminary immunohistochemical study with an anti-procalcitonin antibody. PMID- 28728073 TI - Sudden perinatal death due to rupture of congenital cardiac diverticulum. Pathological findings and medico-legal investigations in malpractice charge. AB - Congenital diverticula of the left ventricle, very rare malformations, are determined by an abnormal embryonic development of the ventricular wall and can be isolated or associated to other cardiac anomalies. In most of the cases, these pathologies are not symptomatic and in some patients can be associated to ventricular arrhythmia, cardiac rupture with tamponade and sudden death. Authors are presenting the case of a sudden death in an 8-weeks-old newborn due to rupture of a cardiac congenital diverticulum of the left ventricle, discovered only at the moment of the autopsic examination. The parents of the victim pressed charges against the medical staff that was appointed to the cares, blaming them with malpractice. The missed diagnosis of a cardiac congenital diverticulum of the left ventricle, a rare pathology, reflects the trickiness of the medical management that can lead to medico-legal controversies and, even though such rare conditions must be always taken into consideration when investigating possible dysfunction causing the death, diagnostic difficulties, in the case in exam, justify the missed diagnosis intra-vitam of cardiac ventricular diverticulum. PMID- 28728074 TI - No pain no gain? Adjuvant effects of alum and monophosphoryl lipid A in pertussis and HPV vaccines. AB - Development of non-infectious subunit vaccines is hampered by a slow pipeline of new adjuvants to replace or enhance alum in part because expectations of safety are high. Transient vaccine side effects are not clinical priorities because they cause no lasting harm and vaccine development has appropriately been focused on avoidance of serious adverse events. As a result, surprisingly little is known about the extent to which side effects caused by a vaccine's reactogencicity are predictive of successful immunization outcomes. Recent clinical studies of pertussis and human papillomavirus vaccines adjuvanted with alum or the TLR4 agonist monophosphoryl lipid A can be used to advance understanding of the relationship between vaccine side effects and immunization outcomes. PMID- 28728076 TI - Age explains limited hip extension recovery at one year from total hip arthroplasty. AB - BACKGROUND: To investigate the dependency of the one-year recovery in gait after total hip arthroplasty on age and preoperative conditions. METHODS: Longitudinal retrospective study on 20 elderly patients with unilateral total hip arthroplasty consequent to hip osteoarthritis, assessed by gait analysis before surgery (T0), 2weeks (T1), 6 (T2) and 12months (T3) post-surgery. A set of variables assessing primary gait deviations and compensatory mechanisms were extracted from gait analysis data. Their variations throughout the one-year period were analyzed through a repeated measures ANOVA. Their dependency on preoperative conditions (age, hip passive limitations and Thomas Test) at one year after surgery were assessed through a correlation analysis and an ANCOVA. FINDINGS: Hip sagittal range significantly increased (P<0.05) after each measurement session from mean 21 (SD 10) degrees at T0, to 31 (6) at T1, to 34 (6) at T2 until 36 (4) degrees at T3. The peak of hip and ankle power generation significantly increased from T0 to T3, with a progressive reduction of compensatory mechanisms towards normal values. At T3, preoperative hip passive extension and Thomas Test score did not affect hip sagittal range during gait, while age did (P<0.05, R2=0.36). Ankle and hip peak powers were also correlated with age (P=0.033 and P=0.008, respectively). In our sample, age was the main cause of hip sagittal joint range limitation. INTERPRETATION: At one year from total hip arthroplasty, age affects hip joint limitations and gait recovery more than preoperative passive restrictions due to muscle shortening. PMID- 28728077 TI - Comparison of spinal stability following motor control and general exercises in nonspecific chronic low back pain patients. AB - BACKGROUND: Motor control exercise was claimed to improve spinal stability in patients with chronic non-specific back pain, but to investigate the effectiveness of this exercise, other outcome measures have been used rather than spinal stability itself. The aim of our study is to assess motor control exercise effects on spinal stability using a biomechanical model. METHODS: Fifty-one patients were assigned to either motor control or general exercises. Before and after trainings, participants were tested for spinal stability at seven isometric tasks. Electromyography signals were recorded from ten superficial muscles, and a hybrid EMG-driven musculoskeletal model estimated spinal stability indices at each task. FINDINGS: Pain and disability significantly decreased in both groups. After trainings, patients had both increase and decrease in stability depending on the task, and stability did not increase/decrease uniformly in all patients. In the motor control group, stability increased at all positions but reached to significance only at right lateral pulling. In the general exercise group, except for pulling the trunk backward, stability decreased at other positions and reached to statistical significance only at pulling the trunk forward. No significant difference between groups was found in changing stability after the intervention. INTERPRETATION: Interventions yielded no significant difference in disability, pain and stability index between two groups. Significant increase of stability in the motor control group at right lateral pulling may be attributed to more activity of abdominal muscles, and significant decrease of stability in the general exercise group at forward pulling may be attributed to more optimal activity of back muscles. PMID- 28728075 TI - Immunological tolerance as a barrier to protective HIV humoral immunity. AB - HIV-1 infection typically eludes antibody control by our immune system and is not yet prevented by a vaccine. While many viral features contribute to this immune evasion, broadly neutralizing antibodies (bnAbs) against HIV-1 are often autoreactive and it has been suggested that immunological tolerance may restrict a neutralizing antibody response. Indeed, recent Ig knockin mouse studies have shown that bnAb-expressing B cells are largely censored by central tolerance in the bone marrow. However, the contribution of peripheral tolerance in limiting the HIV antibody response by anergic and potentially protective B cells is poorly understood. Studies using mouse models to elucidate how anergic B cells are regulated and can be recruited into HIV-specific neutralizing antibody responses may provide insight into the development of a protective HIV-1 vaccine. PMID- 28728078 TI - Femoral head necrosis: A finite element analysis of common and novel surgical techniques. AB - BACKGROUND: Femoral head necrosis is a common cause of secondary osteoarthritis. At the early stages, treatment strategies are normally based on core decompression techniques, where the number, location and diameter of the drilling holes varies depending on the selected approach. The purpose of this study was to investigate the risk of femoral head, neck and subtrochanteric fracture following six different core decompression techniques. MATERIALS: Five common and a newly proposed techniques were analyzed in respect to their biomechanical consequences using finite element analysis. The geometry of a femur was reconstructed from computed-tomography images. Thereafter, the drilling configurations were simulated. The strains in the intact and drilled femurs were determined under physiological, patient-specific, muscle and joint contact forces. FINDINGS: The following results were observed: i) - an increase in collapse and fracture risk of the femur head by disease progression ii) - for a single hole approach at the subtrochanteric region, the fracture risk increases with the diameter iii) - the highest fracture risks occur for an 8mm single hole drilling at the subtrochanteric region and approaches with multiple drilling at various entry points iv) - the proposed novel approach resulted in the most physiological strains (closer to the experienced by the healthy bone). INTERPRETATION: Our results suggest that all common core decompression methods have a significant impact on the biomechanical competence of the proximal femur and impact its mechanical potential. Fracture risk increases with drilling diameter and multiple drilling with smaller diameter. We recommend the anterior approach due to its reduced soft tissue trauma and its biomechanical performance. PMID- 28728080 TI - Neural correlates underlying the comprehension of deceitful and ironic communicative intentions. AB - Neuroimaging studies have shown that a left fronto-temporo-parietal cerebral network is recruited in the comprehension of both deceitful and ironic speech acts. However, no studies to date have directly compared neural activation during the comprehension of these pragmatic phenomena. We used fMRI to investigate the existence of common and specific neural circuits underlying the comprehension of the same speech act, uttered with different communicative intentions, i.e., of being sincere, deceitful or ironic. In particular, the novelty of the present study is that it explores the existence of a specific cerebral area involved in the recognition of irony versus deceit. We presented 23 healthy participants with 48 context stories each followed by a target sentence. For each story we designed different versions eliciting, respectively, different pragmatic interpretations of the same target sentence - literal, deceitful or ironic-. We kept the semantic and syntactic complexity of the target sentence constant across the conditions. Our results showed that the recognition of ironic communicative intention activated the left temporo-parietal junction (lTPJ), the left inferior frontal gyrus (lIFG), the left middle frontal gyrus (lMFG), the left middle temporal gyrus (lMTG), and the left dorsolateral prefrontal cortex (lDLPFC). Comprehension of deceitful communicative intention activated the lIFG, the lMFG, and the lDLPFC. fMRI analysis revealed that a left fronto-temporal network-including the inferior frontal gyrus (IFG), the dorsolateral prefrontal cortex (DLPFC) and the middle frontal gyrus (MFG)-is activated in both irony and deceit recognition. The original result of the present investigation is that the lMTG was found to be more active in the comprehension of ironic versus deceitful communicative intention, thus suggesting its specific role in irony recognition. To conclude, our results showed that common cerebral areas are recruited in the comprehension of both pragmatic phenomena, while the lMTG has a key role in the recognition of ironic versus deceitful communicative intention. PMID- 28728079 TI - Probucol ameliorates renal injury in diabetic nephropathy by inhibiting the expression of the redox enzyme p66Shc. AB - AIMS: Probucol is an anti-hyperlipidemic agent and a potent antioxidant drug that can delay progression of diabetic nephropathy (DN) and reverses renal oxidative stress in diabetic animal models; however, the mechanisms underlying these effects remain unclear. p66Shc is a newly recognized mediator of mitochondrial ROS production in renal cells under high-glucose (HG) ambience. We previously showed that p66Shc can serve as a biomarker for renal oxidative injury in DN patients and that p66Shc up-regulation is correlated with renal damage in vivo and in vitro. Here, we determined whether probucol ameliorates renal injury in DN by inhibiting p66Shc expression. RESULTS: We found that the expression of SIRT1, Ac-H3 and p66Shc in kidneys of DN patients was altered. Also, probucol reduced the levels of serum creatinine, urine protein and LDL-c and attenuated renal oxidative injury and fibrosis in STZ induced diabetic mice. In addition, probucol reversed p-AMPK, SIRT1, Ac-H3 and p66Shc expression. Correlation analyses showed that p66Shc expression was correlated with p-AMPK and Sirt1 expression and severity of renal injury. In vitro pretreatment of HK-2 cells with p-AMPK and SIRT1 siRNA negated the beneficial effects of probucol. Furthermore, we noted that probucol activates p-AMPK and Sirt1 and inhibits p66shc mRNA transcription by facilitating the binding of Sirt1 to the p66Shc promoter and modulation of Ac H3 expression in HK-2 cells under HG ambience. INNOVATION AND CONCLUSION: Our results suggest for the first time that probucol ameliorates renal damage in DN by epigenetically suppressing p66Shc expression via the AMPK-SIRT1-AcH3 pathway. PMID- 28728081 TI - Brain state-dependent recruitment of high-frequency oscillations in the human hippocampus. AB - Ripples are high-frequency bouts of coordinated hippocampal activity believed to be crucial for information transfer and memory formation. We used intracortical macroelectrodes to record neural activity in the human hippocampus of awake subjects undergoing surgical treatment for refractory epilepsy and distinguished two populations of ripple episodes based on their frequency spectrum. The phase coupling of one population, slow ripples (90-110 Hz), to cortical delta oscillations was differentially modulated by cognitive task; whereas the second population, fast ripples (130-170 Hz), was not seemingly correlated to local neural activity. Furthermore, as cognitive tasks changed, the ongoing coordination of neural activity associated to slow ripples progressively augmented along the parahippocampal axis. Thus, during resting states, slow ripples were coordinated in restricted hippocampal territories; whereas during active states, such as attentionally-demanding tasks, high frequency activity emerged across the hippocampus and parahippocampal cortex, that was synchronized with slow ripples, consistent with ripples supporting information transfer and coupling anatomically distant regions. Hence, our results provide further evidence of neural diversity in hippocampal high-frequency oscillations and their association to cognitive processing in humans. PMID- 28728082 TI - Oral infections, comorbidities and sensory evidences in elderly: Cross-sectional study. AB - BACKGROUND: Oral infections affect the general health and overlap with chronic diseases due to infectious-immune mechanisms. On the other side, sensory abnormalities may be symptoms of this association. OBJECTIVE: To evaluate the prevalence of oral infections, comorbidities, health parameters and sensory abnormalities in elderly patients. METHODS: Thirty (30) elderly with mean age 70.4 yo, distributed according to ages were evaluated with a protocol that included demographics, comorbidities, medications, laboratory tests, blood pressure, heart rate, mini-mental state examination, clinical oral evaluation and systematized sensory testing (gustative, olfactory, thermal, mechanical and pain thresholds). Data were tabled and statistically analyzed. RESULTS: Twenty-three (76.6%) subjects had chronic diseases that increased according to the age. Seventeen (56.7%) elderly were having medication. Mean probing pocket depth was 1.90mm+/-0.39mm, mean clinical attachment level was 0.76mm+/-0.54mm and mean gingival bleeding index was 29.10%+/-29.05%. All periodontal indexes increased with age (p <0.05) and were associated with comorbidities and use of medication. Patients with chronic diseases had more numbness and pricking sensations (p=0.031; p=0.000). Main sensory findings were: abnormal gustative and vibratory thresholds, which were associated with hematological parameters (blood count, cholesterol levels and glycaemia). Periodontal parameters were associated with facial cold threshold (p=0.000). CONCLUSION: This study showed an association between systemic diseases, periodontal indexes and sensory thresholds. Sensory findings were associated with blood parameters and are potential tools for periodical health evaluation. Inflammatory or neural mechanisms need further investigation. PMID- 28728083 TI - Sleep disturbances and risk of falls in an old Chinese population-Rugao Longevity and Ageing Study. AB - BACKGROUND: To explore the relationship between sleep disturbances and falls in an elderly Chinese population. METHODS: Data from 1726 individuals aged 70-87 years from the Rugao Longevity and Ageing Study were used. The Pittsburgh Sleep Quality Index (PSQI) was used to assess sleep variables. Outcomes were falls >=1 time per year and falls >=2 times per year. RESULTS: A total of 22.7% of the participants experienced >=1 fall, and 9.8% experienced >=2 falls per year. Poor sleep quality was associated with >=1 fall (OR 1.08, 95% CI 1.05-1.12; OR 1.27, 95% CI 1.14-1.41) and >=2 falls (OR 1.08, 95% CI 1.03-1.14; OR 1.28, 95% CI 1.10 1.48), with an increase per PSQI score and SD PSQI score, respectively. In addition, sleep quality, sleep latency, sleep efficiency, and sleep disturbance subcomponents were associated with an increased risk of >=1 fall with ORs of 1.44 (95% CI, 1.21-1.72), 1.23 (95%CI,1.09-1.40), 1.12 (95%CI, 1.01-1.23) and 1.70 (95% CI,1.35-2.14), respectively, and were associated with an increased risk of >=2 falls with ORs 1.54 (95%CI, 1.22-1.96), 1.21(95%CI, 1.02-1.44), 1.17 (95% CI 1.02-1.33), and 1.78 (95%CI, 1.31-2.44), respectively. Further, participants slept <=5h per night had an increased risk of >=1 fall (OR 2.34; 95%CI, 1.59 3.46) and >=2 falls (OR 2.19; 95%CI, 1.30-3.69). CONCLUSIONS: Poor sleep quality and several subcomponent sleep symptoms were consistently associated with increased risk of falls >=1 time and >=2 times in Chinese elderly. The identification of sleep disturbances may help identify high-risk Chinese elders who may benefit from fall prevention education. PMID- 28728084 TI - Purification of monoclonal antibodies entirely in flow-through mode. AB - A depth filter is widely used in biopharmaceutical manufacturing process. In this study, we found that buffer exchange to reduce conductivity dramatically improved the removal of impurities in depth filtration. The host cell protein clearance was comparable to that of protein A affinity chromatography, which is generally used as a first capture step in monoclonal antibody purification. In addition, a combination of different depth filters showed enhanced purification. Additional flow-through purification is possible without any sample preparation, and a biopharmaceutical-quality purity level (<100ppm for host cell protein and <5% for high molecular weight species) can be attained. These results represent the possibility of an antibody manufacturing process using an entirely flow-through mode. PMID- 28728085 TI - Preparation of a 6-OH quaternized chitosan derivative through click reaction and its application to novel thermally induced/polyelectrolyte complex hydrogels. AB - In the present study, a chitosan derivative with long chain quaternary ammonium locating grafted at 6-OH (CTS-6-QAS) was designed and prepared via a novel click reaction. The structure and thermal stability of the products of each step were determined with Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD) and thermogravimetric analysis (TGA). Rheological tests indicate that CTS-6 QAS possesses excellent thermally induced hydrogel formation property in the presence of beta-glycerophosphate (beta-GP). Based on these results, a novel thermally induced/polyelectrolyte complex CTS-6-QAS/alginate (SA)/beta-GP dual network hydrogel was designed. This controllable preparation method can avoid the disadvantages of the preparation methods for single thermo-induced hydrogels and polyelectrolyte complex hydrogels, and promote the homogeneity of the hydrogel. Porous sponges were prepared by freeze-drying the CTS-6-QASSA/beta-GP hydrogels. The effects of hydrogel preparation conditions on the porous structure and swelling property of the sponges were quantitatively investigated. Tea tree oil (TTO), a natural antibacterial agent, was successfully embedded in the hydrogel due to the lipophilicity of the long chain quaternary ammonium grafted at 6-OH of chitosan. The sustained release of TTO from the hydrogel was studied. PMID- 28728086 TI - Nanostructured lipid systems modified with waste material of propolis for wound healing: Design, in vitro and in vivo evaluation. AB - Propolis, a natural compound that can accelerate the wound healing process, is mainly used as ethanolic extract. The extractive solution may also be obtained from the propolis by-product (BP), transforming this waste material into a pharmaceutical active ingredient. Even if propolis does not show toxicity, when used as an extract over harmed skin or mucosa, the present ethanol content may be harmful to the tissue recovering, besides hindering the drug release. This study describes the development of solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) as topical propolis delivery systems and the investigation of their in vitro and in vivo activities. The extracts were evaluated to guarantee their quality, and the lipid dispersions were characterized with respect to morphology (cryo-TEM), size and diffractometry (X-ray) properties. The occlusive capacity of formulations was also evaluated by an in vitro technique, which determines the occlusion factor. The drug entrapment efficiency (EE), as well as the in vitro drug release profile from the nanoparticulate systems was investigated as well. The size analysis performed through 90days was favorable to a topical administration and the polydispersity index, though not ideal in all cases due to the high content of resins and gums from the extracts, were relatively stable for the SLN. The propolis extract contributes to the occlusive potential of the formulations. The human immortalized keratinocytes presented good cell viability when tested with both extracts (propolis and BP) freely or entrapped in the systems. SLN modified with propolis material provided an acceleration of the in vivo wound healing process. PMID- 28728087 TI - Surface imprinted bacterial cellulose nanofibers for hemoglobin purification. AB - There is a significant need for the development of the novel adsorbents in the field of protein purification. In this study, thin hemoglobin imprinted film (MIP) was fabricated onto the bacterial cellulose nanofibers' (BCNFs) by surface imprinting method using metal ion coordination interactions with N-methacryloyl (L)-histidinemethylester (MAH) and copper ions. The hemoglobin surface imprinted bacterial cellulose nanofibers (MIP-BCNFs) was applied to selective recognition of hemoglobin and purification from hemolysate. The characterization of the MIP BCNFs was carried out by the Fourier Transformed Infrared Spectroscopy (FT-IR), Scanning Electron Microscopy (SEM), micro-Computerized Tomography (MUCT), atomic force microscopy (AFM) and surface area measurements. The adsorption experiments of hemoglobin onto the MIP-BCNFs and NIP-BCNFs from aqueous hemoglobin solutions were investigated in a batch system. The results showed that MIP-BCNFs are promising materials for purification of hemoglobin with high adsorption capacity, significant selectivity and reusability. PMID- 28728088 TI - Phthalate and non-phthalate plasticizers in indoor dust from childcare facilities, salons, and homes across the USA. AB - The quality of indoor environment has received considerable attention owing to the declining outdoor human activities and the associated public health issues. The prolonged exposure of children in childcare facilities or the occupational exposure of adults to indoor environmental triggers can be a culprit of the pathophysiology of several commonly observed idiopathic syndromes. In this study, concentrations of potentially toxic plasticizers (phthalates as well as non phthalates) were investigated in 28 dust samples collected from three different indoor environments across the USA. The mean concentrations of non-phthalate plasticizers [acetyl tri-n-butyl citrate (ATBC), di-(2-ethylhexyl) adipate (DEHA), and di-isobutyl adipate (DIBA)] were found at 0.51-880 MUg/g for the first time in indoor dust samples from childcare facilities, homes, and salons across the USA. The observed concentrations of these replacement non-phthalate plasticizer were as high as di-(2-ethylhexyl) phthalate, the most frequently detected phthalate plasticizer at highest concentration worldwide, in most of indoor dust samples. The estimated daily intakes of total phthalates (n = 7) by children and toddlers through indoor dust in childcare facilities were 1.6 times higher than the non-phthalate plasticizers (n = 3), whereas estimated daily intake of total non-phthalates for all age groups at homes were 1.9 times higher than the phthalate plasticizers. This study reveals, for the first time, a more elevated (~3 folds) occupational intake of phthalate and non-phthalate plasticizers through the indoor dust at salons (214 and 285 ng/kg-bw/day, respectively) than at homes in the USA. PMID- 28728089 TI - Volumetric and morphological characteristics of the hippocampus are associated with progression to schizophrenia in patients with first-episode psychosis. AB - BACKGROUND: Abnormalities in the hippocampus have been implicated in the pathophysiology of psychosis. However, it is still unclear whether certain abnormalities are a pre-existing vulnerability factor, a sign of disease progression or a consequence of environmental factors. We hypothesized that first episode psychosis patients who progress to schizophrenia after one year of follow up will display greater volumetric and morphological changes from the very beginning of the disorder. METHODS: We studied the hippocampus of 41 patients with a first-episode psychosis and 41 matched healthy controls. MRI was performed at the time of the inclusion in the study. After one year, the whole sample was reevaluated and divided in two groups depending on the diagnoses (schizophrenia vs. non-schizophrenia). RESULTS: Patients who progressed to schizophrenia showed a significantly smaller left hippocampus volume than control group and no schizophrenia group (F=3.54; df=2, 77; P=0.03). We also found significant differences in the morphology of the anterior hippocampus (CA1) of patients with first-episode psychosis who developed schizophrenia compared with patients who did not. CONCLUSIONS: These results are consistent with the assumption of hyperfunctioning dopaminergic cortico-subcortical circuits in schizophrenia, which might be related with an alteration of subcortical structures, such as the hippocampus, along the course of the disease. According with these results, hippocampus abnormalities may serve as a prognostic marker of clinical outcome in patients with a first-episode psychosis. PMID- 28728090 TI - Remote mood monitoring for adults with bipolar disorder: An explorative study of compliance and impact on mental health service use and costs. AB - BACKGROUND: Remote monitoring of mood disorders may be an effective and low resource option for patient follow-up, but relevant evidence remains very limited. This study explores real-life compliance and health services impacts of mood monitoring among patients with bipolar disorder in the UK. METHODS: Patients with a diagnosis of bipolar disorder who were registered users of the True Colours monitoring system for at least 12months at study assessment were included in this retrospective cohort study (n=79). Compliance was measured as the proportion of valid depression and mania scale messages received in comparison to their expected numbers over the first 12months of monitoring. Mental health service use data were extracted from case notes, costed using national unit costs, and compared 12months before (pre-TC period) and 12months after (TC period) patients' engagement with monitoring. Associations with relevant patient factors were investigated in a multiple regression model. RESULTS: Average compliance with monitoring was 82%. Significant increases in the annual use and costs of psychiatrist contacts and total mental health services were shown for patients newly referred to the clinic during the pre-TC period but not for long term patients of the clinic. Psychiatric medication costs increased significantly between the pre-TC and TC periods (L235, P=0.005) unrelated to patients' referral status. CONCLUSIONS: Remote mood monitoring has good compliance among consenting patients with bipolar disorder. We found no associations between observed changes in mental health service costs and the introduction of monitoring except for the increase in psychiatric medication costs. PMID- 28728091 TI - Age at the time of onset of psychosis: A marker of specific needs rather than a determinant of outcome? AB - BACKGROUND: While there is suggestion that early onset of psychosis is a determinant of outcome; knowledge regarding correlates of later onset age is more limited. This study explores the characteristics of patients developing psychosis after age 26, towards the end of the usual age range of early intervention programs, in order to identify potential specific needs of such patients. METHODS: Two hundred and fifty-six early psychosis patients aged 18-35 were followed-up prospectively over 36 months. Patients with onset after 26 ("later onset", LO) were compared to the rest of the sample. RESULTS: LO patients (32% of the sample) had shorter DUP, were less likely to be male, had better premorbid functioning and were more likely to have been exposed to trauma. They had greater insight at presentation and less negative symptoms overall. The trajectories for positive and depressive symptoms were similar in both groups. Evolution of functional level was similar in both groups, but while LO patients recovered faster, they were significantly less likely to return to premorbid functional level. CONCLUSIONS: Later psychosis onset correlates with better premorbid functioning and higher rate of trauma exposure; the latter should therefore be a treatment focus in such patients. LO patients were less likely to return to premorbid functional level, which suggests that current treatment strategies may not be efficient to help patients maintain employment. The possibility of distinct illness mechanisms according to onset age and the more central role for trauma in patients with onset after age 26 needs to be further explored. PMID- 28728092 TI - Checking the predictive accuracy of basic symptoms against ultra high-risk criteria and testing of a multivariable prediction model: Evidence from a prospective three-year observational study of persons at clinical high-risk for psychosis. AB - BACKGROUND: The aim of this study was to critically examine the prognostic validity of various clinical high-risk (CHR) criteria alone and in combination with additional clinical characteristics. METHODS: A total of 188 CHR positive persons from the region of Zurich, Switzerland (mean age 20.5 years; 60.2% male), meeting ultra high-risk (UHR) and/or basic symptoms (BS) criteria, were followed over three years. The test battery included the Structured Interview for Prodromal Syndromes (SIPS), verbal IQ and many other screening tools. Conversion to psychosis was defined according to ICD-10 criteria for schizophrenia (F20) or brief psychotic disorder (F23). RESULTS: Altogether n=24 persons developed manifest psychosis within three years and according to Kaplan-Meier survival analysis, the projected conversion rate was 17.5%. The predictive accuracy of UHR was statistically significant but poor (area under the curve [AUC]=0.65, P<.05), whereas BS did not predict psychosis beyond mere chance (AUC=0.52, P=.730). Sensitivity and specificity were 0.83 and 0.47 for UHR, and 0.96 and 0.09 for BS. UHR plus BS achieved an AUC=0.66, with sensitivity and specificity of 0.75 and 0.56. In comparison, baseline antipsychotic medication yielded a predictive accuracy of AUC=0.62 (sensitivity=0.42; specificity=0.82). A multivariable prediction model comprising continuous measures of positive symptoms and verbal IQ achieved a substantially improved prognostic accuracy (AUC=0.85; sensitivity=0.86; specificity=0.85; positive predictive value=0.54; negative predictive value=0.97). CONCLUSIONS: We showed that BS have no predictive accuracy beyond chance, while UHR criteria poorly predict conversion to psychosis. Combining BS with UHR criteria did not improve the predictive accuracy of UHR alone. In contrast, dimensional measures of both positive symptoms and verbal IQ showed excellent prognostic validity. A critical re-thinking of binary at-risk criteria is necessary in order to improve the prognosis of psychotic disorders. PMID- 28728093 TI - Obsessive-compulsive disorder in the elderly: A report from the International College of Obsessive-Compulsive Spectrum Disorders (ICOCS). AB - INTRODUCTION: Obsessive-compulsive disorder (OCD) is a highly disabling condition, with frequent early onset. Adult/adolescent OCD has been extensively investigated, but little is known about prevalence and clinical characterization of geriatric patients with OCD (G-OCD>=65years). The present study aimed to assess prevalence of G-OCD and associated socio-demographic and clinical correlates in a large international sample. METHODS: Data from 416 outpatients, participating in the ICOCS network, were assessed and categorized into 2 groups, age=65years, and then divided on the basis of the median age of the sample (age=42years). Socio-demographic and clinical variables were compared between groups (Pearson Chi-squared and t tests). RESULTS: G-OCD compared with younger patients represented a significant minority of the sample (6% vs 94%, P<.001), showing a significantly later age at onset (29.4+/-15.1 vs 18.7+/-9.2years, P<.001), a more frequent adult onset (75% vs 41.1%, P<.001) and a less frequent use of cognitive-behavioural therapy (CBT) (20.8% vs 41.8%, P<.05). Female gender was more represented in G-OCD patients, though not at a statistically significant level (75% vs 56.4%, P=.07). When the whole sample was divided on the basis of the median age, previous results were confirmed for older patients, including a significantly higher presence of women (52.1% vs 63.1%, P<.05). CONCLUSIONS: G OCD compared with younger patients represented a small minority of the sample and showed later age at onset, more frequent adult onset and lower CBT use. Age at onset may influence course and overall management of OCD, with additional investigation needed. PMID- 28728094 TI - Modelling a budgetary impact analysis for funding drug-based smoking cessation therapies for patients with major depressive disorder in Spain. AB - BACKGROUND: Smoking is associated with high healthcare resource utilisation and cost to society. Patients with major depressive disorder (MDD) exhibit high susceptibility to nicotine dependence. Varenicline, bupropion and nicotine replacement therapy are all indicated for smoking cessation; however funding by the Spanish national health system (SNHS) is limited. We modelled a budgetary impact analysis (BIA) to estimate the impact of the SNHS funding drug-based therapies for smoking cessation in smokers with MDD. METHODS: The BIA compared the current unfunded scenario versus a funded scenario (varenicline, bupropion, nicotine replacement therapy combined with medical follow-up and counselling) using the Spanish SNHS and societal perspectives. The BIA design was a hybrid model using a decision tree algorithm (population size: smokers with MDD) and Markov chains (smoking cessation attempts) over a 5-year horizon. Smoking cessation drug efficacy was derived from clinical trials, and smoking cessation costs avoided were taken from an analysis of the Spanish National Health Survey. Results were shown as incremental cost savings. Scenarios and threshold univariate sensitivity analyses tested model robustness. RESULTS: The funded scenario resulted in an increase of 43,478 cessation attempts and 8930 fewer smokers after 5 years compared to the unfunded scenario. The cost of funding was ?25.3 million and costs avoided were ?26.5 million. There was a cumulative 5-year incremental cost saving of ?1.2 million to Spanish society. Results were robust using alternative scenarios. CONCLUSIONS: Funding smoking cessation drugs in patients with MDD is of economic benefit to Spain and could produce net savings from the third year of implementation. PMID- 28728095 TI - Lifetime use of psychiatric medications and cognition at 43years of age in schizophrenia in the Northern Finland Birth Cohort 1966. AB - BACKGROUND: Higher lifetime antipsychotic exposure has been associated with poorer cognition in schizophrenia. The cognitive effects of adjunctive psychiatric medications and lifetime trends of antipsychotic use remain largely unclear. We aimed to study how lifetime and current benzodiazepine and antidepressant medications, lifetime trends of antipsychotic use and antipsychotic polypharmacy are associated with cognitive performance in midlife schizophrenia. METHODS: Sixty participants with DSM-IV schizophrenia from the Northern Finland Birth Cohort 1966 were examined at 43years of age with an extensive cognitive test battery. Cumulative lifetime and current use of psychiatric medications were collected from medical records and interviews. The associations between medication and principal component analysis-based cognitive composite score were analysed using linear regression. RESULTS: Lifetime cumulative DDD years of benzodiazepine and antidepressant medications were not significantly associated with global cognition. Being without antipsychotic medication (for minimum 11months) before the cognitive examination was associated with better cognitive performance (P=0.007) and higher lifetime cumulative DDD years of antipsychotics with poorer cognition (P=0.020), when adjusted for gender, onset age and lifetime hospital treatment days. Other lifetime trends of antipsychotic use, such as a long antipsychotic-free period earlier in the treatment history, and antipsychotic polypharmacy, were not significantly associated with cognition. CONCLUSIONS: Based on these naturalistic data, low exposure to adjunctive benzodiazepine and antidepressant medications does not seem to affect cognition nor explain the possible negative effects of high dose long-term antipsychotic medication on cognition in schizophrenia. PMID- 28728096 TI - Early life stress explains reduced positive memory biases in remitted depression. AB - BACKGROUND: There is contradictory evidence regarding negative memory biases in major depressive disorder (MDD) and whether these persist into remission, which would suggest their role as vulnerability traits rather than correlates of mood state. Early life stress (ELS), common in patients with psychiatric disorders, has independently been associated with memory biases, and confounds MDD versus control group comparisons. Furthermore, in most studies negative biases could have resulted from executive impairments rather than memory difficulties per se. METHODS: To investigate whether memory biases are relevant to MDD vulnerability and how they are influenced by ELS, we developed an associative recognition memory task for temporo-spatial contexts of social actions with low executive demands, which were matched across conditions (self-blame, other-blame, self praise, other-praise). We included fifty-three medication-free remitted MDD (25 with ELS, 28 without) and 24 healthy control (HC) participants without ELS. RESULTS: Only MDD patients with ELS showed a reduced bias (accuracy/speed ratio) towards memory for positive vs. negative materials when compared with MDD without ELS and with HC participants; attenuated positive biases correlated with number of past major depressive episodes, but not current symptoms. There were no biases towards self-blaming or self-praising memories. CONCLUSIONS: This demonstrates that reduced positive biases in associative memory were specific to MDD patients with ELS rather than a general feature of MDD, and were associated with lifetime recurrence risk which may reflect a scarring effect. If replicated, our results would call for stratifying MDD patients by history of ELS when assessing and treating emotional memories. PMID- 28728097 TI - Nonlinear modulation of interacting between COMT and depression on brain function. AB - BACKGROUND: The catechol-O-methyltransferase (COMT) gene is related to dopamine degradation and has been suggested to be involved in the pathogenesis of major depressive disorder (MDD). However, how this gene affects brain function properties in MDD is still unclear. METHODS: Fifty patients with MDD and 35 cognitively normal participants underwent a resting-state functional magnetic resonance imaging scan. A voxelwise and data-drive global functional connectivity density (gFCD) analysis was used to investigate the main effects and the interactions of disease states and COMT rs4680 gene polymorphism on brain function. RESULTS: We found significant group differences of the gFCD in bilateral fusiform area (FFA), post-central and pre-central cortex, left superior temporal gyrus (STG), rectal and superior temporal gyrus and right ventrolateral prefrontal cortex (vlPFC); abnormal gFCDs in left STG were positively correlated with severity of depression in MDD group. Significant disease*COMT interaction effects were found in the bilateral calcarine gyrus, right vlPFC, hippocampus and thalamus, and left SFG and FFA. Further post-hoc tests showed a nonlinear modulation effect of COMT on gFCD in the development of MDD. Interestingly, an inverted U-shaped modulation was found in the prefrontal cortex (control system) but U-shaped modulations were found in the hippocampus, thalamus and occipital cortex (processing system). CONCLUSION: Our study demonstrated nonlinear modulation of the interaction between COMT and depression on brain function. These findings expand our understanding of the COMT effect underlying the pathophysiology of MDD. PMID- 28728098 TI - Longitudinal study of religiosity and mental health of adolescents with psychiatric problems. The TRAILS study. AB - PURPOSE: This study used longitudinal data to examine the influence of the religiosity of pre-adolescents with psychiatric problems on the course of mental health during adolescence. METHODS: In the TRAILS clinical cohort of 543 pre adolescents (10-12 years), mental health problems were assessed using self-report at baseline, T2 (12-14 years), T3 (14-17 years), and T4 (17-21 years). The Youth Self Report (YSR) was used at baseline, T2, and T3, and the Adult Self Report (ASR) was used at T4. Religiosity was assessed at baseline using self-report and information from mothers and fathers, resulting in three categorical religiosity variables and six SOCON (Social Cultural Developments Questionnaire) religiosity scales that assess religiosity in greater detail. Repeated measure ANOVA analyses were performed for each independent religiosity variable with internalizing and externalizing problem behavior as dependent variables, gender as a factor and time (T1, T2, T3 and T4) as within factor. Results were adjusted for marital status of parents and socioeconomic status and corrected for multiple testing. RESULTS: There were main effects of the self-report SOCON scale "Humanistic beliefs" and gender and gender "by Humanistic beliefs" interaction effect on internalizing problems. Follow-up tests revealed that among females "high" scores on "Humanistic beliefs" were associated with increased internalizing problems. CONCLUSIONS: There were hardly any associations between religiosity and mental health in a clinical cohort of pre-adolescents up to adolescence. The exception being that among females strong humanistic beliefs were associated with internalizing problems. Implications of these findings are discussed. PMID- 28728099 TI - Endogenous viruses of parasitic wasps: variations on a common theme. AB - In a remarkable example of convergent evolution, several parasitic wasp lineages have independently captured and maintained complex DNA virus machineries, used to transfer virulence factors. Parasitic wasps, which develop inside the larvae of their insect hosts, may inject Polydnaviruses (PDVs) or Virus-Like particles (VLPs), derived from the recurrent endogenization of several large DNA viruses. PDVs evolved from the domestication in braconid and ichneumonid wasps of viruses from different families and function as gene transfer agents. In contrast, the independent domestication of nudiviruses led to the evolution of both PDV and VLP strategies. In Venturia canescens, the endogenous nudivirus has lost the ability to encapsidate DNA, instead VLPs cargo virulence molecules of wasp origin to the parasitized host. PMID- 28728100 TI - Photophysics of a coumarin based Schiff base in solvents of varying polarities. AB - The present work reports detailed photophysics of a coumarin based Schiff base, namely, (E)-7-(((8-hydroxyquinolin-2-yl)methylene)amino)-4-methyl-2H-chromen-2 one (HMC) in different solvents of varying polarity exploiting steady state absorption, fluorescence and time resolved fluorescence spectroscopy. The dominant photophysical features of HMC are discussed in terms of emission from an intramolecular charge transfer (ICT) excited state. Molecular orbital (MO) diagrams as obtained from DFT based computational analysis confirms the occurrence of charge transfer from 8'-hydroxy quinoline moiety of the molecule to the coumarin part. The notable difference in the photophysical response of HMC from its analogous coumarin (C480) lies in a lower magnitude of fluorescence quantum yield of the former, particularly in the solvents of low polarity, which is rationalized by considering the higher rate of non-radiative decay of HMC in apolar solvents. Phosphorescence emission as well as phosphorescence lifetime of HMC has also been reported in 77K frozen matrix. PMID- 28728101 TI - A "rising" transpedicular access to anterior vertebral body: A case report. AB - INTRODUCTION: The transpedicular access is a common and effective procedure used to reach anterior vertebral body without passing through critical structures. after a transpedicular instrumentation, it is difficult to reach the anterior vertebral body because screws are placed in the way. We assume that an innovative transdiscal route could be used in patients with previous instrumentation, in order to perform a vertebroplasty or biopsy. PRESENTATION OF CASE: We report the case of a 65-years-old woman who came to our Department complaining low back pain. Neurological examination showed a stable L4 wedge fracture under a previous lumbar L3-L4 posterolateral fusion performed 2 years before. DISCUSSION: In order to perform a vertebroplasty and a biopsy of the collapsed L4 anterior vertebral body we had to deal with transpedicular screws, which prevent any standard transpedicular pproach. CONCLUSION: In order to reach the L4 collapsed body we used an ascending transpedicular approach. We performed a biopsy and a subsequent vertebroplasty. Two days after surgery the patient reported a complete pain remission and was allowed to walk. PMID- 28728102 TI - Uterine necrosis following a combination of uterine compression sutures and vascular ligation during a postpartum hemorrhage: A case report. AB - INTRODUCTION: The Postpartum bleeding is the first cause of maternal mortality in Morocco. It is an obstetrical emergency that requires a fast multimodal management including medical care, interventional procedure and in few cases a salvatory surgery. CLINICAL CASE: We report a rare case of uterine necrosis following postpartum hemorrhage, refractory to medical therapy, and which was controlled by a combination of uterine hemostatic techniques and vascular ligation three days after surgery, the patient developed a fever (39 degrees C). At day 3 of postoperative period, the patient developed a fever (39 degrees C) associated with diffuse abdominal pain, diarrhea and non-fetid lochia. At day 5, she presented a state of sepsis. Abdominal and pelvic CT objectified gas bubbles in the uterine myometrium suggestive of necrosis. An exploratory laparotomy was performed. After adhesiolysis, exploration found a complete necrosis of the uterus DISCUSSION: There are many surgical techniques for the management of postpartum bleeding, and hysterectomy remains the reference solution in this context. However, new conservative surgical techniques that are easier to perform and are less aggressive have emerged and are becoming more commonly used. CONCLUSION: We emphasize on the importance of choosing surgical techniques that lead to the preservation of uterine vascularization. PMID- 28728103 TI - Freiberg's infraction: A modified closing wedge osteotomy for an undiagnosed case. AB - INTRODUCTION: Freiberg's infraction is an osteonecrosis affecting the metatarsal head whose pathogenesis is not fully understood, although stress overloading by multiple microtraumas remains the most widely accepted cause. Operative treatment, by different techniques, is necessary when conservative treatment fails. PRESENTATION OF CASE: A 31-year old woman presented with left foot severe pain, especially at the level of the metatarsophalangeal joint (MTPJ) of the second ray, underestimated upon initial evaluation. She had a history of repetitive microtraumas, a long second metatarsal bone and altered forefoot kinematics. Clinical and radiographic findings were compatible with Freiberg's infraction. A dorsal closing-wedge osteotomy with single screw stabilization was performed. At last follow-up, the patient was completely asymptomatic with a normal MTPJ range of motion. DISCUSSION: Our patient had a history of repetitive microtraumas combined with a long second metatarsal bone and altered forefoot kinematics. Initially, because of the low frequency of the disease and lack of knowledge about it, even among general orthopaedic surgeons, the infraction was not diagnosed. However, the radiological characteristics of the lesion, combined with intra-operative observation and histological exams associated with the medical history and clinical exam of the patient, revealed a disease compatible with Freiberg's syndrome. A closing-wedge osteotomy, performed by using a straight burr, appeared to be the most correct treatment. CONCLUSION: This case shows how Freiberg's infraction can pass unrecognized or underestimated and how dorsal closing-wedge osteotomy can be an efficient surgical treatment. PMID- 28728104 TI - Design, synthesis and evaluation of coumarin-pargyline hybrids as novel dual inhibitors of monoamine oxidases and amyloid-beta aggregation for the treatment of Alzheimer's disease. AB - A series of coumarin-pargyline hybrids (4a-x) have been designed, synthesized and evaluated as novel dual inhibitors of Alzheimer's disease (AD). Most of the compounds exhibited a potent ability to inhibit amyloid-beta (Abeta) aggregation and monoamine oxidases. In particular, compound 4x exhibited remarkable inhibitory activities against monoamine oxidases (IC50, 0.027 +/- 0.004 MUM for MAO-B; 3.275 +/- 0.040 MUM for MAO-A) and Abeta1-42 aggregation (54.0 +/- 1.1%, 25 MUM). Moreover, compound 4x showed low toxicity according to in vitro cell toxicity test. The results of the parallel artificial membrane permeability assay for blood-brain barrier indicated that compound 4x would be potent to cross the blood-brain barrier. Collectively, these findings demonstrate that compound 4x was an effective and promising candidate for AD therapy. PMID- 28728105 TI - Discovery of imidazopyridines containing isoindoline-1,3-dione framework as a new class of BACE1 inhibitors: Design, synthesis and SAR analysis. AB - Alzheimer's disease is characterized by chronic neurodegeneration leading to dementia. The main cause of neurodegeneration is considered to be the accumulation of amyloid-beta. Inhibiting BACE1 is a well-studied approach to lower the burden of amyloid-beta aggregates. We designed a series of imidazopyridines-based compounds bearing phthalimide moieties as inhibitors of BACE1. The compounds 8a-o were synthesized by the Groebke-Blackburn-Bienayme three-component reaction of heteroaromatic amidines, aldehydes and isocyanides. Evaluating the BACE1 inhibitory effects of the synthesized compounds revealed that introducing an aminocyclohexyl moiety in the imidazopyridine core resulted in a significant improvement in its BACE1 inhibitory potential. In this regard, compound 8e was the most potent against BACE1 with an IC50 value of 2.84 (+/ 0.95) MUM. Molecular docking revealed that the nitrogen atom of imidazopyridines and the oxygen atom of the phenoxypropyl linker were involved in hydrogen bound interactions with Asp228 and Asp32 of BACE1 active site, respectively. The phthalimide moiety oriented toward the flap pocket and interacted with phe108, lle110, Trp115, Ile118 through van der Waal's and hydrophobic interactions. These findings demonstrate that imidazopyridines-based compounds bearing phthalimide moiety have the potential to decrease amyloid-beta levels and ameliorate the symptoms of Alzheimer's disease. PMID- 28728106 TI - Multipotent AChE and BACE-1 inhibitors for the treatment of Alzheimer's disease: Design, synthesis and bio-analysis of 7-amino-1,4-dihydro-2H-isoquilin-3-one derivates. AB - In this paper, the preparation of a new class of multi-target-directed ligands (MTDLs) based on a 7-amino-1,4-dihydro-2H-isoquilin-3-one, whose lead (compound I) showed promising properties in acetylcholinesterase (AChE) inhibitory activity [1], is described. The results of in vitro activities and molecular docking demonstrated that the target molecule (compounds 10a-n) with three parts of aromatic moieties and appropriate structural length can interact with aromatic residues in catalytic active site (CAS), peripheral anionic site (PAS) and the channel of AChE. And the introduce of connecting amide bonds, enables the target molecules provide sufficient hydrogen bond donors and acceptors to interact with the catalytic site of BACE-1. Notably, compound 10d exerted excellent AChE inhibition (IC50 = 18.93 +/- 1.02 pM, 181-fold more inhibitory effect compared with donepezil), BACE-1 inhibition (97.68 +/- 8.01% at 20 MUM), and good metal chelating property, which can be chosen as lead compound for further optimization of novel small ligand for the treatment of Alzheimer's disease. PMID- 28728107 TI - Developing potential agents against atherosclerosis: Design, synthesis and pharmacological evaluation of novel dual inhibitors of oxidative stress and Squalene Synthase activity. AB - For the treatment of multifactorial and complex diseases, it has become increasingly apparent that compounds acting at multiple targets often deliver superior efficacy compared to compounds with high specificity for only a single target. Based on previous studies demonstrating the important antioxidant and anti-hyperlipidemic effect of morpholine and 1,4-benzo(x/thi)azine derivatives (A E), we hereby present the design, synthesis and pharmacological evaluation of novel dual-acting molecules as a therapeutic approach for atherosclerosis. Analogues 1-10 were rationally designed through structural modifications of their parent compounds (A-E) in order for structure-activity relationship studies to be carried out. Most compounds showed a significant inhibition against Squalene Synthase activity exhibiting at the same time a very potent multimodal antioxidant (against lipid peroxidation and as free-radical scavengers) effect, thus bringing to light the 2-aryl-1,4-benzo(x/thia)zin-2-ol scaffold as an outstanding pharmacophore for the design of potent antioxidants. Finally, the replacement of the octahydro-1,4-benzoxazine moiety of lead compound D with its respective 1,4-benzothiazine (compound 4), although conserved (anti hypercholesterolemic) or even improved (anti-hyperlipidemic) activity, did not preserve the anti-diabetic effect of D. PMID- 28728108 TI - New tacrine dimers with antioxidant linkers as dual drugs: Anti-Alzheimer's and antiproliferative agents. AB - We have designed a series of tacrine-based homo- and heterodimers that incorporate an antioxidant tether (selenoureido, chalcogenide) as new dual compounds: for the treatment of Alzheimer's disease and as antiproliferative agents. Symmetrical homodimers bearing a dichalcogenide or selenide-based tether, the best compounds in the series, were found to be strong and highly selective electric eel AChE inhibitors, with inhibition constants within the low nanomolar range. This high inhibitory activity was confirmed on recombinant human AChE for the most interesting derivatives. The three most promising homodimers also showed a good inhibitory activity towards amyloid-beta self aggregation. The symmetric disulfide derivative bis[5-(1',2',3',4'-tetrahydroacridin-9' ylamino)pentyl]disulfide (19) showed the best multipotent profile and was not neurotoxic on immortalized mouse cortical neurons even at 50 MUM concentration. These results represent an improvement in activity and selectivity compared to parent tacrine, the first marketed drug against Alzheimer's disease. Title compounds also exhibited excellent in vitro antiproliferative activities against a panel of 6 human tumor cell lines, with GI50 values within the submicromolar range for the most potent derivatives (0.12-0.95 MUM); such values represent a spectacular increase compared to currently-used chemotherapeutic agents, such as 5-FU (up to 306-fold) and cisplatin (up to 162-fold). Cell cycle experiments indicated the accumulation of cells in the G1 phase of the cycle, a different mechanism than the reported for cisplatin. The breast cancer cell lines turned out to be the most sensitive one of the panel tested. PMID- 28728109 TI - Zero-valent aluminum for reductive removal of aqueous pollutants over a wide pH range: Performance and mechanism especially at near-neutral pH. AB - Zero-valent aluminum (ZVAl) draws much attention due to its strong reducibility. However, under neutral pH conditions, the reduction ability of ZVAl for pollutant removal has still been suspected because of the formed compact surface film of Al (hydr)oxide. In this study, unmodified ZVAl was employed to reductively remove aqueous pollutants over a wide pH range, and its performance and mechanism, especially at near-neutral pH, were systematically studied for the first time. Results demonstrated that ZVAl had a wide range of pH applicability from 2 to 12, even in neutral environment. Typical nitro compound nitrobenzene (NB), typical azo dye acid orange 7 (AO7), and typical inorganic heavy metal ion Cr(VI) can be effectively removed at initial pH 7. Based on the changes of pH, ORP, DO, Al ions and TOC of the reaction solution, and the determination of reduction products of NB by UV-Vis and GC-MS, we found that NB removal by ZVAl can be primarily attributed to the reduction role. NB was reduced to nitrosobenzene firstly, and to aniline finally. Meanwhile, the adsorption phenomenon existed in this system. Next, the surface reaction mechanism was deeply revealed through the characterization of ZVAl particles before and after reaction by SEM-EDS, TEM, HRTEM, XRD, and XPS. It was found that ZVAl powders with core/shell structure participated in the redox reaction, and that ZVAl core was corroded, generating Al-(hydr)oxide. ZVAl surface oxide film was not directly removed, instead of a rougher one. Finally, the proposed reductive mechanism of aqueous pollutants by ZVAl was speculated from the angle of electronic competition. In water environment, O2, H2O and pollutants, with a clear competitive relationship, can capture electrons released from ZVAl. When pollutant's opportunities for getting electrons are enhanced, efficiently reductive reactions for pollutant removal can take place, even at near-neutral pH. In a word, ZVAl is a promising material to remove aqueous pollutants over a wide pH range, even in neutral environment, which exhibits its great potential as an effective and environment-friendly agent for pollutant removal from water. PMID- 28728111 TI - A heteropoly blue as environmental friendly material: An excellent heterogeneous Fenton-like catalyst and flocculent. AB - The first 3D heteropoly blue Ba2Na4[SiW4VW8VIO40].19H2O (1) as heterogeneous Fenton-like catalyst and flocculent was hydrothermally synthesized and fully characterized by various methods 1 was an efficient Fenton-like catalyst for degradation of phenol with degradation rate of 92.1% (visible light irradiation), and 89.0% (no light) in 90min, respectively. The degradation efficiency of anionic dye methyl orange was 97.0% in 5min, when 1 was used as photo-Fenton-like catalyst under visible light. And 1 was a nice flocculent for cationic dyes methylene blue and rhodamine B, the removal rates were both above 95%. Moreover, 1 could degrade methyl orange and flocculate rhodamine B at the same time, but the degradation rate decreased from 100% to 77.5% in 60min, while the flocculation of RhB in 10min was not affected. PMID- 28728112 TI - Reductive defluorination of perfluorooctanoic acid by titanium(III) citrate with vitamin B12 and copper nanoparticles. AB - Perfluorooctanoic acid (PFOA) is widespread in the environment, which causes serious health and safety concerns. A mechanistic study on reductive defluorination of PFOA by titanium(III) citrate in the presence of catalysts was conducted. Vitamin B12 was used to catalyze reduction reactions by shuttling electrons from a reducing agent (electron donor) to PFOA to produce a Co-carbon bond intermediates. In the presence of copper nanoparticles, a precursor complex, B12-C7F14COOH, adsorbed on the metal surface, followed by a hydrogenolytic reaction to form less-fluorinated products. The synergistic effect between vitamin B12 and copper nanoparticles enhances the reductive activities by electron-transfer reactions and hydrogenolysis. The efficient reduction of PFOA to less-noxious compounds was demonstrated with a copper dose of 2gL-1, titanium(III) citrate (45mM), and vitamin B12 (0.2mM) with an initial pH of 9.0 and 70 degrees C. In this anoxic aqueous solution, the biomimetic reductive system effectively removed 65% of PFOA. The mass balance on fluoride matched the observed degradation of PFOA, while no short-chain intermediates were detected. PMID- 28728110 TI - Development of a bioanalytical test battery for water quality monitoring: Fingerprinting identified micropollutants and their contribution to effects in surface water. AB - Surface waters can contain a diverse range of organic pollutants, including pesticides, pharmaceuticals and industrial compounds. While bioassays have been used for water quality monitoring, there is limited knowledge regarding the effects of individual micropollutants and their relationship to the overall mixture effect in water samples. In this study, a battery of in vitro bioassays based on human and fish cell lines and whole organism assays using bacteria, algae, daphnids and fish embryos was assembled for use in water quality monitoring. The selection of bioassays was guided by the principles of adverse outcome pathways in order to cover relevant steps in toxicity pathways known to be triggered by environmental water samples. The effects of 34 water pollutants, which were selected based on hazard quotients, available environmental quality standards and mode of action information, were fingerprinted in the bioassay test battery. There was a relatively good agreement between the experimental results and available literature effect data. The majority of the chemicals were active in the assays indicative of apical effects, while fewer chemicals had a response in the specific reporter gene assays, but these effects were typically triggered at lower concentrations. The single chemical effect data were used to improve published mixture toxicity modeling of water samples from the Danube River. While there was a slight increase in the fraction of the bioanalytical equivalents explained for the Danube River samples, for some endpoints less than 1% of the observed effect could be explained by the studied chemicals. The new mixture models essentially confirmed previous findings from many studies monitoring water quality using both chemical analysis and bioanalytical tools. In short, our results indicate that many more chemicals contribute to the biological effect than those that are typically quantified by chemical monitoring programs or those regulated by environmental quality standards. This study not only demonstrates the utility of fingerprinting single chemicals for an improved understanding of the biological effect of pollutants, but also highlights the need to apply bioassays for water quality monitoring in order to prevent underestimation of the overall biological effect. PMID- 28728113 TI - Catalase based hydrogen peroxide biosensor for mercury determination by inhibition measurements. AB - A new amperometric hydrogen peroxide enzyme inhibition biosensor for the indirect determination of toxic mercury ions, Hg2+, based on catalase immobilized on a glassy carbon electrode surface by cross-linking with glutaraldehyde and bovine serum albumin, is reported. The parameters influencing biosensor performance were optimized, including enzyme loading, the amount of hydrogen peroxide, the applied potential and electrolyte pH. It was shown that the inhibition of catalase by Hg2+ species is irreversible, with a linear inhibition response between 5*10-11 and 5*10-10M. The limit of detection calculated as 10% inhibition was 1.8*10-11M and is the lowest reported until now. Electrochemical impedance spectroscopy was successfully used as a diagnostic of inhibition. Interferences from other heavy metal ions and organic pesticides were evaluated and the inhibition showed very good selectivity towards Hg2+. The method was successfully applied to the determination of mercury ions in different types of water sample. PMID- 28728114 TI - Variation in receipt of pharmacotherapy for alcohol use disorders across racial/ethnic groups: A national study in the U.S. Veterans Health Administration. AB - OBJECTIVE: Pharmacologic treatment is recommended for alcohol use disorders (AUD), but most patients do not receive it. Although racial/ethnic minorities have greater AUD consequences than whites, whether AUD medication receipt varies across race/ethnicity is unknown. We evaluate this in a national sample. METHODS: Electronic health records data were extracted for all black, Hispanic, and/or white patients who received care at the U.S. Veterans Health Administration (VA) during Fiscal Year 2012 and had a documented AUD diagnosis. Mixed effects regression models, with a random effect for facility, determined the likelihood of receiving AUD pharmacotherapy (acamprosate, disulfiram, topirimate or oral or injectable naltrexone <=180days after AUD diagnosis) for black and Hispanic patients relative to white patients. Models were unadjusted and then adjusted for patient- and facility-level factors. RESULTS: 297,506 patients had AUD; 26.4% were black patients, 7.1% were Hispanic patients and 66.5% were white patients; 5.1% received AUD medications. Before adjustment, black patients were less likely than white [Odds Ratio (OR) 0.77; 95% Confidence Interval (CI) 0.75 -0.82; (p<0.001)], while Hispanic patients were more likely than white (OR 1.09; 95% CI 1.01-1.16) to receive AUD medications. After adjustment, black patients remained less likely than white to receive AUD medications (OR 0.68; 95% CI 0.65-0.71; p<0.0001); no difference between Hispanic and white patients was observed (OR 0.94; 95% CI 0.87-1.00; p=0.07). CONCLUSIONS: In this national study of patients with AUD, blacks were less likely to receive AUD medications than whites. Future research is needed to identify why these disparities exist. PMID- 28728115 TI - Smoked marijuana attenuates performance and mood disruptions during simulated night shift work. AB - Individuals who work nonstandard schedules, such as rotating or night shifts, are more susceptible to workplace injuries, performance decrements, and reduced productivity. This population is also almost twice as likely to use illicit drugs as individuals working a standard day shift. The purpose of this study was to examine the effects of smoked marijuana on performance, mood, and sleep during simulated shift work. Ten experienced marijuana smokers completed this 23-day, within-participant residential study. They smoked a single marijuana cigarette (0, 1.9, 3.56% Delta9-THC) one hour after waking for three consecutive days under two shift conditions: day shift and night shift. Shifts alternated three times during the study, and shift conditions were separated by an 'off' day. When participants smoked placebo cigarettes, psychomotor performance and subjective effect ratings were altered during the night shift compared to the day shift: performance (e.g., vigilance) and a few subjective ratings were decreased (e.g., "Self-Confident"), whereas other ratings were increased (e.g., "Tired"). Objective and subjective measures of sleep were also disrupted, but to a lesser extent. Marijuana attenuated some performance, mood, and sleep disruptions: participants performed better on vigilance tasks, reported being less miserable and tired and sleep a greater number of minutes. Limited negative effects of marijuana were noted. These data demonstrate that abrupt shift changes produce performance, mood, and sleep decrements during night shift work and that smoked marijuana containing low to moderate Delta9-THC concentrations can offset some of these effects in frequent marijuana smokers. PMID- 28728116 TI - Response of soil physico-chemical properties to restoration approaches and submergence in the water level fluctuation zone of the Danjiangkou Reservoir, China. AB - With the completion of the Danjiangkou Dam, the impoundment and drainage of dams can significantly alter shorelines, hydrological regime, and sediment and can result in the loss of soil and original riparian vegetation. Revegetation may affect soil properties and have broad important implications both for ecological services and soil recovery. In this work, we investigated the soil properties under different restoration approaches, and before and after submergence in the water level fluctuation zone (WLFZ) of the Danjiangkou Reservoir. Soil physical (bulk density and soil moisture), chemical (pH, soil organic carbon, nitrogen, phosphorus and potassium contents), and heavy metals were determined. This study reported that restoration approaches have impacts on soil moisture, pH, N, soil organic carbon, P, K and heavy metals in the WLFZ of the Danjiangkou Reservoir. Our results indicated that different restoration approaches could increase the soil moisture while decrease soil pH. Higher soil organic carbon in propagule banks transplantation (PBT) and shrubs restoration (SR) indicate that PBT and SR may provide soil organic matter more quickly than trees restoration (TR). SR and TR could significantly improve the soil total P and available P. PBT and SR could improve the soil total K and available K. SR and TR could significantly promote Cu and Zn adsorption, and Pb and Fe release by plant. Submergence could significantly affect the soil pH, NO3--N, NH4+-N, total P and available P. Submergence could promote NO3--N and available P adsorption, and NH4+-N and total P release by soil. The soil quality index (SQI) values implied that TR and PBT greatly improved soil quality. The present study suggests that PBT and TR could be effective for soil restoration in WLFZ of the Danjiangkou Reservoir. PMID- 28728117 TI - Alzheimer's disease markers in the aged sheep (Ovis aries). AB - This study reports the identification and characterization of markers of Alzheimer's disease (AD) in aged sheep (Ovis aries) as a preliminary step toward making a genetically modified large animal model of AD. Importantly, the sequences of key proteins involved in AD pathogenesis are highly conserved between sheep and human. The processing of the amyloid-beta (Abeta) protein is conserved between sheep and human, and sheep Abeta1-42/Abeta1-40 ratios in cerebrospinal fluid (CSF) are also very similar to human. In addition, total tau and neurofilament light levels in CSF are comparable with those found in human. The presence of neurofibrillary tangles in aged sheep brain has previously been established; here, we report for the first time that plaques, the other pathologic hallmark of AD, are also present in the aged sheep brain. In summary, the biological machinery to generate the key neuropathologic features of AD is conserved between the human and sheep, making the sheep a good candidate for future genetic manipulation to accelerate the condition for use in pathophysiological discovery and therapeutic testing. PMID- 28728118 TI - Threatening events theme of cognitive biases mediates the relationship between fear of social situations and delusion-like experiences among healthy adults. AB - Social anxiety (SA) is frequently observed among patients diagnosed with psychosis as well as among individuals with delusion-like experiences (DLEs). A heightened level of SA has been recognized to precede the development of psychotic symptoms; however, the detailed mechanisms that link SA to delusional ideation remain unrecognized. Since social anxiety is associated with the presence of cognitive biases and biased cognitive processes have been found to play a role in the development and maintenance of delusions, we hypothesized that cognitive biases may mediate in the relationship between social anxiety and DLEs. A total sample of 202 healthy individuals with mean age 35.59 (SD = 17.15) was assessed for the presence of delusion-like experiences, social anxiety, as well as the threatening events theme and anomalous perception theme of cognitive biases. The threatening events theme was found to fully mediate the linkage between fear of social situations and DLEs (beta = 0.12, p < 0.05). The threatening events theme was also found to be a partial mediator in the association between social avoidance and DLEs (beta = 0.20, p < 0.05), and between the overall level of social anxiety and DLEs (beta = 0.18, p < 0.05). Our findings suggest that social anxiety may influence DLEs by providing the threatening events theme of cognitive biases. PMID- 28728119 TI - NF-kappaB-mediated inflammation correlates with calcium overload under arsenic trioxide-induced myocardial damage in Gallus gallus. AB - Arsenic is a known environmental pollutant and highly hazardous toxin to human health. Due to the biological accumulation, arsenic produces a variety of cardiovascular diseases. However, the exact mechanism is still unclear. Here, our objective was to evaluate myocardial damage and determine the potential mechanism under arsenic exposure in chickens. Arsenic trioxide (As2O3) (1.25 mg/kg BW, corresponding 15 mg/kg feed) was administered as basal diet to male Hy-line chickens (one-day-old) for 4, 8 and 12 weeks. The results showed that As2O3 induced histological and ultrastructural damage in heart accompanied with significantly Ca2+ overload and increased the activities of myocardial enzymes. Moreover, As2O3 exposure significantly increased (P < 0.05) the mRNA levels of ITPR3, PMCA, TRPC1, TRPC3, STIM1, ORAI1 and pro-inflammatory genes, while the mRNA levels of ITPR1, ITPR2, RyR1, RyR3, SERCA, SLC8A1, CACNA1S and interleukin 10 were decreased (P < 0.05) by As2O3 exposure at 4, 8 and 12 weeks as compared with the corresponding control group. Western blot results showed that As2O3 exposure decreased the expression of SERCA and SLC8A1 protein, while the expression of TNF-alpha, NF-kappaB, iNOS and PMCA1 increased compared with the corresponding control group. Additionally, correlation analysis and protein protein interaction prediction shown that NF-kappaB-mediated inflammatory response have a function correlation with calcium (Ca) regulation-related genes. In conclusion, this study indicated that As2O3-induced inflammatory response might dependent on Ca overload in myocardial damage of chickens. Our work has implications for the development of potential therapeutic approaches by resisting Ca overload for arsenic-induced myocardial damage. PMID- 28728120 TI - Cadmium and high temperature effects on brain and behaviour of Lymantria dispar L. caterpillars originating from polluted and less-polluted forests. AB - Insects brain as a part of nervous system is the first-line of fast stress response that integrate stress signals to regulate all aspects of insect physiology and behaviour. The cadmium (Cd) bioaccumulation factor (BF), activity of the neurotoxicity biomarker acetylcholinesterase (AChE), dopamine content, expression and amount of Hsp70 in the brain and locomotor activity were evaluated in the 4th instar of Lymantria dispar L. caterpillars fed a Cd supplemented diet and reared in an optimal temperature regime (23 degrees C) and/or exposed to high temperature (28 degrees C). The insects originated from two forests, one close to "Nikola Tesla" thermoelectric power plant, Obrenovac (polluted population), and the other Kosmaj mountain (less-polluted population, far from any industrial region). The Cd BF was higher in the less-polluted than in the polluted population especially at the high ambient temperature. AChE activity and dopamine content were changed in the brains of L. dispar from both populations in the same manner. Hsp70 concentration in caterpillar brains showed opposite trends, a decrease in the less-polluted and an increase in the polluted population. Locomotor activity was modified in both Lymantria dispar populations, but the pattern of changes depended on the stressors and their combined effect. ACh activity and dopamine content are sensitive parameters to Cd exposure, regardless of pollutant experience, and might be promising biomarkers in monitoring forest ecosystems. PMID- 28728121 TI - Effect of residual H2O2 from advanced oxidation processes on subsequent biological water treatment: A laboratory batch study. AB - H2O2 residuals from advanced oxidation processes (AOPs) may have critical impacts on the microbial ecology and performance of subsequent biological treatment processes, but little is known. The objective of this study was to evaluate how H2O2 residuals influence sand systems with an emphasis on dissolved organic carbon (DOC) removal, microbial activity change and bacterial community evolution. The results from laboratory batch studies showed that 0.25 mg/L H2O2 lowered DOC removal by 10% while higher H2O2 concentrations at 3 and 5 mg/L promoted DOC removal by 8% and 28%. A H2O2 dosage of 0.25 mg/L did not impact microbial activity (as measured by ATP) while high H2O2 dosages, 1, 3 and 5 mg/L, resulted in reduced microbial activity of 23%, 37% and 37% respectively. Therefore, DOC removal was promoted by the increase of H2O2 dosage while microbial activity was reduced. The pyrosequencing results illustrated that bacterial communities were dominated by Proteobacteria. The presence of H2O2 showed clear influence on the diversity and composition of bacterial communities, which became more diverse under 0.25 mg/L H2O2 but conversely less diverse when the dosage increased to 5 mg/L H2O2. Anaerobic bacteria were found to be most sensitive to H2O2 as their growth in batch reactors was limited by both 0.25 and 5 mg/L H2O2 (17-88% reduction). In conclusion, special attention should be given to effects of AOPs residuals on microbial ecology before introducing AOPs as a pre-treatment to biological (sand) processes. Additionally, the guideline on the maximum allowable H2O2 concentration should be properly evaluated. PMID- 28728122 TI - Mutagenicity and estrogenicity of raw water and drinking water in an industrialized city in the Yangtze River Delta. AB - Public concern was aroused by frequently reported water pollution incidents in Taihu Lake and the Yangtze River. The pollution also caught and sustained the attention of the scientific community. From 2010 to 2016, raw water and drinking water samples were continually collected at Waterworks A and B (Taihu Lake) and Waterworks C (Yangtze River). The non-volatile organic pollutants in the water samples were extracted by solid phase extraction. Ames tests and yeast estrogen screen (YES) assays were conducted to evaluate the respective mutagenic and estrogenic effects. Water samples from the Yangtze River-based Waterworks C possessed higher mutagenicity than those from Taihu Lake-based Waterworks A (P<0.001) and Waterworks B (P = 0.026). Water treatment enhanced the direct mutagenicity (P = 0.022), and weakened the estrogenicity of the raw water (P<0.001) with a median removal rate of 100%. In fact, very few of the finished samples showed estrogenic activity. Raw water samples from Waterworks A showed weaker estrogenicity than those from Waterworks B (P = 0.034) and Waterworks C (P = 0.006). In summary, mutagenic effects in drinking water and estrogenic effects in raw water merited sustained attention. The Yangtze River was more seriously polluted by mutagenic and estrogenic chemicals than Taihu Lake was. PMID- 28728123 TI - Analysis of sugarcane herbicides in marine turtle nesting areas and assessment of risk using in vitro toxicity assays. AB - Agricultural processes are associated with many different herbicides that can contaminate surrounding environments. In Queensland, Australia, herbicides applied to agricultural crops may pose a threat to valuable coastal habitats including nesting beaches for threatened loggerhead turtles (Caretta caretta). This study 1) measured concentrations of herbicides in the beach sand of Mon Repos, an important marine turtle nesting beach in Australia that is adjacent to significant sugarcane crops, and 2) investigated the toxicity of these herbicides to marine turtles using a cell-based assay. Samples of sand from turtle nest depth and water from surrounding agricultural drains and wetlands were collected during the wet season when herbicide runoff was expected to be the greatest and turtles were nesting. Samples were extracted using solid phase extraction and extracts were analysed using chemical analysis targeting herbicides, as well as bioanalytical techniques (IPAM-assay and loggerhead turtle skin cell cytotoxicity assay). Twenty herbicides were detected in areas between sugarcane crops and the nesting beach, seven of which were also detected in the sand extracts. Herbicides present in the nearby wetland were also detected in the beach sand, indicating potential contamination of the nesting beach via the river outlet as well as ground water. Although herbicides were detected in nesting sand, bioassays using loggerhead turtle skin cells indicated a low risk of acute toxicity at measured environmental concentrations. Further research should investigate potentially more subtle effects, such as endocrine disruption and mixture effects, to better assess the threat that herbicides pose to this population of marine turtles. PMID- 28728124 TI - Thin ferrihydrite sediment capping sequestrates phosphorus experiencing redox conditions in a shallow temperate lacustrine wetland. AB - Synthesized ferrihydrite (Fh) with the dosages of 0.3, 0.6 and 0.9 cm thickness (labeled as Fh, 2Fh and 3Fh respectively, equivalent to 248-774 g/m2) were deployed to serve as the reactive capping layer covering the Ornamental Lake sediments, the Royal Botanic Garden of Melbourne. The sediments were exposed to an alternating regime of oxic/anoxic conditions using laboratory reactors for 45 days. Dynamics of dissolved oxygen (DO), pH, filterable reactive phosphorus (FRP), filterable ammonium (NH4+), nitrate and nitrite (NOx), total dissolved nitrogen (TDN) and dissolved iron (Fe) of overlying water were examined. After incubation, O2 and H2S profiles across the water-sediment interface were observed with microelectrodes. The element distributions in the upper sediments were tested as well. Results showed that DO and pH kept relatively stable during oxic period, while decreased significantly during anoxic period. Fh cappings decreased both DO and pH, and inhibited the release of FRP. No significant increments of FRP in overlying waters were observedduring anoxic period. Fh cappings prompted the releases of NH4+ and TDN, while inhibited that of NOx.NH4+increased while NOx decreased during anoxic period. Fe(II) and TFe increased only in 3Fh, especially during anoxic conditions. Fh cappings increased O2 and H2S concentrations across the water-sediment interfaces. TP and TN in the sediments decreased after capping, while TFe increased significantly. We concluded that 0.6 cm thickness of (496 g/m2) Fh capping could sequestrate P, even experiencing redox conditions. PMID- 28728125 TI - Assessment and prediction of joint algal toxicity of binary mixtures of graphene and ionic liquids. AB - Graphene and ionic liquids (ILs) released into the environment will interact with each other. So far however, the risks associated with the concurrent exposure of biota to graphene and ILs in the environment have received little attention. The research reported here focused on observing and predicting the joint toxicity effects in the green alga Scenedesmus obliquus exposed to binary mixtures of intrinsic graphene (iG)/graphene oxide (GO) and five ILs of varying anionic and cationic types. The isolated ILs in the binary mixtures were the main contributors to toxicity. The binary GO-IL mixtures resulted in more severe joint toxicity than the binary iG-IL mixtures, irrespective of mixture ratios. The mechanism of the joint toxicity may be associated with the adsorption capability of the graphenes for the ILs, the dispersion stability of the graphenes in aquatic media, and modulation of the binary mixtures-induced oxidative stress. A toxic unit assessment showed that the graphene and IL toxicities were additive at low concentration of the mixtures but antagonistic at high concentration of the mixtures. Predictions made using the concentration addition and independent action models were close to the observed joint toxicities regardless of mixture types and mixture ratios. These findings provide new insights that are of use in the risk assessment of mixtures of engineered nanoparticles and other environmentally relevant contaminants. PMID- 28728126 TI - Electrospun cerium-based TiO2 nanofibers for photocatalytic oxidation of elemental mercury in coal combustion flue gas. AB - Photocatalytic oxidation is an attractive method for Hg-rich flue gas treatment. In the present study, a novel cerium-based TiO2 nanofibers was prepared and selected as the catalyst to remove mercury in flue gas. Accordingly, physical/chemical properties of those nanofibers were clarified. The effects of some important parameters, such as calcination temperature, cerium dopant content and different illumination conditions on the removal of Hg0 using the photocatalysis process were investigated. In addition, the removal mechanism of Hg0 over cerium-based TiO2 nanofibers focused on UV irradiation was proposed. The results show that catalyst which was calcined at 400 degrees C exhibited better performance. The addition of 0.3 wt% Ce into TiO2 led to the highest removal efficiency at 91% under UV irradiation. As-prepared samples showed promising stability for long-term use in the test. However, the photoluminescence intensity of nanofibers incorporating ceria was significantly lower than TiO2, which was attributed to better photoelectron-hole separation. Although UV and O2 are essential factors, the enhancement of Hg0 removal is more obviously related to the participation of catalyst. The coexistence of Ce3+ and Ce4+, which leads to the efficient oxidation of Hg0, was detected on samples. Hg2+ is the final product in the reaction of Hg0 removal. As a consequence, the emissions of Hg0 from flue gas can be significantly suppressed. These indicate that combining photocatalysis technology with cerium-based TiO2 nanofibers is a promising strategy for reducing Hg0 efficiently. PMID- 28728127 TI - Is bacterial luminescence response to low-dose radiation associated with mutagenicity? AB - Luminous marine bacteria are widely used in bioassays with luminescence intensity being a physiological parameter tested. The purpose of the study was to determine whether bacterial genetic alteration is responsible for bioluminescence kinetics change under low-dose radiation exposure. The alpha-emitting radionuclide 241Am and beta-emitting radionuclide 3H were used as the sources of low-dose ionizing radiation. Changes of bioluminescence kinetics of Photobacterium phosphoreum in solutions of 241Am(NO3)3, 7 kBq/L, and tritiated water, 100 MBq/L, were studied; bioluminescence kinetics stages (absence of effect, activation, and inhibition) were determined. Bacterial suspension was sampled at different stages of the bioluminescent kinetics; the doses accumulated by the samples were close or a little higher than a tentative limit of a low-dose interval: 0.10 and 0.85 Gy for 241Am, or 0.11 and 0.18 Gy for 3H. Sequence analysis of the 16S ribosomal RNA gene did not reveal a mutagenic effect of low-dose alpha and beta radiation in the bacterial samples. Previous results on bacterial DNA exposed to low-dose gamma radiation (0.25 Gy) were analyzed and compared to those for alpha and beta irradiation. It is concluded that bioluminescence activation and/or inhibition under the applied conditions of low-dose alpha, beta and gamma radioactive exposure is not associated with DNA mutations in the gene sequences tested. PMID- 28728128 TI - Radionuclide biokinetics in the Russian sturgeon and phylogenetic consistencies with cartilaginous and bony marine fishes. AB - The biokinetics of eight radionuclides (241Am, 109Cd, 134Cs, 75Se, 54Mn, 110mAg, 65Zn, 60Co) absorbed from the aquatic medium by juvenile Russian sturgeon (Acipenser gueldenstaedtii) were experimentally determined in fresh (0.420/00) and brackish (9.00/00) waters, of a similar salinity range to the Caspian Sea, and in conjunction with chemical speciation modelling. Uptake and loss rate constants were determined for each radionuclide for a 14 day exposure at each salinity and during 28 days of exposure to radionuclide-free conditions. Whole body (wet): water concentration factors (CF) achieved over 14 days for these eight radionuclides were used in a comparison with the same radionuclide CFs previously determined experimentally for six species of marine teleosts and chondrichthyans, to further test a phylogeny-based model of multi-nuclide bioaccumulation based on marine chordates. Multivariate analyses (multidimensional scaling and hierarchical clustering) identified the relative affinities among these taxa and also those radionuclides which distinguished most between them, in their differing CFs. They consistently showed that sturgeon aggregated as a group, which was also slightly differentiated with salinity. Sturgeon were distinguished from all teleosts and chondrichthyans but were more dissimilar from chondrichthyans than teleosts, in accordance with sturgeon's different periods of divergence from them in evolutionary time. Variable salinity among experiments may also cause changes in radionuclide bioaccumulation due to variations in (i) bioavailability (ii) osmolarity, and (iii) competitive inhibition of a radionuclide's bioaccumulation by its stable analogue or metabolic model. Their potentially confounding effects on these patterns of radionuclide CFs among taxa were critically evaluated for those radionuclides which discriminated most between sturgeon and teleosts or chondrichthyans. Bioavailability, osmolarity and competitive inhibition effects were identified among salinity treatments, however they were not appreciable enough to override the phylogeny-based signal. The results of this study are thus consistent with a phylogeny-based model of radionuclide bioaccumulation by marine chordates being valid for a fish species living in lower salinity regimes. PMID- 28728129 TI - A finite element model development for simulation of the impact of slab thickness, joints, and membranes on indoor radon concentration. AB - The focus of this study is broadly to define the physics involved in radon generation and transport through the soil and other materials using different parameter-estimation tools from the literature. The effect of moisture in the soil and radon transport via water in the pore space was accounted for with the application of a porosity correction coefficient. A 2D finite element model is created, which reproduces the diffusion and advection mechanisms resulting from specified boundary conditions. A comparison between the model and several analytical and numerical solutions obtained from the literature and field studies validates the model. Finally, the results demonstrate that the model can predict radon entry through different building boundary conditions, such as concrete slabs with or without joints, variable slab thicknesses and diffusion coefficients, and the use of several radon barrier membranes. Cracks in the concrete or the radon barrier membrane have been studied to understand how indoor concentration is affected by these issues. PMID- 28728130 TI - Superficial plantar cutaneous sensation does not trigger barefoot running adaptations. AB - : It has long been proposed that the gait alterations associated with barefoot running are mediated by alterations in sensory feedback, yet there has been no data to support this claim. Thus, the purpose of this study was to examine the role of superficial plantar cutaneous feedback in barefoot and shod running. METHODS: 10 healthy active subjects (6 male, 4 female); mass: 65.2+9.7kg; age: 27+7.1years participated in this study. 10 over-ground running trials were completed in each of the following conditions: barefoot (BF), shod (SHOD), anesthetized barefoot (ANEST BF) and anesthetized shod (ANEST SHOD). For the anesthetized conditions 0.1-0.3mL of 1% lidocaine was injected into the dermal layer of the plantar foot below the metatarsal heads, lateral column and heel. 3 dimensional motion analysis and ground reaction force (GRF) data were captured as subjects ran over a 20m runway with a force plate at 12m. Kinematic and kinetic differences were analyzed via two-way repeated measure ANOVAs. RESULTS: The differences in gait between the BF and SHOD conditions were consistent with previous research, with subjects exhibiting a significant decrease in stride length and changing from rearfoot strike when SHOD to fore/midfoot strike when BF. Additionally, BF running was associated with decreased impact peak magnitudes and peak vertical GRFs. Despite anesthetizing the plantar surface, there was no difference between the BF and ANEST BF conditions in terms of stride length, foot strike or GRFs. CONCLUSION: Superficial cutaneous sensory receptors are not primarily responsible for the gait changes associated with barefoot running. PMID- 28728131 TI - The distribution of organochlorine pesticides in sediments from iSimangaliso Wetland Park: Ecological risks and implications for conservation in a biodiversity hotspot. AB - The iSimangaliso Wetland Park World Heritage site, located on the east coast of South Africa, spans ~3300 km2 and constitutes the largest protected estuarine environment for hippopotami, crocodiles and aquatic birds in Africa. Given the ecological importance of this site and continued use of organochlorine pesticides (OCPs) in the region, this study focused on the nature, distribution and potential sources of organochlorine contamination within iSimangaliso Wetland Park. OCPs were widely distributed in surface sediment samples obtained from the four main Ramsar wetland systems within the park (Lake St Lucia, Mkhuze, Lake Sibaya and Kosi Bay). ?HCH and ?DDT were the dominant contaminants detected with concentrations in the range of 26.29-282.5 ng/g and 34.49-262.4 ng/g, respectively. ?DDT concentrations revealed a distinctive gradient, with significantly higher concentrations at Kosi Bay and Lake Sibaya attributed to the application of DDT for malaria control. p,p'-DDE and p,p'-DDD were the dominant isomers detected, but the detection of p,p'-DDT in a number of samples reflects recent inputs of technical DDT. Highest concentrations of HCH, endosulfan and heptachlor were detected in sediments from Mkhuze and reflect the substantial residue load these wetlands receive from agricultural activities within the catchment area. Isomeric compositions indicate that endosulfan and heptachlor residues are derived mainly from historical application, while inputs of HCH, aldrin and endrin could be attributed to more recent usage at several sites. OCP sediment concentrations from iSimangaliso represent the highest yet recorded in South Africa and some of the highest reported globally this century. Sediments found within the lakes and wetlands of iSimangaliso represent large reservoirs of contaminants that pose ecotoxicological threats to this globally important biodiversity hotspot. Detailed investigation into the bioaccumulation and toxicological risks of OCPs within the wetland park is urgently required. PMID- 28728132 TI - Melatonin protect the development of preimplantation mouse embryos from sodium fluoride-induced oxidative injury. AB - Recently study shows that melatonin can protect embryos from the culture environment oxidative stress. However, the protective effect of melatonin on the mouse development of preimplantation embryos under sodium fluoride (NaF) induced oxidative stress is still unclear. Here, we showed that exposure to NaF significantly increased the reactive oxygen species (ROS) level, decreased the blastocyst formation rates, and increased the fragmentation, apoptosis and retardation of blastocysts in the development of mouse preimplantation embryos. However, the protective of melatonin remarkable increased the of blastocyst formation rates, maintained mitochondrial function and total antioxidant capacity by clearing ROS. Importantly the data showed that melatonin improved the activity of enzymatic antioxidants, including glutathione(GSH), superoxide dismutase(SOD), and malonaldehyde (MDA), and increased the expression levels of antioxidative genes. Taken together, our results indicate that melatonin prevent NaF-induced oxidative damage to mouse preimplantation embryo through down regulation of ROS level, stabilization of mitochondrial function and modulation of the activity of antioxidases and antioxidant genes. PMID- 28728133 TI - Zebrafish have an ethanol-inducible hepatic 4-nitrophenol hydroxylase that is not CYP2E1-like. AB - Zebrafish are an attractive model organism for toxicology; however, an important consideration in translating between species is xenobiotic metabolism/bioactivation. CYP2E1 metabolizes small hydrophobic molecules, e.g. ethanol, cigarette smoke, and diesel exhaust components. CYP2E1 is thought to only be conserved in mammals, but recent reports identified homologous zebrafish cytochrome P450s. Herein, ex vivo biochemical measurements show that unlike mammals, zebrafish possess a low-affinity 4-nitrophenol hydroxylase (Km ~0.6 mM) in hepatic microsomes and mitochondria that is inducible only 1.5- to 2-fold by ethanol and is insensitive to 4-methylpyrazole inhibition. In closing, we suggest creating improved models to study CYP2E1 in zebrafish. PMID- 28728134 TI - Serum Vitamin D and Risk of Breast Cancer within Five Years. AB - BACKGROUND: Vitamin D is an environmental and dietary agent with known anticarcinogenic effects, but protection against breast cancer has not been established. OBJECTIVE: We evaluated the association between baseline serum 25 hydroxyvitamin D [25(OH)D] levels, supplemental vitamin D use, and breast cancer incidence over the subsequent 5 y of follow-up. METHODS: From 2003-2009, the Sister Study enrolled 50,884 U.S. women 35-74 y old who had a sister with breast cancer but had never had breast cancer themselves. Using liquid chromatography mass spectrometry, we measured 25(OH)D in serum samples from 1,611 women who later developed breast cancer and from 1,843 randomly selected cohort participants. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for the risk of developing breast cancer using Cox proportional hazards models. RESULTS: We found that 25(OH)D levels were associated with a 21% lower breast cancer hazard (highest versus lowest quartile: adjusted ; CI: 0.63, 0.98). Analysis of the first 5 y of follow-up for all 50,884 Sister Study participants showed that self-reported vitamin D supplementation was associated with an 11% lower hazard [ (CI: 0.81, 0.99)]. These associations were particularly strong among postmenopausal women [ (CI: 0.57, 0.93) and (CI: 0.74, 0.93), respectively]. CONCLUSIONS: In this cohort of women with elevated risk, high serum 25(OH)D levels and regular vitamin D supplement use were associated with lower rates of incident, postmenopausal breast cancer over 5 y of follow-up. These results may help to establish clinical benchmarks for 25(OH)D levels; in addition, they support the hypothesis that vitamin D supplementation is useful in breast cancer prevention. https://doi.org/10.1289/EHP943. PMID- 28728135 TI - Prostate Cancer Risk and DNA Methylation Signatures in Aging Rats following Developmental BPA Exposure: A Dose-Response Analysis. AB - BACKGROUND: Previous studies have uncovered heightened prostatic susceptibility to hormone-induced neoplasia from early-life exposure to low-dose bisphenol A (BPA). However, significant data gaps remain that are essential to address for biological relevance and necessary risk assessment. OBJECTIVES: A complete BPA dose-response analysis of prostate lesions across multiple prostatic lobes was conducted that included internal BPA dosimetry, progression to adenocarcinoma with aging and mechanistic connections to epigenetically reprogramed genes. METHODS: Male neonatal Sprague-Dawley rats were briefly exposed to 0.1 to 5,000 MUg BPA/kg BW on postnatal days (PND) 1, 3, and 5. Individual prostate lobes plus periurethral prostatic ducts were evaluated at 7 mo or 1 y of age without or with adult testosterone plus estradiol (T+E) to promote carcinogenesis. DNA methylation of five genes was quantified by bisulfite genomic sequencing in d-200 dorsal prostates across BPA doses. Serum free-BPA and BPA-glucuronide were quantitated in sera of individual PND 3 pups collected 1 hr postexposure utilizing ultra-high-pressure tandem mass spectrometry (UHPLC-MS-MS). RESULTS: The lowest BPA dose initiated maximal hormonal carcinogenesis in lateral prostates despite undetectable free BPA 1 hr postexposure. Further, prostatic intraepithelial neoplasia (PIN) progressed to carcinoma in rats given neonatal low-dose BPA with adult T+E but not in rats given adult T+E alone. The dorsal and ventral lobes and periurethral prostatic ducts exhibited a nonmonotonic dose response with peak PIN, proliferation and apoptotic values at 10-100 MUg/kg BW. This was paralleled by nonmonotonic and dose-specific DNA hypomethylation of genes that confer carcinogenic risk, with greatest hypomethylation at the lowest BPA doses. CONCLUSIONS: Developmental BPA exposures heighten prostate cancer susceptibility in a complex dose- and lobe-specific manner. Importantly, elevated carcinogenic risk is found at doses that yield undetectable serum free BPA. Dose specific epigenetic modifications of selected genes provide a mechanistic framework that may connect early-life BPA to later-life predisposition to prostate carcinogenesis. https://doi.org/10.1289/EHP1050. PMID- 28728136 TI - Indoor Wood-Burning Stove and Fireplace Use and Breast Cancer in a Prospective Cohort Study. AB - BACKGROUND: Indoor burning of fuel for heating or cooking releases carcinogens. Little is known about the impact of indoor air pollution from wood-burning stoves or fireplaces on breast cancer risk. OBJECTIVES: In a large prospective cohort study, we evaluated the risk of breast cancer in relation to indoor heating and cooking practices. METHODS: Sister Study participants (n=50,884) were recruited from 2003-2009. Breast cancer-free women in the United States or Puerto Rico, 35 74 y old, with a sister with breast cancer were eligible. Participants completed questionnaires on indoor heating and cooking practices for both their enrollment and their longest adult residence. Cox regression was used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (95% CIs) for the association between indoor heating/cooking and breast cancer. RESULTS: A total of 2,416 breast cancer cases were diagnosed during follow-up (mean=6.4 y). Having an indoor wood-burning stove/fireplace in the longest adult residence was associated with a higher breast cancer risk [HR=1.11 (95% CI: 1.01, 1.22)]; the risk increased with average frequency of use [>=once/week, HR=1.17 (95% CI: 1.02, 1.34)] (p for trend=0.01). An elevated HR was seen for women burning wood [HR=1.09 (95% CI: 0.98, 1.21)] or natural gas/propane [HR=1.15 (95% CI: 1.00, 1.32)]. No association was observed for burning artificial fire-logs [HR=0.98 (95% CI: 0.85, 1.12)] except among women from western states [HR=1.36 (95% CI: 1.02, 1.81)]. CONCLUSIONS: In this prospective study, using an indoor wood burning stove/fireplace in the longest adult residence at least once a week and burning either wood or natural gas/propane was associated with a modestly higher risk of breast cancer. https://doi.org/10.1289/EHP827. PMID- 28728137 TI - Rice versus Drinking Water: Estimating the Primary Source of Arsenic in the U.S. Diet. PMID- 28728138 TI - First-Trimester Urinary Bisphenol A Concentration in Relation to Anogenital Distance, an Androgen-Sensitive Measure of Reproductive Development, in Infant Girls. AB - INTRODUCTION: Evidence from animal models suggests that prenatal exposure to bisphenol A (BPA), a ubiquitous endocrine-disrupting chemical, is associated with adverse reproductive outcomes in females. Exposure during early gestation, a critical period for reproductive development, is of particular concern. Anogenital distance (AGD) is a sensitive biomarker of the fetal hormonal milieu and a measure of reproductive toxicity in animal models. In some studies, the daughters of BPA-exposed dams have shorter AGD than controls. Here, we investigate this relationship in humans. METHODS: BPA was assayed in first trimester urine samples from 385 participants who delivered infant girls in a multicenter pregnancy cohort study. After birth, daughters underwent exams that included two measures of AGD (AGD-AC: distance from center of anus to clitoris; AGD-AF: distance from center of anus to fourchette). We fit linear regression models to examine the association between specific gravity-adjusted (SPG-adj) maternal BPA concentrations and infant AGD, adjusting for covariates. RESULTS: BPA was detectable in 94% of women. In covariate-adjusted models fit on 381 eligible subjects, the natural logarithm of SpG-adj maternal BPA concentration was inversely associated with infant AGD-AC [beta=-0.56, 95% confidence interval (CI): -0.97, -0.15]. We observed no association between maternal BPA and infant AGD-AF. CONCLUSION: BPA may have toxic effects on the female reproductive system in humans, as it does in animal models. Higher first-trimester BPA exposure was associated with significantly shorter AGD in daughters, suggesting that BPA may alter the hormonal environment of the female fetus. https://doi.org/10.1289/EHP875. PMID- 28728139 TI - A Longitudinal Analysis of the Influence of the Neighborhood Environment on Recreational Walking within the Neighborhood: Results from RESIDE. AB - BACKGROUND: There is limited longitudinal evidence confirming the role of neighborhood environment attributes in encouraging people to walk more or if active people simply choose to live in activity-friendly neighborhoods. Natural experiments of policy changes to create more walkable communities provide stronger evidence for a causal effect of neighborhood environments on residents' walking. OBJECTIVES: We aimed to investigate longitudinal associations between objective and perceived neighborhood environment measures and neighborhood recreational walking. METHODS: We analyzed longitudinal data collected over 8 yr (four surveys) from the RESIDential Environments (RESIDE) Study (Perth, Australia, 2003-2012). At each time point, participants reported the frequency and total minutes of recreational walking/week within their neighborhood and neighborhood environment perceptions. Objective measures of the neighborhood environment were generated using a Geographic Information System (GIS). RESULTS: Local recreational walking was influenced by objectively measured access to a medium-/large-size park, beach access, and higher street connectivity, which was reduced when adjusted for neighborhood perceptions. In adjusted models, positive perceptions of access to a park and beach, higher street connectivity, neighborhood esthetics, and safety from crime were independent determinants of increased neighborhood recreational walking. Local recreational walking increased by 9 min/wk (12% increase in frequency) for each additional perceived neighborhood attribute present. CONCLUSIONS: Our findings provide urban planners and policy makers with stronger causal evidence of the positive impact of well connected neighborhoods and access to local parks of varying sizes on local residents' recreational walking and health. https://doi.org/10.1289/EHP823. PMID- 28728140 TI - Effects of Inorganic Arsenic, Methylated Arsenicals, and Arsenobetaine on Atherosclerosis in the Mouse Model and the Role of As3mt-Mediated Methylation. AB - BACKGROUND: Arsenic is metabolized through a series of oxidative methylation reactions by arsenic (3) methyltransferase (As3MT) to yield methylated intermediates. Although arsenic exposure is known to increase the risk of atherosclerosis, the contribution of arsenic methylation and As3MT remains undefined. OBJECTIVES: Our objective was to define whether methylated arsenic intermediates were proatherogenic and whether arsenic biotransformation by As3MT was required for arsenic-enhanced atherosclerosis. METHODS: We utilized the apoE /- mouse model to compare atherosclerotic plaque size and composition after inorganic arsenic, methylated arsenical, or arsenobetaine exposure in drinking water. We also generated apoE-/-/As3mt-/- double knockout mice to test whether As3MT-mediated biotransformation was required for the proatherogenic effects of inorganic arsenite. Furthermore, As3MT expression and function were assessed in in vitro cultures of plaque-resident cells. Finally, bone marrow transplantation studies were performed to define the contribution of As3MT-mediated methylation in different cell types to the development of atherosclerosis after inorganic arsenic exposure. RESULTS: We found that methylated arsenicals, but not arsenobetaine, are proatherogenic and that As3MT is required for arsenic to induce reactive oxygen species and promote atherosclerosis. Importantly, As3MT was expressed and functional in multiple plaque-resident cell types, and transplant studies indicated that As3MT is required in extrahepatic tissues to promote atherosclerosis. CONCLUSION: Taken together, our findings indicate that As3MT acts to promote cardiovascular toxicity of arsenic and suggest that human AS3MT SNPs that correlate with enzyme function could predict those most at risk to develop atherosclerosis among the millions that are exposed to arsenic. https://doi.org/10.1289/EHP806. PMID- 28728143 TI - Advances in Cancer Therapy: Liquid Biopsy. PMID- 28728141 TI - Estimates of Soil Ingestion in a Population of Chinese Children. AB - BACKGROUND: China's soil pollution poses serious health risks. However, data regarding the soil ingestion rate (SIR) of the Chinese population, which is critical to assessing associated health risks, are lacking. OBJECTIVES: We estimated soil ingestion of 177 Chinese children from Guangdong, Hubei, and Gansu Provinces. METHODS: We conducted this investigation by employing a tracer mass balance method. We collected a duplicate of all food consumed and all feces and urine excreted on 1 d (n=153) and over 3 consecutive d (n=24), as well as soil samples from play areas and drinking-water samples. We analyzed concentrations of the tracer elements Al, Ba, Ce, Mn, Sc, Ti, V, and Y in these samples using ICP AES and ICP-MS and estimated the SIR for each subject. RESULTS: The estimated SIR data based on each tracer element were characterized by a skewed distribution, as well as higher inter-tracer and inter-subject variation, with several outliers. After removing the outliers, daily SIR median (range) values in milligrams per day were Al, 27.8 (-42.0 to 257.3); Ba, 36.5 (-230.3 to 412.7); Ce, 35.3 (-21.2 to 225.8); Mn, 146.6 (-1259.4 to 1827.7); Sc, 54.8 (-4.5 to 292.0); Ti, 36.7 ( 233.7 to 687.0); V, 92.1 (10.4 to 308.0); and Y, 59.1 (-18.4 to 283.0). Daily SIR median/95th percentile (range) values based on the best tracer method (BTM) were 51.7/216.6 (-9.5 to 297.6) mg/d. CONCLUSIONS: Based on the BTM, recommended SIR values for the general population of Chinese children (2.5 to 12 years old) are 52 mg/d for the central tendency and 217 mg/d for the upper percentile. We did not differentiate between outside soil and indoor dust. Considering the lower concentration of tracer elements in indoor dust than outside soil, actual soil and dust ingestion rates could be higher. https://doi.org/10.1289/EHP930. PMID- 28728142 TI - Strategies to Improve Private-Well Water Quality: A North Carolina Perspective. AB - BACKGROUND: Evidence suggests that the 44.5 million U.S. residents drawing their drinking water from private wells face higher risks of waterborne contaminant exposure than those served by regulated community water supplies. Among U.S. states, North Carolina (N.C.) has the second-largest population relying on private wells, making it a useful microcosm to study challenges to maintaining private-well water quality. OBJECTIVES: This paper summarizes recommendations from a two-day summit to identify options to improve drinking-water quality for N.C. residents served by private wells. METHODS: The Research Triangle Environmental Health Collaborative invited 111 participants with knowledge of private-well water challenges to attend the Summit. Participants worked in small groups that focused on specific aspects and reconvened in plenary sessions to formulate consensus recommendations. DISCUSSION: Summit participants highlighted four main barriers to ensuring safe water for residents currently relying on private wells: (1) a database of private well locations is unavailable; (2) racial disparities have perpetuated reliance on private wells in some urbanized areas; (3) many private-well users lack information or resources to monitor and maintain their wells; and (4) private-well support programs are fragmented and lack sufficient resources. The Summit produced 10 consensus recommendations for ways to overcome these barriers. CONCLUSIONS: The Summit recommendations, if undertaken, could improve the health of North Carolinians facing elevated risks of exposure to waterborne contaminants because of their reliance on inadequately monitored and maintained private wells. Because many of the challenges in N.C. are common nationwide, these recommendations could serve as models for other states. https://doi.org/10.1289/EHP890. PMID- 28728144 TI - Retinal Penetration of Intravitreally Injected Tissue Plasminogen Activator: A Rat Model Study. AB - PURPOSE: To determine whether intravitreal unconjugated tissue plasminogen activator (tPA) (alteplase) can penetrate the intact neural retina and reach the subretinal space in an experimental model. METHODS: This study was performed in 24 Sprague-Dawley rats aged 12 weeks. Under general anesthesia, the right eye was injected with either 0.75 MUg of 3 MUL tPA (14 rats; study group) or saline (10 rats, control group) into the vitreous. Animals were euthanized at 3, 24, and 48 h. The eyes were enucleated, and cryosections were prepared for immunofluorescence staining. Goat anti-tPA antibody was used to detect tPA. RESULTS: In the study group, staining for tPA was detected in the deep retinal layers in all eyes. The staining was deeper and more intense at 3 and 24 h than at 48 h. There was no tPA staining in the retina of eyes injected with saline. CONCLUSIONS: This experimental study shows that unconjugated tPA administered into the vitreous is capable of penetrating the deep retinal layers and the subretinal space. These findings suggest that further clinical research is warranted on the benefits of intravitreal tPA in the treatment of submacular hemorrhage. PMID- 28728145 TI - Extracellular DNA Contributes to Dental Biofilm Stability. AB - Extracellular DNA (eDNA) is a major matrix component of many bacterial biofilms. While the presence of eDNA and its role in biofilm stability have been demonstrated for several laboratory biofilms of oral bacteria, there is no data available on the presence and function of eDNA in in vivo grown dental biofilms. This study aimed to determine whether eDNA was part of the matrix in biofilms grown in situ in the absence of sucrose and whether treatment with DNase dispersed biofilms grown for 2.5, 5, 7.5, 16.5, or 24 h. Three hundred biofilms from 10 study participants were collected and treated with either DNase or heat inactivated DNase for 1 h. The bacterial biovolume was determined with digital image analysis. Staining with TOTO(r)-1 allowed visualization of eDNA both on bacterial cell surfaces and, with a cloud-like appearance, in the intercellular space. DNase treatment strongly reduced the amount of biofilm in very early stages of growth (up to 7.5 h), but the treatment effect decreased with increasing biofilm age. This study proves the involvement of eDNA in dental biofilm formation and its importance for biofilm stability in the earliest stages. Further research is required to uncover the interplay of eDNA and other matrix components and to explore the therapeutic potential of DNase treatment for biofilm control. PMID- 28728146 TI - Chronic Kidney Disease Predicts Survival in Patients with Idiopathic Pulmonary Fibrosis. AB - BACKGROUND: The prevalence of chronic kidney disease (CKD) increases with age as with idiopathic pulmonary fibrosis (IPF). OBJECTIVES: We assessed the prevalence of CKD (stages 3-5) and investigated the relationship of CKD to clinical features and outcomes in patients with IPF. METHODS: This study comprised 123 patients with IPF; 61 subjects with chronic obstructive pulmonary disease (COPD), which was reportedly associated with CKD, were also enrolled as a disease control. CKD (stages 3-5) was defined as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2. RESULTS: Thirty-seven patients (30%) with IPF and 14 controls (23%) with COPD were diagnosed with CKD, and these frequencies were not significantly different. The patients with IPF and CKD were older (p < 0.01) and had a higher frequency of hypertension (p = 0.048) and ischemic heart disease (p = 0.02) than those with IPF but without CKD. Furthermore, the diffusing capacity of the lung for carbon monoxide (DLCO) and the 6-min walking distance in the patients with CKD were significantly lower (40.0 +/- 13.2 vs. 45.9 +/- 14.4%, p = 0.04, and 416 +/- 129 vs. 474 +/- 84 m, p = 0.01, respectively) than in the patients without CKD. The outcome of the patients with CKD showed significantly worse survival compared with the patients without CKD (p = 0.04). Moreover, eGFR remained an independent predictor of survival after adjusting for age and pulmonary function data. CONCLUSION: A substantial percentage of IPF patients have CKD. CKD with a low eGFR was associated with decreased survival in IPF. PMID- 28728147 TI - Efficient Maximum Likelihood Estimation for Pedigree Data with the Sum-Product Algorithm. AB - OBJECTIVE: We analyze data sets consisting of pedigrees with age at onset of colorectal cancer (CRC) as phenotype. The occurrence of familial clusters of CRC suggests the existence of a latent, inheritable risk factor. We aimed to compute the probability of a family possessing this risk factor as well as the hazard rate increase for these risk factor carriers. Due to the inheritability of this risk factor, the estimation necessitates a costly marginalization of the likelihood. METHODS: We propose an improved EM algorithm by applying factor graphs and the sum-product algorithm in the E-step. This reduces the computational complexity from exponential to linear in the number of family members. RESULTS: Our algorithm is as precise as a direct likelihood maximization in a simulation study and a real family study on CRC risk. For 250 simulated families of size 19 and 21, the runtime of our algorithm is faster by a factor of 4 and 29, respectively. On the largest family (23 members) in the real data, our algorithm is 6 times faster. CONCLUSION: We introduce a flexible and runtime efficient tool for statistical inference in biomedical event data with latent variables that opens the door for advanced analyses of pedigree data. PMID- 28728148 TI - The Role of Cytotoxic Chemotherapy in Advanced Pancreatic Neuroendocrine Tumors. AB - BACKGROUND: Pancreatic neuroendocrine tumors (PNETs) are rare neoplasms accounting for less than 5% of all pancreatic malignancies. These tumors are characterized by clinical and prognostical heterogeneity and are predominantly diagnosed in a metastatic stage. Cytotoxic chemotherapy, along with alkylating agents and antimetabolites as well as molecular targeted agents (everolimus, sunitinib), is used in the treatment of advanced PNETs. After the approval of lanreotide for unresectable PNETs, an additional therapeutic option has become available; however, the best sequence of therapies and patient stratification to different treatments remains challenging. Furthermore, no randomized phase-3 trials or head-to-head comparisons are available to support treatment decisions. SUMMARY: The publication of 3 large single-center retrospective studies on streptozocin-(STZ)-based chemotherapy in advanced PNETs in 2015 confirmed the effectiveness of this treatment as described in previously reported trials. All studies investigated markers for progression-free and overall survival and strongly supported the value of the Ki-67 index as a robust prognostic marker. Interestingly, chemotherapy consistently displayed antitumor efficacy in different therapeutic lines. Moreover, a recent study of dacarbazine (DTIC) in a cohort of patients predominantly with PNETs demonstrated that a once monthly infusional DTIC schedule was well tolerated and yielded similar response rates (RR) as STZ-based schedules. Given the overall good tolerability of a monthly infusion and RR similar to STZ schedules, DTIC thus represents a feasible alternative or additional treatment option for PNETs. In this article, we review the current standard and summarize the most recent advances in the field of cytotoxic chemotherapy for PNET patients. Key Messages: (1) Despite the lack of phase3 trials, cytotoxic chemotherapy offers efficacy for patients with advanced PNETs; (2) the best therapeutic option and sequence remain open since comparable randomized studies are lacking; (3) careful patient selection and treatment stratification may increase overall outcome; and (4) currently, no biomarkers for clinical routine exist to predict response to chemotherapy. PMID- 28728149 TI - Higher Rates of Operative Delivery and Maternal and Neonatal Complications in Persistent Occiput Posterior Position with a Large Head Circumference: A Retrospective Cohort Study. AB - INTRODUCTION: We investigated whether large head circumference (HC) combined with persistent occiput posterior (OP) position is associated with higher rates of operative delivery and obstetric and neonatal complications than OP deliveries without large HC or in occiput anterior (OA) position. MATERIALS AND METHODS: Term singleton deliveries in our centers from January 2010 to December 2014, delivered in cephalic OA (n = 41,038) or OP position (n = 1,740), were assessed. We compared delivery modes, maternal and neonatal complications in OA versus OP deliveries, and HC >=90th centile versus HC <90th centile in persistent OP position. RESULTS: Persistent OP position combined with HC >=90th centile was associated with higher rates of vacuum extraction and unplanned cesarean delivery than HC <90th centile in OP position (20.1 vs. 17.2%, OR 1.53 [95% CI 0.99-2.36], and 23.4 vs. 9.2%, OR 3.326 [95% CI 2.17-5.11], respectively). Rates of prolonged second stage of labor and neonatal intensive care unit admission were also increased compared to those in either OA position with HC >=90th centile or OP position with HC <90th centile. DISCUSSION: Large HC combined with OP position is associated with higher rates of operative delivery and prolonged second stage of labor compared to OP delivery with HC <90th centile. HC might be included with other measures to assess women in labor, as it is associated with fetal outcomes in OP deliveries. PMID- 28728150 TI - Fisher Discrimination of Metabolic Changes in Rats Treated with Aspirin and Ibuprofen. AB - BACKGROUND: Aspirin and ibuprofen are the most frequently prescribed non steroidal anti-inflammatory drugs in the world. However, both are associated with a variety of toxicities. We applied serum metabonomics and Fisher discrimination for the early diagnosis of its toxic reaction in order to help diagnose these toxicities. METHODS: A total of 45 rats were randomly divided into Control group, Aspirin group, and Ibuprofen groups. The experiment groups were given intragastric aspirin (15 mg/kg) or ibuprofen (15 mg/kg) for 3 weeks. Liver function tests were performed and blood metabonomics were analyzed by gas chromatography-mass spectrometry. RESULTS: The most important compounds altered were trihydroxybutyric acid and l-alanine in the aspirin group, and acetoacetic acid, l-alanine, and trihydroxybutyric acid in the ibuprofen group. With respect to metabolic profiles, all 3 groups were completely distinct from one another. Fisher discrimination showed that 91.1% of the original grouped cases were correctly classified by the third week. However, only 55.6% of liver function tests were able to classify grouped cases correctly. CONCLUSION: Trihydroxybutyric acid, l-alanine, and acetoacetic acid were the most significant indicators of altered serum metabolites following intragastric administration of aspirin and ibuprofen in rates. These metabolomic data may be used for classification of aspirin and ibuprofen toxicity. PMID- 28728152 TI - Use of the Putamen as a Surrogate Anatomical Marker for the Internal Segment of the Globus Pallidus in Deep Brain Stimulation Surgery. AB - OBJECTIVE: The success of deep brain stimulation (DBS) of the internal segment of the globus pallidus (GPi) depends on accurately placing the electrode into the GPi motor territory. Direct targeting can be difficult as GPi laminar borders are not always clearly identifiable on MRI. Here, we report a method for using the putamen (PUT) as a surrogate anatomical marker to target the GPi. METHODS: We developed a PUT-based GPi targeting using the FGATIR (fast gray matter acquisition T1-weighted inversion recovery) MRI sequence and compared it with consensus coordinate-based indirect targeting. Stereotactic target coordinates were obtained and analyzed. RESULTS: In our GPi DBS case sequences, GPi borders were unresolvable on T2-weighted MRI. However, in all cases, application of the PUT-based method resulted in consistently localized GPi targets, which were confirmed by merging the T2-weighted MRI with the FGATIR MRI. Significant differences were noted in the target coordinates between the PUT-based method and indirect targeting based on both the distance from the anterior commissure and the distance from the intercommissural plane. The mean differences for mediolateral distance and anteroposterior distance were 1.4 and 1.42 mm, respectively. In addition, the PUT-based method estimated a target that was closer to the nearest implanted electrode. CONCLUSION: Our PUT-based method allows consistent and precise patient-specific GPi targeting. Further study is planned to correlate PUT-based GPi targeting with microelectrode recording, location of active contact of the DBS electrode and clinical outcome. PMID- 28728153 TI - Genetic Variants of Cytochrome CYP2D6 in Two Mixed Chilean Populations. AB - OBJECTIVES: It is known that the interindividual and interethnic variability of the genetic polymorphisms of CYP2D6 plays an important role in the presentation of adverse drug reactions and concerning lack of therapeutic effects in humans. However, there are few data available from mixed populations of Latin America, including the Chilean. The aim of this study was therefore to estimate the frequencies of CYP2D6 variants in two samples of hospitals from the northern (Hospital San Jose, HSJ) and eastern (Clinica Las Condes, CLC) parts of Santiago, Chile, with different degrees of Amerindian admixture (HSJ: 34.5%; CLC: 15.9%). METHODS: We used polymerase chain reaction followed by restriction endonuclease digestion (PCR-RFLP) to genotype 7 CYP2D6 alleles in 250 healthy unrelated individuals of Chilean Mestizo background. The detection of allele CYP2D6*5 and the duplication of this gene was performed by long-PCR. RESULTS: The degrees of Amerindian admixture are reflected in the observed frequencies of the CYP2D6*1 (HSJ: 58.26%; CLC: 41.06%), CYP2D6*2 (HSJ: 28.10%; CLC: 40.65%), and CYP2D6*4 (HSJ: 8.26%; CLC: 12.60%) alleles; the frequencies of CYP2D6*1 (p = 0.0002) and CYP2D6*2 (p = 0.0036) are significantly different between the samples. Four individuals (CLC: 0.41%; HSJ: 1.24%) could not be assigned to a genotype. We identified 3.25% of the genotypes which predict a poor metabolizer phenotype in CLC and 1.65% in HSJ. CONCLUSION: Our data indicate ethnic group-dependent genetic differences in the vulnerability to treatment with the large variety of drugs metabolized by the enzyme CYP2D6. PMID- 28728151 TI - A Modified Classification of Prognostic Factors Based on Pathological Stage and Tumor Regression Grade in Patients with Rectal Cancer Who Receive Preoperative Chemoradiotherapy. AB - OBJECTIVE: The histologic response to neoadjuvant chemoradiotherapy (CRT) has been intimately related to outcomes in locally advanced rectal cancer. However, reliable prognostic factors have yet to be established. SUBJECTS AND METHODS: The study group comprised 198 patients with locally advanced rectal cancer who received CRT. A modified classification based on the combination of ypStage and tumor regression grade (TRG) was developed. ypStage II with TRG 2 was classified as ypTRGstage IIA, and ypStage II with TRG 3 or 4 was classified as ypTRGstage IIB. ypStage 0 and ypStage I were classified as ypTRGstage I, and ypStage III was classified as ypTRGstage III. RESULTS: The 5-year disease-free survival (DFS) was 83% in ypTRGstage I, 86% in ypTRGstage IIA, 57% in ypTRGstage IIB, and 60% in ypTRGstage III (p = 0.0001). The 5-year DFS in ypTRGstage IIA did not differ significantly from that in ypStage 0 (p = 0.865) or ypStage I (p = 0.585). The 5 year DFS in ypStage IIB did not differ from that in ypStage III (p = 0.912). Multivariate analysis showed that ypTRGstage was an independent risk factor for DFS. CONCLUSION: A modified classification allows patients with ypStage II locally advanced rectal cancer to be clearly divided into two groups: responders and nonresponders. PMID- 28728154 TI - Prevalence of Primary Headache Disorders in Kuwait. AB - BACKGROUND: Only an insignificant quantum of data exists on the prevalence of primary headaches among those living in Kuwait. We aimed to determine the prevalence of primary headaches among the Kuwaiti population. METHODS: This community-based study included Kuwaiti population aged 18-65 years. Using systematic random sampling, data was collected by the Headache-Attributed Restriction, Disability, Social Handicap and Impaired Participation questionnaire. Responses to the diagnostic questions were transformed into diagnoses algorithmically to confirm the diagnosis of primary headache. RESULTS: A total of 15,523 patients were identified of whom 9,527 (61%) were diagnosed with primary headache disorder; a female predominance of 62.2% was observed. The mean age was 34.84 +/- 10.19. Tension-type headache (TTH) was the most prevalent at 29% followed by episodic migraine (23.11%), chronic migraine (5.4%), and medication overuse headache (2.4%). Primary headache prevalence declined steadily from 71% in those aged 18-30 years to 23% in those over 50 (p < 0. 037). The female:male ratio was 1.7:1. Frequency and severity of primary headache were correlated significantly with lost work days (r = 0.611, p < 0.001 and r = 0.102, p = 0.001, respectively). CONCLUSIONS: In Kuwait, primary headache disorder is more frequent in young adults and females. TTH followed by episodic migraine were the more prevalent types of headache. Higher frequency and severe headaches were associated with increasing social and work-related burden. PMID- 28728155 TI - Morphological and Functional Imaging for Detecting and Assessing the Resectability of Neuroendocrine Liver Metastases. AB - This review evaluates the diagnostic efficacy of different morphological and functional imaging modalities (ultrasound [US], computed tomography [CT], magnetic resonance [MR] imaging, scintigraphy, and positron emission tomography [PET]) in detecting neuroendocrine liver metastases (NELM), assessing vascular and biliary involvement, and the presence of extrahepatic disease. MR imaging is superior for depicting NELM compared to US, CT, and somatostatin receptor scintigraphy. Diffusion-weighted MR imaging is more sensitive for detecting NELM than both T2-weighted and dynamic gadolinium-enhanced MR sequences, and should be systematically performed. Similarly, gadoxetic acid-enhanced MR imaging is more sensitive for detecting liver metastases than conventional extracellular gadolinium chelate-enhanced MR sequences. Its role in detecting NELM remains investigational but appears promising. Somatostatin receptor-targeted PET/CT is a highly effective approach in assessing the resectability of well-differentiated NELM due to very high specificity (and high sensitivity) and its ability to detect small volume extrahepatic disease; this molecular imaging modality is becoming increasingly available in and outside Europe after the recent approval of 6868-DOTATATE in the US. In addition, the information from multiphase, contrast-enhanced CT with 3D reconstruction - obtained concurrently with the information on somatostatin receptor expression of the metastases - is very helpful in planning the extent and type of resection of NELM. PMID- 28728157 TI - 3-D Volume Assessment of the Corpus Callosum and Cerebellar Vermis Using Various Volume Acquisition and Post-Processing Protocols. AB - OBJECTIVES: To determine which 3-D techniques are most effective for "real time" prenatal ultrasound assessment of the corpus callosum and cerebellar vermis. METHODS: A prospective study involving 100 consecutive normal singleton pregnancies attending routine anomaly scan at 19-23 weeks' gestation. Midsagittal structures of the fetal brain were assessed using six different methods of 3-D image acquisition and three post-processing techniques. The quality of the resulting images were then assessed and scored by a second operator. The significance of the difference between various techniques was assessed using the Friedman test. RESULTS: The best method for visualization of both corpus callosum and cerebellar vermis in one image involved 3-D acquisition in a sagittal plane through the sagittal suture with manipulated 3-D OVIXTM (Oblique View eXtended Imaging) reconstruction. Five other methods scored closely and were not significantly different; all were based on 3-D acquisition in the sagittal plane through either sagittal suture or anterior fontanel. CONCLUSIONS: We have applied described techniques for 3-D central nervous system volume acquisition and have shown that the best method of assessment, allowing assessment of both the corpus callosum and the cerebellar vermis, involves midsagittal acquisition through the sagittal suture with 3-D OVIX reconstruction. This technique can be applied successfully in 83% of cases. PMID- 28728158 TI - Liquid Biopsy: Value for Melanoma Therapy. PMID- 28728156 TI - Predicting the Risk to Develop Preeclampsia in the First Trimester Combining Promoter Variant -98A/C of LGALS13 (Placental Protein 13), Black Ethnicity, Previous Preeclampsia, Obesity, and Maternal Age. AB - BACKGROUND: LGALS13 (placental protein 13 [PP13]) promoter DNA polymorphisms was evaluated in predicting preeclampsia (PE), given PP13's effects on hypotension, angiogenesis, and immune tolerance. METHODS: First-trimester plasma samples (49 term and 18 intermediate) of PE cases matched with 196 controls were collected from King's College Hospital, London, repository. Cell-free DNA was extracted and the LGALS13 exons were sequenced after PCR amplification. Expression of LGALS13 promoter reporter constructs was determined in BeWo trophoblast-like cells with luciferase assays. Adjusted odds ratio (OR) was calculated for the A/A genotype combined with maternal risk factors. RESULTS: The A/A, A/C, and C/C genotypes in the -98 promoter position were in Hardy-Weinberg equilibrium in the control but not in the PE group (p < 0.036). The dominant A/A genotype had higher frequency in the PE group (p < 0.001). The A/C and C/C genotypes protected from PE (p < 0.032). The ORs to develop term and all PE, calculated for the A/A genotype, previous PE, body mass index (BMI) >35, black ethnicity, and maternal age >40 were 15.6 and 11.0, respectively (p < 0.001). In luciferase assays, the "-98A" promoter variant had lower expression than the "-98C" variant in non differentiated (-13%, p = 0.04) and differentiated (-26%, p < 0.001) BeWo cells. Forskolin-induced differentiation led to a larger expression increase in the " 98C" variant than in the "-98A" variant (4.55-fold vs. 3.85-fold, p < 0.001). CONCLUSION: Lower LGALS13 (PP13) expression with the "A" nucleotide in the -98 promoter region position (compared to "C") and high OR calculated for the A/A genotype in the -98A/C promoter region position, history of previous PE, BMI >35, advanced maternal age >40, and black ethnicity could serve to aid in PE prediction in the first trimester. PMID- 28728159 TI - Oxamate Enhances the Anti-Inflammatory and Insulin-Sensitizing Effects of Metformin in Diabetic Mice. AB - Metformin (MET) is the first-line drug for treating type 2 diabetes mellitus (T2DM). However, MET increases blood lactate levels in patients with T2DM. Lactate possesses proinflammatory properties and causes insulin resistance (IR). Oxamate (OXA), a lactate dehydrogenase inhibitor, can decrease tissue lactate production and blood lactate levels. This study was conducted to examine the effects of the combination of OXA and MET on inflammation, and IR in diabetic db/db mice. Supplementation of OXA to MET led to lowered tissue lactate production and serum lactate levels compared to MET alone, accompanied with further decreased tissue and blood levels of pro-inflammatory cytokines, along with better insulin sensitivity, beta-cell mass, and glycemic control in diabetic db/db mice. These results show that OXA enhances the anti-inflammatory and insulin-sensitizing effects of MET through the inhibition of tissue lactate production in db/db mice. PMID- 28728160 TI - Structural Changes of the Macula on Optical Coherence Tomography after Vitrectomy for Proliferative Diabetic Retinopathy. AB - PURPOSE: This study aimed to evaluate the relationship between macular structural changes and visual prognosis after pars plana vitrectomy (PPV) for proliferative diabetic retinopathy. METHODS: The study included 60 eyes that had undergone PPV. Macular optical coherence tomography (OCT) findings were classified into 5 groups preoperatively and 10 groups postoperatively. Best-corrected visual acuity (BCVA) were analyzed according to pre- and postoperative OCT. RESULTS: From the preoperative OCT, normal fovea with/without traction, normal fovea with preretinal hemorrhage, and tractional retinal detachment involving fovea showed an increase in BCVA after PPV (all p < 0.05). Normal fovea, epiretinal membrane and macular thickening were common after surgery. Normal fovea, epiretinal membrane and edema outside of the fovea showed good visual prognosis (BCVA >20/50). Subfoveal fibrosis, macular hole, loss of foveal depression, and serous foveal detachment showed poor visual prognosis (BCVA <20/100). CONCLUSION: Macular structural changes were various after PPV, and visual prognosis correlated with these changes. PMID- 28728161 TI - Quality of Life and Caregivers' Burden of Parkinson's Disease. AB - AIM: This study focused on the impact of the clinical features on the quality of life (QoL) of Parkinson's disease (PD) patients and of their caregivers. METHODS: This study included PD patients along with their caregivers and was undertaken at the Malaysian Parkinson's Disease Association from June 2016 to November 2016. Clinical features of PD patients were assessed using the Movement Disorder Society revised Unified Parkinson Disease Rating Scale; the Hoehn and Yahr stage and the Schwab and England Activities of Daily Living Scale were used to assess the severity and the ability of PD patients respectively. QoL of PD patients was measured using the Parkinson's Disease Questionnaire-39 (PDQ-39). The revised version of the Zarit Burden Interview assessed caregiver burden. RESULTS: At least one of the clinical features affected PD patients' QoL, and at least one of the QoL domains affected the caregivers' burden. Clinical features "saliva and drooling" and "dyskinesia" explained 29% of variance in QoL of PD patients. The QoL domains "stigma," along with "emotional well-being" explained 48.6% of variance in caregivers' burden. CONCLUSIONS: The clinical features "saliva and drooling" and "dyskinesia" impacted the QoL of PD patients, and the QoL domains "stigma" and "emotional well-being" of PD patients impacted their caregivers' burden. PMID- 28728162 TI - Realistic Lenalidomide Dose Adjustment Strategy for Transplant-Ineligible Elderly Patients with Relapsed/Refractory Multiple Myeloma: Japanese Real-World Experience. AB - Lenalidomide is an immunomodulatory drug administered orally in the treatment of multiple myeloma. Some elderly patients require a reduced lenalidomide dose because of comorbidities and/or adverse events. This study investigated the actual dose of lenalidomide in elderly patients, finding that most received reduced (5-10 mg) doses. The most common reasons for dose reduction were renal dysfunction (54% of patients), fatigue (grade >=3; 20%), hematologic disorder (grade >=3; 14%), and rash (grade >=3; 9%). Their median time to progression was 11.8 months and their median overall survival was 39.2 months. The overall response rate was 73%, including 17% with a complete response, 19% with a very good partial response, and 37% with a partial response. These results showed that, contrary to western countries, most patients were treated with a reduced dose of lenalidomide in Japan. However, it is suggested that continued treatment with a tolerable dose may yield favorable outcomes. PMID- 28728163 TI - Nuclear expression of Gli-1 is predictive of pathologic complete response to chemoradiation in trimodality treated oesophageal cancer patients. AB - BACKGROUND: Predictive biomarkers or signature(s) for oesophageal cancer (OC) patients undergoing preoperative therapy could help administration of effective therapy, avoidance of ineffective ones, and establishment new strategies. Since the hedgehog pathway is often upregulated in OC, we examined its transcriptional factor, Gli-1, which confers therapy resistance, we wanted to assess Gli-1 as a predictive biomarker for chemoradiation response and validate it. METHODS: Untreated OC tissues from patients who underwent chemoradiation and surgery were assessed for nuclear Gli-1 by immunohistochemistry and labelling indices (LIs) were correlated with pathologic complete response (pathCR) or 5% of MGUS patients there is a second MGUS clone (biclonal gammopathy of undetermined significance; BGUS), yet, at myeloma diagnosis, presentation of biclonal gammopathy myeloma (BGMy) is considered less frequent, implying that myeloma eradicates coexisting MGUS. METHODS: In the largest study of its kind, we assessed BGMy frequency amongst 6399 newly diagnosed myeloma patients enrolled in recent UK clinical trials. RESULTS: Compared to expected prevalence (i.e., >5% of MGUS have BGUS), only 58 of 6399 (0.91%) newly diagnosed myeloma patients had BGMy, indicating myeloma typically eliminates coexistent MGUS. In these 58 BGMy cases, the MGUS plasma cell clone was greatly suppressed in size compared to typical levels observed in conventional MGUS; contrarily, the MGUS clone did not inhibit the myeloma plasma cell clone in BGMy. CONCLUSION: Myeloma eliminates the majority of competing MGUS, and when it does not, the MGUS clone is substantially reduced in size. PMID- 28728166 TI - Whole-genome sequencing revealed novel prognostic biomarkers and promising targets for therapy of ovarian clear cell carcinoma. AB - BACKGROUND: Ovarian clear cell carcinoma (OCCC) is mostly resistant to standard chemotherapy that results in poor patient survival. To understand the genetic background of these tumours, we performed whole-genome sequencing of OCCC tumours. METHODS: Tumour tissue samples and matched blood samples were obtained from 55 Japanese women diagnosed with OCCC. Whole-genome sequencing was performed using the Illumina HiSeq platform according to standard protocols. RESULTS: Alterations to the switch/sucrose non-fermentable (SWI/SNF) subunit, the phosphatidylinositol-3-kinase (PI3K)/Akt signalling pathway, and the receptor tyrosine kinase (RTK)/Ras signalling pathway were found in 51%, 42%, and 29% of OCCC tumours, respectively. The 3-year overall survival (OS) rate for patients with an activated PI3K/Akt signalling pathway was significantly higher than that for those with inactive pathway (91 vs 40%, hazard ratio 0.24 (95% confidence interval (CI) 0.10-0.56), P=0.0010). Similarly, the OS was significantly higher in patients with the activated RTK/Ras signalling pathway than in those with the inactive pathway (91 vs 53%, hazard ratio 0.35 (95% CI 0.13-0.94), P=0.0373). Multivariable analysis revealed that activation of the PI3K/Akt and RTK/Ras signalling pathways was an independent prognostic factor for patients with OCCC. CONCLUSIONS: The PI3K/Akt and RTK/Ras signalling pathways may be potential prognostic biomarkers for OCCC patients. Furthermore, our whole-genome sequencing data highlight important pathways for molecular and biological characterisations and potential therapeutic targeting in OCCC. PMID- 28728167 TI - Long-term outcomes of patients with 10 or more colorectal liver metastases. AB - BACKGROUND: Although the number of colorectal liver metastases (CLM) is decreasingly considered as a contraindication to surgery, patients with 10 CLM or more are often denied liver surgery. This study aimed to evaluate the outcome after liver surgery and to identify prognostic factors of survival in such patients. METHODS: The study population consisted of a multicentre cohort of patients with CLM (N=12 406) operated on, with intention to resect, from January 2005-June 2013 and whose data were prospectively collected in the LiverMetSurvey registry. RESULTS: Overall, the group ?10 CLM (N=529, 4.3%) experienced a 5-year overall survival (OS) of 30%. A macroscopically complete (R0/R1) resection (72.8% of patients) was associated with a 3- and 5-year OS of 61% and 39% vs 29% and 5% for R2/no resection patients (P<0.0001). At multivariate analysis, R0/R1 resection emerged as the strongest favourable factor of OS (HR 0.35 (0.26-0.48)). Other independent favourable factors were as follows: maximal tumour size <40 mm (HR 0.67 (0.49-0.92)); age <60 years (HR 0.66 (0.50-0.88)); preoperative MRI (HR 0.65 (0.47-0.89)); and adjuvant chemotherapy (HR 0.73 (0.55-0.98)). The model showed that 5-year OS rates of 30% was possible provided R0/R1 resection associated with at least an additional favourable factor. CONCLUSIONS: Liver resection might provide long-term survival in patients with ?10 CLM staged with preoperative MRI, provided R0/R1 resection followed by adjuvant therapy. A validation of these results in another cohort is needed. PMID- 28728168 TI - Lung cancer prognostic index: a risk score to predict overall survival after the diagnosis of non-small-cell lung cancer. AB - INTRODUCTION: Non-small-cell lung cancer outcomes are poor but heterogeneous, even within stage groups. To improve prognostic precision we aimed to develop and validate a simple prognostic model using patient and disease variables. METHODS: Prospective registry and study data were analysed using Cox proportional hazards regression to derive a prognostic model (hospital 1, n=695), which was subsequently tested (Harrell's c-statistic for discrimination and Cox-Snell residuals for calibration) in two independent validation cohorts (hospital 2, n=479 and hospital 3, n=284). RESULTS: The derived Lung Cancer Prognostic Index (LCPI) included stage, histology, mutation status, performance status, weight loss, smoking history, respiratory comorbidity, sex, and age. Two-year overall survival rates according to LCPI in the derivation and two validation cohorts, respectively, were 84, 77, and 68% (LCPI 1: score?9); 61, 61, and 42% (LCPI 2: score 10-13); 33, 32, and 14% (LCPI 3: score 14-16); 7, 16, and 5% (LCPI 4: score ?15). Discrimination (c-statistic) was 0.74 for the derivation cohort, 0.72 and 0.71 for the two validation cohorts. CONCLUSIONS: The LCPI contributes additional prognostic information, which may be used to counsel patients, guide trial eligibility or design, or standardise mortality risk for epidemiological analyses. PMID- 28728170 TI - A Normative Data Set for the Clinical Assessment of Achromatic and Chromatic Contrast Sensitivity Using a qCSF Approach. AB - Purpose: The measurement of achromatic sensitivity has been an important tool for monitoring subtle changes in vision as the result of disease or response to therapy. In this study, we aimed to provide a normative data set for achromatic and chromatic contrast sensitivity functions within a common cone contrast space using an abbreviated measurement approach suitable for clinical practice. In addition, we aimed to provide comparisons of achromatic and chromatic binocular summation across spatial frequency. Methods: We estimated monocular cone contrast sensitivity functions (CCSFs) using a quick Contrast Sensitivity Function (qCSF) approach for achromatic as well as isoluminant, L/M cone opponent, and S cone opponent stimuli in a healthy population of 51 subjects. We determined the binocular CCSFs for achromatic and chromatic vision to evaluate the degree of binocular summation across spatial frequency for these three different mechanisms in a subset of 20 subjects. Results: Each data set shows consistent contrast sensitivity across the population. They highlight the extremely high cone contrast sensitivity of L/M cone opponency compared with the S-cone and achromatic responses. We also find that the two chromatic sensitivities are correlated across the healthy population. In addition, binocular summation for all mechanisms depends strongly on stimulus spatial frequency. Conclusions: This study, using an approach well suited to the clinic, is the first to provide a comparative normative data set for the chromatic and achromatic contrast sensitivity functions, yielding quantitative comparisons of achromatic, L/M cone opponent, and S cone opponent chromatic sensitivities as a function of spatial frequency. PMID- 28728169 TI - Correlations Between Macular, Skin, and Serum Carotenoids. AB - Purpose: Ocular and systemic measurement and imaging of the macular carotenoids lutein and zeaxanthin have been employed extensively as potential biomarkers of AMD risk. In this study, we systematically compare dual wavelength retinal autofluorescence imaging (AFI) of macular pigment with skin resonance Raman spectroscopy (RRS) and serum carotenoid levels in a clinic-based population. Methods: Eighty-eight patients were recruited from retina and general ophthalmology practices from a tertiary referral center and excluded only if they did not have all three modalities tested, had a diagnosis of macular telangiectasia (MacTel) or Stargardt disease, or had poor AFI image quality. Skin, macular, and serum carotenoid levels were measured by RRS, AFI, and HPLC, respectively. Results: Skin RRS measurements and serum zeaxanthin concentrations correlated most strongly with AFI macular pigment volume under the curve (MPVUC) measurements up to 9 degrees eccentricity relative to MPVUC or rotationally averaged macular pigment optical density (MPOD) measurements at smaller eccentricities. These measurements were reproducible and not significantly affected by cataracts. We also found that these techniques could readily identify subjects taking oral carotenoid-containing supplements. Conclusions: Larger macular pigment volume AFI and skin RRS measurements are noninvasive, objective, and reliable methods to assess ocular and systemic carotenoid levels. They are an attractive alternative to psychophysical and optical methods that measure MPOD at a limited number of eccentricities. Consequently, skin RRS and MPVUC at 9 degrees are both reasonable biomarkers of macular carotenoid status that could be readily adapted to research and clinical settings. PMID- 28728171 TI - Optical Coherence Tomography Angiography of the Superficial Microvasculature in the Macular and Peripapillary Areas in Glaucomatous and Healthy Eyes. AB - Purpose: To quantitatively evaluate the superficial microvasculature in the macular and peripapillary areas in glaucomatous and healthy eyes using optical coherence tomography angiography (OCT-A). Methods: We enrolled 26 eyes of medically managed primary open-angle glaucoma patients and 27 eyes of healthy subjects were enrolled in this prospective study. Measurements of OCT-A vessel density were acquired both in the macular and peripapillary areas. We compared vessel density values, the circumpapillary retinal nerve fiber layer (cpRNFL), the ganglion cell complex (GCC), and standard automated perimetry (SAP) parameters across study groups. Areas under the receiver operating characteristic (AUROC) curves were used to evaluate diagnostic accuracy. Quadratic regression models were used to determine the correlations between SAP severity and outcome measures. Results: The whole image vessel density (wiVD) in glaucomatous eyes was lower than that in healthy eyes in the macular (38.5% +/- 2.2% vs. 43.2% +/- 2.3%, P < 0.001) and peripapillary areas (43.8% +/- 5.7% vs. 53.3% +/- 3.0%, P < 0.001). The circumpapillary vessel density (cpVD) was also lower in glaucomatous eyes (53.3% +/- 7.0% vs. 61.5% +/- 3.2%, P < 0.001). We found the AUROCs for discriminating between glaucomatous and healthy eyes were highest for cpRNFL (0.95) and GCC (0.95); followed by macular wiVD (0.94); peripapillary wiVD (0.93); and cpVD (0.89). The correlations between SAP severity were strongest with peripapillary wiVD (R2 = 0.58); followed by cpVD (R2 = 0.55); GCC (R2 = 0.51); cpRNFL (R2 = 0.42); and macular wiVD (R2 = 0.36). Conclusions: Medically managed glaucomatous eyes show sparser superficial microvasculature in the macular area than do healthy eyes. The measurement of the macular superficial vessel density had similar diagnostic accuracy to peripapillary RNFL and macular GCC thickness for differentiating between glaucomatous and healthy eyes. PMID- 28728172 TI - Blur Adaptation to Central Retinal Disease. AB - Purpose: The long-term, low-resolution vision experienced by individuals affected by retinal disease that causes central vision loss (CVL) may change their perception of blur through adaptation. This study used a short-term adaptation paradigm to evaluate adaptation to blur and sharpness in patients with CVL. Methods: A variation of Webster's procedure was used to measure the point of subjective neutrality (PSN). The image that appeared normal after adaptation to each of seven blur and sharpness levels (PSN) was measured in 12 patients with CVL (20/60 to 20/320) and 5 subjects with normal sight (NS). Patients with CVL used a preferred retinal locus to view the images. Small control studies investigated the effects of long-term and medium-term (1 hour) defocus and diffusive blur. Results: Adaptation was reliably measured in patients with CVL and in the peripheral vision of NS subjects. The shape of adaptation curves was similar in patients with CVL and both central and peripheral vision of NS subjects. No statistical correlations were found between adaptation and age, visual acuity, retinal eccentricity, or contrast sensitivity. Long-term blur experience by a non-CVL myopic participant caused a shift in the adaptation function. Conversely, medium-term adaptation did not cause a shift in the adaptation function. Conclusions: Blur and sharp short-term adaptation occurred in peripheral vision of normal and diseased retinas. In most patients with CVL, neither adaptation nor blur perception was affected by long-term attention to peripheral low-resolution vision. The impact of blur/sharp adaptation on the benefit of image enhancement techniques for patients with CVL is discussed. PMID- 28728173 TI - Glucocorticoid-Induced Leucine Zipper Protects the Retina From Light-Induced Retinal Degeneration by Inducing Bcl-xL in Rats. AB - Purpose: The aim of the present study was to investigate the neuroprotective effects of glucocorticoid-induced leucine zipper (GILZ) in a light-induced retinal degeneration model and to explore the underlying mechanisms. Methods: Intravitreal injection of recombinant GILZ-overexpressing lentivirus (OE-GILZ rLV) and short hairpin RNA targeting GILZ recombinant lentivirus (shRNA-GILZ-rLV) was performed to up- and downregulate retinal GILZ, respectively. Three days after stable transduction, rats were exposed to continuous bright light (5000 lux) for 2 days. Retinal function was assessed by full-field electroretinography (ERG), and the retinal structure was examined for photoreceptor survival and death in rats kept under a 12-hour light:2-hour dark cycle following light exposure. The expression levels of retinal Bcl-xL, caspase-9, and caspase-3 were examined by Western blotting or real-time PCR at 1, 3, 5, and 7 days after light exposure. Results: Exposure to bright light downregulated retinal GILZ in parallel with the downregulation of Bcl-xL and the upregulation of active caspase 3. Overexpression of retinal GILZ attenuated the decrease of Bcl-xL and the activation of caspase-9 and caspase-3 at 1, 3, 5, and 7 days after bright light exposure, respectively. GILZ silencing aggravated the downregulation of Bcl-xL induced by bright light exposure. Bright light exposure reduced the amplitude of ERG, increased the number of apoptotic photoreceptor cells, and decreased retinal thickness; and GILZ overexpression could attenuate all these effects. Conclusions: Overexpression of GILZ by OE-GILZ-rLV transduction protected the retina from light-induced cellular damage by activating antiapoptotic pathways. PMID- 28728175 TI - Alternative Routes to Perfuse the Optic Nerve Head. PMID- 28728174 TI - A Global View on Output and Outcomes of Cataract Surgery With National Indices of Socioeconomic Development. AB - Purpose: Cataract blindness accounts for a substantial proportion of blindness worldwide. Understanding the correlations between national levels of socioeconomic development with the quantity and quality of cataract surgery may provide insight for the prioritization and resource allocation for blindness prevention programs. Methods: The relationships between human development index (HDI), gross domestic product (GDP) per capita, and cataract surgical coverage (CSC) and visual outcome of cataract surgery were examined in a multinational study utilizing secondary data from the repository for Rapid Assessment of Avoidable Blindness (RAAB), World Health Organization, Global Burden of Disease, United Nations, and the World Bank. Results: A total of 266 RAAB studies across 73 countries/territories were retrieved. Linear regression model results revealed strong associations of HDI with prevalence of cataract blindness (beta = -7.056, P < 0.001), CSC (beta = 60.808, P = 0.004), proportion of intraocular lens (IOL) implantation (beta = 87.040, P = 0.001), and proportion of cases with good vision outcomes among operated eyes (beta = 73.351, P < 0.001) in studies performed between 1995 and 2009. Similar associations were observed for studies performed between 2010 and 2015. In addition, countries with lower GDP per capita showed a higher rate of cataract blindness (beta = -0.527, P = 0.001), lower CSC (beta = 9.800, P < 0.001), lower percentage of IOL implantation (beta = 6.871, P = 0.001), and fewer patients with good vision outcomes after surgery (beta = 7.959, P < 0.001). After controlling survey year, country, and other factors, GDP per capita and HDI were also found to be significantly associated with CSC and visual outcomes after cataract surgery (all P < 0.05). Conclusions: We documented the strong associations of socioeconomic indices with quantity and quality of cataract surgery. These socioeconomic indicators should be considered as important factors for developing strategies aimed to improve worldwide cataract surgery service delivery. PMID- 28728176 TI - The Epidemiology of Retinopathy of Prematurity in the United States. AB - BACKGROUND AND OBJECTIVE: Retinopathy of prematurity (ROP) is a leading cause of blindness in premature and low birth weight infants. Here, the authors examine the incidence of ROP in the United States and evaluate risk factors associated with ROP development. PATIENTS AND METHODS: The National Healthcare Cost and Utilization Project Kids' Inpatient Database was queried for all newborns with and without ROP. Adjusted odds ratios were constructed for predictors of ROP using multivariate logistic regression modeling. RESULTS: The incidence of ROP increased from 14.70% in 2000 to 19.88% in 2012. Multivariate regression analysis indicated that female gender, birth weight, and gestational age predicted ROP. The frequency of ROP was 2.40% in newborns weighing more than 2,500 grams (g) and 30.22% in newborns with a birth weight between 750 g and 999 g. CONCLUSIONS: The authors' report examines a nationwide cohort of ROP infants and reveals an increase in the incidence of ROP from 2000 to 2012. This trend is inversely related to a simultaneous decline in newborn mortality. [ Ophthalmic Surg Lasers Imaging Retina . 2017;48:553-562.]. PMID- 28728177 TI - Porcine Collagen Transconjunctival Wound Closure System for Microincisional Vitrectomy Surgery. AB - BACKGROUND AND OBJECTIVE: Microincisional vitrectomy surgery has improved outcomes for vitrectomies; however, wound closure complications remain an important concern. The authors introduce a technique to improve transconjunctival wound closure in vitrectomy surgery. PATIENTS AND METHODS: The authors evaluated the efficacy of porcine collagen plugs on stopping leakage from sclerotomy test sites in vitro and in vivo and assessed wound site healing with histology samples. RESULTS: The porcine collagen plugs successfully prevented leakage of trypan blue dye in enucleated rabbit eyes and of fluid flow in the rabbit model. Histology showed excellent wound reconstruction and healing, with essentially no inflammation for either angled or straight incisions with a 23-gauge system. CONCLUSIONS: The authors describe a simple and effective novel approach to wound closure in any-gauge vitrectomy surgery using porcine collagen plugs. This method can help reduce complications related to wound leakage. The authors plan to conduct human studies to demonstrate the safety of the approach in the future. [ Ophthalmic Surg Lasers Imaging Retina. 2017;48:576-579.]. PMID- 28728179 TI - Erratum for "Retinal Ganglion Cell Loss in Children With Type 1 Diabetes Mellitus Without Diabetic Retinopathy". PMID- 28728178 TI - Letter to the Editor: Aflibercept For Diabetic Macular Edema in Eyes Previously Treated With Ranibizumab And/Or Bevacizumab May Further Improve Macular Thickness. PMID- 28728180 TI - The Evolution of Vitreoretinal Surgery Platforms. PMID- 28728181 TI - The Value of Diagnostic Work-Up in the Evaluation of White Dot Syndromes. AB - BACKGROUND AND OBJECTIVE: To determine the diagnostic yield of systemic work-up in white dot syndromes. PATIENTS AND METHODS: A retrospective chart review. RESULTS: Eighty-six consecutive patients with a diagnosis of a white dot syndrome were identified. Forty-three had a diagnosis of birdshot chorioretinopathy. Overall, 395 diagnostic tests were performed with a diagnostic yield of 11.9%. The test with the greatest diagnostic yield was HLA-A29 typing (89%). Four patients had abnormal angiotensin converting enzyme levels. No patients had a positive rapid plasma reagin or fluorescent treponemal antibody absorption test. Four patients had positive tuberculosis testing and required treatment. The mean number of tests performed per diagnosis group ranged from 0.3 in multiple evanescent white dot syndrome to 5.6 in multifocal choroiditis and panuveitis. Diagnostic testing was found to be the most expensive in birdshot chorioretinopathy, with a mean cost of $504.82. CONCLUSIONS: Diagnostic yield of systemic work-up was low in this patient population. Rather than performing an exhaustive work-up, the authors advocate for a limited work-up tailored to pretest clinical suspicion. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:540 545.]. PMID- 28728182 TI - Endophthalmitis and Concurrent or Delayed-Onset Rhegmatogenous Retinal Detachment Managed With Pars Plana Vitrectomy, Intravitreal Antibiotics, and Silicone Oil. AB - BACKGROUND AND OBJECTIVE: The current study describes the treatment outcomes in patients with endophthalmitis and concurrent or delayed-onset retinal detachment managed with pars plana vitrectomy, intravitreal antibiotics, and silicone oil. PATIENTS AND METHODS: In this noncomparative, retrospective case series, the medical records of patients diagnosed with endophthalmitis and retinal detachment from January 1991 through December 2014 at a tertiary eye care center in South India were reviewed. All patients received silicone oil for the management of retinal detachment either concurrently or during follow-up treatment. RESULTS: A total of 93 patients were included in the current study. Retinal detachment was diagnosed at presentation in 20 of 93 patients (21.5%) (concurrent group: Group 1) and during follow-up in the remaining 73 of 93 patients (78.5%) (delayed-onset group: Group 2). In Group 1, the initial treatment consisted of vitrectomy, intravitreal antibiotics, and silicone oil injection in 19 of 20 patients. In Group 2, patients did not receive silicone oil during initial treatment but underwent silicone oil injection during subsequent surgery for repair of retinal detachment. Rates of complete retinal reattachment and visual acuity of 20/400 or better were 73.7% and 30.0%, respectively, in Group 1 and 98.5% and 39.7%, respectively, in Group 2. The median visual acuity at last follow-up in 44 eyes undergoing silicone oil removal was 20/100 (logMAR 0.7), whereas in the remaining 49 eyes that did not undergo silicone oil removal, median visual acuity was 20/2000 (logMAR 2.0). CONCLUSION: In these patients with endophthalmitis with concurrent or delayed-onset retinal detachment, the use of silicone oil can be a useful adjunct. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:546-551.]. PMID- 28728183 TI - Early Focal Laser Photocoagulation in Acute Central Serous Chorioretinopathy: A Prospective, Randomized Study. AB - BACKGROUND AND OBJECTIVE: To evaluate the role of early focal laser photocoagulation in acute central serous chorioretinopathy (CSC). PATIENTS AND METHODS: A total of 58 eyes with acute naive CSC (less than 2 months' duration) with focal leak on fundus fluorescein angiography (FFA) were randomized into either a laser or a sham laser group. Eyes with chronic CSC and subfoveal leak were excluded. Visual acuity assessment, microperimetry, optical coherence tomography, and FFA were done at baseline, 1 month (minus FFA), 3 months, and 6 months after treatment. RESULTS: There was a significant improvement in best corrected visual acuity, low-contrast visual acuity, retinal sensitivity, and central macular thickness at all visits in both groups (P < .001); however, there was no significant difference between the groups regarding time of resolution. Four eyes in the sham laser group needed rescue laser compared with one eye in early laser group (P = .16). CONCLUSION: Early laser photocoagulation is not superior to sham laser for acute CSC; therefore, observation appears to the safest and most effective strategy. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:564-571.]. PMID- 28728184 TI - Multi-Spectral Imaging of Circumscribed Choroidal Hemangioma Introduction. AB - BACKGROUND AND OBJECTIVE: To illustrate the features of a circumscribed choroidal hemangioma (CCH) using Annidis RHA multi-spectral imaging (MSI) technology (Annidis Corporation, Ottawa, Canada). This novel imaging technique uses non overlapping, narrow-band LED light sources ranging from 520 nm to 940 nm to create a monochromatic series of en face fundus images and oxy/deoxyhemoglobin contrasted maps of the retina and choroid. PATIENTS AND METHODS: Annidis RHA MSI images were taken of a 67-year-old Chinese male with CCH. These en face fundus images are presented alongside the traditional fundus photograph, optical coherence tomography, and fluorescein and indocyanine green angiograms. RESULTS: Multi-spectral en face images of the outer retina and choroid demonstrated a clearly delineated lesion with a disorganized choroidal vascular network and increased reflectance/ oxyhemoglobin levels within. CONCLUSION: MSI technology is a noninvasive imaging technique that can depict the vascular features and choroidal oxygenation of CCH lesions and has a potential role in monitoring its growth complications. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:572-575.]. PMID- 28728185 TI - Novel Presenting Phenotype in a Child With Autosomal Dominant Best's Vitelliform Macular Dystrophy. AB - Best's macular dystrophy (BMD) usually manifests with visual failure in the first or second decade of life; however, there is a large variability in expressivity of the disease, and some patients have no manifestation other than a pathological electro-oculogram (EOG). Autosomal dominant Best's vitelliform macular dystrophy (AD-BVMD) has a very specific phenotype that varies with the stage of the disease. In recent years, the authors have seen description of another clinical entity known as autosomal recessive BMD. Herein, the authors describe a 5-year old girl referred from a peripheral hospital for investigation with a positive family history of BMD. Clinical findings included best-corrected visual acuity of 0.325 and 0.300 in the right and left eyes, respectively, by Sonksen logMar test, full color vision, normal orthoptic examination, and a small degree of hyperopia consistent with age. Macular optical coherence tomography (OCT) showed intraretinal fluid cysts and EOG showed reduced Arden ratio. Genetic testing was done for the proband and her father, who were found to be heterozygous for c.37C>T p. (Arg13Cys). The proband's younger sister will be reviewed and followed up once of age. The authors identified a new phenotype of AD-BVMD; although this is a single patient, more young children with BMD can now be scanned with the availability of hand-held OCT with better knowledge of the phenotype. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:580-585.]. PMID- 28728186 TI - Choroidal Neovascularization and Geographic Atrophy are Potential Complications of Early Onset Large Colloid Drusen. AB - The authors report a case of large colloid drusen (LCD) complicated by choroidal neovascularization (CNV) and geographic atrophy (GA). A 54-year-old man was referred to the authors' department with diagnosis of early onset retinal drusen. Multimodal imaging led to a diagnosis of LCD complicated by GA in the right eye and CNV in the left eye. The patient received a single injection of intravitreal aflibercept (Eylea; Regeneron, Tarrytown, NY) in the left eye. Six months later, best-corrected visual acuity improved to 20/25, and spectral-domain optical coherence tomography still showed absence of subretinal and intraretinal fluid. GA and CNV are possible complications of LCD, and contrary to previous beliefs, it should therefore not be considered as a benign condition. Intravitreal aflibercept could be considered as a useful treatment in cases complicated by CNV. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:586-590.]. PMID- 28728187 TI - In Vivo Microvascular Pattern of Solitary Juxtapapillary Capillary Hemangioma on OCT Angiography. AB - Juxtapapillary capillary hemangioma (JCH) is a vascular hamartoma. Fluorescein fundus angiography aids in diagnosis. The vascular morphology of this tumor has not been documented with optical coherence tomography angiography (OCTA), a new, noninvasive diagnostic modality that provides high-resolution images of vascular pattern based on blood flow in the retina and choroid. Although mainly a clinical diagnosis, OCTA helps in studying the intrinsic vascularity of the tumor and helps in differentiating it from other vascular tumors. The authors report the case of a young male with unilateral solitary JCH and its microvascular pattern, as seen on OCTA. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:592-595.]. PMID- 28728188 TI - Diagnosing Choroidal Neovascularization in Asymptomatic Individuals Using Optical Coherence Tomography Angiography. AB - Optical coherence tomography angiography (OCTA) is a noninvasive, rapid imaging technique that generates angiographic images without intravenous dye injections. Cross-sectional studies have described the presence of asymptomatic choroidal neovascularization (CNV) in patients with intermediate age-related macular degeneration (AMD). This case report describes the OCT features on longitudinal follow-up of a patient who started with unilateral asymptomatic CNV and eventually developed symptomatic exudative AMD. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:596-598.]. PMID- 28728190 TI - 8 Questions with Darius Moshfeghi. PMID- 28728189 TI - Spontaneous Globe Rupture Due to Rapidly Evolving Endogenous Hypermucoid Klebsiella Pneumoniae Endophthalmitis. AB - In this retrospective report, the authors describe a rare case of spontaneous globe rupture from Klebsiella pneumoniae endophthalmitis in a middle-aged man with poorly controlled type 2 diabetes mellitus. There have been only four previously reported cases of spontaneous globe rupture from endophthalmitis. Out of the now five reported cases, all have been due to endogenous endophthalmitis, four have been due to gram-negative bacteria, and three have been due to K. pneumoniae. K. pneumoniae, especially the hypermucoid variant with a protective polysaccharide capsule, is an emerging pathogen with remarkable virulence. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:600-601.]. PMID- 28728191 TI - Athletic Incontinence: Proposal of a New Term for a New Woman. PMID- 28728192 TI - Role of Thyroid Deficiency on Adiponectin, Leptin, and Metabolic Status in Visceral Obesity: A Cross-Sectional Study. PMID- 28728193 TI - Monitoring of Free Flaps with Combined Tissue Spectrophotometry and Laser Doppler Flowmetry in an Animal Experimental Model. PMID- 28728194 TI - [Relevance of Living Wills During Post-Resuscitation Care]. AB - Background There is hardly any evidence about the influence of living wills on acute life-threatening disease like out-of-hospital cardiac-arrest (OHCA). We therefore initiated this study to quantify the percentage of victims of OHCA who's living wills are available during post-resuscitation care. Methods All victims of OHCA who were admitted to our hospital between January 1st 2008 and July 31th 2016 were identified by analysis of our central admission register. Data from individual patients were collected from the patient's health records and anonymously stored on a central database. Results Altogether, there were 343 victims of OHCA admitted to our hospital between January 1st 2008 and July 31th 2016, including 16 patients (4.7 %) with living wills and 18 patients (5.2 %) with legal health care proxy. Survival rates were 31.2 % in patients with living wills, 27.8 % in patients with legal health care proxy and 33.3 % in patients without such a document. Conclusion In this study, the percentage of victims of OHCA with available living wills during post-resuscitation care was low. The presentation of living wills or legal health care proxies during post resuscitation care of victims from OHCA was not equivalent to the patient's death. Most often, discussion with relatives led to the decision to withdraw further therapy. PMID- 28728195 TI - [Multimorbidity - choosing wisely inspite of lacking data]. PMID- 28728196 TI - [A 19-Year-Old Female Athlete with an Abnormal ECG]. PMID- 28728197 TI - [Is Age a Comorbidity?] AB - Aging is normal process, only somehow questioned by the "anti-aging wave". Normal and pathological aging are therefore separate developments. Older adults often suffer from the frailty syndrome, partly due to diminished resilience. Aging per se is not a comorbidity. PMID- 28728198 TI - [Nutrition of Polymorbid Patients - Data or Opinions?] AB - Polymorbidity and old age are rather the rule than the exception in hospitalised patients. Malnutrition is common in such patients and should be identified by appropriate screening and assessment measures in order to devise a nutrition plan and act accordingly. Unlike in the UK or The Netherlands, malnutrition screening and nutrition teams are not mandatory for German hospitals. Malnutrition and, in particular, sarcopenia are indicators of a nutrition associated risk or increased morbidity and mortality. Malnutrition can affect patients of any medical discipline and, therefore, is managed most efficiently by the interdisciplinary and multiprofessional nutrition team. By this approach goal directed nutrition therapy can improve morbidity and mortality of hospitalised patients. PMID- 28728199 TI - [Polypharmacy - Solutions for Enhanced Drug Safety]. AB - Polypharmacy (>= 5 drugs) is common among older people and may lead to falls, ADEs and delirium. Adherence is an important part in the medication management. Simple questions (i. e. for OTC, handling and omission of drugs) are effective. As most old people are treated by general practitioners (GP), they play a key role for drug safety and reducing polypharmacy. The involvement of pharmacists in analyzing one patient's drugs can enhance solutions for drug problems ("two-man rule"). An IT-based medication plan acts as an important communication tool for an enhanced team work between doctors, pharmacists and nursing care. PMID- 28728200 TI - [Heart Failure - A Model for Multimorbidity]. AB - Heart failure frequently is the consequence of different cardiac diseases and is associated with multiple cardiac and non-cardiac co-morbidities. It may be exemplary for multi-morbidity in the elderly, has negative impact on various organ systems and may induce further comorbidities. The following article addresses heart failure as a multisystem disorder. PMID- 28728201 TI - [Fever and Headache after a Vacation in Thailand]. AB - History 50 year-old man with fever and headache starting one week after returning from his vacation in Thailand. His general practitioner prescribed amoxicillin/clavulanic acid, without further analyses to pinpoint the infection. Examinations The examination of cerebro-spinal fluid was crucial for the final diagnosis. Lumbar puncture demonstrated a predominantly mononuclear pleocytosis of 80 cells/ul (< 5) with an elevated protein of 782 mg/l (< 450); glucose and lactate were within normal limits. Treatment and course Initially we tried to treat a broad range of organisms potentially causing meningitis or encephalitis. Typical bacteria and viruses endemic to Switzerland were not found, thus anti infective treatment was stopped. Also the search for malaria, HIV, Chikungunya and Dengue infections yielded negative results. After 10 days we received a positive serologic test for Japanese encephalitis virus (JEV). Conclusions The Japanese encephalitis virus is transmitted by mosquitoes and is epidemiologically one of the most important transmissible neurologic diseases in Asia. Although only a minority of infected patients are gravely ill, their sequelae and death toll are considerable. Since 2009 a well-tolerated vaccine is available. PMID- 28728202 TI - [Pyogenic liver abscess: Changes of Organisms and Consequences for Diagnosis and Therapy]. AB - Liver abscess is a rare but potentially fatal disease with mortality rates of 2 - 12 %. The spectrum of causative microorganisms varies across the world and is changing due to increasing worldwide travel activity. As a result, previously less frequent pathogens must increasingly be considered in the differential diagnosis. The most common pathogens of liver abscess are so-called abscess streptococci, anaerobes and Gram-negative bacteria such as Escherichia coli and Klebsiella pneumoniae. Certain clones among the Gram-negatives, typically among Klebsiella spp., harbour specific virulence factors and are therefore referred to as hypervirulent clones which spread worldwide. In any case, the causative agent should be identified before anti-infective treatment is initiated. Several pathogens such as Candida spp., Pseudomonas aeruginosa or Staphylococcus aureus are uncommon and only detected in a specific context. Various therapeutic regimens are available for anti-infective therapy. Usually an empirical therapy is started, combining mostly beta-lactam antibiotics or quinolones with anaerobically active substances. PMID- 28728203 TI - [Noninvasive Ventilation: step by step]. PMID- 28728204 TI - How Do Obstetric and Neonatology Teams Communicate Prior to High-Risk Deliveries? AB - BACKGROUND: Improving communication in healthcare improves the quality of care and patient outcomes, but communication between obstetric and neonatal teams before and during a high-risk delivery is poorly studied. STUDY DESIGN: We developed a survey to study communication between obstetric and neonatal teams around the time of a high-risk delivery. We surveyed neonatologists from North America and asked them to answer questions about their institutions' communication practices. RESULTS: The survey answers revealed variations in communication practices between responders. Most institutions relied on nursing to communicate obstetric information to the neonatal team. Although a minority of institutions used a standardized communication process to summon neonatology team or to communicate in the delivery room, these reported higher rates of information sharing and greater satisfaction with communication between services. CONCLUSION: Standardized communication procedures are an underutilized method of communication and have the potential to improve communication around high-risk deliveries. PMID- 28728205 TI - [Predictability of Postoperative Pain and Satisfaction. How Precise Are We and What Is the Role of Professional Experience?] AB - Background The indication for surgery is justified by an expected improvement for the patient. To evaluate the probability and extent of individual postoperative patient benefit, the surgeon needs to elaborate numerous parameters of potential relevance for the outcome beyond his key competence, that is the technical dimension of the operation. Despite the highest medical standards, individual postoperative satisfaction with surgery is highly variable, even in cases with a technically good result. The aim of the present study was to investigate the individual predictability of postoperative pain and satisfaction in patients with elective musculoskeletal surgery. Moreover, it was analysed whether the quality of the prediction of the outcome depends on professional experience and if a better prediction can be obtained in such a highly standardised procedure as primary total arthroplasty. Patients/Material and Methods In our hospital on the day before surgery, patients with their medical history are presented to the head of department and a short clinical examination is performed as well as a joint analysis of radiographic images. During this grand round, doctors gave a written preoperative estimation of both expected postoperative satisfaction and pain at 6 months after surgery on a scale from 0 - 10. At 6 months postoperatively, patients were asked to give their actual level for these two parameters. Preoperative estimations were obtained from both senior and resident physicians and compared with the values actually reported by the patient. Results A total of 194 physicians' predictions of 63 patients were analysed. Preoperative pain levels were reduced markedly by surgery from a median NRS of 6.25 to 2.5 (p < 0.001). Median prediction for postoperative pain was 2 (IQR 2), which is only slightly more optimistic than reported. On an individual level, the discrepancy between prediction and actual outcome was, however, considerable - with a median absolute difference of 2 (IQR 3) values on the scale. This means that only 50% of all predictions were close enough to the actual value to be at least in the correct half of the entire scale. When looking at prediction precision as a function of professional experience, no difference could be observed between senior and junior doctors (p = 0.738 for postoperative pain and p = 0.370 for satisfaction with surgery). Even in primary arthroplasty patients (n = 17), precision of outcome prediction for pain was no better that in the remaining collective (p = 0.634). With respect to postoperative satisfaction, precision of prediction was even worse (p = 0.042), as satisfaction was slightly underestimated by the physicians in the primary arthroplasty group, by a median of 1. Conclusion While general prediction showed almost perfect agreement with actual postoperative values, individual predictability showed highly variable results. Even in such a standardised collective as primary arthroplasty, this scattering of deviation was observed. Since professional experience did not lead to improved results, it can be speculated that, beside the technical dimension of surgery, other factors such as patient expectation are of crucial relevance for postoperative outcome. To further improve outcome and patient satisfaction with surgery we therefore recommend developing an individualised and realistic prognosis together with each patient, but bearing in mind own limits of outcome prediction. PMID- 28728207 TI - [Female urethral diverticulum with calculus formation imitating stress incontinence]. AB - A female urethral diverticulum (UD) is a rare condition with a prevalence of 0.6 4.7 %. Possible aetiologies include chronic infection of the periurethral glands, childbirth trauma, and iatrogenic lesions after urethral manipulation. The main symptoms are recurrent urinary tract infections, post-void dribbling and leakage of urine or purulent discharge by movement, which is caused by the emptying of the diverticular lumen (paradoxical incontinence). As this may imitate stress urinary incontinence, the final diagnosis is a challenge for urologists. We report the case of a female UD containing multiple calculi, which were diagnosed during diagnostic work-up of incontinence. Based on this case report, we want to present and analyse the symptoms as well as the diagnostic evaluation and treatment of UD as reported in the literature. Also we wish to emphasise that the differential diagnosis between a complicated diverticulum and stress urinary incontinence requires a precise knowledge of the symptoms and the diagnostic algorithm for the detection of a DU because the symptoms of these two conditions are similar. PMID- 28728206 TI - [Subaxial Cervical Spine Injuries: Treatment Recommendations of the German Orthopedic and Trauma Society]. AB - In a consensus process during four sessions in 2016, the working group "lower cervical spine" of the German Society for Orthopedic and Trauma Surgery (DGOU), formulated "Therapeutic Recommendations for the Lower Cervical Spine", taking into consideration the current literature. Therapeutic goals are a permanently stable, painless cervical spine and the protection against secondary neurologic damage while retaining the greatest possible amount of motion and spinal profile. Due to its ease of use and its proven good reliability, the AOSpine classification for subaxial cervical injuries should be used. The Canadian C Spine Rule is recommended as a clinical decision rule whether to perform imaging or not. If a structural or unstable injury is suspected by patient history or clinical findings, a spiral CT scan of the cervical spine is the favoured diagnostic modality. Conventional X-ray is reserved for patients in whom there is no "dangerous mechanism of injury". MR imaging is recommended in case of unexplained neurologic deficit, prior to closed reduction and open posterior surgery and to exclude disco-ligamentous injuries. Urgency of MR imaging depends on the specific findings. CT angiography is recommended in higher-grade facet joint injuries or in the presence of vertebra-basilar symptoms. Flexion-extension imaging is recommended only as a physician-guided dynamic fluoroscopy, when an unstable lesion is still suspected. The therapeutic strategy is mainly dependent on morphologic criteria, which are described using the AOSpine classification. A0 injuries are treated conservatively. A1- and A2-injuries are treated conservatively in the majority of cases, and in single cases a gross kyphotic deformity might indicate surgical stabilisation. A3-injuries do indicate a surgical therapy in the majority of cases, but certain cases might be treated conservatively. A4-fractures as well as B- and C-type injuries are to be treated surgically. Most injuries can be treated by anterior plate stabilisation with interbody support; when a complete burst fracture is present, corpectomy and vertebral body replacement is necessary. In certain cases, an additive posterior or pure posterior instrumentation might be possible or even mandatory. In most of these cases, lateral mass screws are sufficient; when pedicle screws are applied in C3 to C6, a 3D-navigation system is recommended. Injuries in an ankylosing spine (M3-modifier) should be treated preferably from posterior with long-segment instrumentation. PMID- 28728208 TI - The Role of 18F-FDG PET/CT Scan in Predicting Histological Type of Thymic Epithelial Tumors: Indications and Practical Clinical Considerations. PMID- 28728209 TI - Fluorodeoxyglucose Positron Emission Tomography Can Provide Useful Information for Differentiating Thymic Epithelial Tumors. AB - BACKGROUND: We examined the usefulness of fluorodeoxyglucose (FDG) positron emission tomography (PET) in predicting the World Health Organization (WHO) histologic type and Masaoka stage of thymic epithelial tumors. METHODS: A total of 73 patients with thymic epithelial tumors who underwent preoperative FDG-PET were included. Relationships between the maximum standardized uptake value (SUVmax) and WHO histologic type and the Masaoka stage of the tumor were examined. Differences in SUVmax between the various groups were calculated. To avoid the effect of the tumor size on SUVmax, the ratio of SUVmax to tumor size (SUVmax/T) was also examined. RESULTS: There was a significant relationship between SUVmax and WHO histologic type. SUVmax of high-risk thymomas (types B2 and B3) was significantly higher than that of low-risk thymomas (types A, AB, and B1). SUVmax of thymic carcinomas was also significantly higher than those of the low-risk and high-risk groups. The relationship between the SUVmax/T and WHO histologic type showed more significant results. SUVmax and SUVmax/T showed higher values in patients with advanced Masaoka stage disease than in those with early-stage disease. CONCLUSIONS: FDG-PET can provide useful information for differentiating thymic epithelial tumors. The SUVmax/T is more useful than the SUVmax for differentiating between low-risk and high-risk thymomas. PMID- 28728210 TI - Herbal multicomponent extracts enhance wound healing after incision of perianal abscess and in a rat model of infected wounds. PMID- 28728211 TI - Cutaneous larva migrans occurring concurrently in a father and son. PMID- 28728212 TI - Men's information-seeking behavior regarding cancer risk and screening: A meta narrative systematic review. AB - OBJECTIVE: Preventive strategies are known to reduce cancer risk and incidence and improve prognosis. Men seldom seek medical information about cancer prevention and risk reduction. The aim of this meta-narrative systematic review was to critically appraise evidence from qualitative, quantitative, and mixed methods studies that explored men's information-seeking behaviors in relation to cancer prevention and risk reduction. METHODS: MEDLINE, CINAHL Plus with Full Text, PsycINFO, PsycARTICLES, Psychology and Behavioral Sciences Collection, Education Full Text, and ERIC were systematically searched for studies published in English between January 1, 2006 and May 30, 2016. A total of 4117 titles were identified; of which, 31 studies were included (21 qualitative studies, 9 quantitative studies, and 1 mixed-methods study). The methodological quality of the studies was appraised by using different tools. RESULTS: Most studies focused on screening for prostate (n = 18) and colorectal cancer (n = 7). Most men were passive information-gatherers rather than active information-seekers. Key sources of information included the Internet for active information-seekers and health care professionals for passive information-gatherers. Barriers to information seeking included information overload, embarrassment, and fear. Low literacy and health literacy levels were addressed in 3 studies and were identified as impediments to active information-seeking. Facilitators to information-seeking included family support, media, celebrity endorsements, and targeted information. CONCLUSIONS: Men's information-seeking behavior regarding cancer risk reduction, prevention, and screening is influenced by several factors. This necessitates targeted interventions aimed at raising awareness of cancer prevention and screening, while accounting for men's informational needs, preferred learning strategies, and literacy levels. PMID- 28728213 TI - Performance of non-invasive prenatal screening for fetal aneuploidy in twin pregnancies: a meta-analysis. AB - OBJECTIVE: The objectives of this study were to review the published studies of non-invasive prenatal screening (NIPS) in twin pregnancies and to evaluate the performance for screening fetal trisomies 21, 18, and 13 in twin pregnancies. METHOD: Ten eligible studies were included in this meta-analysis. Data analysis, heterogeneity exploring, meta-regression, and subgroup analysis were all conducted with Meta-DiSc 1.4. Quality assessments were carried out with the Quality Assessment Tool for Diagnostic Accuracy Studies. RESULTS: Non-invasive prenatal screening for trisomy 21 screening in twin pregnancies showed a pooled sensitivity of 0.99 (95% CI, 0.92-1.00), a specificity of 1.00 (95% CI, 0.99 1.00), a positive likelihood ratio (LR) of 116.46 (95% CI, 53.84-251.92), a negative LR of 0.11 (95% CI, 0.06-0.22), and a diagnostic odds ratio of 1297.73 (95% CI, 438.06-3844.42). But the difference of detection rates between monozygotic and dichorionic twin pregnancies was uncertain for only a very small number of monochorionic twins available. For trisomy 18 screening, the pooled sensitivity, specificity, positive LR, negative LR, and diagnostic odds ratio were 0.85 (95% CI, 0.55-0.98), 1.00 (95% CI, 0.99-1.00), 86.11 (95% CI, 32.45 228.47), 0.25 (95% CI, 0.11-0.56), and 333.90 (95% CI, 35.15-3171.78), respectively. For trisomy 13 screening, three cases in three studies were all detected accurately. CONCLUSION: The meta-analysis results from 10 eligible studies demonstrated that NIPS has both high sensitivity and specificity for trisomy 21 screening in twin pregnancies. The results for trisomy 18 screening are less satisfactory than those for trisomy 21. The performance for trisomy 13 screening could not be determined as only three cases were identified. (c) 2017 John Wiley & Sons, Ltd. PMID- 28728215 TI - Dermoscopy of a pigmented apocrine porocarcinoma arising from a pigmented hidroacanthoma simplex. PMID- 28728216 TI - [Introduction of embryonal trmours in the 2016 WHO classification of trmors of the central nervous system]. PMID- 28728217 TI - [Summary of molecular markers and detection methods in the 2016 WHO classification of trmors of the central nervous system]. PMID- 28728218 TI - [Concensus on pathologic diagnosis of peripheral neuroblastic tumors]. PMID- 28728214 TI - P2X receptor channels in chronic pain pathways. AB - : Chronic pain is a highly prevalent debilitating condition for which treatment options remain limited for many patients. Ionotropic ATP signalling through excitatory and calcium-permeable P2X receptor channels is now rightfully considered as a critical player in pathological pain generation and maintenance; therefore, their selective targeting represents a therapeutic opportunity with promising yet untapped potential. Recent advances in the structural, functional and pharmacological characterization of rodent and human ATP-gated P2X receptor channels have shed brighter light on the role of specific subtypes in the pathophysiology of chronic inflammatory, neuropathic or cancer pain. Here, we will review the contribution of P2X3, P2X4 and P2X7 receptors to chronic pain and discuss the opportunities and challenges associated with the pharmacological manipulation of their function. LINKED ARTICLES: This article is part of a themed section on Recent Advances in Targeting Ion Channels to Treat Chronic Pain. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.12/issuetoc. PMID- 28728219 TI - [Solitary fibrous tumor/hemangiopericytoma of central nervous system: a clinicopathologic analysis of 71 cases]. AB - Objective: As solitary fibrous tumor (SFT) and hemangiopericytoma (HPC) share the same molecular genetics features, the 2016 WHO classification of central nervous system (CNS) tumors had created the combined term SFT/HPC and assigns three grades. This study aims to investigate the clinicopathologic characteristics, diagnosis, differential diagnosis and prognosis of CNS SFT/HPC. Methods: Seventy one cases of CNS SFT and HPC were retrospectively reclassified and studied. Histopathological, immunohistochemical and imaging features were analyzed. The follow-up data were analyzed. Results: There were 37 male and 34 female patients. The median age was 48 years (range, 3-77 years). Twelve cases (17%) were WHO grade I, 26 (37%) were WHO grade II and 33 (46%) were WHO grade III. Microscopically the tumor could show traditional SFT phenotype, HPC phenotype or mixed phenotype. Immunochemically, 97%(69/71) were positive for STAT6, with 96%(66/69)showing diffuse strong staining. Approximately 90% were diffusely positive for bcl-2, CD99 and vimentin. The expression rate of CD34 decreased with increasing tumor grade, and the mean expression rate was 78%. SSTR2a was variably expressed in 10% (7/71) of cases including one case showing strong cytoplasmic staining. A few cases expressed EMA, CD57 and S-100 focally. The Ki-67 index ranged from 1% to 50%. Thirty four patients were followed up for 8-130 months; 12 patients(35%)had recurrences, and two (6%) had liver metastases. Conclusions: CNS SFT/HPC is relatively uncommon. There was significant morphological overlap or transition between different grades. STAT6 is a specific marker for the diagnosis of this tumor. Surgical resection is the preferred treatment. WHO grade II and III SFT/HPC show rates of local recurrence and systemic metastasis, with liver being the most common site of extracranial metastasis. PMID- 28728220 TI - [Diagnostic utility of tyrosine hydroxylase in peripheral neuroblastic tumors]. AB - Objective: To investigation the diagnostic utility of tyrosine hydroxylase (TH) immunohistochemically as a marker of peripheral neuroblastic tumors(pNT). Methods: The study included 1 024 cases, 643 primary and metastatic pNT cases, 381 non-pNT cases, including small round cell tumors such as primitive neuroectodermal tumor (PNET), rhabdomyosarcoma, lymphoma, nephroblastoma, as well as other more common tumors (medulloblastoma, hepatoblastoma, pleuropulmonary blastoma, renal clear cell sarcoma, Langerhans cell histiocytosis, lipoblatoma etc). Tissue slides of these 1 024 cases were stained with TH and other common antibodies to evaluate whether TH was useful to identify pNT. Results: TH showed cytoplasmic staining in 100.0% (643/643) of pNT and 3.9% (15/381) of non-pNT. TH expression was seen in some poorly differentiated and undifferentiated tumors with focal or scattered patterns. In some cases, more scattering was seen in neuroblastoma with poor differentiation. The sensitivity, specificity, positive predictive value and negative predictive value of TH was 100.0% (643/643), 96.1%(366/381), 97.7%(643/658) and 100.0% (366/366), respectively. There was no TH expression in the 248 cases of other small round cell tumors (PNET, rhabdomyosarcoma, lymphoma, etc), thus suggesting TH was useful to differentiate between PNET and neuroblastoma. As CD99 was positive in 95% PNET, some PNET would be CD99 negative. In those cases, particularly with diffuse rosettes forming, TH immunostaining would be useful. Conclusion: TH is sensitive and specific for pNT in the differential diagnosis from other tumors of childhood and shows high diagnostic utility. PMID- 28728221 TI - [Correlation between androgen receptor expression and surrogate molecular subtypes in invasive breast carcinoma]. AB - Objective: To investigate androgen receptor(AR)expression in invasive breast carcinoma and the correlation with surrogate molecular breast carcinoma subtypes. Methods: Immunohistochemical staining of AR and other biomarkers was performed in a cohort of 870 cases of primary invasive breast carcinomas collected from August to December, 2016. The association of AR expression with different histological and surrogate molecular subtypes was analyzed. Results: The positive expression rate of AR in the immunohistochemistry-based surrogate subtypes was 96.3%(207/215) for Luminal A, 89.8%(378/421) for Luminal B, 82.4%(75/91) for HER2 overexpression and 37.1%(53/143) for triple negative breast carcinoma, with significant differences among the four groups (P<0.01). AR correlated positively with the expression of ER(P<0.01), PR(P<0.01), HER2(P=0.007), GATA3(P<0.01), GCDFP15(P<0.01)and mammaglobin(P<0.01), while negatively with the expression of Ki-67(P<0.01), CK5/6(P<0.01)and CK14(P<0.01). Conclusions: AR exhibits a high expression in invasive breast carcinoma, which is mainly correlated with ER positive breast carcinoma. Regardless of the relatively low expression rate, AR is a potential therapeutic target in triple negative breast carcinoma. PMID- 28728222 TI - [Application of p16/Ki-67 immunocytochemistry in triage of patients with atypical squamous cells of undetermined significance]. AB - Objective: To investigate the clinical value of p16/Ki-67 immunocytochemistry in patients with atypical squamous cells of undetermined significance(ASC-US). Methods: One hundred and seventy-one cases of thin-prep cytology test (TCT) diagnosed as ASC-US underwent p16/Ki-67 immunocytochemistry. All patients had colposcopy and biopsy from March 2015 to January 2016. Ninety of the 171 cases underwent high-risk HPV test at the same time. Results: p16/Ki-67 immunocytochemistry was positive in 43.9% (75/171) of the 171 cytology samples; the sensitivity and specificity of p16/Ki-67 immunocytochemistry were 77.6%(52/67) and 77.9%(81/104) in detecting CIN2+ , and the positive and negative predictive value were 69.3%(52/75) and 84.4%(81/96), respectively. The sensitivity and specificity in diagnosing CIN2+ were 100.0%(34/34) and 10.7%(6/56) for HPV test, and the positive and negative predictive value were 40.5%(34/84) and 6/6. p16/Ki-67 immunocytochemistry showed lower sensitivity but obviously higher specificity than high-risk HPV detection. Conclusion: p16/Ki-67 immunocytochemistry is a good triage test for identifying CIN2+ in ASC-US specimens. PMID- 28728223 TI - [Expression and bioinformatics analysis of long-chain non-coding RNA PVT1 in tumors]. AB - Objective: To study the expression and mechanism of long-chain non-coding RNA PVT1 in tumor by bioinformatics analysis and experimental verification, and to provide new ideas for the study of the pathogenesis of tumors. Methods: The expression of PVT1 in 14 common tumors was downloaded from starBase v2.0 public database, which also was verified by PVT1 RNA-in situ hybridization.The upstream transcription factors, the downstream target microRNA(miRNA) for PVT1 and the target genes for the target miRNAs were predicted and analyzed by using bioinformatics based on the database of UCSC Genome Browser, HMDD v2.0, miRTar Base, JASPAR databases. Results: StarBase database analysis and RNA in situ hybridization showed that PVT1 was highly expressed in kidney clear cell carcinoma and colon and rectal adenocarcinoma. PVT1 was regulated by the upstream transcription factors CREB1, Atf1, SP1, KLF5, STAT3, while it could control the expression of the downstream target miR-16. bcl-2, VEGFA, CCNE1, CCND1 and SHOC2 showed an interaction with the transcription factor of PVT1, which formed a feedback regulatory pathway. Conclusions: PVT1 is highly expressed in kidney clear cell carcinoma and colon and rectal adenocarcinoma.The predictive analysis of bioinformatics demonstrates that transcription factor/PVT1/miR-16/target gene signal axon may be an important molecular mechanism, which provide a valuable clue for further functional mechanism research of long-chain non-coding RNA. PMID- 28728225 TI - [Breast cancerwith heteroploid chromosome 17: a clinicopathologic analysis of 76 cases]. PMID- 28728224 TI - [Antagonism of lovastatin on oxidative stress and apoptosis in primary rat hippocampal neurons induced by beta-amyloid peptide]. AB - Objective: To investigate the effect of lovastatin on oxidative stress and apoptosis in neurons induced by beta-amyloid peptide (Abeta). Methods: Primary culture of rat hippocampal neuron was treated with Abeta oligomers alone or combined with lovastatin. The levels of OH(-), H(2)O(2), O(2).(-), malondialdehyde, superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) activities were measured by biochemical methods and protein expression of caspase 3 and bcl-2 was detected by Western blot. Results: As compared with the control group, treatment of 0.5 MUmol/L Abeta oligomers for 48 h led to significant increase of OH(-), H(2)O(2), O(2).(-) and malondialdehyde content, inhibition of SOD and GSH-PX activities, enhanced caspase-3 expression and decreased bcl-2 expression. Interestingly, these neurotoxic modifications on the levels of OH(-), H(2)O(2), O(2).(-) and malondialdehyde content, SOD and GSH-PX activities, and the protein expression of cleaved caspase-3 and bcl-2 were significantly attenuated when the cells were pretreated with 0.1 MUmol/L lovastatin for 24 h before exposure of Abeta oligomers. Conclusion: Lovastatin may play an important role in antagonizing the neurotoxicity of Abeta through a mechanism likely related to the inhibition of oxidative stress. PMID- 28728226 TI - [Clinicopathologic characteristic of oncocytic mucoepidermoid carcinoma: report of 8 cases]. PMID- 28728227 TI - [Clinicopathologic study of biphenotypic sinonasal sarcoma]. PMID- 28728228 TI - [Composite pheochromocytoma in adrenal gland: report of a case]. PMID- 28728230 TI - [Right ventricular ectopic thyroid tissue: report of a case]. PMID- 28728229 TI - [Malignant epithelioid angimyolipoma of kidney with polyploid chromosome X and TFE3 gene amplification: report of a case]. PMID- 28728231 TI - [Research progress of molecular markers of glioma in diagnosis and treatment]. PMID- 28728232 TI - [Precision medical research progress in Alzheimer's disease]. PMID- 28728233 TI - [Research progress on anti-PD-L1 antibody in treatment of malignant melanoma]. PMID- 28728234 TI - [Understanding of the complexity of allergy rhinitis]. PMID- 28728235 TI - [Effects of vidian neurectomy on allergic rhinitis]. PMID- 28728236 TI - [Epidemiological investigation of allergic rhinitis in Ningxia]. AB - Objective: To investigate the epidemiological characteristics of allergic rhinitis (AR) in Ningxia and to analyze its related factors. Methods: From March to September of 2013, a multi-stage and cluster sampling method was used to investigate the diagnosis and treatment of AR in Ningxia Area (3 years and above). Guidelines for diagnosis and treatment of allergic rhinitis (2009, Wuyishan) was used as the basis for the diagnosis of adult AR, while Guidelines for diagnosis and treatment of pediatric allergic rhinitis (2010, Chongqing) was used as the basis for children. SPSS 16.0 software was used to complete the statistical analysis. Results: The total number of questionnaires was 6 000, and the number of effective questionnaire was 5 236, the recovery rate was 87.27%. With 684 cases diagnosed of AR, the prevalence of AR in Ningxia was 13.06% (684/5 236), including 13.40% (325/2 425) of males, 12.77% (359/2 811) of females. The difference was not statistically significant (chi(2)=0.456, P>0.05). There was significant difference in the prevalence between Hui and Han [14.35% (452/3 150) vs 11.12% (232/2 086), chi(2)=11.51, P<0.05]. According to ARIA criteria, persistent AR was 27.63% (189/684), intermittent AR was 72.37% (495/684). The month with highest incidence of AR in Ningxia Area was September, accounting for 71.78% (491/684). The prevalence of urban population was 14.54%, with the prevalence of rural population was 11.90%, and the difference was significant between urban and rural residents (chi(2)=7.90, P<0.05). The age group with highest prevalence rate was 21~30 years old. The main inhalation allergens were mugwort (68.42%), weeds (58.48%) and ragweed (55.56%). The main dietary allergens were wheat flour (14.33%), peanut (13.74%) and walnut kernel (11.99%). The most common complication was allergic conjunctivitis [82.02% (561/684)]. Conclusion: The epidemiology of AR in Ningxia Area is preliminarily understood, which will provide the epidemiological evidence for the prevention and treatment of AR and the formulation of public health policy. PMID- 28728237 TI - [Evaluation of efficacy of 1 year after completing the 2-year specific sublingual immunotherapy treatment course in allergic rhinitis]. AB - Objective: To evaluate the efficacy of treatment at 1 year after completing the 2 year specific sublingual immunotherapy in patients with allergic rhinitis (AR). Methods: A retrospective analysis of 124 patients with AR who were allergic to dust mite and treated in the First Affiliated Hospital of Wenzhou Medical University since 2012 was performed. All patients achieved sublingual immunotherapy (SLIT) for 2 years and had a regular follow-up over 1 year. Efficacy evaluation index such as VAS score, total nasal symptom score and total medication score were compared between the time of SLIT for 2 years, and 1 year after termination of SLIT. Paired t test was used for the comparison of scores. Results: Compared with those before treatment, the VAS score, total nasal symptom score and total medication score at the time of SLIT for 2 years were significantly decreased in all patients with AR [(9.40+/-5.96) vs (24.78+/-6.36), (4.53+/-2.06) vs (9.51+/-2.02), (0.42+/-0.87) vs (3.02+/-0.41), t value was 17.627, 24.600, 5.331, respectively, all P<0.01]. Compared with 2 years SLIT treatment, VAS score and total nasal symptom score were significantly increased than 1 year after termination of immunotherapy [(12.52+/-6.92) vs (9.40+/-5.96), (5.30+/-2.36) vs (4.53+/-2.06), t=5.199, 3.744, respectively, all P<0.01], but the total medication score showed no significant difference [(0.34+/-0.84) vs (0.42+/-0.87), t=-1.043, P>0.05]. Conclusions: The symptoms after 2 years SLIT in patients with AR have been well controlled. One year after the termination of SLIT, there is a certain rebound in symptoms, 2 years SLIT may not be the ideal treatment cycle for AR. PMID- 28728238 TI - [The comparation of establishing the allergic rhinitis model between Kunming mice and BALB/c mice]. AB - Objective: To discusses the feasibility of establishing the allergic rhinitis (AR) model in Kunming mice. Methods: Kunming mice (n=20) and BALB/c mice (n=20) were sensitized and motivated by ovalbumin (OVA) and aluminium hydroxide. The symptoms rating scale (symptoms score>5 as successful model) was used to evaluate AR symptoms of two kinds of mice after the AR model were set up. The differences of OVA serum specific IgE (OVA-sIgE) and the levels of interleukin 4 (IL-4) in Kunming mice model group and Kunming mice blank group were evaluated, the symptom scores, OVA serum specific IgE (OVA-sIgE) and the levels of interleukin 4 (IL-4) of successful model of Kunming mice and BALB/c mice were compared, and the difference between two kinds of animal models. SPSS 22.0 statistical software was used for statistical analysis was analysed. SPSS 22.0 statistical software was used for statistical analysis. Results: During the experiment, 2 mice died in BALB/c mouse model group, and no mouse died in Kunming mouse model group. Kunming model group gained a certain incease of weight. The clinical symptom scores, OVA sIgE levels, serum IL - 4 levels of Kunming mouse model group were significantly higher than those of blank control group. The difference was statistically significant [(6.100+/-0.568) vs (2.700+/-0.823), (29.083+/-10.470) ng/ml vs (3.908+/-1.984) ng/ml, (219.250+/-30.821) pg/ml vs (140.056+/-27.684) pg/ml, all P<0.05]. Compared with BALB/c mice model group, the symptom score and serum level of IL-4 of Kunming mice model group had no statistically significant differences (6.100+/-0.568) vs (6.313+/-0.704), (219.250+/-30.821) pg/ml vs (253.294+/ 53.953) pg/ml, all P>0.05), and the difference of serum level of OVA-sIgE was statistically significant ((29.083+/-10.470) ng/ml vs (76.277+/-25.724) ng/ml, P<0.05). Conclusions: Kunming mice are able to obtain a clinically significant AR model through OVA modeling, with a significant increase in serum OVA-SIgE and IL 4. Kunming mice AR model shows good tolerance, and could reduce the losses in animal experiment. PMID- 28728239 TI - [Effect of hydrogen-rich saline on the CD4(+) CD25(+) Foxp3(+) Treg cells of allergic rhinitis guinea pigs model]. AB - Objective: To explore the effect of hydrogen-rich saline on the CD4(+) CD25(+) Foxp3(+) Treg cells in a guinea pig model of allergic rhinitis (AR) and investigate the underling anti-inflammatory mechanism. Methods: Using random number table, eighteen guinea pigs were divided into three groups (control group/AR group/HRS group, n=6 of each group). AR guinea pig model was built with ovalbumin and aluminum. The guinea pigs were injected with hydrogen-rich saline (HRS group) for ten days after sensitation. And control group was injected with equal normal saline at the same time. Number of sneezes, degree of runny nose and nasal rubbing movements were scored. Peripheral blood eosinophil count was recorded. The content of interleukin 10(IL-10) and transforming growth factor beta (TGF-beta) in the serum were detected by enzyme-linked immunosorbent assay (ELISA). Immunohistochemical method was taken to detect IL-10 and TGF-beta in nasal mucosa. The proportion of CD4(+) CD25(+) Foxp3(+) T cells in the CD4(+) T cells of spleen and peripheral blood were determined with flow cytometry. SPSS 17.0 software was used to analyze the data. Results: There was significant difference in symptom scores among them. The scores of AR group preceded control group, and HRS could decrease the scores of AR ((6.29+/-1.79) vs (1.01+/-0.71), (4.50+/-0.84) vs (6.29+/-1.79), F=24.725, all P<0.05). The highest number of eosinophils in the peripheral blood belonged to control group, and the number of eosinophils were dramatically reduced after HRS administration ((0.41+/ 0.05)*10(9)/L vs (0.25+/-0.03 )*10(9)/L, (0.32+/-0.03)*10(9)/L vs (0.41+/ 0.05)*10(9)/L, F=70.05, all P<0.05). The content of IL-10 and TGF-beta in control group is peak ((86.88+/-17.17) pg/ml, (598.28+/-72.70) pg/ml, respectively), and compared with AR group, HRS also increased the expression of IL-10 and TGF-beta of peripheral blood ((72.54+/-11.75) pg/ml vs (53.49+/-10.07) pg/ml, (530.23+/ 57.15) pg/ml vs (482.69+/-65.96) pg/ml, F value was 28.357, 14.128, respectively, all P<0.05). The proportion of CD4(+) CD25(+) Foxp3(+) Treg cells in controls exceeded HRS group and AR group (1.81%+/-0.10%, 1.29%+/-0.74%, respectively), and HRS treatment increased the ratio of CD4(+) CD25(+) Foxp3(+) Treg cells than AR group of peripheral blood ((1.50%+/-0.11%) vs (1.15%+/-0.11%), F=168.96, P<0.05). But there was no significant diferences in splene tissue ((1.01%+/-0.08%) vs (0.98%+/-0.09%), F=97.381, P>0.05). Conclusion: Both the number and the cytokine secretion of CD4(+) CD25(+) Foxp3(+) Treg cells are decreased in AR group, HRS may inhibit inflammatory response and ameliorate AR via improving the number and the cytokine secretion. PMID- 28728240 TI - [The implantation of Bonebridge in bilateral congenital malformation of external and middle ear]. AB - Objective: To evaluate the auditory efficacy of Bonebridge implantation in patients with bilateral congenital malformation of external and middle ear. Methods: Eleven cases (6 males and 5 females) had unilateral Bonebridge implantation. The age ranged from 8 to 26 and the average age was 16.9. Seven to ten days after operation, the first fitting was undergone. In acoustic sound field, the average auditory thresholds were respectively measured for unaided ears and Bonebridge implanted ears by pure tone auditory (PTA, 0.25, 0.5, 1, 2 and 4 kHz). For the group over 12-year-old, MSTM was applied to evaluate speech discrimination score (SDS). For the other cases, MLNT was used as the test material. The auditory efficacy post Bonebridge implantation would be analyzed and evaluated by comparing the differences between unaided ears and Bonebridge implanted ears. Results: The bone conduction audibility threshold after Bonebridge implantation was as well as the preoperative. The auditory threshold with Bonebridge aided was improved to 25-35 dB HL, when compared to that of the unaided ears in the sound field. The SDS in the group over 12-year-old was improved about 50%; the efficacy was slightly limited for the other two cases (both less than 12 years old). Statistical analysis showed that there were significant differences between unaided ears and Bonebridge implanted ears in the sound field and SDS(P<0.05). Conclusions: The auditory efficacy of Bonebridge is significant and noticeable in patients with bilateral congenital malformation of external and middle ear. Bonebridge provides a new and effective way for patient with congenital malformation of external and middle ear to reconstruct hearing. PMID- 28728241 TI - [Petrous bone cholesteatoma: surgery approach and outcomes]. AB - Objective: To investigate the choice of surgical approach of petrous bone cholesteatoma (PBC)and surgical outcomes. Methods: A retrospective study was performed on 90 patients diagnosed and treated for PBC from January 2000 to December 2014 by the Chinese People's Liberation Army General Hospital otolaryngologists. According to Sanna's classification, 40 out of the 90 cases were supralabyrinthine, five infralabyrinthine, four infralabyrinthine-apical, 25 massive and 16 apical. Five cases underwent transmastoid and retrolabyrinthine approach, translabyrinthine approach was performed on six patients, 19 cases underwent subtotal petrosectomy, seven cases underwent transotic approach, 41 cases underwent middle fossa approach, combined transmastoid/middle fossa approach was performed on 11 cases, translabyrinthine and sphenoid sinus approach were performed on one case. Supralabyrinthine cases mainly applied middle fossa approach (77.5%, 31/40) and combined transmastoid and middle-fossa approach(20.0%, 8/40). Combined transmastoid-retrolabyrinthine approach were applied for all the infralabyrinthine cases (100.0%, 5/5). Infralabyrinthine apical cases mainly applied subtotal petrosectomy (75.0%, 3/4). Massive cases mainly applied subtotal petrosectomy (60.0%, 15/25), transcochlear approach (20.0%, 5/25), and translabyrinthine approach (16.0%, 4/25). Apical cases mainly applied middle fossa approach (62.5%, 10/16). Results: Ninty percent (18/20) of the patients who had preoperative grade I facial nerve function maintained in the postoperative period. Out of 90 cases, only 11 cases received open cavity, and the rest cases received cavityobliteration. There were three cases of recurrence, four cases of cavity infection, three cases of cerebrospinal fluid leakage, and one case of epidural hematoma, who all received surgeries. Conclusions: Sanna's classification should be used to classify different kinds of PBC cases, choose the best surgical approach for different cases, and preserve or repair facial function during removal of PBC, and thus reduce recurrence and complications. PMID- 28728242 TI - [Expression and significance of pepsin in lingual tonsil hypertrophy]. AB - Objective: To discuss the relationship between lingual tonsil hypertrophy and laryngopharyngeal reflux. Methods: Ninety-two patients who received throat surgery in Nanfang Hospital between October 2015 and October 2016 were enrolled. Twenty-six healthy volunteers were recruited as normal controls. All participants were assessed with the reflux finding score(RFS) and the size of lingual tonsils were evaluated using a clinical grading system proposed by Friedman under electronic laryngoscope. The score of reflux symptom index(RSI), personal history and medical history were gathered. Biopsy specimens of lingual tonsils were taken from all participants for the immunohistochemical stain of pepsin.SPSS 19.0 software was used for statistical analysis. Results: There were 46.2% (12/26) pepsin-positive and 53.8% (14/26) pepsin-negative volunteers in normal controls. There were 87.0% (80/92) pepsin-positive and 13.0% (12/92) pepsin-negative patients in study group. The severity of lingual tonsil hypertrophy and expression intensity of pepsin in patients were significantly higher in volunteers (Z=-3.636, Z=-5.273, P<0.01). The severity of lingual tonsil hypertrophy was positively associated with the pepsin level in patients (r=0.556, P<0.01). The patients with pepsin-positive expression showed significant correlation between lingual tonsil hypertrophy and the positive rate of RSI and RFS (r=0.258, r=0.225, P<0.05). Analysis of correlated factors indicated that lingual tonsil hypertrophy was associated with smoking (chi(2)=8.502, P<0.05). Conclusions: The expression of pepsin can be detected in lingual tonsil tissues. The lingual tonsil hypertrophy is closely related to laryngopharyngeal reflux. PMID- 28728244 TI - [Five-cases report of pharyngeal hairy polyps in infant]. PMID- 28728243 TI - [The treatment effect of eustachian tube atresia with laser and connical plastic tube after radiotherapy for nasopharyngeal carcinoma]. AB - Objective: To investigate the method in treatment of Eustschian tube atresia caused by radiotherapy. Methods: Two cases diagnosed of Eustschian tube atresia following radiotherapy were retrospectively analyzed in Department of Otorhinolaryngology, Divided Hospital of Shanghai University Communication Affiliated First People Hospital in Apr. 2014 and Oct. 2015. Both cases were female, 65 and 64 years old, and accepted radiotherapy six and 20 years ago respectively. The pharyngeal orifices of Eustschian tube were found to be totally closed under endoscope. The closed Eustschian tubes were re-opened by laser and re-shaped by a slim and conical plastic tube for more than six months. They were followed up and evaluated over 12 months. Results: At six and 12 months after treatment, round mouths were formed in the pharyngeal orifice of Eustachian tube, and the patients had no resistance in Valsalva's test. No shrink or abnormal opening of orifice was found at follow-up of 20 and 12 months. Conclusion: The method of re-opening by laser and re-shaping by a slim and conical plastic tube is recommended to treat Eustschian tube occlusion caused by radiotherapy. PMID- 28728245 TI - [Prophylactic thyroidectomy in two children indentified RET germline mutations with multiple endocrine neoplasia type 2A]. PMID- 28728246 TI - [Clinical analyses of 3 cases of cervical necrotizing fasciitis]. PMID- 28728247 TI - [Small cell neuroendocrine carcinoma in paranasal sinus: report of two cases]. PMID- 28728248 TI - [A case report of recurrent mental cell lymphoma involving tonsils]. PMID- 28728249 TI - [Application of narrow band imaging endoscopy in identifying of extent disease after chemotherapy for laryngeal carcinoma]. PMID- 28728250 TI - [Paraganglioma in the bottom of tongue: one case report]. PMID- 28728251 TI - [Progress of dopamine in obstructive sleep apnea hypopnea syndrome]. AB - The etiology and pathogenesis of sleep obstructive apnea hypopnea syndrome (OSAHS) is not yet definitive, evidence shows that the dysfunction of pharyngeal nerve and the atonia of the muscle innervated by these nerve could play an important role in the progress of OSAHS. Dopamine is a neurotransmitter in the central nervous system which significantly affects the sleep-awake regulation. So far mounting evidence shows that dopamine has a potential role in the modulation of hypoglossal nucleus. The progress of dopamine in obstructive sleep apnea hypopnea syndrome is reviewed in this article. PMID- 28728252 TI - [Diagnosis and treatment of vocal diseases due to unhealthy phonation]. PMID- 28728254 TI - [Prebiotics and infant intestinal health]. PMID- 28728253 TI - [Effects of prebiotics on infants]. PMID- 28728255 TI - [Expert consensus of food allergic gastrointestinal disease]. PMID- 28728256 TI - [Single center retrospective study of 184 children with inflammatory bowel disease seen from 2000-2014]. AB - Objective: To investigate the clinical data of children with inflammatory bowel disease (IBD) retrospectively, including Crohn's disease (CD) and ulcerative colitis (UC) and identify the clinical characteristics and trends of change. Method: Clinical data of hospitalized patients diagnosed as IBD in Beijing Children's Hospital from January 2000 to December 2014 were collected and retrospectively analyzed. Patients were divided into six groups based on type of disease and year of admission: Group A1(CD, 2000-2004) included 12 patients, Group B1(CD, 2005-2009) included 11, Group C1(CD, 2010-2014) included 51; Group A2(UC, 2000-2004) included 17, Group B2(UC, 2005-2009) included 25, Group C2(UC, 2010-2014) included 68. Result: A total of 184 IBD patients were included in the study, 74 had CD and 110 had UC. The hospitalization constituent ratio of CD increased from 0.6/10 000 in Year 2000 to 2.9/10 000 in Year 2014. The hospitalization constituent ratio of UC increased from 0.5/10 000 in Year 2001 to 3.9/10 000 in Year 2014. The hospitalization constituent ratios of CD and UC both increased gradually(P<0.05). Up to 61.4%(113/184) of IBD patients belong to early onset IBD, furthermore the very early onset IBD and infantile IBD accounted for 41.8%(77/184) and 26.6%(49/184) respectively. For CD, ileocolonic type(47.3%, 35/74) and non-structuring, non-penetrating type (67.6%, 50/74) were more common. Perianal disease occured in 31.1%(23/74) of CD patients; 81.1%(60/74) of CD patients had moderate/severe activity. For UC, pancolitis type(59.1%, 65/110) was more common. There were no significant changes for location of pathological change, disease behavior, activity degree of CD, extent of UC lesion and incidence of surgery, intestinal perforation and hemorrhage of gastrointestinal tract for IBD in the past 15 years(P>0.05). Severe UC(S3) was more common in Group A2(64.7%, 11/17), but moderate UC(S2) was more common in Group C2(48.5%, 33/68), the difference was statistically significant (P=0.001 7). Conclusion: During the past 15 years, the hospitalization constituent ratio for IBD in our hospital showed a growing trend. The ratio of infantile IBD and very early onset IBD was high. For CD, perianal disease was commonly seen and most patients had moderate/severe activity. The surgery rate and incidence of intestinal obstruction and perforation were higher in the CD patients than UC patients. For UC, the lesions were more extensively combined with higher disease activity. PMID- 28728257 TI - [Eosinophilic esophagitis in children: analysis of 22 cases]. AB - Objective: Eosinophilic esophagitis (EoE) is a chronic immune-mediated esophageal disease.The current domestic reports of EoE in children is rare.The aim of this study was to analyze the clinical features, the diagnosis and treatment advance of EoE in children by case analysis and literature review. Method: Clinical data of 22 children with EoE from January, 2011 to December, 2015 in Children's Hospital, Zhejiang University School of Medicine were recorded, retrospective analysis was performed on clinical presentation, gastroendoscopy and histopathological examination features and the treatment. Result: (1) Clinical data: EoE can occur at any age in children (5 months to 13 years). The most common clinical manifestations of EoE are vomiting and abdominal pain, 45% (10/22) and 41%(9/22) respectively. (2) Endoscopy and pathological features of esophageal mucosa: 11 cases with coarse mucous membrane (50%), 6 cases with congestion or erosion of esophageal membrane (27%), 5 cases with longitudinal crack (23%), 3 cases with ring uplift (14%), 3 cases with granular uplift (14%), 3 cases with normal mucosa(14%). Histopathologic manifestation is eosinophil infiltration and the eosinophil counts were all more than or equal to 15/HP. (3) Laboratory results: 13 cases had increasing eosinophil counts and eosinophils proportion (62%). (4)Allergy history: among 22 cases, 7 patients had allergy history (32%). (5) Situation of treatment and remission: 16 cases had clinical remission by oral omeprazole; 2 cases had clinical remission by oral Omeprazole and Montelukast sodium; 1 case acquired remission by elimination diet; 1 case acquired remission by elimination diet and oral prednisone. 2 cases dropped out; Only 2 patients received gastroendoscopy re-examination after 3 months and revealed esophageal mucosal histologic complete recovery. Conclusion: The clinical symptoms of EoE in children varies.Esophageal mucosal features of gastroendoscopy examination in children with EoE were longitudinal crack, white exudates or plaques, paper mucosa, ring uplift and granular uplift.Most patients could achieve remission by using proton-pump inhibitors, only few children needed elimination diet and change formula, or even oral glucocorticoids. PMID- 28728258 TI - [Follow-up and genetic study of 43 Chinese children with type I Alexander disease]. AB - Objective: To identify the clinical and genetic characteristics in 43 Chinese children diagnosed with type I Alexander disease (AxD). Method: Forty-three type I AxD cases identified by glial fibrillary acidic protein (GFAP) gene mutations in Peking University First Hospital from 2005 to 2016 were followed up. The data of medical history, physical examination and magnetic resonance imaging (MRI) were collected. All these patients were followed up in December 2010, Febury 2012, June 2014 and January 2016, respectively. Result: Forty-three patients were genetically confirmed as type I AxD and the median age at the last visit was 11.71 years (10.27, 13.15). The characteristic clinical manifestations of these type I AxD patients were developmental delay (79%, 34/43), seizures (86%, 37/43), macrocephaly (the median percentile of head circumference is 90%), and paroxysmal deterioration (27%, 13/43). All the 43 patients' brain MRI satisfied typical MRI features proposed by van der Knaap. According to the analysis of the long-term follow-up, patients with type I AxD began to have obvious regression in motor function after 7 years of age, and the social life ability was milally impaired 8(6, 10)scores at the last follow-up. Seventeen heterozygous missense mutations of GFAP were identified in 43 genetically confirmed patients, and 4 mutations were novel. The mutations in 41 patients (95%, 41/43) were de novo. Three hot spots of mutation in Chinese patients were found: p. Arg239(35%, 15/34), p. Arg79 (26%, 11/43) and p. R88 (16%, 7/43). Conclusion: The characteristic clinical manifestations of type I AxD patients are developmental delay, seizures, macrocephaly and paroxysmal deterioration. Moreover, a few patients may present with brain stem symptoms, mental abnormalities, scoliosis or kyphosis. Patients with type I AxD may show significant regression in motor function after 7 years of age. PMID- 28728259 TI - [Impact of allergic airway diseases on risk of attention deficit hyperactivity disorder in school-age children]. AB - Objective: To investigate the impact of allergic airway diseases on the risk of attention deficit hyperactivity disorder (ADHD) in school-age children. Method: Used stratified cluster sampling method, school-age children in first to sixth grade in primary schools in 9 randomly selected cities including Shanghai, Guangzhou, Xi'an, and Wuhan were enrolled in the study. Interview of parents with questionnaires, which included school-age individual and family social environment questionnaire (including history of diagnosed ADHD, allergic rhinitis, and bronchial asthma) and Children's Sleep Habits Questionnaire (CSHQ), were finished and collected during November to December in 2005.Diagnosed allergic rhinitis and asthma by specialist were independent variables and divided into following three categories as no allergic diseases (neither allergic rhinitis nor asthma), single allergic disease (allergic rhinitis or asthma), and combined allergic diseases (allergic rhinitis and asthma). Diagnosed ADHD as dependent variable, binary logistic regress model was used to analyze the risks of ADHD in school-age children. Result: Totally 23 791 questionnaires were handed out, while 22 018 were collected. The children had an average age of (8.8+/-1.8) years, within which 10 869 were male, and 11 021 were female. The risk ratios of ADHD were 2.197 (95%CI: 1.823-2.648) and 3.150 (95%CI: 2.082-4.760) in children with single allergic disease and combined allergic diseases separately. There was no significant difference after adjusting for the factor of sleep habits, as the risk ratios were 2.055 (95%CI: 1.683-2.508) and 3.140 (95%CI: 2.061-4.784) in children with single and combined allergic airway disease separately. Conclusion: Allergic rhinitis and bronchial asthma increased the risk of ADHD, not depending on sleep habits. Hence, allergic airway diseases could be independent risk factors of ADHD. PMID- 28728260 TI - [Clinical analysis of pacing therapy and treatment of complications during follow up in children]. AB - Objective: To analyze characteristics of permanent pacemaker implantation in children as well as treatment and prognosis of complications. Method: Clinical data of children who underwent endocardial or epicardial permanent pacemaker implantation between April 2000 and June 2016 in Shanghai Xinhua Hospital and Shanghai Children's Medical Center were analyzed retrospectively. These patients were discharged 5 days after implantation. Electrocardiogram, chest X ray, echocardiography and pacemaker programming were performed during follow-up. Treatment regimes, complication management and prognosis were analyzed retrospectively. Result: Data of a total of 193 cases were collected. One hundred and six patients were male and 87 patients were female.The average age was (5.09+/-4.05) years(0.4-16 years)and the average weight was (20.47+/-11.62) kg.133(68.9%); patients were implanted with endocardial pacemakers and 60(31.1%)patients were implanted with epicardial pacemakers; 135(69.9%)patients were single-chamber paced with 87 from RVA and 48 from RVOT. fifty eight(30.1%)patients were dual chamber paced. These included 122(63.2%)postoperative third degree AV block(III-AVB), 38 (19.7%)congenital complete AV block (CCAVB), 3(1.6%)post ventricular septal defect (VSD) interventional therapy AV block, 23 (11.9%)sick sinus syndrome (SSS) and 7(3.6%)III-AVB after fulminant myocarditis. One hundred and thirty seven(71%)patients were followed up for an average duration of 5.32 years(0.3-10 years). Pacemaker exchange were performed in 46 patients due to battery exhaustion.The average life of battery was 5.4 years (1-9 years). Sixteen patients underwent lead exchange due to dislocation or separation.One patient underwent lead extraction due to recovery of AV conduction 21 days after surgery for complete transposition of great arteries (D-TGA/VSD). Skin abrasion, infection or dehiscence occured in 6 patients. Heart failure occurred in 2 patients at 6 and 8 years after implantation whose heart functions improved after switching from VVI to DDD or adding ACEI . One patient died suddenly due to ineffective pacing caused by lead fracture. Another patient under DDD pacing was found to have atrial myocardial perforation with normal sensing and pacing so that no intervention was performed. Conclusion: The pacing mode and path through which leads are implanted for permanent pacemaker implantation in children have their peculiar characteristics.Some complications might occur during follow-up with good prognosis if appropriately treated. PMID- 28728261 TI - [Characteristics of the joint involvement in fibrodysplasia ossificans progressiva and follow up]. AB - Objective: To summarize the clinical data of 15 patients with fibrodysplasia ossificans progressiva (FOP), follow up and analyze the characteristics of the joint involvement in FOP. Method: From May 2005 to December 2016, fifteen FOP cases had been diagnosed in the Children's Hospital Capital Institute of Pediatrics. All medical records and follow-up data were collected and a retrospective analysis was made on the joint involvement in FOP. Pearson correlation analysis was used for data, P<0.05 for the difference was statistically significant. Result: There were 8 males and 7 females in 15 cases. The age of onset was 2(1-6)years. The age at diagnosis was 6 (4-9) years. All cases had hallux valgus deformity and bone mass formation. Twelve cases had joints involvement on enrollment into this study: 8 cervical vertebra, 7 shoulder joint, 5 hip joint, 4 elbow joint, 3 wrist joint, 2 temporomandibular joint, 2 lumbar vertebra. The age of diagnosis and duration of disease were positively correlated with the number of the involved joints (r=0.523, 0.628; P=0.045, 0.012); mild changes were found in joint imaging. Thirteen cases received telephone follow-up, the average duration of follow-up was 6(3-7)years, no change in 11 cases, disease progress in 2 cases. Conclusion: Joint involvement is a common complication of FOP, especially the cervical vertebra.Multiple joints involvement, dominant functional impairment, and mild imaging changes are the characteristics of joint lesions caused by FOP.The number of involved joints gradually increases with increase of age of the patients and the prolonged course of the disease. PMID- 28728262 TI - [Evaluation of efficacy of immunosuppressive therapy plus recombinant human thrombopoietin for children with severe aplastic anemia]. AB - Objective: To evaluate the therapeutic efficacy and safety of immunosuppressive therapy (IST) combined with recombinant human thrombopoietin (rhTPO) for severe aplastic anemia (SAA) in pediatric patients. Method: A retrospective case-control study was conducted and the clinical data of 45 pediatric patients with de novo SAA admitted to the Anemia Diagnosis and Treatment Center of Chinese Academy of Medical Sciences & Blood Disease Hospital during the period from December 2009 to December 2014 were analyzed. Among them, 15 patients were treated with the regimen of IST together with rhTPO and 30 patients were given IST treatment only. The variation characteristics of the peripheral blood routine as well as the transfusion of blood products was dynamically observed, and the therapeutic efficacy was assessed respectively after 3, 6 and 12 months after the treatment. In the meantime, adverse effects related to rhTPO application were recorded. Thereafter, the statistics of the two groups were compared by non-parametric rank sum test. Result: Among 45 pediatric patients, there were 26 male and 19 female, and the median age was 11 years (6-14). The number of patients received good hematological response(complete remission (CR) plus good partial response (GPR)) in the combinatory group versus vs. the IST group was 6 vs. 3 patients (chi(2)=3.906, P=0.048) at the 3rd month, 7 vs. 7 patients (chi(2)=1.568, P=0.210) at the 6th month, and 13 vs. 14 patients (chi(2)=6.667, P=0.01) at the 12th month respectively. For those achieved good hematological response at the 3rd month, the amount of platelets transfusion and red blood cells transfusion of the combined group were both less than that of the IST group during the period from the 10th to the 12th weeks (platelets transfusion: 1.4 U vs. 2.9 U, t= 3.523, P=0.002; red blood cells transfusion: 0.8 U vs. 2.6 U, t=-2.392, P=0.026). No serious adverse effect related to rhTPO application was observed in the IST combined with rhTPO group. Conclusion: Application of rhTPO can improve the short term therapeutic efficacy of IST for pediatric SAA, alleviate transfusion dependence, and has a good safety profile. PMID- 28728263 TI - [Identification of mutations associated with coronary artery lesion susceptibility in Kawasaki disease by targeted enrichment of genomic region sequencing technique]. AB - Objective: To screen and identify the mutations in Kawasaki disease by targeted enrichment of genomic region sequencing technique and investigate susceptibility genes associated with coronary artery lesion. Method: This was a case-control study.A total of 114 patients diagnosed as Kawasaki disease treated in Shanghai Children's Hospital between December 2015 and November 2016 were studied and another 45 healthy children who were physically examined in outpatient department were enrolled as control group. Patients were divided into two groups based on the results of echocardiogram. Peripheral venous blood was obtained from patients and controls. Genomic DNA was extracted. SeqCap EZ Choice libraries were prepared by targeted enrichment of genomic region technology. Then the libraries were sequenced to identify susceptibility genes associated with coronary artery lesion in patients diagnosed as Kawasaki disease.Susceptible genes were identified by Burden test, Pearson chi-square test or Fisher's exact probability test. Result: There was statistically significant difference in TNFRSF11B(rs2073618)G>C(p.N3K)mutation and GG/GC/CC genotype between Kawasaki disease group and control group(chi(2)=15.52, P=0.00). There was statistically significant difference in TNFRSF13B(rs34562254)C>T(p.P251L)mutation(chi(2)=10.40, P=0.01)and LEFTY1(rs360057)T>G(p.D322A)mutation(chi(2)=8.505, P=0.01)between patients with coronary artery lesions and those without. Conclusion: Targeted enrichment of genomic region sequencing technology can be used to do primary screening for the susceptible genes associated with coronary artery lesions in Chinese Kawasaki patients and may provide theoretical basis for larger sample investigation of risk prediction score standard in Kawasaki disease. PMID- 28728264 TI - [Exploratory research on diagnostic essentials of pediatric tuberculous pleurisy]. AB - Objective: To summarize the clinical diagnostic essentials of pediatric tuberculous pleurisy so as to reduce the misdiagnosis rate. Method: A retrospective study was conducted on 113 cases of tuberculous pleurisy who were seen from August 2006 to September 2014 in the second Department of Respiratory Medicine, Beijing Children's Hospital Affiliated to Capital Medical University. Meanwhile, another 113 cases of children over 5 years of age with mycoplasma pneumoniae pneumonia complicated with pleural effusion were randomly selected as control group. The following five items were analyzed in relation to the diagnosis: fever, cough, lung lesions, pleural effusion(unilateral or bilateral), adenosine deaminase (ADA) level in pleural effusion, tuberculin skin test(PPD). The sensitivity and specificity of single item and combined items in diagnosis were studied. Result: (1) Among two groups, the proportion of patients with persisting fever was 92.0% (104 cases) and 98.2% (111 cases), while the proportion of patients with cough was 47.8% (54 cases) and 99.1% (112 cases) (chi(2)=76.3, P<0.01), respectively. There were 25(22.1%) cases and 113(100.0%) cases with lung lesions (except for atelectasis) in two groups (chi(2)=144.1, P<0.01), respectively. The proportion of patients with unilateral pleural effusion was 94.7%(107 cases) and 71.7%(81 cases)(chi(2)=21.4, P<0.01) while the patients with positive PPD results was 93.8%(106 cases) and 3.5%(4 cases)(chi(2)=184.3, P<0.01). The level of ADA in pleural effusion in both groups are comparable[46.4(22.0-70.9)U/L]and[39.5(26.3-78.5)U/L]. (2)The sensitivity of the lack of cough, lack of lung lesions, unilateral pleural effusion and PPD test positive in diagnosis of tuberculous pleurisy were 52.2%, 77.9%, 94.7%, 93.8%, while the specificity was 99.1%, 100.0%, 28.3%, 96.5%, respectively. Among the four items, the specificity of unilateral pleural effusion was only 28.3%, so it needed to be added with other indicators to improve the specificity. The sensitivity of unilateral pleural effusion combined with positive PPD, lack of cough, lack of lung lesions were 88.5%, 50.4% and 73.5%, while the specificity was 96.5%, 99.1%, and 100.0%, respectively, which significantly improved the specificity so as to reduce misdiagnosis. Conclusion: In children aged over 5 years who present with persistent fever and pleural effusion, tuberculous pleurisy should be considered even in the absence of cough or lung lesions(except for atelectasis), or with positive PPD result, any of the three features is specific for the diagnosis. Unilateral pleural effusion is more meaningful for the diagnosis when it is combined with any of the above three features. PMID- 28728266 TI - [A STAT1 mutation causing hematological autoimmunity with chronic mucocutaneous candidiasis]. PMID- 28728265 TI - [Mass spectrometry combined with gene analysis for prenatal diagnosis of glutaric acidemia type I]. AB - Objective: To investigate the value of amniotic fluid metabolite detection by mass spectrometry combined with gene mutation analysis in the prenatal diagnosis of glutaric acidemia type I (GA-I). Method: From January 2009 to December 2016, Department of Pediatric Endocrinology and Genetic, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine carried out prenatal diagnosis for 24 cases of pregnant women with GA-Iproband. 24 pregnant women without organic acidemia proband for conventional prenatal diagnosis at the same period were used as the control group. The pregnant women of the two groups had the amniocentesis at 16 to 20 weeks of gestation.The levels of glutaryl carnitine (C5DC) and octanoylcarnitine (C8) in amniotic fluid were detected by tandem mass spectrometry, and the levels of glutaric acid was determined by gas chromatography-mass spectrometry. All the amniotic fluid cells underwent GCDH gene testing. Result: A total of 4 cases of fetuses were diagnosed by gene mutation analysis combined with mass spectrometry detection, the levels of C5DC (1.58(0.89-2.85) MUmol/L), C5DC/C8 (19.74(12.40-25.93))and glutaric acid (129.96 (90.09-66.02) mmol/mol Cr) were significantly higher than the upper limit of the reference, of which in one case with the proband only on mutation was detected, and in the amniotic fluid cells also only one mutation was detected, the diagnosis was made according to the significantly increased levels of amniotic fluid C5DC, C5DC/C8 and glutaric acid. Twenty cases of fetuses were identified as non-GA-Ichildren, of whom in 2 cases of proband only one mutation was detected, and also in amniotic fluid cells one mutation was detected, in 2 cases the diagnosis was excluded because the normal levels of C5DC, C5DC/C8 and glutaric acid. There were 2 cases whose levels of C5DC or glutaric acid were slightly higher than the upper limit of the reference, but the diagnosis was excluded according to genetic testing. Conclusion: Prenatal diagnosis cannot be made by gene analysis when the proband mutation is not clear, and it cannot determine whether the fetus is patient when the mass spectrometry detection of amniotic fluid metabolite is mildly abnormal, while mass spectrometry detection of amniotic fluid C5DC, C5DC/C8 and glutaric acid levels combined with GCDH gene analysis can make up the deficiencies, and make the prenatal diagnosis of GA-I more reliably. PMID- 28728267 TI - [Report of a case with succinyl-CoA: 3-ketoacid CoA transferase (SCOT)]. PMID- 28728268 TI - [infantile hepatic hemangioendothelioma camplicated with persistent plmonary hypertension: three cases report]. PMID- 28728270 TI - [The advance of clinical research on Eosinophilic esophagitis in children]. PMID- 28728269 TI - [Calcium-sensitive potassium channelopathy with de novo KCNMA1 mutation: a case report]. PMID- 28728271 TI - [Research progress in inflammatory bowel disease associated serological markers in children]. PMID- 28728273 TI - [A retrospective study of the perioperative complications following whole lung lavage in the treatment of pulmonary alveolar proteinosis]. AB - Objective: To evaluate the safety of the procedures of whole lung lavage(WLL) for pulmonary alveolar proteinosis(PAP) in perioperative period. Methods: In this retrospective study, we collected clinical data from 78 WLL procedures of PAP patients from January 2006 to June 2016 in Guangzhou Institute of Respiratory Disease. The causes of perioperative complications were analyzed. Results: Eighteen (23.07%) of the 78 procedures developed complications, including pleural effusion(n=4), pneumonia(n=4), cardiac failure(n=2), cardiac arrhythmia (n=2), pneumothorax(n=2), atelectasis(n=1), lung edema(n=1), laryngeal edema(n=1), pleural effusion and pneumonia(n=1). All complications were mild and easy to treat. Seventy-four procedures had successful extubation, but 4 procedures developed a prolonged time of extubation. Age, DSS, PaCO(2,)FEV(1,)lavage volume, lavage times and underlying diseases were not predictors for any complications(each P>0.05). High fluid recovering rate had a protective effect against the occurring of complications (Wald=7.672, OR<0.01, P<0.05). Conclusions: Whole lung lavage was a safe procedure in the treatment of PAP. Complications could recovery after proper therapy. The perioperative complications showed a correlation with low fluid recover rate. Operation under guideline was the key to avoid complications. PMID- 28728272 TI - [The level of asthma control in China from a national asthma control survey]. AB - Objective: To assess the overall asthma control level in urban China. Methods: A multi-center, cross-sectional, questionnaire-based survey was carried out in 30 provinces in China (except Tibet). Asthmatic outpatients who met the inclusion criteria were recruited consecutively from 30 sub-centers from October 2015 to May 2016. Data of demographic characteristics, asthma control, asthma management, asthma exacerbations and self-management, and disease perception were collected by face-to-face interviews. Results: Totally 3 875 asthmatic outpatients were recruited. Asthma control level was assessed according to GINA 2015. The prevalence of asthma control was 28.5%(1 099/3 854). Among 10 cities, which were also involved in the asthma control survey in 2008, the level of asthma control improved from 28.7% in 2008 to 39.2%(533/1 361) in 2016. The rate of hospitalizations due to asthma exacerbations was 26.4%(1 017/3 858) and the rate of emergency visits was 22.4%(864/3 858). Among adult patients, 18.4%(568/3 092) of them had been absent from work while 63.6%(63/99) adolescent patients had been absent from school because of asthma attacks in the previous year. Conclusion: Although the level of asthma control in China is still far from ideal at present, the status has been improved in some cities. Poorly controlled asthma resulted in increase of hospitalizations, emergency department visits and work/school absences. PMID- 28728274 TI - [A retrospective study of 10 cases of post-transplant bronchiolitis obliterans]. AB - Objective: To analyze the clinical features of bronchiolitis obliterans syndrome (BOS) in patients with allogeneic hematopoietic stem cell transplantation (HSCT). Methods: This retrospective study included patients who underwent allogeneic HSCT from January 1998 to December 2016. The clinical features, radiological manifestations and treatment of clinically proven BOS were reviewed. Results: Of 681 patients who experienced HSCT, 10(1.47%) met the diagnostic criteria. The duration of BOS onset after transplantation was 5-48 months, averaging (18+/-15) months. Cough and worsening dyspnea were present in most cases, and 9 (90%) of the cases had manifestations of chronic graft versus host disease. Hyperinflation with areas of decreased attenuation and bronchiectasis were present in 7 (70%) cases and air trapping was present during the expiratory phase of imaging. The management of BOS consisted of high dose systemic corticosteroids and immunosuppressive therapy. Patients were treated with bronchodilators if they were symptomatic and during acute exacerbations of respiratory symptoms. In 5 (50%) patients the condition deteriorated and caused death, while in 3 patients the condition was improved. Two patients were lost to follow up. Conclusion: BOS is the most common late noninfectious pulmonary complication following allogeneic HSCT and has a poor prognosis. PMID- 28728275 TI - [Changes and differences of DNA methylation in human macrophages infected with virulent and avirulent Mycobacterium tuberculosis]. AB - Objective: To profile DNA methylation and compare differentially methylated region (DMR) of macrophages infected with virulent and avirulent strains of Mycobacterium tuberculosis (MTB). Methods: PMA(50 ng/ml) treated THP-1 macrophages were left uninfected or infected with the virulent H37Rv(THP-1/Rv) or avirulent H37Ra(THP-1/Ra). The genomic DNA was then extracted and DNA methylation was profiled via Reduced Representation Bisulfite Sequencing (RRBS). The DNA methylation pattern and DMRs between the tested samples were indentified. DMRs associated genes were annotated, clustered by Gene Ontology (GO), and the pathways analyzed by Kyoto Encyclopedia of Genes and Genomes (KEGG). mRNA expression of several DMR-associated genes were verified by Q-PCR, and Student's t-test was used to analyze the differential expression between either 2 samples. Results: The mostly DNA methylated C in 3 samples was in CG, accounting for 98% of all types of methylated C(CG, CGH, CHH). Besides, the average DNA methylation level in THP-1/Rv, THP-1/Ra and THP-1/NC were 7.72%, 7.38% and 7.58% in the promoter, and 9.90%, 9.57% and 9.80% in the CpG island (CGI), respectively. We identified 58 DMRs between H37Rv and H37Ra infected THP-1 macrophages with an average length of 152 bp. Six DMRs-associated genes were enriched. Among them, AP 1 and DDIT4 were differentially expressed in cells infected with H37Rv and H37Ra. Conclusions: Infection with MTB is not correlated with a large-scale gain or loss in DNA methylation in host cells. AP-1 and DDIT4 might be novel virulence-related genes regulated by DNA methylation of their corresponding promoter regions. PMID- 28728276 TI - [The role of HuR in mediating snail expression in human small airway epithelium induced by cigarette smoke extract]. AB - Objective: To investigate the abundance of human antigen R (HuR) in small airway epithelial cells stimulated by cigarette smoke extract (CSE) as well as the role of HuR in mediating snail which is recognized as a key transcription factor in regulating epithelial-mesenchymal transition (EMT). Methods: Human small airway epithelial cells (HSAEpiC) cultured in vitro were exposed to cigarette smoke extract (CSE) to model COPD status. Real-time PCR and western blotting analysis were used in detecting HuR protein and mRNA expression in cells with CSE which were divided into 5 groups: a control group, a 1%-24 h group, a 3%-24 h group, a 1%-48 h group and a 3%-48 h group. Small interfering RNA (siRNA) transfection was used to decrease HuR abundance. HuR expression at both mRNA and protein levels was detected using Real-time PCR and Western blotting analysis respectively, and the experiment was divided into 3 groups: a control group, a transfection control group and a transfection group. Snail, E-cadherin and vimentin levels were determined using Western blotting test in cells with both CSE exposure and HuR siRNA transfection which were divided into three groups: control group, CSE group and CSE + transfection group. Results: After CSE stimulation, HuR expression was increased at both mRNA and protein levels [mRNA 1%-24 h group (1.12+/-0.04), 3% 24 h group (1.41+/-0.06), 1%-48 h group (1.26+/-0.05), 3%-48 h group (1.49+/ 0.06), protein 3%-24 h group (1.35+/-0.08), 1%-48 h group (1.17+/-0.06), 3%-48h group (1.42+/-0.06) all P<0.05]. Compared with the control siRNA, after HuR siRNA transfection, HuR mRNA and protein levels were significantly reduced [mRNA level (0.33+/-0.06) vs (1.02+/-0.10), protein level (0.46+/-0.07) vs (0.97+/-0.06), all P<0.01]. Control siRNA transfection had no effect on HuR expression [mRNA level (1.02+/-0.10), protein level (0.97+/-0.06), all P>0.05]. After 48 h stimulation with 3% CSE, the expression of HuR (1.47+/-0.11), snail (1.46+/-0.05) and vimentin (1.56+/-0.05) increased and the expression of E-cadherin (0.49+/-0.05) decreased. After transfection and CSE stimulation, the expression of HuR (0.84+/ 0.06), snail (1.22+/-0.06) and vimentin (1.11+/-0.09) decreased and the expression of E-cadherin (0.73+/-0.06) increased. (All P>0.05). Conclusions: CSE promoted the expression of HuR in human small airway epithelial cells. HuR participated in the regulation process of EMT key transcription factor snail and might regulate EMT process by this action. PMID- 28728277 TI - [Effects of PI3Kdelta-RhoA pathway on phagocytosis defect of alveolar macrophages in a mouse model of chronic obstructive pulmonary disease]. AB - Objective: To investigate effects of Phosphoinositide3-Kinases (PI3Kdelta)-Ras homolog gene family member A(RhoA) pathway on phagocytosis deficiency of alveolar macrophages (AMs) in a mouse model of chronic obstructive pulmonary disease (COPD). Methods: Twenty mice were exposed to cigarette smoking to establish the COPD model, with 20 mice as the control group. AMs were isolated from lung tissue by discontinuous density gradient centrifugation and then divided into a healthy control group, a COPD group, a healthy IC87114 group and a COPD IC87114 group. The culture of IC87114 group was mixed with a final concentration of 1 nmol/L IC87114 for 24 hours. Mean fluorescence intensity (MFI) and the positive percent of AMs engulfing flurescein isothiocyanate-labeled Escherichina coli (FITC E.coli) (AM%) were detected by flow cytometry. Real-Time PCR(RT-PCR)and Western blot were applied to detect mRNA and protein. G-LISA RhoA Kit was used to detect the activity of RhoA, and laser scanning confocal microscopy was used to observe the cytoskeleton structure of AMs. Results: Phagocytosis of AM: MFI and AM %in the COPD group [(4 512+/-517), (32.2+/-4.6)%] were decreased than those in the healthy control group [(9 857+/-1 042), (68.0+/-4.0)%, all P<0.01]. Compared with the COPD group, MFI and AM% in the COPD IC87114 group [(6 894+/-472), (50.6+/ 2.1)%] were increased (all P<0.01). The expressions of mRNA and protein of PI3Kdelta in the COPD group (3.14+/-0.54, 0.84+/-0.08) were increased than those in the healthy control group (1.00+/-0.00, 0.57+/-0.07) (all P<0.01). Compared with the COPD group, the expressions of mRNA and protein of PI3Kdelta in the COPD IC87114 group (1.52+/-0.28, 0.66+/-0.13) were decreased (all P<0.01). The RhoA mRNA, protein and activity in the COPD group (0.70+/-0.07, 0.41+/-0.10, 0.70+/ 0.06) were decreased compared to those in the healthy control group (1.00+/-0.00, 0.56+/-0.09, 1.19+/-0.09) (all P<0.01). Compared with the COPD group, the expression of mRNA, protein and activity of RhoA in the COPD IC87114 group(0.91+/ 0.08, 0.48+/-0.06, 0.86+/-0.06) were increased (P<0.01, P<0.05). Cytoskeleton of AM: The pseudopods of the healthy control group and the healthy IC87114 group extended well, and the ability of phagocytosing FITC-E.coli was intact, but there were some defects in the COPD group. Compared with the COPD group, the COPD IC87114 group was better, both in phagocytosing and extending of pseudopods. Negative correlations existed between the mRNA, protein of PI3Kdelta with mRNA, protein and activity of RhoA. Negative correlations also existed between the mRNA, protein of PI3Kdelta with MFI, but positive correlations between RhoA and MFI were observed in all groups. Conclusion: The phagocytosis of AMs in COPD mice was defective, with abnormal rearrangement of the cytoskeleton. PI3Kdelta negatively regulated RhoA, while PI3Kdelta over activation resulted in decreasing activity of RhoA and then induced abnormal cytoskeleton rearrangement in AMs, which led to phagocytosis deficiency.IC87114 inhibited PI3Kdelta activation, improved the activity of RhoA and partly recovered phagocytosis of AMs. PMID- 28728279 TI - [Update of treatment for the systemic sclerosis associated interstitial lung disease]. PMID- 28728278 TI - [New therapeutic advances in noninvasive ventilation of obesity hypoventilation syndrome]. PMID- 28728280 TI - [The problems and challenges in the current eye health management in China]. AB - The core goal of "Thirteenth Five-Year Plan for National Eye Health (2016 to 2020)" is to obtain eye health. At present, there are still several problems hampering Chinese eye health management system development, including the lack of top policy design, system protection and financial investment, weak support from primary health care institutions, other medical disciplines and social forces, and insufficient digital information. To achieve effective eye health management, it is necessary to address the sustainability of eye health management, the integrity of eye health digital information data and the feasibility of eye health payment. It is recommended that eye health-related medical workers take positive actions to strengthen the digital information construction and service capacity construction of eye disease prevention and control network, carry out health promotion extensively, and conduct eye health management mode research and practice.(Chin J Ophthalmol, 2017, 53: 481-483). PMID- 28728281 TI - [A cross-sectional study of cataract in residents with type 2 diabetes living in Xinjing Town, Shanghai]. AB - Objective: To investigate the prevalence, subtypes and risk factors of cataract in type 2 diabetic individuals. Methods: Geographically defined cluster sampling method was used in this population-based, cross-sectional study. There were 7 756 type 2 diabetes individuals in Xinjing Town with a residential population of 88 864. The type 2 diabetic individuals were randomly selected from 20 basic sample units in Xinjing Town of Changning District from April to June 2016. All participants received visual acuity measurement and eye examination. The standard of lens opacity assessment was according to the Lens Opacities Classification SystemII(LOCSII). The prevalence of cataract in diabetic individuals was calculated with LOCS>=2. Multivariate Logistic regression analysis was used to explore the relevant factors of cataract in type 2 diabetic individuals. Results: A total of 1 719 type 2 diabetic individuals were included in the analysis. There were 682 men (39.67%) and 1 037 women (60.33%) in this population. There were 434 cataract individuals and the prevalence of cataract was 25.25%. There were 269 cases of nuclear type (15.7%), 38 cases of cortical type (2.2%), 2 cases of posterior subcapsular type (0.12%) and 42 cases of mixed type (2.4%) in the 1 719 individuals. Multivariate Logistic regression analysis showed that age (P<0.001), duration of diabetes (P<0.001), education (P=0.005), fasting blood glucose (P(6.1 7.7mmol/L)=0.025, P(7.8-24.3mmol/L)=0.022, compared with 3.6-6.0 mmol/L of fasting blood glucose), and ocular axial length (P<0.001) were associated with cataract. Conclusion: Cataract is a common ophthalmic disease in adults with type 2 diabetes in Xinjing Town. Regular screening of diabetes in the high risk population and intensive control of both glucose and blood pressure in diabetic patients are recommended to prevent and delay the development of cataract. (Chin J Ophthalmol, 2017, 53: 489-494). PMID- 28728282 TI - [Epidemiologic study of tear film lipid layer thickness measurement in the population of Taishitun Community in Beijing]. AB - Objective: To investigate the distribution of tear film lipid layer thickness (LLT) and the relationship between symptoms and signs of dry eye and tear film LLT in the population of Taishitun Community in Beijing. Methods: A cross sectional study. From May 2016 to August 2016, three streets of Taishitun Community were randomly selected as survey districts and 540 persons were taken as investigation subjects. Every participant completed 6 items of dry eye examinations as follows: questionnaire (Ocular Surface Disease Index, OSDI), measurement of tear film LLT, tear film break-up time (TBUT), corneal and conjunctival staining, SchirmerItest and the infrared meibomian photography. According to their age, all participants were divided into four groups: junior group (<18 years old), youth group (18 to 40 years old), middle-aged group (41 to 59 years old) and the elderly group (over 60 years old). With the OSDI criteria, no dry eye symptom group (score, <12 points), mild to moderate dry eye symptom group (score, 12 to 32) and severe dry eye symptom group (score, 33-100) were included. With the statistical methods of variance analysis and multivariate Logistic regression analysis, distribution of the variables of LLT and the relationship between dry eye symptoms and LLT were studied. Results: A total of 473 residents finally participated in this study, and the response ratio was 87.6%. The values of LLT were normally distributed. The average LLT was (59.87+/ 18.50) nm [(60.16+/-19.15) nm in males and (59.67+/-18.57) nm in females], and the comparison of LLT with different genders was not statistically significant (t=0.198, P=0.843). The tear film LLT of four different age groups had statistical significance (F=15.092, P<0.05), and increased with age [(56.10+/ 18.33) nm in the junior group, (54.60+/-16.29) nm in the youth group, (60.61+/ 19.18) nm in the middle-aged group and (73.25+/-14.58) nm in the elderly group]. The LLT was inversely proportional to the severity of dry eye symptoms. With a thinner LLT, the symptoms of the subjects turned severe. In the elderly with different degrees of symptoms, the LLT was significantly different (F=0.019, P<0.05), while in the youth and middle-aged groups with different degrees of symptoms, the LLT was not significantly different (F=0.096, P>0.05. F=0.538, P>0.05). In the OSDI symptom questionnaire, only blurred vision and decreased visual acuity were related to the tear film LLT (P<0.05). There was no significant correlation between the TBUT, SchirmerItest result, meibomian gland loss rate and the tear film LLT (P>0.05). Conclusions: In Taishitun Community of Beijing, the values of tear film LLT had a normal distribution. The LLT was positively correlated with age, but inversely correlated with the severity of the symptoms of dry eye. There was no significant correlation between the LLT and the TBUT, SchirmerItest result and meibomian gland loss rate.(Chin J Ophthalmol, 2017, 53: 495-501). PMID- 28728283 TI - [Epidemiological survey of visual impairment in Funing County, Jiangsu]. AB - Objective: To investigate the prevalence of visual impairment and factors associated with visual impairment among people aged 50 years and above in Funing County, Jiangsu Province. Methods: Cross-sectional study. Random cluster sampling was used in selecting individuals aged >=50 years in 30 clusters, and 5 947 individuals received visual acuity testing and eye examination. Stata 13.0 software was used to analyze the data. Multivariate logistic regression was used to detect possible factors of visual impairment such as age, gender and education. Statistical significance was defined as P< 0.05. Results: A total of 6 145 persons aged 50 years and above were enumerated, and 5 947 (96.8%) participants were examined. Based on the criteria of World Health Organization (WHO) visual impairment classification and presenting visual acuity, 138 persons were diagnosed as blindness, and 1 405 persons were diagnosed as low vision. The prevalence of blindness and low vision was 2.32% and 23.63%, respectively. And the prevalence of visual impairment was 25.95%. Based on the criteria of WHO visual impairment classification and best-corrected visual acuity, 92 persons were diagnosed as blindness, and 383 persons were diagnosed as low vision. The prevalence of blindness and low vision was 1.55% and 6.44%, respectively. And the prevalence of visual impairment was 7.99%. Concerning presenting visual acuity and best-corrected visual acuity, the prevalence of blindness and low vision was higher in old people, females and less educated persons. Cataract (46.63%) was the leading cause of blindness. Uncorrected refractive error (36.51%) was also a main cause of visual impairment. Conclusion: The prevalence of visual impairment is higher in old people, females and less educated persons in Funing County, Jiangsu Province. Cataract is still the leading cause of visual impairment. (Chin J Ophthalmol, 2017, 53: 502-508). PMID- 28728284 TI - [Association of diabetic retinopathy with diabetic peripheral neuropathy in type 2 diabetic patients: the Beijing Desheng Diabetic Eye Disease Study]. AB - Objective: To determine the prevalence of diabetic retinopathy (DR) and diabetic peripheral neuropathy (DPN) in the Beijing Desheng Diabetic Eye Disease Study cohort and to investigate the association between DR and DPN. Methods: Cross sectional study in a type 2 diabetic cohort. Questionnaires were collected and physical examinations were performed. Ophthalmologic examinations consisted of visual acuity with pinhole, slit-lamp examination of the anterior segment and seven-field 30(o) mydriatic fundus photography. The severity of DR was graded using a modified ETDRS method. Peripheral neuropathy examinations included 10-g Semmes-Weinstein monofilament, 128-Hz tuning fork and Tip-Therm. Statistical analysis was performed using SPSS software version 19.0. Results: A total of 959 patients with type 2 diabetes mellitus were enrolled, among whom 354 (36.9%) had DR and 523 (54.5%) had DPN. The prevalence of DPN was 61.8% in patients with DR and 50% in patients with no DR (chi(2)=13.66, P<0.01). Logistic regression analysis showed that DR was associated significantly with age (OR=1.03, 95%CI: 1.01-1.06) and gender (male) (OR=2.32, 95%CI: 1.51-3.58), whereas the presence of DPN increased the risk of DR (OR=1.5, 95%CI: 1.12-2.01). Conclusions: DPN is commonly seen in patients with type 2 diabetes mellitus and increases the risk of DR. (Chin J Ophthalmol, 2017, 53: 509-513). PMID- 28728285 TI - [Prevalence and surgery status of cataract among adults aged 60 years or above in two villages of Nantong]. AB - Objective: To assess the prevalence, surgical coverage rate and social burden rate of cataract blindness among adults aged >=60 years in the suburban population of Nantong, Jiangsu, China. Methods: It was a population-based cross section study. A census with individuals aged >=60 years was conducted in two villages of the suburb area in Nantong from June to August, 2008. A total of 1 305 individuals received visual acuity and eye examinations. Lens and cataract operative status were evaluated by slit-lamp biomicroscopy. Multiple logistic regression analysis was employed to analyze the prevalence of cataract, cataract surgical coverage rate and cataract blindness social burden rate among different ages, genders, educational backgrounds, marital statuses and salary levels. The results in the suburb were compared to the urban and rural areas. Results: Among 1 305 individuals, 376 cases of cataract were found. The prevalence of cataract was 28.81%. The rate was higher in the aged, less educated and low salary persons (P<0.01). In 47 eyes with cataract surgery, 19.15% of eyes were treated by modern extra-capsular surgery and 38.30% received phacoemulsification. The rate of intraocular lens implantation was 57.45%. The cataract surgical coverage rate was 40.48% and the cataract blindness social burden rate was 3.22%. The cataract surgical coverage rate was higher in the primary-educational persons than illiterate persons (P<0.05). The cataract blindness social burden rate was higher in >=80-year-old persons than >=60-year-old persons (P<0.05) and lower in married persons than single persons (P<0.05). The cataract surgical coverage rate was lower in the suburb area than in the city area, while the cataract blindness social burden rate was opposite. The rate of postoperative presenting visual acuity and best-corrected visual acuity of over 0.7 was 14.89% and 23.40% in the operated eyes, respectively. The main causes of unfavorable postoperative visual acuity (<0.3) were retinal disorders, post-capsular opacity, corneal opacity, refractive errors and glaucoma. Conclusions: Cataract is the most common and important eye disease that may lead to blindness and severe visual impairment among adults aged 60 years or above in the suburb of Nantong City. The prevalence of cataract is related to age, education background and economy level. The cataract surgical coverage rate is low and the cataract blindness social burden rate is high. The first important task in blindness prevention is still the elimination of cataract blindness and the improvement of visual outcomes after cataract surgery. (Chin J Ophthalmol, 2017, 53: 514-521). PMID- 28728286 TI - [Corneal astigmatism among 2 085 age-related cataract patients before surgery]. AB - Objective: To investigate the characteristics and distribution of corneal astigmatism before surgery among age-related cataract patients in the Hubei area. Methods: Retrospective study. From January 1, 2012 to July 31, 2016, IOL Master measurements of all qualified cataract surgery candidates were retrospectively collected. Descriptive statistical analysis was used to assess the degree, distribution and type of corneal astigmatism. Kolmogorov-Smirnov (K-S) test was used to evaluate the normal distribution of variables. One-way analysis of variance and Kruskal-Wallis test were applied for the comparison of variance for normally and non-normally distributed quantitative data among different age groups. Spearman's rank test was used to assess the relationship between age and corneal astigmatism. Results: The mean age of the 2 085 patients (3 586 eyes) involved was (73.1+/-9.43) years old, with more women (58.3%) than men. The mean value of corneal curvature was 44.33 D (95%CI: 44.28-44.39), and the mean corneal astigmatism was 1.06 D (range, 0.05 D to 6.74 D). K-S test indicated the distribution of corneal curvature was normal (P=0.18), while corneal astigmatism did not obey the normal distribution (P<0.01). Corneal astigmatism was between 0.25 D and 1.25 D in 67.7% of the eyes, >1.25 D in 29.7%, and<0.25 D in 4.2%. Corneal astigmatism degree increased with the age increase (P<0.01). There was no statistical difference in corneal astigmatism between women and men (P=0.075). However, women had steeper corneal curvatures than men with statistical difference (P<0.01). Corneal astigmatism with the rule was observed in 29.0% of the eyes, while astigmatism against the rule was found in 53.0%. And astigmatism against the rule increased with age. Conclusion: Corneal astigmatism mostly distributes between 0.25 D and 1.25 D in age-related cataract patients who lived in Hubei. Corneal astigmatism degree increased with age, and the dominant type was astigmatism against the rule. There was no difference in astigmatism between men and women patients aged 50 years and above, but in 70- to 79-year-old patients, women had a higher astigmatism degree than men. The corneal curvature of women was steeper than men in general and in each age group. (Chin J Ophthalmol, 2017, 53: 522-527). PMID- 28728287 TI - [Analysis of structure and function of meibomian glands in healthy population at different ages]. AB - Objective: To observe the structure and function of meibomian glands in normal population at different ages. Methods: From October 2011 to August 2012, meibomian gland information was collected in healthy volunteers without any symptoms of ocular discomfort, aged more than 5 years. The people were grouped by every 10 years of age. The meibomian gland opening, secretion state and characteristics and Max's line were observed by slit lamp microscopic examination, and the meibomian gland dropouts were examined by noncontact infrared meibomian gland microscopy. The changes of meibomian glands were scored from 0 to 3, 0 for a normal state, 1 for mild abnormality, 2 for moderate abnormality and 3 for severe abnormality. The Mann-Whitney U test was used to compare the meibomian scores between male and female, and between left and right eyes. The correlation of these scores and the age of volunteers was analyzed by the Spearman test. Results: Among all the 100 volunteers, there were 47 males and 53 females, aged from 5 to 83 years (mean, 40.9+/-22.9). The meibomian gland dropouts were gradually increasing with age, significantly faster after 40 years old (scores for each age group were 2(1), 2(1), 2(1), 2(1), 3(2), 3.5(1.75), 4(3), 6(2). Meibomian gland opening, secretion traits and secretor status gradually became poorer with age, and changes were dramatically fast in the group of 40-49 years of age [scores of this group were 3(1.5), 3(3) and 2(2)], but slowed down after age of 50 years. Moreover, the Max's line position moved to the front gradually with age, with a marked change in the group of 40-49 years of age [scores for each age group were 0(1), 1(1), 2(2), 2(2), 3(2), 2(2), 3(2)], 4 gland changes showed a significantly positive relation to age(r=0.729, 0.635, 0.669, 0.639, 0.470. P<0.01), but not to gender and eye dominance (P>0.05). Conclusions: Meibomian gland opening and meibomian gland secretion become worse with age. The age of 50 years old is the key period for the meibomian gland changes. (Chin J Ophthalmol, 2017, 53: 528-533). PMID- 28728288 TI - [Descemet's membrane endothelial keratoplasty for treatment of patients with corneal endothelial decompensation]. AB - Objective: To evaluate the clinical outcomes of Descemet's membrane endothelial keratoplasty (DMEK) for treatment of patients with corneal endothelial decompensation in China. Methods: Interventional case series. Ten patients (10 eyes) with the diagnosis of corneal endothelial decompensation received DMEK during July 2016 and September 2016 in Zhongshan Ophthalmic Center. Descemet's membrane of the donor tissue was carefully stripped from the underlying stroma manually and cut with a 7.75- or 8.0-mm-diameter donor punch. After stained with 0.06% typan blue, the donor disc loaded on an inserter was gently inserted into the anterior chamber of the recipient. When the rolled graft was unfolded, air was carefully injected into the anterior chamber underneath the graft, so that the graft attached to the stroma of the recipient. All patients were followed up for 3-6 months. The best spectacle corrected visual acuity, the status of donor disc, corneal thickness and corneal endothelial cell density were documented and analyzed. Results: At 1 day after surgery, 1 donor disc presented a rolled edge, and repeated DMEK surgery was performed for this patient. The remaining 9 donor discs presented in place well. At 1 month after surgery, 7 donor discs were found to well attach to the back surface of the recipient stroma with normal corneal posterior surface using anterior segment optical coherence tomography. The average corneal thickness reduced to (620+/-67) MUm from preoperative (680+/ 78.3) MUm (t=2.677, P=0.025). At 3 months after surgery, 6 patients achieved clear corneas with best spectacle corrected visual acuity ranging from 0.4 to 0.8. The endothelial cell density was 1 342.3+/-436.5 (872 to 1 933) cells/mm(2) in the patients with clear corneas. The average corneal thickness reduced to (612+/-70) MUm (t=2.971, P=0.016). Conclusions: DMEK could improve visual acuity for corneal endothelial decompensation, but there were more technical difficulties in Chinese eyes. (Chin J Ophthalmol, 2017, 53: 534-539). PMID- 28728289 TI - [The protective effect of pigment epithelial-derived factor modified human umbilical cord mesenchymal stem cells on rats with diabetic retinopathy]. AB - Objective: To investigate the effect of pigment epithelial-derived factor (PEDF) gene-modified human umbilical cord mesenchymal stem cells (MSC) on rats with diabetic retinopathy (DR). Methods: Experimental study. Human umbilical cord MSC were transfected by lentivirus packaging PEDF-MSC-green fluorescent protein (GFP) and GFP-MSC plasmid vectors, and the expression of PEDF and vascular endothelial growth factor (VEGF) was measured in the cell culture medium. Fifty adult male Sprague-Dawley rats were randomly divided into five groups: normal control group (group A), DR control group (group B), phosphate-buffered saline (PBS) treated group (group C), GFP-MSC treated group (group D) and PEDF-MSC-GFP treated group (group E), with 10 rats in each group. Streptozotocin was intraperitoneally injected to make early DR models. After four-month intervention, groups D and E were given intravitreal injection of GFP-MSC and PEDF-MSC-GFP; group C was given intravitreal injection of phosphate-buffered saline; groups A and B did not receive special treatment. The changes of retina in different groups were detected by hematoxylin and eosin staining, and the thickness of inner plexiform layer, inner nuclear layer and outer nuclear layer was measured by computer-based image analytical system. Immunohistochemistry was applied to observe PEDF and VEGF. Real-time quantitative polymerase chain reaction was used to detect the expression of PEDF and VEGF mRNA. Results: The expression of CD105, CD73 and CD90 was positive, while the expression of CD34, CD45, CD11b, CD19 and HLA-DR was negative. ELISA results showed that after transfection PEDF protein expression in the supernatant of PEDF-MSC (84.09+/-7.07) MUg/L was higher than the control group (9.03+/-0.14) MUg/L (P<0.05). At 2 weeks after intravitreal injection, green fluorescence was observed in the rat vitreous of groups D and E under a fluorescence microscope; no obvious green fluorescence was found in the retina. After 2 months of intravitreal injection, the thickness of inner plexiform layer in group E was significantly decreased; the thickness of inner nuclear layer and outer nuclear layer was higher (P<0.05). Immunohistochemical staining showed that 2 months after intravitreal treatment, the average optical density values of PEDF were improved, but the average optical density values of VEGF were decreased in group E (P<0.05). Real-time polymerase chain reaction showed that 2 months after treatment, the expression level of PEDF mRNA in group E was improved, but the expression level of VEGF mRNA was decreased (P<0.05). Conclusions: Intravitreal injection of PEDF-MSC could up-regulate the expression of PEDF and down-regulate the expression of VEGF in diabetic rats and may represent a novel candidate resource for cell therapy of DR nerve damage. (Chin J Ophthalmol, 2017, 53, 540 547). PMID- 28728290 TI - [Advances in research of divergence insufficiency]. AB - Divergence insufficiency is acquired esotropia at distance fixation with symptomatic uncrossed diplopia but fusion at near. It can be divided into two forms: primary isolated form and secondary form associated with neurologic abnormalities, also called divergence palsy. The clinical features of divergence insufficiency include small esotropia only at distance but orthotropia or small esophoria at near, comitant deviation at lateral gaze, reduced divergence fusion, full abduction and normal saccadic velocities in abduction. Primary divergence insufficiency is a benign condition predominantly occurring in adults older than 50 years. Recently, studies on the etiology of age-related distance esotropia, also called sagging eye syndrome, have demonstrated that the degenerative changes of orbital tissue could induce the inferior displacement of the inferior rectus pulley, different from the neurological etiology in abducens nerve palsy and secondary divergence insufficiency. The treatment goal is to relieve diplopia. Both prism and regular surgeries including medial rectus recession and lateral rectus resection are effective. Some unusual surgeries have been applied in divergence insufficiency, but further investigations with large samples are needed. The recent research advances in the etiology, diagnosis, differential diagnosis and treatment of divergence insufficiency are reviewed in this article. (Chin J Ophthalmol, 2017, 53: 552-556). PMID- 28728291 TI - [Relationship of endometrial thickness and endometrial cancer risk in postmenopausal women]. AB - Evaluation of the vaginal bleeding of postmenopausal women is crucial to diagnose endometrial lesions. Endometrial thickness measured by transvaginal ultrasonography provides an important reference for diagnosis. Currently, no specific cut-off value of endometrial thickness has been identified to predict the malignant risk for endometrial thickening and postmenopausal women without any symptoms. Most of resected endometrial specimens from postmenopausal women without any symptoms are diagnosed as benign or normal tissues. It seems that postmenopausal women without any symptoms have no need for general screen or intervention of endometrial cancer. PMID- 28728292 TI - [Detection and clinical significance of circulating tumor cells in osteosarcoma using immunofluorescence combined with in situ hybridization]. AB - Objective: To investigate the clinical significance of detection of circulating tumor cells (CTCs) in peripheral blood from patients with osteosarcoma (OS) using the iFISH (immunofluorescence and fluorescence in situ hybridization) method. Methods: The live cells recovery rate of immune-magnetic beads was evaluated by live-cell fluorescent tracer technology. The expression of CD45 and CK18 on the cell surface of HOS and HepG2 cells was measured by flow cytometry. And the chromosome aneuploidy was detected by centromeric FISH probe CEP8. Subsequently, 23 OS patients were enrolled and divided into two groups, relapse or metastasis group and primary group. And the prognostic significance of CTCs numbers was analyzed. Results: The live cells recovery rate of immune-magnetic beads was higher than 90%. The flow cytometry results showed that HOS cells were double negative for the surface biomarkers of CD45 and CK18. In addition, the FISH-CEP8 signal abnormality rate were 96.5% in HOS cells. Thus, CTC was identified using the criteria as follows: the cells with CEP8-positive signal >2 accounted for more than 96.5% of the total cells, of which the cells with >3 positive signal were more than 65.0%. Among the enrolled patients, 19 patients had detectable CTCs in the peripheral blood. The CTCs numbers in the relapse or metastasis group and primary group were 2.846+/-1.281 and 1.400+/-1.506, respectively. The results showed that the CTCs in patients with recurrence or metastasis were significantly higher than those in primary patients (P=0.021). Conclusions: To our knowledge, this is the first evidence of existence of CTCs in OS patients. The CTCs numbers were positively associated with disease progression and poor prognosis. These results may provide a potential prognostic tool for monitoring metastasis and recurrence in OS patients. Trial registration: Chinese Clinical Trial Registry, ChiCTR-OOC-15005925. PMID- 28728293 TI - [Curcumin induces apoptosis and protective autophagy in human gastric cancer cells with different degree of differentiation]. AB - Objective: To investigate the effect of curcumin on the apoptosis and autophagy of human gastric cancer cells with different degree of differentiation. Methods: Gastric cancer cell lines BGC-823 and MKN-28 were treated with curcumin at different concentrations. The effect of curcumin on cell proliferation was measured by MTT assay. Apoptosis was assessed by flow cytometry. Autophagy status was analyzed by acridine orange staining. The expression levels of apoptotic and autophagy-related proteins were detected by Western blot. Results: The cell viability of BGC-823 and MKN-28 was inhibited by curcumin in a time- and dose dependent manner. At 48 h after treatment, the IC(50) value of BGC-823 (15.18 MUmol/L) was close to that of MKN-28 (15.84 MUmol/L), and the difference was not statistically significant (P=0.513). Meanwhile, flow cytometry showed that curcumin induced the apoptosis of gastric cancer cells in a dose-dependent manner. Western blot results showed that the expression of pro-apoptotic proteins bax, active-caspase-3 and active-caspase-9 was significantly increased in BGC-823 and MKN-28 cells, whereas that of the anti-apoptotic protein bcl-2 was strikingly reduced. In addition, the formation of acidic vesicular organelles in cytoplasm, conversion of LC3-I to LC3-II and increased levels of autophagy-related proteins Beclin1, Atg7 and Atg5-Atg12 were observed in curcumin-treated cells. Moreover, activation of PI3K/Akt/mTOR signaling pathway was also significantly suppressed after curcumin treatment. Blocking autophagy by adding the autophagy inhibitor 3 methyladenine (3-MA) significantly promoted the apoptotic cell death induced by curcumin. Conclusions: Curcumin induces apoptosis and protective autophagy in human gastric cancer cells in vitro. Curcumin combined with autophagy inhibitor may provide a more effective strategy for its clinical application. PMID- 28728294 TI - [Depletion of GP73 inhibits invasion and metastasis of hepatocellular carcinoma cells]. AB - Objective: To explore the in vitro and in vivo effect of GP73 on the proliferation, invasion and metastasis in hepatocellular carcinoma. Methods: GP73 gene was knocked out using CRISPR/Cas9 gene editing system in H22 and HepG2 cells, and stable knock out strains were constructed. The knockout efficiency was measured by western blot. Colony formation assay was used to detect the effect of GP73 on long-term survival ability. Cells were then highly synchronized in G(1) phase upon treatment with cell synchronization reagents (mimosine), and the percentage of cells in G(2)/M phase at different time points was detected by flow cytometry. The invasive and metastasis abilities of hepatocellular carcinoma cells were detected by TranswellTM assay. Furthermore, the tumor formation abilities in vivo were examined using subcutaneous xenograft models. Results: The stable knock out strains of GP73 in H22 and HepG2 cells were successfully established via puromycin selection. The number of colonies of GP73 knock out groups in HepG2 and H22 cells 10 days after transfection were 400+/-70 and 248+/ 60, respectively. They were significantly lower than those in the control groups (980+/-40 and 1 100+/-50, respectively; P<0.01). In addition, GP73 knockout slowed down the cell cycle progression. Moreover, the cell numbers that had migrated to the underside of the filters were 312+/-50 and 305+/-49 in the GP73 knockout groups of HepG2 and H22 cells, respectively, significantly lower than 1 540+/-87 and 1 270+/-86 in the controls (P<0.01). For transwell invasion assay, the cell number that had invaded into the underside of the filters were 230+/-47 and 238+/-54 in the GP73 knockout groups of HepG2 and H22 cells, respectively, significantly lower than 648+/-74 and 596+/-63 in the controls(P<0.01). Furthermore, the tumor volume of GP73 knockout group was (70+/-170) mm(3,) significantly smaller than (1 200+/-110)mm(3) of the control guoup (P<0.01). Conclusions: GP73 knockout decreases the proliferation, invasive and migratory abilities of HepG2 and H22 cells in vitro and in vivo. GP73 may contribute to tumorigenesis of hepatocellular carcinoma. PMID- 28728295 TI - [Effect of 21-gene recurrence score on chemotherapy decisions for patients with estrogen receptor-positive, epidermal growth factor receptor 2-negative and lymph node-negative early stage-breast cancer]. AB - Objective: To investigate the effect of 21-gene recurrence score on adjuvant chemotherapy decisions for patients with estrogen receptor (ER)-positive, epidermal growth factor receptor 2 (HER-2)-negative and lymph node (LN)-negative early stage-breast cancer. Methods: One hundred and forty-eight patients with ER+ , HER-2- and LN- early stage breast cancer were recruited in the Ruijin hospital, Shanghai Jiao Tong University School of Medicine. The 21-gene recurrence score (RS)assay was performed and systemic therapeutic decisions were made before and after knowing the RS results under multidisciplinary discussion. The effects of RS assay and the other influential factors on adjuvant chemotherapy decision were further analyzed. Results: After knowing the RS results, treatment decisions were changed in 26 out of 148 patients(17.6%). Among them, 9 out of 26 patients were not recommended for chemotherapy; 16 of 26 had treatment recommendation changed to chemotherapy, and chemotherapy regimen was changed in the last one patient. Multivariate analysis showed that RS, age and histological grade were independent factors of decision-making for adjuvant chemotherapy. Conclusion: Our results suggest that 21-gene recurrence score significantly influences decision making for adjuvant chemotherapy in patients with ER+ , HER-2- and LN- early stage breast cancer. PMID- 28728296 TI - [Intramural gastric metastasis of esophageal squamous cell carcinoma: an analysis of imaging findings and clinicopathological features]. AB - Objective: To discuss the imaging findings and clinicopathological features of the intramural gastric metastasis (IGM) of esophageal squamous cell carcinoma. Methods: The imaging findings of 11 patients with IGM confirmed by surgical pathology were reviewed retrospectively, and compared with clinicopathological features. Of the 11 cases, eight underwent upper gastrointestinal radiography, ten underwent contrast enhanced computed tomography (CT) scans and one underwent plain CT scanning. Results: In all 11 cases, the primary cancer was located in the middle or lower thoracic esophagus, and nine of 11 had lymph nodes metastasis. All of the 11 tumors within the stomach were located in the upper one third of the stomach, with the maximum diameter of tumor ranging from 1.0 cm to 12.0 cm. Gastrointestinal radiography showed irregular filling defect of the stomach in three cases with clear border resembled a submucosal tumor. Mucosal folds of the stomach were irregular and rough in two cases. On CT scans, nodule or mass in the gastric wall was found in seven patients, and two of them were accompanied with ulcer formation. Eccentric or nodular gastric wall thickening was found in the other two patients. All of them were heterogeneous mild-to moderate enhancement. Conclusions: The imaging appearances of IGM have certain characteristics, but final diagnosis depends on histopathology. The prognosis of IGM was extremely poor, so the preoperative diagnosis is very important to guide clinical treatment. PMID- 28728297 TI - [The prognosis and clinicopathological characteristics of 70 gastric cancer patients with elevated serum AFP]. AB - Objective: This study aimed to review the clinicopathological characteristics and prognosis of advanced gastric cancer patients with elevated serum Alpha fetoprotein (AFP). Methods: From August 2006 to May 2016, 70patients with advanced gastric cancer were enrolled retrospectively. All these patients had pathologically confirmed gastric adenocarcinoma, had a serum AFP level of more than 20 ng/ml, and received at least first-line treatment. The clinicopathological data and follow-up data were collected for analysis. Results: Liver metastasis was more common in patients with AFP>=1 000 ng/ml, compared with AFP<1 000 ng/ml patients (78.6% vs 57.1%, P=0.064). In patients whose AFP level decreased >=50% after first-line chemotherapy, the disease control rate and overall survival were both better than those in patients with AFP decreased <50%(96.3% vs 56.7%, P=0.001; 17.2 m vs 8.8 m P=0.007). The overall survival of all these 70 patients ranged from 0.5-50.0 months. 31 patients received chemotherapy only, and 39 patients received combined therapy modality. The overall survival of these two groups were similar(11.0 m and 15.6 m, respectively, P=0.070). Conclusions: Serum AFP-elevated gastric cancer is a special subtype of gastric cancer. It's a heterogeneous cancer with different clinical outcomes. The extent of decrease of serum AFP level during follow-up may be a sensitive prognostic and predictive biomarker. Liver metastasis were more common in these patients, and combined treatment may improve survival. PMID- 28728298 TI - [The prognostic analysis of hepatocellular carcinoma based on the tumor neo vessels, macrophages and alpha-SMA in tumor microenvironment]. AB - Objective: To analyze the quantitative expression and prognostic significance of tumor neo-vessels, macrophages and fibroblasts in tumor microenvironment of hepatocellular carcinoma (HCC). Methods: The clinic-pathological features and tissue samples for 101 HCC cases were collected. Immunohistochemistry was used to stain the tumor neo-vessels, macrophages and fibroblasts on tumor tissue. The distribution results and quantitative data of above key components were acquired by inverted microscopy equipped with CRi Nuance multispectral analysis system. The number of tumor neo-vessels and macrophages on HCC tissue were counted and the thickness of cancer stroma based on the expression of fibroblasts was measured. The clinic-pathological characteristics and overall survival were analyzed. Results: The median disease free survival (DFS) of 101 HCC cases was 5 month. The quantitative analysis of tumor neo-vessels, macrophages and fibroblasts showed that the expression range was 51-429 with median 218, 110-555 with median 259, 35.61-555.35 with median 246.98, respectively. To take the median as cutoff, all the cases could be classified into high and low expression group. The survival analysis demonstrated that the high density group of macrophages (P=0.022) and fibroblasts (P<0.001) has shorter DFS than low density group, with statistical significance. The high tumor neo-vessels group has shorter DFS with median 5 month than low density group with median 7 month. However, there was no statistical significance between these two group (P=0.197). Combined with above the three stromal components, all the cases could be classified into low, middle and high group. The survival analysis demonstrated that the high density group of stromal components has shorter DFS than the other two groups with median 3 month (P=0.001). Multivariate analysis by Cox regression indicated that cirrhosis, metastasis status, macrophages and fibroblasts density were the independent prognostic factors. Conclusion: The key elements in tumor microenvironment including tumor neo-vessels, macrophages and fibroblasts were heterogenic in HCC tissues and played significant roles in HCC invasion and metastasis. PMID- 28728299 TI - [The value of B7-H4 and carcinoembryonic antigen in diagnosing the benign and malignant pleural effusion]. AB - Objective: To evaluate the value of combined detection of negative costimulatory molecule B7-H4 and carcinoembryonic antigen (CEA) in diagnosing malignant and benign pleural effusion. Methods: Ninety-seven pleural effusion specimen were collected, 55 of which were diagnosed as malignant pleural effusion and 42 were benign pleural effusion. Enzyme-linked immunosorbent assay(ELISA) was used to examine the concentration of B7-H4 and CEA in pleural effusion. Electro chemiluminescence immunoassay was used to detect the CEA level in pleural effusion. Receiver operating characteristic (ROC) curve was established to analyze and evaluate the single or combined detection of B7-H4 and CEA in diagnosing malignant and benign pleural effusion. Results: The concentrations of B7-H4 and CEA in malignant pleural effusion (MPE) group were (60.08+/-35.04) ng/ml and (41.49+/-37.16) ng/ml, respectively, obviously higher than (27.26+/ 9.55) ng/ml and (2.41+/-0.94) ng/ml of benign pleural effusion (BPE) group (both P<0.01). Area under curve (AUC) of B7-H4 was 0.884 in MPE groupand the diagnostic sensitivity and specificity were 81.8% and 90.5%, respectively, at the optimized cut off value of 37.25 ng/ml. Likewise, area under curve (AUC) of CEA was 0.954 and the sensitivity and specificity were 87.3% and 95.2%, respectively, at the cut off value of 4.18 ng/ml. When B7-H4 >37.25 ng/ml or CEA>4.18 ng/ml, the sensitivity of diagnosis as MPE was down-regulated to 90.9% and the specificity was elevated to 88.1%. When B7-H4 >37.25 ng/ml and CEA>4.18 ng/ml, the sensitivity of diagnosis as MPE was down-regulated to 78.2% and the specificity was elevated to 97.6%. The sensitivity and specificity of combined detection of B7-H4 and CEA to diagnose MPE were elevated to 90.9% and 97.6%, respectively. The level of B7-H4 in MPE and BPE were both positively correlated with CEA (r=0.670, P=0.001 in MPE and r=0.002, P=0.001 in BEP). Conclusions: B7-H4 is a potential tumor marker in diagnosing the benign and malignant pleural effusion. Although the diagnostic value of B7-H4 may not precede to CEA, the combined detection of B7-H4 and CEA can improve the diagnostic sensitivity and specificity of MPE. PMID- 28728300 TI - [Evaluate the value of (18)F-FDG PET-CT imaging in predicting the mutationsin epidermal growth factor receptor in lung adenocarcinoma]. AB - Objective: To investigate the value of maximum Standardized Uptake Value(SUVmax), Metabolic Tumor Volume (MTV) and Total Lesion Glycolysis (TLG) calculated from (18)F-FDG PET-CT in predicting the presence of epidermal growth factor receptor (EGFR) mutations in lung adenocarcinoma. Methods: We retrospectively reviewed 137 lung adenocarcinoma patients with EGFR mutations testing and pretreatment (18)F FDG PET-CT. Receiver Operating Characteristic (ROC) curve analysis was performed to quantify the predictive value of SUVmax,MTV,TLG. A multivariate logistic regression analysis was used to evaluate the predictive value of EGFR mutation. Results: Among 137 lung adenocarcinoma patients, 86(62.8%, 86/137) were identified with EGFR mutations. The SUVmax, MTV and TLG were 7.4, 5.28 cm(3,) 20.20, respectively. The optimal cut-off values of SUVmax, MTV and TLG were 7.99(AUC=0.658, 95% CI=0.566~0.752, P=0.002), 6.09 cm(3)(AUC=0.644, 95% CI=0.550~0.737, P=0.005), 35.08(AUC=0.650, 95% CI= 0.557~0.744, P=0.003), respectively. Multivariate analysis showed that TLG and smoking status were the most significant predictors of EGFR mutation(all P<0.05). Conclusion: TLG in (18)F-FDG PET/CT is an independent factor for predicting EGFR mutation in patients with lung adenocarcinoma, and has certain reference value for predicting EGFR mutation. PMID- 28728301 TI - [Surgical resection for gastric cancer patients with liver metastasis]. AB - Objective: To explore the surgical results and clinicopathological features of gastric cancer patients with liver metastases. Methods: The clinicopathological data and post-operative survival of 37 patients who underwent resection of liver metastasis from gastric cancer at our department from Dec. 2007 to Dec. 2014 were analyzed. Results: The 1-, 3-, and 5-year overall survival rates after resection were 91.4%, 57.9%, and 22.0%, respectively, with a median survival of 37 months. Univariate analysis revealed that lymph node metastasis, multiple hepatic metastases and no preoperative chemotherapy are unfavorable prognostic factors for overall survival. Multivariate analysis identified that lymph node metastasis and number of liver metastasis are independent prognostic factors. Conclusions: Gastric cancer patients with a solitary liver metastasis may be good candidates for gastric D2 resection combined with liver R0 resection. PMID- 28728302 TI - [Clinical efficacy of ladder neoadjuvant therapy in treatment of advanced mid-low rectal cancer]. AB - Objective: To explore the clinical efficacy of ladder neoadjuvant therapy in treatment of advanced mid-low rectal cancer. Methods: We performed a retrospective study of one hundred and eighty mid and low rectal cancer patients who underwent ladder neoadjuvant therapy(neoadjuvant chemotherapy followed by surgery if neoadjuvant chemotherapy was effective; neoadjuvant chemotherapy followed by neoadjuvant chemoradiotherapy if neoadjuvant chemotherapy was ineffective)(n=90) or neoadjuvant chemoradiotherapy (n=90). Results: In the ladder neoadjuvant therapy group, the descent stage rate was 85.6% (77/90), the anastomosis rate was 50.0% (45/90), the pre-sacral infection rate was 4.4% (4/90), the pathological complete remission (pCR) was 13.3%(12/90), R0 resection rate was 85.6% (77/90), the 2-year disease control rate was 76.7% (69/90), and the 2-year survival rate was 90.0% (81/90). In the control group, the descent stage rate was 88.9% (80/90), The anastomosis rate was 45.6% (41/90), the rate of pre-sacral infection was 11.1% (10/90), pCR was 16.7% 15/90), R0 resection rate was 88.9% (80/90), the 2-year disease control rate was 78.9% (71/90), and the 2 year survival rate was 87.8% (79/90). The difference was not statistically significant (P>0.05). The ladder neoadjuvant therapy group had lower prophylactic transverse colostomyrate(10.0% vs 34.4%), lower radiation injury rate (6.7% vs 27.8%), and lower sexual dysfunction rate (38.9% vs 87.8)compared to the control group. Conclusions: The ladder neoadjuvant therapy might reduce side injury caused by radiotherapy, improve compliance of patients, and reduce treatment costs. Moreover, the RO resection rate, 2-year local control rate and 2-year survival rate of ladder neoadjuvant therapy group was comparable with neoadjuvant chemoradiotherapy. PMID- 28728303 TI - [Enhancing Soft-tissue Reattachment with Artificial Mesh in Joint Endoprosthetic Reconstruction for Bone Tumors]. AB - Objective: To investigate the operative method and clinical application of the BARD((r)) Mesh in enhancing joint stability and function of endoprosthetic reconstruction for bone tumors. Methods: From Jan 2013 to Jun 2015, the clinical data of 51 patients aged (44.75+/-23.18) years underwent wide resection of tumor and endoprosthetic reconstruction using the BARD((r)) Mesh were collected. Among them, 27 were male and 24 were female. The surgical treatments received by these patients included 5 shoulder arthroplasties, 12 elbow replacements, 12 hip replacements and 32 knee replacements (including 24 femoral tumors and 8 tibial tumors). According to the pathologic type, there were 12 metastatic tumors, 20 osteosarcomas, 7 chondrosarcomas, 5 malignant fibrous histiocytomas, 4 giant cell tumors of bone, 1 Ewing sarcoma, 1 leiomyosarcoma and 1 pigmented villonodular synovitis (pvns). These patients received extensive tumor resection, tumorous prosthesis replacement, preserved articular capsule and muscles repair with artificial mesh and endoprosthesis wrapping. The curative effect including joints range of motion and Musculoskeletal Tumour Society Scores (MSTS) were evaluated. Results: The median follow-up time was (19.75+/-8.17) months. The drainages were removed out on an average of 4 days after operation. The postoperative complications included 2 superficial incision infection, 1 deep incision infection and 1 osteofascial compartment syndrome, infection or dislocation of prosthesis wasn't observed. The mean active flexion of shoulder joint after replacement was (34.00+/-10.84) degrees , mean active abduction was (20.00+/ 9.35) degrees and the mean MSTS was 19.80+/-9.54. The superior rate of shoulder flexion function was 0. The mean active flexion of elbow joint after replacement was (75.00+/-7.07) degrees , mean active abduction was (-5.00+/-7.07) degrees and the mean MSTS was 25.00+/-2.83. The superior rate of elbow flexion function was 50.0% (1/2). The mean active flexion of hip joint after replacement was (86.67+/-20.60) degrees , mean active abduction was (2.08+/-4.98) degrees and the mean MSTS was 25.42+/-1.78. The superior rate of hip flexion function was 83.3% (10/12). The mean active flexion of knee joint after replacement was (89.69+/-22.39) degrees , mean active abduction was (-0.63+/-1.68) degrees and the mean MSTS was 23.31+/-2.09. The superior rate of knee flexion function was 50.0%(16/32). Among them, the superior rate of femoral flexion function was 66.7% (16/24), the superior rate of tibial flexion function was 0. All of patients were satisfied with the curative effect of operation at the end of follow-up time. Conclusions: The BARD((r)) Mesh may enhance the attachment of soft-tissue to endoprosthesis, improve the joint stability, decrease the endoprosthetic infection and dislocation, facilitate the attachment of tendon to endoprosthesis and recover the muscular motivation after endoprosthetic reconstruction. This plays an important role in joint stability and motivation reconstruction of soft tissue impairment, effectively prevents surgical complications. PMID- 28728304 TI - [Percutaneous Microwave/Radiofrequency Ablation Liver Partition and Portal Vein Embolization for Planned Hepatectomy for Colorectal Liver Metastases with Insufficient Future Liver Remnant]. PMID- 28728305 TI - [Incidence and mortality of stomach cancer in China, 2013]. AB - Objective: To estimate the incidence and mortality of stomach cancer in China based on the cancer registration data in 2013, collected by the National Central Cancer Registry (NCCR). Methods: There were 347 cancer registries that submitted stomach cancer incidence and deaths occurred in 2013 to NCCR. After evaluating the data quality, 255 registries' data were accepted for analysis and stratified by areas (urban/rural), sex, and age group. Combined with data on national population in 2013, the nationwide incidence and mortality of stomach cancer were estimated. Chinese population census in 2000 and Segi's population were used for age-standardized incidence/mortality rates. Results: Qualified 255 cancer registries covered a total of 226 494 490 populations (111 595 772 in urban and 114 898 718 in rural areas). The percentage of cases morphologically verified and death certificate-only cases were 76.27% and 1.98%, respectively, and the mortality to incidence rate ratio was 0.72. It is estimated that there were 427 000 new cases for stomach cancer nationwide, with a crude incidence rate of 31.38 per 100 000 (42.85 per 100 000 in males, 19.33 per 100 000 in females). The age standardized incidence rates by Chinese standard population (ASR China) and by world standard population (ASR world) were 21.40 per 100 000 and 21.32 per 100 000, respectively, with a cumulative incidence rate (0-74 age years old) of 2.66%. The crude and ASR China incidence rates of stomach cancer in urban areas were 27.80 per 100 000 and 18.48 per 100 000, respectively, whereas those were 35.54 per 100 000 and 24.93 per 100 000 in rural areas. It is estimated that there were 301 000 deaths for stomach cancer nationwide, with a crude mortality rate of 22.13 per 100 000 (29.85 per 100 000 in males, 14.03 per 100 000 in females). The ASR China and ASR world mortality rates were 14.68 per 100 000 and 14.54 per 100 000, respectively, with a cumulative mortality rate (0-74 years old) of 1.70%. The crude and ASR China mortality rates were 18.94 per 100 000 and 12.20 per 100 000 in urban areas, respectively, whereas those were 25.84 per 100 000 and 17.67 per 100 000 in rural areas. Conclusions: There is still a heavy burden of stomach cancer in China. The burden and patterns of stomach cancer shows different gender and urban-rural differences. Prevention and control strategies should be implemented referring to local status. PMID- 28728306 TI - [Interpretation of guidance for establishing the performance characteristics of in vitro diagnostic devices for the detection or detection and differentiation of high-risk human papillomaviruses issued by Food and Drug Administration of United States and China]. AB - To establish the standardization of clinical verification designs for in vitro diagnostic devices(IVDs) of human papillomavirus, China Food and Drug Administration (CFDA) and United States Food and Drug Administration (FDA) issued guidelines of detailed study designs and effectiveness evaluation for accuracy validation and clinical performance of nucleic acid detection, respectively, including triage of a typical squamous cells of undetermined significance(ASC-US) patients and validation of combined screening and preliminary screening. The design, study population, sample size estimation and statistical analysis of guidelines were moderately different from America to China, however, the evaluation indication was similar. According to the guideline issued by CFDA, prospective design suggested by FDA could be replaced by cross sectional study design to validate the triage of ASC-US patients. Alternatively, prospective design could be used to conduct the HPV product declaration and cellular parallel detection for the same natural population, and the clinical effectiveness of declared products could be validated by at least 3 years follow-up of cytology. PMID- 28728307 TI - Changes in reference evapotranspiration and its driving factors in the middle reaches of Yellow River Basin, China. AB - Reference evapotranspiration (ET0) is important for agricultural, environmental and other studies, and understanding the attribution of its change is helpful to provide information for irrigation scheduling and water resources management. The present study investigates the attribution of the change of ET0 at 49 meteorological stations in the middle reaches of Yellow River basin (MRYRB) of China from 1960 to 2012. Results show that annual ET0 increases from the northwest to the southeast of MRYRB in space. We find that annual ET0 clearly presents a zigzag change pattern rather than a monotonically change during the whole period. The detected three breakpoints at 1972, 1988 and 1997 divide the whole period into four subperiods. The sensitivity analysis indicates that the ET0 is the most sensitive to surface solar radiation (Rs), followed by relative humidity (RH) and mean air temperature (T), and the least sensitive to wind speed (u) in our study area. Furthermore, we find that ET0 is becoming less sensitive to RH and more sensitive to T during 1960-2012. The attributions of the change in ET0 vary largely at different regions and subperiods. The declined wind speed is the dominant factor, followed by Rs to the ET0 reduction during 1960-2012. Further analysis shows that Rs and u are the two major contributing factors that control the change of ET0 at most stations and during most subperiods. Our study confirms that the change of ET0 is influenced by the complex interactions of climatic factors, and the dominant factor to the change of ET0 is different in various regions and time periods. The results presented here can provide a reference for agricultural production and water resources management in MRYRB as well as other semi-arid and semi-humid regions. PMID- 28728308 TI - Methane uptake in global forest and grassland soils from 1981 to 2010. AB - Methane (CH4) is one of the most potent greenhouse gases. Although forest and grassland soils generally consume atmospheric CH4, the quantities and spatiotemporal changes in CH4 uptake remain largely uncertain for these ecosystems at the global scale. In this study, we developed an empirical model to estimate the CH4 uptake in global forest and grassland soils during the period 1981-2010. We estimated that the mean values of CH4 uptake were 9.16 (+/- 3.84) Tg yr-1 in forest soils and 3.73 (+/- 1.41) Tg yr-1 in grassland soils during the study period. Tropical forest and grassland soils were determined to be the largest CH4 sink, contributing 58% to the global total. During the 30-year period, the CH4 uptake in cool temperate dry and warm temperate dry soils and in polar/boreal grassland soils increased significantly (P<0.05) at rates of 0.30 2.95Ggyr-1 owing mainly to increases in mean temperatures. However, the uptake decreased significantly (P<0.01) in tropical dry grassland soils, at 1.22Ggyr-1, owing mainly to increases in precipitation. Ultimately, our simulation indicated that the global CH4 uptake by forest and grassland soils increased significantly (P<0.05) at rates of 4.67Ggyr-1 and 2.98Ggyr-1, respectively, during the period 1981-2010. The trend of increasing sinks from forest and grassland and its relationship with temperature and precipitation variability imply that forest and grassland CH4 sinks will play a positive role in climate change mitigation in the future. PMID- 28728309 TI - Escherichia coli outer membrane protein F (OmpF): an immunogenic protein induces cross-reactive antibodies against Escherichia coli and Shigella. AB - Diarrhea caused by pathogenic Escherichia coli (E. coli) is one of the most serious infectious diseases in humans and animals. Due to antibiotics resistance and the lack of efficient vaccine, more attention should be paid to find potential versatile vaccine candidates to prevent diseases. In this study, the sequence homology analysis indicated that OmpF from E. coli CVCC 1515 shares a high identity (90-100%) with about half of the E. coli (46.7%) and Shigella (52.8%) strains. Then the recombinant OmpF was supposed to be developed as a versatile vaccine to prevent E. coli infection. OmpF was expressed in E. coli BL21 (DE3) using the auto-induction method. The recombinant OmpF (rOmpF) protein had an average molecular weight of 40 kDa with the purity of 90%. Immunological analysis indicated that the titers of anti-rOmpF sera against rOmpF and whole cells were 1:240,000 and 1:27,000, respectively. The opsonophagocytosis result showed that 72.21 +/- 11.39 and 11.04 +/- 3.90% of bacteria were killed in the rOmpF immunization and control groups, respectively. The survival ratio of mice immunized with rOmpF ranged between 40 and 60% as observed within 36 h after challenge, indicating mice were partially protected from E. coli CVCC 1515 infection. The expressed rOmpF protein induced an effective immune response, but only provide a weak protection against pathogenic E. coli CVCC 1515 and a small reduction in E. coli CICC 21530 (O157:H7) excretion in a mouse infection model. Native forms of the OmpF antigen may be studied for immunogenicity and potential protective efficacy. PMID- 28728310 TI - The Effect of H2 Receptor Antagonist in Acid Inhibition and Its Clinical Efficacy. AB - The first histamine H2 receptor antagonists (H2RAs) were developed in the early 1970s. They played a dominant role in treating peptic ulcer disease and gastroesophageal reflux disease (GERD). H2RAs block the production of acid by H+, K+-ATPase at the parietal cells and produce gastric luminal anacidity for varying periods. H2RAs are highly selective, and they do not affect H1 receptors. Moreover, they are not anticholinergic agents. Sequential development of H2RAs, proton pump inhibitors (PPIs), and discovery of Helicobacter pylori infection changed the paradigm of peptic ulcer disease with marked decrease of morbidity and mortality. PPIs are known to be the most effective drugs that are currently available for suppressing gastric acid secretion. Many studies have shown its superiority over H2RAs as a treatment for acid-related disorders, such as peptic ulcer disease, GERD, and Zollinger-Ellison syndrome. However, other studies have reported that PPIs may not be able to render stomach achlorhydric and have identified a phenomenon of increasing gastric acidity at night in individuals receiving a PPI twice daily. These nocturnal acid breakthrough episodes can be eliminated with an addition of H2RAs at night. The effectiveness of nighttime dose of H2RA suggests a major role of histamine in nocturnal acid secretion. H2RAs reduce secretion of gastric acid, and each H2RA also has specific effects. For instance, nizitidine alleviates not only symptoms of GERD, but also provokes gastric emptying, resulting in clinical symptom improvement of functional dyspepsia. The aim of this paper was to review the characteristics and role of H2RAs and assess the future strategy and treatment of upper gastrointestinal disease, including acid related disorders. PMID- 28728311 TI - Clinical Approach to Incidental Pancreatic Cystic Neoplasm in Outpatient Clinics. AB - Cystic lesions of the pancreas are increasingly observed due to increased use of abdominal images. The malignant rate of pancreas cystic lesion varies widely between various types. Identification of malignant or high-risk lesions is important when determining the appropriate course of management. Using these image findings, including cyst size, presence of solid components, and pancreatic duct involvement, the 2012 International Association of Pancreatology (IAP) and the 2015 American Gastroenterological Association (AGA) guidelines provide a rationale in identifying higher risk patients requiring further workups using an endoscopic ultrasound (EUS). EUS with fine needle aspiration and cytology allows confirmation of the cyst type and determines the risk of malignancy. Small cysts with no suspicious features may undergo the regular imaging study for regular surveillance due to low risk for malignancy. In this review, the differences between the 2012 IAP and 2015 AGA guidelines are presented, In addition to possible recommendations for management and surveillance. PMID- 28728312 TI - The Value of Computed Tomography in Preoperative N Staging of Early Gastric Cancer Meeting the Endoscopic Resection Criteria. AB - Background/Aims: This study evaluated the value of abdominal computed tomography (CT) in preoperative N staging of early gastric cancers (EGCs) within standard and expanded indications of endoscopic resection (ER) and investigated the factors affecting accuracy. Methods: Between March 2009 and March 2016, a total of 268 patients with EGC within the standard and expanded indications of ER underwent preoperative abdominal CT and surgical gastrectomy with lymph node (LN) dissection. Preoperative N staging of CT was compared with the pathologic result. Results: The accuracy of N staging for EGCs within the standard and expanded indications was 86.1% (235/268). There was no LN metastasis in patients with cN1 in CT staging. LN metastasis was found in 7 patients with EGCs that met the expanded ER indication and cN0 in CT staging. According to the univariate analysis, ulcers, including scars, were associated with the false positive of lymph node metastasis in abdominal CT (odds ratio 3.56; 95% confidence interval 1.56-8.15). Conclusions: The present study suggests that the value of abdominal CT is limited for nodal staging of EGCs that meet the ER indication. PMID- 28728313 TI - The Effect of Helicobacter pylori Eradication on the Metachronous Neoplasm after Endoscopic Resection for Gastric Dysplasia. AB - Background/Aims: Helicobacter pylori (Hp) infection is an important risk factor for gastric carcinogenesis. Although several studies have investigated the effect of Hp eradication on the development of metachronous neoplasm after endoscopic resection of the gastric dysplasia, the evidence is still insufficient to make a clear conclusion. The aims of this study was to evaluate the risk factors for the development of metachronous neoplasm after endoscopic resection of gastric dysplasia and to investigate the effect of Hp eradication. Methods: Between 2005 and 2011, a total of 887 patients underwent endoscopic resection for gastric dysplasia. Among them, 521 patients who had undergone tests for Hp infection and been followed-up for at least one year were included in the final analyses. Of the 292 Hp-positive patients, 116 patients were successfully eradicated, while 176 failed or did not undergo eradication. Results: During a mean follow-up of 59.1 months (range 12-125 months), metachronous neoplasm had developed in 63 patients (12.1%, dysplasia in 38, carcinoma in 25). In multivariate analyses, age >=65 (hazard ratio [HR]=2.247, 95% confidence interval [CI] 1.297-3.895), tumor size (HR=1.283, 95% CI 1.038-1.585), synchronous lesion (HR=2.341, 95% CI 1.244 4.405), family history of gastric cancer (HR=3.240, 95% CI 1.776-5.912), and smoking (HR=1.016, 95% CI 1.003-1.029) were risk factors for metachronous neoplasm after endoscopic resection of gastric dysplasia. However, Hp eradication was not associated with metachronous neoplasm (HR=0.641, 95% CI 0.297-1.384). Conclusions: Hp eradication was not shown to be associated with the development of metachronous cancer after endoscopic resection of gastric dysplasia. PMID- 28728314 TI - Local Recurrence and Its Risk Factor after Incomplete Resection of Colorectal Advanced Adenomas: A Single Center, Retrospective Study. AB - Background/Aims: Colonoscopy can detect precancerous lesions, which can subsequently be removed and reduce incidences of and mortality from colorectal cancer (CRC). However, recently published data have highlighted a significant rate of CRC in patients who previously underwent colonoscopy. Among many reasons, incomplete resection has been considered as a significant contributor. However, to date, there have only been a few studies regarding incompletely resected polyps, especially advanced colorectal adenoma (ACA). Hence, we aimed to evaluate the prognosis of incompletely resected ACA. Methods: We retrospectively reviewed the medical records of patients with ACA who had underwent endoscopic treatment with incomplete resection. The primary outcomes were (1) the incomplete resection rate of ACA, as determined by a histopathologic examination and (2) the recurrence rate of incompletely resected ACA. We also investigated the probable contributing factors that may have led to a relapse of incompletely resected ACA. Results: A total of 7,105 patients had their colorectal polyps resected by endoscopic treatment, and 2,233 of these were considered as ACA. Of these, 354 polyps (15.8%) were resected incompletely, and only 163 patients were followed up. Of those followed-up, 31 patients (19.0%) experienced local recurrence. The risk factors for recurrence after incomplete resection were evaluated; age, morphology of adenoma, and use of rescue therapy, such as argon plasma coagulation, were found to be associated with adenoma recurrence. Conclusions: Incompletely resected ACA in older patients or in patients with sessile-type adenomas should be monitored strictly, and if incomplete resection is suspected, rescue therapy must be considered. PMID- 28728315 TI - Defecographic Findings in Patients with Severe Idiopathic Chronic Constipation. AB - Background/Aims: Chronic constipation is a common gastrointestinal disorder diagnosed using Rome III criteria. Defecography is a radiographic method used to identify anatomic abnormalities of anorectum. The present study aimed to evaluate the defecographic findings in patients with severe idiopathic chronic constipation. Methods: One hundred patients, who complained of severe idiopathic chronic constipation with abnormal balloon expulsion test, underwent defecography after injection of barium. An analysis of radiographs was performed by an expert radiologist for the diagnosis of descending perineum syndrome, rectocele, enterocele, rectal ulcer, rectal prolapse, fecal residue of post defecation, and etc. Then, they were compared between the two sexes. Results: Normal defecography was only observed in two participants. Descending perineum syndrome was the most common abnormality (73.3%). The results showed that rectocele (80.8%) and descending perineum syndrome (69.2%) were most frequent in women. In males, descending perineum syndrome and rectal prolapse were more prevalent (87% and 43.5%, respectively). Compared with men, rectocele and rectal ulcer were more frequently observed in women (p<0.001, and p=0.04, respectively), while men were more affected by descending perineum syndrome (p=0.04). In total, women had a greater incidence of abnormal defecographic findings compared with men (p=0.02). Conclusions: Defecography can be performed to detect anatomic abnormalities in patients with severe idiopathic chronic constipation and abnormal balloon expulsion test. This technique can assist physicians in making the most suitable decision for surgical procedure. PMID- 28728316 TI - Use of Novel Oral Anticoagulant to Treat Pulmonary Thromboembolism in Patient with Ulcerative Colitis Superinfected Cytomegalovirus Colitis. AB - Crohn's disease and ulcerative colitis are the two major types of inflammatory bowel disease, and affect mainly the gastrointestinal tract but also have extraintestinal sequelae, such as arterial and venous thromboembolism. Thromboembolic complications, particularly pulmonary thromboembolism, can be life threatening and require prompt management with anticoagulants. Conventional vitamin K antagonists have been used for the treatment of thromboembolic complications, but the development of novel oral anticoagulants has shifted the paradigm. We report a case of a 42-year-old female with ulcerative colitis who experienced an acute flare-up due to cytomegalovirus superinfection with pulmonary thromboembolism. She was treated with oral mesalamine, intravenous steroid and ganciclovir and low-molecular-weight heparin, followed by rivaroxaban, a novel oral anticoagulant. Her symptoms resolved after treatment, and no recurrence was noted during a 6-month post-treatment follow-up. PMID- 28728318 TI - What Would It Be Like to Lose One's Nose? Gogol's The Nose and the Astronomer Tycho Brahe. PMID- 28728317 TI - Mycoplasma pneumoniae-associated Hepatitis without Lung Involvement. AB - Mycoplasma pneumoniae (M. pneumoniae) is a major cause of community acquired respiratory infections. And it also causes a number of extrapulmonary manifestations including cardiovascular, dermatological, musculoskeletal, and hematological systems. But, acute hepatitis without lung involvement is rare in adults. Here, we report a case of 32-year-old man who presented with fever, chilling, myalgia, and headache. Biochemical analysis showed severely impaired liver function and leukopenia. Laboratory tests and liver biopsy demonstrated a hepatocellular pattern of M. pneumoniae-associated acute hepatitis. Clinical symptoms and laboratory parameters are improved rapidly under treatment with macrolide. Therefore, We recommend that phsycians should consider a possibility of M. pneumoniae infection in acute hepatitis without lung and extrapulmonary involvement, when other more frequent causes have been excluded. PMID- 28728319 TI - Putting Together a Global Effort. PMID- 28728320 TI - Temple and Postauricular Dissection in Face and Neck Lift Surgery. AB - Periauricular paresthesia may afflict patients for a significant amount of time after facelift surgery. When performing face and neck lift surgery, temple and posterior auricular flap dissection is undertaken directly over the auriculotemporal, great auricular, and lesser occipital nerve territory, leading to potential damage to the nerve. The auriculotemporal nerve remains under the thin outer superficial fascia just below the subfollicular level in the prehelical area. To prevent damage to the auriculotemporal nerve and to protect the temporal hair follicle, the dissection plane should be kept just above the thin fascia covering the auriculotemporal nerve. Around the McKinney point, the adipose tissue covering the deep fascia is apt to be elevated from the deep fascia due to its denser fascial relationship with the skin, which leaves the great auricular nerve open to exposure. In order to prevent damage to the posterior branches of the great auricular nerve, the skin flap at the posterior auricular sulcus should be elevated above the auricularis posterior muscle. Fixating the superficial muscular aponeurotic system flap deeper and higher to the tympano-parotid fascia is recommended in order to avoid compromising the lobular branch of the great auricular nerve. The lesser occipital nerve (C2, C3) travels superficially at a proximal and variable level that makes it vulnerable to compromise in the mastoid dissection. Leaving the adipose tissue at the level of the deep fascia puts the branches of the great auricular nerve and lesser occipital nerve at less risk, and has been confirmed not to compromise either tissue perfusion or hair follicles. PMID- 28728321 TI - Review of the Nomenclature of the Retaining Ligaments of the Cheek: Frequently Confused Terminology. AB - Since the time of its inception within facial anatomy, wide variability in the terminology as well as the location and extent of retaining ligaments has resulted in confusion over nomenclature. Confusion over nomenclature also arises with regard to the subcutaneous ligamentous attachments, and in the anatomic location and extent described, particularly for zygomatic and masseteric ligaments. Certain historical terms-McGregor's patch, the platysma auricular ligament, parotid cutaneous ligament, platysma auricular fascia, temporoparotid fasica (Lore's fascia), anterior platysma-cutaneous ligament, and platysma cutaneous ligament-delineate retaining ligaments of related anatomic structures that have been conceptualized in various ways. Confusion around the masseteric cutaneous ligaments arises from inconsistencies in their reported locations in the literature because the size and location of the parotid gland varies so much, and this affects the relationship between the parotid gland and the fascia of the masseter muscle. For the zygomatic ligaments, there is disagreement over how far they extend, with descriptions varying over whether they extend medially beyond the zygomaticus minor muscle. Even the 'main' zygomatic ligament's denotation may vary depending on which subcutaneous plane is used as a reference for naming it. Recent popularity in procedures using threads or injectables has required not only an accurate understanding of the nomenclature of retaining ligaments, but also of their location and extent. The authors have here summarized each retaining ligament with a survey of the different nomenclature that has been introduced by different authors within the most commonly cited published papers. PMID- 28728322 TI - Perioperative Hypertension Management during Facelift under Local Anesthesia with Intravenous Hypnotics. AB - Perioperative hypertension is a phenomenon in which a surgical patient's blood pressure temporarily increases throughout the preoperative and postoperative periods and remains high until the patient's condition stabilizes. This phenomenon requires immediate treatment not only because it is observed in a majority of patients who are not diagnosed with high blood pressure, but also because occurs in patients with underlying essential hypertension who show a sharp increase in their blood pressure. The most common complication following facelift surgery is hematoma, and the most critical risk factor that causes hematoma is elevated systolic blood pressure. In general, a systolic blood pressure goal of <150 mm Hg and a diastolic blood pressure goal of >65 mm Hg are recommended. This article discusses the causes of increased blood pressure and the treatment methods for perioperative hypertension during the preoperative, intraoperative, and postoperative periods, in order to find ways to maintain normal blood pressure in patients during surgery. Further, in this paper, we review the causes of perioperative hypertension, such as anxiety, epinephrine, pain, and postoperative nausea and vomiting. The treatment methods for perioperative hypertension are analyzed according to the following 3 operative periods, with a review of the characteristics and interactions of each drug: preoperative antihypertensive medicine (atenolol, clonidine, and nifedipine), intraoperative intravenous (IV) hypnotics (propofol, midazolam, ketamine, and dexmedetomidine), and postoperative antiemetic medicine (metoclopramide and ondansetron). This article focuses on the knowledge necessary to safely apply local anesthesia with IV hypnotics during facelift surgery without the assistance of an anesthesiologist. PMID- 28728323 TI - Analysis of the Legal Effect of Settlement Agreements Prepared in Medical Litigation Following Plastic Surgery in Korea. AB - BACKGROUND: Settlements between doctors and patients provide a solution to complicated disputes. However, some disputes may be renewed as a result of negligence by both parties. The purpose of this study was to review the legal issues that may potentially arise during the preparation of settlement agreements and to propose a list of requirements for ensuring the effectiveness of these settlement agreements. METHODS: Data from 287 civil cases concerning aesthetic surgery that took place between 2000 and 2015 were collected from a court database in South Korea. Factors that influenced the effectiveness of settlement agreements were analyzed. RESULTS: Among the 287 court precedents, there were 68 cases of covenant not to sue. Eighteen cases were dismissed because the settlement agreements were recognized as effective, and 50 cases were sent forward for judgment on their merits because the agreements were not recognized as effective. The types of surgery and types of complications were classified by frequency. We evaluated the geographical distribution of the precedents, the settlement timing, and the effectiveness and economic impact of the settlements. We found that there was no statistically significant relationship among these factors. Four major factors that made a settlement agreement legally effective were identified, and the data showed that fee-free reoperations were not considered by the court in determining the compensation amount. CONCLUSIONS: When preparing a settlement agreement, it is advisable to review the contents of the agreement rather than to take the preparation of a settlement agreement per se to be legally meaningful. PMID- 28728324 TI - The Chicken Thigh Adductor Profundus Free Muscle Flap: A Novel Validated Non Living Microsurgery Simulation Training Model. AB - BACKGROUND: Simulation training is becoming an increasingly important component of skills acquisition in surgical specialties, including Plastic Surgery. Non living simulation models have an established place in Plastic Surgical microsurgery training, and support the principles of replacement, reduction and refinement of animal use. A more sophisticated version of the basic chicken thigh microsurgery model has been developed to include dissection of a type 1-muscle flap and is described and validated here. METHODS: A step-by-step dissection guide on how to perform the chicken thigh adductor profundus free muscle flap is demonstrated. Forty trainees performed the novel simulation muscle flap on the last day of a 5-day microsurgery course. Pre- and post-course microvascular anastomosis assessment, along with micro dissection and end product (anastomosis lapse index) assessment, demonstrated skills acquisition. RESULTS: The average time to dissect the flap by novice trainees was 82+/-24 minutes, by core trainees 90+/-24 minutes, and by higher trainees 64+/-21 minutes (P=0.013). There was a statistically significant difference in the time to complete the anastomosis between the three levels of training (P=0.001) and there was a significant decrease in the time taken to perform the anastomosis following course completion (P<0.001). Anastomosis lapse index scores improved for all cohorts with post-test average anastomosis lapse index score of 3+/-1.4 (P<0.001). CONCLUSIONS: The novel chicken thigh adductor profundus free muscle flap model demonstrates face and construct validity for the introduction of the principles of free tissue transfer. The low cost, constant, and reproducible anatomy makes this simulation model a recommended addition to any microsurgical training curriculum. PMID- 28728325 TI - The Usefulness of Surgical Treatment in Slow-Flow Vascular Malformation Patients. AB - BACKGROUND: Many difficulties exist in establishing a treatment plan for slow flow vascular malformation (SFVM). In particular, little research has been conducted on the surgical treatment of SFVMs. Thus, we investigated what proportion of SFVM patients were candidates for surgical treatment in clinical practice and how useful surgical treatment was in those patients. METHODS: This study included 109 SFVM patients who received care at the authors' clinic from 2007 to 2015. We classified the patients as operable or non-operable, and analyzed whether the operability and the extent of the excision varied according to the subtype and location of the SFVM. Additionally, we investigated complications and self-assessed satisfaction scores. RESULTS: Of the 109 SFVM patients, 59 (54%) were operable, while 50 (46%) were nonoperable. Total excision could be performed in 44% of the operable SFVM patients. Lymphatic malformations were frequently non-operable, while capillary malformations were relatively operable (P=0.042). Total excision of venous malformations could generally be performed, while lymphatic malformations and combined vascular malformations generally could only undergo partial excision (P=0.048). Complications occurred in 11% of the SFVM patients who underwent surgery; these were minor complications, except for 1 case. The average overall satisfaction score was 4.19 out of 5. CONCLUSIONS: Based on many years of experience, we found that approximately half (54%) of SFVM patients were able to undergo surgery, and around half (44%) of those patients were able to fully recover after a total excision. Among the patients who underwent surgical treatment, high satisfaction was found overall and relatively few complications were reported. PMID- 28728326 TI - The Role of Negative-Pressure Wound Therapy in Latissimus Dorsi Flap Donor Site Seroma Prevention: A Cohort Study. AB - BACKGROUND: Donor site seroma is the most common complication after latissimus dorsi (LD) flap harvest. This study aimed to evaluate the efficacy of negative pressure wound therapy (NPWT) in preventing donor site seroma formation after the harvest of an LD flap for breast reconstruction. METHODS: In this prospective matched-pair study, 40 patients in whom an LD flap was harvested for breast reconstruction were enrolled. NPWT was used in 20 patients, and in a control group composed of another 20 patients, the conventional donor site dressing technique was used. Information was collected regarding postoperative complications, the incidence of seroma, total drainage volume, the number of percutaneous seroma aspirations, and the volume aspirated. RESULTS: In the NPWT group, the incidence of seroma formation after drain removal was significantly lower than in the control group (15% vs. 70%; odds ratio=0.07; relative risk, 0.24). Both the mean percutaneous aspirated volume (P=0.004) and the number of percutaneous aspirations (P=0.001) were also significantly lower in the NPWT group. There were no significant differences in the total drainage volume or the duration of wound drainage between the NPWT dressing group and the control group (P>0.05). CONCLUSIONS: This study showed that NPWT is a promising tool for reducing the incidence of seroma formation after removing the drain at the donor site after LD flap harvesting. It is a simple and safe technique. PMID- 28728327 TI - Non-Melanocytic Skin Cancers of the Head and Neck: A Clinical Study in Jeju Province. AB - BACKGROUND: Jeju Island is geographically and socioeconomically distinct from the mainland of South Korea. Thus, the presentation and management of non-melanocytic skin cancers (NMSC) of the head and neck may differ from those in other regions of the country. We compared the clinical characteristics and treatment modalities of NMSC on Jeju Island with the findings of similar regional studies. METHODS: Patient data, including age, sex, diagnosis, tumor site, treatment, and recurrence, were obtained from the medical and pathology records of patients diagnosed with NMSC between January 2010 and June 2015. RESULTS: In total, 190 patients (57 men) with a mean age of 75 years (range, 42-97) were assessed. Overall, 203 NMSCs were diagnosed, including 123 basal cell carcinomas and 80 squamous cell carcinomas. The tumor sites included the nose, cheeks, periorbital area, and lips (n=55, 54, 25, and 20, respectively). We identified 92 T1-stage and 60 T2-stage tumors, and 120 cases were treated with wide surgical resection and 17 cases were treated with radiation therapy at the medical center. Of the 120 cases treated surgically, 69 required reconstructive surgery using a local skin flap, 22 required full-thickness skin grafting, and 12 underwent primary closure. Basal and squamous cell carcinomas recurred in 2 and 1 cases, respectively. CONCLUSIONS: Compared to the reports from other regions, the average patient age was 10 years higher, with a marked female preponderance. While the proportion of squamous cell carcinoma was higher than in other regions, the tumor distribution and surgical management profiles were similar. PMID- 28728328 TI - Reconstruction of Large Facial Defects via Excision of Skin Cancer Using Two or More Regional Flaps. AB - BACKGROUND: Free-flap surgery and skin grafting can be used to reconstruct large facial defects that may result after skin cancer removal by Mohs micrographic surgery (MMS). However, these two methods may produce low postsurgical patient satisfaction with aesthetics, and free-flap surgery may produce an undue burden for the majority of skin cancer patients, who are of advanced age. Hence, the authors examined outcomes of large facial defect reconstruction using multiple flaps. METHODS: Among patients undergoing MMS for skin cancer at Pusan National University Hospital between January 2013 and December 2015, we evaluated 7 patients (2 males, 5 females; average age, 73.14 years) treated for large facial defects from basal cell carcinoma. Based on operative and follow-up records, we investigated the number and type of flaps used, postsurgical complications, and patients' post-surgical satisfaction. RESULTS: Two and 3 types of flaps were used for 5 and 2 patients, respectively. Most frequently used were nasolabial flaps (7 times in 6 patients) and forehead flaps (once in each of 4 patients). The average follow-up period was 14 months, with no complications-including necrosis, hematoma, or wound dehiscence-observed. Post-surgical satisfaction averaged 4.4 out of a maximum of 5 points. CONCLUSIONS: Reconstruction using two or more flaps for large facial defects after skin cancer removal using MMS produced satisfactory outcomes while preventing aesthetic problems. Practitioners should consider using multiple flaps when choosing a reconstruction method for large facial defects following skin cancer removal. PMID- 28728329 TI - Liposuction in the Treatment of Lipedema: A Longitudinal Study. AB - BACKGROUND: Lipedema is a condition consisting of painful bilateral increases in subcutaneous fat and interstitial fluid in the limbs with secondary lymphedema and fibrosis during later stages. Combined decongestive therapy (CDT) is the standard of care in most countries. Since the introduction of tumescent technique, liposuction has been used as a surgical treatment option. The aim of this study was to determine the outcome of liposuction used as treatment for lipedema. METHODS: Twenty-five patients who received 72 liposuction procedures for the treatment of lipedema completed a standardized questionnaire. Lipedema associated complaints and the need for CDT were assessed for the preoperative period and during 2 separate postoperative follow-ups using a visual analog scale and a composite CDT score. The mean follow-up times for the first postoperative follow-up and the second postoperative follow-up were 16 months and 37 months, respectively. RESULTS: Patients showed significant reductions in spontaneous pain, sensitivity to pressure, feeling of tension, bruising, cosmetic impairment, and general impairment to quality of life from the preoperative period to the first postoperative follow-up, and these results remained consistent until the second postoperative follow-up. A comparison of the preoperative period to the last postoperative follow-up, after 4 patients without full preoperative CDT were excluded from the analysis, indicated that the need for CDT was reduced significantly. An analysis of the different stages of the disease also indicated that better and more sustainable results could be achieved if patients were treated in earlier stages. CONCLUSIONS: Liposuction is effective in the treatment of lipedema and leads to an improvement in quality of life and a decrease in the need for conservative therapy. PMID- 28728330 TI - Hair Diameter Variation in Different Vertical Regions of the Occipital Safe Donor Area. AB - BACKGROUND: Little is known concerning hair diameter variation within the safe donor area for hair transplantation surgery. Thicker or thinner hair may be needed, depending on the recipient area, hairline design, and the purpose of surgery. METHODS: Twenty-seven patients (7 men and 20 women; mean age, 28 years; range, 20-47 years) were included in this study. The midoccipital point was used as the reference point on the horizontal plane at the upper border of the helical rim. The target area width was 15 cm (7.5 cm to the right and left of the reference point) and the height was 8 cm (2 cm above and 6 cm below the reference point). The study area was divided horizontally into 3 5-cm sections (A, B, C) and vertically into 4 2-cm sections (1-4), creating a total of 12 zones. Ten anagen hairs were randomly obtained from each zone and their diameters were measured. RESULTS: Hair diameter in the 4 vertical sections varied significantly, gradually decreasing from sections 1 (superior) to 4 (inferior) in all 3 horizontal sections (A, B, and C). CONCLUSIONS: Our results suggest that sections 1 and 2 of the occipital safe donor area would be useful for obtaining thicker hair, such as in procedures to treat male- and female-pattern hair loss, whereas hair from zones 3 and 4 could be useful for transplantation surgery requiring thinner hair, such as eyebrows, eyelashes, and female hairline correction. Our results may be clinically valuable for planning hair transplant surgery and choosing the optimal donor region. PMID- 28728331 TI - Surgery Requiring Detailed Preoperative Simulation and Scar De-epithelialization to Repair Severe Postoperative Scarring from Gastroschisis. AB - We present the case of a patient with severe postoperative scarring from surgical treatment for gastroschisis, with the intestine located immediately under the dermal scar. Although many patients are unsatisfied with the results of scar repair treatment, few reports exist regarding severe or difficult cases involving the surgical repair of postoperative scar contracture. We achieved an excellent result via simulation involving graph paper drawings that were generated using computed tomography images as a reference, followed by dermal scar deepithelialization. The strategy described here may be useful for other cases of severe postoperative scar contracture after primary surgery for gastroschisis. PMID- 28728332 TI - Skin Necrosis with Oculomotor Nerve Palsy Due to a Hyaluronic Acid Filler Injection. AB - Performing rhinoplasty using filler injections, which improve facial wrinkles or soft tissues, is relatively inexpensive. However, intravascular filler injections can cause severe complications, such as skin necrosis and visual loss. We describe a case of blepharoptosis and skin necrosis caused by augmentation rhinoplasty and we discuss the patient's clinical progress. We describe the case of a 25-year-old female patient who experienced severe pain, blepharoptosis, and decreased visual acuity immediately after receiving a filler injection. Our case suggests that surgeons should be aware of nasal vascularity before performing an operation, and that they should avoid injecting fillers at a high pressure and/or in excessive amounts. Additionally, filler injections should be stopped if the patient complains of severe pain, and appropriate measures should be taken to prevent complications caused by intravascular filler injections. PMID- 28728333 TI - The Lazy S Design: A Novel Skin Closure Design in Skin-Sparing Mastectomy for Implant-Based Breast Reconstruction. AB - Preservation of the breast skin envelope during immediate implant-based breast reconstruction is important for producing symmetrical and natural-looking breasts. We propose the lazy S design for the closure of round-shaped wounds with the hope of improving the aesthetic outcomes and reducing the tension on the wound by preserving the skin. Additionally, the direction of tension is dispersed due to the shape of this design. Patients undergoing implant reconstruction after skin-sparing mastectomy may benefit from the lazy S design. PMID- 28728334 TI - Wide Awake Hand Surgery. PMID- 28728335 TI - The Role of Living Models in the Spending Review Era: How Do You Make the Most of a Rat? PMID- 28728336 TI - Management of a Recurrent Ischial Sore Using a 3-Flap Technique. PMID- 28728337 TI - Usefulness of the Versajet Hydrosurgery System for the Removal of Foreign Body Granuloma. PMID- 28728338 TI - A Novel Method for Intraoperative Breast Implant Pocket Assessment: Air Augmentation. PMID- 28728339 TI - Don't Be Depth Charged by the Depth Gauge. PMID- 28728340 TI - Screening of differential proteins of placenta tissues in patients with pre eclampsia by iTRAQ proteomics techniques. AB - BACKGROUND: Isotopically labeled relative and absolute quantification (iTRAQ) were applied together with liquid chromatogram-tandem mass spectrometry (LC MS/MS) technique to screen and differentiate normal tissues and differential proteins of placenta tissue in the pre-eclampsia group, and to seek for a pre eclampsia biomarker. METHODS: Thirty patients with severe pre-eclampsia (pre eclampsia group) and 30 patients with normal full-term pregnancy (control group), who were admitted by the Obstetrical Department of The Affiliated Hospital of Qingdao University from December 2014 to June 2015, were collected for this study. Part of the placenta tissue was sampled following cesarean section to extract the total protein that was degenerated, reduced and enzymatically hydrolyzed. Following iTRAQ, mass spectroscopy was used for differentiation to obtain differential proteins in the expression. RESULTS: A total of 234 differential proteins were identified. The comparison between the severe pre eclampsia group and the control group indicated over 1.5-folds of expression abundance difference (upregulation ratio >1.50, or downregulation ratio <0.67). The difference was statistically significant in 24 protein points in total, among which the expression of 14 protein points was upregulated compared with that of the control group, and the expression of 10 protein points was downregulated. CONCLUSIONS: iTRAQ combined with the LC-MS/MS technique can effectively screen differential proteins in placenta tissues of patients with pre-eclampsia. PMID- 28728341 TI - DNA microarray technology in HBV genotyping. PMID- 28728342 TI - Role of nuclear paraspeckle assembly transcript 1 as a common molecular marker for prognosis in various cancers. PMID- 28728343 TI - Features of inflammatory bowel disease followed in a second level center in Northern Italy. PMID- 28728344 TI - An update on epidemiology of congenital rubella syndrome: how far from the World Health Organization goals? PMID- 28728345 TI - Safety of Percutaneous Endoscopic Gastrostomy Tubes in Centenarian Patients. AB - BACKGROUND/AIMS: Percutaneous endoscopic gastrostomy (PEG) is a relatively safe procedure; however, no study has evaluated the safety of PEG tube placement in patients over the age of 100 years. METHODS: We conducted a retrospective review of patient records for patients who underwent PEG tube placement. Thirty patients aged 100 years and older were identified and a random sample of 275 patients was selected for comparison. RESULTS: The mean age of the patients was 80.6+/-16.2 years. No procedure-related deaths or major complications were identified; the overall inpatient mortality rate was 7.6%. Minor complications were noted in 4% (n=12) of the patients. Centenarian patients were predominantly female (80% [n=24] vs. 54% [n=147], p=0.006), with a mean age of 100.5+/-0.9 years. There was no significant difference in procedural success rates (93.3% vs. 97.4%, p=0.222) or inpatient mortality (6.7% [n=2] vs. 7.7% [n=21], p=1.000) between the two groups. However, a higher minor complication rate was noted in the older patients (13.3% [n=4] vs. 2.9% [n=8], p=0.022). CONCLUSIONS: Success rates, major complications and inpatient mortality associated with PEG tubes in patients aged over 100 years are comparable to those observed in relatively younger patients at our center; however minor complication rates are relatively higher. These findings lead us to believe that PEG tubes may be safely attempted in carefully selected patients in this subset of the population. PMID- 28728346 TI - Suggestions for the promotion of evidence-based public health in South Korea. AB - Evidence-based public health (EBPH) is defined as public health decision-making based on current best evidence. Debates about the latent tuberculosis infection control program suggested by the Korea Centers for Disease Control and Prevention in 2017 highlight the need to promote EBPH. Three strategies have been proposed, including providing necessary evidence by evaluating policy-evidence gaps; delivering high-quality, relevant, and timely evidence by conducting systematic reviews and adapting public health guidelines; and making value-driven decisions by training and educating public health policymakers. PMID- 28728347 TI - Pros and cons of the health transformation program in Iran: evidence from financial outcomes at the household level. AB - OBJECTIVES: The health transformation program was a recent reform in the health system of Iran that was implemented in early 2014. Some of the program's important goals were to improve the equity of payments and to reduce out-of pocket (OOP) payments and catastrophic health expenditures (CHE). In this study, these goals were evaluated using a before-and-after analysis. METHODS: Data on household income and expenditures in Guilan Province were gathered for the years 2013 and 2015. OOP payments for outpatient, inpatient, and drug services were calculated, and the results were compared using the propensity score matching technique after adjusting for confounding variables. Concentration indices and curves were added to quantify changes in inequity before and after the reform. The incidence of catastrophic expenditures was then calculated. RESULTS: Overall and outpatient service OOP payments increased by approximately 10 dollars, while for other types of services, no significant changes were found. Inequity and utilization of services did not change after the reform. However, a significant reduction was observed in CHE incidence (5.75 to 3.82%). CONCLUSIONS: The reform was successful in decreasing the incidence of CHE, but not in reducing the monetary amount of OOP payments or affecting the frequency of health service utilization. PMID- 28728348 TI - Effect of antiretroviral therapy on changes in the fertility intentions of human immunodeficiency virus-positive women in Addis Ababa, Ethiopia: a prospective follow-up study. AB - OBJECTIVES: With access to antiretroviral therapy (ART), people living with human immunodeficiency virus (HIV) are able to consider childbearing to a greater extent than previously. In many cases, ART has transformed their intentions to have children. The present study aimed to assess changes in fertility intentions 12 months after ART initiation among HIV-positive women in Addis Ababa, Ethiopia. METHODS: An institution-based follow-up study was conducted among 360 HIV positive women in Addis Ababa. A logistic regression model was used to assess the influence of socio-demographic, reproductive health, and clinical characteristics on changes in the fertility intentions of women. RESULTS: Overall, 40.8% (147 of 360) of the women reported that they desired to have a child in the future at the baseline visit, while 48.3% (174 of 360) did so at the 12-month follow-up. The proportion of women who reported that they desired to have a child 12 months after ART initiation was higher among ART-initiated women (55.8%, 106 of 190) than ART-naive women (40.0%, 68 of 170). The adjusted analysis indicated that a change in fertility intentions between baseline and the follow-up visit was significantly associated with ART use (adjusted odds ratio [aOR], 2.47; 95% confidence interval [CI], 1.20 to 5.20) and marital status, with single (aOR, 5.33; 95% CI, 1.10 to 25.92) and married (aOR, 6.35; 95% CI, 1.44 to 27.99) women being more likely to report fertility intentions than divorced/widowed women. CONCLUSIONS: ART use was a significant predictor of change in fertility intentions between the baseline and follow-up visit, which suggests that additional efforts are necessary to integrate family planning and HIV services to address the safe fertility goals of women in the study area. PMID- 28728349 TI - Occupational risk factors among Iranian farmworkers: a review of the available evidence. AB - Farming is one of the most important components of most economies. No comprehensive picture exists of the health status of Iranian farmers and the work related hazards that affect them. We aimed to determine the gaps in the current knowledge regarding the occupational health of Iranian farmworkers. Electronic databases including Medline, Web of Science, Scopus, and Embase, as well as national databases including the Scientific Information Database, MagIran, and Barakat Knowledge System, were searched for articles published through March 2017. All epidemiologic studies regarding the occupational health of farmworkers in Iran were reviewed, regardless of their design, language, time of publication, and location. Of the 86 retrieved articles, 39 studies were ultimately analyzed. Most studies were conducted in Fars, Kerman, and Mazandaran provinces. According to the results of this review, chemical, physical, and biological hazards, along with work-related injuries, may be the main factors threatening the health of farmworkers. The unsafe use of pesticides was related to male infertility, eye and digestive complications, pesticide poisoning, pesticide absorption, hematological changes, non-Hodgkin lymphoma, and multiple myeloma. Chemical hazards (e.g., the unsafe use of pesticides), physical hazards, injuries, and biological hazards (e.g., work-related infectious diseases) threaten the health of Iranian farmworkers. Moreover, farmworkers lack adequate knowledge about the occupational hazards they face and the relevant risk factors. PMID- 28728350 TI - The association between smoking or passive smoking and cardiovascular diseases using a Bayesian hierarchical model: based on the 2008-2013 Korea Community Health Survey. AB - OBJECTIVES: Smoking and passive smoking have been extensively reported as risk factors of cardiovascular morbidity and mortality. Despite the biological mechanisms underlying the impact of hazardous chemical substances contained in tobacco in cardiovascular diseases (CVD), studies investigating the association between smoking and passive smoking with morbidity are at an inchoate stage in Korea. Therefore, this study aimed to estimate the risks of smoking and passive smoking on cardiovascular morbidity at the national and regional levels. METHODS: This study calculated sex-standardized and age-standardized prevalence of CVD and smoking indices in 253 community health centers (si/gun/gu) in Korea using the 2008-2013 Korea Community Health Survey data. Furthermore, a Bayesian hierarchical model was used to estimate the association of smoking and passive smoking with the prevalence of CVD from the national and regional community health centers. RESULTS: At the national level, smoking was significantly associated with stroke (relative risk [RR], 1.060) and hypertension (RR, 1.016) prevalence, whilst passive smoking at home and work were also significantly associated with prevalence of stroke (RR, 1.037/1.013), angina (RR, 1.016/1.006), and hypertension (RR, 1.010/1.004). Furthermore, the effects of smoking and passive smoking were greater in urban-industrial areas than in rural areas. CONCLUSIONS: The findings of this study would provide grounds for national policies that limit smoking and passive smoking, as well as regionally serve as the basis for region-specific healthcare policies in populations with high CVD vulnerability. PMID- 28728351 TI - Analysis of the relationship between community characteristics and depression using geographically weighted regression. AB - OBJECTIVES: Achieving national health equity is currently a pressing issue. Large regional variations in the health determinants are observed. Depression, one of the most common mental disorders, has large variations in incidence among different populations, and thus must be regionally analyzed. The present study aimed at analyzing regional disparities in depressive symptoms and identifying the health determinants that require regional interventions. METHODS: Using health indicators of depression in the Korea Community Health Survey 2011 and 2013, the Moran's I was calculated for each variable to assess spatial autocorrelation, and a validated geographically weighted regression analysis using ArcGIS version 10.1 of different domains: health behavior, morbidity, and the social and physical environments were created, and the final model included a combination of significant variables in these models. RESULTS: In the health behavior domain, the weekly breakfast intake frequency of 1-2 times was the most significantly correlated with depression in all regions, followed by exposure to secondhand smoke and the level of perceived stress in some regions. In the morbidity domain, the rate of lifetime diagnosis of myocardial infarction was the most significantly correlated with depression. In the social and physical environment domain, the trust environment within the local community was highly correlated with depression, showing that lower the level of trust, higher was the level of depression. A final model was constructed and analyzed using highly influential variables from each domain. The models were divided into two groups according to the significance of correlation of each variable with the experience of depression symptoms. CONCLUSIONS: The indicators of the regional health status are significantly associated with the incidence of depressive symptoms within a region. The significance of this correlation varied across regions. PMID- 28728352 TI - The association between physical activity and atrial fibrillation applying the Heaviside function in survival analysis: the Multi-Ethnic Study of Atherosclerosis. AB - OBJECTIVES: Although the effect of physical activity (PA) on the incidence of atrial fibrillation (AF) has been studied, contradictory results have been reported. Such discrepancies may reflect the different effects of various types of PA upon AF, as well as gender interactions. Therefore, we aimed to evaluate the associations of PA types (total, moderate/vigorous, and intentional), as well as walking pace, with AF risk in men and women. METHODS: Using the Multi-Ethnic Study of Atherosclerosis Typical Week Physical Activity Survey, 3 PA measures and walking pace were calculated among 6,487 men and women aged 45-84 years. The incidence of AF over approximately 11 years of follow-up was ascertained. The association of each PA measure and walking pace with AF incidence was estimated using multivariable Cox proportional hazard models. An extended Cox model with Heaviside functions (hv) of time was used to estimate the effects of time-varying covariates. RESULTS: During 11 years of follow-up (49,557 person-years), 242 new AF cases occurred. The incidence rate of AF was 48.83 per 10,000 person-years. The proportional hazard (PH) assumption for total PA among women was not met; hence, we used the hv to calculate the hazard ratio. Total PA in women in the hv2 analysis was negatively associated with AF in all 3 models, although for hv1 no significant association was observed. The PH assumption for walking pace among men was not met, and none of the hv showed a statistically significant association between walking pace and AF in men. CONCLUSIONS: These results suggest that PA is inversely associated with AF in women. PMID- 28728353 TI - Estimation of the rate and number of underreported deliberate self-poisoning attempts in western Iran in 2015. AB - OBJECTIVES: Rates of attempted deliberate self-poisoning (DSP) are subject to undercounting, underreporting, and denial of the suicide attempt. In this study, we estimated the rate of underreported DSP, which is the most common method of attempted suicide in Iran. METHODS: We estimated the rate and number of unaccounted individuals who attempted DSP in western Iran in 2015 using a truncated count model. In this method, the number of people who attempted DSP but were not referred to any health care centers, n0, was calculated through integrating hospital and forensic data. The crude and age-adjusted rates of attempted DSP were estimated directly using the average population size of the city of Kermanshah and the World Health Organization (WHO) world standard population with and without accounting for underreporting. The Monte Carlo method was used to determine the confidence level. RESULTS: The recorded number of people who attempted DSP was estimated by different methods to be in the range of 46.6 to 53.2% of the actual number of individuals who attempted DSP. The rate of underreported cases was higher among women than men and decreased as age increased. The rate of underreported cases decreased as the potency and intensity of toxic factors increased. The highest underreporting rates of 69.9, 51.2, and 21.5% were observed when oil and detergents (International Classification of Diseases, 10th revision [ICD-10] code: X66), medications (ICD-10 code: X60-X64), and agricultural toxins (ICD-10 codes: X68, X69) were used for poisoning, respectively. Crude rates, with and without accounting for underreporting, were estimated by the mixture method as 167.5 per 100,000 persons and 331.7 per 100,000 persons, respectively, which decreased to 129.8 per 100,000 persons and 253.1 per 100,000 persons after adjusting for age on the basis of the WHO world standard population. CONCLUSIONS: Nearly half of individuals who attempted DSP were not referred to a hospital for treatment or denied the suicide attempt for political or sociocultural reasons. Individuals with no access to counseling services are at a higher risk for repeated suicide attempts and fatal suicides. PMID- 28728354 TI - Phytotoxicity of glyphosate in the germination of Pisum sativum and its effect on germinated seedlings. AB - The present study evaluated the effects of glyphosate on Pisum sativum germination as well as its effect on the physiology and biochemistry of germinated seedlings. Different physico-chemical biomarkers, viz., chlorophyll, root and shoot length, total protein and soluble sugar, along with sodium and potassium concentration, were investigated in germinated seedlings at different glyphosate concentrations. This study reports the influence of different concentrations of glyphosate on pea seeds and seedlings. Physicochemical biomarkers were significantly changed by glyphosate exposure after 15 days. The germination of seedlings under control conditions (0 mg/L) was 100% after 3 days of treatment but at 3 and 4 mg/L glyphosate, germination was reduced to 55 and 40%, respectively. Physiological parameters like root and shoot length decreased monotonically with increasing glyphosate concentration, at 14 days of observation. Average root and shoot length (n=30 in three replicates) were reduced to 14.7 and 17.6%, respectively, at 4 mg/L glyphosate. Leaf chlorophyll content also decreased, with a similar trend to root and shoot length, but the protein content initially decreased and then increased with an increase in glyphosate concentration to 3 mg/L. The study suggests that glyphosate reduces the soluble sugar content significantly, by 21.6% (v/v). But internal sodium and potassium tissue concentrations were significantly altered by glyphosate exposure with increasing concentrations of glyphosate. Biochemical and physiological analysis also supports the inhibitory effect of glyphosate on seed germination and biochemical effects on seedlings. PMID- 28728355 TI - Identification of genes related to intramuscular fat content of pigs using genome wide association study. AB - OBJECTIVE: The aim of this study is to identify single nucleotide polymorphisms (SNPs) and genes related to pig IMF and estimate the heritability of intramuscular fat content (IMF). METHODS: Genome-wide association study (GWAS) on 704 inbred Berkshires was performed for IMF. To consider the inbreeding among samples, associations of the SNPs with IMF were tested as random effects in a mixed linear model using the genetic relationship matrix by GEMMA. Significant genes were compared with reported pig IMF quantitative trait loci (QTL) regions and functional classification of the identified genes were also performed. Heritability of IMF was estimated by GCTA tool. RESULTS: Total 365 SNPs were found to be significant from a cutoff of p-value <0.01 and the 365 significant SNPs were annotated across 120 genes. Twenty five genes were on pig IMF QTL regions. Bone morphogenetic protein-binding endothelial cell precursor-derived regulator, forkhead box protein O1, ectodysplasin A receptor, ring finger protein 149, cluster of differentiation, tyrosine-protein phosphatase non-receptor type 1, SRY (sex determining region Y)-box 9 (SOX9), MYC proto-oncogene, and macrophage migration inhibitory factor were related to mitogen-activated protein kinase pathway, which regulates the differentiation to adipocytes. These genes and the genes mapped on QTLs could be the candidate genes affecting IMF. Heritability of IMF was estimated as 0.52, which was relatively high, suggesting that a considerable portion of the total variance of IMF is explained by the SNP information. CONCLUSION: Our results can contribute to breeding pigs with better IMF and therefore, producing pork with better sensory qualities. PMID- 28728356 TI - Antioxidant potential of buffalo and cow milk Cheddar cheeses to tackle human colon adenocarcinoma (Caco-2) cells. AB - OBJECTIVE: The aim of present study was to assess the anti-oxidant potential of water-soluble peptides (WSPs) extract derived from buffalo and cow milk Cheddar cheeses at different stages of ripening. METHODS: The antioxidant potential of WSPs extract was assessed through 2,2'-azinobis-3-ethylbenzothiazoline-6sulfonic acid (ABTS)-radical scavenging activity. In addition, impact of WSPs extract on cell viability and production of reactive oxygen species (ROS) in human colon adenocarcinoma Caco-2 (tert-butylhydroperoxide-induced) cell lines was also evaluated. RESULTS: The ABTS-radical scavenging activity increased progressively with ripening period and dose-dependently in both cheeses. However, peptide extract from buffalo milk Cheddar cheese demonstrated relatively higher activity due to higher contents of water-soluble nitrogen. Intracellular ROS production in Caco-2 cells decreased significantly (p<0.05) till 150th day of cheese ripening and remained constant thereafter. Additionally, dose-dependent response of WSPs extract on antioxidant activity was noticed in the Caco-2 cell line. CONCLUSION: On the basis of current in vitro study, the Cheddar cheese WSPs extract can protect intestinal epithelium against oxidative stress due to their antioxidant activity. PMID- 28728357 TI - Effects of dietary alfalfa flavonoids on the performance, meat quality and lipid oxidation of growing rabbits. AB - OBJECTIVE: The present experiment has tested the effect of dietary alfalfa flavonoids (AAF) supplementation on the productive performances, carcass characteristics, meat quality and lipid oxidation of growing rabbits. METHODS: One hundred and sixty crossbred rabbits (42 days old) were divided into four groups of forty animals each and were fed either a control diet (AAF0) or an AAF0 diet supplemented with 400, 800, or 1,200 mg of AAF/kg per diet (AAF4, AAF8, and AAF12, respectively) from weaning to slaughtering (102 days old). Performance data were recorded over a period of 60 days. At the end of the trial, 12 rabbits were slaughtered per group, and the carcass characteristics were recorded. Moreover, the plasma, liver and dorsal muscles were sampled from 12 rabbits/group, and were analyzed for lipid oxidation. RESULTS: No significant differences were recorded for the performance, carcass characteristics and meat quality traits except for lightness parameter that was lower in the control group. Dietary AAF supplementation significantly (p<0.01) affected the malondialdehyde (MDA) levels of the frozen meat in a dose-related manner, with the lowest value (0.24 mg MDA/kg fresh meat) recorded in the AAF12 group samples. CONCLUSION: These findings indicated that the dietary inclusion of AAF in rabbit diets improved muscle oxidation stability with no adverse effects on the growth performance of the animals even if a slight impact on meat lightness color parameter was recorded. PMID- 28728358 TI - Tropical plant supplementation effects on the performance and parasite burden of goats. AB - OBJECTIVE: Examine the effects of supplementing bahiagrass hay (BG) with potentially anthelmintic quantities of hays of perennial peanut (PEA) or sericea lespedeza (LES) or seeds of velvet bean (Mucuna pruriens L.; MUC) or papaya (PAP) on the intake and nutritive value (Experiment 1), and the performance and parasite burden (Experiment 2) of goats. METHODS: In Experiment 1, 38 male goats (27.4+/-5.7 kg body weight) were randomly assigned to each of 5 treatments: i) BG alone and BG plus; ii) PEA; iii) LES; iv) MUC; and v) PAP. Goats were fed for ad libitum consumption and adapted to the diets for 14 d followed by 7 d of measurement. The PEA, LES, MUC (50%, 50%, and 10% of the diet dry matter [DM], respectively), and PAP (forced-fed at 10 g/d) were fed at rates that would elicit anthelmintic effects. In Experiment 2, goats remained in the same treatments but were allocated to 15 pens (3 pens per treatment) from d 22 to 63. All goats were infected with parasites by grazing an infected bahiagrass pasture from 0800 to 1500 h daily and then returned to the pens. RESULTS: Dry matter intake tended to be greater in goats fed PEA and LES than those fed BG (757 and 745 vs 612 g/d, respectively). Digestibility of DM (59.5% vs 54.9%) and organic matter (60.8% vs 56.0%) were greater in goats fed MUC vs BG, respectively. In Experiment 2, feeding PAP, LES, and PEA to goats reduced nematode fecal egg counts by 72%, 52%, and 32%, reduced abomasal adult worm counts by 78%, 52%, and 42%, and decreased plasma haptoglobin concentrations by 42%, 40%, and 45% relative to feeding BG alone, respectively. CONCLUSION: Supplementation with PEA, LES, and PAP decreased the parasite burden of goats but did not increase their performance. PAP was the most effective anthelmintic supplement. PMID- 28728359 TI - Influence of supplemental canola or soybean oil on milk yield, fatty acid profile and postpartum weight changes in grazing dairy goats. AB - OBJECTIVE: This experiment was designed to evaluate the effect of supplementation with soybean or canola oil on milk production and the composition of long chain fatty acids as well as weight changes in the goats and their kids. METHODS: Thirty nine mulitparous crossed Alpine*Nubian goats (initial body weight [BW] 43.5+/-1.7 kg) from the day of parturition were assigned to the treatments: grazing control (n = 15); grazing plus 20 mL/goat/d of supplemental soybean oil (n = 12); and grazing plus 20 mL/goat/d of supplemental canola oil (n = 12) from November 26, 2014 to March 7, 2015. The planned contrasts were: CI (control vs supplemented with oils); CII (soybean vs canola oil) to compare the treatment effects. RESULTS: The vegetable oil supplementation reduced weight losses in lactating goats (CI: -0.060 vs 0.090 kg/d; p = 0.03) but did not improve milk production or affect kids' growth. The content of C4, C6, C8, C10, C11, C14, and C18:1n9t in the milk was increased (p<0.05) with respect to control. However, C12, C14, C16, C18, C18:1n9c, C18:2n6c, and C18:3n3 were reduced (p<0.05) in supplemented goats. Conjugated linoleic acid (CLA) was increased (p<0.05) in goats supplemented with oils compared to the control group. CONCLUSION: Supplementation with 20 mL/d of soybean or canola oil did not affect milk production or kids' performance; however, it increased CLA concentration and reduced the reduced weight losses in lactating goats. PMID- 28728360 TI - Isolation and characterization of a novel gossypol-degrading bacteria Bacillus subtilis strain Rumen Bacillus Subtilis. AB - OBJECTIVE: The aim of the study was to isolate gossypol-degrading bacteria and to assess its potential for gossypol degradation. METHODS: Rumen liquid was collected from fistulated cows grazing the experimental pasture. Approximately 1 mL of the rumen liquid was spread onto basal medium plates containing 2 g/L gossypol as the only source of carbon and was then cultured at 39 degrees C to isolate gossypol-degrading bacteria. The isolated colonies were cultured for 6 h and then their size and shape observed by microscope and scanning electron microscope. The 16S rRNA gene of isolated colonies was sequenced and aligned using National Center for Biotechnology Information-Basic Local Alignment Search Tool. The various fermentation conditions, initial pH, incubation temperature, inoculum level and fermentationperiod were analyzed in cottonseed meal (CSM). The crude protein (CP), total gossypol (TG), and free gossypol (FG) were determined in CSM after fermentation with isolated strain at 39 degrees C for 72 h. RESULTS: Screening results showed that a single bacterial isolate, named Rumen Bacillus Subtilis (RBS), could use gossypol as a carbon source. The bacterium was identified by 16S rDNA sequencing as being 98% homologous to the sequence of Bacillus subtilis strain GH38. The optimum fermentation conditions were found to be 72 h, 39 degrees C, pH 6.5, moisture 50%, inoculum level 107 cell/g. In the optimum fermentation conditions, the FG and TG content in fermented CSM decreased 78.86% and 49% relative to the control. The content of CP and the essential amino acids of the fermented CSM increased respectively, compared with the control. CONCLUSION: The isolation of a gossypol-degrading bacterium from the cow rumen is of great importance for gossypol biodegradation and may be a valuable potential source for gossypol-degradation of CSM. PMID- 28728361 TI - Influence of barley grain treated with alkaline compounds or organic extracts on ex vivo site and extent of digestion of starch. AB - OBJECTIVE: Two ex vivo experiments were conducted to verify the effect of barley grain (Nusrat cultivar) treated with alkaline compounds (AC) including alum, ammonium, and sodium hydroxide or cation-exchanged organic extracts (OE) prepared from alfalfa hay, sugar beet pulp and Ulva Fasciata, on extent and digestion of starch. METHODS: In the first study, the in vitro first order disappearance kinetic parameters of dry matter (DM), crude protein (CP) and starch were estimated using a non-linear model (D(t) = D(i) . e(-kd . time) + I, where: D(t) = potentially digestible residues at any time, D(i) = potentially digestible fraction at any time, kd = fractional rate constant of digestion (/h), I = indigestible fraction at any time). In the second experiment, the ruminal and post-ruminal disappearance of DM, CP, and starch were determined using in situ mobile nylon bag. RESULTS: Barley grains treated with alum and alfalfa extract had a higher constant rate of starch digestion (0.11 and 0.09/h) than others. Barley grain treated with OE had a higher constant rate of CP digestion and that of treated with AC had a higher constant rate of starch digestion (0.08 and 0.11/h) compared with those of the other treatments. The indigestible fraction of starch treated with alum and sugar beet pulp extract was higher than that of the control group (0.24 and 0.25 vs 0.21). Barley grain treated with AC and OE had significant CP disappearance in the rumen, post-rumen and total tract, and also starch disappearance for post-rumen and total tract compared with the untreated (p<0.001). CONCLUSION: This study demonstrated that AC and OE might have positive effects on the starch degradation of the barley grain. In addition, treating barley grain with alum and sugar beet pulp extract could change the site and extend digestion of protein and starch. PMID- 28728362 TI - Estimation of genetic parameters of the productive and reproductive traits in Ethiopian Holstein using multi-trait models. AB - OBJECTIVE: This study estimated the genetic parameters for productive and reproductive traits. METHODS: The data included production and reproduction records of animals that have calved between 1979 and 2013. The genetic parameters were estimated using multivariate mixed models (DMU) package, fitting univariate and multivariate mixed models with average information restricted maximum likelihood algorithm. RESULTS: The estimates of heritability for milk production traits from the first three lactation records were 0.03+/-0.03 for lactation length (LL), 0.17+/-0.04 for lactation milk yield (LMY), and 0.15+/-0.04 for 305 days milk yield (305-d MY). For reproductive traits the heritability estimates were, 0.09+/-0.03 for days open (DO), 0.11+/-0.04 for calving interval (CI), and 0.47+/-0.06 for age at first calving (AFC). The repeatability estimates for production traits were 0.12+/-0.02, for LL, 0.39+/-0.02 for LMY, and 0.25+/-0.02 for 305-d MY. For reproductive traits the estimates of repeatability were 0.19+/ 0.02 for DO, and to 0.23+/-0.02 for CI. The phenotypic correlations between production and reproduction traits ranged from 0.08+/-0.04 for LL and AFC to 0.42+/-0.02 for LL and DO. The genetic correlation among production traits were generally high (>0.7) and between reproductive traits the estimates ranged from 0.06+/-0.13 for AFC and DO to 0.99+/-0.01 between CI and DO. Genetic correlations of productive traits with reproductive traits were ranged from -0.02 to 0.99. CONCLUSION: The high heritability estimates observed for AFC indicated that reasonable genetic improvement for this trait might be possible through selection. The h2 and r estimates for reproductive traits were slightly different from single versus multi-trait analyses of reproductive traits with production traits. As single-trait method is biased due to selection on milk yield, a multi trait evaluation of fertility with milk yield is recommended. PMID- 28728363 TI - Effect of different levels of protein concentrates supplementation on the growth performance, plasma amino acids profile and mTOR cascade genes expression in early-weaned yak calves. AB - OBJECTIVE: This study evaluated the effects of different levels of protein concentrate supplementation on the growth performance of yak calves, and correlated the growth rate to changes occurring in the plasma- amino acids, insulin profile, and signaling activity of mammalian target of rapamycin (mTOR) cascade to characterize the mechanism through which the protein synthesis can be improved in early weaned yaks. METHODS: For this study, 48 early (3 months old) weaned yak calves were selected, and assigned into four dietary treatments according to randomized complete block design. The four blocks were balanced for body weight and sex. The yaks were either grazed on natural pasture (control diet) in a single herd or the grazing yaks was supplemented with one of the three protein rich supplements containing low (17%; LP), medium (19%; MP), or high (21%; HP) levels of crude proteins for a period of 30 days. RESULTS: Results showed that the average daily gain of calves increased (0.14 vs 0.23-0.26 kg; p<0.05) with protein concentrates supplementation. The concentration of plasma methionine increased (p<0.05; 8.6 vs 10.1-12.4 MUmol/L), while those of serine and tyrosine did not change (p>0.05) when the grazing calves were supplemented with protein concentrates. Compared to control diet, the insulin level of calves increased (p<0.05; 1.86 vs 2.16-2.54 MUIU/mL) with supplementation of protein concentrates. Addition of protein concentrates up-regulated (p<0.05) expression of mTOR-raptor, mammalian vacuolar protein sorting 34 homolog, the translational regulators eukaryotic translation initiation factor 4E binding protein 1, and S6 kinase 1 genes in both Longissimus dorsi and semitendinosus. In contrast, the expression of sequestosome 1 was down-regulated in the concentrate supplemented calves. CONCLUSION: Our results show that protein supplementation improves the growth performance of early weaned yak calves, and that plasma methionine and insulin concentrations were the key mediator for gene expression and protein deposition in the muscles. PMID- 28728364 TI - Growth rate, carcass characteristics and meat quality of growing lambs fed buckwheat or maize silage. AB - OBJECTIVE: This study evaluated inclusion of buckwheat silage to the diet of growing lambs in terms of meat quality as compared to maize silage. METHODS: Buckwheat, rich in total phenols (TP, 33 g/kg dry matter [DM]), was harvested at the end of the milk stage and ensiled in 40 kg plastic bags after wilting (294 g/kg silage DM). A total of 18 growing lambs (21.6+/-1.2) were individually fed isonitrogenous and isoenergetic total mixed rations (TMR) for 75 d that either contained buckwheat or maize silage at DM proportions of 0.50. At the end of feeding trail all lambs were slaughtered to assess carcass characteristics and meat quality. RESULTS: Buckwheat silage increased (p<0.01) the DM intake of lambs as compared to maize silage, but had no effects (p>0.05) on live weight gain and feed efficiency. Carcass weight, dressing percentage, meat pH, water holding capacity, cooking loss, shear force (kg/cm2), and total viable bacteria count of meat did not differ (p>0.05) between the treatments. However, TP content of meat increased (p<0.001) by feeding buckwheat TMR. Feeding buckwheat TMR also decreased (p<0.05) the b* values of meat. CONCLUSION: The results provide that buckwheat silage is palatable and could successfully include TMR of growing lambs with no adverse effects on performance, carcass and meat quality. Additionally, feeding buckwheat silage to lambs offers increased TP in meat. PMID- 28728365 TI - Effects of inclusion level and adaptation period on nutrient digestibility and digestible energy of wheat bran in growing-finishing pigs. AB - OBJECTIVE: This experiment was to evaluate the effect of different inclusion levels and adaptation periods on digestible energy (DE) and the apparent total tract digestibility (ATTD) of chemical constituents in diets supplemented with wheat bran. METHODS: Thirty-six crossbred barrows with an initial body weight of 85.0+/-2.1 kg were allotted to 6 diets in a completely randomized block design with 6 pigs per diet. Diets included a corn-soybean basal diet and 5 additional diets which were formulated by replacing corn and soybean meal in control diet with 15%, 25%, 35%, 45%, or 55% wheat bran. The experiment lasted for 34 d, and feces were collected from d 8 to 13, 15 to 20, 22 to 27, and 29 to 34 respectively. RESULTS: The results showed no interaction effects between inclusion level and adaptation period on the concentration of DE and the ATTD of gross energy (GE) and crude protein (CP) in wheat bran. The DE value and ATTD of GE in wheat bran decreased (p<0.05) significantly as the inclusion level of wheat bran increased, but no difference in the ATTD of CP was observed. The ATTD of CP in wheat bran increased (p<0.10) significantly as the adaptation period for pigs was prolonged. In addition, the concentration of DE and the ATTD of GE in wheat bran decreased linearly (p<0.05) when pigs were fed either an increased level of wheat bran or given an increased adaptation period to the diets. CONCLUSION: Wheat bran showed a negative effect on the concentration of DE and ATTD of GE and CP as the inclusion level increased. A longer adaptation period can gradually increase the DE value and ATTD of GE and CP in wheat bran, and at least 14 to 21 d of adaptation might be recommended for growing-finishing pigs fed the high fiber diets with wheat bran. PMID- 28728366 TI - Effect of dietary beta-mannanase on productive performance, egg quality, and utilization of dietary energy and nutrients in aged laying hens raised under hot climatic conditions. AB - OBJECTIVE: The objective of this experiment was to investigate the effect of dietary beta-mannanase on productive performance, egg quality, and utilization of dietary energy and nutrients in aged laying hens raised under hot climatic conditions. METHODS: A total of 320 84-wk-old Hy-line Brown aged laying hens were allotted to one of four treatments with eight replicates in a completely randomized design. Two dietary treatments with high energy (HE; 2,800 kcal/kg nitrogen-corrected apparent metabolizable energy [AMEn]) and low energy (LE; 2,700 kcal/kg AMEn) were formulated. Two additional diets were prepared by adding 0.04% (MN4) or 0.08% beta-mannanase (MN8) to LE treatment diets. The feeding trial was conducted for 28 d, covering a period from July to August in South Korea. The average daily room temperature and relative humidity were 29.2 degrees C and 83%, respectively. RESULTS: Productive performance, egg quality, and cloacal temperature were not influenced by dietary treatments. The measured AMEn values for MN8 diets were similar to those for HE diets, which were greater (p<0.05) than those for LE and MN4 diets. However, the AMEn values for MN8 diets did not differ from those for LE and MN4 diets. CONCLUSION: The addition of beta mannanase to low energy diets increases energy values for diets fed to aged laying hens. However, this increase has little positive impacts on performance and egg quality. These results indicate that dietary beta-mannanase does not mitigate the heat stress of aged laying hens raised under hot climatic conditions. PMID- 28728367 TI - Comparative analysis on genome-wide DNA methylation in longissimus dorsi muscle between Small Tailed Han and Dorper*Small Tailed Han crossbred sheep. AB - OBJECTIVE: The objective of this study was to compare the DNA methylation profile in the longissimus dorsi muscle between Small Tailed Han and Dorper*Small Tailed Han crossbred sheep which were known to exhibit significant difference in meat production. METHODS: Six samples (three in each group) were subjected to the methylated DNA immunoprecipitation sequencing (MeDIP-seq) and subsequent bioinformatics analyses to detect differentially methylated regions (DMRs) between the two groups. RESULTS: 23.08 Gb clean data from six samples were generated and 808 DMRs were identified in gene body or their neighboring up/downstream regions. Compared with Small Tailed Han sheep, we observed a tendency toward a global loss of DNA methylation in these DMRs in the crossbred group. Gene ontology enrichment analysis found several gene sets which were hypo methylated in gene-body region, including nucleoside binding, motor activity, phospholipid binding and cell junction. Numerous genes were found to be differentially methylated between the two groups with several genes significantly differentially methylated, including transforming growth factor beta 3 (TGFB3), acyl-CoA synthetase long chain family member 1 (ACSL1), ryanodine receptor 1 (RYR1), acyl-CoA oxidase 2 (ACOX2), peroxisome proliferator activated receptor gamma2 (PPARG2), netrin 1 (NTN1), ras and rab interactor 2 (RIN2), microtubule associated protein RP/EB family member 1 (MAPRE1), ADAM metallopeptidase with thrombospondin type 1 motif 2 (ADAMTS2), myomesin 1 (MYOM1), zinc finger, DHHC type containing 13 (ZDHHC13), and SH3 and PX domains 2B (SH3PXD2B). The real-time quantitative polymerase chain reaction validation showed that the 12 genes are differentially expressed between the two groups. CONCLUSION: In the current study, a tendency to a global loss of DNA methylation in these DMRs in the crossbred group was found. Twelve genes, TGFB3, ACSL1, RYR1, ACOX2, PPARG2, NTN1, RIN2, MAPRE1, ADAMTS2, MYOM1, ZDHHC13, and SH3PXD2B, were found to be differentially methylated between the two groups by gene ontology enrichment analysis. There are differences in the expression of 12 genes, of which ACSL1, RIN2, and ADAMTS2 have a negative correlation with methylation levels and the data suggest that DNA methylation levels in DMRs of the 3 genes may have an influence on the expression. These results will serve as a valuable resource for DNA methylation investigations on screening candidate genes which might be related to meat production in sheep. PMID- 28728368 TI - Assessment of frozen storage duration effect on quality characteristics of various horse muscles. AB - OBJECTIVE: The study aimed at assessing the effects of frozen storage duration on quality characteristics, lipid oxidation and sensory quality of various horse muscles. METHODS: Five representative muscles: longissimus dorsi (LD), gluteus medius (GM), semimembranosus (SM), biceps femoris (BF), and triceps brachii (TB) at 24 h post-mortem obtained from 28-mo-old Jeju female breed horses (n = 8) were used in the present investigation. The muscles were vacuum-packaged and frozen at -20 degrees C for 120, 240, and 360 days. All the samples were analyzed for thawing and cooking losses, pH, Warner-Bratzler shear forces (WBSF), color traits, total volatile basic nitrogen (TVBN), thiobarbituric acid reactive substances (TBARS) and sensory traits. The muscle samples analyzed on day 0 of frozen storage (fresh, non-frozen) were used for comparison. RESULTS: Results revealed that thawing and cooking losses significantly (p<0.05) increased in all the muscles after 120 days and then remained unchanged up to 360 days of frozen storage. The TBARS and TVBN contents significantly increased as increasing frozen storage time up to 360 days (p<0.05). While, significant decreases in WBSF values were observed for all the muscles with increased frozen storage time (p<0.05). Frozen storage variously affected the color traits of the muscles for instance; the redness of LD, GM, and BF muscles showed a decreasing tendency during frozen storage while it was not changed in TB and SM muscles. Furthermore, the frozen storage did not produce detrimental effects on sensory quality as it did not cause flavor and juiciness defects whereas it partially improved the tenderness of all the muscles studied. CONCLUSION: Based on the results obtained from our work, it is concluded that frozen storage could be applied to increase the long term shelf life of horsemeat while still retaining its sensory quality. PMID- 28728369 TI - Estimation of heritability and genetic correlation of body weight gain and growth curve parameters in Korean native chicken. AB - OBJECTIVE: This study estimated the genetic parameters for body weight gain and growth curve parameter traits in Korean native chicken (KNC). METHODS: A total of 585 F1 chickens were used along with 88 of their F0 birds. Body weights were measured every 2 weeks from hatching to 20 weeks of age to measure weight gain at 2-week intervals. For each individual, a logistic growth curve model was fitted to the longitudinal growth dataset to obtain three growth curve parameters (alpha, asymptotic final body weight; beta, inflection point; and gamma, constant scale that was proportional to the overall growth rate). Genetic parameters were estimated based on the linear-mixed model using a restricted maximum likelihood method. RESULTS: Heritability estimates of body weight gain traits were low to high (0.057 to 0.458). Heritability estimates for alpha, beta, and gamma were 0.211+/-0.08, 0.249+/-0.09, and 0.095+/-0.06, respectively. Both genetic and phenotypic correlations between weight gain traits ranged from -0.527 to 0.993. Genetic and phenotypic correlation between the growth curve parameters and weight gain traits ranged from -0.968 to 0.987. CONCLUSION: Based on the results of this study population, we suggest that the KNC could be used for selective breeding between 6 and 8 weeks of age to enhance the overall genetic improvement of growth traits. After validation of these results in independent studies, these findings will be useful for further optimization of breeding programs for KNC. PMID- 28728370 TI - Endotoxin-induced inflammation disturbs melatonin secretion in ewe. AB - OBJECTIVE: The study examined the effect of intravenous administration of bacterial endotoxin-lipopolysaccharide (LPS) -on the nocturnal secretion of melatonin and on the expression of enzymes of the melatonin biosynthetic pathway in the pineal gland of ewes, taking into account two different photoperiodic conditions: short-night (SN; n = 12) and long-night (LN; n = 12). METHODS: In both experiments, animals (n = 12) were randomly divided into two groups: control (n = 6) and LPS-treated (n = 6) one. Two hours after sunset, animals received an injection of LPS or saline. Blood samples were collected starting one hour after sunset and continuing for 3 hours after the treatment. The ewes were euthanized 3 hours after LPS/saline treatment. The concentration of hormones in plasma was assayed by radioimmunoassay. In the pineal gland, the content of serotonin and its metabolite was determined by HPLC; whereas the expression of examined genes and protein was assayed using real-time polymerase chain reaction and Western Blot, respectively. RESULTS: Endotoxin administration lowered (p<0.05) levels of circulating melatonin in animals from LN photoperiod only during the first hour after treatment, while in ewes from SN photoperiod only in the third hour after the injection. Inflammation more substantially suppressed biosynthesis of melatonin in ewes from SN photoperiod, which were also characterised by lower (p<0.05) cortisol concentrations after LPS treatment compared with animals from LN photoperiod. In the pineal gland of ewes subjected to SN photoperiod, LPS reduced (p<0.05) serotonin content and the expression of melatonin biosynthetic pathway enzymes, such as tryptophan hydroxylase and arylalkylamine-N acetyltransferase. Pineal activity may be disturbed by circulating LPS and proinflammatory cytokines because the expression of mRNAs encoding their corresponding receptors was determined in this gland. CONCLUSION: The present study showed that peripheral inflammation reduces the secretion of melatonin, but this effect may be influenced by the photoperiod. PMID- 28728371 TI - Expression of fox-related genes in the skin follicles of Inner Mongolia cashmere goat. AB - OBJECTIVE: This study investigated the expression of genes in cashmere goats at different periods of their fetal development. METHODS: Bioinformatics analysis was used to evaluate data obtained by transcriptome sequencing of fetus skin samples collected from Inner Mongolia cashmere goats on days 45, 55, and 65 of fetal age. RESULTS: We found that FoxN1, FoxE1, and FoxI3 genes of the Fox gene family were probably involved in the growth and development of the follicle and the formation of hair, which is consistent with previous findings. Real-time quantitative polymerase chain reaction detecting system and Western blot analysis were employed to study the relative differentially expressed genes FoxN1, FoxE1, and FoxI3 in the body skin of cashmere goat fetuses and adult individuals. CONCLUSION: This study provided new fundamental information for further investigation of the genes related to follicle development and exploration of their roles in hair follicle initiation, growth, and development. PMID- 28728372 TI - Supplementary effects of higher levels of various disaccharides on processing yield, quality properties and sensory attributes of Chinese - style pork jerky. AB - OBJECTIVE: This study evaluated the supplementary effect of higher concentrations of various disaccharides on processing yield, major physicochemical properties, and sensory attributes of Chinese-style pork jerky (CSPJ). METHODS: CSPJ samples were prepared by marinating sliced ham (4 mm) with three dissaccharides, including sucrose, lactose, and maltose, at 0%, 15%, 18%, 21%, and 24%. Subsequently, the CSPJ samples were dried and roasted. The moisture content, water activity, crude protein, moisture-to-protein ratio, pH, processing yield, shear force, color, and sensory attributes of the CSPJ samples were evaluated. RESULTS: The quality characteristics of CSPJ samples prepared with sucrose were more acceptable. By contrast, CSPJ samples prepared with lactose showed the lowest scores. However, the processing yield and moisture content were the highest for CSPJ samples prepared with lactose, which may be associated with improved benefits for cost reduction. Furthermore, sucrose and lactose supplementation resulted in contrasting quality characteristics; for example, CSPJ samples with sucrose and maltose supplementation had higher sensory scores for color than samples with lactose supplementation. Additionally, most quality characteristics of CSPJ samples with sucrose supplementation contrasted with those of the samples with lactose supplementation; for example, the samples with sucrose supplementation had higher scores for sensory attributes than those with lactose supplementation. CONCLUSION: Sucrose supplementation up to 21% to 24% was associated with the highest overall acceptability scores (5.19 to 5.80), enhanced quality characteristics, increased processing yield, and reduced production cost. PMID- 28728373 TI - Substituting oat hay or maize silage for portion of alfalfa hay affects growth performance, ruminal fermentation, and nutrient digestibility of weaned calves. AB - OBJECTIVE: The impact of forage feeding strategy on growth performance, ruminal fermentation and nutrient digestibility in post-weaning calves was investigated. METHODS: Forty-five female Holstein calves (body weight [BW] = 79.79+/-0.38 kg) were enrolled in the 35-d study at one week after weaning and randomly assigned to one of three dietary treatments. All diets were fed as total mixed ration containing 60% (dry matter [DM] basis) of basal starter feed and 40% (DM basis) of forage, but varied in composition of forage source including i) alfalfa (40% DM, AH); ii) alfalfa hay (26.7% DM)+oat hay (13.3% DM; OH); iii) alfalfa hay (26.7% DM)+corn silage (13.3% DM; WS). RESULTS: Dry matter intake was not different among treatment groups (p>0.05). However, BW (p<0.05) and average daily gain (p<0.05) of calves fed AH and OH were greater than WS-fed calves, whereas heart girth was greater in OH-fed calves than those fed AH and WS (p<0.05). Ruminal fermentation parameters including proportion of butyric acid, acetated-to propionate ratio, concentration of total volatile fatty acid, protozoal protein, bacterial protein, and microbial protein in rumen were the highest in OH (p<0.05) and the lowest in WS. Compared with the AH and WS, feeding oat hay to postweaning calves increased crude protein digestibility (p<0.05), and decreased duration of diarrhea (p<0.05) and fecal index (p<0.05). CONCLUSION: Our results suggested that partially replacing alfalfa hay with oat hay improved ruminal fermentation, nitrogen utilization, and reduced incidence of diarrhea in post-weaning dairy calves. PMID- 28728374 TI - Analysis of metabolomic patterns in thoroughbreds before and after exercise. AB - OBJECTIVE: Evaluation of exercise effects in racehorses is important in horseracing industry and animal health care. In this study, we compared metabolic patterns between before and after exercise to screen metabolic biomarkers for exercise effects in thoroughbreds. METHODS: The concentration of metabolites in muscle, plasma, and urine was measured by 1H nuclear magnetic resonance (NMR) spectroscopy analysis and the relative metabolite levels in the three samples were compared between before and after exercise. Subsequently, multivariate data analysis based on the metabolic profiles was performed using orthogonal partial least square discriminant analysis (OPLS-DA) and variable important plots and t test was used for basic statistical analysis. RESULTS: From 1H NMR spectroscopy analysis, 35, 25, and 34 metabolites were detected in the muscle, plasma, and urine. Aspartate, betaine, choline, cysteine, ethanol, and threonine were increased over 2-fold in the muscle; propionate and trimethylamine were increased over 2-fold in the plasma; and alanine, glycerol, inosine, lactate, and pyruvate were increased over 2-fold whereas acetoacetate, arginine, citrulline, creatine, glutamine, glutarate, hippurate, lysine, methionine, phenylacetylglycine, taurine, trigonelline, trimethylamine, and trimethylamine N-oxide were decreased below 0.5-fold in the urine. The OPLS-DA showed clear separation of the metabolic patterns before and after exercise in the muscle, plasma, and urine. Statistical analysis showed that after exercise, acetoacetate, arginine, glutamine, hippurate, phenylacetylglycine trimethylamine, trimethylamine N-oxide, and trigonelline were significantly decreased and alanine, glycerol, inosine, lactate, and pyruvate were significantly increased in the urine (p<0.05). CONCLUSION: In conclusion, we analyzed integrated metabolic patterns in the muscle, plasma, and urine before and after exercise in racehorses. We found changed patterns of metabolites in the muscle, plasma, and urine of racehorses before and after exercise. PMID- 28728375 TI - Dynamics of shearing force and its correlations with chemical compositions and in vitro dry matter digestibility of stylo (Stylosanthes guianensis) stem. AB - OBJECTIVE: The study explored the dynamics of shearing force and its correlation with chemical compositions and in vitro dry matter digestibility (IVDMD) of stylo. METHODS: The shearing force, diameter, linear density, chemical composition, and IVDMD of different height stylo stem were investigated. Linear regression analysis was done to determine the relationships between the shearing force and cut height, diameter, chemical composition, or IVDMD. RESULTS: The results showed that shearing force of stylo stem increased with plant height increasing and the crude protein (CP) content and IVDMD decreased but fiber content increased over time, resulting in decreased forage value. In addition, tall stem had greater shearing force than short stem. Moreover, shearing force is positively correlated with stem diameter, linear density and fiber fraction, but negatively correlated with CP content and IVDMD. CONCLUSION: Overall, shearing force is an indicator more direct, easier and faster to measure than chemical composition and digestibility for evaluation of forage nutritive value related to animal performance. Therefore, it can be used to evaluate the nutritive value of stylo. PMID- 28728376 TI - Effect of condensed tannins from Ficus infectoria and Psidium guajava leaf meal mixture on nutrient metabolism, methane emission and performance of lambs. AB - OBJECTIVE: The study examined the effect of condensed tannins (CT) containing Ficus infectoria and Psidium guajava leaf meal mixture (LMM) supplementation on nutrient metabolism, methane emission and performance of lambs. METHODS: Twenty four lambs of ~6 months age (average body weight 10.1+/-0.60 kg) were randomly divided into 4 dietary treatments (CT-0, CT-1, CT-1.5, and CT-2 containing 0, 1.0, 1.5, and 2.0 percent CT through LMM, respectively) consisting of 6 lambs each in a completely randomized design. All the lambs were offered a basal diet of wheat straw ad libitum, oat hay (100 g/d) along with required amount of concentrate mixture to meet their nutrient requirements for a period of 6 months. After 3 months of experimental feeding, a metabolism trial of 6 days duration was conducted on all 24 lambs to determine nutrient digestibility and nitrogen balance. Urinary excretion of purine derivatives and microbial protein synthesis were determined using high performance liquid chromatography. Respiration chamber study was started at the mid of 5th month of experimental feeding trial. Whole energy balance trials were conducted on individual lamb one after the other, in an open circuit respiration calorimeter. RESULTS: Intake of dry matter and organic matter (g/d) was significantly (p<0.05) higher in CT-1.5 than control. Digestibility of various nutrients did not differ irrespective of treatments. Nitrogen retention and microbial nitrogen synthesis (g/d) was significantly (p<0.01) higher in CT-1.5 and CT-2 groups relative to CT-0. Total body weight gain (kg) and average daily gain (g) were significantly (linear, p<0.01) higher in CT-1.5 followed by CT-1 and CT-0, respectively. Feed conversion ratio (FCR) by lambs was significantly (linear, p<0.01) better in CT-1.5 followed by CT-2 and CT 0, respectively. Total wool yield (g; g/d) was linearly (p<0.05) higher for CT 1.5 than CT-0. Methane emission was linearly decreased (p<0.05) in CT groups and reduction was highest (p<0.01) in CT-2 followed by CT-1.5 and CT-1. Methane energy (kcal/d) was linearly decreased (p<0.05) in CT groups. CONCLUSION: The CT supplementation at 1% to 2% of the diet through Ficus infectoria and Psidium guajava LMM significantly improved nitrogen metabolism, growth performance, wool yield, FCR and reduced methane emission by lambs. PMID- 28728377 TI - Post-prandial decrease in plasma growth hormone levels is not related to the increase in plasma insulin levels in goats. AB - OBJECTIVE: In the present study, we examined whether the post-prandial reduction in plasma growth hormone (GH) levels is related to the increase in plasma insulin levels in ruminants. METHODS: We performed two experiments: intravenous bolus injection of insulin (0.2 IU/kg body weight) or glucose (1.0 mmol/kg body weight) was administered to increase the plasma insulin levels in male Shiba goats. RESULTS: In the insulin injection experiment, significant (p<0.05) increase in GH concentrations was observed, 15 to 20 min after the injection; it was accompanied with a significant (p<0.01) increase in cortisol concentrations at 45 to 90 min, when compared to the concentrations in the saline-injected controls. The glucose injection significantly (p<0.05) increased the plasma GH concentration at 20 to 45 min; this was not accompanied by significantly higher cortisol concentrations than were observed for the saline-injected control. Hypoglycemia induced by the insulin injection, which causes the excitation of the adrenal cortex, might be involved in the increase in insulin levels. CONCLUSION: Based on these results, we conclude that post-prandial increases in plasma insulin or glucose levels do not induce a decrease in GH concentration after feeding in the ruminants. PMID- 28728378 TI - Phenotypic diversity, major genes and production potential of local chickens and guinea fowl in Tamale, northern Ghana. AB - OBJECTIVE: Our study provides information on phenotypes of local chickens and guinea fowl and their body measures as well as on major genes in local chickens in northern Ghana. METHODS: Qualitative and morphometric traits were recorded on 788 local chickens and 394 guinea fowl in urban households in Tamale, Ghana. RESULTS: The results showed considerable variation of color traits and numerous major genes in local chickens, while color variations and related genotypes in guinea fowl were limited. In local chickens, white was preferred for plumage, whereas dark colors were preferred for beak and shanks. More than half of the chickens carried at least one major gene, but the contributions of single gene carriers were low. All calculated allele frequencies were significantly lower than their expected Mendelian allele frequencies. We observed higher mean body weight and larger linear body measures in male as compared to female chickens. In female chickens, we detected a small effect of major genes on body weight and chest circumference. In addition, we found some association between feather type and plumage color. In guinea fowl, seven distinct plumage colors were observed, of which pearl grey pied and pearl grey were the most prevalent. Male pearl grey pied guinea fowl were inferior to pearl grey and white guinea fowl in terms of body weight, body length and chest circumference; their shank length was lower than that of pearl grey fowl. CONCLUSION: Considerable variation in qualitative traits of local chickens may be indicative of genetic diversity within local chicken populations, but major genes were rare. In contrast, phenotypic and genetic diversity in local guinea fowl is limited. Broader genetic diversity studies and evaluation of trait preferences of local poultry producers are required for the design of appropriate breeding programs. PMID- 28728379 TI - Effects of dietary glutamine and arginine supplementation on performance, intestinal morphology and ascites mortality in broiler chickens reared under cold environment. AB - Objective: An experiment was conducted to evaluate the effects of dietary glutamine (Gln) and arginine (Arg) supplementation on performance, intestinal morphology and ascites mortality in broilers. Methods: A total of 675 day old chicks were randomly allocated to 9 experimental groups in a 3*3 factorial arrangement based on a completely randomized design with 5 replicates of 15 chicks. Three levels of dietary Gln (0, 0.5 and 1%) and Arg (100, 130% and 160% of Ross recommendation) supplementation were used in ascites inducing condition (15+/-1 C) from 7 to 42 days of age. Results: Dietary supplementation of Gln increased body weight gain (BWG) during grower, finisher and total periods (P<0.05) and increased feed intake during total period. Ascites mortality was decreased by Gln supplementation (P<0.05). Gln supplementation increased the villus height (VH) and crypt depth (CD) in duodenum and jejunum, and decreased the muscular layer in jejunum and ileum segments (P<0.05). Arg supplementation decreased CD in duodenum and jejunum and increased ileum villus width (VW), villus height /crypt depth ratio (VH/CD) in duodenum and jejunum and also muscular layer in duodenum, jejunum and ileum (P<0.05). Both Gln and Arg increased the goblet cell number (GCN) in duodenum whereas Gln supplementation decreased GCN in jejunum and ileum (P<0.05). The Gln*Arg interaction were observed for VH, VW, CD, VH/CD, muscular and serous layer thickness. Conclusion: It was concluded that dietary 0.5% Gln along with 130% Arg of Ross requirement, improve the intestinal morphology and performance and hence decrease the ascites mortality in broiler chickens with cold induced ascites. PMID- 28728380 TI - Effects of different space allowances on growth performance, blood profile and pork quality in a grow-to-finish production system. AB - OBJECTIVE: This experiment was conducted to evaluate the optimal space allowance on growth performance, blood profile and pork quality of growing-finishing pigs. METHODS: A total of ninety crossbred pigs [(Yorkshire*Landrace)*Duroc, 30.25+/ 1.13 kg] were allocated into three treatments (0.96: four pigs/pen, 0.96 m2/pig; 0.80: five pigs/pen, 0.80 m2/pig; 0.69: six pigs/pen, 0.69 m2/pig) in a randomized complete block design. Pigs were housed in balanced sex and had free access to feed in all phases for 14 weeks (growing phase I, growing phase II, finishing phase I, and finishing phase II). RESULTS: There was no statistical difference in growing phase, but a linear decrease was observed on average daily gain (ADG, p<0.01), average daily feed intake (ADFI, p<0.01), and body weight (BW, p<0.01) with decreasing space allowance in late finishing phase. On the other hand, a quadratic effect was observed on gain to feed ratio in early finishing phase (p<0.03). Consequently, overall ADG, ADFI, and final BW linearly declined in response to decreased space allowance (p<0.01). The pH of pork had no significant difference in 1 hour after slaughter, whereas there was a linear decrease in 24 h after slaughter with decreasing space allowance. Floor area allowance did not affect pork colors, but shear force linearly increased as floor space decreased (p<0.01). There was a linear increase in serum cortisol concentration on 14 week (p<0.05) with decreased space allocation. Serum IgG was linearly ameliorated as space allowance increased on 10 week (p<0.05) and 14 week (p<0.01). CONCLUSION: Data from current study indicated that stress derived from reduced space allowance deteriorates the immune system as well as growth performance of pigs, resulting in poor pork quality. Recommended adequate space allowance in a grow-to-finish production system is more than 0.80 m2/pig for maximizing growth performance and production efficiency. PMID- 28728381 TI - Blood haematology, muscle pH and serum cortisol changes in pigs with different levels of drip loss. AB - OBJECTIVE: An experiment was conducted to study the blood haematology, muscle pH, and serum cortisol changes in pigs with different levels of drip loss. METHODS: Two groups (low and high) of 20 animals were selected from 100 pigs based on drip loss. All [Duroc* (Large White*Landrace)] pigs were slaughtered according to standard slaughtering procedures. At exsanguinations, blood samples were taken for the haematological parameters and serum cortisol analysis. The muscle samples were taken from longissimus dorsi muscle to evaluate the muscle pH and drip loss. RESULTS: Haematological parameters of low drip loss group showed higher content of white blood cells and monocytes than high drip loss group (p<0.05). The low drip loss group had higher muscle pH at 45 min (p<0.05) and 24 h (p<0.001) post mortem than the high drip loss group. However, there was no significant difference in serum cortisol levels (p>0.05). CONCLUSION: Drip loss is mainly affected by the muscle pH decline after slaughter and also might be affected by white blood cells and monocytes. PMID- 28728382 TI - Effects of a traditional Chinese medicine formula and its extraction on muscle fiber characteristics in finishing pigs, porcine cell proliferation and isoforms of myosin heavy chain gene expression in myocytes. AB - OBJECTIVE: This study evaluated the effects of a traditional Chinese medicine formula (TCMF) on muscle fiber characteristics in finishing pigs and the effects of the formula's extract (distilled water, ethyl acetate and petroleum ether extraction) on porcine cell proliferation and isoforms of myosin heavy chain (MyHC) gene expression in myocytes. METHODS: In a completely randomized design, ninety pigs were assigned to three diets with five replications per treatment and six pigs per pen. The diets included the basal diet (control group), TCMF1 (basal diet+2.5 g/kg TCMF) and TCMF2 (basal diet+5 g/kg TCMF). The psoas major muscle was obtained from pigs at the end of the experiment. Muscle fiber characteristics in the psoas major muscle were analyzed using myosin ATPase staining. Cell proliferation was measured using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H tetrazolium bromide (MTT) dye and cytometry. Isoforms of MyHC gene expression were detected by real-time quantitative polymerase chain reaction. RESULTS: The final body weight and carcass weight of finishing pigs were increased by TCMF1 (p<0.05), while the psoas major muscle cross-sectional area was increased by TCMF (p<0.05). The cross-sectional area and diameter of psoas major muscle fiber I, IIA, and IIB were increased by TCMF2 (p<0.05). The cross-sectional area and fiber diameter of psoas major muscle fiber IIA and IIB were increased by diet supplementation with TCMF1 (p<0.05). Psoas major muscle fiber IIA and IIB fiber density from the pigs fed the TCMF1 diet and the type IIB fiber density from the pigs fed the TCMF2 diet were lower compared to pigs fed the control diet (p<0.05). Pigs fed TCMF2 had a higher composition of type I fiber and a lower percentage of type IIB fiber in the psoas major muscle (p<0.05). The expression levels of MyHC I, MyHC IIa, and MyHC IIx mRNA increased and the amount of MyHC IIb mRNA decreased in the psoas major muscle from TCMF2, whereas MyHC I and MyHC IIx mRNA increased in the psoas major muscle from TCMF1 (p<0.05). Peroxisome proliferator-activated receptor gamma coactivator-1alpha and CaN mRNA expression in the psoas major muscle were up-regulated by TCMF (p<0.05). Porcine skeletal muscle satellite cell proliferation was promoted by 4 MUg/mL and 20 MUg/mL TCMF water extraction (p<0.05). Both 1 MUg/mL and 5 MUg/mL of TCMF water extraction increased MyHC IIa, MyHC IIb, and MyHC IIx mRNA expression in porcine myocytes (p<0.05), while MyHC I mRNA expression in porcine myocytes was decreased by 5 MUg/mL TCMF water extraction (p<0.05). Porcine myocyte MyHC I and MyHC IIx mRNA expression were increased, and MyHC IIa and MyHC IIb mRNA expression were down regulated by 5 MUg/mL TCMF ethyl acetate extraction (p<0.05). MyHC I and MyHC IIa mRNA expression in porcine myocytes were increased, and the MyHC IIb mRNA expression was decreased by 1 MUg/mL TCMF ethyl acetate extraction (p<0.05). Four isoforms of MyHC mRNA expression in porcine myocytes were reduced by 5 MUg/mL TCMF petroleum ether extraction (p<0.05). MyHC IIa mRNA expression in porcine myocytes increased and MyHC IIb mRNA expression decreased by 1 MUg/mL in a TCMF petroleum ether extraction (p<0.05). CONCLUSION: These results indicated that TCMF amplified the psoas major muscle cross-sectional area through changing muscle fiber characteristics in finishing pigs. This effect was confirmed as TCMF extraction promoted porcine cell proliferation and affected isoforms of MyHC gene expression in myocytes. PMID- 28728383 TI - Potential influence of kappa-casein and beta-lactoglobulin genes in genetic association studies of milk quality traits. AB - OBJECTIVE: From a review of published information on genetic association studies, a meta-analysis was conducted to determine the influence of the genes kappa casein (CSN3) and beta-lactoglobulin (LGB) on milk yield traits in Holstein, Jersey, Brown Swiss, and Fleckvieh. METHODS: The GLIMMIX procedure was used to analyze milk production and percentage of protein and fat in milk. Models included the main effects and all their possible two-way interactions; not estimable effects and non-significant (p>0.05) two-way interactions were dropped from the models. The three traits analyzed used Poisson distribution and a log link function and were determined with the Interactive Data Analysis of SAS software. Least square means and multiple mean comparisons were obtained and performed for significant main effects and their interactions (p<0.0255). RESULTS: Interaction of breed by gene showed that Holstein and Fleckvieh were the breeds on which CSN3 (6.01%+/-0.19% and 5.98%+/-0.22%), and LGB (6.02%+/-0.19% and 5.70%+/-0.22%) have the greatest influence. Interaction of breed by genotype nested in the analyzed gene indicated that Holstein and Jersey showed greater influence of the CSN3 AA genotype, 6.04%+/-0.22% and 5.59%+/-0.31% than the other genotypes, while LGB AA genotype had the largest influence on the traits analyzed, 6.05%+/-0.20% and 5.60%+/-0.19%, respectively. Furthermore, interaction of type of statistical model by genotype nested in the analyzed gene indicated that CSN3 and LGB genes had similar behavior, maintaining a difference of more than 7% across analyzed genotypes. These results could indicate that both Holstein and Jersey have had lower substitution allele effect in selection programs that include CSN3 and LGB genes than Brown Swiss and Fleckvieh. CONCLUSION: Breed determined which genotypes had the greatest association with analyzed traits. The mixed model based in Bayesian or Ridge Regression was the best alternative to analyze CSN3 and LGB gene effects on milk yield and protein and fat percentages. PMID- 28728384 TI - Analysis of low-marbled Hanwoo cow meat aged with different dry-aging methods. AB - OBJECTIVE: Different dry-aging methods [traditional dry-aging (TD), simplified dry-aging (SD), and SD in an aging bag (SDB)] were compared to investigate the possible use of SD and/or SDB in practical situations. METHODS: Sirloins from 48 Hanwoo cows were frozen (Control, 2 days postmortem) or dry-aged for 28 days using the different aging methods and analyzed for chemical composition, total aerobic bacterial count, shear force, inosine 5'-monophosphate (IMP) and free amino acid content, and sensory properties. RESULTS: The difference in chemical composition, total aerobic bacterial count, shear force, IMP, and total free amino acid content were negligible among the 3 dry-aged groups. The SD and SDB showed statistically similar tenderness, flavor, and overall acceptability relative to TD. However, SDB had a relatively higher saleable yield. CONCLUSION: Both SD and SDB can successfully substitute for TD. However, SDB would be the best option for simplified dry-aging of low-marbled beef with a relatively high saleable yield. PMID- 28728385 TI - Effects of dietary energy sources on early postmortem muscle metabolism of finishing pigs. AB - OBJECTIVE: This study investigated the effects of different dietary energy sources on early postmortem muscle metabolism of finishing pigs. METHODS: Seventy two barrow (Duroc*Landrace*Yorkshire, DLY) pigs (65.0+/-2.0 kg) were allotted to three iso-energetic and iso-nitrogenous diets: A (44.1% starch, 5.9% crude fat, and 12.6% neutral detergent fibre [NDF]), B (37.6% starch, 9.5% crude fat, and 15.4% NDF) or C (30.9% starch, 14.3% crude fat, and 17.8% NDF). After the duration of 28-day feeding experiment, 24 pigs (eight per treatment) were slaughtered and the M. longissimus lumborum (LL) samples at 45 min postmortem were collected. RESULTS: Compared with diet A, diet C resulted in greater adenosine triphosphate and decreased phosphocreatine (PCr) concentrations, greater activity of creatine kinase and reduced percentage bound activities of hexokinase (HK), and pyruvate kinase (PK) in LL muscles (p<0.05). Moreover, diet C decreased the phosphor-AKT level and increased the hydroxy-hypoxia-inducible factor-1alpha (HIF-1alpha) level, as well as decreased the bound protein expressions of HK II, PKM2, and lactate dehydrogenase A (p<0.05). CONCLUSION: Diet C with the lowest level of starch and the highest levels of fat and NDF could enhance the PCr utilization and attenuate glycolysis early postmortem in LL muscle of finishing pigs. PMID- 28728386 TI - The relationship between odd- and branched-chain fatty acids and microbial nucleic acid bases in rumen. AB - OBJECTIVE: This study aims to identify the relationship between odd- and branched chain fatty acids (OBCFAs) and microbial nucleic acid bases in the rumen, and to establish a model to accurately predict microbial protein flow by using OBCFA. METHODS: To develop the regression equations, data on the rumen contents of individual cows were obtained from 2 feeding experiments. In the first experiment, 3 rumen-fistulated dry dairy cows arranged in a 3*3 Latin square were fed diets of differing forage to concentration ratios (F:C). The second experiment consisted of 9 lactating Holstein dairy cows of similar body weights at the same stage of pregnancy. For each lactation stage, 3 cows with similar milk production were selected. The rumen contents were sampled at 4 time points of every two hours after morning feeding 6 h, and then to analyse the concentrations of OBCFA and microbial nucleic acid bases in the rumen samples. RESULTS: The ruminal bacteria nucleic acid bases were significantly influenced by feeding diets of differing forge to concentration ratios and lactation stages of dairy cows (p<0.05). The concentrations of OBCFAs, especially odd-chain fatty acids and C15:0 isomers, strongly correlated with the microbial nucleic acid bases in the rumen (p<0.05). The equations of ruminal microbial nucleic acid bases established by ruminal OBCFAs contents showed a good predictive capacity, as indicated by reasonably low standard errors and high R-squared values. CONCLUSION: This finding suggests that the rumen OBCFA composition could be used as an internal marker of rumen microbial matter. PMID- 28728387 TI - Effects of environmental enrichment on behaviour, physiology and performance of pigs: A review. AB - The aim of this paper is to critically analyse and synthesise existing knowledge concerning the use of environmental enrichment and its effect on behaviour, physiology and performance of pigs housed in intensive production systems. The objective is also to provide clarity as to what constitute successful enrichment and recommend on when and how enrichment should be used. Environmental enrichment is usually understood as an attempt to improve animal welfare and to lesser extent, performance. Common enrichment objects used are straw bedding, suspended rope and wood shavings, toys, rubber tubing, coloured plastic keys, table tennis balls, chains and strings. These substrates need to be chewable, deformable, destructible and ingestible. For enrichment to be successful four goals are the prerequisite. Firstly, enrichment should increase the number and range of normal behaviours (2) prevent the phenomenon of anomalous behaviours or reduce their frequency (3) increase positive use of the environment such as space and (4) increase the ability of the animals to deal with behavioural and physiological challenges. The performance, behaviour and physiology of pigs in enriched environments is similar or in some cases slightly better when compared with barren environments. In studies where there was no improvement, it should be born in mind that enriching the environment may not always be practical and yield positive results due to factors such as type of enrichment substrates, duration of provision and type of enrichment used. The review also identifies possible areas which still need further research, especially in understanding the role of enrichment, novelty, breed differences and other enrichment alternatives. PMID- 28728388 TI - Characterization of culturable yeast species associating with whole crop corn and total mixed ration silage. AB - OBJECTIVE: This study investigated the association of yeast species with improved aerobic stability of total mixed ration (TMR) silages with prolonged ensiling, and clarified the characteristics of yeast species and their role during aerobic deterioration. METHODS: Whole crop corn (WCC) silages and TMR silages formulated with WCC were ensiled for 7, 14, 28, and 56 d and used for an aerobic stability test. Predominant yeast species were isolated from different periods and identified by sequencing analyses of the 26S rRNA gene D1/D2 domain. Characteristics (assimilation and tolerance) of the yeast species and their role during aerobic deterioration were investigated. RESULTS: In addition to species of Candida glabrata and Pichia kudriavzevii (P. kudriavzevii) previously isolated in WCC and TMR, Pichia manshurica (P. manshurica), Candida ethanolica (C. ethanolica), and Zygosaccharomyces bailii (Z. bailii) isolated at great frequency during deterioration, were capable of assimilating lactic or acetic acid and tolerant to acetic acid and might function more in deteriorating TMR silages at early fermentation (7 d and 14 d). With ensiling prolonged to 28 d, silages became more (p<0.01) stable when exposed to air, coinciding with the inhibition of yeast to below the detection limit. Species of P. manshurica that were predominant in deteriorating WCC silages were not detectable in TMR silages. In addition, the predominant yeast species of Z. bailii in deteriorating TMR silages at later fermentation (28 d and 56 d) were not observed in both WCC and WCC silages. CONCLUSION: The inhibition of yeasts, particularly P. kudriavzevii, probably account for the improved aerobic stability of TMR silages at later fermentation. Fewer species seemed to be involved in aerobic deterioration of silages at later fermentation and Z. bailii was most likely to initiate the aerobic deterioration of TMR silages at later fermentation. The use of WCC in TMR might not influence the predominant yeast species during aerobic deterioration of TMR silages. PMID- 28728389 TI - Influence of substituting steam-flaked corn for dry rolled corn on feedlot cattle growth performance when cattle are allowed either ad libitum or restricted access to the finishing diet. AB - OBJECTIVE: The influence of substituting steam-flaked corn (SFC) for dry rolled corn (DRC) on feedlot cattle growth performance and dietary net energy when cattle are allowed either ad libitum or 2-h restricted access to the finishing diet was evaluated. METHODS: Treatment effects were tested using 96 crossbred steers (251+/-2 kg) during the initial 56 d of the finishing phase. Cattle were blocked by weight and randomly assigned within blocks to 16 pens (4 pens/treatment). Bunk space was sufficient (41 cm/head) to allow all steers access to the feed bunk at the same time. Treatments consisted of two finishing diets containing (dry matter basis) 77.1% corn grain processed by dry rolling (density = 0.50 kg/L) or steam flaking (density = 0.36 kg/L). Cattle were fed twice daily at 06:00 and 14:00 h, allowing for approximately 5% residual. In the case of restricted feeding, steers were allowed access to feeders for 1 h following each feeding, after which residual feed was withdrawn. RESULTS: There were no treatment interactions on dry matter intake (DMI), average daily gain (ADG), gain efficiency (G:F), or dietary net energy (NE). Restricting feed access time reduced (p <0.01) feed intake, and hence, ADG. Substitution of SFC for DRC increased (p<0.01) ADG, feed efficiency (G:F), and estimated dietary NE, without affecting DMI. Based on tabular net energy of maintenance (NEm) value (2.18 Mcal/kg) for DRC, the estimated NEm value for SFC using the replacement technique, averaged 2.44 Mcal/kg; an improvement of 10.7%. The ratio of observed to-expected dietary NE was not affected by feed access time. CONCLUSION: Substitution of SFC for DRC in finishing diets for feedlot cattle enhanced ADG, gain efficiency, and the NE value of the diet. Although restriction of feed access time depressed DMI and ADG, it did not affect the comparative benefit of steam flaking toward enhancement of ADG, G:F, and dietary NE. PMID- 28728390 TI - Effect of dietary net energy concentrations on growth performance and net energy intake of growing gilts. AB - OBJECTIVE: This experiment investigated the effect of dietary net energy (NE) concentrations on growth performance and NE intake of growing gilts. METHODS: Five diets were formulated to contain 9.6, 10.1, 10.6, 11.1, and 11.6 MJ NE/kg, respectively. A metabolism trial with 10 growing pigs (average body weight [BW] = 15.9+/-0.24 kg) was conducted to determine NE concentrations of 5 diets based on French and Dutch NE systems in a 5*5 replicated Latin square design. A growth trial also was performed with five dietary treatments and 12 replicates per treatment using 60 growing gilts (average BW = 15.9+/-0.55 kg) for 28 days. A regression analysis was performed to predict daily NE intake from the BW of growing gilts. RESULTS: Increasing NE concentrations of diets did not influence average daily gain and average daily feed intake of growing gilts. There was a quadratic relationship (p = 0.01) between dietary NE concentrations and feed efficiency (G:F), although the difference in G:F among treatment means was relatively small. Regression analysis revealed that daily NE intake was linearly associated with the BW of growing gilts. The prediction equations for NE intake with the BW of growing gilts were: NE intake (MJ/d) = 1.442+(0.562*BW, kg), R2 = 0.796 when French NE system was used, whereas NE intake (MJ/d) = 1.533+(0.614*BW, kg), R2 = 0.810 when Dutch NE system was used. CONCLUSION: Increasing NE concentrations of diets from 9.6 to 11.6 MJ NE/kg have little impacts on growth performance of growing gilts. Daily NE intake can be predicted from the BW between 15 and 40 kg in growing gilts. PMID- 28728391 TI - Dietary maifanite supplementation did not affect the apparent total tract digestibility of calcium and phosphorus in growing pigs. AB - OBJECTIVE: This study was conducted to determine the effects of dietary maifanite supplementation and fecal collection method on the apparent total tract digestibility (ATTD) of calcium (Ca) and phosphorus (P) and blood parameters in growing pigs. METHODS: Thirty-six growing barrows (Duroc*Landrace*Yorkshire; 27.0+/-2.6 kg) were allotted to six dietary treatments with 6 pigs per treatment according to body weight in a completely randomized design. The experimental treatments were: i) Low Ca+cornstarch (2.25%), ii) Low Ca+maifanite (2.25%), iii) Medium Ca+cornstarch (1.42%), iv) Medium Ca+maifanite (1.42%), v) High Ca+cornstarch (0.64%), and vi) High Ca+maifanite (0.64%). Feces were collected by the total collection (TC) and indicator method (IM). At the beginning and the end of the experiment, blood samples were collected from each pig. RESULTS: For the TC method, there were no difference in Ca intake, fecal Ca output, Ca retention and the ATTD of Ca between cornstarch and maifanite diets at the same dietary Ca level. However, urinary Ca excretion was lower (p = 0.01) in pigs fed low Ca diets without maifanite supplementation compared with other dietary treatments. Dietary maifanite supplementation had no effect on the P metabolism in growing pigs. For the IM method, there was no difference in Ca digestibility between cornstarch and maifanite diets at the same dietary Ca level. The ATTD of P was greater (p<0.01) in pigs fed the high Ca diet with maifanite supplementation compared with the high Ca diet with cornstarch treatment. Dietary inclusion of maifanite had no effect on blood parameters in growing pigs. CONCLUSION: Dietary maifanite supplementation had no effect on the ATTD of Ca and P and serum parameters in growing pigs. The IM resulted in lower digestibility values than the TC method. PMID- 28728392 TI - Effects of selection index coefficients that ignore reliability on economic weights and selection responses during practical selection. AB - OBJECTIVE: In practical breeding, selection is often performed by ignoring the accuracy of evaluations and applying economic weights directly to the selection index coefficients of genetically standardized traits. The denominator of the standardized component trait of estimated genetic evaluations in practical selection varies with its reliability. Whereas theoretical methods for calculating the selection index coefficients of genetically standardized traits account for this variation, practical selection ignores reliability and assumes that it is equal to unity for each trait. The purpose of this study was to clarify the effects of ignoring the accuracy of the standardized component trait in selection criteria on selection responses and economic weights in retrospect. METHODS: Theoretical methods were presented accounting for reliability of estimated genetic evaluations for the selection index composed of genetically standardized traits. RESULTS: Selection responses and economic weights in retrospect resulting from practical selection were greater than those resulting from theoretical selection accounting for reliability when the accuracy of the estimated breeding value (EBV) or genomically enhanced breeding value (GEBV) was lower than those of the other traits in the index, but the opposite occurred when the accuracy of the EBV or GEBV was greater than those of the other traits. This trend was more conspicuous for traits with low economic weights than for those with high weights. CONCLUSION: Failure of the practical index to account for reliability yielded economic weights in retrospect that differed from those obtained with the theoretical index. Our results indicated that practical indices that ignore reliability delay genetic improvement. Therefore, selection practices need to account for reliability, especially when the reliabilities of the traits included in the index vary widely. PMID- 28728393 TI - Effects of dietary supplementation with detoxified Rhus verniciflua sap on egg production, yolk lipid and intestinal microflora in laying hens. AB - OBJECTIVE: This study was conducted to investigate the effects of dietary detoxified Rhus verniciflua sap (RVS) on production performance, egg quality, lipid fractions of egg yolk, liver and serum, and the profile of cecal microflora in laying hens. METHODS: Two hundred 52-week-old Hy-Line Brown layers were randomly divided into 4 groups with 5 replicates per group (2 hens per cage, 5 cages per replicate) and were provided with one of 4 experimental diets containing 0%, 0.05%, 0.1%, or 0.2% RVS, for 6 weeks. Due to unequal intervals of RVS doses, the interactive matrix language procedure of the SAS program was used to correct the contrast coefficients of orthogonal polynomials. RESULTS: There were no differences in feed intake and egg weight among the groups. Egg production increased (linearly and quadratically, p<0.05) with increasing levels of RVS. Eggshell thickness increased (linear, p<0.05) as the level of RVS in diets increased. The levels of blood cholesterol and activities of glutamic oxaloacetic transaminase and glutamic-pyruvic transaminase were not altered by dietary treatments. Increasing level of RVS increased (linear, p<0.05) the populations of cecal lactic acid bacteria. The content of yolk cholesterol decreased (linear, p< 0.05) with increasing levels of dietary RVS, although there were no significant differences in each lipid fraction of the liver. CONCLUSION: This study indicates that dietary RVS could improve laying performance and eggshell quality, and affect cecal lactic acid bacteria in a dose-dependent manner. PMID- 28728394 TI - Characterization of porcine cytokine inducible SH2-containing protein gene and its association with piglet diarrhea traits. AB - OBJECTIVE: The cytokine inducible SH2-containing protein (CISH), which might play a role in porcine intestine immune responses, was one of the promising candidate genes for piglet anti-disease traits. An experiment was conducted to characterize the porcine CISH (pCISH) gene and to evaluate its genetic effects on pig anti disease breeding. METHODS: Both reverse transcription polymerase chain reaction (RT-PCR) and PCR were performed to obtain the sequence of pCISH gene. A pEGFP-C1 CISH vector was constructed and transfected into PK-15 cells to analysis the distribution of pCISH. The sequences of individuals were compared with each other to find the polymorphisms in pCISH gene. The association analysis was performed in Min pigs and Landrace pigs to evaluate the genetic effects on piglet diarrhea traits. RESULTS: In the present research, the coding sequence and genomic sequence of pCISH gene was obtained. Porcine CISH was mainly localized in cytoplasm. TaqI and HaeIII PCR restriction fragment length polymorphism (RFLP) assays were established to detect single nucleotide polymorphisms (SNPs); A-1575G in promoter region and A2497C in Intron1, respectively. Association studies indicated that SNP A-1575G was significantly associated with diarrhea index of Min piglets (p<0.05) and SNP A2497C was significantly associated with the diarrhea trait of both Min pig and Landrace piglets (p<0.05). CONCLUSION: This study suggested that the pCISH gene might be a novel candidate gene for pig anti disease traits, and further studies are needed to confirm the results of this preliminary research. PMID- 28728395 TI - Effect of supplementary glycerin on milk composition and heat stability in dairy goats. AB - OBJECTIVE: This experiment was studied the effects of various levels of crude glycerin (CG) in dairy goat diet on daily intake, milk yield, milk composition, some physical properties and some quality changes of goat milk after sterilization. METHODS: Twelve 75% Saanen dairy goats (body weight = 49+/-3 kg; days in milk = 60+/-12 d) were randomly assigned in a completely randomized design to evaluate the effects of three experimental diets consisting of 0%, 5%, and 10% CG (dry matter basis) which were formulated to meet or exceed the nutrient requirements of goats. Experimental dairy goats were evaluated for feed and milk yield. Milk samples were analyzed for their composition, including fatty acids, casein profile, fat globule size, and color, and were sterilized to evaluate milk heat stability. RESULTS: There were no significant differences between 0% and 5% CG treatments infeed. Increasing CG supplementation from 0% to 5% increased milk yield from 2.38+/-0.12 to 2.64+/-0.23 kg/goat/d. In addition, milk samples from 5% CG treatment had the highest total solids, fat content and lactose content, and largest fat globule size. Increasing CG to 10% resulted in a decrease in milk fat. After sterilizing at 116 degrees C, F 0 = 3 min, goat milk samples from 5% CG treatment had slightly higher sediment content and comparatively higher degree of browning. CONCLUSION: Considering milk yield, milk fat content and quality of sterilized milk, 5% CG supplementation in a total mixed ration has a potential for implementation in dairy goats. PMID- 28728396 TI - Characterization and functional inferences of a genome-wide DNA methylation profile in the loin (longissimus dorsi) muscle of swine. AB - OBJECTIVE: DNA methylation plays a major role in regulating the expression of genes related to traits of economic interest (e.g., weight gain) in livestock animals. This study characterized and investigated the functional inferences of genome-wide DNA methylome in the loin (longissimus dorsi) muscle (LDM) of swine. METHODS: A total of 8.99 Gb methylated DNA immunoprecipitation sequence data were obtained from LDM samples of eight Duroc pigs (four pairs of littermates). The reference pig genome was annotated with 78.5% of the raw reads. A total of 33,506 putative methylated regions (PMR) were identified from methylated regions that overlapped at least two samples. RESULTS: Of these, only 3.1% were commonly observed in all eight samples. DNA methylation patterns between two littermates were as diverse as between unrelated individuals (p = 0.47), indicating that maternal genetic effects have little influence on the variation in DNA methylation of porcine LDM. The highest density of PMR was observed on chromosome 10. A major proportion (47.7%) of PMR was present in the repeat regions, followed by introns (21.5%). The highest conservation of PMR was found in CpG islands (12.1%). These results show an important role for DNA methylation in species- and tissue-specific regulation of gene expression. PMR were also significantly related to muscular cell development, cell-cell communication, cellular integrity and transport, and nutrient metabolism. CONCLUSION: This study indicated the biased distribution and functional role of DNA methylation in gene expression of porcine LDM. DNA methylation was related to cell development, cell-cell communication, cellular integrity and transport, and nutrient metabolism (e.g., insulin signaling pathways). Nutritional and environmental management may have a significant impact on the variation in DNA methylation of porcine LDM. PMID- 28728397 TI - Effects of dietary valine:lysine ratio on the performance, amino acid composition of tissues and mRNA expression of genes involved in branched-chain amino acid metabolism of weaned piglets. AB - OBJECTIVE: The goal of this study was to investigate the effects of dietary standard ileal digestible (SID) valine:lysine ratios on performance, intestinal morphology, amino acids of liver and muscle, plasma indices and mRNA expression of branched-chain amino acid (BCAA) metabolism enzymes. METHODS: A total of 144 crossbred pigs (Duroc*Landrace*Large White) weaned at 28+/-4 days of age (8.79+/ 0.02 kg body weight) were randomly allotted to 1 of 4 diets formulated to provide SID valine:lysine ratios of 50%, 60%, 70%, or 80%. Each diet was fed to 6 pens of pigs with 6 pigs per pen (3 gilts and 3 barrows) for 28 days. RESULTS: Average daily gain increased quadratically (p<0.05), the villous height of the duodenum, jejunum and ileum increased linearly (p<0.05) as the SID valine:lysine ratio increased. The concentrations of plasma alpha-keto isovaleric and valine increased linearly (p<0.05), plasma aspartate, asparagine and cysteine decreased (p<0.05) as the SID valine:lysine ratio increased. An increase in SID lysine:valine levels increased mRNA expression levels of mitochondrial BCAA transaminase and branched-chain alpha-keto acid dehydrogenase in the longissimus dorsi muscle (p<0.05). CONCLUSION: Using a quadratic model, a SID valine:lysine ratio of 68% was shown to maximize the growth of weaned pigs which is slightly higher than the level recommended by the National Research Council [6]. PMID- 28728398 TI - Effects of dietary energy levels on physiological parameters and reproductive performance of gestating sows over three consecutive parities. AB - OBJECTIVE: This experiment was to evaluate the effects of the dietary energy levels on the physiological parameters and reproductive performance during gestation over three parities in sows. METHODS: A total of 52 F1 gilts (Yorkshire*Landrace) were allotted to one of four dietary treatments using a completely randomized design. The treatments contained 3,100, 3,200, 3,300, or 3,400 kcal of metabolizable energy (ME)/kg diet but feed was provided at 2.0, 2.2, and 2.4 kg/d in the first, second and third parity, respectively. RESULTS: The body weight and body weight gain during gestation increased as the dietary energy level increased (p<0.05, and p<0.01) in the first parity. In the second parity, the body weight of sows was the lowest (p<0.05) when 3,100 kcal of ME/kg treatment diet was provided. The body weight was higher as the dietary energy level increased (p<0.05) during the gestation period in the third parity. During lactation, the voluntary feed intake of lactating sows tended to decrease when gilts were fed higher energy treatment diet (p = 0.08) and the body weight, body weight gain were increased by dietary energy level during gestation (p< 0.05). Backfat thickness was not affected by dietary treatment during the gestation period in three parities, interestingly backfat change from breeding to d 110 of gestation was higher as the dietary energy level increased at the first parity (p<0.05). When gilts were fed 3,400 kcal of ME/kg treatment diet a higher number of weaning piglets was observed in the first parity (p<0.05). The highest culling rate (69%) was seen when gestating sows were fed 3,100 kcal/kg ME treatment diet during three parities. CONCLUSION: In conclusion, the adequate energy intake of gestating sows should be 6,400 or 6,600 kcal of ME/d, 7,040 or 7,260 kcal of ME/d, and 7,680 or 7,920 kcal of ME/d for parity 1, 2, and 3, respectively. PMID- 28728399 TI - Fermentation quality and in vitro methane production of sorghum silage prepared with cellulase and lactic acid bacteria. AB - OBJECTIVE: The effects of lactic acid bacteria (LAB) and cellulase enzyme on fermentation quality, microorganism population, chemical composition and in vitro gas production of sorghum silages were studied. METHODS: Commercial inoculant Lactobacillus plantarum Chikuso 1 (CH), local selected strain Lactobacillus casei (L. casei) TH 14 and Acremonium cellulase (AC) were used as additives in sorghum silage preparation. RESULTS: Prior to ensiling Sorghum contained 104 LAB and 106 cfu/g fresh matter coliform bacteria. The chemical compositions of sorghum was 26.6% dry matter (DM), 5.2% crude protein (CP), and 69.7% DM for neutral detergent fiber. At 30 days of fermentation after ensiling, the LAB counts increased to a dominant population; the coliform bacteria and molds decreased to below detectable level. All sorghum silages were good quality with a low pH (<3.5) and high lactic acid content (>66.9 g/kg DM). When silage was inoculated with TH14, the pH value was significantly (p<0.05) lower and the CP content significantly (p<0.05) higher compared to control, CH and AC-treatments. The ratio of in vitro methane production to total gas production and DM in TH 14 and TH 14+AC treatments were significantly (p<0.05) reduced compared with other treatments while in vitro dry matter digestibility and gas production did not differ among treatments. CONCLUSION: The results confirmed that L. casei TH14 could improve sorghum silage fermentation, inhibit protein degradation and decrease methane production. PMID- 28728400 TI - Studies on meat color, myoglobin content, enzyme activities, and genes associated with oxidative potential of pigs slaughtered at different growth stages. AB - OBJECTIVE: This experiment investigated meat color, myoglobin content, enzyme activities, and expression of genes associated with oxidative potential of pigs slaughtered at different growth stages. METHODS: Sixty 4-week-old Duroc*Landrace*Yorkshire pigs were assigned to 6 replicate groups, each containing 10 pigs. One pig from each group was sacrificed at day 35, 63, 98, and 161 to isolate longissimus dorsi and triceps muscles. RESULTS: Meat color scores were higher in pigs at 35 d than those at 63 d and 98 d (p<0.05), and those at 98 d were lower than those at 161 d (p<0.05). The total myoglobin was higher on 161 d compared with those at 63 d and 98 d (p<0.05). Increase in the proportions of metmyoglobin and deoxymyoglobin and a decrease in oxymyoglobin were observed between days 35 and 161 (p<0.05). Meat color scores were correlated to the proportion of oxymyoglobin (r = 0.59, p<0.01), and negatively correlated with deoxymyoglobin and metmyoglobin content (r = -0.48 and -0.62, p<0.05). Malate dehydrogenase (MDH) activity at 35 d and 98 d was higher than that at 161 d (p<0.05). The highest lactate dehydrogenase/MDH ratio was achieved at 161 d (p<0.05). Calcineurin mRNA expression decreased at 35 d compared to that at 63 d and 98 d (p<0.05). Myocyte enhancer factor 2 mRNA results indicated a higher expression at 161 d than that at 63 d and 98 d (p<0.05). CONCLUSION: Porcine meat color, myoglobin content, enzyme activities, and genes associated with oxidative potential varied at different stages. PMID- 28728401 TI - Research trends in outdoor pig production - A review. AB - Since the industrialization of swine production in the late 1900s, swine farms in the United States, as well as in Europe, have largely become consolidated. Pig farms became larger in size but fewer in number, with 91% of market pigs being produced by large operations with 5,000 or more pigs on-site in the US, and only 3% of the total utilized agricultural land representing organic farming. Such change in the market made it difficult for small farmers to stay competitive, forcing them to find alternative ways to reduce the cost of production and increase profit using the outdoor production system. In contrast to the indoor confinement system, outdoor production system uses pasture-based units and/or deep-bedded hoop structures that promote animal welfare and environmental sustainability with a lower capital investment. In accord with the growing concern for animal and environmental welfare and food safety by the consumers, small farmers practicing an outdoor production system are seeing increased opportunities for marketing their products in the pork niche market. Unlike the general belief that the reproductive and growth performance measures of the outdoor sows and piglets are poorer in comparison with the animals reared indoors, studies showed that there was no significant difference in the performance measures, and some traits were even better in outdoor animals. Improved reproductive and production traits can increase the sustainability of outdoor farming. Present study reviewed the recent studies comparing the performance measures, meat quality and health of indoor and outdoor animals, as well as the efforts to improve the outdoor production system through changes in management such as hut types and breed of animals. PMID- 28728402 TI - Influence of body condition score at calving on the metabolic status and production performance of Murrah buffaloes (Bubalus bubalis) during the transition period. AB - OBJECTIVE: The purpose of this study was to evaluate the influence of body condition score (BCS) at calving on the metabolic status of female Murrah buffaloes in the transition period. METHODS: Thirty-seven pregnant buffaloes (multiparous) were selected and monitored during the transition period based on their body condition score and on the estimated calving date. Two groups were formed: i) buffaloes with a BCS>3.5 (n = 17); this group was classified and named 'high BCS at calving' (HBCS); and ii) buffaloes with a BCS<=3.5 (n = 20); this group was classified and named 'low BCS at calving' (LBCS). All animals were monitored during the last 30 days of pregnancy and the first 70 days post-calving and kept in the same environment and under the same feeding and management conditions. Mean values for BCS at calving were 2.98+/-0.9 (mean+/-standard error of the mean [SEM]) and 4.21+/-0.9 (mean+/-SEM) for the HBCS and LBCS groups, respectively. RESULTS: The HBCS group showed higher milk fat content (p = 0.007) and milk fat yield (p = 0.027) and a higher concentration of milk urea nitrogen (p = 0.001) than LBCS buffaloes, which in turn had a lower urine pH value (p = 0.033) than HBCS buffaloes in the pre-calving period (7.86 for HBCS vs 7.76 for LBCS). The HBCS animals had a higher concentration of erythrocytes (p = 0.001) and hematocrit (p = 0.012) post-calving and a higher hemoglobin concentration (p = 0.004) pre-calving. CONCLUSION: Buffaloes during the transition period exhibited some variations in the oxidative stress related to their metabolic status. After calving, buffaloes with a high BCS at calving and greater lipid mobilization have a more marked alteration in oxidative status, but improved production performance. PMID- 28728403 TI - Newborn traits associated with pre-weaning growth and survival in piglets. AB - OBJECTIVE: Piglet pre-weaning mortality is an important variable indicating the efficacy of farrowing management and animal well-being during lactation. The present study determined the association of newborn traits measured soon after birth with piglet pre-weaning mortality and growth. METHODS: In total, 805 piglets born from 57 multiparous sows were investigated. Their blood oxygen saturation, blood glucose and rectal temperature at 24 h after birth (RT24h) were monitored. Birth order, sex, skin color, integrity of the umbilical cord, attempts to stand and birth intervention were monitored. Piglets were weighed at day 0, 7, and 21 to evaluate average daily gain (ADG). RESULTS: Piglet pre weaning mortality for lactation period was 12.6% and cumulative mortality during the first 7 days of age was 8.6%. A higher proportion of piglets with pale skin color died compared to piglets with normal skin color (26.7% vs 7.7%, p<0.001). A higher (p<0.001) proportion of piglets that attempted to stand after 5 min (38.5%) died compared to piglets that attempted to stand within 1 min (6.3%) after birth. Piglet body weight at birth (BWB), blood glucose and the number of piglets born alive (BA) were correlated with ADG (p<0.05). Piglets with BWB <1.30 kg had higher (p<0.001) mortality rate than piglets with BWB>=1.80 kg (19.0% vs 3.3%) and piglets with BWB 1.30 to 1.79 kg (4.0%). Piglet with RT24h <37.0 degrees C had higher (p<0.001) mortality rate (86.2%) than piglets with RT24h >38.5 degrees C (3.9%). CONCLUSION: Low BWB and low RT24h compromise piglet survival during the lactation period in the tropical conditions. Piglets in the litters with a high BA, low BWB and low blood glucose have reduced ADG. PMID- 28728404 TI - Quality of steak restructured from beef trimmings containing microbial transglutaminase and impacted by freezing and grading by fat level. AB - OBJECTIVE: The objective of this research was to evaluate the physico-chemical, microbiological and sensorial qualities of restructured steaks processed from beef trimmings (grade I and II) and frozen beef (fresh beef as control and frozen beef). METHODS: Beef trimmings from commercial butcher were collected, designated into 4 treatments differing in beef trimmings grade and freezing, processed into restructured steaks with 1% microbial transglutaminase and then analyzed for product quality. RESULTS: The results showed that all meat from different groups could be tightly bound together via cross-linking of myosin heavy chain and actin as observed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Microbial counts of psychrotrophic and mesophilic bacteria were not affected by treatments (p>0.05), and no detectable of thermophilic bacteria were found. Regarding effect of beef trimmings grade, steaks made from beef trimmings grade II (16.03% fat) showed some superior sensorial qualities including higher tenderness score (p<0.05) and tendency for higher scores of juiciness and overall acceptability (p<0.07) than those made from beef trimmings grade I (2.15% fat). Moreover, a hardness value from texture profile analysis was lower in steaks processed from beef trimmings grade II than those made from grade I (p< 0.05). Although some inferior qualities in terms of cooking loss and discoloration after cooking were higher in steaks made from beef trimmings grade II than those made from beef trimmings grade I (p<0.05), these differences did not affect the sensory evaluation. Frozen beef improved the soft texture and resulted in effective meat binding as considered by higher cohesiveness and springiness of the raw restructured product as compared to fresh beef (p<0.05). CONCLUSION: The results indicated the most suitable raw beef for producing restructured steaks without detrimental effect on product quality was beef trimmings grade II containing up to 17% fat which positively affected the sensory quality and that frozen beef trimmings increased tenderness and meat binding of restructured beef steaks. PMID- 28728405 TI - Effect of rapeseed meal supplementation to gestation diet on reproductive performance, blood profiles and milk composition of sows. AB - OBJECTIVE: This experiment evaluated the effect of dietary supplementation levels of rapeseed meal (RSM) in gestation diets on reproductive performance, blood profiles, milk composition of sows, and growth of their progeny. METHODS: A total of 55 mixed-parity sows (Yorkshire*Landrace; average parity = 3.82) with an initial body weight (BW) of 193.0 kg were used in this experiment. Sows were allotted to one of 5 treatments at breeding based on BW and backfat thickness in a completely randomized design. Treatments consisted of dietary RSM supplementation levels (0%, 3%, 6%, 9%, and 12%) in gestation diets. During lactation all sows were fed a common lactation diet with no RSM supplementation. RESULTS: Body weight, backfat thickness, litter size, lactation feed intake, and milk composition of sows, and growth of their progeny were not different among dietary treatments. In blood profiles, a quadratic increase (Quadratic, p<0.05) in serum triiodothyronine (T3) concentration and a linear increase (Linear, p<0.01) in serum thyroxine (T4) concentration were observed at d 110 of gestation as dietary RSM supplementation levels increased. However, serum T3 and T4 concentrations in lactating sows and their piglets were not affected by RSM supplementation of gestation diets. Concentrations of serum total cholesterol and low density lipoprotein cholesterol in sows were not influenced by dietary treatments, whereas serum glucose level in sows decreased linearly at d 110 of gestation (Linear, p<0.05) by increasing dietary RSM supplementation in gestation diets. CONCLUSION: The RSM could be supplemented to gestation diets up to 12% with no detrimental effects on reproductive performance and growth of their progeny. However, increasing supplementation levels of RSM in gestation diets may increase serum T3 and T4 concentrations and decrease serum glucose concentration of sows in late gestation. PMID- 28728406 TI - Early weaning of calves after different dietary regimens affects later rumen development, growth, and carcass traits in Hanwoo cattle. AB - OBJECTIVE: The main objective of this study was to determine the effect of different diets for early-weaned (EW) calves on rumen development, and how this affects fat deposition in the longissimus dorsi of adult Korean Hanwoo beef cattle. METHODS: Three EW groups were established (each n = 12) in which two- week-old Hanwoo calves were fed for ten weeks with milk replacer+concentrate (T1), milk replacer+concentrate+ roughage (T2), or milk replacer+concentrate+30% starch (T3); a control group (n = 12) was weaned as normal. At six months, 5 calves of each group were slaughtered and their organs were assessed and rumen papillae growth rates were measured. The remaining calves (n = 7 in each group) were raised to 20 months for further analysis. RESULTS: Twenty-month-old EW calves had a higher body weight (BW), backfat thickness (BF), longissimus dorsi muscle area (LMA) and intramuscular fat (IMF) than the control (p<0.05). Organ growth, rumen histology, and gene expression patterns in the 6-month-old calves were positively related to the development of marbling in the loin, as assessed by ultrasound analysis (p<0.05). In the group fed the starch-enriched diet (T3), higher BW, BF, LMA, and IMF were present. The IMF beef quality score of 20-month old cattle was 1+ for the T2 and T3 diets and 1 for the T1 diet (p<0.05). CONCLUSION: Papillae development was significantly greater in calves fed on high concentrate diets and this may have resulted in the improved beef quality in the EW dietary groups compared to the control. PMID- 28728407 TI - Effects of cooking method and final core-temperature on cooking loss, lipid oxidation, nucleotide-related compounds and aroma volatiles of Hanwoo brisket. AB - OBJECTIVE: This study observed the effects of cooking method and final core temperature on cooking loss, lipid oxidation, aroma volatiles, nucleotide-related compounds and aroma volatiles of Hanwoo brisket (deep pectoralis). METHODS: Deep pectoralis muscles (8.65% of crude fat) were obtained from three Hanwoo steer carcasses with 1+ quality grade. Samples were either oven-roasted at 180 degrees C (dry heat) or cooked in boiling water (moist heat) to final core temperature of 70 degrees C (medium) or 77 degrees C (well-done). RESULTS: Boiling method reduced more fat but retained more moisture than did the oven roasting method (p<0.001), thus no significant differences were found on cooking loss. However, samples lost more weight as final core temperature increased (p<0.01). Further, total saturated fatty acid increased (p = 0.02) while total monounsaturated fatty acid decreased (p = 0.03) as final core temperature increased. Regardless the method used for cooking, malondialdehyde (p<0.01) and free iron contents (p<0.001) were observed higher in samples cooked to 77 degrees C. Oven roasting retained more inosinic acid, inosine and hypoxanthine in samples than did the boiling method (p<0.001), of which the concentration decreased as final core temperature increased except for hypoxanthine. Samples cooked to 77 degrees C using oven roasting method released more intense aroma than did the others and the aroma pattern was discriminated based on the intensity. Most of aldehydes and pyrazines were more abundant in oven-roasted samples than in boiled samples. Among identified volatiles, hexanal had the highest area unit in both boiled and oven-roasted samples, of which the abundance increased as the final core temperature increased. CONCLUSION: The boiling method extracted inosinic acid and rendered fat from beef brisket, whereas oven roasting intensified aroma derived from aldehydes and pyrazines and prevented the extreme loss of inosinic acid. PMID- 28728408 TI - Evaluation of trace mineral source and preharvest deletion of trace minerals from finishing diets on tissue mineral status in pigs. AB - OBJECTIVE: An experiment was conducted to evaluate dietary supplemental trace mineral source and deletion on mineral content in tissues. METHODS: Weanling crossbred pigs (n = 144; 72 barrows and 72 gilts; body weight [BW] = 7.4+/-1.05 kg) were used. A basal diet was prepared, and trace mineral premix containing either inorganic (ITM) or organic (OTM) trace minerals (Cu, Fe, Mn, and Zn) was added to the basal diet. Pigs were blocked by sex and BW and randomly allotted to 24 pens for a total of 6 pigs per pen, and fed a diet containing either ITM or OTM supplemented at the 1998 NRC requirement estimates for each of 5 BW phases (Phase I to V) from 7 to 120 kg. The trace mineral supplementation was deleted for 6, 4, 2, and 0 wk of Phase V; regarding nutrient adequacy during this phase, the indigenous dietary Fe and Mn was sufficient, Cu was marginal and Zn was deficient. RESULTS: At the end of Phase IV, Mn content (mg/kg on the dry matter basis) was greater (p<0.05) in heart (0.77 vs 0.68), kidney (6.32 vs 5.87), liver (9.46 vs 8.30), and longissimus dorsi (LD; 0.30 vs 0.23) of pigs fed OTM. The pigs fed OTM were greater (p<0.05) in LD Cu (2.12 vs 1.89) and Fe (21.75 vs 19.40) and metacarpal bone Zn (141.86 vs 130.05). At the end of Phase V, increased length of deletion period (from 0 to 6 wk) resulted in a decrease (linear, p<0.01) in liver Zn (196.5 to 121.8), metacarpal bone Zn (146.6 to 86.2) and an increase (linear, p<0.01) in heart Mn (0.70 to 1.08), liver Mn (7.74 to 12.96), and kidney Mn (5.58 to 7.56). The only mineral source by deletion period interaction (p<0.05) was observed in LD Zn. CONCLUSION: The results demonstrated differential effects of mineral deletion on tissue mineral content depending on both mineral assessed and source of the mineral. PMID- 28728409 TI - Heterogeneous Reactions between Toluene and NO2 on Mineral Particles under Simulated Atmospheric Conditions. AB - Heterogeneous reactions between organic and inorganic gases with aerosols are important for the study of smog occurrence and development. In this study, heterogeneous reactions between toluene and NO2 with three atmospheric mineral particles in the presence or absence of UV light were investigated. The three mineral particles were SiO2, alpha-Fe2O3, and BS (butlerite and szmolnokite). In a dark environment, benzaldehyde was produced on alpha-Fe2O3. For BS, nitrotoluene and benzaldehyde were obtained. No aromatic products were produced in the absence of NO2 in the system. In the presence of UV irradiation, benzaldehyde was detected on the SiO2 surface. Identical products were produced in the presence and absence of UV light over alpha-Fe2O3 and BS. UV light promoted nitrite to nitrate on mineral particles surface. On the basisi of the X ray photoelectron spectroscopy (XPS) results, a portion of BS was reduced from Fe3+ to Fe2+ with the adsorption of toluene or the reaction with toluene and NO2. Sulfate may play a key role in the generation of nitrotoluene on BS particles. From this research, the heterogeneous reactions between organic and inorganic gases with aerosols that occur during smog events will be better understood. PMID- 28728410 TI - Microbial Electrolytic Capture, Separation and Regeneration of CO2 for Biogas Upgrading. AB - Biogas upgrading to natural gas quality is essential for the efficient use of biogas in various applications. Carbon dioxide (CO2) which constitutes a major part of the biogas is generally removed by physicochemical methods. However, most of the methods are expensive and often present environmental challenges. In this study, an innovative microbial electrolytic system was developed to capture, separate and regenerate CO2 for biogas upgrading without external supply of chemicals, and potentially to treat wastewater. The new system was operated at varied biogas flow rates and external applied voltages. CO2 was effectively separated from the raw biogas and the CH4 content in the outlet reached as high as 97.0 +/- 0.2% at the external voltage of 1.2 V and gas flow rate of 19.6 mL/h. Regeneration of CO2 was also achieved in the regeneration chamber with low pH (1.34 +/- 0.04). The relatively low electric energy consumption (<=0.15 kWh/m3 biogas) along with the H2 production which can contribute to the energy input makes the overall energy need of the system low, and thereby makes the technology promising. This work provides the first attempt for development of a sustainable biogas upgrading technology and potentially expands the application of microbial electrochemical technologies. PMID- 28728411 TI - Isolation and Characterization of Lactoferrin Peptides with Stimulatory Effect on Osteoblast Proliferation. AB - Lactoferrin is reported to be a potential food protein with osteogenic activity. However, the activity of lactoferrin peptides is questionable. In the present study, we isolated and characterized peptides from lactoferrin with stimulatory effect on osteoblast proliferation. Peptides from the lactoferrin pepsin hydrolysate were purified using cation-exchange and gel-filtration chromatography. Effects of different hydrolysates and peptides on the proliferation of osteoblast MC3T3-E1 cells were compared by MTT assay. Results showed that fraction P5-a from Superdex Peptide 10/300 GL gel chromatography showed better activity. Tricine-sodium dodecyl sulfate polyacrylamide gel electrophoresis and high-performance liquid chromatography coupled to electrospray ionization tandem mass spectrometry confirmed that two peptides components of P5-a corresponded to fractions of 20-78 and 191-277 amino acids in Bos taurus lactoferrin molecule (GI: 221706349). These results will provide some theoretical and practical data for the preparation and application of osteogenic peptides in functional food industry. PMID- 28728412 TI - Role of Interfaces in Elasticity and Failure of Clay-Organic Nanocomposites: Toughening upon Interface Weakening? AB - Synthetic organic-inorganic composites constitute a new class of engineering materials finding applications in an increasing range of fields. The interface between the constituting phases plays a pivotal role in the enhancement of mechanical properties. In exfoliated clay-organic nanocomposites, individual, high aspect ratio clay sheets are dispersed in the organic matrix providing large interfaces and hence efficient stress transfer. In this study, we aim at elucidating molecular-scale reinforcing mechanisms in a series of model clay organic composite systems by means of reactive molecular simulations. In our models, two possible locations of failure initiation are present: one is the interlayer space of the clay platelet, and the other one is the clay-organic interface. We systematically modify the cohesiveness of the interface and assess how the failure mechanism changes when the different model composites are subjected to a tensile test. Besides a change in the failure mechanism, an increase in the released energy at the interface (meaning an increased overall toughness) are observed upon weakening the interface by bond removal. We propose a theoretical analysis of these results by considering a cohesive law that captures the effect of the interface on the composite mechanics. We suggest an atomistic interpretation of this cohesive law, in particular, how it relates to the degree of bonding at the interface. In a broader perspective, this work sheds light on the importance of the orthogonal behavior of interfaces to nanocomposites. PMID- 28728413 TI - Detection, Occurrence, and Fate of Fluorotelomer Alcohols in Municipal Wastewater Treatment Plants. AB - Fluorotelomer alcohols (FTOHs) are the most well-known precursors of perfluoroalkyl carboxylic acids (PFCAs), but limited information is available on their occurrence and fate in municipal wastewater treatment plants (WWTPs). The occurrence of FTOHs was investigated in influent, secondary effluent, and sludge of 12 municipal WWTPs in nine cities of China. FTOHs were detected in all WWTPs, and 8:2 FTOH was the predominant congener, with concentrations of 2.10-11.0 ng/L, 3.05-12.4 ng/L, and 0.36-1.91 ng/g dry weight in the influent, secondary effluent, and sludge, respectively. Relatively high proportions of long-chain FTOHs (C10-16) were mainly detected in sludge samples. The mass balance of FTOHs and PFCAs in one of the WWTPs with an anaerobic-anoxic-oxic process was further explored. The decrease of mass loads was observed for 4:2 FTOH (mass change percentage: 21 +/- 3.3%), 8:2 FTOH (22 +/- 1.5%), and 10:2 FTOH (29 +/- 7.3%) through aerobic treatment, while the increase of mass loads was observed for 12 PFCAs from 18 +/- 16% (perfluorononanoic acid) to 165 +/- 15% (perfluorobutyric acid)), suggesting the potential biotransformation of FTOHs to PFCAs in the aerobic unit. This work provides the first report on the occurrence of FTOHs in sludge samples of municipal WWTPs and their mass balance and highlights a new emission route to environment via WWTPs. PMID- 28728414 TI - Putting a New Spin on Supramolecular Metallacycles: Co3 Triangle and Co4 Square Bearing Tetrazine-Based Radicals as Bridges. AB - The synthesis of two new radical-bridged compounds [Co3(bptz)3(dbm)3].2toluene (1) and [Co4(bptz)4(dbm)4].4MeCN (2) (bptz = 3,6-bis(pyridyl)-1,2,4,5-tetrazine; dbm = 1,3-diphenyl-1,3-propanedionate) is reported. The presence of the ligand centered radical has been confirmed by X-ray crystallography and SQUID magnetometry. These complexes are the first metallacycles bearing nitrogen heterocyclic radicals as bridges. Magnetic studies reveal strong antiferromagnetic metal...radical coupling with coupling constants of J = -67.5 and -66.8 cm-1 for 1 and 2, respectively. DFT calculations further support the strong antiferromagnetic coupling between CoII ions and bptz radicals and confirm S = 3 and S = 4 spin ground states for 1 and 2, respectively. PMID- 28728418 TI - IWBDA 2016. PMID- 28728415 TI - 177Lu Labeled Cyclic Minigastrin Analogues with Therapeutic Activity in CCK2R Expressing Tumors: Preclinical Evaluation of a Kit Formulation. AB - Minigastrin (MG) analogues specifically target cholecystokinin-2 receptors (CCK2R) expressed in different tumors and enable targeted radiotherapy of advanced and disseminated disease when radiolabeled with a beta emitter such as 177Lu. Especially truncated MG analogues missing the penta-Glu sequence are associated with low kidney retention and seem therefore most promising for therapeutic use. Based on [d-Glu1,desGlu2-6]MG (MG11) we have designed the two cyclic MG analogues cyclo1,9[gamma-d-Glu1,desGlu2-6,d-Lys9]MG (cyclo-MG1) and cyclo1,9[gamma-d-Glu1,desGlu2-6,d-Lys9,Nle11]MG (cyclo-MG2). In the present work we have developed and preclinically evaluated a pharmaceutical kit formulation for the labeling with 177Lu of the two DOTA-conjugated cyclic MG analogues. The stability of the kits during storage as well as the stability of the radiolabeled peptides was investigated. A cell line stably transfected with human CCK2R and a control cell line without receptor expression were used for in vitro and in vivo studies with the radioligands prepared from kit formulations. In terms of stability 177Lu-DOTA-cyclo-MG2 showed advantages over 177Lu-DOTA-cyclo-MG1. Still, for both radioligands a high receptor-mediated cell uptake and favorable pharmacokinetic profile combining receptor-specific tumor uptake with low unspecific tissue uptake and low kidney retention were confirmed. Investigating the therapy efficacy and treatment toxicity in xenografted BALB/c nude mice a receptor-specific and comparable therapeutic effect could be demonstrated for both radioligands. A 1.7- to 2.6-fold increase in tumor volume doubling time was observed for receptor-positive tumors in treated versus untreated animals, which was 39-73% higher when compared to receptor-negative tumors. The treatment was connected with transient bone marrow toxicity and minor signs of kidney toxicity. All together the obtained results support further studies for the clinical translation of this new therapeutic approach. PMID- 28728423 TI - Changing Antibiotic Prescribing in a Primary Care Network: The Role of Readiness to Change and Group Dynamics in Success. AB - Overuse of broad-spectrum antibiotics in outpatient pediatrics remains a significant issue and there is limited evidence on how to effectively implement outpatient stewardship interventions. This study examines the relationship between readiness to change and modifiable factors affecting success of a primary care network antibiotic stewardship intervention. A survey designed to measure readiness to accept a health care innovation was administered to 209 clinicians. Practices were split in half into "high" versus "low" readiness to change. Semistructured qualitative interviews were conducted with 2 to 3 clinicians from 6 practices in each readiness group. High readiness practices trended toward greater improvements between years (8% to 26% vs 2% to 10% mean improvement). High readiness practice clinicians described more open communication, active group change process, and supportive underlying group cohesion. Low readiness practice clinicians functioned more independently and were influenced more by external forces but were developing group cohesion through the initiative. System wide interventions should be appropriately tailored to different levels of readiness to change, specifically addressing group dynamics and their differing foci of influence. PMID- 28728419 TI - Apoferritin Nanocage for Brain Targeted Doxorubicin Delivery. AB - An ideal brain-targeted nanocarrier must be sufficiently potent to penetrate the blood-brain barrier (BBB) and sufficiently competent to target the cells of interest with adequate optimized physiochemical features and biocompatibility. However, it is an enormous challenge to the researchers to organize the above mentioned properties into a single nanocarrier particle. New frontiers in nanomedicine are advancing the research of new biomaterials. Herein, we demonstrate a straightforward strategy for brain targeting by encapsulating doxorubicin (DOX) into a naturally available and unmodified apoferritin nanocage (DOX-loaded APO). APO can specifically bind to cells expressing transferrin receptor 1 (TfR1). Because of the high expression of TfR1 in both brain endothelial and glioma cells, DOX-loaded APO can cross the BBB and deliver drugs to the glioma with TfR1. Subsequent research demonstrated that the DOX-loaded APO had good physicochemical properties (particle size of 12.03 +/- 0.42 nm, drug encapsulation efficiency of 81.8 +/- 1.1%) and significant penetrating and targeting effects in the coculture model of bEnd.3 and C6 cells in vitro. In vivo imaging revealed that DOX-loaded APO accumulated specifically in brain tumor tissues. Additionally, in vivo tumor therapy experiments (at a dosage of 1 mg/kg DOX) demonstrated that a longer survival period was observed in mice that had been treated with DOX-loaded APO (30 days) compared with mice receiving free DOX solution (19 days). PMID- 28728424 TI - False-negative results in the immunoassay analysis of drugs of abuse: can adulterants be detected by sample check test? AB - Background The dilution or adulteration of urine is a serious problem in drugs of abuse testing. Tests to identify adulteration are currently available. This study investigated the ability of the CEDIA(r) sample check to detect adulteration. Methods Eight different drugs of abuse were added to a urine sample obtained from a healthy, drug-free subject: 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), 3,4-methylenedioxyamphetamine, benzoylecgonine, D-amphetamine sulphate, ethyl-D-glucuronide, morphine sulphate, oxazepam, (-)-11-nor-9-carboxy-Delta9 tetrahydrocannabinol. Urine samples were diluted to yield three samples of drugs of abuse concentrations close to general cut-offs as used in methadone treatment centres, by health authorities for psychological tests and in traffic medicine. Aspirin, citric acid, CrO3, H2O2, soap, sodium metaborate, vitamin C were added in three, HCl and NaOH in one, and NaN3 in two concentrations. All samples were measured with commercially available immunological assays shortly after sample preparation and 24 h later. All samples were further analysed with the CEDIA(r) sample check reaction which may identify adulteration. Results Oxidizing reagents (H2O2 or CrO3) are most effective in interfering in the measurement of benzoylecgonine, EDDP, ethyl-D-glucuronide and morphine sulphate. The measurement of (-)-11-nor-9-carboxy-Delta9-tetrahydrocannabinol is affected by many adulterants. Adulteration with HCl and NaOH was identified with the sample check reaction. NaN3 generated false negative results for a number of drugs of abuse. Conclusions Urine samples with drugs of abuse concentrations above cut-offs can be successfully tampered with adulterants in a way which cannot be detected with the CEDIA(r) sample check assay. PMID- 28728425 TI - Qatari intersections with global genetics research and discourse. AB - Genetic discourses have taken a predominant role in approaches to combating a number of conditions that affect Qataris. This paper is derived from an exploration of Qatari encounters with globalizing discourses of genetics, particularly as they relate to notions of risk. It explores Qataris negotiations of global interactions and influences, including the discourses around genetic risk and cousin marriage. It suggests that family marriage can be seen as one of the main platforms of resistance and a means for modern, cosmopolitan and tradition to be negotiated. PMID- 28728426 TI - Osteochondroma of the Hyoid: First Pediatric Case and Literature Review. AB - Osteochondromas, the most common benign bone tumors, are cartilaginous neoplasms of unknown origin with rare malignant potential. Osteochondromas rarely occur in the head and neck, and diagnosis relies on a combination of clinical, radiological, and histological criteria. Excision is often curative. We describe the first reported case of hyoid osteochondroma in an adolescent male with multiple osteochondroma, discuss its surgical management, and perform a review of the salient literature. Osteochondroma represents a rare diagnosis to include in the differential of any midline neck mass. PMID- 28728427 TI - Postdrome symptoms in pediatric migraine: A questionnaire retrospective study by phone in 100 patients. AB - Background No study dedicated to postdrome symptoms of migraine attacks is available in children and adolescents. Objective To study the resolution phase of the migraine attack in children and adolescents. Methods 100 children and adolescents with ICHD-3 beta migraine without and/or with typical aura were included. Each patient, and one of her/his parents, were interviewed by phone about the postdrome phrase of their last six months' migraine attacks. They were specifically instructed to distinguish symptoms that had begun before and went on after migraine headache cessation (referred to as persistent symptoms), and symptoms whose onset was strictly after headache cessation (referred to as true postdromes). Results 91% of patients reported persistent symptoms, with a mean of 2.9 and a median of 2; asthenia, cognitive difficulties, pallor, cognitive slowing, anorexia, somnolence, and nausea were the most frequently reported. They lasted less than 12 h in 71% of patients. True postdromes were reported by 82% of patients, with a mean of 2.6 and a median of 2; thirst, somnolence, visual disturbances, food craving, paraesthesias, and ocular pain being the most frequently reported. They lasted less than 12 h in 94% of patients. Conclusions This study showed that children and adolescents with migraine had both frequent persistent symptoms and true postdromes. Both were notably different from those reported in adults. PMID- 28728428 TI - Consequence of dopamine D2 receptor blockade on the hyperphagic effect induced by cannabinoid CB1 and CB2 receptors in layers. AB - 1. Endocannabinoids (ECBs) and their receptors play a regulatory function on several physiological processes such as feed-intake behaviour, mainly in the brain. This study was carried out in order to investigate the effects of the dopaminergic D1 and D2 receptors on CB1/CB2 ECB receptor-induced hyperphagia in 3 h feed-deprived neonatal layer chickens. 2. A total of 8 experiments were designed to explore the interplay of these two modulatory systems on feed intake in neonatal chickens. In Experiment 1, chickens were intracerebroventricular (ICV) injected with control solution, l-DOPA (levo-dihydroxyphenylalanine as precursor of dopamine; 125 nmol), 2-AG (2-arachidonoylglycerol as CB1 receptor agonist; 2 ug) and co-administration of l-DOPA (125 nmol) plus 2-AG (2 ug). Experiments 2-4 were similar to Experiment 1 except birds were injected with either 6-OHDA (6-hydroxydopamine as dopamine synthesis inhibitor; 150 nmol), SCH23390 (D1 receptor antagonist; 5 nmol) and AMI-193 (D2 receptor antagonist; 5 nmol) instead of l-DOPA, respectively. Additionally, Experiments 5-8 followed the previous ones using the same dose of l-DOPA, 6-OHDA and dopamine antagonists except that birds were injected with CB65 (CB2 receptor agonist; 5 ug) instead of 2-AG. Coadministrations were at the same dose for each experiment. Cumulative feed intakes were measured until 120 min after each injection. 3. ICV administration of 6-OHDA and AMI-193 significantly attenuated 2-AG-induced hyperphagia. Interestingly, the hyperphagic effect of CB65 was significantly attenuated by administration of l-DOPA, whereas the administration of 6-OHDA and AMI-193 together amplified the hyperphagic effect of CB65. 4. It was concluded that cannabinoid-induced feeding behaviour is probably modulated by dopamine receptors in neonatal layer-type chickens. It seems that their interaction may be mediated by the D2-dopamine receptor. PMID- 28728429 TI - Palliative care for respiratory disease: An education model of care. AB - That palliative care improves quality of life for seriously ill patients and their families is well known - but how can healthcare providers ensure that the palliative needs of all patients are being assessed and addressed? A growing number of curricula in core palliative care practices have been developed to ensure that clinicians from all specialties and disciplines have the necessary training to manage pain and symptoms and discuss care goals with patients and families. Through broad-based training in core palliative care skills, combined with referral to specialty palliative care for high-need patients, providers can improve quality of life for their patients with respiratory disease. PMID- 28728430 TI - Patient Handoff Education: Are Medical Schools Catching Up? AB - Communication errors during shift-to-shift handoffs are a leading cause of preventable adverse events. Nevertheless, handoff skills are variably taught at medical schools. The authors administered questionnaires on handoffs to interns during orientation. Questions focused on medical school handoff education, experiences, and perceptions. The majority (546/718) reported having some form of education on handoffs during medical school, with 48% indicating this was 1 hour or less. Most respondents (98%) reported that they believe patients experience adverse events because of inadequate handoffs, and more than one third had witnessed a patient safety issue. Results show that medical school graduates are not receiving adequate handoff training. Yet graduates are expected to conduct safe patient handoffs at the start of residency. Given that ineffective handoffs pose a significant patient safety risk, medical school graduates should have a baseline competency in handoff skills. This will require medical schools to develop, implement, and study handoff education. PMID- 28728431 TI - Radiographic temporal subtraction analysis can detect finger joint space narrowing progression in rheumatoid arthritis with clinical low disease activity. AB - Background Recent papers suggest that finger joints with positive synovial vascularity (SV) assessed by ultrasonography under clinical low disease activity (CLDA) in rheumatoid arthritis (RA) patients may cause joint space narrowing (JSN) progression. Purpose To investigate the performance of a computer-based method by directly comparing with the conventional scoring method in terms of the detectability of JSN progression in hand radiography of RA patients with CLDA. Material and Methods Fifteen RA patients (13 women, 2 men) with long-term sustained CLDA of >2 years were included. Radiological progression of finger joints was measured or scored using the computer-based method which can detect JSN progression between two radiographic images as the joint space difference index (JSDI), as well as the Genant-modified Sharp score (GSS). We also quantitatively assessed SV of these joints using ultrasonography. Results Out of 270 joints, we targeted 259 finger joints after excluding nine damaged joints (four ankylosis, three complete luxation, and two subluxation) and two improved joints according to the GSS results. The JSDI of finger joints with JSN progression was significantly higher than those without JSN progression ( P = 0.018). The JSDI of finger joints with ultrasonographic SV was significantly higher than those without ultrasonographic SV ( P = 0.004). Progression in JSDI showed stronger associations with ultrasonographic SV than progression in GSS (odds ratio [95% confidence interval]: 7.19 [3.37-15.36] versus 5.84 [2.76 12.33]). Conclusion The computer-based method was comparable to the conventional scoring method regarding the detectability of JSN progression in RA patients with CLDA. PMID- 28728432 TI - Postoperative Recurrence of Instability Due to New Anterior Glenoid Rim Fractures After Arthroscopic Bankart Repair. AB - BACKGROUND: Computed tomography (CT) sometimes reveals a new fracture of the anterior glenoid rim in patients with postoperative recurrence of instability after arthroscopic Bankart repair using suture anchors, but there have been few previous reports about such fractures. HYPOTHESIS: The placement of a large number of suture anchors during arthroscopic Bankart repair might be associated with a new glenoid rim fracture. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Screw-in metal suture anchors were used until June 2011 and suture based soft anchors from July 2011. A follow-up of at least 2 years was conducted for 128 shoulders treated using metal anchors (metal anchor group) and 129 shoulders treated using soft anchors (soft anchor group). The frequency and features of new glenoid rim fractures were investigated, and the influence of the number of suture anchors and other factors on fractures was also assessed. RESULTS: There were 19 shoulders (14.8%) with postoperative recurrence in the metal anchor group and 23 shoulders (17.8%) in the soft anchor group. Among 37 shoulders evaluated by CT at recurrence, a new glenoid rim fracture was detected in 13 shoulders (35.1%; 5 shoulders in the metal anchor group and 8 shoulders in the soft anchor group). A fracture at the anchor insertion site was recognized in 4 shoulders from the metal anchor group and 6 shoulders from the soft anchor group, although linear fractures connecting several anchor holes were only seen in the soft anchor group. While new glenoid fractures occurred regardless of the number of suture anchors used, new fractures were significantly more frequent in teenagers at surgery and in junior high school or high school athletes. Such fractures did not only occur in contact athletes but were also found in overhead athletes. CONCLUSION: Postoperative recurrence of instability associated with a new glenoid rim fracture along the suture anchor insertion site was frequent after arthroscopic Bankart repair. These fractures might be related to placing multiple soft suture anchors in a linear arrangement. PMID- 28728433 TI - Subgaleal Hematoma Masking Fatal Complications of Cephalohematoma in a Preterm Infant. PMID- 28728434 TI - Economic Model Predictive Control of Bihormonal Artificial Pancreas System Based on Switching Control and Dynamic R-parameter. AB - BACKGROUND: Blood glucose (BG) regulation is a long-term task for people with diabetes. In recent years, more and more researchers have attempted to achieve automated regulation of BG using automatic control algorithms, called the artificial pancreas (AP) system. In clinical practice, it is equally important to guarantee the treatment effect and reduce the treatment costs. The main motivation of this study is to reduce the cure burden. METHODS: The dynamic R parameter economic model predictive control (R-EMPC) is chosen to regulate the delivery rates of exogenous hormones (insulin and glucagon). It uses particle swarm optimization (PSO) to optimize the economic cost function and the switching logic between insulin delivery and glucagon delivery is designed based on switching control theory. RESULTS: The proposed method is first tested on the standard subject; the result is compared with the switching PID and the switching MPC. The effect of the dynamic R-parameter on improving the control performance is illustrated by comparing the results of the EMPC and the R-EMPC. Finally, the robustness tests on meal change (size and timing), hormone sensitivity (insulin and glucagon), and subject variability are performed. All results show that the proposed method can improve the control performance and reduce the economic costs. CONCLUSIONS: The simulation results verify the effectiveness of the proposed algorithm on improving the tracking performance, enhancing robustness, and reducing economic costs. The method proposed in this study owns great worth in practical application. PMID- 28728435 TI - Hyperglycemia as a Predictor for Adverse Outcome in ICU Patients With and Without Diabetes. PMID- 28728436 TI - Now Is the Time for a Security and Safety Standard for Consumer Smartphones Controlling Diabetes Devices. PMID- 28728437 TI - Does Continuous Diffusion of Oxygen Improve Diabetic Foot Ulcer Healing? AB - The objective of this article is to evaluate the study design, rational and results of Continuous Diffusion of Oxygen Therapy (CDOT) to heal diabetic foot ulcers (DFUs). The study was a double-blinded placebo controlled randomized clinical study to evaluate DFUs over a 12-week period. The primary outcome was the proportion of ulcers that healed and the secondary outcome that was reported was the time to ulcer healing. In the per protocol analysis and in the intent to treat analysis, a higher proportion of DFUs healed in the CDOT group (per protocol 46% vs 22%, P = .02, intent to treat 31.5% vs 15.1%, P = .03). CDOT patients healed ulcers faster compared to the in the sham treatment arm ( P = .026). PMID- 28728438 TI - Supine Percutaneous Nephrolithotomy in the Galdako-Modified Valdivia Position: A High-Volume Single Center Experience. AB - OBJECTIVE: To describe the technique and outcomes of supine percutaneous nephrolithotomy (PCNL) in the Galdako-modified Valdivia position. MATERIALS AND METHODS: Prospective data were collected from 303 patients undergoing PCNL in the Galdako-modified Valdivia position at our institution between 2007 and 2015. We report our technique with outcomes of operative times, stone-free rate (SFR), and complications. RESULTS: A total of 202 solitary stones with a mean size of 17.19 +/- 5.82 mm, 42 stones in multiple calices, and 57 staghorns were treated. Mean operative time was 79.79 +/- 35.72 minutes. A total of 244/303 (80.5%) patients had clearance or <2 mm stone on postoperative CT. Minor complications (Clavien Dindo Classification [CDC] 1-2) occurred in 59 (19.5%) cases and major complications (CDC >=3) occurred in 22 (7.3%) cases. Five (1.7%) cases required postoperative blood transfusion for bleeding complications. CONCLUSION: We demonstrate that PCNL in a high-volume center to be safe and efficacious in the Galdalko-modified Valdivia position. We show equivalent SFR and complication rates to large studies of prone PCNL, with potential to decrease operative time. In particular, supine position is optimum for obese or high-risk patients with complex stone disease, because of ease of positioning and lower theoretical risk of anesthetic complications. PMID- 28728439 TI - Translation of the Leicester Cough Questionnaire into Swedish, and validity and reliability in chronic obstructive pulmonary disease. AB - PURPOSE: The purpose of this study was to translate and culturally adapt the Leicester Cough Questionnaire into Swedish and to test the validity and reliability of the Swedish version, in patients with chronic obstructive pulmonary disease. METHODS: The original Leicester Cough Questionnaire was translated into Swedish by a method, which followed an established forward backward procedure, including cross-cultural adaptation and pretest. To test the validity of the final version of Leicester Cough Questionnaire in Swedish, the St George's Respiratory Questionnaire and the COPD Assessment Test were used (n =112) and to test reliability, the questionnaire was repeated (n = 86). RESULTS: The Leicester Cough Questionnaire in Swedish showed proof of construct validity and proof of internal consistency (Cronbach's alpha coefficient 0.97). All domains and total scores had good-excellent test-retest reliability (intra-class correlation coefficient 2,1 > 0.94). The standard error of measurement, (standard error of measurement percent), for the Leicester Cough Questionnaire in Swedish was 0.84 (5.15%). The smallest real difference, (smallest real difference percent), derived from cross sectional standard error of measurement was 2.33 (14.25%). The Bland-Altman plot indicated no systemic change in the mean. CONCLUSION: The Leicester Cough Questionnaire in Swedish is a valid and reliable instrument to measure health-related quality of life in patients with chronic obstructive pulmonary disease and can be used in clinical settings. Implications for Rehabilitation The Leicester Cough Questionnaire, has been translated into Swedish, following an established forward-backward procedure, including cross cultural adaptation The Swedish version of the Leicester Cough Questionnaire, is a valid, reliable instrument for measuring health-related quality of life regarding cough in patients with chronic obstructive pulmonary disease The Swedish version of the Leicester Cough Questionnaire is easy to administer and can be used in clinical and rehabilitation settings and for research purposes The absolute reliability presented at group and individual levels to indicate a real improvement is an advantage to assist when interpreting a clinically relevant difference. PMID- 28728440 TI - Rituximab subcutaneous in B-cell non-Hodgkin lymphoma: clinical experience in a single center. PMID- 28728441 TI - Ability of pulmonary function decline to predict death in amyotrophic lateral sclerosis patients. AB - OBJECTIVES: Objectives were to evaluate the relative risk of death associated with lung function decline in patients with amyotrophic lateral sclerosis (ALS), and to examine the ability of ALS patients to perform volitional pulmonary function tests (PFTs). METHODS: The PFTs of 256 consecutive patients referred to the Strasbourg University Hospital ALS Centre over an eight-year period were reviewed. Slow vital capacity (VC), maximal inspiratory and expiratory pressures (MIP, MEP), sniff nasal inspiratory pressure (SNIP), and peak cough flow (PCF) were performed at diagnosis and then every four months. The instantaneous risk of death associated with PFTs deterioration was calculated using time-dependent covariate Cox models. The changes of each PFT over time were examined and compared. RESULTS: A total of 985 acceptable PFT sessions were recorded. The risk of death was significantly associated with the decline in pulmonary function, regardless of the PFT parameter and its expression. When VC, MIP/SNIP and MEP (% of predicted) decreased by 10%, or PCF decreased by 50 L/min, the risk of death was multiplied by 1.31 (95% CI 1.21-1.41), 1.48 (1.32-1.66), 1.54 (1.32-1.79), and 1.32 (1.19-1.75), respectively. MIP, SNIP and MEP were decreased earlier in the course of disease and plunged deeper than VC within months before death, but were more affected by learning effect. CONCLUSIONS: This study provides tools to calculate the increase in risk of death from a PFT decline. At an individual level, since each test showed some flaws, the use of a combination of PFTs for ALS respiratory monitoring is recommended. PMID- 28728442 TI - An integrated platform for small-animal hyperthermia investigations under ultra high-field MRI guidance. AB - PURPOSE: Integrating small-animal experimental hyperthermia instrumentation with magnetic resonance imaging (MRI) affords real-time monitoring of spatial temperature profiles. This study reports on the development and preliminary in vivo characterisation of a 2.45 GHz microwave hyperthermia system for pre clinical small animal investigations, integrated within a 14 T ultra-high-field MRI scanner. MATERIALS AND METHODS: The presented system incorporates a 3.5 mm (OD) directional microwave hyperthermia antenna, positioned adjacent to the small animal target, radiating microwave energy for localised heating of subcutaneous tumours. The applicator is integrated within the 30 mm bore of the MRI system. 3D electromagnetic and biothermal simulations were implemented to characterise hyperthermia profiles from the directional microwave antenna. Experiments in tissue mimicking phantoms were performed to assess hyperthermia profiles and validate MR thermometry against fibre-optic temperature measurements. The feasibility of delivering in vivo hyperthermia exposures to subcutaneous 4T1 tumours in experimental mice under simultaneous MR thermometry guidance was assessed. RESULTS: Simulations and experiments in tissue mimicking phantoms demonstrated the feasibility of heating 21-982 mm3 targets with 8-12 W input power. Minimal susceptibility and electrical artefacts introduced by the hyperthermia applicator were observed on MR imaging. MR thermometry was in excellent agreement with fibre-optic temperatures measurements (max. discrepancy <=0.6 degrees C). Heating experiments with the reported system demonstrated the feasibility of heating subcutaneous tumours in vivo with simultaneous MR thermometry. CONCLUSIONS: A platform for small-animal hyperthermia investigations under ultra-high-field MR thermometry was developed and applied to heating subcutaneous tumours in vivo. PMID- 28728443 TI - Functional assessment of coronary artery disease by cardiac computed tomography. AB - INTRODUCTION: Rapid technological advances in computed tomography (CT) have allowed CT coronary angiography (CTCA) to be delivered at low radiation dose and high diagnostic accuracy. Due to its high negative predictive value for coronary artery disease, it has become a gatekeeper for the assessment of patients with chest pain of recent onset. Second line functional assessment of a detected coronary stenosis relies mostly on other imaging modalities. Functional assessment of coronary artery disease by CT is therefore an attractive addition to CTCA. Areas covered: This review will discuss the current evidence base and future development for CT perfusion imaging. Furthermore, this review will discuss CT-derived fractional flow reserve and CT coronary plaque characteristics as alternative approaches for functional evaluation of coronary artery disease. Finally, combining coronary anatomy and functional assessment of coronary flow with myocardial tissue characterization by CT may be attractive allowing triple assessment by CT. Expert commentary: The combined use of CTCA and functional assessment of coronary artery stenosis by CT perfusion or CT-derived fractional flow reserve is an attractive diagnostic pathway that requires further evaluation. PMID- 28728444 TI - Determinants of pain, disability, health-related quality of life and physical performance in patients with knee osteoarthritis awaiting total joint arthroplasty. AB - PURPOSE: In patients suffering from knee osteoarthritis awaiting knee arthroplasty, to measure associations between several selected determinants and pain, disability, health-related quality of life and physical performance. MATERIAL AND METHODS: Validated self-reported measures were collected: (1) Western Ontario and McMaster Universities Osteoarthritis Index, (2) Lower Extremity Functional Scale (LEFS) and (3) Short-Form 36 (SF-36). Physical performance was also assessed with four validated performance tests. Demographic, socioeconomic, psychosocial and clinical characteristics of the participants were also measured. Multivariate regression analyses were used to evaluate potential associations. RESULTS: Higher fear-avoidance beliefs, greater comorbidities, psychological distress and use of a walking aid were significantly associated with worse pain, function or HRQOL (p < 0.05) and explained 12%-35% of the variances of the self-reported measure scores. Pretest pain and change in pain during posttest, greater comorbidities, psychological distress and use of a walking aid were significantly associated with worse performance on the physical tests (p < 0.05) and explained 41%-59% of the variances of the different physical tests results. CONCLUSIONS: Several determinants were significantly associated with worse pain, disability, health-related quality of life or physical performance. Several of these associations may be considered clinically important, including psychosocial determinants in relation to self-reported measures, but to physical performance as well. Implications for rehabilitation Knee osteoarthritis is a highly prevalent and disabling condition incurring important socioeconomic costs. Several modifiable determinants have been shown to contribute to pain and disability in individuals suffering from knee OA awaiting TKA. Recent studies demonstrated the efficacy of education and rehabilitation (prehabilitation) in individuals awaiting TKA. PMID- 28728445 TI - The mediating and moderating role of planning on mothers' decisions for early childhood dietary behaviours. AB - OBJECTIVE: Examine the roles of action and coping planning on the intention behaviour relationship for mothers' decisions for their young children's dietary behaviours. DESIGN: Prospective design with two waves of data collection, one week apart. MAIN OUTCOME MEASURES: Mothers (N = 197, Mage = 34.39, SD = 5.65) of children aged 2-3 years completed a main questionnaire assessing planning constructs and intentions, and a one-week follow-up of the target behaviours - 'healthy eating' and 'discretionary choices'. RESULTS: Intention was the strongest predictor of behaviour for both dietary behaviours. For healthy eating, intention moderated the indirect relationship between intention-behaviour via planning; coping planning was less important when intention was strong. Further, intention was not a direct predictor of behaviour when intention was relatively low. Action planning was not a direct predictor of either behaviour after accounting for intention and coping planning; action planning on behaviour was mediated by coping planning (only for healthy eating). Intention was not a direct predictor of coping planning; intention on coping planning was mediated by action planning. Neither type of planning predicted discretionary choices. CONCLUSION: Current findings contribute novel information on the mechanisms underpinning the effect of action and coping planning on the intention-behaviour relationship. PMID- 28728447 TI - Corrigendum. PMID- 28728446 TI - HPMA copolymer-phospholipase C and dextrin-phospholipase A2 as model triggers for polymer enzyme liposome therapy (PELT). AB - 'Polymer Enzyme Liposome Therapy' (PELT) is a two-step anticancer approach in which a liposomal drug and polymer-phospholipase conjugate are administered sequentially to target the tumour interstitium by the enhanced permeability and retention effect, and trigger rapid, local, drug release. To date, however, the concept has only been described theoretically. We synthesised two polymer conjugates of phospholipase C (PLC) and A2 (PLA2) and evaluated their ability to trigger anthracycline release from the clinically used liposomes, Caelyx(r) and DaunoXome(r). N-(2-Hydroxypropyl)methacrylamide (HPMA) copolymer-PLC and a dextrin-PLA2 were synthesised and their enzymatic activity characterised. Doxorubicin release from polyethyleneglycol-coated (PEGylated) Caelyx(r) was relatively slow (<20%, 60 min), whereas daunomycin was rapidly released from non PEGylated DaunoXome(r) (~87%) by both enzymes. Incubation with dextrin-PLA2 triggered significantly less daunomycin release than HPMA copolymer-PLC, but when dextrin-PLA2 was pre-incubated with alpha-amylase, the rate of daunomycin release increased. DaunoXome(r)'s diameter increased in the presence of PLA2, while Caelyx(r)'s diameter was unaffected by free or conjugated PLA2. Dextrin-PLA2 potentiated the cytotoxicity of DaunoXome(r) to MCF-7 cells to a greater extent than free PLA2, while combining dextrin-PLA2 with Caelyx(r) resulted in antagonism, even in the presence of alpha-amylase, presumably due to steric hindrance by PEG. Our findings suggest that in vivo studies to evaluate PELT combinations should be further evaluated. PMID- 28728448 TI - Pregnancy and child health outcomes in pediatric and young adult leukemia and lymphoma survivors: a systematic review. AB - As long-term survival is high for children and young adults diagnosed with leukemia and lymphoma, delineating maternal, fetal and offspring health risks is important to their family planning. This systematic review examined data comparing these health risks between leukemia and lymphoma survivors and women without a history of cancer. Following a search of Embase, PubMed, CINAHL, Cochrane, and Web of Science, 142 articles were screened and 18 were included in this review. No higher risks of spontaneous abortion, maternal diabetes and anemia, stillbirth, birth defects, or childhood cancer in offspring were observed in survivors compared to controls. Important to counseling and clinical care, live birth rates were lower, while preterm birth and low birth weight risks were modestly higher in survivors compared to controls. Findings were largely reassuring but highlight the lack of data on maternal cardiopulmonary risks, differential risk by cancer treatment type, and interventions to decrease these risks. PMID- 28728449 TI - Efficiency and cytotoxicity analysis of cationic lipids-mediated gene transfection into AGS gastric cancer cells. AB - In this effort, we provided comparative study on optimization of transfection conditions for AGS human gastric cancer cell line using two commercial non liposomal cationic lipids. Using reporter vector pEGFP-N1, transfection efficiency of AttracteneTM and X-tremeGENE HPTM transfection reagents in terms of cell densities and DNA/reagent ratios was determined in AGS cells by flow cytometry and fluorescence microscopy. In addition, influence of transfection reagents on direct cytotoxicity and cell viability was respectively, measured using lactate dehydrogenase (LDH) leakage and MTT assays. Provided that the transfection rate of 29% and the mean fluorescence intensity of 437.5, the DNA/reagent ratio of 0.4/1.5 was selected as the optimal condition using AttracteneTM, whereas the optimum condition using X-tremeGENE HPTM was obtained by the ratio of 1/2 with a higher transfection rate of 36.9% and an MFI of 833. Very low direct cytotoxicity (<5% and 6-9% using AttracteneTM and X-tremeGENE HPTM, respectively) and high cell viability (74.5-95.5% versus 68-75%) showed the biodegradable attribute for both transfection reagents. Altogether, X-tremeGENE HPTM exhibited superiority over AttracteneTM as a transfection reagent for AGS cells. In the present research, we have established the optimized protocols for efficient transfection of AGS cells with potential applications in gene function and expression studies as well as gene therapy. PMID- 28728450 TI - Chronic lymphocytic leukemia in a patient with well-controlled HIV infection: successful treatment with ibrutinib. PMID- 28728451 TI - ESC expert statement on the effects on mood of the natural cycle and progestin only contraceptives. AB - Hormonal fluctuations during the natural cycle, as well as progestins used for hormonal contraception, can exert effects on mood especially in vulnerable women. Negative effects of levonorgestrel-releasing intrauterine contraception on mood are rare. PMID- 28728452 TI - Chemoradiation-induced hearing loss remains a major concern for head and neck cancer patients. AB - OBJECTIVE: Review of the literature regarding hearing loss in patients with head and neck cancer treated with chemoradiation. DESIGN: Studies in the literature are reviewed that pertain to hearing loss sustained in head and neck cancer patients receiving cisplatin-based chemoradiation. Personal observations noted while treating these patients are also detailed. STUDY SAMPLE: PubMed was searched for pertinent articles regarding hearing loss in head and neck cancer patients receiving cisplatin chemotherapy and/or radiation. RESULTS: Studies on the incidence and severity of hearing loss in head and neck cancer patients are limited, but those studies suggest that the risk of hearing loss is greater with higher-dose regimens. CONCLUSIONS: Newer cisplatin chemotherapy regimens using lower, weekly doses may be associated with a lower incidence and severity of hearing loss; however, large prospective studies are needed. Such information will be paramount to effective pre-treatment counselling of head and neck cancer patients. PMID- 28728453 TI - Incomplete metabolism of phytoestrogens by gut microbiota from children under the age of three. AB - Phytoestrogens are plant-derived polyphenols with structural and functional similarities to mammalian oestrogens. The aim of this work was to study the metabolism of phytoestrogens by children's intestinal microbiota and to compare it with previous results in adults. Faecal samples of 24 healthy children were subjected to phytoestrogen fermentation assay. Only one child produced equol, while O-desmethylangolensin was found in all. Urolithin production was detected in 14 children and enterolactone in 10. Further comparison with the metabolism of phytoestrogens by adult intestinal microbiota reflected that glycitein, dihydrogenistein, urolithins D and E, enterolactone, secoisolariciresinol and arctigenin were the most important metabolites differentiating between adult and child microbial gut metabolism. Although the child intestinal microbiota showed the ability to metabolise isoflavones, ellagitannins and lignans to a certain extent, it generally showed a reduced metabolism of phytoestrogens, with a lack of 5-hydroxy equol and enterodiol, and less urolithins and enterolactone producers. PMID- 28728454 TI - Quantification of marrow hematogones following autologous stem cell transplant in adult patients with plasma cell myeloma or diffuse large B-cell lymphoma and correlation with outcome. AB - In this retrospective study, we quantified the hematogone (normal B-lineage precursor) population by flow cytometric immunophenotyping in post-transplant bone marrow biopsy specimens from adult patients who received an autologous stem cell transplant for either plasma cell myeloma (n = 57) or diffuse large B-cell lymphoma (n = 73). The majority of patients (80%) had <5% marrow hematogones post transplant. Extreme (>10%) hematogone percentages were quite rare, seen in only four patients, and were not associated with disease progression. There was a positive association between the post-transplant day and hematogone percentage within the first year after transplant, and a negative association thereafter. Plasma cell myeloma patients with >=5% hematogones in any post-transplant flow cytometry study had a worse overall survival as did plasma cell myeloma patients with increased hematogones (as defined by percentile) at 100 days post transplant. These findings require further study, ideally in a prospective study design. PMID- 28728455 TI - Asparagine preserves intestinal barrier function from LPS-induced injury and regulates CRF/CRFR signaling pathway. AB - Stress causes intestinal inflammation and barrier dysfunction. Corticotrophin releasing factor (CRF)/CRF receptor (CRFR) signaling pathway has been shown to be important for stress-induced intestinal mucosal alteration. L-Asparagine (ASN) is a powerful stimulator of ornithine decarboxylase and cell proliferation in a variety of cell types, including colonic cells. In the present study, we investigated whether dietary ASN supplementation could alleviate the damage of intestinal barrier function caused by LPS through modulation of CRF/CRFR signaling pathway. Twenty-four weaned pigs were randomly divided into one of four treatments: (1) non-challenged control; (2) Escherichia coli LPS challenged control; (3) LPS + 0.5% ASN; (4) LPS + 1.0% ASN. LPS stress induced villous atrophy, intestinal morphology disruption and decreased claudin-1 expression. ASN supplementation increased intestinal claudin-1 protein expression and alleviated villous atrophy and intestinal morphology impairment caused by LPS stress. In addition, ASN supplementation increased the number of intestinal intraepithelial lymphocytes and reversed the elevations of intestinal mast cell number and neutrophil number induced by LPS stress. Moreover, ASN decreased the mRNA expression of intestinal CRF, glucocorticoid receptors and tryptase. These results indicate that ASN attenuates intestinal barrier dysfunction induced by LPS stress, and regulates CRF/CRFR1 signaling pathway and mast cell activation. PMID- 28728457 TI - Educated but anxious: How emotional states and education levels combine to influence online health information seeking. AB - This study combined conceptual frameworks from health information seeking, appraisal theory of emotions, and social determinants of health literatures to examine how emotional states and education predict online health information seeking. Nationally representative data from the Health Information National Trends Survey (HINTS 4, Cycle 3) were used to test the roles of education, anxiety, anger, sadness, hope, happiness, and an education by anxiety interaction in predicting online health information seeking. Results suggest that women, tablet owners, smartphone owners, the college educated, those who are sad some or all of the time, and those who are anxious most of the time were significantly more likely to seek online health information. Conversely, being angry all of the time decreased the likelihood of seeking. Furthermore, two significant interactions emerged between anxiety and education levels. Discrete psychological states and demographic factors (gender and education) individually and jointly impact information seeking tendencies. PMID- 28728456 TI - Quillaja saponaria bark saponin protects Wistar rats against ferrous sulphate induced oxidative and inflammatory liver damage. AB - CONTEXT: Saponins from different sources are historically reported in Chinese medicine to possess many beneficial effects. However, insufficient experimental data are available regarding the hepatoprotective potential of Quillaja bark saponin. OBJECTIVE: The protective effect of Quillaja saponaria Molina (Quillajaceae) bark triterpenoid saponin against iron-induced hepatotoxicity is compared to the standard N-acetylcysteine in adult male Wistar rats. MATERIALS AND METHODS: Animals were divided into (six) groups, namely a normal control, an N-acetylcysteine control (300 mg/kg/day, p.o., 10 days), a saponin control (100 mg/kg/day, p.o., for 10 days), a hepatotoxicity control (two doses of ferrous sulphate, 30 mg/kg/day each, i.p., on 9th and 10th day), an N-acetylcysteine plus ferrous sulphate (standard treatment) and a saponin plus ferrous sulphate (test treatment) group. Hepatocyte integrity loss markers (serum ALT, AST, ALP, GGT and LDH), oxidative stress markers (hepatic MDA, GSH and NOx), dyslipidaemic markers (serum TC and TG) and hepatocyte functioning markers (serum bilirubin and albumin) were assessed. RESULTS: Quillaja bark saponin decreased iron-induced elevation of ALT (reaching 57% of hepatotoxicity control), AST (66%), ALP (76%), GGT (60%), LDH (54%), MDA (65%), NOx (77%), TC (70%), TG (54%), and total (54%), direct (54%) and indirect (54%) bilirubin, coupled with increased GSH (219%) and albumin (159%) levels. Histopathological study strongly supported biochemical estimations, while immunohistochemical study showed marked effect on eNOS and iNOS expression. CONCLUSIONS: Quillaja bark saponin has a good hepatoprotective effect. Amelioration of oxidative stress and suppression of NOS expression, with resultant maintenance of hepatocyte integrity and functioning, may explain this beneficial effect. PMID- 28728458 TI - A low-fidelity serious game for medical-based cultural competence education. AB - Research has shown that the quality of care is compromised when healthcare providers respond inappropriately to patient language and cultural factors. However, research indicates that medical education is not keeping pace with the changing composition of the patient population in culturally diverse societies such as Canada and the United States, and many healthcare providers do not possess the attitudes or skills required to be effective within a culturally diverse healthcare setting. Here, we present Fydlyty, a web-based, low-fidelity serious game for medical-based cultural competence education. Fydlyty includes both a scenario and dialogue editor providing the ability to develop conversations, interpret responses, and respond to questions/answers from the game player. These responses are based on predefined cultural characteristics of the virtual patient and on different moods that the virtual patient may express depending on the situation. The results of a usability experiment conducted with medical professionals and trainees revealed that the game is easy to use, intuitive, and engaging. PMID- 28728459 TI - Effect of a 12-Week Physical Activity Program on Gross Motor Skills in Children. AB - This study examined the effects of a 12-week Comprehensive School Physical Activity Program (CSPAP) on gross motor skill development in children from low income families. Participants were 1,460 school-aged children (mean age = 8.4 +/- 1.8 years; 730 girls, 730 boys) recruited from three schools receiving U.S. governmental financial assistance. Students were recruited from grades K-6. CSPAP was implemented over one semester during the 2014-2015 school year. Select gross motor skill items were assessed during each student's physical education class at baseline and at a 12-week follow-up using the Test for Gross Motor Development 2nd Edition (TGMD-2). Each student's TGMD-2 score was converted to a percentage of the total possible score. A 7 * 2 * 2 analysis of variance test with repeated measures was employed to examine the effects of age, sex, and time on TGMD-2 percent scores, adjusting for clustering within the data structure. There were greater TGMD-2 percent scores at follow-up compared with baseline (82.4% vs. 72.6%, mean difference = 9.8%, p < .001, Cohen's d = 0.67), and greater improvements were seen in younger children compared with older children (mean difference of change = 4.0%-7.5%, p < .01, Cohen's d = 0.30-0.55). PMID- 28728460 TI - Acute Effects of Moderate Alcohol Consumption on Postural Stability in Older Adults. AB - This study involved healthy community-living older adults in an investigation of the association between moderate alcohol consumption (AC) and acute changes in postural stability and whether the association differed according to pre-AC balance skills. Thirty-nine moderate drinkers aged >= 65 years (62% women; mean age: 73.9 +/- 6.1 years) consumed a moderate dose of alcohol (0.4 g/kg; administered as two drinks). Breath alcohol concentration and postural stability were measured at five time points (pre-AC and 40, 80, 120, and 160 minutes post AC) using unipedal stance time (UPST) and center of pressure (CoP) displacement. Pre-AC UPST was used to categorize participants into good-balance (>=30 seconds) and poor-balance (<30 seconds) groups. Peak breath alcohol concentration was 30 mg/dL at 40 minutes post-AC. For all participants, postural stability declined significantly at 80 minutes post-AC (UPST, p = .005; anterior-posterior CoP displacement, p = .029). While the poor-balance group did not show a significant decrease in UPST duration over the course of the study, the good-balance group experienced significant decline at 80 minutes compared with baseline ( p < .001) and remained above the 30-second UPST cutoff. Both groups experienced similar worsening in anterior-posterior CoP displacement at 80 minutes post-AC. Thus, moderate AC was associated with acute decline in postural stability in older adults. The worsened anterior-posterior CoP displacement post-AC in the poor balance group was of particular concern because these participants were already at lower balance functioning pre-AC. Larger, more representative studies of varying groups of participants are needed to further explore how this change relates to fall incidents and fall risk. PMID- 28728461 TI - Rehabilitation of emergent awareness of errors post traumatic brain injury: A pilot intervention. AB - Impaired awareness of errors is common following traumatic brain injury (TBI) and can be a barrier to successful rehabilitation. The objective of this study was to develop and evaluate a computer-based intervention programme aimed at improving error awareness in individuals with TBI. A further aim was to explore its effects on metacognitive awareness and variability of performance. Participants were 11 individuals with TBI and impaired error awareness who performed a sustained attention task twice-weekly for four weeks. The intervention consisted of audio visual feedback-on-errors during the sustained attention task. Six participants received audio-visual feedback-on-error, five did not receive feedback. Emergent and metacognitive awareness were measured pre- and post-intervention. Between groups comparisons of emergent awareness from pre- to post-intervention showed that audio-visual feedback-on-error improved emergent awareness compared to no feedback-on-error. Some changes in metacognitive awareness of executive behaviours as a result of feedback were observed. Audio-visual feedback-on-error improved emergent awareness in individuals with TBI following a four-week/eight session intervention. This improvement was not observed in the no-feedback group. This pilot intervention is not a stand-alone treatment but it has potential to be usefully incorporated into cognitive or clinical rehabilitation programmes to improve emergent awareness. PMID- 28728462 TI - Increased Binding Potential of Brain Adenosine A1 Receptor in Chronic Stages of Patients with Diffuse Axonal Injury Measured with [1-methyl-11C] 8 dicyclopropylmethyl-1-methyl-3-propylxanthine Positron Emission Tomography Imaging. AB - The positron emission tomography (PET) radioligand for adenosine A1 receptor (A1R) [1-methyl-11C] 8-dicyclopropylmethyl-1-methyl-3-propylxanthine (MPDX) has recently been developed for human brain imaging. In the present study, we evaluated the alteration of the A1R in patients with diffuse axonal injury (DAI) in chronic stage in vivo. Ten patients with DAI (7 men and 3 women) were included in this study. Three PET examinations were sequentially performed to measure A1R binding with 11C-MPDX, glucose metabolism with 18F-fluorodeoxyglucose (FDG), and central benzodiazepine receptor binding with 11C-flumazenil (FMZ), and decreases of 11C-FMZ uptake indicate neuronal loss. 11C- MPDX did not depict any lesion with significantly decreased nondisplaceable binding potential (BPND) in comparison to healthy controls (14 men) in region of interest (ROI) analysis. Instead, it showed a significant increase of BPND in the lower frontal and posterior cingulate cortexes and rolandic area (p < 0.05) in ROI analysis. In 18F FDG PET, the standardized uptake values (SUVs) ratio to the whole brain were decreased in anterior and posterior cingulate gyrus compared to controls (14 men and 9 women; p < 0.01). In 11C-FMZ PET, the SUV ratio to the cerebellum was decreased in anterior cingulate gyrus in ROI analysis (controls, 9 men and 6 women; p < 0.01). The area with significantly increased 11C-MPDX binding, lower frontal cortex, rolandic area, and posterior cingulate gyrus, did not overlap with the areas of neuronal loss detected by decreased 11C-FMZ binding and did not completely overlap with area of reduced18F-FDG uptake. We obtained the first 11C MPDX PET images reflecting the A1R BPND in human DAI brain in vivo. 11C-MPDX depicted increased A1R BPND in the areas surrounding the injured brain, whereas 18F-FDG demonstrated reduction throughout the brain. The results suggested that A1R might continuously confer neuroprotective or neuromodulatory effects in DAI even in the chronic stage. PMID- 28728463 TI - Perceived Accessibility to Services and Sites Among Israeli Older Adults. AB - OBJECTIVE: To explore the direct and indirect effects of settlement type (rural kibbutz vs. urban mid-size cities) on perceived accessibility by sociospatial factors: (a) connection to the living area, (b) familiarity with the living area, (c) social participation, and (d) perceived safety of the living area. METHOD: A convenience sample of 279 older adults aged 65 and older was interviewed. Using bootstrapping, we tested the strength and significance of the conditional indirect effects of four simultaneous mediators of the relationship between settlement type and perceived accessibility. MAIN FINDINGS: The relationship between settlement type and perceived accessibility was mediated by social participation and perceived safety of the living area. CONCLUSION: Policy makers should pay attention to the enhancement of sociospatial dimensions to improve the perceived accessibility of older adults. PMID- 28728464 TI - Repeat Mild Traumatic Brain Injury in Adolescent Rats Increases Subsequent beta Amyloid Pathogenesis. AB - Single moderate-to-severe traumatic brain injuries (TBIs) may increase subsequent risk for neurodegenerative disease by facilitating beta-amyloid (Abeta) deposition. However, the chronic effects on Abeta pathogenesis of repetitive mild TBIs (rTBI), which are common in adolescents and young adults, remain uncertain. We examined the effects of rTBI sustained during adolescence on subsequent deposition of Abeta pathology in a transgenic APP/PS1 rat model. Transgenic rats received sham or four individual mild TBIs (rTBIs) separated by either 24- or 72 h intervals at post-natal day 35 (before Abeta plaque deposition). Animals were euthanized at 12 months of age and underwent immunohistochemical analyses of Abeta plaque deposition. Significantly greater hippocampal Abeta plaque deposition was observed after rTBI separated by 24 h relative to rTBI separated by 72 h or sham injuries. These increases in hippocampal Abeta plaque load were driven by increases in both plaque number and size. Similar, though less pronounced, effects were observed in extrahippocampal regions. Increases in Abeta plaque deposition were observed both ipsilaterally and contralaterally to the injury site and in both males and females. rTBIs sustained in adolescence can increase subsequent deposition of Abeta pathology, and these effects are critically dependent on interinjury interval. PMID- 28728465 TI - Evaluating the test-retest reliability of symptom indices associated with the ImPACT post-concussion symptom scale (PCSS). AB - OBJECTIVE: The Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) is a commonly used tool in sports concussion assessment. While test retest reliabilities have been established for the ImPACT cognitive composites, few studies have evaluated the psychometric properties of the ImPACT's Post Concussion Symptom Scale (PCSS). The purpose of this study was to establish the test-retest reliability of symptom indices associated with the PCSS. PARTICIPANTS AND METHODS: Participants included 38 undergraduate students (50.0% male) who underwent neuropsychological testing as part of their participation in their psychology department's research subject pool. The majority of the participants were Caucasian (94.7%) and had no history of concussion (73.7%). All participants completed the ImPACT at two time points, approximately 6 weeks apart. The PCSS was the main outcome measure, and eight symptom indices were calculated (a total symptom score, three symptom summary indices, and four symptom clusters). RESULTS: Pearson correlations (r) and intraclass correlation coefficients (ICCs) were computed as measures of test-retest reliability. Overall, reliabilities ranged from low to high (r = .44 to .80; ICC = .44 to .77). The cognitive symptom cluster exhibited the highest test-retest reliability (r = .80, ICC = .77), followed by the positive symptom total (PST) index, an indicator of the total number of symptoms endorsed (r = .71, ICC = .69). In contrast, the commonly used total symptom score showed lower test-retest reliability (r = .67, ICC = .62). Paired-samples t tests revealed no significant differences between test and retest for any of the symptom variables (all p > .01). Finally, reliable change indices (RCI) were computed to determine whether differences observed between test and retest represented clinically significant change. RCI values were provided for each symptom index at the 80%, 90%, and 95% confidence intervals. CONCLUSION: These results suggest that evaluating additional symptom indices beyond the total symptom score from the PCSS is beneficial. Findings from this study can be applied to athlete samples to assess reliable change in symptoms following concussion. PMID- 28728466 TI - Pain as a Risk Factor for Loneliness Among Older Adults. AB - OBJECTIVE: The objective of this is to examine whether pain is associated with the onset of loneliness in a sample of community-dwelling older adults. METHODS: We used data from the 2008 and 2012 Health and Retirement Study. We limited the sample to community-dwelling persons aged 60 years and over who were not lonely in 2008 in order to predict the risk of onset of loneliness (incidence) in 2012. Our analytic sample included 1,563 observations. RESULTS: Approximately 31.7% of participants reported loneliness at follow-up (2012). Logistic regression models showed that the odds of loneliness onset was 1.58 higher for those with pain at both time points, compared with those who had pain at neither time point, even after controlling for other covariates. DISCUSSION: The results indicate that pain may increase the risk of loneliness in older adults. This suggests that appropriate pain interventions could prevent future loneliness, which in turn could prevent functional decline, disability, and premature mortality. PMID- 28728467 TI - A potential therapeutic pitfall in the treatment of venous reflux due to variant planar anatomy of varicose segments. AB - Purpose To elaborate on a planar anatomic variant of great saphenous vein as a potential therapeutic pitfall in the treatment of venous reflux. Materials and methods Lower extremity veins in 568 limbs with great saphenous vein insufficiency were sonographically mapped. A rather overlooked variation, the saphenous bow, was studied with emphasis on anatomic clarification and its involvement in venous insufficiency. Results This variation, observed in 5.1% (n = 29) of limbs, comprised two segments; one uninterrupted great saphenous vein proper coursing throughout saphenous compartment and one extra-compartmental segment originating distally from and proximally fusing with it. Venous arch remains within compartment only briefly during take-off and re-entry. Extra compartmental venous arch had reflux either alone (10.3%) or together with intra compartmental segment (75.9%). Conclusion This variation, part of saphenous segmental aplasia/hypoplasia complex, is associated with venous insufficiency. Meticulous mapping of great saphenous vein territory and identification of such variants during planning stage is indispensable for optimal clinical outcomes of treatment. PMID- 28728468 TI - The roles of chronological age and time perspective in memory positivity. AB - The observation that older adults show enhanced cognition for emotionally positive information has been labeled the positivity effect (Reed, Chan, & Mikels, 2014). According to the Socioemotional Selectivity Theory (SST, Carstensen, 1991), a prominent lifespan development theory, cognition is strongly influenced by motivational goals, and these goals are impacted by subjective time perspective. Although the positivity effect is most commonly observed in older adults, as age usually co-varies with time perspective, the SST posits that time perspective, not age, is the key explanatory factor of positivity. We examined the effects of these predictors on positivity in an episodic memory task in younger and older adults and found that age, not time perspective, was a key predictor of memory positivity. Our results add to the growing literature that challenge the notion that time perspective is the driving force behind age related differences in emotional processing and functioning. PMID- 28728469 TI - Characterizing patients with multiple chromosomal aberrations detected by FISH in chronic lymphocytic leukemia. AB - We analyzed the features of chronic lymphocytic leukemia (CLL) with multiple abnormalities (MA) detected by FISH. A local database including 2095 CLL cases was used and 323 with MA (15.4%) were selected. MA was defined by the presence of two or more alterations (deletions of 13q14 (13q-), 11q22 (11q-), 17p13 (17p-) or trisomy 12 (+12)). The combination of 13q- with 11q- and 13q- with 17p-, accounted for 58.2% of the series, in contrast to 11q- with 17p- (3.7%). Patients carrying MA since diagnosis presented a short time to first therapy(TTFT) (27 months) and overall survival (OS) (76 months). The combinations including 17p- had a shorter OS (58 months) than the ones without 17p- (not reached, p = .002). Patients with a complex-FISH were the ones with worse OS (34 months). MA imply poor prognosis when they emerge at diagnosis, probably due to the high incidence of bad prognosis markers, which may be a reflection of a more complex karyotype. PMID- 28728470 TI - Influence of infectious disease seasonality on the performance of the outbreak detection algorithm in the China Infectious Disease Automated-alert and Response System. AB - Objective The Chinese Center for Disease Control and Prevention developed the China Infectious Disease Automated-alert and Response System (CIDARS) in 2008. The CIDARS can detect outbreak signals in a timely manner but generates many false-positive signals, especially for diseases with seasonality. We assessed the influence of seasonality on infectious disease outbreak detection performance. Methods Chickenpox surveillance data in Songjiang District, Shanghai were used. The optimized early alert thresholds for chickenpox were selected according to three algorithm evaluation indexes: sensitivity (Se), false alarm rate (FAR), and time to detection (TTD). Performance of selected proper thresholds was assessed by data external to the study period. Results The optimized early alert threshold for chickenpox during the epidemic season was the percentile P65, which demonstrated an Se of 93.33%, FAR of 0%, and TTD of 0 days. The optimized early alert threshold in the nonepidemic season was P50, demonstrating an Se of 100%, FAR of 18.94%, and TTD was 2.5 days. The performance evaluation demonstrated that the use of an optimized threshold adjusted for seasonality could reduce the FAR and shorten the TTD. Conclusions Selection of optimized early alert thresholds based on local infectious disease seasonality could improve the performance of the CIDARS. PMID- 28728471 TI - Implementing technical refinement in high-level athletics: exploring the knowledge schemas of coaches. AB - This paper explores the approaches adopted by high-level field athletics coaches when attempting to refine an athlete's already well-established technique (long and triple jump and javelin throwing). Six coaches, who had all coached multiple athletes to multiple major championships, took part in semi-structured interviews focused upon a recent example of technique refinement. Data were analysed using a thematic content analysis. The coaching tools reported were generally consistent with those advised by the existing literature, focusing on attaining "buy-in", utilising part-practice, restoring movement automaticity and securing performance under pressure. Five of the six coaches reported using a systematic sequence of stages to implement the refinement, although the number and content of these stages varied between them. Notably, however, there were no formal sources of knowledge (e.g., coach education or training) provided to inform coaches' decision making. Instead, coaches' decisions were largely based on experience both within and outside the sporting domain. Data offer a useful stimulus for reflection amongst sport practitioners confronted by the problem of technique refinement. Certainly the limited awareness of existing guidelines on technique refinement expressed by the coaches emphasises a need for further collaborative work by researchers and coach educators to disseminate best practice. PMID- 28728473 TI - Parents' views on childhood obesity: qualitative analysis of discussion board postings. AB - BACKGROUND: Childhood obesity is an increasing concern for parents and health professionals alike. Parents' perception of obesity as a current health issue for their children is important for the everyday parenting and health choices parents make. As parents are frequently going online to seek and exchange information about parenting and child health, asynchronous online discussion forums provide an opportunity to investigate their perceptions and concerns. Understanding parents' perceptions, beliefs and attitudes is important in any childhood obesity prevention and intervention. AIM: To explore parents' perceptions, perspectives and concerns regarding childhood obesity expressed on asynchronous online discussion forums. METHODS: A qualitative descriptive approach using template analysis to analyse a novel data collection strategy of 34 purposefully sampled threads from two Australian-based asynchronous online discussion forums. RESULTS: Parents on the discussion forum displayed an understanding of childhood obesity as a public health concern, the discussion incorporated issues such as providing a healthy diet and lifestyle for children. Parents shared their own opinions and experiences that challenged or conceded to the status quo of the discussion. Parents discussed the role of health professionals in obesity prevention. There were varied opinions on the relevance of health professionals, particularly nurses, monitoring of growth and risk of obesity. CONCLUSION: This exploratory study highlights that parents perceive childhood obesity as an important public health concern, and that they understand the key public health messages of prevention and intervention. Yet, for many it is difficult to successfully implement these messages into their everyday lives. Health professionals need to play a key role in providing non-judgemental, innovative support and advice to parents to successfully implement prevention and intervention strategies. PMID- 28728472 TI - The Identification of Interferon-gamma as a Key Supportive Factor for Retinal Differentiation of Murine Mesenchymal Stem Cells. AB - Retinal disorders represent the main cause of decreased quality of vision and even blindness worldwide. The loss of retinal cells causes irreversible damage of the retina, and there are currently no effective treatment protocols for most retinal degenerative diseases. A promising approach for the treatment of retinal disorders is represented by stem cell-based therapy. The perspective candidates are mesenchymal stem cells (MSCs), which can differentiate into multiple cell types and produce a number of trophic and growth factors. In this study, we show the potential of murine bone marrow-derived MSCs to differentiate into cells expressing retinal markers and we identify the key supportive role of interferon gamma (IFN-gamma) in the differentiation process. MSCs were cultured for 7 days with retinal extract and supernatant from T-cell mitogen concanavalin A stimulated splenocytes, simulating the inflammatory site of retinal damage. MSCs cultured in such conditions differentiated to the cells expressing retinal cell markers such as rhodopsin, S antigen, retinaldehyde-binding protein, calbindin 2, recoverin, and retinal pigment epithelium 65. To identify a supportive molecule in the supernatants from activated spleen cells, MSCs were cultured with retinal extract in the presence of various T-cell cytokines. The expression of retinal markers was enhanced only in the presence of IFN-gamma, and the supportive role of spleen cell supernatants was abrogated with the neutralization antibody anti IFN-gamma. In addition, differentiated MSCs were able to express a number of neurotrophic factors, which are important for retinal regeneration. Taken together, the results show that MSCs can differentiate into cells expressing retinal markers and that this differentiation process is supported by IFN-gamma. PMID- 28728474 TI - Sperm Donation and the Right to Privacy. AB - Sperm donation is an increasingly common method of assisted reproduction. In the debate on sperm donation, the right to privacy - construed as a right that refers to the limits of the realm of information to which others have access - plays a pivotal role with regard to two questions. The first question is whether the sperm donor's right to privacy implies his right to retain his anonymity, the second is whether the gamete recipients' right to privacy entitles them to withhold information about the circumstances of their conception from their donor conceived offspring. In this contribution, I tackle these two interrelated questions. In part (1), I defend the view that there is a prima facie right of sperm donors to remain anonymous. Part (2) widens the perspective by taking into consideration the welfare of donor-conceived offspring. I argue that anonymity may harm the child only if the gametes' recipients decide to disclose information about the circumstances of her birth to the child. Non-disclosure of these circumstances, however, is morally problematic because it may not necessarily harm, but wrong the child. In section (3), I attempt to rebut some arguments in defense of non-disclosure. In part (4), I defend the view that the best practice of sperm donation would be 'direct donation', i.e. that the identity of the donor is known from the time of conception. Part (5) concludes. PMID- 28728477 TI - Increased rate of penicillin non-susceptible strains of N. meningitidis in Naples, Italy. AB - Neisseria meningitidis is a causative agent of community-acquired sepsis and meningitis in humans. These diseases are associated with high mortality and morbidity if treatment is not started promptly. The empiric antibiotic treatment depends on patient factors and local epidemiology. In the past years, an increased number meningococcal strain with reduced susceptibility to penicillin has also been described. We analysed the susceptibility pattern of 11 N. meningitidis strains isolated between 2013 and 2016. Only three (27%) strains were fully susceptible to penicillin, suggesting that a third-generation cephalosporin, instead of penicillin, as empiric therapy is more reliable when an invasive meningococcal disease is suspected. PMID- 28728476 TI - A perspective on diuretic resistance in chronic congestive heart failure. AB - Chronic congestive heart failure (CHF) is a complex disorder characterized by inability of the heart to keep up the demands on it, followed by the progressive pump failure and fluid accumulation. Although the loop diuretics are widely used in heart failure (HF) patients, both pharmacodynamic and pharmacokinetic alterations are thought to be responsible for diuretic resistance in these patients. Strategies to overcome diuretic resistance include sodium intake restriction, changes in diuretic dose and route of administration and sequential nephron diuretic therapy. In this review, we discuss the definition, prevalence, mechanism of development and management strategies of diuretic resistance in HF patients. PMID- 28728478 TI - Psychosocial Response to New-Onset Diabetes as a Long-Term Effect of Allogeneic Hematopoietic Stem Cell Transplantation. AB - Currently, little information is available to guide health care practitioners on how to facilitate positive outcomes in individuals who develop new-onset diabetes after allogeneic hematopoietic stem cell transplantation (allo HSCT) for treatment of hematological cancers. Results from this constructivist grounded theory study provide a theoretical framework explaining the psychosocial process of change that middle-age and older adults experience when developing new-onset diabetes in this context. Two predominant factors influenced this change: treatment burden and perception of diabetes. Key findings were that participants with ongoing complications, primarily graft-versus-host disease, experienced a high degree of treatment-related burden and unclear perceptions of diabetes when compared with those with no or few post-allo-HSCT complications. These factors limited their capacity to positively respond to and self-manage their condition. Implications for practice are to thoroughly consider these two factors when developing patient-centered interventions for middle-age and older adults with new-onset diabetes after allo HSCT. PMID- 28728479 TI - Stem Cells and Other Emerging Agents as Innovative "Drugs" in Neurodegenerative Diseases: Benefits and Limitations. AB - The brain has a limited process of repair/regeneration linked to the restricted and localized activity of neuronal stem cells. Consequently, it shows a reduced capacity to counteract the age-related loss of neural and glial cells and to repair the consequent injuries/lesions of nervous system. This progressively determines nervous dysfunction and onset/progression of neurodegenerative diseases, which represent a serious social (and economic) problem of our populations. Thus, the research of efficient treatments is encouraged. Stem cell therapy might represent a solution. Today, it, indeed, represents the object of intensive research with the hope of using it, in a near future, as effective therapy for these diseases and preventive treatment in susceptible individuals. Here, we report and discuss the data of the recent studies on this field, underling the obstacles and benefits. We also illustrate alternative measures of intervention, which represent another parallel aim for the care of neurodegenerative pathology-affected individuals. Thus, the road for delaying or retarding these diseases appears hard and long, but the advances might be different. PMID- 28728480 TI - Safety and efficacy of stenting nonthrombotic iliac vein lesions in octogenarians and nonagenarians in an office setting. AB - Objectives Treatment options for venous insufficiency are rapidly evolving in the office setting and include venography, intravascular ultrasound, and venous stenting. Non-thrombotic iliac vein lesions assessment and treatment in an office setting is currently an area of interest. The purpose of this study is to demonstrate the safety and efficacy of evaluating non-thrombotic iliac vein lesion with this office-based procedure in octogenarians and nonagenarians. Methods From January 2012 through December 2013, 300 non-thrombotic iliac vein lesion limbs in 192 patients with venous insufficiency >=80 years old were evaluated for non-thrombotic iliac vein lesion. Patients were evaluated and treated with venography, intravascular ultrasound, and stent placement for significant lesions demonstrated by greater than 50% diameter or cross-sectional area reduction. Group 1: 168 of these patients were octogenarians; female/male ratio was 1.75:1, bilateral in 89/168 patients (53%), left sided in 131/259 limbs (51%), right sided in 128 limbs (49%), average age 83.5 +/- 2.6 years (range 80 89) compared to Group 2: 24 nonagenarians; female/male was 3:1, bilateral in 17/24 patients (70%), left sided in 20/41 limbs (49%), right sided in 21/41 limbs (51%), average age 92.9 +/- 2.2 years (range 90-99). Stent related outcomes were evaluated with communication to the patient within 24 h to assess post-procedure pain followed by serial iliocaval ultrasonography. Results Out of the 300 limbs evaluated, in Group 1, 86% of limbs had stents placed compared to 90% in Group 2 and 11% of both groups had two stents placed. Overall improvement in pain, edema, and ulcers was reported in 147 (59%) of octogenarians and 24 (65%) of nonagenarians. There were no surgical site infections, pseudo-aneurysms, arteriovenous fistulas, or femoral artery injuries. No patients required transfusion within three days post-operatively and there were no 30-day mortalities in both sets of patients. Conclusions Our results demonstrate that there is no statistical difference in the outcome of performing venography, intravascular ultrasound, and stent placement in an office-based setting in octogenarians and nonagenarians. Both groups maintained a similar safety profile with low morbidity and mortality. In conclusion, we believe that the treatment of non-thrombotic iliac vein lesion in an office-based setting is safe and efficacious in both groups. PMID- 28728481 TI - Feasibility of two-dimensional speckle tracking in evaluation of arterial stiffness: Comparison with pulse wave velocity and conventional sonographic markers of atherosclerosis. AB - Objective Arterial stiffening is an early marker of atherosclerosis that has a prognostic value for cardiovascular morbidity and mortality. Although many markers of arterial hardening have been proposed, the search is on for newer, more user-friendly and reliable surrogates. One such potential candidate has emerged from cardiology, the speckle-tracking technique. The aim of this study was to evaluate the feasibility of the two-dimensional speckle tracking for the evaluation of arterial wall stiffness in comparison with standard stiffness parameters. Methods Carotid ultrasound and applanation tonometry were performed in 188 patients with no cardiovascular risk factors. The following parameters were then evaluated: the intima-media complex thickness, distensibility coefficient, beta-stiffness index, circumferential strain/strain rate, and pulse wave velocity and augmentation index. These variables were compared with each other and with patient age, and their reliability was assessed with Bland-Altman plots. Results Strain parameters derived from two-dimensional speckle tracking and intima-media complex thickness correlated better with age and pulse wave velocity than standard makers of arterial stiffness. Moreover, the reliability of these measurements was significantly higher than conventional surrogates. Conclusions Two-dimensional speckle tracing is a reliable method for the evaluation of arterial stiffness. Therefore, together with intima-media complex thickness measurement, it offers great potential in clinical practice as an early marker of atherosclerosis. PMID- 28728482 TI - Impact of persistence and non-persistence in leisure time physical activity on coronary heart disease and all-cause mortality: The Copenhagen City Heart Study. AB - Aims The aim of this study was to investigate the impact of persistence and non persistence in leisure time physical activity on coronary heart disease and all cause mortality. Methods and results In the Copenhagen City Heart Study, we prospectively followed 12,314 healthy subjects for 33 years of maximum follow-up with at least two repeated measures of physical activity. The association between persistence and non-persistence in leisure time physical activity, coronary heart disease and all-cause mortality were assessed by multivariable Cox regression analyses. Coronary heart disease mortality for persistent physical activity in leisure compared to persistent sedentary activity were: light hazard ratio (HR) 0.76; 95% confidence interval (CI) 0.63-0.92, moderate HR 0.52; 95% CI 0.41-0.67, and high physical activity HR 0.51; 95% CI, 0.30-0.88. The differences in longevity were 2.8 years for light, 4.5 years for moderate and 5.5 years for high physical activity. A substantial increase in physical activity was associated with lower coronary heart disease mortality (HR 0.75; 95% CI 0.52-1.08) corresponding to 2.4 years longer life, whereas a substantial decrease in physical activity was associated with higher coronary heart disease mortality (HR 1.61; 95% CI 1.11-2.33) corresponding to 4.2 years shorter life than the unchanged group. A similar pattern was observed for all-cause mortality. Conclusion We found inverse dose-response relationships between persistent leisure time physical activity and both coronary heart disease and all-cause mortality. A substantial increase in physical activity was associated with a significant gain in longevity, whereas a decrease in physical activity was associated with even greater loss of longevity. PMID- 28728483 TI - PCSK9 inhibition in statin-intolerant HeFH patients: What's new? PMID- 28728484 TI - A moderate 1-km treadmill walk predicts mortality in men with mid-range left ventricular dysfunction. PMID- 28728485 TI - Factors associated with global longitudinal strain decline in hypertensive patients with normal left ventricular ejection fraction. AB - Background Early detection of risk factors for left ventricular (LV) dysfunction may be useful in patients with high blood pressure (HBP). Methods Patient from an outpatient HBP clinic underwent a two-dimensional Doppler-coupled echocardiography with determination of LV global longitudinal strain (GLS) by speckle-tracking. Results Among 200 patients (mean age 61.7 +/- 9.7 years), 155 were overweight, 93 had diabetes, 83 had dyslipidemia, and 109 had uncontrolled HBP. LV hypertrophy (LVH) was found in 136 patients (68%), including concentric ( n = 106) and eccentric ( n = 30) LVH. Diastolic dysfunction patterns were observed in 178 patients (89%), and increased filling pressures were observed in 37 patients (18.5%). GLS ranged from -25% to -11.6% (mean -16.9 +/- 3.2%). Low GLS values (>-17%) were found in 91 patients (45.5%), 68 with and 23 without LVH. In univariate analysis, a reduced GLS was associated with HBP lasting for >10 years (odds ratio (OR) = 3.51, 95% confidence interval (CI) 1.73-7.09; p = 0.002), uncontrolled HBP (OR = 3.55, 95% CI 1.96-6.43; p < 0.0001), overweight (OR = 2.01, 95% CI 0.93-4.31; p = 0.0028), diabetes (OR = 2.21, 95% CI 1.25-3.90; p = 0.006), dyslipidemia (OR = 2.16, 95% CI 1.22-3.84; p = 0.008), renal failure (OR = 4.27, 95% CI 1.80-10.10; p = 0.001), an increased Cornell index (OR = 3.70, 95% CI 1.98-6.90; p < 0.0001), concentric LVH (OR = 9.26, 95% CI 2.62-32.73; p = 0.001), remodeling (OR = 8.51, 95% CI 2.18-33.23; p = 0.002), and filling pressures (OR = 7.1, 95% CI 2.9-17.3; p < 0.0001). In multivariable analysis, duration of HBP ( p = 0.038), uncontrolled BP ( p = 0.006), diabetes ( p = 0.023), LVH ( p = 0.001), and increased filling pressures ( p = 0.003) remained associated with GLS decline. Conclusion Early impairment of LV function, detected by a reduced GLS, is associated with long-lasting, uncontrolled HBP, overweight, related metabolic changes, and is more pronounced in patients with LVH. PMID- 28728486 TI - Relationship between neck circumference, insulin resistance and arterial stiffness in overweight and obese subjects. AB - Background Only a few studies have investigated the relationship between neck circumference and cardiometabolic risk. The aim of this study was to assess the relationships between neck circumference, waist circumference, metabolic variables and arterial stiffness in a group of overweight and obese subjects evaluating a possible independent role of neck circumference in determining arterial stiffness. Methods and results We studied 95 subjects (53 women) with an age range of 20-77 years and body mass index range from 25.69 to 47.04 kg/m2. In each subject we evaluated body mass index, waist, hip and neck circumference, systolic and diastolic blood pressure, insulin, fasting glucose, cholesterol, low density lipoprotein and high-density lipoprotein cholesterol and triglycerides. Arterial stiffness was assessed by carotid-femoral pulse wave velocity (PWVcf) and carotid-radial pulse wave velocity (PWVcr). Both PWVcf and PWVcr were higher in subjects with high values of neck circumference compared with subjects with normal values of neck circumference. Subjects with high values of neck circumference and abdominal obesity presented higher values of mean arterial pressure, PWVcr and homeostasis model assessment (HOMA) index and lower values of high-density lipoprotein than subjects with only abdominal obesity. Two models of stepwise multiple regression were performed in order to evaluate the combined effect of independent variables on arterial stiffness. In the first model PWVcf was considered a dependent variable, and age, gender, systolic blood pressure, triglycerides, high-density lipoprotein cholesterol, waist circumference, neck circumference, HOMA index and the use of anti-hypertensive medications were considered independent variables. Age, systolic blood pressure, triglycerides and waist circumference were significant predictors of PWVcf, explaining 65% of its variance. In the second model, in which PWVcr was considered a dependent variable, neck circumference and gender were significant predictors of PWVcr, explaining 24% of its variance. Conclusions These findings emphasise the need to measure not only waist but even neck circumference to better stratify and identify individuals at increased cardiometabolic risk, as upper-body subcutaneous fat is a novel, easily measured fat depot. PMID- 28728487 TI - Feasibility and characteristics of arterial stiffness measurement in preschool children. AB - Background Arterial stiffness is an important predictor of cardiovascular risk in adult life. Increased arterial stiffness can also be present in children and may be associated with several other cardiovascular risk factors. Until now, however, we know little about measuring arterial stiffness in preschool children. In this study, we assessed the feasibility of measuring arterial stiffness in preschool children and explored possible determinants related to arterial stiffness at this age. Methods We studied 168 healthy children, aged 3.3-4.1 years, who were recruited from a prospective birth cohort. We measured arterial stiffness, expressed in aortic pulse wave velocity and augmentation index, using a non invasive oscillometric device (Arteriograph). We measured anthropometry and recorded other determinants using a questionnaire. Results In 100 children (59.5%) at least one valid arterial stiffness measurement was obtained. Of these infants, 89 had at least two valid measurements and 73 infants had at least three valid measurements. The mean aortic pulse wave velocity was 5.56 m/s (SD 0.77), and the mean augmentation index of the aorta was 19.7 m/s (SD 7.0). The augmentation index was significantly inversely associated with body height, with a regression coefficient of -0.78 (m/s)/cm (95% confidence interval -1.13 to 0.42). The augmentation index was not significantly associated with age, sex or (birth) weight. Conclusion The feasibility of measuring arterial stiffness in preschool children using the Arteriograph is moderate. We identified height as the most important determinant of the augmentation index in preschool children. PMID- 28728489 TI - Idarucizumab for the treatment of hemorrhage and dabigatran reversal in patients requiring urgent surgery or procedures. AB - INTRODUCTION: Idarucizumab is a specific antagonist for dabigatran etexilate (DE). The recent market authorization of idarucizumab in Europe and the USA may reassure prescribers of DE, as it can increase the safety of the emergency management of patients taking this anticoagulant. However, idarucizumab use should be limited to specific indications to avoid unnecessary risks to patients and costs to healthcare systems. Areas covered: The authors provide an overview of idarucizumab development and its pharmacokinetic and pharmacodynamic properties. The results of the clinical phase III trial RE-VERSE AD and a review of recent case reports of idarucizumab use in emergency contexts are also discussed. Expert opinion: Although idarucizumab has shown clear efficacy in reversing dabigatran-induced coagulopathy, its overall effects on patient outcome have not been proven. Information regarding the clinical context in which patients on DE are admitted for emergency treatment, and accurate laboratory tests of dabigatran plasma level during reversal may inform selection and help with the follow-up of patients who may benefit from idarucizumab. Idarucizumab should be integrated into protocol for the emergency management of patients on DE. Furthermore, the benefit of idarucizumab in specific indications such as acute ischemic stroke should be investigated. PMID- 28728490 TI - Relationship of breastfeeding self-efficacy with quality of life in Iranian breastfeeding mothers. AB - INTRODUCTION: Due to the importance of breastfeeding, we decided to conduct a study to examine the relationship between breastfeeding self-efficacy and quality of life. MATERIALS AND METHODS: This study was a cross-sectional study, which was carried out on 547 breastfeeding mothers that had 2-6 months old infants. The participants were selected randomly, and the sociodemographic characteristics questionnaire, Dennis' breastfeeding self-efficacy scale, and WHO's Quality of Life (WHOQOL) questionnaire were completed through interview. The multivariate linear regression model was used for data analysis. FINDINGS: The means (standard deviations) of breastfeeding self-efficacy score and quality of life score were 134.5 (13.3) and 67.7 (13.7), respectively. Quality of life and all of its dimensions were directly and significantly related to breastfeeding self efficacy. According to the results of multivariate linear regression analysis, there was a relationship between breastfeeding self-efficacy and the following variables: environmental dimension of quality of life, education, spouse's age, spouse's job, average duration of previous breastfeeding period and receiving breastfeeding training. DISCUSSION AND CONCLUSION: Findings showed that there is direct and significant relationship between breastfeeding self-efficacy and quality of life. Moreover, it seems that the development of appropriate training programs is necessary for improving the quality of life of pregnant women, as it consequently enhances breastfeeding self-efficacy. PMID- 28728491 TI - CATALOGIC 301C model - validation and improvement. AB - In Europe, REACH legislation encourages the use of alternative in silico methods such as (Q)SAR models. According to the recent progress of Chemical Substances Control Law (CSCL) in Japan, (Q)SAR predictions are also utilized as supporting evidence for the assessment of bioaccumulation potential of chemicals along with read across. Currently, the effective use of read across and QSARs is examined for other hazards, including biodegradability. This paper describes the results of external validation and improvement of CATALOGIC 301C model based on more than 1000 tested new chemical substances of the publication schedule under CSCL. CATALOGIC 301C model meets all REACH requirements to be used for biodegradability assessment. The model formalism built on scientific understanding for the microbial degradation of chemicals has a well-defined and transparent applicability domain. The model predictions are adequate for the evaluation of the ready degradability of chemicals. PMID- 28728492 TI - The bioactivity of Hedysarum coronarium extracts on skin enzymes and cells correlates with phenolic content. AB - CONTEXT: The search for bioactive compounds from botanical sources is attracting much interest. However, differences in chemical composition may occur within the same species depending on different geographical origins. OBJECTIVES: We evaluated the properties on skin enzymes and cells of extracts from sulla legume crop Hedysarum coronarium L. (Fabaceae), collected at two Italian sites near Pisa and Ventimiglia, for possible dermatological and cosmetic applications. MATERIAL AND METHODS: Plant aerial portions were extracted in MTBE/ethyl acetate/acetone, obtaining two extracts named Pisa sulla extract (PSE) and Ventimiglia sulla extract (VSE). Extracts were subjected to chemical characterization, LC-MS/MS analysis and biological assays. RESULTS: PSE showed stronger antiradical scavenging and higher phenolic and flavonoid contents with respect to VSE. LC MS/MS analysis revealed similar composition for the two extracts, but PSE was richer in condensed tannins and flavonoids, principally rhoifolin, quercetin, naringenin and derivatives. PSE induced stronger inhibition on collagenase and elastase by in vitro enzyme assays, possibly due to higher levels of condensed tannins and quercetin. ELISA bioassay on human dermal fibroblasts revealed stronger PSE induction of collagen production. Determination of glycerol release from adipocytes disclosed stronger stimulation of lipolysis by PSE, allegedly ascribed to higher charge of quercetin and derivatives. In summary, the higher richness in phenolics of PSE is strictly related to stronger bioactivity. DISCUSSION AND CONCLUSIONS: Data indicate that aerial H. coronarium material is suitable for the development of dermatological and cosmeceutical products, but the geographical origin is an important factor for maximally exploiting the biological properties of this species. PMID- 28728493 TI - Treating breast cancer with cell-based approaches: an overview. AB - INTRODUCTION: Breast cancer is the most common malignancy in women. Despite there being considerable progress in the treatment of this disease, metastatic dissemination is still considered an incurable condition at the present time, causing 500,000 deaths worldwide every year. Although most of the research efforts have been focused on pharmacological approaches, over the last three decades, the use of bone marrow and peripheral blood-derived cell therapy approaches have been attempted and developed. Areas covered: This review will briefly address cell therapy for breast cancer, including autologous stem cell transplantations for overcoming the myelosuppressive effects of high-dose chemotherapy, allogeneic stem cell transplants and adoptive immunotherapy using bone-marrow derived T-cells. Expert opinion: The treatment of breast cancer using bone marrow or peripheral-blood derived cells has evolved from a supportive care approach to allow dose escalation of conventional chemotherapy to a therapeutic strategy aimed at eliciting immune cell mediated anticancer immunity. This latter principle has led to the development of adoptive immunotherapies, either with 'natural' or genetically engineered effectors, which are being intensively investigated for their great potential against several solid tumors, including breast cancer. PMID- 28728494 TI - The clinical significance of QT prolongation associated with tamoxifen: A review of the literature. AB - Objective To review the literature discussing QT prolongation associated with the use of tamoxifen in order to evaluate the clinical significance. Data sources A search of PubMed (1946 to 2017), MEDLINE (1946 to 2017) and EMBASE (1947 to 2017) was performed using a combination of the following search terms: tamoxifen, estrogen antagonist, selective estrogen receptor modulator, QT prolongation, QT interval, long QT syndrome and torsades de pointes. All searches were limited to human subjects. Reference lists of the literature found were also reviewed but did not reveal any further articles. Study selection Articles reviewed were relating to humans only and included clinical trials and case reports that mentioned QT prolongation in association with the use of tamoxifen. Data synthesis It can be common for patients on tamoxifen to also be on a number of different medications being used to treat comorbid medical conditions. Such combinations of medications increase the potential risk for drug interactions, such as drug-induced QT prolongation. Tamoxifen is often flagged by tertiary drug information sources as a drug with indeterminate effects on the QT interval. However, the risk may be elevated when combined with other QT-prolonging agents. A total of five publications were identified, including two phase I clinical trials and three case reports, which discussed the association between tamoxifen and QT prolongation. Conclusions Tertiary drug information sources identify tamoxifen as an agent that may cause QT prolongation when used in combination with other QT-prolonging agents. However, based on the limited number of published reports found, it would suggest that the use of tamoxifen concurrently with other agents known to prolong the QT interval is likely to be of low risk for causing a clinically significant QT-prolonging event, especially at a dose of 20 mg daily. PMID- 28728495 TI - An evaluation of chemotherapy drug preparation process in hospitals in Turkey - A pilot study. AB - OBJECTIVE: To identify the practice differences among chemotherapy units and the opinions of pharmacists on safety precautions for handling antineoplastic drugs in hospitals. METHOD: The survey was administered to hospital pharmacists in Turkey. The pharmacists who work in chemotherapeutic drug preparation units were asked to participate if they are volunteered. The participating pharmacists were asked questions about the type of chemotherapy units, order and verification process of chemotherapy protocols and potential shortcomings of chemotherapy preparation. The questions were initially assessed in a small sample of pharmacists and subsequently revised and refined. The filled and returned questionnaires were accepted as given consent. RESULTS: A total of 97 questionnaires were delivered and 40 (41%) were returned by pharmacists. The median age and practicing years in hospitals of the pharmacists were 38.0 and 6.25 years, respectively. Fully automated chemotherapy units were used by 42.5% of respondents, whereas 30% prepare chemotherapeutics manually; furthermore, 87.5% provide chemotherapeutic drug preparations (admixtures) less than 120 per day. With regard to the drug preparation process, more than half of the respondents 'always' use protective equipment without foot covers (32.3%). Almost 90% of respondents 'always' use a coat, mask and biological safety cabinets; however, 20% of respondents 'often' use closed-system drug transfer sets. More than 50% of pharmacists expressed that they have sufficient knowledge on cytotoxics and the risk of exposure, protective precautions, selection and usage of personal protective equipment and correct storage of cytotoxics. CONCLUSION: Pharmacists acknowledge sufficient understanding of safe preparation and handling of chemotherapeutics, but reported practices by pharmacists in hospitals are not consistent with published recommendations. Providing theoretical and practical educations for pharmacists and developing standard procedures for preparing chemotherapy may be beneficial in improving the preparation and use of antineoplastics in Turkey. PMID- 28728496 TI - A Missing Piece in Clinical Trial Inspections in Latin America: Interviews With Research Subjects in Peru. AB - Most regulatory agencies conduct clinical trial (CT) site inspections, but the experiences and behaviors of research subjects and their knowledge of the rights and obligations that ensue from participating in a CT are seldom explored. The authors assessed the technical feasibility of incorporating interviews with participants in CT inspections. This article analyzes the responses of 13 CT participants, 14% ( n = 96) of those included in three tuberculosis (TB) CTs. Participants did not object to being interviewed and provided information not obtained during regular inspections. Participants were appreciative of the agency's concern for the integrity of the CT process. Most interviewees did not understand the consent form and were unaware that they were participating in an experiment with unapproved new drugs. Participants' decision to enroll in CT related to undue inducement and therapeutic misconception. Some patients' behaviors, undisclosed to researchers, could have compromised the integrity of the data collected. PMID- 28728497 TI - The Significance of Benefit Perceptions for the Ethics of HIV Research Involving Adolescents in Kenya. AB - Assessment of benefits is traditionally regarded as crucial to the ethical evaluation of research involving human participants. We conducted focus group discussions (FGDs) with health and other professionals engaged with adolescents, caregivers/parents, and adolescents in Siaya County, Kenya, to solicit opinions about appropriate ways of conducting HIV research with adolescents. Our data revealed that many focus group participants have a profoundly positive conception of participation in health research, including studies conferring seemingly few benefits. In this article, we identify and analyze five different but interrelated types of benefits as perceived by Kenyan adolescent and adult stakeholders in HIV research, and discuss their ethical significance. Our findings suggest that future empirical and conceptual research should concentrate on factors that may trigger researcher obligations to improve benefit perceptions among research participants. PMID- 28728499 TI - Acute central nervous system complications and ammonium levels in adult patients with acute lymphoblastic leukemia receiving l-asparaginase. AB - We analyzed ammonium levels and acute central nervous complications in adult patients receiving chemotherapy for acute lymphoblastic leukemia with or without asparaginase (l-asp). Twenty patients with a median age of 40.3 years were included. Ammonium-levels were measured during 88 chemotherapy cycles, 60 cycles (68%) with l-asp, and 28 cycles (32%) without l-asp. Ammonium was elevated in 87% of all l-asp containing cycles, with median ammonium levels of 169 MUmol/l (interquartile range (IQR) 91-269 MUmol/l). These values were higher when compared to ammonium levels at baseline (31.5 MUmol/l, IQR 24-40 MUmol/l, p < .001), and when compared to levels in cycles without l-asp (30 MUmol/l, IQR 19-41 MUmol/l, p < .001). Acute hyperammonemic encephalopathy was diagnosed in one patient, and encephalopathy for other reasons, but with hyperammonemia as a possible contributing factor in four patients. In conclusion, ammonium levels are elevated in all adult patients receiving l-asparaginase, but only some patients will present symptoms of encephalopathy. PMID- 28728498 TI - Variations in Unrealistic Optimism Between Acceptors and Decliners of Early Phase Cancer Trials. AB - Research has found that patient-subjects in early phase cancer trials exhibit unrealistic optimism regarding the risks and possible benefits of trial participation. Unrealistic optimism is associated with therapeutic misconception and failures to appreciate research-related information. This is the first study to assess whether those who decline to participate in these trials also exhibit unrealistic optimism. It is also the first study to assess whether there are significant differences in appreciation of research-related risks/benefits and therapeutic misconception between these two groups. We approached 261 patients at two academic medical centers who were offered enrollment in a Phase I, II, or I/II cancer trial (between 2012 and 2016). Two hundred thirty-three patients agreed to enroll in an early phase cancer trial, 171 of whom agreed to be interviewed for the study. Twenty-eight patients declined the offer to enroll, 15 of whom agreed to be interviewed for the study. Subjects participated in a structured face-to-face interview with a research associate trained to administer the study questionnaires. Acceptors demonstrated a significantly higher level of unrealistic optimism than decliners ( p < .05). Decliners had significantly less therapeutic misconception than acceptors (3.37 [ SD = 0.85] vs. 3.79 [ SD = 0.77], p = .042). There was a significant difference on one of the appreciation questions between acceptors and decliners ( p = .009). Comparative assessment of acceptors and decliners to early phase cancer trials casts light on whether unrealistic optimism is consequential for the decision to participate in these trials. The different levels of unrealistic optimism exhibited by these groups suggest that it may be a factor that affects the decision to participate. PMID- 28728502 TI - Using survey methods in telehealth research: A practical guide. AB - Surveys are a common method for assessing patient and clinician perceptions, attitudes and outcomes of telehealth. However, inadequacies in both the conduct and reporting of survey studies are common in telehealth research. This article provides clinicians and researchers with practical guidance on the appropriate selection, use and reporting of survey tools for telehealth research. We identify common survey outcomes and instruments used in telehealth research, and methods to assess the validity and psychometric properties of survey tools. Enhancing the quality and reporting of telehealth research is important to improve our understanding of which telehealth-supported models of care improve outcomes and for which patient groups. PMID- 28728503 TI - Facilitators and Barriers to International Collaboration in Spinal Cord Injury: Results from a Survey of Clinicians and Researchers. AB - International collaboration in spinal cord injury (SCI) research is necessary to overcome the challenges often encountered by clinicians and researchers, including participant recruitment, high cost, and the need for specialized expertise. However, international collaboration poses its own obstacles. The objective of this study was to conduct an international online survey to assess barriers and facilitators to international SCI clinical research, potential initiatives to facilitate future collaborations, and the use of SCI-specific data sets and standards. Results were analyzed using descriptive statistics. Of 364 total respondents, 213 completed the survey, with the majority of these participants based in North America (38%), Asia (22%), Europe (18%), and Oceania (16%). Over half had more than 10 years of experience in SCI research or clinical practice (57%) and 60% had previous experience with international collaborations. Funding was identified as a top barrier (82%), a facilitator (93%), and a proposed future initiative (97%). Communication and technology were also identified as strong facilitators and proposed future initiatives. The International Standards for Neurological Classification of SCI were used by 69% of participants, the International Standards to document remaining Autonomic Function after SCI by 13% of participants, and the International SCI Data Sets by 45% of participants. As the need for international collaborations in SCI research increases, it is important to identify how clinicians and researchers can be supported by SCI consumer and professional organizations, funders, and networks. Furthermore, unique solutions to overcome modifiable barriers and creation of new facilitators are also needed. PMID- 28728504 TI - The diverse expression of the WT1 gene in patients with acquired bone marrow failure syndromes. AB - Acquired bone marrow failure syndromes (aBMFS) encompass a wide range of diseases. A study to investigate WT1 expression in BM was conducted in 387 patients with aBMFS in China. The WT1 level in patients with aplastic anemia (AA) was significantly lower than that in patients with paroxysmal nocturnal hemoglobinuria (PNH, p = .023) and myelodysplastic syndrome (MDS, p < .001). In addition, the WT1 level in patients with MDS significantly increased as the disease progressed to an advanced stage. Patients with hypoplastic MDS had a differentiated expression level of WT1 compared with that of NSAA (p < .001). Furthermore, post-treatment patients of AA with partial response (PR) or complete response (CR) status had relatively higher WT1 levels than those with naive AA (p = .017, p = .003, respectively). Thus, the WT1 expression level could be a useful genetic marker for routine clinical work in aBMFS. PMID- 28728506 TI - Microsatellite Instability and Promoter Hypermethylation of DNA repair genes in Hematologic Malignancies: a forthcoming direction toward diagnostics. AB - OBJECTIVE: The objective of our review is to highlight the significance of microsatellite hypervariation in diagnostics of hematologic malignancies. METHODS: For the past few decades, extensive experiments in cancer research have explored all the possible pathways and a number of deleterious mutations that either make the tumor suppressor genes (TSGs) dysfunctional or cause the proto oncogenes to behave abnormally by changing the cellular phenotype hence rendering disease. To prevent the deleterious effects of mutations and to protect the genomic integrity, our system possesses multiple repair mechanisms. DNA Mismatch Repair (MMR) and Direct Reversal of Damage (DRD) are two repair mechanisms which help in removal of faulty base pairs and alkyl adduct formation respectively to avoid long term effects of toxicity, tumorigenesis and mutagenesis. There are nine major MMR genes - MutS homolog (MSH2, MSH3, MSH4, MSH5, MSH6), MutL homolog (MLH1, MLH3), human post-meiotic segregation genes (PMS1, PMS2), and three major damage reversal genes - O6-methylguanine-DNA-methyltransferase (MGMT), ABH2 and DEPC1. RESULTS: Any malfunction in DNA repair machinery can cause microsatellite instability (MSI), a form of genomic abnormality with hyper mutable repeats that is directly associated with cancer. Microsatellites are short, repetitive sequences, non-randomly distributed and localized in 3'-UTR (Untranslated Region), introns, coding regions and promoters. Besides MSI, evidence on promoter hypermethylation of selected repair genes also points toward a prominent reason for cancer initiation and progression. CONCLUSION: The presence of specific microsatellite marker hyper-mutability and consistent promoter hypermethylation in leukemia or lymphoma can be considered as a part of routine diagnostic test in clinical laboratories. PMID- 28728505 TI - In Vitro Comparison of Stone Fragmentation When Using Various Settings with Modern Variable Pulse Holmium Lasers. AB - INTRODUCTION AND OBJECTIVE: There are limited data regarding optimal laser and energy settings during stone fragmentation. We assessed effects on fragmentation using a variety of energy and frequency settings with two laser systems. METHODS: Artificial stones were created using BegoStone. A clear polyvinylchloride (PVC) tube with an inner diameter of 13 mm was closed at one end with a removable plug to create the in vitro ureteral and caliceal environments. The Lumenis Pulse 120H and the Cook Rhapsody H-30 holmium lasers were studied in the caliceal and ureteral models. A single urologist fragmented each stone to <2 mm. The caliceal studies assessed the time to fragmentation (n = 56). The ureteral studies measured the retropulsion distance of each stone phantom after 5 minutes of laser treatment time using different pulse width settings (n = 15). RESULTS: Complete treatment of the stone with the 120H required 10.9 minutes at >=1 J vs 26.9 minutes at <1 J (p < 0.001). The H-30 showed similar results with treatment times of 11.2 minutes at >=1 J vs 22.8 minutes at <1 J (p < 0.001). There was no significant difference in treatment time when comparing the two lasers using settings of 0.8 J * 8 Hz and 1.5 J * 10 Hz (25.5 minutes vs 24.8 minutes, p = 0.861; and 13.2 minutes vs 9.5 minutes, p = 0.061; respectively). Retropulsion distances using the 120H were 13.9 cm using long pulse, 25.2 cm using medium pulse, and 56.6 cm using short pulse. Retropulsion distances using the H-30 laser were 7 cm using long pulse and 14.5 cm using short pulse, which differed from the 120H (p < 0.001). CONCLUSIONS: Laser fragmentation was faster with both lasers when energy settings of >=1 J were used. Treatment times using the 120H and the H 30 lasers were equivalent. Retropulsion distances were less with both lasers when longer pulse widths were used. The H-30 resulted in less stone retropulsion compared with the 120H. PMID- 28728507 TI - Disease-specific quality of life in patients with lupus nephritis. AB - Background Patient-reported outcomes in lupus nephritis (LN) are not well studied. Studies with disease-targeted PRO tool in LN do not exist. Herein, we describe quality of life (QOL: HRQOL & non-HRQOL) among LN patients using LupusPRO. Methods International, cross-sectional data from 1259 patients with systemic lupus erythematosus (SLE) and LupusPRO were compared, stratified by (a) presence of LN (ACR classification criteria (ACR-LN)) at any time and, (b) active LN (on SLEDAI) at study visit. Damage was assessed by SLICC/ACR-SDI. Multivariate regression analyses for QOL against ACR-LN (active LN) after adjusting for age, gender, ethnicity and country of recruitment were performed. Results Mean (SD) age was 41.7 (13.5) yrs, 93% were women. Five hundred and thirty-nine of 1259 SLE patients had ACR-LN. ACR-LN group was younger, were more often on immunosuppressive medications, had worse QOL on lupus medications and procreation than non-ACR-LN patients. HRQOL and non-HRQOL scores were similar in both groups. One hundred and twenty-nine of 539 ACR-LN patients had active LN. Active LN group was younger, had greater disease activity and had worse HRQOL and non-HRQOL compared to patients without active LN. Specific domains adversely affected were lupus symptoms, lupus medications, procreation, emotional health, body image and desires-goals domains. Patients with ACR-LN and active LN fared significantly worse in lupus medications and procreation HRQOL domains, even after adjusting for age, ethnicity, gender and country of recruitment. Conclusions Lupus nephritis patients have poor QOL. Patients with active LN have worse HRQOL and non-HRQOL. Most domains affected are not included in the generic QOL tools used in SLE. LN patients must receive discussion on lupus medications and procreation issues. Patients with active LN need comprehensive assessments and addressal of QOL, along with treatment for active LN. PMID- 28728508 TI - Immunodeficiency and autoimmunity coming together: a nearly missed diagnosis. AB - The coexistence of human immunodeficiency virus (HIV) and systemic lupus erythematosus (SLE) appears to be unusual and the prevalence of patients who carry the dual diagnosis is currently unknown. We hereby present a case of a C4 deficient HIV-1 positive Caucasian female under highly active antiretroviral therapy for the past eight years, admitted to hospital with an aggressive and potentially fatal clinical presentation of SLE. There was a favorable outcome despite a significant diagnostic delay. Despite its rarity, the case highlights that this association is remarkable and may be overlooked by clinicians familiar with either condition. PMID- 28728509 TI - Do adverse pregnancy outcomes contribute to accelerated cardiovascular events seen in young women with systemic lupus erythematosus? AB - Cardiovascular events (CVEs) are prevalent in patients with systemic lupus erythematosus (SLE), and it is the young women who are disproportionately at risk. The risk factors for accelerated cardiovascular disease remain unclear, with multiple studies producing conflicting results. In this paper, we aim to address both traditional and SLE-specific risk factors postulated to drive the accelerated vascular disease in this cohort. We also discuss the more recent hypothesis that adverse pregnancy outcomes in the form of maternal-placental syndrome and resultant preterm delivery could potentially contribute to the CVEs seen in young women with SLE who have fewer traditional cardiovascular risk factors. The pathophysiology of how placental-mediated vascular insufficiency and hypoxia (with the secretion of placenta-like growth factor (PlGF) and soluble fms tyrosine-like kinase-1 (sFlt-1), soluble endoglin (sEng) and other placental factors) work synergistically to damage the vascular endothelium is discussed. Adverse pregnancy outcomes ultimately are a small contributing factor to the complex pathophysiological process of cardiovascular disease in patients with SLE. Future collaborative studies between cardiologists, obstetricians, obstetric physicians and rheumatologists may pave the way for a better understanding of a likely multifactorial aetiological process. PMID- 28728510 TI - Serum level of anti-alpha-enolase antibody in untreated systemic lupus erythematosus patients correlates with 24-hour urine protein and D-dimer. AB - Objective The objective of this report is to evaluate the prevalence and clinico serological correlations of anti-alpha-enolase antibody (Ab) in patients with systemic lupus erythematosus (SLE). Methods Thirty-two untreated patients with SLE and 20 age- and sex-matched healthy controls were evaluated by rheumatologic examinations. The serum levels of anti-alpha-enolase Ab were measured by an enzyme-linked immunosorbent assay (ELISA). Clinical, biochemical and serological markers of disease activity were measured by standard laboratory procedure. Results The serum levels of anti-alpha-enolase Ab in SLE patients were higher significantly than those in healthy controls. Moreover, patients with lupus nephritis displayed significantly higher levels of serum anti-alpha-enolase Ab than those without renal involvement. The serum anti-alpha-enolase Ab levels were positively correlated with serum whole IgG and 24-hour urine protein and negatively correlated with serum D-dimer level. Conclusion These data suggest that anti-alpha-enolase Ab associates with active renal disease in SLE and might reflect a state of active autoimmunity and fibrinolysis inhibition. PMID- 28728512 TI - Antiphospholipid (Hughes) syndrome: insights for orthopedics. PMID- 28728511 TI - Anticoagulation withdrawal in antiphospholipid syndrome: a retrospective matched control study. AB - Background/Purpose Long-term anticoagulation is the standard treatment for thrombotic antiphospholipid syndrome (APS). However, in daily practice, the question of withdrawing anticoagulation may arise, without any evidence-based recommendations. This study aimed to assess outcomes in APS patients after anticoagulation withdrawal. Methods Thrombotic APS patients followed in our centre, whose anticoagulation was withdrawn after APS diagnosis, were retrospectively selected, and were match-controlled with patients under anticoagulation, based on sex, age, APS clinical phenotype and disease duration. Results Thirty cases with anticoagulation withdrawal were included. Median follow up was 51 months (12-124). The risk of thrombotic relapse was higher in cases compared to controls (7.3% versus 1.5% patient-year ( p = 0.01); hazard ratio 4.8; 95% confidence interval (1.4-16.7)). Male gender, anti-beta2GP1 and triple positivity at inclusion were predictive factors for thrombotic relapse. Conversely, aspirin prescription was a protective factor against relapses. Persistence of LA, anti-beta2GP1 and triple positivity over time were associated with a higher risk of thrombosis and aPL disappearance with a lower risk. Conclusion In our study, anticoagulation withdrawal was associated with an increased risk of thrombotic relapse. Our findings emphasize the influence of anti-beta2GP1 and triple positivity persistence over time on the risk of relapse and the benefit of aspirin prescription when anticoagulation has been withdrawn. PMID- 28728513 TI - Ingratiation Attempts in Real Life: Determinants of Their Success. AB - A total of 272 students at a German university were asked to write down the story of an ingratiation attempt they had made and one they had received. They were then asked to reflect on each episode via a questionnaire. All but one participant reported that they had performed at least one of the four tactics postulated in Jones's ingratiation theory: compliments, favor-doing, opinion conformity, and positive self-presentation. In the case of received ingratiation, we found higher success ratings for nondependent (vs. dependent) partners, for just-being-friendly (vs. attraction-seeking) as the attributed motive, and for honest (vs. nonhonest) compliments and self-presentation. Female senders reported more success than did males (interpretable through existing research on gender differences). Finally, success levels were higher in the sender than in the receiver condition. Thus with our new autobiographical method we have extended the validity of three known determinants of the success of ingratiation attempts and discovered two "novel" factors deserving further research. PMID- 28728514 TI - Development and Initial Validation of a Multidimensional Scale Assessing Subjective Well-Being: The Well-Being Scale (WeBS). AB - Numerous scales currently exist that assess well-being, but research on measures of well-being is still advancing. Conceptualization and measurement of subjective well-being have emphasized intrapsychic over psychosocial domains of optimal functioning, and disparate research on hedonic, eudaimonic, and psychological well-being lacks a unifying theoretical model. Lack of systematic investigations on the impact of culture on subjective well-being has also limited advancement of this field. The goals of this investigation were to (1) develop and validate a self-report measure, the Well-Being Scale (WeBS), that simultaneously assesses overall well-being and physical, financial, social, hedonic, and eudaimonic domains of this construct; (2) evaluate factor structures that underlie subjective well-being; and (3) examine the measure's psychometric properties. Three empirical studies were conducted to develop and validate the 29-item scale. The WeBS demonstrated an adequate five-factor structure in an exploratory structural equation model in Study 1. Confirmatory factor analyses showed that a bifactor structure best fit the WeBS data in Study 2 and Study 3. Overall WeBS scores and five domain-specific subscale scores demonstrated adequate to excellent internal consistency reliability and construct validity. Mean differences in overall well-being and its five subdomains are presented for different ethnic groups. The WeBS is a reliable and valid measure of multiple aspects of well-being that are considered important to different ethnocultural groups. PMID- 28728515 TI - The prevalence of constipation at admission and after 1 week of palliative care: a multi-center study. AB - AIM: To assess the prevalence and intensity of constipation in advanced-cancer patients referred to palliative care, and to assess changes after 1 week of specialist palliative care. METHODS: This was a prospective multi-center study in advanced patients for a period of 1 year. At admission (T0), age, gender, primary tumor, concomitant diseases, Karnofsky status, Palliative prognostic score (PaP), Edmonton Symptom Assessment scale (ESAS), Memorial Delirium Assessment Scale (MDAS), and bowel function index (BFI) were collected. In BFI, high values represent severe constipation. The use of medication was also recorded, as well as possible causes of constipation. The same parameters were recorded 1 week after admission for palliative care (T7). RESULTS: A total of 246 patients were screened for constipation. The mean BFI at T0 was 42.4 (SD = 26.92). One hundred and sixty-three patients (66.3%) had a BFI >28. The mean BFI at T7 was 35.7 (SD = 28.8), with a significant decrease from T0 to T7 (p = .000). A significant decrease of BFI in patients with a BFI >28 was reported (p = .000). In patients with a BFI <=28 there was a significant worsening of constipation (p = .000). In patients with a BFI >28 at T0 there was a significant increase in the use of laxatives at T7 in comparison with patients having a BFI <=28 (p = .002). In patients with a BFI <=28 at T0, who had a significant worsening of BFI (Delta > 12), the use of laxatives was significantly lower in comparison to patients who had a BFI >28 (p = .000). In the multivariate analysis, dehydration and the use of benzodiazepines were independently associated with higher BFI scores. CONCLUSION: Constipation is present in approximately two-thirds of patients, and is principally associated with dehydration and the use of benzodiazepines. Patients with normal bowel function at initial assessment may see a worsening in their condition a week later due to lack of prevention or subsequent under treatment. PMID- 28728516 TI - A rare cause of severe epigastric pain, emesis and increased lipase. AB - INTRODUCTION: Gastric volvulus is an uncommon, but severe pathology requiring early diagnosis and urgent treatment. Its atypical symptoms and rarity make it difficult to diagnose, possibly leading to delayed treatment and fatal complications. PATIENTS AND METHODS: We present a case of a 73-year-old patient with Parkinson's disease with complaints of severe epigastric pain, emesis and an increased lipase. RESULTS: Diagnosis of an organo-axial gastric volvulus was made. Treatment consisted of reduction of the volvulus by decompression via nasogastric tube. The underlying cause was a para-esophageal hernia that was repaired by Nissen-fundoplication later on. CONCLUSIONS: We describe symptomatology, diagnostic and therapeutic options of gastric volvulus. PMID- 28728517 TI - Using molecular dynamics for the refinement of atomistic models of GPCRs by homology modeling. AB - Despite GPCRs sharing a common seven helix bundle, analysis of the diverse crystallographic structures available reveal specific features that might be relevant for ligand design. Despite the number of crystallographic structures of GPCRs steadily increasing, there are still challenges that hamper the availability of new structures. In the absence of a crystallographic structure, homology modeling remains one of the important techniques for constructing 3D models of proteins. In the present study we investigated the use of molecular dynamics simulations for the refinement of GPCRs models constructed by homology modeling. Specifically, we investigated the relevance of template selection, ligand inclusion as well as the length of the simulation on the quality of the GPCRs models constructed. For this purpose we chose the crystallographic structure of the rat muscarinic M3 receptor as reference and constructed diverse atomistic models by homology modeling, using different templates. Specifically, templates used in the present work include the human muscarinic M2; the more distant human histamine H1 and the even more distant bovine rhodopsin as shown in the GPCRs phylogenetic tree. We also investigated the use or not of a ligand in the refinement process. Hence, we conducted the refinement process of the M3 model using the M2 muscarinic as template with tiotropium or NMS docked in the orthosteric site and compared with the results obtained with a model refined without any ligand bound. PMID- 28728518 TI - Successful preemptive donor lymphocyte infusions from a haploidentical donor in a boy with E2A-HLF-positive ALL. PMID- 28728519 TI - A methodology to have a reliable condylar position during CBCT scans. PMID- 28728520 TI - In- and out-hospital mortality rate in surgical patients. AB - BACKGROUND: Death rates after surgery are increasingly analysed for clinical audit and quality assessment. Many studies commonly provide information only on deaths that occur during hospital stay, known as in-hospital death rates. By using hospital data set linked to death certificate registry, we recorded in- and out-hospital deaths within 30 and 60 post-operative days. METHODS: The study included all consecutive surgical procedures (denominator) under general or locoregional anaesthesia in adult patients admitted for elective or non-elective inpatient surgery. Patients undergoing planned day-case surgery or obstetrical procedures were excluded. The primary outcome was 30- and 60-day post-operative mortality rate (numerator) whether before or after discharge. RESULTS: The study material consisted of a sample of 36,494 surgical procedures corresponding to 28,202 patients. At 30-day, 384 (crude mortality rate of 1.1%) patients died, 314 (82%) during their hospitalisation and 70 (18%) after discharge. Factors that were associated with in-hospital mortality are ASA scores, emergency, duration of surgery and rate of admission to critical care unit. Within the 30-60 days interval, we recorded 231 supplemental deaths, 103 (45%) after discharge. CONCLUSION: In-hospital mortality alone is an incomplete measure of mortality even within 30 days of care. To identify the missing deaths, hospital records need to be linked to data from death certificate. This connection with the national death registry will allow obtaining the rate of in-hospital and out hospital death. PMID- 28728521 TI - Omokanye-Adebola-Alabi (OAA) temporal bone holder. PMID- 28728522 TI - Striking decrease in blood loss with a urologist-assisted standardized multidisciplinary approach in the management of abnormally invasive placenta. AB - OBJECTIVE: The aim of this study was to investigate the outcome of a standardized multidisciplinary approach using a modified surgical technique in the management of abnormally invasive placenta (AIP), with special reference to blood loss and the need for transfusion. MATERIALS AND METHODS: Data were collected retrospectively in women managed with a recently adopted multidisciplinary strategy using a modified surgical approach, involving a urologist (study group: 10 patients). Women managed before the introduction of this standardized management served as a control group (nine patients). Comparisons were made between the study group and the control group. The main outcome measures were blood loss and the need for transfusion in the two groups. RESULTS: Standardized multidisciplinary management, involving a modified surgical technique performed by a urologist, decreased blood loss in the study group compared with the control group [median 1400 ml (range 400-3000 ml) vs median 8000 ml (2300-40000 ml); p < .001]. It also decreased postoperative complications and the need for transfusion of blood products. CONCLUSIONS: Standardized multidisciplinary management of patients with AIP, using a modified surgical technique, reduces the risks of massive obstetric hemorrhage, the need for massive transfusion and the risk of postoperative complications. Involving an experienced urologist appears to be of paramount importance in the management of AIP. PMID- 28728523 TI - Structural insights into the binding of small ligand molecules to a G-quadruplex DNA located in the HIV-1 promoter. AB - Targeting guanine (G)-rich DNA sequences, folded into non-canonical G-quadruplex (G4) structures, by small ligand molecules is a promising strategy for gene therapy of various diseases. There is experimental proposal that, among eight studied ligands, nitidine chloride - NC and a benzo phenanthridine derivative - BPD have the highest binding affinity for such a sequence (5' T1G2G3C4C5T6G7G8G9C10G11G12G13A14C15T16G17G18G19-3') in the HIV-1 promoter, indicating that an anti-HIV-1 prodrug may regulate the expression of the promoter. Herein, this experimental indication is elaborated by using molecular docking simulations and by characterizing the modes of binding of the eight natural molecules to the particular G4. Moreover, the configurational entropy, as an upper bound of the true entropy contribution to the free energy in noncovalent binding, is employed to see into the structural changes experienced by the G4-DNA upon ligand binding. For various parts (complete structure, backbone, system of all bases, bases of G-tetrads) of the G4-DNA structure, a subtle molecular dynamics (MD) is exploited to determine the change of asymptotic (for infinitely long MD simulation) configurational entropy, being the thermodynamic consequence of DNA flexibility change upon complex formation. While NC increases rigidity of G4 (mainly through the system of all nucleobases), BPD increases flexibility of G4 (more than 50% stems from the sugar-phosphate backbone). These insights are further dissected and substantiated by considering the configurational entropy contributions at the level of individual base pairs making the two G-tetrads (G2G7G13G17 and G3G8G12G18) and by exploring the estimates of the total intra base pair and inter-base pair entropies. This work makes the structural origin of enhanced stability of G4-DNA more certain - useful information when attempting to design optimal G4-DNA binders. PMID- 28728524 TI - What's at Stake in U.S. Health Reform: A Guide to the Affordable Care Act and Value-Based Care. AB - The U.S. presidential election of 2016 accentuated the divided perspectives on the Patient Protection and Affordable Care Act of 2010, commonly known as Obamacare. The perspectives included a pledge from then candidate Donald J. Trump to "repeal and replace on day one"; Republican congressional leaders' more temperate suggestions in the first weeks of the Trump administration to "repair" the Affordable Care Act (ACA); and President Trump's February 5, 2017 statement 16 days after inauguration-that a Republican replacement for the ACA may not be ready until late 2017 or 2018. The swirling rhetoric, media attention, and the dizzying rate of U.S. health and payment reforms both within and outside of the ACA makes it difficult for nurses, both United States and globally, to discern which health policy issues are grounded in the ACA and which aspects reflect payer-driven "volume to value" reimbursement changes. Moreover, popular and controversial elements of the ACA-for example, the clause that prohibits insurance carriers to deny coverage to those with preexisting health conditions and the more controversial individual mandate that bears Supreme Court support as a constitutional provision-are paired in ways that might be unclear to those unfamiliar with nuances of insurance rate determination. To support nurses' capacity to maximize their impact on health policy, this overview distills the 906-page ACA into major themes and describes payment reform legislation and initiatives that are external to the ACA. Understanding the political and societal forces that affect health care policy and delivery is necessary for nurses to effectively lead and advocate for the best interests of their patients. PMID- 28728525 TI - Gender differences in causes of death among persons with HIV/AIDS in San Francisco, California, 1996-2013. AB - The objective was to examine gender differences in causes of death using the San Francisco HIV/AIDS and death registries. Data from San Francisco residents diagnosed with HIV/AIDS who died from 1996 to 2013 were analyzed. Age, race/ethnicity, year, and gender-adjusted standardized mortality ratios and Poisson 95% confidence intervals were calculated for underlying causes of death. Among the 6268 deaths, deaths attributed to drug use, mental disorders due to substance use, cerebrovascular disease, chronic obstructive pulmonary disease, renal disease, and septicemia were more likely among women than among men. Compared to the California population, women had elevated standardized mortality ratios for drug overdose (25.37), mental disorders due to substance abuse (27.21), cerebrovascular disease (2.83), chronic obstructive pulmonary disease (7.37), heart disease (2.37), and liver disease (5.54), and these were higher than the standardized mortality ratios for the men in our study. Men, but not women, had elevated standardized mortality ratios for suicide (2.70), undetermined intent (3.88), renal disease (2.29), and non-AIDS cancer (1.68) compared to population rates. Continued efforts to reduce HIV-related illnesses and an increased emphasis on diagnosing and treating preventable causes of death, including substance use, heart disease, and mental health disorders, are needed as part of comprehensive HIV care. PMID- 28728526 TI - 'I'm still here, I'm still alive': Understanding successful aging in the context of HIV. AB - As people living with HIV (PLWH) live longer, increased understanding of individuals' values and perceptions of successful aging can assist health providers in working with PLWH to set meaningful goals as they age. The purpose of this qualitative study was to understand how PLWH define successful aging and their perceptions of contributors to successful aging. Fourteen men and ten women over the age of 50 years (mean age 57 years; mean time since diagnosis 18 years) participated in individual interviews. Interviews were analyzed using directed content analysis. Six themes emerged: accepting limitations, staying positive, maintaining social supports, taking responsibility, living a healthy lifestyle, and engaging in meaningful activities. The participants emphasized individual control. This highlights the importance of working with PLWH to understand their values and aspirations, and create patient-centered goals. From a research perspective this reinforces calls to include the subjective experiences of older adults in developing successful aging criteria. PMID- 28728527 TI - Antiretroviral nonadherence and condomless sex in the HIV Outpatient Study, USA, 2007-2014. AB - Effective antiretroviral therapy (ART) reduces plasma HIV RNA viral load (VL) to undetectable levels and its effectiveness depends on consistent adherence. Consistent adherence and use of safe sex practices may substantially decrease the risk of HIV transmission. We sought to explore the potential association between self-reported nonadherence to ART and engaging in unsafe sexual practices capable of transmitting HIV. Using clinical and audio computer-assisted self-interview data from the prospective HIV Outpatient Study from 2007 to 2014, we assessed the frequency of self-reported ART nonadherence during the three days prior to the survey among HIV-infected persons in care and factors associated with self reported ART nonadherence. Of 1729 patients included in this analysis (median age = 48 years, 74.3% men who have sex with men), 17% were nonadherent, 15% had a detectable VL, and 42% reported condomless anal or vaginal sex in the past six months. In multivariable analysis, self-reported nonadherence was independently associated with younger age (adjusted odds ratio [aOR] 0.8 per additional ten years, [95% CI] 0.7-1.0), non-Hispanic black race/ethnicity (aOR 1.9; 95% CI 1.4 2.6 versus white), public health insurance (aOR 1.6, 95% CI 1.2-2.3 compared with private), survey date in 2011-2014 versus 2007-2010 (aOR 0.7, 95% CI 0.5-0.9), CD4 cell count >= 500 versus < 200 cells/mm3 (aOR 0.3, 95% CI 0.2-0.5), greater number of ART regimen doses (aOR 1.6, 95% CI 1.3-2.2), and binge drinking (aOR 1.4, 95% CI, 1.1-1.9). In this analysis, self-reported nonadherence was not associated with engaging in condomless sex. PMID- 28728528 TI - Between Concealing and Revealing Intersexed Bodies: Parental Strategies. AB - Parents of intersex children are perceived in many studies as hopeless, highly dependent on the medical system, and as gate keepers of normative gendered bodies. In this article, we challenge these perceptions and argue that parents of intersex children are problematically positioned between their children's needs for care and well-being and the socialmedical forces that aim to "normalize" them. Their in-between position leads them to establish different parental strategies within and outside of traditional sex/gender norms. We focus on three intertwined parental strategy frameworks: bodily dialogue, sex/gender framing, and concealing/revealing practices, and describe how, in each of these strategic frameworks, the parents maneuver, act in accordance with or against, react to, and challenge the medical system, social interactions, and the sex/gender paradigm. This is a comparative study based on narrative interviews with 22 parents of intersex children in Germany and Israel. PMID- 28728529 TI - Islamic Influence on HIV Risk and Protection Among Central Asian Male Migrant Workers in Kazakhstan. AB - HIV incidence is increasing in Central Asia, where migrant workers experience risks for acquiring sexually transmitted HIV. As a social and structural factor that may influence perceptions and behavior, we examine how Islam shapes HIV risk and protection. Phenomenological qualitative interviews examine religion and contexts of HIV risk among 48 male Central Asian migrant workers residing in Almaty, Kazakhstan. Men described nonvaginal sex, alcohol use, premarital sex, and extramarital sex as forbidden or frowned upon. Religious networks were unlikely to discuss HIV risks, and some men viewed religious affiliation or practices as protective. Marital practices including neke (religious marriage), polygyny, and bride kidnapping may be linked to risk. Findings suggest adhering to Islamic ideals may be protective for some men, but for others, assumptions of protection may enhance risk. HIV prevention strategies among Central Asian migrants may be strengthened by attention to religious and cultural understandings of risk and protection. PMID- 28728530 TI - The Fate of Unused Embryos: Discourses, Action Possibilities, and Subject Positions. AB - Although in vitro fertilization (IVF) has offered hope to those struggling with infertility, it has also had some unintended consequences, including the fate of embryos that may be "surplus" to requirement following IVF treatment. The number of embryos in storage across the world is high, creating a dilemma for patients who need to make disposal decisions, as well as presenting an administrative and practical dilemma for clinics. Research has suggested that patients' views of the status of their embryo/s may affect their disposal decisions, and yet the nature of the links between views of the embryo and decisions to either donate or discard remain unclear. In this article, we engage in a discursive analysis of literature on disposal decisions. We discuss the range of ways in which embryos may be constructed, and demonstrate how these discourses make available or constrain particular action possibilities, and offer particular subject positions for patients. The analysis highlights the complexity of the relationship between embryo status and decision making, and may assist clinicians in supporting and guiding patients' decisions. PMID- 28728531 TI - Disclosures of Cystic Fibrosis-Related Information to Romantic Partners. AB - In this article, we offer insights into how individuals with cystic fibrosis (CF) share information about their disease with a romantic partner. Using communication privacy management as a sensitizing theoretical construct, four themes emerged following 13 qualitative interviews with persons with CF. Themes about sharing CF-related information with a romantic partner include weighing the risks and benefits of sharing information, the role of health-related triggered rules, the motivations for disclosures, and the reactions from outsiders. Implications of the research suggest a need for more nuanced understandings of how privacy rules are communicated in relationships, how the mismanagement of co owned information influences future disclosures, how the public-private nature of rare genetic illnesses is managed, and how people with genetic illnesses make disclosure decisions. PMID- 28728532 TI - Unintended Consequences of Gender Equality Promotion in Swedish Multicultural Contraceptive Counseling: A Discourse Analysis. AB - In this article, we explore how reproductive health care providers in Sweden, a country often described as one of the most gender-equal countries in the world, incorporate gender equality ideals in multicultural contraceptive counseling. In the tension between gender equality promotion on one hand and respect for cultural diversity and individualized care on the other, we will demonstrate that values of gender equality were often given priority. This is not necessarily undesirable. Nevertheless, our proposal is that the gender equality ideology may inhibit providers' ability to think differently about issues at stake in contraceptive counseling, which may negatively influence women's possibilities to obtain adequate support. At the end of the article, we suggest how health care providers' reflexivity might be used as a working tool for increased awareness about the taken-for-granted cultural norms that exist in their clinical milieu. PMID- 28728533 TI - Lifestyle Inequalities: Explaining Socioeconomic Differences in Preventive Practices of Clinically Overweight Women After Menopause. AB - Excess weight and menopause are two major factors increasing aging women's vulnerability to chronic diseases. However, social position and socioeconomic status have also been identified as major determinants influencing both health behaviors and the development of such diseases. This study focuses on the socioeconomic variations of behavioral risk factors of chronic diseases in aging women. By drawing on Bourdieu's sociocultural theory of practice, 40 semistructured interviews were conducted to investigate preventive health practices of clinically overweight, postmenopausal women from contrasting socioeconomic classes living in Canada. Findings emphasize class-based differences with respect to long-term health and preventive practices according to three major themes: priority to long-term time horizons, attention given to risk factors of diseases, and control over future health. Health care providers should strive to work in concert with all subgroups of women to better understand their values, worldviews, and needs to decrease health inequalities after menopause. PMID- 28728534 TI - Comparisons of ASPECTS 5 and 6 for endovascular treatment in anterior circulation occlusive stroke. AB - Background Whether ASPECTS 5 and ASPECTS 6 were significantly different on clinical outcomes in acute anterior circulation ischemic stroke undergoing endovascular treatment remains unclear. We aimed to retrospectively compare the effectiveness and safety of ASPECTS 5 and ASPECTS 6 in acute anterior circulation large-artery occlusive stroke patients. Methods A total of 41 patients, 14 in the ASPECTS 5 group and 27 in the ASPECTS 6 group, were enrolled between January 2014 and June 2016. Modified Rankin Scale 0-2 was considered as good functional outcome. Symptomatic intracerebral hemorrhage at 72 hours and mortality at 90 days were recorded. Results Good functional outcome at 90 days in the ASPECTS 5 group (0% (0/14)) was significantly lower than that in the ASPECTS 6 group (25.9% (7/27)) ( p = 0.04). Rates of symptomatic intracranial hemorrhage (21.4 (3/14) vs 18.5% (5/27), p = 0.83) and mortality (64.3% (9/14) vs 44.4% (12/27), p = 0.23) within 90 days were not significantly different. There is a trend for a lower rate of successful reperfusion in the ASPECTS 5 group (71.4% (10/14) for ASPECTS 5 vs 92.6% (25/27) for ASPECTS 6, p = 0.07). Conclusions ASPECTS 5 has very little chance to reach good functional outcome in Chinese patients with anterior circulation large-artery occlusive stroke. Future studies with large sample sizes are needed. PMID- 28728535 TI - Endovascular occlusion of pial arteriovenous macrofistulae, using pCANvas1 and adenosine-induced asystole to control nBCA injection. AB - Background In large-caliber pial macrofistulae (pMF), the combination of high blood flow velocity and large efferent artery diameter makes control over the endovascular vessel occlusion difficult and may result in the inadvertent venous passage of occlusive devices or embolic agents. Case descriptions Patient 1: A 27 year-old man presented with headache and ataxia. An infratentorial pMF supplied by both superior cerebellar arteries with venous ectasia was found. The first treatment attempt using balloons and coils failed since the position of either device could not be controlled because of a distal diameter of the feeding artery of 8 mm. In a second session a pCANvas1 (phenox) was deployed at the level of the arteriovenous connection and adenosine-induced asystole allowed the controlled injection of nBCA/Lipiodol with partial occlusion of the pMF. A remaining arteriovenous shunt was occluded under asystole in a third session. The procedures were well tolerated, the patient returned to normal and DSA confirmed the occlusion of the fistula. Patient 2: A 13-year-old boy with hereditary hemorrhagic teleangiectasia presented with an intracerebral hemorrhage from an aneurysm of the left MCA. Twelve weeks after the aneurysm treatment a feeding MCA branch (diameter 4.5 mm) of a right frontal pMF was catheterized. The macrofistula was occluded by deployment of a pCANvas1, followed by the injection of nBCAl/Lipiodol under adenosine-induced asystole. Conclusion pCANvas1 and adenosine-induced asystole allow a controlled injection of nBCA/Lipiodol for the endovascular occlusion of high-flow pMF without venous passage of the embolic agent. PMID- 28728536 TI - Postnatal delayed exacerbation of dural sinus malformation associated with brainstem cavernous malformations: A case report. AB - Dural sinus malformation (DSM) is a rare paediatric vascular malformation characterised by abnormal dilation of the posterior dural sinus. Owing to its rarity, the pathophysiology of DSM has not been fully elucidated. We report a case of prenatally diagnosed DSM with an unusual clinical course. We detected DSM in a male foetus in the 26th week of gestation by using foetal ultrasonography. Although the DSM regressed during the foetal stage and the arteriovenous shunt was insignificant in the neonate, the shunt rapidly developed four months after birth. The neonate also had postnatal de novo brainstem cavernous malformation (CM), which also developed rapidly, supposedly due to the aggravated venous hypertension resulting from the DSM. We successfully treated the aggravated shunts by endovascular transarterial and transvenous embolisation six times over two years and, subsequently, the clinical condition and the size of the brainstem CM became stable. The DSM and CM seemed to have a metameric origin. Such aberrant cases could help to further the understanding of DSM. PMID- 28728537 TI - Super-selective coil embolization of a basilar perforator artery aneurysm previously treated by the stent-in-stent technique, using an extremely soft bare coil delivered through a one-marker microcatheter. AB - Background Aneurysms of the perforating arteries arising from the basilar artery trunk are rare and represent a therapeutic challenge. Methods A basilar perforator aneurysm was initially treated by the stent-in-stent technique. Enlargement of the aneurysm was seen on follow up and the sac was secondarily coiled using two extremely soft bare coils, delivered through a one-marker microcatheter. Results At 6 months, the patient had a modified Rankin Scale score of 0 and cerebral arteriography demonstrated complete occlusion of the lesion. Conclusions We describe, as far as we are aware, the first case of basilar perforator aneurysm occlusion using extremely soft bare coils, inserted through the mesh of two stents previously placed in the basilar trunk. PMID- 28728538 TI - Effects of Cataract Opacity and Surgery on Sleep Quality. AB - This study aimed to identify the type of cataract opacity associated with subjective sleep quality for cataract patients. A total of 180 consecutive patients (average age 74.2 years) underwent cataract surgery with implantation of an ultraviolet-blocking or blue light-blocking intraocular lens. The participants' subjective sleep quality was evaluated using the Pittsburgh sleep quality index (PSQI) before and at 2 months after surgery. Patients were divided into two groups for analysis: normal sleepers (preoperative PSQI <=5) and poor sleepers (preoperative PSQI >=6). The preoperative and postoperative PSQI scores were 2.8 +/- 1.5 and 3.2 +/- 2.0, respectively, for normal sleepers (n = 99), and 8.5 +/- 2.9 and 7.4 +/- 3.3, respectively, for poor sleepers (n = 81). The improvement in PSQI was significant in poor sleepers (p < 0.0001, Wilcoxon's test) with measured values of 0.22 +/- 0.96 hours extension in sleep duration and 0.16 +/- 0.62 hours shortening in sleep latency. Patients with posterior subcapsular cataract (PSC) and nuclear opacity showed the greatest improvement in PSQI score, with regression analysis identifying PSC as having a significant effect on improvement in PSQI. Significant correlations were found between the subjective sleep and cataract opacity in cataract patients. Ophthalmic personnel should therefore be aware that cataract patients with PSC have a greater potential for disability and predictable benefits from surgery in vision and subjective sleep. PMID- 28728539 TI - Editorial: DNA Damage as a Strategy for Anticancer Chemotherapy. AB - Amongst all currently used drugs in the field of cancer therapy, the most prominent group of agents which induce DNA, damage both directly or indirectly. Intuitively DNA should not be a perfect target for relatively unspecific small molecular weight drugs. However, the current understanding is that not damage per se but cellular response to DNA damage induced by antitumor agents is responsible for their specific targeted effect towards cancer cells in comparison to the normal cells. DNA damaging chemotherapeutics include compounds with diferent activities namely: directly or indirectly induce DNA strand breaks, covalently modify DNA bases, change the chromatin structure and topology by inhibiting chromatin-modifying enzymes. In this special issue of Current Medicinal Chemistry entitled.... PMID- 28728540 TI - PREFACE: Is Renal Denervation Effective Option for Management of Hypertension in Asia? PMID- 28728541 TI - EDITORIAL: Different Aspects of Early Vascular Aging in Hypertension. PMID- 28728542 TI - CLOVE: classification of genomic fusions into structural variation events. AB - BACKGROUND: A precise understanding of structural variants (SVs) in DNA is important in the study of cancer and population diversity. Many methods have been designed to identify SVs from DNA sequencing data. However, the problem remains challenging because existing approaches suffer from low sensitivity, precision, and positional accuracy. Furthermore, many existing tools only identify breakpoints, and so not collect related breakpoints and classify them as a particular type of SV. Due to the rapidly increasing usage of high throughput sequencing technologies in this area, there is an urgent need for algorithms that can accurately classify complex genomic rearrangements (involving more than one breakpoint or fusion). RESULTS: We present CLOVE, an algorithm for integrating the results of multiple breakpoint or SV callers and classifying the results as a particular SV. CLOVE is based on a graph data structure that is created from the breakpoint information. The algorithm looks for patterns in the graph that are characteristic of more complex rearrangement types. CLOVE is able to integrate the results of multiple callers, producing a consensus call. CONCLUSIONS: We demonstrate using simulated and real data that re-classified SV calls produced by CLOVE improve on the raw call set of existing SV algorithms, particularly in terms of accuracy. CLOVE is freely available from http://www.github.com/PapenfussLab . PMID- 28728543 TI - Integrative analysis of the Pekin duck (Anas anas) MicroRNAome during feather follicle development. AB - BACKGROUND: The quality and yield of duck feathers are very important economic traits that might be controlled by miRNA regulation. The aim of the present study was to investigate the mechanism underlying the crosstalk between individual miRNAs and the activity of signaling pathways that control the growth of duck feathers during different periods. We therefore conducted a comprehensive investigation using Solexa sequencing technology on the Pekin duck microRNAome over six stages of feather development at days 11, 15, and 20 of embryonic development (during the hatching period), and at 1 day and 4 and 10 weeks posthatch. RESULTS: There were a total of 354 known miRNAs and 129 novel candidate miRNAs found based on comparisons with known miRNAs in the Gallus gallus miRBase. The series of miRNAs related to feather follicle formation as summarized in the present study showed two expression patterns, with primary follicle developed during embryonic stage and secondary follicle developed mainly at early post hatch stage. Analysis of miRNA expression profiles identified 18 highly expressed miRNAs, which might be directly responsible for regulation of feather development. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis suggested that in addition to Wnt and transforming growth factor (TGFbeta) signaling pathways, which were widely reported in response to follicle formation, another group of signaling pathways that regulate lipid synthesis and metabolism, such as the phosphatidylinositol signaling system and glycerolipid metabolism and signaling, are also responsible for follicle formation. CONCLUSION: The highly expressed miRNAs provide a valuable reference for further investigation into the functional miRNAs important for feather development. Lipid synthesis and metabolism related signaling pathways might be responsible for lipid formation on the surface of feather, and should be paid much more attention for their relation to feather quality. PMID- 28728544 TI - Cladosporol A triggers apoptosis sensitivity by ROS-mediated autophagic flux in human breast cancer cells. AB - BACKGROUND: Endophytes have proven to be an invaluable resource of chemically diverse secondary metabolites that act as excellent lead compounds for anticancer drug discovery. Here we report the promising cytotoxic effects of Cladosporol A (HPLC purified >98%) isolated from endophytic fungus Cladosporium cladosporioides collected from Datura innoxia. Cladosporol A was subjected to in vitro cytotoxicity assay against NCI60 panel of human cancer cells using MTT assay. We further investigated the molecular mechanism(s) of Cladosporol A induced cell death in human breast (MCF-7) cancer cells. Mechanistically early events of cell death were studied using DAPI, Annexin V-FITC staining assay. Furthermore, immunofluorescence studies were carried to see the involvement of intrinsic pathway leading to mitochondrial dysfunction, cytochrome c release, Bax/Bcl-2 regulation and flowcytometrically measured membrane potential loss of mitochondria in human breast (MCF-7) cancer cells after Cladosporol A treatment. The interplay between apoptosis and autophagy was studied by microtubule dynamics, expression of pro-apoptotic protein p21 and autophagic markers monodansylcadaverine staining and LC3b expression. RESULTS: Among NCI60 human cancer cell line panel Cladosporol A showed least IC50 value against human breast (MCF-7) cancer cells. The early events of apoptosis were characterized by phosphatidylserine exposure. It disrupts microtubule dynamics and also induces expression of pro-apoptotic protein p21. Moreover treatment of Cladosporol A significantly induced MMP loss, release of cytochrome c, Bcl-2 down regulation, Bax upregulation as well as increased monodansylcadaverine (MDC) staining and leads to LC3-I to LC3-II conversion. CONCLUSION: Our experimental data suggests that Cladosporol A depolymerize microtubules, sensitize programmed cell death via ROS mediated autophagic flux leading to mitophagic cell death. The proposed mechanism of Cladosporol A -triggered apoptotic as well as autophagic death of human breast cancer (MCF-7) cells. The figure shows that Cladosporol A induced apoptosis through ROS mediated mitochondrial pathway and increased p21 protein expression in MCF-7 cells in vitro. PMID- 28728545 TI - The potential value of serum pepsinogen for the diagnosis of atrophic gastritis among the health check-up populations in China: a diagnostic clinical research. AB - BACKGROUND: The aim of this study is to assess the validity of the measurement of pepsinogen as a screening test for chronic atrophic gastritis (AG) in health check-up populations in China. METHODS: Patients from consecutive regular health check-up were enrolled from January 2014 to June 2015. Endoscopy, combined with monitoring the Helicobacter pylori (Hp) infections, and measuring the serum pepsinogen (PG) were used to determine the diagnostic accuracy of PG for the screening of atrophic gastritis. Histopathology was assessed by the Operative Link on Gastritis Assessment (OLGA) system. Statistical analysis was performed using SPSS statistical software. RESULTS: The total Hp infection rate was 40%. Based on pathology, the 996 participants were divided into three groups: non atrophic (NAG), mild-moderate atrophic (MAG): stage I and II of the OLGA classification, and severe atrophic (SAG): stage III and IV of the OLGA classification. Compared with NAG and MAG groups, PGR decreased significantly in SAG group (p < 0.05). PGI and PGII levels were significantly elevated in Hp positive group, while the PGR was markedly decreased (p < 0.01). When MAG and SAG groups were combined and compared with NAG group, the best cutoff value for atrophy diagnosis was PGI <=50.3 ng/ml; the cutoff value in Hp-negative group was absolutely higher than in Hp-positive group. When NAG and MAG groups were combined and compared with the SAG group, the best cutoff value for diagnosis of severe atrophy was at PGR <=4.28. The cutoff values in Hp-negative and Hp positive groups were calculated at PGR <=6.28 and <=4.28, respectively. CONCLUSIONS: Pepsinogens play an important role in the identification of patients with atrophic gastritis and severe AG. Use of different cutoff values of PG for Hp-negative and Hp-positive groups may offer greater efficacy in the diagnosis of AG. PMID- 28728546 TI - Successful rescue combination of extracorporeal membrane oxygenation, high frequency oscillatory ventilation and prone positioning for the management of severe methicillin-resistant Staphylococcus aureus pneumonia complicated by pneumothorax: a case report and literature review. AB - BACKGROUND: To describe the experience of combination therapy with extracorporeal membrane oxygenation(ECMO), high-frequency oscillatory ventilation(HFOV) and prone positioning in treating severe respiratory failure caused by community acquired methicillin resistant Staphylococcus aureus(CA-MRSA). CASE PRESENTATION: A 30-year-old female presented with fever and dyspnea for 3 days. She was diagnosed CA-MRSA pneumonia complicated by severe respiratory failure, pneumothorax and neutropenia. Venovenous ECMO was applied within 8 h of the pneumothorax diagnosis. For amelioration of ventilator-induced lung injury, HFOV and prone positioning were combined with ECMO. The patient's condition improved considerably. ECMO was weaned on day 19, and she was discharged on day 48 with good lung recovery. CONCLUSIONS: To the best of our knowledge, this was the first case in which ECMO was combined with HFOV and prone positioning to treat severe necrotic CA-MRSA pneumonia complicated with pneumothorax. This combination therapy may provide safe respiratory support, may minimize the risk of barotrauma, and provide better drainage of secretions in patients with necrotizing pneumonia. PMID- 28728548 TI - Social brain circuitry and social cognition in infants born preterm. AB - Preterm birth is associated with an increased risk of adverse neurologic, psychiatric, and cognitive outcomes. The brain circuits involved in processing social information are critical to all of these domains, but little work has been done to examine whether and how these circuits may be especially sensitive to prematurity. This paper contains a brief summary of some of the cognitive, psychiatric, and social outcomes associated with prematurity, followed by a description of findings from the modest body of research into social-cognitive development in infants and children born preterm. Next, findings from studies of structural and functional brain development in infants born preterm are reviewed, with an eye toward the distinctive role of the brain circuits implicated in social functioning. The goal of this review is to investigate the extent to which the putative "social brain" may have particular developmental susceptibilities to the insults associated with preterm birth, and the role of early social-cognitive development in later neurodevelopmental outcomes. Much work has been done to characterize neurobehavioral outcomes in the preterm population, but future research must incorporate both brain and behavioral measures to identify early biomarkers linked to later emerging social-cognitive clinical impairment in order to guide effective, targeted intervention. PMID- 28728547 TI - Community-based initiatives improving critical health literacy: a systematic review and meta-synthesis of qualitative evidence. AB - BACKGROUND: Critical health literacy enables older adults to make informed health decisions and take actions for the health and wellbeing of themselves and their community, within their own social and cultural context. A community-based approach has the potential to improve the critical health literacy of older adults and their communities. However, it is not clear how such initiatives consider critical health literacy. Therefore, this study explored how community based initiatives address the critical health literacy of older adults and their communities. METHODS: A systematic literature search was conducted. Two reviewers independently screened titles and abstracts, as well as the quality of the methodological and community-based elements of the studies. In addition, a meta synthesis was carried out, consisting of a qualitative text analysis of the results sections of the 23 included studies. RESULTS: We identified two main themes, which are practices that contribute to the critical health literacy of older adults as well as their communities: 1) collaborative learning, and 2) social support. In these practices we identified reciprocity as a key characteristic of both co-learning and social support. CONCLUSIONS: This study provides the first overview of community-based initiatives that implicitly address the critical health literacy of older adults and their community. Our results demonstrate that in the context of one's own life collaborative learning and social support could contribute to people's understanding and ability to judge, sift and use health information. We therefore suggest to add these two practices to the definition of critical health literacy. PMID- 28728549 TI - Binomial outcomes in dataset with some clusters of size two: can the dependence of twins be accounted for? A simulation study comparing the reliability of statistical methods based on a dataset of preterm infants. AB - BACKGROUND: The analysis of perinatal outcomes often involves datasets with some multiple births. These are datasets mostly formed of independent observations and a limited number of clusters of size two (twins) and maybe of size three or more. This non-independence needs to be accounted for in the statistical analysis. Using simulated data based on a dataset of preterm infants we have previously investigated the performance of several approaches to the analysis of continuous outcomes in the presence of some clusters of size two. Mixed models have been developed for binomial outcomes but very little is known about their reliability when only a limited number of small clusters are present. METHODS: Using simulated data based on a dataset of preterm infants we investigated the performance of several approaches to the analysis of binomial outcomes in the presence of some clusters of size two. Logistic models, several methods of estimation for the logistic random intercept models and generalised estimating equations were compared. RESULTS: The presence of even a small percentage of twins means that a logistic regression model will underestimate all parameters but a logistic random intercept model fails to estimate the correlation between siblings if the percentage of twins is too small and will provide similar estimates to logistic regression. The method which seems to provide the best balance between estimation of the standard error and the parameter for any percentage of twins is the generalised estimating equations. CONCLUSIONS: This study has shown that the number of covariates or the level two variance do not necessarily affect the performance of the various methods used to analyse datasets containing twins but when the percentage of small clusters is too small, mixed models cannot capture the dependence between siblings. PMID- 28728550 TI - Exploring status and determinants of prenatal and postnatal visits in western China: in the background of the new health system reform. AB - BACKGROUND: Prenatal and postnatal visits are two effective interventions for protection and promotion of maternal health by reducing maternal mortality and improving the quality of birth. There is limited nationally representative data regarding the changes of prenatal and postnatal visits since the latest health system reform initiated in 2009 in Shaanxi, China. The aim of this study was to explore the current status and determinants of prenatal and postnatal visits in the background of new health system reform. METHODS: Data were drawn from two waves of National Health Service Surveys in Shaanxi Province which were conducted prior and post the health system reform in 2008 and 2013, respectively. A concentration index was employed to measure the degree of income-related inequality of maternal health services utilization. Multilevel mix-effects logistic regressions were applied to study the factors associated with prenatal and postnatal visits. RESULTS: The study sample consists of 2398 women aged 15-49 years old. The data of the 5th National Health Services Survey in 2013 showed in the criterion of the World Health Organization (WHO), the percentage of women receiving >=4 prenatal visits was 84.79% for urban women and 82.20% for rural women, with women receiving >=3 postnatal visits were 26.48 and 25.29% for urban and rural women respectively. In the criterion of China's >= 5 prenatal visits the percentages were 72.25% for urban women and 70.33% for rural women; 61.69% of urban women and 71.50% of rural women received >=1 postnatal visits. As for urban women, the concentration index of postnatal visit utilization was -0.075 (95% CI: 0.148, -0.020) after the health system reform. The determinants related to prenatal and postnatal visits were the change of reform, women's education, parity and the delivery institution. CONCLUSIONS: This study showed the utilization of prenatal and postnatal visits met the requirement of the WHO, higher than other areas in China and other developing countries after the new health system reform. The new health system reform increased the utilization of postnatal visits in poor urban women and improved the frequency of prenatal and postnatal visits in rural women. PMID- 28728551 TI - Reduced glutathione and glutathione disulfide in the blood of glucose-6-phosphate dehydrogenase-deficient newborns. AB - BACKGROUND: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is commonly detected during mass screening for neonatal disease. We developed a method to measure reduced glutathione (GSH) and glutathione disulfide (GSSG) using tandem mass spectrometry (MS/MS) for detecting G6PD deficiency. METHODS: The concentration of GSH and the GSH/GSSG ratio in newborn dry-blood-spot (DBS) screening and in blood plus sodium citrate for test confirmation were examined by MS/MS using labeled glycine as an internal standard. RESULTS: G6PD-deficient newborns had a lower GSH content (242.9 +/- 15.9 MUmol/L)and GSH/GSSG ratio (14.9 +/- 7.2) than neonatal controls (370.0 +/- 53.2 MUmol/L and 46.7 +/- 19.6, respectively). Although the results showed a significance of P < 0.001 for DBS samples plus sodium citrate that were examined the first day after preparation, there were no significant differences in the mean GSH concentration and GSH/GSSG ratio between the G6PD deficiency-positive and negative groups when examined three days after sample preparation. CONCLUSION: The concentration of GSH and the ratio of GSH/GSSG in blood measured using MS/MS on the first day of sample preparation are consistent with G6PD activity and are helpful for diagnosing G6PD deficiency. PMID- 28728552 TI - Study protocol for a comparative effectiveness trial of two models of perinatal integrated psychosocial assessment: the PIPA project. AB - BACKGROUND: Studies examining psychosocial and depression assessment programs in maternity settings have not adequately considered the context in which psychosocial assessment occurs or how broader components of integrated care, including clinician decision-making aids, may optimise program delivery and its cost-effectiveness. There is also limited evidence relating to the diagnostic accuracy of symptom-based screening measures used in this context. The Perinatal Integrated Psychosocial Assessment (PIPA) Project was developed to address these knowledge gaps. The primary aims of the PIPA Project are to examine the clinical- and cost-effectiveness of two alternative models of integrated psychosocial care during pregnancy: 'care as usual' (the SAFE START model) and an alternative model (the PIPA model). The acceptability and perceived benefit of each model of care from the perspective of both pregnant women and their healthcare providers will also be assessed. Our secondary aim is to examine the psychometric properties of a number of symptom-based screening tools for depression and anxiety when used in pregnancy. METHODS: This is a comparative-effectiveness study comparing 'care as usual' to an alternative model sequentially over two 12-month periods. Data will be collected from women at Time 1 (initial antenatal psychosocial assessment), Time 2 (2-weeks after Time 1) and from clinicians at Time 3 for each condition. Primary aims will be evaluated using a between-groups design, and the secondary aim using a within group design. DISCUSSION: The PIPA Project will provide evidence relating to the clinical- and cost- effectiveness of psychosocial assessment integrated with electronic clinician decision making prompts, and referral options that are tailored to the woman's psychosocial risk, in the maternity care setting. It will also address research recommendations from the Australian (2011) and NICE (2015) Clinical Practice Guidelines. TRIAL REGISTRATION: ACTRN12617000932369. PMID- 28728553 TI - Supporting and retaining Village Health Teams: an assessment of a community health worker program in two Ugandan districts. AB - BACKGROUND: Uganda's national community health worker program involves volunteer Village Health Teams (VHTs) delivering basic health services and education. Evidence demonstrates their positive impact on health outcomes, particularly for Ugandans who would otherwise lack access to health services. Despite their impact, VHTs are not optimally supported and attrition is a growing problem. In this study, we examined the support needs and existing challenges of VHTs in two Ugandan districts and evaluated specific factors associated with long-term retention. We report on findings from a standardized survey of VHTs and exploratory interviews with key stakeholders and draw conclusions that inform efforts to strengthen and sustain community health care delivery in Uganda. METHODS: A mixed-methods approach was employed through a survey of 134 individual VHT members and semi-structured interviews with six key stakeholders. Descriptive and bivariate regression analysis of quantitative survey data was performed along with thematic analysis of qualitative data from surveys and interviews. In the regression analysis, the dependent variable is 10-year anticipated longevity among VHTs, which asked respondents if they anticipate continuing to volunteer as VHTs for at least 10 more years if their current situation remains unchanged. RESULTS: VHTs desire additional support primarily in the forms of money (e.g. transportation allowance) and material supplies (e.g. rubber boots). VHTs commonly report difficult working conditions and describe a lack of respect from their communities and other health workers. If their current situation remains unchanged, 57% of VHTs anticipate remaining in their posts for at least 10 years. Anticipated 10-year longevity was positively associated with stronger partnerships with local health center staff and greater ease in home visiting. CONCLUSIONS: Supporting and retaining Uganda's VHTs would be enhanced by building stronger partnerships between VHTs and other health workers and regularly providing supplies and transportation allowances. Pursuing such measures would likely improve equity in access to healthcare for all Ugandans. PMID- 28728554 TI - The rise and fall of dental therapy in Canada: a policy analysis and assessment of equity of access to oral health care for Inuit and First Nations communities. AB - BACKGROUND: Inequality between most Canadians and those from Inuit and First Nations communities, in terms of both access to oral health care services and related health outcomes, has been a long-standing problem. Efforts to close this equity gap led to the creation of dental therapy training programs. These programs were designed to produce graduates who would provide services in rural and northern communities. The closure of the last dental therapy program in late 2011 has ended the supply of dental therapists and governments do not appear to have any alternative solutions to the growing gap in access to oral health care services between most Canadians and those from Inuit and First Nations communities. METHODS: A policy analysis of the rise and fall of the dental therapy profession in Canada was conducted using historical and policy documents. The analysis is framed within Kingdon's agenda-setting framework and considers why dental therapy was originally pursued as an option to ensure equitable access to oral health care for Inuit and First Nations communities and why this policy has now been abandoned with the closure of Canada's last dental therapy training school. RESULTS: The closure of the last dental therapy program in Canada has the potential to further reduce access to dental care in some Inuit and First Nations communities. Overlaps between federal and provincial jurisdiction have contributed to the absence of a coordinated policy approach to address the equity gap in access to dental care which will exacerbate the inequalities in comparison to the general population. The analysis suggests that while a technically feasible policy solution is available there continues to be no politically acceptable solution and thus it remains unlikely that a window of opportunity for policy change will open any time soon. CONCLUSION: In the absence of federal government leadership, the most viable option forward may be incremental policy change. Provincial governments could expand the scope of practice for dental hygienists in the hope that it may support enhanced access, consumer choice, and efficiency in the delivery of oral health care to Inuit and First Nations communities in Canada. PMID- 28728555 TI - Medical homelessness and candidacy: women transiting between prison and community health care. AB - BACKGROUND: Women in contact with the prison system have high health needs. Short periods in prison and serial incarcerations are common. Examination of their experiences of health care both in prison and in the community may assist in better supporting their wellbeing and, ultimately, decrease their risk of returning to prison. METHODS: We interviewed women in prisons in Sydney, Australia, using pre-release and post-release interviews. We undertook thematic analysis of the combined interviews, considering them as continuing narratives of their healthcare experiences. We further reviewed the findings using the theoretical lens of candidacy to generate additional insights on healthcare access. RESULTS: Sixty-nine interviews were conducted with 40 women pre-release and 29 of these post-release. Most had histories of substance misuse. Women saw prison as an opportunity to address neglected health problems, but long waiting lists impeded healthcare delivery. Both in prison and in the community, the dual stigmas of substance misuse and being a prisoner could lead to provider judgements that their claims to care were not legitimate. They feared they would be blocked from care even if seriously ill. Family support, self-efficacy, assertiveness, overcoming substance misuse, compliance with health system rules and transitional care programs increased their personal capacity to access health care. CONCLUSIONS: For women in transition between prison and community, healthcare access could be experienced as 'medical homelessness' in which women felt caught in a perpetual state of waiting and exclusion during cycles of prison and community-based care. Their healthcare experiences were characterized by ineffectual attempts to access care, transient relationships with healthcare providers, disrupted medical management and a fear that stigma would prevent candidacy to health care even in the event of serious illness. Consideration of the vulnerabilities and likely points of exclusion for women in contact with the criminal justice system will assist in increasing healthcare access for this marginalised population. PMID- 28728556 TI - Influence of Staphylococcus aureus on Outcomes after Valvular Surgery for Infective Endocarditis. AB - BACKGROUND: As Staphylococcus aureus (SA) remains one of the leading cause of infective endocarditis (IE), this study evaluates whether S. aureus is associated with more severe infections or worsened outcomes compared to non-S. aureus (NSA) organisms. METHODS: All patients undergoing valve surgery for bacterial IE between 1995 and 2013 at our institution were included in this study (n = 323). Clinical data were retrospectively collected from the chart review. Patients were stratified according to the causative organism; SA (n = 85) and NSA (n = 238). Propensity score matched pairs (n = 64) of SA versus NSA were used in the analysis. RESULTS: SA patients presented with more severe IE compared to NSA patients, with higher rates of preoperative vascular complications, preoperative septic shock, preoperative embolic events, preoperative stroke, and annular abscess. Among the matched pairs, there were no significant differences in 30-day (9.4% SA vs. 7.8% NSA, OR = 1.20, p = 0.76) or 1-year mortality (20.3% SA vs. 14.1% NSA, OR = 1.57, p = 0.35) groups, though late survival was significantly worse in SA patients. There was also no significant difference in postoperative morbidity between the two matched groups. CONCLUSIONS: SA IE is associated with a more severe clinical presentation than IE caused by other organisms. Despite the clearly increased preoperative risk, valvular surgery may benefit SA IE patients by moderating the post-operative mortality and morbidity. PMID- 28728557 TI - The impact of illegal waste sites on a transmission of zoonotic viruses. AB - BACKGROUND: Illegal waste disposal impacts public health and causes aesthetic and environmental pollution. Waste disposed in places without permitted and controlled facilities can provide a ready source of nutrition and shelter for rodents and thus promote the spread of their ecto- and endoparasites. The presence of two distinct zoonotic viruses, lymphocytic choriomeningitis virus (LCMV) and tick-borne encephalitis virus (TBEV), was searched at illegal waste sites. The aim of this study was to determine the prevalence of infection with both viruses in rodents and to discuss the virus-rodent relations in such environments. METHODS: Rodents sampled between October 2011 and April 2013 at 7 locations in the Istrian peninsula, were identified morphologically and genetically to minimize misidentification. Serological and molecular techniques were used to determine seroprevalence of infection in rodents and to detect viral RNAs. Serological testing was performed by immune fluorescence assay for detection of LCMV and TBEV specific antibodies. Real-time RT PCR was used for the detection of LCMV nucleoprotein gene and TBEV 3' non-coding region. Data were statistically analysed using SPSS statistic v2.0. RESULTS: Out of 82 rodent sera tested, the presence of LCMV antibodies was demonstrated in 24.93%. The highest prevalence of LCMV infection was found in commensal Mus musculus (47.37%), followed by 11.53%, 19.04% and 25% prevalence of infection in A. agrarius, A. flavicolis and A. sylvaticus, respectively. The highest prevalence of infection in rodents (53.33%) was found in locations with large waste sites and high anthropogenic influence. LCMV seroprevalence was significantly lower in rodents sampled from natural habitats. Viral nucleic acids were screened in 46 samples but yielded no amplicons of LCMV or TBEV. In addition, TBEV specific antibodies were not detected. CONCLUSIONS: Illegal waste sites have considerable impact on the area where they are located. Results have shown that the transmission of human pathogens can be significantly increased by the presence of waste sites. However, the pathogen must be endemic in the environment where the waste site is located. The introduction of a human pathogen as a consequence of the waste site in the area of interest could not be proven. PMID- 28728558 TI - Accuracy of a Plasmodium falciparum specific histidine-rich protein 2 rapid diagnostic test in the context of the presence of non-malaria fevers, prior anti malarial use and seasonal malaria transmission. AB - BACKGROUND: It remains challenging to distinguish malaria from other fever causing infections, as a positive rapid diagnostic test does not always signify a true active malaria infection. This study was designed to determine the influence of other causes of fever, prior anti-malarial treatment, and a possible seasonality of the performance of a PfHRP2 RDT for the diagnosis of malaria in children under-5 years of age living in a malaria endemic area. METHODS: A prospective etiology study was conducted in 2015 among febrile children under 5 years of age in Burkina Faso. In order to assess the influence of other febrile illnesses, prior treatment and seasonality on the performance of a PfHRP2 RDT in diagnosing malaria, the RDT results were compared with the gold standard (expert microscopic diagnosis of Plasmodium falciparum) and test results were analysed by assuming that prior anti-malarial use and bacterial/viral infection status would have been known prior to testing. To assess bacterial and viral infection status blood, urine and stool samples were analysed. RESULTS: In total 683 blood samples were analysed with microscopy and RDT-PfHRP2. Plasmodium falciparum malaria was diagnosed in 49.8% (340/683) by microscopy compared to 69.5% (475/683) by RDT PfHRP2. The RDT-PfHRP2 reported 29.7% (141/475) false positive results and 1.8% (6/340) false negative cases. The RDT-PfHRP2 had a high sensitivity (98.2%) and negative predictive value (97.1%), but a low specificity (58.9%) and positive predictive value (70.3%). Almost 50% of the alternative cause of fever were diagnosed by laboratory testing in the RDT false positive malaria group. CONCLUSIONS: The use of a malaria RDT-PfHRP2 in a malaria endemic area may cause misdiagnosis of the actual cause of fever due to false positive test results. The development of a practical diagnostic tool to screen for other causes of fever in malaria endemic areas is required to save lives. PMID- 28728559 TI - Effect of insulin therapy and dietary adjustments on safety and performance during simulated soccer tests in people with type 1 diabetes: study protocol for a randomized controlled trial. AB - BACKGROUND: Despite the reduction in glycemic derangement in patients with type 1 diabetes mellitus (T1D) through dietary and therapeutic adjustments implemented before, during and after continuous exercise, evidence for its effectiveness with intermittent forms of exercise, such as soccer, is still lacking. METHODS/DESIGN: We designed a study protocol for a randomized, crossover, double-blinded, controlled trial, for the evaluation of the effect that a strategy of dietary and therapeutic modifications may have on safety and performance of persons with T1D in soccer training sessions and cognitive testing. Inclusion criteria comprise: age older than 18 years, more than 2 years since T1D diagnosis, low C-peptide level, a stable insulin regimen, HbA1c less than 9.0% and regular participation in soccer activities. Our primary outcome evaluates safety regarding hypoglycemia events in patients using dietary and therapeutic adjustments, compared with the performance under the implementation of current American Diabetes Association (ADA) usual recommendations for nutritional and pharmacological adjustments for exercise. Additionally, we will evaluate as secondary outcomes: soccer performance, indexed by performance in well-established soccer skill tests, cognitive functions (indexed by Stroop, digital vigilance test (DVT), Corsi block tapping task (CBP), and rapid visual information processing (RVIP) tests), and glycemic control measured with a continuous glucose monitor (CGM). DISCUSSION: Dietary and insulin adjustments standardized under a 4-step method strategy have never been tested in a clinical trial setting with intermittent forms of exercise, such as soccer. We hypothesize that through this strategy we will observe better performance by persons with T1D in soccer and cognitive evaluations, and more stable control of glycemic parameters before, during and after exercise execution, indexed by CGM measurements. TRIAL REGISTRATION: ISRCTN, ISRCTN17447843. Registered on 5 January 2017. PMID- 28728561 TI - Understanding the genetics behind complex human disease with large-scale iPSC collections. AB - Three recent studies analyzing large-scale collections of human induced pluripotent stem cell lines provide valuable insight into how genetic regulatory variation affects cellular and molecular traits. PMID- 28728560 TI - Patient-oriented education and medication management intervention for people with decompensated cirrhosis: study protocol for a randomized controlled trial. AB - BACKGROUND: People with decompensated cirrhosis require complex medical care and are often prescribed an intricate and frequently changing medication and lifestyle regimen. However, many patients mismanage their medications or have poor comprehension of their disease and self-management tasks. This can lead to harm, hospitalization, and death. METHODS/DESIGN: A patient-oriented education and medication management intervention has been developed for implementation at a tertiary hospital hepatology outpatient center in Queensland, Australia. Consenting patients with decompensated cirrhosis will be randomly allocated to education intervention or usual care treatment arms when they attend routine follow-up appointments. In the usual care arm, participants will be reviewed by their hepatologist according to the current model of care in the hepatology clinic. In the intervention arm, participants will be reviewed by a clinical pharmacist to receive the education and medication management intervention at baseline in addition to review by their hepatologist. Intervention participants will also receive three further educational contacts from the clinical pharmacist within the following 6-month period, in addition to routine hepatologist review that is scheduled within this time frame. All participants will be surveyed at baseline and follow-up (approximately 6 months post-enrollment). Validated questionnaire tools will be used to determine participant adherence, medication beliefs, illness perceptions, and quality of life. Patients' knowledge of dietary and lifestyle modifications, their current medications, and other clinical data will be obtained from the survey, patient interview, and medical records. Patient outcome data will be collected at 52 weeks. DISCUSSION: The intervention described within this protocol is ready to adapt and implement in hepatology ambulatory care centers globally. Investigation of potentially modifiable variables that may impact medication management, in addition to the effect of a clinical pharmacist-driven education and medication management intervention on modifying these variables, will provide valuable information for future management of these patients. TRIAL REGISTRATION: Australian and New Zealand Clinical Trial Registry identifier: ACTRN12616000780459 . Registered on 15 June 2016. PMID- 28728562 TI - Low oxygen tension increases mitochondrial membrane potential and enhances expression of antioxidant genes and implantation protein of mouse blastocyst cultured in vitro. AB - BACKGROUND: In human IVF, embryos cultured with a lower O2 tension (5%) can give rise to higher success rates when compared with normoxic conditions (20%). However, the mechanisms behind the beneficial effects of reduced oxygen tension in embryogenesis remain unclear. The aim of this study was to evaluate the expression of oxygen related and antioxidant genes and mitochondrial function in mouse embryo cultured under hypoxic and normoxic conditions, to investigate the beneficial effect of low oxygen tension in preimplantation embryogenesis. METHODS: Two-cell ICR mouse embryos were cultured to blastocysts under different oxygen tension (3% and 20%). The gene expression of oxygen-related proteins (hypoxia-inducible factor, HIF), HIF targets (vascular endothelial growth factor, VEGF; glucose transporter 3, GLUT-3) and antioxidants (manganese superoxide dismutase, MnSOD; peroxiredoxin 5, PRDX5) were assessed using quantitative RT-PCR and implantation-related protein (Leukemia Inhibitory Factor Receptor, LIFR) was validated by immunofluorescence. Apoptosis, mitochondrial membrane potential (MtMP) and ROS levels were measured by TUNEL, JC-1 and DCFDA assays, respectively. RESULTS: Blastocyst development rate (92.3% vs. 79.4%) and hatch rate (80% vs. 70.4%) were both higher in embryos cultured in 3% O2 than in 20% O2. The transcription levels of MnSOD, PRDX5, VEGF and GLUT-3 also significantly increased in 3% O2 compared with 20% O2 (P < 0.05). Immunofluorescence showed that the intensity of staining for HIF-2alpha, MnSOD and LIFR were higher in 3% O2. Blastocysts cultured under 3% O2 exhibited significantly higher MtMP compared with 20% O2. ROS and Apoptosis levels were significantly higher in the 20% O2 group than in the 3% O2 group (P < 0.05). CONCLUSIONS: Low O2 tension may improve embryo viability by increasing expression of antioxidant enzymes and glucose transporter activities. It provides an environment conducive to viability by upregulation of LIFR/VEGF and increased MtMP which could enhance implantation potential and reduce apoptosis in mouse blastocyst. These effects may be initiated and regulated by HIF-2alpha, a key mediator in a hypoxic environment. PMID- 28728564 TI - Comparison of the protein-coding genomes of three deep-sea, sulfur-oxidising bacteria: "Candidatus Ruthia magnifica", "Candidatus Vesicomyosocius okutanii" and Thiomicrospira crunogena. AB - OBJECTIVE: " Candidatus Ruthia magnifica", "Candidatus Vesicomyosocius okutanii" and Thiomicrospira crunogena are all sulfur-oxidising bacteria found in deep-sea vent environments. Recent research suggests that the two symbiotic organisms, "Candidatus R. magnifica" and "Candidatus V. okutanii", may share common ancestry with the autonomously living species T. crunogena. We used comparative genomics to examine the genome-wide protein-coding content of all three species to explore their similarities. In particular, we used the OrthoMCL algorithm to sort proteins into groups of putative orthologs on the basis of sequence similarity. RESULTS: The OrthoMCL inflation parameter was tuned using biological criteria. Using the tuned value, OrthoMCL delimited 1070 protein groups. 63.5% of these groups contained one protein from each species. Two groups contained duplicate protein copies from all three species. 123 groups were unique to T. crunogena and ten groups included multiple copies of T. crunogena proteins but only single copies from the other species. "Candidatus R. magnifica" had one unique group, and had multiple copies in one group where the other species had a single copy. There were no groups unique to "Candidatus V. okutanii", and no groups in which there were multiple "Candidatus V. okutanii" proteins but only single proteins from the other species. Results align with previous suggestions that all three species share a common ancestor. However this is not definitive evidence to make taxonomic conclusions and the possibility of horizontal gene transfer was not investigated. Methodologically, the tuning of the OrthoMCL inflation parameter using biological criteria provides further methods to refine the OrthoMCL procedure. PMID- 28728565 TI - Identification of differential co-expressed gene networks in early rheumatoid arthritis achieving sustained drug-free remission after treatment with a tocilizumab-based or methotrexate-based strategy. AB - BACKGROUND: Methotrexate is endorsed to be used as first-line treatment in rheumatoid arthritis (RA). However, a large proportion of patients need additional treatment with a biological disease-modifying anti-rheumatic drug (DMARD) to adequately suppress their disease activity. A better understanding of genotypes could help to distinguish between patients with different pathogenic mechanisms. The aim of this study was therefore to identify networks of genes within DMARD-naive early RA patients associated with achieving sustained drug free remission (sDFR) after initiating tocilizumab plus methotrexate, tocilizumab, or methotrexate therapy. METHODS: Samples were used from 60 patients from the U-Act-Early study who received tocilizumab plus methotrexate, tocilizumab, or methotrexate therapy, and who achieved sDFR (>=3 months in drug free remission until the end of the study, n = 37) after therapy was tapered and subsequently stopped, or who were not able to discontinue the therapy as controls (n = 23). Whole blood samples were collected and ribonucleic acid (RNA) was isolated from positive cluster of differentiation 4 (CD4+) and CD14+ cells and analysed using high-throughput sequencing. Weighted gene co-expression network analyses were performed to identify clusters (i.e. modules) of differently expressed genes associated with achieving sDFR and which were subsequently used for pathway analyses. RESULTS: Network analyses within CD4+ cells identified two significant modules in the tocilizumab plus methotrexate arm and four modules in the tocilizumab and methotrexate arms, respectively (p <= 0.039). Important pathways in the module best correlating with achieving sDFR were in the tocilizumab plus methotrexate arm related to processes involved with transcription and translation; in the tocilizumab arm, pathways were related to migration of white blood cells and G-protein coupled receptors, and in the methotrexate arm pathways were involved with the response to a bacterial or biotic (i.e. biological material)-related stimulus. No relevant networks could be identified in the sequenced CD14+ cells. CONCLUSIONS: Within networks of co expressed genes, several pathways were found related to achieving sDFR after initiating therapy with tocilizumab, methotrexate, or the combination. Between the three strategy arms, we identified different networks of predisposing genes which indicates that specific gene expression profiles, depending on the treatment strategy chosen, are associated with a higher chance of achieving sDFR. TRIAL REGISTRATION: Clinicaltrials.gov, NCT01034137 . Registered on 16 December 2009. PMID- 28728566 TI - Genomic fingerprints of Escherichia coli strains isolated from surface water in Alborz province, Iran. AB - BACKGROUND: Consistent use of suitable diagnostic methods is essential to evaluate the genomic diversity of E. coli strains. Advance of efficient methods to discriminate the causes of E. coli in aquatic environments is important. This study aimed to describe the strain diversity of an E. coli population retrieved from surface water. METHODS: One hundred water samples were drawn within a period of 1 year, from May 2012 to May 2013, and E. coli bacteria have been isolated from water samples. The genomic diversity analysis of 100 isolates of E. coli (one isolate per sample) has been carried out with the use of the ERIC-PCR fingerprinting method. RESULTS: Overall, our data indicated that complex fingerprint patterns have been obtained for totally of the isolates. Highest number of strains were in E4 (20 strains with more than 20% similarity) and lowest number of strains were in E3 (5 strains) group. In addition, there was no similarity in E1 (9 strains), E8 (10 strains) and E9 (7 strains) clusters. CONCLUSION: Therefore, the occurrence of potential pathogenic E. coli and diversity of E. coli strains in surface water in Alborz province, Iran could pose a possible risk to animal health and human if not disinfected well. PMID- 28728567 TI - Settings and artefacts relevant for Doppler ultrasound in large vessel vasculitis. AB - Ultrasound is used increasingly for diagnosing large vessel vasculitis (LVV). The application of Doppler in LVV is very different from in arthritic conditions. This paper aims to explain the most important Doppler parameters, including spectral Doppler, and how the settings differ from those used in arthritic conditions and provide recommendations for optimal adjustments. This is addressed through relevant Doppler physics, focusing, for example, on the Doppler shift equation and how angle correction ensures correctly displayed blood velocity. Recommendations for optimal settings are given, focusing especially on pulse repetition frequency (PRF), gain and Doppler frequency and how they impact on detection of flow. Doppler artefacts are inherent and may be affected by the adjustment of settings. The most important artefacts to be aware of, and to be able to eliminate or minimize, are random noise and blooming, aliasing and motion artefacts. Random noise and blooming artefacts can be eliminated by lowering the Doppler gain. Aliasing and motion artefacts occur when the PRF is set too low, and correct adjustment of the PRF is crucial. Some artefacts, like mirror and reverberation artefacts, cannot be eliminated and should therefore be recognised when they occur. The commonly encountered artefacts, their importance for image interpretation and how to adjust Doppler setting in order to eliminate or minimize them are explained thoroughly with imaging examples in this review. PMID- 28728568 TI - Transarterial chemoembolization combined with recombinant human adenovirus type 5 H101 prolongs overall survival of patients with intermediate to advanced hepatocellular carcinoma: a prognostic nomogram study. AB - BACKGROUND: Patients with intermediate to advanced hepatocellular carcinoma (HCC) are most commonly treated with transarterial chemoembolization (TACE). Previous studies showed that TACE combined with recombinant human adenovirus type 5 (H101) may provide a clinical survival benefit. In the present study, we aimed to determine the survival benefit of TACE with or without H101 for patients with intermediate to advanced HCC and to develop an effective nomogram for predicting individual survival outcomes of these patients. METHODS: We retrospectively collected data from 590 patients with intermediate to advanced HCC who were treated at Sun Yat-sen University Cancer Center between January 2007 and July 2015. After propensity score matching, 238 patients who received TACE with H101 (TACE with H101 group) and 238 patients who received TACE without H101 (TACE group) were analyzed. Overall survival (OS) was evaluated using the Kaplan-Meier method; the nomogram was developed based on Cox regression analysis. Discrimination and calibration were measured using the concordance index (c index) and calibration plots. RESULTS: Clinical and radiologic features were similar between the two groups. OS rates were significantly lower in the TACE group than in the TACE with H101 group (1-year OS rate, 53.8% vs. 61.3%; 2-year OS rate, 33.4% vs. 44.2%; 3-year OS rate, 22.4% vs. 40.5%; all P < 0.05). Multivariate Cox regression analysis for the entire cohort showed that alpha fetoprotein level, alkaline phosphatase level, tumor size, metastasis, vascular invasion, and TACE with or without H101 were independent factors for OS, all of which were included in the nomogram. Calibration curves showed good agreement between nomogram-predicted survival and observed survival. The c-index of the nomogram for predicting OS was 0.716 (95% confidence interval 0.686-0.746). CONCLUSIONS: TACE plus H101 extends the survival of patients with intermediate to advanced HCC. Our proposed nomogram provides individual survival prediction and stratification for patients with intermediate to advanced HCC who receive TACE with or without H101. PMID- 28728569 TI - Parents' and caregivers' experiences and behaviours when eating out with children with a food hypersensitivity. AB - BACKGROUND: For parents and caregivers of food hypersensitive (FH) children, accommodating their child's dietary needs when eating out can be a challenging experience. This study explored caregivers' experiences and behaviours when eating out with their FH child in order to gain insights into how they support and prepare their child in negotiating safe eating out experiences. METHODS: A cross-sectional, qualitative design was used. In depth, semi-structured interviews were carried out with 15 caregivers of children with FH. Interviews were analysed using framework analysis. RESULTS: Caregivers reported a number of issues relating to eating out with their FH child, or allowing their child to eat out without their supervision. Through themes of 'family context', 'child-focused concerns', and 'venue issues', caregivers described how they managed these and explained the limitations and sacrifices that FH imposed on their child, themselves, and family members. CONCLUSIONS: Through deeper understanding of the anxieties, negotiations and compromises experienced by caregivers of children with FH when they are eating out, clinicians and support charities can tailor their support to meet the needs of caregivers and children. Support and education provision should focus on providing caregivers of children with FH the tools and strategies to help enable safe eating out experiences. PMID- 28728570 TI - Health promotion interventions for community-dwelling older people with mild or pre-frailty: a systematic review and meta-analysis. AB - BACKGROUND: Mild or pre-frailty is common and associated with increased risks of hospitalisation, functional decline, moves to long-term care, and death. Little is known about the effectiveness of health promotion in reducing these risks. This systematic review aimed to synthesise randomised controlled trials (RCTs) evaluating home and community-based health promotion interventions for older people with mild/pre-frailty. METHODS: We searched 20 bibliographic databases and 3 trials registers (January 1990 - May 2016) using mild/pre-frailty and associated terms. We included randomised controlled and crossover trials of health promotion interventions for community-dwelling older people (65+ years) with mild/pre-frailty and excluded studies focussing on populations in hospital, long term care facilities or with a specific condition. Risk of bias was assessed by two reviewers using the Cochrane Risk of Bias tool. We pooled study results using standardised mean differences (SMD) where possible and used narrative synthesis where insufficient outcome data were available. RESULTS: We included 10 articles reporting on seven trials (total n = 506 participants) and included five trials in a meta-analysis. Studies were predominantly small, of limited quality and six studies tested group exercise alone. One study additionally investigated a nutrition and exercise intervention and one evaluated telemonitoring. Interventions of exercise in groups showed mixed effects on functioning (no effects on self-reported functioning SMD 0.19 (95% CI -0.57 to 0.95) n = 3 studies; positive effects on performance-based functioning SMD 0.37 (95% CI 0.07 to 0.68) n = 3 studies). No studies assessed moves to long-term care or hospitalisations. CONCLUSIONS: Currently the evidence base is of insufficient size, quality and breadth to recommend specific health promotion interventions for older people with mild or pre- frailty. High quality studies of rigorously developed interventions are needed. PROSPERO REGISTRATION: CRD42014010370 (Review 2). PMID- 28728571 TI - The prevalence and risk factors of preterm small-for-gestational-age infants: a population-based retrospective cohort study in rural Chinese population. AB - BACKGROUND: Preterm birth and small for gestational age (SGA) are strong indicators of neonatal adverse outcomes. With the growing importance of preterm SGA infants, we aim to evaluate the prevalence and risk factors for preterm SGA in China. METHOD: We analyzed the data of parents and infants from a population based cohort research of the free National Pre-pregnancy Checkups Project (NPCP) in rural China. Only singleton live births that occurred between 24 weeks +0 days and 36 weeks +6 days of pregnancy were included in this study. SGA was defined as birth weight less than the 10th percentile of the reference birth-weight-for gestational-age population. A multiple logistic regression model was built using the statistically significant variables from the 371 variables in the questionnaire. RESULTS: A total of 11,474 singleton, preterm, live-birth infants were included. Of the total infants, 317 (2.77%) were preterm SGA infants. A higher risk of preterm SGA infants was observed among mothers who were on oral contraceptives (OR: 8.162, 95% CI: 1.622-41.072), mothers who had syphilis (OR: 12.800, 95% CI: 1.250-131.041), and mothers with a high eosinophil percentage (OR: 13.292, 95% CI: 1.282-135.796). Maternal intake of folic acid at least 3 months before pregnancy (OR: 0.284, 95% CI:0.124-0.654) and paternal intake of egg and meat (OR: 0.097,95% CI:0.030-0.315) were protective factors. Compared with North China, the incidence of preterm SGA infants was higher in South China. CONCLUSION: Preterm SGA infants were associated with both maternal and paternal factors. PMID- 28728572 TI - Knowledge, attitudes and practices on malaria transmission in Mamfene, KwaZulu Natal Province, South Africa 2015. AB - BACKGROUND: In South Africa malaria is endemic in Mpumalanga, Limpopo and the north-eastern areas of KwaZulu-Natal provinces. South Africa has set targets to eliminate malaria by 2018 and research into complementary vector control tools such as the Sterile Insect Technique (SIT) is ongoing. It is important to understand community perceptions regarding malaria transmission and control interventions to enable development of community awareness campaign messages appropriate to the needs of the community. We aimed to assess knowledge, attitudes, and practices regarding malaria transmission to inform a public awareness campaign for SIT in Jozini Local Municipality, Mamfene in KwaZulu-Natal province. METHODS: We conducted a cross-sectional survey in three communities in Mamfene, KwaZulu-Natal during 2015. A structured field piloted questionnaire was administered to 400 randomly selected heads of households. Descriptive statistics were used to summarize data. RESULTS: Of the 400 participants interviewed, 99% had heard about malaria and correctly associated it with mosquito bites. The sources of malaria information were the local health facility (53%), radio (16%) and community meetings (7%). Approximately 63% of the participants were able to identify three or four symptoms of malaria. The majority (76%) were confident that indoor residual spraying (IRS) kills mosquitoes and prevents infection. Bed nets were used by 2% of the participants. SIT knowledge was poor (9%), however 63% of the participants were supportive of mosquito releases for research purposes. The remaining 37% raised concerns and fears, including fear of the unknown and lack of information on the SIT. CONCLUSION: Appropriate knowledge, positive attitude and acceptable treatment-seeking behaviour for malaria were demonstrated by members of the community. Community involvement will be crucial in achieving success of the SIT and future studies should further investigate concerns raised by the community. The existing communication channels used by the malaria control program can be used; however additional channels should be investigated. PMID- 28728573 TI - Splicing arrays reveal novel RBM10 targets, including SMN2 pre-mRNA. AB - BACKGROUND: RBM10 is an RNA binding protein involved in message stabilization and alternative splicing regulation. The objective of the research described herein was to identify novel targets of RBM10-regulated splicing. To accomplish this, we downregulated RBM10 in human cell lines, using small interfering RNAs, then monitored alternative splicing, using a reverse transcription-PCR screening platform. RESULTS: RBM10 knockdown (KD) provoked alterations in splicing events in 10-20% of the pre-mRNAs, most of which had not been previously identified as RBM10 targets. Hierarchical clustering of the genes affected by RBM10 KD revealed good conservation of alternative exon inclusion or exclusion across cell lines. Pathway annotation showed RAS signaling to be most affected by RBM10 KD. Of particular interest was the finding that splicing of SMN pre-mRNA, encoding the survival of motor neuron (SMN) protein, was influenced by RBM10 KD. Inhibition of RBM10 resulted in preferential expression of the full-length, exon 7 retaining, SMN transcript in four cancer cell lines and one normal skin fibroblast cell line. SMN protein is expressed from two genes, SMN1 and SMN2, but the SMN1 gene is homozygously disrupted in people with spinal muscular atrophy; as a consequence, all of the SMN that is expressed in people with this disease is from the SMN2 gene. Expression analyses using primary fibroblasts from control, carrier and spinal muscle atrophy donors demonstrated that RBM10 KD resulted in preferential expression of the full-length, exon 7 retaining, SMN2 transcript. At the protein level, upregulation of the full-length SMN2 was also observed. Re expression of RBM10, in a stable RBM10 KD cancer cell line, correlated with a reversion of the KD effect, demonstrating specificity. CONCLUSION: Our work has not only expanded the number of pre-mRNA targets for RBM10, but identified RBM10 as a novel regulator of SMN2 alternative inclusion. PMID- 28728574 TI - Creation of a core outcome set for clinical trials of people with shoulder pain: a study protocol. AB - BACKGROUND: The selection of appropriate outcomes or domains is crucial when designing clinical trials, to appreciate the effects of different interventions, pool results, and make valid comparisons between trials. If the findings are to influence policy and practice, then the chosen outcomes need to be relevant and important to key stakeholders, including patients and the public, healthcare professionals and others making decisions about health care. There is a growing recognition that insufficient attention has been paid to the outcomes measured in clinical trials. Recent reviews of the measurement properties of patient-reported outcome measures for shoulder disorders revealed a large selection of diverse measures, many with questionable validity, reliability, and responsiveness. These issues could be addressed through the development and use of an agreed standardized collection of outcomes, known as a core outcome set (COS), which should be measured and reported in all trials of shoulder disorders. The purpose of the present project is to develop and disseminate a COS for clinical trials in shoulder disorders. METHODS/DESIGN: The methods for the COS development will include 3 phases: (1) a comprehensive review of the core domains used in shoulder disorder trials; (2) an international Delphi study involving relevant stakeholders (patients, clinicians, scientists) to define which domains should be core; and (3) an international focus group informed by the evidence identified in phases 1 and 2, to determine which measurement instruments best measure the core domains and identification of any evidence gaps that require further empiric evidence. DISCUSSION: The aim of the current proposal is to convene several meetings of international experts and patients to develop a COS for clinical trials of shoulder disorders and to develop an implementation strategy to ensure rapid uptake of the core set of outcomes in clinical trials. There would be an expectation that the core set of outcomes would always be collected and reported, but it would not preclude use of additional outcomes in a particular trial. PMID- 28728575 TI - Genome-wide association study identifies a major gene for beech bark disease resistance in American beech (Fagus grandifolia Ehrh.). AB - BACKGROUND: The American Beech tree (Fagus grandifolia Ehrh.), native to eastern North America, is ecologically important and provides high quality wood products. This species is susceptible to beech bark disease (BBD) and is facing high rates of mortality in North America. The disease occurs from an interaction between the woolly beech scale insect (Cryptococcus fagisuga), one of two species of the fungus Neonectria (N. faginata or N. ditissima), and American Beech trees. METHODS: In this case-control genome-wide association study (GWAS), we tested 16 K high quality SNPs using the Affymetrix Axiom 1.5 K - 50 K assay to genotype an association population of 514 individuals. We also conducted linkage analysis in a full-sib family of 115 individuals. Fisher's exact test and logistic regression tests were performed to test associations between SNPs and phenotypes. RESULTS: Association tests revealed four highly significant SNPs on chromosome (Chr) 5 for a single gene (Mt), which encodes a mRNA for metallothionein-like protein (metal ion binding) in Fagus sylvatica. Metallothioneins represent Cys-rich metal chelators able to coordinate metal atoms and may play an important role in the resistance mechanisms against beech scale insect. CONCLUSION: The GWAS study has identified a single locus of major effect contributing to beech bark disease resistance. Knowledge of this genetic locus contributing to resistance might be used in applied breeding, conservation and restoration programs. PMID- 28728576 TI - Beneficial effect of kidney transplantation from a deceased donor on severe chronic refractory intradialytic hypotension - a case report. AB - BACKGROUND: Chronic refractory hypotension (IDH, intradialytic hypotension) is a rare but serious problem encountered in patients on hemodialysis. Patients with chronic hypotension are often disqualified by transplant teams from renal transplantation. This is due to the possibility of an enormous risk of ischemic complications. CASE PRESENTATION: We describe a 44-year old female patient with severe refractory hypotension (mean BP 60/30 mmHg, the lowest 48/28 mmHg), which appeared after bilateral laparoscopic nephrectomy of the infected kidneys. The kidney transplantation from a deceased donor, with infusion of the two pressor amines (dopamine, dobutamine) was performed without technical complications and the blood pressure measurements were 100-120/70-80 mmHg. The immunosuppression regimen was tacrolimus (TAC) + mycophenolate mophetil (MMF) and steroids (GS). Pressor amines were discontinued on the 18th day after the transplantation. Because of delayed graft function, 4 hemodialysis treatments were performed. The patient was discharged from the hospital on the 22nd day with good function of the transplanted kidney (the concentration of serum creatinine 117 MUmol/l). During one-year follow-up, the patient has been remaining stable with a very good graft function (serum creatinine 84 MUmol/l) and normal blood pressure (115/70 mmHg). CONCLUSIONS: Proper preparation and adequate perioperative treatment allowed for safely performing kidney transplantation in the patient with severe IDH. PMID- 28728577 TI - Integrating data from randomized controlled trials and observational studies to predict the response to pregabalin in patients with painful diabetic peripheral neuropathy. AB - BACKGROUND: More patient-specific medical care is expected as more is learned about variations in patient responses to medical treatments. Analytical tools enable insights by linking treatment responses from different types of studies, such as randomized controlled trials (RCTs) and observational studies. Given the importance of evidence from both types of studies, our goal was to integrate these types of data into a single predictive platform to help predict response to pregabalin in individual patients with painful diabetic peripheral neuropathy (pDPN). METHODS: We utilized three pivotal RCTs of pregabalin (398 North American patients) and the largest observational study of pregabalin (3159 German patients). We implemented a hierarchical cluster analysis to identify patient clusters in the Observational Study to which RCT patients could be matched using the coarsened exact matching (CEM) technique, thereby creating a matched dataset. We then developed autoregressive moving average models (ARMAXs) to estimate weekly pain scores for pregabalin-treated patients in each cluster in the matched dataset using the maximum likelihood method. Finally, we validated ARMAX models using Observational Study patients who had not matched with RCT patients, using t tests between observed and predicted pain scores. RESULTS: Cluster analysis yielded six clusters (287-777 patients each) with the following clustering variables: gender, age, pDPN duration, body mass index, depression history, pregabalin monotherapy, prior gabapentin use, baseline pain score, and baseline sleep interference. CEM yielded 1528 unique patients in the matched dataset. The reduction in global imbalance scores for the clusters after adding the RCT patients (ranging from 6 to 63% depending on the cluster) demonstrated that the process reduced the bias of covariates in five of the six clusters. ARMAX models of pain score performed well (R 2 : 0.85-0.91; root mean square errors: 0.53 0.57). t tests did not show differences between observed and predicted pain scores in the 1955 patients who had not matched with RCT patients. CONCLUSION: The combination of cluster analyses, CEM, and ARMAX modeling enabled strong predictive capabilities with respect to pain scores. Integrating RCT and Observational Study data using CEM enabled effective use of Observational Study data to predict patient responses. PMID- 28728578 TI - Development of an optimised key worker framework for people with dementia, their family and caring unit living in the community. AB - BACKGROUND: In Australia, dementia is a national health priority. With the rising number of people living with dementia and shortage of formal and informal carers predicted in the near future, developing approaches to coordinating services in quality-focused ways is considered an urgent priority. Key worker support models are one approach that have been used to assist people living with dementia and their caring unit coordinate services and navigate service systems; however, there is limited literature outlining comprehensive frameworks for the implementation of community dementia key worker roles in practice. In this paper an optimised key worker framework for people with dementia, their family and caring unit living in the community is developed and presented. METHODS: A number of processes were undertaken to inform the development of a co-designed optimised key worker framework: an expert working and reference group; a systematic review of the literature; and a qualitative evaluation of 14 dementia key worker models operating in Australia involving 14 interviews with organisation managers, 19 with key workers and 15 with people living with dementia and/or their caring unit. Data from the systematic review and evaluation of dementia key worker models were analysed by the researchers and the expert working and reference group using a constant comparative approach to define the essential components of the optimised framework. RESULTS: The developed framework consisted of four main components: overarching philosophies; organisational context; role definition; and key worker competencies. A number of more clearly defined sub-themes sat under each component. Reflected in the framework is the complexity of the dementia journey and the difficulty in trying to develop a 'one size fits all' approach. CONCLUSIONS: This co-designed study led to the development of an evidence based framework which outlines a comprehensive synthesis of components viewed as being essential to the implementation of a dementia key worker model of care in the community. The framework was informed and endorsed by people living with dementia and their caring unit, key workers, managers, Australian industry experts, policy makers and researchers. An evaluation of its effectiveness and relevance for practice within the dementia care space is required. PMID- 28728579 TI - Circulating sortilin level as a potential biomarker for coronary atherosclerosis and diabetes mellitus. AB - CONTEXT: A previous genome-wide association study showed that a genetic variant of sortilin was associated with the risk of coronary artery disease (CAD). However, the role of circulating sortilin is still unknown. We investigated the potential role of plasma sortilin as a biomarker for CAD and diabetes mellitus. METHODS: We enrolled statin-naive subjects with CAD (n = 31) who underwent coronary artery bypass surgery and control subjects (n = 116) who were free from CAD as evaluated by coronary CT angiography. The presence of diabetes mellitus was evaluated and plasma sortilin levels were measured with a commercial ELISA kit. RESULTS: Plasma sortilin levels were higher in subjects with CAD and subjects with diabetes mellitus than in those without CAD or diabetes mellitus. Subjects in the highest sortilin tertile group were older and had higher glucose and HbA1c levels, but lipid profiles in the three tertile groups were comparable. Multivariable logistic regression analysis revealed that sortilin levels were independently associated with CAD. In addition, the receiver operating characteristic curve analysis showed that plasma sortilin levels could identify the presence of CAD or diabetes mellitus. CONCLUSIONS: Elevated circulating sortilin levels are associated with CAD and diabetes mellitus and can be used as a biomarker of both diseases in statin-naive subjects. PMID- 28728580 TI - Lumbar microdiscectomy and post-operative activity restrictions: a protocol for a single blinded randomised controlled trial. AB - BACKGROUND: Lumbar microdiscectomy is the most commonly performed spinal surgery procedure, with over 300,000 cases performed annually in the United States alone. Traditionally, patients were advised to restrict post-operative activity as this was believed to reduce the risk of disc reherniation and progressive instability. However, this practice would often delay patients return to work. In contemporary practice many surgeons do not restrict patient post-operative activity due to the perception this practice is unnecessary. We describe a randomised controlled trial to assess the impact of activity restrictions on clinical outcome following lumbar discectomy. METHODS/DESIGN: The lumbar microdiscectomy and post-operative activity restriction trial is a multi-centre, randomised, controlled single blinded trial. Two hundred ten patients due to undergo single level lumbar microdiscectomy without a history of previous spine surgery, infection or fracture are randomised to be advised either restricted or unrestricted activity for a period of 30 days following lumbar microdiscectomy. Actual adherence with trial allocation will be monitored bioelectronically via a wearable device. Outcome assessment at follow up will occur at 1, 3, 6 and 12 months. The primary outcome will be a composite endpoint comprising changes in Visual Analogue Scale (Leg and Back), Oswestry Disability Index and the absence of intervertebral disc reherniation or secondary intervention. DISCUSSION: This randomised controlled trial will directly compare post-operative protocols of activity restrictions and no restrictions following lumbar discectomy with adherence monitored bioelectronically. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry: ACTRN12616001360404 (retrospectively registered 30/09/2016). PMID- 28728581 TI - A gestational choriocarcinoma of the ovary diagnosed by DNA polymorphic analysis: a case report and systematic review of the literature. AB - BACKGROUND: Choriocarcinoma of the ovary is rare. This tumor can arise from gestational tissue or pure germ cells of the ovary, the former results in gestational choriocarcinoma. The clinical characteristics and histology of both tumor types are identical, differentiation of these tumors is necessary for effective treatment. One strategy for the differentiation of these tumors types is to identify the presence of paternal DNA by DNA polymorphic analysis. CASE PRESENTATION: In the present case, a 27-year-old patient with a history of amenorrhea, lower abdominal pain and vaginal bleeding received a laparoscopic dissection of cystic mass of the right ovary according to an initial diagnosis of ectopic pregnancy. Primary choriocarcinoma of the ovary was diagnosed by pathology, but its origin was uncertain. DNA polymorphic analysis was then performed and a gestational origin was confirmed. The patient subsequently exhibited an excellent response to chemotherapy, achieved complete remission and gave birth to a healthy baby. CONCLUSION: Differentiation between two etiologies of primary choriocarcinoma can be achieved with DNA polymorphic analysis and it is necessary to distinguish between them to approach to an appropriate treatment of a patient. PMID- 28728582 TI - Basic parametric analysis for a multi-state model in hospital epidemiology. AB - BACKGROUND: The extended illness-death model is a useful tool to study the risks and consequences of hospital-acquired infections (HAIs). The statistical quantities of interest are the transition-specific hazard rates and the transition probabilities as well as attributable mortality (AM) and the population-attributable fraction (PAF). In the most general case calculation of these expressions is mathematically complex. METHODS: When assuming time-constant hazards calculation of the quantities of interest is facilitated. In this situation the transition probabilities can be expressed in closed mathematical forms. The estimators for AM and PAF can be easily derived from these forms. RESULTS: In this paper, we show how to explicitly calculate all the transition probabilities of an extended-illness model with constant hazards. Using a parametric model to estimate the time-constant transition specific hazard rates of a data example, the transition probabilities, AM and PAF can be directly calculated. With a publicly available data example, we show how the approach provides first insights into principle time-dynamics and data structure. CONCLUSION: Assuming constant hazards facilitates the understanding of multi state processes. Even in a non-constant hazards setting, the approach is a helpful first step for a comprehensive investigation of complex data. PMID- 28728583 TI - Birth weight differences between those offered financial voucher incentives for verified smoking cessation and control participants enrolled in the Cessation in Pregnancy Incentives Trial (CPIT), employing an intuitive approach and a Complier Average Causal Effects (CACE) analysis. AB - BACKGROUND: The Cessation in Pregnancy Incentives Trial (CPIT), which offered financial incentives for smoking cessation during pregnancy showed a clinically and statistically significant improvement in cessation. However, infant birth weight was not seen to be affected. This study re-examines birth weight using an intuitive and a complier average causal effects (CACE) method to uncover important information missed by intention-to-treat analysis. METHODS: CPIT offered financial incentives up to L400 to pregnant smokers to quit. With incentives, 68 women (23.1%) were confirmed non-smokers at primary outcome, compared to 25 (8.7%) without incentives, a difference of 14.3% (Fisher test, p < 0.0001). For this analysis, randomised groups were split into three theoretical sub-groups: independent quitters - quit without incentives, hardened smokers - could not quit even with incentives and potential quitters - required the addition of financial incentives to quit. Viewed in this way, the overall birth weight gain with incentives is attributable only to potential quitters. We compared an intuitive approach to a CACE analysis. RESULTS: Mean birth weight of potential quitters in the incentives intervention group (who therefore quit) was 3338 g compared with potential quitters in the control group (who did not quit) 3193 g. The difference attributable to incentives, was 3338 - 3193 = 145 g (95% CI -617, +803). The mean difference in birth weight between the intervention and control groups was 21 g, and the difference in the proportion who managed to quit was 14.3%. Since the intervention consisted of the offer of incentives to quit smoking, the intervention was received by all women in the intervention group. However, "compliance" was successfully quitting with incentives, and the CACE analysis yielded an identical result, causal birth weight increase 21 g / 0.143 = 145 g. CONCLUSIONS: Policy makers have great difficulty giving pregnant women money to stop smoking. This study indicates that a small clinically insignificant improvement in average birth weight is likely to hide an important clinically significant increase in infants born to pregnant smokers who want to stop but cannot achieve smoking cessation without the addition of financial voucher incentives. TRIAL REGISTRATION: ISRCTN Registry, ISRCTN87508788 . Registered on 1 September 2011. PMID- 28728584 TI - Professionals' perception of intimate partner violence in young people: a qualitative study in northern Spain. AB - BACKGROUND: Intimate partner violence (IPV) is a public health problem with devastating effects on young women's health. These negative effects increase when the exposure to IPV lasts for a long time and exposure at an early age increases the risk of adult IPV. Despite efforts made in the last few decades, data show little progress has been made towards its reduction. Thus, the aim of the study reported here is to explore professionals' perceptions regarding intimate partner violence (IPV) among young people, focusing on the characteristics of the phenomenon and their perceptions about existing programmes and campaigns aimed at addressing it. METHODS: Twelve professionals from education, health and municipal social services were interviewed. All but one of the interviews were recorded and transcribed verbatim. Data were analysed according to the methodology of inductive thematic analysis, with the support of Atlas.ti software. The transcripts were read several times and coded line by line. Afterwards, codes were grouped into themes. The developed themes were refined into two phases with the participation of all the authors. RESULTS: From the analysis, the following three themes were identified: "A false sense of gender equity", "IPV among young people: subtle, daily and normalized", and "Mass media campaigns do not fit young people's needs". According to the participants, psychological abuse in the form of controlling behaviour by their partners is the most common type of IPV young women are exposed to, although exposure to other types of IPV was also acknowledged. This violence was described as something subtle, daily and normalized and, consequently, not something that is easy to recognize for the girls that are exposed to it, nor for adults working with young people. CONCLUSIONS: The study participants showed good knowledge of the characteristics IPV has among young people. This knowledge was reflected in locally implemented IPV prevention projects, which they considered successful in addressing young people's needs. However, these interventions lacked formal evaluation, political support and continuation. The study participants did not believe that nationwide mass media campaigns realistically reflected the specific characteristics of IPV among young people. Thus, participants perceived these campaigns to be ineffective. PMID- 28728585 TI - Neuroscience in the third dimension: shedding new light on the brain with tissue clearing. AB - For centuries analyses of tissues have depended on sectioning methods. Recent developments of tissue clearing techniques have now opened a segway from studying tissues in 2 dimensions to 3 dimensions. This particular advantage echoes heavily in the field of neuroscience, where in the last several years there has been an active shift towards understanding the complex orchestration of neural circuits. In the past five years, many tissue-clearing protocols have spawned. This is due to varying strength of each clearing protocol to specific applications. However, two main protocols have shown their applicability to a vast number of applications and thus are exponentially being used by a growing number of laboratories. In this review, we focus specifically on two major tissue-clearing method families, derived from the 3DISCO and the CLARITY clearing protocols. Moreover, we provide a "hands-on" description of each tissue clearing protocol and the steps to look out for when deciding to choose a specific tissue clearing protocol. Lastly, we provide perspectives for the development of tissue clearing protocols into the research community in the fields of embryology and cancer. PMID- 28728586 TI - A never-before opportunity to strengthen investment and action on adolescent contraception, and what we must do to make full use of it. AB - BACKGROUND: Increasingly, the health and rights of adolescents are being recognized and prioritized on the global agenda. This presents us with a "never before" opportunity to address adolescent contraception. This is timely, as there are enormous numbers of adolescents who are currently unable to obtain and use contraceptives. From research evidence and programmatic experience, it is clear that we need to do things differently to meet their needs/fulfil their rights. MAIN BODY: In this commentary, we call for action in several key areas to address adolescents' persistent inability to obtain and use contraceptives. We must move away from one-size-fits-all approaches, from a 'condoms-only' mind set, from separate services for adolescents, from ignoring the appeal of pharmacies and shops, and from one-off-training to make health workers adolescent friendly. Our efforts to expand access to quality contraceptive services to adolescents must be combined with efforts to build their desire and ability to use them, and to do so consistently. In order for these changes to be made, action must be taken on several levels. This includes the formulation of sound national policies and strategies, robust programme implementation with monitoring, regular programmatic reviews, and implementation research. Further, high-quality collection, analysis, and dissemination of data must underlie all of our efforts. As we move ahead, we must also recognize and draw lessons from positive examples of large scale and sustained programmes in countries that have led the way in increasing contraceptive use by adolescents. CONCLUSION: This unprecedented moment in history gives us a real opportunity to bring about transformational change, particularly when there is so much at stake. PMID- 28728587 TI - Minimally invasive unilateral pedicle screws and a translaminar facet screw fixation and interbody fusion for treatment of single-segment lower lumbar vertebral disease: surgical technique and preliminary clinical results. AB - BACKGROUND: Conventional open transforaminal lumbar interbody fusion (TLIF) using unilateral pedicle screws and a translaminar facet screw has been performed for many years with good results. The outcomes of minimally invasive TLIF (MIS TLIF) are similar to the good outcomes of open TLIF, with the additional benefits of reducing iatrogenic injury, shortening hospital stays, and reducing the recovery duration. Instead of using small cuts on both sides, we performed MIS TLIF through a single cut using unilateral pedicle screws and a translaminar facet screw. The operative feasibility, efficacy safety, and benefits of single-level MIS TLIF of such techniques require further clarification. METHODS: A total of 60 patients with various single-segment lower lumbar vertebral diseases were treated in our department from January 2010 to March 2013. All the patients were initially performed single-level MIS TLIF using a hybrid construction of unilateral pedicle screws and a translaminar facet screw. Patient demographics and operative data were collected. The clinical outcomes were assessed before surgery and 3, 6, 12, and 24 months after surgery using the visual analog scale (VAS) for back and leg pain and the Oswestry Disability Index (ODI). Radiologic assessment of the lumbar spine with static and dynamic plain radiographs was performed 3, 6, 12, and 24 months after surgery. The fusion rates were assessed by an independent radiologist 2 years after surgery according to the Bridwell interbody fusion grading system. RESULTS: No patients experienced significant postoperative complications. Excepting two cases, 58 cases were followed up for 24-38 months, averaged 29.9 +/- 4.1 months. The patients' average age was 46.6 +/ 11.5 years, operative time 109.7 +/- 17.8 min, intraoperative blood loss 67.3 +/ 29.7 ml, length of incision 29.0 +/- 3.2 mm, fluoroscopy time 31.1 +/- 7.2 s, time to ambulation 20.3 +/- 7.0 h, length of hospital stay 5.1 +/- 1.1 days, and length of the translaminar facet screw 51.7 +/- 3.4 mm. Screw position results: type I, 54 cases with 54 segments; type II, four cases with four segments. There were two (3.4%) translaminar facet screw failures, which were intraoperatively converted to a bilateral pedicle screw fixation procedure and excluded from the research. The postoperative images showed good positioning of the hybrid internal fixation, and all of the translaminar facet screws penetrated the facet joint. Two (3.6%) translaminar facet screws penetrated the lateral lamina and two (3.6%) translaminar facet screws penetrated the medial lamina without any serious neural complications. During the follow-up, there was no screw loosening or pedicle fracture observed. The VAS and ODI scores were significantly improved compared with the preoperative scores (P < 0.05), and the symptoms disappeared gradually. Fifty-one patients (87.9%) achieved grade I fusion radiographically at the final follow-up. CONCLUSIONS: MIS TLIF using a hybrid construction of unilateral pedicle screws and a translaminar facet screw is safe and effective in the treatment of single-segment lower lumbar vertebral disease, and it can be used as an optimal choice for fixation and fusion of some single-segment lower lumbar vertebral diseases. PMID- 28728588 TI - Genetic structure and gene flow of the flea Xenopsylla cheopis in Madagascar and Mayotte. AB - BACKGROUND: The flea Xenopsylla cheopis (Siphonaptera: Pulicidae) is a vector of plague. Despite this insect's medical importance, especially in Madagascar where plague is endemic, little is known about the organization of its natural populations. We undertook population genetic analyses (i) to determine the spatial genetic structure of X. cheopis in Madagascar and (ii) to determine the potential risk of plague introduction in the neighboring island of Mayotte. RESULTS: We genotyped 205 fleas from 12 sites using nine microsatellite markers. Madagascan populations of X. cheopis differed, with the mean number of alleles per locus per population ranging from 1.78 to 4.44 and with moderate to high levels of genetic differentiation between populations. Three distinct genetic clusters were identified, with different geographical distributions but with some apparent gene flow between both islands and within Malagasy regions. The approximate Bayesian computation (ABC) used to test the predominant direction of flea dispersal implied a recent population introduction from Mayotte to Madagascar, which was estimated to have occurred between 1993 and 2012. The impact of this flea introduction in terms of plague transmission in Madagascar is unclear, but the low level of flea exchange between the two islands seems to keep Mayotte free of plague for now. CONCLUSION: This study highlights the occurrence of genetic structure among populations of the flea vector of plague, X. cheopis, in Madagascar and suggests that a flea population from Mayotte has been introduced to Madagascar recently. As plague has not been reported in Mayotte, this introduction is unlikely to present a major concern for plague transmission. Nonetheless, evidence of connectivity among flea populations in the two islands indicates a possibility for dispersal by fleas in the opposite direction and thus a risk of plague introduction to Mayotte. PMID- 28728589 TI - Occurrence of strongyloidiasis in privately owned and sheltered dogs: clinical presentation and treatment outcome. AB - BACKGROUND: The increasing number of reports of human infections by Strongyloides stercoralis from a range of European countries over the last 20 years has spurred the interest of the scientific community towards this parasite and, in particular, towards the role that infections of canine hosts may play in the epidemiology of human disease. Data on the epidemiology of canine strongyloidiasis is currently limited, most likely because of the inherent limitations of current diagnostic methods. METHODS: Faecal samples were collected directly from the rectal ampulla of 272 animals of varying age and both genders living in Apulia, southern Italy. Dogs included were either privately owned (n = 210), living in an urban area but with unrestricted outdoor access (Group 1), or shelter dogs (n = 62 out of ~400) hosted in a single shelter in the province of Bari in which a history of diarrhoea, weight loss, reduced appetite and respiratory symptoms had been reported (Group 2). Strongyloides stercoralis infection was diagnosed by coproscopy on direct faecal smear and via the Baermann method. RESULTS: Six of 272 dogs were positive for S. stercoralis at the Baermann examination; all but one were from the shelter (Group 2) and displayed gastrointestinal clinical signs. The only owned dog (Group 1) infected with S. stercoralis, but clinically healthy, had been adopted from a shelter 1 year prior to sampling. Five infected dogs were treated with fenbendazole (Panacur(r), Intervet, Animal Health, 50 mg/kg, PO daily for 5 days), or with a combination of fenbendazole and moxidectin plus imidacloprid spot-on (Im/Mox; Advocate(r) spot on, Bayer). Post-treatment clearance of infection was confirmed in three dogs by Baermann examination, whereas treatment failure was documented in two dogs by Baermann and/or post-mortem detection of adult parasites. CONCLUSIONS: This study describes, for the first time, the presence of S. stercoralis infection in sheltered dogs from southern Italy. Data indicate that S. stercoralis infection may pose a concern for sheltered animals and raise questions on potential risks of infection for staff of municipal shelters in southern European countries. Given that a single course of treatment with fenbendazole, associated or not with Im/Mox spot-on, may not eliminate the infection, effective treatment protocols should be investigated and control strategies targeting the environment considered for reducing the risk of zoonotic infection. PMID- 28728590 TI - Chikungunya virus infection in Cynomolgus macaques following Intradermal and aerosol exposure. AB - BACKGROUND: Chikungunya virus (CHIKV) is transmitted via mosquito bite and potentially by aerosol, causing chikungunya fever and arthritic disease in humans. There are currently no licensed vaccines or antiviral therapeutics to protect against CHIKV infection in humans. Animal models recapitulating human disease, especially for transmission by aerosol, are needed for licensure of such medical countermeasures. METHODS: Cynomolgus macaques (CMs) were challenged by intradermal (ID) inoculation or exposure to an aerosol containing CHIKV Ross strain at different target infectious doses (103-107 plaque forming units (PFU)). The clinical and virologic courses of disease were monitored up to 14 days post exposure. RESULTS: ID infection of CMs led to overt clinical disease, detectable viremia, and increased blood markers of liver damage. Animals challenged by aerosol exhibited viremia and increased liver damage biomarkers with minimal observed clinical disease. All animals survived CHIKV challenge. CONCLUSIONS: We have described CHIKV infection in CMs following ID inoculation and, for the first time, infection by aerosol. Based on limited reported cases in the published literature, the aerosol model recapitulates the virologic findings of human infection via this route. The results of this study provide additional evidence for the potential use of CMs as a model for evaluating medical countermeasures against CHIKV. PMID- 28728591 TI - Antimicrobial susceptibility pattern of clinical isolates of Burkholderia pseudomallei in Bangladesh. AB - BACKGROUND: Melioidosis an infectious disease, caused by a Gram negative bacterium called Burkholderia pseudomallei, is endemic in Bangladesh. This organism is sensitive to limited number of antimicrobial agents and need prolonged treatment. There is no comprehensive data on the antimicrobial susceptibility profile of B. pseudomallei isolated in Bangladesh over last several years. The present study aimed to determine the antimicrobial susceptibility pattern of B. pseudomallei isolated in a tertiary care hospital of Dhaka city from 2009 to 2015. METHODS: All B. pseudomallei isolated from melioidosis patients over a period of 7 years (2009-2015) in the Department of Microbiology of a 725-bed tertiary care referral hospital in Dhaka city, Bangladesh were included in the study. B. pseudomallei was identified by Gram stain, culture, specific biochemical tests, serology and PCR using specific primers constructed from 16s rRNA region of B. pseudomallei. Antimicrobial susceptibility to specific agents was determined by disk diffusion and minimum inhibitory concentration methods. RESULTS: A total of 20 isolates of B. pseudomallei which were isolated from patients coming from different geographic locations of Bangladesh were included in the study. All the isolates were uniformly sensitive (100%) to ceftazidime, imipenem, piperacillin-tazobactam, amoxicillin-clavulanic acid and tetracycline by both disk diffusion and MIC methods. Two strains were resistant to trimethoprim-sulfamethoxazole by disk diffusion method but were sensitive by MIC method. The MIC50 and MIC90 values of the above antimicrobial agents were almost similar. All the isolates were resistant to amikacin by both MIC and disk diffusion methods. CONCLUSION: The results of the study suggest that B. pseudomallei prevalent in Bangladesh were still susceptible to all recommended antimicrobial agents used for the treatment of melioidosis. However, regular monitoring is needed to detect any emergence of resistance and shifting of MIC50 and MIC90 values. PMID- 28728592 TI - Examination of the gait pattern based on adjusting and resulting components of the stride-to-stride variability: proof of concept. AB - BACKGROUND: Stride-to-stride variability may be used as an indicator in the assessment of gait performance, but the evaluation of this parameter is not trivial. In the gait pattern, a deviation in one stride must be corrected within the next strides (elemental variables) to ensure a steady gait (performance variable). The variance in these elemental and performance variables may therefore be evaluated as adjusting and resulting components of variability. We explored this approach to gait evaluation by matching the velocity of one stride to a subsequent stride with four different time lags ranging from 0.5 to 2 strides with 0.5 stride increments. The time lag values corresponded to the following contralateral stride, the following ipsilateral stride, the second following contralateral stride and the second following ipsilateral stride. METHODS: Twenty asymptomatic young adults walked on an instrumented treadmill at their preferred gait speed. The stride velocity was calculated, and variances in the stride-to-stride differences and in the stride-to-stride sums represented the adjusting and the resulting variances, respectively. A ratio between these values of greater than one indicated a meaningful stride-to-stride interaction. RESULTS: For the four time lags (0.5, 1, 1.5, and 2 strides), the adjusting/resulting variance ratios (mean and CI 95%) were 1.0 (0.8-1.2), 2.9 (2.3-3.6), 1.2 (1.0 1.4) and 1.2 (0.9-1.4), respectively. CONCLUSIONS: This new approach to the evaluation of stride-to-stride variability suggests that gait velocity adjustments occurred within one full stride cycle during treadmill walking among asymptomatic young adults. The validity of the approach needs to be tested in over-ground walking. PMID- 28728593 TI - High throughput sequencing of small RNAs reveals dynamic microRNAs expression of lipid metabolism during Camellia oleifera and C. meiocarpa seed natural drying. AB - BACKGROUND: Camellia species are ancient oilseed plants with a history of cultivation over two thousand years. Prior to oil extraction, natural seed drying is often practiced, a process affecting fatty acid quality and quantity. MicroRNAs (miRNA) of lipid metabolism associated with camellia seed natural drying are unexplored. To obtain insight into the function of miRNAs in lipid metabolism during natural drying, Illumina sequencing of C. oleifera and C. meiocarpa small-RNA was conducted. RESULTS: A total of 274 candidate miRNAs were identified and 3733 target unigenes were annotated by performing a BLASTX. Through integrated GO and KEGG function annotation, 23 miRNA regulating 131 target genes were identified as lipid metabolism, regulating fatty acid biosynthesis, accumulation and catabolism. We observed one, two, and four miRNAs of lipid metabolism which were specially expressed in C. Meiocarpa, C. oleifera, and the two species collectively, respectively. At 30% moisture contents, C. meiocarpa and C. oleifer produced nine and eight significant differentially expressed miRNAs, respectively, with high fatty acid synthesis and accumulation activities. Across the two species, 12 significant differentially expressed miRNAs were identified at the 50% moisture content. CONCLUSIONS: Sequencing of small-RNA revealed the presence of 23 miRNAs regulating lipid metabolism in camellia seed during natural drying and permitted comparative miRNA profiles between C. Meiocarpa and C. oleifera. Furthermore, this study successfully identified the best drying environment at which the quantity and quality of lipid in camellia seed are at its maximum. PMID- 28728594 TI - Implementing the EffTox dose-finding design in the Matchpoint trial. AB - BACKGROUND: The Matchpoint trial aims to identify the optimal dose of ponatinib to give with conventional chemotherapy consisting of fludarabine, cytarabine and idarubicin to chronic myeloid leukaemia patients in blastic transformation phase. The dose should be both tolerable and efficacious. This paper describes our experience implementing EffTox in the Matchpoint trial. METHODS: EffTox is a Bayesian adaptive dose-finding trial design that jointly scrutinises binary efficacy and toxicity outcomes. We describe a nomenclature for succinctly describing outcomes in phase I/II dose-finding trials. We use dose-transition pathways, where doses are calculated for each feasible set of outcomes in future cohorts. We introduce the phenomenon of dose ambivalence, where EffTox can recommend different doses after observing the same outcomes. We also describe our experiences with outcome ambiguity, where the categorical evaluation of some primary outcomes is temporarily delayed. RESULTS: We arrived at an EffTox parameterisation that is simulated to perform well over a range of scenarios. In scenarios where dose ambivalence manifested, we were guided by the dose transition pathways. This technique facilitates planning, and also helped us overcome short-term outcome ambiguity. CONCLUSIONS: EffTox is an efficient and powerful design, but not without its challenges. Joint phase I/II clinical trial designs will likely become increasingly important in coming years as we further investigate non-cytotoxic treatments and streamline the drug approval process. We hope this account of the problems we faced and the solutions we used will help others implement this dose-finding clinical trial design. TRIAL REGISTRATION: Matchpoint was added to the European Clinical Trials Database ( https://www.clinicaltrialsregister.eu/ctr-search/trial/2012-005629-65/GB ) on 2013-12-30. PMID- 28728596 TI - Implementation of longevity-promoting supplements and medications in public health practice: achievements, challenges and future perspectives. AB - BACKGROUND: Most modern societies undergo rapid population aging. The rise in life expectancy, nevertheless, is not accompanied, to date, by the same increment of healthspan. Efforts to increase healthspan by means of supplements and pharmaceuticals targeting aging-related pathologies are presently in spotlight of a new branch in geriatric medicine, geroscience, postulating that aging could be manipulated in such a way that will in parallel allow delay the onset of all age associated chronic disorders. DISCUSSION: Currently, the concept of the "longevity dividend" has been developed pointed out that the extension of healthspan by slowing the rate of aging is the most efficient way to combat various aging-related chronic illnesses and disabling conditions than combating them one by one, what is the present-day approach in a generally accepted disease based paradigm. The further elaboration of pharmaceuticals specifically targeted at age-associated disorders (commonly referred to as 'anti-aging drugs') is currently one of the most extensively developed fields in modern biogerontology. Some classes of chemically synthesized compounds and nutraceuticals such as calorie restriction mimetics, autophagy inductors, senolytics and others have been identified as having potential for anti-aging intervention through their possible effects on basic processes underlying aging. In modern pharmaceutical industry, development of new classes of anti-aging medicines is apparently one of the most hopeful directions since potential target group may include each adult individual. Implementation of the geroscience-based approaches into healthcare policy and practice would increase the ratio of healthy to unhealthy population due to delaying the onset of age-associated chronic pathologies. That might result in decreasing the biological age and increasing the age of disability, thus increasing the age of retirement and enhancing income without raising taxes. Economic, social and ethical aspects of applying the healthspan- and lifespan promoting interventions, however, have to be comprehensively debated prior to their implementation in public health practice. PMID- 28728595 TI - Malaria after international travel: a GeoSentinel analysis, 2003-2016. AB - BACKGROUND: More than 30,000 malaria cases are reported annually among international travellers. Despite improvements in malaria control, malaria continues to threaten travellers due to inaccurate perception of risk and sub optimal pre-travel preparation. METHODS: Records with a confirmed malaria diagnosis after travel from January 2003 to July 2016 were obtained from GeoSentinel, a global surveillance network of travel and tropical medicine providers that monitors travel-related morbidity. Records were excluded if exposure country was missing or unascertainable or if there was a concomitant acute diagnosis unrelated to malaria. Records were analyzed to describe the demographic and clinical characteristics of international travellers with malaria. RESULTS: There were 5689 travellers included; 325 were children <18 years. More than half (53%) were visiting friends and relatives (VFRs). Most (83%) were exposed in sub-Saharan Africa. The median trip duration was 32 days (interquartile range 20-75); 53% did not have a pre-travel visit. More than half (62%) were hospitalized; children were hospitalized more frequently than adults (73 and 62%, respectively). Ninety-two per cent had a single Plasmodium species diagnosis, most frequently Plasmodium falciparum (4011; 76%). Travellers with P. falciparum were most frequently VFRs (60%). More than 40% of travellers with a trip duration <=7 days had Plasmodium vivax. There were 444 (8%) travellers with severe malaria; 31 children had severe malaria. Twelve travellers died. CONCLUSION: Malaria remains a serious threat to international travellers. Efforts must focus on preventive strategies aimed on children and VFRs, and chemoprophylaxis access and preventive measure adherence should be emphasized. PMID- 28728597 TI - Interaction of direct and social genetic effects with feeding regime in growing rabbits. AB - BACKGROUND: Most rabbit production farms apply feed restriction at fattening because of its protective effect against digestive diseases that affect growing rabbits. However, it leads to competitive behaviour between cage mates, which is not observed when animals are fed ad libitum. Our aim was to estimate the contribution of direct ([Formula: see text]) and social ([Formula: see text]) genetic effects (also known as indirect genetic effects) to total heritable variance of average daily gain ([Formula: see text]) in rabbits on different feeding regimens (FR), and the magnitude of the interaction between genotype and FR (G * FR). METHODS: A total of 6264 contemporary kits were housed in cages of eight individuals and raised on full ([Formula: see text]) or restricted ([Formula: see text]) feeding to 75% of the ad libitum intake. A Bayesian analysis of weekly records of [Formula: see text] (from 32 to 60 days of age) in rabbits on [Formula: see text] and [Formula: see text] was performed with a two trait model including [Formula: see text] and [Formula: see text]. RESULTS: The ratio between total heritable variance and phenotypic variance ([Formula: see text]) was low (<0.10) and did not differ significantly between FR. However, the ratio between [Formula: see text] (i.e. variance of [Formula: see text] relative to phenotypic variance) and [Formula: see text] was ~0.52 and 0.86 for animals on [Formula: see text] and [Formula: see text], respectively, thus [Formula: see text] contributed more to the heritable variance of animals on [Formula: see text] than on [Formula: see text]. Feeding regimen also affected the sign and magnitude of the correlation between [Formula: see text] and [Formula: see text], i.e. -0.5 and ~0 for animals on [Formula: see text] and [Formula: see text], respectively. The posterior mean (posterior sd) of the correlation between estimated total breeding values (ETBV) of animals on [Formula: see text] and [Formula: see text] was 0.26 (0.20), indicating very strong G * FR interactions. The correlations between [Formula: see text] and [Formula: see text] in rabbits on [Formula: see text] and [Formula: see text] ranged from -0.47 ([Formula: see text] on [Formula: see text] and [Formula: see text] on [Formula: see text]) to 0.64. CONCLUSIONS: Our results suggest that selection of rabbits for [Formula: see text] under [Formula: see text] may completely fail to improve [Formula: see text] in rabbits on [Formula: see text]. Social genetic effects contribute substantially to ETBV of rabbits on [Formula: see text] but not on [Formula: see text]. Selection for [Formula: see text] should be performed under production conditions regarding the FR, by accounting for [Formula: see text] if the amount of food is limited. PMID- 28728598 TI - Multi-walled carbon nanotubes-induced alterations in microRNA let-7 and its targets activate a protection mechanism by conferring a developmental timing control. PMID- 28728599 TI - A phase III, randomized, two-armed, double-blind, parallel, active controlled, and non-inferiority clinical trial to compare efficacy and safety of biosimilar adalimumab (CinnoRA(r)) to the reference product (Humira(r)) in patients with active rheumatoid arthritis. AB - BACKGROUND: This study aimed to compare efficacy and safety of test-adalimumab (CinnoRA(r), CinnaGen, Iran) to the innovator product (Humira(r), AbbVie, USA) in adult patients with active rheumatoid arthritis (RA). METHODS: In this randomized, double-blind, active-controlled, non-inferiority trial, a total of 136 patients with active RA were randomized to receive 40 mg subcutaneous injections of either CinnoRA(r) or Humira(r) every other week, while receiving methotrexate (15 mg/week), folic acid (1 mg/day), and prednisolone (7.5 mg/day) over a period of 24 weeks. Physical examinations, vital sign evaluations, and laboratory tests were conducted in patients at baseline and at 12-week and 24 week visits. The primary endpoint in this study was the proportion of patients achieving moderate and good disease activity score in 28 joints-erythrocyte sedimentation rate (DAS28-ESR)-based European League Against Rheumatism (EULAR) response. The secondary endpoints were the proportion of patients achieving American College of Rheumatology (ACR) criteria for 20% (ACR20), 50% (ACR50), and 70% (ACR70) responses along with the disability index of health assessment questionnaire (HAQ), and safety. RESULTS: Patients who were randomized to CinnoRA(r) or Humira(r) arms had comparable demographic information, laboratory results, and disease characteristics at baseline. The proportion of patients achieving good and moderate EULAR responses in the CinnoRA(r) group was non inferior to the Humira(r) group at 12 and 24 weeks based on both intention-to treat (ITT) and per-protocol (PP) populations (all p values >0.05). No significant difference was noted in the proportion of patients attaining ACR20, ACR50, and ACR70 responses in the CinnoRA(r) and Humira(r) groups (all p values >0.05). Further, the difference in HAQ scores and safety outcome measures between treatment arms was not statistically significant. CONCLUSION: CinnoRA(r) was shown to be non-inferior to Humira(r) in terms of efficacy at week 24 with a comparable safety profile to the reference product. TRIAL REGISTRATION: IRCT.ir, IRCT2015030321315N1 . Registered on 5 April 2015. PMID- 28728600 TI - Comparison of the polyphenolic profile and antibacterial activity of the leaves, fruits and flowers of Rhododendron ambiguum and Rhododendron cinnabarinum. AB - BACKGROUND: Rhododendron species have been traditionally used in countries like China, Nepal, Russia and North America for treating human diseases. These species are known to be a good source of polyphenolic plant secondary plant metabolites. They are known to have beneficial health properties for humans and have been used to treat diseases like asthma, skin diseases. In this contribution we investigate the phenolic profile and antibacterial activity of extracts from several plant organs including for the first time from leaves of different development stages. METHODS: In this study, the polyphenolic profile of fruits, flowers and leaves of different ages of Rhododendron ambiguum and Rhododendron cinnabarinum were studied by using HPLC-MS and compounds identified based on high resolution masses and identity of tandem mass spectra, UV/VIS spectra and retention times if compared to standards. RESULTS: Fifty-nine different polyphenols including isomers were identified in these species by their fragmentation pattern and high resolution data. Also, the antibacterial activity of these parts (leaves, fruits and flowers) against gram-positive bacteria was studied. CONCLUSION: The leaves and fruits contained more polyphenols than the flowers. With the exception of flowers, the fruits and leaves of both species were also determined to have a significant antibacterial effect against four gram-positive bacteria. PMID- 28728601 TI - Transabdominal laparoscopic retroperitoneal neurectomy for chronic pain after inguinal hernia repair and appendicectomy -a matched-pair study. AB - BACKGROUND: Chronic debilitating pain is a rare but significant cause of postoperative morbidity after inguinal surgery. Such pain is usually of neuropathic origin and frequently caused by intraoperative nerve damage. In this retrospective matched-pair study we analysed results of a minimal-invasive approach to neurectomy on quality of life and pain relief. METHODS: From March 2010 to January 2012, 9 patients developing chronic neuropathic pain after inguinal hernia repair (8 patients) or open appendicectomy (one patient) were operated using a laparoscopic transabdominal approach in our department. Clinical examinations and specific questionnaires on pain and quality of life (PainDetect, SF-36) were completed 6 months to 3 years after neurectomy. Every patient was matched with one patient without chronic pain. RESULTS: Seven of nine patients had severe or very severe pain before neurectomy, two had mild pain but refused a conservative treatment. Four patients were free of pain after neurectomy, three described an improved pain status, whereas two did not observe any change in pain. Within a follow-up period of 14,3 months, no deterioration of pain or other complications were observed. Patients who underwent neurectomy had significantly lower quality of life compared to the control group. No postoperative complications were observed. CONCLUSIONS: Laparoscopic transabdominal neurectomy represents a possible surgical approach in treating patients with chronic disabling postoperative groin pain requiring surgery. This technique was feasible, safe, and effective in our series to relieve chronic debilitating pain in the majority of our patients with comparable results to other published approaches. PMID- 28728603 TI - The effect of using social pressure in cover letters to improve retention in a longitudinal health study: an embedded randomised controlled retention trial. AB - BACKGROUND: Retention of participants in cohort studies is important for validity. One way to promote retention is by sending a persuasive cover letter with surveys. The study aimed to compare the effectiveness of a covering letter containing social pressure with a standard covering letter on retention in a health cohort study. Social pressure involves persuading people to behave in a certain way by the promise that their actions will be made know to others. We implemented a mild form of social pressure, where the recipient was told that information about whether they responded to the current survey would be noted by the research team and printed on future correspondence from the research team to the recipient. METHODS: The design was an embedded randomised controlled retention trial, conducted between July 2015 and April 2016 in Salford, UK. Participants in the host health cohort study were eligible. They received either: (1) a covering letter with two consecutive surveys (sent six and twelve months after recruitment), containing a social pressure intervention; or (2) a matching letter without the social pressure text. The primary outcome was retention in the host study, defined as return of both surveys. Randomisation was computer generated, with stratification by household size. Participants were blinded to group assignment. Researchers were blinded for outcome ascertainment. RESULTS: Adults (n = 4447) aged over 65 years, with a long-term condition and enrolled in the host study, were randomly allocated to receive a social pressure covering letter (n = 2223) or control (n = 2224). All 4447 participants were included in the analysis. Both questionnaires were returned by 1577 participants (71%) sent the social pressure letters and 1511 (68%) sent control letters, a risk difference of 3 percentage points (adjusted odds ratio = 1.16 (95% confidence interval = 1.02-1.33)). CONCLUSION: A mild form of social pressure made a small but significant improvement in retention of older adults in a health cohort study. Investigation of social pressure across other research contexts and stronger social pressure messages is warranted. TRIAL REGISTRATION: The host cohort study, the Comprehensive Longitudinal Assessment of Salford Integrated Care (CLASSIC) study is associated with the CLASSIC PROTECTs trial, which is registered on the ISRCTN registry. TRIAL REGISTRATION NUMBER: ISRCTN12286422 . Date of registration 19 June 2014. PMID- 28728602 TI - Robot Assisted Training for the Upper Limb after Stroke (RATULS): study protocol for a randomised controlled trial. AB - BACKGROUND: Loss of arm function is a common and distressing consequence of stroke. We describe the protocol for a pragmatic, multicentre randomised controlled trial to determine whether robot-assisted training improves upper limb function following stroke. METHODS/DESIGN: Study design: a pragmatic, three-arm, multicentre randomised controlled trial, economic analysis and process evaluation. SETTING: NHS stroke services. PARTICIPANTS: adults with acute or chronic first-ever stroke (1 week to 5 years post stroke) causing moderate to severe upper limb functional limitation. Randomisation groups: 1. Robot-assisted training using the InMotion robotic gym system for 45 min, three times/week for 12 weeks 2. Enhanced upper limb therapy for 45 min, three times/week for 12 weeks 3. Usual NHS care in accordance with local clinical practice Randomisation: individual participant randomisation stratified by centre, time since stroke, and severity of upper limb impairment. PRIMARY OUTCOME: upper limb function measured by the Action Research Arm Test (ARAT) at 3 months post randomisation. SECONDARY OUTCOMES: upper limb impairment (Fugl-Meyer Test), activities of daily living (Barthel ADL Index), quality of life (Stroke Impact Scale, EQ-5D-5L), resource use, cost per quality-adjusted life year and adverse events, at 3 and 6 months. Blinding: outcomes are undertaken by blinded assessors. Economic analysis: micro costing and economic evaluation of interventions compared to usual NHS care. A within-trial analysis, with an economic model will be used to extrapolate longer term costs and outcomes. Process evaluation: semi-structured interviews with participants and professionals to seek their views and experiences of the rehabilitation that they have received or provided, and factors affecting the implementation of the trial. SAMPLE SIZE: allowing for 10% attrition, 720 participants provide 80% power to detect a 15% difference in successful outcome between each of the treatment pairs. Successful outcome definition: baseline ARAT 0-7 must improve by 3 or more points; baseline ARAT 8-13 improve by 4 or more points; baseline ARAT 14-19 improve by 5 or more points; baseline ARAT 20-39 improve by 6 or more points. DISCUSSION: The results from this trial will determine whether robot-assisted training improves upper limb function post stroke. TRIAL REGISTRATION: ISRCTN, identifier: ISRCTN69371850 . Registered 4 October 2013. PMID- 28728604 TI - Target-D: a stratified individually randomized controlled trial of the diamond clinical prediction tool to triage and target treatment for depressive symptoms in general practice: study protocol for a randomized controlled trial. AB - BACKGROUND: Depression is a highly prevalent and costly disorder. Effective treatments are available but are not always delivered to the right person at the right time, with both under- and over-treatment a problem. Up to half the patients presenting to general practice report symptoms of depression, but general practitioners have no systematic way of efficiently identifying level of need and allocating treatment accordingly. Therefore, our team developed a new clinical prediction tool (CPT) to assist with this task. The CPT predicts depressive symptom severity in three months' time and based on these scores classifies individuals into three groups (minimal/mild, moderate, severe), then provides a matched treatment recommendation. This study aims to test whether using the CPT reduces depressive symptoms at three months compared with usual care. METHODS: The Target-D study is an individually randomized controlled trial. Participants will be 1320 general practice patients with depressive symptoms who will be approached in the practice waiting room by a research assistant and invited to complete eligibility screening on an iPad. Eligible patients will provide informed consent and complete the CPT on a purpose-built website. A computer-generated allocation sequence stratified by practice and depressive symptom severity group, will randomly assign participants to intervention (treatment recommendation matched to predicted depressive symptom severity group) or comparison (usual care plus Target-D attention control) arms. Follow-up assessments will be completed online at three and 12 months. The primary outcome is depressive symptom severity at three months. Secondary outcomes include anxiety, mental health self-efficacy, quality of life, and cost-effectiveness. Intention-to-treat analyses will test for differences in outcome means between study arms overall and by depressive symptom severity group. DISCUSSION: To our knowledge, this is the first depressive symptom stratification tool designed for primary care which takes a prognosis-based approach to provide a tailored treatment recommendation. If shown to be effective, this tool could be used to assist general practitioners to implement stepped mental-healthcare models and contribute to a more efficient and effective mental health system. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR 12616000537459 ). Retrospectively registered on 27 April 2016. See Additional file 1 for trial registration data. PMID- 28728605 TI - Surrogate endpoints in oncology: when are they acceptable for regulatory and clinical decisions, and are they currently overused? AB - BACKGROUND: Surrogate outcomes are not intrinsically beneficial to patients, but are designed to be easier and faster to measure than clinically meaningful outcomes. The use of surrogates as an endpoint in clinical trials and basis for regulatory approval is common, and frequently exceeds the guidance given by regulatory bodies. DISCUSSION: In this article, we demonstrate that the use of surrogates in oncology is widespread and increasing. At the same time, the strength of association between the surrogates used and clinically meaningful outcomes is often unknown or weak. Attempts to validate surrogates are rarely undertaken. When this is done, validation relies on only a fraction of available data, and often concludes that the surrogate is poor. Post-marketing studies, designed to ensure drugs have meaningful benefits, are often not performed. Alternatively, if a drug fails to improve quality of life or overall survival, market authorization is rarely revoked. We suggest this reliance on surrogates, and the imprecision surrounding their acceptable use, means that numerous drugs are now approved based on small yet statistically significant increases in surrogates of questionable reliability. In turn, this means the benefits of many approved drugs are uncertain. This is an unacceptable situation for patients and professionals, as prior experience has shown that such uncertainty can be associated with significant harm. CONCLUSION: The use of surrogate outcomes should be limited to situations where a surrogate has demonstrated robust ability to predict meaningful benefits, or where cases are dire, rare or with few treatment options. In both cases, surrogates must be used only when continuing studies examining hard endpoints have been fully recruited. PMID- 28728606 TI - Levels of serum biomarkers from a two-year multicentre trial are associated with treatment response on knee osteoarthritis cartilage loss as assessed by magnetic resonance imaging: an exploratory study. AB - BACKGROUND: There is an obvious need to identify biomarkers that could predict patient response to an osteoarthritis (OA) treatment. This post hoc study explored in a 2-year randomized controlled trial in patients with knee OA, the likelihood of some serum biomarkers to be associated with a better response to chondroitin sulfate in reducing cartilage volume loss. METHODS: Eight biomarkers were studied: hyaluronic acid (HA), C reactive protein (CRP), adipsin, leptin, N terminal propeptide of collagen IIalpha (PIIANP), C-terminal crosslinked telopeptide of type I collagen (CTX-1), matrix metalloproteinase-1 (MMP-1), and MMP-3. Patients were treated with chondroitin sulfate (1200 mg/day; n = 57) or celecoxib (200 mg/day; n = 62). Serum biomarkers were measured at baseline. The cartilage volume at baseline and its loss at 2 years were assessed by quantitative magnetic resonance imaging (MRI). Statistical analysis included analysis of covariance. RESULTS: As data from the original MOSAIC trial showed no differences in cartilage volume and loss in the lateral compartment of the knee joint between the two treatment groups in any comparison, only the medial compartment and its subregions were studied. Stratification according to the median biomarker levels was used to discriminate treatment effect. In patients with levels of biomarkers of inflammation (HA, leptin and adipsin) lower than the median, those treated with chondroitin sulfate demonstrated less cartilage volume loss in the medial compartment, condyle, and plateau (p <= 0.047). In contrast, patients treated with chondroitin sulfate with higher levels of MMP-1 and MMP-3, biomarkers of cartilage catabolism, had less cartilage volume loss in the medial compartment, condyle, and plateau (p <= 0.050). Patients with higher levels of PIIANP and CTX-1, biomarkers related to collagen anabolism and bone catabolism, respectively, had reduced cartilage volume loss in the medial condyle (p <= 0.026) in the chondroitin sulfate group. CONCLUSION: This study is suggestive of a potentially greater response to chondroitin sulfate treatment on cartilage volume loss in patients with knee OA with low level of inflammation and/or greater level of cartilage catabolism. TRIAL REGISTRATION: This is a post hoc study. Original trial registration: ClinicalTrials.gov, NCT01354145 . Registered on 13 May 2011. PMID- 28728607 TI - Zika virus transmission to mouse ear by mosquito bite: a laboratory model that replicates the natural transmission process. AB - BACKGROUND: Zika disease has transformed into a serious global health problem due to the rapid spread of the arbovirus and alarming severity including congenital complications, microcephaly and Guillain-Barre syndrome. Zika virus (ZIKV) is primarily transmitted to humans through the bite of an infective mosquito, with Aedes aegypti being the main vector. METHODS: We successfully developed a ZIKV experimental transmission model by single infectious Ae. aegypti bite to a laboratory mouse using circulating Brazilian strains of both arbovirus and vector. Mosquitoes were orally infected and single Ae. aegypti were allowed to feed on mouse ears 14 days post-infection. Additionally, salivary gland (SG) homogenates from infected mosquitoes were intrathoracically inoculated into naive Ae. aegypti. Mosquito and mouse tissue samples were cultured in C6/36 cells and processed by quantitative real-time PCR. RESULTS: A total of 26 Ae. aegypti were allowed to feed individually on mouse ears. Of these, 17 mosquitoes fed, all to full engorgement. The transmission rate of ZIKV by bite from these engorged mosquitoes to mouse ears was 100%. The amount of virus inoculated into the ears by bites ranged from 2 * 102-2.1 * 1010 ZIKV cDNA copies and was positively correlated with ZIKV cDNA quantified from SGs dissected from mosquitoes post feeding. Replicating ZIKV was confirmed in macerated SGs (2.45 * 107 cDNA copies), mouse ear tissue (1.15 * 103 cDNA copies, and mosquitoes 14 days post intrathoracic inoculation (1.49 * 107 cDNA copies) by cytopathic effect in C6/36 cell culture and qPCR. CONCLUSIONS: Our model illustrates successful transmission of ZIKV by an infectious mosquito bite to a live vertebrate host. This approach offers a comprehensive tool for evaluating the development of infection in and transmission from mosquitoes, and the vertebrate-ZIKV interaction and progression of infection following a natural transmission process. PMID- 28728608 TI - Influence of apelin-12 on troponin levels and the rate of MACE in STEMI patients. AB - BACKGROUND: During acute myocardial infarction, phosphorylated TnI levels, Ca2+ sensitivity and ATPase activity are decreased in the myocardium, and the subsequent elevation in Ca2+ levels activates protease I (caplain I), leading to the proteolytic degradation of troponins. Concurrently, the levels of apelin and APJ expression are increased by limiting myocardial injury. METHODS: In this prospective observational study, 100 consecutive patients with ST-elevation acute myocardial infarction were included. Patients meeting the following criteria were included in our study: (1) continuous chest pain lasting for >30 min, (2) observation of ST-segment elevation of more than 2 mm in two adjacent leads by electrocardiography (ECG), (3) increased cardiac troponin I levels, and (4) patients who underwent reperfusion therapy. We evaluated the levels of apelin-12 and troponin I on the first and seventh days after reperfusion therapy in all patients. RESULTS: Apelin-12 was inversely correlated with troponin I levels (Spearman's correlation = -0.40) with a p value <0.001. There was variability in the apelin values on the seventh day (Kruskal-Wallis test) based on major adverse cardiac events (MACE) (p = 0.012). Using ROC curve analyses, a cut-off value of >2.2 for the association of apelin with MACE was determined, and the AUC was 0.71 (95% CI, 0.58-0.84). Survival analysis using the Kaplan-Meier method showed a lower rate of MACE among patients with apelin levels >2.2 (p = 0.002), and the ROC curve analysis showed a statistically significant difference in the area under the curve (p = 0.004). CONCLUSION: The influence of apelin levels on troponin levels in the acute phase of STEMI is inversely correlated, whereas in the non-acute phase, low apelin values were associated with a high rate of MACE. PMID- 28728609 TI - Multiple myeloma can be accurately diagnosed in acute kidney injury patients using a rapid serum free light chain test. AB - BACKGROUND: Acute kidney injury (AKI) is common in patients with multiple myeloma (MM). Whether serum free light chain (sFLC) measurements can distinguish between myeloma and other causes of AKI requires confirmation to guide early treatment. A rapid and portable sFLC test (Seralite(r)) is newly available and could reduce delays in obtaining sFLC results and accelerate diagnosis in patients with unexplained AKI. This study evaluated the accuracy of Seralite(r) to identify MM as the cause of AKI. METHOD: sFLCs were retrospectively analysed in patients with AKI stage 3 as per KDIGO criteria (i.e. serum creatinine >=354 MUmol/L or those on dialysis treatment) (n = 99); 45/99 patients had a confirmed MM diagnosis. RESULTS: The Seralite(r) kappa:lambda FLC ratio accurately diagnosed all MM patients in the presence of AKI: a range of 0.14-2.02 returned 100% sensitivity and specificity for identifying all non-myeloma related AKI patients. The sFLC difference (dFLC) also demonstrated high sensitivity (91%) and specificity (100%): an optimal cut-off of 399 mg/L distinguished between myeloma and non myeloma AKI patients. We propose a pathway of patient screening and stratification in unexplained AKI for use of Seralite(r) in clinical practice, with a kappa:lambda ratio range of 0.14-2.02 and dFLC 400 mg/L as decision points. CONCLUSIONS: Seralite(r) accurately differentiates between AKI due to MM and AKI due to other causes in patients considered at risk of myeloma. This rapid test can sensitively screen for MM in patients with AKI and help inform early treatment intervention. PMID- 28728610 TI - Breaking bad news in assisted reproductive technology: a proposal for guidelines. PMID- 28728611 TI - Effect of electrode position of low intensity neuromuscular electrical stimulation on the evoked force in the quadriceps femoris muscle. AB - OBJECTIVE: The present study aimed to test the effect of the electrode position and inter-electrode distance on the evoked force by neuromuscular electrical stimulation (NMES) with a low current intensity and a single pair of electrodes. Knee extensor forces during NMES to quadriceps femoris muscles were compared among four different electrode configurations in seven healthy men. Electrodes were located at 10 cm proximal and 15 cm distal (P10-D15), 10 cm proximal and 10 cm distal (P10-D10), 5 cm proximal and 15 cm distal, and 5 cm proximal and 10 cm distal (P5-D10) to the center of the longitudinal axis of the quadriceps femoris muscles. RESULTS: The evoked force-time area for P5-D10 was significantly higher than those for P10-D15 and P10-D10 (p < 0.05). When using NMES devices with a low current intensity, a shorter inter-electrode distance and relatively distal locations can promote greater evoked forces in the quadriceps femoris muscles. PMID- 28728612 TI - Injury prevention in the emergency department: An ongoing challenge Reference to: Emergency Physicians as human billboards for injury prevention: A randomized controlled trial by Emily Sullivan et al. PMID- 28728613 TI - Echocardiographic Parameters of Clinically Normal Geriatric Rhesus Macaques (Macacamulatta). AB - The goal of this study was to generate reference intervals for echocardiographic variables in a population of clinically normal geriatric rhesus macaques (Macaca mulatta). To do this, we studied 51 animals (age, 18-29 y; weight, 5.24-17.04 kg). The normal values for cardiac indices, including geometry and systolic and diastolic function, were determined by 2D, M-mode, spectral Doppler, and tissue Doppler echocardiography under ketamine hydrochloride sedation. Statistical correlations between the echocardiographic parameters and age, body weight, sex, and heart rate were investigated. All echocardiographic indices were acquired, and their reference intervals were established. Multiple weak to strong correlations emerged between variables and echocardiographic parameters, but no moderate or strong correlations between body weight or sex and these parameters were noted. Of the 51 geriatric rhesus macaques evaluated, 36 (71%) fulfilled the criteria for diastolic dysfunction. Valve regurgitation, especially tricuspid regurgitation (43%), and aortic regurgitation (51%) also were common in geriatric rhesus macaques. Although these findings merit follow-up, they are unlikely to have clinical significance given their prevalence in these apparently healthy animals. PMID- 28728614 TI - Upper Airway Stimulation for Treatment of Obstructive Sleep Apnea: An Evaluation and Comparison of Outcomes at Two Academic Centers. AB - STUDY OBJECTIVES: Data from patients at Thomas Jefferson University Hospital (TJUH) and University of Pittsburgh Medical Center (UPMC) undergoing upper airway stimulation (UAS) were analyzed. We hypothesize that treatment with UAS will improve both subjective and objective outcome measures and results will be reproducible between institutions. METHODS: We reviewed patients undergoing UAS between May 2014 and August 2016. We recorded demographic data, Epworth Sleepiness Scale (ESS), and preoperative and postoperative polysomnographic information. We compared outcome data between institutions and subsequently combined the cohorts and compared baseline to posttreatment results. RESULTS: The TJUH cohort consisted of 30 males and 18 females with a mean age of 60.88 years and body mass index of 29.29. The mean preoperative apnea-hypopnea index (AHI), O2 nadir, and ESS were 35.88, 80.96, and 11.09, respectively. The mean postoperative AHI, O2 nadir, and ESS were 6.34, 88.04, and 5.77, respectively. The UPMC cohort consisted of 30 males and 19 females with a mean age of 62.84 years and body mass index of 27.74. The mean preoperative AHI, O2 nadir, and ESS were 35.29, 79.58, and 10.94, respectively. The mean postoperative AHI, O2 nadir, and ESS were 6.28, 84.35, and 6.60, respectively. We found no difference in patients reaching a postoperative AHI less than 15, 10, and 5 when comparing the cohorts. After combining cohorts, we found a significant improvement in postoperative AHI, O2 nadir, and ESS compared to preoperative values. CONCLUSIONS: UAS appears to provide a viable alternative to continuous positive airway pressure, producing improvement in both polysomnographic and quality-of life measures. Results are reproducible at high-volume centers. PMID- 28728615 TI - Success of Tonsillectomy for Obstructive Sleep Apnea in Children With Down Syndrome. AB - STUDY OBJECTIVES: Obstructive sleep apnea (OSA) is common in children with Down syndrome (DS) and associated with significant morbidity. In the current study we examined polysomnographic outcomes of children with DS who underwent tonsillectomy. METHODS: A retrospective chart review of children with DS who underwent a tonsillectomy between 2009-2015 was performed. All children had either a concurrent adenoidectomy or had previously underwent an adenoidectomy. Children with preoperative and postoperative polysomnograms within 6 months of surgery were included in the analysis. Preoperative OSA severity was categorized by obstructive apnea-hypopnea index (OAHI) as follows: mild = 1.5-4.9 events/h; moderate = 5-9.9 events/h; severe >= 10 events/h. RESULTS: Seventy-five children with DS met inclusion criteria. The cohort included 41 males and 34 females with mean age of 5.1 years (+/- 3.6 years), range of 0.51-16.60 years. Preoperative OSA severity was as follows, mild = 8/75; moderate = 16/75; severe = 51/75. Cure rates varied depending on definition: 12% for OAHI < 1 event/h and 21% for OAHI < 2 events/h. 48% had residual OAHI < 5 events/h. On postoperative PSG 16/75 saw resolution (OAHI < 2) in OSA; mild = 21/75; moderate = 20/75; severe = 18/75. 48% moderate/severe patients saw conversion to mild or cure. Overall, tonsillectomy resulted in significant improvements in multiple respiratory parameters, including OAHI (OAHI; 21.3 +/- 19.7 to 8.0 +/- 8.1, P < .001), percent sleep time with oxygen saturations < 90% (19.0 +/- 25.0 to 6.1 +/- 10.1, P < .001), and percent sleep time with end-tidal carbon dioxide above 50 mmHg (7.7 +/- 18.0 to 1.8 +/- 6.6, P = .001). Average asleep oxygen saturation was associated with postoperative OSA severity. CONCLUSIONS: Children with DS and OSA who undergo tonsillectomy experience improvements in both respiratory event frequency and gas exchange but approximately half still have moderate to severe residual OSA. PMID- 28728616 TI - Efficacy of the Addition of a Cervical Collar in the Treatment of Persistent Obstructive Apneas Despite Continuous Positive Airway Pressure. AB - ABSTRACT: Continuous positive airway pressure (CPAP) is currently the reference treatment for obstructive sleep apnea (OSA). The use of a face mask, although sometimes necessary, is often associated with increased airway obstruction due to mandibular retrusion. We report a small group of patients in whom addition of a cervical collar to a face mask allowed correction of obstructive events. PMID- 28728617 TI - Self-Reported Sleep Quality, Duration, and Health-Related Quality of Life in Older Chinese: Evidence From a Rural Town in Suzhou, China. AB - STUDY OBJECTIVES: To determine the associations of self-reported sleep quality and duration with health-related quality of life (HRQOL) in older Chinese. METHODS: We analyzed community-based cross-sectional data of 5,539 individuals aged 60 years and older in the Weitang Geriatric Disease Study. Information of sleep quality and duration were self-reported through participants' responses to predefined questions; HRQOL data were collected by using the European Quality of Life-5 Dimensions (EQ-5D). We estimated the associations of sleep quality and duration with the EQ-5D index and visual analog scale (VAS) scores using linear regression models. The associations between sleep quality and duration and EQ-5D detected health problems were modeled using logistic regression. RESULTS: In multiple linear models adjusting sociodemographic factors, health conditions, and lifestyle habits, both EQ-5D index and VAS scores declined with deterioration of sleep quality. The coefficients for poor and intermediate sleep quality were 0.053 (95% confidence interval [CI]:-0.065, -0.042) and -0.022 (95% CI: -0.030, 0.013), respectively, in relation to EQ-5D index score. They were -5.2 (95% CI: 6.7, -2.4) and - 3.8 (95% CI: -4.9, -2.7) in modeling the EQ-5D VAS score. HRQOL declined as sleep duration decreased below 7.01 hours or exceeded 8.01 hours, though most of the associations did not reach statistical significance. In multiple logistic models, poor sleep quality was associated with problems of mobility, pain/discomfort, and anxiety/ depression; short sleep duration was associated with mobility problems. CONCLUSIONS: Poor sleep quality and extreme sleep durations appeared to be negatively associated with HRQOL in older Chinese adults. PMID- 28728618 TI - Binge Viewing, Sleep, and the Role of Pre-Sleep Arousal. AB - STUDY OBJECTIVES: To investigate the prevalence of binge viewing, its association with sleep and examine arousal as an underlying mechanism of this association. METHODS: Four hundred twenty-three adults (aged 18-25 years old, 61.9% female) completed an online survey assessing regular television viewing, binge viewing, sleep quality (Pittsburgh Sleep Quality Index), fatigue (Fatigue Assessment Scale), insomnia (Bergen Insomnia Scale), and pre-sleep arousal (Pre-Sleep Arousal Scale). Regression analyses were conducted. Mediation analysis was performed using PROCESS Macro. RESULTS: There were 80.6% who identified themselves as a binge viewer. Among those who binge viewed (n = 341), 20.2% had binge viewed at least a few times a week during the past month. Among poor sleepers (Pittsburgh Sleep Quality Index > 5), 32.6% had a poor sleep quality associated with being a binge viewer. Higher binge viewing frequency was associated with a poorer sleep quality, increased fatigue and more symptoms of insomnia, whereas regular television viewing was not. Cognitive pre-sleep arousal fully mediated these relationships. CONCLUSIONS: New viewing styles such as binge viewing are increasingly prevalent and may pose a threat to sleep. Increased cognitive arousal functions as the mechanism explaining these effects. Measures of media exposure should take into account the user's level of engagement with media. Interventions aimed at (1) alerting viewers about excessive viewing duration and (2) reducing arousal before sleep may be useful ways to tackle sleep problems in binge viewers. PMID- 28728619 TI - Restless Genital Syndrome: Differential Diagnosis and Treatment With Pramipexole. AB - ABSTRACT: Restless genital syndrome refers to excessive and persistent sensations of genital and clitoral arousal with the absence of conscious feeling of sexual desire. These sensations have been linked to symptoms of restless legs syndrome (RLS) or an overactive bladder. Restless genital syndrome may be related to small fiber sensory neuropathy of the dorsal nerve of the clitoris, so it more frequently occurs in women. The association with RLS suggests a possible dopaminergic mechanism. We report a case of a 74-year-old woman who presented restless genital symptoms every night in association with RLS symptoms. During polysomnography she reported 3 awakenings from rapid eye movement sleep with associated genital symptoms followed by a period of insomnia with RLS symptoms and sexual activity. The frequency and the intensity of the symptoms were responsive to treatment by pramipexole after 1 week of treatment and the efficacy was maintained at follow-up. PMID- 28728620 TI - Insulin Resistance and Hypertension in Obese Youth With Sleep-Disordered Breathing Treated With Positive Airway Pressure: A Prospective Multicenter Study. AB - STUDY OBJECTIVES: There is evidence that cardiometabolic disease associated with obesity and sleep-disordered breathing (SDB) in adults is present in youth. SDB is often treated with positive airway pressure (PAP) in youth with obesity. Our aims were to determine: (1) the prevalence of cardiometabolic disease and (2) whether PAP improves markers of cardiometabolic disease, in youth with obesity and newly diagnosed moderate-severe SDB. METHODS: A prospective multicenter cohort study was conducted in youth (8 to 16 years old) with obesity, prescribed PAP therapy for newly diagnosed moderate-severe SDB. Assessments occurred at baseline and at 6 and 12 months. Outcomes included markers of insulin resistance (change in homeostasis model assessment of insulin resistance (HOMA-IR) at 6 months = primary outcome), hypertension (24-hour ambulatory/blood pressure) and inflammation (high-sensitivity C-reactive protein: hs-CRP). RESULTS: Twenty-seven participants were enrolled. Of those with baseline testing available, 10/25 (40%) had HOMA-IR above the 97th percentile, 10/23 (44%) were hypertensive, 16/23 (70%) had loss of nocturnal blood pressure dip and hs-CRP was elevated in 16/27 (64%). There were no significant changes over time in markers of metabolic dysfunction or blood pressure, nor between PAP-adherent and non-adherent subgroups. CONCLUSIONS: In youth with obesity and SDB, metabolic dysfunction and hypertension were highly prevalent. There were no statistically significant improvements in cardiometabolic markers 1 year after the prescription of PAP therapy, although clinically relevant improvements were seen in insulin resistance and systolic blood pressure load, important predictors of future risk of cardiovascular disease. Larger, longer-term studies are needed to determine whether PAP improves cardiometabolic outcomes in obese youth. COMMENTARY: A commentary on this article appears in this issue on page 1025. PMID- 28728621 TI - High-Flow, Heated, Humidified Air Via Nasal Cannula Treats CPAP-Intolerant Children With Obstructive Sleep Apnea. AB - STUDY OBJECTIVES: Continuous positive airway pressure (CPAP) is effective but challenging for children with obstructive sleep apnea (OSA). High-flow air via open nasal cannula (HFNC) as treatment in children remains controversial. We report the efficacy of HFNC in children with OSA and CPAP intolerance, a titration protocol, and a discussion of potential mechanisms. METHODS: Patients aged 1 to 18 years with OSA (defined by obstructive apnea-hypopnea index [OAHI] greater than 1 event/h) and CPAP intolerance were enrolled. Routine polysomnography data obtained during 1 night wearing HFNC was compared with diagnostic data by Wilcoxon rank-sum test. RESULTS: Ten school-age subjects (representing all patients attempting HFNC at our institution to date) with varied medical conditions, moderate to severe OSA, and CPAP intolerance wore HFNC from 10 to 50 L/min of room air with oxygen supplementation if needed (room air alone for 6 of the 10). HFNC reduced median OAHI from 11.1 events/h (interquartile range 8.7-18.8 events/h) to 2.1 events/h (1.7-2.2 events/h; P = .002); increased oxyhemoglobin saturation (SpO2) mean from 91.3% (89.6% to 93.5%) to 94.9% (92.4% to 96.0%; P < .002); increased SpO2 nadir from 76.0% (67.3% to 82.3%) to 79.5% (77.2% to 86.0%; P = .032); decreased SpO2 desaturation index from 19.2 events/h (12.7-25.8 events/h) to 6.4 events/h (4.7-10.7 events/h; P = .013); and reduced heart rate from 88 bpm (86-91 bpm) to 74 bpm (67-81 bpm; P = .004). Stratified analysis of the 6 subjects with only room air via HFNC, the OAHI, obstructive hypopnea index, and mean SpO2 still demonstrated improvements (P = .031). CONCLUSIONS: High-flow nasal cannula reduces respiratory events, improves oxygenation, reduces heart rate, and may be effective for CPAP intolerant children with moderate to severe OSA. Our data suggest HFNC warrants further study and consideration by payers as OSA therapy. PMID- 28728622 TI - Psychomotor Vigilance Test and Its Association With Daytime Sleepiness and Inflammation in Sleep Apnea: Clinical Implications. AB - STUDY OBJECTIVES: Excessive daytime sleepiness (EDS) is a key symptom of obstructive sleep apnea (OSA). The Psychomotor Vigilance Task (PVT) has been suggested as an objective easy-to-use, inexpensive alternative to the Multiple Sleep Latency Test (MSLT) to measure EDS. In patients with OSA, physiological sleepiness, but not subjective EDS (Epworth Sleepiness Scale [ESS]), has been associated with increased levels of the sleep- inducing proinflammatory cytokine interleukin-6 (IL-6). The goal of this study was to assess the association of PVT with objectively measured sleepiness (MSLT) and subjectively measured sleepiness (ESS) and IL-6 levels in patients with OSA. METHODS: We studied 58 untreated patients with OSA who underwent an 8-hour in-laboratory polysomnography for 4 consecutive nights. MSLT, PVT, and 24-hour serial profiles of IL-6 were assessed on the fourth day. PVT variables included number of lapses, mean reciprocal of the fastest 10% and slowest 10% reaction times, and median of 1/reaction time. ESS was assessed on day 1 of the study. RESULTS: Higher ESS scores were significantly associated with greater number of lapses (beta = .34, P = .02) and lower values of 1/RT (beta = -.36, P = .01) and slowest 10% RTs (beta = -.30, P = .04). No significant association was observed between PVT and MSLT, nor PVT and IL-6 levels. CONCLUSIONS: Our findings suggest that PVT is associated with subjectively assessed daytime sleepiness, but not with physiological sleepiness nor IL-6 levels in patients with OSA. It appears that ESS and PVT may be useful in predicting risks associated with impaired performance, such as traffic accidents, in patients with OSA. PMID- 28728623 TI - Veterans Affairs Primary Care Provider Perceptions of Insomnia Treatment. AB - STUDY OBJECTIVES: Insomnia is a widespread issue among United States adults and rates of insomnia among veterans are even higher than the general population. Prior research examining primary care provider (PCP) perspectives on insomnia treatment found that: sleep hygiene and pharmacotherapy are the primary treatments offered; PCPs tend to focus on perceived causes of insomnia rather than the insomnia itself; and neither patients nor providers are satisfied with insomnia treatment options. Although insomnia complaints are typically first reported to primary care providers, little research has focused on perspectives regarding insomnia treatment among PCPs working in the largest integrated health care system in the United States-the Veterans Affairs (VA) health care system. This study was conducted to examine VA PCP perceptions of the availability of insomnia treatments, identify specific strategies offered by PCPs, and examine perceptions regarding the importance of treating insomnia and the role of comorbid conditions. METHODS: A survey was conducted within the VA health care system. Primary care providers completed surveys electronically. RESULTS: A high percentage of veterans (modal response = 20% to 39%) seen in VA primary care settings report an insomnia complaint to their provider. Almost half of respondents do not consistently document insomnia in the medical record (46% endorsed "sometimes," "rarely," or "never"). PCPs routinely advise sleep hygiene recommendations for insomnia (ie, avoid stimulants before bedtime [84.3%], and keep the bedroom environment quiet and dark and comfortable [68.6%]) and many are uncertain if cognitive behavioral therapy for insomnia is available at their facility (43.1%). CONCLUSIONS: Findings point to the need for systems-level changes within health care systems, including the adoption of evidence-based clinical practice standards for insomnia and PCP education about the processes that maintain insomnia. COMMENTARY: A commentary on this article appears in this issue on page 937. PMID- 28728624 TI - The National Healthy Sleep Awareness Project Sleep Health Surveillance Questionnaire as an Obstructive Sleep Apnea Surveillance Tool. AB - STUDY OBJECTIVES: To validate the previously published National Healthy Sleep Awareness Project (NHSAP) Surveillance and Epidemiology Workgroup questionnaire for ability to determine risk for moderate to severe obstructive sleep apnea (OSA). METHODS: The NHSAP sleep questions, part of the next Behavioral Risk Factor Surveillance System (BRFSS), were constructed to mimic elements of the STOP sleep apnea questionnaire, and included number of days with sleep disruption and unintentional dozing and a history of snoring and apneas. The responses to four sleep questions from the BRFSS were collected from 352 adults undergoing in laboratory polysomnography at Mayo Clinic, Rochester, Minnesota. Demographic and clinical information, including sex, age, body mass index (BMI), and presence of hypertension, which will be available in other parts of the complete BRFSS, were obtained by chart review. Univariate and logistic regression analyses were performed, and values of P < .05 were considered to be statistically significant. RESULTS: Fifty-five percent of subjects were men and 45% were women with a median age of 58 years and BMI 32.2 kg/m2. Sixty percent had no or mild OSA, and 40% had moderate to severe OSA. No single question was superior in screening for moderate to severe OSA, although a history of snoring and witnessed apneas was more likely to predict moderate to severe OSA. Male sex, age >= 50 years, BMI >= 30 kg/m2, presence of hypertension, and a history of snoring and witnessed apneas were the most highly weighted factors in predicting moderate to severe OSA. When each variable was dichotomized to a single point, a cutoff of 5 points significantly predicted a high risk of moderate to severe OSA with an odds ratio of 3.87 (2.39 6.27). CONCLUSIONS: Although many variables were positively associated with the apnea-hypopnea index, no single factor was superior in predicting moderate to severe OSA. Male sex, increased age, higher BMI, hypertension, and a history of snoring and witnessed apneas are the most highly predictive of moderate to severe OSA. Combined use of the NHSAP questionnaire and demographic and clinical characteristics could be considered for screening for moderate to severe OSA. PMID- 28728625 TI - Parental Fitness Questioned on the Grounds of Narcolepsy: Presentation of Two Cases. AB - ABSTRACT: We report two cases of fathers whose parental fitness was questioned during divorce and custody litigation because of narcolepsy type 2 and type 1, respectively. These cases highlighted both the existence of a narcolepsy-related stigma and the need to involve sleep experts in custody assessments when concerns about the parental fitness are related to a sleep disorder, expanding the field of interest of the growing "sleep forensics." PMID- 28728626 TI - Insomnia in Primary Care: Misreported, Mishandled, and Just Plain Missed. PMID- 28728628 TI - Editor's Corner: A Call to Action: Consideration of Sex and Gender Equity in Research Published in the Journal of Studies on Alcohol and Drugs. PMID- 28728627 TI - Sharing knowledge of falls prevention for people with dementia: insights for community care practice. AB - People living with dementia (PLWD) fall more frequently, with more adverse consequences, than general community-dwelling older people; however, falls prevention evidence for PLWD is limited. Increased success of falls prevention strategies for PLWD may rely on tailored interventions to address dementia specific risk factors. The Australian person-centred care environment highlights the need to better understand sharing of falls prevention knowledge between clients, carers and health professionals. This study aims to examine knowledge of falls prevention for PLWD among community care health professionals (CCHPs) and explore effectiveness of an action-research approach to enhance falls prevention practice. Consecutive action-research sessions were conducted with four groups of Australian multidisciplinary CCHPs (n=18), including a knowledge survey of CCHPs, followed by implementation of action plans. Thematic analysis of the transcribed discussion was undertaken. Results showed limited knowledge and understanding of evidence-based falls prevention strategies, but small incremental changes made by CCHPs through action research offered insights into enhancing knowledge and awareness. Appropriate professional development for community care health professionals is needed to support falls prevention for PLWD, along with associated organisational changes, to ensure knowledge is adequate. PMID- 28728629 TI - Editor's Corner: Binge Drinking and the Evolving Language of Alcohol Research. PMID- 28728630 TI - Duterte's War on Drugs and the Silence of the Addiction Science Community. PMID- 28728631 TI - Genes, Environments, and Sex Differences in Alcohol Research. AB - OBJECTIVE: The study of sex differences has been identified as one way to enhance scientific reproducibility, and the National Institutes of Health (NIH) have implemented a new policy to encourage the explicit examination of sex differences. Our goal here is to address sex differences in behavioral genetic research on alcohol outcomes. METHOD: We review sex differences for alcohol outcomes and whether the source and magnitude of genetic influences on alcohol consumption and alcohol use disorder (AUD) are the same across sexes; describe common research designs for studying sex-specific gene-by-environment interaction (G * E) effects; and discuss the role of statistical power and theory when testing sex-specific genetic effects. RESULTS: There are robust sex differences for many alcohol outcomes. The weight of evidence suggests that the source and magnitude of genetic influences on alcohol consumption and AUD are the same across sexes. Whether there are sex-specific G * E effects has received less attention to date. CONCLUSIONS: The new NIH policy necessitates a systematic approach for studying sex-specific genetic effects in alcohol research. Researchers are encouraged to report power for tests of these effects and to use theory to develop testable hypotheses, especially for studies of G * E. PMID- 28728632 TI - Binge Drinking Episodes in Young Adults: How Should We Measure Them in a Research Setting? AB - OBJECTIVE: Worldwide, consequences of binge drinking are a major health and policy concern. This article reviews contemporary binge drinking definitions as well as different questionnaires and biomarkers that have been used in research settings to examine binge drinking behavior among young adults. METHOD: A review of electronic databases was conducted for binge drinking definitions, questionnaires, and biomarkers for the measurement of binge drinking in young adults (18-30 years). RESULTS: Binge drinking is often defined as four or more drinks for females and five or more drinks for males on an occasion or in one sitting within a designated time frame (2 weeks vs. past 30 days). Several tools and questionnaires are available to identify young adult repeated binge drinkers. Biomarkers have been used to corroborate self-reported alcohol consumption, of which direct biomarkers such as phosphatidylethanol may be useful in confirming recent heavy drinking. CONCLUSIONS: It is important to measure binge drinking along a continuum and to use questions that allow for assessment of intensity, frequency, duration, and daily versus weekend consumption patterns. Open-ended questions that allow for intensity (number of drinks) and frequency can be used to determine dose-response relationships with respect to specific outcome measures. Direct alcohol biomarkers reflecting alcohol consumption over a period of several days are useful in conjunction with questionnaire data for identifying young adult binge drinkers. PMID- 28728633 TI - Drinking Status Between Ages 50 and 55 for Men From the San Diego Prospective Study Who Developed DSM-IV Alcohol Abuse or Dependence in Prior Follow-Ups. AB - OBJECTIVE: Although alcohol use disorders (AUDs) are prevalent among older individuals, few studies have examined the course and predictors of AUDs from their onset into the person's 50s. This study describes the AUD course from ages 50 to 55 in participants who developed AUDs according to criteria from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), during the San Diego Prospective Study (SDPS). METHOD: Among the 397 university students in the SDPS who were followed about every 5 years from age 20 (before AUD onset), 165 developed AUDs, 156 of whom were interviewed at age 55. Age 50-55 outcomes were compared regarding age 20-50 characteristics. Variables that differed significantly across outcome groups were evaluated using binary logistic regression analyses predicting each outcome type. RESULTS: Between ages 50 and 55, 16% had low-risk drinking, 36% had high-risk drinking, 38% met DSM-5 AUD criteria, and 10% were abstinent. Baseline predictors of outcome at ages 50-55 included earlier low levels of response to alcohol predicting DSM-5 AUDs and abstinence, higher drinking frequency predicting DSM-5 diagnoses and lower predicting low-risk drinking, higher participation in treatment and/or self-help groups predicting abstinence and lower predicting DSM-5 AUDs, later ages of AUD onset predicting high-risk drinking, and cannabis use disorders predicting abstinent outcomes. CONCLUSIONS: Despite the high functioning of these men, few were abstinent or maintained low-risk drinking during the recent 5 years, and 38% met DSM-5 AUD criteria. The data may be helpful to both clinicians and researchers predicting the future course of AUDs in their older patients and research participants. PMID- 28728634 TI - Prospective Effects of Parenting on Substance Use and Problems Across Asian/Pacific Islander and European American Youth: Tests of Moderated Mediation. AB - OBJECTIVE: Parental warmth and knowledge are protective factors against substance use, whereas parental psychological control is a risk factor. However, the interpretation of parenting and its effects on developmental outcomes may vary cross-culturally. This study examined direct and indirect effects of three parenting dimensions on substance use across Asian/Pacific Islander (API) and European Americans. METHOD: A community sample of 97 API and 255 European Americans were followed from Grades 6 to 12. Participants reported on parenting in Grade 7, academic achievement and externalizing behaviors in Grades 7 and 8, and substance use behaviors in Grades 7, 9, and 12. RESULTS: Direct effects of parenting were not moderated by race. Overall, mother psychological control was a risk factor for substance use problems in Grade 9, whereas father knowledge was protective against alcohol use in Grade 9, substance use problems in Grades 9 and 12, and alcohol dependence in Grade 12. Moderated mediation analyses indicated significant mediational links among European Americans only: Mother knowledge predicted fewer externalizing problems in Grade 8, which in turn predicted fewer substance use problems in Grades 9 and 12. Father warmth predicted better academic achievement in Grade 8, which in turn predicted fewer substance use problems in Grades 9 and 12, as well as alcohol and marijuana dependence in Grade 12. CONCLUSIONS: Better academic achievement and fewer externalizing behaviors explain how positive parenting reduces substance use risk among European Americans. Promoting father knowledge of adolescents' whereabouts can reduce substance use risk among both European and API Americans. PMID- 28728636 TI - Magnitude and Trends in Heavy Episodic Drinking, Alcohol-Impaired Driving, and Alcohol-Related Mortality and Overdose Hospitalizations Among Emerging Adults of College Ages 18-24 in the United States, 1998-2014. AB - OBJECTIVE: This article estimates percentages of U.S. emerging adults ages 18-24 engaging in past-month heavy episodic drinking and past-year alcohol-impaired driving, and numbers experiencing alcohol-related unintentional injury deaths and overdose hospitalizations between 1998 and 2014. METHOD: We analyzed national injury mortality data from coroner, census, and college enrollment statistics, the National Survey on Drug Use and Health, and the Nationwide Inpatient Sample. RESULTS: From 1999 to 2005, percentages of emerging adults ages 18-24 reporting past-month heavy episodic drinking rose from 37.1% to 43.1% and then declined to 38.8% in 2014. Alcohol-impaired driving rose from 24% to 25.5% and then declined to 16.0%. Alcohol-related unintentional injury deaths increased from 4,807 in 1998 to 5,531 in 2005 and then declined to 4,105 in 2014, a reduction of 29% per 100,000 since 1998. Alcohol-related traffic deaths increased from 3,783 in 1998 to 4,114 in 2005 and then declined to 2,614 in 2014, down 43% per 100,000 since 1998. Alcohol-related overdose deaths increased from 207 in 1998 to 891 in 2014, a 254% increase per 100,000. Other types of nontraffic unintentional injury deaths declined. Alcohol-overdose hospitalizations rose 26% per 100,000 from 1998 to 2014, especially from increases in alcohol/other drug overdoses, up 61% (alcohol/opioid overdoses up 197%). CONCLUSIONS: Among emerging adults, a trend toward increased alcohol-related unintentional injury deaths, heavy episodic drinking, and alcohol-impaired driving between 1998 and 2005 was reversed by 2014. Persistent high levels of heavy episodic drinking and related problems among emerging adults underscore a need to expand individually oriented interventions, college/community collaborative programs, and evidence-supported policies to reduce their drinking and related problems. PMID- 28728635 TI - Gene-by-Environment Interactions on Alcohol Use Among Asian American College Freshmen. AB - OBJECTIVE: Among northeast Asians, the variant aldehyde dehydrogenase allele, ALDH2*2 (rs671, A/G, minor/major), has been inversely associated with alcohol dependence. The strength of the associations between ALDH2*2 and drinking behaviors depends on the developmental stage, the phenotype studied, and other moderating variables. This study examined ALDH2 gene status as a moderator of the associations between parental drinking, peer drinking, and acculturation with alcohol use among 222 Chinese American and Korean American college freshmen. METHOD: Negative binomial regressions were used to test the main and interactive effects of ALDH2 with contextual factors on alcohol frequency (drinking days) and quantity (drinks per drinking day) in the past 3 months. RESULTS: ALDH2*2 was associated with more subjective flushing symptoms and longer length of flushing but was unrelated to both alcohol frequency and quantity. Peer drinking was positively associated with both alcohol frequency and quantity, but neither was moderated by ALDH2. We observed a nonsignificant trend for the interaction between parental drinking and ALDH2 on alcohol frequency, where parental drinking was positively associated with alcohol frequency only among participants with ALDH2*2. We found a significant interaction between acculturation and ALDH2 on alcohol frequency, where acculturation was positively associated with alcohol frequency only among those with ALDH2*2. Exploratory analyses stratified by Asian ethnic subgroup indicated that this interaction was driven primarily by the Korean subsample. CONCLUSIONS: Parental drinking and acculturation may facilitate more frequent drinking among those who have more intense reactions to alcohol (i.e., those with ALDH2*2) during the transition from high school to college. PMID- 28728637 TI - Drinking Location and Drinking Culture and Their Association With Alcohol Use Among Girls and Boys in Europe. AB - OBJECTIVE: This study aimed to (a) investigate the relationship between drinking location and adolescent alcohol use, (b) analyze the association of drinking culture indicators with alcohol use, and (c) explore interaction effects of drinking location and drinking culture indicators. METHOD: Analyses were based on the 2011 European School Survey Project on Alcohol and Other Drugs (ESPAD). The analytical sample consisted of 15- to 16-year-old students (N = 36,366; 51.6% female) from 11 countries. Alcohol volume and perceived drunkenness were used as outcomes. Drinking location was used as predictor variable. Per capita consumption and restrictions on public drinking were used as country-level predictors. Sex-stratified generalized linear models with cluster robust standard errors were applied. RESULTS: Compared with drinking outdoors, the reported alcohol volume was lower when drinking at home and higher when drinking in multiple locations or at someone else's home. Drunkenness was highest among boys drinking at someone else's home and, compared with drinking outdoors, lower among girls drinking on premise. Per capita consumption was positively associated with alcohol volume. Among girls, the association between per capita consumption and both outcomes was stronger when drinking in multiple locations than when drinking outdoors. A ban on public drinking showed a negative effect on drinking volume and drunkenness among girls. CONCLUSIONS: The role of different drinking locations in alcohol use as well as sex differences should be considered in prevention and intervention of adolescent heavy drinking. Setting-specific prevention and intervention measures are of greater importance in medium- or high consumption societies. PMID- 28728638 TI - Age-Related Changes in Associations Between Reasons for Alcohol Use and High Intensity Drinking Across Young Adulthood. AB - OBJECTIVE: Analyses focus on whether self-reported reasons for drinking alcohol change in their associations with high-intensity drinking across the transition to adulthood. METHOD: Self-report data on high-intensity drinking (10+ drinks) collected from the national Monitoring the Future study in 2005 to 2014 from those ages 18-26 were used (N = 2,664 [60% women] for all drinkers and 1,377 for heavy episodic [5+] drinkers; up to 6,541 person-waves). Time-varying effect modeling examined changes in the direction and magnitude of associations between eight reasons for drinking and high-intensity alcohol use across continuous age. RESULTS: Four reasons to drink showed quite stable associations with high intensity drinking across age: drinking to get away from problems, to get high, to relax, and to sleep. Associations between two reasons and high-intensity drinking decreased with age: anger/frustration and to have a good time. The association between drinking because of boredom and high-intensity drinking increased with age. Drinking because it tastes good had a weak association with high-intensity drinking. Among heavy episodic drinkers, reasons for use also differentiated high-intensity drinking, with two exceptions: drinking to have a good time and to relax did not distinguish drinking 10+ drinks from drinking 5-9 drinks. CONCLUSIONS: Reasons for drinking are differentially associated with high intensity drinking, compared with any other drinking and compared with lower intensity heavy drinking, across age during the transition to adulthood. Intervention programs seeking to mitigate alcohol-related harms should focus on reasons for use when they are the most developmentally salient. PMID- 28728639 TI - Efficacy of the College Drinkers Check-Up for Student Drinkers Living Off Campus. AB - OBJECTIVE: Students living in off-campus housing consume more alcohol and experience more alcohol-related consequences than those living on campus, yet prevention efforts have not targeted this high-risk group specifically. The present study evaluated the efficacy of a brief, computer-delivered, alcohol intervention (the College Drinkers Check-Up [CDCU]) in reducing alcohol use and related consequences in a sample of college students living off campus. METHOD: Students who lived off campus and reported at least one heavy drinking episode (4+/5+ drinks for females/males in one occasion) in the past 30 days completed the CDCU or assessment only during the first month of the school year (n = 326; 61% female). Participants in both conditions completed follow-up assessments at 1, 3, and 6 months. We hypothesized that participants who completed the CDCU would report fewer drinks per week and heavy drinking episodes, lower peak drinking quantities, and fewer alcohol-related consequences than those in the control group. RESULTS: Hierarchical linear modeling was used to examine changes in drinking outcomes across groups from baseline to 1-, 3-, and 6-month follow ups. Significant effects of time indicated less drinking and fewer consequences at each follow-up relative to baseline. Compared with those in the control group, participants who received the CDCU reported significantly fewer heavy drinking episodes at 1 month, lower peak drinking quantities at 3 months, and fewer alcohol-related consequences at 1 and 3 months. Neither sex nor baseline drinking severity moderated intervention effects. CONCLUSIONS: The brief, online CDCU reduces heavy drinking and alcohol consequences in the short term among atrisk college students living off campus. PMID- 28728640 TI - Hangover Symptoms, Heavy Episodic Drinking, and Depression in Young Adults: A Cross-Lagged Analysis. AB - OBJECTIVE: The objective of this study was to examine associations between symptoms of alcohol hangover and depression, both cross-sectionally and prospectively. METHOD: Data were from a survey of young adults (N = 986, 60% female) initially recruited as part of an observational study of youth smoking. Participants reported past-year hangover symptoms, past-year frequency of heavy episodic drinking (HED), and past-week depression symptoms on two occasions separated by 1 year. Path analysis was used to evaluate prospective, directional associations linking symptoms of depression and hangover after taking into account their stabilities and cross-sectional associations. Individual differences in HED frequency were accounted for to permit interpretation of residual hangover score variance in terms of susceptibility to hangover effects. RESULTS: Past-week depression and past-year hangover symptoms were associated at Time 1. Path analysis indicated that Time 1 depression symptoms were associated with elevated hangover symptoms a year later at Time 2. In contrast, Time 1 hangover symptoms did not predict future depression. CONCLUSIONS: Depression symptoms are associated with current and future hangover susceptibility. Hangover and depression overlap symptomatically and are empirically associated with one another, suggesting the possibility that common underlying causal mechanisms may contribute to both phenomena. PMID- 28728641 TI - Association Between Process-Based Quality Indicators and Mortality for Patients With Substance Use Disorders. AB - OBJECTIVE: Substance use disorders (SUDs) are associated with elevated rates of mortality. Little is known about whether receiving appropriate care is associated with lower mortality for patients with SUDs. This study examined the association between the receipt of care for SUDs and subsequent 12- and 24-month mortality. METHOD: This was a retrospective cohort study of veterans who received care for SUDs paid for by the Veterans Health Administration during October 2006- September 2007 (n = 339,966). Logistic regressions were used to examine the association between quality indicators measuring receipt of care and mortality while controlling for patient characteristics and facility service area. RESULTS: There were four quality indicators: SUD treatment initiation, SUD treatment engagement, SUD-related psychosocial treatment, and SUD-related psychotherapy. Outcomes measured were mortality 12 and 24 months after the end of the observation period, through September 2009. Receipt of indicated care ranged from 26.5% to 58.6%, and 12- and 24-month mortality rates were 3% and 6%, respectively. Adjusted odds ratios [95% CI] of 12-month mortality by indicator were: initiation, 0.86 [0.79, 0.93]; engagement, 0.65 [0.58, 0.74]; psychosocial treatment, 0.88 [0.84, 0.92]; and psychotherapy, 0.84 [0.79, 0.89]. For the 24 month mortality outcome, adjusted odds ratios were: initiation, 0.88 [0.84, 0.93]; engagement, 0.78 [0.71, 0.85]; psychosocial treatment, 0.91 [0.88, 0.94]; and psychotherapy, 0.87 [0.83, 0.91]. Results were similar when controlling for facility service area. CONCLUSIONS: Receiving appropriate care is associated with lower mortality for patients with SUDs. Significant overall and within-facility service area associations of quality indicators and mortality support their use in encouraging providers to deliver the indicated care. These indicators should be prioritized above others lacking comparably strong process-outcome associations. PMID- 28728643 TI - Sharing of Alcohol-Related Content on Social Networking Sites: Frequency, Content, and Correlates. AB - OBJECTIVE: The present study aimed to explore students' reports of their sharing of alcohol-related content on different social networking sites (i.e., frequency of sharing and connotations of alcohol-related posts), and to identify indicators of such posting. METHOD: Students at the four largest institutions for higher education in Bergen, Norway, were invited to participate in an Internet-based survey. The sample size was 11,236 (a 39.4% response rate). The survey included questions about disclosure of alcohol-related content on social networking sites, alcohol use (using the Alcohol Use Disorders Identification Test), personality factors (using the Mini-IPIP), and demographic characteristics. Binary logistic regressions were used to analyze indicators of frequent sharing of alcohol related content depicting positive and negative aspects of alcohol use. RESULTS: A majority of the students had posted alcohol-related content (71.0%), although few reported having done so frequently. Positive aspects of alcohol use (e.g., enjoyment or social community) were most frequently shared. Young, single, and extroverted students with high alcohol consumption were more likely to report frequent sharing of alcohol-related content. Positive attitudes toward posting alcohol-related content and reports of exposure to such content particularly increased the likelihood of one's own posting of alcohol-related content. CONCLUSIONS: Positive aspects of alcohol use seem to be emphasized on social networking sites. Sharing of alcohol-related content is associated with heightened alcohol use, which implies that such sites can be relevant for prevention agents. Social influence from social networking sites, such as exposure to others' alcohol-related content, is associated with one's own sharing of similar content. PMID- 28728642 TI - A Latent Profile Analysis of Aggression and Victimization Across Relationship Types Among Veterans Who Use Substances. AB - OBJECTIVE: This study examined patterns of violence victimization and aggression in both intimate partner and nonpartner relationships among U.S. military veterans using latent profile analysis to identify subtypes of violence involvement. METHOD: Participants were 839 substance use treatment-seeking veterans (93% male) from a large Veterans Affairs Medical Center who completed screening measures for a randomized controlled trial. RESULTS: Past-year violence involvement, including both intimate partner violence (IPV) and nonpartner violence (NPV), was common in the sample, although NPV occurred at somewhat higher rates. When we included either IPV or NPV aggression or victimization, more than 40% reported involvement with physical violence, 30% with violence involving injury, and 86% with psychological aggression. Latent profile analysis including both aggression and victimization in partner and nonpartner relationships indicated a four-profile solution: no/low violence (NLV; n = 377), predominantly IPV (n = 219), predominantly NPV (n = 134), and high general violence (HGV; n = 109). Multinomial logistic regression analyses revealed that, compared with the NLV group, the remaining three groups differed in age, cocaine use, posttraumatic stress disorder (PTSD) symptoms, and legal involvement. Legal issues appeared to differentiate the profiles most, with the predominantly NPV and HGV profiles reporting more instances of driving under the influence and the HGV profile reporting legal problems related to aggression. CONCLUSIONS: IPV and NPV are fairly common among veterans seeking substance use treatment. The clinical characteristics of violence profiles indicate that cocaine use, PTSD symptoms, and legal involvement are treatment needs that vary with violence profile and may be useful for clinical decision making. PMID- 28728644 TI - Differential Associations of UPPS-P Impulsivity Traits With Alcohol Problems. AB - OBJECTIVE: The UPPS-P model posits that impulsivity comprises five factors: positive urgency, negative urgency, lack of planning, lack of perseverance, and sensation seeking. Negative and positive urgency are the traits most consistently associated with alcohol problems. However, previous work has examined alcohol problems either individually or in the aggregate, rather than examining multiple problem domains simultaneously. Recent work has also questioned the utility of distinguishing between positive and negative urgency, as this distinction did not meaningfully differ in predicting domains of psychopathology. The aims of this study were to address these issues by (a) testing unique associations of UPPS-P with specific domains of alcohol problems and (b) determining the utility of distinguishing between positive and negative urgency as risk factors for specific alcohol problems. METHOD: Associations between UPPS-P traits and alcohol problem domains were examined in two cross-sectional data sets using negative binomial regression models. RESULTS: In both samples, negative urgency was associated with social/interpersonal, self-perception, risky behaviors, and blackout drinking problems. Positive urgency was associated with academic/occupational and physiological dependence problems. Both urgency traits were associated with impaired control and self-care problems. Associations for other UPPS-P traits did not replicate across samples. CONCLUSIONS: Results indicate that negative and positive urgency have differential associations with alcohol problem domains. Results also suggest a distinction between the type of alcohol problems associated with these traits-negative urgency was associated with problems experienced during a drinking episode, whereas positive urgency was associated with alcohol problems that result from longer-term drinking trends. PMID- 28728647 TI - Alcohol Industry and Public Health: Friends or Foes? PMID- 28728645 TI - Elevated Behavioral Economic Demand for Alcohol in a Community Sample of Heavy Drinking Smokers. AB - OBJECTIVE: Cigarette smokers are more likely to consume alcohol at higher levels and experience poorer response to treatment for alcohol problems than are nonsmokers. One previous study in university students suggests that a potential reason for the high overlap between alcohol and tobacco use is that concurrent smoking is associated with overvaluation of alcohol, as reflected in elevated behavioral economic demand. The present study sought to extend these initial findings in a community sample with heavier levels of alcohol and tobacco use. METHOD: Participants were 111 non-treatment-seeking heavy drinkers(defined as 18+/14+ drinks per week for men/women) from a larger study on alcohol pharmacotherapy mechanisms. Forty-nine participants (44%) reported regular smoking (>=5 cigarettes/day). Participants completed a hypothetical alcohol purchase task assessing alcohol consumption at escalating levels of price. Covariates included demographics, drinking quantity, alcohol use disorder severity, depression, and delay discounting. RESULTS: In covariate-adjusted models, smokers reported significantly higher maximum alcohol expenditures (Omax) and breakpoint price (first price suppressing consumption to zero) compared with nonsmokers. Elevated alcohol demand correlated with drinking quantity and severity in the entire sample, but not with smoking frequency or nicotine dependence among smokers only. CONCLUSIONS: This study offers further evidence of increased reinforcing value of alcohol among smokers in a sample of heavy drinkers from the community. Clinical implications and potential mechanisms underlying this relationship are discussed. PMID- 28728646 TI - Efficacy of Naltrexone for the Treatment of Alcohol Dependence in Latino Populations. AB - OBJECTIVE: Naltrexone has been identified as a promising psychopharmacological treatment for alcohol dependence. Previous studies have suggested that its efficacy may vary based on ethnic background. The current study examined the efficacy of naltrexone in the treatment of alcohol dependence in Latino adults, a previously unexplored population. METHOD: This was a secondary analysis of the Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence (COMBINE) Study. The overall COMBINE sample consisted of 1,383 adult participants who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria for alcohol dependence, including 155 Latinos, who are the focus of this report. Consistent with the main trial, primary drinking outcomes, including percentage of days abstinent (PDA) and time to first heavy drinking day (TTHD), were examined. In addition, we examined the effects of naltrexone on a clinically relevant secondary outcome measure, global clinical outcome of alcohol consumption and alcohol-related problems. RESULTS: As seen with the subsample of African Americans from the COMBINE Study, results of the present analysis indicated that there were no significant effects of naltrexone on PDA and TTHD despite these significant effects in the original study. However, contrary to findings in the African American subsample, for Latino participants naltrexone was a significant predictor of a good global clinical outcome (i.e., abstinence or moderate drinking without problems). CONCLUSIONS: Naltrexone was not significantly associated with improvements in the primary drinking outcomes of PDA or TTHD at the end of treatment or at follow-up. However, Latinos appeared to benefit from naltrexone as demonstrated by improved ratings of global clinical outcome. These results indicate mixed findings for the efficacy of naltrexone among Latinos in the COMBINE Study. PMID- 28728648 TI - Moderate Alcohol Consumption and Cardioprotection: A Biochemist's View. PMID- 28728649 TI - Foreword. PMID- 28728651 TI - Percutaneous Treatment of Extremely Small Coronary Vessels: Does Size Matter in Terms of Performance? PMID- 28728650 TI - First Report of the Resolute Onyx 2.0-mm Zotarolimus-Eluting Stent for the Treatment of Coronary Lesions With Very Small Reference Vessel Diameter. AB - OBJECTIVES: The aim of this study was to explore the safety and efficacy of a dedicated drug-eluting stent for the treatment of coronary lesions with very small reference vessel diameter (RVD). BACKGROUND: Smaller RVD is associated with increased risk for restenosis and target lesion failure (TLF) after stent implantation. METHODS: This was a prospective, single-arm, multicenter trial of the Resolute Onyx 2.0-mm zotarolimus-eluting stent. The primary endpoint was 12 month TLF, which was compared with a pre-specified performance goal. Subjects with stable or unstable angina or ischemia, target lesions <=27 mm in length, and RVD >=2.0 and <2.25 mm were eligible for enrollment. A subset of subjects underwent follow-up angiography at 13 months post-procedure. RESULTS: A total of 101 subjects with 104 lesions were enrolled. The mean age was 67.3 +/- 9.6 years, 47% of subjects had diabetes, the mean lesion length was 12.6 +/- 6.3 mm, and the mean RVD was 1.91 +/- 0.26 mm. The rate of TLF at 12 months was 5.0%, fulfilling the pre-specified performance goal of 19% (p < 0.001). The rates of target lesion revascularization and target vessel myocardial infarction were 2.0% and 3.0%, respectively. There were no episodes of stent thrombosis. In-stent late lumen loss was 0.26 +/- 0.48 mm, and the rate of binary restenosis was 12.0%. CONCLUSIONS: In this first report of a drug-eluting stent with a dedicated size to treat lesions with RVD <2.25 mm, the Resolute Onyx 2.0-mm zotarolimus-eluting stent was associated with a low rate of TLF and late lumen loss, without a signal for stent thrombosis. This novel-sized drug-eluting stent appears to be a feasible option for the treatment of coronary lesions in extremely small vessels. (Medtronic Resolute Onyx 2.0 mm Clinical Study; NCT02412501). PMID- 28728653 TI - Fractional Flow Reserve: A Powerful and Simple, Yet Nuanced, Tool. PMID- 28728652 TI - Accuracy of Fractional Flow Reserve Measurements in Clinical Practice: Observations From a Core Laboratory Analysis. AB - OBJECTIVES: The aim of this study was to compare site-reported measurements of fractional flow reserve (FFR) with FFR analysis by an independent core laboratory (CL). BACKGROUND: FFR is an index of coronary stenosis severity that has been validated in multiple trials and is widely used in clinical practice. However, the incidence of suboptimal FFR measurements is unknown. METHODS: Patients undergoing FFR assessment within the CONTRAST (Can Contrast Injection Better Approximate FFR Compared to Pure Resting Physiology) study had paired, repeated measurements of multiple physiological metrics per local practice. An independent central physiology CL analyzed blinded pressure tracings off-line in a standardized fashion for comparison. RESULTS: A total of 763 patients were included in the study; 4,946 distal coronary artery pressure/aortic pressure (nonhyperemic) and FFR tracings were analyzed by the CL (mean 6.5 tracings per patient). Pull-back data were available for 616 patients (80.7%), of whom 108 (17.5%) had signal drift, defined as distal coronary artery pressure/aortic pressure (nonhyperemic) <0.97 or >1.03. Among the remaining 4,217 tracings without evidence of signal drift, 222 (5.3%) were noted to have ventricularization of the aortic waveform, and 168 (4.0%) had aortic waveform distortion. Excluding cases with signal drift and waveform distortion, there was excellent agreement between CL-calculated and site-reported FFR, with a mean difference of 0.003 +/- 0.02. Predictors of distorted waveforms were smaller guiding catheter size (odds ratio: 6.30; 95% confidence interval: 3.22 to 12.32; p < 0.001) and intracoronary adenosine use (odds ratio: 0.13; 95% confidence interval: 0.05 to 0.33; p < 0.001). CONCLUSIONS: This FFR CL analysis showed that almost 10% of tracings demonstrated waveform artifacts, and an additional 17.5% had signal drift. Among adequate tracings, there was a close correlation between site-reported and CL-analyzed FFR values. Attention to detail is critical for FFR studies to ensure adequate technique and optimal results. PMID- 28728655 TI - Complete Coronary Revascularization: The End Justifies the Means, as Long as Something Justifies the End. PMID- 28728654 TI - Comparison of Stenting Versus Bypass Surgery According to the Completeness of Revascularization in Severe Coronary Artery Disease: Patient-Level Pooled Analysis of the SYNTAX, PRECOMBAT, and BEST Trials. AB - OBJECTIVES: The aim of this study was to compare long-term survival between patients with severe coronary artery disease undergoing coronary artery bypass grafting (CABG) and those undergoing percutaneous coronary intervention (PCI) achieving complete revascularization (CR) or incomplete revascularization. BACKGROUND: The importance of CR in decision making regarding revascularization strategy in patients with severe coronary artery disease is unknown. METHODS: Data were pooled from the SYNTAX (Synergy Between PCI With Taxus and Cardiac Surgery), PRECOMBAT (Premier of Randomized Comparison of Bypass Surgery Versus Angioplasty Using Sirolimus-Eluting Stent in Patients With Left Main Coronary Artery Disease), and BEST (Randomized Comparison of Coronary Artery Bypass Surgery and Everolimus-Eluting Stent Implantation in the Treatment of Patients With Multivessel Coronary Artery Disease) trials. The primary outcome was death from any cause and was compared in an as-treated analysis. RESULTS: The rate of CR was 61.7% (57.2% with PCI and 66.8% with CABG). During a median 4.9-year follow-up period (interquartile range: 4.5 to 5.0 years), compared with patients undergoing CABG with CR, those undergoing PCI with incomplete revascularization had a higher risk for death from any cause (adjusted hazard ratio [aHR]: 1.43; 95% confidence interval [CI]: 1.03 to 2.00; p = 0.036) and the composite of death, myocardial infarction, and stroke (aHR: 1.48; 95% CI: 1.14 to 1.92; p = 0.003). However, there was no significant difference between patients undergoing CABG with CR and those undergoing PCI with CR regarding the risk for death from any cause (aHR: 1.16; 95% CI: 0.83 to 1.63; p = 0.39) and the composite of death, myocardial infarction, and stroke (aHR: 1.14; 95% CI: 0.87 to 1.48; p = 0.35). Subgroup analysis of multivessel coronary disease, high SYNTAX score (>32), and diabetes showed consistent findings. CONCLUSIONS: For the treatment of left main or multivessel coronary artery disease, PCI resulting in CR was associated with a similar long-term survival rate to CABG resulting in CR. Therefore, the ability to achieve CR should enter into the decision algorithm for choice of revascularization strategy. PMID- 28728656 TI - The Prognostic Effects of Coronary Disease Severity and Completeness of Revascularization on Mortality in Patients Undergoing Transcatheter Aortic Valve Replacement. AB - OBJECTIVES: The study sought to examine the effect of coronary artery disease (CAD) on mortality in patients undergoing transcatheter aortic valve replacement (TAVR). BACKGROUND: CAD is common in the TAVR population. However, there are conflicting data on the prognostic significance of CAD and its treatment in this population. METHODS: The authors analyzed 1,270 consecutive patients with severe aortic stenosis (AS) undergoing TAVR at 3 Israeli centers. They investigated the association of CAD severity (no CAD, nonsevere CAD [i.e., SYNTAX score (SS) <22], severe CAD [SS >22]) and revascularization completeness ("reasonable" incomplete revascularization [ICR] [i.e., residual SS <8]; ICR [residual SS >8]) with all cause mortality following TAVR using a Cox proportional hazards ratio model adjusted for multiple prognostic variables. RESULTS: Of the 1,270 patients, 817 (64%) had no CAD, 331 (26%) had nonsevere CAD, and 122 (10%) had severe CAD. Over a median follow-up of 1.9 years, 311 (24.5%) patients died. Mortality was higher in the severe CAD and the ICR groups, but not in the nonsevere CAD or "reasonable" ICR groups, versus no CAD. After multivariate adjustment, both severe CAD (hazard ratio: 2.091; p = 0.017) and ICR (hazard ratio: 1.720; p = 0.031) were associated with increased mortality. CONCLUSIONS: Only severe CAD was associated with increased mortality post-TAVR. More complete revascularization pre-TAVR may attenuate the association of severe CAD and mortality. PMID- 28728658 TI - Bleeding After Aortic Valve Replacement Matters: Important Mortality Risk. PMID- 28728657 TI - Frequency, Timing, and Impact of Access-Site and Non-Access-Site Bleeding on Mortality Among Patients Undergoing Transcatheter Aortic Valve Replacement. AB - OBJECTIVES: The aim of this study was to examine the frequency, timing, and association of access-site and non-access-site bleeding with mortality in the setting of transcatheter aortic valve replacement (TAVR) during long-term follow up. BACKGROUND: Bleeding is frequent and associated with impaired prognosis in patients undergoing TAVR. It is currently unknown whether the site of bleeding differentially influences the outcomes of TAVR patients. METHODS: In total, 926 consecutive patients undergoing TAVR from 2007 through 2014 were evaluated. Bleeding was assessed according to the Valve Academic Research Consortium 2 criteria. The primary outcome of interest was all-cause mortality up to 5 years of follow-up. RESULTS: A total of 285 patients (30.7%) experienced at least 1 (minor, major, or life-threatening) bleeding event up to 5 years. Compared with patients not experiencing bleeding, the adjusted risk for all-cause mortality was significantly increased among patients with access-site (hazard ratio: 1.34; 95% confidence interval: 1.01 to 1.76; p = 0.04) and non-access-site bleeding (hazard ratio: 2.08; 95% confidence interval: 1.60 to 2.71; p < 0.001). However, non access-site bleeding conferred a significantly higher risk for mortality compared with access-site bleeding (hazard ratio: 1.56; 95% confidence interval: 1.12 to 2.18; p = 0.009). At multivariate analysis, female sex was a significant correlate of access-site bleeding, whereas chronic kidney disease and the Society of Thoracic Surgeons score were significantly associated with non-access-site bleeding. CONCLUSIONS: Among patients with severe aortic stenosis undergoing TAVR, access-site and non-access-site bleeding were independently associated with an increased risk for mortality, with the greatest risk related to non-access site bleeding during long-term follow-up. PMID- 28728660 TI - The Cow Deserves a Fair Trial. PMID- 28728659 TI - A Systematic Review of Infective Endocarditis in Patients With Bovine Jugular Vein Valves Compared With Other Valve Types. AB - OBJECTIVES: The aim of this study was to systematically evaluate the incidence of infective endocarditis (IE) in right ventricle-to-pulmonary artery conduits and valves, comparing bovine jugular vein (BJV) valves with all others. BACKGROUND: Recent evidence suggests that the incidence of IE is higher in patients with congenital heart disease who have undergone implantation of BJV valves in the pulmonary position compared with other valves. METHODS: Systematic searches of published research were conducted using electronic databases (MEDLINE, Embase, and CINAHL) and citations cross-referenced current to April 2016. Included studies met the following criteria: patients had undergone right ventricle-to pulmonary artery conduit or percutaneous pulmonary valve implantation, and investigators reported on the type of conduit or valve implanted, method of intervention (surgery or catheter based), IE incidence, and follow-up time. RESULTS: Fifty studies (Levels of Evidence: 2 to 4) were identified involving 7,063 patients. The median cumulative incidence of IE was higher for BJV compared with other valves (5.4% vs. 1.2%; p < 0.0001) during a median follow-up period of 24.0 and 35.5 months, respectively (p = 0.03). For patients with BJV valves, the incidence of IE was not different between surgical and catheter-based valve implantation (p = 0.83). CONCLUSIONS: There was a higher incidence of endocarditis with BJV valves than other types of right ventricle-to-pulmonary artery conduits. There was no difference in the incidence of endocarditis between catheter-based bovine valves and surgically implanted bovine valves, suggesting that the substrate for future infection is related to the tissue rather than the method of implantation. PMID- 28728661 TI - Real-Time Continuous Left Atrial Pressure Monitoring During Mitral Valve Repair Using the MitraClip NT System: A Feasibility Study. PMID- 28728662 TI - Duration of Double Antiplatelet Therapy in Patients With Coronary and Peripheral Arterial Disease: The Key Might Be in the Type of Drug. PMID- 28728663 TI - Reply: Duration of the Double Antiplatelet Therapy in Patients With Coronary and Peripheral Arterial Disease: The Key Might Be in the Type of Drug. PMID- 28728664 TI - Pulse on Spontaneous Coronary Artery Dissections: Experience-Based Survey. PMID- 28728665 TI - Dual Antiplatelet Therapy After Bioresorbable Vascular Scaffold Implantation: Insights From the Milan Cohort. PMID- 28728666 TI - JACC: Cardiovascular Interventions 2.0: The Journey Begins. PMID- 28728667 TI - A comparison between liquid drops and solid particles in partial wetting. AB - In this critical review we compare two geometries in partial wetting: a liquid drop on a planar substrate and a spherical particle at a planar liquid interface. We show that this comparison is far from being trivial even if the same physical interactions are at play in both geometries. Similarities and differences in terms of free energies and frictions will be discussed. Contact angle hysteresis, the impact of surface roughness and line pinning on wetting will be described and compared to selected experimental findings. PMID- 28728668 TI - From the belly of the beast.... PMID- 28728669 TI - Is there a role for combined sclerotherapy and ligation in the endoscopic treatment of gastroesophageal varices? PMID- 28728670 TI - Fifteen years of ERCP. PMID- 28728671 TI - Stenosis after colorectal endoscopic submucosal dissection: When to expect, how to manage? PMID- 28728672 TI - Blue laser imaging: A promising new kid on the block or another tool to increase detection of low-risk adenomas? PMID- 28728673 TI - Distance from hospital in clinical practices. PMID- 28728674 TI - Utilizing trauma admissions as an opportunity to identify developmental and behavioral concerns. AB - BACKGROUND: Developmental and behavioral problems are often underdiagnosed in the pediatric population, and are risk factors for injury from trauma. Early intervention for these concerns yields improved outcomes. No prior research has screened for these difficulties during pediatric trauma admissions. METHODS: The current study utilized "The Survey of Wellbeing of Young Children" (SWYC) to assess for possible areas of concern by parent report. Concerns were compared to the presence of screening documented in their pediatrician's last well-child visit note. RESULTS: Of the 27 participants, 59.3% had developmental, behavioral, parental, or familial concerns. Overall, 46.2% of pediatricians had formally screened for concerns at the child's last well child visit, resulting in 25.9% being identified with new concerns found on the SWYC. CONCLUSIONS: Pediatric trauma admissions provide an important opportunity to screen for behavioral and developmental concerns in a population that is at risk for these concerns and that could greatly benefit from having problems identified. PMID- 28728675 TI - Increased Striatal Dopamine Synthesis Capacity in Gambling Addiction. AB - BACKGROUND: The hypothesis that dopamine plays an important role in the pathophysiology of pathological gambling is pervasive. However, there is little to no direct evidence for a categorical difference between pathological gamblers and healthy control subjects in terms of dopamine transmission in a drug-free state. Here we provide evidence for this hypothesis by comparing dopamine synthesis capacity in the dorsal and ventral parts of the striatum in 13 pathological gamblers and 15 healthy control subjects. METHODS: This was achieved using [18F]fluoro-levo-dihydroxyphenylalanine dynamic positron emission tomography scans and striatal regions of interest that were hand-drawn based on visual inspection of individual structural magnetic resonance imaging scans. RESULTS: Our results show that dopamine synthesis capacity was increased in pathological gamblers compared with healthy control subjects. Dopamine synthesis was 16% higher in the caudate body, 17% higher in the dorsal putamen, and 17% higher in the ventral striatum in pathological gamblers compared with control subjects. Moreover, dopamine synthesis capacity in the dorsal putamen and caudate head was positively correlated with gambling distortions in pathological gamblers. CONCLUSIONS: Taken together, these results provide empirical evidence for increased striatal dopamine synthesis in pathological gambling. PMID- 28728676 TI - Efficacy of Esketamine in the Treatment of Depression With Psychotic Features: A Case Series. PMID- 28728678 TI - Hubrecht Institute Centennial - From embryos to stem cells. AB - During the last 100 years, the Hubrecht Institute evolved from a small laboratory aimed at providing research material to the scientific community to a modern, fully equipped research institute with state-of-the-art infrastructure, performing research at the highest standard. The past 100 years have been eventful for the Hubrecht Institute with many glorious moments, but also threats to be shut down on several occasions. Here, we will briefly review the rich history of the Hubrecht Institute. PMID- 28728677 TI - Dynamically Timed Stimulation of Corticolimbic Circuitry Activates a Stress Compensatory Pathway. AB - BACKGROUND: The prefrontal cortex plays a critical role in regulating emotional behaviors, and dysfunction of prefrontal cortex-dependent networks has been broadly implicated in mediating stress-induced behavioral disorders including major depressive disorder. METHODS: Here we acquired multicircuit in vivo activity from eight cortical and limbic brain regions as mice were subjected to the tail suspension test (TST) and an open field test. We used a linear decoder to determine whether cellular responses across each of the cortical and limbic areas signal movement during the TST and open field test. We then performed repeat behavioral testing to identify which brain areas show cellular adaptations that signal the increase in immobility induced by repeat TST exposure. RESULTS: The increase in immobility observed during repeat TST exposure is linked to a selective functional upregulation of cellular activity in infralimbic cortex and medial dorsal thalamus, and to an increase in the spatiotemporal dynamic interaction between these structures. Inducing this spatiotemporal dynamic using closed-loop optogenetic stimulation is sufficient to increase movement in the TST in stress-naive mice, while stimulating above the carrier frequency of this circuit suppressed movement. This demonstrates that the adaptations in infralimbic cortex-medial dorsal thalamus circuitry observed after stress reflect a compensatory mechanism whereby the brain drives neural systems to counterbalance stress effects. CONCLUSIONS: Our findings provide evidence that targeting endogenous spatiotemporal dynamics is a potential therapeutic approach for treating stress-induced behavioral disorders, and that dynamics are a critical axis of manipulation for causal optogenetic studies. PMID- 28728679 TI - Recent advances in understanding the role of protein-tyrosine phosphatases in development and disease. AB - Protein-tyrosine phosphatases (PTPs) remove phosphate groups from tyrosine residues, and thereby propagate or inhibit signal transduction, and hence influence cellular processes such as cell proliferation and differentiation. The importance of tightly controlled PTP activity is reflected by the numerous mechanisms employed by the cell to control PTP activity, including a variety of post-translational modifications, and restricted subcellular localization. This review highlights the strides made in the last decade and discusses the important role of PTPs in key aspects of embryonic development: the regulation of stem cell self-renewal and differentiation, gastrulation and somitogenesis during early embryonic development, osteogenesis, and angiogenesis. The tentative importance of PTPs in these processes is highlighted by the diseases that present upon aberrant activity. PMID- 28728680 TI - At the base of colinear Hox gene expression: cis-features and trans-factors orchestrating the initial phase of Hox cluster activation. AB - Hox genes are crucial players in the generation and pattering of the vertebrate trunk and posterior body during embryogenesis. Their initial expression takes place shortly after the establishment of the primitive streak, in the posterior most part of the mouse embryo and is a determinant step for setting up the definitive Hox expression boundaries along the antero-posterior body axis. The developmental signals and epigenetic mechanisms underlying this early activation remained unsolved until recently. The development of novel embryo-derived model systems, combined with methods that examine chromatin status and chromosome conformation, led to deeper understanding of the process of Hox activation in the early embryo. Here we summarize how the early Hox cis-regulatory landscape becomes active upon receiving the appropriate developmental signal, and we discuss the importance of the local topological segmentation of the HoxA cluster during early Hox activation. PMID- 28728681 TI - Embryonic hematopoiesis under microscopic observation. AB - Hematopoietic stem cells (HSCs) are at the origin of adult hematopoiesis, providing an organism with all blood cell types needed throughout life. During embryonic development a first wave of hematopoiesis (independent of HSCs) allows the survival and growth of the embryo until birth. A second wave of hematopoiesis that will last into adulthood depends on the production of HSCs that begins at mid-gestation in large arteries such as the aorta. HSC production occurs through a hemogenic endothelial to hematopoietic transition (EHT) process and the formation of hematopoietic clusters in most vertebrate species. Advances in understanding EHT, cluster formation and HSC production were triggered by combined progresses made in the development of in vivo assays, microscopy, imaging and fluorescence tools. Here, we review the current knowledge on developmental hematopoiesis with a focus on the first step of HSC production in the aorta and how microscopic approaches have contributed to a better understanding of the vital process of blood cell formation. PMID- 28728682 TI - [Statin and risk of falls in the elderly: A sytematic review of the literature]. AB - BACKGROUND: With the high incidence of cardiovascular events in the elderly population the effectiveness of statins in reducing mortality from coronary events has been demonstrated. However, there have been adverse effects, such as myalgia, myopathy, myonecrosis, not to mention the falls as a result of muscle damage with statin use. OBJECTIVE: The purpose of this study is to conduct a systematic review to assess the literature on the association between statin use and the risk of falls. METHODS: The databases that were included PUBMED AND SCOPUS, with articles published from January 2000 to May 2016. The MESH terms used for the search were "FALLS" AND "STATIN". Selected studies included cohort populations from the community (>50 years old), and analysed using the Scottish Intercollegiate (SIGN) methodology guidelines, as no randomised controlled study was found. RESULTS: In the study by Ham et al., statin use was shown to be a protective factor for presence of falls. In the second study by Scott et al., there was an increased risk of falls (P=.029) and an impairment in muscle strength and quality muscle (P=.033 and P=.046, respectively). In the third study Haerer et al., found an increased risk of falls (P=.63). CONCLUSIONS: The association between use of statins and risk of falls could not be determined with the available evidence, although an association with the involvement of some determinants of muscular function was found. PMID- 28728683 TI - Nutritional intervention in acute heart failure patients with undernutrition and normalbuminemia: A subgroup analysis of PICNIC study. AB - BACKGROUND & AIMS: Hypoalbuminemia is common in acute heart failure (HF) patients and has been associated with increased hospital mortality and long-term mortality. Undernutrition is a factor causing hypoalbuminemia. The PICNIC study results show that a nutritional intervention in undernourished acute HF patients reduces the risks of all-cause death and of readmission for HF. We aimed to investigate whether the efficacy of a nutritional intervention is consistent among the subgroups of patients with and without hypoalbuminemia. METHODS: In PICNIC study, a total of 120 malnourished hospitalized patients due to acute HF were randomized to conventional HF treatment or conventional HF treatment combined with an individualized nutritional intervention. The primary endpoint was a composite of all-cause death or readmission for worsening of HF, with a maximum follow-up of 12 months. In this post-hoc sub-analysis we assessed the interaction of the effects of a nutritional intervention among patients with and without hypoalbuminemia. Analysis was by intention to treat. RESULTS: 59 (49,2%) patients demonstrated hypoalbuminemia and 61 (50,8%) had normalbuminemia. At 12 months, the number of events for the primary endpoint in the intervention group compared with the control group was consistent among patients with hypoalbuminemia (28.6% intervention vs 61.3% control, HR 0,35, 95% CI 0,15-0,81) and those without (25.8% intervention vs 60% control, HR 0,35, 95% CI 0,15-0,79; interaction p = 0,86). CONCLUSION: There was no evidence that the relative efficacy of a nutritional intervention in undernourished acute HF patients was different between patients with normalbuminemia and those with hypoalbuminemia. PMID- 28728685 TI - Healthy Plant-Based Diet: What Does it Really Mean? PMID- 28728684 TI - Healthful and Unhealthful Plant-Based Diets and the Risk of Coronary Heart Disease in U.S. Adults. AB - BACKGROUND: Plant-based diets are recommended for coronary heart disease (CHD) prevention. However, not all plant foods are necessarily beneficial for health. OBJECTIVES: This study sought to examine associations between plant-based diet indices and CHD incidence. METHODS: We included 73,710 women in NHS (Nurses' Health Study) (1984 to 2012), 92,329 women in NHS2 (1991 to 2013), and 43,259 men in Health Professionals Follow-up Study (1986 to 2012), free of chronic diseases at baseline. We created an overall plant-based diet index (PDI) from repeated semiquantitative food-frequency questionnaire data, by assigning positive scores to plant foods and reverse scores to animal foods. We also created a healthful plant-based diet index (hPDI) where healthy plant foods (whole grains, fruits/vegetables, nuts/legumes, oils, tea/coffee) received positive scores, whereas less-healthy plant foods (juices/sweetened beverages, refined grains, potatoes/fries, sweets) and animal foods received reverse scores. To create an unhealthful PDI (uPDI), we gave positive scores to less-healthy plant foods and reverse scores to animal and healthy plant foods. RESULTS: Over 4,833,042 person years of follow-up, we documented 8,631 incident CHD cases. In pooled multivariable analysis, higher adherence to PDI was independently inversely associated with CHD (hazard ratio [HR] comparing extreme deciles: 0.92; 95% confidence interval [CI]: 0.83 to 1.01; p trend = 0.003). This inverse association was stronger for hDPI (HR: 0.75; 95% CI: 0.68 to 0.83; p trend <0.001). Conversely, uPDI was positively associated with CHD (HR: 1.32; 95% CI: 1.20 to 1.46; p trend <0.001). CONCLUSIONS: Higher intake of a plant-based diet index rich in healthier plant foods is associated with substantially lower CHD risk, whereas a plant-based diet index that emphasizes less-healthy plant foods is associated with higher CHD risk. PMID- 28728686 TI - Spontaneous Coronary Artery Dissection Associated With Pregnancy. AB - BACKGROUND: Spontaneous coronary artery dissection (SCAD) is the most common cause of pregnancy-associated myocardial infarction and remains poorly characterized. OBJECTIVES: This study sought to assess presentation, clinical factors, and outcomes of pregnancy-associated spontaneous coronary artery dissection (P-SCAD) compared with spontaneous coronary artery dissection not associated with pregnancy (NP-SCAD). METHODS: A Mayo Clinic registry was established in 2010 to include comprehensive retrospective and prospective SCAD data. Records were reviewed to identify women who were pregnant or <=12 weeks postpartum at time of SCAD. Complete records were available for 323 women; 54 women met criteria for P-SCAD (4 during pregnancy) and they were compared with 269 women with NP-SCAD. RESULTS: Most events occurred within the first month postpartum (35 of 50). Compared with NP-SCAD, P-SCAD patients more frequently presented with ST-segment elevation myocardial infarction (57% vs. 36%; p = 0.009), left main or multivessel SCAD (24% vs. 5%; p < 0.0001; and 33% vs. 14%; p = 0.0027, respectively), and left ventricular function <=35% (26% vs. 10%; p = 0.0071). Among women with imaging of other vascular territories, P-SCAD was less likely with a diagnosis of fibromuscular dysplasia and extracoronary vascular abnormalities (42% vs. 64%; p = 0.047; and 46% vs. 77%; p = 0.0032, respectively). Compared with U.S. birth data, women with P-SCAD were more often multiparous (p = 0.0167), had a history of infertility therapies (p = 0.0004), and had pre-eclampsia (p = 0.001). On long-term follow-up (median 2.3 years) recurrent SCAD occurred in 51 patients, with no difference in the Kaplan Meier 5 year recurrence rates (10% vs. 23%; p = 0.18). CONCLUSIONS: P-SCAD patients had more acute presentations and high-risk features than women with NP-SCAD did. The highest frequency of P-SCAD occurred during the first postpartum month and P-SCAD patients less often had extracoronary vascular abnormalities. Hormonal, hemodynamic variations, and yet-undefined mechanisms might be significant contributors to P-SCAD. (The "Virtual" Multicenter Spontaneous Coronary Artery Dissection [SCAD] Registry [SCAD]; NCT01429727; Genetic Investigations in Spontaneous Coronary Artery Dissection [SCAD]; NCT01427179). PMID- 28728687 TI - Spontaneous Coronary Artery Dissection: The Zebra Has Been Spotted: Now Let's Study its Stripes. PMID- 28728689 TI - Effectiveness in a Real-World Observation Confirms Efficacy of Controlled Clinical Trials. PMID- 28728688 TI - Transcatheter Versus Surgical Aortic Valve Replacement: Propensity-Matched Comparison. AB - BACKGROUND: Randomized trials support the use of transcatheter aortic valve replacement (TAVR) for the treatment of aortic stenosis in high- and intermediate risk patients, but the generalizability of those results in clinical practice has been challenged. OBJECTIVES: The aim of this study was to determine the safety and effectiveness of TAVR versus surgical aortic valve replacement (SAVR), particularly in intermediate- and high-risk patients, in a nationally representative real-world cohort. METHODS: Using data from the Transcatheter Valve Therapy Registry and Society of Thoracic Surgeons National Database linked to Medicare administrative claims for follow-up, 9,464 propensity-matched intermediate- and high-risk (Society of Thoracic Surgeons Predicted Risk of Mortality score >=3%) U.S. patients who underwent commercial TAVR or SAVR were examined. Death, stroke, and days alive and out of the hospital to 1 year were compared, as well as discharge home, with subgroup analyses by surgical risk, demographics, and comorbidities. RESULTS: In a propensity-matched cohort (median age 82 years, 48% women, median Society of Thoracic Surgeons Predicted Risk of Mortality score 5.6%), TAVR and SAVR patients experienced no difference in 1-year rates of death (17.3% vs. 17.9%; hazard ratio: 0.93; 95% confidence interval [CI]: 0.83 to 1.04) and stroke (4.2% vs. 3.3%; hazard ratio: 1.18; 95% CI: 0.95 to 1.47), and no difference was observed in the proportion of days alive and out of the hospital to 1 year (rate ratio: 1.00; 95% CI: 0.98 to 1.02). However, TAVR patients were more likely to be discharged home after treatment (69.9% vs. 41.2%; odds ratio: 3.19; 95% CI: 2.84 to 3.58). Results were consistent across most subgroups, including among intermediate- and high-risk patients. CONCLUSIONS: Among unselected intermediate- and high-risk patients, TAVR and SAVR resulted in similar rates of death, stroke, and DAOH to 1 year, but TAVR patients were more likely to be discharged home. PMID- 28728691 TI - Evolution in Managing Long QT Syndrome: From Registries to Centers of Excellence. PMID- 28728690 TI - Contemporary Outcomes in Patients With Long QT Syndrome. AB - BACKGROUND: Long QT syndrome (LQTS) is a potentially lethal cardiac channelopathy with a 1% to 5% annual risk of LQTS-triggered syncope, aborted cardiac arrest, or sudden cardiac death. OBJECTIVES: This study sought to evaluate LQTS outcomes from a single center in the contemporary era. METHODS: The authors conducted a retrospective study comprising the 606 patients with LQTS (LQT1 in 47%, LQT2 in 34%, and LQT3 in 9%) who were evaluated in Mayo Clinic's Genetic Heart Rhythm Clinic from January 1999 to December 2015. Breakthrough cardiac events (BCEs) were defined as LQTS-attributable syncope or seizures, aborted cardiac arrest, appropriate ventricular fibrillation-terminating implantable cardioverter defibrillator shocks, and sudden cardiac death. RESULTS: There were 166 (27%) patients who were symptomatic prior to their first Mayo Clinic evaluation. Median age at first symptom was 12 years. Treatment strategies included no active therapy in 47 (8%) patients, beta-blockers alone in 350 (58%) patients, implantable cardioverter-defibrillators alone in 25 (4%) patients, left cardiac sympathetic denervation alone in 18 (3%) patients, and combination therapy in 166 (27%) patients. Over a median follow-up of 6.7 (IQR: 3.9 to 9.8) years, 556 (92%) patients have not experienced an LQTS-triggered BCE. Only 8 of 440 (2%) previously asymptomatic patients have experienced a single BCE. In contrast, 42 of 166 (25%) previously symptomatic patients have experienced >=1 BCE. Among the 30 patients with >=2 BCEs, 2 patients have died and 3 LQT3 patients underwent cardiac transplantation. CONCLUSIONS: Although outcomes have improved markedly, further optimization of treatment strategies is still needed given that 1 in 4 previously symptomatic patients experienced at least 1 subsequent, albeit nonlethal, LQTS-triggered cardiac event. PMID- 28728693 TI - Broadening the Phenotypic Spectrum and the Diagnostic Needs of TTR-Related Cardiac Amyloidosis. PMID- 28728692 TI - Magnetic Resonance in Transthyretin Cardiac Amyloidosis. AB - BACKGROUND: Cardiac transthyretin amyloidosis (ATTR) is an increasingly recognized cause of heart failure. Cardiac magnetic resonance (CMR), with late gadolinium enhancement (LGE) and T1 mapping, is emerging as a reference standard for diagnosis and characterization of cardiac amyloidosis. OBJECTIVES: The authors used CMR with extracellular volume fraction (ECV) measurement to characterize cardiac involvement in relation to outcome in ATTR. METHODS: Subjects comprised 263 patients with cardiac ATTR corroborated by grade 2 to 3 99mTc-DPD (99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid) cardiac uptake, 17 with suspected cardiac ATTR (grade 1 99mTc-DPD), and 12 asymptomatic individuals with amyloidogenic transthyretin (TTR) mutations. Fifty patients with cardiac light-chain (AL) amyloidosis acted as disease comparators. RESULTS: Unlike cardiac AL amyloidosis, asymmetrical septal left ventricular hypertrophy (LVH) was present in 79% of patients with ATTR (70% sigmoid septum and 30% reverse septal contour), whereas symmetrical LVH was present in 18%, and 3% had no LVH. In patients with cardiac amyloidosis, the pattern of LGE was always typical for amyloidosis (29% subendocardial, 71% transmural), including right ventricular LGE (96%). During follow-up (19 +/- 14 months), 65 patients died. ECV independently correlated with mortality and remained independent after adjustment for age, N terminal pro-B-type natriuretic peptide, ejection fraction, E/E', and left ventricular mass (hazard ratio: 1.164; 95% confidence interval: 1.066 to 1.271; p < 0.01). CONCLUSIONS: Asymmetrical hypertrophy, traditionally associated with hypertrophic cardiomyopathy, was the commonest pattern of ventricular remodeling in ATTR. LGE imaging was typical in all patients with cardiac ATTR. ECV correlated with amyloid burden and was an independent prognostic factor for survival in this cohort of patients. PMID- 28728694 TI - Alcohol Septal Ablation for Obstructive Hypertrophic Cardiomyopathy: A Word of Endorsement. AB - Twenty years after the introduction of alcohol septal ablation (ASA) for the treatment of obstructive hypertrophic cardiomyopathy, the arrhythmogenicity of the ablation scar appears to be overemphasized. When systematically reviewing all studies comparing ASA with myectomy with long-term follow-up, (aborted) sudden cardiac death and mortality rates were found to be similarly low. The focus should instead shift toward lowering the rate of reinterventions and pacemaker implantations following ASA because, in this area, ASA still seems inferior to myectomy. Part of the reason for this difference is that ASA is limited by the route of the septal perforators, whereas myectomy is not. Improvement may be achieved by: 1) confining ASA to hypertrophic cardiomyopathy centers of excellence with high operator volumes; 2) improving patient selection using multidisciplinary heart teams; 3) use of (3-dimensional) myocardial contrast echocardiography for selecting the correct septal (sub)branch; and 4) use of appropriate amounts of alcohol for ASA. PMID- 28728695 TI - Alcohol Septal Ablation for Obstructive Hypertrophic Cardiomyopathy: A Word of Balance. AB - The management of drug-refractory symptoms of obstructive hypertrophic cardiomyopathy has long been debated and is primarily centered on the choice between surgical myectomy and alcohol septal ablation. Decision making in these patients requires consideration of procedural risk, expertise and efficacy, and the long-term impact on patients' survival. Although there have been numerous reports on these procedures that may help guide decision making, these data continue to be self-reported and voluntary. Greater insight into the real-world experience for these therapies and how they should be applied in practice would be gained from mandatory reporting, akin to other multidisciplinary, transcatheter-based therapies. PMID- 28728696 TI - Percutaneous Edge-to-Edge Repair of Recurrent Severe Mitral Regurgitation After Surgical Mitral Valve Repair. PMID- 28728697 TI - Telomere Length and Risk of Cardiovascular Disease and Cancer. PMID- 28728698 TI - Reply: Relevance of Indications for CABG in Evaluating the Effect of Dual Antiplatelet Therapy. PMID- 28728699 TI - Relevance of Indications for CABG in Evaluating the Effect of Dual Antiplatelet Therapy. PMID- 28728700 TI - Hypertension Treatment in the Elderly: Individualized Target or Intensive Blood Pressure Lowering? PMID- 28728701 TI - The Importance of Invasive Hemodynamics for Pulmonary Hypertension Screening in TAVR Patients. PMID- 28728702 TI - Reply: Hypertension Treatment in the Elderly: Individualized Target or Intensive Blood Pressure Lowering? PMID- 28728703 TI - Correction. PMID- 28728704 TI - Correction. PMID- 28728705 TI - Correction. PMID- 28728706 TI - [An unusual case of renal failure in a 22-year-old woman]. PMID- 28728707 TI - Complex Pediatric Constipation: A Case Study of a Child With a Malone Appendicostomy. PMID- 28728708 TI - Effect of partitioning the nonfiber carbohydrate fraction and neutral detergent fiber method on digestibility of carbohydrates by dairy cows. AB - Many nutrition models rely on summative equations to estimate feed and diet energy concentrations. These models partition feed into nutrient fractions and multiply the fractions by their estimated true digestibility, and the digestible mass provided by each fraction is then summed and converted to an energy value. Nonfiber carbohydrate (NFC) is used in many models. Although it behaves as a nutritionally uniform fraction, it is a heterogeneous mixture of components. To reduce the heterogeneity, we partitioned NFC into starch and residual organic matter (ROM), which is calculated as 100 - CP - LCFA - ash - starch - NDF, where crude protein (CP), long-chain fatty acids (LCFA), ash, starch, and neutral detergent fiber (NDF) are a percentage of DM. However, the true digestibility of ROM is unknown, and because NDF is contaminated with both ash and CP, those components are subtracted twice. The effect of ash and CP contamination of NDF on in vivo digestibility of NDF and ROM was evaluated using data from 2 total collection digestibility experiments using lactating dairy cows. Digestibility of NDF was greater when it was corrected for ash and CP than without correction. Conversely, ROM apparent digestibility decreased when NDF was corrected for contamination. Although correcting for contamination statistically increased NDF digestibility, the effect was small; the average increase was 3.4%. The decrease in ROM digestibility was 7.4%. True digestibility of ROM is needed to incorporate ROM into summative equations. Data from multiple digestibility experiments (38 diets) using dairy cows were collated, and ROM concentrations were regressed on concentration of digestible ROM (ROM was calculated without adjusting for ash and CP contamination). The estimated true digestibility coefficient of ROM was 0.96 (SE = 0.021), and metabolic fecal ROM was 3.43 g/100 g of dry matter intake (SE = 0.30). Using a smaller data set (7 diets), estimated true digestibility of ROM when calculated using NDF corrected for ash and CP contamination was 0.87 (SE = 0.025), and metabolic fecal ROM was 3.76 g/100 g (SE = 0.60). Regardless of NDF method, ROM exhibited nutritional uniformity. The ROM fraction also had lower errors associated with the estimated true digestibility and its metabolic fecal fraction than did NFC. Therefore, ROM may result in more accurate estimates of available energy if integrated into models. PMID- 28728710 TI - Comment on comparing the outcomes of different compression screw systems in the fixation of mandibular fractures. PMID- 28728709 TI - Counterclockwise maxillomandibular advancement surgery and disc repositioning: can condylar remodeling in the long-term follow-up be predicted? AB - This study investigated predictive risk factors of condylar remodeling changes after counterclockwise maxillomandibular advancement (CCW-MMA) and disc repositioning surgery. Forty-one female patients (75 condyles) treated with CCW MMA and disc repositioning had cone beam computed tomography (CBCT) scans taken pre-surgery, immediately after surgery, and at an average 16 months post-surgery. Pre- and post-surgical three-dimensional models were superimposed using automated voxel-based registration on the cranial base to evaluate condylar displacements after surgery. Regional registration was performed to assess condylar remodeling in the follow-up period. Three-dimensional cephalometrics, shape correspondence (SPHARM-PDM), and volume measurements were applied to quantify changes. Pearson product-moment correlations and multiple regression analysis were performed. Highly statistically significant correlation showed that older patients were more susceptible to overall condylar volume reduction following CCW-MMA and disc repositioning (P<=0.001). Weak but statistically significant correlations were observed between condylar remodeling changes in the follow-up period and pre surgical facial characteristics, magnitude of the surgical procedure, and condylar displacement changes. After CCW-MMA and disc repositioning, the condyles moved mostly downwards and medially, and were rotated medially and counterclockwise; displacements in the opposite direction were correlated with a greater risk of condylar resorption. Moreover, positional changes with surgery were only weakly associated with remodeling in the follow-up period, suggesting that other risk factors may play a role in condylar resorption. PMID- 28728711 TI - Cardiac Screening in the Noncardiac Surgery Patient. AB - This article will address common cardiac conditions that require evaluation prior to noncardiac surgery, characterization of urgency and the risk associated with surgical procedures, calculation of preoperative risk assessment, indications for diagnostic testing to quantify cardiac risk, and perioperative strategies to minimize the risk of cardiac complications. PMID- 28728712 TI - Diagnostic Imaging and Newer Modalities for Thoracic Diseases: PET/Computed Tomographic Imaging and Endobronchial Ultrasound for Staging and Its Implication for Lung Cancer. AB - Modalities to detect and characterize lung cancer are generally divided into those that are invasive [endobronchial ultrasound (EBUS), esophageal ultrasound (EUS), and electromagnetic navigational bronchoscopy (ENMB)] versus noninvasive [chest radiography (CXR), computed tomography (CT), positron emission tomography (PET), and magnetic resonance imaging (MRI)]. This chapter describes these modalities, the literature supporting their use, and delineates what tests to use to best evaluate the patient with lung cancer. PMID- 28728713 TI - Lung Cancer Screening and Its Impact on Surgical Volume. AB - Lung cancer screening has demonstrated a reduction in lung cancer mortality by 20%. Annual low-dose computed tomography examination in high-risk individuals is now recommended by multiple national health care organizations and is covered under Medicare and Medicaid services. The impact of this public health intervention is projected to increase the case load for the thoracic surgery workforce. PMID- 28728714 TI - The Impact of Minimally Invasive Esophageal Surgery. AB - Many esophageal patients with cancer were undertreated for their malignancy, which played a role in the poor long-term survival rate. Surgeons have been eager to see real change in short-term and long-term outcomes. Dramatic and profound advances continue toward improving surgical outcomes, techniques, and expanding the reach of esophagectomy, especially the use of minimally invasive techniques. This article discusses the surgical innovations that have occurred in the last decade and their impact on patients with esophageal cancer. PMID- 28728715 TI - Robotic Lobectomy and Segmentectomy: Technical Details and Results. AB - Robotic-assisted pulmonary lobectomy can be considered for patients fit for conventional lobectomy. Contraindications include prohibitive lung function or medical comorbidities, multistation N2, gross N2 disease, or evidence of N3 disease. Team training, familiarity with equipment, troubleshooting, and preparation are critical for successful robotic lobectomy. Similar to video assisted thoracoscopic surgery (VATS) lobectomy, robotic lobectomy is associated with decreased blood loss, blood transfusion, air leak, chest tube duration, duration of stay, and mortality compared with thoracotomy. Robotic lobectomy offers many of the same benefits in perioperative morbidity and mortality, and the advantages of optics, dexterity, and surgeon ergonomics compared with VATS lobectomy. PMID- 28728716 TI - Thoracic Trauma: Injuries, Evaluation, and Treatment. AB - Thoracic injury is common in high-energy and low-energy trauma, and is associated with significant morbidity and mortality. Evaluation requires a systematic approach prioritizing airway, respiration, and circulation. Chest injuries have the potential to progress rapidly and require prompt procedural intervention. For the diagnosis of nonemergent injuries, a careful secondary survey is essential. Although medicine and trauma management have evolved throughout the decades, the basics of thoracic trauma care have remained the same. PMID- 28728717 TI - Team-Based Care: The Changing Face of Cardiothoracic Surgery. AB - Cardiothoracic surgical care is a team sport. The increased complexity and sophistication of this field have resulted in the development of highly functioning multidisciplinary and interprofessional teams to optimize clinical outcomes. This article provides an overview of a team-based, patient-centric "systems" approach to the care of cardiothoracic surgery patients. PMID- 28728718 TI - Cardiothoracic Critical Care. AB - High-value CCC is rapidly evolving to meet the demands of increased patient acuity and to incorporate advances in technology. The high-performing CCC system and culture should aim to learn quickly and continuously improve. CCC demands a proactive, interactive, precise, an expert team, and continuity. PMID- 28728719 TI - The Surgical Treatment of Coronary Artery Occlusive Disease: Modern Treatment Strategies for an Age Old Problem. AB - Coronary artery disease remains a formidable challenge to clinicians. Percutaneous interventions and surgical techniques for myocardial revascularization continue to improve. Concurrently, in light of emerging data, multiple practice guidelines have been published guiding clinicians in their therapeutic decisions. The multidisciplinary Heart Team concept needs to be embraced by all cardiovascular providers to optimize patient outcomes. PMID- 28728720 TI - Mitral Valve Repair: The French Correction Versus the American Correction. AB - Degenerative mitral valve disease causing mitral regurgitation is the most common organic valve pathology and is classified based on leaflet motion. The "French correction" mitral valve repair method restores normal valvular anatomy with extensive leaflet resection, chordal manipulation, and rigid annuloplasty. The American correction attempts to restore normal valve function through minimal leaflet resection, flexible annuloplasty, and use of artificial chordae. These differing methods of mitral valve repair reflect an evolution in principles, but both require understanding of the valve pathology and correction of leaflet prolapse and annular dilatation. Adhering to those unifying principles and ensuring that no patient leaves the operating room with significant persistent mitral regurgitation produces durable results and satisfactory patient outcomes. PMID- 28728721 TI - Updates in Minimally Invasive Cardiac Surgery for General Surgeons. AB - Significant improvement and development have occurred in minimally invasive cardiac surgery over the past 20 years. Although most studies have consistently demonstrated equivalent or improved outcomes compared with conventional cardiac surgery, with significantly shorter recovery times, adoption continues to be limited. In addition, cost data have been inconsistent. Further ongoing trials are needed to help determine the exact roles for these innovative procedures. PMID- 28728722 TI - Transcatheter Aortic Valve Replacement: A Review. AB - Patients with inoperable, high-risk, and intermediate-risk aortic stenosis can now be treated with transcatheter aortic valve replacement. Centers for Medicare and Medicaid Services and the Food and Drug Administration selectively choose centers based on experience and require a collaborative, multidisciplinary team approach in the treatment and decision making for these patients. The work-up has been streamlined. Gated multislice computed tomography angiogram has emerged as the gold standard for assessment of valve anatomy and sizing of the transcatheter heart valve. Assessment of risk has evolved to include a more comprehensive functional and frailty evaluation. Long term-results are needed before the expansion of transcatheter aortic valve replacement into the low-risk category. PMID- 28728724 TI - Foreword. PMID- 28728723 TI - Surgical Treatment of Heart Failure. AB - More than 5 million Americans suffer from heart failure and more than 250,000 die annually. Cardiac surgery, as applied to advanced heart failure, has evolved significantly in the past 50 years. Current therapeutic interventions are focused on the appropriate assessment of myocardial dysfunction as a means to select the right patient for the appropriate procedure using state-of-the-art myocardial viability testing and metabolic testing to determine candidacy for conventional interventions, mechanical devices, or transplant. Advances in mechanical circulatory support with more efficient and less morbid ventricular assist devises offer the potential to change the trajectory of this growing epidemiologic dilemma. PMID- 28728725 TI - Preface. PMID- 28728727 TI - Patient Assessment. PMID- 28728728 TI - Cleft and Craniofacial Surgery. PMID- 28728729 TI - Trauma Surgery. PMID- 28728730 TI - Temporomandibular Joint Surgery. PMID- 28728732 TI - Diagnosis and Management of Pathological Conditions. PMID- 28728733 TI - Reconstructive Surgery. PMID- 28728734 TI - Facial Cosmetic Surgery. PMID- 28728735 TI - Anesthesia in Outpatient Facilities. PMID- 28728736 TI - Introduction. PMID- 28728737 TI - Application of Parameters of Care to Clinical Practice. PMID- 28728738 TI - Dentoalveolar Surgery. PMID- 28728739 TI - Applicability and Utility of Parameters of Care to Patient Care. PMID- 28728740 TI - Dental and Craniomaxillofacial Implant Surgery. PMID- 28728741 TI - Surgical Correction of Maxillofacial Skeletal Deformities. PMID- 28728742 TI - A Clinical Score Model to Predict Lethal Events in Young Patients (<=19 Years) With the Brugada Syndrome. AB - Risk stratification in Brugada syndrome in young patients remains challenging. We investigated the clinical characteristics, prognosis, and risk in young patients with the Brugada syndrome. We studied 95 patients with the Brugada syndrome aged <=19 years. The median age at diagnosis was 12.9 years. The clinical presentation was sudden cardiac death in 7% and syncope in 21%. The remaining 72% were asymptomatic at diagnosis. Electrical abnormalities were present in 36%, including spontaneous type I electrocardiogram (12%), sinus node dysfunction (9%), atrioventricular block (17%), intraventricular conduction delay (16%), and atrial arrhythmias (8%). An electrophysiologic study was performed in 75%; ventricular arrhythmias were induced in 3%. An implantable cardioverter defibrillator was placed in 25%. During a mean follow-up of 59 months, 9 patients presented with arrhythmic events (event rate: 1.9% per year). Variables significantly associated with events were: presentation with sudden cardiac death or syncope, spontaneous type I electrocardiogram, sinus node dysfunction and/or atrial tachycardia, conduction abnormality, and induction of ventricular arrhythmias during programmed ventricular stimulation. A model including the previous 4 main clinical variables (1, sudden cardiac death or syncope; 2, spontaneous type I electrocardiogram; 3, sinus node dysfunction and/or atrial tachycardia; and 4, conduction abnormality) had a high predictive power (C: 0.93) for the risk of lethal events. A score of >=4 conferred a 5-year event probability of 30% that increased to 53% if the score was >=6. In conclusion, our study validated a model to predict risk in young patients with the Brugada syndrome, which takes into account 4 clinical measures. PMID- 28728743 TI - Outcomes of ST Elevation Myocardial Infarction Complicated by Out-of-Hospital Cardiac Arrest (from the Los Angeles County Regional System). AB - The objective of this study was to evaluate the time to primary percutaneous coronary intervention (PCI) and the outcome for patients with ST elevation myocardial infarction (STEMI) complicated by out-of-hospital cardiac arrest (OHCA). In this regional system, all patients with STEMI and/or OHCA with return of spontaneous circulation were transported to STEMI Receiving Centers. The outcomes registry was queried for patients with STEMI with underwent primary PCI from April 2011 to December 2014. Patients with STEMI complicated by OHCA were compared with a reference group of STEMI without OHCA. The primary end point was the first medical contact-to-device time. Of 4,729 patients with STEMI who underwent primary PCI, 422 patients (9%) suffered OHCA. Patients with OHCA were on average 2 years (95% confidence interval 0.7 to 3.0) older and had a slightly higher male predominance. The first medical contact-to-device time was longer in STEMI with OHCA compared with STEMI alone (94 +/- 37 vs. 86 +/- 34 minutes, p < 0.0001). In-hospital mortality was higher after OHCA, 38% versus 6% in STEMI alone, odds ratio 6.3 (95% confidence interval 5.3 to 7.4). Among OHCA survivors, 193 (73%) were discharged with a cerebral performance category score of 1 or 2. In conclusion, despite longer treatment intervals, neurologic outcome was good in nearly half of the surviving patients with STEMI complicated by OHCA, suggesting that these patients can be effectively treated with primary PCI in a regionalized system of care. PMID- 28728744 TI - Serial Heart Rates, Guideline-Directed Beta Blocker Use, and Outcomes in Patients With Chronic Heart Failure With Reduced Ejection Fraction. AB - A single heart rate (HR) measurement may inform future prognosis in chronic heart failure with reduced ejection fraction (HFrEF). The importance of elevated HR across serial assessment is uncertain, particularly with well-applied guideline directed medical therapy (GDMT) with beta blockers (BBs). In this post hoc analysis of 129 patients with chronic HFrEF in sinus rhythm, who had aggressive medication titration over 10.6 months, HR and BB use were assessed at each visit (average of 6 visits per patient). All-cause mortality was assessed. At baseline, 81 subjects (62.8%) had HR >=70 beats/min; 40 subjects (31.0%) had high HR despite being on >=50% of GDMT BB dose. At final visit, 30.4% of the subjects still had high HR despite achieving >=50% target BB dose. There were no significant baseline differences in demographics or BB doses in patients with HR <70 vs HR >=70 beats/min. In adjusted model in which HR was treated as time dependent covariate, an increase in HR of 10 beats/min was associated with an increased hazard of all-cause mortality during follow-up (adjusted hazard ratio per 10 beats/min = 2.46; 95% confidence interval 1.46-4.16, p <0.001). In conclusion, in well-managed patients with HFrEF, high HR was frequent even after aggressive medication titration, and often despite being on at least 50% of GDMT BB dose. An increase in HR was associated with worse clinical outcomes (Clinicaltrials.gov NCT#00351390). PMID- 28728745 TI - Early Readmissions After Acute Myocardial Infarction. AB - This study aims to evaluate the rate, predictors, and causes of 30-day readmissions in a single tertiary hospital in the United Kingdom. We conducted a retrospective study of all patients admitted between 2012 and 2014 with a diagnosis of acute myocardial infarction, who were in the Myocardial Infarction National Audit Project register. Data on patient demographics, comorbidities, care received, and in-hospital mortality were collected. Rates of 30-day readmission and causes of readmission were evaluated. Univariate and multiple logistic regressions were used to identify predictors of all-cause, cardiac, and noncardiac readmission. A total of 1,869 patients were included in the analysis and 171 had an unplanned readmission with 30 days (9%). Noncardiac problems represented half of all readmissions with the dominant cause noncardiac chest pain (50%). A variety of other noncardiac causes for readmission were identified and the most common were lower respiratory tract infection (4.3%), gastrointestinal problems (4.9%), bleeding (3.7%), dizziness, syncope, or fall (3.0%), and pulmonary embolus (2.4%). For cardiac causes of readmissions, common causes included acute coronary syndrome (17.1%), stable angina (11.6%), and heart failure (9.8%). Readmitted patients were more likely to be older, anemic, and less likely to receive coronary angiogram and percutaneous coronary intervention. After adjustment, the only predictor of all-cause readmission was older age. For noncardiac readmission, previous myocardial infarction was associated with significantly fewer readmissions. Our results suggest that early readmission after discharge with diagnosis of acute myocardial infarction is common. Chest pain is the most frequent cause of readmission, and interventions to reduce noncardiac chest pain admissions are needed. PMID- 28728746 TI - Linking Sex Differences in Non-Alcoholic Fatty Liver Disease to Bile Acid Signaling, Gut Microbiota, and High Fat Diet. AB - This commentary highlights the article by Jena et al that studied the complex interplay between diet, bile acids, sex, and dysbiosis in hepatic steatosis and inflammation. PMID- 28728747 TI - Endothelial-to-Mesenchymal Transition in Bone Marrow and Spleen of Primary Myelofibrosis. AB - Primary myelofibrosis is characterized by the development of fibrosis in the bone marrow that contributes to ineffective hematopoiesis. Bone marrow fibrosis is the result of a complex and not yet fully understood interaction among megakaryocytes, myeloid cells, fibroblasts, and endothelial cells. Here, we report that >30% of the endothelial cells in the small vessels of the bone marrow and spleen of patients with primary myelofibrosis have a mesenchymal phenotype, which is suggestive of the process known as endothelial-to-mesenchymal transition (EndMT). EndMT can be reproduced in vitro by incubation of cultured endothelial progenitor cells or spleen-derived endothelial cells with inflammatory cytokines. Megakaryocytes appear to be implicated in this process, because EndMT mainly occurs in the microvessels close to these cells, and because megakaryocyte derived supernatant fluid can reproduce the EndMT switch in vitro. Furthermore, EndMT is an early event in a JAK2-V617F knock-in mouse model of primary myelofibrosis. Overall, these data show for the first time that microvascular endothelial cells in the bone marrow and spleen of patients with primary myelofibrosis show functional and morphologic changes that are associated to the mesenchymal phenotype. PMID- 28728748 TI - Metastatic renal cell carcinoma: Patterns and predictors of metastases-A contemporary population-based series. AB - OBJECTIVE: To assess the patterns and predictors of metastatic disease in renal cell carcinoma (RCC) at the time of diagnosis in a contemporary series. METHODS: The Surveillance, Epidemiology, and End Results database was queried for all patients with kidney RCC from 2010 to 2013 (N = 50,815). Distribution and predictors of distant metastases at diagnosis were assessed. Multivariate logistic regression hazard analyses were performed to determine covariates associated with the likelihood of having metastases at diagnosis, whereas competing risks regression analysis was used to assess predictors of cancer specific mortality (CSM) in patients with metastatic disease. RESULTS: Lung (7.73%) and bone (5.17%) metastases were the most common. The strongest predictors of metastatic disease were disease-specific factors, such as clinical T-stage (cT4 vs. cT1; odds ratio = 43.08; P<0.01) and higher Fuhrman grade (FG4 vs. FG1; odds ratio = 5.09; P<0.01). Papillary RCC and chromophobe RCC were associated with localized disease at the time of diagnosis. For CSM, the presence of brain and liver metastases were associated with worse CSM than lung or bone metastases. Although patient factors did not contribute to the presence of metastases at diagnosis, lower socioeconomic status and being widowed/divorced predicted worse CSM. CONCLUSION: Understanding the distribution of distant metastases and associated CSM is important to counseling patients with newly diagnosed metastatic RCC. Although pathologic factors drive the presence of metastases at diagnosis, health care deficits in treatment remain. PMID- 28728749 TI - Numb chin with mandibular pain or masticatory weakness as indicator for systemic malignancy - A case series study. AB - BACKGROUND/PURPOSE: Numb chin syndrome (NCS) is a critical sign of systemic malignancy; however it remains largely unknown by clinicians and dentists. The aim of this study was to investigate NCS that is more often associated with metastatic cancers than with benign diseases. METHODS: Sixteen patients with NCS were diagnosed and treated. The oral and radiographic manifestations were assessed. RESULTS: Four (25%) of 16 patients with NCS were affected by nonmalignant diseases (19% by medication-related osteonecrosis of the jaw and 6% by osteopetrosis); yet 12 (75%) patient conditions were caused by malignant metastasis, either in the mandible (62%) or intracranial invasion (13%). NCS was unilateral in 13 cases and bilateral in three cases. Mandibular pain and masticatory weakness often dominate the clinical features in NCS associated with cancer metastasis. In two patients, NCS preceded the discovery of unknown malignancy (breast cancer and leukemia). In nine others, NCS heralded malignancy relapse and progression. Metastatic breast cancer in four (36%) cases accounted for the most common malignancy. Other metastatic diseases included two multiple myelomas, and one each of leukemia, prostate cancer, colon cancer, lung cancer, maxillary sinus adenoid cystic carcinoma and adrenal gland neuroblastoma. Radiographic examinations showed obvious mandibular metastasis with compression of the inferior alveolar nerve or mental nerve in nine patients, and leptomeningeal seeding or intracranial metastasis to the trigeminal nerve root at the skull base in two patients. CONCLUSION: NCS without obvious odontogenic causes or trauma often signals systemic malignancy. It may be the first clue of occult malignancy. PMID- 28728750 TI - Trigeminocardiac reflex during non-surgical root canal treatment of teeth with irreversible pulpitis. AB - BACKGROUND/PURPOSE: Trigeminocardiac reflex (TCR) is a unique clinical incident of acute change in hemodynamic balance, which may lead to hypotension, bradycardia, and even clinical crisis. Up to date, no study so far considers the impact of non-surgical root canal treatment (NSRCT) of irreversible pulpitis teeth under either local infiltration or block anesthesia on hemodynamic change possibly related to TCR. METHODS: This study enrolled 111 patients with 138 irreversible pulpitis teeth that were treated by two sessions of NSRCT. The first session involved mainly the removal of vital pulp tissue with the direct stimulation of the dental branches of the trigeminal nerve, and the second session included the root canal enlargement and debridement with minimal disturbance to the dental branches of the trigeminal nerve. Vital signs mainly the blood pressure were recorded during both NSRCT sessions. RESULTS: The incidences of NSRCT patients with MABP decrease ?10%, ?15%, or ?20% were all significantly higher in the first NSRCT session than in the second NSRCT session (all the P-values < 0.001). In the first NSRCT session, the incidence of patients with MABP decrease ?10% was significantly associated with tooth type. For both upper and lower teeth, the patients with premolars treated by NSRCR had significantly higher incidences of MABP decrease ?10% than those with either anterior or molar teeth treated by NSRCR (all the P-values < 0.05). CONCLUSION: We conclude that vital pulp extirpation may lead to a substantial drop in patient's blood pressure possibly related to TCR. PMID- 28728752 TI - Nano-structured antimicrobial surfaces: From nature to synthetic analogues. AB - The scientific and industrial interest in antimicrobial surfaces has significantly increased in recent times. This interest is largely in response to the persistent microbial contamination of industrial and, importantly, medical implant surfaces. Bacterial contamination of implant surfaces often leads to infection at the implant-tissue interface, and with the prevalence of increasing levels of antimicrobial resistance, the treatment of these infections is becoming far more challenging. Recently, many naturally occurring, high-aspect-ratio surface topographies have been discovered that exhibit high levels of biocidal efficacy. These include epicuticular lipid nano-architectures that are formed on the surfaces of insect wings, such as cicadae and dragonflies. The antimicrobial activity of such surfaces has been found to be a consequence of the physical interactions between the nanoscale topography of the substrate and the attaching pathogenic cells, meaning that the activity is independent of biochemical surface functionality. Importantly, these desirable surface properties can be translated to synthetic biomimetic surfaces, which, when mimicked, lead to a substantial increase in the antimicrobial properties of such surfaces. This paper reviews the recent advances in understanding the basis of these mechanical antimicrobial mechanisms, and discusses the progress being made towards the fabrication of optimised, biocompatible, synthetic analogues. PMID- 28728753 TI - A 27-year-old Ecuadorian male with painful swelling of his left foot. PMID- 28728751 TI - A phase II evaluation of brivanib in the treatment of persistent or recurrent carcinoma of the cervix: An NRG Oncology/Gynecologic Oncology Group study. AB - BACKGROUND: Brivanib is an oral, tyrosine kinase inhibitor against vascular endothelial growth factor (VEGF) and fibroblast growth factor receptor (FGFR). We studied its efficacy and tolerability in persistent or recurrent cervical cancer patients. METHODS: Eligible patients had at least one prior cytotoxic regimen for recurrence and with measurable disease. Brivanib 800mg was administered orally every day (1cycle=28days) until disease progression or prohibitive toxicity. Primary endpoints were progression-free survival (PFS) >6months and objective tumor response. RESULTS: Of 28 eligible and evaluable women enrolled, 11 (39%) had primary surgery and 25 (89%) had prior radiation. Eighteen (64%) received one prior cytotoxic treatment and 10 (36%) had 2 prior regimens. Twelve (43%) had >2cycles of brivanib with 4 (14%) receiving >10cycles (range: 1-20). Seven (25%) patients had PFS >6months (90% CI: 7.3%-33.9%). Two (7%) (90% CI: 1.3%-20.8%) patients had partial tumor response with duration of 8 and 22months and 12 (43%) had stable disease. The median PFS was 3.2months (90% CI: 2.1-4.4). The median overall survival was 7.9months (90% CI: 6.1-11.7). More common grade 3 adverse events were hypertension, anemia, hyponatremia, hyperglycemia, elevated liver enzymes, nausea, headache, and colon hemorrhage. Grade 4 adverse events included sepsis and hypertension. CONCLUSIONS: Based on early results of this phase II trial, brivanib was well tolerated and demonstrated sufficient activity after first stage but trial was stopped due to lack of drug availability. PMID- 28728754 TI - Copper-based reactions in analyte-responsive fluorescent probes for biological applications. AB - Copper chemistry has been capitalized on in a wide spectrum of biological events. The central importance of copper in biology lies in the diverse chemical reactivity of the redox-active transition metal ranging from electron transfer, small molecule binding and activation, to catalysis. In addition to its many different roles in natural biological systems, the diverse chemical reactivity of copper also represents a rich opportunity and resource to develop synthetic bioanalytical tools for the study of biologically important species and molecules. In this mini-review, fluorescent probes featuring a specific copper based chemical reaction to selectively detect a biologically relevant analyte will be discussed. In particular, fluorescent probes for sensing labile copper ions, amino acids and small reactive species will be highlighted. The chemical principles, advantages and limitations of the different types of copper-mediated chemical reactions in these fluorescent probes will be emphasized. PMID- 28728755 TI - [Magnetic resonance in traumatic brain injury: A comparative study of the different conventional magnetic resonance imaging sequences and their diagnostic value in diffuse axonal injury]. AB - OBJECTIVE: To compare the identification capability of traumatic axonal injury (TAI) by different sequences on conventional magnetic resonance (MR) studies in traumatic brain injury (TBI) patients. MATERIAL AND METHODS: We retropectevely analyzed 264 TBI patients to whom a MR had been performed in the first 60 days after trauma. All clinical variables related to prognosis were registered, as well as the data from the initial computed tomography. The MR imaging protocol consisted of a 3-plane localizer sequence T1-weighted and T2-weighted fast spin echo, FLAIR and gradient-echo images (GRET2*). TAI lesions were classified according to Gentry and Firsching classifications. We calculated weighted kappa coefficients and the area under the ROC curve for each MR sequence. A multivariable analyses was performed to correlate MR findings in each sequence with the final outcome of the patients. RESULTS: TAI lesions were adequately visualized on T2, FLAIR and GRET2* sequences in more than 80% of the studies. Subcortical TAI lesions were well on FLAIR and GRET2* sequences visualized hemorrhagic TAI lesions. We saw that these MR sequences had a high inter-rater agreement for TAI diagnosis (0.8). T2 sequence presented the highest value on ROC curve in Gentry (0.68, 95%CI: 0.61-0.76, p<0.001, Nagerlkerke-R2 0.26) and Firsching classifications (0.64, 95%CI 0.57-0.72, p<0.001, Nagerlkerke-R2 0.19), followed by FLAIR and GRET2* sequences. Both classifications determined by each of these sequences were associated with poor outcome after performing a multivariable analyses adjusted for prognostic factors (p<0.02). CONCLUSIONS: We recommend to perform conventional MR study in subacute phase including T2, FLAIR and GRET2* sequences for visualize TAI lesions. These MR findings added prognostic information in TBI patients. PMID- 28728757 TI - Value of whole-lesion apparent diffusion coefficient (ADC) first-order statistics and texture features in clinical staging of cervical cancers. AB - AIM: To explore the value of whole-lesion apparent diffusion coefficient (ADC) first-order statistics and texture features in clinical staging of cervical cancers. MATERIALS AND METHODS: Fifty-six women (mean age, 51 years) with histopathologically confirmed cervical cancers underwent 3 T pelvic magnetic resonance imaging including diffusion-weighted imaging (b=0, 800 s/mm2) prospectively. The ADC first-order statistics and texture features derived from the whole volume of cervical cancers were correlated with International Federation of Gynecology and Obstetrics (FIGO) stages (i.e., stages I, II, III, and IV). RESULTS: The first-order statistics of skewness, kurtosis, and entropy, and the texture features of entropy(H) and homogeneity correlated positively, while the texture feature of energy correlated negatively with FIGO stages (all p<0.05). Skewness, kurtosis, entropy, entropy(H), and homogeneity were significantly higher, while energy was significantly lower in cervical cancers at higher (IIB-IVA) than lower (IB-IIA) FIGO stages (all p<0.05). Kurtosis and energy had the largest areas under the receiver operating characteristic (ROC) curve of 0.749 and 0.746 in differentiating cervical cancers at lower (IB-IIA) from higher (IIB-IVA) FIGO stages. CONCLUSION: Whole-lesion ADC first-order statistics and texture features proved relevant and meaningful in the clinical staging of cervical cancers. PMID- 28728756 TI - Circulating soluble urokinase plasminogen activator receptor levels and peripheral arterial disease outcomes. AB - BACKGROUND AND AIMS: Circulating soluble urokinase plasminogen activator receptor (suPAR) is a marker of immune activation associated with atherosclerosis. Whether suPAR levels are associated with prevalent peripheral arterial disease (PAD) and its adverse outcomes remains unknown and is the aim of the study. METHODS: SuPAR levels were measured in 5810 patients (mean age 63 years, 63% male, 77% with obstructive coronary artery disease [CAD]) undergoing cardiac catheterization. The presence of PAD (n = 967, 17%) was classified as carotid (36%), lower/upper extremities (30%), aortic (15%) and multisite disease (19%). Multivariable logistic and Cox regression models were used to determine independent predictors of prevalent PAD and outcomes including all-cause death, cardiovascular death and PAD-related events after adjustment for age, gender, race, body mass index, smoking, diabetes, hypertension, hyperlipidemia, renal function, heart failure history, and obstructive CAD. RESULTS: Plasma suPAR levels were 22.5% (p < 0.001) higher in patients with PAD compared to those without PAD. Plasma suPAR was higher in patients with more extensive PAD (>=2 compared to single site) p < 0.001. After multivariable adjustment, suPAR was associated with prevalent PAD; odds ratio (OR) for highest compared to lowest tertile of 2.0, 95% CI (1.6-2.5) p < 0.001. In Cox survival analyses adjusted for clinical characteristics and medication regimen, suPAR (in the highest vs. lowest tertile) remained an independent predictor of all-cause death [HR 3.1, 95% CI (1.9-5.3)], cardiovascular death [HR 3.5, 95% CI (1.8-7.0)] and PAD-related events [HR = 1.8, 95% CI (1.3-2.6) p < 0.001 for all]. CONCLUSIONS: Plasma suPAR level is predictive of prevalent PAD and of incident cardiovascular and PAD-related events. Whether SuPAR measurement can help screen, risk stratify, or monitor therapeutic responses in PAD requires further investigation. PMID- 28728758 TI - Large Genetic Study Uncovers 14 New Genes Responsible for Developmental Disorders in Children. AB - The exomes of 4293 families with individuals with undiagnosed developmental disorders were sequenced to identify de novo mutations. The researchers identified 14 new genetic disorders. PMID- 28728759 TI - School Nurses' Experiences and Perceptions of Healthy Eating School Environments. AB - School nurses provide health promotion and health services within schools, as healthy children have a greater potential for optimal learning. One of the school nurses' role is in encouraging healthy eating and increasing the availability of fruits and vegetables in the school. The purpose of this study was to explore and describe school nurses' perceptions of their role in promoting increased fruit and vegetable consumption in the school setting. One avenue to increased availability of fruits and vegetables in schools is Farm to School programs mandated by the Federal government to improve the health of school children. School nurses are optimally positioned to work with Farm to School programs to promote healthy eating. A secondary aim was to explore school nurses' knowledge, experiences and/or perceptions of the Farm to School program to promote fruit and vegetable consumption in the school setting. Three themes emerged from the focus groups: If There Were More of Me, I Could Do More; Food Environment in Schools; School Nurses Promote Health. School nurses reported that they addressed health issues more broadly in their roles as educator, collaborator, advocate and modeling healthy behaviors. Most of the participants knew of Farm to School programs, but only two school nurses worked in schools that participated in the program. Consequently, the participants reported having little or no experiences with the Farm to School programs. PMID- 28728760 TI - ADHD and Everyday Life: Healthcare as a Significant Lifeline. AB - AIM: The aim of this qualitative study was to explore parental experiences of how healthcare practices and healthcare professionals in hospital clinics in Denmark influence everyday life of parents with a child with ADHD. DESIGN AND METHODS: The methodology was focused ethnography. Participant observation and interviews were used as the primary data collection methods. Fifteen families of children with ADHD were included from somatic and psychiatric hospital clinics. RESULTS: Three main themes emerged from the experiences of the families: When the house of cards collapses in everyday life, Treading water before and after receiving the ADHD diagnosis, and Healthcare as a significant lifeline. CONCLUSIONS: Accessibility to healthcare, trusting relationships and healthcare professionals recognizing how ADHD pervades all aspects of everyday life appear to be important factors in providing a lifeline for parents to help them regain confidence and control in disruptive phases. The parents depend on help from healthcare professionals and family-centred care to manage the complex challenges in everyday life. PMID- 28728761 TI - Predictors of Co-occurring Neurodevelopmental Disabilities in Children With Autism Spectrum Disorders. AB - PURPOSE: Co-occurring neurodevelopmental disabilities (including cognitive and language delays and attention deficit hyperactivity disorder) affect over half of children with ASD and may affect later behavioral, language, and cognitive outcomes beyond the ASD diagnosis. However, no studies have examined predictors of co-occurring neurodevelopmental disabilities in children with ASD. This study investigated whether maternal sociodemographic, perinatal and neonatal factors are associated with co-occurring disabilities. DESIGN AND METHODS: This study involved a retrospective analysis of medical records for children diagnosed with ASD between 2009 and 2010 at an Autism Center in the southeast United States. Logistic regression was used to identify predictors of co-occurring neurodevelopmental disabilities. RESULTS: Of the 385 children in the sample, 61% had a co-occurring neurodevelopmental disability. Children whose mothers had less education (OR: 0.905), had never been married (OR: 1.803), or had bleeding during pregnancy (OR: 2.233) were more likely to have a co-occurring neurodevelopmental disability. Both preterm birth and African American race were associated with bleeding during pregnancy. CONCLUSIONS: Several maternal and perinatal risk factors for ASD were found to put children at risk for further diagnoses of co occurring neurodevelopmental disabilities. While prematurity, a well-established risk factor for ASD, as well as maternal ethnicity was not found to increase the risk of a co-occurring disability, this study suggests that bleeding during pregnancy may moderate these relationships. PRACTICE IMPLICATIONS: Understanding maternal, perinatal, and neonatal risk factors may inform healthcare provider screening for ASD and co-occurring neurodevelopmental disabilities by helping providers recognize infants who present with multiple risk factors. PMID- 28728762 TI - Technology to Support Motivational Interviewing. AB - PURPOSE: This paper reports the findings of motivational interviewing (MI) training with and without technology support on school-based health center (SBHC) providers' satisfaction with MI training, providers' self-report of behavioral counseling related to childhood overweight/obesity, and parents' perception of care after training. DESIGN AND METHODS: The effects of training and technology on MI is part of a larger comparative effectiveness, cluster randomized trial. Twenty-four SBHCs in six states received virtual training on MI. Half the sites received HeartSmartKidsTM, a bilingual (English/Spanish), decision-support technology. The technology generated tailored patient education materials. Standard growth charts were plotted and health risks were highlighted to support MI counseling. The results of the MI training included provider satisfaction with MI training and parent assessment of the components of MI in their child's care. Providers and parents were surveyed at baseline, after training, and six months after training. RESULTS: Providers were satisfied with training and reported improvements in counseling proficiency (p<0.0007) and psychological/emotional assessment (p=0.0004) after training. Parents in the technology group reported significant improvement in provider support for healthy eating (p=0.04). CONCLUSION: Virtual training has the potential of preparing providers to use MI to address childhood obesity. Technology improved parent support for healthy eating. Future research should evaluate the impact of technology to support MI on patient outcomes. PRACTICE IMPLICATIONS: Childhood obesity guidelines emphasize that MI should be used to promote healthy weight in children. Training providers on MI may help more providers incorporate obesity guidelines in their practice. PMID- 28728764 TI - Experiences of Daily Life Among Adolescents With Asthma - A Struggle With Ambivalence. AB - OBJECTIVE: There is limited knowledge about how adolescents with asthma view their disease in daily life and how these views impact on management. The aim of this study was to describe experiences of daily life, with particular focus on thoughts, feelings and management of adolescents with asthma. METHODS: In this qualitative study, data were obtained from 10 interviews with adolescents (aged 16-18 years) with asthma recruited from the Swedish population-based prospective birth cohort, BAMSE. Data were analysed through Systematic Text Condensation. RESULTS: Experiences of daily life among adolescents with asthma were defined in four categories: Insight and understanding; Asthma not the focus of daily life; Being acknowledged and, Being affected by asthma symptoms. The adolescents had developed an insight into and understanding of their disease, but did not want asthma to be the focus of their daily lives. The adolescents wanted their asthma to be acknowledged, but not to the point that they were defined by their asthma. They reported having many asthma symptoms, especially during physical activity, but also described a desire to feel healthy, "normal" and like their peers. CONCLUSIONS: Having asthma in adolescence involves several struggles with ambivalence between adapting socially, feeling healthy and managing one's asthma. IMPLICATIONS IN CLINICAL PRACTICE: The provision of person-centred care may be one way to handle the ambivalence among adolescents with asthma and thereby help them to manage their asthma. PMID- 28728763 TI - Implementation of a School Nurse-led Intervention for Children With Severe Obesity in New York City Schools. AB - PURPOSE: The Healthy Options and Physical Activity Program (HOP) is a school nurse-led intervention for children with severe obesity. HOP was developed by experts at the New York City Department of Health and Mental Hygiene and implemented in New York City schools beginning in 2012. The purpose of this study was to evaluate HOP implementation with the goal of informing HOP refinement and potential future HOP dissemination. DESIGN AND METHODS: This study entailed a retrospective analysis of secondary data. Analytic methods included descriptive statistics, Wilcoxon rank sum and Chi square tests, and multivariate logistic regression. RESULTS: During the 2012-2013 school year, 20,518 children were eligible for HOP. Of these, 1054 (5.1%) were enrolled in the program. On average, enrolled children attended one HOP session during the school year. Parent participation was low (3.2% of HOP sessions). Low nurse workload, low school poverty, higher grade level, higher BMI percentile, and chronic illness diagnosis were associated with student enrollment in HOP. CONCLUSIONS: As currently delivered, HOP is not likely to be efficacious. Lessons learned from this evaluation are applicable to future nurse-led obesity interventions. PRACTICE IMPLICATIONS: Prior to implementing a school nurse-led obesity intervention, nursing workload and available support must be carefully considered. Interventions should be designed to facilitate (and possibly require) parent involvement. Nurses who deliver obesity interventions may require additional training in obesity treatment. With attention to these lessons learned, evidence based school nurse-led obesity interventions can be developed. PMID- 28728765 TI - Sense of Coherence and Parenting Representation among Parents of Adolescents with Type 1 Diabetes. AB - INTRODUCTION: This study examines the association between parental sense of coherence (SOC) and maternal and paternal representations of parents of adolescents diagnosed with type 1 diabetes (IDDM). METHOD: Seventy five mothers and fathers of adolescents (age 13-18) diagnosed with IDDM, were recruited. Data were gathered from a demographic and SOC questionnaires, and the Parenting Representations Interview (PRI-A). RESULTS: A significant association was found between mothers' and fathers' SOC and a more balanced description of parenting, and positive correlations between mothers' and fathers' SOC and their representations of the self as parent, representations of the adolescent, and relationships representations. Furthermore, a negative correlation was found between parents' SOC and less differentiated relationships. CONCLUSIONS: SOC may promote well-being in spite of exposure to challenging circumstances as parenting an adolescent with IDDM. It appears that fathers and mothers need to and can be addressed as significant caregivers in any treatment or clinical intervention, as they have a relative involvement in taking care of children and therefore sharing the caregiving responsibilities and functioning as co-primary caregivers. PMID- 28728766 TI - Assessment of Safe Sleep: Validation of the Parent Newborn Sleep Safety Survey. AB - PURPOSE: Sudden Infant Death Syndrome (SIDS) and suffocation account for more than half of all Sudden Unexpected Infant Deaths (SUID). The American Academy of Pediatrics (AAP) recommendations describe the safest environments to protect infants. This study compared parent responses on the Newborn Sleep Safety Survey and observational assessments (N=72) of infant sleep environments in families thought to be at high-risk for non-compliance with AAP recommendations. DESIGN AND METHODS: A naturalistic study of participants enrolled in two home visitation support programs was used. Observed risks ranged from 36.6% (never use pacifier) to 4.3% (never use firm mattress). RESULTS: Results comparing report to observation demonstrated acceptable concordance. Five items had fair concordance (Kappa>.4), four showed moderate concordance (Kappa>.6), and one excellent concordance (Kappa>.8). Although direct observation of safety behaviors is the gold standard in the injury prevention field, direct observation is logistically difficult, time consuming, and costly. CONCLUSIONS: Research and interventions aimed at a reduction of Sudden Infant Death Syndrome (SIDS) and suffocation require accurate assessment of the infant sleep environment. This study provides acceptable evidence for the use of the Newborn Sleep Safety Survey as an alternative to direct observation to assess parent adherence to recommendations. Limitations are discussed. PRACTICAL IMPLICATIONS: This study provided evidence of the usefulness of the Newborn Sleep Safety Survey, a parent survey of infant sleep environments. This tool will provide medical and research professionals a reliable, inexpensive tool to evaluation of the quality of sleep environments using a standard definition. PMID- 28728768 TI - Maintaining Integrity: How Nurses Navigate Boundaries in Pediatric Palliative Care. AB - PURPOSE: To explore how nurses manage personal and professional boundaries in caring for seriously ill children and their families. DESIGN AND METHODS: Using a constructivist grounded theory approach, a convenience sample of 18 registered nurses from four practice sites was interviewed using a semi-structured interview guide. RESULTS: Nurses across the sites engaged in a process of maintaining integrity whereby they integrated two competing, yet essential, aspects of their nursing role - behaving professionally and connecting personally. When skillful in both aspects, nurses were satisfied that they provided high-quality, family centered care to children and families within a clearly defined therapeutic relationship. At times, tension existed between these two aspects and nurses attempted to mitigate the tension. Unsuccessful mitigation attempts led to compromised integrity characterized by specific behavioral and emotional indicators. Successfully mitigating the tension with strategies that prioritized their own needs and healing, nurses eventually restored integrity. Maintaining integrity involved a continuous effort to preserve completeness of both oneself and one's nursing practice. CONCLUSIONS: Study findings provide a theoretical conceptualization to describe the process nurses use in navigating boundaries and contribute to an understanding for how this specialized area of care impacts health care providers. PRACTICE IMPLICATIONS: Work environments can better address the challenges of navigating boundaries through offering resources and support for nurses' emotional responses to caring for seriously ill children. Future research can further refine and expand the theoretical conceptualization of maintaining integrity presented in this paper and its potential applicability to other nursing specialties. PMID- 28728767 TI - Precision, Sensitivity and Patient Preference of Non-Invasive Thermometers in a Pediatric Surgical Acute Care Setting. AB - PURPOSE: The purpose of the project was to compare the temporal artery thermometer (TAT) to the digital probe thermometer readings at axillary or oral sites, to determine the relative precision and sensitivity of the three methods of thermometry, to compare their readings to core temperature when feasible, and to survey patient and family thermometer preferences. DESIGN & METHODS: A randomized crossover design in a 70-bed surgical unit over eight months. Two sets of temperature measurements were obtained for each patient: TAT, axillary, oral (depending on patient ability) and a bladder temperature representing core body temperature (when available). Each method was used twice on each patient, to examine within-method precision. Following measurement, patients or caregivers provided their thermometer preference. For younger/nonverbal patients, a professional observer recorded a disruption score. N=298 patients were enrolled RESULTS: TAT was more precise than oral and axillary thermometers (p<0.001 vs. axillary, p=0.001 vs. oral). TAT measurements were higher on average than axillary and oral, by 0.7 degrees C and 0.6 degrees C respectively (p<0.001). TAT's disruption score for younger patients was 0.6 points lower on average than axillary (p<0.001). 84% of patients and families who indicated a clear thermometry preference chose TAT. Only 3 patients had bladder-temperature devices, and therefore accuracy could not be analyzed. CONCLUSIONS: TAT is more precise, more fever sensitive, less disruptive to younger children, and more preferred by patients and families. PRACTICE IMPLICATIONS: TAT is an acceptable temperature measure that could be substituted for oral or axillary temperature in acute care pediatric settings. PMID- 28728769 TI - Social Inclusion of Children With Down Syndrome: Jewish and Muslim Mothers' Knowledge, Attitudes, Beliefs, and Behavioral Intentions. AB - PURPOSE: The current study examined mothers' knowledge, beliefs, attitudes, and intention to socially integrate children with Down syndrome (DS) in the family, with children without disabilities and school system. DESIGN AND METHODS: A questionnaire based on a descriptive, cross-sectional design was administered to Jewish and Muslim mothers. The questionnaire included demographics, knowledge, beliefs, attitudes, and intention to integrate children with DS. Analysis included a regression test of intention to integrate children with DS and a one way ANOVA for differences between Jewish and Muslim mothers. RESULTS: Nearly all the Jewish mothers (93.7%) and about half the Muslim mothers (52.8%) had performed screening tests for DS during their pregnancy. All mothers displayed low knowledge level about DS. Being Jewish (t=2.89; p=0.005) and holding more positive beliefs (t=3.39; p=0.001) were associated with a higher intention to socially integrate children with DS. Significant positive correlations were found between beliefs and attitudes (r=0.65; p<0.001) and between attitudes and intention to socially integrate children with DS (r=0.39; p<0.001). CONCLUSIONS: This study shows that Jewish and Muslim mothers' beliefs and attitudes towards social inclusion of children with DS are quite positive and the intention to integrate children with DS in the family, with children without disabilities, and in the mainstream school system is high. However, their level of knowledge about DS is low. PRACTICE IMPLICATIONS: Nurses, as a critical source of information about DS, should develop an ethno-cultural sensitivity to diverse populations in order to influence attitudes and beliefs regarding the social integration of children with DS. PMID- 28728770 TI - Don't Push Your Luck! Educational Family Board (Not Bored) Game for School-Age Children Living with Chronic Conditions. AB - PURPOSE: Children who are living with chronic conditions may be supported in self care through enjoyable active learning and family social processes. This research focused on development and evaluation of "Don't Push Your Luck!", an educational board game designed to inspire family discussion about chronic conditions, and help affected children learn about self-care choices and consequences. DESIGN AND METHODS: Mixed-method research was conducted with families from one outpatient Cystic Fibrosis Clinic and four Hemophilia Treatment Centres in Canada and United States (N=72). In phase I, board game prototype and questionnaires were refined with affected boys, siblings, and parents living with hemophilia (n=11), compared with families living with cystic fibrosis (n=11). In phase II, final board game was evaluated with families living with hemophilia (n=50). Data collection included pre-post-game questionnaires on decision-making and Haemo-QoL Index(c), and post-game enjoyment. Analysis included descriptive statistics, inferential statistics (non-parametric), and qualitative themes. RESULTS: Findings revealed this game was an enjoyable and effective resource to engage families in self-care discussions. Key themes included communication, being involved, knowing, decisions and consequences, and being connected. Qualitative and quantitative findings aligned. Statistical significance suggests the game enhanced family engagement to support decision-making skills, as parents identified that the game helped them talk about important topics, and children gained insight regarding family supports and self-care responsibility. CONCLUSIONS: This board game was an effective, developmentally appropriate family resource to facilitate engagement and conversation about everyday life experiences in preparation for self-care. PRACTICE IMPLICATIONS: There is promising potential to extend this educational family board game intervention with a greater range of school-age children and families living with chronic conditions. PMID- 28728771 TI - Contribution of Benson's Relaxation Technique and Brief Psycho-Educational Intervention on Quality of Life of Primary Caregivers of Iranian Children with Chronic Diseases. AB - BACKGROUND: Chronic diseases leave a significant effect on not only the afflicted children but also their parents. Chronic diseases in children may also influence their parents' or primary caregivers' quality of life (QoL). OBJECTIVE: To determine the effectiveness of a Brief Psycho-educational Intervention (BPI) and Benson's Relaxation Technique (BRT) on the QoL of primary caregivers of children with chronic diseases. METHODS: The present quasi-experimental pre-test post-test design was conducted on 100 parents with children who had one chronic disease (50 in each of the control and intervention groups) and were admitted to two state run pediatric hospitals in Tehran, Iran in 2014. The primary caregivers' QoL was assessed using the SF-36 questionnaire before (T1) and four weeks after the intervention (T2). The training was done in four 60-70minute sessions over one week with a 4-week follow-up. Paired t-test, independent t-test, chi-square and Fisher's exact tests were used to analyze the data. RESULTS: On average, large effect sizes (ES>=0.80) were observed after interventions in SF-36 subscales that measured the effect of emotional roles. Small (0.20-0.49) to moderate (0.50-0.79) ESs were found in subscales measuring physical functioning, physical-role, bodily pain, vitality, social functioning and mental health. General health scores remained relatively unchanged at T2. CONCLUSION: These results suggested that BPI and BRT were effective strategies to improve the QoL of primary caregivers. Furthermore, interventions with low cost, and good safety and outcome could improve the QoL of primary caregivers of children with chronic diseases. PMID- 28728772 TI - A Pilot Study Evaluating the Impact of an Adherence-promoting Intervention Among Nonadherent Youth With Inflammatory Bowel Disease. AB - PURPOSE: This study examined the feasibility and impact of a multicomponent adherence intervention among youth with Inflammatory Bowel Disease (IBD) who presented to clinic with poor adherence. DESIGN AND METHODS: Medical providers referred twelve adolescents for the intervention, who participated in 4 weekly visits with a caregiver aimed at improving adherence. RESULTS: Intervention session attendance was 100% and the intervention was rated as feasible and acceptable. Mean adherence increased 12% from baseline to post-intervention (p<0.01), and 6% from baseline to 1-month follow-up (p<0.025). A generalized linear model revealed significantly greater adherence from baseline to post intervention (p<0.001), and from baseline to 1-month follow-up (p<0.01). Logistic Regression revealed a nearly 2:1 odds ratio during post-intervention when compared to the Baseline period (p<0.001). CONCLUSIONS: Findings suggest that the delivery of a multicompoment adherence intervention to poorly adherent youth with IBD can result in significant improvements in their adherence to oral medication. PRACTICE IMPLICATIONS: An intervention individually tailored to each family's unique adherence barriers is a feasible and promising treatment approach for improving medication adherence among nonadherent youth seen in clinical care. PMID- 28728773 TI - Psychometric Properties of the Turkish Version of Caregiver Burden Index (CBI) for Parents of Children with Allergies. AB - : Childhood chronic diseases have a great impact, including physiological, social and financial burdens, on parents. The concept of "caregiver burden" is gaining importance to understand the effects of allergic diseases and plan family centered strategies. PURPOSE: The purpose of this study was to examine the psychometric properties of the Caregiver Burden Index (CBI) in Turkish mothers of children with allergies. METHOD: The participants of this methodological study were 213 mothers of children with allergies between 6 and 12years. Construct validity was evaluated through factor analysis and reliability was evaluated through internal consistency and item-total correlation. RESULTS: In reliability analysis, the overall Cronbach's alpha value (0.85) demonstrated a high level of reliability. The corrected item-total correlation varied between 0.63 and 0.84. In exploratory factor analysis, it was detected that 3 factors structure explained 73.6% of the total variance. CONCLUSION: This study indicated that the CBI is a valid and reliable tool to assess the caregiver burden of mothers of Turkish children with allergies. IMPLICATION FOR PRACTICES: The results of this study contribute to the development and implementation of evidence based models of care that address the caregiver burden needs of parents whose children have allergies. PMID- 28728774 TI - Utilizing virtual reality and immersion video technology as a focused learning tool for children with autism spectrum disorder. PMID- 28728775 TI - Mexican Adolescents' Self-Reports of Parental Monitoring and Sexual Communication for Prevention of Sexual Risk Behavior. AB - PURPOSE: Assess perceptions of parental monitoring and sexual communication for sexual health promotion among adolescents who are Mexican. DESIGN AND METHODS: Adolescents (N=153, n=85 females, n=68 males) between 14years (n=80) and 15 years (n=73) were recruited at a public high school in Monterrey in the state of Nuevo Leon, Mexico. All participants were living with a parent(s). Descriptive statistical analyses were conducted to assess sociodemographic characteristics of the group. Chi-square analyses were conducted to identify potential group differences among the adolescents by age, gender and sexual activity regarding responses to each item of the Spanish Version Parental Monitoring and Sexual Communication Scale (a=0.88). RESULTS: Eleven percent of adolescents self reported sexual activity. Significant group differences by age, gender and sexual activity were identified concerning parental monitoring and sexual communication including: less parental monitoring with older age (14 versus 15 year olds); more parental monitoring for females than males; less monitoring for sexually active adolescents; greater sexual communication for males than females, and among adolescents who were sexually active. CONCLUSIONS: An assessment of adolescents' perceptions of parental monitoring and sexual communication is useful for development of strategies concerning sexual health promotion in Mexico. PRACTICE IMPLICATIONS: The Spanish Version Parental Monitoring and Sexual Communication Scale can be used for assessment and modification of interventions for adolescent populations in Mexico. Information obtained from this assessment can be used to assist parents to enhance positive outcomes for parental monitoring and sexual communication with their children. PMID- 28728776 TI - Collaborating With Parents of Children With Chronic Conditions and Professionals to Design, Develop and Pre-pilot PLAnT (the Parent Learning Needs and Preferences Assessment Tool). AB - PURPOSE: This study aimed to design, develop and pre-pilot an assessment tool (PLAnT) to identify parents' learning needs and preferences when carrying out home-based clinical care for their child with a chronic condition. DESIGN AND METHODS: A mixed methods, two-phased design was used. Phase 1: a total of 10 parents/carers and 13 professionals from six UK's children's kidney units participated in qualitative interviews. Interview data were used to develop the PLAnT. Eight of these participants subsequently took part in an online survey to refine the PLAnT. Phase 2: thirteen parents were paired with one of nine professionals to undertake a pre-pilot evaluation of PLAnT. Data were analyzed using the Framework approach. RESULTS: A key emergent theme identifying parents' learning needs and preferences was identified. The importance of professionals being aware of parents' learning needs and preferences was recognised. Participants discussed how parents' learning needs and preferences should be identified, including: the purpose for doing this, the process for doing this, and what would the outcome be of identifying parents' needs. CONCLUSIONS: The evidence suggests that asking parents directly about their learning needs and preferences may be the most reliable way for professionals to ascertain how to support individual parents' learning when sharing management of their child's chronic condition. PRACTICE IMPLICATIONS: With the increasing emphasis on parent professional shared management of childhood chronic conditions, professionals can be guided by PLAnT in their assessment of parents' learning needs and preferences, based on identified barriers and facilitators to parental learning. PMID- 28728778 TI - Editor's Notes for Authors, Reviewers and Readers. PMID- 28728777 TI - The Emerging Nutritional Problems of School Adolescents: Overweight/Obesity and Associated Factors in Jimma Town, Ethiopia. AB - BACKGROUND: Globally, overweight is rapidly becoming one of the most important medical and public health problems. Adolescent obesity is a multisystem disease with potentially devastating consequences that persist into adulthood. However, there is a paucity of available information regarding the adolescent overweight and obesity in Ethiopia, particularly in the study area. METHODS: A school-based cross-sectional study was conducted from March to April/2015 among 546 adolescents. Study participants were selected using a multi-stage, stratified random sampling method. An interviewer administered questionnaire was used to collect data. Multivariable logistic regression analysis was used to identify independent predictors of overweight and obesity at 95% confidence intervals. RESULTS: The mean dietary diversity score of school adolescents was 6.97+/-1.15. Cereal based diets (99.6%) and vegetables (73.9%) are the two common foods of adolescents. The prevalence of overweight/obesity was 13.3%. Overweight/Obesity was significantly associated with being a female (AOR=3.57 [95% CI:1.28-9.9]), attending private schools (AOR=7.53 [2.51-22.3]), lack of paternal education (AOR=5.57 [95% CI:1.53-20.26]), wealthy households (AOR=3 [95% CI:1.09-8.26]) and not being a vegetarian (AOR=9.23 [95% CI:1.68-50.8]). Adolescents who are physically inactive (AOR=3.7 [95% CI:1.06-13.02]) and those with sedentary lifestyles (AOR=3.64 [95% CI:1.39-9.5]) were more obese compared to their counter peers. CONCLUSIONS: The proportion of overweight/obesity among school adolescent was considerably high. Being a female, learning in private school, high household economic status, not being a vegetarian and having a sedentary life were significantly associated with overweight/obesity. PRACTICE IMPLICATIONS: Findings of this study can be used to guide the development of programs aimed at preventing overweight/obesity in Ethiopia by informing policymakers and other stakeholders about this emerging nutrition-related problem among school adolescents. PMID- 28728779 TI - "Miner's cap-like" solitary frontal bone metastasis from rectal adenocarcinoma on 18F-FDG PET/CT. PMID- 28728781 TI - A yeast two-hybrid assay reveals CMYA1 interacting proteins. AB - CMYA1 is a protein that plays an important role in muscle development and contains a highly conserved Xin repeats region. However, the function of the Xin repeats in CMYA1 is unknown, and there is little information regarding proteins that interact with the CMYA1/Xin-repeats in the bovine system. In this study, we generated a high-quality bovine muscle cDNA library and performed a yeast two hybrid screen twice using both CMYA1 and the Xin-repeats as bait. There were 27 candidate-interacting proteins identified in this screen. Three of the 27 proteins (RPL35A, RPL21 and EIF3G) interacted with both CMYA1 and the Xin repeats, and this interaction was further confirmed using one-to-one Y2H mating. These results showed that the three candidate proteins interacted with CMYA1/Xin repeats and indicated that the Xin-repeats is a key region of CMYA1 required for protein interaction. In conclusion, our results provide new targets on the bovine CMYA1/Xin-repeats interacting proteins, and these findings provide an important reference for the study of how bovine muscle development is regulated. PMID- 28728782 TI - Novel, nonresectional mitral valve repair-another tool in the mitral surgeon's armamentarium. PMID- 28728780 TI - Detecting Regional Stiffness Changes in Aortic Aneurysmal Geometries Using Pressure-Normalized Strain. AB - Transabdominal ultrasound elasticity imaging could improve the assessment of rupture risk for abdominal aortic aneurysms by providing information on the mechanical properties and stress or strain states of vessel walls. We implemented a non-rigid image registration method to visualize the pressure-normalized strain within vascular tissues and adapted it to measure total strain over an entire cardiac cycle. We validated the algorithm's performance with both simulated ultrasound images with known principal strains and anatomically accurate heterogeneous polyvinyl alcohol cryogel vessel phantoms. Patient images of abdominal aortic aneurysm were also used to illustrate the clinical feasibility of our imaging algorithm and the potential value of pressure-normalized strain as a clinical metric. Our results indicated that pressure-normalized strain could be used to identify spatial variations in vessel tissue stiffness. The results of this investigation were sufficiently encouraging to warrant a clinical study measuring abdominal aortic pressure-normalized strain in a patient population with aneurysmal disease. PMID- 28728783 TI - Enhanced recovery pathway versus standard care in patients undergoing video assisted thoracoscopic lobectomy. AB - OBJECTIVE: The objective of this study was to compare outcomes after video assisted thoracoscopic lobectomy or segmentectomy before and after introduction of an enhanced recovery program. METHODS: Data from 600 patients undergoing video assisted lobectomy or segmentectomy between April 2014 and January 2017 were analyzed. A comparative analysis was performed between patients undergoing operation before (365 patients) and after (235 patients) the start of the enhanced recovery program. The incidence of cardiopulmonary complications and 30 day and 90-day mortality, postoperative length of stay, and 30-day and 90-day hospital readmission rates were evaluated. Risk-adjusted cardiopulmonary morbidity and 30-day mortality were calculated for each group and compared. RESULTS: The 2 groups had a similar postoperative length of stay (enhanced recovery pathway median 5 days vs pre-enhanced recovery pathway 4, P = .44), cardiopulmonary complication rates (enhanced recovery pathway 22.6% vs pre enhanced recovery pathway 22.4%, P = .98), 30-day mortality rates (enhanced recovery pathway 3.8% vs pre-enhanced recovery pathway 2.2%, P = .31), and 90-day mortality rates (enhanced recovery pathway 4.7% vs pre-enhanced recovery pathway 3.0%, P = .37). No differences were noted in terms of 30-day (enhanced recovery pathway 7.2% vs pre-enhanced recovery pathway 7.4%, P = .94) or 90-day readmission rates (enhanced recovery pathway 9.8% vs pre-enhanced recovery pathway 12.3%, P = .34). The risk-adjusted cardiopulmonary morbidity rates were similar in the 2 periods (P = .76), whereas the risk-adjusted 30-day mortality was higher in the enhanced recovery pathway period compared with the pre-enhanced recovery pathway mortality (P = .0004). CONCLUSIONS: We found no benefit conferred by the enhanced recovery program on outcomes such as cardiopulmonary complications, 30- and 90-day mortality, length of stay, and readmissions. Enhanced recovery program elements may be insufficiently different than previous standards of perioperative care to confer detectable benefits in our settings. PMID- 28728784 TI - Mitral annuloplasty ring suture forces: Impact of surgeon, ring, and use conditions. AB - OBJECTIVE: The study objective was to quantify the effect of ring type, ring annulus sizing, suture position, and surgeon on the forces required to tie down and constrain a mitral annuloplasty ring to a beating heart. METHODS: Physio (Edwards Lifesciences, Irvine, Calif) or Profile 3D (Medtronic, Dublin, Ireland) annuloplasty rings were instrumented with suture force transducers and implanted in ovine subjects (N = 23). Tie-down forces and cyclic contractile forces were recorded and analyzed at 10 suture positions and at 3 levels of increasing peak left ventricular pressure. RESULTS: Across all conditions, tie-down force was 2.7 +/- 1.4 N and cyclic contractile force was 2.0 +/- 1.2 N. Tie-down force was not meaningfully affected by any factor except surgeon. Significant differences in overall and individual tie-down forces were observed between the 2 primary implanting surgeons. No other factors were observed to significantly affect tie down force. Contractile suture forces were significantly reduced by ring-annulus true sizing. This was driven almost exclusively by Physio cases and by reduction along the anterior aspect, where dehiscence is less common clinically. Contractile suture forces did not differ significantly between ring types. However, when undersizing, Profile 3D forces were significantly more uniform around the annular circumference. A suture's tie-down force did not correlate to its eventual contractile force. CONCLUSIONS: Mitral annuloplasty suture loading is influenced by ring type, ring-annulus sizing, suture position, and surgeon, suggesting that reports of dehiscence may not be merely a series of isolated errors. When compared with forces known to cause suture dehiscence, these in vivo suture loading data aid in establishing potential targets for reducing the occurrence of ring dehiscence. PMID- 28728786 TI - The slippery slope of nonoperative therapy in early-stage lung cancer. PMID- 28728785 TI - Operative strategies to reduce cerebral embolic events during on- and off-pump coronary artery bypass surgery: A stratified, prospective randomized trial. AB - OBJECTIVE: To determine the impact of different aortic clamping strategies on the incidence of cerebral embolic events during coronary artery bypass grafting (CABG). METHODS: Between 2012 and 2015, 142 patients with low-grade aortic disease (epiaortic ultrasound grade I/II) undergoing primary isolated CABG were studied. Those undergoing off-pump CABG were randomized to a partial clamp (n = 36) or clampless facilitating device (CFD; n = 36) strategy. Those undergoing on pump CABG were randomized to a single-clamp (n = 34) or double-clamp (n = 36) strategy. Transcranial Doppler ultrasonography (TCD) was performed to identify high-intensity transient signals (HITS) in the middle cerebral arteries during periods of aortic manipulation. Neurocognitive testing was performed at baseline and 30-days postoperatively. The primary endpoint was total number of HITS detected by TCD. Groups were compared using the Mann-Whitney U test. RESULTS: In the off-pump group, the median number of total HITS were higher in the CFD subgroup (30.0; interquartile range [IQR], 22-43) compared with the partial clamp subgroup (7.0; IQR, 0-16; P < .0001). In the CFD subgroup, the median number of total HITS was significantly lower for patients with 1 CFD compared with patients with >1 CFD (12.5 [IQR, 4-19] vs 36.0 [IQR, 25-47]; P = .001). In the on-pump group, the median number of total HITS was 10.0 (IQR, 3-17) in the single-clamp group, compared with 16.0 (IQR, 4-49) in the double-clamp group (P = .10). There were no differences in neurocognitive outcomes across the groups. CONCLUSIONS: For patients with low-grade aortic disease, the use of CFDs was associated with an increased rate of cerebral embolic events compared with partial clamping during off-pump CABG. A single-clamp strategy during on-pump CABG did not significantly reduce embolic events compared with a double-clamp strategy. PMID- 28728788 TI - Emission characteristics and variation of volatile odorous compounds in the initial decomposition stage of municipal solid waste. AB - The odour pollution occurring in the initial decomposition stage of municipal solid waste (MSW), including collection, transfer and transportation, has not been sufficiently emphasised. Thus the emission characteristics of and variation in odorant generation in this stage were investigated through simulation experiments at different temperatures, waste composition and processing durations. Out of 120 odorous compounds, 52 were detected in seven categories under all tested conditions, with significant variations. In the total concentration and emission rate, ethanol generally showed the largest proportion (larger than 80% on average), followed by unsaturated hydrocarbons which were dominated by propylene (13.1% on average of concentration proportion). The total emissions rapidly increased with processing duration when the temperatures were 15 degrees C to 30 degrees C. The proportion of ethanol increased significantly from 40.1% at 6h to 82.9% at 24h at 30 degrees C. By contrast, a low temperature (5 degrees C) resulted in low concentrations, and propylene accounted for the largest proportion instead of ethanol. With increasing temperature, biogenic compounds with large proportions increased more rapidly than xenobiotic compounds because of accelerated biological process and volatilisation. The emission rates of oxygenated compounds, saturated hydrocarbons, unsaturated hydrocarbons and halogenated compounds significantly increased (by approximately 20% to 50%) with an increase in easily biodegradable portion in the MSW. The proportions were relatively stable with the MSW composition variation, suggesting that most xenobiotic compounds were also derived from easily degradable portions. The olfactory evaluation showed that organic sulphur compounds contributed the most (approximately 75% to 95%) to odour pollution at the beginning of the stage because of their extremely low olfactory thresholds, with methanethiol as the dominant contributor (approximately 50% to 80% when detected). Results of this study can provide useful information for an improved understanding and monitoring of odorant emissions in the initial decomposition stage of MSW. PMID- 28728787 TI - Prenatal co-exposure to manganese and depression and 24-months neurodevelopment. AB - BACKGROUND: Normal prenatal neurodevelopment follows stages that are potentially influenced by both chemical and psychosocial environments. Exposure to elevated manganese during this critically vulnerable period has been found to be neurotoxic. Independently, maternal prenatal depression has been associated with subsequent neurodevelopmental decrements in children. The association between child neurodevelopment and prenatal co-exposure to manganese and maternal depression has not been sufficiently studied. METHODS: During pregnancy and at birth, we measured maternal blood and cord blood manganese levels respectively. Maternal depression was assessed in the 3rd trimester of pregnancy using the Edinburgh Depression Scale. Neurodevelopment was evaluated at 24 months of age with the Bayley Scales of Infant Development. A multivariate multiple regression model was used to analyze cognitive, language and motor scores simultaneously for 473 children from the PROGRESS birth cohort in Mexico City. RESULTS: Over 25% of our study participants reported having depressive symptoms. 3rd trimester blood manganese as well as depressive symptoms were independently negatively associated with all neurodevelopment scores in adjusted models. In stratified analyses, the negative association between manganese (maternal as well as cord blood) and 24 month language scores was stronger among women with depressive symptoms. Receptive language was mostly affected. Inverted U-shaped curves were seen for the association between with cord blood manganese and neurodevelopment scores. CONCLUSIONS: Our findings are in line with previous studies of manganese and depression neurotoxicity. The prenatal period may be particularly sensitive to manganese and depression co-exposures and should be of interest for public health interventions to promote healthy emotional and nutritional pregnancies. PMID- 28728789 TI - Evaluation of the environmental sustainability of different waste-to-energy plant configurations. AB - Residual municipal solid waste (MSW) has an average lower heating value higher than 10GJ/Mg in the EU, and can be recovered in modern Waste-to-Energy (WtE) plants, producing combined heat and power (CHP) and reaching high levels of energy recovery. CHP is pinpointed as the best technique for energy recovery from waste. However, in some cases, heat recovery is not technically feasible - due to the absence of a thermal user (industrial plant or district heating) in the vicinity of the WtE plant - and power production remains the sole possibility. In these cases, there are some challenges involved in increasing the energy performance as much as possible. High energy recovery efficiency values are very important for the environmental sustainability of WtE plants. The more electricity and heat is produced, the better the saving of natural resources that can be achieved. Within this frame, the aim of this work is to carry out an environmental assessment, through Life Cycle Assessment, of an MSW WtE plant, considering different sizes and operated in different ways, from power production only to full cogeneration. The main assumption is that the electric conversion efficiency increases as the plant size increases, introducing technical improvements thanks to the economies of scale. Impact assessment results were calculated using ReCiPe 2008 methods. The climate change indicator is positive when the WtE plant is operated in power production only mode, with values decreasing for the increasing size. Values for the climate change are negative when cogeneration is applied, requiring increasing cogeneration ratios for decreasing size. Similarly, the fossil fuel depletion indicator benefits from increase of both the plant size and the cogeneration rate, but it is always negative, meaning that the residual MSW burning with energy recovery always provides a saving of fossil primary energy. Other indicator values are in general negative and are also beneficially affected by increasing the plant size, but they worsen when increasing the cogeneration rate. The remaining indicators - i.e. human toxicity and terrestrial ecotoxicity - always have positive values, which decrease for increasing plant size and increase as the cogeneration rate increases. However, the local context should be evaluated carefully with reference to the type of electricity which is substituted and in view of a future massive production of renewable electricity, because conclusions change accordingly. Finally, it was evaluated that the inclusion of bottom ash recovery instead of landfilling - can significantly improve the values of several impact assessment indicators. PMID- 28728790 TI - A mechanistic damage model for ligaments. AB - PURPOSE: The accuracy of biomechanical models is predicated on the realism by which they represent their biomechanical tissues. Unfortunately, most models use phenomenological ligament models that neglect the behaviour in the failure region. Therefore, the purpose of this investigation was to test whether a mechanistic model of ligamentous tissue portrays behaviour representative of actual ligament failure tests. MODEL: The model tracks the time-evolution of a population of collagen fibres in a theoretical ligament. Each collagen fibre is treated as an independent linear cables with constant stiffness. Model equations were derived by assuming these fibres act as a continuum and applying a conservation law akin to Huxley's muscle model. A breaking function models the rate of collagen fibre breakage at a given displacement, and was chosen to be a linear function for this preliminary analysis. METHODS: The model was fitted to experimental average curves for the cervical anterior longitudinal ligament. In addition, the model was cyclically loaded to test whether the tissue model behaves similarly. RESULTS: The model agreed very well with experiment with an RMS error of 14.23 N and an R2 of 0.995. Cyclic loading exhibited a reduction in force similar to experimental data. DISCUSSION AND CONCLUSION: The proposed model showcases behaviour reminiscent of actual ligaments being strained to failure and undergoing cyclic load. Future work could incorporate viscous effects, or validate the model further by testing it in various loading conditions. Characterizing the breaking function more accurately would also lead to better results. PMID- 28728791 TI - The effects of Achilles tendon compliance on triceps surae mechanics and energetics in walking. AB - Achilles tendon (AT) compliance can affect the generation and transmission of triceps surae muscle forces, and thus has important biomechanical consequences for walking performance. However, the uniarticular soleus (SOL) and the biarticular (GAS) function differently during walking, with in vivo evidence suggesting that their associated fascicles and tendinous structures exhibit unique kinematics during walking. Given the strong association between muscle fiber length, velocity and force production, we conjectured that SOL and GAS mechanics and energetic behavior would respond differently to altered AT compliance. To test this, we characterized GAS and SOL muscle and tendon mechanics and energetics due to systematic changes in tendon compliance using musculoskeletal simulations of walking. Increased tendon compliance enlarged GAS and SOL tendon excursions, shortened fiber operation lengths and affected muscle excitation patterns. For both muscles, an optimal tendon compliance (tendon strains of approximately 5% with maximum isometric force) existed that minimized metabolic energy consumption. However, GAS muscle-tendon mechanics and energetics were significantly more sensitive to changes in tendon compliance than were those for SOL. In addition, GAS was not able to return stored tendon energy during push off as effectively as SOL, particularly for larger values of tendon compliance. These fundamental differences between GAS and SOL sensitivity to altered tendon compliance seem to arise from the biarticular nature of GAS. These insights are potentially important for understanding the functional consequences of altered Achilles tendon compliance due to aging, injury, or disease. PMID- 28728792 TI - Schnitzler Syndrome With Response to Anakinra Monotherapy: 7 Years of Follow-up. PMID- 28728793 TI - Primary Mucinous Carcinoma of the Skin: A Case Report. PMID- 28728794 TI - Myeloid suppressor cells in cancer and autoimmunity. AB - A bottleneck for immunotherapy of cancer is the immunosuppressive microenvironment in which the tumor cells proliferate. Cancers harness the immune regulatory mechanism that prevents autoimmunity from evading immunosurveillance and promoting immune destruction. Regulatory T cells, myeloid suppressor cells, inhibitory cytokines and immune checkpoint receptors are the major components of the immune system acting in concert with cancer cells and causing the subversion of anti-tumor immunity. This redundant immunosuppressive network poses an impediment to efficacious immunotherapy by facilitating tumor progression. Tumor associated myeloid cells comprise heterogeneous populations acting systemically (myeloid-derived suppressor cells/MDSCs) and/or locally in the tumor microenvironment (MDSCs and tumor-associated macrophages/TAMs). Both populations promote cancer cell proliferation and survival, angiogenesis and lymphangiogenesis and elicit immunosuppression through different pathways, including the expression of immunosuppressive cytokines and checkpoint inhibitors. Several evidences have demonstrated that myeloid cells can express different functional programs in response to different microenvironmental signals, a property defined as functional plasticity. The opposed extremes of this functional flexibility are generally represented by the classical macrophage activation, which identifies inflammatory and cytotoxic M1 polarized macrophages, and the alternative state of macrophage activation, which identifies M2 polarized anti-inflammatory and immunosuppressive macrophages. Functional skewing of myeloid cells occurs in vivo under physiological and pathological conditions, including cancer and autoimmunity. Here we discuss how myeloid suppressor cells can on one hand support tumor growth and, on the other, limit autoimmune responses, indicating that their therapeutic reprogramming can generate opportunities in relieving immunosuppression in the tumor microenvironment or reinstating tolerance in autoimmune conditions. PMID- 28728795 TI - [Artifex spondet peritiam artis (The artisan responds to his art)]. PMID- 28728796 TI - [Lifetime Psychiatric Disorders: a Comparision Study Between Offspring of Parents With Bipolar Disorder Type-I Versus the Offspring of Community Controls Parents]. AB - INTRODUCTION: Literature reports show that Bipolar Offspring (BO) present with a wide range of psychiatric disorders. Comparison between BO and Control Parent Offspring (CPO) may help to identify which psychopathological findings are specific to this high-risk group. OBJECTIVE: To compare the psychopathological characteristics between a group of BO type-I and a group of CPO, by identifying the presence of psychiatric disorders according the DSM-IV-TR. METHODS: A descriptive-correlational, cross-sectional and comparative study was conducted with 127 offspring of parents with bipolar disorder type-I from the multimodal intervention program (PRISMA) and with 150 CPO between 6 and 30 years of age. Subjects were evaluated with validated diagnostic interviews (K-SADS-PL and DIGS). RESULTS: The BO group showed higher frequencies for bipolar disorder (Prevalence Ratio [PR]=17.70; 95% confidence interval [CI]; 1.02 - 306.83), bipolar disorder not otherwise specified (PR=23.07, 95% CI; 2.8 - 189.0, P=.0001), disorders due to psychoactive substance use (PR=9.52, 95% CI; 2.93 30.90), oppositional defiant disorder (PR=4.10, 95% CI; 1.70 -9.89), posttraumatic stress disorder (PR=3.90, 95% CI 1.30 -11.66), disorder due to alcohol use (PR=3.84, 95% CI; 1.28 -11.48), attention deficit/hyperactivity disorder (PR=2.26, 95% CI; 1.37 -3.75), and major depressive disorder (PR=2.25, 95% CI; 1.13 -4.50). Statistically significant differences were also found in the CGAS and GAF functional scales, with lower scores for the BO group. CONCLUSION: These findings confirm previous literature reports showing that BO have higher rates of affective and non-affective psychiatric disorders than control subjects, and also a lower level of global functioning. PMID- 28728797 TI - [Prevalence of Hypothyroidism in Major Psychiatric Disorders in Hospitalised Patients in Montserrat Hospital During the period March to October 2010]. AB - INTRODUCTION: Hypothyroidism results from inadequate production of thyroid hormone. It is known that there is a relationship between the major psychiatric disorders and hypothyroidism. OBJECTIVE: To determine the prevalence of hypothyroidism in patients admitted due to major psychiatric disorders in Montserrat Hospital during the period from March to October 2010. MATERIAL AND METHODS: A descriptive cross-sectional study was conducted on 105 patients admitted to Montserrat Hospital with a primary diagnosis of major psychiatric disorder (major depression, bipolar affective disorder, generalised panic disorder, panic disorder, mixed anxiety-depressive disorder, and schizophrenia) in the aforementioned period. Thyroid Stimulating Hormone (TSH) was performed to assess the evidence of hypothyroidism. RESULTS: The overall prevalence of hypothyroidism was found to be 10.5% (95% CI; 5%-16%). It was 12.5% in anxiety disorder, 11.1% in depressive disorder, with a lower prevalence of 10.3% for bipolar disorder, and 9.9% for schizophrenia. CONCLUSIONS: The overall prevalence of hypothyroidism was found to be less than in the general population, which is between 4.64% and 18.5%, and hypothyroidism was found in disorders other than depression. PMID- 28728798 TI - [Multiple-Victimisation due to Armed Conflict and Emotional Distress in the State of Magdalena, Colombia]. AB - BACKGROUND: Emotional distress is common in Colombian armed conflict victims. Multiple-victimisation is associated with an increase in emotional distress than victimisation due a single event. However, the association between poly victimisation and emotional distress among victims of the armed conflict in Colombia has not been documented. OBJECTIVE: To study the association between multiple-victimisation and emotional distress in victims of armed conflict in the State of Magdalena, Colombia. METHODS: A cross-sectional study was designed, with a secondary analysis of registration of the Psychosocial Care Program and Victim Integral Health (PAPSIVI) in the State of Magdalena, from 2013 to 2014. The profile formula grouped demographic variables, victimising events, and a set of symptoms of emotional distress (perceived discrimination, depressive and anxiety stress). Odds ratio (OR, 95%CI) were established as measures of association. RESULTS: A total of 943 people were included, with 67.4% women, and ages between18 and 94 years (mean 47.9+/-14.2). A total of 109 (11.7%) suffered from multiple victimisation. Multiple victimisation events were associated with more emotional distress, depressive symptoms (OR=1.5; 95%CI, 1.3-1.8), perceived stigma (OR=1.3; 95%CI, 1.1-1.5), and anxiety-stress (OR=1.2; 95%CI 1.0-1.4) than a single event. CONCLUSIONS: There is more emotional distress in multiple victimisations than in a single victimisation event during armed conflict in this region of Colombia. Further studies are required on this topic. PMID- 28728799 TI - [Mental Health Determines the Quality of Life in Patients With Cancer-Related Neuropathic Pain in Quito, Ecuador]. AB - OBJECTIVE: To identify the main factors determining the health related quality of life (HRQL) in patients with cancer-related neuropathic pain in a tertiary care hospital. METHODS: A cross-sectional analytical study was performed on a sample of 237 patients meeting criteria for cancer-related neuropathic pain. Clinical and demographic variables were recorded including, cancer type, stage, time since diagnosis, pain intensity, physical functionality with the Palliative Performance Scale (PPS), and anxiety and depression with the Hospital Anxiety and Depression Scale (HADS). Their respective correlation coefficients (r) with HRQL assessed with the SF-36v2 Questionnaire were then calculated. Linear regression equations were then constructed with the variables that showed an r>=.5 with the HRQL. RESULTS: The HRQL scores of the sample were 39.3+/-9.1 (Physical Component) and 45.5+/-13.8 (Mental Component). Anxiety and depression strongly correlated with the mental component (r=-.641 and r=-.741, respectively) while PPS score correlated with the physical component (r=.617). The linear regression model that better explained the variance of the mental component was designed combining the Anxiety and Depression variables (R=77.3%; P<.001). CONCLUSIONS: The strong influence of psychiatric comorbidity on the HRQL of patients with cancer-related neuropathic pain makes an integral management plan essential for these patients to include interventions for its timely diagnosis and treatment. PMID- 28728801 TI - [Muscle Dysmorphia and Use of Ergogenics Substances. A Systematic Review]. AB - The use of ergogenic substances (UES) is not restricted to achieving a better athletic performance, but also it is a behavior for body changing through muscle development; however, little is known about the relationship between muscle dysmorphia (MD) and UES. Therefore, it was conducted a systematic review of those empirical papers that have studied this relationship over the last decade (2004 2014). First it is highlighted that of the 22 articles analyzed, only 13 explicitly aimed this interest. Besides, although the documented data outlined some relevant aspects such as the existence of a high co-occurrence (60-90%) between MD and UES. In general, the evidence is still incipient and uncertain, mainly because of the large disparity between the methodologies of the studies, particularly in terms of indicators, parameters and measures utilized to assess UES within the context of MD. PMID- 28728800 TI - [Cross-cultural Adaptation of the PedsQL Questionnaire Cancer Module, Version 3.0 for Use in Colombia]. AB - INTRODUCTION: Quality of life is an important outcome in paediatric cancer patients. Its evaluation at different times during the clinical course of the disease is essential for clinical practice focused on the needs of the patients. There is not a specific assessment tool for this purpose in Colombia. OBJECTIVE: To perform the cultural adaptation of the quality of life scale PedsQL (Paediatric Quality of Life) Cancer Module, Version 3.0 for use in Colombia. METHODS: Permission for use of the scale was obtained and the algorithm steps of the Mapi Research Trust group were followed: Direct and independent translations of scale by two native Colombian Spanish speaking translators, obtaining a preliminary version from the translations. This was followed by a back translation by a native English speaking translator and a review of the process by the author of the scale, inclusion of suggestions, and implementation of the pilot study. RESULTS: Direct translations were similar in the instructions and response options; a consensus meeting in 8 of the 27 items was required to choose the best translation. The author made no suggestions and gave his endorsement to the implementation of the pilot, in which, 2 items were modified in order to improve their understanding. CONCLUSIONS: There is a Colombian Spanish version of the PedsQL questionnaire 3.0 Cancer Module, to be submitted for a validation study prior to its use in the assessment of quality of life in paediatric cancer patients. PMID- 28728802 TI - [Psychotherapies for the Treatment of Phantom Limb Pain]. AB - INTRODUCTION: The phantom limb pain has been described as a condition in which patients experience a feeling of itching, spasm or pain in a limb or body part that has been previously amputated. Such pain can be induced by a conflict between the representation of the visual and proprioceptive feedback of the previously healthy limb. The phantom limb pain occurs in at least 42 to 90% of amputees. Regular drug treatment of phantom limb pain is almost never effective. METHODS: A systematic review of the literature was conducted in Medline and Cochrane using the MESH terms "phantom limb pain" and "psychotherapy", published in the last 10 years, in English and Spanish, finding 49 items. After reviewing the abstracts, 25 articles were excluded for not being related to the objective of the research. Additionally cross references of included articles and literature were reviewed. OBJECTIVES: To describe the psychotherapies used in the management of phantom limb pain, their effectiveness and clinical application reported in the literature. AIMS: The mechanisms underlying phantom limb pain were initially explained, as were the published studies on the usefulness of some psychotherapies such as mirror visual feedback and immersive virtual reality, visual imagery, desensitization and reprocessing eye movements and hypnosis. CONCLUSIONS: The phantom limb pain is a complex syndrome that requires pharmacological and psychotherapeutic intervention. The psychotherapies that have been used the most as adjuvants in the treatment of phantom limb pain are mirror visual feedback, desensitization and reprocessing eye movements, imagery and hypnosis. Studies with more representative samples, specifically randomized trials are required. PMID- 28728803 TI - Neural Foundations of Creativity: A Systematic Review. AB - When considering the importance of the human cognitive function of creativity, we often overlook the fact that it is due to human creativity and to the constant search for new sensory stimuli that our world has, throughout the years, been one of innovation in every aspect of our existence -in the sciences, the humanities, and the arts. Almost everything that surrounds us is the result of human creativity, therefore it is not difficult to understand that although neuroscientific research has led to valuable perceptions into the probable underpinnings of this multifaceted ability, the precise neurological substrates that underlie creativity are yet to be determined. Despite the establishment of a strong link between creativity and divergent thinking, other brain networks have been implicated in this mental process. The following review underlines recent studies on the neural foundations of creativity. A comprehensive analysis of the upmost important facts will be presented, with emphasis on concepts, tests, and methods that have been used to study creativity, and how they have outlined a pathway to the key understanding of this unique human ability. PMID- 28728804 TI - Pharmacy technician self-efficacies: Insight to aid future education, staff development, and workforce planning. AB - BACKGROUND: The roles of pharmacy technicians are increasingly prominent given pharmacy's transition to patient-centered activities and evolving scopes of practice in many U.S. states and throughout the world. OBJECTIVES: The aims of this study were to assess U.S. pharmacy technicians' self-efficacies for and attitudes toward performing current and emerging roles in hospital and in community pharmacy and to identify factors related to pharmacy technician self efficacies in these roles. METHODS: A total of 5000 pharmacy technicians from 8 U.S. states were sent an electronic survey eliciting data on current involvement, self-efficacies, and attitudes for practicing in an expansive list of practice activities. The 8 states from which the sample was drawn were selected from a stratified randomized procedure using U.S. Census Bureau geographically defined regions. Pre-notification and response reminders were employed. Data were analyzed descriptively and with univariate, inferential tests, as appropriate, to determine associations with commitment, practice environment, experience level, and other variables. RESULTS: Of the 612 participants who responded, 494 were currently working as a technician and not enrolled in a PharmD program of study. Participants reported various activities in which they were highly engaged. Overall, attitudes toward performing most of the activities and self-efficacies were quite favorable, even for those activities in which technicians were currently less involved. There were some notable differences between technicians practicing in community versus hospital settings. Years of experience, profession commitment, and advanced employee ranking were associated with higher levels of self-efficacy, overall. CONCLUSIONS: This initial examination of pharmacy technician self-efficacies identified areas that along with other factors could help employers with further expanding technician practice activities and vocational institutions with considerations for education and development of these key members of the workforce. The results would suggest technicians to be ready for continued evolution in their practice. PMID- 28728805 TI - Associations of C-reactive protein and psychological distress are modified by antidepressants, supporting an inflammatory depression subtype: Findings from UKHLS. AB - BACKGROUND: Clinical evidence increasingly suggests inflammation may be important specifically for an etiologically distinct depression subtype, characterised by resistance to antidepressant medication. However, epidemiological investigations of the relationship of inflammation with depression and psychological distress have failed to acknowledge these developments, which may have resulted in bias or masking of associations driven by the subtype. This may have contributed to inconsistent results in epidemiological studies, and equivocal support for an inflammation-depression link. METHODS: An antidepressant-resistant, inflammatory depression subtype would result in stronger associations of depressive symptomatology with inflammation among antidepressant users than non-users, due to over-representation of subtype individuals among antidepressant users experiencing severe or persistent symptoms. We investigate, in a sample of 10,363 UK adults aged 16-98, modification by antidepressants of cross-sectional and longitudinal associations between C-reactive protein and psychological distress (General Health Questionnaire score, GHQ). We account for confounding by age, gender, income, inflammatory somatic illness, body mass index and, in longitudinal models, baseline psychological distress. Sensitivity analyses consider smoking, ethnicity, and other medications. RESULTS: Robust associations of log-CRP and GHQ were seen for antidepressant users but not for non-users in both cross-sectional (coeff: 0.54, p=0.01vs 0.06, p=0.28) and longitudinal models (coeff: 0.57, p=0.006vs 0.04, p=0.39 two waves post-baseline). Cross-sectional associations were strongest for tricyclic users, and longitudinal associations strongest for SSRI users. In multilevel, repeated-measures longitudinal models, associations for antidepressant users peaked two waves after baseline before declining. CONCLUSIONS: Results suggest evidence for existence of an inflammatory depression subtype. Previous studies' exclusion of antidepressant users and failure to consider interactive effects may have obscured associations driven by the subgroup. Follow-up work is now needed in community samples with clinical depression measures and prescription histories, to further elucidate the mechanisms involved. PMID- 28728806 TI - FoxP3 and TLR2 in co-expression in oral cancer. PMID- 28728807 TI - The impact of team-based primary care on health care services utilization and costs: Quebec's family medicine groups. AB - We investigate the effects on health care costs and utilization of team-based primary care delivery: Quebec's Family Medicine Groups (FMGs). FMGs include extended hours, patient enrolment and multidisciplinary teams, but they maintain the same remuneration scheme (fee-for-service) as outside FMGs. In contrast to previous studies, we examine the impacts of organizational changes in primary care settings in the absence of changes to provider payment and outside integrated care systems. We built a panel of administrative data of the population of elderly and chronically ill patients, characterizing all individuals as FMG enrollees or not. Participation in FMGs is voluntary and we address potential selection bias by matching on GP propensity scores, using inverse probability of treatment weights at the patient level, and then estimating difference-in-differences models. We also use appropriate modelling strategies to account for the distributions of health care cost and utilization data. We find that FMGs significantly decrease patients' health care services utilization and costs in outpatient settings relative to patients not in FMGs. The number of primary care visits decreased by 11% per patient per year among FMG enrolees and specialist visits declined by 6%. The declines in costs were of roughly equal magnitude. We found no evidence of an effect on hospitalizations, their associated costs, or the costs of ED visits. These results provide support for the idea that primary care organizational reforms can have impacts on the health care system in the absence of changes to physician payment mechanisms. The extent to which the decline in GP visits represents substitution with other primary care providers warrants further investigation. PMID- 28728808 TI - Wolves in sheep's clothing: Is non-profit status used to signal quality? AB - Why do many firms in the healthcare sector adopt non-profit status? One argument is that non-profit status serves as a signal of quality when consumers are not well informed. A testable implication is that an increase in consumer information may lead to a reduction in the number of non-profits in a market. We test this idea empirically by exploiting an exogenous increase in consumer information in the US nursing home industry. We find that the information shock led to a reduction in the share of non-profit homes, driven by a combination of home closure and sector switching. The lowest quality non-profits were the most likely to exit. Our results have important implications for the effects of reforms to increase consumer provision in a number of public services. PMID- 28728809 TI - Scrofula in a Child. PMID- 28728810 TI - Beyond Folliculitis: Recognizing Herpes Gladiatorum in Adolescent Athletes. PMID- 28728811 TI - Newborn Screening for Lysosomal Storage Disorders in Illinois: The Initial 15 Month Experience. AB - OBJECTIVES: To assess the outcomes of newborn screening for 5 lysosomal storage disorders (LSDs) in the first cohort of infants tested in the state of Illinois. STUDY DESIGN: Tandem mass spectrometry was used to assay for the 5 LSD-associated enzymes in dried blood spot specimens obtained from 219 973 newborn samples sent to the Newborn Screening Laboratory of the Illinois Department of Public Health in Chicago. RESULTS: The total number of cases with a positive diagnosis and the incidence for each disorder were as follows: Fabry disease, n = 26 (1 in 8454, including the p.A143T variant); Pompe disease, n = 10 (1 in 21 979); Gaucher disease, n = 5 (1 in 43 959); mucopolysaccharidosis (MPS) type 1, n = 1 (1 in 219 793); and Niemann-Pick disease type A/B, n = 2 (1 in 109 897). Twenty-two infants had a positive screen for 1 of the 5 disorders but could not be classified as either affected or unaffected after follow-up testing, including genotyping. Pseudodeficiencies for alpha-L-iduronidase and alpha-glucosidase were detected more often than true deficiencies. CONCLUSIONS: The incidences of Fabry disease and Pompe disease were significantly higher than published estimates, although most cases detected were predicted to be late onset. The incidences of Gaucher disease, MPS I, and Niemann-Pick disease were comparable with previously published estimates. A total of 16 infants could not be positively identified as either affected or unaffected. To validate the true risks and benefits of newborn screening for LSD, long term follow-up in these infants and those detected with later-onset disorders will be essential. PMID- 28728812 TI - Longitudinal Association between Obesity and Dental Caries in Adolescents. AB - OBJECTIVE: To investigate the longitudinal association between obesity and dental caries among adolescents. STUDY DESIGN: The present cohort study was conducted among a random sample of 12-year-old adolescents in Hong Kong. Two rounds of follow-up were performed when the participants were aged 15 and 18 years. A total of 668 participants were included at age 12 years, and 282 of them completed all 3 phases of data collection. Body mass index, waist circumference, waist-to-hip (WHR) ratio, waist-to-height ratio, and triceps skinfold thickness were measured as indices of obesity. Dental caries were assessed by the number of decayed, missing, and filled permanent teeth (DMFT). RESULTS: The percentage of underweight adolescents increased significantly from 6.0% to 23.8% during the observation period (P <.001). Body mass index, waist circumference, waist-to-hip ratio, and waist-to-height ratio were related to frequency of tooth brushing at age 15 and 18 years. The prevalence of dental caries was 25.5%, 53.2%, and 62.1% at 12, 15 and 18 years, respectively. At age 18 years, mean DMFT of participants whose WHR at age 15 years was below the median value was 0.707 times (ie, 29.3%) lower than the DMFT of those whose WHR was above the median (P = .028). Participants with greater DMFT at age 15 demonstrated significantly increased probability of having WHR above the median (OR 1.135; 95% CI 1.01-1.28; P = .041) at age 18 years. CONCLUSION: There is longitudinal association between central obesity and dental caries experience among adolescents aged 15-18 years. PMID- 28728813 TI - Central nervous system involvement in primary hyperoxaluria demonstrated by brain ultrasonography. PMID- 28728814 TI - A Tour de Force: The Discovery, Properties, and Function of Piezo Channels. AB - Mechanical transducers appear throughout cell biology and are used to convert mechanical stress into chemical or electrical signals that allow the cell to respond to environmental changes. In the past six years, a eukaryotic mechanical channel family with two members, Piezo1 and Piezo2, has been identified. Piezo1 was shown to be a cation-selective channel that does not require ancillary proteins for activity. Mouse Piezo1 is large, with over 2500 amino acids, and is not homologous to other ion channels. Both piezo channels have rapid voltage dependent inactivation with a reversal potential near 0mV. The CryoEm structure of Piezo1 at 4.8A shows trimer stoichiometry. Since the discovery of the piezo channels, their roles in the physiological response of cells have started to emerge. Significant progress has been made in understanding the intrinsic properties of the channels and how these properties are modulated by cytoskeletal elements. Specific diseases, such as hereditary xerocytosis affecting red blood cells, have mutations in Piezo1 that alter the cell's response to force, typically slowing inactivation and introducing a latency for activation. A number of physiological functions for piezo channels have been identified. These range from sensing the stiffness of surrounding substrate, to the response to light touch, to serotonin release from the gut. This review provides a general overview of the properties and roles of Piezo1 and Piezo2 in eukaryotic mechanotransduction. PMID- 28728815 TI - The Structural Basis for Sensing by the Piezo1 Protein. AB - Mechanotransduction is one of the processes by which cells sense and convert mechanical stimuli into biological signals. Experimental data from various species have revealed crucial roles for mechanotransduction in organ development and a plethora of physiological activities. Piezo proteins have recently been identified as the long-sought-after mechanically activated cation channels in eukaryotes. The architecture of mouse Piezo1 (mPiezo1) channel determined by cryoelectron microscopic single-particle analysis at medium resolution yielded important insights into the mechanical force sensing mechanism. mPiezo1 is found to form a trimeric propeller-like structure with the extracellular domains resembling three distal blades and a central cap. The transmembrane region consists of a central pore module that likely determines the ion-conducting properties of mPiezo1, and three peripheral wings formed by arrays of paired transmembrane helices. Compared with the central pore module, the three distal blades display considerably larger flexibility. In the intracellular region, three long beam-like domains (~80A in length) support the whole transmembrane region and connect the mobile peripheral regions to the central pore module. This unique design suggests that the trimeric mPiezo1 may mechanistically function in similar principles as how propellers sense and transduce force to control the ion conductivity. This review summarizes the current knowledge on the structure and proposes possible gating mechanisms of mPiezo1. PMID- 28728816 TI - In Touch With the Mechanosensitive Piezo Channels: Structure, Ion Permeation, and Mechanotransduction. AB - Mechanotransduction, the conversion of mechanical forces into biological signals, plays critical roles in various physiological and pathophysiological processes in mammals, such as conscious sensing of touch, pain, and sound, as well as unconscious sensing of blood flow-associated shear stress, urine flow, and bladder distention. Among the various molecules involved in mechanotransduction, mechanosensitive (MS) cation channels have long been postulated to represent one critical class of mechanotransducers that directly and rapidly converts mechanical force into electrochemical signals. Despite the awareness of their functional significance, the molecular identities of MS cation channels in mammals had remained elusive for decades till the groundbreaking finding that the Piezo family of genes, including Piezo1 and Piezo2, constitutes their essential components. Since their identification about 6years ago, tremendous progress has been made in understanding their physiological and pathophysiological importance in mechanotransduction and their structure-function relationships of being the prototypic class of mammalian MS cation channels. On the one hand, Piezo proteins have been demonstrated to serve as physiologically and pathophysiologically important mechanotransducers for most, if not all, mechanotransduction processes. On the other hand, they have been shown to form a remarkable three-bladed, propeller-shaped homotrimeric channel complex comprising a separable ion conducting pore module and mechanotransduction modules. In this chapter, we review the major advancements, with a particular focus on the structural and biophysical features that enable Piezo proteins to serve as sophisticated MS cation channels for force sensing, transduction, and ion conduction. PMID- 28728817 TI - Piezo2 in Cutaneous and Proprioceptive Mechanotransduction in Vertebrates. AB - Mechanosensitivity is a fundamental physiological capacity, which pertains to all life forms. Progress has been made with regard to understanding mechanosensitivity in bacteria, flies, and worms. In vertebrates, however, the molecular identity of mechanotransducers in somatic and neuronal cells has only started to appear. The Piezo family of mechanogated ion channels marks a pivotal milestone in understanding mechanosensitivity. Piezo1 and Piezo2 have now been shown to participate in a number of processes, ranging from arterial modeling to sensing muscle stretch. In this review, we focus on Piezo2 and its role in mediating mechanosensation and proprioception in vertebrates. PMID- 28728819 TI - Regulation of Piezo Channels by Cellular Signaling Pathways. AB - The recently identified mechanically activated Piezo1 and Piezo2 channels play major roles in various aspects of mechanosensation in mammals, and their mutations are associated with human diseases. Recent reports show that activation of cell surface receptors coupled to heterotrimeric Gq proteins increase the sensitivity of Piezo2 channels to mechanical stimuli. Activation of the cyclic adenosine monophosphate pathway was also shown to potentiate Piezo2 channel activity. This phenomenon may play a role in mechanical allodynia or hyperalgesia during inflammation. Both Piezo1 and Piezo2 channels are inhibited upon depletion of plasma membrane phosphoinositides, in response to phospholipase C activation by Ca2+ influx via the transient receptor potential vanilloid 1 channels. This review will discuss current knowledge on regulation of Piezo channels by these intracellular signaling pathways. PMID- 28728818 TI - Mechanosensitive Piezo Channels in the Gastrointestinal Tract. AB - Sensation of mechanical forces is critical for normal function of the gastrointestinal (GI) tract and abnormalities in mechanosensation are linked to GI pathologies. In the GI tract there are several mechanosensitive cell types epithelial enterochromaffin cells, intrinsic and extrinsic enteric neurons, smooth muscle cells and interstitial cells of Cajal. These cells use mechanosensitive ion channels that respond to mechanical forces by altering transmembrane ionic currents in a process called mechanoelectrical coupling. Several mechanosensitive ionic conductances have been identified in the mechanosensory GI cells, ranging from mechanosensitive voltage-gated sodium and calcium channels to the mechanogated ion channels, such as the two-pore domain potassium channels K2P (TREK-1) and nonselective cation channels from the transient receptor potential family. The recently discovered Piezo channels are increasingly recognized as significant contributors to cellular mechanosensitivity. Piezo1 and Piezo2 are nonselective cationic ion channels that are directly activated by mechanical forces and have well-defined biophysical and pharmacologic properties. The role of Piezo channels in the GI epithelium is currently under investigation and their role in the smooth muscle syncytium and enteric neurons is still not known. In this review, we outline the current state of knowledge on mechanosensitive ion channels in the GI tract, with a focus on the known and potential functions of the Piezo channels. PMID- 28728820 TI - Role of Piezo Channels in Joint Health and Injury. AB - Cartilage is an intrinsically mechanically sensitive tissue composed of chondrocytes as the only cell type. Chondrocyte mechanotransduction is not well understood, but recently we identified critical components of the mechanotransduction machinery demonstrating how mechanical stimulation of these cells can be converted into cellular calcium signals. Physiologic mechanical cues induce anabolic responses of (post-mitotic) chondrocytes via transient receptor potential vanilloid 4 ion channels, whereas injurious mechanical stress is transduced by Piezo1 jointly with Piezo2 ion channels. This chapter sheds light on the latter discovery and provides a rationale for follow-up questions, such as the nature of interaction between Piezo1 and Piezo2, and their tethering to the cytoskeleton. These recent insights can be leveraged toward translational medical progress to benefit diagnosis and treatment of osteoarthritis, representing a large and growing unmet medical need in the United States and large parts of the world. PMID- 28728821 TI - The Kinetics and the Permeation Properties of Piezo Channels. AB - Piezo channels are eukaryotic, cation-selective mechanosensitive channels (MSCs), which show rapid activation and voltage-dependent inactivation. The kinetics of these channels are largely consistent across multiple cell types and different stimulation paradigms with some minor variability. No accessory subunits that associate with Piezo channels have been reported. They are homotrimers and each ~300kD monomer has an N-terminal propeller blade-like mechanosensing module, which can confer mechanosensing capabilities on ASIC-1 (the trimeric non-MSC, acid-sensing ion channel-1) and a C-terminal pore module, which influences conductance, selectivity, and channel inactivation. Repeated stimulation can cause domain fracture and diffusion of these channels leading to synchronous loss of inactivation. The reconstituted channels spontaneously open only in asymmetric bilayers but lack inactivation. Mutations that cause hereditary xerocytosis alter PIEZO1 kinetics. The kinetics of the wild-type PIEZO1 and alterations thereof in mutants (M2225R, R2456K, and DhPIEZO1) are summarized in the form of a quantitative model and hosted online. The pore is permeable to alkali ions although Li+ permeates poorly. Divalent cations, notably Ca2+, traverse the channel and inhibit the flux of monovalents. The large monovalent organic cations such as tetramethyl ammonium and tetraethyl ammonium can traverse the channel, but slowly, suggesting a pore diameter of ~8A, and the estimated in-plane area change upon opening is around 6-20nm2. Ruthenium red can enter the channel only from the extracellular side and seems to bind in a pocket close to residue 2496. PMID- 28728822 TI - A Microfluidic Approach for Studying Piezo Channels. AB - Microfluidics is an interdisciplinary field intersecting many areas in engineering. Utilizing a combination of physics, chemistry, biology, and biotechnology, along with practical applications for designing devices that use low volumes of fluids to achieve high-throughput screening, is a major goal in microfluidics. Microfluidic approaches allow the study of cells growth and differentiation using a variety of conditions including control of fluid flow that generates shear stress. Recently, Piezo1 channels were shown to respond to fluid shear stress and are crucial for vascular development. This channel is ideal for studying fluid shear stress applied to cells using microfluidic devices. We have developed an approach that allows us to analyze the role of Piezo channels on any given cell and serves as a high-throughput screen for drug discovery. We show that this approach can provide detailed information about the inhibitors of Piezo channels. PMID- 28728823 TI - Piezo1 Channels in Vascular Development and the Sensing of Shear Stress. AB - A critical point in mammalian development occurs before mid-embryogenesis when the heart starts to beat, pushing blood into the nascent endothelial lattice. This pushing force is a signal, detected by endothelial cells as a frictional force (shear stress) to trigger cellular changes that underlie the essential processes of vascular remodeling and expansion required for embryonic growth. The processes are complex and multifactorial and Piezo1 became a recognized player only 2years ago, 4years after Piezo1's initial discovery as a functional membrane protein. Piezo1 is now known to be critical in murine embryonic development just at the time when the pushing force is first detected by endothelial cells. Murine Piezo1 gene disruption in endothelial cells is embryonic lethal and mutations in human PIEZO1 associate with severe disease phenotype due to abnormal lymphatic vascular development. Piezo1 proteins coassemble to form calcium-permeable nonselective cationic channels, most likely as trimers. They are large proteins with little if any resemblance to other proteins or ion channel subunits. The channels appear to sense mechanical force directly, including the force imposed on endothelial cells by physiological shear stress. Here, we review current knowledge of Piezo1 in the vascular setting and discuss hypotheses about how it might serve its vascular functions and integrate with other mechanisms. Piezo1 is a new important player for investigators in this field and promises much as a basis for better understanding of vascular physiology and pathophysiology and perhaps also discovery of new therapies. PMID- 28728824 TI - Origin of the Force: The Force-From-Lipids Principle Applied to Piezo Channels. AB - Piezo channels are a ubiquitously expressed, principal type of molecular force sensor in eukaryotes. They enable cells to decode a myriad of physical stimuli and are essential components of numerous mechanosensory processes. Central to their physiological role is the ability to change conformation in response to mechanical force. Here we discuss the evolutionary origin of Piezo in relation to other MS channels in addition to the force that gates Piezo channels. In particular, we discuss whether Piezo channels are inherently mechanosensitive in accordance with the force-from-lipid paradigm which has been firmly established for bacterial MS channels and two-pore domain K+ (K2P) channels. We also discuss the evidence supporting a reliance on or direct interaction with structural scaffold proteins of the cytoskeleton and extracellular matrix according to the force-from-filament principle. In doing so, we explain the false dichotomy that these distinctions represent. We also discuss the possible unifying models that shed light on channel mechanosensitivity at the molecular level. PMID- 28728825 TI - Genetic Diseases of PIEZO1 and PIEZO2 Dysfunction. AB - Mutations in the genes encoding the mechanosensitive cation channels PIEZO1 and PIEZO2 are responsible for multiple hereditary human diseases. Loss-of-function mutations in the human PIEZO1 gene cause autosomal recessive congenital lymphatic dysplasia. Gain-of-function mutations in the human PIEZO1 gene cause the autosomal dominant hemolytic anemia, hereditary xerocytosis (also known as dehydrated stomatocytosis). Loss-of-function mutations in the human PIEZO2 gene cause an autosomal recessive syndrome of muscular atrophy with perinatal respiratory distress, arthrogryposis, and scoliosis. Gain-of-function mutations in the human PIEZO2 gene cause three clinical types of autosomal dominant distal arthrogryposis. This chapter will review the hereditary diseases caused by mutations in the PIEZO genes and will discuss additional physiological systems in which PIEZO channel dysfunction may contribute to human disease pathophysiology. PMID- 28728826 TI - Preface. PMID- 28728827 TI - The use of perioperative ketorolac in the surgical treatment of pediatric spontaneous pneumothorax. AB - BACKGROUND: We sought to determine the effect of ketorolac on pediatric primary spontaneous pneumothorax recurrence after operation. METHODS: The Pediatric Health Information System database was queried for patients ages 10-16years discharged in the years 2004-2014 with pneumothorax or pleural bleb and a related operative procedure. Deaths and secondary pneumothorax were excluded. Variables included demographics, chronic disease, intensive care unit admission, mechanical ventilation, and lung resection or plication. The primary variable was any ketorolac administration between post-operative day 0 and 5. Outcomes included reintervention within 1year, readmission, post-operative length of stay (LOS), and cost. Bivariate and multivariate logistic regression analyses were performed. RESULTS: Of 1678 records that met inclusion criteria, 395 (23%) were subsequently excluded, leaving 1283 patients for analysis. Most patients had a lung resection recorded (78%) and the majority were administered ketorolac (57%); few required reintervention (20%) or readmission (18%). Mean postoperative LOS was 5.2+/ 3.8days and mean cost was $17,649+/-$10,599. On bivariate analysis, ketorolac administration did not correlate with any measured outcome. On both bivariate and multivariate analysis, no variable was predictive of reintervention, and only lung resection correlated with readmission (adjusted odds ratio 0.63 [95% C.I. 0.45-0.90]). CONCLUSION: Post-operative ketorolac administration was not associated with an increased likelihood of reintervention or readmission within 1year of operative treatment of primary spontaneous pneumothorax, suggesting that it may be used safely as part of a post-operative pain control regimen. Effects on postoperative length of stay and cost, however, were not demonstrated. LEVEL OF EVIDENCE AND TYPE OF STUDY: Level III treatment study. PMID- 28728828 TI - Obstruction of peritoneal dialysis catheter is associated with catheter type and independent of omentectomy: A comparative data analysis from a transplant surgical and a pediatric surgical department. AB - BACKGROUND: Peritoneal dialysis (PD) catheter occlusion is a common complication with up to 36% of catheter obstructions described in the literature. We present a comparison of complications and outcome after implantation of PD catheters in a transplant surgical and a pediatric surgical department. METHODS: We retrospectively analyzed 154 PD catheters, which were implanted during 2009-2015 by transplant surgeons (TS, University Medical Center Hamburg-Eppendorf, Germany, n=85 catheters) and pediatric surgeons (PS, Charite University Medicine Berlin, Germany, n=69 catheters) in 122 children (median (range) age 3.0 (0.01-17.1) years) for acute (n=65) or chronic (n=89) renal failure. All catheters were one cuffed or double-cuffed curled catheters, except that straight catheters were implanted into smaller children (n=19) by TS in Hamburg. RESULTS: Patient characteristics and operation technique did not differ between the departments. Peritonitis was the most common complication (33 catheters, 21.4%). Leakage (n=18 catheters, 11.7%) occurred more often in children weighing <10kg (p<0.001). The incidence of obstruction and dysfunction was significantly higher in catheters used in PS than catheters used in TS (30.4% vs. 11.8%, p=0.004). Omentectomy did not reduce the incidence of catheter obstruction (p=1.0). Perforation at the catheter tips was larger and appeared to be rougher in catheters used in PS than the catheters in TS. CONCLUSIONS: The type of catheter and presumably the type of perforation at the catheter tip may influence the incidence of peritoneal dialysis catheter obstruction. PMID- 28728829 TI - Short-term "double natural orifice catheterization": Nonoperative management of hydrocolpos in persistent cloaca patients - case series. AB - PURPOSE: Management of hydrocolpos in cloaca patients is of clinical importance. We report a nonoperative method for the management of hydrocolpos in the form of initial catheter decompression, followed by an endoscopy with catheters placement into both the bladder and vagina, and leaving these catheters for 9 and 14days respectively. METHODS: The medical records of six cloaca patients with hydrocolpos in the last 12years were reviewed. The outcomes measured were the renal function, bladder emptying, the presence/resolution of hydronephrosis, and the recurrence of hydrocolpos. RESULTS: Complete drainage of hydrocolpos was achieved in four out of six cases and partial drainage in two. On common channel endoscopy, in four patients the structures were identified and balloon catheters inserted. After catheter removal, the vagina and urinary tract remained adequately drained through the natural cloacal opening with no post-micturition residual urine, resolution of hydroneprosis within 60days, preserved renal function, and no hydrocolpos reaccumulation. CONCLUSION: Initial decompression and short time catheterization can be the definite solution for some cloaca patients with hydrocolpos. Our case-series showed a success rate in two-thirds of patients by achieving the three main goals; permanent hydrocolpos derivation, undisturbed voiding, and preservation of renal function. LEVEL OF EVIDENCE: Study can be classified as a Treatment Study, LEVEL IV Case series with no comparison group. PMID- 28728830 TI - The echinococcoses in Asia: The present situation. AB - Human alveolar and cystic echinococcosis, caused by the accidental ingestion of eggs of the tapeworms Echinococcus multilocularis and Echinococcus granulosus sensu lato, respectively, are endemic in Asia. Various Echinococcus species are maintained in domesticated and/or wild mammals through predator-prey interactions. Molecular analysis is used to help differentiate infecting parasite species and genotypes, with the goal of better understanding parasite life cycles in order to aid in the planning and implementation of control programs. This paper discusses the various echinococcoses in Asia, with limited reference to neighboring areas, including parts of Central Asia, Russia, Europe and North America. PMID- 28728831 TI - Hepatitis B reactivation in a patient with chronic hepatitis C treated with direct-acting antivirals. PMID- 28728832 TI - Contributions to our understanding of fulminant hepatitis from the Liver ICU of Hospital Clinic Barcelona: Historical review. PMID- 28728833 TI - Unexplained abdominal pain in morbidly obese patients after bariatric surgery. AB - BACKGROUND: There is an overall complication rate of 6.3%-10% after bariatric surgery. After ruling out anatomic/physical causes, there is a substantial group of patients who develop unexplained postsurgical abdominal pain. OBJECTIVES: To inventory the prevalence of unexplained abdominal pain after laparoscopic Roux-en Y gastric bypass or laparoscopic sleeve gastrectomy and to determine predictive factors for unexplained abdominal pain. SETTING: Obesity Center Amsterdam, Amsterdam, the Netherlands. METHODS: A retrospective study in a prospective database was performed. Baseline characteristics and postoperative course were evaluated. RESULTS: A total of 1788 patients underwent laparoscopic Roux-en-Y gastric bypass or laparoscopic sleeve gastrectomy between November 2007 and April 2015. The average follow-up consisted of 33.5 months, without loss to follow-up. Abdominal pain was presented in 387 patients (21.6%). The study population consisted of 337 women (87.1%) and 50 men (12.9%); the mean age was 43.3 years (standard deviation 10.1) and the median preoperative body mass index was 43.7 kg/m2. An explanation for abdominal pain was found in 246 of 387 patients (63.6%), whereas no explanation was found in 133 patients (34.4%). Revisional surgery was a significant predictor for unexplained pain (odds ratio 1.7; confidence interval 1.0-2.8; P = 0.037). CONCLUSION: A total of 133 patients (7.4%) experienced unexplained abdominal pain after laparoscopic bariatric surgery. Revisional surgery was found to be a significant predictive factor for this outcome. Present study results suggest that postoperative unexplained abdominal pain is a significant morbidity and should be part of the informed consent. More research is needed regarding further diagnosis and management and treatment. PMID- 28728835 TI - A multiplex PCR for detection of six viruses in ducks. AB - In this study, six pairs of specific primers that can amplify DNA fragments of different sizes were designed and synthesized according to viral protein gene sequences published in GenBank. Then, a multiplex PCR method was established for rapid detection of duck hepatitis virus 1, duck plague virus, duck Tembusu virus, muscovy duck parvovirus, muscovy duck reovirus, and duck H9N2 avian influenza virus, and achieve simple and rapid detection of viral diseases in ducks. Single PCR was used to confirm primer specificity, and PCR conditions were optimized to construct a multiplex PCR system. Specificity and sensitivity assays were also developed. The multiplex PCR was used to detect duck embryos infected with mixed viruses and those with clinically suspected diseases to verify the feasibility of the multiplex PCR. Results show that the primers can specifically amplify target fragments, without any cross-amplification with other viruses. The multiplex PCR system can amplify six DNA fragments from the pooled viral genomes and specifically detect nucleic acids of the six duck susceptible viruses when the template amount is 102 copies/MUl. In addition, the system can be used to detect viral nucleic acids in duck embryos infected with the six common viruses. The detection results for clinical samples are consistent with those detected by single PCR. Therefore, the established multiplex PCR method can perform specific, sensitive, and high-throughput detection of six duck-infecting viruses and can be applied to clinical identification and diagnosis of viral infection in ducks. PMID- 28728836 TI - Chromosome Intermingling: Mechanical Hotspots for Genome Regulation. AB - Cells sense physical and chemical signals from their local microenvironment and transduce them to the nucleus to regulate genomic programs. In this review, we first discuss different modes of mechanotransduction to the nucleus. We then highlight the role of the spatial organization of chromosomes for integrating these signals. In particular, we emphasize the importance of chromosome intermingling for gene regulation. We also discuss various geometric models and recent advances in microscopy and genomics that have allowed access to these nanoscale chromosome intermingling regions. Taken together, the recent work summarized in this review culminates in the hypothesis that chromosome intermingling regions are mechanical hotspots for genome regulation. Maintenance of such mechanical hotspots is crucial for cellular homeostasis, and alterations in them could be precursors for various cellular reprogramming events, including diseases. PMID- 28728834 TI - Calcium signaling and molecular mechanisms underlying neurodegenerative diseases. AB - Calcium (Ca2+) is a ubiquitous second messenger that regulates various activities in eukaryotic cells. Especially important role calcium plays in excitable cells. Neurons require extremely precise spatial-temporal control of calcium-dependent processes because they regulate such vital functions as synaptic plasticity. Recent evidence indicates that neuronal calcium signaling is abnormal in many of neurodegenerative disorders such as Alzheimer's disease (AD), Huntington's disease (HD) and Parkinson's disease (PD). These diseases represent a major medical, social, financial and scientific problem, but despite enormous research efforts, they are still incurable and only symptomatic relief drugs are available. Thus, new approaches and targets are needed. This review highlight neuronal calcium-signaling abnormalities in these diseases, with particular emphasis on the role of neuronal store-operated Ca2+ entry (SOCE) pathway and its potential relevance as a therapeutic target for treatment of neurodegeneration. PMID- 28728837 TI - Epileptic apnea in a patient with inherited glycosylphosphatidylinositol anchor deficiency and PIGT mutations. AB - We report an 11-month-old boy with acetazolamide-responsive epileptic apnea and inherited glycosylphosphatidylinositol (GPI)-anchor deficiency who presented with decreased serum alkaline phosphatase associated with compound PIGT mutations. The patient exhibited congenital anomalies, severe intellectual disability, and seizures, including epileptic apnea with epileptiform discharges from bilateral temporal areas. Brain magnetic resonance imaging revealed delayed myelination and progressive atrophy of the brainstem, cerebellum, and cerebrum. Whole-exome sequencing revealed compound heterozygous mutations in PIGT (c.250G>T, p.Glu84X and c.1096G>T, p.Gly366Trp), which encodes a subunit of the GPI transamidase complex. Flow cytometry revealed decreased expression of CD16 (a GPI anchor protein) on granulocytes, supporting the putative pathogenicity of the mutations. Phenobarbital, clonazepam, and potassium bromide decreased the frequency of tonic seizure and acetazolamide decreased epileptic apnea. To our knowledge, this is the first reported case of intractable seizures accompanied by epileptic apnea associated with GPI anchor deficiency and a compound PIGT mutation. PMID- 28728838 TI - KCNQ2 encephalopathy: A case due to a de novo deletion. AB - KCNQ2 encephalopathy is characterized by severely abnormal EEG, neonatal-onset epilepsy and developmental delay. It is caused by mutations (typically missense) in the KCNQ2 gene, encoding the voltage gated potassium channel Kv7.2 and leading to a negative-dominant effect. We present one case experiencing recurrent neonatal seizures with changing hemispheres of origin, reminiscent of epilepsy of infancy with migrating focal seizures. At 9months of age the patient is still seizure-free on carbamazepine, although he is developing a spastic-dystonic tetraplegia with severe dysphagia. He harbors a de novo deletion (c.913_915del [p.Phe305del)]), only described once in a couple of severely affected twins, and leading to the deletion of a phenylalanine residue in the pore domain of the channel. In conclusion, our case is the second described with encephalopathy due to this specific deletion (the one and only deletion so far reported in KCNQ2 encephalopathy). Thus, deletion is a newly described mechanism highlighting how not only missense mutations but also deletions in the channel hot spots can lead to a severe phenotype. Furthermore he presented ictal EEG features similar to epilepsy of infancy with migrating focal seizures not previously described. PMID- 28728839 TI - Sleep apneas and cardiovascular risk after Sleep Apnea Cardiovascular Endpoints Study (SAVE). What next? PMID- 28728840 TI - Antitumor effect of the integrin alpha4 signaling inhibitor JK273 in non-small cell lung cancer NCI-H460 cells. AB - Lung cancer accounts for the highest death rate among cancers worldwide, with most patients being diagnosed with non-small cell lung cancer (NSCLC), urging more effective therapies. We report that JK273, a pyrrolo[2,3-d]pyrimidine analog, which inhibits alpha4 integrin signaling, showed a selective cytotoxic effect against HCI-H460 NSCLC cells, with an IC50 of 0.98 +/- 0.15 MUM, but showed less sensitivity to fibroblasts with a selectivity index (SI) greater than 30. This effect was attributed to cell cycle arrest at S phase by JK273 treatment, resulting in the apoptosis of NCI-H460 cells, further confirmed by exposing phosphatidylserine and morphological changes. Taken together with the previous study of JK273 inhibiting cell migration, we propose that JK273 could serve as an antitumor compound to specifically target cancer cells but not non cancerous cells by triggering programmed cell death, in addition to anti metastatic effects in cancer therapy. PMID- 28728841 TI - Redox imbalance in a model of rat mimicking Hutchinson-Gilford progeria syndrome. AB - Although several etiological factors contribute to the complexity of the aging process, the ultimate component of macromolecular damage and consequent cell death involves the altered redox balance inclined towards increased ROS production and/or decreased antioxidant protection. Given that, the chronic dihydrotachysterol (DHT) intoxication in rats induce Hutchinson Gilford progeria like syndrome, the present study provides the evidence for altered redox balance as evidenced by alteration in parameters of oxidative stress in blood plasma and erythrocytes including MDA, GSH, FRAP AOPP PMRS, AGEs, AChE and osmotic fragility which substantiate the suitability of the model for aging studies. PMID- 28728842 TI - gamma-Oryzanol suppresses COX-2 expression by inhibiting reactive oxygen species mediated Erk1/2 and Egr-1 signaling in LPS-stimulated RAW264.7 macrophages. AB - Cyclooxygenase (COX)-2 produces prostanoids, which contribute to inflammatory responses. Nuclear factor (NF)-kappaB is a key transcription factor mediating COX 2 expression. gamma-Oryzanol is an active component in rice bran oil, which inhibits lipopolysaccharide (LPS)-mediated COX-2 expression by inhibiting NF kappaB. However, the inhibition of COX-2 expression by gamma-oryzanol independently of NF-kappaB is poorly understood. We found that LPS upregulated Egr-1 expression at the transcriptional level. Forced expression of Egr-1 trans activated the Cox-2 promoter independently of NF-kappaB. In contrast, silencing of Egr-1 abrogated LPS-mediated COX-2 expression. LPS produced reactive oxygen species (ROS), which, in turn, induced Egr-1 expression via the Erk1/2 MAPK pathway. ROS scavenging activity of gamma-oryzanol suppressed Egr-1 expression by inhibiting the Erk1/2 MAPK pathway. Our results suggest that gamma-oryzanol inhibits LPS-mediated COX-2 expression by suppressing Erk1/2-mediated Egr-1 expression. This study supports that gamma-oryzanol may be useful for ameliorating LPS-mediated inflammatory responses. PMID- 28728843 TI - Expression and prognostic role of orphan receptor GPR110 in glioma. AB - Glioma is the most common type of malignancy in the central nervous system, which has a poor prognosis due to its rapid progression and diffuse invasion. Identification of novel biomarkers for glioma would be invaluable for studying disease mechanism and improving prognosis. Orphan G protein-coupled receptor 110 (GPR110) belongs to the subfamily VI of adhesion GPCR. The knowledge of the ligand, signaling pathway or physiology function of GPR110 is poorly elucidated. The potential role of GPR110 as an oncogene in mouse has been recently reported by mutagenesis screen. However, its expression and role in human glioma hasn't been identified. Here in the current study, we initially explored the RNA and protein expression of GPR110 in patients with glioma. Statistical analysis proved that GPR110 was highly expressed in some patients, which was correlated with advanced disease stages. Furthermore, univariate and multivariate analyses revealed its role as an independent prognostic biomarker for the overall survival of glioma patients. Interestingly, cellular studies showed that overexpression or knockdown of GPR110 in U87 cells didn't affect cell proliferation and migration. However, the invasion of U87 cells was significantly enhanced by GPR110 overepxression, while inhibited by GPR110-knockdown. The detailed mechanisms remain further investigation although our results suggested the possible participation of STAT3 instead of ERK in the GPR110 signaling pathways. PMID- 28728844 TI - Long non-coding RNA PCAT7 regulates ELF2 signaling through inhibition of miR-134 5p in nasopharyngeal carcinoma. AB - While some long noncoding RNAs (lncRNAs) might promote nasopharyngeal carcinoma (NPC) initiation and progression, the involved molecular mechanisms remain largely unclear. Here, we discovered the novel LncRNA, prostate cancer associated transcript 7 (PCAT7), which was overexpressed and associated with worse prognosis in NPC. Decreased PCAT7 expression was found to significantly suppress tumor cell proliferation in vitro, and inhibited tumor growth and reduced the expression of proliferation antigen Ki-67 in vivo. Rescue assay was performed to further confirm that PCAT7 contributed to the progression of NPC through regulating miR 134-5p/ELF2 signal pathway. These results indicated that PCAT7 might contribute to the tumor progression in NPC by functioning as a ceRNA to sponge miR-134-5p. PMID- 28728845 TI - Crystal structure of cis-dihydrodiol naphthalene dehydrogenase (NahB) from Pseudomonas sp. MC1: Insights into the early binding process of the substrate. AB - The bacterial strain Pseudomonas sp. MC1 harbors an 81-kb metabolic plasmid, which encodes enzymes involved in the conversion of naphthalene to salicylate. Of these, the enzyme NahB (cis-dihydrodiol naphthalene dehydrogenase), which catalyzes the second reaction of this pathway, binds to various substrates such as cis-1,2-dihydro-1,2-dihydroxy-naphthalene (1,2-DDN), cis-2,3-dihydro-2,3 dihydroxybiphenyl (2,3-DDB), and 3,4-dihydro-3,4-dihydroxy-2,2',5,5' tetrachlorobiphenyl (3,4-DD-2,2',5-5-TCB). However, the mechanism underlying its broad substrate specificity is unclear owing to the lack of structural information. Here, we determined the first crystal structures of NahB in the absence and presence of NAD+ and 2,3-dihydroxybiphenyl (2,3-DB). Structure analysis suggests that the flexible substrate-binding loop allows NahB to accommodate diverse substrates. Furthermore, we defined the initial steps of substrate recognition and identified the early substrate-binding site in the substrate recognition process through the complex structure with ligands. PMID- 28728846 TI - The effects of type I interferon on glioblastoma cancer stem cells. AB - Glioblastomas (GBMs) are highly invasive brain tumors that are extremely deadly. The highly aggressive nature of GBM as well as its heterogeneity at the molecular and cellular levels has been attributed to a rare subpopulation of GBM stem-like cells (GSCs). Interferons (IFNs) are a family of endogenous antiviral proteins that have anticancer activity in vitro, and have been used clinically to treat GBM. IFN inhibits the proliferation of various established GBM cell lines, but the effects of IFNs on GSCs remain relatively unknown. The present study explored the effects of IFN on the proliferation and the differentiation capacity of GSCs isolated from GBM patient-derived xenolines (PDXs) grown as xenografts in immunocompromised mice. We show that IFN inhibits the proliferation of GSCs, inhibits the sphere forming capacity of GSCs that is a hallmark of cancer stem cells, and inhibits the ability of GSCs to differentiate into astrocytic cells. In addition, we show that IFN induces transient STAT3 activation in GSCs, while induction of astrocytic differentiation in GSCs results in sustained STAT3 activation. PMID- 28728847 TI - A novel role for bone-derived cells in ankylosing spondylitis: Focus on IL-23. AB - The main aim of this study are to explore the role of bone-derived cells (BdCs) in ankylosing spondylitis (AS) and determine the underlying molecular mechanisms of IL-23 production. Primary BdCs were isolated from diced bone of facet joints obtained during surgery from seven AS patients and seven disease control (Ct) patients. Osteoblastic activity of BdCs was assessed by measuring their alkaline phosphatase activity and by alizarin red staining. Osteoblast and endoplasmic reticulum (ER) stress-related genes were assessed by quantitative PCR, immunoblotting, immunofluorescence, and immunohistochemistry. In addition, expression of IL-23 in response to BIX (selective BIP inducer X)-induced ER stress was evaluated by qPCR and ELISA. Protein interaction and binding to IL-23 promoter were confirmed by Immunoprecipitation and Chromatin immunoprecipitation, respectively. Transcript levels of genes involved in osteoblast function, as well as of the ER stress marker were higher in the AS group than the Ct group, and elevated RUNX2, BiP and IL-23 expression were observed in the BdCs, serum, and bone biopsies from the AS group. BIX-induced ER stress stimulated osteoblastic activity and IL-23 secretion by upregulating RUNX2 expression. Furthermore, in AS BdCs, RUNX2 interacted with C/EBPbeta to bind to IL-23 promoter and RUNX2 knockdown suppressed IL-23 secretion. These finding may provide a molecular mechanism involved in sustained ER stress in AS BdCs stimulates the activation of RUNX2 and C/EBPbeta genes, leading to IL-23 production. PMID- 28728849 TI - WITHDRAWN: Lymphocyte-to-monocyte ratio is an independent predictor for higher SYNTAX scores and associated with adverse events in acute coronary syndrome. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our business/policies/article-withdrawal. PMID- 28728848 TI - Endoplasmic reticulum stress participates in the progress of senescence and apoptosis of osteoarthritis chondrocytes. AB - Endoplasmic reticulum stress (ERS) has been shown to participate in many disease pathologies. Recent reports have reported that ERS exists in human osteoarthritis (OA) chondrocytes. During OA, chondrocytes exhibit increased level of some senescence marker, such as senescence-associated beta-galactosidase (SA beta-gal) activity. However, the persistence and accumulation of senescent cells in various tissues can also impair function and have been involved in the pathogenesis of many age-related diseases, including OA. In this present study, we used IL-1beta (10 ng/ml) to mimic OA chondrocytes and we found that IL-1beta stimulated chondrocytes caused the increasing expression of ADAMTS5 and MMP13, decreasing COL2A1 expression, which were in accord with OA chondrocytes changes. Our data also showed that ERS is involved in the OA chondrocytes, SA beta-gal activity significantly increases and inhibition of ERS can decrease the SA beta-gal activity, apoptosis of OA chondrocytes and increase cell viability. These results help us to open new perspectives for the development of molecular-targeted treatment approaches and thus present an effective novel therapeutic approach for OA. PMID- 28728850 TI - Decline in risk of recurrent cardiovascular events in the period 1996 to 2014 partly explained by better treatment of risk factors and less subclinical atherosclerosis. AB - BACKGROUND: To quantify the decline in recurrent major cardiovascular events (MCVE) risk in patients with clinically manifest vascular disease between 1996 and 2014 and to assess whether the improvements in recurrent MCVE-risk can be explained by reduced prevalence of risk factors, more medication use and less subclinical atherosclerosis. METHODS AND RESULTS: The study was conducted in the Second Manifestations of ARTerial disease (SMART) cohort in patients entering the cohort in the period 1996-2014. The prevalence of risk factors and subclinical atherosclerosis was measured at baseline. Incidence rates per 100person-years for recurrent MCVE (including stroke, myocardial infarction, retinal bleeding, retinal infarction, terminal heart failure, sudden death, fatal rupture of abdominal aneurysm) were calculated, stratified by the year of study enrolment. For the attributable risk of changes in risk factors, risk factor treatment, and subclinical atherosclerosis on the incidence rates of recurrent MCVE, adjusted rate ratios were estimated with Poisson regression. 7216 patients had a median follow-up of 6.5years (IQR 3.4-9.9). The crude incidence of recurrent MCVE declined by 53% between 1996 and 2014 (from 3.68 to 1.73 events per 100person years) and by 75% adjusted for age and sex. This improvement in vascular prognosis was 36% explained by changes in risk factors, medication use and subclinical atherosclerosis. CONCLUSION: The risk of recurrent MCVE in patients with clinically manifest vascular disease has strongly declined in the period between 1996 and 2014. This is only partly attributable to lower prevalence of risk factors, improved medication use and less subclinical atherosclerosis. PMID- 28728851 TI - Predictors of incident heart failure in patients after an acute coronary syndrome: The LIPID heart failure risk-prediction model. AB - BACKGROUND: Coronary heart disease is a major cause of heart failure. Availability of risk-prediction models that include both clinical parameters and biomarkers is limited. We aimed to develop such a model for prediction of incident heart failure. METHODS: A multivariable risk-factor model was developed for prediction of first occurrence of heart failure death or hospitalization. A simplified risk score was derived that enabled subjects to be grouped into categories of 5-year risk varying from <5% to >20%. RESULTS: Among 7101 patients from the LIPID study (84% male), with median age 61years (interquartile range 55 67years), 558 (8%) died or were hospitalized because of heart failure. Older age, history of claudication or diabetes mellitus, body mass index>30kg/m2, LDL cholesterol >2.5mmol/L, heart rate>70 beats/min, white blood cell count, and the nature of the qualifying acute coronary syndrome (myocardial infarction or unstable angina) were associated with an increase in heart failure events. Coronary revascularization was associated with a lower event rate. Incident heart failure increased with higher concentrations of B-type natriuretic peptide >50ng/L, cystatin C>0.93nmol/L, D-dimer >273nmol/L, high-sensitivity C-reactive protein >4.8nmol/L, and sensitive troponin I>0.018MUg/L. Addition of biomarkers to the clinical risk model improved the model's C statistic from 0.73 to 0.77. The net reclassification improvement incorporating biomarkers into the clinical model using categories of 5-year risk was 23%. CONCLUSION: Adding a multibiomarker panel to conventional parameters markedly improved discrimination and risk classification for future heart failure events. PMID- 28728852 TI - In vitro characteristics of an Atlantic salmon (Salmo salar L.) hind gut microbial community in relation to different dietary treatments. AB - In this study, microbial community dynamics were assessed within a simple in vitro model system in order to understand those changes influenced by diet. The abundance and diversity of bacteria were monitored within different treatment slurries inoculated with salmon faecal samples in order to mimic the effects of dietary variables. A total of five complete diets and two ingredients (plant meal) were tested. The total viable counts (TVCs) and sequencing data revealed that there was very clear separation between the complete diets and the plant meal treatments, suggesting a dynamic response by the allochthonous bacteria to the treatments. Automated ribosomal intergenic spacer analysis (ARISA) results showed that different diet formulations produced different patterns of fragments, with no separation between the complete diets. However, plant-based protein ingredients were clearly separated from the other treatments. 16S rRNA Illumina based sequencing analysis showed that members of the genera Aliivibrio, Vibrio and Photobacterium became predominant for all complete diets treatments. The plant-based protein ingredient treatments only sustained weak growth of the genus Sphingomonas. In vitro based testing of diets could be a useful strategy to determine the potential impact of either complete feeds or ingredients on major fish gastrointestinal tract microbiome members. PMID- 28728853 TI - Eve's garden: myths, legends and secrets unmasked. AB - This special issue of Research in Microbiology aims to provide some insights in one of women's most fascinating interacting microbial communities: the vaginal microbiome. Even in the 21st century, with many advanced methods at hand, the definition of the healthy vaginal microbiome remains under debate. The interest in studying the dysbiosis of the vaginal microbiome is increasing and goes well beyond the study of bacterial vaginosis. The selection of contributions in this issue summarizes what is currently known in terms of inter- and intra microorganisms interaction as well as the virulence factors that some of them may deploy. PMID- 28728854 TI - Potential Use of American College of Radiology BI-RADS Mammography Atlas for Reporting and Assessing Lesions Detected on Dedicated Breast CT Imaging: Preliminary Study. AB - RATIONALE AND OBJECTIVES: Dedicated breast computed tomography (DBCT) is an emerging and promising modality for breast lesions. The objective of this study was to evaluate the potential use of applying the BI-RADS Mammography Atlas 5th Edition for reporting and assessing breast lesions on DBCT. Currently, no atlas exists for DBCT. MATERIALS AND METHODS: Four radiologists trained in breast imaging were recruited in this institutional review board-approved, Health Insurance Portability and Accountability Act-compliant study. The enrolled radiologists, who were blinded to mammographic and histopathologic findings, individually reviewed 30 randomized DBCT cases that contained marked lesions. Thirty-four lesions were included in this study: 24 (70.6%) masses, 7 (20.6%) calcifications, and 3 (8.8%) architectural distortions. Eight (23.5%) lesions were malignant and 26 (76.5%) were benign. The reader was asked to specify according to the BI-RADS Mammography Atlas for each marked DBCT lesion: primary findings, features, breast density, and final assessment. We calculated readers' diagnostic performances for differentiating between benign and malignant lesions and interobserver variability for reporting and assessing lesions using a generalized estimating equation and the Fleiss kappa (kappa) statistic. RESULTS: The estimated overall sensitivity of the readers was 0.969, and the specificity was 0.529. There were no significant differences in the sensitivity and the specificity between lesion types. For reporting the presence of a primary finding, the overall substantial agreement (kappa = 0.70) was seen. In assigning the breast density and the final assessment, the overall agreement was moderate (kappa = 0.53) and fair (kappa = 0.30). CONCLUSION: The use of the BI-RADS Mammography Atlas 5th Edition for DBCT showed high performance and good agreement among readers. PMID- 28728855 TI - Tissue plasminogen activator (tPA) signal sequence enhances immunogenicity of MVA based vaccine against tuberculosis. AB - Tuberculosis (TB) remains a serious health problem worldwide, and the only available vaccine, bacillus Calmette-Guerin (BCG), has shown highly variable efficacy in adults against TB. New vaccines are urgently needed, and the modified vaccinia virus Ankara (MVA)-based vaccine has emerged as one of the most promising candidates based on many preclinical and early clinical studies over the past few years. However, the maximum tolerable dose and strength of induced immune responses have limited the protective effect of MVA-based prophylactic vaccines. To improve the immunogenicity of MVA-based vaccines, we introduced the tPA signal sequence in order to increase the antigen expression and secretion. Two recombinant MVA vectors expressing the Ag85B-TB10.4 fusion protein with or without tPA signal sequence were constructed and verified. Following the homologous prime-boost administration regimen in mice, levels of antigen-specific antibodies and cytokines (e.g., IFN-gamma, TNF-alpha, IL-5, IL-6) and the percent of activated T cells were found to be significantly increased by the tPA signal sequence. However, the mean IgG2a/IgG1 ratios in the two recombinant MVA immunization groups were similar. Our present study demonstrated that the tPA signal sequence could enhance the immunogenicity of an MVA-based vaccine against TB without changing the balance of Th1 and Th2 immune responses. Thus, the tPA signal sequence may be applied to MVA-vector based vaccines for providing a better immune effect. PMID- 28728856 TI - Achaete-scute complex homologue 2 accelerates the development of Sjogren's syndrome-like disease in the NOD/ShiLtJ mouse. AB - Achaete-scute complex homologue 2 (Ascl2) has been reported to induce the differentiation and activation of follicular helper T (TFH) cells, which are essential for development of Sjogren's syndrome (SS). This study examined whether Ascl2 plays a role in the development of SS. NOD/ShiLtJ mice were injected with an Ascl2-overexpression vector, and the infiltration of lymphocytes into salivary and lacrimal glands was assessed. The expression of inflammatory cytokines and chemoattractants for T or B cells was measured. The activation of TFH cells was assessed using a specific marker of TFH cells. Ascl2 level was also measured in SS patients. Overexpression of Ascl2 increased the expression of C-X-C chemokine receptor type 5 (CXCR5) in both salivary and lacrimal glands (p<0.0001). Overexpression of Ascl2 also increased the expression of proinflammatory cytokines and chemoattractants including interleukin 6 (IL-6), tumor necrosis factor-alpha, IL-8, programmed cell death 1 (PD-1), IL-21, and B-cell lymphoma 6 (Bcl-6). Overexpression of Ascl2 increased the populations of CD4+CXCR5+, CD4+ICOS+, and CD4+PD-1+ cells. The Ascl2 level was higher in peripheral blood mononuclear cells from SS patients compared with those from healthy controls. Our findings suggest that Ascl2 may play a role in the development and progression of SS and may be a therapeutic target in the treatment of SS. PMID- 28728857 TI - [Rosacea: New data for better care]. AB - In the last 10 years, numerous studies have been published that throw new light on rosacea, in all areas of the disease. This overview summarises all the key developments, based on the indexed bibliography appearing in Medline between 2007 and 2017. Recent epidemiological data show that the prevalence of the disease is doubtless greater than estimated hitherto (more than 10% of adults in some countries) and that we should not overlook rosacea in subjects with skin phototypes V or VI, a condition that exists on all continents. A new classification of rosacea by phenotype comprising major and minor signs has been put forward; it provides a more rational approach to suitable management based upon symptoms, the severity of which may be graded into 5 classes. The treatments with the best-demonstrated efficacy (updated Cochrane study) are topical metronidazole, azelaic acid and ivermectin, and oral doxycycline; isotretinoin is effective against resistant forms but is off-label. In ocular rosacea, the reference treatment is doxycycline in combination with topical therapy of the eyelids. The physiopathology is complex and involves several factors: vascular (vasodilatation, vascular growth factors), neurovascular (hypersensitivity, neuropathic pain, neuropeptides), infectious (Demodex folliculorum and its microbiota) and inflammatory (abnormal production of pro-inflammatory peptides of the innate immune system). In addition, there is a genetic predisposition as demonstrated by the weight of familial history and comparison of homozygous and heterozygous twins. There is also activation of several genes involved in immunity, inflammation and lipid metabolism; the theory of hydrolipid film anomalies has been posited once more. There has thus been a tremendous leap forward in the field of rosacea research, with therapeutic progress and improved understanding of the underlying mechanisms, which should enable the future development of more targeted treatments as well as global management of this disease, which has major social and emotional consequences on the life of patients. PMID- 28728858 TI - [DRESS complicated by hemophagocytic lymphohistiocytosis in an infant treated for congenital toxoplasmosis]. AB - BACKGROUND: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe disease that may be complicated by hemophagocytic lymphohistiocytosis but this is rarely described in children. PATIENTS AND METHODS: We report the case of a 5-week old infant hospitalized in a pediatric intensive care unit for hemophagocytic lymphohistiocytosis with prolonged fever, splenomegaly, cytopenia, fibrinogen<=1.5g/L, ferritin>=500MUg/L, and soluble IL-2 receptor>=2400U/mL. As a result of the presence of a diffuse skin rash, eosinophilia and multiple organ failure that started three weeks after the initiation of a congenital toxoplasmosis treatment, association with DRESS was suggested. DISCUSSION: Exposure to sulfadiazine remains the main factor leading to DRESS in this case. This is probably the trigger event, secondarily complicated by hemophagocytic lymphohistiocytosis, although in our case the diagnosis was made subsequently. The unfortunately poor outcome of this association is probably exacerbated in fragile patients such as young infants. CONCLUSION: Clinicians should be aware of the possibility of DRESS of every early onset associated with hemophagocytic lymphohistiocytosis linked to a treatment started during the neonatal period to avoid any delay in care that might adversely affect the prognosis. PMID- 28728859 TI - [Multiple granular cell tumours in a patient with Noonan's syndrome and juvenile myelomonocytic leukaemia]. AB - BACKGROUND: Granular cell tumour (GCT) is a rare form of tumour comprising Schwann cells. Herein, we report a case of a child presenting Noonan syndrome complicated by juvenile myelomonocytic leukaemia (JMML) and who also developed a multiple form of GCT. We discussed the molecular mechanisms that might account for this association. PATIENTS AND METHODS: A six-year-old boy with Noonan syndrome complicated by JMML presented three asymptomatic subcutaneous nodules on his back, forearm and neck. Histological analysis revealed GCT. A literature review revealed seven cases of Noonan syndrome presenting GCT, none of which were associated with JMML. Mutation of gene PTPN11, via hyperactivation of intracellular Ras signalling may cause the development of GCT and JMML in children presenting Noonan syndrome. DISCUSSION: Detailed clinical examination is recommended in children presenting GCT to screen for multiple forms and for signs of malformation suggestive of a genetic syndrome. Ours is the first case to be described of Noonan syndrome complicated by JMML associated with multiple GCT. This association once again raises the important question of the role of the Ras MAPK signalling pathway in the development of benign and malignant tumours of solid organs or blood, associated with genetic syndromes. PMID- 28728860 TI - ["Palimpsest scar" lesions in a context of torture (Darfur, Sudan)]. AB - BACKGROUND: As a result of the current exponentially growing refugee population from the Middle-East and East Africa (Sudan, Darfur, Eritrea), clinicians (including forensic pathologists) are seeing atypical skin lesions, mainly of a traumatic nature, but in some cases associated with long-standing lesions related to ethnic practices. PATIENTS AND METHODS: A case of torture sequelae is presented herein in a patient originally from Darfur (Sudan): cutaneous incisions were made on old scars several times using a knife. DISCUSSION: The clinical presentation of scarification lesions and that of atypically healed wounds (presumably an effect of inflammation induced by the introduction of irritating foreign bodies such as sand, salt, etc.) are completely different: in all cases they indicate a relative timeframe of the facts, which the clinician should not overlook in reconstructing the patient's course and the injuries to which he has been subjected (hence the proposed designation of "palimpsest scar", in the sense that a palimpsest is a manuscript on a parchment that previously contained writing but has been scratched clean to be overwritten). Thus, a "palimpsest scar" constitutes a fresh scar on top of and hiding another (ritual) scar in a context of ethnic cleansing. The diagnostic and clinical significance comes from the importance of differentiating between ethnic-type lesions and those induced by physical violence and abuse in a context of war. PMID- 28728861 TI - [Vitiligo occurring on dermal melanocytosis (nevus of Ota) in a dark-skinned patient]. AB - BACKGROUND: Nevus of Ota is a rare disease most frequently found in Asians. It presents clinically as a bluish gray hyperpigmentation of one side of the face. Transformation into melanoma and glaucoma are the main risks. The appearance of vitiligo lesions with poliosis within a nevus of Ota is exceptional. PATIENTS AND METHODS: A 22-year-old female patient with a nevus of Ota consulted for depigmentation of the eyelashes. Physical examination revealed hyperpigmentation in the right orbitofrontal part of her face, achromic macules and eyelash poliosis. A diagnosis was made of vitiligo developing on a nevus of Ota. Ophthalmologic examination showed hyperpigmentation of the sclera. Regular dermatologic and ophthalmologic follow-up was instituted. DISCUSSION: Vitiligo is a condition characterized by the development of depigmented lesions secondary to chronic degradation of the melanocytes of the epidermis and the follicles. Its occurrence on congenital nevus and melanoma has already been reported. However, its appearance in dermal melanocytosis is very rare. Since the first observation of this association in 1979, only 4 other cases have been reported. The pathogenic mechanisms of this association are still poorly understood. Histopathological examination generally shows a loss of epidermal melanocytes, especially in the basal layer, while dermal melanocytes remain unaffected. In this context, vitiligo developed on dermal melanosis appears to result from the difference between the properties of normal (epidermal) melanocytes and ectopic (dermal) melanocytes. CONCLUSION: Association of vitiligo with nevus of Ota is rare. Herein, we report a new case in a dark-skinned subject. PMID- 28728862 TI - Seminal plasma proteins modify the distribution of sperm subpopulations in cryopreserved semen of rams with lesser fertility. AB - Any physiological mechanism involved in sperm selection and semen improvement has effects on heterogeneous sperm populations. This is mainly due to the fact that sperm populations within a single ejaculate have considerable heterogeneity for many variables, such as motility which is meaningful in terms of understanding how some sperm cells possess fertility advantages as compared with other cells. In the present research, initially there was a multivariate and clustering analysis used to assess sperm motility data from cryopreserved ram semen to identify subpopulations and compare the distribution of these clusters between rams with lesser and greater fertility. There were four classifications made of sperm subpopulations (clusters): CL1 fast/linear/progressive sperm; CL2 fast/non linear sperm; CL3 very fast/linear sperm with vigorous beating and CL4 slow/non linear sperm. Rams with greater fertility had a lesser proportion of sperm considered as "hyperactivated" (CL2) and a greater proportion of slow and non linear sperm (CL4) than sperm of rams with lesser fertility. In addition, the effects were assessed for the capacity of seminal plasma (SP) and interacting SP proteins (iSPP) that were present during different seasons of the year to improve the distribution of sperm within subpopulations of semen from rams with lesser fertility. The iSPP and SP were obtained by artificial vagina (AV) and electroejaculation (EE) during breeding and non-breeding seasons and added to thawed semen. All the aggregates had a significant effect on the distribution of sperm subpopulations and effects differed among seasons of the year and depending on collection method used. Even though, future studies are needed to assess the contribution of each subpopulation on ram sperm fertility, it is important that a multivariate analysis be used to evaluate the effect of a treatment on sperm quality variables. PMID- 28728863 TI - A mechanistic force model for simulating haptics of hand-held bone burring operations. AB - This paper presents a mechanistic model to predict the forces experienced during bone burring with application to haptic feedback for virtual reality surgical simulations. Bone burring is a hand-held operation where the force perceived by the surgeon depends on the cutting tool orientation and motion. The model of this study adapted the concept of specific cutting energy and material removal rate based on machining theory to calculate force distribution on the spherical tool surface in a three-dimensional setting. A design of experiments with three tool cutting angles and three feed motions was performed to calibrate and validate the model. Despite some variance in the results, model predictions showed similar trends to experimental force patterns. While the actual force profile also exhibits significant oscillation, the dominant frequencies of this oscillating force component were found to be independent of cutting and non-cutting instances, and hence could be imposed as a uniform background signal. Though the presented model is primarily applicable to abrasive burrs, it has far-reaching applications within other types of surgical simulations as well. PMID- 28728864 TI - Development of a multi-DoF transhumeral robotic arm prosthesis. AB - An anthropomorphic transhumeral robotic arm prosthesis is proposed in this study. It is capable of generating fifteen degrees-of-freedom, seven active and eight passive. In order to realize wrist motions, a parallel manipulator-based mechanism is proposed. It simulates the human anatomical structure and generates motions in two axes. The hand-of-arm prosthesis consists of under-actuated fingers with intrinsic actuation. The finger mechanism is capable of generating three degrees of freedom, and it exhibits the capability of adjusting the joint angles passively according to the geometry of the grasping object. Additionally, a parameter to evaluate finger mechanisms is introduced, and it measures the adoptability of a finger mechanism. In order to verify the mechanism's efficacy in terms of motion generation, motion simulation and kinematic analysis were carried out. Results demonstrated that the mechanisms are capable of generating the required motions. PMID- 28728865 TI - Mass-spring models for the simulation of mitral valve function: Looking for a trade-off between reliability and time-efficiency. AB - Patient-specific finite element (FE) models can assess the impact of mitral valve (MV) repair on the complex MV anatomy and function. However, FE excessive time requirements hamper their use for surgical planning; mass-spring models (MSMs) represent a more approximate approach but can provide almost real-time simulations. On this basis, we implemented MSMs of three healthy MVs from cardiac magnetic resonance (cMR) imaging to simulate the systolic MV closure, including the in vivo papillary muscles and annular kinematics, and the anisotropic and non linear mechanical response of MV tissues. To test MSM reliability we compared the systolic peak configurations computed by MSMs and FE: mismatches by less than twice the in-plane cMR image resolution were detected over 75% of the leaflets' surface, independently of the MSM mesh refinement and of the specific MV anatomy. Data on MSMs time-efficiency and data from the comparison of MSMs vs. FE models suggest that MSM could represent a suitable trade-off between almost real-time simulations and reliability when computing MV systolic configuration, with the potential to be used in a clinical setting either as a support to the decisional process or as a virtual training tool. PMID- 28728866 TI - Deformability- and size-based microcapsule sorting. AB - Biomedical applications often require to sort cells according to their physical properties, such as size, density or deformability. In recent years, microfluidics has provided a variety of tools to sort micro-objects. We present here a simple microfluidic device consisting of a channel containing a semi cylindrical obstacle against which capsules are squeezed by the flow, followed by a diverging chamber where streamlines separate. We demonstrate that this basic system is capable of sorting elastic microcapsules according to their size at low flow strength, and according to the stiffness of their membrane at high flow strength. Contrary to most existing sorting devices, we show that the present one is very sensitive and capable of discriminating between capsules with differences in membrane elasticity of order unity. PMID- 28728867 TI - Finite element analysis of TAVI: Impact of native aortic root computational modeling strategies on simulation outcomes. AB - In the last few years, several studies, each with different aim and modeling detail, have been proposed to investigate transcatheter aortic valve implantation (TAVI) with finite elements. The present work focuses on the patient-specific finite element modeling of the aortic valve complex. In particular, we aim at investigating how different modeling strategies in terms of material models/properties and discretization procedures can impact analysis results. Four different choices both for the mesh size (from 20 k elements to 200 k elements) and for the material model (from rigid to hyperelastic anisotropic) are considered. Different approaches for modeling calcifications are also taken into account. Post-operative CT data of the real implant are used as reference solution with the aim of outlining a trade-off between computational model complexity and reliability of the results. PMID- 28728868 TI - PDL1 expression in desmoplastic melanoma is associated with tumor aggressiveness and progression. AB - BACKGROUND: The prognostic role of programmed death ligand 1 (PDL1), CD8, and forkhead box p3 (FoxP3) expression in desmoplastic melanomas is unclear. METHODS: We correlated PDL1, p53, and Ki-67 expression with CD8+ and FoxP3+ immune infiltrates with clinicopathologic variables and patient outcomes in a series of 66 desmoplastic melanomas. RESULTS: Tumoral PDL1 expression (>=25%), which was seen in 21% of patients (14 of 66), significantly correlated with mixed histology, tumor thickness, mitoses, recurrence, and metastasis. According to linear regression analysis, tumoral PDL1 expression correlated with thickness (P = .0041); p53 expression (P = .019); Ki-67 proliferation index (P = .0018); and tumoral CD8 (P = .0084), stromal CD8 (P < .0001), and FoxP3 (P < .0001) T-cell counts. According to univariate analyses, PDL1 expression of 25% or higher correlated with shorter progression-free survival (P < .0001) and melanoma specific survival (P = .034). According to multivariate analyses, PDL1 expression of 25% or more (P = .026) and mixed histology (P = .039) independently predicted shorter progression-free survival, and presence of lymphovascular invasion predicted shorter overall survival (P = .018). LIMITATIONS: Small study size. CONCLUSION: Tumoral and stromal CD8+ and FoxP3+ lymphocyte counts correlated with tumoral PDL1 expression, which is supportive of an adaptive immune response. PDL1 expression in desmoplastic melanoma was associated with tumor aggressiveness and progression. Although PDL1 expression is typically low in melanoma, its frequency and level of expression in desmoplastic melanoma may identify a subset of melanomas that are likely to respond to immunotherapy. PMID- 28728869 TI - Aesthetic outcome and complications of simple interrupted versus running subcuticular sutures in facial surgery: A randomized controlled trial. AB - BACKGROUND: The suturing technique and its associated complications could affect cosmetic outcome after facial surgery. Literature on this topic is limited. OBJECTIVE: To compare the cosmetic results 12 months after treatment and complications associated with simple interrupted sutures (SIS) versus running subcuticular sutures (RSS) in facial surgery. METHODS: A randomized, controlled multicenter trial was performed. Adults receiving dermatologic surgery on the face were randomized to receive SIS or RSS for wound closure. The primary outcome was the overall opinion score on the Patient and Observer Scar Assessment Scale (POSAS) 12 months after surgery. Secondary outcomes were the complication rates and scores according to alternative methods for assessment of cosmetic outcome. The observer of cosmetic outcome was blinded to treatment assignment. RESULTS: 142 patients were randomized to receive SIS (n = 73) or RSS (n = 69). Twelve months after surgery, the median score of the overall opinion on the POSAS was 2.0 (range 1-8) according to the patients and 3.0 (range 1-8) according to the observer in both groups. In the RSS group, hyper- or hypoesthesia was reported more often. LIMITATIONS: The cosmetic result was assessed by 1 observer. CONCLUSION: SIS and RSS in facial surgery resulted in comparable cosmetic outcomes. RSS was more often associated with hyper- or hypoesthesia. PMID- 28728870 TI - Outpatient dermatology consultation impacts the diagnosis and management of pediatric oncology patients: A retrospective study. AB - BACKGROUND: The impact of dermatology consultation on the care of children with oncologic conditions is unknown. OBJECTIVE: To review outpatient dermatology visits and the resulting impact on diagnosis and management of pediatric oncology patients. METHOD: Retrospective review of pediatric oncology patients with outpatient dermatology visits at a tertiary care center from 2008 to 2015. RESULTS: The most common dermatologic diagnoses in 516 patients were skin infections (21.3%) and nonmalignant skin eruptions (33.4%). A diagnosis of significant impact (ie, malignancy, adverse cutaneous drug reaction, graft-versus host disease, varicella-zoster virus, or herpes simplex virus infection), was made at the dermatology clinic in 14.7% of visits. Consultation resulted in a change in diagnosis in 59.8% of patients, change in dermatologic management in 72.4% of patients, and change in management of noncutaneous issues in 12.4% of patients. LIMITATIONS: The use of electronic medical records, the nongeneralizable study population, and the retrospective design represent potential limitations. CONCLUSION: Outpatient dermatology consultation can affect the care of pediatric oncology patients with respect to diagnosis and treatment of skin conditions and management of nondermatologic issues. PMID- 28728871 TI - Phosphodiesterase type 5 inhibitors and risk of melanoma: A meta-analysis. AB - BACKGROUND: The association between phosphodiesterase type 5 (PDE5) inhibitors and melanoma risk is controversial. OBJECTIVE: We quantify the association between use of PDE5 inhibitors and melanoma. METHODS: We systematically searched PubMed, Embase, the Cochrane Central Register of Controlled Trials, Web of Science, and ClinicalTrials.gov for studies that were conducted up to July 13, 2016, and evaluated the association between PDE5 inhibitors and skin cancer. Random effects meta-analyses were used to calculate the adjusted odds ratio (OR) with the 95% confidence interval (CI). RESULTS: Five observational studies were included. Compared with PDE5 inhibitor nonuse, PDE5 inhibitor use was slightly but significantly associated with an increased risk for development of melanoma (OR, 1.12; 95% CI, 1.03-1.21) and basal cell carcinoma (OR, 1.14; 95% CI, 1.09 1.19) but not squamous cell carcinoma. For melanoma risk, none of the prespecified factors (dose of PDE5 inhibitor, study design, and study region) significantly affected the results (P > .05). Our sensitivity analysis confirmed the stability of the results. LIMITATIONS: We included only observational studies, which had some heterogeneities and inconsistent controlling for potential confounders. CONCLUSIONS: Use of PDE5 inhibitors may be associated with a slightly increased risk for development of melanoma and basal cell carcinoma but not squamous cell carcinoma. However, further large well-conducted prospective studies with adequate adjustment for potential confounders are required for confirmation. PMID- 28728872 TI - Oropharyngeal lesions in pityriasis rosea. AB - BACKGROUND: Pityriasis rosea (PR) is an exanthematous disease associated with the endogenous systemic reactivation of human herpesvirus-6 (HHV-6) and human herpesvirus-7 (HHV-7). Oropharyngeal lesions may be associated with the exanthema, but anecdotal evidence suggests that few dermatologists are aware of their occurrence. OBJECTIVE: Classifying oropharyngeal lesions in PR, establishing their prevalence, and assessing their possible association with different PR forms. METHODS: The records of all PR cases diagnosed in the Dermatology Clinic of Genoa University between 2003 and 2016 were retrospectively reviewed to examine sex and age of the patients, PR type, presence of enanthema, systemic symptoms, specific anti-HHV-6 and or HHV-7 serology, and HHV-6 and/or HHV-7 DNA loads. RESULTS: The oropharyngeal mucosa was carefully examined in 527 patients with PR. Painless oropharyngeal lesions were observed in 149 patients with PR (28%) and classified as erythematomacular, macular and papular, erythematovesicular, and petechial lesions. The petechial and macular and papular patterns were those most frequently observed. There was no statistically significant difference in the levels of HHV-6 and HHV-7 viremia in the plasma of patients with enanthema and those without. LIMITATIONS: Because this was a retrospective study, biopsies on mucosal lesions were not performed. CONCLUSION: Our findings showed that enanthemas are frequently associated with forms of PR different from the classic form. PMID- 28728873 TI - Inactivation of Alicyclobacillus acidoterrestris ATCC 49025 spores in apple juice by pulsed light. Influence of initial contamination and required reduction levels. AB - The purpose of this study was to analyze the response of different initial contamination levels of Alicyclobacillus acidoterrestris ATCC 49025 spores in apple juice as affected by pulsed light treatment (PL, batch mode, xenon lamp, 3pulses/s, 0-71.6J/cm2). Biphasic and Weibull frequency distribution models were used to characterize the relationship between inoculum size and treatment time with the reductions achieved after PL exposure. Additionally, a second order polynomial model was computed to relate required PL processing time to inoculum size and requested log reductions. PL treatment caused up to 3.0-3.5 log reductions, depending on the initial inoculum size. Inactivation curves corresponding to PL-treated samples were adequately characterized by both Weibull and biphasic models (Radj2 94-96%), and revealed that lower initial inoculum sizes were associated with higher inactivation rates. According to the polynomial model, the predicted time for PL treatment increased exponentially with inoculum size. PMID- 28728875 TI - The use and uptake of pupillometers in the Intensive Care Unit. AB - BACKGROUND: Traumatic brain injury (TBI) is a significant public health issue. Assessing pupil reactivity is a crucial aspect of its management and the pupillometer has been shown to be a more objective tool compared to the standard penlight. Its use, however, is not widespread. OBJECTIVE: To investigate the paucity in uptake, we examined the frequency of use of pupillometers (NeurOptics(r)NPi-100TM) amongst Intensive Care Unit (ICU) doctors and nurses, evaluated its user-friendliness and explored barriers to its use. DESIGN: An online cross-sectional survey. METHODS: Surveys were distributed five months after the introduction of pupillometers (in May 2015) to ICU doctors and nurses working in a quaternary referral centre providing state services for trauma. The survey included sections on: questions on demographics and experience, methods of conventional pupillary assessment in patients with TBI, experience of using the pupillometer, and questions on barriers to its use. Responses were collated as discrete variables and summarised using counts and proportions. Comparisons among proportions were undertaken using the chi-squared test and reported with 95% confidence intervals. RESULTS: A total of 79 responses were recorded, predominantly 94.9% (n=75) from nursing staff. A total of 50 (63.3%) responders were using the pupillometers, with a mean frequency-of-use rating of 4.67 out of 10 and a mean user-friendliness rating of 6.28 out of 10. There was no association between frequency of use and user-friendliness (p=0.36). The main identified barriers to its use included a lack of education with regards to its use, a perceived lack of clinical significance, a lack of standardisation of documenting findings, and difficulties with access to disposable patient shields (Smartguards). CONCLUSIONS: There was good adoption of the technology in the early phases of ICU implementation with user-friendliness rated favourably. In this paper we identify barriers to use and discuss possible solutions to increase clinical utility. PMID- 28728874 TI - Profile of chronic kidney disease related-mineral bone disorders in newly diagnosed advanced predialysis diabetic kidney disease patients: A hospital based cross-sectional study. AB - AIM: Chronic kidney disease related-mineral bone disorder (CKD-MBD) has been poorly studied in pre-dialysis Indian CKD population. There are limited data on the pattern of these disturbances in diabetic CKD patients. Therefore, a study was conducted to find out the profile of mineral bone disorders in T2DM patients with pre-dialysis CKD. METHODS: In this cross-sectional design, diabetic patients with newly-diagnosed stage 4 and 5 CKD were evaluated. Serum levels of calcium, phosphorus, intact parathyroid hormone (iPTH), 25 hydroxy vitamin D and total alkaline phosphatase (ALP) were measured in all patients. Bone mineral density (BMD) was measured using dual-energy X-ray absorptiometry (DXA). RESULTS: A total of 72 eligible patients participated (44 males, 28 females; age 54.2+/-11.7). Patients with CKD Stage 5 had a lower level of corrected serum calcium and significantly higher level of inorganic phosphorus, total ALP and iPTH as compared to stage 4 patients. Overall, 38.5% were hypocalcemic, 31.43% were hyperphosphatemic. 24.2% of CKD subjects were vitamin D deficient (<10ng/ml) and 41.4% having vitamin D insufficiency (10-20ng/ml). In stage 4, hyperparathyroidism (iPTH>110pg/ml) was detected in nearly 43% of patients. In stage 5, only 32% patients was found to have hyperparathyroidism (iPTH>300pg/ml). There was a good correlation between iPTH and total ALP (r=0.5, p=0.0001) in this cohort. 25 (OH) vitamin D was inversely correlated with ALP (r=-0.39, P=0.001) and showed negative correlation with urine ACR (r=-0.37, P=0.002). As a group, the osteoporotic CKD subjects exhibited higher iPTH (220.1+/-153.8 vs. 119+/ 108pg/ml, p<0.05) as compared to those who were osteopenic or had normal bone density. There was significant correlation between BMD and iPTH (adjusted r= 0.436; P=0.001). In the multivariate regression model, we found intact PTH to predict BMD even after adjustment of all the confounders. CONCLUSION: The current study showed that adynamic bone disease is prevalent even in pre-dialysis CKD population. High bone turnover disease may not be the most prevalent type in diabetic CKD. However, it could contribute to the development of osteoporosis in CKD subjects. Serum total ALP can serve as a biochemical marker to identify pattern of bone turnover where intact PTH is not available. PMID- 28728876 TI - Is Technetium-99m Sestamibi Imaging Able to Predict Pathologic Nonresponse to Neoadjuvant Chemotherapy in Breast Cancer? A Meta-analysis Evaluating Current Use and Shortcomings. AB - BACKGROUND: Interest in technetium-99m (99mTc)-sestamibi imaging for neoadjuvant chemotherapy (NAC) response monitoring in locally advanced breast cancer (LABC) is increasing but remains matter of discussion. The present study conducted a meta-analysis of the diagnostic performance of 99mTc-sestamibi to predict pathologic nonresponse to NAC for primary LABC. MATERIALS AND METHODS: A systematic data search was performed. Studies with a minimum of 10 LABC patients that had evaluated 99mTc-sestamibi imaging for NAC nonresponse using conventional planar scintimammography, breast-specific gamma-imaging, and/or single photon emission computed tomography/computed tomography (SPECT/CT) were included. The histopathologic findings were the reference standard. The meta-analysis was performed using a mixed logistic regression model. RESULTS: The search revealed 14 eligible studies with 529 patients. Of the 14 studies, 11 had evaluated scintimammography and 3 breast-specific gamma-imaging. No studies examining SPECT or SPECT/CT were found. The overall estimated pooled sensitivity, specificity, and positive and negative likelihood ratios of 99mTc-sestamibi imaging to predict nonresponsiveness to NAC were 70.3% (95% confidence interval [CI], 56.5%-81.3%%), 90.1% (95% CI, 77.5%-96.0%), 7.13 (95% CI, 3.08-16.53), and 0.33 (95% CI, 0.22 0.49), respectively. Only 3 studies (107 patients) evaluated 99mTc-sestamibi imaging during NAC, reported an estimated pooled sensitivity of 87% (95% CI, 72% 100%) and specificity of 93% (95% CI, 85%-100%). CONCLUSION: Only planar 99mTc sestamibi imaging has been investigated for NAC nonresponse in LABC but showed low sensitivity to predict pathologic nonresponse. However, most studies focused on the prediction of pathologic complete response after NAC. Although experience is limited, 99mTc-sestamibi uptake during NAC seems highly sensitivity for the prediction of nonresponsiveness. Features such as SPECT/CT imaging, standardized quantification, relation to tumor subtypes, and proper timing have been insufficiently evaluated and require further investigation. PMID- 28728877 TI - Genotype, phenotype and disease severity reflected by serum LysoGb3 levels in patients with Fabry disease. AB - BACKGROUND: Fabry disease (FD) is a rare X-linked lysosomal storage disease caused by mutations in the alpha-galactosidase A (GLA) gene causing deficiency of alpha-galactosidase A which results in progressive glycosphingolipid accumulation, especially globotriaosylceramide (Gb3), in body liquids and lysosomes. In a large cohort of FD patients, we aimed to establish genotype/phenotype relations as indicated by serum LysoGb3 (deacylated Gb3). METHODS: In 69 consecutive adult FD patients (males: n=28 (41%)) with a GLA mutation confirmed diagnosis, we conducted a multidisciplinary clinical characterization during their routine annual examinations, and measured serum LysoGb3 levels by high-sensitive electrospray ionization liquid chromatography tandem mass spectrometry. RESULTS: Serum levels of LysoGb3 were significantly higher in Classic compared with Later-Onset phenotype and higher in the latter compared with controls, both in males (52 [40-83] vs 9.5 [4.5-20] vs 0.47 [0.41 0.61] ng/ml, P<0.001) and in females (9.9 [7.9-14] vs 4.9 [1.6-4.9] vs 0.41 [0.33 0.48] ng/ml, P<0.001), respectively. Multivariate linear regression analysis showed that LysoGb3 levels were independently associated with, serum creatinine (beta=0.09, 95%CI 0.04-0.13, P<0.001) and the presence of cardiomyopathy (beta=25, 95%CI 9.8-41, P=0.002). LysoGb3 levels were higher in males with frame shift and nonsense mutations than in males with missense mutations (84 [72-109] vs 41 [37-52] ng/ml, P=0.002). CONCLUSION: LysoGb3 relates to disease severity, enzyme replacement response, and to the genotype severity in males. LysoGb3 supports identifying patients at risk who require intensive monitoring and treatment. LysoGb3 appears to be one marker of metabolic phenotyping of FD. PMID- 28728879 TI - Identification of universal diagnostic peptide candidates for neglected tropical diseases caused by cestodes through the integration of multi-genome-wide analyses and immunoinformatic predictions. AB - Neglected tropical diseases caused by helminth infections currently affect millions of people worldwide. Among them, there are three tapeworm species of outstanding importance: Echinococcus granulosus, E. multilocularis, and Taenia solium, which are responsible for cystic echinococcosis, alveolar echinococcosis, and cysticercosis, respectively. Despite several attempts, there is still a need for an effective and low-cost serological diagnostic test that can be used in endemic countries. In the present work, we described an innovative bioinformatic workflow for a rational prediction of putative peptide candidates for one-step serological diagnosis of any of these infections. First, we predicted the theoretical secretome shared by the three tapeworms starting from their full reported proteomes. Then, through immunoinformatics, we identified proteins within the shared secretome displaying high antigenicity scores and bearing T cell epitopes able to bind most human MHC-II alleles. Secondly, in such proteins, we identified linear B cell epitopes without post-translational modifications, and mapped them on 3D modelled structures to visualize their antibody accessibilities. As a result, we finally suggested two antigenic peptides shared between the secretomes of the three parasite species, which could be further tested for their immunodiagnostic potential. PMID- 28728880 TI - Genetic adaptation to historical pathogen burdens. AB - Historical pathogen burdens are examined as possible triggers for genetic adaptation. Evidence of adaptation emerges for the acid phosphatase locus 1 (ACP1), interleukin-6 (IL6), interleukin-10 (IL10 ), human leukocyte antigen (HLA) polymorphisms, along with a measure of heterozygosity over 783 alleles. Results are robust to controlling for the physical and historical environment humans faced, and to endogeneity of the historical pathogen burden measure. The present study represents a proof-of-concept which may pave the way to the analysis of future aggregate measures coming from whole-genome sequencing/genotyping data. PMID- 28728878 TI - A mass spectrometry-based proteomic analysis of Homer2-interacting proteins in the mouse brain. AB - : In the brain, the Homer protein family modulates excitatory signal transduction and receptor plasticity through interactions with other proteins in dendritic spines. Homer proteins are implicated in a variety of psychiatric disorders such as schizophrenia and addiction. Since long Homers serve as scaffolding proteins, identifying their interacting partners is an important first step in understanding their biological function and could help to guide the design of new therapeutic strategies. The present study set out to document Homer2-interacting proteins in the mouse brain using a co-immunoprecipitation-based mass spectrometry approach where Homer2 knockout samples were used to filter out non specific interactors. We found that in the mouse brain, Homer2 interacts with a limited subset of its previously reported interacting partners (3 out of 31). Importantly, we detected an additional 15 novel Homer2-interacting proteins, most of which are part of the N-methyl-D-aspartate receptor signaling pathway. These results corroborate the central role Homer2 plays in glutamatergic transmission and expand the network of proteins potentially contributing to the behavioral abnormalities associated with altered Homer2 expression. SIGNIFICANCE: Long Homer proteins are scaffolding proteins that regulate signal transduction in neurons. Identifying their interacting partners is key to understanding their function. We used co-immunoprecipitation in combination with mass spectrometry to establish the first comprehensive list of Homer2-interacting partners in the mouse brain. The specificity of interactions was evaluated using Homer2 knockout brain tissue as a negative control. The set of proteins that we identified minimally overlaps with previously reported interacting partners of Homer2; however, we identified novel interactors that are part of a signaling cascade activated by glutamatergic transmission, which improves our mechanistic understanding of the role of Homer2 in behavior. PMID- 28728881 TI - On new regulation of cell therapy and regenerative medicine in the Russian Federation. PMID- 28728882 TI - Variation in the cost of 5 common operations in the United States. AB - BACKGROUND: Health care costs are an important policy focus in the United States. The magnitude and drivers of variation in the costs of common operative procedures are not well understood. We sought to characterize variation in costs across hospitals. METHODS: We used data from the Nationwide Inpatient Sample from 2001-2011 for 5 elective operations: colectomy, coronary artery bypass graft, total knee arthroplasty, cesarean section, and lung resection. Hospitals were benchmarked for each using hierarchical risk- and reliability-adjustment methods to generate an observed-to-expected cost ratio, which was adjusted for patient demographics, comorbidity, wage index, and procedure complexity. Hospitals were divided into quintiles. Characteristics of high- and low-quintile hospitals and their adjusted outcomes were examined. RESULTS: Cost observed-to-expected ratios ranged widely for all 5 procedures: 14.9-fold for colectomy, 5.5-fold for coronary artery bypass graft, 12.5-fold for lung resection, 10.6-fold for total knee arthroplasty, and 28.0-fold for cesarean section. Comparing highest to lowest cost quintiles of hospitals, high-cost hospitals were more likely to serve minority and Medicaid patients. Mortality was elevated significantly in high-cost hospitals for colectomy, coronary artery bypass graft, and lung resection (adjusted odds ratio 1.99, 1.32, 2.57; respectively). Service lines were correlated at low-cost hospitals. There was a significant association between greater procedure volume and low-cost hospitals for colectomy, coronary artery bypass graft, and total knee arthroplasty. CONCLUSION: Despite robust adjustment, there is wide cost variation for common operative procedures in the United States. High-cost hospitals may need to focus on cost reduction at the hospital level to reduce cost across service lines. Benchmarking costs may identify significant opportunities to promote value, or the balance between cost and quality, in operative care in the United States. PMID- 28728883 TI - Long-term Survival Outcomes of Primary Breast Cancer in Women With or Without Preoperative Magnetic Resonance Imaging: A Matched Cohort Study. AB - AIMS: To investigate whether preoperative magnetic resonance imaging (MRI) in patients with primary breast cancer is predictive of disease-free (DFS) and overall survival and to determine the prognostic factors indicating survival. MATERIALS AND METHODS: This retrospective study was approved by the institutional review board and the requirement for informed consent was waived. From 2009 to 2010, 828 women with primary breast cancer and preoperative MRI were matched with 1613 women without such imaging. Patients were matched with regards to 25 patient and tumour-related covariates. A Cox proportional hazards model was used to investigate the time to recurrence and to estimate the hazard ratio for preoperative MRI. Log-rank tests and Cox proportional hazards survival analysis were carried out on total recurrence DFS and overall survival in the unmatched datasets. RESULTS: In total, 799 matched pairs were available for survival analysis. The MRI group showed a tendency towards better survival outcome; however, there were no significant differences in DFS and overall survival. Age at diagnosis (DFS hazard ratio = 0.98; overall survival hazard ratio = 1.04), larger tumour size (DFS hazard ratio = 1.01; overall survival hazard ratio = 1.02), triple negative breast cancer (DFS hazard ratio = 2.64; overall survival hazard ratio = 3.44) and the presence of lymphovascular invasion (DFS hazard ratio = 2.12; overall survival hazard ratio = 2.70) were independent significant variables for worse DFS and overall survival. CONCLUSION: Preoperative MRI did not result in an improvement in a patient's outcome. Age at diagnosis, tumour size, molecular subtype and lymphovascular invasion were significant independent factors affecting both DFS and overall survival. PMID- 28728884 TI - Glucocorticoid programming of neuroimmune function. AB - Throughout life physiological systems strive to maintain homeostasis and these systems are susceptible to exposure to maternal or environmental perturbations, particularly during embryonic development. In some cases, these perturbations may influence genetic and physiological processes that permanently alter the functioning of these physiological systems; a process known as developmental programming. In recent years, the neuroimmune system has garnered attention for its fundamental interactions with key hormonal systems, such as the hypothalamic pituitary adrenal (HPA) axis. The ultimate product of this axis, the glucocorticoid hormones, play a key role in modulating immune responses within the periphery and the CNS as part of the physiological stress response. It is well-established that elevated glucocorticoids induced by developmental stress exert profound short and long-term physiological effects, yet there is relatively little information of how these effects are manifested within the neuroimmune system. Pre and post-natal periods are prime candidates for manipulation in order to uncover the physiological mechanisms that underlie glucocorticoid programming of neuroimmune responses. Understanding the potential programming role of glucocorticoids may be key in uncovering vulnerable windows of CNS susceptibility to stressful experiences during embryonic development and improve our use of glucocorticoids as therapeutics in the treatment of neurodegenerative diseases. PMID- 28728885 TI - Characterization of the neuropeptidome of a Southern Ocean decapod, the Antarctic shrimp Chorismus antarcticus: Focusing on a new decapod ITP-like peptide belonging to the CHH peptide family. AB - As part of the study of the resilience of Antarctic crustaceans to global warming, the shrimp Chorismus antarcticus was subjected to an analysis of global approach using the Next Generation Sequencing Illumina Hi-Seq platform. With this data a detailed study into the principal neuropeptides and neurohormones of this species have been undertaken. Total RNAs from whole animals were enriched with eyestalk extracts to ensure maximum sequencing depth of the different neurohormones and neuropeptides mainly expressed into the X organ-sinus gland complex, which is a major endocrine organ of their synthesis. Apart from the information that can provide the availability of the transcriptome of a polar crustacean, the study of neuropeptides of a caridean shrimp will partially fill the limited data available for this taxon. Illumina sequencing was used to produce a transcriptome of the polar shrimp. Analysis of the Trinity assembled contigs produced 55 pre-pro-peptides, coding for 111 neuropeptides belonging to the following families: adipokinetic-corazonin-like peptide, Allatostatins (A, B et C), Bursicon (alpha), CCHamide, Crustacean Hyperglycemic Hormones (CHH), Crustacean Cardioactive Peptide (CCAP), Corazonin, Crustacean Female Sex Hormone (CSFH), Diuretic Hormones 31 and 45 (DH), Eclosion Hormone (EH), FLRFamide, GSEFLamide, Intocin, Ion Transport Peptide-like (ITP-like), Leucokinin, Molt inhibiting Hormone, Myosuppresin, Neuroparsin, Neuropeptide F (NPF), Orcokinin, Orcomyotropin, Pigment Dispersing Hormone (PDH), Pyrokinin, Red Pigment Concentrating Hormone (RPCH), SIFamide, small Neuropeptide F (sNPF), Sulfakinin and finally Tachykinin Related peptides. Among the new peptides highlighted in this study, the focus was placed on the peptides of the CHH family and more particularly on a new ITP-like in order to confirm its belonging to a new group of peptides of the family. A phylogeny made from more than 200 sequences of peptides, included new sequences from new species besides Chorismus antarcticus, confirms the peculiarity of this new set of peptides gathered under the name ITP like. PMID- 28728886 TI - Effect of a physical activity intervention on suPAR levels: A randomized controlled trial. AB - OBJECTIVES: Soluble urokinase-type plasminogen activator receptor (suPAR) is a novel inflammatory marker, associated with lifestyle diseases and mortality risk. No studies have investigated whether physical activity may reduce suPAR levels using a randomized controlled design. DESIGN AND METHODS: suPAR and C-reactive protein (CRP) levels were determined in blood samples from a previous randomized controlled trial with Pakistani immigrants in Norway, 2008. The study included physically inactive men that were randomized to an intervention group (supervised group exercises) or a control group and followed for 5 months. A linear regression model was used and adjusted for age, inactivity level at baseline, and mean difference in CRP levels. RESULTS: Overall, 80 and 53 participants were included in the intervention and control group, respectively. Obesity and smoking were associated with higher suPAR levels at baseline. The intervention group had a mean suPAR level of 2.65 (95% CI=2.48-2.78)ng/mL at baseline compared to 2.80 (95% CI=2.65-2.95)ng/mL at post-test, and thereby significantly increased suPAR levels after intervention (p=0.02). In the control group, mean suPAR level significantly increased from 2.93 (95% CI=2.68-3.16)ng/mL at baseline to 3.09 (95% CI=2.81-3.38)ng/mL at post-test (p=0.04). When comparing change from baseline to post-test in suPAR levels for the intervention group versus the control group, no significant change in the unadjusted model was found (beta= 0.002, 95% CI=-0.219-0.215). Similar results were found for CRP levels. CONCLUSION: There was no change in suPAR levels after regular exercise compared to a control group implying that suPAR rather reflects underlying harmful inflammatory responses associated with disease development. PMID- 28728887 TI - Effectiveness of exercise intervention on improving fundamental movement skills and motor coordination in overweight/obese children and adolescents: A systematic review. AB - OBJECTIVES: Childhood obesity is negatively associated with fundamental movement skill and motor coordination, which in turn constrains physical activity participation and adherence thereby forming a 'vicious cycle'. However, developing motor skill and coordination in childhood could help to break the vicious cycle to reduce childhood obesity. The objective of this systematic review was to determine the effectiveness of exercise and physical activity interventions on improving fundamental movement skill and motor coordination in overweight/obese children and adolescents. DESIGN: A systematic review with quality assessment. METHODS: A comprehensive systematic search was conducted from MEDLINE, SPORTDiscus, CINAHL, Scopus, Web of Science, EMBASE without date restriction for randomized control trials, interventions or longitudinal studies of movement skill/motor skill/motor coordination in overweight/obese participants between 0-18 years of age. A total of 3944 publications were screened, and 17 published studies were included. RESULTS: Altogether 38 tests for locomotor, object-control, balance and complex task tests were examined in selected studies, with 33 reporting increases after interventions, while only five tests indicated no change. The evidence strongly suggests that exercise/physical activity interventions were effective in improving locomotor skill, object-control skill and complex tasks in overweight/obese peers. However, the results for balance were equivocal. CONCLUSIONS: Results from existing studies suggest overweight/obese peers have lower levels of fundamental movement skill than their healthy weight peers. However, exercise/physical activity interventions are effective in improving their skills. To maximize skill improvement, we recommend focused fundamental movement skill and motor coordination activities for skill development. These progressions in interventions may help break the vicious cycle of childhood obesity. PMID- 28728888 TI - Laparoscopic coledochoduodenostomy for chronic biliary stricture (with video). PMID- 28728890 TI - Clinical influence of preoperative factor XIII activity in patients undergoing pancreatoduodenectomy. AB - BACKGROUND: The influence of decreased factor XIII (FXIII) activity on perioperative bleeding has been reported in some surgical procedures. The purposes of this study were to investigate the perioperative dynamics of FXIII in patients undergoing pancreatoduodenectomy and to clarify the effects of low preoperative FXIII activity on intraoperative bleeding and postoperative complications. METHODS: Total of 43 patients who underwent a pancreatoduodenectomy were enrolled. The perioperative FXIII activities were measured, and their associations with intraoperative bleeding and postoperative outcomes were analyzed. RESULTS: Fifteen patients (35%) had low FXIII activities (<70%, lower than the institutional normal range). The patients with preoperative FXIII activities <70% experienced significantly greater blood loss (median, 1309 mL) during surgery compared to those with FXIII levels of >=70% (median, 710 mL) (p = 0.001). The postoperative morbidity rates, including pancreatic fistula, were comparable between the patients with FXIII activities <70% and those with FXIII activities >=70%. The FXIII levels substantially decreased on postoperative day 1 and remained at low levels until postoperative day 7. CONCLUSION: Unexpectedly high proportions of patients undergoing pancreatoduodenectomy had low preoperative FXIII activities. Preoperative FXIII deficiency may increase intraoperative bleeding but had no influence on the postoperative outcomes. PMID- 28728889 TI - Cognitive and motor functioning in elderly glucocerebrosidase mutation carriers. AB - Mutations in the glucocerebrosidase (GBA) gene are a strong genetic risk factor for the development of Parkinson's disease and dementia with Lewy Bodies. However the penetrance of GBA mutations is low for these diseases in heterozygous carriers. The aim of this study was to examine the relationship between mutation status and cognitive and motor functioning in a sample of community-dwelling older adults. Using linear mixed effects models, we examined the effect of heterozygous mutation status on 736 community-dwelling older adults (>=70 years) without dementia or Parkinson's disease assessed over an average of 6 years, 28 of whom had a single GBA mutation (primarily N370S). Verbal memory was measured using the picture version of the Free and Cued Selective Reminding Test, and carriers showed significantly (p < 0.05) greater decline in verbal memory over time. There was no difference in motor function or any other cognitive domain. Taken together, these results suggest an effect, but an overall limited burden, of harboring a single GBA mutation in aging mutation carriers. PMID- 28728892 TI - [Pediatric preparations of blood products]. AB - The transfusion in pediatrics may require specific preparations to adapt to the various characteristics from preterm neonates to big child: weight, immaturity, immune system, blood volume, long and short-term prognosis, and to meet the needs of pathologies related to the perinatal period. The knowledge of the process for preparation, conservation and administration of these particular products shall permit a transfusion in safe conditions by supporting the prescribers in a personalized blood management. PMID- 28728891 TI - Impact of adjuvant chemotherapy on survival in patients with intrahepatic cholangiocarcinoma: a multi-institutional analysis. AB - BACKGROUND: The benefit of adjuvant chemotherapy for resected intrahepatic cholangiocarcinoma (ICC) is unclear. The aim of the current study was to investigate the impact of adjuvant chemotherapy on survival among patients undergoing resection of ICC using a multi-institutional database. METHODS: 1154 ICC patients undergoing curative-intent hepatectomy between 1990 and 2015 were identified from 14 institutions. Cox proportional hazard modeling was used to determine the impact of adjuvant chemotherapy on overall survival (OS). RESULTS: Following resection, 347 (30%) patients received adjuvant chemotherapy, most commonly a gemcitabine-based regimen (n = 184, 52%). Patients with T2/T3/T4 disease were more likely to receive adjuvant therapy compared with patients with T1a/T1b disease (OR 2.5, 95%CI 1.89-3.23; P < 0.001). Among patients who did and did not receive adjuvant therapy, patients with T2/T3/T4 tumors had a 5-year OS of 37% (95%CI 28.9-44.4) versus 30% (95%CI 23.8-35.6), respectively (p = 0.006). Similarly patients with N1 disease who received adjuvant chemotherapy tended to have improved 5-year OS (18.3%, 95%CI 9.0-30.1 vs. no adjuvant therapy 12%, 95%CI 3.9-24.4; P = 0.050). CONCLUSIONS: While adjuvant chemotherapy did not influence the prognosis of all ICC patients following surgical resection, it was associated with a potential survival benefit in subgroups of patients at increased risk for recurrence, such as those with advanced tumors. PMID- 28728893 TI - 2015 revised Utstein-style recommended guidelines for uniform reporting of data from drowning-related resuscitation: An ILCOR advisory statement. AB - BACKGROUND: Utstein-style guidelines use an established consensus process, endorsed by the international resuscitation community, to facilitate and structure resuscitation research and publication. The first "Guidelines for Uniform Reporting of Data From Drowning" were published over a decade ago. During the intervening years, resuscitation science has advanced considerably, thus making revision of the guidelines timely. In particular, measurement of cardiopulmonary resuscitation elements and neurological outcomes reporting have advanced substantially. The purpose of this report is to provide updated guidelines for reporting data from studies of resuscitation from drowning. METHODS: An international group with scientific expertise in the fields of drowning research, resuscitation research, emergency medical services, public health, and development of guidelines met in Potsdam, Germany, to determine the data that should be reported in scientific articles on the subject of resuscitation from drowning. At the Utstein-style meeting, participants discussed data elements in detail, defined the data, determined data priority, and decided how data should be reported, including scoring methods and category details. RESULTS: The template for reporting data from drowning research was revised extensively, with new emphasis on measurement of quality of resuscitation, neurological outcomes, and deletion of data that have proved to be less relevant or difficult to capture. CONCLUSIONS: The report describes the consensus process, rationale for selecting data elements to be reported, definitions and priority of data, and scoring methods. These guidelines are intended to improve the clarity of scientific communication and the comparability of scientific investigations. PMID- 28728894 TI - What is the key contributor in achieving return of spontaneous circulation in the field from out-of-hospital cardiac arrest? PMID- 28728895 TI - Saving lives despite 'failed' extracorporeal resuscitation. PMID- 28728896 TI - Platinum(IV) complexes conjugated with phenstatin analogue as inhibitors of microtubule polymerization and reverser of multidrug resistance. AB - Pt(IV) complexes comprising a phenstatin analogue, as dual-targeting Pt(IV) prodrug, were designed and synthesized. They were found not only to carry the DNA binding platinum warhead into the tumor cells, but also to have a small molecular unit to inhibit tubulin polymerization. In vitro evaluation results revealed that Pt(IV) complexes showed better and more potent activity against the test human cancer cells including cisplatin resistant cell lines than their corresponding Pt(II) counterparts. In addition, the Pt(IV) derivative of cisplatin, complex 10, exhibited highly selective inhibition in human cancer cells and displayed no obvious toxicity to two human normal cell lines, respectively. Mechanism study suggested that complex 10 induced cell-cycle arrest at the G2/M phase and caused apoptotic cell death of human lung cancer NCI-H460 cells through the mitochondrial mediated pathway. Moreover, complex 10 effectively inhibited the tumor growth in the NCI-H460 xenograft model. PMID- 28728897 TI - 1,3-Oxazole-based selective picomolar inhibitors of cytosolic human carbonic anhydrase II alleviate ocular hypertension in rabbits: Potency is supported by X ray crystallography of two leads. AB - Two lead 1,3-oxazole-based carbonic anhydrase inhibitors (CAIs) earlier identified as selective, picomolar inhibitors of hCA II (a cytosolic target for treatment of glaucoma) have been investigated further. Firstly, they were found to be conveniently synthesized on multigram scale, which enables further development. These compounds were found to be comparable in efficacy to dorzolamide eye drops when applied in the eye drop form as well. Finally, the reasons for unusually high potency of these compounds became understood from their high-resolution X-ray crystallography structures. These data significantly expand our understanding of heterocycle-based primary sulfonamides, many of which have recently emerged from our labs - particularly, from the corneal permeability standpoint. PMID- 28728898 TI - KBE009: An antimalarial bestatin-like inhibitor of the Plasmodium falciparum M1 aminopeptidase discovered in an Ugi multicomponent reaction-derived peptidomimetic library. AB - Malaria is a global human parasitic disease mainly caused by the protozoon Plasmodium falciparum. Increased parasite resistance to current drugs determines the relevance of finding new treatments against new targets. A novel target is the M1 alanyl-aminopeptidase from P. falciparum (PfA-M1), which is essential for parasite development in human erythrocytes and is inhibited by the pseudo-peptide bestatin. In this work, we used a combinatorial multicomponent approach to produce a library of peptidomimetics and screened it for the inhibition of recombinant PfA-M1 (rPfA-M1) and the in vitro growth of P. falciparum erythrocytic stages (3D7 and FcB1 strains). Dose-response studies with selected compounds allowed identifying the bestatin-based peptidomimetic KBE009 as a submicromolar rPfA-M1 inhibitor (Ki=0.4MUM) and an in vitro antimalarial compound as potent as bestatin (IC50=18MUM; without promoting erythrocyte lysis). At therapeutic-relevant concentrations, KBE009 is selective for rPfA-M1 over porcine APN (a model of these enzymes from mammals), and is not cytotoxic against HUVEC cells. Docking simulations indicate that this compound binds PfA-M1 without Zn2+ coordination, establishing mainly hydrophobic interactions and showing a remarkable shape complementarity with the active site of the enzyme. Moreover, KBE009 inhibits the M1-type aminopeptidase activity (Ala-7-amido-4-methylcoumarin substrate) in isolated live parasites with a potency similar to that of the antimalarial activity (IC50=82MUM), strongly suggesting that the antimalarial effect is directly related to the inhibition of the endogenous PfA-M1. These results support the value of this multicomponent strategy to identify PfA-M1 inhibitors, and make KBE009 a promising hit for drug development against malaria. PMID- 28728900 TI - Ultra-sensitive aptasensor based on a GQD nanocomposite for detection of hepatitis C virus core antigen. AB - In the present study, by using the aptamer proximity binding assay strategy, a novel electrochemical aptasensor is described for ultrasensitive detection of hepatitis C virus (HCV) core antigen. The immobilization surface is prepared by the modification of a glassy carbon electrode (GCE) with a graphene quantum dots (GQD). GQD were introduced as a novel and suitable substrate for aptamers through pi-pi stacking interactions, the richness of hydrophilic edges as well as hydrophobic plane in GQD which enhances the aptamer absorption on the electrode surface. Electrochemical impedance spectroscopy (EIS) and cyclic voltammetry (CV) and differential pulse voltammetry (DPV) were performed at each stage of the chemical modification process to confirm the resulting surface changes. EIS technique was used as an efficient alternative detection system for HCV core antigen measurement with detection limit 3.3 pg mL-1 and two linear concentration range 10-70 pg mL-1 and 70-400 pg mL-1. Moreover, the fabricated aptasensor could accurately detect HCV core antigen concentration in human serum samples. Such an aptasensor opens a rapid, selective and sensitive route for HCV core antigen detection and provides a promising strategy for potential applications in clinical diagnostics. PMID- 28728899 TI - Machine learning-enabled discovery and design of membrane-active peptides. AB - Antimicrobial peptides are a class of membrane-active peptides that form a critical component of innate host immunity and possess a diversity of sequence and structure. Machine learning approaches have been profitably employed to efficiently screen sequence space and guide experiment towards promising candidates with high putative activity. In this mini-review, we provide an introduction to antimicrobial peptides and summarize recent advances in machine learning-enabled antimicrobial peptide discovery and design with a focus on a recent work Lee et al. Proc. Natl. Acad. Sci. USA 2016;113(48):13588-13593. This study reports the development of a support vector machine classifier to aid in the design of membrane active peptides. We use this model to discover membrane activity as a multiplexed function in diverse peptide families and provide interpretable understanding of the physicochemical properties and mechanisms governing membrane activity. Experimental validation of the classifier reveals it to have learned membrane activity as a unifying signature of antimicrobial peptides with diverse modes of action. Some of the discriminating rules by which it performs classification are in line with existing "human learned" understanding, but it also unveils new previously unknown determinants and multidimensional couplings governing membrane activity. Integrating machine learning with targeted experimentation can guide both antimicrobial peptide discovery and design and new understanding of the properties and mechanisms underpinning their modes of action. PMID- 28728901 TI - Using Au@nano-C60 nanocomposite as an enhanced sensing platform in modeling a TNT aptasensor. AB - Based on the unique characteristics of the combination of fullerene and gold nanoparticles, we successfully designed a new and facile nanocomposite (Au@nano C60) to fabricate an aptasensor for the ultra-sensitive and selective detection of TNT. The gold nanoparticles decorated fullerene onto a glassy carbon electrode was prepared using an electrochemical method by the in situ generation of Au nanoparticles onto the surface of the glassy carbon electrode modified with activated fullerene. Successively, the NH2-Apt as a receptor molecule of 2,4,6 Trinitrotoluen was covalently attached onto the modified electrode surface with the resultant nanocomposite. With the addition of the target onto the aptasensor surface and the formation of target/Apt complex, a linear response was obtained from 0.50 fM to 5 MUM as well as a limit of detection down to 0.17 fM. The proposed aptasensor shows a wider linear response range and lower limit of detection for the specific detection of 2,4,6-Trinitrotoluen. This newly developed strategy will pave the way to partly meet the requirements in the field of homeland security and public safety. PMID- 28728902 TI - Role of miRNAs in development and disease: Lessons learnt from small organisms. AB - MicroRNAs (miRNAs) constitute a class of small (18-22 nucleotides) non-coding RNAs that regulate gene expression at the post-transcriptional level. Caenorhabditis elegans, Drosophila melanogaster, and many other small organisms have been instrumental in deciphering the biological functions of miRNAs. While some miRNAs from small organisms are highly conserved across the taxa, others are organism specific. The miRNAs are known to play a crucial role during development and in various cellular functions such as cell survival, cell proliferation, and differentiation. The miRNAs associated with fragile X syndrome, Parkinson's disease, Alzheimer's disease, diabetes, cancer, malaria, infectious diseases and several other human diseases have been identified from small organisms. These organisms have been used as platforms in deciphering the functions of miRNAs in the pathogenesis of human diseases and to study miRNA biogenesis. Small organisms have also been used in the development of miRNA-based diagnostic, prognostic and therapeutic strategies. The molecular techniques such as genome sequencing, northern blot analysis, and quantitative RT-PCR, have been used in deciphering the functions of miRNAs in small organisms. How miRNAs from small organisms especially those from Drosophila and C. elegans regulate development and disease pathogenesis is the focus of this review. The outstanding questions raised by our current understanding are discussed. PMID- 28728903 TI - Utility of Magnetic Resonance Imaging for the Diagnosis of Appendicitis During Pregnancy: A Canadian Experience. AB - PURPOSE: The objective of the study was to evaluate the performance of magnetic resonance imaging (MRI) for the diagnosis of appendicitis during pregnancy. METHODS: We conducted a retrospective review of all MRI scans performed at our institution, between 2006 and 2012, for the evaluation of suspected appendicitis in pregnant women. Details of the MRI scans performed were obtained from the radiology information system as well as details of any ultrasounds carried out for the same indication. Clinical and pathological data were obtained by retrospective chart review. RESULTS: The study population comprised 63 patients, and 8 patients underwent a second MRI scan during the same pregnancy. A total of 71 MRI scans were reviewed. The appendix was identified on 40 scans (56.3%). Sensitivity of MRI was 75% and specificity was 100% for the diagnosis of appendicitis in pregnant women. When cases with right lower quadrant inflammatory fat stranding or focal fluid, without appendix visualization, were classified as positive for appendicitis, MRI sensitivity increased to 81.3% but specificity decreased to 96.4%. CONCLUSIONS: MRI is sensitive and highly specific for the diagnosis of appendicitis during pregnancy and should be considered as a first line imaging study for this clinical presentation. PMID- 28728904 TI - Clostridium tetani bacteremia in a patient with cirrhosis following transarterial chemoembolization treatment for hepatocellular carcinoma. PMID- 28728905 TI - Perceptions of Clostridium difficile infections among infection control professionals in Taiwan. AB - BACKGROUND: High Clostridium difficile colonization and infection rates among hospitalized patients had been noted in Taiwan. Nevertheless, the cognition about clinical diagnosis and management of CDI among infection control professionals in Taiwan is not clear. MATERIAL AND METHODS: A 24-item survey questionnaire about the diagnosis, therapy, or infection control policies toward CDI was distributed in the annual meeting of the Infectious Disease Society of Taiwan (IDST) in October 2015 and Infectious Control Society of Taiwan (ICST) in April 2016. RESULTS: Totally 441 individuals responded to the survey, and 280 (63.5%) participants would routinely monitor the prevalence of CDI and 347 (78.7%) reported the formulation of infection control policies of CDI in their hospital, including contact precaution (75.7%), wearing gloves (88.9%) or dressing (80.0%) at patient care, single room isolation (49.7%), preference of soap or disinfectant-based sanitizer (83.2%) and avoidance of alcohol-based sanitizer (63.3%), and environmental disinfection with 1000 ppm bleach (87.1%). For the timing of contact precaution discontinuation isolation for CDI patients, most (39.9%) participants suggested the time point of the absence of C. difficile toxin in feces. To treat mild CDI, most (61.9%) participants preferred oral metronidazole, and for severe CDI 26.1% would prescribe oral vancomycin as the drug of choice. CONCLUSION: There were substantial gaps in infection control polices and therapeutic choices for CDI between international guidelines and the perceptions of medical professionals in Taiwan. Professional education program and the setup of guideline for CDI should be considered in Taiwan. PMID- 28728906 TI - Surgical management of strabismus following choroidal melanoma plaque brachytherapy. AB - PURPOSE: To characterize intraoperative findings, surgical approach, and postoperative outcomes in patients undergoing strabismus surgery following plaque brachytherapy for ocular melanoma. METHODS: The records of all patients who underwent plaque brachytherapy for choroidal melanoma between May 2007 and June 2016 were reviewed retrospectively to identify those who subsequently required strabismus surgery. RESULTS: Of the 461 patients who underwent plaque brachytherapy during the study period, 13 (2.8%) met inclusion criteria. Visual acuity of the affected eye was 20/40 or better in 9 patients (69%). Preoperative horizontal deviation ranged from 0Delta to 52Delta; vertical deviation, from 2Delta to 25Delta. At final follow-up mean horizontal deviation ranged from 0 to 4Delta; vertical deviation, from 0Delta to 12Delta. Intraoperatively, all muscles directly adjacent to the treated area appeared macroscopically thicker than normal despite being functionally underacting. Magnetic resonance imaging showed enlarged muscles adjacent to the plaque radiotherapy. Microscopic examination of muscles in 2 patients showed reactive enlargement of the muscle fibers, granulation tissue, and inflammation. CONCLUSIONS: Persistent strabismus after plaque brachytherapy is rare. Typical findings include enlarged, underacting rectus muscles adjacent to the area of the plaque, restrictive connective tissue, and incomitant strabismus. Previously disinserted muscles may be found in abnormal locations. In this patient cohort scar tissue removal in conjunction with tightening procedures on the muscle adjacent to the plaque combined with recession of the antagonist muscle frequently resulted in good anatomical outcome. PMID- 28728907 TI - Sequential Extended Thoracoscopic Sympathicotomy for Palmo-Axillo-Plantar Hyperhidrosis. AB - BACKGROUND: Palmo-axillo-plantar hyperhidrosis (HH) exists in approximately 70% to 100% of patients complaining of HH. Many studies have documented variable effects of thoracoscopic sympathicotomy (TS) on plantar sweating. The present trial evaluated sequential extended thoracoscopic sympathicotomy for the treatment of palmo-axillo-plantar HH regarding its feasibility and outcome on each domain of HH, particularly the plantar domain METHODS: Forty-two patients with severe palmo-axillo-plantar HH underwent sequential extended (T3 to T12) thoracoscopic sympathicotomy. Improvement in HH was assessed using visual analog scale and iodine-starch test, and quality of life was evaluated using the Keller quality of life questionnaire preoperatively and 2 years postoperatively. RESULTS: Included were 16 men and 26 women with a mean age of 24.3 +/- 5.3 years. The average preoperative VAS for the palmar, axillary, and plantar HH was 9 +/- 0.66, which declined significantly (p < 0.0001) at 24 months of follow-up to a mean of 0.74 +/- 0.4 for the palmar and axillary domains and to 1.26 +/- 0.7 for plantar HH. Improvement in quality of life was observed in all patients at 24 months of follow-up as the overall median score decreased from 120.5 to 3.5. CONCLUSIONS: Sequential extended thoracoscopic sympathicotomy proved to be an effective method for the treatment of combined HH because it achieved satisfactory and sustained improvement of palmar, axillary, and plantar sweating. Although the benefits of sequential extended thoracoscopic sympathicotomy outweigh its drawbacks and technical difficulties, further prospective studies are required to ascertain the effectiveness of this new technique. PMID- 28728908 TI - The proteasome maturation protein POMP increases proteasome assembly and activity in psoriatic lesional skin. AB - BACKGROUND: The ubiquitin proteasome pathway is involved in the pathogenesis of psoriasis and proteasome subunits are increased in lesional psoriatic skin. Recent works have highlighted that proteasome levels can be regulated through modulation of proteasome assembly notably by the proteasome maturation protein POMP. OBJECTIVES: To investigate whether proteasome assembly and POMP expression are modified in psoriatic skin. METHODS: Proteasome assembly as well as expression of proteasome regulators were assessed in non-lesional and lesional psoriatic skin using native gel electrophoresis and western blots respectively. The protein and mRNA expression levels of POMP were compared by western blots, immunohistochemistry and quantitative polymerase chain reaction. The role of POMP in keratinocyte proliferation and differentiation was assessed by silencing POMP gene expression by RNA interference in human immortalized keratinocyte HaCaT cells. RESULTS: Both 20S and 26S proteasomes (and their respective proteolytic activities) as well as the main proteasome regulators are increased in lesional psoriatic skin. POMP binds to 20S precursor complexes and is overexpressed in lesional epidermal psoriatic skin, supporting that POMP-mediated proteasome assembly is increased in psoriatic skin. POMP silencing inhibited HaCaT cell proliferation and induced apoptosis through the inhibition of the proteasome assembly. Moreover POMP partial depletion decreased the expression of the differentiation markers keratin 10 and involucrin during the [Ca2+]-induced HaCaT cells differentiation. CONCLUSION: Altogether these results establish a potential role for POMP and proteasome assembly in psoriasis pathogenesis. PMID- 28728909 TI - Assessing impacts of DNA extraction methods on next generation sequencing of water and wastewater samples. AB - Next Generation Sequencing (NGS) is increasingly affordable and easier to perform. However, standard protocols prior to the sequencing step are only available for few selected sample types. Here we investigated the impact of DNA extraction methods on the consistency of NGS results. Four commercial DNA extraction kits (QIAamp DNA Mini Kit, QIAamp DNA Stool Mini Kit, MO BIO Power Water Kit, and MO BIO Power Soil DNA Isolation Kit) were used on sample sources including lake water and wastewater, and sample types including planktonic and biofilm bacteria communities. Sampling locations included a lake water reservoir, a trickling filter, and a moving bed biofilm reactor (MBBR). Unique genera such as Gemmatimonadetes, Elusimicrobia, and Latescibacteria were found in multiple samples. The Stool Mini Kit was least efficient in terms of diversity in sampling results with freshwater lake samples, and surprisingly the Power Water Kit was the least efficient across all sample types examined. Detailed NGS beta diversity comparisons indicated that the Mini Kit and PowerSoil Kit are best suited for studies that extract DNA from a variety of water and wastewater samples. We ultimately recommend application of Mini Kit or PowerSoil Kit as an improvement to NGS protocols for these sampling environments. These results are a step toward achieving accurate comparability of complex samples from water and wastewater environments by applying a single DNA extraction method, further streamlining future investigations. PMID- 28728910 TI - Rapid differentiation of bacterial communities using high resolution melting analysis. AB - Analysis of microbial communities is of broad interest in biology and high throughput sequencing is now the preferred method. However, some studies may not need the level of detail high throughput sequencing provides and its cost may limit the number of samples that can be sequenced. High resolution melting analysis (HRM) of 16S rRNA gene variable regions has been proposed as an efficient and low cost method to prioritize samples for sequencing but more specific primers are needed and its efficacy needs to be confirmed. We tested a more specific pair of primers and compared results concerning the structure of microbial communities in tadpole intestine and feces obtained using HRM, denaturing gradient gel electrophoresis (DGGE) and high-throughput sequencing performed in parallel. All three methods showed similar conclusions concerning the communities and revealed communities that differed among intestinal regions and feces. The improved HRM method targets a shorter amplicon in the V3 region of the 16S rRNA gene and uses non-degenerate primers, both of which increase the sensitivity of HRM. The HRM approach was shown to be as effective as DGGE for comparing microbial communities, is considerably easier to perform, and can be used to assess differences in microbial community structure among a large number of samples before committing to sequencing. PMID- 28728911 TI - Effects of riluzole on spinal seizure-like activity in the brainstem-spinal cord preparation of newborn rat. AB - Riluzole blocks persistent Na+ current, inhibits generation of neuronal bursts and decreases glutamate-induced excitotoxicity. In previous studies of respiratory activity, riluzole suppressed inspiratory-related burst generation activity in rat slice or en bloc preparations. We examined riluzole's effects on inspiratory burst generation and drug-induced seizure-like activity in newborn rat en bloc preparations. Medulla-spinal cord preparations from postnatal day 0-3 Wistar rats were isolated under deep isoflurane anesthesia and were superfused with artificial cerebrospinal fluid equilibrated with 95% O2 and 5% CO2, pH 7.4, at 25-26 degrees C. Inspiratory activity was monitored from the fourth cervical ventral root. Seizure-like activity was induced by application of 20MUM DL-threo beta-benzyloxyasparatate (TBOA, a glutamate uptake blocker preferentially acting on astrocytes) or coadministration of GABAA antagonist bicuculline (10MUM) and glycine antagonist strychnine (10MUM). Pretreatment and co-application with 10MUM riluzole abolished the seizure-like burst activity induced by TBOA or bicuculline/strychnine. N-methyl-d-aspartic acid receptor antagonist MK801 (10MUM) also depressed this activity. Riluzole may attenuate excessive glutamate action involved in pathological hyperexcitability of motor neurons with no major effect on generation of respiratory activity. Riluzole at the optimal dose could be a potential treatment to protect drug-induced epileptic brain tissue from excitotoxic damage without inducing respiratory suppression. PMID- 28728912 TI - Electric stimulation of the right temporo-parietal junction induces a task specific effect in deceptive behaviors. AB - How the brain generates a lie is an important and unsolved issue in neuroscience. Previous studies indicated that mentalizing, the ability to understand and manipulate the mental states of others, plays a critical role in successful deception. Accordingly, recent neuroimaging studies reported deception-related activity in the right temporo-parietal junction (rTPJ), a brain region closely related to the mentalizing ability. Detailed functions of rTPJ in deception, however, remain unclear. In the present study, we investigated a causal relationship between rTPJ and deception using transcranial direct-current stimulation (tDCS). Subjects received anodal tDCS to their rTPJ or V1 (control) and then performed three tasks in which they aimed to deceive another participant to get monetary rewards. In one of the three tasks, we found a significant decrease in a rate of successful deception when rTPJ was stimulated, indicating that neural enhancement of rTPJ caused poorer (not better) deceptive performances. Our results suggest that, in some tasks involving selfish (money motivated) lying, neural processing in rTPJ does not contribute to successful deception through the metalizing ability. Rather, it would be related to the self monitoring of morally-unacceptable behaviors (lying). The neural enhancement of rTPJ therefore increased the psychological resistance to lying, resulting in poorer deceptive performances. PMID- 28728913 TI - Considerations in repetitive activation of light sensitive ion channels for long term studies: Channel rhodopsin in the Drosophila model. AB - Optogenetics is a technique used in various animal models and holds a potential for therapeutic possibilities in mammals. There are technical issues with the use of light sensitive ion channels: reproducible effects over time, controlling where the non-native proteins are targeted within the cell and changes in the biophysical properties of the cells they are expressed in. We used a variant of channel rhodopsin (ChR2-XXL) and targeted expression in neurons of larval Drosophila to investigate the acute and chronic activation, with light pulses, of the channels on synaptic function. The rhodopsin channel modifier all trans retinal (ATR) also plays a role in the sensitivity of the channel to light. Periods of acute, repetitive, and pulsatile blue light exposure over larval development produced attenuated responses. These blue light sensitive ion channels, with ATR, show accommodation and produce an electrical refractory period in inducing synaptic responses. The biological significance and aim of this study is to demonstrate that in controlling particular neurons or neuronal circuits with optogenetics, over time and throughout development, one will have to understand the dynamic nature of activating and silencing the light sensitive channels as well as the biophysical effects on neuronal activity. PMID- 28728914 TI - Hydroxycinnamoyl derivatives and secoiridoid glycoside derivatives from Syringa vulgaris flowers and their effects on the pro-inflammatory responses of human neutrophils. AB - Thirteen new compounds including caffeoyl-glucaric and p-coumaroyl-altraric acid derivatives, one monoterpenoid glucoside, four secoiridoid glycosides, and three hydroxycinnamoyl phenylpropanoid glycosides esterified with an oleoside 11-methyl ester along with fifteen known compounds were isolated from flowers of Syringa vulgaris L. (Oleaceae). Their structures were elucidated by high-resolution spectroscopic methods. The tested compounds were able to decrease the production of reactive oxygen species. Moreover, oleoechinacoside (13), demethylhydroxyoleonuezhenide (14), demethyloleonuezhenide (15), syringaoleoacteoside (25) and oleoacteoside (26) at the concentration of 50MUM, moderately suppressed the LPS-stimulated release of pro-inflammatory chemokine IL 8 and TNF-alpha from human neutrophils. Moreover, oleonuezhenide (12), oleoside 11-methyl ester (16) and oleoacteoside (26) at the concentration of 50MUM were able to induce the surface expression of interleukin 10 receptor, which is suppressed by the incubation of monocyte/macrophage cells with LPS. PMID- 28728915 TI - Continuous glucose monitoring adds information beyond HbA1c in well-controlled diabetes patients with early cardiovascular autonomic neuropathy. AB - AIMS: Hyperglycemia as evaluated by HbA1c is a risk factor for the development of cardiovascular autonomic neuropathy (CAN). The aim of the present study was to investigate whether continuous glucose monitoring (CGM) may add information beyond HbA1c in patients with type 2 diabetes and CAN. METHODS: 81 patients with type 2 diabetes (43 men, mean age 58+/-11year, HbA1c 6.6+/-0.5%). Patients were tested for CAN using cardiovascular reflex tests (response to standing, deep breathing and Valsalva maneuver) and underwent CGM for three days. CAN was defined as early (one test abnormal), or manifest (two or three tests abnormal). RESULTS: Twenty patients had early CAN and two patients had manifest CAN. Blood pressure, HbA1c, cholesterol levels and smoking habits were comparable in patients with vs. without CAN. Post-breakfast glycemic peak was significantly higher in patients with CAN (peak 207 vs 176mg/dL, P=0.009). Furthermore, the nocturnal glucose drop and dawn glucose was significantly higher in patients with CAN compared with patients without CAN (mean 134 vs. 118mg/dL, P=0.017 and mean 143 vs. 130mg/dL, P=0.045, respectively). Removing the two patients with manifest CAN from the statistical analysis didn't change the results. CONCLUSIONS: These findings emphasize the importance of monitoring glucose patterns over 24-h and not only rely on HbA1c as therapeutic target in patients with type 2 diabetes and CAN. PMID- 28728916 TI - Effects of spinal immobilization at a 20 degrees angle on cerebral oxygen saturations measured by INVOSTM. AB - BACKGROUND AND AIM OF THE STUDY: In this study, we aimed to investigate whether performing the immobilization at 20 degrees instead of 0 degrees changes cerebral oxygenation. MATERIALS AND METHODS: 33 volunteers were put in a hard cervical collar and backboard at 0 degrees and immobilized for 30min. The cerebral oxygen saturations of the volunteers were measured at 1, 5, and 30min after the start of the procedure (Group 1). The volunteers were asked to return the day after the Group 1 procedure but at the same time. Serial cerebral oxygen saturations were obtained at the same time intervals as in Group 1, but for Group 2, the backboard was set to 20 degrees . RESULTS: When the cerebral oxygen saturations of the two groups were compared, there was a slight decrease when the backboard position was changed from 0 degrees to 20 degrees , but it was not statistically significant (P=0.220 and P=0.768, respectively). The results revealed that immobilizing the patients with a spinal backboard at 20 degrees instead of 0 degrees did not alter the cerebral oxygen saturations. CONCLUSION: Our study results revealed that spinal immobilization at 20 degrees , which was a new suggestion for spinal immobilization following a report that this position reduced the decrease in pulmonary function secondary to spinal immobilization, did not alter the cerebral oxygenation, so this suggestion is safe at least from the standpoint of cerebral oxygenation. PMID- 28728917 TI - Global alteration of the drug-binding pocket of human P-glycoprotein (ABCB1) by substitution of fifteen conserved residues reveals a negative correlation between substrate size and transport efficiency. AB - P-glycoprotein (P-gp), an ATP-dependent efflux pump, is linked to the development of multidrug resistance in cancer cells. However, the drug-binding sites and translocation pathways of this transporter are not yet well-characterized. We recently demonstrated the important role of tyrosine residues in regulating P-gp ATP hydrolysis via hydrogen bond formations with high affinity modulators. Since tyrosine is both a hydrogen bond donor and acceptor, and non-covalent interactions are key in drug transport, in this study we investigated the global effect of enrichment of tyrosine residues in the drug-binding pocket on the drug binding and transport function of P-gp. By employing computational analysis, 15 conserved residues in the drug-binding pocket of human P-gp that interact with substrates were identified and then substituted with tyrosine, including 11 phenylalanine (F72, F303, F314, F336, F732, F759, F770, F938, F942, F983, F994), two leucine (L339, L975), one isoleucine (I306), and one methionine (M949). Characterization of the tyrosine-rich P-gp mutant in HeLa cells demonstrated that this major alteration in the drug-binding pocket by introducing fifteen additional tyrosine residues is well tolerated and has no measurable effect on total or cell surface expression of this mutant. Although the tyrosine-enriched mutant P-gp could transport small to moderate size (<1000 Daltons) fluorescent substrates, its ability to transport large (>1000 Daltons) substrates such as NBD cyclosporine A, Bodipy-paclitaxel and Bodipy-vinblastine was significantly decreased. This was further supported by the physico-chemical characterization of seventeen tested substrates, which revealed a negative correlation between drug transport and molecular size for the tyrosine-enriched P-gp mutant. PMID- 28728918 TI - Financing transformative health systems towards achievement of the health Sustainable Development Goals: a model for projected resource needs in 67 low income and middle-income countries. AB - BACKGROUND: The ambitious development agenda of the Sustainable Development Goals (SDGs) requires substantial investments across several sectors, including for SDG 3 (healthy lives and wellbeing). No estimates of the additional resources needed to strengthen comprehensive health service delivery towards the attainment of SDG 3 and universal health coverage in low-income and middle-income countries have been published. METHODS: We developed a framework for health systems strengthening, within which population-level and individual-level health service coverage is gradually scaled up over time. We developed projections for 67 low income and middle-income countries from 2016 to 2030, representing 95% of the total population in low-income and middle-income countries. We considered four service delivery platforms, and modelled two scenarios with differing levels of ambition: a progress scenario, in which countries' advancement towards global targets is constrained by their health system's assumed absorptive capacity, and an ambitious scenario, in which most countries attain the global targets. We estimated the associated costs and health effects, including reduced prevalence of illness, lives saved, and increases in life expectancy. We projected available funding by country and year, taking into account economic growth and anticipated allocation towards the health sector, to allow for an analysis of affordability and financial sustainability. FINDINGS: We estimate that an additional $274 billion spending on health is needed per year by 2030 to make progress towards the SDG 3 targets (progress scenario), whereas US$371 billion would be needed to reach health system targets in the ambitious scenario-the equivalent of an additional $41 (range 15-102) or $58 (22-167) per person, respectively, by the final years of scale-up. In the ambitious scenario, total health-care spending would increase to a population-weighted mean of $271 per person (range 74-984) across country contexts, and the share of gross domestic product spent on health would increase to a mean of 7.5% (2.1-20.5). Around 75% of costs are for health systems, with health workforce and infrastructure (including medical equipment) as the main cost drivers. Despite projected increases in health spending, a financing gap of $20-54 billion per year is projected. Should funds be made available and used as planned, the ambitious scenario would save 97 million lives and significantly increase life expectancy by 3.1-8.4 years, depending on the country profile. INTERPRETATION: All countries will need to strengthen investments in health systems to expand service provision in order to reach SDG 3 health targets, but even the poorest can reach some level of universality. In view of anticipated resource constraints, each country will need to prioritise equitably, plan strategically, and cost realistically its own path towards SDG 3 and universal health coverage. FUNDING: WHO. PMID- 28728919 TI - Financing health systems to achieve the health Sustainable Development Goals. PMID- 28728920 TI - All roads lead to universal health coverage. PMID- 28728921 TI - Web-based questionnaires to assess perinatal outcome proved to be valid. AB - OBJECTIVES: The objective of this study was to validate a Web-based questionnaire completed by the mother to assess perinatal outcome used in a prospective cohort study. STUDY DESIGN AND SETTING: For 882 women with an estimated date of delivery between February 2012 and February 2015 who participated in the PRegnancy and Infant DEvelopment (PRIDE) Study, we compared data on pregnancy outcome, including mode of delivery, plurality, gestational age, birth weight and length, head circumference, birth defects, and infant sex, from Web-based questionnaires administered to the mothers 2 months after delivery with data from obstetric records. For continuous variables, we calculated intraclass correlation coefficients (ICCs) with 95% confidence intervals (CIs), whereas sensitivity and specificity were determined for categorical variables. RESULTS: We observed only very small differences between the two methods of data collection for gestational age (ICC, 0.91; 95% CI, 0.90-0.92), birth weight (ICC, 0.96; 95% CI, 0.95-0.96), birth length (ICC, 0.90; 95% CI, 0.87-0.92), and head circumference (ICC, 0.88; 95% CI, 0.80-0.93). Agreement between the Web-based questionnaire and obstetric records was high as well, with sensitivity ranging between 0.86 (termination of pregnancy) and 1.00 (four outcomes) and specificity between 0.96 (term birth) and 1.00 (nine outcomes). CONCLUSION: Our study provides evidence that Web-based questionnaires could be considered as a valid complementary or alternative method of data collection. PMID- 28728922 TI - Existing reporting guidelines for clinical trials are not completely relevant for implantable medical devices: a systematic review. AB - OBJECTIVES: The aim of this study was to determine relevant items for reporting clinical trials on implantable medical devices (IMDs) and to identify reporting guidelines which include these items. STUDY DESIGN AND SETTING: A panel of experts identified the most relevant items for evaluating IMDs from an initial list based on reference papers. We then conducted a systematic review of articles indexed in MEDLINE. We retrieved reporting guidelines from the EQUATOR network's library for health research reporting. Finally, we screened these reporting guidelines to find those using our set of reporting items. RESULTS: Seven relevant reporting items were selected that related to four topics: randomization, learning curve, surgical setting, and device information. A total of 348 reporting guidelines were identified, among which 26 met our inclusion criteria. However, none of the 26 reporting guidelines presented all seven items together. The most frequently reported item was timing of randomization (65%). On the contrary, device information and learning curve effects were poorly specified. CONCLUSION: To our knowledge, this study is the first to identify specific items related to IMDs in reporting guidelines for clinical trials. We have shown that no existing reporting guideline is totally suitable for these devices. PMID- 28728923 TI - Ruptured Sinus of Valsalva Aneurysm Causing Acute Right Heart and Hepatorenal Failure Requiring Urgent Surgery. AB - A sinus of Valsalva aneurysm is a rare cardiac anomaly that may be congenital or acquired. Very rarely, they present with acute symptoms as a result of rupture into the cardiac chamber. If left untreated, they almost always result in deteriorating cardiac function. We report a patient presenting with acute right heart failure and hepatorenal syndrome requiring urgent surgery and double patch repair. PMID- 28728924 TI - Strabismus Measurements with Novel Video Goggles. AB - PURPOSE: To assess the validity of a novel, simplified, noninvasive test for strabismus using video goggles. DESIGN: Cross-sectional method comparison study in which the new test, the strabismus video goggles, is compared with the existing reference standard, the Hess screen test. PARTICIPANTS: We studied 41 adult and child patients aged >=6 years with ocular misalignment owing to congenital or acquired paralytic or comitant strabismus and 17 healthy volunteers. METHODS: All participants were tested with binocular infrared video goggles with built-in laser target projection and liquid crystal display shutters for alternate occlusion of the eyes and the conventional Hess screen test. In both tests, ocular deviations were measured on a 9-point target grid located at 0+/-15 degrees horizontal and vertical eccentricity. MAIN OUTCOME MEASURES: Horizontal and vertical ocular deviations at 9 different gaze positions of each eye were measured by the strabismus video goggles and the Hess screen test. Agreement was quantified as the intraclass correlation coefficient. Secondary outcomes were the utility of the goggles in patients with visual suppression and in children. RESULTS: There was good agreement between the strabismus video goggles and the Hess screen test in the measurements of horizontal and vertical deviation (intraclass correlation coefficient horizontal 0.83, 95% confidence interval [0.77, 0.88], vertical 0.76, 95% confidence interval [0.68, 0.82]). Both methods reproduced the characteristic strabismus patterns in the 9-point grid. In contrast to Hess screen testing, strabismus video goggle measurements were even possible in patients with comitant strabismus and visual suppression. CONCLUSIONS: The new device is simple and is fast and accurate in measuring ocular deviations, and the results are closely correlated with those obtained using the conventional Hess screen test. It can even be used in patients with visual suppression who are not suitable for the Hess screen test. The device can be applied in children as young as 6 years of age. PMID- 28728925 TI - Potential anti-cancer activity of 7-O-pentyl quercetin: Efficient, membrane targeted kinase inhibition and pro-oxidant effect. AB - Quercetin is a redox-active plant-derived flavonoid with potential anticancer effects, stemming largely from its interaction with a number of proteins, and in particular from inhibition of pro-life kinases. To improve efficacy, we reasoned that a local increase in concentration of the compound at the level of cell membranes would result in a more efficient interaction with membrane-associated signaling kinases. We report here the synthesis of all five isomeric quercetin derivatives in which an n-pentyl group was linked via an ether bond to each hydroxyl of the flavonoid kernel. This strategy proved effective in directing quercetin to cellular membranes, and revealed a remarkable dependence of the derivatives' bioactivity on the specific site of functionalization. The isomer bearing the pentyl group in position 7, Q-7P, turned out to be the most effective and promising derivative, selectively inducing apoptosis in tumoral and fast growing cells, while sparing slow-growing, non-tumoral ones. Cytotoxicity for tumoral cells was strongly enhanced compared to quercetin itself. Q-7P induced massive ROS production, which however accounted only partially for cell death. Alterations in the levels of various signaling phospho-proteins were observed in a proteomics screen. An important contribution seems to come from inhibition of the PI3K/Akt pathway. This work opens new perspectives in developing membrane associating, polyphenol-based anticancer agents. PMID- 28728926 TI - Diagnostic delays in 537 symptomatic cases of Middle East respiratory syndrome coronavirus infection in Saudi Arabia. AB - BACKGROUND: Although the literature indicates that patient delays in seeking medical support for Middle East respiratory syndrome coronavirus (MERS-CoV) infections are associated with poor clinical outcomes, delays in the diagnosis itself remain poorly understood in these patients. This study aimed to determine the median time interval from symptom onset to a confirmed diagnosis and to identify the potential predictors of this interval in Saudi Arabian MERS patients. METHODS: This was a retrospective study of patients with confirmed MERS who were publicly reported by the World Health Organization (WHO). RESULTS: Five hundred and thirty-seven symptomatic cases of MERS-CoV infection were included. The median time interval between symptom onset and confirmation of the MERS diagnosis was 4 days (interquartile range 2-7 days), ranging from 0 to 36 days. According to the negative binomial model, the unadjusted rate ratio (RR) of delays in the diagnosis was significantly higher in older patients (>65 years) (RR 1.42), non-healthcare workers (RR 1.74), patients with severe illness (RR 1.22), those with an unknown source of infection (RR 1.84), and those who had been in close contact with camels (RR 1.74). After accounting for confounders, the adjusted rate ratio (aRR) of delays in the diagnosis was independently associated with unknown source of infection (aRR 1.68) and close contact with camels (aRR 1.58). CONCLUSIONS: The time interval from symptom onset to diagnosis was greater in older patients, non-healthcare workers, patients with severe illness, patients with an unknown source of infection, and patients who had been in close contact with camels. The findings warrant educational interventions to raise general public awareness of the importance of early symptom notification. PMID- 28728927 TI - HCV mono-infected and HIV/HCV co-infected individuals treated with direct-acting antivirals: to what extent do they differ? AB - BACKGROUND: Direct-acting antiviral (DAA)-based treatment of hepatitis C virus (HCV) has been associated with high sustained virological response (SVR) rates and good tolerability in randomized clinical trials. This study was performed to assess the safety and effectiveness of DAAs in both HCV mono-infected and HIV/HCV co-infected patients. METHODS: All consecutive HCV-infected patients, including HIV/HCV co-infected patients, receiving DAA-based treatment from February 2015 to September 2016 at the study clinic were included. Clinical, virological, and biochemical data were retrieved. The primary end-point was the SVR12 (HCV RNA undetectable 12 weeks after the end of treatment) is commonly used worldwide. The secondary end-point was the safety profile of DAAs during the treatment period. RESULTS: A total of 382 patients were included; 62 were HIV/HCV co-infected. Cirrhosis was found in 256 patients (67.4%). SVR12 was achieved in 365/382 (95.5%) individuals (58/62 HIV/HCV co-infected, 93.5%) in the intention-to-treat (ITT) analysis. A platelet count <90*109/l (odds ratio (OR) 4.12, 95% confidence interval (CI) 1.5-11.3, p=0.006), HCV genotype 3 infection (OR 5.49, 95% CI 1.9 15.7, p=0.002), liver stiffness >20kPa (OR 3.05, 95% CI 1.03-8.96, p=0.04), and Model for End-Stage Liver Disease (MELD) score >10 (OR 5.27, 95% CI 1.16-23.8, p=0.03) were associated with lower SVR rates. On multivariate analysis, only genotype 3 infection remained a negative predictor of SVR (OR 21.6, 95% CI 3.81 123, p=0.001). Treatment discontinuation was observed in 10 subjects. Severe adverse events (SAEs) occurred in 17 patients (4.5%). CONCLUSIONS: High SVR12 rates were observed in both HCV mono-infected and HIV/HCV co-infected individuals. Overall, DAA-based treatment was safe and there were no differences in terms of SAEs and treatment discontinuation between the two groups. PMID- 28728928 TI - GTF-231, a Mixture of Gymnemic Acid, Trigonelline and Ferulic Acid Significantly Ameliorates Oxidative Stress in Experimental Type 2 Diabetes in Rats. AB - OBJECTIVES: According to a report by the United States National Health and Nutrition Examination Survey, nearly 60% of patients with diabetes have more than one complication caused by chronic diabetes. Type 2 diabetes is a multifactorial metabolic disorder that accounts for more than 95% of people with diabetes and usually requires multitargeted therapeutic interventions. It arises due to insufficient insulin secretion or its action or both. Recently, we reported that the oral administration of gymnemic acid, trigonelline and ferulic acid in the ratio of 2:3:1 (GTF-231), a mixture of 3 phytoingredients at a concentration of 300 mg/kg body weight significantly improved the glucose homeostasis in rats with low-dose streptozotocin-induced type 2 diabetes that were fed with high-fat diet. METHODS: In the present study, an effort was made to evaluate the antioxidant potential of GTF-231 in rats with type 2 diabetes. Type 2 diabetes was induced in experimental rats by administration of low-dose streptozotocin (35 mg/kg body weight) and high-fat diet. The biochemical parameters analyzed included levels of fasting blood glucose, glycated hemoglobin, plasma insulin, homeostatic model assessment-insulin resistance, homeostatic model assessment beta-cell function, advanced glycation end products, advanced oxidation protein products, hydroperoxides, malondialdehyde and enzymatic as well as nonenzymatic antioxidants and proinflammatory cytokines, such as tumor necrosis factor-alpha, interleukin 1 beta, interleukin-6, nuclear factor-kappaB and nitric oxide. Histologic observations were made on the pancreatic tissues. RESULTS: The data obtained showed the significant antioxidant properties of GTF-231, which were further evidenced by the histologic observations made on the pancreatic tissue. CONCLUSIONS: The observed antioxidant potential of GTF-231 may account for its significant antidiabetic properties. PMID- 28728929 TI - An evaporation-assisted dispersive liquid-liquid microextraction technique as a simple tool for high performance liquid chromatography tandem-mass spectrometry determination of insecticides in wine. AB - A sample pre-treatment technique based on evaporation-assisted dispersive liquid liquid microextraction (EVA-DLLME), followed by HPLC-MS/MS has been developed for the determination of organophosphate insecticides (malathion, diazinon, phosalone) in wine samples. The procedure includes the addition of mixture of organic solvents (with density higher than water), consisting of the extraction (low density) and volatile (high density) solvents, to aqueous sample followed by heating of the mixture obtained, what promotes the volatile solvent evaporation and moving extraction solvent droplets from down to top of the aqueous sample and, as a consequence, microextraction of target analytes. To initiate the evaporation process an initiator is required. It was established that hexanol (extraction solvent) and dichloromethane (volatile solvent) mixture (1:1, v/v) provides effective microextraction of the insecticides from wine samples with recovery from 92 to 103%. The conditions of insecticides' microextraction such as selection of extraction solvent, ratio of hexanol/dichloromethane and hexanol/sample, type and concentration of initiator, and effect of ethanol as one of the main components of wine have been studied. Under optimal experimental conditions the linear detection ranges were found to be 10-7-10-3gL-1 for malathion, 10-9-10-4gL-1 for diazinon, and 10-6-10-2gL-1 for phosalone. The LODs, calculated from a blank test, based on 3sigma, found to be 3*10-8gL-1 for malathion, 3*10-10gL-1 for diazinon and 3*10-7gL-1 for phosalone. The advantages of EVA-DLLME are the rapidity, simplicity, high sample throughput and low cost. As an outcome, the analytical results agreed fairly well with the results obtained by a reference GC-MS method. PMID- 28728930 TI - Specific enrichment of glycoproteins with polymer monolith functionalized with glycocluster grafted beta-cyclodextrin. AB - The low abundance of glycoproteins in complex samples results in the prerequisite role of efficient and selective enrichment of them. In the present work, we designed a new kind of glycosylation poly(hydroxyethyl methacrylate pentaerythritol triacrylate) monolith functionalized with glycocluster grafted beta-cyclodextrin for the enrichment of glycoproteins. The introduced modifiers endowed the monolithic material with enhanced hydrophilicity and surface area, which benefitted to improve the enrichment selectivity and extraction efficiency for glycopeptides. By combining with MALDI-MS detections, 22 glycopeptides from horseradish peroxidase digest were captured with the developed monolith while 4 glycopeptides were enriched by commercially available agarose matrix column. LOD of 6.6pmol was attained. When applied to the enrichment of glycopeptides from complex protein samples and human lymphoma (U937) cell line, the prepared monolith exhibited high selectivity for glycopeptides. PMID- 28728931 TI - New anthracenyl polar embedded stationary phases with enhanced aromatic selectivity, a combined experimental and theoretical study: Part 1-experimental study. AB - New polar embedded aromatic stationary phases of different functionalities (mono- and trifunctional) and on different silica supports (Fully Porous Particle (FPP) and Superficially Porous Particle (SPP)) were synthesized to determine the impact of the functionality on the retention process and the selectivity towards aromatic compounds. A full experimental characterization was performed using a combination of techniques (elemental analysis, thermogravimetric measurements, infrared spectroscopy and solid-state NMR) to differentiate unambiguously the mono- and trifunctional Stationary Phases (SP). Commercially available columns with either an aromatic group or a polar embedded group were compared to the new stationary phases. The latter presented enhanced affinity for polycyclic aromatic hydrocarbons (PAH) structures compared to alkylbenzenes, especially when using methanol instead of acetonitrile as the organic modifier. PMID- 28728932 TI - The "Complex Restrictive" Pulmonary Function Pattern: Clinical and Radiologic Analysis of a Common but Previously Undescribed Restrictive Pattern. AB - BACKGROUND: Most patients with restriction have a pulmonary function test (PFT) pattern in which total lung capacity (TLC), FVC, and FEV1 are reduced to a similar degree. This pattern is called "simple restriction" (SR). In contrast, we commonly observe a pattern in which FVC percent predicted (pp) is disproportionately reduced relative to TLCpp. This pattern is termed "complex restriction" (CR), and we attempted to characterize its clinical, radiologic, and physiologic features. METHODS: This study reviewed PFT results of patients tested between November 2009 and June 2013 who had restriction (TLC less than the lower limit of normal). SR was defined as TLCpp-FVCpp <= 10%, and CR was stratified into four classes based on TLCpp-FVCpp discrepancy: Class 1 CR, TLCpp-FVCpp > 10% and <= 15%; Class 2 CR, TLCpp-FVCpp > 15% and <=20%; Class 3 CR, TLCpp-FVCpp > 20% and <= 25%; and Class 4 CR, TLCpp-FVCpp > 25%. The medical records of 150 randomly selected patients with SR and 50 patients from each CR class were reviewed. RESULTS: Of 39,277 PFTs completed, we identified 4,532 patients (11.5%) with restriction: 2,407 (6.1%) with SR, 1,614 (4.1%) with CR, and 511 (1.3%) with a mixed pattern. Patients with CR were younger, were more often women, and had a higher prevalence of neuromuscular disease, BMI > 40 kg/m2 or < 18.5 kg/m2, diaphragmatic dysfunction, bronchiectasis, CT mosaic attenuation, and pulmonary hypertension (P < .0001, < .0001, < .001, .004, .0008, .002, .008, .009, .053, and .01, respectively) and a lower prevalence of interstitial lung disease (P < .0001). CONCLUSIONS: CR is a common PFT pattern with distinct clinical features. The associated clinical entities share impaired lung emptying (eg, neuromuscular disease, occult obstruction, chest wall limitation). Clinicians should be aware of this novel PFT pattern and how it shapes the differential diagnosis. PMID- 28728933 TI - Predictors of Mortality in Pulmonary Sarcoidosis. AB - OBJECTIVE: The goal of this study was to assess the prognostic strength of factors in predicting respiratory death in a large cohort of patients with sarcoidosis with at least 8 years' follow-up. METHODS: Data were collected on age, sex, self-declared race, time of death, spirometry findings, diffusing capacity for carbon monoxide, chest radiograph stage, extent of fibrosis on high resolution CT (HRCT) scanning, and presence of precapillary pulmonary hypertension (PH). The Gender-Age-Physiology (GAP) index and Walsh model criteria for high vs low risk were calculated. RESULTS: A total of 452 patients were identified who had complete pulmonary function testing and chest imaging. The median age at time of entry into the study was 50 years (range, 25-78 years). PH was confirmed by right heart catheterization in 29 (6.4%). Of 452 patients, 42 died during the time of the study, including 38 (8.4%) who died of sarcoidosis associated respiratory failure and 4 who died of non-sarcoidosis causes. The overall mortality from sarcoidosis was 3.9% and 9.0% at 5 and 10 years, respectively. Alive patients were significantly younger than patients who died from sarcoidosis. Increased mortality was seen for black patients, stage 4 chest radiographs, > 20% fibrosis on HRCT scanning, or PH. The two composite scores (GAP and the Walsh model) were predictive of increased mortality according to univariate analysis. Using the Cox proportional hazards regression model, only age, extent of fibrosis on HRCT scanning, and PH were independent predictors of mortality. CONCLUSIONS: Although most patients with sarcoidosis do well, increased mortality was seen in those patients who were older, had extensive fibrosis on HRCT scanning, or who had PH. PMID- 28728935 TI - Transcatheter Arterial Chemoembolization with Spherical Embolic Agent in Patients with Pulmonary or Mediastinal Metastases from Breast Cancer. AB - PURPOSE: To evaluate safety and feasibility of transcatheter arterial chemoembolization with superabsorbent polymer microspheres (SAP-MS) for patients with pulmonary or mediastinal metastasis from breast cancer. METHODS: Between November 2002 and January 2015, 14 patients with 29 unresectable pulmonary or mediastinal breast cancer metastases underwent transcatheter arterial chemoembolization using SAP-MS (50-100 MUm) after injection of a combination of 2 4 types of anticancer drugs (eg, cisplatin [30 mg] + fluorouracil [500 mg], or epirubicin [40 mg] + mitomycin C [4 mg] + fluorouracil [500 mg]). As a primary endpoint, local tumor response and adverse events were evaluated 1 month after the first transcatheter arterial chemoembolization, according to Response Evaluation Criteria In Solid Tumors Version 1.1 and Common Terminology Criteria for Adverse Events Version 4 criteria. Transcatheter arterial chemoembolization was repeated as needed. Overall survival was analyzed as a secondary endpoint. RESULTS: Response rate was 28.6% (partial response, 4 patients; stable disease, 10 patients). Median progression rate was -12.7%. No cases of hematologic toxicity of grade 3 or higher were observed. A grade 3 maculopapular rash was observed in 1 patient. After the first transcatheter arterial chemoembolization sessions, 63 additional transcatheter arterial chemoembolization sessions were performed (average, 5.5 sessions per patient; range, 2-10 sessions). The median overall survival time after the first session was 29 months, and the 5-year survival rate was 49.5%. CONCLUSIONS: Transcatheter arterial chemoembolization with SAP-MS is a well-tolerated and feasible palliative treatment option for patients with pulmonary or mediastinal metastasis from breast cancer. PMID- 28728934 TI - Beyond BMI: Obesity and Lung Disease. AB - The worldwide prevalence of obesity has increased rapidly in the last 3 decades, and this increase has led to important changes in the pathogenesis and clinical presentation of many common diseases. This review article examines the relationship between obesity and lung disease, highlighting some of the major findings that have advanced our understanding of the mechanisms contributing to this relationship. Changes in pulmonary function related to fat mass are important, but obesity is much more than simply a state of mass loading, and BMI is only a very indirect measure of metabolic health. The obese state is associated with changes in the gut microbiome, cellular metabolism, lipid handling, immune function, insulin resistance, and circulating factors produced by adipose tissue. Together, these factors can fundamentally alter the pathogenesis and pathophysiology of lung health and disease. PMID- 28728936 TI - Cell-free pipeline for discovery of thermotolerant xylanases and endo-1,4-beta glucanases. AB - The rapid expansion in the number of sequenced genomes and metagenomes provides an exceptional resource for mining of the enzymes with biotechnologically relevant properties. However, the majority of protein production and analysis methods are not sufficiently cost-efficient and scalable to experimentally verify the results of computational genomic mining. Here, we present a pipeline based on Leishmania tarentolae cell-free system that was used to characterize 30 putative thermostable endo-1,4-beta-glucanases and xylanases identified in public genomic databases. In order to analyse the recombinant proteins without purification, novel high-throughput assays for glucanase and xylanase activities were developed. The assays rely on solubilisation of labelled particulate substrates performed in multiwell plates. Using this approach both acidophilic and thermophilic enzymes were identified. The developed approach enables rapid discovery of new biotechnologically useful enzymes. PMID- 28728937 TI - The impact of machine learning techniques in the study of bipolar disorder: A systematic review. AB - Machine learning techniques provide new methods to predict diagnosis and clinical outcomes at an individual level. We aim to review the existing literature on the use of machine learning techniques in the assessment of subjects with bipolar disorder. We systematically searched PubMed, Embase and Web of Science for articles published in any language up to January 2017. We found 757 abstracts and included 51 studies in our review. Most of the included studies used multiple levels of biological data to distinguish the diagnosis of bipolar disorder from other psychiatric disorders or healthy controls. We also found studies that assessed the prediction of clinical outcomes and studies using unsupervised machine learning to build more consistent clinical phenotypes of bipolar disorder. We concluded that given the clinical heterogeneity of samples of patients with BD, machine learning techniques may provide clinicians and researchers with important insights in fields such as diagnosis, personalized treatment and prognosis orientation. PMID- 28728938 TI - Didelphis albiventris naturally infected with Hepatozoon canis in southeastern Brazil. AB - Hepatozoon species are vector-borne pathogens that infect domestic and wild animals. Marsupials of the species Didelphis albiventris are adapted to urban and peri-urban areas and act as reservoir hosts for several parasites. The present study evaluated the occurrence of infection by Hepatozoon species in synantropic D. albiventris from Botucatu, Sao Paulo, Brazil. Blood samples and ectoparasites from 19 D. albiventris were collected from urban and peri-urban areas. Hepatozoon spp. detection was performed by microscopy and molecular analysis. One opossum was positive for Hepatozoon spp. in microscopy analysis and PCR, while another animal was positive only in PCR. The obtained sequences were 100% identical to Hepatozoon canis. Six species of ticks and two species of fleas were detected on D. albiventris. This is the first report of H. canis in synantropic D. albiventris. In Brazil, H. canis transmission among dog populations is not well established, which highlights the importance of investigating the role that opossums might play in the epidemiology of this protozoan. PMID- 28728939 TI - Autonomic dysreflexia: Somatosympathetic and viscerosympathetic vasoconstrictor responses to innocuous and noxious sensory stimulation below lesion in human spinal cord injury. AB - Autonomic dysreflexia is a dangerous elevation in blood pressure in people with spinal cord injury (SCI), produced by a spinally-mediated reflex activation of sympathetic vasoconstrictor neurones supplying skeletal muscle and the gut. Current dogma states that, apart from visceral inputs - such as those originating from a distended bladder or impacted colon - autonomic dysreflexia is triggered by noxious inputs below the lesion. However, while selective stimulation of small diameter afferents in muscle or skin evokes a sustained increase in muscle sympathetic nerve activity and blood pressure, and a transient increase in skin sympathetic nerve activity and decrease in skin blood flow in able-bodied subjects, such noxious inputs have no effects on blood pressure and skin blood flow in SCI individuals. Conversely, weak electrical stimulation over the abdominal wall, which in able-bodied subjects is not painful and activates large diameter cutaneous afferents, causes a marked increase in blood pressure in SCI but not in able-bodied subjects. Moreover, vibration of the penis in spinal injured men, which is not noxious, caused marked vasoconstriction and increases in blood pressure, similar to those produced by non-noxious distension of the bladder during urodynamics procedures. This suggests that activation of large diameter somatic afferents, not small-diameter afferents, triggers the increases in vasoconstrictor drive that lead to autonomic dysreflexia, arguing against current dogma on the importance of noxious inputs in triggering autonomic dysreflexia. PMID- 28728940 TI - Silicone infusion tubing instead of Hunter rods for two-stage zone 2 flexor tendon reconstruction in a resource-limited surgical environment. AB - The authors describe their experience using silicone infusion tubing in place of Hunter rods for two-stage zone 2 flexor tendon reconstruction in a resource limited surgical environment. This case report features a 47-year-old, right handed man who had no active PIP and DIP joint flexion in four fingers of the right hand 5 months after an injury. During the first repair stage, the A2 and A4 pulleys were reconstructed using an extensor retinaculum graft. An infusion tube was inserted instead of Hunter rods. During the second stage, formation of a digital neo-canal around the infusion tubing was observed. The infusion tubing was removed and replaced with a palmaris longus tendon graft according to the conventional technique. Physiotherapy and rehabilitation followed surgery. At 6 months, very significant progress had been made with complete recovery of PIP and DIP flexion in the four fingers. PMID- 28728941 TI - Comparison of calcimimetic R568 and calcitriol in mineral homeostasis in the Hyp mouse, a murine homolog of X-linked hypophosphatemia. AB - X-linked hypophosphatemia (XLH) caused by mutations in the Phex gene is the most common human inherited phosphate wasting disorder characterized by enhanced synthesis of fibroblast growth factor 23 (FGF23) in bone, renal phosphate wasting, 1,25(OH)2D3 (1,25D) deficiency, rickets and osteomalacia. Here we studied the effects of calcimimetic R568 and calcitriol treatment in the Hyp mouse, a murine homolog of XLH. We hypothesized that mineral homeostasis is differentially affected by R568 and 1,25D with respect to the PTH-vitamin D-FGF23 Klotho axis and bone health. Four-week-old male Hyp mice received R568 in different doses, 1,25D or vehicle for 28days. Vehicle-treated wild-type mice served as controls. Both R568 and 1,25D reduced PTH levels, yet only 1,25D raised serum phosphate levels in Hyp mice. 1,25D increased calciuria and further enhanced FGF23 synthesis in bone and circulating FGF23 levels. By contrast, R568 reduced bone FGF23 expression and serum total but not intact FGF23 concentrations. Renal 1,25D metabolism was further impaired by 1,25D and improved although not normalized by R568. Hyp mice showed reduced renal Klotho levels, which were increased by 1,25D and high dose R568. 1,25D, but not R568, significantly improved femur growth, and weight gain, and partially restored growth plate morphology and bone mineralization. Although a significant improvement of trabecular bone was noted by MUCT, compared to 1,25D the effects of R568 on bone histomophometric parameters were marginal. Our data indicate that monotherapy with R568 reduced PTH and FGF23 synthesis in bone, but failed to restore vitamin D and phosphate metabolism and skeletal abnormalities in Hyp mice. By contrast, 1,25D improved body growth, and defective mineralization despite further enhancement of skeletal FGF23 synthesis thereby highlighting the importance of vitamin D in bone mineralization in Hyp mice. PMID- 28728942 TI - Response letter to J.Hall et al. PMID- 28728943 TI - Production and biophysical characterization of a mini-membrane protein, Ost4V23D: A functionally important mutant of yeast oligosaccharyltransferase subunit Ost4p. AB - N-linked glycosylation of proteins is an essential and highly conserved co- and post-translational protein modification reaction that occurs in all eukaryotes. Oligosaccharyltransferase (OST), a multi-subunit membrane-associated enzyme complex, carries out this reaction. In the central reaction, a carbohydrate group is transferred to the side chain of a consensus asparagine residue in the newly synthesized protein. Genetic defects in humans cause a series of disorders known as congenital disorders of glycosylation (CDG) that include mental retardation, developmental delay, hypoglycemia etc. Complete loss of N-glycosylation is lethal in all organisms. In Saccharomyces cerevisiae, OST consists of nine non-identical protein subunits. Ost4p is the smallest subunit containing 36 residues. It bridges catalytic subunit Stt3p to Ost3p/Ost6p subunit. Mutation of Valine (V) at position 23 in Ost4p to Aspartate (D) causes defects in the N-glycosylation process. To understand the structure, function and role of Ost4p in N glycosylation, characterization of Ost4p and its functionally important mutant/s are critical. We report the mutagenesis, heterologous overexpression, purification, reconstitution in DPC micelles and biophysical characterization of Ost4V23D and compare its secondary structure and conformation to that of Ost4p. CD and NMR data suggest that mutation of Val23 to Asp impacts the secondary structure and conformation of Ost4p. PMID- 28728944 TI - Ultrasound-guided thoracic paravertebral block: cadaveric study in foxes (Vulpes vulpes). AB - OBJECTIVE: To describe an ultrasound-guided thoracic paravertebral block in canidae. STUDY DESIGN: Prospective, experimental, cadaveric study. ANIMALS: Twelve thawed fox cadavers. METHODS: A 15 MHz linear transducer was used to visualize the paravertebral space at the level of the fifth thoracic vertebrae. Iohexol (300 mg mL-1) at 0.2 mL kg-1 was injected into the right and left paravertebral spaces under ultrasound guidance using a Tuohy needle. The needle was advanced in a lateral to medial direction using an in-plane technique. Injections were performed by two operators, each performing 12 injections in six fox cadavers. A thoracic computed tomography was then performed and evaluated by a single operator. The following features were recorded: paravertebral contrast location (yes/no), length of contrast column (number of intercostal spaces), location of contrast relative to the fifth thoracic vertebrae (cranial/caudal/mixed), epidural contrast contamination (yes/no), pleural contrast contamination (yes/no) and mediastinal contrast contamination (yes/no). RESULTS: All injections resulted in paravertebral contrast distribution (24/24). The mean length of the contrast column was five intercostal spaces. Contrast spread was caudal to the injection site in 54% (7/24), cranial in 29% (4/24) and mixed in 17% (3/24). Pleural contamination was observed in 50% (12/24) of injections; 42% (10/24) and 4% (1/24) of the injections resulted in mediastinal and epidural contamination, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Injection of the paravertebral space in canidae is possible using the technique described. Possible complications include epidural, pleural and mediastinal contamination. To establish clinical efficacy and safety of this technique, further studies are required. PMID- 28728945 TI - Clasper flaring in a guitarfish (Zapteryx brevirostris Elasmobranchii, Rhinobatidae) under anesthesia. PMID- 28728946 TI - Serum galectin-1 levels are positively correlated with body fat and negatively with fasting glucose in obese children. AB - Galectin-1, a recently identified peptide, is primarily released from the adipose tissue. Although galectin-1 was shown to have an anti-inflammatory effect, its specific function is not clearly understood. We aimed to evaluate the relationship of serum galectin-1 levels with clinical and laboratory parameters in childhood obesity. A total of 45 obese children (mean age: 12.1+/-3.1years) and 35 normal-weight children (mean age: 11.8+/-2.2years) were enrolled. Clinical [body mass index (BMI), waist circumference (WC), percentage of body fat and blood pressure] and biochemical [glucose, insulin, lipids, galectin-1, high sensitive C-reactive protein (hsCRP) and leptin levels] parameters were assessed. Serum galectin-1, hsCRP and leptin levels were significantly higher in obese children than those in normal-weight children (12.4 vs 10.2ng/mL, p<0.001; 3.28 vs 0.63mg/L, p<0.001; 8.3 vs 1.2ng/mL, p<0.001, respectively). In obese children, galectin-1 levels correlated negatively with fasting glucose (r=-0.346, p=0.020) and positively with fat mass (r=0.326, p=0.026) and WC standard deviation score (SDS) (r=0.451, p=0.002). The multivariate regression analysis demonstrated that serum galectin-1 levels were significantly associated with fasting glucose and WC SDS. This study showed that obese children had significantly higher galectin-1 levels in proportion to fat mass in obese cases than those in healthy children, which may be interpreted as a compensatory increase in an attempt to improve glucose metabolism. PMID- 28728947 TI - An actual load forecasting methodology by interval grey modeling based on the fractional calculus. AB - The operation processes for thermal power plant are measured by the real-time data, and a large number of historical interval data can be obtained from the dataset. Within defined periods of time, the interval information could provide important information for decision making and equipment maintenance. Actual load is one of the most important parameters, and the trends hidden in the historical data will show the overall operation status of the equipments. However, based on the interval grey parameter numbers, the modeling and prediction process is more complicated than the one with real numbers. In order not lose any information, the geometric coordinate features are used by the coordinates of area and middle point lines in this paper, which are proved with the same information as the original interval data. The grey prediction model for interval grey number by the fractional-order accumulation calculus is proposed. Compared with integer-order model, the proposed method could have more freedom with better performance for modeling and prediction, which can be widely used in the modeling process and prediction for the small amount interval historical industry sequence samples. PMID- 28728948 TI - Automated gesture tracking in head-fixed mice. AB - BACKGROUND: The preparation consisting of a head-fixed mouse on a spherical or cylindrical treadmill offers unique advantages in a variety of experimental contexts. Head fixation provides the mechanical stability necessary for optical and electrophysiological recordings and stimulation. Additionally, it can be combined with virtual environments such as T-mazes, enabling these types of recording during diverse behaviors. NEW METHOD: In this paper we present a low cost, easy-to-build acquisition system, along with scalable computational methods to quantitatively measure behavior (locomotion and paws, whiskers, and tail motion patterns) in head-fixed mice locomoting on cylindrical or spherical treadmills. EXISTING METHODS: Several custom supervised and unsupervised methods have been developed for measuring behavior in mice. However, to date there is no low-cost, turn-key, general-purpose, and scalable system for acquiring and quantifying behavior in mice. RESULTS: We benchmark our algorithms against ground truth data generated either by manual labeling or by simpler methods of feature extraction. We demonstrate that our algorithms achieve good performance, both in supervised and unsupervised settings. CONCLUSIONS: We present a low-cost suite of tools for behavioral quantification, which serve as valuable complements to recording and stimulation technologies being developed for the head-fixed mouse preparation. PMID- 28728949 TI - Diffuse hematoma caused by spontaneous rupture of a parathyroid adenoma: a case report. PMID- 28728950 TI - Anthropometric study of the caucasian nose in the city of Curitiba: relevance of population evaluation. AB - INTRODUCTION: Norms and patterns of nasal esthetics are essential for an adequate preoperative evaluation and surgical programming. The esthetic nasal patterns used are a blend of artistic beauty ideals and tracings in models and celebrities. Because they do not consider population measures, they vary according to the period, and allow a discrepancy between the surgeon's preference and the patient's real desire for rhinoplasty. Not all populations wish to obtain an esthetic result according to these values, but prefer a natural result, that is, one with some of the nasal characteristics of the population to which they belong to. The Brazilian population lacks population studies to evaluate its nose measurements. OBJECTIVE: (1) To evaluate the anthropometric measures of Caucasian noses of people living in the city of Curitiba (state of Parana), and to compare them to the ideal esthetic pattern of the literature; (2) To compare them between genders. METHODS: This is a prospective cohort study involving 100 Caucasian volunteers at a tertiary hospital in Southern Brazil. Through the frontal and lateral view photos, intercanthal distance, alar distance, nasal dorsum length, nasofrontal angle, nasolabial angle, and nasal tip projection (Goode's method) were obtained. A statistical analysis was performed to compare the measures obtained between genders and with the ideal patterns. RESULTS: Comparing the results obtained with those predicted by the esthetic ideals, the sample presented: similar nasolabial angle (p=0.07), alar width greater than intercanthal distance (p<0.001), higher nasal tip projection (p<0.001), larger width-length ratio (p<0.001), and more obtuse nasofrontal angle (p<0.001). The nasofrontal angle (p=0.0008) and the tip projection (p=0.032) were statistically different between the genders. Men had a smaller nasofrontal angle, and a larger Goode's ratio. CONCLUSION: Except for the nasolabial angle, the measures obtained in the population sample differed from the published esthetic ideals. Comparing the genders, men had a sharper nasofrontal angle, and higher tip projection than women. PMID- 28728951 TI - Quality of life and cochlear implant: results in adults with postlingual hearing loss. AB - INTRODUCTION: Considering the variability of results found in the clinical population using a cochlear implant, researchers in the area have been interested in the inclusion of quality of life measures to subjectively assess the benefits of the implantation. OBJECTIVE: To assess the quality of life of adult users of cochlear implant. METHODS: A cross-sectional and clinical study in a group of 26 adults of both genders, with mean duration of cochlear implant use of 6.6 years. The Nijmegen Cochlear Implantation Questionnaire and the generic World Health Organization Quality of Life questionnaire were sent electronically. RESULTS: The best assessed domain in the quality of life assessment for the cochlear implantation questionnaire was the social domain, whereas for the quality of life questionnaire it was the psychological domain. The variables, gender, time of cochlear implant use and auditory modality did not influence the results of both questionnaires. Only the variable level of education was correlated with the environment domain of the quality of life questionnaire. The variable telephone speech comprehension was associated with a better perception of quality of life for all the domains of the specific questionnaire and for the self-assessment of quality of life in general. CONCLUSION: From the users' perspective, both questionnaires showed that cochlear implant brought benefits to different aspects related to quality of life. PMID- 28728952 TI - Pneumatic vitreolysis for symptomatic vitreomacular traction: case report. PMID- 28728953 TI - Diplopia secondary to giant frontoethmoidal osteoma. PMID- 28728954 TI - Ultrasound, histopathological, and genetic features of uveal melanoma in a Mexican-Mestizo population. AB - OBJECTIVE: To describe the ultrasound, histopathological and genetic characteristics of uveal melanoma in a Mexican-Mestizo population. MATERIAL AND METHODS: A total of 39 enucleated eyes with a histopathological diagnosis of uveal melanoma were assessed by describing the clinical findings, and ultrasound, histopathological and genetic features. RESULTS: A high correlation was observed between tumour height measurement using ultrasound and histopathology. In our cases, tumour size and reflectivity were higher compared with those reported in the literature. The preliminary data on the molecular assessment of the tumours show the presence of an unreported polymorphism (T>C IVS5+34) and one sample with GNAQ mutation (A>C CAA>CCA Gln 209 Pro). CONCLUSION: Ultrasound is a reliable method to identify the size of the tumour. Furthermore, knowledge of the molecular mechanisms promises new perspectives for the development of new targeted therapeutics. Fortunately this leads to progress in the treatment of patients with metastatic disease or prevents it in those at high risk. PMID- 28728955 TI - John Taylor, "the Chevalier". PMID- 28728957 TI - Treatment of Duchenne muscular dystrophy: first small steps. PMID- 28728956 TI - Ataluren in patients with nonsense mutation Duchenne muscular dystrophy (ACT DMD): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. AB - BACKGROUND: Duchenne muscular dystrophy (DMD) is a severe, progressive, and rare neuromuscular, X-linked recessive disease. Dystrophin deficiency is the underlying cause of disease; therefore, mutation-specific therapies aimed at restoring dystrophin protein production are being explored. We aimed to assess the efficacy and safety of ataluren in ambulatory boys with nonsense mutation DMD. METHODS: We did this multicentre, randomised, double-blind, placebo controlled, phase 3 trial at 54 sites in 18 countries located in North America, Europe, the Asia-Pacific region, and Latin America. Boys aged 7-16 years with nonsense mutation DMD and a baseline 6-minute walk distance (6MWD) of 150 m or more and 80% or less of the predicted normal value for age and height were randomly assigned (1:1), via permuted block randomisation (block size of four) using an interactive voice-response or web-response system, to receive ataluren orally three times daily (40 mg/kg per day) or matching placebo. Randomisation was stratified by age (<9 years vs >=9 years), duration of previous corticosteroid use (6 months to <12 months vs >=12 months), and baseline 6MWD (<350 m vs >=350 m). Patients, parents and caregivers, investigational site personnel, PTC Therapeutics employees, and all other study personnel were masked to group allocation until after database lock. The primary endpoint was change in 6MWD from baseline to week 48. We additionally did a prespecified subgroup analysis of the primary endpoint, based on baseline 6MWD, which is reflective of anticipated rates of disease progression over 1 year. The primary analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01826487. FINDINGS: Between March 26, 2013, and Aug 26, 2014, we randomly assigned 230 patients to receive ataluren (n=115) or placebo (n=115); 228 patients comprised the intention-to-treat population. The least-squares mean change in 6MWD from baseline to week 48 was -47.7 m (SE 9.3) for ataluren-treated patients and -60.7 m (9.3) for placebo-treated patients (difference 13.0 m [SE 10.4], 95% CI -7.4 to 33.4; p=0.213). The least-squares mean change for ataluren versus placebo in the prespecified subgroups was -7.7 m (SE 24.1, 95% CI -54.9 to 39.5; p=0.749) in the group with a 6MWD of less than 300 m, 42.9 m (15.9, 11.8 74.0; p=0.007) in the group with a 6MWD of 300 m or more to less than 400 m, and 9.5 m (17.2, -43.2 to 24.2; p=0.580) in the group with a 6MWD of 400 m or more. Ataluren was generally well tolerated and most treatment-emergent adverse events were mild to moderate in severity. Eight (3%) patients (n=4 per group) reported serious adverse events; all except one event in the placebo group (abnormal hepatic function deemed possibly related to treatment) were deemed unrelated to treatment. INTERPRETATION: Change in 6MWD did not differ significantly between patients in the ataluren group and those in the placebo group, neither in the intention-to-treat population nor in the prespecified subgroups with a baseline 6MWD of less than 300 m or 400 m or more. However, we recorded a significant effect of ataluren in the prespecified subgroup of patients with a baseline 6MWD of 300 m or more to less than 400 m. Baseline 6MWD values within this range were associated with a more predictable rate of decline over 1 year; this finding has implications for the design of future DMD trials with the 6-minute walk test as the endpoint. FUNDING: PTC Therapeutics. PMID- 28728958 TI - Effectiveness of resistance exercise compared to aerobic exercise without insulin therapy in patients with type 2 diabetes mellitus: a meta-analysis. AB - BACKGROUND: Physical exercise has been used to mitigate the metabolic effects of diabetes mellitus. OBJECTIVE: To evaluate the effect of resistance exercise when compared to aerobic exercise without insulin therapy on metabolic and clinical outcomes in patients with type 2 diabetes mellitus. METHODS: Papers were searched on the databases MEDLINE/PubMed, CINAHL, SPORTDiscus, LILACS, and SCIELO, without language or date of publication limits. Clinical trials that compared resistance exercise to aerobic exercise in adults with type 2 diabetes mellitus who did not use insulin therapy were included. The quality of evidence and risk of bias were assessed using the GRADE system and the Cochrane Risk of Bias tool, respectively. Meta-analysis was also used, whenever possible. Two reviewers extracted the data independently. Eight eligible articles were included in this study, with a total of 336 individuals, with a mean age of 48-58 years. The protocols of aerobic and resistance exercise varied in duration from eight to 22 weeks, 30-60min/day, three to five times/week. RESULTS: Overall the available evidence came from a very low quality of evidence and there was an increase in Maximal oxygen consumption (mean difference: -2.86; 95% CI: -3.90 to -1.81; random effect) for the resistance exercise and no difference was found in Glycated hemoglobin, Body mass index, High-density lipoprotein cholesterol, Low-density lipoprotein cholesterol, triglycerides, and total cholesterol. CONCLUSIONS: Resistance exercise appears to be more effective in promoting an increase in Maximal oxygen consumption in protocols longer than 12 weeks and there is no difference in the control of glycemic and lipid levels between the two types of exercise. PMID- 28728959 TI - Mechanisms contributing to gait speed and metabolic cost in children with unilateral cerebral palsy. AB - BACKGROUND: Gait speed and metabolic cost are indicators of functional capacity in children with cerebral palsy. Uncovering their mechanisms helps guide therapeutic actions. OBJECTIVES: To investigate the contributions of energy generating and energy-conserving mechanisms to gait speed and metabolic cost of children with unilateral cerebral palsy. METHODS: Data on eccentric and concentric muscle work, co-contraction, elastic torque and vertical stiffness of the affected-limb, forcing torque of the non-affected limb, gait speed and metabolic cost were collected from 14 children with unilateral cerebral palsy, aged 6-12 years. Analyses included two groups of multiple regression models. The first group of models tested the association between each dependent variable (i.e., speed and metabolic cost) and the independent variables that met the input criteria. The second group verified the contribution of the non-selected biomechanical variables on the predictors of the first model. RESULTS: Gait speed (R2=0.80) was predicted by elastic torque (beta=0.62; 95%CI: 0.60, 0.63), vertical stiffness (beta=-0.477; 95%CI: -0.479, -0.474) and knee co-contraction (beta=0.27; 95%CI: -1.96, 2.49). The production of eccentric work by the affected limb proved relevant in adjusting the vertical stiffness (R2=0.42; beta=-0.64; 95%CI: 0.86, -0.42); elastic torque of the affected-leg was associated with impulsive torque of the non-affected leg (R2=0.31; beta=0.55; 95%CI: 0.46, 0.64). Metabolic cost of gait (R2=0.48) was partially predicted by knee co-contraction (beta=0.69; 95%CI: 0.685, 0.694). CONCLUSIONS: The chain of associations revealed by the two steps models helped uncover the mechanisms involved in the locomotion of children with unilateral cerebral palsy. Intervention that changes specific energy conserving and generating mechanisms may improve gait of these children. PMID- 28728960 TI - Effect of high-intensity home-based respiratory muscle training on strength of respiratory muscles following a stroke: a protocol for a randomized controlled trial. AB - BACKGROUND: Respiratory muscle training has shown to increase strength of the respiratory muscles following a stroke. However, low duration and/or intensity of training may be responsible for the small effect size seen and/or absence of carry-over effects to an activity, e.g., walking. Therefore, an investigation of the effects of long-duration, high-intensity respiratory muscle training is warranted. OBJECTIVE: This proposed protocol for a randomized clinical trial will examine the efficacy of high-intensity respiratory muscle training to increase strength and improve activity following a stroke. METHODS: This study will be a two-arm, prospectively registered, randomized controlled trial, with blinded assessors. Thirty-eight individuals who have suffered a stroke will participate. The experimental group will undertake a 40-min of respiratory muscle training program, seven days/week, for eight weeks in their homes. Training loads will be increased weekly. The control group will undertake a sham respiratory muscle training program with equivalent duration and scheduling of training. The primary outcome will be the strength of the inspiratory muscles, measured as maximal inspiratory pressure. Secondary outcomes will include expiratory muscle strength, inspiratory muscle endurance, dyspnea, respiratory complications, and walking capacity. Outcomes will be collected by a researcher blinded to group allocation at baseline (Week 0), after intervention (Week 8), and one month beyond intervention (Week 12). CONCLUSION: High-intensity respiratory muscle training may have the potential to optimize the strength of the respiratory muscles following a stroke. If benefits are carried over to activity, the findings may have broader implications, since walking capacity has been shown to predict physical activity and community participation on this population. PMID- 28728961 TI - Avascular necrosis of the femoral head in patients treated for leukaemia. Assessment of the need for a diagnostic protocol. AB - OBJECTIVE: To evaluate the incidence of avascular necrosis of the hip in leukaemia patients treated in our hospital with high doses of corticosteroids in order to evaluate the necessity for an early detection protocol. MATERIAL AND METHODS: Observational-descriptive and retrospective study from 2005 to 2016 of 253 patients diagnosed with paediatric leukaemia. Patients with musculoskeletal pathology were identified and patients with avascular necrosis were analysed. RESULTS: A total of 26 patients (10%) had musculoskeletal symptoms. Three patients with avascular necrosis (1.2%) were analysed. One girl, 7 years old, was treated conservatively with traction - suspension and discharge. Two boys, an 11 and a 15.4 year-old,who developed graft-versus-host disease secondary to bone marrow transplantation, and whose treatment included high doses of corticosteroids, developed avascular necrosis of the hip. One was treated with bisphosphonates and forage and the other ended up with a total hip arthroplasty. DISCUSSION: The occurrence of musculoskeletal symptoms during the treatment of leukaemia is different according to the bibliographic series (0.43 -12.6%). Some authors observe an increased risk in female patients between the ages of 10 and 17. A retrospective study reveals that there is a delay of 3.9 months in the diagnosis of CAP since the onset of pain. Other authors relate NAV to loading joints, age and high doses of corticosteroids. CONCLUSION: Based on the low incidence of avascular necrosis of the hip in our 14-year-old population treated for leukaemia, the creation of diagnostic protocols seems not to be necessary. However, close monitoring of patients with potential risk factors recognized in the literature, is advisable. PMID- 28728962 TI - Oncologic Safety of Nipple-Sparing Mastectomy in Women with Breast Cancer. AB - BACKGROUND: Nipple-sparing mastectomy (NSM) has gained popularity for breast cancer treatment and prevention. There are limited data about long-term oncologic safety of this procedure. STUDY DESIGN: We reviewed oncologic outcomes of consecutive therapeutic NSM at a single institution. Nipple-sparing mastectomy was offered to patients with no radiologic or clinical evidence of nipple involvement. RESULTS: There were 2,182 NSM performed from 2007 to 2016. Long-term outcomes were assessed in the 311 NSM performed in 2007 to 2012 for Stages 0 to 3 breast cancer; 240 (77%) NSM were for invasive cancer and 71 (23%) were for ductal carcinoma in situ. At 51 months median follow-up, 17 patients developed a recurrence of their cancer. Estimated disease-free survival was 95.7% at 3 years and 92.3% at 5 years. There were 11 (3.7%) locoregional recurrences and 8 (2.7%) distant recurrences; 2 patients had simultaneous locoregional and distant recurrences. There were 2 breast cancer-related deaths in patients with isolated distant recurrences. No patient in the entire 2,182 NSM cohort has had a recurrence in the retained nipple-areola complex. CONCLUSIONS: Rates of locoregional and distant recurrence are acceptably low after nipple-sparing mastectomy in patients with breast cancer. No patient in our series has had a recurrence involving the retained nipple areola complex. PMID- 28728963 TI - Structural Principles of Fluorescent RNA Aptamers. AB - Several aptamer RNAs have been selected in vitro that bind to otherwise weakly fluorescent small molecules and enhance their fluorescence several thousand-fold. By genetically tagging cellular RNAs of interest with these aptamers and soaking cells in their cell-permeable cognate small-molecule fluorophores, it is possible to use them to study RNA localization and trafficking. These aptamers have also been fused to metabolite-binding RNAs to generate fluorescent biosensors. The 3D structures of three unrelated fluorogenic RNAs have been determined, and reveal a shared reliance on base quadruples (tetrads) to constrain the photo-excited chromophore. The structural diversity of fluorogenic RNAs and the chemical diversity of potential fluorophores to be activated are likely to yield a variety of future fluorogenic RNA tags that are optimized for different applications in RNA imaging and in the design of fluorescent RNA biosensors. PMID- 28728965 TI - Survival analysis of metal crowns versus restorations in primary mandibular molars. AB - BACKGROUND: The effectiveness of stainless steel crowns (SSCs) versus direct restorations when placed in primary mandibular molars (teeth nos. L and S) is uncertain. The authors evaluated effectiveness by gauging longevity of treatment. METHODS: The authors obtained private dental insurance claims (2004-2016) from a national dental data warehouse. Paid insurance claims records (n = 1,323,489) included type of treating dentist, treatment placed, and patient age. RESULTS: Dentist specialty, type of treatment, and patient age were significant in predicting failure after the first restoration. The authors found high survival rates for all treatments (> 90%) after 5 years; however, as soon as within 3 years after treatment, SCCs had approximately 6% better survival. CONCLUSIONS: Teeth nos. L and S first treated with SSCs lasted longer without new treatment compared with teeth first treated with direct restorations; the difference was small. Teeth treated by pediatric dentists had better survival rates. PRACTICAL IMPLICATIONS: Primary mandibular first molars initially treated with SSCs lasted longer without new treatment compared with direct restorations. Overall dental care costs of the former were considerably higher. PMID- 28728964 TI - Association Between Proton Pump Inhibitor Use and Cognitive Function in Women. AB - BACKGROUND & AIMS: Studies have reported associations between proton pump inhibitor (PPI) use and dementia. However, data are lacking on long-term PPI use and cognitive function. We therefore examined associations between PPI use and performance in tests of cognitive function. Because of shared clinical indications, we examined associations for H2 receptor antagonists (H2RAs) as a secondary aim. METHODS: We used prospectively collected data on medication use and other potential risk factors from 13,864 participants in the Nurses' Health Study II who had completed a self-administered computerized neuropsychological test battery. Multivariable linear regression models were used to examine associations between medication use and composite scores of psychomotor speed and attention, learning and working memory, and overall cognition. RESULTS: We observed a modest association between duration of PPI use and scores for psychomotor speed and attention (mean score difference for PPI use of 9-14 years vs never users, -0.06; 95% confidence interval, -0.11 to 0.00; Ptrend = .03). After controlling for H2RA use, the magnitude of this score difference was attenuated. Among individuals who did not use PPIs regularly, duration of H2RA use was associated with poorer cognitive scores, with the strongest association apparent for learning and working memory (mean score difference for H2RA users of 9-14 years vs never users, -0.20; 95% confidence interval, -0.32 to -0.08; Ptrend < .001). CONCLUSIONS: In an analysis of data from the Nurses' Health Study II, we did not observe a convincing association between PPI use and cognitive function. Our data do not support the suggestion that PPI use increases dementia risk. Because our primary hypothesis related to PPI use, our findings for H2RAs should be interpreted with caution. PMID- 28728966 TI - Advances and perspectives in tissue clearing using CLARITY. AB - CLARITY is a tissue clearing method, which enables immunostaining and imaging of large volumes for 3D-reconstruction. The method was initially time-consuming, expensive and relied on electrophoresis to remove lipids to make the tissue transparent. Since then several improvements and simplifications have emerged, such as passive clearing (PACT) and methods to improve tissue staining. Here, we review advances and compare current applications with the aim of highlighting needed improvements as well as aiding selection of the specific protocol for use in future investigations. PMID- 28728967 TI - Impact of the Microbiota on Bacterial Infections during Cancer Treatment. AB - Patients being treated for cancer are at high risk for infectious complications, generally due to colonizing organisms that gain access to sterile sites via disrupted epithelial barriers. There is an emerging understanding that the ability of bacterial pathogens, including multidrug-resistant organisms, to colonize and subsequently infect humans is largely dependent on protective bacterial species present in the microbiome. Thus, herein we review recent studies demonstrating strong correlations between the microbiome of the oncology patient and infections occurring during chemotherapy. An increased knowledge of the interplay between potential pathogens, protective commensals, and the host immune system may facilitate the development of novel biomarkers or therapeutics that could help ameliorate the toll that infections take during the treatment of cancer. PMID- 28728968 TI - Hybrid time-space dynamical systems of growth bacteria with applications in segmentation. AB - A biological dynamic system carries engineering properties such as control systems and signal processing (or image processing) addicted to molecular biology at the level of bio-molecular communication networks. Dynamical system features and signal reply functions of cellular signaling pathways are some of the main topics in biological dynamic systems (for example the biological segmentation). In the present paper, we introduce new generalized hybrid time-space dynamical systems of growing bacteria. We impose the approximate analytic solution for the system. The generalization adapted the concepts of the Riemann-Liouville fractional operators for time and the Srivastava-Owa fractional operators for space. Moreover, we introduce a numerical perturbation method of two operators to obtain the approximate solutions. We establish the existence and uniqueness results and impose some applications in the sequel. Moreover, we study the Ulam stability and apply these stable solutions to improve the segmentation of a class of growing bacteria. PMID- 28728969 TI - A nanoporous titanium surface promotes the maturation of focal adhesions and formation of filopodia with distinctive nanoscale protrusions by osteogenic cells. AB - : While topography is a key determinant of the cellular response to biomaterials, the mechanisms implicated in the cell-surface interactions are complex and still not fully elucidated. In this context, we have examined the effect of nanoscale topography on the formation of filopodia, focal adhesions, and gene expression of proteins associated with cell adhesion and sensing. Commercially pure titanium discs were treated by oxidative nanopatterning with a solution of H2SO4/H2O2 50:50 (v/v). Scanning electron microscopy and atomic force microscopy characterizations showed that this facile chemical treatment efficiently creates a unique nanoporous surface with a root-mean-square roughness of 11.5nm and pore diameter of 20+/-5nm. Osteogenic cells were cultured on polished (control) and nanotextured discs for periods of 6, 24, and 72h. Immunofluorescence analysis revealed increases in the adhesion formation per cell area, focal adhesion length, and maturity on the nanoporous surface. Gene expression for various focal adhesion markers, including paxillin and talin, and different integrins (e.g. alpha1, beta1, and alpha5) was also significantly increased. Scanning electron microscopy revealed the presence of more filopodia on cells grown on the nanoporous surface. These cell extensions displayed abundant and distinctive nanoscale lateral protrusions of 10-15nm diameter that molded the nanopore walls. Together the increase in the focal adhesions and abundance of filopodia and associated protrusions could contribute to strengthening the adhesive interaction of cells with the surface, and thereby, alter the nanoscale biomechanical relationships that trigger cellular cascades that regulate cell behavior. STATEMENT OF SIGNIFICANCE: Oxidative patterning was exploited to create a unique three-dimensional network of nanopores on titanium surfaces. Our study illustrates how a facile chemical treatment can be advantageously used to modulate cellular behavior. The nanoscale lateral protrusions on filopodia elicited by this surface are novel adhesive structures. Altogether, the increases in focal adhesion, length, maturity, and filopodia with distinctive lateral protrusions could substantially increase the contact area and adhesion strength of cells, thereby promoting the activation of cellular signaling cascades that may explain the positive osteogenic outcomes previously achieved with this surface. Such physicochemical cueing offers a simple attractive alternative to the use of bioactive agents for guiding tissue repair/regeneration around implantable metals. PMID- 28728970 TI - The Staphylococcus aureus FASII bypass escape route from FASII inhibitors. AB - Antimicrobials targeting the fatty acid synthesis (FASII) pathway are being developed as alternative treatments for bacterial infections. Emergence of resistance to FASII inhibitors was mainly considered as a consequence of mutations in the FASII target genes. However, an alternative and efficient anti FASII resistance strategy, called here FASII bypass, was uncovered. Bacteria that bypass FASII incorporate exogenous fatty acids in membrane lipids, and thus dispense with the need for FASII. This strategy is used by numerous Gram-positive low GC % bacteria, including streptococci, enterococci, and staphylococci. Some bacteria repress FASII genes once fatty acids are available, and "constitutively" shift to FASII bypass. Others, such as the major pathogen Staphylococcus aureus, can undergo high frequency mutations that favor FASII bypass. This capacity is particularly relevant during infection, as the host supplies the fatty acids needed for bacteria to bypass FASII and thus become resistant to FASII inhibitors. Screenings for anti-FASII resistance in the presence of exogenous fatty acids confirmed that FASII bypass confers anti-FASII resistance among clinical and veterinary isolates. Polymorphisms in S. aureus FASII initiation enzymes favor FASII bypass, possibly by increasing availability of acyl-carrier protein, a required intermediate. Here we review FASII bypass and consequences in light of proposed uses of anti-FASII to treat infections, with a focus on FASII bypass in S. aureus. PMID- 28728971 TI - A multi-objective optimization approach for the selection of working fluids of geothermal facilities: Economic, environmental and social aspects. AB - The selection of the working fluid for Organic Rankine Cycles has traditionally been addressed from systematic heuristic methods, which perform a characterization and prior selection considering mainly one objective, thus avoiding a selection considering simultaneously the objectives related to sustainability and safety. The objective of this work is to propose a methodology for the optimal selection of the working fluid for Organic Rankine Cycles. The model is presented as a multi-objective approach, which simultaneously considers the economic, environmental and safety aspects. The economic objective function considers the profit obtained by selling the energy produced. Safety was evaluated in terms of individual risk for each of the components of the Organic Rankine Cycles and it was formulated as a function of the operating conditions and hazardous properties of each working fluid. The environmental function is based on carbon dioxide emissions, considering carbon dioxide mitigation, emission due to the use of cooling water as well emissions due material release. The methodology was applied to the case of geothermal facilities to select the optimal working fluid although it can be extended to waste heat recovery. The results show that the hydrocarbons represent better solutions, thus among a list of 24 working fluids, toluene is selected as the best fluid. PMID- 28728972 TI - Numerical characterisation of one-step and three-step solar air heating collectors used for cocoa bean solar drying. AB - In the northern coastal and jungle areas of Peru, cocoa beans are dried using artisan methods, such as direct exposure to sunlight. This traditional process is time intensive, leading to a reduction in productivity and, therefore, delays in delivery times. The present study was intended to numerically characterise the thermal behaviour of three configurations of solar air heating collectors in order to determine which demonstrated the best thermal performance under several controlled operating conditions. For this purpose, a computational fluid dynamics model was developed to describe the simultaneous convective and radiative heat transfer phenomena under several operation conditions. The constructed computational fluid dynamics model was firstly validated through comparison with the data measurements of a one-step solar air heating collector. We then simulated two further three-step solar air heating collectors in order to identify which demonstrated the best thermal performance in terms of outlet air temperature and thermal efficiency. The numerical results show that under the same solar irradiation area of exposition and operating conditions, the three step solar air heating collector with the collector plate mounted between the second and third channels was 67% more thermally efficient compared to the one step solar air heating collector. This is because the air exposition with the surface of the collector plate for the three-step solar air heating collector former device was twice than the one-step solar air heating collector. PMID- 28728973 TI - Sewer-mining: A water reuse option supporting circular economy, public service provision and entrepreneurship. AB - Water scarcity, either due to increased urbanisation or climatic variability, has motivated societies to reduce pressure on water resources mainly by reducing water demand. However, this practice alone is not sufficient to guarantee the quality of life that high quality water services underpin, especially within a context of increased urbanisation. As such, the idea of water reuse has been gaining momentum for some time and has recently found a more general context within the idea of the Circular Economy. This paper is set within the context of an ongoing discussion between centralized and decentralized water reuse techniques and the investigation of trade-offs between efficiency and economic viability of reuse at different scales. Specifically, we argue for an intermediate scale of a water reuse option termed 'sewer-mining', which could be considered a reuse scheme at the neighbourhood scale. We suggest that sewer mining (a) provides a feasible alternative reuse option when the geography of the wastewater treatment plant is problematic, (b) relies on mature treatment technologies and (c) presents an opportunity for Small Medium Enterprises (SME) to be involved in the water market, securing environmental, social and economic benefits. To support this argument, we report on a pilot sewer-mining application in Athens, Greece. The pilot, integrates two subsystems: a packaged treatment unit and an information and communications technology (ICT) infrastructure. The paper reports on the pilot's overall performance and critically evaluates the potential of the sewer-mining idea to become a significant piece of the circular economy puzzle for water. PMID- 28728974 TI - Activation of cryptic phthoxazolin A production in Streptomyces avermitilis by the disruption of autoregulator-receptor homologue AvaR3. AB - The genomes of actinomycetes encode many cryptic novel/useful bioactive compounds, but access to these cryptic secondary metabolites remains limited. Streptomyces avermitilis predominantly produces three polyketide antibiotics (avermectin, filipin, and oligomycin) but has the potential to produce more secondary metabolites based on the number of cryptic biosynthetic gene clusters. Here, we extensively investigated the metabolite profiles of a gene disruptant of AvaR3 (an autoregulator receptor homologue), which is involved in the pleiotropic regulation of antibiotic production and cell morphology. Unlike the wild-type strain, the avaR3 mutant accumulated compound 3 in the culture. The chemical structure of compound 3 was elucidated on the basis of various spectroscopic analyses, and was identified as phthoxazolin A, a cellulose synthesis inhibitor. Bioassays demonstrated that compound 3 exerts growth inhibitory activity against a broad range of plant pathogenic oomycetes. Moreover, unlike avermectin production, phthoxazolin A (3) production was negatively controlled by avenolide, a new type of autoregulator in streptomycetes, through the function of AvaR3. These results suggest that the genetic manipulation of autoregulator receptor homologues would be a valuable tool for the discovery of cryptic bioactive compounds. PMID- 28728975 TI - Continuous nitrogen removal by a single-stage reactor packed with ring-laced string medium. AB - The efficiency of nitrogen removal by a partial-nitritation/anammox (PNA) reaction was investigated using a packed-bed reactor in which ring-laced strings were used as the supporting medium. A stable population of PNA microorganisms was established from typical activated sludge, after less than two months of acclimation in the packed-bed reactor, by applying a high nitrogen-loading rate (NLR: 0.53 kg/m3/d) and short hydraulic retention time (HRT: 1.8 h). The stability of reactor performance was confirmed in industrial wastewater (IW), demonstrating a nitrogen removal efficiency (NRE) of greater than 77% during 260 days of continuous operation, between 0.19 and 0.53 kg/m3/d of NLR. Partial nitrification was adequately controlled by low-level oxygen supply to the reactor. Pyro-tag sequencing analysis of the biofilm revealed a clear abundance of anammox bacteria in the inner part of the biofilm and ammonium-oxidizing bacteria in the outer part. In the synthetic inorganic medium (SIM), the microbial community structure did not change drastically between the early and late phases of the experiment's continuous operation, which lasted over 200 days. In IW, however, the existence ratio of anammox bacteria decreased to 4% on day 249 of continuous operation. The number of detected operational taxonomic units (OTUs) increased in the IW, implying that the community structure was widely diversified. However, anammox bacteria could propagate sufficiently to catalyze nitrogen removal under this condition because the NRE was stable at approximately 88%. PMID- 28728976 TI - Effect of alkylaminophenols on growth inhibition and apoptosis of bone cancer cells. AB - In this work, we report the anticancer properties of a series of 11 chemically synthesized alkylaminophenols against human osteosarcoma U2OS tumor cell line. Several assays including cytotoxicity, inhibitor kinetic study, cell migration, Annexin-V/PI double staining, reactive oxygen species (ROS) and caspase 3/7 assays were conducted on this cell line. Cytotoxic 2-((3,4-dihydroquinolin-1(2H) yl)(p-tolyl)methyl)phenol was determined to have an IC50 value of 36.6MUM against U2OS cells and it also inhibits the cell growth in time-dependent manner. The potent activity of lead compound against the growth of multiple cell lines, U2OS, MG-65 and HEK-293T, confirms the osteosarcoma cell specific inhibition. Further studies indicated that such compound is an inhibitor of metastatic property of tumor cells and inducing apoptosis agent. The ability of increasing ROS and inducing caspases 3 and 7 further confirm the contribution of programmed cell death in U2OS and HEK-293T cells. Additionally, four compounds based on the 2 (indolin-1-yl(aryl)methyl)-4-nitrophenol core were also identified to be cytotoxic with IC50 values in the 66-88MUM range. This work further demonstrates the anticancer properties of phenol derivatives, adding one more entry to the collection of promising chemotherapeutic agents for cancer treatment. PMID- 28728977 TI - Synthesis and characterization of boron fenbufen and its F-18 labeled homolog for boron neutron capture therapy of COX-2 overexpressed cholangiocarcinoma. AB - Boron neutron capture therapy (BNCT) is a binary therapy that employs neutron irradiation on the boron agents to release high-energy helium and alpha particles to kill cancer cells. An optimal response to BNCT depends critically on the time point of maximal 10B accumulation and highest tumor to normal ratio (T/N) for performing the neutron irradiation. The aggressive cholangiocarcinoma (CCA) representing a liver cancer that overexpresses COX-2 enzyme is aimed to be targeted by COX-2 selective boron carrier, fenbufen boronopinacol (FBPin). Two main works were performed including: 1) chemical synthesis of FBPin as the boron carrier and 2) radiochemical labeling with F-18 to provide the radiofluoro congener, m-[18F]fluorofenbufen ester boronopinacol (m-[18F]FFBPin), to assess the binding affinity, cellular accumulation level and distribution profile in CCA rats. FBPin was prepared from bromofenbufen via 3 steps with 82% yield. The binding assay employed [18F]FFBPin to compete FBPin for binding to COX-1 (IC50=0.91+/-0.68MUM) and COX-2 (IC50=0.33+/-0.24MUM). [18F]FFBPin-derived 60-min dynamic PET scans predict the 10B-accumulation of 0.8-1.2ppm in liver and 1.2 1.8ppm in tumor and tumor to normal ratio=1.38+/-0.12. BNCT was performed 40 55min post intravenous administration of FBPin (20-30mg) in the CCA rats. CCA rats treated with BNCT display more tumor reduction than that by NCT with respect of 2-[18F]fluoro-2-deoxy glucose uptake in the tumor region of interest, 20.83+/ 3.00% (n=12) vs. 12.83+/-3.79% (n=10), P=0.05. The visualizing agent [18F]FFBPin resembles FBPin to generate the time-dependent boron concentration profile. Optimal neutron irradiation period is thus determinable for BNCT. A boron substituted agent based on COX-2-binding features has been prepared. The moderate COX-2/COX-1 selectivity index of 2.78 allows a fair tumor selectivity index of 1.38 with a mild cardiovascular effect. The therapeutic effect from FBPin with BNCT warrants a proper COX-2 targeting of boron NSAIDs. PMID- 28728979 TI - pLoc-mVirus: Predict subcellular localization of multi-location virus proteins via incorporating the optimal GO information into general PseAAC. AB - Knowledge of subcellular locations of proteins is crucially important for in depth understanding their functions in a cell. With the explosive growth of protein sequences generated in the postgenomic age, it is highly demanded to develop computational tools for timely annotating their subcellular locations based on the sequence information alone. The current study is focused on virus proteins. Although considerable efforts have been made in this regard, the problem is far from being solved yet. Most existing methods can be used to deal with single-location proteins only. Actually, proteins with multi-locations may have some special biological functions. This kind of multiplex proteins is particularly important for both basic research and drug design. Using the multi label theory, we present a new predictor called "pLoc-mVirus" by extracting the optimal GO (Gene Ontology) information into the general PseAAC (Pseudo Amino Acid Composition). Rigorous cross-validation on a same stringent benchmark dataset indicated that the proposed pLoc-mVirus predictor is remarkably superior to iLoc Virus, the state-of-the-art method in predicting virus protein subcellular localization. To maximize the convenience of most experimental scientists, a user friendly web-server for the new predictor has been established at http://www.jci bioinfo.cn/pLoc-mVirus/, by which users can easily get their desired results without the need to go through the complicated mathematics involved. PMID- 28728978 TI - Anticancer drug-loaded quantum dots engineered polymeric nanoparticles: Diagnosis/therapy combined approach. AB - Primary Effusion Lymphoma (PEL) is an HHV-8-related non Hodgkin lymphoma localized in body cavities (as pleural, peritoneal and pericardial) presenting lymphomatous effusion that, until now, lack of an effective therapy. Curcumin was reported to display pro-apoptotic effect via the inhibition of the JAK/STAT pathway, that is overexpressed in PEL cells, as consequence of virus infection. The administration of curcumin is severely restricted by its physicochemical properties, mainly its low solubility in biological fluid and consequently low bioavailability. Encapsulation into biocompatible and biodegradable PLGA nanoparticles (NPs) could be a strategy to overcome biological limits of curcumin, offering a valuable step forward for its clinical application. In this study we described single-emulsion process for curcumin loading into NPs (encapsulation efficiency about 35%). We applied a post-formulation strategy (NHS/EDC reaction) to decorate the surface of the curcumin-loaded NPs with quantum dots (QDs) as imaging agents (QDs-NPs-Cur, 24pmol of QDs per 100mg of NPs) obtaining tools useful for possible application in theranostic approach. Bifunctionalized NPs were tested in vitro on two PEL's cell line (BCBL-1 and HBL 6). The efficacy of the treatment was evaluated by cytofluorimetric assay by measuring both cell viability and cell density. We found that the NPs significantly improve the cellular effect of curcumin (respect to free drug). Moreover, by means of confocal microscopy, both the localization of bifunctional NPs and of the released drug were easily detectable. Thus, we conclude that the delivery of curcumin using bifunctional traceable NPs is a promising future approach for the diagnosis and the treatment of PEL. PMID- 28728980 TI - The Role of Hexon Protein as a Molecular Mold in Patterning the Protein IX Organization in Human Adenoviruses. AB - Adenoviruses are respiratory, ocular and enteric pathogens that form complex capsids, which are assembled from seven different structural proteins and composed of several core proteins that closely interact with the packaged dsDNA genome. The recent near-atomic resolution structures revealed that the interlacing continuous hexagonal network formed by the protein IX molecules is conserved among different human adenoviruses (HAdVs), but not in non-HAdVs. In this report, we propose a distinct role for the hexon protein as a "molecular mold" in enabling the formation of such hexagonal protein IX network that has been shown to preserve the stability and infectivity of HAdVs. PMID- 28728981 TI - Viral Moulds and Cement: How Interactions among Human Adenovirus Hexons and Their Protein IX Cement May Buttress Human Adenovirus Particles. PMID- 28728982 TI - NMR Studies of Large Proteins. AB - Recent breakthroughs in isotope-labeling and pulse sequence techniques have enabled the NMR characterization of large protein systems with molecular masses of hundreds of kilodaltons. NMR studies of a great variety of large proteins have provided unique insights into the binding, dynamic, and allosteric mechanisms. Here we present a brief summary of these developments by highlighting few cases that exemplify the uniqueness of NMR in providing atomic resolution information into key dynamic processes and structures of protein complexes with high degree of flexibility. PMID- 28728984 TI - Operative versus non-operative management of adhesive small bowel obstruction: A systematic review and meta-analysis. AB - OBJECTIVES: To investigate outcomes of operative and non-operative management of adhesive small bowel obstruction (SBO). METHODS: We performed a systematic review in accordance with Preferred Reporting Items for Systematic Reviews and Meta Analyses statement standards. We conducted a search of electronic information sources to identify all randomised controlled trials (RCTs) and observational studies investigating outcomes of operative versus non-operative management of patients with adhesive SBO. We used the Cochrane risk of bias tool and the Newcastle-Ottawa scale to assess the risk of bias of RCTs and observational studies, respectively. Fixed-effect or random-effects models were applied to calculate pooled outcome data. RESULTS: We found one RCT, two prospective and three retrospective observational studies, enrolling a total of 876 patients. The analyses showed that operative management of adhesive SBO was associated with a lower risk of future recurrence [odds ratio (OR) 0.54, 95% confidence interval (CI) 0.38-0.76, P = 0.0005] but a higher risk of mortality [risk difference (RD) 0.03, 95% CI 0.01-0.06, P = 0.01] and complications (OR 5.39, 95% CI 2.97-9.78, P < 0.00001). There was no difference in need for surgical re-intervention rate (OR 0.72, 95% CI 0.35-1.47, P = 0.36) and length of stay [mean difference (MD) 5.07, 95% CI -2.36-12.49, P = 1.0] between operative and non-operative managements. The baseline suspicion of strangulation was a major confounding factor. When the baseline suspicion of strangulation was higher in the operative group, the risk of mortality (RD 0.04, 95% CI 0.02-0.07, P = 0.0006) and complications (OR 8.14, 95% CI 4.16-15.94, P = 0.00001) were higher in the operative group but the risk of recurrence was lower (OR 0.62, 95% CI 0.43-0.90, P = 0.01). When the baseline suspicion of strangulation was low in both groups, there was no difference in any of the outcomes except recurrence (OR 0.09, 95% CI 0.02-0.37, P = 0.0009) which was lower in the operative group. CONCLUSIONS: The difference in baseline suspicion of strangulation between operative and non-operative groups is a major confounding factor in current literature. The benefit of surgical treatment should be balanced with the risks associated with surgery, patient's co morbidities, and presence or absence of strangulation. Based on the best available evidence it could be argued that surgical intervention could be preserved for cases with high suspicion or evidence of bowel strangulation. The controversy still remains for optimum length of conservative management and timing of surgery (early or late) for cases with low baseline suspicion of strangulation. Randomised controlled trials are required to compare outcomes of early operation (<24 h) versus late operation (>24 h) and early operation versus conservative management in patients with low suspicion of strangulation. PMID- 28728983 TI - ETV4 and AP1 Transcription Factors Form Multivalent Interactions with three Sites on the MED25 Activator-Interacting Domain. AB - The recruitment of transcriptional cofactors by sequence-specific transcription factors challenges the basis of high affinity and selective interactions. Extending previous studies that the N-terminal activation domain (AD) of ETV5 interacts with Mediator subunit 25 (MED25), we establish that similar, aromatic rich motifs located both in the AD and in the DNA-binding domain (DBD) of the related ETS factor ETV4 interact with MED25. These ETV4 regions bind MED25 independently, display distinct kinetics, and combine to contribute to a high affinity interaction of full-length ETV4 with MED25. High-affinity interactions with MED25 are specific for the ETV1/4/5 subfamily as other ETS factors display weaker binding. The AD binds to a single site on MED25 and the DBD interacts with three MED25 sites, allowing for simultaneous binding of both domains in full length ETV4. MED25 also stimulates the in vitro DNA binding activity of ETV4 by relieving autoinhibition. ETV1/4/5 factors are often overexpressed in prostate cancer and genome-wide studies in a prostate cancer cell line indicate that ETV4 and MED25 occupy enhancers that are enriched for ETS-binding sequences and are both functionally important for the transcription of genes regulated by these enhancers. AP1-motifs, which bind JUN and FOS transcription factor families, were observed in MED25-occupied regions and JUN/FOS also contact MED25; FOS strongly binds to the same MED25 site as ETV4 AD and JUN interacts with the other two MED25 sites. In summary, we describe features of the multivalent ETV4- and AP1 MED25 interactions, thereby implicating these factors in the recruitment of MED25 to transcriptional control elements. PMID- 28728985 TI - Adjuvant hepatic arterial infusion chemotherapy is beneficial for selective patients with Hepatocellular carcinoma undergoing surgical treatment. AB - BACKGROUND: Recurrence rate after curative surgical resection of Hepatocellular carcinoma (HCC) remains high. Postoperative hepatic arterial infusion chemotherapy (HAIC) has been suggested to improve survival. This study is to investigate the efficacy of HAIC in the patients with poor tumor factors such as vascular invasion or multiplicity. METHODS: From 2006 to 2014, 221 patients with HCC undergoing hepatectomy and pathologically staged as ? T2 (American Joint Committee on Cancer TNM staging system, 7th edition) were included. 61 patients received adjuvant HAIC with 5-fluorouracil, cisplatin, and epirubicin. 160 patients received surgery alone. The overall survival time (OST) and disease free survival time (DFST) were compared between the two groups. RESULTS: In all patients, the multivariate analysis of survival data showed that resection margin less than 10 mm was the independent poor prognostic factors. The median OST and DFST between the HAIC and surgery alone groups were 56.4 vs. 56.9 months (p = 0.76), and 50.6 vs. 54.5 months (p = 0.905), respectively. There was no significant difference. For patients with multiple tumors and concomitantly microvascular invasion, the OST was better in the HAIC group (69.7 vs. 54.6 months, p < 0.05). Based on the image and operative finding, we classified multiple HCC's into two types. Type A: multiple small nodules were close to each other or a huge tumor with several satellite nodules. Type B: two or more tumors scattering in separate segments. Our study showed that type A group benefits from adjuvant HAIC much more than type B. (the median OST in type A versus type B were 85.06 vs. 41.53 months, p = 0.0036). CONCLUSION: The surgical outcome for the patients with multiple HCC's and vascular invasion was poor. Our study showed adjuvant HAIC was beneficial in these patients and formed the basis for further randomized controlled trials. PMID- 28728986 TI - Intra-capsular total thyroid enucleation versus total thyroidectomy in treatment of benign multinodular goiter. A prospective randomized controlled clinical trial. AB - BACKGROUND: Due to high recurrence rate after subtotal thyroidectomy, most of centers have shifted to total thyroidectomy as a surgical treatment for benign multinodular goiter (BMNG), but serious complications, as laryngeal nerve affection & hypocalcaemia, are still present. This study aimed to evaluate treatment of BMNG using intra-capsular total thyroid enucleation in comparison to standard total thyroidectomy. PATIENTS &METHODS: This is a prospective randomized controlled clinical trial conducted in a hospital in the period from December 2009 to December 2015. Of total 224 patients with clinically BMNG. 112 patients operated by intracapsular total thyroid enucleation (ITTE group) and the other 112 patients operated by standard total thyroidectomy (STT group). The minimal follow up period was 36 months. RESULTS: The mean operative time in ITTE group was (93.7 +/- 9.6 min) compared to (86.9 +/- 8.3 min) in STT group. Transient recurrent laryngeal nerve (RLN) palsy was 0% in ITTE group VS 7.1% in STT group. No cases (0%) developed permanent RLN palsy in ITTE group VS 0.9% in STT group. Symptomatic transient hypocalcaemia occurred in 1.8% in ITTE group VS 11.6% in STT group. No cases (0%) developed permanent hypocalcaemia in ITTE group VS 0.9% in STT group. No recurrence (0%) in both groups after minimal 3 years of follow up. CONCLUSION: Intracapsular Total thyroid enucleation technique is safe with the least serious complications, especially RLN injury and hypoparathyroidism, with no recurrence, but this technique still not radical so couldn't be used in suspicious cases for malignancy. PMID- 28728987 TI - Genetic analysis of virulence in the Pyrenophora teres f. teres population BB25*FGOH04Ptt-21. AB - Pyrenophora teres f. teres is the causal agent of net form net blotch (NFNB) of barley. In order to map the genetics of avirulence/virulence in P. teres f. teres, a fungal population was developed using P. teres f. teres isolates BB25 (Denmark) and FGOH04Ptt-21 (North Dakota, USA) due to these two isolates differing in virulence on several common barley lines. 109 progeny isolates were obtained from the BB25 by FGOH04Ptt-21 cross that were then used for NFNB disease evaluation across eight barley lines, four of which have been used commonly as NFNB differential lines as well as four cultivars commonly used in barley production in the Northern Great Plains. BB25 was virulent on one of the barley lines and avirulent on seven of the barley lines whereas, FGOH04Ptt-21 was virulent on all eight barley lines evaluated. Genetic maps were generated with single nucleotide polymorphism (SNP) markers obtained using a restriction associated DNA genotyping by sequencing (RAD-GBS) approach. Sixteen linkage groups were formed and were used to identify quantitative trait loci (QTL) associated with avirulence/virulence. Nine unique QTL were identified on eight linkage groups out of which three QTL had major effects (R2>=45%) while the remaining six QTL were relatively minor (R2<20%). One or two major effect loci were identified for the lines commonly used as differentials. Conversely, variation in virulence on the local barley cultivars was mostly associated with small effect loci that contributed quantitatively to disease. PMID- 28728988 TI - Survey of hip fractures in Japan: Recent trends in prevalence and treatment. AB - BACKGROUND: A nationwide survey of hip fractures by the Japanese Orthopaedic Association (JOA) from 1998 to 2008 found a drastic increase in incidence. The aims of this study were to elucidate the status of hip fractures from 2009 to 2014 and to survey the causes for delayed surgery. METHODS: A tally of all hip fractures that occurred in patients from 2009 to 2014 was conducted in hospitals authorized by the JOA or in clinics with inpatient facilities of the Japanese Clinical Orthopaedic Association (JCOA). A survey of the causes for delay in surgery was conducted at 849 sites and 526 sites participated. RESULTS: A total of 488,759 hip fractures were registered. Increases in incidence from 2009 to 2014 were prominent in the 90-94-year-old age group among women and the 85-89 year-old age group among men. More trochanteric fractures than neck fractures occurred; however, the neck/trochanter ratio increased over time. The mean duration of preoperative hospital stay was 4.8 and 4.5 days, and the mean duration of hospitalization was 40.5 and 36.8 days in 2009 and 2014, respectively. There were significant differences between patients who waited for surgery up to 3 days and those who waited longer than 3 days in date of hospitalization, fracture type, comorbidities, anticoagulant use, surgical procedure, type of physician who administered anesthesia, type of anesthesia, and operating room schedule. Physicians in charge of each patient who waited for surgery for more than 3 days most frequently cited difficulties in securing operating rooms as the cause for delayed surgery. CONCLUSION: A drastic increase occurred in the number of patients with hip fractures with time in Japan. One problem in the treatment of hip fractures is the long waiting time from hospitalization to surgery resulting from difficulties in securing operating rooms. PMID- 28728989 TI - Caution with Use of the EPIC-50 Urinary Bother Scale: How Voiding Dysfunction Modifies its Performance. AB - PURPOSE: We evaluated agreement between patient reported urinary function and bother, and sexual function and bother in patients treated with radical prostatectomy to help inform possible nonfunctional, modifiable mechanisms for patient bother. MATERIALS AND METHODS: Patients were recruited from 2011 to 2014 at Washington University, and Brigham and Women's Hospital. Urinary and sexual outcomes were assessed by EPIC-50 (Expanded Prostate Cancer Index Composite-50) before, 5 weeks and 12 months after radical prostatectomy. Spearman rank correlation coefficients and agreement/disagreement categories were used to describe the relation between function and bother. RESULTS: Despite moderate to good agreement between function and bother (urinary r = 0.51-0.69 and sexual r = 0.65-0.80) discordant groups were observed. In the urinary domain these groups were men disproportionately bothered by function at baseline (16.9%) and 12 months after radical prostatectomy (6.1%) and men less bothered by function 5 weeks (26.8%) and 12 months (9.9%) after radical prostatectomy. Discordant groups in the sexual domain were men less bothered by function at baseline (20.8%), and 5 weeks (21.1%) and 12 months (15.7%) after radical prostatectomy. Splitting the urinary bother scale into 2 subscales, including one for incontinence related bother to complement the urinary function scale which measures only incontinence, and one for voiding dysfunction related bother yielded considerably better agreement (urinary function and incontinence related bother r = 0.78-0.83). Factors contributing to the group less bothered by sexual function were unclear. CONCLUSIONS: When using EPIC-50, investigators should consider splitting the urinary bother scale by the relation to incontinence to prevent distortions of function-bother and comparisons before vs after radical prostatectomy by coexisting voiding dysfunction. PMID- 28728990 TI - Long-Term Testosterone Therapy Improves Urinary and Sexual Function, and Quality of Life in Men with Hypogonadism: Results from a Propensity Matched Subgroup of a Controlled Registry Study. AB - PURPOSE: We investigated the effects of long-term testosterone therapy on urinary and sexual function, and quality of life in hypogonadal men. MATERIALS AND METHODS: We performed an observational, prospective, cumulative registry study in 656 men with a mean +/- SD age of 60.7 +/- 7.2 years who had total testosterone 12.1 nmol/l or less and symptoms of hypogonadism. In the testosterone treated group 360 men received parenteral testosterone undecanoate 1,000 mg/12 weeks for up to 10 years. The 296 men who elected against testosterone therapy served as controls. From each group 82 patients were propensity matched by age, waist circumference and body mass index, resulting in 82 matched pairs of 164 men. Data were analyzed and estimated differences between the groups were adjusted for components of metabolic syndrome and quality of life. RESULTS: We found significant decreases in I-PSS (International Prostate Symptom Score) and post void bladder volume (each p <0.0001) in patients receiving testosterone therapy but not in the untreated group. We recorded a decrease in AMS (Aging Males' Symptoms Scale) in the testosterone treated group but not in the untreated group (p <0.0001). We also recorded significant improvement in the IIEF-EF (International Index of Erectile Function-Erectile Function) domain in the testosterone treated group but not in the untreated group (p <0.0001). The improvement was maintained throughout followup. CONCLUSIONS: Long-term testosterone therapy in hypogonadal men resulted in significant improvements in urinary and sexual function, and in quality of life. In untreated hypogonadal men voiding and erectile function deteriorated with continued followup. PMID- 28728991 TI - Analysis of Factors Associated with Patient or Caregiver Regret following Surgery for Fecal Incontinence. AB - PURPOSE: Malone antegrade continence enema has been a successful and widely used procedure for achieving fecal continence in children. We present data on the previously uninvestigated issue of patient and caregiver regret following surgery for intractable constipation and fecal incontinence. MATERIALS AND METHODS: We reviewed all patients undergoing antegrade continence enema or cecostomy creation at a single institution between 2006 and 2016. Patients and caregivers were assessed for decisional regret using the Decisional Regret Scale. Results were correlated with demographics, surgical outcomes and complications. RESULTS: A total of 81 responses (49 caregivers and 32 patients) were obtained. Mean followup was 49 months. Decisional regret was noted in 43 subjects (53%), including mild regret in 38 (47%) and moderate to severe regret in 5 (6%). No statistical difference in regret was noted based on gender, complications or performance of concomitant procedures. On regression analysis incontinence was strongly associated with decisional regret (OR 4.4, 95% CI 1.1-18.1, p <0.001) and regret increased as age at surgery increased, particularly when patients were operated on at age 13 to 15 years (OR 2.6, 95% CI 1.0-6.4 for age 13 years; OR 2.9, 95% CI 1.1-7.8 for age 14 years; OR 3.1, 95% CI 1.1-8.8 for age 15 years). CONCLUSIONS: This is the first known study describing decisional regret following surgery for fecal incontinence. Surgical factors aimed at achieving continence may be effective in decreasing postoperative regret. The finding of increased regret in teenage patients compared to younger children should be shared with families since it may impact the age at which surgery is pursued. PMID- 28728992 TI - Retroperitoneal Lymphadenectomy for High Risk, Nonmetastatic Renal Cell Carcinoma: An Analysis of the ASSURE (ECOG-ACRIN 2805) Adjuvant Trial. AB - PURPOSE: Lymphadenectomy is a well established practice for many urological malignancies but its role in renal cell carcinoma is less clear. Our primary objective was to determine whether lymphadenectomy impacted survival in patients with fully resected, high risk renal cell carcinoma. MATERIALS AND METHODS: Patients with fully resected, high risk, nonmetastatic renal cell carcinoma were randomized to adjuvant sorafenib, sunitinib or placebo in the ASSURE (Adjuvant Sorafenib and Sunitinib for Unfavorable Renal Carcinoma) trial. Lymphadenectomy was performed for cN+ disease or at surgeon discretion. Patients treated with lymphadenectomy were compared to patients in the trial who did not undergo lymphadenectomy. The primary outcome was overall survival associated with lymphadenectomy. Secondary outcomes were disease free survival, factors associated with performing lymphadenectomy and surgical complications. RESULTS: Of the 1,943 patients in ASSURE 701 (36.1%) underwent lymphadenectomy, including all resectable patients with cN+ and 30.1% of those with cN0 disease. A median of 3 lymph nodes (IQR 1-8) were removed and the rate of pN+ disease in the lymphadenectomy group was 23.4%. There was no overall survival benefit for lymphadenectomy relative to no lymphadenectomy (HR 1.14, 95% CI 0.93-1.39, p = 0.20). In patients with pN+ disease who underwent lymphadenectomy no improvement in overall or disease-free survival was observed for adjuvant therapy relative to placebo. Lymphadenectomy did not confer an increased risk of surgical complications (14.2% vs 13.4%, p = 0.63). CONCLUSIONS: The benefit of lymphadenectomy in patients undergoing surgery for high risk renal cell carcinoma remains uncertain. Future strategies to answer this question should include a prospective trial in which patients with high risk renal cell carcinoma are randomized to specific lymphadenectomy templates. PMID- 28728993 TI - Value of Tracking Biopsy in Men Undergoing Active Surveillance of Prostate Cancer. AB - PURPOSE: We compared the upgrading rate obtained by resampling precise spots of prostate cancer (tracking biopsy) vs conventional systematic resampling during followup of men on active surveillance. MATERIALS AND METHODS: From 2009 to 2017 in 352 men prostate cancer was Gleason 3 + 3 in 268 and Gleason 3 + 4 in 84 at initial magnetic resonance imaging-ultrasound fusion biopsy. These men subsequently underwent a second fusion biopsy. At the first biopsy session all men underwent 12-core systematic biopsies and, when magnetic resonance imaging visible lesions were present, targeted biopsies. All cancerous sites were recorded electronically. During active surveillance at a second fusion biopsy session 6 to 18 months later tracking and systematic nontracking samples were obtained. The primary outcome measure was an increase in Gleason score (upgrading) at followup sampling, which was stratified by biopsy method. RESULTS: Overall 91 of the 352 men (25.9%) experienced upgrading at the second biopsy during a median 11-month interval. The upgrade rate in the Gleason 3 + 3 and 3 + 4 groups was 26.9% and 22.6%, respectively. The mean number of cores taken at second biopsy was 12.2 +/- 3.3 in men with upgrading and 12.4 +/- 4.1 in those who remained stable (p not significant). Men with grade 0 to 4 magnetic resonance imaging targets were all upgraded at approximately the same rate of 20% to 30% (p not significant). However, 58.8% of the men with grade 5 magnetic resonance imaging targets were upgraded. Of the 91 upgrades 48 (53%) were detected only by tracking. CONCLUSIONS: The tracking function of magnetic resonance imaging ultrasound fusion biopsy warrants further study. When specific sites are resampled in men undergoing active surveillance of prostate cancer, upgrading is detected more often than by nontracking biopsy. PMID- 28728994 TI - A Comprehensive Analysis of Cribriform Morphology on Magnetic Resonance Imaging/Ultrasound Fusion Biopsy Correlated with Radical Prostatectomy Specimens. AB - PURPOSE: Recently a large body of evidence has emerged indicating that cribriform morphology is an aggressive prostate cancer morphological pattern associated with higher cancer specific mortality. In a comprehensive analysis we compared traditional and contemporary prostate biopsy techniques to detect prostate cancer with cribriform morphology with radical prostatectomy serving as the reference standard. MATERIALS AND METHODS: We queried a retrospectively maintained, single institution, multiparametric magnetic resonance imaging database of 1,001 patients to identify 240 who underwent magnetic resonance imaging-ultrasound fusion targeted biopsy and concurrent systematic biopsy from December 2014 to December 2016. Of the 3,978 biopsy cores obtained 694 positive cores were rereviewed by a genitourinary pathologist for pattern 4 subtype (cribriform, fused and poorly formed glands). Using paired analysis pathological results among 3 biopsy methods (systematic biopsy, targeted biopsy and systematic plus targeted biopsy) were compared. Prostatectomy specimens were also pathologically reviewed. RESULTS: Systematic plus targeted biopsy was superior to systematic biopsy alone or targeted biopsy alone to detect cribriform morphology (all p <0.0001). On final histopathology cribriform tumor foci were associated with an increased percent of pattern 4 involvement and extraprostatic extension (p <0.0001 and 0.003, respectively). Only 17.4% of cribriform tumors in pure form were visible on multiparametric magnetic resonance imaging. Based on final histopathology the sensitivity of systematic biopsy, targeted biopsy and systematic plus targeted biopsy for cribriform morphology was 20.7%, 28.6% and 37.1%, respectively. CONCLUSIONS: Although systematic plus targeted biopsy was the most accurate biopsy method to detect cribriform morphology, biopsy sensitivity and specificity remained poor. PMID- 28728995 TI - A mechanistic model quantifies artemisinin-induced parasite growth retardation in blood-stage Plasmodium falciparum infection. AB - Falciparum malaria is a major parasitic disease causing widespread morbidity and mortality globally. Artemisinin derivatives-the most effective and widely-used antimalarials that have helped reduce the burden of malaria by 60% in some areas over the past decade-have recently been found to induce growth retardation of blood-stage Plasmodium falciparum when applied at clinically relevant concentrations. To date, no model has been designed to quantify the growth retardation effect and to predict the influence of this property on in vivo parasite killing. Here we introduce a mechanistic model of parasite growth from the ring to trophozoite stage of the parasite's life cycle, and by modelling the level of staining with an RNA-binding dye, we demonstrate that the model is able to reproduce fluorescence distribution data from in vitro experiments using the laboratory 3D7 strain. We quantify the dependence of growth retardation on drug concentration and identify the concentration threshold above which growth retardation is evident. We estimate that the parasite life cycle is prolonged by up to 10 hours. We illustrate that even such a relatively short delay in growth may significantly influence in vivo parasite dynamics, demonstrating the importance of considering growth retardation in the design of optimal artemisinin based dosing regimens. PMID- 28728996 TI - Conditions for success of engineered underdominance gene drive systems. AB - Engineered underdominance is one of a number of different gene drive strategies that have been proposed for the genetic control of insect vectors of disease. Here we model a two-locus engineered underdominance based gene drive system that is based on the concept of mutually suppressing lethals. In such a system two genetic constructs are introduced, each possessing a lethal element and a suppressor of the lethal at the other locus. Specifically, we formulate and analyse a population genetics model of this system to assess when different combinations of release strategies (i.e. single or multiple releases of both sexes or males only) and genetic systems (i.e. bisex lethal or female-specific lethal elements and different strengths of suppressors) will give population replacement or fail to do so. We anticipate that results presented here will inform the future design of engineered underdominance gene drive systems as well as providing a point of reference regarding release strategies for those looking to test such a system. Our discussion is framed in the context of genetic control of insect vectors of disease. One of several serious threats in this context are Aedes aegypti mosquitoes as they are the primary vectors of dengue viruses. However, results are also applicable to Ae. aegypti as vectors of Zika, yellow fever and chikungunya viruses and also to the control of a number of other insect species and thereby of insect-vectored pathogens. PMID- 28728997 TI - Sepsis reconsidered: Identifying novel metrics for behavioral landscape characterization with a high-performance computing implementation of an agent based model. AB - OBJECTIVES: Sepsis affects nearly 1 million people in the United States per year, has a mortality rate of 28-50% and requires more than $20 billion a year in hospital costs. Over a quarter century of research has not yielded a single reliable diagnostic test or a directed therapeutic agent for sepsis. Central to this insufficiency is the fact that sepsis remains a clinical/physiological diagnosis representing a multitude of molecularly heterogeneous pathological trajectories. Advances in computational capabilities offered by High Performance Computing (HPC) platforms call for an evolution in the investigation of sepsis to attempt to define the boundaries of traditional research (bench, clinical and computational) through the use of computational proxy models. We present a novel investigatory and analytical approach, derived from how HPC resources and simulation are used in the physical sciences, to identify the epistemic boundary conditions of the study of clinical sepsis via the use of a proxy agent-based model of systemic inflammation. DESIGN: Current predictive models for sepsis use correlative methods that are limited by patient heterogeneity and data sparseness. We address this issue by using an HPC version of a system-level validated agent-based model of sepsis, the Innate Immune Response ABM (IIRBM), as a proxy system in order to identify boundary conditions for the possible behavioral space for sepsis. We then apply advanced analysis derived from the study of Random Dynamical Systems (RDS) to identify novel means for characterizing system behavior and providing insight into the tractability of traditional investigatory methods. RESULTS: The behavior space of the IIRABM was examined by simulating over 70 million sepsis patients for up to 90 days in a sweep across the following parameters: cardio-respiratory-metabolic resilience; microbial invasiveness; microbial toxigenesis; and degree of nosocomial exposure. In addition to using established methods for describing parameter space, we developed two novel methods for characterizing the behavior of a RDS: Probabilistic Basins of Attraction (PBoA) and Stochastic Trajectory Analysis (STA). Computationally generated behavioral landscapes demonstrated attractor structures around stochastic regions of behavior that could be described in a complementary fashion through use of PBoA and STA. The stochasticity of the boundaries of the attractors highlights the challenge for correlative attempts to characterize and classify clinical sepsis. CONCLUSIONS: HPC simulations of models like the IIRABM can be used to generate approximations of the behavior space of sepsis to both establish "boundaries of futility" with respect to existing investigatory approaches and apply system engineering principles to investigate the general dynamic properties of sepsis to provide a pathway for developing control strategies. The issues that bedevil the study and treatment of sepsis, namely clinical data sparseness and inadequate experimental sampling of system behavior space, are fundamental to nearly all biomedical research, manifesting in the "Crisis of Reproducibility" at all levels. HPC-augmented simulation-based research offers an investigatory strategy more consistent with that seen in the physical sciences (which combine experiment, theory and simulation), and an opportunity to utilize the leading advances in HPC, namely deep machine learning and evolutionary computing, to form the basis of an iterative scientific process to meet the full promise of Precision Medicine (right drug, right patient, right time). PMID- 28728998 TI - Sialylation of IgG antibodies inhibits IgG-mediated allergic reactions. PMID- 28728999 TI - Histamine H2 receptor stimulation upregulates TH2 chemokine CCL17 production in human M2a macrophages. PMID- 28729001 TI - The "dangers" of chronic proton pump inhibitor use. PMID- 28729002 TI - Phosphenes, retinal discrete dark noise, negative afterimages and retinogeniculate projections: A new explanatory framework based on endogenous ocular luminescence. AB - Cellular luminescence is the emission of photons by living cells due to various biophysical and biochemical processes, mostly associated with cellular metabolism. In this review paper we summarize today's understanding of four luminescence-dependent phenomena in the eye, i.e., phosphenes, retinal discrete dark noise, negative afterimages and the development of retinogeniculate projections in the brain. We review the phenomena above in the context of knowledge gained from experimental and theoretical works. Finally, we discuss this knowledge in terms of its physiological significance. PMID- 28729003 TI - The Effects of an Activity Promotion System on active living in overweight subjects with metabolic abnormalities. AB - OBJECTIVES: The aim of this study is to examine the effects of Activity Promotion System (APs) on promoting physical activity (PA) for overweight subjects with metabolic abnormalities. METHODS: We designed a six-month randomised controlled trial with a cross-over design, and recruited 53 subjects. Subjects in group A used APs with a wearable device measuring whole-day PA, including sleep time, sedentary, light, moderate and vigorous PA and a web-based feedback system in the first three months and followed by usual care with traditional health education in the next three months. Subjects in group B received the above programs in a reverse order. PA and metabolic profiles were measured prior to the intervention (T1), three months after the first intervention (T2), and six months after the other intervention (T3), respectively. An independent t test was used to test the differences between periods with and without Aps. RESULTS: This study found that the APs had short-term effects on decreasing sedentary time and increasing mild PA, total PA, daily step counts, and calories burnt. With regard to the secondary outcome measures of metabolic abnormalities, the results showed that APs had had no effect on metabolic abnormalities, except a borderline decreasing of waist circumference. CONCLUSION: Using this APs might be an effective approach to decrease sedentary time and increase PA for an overweight non-elderly adult population with only metabolic abnormalities. However, long-term studies with APs are needed to further confirm the effectiveness of this innovative Activity Promotion System. PMID- 28729004 TI - Health-related quality of life in metabolically healthy obese individuals. PMID- 28729005 TI - Influence of late fluid management on the outcomes of severe trauma patients: A retrospective analysis of 294 severely-injured patients. AB - BACKGROUND: Liberal late fluid management (LFM) is associated with higher morbi mortality in critically ill populations. The aim of the study was to assess the association between LFM and duration of mechanical ventilation in a severe trauma population. METHODS: A retrospective analysis of consecutive patients with an ISS>=16 and a length of stay in the intensive care unit (ICU)>=7 days was performed. The conservative LFM group included patients with at least 2 consecutive days with a negative fluid balance between day 3 and day 7; other patients were allocated to the liberal LFM group. RESULTS: 294 severely injured patients were included, 157 (53%) as conservative LFM and 137 (47%) as liberal LFM. The groups did not differ significantly in terms of baseline characteristics, severe injuries, severity criteria or transfusion needs. Liberal LFM was significantly associated with more ventilation days (11 vs 8.5days; P=0.02), less ventilator-free days at day 30 (19 vs 21days; P=0.03), longer ICU stay (19 vs 16days; P=0.03) and longer hospital stay (30 vs 25days; P=0.04). Mortality rates were comparable between groups (6%). Liberal LFM was significantly associated in multivariable analysis with a reduced number of ventilator-free days at day 30 (beta=-2.14 [95% CI, -4.2 to -0.08], P=0.042). CONCLUSIONS: Liberal LFM was associated with higher morbidity in severe trauma patients, longer duration of ventilation, and longer ICU and hospital stays. These results were observed despite similar severity on admission and early fluid management. PMID- 28729006 TI - A representative assessment of the management of open fractures of the lower limb within UK orthoplastic centres: A two-centre audit of compliance with national standards. AB - BACKGROUND: Open fractures of the lower limb represent a complex and varied array of injuries. The BOAST 4 document produced by BAPRAS and the BOA provides standards on how to manage these patients, and NICE have recently produced additional guidance. We aimed to assess concordance with these standards in a large cohort representative of UK orthoplastic centres. METHODS: Patients admitted to the orthoplastic units at Norfolk and Norwich University Hospital and Royal Stoke University Hospital with open lower limb fractures between 2009 and 2014 were included. Data was gathered from notes and endpoints based on the BOAST 4 document. RESULTS: In total, 84 patients were included across the two sites, with 83 having their initial debridement within 24h (98.8%). Forty-two patients had a documented out-of-hours initial surgery. Of these, 10 (23.8%) had an indication for urgent surgery. This pattern was consistent across both hospitals. A plastic surgeon was present at 33.3% of initial operations. Of 78 patients receiving definitive soft tissue cover, 56.4% had cover within 72h and 78.2% within 7days. Main reasons for missing these targets were transfer from other hospitals, plastic surgeons not present at initial operation and intervening critical illness. CONCLUSIONS: This study has identified key areas for improving compliance with the national BOAST 4 and NICE standards. Out-of-hours operating is occurring unnecessarily and time targets are being missed. The development of dedicated referral pathways and a true orthoplastic approach are required to improve the management of this complex set of injuries. PMID- 28729007 TI - The feasibility of point-of-care ankle ultrasound examination in patients with recurrent ankle sprain and chronic ankle instability: Comparison with magnetic resonance imaging. AB - OBJECTIVE: To evaluate the feasibility of point-of-care ankle ultrasound compared with magnetic resonance imaging (MRI) for diagnosing major ligaments and Achilles tendon injuries in patients with recurrent ankle sprain and chronic instability, and to evaluate inter-observer reliability between an emergency physician and a musculoskeletal radiology fellow. MATERIAL AND METHODS: A prospective cross sectional study was conducted in an emergency department. Patients with recurrent ankle sprain and chronic instability were recruited. An emergency physician and a musculoskeletal radiology fellow independently evaluated the anterior talofibular ligament (ATFL), calcaneofibular ligament (CFL), distal anterior tibiofibular ligament (ATiFL), deltoid ligament, and Achilles tendon using point-of-care ankle ultrasound. Findings were classified normal, partial tear, and complete tear. MRI was used as the reference standard. We calculated diagnostic values for point-of care ankle ultrasound for both reviewers and compared them using DeLong's test. Intra-class correlation coefficients (ICCs) were calculated for agreement between each reviewer and the reference standard, and between the two reviewers. RESULTS: Eighty-five patients were enrolled. Point-of-care ankle ultrasound showed acceptable sensitivity (96.4-100%), specificity (95.0-100%), and accuracy (96.5 100%); these performance markers did not differ significantly between reviewers. Agreement between each reviewer and the reference standard was excellent (emergency physician, ICC=0.846-1.000; musculoskeletal radiology fellow, ICC=0.930-1.000), as was inter-observer agreement (ICC=0.873-1.000). CONCLUSION: Point-of-care ankle ultrasound is as precise as MRI for detecting major ankle ligament and Achilles tendon injuries; it could be used for immediate diagnosis and further pre-operative imaging. Moreover, it may reduce the interval from emergency department admission to admission for surgical intervention, and may save costs. PMID- 28729008 TI - The Implementation of Measuring What Matters in Research and Practice: Series Commentary. AB - The Measuring What Matters (MWM) initiative identified 10 indicators of high quality palliative and hospice care. Members of the AAHPM Research Committee, through a special series of articles, examined applications of the MWM quality indicators in research and practice settings. Many themes were present in these articles, including the important role of electronic health records in quality measurement, challenges and strategies for implementing and tracking measures over time, and the importance of identifying new measures. This article is the final commentary of the series and includes recommendations for next steps in quality measurement. PMID- 28729009 TI - Development of Entrustable Professional Activities for Hospice and Palliative Medicine Fellowship Training in the United States. AB - CONTEXT: Entrustable Professional Activities (EPAs) represent the key physician tasks of a specialty. Once a trainee demonstrates competence in an activity, they can then be "entrusted" to practice without supervision. A physician workgroup of the American Academy of Hospice and Palliative Medicine sought to define Hospice and Palliative Medicine (HPM) EPAs. OBJECTIVE: The objective of this study was to describe the development of a set of consensus EPAs for HPM fellowship training in the United States. METHODS: A set of HPM EPAs was developed through an iterative consensus process involving an expert workgroup, vetting at a national meeting with HPM educators, and an electronic survey from a national registry of 3550 HPM physicians. Vetting feedback was reviewed, and survey data were statistically analyzed. Final EPA revisions followed from the multisource feedback. RESULTS: Through the iterative consensus process, a set of 17 HPM EPAs was created, detailed, and revised. In the national survey, 362 HPM specialists responded (10%), including 58 of 126 fellowship program directors (46%). Respondents indicated that the set of 17 EPAs well represented the core activities of HPM physician practice (mean 4.72 on a five-point Likert scale) and considered all EPAs to either be "essential" or "important" with none of the EPAs ranking "neither essential, nor important." CONCLUSIONS: A set of 17 EPAs was developed using national input of practicing physicians and program directors and an iterative expert workgroup consensus process. The workgroup anticipates that EPAs can assist fellowship directors with strengthening competency-based training curricula. PMID- 28729010 TI - Evaluation of Emergency Department Management of Opioid-Tolerant Cancer Patients With Acute Pain. AB - CONTEXT: There are no previously published studies examining opioid doses administered to opioid-tolerant cancer patients during emergency department (ED) encounters. OBJECTIVES: To determine if opioid-tolerant cancer patients presenting with acute pain exacerbations receive adequate initial doses of as needed (PRN) opioids during ED encounters based on home oral morphine equivalent (OME) use. METHODS: We performed a retrospective cohort study of opioid-tolerant cancer patients who received opioids in our ED over a two-year period. The percentage of patients who received an adequate initial dose of PRN opioid (defined as >=10% of total 24-hour ambulatory OME) was evaluated. Logistic regression was used to establish the relationship between 24-hour ambulatory OME and initial ED OME to assess whether higher home usage was associated with higher likelihood of being undertreated. RESULTS: Out of 216 patients, 61.1% of patients received an adequate initial PRN dose of opioids in the ED. Of patients taking <200 OMEs per day at home, 77.4% received an adequate initial dose; however, only 3.2% of patients taking >400 OMEs per day at home received an adequate dose. Patients with ambulatory 24-hour OME greater than 400 had 99% lower odds of receiving an adequate initial dose of PRN opioid in the ED compared to patients with ambulatory 24-hour OME less than 100 (OR <0.01, CI 0.00-0.02, P < 0.001). CONCLUSIONS: Patients with daily home use less than 200 OMEs generally received adequate initial PRN opioid doses during their ED visit. However, patients with higher home opioid usage were at increased likelihood of being undertreated. PMID- 28729011 TI - Iranian Brief Pain Inventory: Validation and Application in Elderly People With Cancer Pain. AB - CONTEXT: Cancer is a major health problem in the elderly, and pain is one of the most common symptoms among older patients with cancer. Sufficient pain treatments depend on the accuracy of the pain assessment tool. OBJECTIVES: This study aimed to assess the psychometric properties of the Iranian version of the Brief Pain Inventory (BPI-IR) among elderly individuals with cancer. METHODS: This validation study was conducted with 368 people aged 60+ years old who were undergoing oncology treatments. The BPI-IR was applied to the elderly participants through face-to-face interviews. Reliability of the BPI-IR was evaluated using Cronbach's alpha coefficient and intraclass correlation coefficient between test-retest scores. Criterion validity was determined by calculating the Spearman's correlation coefficient between scores on the BPI-IR and those on the SF-36 physical function, Activities of Daily Living, Instrumental Activities of Daily Living, Center for Epidemiological Studies Depression, Patient Pain Questionnaire, and Symptom Distress Scale. Construct validity of the BPI-IR was evaluated using exploratory factor analyses. RESULTS: Cronbach's alpha coefficient was calculated to be 0.94, and the intraclass correlation coefficient between twice the BPI-IR scores over two weeks obtained was 0.89. There were moderate-to-high correlations between the BPI-IR and the Patient Pain Questionnaire (r = 0.886), Symptom Distress Scale (r = 0.492), SF-36 physical function (r = 0.554), and Center for Epidemiological Studies Depression (r = 0.608). Two factors were extracted in exploratory factor analyses, and they explained 73.86% of total variance. CONCLUSION: The BPI-IR is a reliable and valid tool for assessing pain among older adults with cancer. PMID- 28729012 TI - Evidence that children born at early term (37-38 6/7 weeks) are at increased risk for diabetes and obesity-related disorders. AB - BACKGROUND: Prematurity is known to be associated with high rates of endocrine and metabolic complications in the offspring. Offspring born early term (37-38 6/7 weeks' gestation) were also shown to exhibit long-term morbidity resembling that of late preterm, in several health categories. OBJECTIVE: We aimed to determine whether early term delivery impacts on the long-term endocrine and metabolic health of the offspring. STUDY DESIGN: A population-based cohort analysis was performed, including all term singleton deliveries occurring from 1991 through 2013 at a single regional tertiary medical center. Congenital malformations and multiple pregnancies were excluded. Gestational age upon delivery was subdivided into early term deliveries and deliveries occurring at full term and later (>=39 weeks' gestation, comparison group). Endocrine and metabolic morbidity (including diabetes, obesity, hypoglycemia, hyperlipidemia, and hypothyroidism) of the offspring, up to the age of 18 years, was evaluated according to hospitalization files. Kaplan-Meier survival curves were used to compare cumulative morbidity incidence. A Weibull parametric survival model was used to control for time to event, siblings, and other confounders. RESULTS: During the study period 225,260 term deliveries met the inclusion criteria. Of them, 24% (n = 54,073) occurred at early term. Endocrine and metabolic morbidity was significantly more common in the early term group (0.51% vs 0.41%, P = .003). Specifically, overweight and obesity were more common among the early term group (P = .002). Differences were more prominent among children >5 years, who exhibited higher rates of type 1 diabetes mellitus, as well as obesity, when born at early term (P < .05). The survival curves demonstrated higher cumulative incidence of total endocrine and metabolic morbidity in the early term group. Using the Weibull parametric survival model, while controlling for siblings, maternal diabetes, hypertension, labor induction, and Apgar score, early term delivery exhibited an independent association with long-term childhood endocrine and metabolic morbidity of the offspring (adjusted hazard ratio, 1.17; 95% confidence interval, 1.01-1.34) and more so for age >5 years (adjusted hazard ratio, 1.30; 95% confidence interval, 1.08-1.56). CONCLUSION: Deliveries occurring at early term are associated with higher rates of long-term pediatric endocrine and metabolic morbidity of the offspring as compared with deliveries occurring at a later gestational age. This association may be due to absence of full maturity of the hormonal axis in early term neonates or, alternatively, suggest an underlying fetal endocrine dysfunction as the initial mechanism responsible for spontaneous early term delivery. PMID- 28729000 TI - Airway microbiota signals anabolic and catabolic remodeling in the transplanted lung. AB - BACKGROUND: Homeostatic turnover of the extracellular matrix conditions the structure and function of the healthy lung. In lung transplantation, long-term management remains limited by chronic lung allograft dysfunction, an umbrella term used for a heterogeneous entity ultimately associated with pathological airway and/or parenchyma remodeling. OBJECTIVE: This study assessed whether the local cross-talk between the pulmonary microbiota and host cells is a key determinant in the control of lower airway remodeling posttransplantation. METHODS: Microbiota DNA and host total RNA were isolated from 189 bronchoalveolar lavages obtained from 116 patients post lung transplantation. Expression of a set of 11 genes encoding either matrix components or factors involved in matrix synthesis or degradation (anabolic and catabolic remodeling, respectively) was quantified by real-time quantitative PCR. Microbiota composition was characterized using 16S ribosomal RNA gene sequencing and culture. RESULTS: We identified 4 host gene expression profiles, among which catabolic remodeling, associated with high expression of metallopeptidase-7, -9, and -12, diverged from anabolic remodeling linked to maximal thrombospondin and platelet-derived growth factor D expression. While catabolic remodeling aligned with a microbiota dominated by proinflammatory bacteria (eg, Staphylococcus, Pseudomonas, and Corynebacterium), anabolic remodeling was linked to typical members of the healthy steady state (eg, Prevotella, Streptococcus, and Veillonella). Mechanistic assays provided direct evidence that these bacteria can impact host macrophage-fibroblast activation and matrix deposition. CONCLUSIONS: Host microbes interplay potentially determines remodeling activities in the transplanted lung, highlighting new therapeutic opportunities to ultimately improve long-term lung transplant outcome. PMID- 28729013 TI - Do maternal obesity or smoking explain the lack of effectiveness of 17-alpha hydroxyprogesterone caproate? PMID- 28729015 TI - Reply. PMID- 28729014 TI - Evaluating ureteral patency in the post-indigo carmine era: a randomized controlled trial. AB - BACKGROUND: Many gynecologic, urologic, and pelvic reconstructive surgeries require accurate intraoperative evaluation of ureteral patency. OBJECTIVE: We performed a randomized controlled trial to compare surgeon satisfaction with 4 methods of evaluating ureteral patency during cystoscopy at the time of benign gynecologic or pelvic reconstructive surgery: oral phenazopyridine, intravenous sodium fluorescein, mannitol bladder distention, and normal saline bladder distention. STUDY DESIGN: We conducted an unblinded randomized controlled trial of the method used to evaluate ureteral patency during cystoscopy at time of benign gynecologic or pelvic reconstructive surgery. Subjects were randomized to receive 200 mg oral phenazopyridine, 25 mg intravenous sodium fluorescein, mannitol bladder distention, or normal saline bladder distention during cystoscopy. The primary outcome was surgeon satisfaction with the method, assessed via a 100-mm visual analog scale with 0 indicating strong agreement and 100 indicating strong disagreement with the statement. Secondary outcomes included comparing visual analog scale responses about ease of each method and visualization of ureteral jets, bladder mucosa and urethra, and operative information, including time to surgeon confidence in the ureteral jets. Adverse events were evaluated for at least 6 weeks after the surgical procedure, and through the end of the study. All statistical analyses were based on the intent to-treat principle, and comparisons were 2-tailed. RESULTS: In all, 130 subjects were randomized to phenazopyridine (n = 33), sodium fluorescein (n = 32), mannitol (n = 32), or normal saline (n = 33). At randomization, patient characteristics were similar across groups. With regard to the primary outcome, mannitol was the method that physicians found most satisfactory on a visual analog scale. The median (range) scores for physicians assessing ureteral patency were 48 (0-83), 20 (0-82), 0 (0-44), and 23 (3-96) mm for phenazopyridine, sodium fluorescein, mannitol, and normal saline, respectively (P < .001). Surgery length, cystoscopy length, and time to surgeon confidence in visualization of ureteral jets were not different across the 4 randomized groups. During the 189 day follow-up, no differences in adverse events were seen among the groups, including urinary tract infections. CONCLUSION: The use of mannitol during cystoscopy to assess ureteral patency provided surgeons with the most overall satisfaction, ease of use, and superior visualization without affecting surgery or cystoscopy times. There were no differences in adverse events, including incidence of urinary tract infections. PMID- 28729016 TI - Learning-based structurally-guided construction of resting-state functional correlation tensors. AB - Functional magnetic resonance imaging (fMRI) measures changes in blood oxygenation-level-dependent (BOLD) signals to detect brain activities. It has been recently reported that the spatial correlation patterns of resting-state BOLD signals in the white matter (WM) also give WM information often measured by diffusion tensor imaging (DTI). These correlation patterns can be captured using functional correlation tensor (FCT), which is analogous to the diffusion tensor (DT) obtained from DTI. In this paper, we propose a noise-robust FCT method aiming at further improving its quality, and making it eligible for further neuroscience study. The novel FCT estimation method consists of three major steps: First, we estimate the initial FCT using a patch-based approach for BOLD signal correlation to improve the noise robustness. Second, by utilizing the relationship between functional and diffusion data, we employ a regression forest model to learn the mapping between the initial FCTs and the corresponding DTs using the training data. The learned forest can then be applied to predict the DTI-like tensors given the initial FCTs from the testing fMRI data. Third, we re estimate the enhanced FCT by utilizing the DTI-like tensors as a feedback guidance to further improve FCT computation. We have demonstrated the utility of our enhanced FCTs in Alzheimer's disease (AD) diagnosis by identifying mild cognitive impairment (MCI) patients from normal subjects. PMID- 28729017 TI - Daily levels and rhythm in circulating corticosterone and insulin are altered with photostimulated seasonal states in night-migratory blackheaded buntings. AB - The circadian rhythms are involved in the photostimulation of seasonal responses in migratory blackheaded buntings. Here, we investigated whether changes in daily levels and rhythm in corticosterone (cort) and insulin secretions were associated with transitions in the photoperiodic seasonal states. Buntings were exposed to short days to maintain the winter (photosensitive) non-migratory state, and to long days for varying durations to induce the premigratory, migratory (shown by migratory restlessness at night, Zugunruhe) and summer non-migratory (photorefractory) states. We monitored activity patterns, and measured plasma cort and insulin levels at six and four times, respectively, over 24h in each seasonal state. Buntings were fattened and weighed heavier, and exhibited intense nighttime activity in the migratory state. The daytime activity patterns also showed seasonal differences, with a bimodal pattern with morning and evening activity bouts only in the summer non-migratory state. Further, the average baseline hormone levels were significantly higher in premigratory and migratory than in the winter non-migratory state. Both cort and insulin levels showed a significant daily rhythm, but with seasonal differences. Whereas, cort rhythm acrophases (estimated time of peak secretion over 24h) were at night in the winter non-migratory, premigratory and migratory states, the insulin rhythm acrophases were found early in the day and night in winter and summer non migratory states, respectively. These results suggest that changes in daily levels and rhythm in cort and insulin mediate changes in the physiology and behavior with photostimulated transition in seasonal states in migratory blackheaded buntings. PMID- 28729018 TI - Sustained reduction in vaccine-type invasive pneumococcal disease despite waning effects of a catch-up campaign in Kilifi, Kenya: A mathematical model based on pre-vaccination data. AB - BACKGROUND: In 2011, Kenya introduced the 10-valent pneumococcal conjugate vaccine together with a catch-up campaign for children aged <5years in Kilifi County. In a post-vaccination surveillance study based in Kilifi, there was a substantial decline in invasive pneumococcal disease (IPD). However, given the continued circulation of the vaccine serotypes it is possible that vaccine serotype disease may re-emerge once the effects of the catch-up campaign wear off. METHODS: We developed a compartmental, age-structured dynamic model of pneumococcal carriage and invasive disease for three serotype groups: the 10 valent vaccine serotypes and two groups of non-vaccine serotypes based on their susceptibility to mutual competition. The model was calibrated to age- and serotype-specific data on carriage and IPD in the pre-vaccination era and used to predict carriage prevalence and IPD up to ten years post-vaccination in Kilifi. The model was validated against the observed carriage prevalence after vaccine introduction. RESULTS: The model predicts a sustained reduction in vaccine-type pneumococcal carriage prevalence from 33% to 8% in infants and from 30% to 8% in 1-5year olds over the 10-year period following vaccine introduction. The incidence of IPD is predicted to decline across all age groups resulting in an overall reduction of 56% in the population, corresponding to 10.4 cases per 100,000 per year. The vaccine-type IPD incidence is estimated to decline by 83% while non-vaccine-type IPD incidence is predicted to increase by 52%. The model's predictions of carriage prevalence agrees well with the observed data in the first five years post-vaccination. CONCLUSION: We predict a sustained and substantial decline in IPD through PCV vaccination and that the current regimen is insufficient to fully eliminate vaccine-serotype circulation in the model. We show that the observed impact is likely to be sustained despite waning effects of the catch-up campaign. PMID- 28729019 TI - Safety, reactogenicity and immunogenicity of two investigational pneumococcal protein-based vaccines: Results from a randomized phase II study in infants. AB - INTRODUCTION: Vaccination with formulations containing pneumococcal protein antigens such as pneumolysin toxoid (dPly) and histidine-triad protein D (PhtD) may extend serotype-related protection of pneumococcal conjugate vaccines (PCVs) against Streptococcus pneumoniae. METHODS: This phase II, multi-center, observer blind trial conducted in Europe (NCT01204658) assessed 2 investigational vaccines containing 10 serotype-specific polysaccharide conjugates of PHiD-CV and either 10 or 30ug of dPly and PhtD each. Infants randomized 1:1:1:1 received 4 doses of PHiD-CV/dPly/PhtD-10, PHiD-CV/dPly/PhtD-30, PHiD-CV, or 13-valent PCV (PCV13), co administered with DTPa-HBV-IPV/Hib, at ages ~2, 3, 4 and 12-15months. Occurrences of fever >40.0 degrees C following primary vaccination with PHiD-CV/dPly/PhtD vaccines compared to PHiD-CV (non-inferiority objective), dose superiority, safety and immunogenicity were assessed. RESULTS: 575 children received primary vaccination, and 564 booster vaccination. The non-inferiority objective was met; no fever >40.0 degrees C causally related to vaccination was reported during primary vaccination. Incidence of adverse events appeared similar between the 3 PHiD-CV groups. Serious adverse events were reported in 13, 9, 21 (1 related to vaccination), and 17 children in the PHiD-CV/dPly/PhtD-10, PHiD-CV/dPly/PhtD-30, PHiD-CV, and PCV13 groups, respectively. PHiD-CV/dPly/PhtD-30 was superior to PHiD-CV/dPly/PhtD-10 in terms of post-dose 3 anti-Ply and Anti-PhtD antibody levels. Anti-Ply and anti-PhtD antibody levels were higher in both PHiD CV/dPly/PhtD groups than in controls and increased from post-primary to post booster timepoint. Post-primary and booster vaccination, for each PHiD-CV serotype, >=98.5% of participants in PHiD-CV/dPly/PhtD groups had antibody concentrations >= 0.2MUg/mL, except for 6B (>=72.3%) and 23F (>=82.7%) post primary vaccination. Similar results were observed in the PHiD-CV group. Immune responses to protein D and DTPa-HBV-IPV/Hib were within similar ranges for the 3 PHiD-CV groups. CONCLUSION: Both PHiD-CV/dPly/PhtD formulations co-administered with DTPa-HBV-IPV/Hib in infants were well-tolerated and immunogenic for dPly and PhtD antigens, while immune responses to serotype-specific, protein D and co administered antigens did not appear altered in comparison to PHiD-CV group. PMID- 28729020 TI - Purification of cell culture-derived influenza A virus via continuous anion exchange chromatography on monoliths. AB - The continuously increasing demand for potent and safe vaccines and the intensifying economic pressure on health care systems underlines the need for further optimization of vaccine manufacturing. Here, we focus on downstream processing of human influenza vaccines, investigating the purification of serum free cell culture-derived influenza virus (A/PR/8/34 H1N1) using continuous chromatography. Therefore, quaternary amine anion exchange monoliths (CIM(r) QA) were characterized for their capacity to capture virus particles from animal cells cultivated in different media and their ability to separate virions from contaminating host cell proteins and DNA. The continuous chromatography was implemented as simulated moving bed chromatography (SMB) in a three zone open loop configuration with a detached high salt zone for regeneration. SMBs exploiting 10% and 50% of the monoliths' dynamic binding capacity, respectively, allowed the depletion of >98% of the DNA and >52% of the total protein. Based on the hemagglutination assay (HA assay), the virus yield was higher at 10% capacity use (89% vs. 45%). Both SMB separations resulted in a ratio of total protein to hemagglutinin antigen (based on single radial diffusion assay, SRID assay) below the required levels for manufacturing of human vaccines (less than 100ug of protein per virus strain per dose). The level of contaminating DNA was five-times lower for the 10% loading, but still exceeded the required limit for human vaccines. A subsequent Benzonase(r) treatment step, however, reduced the DNA contamination below 10ng per dose. Coupled to continuous cultivations for virus propagation, the establishment of integrated processes for fully continuous production of vaccines seems to be feasible. PMID- 28729021 TI - ASCEND-8: A Randomized Phase 1 Study of Ceritinib, 450 mg or 600 mg, Taken with a Low-Fat Meal versus 750 mg in Fasted State in Patients with Anaplastic Lymphoma Kinase (ALK)-Rearranged Metastatic Non-Small Cell Lung Cancer (NSCLC). AB - INTRODUCTION: Ceritinib, 750 mg fasted, is approved for treatment of patients with ALK receptor tyrosine kinase gene (ALK)-rearranged (ALK-positive) NSCLC previously treated with crizotinib. Part 1 of the ASCEND-8 study determined whether administering ceritinib, 450 mg or 600 mg, with a low-fat meal may enhance gastrointestinal (GI) tolerability versus 750 mg fasted in patients with ALK-positive NSCLC while maintaining similar exposure. METHODS: ASCEND-8 is a multicenter, randomized, open-label, phase 1 study. Part 1 investigated the steady-state pharmacokinetics (PK) and safety of ceritinib, 450 mg or 600 mg, taken with a low-fat meal versus 750 mg fasted in patients with advanced ALK positive NSCLC who were either treatment naive or pretreated with chemotherapy and/or crizotinib. Part 2 will assess efficacy and safety of ceritinib in treatment-naive patients. RESULTS: As of June 16, 2016, 137 patients were randomized (450 mg fed [n = 44], 600 mg fed [n = 47], and 750 mg fasted [n = 46]); 135 patients received ceritinib. Median follow-up duration was 4.14 months. At steady state, relative to 750 mg fasted, 450 mg with food demonstrated comparable PK as assessed by maximum (peak) concentration of drug in plasma and area under the plasma concentration-time curve from time zero to 24 hours, whereas 600 mg with food demonstrated approximately 25% higher PK. Relative to 750 mg fasted, 450 mg with food was associated with a lower proportion of patients with GI toxicities, mostly grade 1 (diarrhea [43.2%], nausea [29.5%], and vomiting [18.2%]); there were no grade 3 or 4 events, study drug discontinuations, or serious AEs due to GI toxicities. CONCLUSION: Ceritinib, 450 mg with food, had similar exposure and a more favorable GI safety profile than ceritinib, 750 mg in fasted patients with ALK-positive NSCLC. PMID- 28729022 TI - Boldness psychopathic traits predict reduced gaze toward fearful eyes in men with a history of violence. AB - Research with developmental and adult samples has shown a relationship of psychopathic traits with reduced eye gaze. However, these relationships remained to be investigated among forensic samples. Here we examined the eye movements of male violent offenders during an emotion recognition task. Violent offenders performed similar to non-offending controls, and their eye movements varied with the emotion and intensity of the facial expression. In the violent offender group Boldness psychopathic traits, but not Meanness or Disinhibition, were associated with reduced dwell time and fixation counts, and slower first fixation latencies, on the eyes compared with the mouth. These results are the first to show a relationship of psychopathic traits with reduced attention to the eyes in a forensic sample, and suggest that Boldness is associated with difficulties in orienting attention toward emotionally salient aspects of the face. PMID- 28729023 TI - MicroRNAs in DNA Damage Response, Carcinogenesis, and Chemoresistance. AB - In the classical model of tumorigenesis, cancer develops via slowly accumulating mutations that facilitate uncontrolled cell growth and allow cells to escape apoptosis. Oncogenes and tumor suppressor genes regulate the key signaling pathways involved in tumorigenesis and cancer progression. Moreover, studies indicate that MicroRNAs (MiRNAs) are also key parts of these processes. MiRNAs are short, noncoding RNAs that regulate the expression of target genes at the posttranscriptional level. By regulating the expression of numerous cytokines, MiRNAs play crucial roles in cell growth, apoptosis, and stemness maintenance. Abundant evidence demonstrates that MiRNAs can function as both oncogenes and tumor suppressors in accommodating the proliferation and invasion of cancer cells in solid tumors. Targeting these MiRNAs may significantly alter oncogenic signaling pathways and slow or halt progression of many different types of tumors. A better understanding of the functions of MiRNAs in cancer will enable the development of new treatment strategies for chemoresistant malignancies. This review discusses recent findings about the connections between MiRNAs and carcinogenesis and provides insight into the role of MiRNAs in generating chemoresistance. PMID- 28729024 TI - Understanding the Genomic Ultraconservations: T-UCRs and Cancer. AB - Transcribed ultraconserved regions (T-UCRs) are genomic regions conserved across large evolutionary distances, which encode for noncoding RNAs that serve as regulators of gene expression. Although T-UCRs have been linked to multiple aspects of mammalian gene regulation, the roles of their extreme evolutionary conservation remain largely unexplained. Growing body of literature is now focusing on T-UCRs as potential cancer biomarkers or as new drug targets. Here we present an overview of the discoveries so far published about the role of T-UCR in cancer and disease. PMID- 28729025 TI - Following MicroRNAs Through the Cancer Metastatic Cascade. AB - Approximately a decade ago the first MicroRNAs (MiRNAs) participating in cancer metastasis were identified and metastmiRs were initially only a handful. Since those first reports, MiRNA research has explosively thrived, mainly due to their revolutionary mechanism of action and the hope of having at hand a novel tool to control cancer aggressiveness. This has ultimately led to delineate an almost impenetrable regulatory network: hundreds of MiRNAs transversally dominating every aspect of normal and cancer biology, each MiRNA having hundreds of targets and context-dependent activity. Providing a comprehensive description of MiRNA roles in cancer metastasis is a daunting task; nevertheless, we still believe that grasping the big picture of MiRNAs in cancer metastasis can give a different perspective on the potential insights and approaches that MiRNAs can offer to understand cancer complexity (e.g., as predictive and prognostic markers) and to tackle cancer metastasis (e.g., as therapeutic targets or tools). This chapter presents a schematic overview of the role of MiRNAs in governing cancer metastasis, describing step by step the cellular and molecular processes whereby cancer cells conquer distant organs and can grow as secondary tumors at different distant sites, and for each step, we will introduce how MiRNAs impinge on each one of them. We deeply apologize with our colleagues for any of their research work that, for clarity, for our effort to streamline and due to space limitations, we did not cite. PMID- 28729026 TI - MicroRNAs in Oncogenesis and Tumor Suppression. AB - MicroRNAs (MiRNAs) have emerged in the last 15 years as central players in the biology of cancer. Increasing lines of evidence have supported their regulatory role in the expression of both oncogenes and tumor-suppressor genes, progressively clarifying which genes are modulated by specific MiRNAs dysregulated in cancer. Intriguingly, a "target-specific" understanding of MiRNA function in oncology has been replaced by a more "pathway-specific" vision of their involvement in cancer biology. This work provides a state-of-the-art knowledge of the role of MiRNAs in the most frequently altered signaling pathways in cancer cells and provides an updated overview on some of the most relevant findings trying to decode the complex molecular mechanisms of cancer. PMID- 28729027 TI - MicroRNAs as Multifaceted Players in Glioblastoma Multiforme. AB - Glioblastoma multiforme (GBM) is the most common and inevitably lethal primary brain tumor, with a median survival rate of only 15 months from diagnosis. The current standard treatment involves maximal surgical resection flanked by radiotherapy and chemotherapy with the alkylating agent temozolomide. However, even such aggressive treatment is never curative, and recurrent tumors always arise, commonly in more aggressive, chemo- and radio-resistant forms, leading to untreatable and deadly tumors. MicroRNAs, recognized major players in cancer, are deeply involved in GBM, as shown by more than a decade of studies. In this review, we revise the main milestones of MicroRNA studies in GBM, and the latest relevant discoveries in this field. Examples are given of MicroRNAs working as "oncomiRs" or tumor suppressors, with specific connections with GBM clinical subtypes, patients' survival, and resistance to therapies. As the interaction of GBM cells with the microenvironment was proven as a key determinant of tumor growth, the role of MicroRNAs in GBM microenvironment, tumor angiogenesis, and tumor-secreted microvesicles is also reviewed. Finally, we discuss the latest findings presenting MicroRNAs as possible therapeutic targets for GBM, or their use as circulating biomarkers in diagnosis and prognosis. PMID- 28729028 TI - MicroRNAs as Key Effectors in the p53 Network. AB - The guardian of the genome p53 is embedded in a fine-spun network of MicroRNAs. p53 is able to activate or repress directly the transcription of MicroRNAs that are participating in the tumor-suppressive mission of p53. On the other hand, the expression of p53 is under tight control of MicroRNAs that are either targeting directly p53 or factors that are modifying its protein level or activity. Although the most important function of p53 is suggested to be transcriptional regulation, there are several nontranscriptional functions described. One of those regards the modulation of MicroRNA biogenesis. Wild-type p53 is increasing the maturation of selected MicroRNAs from the primary transcript to the precursor MiRNA by interacting with the Microprocessor complex. Furthermore, p53 is modulating the mRNA accessibility for certain MicroRNAs by association with the RISC complex and transcriptional regulation of RNA-binding proteins. In this way p53 is able to remodel the MiRNA-mRNA interaction network. As wild-type p53 is employing MicroRNAs to suppress cancer development, gain-of-function mutant p53 proteins use MicroRNAs to confer oncogenic properties like chemoresistance and the ability to drive metastasis. Like its wild-type counterpart mutant p53 is able to regulate MicroRNAs transcriptionally and posttranscriptionally. Mutant p53 affects the MiRNA processing at two cleavage steps through interfering with the Microprocessor complex and by downregulating Dicer and KSRP, a modulator of MiRNA biogenesis. Thus, MicroRNAs are essential components in the p53 pathway, contributing substantially to combat or enhance tumor development depending on the wild-type or mutant p53 context. PMID- 28729029 TI - Impact of MicroRNAs in the Cellular Response to Hypoxia. AB - In mammalian cells, hypoxia, or inadequate oxygen availability, regulates the expression of a specific set of MicroRNAs (MiRNAs), termed "hypoxamiRs." Over the past 10 years, the appreciation of the importance of hypoxamiRs in regulating the cellular adaptation to hypoxia has grown dramatically. At the cellular level, each hypoxamiR, including the master hypoxamiR MiR-210, can simultaneously regulate expression of multiple target genes in order to fine-tune the adaptive response of cells to hypoxia. This review addresses the complex molecular regulation of MiRNAs in both physiological and pathological conditions of low oxygen adaptation and the multiple functions of hypoxamiRs in various hypoxia associated biological processes, including apoptosis, survival, proliferation, angiogenesis, inflammation, and metabolism. From a clinical perspective, we also discuss the potential use of hypoxamiRs as new biomarkers and/or therapeutic targets in cancer and aging-associated diseases including cardiovascular and fibroproliferative disorders. PMID- 28729030 TI - Natural language processing systems for capturing and standardizing unstructured clinical information: A systematic review. AB - We followed a systematic approach based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses to identify existing clinical natural language processing (NLP) systems that generate structured information from unstructured free text. Seven literature databases were searched with a query combining the concepts of natural language processing and structured data capture. Two reviewers screened all records for relevance during two screening phases, and information about clinical NLP systems was collected from the final set of papers. A total of 7149 records (after removing duplicates) were retrieved and screened, and 86 were determined to fit the review criteria. These papers contained information about 71 different clinical NLP systems, which were then analyzed. The NLP systems address a wide variety of important clinical and research tasks. Certain tasks are well addressed by the existing systems, while others remain as open challenges that only a small number of systems attempt, such as extraction of temporal information or normalization of concepts to standard terminologies. This review has identified many NLP systems capable of processing clinical free text and generating structured output, and the information collected and evaluated here will be important for prioritizing development of new approaches for clinical NLP. PMID- 28729031 TI - Knockout of the urate oxidase gene provides a stable mouse model of hyperuricemia associated with metabolic disorders. AB - The urate oxidase (Uox) gene encodes uricase that in the rodent liver degrades uric acid into allantoin, forming an obstacle for establishing stable mouse models of hyperuricemia. The loss of uricase in humans during primate evolution causes their vulnerability to hyperuricemia. Thus, we generated a Uox-knockout mouse model on a pure C57BL/6J background using the transcription activator-like effector nuclease (TALEN) technique. These Uox-knockout mice spontaneously developed hyperuricemia (over 420 MUmol/l) with about 40% survival up to 62 weeks. Renal dysfunction (elevated serum creatinine and blood urea nitrogen) and glomerular/tubular lesions were observed in these Uox-knockout mice. Male Uox knockout mice developed glycol-metabolic disorders associated with compromised insulin secretion and elevated vulnerability to streptozotocin-induced diabetes, whereas female mice developed hypertension accompanied by aberrant lipo metabolism. Urate-lowering drugs reduced serum uric acid and improved hyperuricemia-induced disorders. Thus, uricase knockout provides a suitable mouse model to investigate hyperuricemia and associated disorders mimicking the human condition, suggesting that hyperuricemia has a causal role in the development of metabolic disorders and hypertension. PMID- 28729032 TI - A novel model of autosomal recessive polycystic kidney questions the role of the fibrocystin C-terminus in disease mechanism. AB - Autosomal recessive polycystic kidney disease (OMIM 263200) is a serious condition of the kidney and liver caused by mutations in a single gene, PKHD1. This gene encodes fibrocystin/polyductin (FPC, PD1), a large protein shown by in vitro studies to undergo Notch-like processing. Its cytoplasmic tail, reported to include a ciliary targeting sequence, a nuclear localization signal, and a polycystin-2 binding domain, is thought to traffic to the nucleus after cleavage. We now report a novel mouse line with a triple HA-epitope "knocked-in" to the C terminus along with lox P sites flanking exon 67, which encodes most of the C terminus (Pkhd1Flox67HA). The triple HA-epitope has no functional effect as assayed by phenotype and allows in vivo tracking of Fibrocystin. We used the HA tag to identify previously predicted Fibrocystin cleavage products in tissue. In addition, we found that Polycystin-2 fails to co-precipitate with Fibrocystin in kidney samples. Immunofluorescence studies with anti-HA antibodies demonstrate that Fibrocystin is primarily present in a sub-apical location the in kidney, biliary duct, and pancreatic ducts, partially overlapping with the Golgi. In contrast to previous studies, the endogenous protein in the primary cilia was not detectable in mouse tissues. After Cre-mediated deletion, homozygous Pkhd1Delta67 mice are completely normal. Thus, Pkhd1Flox67HA is a valid model to track Pkhd1 derived products containing the C-terminus. Significantly, exon 67 containing the nuclear localization signal and the polycystin-2 binding domain is not essential for Fibrocystin function in our model. PMID- 28729033 TI - Metabolic acidosis is common and associates with disease progression in children with chronic kidney disease. AB - Recent studies in adult chronic kidney disease (CKD) suggest that metabolic acidosis is associated with faster decline in estimated glomerular filtration rate (eGFR). Alkali therapies improve the course of kidney disease. Here we investigated the prevalence and determinants of abnormal serum bicarbonate values and whether metabolic acidosis may be deleterious to children with CKD. Associations between follow-up serum bicarbonate levels categorized as under 18, 18 to under 22, and 22 or more mmol/l and CKD outcomes in 704 children in the Cardiovascular Comorbidity in Children with CKD Study, a prospective cohort of pediatric patients with CKD stages 3-5, were studied. The eGFR and serum bicarbonate were measured every six months. At baseline, the median eGFR was 27 ml/min/1.73m2 and median serum bicarbonate level 21 mmol/l. During a median follow-up of 3.3 years, the prevalence of metabolic acidosis (serum bicarbonate under 22 mmol/l) was 43%, 60%, and 45% in CKD stages 3, 4, and 5, respectively. In multivariable analysis, the presence of metabolic acidosis as a time-varying covariate was significantly associated with log serum parathyroid hormone through the entire follow-up, but no association with longitudinal growth was found. A total of 211 patients reached the composite endpoint (ESRD or 50% decline in eGFR). In a multivariable Cox model, children with time-varying serum bicarbonate under 18 mmol/l had a significantly higher risk of CKD progression compared to those with a serum bicarbonate of 22 or more mmol/l (adjusted hazard ratio 2.44; 95% confidence interval 1.43-4.15). Thus, metabolic acidosis is a common complication in pediatric patients with CKD and may be a risk factor for secondary hyperparathyroidism and kidney disease progression. PMID- 28729034 TI - Prolonged renal survival in light chain amyloidosis: speed and magnitude of light chain reduction is the crucial factor. AB - Renal involvement causing progressive chronic kidney disease (CKD) is present in 70% of patients with systemic Ig light-chain (AL) amyloidosis at diagnosis. Chemotherapy that substantially suppresses free light chain production is associated with improved patient survival, but its benefit in delaying the onset of renal replacement therapy among patients who present with established advanced CKD has not been studied. To evaluate this, we studied 1000 patients enrolled in the prospective UK AL amyloidosis chemotherapy study (ALchemy). Of these, 84 patients had advanced amyloid-related CKD defined by an estimated glomerular filtration rate (eGFR) under 20 ml/min/1.73 m2. We determined outcomes among these 84 patients, who had a median eGFR of 10 ml/min/1.73 m2, in relation to response to chemotherapy evaluated at three, six, and 12 months from baseline. Patients who achieved suppression of 90% or more in their amyloidogenic free light chain (dFLC) within three months of baseline had significantly better overall survival, prolonged time to dialysis, and prolonged time to the composite endpoint of 'death or dialysis' compared to those who achieved lesser degrees of clonal response at the same time point. Even when this target of greater than 90% dFLC response was achieved but was delayed beyond 3 months, it was associated with worse outcomes. Cox regression analyses confirmed that a 90% or better dFLC response within 3 months was the only significant independent predictor of all three of these outcome measures. Thus, renal survival among patients with systemic immunologic light chain amyloidosis who present with advanced CKD is strongly dependent upon the magnitude and speed with which the underlying hematologic disorder is suppressed by chemotherapy. PMID- 28729035 TI - A novel CFHR1-CFHR5 hybrid leads to a familial dominant C3 glomerulopathy. AB - The intrinsic similarity shared between the members of the complement factor H family, which comprises complement factor H and five complement factor H-related (CFHR) genes, leads to various recombination events. In turn these events lead to deletions of some genes or abnormal proteins, which are found in patients with atypical hemolytic uremic syndrome or C3 glomerulopathies. Here we describe a novel genetic rearrangement generated from a heterozygous deletion spanning 146 Kbp involving multiple CFHR genes leading to a CFHR1-R5 hybrid protein. This deletion was found in four family members presenting with a familial dominant glomerulopathy histologically classified as an overlap of dense deposit disease and C3 glomerulonephritis. Affected patients exhibited permanently low C3 and factor B levels and high amounts of activation fragments sC5b9 and Bb, indicating a systemic alternative pathway dysregulation. The abnormal protein, characterized by Western blot and immunoprecipitation, was shown to circulate in association with CFHR1 and CFHR2, attributable to its two N-terminal dimerization motifs. The presence of this protein is associated with a perturbation of Factor H activity on the C3 convertase decay. Thus, our study highlights the role of CFHRs in the physiopathology of C3 glomerulopathies and stresses the importance of screening CFHRs in all familial C3 glomerulopathies. Such hybrids described till now were always associated with familial forms. PMID- 28729036 TI - Molecular mechanisms of renal aging. AB - Epidemiologic, clinical, and molecular evidence suggest that aging is a major contributor to the increasing incidence of acute kidney injury and chronic kidney disease. The aging kidney undergoes complex changes that predispose to renal pathology. The underlying molecular mechanisms could be the target of therapeutic strategies in the future. Here, we summarize recent insight into cellular and molecular processes that have been shown to contribute to the renal aging phenotype.The main clinical finding of renal aging is the decrease in glomerular filtration rate, and its structural correlate is the loss of functioning nephrons. Mechanistically, this has been linked to different processes, such as podocyte hypertrophy, glomerulosclerosis, tubular atrophy, and gradual microvascular rarefaction. Renal functional recovery after an episode of acute kidney injury is significantly worse in elderly patients. This decreased regenerative potential, which is a hallmark of the aging process, may be caused by cellular senescence. Accumulation of senescent cells could explain insufficient repair and functional loss, a view that has been strengthened by recent studies showing that removal of senescent cells results in attenuation of renal aging. Other potential mechanisms are alterations in autophagy as an important component of a disturbed renal stress response and functional differences in the inflammatory system. Promising therapeutic measures to counteract these age-related problems include mimetics of caloric restriction, pharmacologic renin-angiotensin-aldosterone system inhibition, and novel strategies of senotherapy with the goal of reducing the number of senescent cells to decrease aging-related disease in the kidney. PMID- 28729037 TI - Increased gyrification in schizophrenia and non affective first episode of psychosis. AB - BACKGROUND: Prefrontal cortex gyrification has been suggested to be altered in patients with schizophrenia and first episode psychosis. Therefore, it may represent a possible trait marker for these illnesses and an indirect evidence of a disrupted underlying connectivity. The aim of this study was to add further evidence to the existing literature on the role of prefrontal gyrification in psychosis by carrying out a study on a sizeable sample of chronic patients with schizophrenia and non-affective first-episode psychosis (FEP-NA) patients. METHODS: Seventy-two patients with schizophrenia, 51 FEP-NA patients (12 who later develop schizophrenia) and 95 healthy controls (HC) underwent magnetic resonance imaging (MRI). Cortical folding was quantified using the automated gyrification index (GI). GI values were compared among groups and related to clinical variables. RESULTS: Both FEP-NA and patients with schizophrenia showed a higher mean prefrontal GI compared to HC (all p<0.05). Interestingly, no differences have been observed between the two patients groups as well as between FEP-NA patients who did and did not develop schizophrenia. CONCLUSIONS: Our results suggest the presence of a shared aberrant prefrontal GI in subjects with both schizophrenia and first-episode psychosis. These findings support the hypothesis that altered GI represents a neurodevelopmental trait marker for psychosis, which may be involved in the associated neurocognitive deficits. PMID- 28729038 TI - Spatial-temporal distribution and risk assessment of mercury in different fractions in surface sediments from the Yangtze River estuary. AB - The temporal and spatial distributions of mercury in different fractions and its potential ecological risk were investigated in sediments from the Yangtze River estuary (YRE) by analyzing data collected from the study area. The results showed that mercury in the organic and residual fractions had dominant proportions, from 15.2% to 48.52% and from 45.96% to 81.59%, respectively. The fractions were more susceptible to seasonal changes than other fractions. Higher proportions of mercury in organic fraction were found in wet seasons; the opposite was true for mercury in residual fraction. With respect to the spatial distribution, the concentration mercury in exchangeable, carbonate and Fe-Mn oxide fractions showed a decreasing trend from the inner estuary to the outer estuary, but no obvious trends were found in the distributions of mercury in the organic and residual fractions. The risk assessment code (RAC) was used to evaluate the potential ecological risk in the study area based on the proportions of exchangeable and carbonate fractions. The average RAC values during the four periods were 6.00%, 2.20%, 2.83%, and 0.61%. Although these values show that the risk in the study area is generally low, the distribution of RAC values indicates that the inner estuary has a medium risk, with a value up to 10%. PMID- 28729039 TI - Congenital myopathy due to myosin heavy chain 2 mutation presenting as chronic aspiration pneumonia in infancy. AB - A 7-week-old infant presented with persistent noisy breathing and aspirations during swallowing. Neurological examination and brain MRI were normal. His 12 year-old brother underwent pneumonectomy at the age of 10 years due to recurrent aspirations leading to severe lung damage. The older brother developed subsequently ophthalmoplegia and nystagmus along with mild weakness of the neck flexors and proximal muscles. Exome analysis revealed homozygosity for a novel truncating mutation p.G800fs27* in the Myosin Heavy Chain 2 (MYH2) gene in both brothers, while parents and an unaffected sibling were heterozygous. A muscle biopsy from the older brother showed absence of type-2 muscle fibers and predominance of type-1 fibers. The aspirations causing pneumonia likely result from weakness of the laryngeal muscles, normally rich in type-2 fibers. The findings expand the phenotypic spectrum of MYH2 deficiency. MYH2 mutations should be included in the differential diagnosis of infants presenting with recurrent aspirations. PMID- 28729040 TI - [Long-term effects of intensive intervention on changes in lifestyle in patients with hyperfibrinogenaemia and moderate-high cardiovascular risk]. AB - OBJECTIVES: To determine whether the benefit on cardiovascular risk factors (CVRF) persists 5 years after an intensive intervention in lifestyle (LS) that lasted 2 years, in patients with hyperfibrinogenaemia and moderate or high cardiovascular risk. DESIGN: multicentre prospective observational study. LOCATION: 13 Primary Care Centres in Barcelona and Baix Llobregat. PARTICIPANTS: A total of 300 patients who completed the EFAP study (146 intervention group, 154 control group). INTERVENTIONS: The EFAP study, conducted on patients with normal cholesterol and elevated fibrinogen showed that lifestyle interventions are effective in reducing CVRF. After the EFAP study, the 2 groups followed the usual controls, and re-assessed after 5 years. MAIN MEASUREMENTS: Age, gender, cardiovascular diseases (CVD) (diabetes, dyslipidaemia, hypertension, obesity), laboratory parameters (fibrinogen, glucose, full blood count, cholesterol, triglycerides), blood pressure, weight, height, body mass index (BMI), tobacco and alcohol use, REGICOR. RESULTS: At 5 years, the intervention group had a lower abdominal circumference (98 and 101cm, respectively, P=.043), a lower weight (76.30 and 75.04kg, respectively, P<.001), and BMI (29.5 and 30.97kg/m2, P=.018). Fibrinogen level was lower in the intervention group (330.33 and 320.27 mg/dl respectively, P < .001), and REGICOR risk was also lower in the intervention group (5.65 and 5.59 respectively, P < .06). CONCLUSION: The benefit of an intensive intervention in LS for 2 years to reduce CVRF persists at 5 years, but decreases its intensity over time. It is recommended to repeat the interventions periodically to maintain the beneficial effect on LS. PMID- 28729041 TI - Pharmacological preclinical characterization of LAS190792, a novel inhaled bifunctional muscarinic receptor antagonist /beta2-adrenoceptor agonist (MABA) molecule. AB - LAS190792 is a novel muscarinic antagonist and beta2-adrenoceptor agonist in development for chronic respiratory diseases. This study investigated the pharmacological profile of LAS190792 in comparison to batefenterol, tiotropium, indacaterol and olodaterol. LAS190792 is potent at the human M3 receptor (pIC50: 8.8 in binding assays). It is selective for the beta2-adrenoceptor over the beta1 and beta3-adrenoceptor, and shows a functional potency in a similar range to batefenterol and LABA compounds (pEC50 in spontaneous tone isolated trachea: 9.6). The relaxant potency of LAS190792 in electrically stimulated tissue is similar to batefenterol, with an antimuscarinic activity in presence of propranolol slightly higher than batefenterol (pIC50 of 8.3 versus 7.9 in human tissue). LAS190792 exhibits a sustained duration of action in isolated tissue longer than that of batefenterol. Nebulized LAS190792 inhibits acetylcholine induced bronchoconstriction in dog with minimal cardiac effects and sustained bronchodilation (t1/2: 13.3 h). In conclusion, these studies suggest that LAS190792 is a dual-acting muscarinic antagonist beta2-adrenoceptor agonist that has the potential to be a next generation bronchodilator with long-lasting effects and wide safety margin in humans. PMID- 28729043 TI - Individualized Assessment of Fracture Risk: Contribution of "Osteogenomic Profile". AB - Over the past decade, several genetic variants or genes for osteoporosis have been identified through genome-wide association studies and candidate gene association studies. These genetic variants are common in the general population but have modest effect sizes, with odds ratio ranging from 1.1 to 1.5. Thus, the utility of any single variant is limited. However, theoretical and empirical studies have suggested that a profiling of multiple variants that are associated with bone phenotypes (i.e., "osteogenomic profile") can improve the accuracy of fracture prediction and classification beyond that obtained by conventional clinical risk factors. These results support the view that an osteogenomic profile, when integrated into existing models, can help clinicians and patients alike to better assess the risk fracture for an individual, and raise the possibility of personalized osteoporosis care. PMID- 28729042 TI - Effects of beta-blockers on house dust mite-driven murine models pre- and post development of an asthma phenotype. AB - BACKGROUND: Our previous studies suggested certain beta-adrenoceptor blockers (beta-blockers) attenuate the asthma phenotype in ovalbumin driven murine models of asthma. However, the ovalbumin model has been criticized for lack of clinical relevance. METHODS: We tested the non-selective beta-blockers, carvedilol and nadolol, in house dust mite (HDM) driven murine asthma models where drugs were administered both pre- and post-development of the asthma phenotype. We measured inflammation, mucous metaplasia, and airway hyper-responsiveness (AHR). We also measured the effects of the beta-blockers on extracellular-signal regulated kinase (ERK 1/2) phosphorylation in lung homogenates. RESULTS: We show that nadolol, but not carvedilol, attenuated inflammation and mucous metaplasia, and had a moderate effect attenuating AHR. Following HDM exposure, ERK1/2 phosphorylation was elevated, but the level of phosphorylation was unaffected by beta-blockers, suggesting ERK1/2 phosphorylation becomes dissociated from the asthma phenotype. CONCLUSION: Our findings in HDM models administering drugs both pre- and post-development of the asthma phenotype are consistent with previous results using ovalbumin models and show differential effects for nadolol and carvedilol on the asthma phenotype. Lastly, our data suggest that ERK1/2 phosphorylation may be involved in development of the asthma phenotype, but may have a limited role in maintaining the phenotype. PMID- 28729044 TI - The Clinical Utility of Vertebral Fracture Assessment in Predicting Fractures. AB - Vertebral fracture (VF) is the most common type of osteoporotic fracture. VFs are associated with diminished quality of life and high morbidity and mortality. The presence of a VF, especially a recent one, is an important risk factor for developing another fracture. However, most VFs are not clinically recognized. VF assessment by dual-energy X-ray absorptiometry is a convenient, low-cost, low radiation, reliable method to identify VFs during bone mineral density measurement. The finding of a previously unrecognized VF may change the diagnostic classification, assessment of fracture risk, and treatment strategies. This paper focuses on the utility of VF assessment in clinical practice. PMID- 28729045 TI - Fracture Risk Assessment: From Population to Individual. AB - Fracture caused by osteoporosis remains a major public health burden on contemporary populations because fracture is associated with a substantial increase in the risk of mortality. Early identification of high-risk individuals for prevention is a priority in osteoporosis research. Over the past decade, few risk prediction models, including the Garvan Fracture Risk Calculator (Garvan) and FRAX(r), have been developed to provide absolute (individualized) risk of fracture. Recent validation studies suggested that the area under the receiver operating characteristic curve in fracture discrimination ranged from 0.61 to 0.83 for FRAX(r) and from 0.63 to 0.88 for Garvan, with hip fractures having a better discrimination than fragility fractures as a group. Although the prognostic performance of Garvan and FRAX(r) for fracture prediction is not perfect and there is room for further improvement, these predictive models can aid patients and doctors communicate about fracture risk in the medium term and to make rational decisions. However, the application of these predictive models in making decisions for an individual should take into account the individual's perception of the importance of fracture relative to other diseases. PMID- 28729046 TI - Bone Mineralization and Fracture Risk Assessment in the Pediatric Population. AB - Identifying children most susceptible to clinically significant fragility fractures (low trauma fractures or vertebral compression fractures) or recurrent fractures is an important issue facing general pediatricians and subspecialists alike. Over the last decade, several imaging technologies, including dual-energy X-ray absorptiometry and peripheral quantitative computed tomography, have become useful to identify abnormal bone mineralization in children and in adolescents. This review aimed to summarize the latest literature on the utility of these modalities as they pertain to use in pediatrics. In addition, we review several disease states associated with poor bone health and increased fracture risk in children, and discuss the implications of low bone mineral density in these patients. Finally, we will highlight the gaps in knowledge with regard to pediatric bone health and make recommendations for future areas of research. PMID- 28729047 TI - P53 deregulation in Epstein-Barr virus-associated gastric cancer. AB - TP53 is a tumour suppressor gene frequently mutated in human cancers; nevertheless, in EBV-associated malignancies mutations are uncommon despite frequent deregulation of the p53 pathway. In this study, we aimed to investigate p53 expression, TP53 mRNA levels and TP53 mutations in EBV-associated gastric carcinoma (EBVaGC). A case-control study was performed using 46 patients: 15 EBVaGC and 31 EBV-negative GC (EBVnGC) cases. p53 expression was detected by immunohistochemistry (IHC), the evaluation of p53 mRNA levels was performed by RT qPCR and TP53 mutations were investigated only in EBVaGC cases using the DNA sanger sequencing method. p53 expression was found in 97.8% (45/46) of all gastric cancer cases (including EBVaGC and EBVnGC groups). Despite the high frequency of p53 expression in both groups, the percentages of cells are significantly higher among EBVaGC cases (p = 0.027). Regarding the mRNA levels, we found a significantly increased expression of p53 mRNA in EBVnGC (2 DeltaDeltaCt = 13.4 +/- 2.4; p = 0.0029) when compared with EBVaGC. Furthermore, the sequencing analysis of TP53 gene revealed that only one of the 15 EBVaGC cases presented a missense mutation. Our results demonstrated that EBV-associated gastric carcinomas are characterized by a significant decrease of TP53 mRNA levels with a strong p53 expression and rare TP53 mutations when compared with EBV-negative cancers. Considering these results, EBV seems to induce a stabilization of p53 in the EBVaGC independently of the presence of mutations, which remains to be explained. PMID- 28729048 TI - Modified-FOLFIRINOX in metastatic pancreatic cancer: A prospective study in Chinese population. AB - FOLFIRINOX chemotherapy has shown remarkable responses in patients with metastatic pancreatic cancer (MPC), and has significantly improved prognosis. However, FOLFIRINOX is currently not frequently applied in China because of its high incidence of adverse events, and there is no recognized optimization for this therapy in Chinese population. Modification of FOLFIRINOX may be better for its acceptance in China. In this study, we evaluated the efficacy and safety of modified-FOLFIRINOX in patients with MPC. A total of 62 MPC patients were treated with modified-FOLFIRINOX (no Fluorouracil bolus, 85% Oxaliplatin and 75% Irinotecan) between April 2014 and April 2017 in our institute. 40 of them were evaluated, with a response rate of 32.5% (13/40). The frequent grade 3/4 adverse events are neutropenia (29%) and alanine aminotransferase elevation (14.5%). No treatment-related death was observed. The median overall survival and median progression-free survival are 10.3 months and 7.0 months, respectively. In conclusion, modified-FOLFIRINOX had significantly improved tolerance with similar efficacy to FOLFIRINOX. These findings may provide evidence for the use of FOLFIRINOX in Chinese patients with MPC. PMID- 28729049 TI - Quantification of metastatic load in a syngeneic murine model of metastasis. AB - Bioluminescence imaging (BLI) is an established method for evaluating metastatic load in preclinical cancer models; however, BLI can produce observational error due to differences in substrate concentration and signal depth. In our syngeneic murine model of metastasis (VM-M3), we used a quantitative polymerase chain reaction (qPCR) method of DNA quantification to bypass these limitations. Liver, spleen, and brain from VM/Dk (VM) mice bearing VM-M3 tumor cells were first imaged ex vivo with BLI. qPCR quantification of tumor cell DNA was then performed on DNA extracted from these organs. Linear regression indicated that qPCR data predicted BLI data in solid tissue. Furthermore, the tumor cell detection limit was lower for qPCR analysis than for BLI analysis. In order to validate qPCR for use in detecting blood metastases, qPCR quantification was performed on whole blood collected from mice whose global organ metastatic load (summation of liver, spleen, kidneys, lungs, and brain) was quantified through BLI. Linear regression indicated that qPCR data in blood predicted BLI data in solid tissue. The results demonstrate that qPCR is an accurate and sensitive method of metastatic quantification in syngeneic murine models. PMID- 28729050 TI - An infant with concurrent serotype 6C invasive pneumococcal disease and infectious mononucleosis. AB - Streptococcus pneumoniae is a main causative agent of serious invasive bacterial infections. However, concurrent infection with invasive pneumococcal disease (IPD) and viral infectious mononucleosis (IM) is rare. We report an infant with serotype 6C infection causing IPD occurring simultaneously with IM. A previously healthy 11-month-old girl referred to our hospital because of fever, leukopenia, and elevated C-reactive protein presented to us with disturbance of consciousness, tachycardia, tachypnea and agranulocytosis. Other findings included tonsillitis with purulent exudates and white spots, bilateral cervical adenopathy, and hepatosplenomegaly. We diagnosed her illness as sepsis and administered a broad-spectrum antibiotic, an antiviral agent, and granulocyte transfusions. After treatment was initiated, fever gradually decreased and general condition improved. IPD was diagnosed based upon isolation of S. pneumoniae of serotype 6C from blood cultures obtained on admission. Concurrently the girl had IM, based upon quantitation of Epstein-Barr viral DNA copies in blood and fluctuating serum antibody titers. Although simultaneous IPD and IM is a rare occurrence, this possibility is important to keep in mind. PMID- 28729051 TI - Inhibiting effects of fructanase on competence-stimulating peptide-dependent quorum sensing system in Streptococcus mutans. AB - Streptococcus mutans produces glucosyltransferases encoded by the gtfB and gtfC genes, which synthesize insoluble glucan, and both insoluble and soluble glucans by conversion of sucrose, and are known as principal agents to provide strong biofilm formation and demineralization on tooth surfaces. S. mutans possess a Com dependent quorum sensing (QS) system, which is important for survival in severe conditions. The QS system is stimulated by the interaction between ComD {Receptor to competence-stimulating peptide (CSP)} encoded by the comD and CSP encoded by the comC, and importantly associated with bacteriocin production and genetic competence. Previously, we found enzyme fructanase (FruA) as a new inhibitor for the glucan-dependent biofilm formation. In the present study, inhibiting effects by FruA on glucan-independent biofilm formation of S. mutans UA159, UA159.gtfB-, UA159.gtfC-, and UA159.gtfBC- were observed in sucrose and no sucrose sugars supplemented conditions using the plate assay. The reduction of UA159.comC- and UA159.comD- biofilm formation were also observed as compared with UA159 in same conditions. These results suggested that inhibitions of glucan-independent and Com-dependent biofilm formation were involved in the inhibiting mechanism by FruA. To more thoroughly investigate effects by FruA on the QS system, we examined on CSP-stimulated and Com-dependent bacteriocin production and genetic transformation. FruA inhibited bacteriocin production in collaboration with CSP and genetic transformation in bacterial cell conditions treated with FruA. Our findings show that FruA has multiple effects that inhibit survival functions of S. mutans, including biofilm formation and CSP-dependent QS responses, indicating its potential use as an agent for prevention of dental caries. PMID- 28729052 TI - Tedizolid inhibits MUC5AC production induced by methicillin-resistant Staphylococcus aureus in human airway epithelial cells. AB - The innate immune system plays an important role in early immunity against respiratory tract infection. Although airway epithelial cells produce mucus to eliminate pathogens and irritants, hypersecretion of mucus is harmful for the host as it may cause airway obstruction and inhibit influx of antimicrobial agents. It has been reported that several antimicrobial agents have an immunomodulatory effect in vitro and in vivo, but little is known about whether tedizolid, a novel oxazolidinone, can modulate immune responses. In this study, we evaluated whether tedizolid can suppress MUC5AC production in human airway epithelial cells stimulated by methicillin-resistant Staphylococcus aureus (MRSA). Compared with the control, tedizolid significantly inhibited MUC5AC protein production and mRNA overexpression at concentrations of both 2 and 10 MUg/mL (representative of trough and peak concentrations in human epithelial lining fluid). Among the mitogen-activated protein kinase inhibitors tested, only extracellular signal-regulated protein kinase 1/2 (ERK1/2) phosphorylation was inhibited by tedizolid as indicated by western blot analysis. These results indicate that tedizolid inhibits the overproduction of MUC5AC protein by inhibiting phosphorylation of ERK1/2. This study revealed that tedizolid suppresses excessive mucin production in human airway epithelial cells. The immunomodulatory effect of tedizolid may improve outcomes in patients with severe respiratory infectious diseases caused by MRSA. PMID- 28729053 TI - Bioactive polyprenylated benzophenone derivatives from the fruits extracts of Garcinia xanthochymus. AB - Two new polycyclic prenylated xanthones (1 and 2) and a new phenylpropanoid glycoside (3), along with seven known compounds (4-10) were isolated from the fruits of Garcinia xanthochymus. The structures were elucidated by 1D- and 2D NMR, and HRMS experiments. The isolates were evaluated for their inhibitory effects against the viability of U251MG glioblastoma and MDA-MB-231 breast cancer cells that harbor an aberrantly active signal transducer and exhibit activation of transcription 3 (STAT3), and compared to normal NIH3T3 mouse fibroblasts. Among the isolates, compounds 1, 2, 5, and 6-9 inhibited the viability of glioma cancer cells with IC50 values in the range of 1.6-6.5MUM. Furthermore, treatment of U251MG with 6 and 7 inhibited intracellular STAT3 tyrosine phosphorylation and glioma cell migration in vitro, respectively. PMID- 28729054 TI - Isosorbide-based peptidomimetics as inhibitors of hepatitis C virus serine protease. AB - Hepatitis C infection is a cause of chronic liver diseases such as cirrhosis and carcinoma. The current therapy for hepatitis C has limited efficacy and low tolerance. The HCV encodes a serine protease which is critical for viral replication, and few protease inhibitors are currently on the market. In this paper, we describe the synthesis and screening of novel isosorbide-based peptidomimetic inhibitors, in which the compounds 1d, 1e, and 1i showed significant inhibition of the protease activity in vitro at 100uM. The compound 1e also showed dose-response (IC50=36+/-3uM) and inhibited the protease mutants D168A and V170A at 100uM, indicating it as a promising inhibitor of the HCV NS3/4A protease. Our molecular modeling studies suggest that the activity of 1e is associated with a change in the interactions of S2 and S4 subsites, since that the increased flexibility favors a decrease in activity against D168A, whereas the appearance of a hydrophobic cavity in the S4 subsite increase the inhibition against V170A strain. PMID- 28729055 TI - Novel 1,2-dihydroquinazolin-2-ones: Design, synthesis, and biological evaluation against Trypanosoma brucei. AB - In 2014, a published report of the high-throughput screen of>42,000 kinase inhibitors from GlaxoSmithKline against T. brucei identified 797 potent and selective hits. From this rich data set, we selected NEU-0001101 (1) for hit-to lead optimization. Through our preliminary compound synthesis and SAR studies, we have confirmed the previously reported activity of 1 in a T. brucei cell proliferation assay and have identified alternative groups to replace the pyridyl ring in 1. Pyrazole 24 achieves improvements in both potency and lipophilicity relative to 1, while also showing good in vitro metabolic stability. The SAR developed on 24 provides new directions for further optimization of this novel scaffold for anti-trypanosomal drug discovery. PMID- 28729057 TI - Neuropathic pain-alleviating effects of pyrazole-conjugated arylsulfonamides as 5 HT6 receptor antagonists. AB - A novel series of arylsulfonylaminomethyl-3-(1-phenyl-5-isopropyl)pyrazoles was evaluated for serotonin receptor subtype 6 (5-HT6R) antagonistic effects in vitro. We also investigated their neuropathic pain-alleviating effects in vivo using a rat spinal nerve ligation (SNL) model. Bicyclic aromatic sulfonamino groups, such as naphthalene and quinolin-substituted derivatives, showed good 5 HT6 inhibitory activity in vitro. Among them, selected compounds, 12 and 13, having 8-quinoylsulfonamino groups, showed potent neuropathic pain-alleviating effects in the rat model. PMID- 28729056 TI - Discovery and structure-activity relationship of auriculatone: A potent hepatoprotective agent against acetaminophen-induced liver injury. AB - Acetaminophen (APAP, paracetamol) overdose has been the most frequent cause of drug-induced liver failure. APAP-induced liver toxicity can be fatal in many cases even with treatment of the clinically used N-acetylcysteine (NAC), and the need for novel therapeutic agents is apparent. Through evaluating the hepatoprotective effects of the co-occurring substances present in oleanolic acid tablets which have been used in China for decades as an adjuvant therapy for acute and chronic hepatitis, auriculatone was found to protect HL-7702 cells from APAP-induced liver injury comparable to NAC at the concentration of 10MUM. Structure activity relationship on auriculatone and its analogs showed that absence of the C17 carboxyl group of auriculatone was essential to achieve good hepatoprotective activity, and that the C3-OH, C16 carbonyl and C12-C13 olefinic group were critical for retaining the exceptional activity of auriculatone. Any modifications in the current investigation were all detrimental to the hepatoprotective activity. Docking and drug-metabolizing activity studies demonstrated that CYP3A4 was likely the main target of auriculatone, and that auriculatone elicited the hepatoprotective effect possibly through inhibiting CYP3A4's metabolism of APAP to the toxic metabolite NAPQI. The work may pave the way for the use of auriculatone in the treatment of APAP-induced liver injury. PMID- 28729058 TI - Impacts of Sensation, Perception, and Motor Abilities of the Ipsilesional Upper Limb on Hand Functions in Unilateral Stroke: Quantifications From Biomechanical and Functional Perspectives. AB - BACKGROUND: The presence of subtle losses in hand dexterity after stroke affects the regaining of independence with regard to activities of daily living. Therefore, awareness of ipsilesional upper extremity (UE) function may be of importance when developing a comprehensive rehabilitation program. However, current hand function tests seem to be unable to identify asymptomatic UE impairments. OBJECTIVES: To assess the motor coordination as well as the sensory perception of an ipsilesional UE using biomechanical analysis of performance oriented tasks and conducting a Manual Tactile Test (MTT). DESIGN: Case controlled study. SETTING: A university hospital. PARTICIPANTS: A total of 21 patients with unilateral stroke, along with 21 matched healthy control subjects, were recruited. METHODS: Each participant was requested to perform a pinch holding-up activity (PHUA) test, object-transport task, and reach-to-grasp task via motion capture, as well as the MTT. MAIN OUTCOME MEASUREMENTS: The kinetic data of the PHUA test, kinematics analysis of functional movements, and time requirement of MTT were analyzed. RESULTS: Patients with ipsilesional UE had an inferior ability to scale and produce pinch force precisely when conducting the PHUA test compared to the healthy controls (P < .05). The movement time was statistically longer and peak velocity was significantly lower (P < .05) in the performance-oriented tasks for the ipsilesional UE patients. The longer time requirement in 3 MTT subtests showed that the ipsilesional UE patients experienced degradation in sensory perception (P < .001). CONCLUSION: Comprehensive sensorimotor assessments based on functional perspectives are valid tools to determine deficits in the sensation-perception-motor system in the ipsilesional UE. Integration of sensorimotor training programs for ipsilesional UE in future neuro-rehabilitation strategies may provide more beneficial effects to regain patients' motor recovery and to promote daily living activity independence than focusing on paretic arm motor training alone. LEVEL OF EVIDENCE: III. PMID- 28729059 TI - Ultrasonographic Assessment of Femoral Cartilage Thickness in Patients With Cerebral Palsy. AB - BACKGROUND: Cerebral palsy (CP) is one of the most disabling syndromes in children. To our knowledge, there has not yet been any reported evaluation by ultrasonography of the effect of CP on distal femoral cartilage. The value of understanding this effect on cartilage is that sonographic evaluation of cartilage thickness may help physicians to predict the joint health of these children. OBJECTIVE: To determine whether femoral cartilage thickness in patients with CP is different from that in healthy control subjects. DESIGN: Cross sectional study. SETTING: National tertiary rehabilitation center. PATIENTS: The study included 40 patients with diplegic CP (23 male and 17 female) and 51 healthy control subjects (29 male and 22 female). METHODS: Demographic and clinical characteristics were recorded. Cartilage thicknesses were measured. MAIN OUTCOME MEASURE: Cartilage thickness measurements were taken from the medial and lateral condyles, and intercondylar areas of both knees. RESULTS: Both groups were similar in terms of age, gender, and weight (P > .05). The mean cartilage thickness measurements of the medial condyle and intercondylar area of knees in the CP group were significantly less than those in the healthy control group (all P < .05). There was moderate negative correlation between age and all femoral cartilage thickness measurements in the CP group. There was no correlation between age and femoral cartilage thickness measurements in the healthy group. There was a negative correlation between Gross Motor Functional Classification System levels and cartilage thickness in the CP group. The highest cartilage thickness measurements were detected in level 1 patients, and the lowest measurements were detected in level 5 patients. CONCLUSION: This study showed that patients with CP have a thinner femoral cartilage than healthy control subjects. Management of patients with CP should include close surveillance. LEVEL OF EVIDENCE: III. PMID- 28729060 TI - Correlation of Joint Volume and Passive Range of Motion With Capsulo-Synovial Thickness Measured by Contrast-Enhanced Magnetic Resonance Imaging in Adhesive Capsulitis. AB - BACKGROUND: No study has investigated the relationship between the findings of contrast-enhanced magnetic resonance imaging (CE-MRI) and the joint volume of the shoulder, which has been considered the standard reference for diagnosis of adhesive capsulitis (AC). OBJECTIVE: To investigate the relationships among the capsulo-synovial thickness measured by CE-MRI, joint volume, and passive range of motion (ROM) in patients with AC. DESIGN: This was a retrospective study. SETTING: The study took place at an institutional practice. PATIENTS: Medical record of 103 patients (46 male and 57 female), who were treated with sonographically guided intra-articular injection with diagnosis of AC and underwent CE-MRI to rule out other concomitant shoulder disease, were retrospectively reviewed. METHODS: Passive ROM and glenohumeral joint (GHJ) volume were measured before and during sonographically guided injection. The thickness of the enhancing portion of the capsulo-synovium was measured at the axillary recess and rotator interval on CE-MRI. MAIN OUTCOME MEASUREMENTS: The relationship among the thickness of the enhancing portion on CE-MRI, GHJ volume, and passive ROM was analyzed using the Pearson correlation coefficient. RESULTS: Capsulo-synovial thickness measured by CE-MRI at the enhancing portion of the axillary recess inversely correlated with GHJ volume (rho = -0.444, P < .001), whereas at the rotator interval, this finding was not observed. At the axillary recess, the capsulo-synovial thickness inversely correlated with abduction (rho = -0.400, P < .001), forward elevation (rho = -0.378, P < .001), and external rotation (rho = -0.297, P < .01), but at the rotator interval, such statistically significant correlations were not shown. CONCLUSION: The capsulo-synovial thickness measured by CE-MRI at the enhancing portion of the axillary recess could represent obliterated joint capacity and clinical impairment (restricted passive ROM), which could help in diagnosing AC and in differentiating other shoulder diseases that may mimic this condition. LEVEL OF EVIDENCE: III. PMID- 28729061 TI - Biomarkers for Alzheimer Disease: Classical and Novel Candidates' Review. AB - The biomarkers may be useful for predictive diagnosis of Alzheimer's disease (AD). The current challenge is to diagnose it in its preclinical phase. The combination of cerebrospinal fluid (CSF) biomarkers and imaging has been investigated extensively for a number of years. It can provide an increased diagnostic accuracy. This review discusses the contribution of classical biomarkers to predict AD and highlights novel candidates identified as potential markers for AD. We referred to the electronic databases PubMed/Medline and Web of Science to search for articles that were published until February 2016. Sixty-two records were included in qualitative synthesis. In the first section, the results show the contribution of biomarkers to predict and track AD considered as classical biomarkers. In the second section, the results highlight the involvement of novel candidates that should be considered for future evaluation in the characterization of the AD progression. Reported findings open prospect to define noninvasive biomarkers to predict AD before symptoms onset. PMID- 28729062 TI - Pharmacological activation of AMPK inhibits incision-evoked mechanical hypersensitivity and the development of hyperalgesic priming in mice. AB - New therapeutics to manage post-surgical pain are needed to mitigate the liabilities of opioid and other analgesics. Our previous work shows that key modulators of excitability in peripheral nociceptors, such as extracellular signal-regulated kinases (ERK) are inhibited by activation of adenosine monophosphate activated protein kinase (AMPK). We hypothesized that AMPK activation would attenuate acute incision-evoked mechanical hypersensitivity and the development of hyperalgesic priming caused by surgery in mice. Here we have used a variety of administration routes and combinations of AMPK activators to test this hypothesis. Topical administration of a resveratrol-based cream inhibited acute mechanical hypersensitivity evoked by incision and blocked the development of hyperalgesic priming. We also observed that systemic administration of metformin dose-dependently inhibited incision-evoked mechanical hypersensitivity and hyperalgesic priming. Interestingly, low doses of systemic metformin and local resveratrol that had no acute effect were able to mitigate development of hyperalgesic priming. Combined treatment with doses of systemic metformin and local resveratrol that were not effective on their own enhanced the acute efficacy of the individual AMPK activators for post-surgical mechanical pain alleviation and blocked the development of hyperalgesic priming. Finally, we used dorsal root ganglion (DRG) neurons in culture to show that resveratrol and metformin given in combination shift the concentration-response curve for AMPK activation to the left and increase the magnitude of AMPK activation. Therefore, we find that topical administration is an effective treatment route of administration and combining systemic and local treatments led to anti nociceptive efficacy in acute mechanical hypersensitivity at doses that were not effective alone. Collectively our work demonstrates a specific effect of AMPK activators on post-surgical pain and points to novel therapeutic opportunities with potential immediate impact in the clinical setting. PMID- 28729063 TI - EEG source reconstruction evidence for the noun-verb neural dissociation along semantic dimensions. AB - One of the long-standing issues in neurolinguistic research is about the neural basis of word representation, concerning whether grammatical classification or semantic difference causes the neural dissociation of brain activity patterns when processing different word categories, especially nouns and verbs. To disentangle this puzzle, four orthogonalized word categories in Chinese: unambiguous nouns (UN), unambiguous verbs (UV), ambiguous words with noun-biased semantics (AN), and ambiguous words with verb-biased semantics (AV) were adopted in an auditory task for recording electroencephalographic (EEG) signals from 128 electrodes on the scalps of twenty-two subjects. With the advanced current density reconstruction (CDR) algorithm and the constraint of standardized low resolution electromagnetic tomography, the spatiotemporal brain dynamics of word processing were explored with the results that in multiple time periods including P1 (60-90ms), N1 (100-140ms), P200 (150-250ms) and N400 (350-450ms), noun-verb dissociation over the parietal-occipital and frontal-central cortices appeared not only between the UN-UV grammatical classes but also between the grammatically identical but semantically different AN-AV pairs. The apparent semantic dissociation within one grammatical class strongly suggests that the semantic difference rather than grammatical classification could be interpreted as the origin of the noun-verb neural dissociation. Our results also revealed that semantic dissociation occurs from an early stage and repeats in multiple phases, thus supporting a functionally hierarchical word processing mechanism. PMID- 28729064 TI - Effects of Cannabinoid Drugs on Aversive or Rewarding Drug-Associated Memory Extinction and Reconsolidation. AB - Posttraumatic stress and drug use disorders may stem from aberrant memory formation. As the endocannabinoid (eCB) system has a pivotal role in emotional memory processing and related synaptic plasticity, here we seek to review and discuss accumulating evidence on how and where in the brain interventions targeting the eCB system would attenuate outcomes associated with traumatic events and/or drug addiction through memory extinction facilitation or reconsolidation disruption. Currently available data from mouse, rat, monkey and healthy human studies investigating the effects of cannabinoid drugs on extinction and reconsolidation of aversive memories are more consistent than those related to rewarding drug-associated memories. Interventions able to attenuate aversive memories by extinction facilitation or reconsolidation disruption have boosted the anandamide-induced activation of cannabinoid type-1 (CB1) receptors. A still limited number of studies report that CB1 receptor activation could also be effective in facilitating the extinction or disrupting the reconsolidation of rewarding drug-associated memories. The reinstatement of extinguished drug memories (relapse) is reduced by CB1 receptor antagonism. The cannabidiol has shown to be effective in any of the aforementioned cases, albeit its mechanism of action is not fully understood. Brain areas in which cannabinoid drugs induce these effects include the prefrontal cortex, amygdala, hippocampus, and/or nucleus accumbens. The potential role of 2-arachidonoylglycerol (2-AG) and cannabinoid type-2 (CB2) receptors in emotional memory extinction and reconsolidation is currently under investigation. Overall, preclinical data support a closer look into certain cannabinoid drugs owing to their safety and potential therapeutic value against stress-related and drug use disorders. PMID- 28729065 TI - Neural Circuits for Social Cognition: Implications for Autism. AB - Social neuroscience, the study of the neurobiological basis of social behavior, has become a major area of current research in behavioral neuroscience and psychiatry, since many psychiatric disorders are characterized by social deficits. Social behavior refers to the behavioral response with regard to socially relevant information, and requires the perception and integration of social cues through a complex cognition process (i.e. social cognition) that involves attention, memory, motivation and emotion. Neurobiological and molecular mechanisms underlying social behavior are highly conserved across species, and inter- and intra-specific variability observed in social behavior can be explained to large extent by differential activity of this conserved neural network. Human functional magnetic resonance imaging (fMRI) studies have greatly informed about the brain structures and their connectivity networks that are important for social cognition. Animal research has been crucial for identifying specific circuits and molecular mechanisms that modulate this structural network. From a molecular neurobiology perspective, activity in these brain structures is coordinated by neuronal circuits modulated by several neurotransmitters and neuromodulators. Thus, quantitative variation in the levels, release and/or receptor density of these molecules could affect the observed behavioral response. The present review presents an overall framework of the components of the social brain circuitry and its modulation. By integrating multiple research approaches, from human fMRI studies to animal models we can start shedding light into how dysfunction in these circuits could lead to disorders of social functioning such as Autism. PMID- 28729066 TI - The effect of high fat diet on daily rhythm of the core clock genes and muscle functional genes in the skeletal muscle of Chinese soft-shelled turtle (Trionyx sinensis). AB - In the present study, we sought to investigate the influence of high fat diet on the core clock genes and the muscle functional genes daily expression in the skeletal muscle of Chinese soft-shelled turtle. The turtles were fed by two diets including a control fat diet (the CON treatment, 7.98% lipid) and a high fat diet (the HFD treatment, 13.86% lipid) for six weeks and administrated by the photophase regimen of 24h light/dark (12L:12D) cycle. After the feeding trial experiment, we measured the daily expression levels of 17 core clock genes (Clock, Bmal1/2, NPAS2, Tim, Cry1/2, Per1/2, DBP, AANAT, NIFL3, BHLHE40, NR1D2, RORA, RORB, RORC) and 12 muscle functional genes (FBXO32, MBNL1, MSTN, Myf5, Myf6, MyoD, MyoG, MyoM1, PPARa, PDK4, Trim63, UCP3) in the skeletal muscle of the two treatments. The results showed that except for Bmal1, NPAS2, Per2 and RORB, the expression of the other 13 core clock genes exhibited circadian oscillation in the CON treatment. Among the 12 muscle functional genes, MBNL1, PDK4 and MyoM1 did not exhibit circadian oscillation in the CON treatment. In the HFD treatment, the circadian rhythms expressional patterns of the 8 core clock genes (Clock, Bmal2, Cry2, Per1, DBP, NFIL3, BHLHE40 and RORA) and 6 muscle functional genes (MSTN, Myf5, MyoD, MyoG, PPARa and Trim63) were disrupted. In addition, compared with the CON treatment, the circadian expression of the 5 core clock genes (Tim, Cry1, AANAT, NR1D2, RORC) and the 3 muscle functional genes (FBXO32, Myf6, UCP3) showed the advanced or delayed expression peaks in the HFD treatment. In CON treatment, the circadian expression of the MyoG, MyoD, Myf6, FBXO32 and PPARa showed positive or negative correlation with the transcription pattern of Clock, Bmal2, Cry1/2, Per1/2. However, only the FBXO32 and Myf6 presented positive or negative correlation with the circadian expression of Cry1, RORB, AANAT and Tim in HFD treatment. In summary, these results demonstrate that the disruption of the circadian rhythm of the core clock genes and muscle functional genes in the skeletal muscle is closely associated with feeding high fat diet to Chinese soft shelled turtle. PMID- 28729067 TI - Real-world Characteristics and Outcomes of Patients With Metastatic Castration resistant Prostate Cancer Receiving Chemotherapy Versus Androgen Receptor targeted Therapy After Failure of First-line Androgen Receptor-targeted Therapy in the Community Setting. AB - BACKGROUND: In metastatic castration-resistant prostate cancer (mCRPC), optimal treatment sequences are unknown. We assessed second-line taxane (TT) versus androgen receptor-targeted therapy (ART), after initial ART failure, in United States oncology community practices. PATIENTS AND METHODS: Using electronic medical records, patients with mCRPC receiving first-line ART and second-line therapy (TT, ART) were identified. Response and overall survival (OS) were evaluated from second-line therapy initiation. Multivariate analyses were adjusted for year, age, metastases, opioid use, prostate-specific antigen (PSA), hemoglobin, alkaline phosphatase, and albumin levels. RESULTS: Of 546 patients receiving first-line ART, 206 and 340 received second-line TT and ART. Compared with patients receiving second-line ART, patients receiving TT were younger (median, 74 vs. 79 years), more had intermediate-high Halabi risk scores (59% vs. 35%), had higher opioid use (42% vs. 22%), median PSA (116 vs. 48 ng/mL), alkaline phosphatase (112 vs. 87 U/L), and lactate dehydrogenase (254 vs. 201 U/L), and had lower hemoglobin (11.2 vs. 12.3 g/dL) and albumin levels (3.8 vs. 4.0 g/dL); all P < .001. Response rates were higher with second-line TT versus ART (clinical response, 44.2% vs. 24.7%; P = .006; PSA response, 44.5% vs. 28.7%; P = .004). OS did not differ between cohorts (hazard ratio [HR], 0.90; P = .511). Among patients with a poor prognosis (hemoglobin < 11 g/d; albumin < lower limit of normal), those receiving second-line TT versus ART showed improved OS (HR, 0.52; P = .004 and HR, 0.36; P = .003, respectively). CONCLUSIONS: Despite more severe disease profiles, patients with mCRPC receiving second-line TT versus ART achieved higher response rates after initial ART. Poor prognosis patients had improved OS with second-line TT versus ART. PMID- 28729068 TI - Submentalizing Cannot Explain Belief-Based Action Anticipation in Apes. PMID- 28729069 TI - The powerful hemostatic devices are one of the milestones for successful laparoscopic surgery. PMID- 28729070 TI - ABC transporters in the liver fluke Opisthorchis felineus. AB - ATP-binding cassette transporters (ABC transporters) are essential components of normal cellular physiological machinery in all eukaryotic and prokaryotic species, including parasites. Some ABC transporters, e.g., P-glycoproteins, are involved in the efflux of toxins and xenobiotics from the cell. At present, nothing is known about ABC transporter genes in epidemiologically important liver flukes from the Opisthorchiidae family, including European liver fluke Opisthorchis felineus. Opisthorchiasis caused by O. felineus is a serious public health problem on the territory of Russia and other Eastern European countries. ABC drug transporters are attractive objects of research on molecular markers of resistance and on ways to potentiate sensitivity to anthelmintics through suppression of the transporters themselves with specific inhibitors. Here we aimed at the identification of ABC transporters in the O. felineus transcriptome and identification of P-glycoproteins. In addition, our aim was to assess ABC transcript abundance in the RNA-seq data, to study the mRNA expression of P glycoprotein genes by Droplet Digital PCR throughout the life cycle of O. felineus, and to test the gene induction in response to xenobiotics or anthelminthic agents. We found 23 nucleotide sequences encoding ABC transporters belonging to different subfamilies, including four sequences of P-glycoproteins. According to the transcript abundance in the RNA-seq data, one of P-glycoproteins (P4) has the highest expression among all ABC genes in the adult worm. P glycoproteins showed substantially differential mRNA expression throughout the fluke life cycle, with high expression in the adult worms. Putative activity of P glycoproteins as xenobiotic efflux pumps was found to be linked to the excretory system of O. felineus and to be inhibited by verapamil or tariquidar. Thus, ABC drug transporters in the liver fluke O. felineus are functionally active, indicating that ABC drug transporters are likely to be molecular targets for a combination therapy aimed at prevention of a xenobiotic removal from helminth tissues and at increasing the drug concentration in the tissues. PMID- 28729071 TI - Transient transfection of intraerythrocytic Babesia gibsoni using elongation factor-1 alpha promoter. AB - The development of gene manipulation techniques has been reported in many protozoan parasites over the past few years. However, these techniques have not yet been established for Babesia gibsoni. Here, we report for the first time, the successful transient transfection of B. gibsoni. The plasmid containing the firefly luciferase reporter gene (pBS-ELA) was transfected into B. gibsoni by an AMAXA 4D NucleofectorTM device. Transfection using program FA113 and Lonza buffer SF showed the highest luciferase expression. Twenty micrograms of plasmid produced the highest relative transfection efficiency. The fluorescent protein expressing parasites were determined by GFP-containing plasmid (pBS-EGA) at 48 and 72h post transfection. This finding is the first step towards a stable transfection method for B. gibsoni, which may contribute to a better understanding of the biology of the parasite. PMID- 28729072 TI - Recycling of food waste for fuel precursors using an integrated bio-refinery approach. AB - The main aim was to integrate FW-recycling with cultivation of Rhodotorula glutinis and anaerobic digestion (AD) for bio-energy and -fuel recovery. Mixed FW was mechanically macerated (Pcon) and hydrolysed (at 250gL-1 water) via chemical (Ch), thermal (Th) and TCh (combined Ch and Th) treatments. Cleared hydrolysates from individual pre-treatment processes were used as culture medium for cultivation of R. glutinis, while the residual solids (RS) were subjected to AD. Pcon cultivation yielded maximal R. glutinis dry weight biomass (5.18gL-1) and total fatty acid contents (1.03gg-1 DWbiomass). Dominant fatty acid methyl esters (FAME) were Palmitic - (C16:0-26%); Stearic - (C18:0-17%) and Oleic acids (C18:1 38%), ideal for bio-diesel production. Highest methane yields (actual ~0.139m3kg 1 volatile solids) were measured from AD of Th-derived RS. Thus integrated FW recycling approaches will be more feasible for generating energy and economic incentives. PMID- 28729073 TI - Reeducation of vergence dynamics improves postural control. AB - INTRODUCTION: The purpose was to investigate the effect of vergence reeducation on postural control, in subjects with isolated vergence disorders. MATERIAL AND METHODS: We studied the dynamics of vergence in 19 subjects (20-44 years old) using video-oculography (Eye See Cam). On the basis of orthoptic and symptomatology assessments, ten of the subjects were diagnosed for vergence disorders then vergence eye movements were reeducated with the REMOBI method (US8851669, 5 weekly sessions lasting for 35min). Postural control was measured before and after reeducation, postural recording was done in upright stance (Dynaport), with both eyes closed or open and looking a visual target located at 2m distance. RESULTS: After reeducation with REMOBI, the visual symptomatology faded away and the stereoacuity improved at least for some subjects; the vergence latency decreased significantly and the vergence accuracy increased significantly. In terms of posture, the Mean Power Frequency (MPF) of the body sway decreased significantly in both eyes open and eyes closed conditions. Considering all subjects together (i.e. healthy subjects and subjects with vergence disorders before the reeducation), the antero-posterior body sway (Root Mean Square A/P) was positively correlated with the visual symptomatology: the higher the visual symptomatology, the higher was the body sway. CONCLUSION: The results bring evidence for synergy between the quality of vergence and the quality of postural control. They open a new research line that bridges the gap between neuroscience, ophthalmology-orthoptics and posturology. PMID- 28729074 TI - Proteomic analysis of the effects of Nur77 on lipopolysaccharide-induced microglial activation. AB - Microglia are critical components of the immune response in the central nervous system. Our study aims to explore potential role of Nur77 in lipopolysaccharide (LPS)-induced microglial activation. Primary wild-type and Nur77-/- microglia were stimulated with LPS and protein extracts were detected via mass spectrometry. Q-PCR and western blotting were performed to validate candidate proteins. A total of 2004 proteins were identified, with 749 and 677 significantly differentially expressed proteins in wild-type and Nur77-/- microglia in resting and activated states, respectively. Signaling pathway analysis showed that significantly differentially expressed proteins in LPS treated Nur77-/- microglia were present in important signaling pathways of microglial activation, including the Toll-like receptor signaling pathway, the MAPK signaling pathway, FcgammaR-mediated phagocytosis, and chemokine signaling pathways. Furthermore, we found that Nur77 could be the upstream protein of the vav1 and ERK1/2 signaling pathway. This study provided new insights into the understanding the mechanisms of the effects of Nur77 on LPS-activated microglia. PMID- 28729075 TI - Effects of environmental enrichment during abstinence in morphine dependent parents on anxiety, depressive-like behaviors and voluntary morphine consumption in rat offspring. AB - Chronic morphine exposure during puberty increased morphine-induced rewarding effects and sensitization in the next generation. Given the well-known beneficial effects of environmental enrichment on the severity of physical and psychological dependence on morphine, we examined effects of enriched environment during morphine abstinence in morphine dependent parental rats before mating on the anxiety and depressive-like behaviors, and voluntary morphine consumption in their offspring. Paternal and/or maternal rats were injected with bi-daily doses (10mg/kg, 12h intervals) of morphine for 14days followed by rearing in a standard environment (SE) or enriched environment (EE) during 30days of morphine abstinence before mating. The pubertal male and female rat offspring were tested for anxiety (the elevated plus maze- EPM) and depression (sucrose preference test SPT), and voluntary morphine consumption using a two-bottle choice (TBC) paradigm. The results showed that EE experience in morphine-dependent both parents result in an increase in the percentage of time spent into open arms/time spent on both arms using EPM in male offspring, higher levels of sucrose preference in female offspring and lower levels of voluntary morphine consumption in male and female offspring. Thus, EE experience in morphine-dependent both parents reduced anxiety, depressive-like behavior and also the voluntary morphine consumption in their offspring during puberty which may prevent the vulnerability of the next generation to drug abuse. PMID- 28729076 TI - Single nucleotide polymorphisms in the toll-like receptor 2 (TLR2) gene are associated with sporadic Parkinson's disease in the North-eastern Han Chinese population. AB - Growing evidences suggested that inflammatory process played a critical role in the pathogenesis of Parkinson's disease (PD). Given that TLR2 has been implicated in the perpetuation of inflammatory responses in the central nervous system (CNS), we investigated the association between two genetic variants (rs3804099 and rs3804100) of TLR2 and sporadic PD in Han Chinese population. 395 Han Chinese sporadic PD patients and 413 healthy age and gender-matched controls were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The sporadic PD patients showed a higher T allele frequency than the healthy-matched control (p=0.019). Furthermore rs3804099 dominate model TT versus (vs.) TC+CC increase the risk of sporadic PD (OR=1.376, 95%CI=1.043-1.814, p=024). From the subgroup analysis, the variant allele T of rs3804099 was higher in sporadic PD cases (73.1%) than in controls (67.4%) in the late-onset cohort. Meanwhile rs3804099 revealed significant association in dominant model: Subjects with TT genotypes vs. those with TC+CC genotype showed evident significant in late-onset cohort (LOPD OR=1.417, 95%CI=1.051-1.911, p=022). In contrast, allele frequencies at rs3804100 were similar between patients and controls. Taken together, this study reveals that polymorphism of TLR2 locus is associated with risk of sporadic PD in the North-eastern part of Han Chinese population. Further studies are required to evaluate the association. PMID- 28729077 TI - White matter microstructure degenerates in patients with postherpetic neuralgia. AB - OBJECTIVE: The central mechanisms underlying postherpetic neuralgia (PHN) pain remains unknown. The primary purpose of this study was to identify microstructural white matter changes closely related to the PHN pain by means of diffusion tensor imaging (DTI) and tract-based spatial statistics (TBSS) analysis. METHODS: DTI data of the brains were obtained from 8 PHN patients and 8 healthy controls (HC) that were matched in age, gender, and educational level. DTI metrics, including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD), were separately compared between the two groups using TBSS analysis to detect subtle microstructural changes. Partial correlation analyses were also conducted to evaluate the association between the altered DTI measures and clinical features. RESULTS: Average diffusion indices of white matter skeletons in the whole-brain showed no significant difference between the two groups. However, compared to the HC group, patients with PHN pain revealed reductions in localized FA and AD values in white matter underlying insula, occipital lobe, cerebellum, precentral gyrus, and many other regions, but without distinct change in regional MD and RD levels. In addition, decline of FA and AD values in patients represented significant negative correlations with PHN pain duration when the effect of VAS scores were excluded. CONCLUSION: The current study suggest that there exists altered microstructure integrity of white matter in multiple brain regions in patients with PHN, and these changes increase in size as the duration of the pain increases. These findings might provide a new insight into the mechanism of PHN pain in brain. PMID- 28729078 TI - A negative pressure wound therapy for complex infected cranial defects overlying dura mater: An effective and safe procedure. PMID- 28729079 TI - The Indian nose: An anthropometric analysis. AB - Anthropometric measurements of the nose are of great importance in planning aesthetic nasal surgery. Abundant literature is available on anthropometric analysis of Caucasians and Orientals, without similar references on the Indian nose and its regional differences. Thus, we conducted a descriptive cross sectional epidemiological study of 1000 volunteers, with equal number of subjects derived from five geographic groups, namely North, Central, West, South, and the Himalayan region, to determine differences in nasal morphology of Indian population and among its various regions. The objective was to establish a standard Indian data for guidance in nasal surgery. All measurements were deduced using photographic analysis. The mean nasal height and width of our study population was 50.48 and 36.59 mm, respectively. Nasal profile varied among all five regions of the country. North Indians had the longest (52.69 mm nasal height) but the narrowest nose (35.01 mm width), thus having a leptorrhine nose with Caucasoid features. South Indians had the broadest nose (nasal width = 38.66 mm), whereas subjects from the Himalayan region had the shortest nose (nasal height = 47.2 mm). Indians on average had a mesorrhine nose as compared to Caucasians and Orientals who have a leptorrhine nose and Africans who have a platyrrhine nose. We thus conclude that the Indian nose should be considered a different entity in comparison to the nose of Caucasian, Oriental, and African populations. There are obvious differences in the facial architecture of people from different regions within the country. Therefore, appropriate adjustments need to be made according to different racial descents during nasal surgeries so as to give patients results that blend harmoniously with other facial features. PMID- 28729080 TI - Association Between High-Density Lipoprotein Cholesterol and Hyponatremia: Is There Something Else Low? PMID- 28729081 TI - Axillary Mass and Hypercalcemia: The Value of a Physical Examination. PMID- 28729082 TI - Oral Glycerol Ingestion Causes Pseudohypertriglyceridemia. PMID- 28729083 TI - Urschel's Sign in Paget Schroetter Syndrome. PMID- 28729084 TI - Disseminated Zoster After Trauma in an Immunocompetent Patient. PMID- 28729085 TI - 'Lies, Damned Lies, and Statistics': Biostatistics and Prognostication for Patients. PMID- 28729088 TI - Chronic asymmetric tremor and levodopa-responsive parkinsonism due to a vein of Galen aneurysmal malformation. PMID- 28729087 TI - Real-world Effectiveness of Biologic Disease-modifying Antirheumatic Drugs for the Treatment of Rheumatoid Arthritis After Etanercept Discontinuation in the United Kingdom, France, and Germany. AB - PURPOSE: The purpose of this study was to assess the real-world effectiveness of patients with rheumatoid arthritis (RA) who discontinued etanercept treatment and subsequently received another tumor necrosis factor alpha (TNF-alpha) inhibitor or a non-TNF-alpha biologic in the United Kingdom, France, and Germany. METHODS: Medical record data of patients with RA were collected from a panel of rheumatologists in the United Kingdom, France, and Germany. Patients were required to have a diagnosis of RA, be >=18 years old, and have initiated use of another TNF-alpha inhibitor (adalimumab, certolizumab pegol, golimumab, or infliximab) or a non-TNF-alpha biologic (abatacept or tocilizumab) between January 2014 and May 2015 after discontinuing use of etanercept. Reasons for discontinuing use of etanercept and selecting a second biologic disease-modifying antirheumatic drug (DMARD) were described. Study outcomes included European League Against Rheumatism (EULAR) response and change in Clinical Disease Activity Index (CDAI) score. The study outcomes were compared among treatment groups (ie, TNF-alpha inhibitors and non-TNF-alpha biologics) using descriptive and multivariable-adjusted analyses. As a secondary analysis, the study outcomes were also descriptively compared between each of the TNF-alpha inhibitors. Because adalimumab is one of the most commonly used TNF-alpha inhibitor to treat RA, a secondary analysis was conducted to compare the outcomes among adalimumab, other TNF-alpha inhibitors, and non-TNF-alpha inhibitors. FINDINGS: Patient characteristics before initiating treatment with a second DMARD were similar across treatment groups (all TNF-alpha inhibitors [n = 296] and non-TNF-alpha biologics [n = 276]). The most common reasons for discontinuing etanercept treatment were inadequate response, adverse effects, and patient preference. After etanercept, TNF-alpha inhibitors overall were associated with a significantly lower EULAR good response rate (56.0% vs. 64.4%, P < 0.05) and smaller CDAI score change (-6.3 vs -7.3, P = .06) relative to non-TNF-alpha biologics. However, the proportion of patients achieving an EULAR good response was numerically higher for adalimumab versus other TNF-alpha inhibitors (61.1% vs 51.6%, P = 0.11) and comparable versus non-TNF-alpha biologics (61.1% vs 64.4%, P = 0.52). Adalimumab was also associated with a CDAI score change significantly greater than that of other TNF-alpha inhibitors (-7.1 vs -5.8, P < 0.05) and comparable to that of non-TNF-alpha biologics (-7.1 vs -7.3, P = 0.79). The results were consistent in the multivariable-adjusted analysis and secondary analysis. IMPLICATIONS: In this retrospective analysis of patients with RA in the United Kingdom, France, and Germany, after discontinuation of etanercept treatment, TNF-alpha inhibitors as a class were overall less effective as second biologic DMARDs relative to non-TNF-alpha biologics; however, adalimumab was more or as effective as other TNF-alpha inhibitors and non-TNF-alpha biologics. PMID- 28729089 TI - Choreiform dyskinesias following levodopa treatment of parkinsonism due to osmotic demyelination syndrome. PMID- 28729086 TI - Non-human primates as a model for aging. AB - There has been, and continues to be, a dramatic shift in the human population towards older ages necessitating biomedical research aimed at better understanding the basic biology of aging and age-related diseases and facilitating new and improved therapeutic options. As it is not practical to perform the breadth of this research in humans, animal models are necessary to recapitulate the complexity of the aging environment. The mouse model is most frequently chosen for these endeavors, however, they are frequently not the most appropriate model. Non-human primates, on the other hand, are more closely related to humans and recapitulate the human aging process and development of age related diseases. Extensive aging research has been performed in the well characterized rhesus macaque aging model. More recently, the common marmoset, a small non-human primate with a shorter lifespan, has been explored as a potential aging model. This model holds particular promise as an aging disease model in part due to the successful creation of transgenic marmosets. Limitations to the use of non-human primates in aging research exist but can be mitigated somewhat by the existence of available resources supported by the National Institutes of Health. This article is part of a Special Issue entitled: Animal models of aging edited by "Houtkooper Riekelt". PMID- 28729090 TI - The overlap between Essential tremor and Parkinson disease. AB - INTRODUCTION: Essential tremor (ET) and Parkinson's disease (PD) are common disorders especially in the aging population and can have overlapping features that can make it difficult to differentiate between the two. In addition, a possible overlap from a pathophysiological standpoint has been often advocated in the past. METHODS: In this review article, we gather the recent evidence in favor or against a possible relationship between ET and PD. This exercise follows the new advances in the field of tremor from both a pathophysiological and nosological perspective. RESULTS: Dividing ET patients into early onset and late onset disease subtypes can prove useful in ascertaining the phenotypic, epidemiological and genetic characteristics defining its relationships to PD. The only way to ascertain whether ET increases the risk of future PD would be to conduct a longitudinal cohort study on early-onset ET patients. On the other hand, ET-plus patients or late-onset cases with ET of short-duration might represent a group of PD patients in their pre-diagnostic phase after the pre motor stage. CONCLUSION: In spite of the growing body of literature in recent years of an overlap between ET and PD, we are far from elucidating the relationship (if any) between these two common disorders. PMID- 28729091 TI - Phosphatase activity of soluble epoxide hydrolase. AB - Soluble epoxide hydrolase (sEH) is a bifunctional enzyme that exhibits lipid epoxide hydrolase (sEH-H) and lipid phosphatase activity (sEH-P), with each being located in its own distinct domain. While the epoxide hydrolase activity is well investigated, the role of the phosphatase domain remains unclear. This article briefly summarizes the evolution, structure and SNPs of the human sEH, with a special focus on the function and postulated role of the N-terminal domain of sEH. Furthermore, the article provides an overview of tools to study sEH-P. PMID- 28729092 TI - Annexin A2-modulated proliferation of pulmonary arterial smooth muscle cells depends on caveolae and caveolin-1 in hepatopulmonary syndrome. AB - We have established that annexin A2 (ANXA2) is an important factor in the experimental hepatopulmonary syndrome (HPS) serum-induced proliferation of pulmonary arterial smooth muscle cells (PASMCs). However, the detailed mechanism remains unclear. ANXA2 translocated to the caveolin-enriched microdomains (caveolae) in PASMCs upon HPS serum stimulation. The disruption of caveolae by Methyl-beta-cyclodextrin (MbetaCD) alleviated the caveolae recruitment of ANXA2 and the ANXA2-mediated activation of ERK1/2 and NF-kappaB, so that ANXA2 modulated PASMC proliferation was suppressed. The over-expression of Cav-1 resulted in the relocation of ANXA2 from caveolae and negatively regulated ERK1/2 and NF-kappaB activation, which inhibited the ANXA2-modulated PASMC proliferative behavior. These data indicate that caveolae function as a signaling platform for ANXA2-induced proliferative behavior and Cav-1 participates upstream of ANXA2 in the activation of ERK1/2 and NF-kappaB. PMID- 28729094 TI - Excerpts from the World Medical Literature. PMID- 28729095 TI - ? PMID- 28729093 TI - PIM kinases 1, 2 and 3 in intracellular LIF signaling, proliferation and apoptosis in trophoblastic cells. AB - Proviral insertion in murine (PIM) lymphoma proteins are mainly regulated by the Janus Kinase/Signal Transducer Activator of Transcription (JAK/STAT) signaling pathway, which can be activated by members of the Interleukin-6 (IL-6) family, including Leukemia Inhibitory Factor (LIF). Aim of the study was to compare PIM1, PIM2 and PIM3 expression and potential cellular functions in human first and third trimester trophoblast cells, the immortalized first trimester extravillous trophoblast cell line HTR8/SVneo and the choriocarcinoma cell line JEG-3. Expression was analyzed by qPCR and immunochemical staining. Functions were evaluated by PIM inhibition followed by analysis of kinetics of cell viability as assessed by MTS assay, proliferation by BrdU assay, and apoptosis by Western blotting for BAD, BCL-XL, (cleaved) PARP, CASP3 and c-MYC. Apoptosis and necrosis were tested by flow cytometry (annexin V/propidium iodide staining). All analyzed PIM kinases are expressed in primary trophoblast cells and both cell lines and are regulated upon stimulation with LIF. Inhibition of PIM kinases significantly reduces viability and proliferation and induces apoptosis. Simultaneously, phosphorylation of c-MYC was reduced. These results demonstrate the involvement of PIM kinases in LIF-induced regulation in different trophoblastic cell lines which may indicate similar functions in primary cells. PMID- 28729096 TI - Can the Presence of a Surrounding Endometrium Differentiate Eccentrically Located Intrauterine Pregnancy from Interstitial Ectopic Pregnancy? AB - OBJECTIVES: Differentiation of an eccentric intrauterine pregnancy (IUP) from an interstitial ectopic pregnancy (EP) is challenging. No sign for differentiation is reported. The purpose of this study was to determine whether the presence of surrounding endometrium (SE) can distinguish eccentric IUP from interstitial EP. METHODS: This study was approved by the institutional ethics board; consent acquisition was waived. Cases were identified using ultrasound (US) reports that included the words "interstitial," "cornual," and "angular." Blinded to official reports, one reviewer reviewed US examinations retrospectively for the presence of SE, defined as the extension of endometrial lining around the gestational sac (GS) as an indication of an eccentric IUP. US examinations without SE on the retrospective review were diagnosed as interstitial EP. RESULTS: Forty-four cases were identified from 2007 to 2015. On retrospective review, 20 cases were labeled as eccentric IUP and 24 as interstitial EP. Ten of the 20 cases retrospectively labeled as eccentric IUP had been reported and managed as eccentric IUP prospectively: four followed to a viable second trimester, and six had spontaneous abortion/termination. The remaining 10 cases retrospectively labeled eccentric IUPs because of the presence of SE had been reported and managed as interstitial EP on the official prospective report. There was follow-up suggestion of eccentric IUP in six of the latter discordant pregnancies with non concordant retrospective and prospective diagnosis: three had hysteroscopy/curettage demonstrating retained products, two had US follow-up showing the GS moving farther down in the uterine cavity, and in one patient, the GS was shown to pass per vagina. Twenty-four of the 44 cases were called interstitial EP both on the retrospective and prospective reviews and were managed as interstitial EP. None of these patients (without SE) had follow-up suggestive of eccentric IUP. CONCLUSION: Our results suggest that the presence of surrounding endometrium around the GS allows for differentiation of eccentric IUP from interstitial EP. PMID- 28729097 TI - Post-Caesarean Section Surgical Site Infection Surveillance Using an Online Database and Mobile Phone Technology. AB - BACKGROUND: Obstetric surgical site infections (SSIs) are common and expensive to the health care system but remain under reported given shorter postoperative hospital stays and suboptimal post-discharge surveillance systems. SSIs, for the purpose of this paper, are defined according to the Center for Disease Control and Prevention (1999) as infection incurring within 30 days of the operative procedure (in this case, Caesarean section [CS]). PRIMARY OBJECTIVE: Demonstrate the feasibility of real-life use of a patient driven SSIs post-discharge surveillance system consisting of an online database and mobile phone technology (surgical mobile app - how2trak) among women undergoing CS in a Canadian urban centre. SECONDARY OBJECTIVE: Estimate the rate of SSIs and associated predisposing factors. METHODS: Prospective cohort of consecutive women delivering by CS at one urban Canadian hospital. Using surgical mobile app-how2trak predetermined demographics, comorbidities, procedure characteristics, and self reported symptoms and signs of infection were collected and linked to patients' incision self-portraits (photos) on postpartum days 3, 7, 10, and 30. RESULTS: A total of 105 patients were enrolled over a 5-month period. Mean age was 31 years, 13% were diabetic, and most were at low risk of surgical complications. Forty-six percent of surgeries were emergency CSs, and 104/105 received antibiotic prophylaxis. Forty-five percent of patients (47/105) submitted at least one photo, and among those, one surgical site infection was detected by photo appearance and self-reported symptoms by postpartum day 10. The majority of patients whom uploaded photos did so multiple times and 43% of them submitted photos up to day 30. Patients with either a diagnosis of diabetes or self reported Asian ethnicity were less likely to submit photos. CONCLUSIONS: Post discharge surveillance for CS-related SSIs using surgical mobile app how2trak is feasible and deserves further study in the post-discharge setting. PMID- 28729098 TI - A Multicentre Retrospective Review of Clinical Characteristics of Uterine Sarcoma. AB - OBJECTIVE: Professional societies have recently urged gynaecologists to counsel patients about the risks of encountering uterine sarcoma at fibroid surgery especially when morcellation is used. Our objective was to learn the preoperative and postoperative characteristics of patients with uterine sarcoma to better counsel patients undergoing surgery for presumably benign fibroids. METHODS: This is a multicentre, retrospective cohort study. Three academic tertiary cancer centres in Southern Ontario over a 13-year period (2001-2014). Patients diagnosed with leiomyosarcoma or endometrial stromal sarcoma were included after identification using pathology databases. A retrospective chart review was conducted to determine clinical characteristics and survival data. RESULTS: The study included 302 patients with uterine sarcomas (221 leiomyosarcomas, 81 endometrial stromal sarcomas). Mean age at diagnosis was 55 years, and 59% were postmenopausal. Sarcoma diagnosis was made following endometrial sampling (25%), hysterectomy (69% laparotomy, 2.7% laparoscopic/vaginal), and myomectomy (3.3%). Of all the patients who underwent endometrial sampling, 65% were diagnosed with a uterine sarcoma in this manner. A general gynaecologist performed the primary surgical procedure in 166 of 302 patients (55%). Tumour disruption at the time of primary surgery occurred in 57 of 295 patients (19%): subtotal hysterectomy (21), myomectomy (10), dissection of adherent tumour (17), and morcellation (9). Morcellation, to facilitate a minimally invasive approach, was performed with scalpel (2 at laparotomy, 5 vaginally) and with a laparoscopic electro-mechanical morcellator (2). At a median follow-up of 2.9 years, there was no significant difference in survival for stage I and II patients with tumour disruption (n = 32) compared with those without tumour disruption (n = 143), regardless of sarcoma type (P = 0.6). CONCLUSION: The majority of patients with uterine sarcomas were postmenopausal. Many can be diagnosed preoperatively with endometrial sampling. Forty-one percent of patients with uterine sarcomas had a high preoperative index of suspicion, resulting in intervention by an oncologist. Morcellation with laparoscopic electro-mechanical morcellator was rare. PMID- 28729099 TI - Implementing a Cervical Sentinel Lymph Node Biopsy Program: Quality Improvement in Gynaecologic Oncology. AB - OBJECTIVE: Sentinel lymph node (SLN) biopsy is becoming a reasonable alternative to pelvic lymphadenectomy in early-stage cervical cancer. It is therefore imperative that centres without prior experience are able to successfully implement the procedure. The objectives of the current study were to (1) describe the process of implementing an SLN biopsy program with a novel peer mentorship component and (2) assess post-program quality improvement metrics, including SLN detection rate (DR) and diagnostic parameters. METHODS: An institutional SLN biopsy protocol was developed collaboratively by gynaecologic oncology, nuclear medicine, and pathology departments at University Health Network, Toronto, Ontario. All decisions were based on the best evidence available. Newly diagnosed, early-stage cervical cancer patients undergoing primary surgery were then recruited prospectively for SLN biopsy with combined technique, followed by pelvic lymphadenectomy to evaluate key quality indicators, including SLN DR, sensitivity, and negative predictive value. Surgeons with previous SLN biopsy experience mentored surgeons unfamiliar with the technique. Interim analyses and multidisciplinary rounds were regularly carried out to identify failures of technique or protocol. RESULTS: Thirty-nine patients (median age 42) were enrolled in the study between August 2010 and February 2014. The median number of SLNs and total pelvic lymph nodes removed per patient were 3 and 19, respectively. SLN DRs were 92% per patient (36/39), 88.5% per hemipelvis (69/78), and 85% bilaterally (33/39). SLN biopsy correctly identified seven of eight hemipelvises with nodal metastases, yielding a sensitivity of 88% (95% CI 0.47 to 1.00) and a false negative rate of 12% (95% CI 0 to 0.53). Surgeons undergoing peer mentorship (n = 3) performed as effectively (DR 100%) as surgeons (n = 2) with prior experience (DR 85%). CONCLUSIONS: This study provides a model upon which other centres can adopt and validate cervical SLN biopsy. High SLN DRs and accurate identification of lymph node metastases can be achieved by focusing on multidisciplinary collaboration, knowledge translation with creation of evidence based protocols, peer mentorship, and ongoing quality control. PMID- 28729100 TI - An Evaluation of Introduction of Rapid HIV Testing in a Perinatal Program. AB - OBJECTIVE: This study was conducted to evaluate the roll-out of rapid HIV testing as part of an emergency Prevention of Perinatal HIV Transmission Program. Specifically, HIV prevalence in this population, the reason(s) for performing the rapid HIV test, and compliance with recommendations for antiretroviral prophylaxis were assessed. METHODS: Since November 2011, all women presenting to a tertiary labour and delivery unit with unknown HIV status or with ongoing risk of HIV infection since their last HIV test were offered rapid HIV testing. Through retrospective chart review, demographic data, HIV risk and prior testing history, and antiretroviral prophylaxis, data were collected and descriptive statistics were performed. RESULTS: One hundred fourteen rapid HIV tests were conducted and there were two preliminary reactive rapid results (one true positive, one false positive). None of the infants was HIV infected. Sixty-three percent of women had multiple risk factors for HIV acquisition, most commonly intravenous drug use (54%). Forty-four percent of women were within the 4-week seroconversion window at the time of delivery; 25% of these women and 52% of their infants received prophylactic drug therapy. CONCLUSION: Rapid HIV testing identified a high-risk cohort and enabled aggressive management of a newly diagnosed HIV-positive pregnancy, successfully preventing perinatal HIV transmission. Risk factors for HIV acquisition were ongoing within the seroconversion window for over half of the women, impacting the utility of the test in eliminating unnecessary antiretroviral prophylaxis in this population because prophylaxis is recommended despite a negative rapid HIV test in these cases. PMID- 28729101 TI - Correction. PMID- 28729102 TI - ? PMID- 28729103 TI - ? AB - OBJECTIF: Le present document resume notre experience limitee quant a la presence du SRAS pendant la grossesse et suggere des lignes directrices quant a sa prise en charge. ISSUES: Les exposes de cas issus d'Asie laissent entendre que les issues maternelles et foetales sont aggravees par la presence du SRAS pendant la grossesse. ReSULTATS: Des recherches ont ete menees dans Medline afin d'en tirer les articles pertinents publies en anglais entre 2000 et 2007. Des exposes de cas ont ete analyses et nous avons sollicite l'opinion de specialistes. VALEURS: Les recommandations ont ete formulees conformement aux lignes directrices elaborees par le Groupe d'etude canadien sur les soins de sante preventifs. COMMANDITAIRE: La Societe des obstetriciens et gynecologues du Canada. RECOMMANDATIONS. PMID- 28729104 TI - No. 225-Management Guidelines for Obstetric Patients and Neonates Born to Mothers With Suspected or Probable Severe Acute Respiratory Syndrome (SARS). AB - OBJECTIVE: This document summarizes the limited experience of SARS in pregnancy and suggests guidelines for management. OUTCOMES: Cases reported from Asia suggest that maternal and fetal outcomes are worsened by SARS during pregnancy. EVIDENCE: Medline was searched for relevant articles published in English from 2000 to 2007. Case reports were reviewed and expert opinion sought. VALUES: Recommendations were made according to the guidelines developed by the Canadian Task Force on Preventive Health Care. SPONSORS: The Society of Obstetricians and Gynaecologists of Canada. RECOMMENDATIONS: PMID- 28729105 TI - ? AB - OBJECTIF: Analyser les avantages d'un examen echographique exhaustif au cours du deuxieme trimestre et les conditions necessaires a sa tenue, ainsi que la documentation requise. ISSUES: Un examen echographique exhaustif au cours du deuxieme trimestre offre des renseignements au sujet du nombre de foetus, de l'age gestationnel, de l'emplacement du placenta et de l'anatomie foetale et maternelle. ReSULTATS: Dans le cadre de la redaction du present document, le document " Practice Guideline for the Performance of Obstetric Ultrasound Examinations " du American Institute of Ultrasound in Medicine, le bulletin de pratique " Ultrasound in Pregnancy " du American College of Obstetricians and Gynaecologists et le rapport de groupe de travail " Ultrasound Screening " du Royal College of Obstetricians and Gynaecologists ont ete analyses. Des recherches ont ete menees dans PubMed et Cochrane Database au moyen des mots " routine second trimester obstetrical ultrasound ". VALEURS: Les resultats ont ete evalues au moyen des lignes directrices elaborees par le Groupe d'etude canadien sur les soins de sante preventifs. AVANTAGES, DeSAVANTAGES ET COuTS: La tenue systematique d'un examen echographique exhaustif au cours du deuxieme trimestre (entre la 18e et la 22e semaine de gestation) et la redaction d'un rapport d'echographie exhaustif offrent la meilleure occasion de diagnostiquer les anomalies foetales et de contribuer a la gestion des soins prenatals. Ils permettent egalement de diminuer le nombre d'examens echographiques menes au cours du deuxieme trimestre aux fins de l'exploration de l'anatomie foetale. Les couts sont ceux qui sont mis en jeu dans le cadre de l'execution d'une echographie obstetricale. VALIDATION: Il s'agit de la revision d'une directive clinique deja publiee; des donnees issues d'autres analyses de consensus tirees de publications medicales ont ete utilisees. COMMANDITAIRE: La Societe des obstetriciens et gynecologues du Canada RECOMMANDATIONS. PMID- 28729106 TI - No. 223-Content of a Complete Routine Second Trimester Obstetrical Ultrasound Examination and Report. AB - OBJECTIVE: To review the benefits of and requirements for a complete second trimester ultrasound and the documentation needed. OUTCOMES: A complete second trimester ultrasound provides information about the number of fetuses, the gestational age, the location of the placenta, and fetal and maternal anatomy. EVIDENCE: In the production of this document, the American Institute of Ultrasound in Medicine's "Practice Guideline for the Performance of Obstetric Ultrasound Examinations," the American College of Obstetricians and Gynecologists' practice bulletin, "Ultrasound in Pregnancy," and the Royal College of Obstetricians and Gynaecologists' Working Party Report, "Ultrasound Screening" were reviewed. PubMed and the Cochrane Database were searched using the words "routine second trimester obstetrical ultrasound." VALUES: The evidence was evaluated using the guidelines developed by the Canadian Task Force on Preventive Health Care. BENEFITS, HARMS, AND COSTS: A routine complete second trimester ultrasound between 18 and 22 weeks and a complete ultrasound report will provide the best opportunity to diagnose fetal anomalies and to assist in the management of prenatal care. It will also reduce the number of ultrasound examinations done during the second trimester for completion of fetal anatomy survey. The costs are those involved with the performance of obstetrical ultrasound. VALIDATION: This is a revision of previous guidelines; information from other consensus reviews from medical publications has been used. SPONSORS: The Society of Obstetricians and Gynaecologists of Canada. RECOMMENDATIONS: PMID- 28729107 TI - ? PMID- 28729108 TI - No. 214-Guidelines for the Management of Pregnancy at 41+0 to 42+0 Weeks. AB - OBJECTIVE: To provide evidence-based guidelines for the management of pregnancy at 41+0 to 42+0 weeks. OUTCOMES: Reduction of perinatal mortality associated with Caesarean section at 41+0 to 42+0 weeks of pregnancy. EVIDENCE: The Medline database, the Cochrane Library, and the American College of Obstetricians and Gynecologists and the Royal College of Obstetricians and Gynecologists, were searched for English language articles published between 1966 and March 2007, using the following key words: prolonged pregnancy, post-term pregnancy, and postdates pregnancy. The quality of evidence was evaluated and recommendations were made according to guidelines developed by the Canadian Task Force on Preventive Health Care. RECOMMENDATIONS: PMID- 28729109 TI - ? AB - OBJECTIF: Analyser les resultats et fournir des recommandations au sujet du depistage et de la prise en charge de la vaginose bacterienne pendant la grossesse. OPTIONS: Les options de pratique clinique prises en consideration au moment de formuler la presente directive clinique. ISSUES: Parmi les issues evaluees, on trouve les taux d'efficacite et de guerison de l'antibiotherapie, et l'influence de la prise en charge de la vaginose bacterienne sur les taux d'issues de grossesse indesirables (tels que le travail et l'accouchement pretermes, et la rupture prematuree des membranes preterme). ReSULTATS: Des recherches ont ete menees dans les bases de donnees Medline, EMBASE, CINAHL et Cochrane afin d'en tirer les articles, publies en anglais avant le fin de juin 2007, traitant de la vaginose bacterienne pendant la grossesse. VALEURS: Les donnees obtenues ont ete evaluees au moyen des criteres elabores par le Groupe d'etude canadien sur les soins de sante preventifs. Avantages, desavantages et couts : La mise en oeuvre de la presente directive clinique aidera le praticien a elaborer une approche quant au diagnostic et a la prise en charge de la vaginose bacterienne chez les femmes enceintes. Les patientes beneficieront d'une prise en charge appropriee de cette pathologie. VALIDATION: La presente directive clinique a ete redigee par le comite sur les maladies infectieuses et approuvee par le comite executif et le Conseil de la Societe des obstetriciens et gynecologues du Canada. COMMANDITAIRE: La Societe des obstetriciens et gynecologues du Canada. RECOMMANDATIONS: Il n'existe presentement aucun consensus quant a la question de savoir s'il faut proceder au depistage ou a la prise en charge de la vaginose bacterienne, au sein de la population generale de femmes enceintes, afin de prevenir la survenue d'issues indesirables (telles que l'accouchement preterme). PMID- 28729110 TI - No. 211-Screening and Management of Bacterial Vaginosis in Pregnancy. AB - OBJECTIVE: To review the evidence and provide recommendations on screening for and management of bacterial vaginosis in pregnancy. OPTIONS: The clinical practice options considered in formulating the guideline. OUTCOMES: Outcomes evaluated include antibiotic treatment efficacy and cure rates, and the influence of the treatment of bacterial vaginosis on the rates of adverse pregnancy outcomes such as preterm labour and delivery and preterm premature rupture of membranes. EVIDENCE: Medline, EMBASE, CINAHL, and Cochrane databases were searched for articles, published in English before the end of June 2007 on the topic of bacterial vaginosis in pregnancy. VALUES: The evidence obtained was rated using the criteria developed by the Canadian Task Force on Preventive Health Care. BENEFITS, HARMS, AND COSTS: Guideline implementation will assist the practitioner in developing an approach to the diagnosis and treatment of bacterial vaginosis in pregnant women. Patients will benefit from appropriate management of this condition. VALIDATION: These guidelines have been prepared by the Infectious Diseases Committee of the SOGC, and approved by the Executive and Council of the SOGC. SPONSORS: The Society of Obstetricians and Gynaecologists of Canada. RECOMMENDATIONS: There is currently no consensus as to whether to screen for or treat bacterial vaginosis in the general pregnant population in order to prevent adverse outcomes, such as preterm birth. PMID- 28729111 TI - ? PMID- 28729112 TI - No. 208-Guidelines for the Management of Herpes Simplex Virus in Pregnancy. AB - OBJECTIVE: To provide recommendations for the management of genital herpes infection in women who want to get pregnant or are pregnant and for the management of genital herpes in pregnancy and strategies to prevent transmission to the infant. OUTCOMES: More effective management of complications of genital herpes in pregnancy and prevention of transmission of genital herpes from mother to infant. EVIDENCE: Medline was searched for articles published in French or English related to genital herpes and pregnancy. Additional articles were identified through the references of these articles. All study types and recommendation reports were reviewed. VALUES: Recommendations were made according to the guidelines developed by the Canadian Task Force on Preventive Health Care. RECOMMENDATIONS: VALIDATION: These guidelines have been reviewed and approved by the Infectious Diseases Committee of the SOGC. SPONSOR: The Society of Obstetricians and Gynaecologists of Canada. PMID- 28729113 TI - Activation of RAGE/STAT3 pathway by methylglyoxal contributes to spinal central sensitization and persistent pain induced by bortezomib. AB - Bortezomib is a first-line chemotherapeutic drug widely used for multiple myeloma and other nonsolid malignancies. Although bortezomib-induced persistent pain is easily diagnosed in clinic, the pathogenic mechanism remains unclear. Here, we studied this issue with use of a rat model of systemic intraperitoneal administration of bortezomib for consecutive 5days. Consisted with our previous study, we found that bortezomib treatment markedly induced mechanical allodynia in rats. Furthermore, we first found that bortezomib treatment significantly induced the upregulation of methylglyoxal in spinal dorsal horn of rats. Spinal local application of methylglyoxal also induced mechanical allodynia and central sensitization in normal rats. Moreover, administration of bortezomib upregulated the expression of receptors for advanced glycation end products (RAGE) and phosphorylated STAT3 (p-STAT3) in dorsal horn. Importantly, intrathecal injection of metformin, a known scavenger of methylglyoxal, significantly attenuated the upregulation of methylglyoxal and RAGE in dorsal horn, central sensitization and mechanical allodynia induced by bortezomib treatment, and blockage of RAGE also prevented the upregulation of p-STAT3, central sensitization and mechanical allodynia induced by bortezomib treatment. In addition, inhibition of STAT3 activity by S3I-201 attenuated bortezomib-induced mechanical allodynia and central sensitization. Local knockdown of STAT3 also ameliorated the mechanical allodynia induced by bortezomib administration. Our results suggest that accumulation of methylglyoxal may activate the RAGE/STAT3 signaling pathway in dorsal horn, and contributes to the spinal central sensitization and persistent pain induced by bortezomib treatment. PMID- 28729114 TI - Altered intrinsic functional connectivity in the latent period of epileptogenesis in a temporal lobe epilepsy model. AB - The latent period, a seizure-free phase, is the duration between brain injury and the onset of spontaneous recurrent seizures (SRSs) during epileptogenesis. The latent period is thought to involve several progressive pathophysiological events that lead to the evolution of the chronic epilepsy phase. Hence, it is vital to investigate the changes in the latent period during epileptogenesis in order to better understand temporal lobe epilepsy (TLE), and to achieve early diagnosis and appropriate management of the condition. Accordingly, recent studies with patients with TLE using resting-state functional magnetic resonance imaging (rs fMRI) have reported that alterations of resting-state functional connectivity (rsFC) during the chronic period are associated with some clinical manifestations, including learning and memory impairments, emotional instability, and social behavior deficits, in addition to repetitive seizure episodes. In contrast, the changes in the intrinsic rsFC during epileptogenesis, particularly during the latent period, remain unclear. In this study, we investigated the alterations in intrinsic rsFC during the latent and chronic periods in a pilocarpine-induced TLE mouse model using intrinsic optical signal imaging (IOSI). This technique can monitor the changes in the local hemoglobin concentration according to neuronal activity and can help investigate large-scale brain intrinsic networks. After seeding on the anatomical regions of interest (ROIs) and calculating the correlation coefficients between each ROI, we established and compared functional correlation matrices and functional connectivity maps during the latent and chronic periods of epilepsy. We found a decrease in the interhemispheric rsFC at the frontal and temporal regions during both the latent and chronic periods. Furthermore, a significant decrease in the interhemispheric rsFC was observed in the somatosensory area during the chronic period. Changes in network configurations during epileptogenesis were examined by graph theoretical network analysis. Interestingly, increase in the power of low frequency oscillations was observed during the latent period. These results suggest that, even if there are no apparent ictal seizure events during the latent period, there are ongoing changes in the rsFC in the epileptic brain. Furthermore, these results suggest that the pathophysiology of epilepsy may be related to widespread altered intrinsic functional connectivity. These findings can help enhance our understanding of epileptogenesis, and accordingly, changes in intrinsic functional connectivity can serve as an early diagnosis. PMID- 28729117 TI - Term respiratory distress. PMID- 28729116 TI - Convergence of glycogen synthase kinase 3beta and GR signaling in response to fluoxetine treatment in chronically stressed female and male rats. AB - Accumulating evidence strongly suggest that impaired glucocorticoid receptor (GR) signaling is involved in stress-related mood disorders, and nominate GR as a potential target for antidepressants (ADs). It is known that different classes of ADs affects the GR action via modifying its phosphorylation, while the mechanism through which ADs alter GR phosphorylation targeted by GSK3beta, a kinase modulated via serotonin neurotransmission, are unclear. On this basis, we investigated whether GSK3beta-GR signaling could be a convergence point of fluoxetine action on brain function and behavior, by examining its effect on GSK3beta targeted-GR phosphorylation on threonine 171 (pGR171), and expression of GR-regulated genes in the hippocampus of female and male rats exposed to chronic isolation stress. Stress induced sex-specific GSK3beta-targeted phosphorylation of pGR171 in the nucleus of the hippocampus of stressed animals. Namely, while in females stress triggered coupled action of GSK3beta-pGR171 signaling, in males changes in pGR171 levels did not correspond to GSK3beta activity. On the other hand, fluoxetine managed to up-regulate this pathway in sex-unbiased manner. Furthermore, fluoxetine reverted stress-induced changes in most of the analyzed genes in males, CRH, 5-HT1a and p11, while in females its effect was limited to CRH. These data further suggest that pGR171 signaling affects cellular localization of GR in response to chronic stress and fluoxetine in both sexes. Collectively, our results describe a novel convergence point between GR signaling and GSK3beta pathway in rat hippocampus in response to stress and fluoxetine in both sexes and its involvement in fluoxetine-regulated brain function in males. PMID- 28729115 TI - Arousal and drug abuse. AB - The reticular activating system (RAS) is not an amorphous region but distinct nuclei with specific membrane properties that dictate their firing during waking and sleep. The locus coeruleus and raphe nucleus fire during waking and slow wave sleep, with the pedunculopontine nucleus (PPN) firing during both waking and REM sleep, the states manifesting arousal-related EEG activity. Two important discoveries in the PPN in the last 10 years are, 1) that some PPN cells are electrically coupled, and 2) every PPN cell manifests high threshold calcium channels that allow them to oscillate at beta/gamma band frequencies. The role of arousal in drug abuse is considered here in terms of the effects of drugs of abuse on these two mechanisms. Drug abuse and the perception of withdrawal/relapse are mediated by neurobiological processes that occur only when we are awake, not when we are asleep. These relationships focus on the potential role of arousal, more specifically of RAS electrical coupling and gamma band activity, in the addictive process as well as the relapse to drug use. PMID- 28729119 TI - Effect of flowable composites on the clinical performance of non-carious cervical lesions: A systematic review and meta-analysis. AB - OBJECTIVES: To answer the following PICO question (participant, intervention, comparator and outcome): Does flowable resin composite restorations compared with regular resin composites improve the marginal adaptation, marginal discoloration and retention rates of restorations placed in non-carious cervical lesions [NCCLs] of adults?, through a systematic review and meta-analysis. SOURCE: MEDLINE, Scopus, Web of Science, LILACS, BBO, Cochrane Library and SIGLE were searched without restrictions, as well as the abstracts of the IADR, clinical trials registries, dissertations and theses in May 2016 (updated in April 2017). STUDY SELECTION: We included randomized clinical trials (RCTs) that answered the PICO question. RCTs were excluded if cavities other than NCCLs were treated; indirect restorations; polyacid-based resins instead of composite resins were employed, restorations in primary teeth and restorations were placed in carious cervical lesions. The risk of bias tool of the Cochrane Collaboration was applied in the eligible studies and the GRADE tool was used to assess the quality of the evidence. DATA: After duplicates removal, 5137 articles were identified. After abstract and title screening, 8 studies remained. Six were at "unclear" risk of bias. The study follow-ups ranged from 1 to 3 years. No significant difference was observed between groups for loss of retention and marginal discoloration in all follow-ups. Better marginal adaptation was observed for restorations performed with flowable composites. At 1-year (risk ratio=0.27 [0.10 to 0.70]) and 3-year (risk ratio=0.34 [0.17 to 0.71]) follow-ups, flowable composites showed a risk 73% and 66% lower than regular composites for lack of adaptation, respectively. The evidence was graded as moderate quality for loss or retention at 3 years due to risk of bias and low and very low for all other outcomes due to risk of bias, imprecision and inconsistency. CONCLUSIONS: We have moderate confidence that the resin composite viscosity does not influence the retention rates at 3 years. Similar marginal discoloration and better marginal adaptation was observed for flowable composites but the quality of evidence is doubtful. (PROSPERO CRD42015019560). PMID- 28729118 TI - HBK-14 and HBK-15, triple 5-HT1A, 5-HT7 and 5-HT3 antagonists with potent antidepressant- and anxiolytic-like properties, increase seizure threshold in various seizure tests in mice. AB - Most antidepressants lower seizure threshold, which might be due to the modulation of serotonergic neurotransmission. Here, we investigated the effects of two 5-HT1A, 5-HT7 and 5-HT3 antagonists, i.e., 1-(2-(2-(2,6 dimethylphenoxy)ethoxy)ethyl)-4-(2-methoxyphenyl)piperazine hydrochloride (HBK 14) and 1-{2-[2-(2-chloro-6-methylphenoxy)ethoxy]ethyl}-4-(2 methoxyphenyl)piperazine hydrochloride (HBK-15), with antidepressant- and anxiolytic-like properties, on seizure thresholds in three acute seizure tests, i.e., the intravenous pentylenetetrazole, maximal electroshock seizure threshold (MEST), and 6-Hz corneal stimulation test in mice. We also evaluated their affinity for voltage-gated sodium channels. Our results indicate that HBK-14 increased seizure thresholds in three seizure tests in mice, while HBK-15 was active in the MEST and 6-Hz tests. None of the compounds affected neuromuscular strength or motor coordination at active doses. We showed that both compounds had high affinity for voltage-dependent sodium channels, which combined with the influence on 5-HT1A, 5-HT7 and 5-HT3 receptors, might underlie their anticonvulsant effects. Since most antidepressants lower the seizure threshold, the fact that both compounds with potent antidepressant-like activity, increased or had no influence on seizure threshold is worth investigating. PMID- 28729120 TI - Hematopoietic Stem Cell Transplantation for Multiple Myeloma. AB - OBJECTIVE: To provide an overview of the hematopoietic stem cell transplantation (HSCT) process specific to patients with multiple myeloma (MM) and their caregivers. DATA SOURCES: Research studies, book chapters, websites, expert knowledge, and journal articles. CONCLUSION: Although not curative, autologous HSCT is an important, manageable treatment modality, and continues to be a standard of care in MM for those patients who are eligible. IMPLICATIONS FOR NURSING PRACTICE: Although an area of specialty practice, an understanding of the HSCT process is important to broaden the knowledge of all nurses who care for patients with MM. PMID- 28729121 TI - Multiple Myeloma Genomics: A Systematic Review. AB - OBJECTIVES: This integrative review describes the genomic variants that have been found to be associated with poor prognosis in patients diagnosed with multiple myeloma (MM). Second, it identifies MM genetic and genomic changes using next generation sequencing, specifically whole-genome sequencing or exome sequencing. DATA SOURCE: A search for peer-reviewed articles through PubMed, EBSCOhost, and DePaul WorldCat Libraries Worldwide yielded 33 articles that were included in the final analysis. CONCLUSION: The most commonly reported genetic changes were KRAS, NRAS, TP53, FAM46C, BRAF, DIS3, ATM, and CCND1. These genetic changes play a role in the pathogenesis of MM, prognostication, and therapeutic targets for novel therapies. IMPLICATIONS FOR NURSING PRACTICE: MM genetics and genomics are expanding rapidly; oncology nurse clinicians must have basic competencies in genetics and genomics to help patients understand the complexities of genetic and genomic alterations and be able to refer patients to appropriate genomic professionals if needed. PMID- 28729122 TI - Evidence-Based Guidelines for Preventing and Managing Side Effects of Multiple Myeloma. AB - OBJECTIVE: To review disease-related symptoms and side effects of treatment in patients with multiple myeloma (MM). DATA SOURCES: Peer-reviewed articles, research studies, and clinical guidelines. CONCLUSION: New therapies provide patients with extended survival, but in many cases this benefit is counterbalanced by an increased incidence of side effects. Preservation of organ function, while managing side effects, is essential for the care of patients with MM. IMPLICATIONS FOR NURSING PRACTICE: Disease- and treatment-related adverse events are prevalent in patients with MM. Patient, family, and health care professional education is essential to monitor and manage these side effects. PMID- 28729123 TI - Increased colistin resistance upon acquisition of the plasmid-mediated mcr-1 gene in Escherichia coli isolates with chromosomally encoded reduced susceptibility to polymyxins. PMID- 28729124 TI - Trends in antimicrobial resistance in Neisseria gonorrhoeae and molecular characteristics of N. gonorrhoeae with decreased susceptibility to ceftriaxone in Shandong, China, 2007 to 2014. AB - In this study, the trends of antimicrobial resistance in Neisseria gonorrhoeae were analysed in Shandong Province of China during 2007 to 2014. Furthermore, the ceftriaxone (CRO) genetic resistance determinants, including penA, mtrR, penB, ponA, and pilQ genes, were sequenced and the molecular mechanisms of decreased susceptibility or resistance to CRO in N. gonorrhoeae were elucidated. Overall, the increasing trends of resistance to penicillin (PEN), tetracycline (TET), and ciprofloxacin (CIP), and decreasing trends of susceptibility to CRO and azithromycin (AZM) were observed in Shandong Province between 2007 and 2014. The proportions of PPNG, TRNG, PP/TRNG, and MDR isolates increased sharply in this district. PenA mosaic structure, the substitution of A501V, and an insertion of aspartate in amino acid position 345 were identified in the N. gonorrhoeae isolates with decreased susceptibility or resistance to CRO. All the 28 N. gonorrhoeae isolates had substitutions at Gly-120 and Ala-121 of porin encoded by penB, substitution of L421P in PBP1, and a single nucleotide (A) deletion in the 13 bp inverted repeat located between the -10 and -35 sequences in the mtrR promoter. Additionally, 21 N.gonorrhoeae isolates had substitutions of A39T/G45D in MtrR, and three new substitutions of R44G, L47R, and/or H105F in MtrR were observed. Therefore, PenA mosaic structure in N. gonorrhoeae and the substitutions of Ala-501 in PBP2 may considerably increase CRO MICs. A close association between the genetic polymorphisms in mtrR, penB, and ponA and the development of decreased susceptibility to CRO might be confirmed. PMID- 28729126 TI - What You Need to Know about Pediatric and Adolescent Gynecology: Clinically Relevant Reviews Published in the Journal of Pediatric and Adolescent Gynecology. PMID- 28729125 TI - Comparative effects of vitamin D and methylprednisolone against ischemia/reperfusion injury of rabbit spinal cords. AB - INTRODUCTION: Recent studies have demonstrated the neuroprotective and immunomodulatory effects of 1,25-dihydroxyvitamin D3 (calcitriol), but no previous study has examined these effects on spinal cord ischemia/reperfusion (I/R) injury. Therefore, the present study aimed to evaluate whether calcitriol protects the spinal cord from I/R injury. METHODS: Rabbits were randomized into four groups of eight animals: group 1 (laparotomy control), group 2 (ischemia control), group 3 (30mg/kg intraperitoneal methylprednisolone at surgery), and group 4 (0.5MUg/kg, intraperitoneal calcitriol for 7 days before I/R injury). The rabbits in the laparotomy control group underwent laparotomy only, whereas all rabbits in the other groups were subject to spinal cord ischemia by aortic occlusion for 20min, just caudal to the renal artery. Malondialdehyde and catalase levels, myeloperoxidase and xanthine oxidase activities, and caspase-3 concentrations were analyzed. Finally, histopathological, ultrastructural, and neurological evaluations were performed. RESULTS: After I/R injury, increases in malondialdehyde levels, myeloperoxidase and xanthine oxidase activities, and caspase-3 concentrations were found (p<0.001 for all); by contrast, catalase levels decreased (p<0.001). Calcitriol pretreatment was associated with lower malondialdehyde levels (p<0.001), reduced myeloperoxidase (serum, p=0.018; tissue, p<0.001) and xanthine oxidase (p<0.001) activities, and caspase-3 concentrations (p<0.001), but increased catalase levels (p<0.001). Furthermore, calcitriol pretreatment was associated with better histopathological, ultrastructural, and neurological scores. CONCLUSION: Calcitriol pretreatment provided significant neuroprotective benefits following spinal cord I/R injury. PMID- 28729127 TI - Variation in Safe Sleep and Breastfeeding Practices Among Non-Hispanic Black Mothers in the United States According to Birth Country. AB - OBJECTIVE: To examine variation in safe sleep and breastfeeding practices among US non-Hispanic black (NHB) mothers according to birth country. METHODS: We analyzed NHB mothers who were surveyed regarding safe sleep and breastfeeding practices when their infants were 2 to 6 months of age in 2011 to 2014, as part of a larger national study. We examined prevalences of safe sleep and breastfeeding practices according to birth country and examined odds of adherence to American Academy of Pediatrics recommended safe sleep and breastfeeding practices in foreign-born NHB mothers, compared with US-born NHB mothers. Our multivariate models included adjustment for maternal age, education, income, and US geographic region, and infant age at the time of the survey. RESULTS: Among 828 NHB mothers, 690 (83%) were US-born, 42 (5%) were African-born, 47 (6%) were Haitian-born, 24 (3%) were Jamaican-born, and 25 (3%) were born elsewhere. In the analysis of 803 US, African-, Haitian-, and Jamaican-born mothers, we found that Jamaican-born mothers had a lower rate of supine sleep compared with US-born mothers (40% vs 66%; adjusted odds ratio, 0.34; 95% confidence interval, 0.18 0.63). African-born mothers had lower rates of bedsharing compared with US-born mothers (11% vs 25% adjusted odds ratio, 0.22; 95% confidence interval, 0.11 0.46). Foreign-born mothers had higher rates of any and exclusive breastfeeding, compared with US-born mothers (85% and 40% vs 23% and 13%, respectively). CONCLUSIONS: Safe sleep and breastfeeding practices vary among US NHB mothers according to birth country. These data illustrate the importance of recognizing heterogeneity of safe sleep and breastfeeding practices within racial/ethnic groups. PMID- 28729128 TI - Rosettes, Engrailed Edges, and Star-Shaped Patterns: Between Rediscovery and Forgetfulness in the Early Accounts of Vibrating Liquid Drops Floating over Hot Surfaces. AB - Small drops of liquid brought into contact with very hot surfaces float above it as beautiful, slightly flattened spheroids without coming to the boil. An example of film boiling, drops that are sessile can often suddenly and quite unexpectedly start to oscillate forming highly symmetric patterns of surprising pulchritude. The rim of these oscillating drops take on "star-shaped" patterns with many different modes of vibration possible. Still an object of study today, their discovery, early accounts, rediscovery and ensuing controversies over claims of priority, before quietly slipping away from the collective memory of the scientific community to become all but forgotten makes for a compelling story in the early history of film boiling. The episode serves not only as a valuable reminder of the importance the history of science can play in highlighting past achievements that would otherwise remain unknown to the modern practitioner. It also provides an example of how external pressures and personal ambition can often influence the work of a scientist in their pursuit of self-recognition and acclaim amongst their peers. PMID- 28729129 TI - Exploring beliefs on diabetes treatment adherence among Dutch type 2 diabetes patients and healthcare providers. AB - OBJECTIVE: Despite well-known beneficial effects, adherence to core elements of diabetes treatment is suboptimal. This study, conducted in the Netherlands, aimed to explore if and how treatment adherence success factors are applied in diabetes consultations, and to explore salient personal beliefs about type 2 diabetes treatment including both healthy lifestyle adaptations and pharmacotherapy. METHODS: A qualitative study using semi-structured interviews among nine Dutch healthcare providers predominantly involved in diabetes management and 19 Dutch type 2 diabetes patients. Data was systematically analysed through deductive coding analysis using Nvivo. RESULTS: Most patients visited their consultations unprepared. Patients did not or vaguely experience goal-setting in consultations, whereas healthcare providers indicated to set treatment goals. Shared-decision making was applied, however patients were rather passive collaborators as mostly healthcare providers were in charge of making treatment decisions. Despite suboptimal treatment adherence, many advantages and few disadvantages of treatment strategies were reported. Adherence self-efficacy was lower in situations outside daily routine. CONCLUSION: Treatment adherence success factors are not optimally applied, and in particular treatment adherence self-efficacy could be improved. PRACTICE IMPLICATIONS: The application of treatment adherence success factors in consultations could be improved, and personal beliefs should be addressed to improve treatment adherence and optimize counselling. PMID- 28729130 TI - Information needs about palliative care and euthanasia: A survey of patients in different phases of their cancer trajectory. AB - OBJECTIVE: We assessed information provision and information needs about illness course, treatments, palliative care and euthanasia in cancer patients. METHODS: Cancer patients consulting a university hospital (N=620) filled out a questionnaire. Their cancer related data were collected through the treating oncologist. This study is performed in Belgium, where "palliative care for all" is a patient's right embedded in the law and euthanasia is possible under certain conditions. RESULTS: Around 80% received information about their illness course and treatments. Ten percent received information about palliative care and euthanasia. Most information about palliative care and euthanasia was given when the patient had a life expectancy of less than six months. However, a quarter of those in earlier phases in their illness trajectory, particularly those who experienced high pain, fatigue or nausea requested more information on these topics. CONCLUSION: Many patients want more information about palliative care and euthanasia than what is currently provided, also those in an earlier than terminal phase of their disease. PRACTICE IMPLICATIONS: Healthcare professionals should be more responsive, already from diagnosis, to the information needs about palliative care and possible end-of-life decisions. This should be patient tailored, as some patients want more and some patients want less information. PMID- 28729131 TI - Eosinophilic hyperplastic lymphogranuloma: Clinical diagnosis and treatment experience of 41 cases. AB - PURPOSE: The purpose of this study was to investigate the clinical features of eosinophilic hyperplastic lymphogranuloma (EHLG) in the head and neck. MATERIALS AND METHODS: Collecting the patients who diagnose with EHLG by pathological examination. The EHLG patients with the masses involved regions, such as involved inguinal region, chest wall, abdominal wall, anterior superior iliac spine or clavicle, instead of head and neck were excluding. All of the participants will sign the informed consent form. The history data includes: clinical history, blood routine test, pathological examination, and recurrence will be collected. RESULTS: A total of 41 patients of EHLG were included. These patients predominantly presented as an enlarging and painless single or multiple masses with a history of repeated swelling. There were the complaint of itchy skin and pigmentation. The routine blood test showed that the percentage value of eosinophil increased in almost patients including 26 cases had raised absolute eosinophil count. The serum level of lgE was increased in 29 cases remarkably. With the methods of treatments, 36 patients received surgical excision, 3 patients accepted hormonotherapy, and another 2 patients for radiotherapy. The recurrence of EHLG was in 9 patients. CONCLUSIONS: EHLG is a rare disease. The clinical manifestation (itchy skin and pigmentation) and increased eosinophil play critical values to the diagnosis of EHLG. Confirmed diagnosis always depends on pathological examination. Surgery is a preferred treatment, while low dose of radiotherapy is necessary for preventing relapse after operation and hormonotherapy. PMID- 28729132 TI - MeClas: An online tool for hazard identification and classification of complex inorganic metal-containing materials. AB - MeClas is a web-based tool to generate (eco)toxicity hazard categories and corresponding classification & labelling information of inorganic metal containing complex materials such as ores, concentrates, intermediates or alloys for which the manual application of the GHS/CLP rules is very complex and requires a high level of consistency. The tool comprises several tiers, aimed at the progressive refinement of classification through recognition of specific mineral content, speciation/mineralogy up to bio-availability corrections. Where relevant in a regional jurisdiction (EU and US), mandatory classification references are used complementary to high quality (eco)toxicity reference values (ERV/TRV) and self-classifications. MeClas addresses the GHS human health and environmental hazard endpoints, is based on an unambiguous algorithm defined under GHS/CLP, has a well defined domain of applicability and robust predictability. MeClas allows a consistent approach across companies in line with GHS ruling (and regional implementations), considering the metal specificities and related classification GHS/CLP Guidance, and the most up to date (eco) toxicological hazard information on self-classifications and ERV/TRV. PMID- 28729133 TI - Hybrid framework for feasible modeling of an edge illumination X-ray phase contrast imaging system at a human scale. AB - Here, we present a hybrid approach for simulating an edge illumination X-ray phase-contrast imaging (EIXPCi) set-up using graphics processor units (GPU) with a high degree of accuracy. In this study, the applicability of pixel, mesh and non-uniform rational B-splines (NURBS) objects to carry out realistic maps of X ray phase-contrast distribution at a human scale is accounted for by using numerical anthropomorphic phantoms and a very fast and robust simulation framework which integrates total interaction probabilities along selected X-ray paths. We exploit the mathematical and algorithmic properties of NURBS and describe how to represent human scale phantoms in an edge illumination X-ray phase-contrast model. The presented implementation allows the modeling of a variety of physical interactions of x-rays with different mathematically described objects and the recording of quantities, e.g. path integrals, interaction sites and deposited energies. Furthermore, our efficient, scalable and optimized hybrid Monte Carlo and ray-tracing projector can be used in iterative reconstruction algorithms on multi GPU heterogeneous systems. The preliminary results of our innovative approach show the fine performance of an edge illumination X-ray phase-contrast medical imaging system on various human like soft tissues with noticeably reduced computation time. Our approach to the EIXPCi modeling confirms that building a true imaging system at a human scale should be possible and the simulations presented here aim at its future development. PMID- 28729134 TI - Macrophage migration inhibitory factor levels in serum from patients with acute intracerebral hemorrhage: Potential contribution to prognosis. AB - BACKGROUND: Intracerebral hemorrhage (ICH) pathophysiology involves inflammation. Macrophage migration inhibition factor (MIF), a pro-inflammatory cytokine, is related to prognosis of ischemic stroke. The aim of this study was to investigate whether serum MIF levels are associated with severity and outcomes in patients with acute ICH. METHODS: We enrolled a total of 120 consecutive ICH patients and 120 healthy controls and sampled blood on admission and at study entry respectively. Enzyme-linked immunosorbent assay was used to quantify serum MIF levels. RESULTS: Serum MIF levels were higher in patients compared with controls and correlated with hematoma volume, National Institutes of Health Stroke Scale (NIHSS) scores and plasma C-reactive protein levels. After adjusting for other significant outcome predictors, MIF in serum was an independent predictor of 6 month overall survival and unfavorable outcome (modified Rankin Scale score >2). Areas under receiver-operating characteristic curve (ROC) of serum MIF levels, hematoma volume and NIHSS scores were similar for 6-month unfavorable outcome. Moreover, serum MIF levels significantly improved areas under ROC of hematoma volume and NIHSS scores. CONCLUSIONS: MIF in serum might be a potential biomarker for reflecting inflammation, severity and prognosis of ICH patients. PMID- 28729135 TI - Tumor-stroma ratio(TSR) as a potential novel predictor of prognosis in digestive system cancers: A meta-analysis. AB - MAIN PROBLEM: The tumor-stroma ratio (TSR) has been reported as a prognosis predictor in multiple cancers. The aim of this meta-analysis was to investigate the potential value of TSR as a prognostic predictor of cancer in the digestive system. METHODS: We searched PubMed, Embase, Elsevier and Web of Science. All studies exploring the association of TSR with overall survival (OS) or disease free survival (DFS), and lymph node metastasis (LNM) were identified. RESULTS: In total, eight studies were eligible for analysis, and they included 1959 patients. Meta-analysis showed that the low TSR in the tumor could predict poor overall survival (OS) in multiple cancers (pooled Hazard Ratio [HR]: 2.15, 95%CI: 1.80 2.57, P<0.00001, fixed effects). For disease-free survival (DFS), low TSR was also a significant predictor (pooled Hazard Ratio [HR]: 2.31, 95%CI: 1.88-2.83, P<0.00001, fixed effects). In addition, low TSR was correlated with tumor stage. DISCUSSION: The tumor-stroma ratio (TSR) may potentially serve as a poor prognostic predictor for the metastasis and prognosis of cancer. PMID- 28729136 TI - Heparinase enables reliable quantification of circulating tumor DNA from heparinized plasma samples by droplet digital PCR. AB - BACKGROUND: Heparin is often used as a blood anticoagulant for tumor marker analysis but results in the inhibition of PCR detection of circulating tumor DNA (ctDNA), which has been deemed a potential "liquid biopsy". We aimed to evaluate the impact of heparinase addition on heparinized plasma samples to allow ctDNA analysis. METHODS: Plasma samples were collected in heparinized (n=194) and EDTA (n=8) tubes from hormone receptor-positive metastatic breast cancer (HR+MBC) (n=144) and pancreatic adenocarcinoma (PA) patients (n=50). Circulating ESR1 and KRAS mutations were detected with or without heparinase by digital PCR in HR+MBC and PA patients, respectively. Patients were classified into 2 subgroups i) inhibition, I+ and ii) no inhibition, I- based on a threshold of 200copies/MUL for PCR inhibition by heparin. RESULTS: In the I+ subgroup (91/144 HR+MBC and 26/50 PA), heparinase treatment significantly improved PCR efficacy, enabling ctDNA detection in 22/91 and 13/26 patients. Moreover, comparable results for ctDNA detection (4/8) were obtained with heparinized and EDTA PA samples. In the I- subgroup, heparinase addition did not quantitatively and qualitatively alter ctDNA detection. CONCLUSION: Heparinase addition removes the heparin inhibition and allows accurate ctDNA detection in heparinized samples. These findings could make the samples from heparinized blood suitable for ctDNA analysis. PMID- 28729137 TI - Discussion. PMID- 28729138 TI - Spatial working memory in the touchscreen operant platform is disrupted in female rats by ovariectomy but not estrous cycle. AB - Learning and memory deficits have been described in rats and mice after ovariectomy (OVX) and across the estrous cycle. Preclinical researchers therefore often avoid using female animals and, consequently, a large male bias exists in the preclinical cognitive literature. In the present study we examined the role of sex hormones in the touchscreen operant platform using the spatial working memory trial unique nonmatching-to-location (TUNL) task. Twenty-nine Long Evans rats were trained to acquire the TUNL task including three incremental spatial separations (S0, S1, S2). Following 20 consecutive days of training, subjects in experiment 1 (n=15) remained intact and immediately progressed to TUNL testing, while subjects in experiment 2 were OVX (n=6) or sham-operated (n=8) prior to testing. Subjects were tested on 4 spatial separations (S0-3) with a 1s or 6s delay between the sample and nonmatching stimuli. The estrous cycle of intact rats was monitored during the 4weeks of testing. The estrous cycle phase did not significantly affect performance. In contrast, compared to intact rats, OVX impaired performance at larger spatial separations (S2-3) during the 1s delay condition. Further, during the 6s delay, OVX impaired S2 performance, however not S3. Our results suggest a probable shift in cognitive strategy following OVX, when tested with a large and novel spatial separation. Our findings suggest that ovarian hormone deprivation following OVX, but not estrous cycle, impairs spatial working memory as measured by the TUNL task. This research is relevant for future studies utilising the touchscreen TUNL task and for cognitive testing of female rats. PMID- 28729139 TI - Endoscope drying and its pitfalls. AB - Inadequate drying of endoscope channels is a possible cause of replication and survival of remaining pathogens during storage. The presence during storage of potentially contaminated water in endoscope channels may promote bacterial proliferation and biofilm formation. An incomplete drying procedure or lack of drying and not storing in a vertical position are the most usual problems identified during drying and endoscope storage. Inadequate drying and storage procedures, together with inadequate cleaning and disinfection, are the most important sources of endoscope contamination and post-endoscopic infection. Flexible endoscopes may be dried in automated endoscope reprocessors (AERs), manually, or in drying/storage cabinets. Flushing of the endoscope channels with 70-90% ethyl or isopropyl alcohol followed by forced air drying is recommended by several guidelines. Current guidelines recommend that flexible endoscopes are stored in a vertical position in a closed, ventilated cupboard. Drying and storage cabinets have a drying system that circulates and forces the dry filtered air through the endoscope channels. Endoscope reprocessing guidelines are inconsistent with one another or give no exact recommendations about drying and storage of flexible endoscopes. There is no conclusive evidence on the length of time endoscopes can be safely stored before requiring re-disinfection and before they pose a contamination risk. To minimize the risk of disease transmission and nosocomial infection, modification and revision of guidelines are recommended as required to be consistent with one another. PMID- 28729140 TI - Risk of Motor Vehicle Collision and Driving Impairment with Dementia: Clinical Implications. PMID- 28729141 TI - Effects of transjugular intrahepatic portosystemic shunt (TIPS) on blood volume distribution in patients with cirrhosis. AB - BACKGROUND: Cirrhosis is accompanied by portal hypertension with splanchnic and systemic arterial vasodilation, and central hypovolaemia. A transjugular intrahepatic portosystemic shunt (TIPS) alleviates portal hypertension, but also causes major haemodynamic changes. AIMS: To investigate effects of TIPS on regional blood volume distribution, and systemic haemodynamics. METHODS: Thirteen cirrhotic patients had their regional blood volume distribution determined with gamma-camera technique before and after TIPS. Additionally, we measured systemic haemodynamics during liver vein and right heart catheterization. Central and arterial blood volume (CBV) and cardiac output (CO) were determined with indicator dilution technique. RESULTS: After TIPS, the thoracic blood volume increased (+10.4% of total blood volume (TBV), p<0.01), whereas the splanchnic blood volume decreased (-11.9% of TBV, p<0.001). CO increased (+22%, p<0.0001), and systemic vascular resistance decreased (-26%, p<0.001), whereas CBV did not change. Finally, right atrial pressure and mean pulmonary artery pressure increased after TIPS (+50%, p<0.005; +40%, p<0.05, respectively). CONCLUSIONS: TIPS restores central hypovolaemia by an increase in thoracic blood volume and alleviates splanchnic vascular congestion. In contrast, CBV seems unaltered. The improvement in central hypovolaemia is therefore based on an increase in thoracic blood volume that includes both the central venous and arterial blood volume. This is supported by an increase in preload, combined with a decrease in afterload. PMID- 28729142 TI - Nocardia farcinica Brain Abscess: Report of 3 Cases. AB - BACKGROUND: Central nervous system nocardial infection is a rarely reported disease that usually affects patients with predisposing and debilitating conditions but also the immunocompetent population. The most common variant affecting the brain is Nocardia farcinica. Management of brain nocardiosis is troublesome and requires consideration of the severity of the underlying systemic disease, the difficulties in identifying the bacterium, and the frequent delay in initiating adequate therapy. CASE DESCRIPTION: We present 3 cases of N. farcinica brain abscess (single, multiloculated, and multifocal) diagnosed in 3 patients with predisposing factors that could be successfully cured. The patients underwent craniotomy, evacuation of the purulent collection, and partial resection of the abscesses' walls. Confirmation of N. farcinica species was achieved using specific polymerase chain reaction sequencing of the 16S ribosome RNA gene. Antibiotic therapy was selected on susceptibility tests and was maintained for 10 months (1 case) and 12 months (2 cases). CONCLUSIONS: Brain nocardiosis needs to be suspected primarily (though not exclusively) in immunocompromised patients presenting with neurologic deficit and harboring intracerebral lesions resembling brain tumors. Early identification of the specific species is paramount in order to initiate long-term antibiotic therapy, acknowledging the inherent resistance of N. farcinica to third-generation cefalosporins and its susceptibility to trimethoprim-sulphamethoxazole. According to the literature, surgical excision or aspiration of the brain abscess seems to provide good chances of eradication of the disease. In our experience, successful outcome was achieved with subtotal resection and prolonged and adequate antibiotic therapy. PMID- 28729143 TI - The Prognostic Impact of Ventricular Opening in Glioblastoma Surgery: A Retrospective Single Center Analysis. AB - OBJECTIVE: Ventricular opening during glioblastoma (GBM) resection is controversial. Sufficient evidence regarding its prognostic role is missing. We investigated the impact of ventricular opening on overall survival (OS), hydrocephalus development, and postoperative morbidity in patients with GBM. METHODS: Patients who underwent primary GBM resection between 2006 and 2013 were assessed retrospectively. Established predictors for overall survival (age, Karnofsky Performance Status, extent of resection, O-6-methylguanine-DNA methyltransferase promoter methylation status, isocitrate dehydrogenase mutation status) and further clinical data (postoperative status, further treatment, preoperative tumor volume, proximity to the ventricle) were included in univariate and multivariate analyses. RESULTS: Thirteen (5.7%) of 229 patients developed a hydrocephalus. Multivariate logistic regression showed that neither ventricular opening, tumor size, proximity to the ventricle, nor extent of resection were significant risk factors for hydrocephalus. Ventricular opening did not delay postoperative therapy and was not associated with neurological morbidity. Kaplan-Meier analysis demonstrated that patients who underwent ventricular opening (n = 114) exhibited a median OS of 14.3 months (12.9-16.5), whereas patients who did not undergo ventricular opening (n = 115) exhibited a median OS of 18.6 months (16.1-20.8). However, multivariate Cox regression (n = 134) did not confirm ventricular opening as an independent negative predictor of OS (risk ratio 1.09, P = 0.77). Instead, it showed that a greater preoperative tumor volume >22.8 cm3 was a negative predictor of OS (risk ratio 1.76, P = 0.02). CONCLUSIONS: Because extent of resection is a strong independent predictor of OS and ventricular opening is safe, neurosurgeons should consider ventricular opening to achieve maximal tumor resection. PMID- 28729144 TI - Sleep Efficiency Modulates Associations Between Family Stress and Adolescent Depressive Symptoms and Negative Affect. AB - PURPOSE: The goal of this study was to determine whether sleep moderates the associations between family-related stress and depressive symptoms and negative affect outcomes during adolescence. We combined traditional survey measures of stress and depressive symptoms with daily assessments of stress and negative affect to examine whether sleep differentially impacts the link between chronic and acute experiences of stress and affect. METHODS: Participants were 316 adolescents from ethnically diverse backgrounds. Primary caregivers and adolescents reported on stressful family events during the past 12 and 3 months, respectively. Adolescents also reported on their daily experiences of family demands for 15 days and wore actigraph watches for the assessment of sleep during the first eight nights. RESULTS: Regression analyses revealed that more stressful family events were related to more depressive symptoms. This relation was stronger among adolescents with lower sleep efficiency. The same pattern emerged for the relation between daily family demands and negative affect aggregated across the 15 days. Daily-level analyses indicated that daily negative affect was related to daily family demands when sleep efficiency was higher than usual, but only among European American adolescents. CONCLUSIONS: These findings suggest that chronic experiences of lower sleep efficiency, but not sleep duration, may render adolescents more vulnerable to the negative effects of family stress on emotional adjustment. A more complex picture emerged for the role of prior night's sleep in the day-to-day variation in negative affect reactivity to family stress. PMID- 28729145 TI - Anxiety Among Adolescent Survivors of Pediatric Cancer. AB - PURPOSE: The purpose of this review was to synthesize current knowledge about anxiety among adolescent survivors of pediatric cancer and highlights areas for future research. METHODS: Systematic literature searches were conducted in five databases for articles published anytime before December 28, 2015. Manuscripts were reviewed by a team of six coders. Included manuscripts reported outcomes relevant to anxiety, worry, and post-traumatic stress in survivors of pediatric cancer (age at the time of study: 10-22 years) who were off treatment. RESULTS: Twenty-four articles met inclusion criteria. Included results were categorized into the following domains: post-traumatic stress, anxiety, cancer-related worry, and interventions. With the exception of post-traumatic stress, there was little research about anxiety in this population; however, studies generally indicated that adolescent survivors of pediatric cancer are at elevated risk for anxiety, post-traumatic stress symptoms, and cancer-related worry. CONCLUSIONS: This review provides preliminary evidence that anxiety is a relevant, but understudied, psychosocial outcome for adolescent survivors of pediatric cancer. More research is needed to better understand the presentation of anxiety in this population, its effect on survivors' quality of life, and possible areas for intervention. PMID- 28729146 TI - Construction of Nutrition Literacy Indicators for College Students in Taiwan: A Delphi Consensus Study. AB - OBJECTIVE: To use the Delphi process to select nutrition literacy (NL) indicators for Taiwan college students. DESIGN: Initial formulation of 8 principal indicators and 77 subindicators, followed by a 2-round Delphi survey and final selection of indicators. PARTICIPANTS: A total of 28 nutrition experts selected through snowball sampling; 100% response rate. MAIN OUTCOME MEASURES: An expert panel scored and ranked NL themes and indicators for relevance, representativeness, and importance. ANALYSIS: Quantitative analysis. For principal indicators, the defined cutoff was mean (relevance and representativeness) > 4 and SD < 1. For subindicators, screening criteria were: (1) >20 experts ranked the nutrition theme's importance in the top 50% of the 12 themes; (2) mean (relevance and representativeness) > 4 and SD < 1 and >20 experts ranked the indicator's importance in the top 50% of all indicators within a domain. RESULTS: Consensus was reached on 8 principal indicators and 28 subindicators in 8 themes, including 10 in understand, 8 in analyze, 5 in appraise, and 5 in apply. CONCLUSIONS AND IMPLICATIONS: An initial set of NL indicators was developed for Taiwan college students, serving as a basis to develop Taiwan College's Nutrition Literacy Scale and providing information on nutrition education. PMID- 28729149 TI - Is My Child Safe? PMID- 28729147 TI - Adult Umbilical Cord Blood Transplantation Using Myeloablative Thiotepa, Total Body Irradiation, and Fludarabine Conditioning. AB - Treatment-related mortality (TRM) remains elevated in adult patients undergoing umbilical cord blood transplantation (UCBT), including an early rise in TRM suggestive of excessive toxicity associated with the standard myeloablative total body irradiation (TBI), fludarabine, and cyclophosphamide regimen. In an attempt to reduce regimen-related toxicity, we previously studied a modified myeloablative regimen with TBI (1350 cGy) and fludarabine (160 mg/m2); TRM was decreased, but neutrophil engraftment was suboptimal. Therefore, to improve engraftment while still minimizing regimen-related toxicity, we piloted a myeloablative regimen with the addition of thiotepa (10 mg/kg) to TBI and fludarabine conditioning. Thirty-one adult patients (median age, 46 years; range, 19 to 65) with hematologic malignancies (acute leukemia/myelodysplastic syndrome, 77%; lymphoid malignancy, 23%) underwent single (n = 1) or double (n = 30) UCBT from 2010 to 2015 at our institution. The cumulative incidence of neutrophil engraftment was 90% (95% confidence interval [CI], 70% to 97%) by 60 days, with a median time to engraftment of 21 days (95% CI, 19 to 26). The cumulative incidence of platelet engraftment was 77% (95% CI, 57% to 89%) by 100 days, with a median time to engraftment of 47 days (95% CI, 37 to 73). Cumulative incidences of grades II to IV and grades III to IV acute graft-versus-host disease (GVHD) at day 100 were 45% (95% CI, 27% to 62%) and 10% (95% CI, 2% to 23%), respectively. The overall incidence of chronic GVHD at 2 years was 40% (95% CI, 22% to 57%), with 17% of patients (95% CI, 6% to 33%) experiencing moderate to severe chronic GVHD by 2 years. TRM at 180 days was 13% (95% CI, 4% to 27%), at 1 year 24% (95% CI, 10% to 41%), and at 3 years 30% (95% CI, 13% to 49%). Relapse at 1 year was 13% (95% CI, 4% to 27%) and at 3 years 19% (95% CI, 6% to 38%). With a median follow-up of 35.5 months (95% CI, 12.7 to 52.2), disease-free and overall survival at 3 years were 51% (95% CI, 29% to 69%) and 57% (95% CI, 36% to 73%), respectively. This regimen represents a reasonable alternative to myeloablative conditioning with TBI, fludarabine, and cyclophosphamide and warrants further study. PMID- 28729148 TI - Clinical-Grade-Expanded Regulatory T Cells Prevent Graft-versus-Host Disease While Allowing a Powerful T Cell-Dependent Graft-versus-Leukemia Effect in Murine Models. AB - We developed a good manufacturing practices-compatible expansion protocol to improve number and purity of regulatory T cells (Tregs) available for clinical trials. Six clinical-grade separation procedures were performed, followed by expansion with high-dose interleukin (IL)-2, anti-CD3/anti-CD28 TCR stimulation, and rapamycin for 19 days achieving a median of 8.5-fold (range, 6.25 to 13.7) expansion. FOXP3 expression was stably maintained over the culture period, while the percentage of CD127 was significantly reduced. The in vitro suppression assay showed a strong Mixed Lymphocytes Reaction inhibition. In vitro amplification did not induce any karyotypic modification. To evaluate the graft-versus-host disease (GVHD)/graft-versus-leukemia (GVL) bifunctional axis, expanded Tregs and conventional T cells (Tcons) were tested in NOD/SCID/IL2Rgnull mice injected with primary acute myeloid leukemia (AML) cells, AML cell line, acute lymphoid leukemia Philadelphia cell line, or Burkitt-like lymphoma cell line. All mice that received leukemia cells together with expanded Tregs and Tcons were rescued from leukemia and survived without GVHD, showing that Treg expansion procedure did not compromise GVHD control and the strong Tcon-mediated GVL activity. This report might represent the basis for treating high-risk leukemia and/or relapsed/refractory leukemia patients with high-dose Treg/Tcons. PMID- 28729150 TI - Dendritic Cell Recovery Impacts Outcomes after Umbilical Cord Blood and Sibling Donor Transplantation for Hematologic Malignancies. AB - Dendritic cells (DCs) orchestrate immune responses after allogeneic hematopoietic cell transplantation (HCT). We studied the association of donor myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) recovery in the landmark analysis of umbilical cord blood (UCB) and matched related donor (RD) HCT. Eighty patients (42 UCB and 38 RD recipients) with a day 100 blood sample were included in the analysis. Median age was 51 years (range, 20 to 71). Most patients had acute leukemia (50%) or lymphoma (23%) and received reduced-intensity conditioning (75%). After transplantation, UCB recipients had higher DC counts than RD recipients reaching normal levels at day 100 after transplantation (UCB median 4.7 cells/uL versus RD median 1.7 cells/uL). UCB recipients with high day 100 pDCs levels (>= median) had 2-fold lower risk of relapse compared with those with pDClow (14% versus 28%, P = .29) and a trend to improved 1-year survival in multivariate analysis with hazard ratio of .22 (95% confidence interval, .04 to 1.05; P = .057). Cytomegalovirus (CMV) reactivation had adverse impact on DC reconstitution at day 100 in both UCB and RD groups and almost exclusively affected the mDC subset (CMV reactivation: mDC 3.2 cells/uL versus no CMV reactivation: 7.8 cells/uL; P = .004). Collectively, these data suggest that high levels of circulating pDCs at day 100 after UCB transplantation confer a survival advantage at 1 year. PMID- 28729152 TI - Reduced-dose ipilimumab with standard-dose pembrolizumab: is less more? PMID- 28729151 TI - Standard-dose pembrolizumab in combination with reduced-dose ipilimumab for patients with advanced melanoma (KEYNOTE-029): an open-label, phase 1b trial. AB - BACKGROUND: Reduced-dose nivolumab in combination with standard-dose ipilimumab improves objective response and progression-free survival compared with standard dose ipilimumab alone, but increases toxicity. We assessed the safety and anti tumour activity of standard-dose pembrolizumab in combination with reduced-dose ipilimumab. METHODS: In this open-label, phase 1b trial, we recruited patients from 12 medical centres in Australia, New Zealand, and the USA. Eligible patients were aged at least 18 years, had advanced melanoma, had an Eastern Coooperative Oncology Group performance status of 0 or 1, had measurable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, had adequate organ function, had resolution of toxic effects of the most recent previous chemotherapy to grade 1 or less, had no active autoimmune disease requiring systemic steroids or immunosuppressive agents, had no active non infectious pneumonitis, had no uncontrolled thyroid dysfunction or diabetes, had no active brain metastases, and had not received previous immune checkpoint inhibitor therapy. Patients received intravenous pembrolizumab 2 mg/kg plus intravenous ipilimumab 1 mg/kg every 3 weeks for four doses, followed by intravenous pembrolizumab 2 mg/kg every 3 weeks for up to 2 years or disease progression, intolerable toxicity, withdrawal of consent, or investigator decision. The primary endpoint was safety and tolerability. The proportion of patients achieving an objective response assessed per RECIST version 1.1 by independent central review and overall survival were secondary endpoints. We also assessed progression-free survival. The primary endpoint was assessed in all patients who received at least one dose of combination therapy. Activity was assessed in all enrolled patients. This trial is registered with ClinicalTrials.gov, number NCT02089685. Enrolment into this cohort is closed, but patients are still being monitored for safety and anti-tumour activity. FINDINGS: Between Jan 13, 2015, and Sept 17, 2015, we enrolled and treated 153 patients. As of the Oct 17, 2016, cutoff date, median follow-up was 17.0 months (IQR 14.8 18.8). 110 (72%) of 153 patients received all four pembrolizumab plus ipilimumab doses; 64 (42%) remained on pembrolizumab monotherapy. 110 grade 3-4 treatment related adverse events occurred in 69 (45%) patients. No treatment-related deaths occurred. Treatment-related adverse events led to discontinuation of pembrolizumab and ipilimumab in 22 (14%) patients, including 17 (11%) who discontinued both treatments for the same event and five (3%) who discontinued ipilimumab for one event and later discontinued pembrolizumab for another. 12 (8%) patients discontinued ipilimumab only and 14 (9%) discontinued pembrolizumab only because of treatment-related adverse events. 158 immune-mediated adverse events of any grade occurred in 92 (60%) patients, and 50 immune-mediated adverse events of grade 3-4 occurred in 42 (27%) patients; the most common immune mediated adverse events were hypothyroidism (25 [16%]) and hyperthyroidism (17 [11%]). 93 (61% [95% CI 53-69]) patients achieved an objective response. Estimated 1 year progression-free survival was 69% (95% CI 60-75), and estimated 1 year overall survival was 89% (95% CI 83-93). INTERPRETATION: Standard-dose pembrolizumab given in combination with four doses of reduced-dose ipilimumab followed by standard-dose pembrolizumab has a manageable toxicity profile and provides robust anti-tumour activity in patients with advanced melanoma. These data suggest that standard-dose pembrolizumab plus reduced-dose ipilimumab might be a tolerable, efficacious treatment option for patients with advanced melanoma. A randomised phase 2 trial of alternative dosing strategies of this combination is underway. FUNDING: Merck & Co, Inc. PMID- 28729153 TI - CTLA-4 blockade in mesothelioma: ineffective or reason for optimism? PMID- 28729154 TI - Tremelimumab as second-line or third-line treatment in relapsed malignant mesothelioma (DETERMINE): a multicentre, international, randomised, double-blind, placebo-controlled phase 2b trial. AB - BACKGROUND: New therapeutic strategies for malignant mesothelioma are urgently needed. In the DETERMINE study, we investigated the effects of the cytotoxic-T lymphocyte-associated antigen 4 (CTLA-4) monoclonal antibody tremelimumab in patients with previously treated advanced malignant mesothelioma. METHODS: DETERMINE was a double-blind, placebo-controlled, phase 2b trial done at 105 study centres across 19 countries in patients with unresectable pleural or peritoneal malignant mesothelioma who had progressed after one or two previous systemic treatments for advanced disease. Eligible patients were aged 18 years or older with Eastern Cooperative Oncology Group performance status of 0 or 1 and measurable disease as defined in the modified Response Evaluation Criteria In Solid Tumors (RECIST) version 1.0 for pleural mesothelioma or RECIST version 1.1 for peritoneal mesothelioma. Patients were randomly assigned (2:1) in blocks of three, stratified by European Organisation for Research and Treatment of Cancer status (low risk vs high risk), line of therapy (second line vs third line), and anatomic site (pleural vs peritoneal), by use of an interactive voice or web system, to receive intravenous tremelimumab (10 mg/kg) or placebo every 4 weeks for 7 doses and every 12 weeks thereafter until a treatment discontinuation criterion was met. The primary endpoint was overall survival in the intention-to treat population. Safety was assessed in all patients who received at least one dose of study drug. The trial is ongoing but no longer recruiting participants, and is registered with ClinicalTrials.gov, number NCT01843374. FINDINGS: Between May 17, 2013, and Dec 4, 2014, 571 patients were randomly assigned to receive tremelimumab (n=382) or placebo (n=189), of whom 569 patients received treatment (two patients in the tremelimumab group were excluded from the safety population because they did not receive treatment). At the data cutoff date (Jan 24, 2016), 307 (80%) of 382 patients had died in the tremelimumab group and 154 (81%) of 189 patients had died in the placebo group. Median overall survival in the intention to-treat population did not differ between the treatment groups: 7.7 months (95% CI 6.8-8.9) in the tremelimumab group and 7.3 months (5.9-8.7) in the placebo group (hazard ratio 0.92 [95% CI 0.76-1.12], p=0.41). Treatment-emergent adverse events of grade 3 or worse occurred in 246 (65%) of 380 patients in the tremelimumab group and 91 (48%) of 189 patients in the placebo group; the most common were dyspnoea (34 [9%] patients in the tremelimumab group vs 27 [14%] patients in the placebo group), diarrhoea (58 [15%] vs one [<1%]), and colitis (26 [7%] vs none). The most common serious adverse events were diarrhoea (69 [18%] patients in the tremelimumab group vs one [<1%] patient in the placebo group), dyspnoea (29 [8%] vs 24 [13%]), and colitis (24 [6%] vs none). Treatment emergent events leading to death occurred in 36 (9%) of 380 patients in the tremelimumab group and 12 (6%) of 189 in the placebo group; those leading to the death of more than one patient were mesothelioma (three [1%] patients in the tremelimumab group vs two [1%] in the placebo group), dyspnoea (three [1%] vs two [1%]); respiratory failure (one [<1%] vs three [2%]), myocardial infarction (three [1%] vs none), lung infection (three [1%] patients vs none), cardiac failure (one [<1%] vs one [<1%]), and colitis (two [<1%] vs none). Treatment related adverse events leading to death occurred in five (1%) patients in the tremelimumab group and none in the placebo group. The causes of death were lung infection in one patient, intestinal perforation and small intestinal obstruction in one patient; colitis in two patients, and neuritis and skin ulcer in one patient. INTERPRETATION: Tremelimumab did not significantly prolong overall survival compared with placebo in patients with previously treated malignant mesothelioma. The safety profile of tremelimumab was consistent with the known safety profile of CTLA-4 inhibitors. Investigations into whether immunotherapy combination regimens can provide greater efficacy than monotherapies in malignant mesothelioma are ongoing. FUNDING: AstraZeneca. PMID- 28729155 TI - Incidence, mortality, and causes of death in physician-diagnosed primary Sjogren's syndrome in Korea: A nationwide, population-based study. AB - OBJECTIVES: The objective of this study was to investigate the epidemiological features of primary Sjogren's syndrome (pSS) in Korea at a national level, including the incidence, mortality, and causes of death. METHODS: We used a national, population-based registry database called the Rare Intractable Disease Registration Program from the Health Insurance Review and Assessment Service to obtain pSS patient data for the period between 2010 and 2014. pSS was diagnosed by a physician based on uniform criteria. We also used data from Statistics Korea to confirm the mortality and causes of death. RESULTS: Between 2010 and 2014, the total number of patients newly diagnosed with pSS was 5891, resulting in an annual incidence of 2.34 per 100,000 individuals. The female-to-male ratio was 14.5:1. A total of 114 pSS patients died during the study period. The overall survival rate of pSS patients was 99.0%, and the 1-year, 2-year, and 5-year survival rates were 98.7%, 98.1%, and 97.1%, respectively, and the standardized mortality ratio (SMR) was 1.47 (2.14 for males and 1.35 for females). The most common causes of death were respiratory disease (n = 25; 21.9%) followed by circulatory diseases (n = 21; 18.4%), musculoskeletal connective tissue diseases (n = 21; 18.4%), and cancer (n=19; 16.7%). CONCLUSIONS: The national incidence of pSS in Korea presented in this study was lower in comparison with reports from other countries. However, the mortality rate was significantly higher than the corresponding values in the age- and gender-matched general population. The higher mortality in pSS patients is attributable to respiratory diseases and lung cancer. PMID- 28729156 TI - Multivariate pattern analysis utilizing structural or functional MRI-In individuals with musculoskeletal pain and healthy controls: A systematic review. AB - OBJECTIVE: The purpose of this systematic review is to systematically review the evidence relating to findings generated by multivariate pattern analysis (MVPA) following structural or functional magnetic resonance imaging (fMRI) to determine if this analysis is able to: a) Discriminate between individuals with musculoskeletal pain and healthy controls, b) Predict pain perception in healthy individuals stimulated with a noxious stimulus compared to those stimulated with a non-noxious stimulus. METHODS: MEDLINE, CINAHL, Embase, PEDro, Google Scholar, Cochrane library and Web of Science were systematically screened for relevant literature using different combinations of keywords regarding structural and functional MRI analysed with MVPA, both in individuals with musculoskeletal pain and healthy controls. Reference lists of included articles were hand-searched for additional literature. Eligible articles were assessed on risk of bias and reviewed by two independent researchers. RESULTS: The search query returned 18 articles meeting the inclusion criteria. Methodological quality varied from poor to good. Seven studies investigated the ability of machine-learning algorithms to differentiate patient groups from healthy control participants. Overall, the review demonstrated that MVPA can discriminate between individuals with MSK pain and healthy controls with an overall accuracy ranging from 53% to 94%. Twelve studies utilized healthy control participants (using them as their own controls), during experimental pain paradigms aimed to investigate the ability of machine learning to differentiate individuals stimulated with noxious stimuli from those stimulated with non-noxious stimuli, with 'pain' detection rates ranging from 60% to 94%. However, significant heterogeneity in patient conditions, study methodology and brain imaging techniques resulted in various findings that make study comparisons and formal conclusions challenging. CONCLUSION: There is preliminary and emerging evidence that MVPA analyses of structural or functional MRI are able to discriminate between patients and healthy controls, and also discriminate between noxious and non-noxious stimulation. No prospective studies were found in this review to allow determination of the prognostic or diagnostic capabilities or treatment responsiveness of these analyses. Future studies would also benefit from combining various behavioural, genotype and phenotype data into analyses to assist with development of sensitive and specific signatures that could guide future individualized patient treatment options and evaluate how treatments exert their effects. PMID- 28729157 TI - Women in HIV trials: improving adherence and outcomes. PMID- 28729159 TI - What do we know about laminar connectivity? AB - In this brief review, I attempt an overview of the main components of anatomical laminar-level connectivity. These are: extrinsic outputs, excitatory and inhibitory intrinsic connectivity, and intrinsic inputs. Supporting data are biased from the visual system of nonhuman primates (NHPs), but I have drawn as much as possible from a broader span in order to treat the important issue of area-specific variability. In a second part, I briefly discuss laminar connectivity in the context of network organization (feedforward/feedback cortical connections, and the major types of corticothalamic connections). I also point out anatomical issues in need of clarification, including more systematic, whole brain coverage of tracer injections; more data on anterogradely labeled terminations; more complete, area-specific quantitative data about projection neurons, and quantitative data on terminal density and convergence. Postsynaptic targets are largely unknown, but their identification is essential for understanding the finer analysis and principles of laminar patterns. Laminar resolution MRI offers a promising new tool for exploring laminar connectivity: it is potentially fast and macro-scale, and allows for repeated investigation under different stimulus conditions. Conversely, anatomical resolution, although detailed beyond the current level of MRI visualization, offers a rich trove for experimental design and interpretation of fMRI activation patterns. PMID- 28729161 TI - The neural basis of precise visual short-term memory for complex recognisable objects. AB - Recent evidence suggests that visual short-term memory (VSTM) capacity estimated using simple objects, such as colours and oriented bars, may not generalise well to more naturalistic stimuli. More visual detail can be stored in VSTM when complex, recognisable objects are maintained compared to simple objects. It is not yet known if it is recognisability that enhances memory precision, nor whether maintenance of recognisable objects is achieved with the same network of brain regions supporting maintenance of simple objects. We used a novel stimulus generation method to parametrically warp photographic images along a continuum, allowing separate estimation of the precision of memory representations and the number of items retained. The stimulus generation method was also designed to create unrecognisable, though perceptually matched, stimuli, to investigate the impact of recognisability on VSTM. We adapted the widely-used change detection and continuous report paradigms for use with complex, photographic images. Across three functional magnetic resonance imaging (fMRI) experiments, we demonstrated greater precision for recognisable objects in VSTM compared to unrecognisable objects. This clear behavioural advantage was not the result of recruitment of additional brain regions, or of stronger mean activity within the core network. Representational similarity analysis revealed greater variability across item repetitions in the representations of recognisable, compared to unrecognisable complex objects. We therefore propose that a richer range of neural representations support VSTM for complex recognisable objects. PMID- 28729160 TI - Echo-time dependence of the BOLD response transients - A window into brain functional physiology. AB - The blood oxygenation level-dependent (BOLD) fMRI response to neuronal activation results from a complex interplay of induced metabolic and vascular changes. Thus, its transients, such as initial overshoot and post-stimulus undershoot, provide a window into the dynamic relationships of the underlying physiological variables. In this study, we propose multi-echo fMRI as a tool to investigate the physiological underpinnings of the BOLD signal, in particular, and brain functional physiology, in general. In the human visual cortex at 3 T, we observed that the BOLD response is nonlinearly dependent on echo-time (TE) and the amount of nonlinearity varies during the entire time-course. Fitting a linear model to this nonlinear relationship resulted in a positive intercept at TE = 0 ms. The time-course of the intercept exhibited fast and slow modulations, distinctly different both from the BOLD response and cerebral blood flow (CBF). In order to shed light on the TE-dependence of the BOLD signal and the intercept time-course, we performed simulations based on a nonlinear two-compartmental BOLD signal model combined with the dynamic balloon model. The modeling suggests that the intercept time-course reflects a weighted sum of deoxyhemoglobin concentration and venous CBV signal changes. We demonstrate that only CBF-venous blood volume (CBV) uncoupling but not CBF-oxygen metabolism (CMRO2) uncoupling can fully account for our experimental observations. In particular, these results strongly argue for a slow evolution of the venous CBV together with stimulus-type-dependent CBF transients (the latter being tightly coupled with CMRO2) to be responsible for the BOLD signal adaptation during stimulation and for the post-stimulus undershoot. Thus, BOLD signal transients are composed of smoothed version of neuronal time-course as reflected in CBF and CMRO2 and secondary vascular processes due to biomechanics of venous blood vessels, and multi-echo fMRI in combination with modeling provides invaluable insights into these physiological processes. PMID- 28729162 TI - Effect of 3basic life support training programs in future primary school teachers. A quasi-experimental design. AB - AIM: To evaluate the learning of basic life support (BLS) measures on the part of laypersons after 3different teaching programs. DESIGN: A quasi-experimental before-after study involving a non-probabilistic sample without a control group was carried out. SCOPE: Primary school teacher students from the University of Santiago (Spain). PARTICIPANTS: A total of 124 students (68.8% women and 31.2% men) aged 20-39 years (M=22.23; SD=3.79), with no previous knowledge of BLS, were studied. INTERVENTIONS: Three teaching programs were used: a traditional course, an audio-visual approach and feedback devices. MAIN VARIABLES OF INTEREST: Chest compressions as sole cardiopulmonary resuscitation skill evaluation: average compression depth, compression rate, chest recoil percentage and percentage of correct compressions. Automated external defibrillator: time needed to apply a shock before and after the course. RESULTS: There were significant differences in the results obtained after 2minutes of chest compressions, depending on the training program received, with feedback devices having a clear advantage referred to average compression depth (p<0.001), compression rate (p<0.001), chest recoil percentage (p<0.001) and percentage of correct compressions (p<0.001). Regarding automated external defibrillator, statistically significant differences were found in Tafter (p=0.025). CONCLUSIONS: The teaching course using feedback devices obtained the best results in terms of the quality of chest compressions, followed by the traditional course and audio-visual approach. These favorable results were present in both men and women. All 3teaching methods reached the goal of reducing defibrillation time. PMID- 28729158 TI - Fixed-dose combination dolutegravir, abacavir, and lamivudine versus ritonavir boosted atazanavir plus tenofovir disoproxil fumarate and emtricitabine in previously untreated women with HIV-1 infection (ARIA): week 48 results from a randomised, open-label, non-inferiority, phase 3b study. AB - BACKGROUND: Dolutegravir is a once-daily integrase strand transfer inhibitor with no need for pharmacokinetic boosting that is approved for the treatment of HIV-1 infection. Because women are often under-represented in HIV clinical trials, we addressed the safety and efficacy of dolutegravir in women with HIV-1. METHODS: The ARIA study is a randomised, open-label, multicentre, active-controlled, parallel-group, non-inferiority phase 3b study done in 86 hospital and university infectious disease clinics, local health clinics, and private infectious disease clinics in 12 countries and one US territory, in North America, South America, Europe, Africa, and Asia. Eligible participants were women aged 18 years or older who had HIV-1 RNA viral loads of 500 copies per mL or greater, had received 10 days or less of previous antiretroviral therapy, and had tested negative for the HLA-B*5701 allele. Pregnant women were excluded. Eligible women were randomly assigned (1:1) to receive either a single-tablet regimen of dolutegravir plus abacavir and lamivudine once a day (dolutegravir group) or a three-tablet combination of ritonavir-boosted atazanavir plus coformulated tenofovir disoproxil fumarate and emtricitabine once a day (atazanavir group). Random treatment group assignment was stratified by plasma HIV-1 RNA viral loads and CD4 cell count at baseline. The primary endpoint was the proportion of participants with HIV-1 RNA viral loads of less than 50 copies per mL at week 48 in all participants who received at least one dose of study medication (intention-to treat exposed population). We used a non-inferiority margin of -12%. Investigators monitored adverse events to assess safety. This study is registered with ClinicalTrials.gov, number NCT01910402. FINDINGS: Between Aug 22, 2013, and Sept 22, 2015, of 705 women assessed, 499 were randomly assigned to either the dolutegravir group (n=250) or the atazanavir group (n=249); two participants from each group were randomised to treatment but did not receive study medication. At week 48, 203 (82%) of 248 participants in the dolutegravir group compared with 176 (71%) of 247 in the atazanavir group had HIV-1 RNA viral loads of less than 50 copies per mL (mean difference 10.5%, 95% CI 3.1-17.8, p=0.005). One participant in the atazanavir group had nucleoside reverse transcriptase inhibitor-associated resistance that led to reduced emtricitabine susceptibility. Adverse events were similar between the dolutegravir and atazanavir groups; the most common were nausea (46 [19%] of 248 in the dolutegravir group vs 49 [20%] of 247 in the atazanavir group) and headache (28 [11%] vs 32 [13%]). Fewer participants in the dolutegravir group than the atazanavir group reported drug related adverse events (83 [33%] vs 121 [49%]) or adverse events that led to discontinuation (ten [4%] vs 17 [7%]). One death was reported in each treatment group, but neither was considered related to the study medications. INTERPRETATION: The non-inferior efficacy and similar safety profile of the dolutegravir combined regimen compared with the atazanavir regimen support the use of dolutegravir for HIV-1 infection in treatment-naive women. FUNDING: ViiV Healthcare. PMID- 28729163 TI - Computational analysis of interactions of oxidative stress and tetrahydrobiopterin reveals instability in eNOS coupling. AB - In cardiovascular and neurovascular diseases, an increase in oxidative stress and endothelial dysfunction has been reported. There is a reduction in tetrahydrobiopterin (BH4), which is a cofactor for the endothelial nitric oxide synthase (eNOS), resulting in eNOS uncoupling. Studies of the enhancement of BH4 availability have reported mixed results for improvement in endothelial dysfunction. Our understanding of the complex interactions of eNOS uncoupling, oxidative stress and BH4 availability is not complete and a quantitative understanding of these interactions is required. In the present study, we developed a computational model for eNOS uncoupling that considers the temporal changes in biopterin ratio in the oxidative stress conditions. Using the model, we studied the effects of cellular oxidative stress (Qsupcell) representing the non-eNOS based oxidative stress sources and BH4 synthesis (QBH4) on eNOS NO production and biopterin ratio (BH4/total biopterins (TBP)). Model results showed that oxidative stress levels from 0.01 to 1nM.s-1 did not affect eNOS NO production and eNOS remained in coupled state. When the Qsupcell increased above 1nM.s-1, the eNOS coupling and NO production transitioned to an oscillatory state. Oxidative stress levels dynamically changed the biopterin ratio. When Qsupcell increased from 1 to 100nM.s-1, the endothelial cell NO production, TBP levels and biopterin ratio reduced significantly from 26.5 to 2nM.s-1, 3.75 to 0.002MUM and 0.99 to 0.25, respectively. For an increase in BH4 synthesis, the improvement in NO production rate and BH4 levels were dependent on the extent of cellular oxidative stress. However, a 10-fold increase in QBH4 at higher oxidative stresses did not restore the NO-production rate and the biopterin ratio. Our mechanistic analysis reveals that a combination of enhancing tetrahydrobiopterin level with a reduction in cellular oxidative stress may result in significant improvement in endothelial dysfunction. PMID- 28729165 TI - Corrections. PMID- 28729164 TI - Antenatal antipsychotic exposure induces multigenerational and gender-specific programming of adiposity and glucose tolerance in adult mouse offspring. AB - Second-generation antipsychotics (SGAs) are well known for their metabolic side effects in humans, including obesity and diabetes. These compounds are maintained during pregnancy to prevent the relapse of psychoses, but they readily diffuse across the placenta to the fetus, as documented with the widely-prescribed drug olanzapine (OLZ). However, observational studies have provided conflicting results on the potential impact of SGAs on fetal growth and body weight, and their effects on metabolic regulation in the offspring. For this reason, our study has tested whether antenatal exposure of CD1 mice to OLZ influenced metabolic outcomes in the offspring of the first (F1) and second (F2) generations. In F1 mice, OLZ antenatal treatment caused a decrease in neonatal body weight in both genders, an effect that persisted throughout life only in male animals. Interestingly, F1 female mice also displayed altered glucose homoeostasis. F2 mice, generated by mating normal males with F1 female mice exposed to OLZ during antenatal life, exhibited higher neonatal body weights which persisted only in F2 female animals. This was associated with expansion of fat mass and a concordant pattern of adipose tissue gene expression. Moreover, male and female F2 mice were glucose-intolerant. Thus, our study has demonstrated that antenatal OLZ exposure induces multigenerational and gender-specific programming of glucose tolerance in the offspring mice as adults, and points to the need for careful monitoring of children exposed to SGAs during pregnancy. PMID- 28729166 TI - Oral cholera vaccines: exploring the farrago of evidence. PMID- 28729167 TI - Protection against cholera from killed whole-cell oral cholera vaccines: a systematic review and meta-analysis. AB - BACKGROUND: Killed whole-cell oral cholera vaccines (kOCVs) are becoming a standard cholera control and prevention tool. However, vaccine efficacy and direct effectiveness estimates have varied, with differences in study design, location, follow-up duration, and vaccine composition posing challenges for public health decision making. We did a systematic review and meta-analysis to generate average estimates of kOCV efficacy and direct effectiveness from the available literature. METHODS: For this systematic review and meta-analysis, we searched PubMed, Embase, Scopus, and the Cochrane Review Library on July 9, 2016, and ISI Web of Science on July 11, 2016, for randomised controlled trials and observational studies that reported estimates of direct protection against medically attended confirmed cholera conferred by kOCVs. We included studies published on any date in English, Spanish, French, or Chinese. We extracted from the published reports the primary efficacy and effectiveness estimates from each study and also estimates according to number of vaccine doses, duration, and age group. The main study outcome was average efficacy and direct effectiveness of two kOCV doses, which we estimated with random-effect models. This study is registered with PROSPERO, number CRD42016048232. FINDINGS: Seven trials (with 695 patients with cholera) and six observational studies (217 patients with cholera) met the inclusion criteria, with an average two-dose efficacy of 58% (95% CI 42 69, I2=58%) and effectiveness of 76% (62-85, I2=0). Average two-dose efficacy in children younger than 5 years (30% [95% CI 15-42], I2=0%) was lower than in those 5 years or older (64% [58-70], I2=0%; p<0.0001). Two-dose efficacy estimates of kOCV were similar during the first 2 years after vaccination, with estimates of 56% (95% CI 42-66, I2=45%) in the first year and 59% (49-67, I2=0) in the second year. The efficacy reduced to 39% (13 to 57, I2=48%) in the third year, and 26% ( 46 to 63, I2=74%) in the fourth year. INTERPRETATION: Two kOCV doses provide protection against cholera for at least 3 years. One kOCV dose provides at least short-term protection, which has important implications for outbreak management. kOCVs are effective tools for cholera control. FUNDING: The Bill & Melinda Gates Foundation. PMID- 28729168 TI - Ecological Momentary Assessment of Pain, Fatigue, Depressive, and Cognitive Symptoms Reveals Significant Daily Variability in Multiple Sclerosis. AB - OBJECTIVE: To describe the daily variability and patterns of pain, fatigue, depressed mood, and cognitive function in persons with multiple sclerosis (MS). DESIGN: Repeated-measures observational study of 7 consecutive days of home monitoring, including ecological momentary assessment (EMA) of symptoms. Multilevel mixed models were used to analyze data. SETTING: General community. PARTICIPANTS: Ambulatory adults (N=107) with MS recruited through the University of Michigan and surrounding community. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: EMA measures of pain, fatigue, depressed mood, and cognitive function rated on a 0 to 10 scale, collected 5 times a day for 7 days. RESULTS: Cognitive function and depressed mood exhibited more stable within-person patterns than pain and fatigue, which varied considerably within person. All symptoms increased in intensity across the day (all P<.02), with fatigue showing the most substantial increase. Notably, this diurnal increase varied by sex and age; women showed a continuous increase from wake to bedtime, whereas fatigue plateaued after 7 pm for men (wake-bed B=1.04, P=.004). For the oldest subgroup, diurnal increases were concentrated to the middle of the day compared with younger subgroups, which showed an earlier onset of fatigue increase and sustained increases until bed time (wake-3 pm B=.04, P=.01; wake-7 pm B=.03, P=.02). Diurnal patterns of cognitive function varied by education; those with advanced college degrees showed a more stable pattern across the day, with significant differences compared with those with bachelor-level degrees in the evening (wake-7 pm B=-.47, P=.02; wake-bed B=-.45, P=.04). CONCLUSIONS: Findings suggest that chronic symptoms in MS are not static, even over a short time frame; rather, symptoms-fatigue and pain in particular-vary dynamically across and within days. Incorporation of EMA methods should be considered in the assessment of these chronic MS symptoms to enhance assessment and treatment strategies. PMID- 28729169 TI - Pain, Fatigue, and Cognitive Symptoms Are Temporally Associated Within but Not Across Days in Multiple Sclerosis. AB - OBJECTIVE: To examine the temporal associations, within day and day to day, between pain, fatigue, depressed mood, and cognitive function in multiple sclerosis (MS). DESIGN: Repeated-measures study involving 7 days of ecological momentary assessment (EMA) of symptoms 5 times a day; multilevel mixed models were used to analyze data. SETTING: Community. PARTICIPANTS: Ambulatory adults (N=107) with MS. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: EMA of pain, fatigue, depressed mood, and cognitive function rated on a 0 to 10 scale. RESULTS: Fatigue and pain were linked within day such that higher pain was associated with higher subsequent fatigue (B=.09, P=.04); likewise, higher fatigue was associated with higher pain in the following time frame (B=.05, P=.04). Poorer perceived cognitive function preceded increased subsequent pain (B=.08, P=.007) and fatigue (B=.10, P=.01) within day. Depressed mood was not temporally linked with other symptoms. In terms of day-to-day effects, a day of higher fatigue related to decreased next day fatigue (B=-.16, P=.01), and a day of higher depressed mood related to increased depressed mood the next day (B=.17, P=.01). There were no cross-symptom associations from one day to the next. CONCLUSIONS: Findings provide new insights on how common symptoms in MS relate to each other and vary within and over days. Pain and fatigue show evidence of a dynamic bidirectional relation over the course of a day, and worsening of perceived cognitive function preceded worsening of both pain and fatigue. Most temporal associations between symptoms occur within the course of a day, with relatively little carryover from one day to the next. PMID- 28729170 TI - How Do Pain, Fatigue, Depressive, and Cognitive Symptoms Relate to Well-Being and Social and Physical Functioning in the Daily Lives of Individuals With Multiple Sclerosis? AB - OBJECTIVE: To examine the relative association between daily change in pain, fatigue, depressed mood, and cognitive function and 4 outcomes-positive affect and well-being, ability to participate in social roles and activities, upper extremity (UE) functioning, and lower extremity (LE) functioning. DESIGN: Data analysis, multilevel mixed modeling. SETTING: General community. PARTICIPANTS: Ambulatory adults (N=102) with multiple sclerosis. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Customized short-forms of the Quality of Life in Neurological Disorders positive affect and well-being, UE functioning, and LE functioning item banks and the Patient-Reported Outcomes Measurement Information System ability to participate in social roles and activities item bank adapted for daily use and administered as end-of-day diaries. RESULTS: Above and beyond the effects of demographic and clinical covariates, daily pain was associated with 3 of the 4 outcomes; days of higher than usual pain were related to lower same-day social participation (unstandardized beta, B=-1.00; P=.002), UE functioning (B=-1.04; P=.01), and LE functioning (B=-.71; P=.04). Daily fatigue and depressed mood were independently related to daily positive affect and well being; days of worse fatigue (B=-.54; P=.006) and depressed mood (B=-1.17; P<.0001) were related to lower same-day well-being. CONCLUSIONS: The results indicate the role of fluctuations in symptoms in daily functioning and quality of life of individuals with multiple sclerosis. Daily increases in pain intensity are related to social and physical functioning, whereas increases in fatigue and depressed mood are related to lower daily well-being. Findings implicate a person centered approach to monitoring and treating symptoms. PMID- 28729171 TI - Exercise Therapy in Juvenile Idiopathic Arthritis: A Systematic Review and Meta Analysis. AB - OBJECTIVE: To conduct a systematic review to evaluate the efficacy of exercise interventions in improving outcomes across domains of functioning and disability in children and adolescents with juvenile idiopathic arthritis (JIA). DATA SOURCES: Seven electronic databases were systematically searched up to November 16, 2016. STUDY SELECTION: Original data, analytic prospective design, physical therapy-led exercise intervention evaluation, children and adolescents with JIA, and assessment of functional, structural, activity, participation, or quality of life outcomes. DATA EXTRACTION: Two authors screened search results, and discrepancies were resolved by consensus. Of 5037 potentially relevant studies, 9 randomized controlled trials and 1 cohort study were included and scored. DATA SYNTHESIS: Study quality (Downs and Black quality assessment tool) and level of evidence (Oxford Centre of Evidence-Based Medicine model) were assessed and meta analysis conducted where appropriate. Alternatively, a descriptive summary approach was chosen. All randomized controlled trials were moderate-quality intervention studies (level 2b evidence; median Downs and Black score, 20 out of 32; range, 15-27). Interventions included aquatic, strengthening, proprioceptive, aerobic, and Pilates exercises. Pediatric activity capacity (Child Health Assessment Questionnaire) improved with exercise (mean difference, .45; 95% confidence interval, .05-.76). Furthermore, descriptive summaries indicated improved activity capacity, body function and structure (pain and muscle strength), and quality of life outcomes. CONCLUSIONS: Exercise therapy appears to be well tolerated and beneficial across clinically relevant outcomes in patients with JIA. The paucity of high-quality evidence and study heterogeneity limited the ability to provide conclusive, generalizing evidence for the efficacy of exercise therapy and to provide specific recommendations for clinical practice at this time. Future research evaluating exercise program implementation using validated outcomes and detailed adherence and safety assessment is needed to optimize clinical decision pathways in patients with JIA. PMID- 28729172 TI - Ascorbic acid supplementation partially prevents the delayed reproductive development in juvenile male rats exposed to rosuvastatin since prepuberty. AB - Dyslipidemias are occurring earlier in the population due to the increase of obesity and bad eating habits. Rosuvastatin inhibits the enzyme HMG-CoA reductase, decreasing total cholesterol. Ascorbic acid is an important antioxidant compound for male reproductive system. This study aimed to evaluate whether ascorbic acid supplementation may prevent the reproductive damage provoked by rosuvastatin administration at prepuberty. Male pups were distributed into six experimental groups that received saline solution 0.9%, 3 or 10mg/kg/day of rosuvastatin, 150mg/day of ascorbic acid, or 150mg/day of ascorbic acid associated with 3 or 10mg/kg/day of rosuvastatin from post-natal day (PND) 23 until PND53. Rosuvastatin-treated groups showed delayed puberty installation, androgen depletion and impairment on testicular and epididymal morphology. Ascorbic acid partially prevented these reproductive damages. In conclusion, rosuvastatin exposure is a probable risk to reproductive development and ascorbic acid supplementation may be useful to prevent the reproductive impairment of rosuvastatin exposure. PMID- 28729175 TI - Brain targeting efficiency of antimigrain drug loaded mucoadhesive intranasal nanoemulsion. AB - Zolmitriptan (ZT) is a well-tolerated drug in migraine treatment suffering from low bioavailability due to low amount of the drug that reaches the brain after oral and nasal delivery. Development of new nasal mucoadhesive nanoemulsion formulation for zolmitriptan may success in delivering the drug directly from the nose to the brain to achieve rapid onset of action and high drug concentration in the brain which is required for treatment of acute migraine. ZT mucoadhesive nanoemulsion were prepared and characterized for drug content, zeta potential, particle size, morphology, residence time and permeation through the nasal mucosa. The selected formula was tested in-vivo in mice for its pharmacokinetics in comparison with intravenous and nasal solution of zolmitriptan. Results showed that addition of chitosan as mucoadhesive agent in 0.3% concentration to the nanoemulsion enhanced its residence time and zetapotential with no significant effect on the globule size. All tested formulations showed higher permeability coefficients than the zolmitriptan solution through the nasal mucosa. In-vivo studies showed that the mucoadhesive nanoemulsion formulation of zolmitriptan has higher AUC0-8 and shorter Tmax in the brain than the intravenous or the nasal solution. This was related to the small globule size and higher permeability of the formulation. PMID- 28729173 TI - Bisphenol A impairs decidualization of human uterine stromal fibroblasts. AB - This study examined the effect of bisphenol A (BPA) exposure on human uterine stromal fibroblast cells (HuF) undergoing decidualization. HuF cells were isolated and cultured for eight days in the presence of a decidualization inducing cocktail, while concurrently exposed to physiological and supra physiologic doses of BPA (1ng/mL, 10ng/mL, 0.5MUg/mL, 10MUg/mL and 20MUg/mL). Decidualization markers, steroid hormone receptors and cell cycle gene expression were detected by qRT-PCR and cellular proliferation was assessed by KI-67 immunofluorescent staining and MTS assay. BPA impaired decidualization at 10MUg/mL and 20MUg/mL, but not at lower doses. Additionally, BPA at 20MUg/mL decreased progesterone receptor and estrogen receptor-alpha compared to controls. The highest dose of BPA also reduced cellular proliferation and cyclin D2 expression compared to controls. These findings demonstrate that BPA disrupts in vitro decidualization of uterine stromal fibroblasts by altering steroid hormone receptor expression at higher concentrations but not at lower physiological doses. PMID- 28729174 TI - Challenges and strategies to facilitate formulation development of pediatric drug products: Safety qualification of excipients. AB - A public workshop entitled "Challenges and strategies to facilitate formulation development of pediatric drug products" focused on current status and gaps as well as recommendations for risk-based strategies to support the development of pediatric age-appropriate drug products. Representatives from industry, academia, and regulatory agencies discussed the issues within plenary, panel, and case study breakout sessions. By enabling practical and meaningful discussion between scientists representing the diversity of involved disciplines (formulators, nonclinical scientists, clinicians, and regulators) and geographies (eg, US, EU), the Excipients Safety workshop session was successful in providing specific and key recommendations for defining paths forward. Leveraging orthogonal sources of data (eg. food industry, agro science), collaborative data sharing, and increased awareness of the existing sources such as the Safety and Toxicity of Excipients for Paediatrics (STEP) database will be important to address the gap in excipients knowledge needed for risk assessment. The importance of defining risk based approaches to safety assessments for excipients vital to pediatric formulations was emphasized, as was the need for meaningful stakeholder (eg, patient, caregiver) engagement. PMID- 28729176 TI - Infant nephrolithiasis and nephrocalcinosis: Natural history and predictors of surgical intervention. AB - INTRODUCTION: Renal stone disease diagnosed in the first year of life is relatively uncommon. While risk factors such as low birth weight, furosemide exposure, and metabolic disorders are well established, there exists little information regarding resolution rates and need for surgical intervention. Our study objective was to evaluate urolithiasis and renal calcification resolution rates, time to resolution, and need for surgical intervention in children diagnosed in their first year of life. MATERIAL AND METHODS: REB approved retrospective chart review of children younger than 12 months of age (corrected for prematurity) diagnosed with nephrolithiasis and/or nephrocalcinosis in a tertiary pediatric hospital between April 2000 and August 2015 with a minimum 1 year follow-up period. Exact logistic regression was performed to assess the relationship between size of the largest stone (on either side) and the need for surgical intervention. Kaplan-Meier curves were constructed to examine time to stone resolution among those not requiring surgical intervention. RESULTS: 62 patients (61% male) were diagnosed with stones or nephrocalcinosis by ultrasound at a median age of 2.9 months. Of these, 37% had been admitted to the NICU because of prematurity, low birth weight or comorbidities. A total of 45 patients were found to have stones (Table); 35 of these had a stone at initial ultrasound and 10 initially diagnosed as nephrocalcinosis were later confirmed to have a stone. 67% of all stones were asymptomatic on presentation. Metabolic anomalies were present in 56% (35/62), and 16% (10/62) required medical treatment. Seven patients ultimately required surgical intervention. Stone size was found to predict the eventual need for surgical intervention (OR 3.52, 95% CI 1.47-12.78) for each 0.1 mm increase in diameter). Among patients not requiring surgical intervention (n = 38), the estimated median time to spontaneous resolution of urolithiasis was 1.1 years (95% CI 0.89-1.53, range 2 months-6 years) and 1.2 years for nephrocalcinosis (95% CI 0.59-2.13). CONCLUSIONS: Spontaneous resolution was a common outcome for newborns and infants diagnosed with urolithiasis in the first year of life, but high variability in time-to resolution was observed. Only a small proportion who had confirmed stones on ultrasound required surgical intervention (15%), and large stone size was a predictive factor for surgery. PMID- 28729177 TI - The Iowa Voiding Improvement Partnership experience: Early observations with a collaborative pediatric uro-psychologic clinic. AB - INTRODUCTION: Bladder and bowel dysfunction (BBD) are common problems in children presenting for pediatric urology referral. Psychiatric issues may be present in these children, making their treatment difficult. In 2013, the University of Iowa Voiding Improvement Partnership (VIP) Clinic was established for the treatment of these patients. STUDY OBJECTIVE: This study sought to evaluate early experience with this specialized clinic, to determine the pre-existing urologic and psychologic conditions seen in these clinic patients, and to evaluate the clinical outcomes after VIP treatment. STUDY DESIGN: A retrospective, Institutional Review Board-approved review of all patients seen in the VIP Clinic was performed. The following were evaluated: patient demographics, underlying urologic and psychologic diagnosis, and treatment decisions. All patients were asked to complete the University of Iowa Pediatric Bladder and Bowel Dysfunction questionnaire at each visit. Questionnaire scores from the patients' first and most recent clinic visits were compared. RESULTS: To date, 66 patients have been evaluated at the VIP Clinic, accounting for 112 clinic visits. The mean age of the VIP patients was 8.5 years (range, 4-16) and 59% of the patients were female. Pre-existing urological conditions and psychological conditions are shown in the Summary Table. A large number (62%) of patients required further psychological evaluation, secondary to concern for an undiagnosed psychiatric issue. In addition, the clinic had improved patients' BBD symptoms over time. When first evaluated in clinic, patients had an average Iowa BBD Questionnaire score of 31 (range, 47-13), which improved to an average score of 25 (range, 47-7) (P = 0.03). In addition, 23% of the patients improved to where they could be discharged from uro-psychologic care. CONCLUSIONS: It was feasible to establish the present multidisciplinary uro-psychology clinic. Such a clinic may unearth undiagnosed psychological issues, and improve bowel and bladder dysfunction in these difficult-to-treat patients. PMID- 28729178 TI - Elevated Cardiovascular Disease Risk in Patients With Chronic Myelogenous Leukemia Seen in Community-based Oncology Practices in the United States. AB - INTRODUCTION: Current National Comprehensive Cancer Network guidelines recommend that comorbidities, including cardiovascular disease (CVD), be considered when selecting tyrosine kinase inhibitors for the treatment of chronic myelogenous leukemia (CML). We report here the prevalence of CVD and its risk factors in patients with CML treated by community-based United States (US) oncologists. PATIENTS AND METHODS: Adult patients with a confirmed diagnosis of CML and >= 1 encounter after the first date of CML diagnosis in an electronic medical record database between January 1, 2005 and October 31, 2014 were enrolled. CVD conditions/risk factors were assessed at baseline and during the 5-year follow-up period using International Classification of Diseases, 9th Revision, Clinical Modification diagnoses codes and information from physician progress notes. One year prevalence estimates were age- and gender-standardized for comparison to annual rates in the US population. RESULTS: A total of 1639 patients were included. At 5-year follow-up, the prevalence of CVD conditions and CVD risk factors was 33.0% and 77.7%, respectively. Compared with the general US adult population, the standardized prevalence rates at 1 year in patients with CML were significantly higher by factors of 1.3 to 3.5 times for CVD conditions, and 20% to 40% significantly higher for hypertension, diabetes, and obesity (P < .001). The prevalence of cardiovascular risk factors was not significantly higher in patients residing in the US Stroke Belt. CONCLUSION: The increased risk of CVD observed in this real-world analysis of patients with CML underscores the importance of current National Comprehensive Cancer Network recommendations to consider cardiovascular risk when selecting tyrosine kinase inhibitors. PMID- 28729179 TI - Global regression model for moisture content determination using near-infrared spectroscopy. AB - Near-infrared (NIR) global quantitative models were evaluated for the moisture content (MC) determination of three different freeze-dried drug products. The quantitative models were based on 3822 spectra measured on two identical spectrometers to include variability. The MC, measured with the reference Karl Fischer (KF) method, were ranged from 0.05% to 4.96%. Linear and non-linear regression models using Partial Least Square (PLS), Decision Tree (DT), Bayesian Ridge Regression (Bayes-RR), K-Nearest Neighbors (KNN), and Support Vector Regression (SVR) algorithms were created and evaluated. Among them, the SVR model was retained for a global application. The Standard Error of Calibration (SEC) and the Standard Error of Prediction (SEP) were respectively 0.12% and 0.15%. This model was then evaluated in terms of total error and risk-based assessment, linearity, and accuracy. It was observed that MC can be fastly and simultaneously determined in freeze-dried pharmaceutical products thanks to a global NIR model created with different medicines. This innovative approach allows to speed up the validation time and the in-lab release analyses. PMID- 28729180 TI - Symptom and Quality of Life Improvement in LUX-Lung 8, an Open-Label Phase III Study of Second-Line Afatinib Versus Erlotinib in Patients With Advanced Squamous Cell Carcinoma of the Lung After First-Line Platinum-Based Chemotherapy. AB - INTRODUCTION: In the phase III LUX-Lung 8 trial, afatinib significantly improved progression-free survival (PFS) and overall survival (OS) versus erlotinib in patients with squamous cell carcinoma (SCC) of the lung progressing during or after platinum-based chemotherapy. Patient-reported outcomes (PROs) and health related quality of life (QoL) in these patients are presented. PATIENTS AND METHODS: Patients (n = 795) were randomized 1:1 to oral afatinib (40 mg/d) or erlotinib (150 mg/d). PROs were collected (baseline, every 28 days until progression, 28 days after discontinuation) using the European Organization for Research and Treatment of Cancer QoL questionnaire and lung cancer-specific module. The percentage of patients improved during therapy, time to deterioration (TTD), and changes over time were analyzed for prespecified lung cancer-related symptoms and global health status (GHS)/QoL. RESULTS: Questionnaire compliance was 77.3% to 99.0% and 68.7% to 99.0% with afatinib and erlotinib, respectively. Significantly more patients who received afatinib versus erlotinib experienced improved scores for GHS/QoL (36% vs. 28%; P = .041) and cough (43% vs. 35%; P = .029). Afatinib significantly delayed TTD in dyspnea (P = .008) versus erlotinib, but not cough (P = .256) or pain (P = .869). Changes in mean scores favored afatinib for cough (P = .0022), dyspnea (P = .0007), pain (P = .0224), GHS/QoL (P = .0320), and all functional scales. Differences in adverse events between afatinib and erlotinib, specifically diarrhea, did not affect GHS/QoL. CONCLUSION: In patients with SCC of the lung, second-line afatinib was associated with improved prespecified disease-related symptoms and GHS/QoL versus erlotinib, complementing PFS and OS benefits with afatinib. PMID- 28729181 TI - Expression of CYP4V2 in human THP1 macrophages and its transcriptional regulation by peroxisome proliferator-activated receptor gamma. AB - Because macrophages respond to a variety of pathological and pharmacological reagents, understanding the role of P450s in macrophages is important for therapeutic intervention. There has been a lack of research on CYP4 in macrophages, but fatty acid accumulation and lipid trafficking in macrophages have been suggested to be a main cause of atherosclerosis. All human CYP4 genes (n=12) were screened in THP1 macrophages by gene-specific reverse transcriptase polymerase chain reaction (RT-PCR). Only CYP4V2 exhibited strong expression of both mRNA and protein. Expression levels of both CYP4V2 mRNA and protein were significantly reduced after treatment with peroxisome proliferator-activated receptor gamma (PPARgamma) antagonist GW9662. However, the expression levels of CYP4V2 were not changed by PPARalpha antagonist (GW6471) and liver X receptor alpha antagonist (22-S hydroxycholesterol). A metabolite of the CYP4V2 enzyme, 12 hydroxydodecanoic acid, was detected in THP1 macrophages, and this metabolite was significantly decreased after treatment with the PPARgamma inhibitor GW9662 (>80% decreased, p<0.05). In summary, fatty acid metabolizing protein CYP4V2 was identified in human THP1 macrophages, and its expression was regulated by PPARgamma. Further study is required to understand the role of CYP4V2 with regard to fat accumulation in the activated macrophage and atherosclerotic plaque development. PMID- 28729182 TI - Correlation of quantitative MR imaging findings with symptoms in patients with incidentally detected inflammatory sinonasal disease. AB - PURPOSE: To assess the relationships between mucosal thickness, T1-weighted, T2 weighted signals and restricted diffusion on magnetic resonance imaging (MRI) with the degree of symptoms in patients with incidentally detected inflammatory sinonasal disease. MATERIALS AND METHODS: Conventional and diffusion-weighted MRI of 100 patients with incidental sinonasal mucosal thickening were prospectively evaluated. There were 53 men and 47 women, with a mean age of 44.6 years+/-15.17 (SD) (range: 18-81 years). Correlations between quantitative values (T1-signal, T2-signal and apparent diffusion coefficient [ADC]) and three different quality of life questionnaires (chronic sinusitis survey, sinonasal outcomes test-22 and nasal obstruction and septoplasty effectiveness scale [NOSE]) were searched using the Spearman correlation test. RESULTS: The mean SNOT-22 score was 35.81+/-20.36 (SD) (range: 0-83), CSS score was 4.64+/-3.42 (SD) (range: 0-14), and NOSE score was 5.91+/-4.84 (range: 0-18). All patients (100%) had maxillary sinus involvement. Ethmoidal sinus involvement was present in 57% of patients, frontal sinus involvement in 33% and sphenoidal sinus involvement in 27%. Morphologically, 40 patients (40%) had septal deviation, 41 (41%) had maxillary sinus retention cyst and 78 (78%) had hypertrophy of the conchae. No correlations were found between morphological abnormalities, quantitative values and patient scores in none of the questionnaires. CONCLUSION: Incidental morphological abnormalities or restricted diffusion of the paranasal sinuses on MRI do not correlate with the degree of symptoms in patients with incidentally detected inflammatory sinonasal disease. PMID- 28729183 TI - Differentiation between idiopathic granulomatous mastitis and malignant breast lesions using strain ratio on ultrasonic elastography. AB - PURPOSE: The goal of this study was to investigate the strain elastography imaging characteristics of idiopathic granulomatous mastitis (IGM) and compare strain ratio values of IGM with those of breast cancer. MATERIAL AND METHODS: Twenty-three consecutive women with IGM (mean age, 37.9+/-6.6 [SD] years; range: 26-52 years) and 45 women with malignant breast tumor (mean age, 52.8+/-12.0 [SD], range, 32-77 years) who had been scheduled for ultrasound-guided core biopsy were recruited to the study. All had ultrasonography with elastography before biopsy. The strain ratios of lesions were calculated using surrounding normal breast tissue as the reference in both groups and compared between the two groups. Receiver-operating-characteristics (ROC) curves were formed. Sensitivity, specificity, cut-off, and area under curve (AUC) values were calculated. RESULTS: The mean strain ratio on sonoelastography was 1.5+/-0.8 (SD) (range: 0.2-4.0) for IGM and 5.3+/-5.2 (SD) (range: 1.4-33) for malignant lesions. Strain ratio values in IGM lesions were significantly lower than in malignant lesions (P?0.05). ROC test yielded an AUC value of 0.939 (95% confidence interval, 0.882-0.995; P<0.0001). Optimal cut-off value for strain ratio value was 2.5 yielding 87% sensitivity and 96% specificity for the diagnosis of IGM. CONCLUSION: Sonoelastographic strain ratio contributes to differentiate IGM from malignant breast lesions, thus has potential to influence clinical decision making for further biopsies. PMID- 28729184 TI - [Clinical and genetic heterogeneity of congenital hyperinsulinism]. PMID- 28729185 TI - [Testicular tumours in children: Indications for testis-sparing surgery]. AB - INTRODUCTION AND OBJECTIVES: Although standard surgical treatment of a testicular tumour is orchiectomy, use can be made of testis-sparing surgery in selected cases, based on tumour markers, tumour size, and histopathological findings. Our objective is to become acquainted with the indications of testis-sparing surgery as a treatment for the incidental finding of a palpable and non-palpable testicular mass. MATERIAL AND METHODS: A retrospective study was conducted on 22 patients younger than 18 years diagnosed with a testicular tumour between 2000 and 2014. An assessment was made of the condition, the history, ultrasound, histopathology, tumour markers (BHCG, AFP), therapeutic approach, and outcome. RESULTS: Of the 22 patients (10 prepubertal age) studied, 82% had palpable mass, and 18% were incidental findings. Two had cryptorchidism. The BHCG was increased in 27% and AFP in 45% of cases. There were 18 tumorectomies and 4 orchiectomies performed. The histopathology found 72% germ cell, 14 orchiectomy, and 2 tumorectomies (2 teratomas), with 27% non-germ cell tumours in 4 orchiectomies and 2 tumorectomies (2 cells of Leydig). Six patients received post-surgical chemotherapy (mixed tumours). The median tumour size was 1 (0.4-1.5) cm in tumorectomies, and 2.5 (0.5-14) cm in orchiectomies. The mean follow-up was 5 (1 15) years. One patient died due to metastatic disease. There was no local recurrence in the follow up of the tumorectomies. CONCLUSIONS: A change in the trend of our therapeutic approach is demonstrated. We propose that testis-sparing surgery is indicated in prepubertal patients who meet the benignity criteria of the testicular mass (small size and negative tumour markers). PMID- 28729186 TI - [Tuberculosis treatment for children: An update]. AB - Tuberculosis (TB) is the most important infectious disease all over the world, with a high morbidity and mortality. Pediatric tuberculosis has been a neglected epidemic, due to the difficulties in assessing its global impact, reduced incidence and lower infectivity compared to adults. In 2015, the WHO reported 1 million cases of paediatric TB and 169,000 deaths. In Europe, the emergence of MDR TB is a major concern, representing 16% of the new diagnosis in Eastern Europe. In 2014, it was estimated that about 219,000 children were infected by MDR-TB-strains in Europe, and 2,120 developed the disease. Spain is the Western European country with more paediatric cases, with an incidence 4.3/100,000 inhabitants in 2014. Paediatric tuberculosis mortality in Spain is rare, but extra-pulmonary disease is associated with significant complications. The prevalence of paediatric drug resistant TB in Spain is over 4%, higher than the estimated incidence in adult population, representing mayor difficulties for therapeutic intervention. These data reveal that paediatric TB is still a Public Health priority in our country. The difficulties in diagnosis and the lack of optimal paediatric drug formulations are the major challenges for controlling the childhood's tuberculosis epidemic. A group of national paeditric TB experts has reviewed the international guidelines and the most recent evidences, and has established new recommendations for the management of paediatric TB contacts, latent infection and active TB disease, especially focused in drug resistant cases. This document replaces the former national guidelines from the Spanish Society for Pediatric Infectios Diseases, although the prior recommendations on the diagnosis remain valid. PMID- 28729187 TI - Poor Employment Conditions Adversely Affect Mental Health Outcomes Among Surgical Trainees. AB - BACKGROUND: Poor mental health in junior clinicians is prevalent and may lead to poor productivity and significant medical errors. We aimed to provide contemporary data on the mental health of surgical trainees and identify risk factors relating to poorer mental health outcomes. METHODS: A detailed questionnaire was developed comprising questions based on the 36-item short-form health survey (SF-36) and Physical Activity Questionnaire. Each of the questionnaires has proven validity and reliability in the clinical context. Ethics approval was obtained from the Royal Australasian College of Surgeons. The questionnaire was aimed at surgical registrars. We used Physical Activity Questionnaire, SF-36 scores and linear regression to evaluate the effect of putative predictors on mental health. RESULT: A total of 83 responses were collected during the study period, of which 49 (59%) were from men and 34 (41%) were from women. The mean Mental Component Summary (MCS) score for both sexes was significantly lower than the population mean at ages 25-34 (p < 0.001). Poor satisfaction with one's work culture and a feeling of a lack of support at work were extremely strong predictors of a lower MCS score (p < 0.001). Hours of overtime worked, particularly unpaid overtime, were also strong predictors of a poorer score. CONCLUSIONS: Australian surgical trainees reported lower MCS scores from the SF-36 questionnaire compared to the general population. Increasing working hours, unpaid overtime, poor job security, and job satisfaction were associated with poorer scores among trainees. Interventions providing improved working conditions need to be considered by professional training bodies and employers. PMID- 28729188 TI - Assessing Interest and Barriers for Resident and Faculty Involvement in Global Surgery. AB - BACKGROUND: Multiple institutions have developed international electives and sustainable global surgery initiatives to facilitate clinical, research, and outreach opportunities with hospitals in resource-poor areas. Despite increasing interest among programs, many institutions have not successfully reached potential involvement. OBJECTIVE: This study evaluates the experiences of Yale residents and faculty, measures interest in the development of an international surgical elective, and enumerates barriers to developing or participating in these opportunities. This was performed to develop a formalized elective and assess interest and capacity for surgical global health initiatives, as a seemingly increasing number of trainee applicants and residents were expressing interest in working in resource-poor settings. METHODS: Electronic survey of Yale Surgery residents and faculty analyzed using SPSS and Graphpad Prism. RESULTS: Among residents, previous global experience correlates with current interest in international opportunities, with 100% remaining interested, and 78% of those without prior experience also expressing interest (p = 0.018). Barriers to pursuing these activities included the use of vacation time, funding, scheduling, family obligations, and concern for personal safety. Among faculty, 28% of respondents have been involved internationally, and most (86%) expressed interest in additional opportunities and all were willing to take residents. Barriers to faculty participation included funding, relative value unit target reduction, protected time, and the desire for institutional support for such activities. CONCLUSIONS: A substantial proportion of residents and faculty have experience in global health and motivation to pursue additional opportunities. The main barriers to participation are not a lack of interest, but rather needs for funding support, protected time, and institutional recognition of academic contributions. These findings are being used to develop a global surgery elective and establish long-term partnerships with international colleagues. PMID- 28729189 TI - The Quality In-Training Initiative: Giving Residents Data to Learn Clinical Effectiveness. AB - BACKGROUND: Training programs are expected to provide clinical outcomes data to residents. Few systems have the necessary infrastructure. We evaluated initial adoption and use of the Quality In-Training Initiative (QITI) platform linking National Surgical Quality Improvement Program (NSQIP) data to trainees. STUDY DESIGN: Proportions of Accreditation Council for Graduate Medical Education general surgery residency programs with differing levels of NSQIP and QITI affiliation were calculated and program characteristics were compared. All NSQIP sites that captured QITI custom field data from July 2013 to June 2016 were included in case analysis. Differences in case collection were compared between participating (P) sites that actively participated in QITI and nonparticipating (NP) sites that did not. Resident participation by procedure type was examined. RESULTS: Of 268 accredited general surgery residency programs, 92% (n = 248) is affiliated with a NSQIP hospital and 61% of all clinical months is spent at NSQIP sites. For 42% of all programs (n = 114), the primary teaching hospital is affiliated with the QITI. In all, 74 P sites and 89 NP sites captured a total of 417,816 cases. The median number of cases captured per site was statistically higher for P sites (3063) compared with NP sites (2307, p < 0.001). A total of 68.3% of all cases captured had resident participation indicated by postgraduate year (n = 285,469). The most common procedures with resident participation were laparoscopic appendectomy (n = 17,082, 6.0%) and laparoscopic cholecystectomy (n = 15,502, 5.4%). Percentage coverage rates ranged from 17.3% to 91.8%. CONCLUSION: Most general surgery rotations are at NSQIP sites. Identifying resident participation in captured NSQIP cases is feasible on a large scale. Captured cases reflect national case-mix. The platform has the potential to collect data on institutional and program-level variation in resident operative experience that may be used to improve training. PMID- 28729190 TI - Systematic Review of the Use of 3-Dimensional Printing in Surgical Teaching and Assessment. AB - OBJECTIVE: The use of 3-dimensional (3D) printing in medicine has rapidly expanded in recent years as the technology has developed. The potential uses of 3D printing are manifold. This article provides a systematic review of the uses of 3D printing within surgical training and assessment. METHODS: A structured literature search of the major literature databases was performed in adherence to PRISMA guidelines. Articles that met predefined inclusion and exclusion criteria were appraised with respect to the key objectives of the review and sources of bias were analysed. RESULTS: Overall, 49 studies were identified for inclusion in the qualitative analysis. Heterogeneity in study design and outcome measures used prohibited meaningful meta-analysis. 3D printing has been used in surgical training across a broad range of specialities but most commonly in neurosurgery and otorhinolaryngology. Both objective and subjective outcome measures have been studied, demonstrating the usage of 3D printed models in training and education. 3D printing has also been used in anatomical education and preoperative planning, demonstrating improved outcomes when compared to traditional educational methods and improved patient outcomes, respectively. CONCLUSIONS: 3D printing technology has a broad range of potential applications within surgical education and training. Although the field is still in its relative infancy, several studies have already demonstrated its usage both instead of and in addition to traditional educational methods. PMID- 28729191 TI - Hypothermia pretreatment improves cognitive impairment via enhancing synaptic plasticity in a traumatic brain injury model. AB - Posttraumatic hypothermia attenuates cognitive deficits caused by TBI when it is administered at an early stage. However, little is known regarding the effect of hypothermia pretreatment on cognitive deficits one month after TBI. In the current study, the behavior test revealed that hypothermia pretreatment mitigates the learning and memory impairment induced by TBI in mice. Hypothermia treatment significantly increased the expression of PSD93, PSD95 and NR2B one month after TBI in the cortex and hippocampus compared with the normothermia group. Hypothermia pretreatment also restored the decreased spine number and the impairment in LTP and decreased the number of activated microglia one month after TBI. On the other hand, hypothermia pretreatment increased glucose metabolism in TBI mice. Taken together, these data suggested that hypothermia pretreatment is an effective method with which to prevent spine loss, maintain normal LTP and preserve learning and memory function after TBI. The neuroprotective role might be associated with the preservation of postsynaptic protein expression, the inhibition of activated microglia and the increase in glucose metabolism. PMID- 28729192 TI - Butyrylcholinesterase-knockout reduces fibrillar beta-amyloid and conserves 18FDG retention in 5XFAD mouse model of Alzheimer's disease. AB - Alzheimer's disease (AD) is the most common neurodegenerative disorder causing dementia. One hallmark of the AD brain is the deposition of beta-amyloid (Abeta) plaques. AD is also a state of cholinergic dysfunction and butyrylcholinesterase (BChE) associates with Abeta pathology. A transgenic mouse (5XFAD) is an aggressive amyloidosis model, producing Abeta plaques with which BChE also associates. A derived strain (5XFAD/BChE-KO), with the BChE gene knocked out, has significantly lower fibrillar Abeta than 5XFAD mice at the same age. Therefore, BChE may have a role in Abeta pathogenesis. Furthermore, in AD, diminished glucose metabolism in the brain can be detected in vivo with positron emission tomography (PET) imaging following 2-deoxy-2-(18F)fluoro-D-glucose (18FDG) administration. To determine whether hypometabolism is related to BChE-induced changes in fibrillar Abeta burden, whole brain and regional uptake of 18FDG in 5XFAD and 5XFAD/BChE-KO mice was compared to corresponding wild-type (WT5XFAD and WTBChE-KO) strains at 5months. Diminished fibrillar Abeta burden was confirmed in 5XFAD/BChE-KO mice relative to 5XFAD. 5XFAD and 5XFAD/BChE-KO mice demonstrated reduction in whole brain 18FDG retention compared to respective wild-types. Regional analysis of relevant AD structures revealed reduction in 18FDG retention in 5XFAD mice in all brain regions analyzed (save cerebellum) compared to WT5XFAD. Alternatively, 5XFAD/BChE-KO mice demonstrated a more selective pattern of reduced retention in the cerebral cortex and thalamus compared to WTBChE-KO, while retention in hippocampal formation, amygdala and basal ganglia remained unchanged. This suggests that in knocking out BChE and reducing fibrillar Abeta, a possible protective effect on brain function may be conferred in a number of structures in 5XFAD/BChE-KO mice. PMID- 28729193 TI - The pattern of retinal ganglion cell dysfunction in Leber hereditary optic neuropathy. AB - Leber inherited optic neuropathy (LHON) is characterized by subacute bilateral loss of central vision due to dysfunction and loss of retinal ganglion cells (RGCs). Comprehensive visual electrophysiological investigations (including pattern reversal visual evoked potentials, pattern electroretinography and the photopic negative response) performed on 13 patients with acute and chronic LHON indicate early impairment of RGC cell body function and severe axonal dysfunction. Temporal, spatial and chromatic psychophysical tests performed on 7 patients with acute LHON and 4 patients with chronic LHON suggest severe involvement or loss of the midget, parasol and bistratified RGCs associated with all three principal visual pathways. PMID- 28729194 TI - Establishment of human retinal mitoscriptome gene expression signature for diabetic retinopathy using cadaver eyes. AB - Diabetic retinopathy (DR) is a leading cause of blindness due to retinal microvasculature. We used microarray analysis for the first time to establish the retinal mitoscriptome gene expression signature for DR using human cadaver eyes. Among the 1042 genes, 60 (52-down, 8-up) and 39 (36-down, 3-up) genes were differentially expressed in the DR as compared to normal control and diabetic retinas respectively. These genes were mainly responsible for regulating angiogenesis, anti-oxidant defense mechanism, ATP production and apoptosis contributing to the disease pathology of DR. These findings might be useful for the discovery of biomarker and developing therapeutic regimen. PMID- 28729196 TI - Legalization of cannabis: Considerations for intervening with adolescent consumers. AB - Eight states and the District of Columbia have legalized the recreational use of cannabis for adults and more are expected to follow suit. After alcohol, cannabis is the most commonly used drug by adolescents. Consumption of this drug during this developmental period poses unique risks. Therefore, attention must be paid both to how legalization affects adolescents and how tailored interventions can effectively address their needs for assistance. This commentary offers considerations for how legalization might be crafted so as to benefit adolescents. It additionally focuses on how services might be designed to reach and intervene with teens who are questioning their use or are experiencing a cannabis use disorder and desire assistance in quitting. PMID- 28729195 TI - Do high vs. low purchasers respond differently to a nonessential energy-dense food tax? Two-year evaluation of Mexico's 8% nonessential food tax. AB - It is unclear whether response to a nonessential food tax varies across time or for high vs. low-consuming households. The objective is to examine whether the effect of Mexico's 2014 8% nonessential energy-dense foods tax increased in the second year post-implementation and whether it differentially affected households by pre-tax purchasing pattern. We used longitudinal data on Mexican household food purchases (n=6089 households) from 2012 to 2015. Households were classified based on median pre-tax purchases: low untaxed/low taxed ("low"), low untaxed/high taxed ("unhealthy"), high untaxed/low taxed ("healthy"), and high untaxed/high taxed ("high") purchasers. Fixed effects models tested whether observed post-tax purchases differed from the counterfactual, or what would have been expected based on pre-tax trends. Post-tax declines in the % taxed food purchases increased from -4.8% in year one to -7.4% in year two, yielding a 2 year mean decline of 6.0% beyond the counterfactual (p<0.01). Post-tax change in % taxed food purchases varied by pre-tax purchasing level. Healthy purchasers showed no post-tax change in % taxed food purchases beyond the counterfactual, while unhealthy, low and high purchasers decreased (-12.3%, -5.3% and -4.4%, respectively) (p<0.01). The positive effect of Mexico's junk food tax continued in the second year, and households with greater preferences for taxed foods showed a larger decline in taxed food purchases. PMID- 28729197 TI - Estimation and development of 10- and 20-year cardiovascular mortality risk models in an industrial male workers database. AB - We examined the performance of the Framingham Heart Study (FHS) and the European Systematic Coronary Risk Evaluation (SCORE) models for cardiovascular disease (CVD) mortality prediction in Israeli industrial workers, and developed and validated new risk prediction models for CVD mortality incidence in the same population. Our database was a longitudinal Israeli industrial cohort (CORDIS cohort) of 4809 adult males followed-up for 22years. Performance of the FHS and the SCORE prediction models was analyzed by insertion of the CORDIS cohort measurements to each model separately. The standard prognostic variables and results obtained from the new refined Cox regression analyses were used to construct two new 10- and 20-year CVD mortality risk scoring systems: a modified FHS model (FHS/Cox) and an omnibus model with Cox regression (Omnibus/Cox). The SCORE model of high-risk and low-risk charts yielded 10-year mortality mean risks of 1.12% and 0.64%, respectively, for male subjects aged>30years. The new FHS/Cox and Omnibus/Cox models generated a mean predictive 10-year risk of 1.12% and 1.50%, respectively. The mean 20-year risk predicted by the new FHS/Cox and the Omnibus/Cox models was 2.66% and 3.75%, respectively. Internal validation of both models demonstrated a high and stable area under the receiver operating characteristic curve>0.85. No significant differences were found between the two models. In conclusion, the CVD mortality risk prediction scoring systems tailored for the Israeli workers population demonstrated good performance. Additional studies to externally validate these algorithms will indicate which of these quantitative risk estimation platforms should be used in specific settings. PMID- 28729198 TI - E-cigarette awareness, perceived harmfulness, and ever use among U.S. adults. AB - The overarching aims of this study are to (a) estimate and update knowledge on rates and predictors of awareness, perceived harmfulness, and ever use of e cigarettes among U.S. adults and (b) to utilize that information to identify risk factor profiles associated with ever use. Data were collected from the 2015 Health Information National Trends Survey (N=3738). Logistic regression was used to explore relationships between sociodemographics (gender, age, race/ethnicity, sexual orientation, educational attainment, income, and census region), current use of other tobacco products (conventional cigarettes, cigars, and smokeless tobacco), ever use of alternative products (hookah, pipes, roll-your-own cigarettes, and snus) and e-cigarette awareness, perceived harm, and ever use. Classification and regression tree (CART) modeling was used to examine risk factor profiles of e-cigarette ever use. Results showed that most respondents were aware of e-cigarettes (83.6%) and perceived them to be not at all or moderately harmful (54.7%). Prevalence of e-cigarette ever use was 22.4%. Current cigarette smoking and ever use of alternative tobacco products were powerful predictors of use. Other predictors of use of e-cigarettes were age, race/ethnicity, and educational attainment. Awareness and perceived harm were significant predictors among particular smoker subgroups. Fifteen risk profiles were identified across which prevalence of e-cigarette use varied from 6 to 94%. These results underscore the need to continue monitoring patterns of e-cigarette use. They also provide new knowledge regarding risk-profiles associated with striking differences in prevalence of e-cigarette use that have the potential to be helpful when considering the need for or impact of e-cigarette regulatory policies. PMID- 28729199 TI - Violent firearm-related conflicts among high-risk youth: An event-level and daily calendar analysis. AB - Firearm homicide is the leading cause of violence-related youth mortality. To inform prevention efforts, we analyzed event-level data to identify unique precursors to firearm conflicts. Youth (ages:14-24) seeking Emergency Department (ED) treatment for assault or for other reasons and reporting past 6-month drug use were enrolled in a 2-year longitudinal study. Time-line follow-back substance use/aggression modules were administered at baseline and each 6-month follow-up. Violent non-partner conflicts were combined across time-points. Regression analyzed: a)antecedents of firearm-related conflicts (i.e., threats/use) as compared to non-firearm conflicts; and b)substance use on conflict (vs. non conflict) days for those engaged in firearm conflict. During the 24-months, we found that 421-youth reported involvement in violent non-partner conflict (n=829 conflicts;197-firearm/632-non-firearm). Among firearm conflicts, 24.9% involved aggression and 92.9% involved victimization. Retaliation was the most common motivation for firearm-aggression (51.0%), while "shot for no reason" (29.5%) and conflicts motivated by arguments over "personal belongings" (24.0%) were most common for firearm-victimization. Male sex (AOR=5.14), Black race (AOR=2.75), a ED visit for assault (AOR=3.46), marijuana use before the conflict (AOR=2.02), and conflicts motivated by retaliation (AOR=4.57) or personal belongings (AOR=2.28) increased the odds that a conflict involved firearms. Alcohol (AOR=2.80), marijuana (AOR=1.63), and prescription drugs (AOR=4.06) had a higher association with conflict (vs. non-conflict) days among youth reporting firearm conflict. Overall, we found that firearm conflicts are differentially associated with substance use and violence motivations. Addressing substance use, interrupting the cycle of retaliatory violence, and developing conflict resolution strategies that address escalation over infringement on personal belongings may aid in decreasing and preventing adolescent firearm violence. PMID- 28729200 TI - Additive effects of sensory-enhanced satiety and memory for recent eating on appetite. AB - The sensory characteristics of a product have been shown to interact with actual nutrient content to generate satiety. Separately, cued recall of recent eating has also been shown to reduce food intake. Here we explore for the first time how these two effects interact, with the hypothesis that sensory enhancement of satiety might be mediated by more vivid memory of the earlier consumed item. On each of two test sessions, 119 women volunteers consumed a control drink (lemonade) on one morning and then one of two test drinks on the next day 30 min before an ad libitum lunch. The test drinks were equicaloric but one was noticeably thicker and creamier, and expected to generate stronger satiety. Just prior to the test lunch, participants were asked to recall either the test drink (test recall) or the drink from the previous day (control recall). Overall, lunch intake was significantly lower after the thicker and creamier (enhanced sensory ES) than thinner (low sensory: LS) test drink (p < 0.001, eta2 = 0.11) regardless of recall condition (p = 0.65, eta2 < 0.01), but was significantly lower after the test than control recall condition (p < 0.001, eta2 = 0.14). Rated hunger was lower after consuming the ES than LS drink both immediately after consumption (p < 0.001, eta2 = 0.11) and prior to the test lunch (p = 0.007, eta2 = 0.06), while rated hunger just before lunch tended to be lower after recalling the test than control drink (p = 0.052, eta2 = 0.03) regardless of the sensory characteristics (p = 0.27, eta2 = 0.01). Overall these data further demonstrate the power of 'sensory-enhanced satiety' and cued recall of earlier eating as methods to reduce acute food intake, but suggest these effects operate independently. PMID- 28729201 TI - Assessing parents' receptiveness to a vegetable-focussed in-school nutrition intervention. AB - OBJECTIVE: Crunch&Sip is an Australian school-based initiative designed to increase the consumption of fruit, vegetables, and water among primary school children. To address the significant deficiencies in children's vegetable intake, the present study aimed to examine the responsiveness of parents (the main providers of food for Crunch&Sip) to a modified version of the program that focuses primarily on vegetable consumption. PARTICIPANTS: A total of 329 Western Australian parents completed an online questionnaire examining their support for a vegetable focus for Crunch&Sip and any perceived barriers, motivators, and facilitators. RESULTS: Most (80%) parents were supportive of a shift to a vegetable focus for Crunch&Sip. Belief in the effectiveness of Crunch&Sip at improving children's attitudes towards vegetables and increasing children's vegetable consumption was found to be significantly associated with levels of support. The most commonly nominated motivator was to improve their children's eating habits and the main facilitator was the perceived ability of teachers and peers to influence children's food consumption behaviours. Identified potential barriers included the difficulties associated with providing a variety of vegetables, maintaining freshness, and the preparation time required. The primary suggested strategy to overcome these barriers was for schools to conduct education sessions to provide information about vegetable provision options. CONCLUSIONS AND IMPLICATIONS: The results suggest that parents can be supportive of school-based nutrition programs that specifically encourage the consumption of vegetables but they may require guidance to reduce the identified barriers related to vegetable provision. PMID- 28729202 TI - High proportion of modern genotypes of M. tuberculosis and their affinity with drug resistance in northern region of India. AB - OBJECTIVES: Comparative genomics on the basis of TbD1 deletion has differentiated the members of Mycobacterium tuberculosis complex (MTC) in two major genogroups. They exhibit differential distribution and virulence potential. The present study was carried out to see the proportion of these genogroups and their association with drug resistance. METHODS: The drug resistance pattern of 205 culture positive cases of M. tuberculosis and their relation with TbD1 deletion was analysed from the tertiary care centre. Overall proportion of genotypes (TbD1- and Tbd1+) and their association with drug resistance was also observed from the various studies from India. RESULTS: Our study reports that 85.4% of the isolates of M. tuberculosis were modern genotypes (TbD1-) and rest of 14.6% were ancient genotypes (TbD1+). 37 cases were of multiple drug resistant-TB (MDR-TB), 35 of them belongs to modern genogrop and rest of (2) were in ancient genogroup (p=0.12). Overall pooled estimate of proportion of modern genotype is 75.5% (CI 95%, 73.03-77.87) and 24.55% (CI 95%, 22.13-26.97) for ancient genotypes from the studies carried out in India. Modern genotypes were more rarely drug sensitive phenotypes with a relative risk (RR) of 0.89 (CI 95%, 0.74-1.07) while MDR cases were more in this group with an odds ratio (OR) of 2.27 (CI 95%, 0-1.07). CONCLUSIONS: This study demonstrates a higher proportion of modern genotypes in our region/India; which are more likely to be associated with drug resistance. Future, epidemiological/in vitro studies are required to ascertain the relationship between genotypes and their virulence potential. PMID- 28729203 TI - Epidemiological cut-off value of clinical isolates of Burkholderia pseudomallei from Northern Queensland to meropenem, ceftazidime, trimethoprim/sulfamethoxazole and doxycycline by the microbroth dilution method. AB - OBJECTIVES: Melioidosis is caused by the bacterium Burkholderia pseudomallei. The most common antibiotics used to treat melioidosis in Australia are meropenem, ceftazidime, trimethoprim/sulfamethoxazole (SXT) and doxycycline. The European Committee on Antimicrobial Susceptibility Testing (EUCAST) and Clinical and Laboratory Standards Institute (CLSI) do not provide standards for assessing the susceptibility of B. pseudomallei for these agents. The International Standards Organisation (ISO) microbroth dilution method is accepted both by the CLSI and EUCAST as the gold standard of antimicrobial susceptibility testing. Many previous studies of the susceptibility of B. pseudomallei used Etest or disk diffusion and presented the results as aggregate data. Etest and disk diffusion methods have not been standardised for B. pseudomallei and aggregate data cannot be used to determine an epidemiological cut-off value (ECOFF). An ECOFF is vital for the setting of clinical breakpoints. METHODS: In this study, minimum inhibitory concentrations (MICs) of meropenem, ceftazidime, SXT and doxycycline were assessed by microbroth dilution for a library of 234 well characterised clinical isolates of B. pseudomallei from Northern Queensland, Australia. RESULTS: The resultant histograms and aggregate data represent the first MIC profile of a large library of B. pseudomallei that has been successfully produced using microbroth dilution. CONCLUSIONS: The MIC profiles can be used to contribute towards a determination of an ECOFF for this species for these agents, which will aid in the setting and refining of clinical breakpoints for the most important antimicrobials used to treat melioidosis. PMID- 28729204 TI - Characterisation of clinical isolates of oxacillin-susceptible mecA-positive Staphylococcus aureus in China from 2009 to 2014. AB - OBJECTIVES: The aim of this study was to investigate the prevalence and molecular characteristics of clinical oxacillin-susceptible mecA-positive Staphylococcus aureus (OS-MRSA) isolates in China from July 2009 to June 2014. METHODS: A total of 2068 non-duplicate S. aureus isolates were collected from 21 hospitals. Antimicrobial susceptibility testing was performed by the agar dilution method. All OS-MRSA strains were screened for the presence of the genes mecA, mecC and nuc as well as the Panton-Valentine leukocidin gene (pvl). Staphylococcal cassette chromosome mec (SCCmec) typing, staphylococcal protein A (spa) typing and multilocus sequence typing (MLST) were performed to analyse the isolate genotypes. RESULTS: A total of 34 S. aureus isolates were mecA-positive but were susceptible to oxacillin [minimum inhibitory concentration (MIC)<=2mg/L]. All OS MRSA isolates were resistant to cefoxitin and most were also multiresistant to other antibiotics besides beta-lactams. Among the 34 OS-MRSA isolates, nine spa and three SCCmec types were detected and, combined with MLST, ST338/59-t437 SCCmecV (47%; 16/34) was the predominant clone. In addition, 17 strains (50%) carried the pvl gene. CONCLUSIONS: The most frequent clone of OS-MRSA isolates in China was ST338-t437-SCCmecV. Most of the OS-MRSA isolates were susceptible to the majority of antibacterial agents except macrolides, clindamycin and chloramphenicol. PMID- 28729205 TI - Antimicrobial susceptibility of Clostridium difficile isolates in Israel. AB - OBJECTIVES: An increase of Clostridium difficile isolates with reduced susceptibility to various antimicrobial agents has been observed, including isolates that are non-susceptible to antibiotics that are routinely used for treatment of C. difficile, such as vancomycin and metronidazole. We determined the susceptibility rates of C. difficile isolates from hospitals in northern Israel to various antibiotics including tigecycline, which was not previously reported from Israel. METHODS: A total of 81 stool samples were collected from three hospitals in northern Israel from patients with C. difficile infection. Specimens were screened for BI/NAP1/027 ribotype, cultured, and sensitivity tests were performed for vancomycin, metronidazole, moxifloxacin, and tigecycline. Statistical tests were applied for analysing the differences in distribution of resistance between the different antibiotics and between BI/NAP1/027 and resistance of antibiotics. RESULTS: Reduced susceptibility was found among 6/81 isolates for vancomycin, 4/81 for metronidazole, and 17/81 for moxifloxacin. Only 1 isolate had reduced susceptibility to tigecycline, with a mean MIC of 0.05MUg/mL. Reduced susceptibility to moxifloxacin was significantly associated with reduced susceptibility to vancomycin (p=0.016) and to metronidazole (p=0.0276), and reduced susceptibility to metronidazole was associated with reduced susceptibility to vancomycin (p=0.0259). Eight of 81 isolates (9.9%) were positive for BI/NAP1/027 ribotype and had significantly higher non-susceptibility rates to moxifloxacin and vancomycin compared with BI/NAP1/027 negative isolates (p<0.0001 and p=0.0113, respectively). CONCLUSIONS: We found higher non susceptibility rates to vancomycin and metronidazole than most previous studies, while tigecycline resistance rates are very low in northern Israel, rendering it a potential agent for treating CDI. PMID- 28729206 TI - Antimicrobial resistance patterns of Gram-negative bacteria isolated from bloodstream infections in an Iranian referral paediatric hospital: A 5.5-year study. AB - OBJECTIVES: Bloodstream infections (BSIs) are a major cause of paediatric morbidity and mortality worldwide. This study describes the epidemiology and antimicrobial resistance of Gram-negative bacteria (GNB) from BSIs in children admitted to an Iranian paediatric hospital. METHODS: Clinical and microbiological data of patients with positive blood cultures were collected from March 2011 to September 2016. Standard laboratory methods were used for blood culture and bacterial identification. Antimicrobial sensitivity was evaluated by the Kirby Bauer disk diffusion and broth microdilution methods. RESULTS: Of 2325 bacterial pathogens isolated from blood cultures, 41.1% (n=956) were GNB. Most clinical isolates (n=208; 21.8%) were identified in the cardiac intensive care unit. Predominant bacterial isolates were Klebsiella pneumoniae subsp. pneumoniae (n=263; 27.5%), Escherichia coli (n=192; 20.1%), Serratia marcescens (n=151; 15.8%), Pseudomonas aeruginosa (n=111; 11.6%) and Enterobacter spp. (n=100; 10.5%). Enterobacter isolates showed a high level of ampicillin resistance. Escherichia coli were highly resistant to chloramphenicol (100%), cefixime (100%), ceftriaxone (100%) and ampicillin (96%). Cefixime had the least efficacy against Haemophilus spp. (100% resistant). All K. pneumoniae (100%) were ampicillin-resistant. All S. marcescens were ceftazidime-resistant. No Acinetobacter baumannii were resistant to colistin. All P. aeruginosa were resistant to cefotaxime and trimethoprim/sulfamethoxazole. CONCLUSIONS: These results demonstrate the increasing trend in antibiotic resistance among GNB associated with BSI in children, emphasising the importance of continuous screening and surveillance programmes for detection of antibiotic resistance in BSI pathogens for selection of appropriate treatment regimens. PMID- 28729207 TI - First two cases of severe multifocal infections caused by Klebsiella pneumoniae in Switzerland: characterization of an atypical non-K1/K2-serotype strain causing liver abscess and endocarditis. AB - BACKGROUND: We describe the first two multifocal invasive infections due to Klebsiella pneumoniae recently observed in Switzerland. METHODS: Phenotypic (MIC assays and string test) and molecular analyses (PCR/Sequencing for bla, virulence factor genes and whole genome sequencing for one strain) were performed to characterize the causative K. pneumoniae isolates. RESULTS: Both K. pneumoniae isolates (Kp1 and Kp2) were pan-susceptible to antibiotics and produced narrow spectrum SHV beta-lactamases. However, only Kp1 was string test positive. Kp1 was of ST380 and caused liver abscess as well as pneumonia and orbital phlegmon in an Eritrean patient. It belonged to the hypervirulent capsular serotype K2 and harboured the classic virulence-associated rmpA and aerobactin genes, fulfilling both the clinical and microbiological definitions for an invasive K. pneumoniae syndrome. Kp2 was of ST1043 and caused both liver abscess and endocarditis in a Swiss patient. Moreover, it did not possess the classic virulence-associated genes. Whole genome sequencing identified less well-known virulence factors in Kp2 that might have contributed to its virulence. Among these there were genes important for intestinal colonization and/or invasion, such as genes involved in adhesion (e.g., fimABCD and mrkABCD), regulation of capsule polysaccharide biosynthesis (e.g., evgS-evgA), as well as iron uptake (iroN), energy conversion, and metabolism. DISCUSSION: This report confirms the continuous dissemination of hypervirulent K. pneumoniae strains among patients of non-Asian descent in Europe. Moreover, it highlights the genetic background of an atypical hypervirulent K. pneumoniae causing a severe invasive infection despite not possessing the classical virulence characteristics of hypermucoviscous strains. PMID- 28729208 TI - Detection of multidrug resistant (MDR) bacteria in untreated waste water disposals of hospitals in Dhaka City, Bangladesh. AB - BACKGROUND: Emergence of MDR bacteria is a global problem and a major burden for treatment of various infectious diseases. This study was performed to detect antibiotic resistant bacteria in untreated hospital waste. METHOD: Waste water samples were collected from sewerage disposal points of two renowned hospital of Dhaka city and a total of 59 Escherichia coli and 29 Klebsiella pneumonia isolates were isolated. Antibiotic susceptibility were measured by disc diffusion method. RESULTS: Resistance among E. coli and K. pneumoniae to 10 frequently used antibiotic tested were respectively as follows: cefotaxime (CTX) 48 and 45%; ceftazidime (CAZ) 40 and 38%; ampicillin (AMP) 71 and 100%; streptomycin (S) 50 and 34%; sulfamethoxazole-trimethoprim (SXT) 58 and 28%; ciprofloxacin (CIP) 71 and 48%; kanamycin (K) 38 and 10%; chloramphenicol (C) 28 and 10%; gentamycin (CN) 19 and 16% and imipenem (IPM) 12 and 7%. Results also demonstrate that the sites that were at the disposal point of hospital waste have higher degree of resistance. High degree of resistance was observed when 23 high-resistant E. coli isolates were further tested with 15 additional antibiotics. CONCLUSION: This study revealed a significant rise of MDR bacteria in the hospital waste and underscore necessity of hospital waste treatment. PMID- 28729209 TI - Clonal spread of methicillin-resistant Staphylococcus aureus-t6065-CC5-SCCmecV agrII in a Libyan hospital. AB - OBJECTIVES: The aim of this study was to characterize 32 MRSA isolates recovered from wound specimens of patients in a Hospital in Tripoli, Libya, during 2013. METHODS: MRSA isolates were characterized by determining their antibiotic susceptibilities, genes encoding antibiotic resistance and virulence factors, the SCCmec class, agr type, spa typing, PFGE and MLST. RESULTS: PFGE and MLST revealed that all isolates were clonal and belonged to the Clonal Complex 5 (CC5). They harboured the SCCmecV and the agrII and the spa type was t6065. The majority of isolates were resistant to cefoxitin (32, 100%), penicillin (32, 100%), ampicillin (32, 100%), enrofloxacin (32, 100%), ciprofloxacin (32, 100%), fusidic acid (32, 100%), gentamicin (32, 100%), kanamycin (32, 100%), trimethoprim (32, 100%), and erythromycin (30, 93.7%). The main genes encoding antibiotic resistance were: blaZ (31, 96.8%), ermC (30, 93.7%), aph(3')-III a (3, 9.4%), aac6-aph2 (32, 100%), InuA (3, 9.4%), tetM (3, 9.4%), tetL (3, 9.4%), dfrG (28, 87.5%), fusC (32, 100%). All isolates were PVL negative; however, exfoliative-encoding genes (eta: 25) and enterotxin genes (seb: 32, seo: 32, sei: 32, ser: 32, seu: 32, seg: 32, sej: 32, sed: 31, sen: 29, seh: 26, sec: 26, sea: 6, sek: 5), haemolysin (hla (32), hld (32), hlg (32)) and immune evasion cluster proteins (scn: 32, sak: 32) were relevant. CONCLUSION: To the best of our knowledge this is the first report of a specific clonal spread of a multi-drug resistant MRSA-CC5- SCCmecV in a Libyan Hospital. PMID- 28729210 TI - Deficiency of quorum sensing system inhibits the resistance selection of Pseudomonas aeruginosa to ciprofloxacin and levofloxacin in vitro. AB - OBJECTIVES: The objective was to investigate how deficient of quorum sensing system (QS) affects minimal inhibitory concentrations (MICs) of Pseudomonas aeruginosa strains to ciprofloxacin (CIP) and levofloxacin (LEV) in vitro. METHODS: Collected the clinical Pseudomonas aeruginosa isolates. Screened the strains deficient of QS genes by the PCR agarose electrophoresis, and then randomly picked out normal strains with the same number of deficient ones. All strains incubated on the different CIP-concentration Mueller-Hinton agars for five days, the different concentrations of CIP respectively refered to 0.5*MIC, 1*MIC, 2*MIC and 4*MIC. Strains incubated on the first, third and fifth days were saved. MICs of saved strains to CIP and LEV were measured by the agar dilution method. Statistical analysis methods were the repeated measures analysis of variance and the rank sum test. RESULTS: The study totally collected 40 Pseudomonas aeruginosa isolates. 5 deficient strains screened were as follows: one strain lacked of rhlR and lasI genes, one strain lacked of lasI, lasR, rhlI and rhlR genes, four strains lacked of lasR gene. All the final selected strains were sensitive to both CIP and LEV. Statistical analysis results showed deficient strains became resistant more slowly and difficultly than normal strains, whether the resistance was to CIP or LEV. What's more, MICs to LEV showed the half and delayed increase than those to CIP in the vitro selection. CONCLUSIONS: Deficient of QS inhibits the resistance selection of P. aeruginosa to CIP and LEV in vitro. PMID- 28729211 TI - Insight into immunocytes infiltrations in polymorphous light eruption. AB - Polymorphous light eruption (PLE) which is one of the most common photodermatoses has been demonstrated to be immune-mediated disorder. Resistance to UV-induced immunosuppression resulting from differential immune cells infiltration and cytokines secretion has been highlighted in the pathogenesis of PLE. In this study, we reviewed differential patterns of immune cells infiltrations and cytokines secretion that may contribute to PLE occurrence and development. PMID- 28729212 TI - The influence of temperature on viral replication and antiviral-related genes response in hirame rhabdovirus-infected flounder (Paralichthys olivaceus). AB - Hirame rhabdovirus (HIRRV) is a rhabdovirus that causes severe disease in fish. The mortality due to HIRRV infection occurs at temperatures below 15 degrees C, but no mortality is observed over 20 degrees C. In this study, Japanese flounder (Paralichthys olivaceus) was artificially infected with the HIRRV CNPo2015 strain at 10 degrees C or 20 degrees C. Absolute quantitative real-time PCR was employed to examine the viral replication in spleens after HIRRV infection. Expression profiles of four interferon-related genes (type I IFN, Mx, ISG15, MDA5) and two proinflammatory genes (TNF-alpha and IL-1beta) were also investigated by quantitative real-time PCR. Results showed that viral copies in spleens increased gradually over time and peaked at 72 h post infection (hpi) in the 10 degrees C group, while viral copies in the 20 degrees C group increased within 24 hpi, but afterwards decreased to very low levels. Moreover, the expressions of IFNs in the 10 degrees C group reached the highest levels at 72 hpi, whereas their peak levels appeared much earlier in the 20 degrees C group, at 12 hpi. The expression levels of TNF-alpha and IL-1beta in the 10 degrees C group peaked at 12 hpi and then quickly declined. However, the two genes were highly expressed during 6-24 hpi in the 20 degrees C group. Based on these findings, we concluded that HIRRV infection induced an efficient antiviral immune response at 20 degrees C, which might inhibit the viral transcription at early stages and finally prevent HIRRV infection. PMID- 28729213 TI - Physical exercise increases Sestrin 2 protein levels and induces autophagy in the skeletal muscle of old mice. AB - Sestrins and autophagy deficiencies are associated with several aging-related organic dysfunctions and metabolic disorders. Here we evaluate the effects of acute exercise on Sestrin 2 (Sesn2) protein content and autophagy markers in the skeletal muscle of experimental models of aging. Twenty-four months-old C57BL/6J male mice were submitted to a single bout of swimming exercise and the gastrocnemius muscle was evaluated by Western blot. Transcriptomic and phenotypic analysis were also performed by using strains of genetically-diverse BXD mice. The bioinformatics analysis showed a negative correlation between Sesn2 mRNA levels in the skeletal muscle and body weight gain, plasma triglycerides and fasting glucose and positive correlation with several autophagic markers in the muscle of BXD mice. Consistent with these findings, low levels of Sesn2 protein content were observed in the gastrocnemius muscle of C57BL/6J old mice when compared to young group. Interestingly, the acute aerobic exercise induced Sesn2 accumulation and modulated several markers of autophagy in the gastrocnemius muscle old mice, including unc-51-like kinase-1 (Ulk1) phosphorylation and the protein levels of Atg5, Atg7, p62 and LC3-II. Finally, exercise increased insulin sensitivity in old animals, as demonstrated by kITT. Taken together, these findings demonstrated the acutely, aerobic physical exercise recovers Sestrin 2 protein content and induces autophagy in the skeletal muscle of old mice, contributing with the improvement of insulin sensitivity an aging animal model. PMID- 28729214 TI - Milk fat globule membrane supplementation with voluntary running exercise attenuates age-related motor dysfunction by suppressing neuromuscular junction abnormalities in mice. AB - Age-related loss of skeletal muscle mass and function attenuates physical performance, and maintaining fine muscle innervation is known to play an important role in its prevention. We had previously shown that consumption of milk fat globule membrane (MFGM) with habitual exercise improves the muscle mass and motor function in humans and mice. Improvement of neuromuscular junction (NMJ) was suggested as one of the mechanisms underlying these effects. In this study, we evaluated the effect of MFGM intake combined with voluntary running (MFGM-VR) on morphological changes of NMJ and motor function in aging mice. Seven months following the intervention, the MFGM-VR group showed a significantly improved motor coordination in the rotarod test and muscle force in the grip strength test compared with the control group at 13 and 14months of age, respectively. In 14-month old control mice, the extensor digitorum longus muscle showed increased abnormal NMJs, such as fragmentation and denervation, compared with 6-month old young mice. However, such age-related deteriorations of NMJs were significantly suppressed in the MFGM-VR group. Increase in the expression of NMJ formation-related genes, such as agrin and LDL Receptor Related Protein 4 (LRP4), might contribute to this beneficial effect. Rotarod performance and grip strength showed significant negative correlation with the status of denervation and fragmentation of NMJs. These results suggest that MFGM intake with voluntary running exercise effectively suppresses age-related morphological deterioration of NMJ, thus contributing to improvement of motor function. PMID- 28729215 TI - Development of the Parent Responses to School Functioning Questionnaire. AB - : Parents play an important role in supporting school functioning in youth with chronic pain, but no validated tools exists to assess parental responses to child and adolescent pain behaviors in the school context. Such a tool would be useful in identifying targets of change to reduce pain-related school impairment. The goal of this study was to develop and preliminarily validate the Parent Responses to School Functioning Questionnaire (PRSF), a parent self-report measure of this construct. After initial expert review and pilot testing, the measure was administered to 418 parents of children (ages 6-17 years) seen for initial multidisciplinary chronic pain clinic evaluation. The final 16-item PRSF showed evidence of good internal consistency (alpha = .82) and 2-week test-retest reliability (intraclass correlation coefficient = .87). Criterion validity was demonstrated by significant correlations with school absence rates and overall school functioning, and construct validity was demonstrated by correlations with general parental responses to pain. Three subscales emerged capturing parents' personal distress, parents' level of distrust of the school, and parents' expectations and behaviors related to their child's management of challenging school situations. These results provide preliminary support for the PRSF as a psychometrically sound tool to assess parents' responses to child pain in the school setting. PERSPECTIVE: The 16-item PRSF measures parental responses to their child's chronic pain in the school context. The clinically useful measure can inform interventions aimed reducing functional disability in children with chronic pain by enhancing parents' ability to respond adaptively to child pain behaviors. PMID- 28729216 TI - Self-assembled AuNPs for ingrain pigmentation of silk fabrics with antibacterial potency. AB - Nanogold was self-assembled for ingrain pigmentation of silk fabric with antibacterial properties. The functional groups of silk macromolecular polymeric chains were exploited for generation and stabilization of nanogold. Hydrogen peroxide was used for activation of silk molecular chains through increasing their reactivity and accessibility to be functionalized as manufacturer of nanogold without using any external agents. Effect of procedure sequencing was studied through addition of peroxide firstly (group A) and with Au salt (group B). Self-assembly of nanogold inside fabric was confirmed by electron microscope, X-ray diffraction and absorbance spectra. The particle size of the nanogold within fabric was estimated to be in range of 22-66nm (group A) and 18-49nm (group B). Due to LSPR of nanogold, silk fabrics were acquired violet color with good fastness properties. In distilled water and artificial sweat, 33.5-41.0% and 46.2-50.4% of Au was leached out from silk fabric, respectively after 24h. Very good antibacterial properties were estimated for ingrain colored fabric against E. coli and S. aureus via using the optical density measurements. Quite simplicity, timelessness and energy saving are advantages which were realized in the current work for silk functionalization. PMID- 28729217 TI - Preventing postoperative tissue adhesion using injectable carboxymethyl cellulose pullulan hydrogels. AB - An injectable adhesive hydrogel composed of carboxymethyl cellulose (CMC) and pullulan is developed and evaluated as a postoperative anti-adhesion barrier. CMC was modified with tyramine to introduce crosslinking site via an EDC-NHS reaction. The in situ hydrogel was prepared by an enzyme-mediated reaction of tyramine-immobilized CMC with horseradish peroxidase (HRP) and hydrogen peroxide (H2O2). Pullulan was added to the hydrogel solution to improve adhesiveness to the wound area and accelerate biodegradation. The modified CMC was confirmed by ATR-FTIR spectroscopy. The gelation time, storage modulus (G'), and weight loss of the hydrogels were measured as functions of the amounts of HRP and H2O2. The hydrogel group showed negligible cell proliferation and cytotoxicity, compared to that shown by the control group. The in vivo animal test demonstrated that significant decrease of postoperative tissue adhesion by applying the hydrogels. The CMC-pullulan hydrogel could be a useful treatment as an injectable in situ anti-adhesive agent. PMID- 28729218 TI - Spectroscopic study of fluorescent probes based on G-quadruplex oligonucleotides labeled with ethynylpyrenyldeoxyuridine. AB - The design, synthesis, and spectral properties of four pyrene labeled oligonucleotide probes with G-quadruplex structure (Tel22-Tpy, Tel22-Upy, Tel22 6Upy, Tel22-18Upy) based on the 22-mer human telomeric sequence (Tel22) have been reported. Pyrene labels in the form of ethynylpyrenyldeoxyuridine have been inserted efficiently into oligodeoxynucleotides probes using phosphoramidite chemistry. The probes exhibited abilities to fold into G-quadruplex structures and to bind metal cations (Na+ and K+). Folding properties of probes and their spectral behavior were examined by recording the UV-vis, fluorescence, and CD spectra as well as by analyzing melting profiles. Fluorescence characteristics and G-quadruplex folding of probes were also studied at the interface of cationic dioctadecyldimethylammonium bromide (DODAB) monolayer. Investigations included film balance measurements (pi-A isotherms) and fluorescence spectra recording using a fiber optic accessory interfaced with a spectrofluorimeter. PMID- 28729219 TI - Immunomodulatory effects of hydroxyethylated Hericium erinaceus polysaccharide on macrophages RAW264.7. AB - Hericium erinaceus polysaccharide (HEP) has been shown to possess a variety of biological activities. In present study, HEP was successfully modified to obtain its hydroxyethylated derivative hHEP. Its potential immunomodulatory activities on RAW264.7 macrophages were investigated. Results showed that the hHEP were significantly stronger than that of the corresponding unmodified polysaccharide, HEP. Meanwhile, the NO, IL-6 and TNF-alpha production activities of macrophages were enhanced in the RAW264.7 macrophages by stimulation of hHEP. In addition, the hHEP increase significantly higher iNOS expression than HEP. These results indicated that the hydroxyethylated derivative hHEP could enhance the activation of peritoneal macrophages, and hydroxyethylation modification can enhance the immunomodulation function of HEP. PMID- 28729220 TI - Cognitive enhancement and antipsychotic-like activity following repeated dosing with the selective M4 PAM VU0467154. AB - Although selective activation of the M1 muscarinic acetylcholine receptor (mAChR) subtype has been shown to improve cognitive function in animal models of neuropsychiatric disorders, recent evidence suggests that enhancing M4 mAChR function can also improve memory performance. Positive allosteric modulators (PAMs) targeting the M4 mAChR subtype have shown therapeutic potential for the treatment of multiple symptoms observed in schizophrenia, including positive and cognitive symptoms when assessed in acute preclinical dosing paradigms. Since the cholinergic system has been implicated in multiple stages of learning and memory, we evaluated the effects of repeated dosing with the highly selective M4 PAM VU0467154 on either acquisition and/or consolidation of learning and memory when dosed alone or after pharmacologic challenge with the N-methyl-d-aspartate subtype of glutamate receptors (NMDAR) antagonist MK-801. MK-801 challenge represents a well-documented preclinical model of NMDAR hypofunction that is thought to underlie some of the positive and cognitive symptoms observed in schizophrenia. In wildtype mice, 10-day, once-daily dosing of VU0467154 either prior to, or immediately after daily testing enhanced the rate of learning in a touchscreen visual pairwise discrimination task; these effects were absent in M4 mAChR knockout mice. Following a similar 10-day, once-daily dosing regimen of VU0467154, we also observed 1) improved acquisition of memory in a cue-mediated conditioned freezing paradigm, 2) attenuation of MK-801-induced disruptions in the acquisition of memory in a context-mediated conditioned freezing paradigm and 3) reversal of MK-801-induced hyperlocomotion. Comparable efficacy and plasma and brain concentrations of VU0467154 were observed after repeated dosing as those previously reported with an acute, single dose administration of this M4 PAM. Together, these studies are the first to demonstrate that cognitive enhancing and antipsychotic-like activity are not subject to the development of tolerance following repeated dosing with a selective M4 PAM in mice and further suggest that activation of M4 mAChRs may modulate both acquisition and consolidation of memory functions. PMID- 28729221 TI - Sensitivity to cocaine in adult mice is due to interplay between genetic makeup, early environment and later experience. AB - Although early aversive postnatal events are known to increase the risk to develop psychiatric disorders later in life, rarely they determine alone the nature and outcome of the psychopathology, indicating that interaction with genetic factors is crucial for expression of psychopathologies in adulthood. Moreover, it has been suggested that early life experiences could have negative consequences or confer adaptive value in different individuals. Here we suggest that resilience or vulnerability to adult cocaine sensitivity depends on a "triple interaction" between genetic makeup x early environment x later experience. We have recently showed that Repeated Cross Fostering (RCF; RCF pups were fostered by four adoptive mothers from postnatal day 1 to postnatal day 4. Pups were left with the last adoptive mother until weaning) experienced by pups affected the response to a negative experience in adulthood in opposite direction in two genotypes leading DBA2/J, but not C57BL/6J mice, toward an "anhedonia like" phenotype. Here we investigate whether exposure to a rewarding stimulus, instead of a negative one, in adulthood induces an opposite behavioral outcome. To test this hypothesis, we investigated the long-lasting effects of RCF on cocaine sensitivity in C57 and DBA female mice by evaluating conditioned place preference induced by different cocaine doses and catecholamine prefrontal accumbal response to cocaine using a "dual probe" in vivo microdialysis procedure. Moreover, cocaine-induced c-Fos activity was assessed in different brain regions involved in processing of rewarding stimuli. Finally, cocaine induced spine changes were evaluated in the prefrontal-accumbal system. RCF experience strongly affected the behavioral, neurochemical and morphological responses to cocaine in adulthood in opposite direction in the two genotypes increasing and reducing, respectively, the sensitivity to cocaine in C57 and DBA mice. PMID- 28729222 TI - Antiallodynic effect of beta-caryophyllene on paclitaxel-induced peripheral neuropathy in mice. AB - Painful peripheral neuropathy is a common side effect of paclitaxel (PTX). The use of analgesics is an important component for management of PTX-induced peripheral neuropathy (PINP). However, currently employed analgesics have several side effects and are poorly effective. beta-caryophyllene (BCP), a dietary selective CB2 agonist, has shown analgesic effect in neuropathic pain models, but its role in chemotherapy-induced neuropathic pain has not yet been investigated. Herein, we used the mouse model of PINP to show the therapeutic effects of BCP in this neuropathy. Male Swiss mice receiving PTX (2 mg kg-1, ip, four alternate days) were treated with BCP (25 mg kg-1, po, twice a day) either during or after PTX administration. Some groups were also pretreated with AM630 (CB2 antagonist, 3 mg kg-1, ip) or AM251 (CB1 antagonist, 1 mg kg-1, ip). Spinal cord samples were collected in different time points to perform immunohistochemical analysis. BCP attenuated the established mechanical allodynia induced by PTX (p < 0.0001) in a CB2-dependent manner. Of note, when given concomitantly with PTX, BCP was able to attenuate the development of PINP (p < 0.0001). Spinal cord immunohistochemistry revealed that preventive treatment with BCP reduced p38 MAPK and NF-kappaB activation, as well as the increased Iba-1 and IL-1beta immunoreactivity promoted by PTX. Our findings show that BCP effectively attenuated PINP, possibly through CB2-activation in the CNS and posterior inhibition of p38 MAPK/NF-kappaB activation and cytokine release. Taken together, our results suggest that BCP could be used to attenuate the establishment and/or treat PINP. PMID- 28729223 TI - Synthesis, characterization and antimicrobial study of polymeric transition metal complexes of Mn(II), Co(II), Ni(II), Cu(II) and Zn(II). AB - Salen ligands comprising of o-phenylenediamine (salop) and p-phenylenediamine (salpp) have been synthesized. The salen ligand, salop undergo Schiff base reaction with Formaldehyde and Barbituric acid to generate novel polymeric Schiff base, SBOPA in one instance while the second salen ligand, salpp on Schiff base reaction with formaldehyde and piperazine gives another novel polymeric Schiff base, SBPBA. These polymeric Schiff base ligands, SBOPA and SBPBA generates polymeric metal complexes in high yields on reaction with transition metal acetates, M(CH3COO)2.xH2O where M = Mn(II), Co(II), Ni(II), Cu(II) and Zn(II). The polymeric Schiff bases, SBOPA and SBPBA and their transition metal complexes were systematically characterized, using various spectroscopic techniques. The structure, composition and geometry of SBOPA and SBPBA and their metal complexes were confirmed by spectral techniques (FT-IR, and 1H NMR), elemental analysis, and electronic spectra magnetic moment. On the basis of FT-IR, 1HNMR, electronic spectra and magnetic moment values Mn(II), Co(II) and Ni(II) ion were found to have octahedral geometry while Cu(II) and Zn(II) were found to be square-planar in nature. Thermogravimetric analysis (TGA) was used to evaluate their thermal behaviour and Cu(II)-SBOPA and Cu(II)-SBPBA were found to be thermally most stable. The polymeric Schiff base ligands, SBOPA and SBPBA and their metal complexes have also been screened for their plausible antimicrobial activity. Tetracyclin and Miconazole were used as standard drug to study the antibacterial and antifungal activity respectively. The Cu(II)-SBOPA and Cu(II)-SBPBA were found to be most potent antimicrobial agents. PMID- 28729224 TI - Robotic Placement of the FENIX Continence Restoration System in a Patient with Previous Radiation to the Pelvis: A Case Report. AB - Fecal incontinence (FI) is a disabling problem affecting women. Conservative treatment includes dietary modification, antimotility agents, and pelvic floor physical therapy. If conservative medical management is unsuccessful, surgical intervention may be required. Surgical options include rectal sphincteroplasty, bulking agent injection, radiofrequency anal sphincter remodeling, and sacral nerve stimulation therapy. Recently, a new therapy for FI, the FENIX Continence Restoration System (Torax Medical, Inc., Shoreview, MN), has become available. The FENIX device is placed through a perineal incision; however, pelvic radiation and previous anal carcinoma are both contraindications. We report the case of a 62-year-old woman with FI after anal carcinoma. Treatment included surgery, chemotherapy, and pelvic radiation. Initially, she was treated with conservative therapy and sacral nerve stimulation, which were only partially effective. A physical examination showed perineal skin changes consistent with previous radiation, which increased the patient's risk of infection and a nonhealing wound. Therefore, a robotic approach was used to place the FENIX device and improve the patient's quality of life. Our case sets a precedent for expanding the treatment options of FI in patients with previous pelvic radiation and using a robotic approach for the placement of the FENIX device. PMID- 28729225 TI - Gynura divaricata attenuates tumor growth and tumor relapse after cisplatin therapy in HCC xenograft model through suppression of cancer stem cell growth and Wnt/beta-catenin signalling. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Gynura divaricata subsp. formosana is a widely used traditional herbal medicine for treating liver disorders such as hepatitis and liver cancer in Taiwan. AIM OF THE STUDY: This study was aimed to evaluate the anti-cancer and cancer stabilization effect of water extract of the aerial part of G. divaricata (GD extract) both in vitro and in vivo. MATERIALS AND METHODS: Cytotoxicity and anti-proliferative effects of GD extract alone and in combination with cisplatin were determined by alamarBlue and clonogenic assay. Cancer stem cell (CSC) inhibition and the expression of CSC markers were revealed by sphere formation assay and real-time PCR (qPCR). The in vivo anti-cancer effect of GD extract was evaluated in Huh7 xenograft mice model and Ki-67 expression were also measured. The activity of Wnt signalling and the expression level of Wnt target genes and beta-catenin were determined by luciferase reporter assay, qPCR, immunoblotting and IHC. RESULTS: Moderate cytotoxicity of GD extract in liver cancer cells was observed. GD extract sensitized Huh7 cells to cisplatin treatment. Interestingly, GD extract inhibited cancer sphere formation and reduced the expression of CSC markers. Importantly, GD extract suppressed Huh7 tumor growth, Ki-67 expression and prolonged the anti-liver cancer effect of cisplatin in vivo. Treatment of GD extract resulted in reductions of Wnt reporter activity and the expression of Wnt target genes. Moreover, suppression of beta catenin were observed in both GD extract treated Huh7 spheres and xenograft tumors. CONCLUSION: Accordingly, our findings suggest that G. divaricata may target liver CSC by suppressing the Wnt pathway and the combination of G. divaricata and cisplatin could be a candidate regimen for treating HCC. PMID- 28729226 TI - Solanum paniculatum L. decreases levels of inflammatory cytokines by reducing NFKB, TBET and GATA3 gene expression in vitro. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Solanum paniculatum L., popularly known as jurubeba, is a common subtropical plant from Brazil, Paraguay, Bolivia and Argentina, that is used in folk medicine for the treatment of anemia, gastrointestinal disorders and inflammatory conditions in general. In addition to that, an ethnobotanical survey in "Todos os Santos" Bay have pointed out S. paniculatum as an herb to treat asthma. Previous publications have shown that S. paniculatum possesses antibiotic, antioxidant and modulatory effects on gastric acid secretion; however, its anti-inflammatory potential remains unexplored. AIM OF THE STUDY: Herein, we analyzed the S. paniculatum fruits hexane extract (SpE) for the presence of stigmasterol and beta-sitosterol and investigated the anti inflammatory effect of SpE in vitro. MATERIALS AND METHODS: SpE was subjected to high-performance liquid chromatography (HPLC) for standardization and quantification of stigmasterol and beta-sitosterol. Spleen cells from BALB/c mice were cultivated and stimulated with pokeweed mitogen and also exposed to 15, 30 and 60ug/mL of SpE. Following treatment, levels of IFN-gamma, IL-4 and IL-10 in the culture supernatants were assessed by ELISA. We also evaluated nitric oxide (NO) production by murine LPS-stimulated peritoneal macrophages using the Griess technique. In addition, the ability of SpE to stabilize membranes was assessed using a model of hemolysis induced by heat on murine erythrocytes. Gene expression of Th1-cell-specific Tbx21 transcription factor (TBET), zinc-finger transcription factor-3 (GATA3), and nuclear factor-kappaB (NFKB) in murine spleen cells were assessed by quantitative Polymerase Chain Reaction (qRT-PCR). RESULTS: SpE at 15, 30 and 60ug/mL significantly attenuated cell proliferation, decreased IL-4 release, reduced NO production and improved erythrocyte membrane stabilization in a concentration-dependent manner. SpE was also able to decrease the release of IFN-gamma without altering IL-10 levels. The mechanism whereby SpE decreased inflammatory markers may be related to the reduction of NFKB, TBET and GATA3 gene expression. CONCLUSIONS: This study is the first to test the anti inflammatory action of S. paniculatum. Herein, we provided evidence for the popular use of S. paniculatum in inflammatory conditions. Additional studies must be conducted to further explore the anti-inflammatory potential of SpE and to elucidate possible clinical applications. PMID- 28729227 TI - Computational and experimental prediction of molecules involved in the anti melanoma action of berberine. AB - ETHNOPHARMACOLOGIC RELEVANCE: Berberine (BBR) is a naturally occurring alkaloid compound that can be found in Chinese medicinal herbs such as Rhizoma Coptidis and Phellodendri Cortex. These BBR containing herbs are commonly used by Chinese medicine doctors to treat cancers including melanoma. In this study, we explored proteins potentially involved in the anti-melanoma effects of BBR using computational and experimental approaches. MATERIALS AND METHODS: Target proteins of BBR were predicted using the reverse pharmacophore screening, molecular docking and molecular dynamics. Anti-melanoma activities of BBR in melanoma cells were examined by MTT and EdU proliferation assays. Effects of BBR on activities of target proteins in melanoma cells were examined by Western blotting or fluorescence assay. RESULTS: Ten proteins implicated in cancer and with high fit score in the reverse pharmacophore screening were selected as potential targets of BBR. Molecular docking and molecular dynamics revealed that BBR could stably bind to four of the ten proteins, namely 3-phosphoinositide-dependent protein kinase 1 (PDK1), glucocorticoid receptor (GR), p38 mitogen-activated protein kinase (p38) and dihydroorotate dehydrogenase (DHODH). Cellular experiments showed that BBR inhibited cell proliferation, increased the phosphorylation of GR and p38, and inhibited the activity of DHODH in A375 human melanoma cells. CONCLUSIONS: These findings suggest that p38, GR and DHODH are potentially involved in the anti-melanoma action of BBR. This study provided a chemical and pharmacological justification for the clinical use of BBR-containing herbs in melanoma treatment. PMID- 28729228 TI - Tangled history of the European uses of Sphagnum moss and sphagnol. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Sphagnum mosses and peat could have been utilized as wound dressings for centuries, however reliable data on this subject are ambiguous; sometimes even no distinction between peat moss (Sphagnum spp.) and peat is made or these terms become confused. The first scientific account on surgical use of peat comes from 1882: a peat digger who successfully, by himself and in the way unknown to the then medicine, cured an open fracture of his forearm with peat. The peat, and very soon the peat moss itself (which is the major constituent of peat) drew attention of the 19th-century surgeons. AIMS OF THE WORK: We search for reliable information on: (1) inspirations for Sphagnum usage for medical purposes and its beginnings in the 19th century, (2) substances or products named sphagnol and their connections with (1); (3) on the origin of this name, (4) and on the occurrence of this name in medical sources. MATERIALS AND METHODS: We have identified and studied published sources on the uses of peat based and Sphagnum-based preparations and products of any processing level (including herbal stock, distillate, isolated pure or impure active principle, or a mixture of such) in surgery, pharmacy or cosmetics. A special attention was paid to the name sphagnol, which appeared many a time, in more than one context since 1899. Source publications were critically analysed from the taxonomical, pharmacognostical and ethnopharmacological points of view. Gathered data were cross-checked with the modern knowledge of the biologically active principles of Sphagnum and the prospects of their medical use. RESULTS: The application of peat in surgery started 1882. The use of peat moss as dressings was developed in the 1880's. It returned to surgical practice during WW1. The name sphagnol has two meanings: (1) A chemical substance isolated from the cell walls of Sphagnum mosses in 1899. A post-1950 research showed it to be a mixture of phenols dominated by sphagnum acid. (2) A product of dry distillation of peat contains solid and liquid fractions and was applied in skin diseases due to antiseptic properties. It was added to ointments and medicated soaps manufactured up to the late 1960's. Today none of these two sphagnols is in use. CONCLUSIONS: Surgical application of peat had an ethnopharmacological origin: a case of wound treatment with peat as a remedy rather than a dressing (1880, published 1882) shortly shifted the surgeons' attention to peat moss as an absorptive dressing. The 1880's tests of antiseptic properties of peat and peat moss failed, the sterilization methods overrode the physiological effects of Sphagnum dressings. Sphagnan, a polysaccharide from Sphagnum cell walls, discovered 1983, inhibits microbial growth, tans the collagen and removes ammonia from microbial environments. Portions of raw peat could be sterile. The isolation of sphagnol (1899) from Sphagnum cell walls was not inspired by old surgery. Main component of sphagnol, the sphagnic acid, was used clinically during WW2, but was proved a weak antimicrobial agent. A homonymous name sphagnol appeared independently for a product of dry distillation of peat, introduced commercially probably about 1899, too, which gave rise to confusions: a) the commercial, "distilled" sphagnol was not the crystalline principle of Sphagnum cell walls. 2) the "distilled" sphagnol was hardly defined technologically or pharmacologically, never standardized in terms of the substrate (a variety of peat rather than Sphagnum herb) and the production process. This sphagnol, resembling pitch or tar, was an additive to medicated soaps and ointments for skin treatment and care. It must have been a low-scale product although advertised worldwide. Neither sphagnum acid nor sphagnan are used medicinally today. PMID- 28729229 TI - Pharbitis Nil (PN) induces apoptosis and autophagy in lung cancer cells and autophagy inhibition enhances PN-induced apoptosis. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Pharbitis Nil (PN) is used as a main component of the existing drug, DA-9701, which was developed to treat functional dyspepsia (FD) in Korea. PN extracts isolated from its seeds have been reported to have anticancer effects. AIM OF THE STUDY: The purpose of this study was to investigate the underlying mechanism of the chemotherapeutic effects of PN in lung cancer cells. MATERIALS AND METHODS: We performed MTT assays, colony formation assays, flow cytometry assays, Western blot analysis, reverse transcription-polymerase chain reaction (RT-PCR), immunofluorescence analysis, and cell counting assays to study the molecular mechanism of chemotherapeutic effects of PN in lung cancer cells. RESULTS: Our results indicate that PN induced autophagy as well as apoptosis. PN inhibited cell proliferation and survival by inducing apoptosis in several lung cancer cell lines. PN-treated cells also exhibited induction of autophagy, as evidenced by increased protein expression levels and punctuate patterns of LC3 II. Moreover, activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2), which plays an important role in autophagy activation, was shown to be related with PN-induced autophagy. Interestingly, pharmacological blockade of autophagy activation with wortmannin and inhibition of ERK1/2 phosphorylation by U0126 markedly enhanced PN-induced apoptosis and reduced cell viability, suggesting that autophagy induced by PN may have a cytoprotective effect by suppressing apoptosis. PN- induced apoptosis was regulated by signal transducer and activator of transcription 3 (STAT3) deactivation. Moreover, decrease of STAT3 activation in PN-treated cells was associated with reduced survivin expression, further demonstrating that PN induced apoptosis was regulated by STAT3 deactivation. CONCLUSION: We believe that PN, which is already proven to treat human patients with FD, might be a potential anticancer drug for human lung cancer. In addition, our data suggest that the combination of PN treatment with an autophagy inhibitor or traditional anticancer agents may be an effective anticancer therapy. PMID- 28729230 TI - X-Linked Agammaglobulinaemia: Outcomes in the modern era. AB - Colonel Ogden Bruton reported X-Linked Agammaglobulinaemia in 1952 and treated the child with replacement immunoglobulin therapy. Over 60years later, the treatment for XLA has largely remained unchanged. Replacement immunoglobulin lacks the isotypes IgA and IgM, leading to concerns that patients continue to experience recurrent sinopulmonary tract infections and be at increased risk of bronchiectasis. There is potential hope of earlier diagnosis with newborn screening, and a potential cure for these patients, in the form of gene therapy. However, it is first necessary to evaluate current management and outcomes to aid decisions regarding further research and clinical trials. This article reviews current management and outcomes of XLA, whilst identifying gaps in our knowledge base that may need answering before we proceed with novel diagnostic methods and treatment for XLA. PMID- 28729231 TI - Cernunnos deficiency associated with BCG adenitis and autoimmunity: First case from the national Iranian registry and review of the literature. AB - Non-homologous end-joining (NHEJ) is a pathway that repairs double-strand breaks (DSB) in DNA and plays a vital role in V(D)J recombination of immunoglobulin genes. Cernunnos is a DNA repair factor that is involved in nonhomologous end joining (NHEJ) process. Impairment in Cernunnos leads to a genetic disease characterized by neural disorders, immunodeficiency and increased radiosensitivity. We herein describe a severe combined immunodeficiency (SCID) patient with T- B+ phenotype who had a mutation in Cernunnos gene and manifested recurrent infections, microcephaly and growth retardation with hypogammaglobulinemia. Furthermore, our patient was associated with BCG adenitis and autoimmunity that less is observed in patients with Cernunnos deficiency. In contrast to previous reported Cernunnos-deficient patients, our patient had normal B-cell number along with normal IgA and IgM, suggesting a leaky form of the Cernunnos deficiency due to residual count of B cells in our patient. Cernunnos deficiency should be considered in children with recurrent bacterial infections, microcephaly and growth retardation, in spite of having normal B-cell as well as normal IgM and IgA level. PMID- 28729232 TI - Development, Feasibility, and Small-Scale Implementation of a Web-Based Prognostic Tool-Surveillance, Epidemiology, and End Results Cancer Survival Calculator. AB - BACKGROUND: Population datasets and the Internet are playing an ever-growing role in the way cancer information is made available to providers, patients, and their caregivers. The Surveillance, Epidemiology, and End Results Cancer Survival Calculator (SEER*CSC) is a Web-based cancer prognostic tool that uses SEER data, a large population dataset, to provide physicians with highly valid, evidence based prognostic estimates for increasing shared decision-making and improving patient-provider communication of complex health information. OBJECTIVE: The aim of this study was to develop, test, and implement SEER*CSC. METHODS: An iterative approach was used to develop the SEER*CSC. Based on input from cancer patient advocacy groups and physicians, an initial version of the tool was developed. Next, providers from 4 health care delivery systems were recruited to do formal usability testing of SEER*CSC. A revised version of SEER*CSC was then implemented in two health care delivery sites using a real-world clinical implementation approach, and usage data were collected. Post-implementation follow-up interviews were conducted with site champions. Finally, patients from two cancer advocacy groups participated in usability testing. RESULTS: Overall feedback of SEER*CSC from both providers and patients was positive, with providers noting that the tool was professional and reliable, and patients finding it to be informational and helpful to use when discussing their diagnosis with their provider. However, use during the small-scale implementation was low. Reasons for low usage included time to enter data, not having treatment options in the tool, and the tool not being incorporated into the electronic health record (EHR). Patients found the language in its current version to be too complex. CONCLUSIONS: The implementation and usability results showed that participants were enthusiastic about the use and features of SEER*CSC, but sustained implementation in a real world clinical setting faced significant challenges. As a result of these findings, SEER*CSC is being redesigned with more accessible language for a public facing release. Meta-tools, which put different tools in context of each other, are needed to assist in understanding the strengths and limitations of various tools and their place in the clinical decision-making pathway. The continued development and eventual release of prognostic tools should include feedback from multidisciplinary health care teams, various stakeholder groups, patients, and caregivers. PMID- 28729233 TI - DynAMo: A Modular Platform for Monitoring Process, Outcome, and Algorithm-Based Treatment Planning in Psychotherapy. AB - BACKGROUND: In recent years, the assessment of mental disorders has become more and more personalized. Modern advancements such as Internet-enabled mobile phones and increased computing capacity make it possible to tap sources of information that have long been unavailable to mental health practitioners. OBJECTIVE: Software packages that combine algorithm-based treatment planning, process monitoring, and outcome monitoring are scarce. The objective of this study was to assess whether the DynAMo Web application can fill this gap by providing a software solution that can be used by both researchers to conduct state-of-the art psychotherapy process research and clinicians to plan treatments and monitor psychotherapeutic processes. METHODS: In this paper, we report on the current state of a Web application that can be used for assessing the temporal structure of mental disorders using information on their temporal and synchronous associations. A treatment planning algorithm automatically interprets the data and delivers priority scores of symptoms to practitioners. The application is also capable of monitoring psychotherapeutic processes during therapy and of monitoring treatment outcomes. This application was developed using the R programming language (R Core Team, Vienna) and the Shiny Web application framework (RStudio, Inc, Boston). It is made entirely from open-source software packages and thus is easily extensible. RESULTS: The capabilities of the proposed application are demonstrated. Case illustrations are provided to exemplify its usefulness in clinical practice. CONCLUSIONS: With the broad availability of Internet-enabled mobile phones and similar devices, collecting data on psychopathology and psychotherapeutic processes has become easier than ever. The proposed application is a valuable tool for capturing, processing, and visualizing these data. The combination of dynamic assessment and process- and outcome monitoring has the potential to improve the efficacy and effectiveness of psychotherapy. PMID- 28729234 TI - Mobile Phone-Supported Physiotherapy for Frozen Shoulder: Feasibility Assessment Based on a Usability Study. AB - BACKGROUND: Patients with frozen shoulder show limited shoulder mobility often accompanied by pain. Common treatment methods include physiotherapy, pain medication, administration of corticosteroids, and surgical capsulotomy. Frozen shoulder often lasts from months to years and mostly affects persons in the age group of 40 to 70 years. It severely reduces the quality of life and the ability to work. OBJECTIVE: The objective of this study was to evaluate the feasibility of a mobile health (mHealth) intervention that supports patients affected by "stage two" frozen shoulder. Patients were supported with app-based exercise instructions and tools to monitor their training compliance and progress. These training compliance and progress data supplement the patients' oral reports to the physiotherapists and physicians and can assist them in therapy adjustment. METHODS: In order to assess the feasibility of the mHealth intervention, a pilot study of a newly developed app for frozen shoulder patients was conducted with 5 patients for 3 weeks. The main function of the app was the instruction for exercising at home. Standardized questionnaires on usability such as System Usability Scale (SUS) and USE (Usefulness, Satisfaction, and Ease of use), and Technology Acceptance Model-2 (TAM-2) were completed by the study participants at the end of the study. Additionally, a nonstandardized questionnaire was completed by all patients. The correctness of the exercises as conducted by the patients was assessed by a physiotherapist at the end of the study. The mobility of the shoulder and pain in shoulder movement was assessed by a physiotherapist at the start and the end of the study. RESULTS: The pilot study was successfully conducted, and the app was evaluated by the patients after 3 weeks. The results of the standardized questionnaires showed high acceptance (TAM-2) and high usability (SUS) of the developed app. The overall usability of the system as assessed by the SUS questionnaire was very good (an average score of 88 out of 100). The average score of the TAM-2 questionnaire on the intention to further use the app was 4.2 out of 5, which indicated that most patients would use the app if further available. The results of the USE questionnaires highlighted that the patients learned how to use the app easily (an average score of 4.2 out of 5) and were satisfied with the app (an average score of 4.7 out of 5). The frequency of app usage and training was very high based on patient reports and verified by analysis of the usage data. The patients conducted the exercises almost flawlessly. CONCLUSIONS: Our results indicate the feasibility of the mHealth intervention, as the app was easy to use and frequently used by the patients. The app supported the patients' physiotherapy by providing clear exercising instructions. PMID- 28729235 TI - Improving Adherence to Web-Based and Mobile Technologies for People With Psychosis: Systematic Review of New Potential Predictors of Adherence. AB - BACKGROUND: Despite the boom in new technologically based interventions for people with psychosis, recent studies suggest medium to low rates of adherence to these types of interventions. The benefits will be limited if only a minority of service users adhere and engage; if specific predictors of adherence can be identified then technologies can be adapted to increase the service user benefits. OBJECTIVE: The study aimed to present a systematic review of rates of adherence, dropout, and approaches to analyzing adherence to newly developed mobile and Web-based interventions for people with psychosis. Specific predictors of adherence were also explored. METHODS: Using keywords (Internet or online or Web-based or website or mobile) AND (bipolar disorder or manic depression or manic depressive illness or manic-depressive psychosis or psychosis or schizophr* or psychotic), the following databases were searched: OVID including MedLine, EMBASE and PsychInfo, Pubmed and Web of Science. The objectives and inclusion criteria for suitable studies were defined following PICOS (population: people with psychosis; intervention: mobile or Internet-based technology; comparison group: no comparison group specified; outcomes: measures of adherence; study design: randomized controlled trials (RCT), feasibility studies, and observational studies) criteria. In addition to measurement and analysis of adherence, two theoretically proposed predictors of adherence were examined: (1) level of support from a clinician or researcher throughout the study, and (2) level of service user involvement in the app or intervention development. We provide a narrative synthesis of the findings and followed the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines for reporting systematic reviews. RESULTS: Of the 20 studies that reported a measure of adherence and a rate of dropout, 5 of these conducted statistical analyses to determine predictors of dropout, 6 analyzed the effects of specific adherence predictors (eg, symptom severity or type of technological interface) on the effects of the intervention, 4 administered poststudy feedback questionnaires to assess continued use of the intervention, and 2 studies evaluated the effects of different types of interventions on adherence. Overall, the percentage of participants adhering to interventions ranged from 28-100% with a mean of 83%. Adherence was greater in studies with higher levels of social support and service user involvement in the development of the intervention. Studies of shorter duration also had higher rates of adherence. CONCLUSIONS: Adherence to mobile and Web-based interventions was robust across most studies. Although 2 studies found specific predictors of nonadherence (male gender and younger age), most did not specifically analyze predictors. The duration of the study may be an important predictor of adherence. Future studies should consider reporting a universal measure of adherence and aim to conduct complex analyses on predictors of adherence such as level of social presence and service user involvement. PMID- 28729236 TI - Adolescents' Perspectives on Personalized E-Feedback in the Context of Health Risk Behavior Screening for Primary Care: Qualitative Study. AB - BACKGROUND: Electronic health screening tools for primary care present an opportunity to go beyond data collection to provide education and feedback to adolescents in order to motivate behavior change. However, there is limited research to guide feedback message development. OBJECTIVE: The aim of this study was to explore youth perceptions of and preferences for receiving personalized feedback for multiple health risk behaviors and reinforcement for health promoting behaviors from an electronic health screening tool for primary care settings, using qualitative methodology. METHODS: In total, 31 adolescents aged 13-18 years completed the screening tool, received the electronic feedback, and subsequently participated in individual, semistructured, qualitative interviews lasting approximately 60 min. Participants were queried about their overall impressions of the tool, perceptions regarding various types of feedback messages, and additional features that would help motivate health behavior change. Using thematic analysis, interview transcripts were coded to identify common themes expressed across participants. RESULTS: Overall, the tool was well received by participants who perceived it as a way to enhance-but not replace their interactions with providers. They appreciated receiving nonjudgmental feedback from the tool and responded positively to information regarding the consequences of behaviors, comparisons with peer norms and health guidelines, tips for behavior change, and reinforcement of healthy choices. A small but noteworthy minority of participants dismissed the peer norms as not real or relevant and national guidelines as not valid or reasonable. When prompted for possible adaptations to the tool, adolescents expressed interest in receiving follow-up information, setting health-related goals, tracking their behaviors over time, and communicating with providers electronically between appointments. CONCLUSIONS: Adolescents in this qualitative study desired feedback that validates their healthy behavior choices and supports them as independent decision makers by neutrally presenting health information, facilitating goal setting, and offering ongoing technological supports. PMID- 28729237 TI - Development and Use of Health-Related Technologies in Indigenous Communities: Critical Review. AB - BACKGROUND: Older Indigenous adults encounter multiple challenges as their age intersects with health inequities. Research suggests that a majority of older Indigenous adults prefer to age in place, and they will need culturally safe assistive technologies to do so. OBJECTIVE: The aim of this critical review was to examine literature concerning use, adaptation, and development of assistive technologies for health purposes by Indigenous peoples. METHODS: Working within Indigenous research methodologies and from a decolonizing approach, searches of peer-reviewed academic and gray literature dated to February 2016 were conducted using keywords related to assistive technology and Indigenous peoples. Sources were reviewed and coded thematically. RESULTS: Of the 34 sources captured, only 2 concerned technology specifically for older Indigenous adults. Studies detailing technology with Indigenous populations of all ages originated primarily from Canada (n=12), Australia (n=10), and the United States (n=9) and were coded to four themes: meaningful user involvement and community-based processes in development, the digital divide, Indigenous innovation in technology, and health technology needs as holistic and interdependent. CONCLUSIONS: A key finding is the necessity of meaningful user involvement in technology development, especially in communities struggling with the digital divide. In spite of, or perhaps because of this divide, Indigenous communities are enthusiastically adapting mobile technologies to suit their needs in creative, culturally specific ways. This enthusiasm and creativity, coupled with the extensive experience many Indigenous communities have with telehealth technologies, presents opportunity for meaningful, culturally safe development processes. PMID- 28729238 TI - Baby genome screening: paving the way to genetic discrimination? PMID- 28729239 TI - Investigators have a duty to minimise waste in pragmatic trials. PMID- 28729241 TI - The Disputed Champion: Ampicillin and Gentamicin for Febrile Young Infants. PMID- 28729240 TI - Empiric Antibiotic Use and Susceptibility in Infants With Bacterial Infections: A Multicenter Retrospective Cohort Study. AB - OBJECTIVES: To assess hospital differences in empirical antibiotic use, bacterial epidemiology, and antimicrobial susceptibility for common antibiotic regimens among young infants with urinary tract infection (UTI), bacteremia, or bacterial meningitis. METHODS: We reviewed medical records from infants <90 days old presenting to 8 US children's hospitals with UTI, bacteremia, or meningitis. We used the Pediatric Health Information System database to identify cases and empirical antibiotic use and medical record review to determine infection, pathogen, and antimicrobial susceptibility patterns. We compared hospital-level differences in antimicrobial use, pathogen, infection site, and antimicrobial susceptibility. RESULTS: We identified 470 infants with bacterial infections: 362 (77%) with UTI alone and 108 (23%) with meningitis or bacteremia. Infection type did not differ across hospitals (P = .85). Empirical antibiotic use varied across hospitals (P < .01), although antimicrobial susceptibility patterns for common empirical regimens were similar. A third-generation cephalosporin would have empirically treated 90% of all ages, 89% in 7- to 28-day-olds, and 91% in 29- to 89-day-olds. The addition of ampicillin would have improved coverage in only 4 cases of bacteremia and meningitis. Ampicillin plus gentamicin would have treated 95%, 89%, and 97% in these age groups, respectively. CONCLUSIONS: Empirical antibiotic use differed across regionally diverse US children's hospitals in infants <90 days old with UTI, bacteremia, or meningitis. Antimicrobial susceptibility to common antibiotic regimens was similar across hospitals, and adding ampicillin to a third-generation cephalosporin minimally improves coverage. Our findings support incorporating empirical antibiotic recommendations into national guidelines for infants with suspected bacterial infection. PMID- 28729242 TI - Heading for trouble: is dementia a game changer for football? PMID- 28729243 TI - Listening is key, but ask the right questions. PMID- 28729245 TI - A novel mouse model of radiation-induced cancer survivorship diseases of the gut. AB - A deeper understanding of the radiation-induced pathophysiological processes that develop in the gut is imperative to prevent, alleviate, or eliminate cancer survivorship diseases after radiotherapy to the pelvic area. Most rodent models of high-dose gastrointestinal radiation injury are limited by high mortality. We therefore established a model that allows for the delivering of radiation in fractions at high doses while maintaining long-term survival. Adult male C57/BL6 mice were exposed to small-field irradiation, restricted to 1.5 cm of the colorectum using a linear accelerator. Each mouse received 6 or 8 Gy, two times daily in 12-h intervals in two, three, or four fractions. Acute cell death was examined at 4.5 h postirradiation and histological changes at 6 wk postirradiation. Another group was given four fractions of 8 Gy and followed over time for development of visible symptoms. Irradiation caused immediate cell death, mainly limited to the colorectum. At 6 wk postirradiation, several crypts displayed signs of radiation-induced degeneration. The degenerating crypts were seen alongside crypts that appeared perfectly healthy. Crypt survival was reduced after the fourth fraction regardless of dose, whereas the number of macrophages increased. Angiogenesis was induced, likely as a compensatory mechanism for hypoxia. Four months postirradiation, mice began to show radiation-induced symptoms, and histological examination revealed an extensive crypt loss and fibrosis. Our model is uniquely suitable for studying the long-term trajectory and underlying mechanisms of radiation-induced gastrointestinal injury.NEW & NOTEWORTHY A novel mouse model for studying the long-term trajectory of radiation induced gut injury. The method allows for the use of high doses and multiple fractions, with minor impact on animal health for at least 3 mo. Crypt loss and a slow progression of fibrosis is observed. Crypt degeneration is a process restricted to isolated crypts. Crypt degeneration is presented as a convenient proxy endpoint for long-term radiation-induced gut injury. PMID- 28729244 TI - Apoptosis Repressor With Caspase Recruitment Domain Ameliorates Amyloid-Induced beta-Cell Apoptosis and JNK Pathway Activation. AB - Islet amyloid is present in more than 90% of individuals with type 2 diabetes, where it contributes to beta-cell apoptosis and insufficient insulin secretion. Apoptosis repressor with caspase recruitment domain (ARC) binds and inactivates components of the intrinsic and extrinsic apoptosis pathways and was recently found to be expressed in islet beta-cells. Using a human islet amyloid polypeptide transgenic mouse model of islet amyloidosis, we show ARC knockdown increases amyloid-induced beta-cell apoptosis and loss, while ARC overexpression decreases amyloid-induced apoptosis, thus preserving beta-cells. These effects occurred in the absence of changes in islet amyloid deposition, indicating ARC acts downstream of amyloid formation. Because islet amyloid increases c-Jun N terminal kinase (JNK) pathway activation, we investigated whether ARC affects JNK signaling in amyloid-forming islets. We found ARC knockdown enhances JNK pathway activation, whereas ARC overexpression reduces JNK, c-Jun phosphorylation, and c Jun target gene expression (Jun and Tnf). Immunoprecipitation of ARC from mouse islet lysates showed ARC binds JNK, suggesting interaction between JNK and ARC decreases amyloid-induced JNK phosphorylation and downstream signaling. These data indicate that ARC overexpression diminishes amyloid-induced JNK pathway activation and apoptosis in the beta-cell, a strategy that may reduce beta-cell loss in type 2 diabetes. PMID- 28729246 TI - Vagally mediated effects of brain stem dopamine on gastric tone and phasic contractions of the rat. AB - Dopamine (DA)-containing fibers and neurons are embedded within the brain stem dorsal vagal complex (DVC); we have shown previously that DA modulates the membrane properties of neurons of the dorsal motor nucleus of the vagus (DMV) via DA1 and DA2 receptors. The vagally dependent modulation of gastric tone and phasic contractions, i.e., motility, by DA, however, has not been characterized. With the use of microinjections of DA in the DVC while recording gastric tone and motility, the aims of the present study were 1) assess the gastric effects of brain stem DA application, 2) identify the DA receptor subtype, and, 3) identify the postganglionic pathway(s) activated. Dopamine microinjection in the DVC decreased gastric tone and motility in both corpus and antrum in 29 of 34 rats, and the effects were abolished by ipsilateral vagotomy and fourth ventricular treatment with the selective DA2 receptor antagonist L741,626 but not by application of the selective DA1 receptor antagonist SCH 23390. Systemic administration of the cholinergic antagonist atropine attenuated the inhibition of corpus and antrum tone in response to DA microinjection in the DVC. Conversely, systemic administration of the nitric oxide synthase inhibitor nitro l-arginine methyl ester did not alter the DA-induced decrease in gastric tone and motility. Our data provide evidence of a dopaminergic modulation of a brain stem vagal neurocircuit that controls gastric tone and motility.NEW & NOTEWORTHY Dopamine administration in the brain stem decreases gastric tone and phasic contractions. The gastric effects of dopamine are mediated via dopamine 2 receptors on neurons of the dorsal motor nucleus of the vagus. The inhibitory effects of dopamine are mediated via inhibition of the postganglionic cholinergic pathway. PMID- 28729248 TI - End-stage renal disease versus death in a Portuguese cohort of elderly patients: an approach using competing event analysis. AB - Chronic kidney disease (CKD) is higher in elderly, but mortality outweighs the risk of end-stage renal disease (ESRD). Our aim was to identify prognostic markers for ESRD or death in elderly CKD, within a competing-risk analysis. This is a longitudinal study of consecutive newly referred patients with CKD ages 65 years, followed until the time of the first event (ESRD or death), using a competing-risk analysis. A modified Charlson Comorbidity Index (mCCI) was subdivided into subgroups (0-2, 3-4, >=5). Patients were followed for hospitalizations that occurred prior to the outcomes. Among 416 patients, age 76+/-8 years, 52% male, median estimated glomerular filtration rate of 32 mL/min per 1.73 m2, 50% had diabetes, and 67% cardiovascular disease. Over a median follow-up of 3.6 years, 36 patients progressed to ESRD (8.7%) and 103 died (24.8%). Older age (subdistribution HR (sHR)=1. 06; p<0.001), creatinine>=1.6 mg/dL (sHR=2.03, p=0.004), hemoglobin <11 g/dL (sHR=1.91, p=0.003), mCCI score>=5 (sHR=3.01, p<0.001) and having one or more hospitalizations (sHR=1.73, p<0.001) were associated with death before ESRD. The independent predictors for ESRD with competing risk of death were: lower age (sHR=0.94; p=0.009), creatinine>=1.6 mg/dL (sHR=3.26, p=0.006), hemoglobin <11 g/dL (sHR=2.15, p=0.027), peripheral vascular disease (sHR=3.45, p=0.001) and having one or more hospitalizations (sHR=1.56, p=0.031). Elderly referred patients with CKD are near threefold more likely to die than progress to ESRD. A competing-risk framework based on available clinical and laboratory data may discriminate between those outcomes and could be used as a decision-making tool. PMID- 28729247 TI - Adaptive regulation of pancreatic acinar mitochondrial thiamin pyrophosphate uptake process: possible involvement of epigenetic mechanism(s). AB - The essentiality of thiamin stems from its roles as a cofactor [mainly in the form of thiamin pyrophosphate (TPP)] in critical metabolic reactions including oxidative energy metabolism and reduction of cellular oxidative stress. Like other mammalian cells, pancreatic acinar cells (PAC) obtain thiamin from their surroundings and convert it to TPP; mitochondria then take up TPP by a carrier mediated process that involves the mitochondrial TPP (MTPP) transporter (MTPPT; product of SLC25A19 gene). Previous studies have characterized different physiological/biological aspects of the MTPP uptake process, but little is known about its possible adaptive regulation. We addressed this issue using pancreatic acinar 266-6 cells (PAC 266-6) maintained under thiamin-deficient (DEF) and oversupplemented (OS) conditions, as well as thiamin-DEF and -OS transgenic mice carrying the SLC25A19 promoter. We found that maintaining PAC 266-6 under the thiamin-DEF condition leads to a significant induction in mitochondrial [3H]TPP uptake, as well as in the level of expression of the MTPPT protein and mRNA compared with thiamin-OS cells. Similar findings were observed in mitochondria from thiamin-DEF mice compared with thiamin-OS. Subsequently, we demonstrated that adaptive regulation of MTTP protein was partly mediated via transcriptional mechanism(s) via studies with PAC 266-6 transfected with the SLC25A19 promoter and transgenic mice carrying the SLC25A19 promoter. This transcriptional regulation appeared to be, at least in part, mediated via epigenetic mechanism(s) involving histone modifications. These studies report, for the first time, that the PAC mitochondrial TPP uptake process is adaptively regulated by the prevailing thiamin level and that this regulation is transcriptionally mediated and involves epigenetic mechanism(s).NEW & NOTEWORTHY Our findings show, for the first time, that the mitochondrial thiamin pyrophosphate (MTPP) uptake process is adaptively regulated by the prevailing thiamin level in pancreatic acinar cells and this regulation is mediated, at least in part, by transcriptional and epigenetic mechanism(s) affecting the SLC25A19 promoter. PMID- 28729249 TI - Deletion of transcription factor binding motifs using the CRISPR/spCas9 system in the beta-globin LCR. AB - Transcription factors play roles in gene transcription through direct binding to their motifs in genome, and inhibiting this binding provides an effective strategy for studying their roles. Here we applied the CRISPR/spCas9 system to mutate the binding motifs of transcription factors. Binding motifs for erythroid specific transcription factors were mutated in the locus control region hypersensitive sites of the human beta-globin locus. Guide RNAs targeting binding motifs were cloned into lentiviral CRISPR vector containing the spCas9 gene, and transduced into MEL/ch11 cells carrying a human chromosome 11. DNA mutations in clonal cells were initially screened by quantitative PCR in genomic DNA and then clarified by sequencing. Mutations in binding motifs reduced occupancy by transcription factors in a chromatin environment. Characterization of mutations revealed that the CRISPR/spCas9 system mainly induced deletions in short regions of <20 bp and preferentially deleted nucleotides around the fifth nucleotide upstream of Protospacer adjacent motifs. These results indicate that the CRISPR/Cas9 system is suitable for mutating the binding motifs of transcription factors, and, consequently, would contribute to elucidate the direct roles of transcription factors. PMID- 28729252 TI - Health services must encourage pragmatic research. PMID- 28729250 TI - Stellarex Drug-Coated Balloon for Treatment of Femoropopliteal Disease: Twelve Month Outcomes From the Randomized ILLUMENATE Pivotal and Pharmacokinetic Studies. AB - BACKGROUND: Drug-coated balloons (DCBs) are a predominant revascularization therapy for symptomatic femoropopliteal artery disease. Because of the differences in excipients, paclitaxel dose, and coating morphologies, varying clinical outcomes have been observed with different DCBs. We report the results of 2 studies investigating the pharmacokinetic and clinical outcomes of a new DCB to treat femoropopliteal disease. METHODS: In the ILLUMENATE Pivotal Study (Prospective, Randomized, Single-Blind, U.S. Multi-Center Study to Evaluate Treatment of Obstructive Superficial Femoral Artery or Popliteal Lesions With A Novel Paclitaxel-Coated Percutaneous Angioplasty Balloon), 300 symptomatic patients (Rutherford class 2-4) were randomly assigned to DCB (n=200) or standard angioplasty (percutaneous transluminal angioplasty [PTA]) (n=100). The primary safety end point was freedom from device- and procedure-related death through 30 days, and freedom from target limb major amputation and clinically driven target lesion revascularization through 12 months. The primary effectiveness end point was primary patency through 12 months. In the ILLUMENATE PK study (Pharmacokinetic Study of the Stellarex Drug-Coated Angioplasty Balloon), paclitaxel plasma concentrations were measured after last DCB deployment and at prespecified times (at 1, 4, 24 hours and at 7 and 14 days postprocedure) until no longer detectable. RESULTS: In the ILLUMENATE Pivotal Study, baseline characteristics were similar between groups: 50% had diabetes mellitus, 41% were women, mean lesion length was 8.3 cm, and 44% were severely calcified. The primary safety end point was met (92.1% for DCB versus 83.2% for PTA, P=0.025 for superiority) and the primary patency rate was significantly higher with DCB (76.3% for DCB versus 57.6% for PTA, P=0.003). Primary patency per Kaplan-Meier estimates at day 365 was 82.3% for DCB versus 70.9% for PTA (P=0.002). The rate of clinically driven target lesion revascularization was significantly lower in the DCB cohort (7.9% versus 16.8%, P=0.023). Improvements in ankle-brachial index, Rutherford class, and quality of life were comparable, but the PTA cohort required twice as many revascularizations. Pharmacokinetic outcomes showed that all patients had detectable paclitaxel levels after DCB deployment that declined within the first hour (54.4+/-116.9 ng/mL to 1.4+/-1.0 ng/mL). CONCLUSIONS: The data demonstrate superior safety and effectiveness of the Stellarex DCB in comparison with PTA, and plasma levels of paclitaxel fall to low levels within 1 hour. CLINICAL TRIAL REGISTRATION: URL: http://clinicaltrials.gov. Unique identifiers: NCT01858428 and NCT01912937. PMID- 28729251 TI - Inclusion of a Genetic Risk Score into a Validated Risk Prediction Model for Colorectal Cancer in Japanese Men Improves Performance. AB - We previously developed and validated a risk prediction model for colorectal cancer in Japanese men using modifiable risk factors. To further improve risk prediction, we evaluated the degree of improvement obtained by adding a genetic risk score (GRS) using genome-wide association study (GWAS)-identified risk variants to our validated model. We examined the association between 36 risk variants identified by GWAS and colorectal cancer risk using a weighted Cox proportional hazards model in a nested case-control study within the Japan Public Health Center-based Prospective Study. GRS was constructed using six variants associated with risk in this study of the 36 tested. We assessed three models: a nongenetic model that included the same variables used in our previously validated model; a genetic model that used GRS; and an inclusive model, which included both. The c-statistic, integrated discrimination improvement (IDI), and net reclassification improvement (NRI) were calculated by the 5-fold cross validation method. We estimated 10-year absolute risks for developing colorectal cancer. A statistically significant association was observed between the weighted GRS and colorectal cancer risk. The mean c-statistic for the inclusive model (0.66) was slightly greater than that for the nongenetic model (0.60). Similarly, the mean IDI and NRI showed improvement when comparing the nongenetic and inclusive models. These models for colorectal cancer were well calibrated. The addition of GRS using GWAS-identified risk variants to our validated model for Japanese men improved the prediction of colorectal cancer risk. Cancer Prev Res; 10(9); 535-41. (c)2017 AACR. PMID- 28729253 TI - Genome Sequences of the First WHO Repository of Platelet Transfusion-Relevant Bacterial Reference Strains. AB - To develop novel techniques for improving blood safety, dedicated bacterial strains, which are able to persist and to proliferate in blood platelet concentrates, are needed. Here, we present draft genome sequences of the four bacterial strains approved for the first WHO repository of platelet transfusion relevant bacterial reference strains. PMID- 28729254 TI - Finished Whole-Genome Sequences of Clostridium butyricum Toxin Subtype E4 and Clostridium baratii Toxin Subtype F7 Strains. AB - Clostridium butyricum and Clostridium baratii species have been known to produce botulinum toxin types E and F, respectively, which can cause botulism, a rare but serious neuroparalytic disease. Here, we present finished genome sequences for two of these clinically relevant strains. PMID- 28729255 TI - Genome Sequences of Two Listeria monocytogenes Strains from Nectarines Associated with Listeriosis in 2014. AB - Listeria monocytogenes is an important foodborne pathogen. Here, we present the annotated whole genome of Listeria monocytogenes strains F14M01297-C2 and F14M01297-C4, isolated from nectarines distributed by a packing facility in California during an investigation of listeriosis associated with stone fruit in 2014. PMID- 28729256 TI - Complete Genome Sequence of Mycoplasma capricolum subsp. capripneumoniae Strain zly1309F, Isolated from Endangered Tibetan Antelope. AB - Mycoplasma capricolum subsp. capripneumoniae is an important pathogen of goats that causes contagious caprine pleuropneumonia. Here, we report the complete genome sequence of M. capricolum subsp. capripneumoniae strain zly1309F, isolated from a Tibetan antelope (Pantholops hodgsonii) in China. PMID- 28729257 TI - First Complete Genome Sequence of Barley Virus G Identified from Proso Millet (Panicum miliaceum) in South Korea. AB - The complete genome sequence of an Uiseong isolate of barley virus G (BVG) on proso millet plants in a field in South Korea was determined by RNA sequencing and Sanger sequencing. To our knowledge, this is the first complete genome sequence report of BVG infecting proso millet in South Korea. PMID- 28729258 TI - Complete Genome Sequence of a Highly Divergent Dengue Virus Type 2 Strain, Imported into Australia from Sabah, Malaysia. AB - In 2015, a female patient returning to Australia from Sabah, Malaysia, was diagnosed with a suspected sylvatic dengue virus type 2 (DENV-2) infection, becoming the second case of imported highly divergent dengue virus infection recorded in Australia. We describe here the complete genome sequencing of the DENV-2 strain isolated from this patient. PMID- 28729259 TI - Complete Genome Sequence of the Lumpy Skin Disease Virus Isolated from the First Reported Case in Greece in 2015. AB - Lumpy skin disease virus (LSDV) causes an economically important disease in cattle. Here, we report the complete genome sequence of the first LSDV isolate identified in mainland Europe. LSDV isolate Evros/GR/15 was isolated from the first cases reported on 18 August 2015 in the Evros region, Greece. PMID- 28729260 TI - Draft Genome Sequence of the Polysaccharide-Degrading Marine Bacterium Pseudoalteromonas sp. Strain A601. AB - Pseudoalteromonas sp. strain A601 is a marine bacterium with excellent polysaccharide-degrading capabilities. Here, we present a high-quality draft genome sequence of strain A601 with a size of approximately 4.89 Mb and a mean G+C content of 40.0%. Various putative polysaccharide-degrading genes were found in the draft genome. PMID- 28729261 TI - Whole-Genome Sequence of Photobacterium damselae subsp. piscicida Strain 91-197, Isolated from Hybrid Striped Bass (Morone sp.) in the United States. AB - Photobacterium damselae subsp. piscicida is a causative bacterium of fish pasteurellosis, which has caused serious economic damage to aquaculture farms worldwide. Here, the whole-genome sequence of P. damselae subsp. piscicida 91 197, isolated in the United States, suggests that this genome consists of two chromosomes and two plasmids. PMID- 28729262 TI - Genome Sequence of Canine Polyomavirus in Respiratory Secretions of Dogs with Pneumonia of Unknown Etiology. AB - We report here the first canine polyomavirus genome, identified by metagenomics in respiratory secretions of two dogs with severe pneumonia, which tested negative for all canine respiratory pathogens except Mycoplasma cynos The isolate, Canis familiaris polyomavirus 1 (DogPyV-1), is a beta polyomavirus whose closest known LT antigen relatives are primate polyomaviruses. PMID- 28729263 TI - Complete Genomic Sequence of Canine Distemper Virus from an Ethiopian Wolf. AB - Canine distemper virus (CDV) has been implicated in population declines of wildlife, including many threatened species. Here we present the full genome of CDV from an Ethiopian wolf, Canis simensis, the world's rarest and most endangered canid. PMID- 28729264 TI - Complete Genome Sequence of Burkholderia stabilis FERMP-21014. AB - Cholesterol esterase (EC 3.1.1.13) was identified in a bacterium, Burkholderia stabilis strain FERMP-21014. Here, we report the complete genome sequence of B. stabilis FERMP-21014, which has been used in the commercial production of cholesterol esterase. The genome sequence information may be useful for improving production levels of cholesterol esterase. PMID- 28729265 TI - The Complete Genome Sequence of Trueperella pyogenes UFV1 Reveals a Processing System Involved in the Quorum-Sensing Signal Response. AB - We present here the complete genome sequence of Trueperella pyogenes UFV1. The 2.3-Mbp genome contains an extremely interesting AI-2 transporter and processing system related to the quorum-sensing signal response. This specific feature is described in this species for the first time and might be responsible for a new pathogenic behavior. PMID- 28729266 TI - Draft Genome Sequence of Streptomyces sp. M1013, a Close Relative of Streptomyces ambofaciens and Streptomyces coelicolor. AB - We report the draft genome sequence of Streptomyces sp. M1013, a strain isolated from the Medicago arborea rhizosphere in Izmir, Turkey. An average nucleotide identity (ANI) analysis reveals that this strain belongs to the same species as Streptomyces canus ATCC12647 and is closely related to Streptomyces ambofaciens and Streptomyces coelicolor. PMID- 28729267 TI - Draft Genome Sequence of the blaOXA-436- and blaNDM-1-Harboring Shewanella putrefaciens SA70 Isolate. AB - We sequenced a carbapenem-resistant Shewanella putrefaciens isolate cultured from the sink handle of a Pakistan hospital room. Assembly annotation indicates that the isolate has a chromosomal blaOXA-436 carbapenemase and a plasmid-borne blaNDM 1 gene. To our knowledge, this is the first report of a Shewanella species harboring blaNDM. PMID- 28729268 TI - Draft Genome Sequence of Root-Associated Sugarcane Growth-Promoting Microbispora sp. Strain GKU 823. AB - The endophytic plant growth-promoting Microbispora sp. strain GKU 823 was isolated from the roots of sugarcane cultivated in Thailand. It has an estimated 9.4-Mbp genome and a G+C content of 71.3%. The genome sequence reveals several genes associated with plant growth-promoting traits and extensive specialized metabolite biosynthesis. PMID- 28729269 TI - Multiple Genome Sequences of Lactobacillus plantarum Strains. AB - We report here the genome sequences of four Lactobacillus plantarum strains which vary in surface hydrophobicity. Bioinformatic analysis, using additional genomes of Lactobacillus plantarum strains, revealed a possible correlation between the cell wall teichoic acid-type and cell surface hydrophobicity and provide the basis for consecutive analyses. PMID- 28729270 TI - Draft Genome Sequences of Three Lactobacillusparacasei Strains, Members of the Nonstarter Microbiota of Mature Cheddar Cheese. AB - Lactobacillus paracasei strains are common members of the nonstarter microbiota present in various types of cheeses. The draft genome sequences of three strains isolated from mature cheddar cheeses are reported here. PMID- 28729272 TI - Draft Genome Sequence of Paludibacter jiangxiensis NM7T, a Propionate-Producing Fermentative Bacterium. AB - We report here a high-quality draft genome sequence of Paludibacter jiangxiensis strain NM7T, a mesophilic, anaerobic, propionate-producing fermentative bacterium within the family Porphyromonadaceae of the phylum Bacteroidetes The genome comprises 3,664,884 bp in four contigs, has a G+C content of 42.92%, and contains 2,949 protein-coding sequences and 62 RNAs. PMID- 28729271 TI - Whole-Genome Sequence of Acinetobacter pittii HUMV-6483 Isolated from Human Urine. AB - Acinetobacter pittii strain HUMV-6483 was obtained from urine from an adult patient. We report here its complete genome assembly using PacBio single-molecule real-time sequencing, which resulted in a chromosome with 4.07 Mb and a circular contig of 112 kb. About 3,953 protein-coding genes are predicted from this assembly. PMID- 28729273 TI - Draft Genome Sequence of Microbacterium sp. Strain LEMMJ01, Isolated from Antarctic Ornithogenic Soil. AB - We report here the 3,637,012-bp draft genome sequence of Microbacterium sp. strain LEMMJ01, isolated from ornithogenic soil from King George Island, Antarctica. The total number of genes presented in the draft genome sequence was 3,553, and the total number of coding sequences was 3,497. In addition, genes related to the production of terpene and carotenoids were revealed. PMID- 28729274 TI - Genome Sequences of Two Shewanella spp. Isolated from the Gut of the Sea Cucumber Apostichopus japonicus (Selenka, 1867). AB - In this study, we sequenced the genomes of two Shewanella spp., newly isolated from the gut of the sea cucumber Apostichopus japonicus (Selenka, 1867). The whole-genome sequences reported here will expand the repertoire of genomic information for the members of the genus Shewanella and will provide important insights into their roles within microbial communities. PMID- 28729275 TI - Whole-Genome Sequences of 14 Strains of Bradyrhizobium canariense and 1 Strain of Bradyrhizobium japonicum Isolated from Lupinus spp. in Algeria. AB - We report here the whole-genome sequences of 14 strains of Bradyrhizobium canariense, isolated from root nodules of Lupinus microanthus and Lupinus angustifolius, and 1 strain of Bradyrhizobium japonicum isolated from root nodules from Lupinus angustifolius in Algeria. These sequences add to the known diversity of this agronomically important genus. PMID- 28729276 TI - Draft Genome Sequence of Paenibacillus sp. Strain MY03, a Terrestrial Bacterium Capable of Degrading Multiple Marine-Derived Polysaccharides. AB - The bacterium Paenibacillus sp. strain MY03, isolated from the root soil of cypress, can effectively degrade marine-derived polysaccharides such as agar, alginate, and chitin. Here, we present the draft genome sequence of MY03. Putative enzymes, including 3 agarases, 1 alginate lyase, and 1 chitinase, were found. PMID- 28729277 TI - Draft Genome Sequence of Salmonella enterica subsp. enterica Serovar Infantis Strain SPE101, Isolated from a Chronic Human Infection. AB - We report a 4.99-Mb draft genome sequence of Salmonella enterica subsp. enterica serovar Infantis strain SPE101, isolated from feces of a 5-month-old breast-fed female showing diarrhea associated with severe dehydration and malnutrition. The infection prolonged for 6 months despite antibiotic treatment. PMID- 28729278 TI - High-Quality Genome Sequence of the Highly Resistant Bacterium Staphylococcus haemolyticus, Isolated from a Neonatal Bloodstream Infection. AB - Using Illumina HiSeq and PacBio technologies, we sequenced the genome of the multidrug-resistant bacterium Staphylococcus haemolyticus, originating from a bloodstream infection in a neonate. The sequence data can be used as an accurate reference sequence. PMID- 28729279 TI - Complete Genome Sequence of an Avian Metapneumovirus Subtype A Strain Isolated from Chicken (Gallus gallus) in Brazil. AB - We report here the complete genome sequence of an avian metapneumovirus (aMPV) isolated from a tracheal tissue sample of a commercial layer flock. The complete genome sequence of aMPV-A/chicken/Brazil-SP/669/2003 was obtained using MiSeq (Illumina, Inc.) sequencing. Phylogenetic analysis of the complete genome classified the isolate as avian metapneumovirus subtype A. PMID- 28729280 TI - Complete Genome Sequences of Three phi29-Like Bacillus cereus Group Podoviridae. AB - Three double-stranded DNA phi29-like Bacillus cereus group bacteriophages, BeachBum, Harambe, and SerPounce, were identified and characterized. BeachBum and Harambe are closely related but are remarkably different from previously identified phi29-like phages. SerPounce is substantially closer to other phi29 like phages, enabling the identification of its prohead RNA (pRNA) gene. PMID- 28729281 TI - Complete Genome Sequence of Campylobacter concisus ATCC 33237T and Draft Genome Sequences for an Additional Eight Well-Characterized C. concisus Strains. AB - We report the complete genome sequence of the Campylobacter concisus type strain ATCC 33237 and the draft genome sequences of eight additional well-characterized C. concisus strains. C. concisus has been shown to be a genetically heterogeneous species, and these nine genomes provide valuable information regarding the diversity within this taxon. PMID- 28729282 TI - Draft Genome Sequence of Actinomycessucciniciruminis Strain Am4T, Isolated from Cow Rumen Fluid. AB - Actinomyces succiniciruminis strain Am4T, isolated from cow rumen fluid, can metabolize a range of substrates including complex carbohydrates to organic acids. Here, we report a 3.33-Mbp draft genome of Actinomyces succiniciruminis. PMID- 28729283 TI - Choosing treatments when the effect of alternatives is uncertain. PMID- 28729284 TI - Visualising inflammation after myocardial infarction with the use of iron oxide nanoparticles. PMID- 28729285 TI - Teenage boys shouldn't be given HPV vaccine, says joint committee. PMID- 28729286 TI - Seven days in medicine: 12-18 July 2017. PMID- 28729287 TI - BP Targets in CKD, Mortality, and SPRINT: What Have We Learned? PMID- 28729288 TI - Urinary Extracellular Vesicles of Podocyte Origin and Renal Injury in Preeclampsia. AB - Renal histologic expression of the podocyte-specific protein, nephrin, but not podocin, is reduced in preeclamptic compared with normotensive pregnancies. We hypothesized that renal expression of podocyte-specific proteins would be reflected in urinary extracellular vesicles (EVs) of podocyte origin and accompanied by increased urinary soluble nephrin levels (nephrinuria) in preeclampsia. We further postulated that podocyte injury and attendant formation of EVs are related mechanistically to cellfree fetal hemoglobin (HbF) in maternal plasma. Our study population included preeclamptic (n=49) and normotensive (n=42) pregnant women recruited at delivery. Plasma measurements included HbF concentrations and concentrations of the endogenous chelators haptoglobin, hemopexin, and alpha1- microglobulin. We assessed concentrations of urinary EVs containing immunologically detectable podocyte-specific proteins by digital flow cytometry and measured nephrinuria by ELISA. The mechanistic role of HbF in podocyte injury was studied in pregnant rabbits. Compared with urine from women with normotensive pregnancies, urine from women with preeclamptic pregnancies contained a high ratio of podocin-positive to nephrin-positive urinary EVs (podocin+ EVs-to-nephrin+ EVs ratio) and increased nephrinuria, both of which correlated with proteinuria. Plasma levels of hemopexin, which were decreased in women with preeclampsia, negatively correlated with proteinuria, urinary podocin+ EVs-to-nephrin+ EVs ratio, and nephrinuria. Administration of HbF to pregnant rabbits increased the number of urinary EVs of podocyte origin. These findings provide evidence that urinary EVs are reflective of preeclampsia-related altered podocyte protein expression. Furthermore, renal injury in preeclampsia associated with an elevated urinary podocin+ EVs-to-nephrin+ EVs ratio and may be mediated by prolonged exposure to cellfree HbF. PMID- 28729289 TI - Class II Eplet Mismatch Modulates Tacrolimus Trough Levels Required to Prevent Donor-Specific Antibody Development. AB - Despite more than two decades of use, the optimal maintenance dose of tacrolimus for kidney transplant recipients is unknown. We hypothesized that HLA class II de novo donor-specific antibody (dnDSA) development correlates with tacrolimus trough levels and the recipient's individualized alloimmune risk determined by HLA-DR/DQ epitope mismatch. A cohort of 596 renal transplant recipients with 50,011 serial tacrolimus trough levels had HLA-DR/DQ eplet mismatch determined using HLAMatchmaker software. We analyzed the frequency of tacrolimus trough levels below a series of thresholds <6 ng/ml and the mean tacrolimus levels before dnDSA development in the context of HLA-DR/DQ eplet mismatch. HLA-DR/DQ eplet mismatch was a significant multivariate predictor of dnDSA development. Recipients treated with a cyclosporin regimen had a 2.7-fold higher incidence of dnDSA development than recipients on a tacrolimus regimen. Recipients treated with tacrolimus who developed HLA-DR/DQ dnDSA had a higher proportion of tacrolimus trough levels <5 ng/ml, which continued to be significant after adjustment for HLA-DR/DQ eplet mismatch. Mean tacrolimus trough levels in the 6 months before dnDSA development were significantly lower than the levels >6 months before dnDSA development in the same patients. Recipients with a high-risk HLA eplet mismatch score were less likely to tolerate low tacrolimus levels without developing dnDSA. We conclude that HLA-DR/DQ eplet mismatch and tacrolimus trough levels are independent predictors of dnDSA development. Recipients with high HLA alloimmune risk should not target tacrolimus levels <5 ng/ml unless essential, and monitoring for dnDSA may be advisable in this setting. PMID- 28729291 TI - Stimulator of IFN genes-mediated DNA-sensing pathway is suppressed by NLRP3 agonists and regulated by mitofusin 1 and TBC1D15, mitochondrial dynamics mediators. AB - The stimulator of IFN genes (STING)-mediated DNA-sensing pathway plays an important role in the innate immune response to pathogen infection, autoimmunity, and cancer; however, its regulatory mechanism has not been fully elucidated, and we do not yet know whether the STING pathway is counter-regulated by other innate immune pathways. Here, we show that the NLRP3-activating agonists, ATP and nigericin, prevent STING pathway activation in association with mitochondrial fragmentation; however, the suppression of the STING pathway and mitochondria fission were not dependent on NLRP3 or potassium efflux. Although nigericin induced mitochondria fission was rescued by knockdown of either dynamin-related protein 1 or TBC1 domain family member 15 (TBC1D15), which are two distinct mitochondria fission regulators, only TBC1D15 restored the activity of the STING pathway, which indicates that inflammasome-activating signals curtail STING pathway activation via TBC1D15. Finally, we found that deficiency of mitofusin (MFN) 1, a mediator of mitochondrial fusion, inhibited STING pathway activation, which leads to a decrease in the induction of IFN-beta and its inducible gene, ISG56, in conjunction with diminished activation of the signaling molecules, TANK binding kinase 1 and IFN regulatory factor 3, that are downstream of STING. These results highlight the crucial role of MFN1 in maintaining the competency of the STING pathway. Collectively, our findings reveal that mitochondrial dynamics regulators modulate the activation of the STING signaling pathway.-Kwon, D., Park, E., Kang, S.-J. Stimulator of IFN genes-mediated DNA-sensing pathway is suppressed by NLRP3 agonists and regulated by mitofusin 1 and TBC1D15, mitochondrial dynamics mediators. PMID- 28729290 TI - Choroidal gammadelta T cells in protection against retinal pigment epithelium and retinal injury. AB - gammadelta T cells located near the epithelial barrier are integral components of local inflammatory and innate immune responses. We have previously reported the presence of choroidal gammadelta T cells in a model of chronic degeneration of the retinal pigment epithelium (RPE). The goals of the current study were to further define the functions of choroidal gammadelta T cells and to explore the underlying mechanisms of their action. Our data demonstrate that choroidal gammadelta T cells are activated by RPE injury in response to NaIO3 treatment, and that they express genes that encode immunosuppressive cytokines, such as IL-4 and IL-10. gammadelta-T-cell-deficient mice developed profound RPE and retinal damage at doses that caused minimal effects in wild-type mice, and adoptive transfer of gammadelta T cells prevented sensitization. Intravitreal injection of IL-4 and IL-10 ameliorated RPE toxicity that was induced by NaIO3Ex vivo coculture of gammadelta T cells with RPE explants activated the production of anti-inflammatory cytokines via an aryl hydrocarbon receptor (AhR)-dependent mechanism. AhR deficiency abolished the protective effects of gammadelta T cells after adoptive transfer. Collectively, these findings define important roles for choroid gammadelta T cells in maintaining tissue homeostasis in the outer retina. Zhao, Z., Liang, Y., Liu, Y., Xu, P., Flamme-Wiese, M. J., Sun, D., Sun, J., Mullins, R. F., Chen, Y., Cai, J. Choroidal gammadelta T cells in protection against retinal pigment epithelium and retinal injury. PMID- 28729292 TI - Amide Proton Transfer Imaging Allows Detection of Glioma Grades and Tumor Proliferation: Comparison with Ki-67 Expression and Proton MR Spectroscopy Imaging. AB - BACKGROUND AND PURPOSE: Prognosis in glioma depends strongly on tumor grade and proliferation. In this prospective study of patients with untreated primary cerebral gliomas, we investigated whether amide proton transfer-weighted imaging could reveal tumor proliferation and reliably distinguish low-grade from high grade gliomas compared with Ki-67 expression and proton MR spectroscopy imaging. MATERIALS AND METHODS: This study included 42 patients with low-grade (n = 28) or high-grade (n = 14) glioma, all of whom underwent conventional MR imaging, proton MR spectroscopy imaging, and amide proton transfer-weighted imaging on the same 3T scanner within 2 weeks before surgery. We assessed metabolites of choline and N-acetylaspartate from proton MR spectroscopy imaging and the asymmetric magnetization transfer ratio at 3.5 ppm from amide proton transfer-weighted imaging and compared them with histopathologic grade and immunohistochemical expression of the proliferation marker Ki-67 in the resected specimens. RESULTS: The asymmetric magnetization transfer ratio at 3.5 ppm values measured by different readers showed good concordance and were significantly higher in high grade gliomas than in low-grade gliomas (3.61% +/- 0.155 versus 2.64% +/- 0.185, P = .0016), with sensitivity and specificity values of 92.9% and 71.4%, respectively, at a cutoff value of 2.93%. The asymmetric magnetization transfer ratio at 3.5 ppm values correlated with tumor grade (r = 0.506, P = .0006) and Ki 67 labeling index (r = 0.502, P = .002). For all patients, the asymmetric magnetization transfer ratio at 3.5 ppm correlated positively with choline (r = 0.43, P = .009) and choline/N-acetylaspartate ratio (r = 0.42, P = .01) and negatively with N-acetylaspartate (r = -0.455, P = .005). These correlations held for patients with low-grade gliomas versus those with high-grade gliomas, but the correlation coefficients were higher in high-grade gliomas (choline: r = 0.547, P = .053; N-acetylaspartate: r = -0.644, P = .017; choline/N-acetylaspartate: r = 0.583, P = .036). CONCLUSIONS: The asymmetric magnetization transfer ratio at 3.5 ppm may serve as a potential biomarker not only for assessing proliferation, but also for predicting histopathologic grades in gliomas. PMID- 28729293 TI - 3D Pseudocontinuous Arterial Spin-Labeling MR Imaging in the Preoperative Evaluation of Gliomas. AB - BACKGROUND AND PURPOSE: Previous studies showed conflicting results concerning the value of CBF maps obtained from arterial spin-labeling MR imaging in grading gliomas. This study was performed to investigate the effectiveness of CBF maps derived from 3D pseudocontinuous arterial spin-labeling in preoperatively assessing the grade, cellular proliferation, and prognosis of gliomas. MATERIALS AND METHODS: Fifty-eight patients with pathologically confirmed gliomas underwent preoperative 3D pseudocontinuous arterial spin-labeling. The receiver operating characteristic curves for parameters to distinguish high-grade gliomas from low grade gliomas were generated. Pearson correlation analysis was used to assess the correlation among parameters. Survival analysis was conducted with Cox regression. RESULTS: Both maximum CBF and maximum relative CBF were significantly higher in high-grade gliomas than in low-grade gliomas (P < .001). The areas under the curve for maximum CBF and maximum relative CBF in distinguishing high grade gliomas from low-grade gliomas were 0.828 and 0.863, respectively. Both maximum CBF and maximum relative CBF had no correlation with the Ki-67 index in all subjects and had a moderate negative correlation with the Ki-67 index in glioblastomas (r = -0.475, -0.534, respectively). After adjustment for age, a higher maximum CBF (P = .008) and higher maximum relative CBF (P = .005) were associated with worse progression-free survival in gliomas, while a higher maximum relative CBF (P = .033) was associated with better overall survival in glioblastomas. CONCLUSIONS: 3D pseudocontinuous arterial spin-labeling-derived CBF maps are effective in preoperative evaluation of gliomas. Although gliomas with a higher blood flow are more malignant, glioblastomas with a lower blood flow are likely to be more aggressive. PMID- 28729294 TI - Characteristics of CSF Velocity-Time Profile in Posttraumatic Syringomyelia. AB - BACKGROUND AND PURPOSE: The development of syringomyelia has been associated with changes in CSF flow dynamics in the spinal subarachnoid space. However, differences in CSF flow velocity between patients with posttraumatic syringomyelia and healthy participants remains unclear. The aim of this work was to define differences in CSF flow above and below a syrinx in participants with posttraumatic syringomyelia and compare the CSF flow with that in healthy controls. MATERIALS AND METHODS: Six participants with posttraumatic syringomyelia were recruited for this study. Phase-contrast MR imaging was used to measure CSF flow velocity at the base of the skull and above and below the syrinx. Velocity magnitudes and temporal features of the CSF velocity profile were compared with those in healthy controls. RESULTS: CSF flow velocity in the spinal subarachnoid space of participants with syringomyelia was similar at different locations despite differences in syrinx size and locations. Peak cranial and caudal velocities above and below the syrinx were not significantly different (peak cranial velocity, P = .9; peak caudal velocity, P = 1.0), but the peak velocities were significantly lower (P < .001, P = .007) in the participants with syringomyelia compared with matched controls. Most notably, the duration of caudal flow was significantly shorter (P = .003) in the participants with syringomyelia. CONCLUSIONS: CSF flow within the posttraumatic syringomyelia group was relatively uniform along the spinal canal, but there are differences in the timing of CSF flow compared with that in matched healthy controls. This finding supports the hypothesis that syrinx development may be associated with temporal changes in spinal CSF flow. PMID- 28729295 TI - Imaging Findings of Benign Enhancing Foramen Magnum Lesions. PMID- 28729296 TI - Analysis of 30 Spinal Angiograms Falsely Reported as Normal in 18 Patients with Subsequently Documented Spinal Vascular Malformations. AB - BACKGROUND AND PURPOSE: The early diagnosis of spinal vascular malformations suffers from the nonspecificity of their clinical and radiologic presentations. Spinal angiography requires a methodical approach to offer a high diagnostic yield. The prospect of false-negative studies is particularly distressing when addressing conditions with a narrow therapeutic window. The purpose of this study was to identify factors leading to missed findings or inadequate studies in patients with spinal vascular malformations. MATERIALS AND METHODS: The clinical records, laboratory findings, and imaging features of 18 patients with spinal arteriovenous fistulas and at least 1 prior angiogram read as normal were reviewed. The clinical status was evaluated before and after treatment by using the Aminoff-Logue Disability Scale. RESULTS: Eighteen patients with 19 lesions underwent a total of 30 negative spinal angiograms. The lesions included 9 epidural arteriovenous fistulas, 8 dural arteriovenous fistulas, and 2 perimedullary arteriovenous fistulas. Seventeen patients underwent endovascular (11) or surgical (6) treatment, with a delay ranging between 1 week and 32 months; the Aminoff-Logue score improved in 13 (76.5%). The following factors were identified as the causes of the inadequate results: 1) lesion angiographically documented but not identified (55.6%); 2) region of interest not documented (29.6%); or 3) level investigated but injection technically inadequate (14.8%). CONCLUSIONS: All the angiograms falsely reported as normal were caused by correctible, operator-dependent factors. The nonrecognition of documented lesions was the most common cause of error. The potential for false-negative studies should be reduced by the adoption of rigorous technical and training standards and by second opinion reviews. PMID- 28729297 TI - Association between Intracranial Atherosclerotic Calcium Burden and Angiographic Luminal Stenosis Measurements. AB - BACKGROUND AND PURPOSE: Calcification of the intracranial vasculature is an independent risk factor for stroke. The relationship between luminal stenosis and calcium burden in the intracranial circulation is incompletely understood. We evaluated the relationship between atherosclerotic calcification and luminal stenosis in the intracranial ICAs. MATERIALS AND METHODS: Using a prospective stroke registry, we identified patients who had both NCCT and CTA or MRA examinations as part of a diagnostic evaluation for ischemic stroke. We used NCCTs to qualitatively (modified Woodcock Visual Score) and quantitatively (Agatston-Janowitz Calcium Score) measure ICA calcium burden and used angiography to measure arterial stenosis. We calculated correlation coefficients between the degree of narrowing and calcium burden measures. RESULTS: In 470 unique carotid arteries (235 patients), 372 (79.1%) had atherosclerotic calcification detectable on CT compared with 160 (34%) with measurable arterial stenosis on CTA or MRA (P < .001). We found a weak linear correlation between qualitative (R = 0.48) and quantitative (R = 0.42) measures of calcium burden and the degree of luminal stenosis (P < .001 for both). Of 310 ICAs with 0% luminal stenosis, 216 (69.7%) had measurable calcium scores. CONCLUSIONS: There is a weak correlation between intracranial atherosclerotic calcium scores and luminal narrowing, which may be explained by the greater sensitivity of CT than angiography in detecting the presence of measurable atherosclerotic disease. Future studies are warranted to evaluate the relationship between stenosis and calcium burden in predicting stroke risk. PMID- 28729298 TI - Rapid decline in lung function is temporally associated with greater metabolically active adiposity in a longitudinal study of healthy adults. AB - RATIONALE: Adiposity is associated with low lung function, but the longitudinal relationship between lung function and adiposity is inadequately studied. OBJECTIVE: To examine the bidirectional longitudinal associations between rapid decline in lung function and adiposity phenotypes in healthy adults. METHODS: This secondary analysis used a 25-year longitudinal dataset from the Coronary Artery Risk Development in Young Adults (CARDIA) study that enrolled 5115 participants. MEASUREMENTS: In the first analysis, metabolic syndrome at or before CARDIA year (Y) 10 (Y10) was the predictor, and subsequent rapid decline in forced vital capacity (FVC) or forced expiratory volume in 1 s (FEV1) between Y10 and Y20 was the outcome. In the second analysis, rapid decline was the predictor, and incident metabolic syndrome at Y20 and/or Y25 was the outcome. In the third analysis, rapid decline was the predictor, and subsequent CT-assessed regional fat depots at Y25 were the outcome. RESULTS: Metabolic syndrome at or before Y10 is temporally associated with rapid decline in FVC between Y10 and Y20 (adjusted p=0.04), but this association was explained by body mass index (BMI) at Y10. Rapid decline in FVC or FEV1 is temporally associated with greater incident metabolic syndrome at Y20 and/or Y25 (adjusted OR 2.10 (1.69, 2.61); p<0.001, and 1.56 (1.26, 1.94); p<0.001, respectively) and greater CT-assessed intrathoracic visceral adiposity at Y25 (adjusted standardised beta 0.09; p<0.001 for both analyses). These associations were not explained by BMI levels prior to the outcome measurement. CONCLUSIONS: Healthy adults with rapid decline in lung function are at risk for developing metabolic syndrome and for disproportionate accumulation of intrathoracic visceral fat. Metabolic abnormalities may be an early extrapulmonary manifestation of lung impairment that may be preventable by improving lung health. PMID- 28729299 TI - Notch2 blockade enhances hematopoietic stem cell mobilization and homing. AB - Despite use of newer approaches, some patients being considered for autologous hematopoietic cell transplantation (HCT) may only mobilize limited numbers of hematopoietic progenitor cells (HPCs) into blood, precluding use of the procedure, or being placed at increased risk of complications due to slow hematopoietic reconstitution. Developing more efficacious HPC mobilization regimens and strategies may enhance the mobilization process and improve patient outcome. Although Notch signaling is not essential for homeostasis of adult hematopoietic stem cells (HSCs), Notch-ligand adhesive interaction maintains HSC quiescence and niche retention. Using Notch receptor blocking antibodies, we report that Notch2 blockade, but not Notch1 blockade, sensitizes hematopoietic stem cells and progenitors (HSPCs) to mobilization stimuli and leads to enhanced egress from marrow to the periphery. Notch2 blockade leads to transient myeloid progenitor expansion without affecting HSC homeostasis and self-renewal. We show that transient Notch2 blockade or Notch2-loss in mice lacking Notch2 receptor lead to decreased CXCR4 expression by HSC but increased cell cycling with CXCR4 transcription being directly regulated by the Notch transcriptional protein RBPJ. In addition, we found that Notch2-blocked or Notch2-deficient marrow HSPCs show an increased homing to the marrow, while mobilized Notch2-blocked, but not Notch2 deficient stem cells and progenitors, displayed a competitive repopulating advantage and enhanced hematopoietic reconstitution. These findings suggest that blocking Notch2 combined with the current clinical regimen may further enhance HPC mobilization and improve engraftment during HCT. PMID- 28729300 TI - Rapamycin is highly effective in murine models of immune-mediated bone marrow failure. AB - Acquired aplastic anemia, the prototypical bone marrow failure disease, is characterized by pancytopenia and marrow hypoplasia. Most aplastic anemia patients respond to immunosuppressive therapy, usually with anti-thymocyte globulin and cyclosporine, but some relapse on cyclosporine withdrawal or require long-term administration of cyclosporine to maintain blood counts. In this study, we tested efficacy of rapamycin as a new or alternative treatment in mouse models of immune-mediated bone marrow failure. Rapamycin ameliorated pancytopenia, improved bone marrow cellularity, and extended animal survival in a manner comparable to the standard dose of cyclosporine. Rapamycin effectively reduced Th1 inflammatory cytokines interferon-gamma and tumor necrosis factor-alpha, increased the Th2 cytokine interleukin-10, stimulated expansion of functional regulatory T cells, eliminated effector CD8+ T cells (notably T cells specific to target cells bearing minor histocompatibility antigen H60), and preserved hematopoietic stem and progenitor cells. Rapamycin, but not cyclosporine, reduced the proportion of memory and effector T cells and maintained a pool of naive T cells. Cyclosporine increased cytoplasmic nuclear factor of activated T-cells-1 following T-cell receptor stimulation, whereas rapamycin suppressed phosphorylation of two key signaling molecules in the mammalian target of rapamycin pathway, S6 kinase and protein kinase B. In summary, rapamycin was an effective therapy in mouse models of immune-mediated bone marrow failure, acting through different mechanisms to cyclosporine. Its specific expansion of regulatory T cells and elimination of clonogenic CD8+ effectors support its potential clinical utility in the treatment of aplastic anemia. PMID- 28729301 TI - Changes in the incidence of candidemia and related mortality in patients with hematologic malignancies in the last ten years. A SEIFEM 2015-B report. PMID- 28729302 TI - Vosaroxin in combination with decitabine in newly diagnosed older patients with acute myeloid leukemia or high-risk myelodysplastic syndrome. AB - Vosaroxin is an anti-cancer quinolone-derived DNA topoisomerase II inhibitor. We investigated vosaroxin with decitabine in patients >=60 years of age with newly diagnosed acute myeloid leukemia (n=58) or myelodysplastic syndrome (>=10% blasts) (n=7) in a phase II non-randomized trial. The initial 22 patients received vosaroxin 90 mg/m2 on days 1 and 4 with decitabine 20 mg/m2 on days 1-5 every 4-6 weeks for up to seven cycles. Due to a high incidence of mucositis the subsequent 43 patients were given vosaroxin 70 mg/m2 on days 1 and 4. These 65 patients, with a median age of 69 years (range, 60-78), some of whom with secondary leukemia (22%), adverse karyotype (35%), or TP53 mutation (20%), are evaluable. The overall response rate was 74% including complete remission in 31 (48%), complete remission with incomplete platelet recovery in 11 (17%), and complete remission with incomplete count recovery in six (9%). The median number of cycles to response was one (range, 1-4). Grade 3/4 mucositis was noted in 17% of all patients. The 70 mg/m2 induction dose of vosaroxin was associated with similar rates of overall response (74% versus 73%) and complete remission (51% versus 41%, P=0.44), reduced incidence of mucositis (30% versus 59%, P=0.02), reduced 8-week mortality (9% versus 23%; P=0.14), and improved median overall survival (14.6 months versus 5.5 months, P=0.007). Minimal residual disease negative status by multiparametric flow-cytometry at response (+/- 3 months) was achieved in 21 of 39 (54%) evaluable responders and was associated with better median overall survival (34.0 months versus 8.3 months, P=0.023). In conclusion, the combination of vosaroxin with decitabine is effective and well tolerated at a dose of 70 mg/m2 and warrants randomized prospective evaluation. ClinicalTrials.gov: NCT01893320. PMID- 28729303 TI - Amotosalen/ultraviolet A pathogen inactivation technology reduces platelet activatability, induces apoptosis and accelerates clearance. AB - Amotosalen and ultraviolet A (UVA) photochemical-based pathogen reduction using the InterceptTM Blood System (IBS) is an effective and established technology for platelet and plasma components, which is adopted in more than 40 countries worldwide. Several reports point towards a reduced platelet function after Amotosalen/UVA exposure. The study herein was undertaken to identify the mechanisms responsible for the early impairment of platelet function by the IBS. Twenty-five platelet apheresis units were collected from healthy volunteers following standard procedures and split into 2 components, 1 untreated and the other treated with Amotosalen/UVA. Platelet impedance aggregation in response to collagen and thrombin was reduced by 80% and 60%, respectively, in IBS-treated units at day 1 of storage. Glycoprotein Ib (GpIb) levels were significantly lower in IBS samples and soluble glycocalicin correspondingly augmented; furthermore, GpIbalpha was significantly more desialylated as shown by Erythrina Cristagalli Lectin (ECL) binding. The pro-apoptotic Bak protein was significantly increased, as well as the MAPK p38 phosphorylation and caspase-3 cleavage. Stored IBS treated platelets injected into immune-deficient nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice showed a faster clearance. We conclude that the IBS induces platelet p38 activation, GpIb shedding and platelet apoptosis through a caspase-dependent mechanism, thus reducing platelet function and survival. These mechanisms are of relevance in transfusion medicine, where the IBS increases patient safety at the expense of platelet function and survival. PMID- 28729304 TI - Effectiveness of the management of major depressive episodes/disorder in adults with comorbid chronic physical diseases: a protocol for a systematic review and meta-analysis. AB - INTRODUCTION: Depression is a global-scale public health problem, and a significant association has been established between depression and chronic physical diseases. This growing comorbidity poses a challenge to healthcare systems. We aim to assess the effectiveness of the management of major depressive episodes/disorder in adults with comorbid chronic physical diseases. METHODS AND ANALYSIS: We will conduct a systematic review and meta-analysis of randomised clinical trials. Two databases MEDLINE and Cochrane Library (Cochrane Database for Systematic Reviews and CENTRAL), as well as the reference lists of the included articles, will be searched for studies either in English or Spanish with published results within the 2005-2015 period. Studies must fulfil the following conditions: (1) participants aged 18 years or older, diagnosed as having a major depressive episodes/disorder according to standardised criteria and chronic physical diseases; (2)interventions (be it pharmacological, psychological, psychosocial or a combination) must be compared with control conditions (other 'active' intervention, treatment as usual, waiting list or placebo); (3)and must report reduction in depressive symptoms after treatment, response to treatment, remission of major depressive episodes/disorder and significant improvement in quality of life. Data extraction, risk of bias evaluation, results summarisation and quality of the evidence (GRADE) will be performed as recommended by the Cochrane Collaboration. A qualitative synthesis and a random effects meta analysis will be carried out. Effect sizes will be calculated (relative risk and Cohen's d), I2 and Q statistics will be employed to study heterogeneity and publication bias analysis will be performed. Subgroup analyses and meta regression will be carried out. ETHICS AND DISSEMINATION: Results are expected to be published in specialised peer-reviewed journals (preferred topics: Mental Health, Psychology, Psychiatry and/or Systematic Reviews) and dissemination activities will be targeted to all the healthcare providers. TRIAL REGISTRATION NUMBER: International Prospective Register of Systematic Reviews (CRD42016029166) submitted on 11 January 2016. PMID- 28729305 TI - Biomechanical reposition techniques in anterior shoulder dislocation: a randomised multicentre clinical trial- the BRASD-trial protocol. AB - INTRODUCTION: Glenohumeral (shoulder) dislocations are the most common large joint dislocations seen in the emergency department (ED). They cause pain, often severe, and require timely interventions to minimise discomfort and tissue damage. Commonly used reposition or relocation techniques often involve traction and/or leverage. These techniques have high success rates but may be painful and time consuming. They may also cause complications. Recently, other techniques-the biomechanical reposition techniques (BRTs)-have become more popular since they may cause less pain, require less time and cause fewer complications. To our knowledge, no research exists comparing the various BRTs. Our objective is to establish which BRT or BRT combination is fastest, least painful and associated with the lowest complication rate for adult ED patients with anterior glenohumeral dislocations (AGDs). METHODS AND ANALYSIS: Adults presenting to the participating EDs with isolated AGDs, as determined by radiographs, will be randomised to one of three BRTs: Cunningham, modified Milch or scapular manipulation. Main study parameters/endpoints are ED length of stay and patients' self-report of pain. Secondary study parameters/endpoints are procedure times, need for analgesic and/or sedative medications, iatrogenic complications and rates of successful reduction. ETHICS AND DISSEMINATION: Non-biomechanical AGD repositioning techniques based on traction and/or leverage are inherently painful and potentially harmful. We believe that the three BRTs used in this study are more physiological, more patient friendly, less likely to cause pain, more time efficient and less likely to produce complications. By comparing these three techniques, we hope to improve the care provided to adults with acute AGDs by reducing their ED length of stay and minimising pain and procedure-related complications. We also hope to define which of the three BRTs is quickest, most likely to be successful and least likely to require sedative or analgesic medications to achieve reduction. TRIAL REGISTRATION NUMBER: NTR5839. PMID- 28729306 TI - Hospital variation in allogeneic transfusion and extended length of stay in primary elective hip and knee arthroplasty: a cross-sectional study. AB - OBJECTIVES: Outcomes in total hip and knee arthroplasty (THA and TKA), such as allogeneic transfusions or extended length of stay (LoS), can be used to compare the performance of hospitals. However, there is much variation in these outcomes. This study aims to rank hospitals and to assess hospital differences of two outcomes in THA and TKA: allogeneic transfusions and extended LoS, and to additionally identify factors associated with these differences. DESIGN: Cross sectional medical record review study. SETTING: Data were gathered in 23 Dutch hospitals. PARTICIPANTS: 1163 THA and 986 TKA patient admissions. OUTCOMES: Hospitals were ranked based on their observed/expected (O/E) ratios regarding allogeneic transfusion and extended LoS percentages (extended LoS was defined by postoperative stay >4 days). To assess the reliability of these rankings, we calculated which percentage of the existing variation was based on differences between hospitals as compared with random variation (after adjustment for variation in patient characteristics). Associations between hospital-specific factors and O/E ratios were used to explore potential sources of differences. RESULTS: The variation in O/E ratios between hospitals ranged from 0 to 4.4 for allogeneic transfusion, and from 0.08 to 2.7 for extended LoS. Variation in transfusion could in 21% be explained by hospital differences in THA and 34% in TKA. For extended LoS this was 71% in THA and 78% in TKA. Better performance (low O/E ratios) in transfusion was associated with more frequent tranexamic acid (TXA) use in TKA (R=-0.43, p=0.04). Better performance in extended LoS was associated with more frequent TXA use in THA (R=-0.45, p=0.03) and TKA (R=-0.65, p<0.001) and local infiltration analgesia (LIA) in TKA (R=-0.60, p=0.002). CONCLUSIONS: Ranking hospitals based on allogeneic transfusion is unreliable due to small percentages of variation explained by hospital differences. Ranking based on extended LoS is more reliable. Hospitals using TXA and LIA have relatively fewer patients with transfusions and extended LoS. PMID- 28729307 TI - Occupational class differences in long sickness absence: a register-based study of 2.1 million Finnish women and men in 1996-2013. AB - OBJECTIVES: Sickness absence is consistently higher in lower occupational classes, but attempts to analyse changes over time in socioeconomic differences are scarce. We examined trends in medically certified sickness absence by occupational class in Finland from 1996 to 2013 and assessed the magnitude and changes in absolute and relative occupational class differences. DESIGN: Population-based, repeated cross-sectional study. SETTING: A 70% random sample of Finns aged between 25 and 63 years in the years 1996-2013. PARTICIPANTS: The study focused on 25- to 63 year-old female (n between 572 246 and 690 925) and male (n between 525 698 and 644 425) upper and lower non-manual and manual workers. Disability and old age pensioners, students, the unemployed, entrepreneurs and farmers were excluded. The analyses covered 2 160 084 persons, that is, 77% of the random sample.For primary and secondary outcome measures, we examined yearly prevalence of over 10 working days long sickness absence by occupational class. The Slope Index of Inequality (SII) and the Relative Index of Inequality (RII) were used to assess the magnitude and changes in occupational class differences. RESULTS: Compared with mid-1990s, sickness absence prevalence was slightly lower in 2013 in all occupational classes except for female lower non-manual workers. Hierarchical occupational class differences in sickness absence were found. Absolute differences (SII) peaked in 2005 in both women (0.12, 95% CI 0.12 to 0.13) and men (0.15, 95% CI 0.14 to 0.15) but reached the previous level in women by 2009 and decreased modestly in men until 2013. Relative differences narrowed over time (p<0.001) but levelled off by 2013. CONCLUSIONS: Sickness absence prevalence is currently slightly lower in almost all occupational classes than in the mid-1990s, but occupational class differences have remained large. Ill health and poor working conditions especially in the lower occupational classes should be targeted in order to reduce sickness absence and to achieve longer working lives. PMID- 28729309 TI - The role of a decision-support smartphone application in enhancing community health volunteers' effectiveness to improve maternal and newborn outcomes in Nairobi, Kenya: quasi-experimental research protocol. AB - INTRODUCTION: Improving maternal and newborn survival remains major aspirations for many countries in the Global South. Slum settlements, a result of rapid urbanisation in many developing countries including Kenya, exhibit high levels of maternal and neonatal mortality. There are limited referral mechanisms for sick neonates and their mothers from the community to healthcare facilities with ability to provide adequate care. In this study, we specifically plan to develop and assess the added value of having community health volunteers (CHVs) use smartphones to identify and track mothers and children in a bid to reduce pregnancy-related complications and newborn deaths in the urban slums of Kamukunji subcounty in Nairobi, Kenya. METHODS AND ANALYSIS: This is a quasi experimental study. We are implementing an innovative, mHealth application known as mobile Partnership for Maternal, Newborn and Child Health (mPAMANECH) which uses dynamic mobile phone and web-portal solutions to enable CHVs make timely decisions on the best course of action in their management of mothers and newborns at community level. The application is based on existing guidelines and protocols in use by CHVs. Currently, CHVs conduct weekly home visits and make decisions from memory or using unwieldy manual tools, and thus prone to making errors. mPAMANECH has an in-built algorithm that makes it easier, faster and more likely for CHVs to make the right management decision. We are working with a network of selected CHVs and maternity centres to pilot test the tool. To measure the impact of the intervention, baseline and end-line surveys will be conducted. Data will be obtained through qualitative and quantitative methods. ETHICS AND DISSEMINATION: Ethical approval for the study was obtained from the African Medical Research Foundation. Key messages from the results will be packaged and disseminated through meetings, conference presentations, reports, fact sheets and academic publications to facilitate uptake by policy-makers. PMID- 28729308 TI - The effect of combined resistance exercise training and vitamin D3 supplementation on musculoskeletal health and function in older adults: a systematic review and meta-analysis. AB - OBJECTIVES: In older adults, there is a blunted responsiveness to resistance training and reduced muscle hypertrophy compared with younger adults. There is evidence that both exercise training and vitamin D supplementation may benefit musculoskeletal health in older adults, and it is plausible that in combination their effects may be additive. The aim of this systematic review was to evaluate the effectiveness of combined resistance exercise training and vitamin D3 supplementation on musculoskeletal health in older adults. DATA SOURCES: A comprehensive search of electronic databases, including Science Direct, Medline, PubMed, Google Scholar and Cochrane Central Register of Controlled Trials (Cochrane CENTRAL accessed by Wiley Science) was conducted. Eligible studies were randomised controlled trials including men and women (aged >=65 years or mean age >=65 years); enlisting resistance exercise training and vitamin D3 supplementation; including outcomes of muscle strength, function, muscle power, body composition, serum vitamin D/calcium status or quality of life comparing results with a control group. The review was informed by a preregistered protocol (http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42015020157). RESULTS: Seven studies including a total of 792 participants were identified. Studies were categorised into two groups; group 1 compared vitamin D3 supplementation and exercise training versus exercise alone (describing the additive effect of vitamin D3 supplementation when combined with resistance exercise training) and group 2 compared vitamin D3 supplementation and exercise training versus vitamin D3 supplementation alone (describing the additive effect of resistance exercise training when combined with vitamin D3 supplementation).Meta-analyses for group 1 found muscle strength of the lower limb to be significantly improved within the intervention group (0.98, 95% CI 0.73 to 1.24, p<0.001); all other outcomes showed small but non-significant positive effects for the intervention group. The short physical performance battery (SPPB), timed up and go (TUG), muscle strength of the lower limb and femoral neck bone mineral density showed significantly greater improvements in the intervention group for group 2 comparisons. CONCLUSIONS: This review provides tentative support for the additive effect of resistance exercise and vitamin D3 supplementation for the improvement of muscle strength in older adults. For other functional variables, such as SPPB and TUG, no additional benefit beyond exercise was shown. Further evidence is required to draw firm conclusions or make explicit recommendations regarding combined exercise and vitamin D3 supplementation. PMID- 28729310 TI - Socioeconomic inequalities in caries experience, care level and dental attendance in primary school children in Belgium: a cross-sectional survey. AB - OBJECTIVES: Oral health inequality in children is a widespread and well documented problem in oral healthcare. However, objective and reliable methods to determine these inequalities in all oral health aspects, including both dental attendance and oral health, are rather scarce. AIMS: To explore oral health inequalities and to assess the impact of socioeconomic factors on oral health, oral health behaviour and dental compliance of primary school children. METHODS: Data collection was executed in 2014 within a sample of 2216 children in 105 primary schools in Flanders, by means of an oral examination and a validated questionnaire. Intermutual Agency database was consulted to objectively determine individuals' social state and frequency of utilisation of oral healthcare services. Underprivileged children were compared with more fortunate children for their mean DMFt, DMFs, plaque index, care index (C, restorative index (RI), treatment index (TI), knowledge and attitude. Differences in proportions for dichotomous variables (RI100%, TI100% and being a regular dental attender) were analysed. The present study was approved by the Ethics Committee of the University Hospital Ghent (2010/061). All parents signed an informed consent form prior to data collection. All schools received information about the study protocol and agreed to participate. Children requiring dental treatment or periodic recall were referred to the local dentist. RESULTS: Underprivileged children had higher D1MFT (95% CI 0.87 to 1.36), D3MT (95% CI 0.30 to 0.64), plaque scores (95% CI 0.12 to 0.23) and lower care level (p<0.02). In the low income group, 78.4% was caries-free, compared with 88.4% for the other children. Half of the low-income children could be considered as regular dental attenders, while 12.6% did not have any dental visit during a 5-year period. CONCLUSION: Oral health, oral hygiene, oral healthcare level and dental attendance patterns are negatively affected by children's social class, leading to oral health inequalities in Belgian primary school children. PMID- 28729312 TI - Protocol: A grounded theory of 'recovery'-perspectives of adolescent users of mental health services. AB - INTRODUCTION: Policies internationally endorse the recovery paradigm as the appropriate foundation for youth mental health services. However, given that this paradigm is grounded in the views of adults with severe mental illness, applicability to youth services and relevance to young people is uncertain, particularly as little is known about young people's views. A comprehensive understanding of the experiences and expectations of young people is critical to developing youth mental health services that are acceptable, accessible, effective and relevant. AIM: To inform development of policy and youth services, the study described in this protocol aims to develop a comprehensive account of the experiences and expectations of 12-17 year olds as they encounter mental disorders and transition through specialist mental health services. Data will be analysed to model recovery from the adolescents' perspective. METHOD AND ANALYSIS: This grounded theory study will use quantitative and qualitative data collected in interviews with 12-17 year olds engaged with specialist Child/Youth Mental Health Service in Queensland, Australia. Interviews will explore adolescents' expectations and experiences of mental disorder, and of services, as they transition through specialist mental health services, including the meaning of their experiences and ideas of 'recovery' and how their experiences and expectations are shaped. Data collection and analysis will use grounded theory methods. ETHICS AND DISSEMINATION: Adolescents' experiences will be presented as a mid-range theory. The research will provide tangible recommendations for youth focused mental health policy and practice. Findings will be disseminated within academic literature and beyond to participants, health professionals, mental health advocacy groups and policy and decision makers via publications, research summaries, conferences and workshops targeting different audiences. Ethical and research governance approvals have been obtained from relevant Human Research Ethics committees and all sites involved. PMID- 28729311 TI - A review of rate control in atrial fibrillation, and the rationale and protocol for the RATE-AF trial. AB - BACKGROUND AND OBJECTIVE: Atrial fibrillation (AF) is common and causes impaired quality of life, an increased risk of stroke and death as well as frequent hospital admissions. The majority of patients with AF require control of heart rate. In this article , we summarise the limited evidence from clinical trials that guides prescription, and present the rationale and protocol for a new randomised trial. As rate control has not yet been shown to reduce mortality, there is a clear need to compare the impact of therapy on quality of life, cardiac function and exercise capacity. Such a trial should concentrate on the long-term effects of treatment in the largest proportion of patients with AF, those with symptomatic permanent AF, with the aim of improving patient well being. DESIGN AND INTERVENTION: The RAte control Therapy Evaluation in permanent Atrial Fibrillation (RATE-AF) trial will enrol 160 participants with a prospective, randomised, open-label, blinded end point design comparing initial rate control with digoxin or bisoprolol. This will be the first head-to-head randomised trial of digoxin and beta-blockers in AF. PARTICIPANTS: Recruited patients will be aged AcA0/00AY60 years with permanent AF and symptoms of breathlessness (equivalent to New York Heart Association class II or above), with few exclusion criteria to maximise generalisability to routine clinical practice. OUTCOME MEASURES: The primary outcome is patient-reported quality of life, with secondary outcomes including echocardiographic ventricular function, exercise capacity and biomarkers of cellular and clinical response. Follow-up will occur at 6 and 12 months, with feasibility components to inform the design of a future trial powered to detect a difference in hospital admission. The RATE-AF trial will underpin an integrated approach to management including biomarkers, functions and symptoms that will guide future research into optimal, personalised rate control in patients with AF. ETHICS AND DISSEMINATION: East Midlands-Derby Research Ethics Committee (16/EM/0178); peer-reviewed publications. TRIAL REGISTRATION: Clinicaltrials.gov: NCT02391337; ISRCTN: 95259705. Pre-results. PMID- 28729314 TI - Productivity of public hospitals in Nepal: a data envelopment analysis. AB - OBJECTIVES: Public hospitals in Nepal account for a major share of the total health budget. Therefore, questions are often asked about the performance of these hospitals. Existing measures of performance are limited to historical ratio analyses without any benchmarks. The objective of this study is to explore the trends in inputs, outputs and productivity changes in Nepalese public hospitals from 2011-2012 to 2013-2014. SETTING AND PARTICIPANTS: The study was conducted among 32 Nepalese public hospitals (23 district level and 9 higher level) for the three fiscal years from 2011-2012 to 2013-2014. OUTCOME MEASURES: First, basic ratio analyses were conducted for the input and output measures over the study years. Then, Malmquist productivity change scores were obtained using data envelopment analysis. Aggregated as well as separate analyses were conducted for district level and higher level hospitals. RESULTS: Real expenditures of the sampled hospitals declined over the 3-year period from an average of US$ 371 000 in year 1 to US$ 368 730 in year 2 and US$ 328680 in year 3. The average aggregated hospital outputs increased marginally from 8276 in 2011-2012 to 8613 in 2013-2014. The total factor productivity of the study hospitals declined by 6.9% annually from 2011-2012 to 2013-2014. Of the total 32 hospitals, productivity increased in only 12 (37.5%) hospitals and declined in the remaining 20 hospitals. The total factor productivity loss was influenced by a decline in technology change, despite an increase in efficiency. CONCLUSIONS: In general, productivity of the study hospitals declined over the study period. Availability and accessibility of accurate, detailed and consistent measures of hospital inputs and outputs is a major challenge for this type of analysis. PMID- 28729313 TI - Fetal Doppler velocimetry and bronchopulmonary dysplasia risk among growth restricted preterm infants: an observational study. AB - OBJECTIVE: To investigate whether fetal growth restriction (FGR) diagnosis, based on pathological prenatal fetal Doppler velocimetry, is associated with bronchopulmonary dysplasia (BPD) independently of being small for gestational age (SGA) per se at birth among very preterm infants. DESIGN: Prospective, observational study. FGR was defined as failing fetal growth in utero and fetal Doppler velocimetry abnormalities. SETTING: Policlinico Universitario Agostino Gemelli, Roma, Italy. PATIENTS: Preterm newborns with gestational age <=30 weeks and birth weight (BW) <=1250 g. MAIN OUTCOME MEASURES: Bronchopulmonary dysplasia. RESULTS: In the study period, 178 newborns were eligible for the study. Thirty-nine infants (22%) were considered fetal growth-restricted infants. Among the 154 survived babies at 36 weeks postmenstrual age, 12 out of 36 (33%) of the FGR group developed BPD versus 8 out of 118 (7%) of the NO-FGR group (p<0.001). BPD rate was sixfold higher among the SGA-FGR infants compared with the SGA-NO-FGR infants. In a multivariable model, FGR was significantly associated with BPD risk (OR 5.1, CI 1.4 to 18.8, p=0.01), independently from BW z-score that still remains a strong risk factor (OR 0.5, CI 0.3 to 0.9, p=0.01). CONCLUSION: Among SGA preterm infants, BPD risk dramatically increases when placenta dysfunction is the surrounding cause of low BW. Antenatal fetal Doppler surveillance could be a useful tool for studying placenta wellness and predicting BPD risk among preterm babies. Further research is needed to better understand how FGR affects lung development. PMID- 28729315 TI - Sequence analysis to assess labour market participation following vocational rehabilitation: an observational study among patients sick-listed with low back pain from a randomised clinical trial in Denmark. AB - INTRODUCTION: The return-to-work (RTW) process after long-term sickness absence is often complex and long and implies multiple shifts between different labour market states for the absentee. Standard methods for examining RTW research typically rely on the analysis of one outcome measure at a time, which will not capture the many possible states and transitions the absentee can go through. The purpose of this study was to explore the potential added value of sequence analysis in supplement to standard regression analysis of a multidisciplinary RTW intervention among patients with low back pain (LBP). METHODS: The study population consisted of 160 patients randomly allocated to either a hospital based brief or a multidisciplinary intervention. Data on labour market participation following intervention were obtained from a national register and analysed in two ways: as a binary outcome expressed as active or passive relief at a 1-year follow-up and as four different categories for labour market participation. Logistic regression and sequence analysis were performed. RESULTS: The logistic regression analysis showed no difference in labour market participation for patients in the two groups after 1 year. Applying sequence analysis showed differences in subsequent labour market participation after 2 years after baseline in favour of the brief intervention group versus the multidisciplinary intervention group. CONCLUSION: The study indicated that sequence analysis could provide added analytical value as a supplement to traditional regression analysis in prospective studies of RTW among patients with LBP. PMID- 28729316 TI - Relationship between receipt of substitutable for-fee vaccines and completion of the expanded programme on immunisation: a cross-sectional study in Fujian, China. AB - OBJECTIVE: The aim of this study was to evaluate the relationship between receipt of the substitutable-for-fee vaccines (SFV) and completion of the expanded programme on immunisation (EPI). DESIGN AND SETTINGS: A cross-sectional study was conducted in Fujian province, China. PARTICIPANTS: Children who were born from 1 September 2009 to 31 August 2011, and who had been residing in the township for at least 3 months, were randomly recruited from 34 townships. MAIN OUTCOMES MEASURES: Outcomes were completion rate of the EPI and coverage rate of the SFV. RESULTS: The study included 1428 children, of whom 1350 (94.5%) finished the EPI and 282 (19.7%) received at least one dose of the SFV. Administration of the SFV was associated with an increased likelihood of completing the EPI (OR=3.2, 95% CI 1.3 to 7.6 in the total sample and OR=4.0, 95% CI 1.7 to 9.6 in the subsample of children in regions with the SFV accessibility). The impact of the SFV administration on completion of the EPI was larger among children whose parents have junior school education or less (97.8% and 97.9% vs 92.5% and 91.9%, both p<0.001) and among those with a timely hepatitis B vaccine first dose (98.5% vs 94.0%, p<0.001). CONCLUSIONS: Receipt of SFV is associated with increased likelihood of completion of the EPI in Fujian, China. PMID- 28729317 TI - The effects of physical activity interventions on glycated haemoglobin A1c in non diabetic populations: a protocol for a systematic review and meta-analysis. AB - INTRODUCTION: Epidemiological evidence suggests that physical activity has a positive effect on reducing glycated haemoglobin A1c (HbA1c) levels not only in diabetics, but also in healthy subjects. Moreover, a positive association of HbA1c levels with cardiovascular disease and mortality in non-diabetic populations has recently been reported. This is a protocol for a systematic review and meta-analysis aiming to estimate the effects of physical activity on glycaemic control measured by HbA1c levels in non-diabetic populations; and to determine which type of physical activity has a greater influence on glycaemic control. METHODS AND ANALYSIS: The search will be conducted using MEDLINE, EMBASE, the Cochrane Library and Web of Science databases from inception to mid 2017. Randomised controlled trials, non-randomised experimental studies and controlled pre-post studies written in English, Portuguese, French or Spanish will be included. The Cochrane Collaboration's tool and The Quality Assessment Tool for Quantitative Studies will be used to assess the risk of bias for studies included in the systematic review. Standardised pre-post intervention mean differences of HbA1c will be calculated as the primary outcome. Subgroup analyses will be performed based on the characteristics of physical activity intervention and population included in the studies. ETHICS AND DISSEMINATION: This systematic review will synthesise evidence on the association of physical activity and HbA1c in non-diabetic populations. This study is important from the clinical and public health point because it will estimate the effect of physical activity on the glycemic control, and it will also examine which is the type of physical activity that should be recommended for preventing type 2 diabetes and its complications. The results will be disseminated by publication in a peer-reviewed journal. Ethical approval will not be required because the data used for this systematic review will be obtained from published studies and there will be no concerns about privacy. TRIAL REGISTRATION NUMBER: PROSPERO CRD42016050991. PMID- 28729318 TI - A national survey of Russian physicians' knowledge of diagnosis and management of food-induced anaphylaxis. AB - OBJECTIVES: Food allergy is an increasing burden worldwide and is a common problem within paediatric populations, affecting 5%-8% of children. Anaphylaxis caused by food proteins is a potentially life-threatening condition and all healthcare practitioners should be aware of its recognition and management. Russia is the largest country in Europe but it is still unknown whether physicians are prepared to diagnose and manage food-induced anaphylaxis effectively. We aimed to examine physicians' knowledge of diagnosis and management of food-induced anaphylaxis. SETTING, POPULATION AND OUTCOMES: A survey was designed and published online at VrachiRF.ru website (for registered Russian-speaking practicing physicians). We obtained information on respondents' clinical settings, experience and specialty. Survey questions were based on a characteristic clinical scenario of anaphylaxis due to food ingestion. Outcome measures consisted of correct answers to the anaphylaxis diagnosis and management questions. RESULTS: From a total of 707 of physicians accessed in the survey, 315 (45%) responded to the clinical scenario. 16 respondents reported training in allergy-immunology and have been excluded from the analysis, leaving the final sample size of 299. Respondents were paediatricians (68%) and other specialties adult physicians (32%). Overall, 100 (33%) of respondents diagnosed anaphylaxis, but only 29% of those making the correct diagnosis administered adrenalin (1:1000) intramuscular. Respondents working in secondary/tertiary clinics diagnosed anaphylaxis significantly more often (p=0.04) when compared with primary care/private practice physicians. This difference was also apparent as the most important influence on responses in the multivariate analysis. CONCLUSIONS: In this national sample of Russian physicians, we found poor knowledge in both anaphylaxis diagnosis and management. Our data show that the chance of being properly diagnosed with anaphylaxis is 33% and being appropriately treated with adrenalin is 10%. These findings highlight lack of anaphylaxis knowledge among Russian physicians, both paediatricians and other specialists and illustrates the urgent need for allergy/anaphylaxis training. PMID- 28729320 TI - Construction of a web-based questionnaire for longitudinal investigation of work exposure, musculoskeletal pain and performance impairments in high-performance marine craft populations. AB - OBJECTIVE: High-performance marine craft personnel (HPMCP) are regularly exposed to vibration and repeated shock (VRS) levels exceeding maximum limitations stated by international legislation. Whereas such exposure reportedly is detrimental to health and performance, the epidemiological data necessary to link these adverse effects causally to VRS are not available in the scientific literature, and no suitable tools for acquiring such data exist. This study therefore constructed a questionnaire for longitudinal investigations in HPMCP. METHODS: A consensus panel defined content domains, identified relevant items and outlined a questionnaire. The relevance and simplicity of the questionnaire's content were then systematically assessed by expert raters in three consecutive stages, each followed by revisions. An item-level content validity index (I-CVI) was computed as the proportion of experts rating an item as relevant and simple, and a scale level content validity index (S-CVI/Ave) as the average I-CVI across items. The thresholds for acceptable content validity were 0.78 and 0.90, respectively. Finally, a dynamic web version of the questionnaire was constructed and pilot tested over a 1-month period during a marine exercise in a study population sample of eight subjects, while accelerometers simultaneously quantified VRS exposure. RESULTS: Content domains were defined as work exposure, musculoskeletal pain and human performance, and items were selected to reflect these constructs. Ratings from nine experts yielded S-CVI/Ave of 0.97 and 1.00 for relevance and simplicity, respectively, and the pilot test suggested that responses were sensitive to change in acceleration and that the questionnaire, following some adjustments, was feasible for its intended purpose. CONCLUSIONS: A dynamic web based questionnaire for longitudinal survey of key variables in HPMCP was constructed. Expert ratings supported that the questionnaire content is relevant, simple and sufficiently comprehensive, and the pilot test suggested that the questionnaire is feasible for longitudinal measurements in the study population. PMID- 28729319 TI - Accelerated enhanced Recovery following Minimally Invasive colorectal cancer surgery (RecoverMI): a study protocol for a novel randomised controlled trial. AB - INTRODUCTION: Definitive treatment of localised colorectal cancer involves surgical resection of the primary tumour. Short-stay colectomies (eg, 23-hours) would have important implications for optimising the efficiency of inpatient care with reduced resource utilisation while improving the overall recovery experience with earlier return to normalcy. It could permit surgical treatment of colorectal cancer in a wider variety of settings, including hospital-based ambulatory surgery environments. While a few studies have shown that discharge within the first 24 hours after minimally invasive colectomy is possible, the safety, feasibility and patient acceptability of a protocol for short-stay colectomy for colorectal cancer have not previously been evaluated in a prospective randomised study. Moreover, given the potential for some patients to experience a delay in recovery of bowel function after colectomy, close outpatient monitoring may be necessary to ensure safe implementation. METHODS AND ANALYSIS: In order to address this gap, we propose a prospective randomised trial of accelerated enhanced Recovery following Minimally Invasive colorectal cancer surgery (RecoverMI) that leverages the combination of minimally invasive surgery with enhanced recovery protocols and early coordinated outpatient remote televideo conferencing technology (TeleRecovery) to improve postoperative patien-provider communication, enhance postoperative treatment navigation and optimise postdischarge care. We hypothesise that RecoverMI can be safely incorporated into multidisciplinary practice to improve patient outcomes and reduce the overall 30 day duration of hospitalisation while preserving the quality of the patient experience. ETHICS AND DISSEMINATION: RecoverMI has received institutional review board approval and funding from the American Society of Colorectal Surgeons (ASCRS; LPG103). Results from RecoverMI will be published in a peer-reviewed publication and be used to inform a multisite trial. TRIAL REGISTRATION NUMBER: NCT02613728; Pre-results. PMID- 28729321 TI - Economic evaluation of a brief counselling for smoking cessation in dentistry: a case study comparing two health economic models. AB - OBJECTIVES: This study aimed to compare the cost-effectiveness estimates of a brief counselling of smoking cessation in dentistry by using two different health economic models. DESIGN AND OUTCOME MEASURES: Intervention effectiveness was estimated in a cluster randomised controlled trial. The number of quitters was estimated based on 7-day abstinence and on smoking reduction at follow-up. Health economic evaluation was performed using two models: (1) a population-based model employing potential impact fractions and (2) a Markov model estimating the cost effectiveness of the intervention for the actual participants. The evaluation was performed from healthcare and societal perspectives, and health gains were expressed in quality-adjusted life-years (QALYs). SETTING: Dental clinics in Sweden. PARTICIPANTS: 205 Swedish smokers aged 20-75 years. INTERVENTIONS: A brief, structured behavioural intervention was compared with 'usual care'. RESULTS: The cost per quitter was US$552 in the intervention and US$522 in the 'usual care' condition. The net saving estimated with the population-based model was US$17.3 million for intervention and US$49.9 million for 'usual care', with health gains of 1428 QALYs and 2369 QALYs, respectively, for the whole Swedish population during 10 years. The intervention was thus dominated by 'usual care'. The reverse was true when using the Markov model, showing net societal savings of US$71 000 for the intervention and US$57000 for 'usual care', with gains of 5.42 QALYs and 4.74 QALYs, respectively, for lifelong quitters. CONCLUSION: The comparison of intervention and 'usual care' derived from small-scale studies may be highly sensitive to the choice of the model used to calculate cost effectiveness. TRIAL REGISTRATION: The cluster randomised trial is registered in the ISRCTN register of controlled trials with identification number ISRCTN50627997. PMID- 28729322 TI - Feasibility of a UK community-based, eTherapy mental health service in Greater Manchester: repeated-measures and between-groups study of 'Living Life to the Full Interactive', 'Sleepio' and 'Breaking Free Online' at 'Self Help Services'. AB - OBJECTIVES: There is increasing evidence to support the effectiveness of eTherapies for mental health, although limited data have been reported from community-based services. Therefore, this service evaluation reports on feasibility and outcomes from an eTherapy mental health service. SETTING: 'Self Help Services', an Increasing Access to Psychological Therapies (IAPT) eTherapy service in Greater Manchester. PARTICIPANTS: 1068 service users referred to the service for secondary care for their mental health difficulties. INTERVENTIONS: Participants were triaged into one of three eTherapy programmes: 'Living Life to the Full Interactive' for low mood, stress and anxiety; 'Sleepio' for insomnia; and 'Breaking Free Online' for substance misuse, depending on clinical need. PRIMARY OUTCOMES MEASURES: Standardised psychometric assessments of depression, anxiety and social functioning, collected as part of the IAPT Minimum Data Set, were conducted at baseline and post-treatment. RESULTS: Data indicated baseline differences, with the Breaking Free Online group having higher scores for depression and anxiety than the Living Life to the Full Interactive (depression CI 1.27 to 3.21, p<0.0001; anxiety CI 077 to 1.72, p<0.0001) and Sleepio (depression CI 1.19 to 4.52, p<0.0001; anxiety CI 2.16 to 5.23, p<0.0001) groups. Promising improvements in mental health scores were found within all three groups (all p<0.0001), as were significant reductions in numbers of service users reaching clinical threshold scores for mental health difficulties (p<0.0001). Number of days of engagement was not related to change from baseline for the Living Life to the Full or Sleepio programmes but was associated with degree of change for Breaking Free Online. CONCLUSION: Data presented provide evidence for feasibility of this eTherapy delivery model in supporting service users with a range of mental health difficulties and suggest that eTherapies may be a useful addition to treatment offering in community-based services. PMID- 28729323 TI - Gait outcomes of older adults receiving subacute hospital rehabilitation following orthopaedic trauma: a longitudinal cohort study. AB - OBJECTIVES: This study aimed to describe gait speed at admission and discharge from inpatient hospital rehabilitation among older adults recovering from orthopaedic trauma and factors associated with gait speed performance and discharge destination. DESIGN: A longitudinal cohort study was conducted. SETTING: Australian tertiary hospital subacute rehabilitation wards. PARTICIPANTS: Patients aged >=60 years recovering from orthopaedic trauma (n=746, 71% female) were eligible for inclusion. INTERVENTIONS: Usual care (multidisciplinary inpatient hospital rehabilitation). PRIMARY AND SECONDARY OUTCOME MEASURES: Gait speed was assessed using the timed 10 m walk test. The proportion of patients exceeding a minimum gait speed threshold indicator (a priori 0.8 m/s) of community ambulation ability was calculated. Generalised linear models were used to examine associations between patient and clinical factors with gait speed performance and being discharged to a residential aged care facility. RESULTS: At discharge, 18% of patients (n=135) exceeded the 0.8 m/s threshold indicator for community ambulation ability. Faster gait speed at discharge was found to be associated with being male (B=0.43, 95% CI -0.01 to 0.87), admitted with pelvic (B=0.76, 95% CI 0.14 to 1.37) or multiple fractures (B=1.13, 95% CI 0.25 to 2.01) (vs hip fracture), using no mobility aids (B=-0.93, 95% CI -1.89 to 0.01) and walking at a faster gait speed at admission (B=5.77, 95% CI 5.03 to 6.50). Factors associated with being discharged to residential aged care included older age (OR 1.06, 95% CI 1.03 to 1.10), longer length of stay (OR 1.01, 95% CI 1.01 to 1.02), having an upper limb fracture (vs hip fracture) (OR 2.81, 95% CI 1.32 to 5.97) and lower Functional Independence Measure cognitive score (OR 0.89, 95% CI 0.86 to 0.92). CONCLUSIONS: Patients with a range of injury types, not only those presenting to hospital with hip fractures, are being discharged with slow gait speeds that are indicative of limited functional mobility and a high risk of further adverse health events. PMID- 28729324 TI - Access and quality of maternity care for disabled women during pregnancy, birth and the postnatal period in England: data from a national survey. AB - OBJECTIVES: More disabled women are becoming mothers, and yet, their care is rarely the focus of quantitative research. This study aimed to investigate access and quality of maternity care for women with differing disabilities. DESIGN: Secondary analysis was conducted on data from a 2015 national survey of women's experience of maternity care. Descriptive and adjusted analyses were undertaken for five disability groups: physical disability, sensory impairment, mental health disability, learning disability and multiple disability, and comparisons were made with the responses of non-disabled women. SETTING: Survey data were collected on women's experience of primary and secondary care in all trusts providing maternity care in England. PARTICIPANTS: Women who had given birth 3 months previously, among whom were groups self-identifying with different types of disability. Exclusions were limited to women whose baby had died and those who were younger than 16 years at the time of the recent birth. RESULTS: Overall, 20 094 women completed and returned the survey; 1958 women (9.5%) self-identified as having a disability. The findings indicate some gaps in maternity care provision for these women relating to interpersonal aspects of care: communication, feeling listened to and supported, involvement in decision making, having a trusted and respected relationship with clinical staff. Women from all disability groups wanted more postnatal contacts and help with infant feeding. CONCLUSION: While access to care was generally satisfactory for disabled women, women's emotional well-being and support during pregnancy and beyond is an area that is in need of improvement. Specific areas identified included disseminating information effectively, ensuring appropriate communication and understanding, and supporting women's sense of control to build trusting relationships with healthcare providers. PMID- 28729325 TI - Risk of sarcoidosis and seropositive rheumatoid arthritis from occupational silica exposure in Swedish iron foundries: a retrospective cohort study. AB - OBJECTIVE: To study the impact of occupational silica exposure on the incidence rates of sarcoidosis and rheumatoid arthritis (RA) in a cohort of exposed workers in Swedish iron foundries. DESIGN: The prevalence of sarcoidosis and RA in a cohort of silica exposed workers was compared with the prevalence in the general Swedish population in this register study. A mixed model was used to calculate silica exposure, and individual silica exposures were used to compute dose responses. SETTING: Personnel records from 10 iron foundries were used to identify workers whose employment began before 2005 which was then linked to the national non-primary outpatient visits register. PARTICIPANTS: The final cohort consisted of 2187 silica-exposed male workers who had been employed for at least 1 year and were still alive without having emigrated when the follow-up study began. The cohort's employment period covers 23 807 person-years at risk. MAIN OUTCOME: The presented results indicate that moderate to high levels of silica exposure increase risks for sarcoidosis and seropositive RA. RESULTS: Mean levels of airborne silica dust in the foundries decreased significantly between the 1970s and 2000s. Incidence rates of sarcoidosis (3.94; 95% CI 1.07 to 10.08) and seropositive RA (2.59; 95% CI 1.24 to 4.76) were significantly higher among highly exposed individuals. CONCLUSION: Our results reveal increased risks for sarcoidosis and seropositive RA among individuals with high exposure to silica dust (>0.048 mg/m3) compared with non-exposed and less-exposed groups. PMID- 28729326 TI - Associations between physical function and depression in nursing home residents with mild and moderate dementia: a cross-sectional study. AB - OBJECTIVES: The primary aim of this study is to describe depression and physical function in nursing home residents with dementia, as well as to examine the associations between depression and balance function, lower limb muscle strength, mobility and activities of daily living. The secondary aim is to examine the differences in physical function between the groups classified as depressed and not depressed. DESIGN: The study has a cross-sectional design. SETTING: A convenience sample of 18 nursing homes in, and around, Oslo, Norway, participated. PARTICIPANTS: We included 170 nursing home residents aged 60-100 years with mild or moderate degree of dementia defined by a score of 1 or 2 on the Clinical Dementia Rating Scale (CDR). OUTCOME MEASURES: Assessments used were Cornell Scale for Depression in Dementia (CSDD), Berg Balance Scale (BBS), 'the 6 metre walking test' (walking speed), 30 s Chair Stand Test (CST) and the Barthel Index (BI). RESULTS: Nursing home residents with dementia are a heterogeneous group in terms of physical function and depression. By applying the recommended cut-off of >=8 on CSDD, 23.5% of the participants were classified as being depressed. The results revealed significant associations between higher scores on CSDD (indicating more symptoms of depression) and lower scores on BBS (95% CI 0.12 to -0.02, p=0.006), 30 s CST (95% CI -0.54 to -0.07, p=0.001) as well as maximum walking speed (95% CI -4.56 to -0.20, p=0.003) (indicating lower level of physical function). CONCLUSION: Better muscle strength, balance and higher walking speed were significantly associated with less depressive symptoms. The potential interaction of dementia with poor physical function and depression indicates an area to explore in future epidemiological studies with a prospective design. TRIAL REGISTRATION NUMBER: NCT02262104. PMID- 28729327 TI - Dietary intake and factors influencing eating behaviours in overweight and obese South Asian men living in the UK: mixed method study. AB - OBJECTIVE: It is widely recognised that South Asian men living in the UK are more likely to develop type 2 diabetes mellitus (T2DM) than their white British counterparts. Despite this, limited data have been published quantifying current dietary intake patterns and qualitatively exploring eating behaviours in this population. The objectives of this study were to (1) assess diet, (2) explore perceptions of T2DM, (3) investigate factors influencing eating behaviours in overweight/obese South Asian men and (4) determine the suitability of the UK Diet and Diabetes Questionnaire (UKDDQ) for use in this population. SETTING: Community based setting in the Greater London, UK area. PARTICIPANTS: South Asian men aged 18-64 years, with a body mass index of over 23.0 kg/m2, not previously diagnosed with T2DM. METHODS: A cross-sectional mixed-methods design, including assessment of dietary intake using UKDDQ (n=63), followed by semistructured interviews in a purposive sample (n=36). RESULTS: UKDDQ scores indicated 54% of participants had a 'healthy' diet with a mean sample score of 3.44+/-0.43 out of a maximum of 5. Oily fish consumption was low (1.84+/-1.85). Body weight was positively associated with a high-added sugar subscore (r=0.253, p=0.047), with 69.8% of the men having 'unhealthy' intakes of sugar-sweetened beverages. Cultural commitments (eg, extended family and faith events), motivation and time were identified as key barriers to dietary change, with family support an important facilitator to making healthy dietary changes. Participants stated that UKDDQ was suitable for assessing diets of South Asians and made suggestions for tailoring questions related to rice consumption, providing examples of Indian sweets, and including ghee as a fat source. CONCLUSION: Many of the areas of dietary improvement and factors affecting eating behaviours identified in this study are similar to those observed in the general UK population. Consumption of sugar-sweetened beverages in particular was high; given the association between their consumption and the risk of T2DM, this should be an area of primary focus for healthcare professionals. Nevertheless, there are sociocultural factors unique to this population that need to be considered when designing culturally specific programs to reduce the development of T2DM in this high-risk population. PMID- 28729329 TI - Fluids in Sepsis and Septic Shock (FISSH): protocol for a pilot randomised controlled trial. AB - INTRODUCTION: Observational evidence suggests physiological benefits and lower mortality with lower chloride solutions; however, 0.9% saline remains the most widely used fluid worldwide. Given uncertainty regarding the association of lower chloride on mortality, it is unlikely that practice will change without direct randomised clinical trial (RCT) evidence. This pilot RCT will investigate the feasibility of a large-scale trial directly comparing low chloride with high chloride fluids in patients with septic shock. METHODS AND ANALYSIS: This is a randomised, concealed, blinded parallel-group multicentre pilot trial. We will include adult critically ill patients with septic shock, defined as ongoing hypotension despite 1 L of fluid, or a serum lactate >4 mmol/L, who are within 6 hours of hospital presentation or rapid response team activation. We will exclude patients if they have an aetiology of shock other than sepsis, if they have acute burn injury, elevated intracranial pressure, intent to withdraw life support or previous enrolment in this or a competing trial. Following informed consent, patients will be randomised to a low chloride fluid strategy or a high chloride fluid strategy for the duration of their ICU stay or until 30 days postrandomisation. Clinicians, patients, families and research staff will be blinded. The primary outcome for this trial will be feasibility, assessed by consent rate, recruitment success and protocol adherence. Patient-important clinical outcomes include mortality, receipt of renal replacement therapy, intensive care unit and hospital lengths of stay and surrogate outcomes of incidence of acidosis, hyperkalaemia and acute kidney injury. ETHICS AND DISSEMINATION: This pilot trial will test the feasibility of conducting the main trial, which will examine the effect of high versus low chloride fluids in patients with septic shock on patient-important outcomes. TRIAL REGISTRATION NUMBER: NCT02748382, registered 8 April 2016. PROTOCOL DATE: 1 July 2016. PMID- 28729328 TI - Comparative safety of antiepileptic drugs for neurological development in children exposed during pregnancy and breast feeding: a systematic review and network meta-analysis. AB - OBJECTIVES: Compare the safety of antiepileptic drugs (AEDs) on neurodevelopment of infants/children exposed in utero or during breast feeding. DESIGN AND SETTING: Systematic review and Bayesian random-effects network meta-analysis (NMA). MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials were searched until 27 April 2017. Screening, data abstraction and quality appraisal were completed in duplicate by independent reviewers. PARTICIPANTS: 29 cohort studies including 5100 infants/children. INTERVENTIONS: Monotherapy and polytherapy AEDs including first-generation (carbamazepine, clobazam, clonazepam, ethosuximide, phenobarbital, phenytoin, primidone, valproate) and newer generation (gabapentin, lamotrigine, levetiracetam, oxcarbazepine, topiramate, vigabatrin) AEDs. Epileptic women who did not receive AEDs during pregnancy or breast feeding served as the control group. PRIMARY AND SECONDARY OUTCOME MEASURES: Cognitive developmental delay and autism/dyspraxia were primary outcomes. Attention-deficit hyperactivity disorder, language delay, neonatal seizures, psychomotor developmental delay and social impairment were secondary outcomes. RESULTS: The NMA on cognitive developmental delay (11 cohort studies, 933 children, 18 treatments) suggested that among all AEDs only valproate was statistically significantly associated with more children experiencing cognitive developmental delay compared with control (OR=7.40, 95% credible interval (CrI) 3.00 to 18.46). The NMA on autism (5 cohort studies, 2551 children, 12 treatments) suggested that oxcarbazepine (OR 13.51, CrI 1.28 to 221.40), valproate (OR 17.29, 95% CrI 2.40 to 217.60), lamotrigine (OR 8.88, CrI 1.28 to 112.00) and lamotrigine+valproate (OR 132.70, CrI 7.41 to 3851.00) were associated with significantly greater odds of developing autism compared with control. The NMA on psychomotor developmental delay (11 cohort studies, 1145 children, 18 treatments) found that valproate (OR 4.16, CrI 2.04 to 8.75) and carbamazepine+phenobarbital+valproate (OR 19.12, CrI 1.49 to 337.50) were associated with significantly greater odds of psychomotor delay compared with control. CONCLUSIONS: Valproate alone or combined with another AED is associated with the greatest odds of adverse neurodevelopmental outcomes compared with control. Oxcarbazepine and lamotrigine were associated with increased occurrence of autism. Counselling is advised for women considering pregnancy to tailor the safest regimen. TRIAL REGISTRATION NUMBER: PROSPERO database (CRD42014008925). PMID- 28729330 TI - A smoker with joint pain. PMID- 28729331 TI - Ironing out the role of hepcidin in infection. PMID- 28729332 TI - Check this checkpoint inhibitor in lymphoma. PMID- 28729333 TI - Choosing wisely: RUNX1 alternate promoter use. PMID- 28729334 TI - CD70 turns on NK cells to attack lymphoma. PMID- 28729335 TI - Might broader be better? PMID- 28729336 TI - Prenatal diagnosis by droplet digital PCR. PMID- 28729337 TI - Raising the bar for chronic GVHD trials. PMID- 28729338 TI - A new therapeutic strategy for atypical HUS. PMID- 28729339 TI - Peripheral eosinophilia as the first manifestation of B-cell acute lymphoblastic leukemia with t(5;14)(q31;q32). PMID- 28729340 TI - Classical Hodgkin lymphoma and Castleman disease: a rare morphologic combination. PMID- 28729341 TI - Curtis C, Mineyko A, Massicotte P, et al. Thrombophilia risk is not increased in children after perinatal stroke. Blood. 2017;129(20):2793-2800. PMID- 28729342 TI - Predicting transformation of follicular lymphoma. PMID- 28729343 TI - Flowtrace: simple visualization of coherent structures in biological fluid flows. AB - We present a simple, intuitive algorithm for visualizing time-varying flow fields that can reveal complex flow structures with minimal user intervention. We apply this technique to a variety of biological systems, including the swimming currents of invertebrates and the collective motion of swarms of insects. We compare our results with more experimentally difficult and mathematically sophisticated techniques for identifying patterns in fluid flows, and suggest that our tool represents an essential 'middle ground' allowing experimentalists to easily determine whether a system exhibits interesting flow patterns and coherent structures without resorting to more intensive techniques. In addition to being informative, the visualizations generated by our tool are often striking and elegant, illustrating coherent structures directly from videos without the need for computational overlays. Our tool is available as fully documented open source code for MATLAB, Python or ImageJ at www.flowtrace.org. PMID- 28729344 TI - Exogenous stress hormones alter energetic and nutrient costs of development and metamorphosis. AB - Variation in environmental conditions during larval life stages can shape development during critical windows and have lasting effects on the adult organism. Changes in larval developmental rates in response to environmental conditions, for example, can trade off with growth to determine body size and condition at metamorphosis, which can affect adult survival and fecundity. However, it is unclear how use of energy and nutrients shape trade-offs across life-stage transitions because no studies have quantified these costs of larval development and metamorphosis. We used an experimental approach to manipulate physiological stress in larval amphibians, along with respirometry and 13C-breath testing to quantify the energetic and nutritional costs of development and metamorphosis. Central to larval developmental responses to environmental conditions is the hypothalamic-pituitary-adrenal/interrenal (HPA/I) axis, which regulates development, as well as energy homeostasis and stress responses across many taxa. Given these pleiotropic effects of HPA/I activity, manipulation of the HPA/I axis may provide insight into costs of metamorphosis. We measured the energetic and nutritional costs across the entire larval period and metamorphosis in a larval amphibian exposed to exogenous glucocorticoid (GC) hormones - the primary hormone secreted by the HPA/I axis. We measured metabolic rates and dry mass across larval ontogeny, and quantified lipid stores and nutrient oxidation via 13C-breath testing during metamorphosis, under control and GC-exposed conditions. Changes in dry mass match metamorphic states previously reported in the literature, but dynamics of metabolism were influenced by the transition from aquatic to terrestrial respiration. GC-treated larvae had lower dry mass, decreased fat stores and higher oxygen consumption during stages where controls were conserving energy. GC-treated larvae also oxidized greater amounts of 13C labelled protein stores. These results provide evidence for a proximate cause of the physiological trade-off between larval growth and development, and provide insight into the energetic and nutrient costs that shape fitness trade-offs across life stages. PMID- 28729345 TI - Recent advances in understanding and managing body dysmorphic disorder. AB - Body dysmorphic disorder (BDD) is a relatively common and disabling psychiatric disorder characterised by excessive and persistent preoccupation with perceived defects or flaws in one's appearance, which are unnoticeable to others, and associated repetitive behaviours (eg, mirror checking). The disorder generally starts in adolescence, but often goes unnoticed and is severely underdiagnosed. Left untreated, BDD typically persists and causes marked functional impairment in multiple domains. This clinical review considers recent advances in the epidemiology and classification of BDD, including its reclassification in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders under the new 'Obsessive-Compulsive and Related Disorders' chapter. Key issues in assessment are outlined including the use of validated screening instruments to minimise misdiagnosis and the importance of risk assessment in this population given the high rates of suicidality and inappropriate use of cosmetic treatments. In addition, current knowledge regarding the causes and mechanisms underlying BDD are summarised. The recommended treatments for BDD are outlined, namely cognitive behavioural therapy (CBT) and antidepressants, such as selective serotonin reuptake inhibitors. Both CBT and pharmacotherapy have been shown to be efficacious treatments for BDD in adult populations, and evidence is emerging to support their use in young people. Although the majority of patients improve with existing evidence-based treatment, a large proportion are left with clinically significant residual symptoms. Priorities for future research are therefore discussed including the need to further refine and evaluate existing interventions with the goal of improving treatment outcomes and to increase their availability. PMID- 28729346 TI - Distinct PKA regulatory subunits mediate PGE2 inhibition of TGFbeta-1-stimulated collagen I translation and myofibroblast differentiation. AB - Prostaglandin E2 (PGE2), via cAMP signaling, inhibits a variety of fibroblast functions relevant to fibrogenesis. Among these are their translation of collagen I protein and their differentiation to myofibroblasts. PKA is central to these actions, with cAMP binding to regulatory (R) subunits leading to the release of catalytic subunits. Here we examined the role of specific PKAR subunit isoforms in these inhibitory actions in transforming growth factor beta-1 (TGFbeta-1) stimulated human lung fibroblasts (HLFs). HLFs expressed all four R subunit isoforms. siRNA-mediated knockdown of subunits PKARIalpha and PKARIIalpha had no effect on PGE2 inhibition of either process. However, knockdown of PKARIbeta selectively attenuated PGE2 inhibition of collagen I protein expression, whereas knockdown of PKARIIbeta selectively attenuated PGE2 inhibition of expression of the myofibroblast differentiation marker, alpha-smooth muscle actin (alpha-SMA). cAMP analogs that selectively activate either PKARIbeta or PKARIIbeta exclusively inhibited collagen I synthesis or differentiation, respectively. In parallel, the PKARIbeta agonist (but not a PKARIIbeta agonist) reduced phosphorylation of two proteins involved in protein translation, protein kinase B (AKT) and mammalian target of rapamycin (mTOR). By contrast, the PKARIIbeta agonist (but not a PKARIbeta agonist) reduced levels of the differentiation-associated phosphorylated focal adhesion kinase (p-FAK) as well as the relative mRNA and protein expression of serum response factor (SRF), a transcription factor necessary for myofibroblast differentiation. Our results demonstrate that cAMP inhibition of collagen I translation and myofibroblast differentiation reflects the actions of distinct PKAR subunits. PMID- 28729348 TI - A new target for caffeine in the developing lung: endoplasmic reticulum stress? PMID- 28729347 TI - Lethal avian influenza A (H5N1) virus induces ataxic breathing in mice with apoptosis of pre-Botzinger complex neurons expressing neurokinin-1 receptor. AB - Lethal influenza A (H5N1) induces respiratory failure in humans. Although it also causes death at 7 days postinfection (dpi) in mice, the development of the respiratory failure and the viral impact on pre-Botzinger complex (PBC) neurons expressing neurokinin 1 receptor (NK1R), which is the respiratory rhythm generator, have not been explored. Body temperature, weight, ventilation, and arterial blood pH and gases were measured at 0, 2, 4, and 6 dpi in control, lethal HK483, and nonlethal HK486 viral-infected mice. Immunoreactivities (IR) of PBC NK1R, H5N1 viral nucleoprotein (NP), and active caspase-3 (CASP3; a marker for apoptosis) were detected at 6 dpi. HK483, but not HK486, mice showed the following abnormalities: 1) gradual body weight loss and hypothermia; 2) tachypnea at 2-4 dpi and ataxic breathing with long-lasting apneas and hypercapnic hypoxemia at 6 dpi; and 3) viral replication in PBC NK1R neurons with NK1R-IR reduced by 75% and CASP3-IR colabeled at 6 dpi. Lethal H5N1 viral infection causes tachypnea at the early stage and ataxic breathing and apneas (hypercapnic hypoxemia) leading to death at the late stage. Its replication in the PBC induces apoptosis of local NK1R neurons, contributing to ataxic breathing and respiratory failure. PMID- 28729349 TI - FGF9 prevents pleural fibrosis induced by intrapleural adenovirus injection in mice. AB - Fibroblast growth factor 9 (FGF9) is necessary for fetal lung development and is expressed by epithelium and mesothelium. We evaluated the role of FGF9 overexpression on adenoviral-induced pleural injury in vivo and determined the biological effects of FGF9 on mesothelial cells in vitro. We assessed the expression of FGF9 and FGF receptors by mesothelial cells in both human and mouse lungs. Intrapleural injection of an adenovirus expressing human FGF9 (AdFGF9) or a control adenovirus (AdCont) was performed. Mice were euthanized at days 3, 5, and 14 Expression of FGF9 and markers of inflammation and myofibroblastic differentiation was studied by qPCR and immunohistochemistry. In vitro, rat mesothelial cells were stimulated with FGF9 (20 ng/ml), and we assessed its effect on proliferation, survival, migration, and differentiation. FGF9 was expressed by mesothelial cells in human idiopathic pulmonary fibrosis. FGF receptors, mainly FGFR3, were expressed by mesothelial cells in vivo in humans and mice. AdCont instillation induced diffuse pleural thickening appearing at day 5, maximal at day 14 The altered pleura cells strongly expressed alpha-smooth muscle actin and collagen. AdFGF9 injection induced maximal FGF9 expression at day 5 that lasted until day 14 FGF9 overexpression prevented pleural thickening, collagen and fibronectin accumulation, and myofibroblastic differentiation of mesothelial cells. In vitro, FGF9 decreased mesothelial cell migration and inhibited the differentiating effect of transforming growth factor-beta1. We conclude that FGF9 has a potential antifibrotic effect on mesothelial cells. PMID- 28729351 TI - We still need to beat HIV. PMID- 28729350 TI - Structures of the CRISPR genome integration complex. AB - CRISPR-Cas systems depend on the Cas1-Cas2 integrase to capture and integrate short foreign DNA fragments into the CRISPR locus, enabling adaptation to new viruses. We present crystal structures of Cas1-Cas2 bound to both donor and target DNA in intermediate and product integration complexes, as well as a cryo electron microscopy structure of the full CRISPR locus integration complex, including the accessory protein IHF (integration host factor). The structures show unexpectedly that indirect sequence recognition dictates integration site selection by favoring deformation of the repeat and the flanking sequences. IHF binding bends the DNA sharply, bringing an upstream recognition motif into contact with Cas1 to increase both the specificity and efficiency of integration. These results explain how the Cas1-Cas2 CRISPR integrase recognizes a sequence dependent DNA structure to ensure site-selective CRISPR array expansion during the initial step of bacterial adaptive immunity. PMID- 28729352 TI - Optical imaging of surface chemistry and dynamics in confinement. AB - We imaged the interfacial structure and dynamics of water in a microscopically confined geometry, in three dimensions and on millisecond time scales, with a structurally illuminated wide-field second harmonic microscope. The second harmonic images reported on the orientational order of interfacial water, induced by charge-dipole interactions between water molecules and surface charges. The images were converted into surface potential maps. Spatially resolved surface acid dissociation constant (pKa,s) values were determined for the silica deprotonation reaction by following pH-induced chemical changes on the curved and confined surfaces of a glass microcapillary immersed in aqueous solutions. These values ranged from 2.3 to 10.7 along the wall of a single capillary because of surface heterogeneities. Water molecules that rotate along an oscillating external electric field were also imaged. PMID- 28729353 TI - Recommendation on Design, Execution, and Reporting of Animal Atherosclerosis Studies: A Scientific Statement From the American Heart Association. AB - Animal studies are a foundation for defining mechanisms of atherosclerosis and potential targets of drugs to prevent lesion development or reverse the disease. In the current literature, it is common to see contradictions of outcomes in animal studies from different research groups, leading to the paucity of extrapolations of experimental findings into understanding the human disease. The purpose of this statement is to provide guidelines for development and execution of experimental design and interpretation in animal studies. Recommendations include the following: (1) animal model selection, with commentary on the fidelity of mimicking facets of the human disease; (2) experimental design and its impact on the interpretation of data; and (3) standard methods to enhance accuracy of measurements and characterization of atherosclerotic lesions. PMID- 28729354 TI - Continuous-Flow LVAD Support Causes a Distinct Form of Intestinal Angiodysplasia. AB - RATIONALE: The objective of this autopsy study was to determine whether gastrointestinal angiodysplasia develops during continuous-flow left ventricular assist device (LVAD) support. OBJECTIVE: LVAD support causes pathologic degradation of von Willebrand factor (vWF) and bleeding from gastrointestinal angiodysplasia at an alarming rate. It has been speculated that LVAD support itself may cause angiodysplasia. The relationship to abnormal vWF metabolism is unknown. We tested the hypothesis that abnormal gastrointestinal vascularity develops during continuous-flow LVAD support. METHODS AND RESULTS: Small bowel was obtained from deceased humans, cows, and sheep supported with a continuous flow LVAD (n=9 LVAD, n=11 control). Transmural sections of jejunum were stained with fluorescein isothiocyanate-conjugated isolectin-B4 for endothelium to demarcate vascular structures and quantify intestinal vascularity. Paired plasma samples were obtained from humans before LVAD implantation and during LVAD support (n=41). vWF multimers and degradation fragments were quantified with agarose and polyacrylamide gel electrophoresis and immunoblotting. Abnormal vascular architecture was observed in the submucosa of the jejunum of human patients, cows, and sheep supported with a continuous-flow LVAD. Intestinal vascularity was significantly higher after LVAD support versus controls (5.2+/ 1.0% versus 2.1+/-0.4%, P=0.004). LVAD support caused significant degradation of high-molecular-weight vWF multimers (-9+/-1%, P<0.0001) and accumulation of low molecular-weight vWF multimers (+40+/-5%, P<0.0001) and vWF degradation fragments (+53+/-6%, P<0.0001). CONCLUSIONS: Abnormal intestinal vascular architecture and LVAD-associated vWF degradation were consistent findings in multiple species supported with a continuous-flow LVAD. These are the first direct evidence that LVAD support causes gastrointestinal angiodysplasia. Pathologic vWF metabolism may be a mechanistic link between LVAD support, abnormal angiogenesis, gastrointestinal angiodysplasia, and bleeding. PMID- 28729355 TI - Insurance Clearance for Early-Phase Oncology Clinical Trials Following the Affordable Care Act. AB - Purpose: The Affordable Care Act (ACA) required that private insurance plans allow clinical trial participation and cover standard-of-care costs, but the impact of this provision has not been well-characterized. We assessed rates of insurance clearance for trial participation within our large early-phase clinical trials program, before and after implementation of the requirement.Experimental Design: We analyzed the departmental database for the Clinical Center for Targeted Therapy (CCTT) at MD Anderson Cancer Center (Houston, TX). Among patients referred for sponsored trials, we described rates of insurance clearance and prolonged time to clearance (at least 14 days) from July 2012 to June 2013 (baseline), July 2013-December 2013 (following CCTT staffing changes in July 2103), and January 2014-June 2015 (following implementation of the ACA). We used multivariable logistic regression models to compare rates across these time periods.Results: We identified 2,404 referrals for insurance clearance. Among privately insured patients, insurance clearance rates were higher for those referred from January 2014 to June 2015 than for those referred from July 2012 to June 2013 (OR, 4.72; 95% CI, 2.96-7.51). There was no association between referral period and clearance rates for Medicare/Medicaid patients (P = 0.25). Referral from January 2014 to June 2015 was associated with lower rates of prolonged clearance among both privately insured (OR 0.57; 95% CI, 0.38-0.86) and Medicare/Medicaid patients (OR 0.39; 95% CI, 0.19-0.83).Conclusion: Within our large early-phase clinical trials program, insurance clearance rates among privately insured patients improved following implementation of the ACA's requirement for coverage of standard-of-care costs. Clin Cancer Res; 23(15); 1-8. (c)2017 AACR. PMID- 28729356 TI - Influence of childhood trauma on diagnosis and substance use in first-episode psychosis. AB - BackgroundChildhood trauma has been significantly associated with first-episode psychosis, affective dysfunction and substance use.AimsTo test whether people with first-episode psychosis who had experienced childhood trauma, when compared with those who had not, showed a higher rate of affective psychosis and an increased lifetime rate of substance use.MethodThe sample comprised 345 participants with first-episode psychosis (58% male, mean age 29.8 years, s.d. = 9.7).ResultsSevere sexual abuse was significantly associated with a diagnosis of affective psychosis (chi2 = 4.9, P = 0.04) and with higher rates of lifetime use of cannabis (68% v 41%; P = 0.02) and heroin (20% v 5%; P = 0.02). Severe physical abuse was associated with increased lifetime use of heroin (15% v 5%; P = 0.03) and cocaine (32% v 17%; P = 0.05).ConclusionsPatients with first-episode psychosis exposed to childhood trauma appear to constitute a distinctive subgroup in terms of diagnosis and lifetime substance use. PMID- 28729357 TI - Association between maternal childhood trauma and offspring childhood psychopathology: mediation analysis from the ALSPAC cohort. AB - BackgroundStudies have shown that a mother's history of childhood maltreatment is associated with her child's experience of internalising and externalising difficulties.AimsTo characterise the mediating pathways that underpin this association.MethodData on a mother's history of childhood maltreatment, depression during pregnancy, postnatal depression, maladaptive parenting practices and her child's experience of maltreatment and internalising and externalising difficulties were analysed in an Avon Longitudinal Study of Parents and Children (ALSPAC) sample of 9397 mother-child dyads followed prospectively from pregnancy to age 13.ResultsMaternal history of childhood maltreatment was significantly associated with offspring internalising and externalising difficulties. Maternal antenatal depression, postnatal depression and offspring child maltreatment were observed to significantly mediate this association independently.ConclusionsPsychological and psychosocial interventions focused around treating maternal depression, particularly during pregnancy, and safeguarding against adverse childhood experiences could be offered to mothers with traumatic childhood histories to help protect against psychopathology in the next generation. PMID- 28729360 TI - Potential role of cyclophilin A in regulating cytokine secretion. AB - Cyclophilin A (CypA), a peptidylprolyl cis-trans isomerase, is a ubiquitous and multifunctional protein. In addition to its role as a host-cell receptor for cyclosporine A, CypA has diverse functions in inflammatory conditions and diseases. CypA secreted in response to inflammatory stimuli binds to the cell surface via its receptor CD147 and induces secretion of various inflammatory cytokines. However, silencing and inhibition of either CypA or CD147 inhibits inflammatory cytokine expression and inflammation. This report reviews the literature related to the mechanism of CypA-dependent cytokine secretion and discusses this factor as a possible therapeutic target in inflammatory diseases. PMID- 28729359 TI - The theta-defensin retrocyclin 101 inhibits TLR4- and TLR2-dependent signaling and protects mice against influenza infection. AB - Despite widespread use of annual influenza vaccines, seasonal influenza associated deaths number in the thousands each year, in part because of exacerbating bacterial superinfections. Therefore, discovering additional therapeutic options would be a valuable aid to public health. Recently, TLR4 inhibition has emerged as a possible mechanism for protection against influenza associated lethality and acute lung injury. Based on recent data showing that rhesus macaque theta-defensins could inhibit TLR4-dependent gene expression, we tested the hypothesis that a novel theta-defensin, retrocyclin (RC)-101, could disrupt TLR4-dependent signaling and protect against viral infection. In this study, RC-101, a variant of the humanized theta-defensin RC-1, blocked TLR4 mediated gene expression in mouse and human macrophages in response to LPS, targeting both MyD88- and TRIF-dependent pathways. In a cell-free assay, RC-101 neutralized the biologic activity of LPS at doses ranging from 0.5 to 50 EU/ml, consistent with data showing that RC-101 binds biotinylated LPS. The action of RC 101 was not limited to the TLR4 pathway because RC-101 treatment of macrophages also inhibited gene expression in response to a TLR2 agonist, Pam3CSK4, but failed to bind that biotinylated agonist. Mouse macrophages infected in vitro with mouse-adapted A/PR/8/34 influenza A virus (PR8) also produced lower levels of proinflammatory cytokine gene products in a TLR4-independent fashion when treated with RC-101. Finally, RC-101 decreased both the lethality and clinical severity associated with PR8 infection in mice. Cumulatively, our data demonstrate that RC-101 exhibits therapeutic potential for the mitigation of influenza-related morbidity and mortality, potentially acting through TLR dependent and TLR-independent mechanisms. PMID- 28729361 TI - CETP (Cholesteryl Ester Transfer Protein) Inhibition With Anacetrapib Decreases Production of Lipoprotein(a) in Mildly Hypercholesterolemic Subjects. AB - OBJECTIVE: Lp(a) [lipoprotein (a)] is composed of apoB (apolipoprotein B) and apo(a) [apolipoprotein (a)] and is an independent risk factor for cardiovascular disease and aortic stenosis. In clinical trials, anacetrapib, a CETP (cholesteryl ester transfer protein) inhibitor, causes significant reductions in plasma Lp(a) levels. We conducted an exploratory study to examine the mechanism for Lp(a) lowering by anacetrapib. APPROACH AND RESULTS: We enrolled 39 participants in a fixed-sequence, double-blind study of the effects of anacetrapib on the metabolism of apoB and high-density lipoproteins. Twenty-nine patients were randomized to atorvastatin 20 mg/d, plus placebo for 4 weeks, and then atorvastatin plus anacetrapib (100 mg/d) for 8 weeks. The other 10 subjects were randomized to double placebo for 4 weeks followed by placebo plus anacetrapib for 8 weeks. We examined the mechanisms of Lp(a) lowering in a subset of 12 subjects having both Lp(a) levels >20 nmol/L and more than a 15% reduction in Lp(a) by the end of anacetrapib treatment. We performed stable isotope kinetic studies using 2H3-leucine at the end of each treatment to measure apo(a) fractional catabolic rate and production rate. Median baseline Lp(a) levels were 21.5 nmol/L (interquartile range, 9.9-108.1 nmol/L) in the complete cohort (39 subjects) and 52.9 nmol/L (interquartile range, 38.4-121.3 nmol/L) in the subset selected for kinetic studies. Anacetrapib treatment lowered Lp(a) by 34.1% (P<=0.001) and 39.6% in the complete and subset cohort, respectively. The decreases in Lp(a) levels were because of a 41% reduction in the apo(a) production rate, with no effects on apo(a) fractional catabolic rate. CONCLUSIONS: Anacetrapib reduces Lp(a) levels by decreasing its production. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00990808. PMID- 28729362 TI - Sema3F (Semaphorin 3F) Selectively Drives an Extraembryonic Proangiogenic Program. AB - OBJECTIVE: Molecular pathways governing blood vessel patterning are vital to vertebrate development. Because of their ability to counteract proangiogenic factors, antiangiogenic secreted Sema3 (class 3 semaphorins) control embryonic vascular morphogenesis. However, if and how Sema3 may play a role in the control of extraembryonic vascular development is presently unknown. APPROACH AND RESULTS: By characterizing genetically modified mice, here, we show that surprisingly Sema3F acts instead as a selective extraembryonic, but not intraembryonic proangiogenic cue. Both in vivo and in vitro, in visceral yolk sac epithelial cells, Sema3F signals to inhibit the phosphorylation-dependent degradation of Myc, a transcription factor that drives the expression of proangiogenic genes, such as the microRNA cluster 17/92. In Sema3f-null yolk sacs, the transcription of Myc-regulated microRNA 17/92 cluster members is impaired, and the synthesis of Myc and microRNA 17/92 foremost antiangiogenic target Thbs1 (thrombospondin 1) is increased, whereas Vegf (vascular endothelial growth factor) signaling is inhibited in yolk sac endothelial cells. Consistently, exogenous recombinant Sema3F inhibits the phosphorylation-dependent degradation of Myc and the synthesis of Thbs1 in mouse F9 teratocarcinoma stem cells that were in vitro differentiated in visceral yolk sac epithelial cells. Sema3f-/- mice placentas are also highly anemic and abnormally vascularized. CONCLUSIONS: Sema3F functions as an unconventional Sema3 that promotes extraembryonic angiogenesis by inhibiting the Myc-regulated synthesis of Thbs1 in visceral yolk sac epithelial cells. PMID- 28729358 TI - Targeting C-type lectin receptors: a high-carbohydrate diet for dendritic cells to improve cancer vaccines. AB - There is a growing understanding of why certain patients do or do not respond to checkpoint inhibition therapy. This opens new opportunities to reconsider and redevelop vaccine strategies to prime an anticancer immune response. Combination of such vaccines with checkpoint inhibitors will both provide the fuel and release the brake for an efficient anticancer response. Here, we discuss vaccine strategies that use C-type lectin receptor (CLR) targeting of APCs, such as dendritic cells and macrophages. APCs are a necessity for the priming of antigen specific cytotoxic and helper T cells. Because CLRs are natural carbohydrate recognition receptors highly expressed by multiple subsets of APCs and involved in uptake and processing of Ags for presentation, these receptors seem particularly interesting for targeting purposes. PMID- 28729363 TI - BRG1 (Brahma-Related Gene 1) Promotes Endothelial Mrtf Transcription to Establish Embryonic Capillary Integrity. AB - OBJECTIVE: The chromatin remodeling enzyme BRG1 (brahma-related gene 1) transcriptionally regulates target genes important for early blood vessel development and primitive hematopoiesis. However, because Brg1 deletion in vascular progenitor cells results in lethal anemia by embryonic day 10.5 (E10.5), roles for BRG1 in embryonic vascular development after midgestation are unknown. In this study, we sought to determine whether endothelial cell BRG1 regulates genes important for vascular development or maintenance later in embryonic development. APPROACH AND RESULTS: Using mice with temporally inducible deletion of endothelial BRG1 (Brg1fl/fl;Cdh5(PAC)-CreERT2 ), we found that Brg1 excision between E9.5 and 11.5 results in capillary dilation and lethal hemorrhage by E14.5. This phenotype strongly resembles that seen when the SRF (serum response factor) transcription factor is deleted from embryonic endothelial cells. Although expression of Srf and several of its known endothelial cell target genes are downregulated in BRG1-depleted endothelial cells, we did not detect binding of BRG1 at these gene promoters, indicating that they are not direct BRG1 target genes. Instead, we found that BRG1 binds to the promoters of the SRF cofactors Mrtfa and Mrtfb (myocardin-related transcription factors A and B) in endothelial cells, and these genes are downregulated in Brg1-deficient endothelial cells. CONCLUSIONS: BRG1 promotes transcription of endothelial Mrtfa and Mrtfb, which elevates expression of SRF and SRF target genes that establish embryonic capillary integrity. These data highlight a new and temporally specific role for BRG1 in embryonic vasculature and provide novel information about epigenetic regulation of Mrtf expression and SRF signaling in developing blood vessels. PMID- 28729364 TI - TGF-beta (Transforming Growth Factor-beta) Signaling Protects the Thoracic and Abdominal Aorta From Angiotensin II-Induced Pathology by Distinct Mechanisms. AB - OBJECTIVE: The role of TGF-beta (transforming growth factor-beta) signaling in abdominal aortic aneurysm (AAA) formation is controversial. Others reported that systemic blockade of TGF-beta by neutralizing antibodies accelerated AAA development in angiotensin II-infused mice. This result is consistent with other studies suggesting that TGF-beta signaling prevents AAA. Development of a therapy for AAA that exploits the protective actions of TGF-beta would be facilitated by identification of the mechanisms through which TGF-beta prevents AAA. We hypothesized that TGF-beta signaling prevents AAA by its actions on aortic medial smooth muscle cells. APPROACH AND RESULTS: We compared the prevalence, severity, and histopathology of angiotensin II-induced AAA among control mice (no TGF-beta blockade), mice with antibody-mediated systemic neutralization of TGF-beta, and mice with genetically based smooth muscle-specific loss of TGF-beta signaling. Surprisingly, we found that systemic-but not smooth muscle-specific-TGF-beta blockade significantly increased the prevalence of AAA and tended to increase AAA severity, adventitial thickening, and aortic wall macrophage accumulation. In contrast, abdominal aortas of mice with smooth muscle-specific loss of TGF-beta signaling differed from controls only in having a thinner media. We examined thoracic aortas of the same mice. Here we found that smooth muscle-specific loss of Tgfbr2-but not systemic TGF-beta neutralization-significantly accelerated development of aortic pathology, including increased prevalence of intramural hematomas, medial thinning, and adventitial thickening. CONCLUSION: Our results suggest that TGF-beta signaling prevents both abdominal and thoracic aneurysmal disease but does so by distinct mechanisms. Smooth muscle extrinsic signaling protects the abdominal aorta and smooth muscle intrinsic signaling protects the thoracic aorta. PMID- 28729366 TI - Recommendation on Design, Execution, and Reporting of Animal Atherosclerosis Studies: A Scientific Statement From the American Heart Association. AB - Animal studies are a foundation for defining mechanisms of atherosclerosis and potential targets of drugs to prevent lesion development or reverse the disease. In the current literature, it is common to see contradictions of outcomes in animal studies from different research groups, leading to the paucity of extrapolations of experimental findings into understanding the human disease. The purpose of this statement is to provide guidelines for development and execution of experimental design and interpretation in animal studies. Recommendations include the following: (1) animal model selection, with commentary on the fidelity of mimicking facets of the human disease; (2) experimental design and its impact on the interpretation of data; and (3) standard methods to enhance accuracy of measurements and characterization of atherosclerotic lesions. PMID- 28729365 TI - Induced Pluripotent Stem Cell-Derived Endothelial Cells in Insulin Resistance and Metabolic Syndrome. AB - Insulin resistance leads to a number of metabolic and cellular abnormalities including endothelial dysfunction that increase the risk of vascular disease. Although it has been particularly challenging to study the genetic determinants that predispose to abnormal function of the endothelium in insulin-resistant states, the possibility of deriving endothelial cells from induced pluripotent stem cells generated from individuals with detailed clinical phenotyping, including accurate measurements of insulin resistance accompanied by multilevel omic data (eg, genetic and genomic characterization), has opened new avenues to study this relationship. Unfortunately, several technical barriers have hampered these efforts. In the present review, we summarize the current status of induced pluripotent stem cell-derived endothelial cells for modeling endothelial dysfunction associated with insulin resistance and discuss the challenges to overcoming these limitations. PMID- 28729367 TI - Dementia research focuses on prevention, as drugs fail to deliver. PMID- 28729368 TI - Increased stroke risk among patients with open-angle glaucoma: a 10-year follow up cohort study. AB - BACKGROUND: Although several studies showed the association between stroke and open-angle glaucoma (OAG), there is still lack of longitudinal studies based on large populations. Therefore, in this study, we investigated the risk of stroke after OAG diagnosis over a 10-year follow-up period. METHODS: We performed a retrospective nationwide propensity score-matched cohort study. OAG and comparison groups were selected from a large database from the Korean National Health Insurance Service, comprising 1 025 340 random subjects. The OAG group comprised patients with an initial diagnosis of OAG between January 2004 and December 2007 (n=1520), and the comparison group comprised randomly selected patients (five per glaucoma patient; n=7570). Each cohort was tracked until 2013 for stroke development. Cox proportional hazard regression analysis was performed to determine possible association RESULTS: OAG was associated with increased stroke incidence (HR=1.20, 95% CI 1.03 to 1.40). Hypertension, diabetes mellitus, chronic renal failure, atrial fibrillation, hyperlipidaemia, increasing age and male gender also increased the incidences of stroke. Risk of stroke for patients with OAG was greater in the older age group (>=65 years, HR=1.23, 95% CI 1.02 to 1.47) than in the younger age group (<65 years, HR=1.12, 95% CI 0.86 to 1.46), and greater in males (HR=1.31, 95% CI 1.06 to 1.60) than in females (HR=1.10, 95% CI 0.88 to 1.38). CONCLUSIONS: Patients who were diagnosed with OAG were more likely to experience subsequent stroke than comparison group without OAG, and the risk was greater for older adults and males. PMID- 28729370 TI - Anterior segment optical coherence tomography angle and vault analysis after toric and non-toric implantable collamer lens V4c implantation in patients with high myopia. AB - OBJECTIVE: To assess anterior segment changes, including iridocorneal angle and vault, after toric and non-toric implantable collamer lens (ICL) V4c (STAAR Surgical AG) implantation under different lighting conditions. METHODS: Longitudinal, prospective, case series. Patients with high myopia (>6 dioptres) underwent toric and non-toric ICL V4c implantation. Optical coherence tomography measurements were taken under different lighting conditions preoperatively and at 1 week and 1, 6 and 12 months of follow-up. RESULTS: Seventy-six eyes of 42 patients underwent ICL V4c implantation. Mean age was 27.4 years (+/-5.14 years, range 20 to 39 years). The average iridocorneal angle showed a statistically significant decrease (p<0.05) in all mesopic, scotopic and photopic conditions after 1 week of surgery compared with the preoperative measurements; in mesopic conditions, it decreased 14.1 degrees , in photopic conditions 14.8 degrees and scotopic conditions 13.2 degrees . The angle measurement had a statistically significant change only in mesopic conditions (p=0.01) over the 1-year follow-up. The average vault under mesopic conditions was 0.661+/-0.21 mm at week 1. The vault measurement change was statistically significant over the 1-year follow-up in mesopic conditions (p=0.01). Refractive results showed a significant improvement in both uncorrected and corrected distance visual acuity (p<0.001). CONCLUSION: There is a significant reduction in the iridocorneal angle after ICL V4c implantation. Furthermore, there is a change under mesopic conditions in both the iridocorneal angle and vault during long-term follow-up. PMID- 28729369 TI - Pigmentary retinopathy, rod-cone dysfunction and sensorineural deafness associated with a rare mitochondrial tRNALys (m.8340G>A) gene variant. AB - BACKGROUND/AIM: The rare mitochondrial DNA (mtDNA) variant m.8340G>A has been previously reported in the literature in a single, sporadic case of mitochondrial myopathy. In this report, we aim to investigate the case of a 39-year-old male patient with sensorineural deafness who presented to the eye clinic with nyctalopia, retinal pigmentary changes and bilateral cortical cataracts. METHODS: The patient was examined clinically and investigated with autofluorescence, full field electroretinography, electro-oculogram and dark adaptometry. Sequencing of the mitochondrial genome in blood and muscle tissue was followed by histochemical and biochemical analyses together with single fibre studies of a muscle biopsy to confirm a mitochondrial aetiology. RESULTS: Electrophysiology, colour testing and dark adaptometry showed significant photoreceptor dysfunction with macular involvement. Sequencing the complete mitochondrial genome revealed a rare mitochondrial tRNALys (MTTK) gene variant-m.8340G>A-which was heteroplasmic in blood (11%) and skeletal muscle (65%) and cosegregated with cytochrome c oxidase deficient fibres in single-fibre studies. CONCLUSION: We confirm the pathogenicity of the rare mitochondrial m.8340G>A variant the basis of single fibre segregation studies and its association with an expanded clinical phenotype. Our case expands the phenotypic spectrum of diseases associated with mitochondrial tRNA point mutations, highlighting the importance of considering a mitochondrial diagnosis in similar cases presenting to the eye clinic and the importance of further genetic testing if standard mutational analysis does not yield a result. PMID- 28729371 TI - Geographic atrophy phenotype identification by cluster analysis. AB - BACKGROUND/AIMS: To identify ocular phenotypes in patients with geographic atrophy secondary to age-related macular degeneration (GA) using a data-driven cluster analysis. METHODS: This was a retrospective analysis of data from a prospective, natural history study of patients with GA who were followed for >=6 months. Cluster analysis was used to identify subgroups within the population based on the presence of several phenotypic features: soft drusen, reticular pseudodrusen (RPD), primary foveal atrophy, increased fundus autofluorescence (FAF), greyish FAF appearance and subfoveal choroidal thickness (SFCT). A comparison of features between the subgroups was conducted, and a qualitative description of the new phenotypes was proposed. The atrophy growth rate between phenotypes was then compared. RESULTS: Data were analysed from 77 eyes of 77 patients with GA. Cluster analysis identified three groups: phenotype 1 was characterised by high soft drusen load, foveal atrophy and slow growth; phenotype 3 showed high RPD load, extrafoveal and greyish FAF appearance and thin SFCT; the characteristics of phenotype 2 were midway between phenotypes 1 and 3. Phenotypes differed in all measured features (p<=0.013), with decreases in the presence of soft drusen, foveal atrophy and SFCT seen from phenotypes 1 to 3 and corresponding increases in high RPD load, high FAF and greyish FAF appearance. Atrophy growth rate differed between phenotypes 1, 2 and 3 (0.63, 1.91 and 1.73 mm2/year, respectively, p=0.0005). CONCLUSION: Cluster analysis identified three distinct phenotypes in GA. One of them showed a particularly slow growth pattern. PMID- 28729372 TI - Intraoperative optical coherence tomography-compatible surgical instruments for real-time image-guided ophthalmic surgery. AB - Intraoperative optical coherence tomography (OCT) is a potentially transformational technology that is now commercially available to ophthalmic surgeons. Currently, the use of the technology is primarily limited to a 'stop and image' approach due to the lack of OCT compatibility with surgical instrumentation. In this report, we describe multiple OCT-compatible surgical instruments that were developed for various surgical needs, based on previous evaluation of potential surgical materials for optical features and physical properties. OCT-compatible instrumentation included two membrane scrapers, a surgical pick and vitreoretinal forceps. Imaging during in vitro and ex vivo simulated surgical procedures demonstrated excellent visualisation of the instrument tip and of the tissue-instrument interaction. These OCT-compatible instruments may be a key component to the feasibility of real-time image-guided surgery with intraoperative OCT. PMID- 28729373 TI - The importance of managing the patient and not the gene: expanded phenotype of GLE1-associated arthrogryposis. AB - GLE1 encodes a protein important for mRNA export and appears to play roles in translation initiation and termination as well. Pathogenic variants in GLE1 mutations have been associated with lethal contracture syndrome and lethal arthrogryposis with anterior horn cell disease; phenotypes reported in individuals include fetal akinesia and a severe form of motor neuron disease, typically presenting with prenatal symptoms and perinatal lethality. In this article, we identified biallelic missense mutations in GLE1 by trio whole-exome sequencing in an individual affected with congenital motor weakness and contractures as well as feeding and respiratory difficulties. Muscle biopsy was consistent with anterior horn cell disease and supported the pathogenicity of the sequence variants. Importantly, this individual survived past the perinatal period with respiratory support and currently demonstrates age-appropriate cognition and slow but steady motor developmental progress. We propose that pathogenic variants in GLE1 can be associated with a nonperinatal lethal motor phenotype, and affected individuals can demonstrate motor skill progression, unlike prototypical anterior horn cell diseases such as spinal muscular atrophy. PMID- 28729374 TI - A patient with a painful and swollen hand. PMID- 28729375 TI - Rainforest-initiated wet season onset over the southern Amazon. AB - Although it is well established that transpiration contributes much of the water for rainfall over Amazonia, it remains unclear whether transpiration helps to drive or merely responds to the seasonal cycle of rainfall. Here, we use multiple independent satellite datasets to show that rainforest transpiration enables an increase of shallow convection that moistens and destabilizes the atmosphere during the initial stages of the dry-to-wet season transition. This shallow convection moisture pump (SCMP) preconditions the atmosphere at the regional scale for a rapid increase in rain-bearing deep convection, which in turn drives moisture convergence and wet season onset 2-3 mo before the arrival of the Intertropical Convergence Zone (ITCZ). Aerosols produced by late dry season biomass burning may alter the efficiency of the SCMP. Our results highlight the mechanisms by which interactions among land surface processes, atmospheric convection, and biomass burning may alter the timing of wet season onset and provide a mechanistic framework for understanding how deforestation extends the dry season and enhances regional vulnerability to drought. PMID- 28729376 TI - Long-term peritoneal port-catheter in a patient with cardiac ascites. AB - A peritoneal port-catheter was inserted in a 70-year-old man because of repeated paracentesis due to cardiac ascites. Instead of frequent hospital admissions, the patient could drain his ascites at home, which dramatically improved his quality of life and enabled him to perform his daily activities. PMID- 28729377 TI - Abundant dystrophic calcifications mimicking aortic valve abscess in a patient undergoing elective aortic valve replacement. AB - Dystrophic calcifications of the aortic valve may cause symptomatic aortic stenosis and account for a significant portion of patients who undergo elective valve replacement. Calcifications appearing grossly as a cloudy fluid surrounding the aortic valve leaflets are an uncommon finding. Normally, calcified aortic valves are characterised by large, nodular masses within the aortic cusps. We report a case of dystrophic calcifications on a stenotic aortic valve encountered intraoperatively, which was suggestive of infective endocarditis and abscess formation. Aortic valve leaflets and necrotic-appearing thymic lymph node tissue were submitted for histology and special stains. Cultures were negative and histology did not show evidence of infection. Tissue histology demonstrated extensive dystrophic calcifications, which were polarised to reveal abundant calcium oxalate crystals. The benign nature of this unique pathological finding ruled out any suspicion of infection, avoiding a prolonged course of intravenous antibiotics in this patient. PMID- 28729378 TI - Very early great saphenous vein graft aneurysm treated by percutaneous coronary intervention under ChromaFlo imaging guidance. AB - A 73-year-old man, who had undergone coronary artery bypass grafting (CABG) 10 days prior, presented with a great saphenous vein graft aneurysm (SVGA). CT revealed the increasing size of the aneurysm. Since the SVGA occurred immediately after CABG and there were no other complications, the aneurysm was treated percutaneously. While intravascular ultrasonography (IVUS) and optical coherence tomography failed to detect the entry point, an IVUS catheter with the addition of ChromaFlo imaging clearly revealed the entry point, size and length of the SVGA. To prevent migration and edge restenosis associated with covered stents, the covered stent (3.0*19 mm) was superimposed on a drug-eluting stent (3.0*28 mm) that covered the entry site. A follow-up study demonstrated the absence of flow into the aneurysm. PMID- 28729379 TI - Functioning metastatic paraganglioma of the urinary bladder in a 10-year-old child. AB - Paragangliomas of the urinary bladder are very rare tumours representing less than 1% of bladder tumours. Preoperative diagnosis is essential to avoid perioperative complications related to catecholamine release. A high index of suspicion should be maintained when the classical symptoms of voiding-related paroxysms of headache, palpitation and dizziness are present. We present a rare case of malignant paraganglioma of the urinary bladder in a 10-year-old boy. The patient had the classic presentation. We review the radiological diagnostic tools and findings of this rare entity. PMID- 28729380 TI - Arthroscopic excision of an intra-articular osteoid osteoma in the elbow joint. AB - An osteoid osteoma is a rare, small, benign and painful tumour occurring in the extra-articular portion of long bones seen most commonly in the lower extremities. This is a case report of a 23-year-old female patient who underwent arthroscopic resection of an intra-articular osteoid osteoma. The nidus was completely removed by arthroscopic excision. The diagnosis was confirmed by postoperative histopathological analysis. In the case presented we have shown that intra-articular arthroscopy can be successful in the surgical management of benign bony lesions involving the elbow joint. We also present a review of the literature which reports on similar cases or intra-articular disease, preferred methods of surgical management and limitations in histopathological specimen acquisition for diagnosis. PMID- 28729381 TI - Reconfiguring Health Care Delivery to Improve AKI Outcomes. PMID- 28729382 TI - Recommended Clinical Trial End Points for Dialysis Catheters. AB - Central venous catheters are used frequently in patients on hemodialysis as a bridge to a permanent vascular access. They are prone to frequent complications, including catheter-related bloodstream infection, catheter dysfunction, and central vein obstruction. There is a compelling need to develop new drugs or devices to prevent central venous catheter complications. We convened a multidisciplinary panel of experts to propose standardized definitions of catheter end points to guide the design of future clinical trials seeking approval from the Food and Drug Administration. Our workgroup suggests diagnosing catheter-related bloodstream infection in catheter-dependent patients on hemodialysis with a clinical suspicion of infection (fever, rigors, altered mental status, or unexplained hypotension), blood cultures growing the same organism from the catheter hub and a peripheral vein (or the dialysis bloodline), and absence of evidence for an alternative source of infection. Catheter dysfunction is defined as the inability of a central venous catheter to (1) complete a single dialysis session without triggering recurrent pressure alarms or (2) reproducibly deliver a mean dialysis blood flow of >300 ml/min (with arterial and venous pressures being within the hemodialysis unit parameters) on two consecutive dialysis sessions or provide a Kt/V>=1.2 in 4 hours or less. Catheter dysfunction is defined only if it persists, despite attempts to reposition the patient, reverse the arterial and venous lines, or forcefully flush the catheter. Central vein obstruction is suspected in patients with >70% stenosis of a central vein by contrast venography or the equivalent, ipsilateral upper extremity edema, and an existing or prior history of a central venous catheter. There is some uncertainty about the specific criteria for these diagnoses, and the workgroup has also proposed future high-priority studies to resolve these questions. PMID- 28729384 TI - Characteristics and Outcomes of Patients Discharged Home from an Emergency Department with AKI. AB - BACKGROUND AND OBJECTIVES: Patients discharged home from an emergency department with AKI are not well described. This study describes their characteristics and outcomes and compares these outcomes to two referent groups. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted a population-based retrospective cohort study in Ontario, Canada from 2003 to 2012 of 6346 patients aged >=40 years who were discharged from the emergency department with AKI (defined using serum creatinine values). We analyzed the risk of all-cause mortality, receipt of acute dialysis, and hospitalization within 30 days after discharge. We used propensity score methods to compare all-cause mortality to two referent groups. We matched 4379 discharged patients to 4379 patients who were hospitalized from the emergency department with similar AKI stage. We also matched 6188 discharged patients to 6188 patients who were discharged home from the emergency department with no AKI. RESULTS: There were 6346 emergency department discharges with AKI. The mean age was 69 years and 6012 (95%) had stage 1, 290 (5%) had stage 2, and 44 (0.7%) had stage 3 AKI. Within 30 days, 149 (2%) (AKI stage 1: 127 [2%]; stage 2: 15 [5%]; stage 3: seven [16%]) died, 22 (0.3%) received acute dialysis, and 1032 (16%) were hospitalized. An emergency department discharge versus hospitalization with AKI was associated with lower mortality (3% versus 12%; relative risk, 0.3; 95% confidence interval, 0.2 to 0.3). An emergency department discharge with AKI versus no AKI was associated with higher mortality (2% versus 1%; relative risk, 1.6; 95% confidence interval, 1.2 to 2.0). CONCLUSIONS: Patients discharged home from the emergency department with AKI are at risk of poor 30-day outcomes. A better understanding of care in this at-risk population is warranted, as are testing strategies to improve care. PMID- 28729383 TI - Definitions and End Points for Interventional Studies for Arteriovenous Dialysis Access. AB - This paper is part of the Clinical Trial Endpoints for Dialysis Vascular Access Project of the American Society of Nephrology Kidney Health Initiative. The purpose of this project is to promote research in vascular access by clarifying trial end points which would be best suited to inform decisions in those situations in which supportive clinical data are required. The focus of a portion of the project is directed toward arteriovenous access. There is a potential for interventional studies to be directed toward any of the events that may be associated with an arteriovenous access' evolution throughout its life cycle, which has been divided into five distinct phases. Each one of these has the potential for relatively unique problems. The first three of these correspond to three distinct stages of arteriovenous access development, each one of which has been characterized by objective direct and/or indirect criteria. These are characterized as: stage 1-patent arteriovenous access, stage 2-physiologically mature arteriovenous access, and stage 3-clinically functional arteriovenous access. Once the requirements of a stage 3-clinically functional arteriovenous access have been met, the fourth phase of its life cycle begins. This is the phase of sustained clinical use from which the arteriovenous access may move back and forth between it and the fifth phase, dysfunction. From this phase of its life cycle, the arteriovenous access requires a maintenance procedure to preserve or restore sustained clinical use. Using these definitions, clinical trial end points appropriate to the various phases that characterize the evolution of the arteriovenous access life cycle have been identified. It is anticipated that by using these definitions and potential end points, clinical trials can be designed that more closely correlate with the goals of the intervention and provide appropriate supportive data for clinical, regulatory, and coverage decisions. PMID- 28729385 TI - pyQms enables universal and accurate quantification of mass spectrometry data. AB - Quantitative mass spectrometry (MS) is a key technique in many research areas (1), including proteomics, metabolomics, glycomics, and lipidomics. Because all of the corresponding molecules can be described by chemical formulas, universal quantification tools are highly desirable. Here, we present pyQms, an open-source software for accurate quantification of all types of molecules measurable by MS. pyQms uses isotope pattern matching that offers an accurate quality assessment of all quantifications and the ability to directly incorporate mass spectrometer accuracy. pyQms is, due to its universal design, applicable to every research field, labeling strategy, and acquisition technique. This opens ultimate flexibility for researchers to design experiments employing innovative and hitherto unexplored labeling strategies. Importantly, pyQms performs very well to accurately quantify partially labeled proteomes in large scale and high throughput, the most challenging task for a quantification algorithm. PMID- 28729387 TI - Leg blood flow is impaired during small muscle mass exercise in patients with COPD. AB - Skeletal muscle blood flow is regulated to match the oxygen demand and dysregulation could contribute to exercise intolerance in patients with chronic obstructive pulmonary disease (COPD). We measured leg hemodynamics and metabolites from vasoactive compounds in muscle interstitial fluid and plasma at rest, during one-legged knee-extensor exercise, and during arterial infusions of sodium nitroprusside (SNP) and acetylcholine (ACh), respectively. Ten patients with moderate to severe COPD and eight age- and sex-matched healthy controls were studied. During knee-extensor exercise (10 W), leg blood flow was lower in the patients compared with the controls (1.82 +/- 0.11 vs. 2.36 +/- 0.14 l/min, respectively; P < 0.05), which compromised leg oxygen delivery (372 +/- 26 vs. 453 +/- 32 ml O2/min, respectively; P < 0.05). At rest, plasma endothelin-1 (vasoconstrictor) was higher in the patients with COPD (P < 0.05) and also tended to be higher during exercise (P = 0.07), whereas the formation of interstitial prostacyclin (vasodilator) was only increased in the controls. There was no difference between groups in the nitrite/nitrate levels (vasodilator) in plasma or interstitial fluid during exercise. Moreover, patients and controls showed similar vasodilatory capacity in response to both endothelium-independent (SNP) and endothelium-dependent (ACh) stimulation. The results suggest that leg muscle blood flow is impaired during small muscle mass exercise in patients with COPD possibly due to impaired formation of prostacyclin and increased levels of endothelin-1.NEW & NOTEWORTHY This study demonstrates that chronic obstructive pulmonary disease (COPD) is associated with a reduced blood flow to skeletal muscle during small muscle mass exercise. In contrast to healthy individuals, interstitial prostacyclin levels did not increase during exercise and plasma endothelin-1 levels were higher in the patients with COPD. PMID- 28729388 TI - Effects of acute hypoxia on human cognitive processing: a study using ERPs and SEPs. AB - Although hypoxia has the potential to impair the cognitive function, the effects of acute hypoxia on the high-order brain function (executive and/or inhibitory processing) and somatosensory ascending processing remain unknown. We tested the hypothesis that acute hypoxia impairs both motor executive and inhibitory processing and somatosensory ascending processing. Fifteen healthy subjects performed two sessions (sessions 1 and 2), consisting of electroencephalographic event-related potentials with somatosensory Go/No-go paradigms and somatosensory evoked potentials (SEPs) under two conditions (hypoxia and normoxia) on different days. On 1 day, participants breathed room air in the first and second sessions of the experiment; on the other day, participants breathed room air in the first session, and 12% O2 in the second session. Acute hypoxia reduced the peak amplitudes of Go-P300 and No-go-P300, and delayed the peak latency of Go-P300. However, no significant differences were observed in the peak amplitude or latency of N140, behavioral data, or the amplitudes and latencies of individual SEP components between the two conditions. These results suggest that acute hypoxia impaired neural activity in motor executive and inhibitory processing, and delayed higher cognitive processing for motor execution, whereas neural activity in somatosensory processing was not affected by acute hypoxia.NEW & NOTEWORTHY Hypoxia has the potential to impair the cognitive function, but the effects of acute hypoxia on the cognitive function remain debatable. We investigated the effects of acute hypoxia on human cognitive processing using electroencephalographic event-related potentials and somatosensory-evoked potentials. Acute normobaric hypoxia impaired neural activity in motor executive and inhibitory processing, but no significant differences were observed in neural activity in somatosensory processing. PMID- 28729386 TI - Dormancy in Embryos: Insight from Hydrated Encysted Embryos of an Aquatic Invertebrate. AB - Numerous aquatic invertebrates remain dormant for decades in a hydrated state as encysted embryos. In search for functional pathways associated with this form of dormancy, we used label-free quantitative proteomics to compare the proteomes of hydrated encysted dormant embryos (resting eggs; RE) with nondormant embryos (amictic eggs; AM) of the rotifer Brachionus plicatilisA total of 2631 proteins were identified in rotifer eggs. About 62% proteins showed higher abundance in AM relative to RE (Fold Change>3; p = 0.05). Proteins belonging to numerous putative functional pathways showed dramatic changes during dormancy. Most striking were changes in the mitochondria indicating an impeded metabolism. A comparison between the abundance of proteins and their corresponding transcript levels, revealed higher concordance for RE than for AM. Surprisingly, numerous highly abundant dormancy related proteins show corresponding high mRNA levels in metabolically inactive RE. As these mRNAs and proteins degrade at the time of exit from dormancy they may serve as a source of nucleotides and amino acids during the exit from dormancy. Because proteome analyses point to a similarity in functional pathways of hydrated RE and desiccated life forms, REs were dried. Similar hatching and reproductive rates were found for wet and dried REs, suggesting analogous pathways for long-term survival in wet or dry forms. Analysis by KEGG pathways revealed a few general strategies for dormancy, proposing an explanation for the low transcriptional similarity among dormancies across species, despite the resemblance in physiological phenotypes. PMID- 28729389 TI - Severe energy deficit upregulates leptin receptors, leptin signaling, and PTP1B in human skeletal muscle. AB - In obesity, leptin receptors (OBR) and leptin signaling in skeletal muscle are downregulated. To determine whether OBR and leptin signaling are upregulated with a severe energy deficit, 15 overweight men were assessed before the intervention (PRE), after 4 days of caloric restriction (3.2 kcal.kg body wt-1.day-1) in combination with prolonged exercise (CRE; 8 h walking + 45 min single-arm cranking/day) to induce an energy deficit of ~5,500 kcal/day, and following 3 days of control diet (isoenergetic) and reduced exercise (CD). During CRE, the diet consisted solely of whey protein (n = 8) or sucrose (n = 7; 0.8 g.kg body wt 1.day-1). Muscle biopsies were obtained from the exercised and the nonexercised deltoid muscles and from the vastus lateralis. From PRE to CRE, serum glucose, insulin, and leptin were reduced. OBR expression was augmented in all examined muscles associated with increased maximal fat oxidation. Compared with PRE, after CD, phospho-Tyr1141OBR, phospho-Tyr985OBR, JAK2, and phospho-Tyr1007/1008JAK2 protein expression were increased in all muscles, whereas STAT3 and phospho Tyr705STAT3 were increased only in the arms. The expression of protein tyrosine phosphatase 1B (PTP1B) in skeletal muscle was increased by 18 and 45% after CRE and CD, respectively (P < 0.05). Suppressor of cytokine signaling 3 (SOCS3) tended to increase in the legs and decrease in the arm muscles (ANOVA interaction: P < 0.05). Myosin heavy chain I isoform was associated with OBR protein expression (r = -0.75), phospho-Tyr985OBR (r = 0.88), and phospho Tyr705STAT3/STAT3 (r = 0.74). In summary, despite increased PTP1B expression, skeletal muscle OBR and signaling are upregulated by a severe energy deficit with greater response in the arm than in the legs likely due to SOCS3 upregulation in the leg muscles.NEW & NOTEWORTHY This study shows that the skeletal muscle leptin receptors and their corresponding signaling cascade are upregulated in response to a severe energy deficit, contributing to increase maximal fat oxidation. The responses are more prominent in the arm muscles than in the legs but partly blunted by whey protein ingestion and high volume of exercise. This occurs despite an increase of protein tyrosine phosphatase 1B protein expression, a known inhibitor of insulin and leptin signaling. PMID- 28729390 TI - Walking economy is predictably determined by speed, grade, and gravitational load. AB - The metabolic energy that human walking requires can vary by more than 10-fold, depending on the speed, surface gradient, and load carried. Although the mechanical factors determining economy are generally considered to be numerous and complex, we tested a minimum mechanics hypothesis that only three variables are needed for broad, accurate prediction: speed, surface grade, and total gravitational load. We first measured steady-state rates of oxygen uptake in 20 healthy adult subjects during unloaded treadmill trials from 0.4 to 1.6 m/s on six gradients: -6, -3, 0, 3, 6, and 9 degrees . Next, we tested a second set of 20 subjects under three torso-loading conditions (no-load, +18, and +31% body weight) at speeds from 0.6 to 1.4 m/s on the same six gradients. Metabolic rates spanned a 14-fold range from supine rest to the greatest single-trial walking mean (3.1 +/- 0.1 to 43.3 +/- 0.5 ml O2.kg-body-1.min-1, respectively). As theorized, the walking portion (Vo2-walk = Vo2-gross - Vo2-supine-rest) of the body's gross metabolic rate increased in direct proportion to load and largely in accordance with support force requirements across both speed and grade. Consequently, a single minimum-mechanics equation was derived from the data of 10 unloaded-condition subjects to predict the pooled mass-specific economy (Vo2 gross, ml O2.kg-body + load-1.min-1) of all the remaining loaded and unloaded trials combined (n = 1,412 trials from 90 speed/grade/load conditions). The accuracy of prediction achieved (r2 = 0.99, SEE = 1.06 ml O2.kg-1.min-1) leads us to conclude that human walking economy is predictably determined by the minimum mechanical requirements present across a broad range of conditions.NEW & NOTEWORTHY Introduced is a "minimum mechanics" model that predicts human walking economy across a broad range of conditions from only three variables: speed, surface grade, and body-plus-load mass. The derivation/validation data set includes steady-state loaded and unloaded walking trials (n = 3,414) that span a fourfold range of walking speeds on each of six different surface gradients (-6 to +9 degrees ). The accuracy of our minimum mechanics model (r2 = 0.99; SEE = 1.06 ml O2.kg-1.min-1) appreciably exceeds that of currently used standards. PMID- 28729392 TI - The double-edged sword of intermittent hypoxia-can intermittent hypoxia be both deleterious and protective in OSA? Focus on "Frequency and magnitude of intermittent hypoxia modulate endothelial wound healing in a cell culture model of sleep apnea". PMID- 28729391 TI - Edward F. Adolph Distinguished Lecture: Skin-deep insights into vascular aging. AB - The skin is an accessible model circulation for studying vascular function and dysfunction across the lifespan. Age-related changes, as well as those associated with disease progression, often appear first in the cutaneous circulation. Furthermore, impaired vascular signaling and attendant endothelial dysfunction, the earliest indicators of cardiovascular pathogenesis, occur in a similar fashion across multiple tissue beds throughout the body, including the skin. Because microvascular dysfunction is a better predictor of long-term outcomes and adverse cardiovascular events than is large vessel disease, an understanding of age-associated changes in the control of the human cutaneous microcirculation is important. This review focuses on 1) the merits of using skin-specific methods and techniques to study vascular function, 2) microvascular changes in aged skin (in particular, the role of the endothelial-derived dilator nitric oxide), and 3) the impact of aging on heat-induced changes in skin vasodilation. While skin blood flow is controlled by multiple, often redundant, mechanisms, our laboratory has used a variety of distinct thermal provocations of this model circulation to isolate specific age-associated changes in vascular function. Skin-specific approaches and techniques, such as intradermal microdialysis coupled with laser Doppler flowmetry (in vivo) and biochemical analyses of skin biopsy samples (in vitro), have allowed for the targeted pharmacodissection of the mechanistic pathways controlling skin vasoreactivity and study of the impact of aging and disease states. Aged skin has an attenuated ability to vasodilate in response to warm stimuli and to vasoconstrict in response to cold stimuli. PMID- 28729394 TI - Body fat of rats of different age groups and nutritional states: assessment by micro-CT and skinfold thickness. AB - Obesity presents a growing public health problem. Therefore the analysis of body composition is important in clinical practice as well as in animal research models of obesity; hence precise methods for the assessment of body fat would be essential. We aimed to evaluate in vivo abdominal microcomputed tomography scan restricted to the L1-L3 region [micro-CT(L1-L3)], a skinfold thickness-based method (STM), and postmortem body composition analysis (PMA) with regard to whole body micro-CT scan in rats. Male Wistar rats of different age groups (from 3 to 24 mo) and nutritional states (normally fed, high-fat diet-induced obese, and calorie-restricted) were used. The fat percentage was determined with micro-CT(L1 L3) and whole body scan in anesthetized rats. Their skinfold thickness was measured in five locations with a Lange caliper. Wet weights of epididymal and retroperitoneal fat pads were determined via PMA. With regard to fat mass, the strongest correlation was observed between abdominal and whole body micro-CT. The other methods showed weaker associations with whole body micro-CT and with each other. Micro-CT(L1-L3) and PMA showed similar age-associated increase in fat mass between 3 and 18 mo. Micro-CT(L1-L3), STM, and PMA were efficient to detect differences in fat mass values in groups of different nutritional states. Micro CT(L1-L3) appears to be a useful method for body fat assessment in rats with reduced scanning time. In rats, STM may also be a useful, low priced, noninvasive, and simple in vivo technique to assess obesity. NEW & NOTEWORTHY Body fat of rats assessed by in vivo abdominal microcomputed tomography of the L1 L3 region strongly correlates with values determined by whole body scan. Therefore, it is a useful method for fat assessment with reduced scanning time. Skinfold thickness measurement is an in vivo technique to assess progression of obesity in rats. PMID- 28729393 TI - Time-course effects of aerobic physical training in the prevention of cigarette smoke-induced COPD. AB - A previous study by our group showed that regular exercise training (ET) attenuated pulmonary injury in an experimental model of chronic exposure to cigarette smoke (CS) in mice, but the time-course effects of the mechanisms involved in this protection remain poorly understood. We evaluated the temporal effects of regular ET in an experimental model of chronic CS exposure. Male C57BL/6 mice were divided into four groups: Control (sedentary + air), Exercise (aerobic training + air), Smoke (sedentary + smoke), and Smoke + Exercise (aerobic training + smoke). Mice were exposed to CS and ET for 4, 8, or 12 wk. Exercise protected mice exposed to CS from emphysema and reductions in tissue damping and tissue elastance after 12 wk (P < 0.01). The total number of inflammatory cells in the bronchoalveolar lavage increased in the Smoke group, mainly due to the recruitment of macrophages after 4 wk, neutrophils and lymphocytes after 8 wk, and lymphocytes and macrophages after 12 wk (P < 0.01). Exercise attenuated this increase in mice exposed to CS. The protection conferred by exercise was mainly observed after exercise adaptation. Exercise increased IL 6 and IL-10 in the quadriceps and lungs (P < 0.05) after 12 wk. Total antioxidant capacity and SOD was increased and TNF-alpha and oxidants decreased in lungs of mice exposed to CS after 12 wk (P < 0.05). The protective effects of exercise against lung injury induced by cigarette smoke exposure suggests that anti inflammatory mediators and antioxidant enzymes play important roles in chronic obstructive pulmonary disease development mainly after the exercise adaptation.NEW & NOTEWORTHY These experiments investigated for the first time the temporal effects of regular moderate exercise training in cigarette smoke-induced chronic obstructive pulmonary disease. We demonstrate that aerobic conditioning had a protective effect in emphysema development induced by cigarette smoke exposure. This effect was most likely secondary to an effect of exercise on oxidant-antioxidant balance and anti-inflammatory mediators. PMID- 28729395 TI - Relationship between exercise volume and muscle protein synthesis in a rat model of resistance exercise. AB - Resistance exercise (RE) volume is recognized as an important factor that stimulates muscle protein synthesis (MPS) and is considered, at least in part, to be involved in the mammalian target of rapamycin complex 1 (mTORC1)-associated signaling. However, the effects of relatively high-volume RE on mTORC1 and MPS remain unclear. In the present study, we used an animal model of RE to investigate the relationship between RE volume and MPS. Male Sprague-Dawley rats were subjected to RE, and muscle samples were obtained 6 h after performing 1, 3, 5, 10, or 20 sets of RE. Although 1 set of RE did not increase MPS [measured by the surface sensing of translation (SUnSET) method], multiple sets (3, 5, 10, and 20 sets) significantly increased MPS. However, the increase in MPS reached a plateau after 3 or 5 sets of RE, and no further increase in MPS was observed with additional RE sets. In contrast to the MPS response, we observed that p70S6K phosphorylation at Thr389, a marker of mTORC1 activity, and Ser240/244 phosphorylation of rpS6, a downstream target of p70S6K, gradually increased with higher RE volume. The above results suggest that the relationship between RE volume and MPS was not linear. Thus the increase in MPS with increasing RE volume saturates before p70S6K phosphorylation, suggesting a threshold effect for the relationship between p70S6K activation and MPS.NEW & NOTEWORTHY The aim of this study was to investigate the relationship between resistance exercise (RE) volume and muscle protein synthesis. We found that the relationship between RE volume and p70S6K phosphorylation was almost linear, but the increase in muscle protein synthesis began to plateau after approximately five sets of RE. PMID- 28729396 TI - Acute volume loading exacerbates direct ventricular interaction in a model of COPD. AB - Volume loading increases left ventricular (LV) stroke volume (LVSV) through series interaction, but may paradoxically reduce LVSV in the presence of large increases in right ventricular (RV) afterload because of direct ventricular interaction (DVI). RV afterload is often increased in chronic obstructive pulmonary disease (COPD) as a result of pathological changes to respiratory mechanics, namely increased negative intrathoracic pressure (nITP), dynamic lung hyperinflation (DH), and increased pulmonary vascular resistance (PVR). These hallmarks of COPD negatively impact LV hemodynamics in normovolemia. However, it is unknown how these heart-lung interactions are impacted by acute volume loading. Twenty healthy subjects (23 +/- 2 yr) completed the study protocol, involving acute volume loading via 20 degrees head-down tilt (HDT) in isolation and with 1) inspiratory resistance of -20 cmH2O (HDT+nITP) and 2) nITP, expiratory resistance to induce DH and hypoxic-mediated increases in PVR (HDT+COPD model). LV volumes and geometry were assessed using triplane echocardiography. HDT significantly increased LVSV by 10 +/- 10% through an 8 +/- 6% increase in LV end-diastolic volume (LVEDV). HDT+nITP paradoxically decreased LVSV by 11 +/- 12% and LVEDV by 6 +/- 9% from supine baseline, or -14 +/- 10% LVSV and -15 +/- 13% LVEDV from HDT (P < 0.001). HDT+COPD model decreased LVSV (21 +/- 10% and 28 +/- 11%) and LVEDV (16 +/- 10% and 22 +/- 10%) from both supine and HDT, respectively (P < 0.001). Under all conditions, significant septal flattening (increased radius of septal curvature) occurred, indicating DVI. Thus, when RV afterload is increased and/or an external constraint to ventricular filling exists, acute volume loading appears to paradoxically reduce LVSV. These findings have important implications for understanding how volume status impacts cardiopulmonary interactions in COPD.NEW & NOTEWORTHY Volume loading may exacerbate adverse cardiopulmonary interaction in COPD; however, the mechanisms remain unclear. We found that when negative intrathoracic pressure is increased, acute volume loading paradoxically reduces stroke volume. This reduction in stroke volume is considerably greater in a model of COPD, owing to the effects of lung hyperinflation. PMID- 28729397 TI - The IGF1R/INSR Inhibitor BI 885578 Selectively Inhibits Growth of IGF2 Overexpressing Colorectal Cancer Tumors and Potentiates the Efficacy of Anti-VEGF Therapy. AB - Clinical studies of pharmacologic agents targeting the insulin-like growth factor (IGF) pathway in unselected cancer patients have so far demonstrated modest efficacy outcomes, with objective responses being rare. As such, the identification of selection biomarkers for enrichment of potential responders represents a high priority for future trials of these agents. Several reports have described high IGF2 expression in a subset of colorectal cancers, with focal IGF2 amplification being responsible for some of these cases. We defined a novel cut-off value for IGF2 overexpression based on differential expression between colorectal tumors and normal tissue samples. Analysis of two independent colorectal cancer datasets revealed IGF2 to be overexpressed at a frequency of 13% to 22%. An in vitro screen of 34 colorectal cancer cell lines revealed IGF2 expression to significantly correlate with sensitivity to the IGF1R/INSR inhibitor BI 885578. Furthermore, autocrine IGF2 constitutively activated IGF1R and Akt phosphorylation, which was inhibited by BI 885578 treatment. BI 885578 significantly delayed the growth of IGF2-high colorectal cancer xenograft tumors in mice, while combination with a VEGF-A antibody increased efficacy and induced tumor regression. Besides colorectal cancer, IGF2 overexpression was detected in more than 10% of bladder carcinoma, hepatocellular carcinoma and non-small cell lung cancer patient samples. Meanwhile, IGF2-high non-colorectal cancer cells lines displayed constitutive IGF1R phosphorylation and were sensitive to BI 885578. Our findings suggest that IGF2 may represent an attractive patient selection biomarker for IGF pathway inhibitors and that combination with VEGF targeting agents may further improve clinical outcomes. Mol Cancer Ther; 16(10); 2223-33. (c)2017 AACR. PMID- 28729398 TI - Quercetin Targets hnRNPA1 to Overcome Enzalutamide Resistance in Prostate Cancer Cells. AB - Prostate cancer remains dependent on androgen receptor signaling even after castration. Aberrant androgen receptor signaling in castration-resistant prostate cancer is mediated by mechanisms such as alterations in the androgen receptor and activation of interacting signaling pathways. Clinical evidence confirms that resistance to the next-generation antiandrogen, enzalutamide, may be mediated to a large extent by alternative splicing of the androgen receptor to generate constitutively active splice variants such as AR-V7. The splice variants AR-V7 and ARv567es have been implicated in the resistance to not only enzalutamide, but also to abiraterone and other conventional therapeutics such as taxanes. Numerous studies, including ours, suggest that splicing factors such as hnRNPA1 promote the generation of AR-V7, thus contributing to enzalutamide resistance in prostate cancer cells. In the present study, we discovered that quercetin, a naturally occurring polyphenolic compound, reduces the expression of hnRNPA1, and consequently, that of AR-V7. The suppression of AR-V7 by quercetin resensitizes enzalutamide-resistant prostate cancer cells to treatment with enzalutamide. Our results indicate that quercetin downregulates hnRNPA1 expression, downregulates the expression of AR-V7, antagonizes androgen receptor signaling, and resensitizes enzalutamide-resistant prostate cancer cells to enzalutamide treatment in vivo in mouse xenografts. These findings demonstrate that suppressing the alternative splicing of the androgen receptor may have important implications in overcoming the resistance to next-generation antiandrogen therapy. Mol Cancer Ther; 16(12); 2770-9. (c)2017 AACR. PMID- 28729399 TI - Decitabine Priming Enhances Mucin 1 Inhibition Mediated Disruption of Redox Homeostasis in Cutaneous T-Cell Lymphoma. AB - Cutaneous T-cell lymphoma (CTCL) is a heterogeneous neoplasm and patients with relapsed/refractory disease exhibit resistance to standard therapies. We have previously demonstrated that the Mucin 1 C-terminal subunit (MUC1-C) plays a critical role in protection from oxidative stress in CTCL cells. Targeting of MUC1-C with a pharmacologic inhibitor, GO-203, was associated with apoptosis in CTCL. However, disease responses were incomplete underscoring the need for combinatorial strategies that could exploit the vulnerability of CTCL cells to oxidative signals. Cell lines, primary samples, and xenograft models of CTCL were used to assess synergy of GO-203 with decitabine, a hypomethylating agent. Present studies demonstrate that exposure of CTCL cells to decitabine in combination with GO-203, increased the generation of reactive oxygen species (ROS) levels and decreased levels of scavenger molecules, NADP, NADPH, glutathione, and TIGAR, critical to intracellular redox homeostasis. Dual exposure to GO-203 and decitabine resulted in marked downregulation of DNA methyl transferases demonstrating significant synergy of these agents in inducing global and gene specific hypomethylation. Accordingly, treatment with decitabine and GO 203 upregulated the ROS generating enzymes, NADPH oxidase 4 and dual oxidase 2 potentially due to their effect on epigenomic regulation of these proteins. In concert with these findings, exposure to decitabine and GO-203 resulted in heightened apoptotic death in CTCL cell lines, patient-derived primary samples and in a murine xenograft model. These findings indicate that decitabine intensifies MUC1-C inhibition induced redox imbalance and provides a novel combination of targeted and epigenetic agents for patients with CTCL. Mol Cancer Ther; 16(10); 2304-14. (c)2017 AACR. PMID- 28729402 TI - Wilms Tumor NCAM-Expressing Cancer Stem Cells as Potential Therapeutic Target for Polymeric Nanomedicine. AB - Cancer stem cells (CSC) form a specific population within the tumor that has been shown to have self-renewal and differentiation properties, increased ability to migrate and form metastases, and increased resistance to chemotherapy. Consequently, even a small number of cells remaining after therapy can repopulate the tumor and cause recurrence of the disease. CSCs in Wilms tumor, a pediatric renal cancer, were previously shown to be characterized by neural cell adhesion molecule (NCAM) expression. Therefore, NCAM provides a specific biomarker through which the CSC population in this tumor can be targeted. We have recently developed an NCAM-targeted nanosized conjugate of paclitaxel bound to a biodegradable polyglutamic acid polymer. In this work, we examined the ability of the conjugate to inhibit Wilms tumor by targeting the NCAM-expressing CSCs. Results show that the conjugate selectively depleted the CSC population of the tumors and effectively inhibited tumor growth without causing toxicity. We propose that the NCAM-targeted conjugate could be an effective therapeutic for Wilms tumor. Mol Cancer Ther; 16(11); 2462-72. (c)2017 AACR. PMID- 28729401 TI - JAK1/STAT3 Activation through a Proinflammatory Cytokine Pathway Leads to Resistance to Molecularly Targeted Therapy in Non-Small Cell Lung Cancer. AB - Molecularly targeted drugs have yielded significant therapeutic advances in oncogene-driven non-small cell lung cancer (NSCLC), but a majority of patients eventually develop acquired resistance. Recently, the relation between proinflammatory cytokine IL6 and resistance to targeted drugs has been reported. We investigated the functional contribution of IL6 and the other members of IL6 family proinflammatory cytokine pathway to resistance to targeted drugs in NSCLC cells. In addition, we examined the production of these cytokines by cancer cells and cancer-associated fibroblasts (CAF). We also analyzed the prognostic significance of these molecule expressions in clinical NSCLC samples. In NSCLC cells with acquired resistance to targeted drugs, we observed activation of the IL6-cytokine pathway and STAT3 along with epithelial-to-mesenchymal transition (EMT) features. In particular, IL6 family cytokine oncostatin-M (OSM) induced a switch to the EMT phenotype and protected cells from targeted drug-induced apoptosis in OSM receptors (OSMRs)/JAK1/STAT3-dependent manner. The cross-talk between NSCLC cells and CAFs also preferentially activated the OSM/STAT3 pathway via a paracrine mechanism and decreased sensitivity to targeted drugs. The selective JAK1 inhibitor filgotinib effectively suppressed STAT3 activation and OSMR expression, and cotargeting inhibition of the oncogenic pathway and JAK1 reversed resistance to targeted drugs. In the analysis of clinical samples, OSMR gene expression appeared to be associated with worse prognosis in patients with surgically resected lung adenocarcinoma. Our data suggest that the OSMRs/JAK1/STAT3 axis contributes to resistance to targeted drugs in oncogene driven NSCLC cells, implying that this pathway could be a therapeutic target. Mol Cancer Ther; 16(10); 2234-45. (c)2017 AACR. PMID- 28729400 TI - Vessel-Targeted Chemophototherapy with Cationic Porphyrin-Phospholipid Liposomes. AB - Cationic liposomes have been used for targeted drug delivery to tumor blood vessels, via mechanisms that are not fully elucidated. Doxorubicin (Dox)-loaded liposomes were prepared that incorporate a cationic lipid; 1,2-dioleoyl-3 trimethylammonium-propane (DOTAP), along with a small amount of porphyrin phospholipid (PoP). Near-infrared (NIR) light caused release of entrapped Dox via PoP-mediated DOTAP photo-oxidation. The formulation was optimized to enable extremely rapid NIR light-triggered Dox release (i.e., in 15 seconds), while retaining reasonable serum stability. In vitro, cationic PoP liposomes readily bound to both MIA PaCa-2 human pancreatic cancer cells and human vascular endothelial cells. When administered intravenously, cationic PoP liposomes were cleared from circulation within minutes, with most accumulation in the liver and spleen. Fluorescence imaging revealed that some cationic PoP liposomes also localized at the tumor blood vessels. Compared with analogous neutral liposomes, strong tumor photoablation was induced with a single treatment of cationic PoP liposomes and laser irradiation (5 mg/kg Dox and 100 J/cm2 NIR light). Unexpectedly, empty cationic PoP liposomes (lacking Dox) induced equally potent antitumor phototherapeutic effects as the drug loaded ones. A more balanced chemo and phototherapeutic response was subsequently achieved when antitumor studies were repeated using higher drug dosing (7 mg/kg Dox) and a low fluence phototreatment (20 J/cm2 NIR light). These results demonstrate the feasibility of vessel-targeted chemophototherapy using cationic PoP liposomes and also illustrate synergistic considerations. Mol Cancer Ther; 16(11); 2452-61. (c)2017 AACR. PMID- 28729403 TI - Autophagy Inhibition Improves Sunitinib Efficacy in Pancreatic Neuroendocrine Tumors via a Lysosome-dependent Mechanism. AB - Increasing the efficacy of approved systemic treatments in metastasized pancreatic neuroendocrine tumors (PanNET) is an unmet medical need. The antiangiogenic tyrosine kinase inhibitor sunitinib is approved for PanNET treatment. In addition, sunitinib is a lysosomotropic drug and such drugs can induce lysosomal membrane permeabilization as well as autophagy. We investigated sunitinib-induced autophagy as a possible mechanism of PanNET therapy resistance. Sunitinib accumulated in lysosomes and induced autophagy in PanNET cell lines. Adding the autophagy inhibitor chloroquine reduced cell viability in cell lines and in primary cells isolated from PanNET patients. The same treatment combination reduced tumor burden in the Rip1Tag2 transgenic PanNET mouse model. The combination of sunitinib and chloroquine reduced recovery and induced apoptosis in vitro, whereas single treatments did not. Knockdown of key autophagy proteins in combination with sunitinib showed similar effect as chloroquine. Sunitinib also induced lysosomal membrane permeabilization, which further increased in the presence of chloroquine or knockdown of lysosome-associated membrane protein (LAMP2). Both combinations led to cell death. Our data indicate that chloroquine increases sunitinib efficacy in PanNET treatment via autophagy inhibition and lysosomal membrane permeabilization. We suggest that adding chloroquine to sunitinib treatment will increase efficacy of PanNET treatment and that such patients should be included in respective ongoing clinical trials. Mol Cancer Ther; 16(11); 2502-15. (c)2017 AACR. PMID- 28729404 TI - Exploiting Natural Variation to Uncover an Alkene Biosynthetic Enzyme in Poplar. AB - Alkenes are linear hydrocarbons with one or more double bonds. Despite their potential as biofuels and precursors for specialty chemicals, the underlying biochemistry and genetics of alkene biosynthesis in plants remain elusive. Here, we report on a screen of natural accessions of poplar (Populus trichocarpa), revealing that the leaf cuticular waxes are predominantly composed of alkanes and alkenes. Interestingly, the accumulation of alkenes increases with leaf development, is limited to the abaxial side of the leaf, and is impaired in a few accessions. Among other genes, a beta-ketoacyl CoA synthase gene (PotriKCS1) was downregulated in leaves from non-alkene-producing accessions. We demonstrated biochemically that PotriKCS1 elongates monounsaturated fatty acids and is responsible for the recruitment of unsaturated substrates to the cuticular wax. Moreover, we found significant associations between the presence of alkenes and tree growth and resistance to leaf spot. These findings highlight the crucial role of cuticular waxes as the first point of contact with the environment, and they provide a foundation for engineering long-chain monounsaturated oils in other species. PMID- 28729406 TI - Tumor Evolution as a Therapeutic Target. AB - Recent technological advances in the field of molecular diagnostics (including blood-based tumor genotyping) allow the measurement of clonal evolution in patients with cancer, thus adding a new dimension to precision medicine: time. The translation of this new knowledge into clinical benefit implies rethinking therapeutic strategies. In essence, it means considering as a target not only individual oncogenes but also the evolving nature of human tumors. Here, we analyze the limitations of targeted therapies and propose approaches for treatment within an evolutionary framework.Significance: Precision cancer medicine relies on the possibility to match, in daily medical practice, detailed genomic profiles of a patient's disease with a portfolio of drugs targeted against tumor-specific alterations. Clinical blockade of oncogenes is effective but only transiently; an approach to monitor clonal evolution in patients and develop therapies that also evolve over time may result in improved therapeutic control and survival outcomes. Cancer Discov; 7(8); 1-13. (c)2017 AACR. PMID- 28729405 TI - Superenhancer Analysis Defines Novel Epigenomic Subtypes of Non-APL AML, Including an RARalpha Dependency Targetable by SY-1425, a Potent and Selective RARalpha Agonist. AB - We characterized the enhancer landscape of 66 patients with acute myeloid leukemia (AML), identifying 6 novel subgroups and their associated regulatory loci. These subgroups are defined by their superenhancer (SE) maps, orthogonal to somatic mutations, and are associated with distinct leukemic cell states. Examination of transcriptional drivers for these epigenomic subtypes uncovers a subset of patients with a particularly strong SE at the retinoic acid receptor alpha (RARA) gene locus. The presence of a RARA SE and concomitant high levels of RARA mRNA predisposes cell lines and ex vivo models to exquisite sensitivity to a selective agonist of RARalpha, SY-1425 (tamibarotene). Furthermore, only AML patient-derived xenograft (PDX) models with high RARA mRNA were found to respond to SY-1425. Mechanistically, we show that the response to SY-1425 in RARA-high AML cells is similar to that of acute promyelocytic leukemia treated with retinoids, characterized by the induction of known retinoic acid response genes, increased differentiation, and loss of proliferation.Significance: We use the SE landscape of primary human AML to elucidate transcriptional circuitry and identify novel cancer vulnerabilities. A subset of patients were found to have an SE at RARA, which is predictive for response to SY-1425, a potent and selective RARalpha agonist, in preclinical models, forming the rationale for its clinical investigation in biomarker-selected patients. Cancer Discov; 7(10); 1136-53. (c)2017 AACR.See related commentary by Wang and Aifantis, p. 1065.This article is highlighted in the In This Issue feature, p. 1047. PMID- 28729407 TI - Long-Term Stroke Risk Prediction in Patients With Atrial Fibrillation: Comparison of the ABC-Stroke and CHA2DS2-VASc Scores. AB - BACKGROUND: The ABC-stroke score (age, biomarkers [N-terminal fragment B-type natriuretic peptide, high-sensitivity troponin], and clinical history [prior stroke/transient ischemic attack]) was proposed to predict stroke in atrial fibrillation (AF). This score was derived/validated in 2 clinical trial cohorts in which patients with AF were highly selected and carefully followed-up. However, the median follow-up was 1.9 years in the trial cohort; therefore, its long-term predictive performance remains uncertain. This study aimed to compare the long-term predictive performances of the ABC-stroke and CHA2DS2-VASc (cardiac failure or dysfunction, hypertension, age >=75 [doubled], diabetes mellitus, stroke [doubled]-vascular disease, age 65 to 74 years and sex category [female]) scores in a cohort of anticoagulated patients with AF. METHODS AND RESULTS: We recruited 1125 consecutive patients with AF who were stable on vitamin K antagonists and followed-up for a median of 6.5 years. ABC-stroke and CHA2DS2 VASc (cardiac failure or dysfunction, hypertension, age >=75 [doubled], diabetes mellitus, stroke [doubled]-vascular disease, age 65 to 74 years and sex category [female]) scores were calculated and compared. Median CHA2DS2-VASc and ABC-stroke scores were 4 (interquartile range 3-5) and 9.1 (interquartile range 7.3-11.3), respectively. There were 114 ischemic strokes (1.55% per year) at 6.5 years. The C-index of ABC-stroke at 3.5 years was significantly higher than CHA2DS2-VASc (0.663 versus 0.600, P=0.046), but both C-indexes were nonsignificantly different at 6.5 years. Integrated discrimination improvement showed a small improvement (<2%) in sensitivity at 3.5 and 6.5 years with ABC-stroke. For ABC-stroke, net reclassification improvement was nonsignificantly different at 3.5 years, and showed a negative reclassification at 6.5 years compared with CHA2DS2-VASc. Decision curve analyses did not show a marked improvement in clinical usefulness of the ABC-stroke score over the CHA2DS2-VASc score. CONCLUSIONS: In anticoagulated patients with AF followed-up over a long-term period, the novel ABC-stroke score does not offer significantly better predictive performance compared with the CHA2DS2-VASc score. PMID- 28729408 TI - Femoral Artery Atherosclerosis Is Associated With Physical Function Across the Spectrum of the Ankle-Brachial Index: The San Diego Population Study. AB - BACKGROUND: The ankle-brachial index (ABI) is inadequate to detect early-stage atherosclerotic disease, when interventions to prevent functional decline may be the most effective. We determined associations of femoral artery atherosclerosis with physical functioning, across the spectrum of the ABI, and within the normal ABI range. METHODS AND RESULTS: In 2007-2011, 1103 multiethnic men and women participated in the San Diego Population Study, and completed all components of the summary performance score. Using Doppler ultrasound, superficial and common femoral intima media thickness and plaques were ascertained. Logistic regression was used to assess associations of femoral atherosclerosis with the summary performance score and its individual components. Models were adjusted for demographics, lifestyle factors, comorbidities, lipids, and kidney function. In adjusted models, among participants with a normal-range ABI (1.00-1.30), the highest tertile of superficial intima media thickness was associated with lower odds of a perfect summary performance score of 12 (odds ratio=0.56 [0.36, 0.87], P=0.009), and lower odds of a 4-m walk score of 4 (0.34 [0.16, 0.73], P=0.006) and chair rise score of 4 (0.56 [0.34, 0.94], P=0.03). Plaque presence (0.53 [0.29, 0.99], P=0.04) and greater total plaque burden (0.61 [0.43, 0.87], P=0.006) were associated with worse 4-m walk performance in the normal-range ABI group. Higher superficial intima media thickness was associated with lower summary performance score in all individuals (P=0.02). CONCLUSIONS: Findings suggest that use of femoral artery atherosclerosis measures may be effective in individuals with a normal-range ABI, especially, for example, those with diabetes mellitus or a family history of peripheral artery disease, when detection can lead to earlier intervention to prevent functional declines and improve quality of life. PMID- 28729409 TI - Comparison of Anatomic and Clinical Outcomes in Patients Undergoing Alternative Initial Noninvasive Testing Strategies for the Diagnosis of Stable Coronary Artery Disease. AB - BACKGROUND: The optimal initial noninvasive diagnostic testing strategy for stable coronary artery disease (CAD) is unknown. Although American guidelines recommend an exercise stress test as the first-line test, European guidelines suggest that stress imaging (myocardial perfusion imaging or stress echocardiography) or coronary computed tomography angiography may be preferable. Understanding the relationship between the initial strategy and downstream yield of obstructive CAD and major adverse cardiac events may provide insight as to the optimal strategy. METHODS AND RESULTS: We conducted a population-based retrospective cohort study of adults in Ontario, Canada, using health administrative and clinical data. The relationship between the initial testing strategy and obstructive CAD on invasive angiography was examined. Patients were then followed from their angiogram onward to determine whether they developed a composite end point of major adverse cardiac events. After adjusting for covariates, patients with initial myocardial perfusion imaging (odds ratio: 0.92; 95% confidence interval, 0.85, 1.00), coronary computed tomography angiography (odds ratio: 1.51; 95% confidence interval, 0.91, 2.49), or stress echo (odds ratio: 0.95; 95% confidence interval, 0.84, 1.08) did not a have significantly different yield of obstructive CAD compared with those with an initial exercise stress test. Furthermore, there was no significant difference in downstream major adverse cardiac events after invasive angiography among the 4 initial testing strategies after adjusting for clinically relevant covariates. CONCLUSIONS: Our study found no evidence to suggest significant differences in either yield of obstructive CAD or downstream major adverse cardiac events in patients undergoing an initial noninvasive testing strategy with stress or anatomical imaging compared with those undergoing an initial exercise stress test. PMID- 28729410 TI - Initial Diagnostic Evaluation of Stable Coronary Artery Disease: The Need for a Patient-Centered Strategy. PMID- 28729411 TI - Recognized Obstructive Sleep Apnea is Associated With Improved In-Hospital Outcomes After ST Elevation Myocardial Infarction. AB - BACKGROUND: Obstructive sleep apnea (OSA) is an independent risk factor for many cardiovascular conditions such as coronary artery disease, myocardial infarction, systemic hypertension, pulmonary hypertension, and stroke. However, the association of OSA with outcomes in patients hospitalized for ST-elevation myocardial infarction remains controversial. METHODS AND RESULTS: We used the nation-wide inpatient sample between 2003 and 2011 to identify patients with a primary discharge diagnosis of ST-elevation myocardial infarction and then used the International Classification of Diseases, Clinical Modification code 327.23 to identify a group of patients with OSA. The primary outcome of interest was in hospital mortality, and secondary outcomes were in-hospital cardiac arrest, length of stay and hospital charges. Our cohort included 1 850 625 patients with ST-elevation myocardial infarction, of which 1.3% (24 623) had documented OSA. OSA patients were younger and more likely to be male, smokers, and have chronic pulmonary disease, depression, hypertension, known history of coronary artery disease, dyslipidemia, obesity, and renal failure (P<0.001 for all). Patients with OSA had significantly decreased in-hospital mortality (adjusted odds ratio, 0.78 [95% CI, 0.73-0.84]), longer hospital stay (5.00+/-4.68 versus 4.85+/-5.96 days), and incurred greater hospital charges ($79 460.12+/-70 621.91 versus $62 889.91+/-69 124.15). There was no difference in incidence of in-hospital cardiac arrest (adjusted odds ratio, 0.93 [95% CI, 0.84-1.03]) between these 2 groups. CONCLUSION: ST-elevation myocardial infarction patients with recognized OSA had significantly decreased mortality compared with patients without OSA. Although patients with OSA had longer hospital stays and incurred greater hospital charges, there was no difference in incidence of in-hospital cardiac arrest. PMID- 28729414 TI - Methods of Academic Course Planning for Cancer Biology PhD Students to Enhance Knowledge of Clinical Oncology. AB - Little is known about how clinical oncology concepts are taught to PhD students or the most effective methods of doing so. In this study, electronic surveys were sent to faculty and students at PhD training programs, assessing their institution's methods of clinical oncology education and their perspective on optimal approaches to clinical oncology education. Only 40.0% of students reported any clinical oncology component to their institution's training, and only 26.5% had a clinician on their graduate advisory committee. Forty-three percent of students believed that they had a good understanding for translating basic science research into clinical practice, and 77.2% of all participants believed dual degree MD/PhD students were superior to PhD students in this regard. Lectures on clinical oncology research topics were the most valuable type of experience for all participants and were also the most common type of experience utilized. Working with a clinician to develop a clinical trial with correlative endpoints was also highly valued, but was only utilized by approximately 10% of programs. Faculty rated the value of nearly all types of clinical oncology exposure significantly lower than did students. Inclusion of the approaches identified in this study is likely to enhance PhD training in oncology-related disciplines. Cancer Res; 77(18); 4741-4. (c)2017 AACR. PMID- 28729413 TI - Breast Cancer Suppression by Progesterone Receptors Is Mediated by Their Modulation of Estrogen Receptors and RNA Polymerase III. AB - Greater than 50% of estrogen receptor (ER)-positive breast cancers coexpress the progesterone receptor (PR), which can directly and globally modify ER action to attenuate tumor growth. However, whether this attenuation is mediated only through PR-ER interaction remains unknown. To address this question, we assessed tumor growth in ER/PR-positive patient-derived xenograft models of breast cancer, where both natural and synthetic progestins were found to antagonize the mitogenic effects of estrogens. Probing the genome-wide mechanisms by which this occurs, we documented that chronic progestin treatment blunted ER-mediated gene expression up to 2-fold at the level of mRNA transcripts. Unexpectedly, <25% of all ER DNA binding events were affected by the same treatment. The PR cistrome displayed a bimodal distribution. In one group, >50% of PR binding sites were co occupied by ER, with a propensity for both receptors to coordinately gain or lose binding in the presence of progesterone. In the second group, PR but not ER was associated with a large fraction of RNA polymerase III-transcribed tRNA genes, independent of hormone treatment. Notably, we discovered that PR physically associated with the Pol III holoenzyme. Select pre-tRNAs and mature tRNAs with PR and POLR3A colocalized at their promoters were relatively decreased in estrogen + progestin-treated tumors. Our results illuminate how PR may indirectly impede ER action by reducing the bioavailability of translational molecules needed for tumor growth. Cancer Res; 77(18); 4934-46. (c)2017 AACR. PMID- 28729415 TI - An Essential Role for the Tumor-Suppressor Merlin in Regulating Fatty Acid Synthesis. AB - Neurofibromatosis type 2 (NF2) is an autosomal dominant disorder characterized by the development of multiple tumors in the central nervous system, most notably schwannomas, and meningiomas. Mutational inactivation of the NF2 gene encoding the protein Merlin is found in most sporadic and inherited schwannomas, but the molecular mechanisms underlying neoplastic changes in schwannoma cells remain unclear. We report here that Nf2-deficient cells display elevated expression levels of key enzymes involved in lipogenesis and that this upregulation is caused by increased activity of Torc1. Inhibition or knockdown of fatty acid synthase (FASN), the enzyme that catalyzes the formation of palmitic acid from malonyl-CoA, drove NF2-deficient cells into apoptosis. Treatment of NF2-mutant cells with agents that inhibit the production of malonyl-CoA reduced their sensitivity to FASN inhibitors. Collectively, these results suggest that the altered lipid metabolism found in NF2-mutant cells renders them sensitive to elevated levels of malonyl-CoA, as occurs following blockade of FASN, suggesting new targeted strategies in the treatment of NF2-deficient tumors. Cancer Res; 77(18); 5026-38. (c)2017 AACR. PMID- 28729416 TI - CIB2 Negatively Regulates Oncogenic Signaling in Ovarian Cancer via Sphingosine Kinase 1. AB - Sphingosine kinase 1 (SK1) is a key regulator of the cellular balance between proapoptotic and prosurvival sphingolipids. Oncogenic signaling by SK1 relies on its localization to the plasma membrane, which is mediated by the calcium and integrin binding protein CIB1 via its Ca2+-myristoyl switch function. Here we show that another member of the CIB family, CIB2, plays a surprisingly opposite role to CIB1 in the regulation of SK1 signaling. CIB2 bound SK1 on the same site as CIB1, yet it lacks the Ca2+-myristoyl switch function. As a result, CIB2 blocked translocation of SK1 to the plasma membrane and inhibited its subsequent signaling, which included sensitization to TNFalpha-induced apoptosis and inhibition of Ras-induced neoplastic transformation. CIB2 was significantly downregulated in ovarian cancer and low CIB2 expression was associated with poor prognosis in ovarian cancer patients. Notably, reintroduction of CIB2 in ovarian cancer cells blocked plasma membrane localization of endogenous SK1, reduced in vitro neoplastic growth and tumor growth in mice, and suppressed cell motility and invasiveness both in vitro and in vivo Consistent with the in vitro synergistic effects between the SK1-specific inhibitor SK1-I and standard chemotherapeutics, expression of CIB2 also sensitized ovarian cancer cells to carboplatin. Together, these findings identify CIB2 as a novel endogenous suppressor of SK1 signaling and potential prognostic marker and demonstrate the therapeutic potential of SK1 in this gynecologic malignancy. Cancer Res; 77(18); 4823-34. (c)2017 AACR. PMID- 28729412 TI - Simple Scoring System to Predict In-Hospital Mortality After Surgery for Infective Endocarditis. AB - BACKGROUND: Aspecific scoring systems are used to predict the risk of death postsurgery in patients with infective endocarditis (IE). The purpose of the present study was both to analyze the risk factors for in-hospital death, which complicates surgery for IE, and to create a mortality risk score based on the results of this analysis. METHODS AND RESULTS: Outcomes of 361 consecutive patients (mean age, 59.1+/-15.4 years) who had undergone surgery for IE in 8 European centers of cardiac surgery were recorded prospectively, and a risk factor analysis (multivariable logistic regression) for in-hospital death was performed. The discriminatory power of a new predictive scoring system was assessed with the receiver operating characteristic curve analysis. Score validation procedures were carried out. Fifty-six (15.5%) patients died postsurgery. BMI >27 kg/m2 (odds ratio [OR], 1.79; P=0.049), estimated glomerular filtration rate <50 mL/min (OR, 3.52; P<0.0001), New York Heart Association class IV (OR, 2.11; P=0.024), systolic pulmonary artery pressure >55 mm Hg (OR, 1.78; P=0.032), and critical state (OR, 2.37; P=0.017) were independent predictors of in-hospital death. A scoring system was devised to predict in-hospital death postsurgery for IE (area under the receiver operating characteristic curve, 0.780; 95% CI, 0.734-0.822). The score performed better than 5 of 6 scoring systems for in-hospital death after cardiac surgery that were considered. CONCLUSIONS: A simple scoring system based on risk factors for in-hospital death was specifically created to predict mortality risk postsurgery in patients with IE. PMID- 28729417 TI - Mathematical Modeling of Tumor-Tumor Distant Interactions Supports a Systemic Control of Tumor Growth. AB - Interactions between different tumors within the same organism have major clinical implications, especially in the context of surgery and metastatic disease. Three main explanatory theories (competition, angiogenesis inhibition, and proliferation inhibition) have been proposed, but precise determinants of the phenomenon remain poorly understood. Here, we formalized these theories into mathematical models and performed biological experiments to test them with empirical data. In syngeneic mice bearing two simultaneously implanted tumors, growth of only one of the tumors was significantly suppressed (61% size reduction at day 15, P < 0.05). The competition model had to be rejected, whereas the angiogenesis inhibition and proliferation inhibition models were able to describe the data. Additional models including a theory based on distant cytotoxic log kill effects were unable to fit the data. The proliferation inhibition model was identifiable and minimal (four parameters), and its descriptive power was validated against the data, including consistency in predictions of single tumor growth when no secondary tumor was present. This theory may also shed new light on single cancer growth insofar as it offers a biologically translatable picture of how local and global action may combine to control local tumor growth and, in particular, the role of tumor-tumor inhibition. This model offers a depiction of concomitant resistance that provides an improved theoretical basis for tumor growth control and may also find utility in therapeutic planning to avoid postsurgery metastatic acceleration. Cancer Res; 77(18); 5183-93. (c)2017 AACR. PMID- 28729418 TI - MYC-Regulated Mevalonate Metabolism Maintains Brain Tumor-Initiating Cells. AB - Metabolic dysregulation drives tumor initiation in a subset of glioblastomas harboring isocitrate dehydrogenase (IDH) mutations, but metabolic alterations in glioblastomas with wild-type IDH are poorly understood. MYC promotes metabolic reprogramming in cancer, but targeting MYC has proven notoriously challenging. Here, we link metabolic dysregulation in patient-derived brain tumor-initiating cells (BTIC) to a nexus between MYC and mevalonate signaling, which can be inhibited by statin or 6-fluoromevalonate treatment. BTICs preferentially express mevalonate pathway enzymes, which we find regulated by novel MYC-binding sites, validating an additional transcriptional activation role of MYC in cancer metabolism. Targeting mevalonate activity attenuated RAS-ERK-dependent BTIC growth and self-renewal. In turn, mevalonate created a positive feed-forward loop to activate MYC signaling via induction of miR-33b. Collectively, our results argue that MYC mediates its oncogenic effects in part by altering mevalonate metabolism in glioma cells, suggesting a therapeutic strategy in this setting. Cancer Res; 77(18); 4947-60. (c)2017 AACR. PMID- 28729419 TI - The exocyst is required for photoreceptor ciliogenesis and retinal development. AB - We previously have shown that the highly conserved eight-protein exocyst trafficking complex is required for ciliogenesis in kidney tubule cells. We hypothesized here that ciliogenic programs are conserved across organs and species. To determine whether renal primary ciliogenic programs are conserved in the eye, and to characterize the function and mechanisms by which the exocyst regulates eye development in zebrafish, we focused on exoc5, a central component of the exocyst complex, by analyzing both exoc5 zebrafish mutants, and photoreceptor-specific Exoc5 knock-out mice. Two separate exoc5 mutant zebrafish lines phenocopied exoc5 morphants and, strikingly, exhibited a virtual absence of photoreceptors, along with abnormal retinal development and cell death. Because the zebrafish mutant was a global knockout, we also observed defects in several ciliated organs, including the brain (hydrocephalus), heart (cardiac edema), and kidney (disordered and shorter cilia). exoc5 knockout increased phosphorylation of the regulatory protein Mob1, consistent with Hippo pathway activation. exoc5 mutant zebrafish rescue with human EXOC5 mRNA completely reversed the mutant phenotype. We accomplished photoreceptor-specific knockout of Exoc5 with our Exoc5 fl/fl mouse line crossed with a rhodopsin-Cre driver line. In Exoc5 photoreceptor-specific knock-out mice, the photoreceptor outer segment structure was severely impaired at 4 weeks of age, although a full-field electroretinogram indicated a visual response was still present. However, by 6 weeks, visual responses were eliminated. In summary, we show that ciliogenesis programs are conserved in the kidneys and eyes of zebrafish and mice and that the exocyst is necessary for photoreceptor ciliogenesis and retinal development, most likely by trafficking cilia and outer-segment proteins. PMID- 28729420 TI - Revisiting the substrate specificity of mammalian alpha1,6-fucosyltransferase reveals that it catalyzes core fucosylation of N-glycans lacking alpha1,3-arm GlcNAc. AB - The mammalian alpha1,6-fucosyltransferase (FUT8) catalyzes the core fucosylation of N-glycans in the biosynthesis of glycoproteins. Previously, intensive in vitro studies with crude extract or purified enzyme concluded that the attachment of a GlcNAc on the alpha1,3 mannose arm of N-glycan is essential for FUT8-catalyzed core fucosylation. In contrast, we have recently shown that expression of erythropoietin in a GnTI knock-out, FUT8-overexpressing cell line results in the production of fully core-fucosylated glycoforms of the oligomannose substrate Man5GlcNAc2, suggesting that FUT8 can catalyze core fucosylation of N-glycans lacking an alpha1,3-arm GlcNAc in cells. Here, we revisited the substrate specificity of FUT8 by examining its in vitro activity toward an array of selected N-glycans, glycopeptides, and glycoproteins. Consistent with previous studies, we found that free N-glycans lacking an unmasked alpha1,3-arm GlcNAc moiety are not FUT8 substrates. However, Man5GlcNAc2 glycan could be efficiently core-fucosylated by FUT8 in an appropriate protein/peptide context, such as with the erythropoietin protein, a V3 polypeptide derived from HIV-1 gp120, or a simple 9-fluorenylmethyl chloroformate-protected Asn moiety. Interestingly, when placed in the V3 polypeptide context, a mature bi-antennary complex-type N-glycan also could be core-fucosylated by FUT8, albeit at much lower efficiency than the Man5GlcNAc2 peptide. This study represents the first report of in vitro FUT8 catalyzed core fucosylation of N-glycans lacking the alpha1,3-arm GlcNAc moiety. Our results suggest that an appropriate polypeptide context or other adequate structural elements in the acceptor substrate could facilitate the core fucosylation by FUT8. PMID- 28729421 TI - The small G protein RAS2 is involved in the metabolic compensation of the circadian clock in the circadian model Neurospora crassa. AB - Accumulating evidence from both experimental and clinical investigations indicates a tight interaction between metabolism and circadian timekeeping; however, knowledge of the underlying mechanism is still incomplete. Metabolic compensation allows circadian oscillators to run with a constant speed at different substrate levels and, therefore, is a substantial criterion of a robust rhythm in a changing environment. Because previous data have suggested a central role of RAS2-mediated signaling in the adaptation of yeast to different nutritional environments, we examined the involvement of RAS2 in the metabolic regulation of the clock in the circadian model organism Neurospora crassa We show that, in a ras2-deficient strain, the period is longer than in the control. Moreover, unlike in the WT, in Deltaras2, operation of the circadian clock was affected by glucose; compared with starvation conditions, the period was longer and the oscillation of expression of the frequency (frq) gene was dampened. In constant darkness, the delayed phosphorylation of the FRQ protein and the long lasting accumulation of FRQ in the nucleus were in accordance with the longer period and the less robust rhythm in the mutant. Although glucose did not affect the subcellular distribution of FRQ in the WT, highly elevated FRQ levels were detected in the nucleus in Deltaras2 RAS2 interacted with the RAS-binding domain of the adenylate cyclase in vitro, and the cAMP analogue 8-bromo-cyclic AMP partially rescued the circadian phenotype in vivo We therefore propose that RAS2 acts via a cAMP-dependent pathway and exerts significant metabolic control on the Neurospora circadian clock. PMID- 28729423 TI - Protection of the general stress response sigmaS factor by the CrsR regulator allows a rapid and efficient adaptation of Shewanella oneidensis. AB - To cope with environmental stresses, bacteria have evolved various strategies, including the general stress response (GSR). GSR is governed by an alternative transcriptional sigma factor named sigmaS (RpoS) that associates with RNA polymerase and controls the expression of numerous genes. Previously, we have reported that posttranslational regulation of sigmaS in the aquatic bacterium Shewanella oneidensis involves the CrsR-CrsA partner-switching regulatory system, but the exact mechanism by which CrsR and CrsA control sigmaS activity is not completely unveiled. Here, using a translational gene fusion, we show that CrsR sequesters and protects sigmaS during the exponential growth phase and thus enables rapid gene activation by sigmaS as soon as the cells enter early stationary phase. We further demonstrate by an in vitro approach that this protection is mediated by the anti-sigma domain of CrsR. Structure-based alignments of CsrR orthologs and other anti-sigma factors identified a CsrR specific region characteristic of a new family of anti-sigma factors. We found that CrsR is conserved in many aquatic proteobacteria, and most of the time it is associated with CrsA. In conclusion, our results suggest that CsrR-mediated protection of sigmaS during exponential growth enables rapid adaptation of S. oneidensis to changing and stressful growth conditions, and this ability is probably widespread among aquatic proteobacteria. PMID- 28729422 TI - O-Glycosylation modulates the stability of epidermal growth factor-like repeats and thereby regulates Notch trafficking. AB - Glycosylation in the endoplasmic reticulum (ER) is closely associated with protein folding and quality control. We recently described a non-canonical ER quality control mechanism for folding of thrombospondin type 1 repeats by protein O-fucosyltransferase 2 (POFUT2). Epidermal growth factor-like (EGF) repeats are also small cysteine-rich protein motifs that can be O-glycosylated by several ER localized enzymes, including protein O-glucosyltransferase 1 (POGLUT1) and POFUT1. Both POGLUT1 and POFUT1 modify the Notch receptor on multiple EGF repeats and are essential for full Notch function. The fact that POGLUT1 and POFUT1 can distinguish between folded and unfolded EGF repeats raised the possibility that they participate in a quality control pathway for folding of EGF repeats in proteins such as Notch. Here, we demonstrate that cell-surface expression of endogenous Notch1 in HEK293T cells is dependent on the presence of POGLUT1 and POFUT1 in an additive manner. In vitro unfolding assays reveal that addition of O glucose or O-fucose stabilizes a single EGF repeat and that addition of both O glucose and O-fucose enhances stability in an additive manner. Finally, we solved the crystal structure of a single EGF repeat covalently modified by a full O glucose trisaccharide at 2.2 A resolution. The structure reveals that the glycan fills up a surface groove of the EGF with multiple contacts with the protein, providing a chemical basis for the stabilizing effects of the glycans. Taken together, this work suggests that O-fucose and O-glucose glycans cooperatively stabilize individual EGF repeats through intramolecular interactions, thereby regulating Notch trafficking in cells. PMID- 28729425 TI - A strictly monofunctional bacterial hydroxymethylpyrimidine phosphate kinase precludes damaging errors in thiamin biosynthesis. AB - The canonical kinase (ThiD) that converts the thiamin biosynthesis intermediate hydroxymethylpyrimidine (HMP) monophosphate to the diphosphate can also very efficiently convert free HMP to the monophosphate in prokaryotes, plants, and fungi. This HMP kinase activity enables salvage of HMP, but it is not substrate specific and so allows toxic HMP analogs and damage products to infiltrate the thiamin biosynthesis pathway. Comparative analysis of bacterial genomes uncovered a gene, thiD2 , that is often fused to the thiamin synthesis gene thiE and could potentially encode a replacement for ThiD. Standalone ThiD2 proteins and ThiD2 fusion domains are small (~130-residues) and do not belong to any previously known protein family. Genetic and biochemical analyses showed that representative standalone and fused ThiD2 proteins catalyze phosphorylation of HMP monophosphate, but not of HMP or its toxic analogs and damage products such as bacimethrin and 5-(hydroxymethyl)-2-methylpyrimidin-4-ol. As strictly monofunctional HMP monophosphate kinases, ThiD2 proteins eliminate a potentially fatal vulnerability of canonical ThiD, at the cost of the ability to reclaim HMP formed by thiamin turnover. PMID- 28729426 TI - Glycerol-3-phosphate acyltransferase 2 is essential for normal spermatogenesis. AB - Glycerol-3-phosphate acyltransferases (GPATs) catalyze the first and rate limiting step in the de novo glycerolipid synthesis. The GPAT2 isoform differs from the other isoforms because its expression is restricted to male germ cells and cancer cells. It has been recently reported that GPAT2 expression in mouse testis fluctuates during sexual maturation and that it is regulated by epigenetic mechanisms in combination with vitamin A derivatives. Despite progress made in this field, information about GPAT2 role in the developing male germ cells remains unclear. The aim of the present study was to confirm the hypothesis that GPAT2 is required for the normal physiology of testes and male germ cell maturation. The gene was silenced in vivo by inoculating lentiviral particles carrying the sequence of a short-hairpin RNA targeting Gpat2 mRNA into mouse testis. Histological and gene expression analysis showed impaired spermatogenesis and arrest at the pachytene stage. Defects in reproductive fitness were also observed, and the analysis of apoptosis-related gene expression demonstrated the activation of apoptosis in Gpat2-silenced germ cells. These findings indicate that GPAT2 protein is necessary for the normal development of male gonocytes, and that its absence triggers apoptotic mechanisms, thereby decreasing the number of dividing germ cells. PMID- 28729424 TI - Molecular determinants of acidic pH-dependent transport of human equilibrative nucleoside transporter 3. AB - Equilibrative nucleoside transporters (ENTs) translocate hydrophilic nucleosides across cellular membranes and are essential for salvage nucleotide synthesis and purinergic signaling. Unlike the prototypic human ENT members hENT1 and hENT2, which mediate plasma membrane nucleoside transport at pH 7.4, hENT3 is an acidic pH-activated lysosomal transporter partially localized to mitochondria. Recent studies demonstrate that hENT3 is indispensable for lysosomal homeostasis, and that mutations in hENT3 can result in a spectrum of lysosomal storage-like disorders. However, despite hENT3's prominent role in lysosome pathophysiology, the molecular basis of hENT3-mediated transport is unknown. Therefore, we sought to examine the mechanistic basis of acidic pH-driven hENT3 nucleoside transport with site-directed mutagenesis, homology modeling, and [3H]adenosine flux measurements in mutant RNA-injected Xenopus oocytes. Scanning mutagenesis of putative residues responsible for pH-dependent transport via hENT3 revealed that the ionization states of Asp-219 and Glu-447, and not His, strongly determined the pH-dependent transport permissible-impermissible states of the transporter. Except for substitution with certain isosteric and polar residues, substitution of either Asp-219 or Glu-447 with any other residues resulted in robust activity that was pH-independent. Dual substitution of Asp-219 and Glu-447 to Ala sustained pH-independent activity over a broad range of physiological pH (pH 5.5 7.4), which also maintained stringent substrate selectivity toward endogenous nucleosides and clinically used nucleoside drugs. Our results suggest a putative pH-sensing role for Asp-219 and Glu-447 in hENT3 and that the size, ionization state, or electronegative polarity at these positions is crucial for obligate acidic pH-dependent activity. PMID- 28729427 TI - Sialylated glycosylphosphatidylinositols suppress the production of toxic amyloid beta oligomers. AB - The production of amyloid-beta (Abeta) is a key factor driving pathogenesis in Alzheimer's disease (AD). Increasing concentrations of soluble Abeta oligomers within the brain lead to synapse degeneration and the progressive dementia characteristic of AD. Since Abeta exists in both disease-relevant (toxic) and non toxic forms, the factors that affected the release of toxic Abeta were studied in a cell model. 7PA2 cells expressing the human amyloid precursor protein released Abeta oligomers that caused synapse damage when incubated with cultured neurones. These Abeta oligomers had similar potency to soluble Abeta oligomers derived from the brains of Alzheimer's patients. Although the conditioned media from 7PA2 cells treated with the cellular prion protein (PrPC) contained Abeta, it did not cause synapse damage. The loss of toxicity was associated with a reduction in Abeta oligomers and an increase in Abeta monomers. The suppression of toxic Abeta release was dependent on the glycosylphosphatidylinositol (GPI) anchor attached to PrPC, and treatment of cells with specific GPIs alone reduced the production of toxic Abeta. The efficacy of GPIs was structure-dependent and the presence of sialic acid was critical. The conditioned medium from GPI-treated cells protected neurones against Abeta oligomer-induced synapse damage; neuroprotection was mediated by Abeta monomers. These studies support the hypothesis that the ratio of Abeta monomers to Abeta oligomers is a critical factor that regulates synapse damage. PMID- 28729428 TI - 18F-Labeled Carboplatin Derivative for PET Imaging of Platinum Drug Distribution. AB - Increasing evidence indicates that reduced intracellular drug accumulation is the parameter most consistently associated with platinum drug resistance, emphasizing the need to directly measure the intratumor drug concentration. In the era of precision medicine and with the advent of powerful imaging and proteomics technologies, there is an opportunity to better understand drug resistance by exploiting these techniques to provide new knowledge on drug-target interactions. Here, we contribute to this endeavor by reporting on the development of an 18F labeled carboplatin derivative (18F-FCP) that has the potential to image drug uptake and retention, including intratumoral distribution, by PET. Methods: Fluorinated carboplatin (19F-FCP) was synthesized using 19F-labeled 2-(5-fluoro pentyl)-2-methyl malonic acid (19F-FPMA) as the labeling agent to coordinate with the cisplatin-aqua complex. It was then used to treat cell lines and compared with cisplatin and carboplatin at different concentrations. Manual radiosynthesis and characterization of 18F-FCP were performed using 18F-FPMA for coordination with the cisplatin-aqua complex. Automated radiosynthesis of 18F-FCP was optimized on the basis of manual synthesis procedures. The stability of 18F-FCP was verified using high-performance liquid chromatography. 18F-FCP was evaluated using ex vivo biodistribution and in vivo PET imaging in non-tumor-bearing animals as well as in KB-3-1 and COLO-205 tumor xenograft-bearing nude mice. Results: In vitro cytotoxicity studies demonstrated that 19F-FCP has an antitumor activity profile similar to that of the parent drug carboplatin. In vivo plasma and urine stability analysis showed intact 18F-FCP at 24 h after injection. PET imaging and biodistribution studies showed fast clearance from blood and major accumulation in the kidneys, indicating substantial renal clearance of 18F-FCP. Using 18F-FCP PET, we could image and identify the intratumor drug profile. Conclusion: Our results demonstrated that 19F-FCP, like carboplatin, retains antitumor activity in various cell lines. 18F-FCP could be a useful imaging tool for measuring the intratumor drug distribution. This strategy of using a new therapeutic carboplatin derivative to quantify and track platinum drugs in tumors using PET has the potential to translate into a clinically useful imaging tool for individual patients. PMID- 28729429 TI - Brain Perfusion Imaging Under Acetazolamide Challenge for Detection of Impaired Cerebrovascular Reserve Capacity: Positive Findings with 15O-Water PET in Patients with Negative 99mTc-HMPAO SPECT Findings. AB - Cerebrovascular reserve capacity (CVRC) is an important parameter for treatment decisions in chronic cerebrovascular diseases. It can be assessed by measuring the acetazolamide-induced change in regional cerebral blood flow using SPECT with 99mTc-labeled hexamethylpropyleneamine oxime (99mTc-HMPAO) or PET with 15O-water. Methods: Our database was searched for patients with moyamoya vasculopathy or atherosclerotic cerebrovascular disease who had undergone 15O-water PET after normal 99mTc-HMPAO SPECT results with respect to CVRC. 15O-water PET was analyzed visually and quantitatively. Quantitative analysis was based on parametric CVRC maps generated by voxelwise image subtraction. Results: The search identified 18 patients (43 +/- 15 y, 12 moyamoya vasculopathy). PET revealed impaired CVRC in 8 patients (44%). Quantitative analysis confirmed the positive visual findings in 15O-water PET and the negative findings in 99mTc-HMPAO SPECT. Conclusion:15O water PET enables detection of impaired CVRC in a considerable fraction of symptomatic patients with stenoocclusion and negative 99mTc-HMPAO SPECT. PMID- 28729430 TI - 68Ga-Pentixafor PET/CT Imaging of Chemokine Receptor CXCR4 in Chronic Infection of the Bone: First Insights. AB - Because of its role in infection and inflammatory processes, the chemokine receptor CXCR4 might be a potent target in imaging of infectious and inflammatory diseases. The aim of this pilot study was to determine whether the CXCR4 ligand 68Ga-pentixafor is suitable for imaging chronic infection of the bone. Methods: The study comprised 14 patients with suspected infection of the skeleton who underwent 68Ga-pentixafor PET/CT between April 2015 and February 2017 in our facility. 68Ga-pentixafor PET/CT results were retrospectively evaluated against a histologic, bacteriologic, and clinical standard. The results were also compared with available bone scintigraphy, white blood cell scintigraphy, and 18F-FDG PET/CT results. Results:68Ga-pentixafor PET/CT was positive in 9 of 14 patients. Diagnoses included osteitis or osteomyelitis of peripheral bone, osteomyelitis of the maxilla, and infected endoprostheses. Target-to-background ratios were 5.1-15 (mean, 8.7). Eight of 9 cases were true-positive as confirmed by pathology, bacteriology, or clinical observation. All negative cases were confirmed as true negative by other imaging modalities and follow-up. Conclusion: Imaging of CXCR4 expression with 68Ga-pentixafor PET/CT appears suitable for diagnosing chronic infection of the skeleton. The findings of this study reveal a possible diagnostic gain in suspected chronic infections that are difficult to diagnose by other imaging modalities. PMID- 28729431 TI - Long-Acting Somatostatin Analog Therapy Differentially Alters 68Ga-DOTATATE Uptake in Normal Tissues Compared with Primary Tumors and Metastatic Lesions. AB - Synthetic somatostatin analogs have been posed as a potential source of error in somatostatin receptor imaging through interference with tumor detection; however, experimental models and clinical studies have shown a complex mechanism of the effect of octreotide on tumors. The aim of this study was to assess whether 68Ga DOTATATE uptake before treatment with long-acting somatostatin analogs differs from that after treatment. Methods: Thirty patients (15 men; age [mean +/- SD], 64.6 +/- 13.4 y) who had intermediately differentiated to well-differentiated neuroendocrine tumors and who underwent 68Ga-DOTATATE PET/CT scanning before and after receiving long-acting repeatable octreotide (Sandostatin LAR) were included in the study. The SUVmax and SUVmean of healthy target organs, residual primary tumor, and up to 5 lesions with the highest SUVmax in each organ were compared before and after octreotide treatment. Results: The mean time interval between the 2 68Ga-DOTATATE studies was 9.6 +/- 7.2 mo, and the mean time gap between the last Sandostatin LAR injection and the second 68Ga-DOTATATE study was 25.1 +/- 14.8 d. The pretreatment mean SUVmax and SUVmean were both significantly higher in the thyroid, liver, and spleen (P < 0.05) than the values measured after the administration of Sandostatin LAR. No significant differences were found among the uptake indices for residual primary tumor or any metastatic lesions in the liver, bone, lung, or lymph nodes before and after Sandostatin LAR administration (P > 0.05). Conclusion: Long-acting octreotide treatment diminished 68Ga-DOTATATE uptake in the liver, spleen, and thyroid but did not compromise tracer uptake in residual primary tumor and metastatic lesions. These findings have a direct impact on the interpretation of 68Ga-DOTATATE PET/CT scans. PMID- 28729432 TI - Tropomodulin 1 controls erythroblast enucleation via regulation of F-actin in the enucleosome. AB - Biogenesis of mammalian red blood cells requires nuclear expulsion by orthochromatic erythoblasts late in terminal differentiation (enucleation), but the mechanism is largely unexplained. Here, we employed high-resolution confocal microscopy to analyze nuclear morphology and F-actin rearrangements during the initiation, progression, and completion of mouse and human erythroblast enucleation in vivo. Mouse erythroblast nuclei acquire a dumbbell-shaped morphology during enucleation, whereas human bone marrow erythroblast nuclei unexpectedly retain their spherical morphology. These morphological differences are linked to differential expression of Lamin isoforms, with primary mouse erythroblasts expressing only Lamin B and primary human erythroblasts only Lamin A/C. We did not consistently identify a continuous F-actin ring at the cell surface constriction in mouse erythroblasts, nor at the membrane protein-sorting boundary in human erythroblasts, which do not have a constriction, arguing against a contractile ring-based nuclear expulsion mechanism. However, both mouse and human erythroblasts contain an F-actin structure at the rear of the translocating nucleus, enriched in tropomodulin 1 (Tmod1) and nonmuscle myosin IIB. We investigated Tmod1 function in mouse and human erythroblasts both in vivo and in vitro and found that absence of Tmod1 leads to enucleation defects in mouse fetal liver erythroblasts, and in CD34+ hematopoietic stem and progenitor cells, with increased F-actin in the structure at the rear of the nucleus. This novel structure, the "enucleosome," may mediate common cytoskeletal mechanisms underlying erythroblast enucleation, notwithstanding the morphological heterogeneity of enucleation across species. PMID- 28729433 TI - Selective factor VIII activation by the tissue factor-factor VIIa-factor Xa complex. AB - Safe and effective antithrombotic therapy requires understanding of mechanisms that contribute to pathological thrombosis but have a lesser impact on hemostasis. We found that the extrinsic tissue factor (TF) coagulation initiation complex can selectively activate the antihemophilic cofactor, FVIII, triggering the hemostatic intrinsic coagulation pathway independently of thrombin feedback loops. In a mouse model with a relatively mild thrombogenic lesion, TF-dependent FVIII activation sets the threshold for thrombus formation through contact phase generated FIXa. In vitro, FXa stably associated with TF-FVIIa activates FVIII, but not FV. Moreover, nascent FXa product of TF-FVIIa can transiently escape the slow kinetics of Kunitz-type inhibition by TF pathway inhibitor and preferentially activates FVIII over FV. Thus, TF synergistically primes FIXa dependent thrombin generation independently of cofactor activation by thrombin. Accordingly, FVIIa mutants deficient in direct TF-dependent thrombin generation, but preserving FVIIIa generation by nascent FXa, can support intrinsic pathway coagulation. In ex vivo flowing blood, a TF-FVIIa mutant complex with impaired free FXa generation but activating both FVIII and FIX supports efficient FVIII dependent thrombus formation. Thus, a previously unrecognized TF-initiated pathway directly yielding FVIIIa-FIXa intrinsic tenase complex may be prohemostatic before further coagulation amplification by thrombin-dependent feedback loops enhances the risk of thrombosis. PMID- 28729435 TI - Dysregulation of miR-223 constitutes a promising biomarker that informs about clinical outcomes of acute liver failure. AB - In this issue of Clinical Science, Schueller et al. [Clin. Sci. (2017) 131, 1971 1987] evaluated the role of miR-223 across multiple etiologies of acute and chronic liver insults in murine models and clinical samples. The authors find that while miR-223 is not mechanistically involved in liver injury, its intracellular levels in hepatocytes are increased upon hepatic damage in a broad panel of mechanistically distinct injury models. Furthermore, the authors provide evidence that circulating miR-223 levels provide a promising minimally invasive biomarker for acute liver failure (ALF) that defines a distinct subset of ALF cases and correlates with clinical outcomes. Combined, the highlighted study suggests that miR-223 constitutes a promising biomarker whose clinical validity and utility warrant further investigations. PMID- 28729436 TI - Regulation of adrenal and ovarian steroidogenesis by miR-132. AB - miR-132 is hormonally regulated in steroidogenic cells of the adrenal gland, ovary and testis. Here, we examined the potential role of miR-132 in the control of steroidogenesis. Transfection of Y1 adrenal cells with miR-132 increased mRNAs of 3beta-HSD and 20alpha-HSD enzymes, which catalyze the sequential conversion of pregnenolone to progesterone to biologically inactive 20alpha-hydroxyprogesterone (20alpha-OHP). Overexpression of miR-132 reduced MeCP2 and StAR protein expression, basal progestin (progesterone and 20alpha-OHP) production, but enhanced their production in response to cAMP stimulation. Use of [3H] pregnenolone and free-diffusible 22(R)-hydroxycholesterol further confirmed that miR-132 promotes the production of 20alpha-OHP by upregulating 3beta-HSD and 20alpha-HSD. Evidence is also presented that StAR is a direct target of miR-132. Transient transfection of Y1 cells with miR-132 demonstrated that miR-132 induction of 3beta-HSD and 20alpha-HSD was accompanied by significant suppression of one of its target gene products, MeCP2. In contrast, co-expression of miR-132 plus MeCP2 protein partially blocked the ability of miR-132 to upregulate the expression and function of 3beta-HSD and 20alpha-HSD. Moreover, suppression of MeCP2 protein with siRNA resulted in increased expression of 3beta-HSD and 20alpha-HSD, further demonstrating that miR-132 induces the expression of these two enzymes via inhibition of MeCP2. Likewise, overexpression of miR-132 increased 20alpha-OHP production with and without HDL loading, while knockdown of miR-132 resulted in a significant decrease of 20alpha-OHP production by granulosa cells. In conclusion, our data suggest that miR-132 attenuates steroidogenesis by repressing StAR expression and inducing 20alpha-HSD via inhibition of MeCP2 to generate a biologically inactive 20alpha-OHP. PMID- 28729434 TI - Cohesins and condensins orchestrate the 4D dynamics of yeast chromosomes during the cell cycle. AB - Duplication and segregation of chromosomes involves dynamic reorganization of their internal structure by conserved architectural proteins, including the structural maintenance of chromosomes (SMC) complexes cohesin and condensin. Despite active investigation of the roles of these factors, a genome-wide view of dynamic chromosome architecture at both small and large scale during cell division is still missing. Here, we report the first comprehensive 4D analysis of the higher-order organization of the Saccharomyces cerevisiae genome throughout the cell cycle and investigate the roles of SMC complexes in controlling structural transitions. During replication, cohesion establishment promotes numerous long-range intra-chromosomal contacts and correlates with the individualization of chromosomes, which culminates at metaphase. In anaphase, mitotic chromosomes are abruptly reorganized depending on mechanical forces exerted by the mitotic spindle. Formation of a condensin-dependent loop bridging the centromere cluster with the rDNA loci suggests that condensin-mediated forces may also directly facilitate segregation. This work therefore comprehensively recapitulates cell cycle-dependent chromosome dynamics in a unicellular eukaryote, but also unveils new features of chromosome structural reorganization during highly conserved stages of cell division. PMID- 28729437 TI - Estradiol-induced regulation of GLUT4 in 3T3-L1 cells: involvement of ESR1 and AKT activation. AB - Impaired insulin-stimulated glucose uptake involves reduced expression of the GLUT4 (solute carrier family 2 facilitated glucose transporter member 4, SLC2A4 gene). 17beta-estradiol (E2) modulates SLC2A4/GLUT4 expression, but the involved mechanisms are unclear. Although E2 exerts biological effects by binding to estrogen receptors 1/2 (ESR1/2), which are nuclear transcriptional factors; extranuclear effects have also been proposed. We hypothesize that E2 regulates GLUT4 through an extranuclear ESR1 mechanism. Thus, we investigated the effects of E2 upon (1) subcellular distribution of ESRs and the proto-oncogene tyrosine protein kinases (SRC) involvement; (2) serine/threonine-protein kinase (AKT) activation; (3) Slc2a4/GLUT4 expression and (4) GLUT4 subcellular distribution and glucose uptake in 3T3-L1 adipocytes. Differentiated 3T3-L1 adipocytes were cultivated or not with E2 for 24 h, and additionally treated or not with ESR1 selective agonist (PPT), ESR1-selective antagonist (MPP) or selective SRC inhibitor (PP2). Subcellular distribution of ESR1, ESR2 and GLUT4 was analyzed by immunocytochemistry; Slc2a4 mRNA and GLUT4 were quantified by qPCR and Western blotting, respectively; plasma membrane GLUT4 translocation and glucose uptake were analyzed under insulin stimulus for 20 min or not. E2 induced (1) translocation of ESR1, but not of ESR2, from nucleus to plasma membrane and AKT phosphorylation, effects mimicked by PPT and blocked by MPP and PP2; (2) increased Slc2a4/GLUT4 expression and (3) increased insulin-stimulated GLUT4 translocation and glucose uptake. In conclusion, E2 treatment promoted a SRC mediated nucleus-plasma membrane shuttle of ESR1, and increased AKT phosphorylation, Slc2a4/GLUT4 expression and plasma membrane GLUT4 translocation; consequently, improving insulin-stimulated glucose uptake. These results unravel mechanisms through which estrogen improves insulin sensitivity. PMID- 28729438 TI - Electrophysiological Evidence That the Retrosplenial Cortex Displays a Strong and Specific Activation Phased with Hippocampal Theta during Paradoxical (REM) Sleep. AB - It is widely accepted that cortical neurons are similarly more activated during waking and paradoxical sleep (PS; aka REM) than during slow-wave sleep (SWS). However, we recently reported using Fos labeling that only a few limbic cortical structures including the retrosplenial cortex (RSC) and anterior cingulate cortex (ACA) contain a large number of neurons activated during PS hypersomnia. Our aim in the present study was to record local field potentials and unit activity from these two structures across all vigilance states in freely moving male rats to determine whether the RSC and the ACA are electrophysiologically specifically active during basal PS episodes. We found that theta power was significantly higher during PS than during active waking (aWK) similarly in the RSC and hippocampus (HPC) but not in ACA. Phase-amplitude coupling between HPC theta and gamma oscillations strongly and specifically increased in RSC during PS compared with aWK. It did not occur in ACA. Further, 68% and 43% of the units recorded in the RSC and ACA were significantly more active during PS than during aWK and SWS, respectively. In addition, neuronal discharge of RSC but not of ACA neurons increased just after the peak of hippocampal theta wave. Our results show for the first time that RSC neurons display enhanced spiking in synchrony with theta specifically during PS. We propose that activation of RSC neurons specifically during PS may play a role in the offline consolidation of spatial memories, and in the generation of vivid perceptual scenery during dreaming.SIGNIFICANCE STATEMENT Fifty years ago, Michel Jouvet used the term paradoxical to define REM sleep because of the simultaneous occurrence of a cortical activation similar to waking accompanied by muscle atonia. However, we recently demonstrated using functional neuroanatomy that only a few limbic structures including the retrosplenial cortex (RSC) and anterior cingulate cortex (ACA) are activated during PS. In the present study, we show for the first time that the RSC and ACA contain neurons firing more during PS than in any other state. Further, RSC neurons are firing in phase with the hippocampal theta rhythm. These data indicate that the RSC is very active during PS and could play a key role in memory consolidation taking place during this state. PMID- 28729439 TI - Striatal GPR88 Modulates Foraging Efficiency. AB - The striatum is anatomically and behaviorally implicated in behaviors that promote efficient foraging. To investigate this function, we studied instrumental choice behavior in mice lacking GPR88, a striatum-enriched orphan G-protein coupled receptor that modulates striatal medium spiny neuron excitability. Our results reveal that hungry mice lacking GPR88 (KO mice) were slow to acquire food reinforced lever press but could lever press similar to controls on a progressive ratio schedule. Both WT and KO mice discriminated between reward and no-reward levers; however, KO mice failed to discriminate based on relative quantity-reward (1 vs 3 food pellets) or effort (3 vs 9 lever presses). We also demonstrate preference for the high-reward (3 pellet) lever was selectively reestablished when GPR88 expression was restored to the striatum. We propose that GPR88 expression within the striatum is integral to efficient action-selection during foraging.SIGNIFICANCE STATEMENT Evolutionary pressure driving energy homeostasis favored detection and comparison of caloric value. In wild and laboratory settings, neural systems involved in energy homeostasis bias foraging to maximize energy efficiency. This is observed when foraging behaviors are guided by superior nutritional density or minimized caloric expenditure. The striatum is anatomically and functionally well placed to perform the sensory and motor integration necessary for efficient action selection during foraging. However, few studies have examined this behavioral phenomenon or elucidated underlying molecular mechanisms. Both humans and mice with nonfunctional GPR88 have been shown to present striatal dysfunctions and impaired learning. We demonstrate that GPR88 expression is necessary to efficiently integrate effort and energy density information guiding instrumental choice. PMID- 28729441 TI - Switch-Independent Task Representations in Frontal and Parietal Cortex. AB - Alternating between two tasks is effortful and impairs performance. Previous fMRI studies have found increased activity in frontoparietal cortex when task switching is required. One possibility is that the additional control demands for switch trials are met by strengthening task representations in the human brain. Alternatively, on switch trials, the residual representation of the previous task might impede the buildup of a neural task representation. This would predict weaker task representations on switch trials, thus also explaining the performance costs. To test this, male and female participants were cued to perform one of two similar tasks, with the task being repeated or switched between successive trials. Multivoxel pattern analysis was used to test which regions encode the tasks and whether this encoding differs between switch and repeat trials. As expected, we found information about task representations in frontal and parietal cortex, but there was no difference in the decoding accuracy of task-related information between switch and repeat trials. Using cross classification, we found that the frontoparietal cortex encodes tasks using a generalizable spatial pattern in switch and repeat trials. Therefore, task representations in frontal and parietal cortex are largely switch independent. We found no evidence that neural information about task representations in these regions can explain behavioral costs usually associated with task switching.SIGNIFICANCE STATEMENT Alternating between two tasks is effortful and slows down performance. One possible explanation is that the representations in the human brain need time to build up and are thus weaker on switch trials, explaining performance costs. Alternatively, task representations might even be enhanced to overcome the previous task. Here, we used a combination of fMRI and a brain classifier to test whether the additional control demands under switching conditions lead to an increased or decreased strength of task representations in frontoparietal brain regions. We found that task representations are not modulated significantly by switching processes and generalize across switching conditions. Therefore, task representations in the human brain cannot account for the performance costs associated with alternating between tasks. PMID- 28729440 TI - The Transcription Factor Foxg1 Promotes Optic Fissure Closure in the Mouse by Suppressing Wnt8b in the Nasal Optic Stalk. AB - During vertebrate eye morphogenesis, a transient fissure forms at its inferior part, known as the optic fissure. This will gradually close, giving rise to a healthy, spherical optic cup. Failure of the optic fissure to close gives rise to an ocular disorder known as coloboma. During this developmental process, Foxg1 is expressed in the optic neuroepithelium, with highest levels of expression in the nasal optic stalk. Foxg1-/- mutant mice have microphthalmic eyes with a large ventral coloboma. We found Wnt8b expression upregulated in the Foxg1-/- optic stalk and hypothesized that, similar to what is observed in telencephalic development, Foxg1 directs development of the optic neuroepithelium through transcriptional suppression of Wnt8b To test this, we generated Foxg1-/-;Wnt8b-/- double mutants of either sex and found that the morphology of the optic cup and stalk and the closure of the optic fissure were substantially rescued in these embryos. This rescue correlates with restored Pax2 expression in the anterior tip of the optic fissure. In addition, although we do not find evidence implicating altered proliferation in the rescue, we observe a significant increase in apoptotic cell density in Foxg1-/-;Wnt8b-/- double mutants compared with the Foxg1-/- single mutant. Upregulation of Wnt/beta-catenin target molecules in the optic cup and stalk may underlie the molecular and morphological defects in the Foxg1-/- mutant. Our results show that proper optic fissure closure relies on Wnt8b suppression by Foxg1 in the nasal optic stalk to maintain balanced apoptosis and Pax2 expression in the nasal and temporal edges of the fissure.SIGNIFICANCE STATEMENT Coloboma is an ocular disorder that may result in a loss of visual acuity and accounts for ~10% of childhood blindness. It results from errors in the sealing of the optic fissure (OF), a transient structure at the bottom of the eye. Here, we investigate the colobomatous phenotype of the Foxg1-/- mutant mouse. We identify upregulated expression of Wnt8b in the optic stalk of Foxg1-/- mutants before OF closure initiates. Foxg1-/-;Wnt8b-/- double mutants show a substantial rescue of the Foxg1-/- coloboma phenotype, which correlates with a rescue in molecular and cellular defects of Foxg1-/- mutants. Our results unravel a new role of Foxg1 in promoting OF closure providing additional knowledge about the molecules and cellular mechanisms underlying coloboma formation. PMID- 28729443 TI - theta-Band and beta-Band Neural Activity Reflects Independent Syllable Tracking and Comprehension of Time-Compressed Speech. AB - Recent psychophysics data suggest that speech perception is not limited by the capacity of the auditory system to encode fast acoustic variations through neural gamma activity, but rather by the time given to the brain to decode them. Whether the decoding process is bounded by the capacity of theta rhythm to follow syllabic rhythms in speech, or constrained by a more endogenous top-down mechanism, e.g., involving beta activity, is unknown. We addressed the dynamics of auditory decoding in speech comprehension by challenging syllable tracking and speech decoding using comprehensible and incomprehensible time-compressed auditory sentences. We recorded EEGs in human participants and found that neural activity in both theta and gamma ranges was sensitive to syllabic rate. Phase patterns of slow neural activity consistently followed the syllabic rate (4-14 Hz), even when this rate went beyond the classical theta range (4-8 Hz). The power of theta activity increased linearly with syllabic rate but showed no sensitivity to comprehension. Conversely, the power of beta (14-21 Hz) activity was insensitive to the syllabic rate, yet reflected comprehension on a single trial basis. We found different long-range dynamics for theta and beta activity, with beta activity building up in time while more contextual information becomes available. This is consistent with the roles of theta and beta activity in stimulus-driven versus endogenous mechanisms. These data show that speech comprehension is constrained by concurrent stimulus-driven theta and low-gamma activity, and by endogenous beta activity, but not primarily by the capacity of theta activity to track the syllabic rhythm.SIGNIFICANCE STATEMENT Speech comprehension partly depends on the ability of the auditory cortex to track syllable boundaries with theta-range neural oscillations. The reason comprehension drops when speech is accelerated could hence be because theta oscillations can no longer follow the syllabic rate. Here, we presented subjects with comprehensible and incomprehensible accelerated speech, and show that neural phase patterns in the theta band consistently reflect the syllabic rate, even when speech becomes too fast to be intelligible. The drop in comprehension, however, is signaled by a significant decrease in the power of low-beta oscillations (14-21 Hz). These data suggest that speech comprehension is not limited by the capacity of theta oscillations to adapt to syllabic rate, but by an endogenous decoding process. PMID- 28729442 TI - Adaptive Encoding of Outcome Prediction by Prefrontal Cortex Ensembles Supports Behavioral Flexibility. AB - The prefrontal cortex (PFC) is thought to play a critical role in behavioral flexibility by monitoring action-outcome contingencies. How PFC ensembles represent shifts in behavior in response to changes in these contingencies remains unclear. We recorded single-unit activity and local field potentials in the dorsomedial PFC (dmPFC) of male rats during a set-shifting task that required them to update their behavior, among competing options, in response to changes in action-outcome contingencies. As behavior was updated, a subset of PFC ensembles encoded the current trial outcome before the outcome was presented. This novel outcome-prediction encoding was absent in a control task, in which actions were rewarded pseudorandomly, indicating that PFC neurons are not merely providing an expectancy signal. In both control and set-shifting tasks, dmPFC neurons displayed postoutcome discrimination activity, indicating that these neurons also monitor whether a behavior is successful in generating rewards. Gamma-power oscillatory activity increased before the outcome in both tasks but did not differentiate between expected outcomes, suggesting that this measure is not related to set-shifting behavior but reflects expectation of an outcome after action execution. These results demonstrate that PFC neurons support flexible rule-based action selection by predicting outcomes that follow a particular action.SIGNIFICANCE STATEMENT Tracking action-outcome contingencies and modifying behavior when those contingencies change is critical to behavioral flexibility. We find that ensembles of dorsomedial prefrontal cortex neurons differentiate between expected outcomes when action-outcome contingencies change. This predictive mode of signaling may be used to promote a new response strategy at the service of behavioral flexibility. PMID- 28729446 TI - Meet the First Authors. PMID- 28729444 TI - An Atoh1-S193A Phospho-Mutant Allele Causes Hearing Deficits and Motor Impairment. AB - Atonal homolog 1 (Atoh1) is a basic helix-loop-helix (bHLH) transcription factor that is essential for the genesis, survival, and maturation of a variety of neuronal and non-neuronal cell populations, including those involved in proprioception, interoception, balance, respiration, and hearing. Such diverse functions require fine regulation at the transcriptional and protein levels. Here, we show that serine 193 (S193) is phosphorylated in Atoh1's bHLH domain in vivo Knock-in mice of both sexes bearing a GFP-tagged phospho-dead S193A allele on a null background (Atoh1S193A/lacZ) exhibit mild cerebellar foliation defects, motor impairments, partial pontine nucleus migration defects, cochlear hair cell degeneration, and profound hearing loss. We also found that Atoh1 heterozygous mice of both sexes (Atoh1lacZ/+) have adult-onset deafness. These data indicate that different cell types have different degrees of vulnerability to loss of Atoh1 function and that hypomorphic Atoh1 alleles should be considered in human hearing loss.SIGNIFICANCE STATEMENT The discovery that Atonal homolog 1 (Atoh1) governs the development of the sensory hair cells in the inner ear led to therapeutic efforts to restore these cells in cases of human deafness. Because prior studies of Atoh1-heterozygous mice did not examine or report on hearing loss in mature animals, it has not been clinical practice to sequence ATOH1 in people with deafness. Here, in seeking to understand how phosphorylation of Atoh1 modulates its effects in vivo, we discovered that inner ear hair cells are much more vulnerable to loss of Atoh1 function than other Atoh1-positive cell types and that heterozygous mice actually develop hearing loss late in life. This opens up the possibility that missense mutations in ATOH1 could increase human vulnerability to loss of hair cells because of aging or trauma. PMID- 28729447 TI - The Impact Factor of Circulation Research Reaches a New High. PMID- 28729445 TI - Preferential Disruption of Prefrontal GABAergic Function by Nanomolar Concentrations of the alpha7nACh Negative Modulator Kynurenic Acid. AB - Increased concentrations of kynurenic acid (KYNA) in the prefrontal cortex (PFC) are thought to contribute to the development of cognitive deficits observed in schizophrenia. Although this view is consistent with preclinical studies showing a negative impact of prefrontal KYNA elevation on executive function, the mechanism underlying such a disruption remains unclear. Here, we measured changes in local field potential (LFP) responses to ventral hippocampal stimulation in vivo and conducted whole-cell patch-clamp recordings in brain slices to reveal how nanomolar concentrations of KYNA alter synaptic transmission in the PFC of male adult rats. Our data show that prefrontal infusions of KYNA attenuated the inhibitory component of PFC LFP responses, a disruption that resulted from local blockade of alpha7-nicotinic acetylcholine receptors (alpha7nAChR). At the cellular level, we found that the inhibitory action exerted by KYNA in the PFC occurred primarily at local GABAergic synapses through an alpha7nAChR-dependent presynaptic mechanism. As a result, the excitatory-inhibitory ratio of synaptic transmission becomes imbalanced in a manner that correlates highly with the level of GABAergic suppression by KYNA. Finally, prefrontal infusion of a GABAAR positive allosteric modulator was sufficient to overcome the disrupting effect of KYNA and normalized the pattern of LFP inhibition in the PFC. Thus, the preferential inhibitory effect of KYNA on prefrontal GABAergic transmission could contribute to the onset of cognitive deficits observed in schizophrenia because proper GABAergic control of PFC output is one key mechanism for supporting such cortical functions.SIGNIFICANCE STATEMENT Brain kynurenic acid (KYNA) is an astrocyte-derived metabolite and its abnormal elevation in the prefrontal cortex (PFC) is thought to impair cognitive functions in individuals with schizophrenia. However, the mechanism underlying the disrupting effect of KYNA remains unclear. Here we found that KYNA biases the excitatory-inhibitory balance of prefrontal synaptic activity toward a state of disinhibition. Such disruption emerges as a result of a preferential suppression of local GABAergic transmission by KYNA via presynaptic inhibition of alpha7-nicotinic acetylcholine receptor signaling. Therefore, the degree of GABAergic dysregulation in the PFC could be a clinically relevant contributing factor for the onset of cognitive deficits resulting from abnormal increases of cortical KYNA. PMID- 28729448 TI - Network Mendelian Randomization Study Design to Assess Factors Mediating the Causal Link Between Telomere Length and Heart Disease. PMID- 28729449 TI - Disease Highlights the Cellular Diversity of Neurovascular Units: Sign in Stranger. PMID- 28729450 TI - My Transition From a Postdoctoral Fellowship in the United States to Junior Faculty in Europe: Challenges and Opportunities. PMID- 28729451 TI - Chantal M. Boulanger: Exploring the Endothelium. PMID- 28729452 TI - Setting the Agenda for Preventive Cardiology. PMID- 28729453 TI - PI3K and Calcium Signaling in Cardiovascular Disease. AB - Receptor signaling relays on intracellular events amplified by secondary and tertiary messenger molecules. In cardiomyocytes and smooth muscle cells, cyclic AMP (cAMP) and subsequent calcium (Ca2+) fluxes are the best characterized receptor-regulated signaling events. However, most of receptors able to modify contractility and other intracellular responses signal through a variety of other messengers, and whether these signaling events are interconnected has long remained unclear. For example, the PI3K (phosphoinositide 3-kinase) pathway connected to the production of the lipid second messenger PIP3/PtdIns(3,4,5)P3 (phosphatidylinositol (3,4,5)-trisphosphate) is potentially involved in metabolic regulation, activation of hypertrophy, and survival pathways. Recent studies, highlighted in this review, started to interconnect PI3K pathway activation to Ca2+ signaling. This interdependency, by balancing contractility with metabolic control, is crucial for cells of the cardiovascular system and is emerging to play key roles in disease development. Better understanding of the interplay between Ca2+ and PI3K signaling is, thus, expected to provide new ground for therapeutic intervention. This review explores the emerging molecular mechanisms linking Ca2+ and PI3K signaling in health and disease. PMID- 28729454 TI - Multimodal Regulation of Cardiac Myocyte Proliferation. AB - Efficient cardiac regeneration is closely associated with the ability of cardiac myocytes to proliferate. Fetal or neonatal mouse hearts containing proliferating cardiac myocytes regenerate even extensive injuries, whereas adult hearts containing mostly post-mitotic cardiac myocytes have lost this ability. The same correlation is seen in some homoiotherm species such as teleost fish and urodelian amphibians leading to the hypothesis that cardiac myocyte proliferation is a major driver of heart regeneration. Although cardiomyocyte proliferation might not be the only prerequisite to restore full organ function after cardiac damage, induction of cardiac myocyte proliferation is an attractive therapeutic option to cure the injured heart and prevent heart failure. To (re)initiate cardiac myocyte proliferation in adult mammalian hearts, a thorough understanding of the molecular circuitry governing cardiac myocyte cell cycle regulation is required. Here, we review the current knowledge in the field focusing on the withdrawal of cardiac myocytes from the cell cycle during the transition from neonatal to adult stages. PMID- 28729455 TI - Department of Health balances books-but at a price, say experts. PMID- 28729457 TI - History taking is a complex skill. PMID- 28729456 TI - Mechanistic Multi-Tissue Modeling of Glucocorticoid-Induced Leucine Zipper Regulation: Integrating Circadian Gene Expression with Receptor-Mediated Corticosteroid Pharmacodynamics. AB - The glucocorticoid-induced leucine zipper (GILZ) is an important mediator of anti inflammatory corticosteroid action. The pharmacokinetic/pharmacodynamic/pharmacogenomic effects of acute and chronic methylprednisolone (MPL) dosing on the tissue-specific dynamics of GILZ expression were examined in rats. A mechanism-based model was developed to investigate and integrate the role of MPL and circadian rhythms on the transcriptional enhancement of GILZ in multiple tissues. Animals received a single 50-mg/kg intramuscular bolus or a 7-day 0.3-mg/kg/h subcutaneous infusion of MPL and were euthanized at several time points. An additional group of rats were euthanized at several times and served as 24-hour light/dark (circadian) controls. Plasma MPL and corticosterone concentrations were measured by high performance liquid chromatography. The expression of GILZ and glucocorticoid receptor (GR) mRNA was quantified in tissues using quantitative real-time reverse transcription polymerase chain reaction. The pharmacokinetics of MPL were described using a two-compartment model. Mild-to-robust circadian oscillations in GR and GILZ mRNA expression were characterized in muscle, lung, and adipose tissues and modeled using Fourier harmonic functions. Acute MPL dosing caused significant down-regulation (40%-80%) in GR mRNA and enhancement of GILZ mRNA expression (500%-1080%) in the tissues examined. While GILZ returned to its rhythmic baseline following acute dosing, a new steady-state was observed upon enhancement by chronic dosing. The model captured the complex dynamics in all tissues for both dosing regimens. The model quantitatively integrates physiologic mechanisms, such as circadian processes and GR tolerance phenomena, which control the tissue-specific regulation of GILZ by corticosteroids. These studies characterize GILZ as a pharmacodynamic marker of corticosteroid actions in several tissues. PMID- 28729458 TI - The Junior Faculty Networking Cohort: Filling a gap in support for our community. AB - JGP, in partnership with the Society of General Physiologists, announces a new networking and mentoring program for junior faculty. PMID- 28729459 TI - Enhancing the usability of systematic reviews by improving the consideration and description of interventions. PMID- 28729460 TI - Management of patients after primary percutaneous coronary intervention for myocardial infarction. PMID- 28729462 TI - Archives of and for science: Archives for molecular biology preserve the heritage of science beyond the published record for future scholars. PMID- 28729461 TI - Morphology of the archaellar motor and associated cytoplasmic cone in Thermococcus kodakaraensis. AB - Archaeal swimming motility is driven by archaella: rotary motors attached to long extracellular filaments. The structure of these motors, and particularly how they are anchored in the absence of a peptidoglycan cell wall, is unknown. Here, we use electron cryotomography to visualize the archaellar basal body in vivo in Thermococcus kodakaraensis KOD1. Compared to the homologous bacterial type IV pilus (T4P), we observe structural similarities as well as several unique features. While the position of the cytoplasmic ATPase appears conserved, it is not braced by linkages that extend upward through the cell envelope as in the T4P, but rather by cytoplasmic components that attach it to a large conical frustum up to 500 nm in diameter at its base. In addition to anchoring the lophotrichous bundle of archaella, the conical frustum associates with chemosensory arrays and ribosome-excluding material and may function as a polar organizing center for the coccoid cells. PMID- 28729463 TI - Dietary PUFAs attenuate NLRP3 inflammasome activation via enhancing macrophage autophagy. AB - Dietary PUFAs reduce atherosclerosis and macrophage inflammation, but how nucleotide-binding oligomerization domain leucine-rich repeat-containing receptor protein (NLRP3) inflammasome activation and autophagy influence PUFA-mediated atheroprotection is poorly understood. We fed Ldlr-/- mice diets containing 10% (calories) palm oil (PO) and 0.2% cholesterol, supplemented with an additional 10% of calories as PO, fish oil (FO), echium oil (EO, containing 18:4 n-3), or borage oil (BO, containing 18:3 n-6). Inflammasome activation, autophagic flux, and mitochondrial function were measured in peritoneal macrophages, blood monocytes, or liver from diet-fed mice. Compared with PO, dietary PUFAs (FO, EO, or BO) markedly inhibited inflammasome activation, shown by 1) less macrophage IL 1beta secretion and caspase-1 cleavage in response to NLRP3 inflammasome activators, 2) less IL-1beta secretion and caspase-1 cleavage from liver or hepatocytes in response to lipopolysaccharide (LPS), and 3) attenuated caspase-1 activity in blood monocytes. Furthermore, PUFA-enriched diets increased LC3-II expression in macrophage, aorta, and liver samples and reduced numbers of dysfunctional mitochondria in macrophages in response to LPS and palmitate, suggesting enhanced autophagic activation. Dietary PUFAs did not attenuate NLRP3 inflammasome activation in atg5-deficient macrophages, indicating that autophagic activation is critical for the PUFA-mediated inflammasome inactivation. In conclusion, dietary PUFAs reduce atherosclerosis, in part, by activation of macrophage autophagy and attenuation of NLRP3 inflammasome activation. PMID- 28729464 TI - miR-15a-5p levels correlate with poor ovarian response in human follicular fluid. AB - Poor ovarian response is a significant problem encountered during in vitro fertilization and embryo transfer procedures. Many infertile women may suffer from poor ovarian response and its incidence tends to be increasing in young patients nowadays. It is a major cause of maternal infertility because it is associated with low pregnancy and live birth rates. However, the cause of poor ovarian response is not clear. In this study, we extracted microRNAs from human follicular fluid and performed miRNA sequencing to investigate a potential posttranscriptional mechanism underlying poor ovarian response. The results showed that many miRNAs were obviously different between the poor ovarian response and non-poor ovarian response groups. We then performed quantitative polymerase chain reaction, Western blot analysis and used an in vitro culture system to verify the sequencing results and to study the mechanism. Notably, we found that miRNA-15a-5p was significantly elevated in the young poor ovarian response group. Furthermore, we demonstrated that high levels of miR-15a-5p in the young poor ovarian response group repressed granulosa cell proliferation by regulating the PI3K-AKT-mTOR signaling pathway and promoted apoptosis through BCL2 and BAD. This could explain the reduced oocyte retrieval number seen in poor ovarian response patients. PMID- 28729465 TI - Steroid hormones regulate sperm-oviduct interactions in the bovine. AB - After insemination in the cow, a sperm reservoir is formed within the oviducts, allowing the storage and then progressive release of spermatozoa toward the ovulated oocyte. In order to investigate the hormonal regulation of these events in vitro, the ovarian steroids 17beta-estradiol (E2) and progesterone (P4) were added at various concentrations to monolayers of bovine oviduct epithelial cells (BOEC) before or during co-incubation with spermatozoa. Main findings demonstrate that (1) a 18-h pretreatment of BOEC with 100 pg/mL and 100 ng/mL of E2 decreased by 25% the ability of BOEC to bind spermatozoa after 10 min, and for the highest dose of E2, 60 min of co-incubation; (2) P4 at concentrations of 10, 100 and 1000 ng/mL induced the release within 60 min of 32-47% of bound spermatozoa from BOEC; this sperm-releasing effect was maintained after a 18-h pretreatment of BOEC with 100 pg/mL of E2; (3) E2 in concentrations above 100 pg/mL inhibited the releasing effect of P4 on bound sperm in a dose-dependent manner; (4) spermatozoa bound to BOEC, then released from BOEC by the action of P4-induced higher cleavage and blastocyst rates after in vitro fertilization than the control group. These results support the hypothesis that the dynamic changes in steroid hormones around the time of ovulation regulate the formation of the sperm reservoir and the timed delivery of capacitated spermatozoa to the site of fertilization. PMID- 28729466 TI - Government allocates L325m to England's "most advanced" STPs. PMID- 28729467 TI - STAT3 activation by leptin receptor is essential for TNBC stem cell maintenance. AB - Leptin (LEP) binds to the long form of the leptin receptor (LEPRb), leading to the activation of multiple signaling pathways that are potential targets for disrupting the obesity-breast cancer link. In triple-negative breast cancer (TNBC), LEP is hypothesized to predominantly mediate its tumorigenic effects via a subpopulation of LEPRb-positive tumor cells termed cancer stem cells (CSCs) that can initiate tumors and induce tumor progression. Previously, we showed that LEP promotes CSC survival in vivo Moreover, silencing LEPRb in TNBC cells compromised the CSC state. The mechanisms by which LEPRb regulates TNBC CSC intracellular signaling are not clear. We hypothesized that activation of LEPRb signaling is sufficient to drive CSC maintenance in TNBC. Here, we show that activation of LEPRb in non-CSCs isolated using our CSC reporter system resulted in a transition to the stem cell state. In CSCs, LEP induced STAT3 phosphorylation, whereas LEP did not induce STAT3 phosphorylation in non-CSCs. Introduction of constitutively active STAT3 into LEPRb-transfected non-CSCs significantly induced NANOG, SOX2 and OCT4 expression compared with control non CSCs. To determine the intracellular phospho-tyrosine residue of LEPRb that is necessary for the induction of the stem cell state in non-CSCs, we transfected the tyrosine residue point mutants L985, F1077 and S1138 into non-CSCs. Non-CSCs transfected with the L985 mutant exhibited increased STAT3 phosphorylation, increased SOCS3 expression and an induction of GFP expression compared with non CSCs expressing the F1077 and S1138 mutants. Our data demonstrate that LEPRb induced STAT3 activation is essential for the induction and maintenance of TNBC CSCs. PMID- 28729469 TI - Compulsory vaccination and growing measles threat. PMID- 28729468 TI - A case of a metastatic SDHA mutated paraganglioma re-presenting twenty-three years after initial surgery. PMID- 28729470 TI - Detection and monitoring of lung inflammation in cystic fibrosis during respiratory tract exacerbation using diffusion-weighted magnetic resonance imaging. AB - The aim was to investigate whether diffusion-weighted magnetic resonance imaging (DWI) detects and monitors inflammatory and lung function changes during respiratory tract exacerbations (RTE) treatment in patients with cystic fibrosis (CF).29 patients with RTE underwent DWI pre- and post-antibiotic treatment. A control group of 27 stable patients, matched for age and sex, underwent DWI with the same time gap as those undergoing RTE treatment. Clinical status and lung function were assessed at each DWI time point. The CF-MRI scoring system was used to assess structural lung changes in both CF groups.Significant reduction in the DWI score over the course of antibiotic treatment (p<0.0001) was observed in patients with RTE, but not in the control group. DWI score had a strong inverse correlation with clinical status (r=-0.504, p<0.0001) and lung function (r= 0.635, p<0.0001) in patients with RTE. Interestingly, there were persistent significant differences in the CF-MRI score between the RTE and control group at both baseline and follow-up (p<0.001), while the differences in DWI score were only observed at baseline (p<0.001).DWI is a promising imaging method for noninvasive detection of pulmonary inflammation during RTE, and may be used to monitor treatment efficacy of anti-inflammatory treatment. PMID- 28729472 TI - Rifampicin-resistant tuberculosis: what is the best initial empiric regimen in Mumbai, India? PMID- 28729471 TI - Hypoxic vascular response and ventilation/perfusion matching in end-stage COPD may depend on p22phox. AB - Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease in which the amount of emphysema and airway disease may be very different between individuals, even in end-stage disease. Emphysema formation may be linked to the involvement of the small pulmonary vessels. The NAPDH oxidase (Nox) family is emerging as a key disease-related factor in vascular diseases, but currently its role in hypoxia-induced pulmonary remodelling in COPD remains unclear.Here we investigate the role of p22phox, a regulatory subunit of Nox, in COPD lungs, hypoxic pulmonary vasoconstriction (HPV), hypoxia-induced pulmonary vascular remodelling and pulmonary hypertension.In COPD, compared to control lungs, p22phox expression was significantly reduced. The expression was correlated positively with mean pulmonary arterial pressure and oxygenation index and negatively with the diffusing capacity of the lung for carbon monoxide (p<0.02). This suggests a role of p22phox in ventilation/perfusion ratio matching, vascular remodelling and loss of perfused lung area. In p22phox-/- mice, HPV was significantly impaired. In the chronic hypoxic setting, lack of p22phox was associated with improved right ventricular function and decreased pulmonary vascular remodelling.p22phox-dependent Nox plays an important role in the COPD phenotype, by its action on phase II HPV and chronic vascular remodelling. PMID- 28729473 TI - Automatic versus manual oxygen administration in the emergency department. AB - Oxygen is commonly administered in hospitals, with poor adherence to treatment recommendations.We conducted a multicentre randomised controlled study in patients admitted to the emergency department requiring O2 >=3 L.min-1 Patients were randomised to automated closed-loop or manual O2 titration during 3 h. Patients were stratified according to arterial carbon dioxide tension (PaCO2 ) (hypoxaemic PaCO2 <=45 mmHg; or hypercapnic PaCO2 >45-<=55 mmHg) and study centre. Arterial oxygen saturation measured by pulse oximetry (SpO2 ) goals were 92-96% for hypoxaemic, or 88-92% for hypercapnic patients. Primary outcome was % time within SpO2 target. Secondary endpoints were hypoxaemia and hyperoxia prevalence, O2 weaning, O2 duration and hospital length of stay.187 patients were randomised (93 automated, 94 manual) and baseline characteristics were similar between the groups. Time within the SpO2 target was higher under automated titration (81+/-21% versus 51+/-30%, p<0.001). Time with hypoxaemia (3+/-9% versus 5+/-12%, p=0.04) and hyperoxia under O2 (4+/-9% versus 22+/-30%, p<0.001) were lower with automated titration. O2 could be weaned at the end of the study in 14.1% versus 4.3% patients in the automated and manual titration group, respectively (p<0.001). O2 duration during the hospital stay was significantly reduced (5.6+/-5.4 versus 7.1+/-6.3 days, p=0.002).Automated O2 titration in the emergency department improved oxygenation parameters and adherence to guidelines, with potential clinical benefits. PMID- 28729475 TI - Can toxicities induced by antituberculosis drugs be better managed in diabetic patients? PMID- 28729474 TI - Trilateral overlap of tuberculosis, diabetes and HIV-1 in a high-burden African setting: implications for TB control. AB - The diabetes mellitus burden is growing in countries where tuberculosis (TB) and HIV-1 remain major challenges, threatening TB control efforts. This study determined the association between TB and diabetes/impaired glucose regulation in the context of HIV-1.A cross-sectional study was conducted at a TB clinic in Cape Town (South Africa). Participants were screened for diabetes and impaired glucose regulation using fasting plasma glucose, oral glucose tolerance test and glycated haemoglobin (HbA1c).414 TB and 438 non-TB participants were enrolled. In multivariable analysis, diabetes was associated with TB (OR 2.4, 95% CI 1.3-4.3; p=0.005), with 14% population-attributable risk fraction; however, this association varied by diagnostic test (driven by HbA1c). The association remained significant in HIV-1-infected individuals (OR 2.4, 95% CI 1.1-5.2; p=0.030). A high prevalence of impaired glucose regulation (65.2% among TB cases) and a significant association with TB (OR 2.3, 95% CI 1.6-3.3; p<0.001) was also found.Diabetes and impaired glucose regulation prevalence was high and associated with TB, particularly in HIV-1-infected individuals, highlighting the importance of diabetes screening. The variation in findings by diagnostic test highlights the need for better glycaemia markers to inform screening in the context of TB and HIV-1. PMID- 28729476 TI - Shortened multidrug-resistant tuberculosis treatment in settings with a high prevalence of ofloxacin resistance. PMID- 28729477 TI - Blood eosinophil count and exacerbation risk in patients with COPD. PMID- 28729478 TI - Intelligent oxygen delivery in the acute setting: "Don't think twice, it's all right". PMID- 28729479 TI - Hypoxic pulmonary vasoconstriction in COPD-associated pulmonary hypertension: been there, done that? PMID- 28729480 TI - Home spirometry for idiopathic pulmonary fibrosis: ready for prime time? PMID- 28729481 TI - The Art of Breathing: Exchange. PMID- 28729482 TI - BRCA1 and BRCA2 tumor suppressors protect against endogenous acetaldehyde toxicity. AB - Maintenance of genome integrity requires the functional interplay between Fanconi anemia (FA) and homologous recombination (HR) repair pathways. Endogenous acetaldehyde, a product of cellular metabolism, is a potent source of DNA damage, particularly toxic to cells and mice lacking the FA protein FANCD2. Here, we investigate whether HR-compromised cells are sensitive to acetaldehyde, similarly to FANCD2-deficient cells. We demonstrate that inactivation of HR factors BRCA1, BRCA2, or RAD51 hypersensitizes cells to acetaldehyde treatment, in spite of the FA pathway being functional. Aldehyde dehydrogenases (ALDHs) play key roles in endogenous acetaldehyde detoxification, and their chemical inhibition leads to cellular acetaldehyde accumulation. We find that disulfiram (Antabuse), an ALDH2 inhibitor in widespread clinical use for the treatment of alcoholism, selectively eliminates BRCA1/2-deficient cells. Consistently, Aldh2 gene inactivation suppresses proliferation of HR-deficient mouse embryonic fibroblasts (MEFs) and human fibroblasts. Hypersensitivity of cells lacking BRCA2 to acetaldehyde stems from accumulation of toxic replication-associated DNA damage, leading to checkpoint activation, G2/M arrest, and cell death. Acetaldehyde-arrested replication forks require BRCA2 and FANCD2 for protection against MRE11-dependent degradation. Importantly, acetaldehyde specifically inhibits in vivo the growth of BRCA1/2-deficient tumors and ex vivo in patient-derived tumor xenograft cells (PDTCs), including those that are resistant to poly (ADP-ribose) polymerase (PARP) inhibitors. The work presented here therefore identifies acetaldehyde metabolism as a potential therapeutic target for the selective elimination of BRCA1/2-deficient cells and tumors. PMID- 28729484 TI - Comment on "The [4Fe4S] cluster of human DNA primase functions as a redox switch using DNA charge transport". AB - O'Brien et al (Research Article, 24 February 2017, eaag1789) proposed a novel mechanism of primase function based on redox activity of the iron-sulfur cluster buried inside the C-terminal domain of the large primase subunit (p58C). Serious problems in the experimental design and data interpretation raise concerns about the validity of the conclusions. PMID- 28729483 TI - Epigenetic plasticity and the hallmarks of cancer. AB - Chromatin and associated epigenetic mechanisms stabilize gene expression and cellular states while also facilitating appropriate responses to developmental or environmental cues. Genetic, environmental, or metabolic insults can induce overly restrictive or overly permissive epigenetic landscapes that contribute to pathogenesis of cancer and other diseases. Restrictive chromatin states may prevent appropriate induction of tumor suppressor programs or block differentiation. By contrast, permissive or "plastic" states may allow stochastic oncogene activation or nonphysiologic cell fate transitions. Whereas many stochastic events will be inconsequential "passengers," some will confer a fitness advantage to a cell and be selected as "drivers." We review the broad roles played by epigenetic aberrations in tumor initiation and evolution and their potential to give rise to all classic hallmarks of cancer. PMID- 28729486 TI - Comment on "The [4Fe4S] cluster of human DNA primase functions as a redox switch using DNA charge transport". AB - O'Brien et al (Research Article, 24 February 2017, eaag1789) report that the iron sulfur cluster of primase has a redox role in enzyme activity. Their analysis is based on a partially misfolded structure of the iron-sulfur cluster domain of primase. In the correctly folded structure, two of the three tyrosines putatively involved in electron transfer, Y345 and Y347, contact the RNA/DNA helix, providing an alternative explanation for the data of O'Brien et al. PMID- 28729485 TI - Response to Comments on "The [4Fe4S] cluster of human DNA primase functions as a redox switch using DNA charge transport". AB - Baranovskiy et al and Pellegrini argue that, based on structural data, the path for charge transfer through the [4Fe4S] domain of primase is not feasible. Our manuscript presents electrochemical data directly showing charge transport through DNA to the [4Fe4S] cluster of a primase p58C construct and a reversible switch in the DNA-bound signal with oxidation/reduction, which is inhibited by mutation of three tyrosine residues. Although the dispositions of tyrosines differ in different constructs, all are within range for microsecond electron transfer. PMID- 28729487 TI - How to govern geoengineering? PMID- 28729488 TI - News at a glance. PMID- 28729489 TI - NIH redefines clinical trials, attracting critics. PMID- 28729490 TI - Gender discrimination lawsuit at Salk ignites controversy. PMID- 28729491 TI - The first Australians arrived early. PMID- 28729492 TI - Unlocking a key to maize's amazing success. PMID- 28729493 TI - Zika rewrites maternal immunization ethics. PMID- 28729494 TI - Saving Europe's salamanders. PMID- 28729495 TI - Sulfur injections for a cooler planet. PMID- 28729496 TI - A cirrus cloud climate dial? PMID- 28729497 TI - Sliding chains keep particles together. PMID- 28729498 TI - Tuna fin hydraulics inspire aquatic robotics. PMID- 28729499 TI - A twist on the Majorana fermion. PMID- 28729500 TI - Can immunotherapy treat neurodegeneration? PMID- 28729501 TI - Promote scientific integrity via journal peer review data. PMID- 28729502 TI - Flawed environmental justice analyses. PMID- 28729503 TI - Mexico's basic science funding falls short. PMID- 28729504 TI - Fringe on the brink: Intertidal reefs at risk. PMID- 28729505 TI - Cash for carbon: A randomized trial of payments for ecosystem services to reduce deforestation. AB - We evaluated a program of payments for ecosystem services in Uganda that offered forest-owning households annual payments of 70,000 Ugandan shillings per hectare if they conserved their forest. The program was implemented as a randomized controlled trial in 121 villages, 60 of which received the program for 2 years. The primary outcome was the change in land area covered by trees, measured by classifying high-resolution satellite imagery. We found that tree cover declined by 4.2% during the study period in treatment villages, compared to 9.1% in control villages. We found no evidence that enrollees shifted their deforestation to nearby land. We valued the delayed carbon dioxide emissions and found that this program benefit is 2.4 times as large as the program costs. PMID- 28729506 TI - Highly elastic binders integrating polyrotaxanes for silicon microparticle anodes in lithium ion batteries. AB - Lithium-ion batteries with ever-increasing energy densities are needed for batteries for advanced devices and all-electric vehicles. Silicon has been highlighted as a promising anode material because of its superior specific capacity. During repeated charge-discharge cycles, silicon undergoes huge volume changes. This limits cycle life via particle pulverization and an unstable electrode-electrolyte interface, especially when the particle sizes are in the micrometer range. We show that the incorporation of 5 weight % polyrotaxane to conventional polyacrylic acid binder imparts extraordinary elasticity to the polymer network originating from the ring sliding motion of polyrotaxane. This binder combination keeps even pulverized silicon particles coalesced without disintegration, enabling stable cycle life for silicon microparticle anodes at commercial-level areal capacities. PMID- 28729507 TI - Remobilization of crustal carbon may dominate volcanic arc emissions. AB - The flux of carbon into and out of Earth's surface environment has implications for Earth's climate and habitability. We compiled a global data set for carbon and helium isotopes from volcanic arcs and demonstrated that the carbon isotope composition of mean global volcanic gas is considerably heavier, at -3.8 to -4.6 per mil (0/00), than the canonical mid-ocean ridge basalt value of -6.00/00. The largest volcanic emitters outgas carbon with higher delta13C and are located in mature continental arcs that have accreted carbonate platforms, indicating that reworking of crustal limestone is an important source of volcanic carbon. The fractional burial of organic carbon is lower than traditionally determined from a global carbon isotope mass balance and may have varied over geological time, modulated by supercontinent formation and breakup. PMID- 28729508 TI - Chiral Majorana fermion modes in a quantum anomalous Hall insulator superconductor structure. AB - Majorana fermion is a hypothetical particle that is its own antiparticle. We report transport measurements that suggest the existence of one-dimensional chiral Majorana fermion modes in the hybrid system of a quantum anomalous Hall insulator thin film coupled with a superconductor. As the external magnetic field is swept, half-integer quantized conductance plateaus are observed at the locations of magnetization reversals, giving a distinct signature of the Majorana fermion modes. This transport signature is reproducible over many magnetic field sweeps and appears at different temperatures. This finding may open up an avenue to control Majorana fermions for implementing robust topological quantum computing. PMID- 28729509 TI - Experimentally realized mechanochemistry distinct from force-accelerated scission of loaded bonds. AB - Stretching polymer chains accelerates dissociation of a variety of internal covalent bonds, to an extent that correlates well with the force experienced by the scissile bond. Recent theory has also predicted scenarios in which applied force accelerates dissociation of unloaded bonds and kinetically strengthens strained bonds. We report here unambiguous experimental validation of this hypothesis: Detailed kinetic measurements demonstrate that stretching phosphotriesters accelerates dissociation of the unloaded phosphorus-oxygen bond orthogonal to the pulling axis, whereas stretching organosiloxanes inhibits dissociation of the aligned loaded silicon-oxygen bonds. Qualitatively, the outcome is determined by phosphoester elongation and siloxane contraction along the pulling axis in the respective rate-determining transition states. Quantitatively, the results agree with a simple mechanochemical kinetics model. PMID- 28729510 TI - Tailored semiconductors for high-harmonic optoelectronics. AB - The advent of high-harmonic generation in gases 30 years ago set the foundation for attosecond science and facilitated ultrafast spectroscopy in atoms, molecules, and solids. We explore high-harmonic generation in the solid state by means of nanostructured and ion-implanted semiconductors. We use wavelength selective microscopic imaging to map enhanced harmonic emission and show that the generation medium and the driving field can be locally tailored in solids by modifying the chemical composition and morphology. This enables the control of high-harmonic technology within precisely engineered solid targets. We demonstrate customized high-harmonic wave fields with wavelengths down to 225 nanometers (ninth-harmonic order of 2-micrometer laser pulses) and present an integrated Fresnel zone plate target in silicon, which leads to diffraction limited self-focusing of the generated harmonics down to 1-micrometer spot sizes. PMID- 28729511 TI - An organic-inorganic perovskite ferroelectric with large piezoelectric response. AB - Molecular piezoelectrics are highly desirable for their easy and environment friendly processing, light weight, low processing temperature, and mechanical flexibility. However, although 136 years have passed since the discovery in 1880 of the piezoelectric effect, molecular piezoelectrics with a piezoelectric coefficient d33 comparable with piezoceramics such as barium titanate (BTO; ~190 picocoulombs per newton) have not been found. We show that trimethylchloromethyl ammonium trichloromanganese(II), an organic-inorganic perovskite ferroelectric crystal processed from aqueous solution, has a large d33 of 185 picocoulombs per newton and a high phase-transition temperature of 406 kelvin (K) (16 K above that of BTO). This makes it a competitive candidate for medical, micromechanical, and biomechanical applications. PMID- 28729512 TI - Hydraulic control of tuna fins: A role for the lymphatic system in vertebrate locomotion. AB - The lymphatic system in teleost fish has genetic and developmental origins similar to those of the mammalian lymphatic system, which is involved in immune response and fluid homeostasis. Here, we show that the lymphatic system of tunas functions in swimming hydrodynamics. Specifically, a musculo-vascular complex, consisting of fin muscles, bones, and lymphatic vessels, is involved in the hydraulic control of median fins. This specialization of the lymphatic system is associated with fish in the family Scombridae and may have evolved in response to the demand for swimming and maneuvering control in these high-performance species. PMID- 28729514 TI - The call of the wild. PMID- 28729513 TI - Bidirectional eukaryotic DNA replication is established by quasi-symmetrical helicase loading. AB - Bidirectional replication from eukaryotic DNA replication origins requires the loading of two ring-shaped minichromosome maintenance (MCM) helicases around DNA in opposite orientations. MCM loading is orchestrated by binding of the origin recognition complex (ORC) to DNA, but how ORC coordinates symmetrical MCM loading is unclear. We used natural budding yeast DNA replication origins and synthetic DNA sequences to show that efficient MCM loading requires binding of two ORC molecules to two ORC binding sites. The relative orientation of these sites, but not the distance between them, was found to be critical for MCM loading in vitro and origin function in vivo. We propose that quasi-symmetrical loading of individual MCM hexamers by ORC and directed MCM translocation into double hexamers acts as a unifying mechanism for the establishment of bidirectional replication in archaea and eukaryotes. PMID- 28729515 TI - Assessing the health and well-being of gay, bisexual and other men who have sex with men around the world. PMID- 28729516 TI - High HIV incidence in men who have sex with men following an early syphilis diagnosis: is there room for pre-exposure prophylaxis as a prevention strategy? AB - OBJECTIVES: HIV pre-exposure prophylaxis (PrEP) is becoming a pivotal strategy for HIV prevention. Understanding the impact of risk factors for HIV transmission to identify those at highest risk would favour the implementation of PrEP, currently limited by costs. In this service evaluation, we estimated the incidence of bacterial STIs in men who have sex with men (MSM) diagnosed with early syphilis attending a London sexual health clinic according to their HIV status. In addition, we estimated the incidence of HIV infection in HIV-negative MSM, following a diagnosis of early syphilis. METHODS: We undertook a retrospective case note review of all MSM patients diagnosed with early syphilis between January and June 2014. A number of sexual health screens and diagnoses of chlamydia, gonorrhoea and HIV were prospectively analysed following the syphilis diagnosis. RESULTS: 206 MSM were diagnosed with early syphilis. 110 (53%) were HIV-negative at baseline, 96 (47%) were HIV-positive. Only age (37 vs 32 years, p=0.0005) was significantly different according to HIV status of MSM at baseline. In HIV-negative versus HIV-positive MSM, incidence of rectal chlamydia infection at follow-up was 27 cases vs 50/100 person-years of follow-up (PYFU) (p=0.0039), 33 vs 66/100 PYFU (p=0.0044) for rectal gonorrhoea and 10 vs 26/100 PYFU (p=0.0044) for syphilis reinfection, respectively. Total follow-up for 110 HIV negative MSM was 144 person-years. HIV incidence was 8.3/100 PYFU (CI 4.2 to 14). CONCLUSIONS: A diagnosis of early syphilis carries a high risk of consequent HIV seroconversion and should warrant prioritised access to prevention measures such as PrEP and regular STI screening to prevent HIV transmission. PMID- 28729517 TI - Risk perception in MSM taking prep: a survey. PMID- 28729518 TI - Few men who have sex with men (MSM) attending two inner-city clinics were tested for hepatitis C virus (HCV) despite high risk: a retrospective analysis of sexual health screening in East London. PMID- 28729519 TI - A combined multiplex PCR test for herpes simplex-1/2 and Treponema pallidum: a review of 5-year routine use. PMID- 28729520 TI - Challenges and emerging opportunities for the HIV prevention, treatment and care cascade in men who have sex with men in Asia Pacific. AB - In Asia Pacific, most countries have expanded HIV treatment guidelines to include all those with HIV infection and adopted antiretroviral treatment for prevention (TFP) as a blanket strategy for HIV control. Although the overall epidemic development associated with this focus is positive, the HIV epidemic in men who have sex with men (MSM) is continuing unperturbed without any signs of decline or reversal. This raises doubt about whether TFP as a blanket HIV prevention policy is the right approach. This paper reviews currently available biomedical HIV prevention strategies, national HIV prevention policies and guidelines from selected countries and published data on the HIV cascade in MSM. No evidence for efficacy of TFP in protecting MSM from HIV infection was found. The rationale for this approach is based on assumptions about biological plausibility and external validity of latency-based efficacy found in heterosexual couples. This is different from the route and timing of HIV transmission in MSM. New HIV infections in MSM principally occur in chains of acutely HIV-infected highly sexually active young men, in whom acquisition and transmission are correlated in space and time. By the time TFP renders its effects, most new HIV infections in MSM will have already occurred. On a global level, less than 6% of all reports regarding the HIV care cascade from 1990 to 2016 included MSM, and only 2.3% concerned MSM in low/middle-income countries. Only one report originated from Asia Pacific. Generally, HIV cascade data in MSM show a sobering picture of TFP in engaging and retaining MSM along the continuum. Widening the cascade with a preventive extension, including pre-exposure prophylaxis, the first proven efficacious and only biomedical HIV prevention strategy in MSM, will be instrumental in achieving HIV epidemic control in this group. PMID- 28729521 TI - Influence of block copolymer feature size on reactive ion etching pattern transfer into silicon. AB - A successful realisation of sub-20 nm features on silicon (Si) is becoming the focus of many technological studies, strongly influencing the future performance of modern integrated circuits. Although reactive ion etching (RIE), at both micrometric and nanometric scale has already been the target of many studies, a better understanding of the different mechanisms involved at sub-20 nm size etching is still required. In this work, we investigated the influence of the feature size on the etch rate of Si, performed by a cryogenic RIE process through cylinder-forming polystyrene-block-polymethylmethacrylate (PS-b-PMMA) diblock copolymer (DBC) masks with diameter ranging between 19-13 nm. A sensible decrease of the etch depth and etch rate was observed in the mask with the smallest feature size. For all the DBCs under investigation, we determined the process window useful for the correct transfer of the nanometric cylindrical pattern into a Si substrate. A structural and physicochemical investigation of the resulting nanostructured Si is reported in order to delineate the influence of various RIE pattern effects. Feature-size-dependent etch, or RIE-lag, is proved to significantly affect the obtained results. PMID- 28729522 TI - Site-controlled and advanced epitaxial Ge/Si quantum dots: fabrication, properties, and applications. AB - In this review, we report on fabrication paths, challenges, and emerging solutions to integrate group-IV epitaxial quantum dots (QDs) as active light emitters into the existing standard Si technology. Their potential as laser gain material for the use of optical intra- and inter-chip interconnects as well as possibilities to combine a single-photon-source-based quantum cryptographic means with Si technology will be discussed. We propose that the mandatory addressability of the light emitters can be achieved by a combination of organized QD growth assisted by templated self-assembly, and advanced inter-QD defect engineering to boost the optical emissivity of group-IV QDs at room temperature. Those two main parts, the site-controlled growth and the light emission enhancement in QDs through the introduction of single defects build the main body of the review. This leads us to a roadmap for the necessary further development of this emerging field of CMOS-compatible group-IV QD light emitters for on-chip applications. PMID- 28729523 TI - Malignancy Rates of Thyroid Cytology: Cyst Fluid Benign or Non-Diagnostic? AB - BACKGROUND We sought to investigate subgroup distribution using Bethesda classification and risks for malignancy. We also compared the malignancy risk of cases that were denoted as non-diagnostic due to cystic contents, with cases that were denoted as non-diagnostic due to presence of other features. MATERIAL AND METHODS The study included pathology test results of 1,440 thyroid nodule samples diagnosed using Bethesda classification. Results of 305 thyroidectomy excision specimens from these patients were also compared with cytology results to determine the frequency of malignancy. The non-diagnostic group was divided into two categories: those with cystic contents, and others. Malignancy rates were separately calculated for the two groups, and compared with the other classification groups. RESULTS Distribution of malignancy rates by Bethesda classification were as follows: non-diagnostic 12.5% (6/48), benign 1.5% (3/198), atypia of undetermined significance/follicular lesion of undetermined significance (AFLUS) 9% (1/11), suspicious for follicular neoplasm (SFN) 37.5% (3/8), suspicious malignancy 70% (8/26), malignancy 100% (14/14). CONCLUSIONS Despite the limited number of cases, our study concluded that cystic content was closer to the benign category than the non-diagnostic category if the assessment was based on malignancy rates. In this group, similar to aspirations containing plenty of lymphocytes that indicates colloid or lymphocytic thyroiditis, it is still controversial whether criterion for adequacy of follicular epithelial cells should be sought, or if they should be regarded as benign in order to prevent unnecessarily performance of repeat aspirations. PMID- 28729524 TI - Cardiac Arrest Following Drug Abuse with Intravenous Tapentadol: Case Report and Literature Review. AB - BACKGROUND Tapentadol is a centrally acting opioid analgesic, with a dual mode of action, as a norepinephrine reuptake inhibitor and an agonist of the MU-opioid receptor (MOR). Tapentadol is used for the management of musculoskeletal pain, and neuropathic pain associated with diabetic peripheral neuropathy. CASE REPORT A 32-year-old woman attended hospital for evaluation of an intractable headache. Computed tomography and magnetic resonance imaging of the brain were negative. She was found unresponsive in the bathroom on the day following hospital admission, and despite resuscitative measures, the patient died following cardiac arrest. Autopsy toxicology revealed significantly elevated levels of tapentadol, and bedside evidence suggested that the patient had self-administered this medication intravenously before her death. CONCLUSIONS We report a rare adverse effect of tapentadol causing respiratory depression leading to cardiac arrest. Medical examiners and forensic toxicologists should be aware of the toxicity of this novel opiate drug. PMID- 28729525 TI - Expression of Fibrogenic Markers in Tumor and Tumor-Surrounding Tissue at Time of Transplantation Correlates with Recurrence of Hepatocellular Carcinoma in Patients Undergoing Liver Transplantation. AB - BACKGROUND Liver transplantation (LT) remains the only curative treatment option for patients with defined stages of hepatocellular carcinoma (HCC). Up to 25% of patients show a tumor recurrence following transplantation. The correlation of fibrogenic markers prior to LT with HCC recurrence has not been characterized. We explored the expression of fibrogenic markers in tumor tissue and tumor surrounding liver tissue of patients undergoing LT and correlated these findings with tumor recurrence. MATERIAL AND METHODS Fibrogenic marker expression in explanted livers was assessed using tumor and tumor-surrounding liver tissue from patients who recently underwent liver transplantation at our center with a follow up period of at least 3 years. Tissue was analyzed for the expression of fibrogenic proteins and genes, as well as collagen deposition into the extracellular matrix. Results were correlated with HCC recurrence. RESULTS Patients with recurrent HCC following LT exhibited increased levels of fibrogenic markers on both protein and RNA level within the non-tumorous liver tissue in comparison to the tumor tissue itself. Patients who did not develop tumor recurrence up to 4 years after LT showed a reversed expression pattern of fibrogenic markers with decreased levels of beta-PDGFR, Collagen 1, and alpha-SMA in their non-tumorous liver tissue versus the tumor tissue at time of LT as assessed in protein and mRNA expression analysis. These findings correlated with analysis of collagen deposition in the liver. CONCLUSIONS Fibrogenic markers exhibit a differential expression pattern in HCC versus non-tumorous tissue in explanted livers of patients undergoing LT, showing a correlation with HCC recurrence. PMID- 28729526 TI - High performance surface-modified TiO2/silicone nanocomposite. AB - The mismatch of refractive index (RI) between light emitting diode (LED) chips and packaging resins severely lowers the lighting emitting efficacy of LED. The RI can be enhanced by the introduction of high RI nanoparticles but meanwhile it is a great challenge to maintain the high transparency for resins due to the agglomeration of nanoparticles. In this work, a facile strategy is proposed to fabricate silicone nanocomposites with a high transparency (>88%, less than 2% decrease relative to pure silicone resin), largely enhanced RI (an increase from 1.42 to 1.60) and improved thermal stability (73 degrees C increase in weight loss of 50%). Specifically, the ultra-fine monodispersed TiO2/silicone composites are prepared by direct solvent mixing of 1 wt% surface modified TiO2 nanoparticles (S-TiO2) into the silicone resin, in which S-TiO2 are prepared by direct introduction of titanate coupling agent in the process of TiO2 growth to induce the formation of protective layer on the surfaces of TiO2 nanoparticles. This methodology demonstrated is simple, cost-effective and versatile for the massive fabrication of highly transparent LED packaging materials with greatly enhanced refractive index and meanwhile enhanced thermal stability. PMID- 28729527 TI - Comparative transcriptome analysis of the floral transition in Rosa chinensis 'Old Blush' and R. odorata var. gigantea. AB - The floral transition is a crucial developmental event, but little is known about the underlying regulatory networks in seasonally and continuously flowering roses. In this study, we compared the genetic basis of flowering in two rose species, Rosa chinensis 'Old Blush', which flowers continuously, and R. odorata var. gigantea, which blooms in early spring. Gene ontology (GO) terms related to methylation, light reaction, and starch metabolism were enriched in R. odorata var. gigantea and terms associated with sugar metabolism were enriched in R. chinensis 'Old Blush' during the floral transition. A MapMan analysis revealed that genes involved in hormone signaling mediate the floral transition in both taxa. Furthermore, differentially expressed genes (DEGs) involved in vernalization, photoperiod, gibberellin (GA), and starch metabolism pathways converged on integrators, e.g., LFY, AGL24, SOC1, CAL, and COLs, to regulate the floral transition in R. odorata var. gigantea, while DEGs related to photoperiod, sugar metabolism, and GA pathways, including COL16, LFY, AGL11, 6PGDH, GASA4, and BAM, modulated the floral transition in R. chinensis 'Old Blush.' Our analysis of the genes underlying the floral transition in roses with different patterns of flowering provides a basis for further functional studies. PMID- 28729528 TI - Improved low-rank matrix recovery method for predicting miRNA-disease association. AB - MicroRNAs (miRNAs) performs crucial roles in various human diseases, but miRNA related pathogenic mechanisms remain incompletely understood. Revealing the potential relationship between miRNAs and diseases is a critical problem in biomedical research. Considering limitation of existing computational approaches, we develop improved low-rank matrix recovery (ILRMR) for miRNA-disease association prediction. ILRMR is a global method that can simultaneously prioritize potential association for all diseases and does not require negative samples. ILRMR can also identify promising miRNAs for investigating diseases without any known related miRNA. By integrating miRNA-miRNA similarity information, disease-disease similarity information, and miRNA family information to matrix recovery, ILRMR performs better than other methods in cross validation and case studies. PMID- 28729529 TI - A Novel Matrix Protein, PfY2, Functions as a Crucial Macromolecule during Shell Formation. AB - Biomineralization, including shell formation, is dedicatedly regulated by matrix proteins. PfY2, a matrix protein detected in the ethylene diamine tetraacetic acid (EDTA)-soluble fraction from both prismatic layer and nacreous layer, was discovered by our group using microarray. It may play dual roles during biomineralization. However, the molecular mechanism is still unclear. In this research, we studied the function of PfY2 on crystallization in vivo and in vitro, revealing that it might be a negative regulator during shell formation. Notching experiment indicated that PfY2 was involved in shell repairing and regenerating process. Repression of PfY2 gene affected the structure of prismatic and nacreous layer simultaneously, confirming its dual roles in shell formation. Recombinant protein rPfY2 significantly suppressed CaCO3 precipitation rate, participated in the crystal nucleation process, changed the morphology of crystals and inhibited the transformation of amorphous calcium carbonate (ACC) to stable calcite or aragonite in vitro. Our results may provide new evidence on the biomineralization inhibition process. PMID- 28729530 TI - Achieving ultrahigh triboelectric charge density for efficient energy harvesting. AB - With its light weight, low cost and high efficiency even at low operation frequency, the triboelectric nanogenerator is considered a potential solution for self-powered sensor networks and large-scale renewable blue energy. As an energy harvester, its output power density and efficiency are dictated by the triboelectric charge density. Here we report a method for increasing the triboelectric charge density by coupling surface polarization from triboelectrification and hysteretic dielectric polarization from ferroelectric material in vacuum (P ~ 10-6 torr). Without the constraint of air breakdown, a triboelectric charge density of 1003 uC m-2, which is close to the limit of dielectric breakdown, is attained. Our findings establish an optimization methodology for triboelectric nanogenerators and enable their more promising usage in applications ranging from powering electronic devices to harvesting large-scale blue energy.Triboelectric nanogenerators (TENGs) harvest ambient mechanical energy and convert it into electrical energy. Here, the authors couple surface polarization from contact electrification with dielectric polarization from a ferroelectric material in vacuum to dramatically enhance the TENG output power. PMID- 28729531 TI - Erratum: Tactile Flow Overrides Other Cues To Self Motion. AB - A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper. PMID- 28729532 TI - Doping porous silicon with erbium: pores filling as a method to limit the Er clustering effects and increasing its light emission. AB - Er clustering plays a major role in hindering sufficient optical gain in Er-doped Si materials. For porous Si, the long-standing failure to govern the clustering has been attributed to insufficient knowledge of the several, concomitant and complex processes occurring during the electrochemical Er-doping. We propose here an alternative road to solve the issue: instead of looking for an equilibrium between Er content and light emission using 1-2% Er, we propose to significantly increase the electrochemical doping level to reach the filling the porous silicon pores with luminescent Er-rich material. To better understand the intricate and superposing phenomena of this process, we exploit an original approach based on needle electron tomography, EXAFS and photoluminescence. Needle electron tomography surprisingly shows a heterogeneous distribution of Er content in the silicon thin pores that until now couldn't be revealed by the sole use of scanning electron microscopy compositional mapping. Besides, while showing that pore filling leads to enhanced photoluminescence emission, we demonstrate that the latter is originated from both erbium oxide and silicate. These results give a much deeper understanding of the photoluminescence origin down to nanoscale and could lead to novel approaches focused on noteworthy enhancement of Er-related photoluminescence in porous silicon. PMID- 28729534 TI - UV-activated ZnO films on a flexible substrate for room temperature O2 and H2O sensing. AB - We demonstrate that UV-light activation of polycrystalline ZnO films on flexible polyimide (Kapton) substrates can be used to detect and differentiate between environmental changes in oxygen and water vapor. The in-plane resistive and impedance properties of ZnO films, fabricated from bacteria-derived ZnS nanoparticles, exhibit unique resistive and capacitive responses to changes in O2 and H2O. We propose that the distinctive responses to O2 and H2O adsorption on ZnO could be utilized to statistically discriminate between the two analytes. Molecular dynamic simulations (MD) of O2 and H2O adsorption energy on ZnO surfaces were performed using the large-scale Atomic/Molecular Massively Parallel Simulator (LAMMPS) with a reactive force-field (ReaxFF). These simulations suggest that the adsorption mechanisms differ for O2 and H2O adsorption on ZnO, and are governed by the surface termination and the extent of surface hydroxylation. Electrical response measurements, using DC resistance, AC impedance spectroscopy, and Kelvin Probe Force Microscopy (KPFM), demonstrate differences in response to O2 and H2O, confirming that different adsorption mechanisms are involved. Statistical and machine learning approaches were applied to demonstrate that by integrating the electrical and kinetic responses the flexible ZnO sensor can be used for detection and discrimination between O2 and H2O at low temperature. PMID- 28729533 TI - Common Brain Structure Findings Across Children with Varied Reading Disability Profiles. AB - Dyslexia is a developmental disorder in reading that exhibits varied patterns of expression across children. Here we examined the degree to which different kinds of reading disabilities (defined as profiles or patterns of reading problems) contribute to brain morphology results in Jacobian determinant images that represent local brain shape and volume. A matched-pair brain morphometry approach was used to control for confounding from brain size and research site effects in this retrospective multi-site study of 134 children from eight different research sites. Parietal operculum, corona radiata, and internal capsule differences between cases and controls were consistently observed across children with evidence of classic dyslexia, specific comprehension deficit, and language learning disability. Thus, there can be common brain morphology findings across children with quite varied reading disability profiles that we hypothesize compound the developmental difficulties of children with unique reading disability profiles and reasons for their reading disability. PMID- 28729535 TI - PLD1 promotes dendritic spine development by inhibiting ADAM10-mediated N cadherin cleavage. AB - Synapses are the basic units of information transmission, processing and integration in the nervous system. Dysfunction of the synaptic development has been recognized as one of the main reasons for mental dementia and psychiatric diseases such as Alzheimer's disease and autism. However, the underlying mechanisms of the synapse formation are far from clear. Here we report that phospholipase D1 (PLD1) promotes the development of dendritic spines in hippocampal neurons. We found that overexpressing PLD1 increases both the density and the area of dendritic spines. On the contrary, loss of function of PLD1, including overexpression of the catalytically-inactive PLD1 (PLD1ci) or knocking down PLD1 by siRNAs, leads to reduction in the spine density and the spine area. Moreover, we found that PLD1 promotes the dendritic spine development via regulating the membrane level of N-cadherin. Further studies showed that the regulation of surface N-cadherin by PLD1 is related with the cleavage of N cadherin by a member of the disintegrin and metalloprotease family-ADAM10. Taking together, our results indicate a positive role of PLD1 in synaptogenesis by inhibiting the ADAM10 mediated N-cadherin cleavage and provide new therapeutic clues for some neurological diseases. PMID- 28729537 TI - Control of crystallization behaviour of supercooled liquid composed of lithium disilicate on platinum substrate. AB - Crystalline lithium disilicate (Li2Si2O5, LS2) materials, which have excellent mechanical properties with high transparency, should be obtained efficiently through the crystallization of supercooled liquid composed of LS2. However, in addition to LS2, a lithium monosilicate (Li2SiO3, LS) phase is also precipitated during the crystallization of the liquid. The precipitation of the LS phase renders it difficult to obtain a single-phase LS2 material. Here, we show that by altering the oxygen partial pressure, it is possible to change the selectivity of the precipitated phase by controlling the interfacial phenomena that occur between the liquid and platinum contact material. During cooling of the supercooled liquid, the type of precipitated phase can be controlled by optimizing the atmosphere and type of contact material. This methodology can be applied for the fabrication of other functional materials and does not require the use of other additives. PMID- 28729536 TI - Weakened IL-15 Production and Impaired mTOR Activation Alter Dendritic Epidermal T Cell Homeostasis in Diabetic Mice. AB - Diabetes is associated with impaired wound healing, which may be caused primarily by a deficiency in dendritic epidermal T cells (DETCs). In the epidermis, IL-15, IGF-1, and mTOR are known to regulate the maintenance of DETCs; however, it is unclear how these molecules may intersect to regulate DETC homeostasis in diabetes. Here, we show that the reduction of DETCs in the epidermis of diabetic mice is caused by altered homeostasis mediated by a reduction in IL-15 levels. Both impaired mTOR activation and reduction of IL-15 in the epidermis play important roles in DETC homeostasis. Moreover, IGF-1 drives keratinocytes to produce IL-15. The activation of IL-15 is dependent on mTOR, and conversely, mTOR regulates IGF-1 production in DETC, in a classic feedback regulatory loop. Our data suggest that in the setting of diabetes, reduced IGF-1, impaired mTOR pathway activation and reduced IL-15 in the epidermis function coordinately to promote altered DETC homeostasis and delayed skin wound closure. PMID- 28729538 TI - Geometric Heterogeneity of Continental Shale in the Yanchang Formation, Southern Ordos Basin, China. AB - Favorable prospects for the exploration of shale gas have been demonstrated in the Ordos Basin, China. Outcrop and core observations indicate that there are abundant laminas in the shale strata, which exert a great influence on hydro fracture propagation, gas storage and fluid flow. In this study, the continental shale of the Chang 72 Member, collected from the south of Ordos Basin, was investigated to characterize the geometric heterogeneity. Laminas at multiple scales were observed and measured using conventional logging, borehole TV, core analysis, scanning electron microscopy, and the Particle and Crack Analysis System. These measurement tools correspond to the meter scale, decimeter scale, centimeter scale, millimeter scale and ten-micrometer scale, respectively, with measured thicknesses of 2.26 m, 2.09 dm, 1.70 cm, 1.48 mm and 11.70 MUm, respectively. Fractal theory was used to analyze the power exponent distribution of the lamina thickness, with a resulting fractal dimension of 1.06. Finally, a geometric heterogeneity model was proposed for the Upper Triassic Yanchang Formation in the study area and verified by a modeled thickness of 26.30 m for the Chang 72 Member at the 10-m scale. The model facilitates cross-scale analysis and provides parameter guidance for heterogeneity characterization in the numerical simulation and model test of the shale gas reservoir. PMID- 28729539 TI - Comparative proteomic analysis of human embryonic stem cell-derived and primary human retinal pigment epithelium. AB - Human embryonic stem cell-derived retinal pigment epithelial cells (hESC-RPE) provide an unlimited cell source for retinal cell replacement therapies. Clinical trials using hESC-RPE to treat diseases such as age-related macular degeneration (AMD) are currently underway. Human ESC-RPE cells have been thoroughly characterized at the gene level but their protein expression profile has not been studied at larger scale. In this study, proteomic analysis was used to compare hESC-RPE cells differentiated from two independent hESC lines, to primary human RPE (hRPE) using Isobaric tags for relative quantitation (iTRAQ). 1041 common proteins were present in both hESC-RPE cells and native hRPE with majority of the proteins similarly regulated. The hESC-RPE proteome reflected that of normal hRPE with a large number of metabolic, mitochondrial, cytoskeletal, and transport proteins expressed. No signs of increased stress, apoptosis, immune response, proliferation, or retinal degeneration related changes were noted in hESC-RPE, while important RPE specific proteins involved in key RPE functions such as visual cycle and phagocytosis, could be detected in the hESC-RPE. Overall, the results indicated that the proteome of the hESC-RPE cells closely resembled that of their native counterparts. PMID- 28729540 TI - Direct Growth of MoS2 Nanowalls on Carbon Nanofibers for Use in Supercapacitor. AB - Direct growth of MoS2 nanowalls on vapor grown carbon nanofibers (VGCNFs) has been achieved using a microwave-assisted hydrothermal (MAH) method under an acidic condition. The acidic condition was obtained through the addition of an HCl aqueous solution. We demonstrate that the HCl not only modifies the pH value for limiting the growth rate but also leads to the formation of NaCl, which is the key for the direct and unique growth of MoS2 on the VGCNF surface. A growth mechanism is therefore proposed. The growth of MoS2 onto the high electrically conducting VGCNF creates a unique structure that not only reduces the aggregation of MoS2 but also improves the electrical conductivity of the resulting composite electrode. The MoS2 nanowall/VGCNF composite shows Csp as high as 248 F g-1 at 5 mV s-1 and excellent electrochemical stability with a retention of 96% after 1,000 cycles at a high charge rate of 200 mV s-1. The ease of composite fabrication and electrochemical stability suggest that the MoS2 nanowall/VGCNF composite is a promising candidate electrode material for supercapacitor. PMID- 28729541 TI - An easy gene assembling strategy for light-promoted transfection by combining host-guest interaction of cucurbit[7]uril and gold nanoparticles. AB - Cucurbit[7]uril (CB[7]), a representative member of the host family cucurbit[n]uril, can host-guest interact with many guest molecules such as adamantane, viologen and naphthalene derivatives. This host-guest interaction provides an easy strategy in gene vector assembling. Furthermore, CB[7] can self assemble on gold nanospheres (AuNSs). Herein, the combination of CB[7] and AuNSs provides both advantages of host-guest interaction and photo-thermal effect of AuNSs. In this study, polyethyleneimine (PEI) and polyethylene glycol (PEG) were separately interacted with CB[7] via host-guest interaction. Then by assembling on AuNSs, PEI and PEG were combined together to condense DNA into polyplexes as well as enhance circulation stability of the polyplexes. These gene vectors were found to have high cellular uptake efficiency and low cytotoxicity. Furthermore, the well distributed AuNSs in the polyplexes could transform light into heat under light exposure because of the photo-thermal effect. This was found to effectively promote the entry of gene into cytoplasm and highly enhanced gene transfection efficiency. PMID- 28729542 TI - Reaching Agreement in Quantum Hybrid Networks. AB - We consider a basic quantum hybrid network model consisting of a number of nodes each holding a qubit, for which the aim is to drive the network to a consensus in the sense that all qubits reach a common state. Projective measurements are applied serving as control means, and the measurement results are exchanged among the nodes via classical communication channels. In this way the quantum opeartion/classical-communication nature of hybrid quantum networks is captured, although coherent states and joint operations are not taken into consideration in order to facilitate a clear and explicit analysis. We show how to carry out centralized optimal path planning for this network with all-to-all classical communications, in which case the problem becomes a stochastic optimal control problem with a continuous action space. To overcome the computation and communication obstacles facing the centralized solutions, we also develop a distributed Pairwise Qubit Projection (PQP) algorithm, where pairs of nodes meet at a given time and respectively perform measurements at their geometric average. We show that the qubit states are driven to a consensus almost surely along the proposed PQP algorithm, and that the expected qubit density operators converge to the average of the network's initial values. PMID- 28729543 TI - Evaluation of ATM heterozygous mutations underlying individual differences in radiosensitivity using genome editing in human cultured cells. AB - Ionizing radiation (IR) induces DNA double-strand breaks (DSBs), which are an initial step towards chromosomal aberrations and cell death. It has been suggested that there are individual differences in radiosensitivity within human populations, and that the variations in DNA repair genes might determine this heterogeneity. However, it is difficult to quantify the effect of genetic variants on the individual differences in radiosensitivity, since confounding factors such as smoking and the diverse genetic backgrounds within human populations affect radiosensitivity. To precisely quantify the effect of a genetic variation on radiosensitivity, we here used the CRISPR-ObLiGaRe (Obligate Ligation-Gated Recombination) method combined with the CRISPR/Cas9 system and a nonhomologous end joining (NHEJ)-mediated knock-in technique in human cultured cells with a uniform genetic background. We generated ATM heterozygous knock-out (ATM +/-) cell clones as a carrier model of a radiation-hypersensitive autosomal recessive disorder, ataxia-telangiectasia (A-T). Cytokinesis-blocked micronucleus assay and chromosome aberration assay showed that the radiosensitivity of ATM +/- cell clones was significantly higher than that of ATM +/+ cells, suggesting that ATM gene variants are indeed involved in determining individual radiosensitivity. Importantly, the differences in radiosensitivity among the same genotype clones were small, unlike the individual differences in fibroblasts derived from A-T affected family members. PMID- 28729544 TI - Remarkable hexafunctional anion receptor with operational urea-based inner cleft and thiourea-based outer cleft: Novel design with high-efficiency for sulfate binding. AB - The recognition of anions by designed receptors has attracted much attention in recent days. In particular, the selective binding of sulfate with artificial receptors is important because of its relevance to many biological and environmental applications. However, the development of organized molecular receptors with high-efficiency for sulfate binding still remains a significant challenge. We report a novel para-phenylene-bridged hexafunctional tripodal receptor that contains a urea-based inner cleft and a thiourea-based outer cleft, providing perfect sites for step-wise binding of two anions within a single cavity. The new receptor was synthesized in a three-step process, and was investigated for its anion binding properties by 1H NMR titrations, 2D NOESY experiments and computational studies. As indicated by solution binding studies, the receptor selectively binds sulfate over other oxoanions, forming a 1:2 stoichiometric complex that is stabilized via strong H-bonding interactions. High level DFT calculations reveal that the receptor, owing to the enhanced H-bonding ability of thiourea groups, initially encapsulates one sulfate in its thiourea based outer cleft, followed by a second encapsulation in its urea-based inner cleft. Such a functionalized receptor with the unique combination of urea-based cleft and thiourea-based cleft in a single receptor has not been reported previously. PMID- 28729546 TI - Erratum: PRL3 phosphatase active site is required for binding the putative magnesium transporter CNNM3. AB - A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper. PMID- 28729545 TI - Genetic differentiation of the Schizothorax species complex (Cyprinidae) in the Nujiang River (upper Salween). AB - Phenotypically diverse species from recently evolved groups always share allele/haplotype due to insufficient differentiation in the early process. In this study, we performed population genetics analyses using sequences from the mitochondrial cytochrome b gene, and two nuclear genes to investigate the genetic differentiation of the closely related Schizothorax species complex, comprising a group of alpine fish living in the Nujiang River. The results from both mtDNA and nDNA markers revealed relatively low but pronounced genetic differentiation among the three Schizothorax species, i.e., Schizothorax gongshanensis, S. lissolabiatus, and S. nukiangensis. However, haplotype sharing was frequently occurred among the three species. Divergence time estimation suggested the last glaciation on the Tibetan Plateau (0.075-0.01 Ma) might drive the divergence of the species complex. Gene flow might contribute to the haplotype sharing between S. gongshanensis and S. lissolabiatus, and between S. gongshanensis and S. nukiangensis, whereas retention of ancestral polymorphisms seemed to be a better explanation of the haplotype sharing between S. lissolabiatus and S. nukiangensis. In addition, S. lissolabiatus populations should obtain more protection in the future because of their low genetic diversity and habitat fragmentation. In summary, our study assesses genetic differentiation among the three closely related Schizothorax species and explores the possible driving forces for their differentiation. PMID- 28729547 TI - Antarctic sea ice region as a source of biogenic organic nitrogen in aerosols. AB - Climate warming affects the development and distribution of sea ice, but at present the evidence of polar ecosystem feedbacks on climate through changes in the atmosphere is sparse. By means of synergistic atmospheric and oceanic measurements in the Southern Ocean near Antarctica, we present evidence that the microbiota of sea ice and sea ice-influenced ocean are a previously unknown significant source of atmospheric organic nitrogen, including low molecular weight alkyl-amines. Given the keystone role of nitrogen compounds in aerosol formation, growth and neutralization, our findings call for greater chemical and source diversity in the modelling efforts linking the marine ecosystem to aerosol mediated climate effects in the Southern Ocean. PMID- 28729548 TI - Multiplex polymerase chain reaction for pathogen detection in donor/recipient corneal transplant tissue and donor storage solution. AB - Corneal transplantation is a safe, reliable method of restoring visual acuity in patients with corneal disorders. Although it has a very high success rate, rejection can still occur, especially if the site is infected. Therefore, seeking to find better ways to manage infection risk, this study investigated a new technique, based on multiplex polymerase chain reaction (mPCR), to identify pathogens, including viruses, bacteria, and fungi, in corneal transplantation recipient sites, donor corneas and the donor cornea storage solution. The subjects comprised 50 patients who underwent corneal transplantation at Tohoku University Hospital between July 2014 and April 2015. We obtained extracted (recipient) cornea samples in 37 cases, donor cornea samples in 50 cases, and corneal storage solution samples in 50 cases (18 of these 50 samples contained DNA). Herpes simplex virus type 1 DNA was detected in four recipient corneas, Parvovirus B19 DNA was detected in two recipient corneas, Human herpes virus type 6 was detected in two donor corneas, and Aspergillus DNA was detected in one corneal storage solution sample. Thus, mPCR successfully identified pathogenic DNA in corneal tissues and storage solution, suggesting that evaluation with mPCR may improve the ability to predict the risk of infection after corneal transplantation. PMID- 28729550 TI - Anti-Tumor Activity and Immunotherapeutic Potential of a Bisphosphonate Prodrug. AB - Bisphosphonates have benefits in breast cancer and multiple myeloma patients and have been used with adoptive immunotherapy with gammadelta T cells expressing Vgamma2 Vdelta2 TCRs. Although treatment with gammadelta T cells is safe, it has shown limited efficacy. Present bisphosphonates stimulate gammadelta T cells but were designed to inhibit bone resorption rather than treating cancer and have limited oral absorption, tumor cell entry, and cause bone side effects. The development of phosphate and phosphonate nucleotide prodrugs has led to important drugs for hepatitis C and HIV. Using a similar approach, we synthesized bisphosphonate prodrugs and found that they efficiently limit tumor cell growth. Pivoxil bisphosphonate esters enter cells where esterases convert them to their active acids. The bisphosphonate esters stimulated gammadelta T cells to secrete TNF-alpha in response to a variety of tumor cells more efficiently than their corresponding acids. The most active compound, tetrakis-pivaloyloxymethyl 2 (thiazole-2-ylamino)ethylidene-1,1- bisphosphonate (7), specifically expanded gammadelta T cells and stimulated them to secrete interferon-gamma and kill tumor cells. In preclinical studies, combination therapy with compound 7 and gammadelta T cells prolonged survival of mice inoculated with either human bladder cancer or fibrosarcoma cells. Therefore, bisphosphonate prodrugs could enhance the effectiveness of adoptive cancer immunotherapy with gammadelta T cells. PMID- 28729549 TI - DES-TOMATO: A Knowledge Exploration System Focused On Tomato Species. AB - Tomato is the most economically important horticultural crop used as a model to study plant biology and particularly fruit development. Knowledge obtained from tomato research initiated improvements in tomato and, being transferrable to other such economically important crops, has led to a surge of tomato-related research and published literature. We developed DES-TOMATO knowledgebase (KB) for exploration of information related to tomato. Information exploration is enabled through terms from 26 dictionaries and combination of these terms. To illustrate the utility of DES-TOMATO, we provide several examples how one can efficiently use this KB to retrieve known or potentially novel information. DES-TOMATO is free for academic and nonprofit users and can be accessed at http://cbrc.kaust.edu.sa/des_tomato/, using any of the mainstream web browsers, including Firefox, Safari and Chrome. PMID- 28729551 TI - Change in choroidal blood flow and choroidal morphology due to segmental scleral buckling in eyes with rhegmatogenous retinal detachment. AB - Although scleral buckling is a well-established surgical treatment for rhegmatogenous retinal detachment (RRD), the procedure can reportedly cause problems in the ocular circulation. Segmental scleral bucking without a concomitant encircling procedure was performed on 46 eyes with successfully reattached macula-on RRD. Choroidal blood flow was assessed using laser speckle flowgraphy. Spectral-domain optical coherence tomography was used to image macular regions, to measure the subfoveal choroidal thickness (SFCT), and to calculate the luminal and the stromal areas by the binarization method preoperatively and 1, 4, 8 and 12 weeks postoperatively. Choroidal mean blur rate at the macula did not significantly change, while that at the buckle and unbuckle side significantly reduced at 8 weeks postoperatively in the operated eye (P = 0.007 and P = 0.017, respectively). The SFCT and the luminal area increased temporarily 1 week following surgery in the operated eye (P < 0.001). The trend of SFCT with time coincided with that of the luminal area (P < 0.001). Venous drainage obstruction induced by compression force of scleral buckling leads to SFCT thickening in the acute postoperative phase. The macular choroidal blood flow might be less susceptible because the blood flow at the macula, in contrast to the other areas, does not change following segmental scleral buckling. PMID- 28729552 TI - New insights into the karyotype evolution of the free-living flatworm Macrostomum lignano (Platyhelminthes, Turbellaria). AB - The free-living flatworm Macrostomum lignano is a model organism for evolutionary and developmental biology studies. Recently, an unusual karyotypic diversity was revealed in this species. Specifically, worms are either 'normal' 2n = 8, or they are aneuploid with one or two additional large chromosome(s) (i.e. 2n = 9 or 2n = 10, respectively). Aneuploid worms did not show visible behavioral or morphological abnormalities and were successful in reproduction. In this study, we generated microdissected DNA probes from chromosome 1 (further called MLI1), chromosome 2 (MLI2), and a pair of similar-sized smaller chromosomes (MLI3, MLI4). FISH using these probes revealed that MLI1 consists of contiguous regions homologous to MLI2-MLI4, suggesting that MLI1 arose due to the whole genome duplication and subsequent fusion of one full chromosome set into one large metacentric chromosome. Therefore, one presumably full haploid genome was packed into MLI1, leading to hidden tetraploidy in the M. lignano genome. The study of Macrostomum sp. 8 - a sibling species of M. lignano - revealed that it usually has one additional pair of large chromosomes (2n = 10) showing a high homology to MLI1, thus suggesting hidden hexaploidy in its genome. Possible evolutionary scenarios for the emergence of the M. lignano and Macrostomum sp. 8 genomes are discussed. PMID- 28729553 TI - Enhancement of perpendicular magnetic anisotropy and its electric field-induced change through interface engineering in Cr/Fe/MgO. AB - Recently, perpendicular magnetic anisotropy (PMA) and its voltage control (VC) was demonstrated for Cr/Fe/MgO. In this study, we shed light on the origin of large voltage-induced anisotropy change in Cr/Fe/MgO. Analysis of the chemical structure of Cr/Fe/MgO revealed the existence of Cr atoms in the proximity of the Fe/MgO interface, which can affect both magnetic anisotropy (MA) and its VC. We showed that PMA and its VC can be enhanced by controlled Cr doping at the Fe/MgO interface. For Cr/Fe (5.9 A)/Cr (0.7 A)/MgO with an effective PMA of 0.8 MJ/m3, a maximum value of the voltage-controlled magnetic anisotropy (VCMA) effect of 370 fJ/Vm was demonstrated due to Cr insertion. PMID- 28729554 TI - Comparison of traditional and new generation DNA markers declares high genetic diversity and differentiated population structure of wild almond species. AB - Wild almond species as sources of genetic variation may have crucial importance in breeding. A total of 389 accessions of 18 species have been analysed using inter-retrotransposon amplified polymorphism (IRAP), retrotransposon microsatellite amplified polymorphism (REMAP), sequence-specific amplification polymorphism (S-SAP), amplified fragment length polymorphism (AFLP), inter simple sequence repeat (ISSR) and simple sequence repeats (SSR). Retrotransposon markers indicated the presence and movement of some Ty3-gypsy and Ty1-copia-elements in almond genome. Since transposable elements are associated with large-scale genome alterations, REMAP produced more reliable phylogenetic inferences than AFLP where homoplasy may affect clustering. In addition, high resolution melting (HRM) analysis was developed to detect SNPs. HRM analysis revealed 1:189 bp frequency of SNPs in exon positions, and the transition-to-transversion proportion was 1.84:1. The low transition bias suggests low methylation levels in almond genome. The polymorphic information content (PIC) was the highest for SSR markers, while SNPs had an average PIC of 0.59, which is close to the values of the rest of the markers. Huge genetic diversity, fragmented population structure and footprints of human selection was confirmed by merging information from all marker strategies. Considering time, cost and performance HRM can be a marker of choice in future studies of Prunus diversity. PMID- 28729556 TI - Observation of aggregation triggered by Resonance Energy Transfer (RET) induced intermolecular pairing force. AB - In this report, we showed the existence of RET induced intermolecular pairing force by comparing their fluorescence behaviors under room illumination vs standing in dark area for either PFluAnt solution or PFluAnt&PFOBT mixture. Their prominent emission attenuation under room illumination brought out the critical role of photo, i.e. RET induced intermolecular pairing force in induction of polymer aggregation. Constant UV-Vis absorption and fluorescence spectra in terms of both peak shapes and maximum wavelengths implied no chemical decomposition was involved. Recoverable fluorescence intensity, fluorescence lifetime as well as NMR spectra further exclude photo induced decomposition. The controllable on/off state of RET induced intermolecular pairing force was verified by the masking effect of outside PFluAnt solution which function as filter to block the excitation of inside PFluAnt and thus off the RET induced intermolecular pairing force. Theoretical calculation suggest that magnitude of RET induced intermolecular pairing force is on the same scale as that of van der Waals interaction. Although the absolute magnitude of RET induced intermolecular pairing force was not tunable, its effect can be magnified by intentionally turn it "on", which was achieved by irradiance with 5 W desk lamp in this report. PMID- 28729555 TI - Inhibition of phosphodiesterase-5 suppresses calcineurin/NFAT- mediated TRPC6 expression in pulmonary artery smooth muscle cells. AB - The up-regulation of transient receptor potential channel 6 (TRPC6) has been found to contribute to the proliferation of pulmonary artery smooth muscle cells (PASMCs), and inhibition of phosphodiesterase-5 (PDE5) has been shown to suppress TRPC6 expression in PASMCs. However, the molecular mechanisms underlying the up regulation of TRPC6 expression and PDE5 modulation of TRPC6 expression in PASMCs remain largely unclear. The aim of this study is to address these issues. Endothelin-1 (ET-1) dose and time-dependently up-regulated TRPC6 expression in primary cultured rat PASMCs, and this was accompanied with the activation of calcineurin and subsequent translocation of NFATc4 to the nucleus. Further study indicated that inhibition of calcineurin by cyclosporine A or knockdown of NFATc4 using small interfering RNA suppressed ET-1-induced TRPC6 up-regulation. In addition, luciferase reporter assay showed that NFATc4 directly regulated the expression of TRPC6 in PASMCs. Inhibition of PDE5 by sildenafil suppressed ET-1 induced activation of calcineurin/NFATc4 signaling pathway and consequent TRPC6 up-regulation in PASMCs, while these inhibitory effects of sildenafil were abolished by PKG inhibitor Rp-8Br-cGMPs. Taken together, our study indicates that ET-1 stimulates TRPC6 expression by activation of calcineurin/NFATc4 signaling pathway, and inhibition of PDE5 suppresses calcineurin/NFATc4- mediated TRPC6 expression in PASMCs in a cGMP-PKG-dependent manner. PMID- 28729557 TI - Antifungal treatment of wild amphibian populations caused a transient reduction in the prevalence of the fungal pathogen, Batrachochytrium dendrobatidis. AB - Emerging infectious diseases can drive host populations to extinction and are a major driver of biodiversity loss. Controlling diseases and mitigating their impacts is therefore a priority for conservation science and practice. Chytridiomycosis is a devastating disease of amphibians that is caused by the fungal pathogen Batrachochytrium dendrobatidis (Bd), and for which there is an urgent need to develop mitigation methods. We treated tadpoles of the common midwife toad (Alytes obstetricans) with antifungal agents using a capture-treat release approach in the field. Antifungal treatment during the spring reduced the prevalence of Bd in the cohort of tadpoles that had overwintered and reduced transmission of Bd from this cohort to the uninfected young-of-the-year cohort. Unfortunately, the mitigation was only transient, and the antifungal treatment was unable to prevent the rapid spread of Bd through the young-of-the year cohort. During the winter, Bd prevalence reached 100% in both the control and treated ponds. In the following spring, no effects of treatment were detectable anymore. We conclude that the sporadic application of antifungal agents in the present study was not sufficient for the long-term and large-scale control of Bd in this amphibian system. PMID- 28729558 TI - Early-life disruption of amphibian microbiota decreases later-life resistance to parasites. AB - Changes in the early-life microbiota of hosts might affect infectious disease risk throughout life, if such disruptions during formative times alter immune system development. Here, we test whether an early-life disruption of host associated microbiota affects later-life resistance to infections by manipulating the microbiota of tadpoles and challenging them with parasitic gut worms as adults. We find that tadpole bacterial diversity is negatively correlated with parasite establishment in adult frogs: adult frogs that had reduced bacterial diversity as tadpoles have three times more worms than adults without their microbiota manipulated as tadpoles. In contrast, adult bacterial diversity during parasite exposure is not correlated with parasite establishment in adult frogs. Thus, in this experimental setup, an early-life disruption of the microbiota has lasting reductions on host resistance to infections, which is possibly mediated by its effects on immune system development. Our results support the idea that preventing early-life disruption of host-associated microbiota might confer protection against diseases later in life.Early-life microbiota alterations can affect infection susceptibility later in life, in animal models. Here, Knutie et al. show that manipulating the microbiota of tadpoles leads to increased susceptibility to parasitic infection in adult frogs, in the absence of substantial changes in the adults' microbiota. PMID- 28729559 TI - Effects of poly-gamma-glutamic acid (gamma-PGA) on plant growth and its distribution in a controlled plant-soil system. AB - To demonstrate the responses of plant (Pakchoi) and soil to poly-gamma-glutamic acid (gamma-PGA) is essential to better understand the pathways of the promotional effect of gamma-PGA on plant growth. In this study, the effects of gamma-PGA on soil nutrient availability, plant nutrient uptake ability, plant metabolism and its distribution in a plant-soil system were tested using labeled gamma-PGA synthesized from 13C1-15N-L-glutamic acid (L-Glu). gamma-PGA significantly improved plant uptake of nitrogen (N), phosphorus (P), and potassium (K) and hence increased plant biomass. gamma-PGA greatly strengthened the plant nutrient uptake capacity through enhancing both root biomass and activity. gamma-PGA affected carbon (C) and N metabolism in plant which was evidenced with increased soluble sugar contents and decreased nitrate and free amino acids contents. About 26.5% of the gamma-PGA-N uptake during the first 24 h, after gamma-PGA application, was in the form of intact organic molecular. At plant harvest, 29.7% and 59.4% of gamma-PGA-15N was recovered in plant and soil, respectively, with a 5.64% of plant N nutrition being derived from gamma-PGA-N. The improved plant nutrient uptake capacity and soil nutrient availability by gamma-PGA may partly explain the promotional effect of gamma-PGA, however, the underlying reason may be closely related to L-Glu. PMID- 28729560 TI - Adaptive Control of Ion Yield in Femtosecond Laser Post-ionization for Secondary Ion Mass Spectrometry. AB - Secondary ion mass spectrometry is an excellent technique of analytical chemistry, where primary ions sputter a solid sample generating the secondary ions which are determined. Although the ion yield is inherently low, it can be enhanced by using a post-ionization of sputtered neutral species. Our novel approach integrates this technique with a near infrared femtosecond laser post ionization based on an adaptive control through a laser pulse shaper. The shaping of the laser pulse provides adaptive control to select a mass peak of interest and to enhance this peak intensity. Versatility is confirmed by optimizing the ion yield for different molecules (tryptophan, anthracene, polyethylene, and oxalic acid) with focus on parent ion enhancement, fragmentation process, sublimation effect, and excited secondary species. This proof-of-concept experiment provides not only a nonspecific increase of the overall ion yield, but also the selection of specific secondary species and the adaptive enhancement of their intensities on the order of 100, potentially simplifying data interpretation. Such tailored spectra might advance the (secondary ion) mass spectrometry to new capabilities. PMID- 28729562 TI - Fads, gimmicks and the real thing. PMID- 28729563 TI - Effect of resin infiltration on the color and microhardness of bleached white( )spot lesions in bovine enamel (an in vitro study). AB - This study would appear to give little steer as to which of the many approaches most effectively manage white spot lesions. PMID- 28729567 TI - The importance of acknowledgement of emotions in routine patient psychological assessment: the example of the dental setting. AB - Does active engagement by the dentist exploring their patient's fear, allay dental anxiety? PMID- 28729568 TI - NHS dental service utilisation and social deprivation in older adults in North West England. AB - Objective To explore NHS dental service utilisation (attendance and treatment activity) of older adults.Design Retrospective analysis of dental treatment claim forms (FP17s) over a 15 month period.Population A total of 690,433 older adults in North West England.Results NHS dental care attendance decreased with increasing age; 49% in 65-74 years, 39% in 75-84 years and 23% in the over 85 years age group. Across all older age stratifications, the more deprived patients had a higher rate of examinations, extractions, dentures and preventative advice compared to the least deprived patients. However, the relationship was opposite for the rate of fillings and complex restorative treatment; the rate was higher for the least deprived older adult patients.Conclusions Despite 95% of older adults living in the community, the number of older adults accessing NHS dental care in this data set is thought-provoking. Additionally, there is a complex relationship between the type of treatment provided and the patient's IMD level. The authors acknowledge the major limitations of this dataset; affluent people are more likely to access private dental care and the availability of NHS dental services is likely to vary across different regions. However, the use of 'big data' is necessary to provide a pragmatic approach for future research in the management of older adults in general dental services. PMID- 28729571 TI - A review of implant provision for hypodontia patients within a Scottish referral centre. AB - Background Implant treatment to replace congenitally missing teeth often involves multidisciplinary input in a secondary care environment. High quality patient care requires an in-depth knowledge of treatment requirements.Aim This service review aimed to determine treatment needs, efficiency of service and outcomes achieved in hypodontia patients. It also aimed to determine any specific difficulties encountered in service provision, and suggest methods to overcome these.Methods Hypodontia patients in the Unit of Periodontics of the Scottish referral centre under consideration, who had implant placement and fixed restoration, or review completed over a 31 month period, were included. A standardised data collection form was developed and completed with reference to the patient's clinical record. Information was collected with regard to: the indication for implant treatment and its extent; the need for, complexity and duration of orthodontic treatment; the need for bone grafting and the techniques employed and indicators of implant success.Conclusion Implant survival and success rates were high for those patients reviewed. Incidence of biological complications compared very favourably with the literature. PMID- 28729572 TI - Pharmacology: Common side effects. PMID- 28729573 TI - Interactive group therapy for the management of myofascial temporomandibular pain. AB - Background and aim To evaluate the outcome of a group therapy approach in the management of myofascial temporomandibular pain (TMD) through promotion of self care.Methods A group based interactive session was introduced for those patients who, at initial consultation, were diagnosed with myalgic TMD. Feedback forms and telephone interviews were used to record patient reported outcome measures to assess patient satisfaction with the service.Results Fifty-five patients attended 17 group sessions over ten months. Feedback revealed a high level of satisfaction immediately after the session with 71% (n = 39) of patients opting for discharge, reporting confidence to self-manage in primary care. This effect appears to be sustainable up to 11 months.Conclusions This approach benefits patients with myofascial TMD through promotion of self-management while utilising health care resources efficiently. PMID- 28729574 TI - Shortened dental arch and prosthetic effect on oral health-related quality of life: a systematic review and meta-analysis. AB - Are quality of life measures that embrace the multidimensional nature of oral health, more important than normative need set by experts? PMID- 28729576 TI - RCSEd launches anti-bullying campaign. PMID- 28729580 TI - Erratum. PMID- 28729583 TI - Dentistry, and why it is a great career. AB - The current climate of dentistry is one of sharply rising costs, increased litigation and more common placed stress, alongside the ever existing challenges that have persisted. This Opinion article looks into the reasons for embarking upon and staying within a dental career, despite the alleged drawbacks, and aims to promote a sense of positivity for the career that too often appears to be waning. PMID- 28729584 TI - Using virtual microscopy to deliver an integrated oral pathology course for undergraduate dental students. AB - Dental students in the United Kingdom usually study histopathology as part of their undergraduate curriculum and this has traditionally been delivered using light microscopes in laboratory classes. Beginning in 2005, the oral pathology course in Sheffield was gradually modified by the introduction of virtual microscopy with a focus on creating a more integrated, clinically orientated and dynamic approach to student teaching and learning in histopathology. The purpose of this paper is to describe how virtual microscopy has been used to enhance dental students' learning of oral pathology, and its role in facilitating an integrated oral disease curriculum in Sheffield. PMID- 28729585 TI - Glasgow creates 'world's biggest smile'. PMID- 28729587 TI - Must or should? Interpreting 'Standards for the dental team'. AB - The General Dental Council's Standards for the dental team sets out guidance for the conduct of dental professionals. In a departure from its predecessor, Standards for dental professionals, the words 'must' and 'should' are defined and employed in particular ways. However, this provision of more detailed guidance paradoxically creates greater uncertainty. PMID- 28729589 TI - Public health: Extraordinary heroism. PMID- 28729592 TI - Refugees: addressing the burden of oral disease through prevention. AB - In February 2017 a cohort of dental students travelled to Athens, Greece where they assisted in providing dental care to refugees and conducted oral hygiene workshops in Skaramagas Refugee camp. With respect to patient presentation, caries was found to be extremely prevalent due to patient diet, accessibility to care and oral hygiene practices. Due to the extensive nature of the work, time constraints and resource availability focus was directed on reducing disease burden through prevention. This article explores the challenges of delivering preventative treatment as well as its advantage over conventional therapeutic care in the context of a humanitarian crisis. It also seeks to inspire other healthcare professionals to undertake outreach work within the UK and abroad. PMID- 28729594 TI - A topical solution? PMID- 28729593 TI - Is the shortened dental arch still a satisfactory option? AB - Aims Dental practitioners may hold the view that missing posterior teeth should be replaced to ensure a healthy masticatory system and satisfactory oral function. However, the shortened dental arch (SDA) concept is still in use, but after 35 years is it acceptable? This review searches the literature for the evidence and opinions regarding the suitability of the SDA as a current treatment modality.Methods Medline and PubMed databases were searched for relevant terms, all the abstracts were assessed and articles selected according to the pre-set exclusion and inclusion criteria.Results The search yielded 1,895 articles and after the assessment of the abstracts and application of the exclusion and inclusion criteria, 44 articles were selected for this review. These included 11 cohort studies, two longitudinal studies, two animal studies, three cross sectional studies, eight clinical studies and 18 case control studies. There appears to be a trend over the past three decades for more papers to be opposed to the SDA concept.Conclusion Evidence that the SDA causes pathology is lacking. Clinicians, healthcare authorities and patients have shown favourable attitudes towards the SDA and this continues, although there is an increase in studies opposing the concept and some are dissatisfied with this option. The concept remains viable particularly for the medically compromised patient or where restorations are considered unsuitable but further more specific studies are warranted. PMID- 28729595 TI - Hygienist appointments: Pain vs non pain. PMID- 28729597 TI - Preventive dental visiting: a critical interpretive synthesis of theory explaining how inequalities arise. AB - Positive experiences from dental visits, particularly for those patients from low socioeconomic status, feed into future 'help-seeking behaviour'. PMID- 28729600 TI - Dental education: All of the picture. PMID- 28729602 TI - New CPD requirements announced. PMID- 28729603 TI - Down on the beach with your dentist. PMID- 28729605 TI - Evaluating the effects of material properties of artificial meniscal implant in the human knee joint using finite element analysis. AB - Artificial meniscal implants may replace severely injured meniscus and restore the normal functionality of the knee joint. Implant material stiffness and shape influence the longevity of implantations. This study, using 3D finite element analysis, aimed to evaluate the effects of material stiffness variations of anatomically shaped artificial meniscal implant in the knee joint. Finite element simulations were conducted on five different cases including intact knee, medial meniscectomized knee, and the knee joint with the meniscal implant with three distinct material stiffness. Cartilage contact pressures, compression stresses, shear stresses, and implant kinematics (medial-lateral and posterior-anterior displacement) were evaluated for an axial compressive load of 1150 N at full extension. Compared to the meniscectomized knee, the knee joint with the meniscal implant induced lower peak cartilage contact pressure and reduced the cartilage regions loaded with contact pressures greater than the peak cartilage contact pressure induced by the intact knee. Results of the current study also demonstrate that cartilage contact pressures and implant displacement are sensitive to the implant material stiffness. The meniscal implant with a stiffness of 11 MPa restores the intact knee contact mechanics, thereby reducing the risk of physiological damage to the articular cartilage. PMID- 28729606 TI - Transcriptome profiling of the spermatheca identifies genes potentially involved in the long-term sperm storage of ant queens. AB - Females of social Hymenoptera only mate at the beginning of their adult lives and produce offspring until their death. In most ant species, queens live for over a decade, indicating that ant queens can store large numbers of spermatozoa throughout their long lives. To reveal the prolonged sperm storage mechanisms, we identified enriched genes in the sperm-storage organ (spermatheca) relative to those in body samples in Crematogaster osakensis queens using the RNA-sequencing method. The genes encoding antioxidant enzymes, proteases, and extracellular matrix-related genes, and novel genes that have no similar sequences in the public databases were identified. We also performed differential expression analyses between the virgin and mated spermathecae or between the spermathecae at 1-week and 1-year after mating, to identify genes altered by the mating status or by the sperm storage period, respectively. Gene Ontology enrichment analyses suggested that antioxidant function is enhanced in the spermatheca at 1-week after mating compared with the virgin spermatheca and the spermatheca at 1-year after mating. In situ hybridization analyses of 128 selected contigs revealed that 12 contigs were particular to the spermatheca. These genes have never been reported in the reproductive organs of insect females, suggesting specialized roles in ant spermatheca. PMID- 28729607 TI - Effective Methods of Restraining Diffusion in Terms of Epidemic Dynamics. AB - Removing influential nodes or shortcuts in a network restrains epidemic or information diffusion, but this method destroys the connectivity of the network and changes the topological structure. As an alternative, an additional field can be imposed in the network to affect node behaviors and slow down diffusion dynamics. However, little research has been performed systematically to analyze and compare these methods. This paper investigates epidemic dynamics and proposes the following four methods to restrain the diffusion process: blocking nodes, blocking edges, distracting node attention, and propagating opposite information. We compare differences in the actions of these methods, and investigate their joint effects. Through numerical experiments in a scale-free network and a real network, we observe that these methods change the spreading threshold and final extent with different conditions. The method of blocking nodes is more efficient and economical than blocking edges. Propagating opposite information can effectively prevent diffusion of target information that has a large spreading rate, whereas distracting node attention only takes effect for the information with a small rate. Meanwhile, the effects of these two methods mainly depend on their action time. From the joint effects, we can select the optimal method for different situations. PMID- 28729608 TI - Programmed death one homolog maintains the pool size of regulatory T cells by promoting their differentiation and stability. AB - Programmed death one homolog (PD-1H) is an immunoglobulin superfamily molecule and primarily acts as a coinhibitor in the initiation of T cell response to antigens. Here, we report that genetic ablation of PD-1H in mice blocks the differentiation of naive T cells to Foxp3+ inducible Treg cells (iTreg) with a significant decrease of iTreg in lymphoid organs. This effect of PD-1H is highly specific for iTreg because both naturally generated iTreg in gut-related tissues and in vitro induced iTreg by TGF-beta were decreased whereas the genesis of natural Treg (nTreg) remains normal. The suppressive function of both iTreg and nTreg, however, is not affected by the loss of PD-1H. In addition to decreased production, PD-1H deficient iTreg could also rapidly convert to CD4+ T helper 1 or T helper 17 cells in an inflammatory environment. Our results indicate that PD 1H is required for maintenance of iTreg pool size by promoting its differentiation and preventing its conversion to other CD4+ T cell subsets. These findings may have important implications for manipulating Tregs to control inflammation. PMID- 28729610 TI - Mean Bias in Seasonal Forecast Model and ENSO Prediction Error. AB - This study uses retrospective forecasts made using an APEC Climate Center seasonal forecast model to investigate the cause of errors in predicting the amplitude of El Nino Southern Oscillation (ENSO)-driven sea surface temperature variability. When utilizing Bjerknes coupled stability (BJ) index analysis, enhanced errors in ENSO amplitude with forecast lead times are found to be well represented by those in the growth rate estimated by the BJ index. ENSO amplitude forecast errors are most strongly associated with the errors in both the thermocline slope response and surface wind response to forcing over the tropical Pacific, leading to errors in thermocline feedback. This study concludes that upper ocean temperature bias in the equatorial Pacific, which becomes more intense with increasing lead times, is a possible cause of forecast errors in the thermocline feedback and thus in ENSO amplitude. PMID- 28729609 TI - Maternally-transmitted microbiota affects odor emission and preference in Drosophila larva. AB - Experimental studies show that early sensory experience often affects subsequent sensory preference, suggesting that the heterogeneity of sensory cues in nature could induce significant inter-individual behavioral variation, potentially contributing to maintain intraspecific diversity. To test this hypothesis, we explored the behavioral effect induced by variation in the levels of a self produced chemical, acetoin, and its link with intraspecific diversity. Acetoin is a pheromone-like substance produced by gut-associated microorganisms in Drosophila. Using wild-type Drosophila melanogaster populations producing variable acetoin levels, we (i) characterized factors involved in this variation and (ii) manipulated some of these factors to affect acetoin responses in larvae. We found that increased and decreased variations in acetoin levels were caused by microorganisms associated with the outside and inside of the egg, respectively. Wild-type larvae preferred acetoin-rich food only when they both produced and were exposed to substantial amounts of acetoin. The removal of the outside of the egg or the genetic alteration of olfaction abolished this preference. In contrast, larvae exposed to high doses of synthetic acetoin were repulsed by acetoin. The similar effects obtained with freshly caught wild-type lines suggest that this acetoin "production-preference" link underlies the diversity of acetoin producing microorganisms among natural D. melanogaster populations. PMID- 28729611 TI - Cryptic speciation in pan-tropical sea urchins: a case study of an edge-of-range population of Tripneustes from the Kermadec Islands. AB - Tripneustes is one of the most abundant and ecologically significant tropical echinoids. Highly valued for its gonads, wild populations of Tripneustes are commercially exploited and cultivated stocks are a prime target for the fisheries and aquaculture industry. Here we examine Tripneustes from the Kermadec Islands, a remote chain of volcanic islands in the southwest Pacific Ocean that mark the boundary of the genus' range, by combining morphological and genetic analyses, using two mitochondrial (COI and the Control Region), and one nuclear (bindin) marker. We show that Kermadec Tripneustes is a new species of Tripneustes. We provide a full description of this species and present an updated phylogeny of the genus. This new species, Tripneustes kermadecensis n. sp., is characterized by having ambulacral primary tubercles occurring on every fourth plate ambitally, flattened test with large peristome, one to two occluded plates for every four ambulacral plates, and complete primary series of interambulacral tubercles from peristome to apex. It appears to have split early from the main Tripneustes stock, predating even the split of the Atlantic Tripneustes lineage. Its distinction from the common T. gratilla and potential vulnerability as an isolated endemic species calls for special attention in terms of conservation. PMID- 28729612 TI - Functional distinction of hyphal compartments. AB - Hyphae of higher fungi grow at their tips and are compartmentalized by porous septa that enable inter-compartmental cytoplasmic streaming. Woronin bodies discontinue cytoplasmic streaming by plugging the septal pores. Here, it was assessed whether apical compartments of Aspergillus niger sustain their own growth or whether their growth depends on subapical compartments. Hyphae of wildtype and the DeltahexA strain, lacking Woronin bodies, had a similar morphology and growth rate. A total of 58% and 17% of the hyphae continued growing, respectively, after dissecting the 2nd compartment. Extension rate of the apical compartments that continued growing was not affected, even when the carbon or nitrogen source was limiting. Thus, apical compartments are self sustaining in growth. It was also shown that the first 8 subapical compartments of the wildtype, but not of the DeltahexA strain, function as a backup system for growth by forming new branches when their apical neighbouring compartment has been damaged. This backup system is pivotal in nature because of the life style of fungi to continuously explore their surrounding substrate that may prove hostile. PMID- 28729613 TI - Effects of Sintering Temperature on Crystallization and Fabrication of Porous Bioactive Glass Scaffolds for Bone Regeneration. AB - In this work the sintering ability of borosilicate (S53B50), borophosphate (P40B10) and phosphate (Sr) bioactive glasses was investigated. The glass powders were crushed and sintered in air at a heating rate of 10 degrees C/min for 2 hours at sintering temperatures between 480 degrees C-600 degrees C. The aim was to define the optimum sintering temperature prior to glass crystallization. The density of the samples was found to decrease when the temperature was increased up to 580 degrees C; probably due to the inhibition of the viscous flow of the particles during sintering thereby reducing the densification of the material. Such low porosity is not suitable in tissue engineering. To process highly porous scaffolds with porosity required for scaffold applicable to tissue engineering, the powders were further mixed with 60 vol.% and 70 vol.% of NH4(HCO3) foaming agent. Meanwhile, the density of the samples sintered with NH4(HCO3) was found to decrease with an increase in NH4(HCO3) content. This indicates an increase in porosity of the samples. The glass compositions reached an open porosity of more than 60% at the addition of 70 vol.% NH4(HCO3). In addition, SEM micrograph revealed large pores with good interconnection between the pores. PMID- 28729614 TI - Knockdown of two Cadherin genes confers resistance to Cry2A and Cry1C in Chilo suppressalis. AB - Bacillus thuringiensis (Bt) Cry toxins play an important role in the management of insect pests. Resistance to Bt toxins has been reported in many pest insects but the mechanism responsible for this resistance in rice crop pests remains largely unknown. Cadherin is one of several Bt toxin receptors. At present, only one cadherin gene, CsCAD1, has been documented in the striped rice stem borer, Chilo suppressalis. We amplified a nearly full-length transcript of another C. suppressalis cadherin gene, CsCAD2, and found that it has a different expression pattern to CsCAD1. CsCAD1 was highly expressed in fifth and sixth instar larvae, especially in the midgut, while the expression levels of CsCA2 were equably in each developmental stage. Newly hatched larvae were fed on rice smeared with synthesized siRNA to knockdown either CsCAD1 or CsCAD2, and then were fed transgenic rice expressing either the Cry2A or Cry1C toxins. The siRNA-treatment groups had lower mortality and higher survival rates than the control group, suggesting that reduced expression of CsCAD1 or CsCAD2 increased resistance to Cry2A and Cry1C. We conclude that CsCAD1 and CsCAD2 interact with Bt toxins in C. suppressalis and that this interaction could be the mechanism underlying Bt resistance in this insect. PMID- 28729615 TI - Deletion of the celA gene in Aspergillus nidulans triggers overexpression of secondary metabolite biosynthetic genes. AB - Although much progress has been made in the study of cell wall biosynthetic genes in the model filamentous fungus Aspergillus nidulans, there are still targets awaiting characterization. An example is the gene celA (ANIA_08444) encoding a putative mixed linkage glucan synthase. To characterize the role of celA, we deleted it in A. nidulans, analyzed the phenotype of the mycelium and performed RNA-Seq. The strain shows a very strong phenotype, namely "balloons" along the hyphae and aberrant conidiophores, as well as an altered susceptibility to cell wall drugs. These data suggest a potential role of the gene in cell wall-related processes. The Gene Ontology term Enrichment analysis shows increased expression of secondary metabolite biosynthetic genes (sterigmatocystin in particular) in the deleted strain. Our results show that the deletion of celA triggers a strong phenotype reminiscent of cell wall-related aberrations and the upregulation of some secondary metabolite gene clusters in A. nidulans. PMID- 28729616 TI - Identification of a T cell gene expression clock obtained by exploiting a MZ twin design. AB - Many studies investigated age-related changes in gene expression of different tissues, with scarce agreement due to the high number of affecting factors. Similarly, no consensus has been reached on which genes change expression as a function of age and not because of environment. In this study we analysed gene expression of T lymphocytes from 27 healthy monozygotic twin couples, with ages ranging over whole adult lifespan (22 to 98 years). This unique experimental design allowed us to identify genes involved in normative aging, which expression changes independently from environmental factors. We obtained a transcriptomic signature with 125 genes, from which chronological age can be estimated. This signature has been tested in two datasets of same cell type hybridized over two different platforms, showing a significantly better performance compared to random signatures. Moreover, the same signature was applied on a dataset from a different cell type (human muscle). A lower performance was obtained, indicating the possibility that the signature is T cell-specific. As a whole our results suggest that this approach can be useful to identify age-modulated genes. PMID- 28729617 TI - The Effect of Electrical Stimulation of the Calf Muscle on Leg Fluid Accumulation over a Long Period of Sitting. AB - Leg fluid accumulation during sedentary behaviours such as sitting can lead to leg edema and associated adverse health consequences. This study investigates the use calf muscle electrical stimulation (ES) to reduce seated leg fluid accumulation. Thirteen non-obese, normotensive men (mean age 51 yr.) with sleep apnea were enrolled in the study. Participants first lay supine for 30 minutes to equalize fluid distribution and then sat for 150 minutes. While seated, participants received either active or sham ES of the calf muscles, according to random assignment. Participants returned one-week later to cross over to the other study condition. Leg fluid was measured continuously while sitting using the bioelectrical impedance method. Fluid accumulation in the leg was reduced by more than 40% using active ES, compared to sham ES (? = 51.9 +/- 8.8 ml vs. ? = 91.5 +/- 8.9 ml, P < 0.001). In summary, calf muscle ES is an effective method for reducing accumulation of fluid during long sedentary periods and has potential use as a device for preventing leg edema to treat associated health consequences in at-risk groups and settings. PMID- 28729618 TI - Corrigendum: Possible recent warming hiatus on the northwestern Tibetan Plateau derived from ice core records. AB - This corrects the article DOI: 10.1038/srep32813. PMID- 28729619 TI - Effects of 4(1H)-quinolinone derivative, a novel non-nucleotide allosteric purinergic P2Y 2 agonist, on cardiomyocytes in neonatal rats. AB - Purinergic P2Y 2 receptors, G-protein coupled receptors that primarily couple with Galphaq/11-proteins, are activated equipotently by adenosine-5'-triphosphate (ATP) and uridine-5'-triphosphate. Evidence suggests that P2Y 2 agonists make potential drug candidates for the treatment of cardiovascular diseases. However, selective non-nucleotide, small-molecule P2Y 2 agonists have yet to be developed. In this report, we discuss Compound 89, a novel non-nucleotide allosteric P2Y 2 agonist that was active in signal transduction and gene induction, and in our in vitro cardiac hypertrophy model. Compound 89 exhibited selective P2Y 2 agonistic activity and potentiated responses to the endogenous agonist ATP, while exhibiting no agonistic activities for four other Galphaq/11-coupled human P2Y (hP2Y) receptors and one representative Galphai/o-coupled hP2Y12 receptor. Its P2Y 2 agonistic effect on mouse P2Y 2 receptors suggested non-species-specific activity. Compound 89 acted as a pure positive allosteric modulator in a Ca2+ mobilization assay of neonatal rat cardiomyocytes; it potentiated ATP-induced expression of genes in the nuclear receptor 4A family (negative regulators of hypertrophic stimuli in cardiomyocytes). Additionally, Compound 89 attenuated isoproterenol-induced cardiac hypertrophy, presumably through dose-dependent interaction with pericellular ATP. These results indicate that Compound 89 is potentially efficacious against cardiomyocytes and therefore a good proof-of concept tool for elucidating the therapeutic potential of P2Y2 activation in various cardiovascular diseases. PMID- 28729620 TI - Self-management behaviour and support among primary care COPD patients: cross sectional analysis of data from the Birmingham Chronic Obstructive Pulmonary Disease Cohort. AB - : Self-management support for chronic obstructive pulmonary disease (COPD) patients is recommended by UK national guidelines, but extent of implementation is unknown. We aimed to describe self-management behaviour and support among COPD patients and explore behaviour associated with having a self-management plan. We undertook cross-sectional analysis of self-reported data from diagnosed COPD patients in the Birmingham COPD Cohort study. Questionnaire items relevant to self-management behaviour, knowledge of COPD, receipt of self-management plans and advice from healthcare professionals were examined. Multiple regression models were used to identify behaviour associated with having a self-management plan. One-thousand seventy-eight participants (676 males, 62.7%, mean age 69.8 (standard deviation 9.0) years) were included. The majority reported taking medications as instructed (940, 94.0%) and receiving annual influenza vaccinations (962, 89.2%). Only 400 (40.4%) participants had self-management plans, 538 (49.9%) reported never having received advice on diet/exercise and 110 (42.7%) current smokers had been offered practical help to stop smoking in the previous year. General knowledge about COPD was moderate (mean total Bristol COPD Knowledge Questionnaire score: 31.5 (standard deviation 10.7); max score 65), corresponding to 48.5% of questions answered correctly. Having a self-management plan was positively associated with self-reported adherence to medication (odds ratio 3.10, 95% confidence interval 1.43 to 6.72), attendance at a training course (odds ratio 2.72, 95% confidence interval 1.81 to 4.12), attendance at a support group (odds ratio 6.28, 95% confidence interval 2.96 to 13.35) and better disease knowledge (mean difference 4.87, 95% confidence interval 3.16 to 6.58). Primary care healthcare professionals should ensure more widespread implementation of individualised self-management plans for all patients and improve the lifestyle advice provided. CHRONIC LUNG DISEASE: CALL FOR WIDER IMPLEMENTATION OF SELF-MANAGEMENT PLANS: Health professionals should ensure all patients with chronic lung disease receive individualized self-management plans and lifestyle advice. UK national guidelines state that patients with chronic obstructive pulmonary disease (COPD) should receive personalized self-management plans and comprehensive support to help them manage their disease. Ainee Khan and colleagues at the University of Birmingham analyzed patient questionnaire data gathered during the Birmingham COPD Cohort study to explore self-management behavior, receipt of self-management plans and advice, and patient knowledge of COPD. Of 1,078 participants, only 400 had self-management plans, and less than half reported receiving lifestyle advice or support. Those with plans were more likely to adhere to medication, had greater knowledge about COPD and were more likely to attend support groups and training courses. The authors recommend carefully-planned, wider implementation of COPD self-management plans and associated support. PMID- 28729621 TI - Genotype-environment interaction on human cognitive function conditioned on the status of breastfeeding and maternal smoking around birth. AB - We estimated genotype by environment interaction (G * E) on later cognitive performance and educational attainment across four unique environments, i.e. 1) breastfed without maternal smoking, 2) breastfed with maternal smoking, 3) non breastfed without maternal smoking and 4) non-breastfed with maternal smoking, using a novel design and statistical approach that was facilitated by the availability of datasets with the genome-wide single nucleotide polymorphisms (SNPs). There was significant G * E for both fluid intelligence (p-value = 1.0E 03) and educational attainment (p-value = 8.3E-05) when comparing genetic effects in the group of individuals who were breastfed without maternal smoking with those not breastfed without maternal smoking. There was also significant G * E for fluid intelligence (p-value = 3.9E-05) when comparing the group of individuals who were breastfed with maternal smoking with those not breastfed without maternal smoking. Genome-wide significant SNPs were different between different environmental groups. Genomic prediction accuracies were significantly higher when using the target and discovery sample from the same environmental group than when using those from the different environmental groups. This finding demonstrates G * E has important implications for future studies on the genetic architecture, genome-wide association studies and genomic predictions. PMID- 28729622 TI - Three-dimensional visualization of intrauterine conceptus through the uterine wall by tissue clearing method. AB - Visualization of specific cells in the three-dimensional organ architecture is one of the key steps to develop our knowledge about pathophysiological mechanisms in various organs. In this study, we successfully obtained stereoscopic whole images of the intrauterine murine embryo and placenta through the uterus using a modified tissue clearing CUBIC method. By this procedure, we can recognize the three-dimensional relationships among various tissues within the pregnant uterus and analyze free-angle images of cross-sections with single-cell resolution using a computer system. Based on these data, we can select optimal cross-section angles and then produce the corresponding tissue slices that are adequate for further immunohistochemical examination. Furthermore, using transgenic mice, distinct images of an EGFP-positive embryo and the placenta can be obtained, confirming the precise three-dimensional location of invading trophoblasts in the feto-maternal interface in the uterus. These results indicate that this procedure will significantly contribute to analyzing pathophysiological mechanisms in reproductive organs. PMID- 28729623 TI - 3D-QSAR studies on Maslinic acid analogs for Anticancer activity against Breast Cancer cell line MCF-7. AB - Global prevalence of breast cancer and its rising frequency makes it a key area of research in drug discovery programs. The research article describes the development of field based 3D-QSAR model based on human breast cancer cell line MCF7 in vitro anticancer activity, which defines the molecular level understanding and regions of structure-activity relationship for triterpene maslinic acid and its analogs. The key features such as average shape, hydrophobic regions and electrostatic patterns of active compounds were mined and mapped to virtually screen potential analogs. Then, field points based descriptors were used to develop a 3D-QSAR model by aligning known active compounds onto identified pharmacophore template. The derived LOO validated PLS regression QSAR model showed acceptable r2 0.92 and q2 0.75. After screening through Lipinski's rule of five filter for oral bioavailability, ADMET risk filter for drug like features, and synthetic accessibility for chemical synthesis, out of 593 hits, 39 were left top hits. Docking screening was performed through identified potential targets namely, AKR1B10, NR3C1, PTGS2, and HER2. Finally, compound P-902 was identified as best hit. This study, would be of great help in lead identification and optimization for early drug discovery. PMID- 28729624 TI - Taxanes and platinum derivatives impair Schwann cells via distinct mechanisms. AB - Impairment of peripheral neurons by anti-cancer agents, including taxanes and platinum derivatives, has been considered to be a major cause of chemotherapy induced peripheral neuropathy (CIPN), however, the precise underlying mechanisms are not fully understood. Here, we examined the direct effects of anti-cancer agents on Schwann cells. Exposure of primary cultured rat Schwann cells to paclitaxel (0.01 MUM), cisplatin (1 MUM), or oxaliplatin (3 MUM) for 48 h induced cytotoxicity and reduced myelin basic protein expression at concentrations lower than those required to induce neurotoxicity in cultured rat dorsal root ganglion (DRG) neurons. Similarly, these anti-cancer drugs disrupted myelin formation in Schwann cell/DRG neuron co-cultures without affecting nerve axons. Cisplatin and oxaliplatin, but not paclitaxel, caused mitochondrial dysfunction in cultured Schwann cells. By contrast, paclitaxel led to dedifferentiation of Schwann cells into an immature state, characterized by increased expression of p75 and galectin 3. Consistent with in vitro findings, repeated injection of paclitaxel increased expression of p75 and galectin-3 in Schwann cells within the mouse sciatic nerve. These results suggest that taxanes and platinum derivatives impair Schwan cells by inducing dedifferentiation and mitochondrial dysfunction, respectively, which may be important in the development of CIPN in conjunction with their direct impairment in peripheral neurons. PMID- 28729625 TI - Stable isotopes reveal diet shift from pre-extinction to reintroduced Przewalski's horses. AB - The Przewalski's horse (Equus ferus przewalskii), the only remaining wild horse within the equid family, is one of only a handful of species worldwide that went extinct in the wild, was saved by captive breeding, and has been successfully returned to the wild. However, concerns remain that after multiple generations in captivity the ecology of the Przewalski's horse and / or the ecological conditions in its former range have changed in a way compromising the species' long term survival. We analyzed stable isotope chronologies from tail hair of pre extinction and reintroduced Przewalski's horses from the Dzungarian Gobi and detected a clear difference in the isotopic dietary composition. The direction of the dietary shift from being a mixed feeder in winter and a grazer in summer in the past, to a year-round grazer nowadays, is best explained by a release from human hunting pressure. A changed, positive societal attitude towards the species allows reintroduced Przewalski's horses to utilize the scarce, grass-dominated pastures of the Gobi alongside local people and their livestock whereas their historic conspecifics were forced into less productive habitats dominated by browse. PMID- 28729626 TI - Tool manipulation by rats (Rattus norvegicus) according to the position of food. AB - Tool-use behaviour has been observed in nonhuman animals in the wild and in experimental settings. In the present study, we investigated whether rats (Rattus norvegicus) could manipulate a tool according to the position of food to obtain the food in an experimental setting. Eight rats were trained to use a rake-shaped tool to obtain food beyond their reach using a step-by-step protocol in the initial training period. Following training, the rake was placed at the centre of the experimental apparatus, and food was placed on either the left or right side of the rake. Rats learned to manipulate the rake to obtain food in situations in which they could not obtain the food just by pulling the rake perpendicularly to themselves. Our findings thus indicate that the rat is a potential animal model to investigate the behavioural and neural mechanisms of tool-use behaviour. PMID- 28729627 TI - A Mechanism-based QSTR Model for Acute to Chronic Toxicity Extrapolation: A Case Study of Antibiotics on Luminous Bacteria. AB - The determination of the chronic toxicity is time-consumed and costly, so it's of great interest to predict the chronic toxicity based on acute data. Current methods include the acute to chronic ratios (ACRs) and the QSTR models, both of which have some usage limitations. In this paper, the acute and chronic mixture toxicity of three types of antibiotics, namely sulfonamides, sulfonamide potentiators and tetracyclines, were determined by a bioluminescence inhibition test. A novel QSTR model was developed for predicting the chronic mixture toxicity using the acute data and docking-based descriptors. This model revealed a complex relationship between the acute and chronic toxicity, i.e. a linear correlation between the acute and chronic lg(-lgEC50)s, rather than the simple EC50s or -lgEC50s. In particular, the interaction energies (Ebind) of the chemicals with luciferase and LitR in the bacterial quorum sensing systems were introduced to represent their acute and chronic actions, respectively, regardless of their defined toxic mechanisms. Therefore, the present QSTR model can apply to the chemicals with distinct toxic mechanisms, as well as those with undefined mechanism. This study provides a novel idea for the acute to chronic toxicity extrapolation, which may benefit the environmental risk assessment on the pollutants. PMID- 28729628 TI - A new approach for ratiometric in vivo calcium imaging of microglia. AB - Microglia, resident immune cells of the brain, react to the presence of pathogens/danger signals with a large repertoire of functional responses including morphological changes, proliferation, chemotaxis, production/release of cytokines, and phagocytosis. In vitro studies suggest that many of these effector functions are Ca2+-dependent, but our knowledge about in vivo Ca2+ signalling in microglia is rudimentary. This is mostly due to technical reasons, as microglia largely resisted all attempts of in vivo labelling with Ca2+ indicators. Here, we introduce a novel approach, utilizing a microglia-specific microRNA-9-regulated viral vector, enabling the expression of a genetically-encoded ratiometric Ca2+ sensor Twitch-2B in microglia. The Twitch-2B-assisted in vivo imaging enables recording of spontaneous and evoked microglial Ca2+ signals and allows for the first time to monitor the steady state intracellular Ca2+ levels in microglia. Intact in vivo microglia show very homogenous and low steady state intracellular Ca2+ levels. However, the levels increase significantly after acute slice preparation and cell culturing along with an increase in the expression of activation markers CD68 and IL-1beta. These data identify the steady state intracellular Ca2+ level as a versatile microglial activation marker, which is highly sensitive to the cell's environment. PMID- 28729629 TI - Assembly of "3D" plasmonic clusters by "2D" AFM nanomanipulation of highly uniform and smooth gold nanospheres. AB - Atomic force microscopy (AFM) nanomanipulation has been viewed as a deterministic method for the assembly of plasmonic metamolecules because it enables unprecedented engineering of clusters with exquisite control over particle number and geometry. Nevertheless, the dimensionality of plasmonic metamolecules via AFM nanomanipulation is limited to 2D, so as to restrict the design space of available artificial electromagnetisms. Here, we show that "2D" nanomanipulation of the AFM tip can be used to assemble "3D" plasmonic metamolecules in a versatile and deterministic way by dribbling highly spherical and smooth gold nanospheres (NSs) on a nanohole template rather than on a flat surface. Various 3D plasmonic clusters with controlled symmetry were successfully assembled with nanometer precision; the relevant 3D plasmonic modes (i.e., artificial magnetism and magnetic-based Fano resonance) were fully rationalized by both numerical calculation and dark-field spectroscopy. This templating strategy for advancing AFM nanomanipulation can be generalized to exploit the fundamental understanding of various electromagnetic 3D couplings and can serve as the basis for the design of metamolecules, metafluids, and metamaterials. PMID- 28729630 TI - Mechanically durable liquid-impregnated honeycomb surfaces. AB - Liquid repellent surfaces typically work by keeping the fouling liquid in a metastable state, with trapped pockets of air between the substrate and the liquid. An alternative method with greater long-term stability utilizes liquid impregnated surfaces, where the liquid being repelled slides over an immiscible liquid immobilized on a porous surface. Here, we report a method for creating honeycomb surfaces amenable to liquid-impregnation. Polystyrene dissolved in a water-immiscible, volatile solvent was deposited in a humid environment on a variety of substrates to achieve the necessary porosity. Evaporative cooling results in condensation of water in a breath figure array of droplets, forming a sacrificial template for the drying polymer film. These honeycomb surfaces were further functionalized with fluorosilane and dipped in the lubricating liquid to result in a durable, liquid-repellent surface. These surfaces were found to exhibit repellency towards water and oils with extremely low tilt angles due to the smooth liquid-liquid contact between the lubricating liquid and the liquid being repelled. PMID- 28729632 TI - Erratum: Removal of Diethylhexyl Phthalate from Hands by Handwashing: Evidence from Experimental N-of-1 and Crossover Designs. AB - A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper. PMID- 28729631 TI - Therapeutic effects of long-circulating miR-135a-containing cationic immunoliposomes against gallbladder carcinoma. AB - Gallbladder carcinoma (GBC) is the most common malignant tumour in the biliary tract, but effective therapeutics are lacking. Based on our previous studies, miR 135a is a potential tool to inhibit GBC proliferation. In this study, we constructed miR-135a-loaded DSPE-PEG2000 liposomes modified with Anti-EGFR antibodies (Anti-EGFR-CIL-miR-135a). The results of an analysis of their physicochemical properties indicated the particle size of it was 222.0 +/- 2.1 nm in diameter with an uptake efficiency of 86.5%. Next, the post-treatment biological behaviours of GBC, specifically, invasion, metastasis and apoptosis, were evaluated. miR-135a inhibited GBC invasion and metastasis and promoted apoptosis compared to controls. Additionally, miR-135a targeted and regulated the expression of ROCK1, HOXA10 and BCL-2. Due to the targeted effects of Anti-EGFR CIL-miR-135a, the GBC tumour growth rate was 60% lower in an in vivo xenograft bearing mouse model compared to controls. Thus, Anti-EGFR-CIL-miR-135a is a promising therapeutic strategy to combat GBC. PMID- 28729633 TI - Threats to large brown algal forests in temperate seas: the overlooked role of native herbivorous fish. AB - Canopy-forming algae are declining globally due to multiple disturbances. This decline has recently been on the increase due to the spread of some tropical herbivorous fishes. This new phenomenon has drawn attention to the effects of fish herbivory in temperate areas, which have been assumed to be negligible compared to that of invertebrates, such as sea urchins. In this study, the impact of a Mediterranean native herbivorous fish (Sarpa salpa, salema) was assessed on the canopy-forming seaweed Cystoseira amentacea var. stricta. Cystoseira amentacea forms belts in the infralittoral fringe of wave-exposed shores, which has so far been considered a refuge from fish herbivory. To test the effects of salema feeding on natural C. amentacea belts, an innovative herbivore deterrent device was conceived. Salema had a significant effect on C. amentacea by decreasing algal size, biomass and fertility, by up to 97%. The results suggest that the contribution of salema feeding to the loss of Cystoseira forests in the Mediterranean may have been overlooked. In addition, the analysis of temporal and spatial patterns of salema landings in the Mediterranean Sea suggests that salema abundance may have increased recently. Thus, along with invertebrate herbivory and anthropogenic stressors, fish herbivory may also represent a potential threat to algal forests in temperate areas. PMID- 28729634 TI - Novel Intraperitoneal Treatment With Non-Thermal Plasma-Activated Medium Inhibits Metastatic Potential of Ovarian Cancer Cells. AB - Non-thermal atmospheric pressure plasma has been proposed as a new therapeutic tool for cancer treatment. Recently, plasma-activated medium (PAM) has been widely studied in various cancer types. However, there are only few reports demonstrating the anti-tumour effects of PAM in an animal model reflecting pathological conditions and the accompanying mechanism. Here we investigated the inhibitory effect of PAM on the metastasis of ovarian cancer ES2 cells in vitro and in vivo. We demonstrated that ES2 cell migration, invasion and adhesion were suppressed by PAM at a certain PAM dilution ratio, whereas cell viability remained unaffected. In an in vivo mouse model of intraperitoneal metastasis, PAM inhibited peritoneal dissemination of ES2 cells, resulting in prolonged survival. Moreover, we assessed the molecular mechanism and found that MMP-9 was decreased by PAM. On further investigation, we also found that PAM prevented the activation of the MAPK pathway by inhibiting the phosphorylation of JNK1/2 and p38 MAPK. These findings indicate that PAM inhibits the metastasis of ovarian cancer cells through reduction of MMP-9 secretion, which is critical for cancer cell motility. Our findings suggest that PAM intraperitoneal therapy may be a promising treatment option for ovarian cancer. PMID- 28729635 TI - Superior non-specific motor learning in the blind. AB - It is well established that blindness induces changes in cerebral function and structure, namely affecting the somatomotor regions. However, the behavioural significance of these changes on the motor system, and on motor learning in particular, remains elusive. In this study, we used a modified version of the serial reaction time task (SRTT) with auditory cues to assess sequence specific and non-specific motor learning in blind adults and sighted controls, and compare them with sighted controls performing the classic visual SRTT. Our results show that the auditory SRTT faithfully replicates the typical learning pattern obtained with the visual SRTT. On the auditory SRTT, blind individuals consistently showed faster reaction times than sighted controls, being at par with sighted individuals performing the visual SRTT. On the other hand, blind participants displayed a particular pattern of motor learning in comparison to both sighted groups; while controls improved prominently on sequence specific learning, blind individuals displayed comparable performance on both specific and non-specific learning, markedly outperforming the control groups on non-specific learning. These results show that blindness, in addition to causing long-term changes in cortical organisation, can also influence dynamic neuroplastic mechanisms in systems beyond those typically associated with compensatory sensory processing. PMID- 28729636 TI - Erratum: Influence of different geographical factors on carbon sink functions in the Pearl River Delta. AB - A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper. PMID- 28729637 TI - Genetic variants including markers from the exome chip and metabolite traits of type 2 diabetes. AB - Diabetes-associated metabolites may aid the identification of new risk variants for type 2 diabetes. Using targeted metabolomics within a subsample of the German EPIC-Potsdam study (n = 2500), we tested previously published SNPs for their association with diabetes-associated metabolites and conducted an additional exploratory analysis using data from the exome chip including replication within 2,692 individuals from the German KORA F4 study. We identified a total of 16 loci associated with diabetes-related metabolite traits, including one novel association between rs499974 (MOGAT2) and a diacyl-phosphatidylcholine ratio (PC aa C40:5/PC aa C38:5). Gene-based tests on all exome chip variants revealed associations between GFRAL and PC aa C42:1/PC aa C42:0, BIN1 and SM (OH) C22:2/SM C18:0 and TFRC and SM (OH) C22:2/SM C16:1). Selecting variants for gene-based tests based on functional annotation identified one additional association between OR51Q1 and hexoses. Among single genetic variants consistently associated with diabetes-related metabolites, two (rs174550 (FADS1), rs3204953 (REV3L)) were significantly associated with type 2 diabetes in large-scale meta-analysis for type 2 diabetes. In conclusion, we identified a novel metabolite locus in single variant analyses and four genes within gene-based tests and confirmed two previously known mGWAS loci which might be relevant for the risk of type 2 diabetes. PMID- 28729638 TI - Inhibition of microRNA-214 promotes epithelial-mesenchymal transition process and induces interstitial cystitis in postmenopausal women by upregulating Mfn2. AB - Our study aims to investigate the roles that microRNA-214 (miR-214) plays in the epithelial mesenchymal transition (EMT) process and the development of interstitial cystitis (IC) in postmenopausal women by targeting Mitofusin 2 (Mfn2). IC bladder tissues and adjacent normal bladder tissues were collected from postmenopausal women. Immunohistochemistry (IHC) staining was conducted. The target relationship between miR-214 and Mfn2 was determined by a dual luciferase reporter gene assay. Adipose-derived mesenchymal stem cells (ADMSCs) were extracted from postmenopausal rats and assigned to the blank, mimics, miR-214 inhibitors, mimics negative control (NC), inhibitors NC, Mfn2 siRNA, miR-214 inhibitors and Mfn2 siRNA groups. Exosomes secreted by transfected ADMSCs were instilled into the bladders of postmenopausal rats. The expression of miR-214 and Mfn2 mRNA and EMT markers was assessed by qRT-PCR and western blotting. It was confirmed that Mfn2 was the target gene of miR-214 in IC. Compared with the normal bladder tissues, miR-214 decreased, but Mfn2 increased in IC bladder tissues. Compared with the blank group, the expression of miR-214 and the expression levels of N-cadherin, Fibronectin, Twist1, Snail and Vimentin mRNA and protein increased, whereas the expression levels of Mfn2, E-cadherin and ZO-1 mRNA and protein decreased in the miR-214 mimics and Mfn2 groups. The expression of MiR-214 and the expression levels of N-cadherin, Fibronectin, Twist1, Snail and Vimentin mRNA and protein decreased, whereas the expression levels of Mfn2, E cadherin and ZO-1 mRNA and protein increased in the miR-214 inhibitors group. Our findings indicate that the inhibition of miR-214 promotes the EMT process and contributes to bladder wall fibrosis by up-regulating Mfn2, thus leading to the occurrence of IC in postmenopausal women. PMID- 28729639 TI - Stimulation of osteoclast migration and bone resorption by C-C chemokine ligands 19 and 21. AB - Osteoclasts are responsible for the bone erosion associated with rheumatoid arthritis (RA). The upregulation of the chemokines CCL19 and CCL21 and their receptor CCR7 has been linked to RA pathogenesis. The purpose of this study was to evaluate the effects of CCL19 and CCL21 on osteoclasts and to reveal their underlying mechanisms. The expression of CCL19, CCL21 and CCR7 was higher in RA patients than in osteoarthritis patients. In differentiating osteoclasts, tumor necrosis factor-alpha, interleukin-1beta and lipopolysaccharide stimulated CCR7 expression. CCL19 and CCL21 promoted osteoclast migration and resorption activity. These effects were dependent on the presence of CCR7 and abolished by the inhibition of the Rho signaling pathway. CCL19 and CCL21 promoted bone resorption by osteoclasts in an in vivo mice calvarial model. These findings demonstrate for the first time that CCL19, CCL21 and CCR7 play important roles in bone destruction by increasing osteoclast migration and resorption activity. This study also suggests that the interaction of CCL19 and CCL21 with CCR7 is an effective strategic focus in developing therapeutics for alleviating inflammatory bone destruction. PMID- 28729640 TI - Radiation-induced liver disease: current understanding and future perspectives. AB - Although radiotherapy (RT) is used for the treatment of cancers, including liver cancer, radiation-induced liver disease (RILD) has emerged as a major limitation of RT. Radiation-induced toxicities in nontumorous liver tissues are associated with the development of numerous symptoms that may limit the course of therapy or have serious chronic side effects, including late fibrosis. Although the clinical characteristics of RILD patients have been relatively well described, the understanding of RILD pathogenesis has been hampered by a lack of reliable animal models for RILD. Despite efforts to develop suitable experimental animal models for RILD, current animal models rarely present hepatic veno-occlusive disease, the pathological hallmark of human RILD patients, resulting in highly variable results in RILD-related studies. Therefore, we introduce the concept and clinical characteristics of RILD and propose a feasible explanation for RILD pathogenesis. In addition, currently available animal models of RILD are reviewed, focusing on similarities with human RILD and clues to understanding the mechanisms of RILD progression. Based on these findings from RILD research, we present potential therapeutic strategies for RILD and prospects for future RILD studies. Therefore, this review helps broaden our understanding for developing effective treatment strategies for RILD. PMID- 28729641 TI - The rhizosphere microbiome of burned holm-oak: potential role of the genus Arthrobacter in the recovery of burned soils. AB - After a forest wildfire, the microbial communities have a transient alteration in their composition. The role of the soil microbial community in the recovery of an ecosystem following such an event remains poorly understood. Thus, it is necessary to understand the plant-microbe interactions that occur in burned soils. By high-throughput sequencing, we identified the main bacterial taxa of burnt holm-oak rhizosphere, then we obtained an isolate collection of the most abundant genus and its growth promoting activities were characterised. 16S rRNA amplicon sequencing showed that the genus Arthrobacter comprised more than 21% of the total community. 55 Arthrobacter strains were isolated and characterized using RAPDs and sequencing of the almost complete 16S rRNA gene. Our results indicate that isolated Arthrobacter strains present a very high genetic diversity, and they could play an important ecological role in interaction with the host plant by enhancing aerial growth. Most of the selected strains exhibited a great ability to degrade organic polymers in vitro as well as possibly presenting a direct mechanism for plant growth promotion. All the above data suggests that Arthrobacter can be considered as an excellent PGP rhizobacterium that may play an important role in the recovery of burned holm-oak forests. PMID- 28729642 TI - Imaging of super-fast dynamics and flow instabilities of superconducting vortices. AB - Quantized magnetic vortices driven by electric current determine key electromagnetic properties of superconductors. While the dynamic behavior of slow vortices has been thoroughly investigated, the physics of ultrafast vortices under strong currents remains largely unexplored. Here, we use a nanoscale scanning superconducting quantum interference device to image vortices penetrating into a superconducting Pb film at rates of tens of GHz and moving with velocities of up to tens of km/s, which are not only much larger than the speed of sound but also exceed the pair-breaking speed limit of superconducting condensate. These experiments reveal formation of mesoscopic vortex channels which undergo cascades of bifurcations as the current and magnetic field increase. Our numerical simulations predict metamorphosis of fast Abrikosov vortices into mixed Abrikosov-Josephson vortices at even higher velocities. This work offers an insight into the fundamental physics of dynamic vortex states of superconductors at high current densities, crucial for many applications.Ultrafast vortex dynamics driven by strong currents define eletromagnetic properties of superconductors, but it remains unexplored. Here, Embon et al. use a unique scanning microscopy technique to image steady-state penetration of super-fast vortices into a superconducting Pb film at rates of tens of GHz and velocities up to tens of km/s. PMID- 28729643 TI - Superhydrophobic Drag-Reduction Spherical Bearing Fabricated by Laser Ablation and PEI Regulated ZnO Nanowire Growth. AB - The resistance of the bearing is a significant factor affecting the performance of the ball-disk rotor gyroscope. The micro and nano combined surface with low surface energy material modifications can be hydrophobic. This can reduce the drag when the bearing is lubricated by deionized water. Laser ablation method is utilized to form micron-scaled structures on the surface of the stainless steel rotor ball. And the nanostructures are formed by PEI (Polyetherimide) regulated ZnO nanowires growth. After low surface energy material modification, the water contact angle of processed surface was 163 degrees and the sliding angle was less than 4 degrees . The maximum rotational speed was enhanced by up to 82.77% at 1.5 W driving power. Experiments show that the superhydrophobic drag-reduction spherical bearing has good short-term reliability. At 5 V drive voltage, the bearing can extend the rotational speed of ball-disk rotor gyroscope to 35000 rpm, and maintain the normal operation for longer than 40 minutes. This is quite meaningful for short-term-work or one-time-use rotor gyroscopes. PMID- 28729644 TI - Erratum: Interaction of cochlin and mechanosensitive channel TREK-1 in trabecular meshwork cells influences the regulation of intraocular pressure. AB - A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper. PMID- 28729645 TI - Nano-antenna enhanced two-focus fluorescence correlation spectroscopy. AB - We propose two-focus fluorescence correlation spectroscopy (2fFCS) on basis of plasmonic nanoantennas that provide distinct hot spots that are individually addressable through polarization, yet lie within a single diffraction limited microscope focus. The importance of two-focus FCS is that a calibrated distance between foci provides an intrinsic calibration to derive diffusion constants from measured correlation times. Through electromagnetic modelling we analyze a geometry of perpendicular nanorods, and their inverse, i.e., nanoslits. While we find that nanorods are not suited for nano-antenna enhanced 2fFCS due to substantial background signal, a nanoslit geometry is expected to provide a di tinct cross-correlation between orthogonally polarized detection channels. Furthermore, by utilizing a periodic array of nanoslits instead of a single pair, the amplitude of the cross-correlation can be enhanced. To demonstrate this technique, we present a proof of principle experiment on the basis of a periodic array of nanoslits, applied to lipid diffusion in a supported lipid bilayer. PMID- 28729646 TI - Climate oscillations reflected within the microbiome of Arabian Sea sediments. AB - Selection of microorganisms in marine sediment is shaped by energy-yielding electron acceptors for respiration that are depleted in vertical succession. However, some taxa have been reported to reflect past depositional conditions suggesting they have experienced weak selection after burial. In sediments underlying the Arabian Sea oxygen minimum zone (OMZ), we performed the first metagenomic profiling of sedimentary DNA at centennial-scale resolution in the context of a multi-proxy paleoclimate reconstruction. While vertical distributions of sulfate reducing bacteria and methanogens indicate energy-based selection typical of anoxic marine sediments, 5-15% of taxa per sample exhibit depth-independent stratigraphies indicative of paleoenvironmental selection over relatively short geological timescales. Despite being vertically separated, indicator taxa deposited under OMZ conditions were more similar to one another than those deposited in bioturbated intervals under intervening higher oxygen. The genomic potential for denitrification also correlated with palaeo-OMZ proxies, independent of sediment depth and available nitrate and nitrite. However, metagenomes revealed mixed acid and Entner-Dourdoroff fermentation pathways encoded by many of the same denitrifier groups. Fermentation thus may explain the subsistence of these facultatively anaerobic microbes whose stratigraphy follows changing paleoceanographic conditions. At least for certain taxa, our analysis provides evidence of their paleoenvironmental selection over the last glacial-interglacial cycle. PMID- 28729647 TI - Neural determinants of human goal-directed vs. habitual action control and their relation to trait motivation. AB - Instrumental learning is mediated by goal-directed and habit systems in the brain. While rodent studies implicate distinct prefrontal/striatal regions in goal-directed and habit learning, neural systems underpinning these two processes in humans remain poorly understood. Here, using a validated discrimination learning task that distinguishes goal-directed learning from habit learning in 72 subjects in fMRI, we investigated the corticostriatal correlates of goal-directed learning and tested whether brain activation during learning is associated with trait motivation and behavioral performance in the post-learning test phase. Participants showed enhanced activation in medial prefrontal and posterior cingulate cortices during goal-directed action selection in the training phase, whereas habitual action selection activated bilateral insula, bilateral dorsal caudate and left precentral gyrus. In addition, early phase of learning was associated with increased activation in the frontoparietal control network and dorsal striatum, whereas default mode regions depicted increased activation in the late phase. Finally, avoidance motivation scores measured by Behavioral Inhibition/Activation System (BIS/BAS) correlated with accuracy during goal directed learning and showed a nominally significant correlation with activation in dorsomedial prefrontal cortex during goal-directed acquisition of stimuli. These findings reveal the temporal dynamics of instrumental behavior and suggest that avoidance motivation predicts performance and brain activity during goal directed learning. PMID- 28729649 TI - Effects of single and combined applications of entomopathogenic fungi and nematodes against Rhynchophorus ferrugineus (Olivier). AB - This study was carried out to investigate the insecticidal properties of Beauveria bassiana, Metarhizium anisopliae and Heterorhabditis bacteriophora for their virulence against different larval instars of Rhynchophorus ferrugineus (Olivier). Both fungi were either applied alone or in combination, with H. bacteriophora simultaneously or 1 and 2 weeks after fungal application; EPN were also applied alone. Moreover, assessment of host development, diet consumption, frass production and weight gain were observed at sub-lethal dose rates. In combined treatments, additive and synergistic interactions were observed. Synergism was observed more frequently in H. bacteriophora + B. bassiana combinations than in H. bacteriophora + M. anisopliae combinations, and was higher in early instars than old instars. In 2nd and 4th instars, synergy was noted in H. bacteriophora + B. bassiana combinations at 0, 7 and 14 d intervals and in 6th instar synergy was observed only in H. bacteriophora + B. bassiana combinations (at 0 and 7 d intervals). A decrease in pupation, adult emergence and egg hatching was enhanced in the combined treatments. Furthermore, reduced weights and variation in duration of insect developmental stages were observed among entomopathogens and enhanced in H. bacteriophora + B. bassiana combinations. Larvae treated with sub-lethal concentrations exhibited reductions in food consumption, growth and frass production and weight gain. PMID- 28729648 TI - A haplotype in CFH family genes confers high risk of rare glomerular nephropathies. AB - Despite distinct renal lesions, a series of rare glomerular nephropathies are reportedly mediated by complement overactivation. Genetic variations in complement genes contribute to disease risk, but the relationship of genotype to phenotype has not been straightforward. Here, we screened 11 complement genes from 91 patients with atypical hemolytic uremic syndrome (aHUS), C3 glomerulopathy (C3G) and membranoproliferative glomerulonephritis type I (MPGN I), and identified the concomitant presence of three missense variations located within the human complement Factor H (CFH) gene cluster. The three variations, rs55807605, rs61737525 and rs57960694, have strong linkage disequilibrium; subsequent haplotype analysis indicated that ATA increased the susceptibility of these renal diseases. In silico analysis, the CFHR3 rs61737525-T risk allele altered the physical and structural properties and generated a reduction in binding affinity of the CFHR3/C3b complex. Surface plasmon resonance (SPR) binding analysis further demonstrated the substitution induced a decrease of two orders of magnitude in C3b-binding properties, with a declined cofactor activity in fluid phase. These data suggest that the haplotype carrying the causative allele behaves as a partial C3 convertase deficiency, predisposing individuals to diverse pathologic lesions underlying complement overactivation. Such genotype phenotype discrepancies allow better understanding about these nephropathies mediated by genetic complement disorders. PMID- 28729650 TI - Large-Scale Analysis of Drug Side Effects via Complex Regulatory Modules Composed of microRNAs, Transcription Factors and Gene Sets. AB - Identifying the occurrence mechanism of drug-induced side effects (SEs) is critical for design of drug target and new drug development. The expression of genes in biological processes is regulated by transcription factors(TFs) and/or microRNAs. Most of previous studies were focused on a single level of gene or gene sets, while studies about regulatory relationships of TFs, miRNAs and biological processes are very rare. Discovering the complex regulating relations among TFs, gene sets and miRNAs will be helpful for researchers to get a more comprehensive understanding about the mechanism of side reaction. In this study, a framework was proposed to construct the relationship network of gene sets, miRNAs and TFs involved in side effects. Through the construction of this network, the potential complex regulatory relationship in the occurrence process of the side effects was reproduced. The SE-gene set network was employed to characterize the significant regulatory SE-gene set interaction and molecular basis of accompanied side effects. A total of 117 side effects complex modules including four types of regulating patterns were obtained from the SE-gene sets miRNA/TF complex regulatory network. In addition, two cases were used to validate the complex regulatory modules which could more comprehensively interpret occurrence mechanism of side effects. PMID- 28729652 TI - A genomic glance through the fog of plasticity and diversification in Pocillopora. AB - Scleractinian corals of the genus Pocillopora (Lamarck, 1816) are notoriously difficult to identify morphologically with considerable debate on the degree to which phenotypic plasticity, introgressive hybridization and incomplete lineage sorting obscure well-defined taxonomic lineages. Here, we used RAD-seq to resolve the phylogenetic relationships among seven species of Pocillopora represented by 15 coral holobiont metagenomic libraries. We found strong concordance between the coral holobiont datasets, reads that mapped to the Pocillopora damicornis (Linnaeus, 1758) transcriptome, nearly complete mitochondrial genomes, 430 unlinked high-quality SNPs shared across all Pocillopora taxa, and a conspecificity matrix of the holobiont dataset. These datasets also show strong concordance with previously published clustering of the mitochondrial clades based on the mtDNA open reading frame (ORF). We resolve seven clear monophyletic groups, with no evidence for introgressive hybridization among any but the most recently derived sister species. In contrast, ribosomal and histone datasets, which are most commonly used in coral phylogenies to date, were less informative and contradictory to these other datasets. These data indicate that extant Pocillopora species diversified from a common ancestral lineage within the last ~3 million years. Key to this evolutionary success story may be the high phenotypic plasticity exhibited by Pocillopora species. PMID- 28729653 TI - Microstructure Refinement in W-Y2O3 Alloy Fabricated by Wet Chemical Method with Surfactant Addition and Subsequent Spark Plasma Sintering. AB - With the aim of preparing high performance oxide-dispersion-strengthened tungsten based alloys by powder metallurgy, the W-Y2O3 composite nanopowder precursor was fabricated by an improved wet chemical method with anion surfactant sodium dodecyl sulfate (SDS) addition. It is found that the employment of SDS can dramatically decrease W grain size (about 40 nm) and improve the size uniformity. What's more, SDS addition can also remarkably improve the uniform dispersion of Y2O3 particles during the synthesis process. For the alloy whose powder precursor was fabricated by traditional wet chemical method without SDS addition, only a few Y2O3 dispersoids with size of approximate 10-50 nm distribute unevenly within tungsten grains. Nevertheless, for the sintered alloy whose powder precursor was produced by improved wet chemical method, the Y2O3 dispersoids (about 2-10 nm in size) with near spherical shape are dispersed well within tungsten grains. Additionally, compared with the former, the alloy possesses smaller grain size (approximate 700 nm) and higher relative density (99.00%). And a Vickers microhardness value up to 600 Hv was also obtained for this alloy. Based on these results, the employment of SDS in traditional wet chemical method is a feasible way to fabricate high performance yttria-dispersion-strengthened tungsten based alloys. PMID- 28729651 TI - Combination of ginsenoside Rb1 and Rd protects the retina against bright light induced degeneration. AB - Photoreceptor degeneration is a central pathology of various retinal degenerative diseases which currently lack effective therapies. Antioxidant and anti inflammatory activities are noted for Panax notoginsenoside saponins (PNS) and related saponin compound(s). However, the photoreceptor protective potentials of PNS or related saponin compound(s) remain unknown. The current study revealed that PNS protected against photoreceptor loss in bright light-exposed BALB/c mice. Combination of ginsenoside Rb1 and Rd, two major saponin compounds of PNS, recapitulated the retinal protection of PNS and attenuated retinal oxidative stress and inflammatory changes. Rb1 or Rd partially alleviated all-trans-Retinal induced oxidative stress in ARPE19 cells. Rb1 or Rd suppressed lipopolysaccharides (LPS)-induced proinflammatory gene expression in ARPE19 and RAW264.7 cells. Rb1 or Rd also modulated the expression of proinflammatory microRNA, miR-155 and its direct target, anti-inflammatory SHIP1, in LPS stimulated RAW264.7 cells. The retinal expression of miR-155 and SHIP1 was altered preceding extensive retinal damage, which was maintained at normal level by Rb1 and Rd combination. This work shows for the first time that altered expression of miR-155 and SHIP1 are involved in photoreceptor degeneration. Most importantly, novel retinal protective activities of combination of Rb1 and Rd justify further evaluation for the treatment of related retinal degenerative disorders. PMID- 28729654 TI - Cryopreservation protocol for human biliary tree stem/progenitors, hepatic and pancreatic precursors. AB - Human biliary tree stem/progenitor cells (hBTSCs) are being used for cell therapies of patients with liver cirrhosis. A cryopreservation method was established to optimize sourcing of hBTSCs for these clinical programs and that comprises serum-free Kubota's Medium (KM) supplemented with 10% dimethyl sulfoxide (DMSO), 15% human serum albumin (HSA) and 0.1% hyaluronans. Cryopreserved versus freshly isolated hBTSCs were similar in vitro with respect to self-replication, stemness traits, and multipotency. They were able to differentiate to functional hepatocytes,cholangiocytes or pancreatic islets, yielding similar levels of secretion of albumin or of glucose-inducible levels of insulin. Cryopreserved versus freshly isolated hBTSCs were equally able to engraft into immunocompromised mice yielding cells with human-specific gene expression and human albumin levels in murine serum that were higher for cryopreserved than for freshly isolated hBTSCs. The successful cryopreservation of hBTSCs facilitates establishment of hBTSCs cell banking offering logistical advantages for clinical programs for treatment of liver diseases. PMID- 28729655 TI - A CRISPR/Cas9 guidance RNA screen platform for HIV provirus disruption and HIV/AIDS gene therapy in astrocytes. AB - HIV/AIDS remains a major health threat despite significant advances in the prevention and treatment of HIV infection. The major reason is the inability of existing treatments to eradicate the multiple HIV reservoirs in the human body, including astrocytes in the human brain. CRISPR/Cas9 system is an emerging gene editing technique with the potential to eliminate or disrupt HIV provirus in HIV reservoir cells, which may lead to a complete cure of HIV/AIDS. The key components of CRISPR/Cas9 are guide RNAs (gRNAs) which determine specific sequence targeting of DNAs. This study established a novel, simple and quick screening method to identify gRNA candidates for targeting HIV provirus in astrocytes. Briefly, stable astrocytes clones with an integrated fluorescent HIV reporter and Cas9 expression gene were generated. Various gRNAs were screened for their efficiencies against HIV provirus in these cells. Moreover, these gRNAs and Cas9 protein were successfully tested on HIV latent astrocytes without Cas9 expression to mimic clinical conditions. HIV provirus gene-editing were confirmed by cell genomic DNA PCR and fluorescent marker expression analysis. In the future, the established transgenic cells can be used for other gene-editing studies and is well-suited for high-throughput screen application. PMID- 28729656 TI - Endolysosomal targeting of a clinical chlorin photosensitiser for light-triggered delivery of nano-sized medicines. AB - A major problem with many promising nano-sized biotherapeutics including macromolecules is that owing to their size they are subject to cellular uptake via endocytosis, and become entrapped and then degraded within endolysosomes, which can significantly impair their therapeutic efficacy. Photochemical internalisation (PCI) is a technique for inducing cytosolic release of the entrapped agents that harnesses sub-lethal photodynamic therapy (PDT) using a photosensitiser that localises in endolysosomal membranes. Using light to trigger reactive oxygen species-mediated rupture of the photosensitised endolysosomal membranes, the spatio-temporal selectivity of PCI then enables cytosolic release of the agents at the selected time after administration so that they can reach their intracellular targets. However, conventional photosensitisers used clinically for PDT are ineffective for photochemical internalisation owing to their sub-optimal intracellular localisation. In this work we demonstrate that such a photosensitiser, chlorin e6, can be repurposed for PCI by conjugating the chlorin to a cell penetrating peptide, using bioorthogonal ligation chemistry. The peptide conjugation enables targeting of endosomal membranes so that light triggered cytosolic release of an entrapped nano-sized cytotoxin can be achieved with consequent improvement in cytotoxicity. The photoproperties of the chlorin moiety are also conserved, with comparable singlet oxygen quantum yields found to the free chlorin. PMID- 28729657 TI - Spatial and temporal changes of parasitic chytrids of cyanobacteria. AB - Parasitism is certainly one of the most important driving biotic factors of cyanobacterial blooms which remains largely understudied. Among these parasites, fungi from the phylum Chytridiomycota (i.e. chytrids) are the only eukaryotic microorganisms infecting cyanobacteria. Here, we address spatiotemporal dynamics of the cyanobacterial host Dolichospermum macrosporum (syn. Anabaena macrospora) and its associated chytrid parasites, Rhizosiphon spp., in an eutrophic lake by studying spatial (vertical, horizontal) and temporal (annual and inter-annual) variations. Our results show homogenous chytrid infection patterns along the water column and across sampling stations. However, the prevalence of infection presented drastic changes with time, at both intra- and inter-annual scales. In 2007, a maximum of 98% of vegetative cells were infected by R. crassum whereas this fungal species was not reported seven years later. In opposite, R. akinetum, a chytrid infecting only akinetes, increased its prevalence by 42% during the same period. High chytrid infection rate on the akinetes might have sizeable consequences on host recruitment (and proliferation) success from year to year, as supported by the recorded inter-annual host dynamics (affecting also the success of other chytrid parasites). The spatial homogenous chytrid infection on this cyanobacterium, coupled to both seasonal and inter-annual changes indicates that time, rather than space, controls such highly dynamic host-parasite relationships. PMID- 28729658 TI - Differential control of dNTP biosynthesis and genome integrity maintenance by the dUTPase superfamily enzymes. AB - dUTPase superfamily enzymes generate dUMP, the obligate precursor for de novo dTTP biosynthesis, from either dUTP (monofunctional dUTPase, Dut) or dCTP (bifunctional dCTP deaminase/dUTPase, Dcd:dut). In addition, the elimination of dUTP by these enzymes prevents harmful uracil incorporation into DNA. These two beneficial outcomes have been thought to be related. Here we determined the relationship between dTTP biosynthesis (dTTP/dCTP balance) and the prevention of DNA uracilation in a mycobacterial model that encodes both the Dut and Dcd:dut enzymes, and has no other ways to produce dUMP. We show that, in dut mutant mycobacteria, the dTTP/dCTP balance remained unchanged, but the uracil content of DNA increased in parallel with the in vitro activity-loss of Dut accompanied with a considerable increase in the mutation rate. Conversely, dcd:dut inactivation resulted in perturbed dTTP/dCTP balance and two-fold increased mutation rate, but did not increase the uracil content of DNA. Thus, unexpectedly, the regulation of dNTP balance and the prevention of DNA uracilation are decoupled and separately brought about by the Dcd:dut and Dut enzymes, respectively. Available evidence suggests that the discovered functional separation is conserved in humans and other organisms. PMID- 28729660 TI - A novel optical thermometry based on the energy transfer from charge transfer band to Eu3+-Dy3+ ions. AB - Optical thermometry based on the up-conversion intensity ratio of thermally coupled levels of rare earth ions has been widely studied to achieve an inaccessible temperature measurement in submicron scale. In this work, a novel optical temperature sensing strategy based on the energy transfer from charge transfer bands of W-O and Eu-O to Eu3+-Dy3+ ions is proposed. A series of Eu3+/Dy3+ co-doped SrWO4 is synthesized by the conventional high-temperature solid-state method. It is found that the emission spectra, emission intensity ratio of Dy3+ (572 nm) and Eu3+ (615 nm), fluorescence color, lifetime decay curves of Dy3+ (572 nm) and Eu3+ (615 nm), and relative and absolute sensitivities of Eu3+/Dy3+ co-doped SrWO4 are temperature dependent under the 266 nm excitation in the temperature range from 11 K to 529 K. The emission intensity ratio of Dy3+ (572 nm) and Eu3+ (615 nm) ions exhibits exponentially relation to the temperature due to the different energy transfer from the charge transfer bands of W-O and Eu-O to Dy3+ and Eu3+ ions. In this host, the maximum relative sensitivity Sr can be reached at 1.71% K-1, being higher than those previously reported material. It opens a new route to obtain optical thermometry with high sensitivity through using down-conversion fluorescence under ultraviolet excitation. PMID- 28729661 TI - Surface Modification of Anisotropic Dielectric Elastomer Actuators with Uni- and Bi-axially Wrinkled Carbon Electrodes for Wettability Control. AB - Interest in soft actuators for next-generation electronic devices, such as wearable electronics, haptic feedback systems, rollable flexible displays, and soft robotics, is rapidly growing. However, for more practical applications in diverse electronic devices, soft actuators require multiple functionalities including anisotropic actuation in three-dimensional space, active tactile feedback, and controllable wettability. Herein, we report anisotropic dielectric elastomer actuators with uni- and bi-axially wrinkled carbon black electrodes that are formed through pre-streching and relaxation processes. The wrinkled dielectric elastomer actuator (WDEA) that shows directional actuation under electric fields is used to control the anisotropic wettability. The morphology changes of the electrode surfaces under various electric stimuli are investigated by measuring the contact angles of water droplets, and the results show that the controllable wettability has a broad range from 141 degrees to 161 degrees along the wrinkle direction. The present study successfully demonstrates that the WDEA under electrically controlled inputs can be used to modulate the uni- or bi axially wrinkled electrode surfaces with continous roughness levels. The controllable wrinkled structures can play an important role in creating adaptable water repellency and tunable anisotropic wettability. PMID- 28729659 TI - Identification of a hybrid myocardial zone in the mammalian heart after birth. AB - Noncompaction cardiomyopathy is characterized by the presence of extensive trabeculations, which could lead to heart failure and malignant arrhythmias. How trabeculations resolve to form compact myocardium is poorly understood. Elucidation of this process is critical to understanding the pathophysiology of noncompaction disease. Here we use genetic lineage tracing to mark the Nppa+ or Hey2+ cardiomyocytes as trabecular and compact components of the ventricular wall. We find that Nppa+ and Hey2+ cardiomyocytes, respectively, from the endocardial and epicardial zones of the ventricular wall postnatally. Interposed between these two postnatal layers is a hybrid zone, which is composed of cells derived from both the Nppa+ and Hey2+ populations. Inhibition of the fetal Hey2+ cell contribution to the hybrid zone results in persistence of excessive trabeculations in postnatal heart. Our findings indicate that the expansion of Hey2+ fetal compact component, and its contribution to the hybrid myocardial zone, are essential for normal formation of the ventricular walls.Fetal trabecular muscles in the heart undergo a poorly described morphogenetic process that results into a solidified compact myocardium after birth. Tian et al. show that cardiomyocytes in the fetal compact layer also contribute to this process, forming a hybrid myocardial zone that is composed of cells derived from both trabecular and compact layers. PMID- 28729662 TI - Erratum: The Arabidopsis Cop9 signalosome subunit 4 (CSN4) is involved in adventitious root formation. AB - A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper. PMID- 28729663 TI - A comparative strategy for single-nucleus and single-cell transcriptomes confirms accuracy in predicted cell-type expression from nuclear RNA. AB - Significant heterogeneities in gene expression among individual cells are typically interrogated using single whole cell approaches. However, tissues that have highly interconnected processes, such as in the brain, present unique challenges. Single-nucleus RNA sequencing (SNS) has emerged as an alternative method of assessing a cell's transcriptome through the use of isolated nuclei. However, studies directly comparing expression data between nuclei and whole cells are lacking. Here, we have characterized nuclear and whole cell transcriptomes in mouse single neurons and provided a normalization strategy to reduce method-specific differences related to the length of genic regions. We confirmed a high concordance between nuclear and whole cell transcriptomes in the expression of cell type and metabolic modeling markers, but less so for a subset of genes associated with mitochondrial respiration. Therefore, our results indicate that single-nucleus transcriptome sequencing provides an effective means to profile cell type expression dynamics in previously inaccessible tissues. PMID- 28729664 TI - Spectral function modulation based on nonlinear frequency division multiplexing. AB - A combination of phase and amplitude modulation in nonlinear discrete spectrum is proposed based on nonlinear frequency division multiplexing. Here the integrable nonlinear Schrodinger equation is used as the channel model. We propose the transmission system with designed transmitting signals and implement our scheme with simulation. We use 8QAM constellation and 2 eigenvalues to generate 5 bit signals, which greatly improve spectral efficiency. This method can be expanded for higher order modulation and further improve transmission capacity in limited bandwidth. PMID- 28729665 TI - Identification of proteins that specifically recognize and bind protofibrillar aggregates of amyloid-beta. AB - Protofibrils of the 42 amino acids long amyloid-beta peptide are transient pre fibrillar intermediates in the process of peptide aggregation into amyloid plaques and are thought to play a critical role in the pathology of Alzheimer's disease. Hence, there is a need for research reagents and potential diagnostic reagents for detection and imaging of such aggregates. Here we describe an in vitro selection of Affibody molecules that bind to protofibrils of Abeta42cc, which is a stable engineered mimic of wild type Abeta42 protofibrils. Several binders were identified that bind Abeta42cc protofibrils with low nanomolar affinities, and which also recognize wild type Abeta42 protofibrils. Dimeric head to-tail fusion proteins with subnanomolar binding affinities, and very slow dissociation off-rates, were also constructed. A mapping of the chemical properties of the side chains onto the Affibody scaffold surface reveals three distinct adjacent surface areas of positively charged surface, nonpolar surface and a polar surface, which presumably match a corresponding surface epitope on the protofibrils. The results demonstrate that the engineered Abeta42cc is a suitable antigen for directed evolution of affinity reagents with specificity for wild type Abeta42 protofibrils. PMID- 28729666 TI - Expansion of human midbrain floor plate progenitors from induced pluripotent stem cells increases dopaminergic neuron differentiation potential. AB - Human induced pluripotent stem cells (hiPSCs) are invaluable to study developmental processes and disease mechanisms particularly in the brain. hiPSCs can be differentiated into mature and functional dopaminergic (DA) neurons. Having robust protocols for the generation of differentiated DA neurons from pluripotent cells is a prerequisite for the use of hiPSCs to study disease mechanisms, for drug discovery, and eventually for cell replacement therapy. Here, we describe a protocol for generating and expanding large numbers of homogeneous midbrain floor plate progenitors (mFPPs) that retain efficient DA neurogenic potential over multiple passages and can be cryobanked. We demonstrate that expanded mFPPs have increased DA neuron potential and differentiate more efficiently and rapidly than progenitors generated by standard protocols. In addition, this novel method results in increased numbers of DA neurons that in vitro show characteristic electrophysiological properties of nigrostriatal DA neurons, produce high levels of dopamine, and integrate into host mice when grafted in vivo. Thus, we describe a robust method for producing human mesencephalic DA neurons from hiPSCs. PMID- 28729667 TI - Effect of inoculation of Burkholderia sp. strain SJ98 on bacterial community dynamics and para-nitrophenol, 3-methyl-4-nitrophenol, and 2-chloro-4-nitrophenol degradation in soil. AB - para-Nitrophenol (PNP), 3-methyl-4-nitrophenol (3M4NP), and 2-chloro-4 nitrophenol (2C4NP) are highly toxic compounds that have caused serious environmental issues. We inoculated an artificially contaminated soil with Burkholderia sp. strain SJ98, which has the ability to degrade PNP, 3M4NP, and 2C4NP, and quantified bioremediation. There was accelerated degradation of all nitrophenols in inoculated treatments compared to the un-inoculated treatments. The indigenous bacteria were able to degrade PNP, but not 3M4NP or 2C4NP. Real time PCR targeting the catabolic gene pnpA showed that levels of strain SJ98 remained stable over the incubation period. High-throughput sequencing revealed that both contamination and bioaugmentation influenced the bacterial community structure. Bioaugmentation seemed to protect Kineosporia, Nitrososphaera, and Schlesneria from nitrophenol inhibition, as well as led to a sharp increase in the abundance of Nonomuraea, Kribbella, and Saccharopolyspora. There was a significant increase in the relative abundances of Thermasporomyces, Actinomadura, and Streptomyces in both contaminated and bioaugmented treatments; this indicated that these bacteria are likely directly related to nitrophenol degradation. To our knowledge, this is the first report of the simultaneous removal of PNP, 3M4NP, and 2C4NP using bioaugmentation. This study provides valuable insights into the bioremediation of soils contaminated with nitrophenols. PMID- 28729668 TI - Novel FAM83H mutations in patients with amelogenesis imperfecta. AB - Amelogenesis imperfecta (AI), characterized by a deficiency in the quantity and/or quality of dental enamel, is genetically heterogeneous and phenotypically variable. The most severe type, hypocalcified AI, is mostly caused by truncating mutations in the FAM83H gene. This study aimed to identify genetic mutations in four Chinese families with hypocalcified AI. We performed mutation analysis by sequencing the candidate FAM83H gene. Three novel mutations (c.931dupC, p.V311Rfs*13; c.1130_1131delinsAA, p.S377X; and c.1147 G > T, p.E383X) and one previously reported mutation (c.973 C > T, p.R325X) in the last exon of FAM83H gene were identified. Furthermore, constructs expressing Green fluorescent protein (GFP)-tagged wild-type and three novel mutant FAM83Hs were transfected into rat dental epithelial cells (SF2 cells). Wild-type FAM83H-GFP was localized exclusively in the cytoplasm, especially in the area surrounding the nucleus, while the mutant FAM83H-GFPs (p.V311Rfs*13, p.S377X, and p.E383X) were localized predominantly in the nucleus, with lower levels in the cytoplasm. PMID- 28729669 TI - Active KTaO3 hybrid terahertz metamaterial. AB - The dielectric properties of an active KTaO3 hybrid metamaterial structure and its tunability under external electric fields are investigated at room temperature by means of terahertz time-domain spectroscopy. Application of the electric field leads to an appreciable tuning of the dielectric loss, which is up to 17%. Meanwhile, the refractive index also changes appreciably. These findings are attributed to the internal space charge field in the crystal caused by the excited free carriers. PMID- 28729670 TI - Forest edge disturbance increases rattan abundance in tropical rain forest fragments. AB - Human-induced forest fragmentation poses one of the largest threats to global diversity yet its impact on rattans (climbing palms) has remained virtually unexplored. Rattan is arguably the world's most valuable non-timber forest product though current levels of harvesting and land-use change place wild populations at risk. To assess rattan response to fragmentation exclusive of harvesting impacts we examined rattan abundance, demography and ecology within the forests of northeastern, Australia. We assessed the community abundance of rattans, and component adult (>3 m) and juvenile (<=3 m) abundance in five intact forests and five fragments (23-58 ha) to determine their response to a range of environmental and ecological parameters. Fragmented forests supported higher abundances of rattans than intact forests. Fragment size and edge degradation significantly increased adult rattan abundance, with more in smaller fragments and near edges. Our findings suggest that rattan increase within fragments is due to canopy disturbance of forest edges resulting in preferential, high-light habitat. However, adult and juvenile rattans may respond inconsistently to fragmentation. In managed forest fragments, a rattan abundance increase may provide economic benefits through sustainable harvesting practices. However, rattan increases in protected area forest fragments could negatively impact conservation outcomes. PMID- 28729671 TI - Linking Rheology and Printability for Dense and Strong Ceramics by Direct Ink Writing. AB - Direct ink writing of dense and strong ceramic objects remains an important open challenge. We develop a universal dimensionless criterion for printing such objects. Boehmite, an Al2O3 precursor, was used to assess the rheological properties leading to dense structures in ceramics manufactured by direct ink writing. Boehmite suspensions undergo time dependent gelation, thus providing a rheological laboratory of flow behaviours that can be correlated with printability requirements. We measured the evolution of rheological properties over several days and quantified the deformation of simple printed shapes at different aging times. We then identified the relevant physical parameters leading to printable suspensions. We defined a dimensionless number, Xi, based on measured rheological properties, that predicts deformation of the printed object and determines the printability criterion. An important difference with this criterion is that Xi necessarily accounts for capillary forces and gravitational slumping. We show that boehmite inks reach a printed shape fidelity > 90% when Xi > 1, and that Al2O3 bars printed under these conditions can be sintered to 97% density, without printing defects, and have flexural strengths (500-600 MPa) competitive with commercial aluminas. Using Xi, researchers can rationally design inks for printing dense materials by tailoring their rheological properties such that Xi ~ 1. PMID- 28729672 TI - Plasmodium berghei P47 is essential for ookinete protection from the Anopheles gambiae complement-like response. AB - Malaria is a mosquito-borne disease affecting millions of people every year. The rodent parasite Plasmodium berghei has served as a model for human malaria transmission studies and played a pivotal role in dissecting the mosquito immune response against infection. The 6-cysteine protein P47, known to be important for P. berghei female gamete fertility, is shown to serve a different function in Plasmodium falciparum, protecting ookinetes from the mosquito immune response. Here, we investigate the function of P. berghei P47 in Anopheles gambiae mosquito infections. We show that P47 is expressed on the surface of both female gametocytes and ookinetes where it serves distinct functions in promoting gametocyte-to-ookinete development and protecting ookinetes from the mosquito complement-like response, respectively. The latter function is essential, as ookinetes lacking P47 are targeted for killing while traversing the mosquito midgut cells and eliminated upon exposure to hemolymph proteins of the complement like system. Silencing key factors of the complement-like system restores oocyst development and disease transmission to rodent hosts. Our data establish a dual role of P. berghei P47 in vivo and reinforce the use of this parasite to study the impact of the mosquito immune response on human malaria transmission. PMID- 28729673 TI - Distinct functional relevance of dynamic GTPase cysteine methylation in fission yeast. AB - The final step in post-translational processing of Ras and Rho GTPases involves methylation of the prenylated cysteine residue by an isoprenylcysteine-O-carboxyl methyltransferase (ICMT). ICMT activity is essential for cell growth and development in higher eukaryotes, and inhibition of GTPase methylation has become an attractive target in cancer therapy to inactivate prenylated oncoproteins. However, the specificity and dynamics of the GTPase methylation process remain to be fully clarified. Notably, cells lacking Mam4, the ICMT ortholog in the fission yeast Schizosaccharomyces pombe, are viable. We have exploited this feature to analyze the role of methylation on GTPase localization and function. We show that methylation differentially affects GTPase membrane localization, being particularly relevant for plasma membrane tethering and downstream signaling of palmitoylated and farnesylated GTPases Ras1 and Rho2 lacking C-terminal polybasic motifs. Indeed, Ras1 and Rho2 cysteine methylation is required for proper regulation of differentiation elicited by MAPK Spk1 and for stress-dependent activation of the cell integrity pathway (CIP) and its main effector MAPK Pmk1. Further, Mam4 negatively regulates TORC2 signaling by a cross-inhibitory mechanism relying on Rho GTPase methylation. These results highlight the requirement for a tight control of GTPase methylation in vivo to allow adequate GTPase function. PMID- 28729674 TI - Ab initio calculation of energy levels for phosphorus donors in silicon. AB - The s manifold energy levels for phosphorus donors in silicon are important input parameters for the design and modeling of electronic devices on the nanoscale. In this paper we calculate these energy levels from first principles using density functional theory. The wavefunction of the donor electron's ground state is found to have a form that is similar to an atomic s orbital, with an effective Bohr radius of 1.8 nm. The corresponding binding energy of this state is found to be 41 meV, which is in good agreement with the currently accepted value of 45.59 meV. We also calculate the energies of the excited 1s(T 2) and 1s(E) states, finding them to be 32 and 31 meV respectively. PMID- 28729675 TI - Oxygen-induced impairment in arterial function is corrected by slow breathing in patients with type 1 diabetes. AB - Hyperoxia and slow breathing acutely improve autonomic function in type-1 diabetes. However, their effects on arterial function may reveal different mechanisms, perhaps potentially useful. To test the effects of oxygen and slow breathing we measured arterial function (augmentation index, pulse wave velocity), baroreflex sensitivity (BRS) and oxygen saturation (SAT), during spontaneous and slow breathing (6 breaths/min), in normoxia and hyperoxia (5 L/min oxygen) in 91 type-1 diabetic and 40 age-matched control participants. During normoxic spontaneous breathing diabetic subjects had lower BRS and SAT, and worse arterial function. Hyperoxia and slow breathing increased BRS and SAT. Hyperoxia increased blood pressure and worsened arterial function. Slow breathing improved arterial function and diastolic blood pressure. Combined administration prevented the hyperoxia-induced arterial pressure and function worsening. Control subjects showed a similar pattern, but with lesser or no statistical significance. Oxygen-driven autonomic improvement could depend on transient arterial stiffening and hypertension (well-known irritative effect of free radicals on endothelium), inducing reflex increase in BRS. Slow breathing-induced improvement in BRS may result from improved SAT, reduced sympathetic activity and improved vascular function, and/or parasympathetic-driven antioxidant effect. Lower oxidative stress could explain blunted effects in controls. Slow breathing could be a simple beneficial intervention in diabetes. PMID- 28729676 TI - Proteomic profiling of the weed feverfew, a neglected pollen allergen source. AB - Feverfew (Parthenium hysterophorus), an invasive weed from the Asteraceae family, has been reported as allergen source. Despite its relevance, knowledge of allergens is restricted to a partial sequence of a hydroxyproline-rich glycoprotein. We aimed to obtain the entire sequence for recombinant production and characterize feverfew pollen using proteomics and immunological assays. Par h 1, a defensin-proline fusion allergen was obtained by cDNA cloning and recombinantly produced in E. coli. Using two complementary proteomic strategies, a total of 258 proteins were identified in feverfew pollen among those 47 proteins belonging to allergenic families. Feverfew sensitized patients' sera from India revealed IgE reactivity with a pectate lyase, PR-1 protein and thioredoxin in immonoblot. In ELISA, recombinant Par h 1 was recognized by 60 and 40% of Austrian and Indian sera, respectively. Inhibition assays demonstrated the presence of IgE cross-reactive Par h 1, pectate lyase, lipid-transfer protein, profilin and polcalcin in feverfew pollen. This study reveals significant data on the allergenic composition of feverfew pollen and makes recombinant Par h 1 available for cross-reactivity studies. Feverfew might become a global player in weed pollen allergy and inclusion of standardized extracts in routine allergy diagnosis is suggested in exposed populations. PMID- 28729677 TI - Engineering Tumour Cell-Binding Synthetic Polymers with Sensing Dense Transporters Associated with Aberrant Glutamine Metabolism. AB - Increased glutamine uptake toward the elevated glutaminolysis is one of the hallmarks of tumour cells. This aberrant glutamine metabolism has recently attracted considerable attention as a diagnostic and therapeutic target. Herein, we developed glutamine-functionalized polymer to achieve a selective high affinity to tumour cells overexpressing glutaminolysis-related transporter ASCT2. In in vitro study, our developed polymer exhibited faster and higher cellular uptake in tumour cells than that in normal cells. Uptake inhibition study revealed the dominant contribution of ASCT2 to the polymer-cell interaction. Furthermore, the binding affinity of the polymer to tumour cells was estimated to be comparable to that of the potent ligand molecules reported in the literature. In in vivo study, the polymer showed prolonged retention at tumour site after intratumoral injection. This study offers a novel approach for designing tumour cell-binding synthetic polymers through the recognition of dense transporters related to tumour-associated metabolism. PMID- 28729678 TI - Tumor LDH-A expression and serum LDH status are two metabolic predictors for triple negative breast cancer brain metastasis. AB - There are limited therapeutic methods for triple negative breast cancer in the clinic, which is easy to progress into the brain to form metastatic lesions and evolve into the terminal stage. Because both the primary cancer and the brain metastasis have high glycolysis, we hypothesize that lactate dehydrogenase (LDH), which catalyzes the final step of glycolysis, may be a predictor, as well as a treatment target, for breast cancer brain metastasis. Therefore, the expression of LDH-A was detected on 119 triple negative breast cancer tissues with immunohistochemistry, and the serum LDH levels were also measured. Our results showed that the LDH-A expression inside the tumor was significantly higher than the matched normal tissues. Tumor LDH-A expression, serum LDH status, and the slope of serum LDH status were closely associated with triple negative breast cancer brain metastasis and brain metastasis free survival. This study indicates that tumor LDH and serum LDH status are two predictors for triple negative breast cancer brain metastasis. PMID- 28729679 TI - A population-specific reference panel empowers genetic studies of Anabaptist populations. AB - Genotype imputation is a powerful strategy for achieving the large sample sizes required for identification of variants underlying complex phenotypes, but imputation of rare variants remains problematic. Genetically isolated populations offer one solution, however population-specific reference panels are needed to assure optimal imputation accuracy and allele frequency estimation. Here we report the Anabaptist Genome Reference Panel (AGRP), the first whole-genome catalogue of variants and phased haplotypes in people of Amish and Mennonite ancestry. Based on high-depth whole-genome sequence (WGS) from 265 individuals, the AGRP contains >12 M high-confidence single nucleotide variants and short indels, of which ~12.5% are novel. These Anabaptist-specific variants were more deleterious than variants with comparable frequencies observed in the 1000 Genomes panel. About 43,000 variants showed enriched allele frequencies in AGRP, consistent with drift. When combined with the 1000 Genomes Project reference panel, the AGRP substantially improved imputation, especially for rarer variants. The AGRP is freely available to researchers through an imputation server. PMID- 28729680 TI - The use of radiocobalt as a label improves imaging of EGFR using DOTA-conjugated Affibody molecule. AB - Several anti-cancer therapies target the epidermal growth factor receptor (EGFR). Radionuclide imaging of EGFR expression in tumours may aid in selection of optimal cancer therapy. The 111In-labelled DOTA-conjugated ZEGFR:2377 Affibody molecule was successfully used for imaging of EGFR-expressing xenografts in mice. An optimal combination of radionuclide, chelator and targeting protein may further improve the contrast of radionuclide imaging. The aim of this study was to evaluate the targeting properties of radiocobalt-labelled DOTA-ZEGFR:2377. DOTA-ZEGFR:2377 was labelled with 57Co (T1/2 = 271.8 d), 55Co (T1/2 = 17.5 h), and, for comparison, with the positron-emitting radionuclide 68Ga (T1/2 = 67.6 min) with preserved specificity of binding to EGFR-expressing A431 cells. The long-lived cobalt radioisotope 57Co was used in animal studies. Both 57Co-DOTA ZEGFR:2377 and 68Ga-DOTA-ZEGFR:2377 demonstrated EGFR-specific accumulation in A431 xenografts and EGFR-expressing tissues in mice. Tumour-to-organ ratios for the radiocobalt-labelled DOTA-ZEGFR:2377 were significantly higher than for the gallium-labelled counterpart already at 3 h after injection. Importantly, 57Co DOTA-ZEGFR:2377 demonstrated a tumour-to-liver ratio of 3, which is 7-fold higher than the tumour-to-liver ratio for 68Ga-DOTA-ZEGFR:2377. The results of this study suggest that the positron-emitting cobalt isotope 55Co would be an optimal label for DOTA-ZEGFR:2377 and further development should concentrate on this radionuclide as a label. PMID- 28729682 TI - Memristive property's effects on the I-V characteristics of perovskite solar cells. AB - The unfavorable I-V characteristics of perovskite solar cells (PSCs), such as the I-V hysteresis phenomena, have been one major obstacle for their future practical application. However, corresponding analysis based on traditional theories have shown non-negligible flaws and failed for satisfactory explanation. To present a novel mechanism, here we utilize for the first time the memristive property of the perovskite material to analyze the I-V characteristics of PSCs. The obtained joint physical model and the deduced equation may help solving the long-existent mysteries of the I-V characteristics of PSCs. On the basis of our analysis and memristor theory, we also propose an original device optimization strategy for PSCs, which may help further increase their performance to the limit. PMID- 28729681 TI - Multiomics analysis of the giant triton snail salivary gland, a crown-of-thorns starfish predator. AB - The giant triton snail (Charonia tritonis) is one of the few natural predators of the adult Crown-of-Thorns starfish (COTS), a corallivore that has been damaging to many reefs in the Indo-Pacific. Charonia species have large salivary glands (SGs) that are suspected to produce either a venom and/or sulphuric acid which can immobilize their prey and neutralize the intrinsic toxic properties of COTS. To date, there is little information on the types of toxins produced by tritons. In this paper, the predatory behaviour of the C. tritonis is described. Then, the C. tritonis SG, which itself is made up of an anterior lobe (AL) and posterior lobe (PL), was analyzed using an integrated transcriptomics and proteomics approach, to identify putative toxin- and feeding-related proteins. A de novo transcriptome database and in silico protein analysis predicts that ~3800 proteins have features consistent with being secreted. A gland-specific proteomics analysis confirmed the presence of numerous SG-AL and SG-PL proteins, including those with similarity to cysteine-rich venom proteins. Sulfuric acid biosynthesis enzymes were identified, specific to the SG-PL. Our analysis of the C. tritonis SG (AL and PL) has provided a deeper insight into the biomolecular toolkit used for predation and feeding by C. tritonis. PMID- 28729683 TI - A positive feedback loop mediated by Sigma X enhances expression of the streptococcal regulator ComR. AB - Natural transformation is used by bacteria to take up DNA from their surroundings and incorporate it into their genomes. Streptococci do so during a transient period of competence, triggered by pheromones that they produce, secrete and sense under conditions influenced by the environment. In Streptococcus mutans, Streptococcus suis, and species of the bovis, salivarius and pyogenic groups of streptococci, the pheromone XIP is sensed by the intra-cellular regulator ComR, that in turn activates the transcription of comS, encoding the XIP precursor, and of sigX, encoding the only known alternative sigma factor in streptococci. Although induction of comR during competence has been known for more than fifteen years, the mechanism regulating its expression remains unidentified. By a combination of directional RNA-sequencing, optimal competence conditions, stepwise deletions and marker-less genome editing, we found that SigX is the missing link in overproduction of ComR. In the absence of comR induction, both sigX expression and transformation were significantly reduced. Placing comR and comS transcripts under the control of different regulators so as to form two interlocked positive feedback circuits may enable S. mutans to fine-tune the kinetics and magnitude of the competence response according to their need. PMID- 28729684 TI - Combining Low-dimensional Wavelet Features and Support Vector Machine for Arrhythmia Beat Classification. AB - Automatic feature extraction and classification are two main tasks in abnormal ECG beat recognition. Feature extraction is an important prerequisite prior to classification since it provides the classifier with input features, and the performance of classifier depends significantly on the quality of these features. This study develops an effective method to extract low-dimensional ECG beat feature vectors. It employs wavelet multi-resolution analysis to extract time frequency domain features and then applies principle component analysis to reduce the dimension of the feature vector. In classification, 12-element feature vectors characterizing six types of beats are used as inputs for one-versus-one support vector machine, which is conducted in form of 10-fold cross validation with beat-based and record-based training schemes. Tested upon a total of 107049 beats from MIT-BIH arrhythmia database, our method has achieved average sensitivity, specificity and accuracy of 99.09%, 99.82% and 99.70%, respectively, using the beat-based training scheme, and 44.40%, 88.88% and 81.47%, respectively, using the record-based training scheme. PMID- 28729686 TI - Ultralow voltage operation of biologically assembled all carbon nanotube nanomesh transistors with ion-gel gate dielectrics. AB - The demonstration of field-effect transistors (FETs) based entirely on single walled carbon nanotubes (SWNTs) would enable the fabrication of high-on-current, flexible, transparent and stretchable devices owing to the excellent electrical, optical, and mechanical properties of SWNTs. Fabricating all-SWNT-based FETs via simple solution process, at room temperature and without using lithography and vacuum process could further broaden the applicability of all-SWNT-FETs. In this work, we report on biologically assembled all SWNT-based transistors and demonstrate that ion-gel-gated network structures of unsorted SWNTs assembled using a biological template material enabled operation of SWNT-based transistors at a very low voltage. The compatibility of the biologically assembled SWNT networks with ion gel dielectrics and the large capacitance of both the three dimensional channel networks and the ion gel allowed an ultralow operation voltage. The all-SWNT-based FETs showed an I on /I off value of >102, an on current density per channel width of 2.16 * 10-4 A/mm at VDS = 0.4 V, and a field effect hole mobility of 1.12 cm2/V . s in addition to the low operation voltage of <-0.5 V. We envision that our work suggests a solution-based simple and low cost approach to realizing all-carbon-based FETs for low voltage operation and flexible applications. PMID- 28729685 TI - Nucleocytoplasmic Shuttling of Histone Deacetylase 9 Controls Activity-Dependent Thalamocortical Axon Branching. AB - During development, thalamocortical (TC) axons form branches in an activity dependent fashion. Here we investigated how neuronal activity is converted to molecular signals, focusing on an epigenetic mechanism involving histone deacetylases (HDACs). Immunohistochemistry demonstrated that HDAC9 was translocated from the nucleus to the cytoplasm of thalamic cells during the first postnatal week in rats. In organotypic co-cultures of the thalamus and cortex, fluorescent protein-tagged HDAC9 also exhibited nuclueocytoplasmic translocation in thalamic cells during culturing, which was reversed by tetrodotoxin treatment. Transfection with a mutant HDAC9 that interferes with the translocation markedly decreased TC axon branching in the culture. Similarly, TC axon branching was significantly decreased by the mutant HDAC9 gene transfer in vivo. However, axonal branching was restored by disrupting the interaction between HDAC9 and myocyte-specific enhancer factor 2 (MEF2). Taken together, the present results demonstrate that the nucleocytoplasmic translocation of HDAC9 plays a critical role in activity-dependent TC axon branching by affecting transcriptional regulation and downstream signaling pathways. PMID- 28729687 TI - Canopy physiology, vine performance and host-pathogen interaction in a fungi resistant cv. Sangiovese x Bianca accession vs. a susceptible clone. AB - The present study compares the physiological and cropping response of the new fungi-resistant grapevine Accession 72-096 ('Sangiovese' x 'Bianca' hybrid) against a susceptible 'Sangiovese' clone which was either fully (FS-SG) or partially sprayed (PS-SG). Data logged on Accession 72-096 indicate that while two early season sprays were enough to avoid major downy mildew (DM) and powdery mildew (PM) outbreaks, Accession 72-096 also showed concurrent desirable features such as moderate cropping, loose clusters, fast sugar accumulation coupled with sufficient acidity even at peak total soluble solids (TSS) concentration (around 24 degrees Brix), good color and higher flavonols prompting co-pigmentation. Conversely, FS-SG showed final lower acidity despite the notably lower sugar concentration (?18 degrees Brix), as well as larger clusters and berries that resulted in more compact bunches. From a methodological viewpoint, end of season single-leaf readings appeared to overestimate the limitation of leaf function due to PM and DM infections in SG-PS vines which, when assessed via a whole-canopy approach, did not show significant differences vs. Accession 72-096, a result likely due to counteracting effects linked to a compensation mechanism by healthy tissues. Our data also suggest that a PM infection can lead to a decoupling in sugar-color accumulation patterns. PMID- 28729689 TI - Metal Nanoclusters with Synergistically Engineered Optical and Buffering Activity of Intracellular Reactive Oxygen Species by Compositional and Supramolecular Design. AB - Metal nanoclusters featuring tunable luminescence and high biocompatibility are receiving attention as fluorescent markers for cellular imaging. The recently discovered ability of gold clusters to scavenge cytotoxic reactive oxygen species (ROS) from the intracellular environment extends their applicability to biomedical theranostics and provides a novel platform for realizing multifunctional luminescent probes with engineered anti-cytotoxic activity for applications in bio-diagnostics and conceivably cellular therapy. This goal could be achieved by using clusters of strongly reactive metals such as silver, provided that strategies are found to enhance their luminescence while simultaneously enabling direct interaction between the metal atoms and the chemical surroundings. In this work, we demonstrate a synergic approach for realizing multifunctional metal clusters combining enhanced luminescence with strong and lasting ROS scavenging activity, based on the fabrication and in situ protection of Ag nanoclusters with a supramolecular mantle of thiolated-Au atoms (Ag/Au-t). Confocal imaging and viability measurements highlight the biocompatibility of Ag/Au-t and their suitability as fluorescent bio-markers. ROS concentration tests reveal the remarkable scavenging activity of Ag-based clusters. Proliferation tests of cells in artificially stressed culture conditions point out their prolonged anti-cytotoxic effect with respect to gold systems, ensuring positive cell proliferation rates even for long incubation time. PMID- 28729688 TI - Improved genome recovery and integrated cell-size analyses of individual uncultured microbial cells and viral particles. AB - Microbial single-cell genomics can be used to provide insights into the metabolic potential, interactions, and evolution of uncultured microorganisms. Here we present WGA-X, a method based on multiple displacement amplification of DNA that utilizes a thermostable mutant of the phi29 polymerase. WGA-X enhances genome recovery from individual microbial cells and viral particles while maintaining ease of use and scalability. The greatest improvements are observed when amplifying high G+C content templates, such as those belonging to the predominant bacteria in agricultural soils. By integrating WGA-X with calibrated index-cell sorting and high-throughput genomic sequencing, we are able to analyze genomic sequences and cell sizes of hundreds of individual, uncultured bacteria, archaea, protists, and viral particles, obtained directly from marine and soil samples, in a single experiment. This approach may find diverse applications in microbiology and in biomedical and forensic studies of humans and other multicellular organisms.Single-cell genomics can be used to study uncultured microorganisms. Here, Stepanauskas et al. present a method combining improved multiple displacement amplification and FACS, to obtain genomic sequences and cell size information from uncultivated microbial cells and viral particles in environmental samples. PMID- 28729690 TI - Functional variation of SHP-2 promoter is associated with preterm birth and delayed myelination and motor development in preterm infants. AB - Src homology 2 domain-containing protein tyrosine phosphatase 2 (SHP-2) is a cytoplasmic tyrosine phosphatase that is highly expressed in hematopoietic cells and in the CNS and exerts opposite effects on signal transduction by exerting a neuroprotective or proapoptotic effect. Several mutations of SHP-2 have been found in children with myeloproliferative disorders or malignant leukemia, and some of these can affect brain development. In the present study, we aimed to identify and functionally characterize genetic variations in SHP-2 in 72 preterm and 58 full-term infants and to evaluate the effect of the variations on neurodevelopment in preterm infants. Twelve genetic variations were identified. Among them, two variations in the SHP-2 promoter, g.-317C > T and g.-273G > A, were found to significantly increase promoter activity, and the frequency of g. 273G > A was higher in preterm infants than in full-term infants. Two transcription factors, NF-kappaB and GABPalpha, were found to be involved in the transcriptional regulation of SHP-2 by the two above-mentioned variations. In particular, we found that g.-273G > A was significantly associated with delayed myelination and poor motor development in preterm infants. Our results suggest that a functional promoter variation in SHP-2 is associated with spontaneous preterm birth itself as well as white matter myelination and neurodevelopment. PMID- 28729691 TI - Lowered fasting chenodeoxycholic acid correlated with the decrease of fibroblast growth factor 19 in Chinese subjects with impaired fasting glucose. AB - The gut-derived hormone Fibroblast growth factor 19 (FGF19) could regulate glucose metabolism and is induced by bile acids (BAs) through activating Farnesoid X Receptor (FXR). FGF19 was found to decrease in subjects with isolated impaired fasting glucose (I-IFG) and type 2 diabetes mellitus (T2DM). However, the reason for the change of FGF19 in subjects with different glucometabolic status remained unclear. Here we measured six BAs including chenodeoxycholic acid (CDCA), cholic acid, deoxycholic acid, their glycine conjugates and FGF19 levels during oral glucose tolerance test (OGTT) in normal glucose tolerance (NGT), isolated-impaired glucose tolerance, I-IFG, combined glucose intolerance (CGI) and T2DM subjects. After OGTT, serum FGF19 peaked at 120 min in all subjects. Glycine conjugated BAs peaked at 30 min, while free BAs did not elevated significantly. Consistent with the decrease trend in FGF19 levels, fasting serum CDCA levels in subjects with I-IFG, CGI and T2DM were significantly lower than NGT subjects (P < 0.05). Fasting serum CDCA was independently associated with FGF19. CDCA strongly upregulated FGF19 mRNA levels in LS174T cells in a dose- and time-dependent manner. These results suggest that the decrease of FGF19 in subjects with I-IFG was at least partially due to their decrease of CDCA acting via FXR. PMID- 28729693 TI - Ta2O5-TiO2 Composite Charge-trapping Dielectric for the Application of the Nonvolatile Memory. AB - The charge-trapping memory devices with a structure Pt/Al2O3/(Ta2O5) x (TiO2) 1-x /Al2O3/p-Si (x = 0.9, 0.75, 0.5, 0.25) were fabricated by using rf-sputtering and atomic layer deposition techniques. A special band alignment between (Ta2O5) x (TiO2) 1-x and Si substrate was designed to enhance the memory performance by controlling the composition and dielectric constant of the charge-trapping layer and reducing the difference of the potentials at the bottom of the conduction band between (Ta2O5) x (TiO2) 1-x and Si substrate. The memory device with a composite charge storage layer (Ta2O5) 0.5 (TiO2) 0.5 shows a density of trapped charges 3.84 * 1013/cm2 at +/- 12 V, a programming/erasing speed of 1 us at +/- 10 V, a 8% degradation of the memory window at +/- 10 V after 104 programming/erasing cycles and a 32% losing of trapped charges after ten years. The difference among the activation energies of the trapped electrons in (Ta2O5) x (TiO2) 1-x CTM devices indicates that the retention characteristics are dominated by the difference of energy level for the trap sites in each TTO CTM device. PMID- 28729692 TI - Extensive astrocyte synchronization advances neuronal coupling in slow wave activity in vivo. AB - Slow wave activity (SWA) is a characteristic brain oscillation in sleep and quiet wakefulness. Although the cell types contributing to SWA genesis are not yet identified, the principal role of neurons in the emergence of this essential cognitive mechanism has not been questioned. To address the possibility of astrocytic involvement in SWA, we used a transgenic rat line expressing a calcium sensitive fluorescent protein in both astrocytes and interneurons and simultaneously imaged astrocytic and neuronal activity in vivo. Here we demonstrate, for the first time, that the astrocyte network display synchronized recurrent activity in vivo coupled to UP states measured by field recording and neuronal calcium imaging. Furthermore, we present evidence that extensive synchronization of the astrocytic network precedes the spatial build-up of neuronal synchronization. The earlier extensive recruitment of astrocytes in the synchronized activity is reinforced by the observation that neurons surrounded by active astrocytes are more likely to join SWA, suggesting causality. Further supporting this notion, we demonstrate that blockade of astrocytic gap junctional communication or inhibition of astrocytic Ca2+ transients reduces the ratio of both astrocytes and neurons involved in SWA. These in vivo findings conclusively suggest a causal role of the astrocytic syncytium in SWA generation. PMID- 28729694 TI - Paracrine cyclooxygenase-2 activity by macrophages drives colorectal adenoma progression in the Apc Min/+ mouse model of intestinal tumorigenesis. AB - Genetic deletion or pharmacological inhibition of cyclooxygenase (COX)-2 abrogates intestinal adenoma development at early stages of colorectal carcinogenesis. COX-2 is localised to stromal cells (predominantly macrophages) in human and mouse intestinal adenomas. Therefore, we tested the hypothesis that paracrine Cox-2-mediated signalling from macrophages drives adenoma growth and progression in vivo in the Apc Min/+ mouse model of intestinal tumorigenesis. Using a transgenic C57Bl/6 mouse model of Cox-2 over-expression driven by the chicken lysozyme locus (cLys-Cox-2), which directs integration site-independent, copy number-dependent transgene expression restricted to macrophages, we demonstrated that stromal macrophage Cox-2 in colorectal (but not small intestinal) adenomas from cLys-Cox-2 x Apc Min/+ mice was associated with significantly increased tumour size (P = 0.025) and multiplicity (P = 0.025), compared with control Apc Min/+ mice. Transgenic macrophage Cox-2 expression was associated with increased dysplasia, epithelial cell Cox-2 expression and submucosal tumour invasion, as well as increased nuclear beta-catenin translocation in dysplastic epithelial cells. In vitro studies confirmed that paracrine macrophage Cox-2 signalling drives catenin-related transcription in intestinal epithelial cells. Paracrine macrophage Cox-2 activity drives growth and progression of Apc Min/+ mouse colonic adenomas, linked to increased epithelial cell beta-catenin dysregulation. Stromal cell (macrophage) gene regulation and signalling represent valid targets for chemoprevention of colorectal cancer. PMID- 28729695 TI - The Epstein-Barr Virus BRRF1 Gene Is Dispensable for Viral Replication in HEK293 cells and Transformation. AB - The Epstein-Barr virus (EBV) is a gamma-herpesvirus associated with several malignancies. It establishes a latent infection in B lymphocytes and is occasionally reactivated to enter the lytic cycle. Here we examined the role of the EBV gene BRRF1, which is expressed in the lytic state. We first confirmed, using a DNA polymerase inhibitor, that the BRRF1 gene is expressed with early kinetics. A BRRF1-deficient recombinant virus was constructed using a bacterial artificial chromosome system. No obvious differences were observed between the wild-type, BRRF1-deficient mutant and the revertant virus in HEK293 cells in terms of viral lytic protein expression, viral DNA synthesis, progeny production, pre-latent abortive lytic gene expression and transformation of primary B cells. However, reporter assays indicated that BRRF1 may activate transcription in promoter- and cell type-dependent manners. Taken together, BRRF1 is dispensable for viral replication in HEK293 cells and transformation of B cells, but it may have effects on transcription. PMID- 28729696 TI - Effects of cardiac timing and peripheral resistance on measurement of pulse wave velocity for assessment of arterial stiffness. AB - To investigate the effects of heart rate (HR), left ventricular ejection time (LVET) and wave reflection on arterial stiffness as assessed by pulse wave velocity (PWV), a pulse wave propagation simulation system (PWPSim) based on the transmission line model of the arterial tree was developed and was applied to investigate pulse wave propagation. HR, LVET, arterial elastic modulus and peripheral resistance were increased from 60 to 100 beats per minute (bpm), 0.1 to 0.45 seconds, 0.5 to 1.5 times and 0.5 to 1.5 times of the normal value, respectively. Carotid-femoral PWV (cfPWV) and brachial-ankle PWV (baPWV) were calculated by intersecting tangent method (cfPWVtan and baPWVtan), maximum slope (cfPWVmax and baPWVmax), and using the Moens-Korteweg equation ([Formula: see text] and [Formula: see text]). Results showed cfPWV and baPWV increased significantly with arterial elastic modulus but did not increase with HR when using a constant elastic modulus. However there were significant LVET dependencies of cfPWVtan and baPWVtan (0.17 +/- 0.13 and 0.17 +/- 0.08 m/s per 50 ms), and low peripheral resistance dependencies of cfPWVtan, cfPWVmax, baPWVtan and baPWVmax (0.04 +/- 0.01, 0.06 +/- 0.04, 0.06 +/- 0.03 and 0.09 +/- 0.07 m/s per 10% peripheral resistance), respectively. This study demonstrated that LVET dominates the effect on calculated PWV compared to HR and peripheral resistance when arterial elastic modulus is constant. PMID- 28729697 TI - Identification and structural characterization of LytU, a unique peptidoglycan endopeptidase from the lysostaphin family. AB - We introduce LytU, a short member of the lysostaphin family of zinc-dependent pentaglycine endopeptidases. It is a potential antimicrobial agent for S. aureus infections and its gene transcription is highly upregulated upon antibiotic treatments along with other genes involved in cell wall synthesis. We found this enzyme to be responsible for the opening of the cell wall peptidoglycan layer during cell divisions in S. aureus. LytU is anchored in the plasma membrane with the active part residing in the periplasmic space. It has a unique Ile/Lys insertion at position 151 that resides in the catalytic site-neighbouring loop and is vital for the enzymatic activity but not affecting the overall structure common to the lysostaphin family. Purified LytU lyses S. aureus cells and cleaves pentaglycine, a reaction conveniently monitored by NMR spectroscopy. Substituting the cofactor zinc ion with a copper or cobalt ion remarkably increases the rate of pentaglycine cleavage. NMR and isothermal titration calorimetry further reveal that, uniquely for its family, LytU is able to bind a second zinc ion which is coordinated by catalytic histidines and is therefore inhibitory. The pH dependence and high affinity of binding carry further physiological implications. PMID- 28729698 TI - Dynamic transcriptomic analysis of the early response of female flowers of Populus alba * P. glandulosa to pollination. AB - Pollination is an important event in plant sexual reproduction, and post pollination response is an essential process for reproduction. Populus alba * P. glandulosa is used widely in scientific research, especially in cross breeding as parents. Adult female P. alba * P. glandulosa flowers are highly compatible with pollen from male P. tomentosa, but the early post-pollination response of flowers at the molecular levels is unclear. In this study, RNA-seq was employed to comprehensively understand the response of female P. alba * P. glandulosa flowers to pollination. Enrichment analysis reveals that the 'plant hormone signal transduction' pathway is enhanced during pollen-pistil interaction. Moreover, genes related to auxin, gibberellin and ethylene biosynthesis were significantly up-regulated. Ca2+ and H+-related genes and cell wall-related genes are interrelated, and all of them are essential for pollen tube elongation in pistil, especially, free Ca2+ providing a concentration gradient for pollen tube guidance and involved in signal transduction. Furthermore, RNA-seq results indicate that genes involved in the adhesion and guidance for pollen germination and pollen tube growth are abundantly present in the extracellular matrix. Our study provides an overview and detailed information for understanding the molecular mechanism of early post-pollination response in this hybrid poplar reproduction. PMID- 28729699 TI - PTEN/FOXO3/AKT pathway regulates cell death and mediates morphogenetic differentiation of Colorectal Cancer Cells under Simulated Microgravity. AB - Gravity is a major physical factor determining the stress and strain around cells. Both in space experiments and ground simulation, change in gravity impacts the viability and function of various types of cells as well as in vivo conditions. Cancer cells have been shown to die under microgravity. This can be exploited for better understanding of the biology and identification of novel avenues for therapeutic intervention. Here, we described the effect of microgravity simulated using Rotational Cell Culture System-High Aspect Ratio Vessel (RCCS-HARV) on the viability and morphological changes of colorectal cancer cells. We observed DLD1, HCT116 and SW620 cells die through apoptosis under simulated microgravity (SM). Gene expression analysis on DLD1 cells showed upregulation of tumor suppressors PTEN and FOXO3; leading to AKT downregulation and further induction of apoptosis, through upregulation of CDK inhibitors CDKN2B, CDKN2D. SM induced cell clumps had elevated hypoxia and mitochondrial membrane potential that led to adaptive responses like morphogenetic changes, migration and deregulated autophagy, when shifted to normal culture conditions. This can be exploited to understand the three-dimensional (3D) biology of cancer in the aspect of stress response. This study highlights the regulation of cell function and viability under microgravity through PTEN/FOXO3/AKT pathway. PMID- 28729701 TI - A Model-Based Estimate of Regional Wheat Yield Gaps and Water Use Efficiency in Main Winter Wheat Production Regions of China. AB - Wheat production is of great importance for national food security and is greatly influenced by the spatial variation of climatic variables, soils, cultivars, etc. This study used WheatGrow and CERES-Wheat models integrated with a GIS to estimate winter wheat productivity, yield gap and water use in the main wheat production regions of China. The results showed that the potential wheat yield gradually increased from south to north and from west to east, with a spatial distribution consistent with the accumulated hours of sunshine. The gap between potential and actual yield varied from 382 to 7515 kg ha-1, with the highest values in Shanxi, Gansu and Shaanxi provinces and the lowest values in Sichuan province. The rainfed yield decreased gradually from south to north, roughly following the pattern of the ratio of accumulated precipitation to accumulated potential evapotranspiration. Under the scenario of autoirrigation, relatively high irrigation water use efficiency was found in western Shandong and southern Sichuan, as well as in northern Henan, Shanxi and Shaanxi. Furthermore, the limiting factors were analysed, and effective measures were suggested for improving regional winter wheat productivity. These results can be helpful for national policy making and water redistribution for agricultural production in China. PMID- 28729700 TI - Sphingomimetic multiple sclerosis drug FTY720 activates vesicular synaptobrevin and augments neuroendocrine secretion. AB - Neurotransmission and secretion of hormones involve a sequence of protein/lipid interactions with lipid turnover impacting on vesicle trafficking and ultimately fusion of secretory vesicles with the plasma membrane. We previously demonstrated that sphingosine, a sphingolipid metabolite, promotes formation of the SNARE complex required for membrane fusion and also increases the rate of exocytosis in isolated nerve terminals, neuromuscular junctions, neuroendocrine cells and in hippocampal neurons. Recently a fungi-derived sphingosine homologue, FTY720, has been approved for treatment of multiple sclerosis. In its non-phosphorylated form FTY720 accumulates in the central nervous system, reaching high levels which could affect neuronal function. Considering close structural similarity of sphingosine and FTY720 we investigated whether FTY720 has an effect on regulated exocytosis. Our data demonstrate that FTY720 can activate vesicular synaptobrevin for SNARE complex formation and enhance exocytosis in neuroendocrine cells and neurons. PMID- 28729702 TI - Structure of general-population antibody titer distributions to influenza A virus. AB - Seroepidemiological studies aim to understand population-level exposure and immunity to infectious diseases. Their results are normally presented as binary outcomes describing the presence or absence of pathogen-specific antibody, despite the fact that many assays measure continuous quantities. A population's natural distribution of antibody titers to an endemic infectious disease may include information on multiple serological states - naivete, recent infection, non-recent infection, childhood infection - depending on the disease in question and the acquisition and waning patterns of immunity. In this study, we investigate 20,152 general-population serum samples from southern Vietnam collected between 2009 and 2013 from which we report antibody titers to the influenza virus HA1 protein using a continuous titer measurement from a protein microarray assay. We describe the distributions of antibody titers to subtypes 2009 H1N1 and H3N2. Using a model selection approach to fit mixture distributions, we show that 2009 H1N1 antibody titers fall into four titer subgroups and that H3N2 titers fall into three subgroups. For H1N1, our interpretation is that the two highest-titer subgroups correspond to recent and historical infection, which is consistent with 2009 pandemic attack rates. Similar interpretations are available for H3N2, but right-censoring of titers makes these interpretations difficult to validate. PMID- 28729703 TI - The basal free fatty acid concentration in human saliva is related to salivary lipolytic activity. AB - Fat perception during eating is a complex sensation that involves various sensory modalities, such as texture, aroma and taste. Taste is supported by the discovery of fatty acid receptors in the tongue papillae. Dietary fat is mainly composed of esterified fatty acids, whereas only free fatty acids can bind to taste receptors. Some authors have mentioned the necessity and efficiency of salivary lipolytic activity to hydrolyse the esterified fatty acids present in foods and enable fat perception. Our hypothesis is that salivary lipolytic activity is also involved in regulating the basal level of salivary fatty acids in humans. To test this hypothesis, total fatty acid (TFA) and free fatty acid (FFA) concentrations and selected salivary characteristics (such as lipolytic activity) were analysed in the resting saliva of 54 subjects. The results show differences in the TFA and FFA profiles, with TFA and FFA concentrations of 8.99 and 3.56 ug/mL of saliva, respectively. Interestingly, lipolytic activity had a significant positive correlation with FFA concentration (0.51, p < 0.01). This result highlights a possible physiological role of salivary lipolytic activity in the regulation of the basal FFA concentration. This regulation could be involved in fat taste sensitivity. PMID- 28729704 TI - Growth hormone reverses dyslipidemia in adult offspring after maternal undernutrition. AB - The abnormal intrauterine milieu of fetal growth retardation could lead to dyslipidemia in adulthood. Studies have shown that growth hormone (GH) therapy in small for gestational age (SGA) children would be beneficial for metabolic parameters. Here we investigated whether GH treatment introduced at adolescent period in SGA could reverse dyslipidemia during later life. SGA rat model was established by using semi-starvation treatment during the whole pregnancy. SGA or appropriate for gestational age (AGA) offspring were assigned to receive GH or normal saline (NS). Once-daily subcutaneous injections of GH were administered between 21-35 days of age. In adulthood, as compared to AGA, SGA showed: (1) decreased body weight and length; (2) increased serum triglycerides; (3) down regulated hepatic AMPK-alpha1 but up-regulated SREBP-1c and ACC-1; (4) a significant reduction in histone H3 acetylation at the promoter of AMPK-alpha1. Exogenous GH administration led to a restoration of body weight and length and normalized serum triglycerides by reversing expression of AMPK-alpha1 and its targeted genes SREBP-1c and ACC-1, through increasing H3 acetylation at the promoter of AMPK-alpha1 in SGA in adult period. These results demonstrated positive effects on lipid metabolism by a short treatment course of GH in SGA adult period. PMID- 28729705 TI - Diterpenoid Alkaloids from Delphinium anthriscifolium var. majus. AB - Extensive phytochemical investigation on the whole herbs of Delphinium anthriscifolium var. majus led to the identification of fourteen diterpenoid alkaloids, including three new C20-diterpenoid alkaloids (anthriscifolsines A-C, 1-3), six new C19-diterpenoid alkaloids (anthriscifolrines A-F, 4-9), and five know compounds (10-14). Among them, anthriscifolsine A represents a novel C20 diterpenoid alkaloid characterized by a seco C-ring. The structures of the isolated compounds were elucidated by extensive spectroscopic methods, including HR-ESI-MS, X-ray, and 1D and 2D NMR experiments. Bioactivity of compounds 3-6 was evaluated for their cytotoxicity against the MCF-7, HepG2 and H460 cancer cell lines. PMID- 28729706 TI - Sudan ebolavirus long recovered survivors produce GP-specific Abs that are of the IgG1 subclass and preferentially bind FcgammaRI. AB - Ebolavirus is a highly lethal pathogen, causing a severe hemorrhagic disease with a high fatality rate. To better understand immune correlates of protection by virus specific IgG, we investigated the evolution of the Fcgamma receptors (FcgammaRs)-activating capabilities of antiviral IgG in serum samples of long recovered survivors. To this end, longitudinal serum samples from survivors of Sudan ebolavirus (SUDV) infection, studied over years, were examined for the presence of Ebola-GP specific IgG subclasses, and for their binding to FcgammaRs. We developed a cell-based reporter system to quantitate pathogen-specific antibody binding to FcgammaRIIIA, FcgammaRIIA, FcgammaRIIB and FcgammaRI. With this system, we demonstrate that anti-GP-specific stimulation of the FcgammaRI reporter by survivors' sera was substantially high one year after acute infection, with a slight reduction in activity over a decade post infection. We further demonstrate that GP-specific IgG1 is by far the seroprevalent subclass that retained and even enhanced its presence in the sera, over ten years post infection; the prevalence of other GP-specific IgG subclasses was considerably reduced over time. In accordance, GP-specific FcgammaRI reporter response and GP specific total IgG1 subclass correlated in the studied group of Ebola survivors. These observations are important for further informing Ebola vaccine and therapeutic development. PMID- 28729707 TI - Status, Stress and Performance in Track and Field Athletes during the European Games in Baku (Azerbaijan). AB - This study analyzes the relationship between salivary cortisol and testosterone levels and performance in track and field athletes. In addition, we analyzed the influence of status among athletes (measured based on previous athletic achievement) on hormone levels. Nineteen members of the Austrian track and field team (eleven males, eight females, 25.9 +/- 3.9 years of age, 74.9 +/- 20.1 kg, and 179.3 +/- 10 cm) participated in this study. Data was collected during the European Games in Baku. Athletes delivered saliva samples at various time-points including morning samples and samples directly before and after the competition. Scoring points of the International Association of Athletics Federation were used as an individual measure of relative performance. We found that performance was negatively correlated with rise in testosterone concentrations in the last 24 h prior to the competition. A similar trend was found for cortisol levels, but only when the three least competitive athletes were removed from analysis. Pre competition cortisol levels were significantly increased compared to measurements 24 h earlier. No effect of status on cortisol or testosterone increase in the same timeframe was found. We conclude that the tournament represented a stressor and that excessive endocrine response was associated with reduced performance. PMID- 28729708 TI - New Mycobacterium tuberculosis Beijing clonal complexes in China revealed by phylogenetic and Bayesian population structure analyses of 24-loci MIRU-VNTRs. AB - Beijing lineage of Mycobacterium tuberculosis constitutes the most predominant lineage in East Asia. Beijing epidemiology, evolutionary history, genetics are studied in details for years revealing probable origin from China followed by worldwide expansion, partially linked to higher mutation rate, hypervirulence, drug-resistance, and association with cases of mixed infections. Considering huge amount of data available for 24-loci Mycobacterial Interspersed Repetitive Units Variable Number of Tandem Repeats, we performed detailed phylogenetic and Bayesian population structure analyses of Beijing lineage strains in mainland China and Taiwan using available 24-loci MIRU-VNTR data extracted from publications or the SITVIT2 database (n = 1490). Results on genetic structuration were compared to previously published data. A total of three new Beijing clonal complexes tentatively named BSP1, BPS2 and BSP3 were revealed with surprising phylogeographical specificities to previously unstudied regions in Sichuan, Chongqing and Taiwan, proving the need for continued investigations with extended datasets. Such geographical restriction could correspond to local adaptation of these "ecological specialist" Beijing isolates to local human host populations in contrast with "generalist pathogens" able to adapt to several human populations and to spread worldwide. PMID- 28729709 TI - Sex-based Differences in the Association between Body Composition and Incident Fracture Risk in Koreans. AB - The relative contribution of lean mass and fat mass on bone health is inconclusive. We investigated the relative contributions of lean and fat masses on fragility fracture risk in Korean men and women. This was an ongoing prospective community-dwelling cohort study at Ansung beginning in 2001, which included 2,189 men and 2,625 women over 40 years old. Study subjects were classified into the following four groups according to lean mass (LM)/height2 and percentage fat mass (PF). Clinical fragility fracture events were assessed at baseline and biennially using self-reported questionnaires. During a median follow-up of 9.4 years, 77 (3.5%) men and 203 (7.7%) women experienced at least one incident fracture. In Cox proportional hazard models, men with low LM under normal and high PF had a 2.16 and 2.59- fold higher risk for fragility fractures than normal ones even after adjusting for covariates. However, in women, low LM or high FM was not associated with fracture risk. We demonstrated sex-based differences in the association of body composition and incident fracture risk in Koreans aged over 40 years during a 10-year follow-up duration. Maintaining muscle mass in men is vital to maintaining bone health and preventing fragility fractures in Koreans. PMID- 28729710 TI - Learning a Health Knowledge Graph from Electronic Medical Records. AB - Demand for clinical decision support systems in medicine and self-diagnostic symptom checkers has substantially increased in recent years. Existing platforms rely on knowledge bases manually compiled through a labor-intensive process or automatically derived using simple pairwise statistics. This study explored an automated process to learn high quality knowledge bases linking diseases and symptoms directly from electronic medical records. Medical concepts were extracted from 273,174 de-identified patient records and maximum likelihood estimation of three probabilistic models was used to automatically construct knowledge graphs: logistic regression, naive Bayes classifier and a Bayesian network using noisy OR gates. A graph of disease-symptom relationships was elicited from the learned parameters and the constructed knowledge graphs were evaluated and validated, with permission, against Google's manually-constructed knowledge graph and against expert physician opinions. Our study shows that direct and automated construction of high quality health knowledge graphs from medical records using rudimentary concept extraction is feasible. The noisy OR model produces a high quality knowledge graph reaching precision of 0.85 for a recall of 0.6 in the clinical evaluation. Noisy OR significantly outperforms all tested models across evaluation frameworks (p < 0.01). PMID- 28729712 TI - Unfolded protein response: Reacting to membrane stress. PMID- 28729711 TI - An ecological and digital epidemiology analysis on the role of human behavior on the 2014 Chikungunya outbreak in Martinique. AB - Understanding the spatio-temporal dynamics of endemic infections is of critical importance for a deeper understanding of pathogen transmission, and for the design of more efficient public health strategies. However, very few studies in this domain have focused on emerging infections, generating a gap of knowledge that hampers epidemiological response planning. Here, we analyze the case of a Chikungunya outbreak that occurred in Martinique in 2014. Using time series estimates from a network of sentinel practitioners covering the entire island, we first analyze the spatio-temporal dynamics and show that the largest city has served as the epicenter of this epidemic. We further show that the epidemic spread from there through two different propagation waves moving northwards and southwards, probably by individuals moving along the road network. We then develop a mathematical model to explore the drivers of the temporal dynamics of this mosquito-borne virus. Finally, we show that human behavior, inferred by a textual analysis of messages published on the social network Twitter, is required to explain the epidemiological dynamics over time. Overall, our results suggest that human behavior has been a key component of the outbreak propagation, and we argue that such results can lead to more efficient public health strategies specifically targeting the propagation process. PMID- 28729713 TI - Tunable uptake/release mechanism of protein microgel particles in biomimicking environment. AB - Microgels are intra-molecular crosslinked macromolecules that can be used as vehicles to deliver and release drugs at the point-of-need in the patient's body. Here, gelatin microgels were formed from microfluidics droplets, stabilised by aldehydes and frozen into a spheroidal shape. Microgel morphology and response to external stimuli were characterised. It was found that the behaviour of the spheroidal microgels was sensitive to both pH and ionic strength and that the distribution of charges into the microgels affected the behaviour of swelling and uptake. The uptake of molecules such as Rhodamine B and Methylene Blue were investigated as a model for drug uptake/release mechanisms. Under physiological conditions, the uptake of Rhodamine was rapid and a uniform distribution of the fluorescent molecules was recorded inside the microgels. However, the mechanism of release became slower at lower pH, which mimics the stomach environment. Under physiological conditions, Methylene Blue release occurred faster than for Rhodamine. Anionic and neutral molecules were also tested. In conclusion, the dependence of uptake and release of model drugs on basic/acid conditions shows that microgels could be used for targeted drug delivery. Different shaped microgels, such as spheres, spheroids, and rods, could be useful in tissue engineering or during vascularisation. PMID- 28729714 TI - Maize (Zea mays L.) genome size indicated by 180-bp knob abundance is associated with flowering time. AB - Flowering time is considered one of the most important agronomic traits in maize (Zea mays L.), and previous studies have indicated that this trait is correlated with genome size. We observed a significant difference in genome size between tropical and temperate inbred lines and a moderate positive correlation between genome size and 180-bp knob abundance determined by high-throughput sequencing in maize inbred lines in this study. We assembled the reads that were mapped to 180 bp knob sequences and found that the top ten abundant 180-bp knob sequences are highly variable. Moreover, our results indicate that genome size is associated with the flowering time of both male and female flowers, in both tropical and temperate inbred lines and under both tropical and temperate environments. To identify loci associated with genome size, we performed a genome-wide association study. The analysis identified three genomic regions associated with genome size, of which two were novel while the third one is located close to the known knobs K8L1 and K8L2. Overall, our results indicate that selection for breeding materials with earlier flowering times can be assisted by choosing germplasms with smaller genome sizes and that genome size can be determined based on the abundance of 180-bp knobs. PMID- 28729716 TI - Pharmacogenetic comparison of CYP2D6 predictive and measured phenotypes in a South African cohort. AB - This corrects the article DOI: 10.1038/tpj.2015.76. PMID- 28729715 TI - Inflammatory monocytes regulate Th1 oriented immunity to CpG adjuvanted protein vaccines through production of IL-12. AB - Due to their capacity to skew T cell responses towards Th1 oriented immunity, oligonucleotides containing unmethylated CpG motifs (CpG) have emerged as interesting adjuvants for vaccination. Whereas the signalling pathways in response to CpG mediated TLR9 activation have been extensively documented at the level of the individual cell, little is however known on the precise identity of the innate immune cells that govern T cell priming and polarisation to CpG adjuvanted protein antigens in vivo. In this study, we demonstrate that optimal induction of Th1 oriented immunity to CpG adjuvanted protein vaccines requires the coordinated actions of conventional DCs and of monocytes. Whilst conventional DCs were required for antigen presentation and initial T cell priming, monocytes constitute the main source of the Th1 polarising cytokine IL-12. PMID- 28729717 TI - Dietary constraints can preclude the expression of an honest chemical sexual signal. AB - Identifying the factors that underlie signal divergences remains challenging in studies of animal communication. Regarding the chemical signalling, different compounds can be found in some species but be absent in others. We hypothesized that if the costs that are associated with the expression of some compounds are too high, their presence in the signal may be restricted. However, these compounds may be expressed and be functional when those costs are relaxed. Vitamin E (alpha-tocopherol), a dietary compound with metabolic relevancy, acts as an honest chemical sexual signal in many lizards but no in others such as the Carpetan Rock lizard (Iberolacerta cyreni). We investigated whether dietary supplementation favours the expression of this vitamin in scents of I. cyreni. We show that dietary constraints can preclude the expression of vitamin E in chemical secretions of wild males because was expressed when it was experimentally provided in the diet. Vitamin E supplementation also heightened the immune response of males and increased the interest of their scent for females, highlighting the vitamin E as a chemical sexual signal in this species. We suggest that diet could decisively act as a driver of intra- and interspecific divergences in the chemical signalling of lizards. PMID- 28729718 TI - Magnetic Activated-ATP@Fe3O4 Nanocomposite as an Efficient Fenton-Like Heterogeneous Catalyst for Degradation of Ethidium Bromide. AB - Magnetic attapulgite-Fe3O4 nanocomposites (ATP-Fe3O4) were prepared by coprecipitation of Fe3O4 on ATP. The composites were characterized by scanning electron microscopey, X-ray diffractometry, Brunauer-Emmett-Teller analysis, X ray photoelectron spectroscopy, energy dispersive spectrometer and transmission electron microscopy. Surface characterization showed that Fe3O4 particles with an average size of approximately 15 nm were successfully embedded in matrix of ATP. The capacity of the Fe3O4-activated ATP (A-ATP@Fe3O4) composites for catalytic degradation of ethidium bromide (EtBr, 80 mg/L) at different pH values, hydrogen peroxide (H2O2) concentrations, temperatures, and catalyst dosages was investigated. EtBr degradation kinetics studies indicated that the pseudo-first order kinetic constant was 2.445 min-1 at T = 323 K and pH 2.0 with 30 mM H2O2, and 1.5 g/L of A-ATP@Fe3O4. Moreover, a regeneration study suggested that A ATP@Fe3O4 maintained over 80% of its maximal EtBr degradation ability after five successive cycles. The effects of the iron concentrations and free radical scavengers on EtBr degradation were studied to reveal possible catalytic mechanisms of the A-ATP@Fe3O4 nanocomposites. Electron Paramagnetic Resonance revealed both hydroxyl (?OH) and superoxide anion (?O2-) radicals were involved in EtBr degradation. Radical scavenging experiment suggested EtBr degradation was mainly ascribed to ?OH radicals, which was generated by reaction between Fe2+ and H2O2 on the surface of A-ATP@Fe3O4. PMID- 28729719 TI - Inhibition of TGF-beta signaling supports high proliferative potential of diverse p63+ mouse epithelial progenitor cells in vitro. AB - Mouse models have been used to provide primary cells to study physiology and pathogenesis of epithelia. However, highly efficient simple approaches to propagate mouse primary epithelial cells remain challenging. Here, we show that pharmacological inhibition of TGF-beta signaling enables long-term expansion of p63+ epithelial progenitor cells in low Ca2+ media without the need of progenitor cell-purification steps or support by a feeder cell layer. We find that TGF-beta signaling is operative in mouse primary keratinocytes in conventional cultures as determined by the nuclear Smad2/3 localization. Accordingly, TGF-beta signaling inhibition in crude preparations of mouse epidermis robustly increases proliferative capacity of p63+ epidermal progenitor cells, while preserving their ability of differentiation in response to Ca2+ stimulation. Notably, inhibition of TGF-beta signaling also enriches and expands other p63+ epithelial progenitor cells in primary crude cultures of multiple epithelia, including the cornea, oral and lingual epithelia, salivary gland, esophagus, thymus, and bladder. We anticipate that this simple and efficient approach will facilitate the use of mouse models for studying a wide range of epithelia by providing highly enriched populations of diverse p63+ epithelial progenitor cells in quantity. PMID- 28729720 TI - Comparative gene-expression profiling of the large cell variant of gastrointestinal marginal-zone B-cell lymphoma. AB - Gastrointestinal (g.i.) large cell lymphoma is currently regarded as diffuse large B-cell lymphoma (DLBCL) despite a more favorable clinical outcome compared to other DLBCL. Cluster analyses on a transcriptome signature of NF-kappaB target genes of 30 g.i. marginal zone B-cell lymphomas (MZBL; 8 g.i. MZBL, 22 large cell MZBL - among them 9 with coexisting small cell component) and 6 DLBCL (3 activated B-cell like (ABC), 3 germinal center-like (GCB)) reveals a distinct pattern. The distinctiveness of large cell MZBL samples is further confirmed by a cohort of 270 available B-cell lymphoma and B-cell in silico profiles. Of the NF kappaB genes analyzed, c-REL was overexpressed in g.i. MZBL. c-REL amplification was limited to 6/22 large cell MZBL including the large cell component of 2/9 composite small cell/large cell lymphomas, and c-Rel protein expression was found in the large cell compartment of composite lymphomas. Classification experiments on DLBCL and large cell MZBL profiles support the concept that the large cell MZBL is a distinct type of B-cell lymphoma. PMID- 28729721 TI - Plasma-derived exosome characterization reveals a distinct microRNA signature in long duration Type 1 diabetes. AB - Type 1 diabetes mellitus (T1DM) results from an autoimmune attack against the insulin-producing beta cells which leads to chronic hyperglycemia. Exosomes are lipid vesicles derived from cellular multivesicular bodies that are enriched in specific miRNAs, potentially providing a disease-specific diagnostic signature. To assess the value of exosome miRNAs as biomarkers for T1DM, miRNA expression in plasma-derived exosomes was measured. Nanoparticle tracking analysis and transmission electron microscopy confirmed the presence of plasma-derived exosomes (EXOs) isolated by differential centrifugation. Total RNA extracted from plasma-derived EXOs of 12 T1DM and 12 control subjects was hybridized onto Nanostring human v2 miRNA microarray array and expression data were analyzed on nSolver analysis software. We found 7 different miRNAs (1 up-regulated and 6 down regulated), that were differentially expressed in T1DM. The selected candidate miRNAs were validated by qRT-PCR analysis of cohorts of 24 T1DM and 24 control subjects. Most of the deregulated miRNAs are involved in progression of T1DM. These findings highlight the potential of EXOs miRNA profiling in the diagnosis as well as new insights into the molecular mechanisms involved in T1DM. PMID- 28729722 TI - Structure-Based Discovery of Small Molecule Inhibitors of Cariogenic Virulence. AB - Streptococcus mutans employs a key virulence factor, three glucosyltransferase (GtfBCD) enzymes to establish cariogenic biofilms. Therefore, the inhibition of GtfBCD would provide anti-virulence therapeutics. Here a small molecule library of 500,000 small molecule compounds was screened in silico against the available crystal structure of the GtfC catalytic domain. Based on the predicted binding affinities and drug-like properties, small molecules were selected and evaluated for their ability to reduce S. mutans biofilms, as well as inhibit the activity of Gtfs. The most potent inhibitor was further characterized for Gtf binding using OctetRed instrument, which yielded low micromolar KD against GtfB and nanomolar KD against GtfC, demonstrating selectivity towards GtfC. Additionally, the lead compound did not affect the overall growth of S. mutans and commensal oral bacteria, and selectively inhibit the biofilm formation by S. mutans, indicative of its selectivity and non-bactericidal nature. The lead compound also effectively reduced cariogenicity in vivo in a rat model of dental caries. An analog that docked poorly in the GtfC catalytic domain failed to inhibit the activity of Gtfs and S. mutans biofilms, signifying the specificity of the lead compound. This report illustrates the validity and potential of structure-based design of anti-S. mutans virulence inhibitors. PMID- 28729723 TI - Muscle disorders: FGF19 reduces muscle wasting. PMID- 28729724 TI - Anticancer therapy: Neutrophils deliver the goods. PMID- 28729725 TI - Upcoming market catalysts in Q3 2017. PMID- 28729726 TI - Heart regeneration and repair after myocardial infarction: translational opportunities for novel therapeutics. AB - Current therapies for heart failure after myocardial infarction are limited and non-curative. Although regenerative approaches are receiving significant attention, clinical efforts that involve transplantation of presumed stem and progenitor cells have largely failed to deliver. Recent studies of endogenous heart regeneration in model organisms, such as zebrafish and neonatal mice, are yielding mechanistic insights into the roles of cardiomyocyte proliferation, resident stem cell niches, neovascularization, the immune system and the extracellular matrix. These findings have revealed novel pathways that could be therapeutically targeted to stimulate repair following myocardial infarction and have provided lessons to guide future efforts towards heart regeneration through cellular reprogramming or cardiomyocyte transplantation. PMID- 28729728 TI - Landscape of somatic mutations in different subtypes of advanced breast cancer with circulating tumor DNA analysis. AB - It is particularly important to provide precise therapies and understand tumor heterogeneity based on the molecular typing of mutational landscape. However, the landscape of somatic mutations in different subtypes of advanced breast cancer (ABC) is largely unknown. We applied target-region capture deep sequencing to determine the frequency and spectrum of common cancer-related gene mutations in circulating tumor DNA (ctDNA) among different ABC subtypes and analyze their association with clinical features. In this retrospective study of 100 female advanced breast cancer patients, 96 (96.0%) had somatic genomic alterations in ctDNA, including copy number variants and point mutations. The results revealed that different subtypes of ABC have distinct features in terms of genetic alterations. Multivariate regression analyses revealed that the number of somatic mutations increased with the line of endocrine therapy and the fractions of trunk mutations was positive associated with the line of target therapy. PMID- 28729729 TI - A Novel Methodology using CT Imaging Biomarkers to Quantify Radiation Sensitivity in the Esophagus with Application to Clinical Trials. AB - Personalized cancer therapy seeks to tailor treatment to an individual patient's biology. Therefore, a means to characterize radiosensitivity is necessary. In this study, we investigated radiosensitivity in the normal esophagus using an imaging biomarker of radiation-response and esophageal toxicity, esophageal expansion, as a method to quantify radiosensitivity in 134 non-small-cell lung cancer patients, by using K-Means clustering to group patients based on esophageal radiosensitivity. Patients within the cluster of higher response and lower dose were labelled as radiosensitive. This information was used as a variable in toxicity prediction modelling (lasso logistic regression). The resultant model performance was quantified and compared to toxicity prediction modelling without utilizing radiosensitivity information. The esophageal expansion-response was highly variable between patients, even for similar radiation doses. K-Means clustering was able to identify three patient subgroups of radiosensitivity: radiosensitive, radio-normal, and radioresistant groups. Inclusion of the radiosensitive variable improved lasso logistic regression models compared to model performance without radiosensitivity information. Esophageal radiosensitivity can be quantified using esophageal expansion and K Means clustering to improve toxicity prediction modelling. Finally, this methodology may be applied in clinical trials to validate pre-treatment biomarkers of esophageal toxicity. PMID- 28729727 TI - Senescent cells: an emerging target for diseases of ageing. AB - Chronological age represents the single greatest risk factor for human disease. One plausible explanation for this correlation is that mechanisms that drive ageing might also promote age-related diseases. Cellular senescence, which is a permanent state of cell cycle arrest induced by cellular stress, has recently emerged as a fundamental ageing mechanism that also contributes to diseases of late life, including cancer, atherosclerosis and osteoarthritis. Therapeutic strategies that safely interfere with the detrimental effects of cellular senescence, such as the selective elimination of senescent cells (SNCs) or the disruption of the SNC secretome, are gaining significant attention, with several programmes now nearing human clinical studies. PMID- 28729730 TI - A selective inhibitor of histone deacetylase 3 prevents cognitive deficits and suppresses striatal CAG repeat expansions in Huntington's disease mice. AB - Huntington's disease (HD) is a neurodegenerative disorder whose major symptoms include progressive motor and cognitive dysfunction. Cognitive decline is a critical quality of life concern for HD patients and families. The enzyme histone deacetylase 3 (HDAC3) appears to be important in HD pathology by negatively regulating genes involved in cognitive functions. Furthermore, HDAC3 has been implicated in the aberrant transcriptional patterns that help cause disease symptoms in HD mice. HDAC3 also helps fuel CAG repeat expansions in human cells, suggesting that HDAC3 may power striatal expansions in the HTT gene thought to drive disease progression. This multifaceted role suggests that early HDAC3 inhibition offers an attractive mechanism to prevent HD cognitive decline and to suppress striatal expansions. This hypothesis was investigated by treating HdhQ111 knock-in mice with the HDAC3-selective inhibitor RGFP966. Chronic early treatment prevented long-term memory impairments and normalized specific memory related gene expression in hippocampus. Additionally, RGFP966 prevented corticostriatal-dependent motor learning deficits, significantly suppressed striatal CAG repeat expansions, partially rescued striatal protein marker expression and reduced accumulation of mutant huntingtin oligomeric forms. These novel results highlight RGFP966 as an appealing multiple-benefit therapy in HD that concurrently prevents cognitive decline and suppresses striatal CAG repeat expansions. PMID- 28729731 TI - Anti-asthmatic effect of pitavastatin through aerosol inhalation is associated with CD4+ CD25+ Foxp3+ T cells in an asthma mouse model. AB - Statins are competitive inhibitors of 3-hydroxy-3-methylglutaryl-CoA (HMG-A) reductase, and studies have shown that statins also have anti-inflammatory and immunomodulatory properties. The purpose of this study was to investigate the anti-asthmatic effects of pitavastatin, a type of statin, in an asthma mouse model. Mice were sensitized and challenged with ovalbumin (OVA) to establish the asthma model. These mice were then treated with inhaled pitavastatin (5 mg/kg) or dexamethasone (2 mg/kg), the latter of which served as a positive control. The results of the study showed that pitavastatin reduced allergen-induced increases in airway resistance and alleviated bronchial tube thickness and goblet cell hyperplasia in lung tissues. In addition, the results showed that pitavastatin inhibited OVA-induced increases in eosinophil counts and total inflammatory cell counts in bronchoalveolar lavage fluid (BALF) and increased the percentage of CD4+ CD25+ Foxp3+ Treg in the BALF of asthmatic mice. IL-4 and IL-17 levels were decreased, whereas IFN-gamma levels were significantly increased in the BALF of pitavastatin-treated mice compared with the BALF of OVA-challenged mice. These results suggest that pitavastatin has potential as a therapy for allergic airway disease and that its effects are associated with its ability to regulate CD4+ CD25+ Foxp3+ T cell counts. PMID- 28729732 TI - Evidence of selection on splicing-associated loci in human populations and relevance to disease loci mapping. AB - We performed a whole-genome scan of genetic variants in splicing regulatory elements (SREs) and evaluated the extent to which natural selection has shaped extant patterns of variation in SREs. We investigated the degree of differentiation of single nucleotide polymorphisms (SNPs) in SREs among human populations and applied long-range haplotype- and multilocus allelic differentiation-based methods to detect selection signatures. We describe an approach, sampling a large number of loci across the genome from functional classes and using the consensus from multiple tests, for identifying candidates for selection signals. SRE SNPs in various SNP functional classes show different patterns of population differentiation compared with their non-SRE counterparts. Intronic regions display a greater enrichment for extreme population differentiation among the potentially tissue-dependent transcript ratio quantitative trait loci (trQTLs) than SRE SNPs in general and includ outlier trQTLs for cross-population composite likelihood ratio, suggesting that incorporation of context annotation for regulatory variation may lead to improved detection of signature of selection on these loci. The proportion of extremely rare SNPs disrupting SREs is significantly higher in European than in African samples. The approach developed here will be broadly useful for studies of function and disease-associated variation in the human genome. PMID- 28729733 TI - Extreme coastal erosion enhanced by anomalous extratropical storm wave direction. AB - Extratropical cyclones (ETCs) are the primary driver of large-scale episodic beach erosion along coastlines in temperate regions. However, key drivers of the magnitude and regional variability in rapid morphological changes caused by ETCs at the coast remain poorly understood. Here we analyze an unprecedented dataset of high-resolution regional-scale morphological response to an ETC that impacted southeast Australia, and evaluate the new observations within the context of an existing long-term coastal monitoring program. This ETC was characterized by moderate intensity (for this regional setting) deepwater wave heights, but an anomalous wave direction approximately 45 degrees more counter-clockwise than average. The magnitude of measured beach volume change was the largest in four decades at the long-term monitoring site and, at the regional scale, commensurate with that observed due to extreme North Atlantic hurricanes. Spatial variability in morphological response across the study region was predominantly controlled by alongshore gradients in storm wave energy flux and local coastline alignment relative to storm wave direction. We attribute the severity of coastal erosion observed due to this ETC primarily to its anomalous wave direction, and call for greater research on the impacts of changing storm wave directionality in addition to projected future changes in wave heights. PMID- 28729734 TI - A role for microbial selection in frescoes' deterioration in Tomba degli Scudi in Tarquinia, Italy. AB - Mural paintings in the hypogeal environment of the Tomba degli Scudi in Tarquinia, Italy, show a quite dramatic condition: the plaster mortar lost his cohesion and a white layer coating is spread over almost all the wall surfaces. The aim of this research is to verify if the activity of microorganisms could be one of the main causes of deterioration and if the adopted countermeasures (conventional biocide treatments) are sufficient to stop it. A biocide treatment of the whole environment has been carried out before the conservative intervention and the tomb has been closed for one month. When the tomb was opened again, we sampled the microorganisms present on the frescoes and we identified four Bacillus species and one mould survived to the biocide treatment. These organisms are able to produce spores, a highly resistant biological form, which has permitted the survival despite the biocide treatment. We show that these Bacillus strains are able to produce calcium carbonate and could be responsible for the white deposition that was damaging and covering the entire surface of the frescoes. Our results confirm that the sanitation intervention is non always resolutive and could even be deleterious in selecting harmful microbial communities. PMID- 28729735 TI - The Wnt receptor Ryk is a negative regulator of mammalian dendrite morphogenesis. AB - The unique dendritic architecture of a given neuronal subtype determines its synaptic connectivity and ability to integrate into functional neuronal networks. It is now clear that abnormal dendritic structure is associated with neuropsychiatric and neurodegenerative disorders. Currently, however, the nature of the extrinsic factors that limit dendritic growth and branching within predetermined boundaries in the mammalian brain is poorly understood. Here we identify the Wnt receptor Ryk as a novel negative regulator of dendritic arborisation. We demonstrate that loss of Ryk in mouse hippocampal and cortical neurons promotes excessive dendrite growth and branching in vitro. Conversely, overexpression of wildtype Ryk restricts these processes, confirming that Ryk acts to restrain dendrite arborisation. Furthermore, we identify a hitherto uncharacterized membrane proximal subdomain crucial for Ryk-mediated suppression of dendrite morphogenesis, suggesting that it may act through a novel signalling pathway to constrain dendrite complexity. We also demonstrate that Ryk performs a similar function in vivo as Ryk haploinsufficient postnatal animals exhibit excessive dendrite growth and branching in layer 2/3 pyramidal neurons of the somatosensory cortex. These findings reveal an essential role for Ryk in regulating dendrite complexity and raise the intriguing possibility that it may influence neural plasticity by modifying dendritic structure. PMID- 28729736 TI - The relationship between folding and activity in UreG, an intrinsically disordered enzyme. AB - A growing body of literature on intrinsically disordered proteins (IDPs) led scientists to rethink the structure-function paradigm of protein folding. Enzymes are often considered an exception to the rule of intrinsic disorder (ID), believed to require a unique structure for catalysis. However, recent studies revealed the presence of disorder in several functional native enzymes. In the present work, we address the importance of dynamics for catalysis, by investigating the relationship between folding and activity in Sporosarcina pasteurii UreG (SpUreG), a P-loop GTPase and the first discovered native ID enzyme, involved in the maturation of the nickel-containing urease. The effect of denaturants and osmolytes on protein structure and activity was analyzed using circular dichroism (CD), Site-Directed Spin Labeling (SDSL) coupled to EPR spectroscopy, and enzymatic assays. Our data show that SpUreG needs a "flexibility window" to be catalytically competent, with both too low and too high mobility being detrimental for its activity. PMID- 28729737 TI - Direct binding to GABARAP family members is essential for HIV-1 Nef plasma membrane localization. AB - HIV-1 Nef is an important pathogenic factor for HIV/AIDS pathogenesis. Studies have shown that the association of Nef with the inner leaflet of the plasma membrane and with endocytic and perinuclear vesicles is essential for most activities of Nef. Using purified recombinant proteins in pull-down assays and by co-immunoprecipitation assays we demonstrate that Nef binds directly and specifically to all GABARAP family members, but not to LC3 family members. Based on nuclear magnetic resonance (NMR) experiments we showed that Nef binds to GABARAP via two surface exposed hydrophobic pockets. S53 and F62 of GABARAP were identified as key residues for the interaction with Nef. During live-cell fluorescence microscopy an accumulation of Nef and all GABARAP family members in vesicular structures throughout the cytoplasm and at the plasma membrane was observed. This plasma membrane accumulation was significantly reduced after knocking down GABARAP, GABARAPL1 and GABARAPL2 with respective siRNAs. We identified GABARAPs as the first known direct interaction partners of Nef that are essential for its plasma membrane localization. PMID- 28729738 TI - Human hippocampal pre-activation predicts behavior. AB - The response to an upcoming salient event is accelerated when the event is expected given the preceding events - i.e. a temporal context effect. For example, naming a picture following a strongly constraining temporal context is faster than naming a picture after a weakly constraining temporal context. We used sentences as naturalistic stimuli to manipulate expectations on upcoming pictures without prior training. Here, using intracranial recordings from the human hippocampus we found more power in the high-frequency band prior to high expected pictures than weakly expected ones. We applied pattern similarity analysis on the temporal pattern of hippocampal high-frequency band activity in single hippocampal contacts. We found that greater similarity in the pattern of hippocampal field potentials between pre-picture interval and expected picture interval in the high-frequency band predicted picture-naming latencies. Additional pattern similarity analysis indicated that the hippocampal representations follow a semantic map. The results suggest that hippocampal pre activation of expected stimuli is a facilitating mechanism underlying the powerful contextual behavioral effect. PMID- 28729739 TI - Host plants and obligate endosymbionts are not the sources for biosynthesis of the aphid alarm pheromone. AB - (E)-beta-farnesene (EbetaF) is the major component of the alarm pheromone of many aphid species, but where EbetaF is synthesized in aphids is only partly understood. There are at least three most possible sources for the alarm pheromone: host plants, aphid obligate endosymbiont and aphids themselves. Here we eliminated the possibility of host plants and the obligate endosymbiont Buchnera aphidicola as the sources for EbetaF released by aphids. We excluded the possible effects of host plants on EbetaF biosynthesis by rearing aphids on non plant diets. Both the diet-reared aphids, including the cotton aphid Aphis gossypii and the green peach aphid Myzus persicae, could still release EbetaF based on solid-phase micro-extraction combined with gas chromatography-mass spectrometer analysis. Meanwhile, we treated host aphids with antibiotics to fully eliminate Buchnera bacteria. Though the treatment seriously affected the development and fecundity of host aphids, the treated aphids could still release EbetaF, and there was no significant difference in the EbetaF concentration as per the aphid weight under different rearing conditions. Taken together, our experimental results suggest that host plants and obligate endosymbionts are not the sources for EbetaF released by aphids, indicating that it is most probably the aphid itself synthesizes the alarm pheromone. PMID- 28729740 TI - Annual Performance of a Two-Speed, Dedicated Dehumidification Heat Pump in the NIST Net-Zero Energy Residential Test Facility. AB - A 2715 ft2 (252 m2), two story, residential home of the style typical of the Gaithersburg, Maryland area was constructed in 2012 to demonstrate technologies for net-zero energy (NZE) homes (or ZEH). The NIST Net-Zero Energy Residential Test Facility (NZERTF) functions as a laboratory to support the development and adoption of cost-effective NZE designs, technologies, construction methods, and building codes. The primary design goal was to meet the comfort and functional needs of the simulated occupants. The first annual test period began on July 1, 2013 and ended June 30, 2014. During the first year of operation, the home's annual energy consumption was 13039 kWh (4.8 kWh ft-2, 51.7 kWh m-2), and the 10.2 kW solar photovoltaic system generated an excess of 484 kWh. During this period the heating and air conditioning of the home was performed by a novel air source heat pump that utilized a reheat heat exchanger to allow hot compressor discharge gas to reheat the supply air during a dedicated dehumidification mode. During dedicated dehumidification, room temperature air was supplied to the living space until the relative humidity setpoint of 50% was satisfied. The heat pump consumed a total of 6225 kWh (2.3 kWh ft-2, 24.7 kWh m-2) of electrical energy for cooling, heating, and dehumidification. Annual cooling efficiency was 10.1 Btu W-1h-1 (2.95 W W-1), relative to the rated SEER of the heat pump of 15.8 Btu W-1h-1 (4.63 W W-1). Annual heating efficiency was 7.10 Btu W-1h-1 (2.09 W W 1), compared with the unit's rated HSPF of 9.05 Btu W-1h-1 (2.65 W W-1). These field measured efficiency numbers include dedicated dehumidification operation and standby energy use for the year. Annual sensible heat ratio was approximately 70%. Standby energy consumption was 5.2 % and 3.5 % of the total electrical energy used for cooling and heating, respectively. PMID- 28729741 TI - High-performing visible-blind photodetectors based on SnO2/CuO nanoheterojunctions. AB - We report on the significant performance enhancement of SnO2 thin film ultraviolet (UV) photodetectors (PDs) through incorporation of CuO/SnO2p-n nanoscale heterojunctions. The nanoheterojunctions are self-assembled by sputtering Cu clusters that oxidize in ambient to form CuO. We attribute the performance improvements to enhanced UV absorption, demonstrated both experimentally and using optical simulations, and electron transfer facilitated by the nanoheterojunctions. The peak responsivity of the PDs at a bias of 0.2 V improved from 1.9 A/W in a SnO2-only device to 10.3 A/W after CuO deposition. The wavelength-dependent photocurrent-to-dark current ratio was estimated to be ~ 592 for the CuO/SnO2 PD at 290 nm. The morphology, distribution of nanoparticles, and optical properties of the CuO/SnO2 heterostructured thin films are also investigated. PMID- 28729742 TI - Can Principals Promote Teacher Development as Evaluators? A Case Study of Principals' Views and Experiences. AB - PURPOSE: New teacher evaluation systems have expanded the role of principals as instructional leaders, but little is known about principals' ability to promote teacher development through the evaluation process. We conducted a case study of principals' perspectives on evaluation and their experiences implementing observation and feedback cycles to better understand whether principals feel as though they are able to promote teacher development as evaluators. RESEARCH METHODS: We conducted interviews with a stratified random sample of 24 principals in an urban district that recently implemented major reforms to its teacher evaluation system. We analyzed these interviews by drafting thematic summaries, coding interview transcripts, creating data-analytic matrices, and writing analytic memos. FINDINGS: We found that the evaluation reforms provided a common framework and language that helped facilitate principals' feedback conversations with teachers. However, we also found that tasking principals with primary responsibility for conducting evaluations resulted in a variety of unintended consequences which undercut the quality of evaluation feedback they provided. We analyze five broad solutions to these challenges: strategically targeting evaluations, reducing operational responsibilities, providing principal training, hiring instructional coaches, and developing peer evaluation systems. IMPLICATIONS: The quality of feedback teachers receive through the evaluation process depends critically on the time and training evaluators have to provide individualized and actionable feedback. Districts that task principals with primary responsibility for conducting observation and feedback cycles must attend to the many implementation challenges associated with this approach in order for next-generation evaluation systems to successfully promote teacher development. PMID- 28729743 TI - Superconformal Bottom-Up Gold Deposition in High Aspect Ratio Through Silicon Vias. AB - This work presents superconformal, bottom-up Au filling of high aspect ratio through silicon vias (TSVs) along with a predictive framework based on the coupling of suppression breakdown and surface topography. The work extends a previous study of superconformal Au deposition in lower aspect ratio TSVs. Deposition was performed in a Na3AuSO3 electrolyte containing a branched polyethyleneimine (PEI) deposition-rate suppressing additive. Voltammetric measurements using a rotating disk electrode (RDE) were used to assess the impact of the PEI suppressor concentration and transport on the rate of metal deposition, enabling the interplay between metal deposition and suppressor adsorption to be quantified. The positive feedback associated with suppression breakdown gives rise to an S-shaped negative differential resistance (S-NDR). The derived kinetics for suppressor adsorption and consumption were used in a mass conservation model to account for bottom-up filling of patterned features. Predictions, including the impact of deposition potential and additive concentration on feature filling, are shown to match experimental results for filling of TSVs. This further generalizes the utility of the additive derived S NDR model as a predictive formalism for identifying additives capable of generating localized, void-free filling of TSVs by electrodeposition. PMID- 28729744 TI - Attitudes towards Social Oocyte Freezing from a Socio-cultural Perspective. AB - INTRODUCTION: The tendency to delay parenthood is increasing. It is partly driven by the availability of early reproductive technologies such as social oocyte freezing, the cryopreservation of oocytes for non-medical purposes. The goal of this study was to investigate relationships between attitudes towards social oocyte freezing and different socio-cultural backgrounds in a German sample cohort. MATERIALS AND METHODS: A quantitative online questionnaire was compiled. A total of 643 participants completed the questionnaire which included items on attitudes toward social oocyte freezing, socio-demographics and items, obtained from the German DELTA Institute for Social and Ecological Research, devised to indicate specific milieus. Data were analyzed using parametric and non-parametric methods. RESULTS: There were clear correlations between attitudes towards social oocyte freezing and socio-cultural background, gender, cohort age, fertility problems, and attitudes to fertility. Positive attitudes towards social oocyte freezing were linked to struggles with fertility, a current or general wish to have a child, and flexible, progressive and self-oriented values. Participants who preferred to become parents at a younger age tended to reject cryopreservation. CONCLUSIONS: The huge number of university graduates, persons with fertility problems, and persons from specific socio-cultural backgrounds in our sample point to distinct groups interested in reproductive technologies such as social oocyte freezing. The investigated differences as a function of socio cultural background suggest that more research into the desire to have children in German society is needed. In conclusion, it may be necessary to develop targeted family planning interventions to prevent affected women from buying into a false sense of security, thereby risking unwanted childlessness. PMID- 28729747 TI - Do More of Those in Misery Suffer from Poverty, Unemployment or Mental Illness? AB - Studies of deprivation usually ignore mental illness. This paper uses household panel data from the USA, Australia, Britain and Germany to broaden the analysis. We ask first how many of those in the lowest levels of life-satisfaction suffer from unemployment, poverty, physical ill health, and mental illness. The largest proportion suffers from mental illness. Multiple regression shows that mental illness is not highly correlated with poverty or unemployment, and that it contributes more to explaining the presence of misery than is explained by either poverty or unemployment. This holds both with and without fixed effects. PMID- 28729746 TI - The Incidence and Effects of Alloimmunization in Pregnancy During the Period 2000 - 2013. AB - INTRODUCTION: The objective of the analysis was to examine the epidemiological aspects of maternal alloimmunization and to determine the most common antibody specificities resulting in hemolytic disease of the newborn (HDN). MATERIALS AND METHODS: The retrospective epidemiological study encompasses all pregnant women who underwent immunohematological screening and the newborn treated for HDN in the period from 2000 to 2013 in the Herzegovina region. RESULTS: The indirect Coombs test (ICT) detected antibodies against antigens in 384 (2.4%) pregnant women of the 18 800 who were tested at the Department of Transfusion Medicine. The direct Coombs test (DCT) detected antibodies against antigens in 160 (0.8%) newborn treated for HDN. The results of our 13-year study, in which 60% of the pregnant women had non-RhD antibodies, confirms this finding. CONCLUSION: However, we have reached the 21st century and the burden of alloimmunisation in pregnancy is still on our backs. The problem of immunization and HDN is still present in our region, which is a neonatal and public health problem. PMID- 28729745 TI - Insufficient Angiogenesis: Cause of Abnormally Thin Endometrium in Subfertile Patients? AB - INTRODUCTION: This study investigated subfertile patients with abnormally thin endometrium after infertility treatment. As they had adequate serum concentrations of hormones, an endometrial factor for subfertility was suspected. METHODS: To elucidate the cause of subfertility, endometrial biopsies were taken in each patient in the late proliferative and mid-secretory phases of one menstrual cycle. Endometrial biopsies from women with normal menstrual cycles and confirmed fertility who were undergoing hysterectomy for benign uterine disease were used as positive controls. The tissue samples were investigated for steroid hormone receptor expression and for the proliferation marker Ki-67. Immunohistochemistry was performed with antibodies against the marker molecules for endometrial receptivity - beta 3 integrin, VEGF, LIF, and CD56 (large granular lymphocytes, LGLs). RESULTS: The steroid hormone receptors for estrogen (E2) and progesterone (P) were expressed normally (at the first biopsy) and were down-regulated (at the second biopsy) within the cycle. Strikingly, all of the marker molecules investigated showed negative or weak and inadequate expression in the mid-secretory phase. Numbers of LGLs remained as low as in the proliferative phase. In contrast, fertile patients were found to express these marker molecules distinctly in the mid-secretory phase. CONCLUSIONS: It may be hypothesized that a severe deficiency of these angiogenesis-related marker molecules leads to defective development of the endometrium, which remains thin. Deficient angiogenetic development may thus provide an explanation for the endometrial factor that causes infertility. Further investigations will need to focus on identifying the regulating factors that act between steroid receptor activation and the expression of these marker molecules. PMID- 28729748 TI - On Flare-CME Characteristics from Sun to Earth Combining Remote-Sensing Image Data with In Situ Measurements Supported by Modeling. AB - We analyze the well-observed flare and coronal mass ejection (CME) from 1 October 2011 (SOL2011-10-01T09:18) covering the complete chain of effects - from Sun to Earth - to better understand the dynamic evolution of the CME and its embedded magnetic field. We study in detail the solar surface and atmosphere associated with the flare and CME using the Solar Dynamics Observatory (SDO) and ground based instruments. We also track the CME signature off-limb with combined extreme ultraviolet (EUV) and white-light data from the Solar Terrestrial Relations Observatory (STEREO). By applying the graduated cylindrical shell (GCS) reconstruction method and total mass to stereoscopic STEREO-SOHO (Solar and Heliospheric Observatory) coronagraph data, we track the temporal and spatial evolution of the CME in the interplanetary space and derive its geometry and 3D mass. We combine the GCS and Lundquist model results to derive the axial flux and helicity of the magnetic cloud (MC) from in situ measurements from Wind. This is compared to nonlinear force-free (NLFF) model results, as well as to the reconnected magnetic flux derived from the flare ribbons (flare reconnection flux) and the magnetic flux encompassed by the associated dimming (dimming flux). We find that magnetic reconnection processes were already ongoing before the start of the impulsive flare phase, adding magnetic flux to the flux rope before its final eruption. The dimming flux increases by more than 25% after the end of the flare, indicating that magnetic flux is still added to the flux rope after eruption. Hence, the derived flare reconnection flux is most probably a lower limit for estimating the magnetic flux within the flux rope. We find that the magnetic helicity and axial magnetic flux are lower in the interplanetary space by ~ 50% and 75%, respectively, possibly indicating an erosion process. A CME mass increase of 10% is observed over a range of [Formula: see text]. The temporal evolution of the CME-associated core-dimming regions supports the scenario that fast outflows might supply additional mass to the rear part of the CME. PMID- 28729749 TI - Preparation of 1,5-Dioxaspiro[5.5]undecan-3-one. PMID- 28729750 TI - Hydrodynamic Radius Fluctuations in Model DNA-Grafted Nanoparticles. AB - We utilize molecular dynamics simulations (MD) and the path-integration program ZENO to quantify hydrodynamic radius (Rh) fluctuations of spherical symmetric gold nanoparticles (NPs) decorated with single-stranded DNA chains (ssDNA). These results are relevant to understanding fluctuation-induced interactions among these NPs and macromolecules such as proteins. In particular, we explore the effect of varying the ssDNA-grafted NPs structural parameters, such as the chain length (L), chain persistence length (lp), NP core size (R), and the number of chains (N) attached to the nanoparticle core. We determine Rh fluctuations by calculating its standard deviation (sigmaRh ) of an ensemble of ssDNA-grafted NPs configurations generated by MD. For the parameter space explored in this manuscript, sigmaRh shows a peak value as a function of N, the amplitude of which depends on L, lp and R, while the broadness depends on R. PMID- 28729752 TI - Integral equation and thermodynamic perturbation theory for a two-dimensional model of chain-forming fluid. AB - In this paper we applied analytical theories for the two dimensional chain forming fluid. Wertheims thermodynamic perturbation theory (TPT) and integral equation theory (IET) for associative liquids were used to study thermodynamical and structural properties of the chain-forming model. The model has polymerizing points at arbitrary position from center of the particles. Calculated analytical results were tested against corresponding results obtained by Monte Carlo computer simulations to check the accuracy of the theories. The theories are accurate for the different positions of patches of the model at all values of the temperature and density studied. The IET's pair correlation functions of the model agree well with computer simulations. Both TPT and IET are in good agreement with the Monte Carlo values of the energy, chemical potential and ratios of free, once and twice bonded particles. PMID- 28729751 TI - Severity and Justness Do Not Moderate the Relation Between Corporal Punishment and Negative Child Outcomes: A Multicultural and Longitudinal Study. AB - There is strong evidence of a positive association between corporal punishment and negative child outcomes, but previous studies have suggested that the manner in which parents implement corporal punishment moderates the effects of its use. This study investigated whether severity and justness in the use of corporal punishment moderate the associations between frequency of corporal punishment and child externalizing and internalizing behaviors. This question was examined using a multicultural sample from eight countries and two waves of data collected one year apart. Interviews were conducted with 998 children aged 7-10 years, and their mothers and fathers, from China, Colombia, Italy, Jordan, Kenya, Philippines, Thailand, and the United States. Mothers and fathers responded to questions on the frequency, severity, and justness of their use of corporal punishment; they also reported on the externalizing and internalizing behavior of their child. Children reported on their aggression. Multigroup path models revealed that across cultural groups, and as reported by mothers and fathers, there is a positive relation between the frequency of corporal punishment and externalizing child behaviors. Mother-reported severity and father-reported justness were associated with child-reported aggression. Neither severity nor justness moderated the relation between frequency of corporal punishment and child problem behavior. The null result suggests that more use of corporal punishment is harmful to children regardless of how it is implemented, but requires further substantiation as the study is unable to definitively conclude that there is no true interaction effect. PMID- 28729753 TI - Gesture and intonation are "sister systems" of infant communication: Evidence from regression patterns of language development. AB - This study investigates infants' transition from nonverbal to verbal communication using evidence from regression patterns. As an example of regressions, prelinguistic infants learning American Sign Language (ASL) use pointing gestures to communicate. At the onset of single signs, however, these gestures disappear. Petitto (1987) attributed the regression to the children's discovery that pointing has two functions, namely, deixis and linguistic pronouns. The 1:2 relation (1 form, 2 functions) violates the simple 1:1 pattern that infants are believed to expect. This kind of conflict, Petitto argued, explains the regression. Based on the additional observation that the regression coincided with the boundary between prelinguistic and linguistic communication, Petitto concluded that the prelinguistic and linguistic periods are autonomous. The purpose of the present study was to evaluate the 1:1 model and to determine whether it explains a previously reported regression of intonation in English. Background research showed that gestures and intonation have different forms but the same pragmatic meanings, a 2:1 form-function pattern that plausibly precipitates the regression. The hypothesis of the study was that gestures and intonation are closely related. Moreover, because gestures and intonation change in the opposite direction, the negative correlation between them indicates a robust inverse relationship. To test this prediction, speech samples of 29 infants (8 to 16 months) were analyzed acoustically and compared to parent-report data on several verbal and gestural scales. In support of the hypothesis, gestures alone were inversely correlated with intonation. In addition, the regression model explains nonlinearities stemming from different form-function configurations. However, the results failed to support the claim that regressions linked to early words or signs reflect autonomy. The discussion ends with a focus on the special role of intonation in children's transition from "prelinguistic" communication to language. PMID- 28729754 TI - Occupational Hearing Loss from Non-Gaussian Noise. PMID- 28729756 TI - Corrigendum to "Clinical and Preclinical Cognitive Function Improvement after Oral Treatment of a Botanical Composition Composed of Extracts from Scutellaria baicalensis and Acacia catechu". AB - [This corrects the article DOI: 10.1155/2016/7240802.]. PMID- 28729755 TI - Social Cognition Deficits: Current Position and Future Directions for Neuropsychological Interventions in Cerebrovascular Disease. AB - Neuropsychological assessments of cognitive dysfunction in cerebrovascular illness commonly target basic cognitive functions involving aspects of memory, attention, language, praxis, and number processing. Here, I highlight the clinical importance of often-neglected social cognition functions. These functions recruit a widely distributed neural network, making them vulnerable in most cerebrovascular diseases. Sociocognitive deficits underlie most of the problematic social conduct observed in patients and are associated with more negative clinical outcomes (compared to nonsocial cognitive deficits). In clinical settings, social cognition deficits are normally gleaned from collateral information from caregivers or from indirect inferences made from patients' performance on standard nonsocial cognitive tests. Information from these sources is however inadequate. I discuss key social cognition functions, focusing initially on deficits in emotion perception and theory of mind, two areas that have gained sizeable attention in neuroscientific research, and then extend the discussion into relatively new, less covered but crucial functions involving empathic behaviour, social awareness, social judgements, and social decision making. These functions are frequently impaired following neurological change. At present, a wide range of psychometrically robust social cognition tests is available, and this review also makes the case for their inclusion in neuropsychological assessments. PMID- 28729757 TI - Protein-protein interfaces are vdW dominant with selective H-bonds and (or) electrostatics towards broad functional specificity. AB - Several catalysis, cellular regulation, immune function, cell wall assembly, transport, signaling and inhibition occur through Protein- Protein Interactions (PPI). This is possible with the formation of specific yet stable protein-protein interfaces. Therefore, it is of interest to understand its molecular principles using structural data in relation to known function. Several interface features have been documented using known X-ray structures of protein complexes since 1975. This has improved our understanding of the interface using structural features such as interface area, binding energy, hydrophobicity, relative hydrophobicity, salt bridges and hydrogen bonds. The strength of binding between two proteins is dependent on interface size (number of residues at the interface) and thus its corresponding interface area. It is known that large interfaces have high binding energy (sum of (van der Waals) vdW, H-bonds, electrostatics). However, the selective role played by each of these energy components and more especially that of vdW is not explicitly known. Therefore, it is important to document their individual role in known protein-protein structural complexes. It is of interest to relate interface size with vdW, H-bonds and electrostatic interactions at the interfaces of protein structural complexes with known function using statistical and multiple linear regression analysis methods to identify the prominent force. We used the manually curated non-redundant dataset of 278 hetero-dimeric protein structural complexes grouped using known functions by Sowmya et al. (2015) to gain additional insight to this phenomenon using a robust inter-atomic non-covalent interaction analyzing tool PPCheck (Anshul and Sowdhamini, 2015). This dataset consists of obligatory (enzymes, regulator, biological assembly), immune and nonobligatory (enzyme and regulator inhibitors) complexes. Results show that the total binding energy is more for large interfaces. However, this is not true for its individual energy factors. Analysis shows that vdW energies contribute to about 75% +/- 11% on average among all complexes and it also increases with interface size (r2 ranging from 0.67 to 0.89 with p<0.01) at 95% confidence limit irrespective of molecular function. Thus, vdW is both dominant and proportional at the interface independent of molecular function. Nevertheless, H bond energy contributes to 15% +/- 6.5% on average in these complexes. It also moderately increases with interface size (r2 ranging from 0.43 to 0.61 with p<0.01) only among obligatory and immune complexes. Moreover, there is about 11.3% +/- 8.7% contribution by electrostatic energy. It increases with interface size specifically among non-obligatory regulator inhibitors (r2 = 0.44). It is implied that both H-bonds and electrostatics are neither dominant nor proportional at the interface. Nonetheless, their presence cannot be ignored in binding. Therefore, H-bonds and (or) electrostatic energy having specific role for improved stability in complexes is implied. Thus, vdW is common at the interface stabilized further with selective H-bonds and (or) electrostatic interactions at an atomic level in almost all complexes. Comparison of this observation with residue level analysis of the interface is compelling. The role by H-bonds (14.83% +/- 6.5% and r2 = 0.61 with p<0.01) among obligatory and electrostatic energy (8.8% +/- 4.77% and r2 = 0.63 with p <0.01) among non obligatory complexes within interfaces (class A) having more non-polar residues than surface is influencing our inference. However, interfaces (class B) having less non-polar residues than surface show 1.5 fold more electrostatic energy on average. The interpretation of the interface using inter-atomic (vdW, H-bonds, electrostatic) interactions combined with inter-residue predominance (class A and class B) in relation to known function is the key to reveal its molecular principles with new challenges. PMID- 28729758 TI - Analysis of correlated mutations in Ras G-domain. AB - Ras GTPases are most prevalent proto-oncogenes in human cancer. Mutations in Ras remain untreatable more than three decades after the initial discovery. At the amino acid level, some residues under physical or functional constraints exhibit correlated mutations also known as coevolving/covariant residues. Revealing intra molecular co-evolution between amino acid sites of proteins has become an emerging area of research as it enlightens the importance of variable regions. Here, I have identified and analyzed the coevolving residues in the Ras GTP binding domain (G-domain). The obtained covariant residue position data correlate well with the known experimental data on functionally important residues. Therefore, it is of interest to understand these residue co-variations for designing protein engineering experiments and target oncogenic Ras GTPases. PMID- 28729759 TI - Transcriptome wide identification and characterization of starch branching enzyme in finger millet. AB - Starch-branching enzymes (SBEs) are one of the four major enzyme classes involved in starch biosynthesis in plants and play an important role in determining the structure and physical properties of starch granules. Multiple SBEs are involved in starch biosynthesis in plants. Finger millet is calcium rich important serial crop belongs to grass family and the transcriptome data of developing spikes is available on NCBI. In this study it was try to find out the gene sequence of starch branching enzyme and annotate the sequence and submit the sequence for further use. Rice SBE sequence was taken as reference and for characterization of the sequence different in silico tools were used. Four domains were found in the finger millet Starch branching enzyme like alpha amylase catalytic domain from 925 to2172 with E value 0, N-terminal Early set domain from 634 to 915 with E value 1.62 e-42, Alpha amylase, C-terminal all-beta domain from 2224 to 2511 with E value 5.80e-24 and 1,4-alpha-glucan-branching enzyme from 421 to 2517 with E value 0. Major binding interactions with the GLC (alpha-d-glucose), CA (calcium ion), GOL (glycerol), TRS (2-amino-2-hydroxymethylpropane- 1, 3-diol), MG (magnesium ion) and FLC (citrate anion) are fond with different residues. It was found in the phylogenetic study of the finger millet SBE with the 6 species of grass family that two clusters were form A and B. In cluster A, finger millet showed closeness with Oryzasativa and Setariaitalica, Sorghum bicolour and Zea mays while cluster B was formed with Triticumaestivum and Brachypodium distachyon. The nucleotide sequence of Finger millet SBE was submitted to NCBI with the accession no KY648913 and protein structure of SBE of finger millet was also submitted in PMDB with the PMDB id - PM0080938. This research presents a comparative overview of Finger millet SBE and includes their properties, structural and functional characteristics, and recent developments on their post translational regulation. PMID- 28729760 TI - Structural insight into the binding of C60-derivatives with enoyl-pyruvate transferase from Helicobacter pylori. AB - Helicobacter pylori (H. pylori) is a human pathogen associated with acute gastritis and peptic ulcer. The MurA enzyme is an important drug target for the identification of ligands with improved efficacy and acceptable pharmaco-kinetic properties. We developed a homology model of H. Pylori MurA followed by refinement and molecular dynamics (MD) simulations. A total of 16 C60-derivatives were docked and its docking score were compared. Some of the known inhibitors were also similarly characterized and compared. Results show that five out of the sixteen C60-derivatives have good binding score. The MMPBSA analysis for the top five C60- derivatives shows good binding energy. This study reports the interaction patterns of selected C60 derivatives and MurA enzyme towards fullerene-based drug discovery. PMID- 28729761 TI - Designing of a penta-peptide against drug resistant E. coli. AB - Drug resistant pathogens are vibrant global problem. Penicillin binding protein 5 (PBP5) plays important role in bacterial cell wall biosynthesis. Mutation in PBP5 is a well-known mechanism for development of drug resistant strain of bacteria. In this context we have designed a peptide that fits better at the ligand-binding site of mutant PBP5 compared to wild type PBP5. It is expected that the designed peptide will halt the growth of drug resistant pathogen harboring mutant variety of PBP5. We have recommended experimental validation of the above concept. PMID- 28729762 TI - Combination of bone marrow mesenchymal stem cells and cartilage fragments contribute to enhanced repair of osteochondral defects. AB - Cartilage tissue engineering using stem cells and biomaterials is considered a promising approach despite poor outcomes. We hypothesise that articular cartilage fragments provides native environmental cues to enhance stem cell differentiation. As such we evaluated the chondrogenic differentiation and repair of critical size defect in a human explant osteochondral model (OD) using bone marrow derived mesenchymal stem cells (BM-MSCs) and homogenised cartilage. BM MSCs were established from the bone-marrow plugs of patients undergoing total knee arthroplasty and characterized. Osteochondral tissue was trimmed and a central drill defect (~2mm) was made. Chondrogenic repair was evaluated by filling the OD defect area with either BM-MSCs (Group II), homogenized cartilage (Group III) or a combination of both BM-MSCs and homogenized cartilage (Group IV). OD with no added cell or tissue served as control (Group I). Samples were maintained in chondrogenic differentiation medium for 28 days. Microscopic images showed maximal OD closure in Group IV. Partial OD closure was observed in Group II and to a lesser extent in Group III. Haematoxylin-eosin staining revealed immature cartilaginous matrix in Group II and more mature matrix in Group IV. SircolTM Assay showed increased collagen deposition in both Group II and Group IV. Immunostaining for both groups revealed positive staining for type II collagen. Combining BM-MSCs and homogenised cartilage demonstrated enhanced cartilage formation and defect filling in a human ex-vivo osteochondral model. PMID- 28729763 TI - Serum and Plasma Metabolomic Biomarkers for Lung Cancer. AB - In drug invention and early disease prediction of lung cancer, metabolomic biomarker detection is very important. Mortality rate can be decreased, if cancer is predicted at the earlier stage. Recent diagnostic techniques for lung cancer are not prognosis diagnostic techniques. However, if we know the name of the metabolites, whose intensity levels are considerably changing between cancer subject and control subject, then it will be easy to early diagnosis the disease as well as to discover the drug. Therefore, in this paper we have identified the influential plasma and serum blood sample metabolites for lung cancer and also identified the biomarkers that will be helpful for early disease prediction as well as for drug invention. To identify the influential metabolites, we considered a parametric and a nonparametric test namely student's t-test as parametric and Kruskal-Wallis test as non-parametric test. We also categorized the up-regulated and down-regulated metabolites by the heatmap plot and identified the biomarkers by support vector machine (SVM) classifier and pathway analysis. From our analysis, we got 27 influential (p-value<0.05) metabolites from plasma sample and 13 influential (p-value<0.05) metabolites from serum sample. According to the importance plot through SVM classifier, pathway analysis and correlation network analysis, we declared 4 metabolites (taurine, aspertic acid, glutamine and pyruvic acid) as plasma biomarker and 3 metabolites (aspartic acid, taurine and inosine) as serum biomarker. PMID- 28729764 TI - Deciphering the Role of microRNAs in BRD4-NUT Fusion Gene Induced NUT Midline Carcinoma. AB - NUT midline carcinoma (NMC) is a very aggressive and lethal type of squamous epithelial cell cancer caused due to fusion of BRD4 and NUT genes. The gene fusion results into a new fusion protein that promotes oncogenesis. The detailed molecular mechanisms underlying the NMC are still not clear and new findings are urgently required to complement the current efforts. Abnormal microRNAs (miRNA) expression promotes tumour formation by modulating the functional expression of critical genes other than the parent genes involved in tumour cell proliferation or survival. Here, using Insilco methods, miRNA targeting the transcripts of parent genes (BRD4 and NUT) and the BRD4-NUT fusion gene were predicted. We investigated a situation, wherein abnormal miRNA expression in malignant cells could arise due to deletion and fusion of genomic regions encompassing the target site of miRNA genes. A set of 48 dysregulated miRNAs targeting the critical genes other than the parent genes (BRD4 and NUT) was identified. Functional enrichment analysis of KEGG pathways of target genes of these Ex-miRNAs implicates their role in cancer pathways. Amplification in the expression level of these miRNAs can be used for NMC diagnosis and prognosis. PMID- 28729765 TI - Meta-analysis study to evaluate the association of MTHFR C677T polymorphism with risk of ischemic stroke. AB - Ischemic stroke is a condition characterized by reduced blood supply to part of the brain, initiating the ischemic cascade, leading to dysfunction of the brain tissue in that area. It is one of the leading causes of death and disability and is estimated to cause around 5.7 million deaths worldwide. Methyl tetra hydro folate reductase (MTHFR) is a rate limiting enzyme in the methyl cycle which catalyzes the only biochemical reaction which produces 5, Methyl tetra hydro folate, the co-substrate for the re-methylation of homocystiene to produce methionine. MTFHR C677T is a common mutation of MTHFR and those homozygous for the MTFHR C677T produce a thermo-labile form of the protein with drastically reduced catalytic activity resulting in elevated plasma homocystiene levels - a common risk factor for cardiovascular diseases. However, the role of MTHFR C677T in ischemic stroke remains unclear. To evaluate this association, we carried out a meta-analysis of existing published studies, which included 72 studies involving 12390 cases and 16274 controls. The forest plot was made to evaluate the overall risk of the mutation in the etiology of Ischemic Stroke. The overall Odds- ratio of the study was found to be 1.319 for random effects model, revealing a ~32% increased risk of Ischemic stroke in the presence of MTHFR C667T mutation compared to controls. Publication bias in the study was analyzed using funnel plot which revealed that only 7 studies out of the 72 contributed to publication bias. These 7 studies were excluded and Meta-analysis was repeated for 65 studies and overall odds-ratio was 1.306, which showed that there was a 30% higher risk of Ischemic stroke in the presence of MTHFR C667T. PMID- 28729766 TI - Cancer of head and neck: a multidisciplinary approach. PMID- 28729767 TI - Glasgow prognostic score after concurrent chemoradiotherapy is a prognostic factor in advanced head and neck cancer. AB - OBJECTIVE: This study aims to evaluate the impact and potential prognostic roles of the pre- and post-treatment Glasgow prognostic score (GPS) and the change thereof in patients with advanced head and neck cancer undergoing concurrent chemoradiotherapy (CCRT). METHODS: We collected GPS and clinicopathological data of 139 stage III, IVA, and IVB head and neck cancer patients who underwent CCRT between 2008 and 2011. Their GPSs pre- and post-CCRT and the change thereof were analyzed for correlations with recurrence and survival. RESULTS: The GPS changed in 72 (51.8%) patients, with worse scores observed post-CCRT in 65 (90.3%) of the GPS changed patients. Patients in the improved GPS group showed a tendency toward better survival. From the multivariate analysis, the post-CCRT GPS level was an independent prognostic factor in addition to tumor stage. CONCLUSIONS: After CCRT, a high GPS was revealed to be an important predictor of survival for advanced head and neck cancer. PMID- 28729768 TI - Neck observation versus elective neck dissection in management of clinical T1/2N0 oral squamous cell carcinoma: a retrospective study of 232 patients. AB - OBJECTIVE: The management of early-stage (cT1/2N0) oral squamous cell carcinoma (OSCC) remains a controversial issue. The aim of this study was to compare the clinical outcomes of neck observation (OBS) and elective neck dissection (END) in treating patients with cT1/2N0 OSCC. METHODS: A total of 232 patients with cT1/2N0 OSCC were included in this retrospective study. Of these patients, 181 were treated with END and 51 with OBS. The survival curves of 5-year overall survival (OS), disease-specific survival (DSS), and recurrence-free survival (RFS) rates were plotted using the Kaplan-Meier method for each group, and compared using the Log-rank test. RESULTS: There was no significant difference in 5-year OS and DSS rates between END and OBS groups (OS: 89.0% vs. 88.2%, P=0.906; DSS: 92.3% vs. 92.2%, P=0.998). However, the END group had a higher 5-year RFS rate than the OBS group (90.1% vs. 76.5%, P=0.009). Patients with occult metastases in OBS group (7/51) had similar 5-year OS rate (57.1% vs. 64.1%, P=0.839) and DSS rate (71.4% vs. 74.4%, P=0.982) to those in END group (39/181). In the regional recurrence patients, the 5-year OS rate (57.1% vs. 11.1%, P=0.011) and DSS rate (71.4% vs. 22.2%, P=0.022) in OBS group (7/51) were higher than those in END group (9/181). CONCLUSIONS: The results indicated that OBS policy could obtain the same 5-year OS and DSS as END. Under close follow-up, OBS policy may be an available treatment option for patients with clinical T1/2N0 OSCC. PMID- 28729769 TI - Recurrence and cancerization of ameloblastoma: multivariate analysis of 87 recurrent craniofacial ameloblastoma to assess risk factors associated with early recurrence and secondary ameloblastic carcinoma. AB - OBJECTIVE: The recurrence and progression of ameloblastoma are unpredictable. Therefore, we examined the influence of clinical factors on recurrence time and analyzed the clinical factors associated with early recurrence and cancerization. We then developed a staging system to predict early recurrence and cancerization. METHODS: All of the primary craniofacial ameloblastoma patients treated in Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine were recorded. There were 87 recurrent cases used to create a staging system and tested in a Cox regression analysis for risk factors associated with early recurrence or cancerization following surgery. RESULTS: There were 890 craniofacial ameloblastoma patients, and 72 cases had recurrence. There were also 15 cases with cancerous recurrence. The overall recurrence rate was 9.78%, and the cancer rate was 1.69%. The primary cases were classified into the following 3 stages based on clinicopathological features: stage I, the maximum tumor diameter <=6 cm; stage II, the maximum diameter of tumor >6 cm or tumor invasion to the maxilla sinus/orbital floor/soft tissue; and stage III, tumor invasion of the skull base or metastasis into regional lymph nodes. When the method of surgery was controlled by partial correlation, the staging had significance with recurrence time (P=0.004). The Cox analysis showed the tumor stage was correlated with recurrence time (P=0.027) and cancerization time (P=0.002). However, the surgical method did not influence the recurrence time when adjusted for cofounding variables. CONCLUSIONS: Tumor larger than 6 cm and invasion to soft tissues or adjacent anatomical structures are associated with early recurrence. This staging system can be used to predict the risk factors of early recurrence and cancerization in ameloblastoma patients. PMID- 28729770 TI - Enumeration and molecular characterization of circulating tumor cell using an in vivo capture system in squamous cell carcinoma of head and neck. AB - OBJECTIVE: Detection rate and isolation yield of circulating tumor cell (CTC) are low in squamous cell carcinoma of head and neck (SCCHN) with in vitro approaches due to limited sample volumes. In this study, we applied the CellCollector to capture CTC in vivo from peripheral blood. METHODS: In total, the study included 22 cases with 37 times of detection. All of the patients were newly diagnosed with locally advanced or metastatic SCCHN, including laryngocarcinoma (40.9%, 9/22) and hypopharyngeal carcinoma (59.1%, 13/22). All patients received CTC analysis before treatment. Three patients received induction chemotherapy. Sixteen patients received surgical therapy, of which 13 patients received postoperative detection. Two patients received both induction chemotherapy and surgery treatment. Patients underwent two successive CellCollector applications 24 h before and 7 d after surgical therapy. Nine healthy volunteers were enrolled as the control group. Epidermal growth factor receptor variant type III (EGFRVIII) expression was analyzed with fluorescent dye labeled antibody. RESULTS: With CellCollector isolation, 72.7% (16/22) of the patients were positive for >=1 CTC (CTC; range, 1-17 cells) before treatments and 46.7% (7/15) of patients were CTC positive for >=1 CTC (CTC; range, 1-29 cells) after surgical therapy. Moreover, the detection rate of CellCollector (82.4%, 14/17; CTC count range, 0-17) in advanced SCCHN (stage III-IV) was much higher than that in early stages (stage I-II, 40.0%, 2/5; CTC count range, 0-2) (P<0.05). EGFRVIII expression of CTC was also analyzed with fluorescence staining. One CTCEGFRVIII positive patient was detected from six CTC-positive patients, and the positive expression of EGFRVIII was also found in the tumor tissue of this patient. CONCLUSIONS: In vivo detection of CTCs had high sensitivity in SCCHN, which might improve CTC application in clinic. PMID- 28729771 TI - Microarray gene expression analysis of chemosensitivity for docetaxel, cisplatin and 5-fluorouracil (TPF) combined chemotherapeutic regimen in hypopharyngeal squamous cell carcinoma. AB - OBJECTIVE: To screen out a set of candidate genes which could help to determine whether patients with hypopharyngeal squamous cell carcinoma (HSCC) could benefit from docetaxel, cisplatin and 5-fluorouracil (TPF) induction chemotherapy. METHODS: Gene-expression profiles in 12 TPF-sensitive patients were compared to 9 resistant controls by microarray analysis. Subsequently, expression levels of potential biomarkers in chemosensitive cell line FaDu after TPF treatment were observed by quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: Through microarray analysis, 1,579 differentially expressed genes were identified, of which 815 were up-regulated in TPF chemotherapy-responsive tissues whereas 764 were down-regulated. Gene ontology (GO) analysis suggested these genes participating in physiological processes including transcription and its regulation, cellular signal transduction and metabolic process. Additionally, Kyoto Encyclopedia of Genes and Genomes (KEGG) database revealed that MAPK and Jat/STAT signaling pathways occupied important roles in TPF chemotherapeutic sensitivity. Moreover, in vitro cell culture experiments revealed the expression alternations of IL-6, MAPK14, JUN, CDK5 and CAMK2A exposed to TPF treatment by qRT-PCR, whilst providing an insight into the mechanism underlying TPF chemotherapeutic response in HSCC. CONCLUSIONS: These results provided a battery of genes related to TPF chemotherapeutic sensitivity and might act as molecular targets in HSCC treatment. Moreover, these candidate biomarkers could contribute to HSCC individualized treatment. PMID- 28729772 TI - Serial stimulated thyroglobulin measurements are more specific for detecting distant metastatic differentiated thyroid cancer before radioiodine therapy. AB - OBJECTIVE: Preablative stimulated thyroglobulin (ps-Tg) has the potential to be used in identifying distant metastatic differentiated thyroid carcinoma (DM-DTC), but its single level can be affected by remnant thyroid tissue and thyrotropin (TSH). The objective of this retrospective study was to evaluate the value of serial ps-Tg measurements in identifying DM-DTC specifically. METHODS: A total of 317 DTC patients with serial measurements of ps-Tg, TSH and anti-Tg antibody were divided into M1 (n=72) and M0 (n=245) according to the presence of distant metastasis (DM) or not. The initial ps-Tg measurement, with a corresponding TSH exceeding 30 MUIU/mL, was marked as Tg1, and ps-Tg measured right before radioactive iodine (RAI) therapy was defined as Tg2, with a median interval of 8 days. DeltaTg denotes Tg2-Tg1, and DeltaTSH denotes TSH2-TSH1. Tg1, Tg2, DeltaTg, and DeltaTg/DeltaTSH were tested for efficacy in identifying DM-DTC using receiver operating characteristic (ROC) curve analysis, and further compared with chest computed tomography (CT) and posttreatment whole-body RAI scan (RxWBS). RESULTS: Compared with single ps-Tg measurement (Tg1 or Tg2), both DeltaTg and DeltaTg/DeltaTSH were more narrowly distributed around zero in the M0 group, which made their distribution in the M1 group more distinguished in a relatively dispersed way. DeltaTg/DeltaTSH manifested a higher accuracy (88.64%) and specificity (90.20%) in identifying DM-DTC than Tg1 or Tg2 measurements, with a much higher specificity than chest CT (90.20% vs. 66.00%) and a much higher sensitivity than RxWBS (83.33% vs. 61.11%). CONCLUSIONS: Serial ps-Tg measurements even over as short an interval as 8 days hold incremental value in identifying DM-DTC. DeltaTg/DeltaTSH is a specific early biochemical marker for DM-DTC. PMID- 28729773 TI - Is new American Thyroid Association risk classification for hereditary medullary thyroid carcinoma applicable to Chinese patients? A single-center study. AB - OBJECTIVE: The American Thyroid Association (ATA) proposed a new risk classification for hereditary medullary thyroid carcinoma (MTC) in 2015. This study aimed to assess whether the new guidelines are suitable for the Chinese population, and reported our experience on prophylactic thyroidectomy. METHODS: A total of 73 patients from 22 families were screened as rearranged during transfection (RET) mutation carriers from 2010 to 2016 in Cancer Hospital, Chinese Academy of Medical Science; the medical history for each patient was collected. Based on the initial treatment, we identified the risk factors for poor prognosis by univariate and multivariate logistic regression. Then, 4 RET mutation carriers were enrolled for prophylactic thyroidectomy, and their pathological data and follow-up outcomes were recorded. RESULTS: In univariate and multivariate logistic regression analyses, age at initial surgery and risk classification were significant risk factors for stage III/IV hereditary MTC at initial diagnosis. The likelihood was increased by 11.6% per year of age at initial surgery [95% confidence interval (95% CI), 1.040-1.198; P=0.002). It was 7.888 times more likely to have III/IV stage disease for ATA highest risk patients, compared to ATA moderate risk individuals (95% CI, 1.607-38.717; P=0.003). Postoperative pathological results showed all 4 multiple endocrine neoplasia type 2A (MEN2A) patients had C-cell hyperplasia (CCH); multifocal malignancies were detected in 3 of them. All 4 patients were cured biochemically, and none developed permanent hypoparathyroidism. CONCLUSIONS: In Chinese individuals, hereditary MTC aggressiveness is in line with the new ATA risk classification. Germline RET gene mutation carriers should undergo prophylactic thyroidectomy according to basal serum calcitonin levels. PMID- 28729774 TI - Clinical applications of free medial tibial flap with posterior tibial artery for head and neck reconstruction after tumor resection. AB - Tumor resection causes damage in the head and neck which creates problems in swallowing, chewing, articulation, and vision, all of which seriously affect patients' quality of life. In this work, we evaluated the application of a free medial tibial flap in reconstruction of head and neck defects after tumor resection. We discussed the anatomy, surgical technique, and the advantages and disadvantages of the flap. We found several benefits for the flap, such as, it is especially effective for the defects that require thin-layer epithelium to cover or the separated soft tissue defect; a two-team approach can be used because the donor site is far away from the head and neck; and the flap is easy to integrate because of the subcutaneous fat layer of the free medial tibial flap is thin and the flap is soft. Thus, the medial tibial flap could replace the forearm flap for certain applications. PMID- 28729776 TI - Expenditure of hospital care on cancer in China, from 2011 to 2015. AB - OBJECTIVE: A solid understanding of levels and trends of spending on cancer is important to evaluate whether our healthcare resources were wisely spent and to prioritize future resources for cancer treatment and prevention. However, studies on economic burden of cancers in China are scant and the results are inconsistent. METHODS: The Chinese hospital information database and nearly 350 million inpatient medical record data were used. As the ratios of cancer inpatient payments to total inpatient payments were mainly influenced by the grades and sites of hospitals, the estimates of payments of cancer inpatients in this study were stratified by hospital grades and provinces. Only the payments of cancer inpatients happened in grade 2, grade 3 and specialized cancer hospitals were included in the analyses. The total medical payments of cancers in China were estimated based on the ratios of outpatient payments to inpatient payments in specialized cancer hospitals. RESULTS: From 2011 to 2015, the payments of cancer inpatients in China have increased by 84.1% and the total inpatient payments reached 177.1 billion RMB in 2015, accounting for 4.3% of the total health expenditure in China. Based on the ratio of outpatient payments to inpatient payments, the total payments on cancer treatments in China were estimated to be 221.4 billion RMB in 2015. Among different cancer types, the highest payments were the treatment of trachea, bronchus and lung cancer. The major cancer inpatient payments (67.1% in 2015) spent in grade 3 general hospitals and this ratio increased continually from 2011 to 2015. The expenditure of cancer treatments also varies by region with the major expenditure in the eastern region of China. CONCLUSIONS: This study estimated the total payments of cancer treatments in China and analyzed how the money was spent on cancer treatments in the recent 5 years, which would provide information for decision makings on the allocation of resources to service provisioning, prevention strategies, research funding, and assessing whether the economic burden of cancer is affordable to the governments. PMID- 28729777 TI - Is there an optimal time to initiate adjuvant chemotherapy to predict benefit of survival in non-small cell lung cancer? AB - OBJECTIVE: Adjuvant chemotherapy (AC) after curative resection is known to improve the survival of patients with non-small cell lung cancer (NSCLC); however, few studies have reported the correlation between the time to initiation of AC (TTAC) and survival in NSCLC patients. METHODS: The clinical data of 925 NSCLC patients who received curative resection and post-operative AC at the Cancer Hospital of Chinese Academy of Medical Sciences between 2003 and 2013 were retrospectively analyzed. TTAC was measured from the date of surgery to the initiation of AC. Disease-free survival (DFS) was defined as the duration from surgery to the time of tumor recurrence or last follow-up evaluation. The optimal cut-off value of TTAC was determined by maximally selected log-rank statistics. The DFS curve was estimated using the Kaplan-Meier method, and the Cox proportional hazards regression model was used to identify risk factors independently associated with DFS. Propensity score matching (PSM) was performed for survival analysis using the match data. RESULTS: The optimal discriminating cut-off value of TTAC was set at d 35 after curative resection based on which the patients were assigned into two groups: group A (<=35 d) and group B (>35 d). There was no significant difference in the DFS between the two groups (P=0.246), indicating that the TTAC is not an independent prognostic factor for DFS. A further comparison continued to show no significant difference in the DFS among 258 PSM pairs (P=0.283). CONCLUSIONS: There was no significant correlation between the TTAC and DFS in NSCLC patients. Studies with larger samples are needed to further verify this conclusion. PMID- 28729775 TI - Role of tumor microenvironment in triple-negative breast cancer and its prognostic significance. AB - Breast cancer has been shown to live in the tumor microenvironment, which consists of not only breast cancer cells themselves but also a significant amount of pathophysiologically altered surrounding stroma and cells. Diverse components of the breast cancer microenvironment, such as suppressive immune cells, re programmed fibroblast cells, altered extracellular matrix (ECM) and certain soluble factors, synergistically impede an effective anti-tumor response and promote breast cancer progression and metastasis. Among these components, stromal cells in the breast cancer microenvironment are characterized by molecular alterations and aberrant signaling pathways, whereas the ECM features biochemical and biomechanical changes. However, triple-negative breast cancer (TNBC), the most aggressive subtype of this disease that lacks effective therapies available for other subtypes, is considered to feature a unique microenvironment distinct from that of other subtypes, especially compared to Luminal A subtype. Because these changes are now considered to significantly impact breast cancer development and progression, these unique alterations may serve as promising prognostic factors of clinical outcome or potential therapeutic targets for the treatment of TNBC. In this review, we focus on the composition of the TNBC microenvironment, concomitant distinct biological alteration, specific interplay between various cell types and TNBC cells, and the prognostic implications of these findings. PMID- 28729778 TI - Effect of contrast-enhanced ultrasound on differential diagnosis of intrahepatic cholangiocarcinoma and arterial phase enhanced hepatic inflammatory lesions. AB - OBJECTIVE: To investigate differential diagnosis between intrahepatic cholangiocarcinoma (ICC) and arterial phase enhanced hepatic inflammatory lesions in patients without liver cirrhosis using contrast-enhanced ultrasound (CEUS). METHODS: ICC and hepatic inflammatory lesions cases with CEUS and pathological diagnosis between Sep 2013 and Oct 2016 were investigated retrospectively. Imaging features of conventional ultrasound and CEUS were analyzed. The parameters of time intensity curve (TIC), including the arrival time, peak intensity (PI) in the lesions, the starting time for washout, and the intensity difference at 3 min (DeltaI3) after contrast agent infection between the lesion and the liver parenchyma, were compared between ICC and hepatic inflammatory lesions. RESULTS: Twenty-five ICC and fifteen inflammatory patients were included in this study. Seventeen ICC (68.0%) and two inflammatory cases (13.3%) showed bile duct dilatation on conventional ultrasound. Using CEUS, three ICC cases (12.0%) were misdiagnosed as inflammatory lesions and three inflammatory lesions (20.0%) as ICC; two ICC (8.0%) and one inflammatory case (6.7%) could not be made definite diagnosis. Washout started at 34.5+/-3.5 s and 61.5+/-12.9 s for ICC and inflammatory lesions respectively (P<0.001). The intensity difference between lesion and liver parenchyma at 3 min after contrast agent injection was 10.8+/ 3.1 dB in ICC and 4.2+/-2.3 dB in inflammatory group (P<0.001). The sensitivity and specificity differentiating ICC and inflammatory lesions were 76% and 87% if the cut-off value of the intensity difference was 7.7 dB. CONCLUSIONS: Combined with TIC analysis, and particularly with the characteristic of the early-starting and obvious washout in ICC, CEUS can be useful in differential diagnosis between hepatic inflammatory lesions and ICC. PMID- 28729779 TI - Deep Learning Models of the Retinal Response to Natural Scenes. AB - A central challenge in sensory neuroscience is to understand neural computations and circuit mechanisms that underlie the encoding of ethologically relevant, natural stimuli. In multilayered neural circuits, nonlinear processes such as synaptic transmission and spiking dynamics present a significant obstacle to the creation of accurate computational models of responses to natural stimuli. Here we demonstrate that deep convolutional neural networks (CNNs) capture retinal responses to natural scenes nearly to within the variability of a cell's response, and are markedly more accurate than linear-nonlinear (LN) models and Generalized Linear Models (GLMs). Moreover, we find two additional surprising properties of CNNs: they are less susceptible to overfitting than their LN counterparts when trained on small amounts of data, and generalize better when tested on stimuli drawn from a different distribution (e.g. between natural scenes and white noise). An examination of the learned CNNs reveals several properties. First, a richer set of feature maps is necessary for predicting the responses to natural scenes compared to white noise. Second, temporally precise responses to slowly varying inputs originate from feedforward inhibition, similar to known retinal mechanisms. Third, the injection of latent noise sources in intermediate layers enables our model to capture the sub-Poisson spiking variability observed in retinal ganglion cells. Fourth, augmenting our CNNs with recurrent lateral connections enables them to capture contrast adaptation as an emergent property of accurately describing retinal responses to natural scenes. These methods can be readily generalized to other sensory modalities and stimulus ensembles. Overall, this work demonstrates that CNNs not only accurately capture sensory circuit responses to natural scenes, but also can yield information about the circuit's internal structure and function. PMID- 28729780 TI - Best Practices for Robotic Surgery Programs. AB - BACKGROUND AND OBJECTIVES: Robotic surgical programs are increasing in number. Efficient methods by which to monitor and evaluate robotic surgery teams are needed. METHODS: Best practices for an academic university medical center were created and instituted in 2009 and continue to the present. These practices have led to programmatic development that has resulted in a process that effectively monitors leadership team members; attending, resident, fellow, and staff training; credentialing; safety metrics; efficiency; and case volume recommendations. RESULTS: Guidelines for hospitals and robotic directors that can be applied to one's own robotic surgical services are included with examples of management of all aspects of a multispecialty robotic surgery program. CONCLUSION: The use of these best practices will ensure a robotic surgery program that is successful and well positioned for a safe and productive environment for current clinical practice. PMID- 28729781 TI - Advanced Hysteroscopic Surgery: Quality Assurance in Teaching Hospitals. AB - Advanced hysteroscopic surgery (AHS) is a vitally important technique in the armamentarium for the management of many day-to-day clinical problems, such as menorrhagia, surgical excision of uterine myomata and septa in the management of female infertility, hysteroscopic excision of chronically retained products of conception (placenta accreta), and surgical removal of intramural ectopic pregnancy. In today's climate of accountability, it is necessary that gynecologists take a more active role in assuring the quality of their work. In this article, we discuss the quality assurance system from the point of view of the surgical audit meetings in some of the major teaching hospitals affiliated with the University of Queensland (Brisbane, Queensland, Australia). PMID- 28729782 TI - Holding Strength of Suture: An Experimental Study Using Porcine Kidney. AB - BACKGROUND AND OBJECTIVES: The search for the perfect suture is going on and has resulted in the introduction of many different suture types into the market. The purpose of this study is to investigate the holding strength (HS) of different sutures in the renal parenchyma in an experimental study on pig kidneys. METHODS: The HS that caused sliding of the suture was investigated in 5 adult porcine kidneys with 7 suture variants. HS-caused tearing of the kidney was investigated with 3 suture types on 5 kidneys. The third investigation, performed on 5 porcine kidneys, was a comparison between 2-0 Vicryl sutures with a Hem-o-lok clip and 2 0 V-Loc sutures with 1 knot. The Friedman test was used to compare the groups. Post hoc analysis was performed with the Wilcoxon signed ranks test (Bonferroni corrected). RESULTS: For HS causing sliding of the suture, the mean HSs of the tested sutures were as follows: 2-0 Vicryl with 1 Hem-o-lok clip, 3.26 +/- 0.55 N; 2-0 Vicryl with 2 Hem-o-lok clips, 4.1 +/- 0.46 N; 2-0 V-Loc, 2.52 +/- 0.63 N; 4-0 V-Loc, 1.62 +/- 0.17 N; 0 Quill, 0.48 +/- 0.16 N; 2-0 Vicryl with 1 Hem-o-lok clip (halfway), 3.62 +/- 0.66 N; and 2-0 V-Loc (halfway), 1.02 +/- 0.40 N. For HS causing tearing of the kidney, the mean value of 2-way 2-0 Vicryl (Hem-o-lok in the middle) was 13.28 +/- 1.38 N, 2-0 2-way Vicryl (Hem-o-lok at the end) was 5.86 +/- 0.75 N, and 2-way 2-0 V-Loc was 3.98 +/- 1.60 N. For the third group, the difference between the 2 suture variants was not statistically significant. CONCLUSION: Our study revealed that 2-0 Vicryl (polyglactin 910) sutures with 2 Hem-o-lok clips had the maximum HS in renal parenchyma when compared with other sutures. PMID- 28729783 TI - Cytotoxic evaluation of a new ceramic-based root canal sealer on human fibroblasts. AB - OBJECTIVES: The purpose of this study was to evaluate the cytotoxicity of a new bioceramic-based root canal sealer (BioMM) by direct and indirect contact with human fibroblasts and to compare it with a zinc oxide-eugenol sealer, the Pulp Canal Sealer-extended working time (PCS-EWT). MATERIALS AND METHODS: Cell viability was assessed through direct and indirect contact between human fibroblasts and sealer. Direct contact was performed at 24 h, whereas the indirect contact was performed at 24 and 48 h at different concentrations: 100%, 50%, and 25%. After direct contact, 3-4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide assay was used and the optical density was measured by a spectrophotometer. Giemsa stain was also performed for a qualitative evaluation of the cells. STATISTICAL ANALYSIS USED: Shapiro-Wilk test was used to verify the normality of distribution of the variable. Data were analyzed by analysis of variance and Tukey tests using SPSS for Windows software 18.0. The significance level used was P < 0.05. RESULTS: Direct contact showed a significantly higher cell viability with BioMM as compared to PCS-EWT (P = 0.002). Cell viability at 24 h was significantly higher with BioMM compared to PCS-EWT for the concentrations of 50% (P = 0.004) and 25% (P = 0.003), whereas no significant difference was noted at 100% (P = 0.141). Cell viability at 48 h was significantly higher with BioMM as compared to PCS-EWT at 25% (P = 0.007). No significant difference was observed at 100% (P = 0.484) and 50% (P = 0.185). CONCLUSION: BioMM may be considered minimally cytotoxic if accidentally extruded into the periapical tissues. PMID- 28729784 TI - Discoloration of different esthetic restorative materials: A spectrophotometric evaluation. AB - OBJECTIVE: A crucial property of esthetic restorative materials is their long term color stability. The aim of this in vitro study was to evaluate the color stability of esthetic restorative materials (one microfilled flowable composite, one nanofilled composite, one nanoybrid composite, one microfilled composite, and one nanoybrid ormocer-based composite) after surface roughening with cola and exposure to different staining solutions (coffee and red wine). MATERIALS AND METHODS: All materials were polymerized into silicone rubber rings (2 mm * 6 mm * 8 mm) to obtain 150 specimens identical in size. Seventy-five specimens of Group A were first exposed to cola for 24 h, and then samples were immersed in coffee or red wine over a 28-day test period. A colorimetric evaluation, according to the CIE L*a*b* system, was performed at 7, 14, 21, 28 days. Shapiro-Wilk test and Kruskal-Wallis analysis of variance were applied to assess significant differences among restorative materials. Means were compared with Scheffe's multiple comparison test at the 0.05 level of significance. RESULTS: Specimens of Group A showed higher variations when compared with Group B's specimens (P < 0.05). After 28 days, the immersion protocols caused a clinically perceivable color change for all materials tested (P < 0.05). CeramX Universal and Admira Fusion showed the lowest DeltaE variations (P < 0.05). CONCLUSIONS: Staining beverages caused significant discolorations for all the materials tested. The first exposure to cola enhanced the subsequent staining with coffee or red wine. Nanohybrid composites reported the lowest color variations. PMID- 28729785 TI - Evaluation of dentinal defects during root canal preparation using thermomechanically processed nickel-titanium files. AB - OBJECTIVE: The aim of this study was to compare the incidence of root cracks after root canal instrumentation with thermomechanically processed nickel titanium (Ni-Ti) files with different instrumentation kinematics. MATERIALS AND METHODS: A total of 150 extracted mandibular premolars with mature apices and straight root canals were divided into five groups and used in this study. In Group 1, 30 teeth were prepared using hand K-files and assigned to control group, Group 2 was instrumented using K3XF Rotary files (SybronEndo, Glendora, CA, USA) with continuous rotary motion. The teeth in Group 3 were instrumented by ProTaper Next (Dentsply Maillefer, Ballaigues, Switzerland) rotary files which make asymmetric rotary motion, In Group 4, teeth were instrumented by RECIPROC (VDW, Munich, Germany) with reciprocation motion and in Group 5, teeth were instrumented by Twisted File (TF) Adaptive (SybronEndo, Orange, CA, USA) files that use combination of continuous rotation and reciprocation motion (n = 30/per group). All the roots were horizontally sectioned 3, 6, and 9 mm from the apex with a low speed saw under water cooling. Then, the slices were examined through a stereomicroscope to determine the presence of dentinal microcracks. RESULTS: For the apical (3-mm) and coronal (9-mm) sections, the ProTaper Next and TF Adaptive produced significantly more cracks than the hand files, RECIPROC, and K3XF (P < 0.05). There was no significant difference between the experimental groups and control group at the 6-mm level (P > 0.05). CONCLUSIONS: Within the limitations of this in vitro study, all thermal-treated Ni-Ti instruments and hand files caused microcracks in root canal dentin. PMID- 28729787 TI - Patterns of dental caries among school children assessed using Caries Assessment Spectrum and Treatment tool. AB - OBJECTIVE: The present study aimed to assess and monitor patterns of dental caries among primary and permanent molars using Caries Assessment Spectrum and Treatment (CAST) index and to evaluate integration of CAST tool into patient health information (PHI) system of a Teaching Dental Hospital. MATERIALS AND METHODS: Dental records of n = 348 children, aged 7-9-years, attending University Dental Hospital Sharjah, for routine checkup and treatment as part of School Dental Program were assessed and translated into CAST codes. Dental caries prevalence for the second primary and first permanent molars were recorded. Spearman's correlation coefficient was used to assess the correlation of the status between primary and permanent molar. RESULTS: CAST codes 0-2 were observed only in about 3% of primary and almost 5% in permanent dentition. The prevalence of children with diseased first permanent molar (codes 4-7) was almost 67%, while it was over 70% in second primary molars. A strong correlations were observed in the status between second primary and first permanent molars in the lower jaw on both right and left sides, r was 0.694 and 0.643 (P = 0.001), respectively. In the upper jaw, both right and left second primary molars revealed moderate correlation r = 0.435 (P <= 0.05) between disease stages with their neighboring permanent first molars. The unweighted kappa value for the intraexaminer reliability was 0.97 for second primary and 0.95 for first permanent molars. CONCLUSION: Our study recommends the integration of CAST tool in the PHI system where a simple numerical value can express clinical progress, overcome interruptions of treatment, and ensures continuity of patient care in teaching hospitals. PMID- 28729786 TI - Association of oral health behavior and the use of dental services with oral health literacy among adults in Tehran, Iran. AB - OBJECTIVE: To assess the association of oral health behavior (OHB) and the use of dental services with oral health literacy (OHL) among Iranian adults. METHODS: This was a cross-sectional population study of a random sample of 1031 adults aged 18-65 in Tehran, Iran. We collected data on tooth brushing frequency, the consumption of sugary snacks and beverages, and time since last dental visit. To measure OHL, we used a validated OHL adults' questionnaire (OHL-AQ). In addition to descriptive analysis, we used multiple logistic regression models to assess the association of OHB and the most recent dental visit with OHL while controlling for socioeconomic and demographic factors. RESULTS: The participants' mean age was 36.3 (standard deviation 12.9), and 51% were women. Of the participants, 81.3% reported brushing their teeth daily (>=1/day), 37.6% consumed sugary snacks or beverages between meals less than once daily (<1/day), and 36.8% used dental services within the past 6 months. In the adjusted models, high OHL scores significantly correlated with daily (>=1/day) tooth brushing (odds ratio [OR] = 1.97, 95% confidence interval [CI]: 1.30-2.98), the consumption of sugary snacks or beverages (<1/day between meals) (OR = 1.56, 95% CI: 1.13-2.15) and the recent use of dental services (<=6 months) (OR = 1.59, 95% CI: 1.15-2.21), respectively. CONCLUSIONS: OHL relates significantly to improved OHB and the use of dental services. Oral health promotion programs should, therefore, take into account improvements in adults' OHL, particularly in countries with developing health-care services. PMID- 28729788 TI - A comparative in vitro study on fluoride release and water sorption of different flowable esthetic restorative materials. AB - OBJECTIVES: The objective of the study was to evaluate fluoride release and water sorption of three flowable esthetic restorative materials: a giomer, a fluoride releasing resin composite, and a nonfluoridated resin composite. MATERIALS AND METHODS: Ten samples from a giomer, a fluoride releasing nano-hybrid, and a nonfluoridated nano-hybrid composite were prepared and immersed in deionized water. Fluoride measurements were done using an ion-specific electrode attached to a microprocessor-based fluoride meter after 1 day, 1 week, and 4 weeks. Another thirty samples were made and placed in desiccators. Water sorption was calculated by weighing the specimens before and after water immersion for 1 day, 1 week, and 4 weeks. Data analysis was done using two-way ANOVA, paired t-test (P < 0.05), and Pearson's correlation coefficient to calculate correlations between fluoride release and water sorption. RESULTS: The highest fluoride release was from giomer after 1 day, it was statistically significant from all other groups. Both nano-hybrid composites after 1 day showed significantly lower water sorption which was different than all the other groups. Pearson's correlation showed no significant correlations between fluoride release and water sorption. CONCLUSIONS: Fluoride release is material and time dependent, while water sorption is material dependent. PMID- 28729789 TI - In vitro evaluation of microleakage under orthodontic brackets bonded with different adhesive systems. AB - OBJECTIVE: Adhesives systems have a drawback when utilized for bonding orthodontic brackets: they shrink during photopolymerization creating microleakage. The aim of this study was to assess the stability of different orthodontic adhesives around brackets and enamel. MATERIALS AND METHODS: Sixty noncarious mandibular premolars extracted for orthodontic reasons were randomly divided into six groups of adhesives used for bonding brackets to dental enamel: NeoBond(r) Light Cure Adhesive Kit, TransbondTM Plus Self-Etching, Victory V-Slot APC PLUS(r) + TransbondTM MIP, Rely-A-Bond(r) Kit, Light Cure Orthodontic Adhesive Kit (OptiBond(r)), and TransbondTM MIP. Following bonding, all teeth underwent 2500 cycles of thermal cycling in baths ranging from 5 degrees C to 55 degrees C before being immersed in 2% methylene blue for 24 h. All samples were examined under a binocular microscope to assess the degree of microleakage at the "bracket-adhesive" and "adhesive-enamel" interfaces in the gingival and occlusal regions of the bracket. RESULTS: A significant difference was found at the "occlusal bracket-adhesive" interface. The highest microleakage values were found in the occlusal region, although no significant. Microleakage was observed in all groups. CONCLUSION: Group 2 had the highest microleakage values whereas Group 6 had the lowest values. PMID- 28729790 TI - New dental implant selection criterion based on implant design. AB - OBJECTIVE: A comparative study between threaded and plain dental implant designs was performed to find out a new criterion for dental implant selection. MATERIALS AND METHODS: Several dental implant designs with a systematic increase in diameter and length were positioned in a cylindrical-shaped bone section and analyzed using finite element method. Four loading types were tested on different dental implant designs; tension of 50 N, compression of 100 N, bending of 20 N, and torque of 2 Nm, to derive design curves. RESULTS: Better stress distribution on both spongy and cortical bone was noted with an increase in dental implant diameter and length. With the increase in dental implant side area, a stress reduction in the surrounding bones was observed, where threaded dental implants showed better behavior over the plain ones. CONCLUSIONS: Increasing value of ratio between dental implant side area and its cross-sectional area reduces stresses transferred to cortical and spongy bones. The use of implants with higher ratio of side area to cross-section area, especially with weak jaw bone, is recommended. PMID- 28729791 TI - Correlation between salivary cortisol levels and dental anxiety in children of smokers and nonsmokers. AB - OBJECTIVES: The present study was undertaken to evaluate salivary cortisol levels in children of smokers and nonsmokers and thereby establishing the relationship between cortisol levels in response to anxiety in children based on their father's habit of smoking. MATERIALS AND METHODS: The study population aged between 8 and 10 years includes two groups. Group 1 is comprised 20 children of cigarette smokers and Group 2 is comprised 20 children of nonsmokers. The passive drooling technique was used to collect unstimulated saliva from the children using a sterile container. Salivary cortisol levels were evaluated using Enzyme linked Immunosorbent Assay method. The obtained data were subjected to statistical analysis using SPSS software and paired t-test. RESULTS: Higher mean salivary cortisol levels were found in children of smokers compared to children of nonsmokers and the difference between them was significant statistically (P < 0.05). Higher salivary cortisol levels were found in females compared to males and the result was significant statistically (P < 0.05). CONCLUSION: This study has proved that the smoking habit of the father has a negative influence on the anxiety levels of their children. PMID- 28729792 TI - Evaluation of accuracy of shade selection using two spectrophotometer systems: Vita Easyshade and Degudent Shadepilot. AB - OBJECTIVE: The aim of this in vitro study was to evaluate the accuracy of shade matching using two spectrophotometric devices. MATERIALS AND METHODS: Thirteen patients who require a full coverage restoration for one of their maxillary central incisors were selected while the adjacent central incisor was intact. 3 same frameworks were constructed for each tooth using computer-aided design and computer-aided manufacturing technology. Shade matching was performed using Vita Easyshade spectrophotometer, Shadepilot spectrophotometer, and Vitapan classical shade guide for the first, second, and third crown subsequently. After application, firing, and glazing of the porcelain, the color was evaluated and scored by five inspectors. RESULTS: Both spectrophotometric systems showed significantly better results than visual method (P < 0.05) while there were no significant differences between Vita Easyshade and Shadepilot spectrophotometers (P < 0.05). CONCLUSION: Spectrophotometers are a good substitute for visual color selection methods. PMID- 28729793 TI - Assessment of consistency in the dimension of gutta-percha cones of ProTaper Next and WaveOne with their corresponding number files. AB - OBJECTIVES: To compare the dimensions of gutta-percha (GP) cones of ProTaper Next (25/0.06) and WaveOne (25/0.08) in relation to their corresponding instruments of the same dimension, respectively. MATERIALS AND METHODS: Two groups of GP cones were made with 25 cones in each group. Group 1 consisted of 25 GP cones # 25/0.06 (ProTaper Next). Group 2 consisted of 25 GP cones # 25/0.08 (WaveOne). Measurements were done at D1 (1 mm short of the tip), D3 (3 mm short of the tip), and D11 (11 mm short of the tip) for GP cones of both groups and were compared with their corresponding instruments. RESULTS: Group 1 (ProTaper) 25/.06 GP points showed greater diameters than those of the corresponding instrument, which was statistically significant. Group 2 (WaveOne) 25/0.08 GP points showed greater diameters than those of the corresponding instrument which was statistically significant whereas it was nonsignificant at level D1. CONCLUSION: Diameters of both ProTaper Next and WaveOne GP cones were greater than their corresponding instruments. Hence, there are chances of under obturation with both systems. PMID- 28729794 TI - Assessment of resin-dentin interfacial morphology of two ethanol-based universal adhesives: A scanning electron microscopy study. AB - OBJECTIVE: The objective of this study was to assess the resin-dentin interfacial morphology created by two universal adhesives using scanning electron microscopy (SEM). MATERIALS AND METHODS: The occlusal surfaces of ten (n = 5) molars were reduced to expose a flat surface of dentin. Two universal adhesives, Scotchbond Universal Adhesive and Tetric N-Bond Universal, were independently applied to air dried dentin. Light-cured resin-based composite restorative materials were used to incrementally build a composite "buildup." The specimen was sectioned mesiodistally to expose the resin-dentin interface. The inner surfaces of the specimens were polished. Samples were immersed in hydrochloric acid and then rinsed using distilled water. This was followed by immersion of the samples in 1% sodium hypochlorite solution. Then, samples were thoroughly rinsing with distilled water. Dehydration of samples was performed using ascending concentration of ethyl alcohol. Prepared samples were observed SEM at magnifications *1500 and x4000. RESULTS: Both universal adhesives could penetrate dentin-forming well-defined resin tags, lateral branches as well as a uniform hybrid layer. CONCLUSIONS: Two tested universal adhesives applied in self-etch mode can infiltrate into dentin-producing high-quality interfacial morphology. Similar interfacial morphology may be due to the similarity in composition and application mode. PMID- 28729795 TI - Cone beam computed tomographic evaluation of styloid process: A retrospective study of 1000 patients. AB - OBJECTIVE: The styloid process (SP) is a bony projection, located just anterior to the stylomastoid foramen, the normal length of which is approximately 20-30 mm. The length of SP when exceeds 30 mm it is said to "elongated." The purpose of this retrospective study was to assess the prevalence of elongated SP (ESP) by cone beam computed tomography (CBCT) examination in Turkish subpopulation and its relation to gender and age. MATERIALS AND METHODS: This study analyzed CBCT of 1000 patients who were randomly selected to participate and were aged from 14 to 78 years. Any radiograph with questionable SP was excluded from the study. The apparent length and thickness of the SP were measured by two dental and maxillofacial radiologists. The ESP was classified with radiographic appearance based morphology of elongation. The data were analyzed with the IBM SPSS Statistics 20.0. RESULTS: The mean age of patients was 42.49 +/- 14.83 years. The length of SP was measured over 30 mm in 151 patients (15.1%). A total of 151 CBCT showed ESP, of which 87 (57.6%) were noticed in males and 64 (42.4%) in female patients. The length of right-sided SP ranged from 30.05 to 85.49 mm and left sided SP from 30.14 to 83.72 mm. CONCLUSION: CBCT is a valuable diagnostic imaging tool which makes accurate length measurements. It is important for the clinicians to be aware of natural variations of the SP whose clinical importance is not well understood. PMID- 28729796 TI - Effect of clasp type and pullout location on clasp retention in different environment: In vitro study. AB - OBJECTIVE: The purpose of this study was to investigate the importance of pullout location and clasp types in two different environments to dislodge the clasp. MATERIALS AND METHODS: Mandibular test models with natural premolars and molar teeth were used to test four types of clasp (each 12) (Akers, Rest plate Akers, Half and Half, and Ring clasp) with three different pullout location for each type (ring on the rest, loop on the saddle, and wax arising from both rests) in dry and natural fresh saliva environment. Each clasp was pulled out 10 times with a crosshead speed of 10 mm/min, and the force required to withdraw each was measured. STATISTICAL ANALYSIS USED: A one-way ANOVA and Tukey test were used. RESULTS: The ring on the saddle pullout location has the highest retention force while ring on the rest was the lowest. In addition, ring clasp has the highest retention force. CONCLUSION: Clasp type and pullout location had a significant effect on the retentive force. PMID- 28729797 TI - Hypochlorite solution for root canal irrigation that lacks a chlorinated odor. AB - OBJECTIVES: This is an in vitro study to develop a formulation of a hypochlorite solution for root canal irrigation that lacks a chlorinated odor. The antibacterial effect, tissue dissolution efficacy, and the cytotoxicity of the solution were assessed in cell culture and were compared with those of commercial sodium hypochlorite (NaOCl) solutions. MATERIALS AND METHODS: Trichloroisocyanuric acid (TCA) was used as the source of hypochlorite ions in solution. All required properties of the NaOCl irrigant were evaluated and compared with those of original 2.5% NaOCl solutions currently in use. RESULTS: Our results revealed that a TCA 3.5% + 1/6 Buffer-1 solution passed the short term stability test. Moreover, no odor of chlorine gas was detected by three independent observers. The hypochlorite ion content and pH were stable over an incubation period of 4 weeks. The new solution did not differ from commercial products in terms of the dissolution property on bovine pulpal tissue (P > 0.05). Moreover, the antibacterial effect of this solution on Enterococcus faecalis did not differ from that of the commercial products (P > 0.05). In addition, our biocompatibility analysis demonstrated no difference among the tested solutions (P > 0.05). CONCLUSIONS: According to the results of all properties tested, TCA 3.5% + 1/6 Buffer-1 could be considered an option for NaOCl irrigation with the benefit of no detectable chlorine odor. PMID- 28729798 TI - Evaluation of salivary flow rate and gustatory function in HIV-positive patients with or without highly active antiretroviral therapy. AB - OBJECTIVES: The aim of this study is to evaluate the salivary flow rate and gustatory changes in HIV-positive patients on highly active anti-retroviral therapy (HAART) and without HAART. We also correlated CD4 count and salivary flow rate and gustatory function in both groups. METHODS: Sample size for each group was thirty. After obtaining informed consent, we measured salivary flow rate using Schimer's method and gustatory function using four tastants (sweet, sour, bitter, and salty) of different concentrations. The readings were recorded at 0 month, 2nd, 4th, and 6th month interval. The data obtained was statistically analyzed. RESULTS: The mean salivary flow rate was decreased more in Group I as compared to Group II. The mean identification score for sweet, salty, sour, and bitter was significantly higher in Group II than Group I. The mean detection threshold score for sweet, salty, sour and bitter taste was comparatively higher in Group I than Group II. The Pearson's correlation analysis showed inverse relation between age and salivary flow rate in Group II. No significant correlation was observed in CD4 count and salivary flow rate. CONCLUSION: Along with routine oral health appraisal in seropositive patients, evaluation of salivary flow rate, and taste abnormalities should also be considered an integral part of patient assessment. PMID- 28729799 TI - Evaluation of knowledge among general dentists in treatment of traumatic injuries in primary teeth: A cross-sectional questionnaire study. AB - OBJECTIVE: The purpose of the present study was to assess the knowledge of General dentist regarding the management of dental traumatic injuries of primary teeth. MATERIALS AND METHODS: A total of 100 general dentists were selected and a validated questionnaire was distributed among the dentist to assess their knowledge on treatment strategies regarding traumatized primary teeth. STATISTICAL ANALYSIS: Data were entered into SPSS version 20.0 for percentages. The correct answers were tested in relation to the dentists' years of experience using the Chi-square test. RESULTS: Analyzing the questionnaire for knowledge, 49% of dentists answered accurately regarding avulsed primary teeth, 36% of dentists answered appropriately regarding crown and root fractures, and 55% of dentists gave appropriate answers regarding luxation injuries. Chi-square test showed a statistically significant difference only for 2 questions in relation to the dentist's years of experience (P < 0.05). CONCLUSION: There is a lack of consistency in the knowledge among general dentist regarding traumatic dental injuries of primary teeth. There is a need to create awareness and education regarding traumatic injuries of primary teeth. PMID- 28729800 TI - Dentition status and treatment needs of human immunodeficiency virus-positive patients on anti retro viral therapy in Raichur taluk, Karnataka, India: A cross sectional study. AB - OBJECTIVE: The aim of the study was to assess the dentition status and the treatment needs of the HIV-positive patients on ART for more than a year in Raichur, Karnataka. MATERIALS AND METHODS: Convenience sampling was followed. The sample size was 170. The dentition status and treatment needs of the patients were recorded as per the WHO guidelines. RESULTS: The overall prevalence of dental caries was 79.4%. Males had higher percentage of dental caries than the females, and this was found to be statistically significant. The prevalence of dental caries was higher among the participants who used finger to clean their teeth compared to the toothbrush, neem stick, and charcoal users, and this was found to be statistically significant. CONCLUSION: Higher prevalence of dental caries was observed among the study population. Most of them required some type of treatment. Patients with a low CD4 count required higher treatments than the others. PMID- 28729801 TI - Evaluation of dimensional accuracy for different complete edentulous impressions immersed in different disinfectant solutions. AB - OBJECTIVE: The aim of this study was to evaluate the effects of two different disinfectant solutions' immersion on the dimensional accuracy of different complete edentulous impressions. MATERIALS AND METHODS: A specific custom-made metallic cast template was constructed and used for making both 120 alginate and zinc oxide eugenol (ZOE) paste impressions (60 for each). Disinfectants with 1% sodium hypochlorite and 2% glutaraldehyde were used for 10 and 60 min immersion of both impressions. After immersion time, the impressions were used for constructing 120 completely edentulous master stone models and divided into different groups according to the study. An electronic caliper was used for dimensional accuracy measurements of the casts. The data were collected and statistically analyzed according to the independent paired sample t-test at statistically significant level P < 0 05. One-way ANOVA test was used to compare between significant different groups. RESULTS: There is no statistically significant difference in dimensional accuracy of alginate and ZOE paste impressions as disinfection with 1% sodium hypochlorite and 2% glutaraldehyde for 10 min and ZOE paste impressions for 60 min, where there is statistically significant difference in alginate impressions dimensional accuracy as disinfection with 1% sodium hypochlorite and 2% glutaraldehyde for 60 min. CONCLUSIONS: Possibility of ZOE impressions paste disinfected with 1% sodium hypochlorite and 2% glutaraldehyde for 10 or 60 min, not affecting on dimensional stability, while alginate impressions, only 10 min immersion in disinfectant not affecting the dimensional stability. PMID- 28729802 TI - Size discrepancies in molars and first key to optimal occlusion. AB - OBJECTIVE: The aim of this research project was to determine whether the sizes of the first molars allow clinicians to achieve the first goal of an ideal clinical outcome. MATERIAL AND METHODS: Seventy-eight sets of dental casts that have been presented to the American Board of Orthodontics were evaluated. A Boley gauge was used to measure the length from the mesiobuccal cusp to the distobuccal cusp of the maxillary first molar and the length from the mesiobuccal groove of the mandibular first molar to the occlusal embrasure between the mandibular first and second molars. These two measurements were taken on both sides of each set of dental casts for a total of four measurements per set. RESULTS: The maxillary measurements ranged from 3.6 to 6.9 mm with an average of 5.2 mm. The mandibular measurements ranged from 5.0 to 8.0 mm with an average of 6.5 mm. The data were tested for normality and found to be equally distributed. A t-test revealed significant differences in tooth sizes between maxillary and mandibular first molars on both sides. On average, the mesiodistal length measured on maxillary first molars was about 80% of that of their mandibular counterparts. Only 5 of the 78 sets of dental casts evaluated had equal maxillary and mandibular measurements on one side (either left or right), and none of them had equal measurements on both sides. CONCLUSION: Clinicians have to understand that tooth size discrepancies do exist in patients and that these discrepancies make the completion of a perfect case challenging. PMID- 28729803 TI - Anterosuperior rehabilitation with metal-free fixed prosthesis based on zirconia. AB - The loss of upper front dental elements causes functional and psychosocial problems to the affected individuals. In this case report, the treatment planning considered hard and soft tissue loss for a complex fixed partial denture (FPD) rehabilitation. The six-element, all-ceramic FPD was manufactured using a computer-aided design/computer-aided manufacturing system with zirconia framework, veneered with leucite-reinforced ceramic. Ceramic artificial gum was also produced to guarantee tooth-facial proportions as well as lip support, promoting both esthetics and phonetics. The material's mechanical properties allowed for the coupling of the esthetic and mechanical requirements, proving an alternative to the well-established metal-ceramic technology, optimizing biomimetic. One of the endodontic-treated abutment teeth required a radicular retainer with cast metal post, but because of the opacity of zirconia, the esthetics of the prosthesis was not compromised. The low silica content of high resistance ceramics such as zirconia hampers the adhesive cementation, with numerous studies advocating for different cementation protocols, with no clear scientific consensus so far. In the present case, the internal surface of the FPD was initially blasted with aluminum oxide, followed by the application of a universal adhesive system containing 10-methacryloyloxydecyl dihydrogen phosphate. Finally, cementation to the dental structure was conducted with dual cure self-adhesive resin cement. PMID- 28729804 TI - A case of tooth fracture occurred upon medicating bisphosphonate for an elderly person: Preservation therapy and responses for Stage 0 of bisphosphonate-related osteonecrosis of jaw. AB - This case report aimed to report the progress of preservation therapy and response of symptoms and signs for Stage 0 of bisphosphonate-related osteonecrosis of jaw (BRONJ). A 68-year-old female was recognized having a tooth at the left upper first molar fracture upon medicating bisphosphonate (BP) in 2007. At that time, the extraction of the tooth was an absolute contraindication. Therefore, we performed preservation therapy. We observed the symptoms and signs every month. After 5 months, swelling and redness in the entire first molar tooth were seen and fistula formed partly. Bone exposure was not seen. We administrated antibiotics immediately. As a result, symptoms disappeared. On April 10, 2009, the patient visited us as she felt a sense of incongruity in the lower left first and second molar teeth. Clinically, there were no symptoms of pain. However, we observed the radiolucent finding in about 5 mm diameter at apical position by X ray photography; we considered a possibility of Stage 0 for BRONJ. We immediately administered medicine for 5 days and the symptoms disappeared. At present, no inflammation with signs and symptoms at the upper left first molar and lower left first, second molar parts is shown. We performed preservation therapy for tooth fracture case medicating of BP. Immediate responses for inflammation and symptoms of the Stage 0 of BRONJ have led to success. Hence, dentists should perform regular clinical observation, and enough education to the patient for BRONJ is necessary. PMID- 28729805 TI - Dental treatment considerations for a pediatric patient with incontinentia pigmenti (Bloch-Sulzberger syndrome). AB - Incontinentia pigmenti (IP) is a uncommon gene disorder, heritage with X-linked dominant mode. IP patients have a characteristic dentition varying from marked hypodontia to delayed eruption and conical crowns on both dentitions. A 51/2-year old girl, whose mother and younger sister were also diagnosed with IP, has the whirling-like pigmented skin lesion over her trunk and four extremities. Four primary teeth and multiple permanent tooth germs were found to be congenital missing. Dental considerations of further treatment were discussed with her parents including the preservation of primary molars, possible interim prosthesis in mixed or permanent dentition, full mouth rehabilitation with orthodontic and prosthodontic combined treatment, and implant therapy in adulthood. Early and longitudinal involvement of pediatric dentist to deal with the dental complications of IP can not only solve the esthetic problem and oral function but also maintain the oral health of children with IP to adulthood. PMID- 28729807 TI - Observation of crack growth in a polycrystalline ferroelectric by synchrotron X ray diffraction. AB - Pre-cracked samples of unpoled, polycrystalline, soft ferroelectric lead zirconate titanate were subjected to electrical and mechanical loading whilst using synchrotron X-ray diffraction to map strain-fields. Clear evidence is found of switching around the crack tip and development of a crack-wake. A J-integral estimate based on strain-field data provided a sensitive measure of strain changes during loading. Electrical loading did not cause crack advance or crack tip switching; this provides evidence for electrically permeable crack models. There was also enhancement of electrically-driven switching in the crack-wake region. The results provide improved understanding and a resource for testing fracture models in ferroelectrics. PMID- 28729806 TI - Evidence provided for the use of oscillating instruments in restorative dentistry: A systematic review. AB - Oscillating diamond instruments are considered gentle sources for the removal of demineralized tooth hard tissues and the preparation of cavity angles and margins needed in minimally invasive dentistry. However, there is a question if literature provides enough evidence for their efficacy in restorative dentistry procedures. A literature search until May 2016 was conducted, using PubMed, Scopus, and The Cochrane Central Register of Controlled Trials databases. The quality of the studies was assessed using the recommendation of the Oxford Centre for Evidence-based Medicine. Fifty-five studies were finally included in the study. Of which, 78.2% of them were laboratory studies and only 21.8% were clinical studies. The strength of recommendation was 5 for most of them and D their grade of evidence. Bond strength of adhesives on surfaces prepared with these instruments, effective caries removal and cutting characteristics of the oscillating instruments were the main targets of the studies. Conventional diamond, steel, and chemical vapor deposition diamond tips and systems based on abrasive slurry were the oscillating tips, used in different studies. The strength of recommendation and grade of evidence of the studies were low. Although these devices seem to be useful for many clinical situations, there is a need for more well-structured evidence-based studies with more widely accepted procedures and common devices, to have more meaningful results and conclusions of higher strength. PMID- 28729808 TI - Paleoseismic study of the Kamishiro Fault on the northern segment of the Itoigawa Shizuoka Tectonic Line, Japan. AB - The Mw 6.2 (Mj 6.8) Nagano (Japan) earthquake of 22 November 2014 produced a 9.3 km long surface rupture zone with a thrust-dominated displacement of up to 1.5 m, which duplicated the pre-existing Kamishiro Fault along the Itoigawa-Shizuoka Tectonic Line (ISTL), the plate-boundary between the Eurasian and North American plates, northern Nagano Prefecture, central Japan. To characterize the activity of the seismogenic fault zone, we conducted a paleoseismic study of the Kamishiro Fault. Field investigations and trench excavations revealed that seven morphogenic paleohistorical earthquakes (E2-E8) prior to the 2014 Mw 6.2 Nagano earthquake (E1) have occurred on the Kamishiro Fault during the last ca. 6000 years. Three of these events (E2-E4) are well constrained and correspond to historical earthquakes occurring in the last ca. 1200 years. This suggests an average recurrence interval of ca. 300-400 years on the seismogenic fault of the 2014 Kamishiro earthquake in the past 1200 years. The most recent event prior to the 2014 earthquakes (E1) is E2 and the penultimate and antepenultimate faulting events are E3 and E4, respectively. The penultimate faulting event (E3) occurred during the period of AD 1800-1400 and is associated with the 1791 Mw 6.8 earthquake. The antepenultimate faulting event (E4) is inferred to have occurred during the period of ca. AD 1000-700, likely corresponding to the AD 841 Mw 6.5 earthquake. The oldest faulting event (E8) in the study area is thought to have occurred during the period of ca. 5600-6000 years. The throw rate during the early Holocene is estimated to be 1.2-3.3 mm/a (average, 2.2 mm/a) with an average amount of characteristic offset of 0.7-1.1 m produced by individual event. When compared with active intraplate faults on Honshu Island, Japan, these slip rates and recurrence interval estimated for morphogenic earthquakes on the Kamishiro Fault along the ISTL appear high and short, respectively. This indicates that present activity on this fault is closely related to seismic faulting along the plate boundary between the Eurasian and North American plates. PMID- 28729809 TI - On the rotation of teleseismic seismograms based on the receiver function technique. AB - The receiver function (RF) technique is a well-established method to investigate the crustal and upper mantle structures based on three-component seismograms of teleseismic events. In the present study, we propose a modified automatic procedure to determine the back azimuth and polarization angles of a teleseismic event based on the RF technique. The method is tested for the recording of 3 permanent and 3 temporary broadband seismic stations located in the vicinity of Poland. Additionally, the analysis of Rayleigh wave polarization is conducted to show that the new procedure is not sensitive to incorrect seismometer orientation. The synthetic modelling of RF by a modified ray-tracing method for 2.5D models beneath each seismic station down to a depth of 60 km is performed to show the effectiveness of the proposed method in the calculation of RF for a complex structure with dipping layers. PMID- 28729810 TI - The interplay of electrode- and bio-materials in a redox-cycling-based clozapine sensor. AB - We investigate gold, TiN, and platinum in combination with a chitosan-catechol based redox-cycling system (RCS) for electrochemical detection of the antipsychotic clozapine. We have previously demonstrated the RCS for detection of clozapine in serum, but challenges remain regarding low signal-to-noise ratios. This can be mitigated by selection of electrode materials with beneficial surface morphologies and/or compositions. We employ cyclic voltammetry to assess the redox current generated by clozapine, and differentiate solely surface-area-based effects from clozapine-specific ones using a standard redox couple. We find that nano- and microstructured platinum greatly amplifies the clozapine signal compared to gold (up to 1490-fold for platinum black). However, the material performs poorly in the presence of chloride ions, and RCS modification provides no further amplification. The RCS combined with atomic-layer-deposited (ALD) TiN, on the other hand, increases the signal by 7.54 times, versus 2.86 times for RCS on gold, with a 9.2-fold lower variability, indicating that the homogenous and chemically inert properties of ALD-TiN may make it an ideal electrode material. PMID- 28729811 TI - Medical Errors and Barriers to Reporting in Ten Hospitals in Southern Iran. AB - BACKGROUND: International research shows that medical errors (MEs) are a major threat to patient safety. The present study aimed to describe MEs and barriers to reporting them in Shiraz public hospitals, Iran. METHODS: A cross-sectional, retrospective study was conducted in 10 Shiraz public hospitals in the south of Iran, 2013. Using the standardised checklist of Shiraz University of Medical Sciences (referred to the Clinical Governance Department and recorded documentations) and Uribe questionnaire, we gathered the data in the hospitals. RESULTS: A total of 4379 MEs were recorded in 10 hospitals. The highest frequency (27.1%) was related to systematic errors. Besides, most of the errors had occurred in the largest hospital (54.9%), internal wards (36.3%), and morning shifts (55.0%). The results revealed a significant association between the MEs and wards and hospitals (p < 0.001). Moreover, individual and organisational factors were the barriers to reporting ME in the studied hospitals. Also, a significant correlation was observed between the ME reporting barriers and the participants' job experiences (p < 0.001). CONCLUSION: The medical errors were highly frequent in the studied hospitals especially in the larger hospitals, morning shift and in the nursing practice. Moreover, individual and organisational factors were considered as the barriers to reporting MEs. PMID- 28729812 TI - What are interesterified fats and should we be worried about them in our diet? AB - Interesterified (IE) fats are used in a wide range of food products and were introduced as a replacement for trans fats, which are known to be detrimental to cardiovascular health. However, the effects of interesterification on metabolism and subsequent effects on cardiovascular health are not understood and previous studies have seldom investigated industrially-relevant IE fats. No legislation currently exists regarding the labelling of IE fats in food products and therefore estimates of average consumption rates in the UK population are currently unavailable. In order to meet the urgent need for a systematic investigation of the health effects of consumer-relevant IE fats, it is essential to estimate current IE fat intakes and to investigate biological mechanisms that might mediate acute and chronic cardiometabolic effects of commercially relevant IE fats. PMID- 28729813 TI - Novel Design Integrating a Microwave Applicator into a Crystallizer for Rapid Temperature Cycling. A Direct Nucleation Control Study. AB - The control of nucleation in crystallization processes is a challenging task due to the often lacking knowledge on the process kinetics. Inflexible (predetermined) control strategies fail to grow the nucleated crystals to the desired quality because of the variability in the process conditions, disturbances, and the stochastic nature of crystal nucleation. Previously, the concept of microwave assisted direct nucleation control (DNC) was demonstrated in a laboratory setup to control the crystal size distribution in a batch crystallization process by manipulating the number of particles in the system. Rapid temperature cycling was used to manipulate the super(under)saturation and hence the number of crystals. The rapid heating response achieved with the microwave heating improved the DNC control efficiency, resulting in halving of the batch time. As an extension, this work presents a novel design in which the microwave applicator is integrated in the crystallizer, hence avoiding the external loop though the microwaves oven. DNC implemented in the 4 L unseeded crystallizer, at various count set points, resulted in strong efficiency enhancement of DNC, when compared to the performance with a slow responding system. The demonstrated crystallizer design is a basis for extending the enhanced process control opportunity to other applications. PMID- 28729814 TI - Who Gets Needed Mental Health Care? Use of Mental Health Services among Adults with Mental Health Need in California. AB - BACKGROUND: Timely and appropriate treatment could help reduce the burden of mental illness. PURPOSE: This study describes mental health services use among Californians with mental health need, highlights underserved populations, and discusses policy opportunities. METHODS: Four years of California Health Interview Survey data (2011, 2012, 2013, 2014) were pooled and weighted to the 2013 population to estimate mental health need and unmet need (n=82,706). Adults with mental health need had "unmet need" if they did not use prescription medication and did not have at least four or more mental health visits in the past year. Multivariable logistic regression analysis was performed to predict the probability adults with mental health need did not receive past-year treatment (n=5,315). RESULTS: Seventy-seven percent of Californians with mental health need received no or inadequate mental health treatment in 2013. Men, Latinos, Asians, young people, older adults, people with less education, uninsured adults, and individuals with limited English proficiency were significantly more likely to have unmet need. Cost of treatment and mental health stigma were common reasons for lack of care. CONCLUSION: Unmet mental health need is predominant in California. Policy recommendations include continued expansion of mental health coverage, early identification, and ensuring that treatment is culturally and linguistically appropriate. PMID- 28729815 TI - SYMPOSIUM REPORT: An Evidence-Based Approach to IBS and CIC: Applying New Advances to Daily Practice: A Review of an Adjunct Clinical Symposium of the American College of Gastroenterology Meeting October 16, 2016 * Las Vegas, Nevada. AB - Many nonpharmacologic and pharmacologic therapies are available to manage irritable bowel syndrome (IBS) and chronic idiopathic constipation (CIC). The American College of Gastroenterology (ACG) regularly publishes reviews on IBS and CIC therapies. The most recent of these reviews was published by the ACG Task Force on the Management of Functional Bowel Disorders in 2014. The key objective of this review was to evaluate the efficacy of therapies for IBS or CIC compared with placebo or no treatment in randomized controlled trials. Evidence-based approaches to managing diarrhea-predominant IBS include dietary measures, such as a diet low in gluten and fermentable oligo-, di-, and monosaccharides and polyols (FODMAPs); loperamide; antispasmodics; peppermint oil; probiotics; tricyclic antidepressants; alosetron; eluxadoline, and rifaximin. Evidence-based approaches to managing constipation-predominant IBS and CIC include fiber, stimulant laxatives, polyethylene glycol, selective serotonin reuptake inhibitors, lubiprostone, and guanylate cyclase agonists. With the growing evidence base for IBS and CIC therapies, it has become increasingly important for clinicians to assess the quality of evidence and understand how to apply it to the care of individual patients. PMID- 28729816 TI - Toxicity of Alexandrium lusitanicum to gastropod larvae is not caused by paralytic-shellfish-poisoning toxins. AB - Laboratory grazing experiments compared ingestion of two subclones of the dinoflagellate Alexandrium lusitanicum by gastropod veliger larvae (Nassarius sp.). While the two prey subclones originated from the same monoclonal isolate of A. lusitanicum, one possessed the ability to produce paralytic-shellfish poisoning toxins (PSTs), while the other did not. Ingestion rates on the two Alexandrium subclones were not significantly different over a range of prey concentrations (approximately 100 - 660 cells ml-1), indicating that PSTs did not serve as a grazing deterrent for these larvae. However, ingestion rates on both subclones were low at the higher prey concentrations tested. Mortality of the predators also increased linearly with concentration of either subclone. These observations indicated that both A. lusitanicum subclones produced an unknown substance that inhibited and killed the grazers. Veliger mortality was not induced by culture filtrates or lysates, suggesting either that the substance was either highly labile or that contact with intact cells was required. Because toxic algae can produce multiple bioactive substances, experimental demonstrations of alleopathic effects of toxic species should not be assigned to known toxins without supporting evidence. In addition, the results show that the effectiveness of algal grazing deterrents can increase with cell concentration, which may have implications for bloom dynamics. PMID- 28729817 TI - SSR marker variations in Brassica species provide insight into the origin and evolution of Brassica amphidiploids. AB - BACKGROUND: Oilseed Brassica represents an important group of oilseed crops with a long history of evolution and cultivation. To understand the origin and evolution of Brassica amphidiploids, simple sequence repeat (SSR) markers were used to unravel genetic variations in three diploids and three amphidiploid Brassica species of U's triangle along with Eruca sativa as an outlier. RESULTS: Of 124 Brassica-derived SSR loci assayed, 100% cross-transferability was obtained for B. juncea and three subspecies of B. rapa, while lowest cross-transferability (91.93%) was obtained for Eruca sativa. The average % age of cross transferability across all the seven species was 98.15%. The number of alleles detected at each locus ranged from one to six with an average of 3.41 alleles per primer pair. Neighbor-Joining-based dendrogram divided all the 40 accessions into two main groups composed of B. juncea/B. nigra/B. rapa and B. carinata/B. napus/B. oleracea. C-genome of oilseed Brassica species remained relatively more conserved than A- and B-genome. A- genome present in B. juncea and B. napus seems distinct from each other and hence provides great opportunity for generating diversity through synthesizing amphidiploids from different sources of A- genome. B. juncea had least intra-specific distance indicating narrow genetic base. B. rapa appears to be more primitive species from which other two diploid species might have evolved. CONCLUSION: The SSR marker set developed in this study will assist in DNA fingerprinting of various Brassica species cultivars, evaluating the genetic diversity in Brassica germplasm, genome mapping and construction of linkage maps, gene tagging and various other genomics-related studies in Brassica species. Further, the evolutionary relationship established among various Brassica species would assist in formulating suitable breeding strategies for widening the genetic base of Brassica amphidiploids by exploiting the genetic diversity present in diploid progenitor gene pools. PMID- 28729818 TI - A Cooperative Copper Metal-Organic Framework-Hydrogel System Improves Wound Healing in Diabetes. AB - Chronic non-healing wounds remain a major clinical challenge that would benefit from the development of advanced, regenerative dressings that promote wound closure within a clinically relevant time frame. The use of copper ions has shown promise in wound healing applications possibly by promoting angiogenesis. However, reported treatments that use copper ions require multiple applications of copper salts or oxides to the wound bed, exposing the patient to potentially toxic levels of copper ions and resulting in variable outcomes. Herein we set out to assess whether copper metal organic framework nanoparticles (HKUST-1 NPs) embedded within an antioxidant thermoresponsive citrate-based hydrogel would decrease copper ion toxicity and accelerate wound healing in diabetic mice. HKUST 1 and poly-(polyethyleneglycol citrate-co-N-isopropylacrylamide) (PPCN) were synthesized and characterized. HKUST-1 NP stability in a protein solution with and without embedding them in PPCN hydrogel was determined. Copper ion release, cytotoxicity, apoptosis, and in vitro migration processes were measured. Wound closure rates and wound blood perfusion were assessed in vivo using the splinted excisional dermal wound diabetic mouse model. HKUST-1 NP disintegrated in protein solution while HKUST-1 NPs embedded in PPCN (H-HKUST-1) were protected from degradation and copper ions were slowly released. Cytotoxicity and apoptosis due to copper ion release were significantly reduced while dermal cell migration in vitro and wound closure rates in vivo were significantly enhanced. In vivo, H HKUST-1 induced angiogenesis, collagen deposition, and re-epithelialization during wound healing in diabetic mice. These results suggest that a cooperatively stabilized, copper ion-releasing H-HKUST-1 hydrogel is a promising innovative dressing for the treatment of chronic wounds. PMID- 28729819 TI - Secondhand smoke exposure and risk of wheeze in early childhood: a prospective pregnancy birth cohort study. AB - BACKGROUND: Evidence regarding the independent and additive effects of both pre- and postnatal smoking exposure on the risk of wheeze in children is limited. The purpose of this prospective pregnancy birth cohort study was to examine the association between prenatal and postnatal tobacco smoke exposure during the first year of life and the risk of wheeze in Japanese children aged 23 to 29 months. METHODS: Study subjects were 1354 Japanese mother-child pairs. Information on the variables under study was obtained using repeated questionnaires that were completed by mothers, first prior to delivery, then shortly after birth and subsequently around 4, 12, and 24 months after delivery. Wheeze was defined according to the criteria of the International Study of Asthma and Allergies in Childhood. RESULTS: Compared with no maternal smoking during pregnancy, maternal smoking throughout pregnancy was significantly associated with an increased risk of wheeze in children, yet there were no associations between maternal smoking in the first trimester only or in the second and/or third trimesters and the risk of wheeze. No association was observed between postnatally living with at least one household smoker and the risk of wheeze. An analysis to assess the additive effect of prenatal and postnatal smoking exposure revealed that, compared with children not exposed to maternal smoking during pregnancy and not postnatally living with at least one household smoker, those who were both exposed to maternal smoking during pregnancy and postnatally living with at least one household smoker had twofold odds of developing wheeze. CONCLUSIONS: Our findings suggest that maternal smoking throughout pregnancy might be associated with an increased risk of wheeze in children. There is also the possibility of a positive additive effect of pre- and postnatal smoking exposure on the risk of childhood wheeze. PMID- 28729820 TI - Auditory Mismatch Negativity in Response to Changes of Counter-Balanced Interaural Time and Level Differences. AB - Interaural time differences (ITD) and interaural level differences (ILD) both signal horizontal sound source location. To achieve a unified percept of our acoustic environment, these two cues require integration. In the present study, we tested this integration of ITD and ILD with electroencephalography (EEG) by measuring the mismatch negativity (MMN). The MMN can arise in response to spatial changes and is at least partly generated in auditory cortex. In our study, we aimed at testing for an MMN in response to stimuli with counter-balanced ITD/ILD cues. To this end, we employed a roving oddball paradigm with alternating sound sequences in two types of blocks: (a) lateralized stimuli with congruently combined ITD/ILD cues and (b) midline stimuli created by counter-balanced, incongruently combined ITD/ILD cues. We observed a significant MMN peaking at about 112-128 ms after change onset for the congruent ITD/ILD cues, for both lower (0.5 kHz) and higher carrier frequency (4 kHz). More importantly, we also observed significant MMN peaking at about 129 ms for incongruently combined ITD/ILD cues, but this effect was only detectable in the lower frequency range (0.5 kHz). There were no significant differences of the MMN responses for the two types of cue combinations (congruent/incongruent). These results suggest that-at least in the lower frequency ranges (0.5 kHz)-ITD and ILD are processed independently at the level of the MMN in auditory cortex. PMID- 28729822 TI - Low Intensity Focused tDCS Over the Motor Cortex Shows Inefficacy to Improve Motor Imagery Performance. AB - Transcranial direct current stimulation (tDCS) is a brain stimulation technique that can enhance motor activity by stimulating the motor path. Thus, tDCS has the potential of improving the performance of brain-computer interfaces during motor neurorehabilitation. tDCS effects depend on several aspects, including the current density, which usually varies between 0.02 and 0.08 mA/cm2, and the location of the stimulation electrodes. Hence, testing tDCS montages at several current levels would allow the selection of current parameters for improving stimulation outcomes and the comparison of montages. In a previous study, we found that cortico-cerebellar tDCS shows potential of enhancing right-hand motor imagery. In this paper, we aim to evaluate the effects of the focal stimulation of the motor cortex over motor imagery. In particular, the effect of supplying tDCS with a 4 * 1 ring montage, which consists in placing an anode on the motor cortex and four cathodes around it, over motor imagery was assessed with different current densities. Electroencephalographic (EEG) classification into rest or right-hand/feet motor imagery was evaluated on five healthy subjects for two stimulation schemes: applying tDCS for 10 min on the (1) right-hand or (2) feet motor cortex before EEG recording. Accuracy differences related to the tDCS intensity, as well as MU and beta band power changes, were tested for each subject and tDCS modality. In addition, a simulation of the electric field induced by the montage was used to describe its effect on the brain. Results show no improvement trends on classification for the evaluated currents, which is in accordance with the observation of variable EEG band power results despite the focused stimulation. The lack of effects is probably related to the underestimation of the current intensity required to apply a particular current density for small electrodes and the relatively short inter-electrode distance. Hence, higher current intensities should be evaluated in the future for this montage. PMID- 28729821 TI - Optimized Model of Cerebral Ischemia In situ for the Long-Lasting Assessment of Hippocampal Cell Death. AB - Among all the brain, the hippocampus is the most susceptible region to ischemic lesion, with the highest vulnerability of CA1 pyramidal neurons to ischemic damage. This damage may cause either prompt neuronal death (within hours) or with a delayed appearance (over days), providing a window for applying potential therapies to reduce or prevent ischemic impairments. However, the time course when ischemic damage turns to neuronal death strictly depends on experimental modeling of cerebral ischemia and, up to now, studies were predominantly focused on a short time-window-from hours to up to a few days post-lesion. Using different schemes of oxygen-glucose deprivation (OGD), the conditions taking place upon cerebral ischemia, we optimized a model of mimicking ischemic conditions in organotypical hippocampal slices for the long-lasting assessment of CA1 neuronal death (at least 3 weeks). By combining morphology and electrophysiology, we show that prolonged (30-min duration) OGD results in a massive neuronal death and overwhelmed astrogliosis within a week post-OGD whereas OGD of a shorter duration (10-min) triggered programmed CA1 neuronal death with a significant delay-within 2 weeks-accompanied with drastically impaired CA1 neuron functions. Our results provide a rationale toward optimized modeling of cerebral ischemia for reliable examination of potential treatments for brain neuroprotection, neuro-regeneration, or testing neuroprotective compounds in situ. PMID- 28729823 TI - Administration of Tauroursodeoxycholic Acid Attenuates Early Brain Injury via Akt Pathway Activation. AB - Traumatic brain injury (TBI) is one of the leading causes of trauma-induced mortality and disability, and emerging studies have shown that endoplasmic reticulum (ER) stress plays an important role in the pathophysiology of TBI. Tauroursodeoxycholic acid (TUDCA), a hydrophilic bile acid, has been reported to act as an ER stress inhibitor and chemical chaperone and to have the potential to attenuate apoptosis and inflammation. To study the effects of TUDCA on brain injury, we subjected mice to TBI with a controlled cortical impact (CCI) device. Using western blotting, we first examined TBI-induced changes in the expression levels of GRP78, an ER stress marker, p-PERK, PERK, p-eIF2a, eIF2a, ATF4, p-Akt, Akt, Pten, Bax, Bcl-2, Caspase-12 and CHOP, as well as changes in the mRNA levels of Akt, GRP78, Caspase-12 and CHOP using RT-PCR. Neuronal cell death was assessed by a terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end-labeling (TUNEL) assay, and CHOP expression in neuronal cells was detected by double immunofluorescence staining. Neurological and motor deficits were assessed by modified neurological severity scores (mNSS) and beam balance and beam walking tests, and brain water content was also assessed. Our results indicated that ER stress peaked at 72 h after TBI and that TUDCA abolished ER stress and inhibited p-PERK, p-eIF2a, ATF4, Pten, Caspase-12 and CHOP expression levels. Moreover, our results show that TUDCA also improved neurological function and alleviated brain oedema. Additionally, TUDCA increased p-Akt expression and the Bcl-2/Bax ratio. However, the administration of the Akt inhibitor MK2206 or siRNA targeting of Akt abolished the beneficial effects of TUDCA. Taken together, our results indicate that TUDCA may attenuate early brain injury via Akt pathway activation. PMID- 28729824 TI - Mouse Models of C9orf72 Hexanucleotide Repeat Expansion in Amyotrophic Lateral Sclerosis/ Frontotemporal Dementia. AB - The presence of hexanucleotide repeat expansion (HRE) in the first intron of the human C9orf72 gene is the most common genetic cause underlying both familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Studies aimed at elucidating the pathogenic mechanisms associated of C9orf72 FTD and ALS (C9FTD/ALS) have focused on the hypothesis of RNA and protein toxic gain-of function models, including formation of nuclear RNA foci containing GGGGCC (G4C2) HRE, inclusions containing dipeptide repeat proteins through a non-canonical repeat associated non-ATG (RAN) translation mechanism, and on loss-of-function of the C9orf72 protein. Immense effort to elucidate these mechanisms has been put forth and toxic gain-of-function models have especially gained attention. Various mouse models that recapitulate distinct disease-related pathological, functional, and behavioral phenotypes have been generated and characterized. Although these models express the C9orf72 HRE mutation, there are numerous differences among them, including the transgenesis approach to introduce G4C2-repeat DNA, genomic coverage of C9orf72 features in the transgene, G4C2-repeat length after genomic stabilization, spatiotemporal expression profiles of RNA foci and RAN protein aggregates, neuropathological features, and neurodegeneration-related clinical symptoms. This review aims to (1) provide an overview of the key characteristics; (2) provide insights into potential pathological factors contributing to neurotoxicity and clinical phenotypes through systematic comparison of these models. PMID- 28729825 TI - Dexmedetomidine Protects Mouse Brain from Ischemia-Reperfusion Injury via Inhibiting Neuronal Autophagy through Up-Regulating HIF-1alpha. AB - Stroke is the leading cause of death in China and produces a heavy socio-economic burden in the past decades. Previous studies have shown that dexmedetomidine (DEX) is neuroprotective after cerebral ischemia. However, the role of autophagy during DEX-mediated neuroprotection after cerebral ischemia is still unknown. In this study, we found that post-conditioning with DEX and DEX+3-methyladenine (3 MA) (autophagy inhibitor) reduced brain infarct size and improved neurological deficits compared with DEX+RAPA (autophagy inducer) 24 h after transient middle cerebral artery artery occlusion (tMCAO) model in mice. DEX inhibited the neuronal autophagy in the peri-ischemic brain, and increased viability and decreased apoptosis of primary cultured neurons in oxygen-glucose deprivation (OGD) model. DEX induced expression of Bcl-1 and p62, while reduced the expression of microtubule-associated protein 1 light chain 3 (LC3) and Beclin 1 in primary cultured neurons through inhibition of apoptosis and autophagy. Meanwhile, DEX promoted the expression of hypoxia-inducible factor-1alpha (HIF 1alpha) both in vivo and in vitro, and 2-Methoxyestradiol (2ME2), an inhibitor of HIF-1alpha, could reverse DEX-induced autophagic inhibition. In conclusion, our study suggests that post-conditioning with DEX at the beginning of reperfusion protects mouse brain from ischemia-reperfusion injury via inhibition of neuronal autophagy by upregulation of HIF-1alpha, which provides a potential therapeutic treatment for acute ischemic injury. PMID- 28729826 TI - Sleep-Dependent Oscillatory Synchronization: A Role in Fear Memory Consolidation. AB - Sleep plays an important role in memory consolidation through the facilitation of neuronal plasticity; however, how sleep accomplishes this remains to be completely understood. It has previously been demonstrated that neural oscillations are an intrinsic mechanism by which the brain precisely controls neural ensembles. Inter-regional synchronization of these oscillations is also known to facilitate long-range communication and long-term potentiation (LTP). In the present study, we investigated how the characteristic rhythms found in local field potentials (LFPs) during non-REM and REM sleep play a role in emotional memory consolidation. Chronically implanted bipolar electrodes in the lateral amygdala (LA), dorsal and ventral hippocampus (DH, VH), and the infra-limbic (IL), and pre-limbic (PL) prefrontal cortex were used to record LFPs across sleep wake activity following each day of a Pavlovian cued fear conditioning paradigm. This resulted in three principle findings: (1) theta rhythms during REM sleep are highly synchronized between regions; (2) the extent of inter-regional synchronization during REM and non-REM sleep is altered by FC and EX; (3) the mean phase difference of synchronization between the LA and VH during REM sleep predicts changes in freezing after cued fear extinction. These results both oppose a currently proposed model of sleep-dependent memory consolidation and provide a novel finding which suggests that the role of REM sleep theta rhythms in memory consolidation may rely more on the relative phase-shift between neural oscillations, rather than the extent of phase synchronization. PMID- 28729827 TI - Lateral Hypothalamic Control of the Ventral Tegmental Area: Reward Evaluation and the Driving of Motivated Behavior. AB - The lateral hypothalamus (LH) plays an important role in many motivated behaviors, sleep-wake states, food intake, drug-seeking, energy balance, etc. It is also home to a heterogeneous population of neurons that express and co-express multiple neuropeptides including hypocretin (Hcrt), melanin-concentrating hormone (MCH), cocaine- and amphetamine-regulated transcript (CART) and neurotensin (NT). These neurons project widely throughout the brain to areas such as the locus coeruleus, the bed nucleus of the stria terminalis, the amygdala and the ventral tegmental area (VTA). Lateral hypothalamic projections to the VTA are believed to be important for driving behavior due to the involvement of dopaminergic reward circuitry. The purpose of this article is to review current knowledge regarding the lateral hypothalamic connections to the VTA and the role they play in driving these behaviors. PMID- 28729828 TI - Working Memory Profiles in HIV-Exposed, Uninfected and HIV-Infected Children: A Comparison with Neurotypical Controls. AB - This study compared the working memory profiles of three groups of children, namely HIV-infected (HIV-I; n = 95), HIV-exposed, uninfected (HIV-EU; n = 86) and an HIV-unexposed, uninfected, (HIV-UU; n = 92) neurotypical control group. Working memory, an executive function, plays an important role in frontal lobe controlled behaviors, such as motivation, planning, decision making, and social interaction, and is a strong predictor of academic success in school children. Memory impairments have been identified in HIV-I children, particularly in visuospatial processing. Verbal working memory has not been commonly investigated in this population, while it is unknown how the working memory profiles of HIV-EU children compare to their HIV-I and HIV-UU peers. Of interest was whether the working memory profiles of the HIV-EU children would be more similar to the HIV-I group or to the uninfected control group. The results revealed no significant differences in working memory performance between the HIV-I and HIV-EU groups. However, this does not mean that the etiology of the working memory deficits is the same in the two groups, as these groups showed important differences when compared to the control group. In comparison to the controls, the HIV-I group experienced difficulties with processing tasks irrespective of whether they drew on a verbal or visuospatial modality. This appears to stem from a generalized executive function deficit that also interferes with working memory. In the HIV EU group, difficulties occurred with verbally based tasks, irrespective of whether they required storage or processing. For this group, the dual demands of complex processing and using a second language seem to result in demand exceeding capacity on verbal tasks. Both groups experienced the greatest difficulties with verbal processing tasks for these different reasons. Thus, disruption of different cognitive abilities could result in similar working memory profiles, as evidenced in this study. This has implications for the underlying developmental neurobiology of HIV-I and HIV-EU children, as well the choice of appropriate measures to assist affected children. PMID- 28729829 TI - Cortex Parcellation Associated Whole White Matter Parcellation in Individual Subjects. AB - The investigation of specific white matter areas is a growing field in neurological research and is typically achieved through the use of atlases. However, the definition of anatomically based regions remains challenging for the white matter and thus hinders region-specific analysis in individual subjects. In this article, we focus on creating a whole white matter parcellation method for individual subjects where these areas can be associated to cortex regions. This is done by combining cortex parcellation and fiber tracking data. By tracking fibers out of each cortex region and labeling the fibers according to their origin, we populate a candidate image. We then derive the white matter parcellation by classifying each white matter voxel according to the distribution of labels in the corresponding voxel from the candidate image. The parcellation of the white matter with the presented method is highly reliable and is not as dependent on registration as with white matter atlases. This method allows for the parcellation of the whole white matter into individual cortex region associated areas and, therefore, associates white matter alterations to cortex regions. In addition, we compare the results from the presented method to existing atlases. The areas generated by the presented method are not as sharply defined as the areas in most existing atlases; however, they are computed directly in the DWI space of the subject and, therefore, do not suffer from distortion caused by registration. The presented approach might be a promising tool for clinical and basic research to investigate modalities or system specific micro structural alterations of white matter areas in a quantitative manner. PMID- 28729830 TI - Resting-State Fluctuations of EEG Sensorimotor Rhythm Reflect BOLD Activities in the Pericentral Areas: A Simultaneous EEG-fMRI Study. AB - Blockade of the scalp electroencephalographic (EEG) sensorimotor rhythm (SMR) is a well-known phenomenon following attempted or executed motor functions. Such a frequency-specific power attenuation of the SMR occurs in the alpha and beta frequency bands and is spatially registered at primary somatosensory and motor cortices. Here, we hypothesized that resting-state fluctuations of the SMR in the alpha and beta frequency bands also covary with resting-state sensorimotor cortical activity, without involving task-related neural dynamics. The present study employed functional magnetic resonance imaging (fMRI) to investigate the neural regions whose activities were correlated with the simultaneously recorded SMR power fluctuations. The SMR power fluctuations were convolved with a canonical hemodynamic response function and correlated with blood-oxygen-level dependent (BOLD) signals obtained from the entire brain. Our findings show that the alpha and beta power components of the SMR correlate with activities of the pericentral area. Furthermore, brain regions with correlations between BOLD signals and the alpha-band SMR fluctuations were located posterior to those with correlations between BOLD signals and the beta-band SMR. These results are consistent with those of event-related studies of SMR modulation induced by sensory input or motor output. Our findings may help to understand the role of the sensorimotor cortex activity in contributing to the amplitude modulation of SMR during the resting state. This knowledge may be applied to the diagnosis of pathological conditions in the pericentral areas or the refinement of brain computer interfaces using SMR in the future. PMID- 28729831 TI - Investigating Focal Connectivity Deficits in Alzheimer's Disease Using Directional Brain Networks Derived from Resting-State fMRI. AB - Connectivity analysis of resting-state fMRI has been widely used to identify biomarkers of Alzheimer's disease (AD) based on brain network aberrations. However, it is not straightforward to interpret such connectivity results since our understanding of brain functioning relies on regional properties (activations and morphometric changes) more than connections. Further, from an interventional standpoint, it is easier to modulate the activity of regions (using brain stimulation, neurofeedback, etc.) rather than connections. Therefore, we employed a novel approach for identifying focal directed connectivity deficits in AD compared to healthy controls. In brief, we present a model of directed connectivity (using Granger causality) that characterizes the coupling among different regions in healthy controls and Alzheimer's disease. We then characterized group differences using a (between-subject) generative model of pathology, which generates latent connectivity variables that best explain the (within-subject) directed connectivity. Crucially, our generative model at the second (between-subject) level explains connectivity in terms of local or regionally specific abnormalities. This allows one to explain disconnections among multiple regions in terms of regionally specific pathology; thereby offering a target for therapeutic intervention. Two foci were identified, locus coeruleus in the brain stem and right orbitofrontal cortex. Corresponding disrupted connectivity network associated with the foci showed that the brainstem is the critical focus of disruption in AD. We further partitioned the aberrant connectomic network into four unique sub-networks, which likely leads to symptoms commonly observed in AD. Our findings suggest that fMRI studies of AD, which have been largely cortico-centric, could in future investigate the role of brain stem in AD. PMID- 28729833 TI - Altered Neuronal Activity Topography Markers in the Elderly with Increased Atherosclerosis. AB - Background: Previously, we reported on vascular cognitive impairment (VCI) templates, consisting of patients with VCI associated with carotid stenosis (>60%) using a quantitative electroencephalographic (EEG) technique called neuronal activity topography (NAT). Here using the VCI templates, we investigated the hypothesis that internal carotid artery-intima-media thickness (ICA-IMT) is associated with EEG spectrum intensity (sNAT) and spectrum steepness (vNAT). Methods: A total of 221 community-dwelling elderly subjects were recruited. Four groups were classified according to quartiles of ICA-IMT as assessed by ultrasonography: control group A, normal (<=0.9 mm); group B, mild atherosclerosis (1-1.1 mm); group C, moderate atherosclerosis (1.2-1.8 mm); and group D, severe atherosclerosis (>=1.9 mm). EEG markers of power ratio index (PRI), and the binary likelihood of being in the VCI group vs. the that of being in control group A (sL x:VCI-A , vL x:VCI-A ) were assessed, respectively. Differences in mean total scores for PRI, sL x:VCI-A , vL x:VCI-A , between control group A and the other groups were compared using Dunnett's test, respectively. Results: The mean total scores of the PRI were 3.25, 3.00, 2.77, and 2.26 for groups A, B, C, and D, respectively. There was a significant decrease in the PRI in group D compared with group A (P = 0.0066). The mean total scores of the sL x:VCI-A were -0.14, -0.11, -0.1, and -0.03 for groups A, B, C, and D, respectively. The sL x:VCI-A in group D was significantly higher compared to that in group A (P < 0.0001). The mean total scores of the vL x:VCI-A were 0.04,-0.01, 0.01, and 0.06 for group A, B, C, and D, respectively. The vL x:VCI-A in group D and group C was significantly higher compared to that in group A, respectively (P < 0.0001, P = 0.02). Conclusion: Community-dwelling elderly subjects in the increased carotid atherosclerosis of ICA-IMT (>=1.9 mm) were at greatest risk of an EEG change as assessed by NAT. PMID- 28729834 TI - White Matter Hyperintensity in Elderly Patients with Diabetes Mellitus Is Associated with Cognitive Impairment, Functional Disability, and a High Glycoalbumin/Glycohemoglobin Ratio. AB - Aims: Although evidence has accumulated that white matter hyperintensity (WMH) is associated with the deterioration of cognitive function and impairment of activities of daily living (ADL), the clinical relevance of WMH in elderly patients with diabetes mellitus (DM) is not still clear. The aim of this study was to examine whether WMH volume is associated with ADL and cognitive function and whether glucose control and glucose variability can affect WMH volume in these patients. Methods: This cross-sectional study investigated the associations of WMH with cognitive function and instrumental ADL (IADL), as well as metabolic and vascular risk factors in a total of 178 elderly patients with diabetes. The study assessed WMH volumes and the functional status of cognition and IADL. WMH volumes were evaluated by obtaining axial T2-weighted and fluid-attenuated inversion recovery sequence images on brain magnetic resonance imaging and assessing the images using Software for Neuro-Image Processing in Experimental Research. Results: We found a significant association between WMH volumes and Mini-Mental State Examination (MMSE) scores (p = 0.039) and between WMH and IADL status (p = 0.006). Furthermore, we found significant relations of large WMH volumes with a high glycoalbumin/glycohemoglobin ratio (GA/HbA1c) (p < 0.001). Large WMH volumes were also found to be associated with a low body mass index (p = 0.014) and a low diastolic blood pressure (p = 0.024), but not with HbA1c. Multiple regression analysis showed that high GA/HbA1c, which reflects high glucose variability, was a significant determining factor for large WMH volumes. We also found that GA/HbA1c was negatively associated with both MMSE (p = 0.036) and IADL (p < 0.001). Conclusion: GA/HbA1c, which is a marker of glucose variability, was independently associated with WMH volumes, which could lead to the decline of cognition and IADL in elderly patients with DM. PMID- 28729835 TI - UPLC-ESI-MS/MS and HPTLC Method for Quantitative Estimation of Cytotoxic Glycosides and Aglycone in Bioactivity Guided Fractions of Solanum nigrum L. AB - Solanum nigrum L., is traditionally used for the management of the various liver disorders. Investigating the effect of polarity based fractionation of S. nigrum for its hepatoprotective effect on Hep G2 cells in vitro to provide base of its activity by quantifying in steroidal glycosides responsible for hepatoprotective potential. A new UPLC-ESI-MS/MS method following a high performance thin layer chromatography (HPTLC) has been developed and validated for quantification of steroidal glycosides and aglycone (solasonine, solamargine, and solasodine, respectively). The in vitro antioxidant potential, total phenolics, and flavonoid content were also determined in different fractions. The newly developed UPLC-ESI MS/MS and HPTLC methods were linear (r2 >= 0.99), precise, accurate, and showing recovery more than 97%. The n-butanol enriched fraction of S. nigrum berries was found to be the most potent hepatoprotective fraction against all other fractions as it showed significantly (p < 0.01) better in vitro anti-oxidant potential than other fractions. Quantification by both methods revealed that, content of steroidal glycosides and aglycones are more than 20% in n-butanol fraction as compared to other fractions. The screened steroidal glycoside n-butanol enriched fraction underwent bioefficacy studies against D-galactosamine and H2O2 induced toxicity in HepG2 cell line showing significant (p < 0.05) liver protection. However, developed method can be used for the quality control analysis with respect to targeted metabolites and it can be explored for the pharmacokinetic and pharmacodynamic analysis in future. PMID- 28729832 TI - The Role of Microglia in Retinal Neurodegeneration: Alzheimer's Disease, Parkinson, and Glaucoma. AB - Microglia, the immunocompetent cells of the central nervous system (CNS), act as neuropathology sensors and are neuroprotective under physiological conditions. Microglia react to injury and degeneration with immune-phenotypic and morphological changes, proliferation, migration, and inflammatory cytokine production. An uncontrolled microglial response secondary to sustained CNS damage can put neuronal survival at risk due to excessive inflammation. A neuroinflammatory response is considered among the etiological factors of the major aged-related neurodegenerative diseases of the CNS, and microglial cells are key players in these neurodegenerative lesions. The retina is an extension of the brain and therefore the inflammatory response in the brain can occur in the retina. The brain and retina are affected in several neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and glaucoma. AD is an age-related neurodegeneration of the CNS characterized by neuronal and synaptic loss in the cerebral cortex, resulting in cognitive deficit and dementia. The extracellular deposits of beta-amyloid (Abeta) and intraneuronal accumulations of hyperphosphorylated tau protein (pTau) are the hallmarks of this disease. These deposits are also found in the retina and optic nerve. PD is a neurodegenerative locomotor disorder with the progressive loss of dopaminergic neurons in the substantia nigra. This is accompanied by Lewy body inclusion composed of alpha-synuclein (alpha-syn) aggregates. PD also involves retinal dopaminergic cell degeneration. Glaucoma is a multifactorial neurodegenerative disease of the optic nerve, characterized by retinal ganglion cell loss. In this pathology, deposition of Abeta, synuclein, and pTau has also been detected in retina. These neurodegenerative diseases share a common pathogenic mechanism, the neuroinflammation, in which microglia play an important role. Microglial activation has been reported in AD, PD, and glaucoma in relation to protein aggregates and degenerated neurons. The activated microglia can release pro inflammatory cytokines which can aggravate and propagate neuroinflammation, thereby degenerating neurons and impairing brain as well as retinal function. The aim of the present review is to describe the contribution in retina to microglial mediated neuroinflammation in AD, PD, and glaucomatous neurodegeneration. PMID- 28729836 TI - An Overview of Herbal Products and Secondary Metabolites Used for Management of Type Two Diabetes. AB - Diabetes mellitus is a common effect of uncontrolled high blood sugar and it is associated with long-term damage, dysfunction, and failure of various organs. In the adult population, the global prevalence of diabetes has nearly doubled since 1980. Without effective prevention and management programs, the continuing significant rise in diabetes will have grave consequences on the health and lifespan of the world population, and also on the world economy. Supplements can be used to correct nutritional deficiencies or to maintain an adequate intake of certain nutrients. These are often used as treatments for diabetes, sometimes because they have lower costs, or are more accessible or "natural" compared to prescribed medications. Several vitamins, minerals, botanicals, and secondary metabolites have been reported to elicit beneficial effects in hypoglycemic actions in vivo and in vitro; however, the data remain conflicting. Many pharmaceuticals commonly used today are structurally derived from natural compounds from traditional medicinal plants. Botanicals that are most frequently used to help manage blood glucose include: bitter melon (Momordica charantia), fenugreek (Trigonella foenum graecum), gurmar (Gymnema sylvestre), ivy gourd (Coccinia indica), nopal (Opuntia spp.), ginseng, Russian tarragon (Artemisia dracunculus), cinnamon (Cinnamomum cassia), psyllium (Plantago ovata), and garlic (Allium sativum). In majority of the herbal products and secondary metabolites used in treating diabetes, the mechanisms of action involve regulation of insulin signaling pathways, translocation of GLUT-4 receptor and/or activation the PPARgamma. Several flavonoids inhibit glucose absorption by inhibiting intestinal alpha-amylase and alpha-glucosidase. In-depth studies to validate the efficacies and safeties of extracts of these traditional medicinal plants are needed, and large, well designed, clinical studies need to be carried out before the use of such preparations can be recommended for treatment and/or prevention of diabetes. The main focus of this review is to describe what we know to date of the active compounds in these, along with their glucose-lowering mechanisms, which are either through insulin-mimicking activity or enhanced glucose uptake. PMID- 28729838 TI - Detection of Emodin Derived Glutathione Adduct in Normal Rats Administered with Large Dosage of Polygoni Multiflori Radix. AB - Polygoni Multiflori Radix (PMR) has been commonly used as a tonic in China for centuries. PMR-associated hepatotoxicity has been drawing increasingly more attention in recent years in parallel with its wide utilization. Anthraquinones (AQs) are recognized as the main hepatotoxic components in PMR. However, the exact underlying mechanism of AQs poisoning is still not fully understood. Herein, we proposed a hypothesis that metabolic activation of AQs such as emodin was involved in PMR-induced liver injury, AQs followed to generate the electrophilic reactive metabolites and subsequently formed covalent adduct with cellular nucleophiles in the liver to exert hepatotoxicity. In the present study, the link of cytotoxicity of PMR in primary human hepatocytes and the depletion of glutathione (GSH) was investigated by MTT assay and UHPLC-QqQ-MS/MS analysis. The results showed that PMR depleted GSH and therefore induced cytotoxicity. Then, emodin-GSH adduct was identified in bile of liver injured rats after intragastric administration of PMR or emodin with the aid of UHPLC-QTOF-MS/MS method. Our findings not only provided confirmative evidence that the mechanism of hepatotoxicity induced by AQs in PMR involved key metabolic steps, but also revealed that emodin-GSH adduct had potential to be further developed as a sensitive and traceable biomarker for the assessment of PMR-induced liver injury. PMID- 28729839 TI - The Effect of Low Ambient Relative Humidity on Physical Performance and Perceptual Responses during Load Carriage. AB - Introduction: The study evaluated the effect of low ambient relative humidity on physical performance and perceptual responses during load carriage in a hot environment. Methods: Ten heat-unacclimatized male subjects participated in three 130-min trials, during which they walked on a treadmill, carrying a load of ~35 kg, at a speed of 3.2 km.h-1, with an incident wind at the same velocity and ambient temperature at 45 degrees C. Each trial commenced with a 10-min baseline at 20 degrees C and 50% relative humidity (RH), the subjects transferred to a climatic chamber and commenced their simulated hike, comprising two 50-min walks separated by a 20-min rest period. In two, full protective equipment (FP) trials, RH was 10% (partial pressure of water vapor, p H2O = 7.2 mmHg) in one (FP10), and 20% (p H2O = 14.4 mmHg; FP20) in the other. In the control trial, subjects were semi-nude (SN) and carried the equipment in their backpacks; RH was 20%. Measurements included oxygen uptake, ventilation, heart rate, rectal and skin temperatures, heat flux, temperature perception, and thermal comfort. Results: In FP20, four subjects terminated the trial prematurely due to signs of heat exhaustion; there were no such signs in FP10 or SN. Upon completion of the trials, pulmonary ventilation, heart rate, and rectal temperature were lower in FP10 (33 +/- 5 l/min; 128 +/- 21 bpm; 38.2 +/- 0.4 degrees C) and SN (34 +/- 4 l/min; 113 +/- 18 bpm; 38.1 +/- 0.4 degrees C than in FP20 (39 +/- 8 l/min; 145 +/- 12 bpm; 38.6 +/- 0.4 degrees C). Evaporation was significantly greater in the SN compared to FP10 and FP20 trials. FP10 was rated thermally more comfortable than FP20. Conclusion: A lower ambient partial pressure of water vapor, reflected in a lower ambient relative humidity, improved cardiorespiratory, thermoregulatory, and perceptual responses during load carriage. PMID- 28729837 TI - Optimization and In Vivo Profiling of a Refined Rat Model of Walker 256 Breast Cancer Cell-Induced Bone Pain Using Behavioral, Radiological, Histological, Immunohistochemical and Pharmacological Methods. AB - In the majority of patients with advanced breast cancer, there is metastatic spread to bones resulting in pain. Clinically available drug treatments for alleviation of breast cancer-induced bone pain (BCIBP) often produce inadequate pain relief due to dose-limiting side-effects. A major impediment to the discovery of novel well-tolerated analgesic agents for the relief of pain due to bony metastases is the fact that most cancer-induced bone pain models in rodents relied on the systemic injection of cancer cells, causing widespread formation of cancer metastases and poor general animal health. Herein, we have established an optimized, clinically relevant Wistar Han female rat model of breast cancer induced bone pain which was characterized using behavioral assessments, radiology, histology, immunohistochemistry and pharmacological methods. In this model that is based on unilateral intra-tibial injection (ITI) of Walker 256 carcinoma cells, animals maintained good health for at least 66 days post-ITI. The temporal development of hindpaw hypersensitivity depended on the initial number of Walker 256 cells inoculated in the tibiae. Hindpaw hypersensitivity resolved after approximately 25 days, in the continued presence of bone tumors as evidenced by ex vivo histology, micro-computed tomography scans and immunohistochemical assessments of tibiae. A possible role for the endogenous opioid system as an internal factor mediating the self-resolving nature of BCIBP was identified based upon the observation that naloxone, a non-selective opioid antagonist, caused the re-emergence of hindpaw hypersensitivity. Bolus dose injections of morphine, gabapentin, amitriptyline and meloxicam all alleviated hindpaw hypersensitivity in a dose-dependent manner. This is a first systematic pharmacological profiling of this model by testing standard analgesic drugs from four important diverse classes, which are used to treat cancer induced bone pain in the clinical setting. Our refined rat model more closely mimics the pathophysiology of this condition in humans and hence is well-suited for probing the mechanisms underpinning breast cancer induced bone pain. In addition, the model may be suitable for efficacy profiling of new molecules from drug discovery programs with potential to be developed as novel agents for alleviation of intractable pain associated with disseminated breast cancer induced bony metastases. PMID- 28729840 TI - Cardiac Subtype-Specific Modeling of Kv1.5 Ion Channel Deficiency Using Human Pluripotent Stem Cells. AB - The ultrarapid delayed rectifier K+ current (IKur), mediated by Kv1.5 channels, constitutes a key component of the atrial action potential. Functional mutations in the underlying KCNA5 gene have been shown to cause hereditary forms of atrial fibrillation (AF). Here, we combine targeted genetic engineering with cardiac subtype-specific differentiation of human induced pluripotent stem cells (hiPSCs) to explore the role of Kv1.5 in atrial hiPSC-cardiomyocytes. CRISPR/Cas9-mediated mutagenesis of integration-free hiPSCs was employed to generate a functional KCNA5 knockout. This model as well as isogenic wild-type control hiPSCs could selectively be differentiated into ventricular or atrial cardiomyocytes at high efficiency, based on the specific manipulation of retinoic acid signaling. Investigation of electrophysiological properties in Kv1.5-deficient cardiomyocytes compared to isogenic controls revealed a strictly atrial-specific disease phentoype, characterized by cardiac subtype-specific field and action potential prolongation and loss of 4-aminopyridine sensitivity. Atrial Kv1.5 deficient cardiomyocytes did not show signs of arrhythmia under adrenergic stress conditions or upon inhibiting additional types of K+ current. Exposure of bulk cultures to carbachol lowered beating frequencies and promoted chaotic spontaneous beating in a stochastic manner. Low-frequency, electrical stimulation in single cells caused atrial and mutant-specific early afterdepolarizations, linking the loss of KCNA5 function to a putative trigger mechanism in familial AF. These results clarify for the first time the role of Kv1.5 in atrial hiPSC cardiomyocytes and demonstrate the feasibility of cardiac subtype-specific disease modeling using engineered hiPSCs. PMID- 28729841 TI - Prevalence of Non-responders for Glucose Control Markers after 10 Weeks of High Intensity Interval Training in Adult Women with Higher and Lower Insulin Resistance. AB - Background: Exercise training improves performance and biochemical parameters on average, but wide interindividual variability exists, with individuals classified as responders (R) or non-responders (NRs), especially between populations with higher or lower levels of insulin resistance. This study assessed the effects of high-intensity interval training (HIIT) and the prevalence of NRs in adult women with higher and lower levels of insulin resistance. Methods: Forty adult women were assigned to a HIIT program, and after training were analyzed in two groups; a group with higher insulin resistance (H-IR, 40 +/- 6 years; BMI: 29.5 +/- 3.7 kg/m2; n = 20) and a group with lower insulin resistance (L-IR, 35 +/- 9 years; 27.8 +/- 2.8 kg/m2; n = 20). Anthropometric, cardiovascular, metabolic, and performance variables were measured at baseline and after 10 weeks of training. Results: There were significant training-induced changes [delta percent (Delta%)] in fasting glucose, fasting insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) scores in the H-IR group (-8.8, -26.5, -32.1%, p < 0.0001), whereas no significant changes were observed in the L-IR. Both groups showed significant pre-post changes in other anthropometric variables [waist circumference (-5.2, p < 0.010, and -3.8%, p = 0.046) and tricipital (-13.3, p < 0.010, and -13.6%, p < 0.0001), supra-iliac (-19.4, p < 0.0001, and -13.6%, p < 0.0001), and abdominal (-18.2, p < 0.0001, and -15.6%, p < 0.010) skinfold measurements]. Systolic blood pressure decreased significantly only in the L-IR group (-3.2%, p < 0.010). Both groups showed significant increases in 1RMLE (+12.9, p < 0.010, and +14.7%, p = 0.045). There were significant differences in the prevalence of NRs between the H-IR and L-IR groups for fasting glucose (25 vs. 95%, p < 0.0001) and fasting insulin (p = 0.025) but not for HOMA-IR (25 vs. 45%, p = 0.185). Conclusion: Independent of the "magnitude" of the cardiometabolic disease (i.e., higher vs. lower insulin resistance), no differences were observed in the NRs prevalence with regard to improved HOMA-IR or to anthropometric, cardiovascular, and muscle performance co-variables after 10 weeks of HIIT in sedentary adult women. This research demonstrates the protective effect of HIIT against cardiometabolic disease progression in a sedentary population. PMID- 28729842 TI - A Gene-Based Analysis of Acoustic Startle Latency. AB - Latency of the acoustic startle response is the time required from the presentation of startling auditory stimulus until the startle response is elicited and provides an index of neural processing speed. Latency is prolonged in subjects with schizophrenia compared to controls in some but not all studies and is 68-90% heritable in baseline startle trials. In order to determine the genetic association with latency as a potential inroad into genetically based vulnerability to psychosis, we conducted a gene-based study of latency followed by an independent replication study of significant gene findings with a single nucleotide polymorphism (SNP)-based analysis of schizophrenia and control subjects. 313 subjects from an urban population of low socioeconomic status with mixed psychiatric diagnoses were included in the gene-based study. Startle testing was conducted using a Biopac M150 system according to our published methods. Genotyping was performed with the Omni-Quad 1M or the Omni Express BeadChip. The replication study was conducted on 154 schizophrenia subjects and 123 psychiatric controls. Genetic analyses were conducted with Illumina Human Omni1-Quad and OmniExpress BeadChips. Twenty-nine SNPs were selected from four genes that were significant in the gene-based analysis and also associated with startle and/or schizophrenia in the literature. Linear regressions on latency were conducted, controlling for age, race, and diagnosis as a dichotomous variable. In the gene-based study, 2,870 genes demonstrated the evidence of association after correction for multiple comparisons (false discovery rate < 0.05). Pathway analysis of these genes revealed enrichment for relevant biological processes including neural transmission (p = 0.0029), synaptic transmission (p = 0.0032), and neuronal development (p = 0.024). The subsequent SNP-based replication analysis revealed a strong association of onset latency with the SNP rs901561 on the neuregulin gene (NRG1) in an additive model (beta = 0.21, p = 0.001), indicating that subjects with the AA and AG genotypes had slower mean latency than subjects with GG genotype. In conclusion, startle latency, a highly heritable measure that is slowed in schizophrenia, may be a useful biological probe for genetic contributions to psychotic disorders. Our analyses in two independent populations point to a significant prediction of startle latency by genetic variation in NRG1. PMID- 28729843 TI - Is a Transdisciplinary Theory of Engagement in Organized Settings Possible? A Concept Analysis of the Literature on Employee Engagement, Consumer Engagement and Patient Engagement. AB - Organizations are experiencing increased competition, disruptive innovation, and continuous changes in their social and economic context. Furthermore, the decrease of resources (economic and human) in such a demanding context make it imperative for organizations to find new models and strategies to make their service delivery more sustainable at the economic, environmental and psychological levels. In such a complex scenario the concept of engagement of the individuals involved in organized settings (either as service providers or as final receivers) is a promising lever for innovation. However, despite the number of studies on the matter, the debate on engagement is still very fragmented because the corpus of literature addressing the different areas of engagement is divided and diverse in its nature. In this paper, we discuss the results of a conceptual analysis of the literature conducted in order to investigate overlapping features and areas of divergence among three different areas of investigation and application of the engagement phenomenon in organized settings: the domains of employee engagement, consumer engagement, and patient engagement. These are deliberately selected as prototypical of the phenomenon of engagement along the "inside/outside" of organizational settings. The analysis consisted in a qualitative conceptual survey? Of the scholarly literature indexed with the key terms "employee engagement," "consumer engagement," and "patient engagement." We performed a key-word based survey? Of the literature in the Scopus database. A total of 163 articles were selected and analyzed. The analysis cast light on the following areas of conceptual overlap among employee, consumer and patient engagement: (1) engagement is different from empowerment and activation; (2) engagement is a multi-componential psychological experience; (3) engagement is a self-transformative experience; (4) engagement develops within a relational context; (5) engagement is a systemic phenomenon. These findings, although preliminary and in need of further investigation, suggest the feasibility of promoting a transdisciplinary reflection on the phenomenon of engagement in organized settings. PMID- 28729844 TI - Not Merely Experiential: Unconscious Thought Can Be Rational. AB - Individuals often form more reasonable judgments from complex information after a period of distraction vs. deliberation. This phenomenon has been attributed to sophisticated unconscious thought during the distraction period that integrates and organizes the information (Unconscious Thought Theory; Dijksterhuis and Nordgren, 2006). Yet, other research suggests that experiential processes are strengthened during the distraction (relative to deliberation) period, accounting for the judgment and decision benefit. We tested between these possibilities, hypothesizing that unconscious thought is distinct from experiential processes, and independently contributes to judgments and decisions during a distraction period. Using an established paradigm, Experiment 1 (N = 319) randomly induced participants into an experiential or rational mindset, after which participants received complex information describing three roommates to then consider consciously (i.e., deliberation) or unconsciously (i.e., distraction). Results revealed superior roommate judgments (but not choices) following distraction vs. deliberation, consistent with Unconscious Thought Theory. Mindset did not have an influence on roommate judgments. However, planned tests revealed a significant advantage of distraction only within the rational-mindset condition, which is contrary to the idea that experiential processing alone facilitates complex decision-making during periods of distraction. In a second experiment (N = 136), we tested whether effects of unconscious thought manifest for a complex analytical reasoning task for which experiential processing would offer no advantage. As predicted, participants in an unconscious thought condition outperformed participants in a control condition, suggesting that unconscious thought can be analytical. In sum, the current results support the existence of unconscious thinking processes that are distinct from experiential processes, and can be rational. Thus, the experiential vs. rational nature of a process might not cleanly delineate conscious and unconscious thought. PMID- 28729845 TI - Negative Affect and Excessive Alcohol Intake Incubate during Protracted Withdrawal from Binge-Drinking in Adolescent, But Not Adult, Mice. AB - Binge-drinking is common in underage alcohol users, yet we know little regarding the biopsychological impact of binge-drinking during early periods of development. Prior work indicated that adolescent male C57BL6/J mice with a 2 week history of binge-drinking (PND28-41) are resilient to the anxiogenic effects of early alcohol withdrawal. Herein, we employed a comparable Drinking-in-the Dark model to determine how a prior history of binge-drinking during adolescence (EtOHadolescents) influences emotionality (assayed with the light-dark box, marble burying test, and the forced swim test) and the propensity to consume alcohol in later life, compared to animals without prior drinking experience. For additional comparison, adult mice (EtOHadults) with comparable drinking history (PND56-69) were subdivided into groups tested for anxiety/drinking either on PND70 (24 h withdrawal) or PND98 (28 days withdrawal). Tissue from the nucleus accumbens shell (AcbSh) and central nucleus of the amygdala (CeA) was examined by immunoblotting for changes in the expression of glutamate-related proteins. EtOHadults exhibited some signs of hyperanxiety during early withdrawal (PND70), but not during protracted withdrawal (PND98). In contrast, EtOHadolescents exhibited robust signs of anxiety-l and depressive-like behaviors when tested as adults on PND70. While all alcohol-experienced animals subsequently consumed more alcohol than mice drinking for the first time, alcohol intake was greatest in EtOHadolescents. Independent of drinking age, the manifestation of withdrawal induced hyperanxiety was accompanied by reduced Homer2b expression within the CeA and increased Group1 mGlu receptor expression within the AcbSh. The present data provide novel evidence that binge-drinking during adolescence produces a state characterized by profound negative affect and excessive alcohol consumption that incubates with the passage of time in withdrawal. These data extend our prior studies on the effects of subchronic binge-drinking during adulthood by demonstrating that the increase in alcoholism-related behaviors and glutamate related proteins observed in early withdrawal dissipate with the passage of time. Our results to date highlight a critical interaction between the age of binge drinking onset and the duration of alcohol withdrawal in glutamate-related neuroplasticity within the extended amygdala of relevance to the etiology of psychopathology, including pathological drinking, in later life. PMID- 28729846 TI - What's New in Addiction Prevention in Young People: A Literature Review of the Last Years of Research. AB - Rationale: Addiction prevention is a major public health problem, particularly concerning young people. Despite the consensus that primary prevention is essential, the evaluation of its impact is questioned. Objective: The objective of this paper is to assess the latest knowledge of addiction prevention programs for young people. Method: Review a collection of research articles using a keyword-based search on three databases: Pubmed, Eric, and PsycInfo. The research was carried out using three groups of keywords and the eligibility study was completed using two criteria: articles published between 2010 and 2017, and articles in refereed journals. Results: Of a total of 13,720 articles in the three databases, 32 studies were included in the review and listed in a grid with five themes: authors, type of population, total population, addictive behavior, and results. Four categories were created based on the objective of the studies: the evaluation of prevention strategies, the study of risk factors for consumption, the prevalence study and other subjects studied. The analysis of the corpus was used to establish a list of risk factors to be taken into consideration in future interventions and research. A list of key elements for performing effective interventions and future research is also proposed. Conclusion: The understanding of the prevention strategies implementation process is discussed as a central element for future research, which will combine stakeholders and researchers. The complexity of the situations and the multifactorial aspects of addiction prevention in young people require a multidisciplinary approach involving the various stakeholders and researchers. PMID- 28729847 TI - Effects of Intensive Crew Training on Individual and Collective Characteristics of Oar Movement in Rowing as a Coxless Pair. AB - This case study examined how two rowers adapted their rowing patterns following crew training as a newly formed coxless pair. The two participants were expert (double-oar) single scull-boat rowers. Performing as a crew in the coxless-pair's sweep-boat, where each rower operates a single oar, on-the-water data were collected before and after a 6-week intensive team-training program. Rowing patterns were characterized by the horizontal oar angle, oar angular velocity and linear oar-water velocity profiles during the catch (minimal oar angle) to finish (maximal oar angle) half-cycles of the propulsive water phase. After crew training, rowers demonstrated a tighter synchronization and a closer correspondence in oar angle at the moment of catch, together with a closer matching of the evolution over time of their subsequent oar movements. Most likely due to the inherent asymmetries involved in sweep-boat rowing, the stroke rower also developed a somewhat longer-duration larger-amplitude oar movement than the bow rower. Remarkably, both rowers revealed changes in the inter-cycle variability of their individual patterns of rowing. While the initially more variable stroke rower improved the consistency of his rowing pattern over practice, the initially highly consistent bow rower on the contrary relaxed his tendency to always perform in the same way. We discuss how the crew performance changed over training and to what extent it was associated with changes in individual behaviors. Along the way we demonstrate that the often-used measure of average continuous relative phase does not adequately capture the particularities of the coordination pattern observed. Overall, the results obtained at the individual level of analysis suggest that team benefits were obtained through distinct adaptations of the rowers' individual rowing patterns. PMID- 28729848 TI - The Functional Genetics of Handedness and Language Lateralization: Insights from Gene Ontology, Pathway and Disease Association Analyses. AB - Handedness and language lateralization are partially determined by genetic influences. It has been estimated that at least 40 (and potentially more) possibly interacting genes may influence the ontogenesis of hemispheric asymmetries. Recently, it has been suggested that analyzing the genetics of hemispheric asymmetries on the level of gene ontology sets, rather than at the level of individual genes, might be more informative for understanding the underlying functional cascades. Here, we performed gene ontology, pathway and disease association analyses on genes that have previously been associated with handedness and language lateralization. Significant gene ontology sets for handedness were anatomical structure development, pattern specification (especially asymmetry formation) and biological regulation. Pathway analysis highlighted the importance of the TGF-beta signaling pathway for handedness ontogenesis. Significant gene ontology sets for language lateralization were responses to different stimuli, nervous system development, transport, signaling, and biological regulation. Despite the fact that some authors assume that handedness and language lateralization share a common ontogenetic basis, gene ontology sets barely overlap between phenotypes. Compared to genes involved in handedness, which mostly contribute to structural development, genes involved in language lateralization rather contribute to activity-dependent cognitive processes. Disease association analysis revealed associations of genes involved in handedness with diseases affecting the whole body, while genes involved in language lateralization were specifically engaged in mental and neurological diseases. These findings further support the idea that handedness and language lateralization are ontogenetically independent, complex phenotypes. PMID- 28729851 TI - Development and Validation of an Enzyme-Linked Immunosorbent Assay for the Detection of Binding Anti-Drug Antibodies against Interferon Beta. AB - OBJECTIVE: To develop and validate a method for the detection of binding anti drug antibodies (ADAs) against interferon beta (IFN-beta) in human serum as part of a European initiative (ABIRISK) aimed at the prediction and analysis of clinical relevance of anti-biopharmaceutical immunization to minimize the risk. METHOD: A two-tiered bridging enzyme-linked immunosorbent assay (ELISA) format was selected and validated according to current recommendations. Screening assay: ADA in serum samples form complexes with immobilized IFN-beta and biotinylated IFN-beta, which are then detected using HRP labeled Streptavidin and TMB substrate. Confirmation assay: Screen "putative positive" samples are tested in the presence of excess drug (preincubation of sera with 0.3 ug/mL of soluble IFN beta) and percentage of inhibition is calculated. RESULTS: The assay is precise, and the sensitivity of the assay was confirmed to be 26 ng/mL using commercially available polyclonal rabbit antihuman IFN-beta in human sera as the positive control. CONCLUSION: An ultrasensitive ELISA for IFN-beta-binding ADA testing has been validated. This will form the basis to assess anti-biopharmaceutical immunization toward IFN-beta with regards to its clinical relevance and may allow for the development of predictive tools, key aims within the ABIRISK consortium. PMID- 28729849 TI - Nerve Decompression and Restless Legs Syndrome: A Retrospective Analysis. AB - INTRODUCTION: Restless legs syndrome (RLS) is a prevalent sleep disorder affecting quality of life and is often comorbid with other neurological diseases, including peripheral neuropathy. The mechanisms related to RLS symptoms remain unclear, and treatment options are often aimed at symptom relief rather than etiology. RLS may present in distinct phenotypes often described as "primary" vs. "secondary" RLS. Secondary RLS is often associated with peripheral neuropathy. Nerve decompression surgery of the common and superficial fibular nerves is used to treat peripheral neuropathy. Anecdotally, surgeons sometimes report improved RLS symptoms following nerve decompression for peripheral neuropathy. The purpose of this retrospective analysis was to quantify the change in symptoms commonly associated with RLS using visual analog scales (VAS). METHODS: Forty-two patients completed VAS scales (0-10) for pain, burning, numbness, tingling, weakness, balance, tightness, aching, pulling, cramping, twitchy/jumpy, uneasy, creepy/crawly, and throbbing, both before and 15 weeks after surgical decompression. RESULTS: Subjects reported significant improvement among all VAS categories, except for "pulling" (P = 0.14). The change in VAS following surgery was negatively correlated with the pre-surgery VAS for both the summed VAS (r = 0.58, P < 0.001) and the individual VAS scores (all P < 0.01), such that patients who reported the worst symptoms before surgery exhibited relatively greater reductions in symptoms after surgery. CONCLUSION: This is the first study to suggest improvement in RLS symptoms following surgical decompression of the common and superficial fibular nerves. Further investigation is needed to quantify improvement using RLS-specific metrics and sleep quality assessments. PMID- 28729850 TI - Drug-Resistant Epilepsy: Multiple Hypotheses, Few Answers. AB - Epilepsy is a common neurological disorder that affects over 70 million people worldwide. Despite the recent introduction of new antiseizure drugs (ASDs), about one-third of patients with epilepsy have seizures refractory to pharmacotherapy. Early identification of patients who will become refractory to ASDs could help direct such patients to appropriate non-pharmacological treatment, but the complexity in the temporal patterns of epilepsy could make such identification difficult. The target hypothesis and transporter hypothesis are the most cited theories trying to explain refractory epilepsy, but neither theory alone fully explains the neurobiological basis of pharmacoresistance. This review summarizes evidence for and against several major theories, including the pharmacokinetic hypothesis, neural network hypothesis, intrinsic severity hypothesis, gene variant hypothesis, target hypothesis, and transporter hypothesis. The discussion is mainly focused on the transporter hypothesis, where clinical and experimental data are discussed on multidrug transporter overexpression, substrate profiles of ASDs, mechanism of transporter upregulation, polymorphisms of transporters, and the use of transporter inhibitors. Finally, future perspectives are presented for the improvement of current hypotheses and the development of treatment strategies as guided by the current understanding of refractory epilepsy. PMID- 28729852 TI - Towards Better Understanding of the Pathogenesis of Neuronal Respiratory Network in Sudden Perinatal Death. AB - Sudden perinatal death that includes the victims of sudden infant death syndrome, sudden intrauterine death syndrome, and stillbirth are heartbreaking events in the life of parents. Most of the studies about sudden perinatal death were reported from Italy, highlighting two main etiological factors: prone sleeping position and smoking. Other probable contributory factors are prematurity, male gender, lack of breastfeeding, respiratory tract infections, use of pacifiers, infant botulism, extensive use of pesticides and insecticides, etc. However, extensive studies across the world are required to establish the role of these factors in a different subset of populations. Previous studies confirmed the widely accepted hypothesis that neuropathology of the brainstem is one of the main cause of sudden perinatal death. This study is an effort to summarize the neuropathological evaluation of the brainstems and their association to sudden perinatal death. Brainstem nuclei in vulnerable infants undergo certain changes that may alter the sleep arousal cycle, cardiorespiratory control, and ultimately culminate in death. This review focuses on the roles of different brainstem nuclei, their pathologies, and the established facts in this regard in terms of it's link to such deaths. This study will also help to understand the role of brainstem nuclei in controlling the cardiorespiratory cycles in sudden perinatal death and may provide a better understanding to resolve the mystery of these deaths in future. It is also found that a global initiative to deal with perinatal death is required to facilitate the diagnosis and prevention in developed and as well as developing countries. PMID- 28729853 TI - Role of Melatonin, Galanin, and RFamide Neuropeptides QRFP26 and QRFP43 in the Neuroendocrine Control of Pancreatic beta-Cell Function. AB - Glucose homeostasis is finely regulated by a number of hormones and peptides released mainly from the brain, gastrointestinal tract, and muscle, regulating pancreatic secretion through cellular receptors and their signal transduction cascades. The endocrine function of the pancreas is controlled by islets within the exocrine pancreatic tissue that release hormones like insulin, glucagon, somatostatin, pancreatic polypeptide, and ghrelin. Moreover, both exocrine and endocrine pancreatic functions are regulated by a variety of hormonal and neural mechanisms, such as ghrelin, glucagon-like peptide, glucose-dependent insulinotropic polypeptide, or the inhibitory peptide somatostatin. In this review, we describe the role of neurohormones that have been less characterized compared to others, on the regulation of insulin secretion. In particular, we will focus on melatonin, galanin, and RFamide neuropeptides QRFP26 and QRFP43, which display either insulinotropic or insulinostatic effects. In fact, in addition to other hormones, amino acids, cytokines, and a variety of proteins, brain-derived hormones are now considered as key regulators of glucose homeostasis, representing potential therapeutic targets for the treatment of diabetes and obesity. PMID- 28729854 TI - Microbiome of Trichodesmium Colonies from the North Pacific Subtropical Gyre. AB - Filamentous diazotrophic Cyanobacteria of the genus Trichodesmium, often found in colonial form, provide an important source of new nitrogen to tropical and subtropical marine ecosystems. Colonies are composed of several clades of Trichodesmium in association with a diverse community of bacterial and eukaryotic epibionts. We used high-throughput 16S rRNA and nifH gene sequencing, carbon (C) and dinitrogen (N2) fixation assays, and metagenomics to describe the diversity and functional potential of the microbiome associated with Trichodesmium colonies collected from the North Pacific Subtropical Gyre (NPSG). The 16S rRNA and nifH gene sequences from hand-picked colonies were predominantly (>99%) from Trichodesmium Clade I (i.e., T. thiebautii), which is phylogenetically and ecologically distinct from the Clade III IMS101 isolate used in most laboratory studies. The bacterial epibiont communities were dominated by Bacteroidetes, Alphaproteobacteria, and Gammaproteobacteria, including several taxa with a known preference for surface attachment, and were relatively depleted in the unicellular Cyanobacteria and small photoheterotrophic bacteria that dominate NPSG surface waters. Sequencing the nifH gene (encoding a subcomponent of the nitrogenase enzyme) identified non-Trichodesmium diazotrophs that clustered predominantly among the Cluster III nifH sequence-types that includes putative anaerobic diazotrophs. Trichodesmium colonies may represent an important habitat for these Cluster III diazotrophs, which were relatively rare in the surrounding seawater. Sequence analyses of nifH gene transcripts revealed several cyanobacterial groups, including heterocystous Richelia, associated with the colonies. Both the 16S rRNA and nifH datasets indicated strong differences between Trichodesmium epibionts and picoplankton in the surrounding seawater, and also between the epibionts inhabiting Trichodesmium puff and tuft colony morphologies. Metagenomic and 16S rRNA gene sequence analyses suggested that lineages typically associated with a copiotrophic lifestyle comprised a large fraction of colony-associated epibionts, in contrast to the streamlined genomes typical of bacterioplankton in these oligotrophic waters. Additionally, epibiont metagenomes were enriched in specific genes involved in phosphate and iron acquisition and denitrification pathways relative to surface seawater metagenomes. We propose that the unique microbial consortium inhabiting colonies has a significant impact on the biogeochemical functioning of Trichodesmium colonies in pelagic environments. PMID- 28729855 TI - Desirable Traits of a Good Biocontrol Agent against Verticillium Wilt. AB - The soil-borne fungus Verticillium causes serious vascular disease in a wide variety of annual crops and woody perennials. Verticillium wilt is notoriously difficult to control by conventional methods, so there is great potential for biocontrol to manage this disease. In this study we aimed to review the research about Verticillium biocontrol to get a better understanding of characteristics that are desirable in a biocontrol agent (BCA) against Verticillium wilt. We only considered studies in which the BCAs were tested on plants. Most biocontrol studies were focused on plants of the Solanaceae, Malvaceae, and Brassicaceae and within these families eggplant, cotton, and oilseed rape were the most studied crops. The list of bacterial BCAs with potential against Verticillium was dominated by endophytic Bacillus and Pseudomonas isolates, while non-pathogenic xylem-colonizing Verticillium and Fusarium isolates topped the fungal list. Predominant modes of action involved in biocontrol were inhibition of primary inoculum germination, plant growth promotion, competition and induced resistance. Many BCAs showed in vitro antibiosis and mycoparasitism but these traits were not correlated with activity in vivo and there is no evidence that they play a role in planta. Good BCAs were obtained from soils suppressive to Verticillium wilt, disease suppressive composts, and healthy plants in infested fields. Desirable characteristics in a BCA against Verticillium are the ability to (1) affect the survival or germination of microsclerotia, (2) colonize the xylem and/or cortex and compete with the pathogen for nutrients and/or space, (3) induce resistance responses in the plant and/or (4) promote plant growth. Potential BCAs should be screened in conditions that resemble the field situation to increase the chance of successful use in practice. Furthermore, issues such as large scale production, formulation, preservation conditions, shelf life, and application methods should be considered early in the process of selecting BCAs against Verticillium. PMID- 28729856 TI - Biological Significance of Marine Actinobacteria of East Coast of Andhra Pradesh, India. AB - An attempt was made to identify actinobacterial strains present in the marine soil of East Coast regions viz., Chirala, Bapatla, and Peddaganjam, Andhra Pradesh; Kanyakumari, Tamil Nadu and Goa, Goa along with the study of their antimicrobial potential. Eight out of 73 actinobacterial strains isolated from these regions showed strong antimicrobial activity against Gram positive bacteria, Gram negative bacteria, and Candida albicans. Molecular identification (16S rRNA analysis) of the eight strains revealed that they belong to Dietzia sp., Kocuria sp., Nocardiopsis sp., and Streptomyces spp. ISP (International Streptomyces project) -1, ISP-2 and starch casein media supported high antimicrobial potential after 5-6 days of growth. Production of antimicrobials by the strains varied significantly with different carbon and nitrogen sources. Gas chromatography mass spectrometry (GCMS) analysis of volatile compounds produced by the strains illustrated an array of antimicrobial compounds such as 1, 2 benzene dicarboxylic acid, 2-piperidinone, pyrrolo[1,2-a]pyrazine-1,4-dion, phenyl ethyl alcohol, 3-phenyl propionic acid etc. Ours is the first report on the study and detection of above mentioned antimicrobial metabolites from Dietzia sp. (A3), Kocuria sp. (A5), and Nocardiopsis sp. (A7). By sequence based analysis for secondary metabolites, non-ribosomal peptide synthetase (NRPS) gene cluster was noticed in six strains (A2, A3, A4, A6, A7, and A8) and none of them had polyketide synthase (PKS) system. The present study intimates the biological potentiality of the actinobacterial strains isolated from East Coast of Andhra Pradesh, India which reveals further scope to investigate new bioactive compounds from them by employing both natural product chemistry and modern biotechnological aspects. PMID- 28729857 TI - Nutrient Acquisition and the Metabolic Potential of Photoferrotrophic Chlorobi. AB - Anoxygenic photosynthesis evolved prior to oxygenic photosynthesis and harnessed energy from sunlight to support biomass production on the early Earth. Models that consider the availability of electron donors predict that anoxygenic photosynthesis using Fe(II), known as photoferrotrophy, would have supported most global primary production before the proliferation of oxygenic phototrophs at approximately 2.3 billion years ago. These photoferrotrophs have also been implicated in the deposition of banded iron formations, the world's largest sedimentary iron ore deposits that formed mostly in late Archean and early Proterozoic Eons. In this work we present new data and analyses that illuminate the metabolic capacity of photoferrotrophy in the phylum Chlorobi. Our laboratory growth experiments and biochemical analyses demonstrate that photoferrotrophic Chlorobi are capable of assimilatory sulfate reduction and nitrogen fixation under sulfate and nitrogen limiting conditions, respectively. Furthermore, the evolutionary histories of key enzymes in both sulfur (CysH and CysD) and nitrogen fixation (NifDKH) pathways are convoluted; protein phylogenies, however, suggest that early Chlorobi could have had the capacity to assimilate sulfur and fix nitrogen. We argue, then, that the capacity for photoferrotrophic Chlorobi to acquire these key nutrients enabled them to support primary production and underpin global biogeochemical cycles in the Precambrian. PMID- 28729858 TI - Toxin-Antitoxin Systems in Estuarine Synechococcus Strain CB0101 and Their Transcriptomic Responses to Environmental Stressors. AB - Bacterial toxin-antitoxin (TA) systems are genetic elements composed of a toxin gene and its cognate antitoxin, with the ability to regulate growth. TA systems have not previously been reported in marine Synechococcus or Prochlorococcus. Here we report the finding of seven TA system pairs (Type II) in the estuarine Synechococcus CB0101, and their responses of these TA genes to under different stress conditions, which include; nitrogen and phosphate starvation, phage infection, zinc toxicity, and photo-oxidation. Database searches discovered that eight other marine Synechococcus strains also contain at least one TA pair but none were found in Prochlorococcus. We demonstrate that the relB/relE TA pair was active and resulted in RNA degradation when CB0101 was under oxidative stress caused by either zinc toxicity or high light intensities, but the growth inhibition was released when the stress was removed. Having TA systems allows Synechococcus CB0101 to adapt to the low light and highly variable environments in the Chesapeake Bay. We propose that TA systems could be more important for picocyanobacteria living in the freshwater and estuarine environments compared to those living in the open ocean. PMID- 28729859 TI - Transcriptomic Insight in the Control of Legume Root Secondary Infection by the Sinorhizobium meliloti Transcriptional Regulator Clr. AB - The cAMP-dependent transcriptional regulator Clr of Sinorhizobium meliloti regulates the overall number of infection events on Medicago roots by a so-far unknown mechanism requiring smc02178, a Clr-target gene of unknown function. In order to shed light on the mode of action of Clr on infection and potentially reveal additional biological functions for Clr, we inventoried genomic Clr target genes by transcriptome profiling. We have found that Clr positively controls the synthesis of cAMP-dependent succinoglycan as well as the expression of genes involved in the synthesis of a so-far unknown polysaccharide compound. In addition, Clr activated expression of 24 genes of unknown function in addition to smc02178. Genes negatively controlled by Clr were mainly involved in swimming motility and chemotaxis. Functional characterization of two novel Clr-activated genes of unknown function, smb20495 and smc02177, showed that their expression was activated by the same plant signal as smc02178 ex planta. In planta, however, symbiotic expression of smc02177 proved independent of clr. Both smc02177 and smb20495 genes were strictly required for the control of secondary infection on M. sativa. None of the three smc02177, smc02178 and smb20495 genes were needed for plant signal perception. Altogether this work provides a refined view of the cAMP-dependent Clr regulon of S. meliloti. We specifically discuss the possible roles of smc02177, smc02178, smb20495 genes and other Clr-controlled genes in the control of secondary infection of Medicago roots. PMID- 28729860 TI - Burn Injury Leads to Increase in Relative Abundance of Opportunistic Pathogens in the Rat Gastrointestinal Microbiome. AB - The gastrointestinal microbiome is crucial in human health. With greater than 10 times the cell count of an individual, the gastrointestinal microbiome provides many benefits to the host. It plays an important role in chronic illnesses and immune diseases and also following burns and trauma. This study aimed to determine whether severe burns affect the gastrointestinal microbiome during the early stages of after burn injury and the extent to which the microbiome is disturbed by such burns. We used a rat burn model to investigate any changes occurring in the microbiome after the burn trauma using 16S rRNA sequencing and downstream alpha-diversity, beta-diversity, and taxonomy analysis. With 128631 and 143694 clean sequence reads, an average of 2287 and 2416 operational taxonomic units (OTUs) were recognized before and after the burn injury, respectively. Bacterial diversity within the pre- and post-burn groups was similar according to OTU richness, Chao 1 index, Shannon index and ACE index. However, the constituents of the gastrointestinal microbiota changed after the burn injury. Compared with the pre-burn samples, the post-burn samples showed a tendency to cluster together. The ratio of Firmicutes to Bacteroidetes decreased after the burn injury. Also, the abundance of some probiotic organisms (i.e., butyrate-producing bacteria and Lactobacillus) decreased after the burn injury. In contrast, opportunistic pathogenic bacteria, such as those of the genera Escherichia and Shigella and the phylum of Proteobacteria are more abundant post burn. In conclusion, dysbiosis in the gastrointestinal microbiome was observed after the burn injury. Although the total number of species in the gastrointestinal microbiome did not differ significantly between the pre- and post-burn injury groups, the abundance of some bacterial components was affected to various extents. PMID- 28729861 TI - Comparative Omics and Trait Analyses of Marine Pseudoalteromonas Phages Advance the Phage OTU Concept. AB - Viruses influence the ecology and evolutionary trajectory of microbial communities. Yet our understanding of their roles in ecosystems is limited by the paucity of model systems available for hypothesis generation and testing. Further, virology is limited by the lack of a broadly accepted conceptual framework to classify viral diversity into evolutionary and ecologically cohesive units. Here, we introduce genomes, structural proteomes, and quantitative host range data for eight Pseudoalteromonas phages isolated from Helgoland (North Sea, Germany) and use these data to advance a genome-based viral operational taxonomic unit (OTU) definition. These viruses represent five new genera and inform 498 unaffiliated or unannotated protein clusters (PCs) from global virus metagenomes. In a comparison of previously sequenced Pseudoalteromonas phage isolates (n = 7) and predicted prophages (n = 31), the eight phages are unique. They share a genus with only one other isolate, Pseudoalteromonas podophage RIO-1 (East Sea, South Korea) and two Pseudoalteromonas prophages. Mass-spectrometry of purified viral particles identified 12-20 structural proteins per phage. When combined with 3-D structural predictions, these data led to the functional characterization of five previously unidentified major capsid proteins. Protein functional predictions revealed mechanisms for hijacking host metabolism and resources. Further, they uncovered a hybrid sipho-myovirus that encodes genes for Mu-like infection rarely described in ocean systems. Finally, we used these data to evaluate a recently introduced definition for virus populations that requires members of the same population to have >95% average nucleotide identity across at least 80% of their genes. Using physiological traits and genomics, we proposed a conceptual model for a viral OTU definition that captures evolutionarily cohesive and ecologically distinct units. In this trait-based framework, sensitive hosts are considered viral niches, while host ranges and infection efficiencies are tracked as viral traits. Quantitative host range assays revealed conserved traits within virus OTUs that break down between OTUs, suggesting the defined units capture niche and fitness differentiation. Together these analyses provide a foundation for model system-based hypothesis testing that will improve our understanding of marine copiotrophs, as well as phage-host interactions on the ocean particles and aggregates where Pseudoalteromonas thrive. PMID- 28729862 TI - Rad51 Interacts with Non-structural 3 Protein of Hepatitis C Virus and Regulates Viral Production. AB - Hepatitis C virus (HCV) is a leading cause of chronic liver disease affecting over 170 million people worldwide. Chronic infection with HCV progresses to liver fibrosis, cirrhosis, and hepatocellular carcinoma. HCV exploits host cellular factors for viral propagation. To investigate the cellular factors required for HCV propagation, we screened a siRNA library targeting human cell cycle genes using cell culture grown HCV-infected cells. In the present study, we selected and characterized a gene encoding Rad51. Rad51, a member of a conserved recombinase family, is an essential factor for homologous recombination and repair of double-strand DNA breaks. We demonstrated that siRNA-mediated knockdown of Rad51 significantly inhibited HCV propagation without affecting HCV RNA replication. Silencing of Rad51 impaired secretion of infectious HCV particles and thus intracellular viruses were accumulated. We showed that HCV NS3 specifically interacted with Rad51 and accumulated Rad51 in the cytosol. Furthermore, Rad51 was coprecipitated with NS3 and HCV RNA. By employing membrane flotation and protease protection assays, we also demonstrated that Rad51 was co fractionated with HCV NS3 on the lipid raft. These data indicate that Rad51 may be a component of the HCV RNA replication complex. Collectively, these data suggest that HCV may exploit cellular Rad51 to promote viral propagation and thus Rad51 may be a potential therapeutic target for HCV. PMID- 28729863 TI - Effects of Physiochemical Factors on Prokaryotic Biodiversity in Malaysian Circumneutral Hot Springs. AB - Malaysia has a great number of hot springs, especially along the flank of the Banjaran Titiwangsa mountain range. Biological studies of the Malaysian hot springs are rare because of the lack of comprehensive information on their microbial communities. In this study, we report a cultivation-independent census to describe microbial communities in six hot springs. The Ulu Slim (US), Sungai Klah (SK), Dusun Tua (DT), Sungai Serai (SS), Semenyih (SE), and Ayer Hangat (AH) hot springs exhibit circumneutral pH with temperatures ranging from 43 degrees C to 90 degrees C. Genomic DNA was extracted from environmental samples and the V3 V4 hypervariable regions of 16S rRNA genes were amplified, sequenced, and analyzed. High-throughput sequencing analysis showed that microbial richness was high in all samples as indicated by the detection of 6,334-26,244 operational taxonomy units. In total, 59, 61, 72, 73, 65, and 52 bacterial phyla were identified in the US, SK, DT, SS, SE, and AH hot springs, respectively. Generally, Firmicutes and Proteobacteria dominated the bacterial communities in all hot springs. Archaeal communities mainly consisted of Crenarchaeota, Euryarchaeota, and Parvarchaeota. In beta diversity analysis, the hot spring microbial memberships were clustered primarily on the basis of temperature and salinity. Canonical correlation analysis to assess the relationship between the microbial communities and physicochemical variables revealed that diversity patterns were best explained by a combination of physicochemical variables, rather than by individual abiotic variables such as temperature and salinity. PMID- 28729864 TI - Synechococcus Assemblages across the Salinity Gradient in a Salt Wedge Estuary. AB - Synechococcus are the most abundant and widely distributed picocyanobacteria in the ocean. The salt-wedge type of estuary possesses the complete horizontal and vertical gradient of salinity together with other physical and chemical parameters. In order to reveal whether such a complex environmental gradient harbors a high diversity of Synechococcus, we investigated the abundance, taxonomic composition and pigment genetic diversity of Synechococcus in surface and bottom waters across the salinity gradient in a salt-wedge estuary by flow cytometric analysis and pyrosequencing of the rpoC1 gene and cpcBA operon (encoding phycocyanin). Synechococcus were ubiquitously distributed in the studied region, with clear spatial variations both horizontally and vertically. The abundance and diversity of Synechococcus were low in the freshwater-dominated low salinity waters. By pyrosequencing of the rpoC1 gene, we have shown that with the increase of salinity, the dominant Synechococcus shifted from the freshwater Synechococcus to the combination of phylogenetic subcluster 5.2 and freshwater Synechococcus, and then the strictly marine subcluster 5.1 clade III. Besides, the composition of Synechococcus assemblage in the deep layer was markedly different from the surface in the stratified waters (dissimilarities: 40.32% 95.97%, SIMPER analysis). High abundance of clade III Synechococcus found in the brackish waters may revise our previous understanding that strains of this clade prefers oligotrophic environment. Our data also suggested that both the phylogenetic subcluster 5.3 Synechococcus, a lineage that was not well understood, and subcluster 5.1 clade I, a typical cold water lineage, were widely distributed in the bottom layer of the estuary. Clade I detected in the studied region was mainly contributed by subclade IG. Analysis of the cpcBA operon sequences revealed niche partitioning between type 1 and type 3 Synechococcus, with type 2 distributed broadly across the whole environmental gradients. Our results suggest that the salt wedge estuary provides various niches for different lineages of Synechococcus, making it an environment with high Synechococcus diversity compared with adjacent freshwater and shelf sea environments. PMID- 28729865 TI - A Novel and Validated Protocol for Performing MIC Tests to Determine the Susceptibility of Piscirickettsia salmonis Isolates to Florfenicol and Oxytetracycline. AB - This paper presents a validated protocol, using a novel, specifically formulated medium, to perform broth microdilution antimicrobial susceptibility assays of the salmonid bacterial pathogen Piscirickettsia salmonis. The minimum inhibitory concentrations (MIC) for florfenicol and oxytetracycline against 58 P. salmonis isolates recovered from various outbreaks occurred in Chilean salmonid farms were determined using this protocol. Normalized resistance interpretation (NRI) analysis was applied to these data to calculate appropriate protocol-specific epidemiological cut-off values. These cut-off values allow the isolates to be categorized as either fully susceptible wild type (WT) members of this species, or as manifesting reduced susceptibility non-wild type (NWT). The distribution of MIC values of florfenicol was bimodal and the distribution of the normalized values for the putative WT observation had a standard deviation of 0.896 log2 MUg mL-1. This analysis calculated a cut-off value of <=0.25 MUg mL-1 and categorized 33 (56%) of the isolates as manifesting reduced susceptibility to florfenicol. For the oxytetracycline MIC data the NRI analysis also treated the distribution as bimodal. The distribution of the normalized values for the putative WT observation had a standard deviation of 0.951 log2 MUg mL-1. This analysis gave a cut-off value of <=0.5 MUg mL-1 and categorized five isolates (9%) as manifesting reduced susceptibility to oxytetracycline. The susceptibility testing protocol developed in this study was capable of generating MIC data from all the isolates tested. On the basis of the precision of the data it generated, and the degree of separation of values for WT and NWT it achieved, it is argued that this protocol has the performance characteristics necessary for it to be considered as a standard protocol. PMID- 28729867 TI - Exposure to the Epstein-Barr Viral Antigen Latent Membrane Protein 1 Induces Myelin-Reactive Antibodies In Vivo. AB - Multiple sclerosis (MS) is an autoimmune chronic inflammatory disease of the central nervous system (CNS). Cross-reactivity of neuronal proteins with exogenous antigens is considered one of the possible mechanisms of MS triggering. Previously, we showed that monoclonal myelin basic protein (MBP)-specific antibodies from MS patients cross-react with Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1). In this study, we report that exposure of mice to LMP1 results in induction of myelin-reactive autoantibodies in vivo. We posit that chronic exposure or multiple acute exposures to viral antigen may redirect B cells from production of antiviral antibodies to antibodies, specific to myelin antigen. However, even in inbred animals, which are almost identical in terms of their genomes, such an effect is only observed in 20-50% of animals, indicating that this change occurs by chance, rather than systematically. Cross immunoprecipitation analysis showed that only part of anti-MBP antibodies from LMP1-immunized mice might simultaneously bind LMP1. In contrast, the majority of anti-LMP1 antibodies from MBP-immunized mice bind MBP. De novo sequencing of anti LMP1 and anti-MBP antibodies by mass spectrometry demonstrated enhanced clonal diversity in LMP1-immunized mice in comparison with MBP-immunized mice. We suggest that induction of MBP-reactive antibodies in LMP1-immunized mice may be caused by either Follicular dendritic cells (FDCs) or by T cells that are primed by myelin antigens directly in CNS. Our findings help to elucidate the still enigmatic link between EBV infection and MS development, suggesting that myelin reactive antibodies raised as a response toward EBV protein LMP1 are not truly cross-reactive but are primarily caused by epitope spreading. PMID- 28729868 TI - The C4 Model Grass Setaria Is a Short Day Plant with Secondary Long Day Genetic Regulation. AB - The effect of photoperiod (day:night ratio) on flowering time was investigated in the wild species, Setaria viridis, and in a set of recombinant inbred lines (RILs) derived from a cross between foxtail millet (S. italica) and its wild ancestor green foxtail (S. viridis). Photoperiods totaled 24 h, with three trials of 8:16, 12:12 and 16:8 light:dark hour regimes for the RIL population, and these plus 10:14 and 14:10 for the experiments with S. viridis alone. The response of S. viridis to light intensity as well as photoperiod was assessed by duplicating photoperiods at two light intensities (300 and 600 MUmol.m-2.s-1). In general, day lengths longer than 12 h delayed flowering time, although flowering time was also delayed in shorter day-lengths relative to the 12 h trial, even when daily flux in high intensity conditions exceeded that of the low intensity 12 h trial. Cluster analysis showed that the effect of photoperiod on flowering time differed between sets of RILs, with some being almost photoperiod insensitive and others being delayed with respect to the population as a whole in either short (8 or 12 h light) or long (16 h light) photoperiods. QTL results reveal a similar picture, with several major QTL colocalizing between the 8 and 12 h light trials, but with a partially different set of QTL identified in the 16 h trial. Major candidate genes for these QTL include several members of the PEBP protein family that includes Flowering Locus T (FT) homologs such as OsHd3a, OsRFT1, and ZCN8/12. Thus, Setaria is a short day plant (flowering quickest in short day conditions) whose flowering is delayed by long day lengths in a manner consistent with the responses of most other members of the grass family. However, the QTL results suggest that flowering time under long day conditions uses additional genetic pathways to those used under short day conditions. PMID- 28729866 TI - Cytokine-Induced Killer Cells As Pharmacological Tools for Cancer Immunotherapy. AB - Cytokine-induced killer (CIK) cells are a heterogeneous population of effector CD3+CD56+ natural killer T cells, which can be easily expanded in vitro from peripheral blood mononuclear cells. CIK cells work as pharmacological tools for cancer immunotherapy as they exhibit MHC-unrestricted, safe, and effective antitumor activity. Much effort has been made to improve CIK cells cytotoxicity and treatments of CIK cells combined with other antitumor therapies are applied. This review summarizes some strategies, including the combination of CIK with additional cytokines, dendritic cells, check point inhibitors, antibodies, chemotherapeutic agents, nanomedicines, and engineering CIK cells with a chimeric antigen receptor. Furthermore, we briefly sum up the clinical trials on CIK cells and compare the effect of clinical CIK therapy with other immunotherapies. Finally, further research is needed to clarify the pharmacological mechanism of CIK and provide evidence to formulate uniform culturing criteria for CIK expansion. PMID- 28729869 TI - Genetic Patterns of Myrceugenia correifolia, a Rare Species of Fog-Dependent Forests of Mediterranean Chile: Is It a Climatic Relict? AB - Rare species frequently occur in areas with microclimatic conditions that are atypical for their regions, but that were more common in the past, and that probably have operated as climatic refugia for a long time. Myrceugenia correifolia is a rare arboreal species that grows in deep canyons and hilltops of the Coast Range of north-central Chile between 30 degrees and 35 degrees S. In the northern edge of its distribution M. correifolia grows in small patches of fog-dependent forest surrounding by xeric vegetation. These forest formations are thought to be remnants of an ancient and continuous rainforest that according to some authors became fragmented during aridization of the Neogene (Neogene relict) and to others during warm-dry cycles of the Pleistocene (glacial relicts). Here we asked whether the northernmost populations of M. correifolia are Neogene relicts, glacial relicts, or the result of a recent northward colonization. To answer this question we examined genetic diversity and population divergence of M. correifolia using microsatellite markers, tested various competing population history scenarios with an approximate Bayesian computation (ABC) method, and complemented these data with ecological niche modeling (ENM). We detected three genetic clusters with a distinctive latitudinal pattern (north, center, and south) and high levels of differentiation (FST = 0.36). Demographic inference supported an admixture event 31 kya between two populations that diverged from an ancient population 139 kya. The admixture time coincides with the beginning of a period of wet conditions in north-central Chile that extended from 33 to 19 kya and was preceded by dry and cold conditions. These results suggest that increased precipitation during glacial periods triggered northward expansion of the range of M. correifolia, with subsequent admixture between populations that remained separated during interglacial periods. Accordingly, ENM models showed that suitable habitats for M. correifolia in north-central Chile were larger and less fragmented during the Last Glacial Maximum than at present, suggesting that northernmost populations of this species are glacial relicts. PMID- 28729870 TI - Plastid-Nucleus Distance Alters the Behavior of Stromules. AB - Plastids send "retrograde" signals to the nucleus to deliver information regarding their physiological status. One open question concerning this signal transfer is how the signal bridges the cytoplasm. Based on individual reports of plastid derived tubular membrane extensions connecting to nuclei, these so-called stromules have been suggested to function as communication routes between plastids and nuclei in response to biotic stress. However, based on the data currently available it is unclear whether interactions between stromules and nuclei are truly intentional or observed as a result of an inflated stromule frequency throughout the cell, and are thus a random event. The source of this uncertainty stems from missing information regarding the relative distribution of all plastids and stromules within a given cell. A comprehensive analysis of the upper epidermis of Arabidopsis thaliana rosette leaves was performed via a combination of still images and time-lapse movies of stromule formation in the context of the whole cell. This analysis could definitively confirm that stromule formation is not evenly distributed. Stromules are significantly more frequent within 8 MUm of the nucleus, and approximately 90% of said stromules formed facing the nucleus. Time-lapse movies revealed that this enrichment of stromules is achieved via a 10-fold higher frequency of stromule initiation events within this 8 MUm zone compared to the cell periphery. Following the movement of plastids and nuclei it became evident that movement and formation of stromules is correlated to nucleus movement. Observations suggest that stromules "connecting" to the nucleus are not necessarily the result of plastids sensing the nucleus and reaching out toward it, but are rather pulled out of the surface of nucleus associated plastids during opposing movement of these two organelles. This finding does not exclude the possibility that stromules could be transferring signals to the nucleus. However, this work provides support for an alternative hypothesis to explain stromule-nuclear interactions, suggesting that the main purpose of nucleus associated stromules may be to ensure a certain number of plastids maintain contact with the constantly moving nucleus. PMID- 28729871 TI - Molecular Mapping of Flowering Time Major Genes and QTLs in Chickpea (Cicer arietinum L.). AB - Flowering time is an important trait for adaptation and productivity of chickpea in the arid and the semi-arid environments. This study was conducted for molecular mapping of genes/quantitative trait loci (QTLs) controlling flowering time in chickpea using F2 populations derived from four crosses (ICCV 96029 * CDC Frontier, ICC 5810 * CDC Frontier, BGD 132 * CDC Frontier and ICC 16641 * CDC Frontier). Genetic studies revealed monogenic control of flowering time in the crosses ICCV 96029 * CDC Frontier, BGD 132 * CDC Frontier and ICC 16641 * CDC Frontier, while digenic control with complementary gene action in ICC 5810 * CDC Frontier. The intraspecific genetic maps developed from these crosses consisted 75, 75, 68 and 67 markers spanning 248.8 cM, 331.4 cM, 311.1 cM and 385.1 cM, respectively. A consensus map spanning 363.8 cM with 109 loci was constructed by integrating four genetic maps. Major QTLs corresponding to flowering time genes efl-1 from ICCV 96029, efl-3 from BGD 132 and efl-4 from ICC 16641 were mapped on CaLG04, CaLG08 and CaLG06, respectively. The QTLs and linked markers identified in this study can be used in marker-assisted breeding for developing early maturing chickpea. PMID- 28729872 TI - PLC-Mediated Signaling Pathway in Pollen Tubes Regulates the Gametophytic Self incompatibility of Pyrus Species. AB - Among the Rosaceae species, the gametophytic self-incompatibility (GSI) is controlled by a single multi-allelic S locus, which is composed of the pistil-S and pollen-S genes. The pistil-S gene encodes a polymorphic ribonuclease (S RNase), which is essential for identifying self-pollen. However, the S-RNase system has not been fully characterized. In this study, the self-S-RNase inhibited the Ca2+-permeable channel activity at pollen tube apices and the selectively decreased phospholipase C (PLC) activity in the plasma membrane of Pyrus pyrifolia pollen tubes. Self-S-RNase decreased the Ca2+ influx through a PLC-mediated signaling pathway. Phosphatidylinositol-specific PLC has a 26-amino acid insertion in pollen tubes of the 'Jinzhuili' cultivar, which is a spontaneous self-compatible mutant of the 'Yali' cultivar. 'Yali' plants exhibit a typical S-RNase-based GSI. Upon self-pollination, PLC gene expression is significantly higher in 'Jinzhuili' pollen tubes than that in 'Yali' pollen tubes. Moreover, the PLC in pollen tubes can only interact with one of the two types of S-RNase from the style. In the Pyrus x bretschneideri Rehd, the PLC directly interacted with the S7-RNase in the pollen tube, but not with the S34 RNase. Collectively, our results reveal that the effects of S-RNase on PLC activity are required for S-specific pollen rejection, and that PLC-IP3 participates in the self-incompatibility reaction of Pyrus species. PMID- 28729873 TI - Ageratum enation virus Infection Induces Programmed Cell Death and Alters Metabolite Biosynthesis in Papaver somniferum. AB - A previously unknown disease which causes severe vein thickening and inward leaf curl was observed in a number of opium poppy (Papaver somniferum L.) plants. The sequence analysis of full-length viral genome and associated betasatellite reveals the occurrence of Ageratum enation virus (AEV) and Ageratum leaf curl betasatellite (ALCB), respectively. Co-infiltration of cloned agroinfectious DNAs of AEV and ALCB induces the leaf curl and vein thickening symptoms as were observed naturally. Infectivity assay confirmed this complex as the cause of disease and also satisfied the Koch's postulates. Comprehensive microscopic analysis of infiltrated plants reveals severe structural anomalies in leaf and stem tissues represented by unorganized cell architecture and vascular bundles. Moreover, the characteristic blebs and membranous vesicles formed due to the virus-induced disintegration of the plasma membrane and intracellular organelles were also present. An accelerated nuclear DNA fragmentation was observed by Comet assay and confirmed by TUNEL and Hoechst dye staining assays suggesting virus induced programmed cell death. Virus-infection altered the biosynthesis of several important metabolites. The biosynthesis potential of morphine, thebaine, codeine, and papaverine alkaloids reduced significantly in infected plants except for noscapine whose biosynthesis was comparatively enhanced. The expression analysis of corresponding alkaloid pathway genes by real time-PCR corroborated well with the results of HPLC analysis for alkaloid perturbations. The changes in the metabolite and alkaloid contents affect the commercial value of the poppy plants. PMID- 28729874 TI - Systematic Analysis of Hsf Family Genes in the Brassica napus Genome Reveals Novel Responses to Heat, Drought and High CO2 Stresses. AB - Drought and heat stress are major causes of lost plant crop yield. In the future, high levels of CO2, in combination of other abiotic stress factors, will become a novel source of stress. Little is known of the mechanisms involved in the acclimation responses of plants to this combination of abiotic stress factors, though it has been demonstrated that heat shock transcription factors (Hsfs) are involved in plant response to various abiotic stresses. In this study, we performed a genome-wide identification and a systematic analysis of genes in the Hsf gene family in Brassica napus. A total of 64 genes encoding Hsf proteins were identified and classified into 3 major classes: A, B and C. We found that, unlike in other eudicots, the A9 subclass is absent in rapeseed. Further gene structure analysis revealed a loss of the only intron in the DBD domain for BnaHsf63 and 64 within class C, which is evolutionarily conserved in all Hsf genes. Transcription profile results demonstrated that most BnaHsf family genes are upregulated by both drought and heat conditions, while some are responded to a high CO2 treatment. According to the combined RNA-seq and qRT-PCR analysis, the A1E/A4A/A7 subclasses were upregulated by both drought and heat treatments. Members in class C seemed to be predominantly induced only by drought. Among BnaHsf genes, the A2/A3/B2 subclasses were regulated by all three abiotic stresses. Members in A2/B2 subclasses were upregulated by drought and heat treatments, but were downregulated under high CO2 conditions. While the A3 subclass was upregulated by all the three abiotic stresses. Various stress related cis-acting elements, enriched in promoter regions, were correlated with the transcriptional response of BnaHsfs to these abiotic stresses. Further study of these novel groups of multifunctional BnaHsf genes will improve our understanding of plant acclimation response to abiotic stresses, and may be useful for improving the abiotic stress resistance of crop varieties. PMID- 28729875 TI - Searching for an Accurate Marker-Based Prediction of an Individual Quantitative Trait in Molecular Plant Breeding. AB - Molecular plant breeding with the aid of molecular markers has played an important role in modern plant breeding over the last two decades. Many marker based predictions for quantitative traits have been made to enhance parental selection, but the trait prediction accuracy remains generally low, even with the aid of dense, genome-wide SNP markers. To search for more accurate trait-specific prediction with informative SNP markers, we conducted a literature review on the prediction issues in molecular plant breeding and on the applicability of an RNA Seq technique for developing function-associated specific trait (FAST) SNP markers. To understand whether and how FAST SNP markers could enhance trait prediction, we also performed a theoretical reasoning on the effectiveness of these markers in a trait-specific prediction, and verified the reasoning through computer simulation. To the end, the search yielded an alternative to regular genomic selection with FAST SNP markers that could be explored to achieve more accurate trait-specific prediction. Continuous search for better alternatives is encouraged to enhance marker-based predictions for an individual quantitative trait in molecular plant breeding. PMID- 28729876 TI - Genetic Architecture of Flooding Tolerance in the Dry Bean Middle-American Diversity Panel. AB - Flooding is a devastating abiotic stress that endangers crop production in the twenty-first century. Because of the severe susceptibility of common bean (Phaseolus vulgaris L.) to flooding, an understanding of the genetic architecture and physiological responses of this crop will set the stage for further improvement. However, challenging phenotyping methods hinder a large-scale genetic study of flooding tolerance in common bean and other economically important crops. A greenhouse phenotyping protocol was developed to evaluate the flooding conditions at early stages. The Middle-American diversity panel (n = 272) of common bean was developed to capture most of the diversity exits in North American germplasm. This panel was evaluated for seven traits under both flooded and non-flooded conditions at two early developmental stages. A subset of contrasting genotypes was further evaluated in the field to assess the relationship between greenhouse and field data under flooding condition. A genome wide association study using ~150 K SNPs was performed to discover genomic regions associated with multiple physiological responses. The results indicate a significant strong correlation (r > 0.77) between greenhouse and field data, highlighting the reliability of greenhouse phenotyping method. Black and small red beans were the least affected by excess water at germination stage. At the seedling stage, pinto and great northern genotypes were the most tolerant. Root weight reduction due to flooding was greatest in pink and small red cultivars. Flooding reduced the chlorophyll content to the greatest extent in the navy bean cultivars compared with other market classes. Races of Durango/Jalisco and Mesoamerica were separated by both genotypic and phenotypic data indicating the potential effect of eco-geographical variations. Furthermore, several loci were identified that potentially represent the antagonistic pleiotropy. The GWAS analysis revealed peaks at Pv08/1.6 Mb and Pv02/41 Mb that are associated with root weight and germination rate, respectively. These regions are syntenic with two QTL reported in soybean (Glycine max L.) that contribute to flooding tolerance, suggesting a conserved evolutionary pathway involved in flooding tolerance for these related legumes. PMID- 28729877 TI - Genetic Diversity, Population Structure, and Linkage Disequilibrium of an Association-Mapping Panel Revealed by Genome-Wide SNP Markers in Sesame. AB - The characterization of genetic diversity and population structure can be used in tandem to detect reliable phenotype-genotype associations. In the present study, we genotyped a set of 366 sesame germplasm accessions by using 89,924 single nucleotide polymorphisms (SNPs). The number of SNPs on each chromosome was consistent with the physical length of the respective chromosome, and the average marker density was approximately 2.67 kb/SNP. The genetic diversity analysis showed that the average nucleotide diversity of the panel was 1.1 * 10-3, with averages of 1.0 * 10-4, 2.7 * 10-4, and 3.6 * 10-4 obtained, respectively for three identified subgroups of the panel: Pop 1, Pop 2, and the Mixed. The genetic structure analysis revealed that these sesame germplasm accessions were structured primarily along the basis of their geographic collection, and that an extensive admixture occurred in the panel. The genome-wide linkage disequilibrium (LD) analysis showed that an average LD extended up to ~99 kb. The genetic diversity and population structure revealed in this study should provide guidance to the future design of association studies and the systematic utilization of the genetic variation characterizing the sesame panel. PMID- 28729878 TI - Transcriptional and Genomic Control of Stem Cells in Development and Cancer. PMID- 28729880 TI - Erratum to: Rpl22 is required for IME1 mRNA translation and meiotic induction in S. cerevisiae. AB - [This corrects the article DOI: 10.1186/s13008-016-0024-3.]. PMID- 28729879 TI - Safety and immunogenicity of the quadrivalent human papillomavirus (qHPV) vaccine in HIV-positive Spanish men who have sex with men (MSM). AB - BACKGROUND: Safety and immunogenicity of the quadrivalent human papillomavirus (qHPV) vaccine were evaluated in HIV-positive Spanish MSM. The prevalence of High Squamous Intraepithelial Lesions (HSIL) and genotypes of high-risk human papillomavirus (HR-HPV) were also determined, as well as risk factors associated with the presence of HR-HPV in anal mucosa. METHODS: This is a randomised, double blind, placebo-controlled trial of the quadrivalent HPV (qHPV) vaccine. The study enrolled from May 2012 to May 2014. Vaccine and placebo were administered at 0, 2 and 6 months (V1, V2, V3 clinical visits). Vaccine antibody titres were evaluated at 7 months. Cytology (Thin Prep(r) Pap Test), HPV PCR genotyping (Linear Array HPV Genotyping Test), and high-resolution anoscopy (Zeiss 150 fc(c) colposcope) were performed at V1. RESULTS: Patients (n = 162; mean age 37.9 years) were screened for inclusion; 14.2% had HSIL, 73.1% HR-HPV and 4.5% simultaneous infection with HPV16 and 18. Study participants (n = 129) were randomized to qHPV vaccine or placebo. The most common adverse event was injection-site pain predominating in the placebo group [the first dose (83.6% vs. 56.1%; p = 0.0001]; the second dose (87.8% vs. 98.4%; p = 0.0001); the third dose (67.7% vs. 91.9%; p = 0.0001). The vaccine did not influence either the viral load of HIV or the levels of CD4. Of those vaccinated, 76% had antibodies to HPV vs. 30.2% of those receiving placebo (p = 0.0001). In the multivariate analysis, Older age was associated with lower HR-HPV infection (RR 0.97; 95% CI 0.96-0.99), and risk factor were viral load of HIV >200 copies/uL (RR 1.42 95% CI 1.17-1.73) and early commencement of sexual activity (RR 1.35; 95% CI 1.001-1.811). CONCLUSIONS: This trial showed significantly higher anti-HR-HPV antibody titres in vaccinated individuals than in unvaccinated controls. There were no serious adverse events attributable to the vaccine. In our cohort, 1 of every 7 patients had HSIL and the prevalence of combined infection by genotypes 16 and 18 was low. This suggests that patients could benefit from receiving qHPV vaccine. Older age was the main protective factor against HR-HPV infection, and non-suppressed HIV viremia was a risk factor. Clinical trial registration: ISRCTN14732216 (http://www.isrctn.com/ISRCTN14732216). PMID- 28729881 TI - Outcomes following repair of incarcerated and strangulated ventral hernias with or without synthetic mesh. AB - BACKGROUND: The use of synthetic mesh for ventral hernia repair under contaminated conditions is a controversial issue due to the considerable risk of surgical site infection (SSI). This study aimed to review the outcomes of repair of incarcerated and strangulated ventral hernias with or without synthetic mesh in compliance with established clinical guidelines regarding the incidence of SSI and hernia recurrence. METHODS: The records of patients with complicated ventral hernias who were treated with or without synthetic mesh repair were reviewed. Variables collected included the characteristics of patients and of ventral hernias, type of repair, and incidence of SSI and recurrence. RESULTS: One hundred twenty-two patients (56 males) of a mean age of 56 years were included. Fifty-two (42.6%) and 70 (57.4%) patients presented with incarcerated and strangulated ventral hernias, respectively. Sixty-six (54%) patients were treated with on-lay mesh repair, and 56 (46%) were managed with suture repair. Twenty-one patients required bowel resection. SSI was detected in eight (6.5%) patients. There was no significant difference between both groups regarding the incidence of SSI (7.5% for mesh group vs 5.3% for suture group). Recurrence occurred in seven patients. Median follow-up period was 24 months. The suture repair group had a significantly higher incidence of recurrence than the mesh group. Diabetes mellitus, previous recurrence, and intestinal resection were significant predictors for SSI. CONCLUSION: Following established guidelines, synthetic mesh repair of incarcerated and strangulated ventral hernias attained lower recurrence rate, comparable incidence of SSI, and higher rate of seroma formation than suture repair. TRIAL REGISTRATION: Research Registry, researchregistry1891. PMID- 28729883 TI - The Influence of Health Messaging Source and Frequency on Maternal Smoking and Child Exposure among Low-Income Mothers. AB - Addressing maternal smoking and child tobacco smoke exposure (TSE) remains a public health priority, particularly in low-income, underserved populations which are known to experience the highest TSE rates and tobacco-related morbidity/mortality. Little is known about the types of TSE messaging received in high-risk populations, and which communication channels are influential in promoting smokers' efforts to protect children from TSE. The purpose of this study was to examine associations between reported sources and frequency of TSE reduction health messages maternal smokers received and the effects of the messaging on smoking-and TSE-reduction related behaviors. Maternal smokers from low-income communities in Philadelphia, Pennsylvania who were enrolled at baseline in the Family Rules for Establishing Smokefree Homes (FRESH) trial (N=359) were included in this study. Each participant completed a 60-minute in home baseline interview, which included questions about their smoking history, current smoking patterns, children's TSE, and the TSE-related health messaging they had received prior to enrollment. Multivariable analyses were conducted to determine the effect of source messaging on mothers' knowledge, behavior, and intention regarding their baby's TSE. Results suggest that different sources of messaging may differentially impact smoking behavior and intention to change. For example, messaging from healthcare and dental providers may influence efforts to protect children from TSE whereas friends and family may influence intention to quit. Future studies could examine the value of multilevel health communication strategies, utilizing advice from healthcare providers that is augmented by family and peers to help promote smoking behavior change in this high-risk group of underserved postpartum smokers. PMID- 28729882 TI - Breastfeeding is associated with enhanced learning abilities in school-aged children. AB - OBJECTIVE: The majority of studies on the associations between breastfeeding and cognitive functioning have focused on IQ, with only a few investigating learning skills, and none of the latter adjusting for maternal IQ. We examined the association between breastfeeding and learning abilities in school-aged children using a cross-sectional design. METHODS: We recruited 868 children, aged 8-11 years and parents completed the Learning Disability Evaluation Scale (LDES). Multivariable linear regression models were used and age, gender, area of residence, annual family income, maternal education, and maternal age at delivery, were included as covariates. Maternal IQ was added to further adjust for the effects of maternal cognitive ability. Path analysis was conducted to investigate the mediation effect of maternal IQ between breastfeeding and learning skills. RESULTS: Children who were ever-breastfed had higher learning quotient scores on the LDES (p = 0.001) as well as higher scores on subscales related to speaking (p = 0.001), reading (p = 0.005), writing (p = 0.004), spelling (p = 0.003), and mathematical calculation (p = 0.003) than the never breastfed participants. All of these variables remained significant after adjusting for gestational and socioeconomic factors and for maternal IQ as covariates. The path analysis showed that breastfeeding had both indirect and direct effects on the learning quotient. CONCLUSIONS: The results suggest that breastfeeding is positively associated with learning skills in school-aged children. PMID- 28729884 TI - Genome-wide landscape of position effects on heterogeneous gene expression in Saccharomyces cerevisiae. AB - BACKGROUND: Integration of heterogeneous genes is widely applied in synthetic biology and metabolic engineering. However, knowledge about the effect of integrative position on gene expression remains limited. RESULTS: We established a genome-wide landscape of position effect on gene expression in Saccharomyces cerevisiae. The expression cassette of red fluorescence protein (RFP) gene was constructed and inserted at 1044 loci, which were scattered uniformly in the yeast genome. Due to the different integrative loci on the genome, the maximum relative intensity of RFP is more than 13-fold over the minimum. Plots of the number of strains to RFP relative intensity showed normal distribution, indicating significant position effect on gene expression in yeast. Furthermore, changing the promoters or reporter genes, as well as carbon sources, revealed little consequences on reporter gene expression, indicating chromosomal location is the major determinant of reporter gene expression. CONCLUSIONS: We have examined the position effects to integration genes expression in large number loci around whole genome in S. cerevisiae. The results could guide the design of integration loci for exogenous genes and pathways to maximize their expression in metabolic engineering. PMID- 28729885 TI - CD36 overexpression: a possible etiopathogenic mechanism of atherosclerosis in patients with prediabetes and diabetes. AB - RATIONALE: CD36 is a scavenger receptor located on monocytes which is involved in foam cell transformation. AIM: To evaluate CD36 expression under different glycemic states in both healthy subjects and in atherosclerotic patients. SUBJECTS AND METHODS: In order to evaluate the possible effects of hyperglycemia on CD36 expression in healthy subjects, an in vitro experiment was carried out using monocyte in three different conditions: extreme hyperglycemia (HG), euglycemia (EG) and in the absence of glucose. On the other hand, three groups of atherosclerotic patients were evaluated according to their glycemic conditions: normoglycemic (NG), prediabetic (preDM) and diabetic (DM) patients. CD36 expression (mRNA, non-glycated and glycated protein) was analyzed in monocytes. RESULTS: CD36 mRNA expression in the in vitro experiment peaked at 4 and 24 h under HG conditions. No differences in mRNA levels were found in the EG and control group. The level of non-glycated proteins was higher in HG and EG conditions compared with control group. Glycated protein expression was inhibited by glucose in a sustained manner. In atherosclerotic patients, a significant association was observed when comparing glycated CD36 protein expression in DM with NG patients (p = 0.03). No significant differences were found in mRNA and non-glycated CD36 expression in these patients. Moreover, BMI, insulin, weight and treatment were shown to be related to CD36 expression (mRNA, non-glycated and glycated protein levels, depending of the case) in atherosclerotic patients. CONCLUSIONS: Hyperglycemia is an important modulator of CD36 mRNA and non glycated protein expression in vitro, increasing de novo synthesis in healthy subjects. In atherosclerotic patients, there are progressive increases in CD36 receptors, which may be due to a post-translational stimulus. PMID- 28729886 TI - On-Site Classification of Pansteatitis in Mozambique Tilapia (Oreochromis mossambicus) using a Portable Lipid-Based Analyzer. AB - While no pansteatitis-related large-scale mortality events have occurred since 2008, the current status of pansteatitis (presence and pervasiveness) in the Olifants River system and other regions of South Africa remain largely unknown. In part, this is due to both a lack of known biological markers of pansteatitis and a lack of suitable non-invasive assays capable of rapidly classifying the disease. Here, we propose the application of a point-of-care (POC) device using lipid-based test strips (total cholesterol (TC) and total triglyceride (TG)), for classifying pansteatitis status in the whole blood of pre-spawning Mozambique tilapia (Oreochromis mossambicus). Using the TC strips, the POC device was able to non-lethally classify the tilapia as either healthy or pansteatitis-affected; the sexes were examined independently because sexual dimorphism was observed for TC (males p = 0.0364, females chi2 = 0.0007). No significant difference between diseased and pansteatitis-affected tilapia was observed using the TG strips. This is one of the first described applications of using POC devices for on-site environmental disease state testing. A discussion on the merits of using portable lipid-based analyzers as an in-field disease-state diagnostic tool is provided. PMID- 28729888 TI - Social brain circuitry and social cognition in infants born preterm. AB - Preterm birth is associated with an increased risk of adverse neurologic, psychiatric, and cognitive outcomes. The brain circuits involved in processing social information are critical to all of these domains, but little work has been done to examine whether and how these circuits may be especially sensitive to prematurity. This paper contains a brief summary of some of the cognitive, psychiatric, and social outcomes associated with prematurity, followed by a description of findings from the modest body of research into social-cognitive development in infants and children born preterm. Next, findings from studies of structural and functional brain development in infants born preterm are reviewed, with an eye toward the distinctive role of the brain circuits implicated in social functioning. The goal of this review is to investigate the extent to which the putative "social brain" may have particular developmental susceptibilities to the insults associated with preterm birth, and the role of early social-cognitive development in later neurodevelopmental outcomes. Much work has been done to characterize neurobehavioral outcomes in the preterm population, but future research must incorporate both brain and behavioral measures to identify early biomarkers linked to later emerging social-cognitive clinical impairment in order to guide effective, targeted intervention. PMID- 28729887 TI - Whole-body vibration training improves balance control and sit-to-stand performance among middle-aged and older adults: a pilot randomized controlled trial. AB - BACKGROUND: Aging is associated with decreased balance, which increases falling risk. The objective of the current study was to determine the feasibility and effects of whole-body vibration (WBV) training on knee extensor muscle power, limits of stability, and sit-to-stand performance among community-dwelling middle aged and older adults in the United States. METHODS: A randomized pilot study with participant blinding was conducted. Feasibility outcomes included recruitment and compliance rate. Twenty-nine community-dwelling older adults were randomly assigned to perform body-weight exercises with either an individualized vibration frequency and amplitude, a fixed vibration frequency and amplitude, or no vibration. Isokinetic knee extensor power, limits of stability, and sit-to stand tests were conducted before beginning the exercises (baseline) and after 8 weeks of training. RESULTS: With a favorable recruitment rate (58%) and compliance rates (attrition 9%; adherence 85%), the intervention was deemed feasible. The limits of stability endpoint excursion score for the individualized frequency-amplitude group was increased by 8.8 (12.9%; P = 0.025) after training, and that group's maximum excursion score was increased by 9.2 (11.5%; P = 0.006) after training. The average weight transfer time score was significantly decreased by 0.2 s in the fixed group. The participants in the individualized group demonstrated a significant increase (3.2%) in weight rising index score after 8 weeks of WBV training. CONCLUSIONS: WBV training is feasible for use with elderly people, and this study achieved good recruitment and compliance. The present paper suggests that 8 weeks of WBV training improves limits of stability and sit-to-stand performance. Future studies must determine whether WBV training improves other factors that affect posture control. TRIAL REGISTRATION: This study was registered at the Texas Woman's University Institutional Review Board [TWU IRB 17632] on the 3rd of November 2014. PMID- 28729889 TI - Differential methylation at MHC in CD4+ T cells is associated with multiple sclerosis independently of HLA-DRB1. AB - BACKGROUND: Although many genetic variants have been associated with multiple sclerosis (MS) risk, they do not explain all the disease risk and there remains uncertainty as to how these variants contribute to disease. DNA methylation is an epigenetic mechanism that can influence gene expression and has the potential to mediate the effects of environmental factors on MS. In a previous study, we found a differentially methylation region (DMR) at MHC HLA-DRB1 that was associated within relapsing-remitting MS (RRMS) patients in CD4+ T cells. This study aimed to confirm this earlier finding in an independent RRMS cohort of treatment-naive female patients. METHODS: Total genomic DNA was extracted from CD4+ T cells of 28 female RRMS and 22 age-matched healthy controls subjects. DNA was bisulfite converted and hybridised to Illumina 450K arrays. Beta values for all CpGs were analysed using the DMPFinder function in the MINFI program, and a follow-up prioritisation process was applied to identify the most robust MS-associated DMRs. RESULTS: This study confirmed our previous findings of a hypomethylated DMR at HLA-DRB1 and a hypermethylated DMR at HLA-DRB5 in this RRMS patient cohort. In addition, we identified a large independent DMR at MHC, whereby 11 CpGs in RNF39 were hypermethylated in MS cases compared to controls (max. ?beta = 0.19, P = 2.1 * 10-4). We did not find evidence that SNP genotype was influencing the DMR in this cohort. A smaller MHC DMR was also identified at HCG4B, and two non-MHC DMRs at PM20D1 on chr1 and ERICH1 on chr8 were also identified. CONCLUSIONS: The findings from this study confirm our previous results of a DMR at HLA-DRB1 and also suggest hypermethylation in an independent MHC locus, RNF39, is associated with MS. Taken together, our results highlight the importance of epigenetic factors at the MHC locus in MS independent of treatment, age and sex. Prospective studies are now required to discern whether methylation at MHC is involved in influencing risk of disease onset or whether the disease itself has altered the methylation profile. PMID- 28729890 TI - Varieties of Confidence Intervals. AB - Error bars are useful to understand data and their interrelations. Here, it is shown that confidence intervals of the mean (CI M s) can be adjusted based on whether the objective is to highlight differences between measures or not and based on the experimental design (within- or between-group designs). Confidence intervals (CIs) can also be adjusted to take into account the sampling mechanisms and the population size (if not infinite). Names are proposed to distinguish the various types of CIs and the assumptions underlying them, and how to assess their validity is explained. The various CIs presented here are easily obtained from a succession of multiplicative adjustments to the basic (unadjusted) CI width. All summary results should present a measure of precision, such as CIs, as this information is complementary to effect sizes. PMID- 28729891 TI - Vibrational Excitation of H2 Scattering from Cu(111): Effects of Surface Temperature and of Allowing Energy Exchange with the Surface. AB - In scattering of H2 from Cu(111), vibrational excitation has so far defied an accurate theoretical description. To expose the causes of the large discrepancies with experiment, we investigate how the feature due to vibrational excitation (the "gain peak") in the simulated time-of-flight spectrum of (v = 1, j = 3) H2 scattering from Cu(111) depends on the surface temperature (Ts) and the possibility of energy exchange with surface phonons and electron-hole pairs (ehp's). Quasi-classical dynamics calculations are performed on the basis of accurate semiempirical density functionals for the interaction with H2 + Cu(111). The methods used include the quasi-classical trajectory method within the Born Oppenheimer static surface model, the generalized Langevin oscillator (GLO) method incorporating energy transfer to surface phonons, the GLO + friction (GLO+F) method also incorporating energy exchange with ehp's, and ab initio molecular dynamics with electronic friction (AIMDEF). Of the quasi-classical methods tested, comparison with AIMDEF suggests that the GLO+F method is accurate enough to describe vibrational excitation as measured in the experiments. The GLO+F calculations also suggest that the promoting effect of raising Ts on the measured vibrational excitation is due to an electronically nonadiabatic mechanism. However, by itself, enabling energy exchange with the surface by modeling surface phonons and ehp's leads to reduced vibrational excitation, further decreasing the agreement with experiment. The simulated gain peak is quite sensitive to energy shifts in calculated vibrational excitation probabilities and to shifts in a specific experimental parameter (the chopper opening time). While the GLO+F calculations allow important qualitative conclusions, comparison to quantum dynamics results suggests that, with the quasi classical way of describing nuclear motion and the present box quantization method for assigning the final vibrational state, the gain peak is not yet described with quantitative accuracy. Ways in which this problem might be resolved in the future are discussed. PMID- 28729892 TI - Reversible Charge Trapping in Bis-Carbazole-Diimide Redox Polymers with Complete Luminescence Quenching Enabling Nondestructive Read-Out by Resonance Raman Spectroscopy. AB - The coupling of substituted carbazole compounds through carbon-carbon bond formation upon one-electron oxidation is shown to be a highly versatile approach to the formation of redox polymer films. Although the polymerization of single carbazole units has been proposed earlier, we show that by tethering pairs of carbazoles double sequential dimerization allows for facile formation of redox polymer films with fine control over film thickness. We show that the design of the monomers and in particular the bridging units is key to polymer formation, with the diaminobenzene motif proving advantageous, in terms of the matching to the redox potentials of the monomer and polymer film and thereby avoiding limitations in film thickness (autoinsulation), but introduces unacceptable instability due to the intrinsic redox activity of this moiety. The use of a diimide protecting group both avoids complications due to p-diamino-benzene redox chemistry and provides for a redox polymer in which the photoluminescence of the bis-carbazole moiety can be switched reversibly (on/off) with redox control. The monomer design approach is versatile enabling facile incorporation of additional functional units, such as naphthalene. Here we show that a multicomponent carbazole/naphthalene containing monomer (APCNDI) can form redox polymer films showing both p- and n- conductivity under ambient conditions and allows access to five distinct redox states, and a complex electrochromic response covering the whole of the UV/vis-NIR spectral region. The highly effective quenching of the photoluminescence of both components in poly-APCNDI enables detailed characterization of the redox polymer films. The poly-APCNDI films show extensive charge trapping, which can be read out spectroscopically in the case of films and is characterized as kinetic rather than chemical in origin on the basis of UV/vis NIR absorption and resonance Raman spectroscopic analyses. The strong resonantly enhanced Raman scattering for the various oxidized and reduced states of APCNDI enables nondestructive "read-out" of the state of the polymer, including that in which charges are trapped kinetically at the surface, making poly-APCNDI highly suitable for application as a component in organic nonvolatile memory devices. PMID- 28729893 TI - Mechanically and Electrically Robust Self-Assembled Monolayers for Large-Area Tunneling Junctions. AB - This paper examines the relationship between mechanical deformation and the electronic properties of self-assembled monolayers (SAMs) of the oligothiophene 4 ([2,2':5',2":5",2'''-quaterthiophen]-5-yl)butane-1-thiol (T4C4) in tunneling junctions using conductive probe atomic force microscopy (CP-AFM) and eutectic Ga In (EGaIn). We compared shifts in conductivity, transition voltages of T4C4 with increasing AFM tip loading force to alkanethiolates. While these shifts result from an increasing tilt angle from penetration of the SAM by the AFM tip for the latter, we ascribe them to distortions of the pi system present in T4C4, which is more mechanically robust than alkanethiolates of comparable length; SAMs comprising T4C4 shows about five times higher Young's modulus than alkanethiolates. Density functional theory calculations confirm that mechanical deformations shift the barrier height due to changes in the frontier orbitals caused by small rearrangements to the conformation of the quaterthiophene moiety. The mechanical robustness of T4C4 manifests as an increased tolerance to high bias in large-area EGaIn junctions suggesting that electrostatic pressure plays a significant role in the shorting of molecular junctions at high bias. PMID- 28729894 TI - Analysis of Incomplete Longitudinal Binary Data-A Combined Markov's Transition and Logistic Model for Non-ignorable Missingness. AB - The problem of incomplete data is a common phenomenon in research that involves the longitudinal design approach. We investigate and develop a likelihood-based approach for incomplete longitudinal binary data using the disposition model when the missing value mechanism is non-ignorable. We combined Markov's transition and a logistic regression model to build the dropout process and model the response using conditional logistic regression model. By holding the missingness parameter that is weakly identified constant, we analyzed their effects through a sensitivity analysis as the estimation of parameters in MLE for non-ignorable missing data is not generally plausible. An application of our approach to Schizophrenia clinical trial is presented. PMID- 28729895 TI - What Can Geriatrics Teach Cardiology? PMID- 28729896 TI - Pseudoptosis Correction With the 270 degrees Pedicle Reduction Mammoplasty: An Anatomic and Clinical Study. AB - Background: Reduction mammoplasty techniques have evolved considerably. Today, aesthetically pleasing results and preservation of nipple sensation and vascularity are emphasized. Achieving the aforementioned goals for the patient with pseudoptosis remains challenging. Objective: We present 270 degrees pedicle reduction mammoplasty as a safe and direct technique for treatment of pseudoptosis to reduce size and improve breast shape. Methods: Circumareolar subcutaneous dissection of 10 breasts (5 cadavers) was performed to identify the nerves from the chest wall to the nipple. The trajectory of the nerves to the nipple was identified and dissected to their origin of penetration of the chest fascia. This information provides the basis for lateral chest wall tissue preservation for preserved nipple-areolar innervation, which is incorporated into this technique. Retrospective review of a single surgeon's experience with the 270 degrees pedicle technique for reduction mammoplasty over a 1-year period was performed. Results: Anatomic dissection identified 3 to 5 branches of the fourth intercostal nerve to primarily innervate the nipple on 8 of 10 breast dissections. Accessory innervation from the fifth intercostal nerve provided lateral branches to the nipple in 5 of 10 specimens. Five patients underwent reduction mammoplasty with the 270 degrees pedicle technique. No complications were identified. Excellent aesthetic outcomes were achieved on the basis of patient-reported satisfaction and the surgeon's judgment. All patients demonstrated normal nipple sensation at postoperative follow-up. Follow-up at 1 year did not demonstrate recurrence of ptosis/pseudoptosis or change in nipple position. Conclusions: The 270 degrees technique for pedicle reduction mammoplasty yields aesthetically pleasing results and symptomatic relief from macromastia and preserves nipple sensation. PMID- 28729897 TI - A mus-51 RIP allele for transformation of Neurospora crassa. AB - This report describes the construction and characterization of mus-51RIP70 , an allele for high-efficiency targeted integration of transgenes into the genome of the model eukaryote Neurospora crassa. Two of the mus-51RIP70 strains investigated in this work (RZS27.10 and RZS27.18) can be obtained from the Fungal Genetics Stock Center. The two deposited strains are, to our knowledge, genetically identical and neither one is preferred over the other for use in Neurospora research. PMID- 28729898 TI - Draft genome sequences of strains Salinicola socius SMB35T, Salinicola sp. MH3R3 1 and Chromohalobacter sp. SMB17 from the Verkhnekamsk potash mining region of Russia. AB - Halomonads are moderately halophilic bacteria that are studied as models of prokaryotic osmoadaptation and sources of enzymes and chemicals for biotechnological applications. Despite the progress in understanding the diversity of these organisms, our ability to explain ecological, metabolic, and biochemical traits of halomonads at the genomic sequence level remains limited. This study addresses this gap by presenting draft genomes of Salinicola socius SMB35T, Salinicola sp. MH3R3-1 and Chromohalobacter sp. SMB17, which were isolated from potash mine tailings in the Verkhnekamsk salt deposit area of Russia. The analysis of these genomes confirmed the importance of ectoines and quaternary amines to the capacity of halomonads to tolerate osmotic stress and adapt to hypersaline environments. The study also revealed that Chromohalobacter and Salinicola share 75-90% of the predicted proteome, but also harbor a set of genus-specific genes, which in Salinicola amounted to approximately 0.5 Mbp. These genus-specific genome segments may contribute to the phenotypic diversity of the Halomonadaceae and the ability of these organisms to adapt to changing environmental conditions and colonize new ecological niches. PMID- 28729899 TI - Evolutionary loss of melanogenesis in the tunicate Molgula occulta. AB - BACKGROUND: Analyzing close species with diverse developmental modes is instrumental for investigating the evolutionary significance of physiological, anatomical and behavioral features at a molecular level. Many examples of trait loss are known in metazoan populations living in dark environments. Tunicates are the closest living relatives of vertebrates and typically present a lifecycle with distinct motile larval and sessile adult stages. The nervous system of the motile larva contains melanized cells associated with geotactic and light-sensing organs. It has been suggested that these are homologous to vertebrate neural crest-derived melanocytes. Probably due to ecological adaptation to distinct habitats, several species of tunicates in the Molgulidae family have tailless (anural) larvae that fail to develop sensory organ-associated melanocytes. Here we studied the evolution of Tyrosinase family genes, indispensible for melanogenesis, in the anural, unpigmented Molgula occulta and in the tailed, pigmented Molgula oculata by using phylogenetic, developmental and molecular approaches. RESULTS: We performed an evolutionary reconstruction of the tunicate Tyrosinase gene family: in particular, we found that M. oculata possesses genes predicted to encode one Tyrosinase (Tyr) and three Tyrosinase-related proteins (Tyrps) while M. occulta has only Tyr and Tyrp.a pseudogenes that are not likely to encode functional proteins. Analysis of Tyr sequences from various M. occulta individuals indicates that different alleles independently acquired frameshifting short indels and/or larger mobile genetic element insertions, resulting in pseudogenization of the Tyr locus. In M. oculata, Tyr is expressed in presumptive pigment cell precursors as in the model tunicate Ciona robusta. Furthermore, a M. oculata Tyr reporter gene construct was active in the pigment cell precursors of C. robusta embryos, hinting at conservation of the regulatory network underlying Tyr expression in tunicates. In contrast, we did not observe any expression of the Tyr pseudogene in M. occulta embryos. Similarly, M. occulta Tyr allele expression was not rescued in pigmented interspecific M. occulta * M. oculata hybrid embryos, suggesting deleterious mutations also to its cis-regulatory sequences. However, in situ hybridization for transcripts from the M. occulta Tyrp.a pseudogene revealed its expression in vestigial pigment cell precursors in this species. CONCLUSIONS: We reveal a complex evolutionary history of the melanogenesis pathway in tunicates, characterized by distinct gene duplication and loss events. Our expression and molecular data support a tight correlation between pseudogenization of Tyrosinase family members and the absence of pigmentation in the immotile larvae of M. occulta. These results suggest that relaxation of purifying selection has resulted in the loss of sensory organ associated melanocytes and core genes in the melanogenesis biosynthetic pathway in M. occulta. PMID- 28729900 TI - Unravelling functional neurology: a scoping review of theories and clinical applications in a context of chiropractic manual therapy. AB - BACKGROUND: Functional Neurology (FN), a seemingly attractive treatment approach used by some chiropractors, proposes to have an effect on a multitude of conditions but some of its concepts are controversial. OBJECTIVES AND DESIGN: A scoping review was performed to describe, in the context of chiropractic manual therapy, 1) the FN theories, and 2) its clinical applications (i.e. its indications, examination procedures, treatment modalities, treatment plans, and clinical outcomes) using four sources: i) one key textbook, ii) the scientific peer-reviewed literature, iii) websites from chiropractors using FN, and iv) semi structured interviews of chiropractors using FN. METHODS: The scientific literature was searched in PubMed, PsycINFO, and SPORTDiscus, completed by a hand search in the journal Functional Neurology, Rehabilitation and Ergonomics (November 2016 and March 2017, respectively). The only textbook on the topic we found was included and articles were chosen if they had an element of manual therapy. There was no restriction for study design but discussion papers were excluded. Websites were found in Google using the search term "Functional Neurology". Chiropractors, known to use FN, were invited based on their geographical location. Theories were mainly uncovered in the textbook as were all aspects of the clinical applications except treatment plans. The other three sources were used for the five aspects of clinical applications. Results were summarized and reported extensively in tables. RESULTS: Eleven articles were included, five websites scrutinized, and four semi-structured interviews performed. FN is based on the belief that reversible lesions in the nervous system are the cause of a multitude of conditions and that specific clusters of neurons can be positively affected by manipulative therapy, but also by many other stimuli. Diagnostic procedures include both conventional and unusual tests, with an interpretation specific to FN. Initial treatment is intense and clinical outcomes reported as positive. CONCLUSION: FN gives the impression to be a complex alternative to the old variant of the chiropractic subluxation model, in which the vertebral subluxation is replaced by "physiological lesions" of the brain, and the treatment, spinal adjustments, are complemented by various neurological stimuli. Both models purport to treat not the symptoms but the cause. We conclude there is a need for more scientific documentation on the validity of FN. PMID- 28729902 TI - High tolerance to high-light conditions for the protected species Ariocarpus kotschoubeyanus (Cactaceae). AB - We determined the seasonal ecophysiological performance under perennial plants and under high solar radiation for adult individuals from the 'living rock' cactus Ariocarpus kotschoubeyanus, which occurs equally under nurse plants and in open spaces. We evaluated the effective quantum yield of photosystem II (PhiPSII) and the dissipation of thermal energy [non-photochemical quenching (NPQ)] thorough the year. The maximum apparent electron transport rate (ETRmax) and the saturating photosynthetically active photon flux density for PSII (PFDsat) were also determined from rapid light curves. We found that although the PhiPSII was higher in shaded sites under potential nurse plants than in exposed sites, all values were close to the optimal value of 0.83. The high PhiPSII found for A. kotschoubeyanus plants suggests that they use a great proportion of the absorbed light for photosynthesis, under nurse plants as well as in open spaces. We also found higher NPQ values in exposed sites than in shaded ones but only in Autumn, thus reducing the risk of photoinhibition. In addition, the PFDsat was higher in exposed sites than in shaded ones in Spring, Summer and Autumn, but in Winter there were no differences between treatments. We also found high saturating light levels for ETR (PFDsat higher than 1378 MUmol m-2 s-1) in all seasons but in winter for shaded and non-shaded plants. Our findings indicate that A. kotschoubeyanus plants use a great proportion of the light that they absorb for photosynthesis. This high tolerance to high-light conditions could explain why A. kotschoubeyanus do not show preferences for protected sites under nurse plants. PMID- 28729901 TI - Aptamer-functionalized neural recording electrodes for the direct measurement of cocaine in vivo. AB - Cocaine is a highly addictive psychostimulant that acts through competitive inhibition of the dopamine transporter. In order to fully understand the region specific neuropathology of cocaine abuse and addiction, it is unequivocally necessary to develop cocaine sensing technology capable of directly measuring real-time cocaine transient events local to different brain regions throughout the pharmacokinetic time course of exposure. We have developed an electrochemical aptamer-based in vivo cocaine sensor on a silicon based neural recording probe platform capable of directly measuring cocaine from discrete brain locations using square wave voltammetry (SWV). The sensitivity of the sensor for cocaine follows a modified exponential Langmuir model relationship and complete aptamer target binding occurs in < 2 sec and unbinding in < 4 sec. The resulting temporal resolution is a 75X increase from traditional microdialysis sampling methods. When implanted in the rat dorsal striatum, the cocaine sensor exhibits stable SWV signal drift (modeled using a logarithmic exponential equation) and is capable of measuring real-time in vivo response to repeated local cocaine infusion as well as systemic IV cocaine injection. The in vivo sensor is capable of obtaining reproducible measurements over a period approaching 3 hours, after which signal amplitude significantly decreases likely due to tissue encapsulation. Finally, aptamer functionalized neural recording probes successfully detect spontaneous and evoked neural activity in the brain. This dual functionality makes the cocaine sensor a powerful tool capable of monitoring both biochemical and electrophysiological signals with high spatial and temporal resolution. PMID- 28729903 TI - Tranexamic acid and trauma-induced coagulopathy. AB - Tranexamic acid (TXA) is a synthetic derivative of the amino acid lysine that inhibits fibrinolysis by blocking the interaction of plasminogen with the lysine residues of fibrin. Historically, TXA is commonly used for reduction of blood loss in perioperative situations, while recently it has attracted attention for clinical use in the trauma field. In 2010, the Clinical Randomization of an Antifibrinolytic in Significant Hemorrhage 2 (CRASH-2) trial demonstrated that intravenous administration of TXA improved mortality significantly in trauma patients with significant bleeding. After the launch of its sensational results, the main stream treatment protocol in trauma changed worldwide to include TXA administration. In this review, first we summarize the recent evidence or recommendations in the related guidelines concerning TXA. Also, we next tried to explore in detail not only the benefits but also the harm introduced by TXA in trauma patients, because the main adverse event results for TXA, such as vascular occlusive events in the CRASH-2 trial, are still being discussed in several papers. Thus, we briefly summarized the evidence for the safety of TXA administration by a systematic review method using observational studies. Consequently, the pooled relative risk for venous thromboembolisms was 1.61 (95% CI, 0.86-3.01), indicating a non-significant increase in the venous thromboembolism risk of TXA therapy. Regarding the basic mechanism, TXA potentially possesses the risk of venous thromboembolisms, so it should be used cautiously and selectively. Further investigation is needed to delineate the optimal targeted trauma patients to earn the maximum survival benefits with minimized risk of thrombotic complications. PMID- 28729904 TI - Impact of a sepsis bundle in wards of a tertiary hospital. AB - BACKGROUND: Sepsis is a prevalent disease worldwide and still exhibits high rates of mortality. In the last years, many interventions aiming a positive impact on sepsis evolution have been studied. One of the main is the use of managed care protocols (sepsis bundles), which consist in systematization of diagnosis and treatment, such as standardization of antibiotics, collection of specific tests (cultures, lactate), and fluid replacement. Some studies have shown a reduction in hospital costs and lower mortality with the use of these tools. In the present study, we evaluated the impact of a sepsis bundle in wards of a tertiary hospital. METHODS: One hundred sixty-seven patients were retrospectively studied. The intervention was called "3-h bundle" and consisted of collecting lactate and cultures, start broad-spectrum antibiotics in the first hour of sepsis diagnosis, and volume replacement with crystalloid if hypotension or lactate >=2 mmol/L. RESULTS: The overall mortality was 31.1%. Individuals who received the 3-h bundle showed a 44% lower mortality in comparison with who did not (25.6 vs. 45.7%; p = 0.01). Furthermore, the use of the sepsis bundle was independently correlated with lower mortality (OR = 0.175; CI = 0.04-0.64; p = 0.009). Therefore, a lower need for ICU admission and shorter length of stay in these units were observed in patients who received the intervention. CONCLUSION: The use of a sepsis protocol with systematic care in wards was associated with lower mortality, less need for ICU admission and shorter stay on these units. PMID- 28729905 TI - AN69ST membranes adsorb nafamostat mesylate and affect the management of anticoagulant therapy: a retrospective study. AB - BACKGROUND: In Japan, nafamostat mesylate (NM) is frequently used as an anticoagulant during continuous renal replacement therapy (CRRT). The dialyzer membrane AN69ST has been reported to adsorb NM and affect the management of anticoagulant therapy. However, the adsorbed amount has not yet been quantitatively assessed. Therefore, in this study, we evaluated the pre- and post hemofilter prolongation of the activated clotting time (ACT) in patients with AN69ST and PS membranes. We also measured the adsorption of NM in three types of CRRT membranes using an experimental model. METHODS: In a study of patients who underwent CRRT using AN69ST or PS membranes in 2015 at the Advanced Emergency and Critical Care Center, Okayama University Hospital, pre- and post-hemofilter ACT measurements were extracted retrospectively, and the difference was calculated. In addition, AN69ST (sepXiris100), PS (HEMOFEEL SHG-1.0), and PMMA membranes (HEMOFEEL CH-1.0N) were used in an in vitro model of a dialysis circuit, and the concentrations of NM were measured in pre- and post-hemofilter membranes and filtrates. RESULTS: The ACT difference was significantly lower in the group using AN69ST membranes (p < 0.01). In the in vitro model (n = 4) with adsorption and filtration, the post-hemofilter and filtrate concentrations of NM in AN69ST membranes were significantly lower than those in the PS and PMMA membranes (p < 0.01). The NM adsorption clearance of the AN69ST membrane was significantly higher than that of the PS and PMMA membranes. CONCLUSIONS: The AN69ST membrane had higher NM adsorption than the PS and PMMA membranes. This may have resulted in the lower ACT difference in patients undergoing CRRT using the AN69ST membrane than in patients undergoing CRRT using PS or PMMA membranes. PMID- 28729907 TI - Current status of pediatric transplantation in Japan. AB - Brain-dead donor organ transplantation has been available to children in Japan since the 2010 revision of the Organ Transplant Law. Of the 50-60 brain-dead donor organ transplants performed annually in Japan, however, very few (0-4 per year) are performed in children. Again, while those receiving liver, heart, and kidney transplants are reported to fare better than their counterparts in the rest of the world, organ shortage is becoming a matter of great concern. Very few organs become available from brain-dead donors or are transplanted to adults if made available at all, with some children dying while on the brain-dead organ waiting list. Against this background, living-donor transplants, split-liver transplants, domino transplants, and hepatocyte transplants represent alternative modalities, each of which is shown to be associated with favorable outcomes. Challenges exist, include streamlining the existing framework for promoting organ donation for children and between children. PMID- 28729906 TI - Update on pediatric sepsis: a review. AB - BACKGROUND: Sepsis is one of the leading causes of mortality among children worldwide. Unfortunately, however, reliable evidence was insufficient in pediatric sepsis and many aspects in clinical practice actually depend on expert consensus and some evidence in adult sepsis. More recent findings have given us deep insights into pediatric sepsis since the publication of the Surviving Sepsis Campaign guidelines 2012. MAIN TEXT: New knowledge was added regarding the hemodynamic management and the timely use of antimicrobials. Quality improvement initiatives of pediatric "sepsis bundles" were reported to be successful in clinical outcomes by several centers. Moreover, a recently published global epidemiologic study (the SPROUT study) did not only reveal the demographics, therapeutic interventions, and prognostic outcomes but also elucidated the inappropriateness of the current definition of pediatric sepsis. CONCLUSIONS: With these updated knowledge, the management of pediatric sepsis would be expected to make further progress. In addition, it is meaningful that the fundamental data on which future research should be based were established through the SPROUT study. PMID- 28729908 TI - AKI after pediatric cardiac surgery for congenital heart diseases-recent developments in diagnostic criteria and early diagnosis by biomarkers. AB - BACKGROUND: Acute kidney injury (AKI) after cardiac surgery in children with congenital heart disease is a common complication. AKI is also associated with high morbidity and mortality. The Kidney Diseases Improving Global Outcomes (KDIGO) criteria for AKI classification are now widely used for the definition of AKI. It is noteworthy that a statement about children was added to the criteria. Many studies aimed at finding useful biomarkers are now being performed by using these criteria. Clinicians should be aware of the recent progress in understanding AKI in children. MAIN CONTENTS: Unlike adult patients, young age is one of the major risk factors for AKI in pediatric cardiac surgery. The mechanism of the development of AKI in children might be different from that in adults because the surgical procedure and CPB technique in pediatric patients are greatly different from those in adult patients. There are many biomarkers for early detection of AKI, and some of them are widely used in hospitals. One of the major benefits of such biomarkers is the rapidness of expression for detecting increases in their expression levels. Neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, cystatin C, and albumin have been investigated in some studies, and the usefulness of these biomarkers for detection of AKI and diagnosis of disease severity has been shown. Although there are many interventions for preventing and treating AKI after cardiac surgery in children, there is still no specific effective treatment. Peritoneal dialysis is effective for only maintaining a negative fluid balance early after cardiac surgery. The long-term prognosis of AKI is an issue of interest. Although mortality and morbidity of AKI in the acute phase of disease remain high, the long-term condition in pediatric patients is relatively acceptable unlike in adults. CONCLUSIONS: KDIGO criteria are advocated as a diagnostic tool for common perception. Early recognition and intervention for AKI can be achieved by using several biomarkers. Further studies are needed to establish effective treatment for AKI. PMID- 28729909 TI - Biological effects and mechanisms of shortwave radiation: a review. AB - With the increasing knowledge of shortwave radiation, it is widely used in wireless communications, radar observations, industrial manufacturing, and medical treatments. Despite of the benefits from shortwave, these wide applications expose humans to the risk of shortwave electromagnetic radiation, which is alleged to cause potential damage to biological systems. This review focused on the exposure to shortwave electromagnetic radiation, considering in vitro, in vivo and epidemiological results that have provided insight into the biological effects and mechanisms of shortwave. Additionally, some protective measures and suggestions are discussed here in the hope of obtaining more benefits from shortwave with fewer health risks. PMID- 28729910 TI - Drug-induced gingival hyperplasia: a retrospective study using spontaneous reporting system databases. AB - BACKGROUND: Drug-induced gingival hyperplasia (DIGH) causes problems with chewing, aesthetics, and pronunciation, and leads to the deterioration of the patient's quality of life (QOL). Thus, the aim of this study was to evaluate the incidence of DIGH using spontaneous reporting system (SRS) databases. METHODS: We analyzed reports of DIGH from SRS databases and calculated the reporting odds ratios (RORs) of suspected drugs (immunosuppressants, calcium channel blockers, and anticonvulsants). The SRS databases used were the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) and the Japanese Adverse Drug Event Report (JADER) database. With the data, we evaluated the time to-onset profile and the hazard type using the Weibull shape parameter (WSP). Furthermore, we used the association rule mining technique to discover undetected relationships such as possible risk factors. RESULTS: The FAERS contained 5,821,716 reports. The RORs (95% confidence interval: CI) for cyclosporine, everolimus, sirolimus, mycophenolate mofetil, amlodipine, nifedipine, carbamazepine, clobazam, levetiracetam, phenobarbital, phenytoin, primidone, topiramate, and valproic acid, were 39.4 (95% CI: 30.3-51.2), 4.2 (1.7-10.0), 6.6 (2.5-17.7), 13.1 (7.2-23.2), 94.8 (80.0-112.9), 57.9 (35.7-94.0), 15.1 (10.3 22.3), 65.4 (33.8-126.7), 6.5 (3.6-11.8), 19.7 (8.8-44.0), 65.4 (52.4-82.9), 56.5 (21.1-151.7), 2.9 (1.1-7.7), and 17.5 (12.6-24.4), respectively. The JADER database contained 430,587 reports. The median time-to-onset of gingival hyperplasia values for immunosuppressants, calcium channel blockers, and anticonvulsants use were 71, 262, and 37 days, respectively. Furthermore, the 95% CI of the WSP beta for anticonvulsants was over and excluded 1, which meant that they were wear-out failure type. CONCLUSIONS: Our results suggest that DIGH monitoring of patients administered immunosuppressants, calcium channel blockers, or anticonvulsants is important. We demonstrated the potential risk of DIGH following the long-term use of calcium channel blocker over approximately 260 days. Based on the results of the association rule mining approach, patients with intellectual disability who are administered phenytoin should be monitored carefully. We recommend that patients who experience symptoms related to DIGH should be closely monitored. PMID- 28729911 TI - Vaginal progesterone to reduce preterm birth among HIV-infected pregnant women in Zambia: a feasibility study protocol. AB - BACKGROUND: Women infected with HIV have a risk of preterm birth (PTB) that is twice that among uninfected women, and treatment with antiretroviral therapy (ART) may further increase this risk. Progesterone supplementation reduces the risk of preterm delivery in women who have a shortened cervix in the midtrimester. We propose to study the feasibility of a trial of vaginal progesterone (VP) to prevent PTB among HIV-infected women receiving ART in pregnancy. Given low adherence among women self-administering vaginal study product in recent microbicide trials, we plan to investigate whether adequate adherence to VP can be achieved prior to launching a full-scale efficacy trial. METHODS AND DESIGN: One hundred forty HIV-infected pregnant women in Lusaka, Zambia, will be randomly allocated to daily self-administration of either VP or matched placebo, starting between 20 and 24 gestational weeks. The primary outcome will be adherence, defined as the proportion of participants who achieve at least 80% use of study product, assessed objectively with a validated dye stain assay that confirms vaginal insertion of returned single-use applicators. Secondary outcomes will be study uptake, retention, and preliminary efficacy. We will concurrently perform semi-structured interviews with participants enrolled in the study and with women who decline enrollment to assess the acceptability of VP to prevent PTB and of enrollment to a randomized controlled trial. DISCUSSION: We hypothesize that VP could prevent PTB among women receiving ART in pregnancy. In preparation for a trial to test this hypothesis, we plan to assess whether participants will be adherent to study product and protocol. TRIAL REGISTRATION: ClinicalTrial.gov, NCT02970552. PMID- 28729912 TI - Protection of the biconcave profile of human erythrocytes against osmotic damage by ultraviolet-A irradiation through membrane-cytoskeleton enhancement. AB - To perform various physiological functions, erythrocytes possess a unique biconcave shape provided by a special architecture of the membrane-skeleton system. In the present work, we use a simple irradiation method to treat human erythrocytes with 365 nm ultraviolet-A (UVA) light at the single-cell level in vitro. Depending on the irradiation dose, UVA show protection of the biconcave profile against the detrimental action of distilled water. This protective effect can also be confirmed for saponin that damages the membrane-skeleton by vesiculation and pore formation. Interestingly, at two irradiation doses of UVA pretreatment, erythrocytes still seem to exhibit cell viability as tested by trypan blue assay even if distilled water or saponin is added. The oxidants hydrogen peroxide and cumene hydroperoxide partly simulate the protective effects. Taken together, these results demonstrate that 365 nm UVA irradiation can protect the biconcave profile of human erythrocytes through membrane-skeleton enhancement associated with a production of oxidants. PMID- 28729913 TI - Personality Traits and Perception of Muller-Lyer Illusion in Male Chinese Military Soldiers and University Students. AB - BACKGROUND: In military men, performance such as gun-shooting precision relies on factors such as the ability to resist visual illusion, and this misperception of visual stimulus might be linked with sensation seeking related personality. METHODS: We have invited 103 male military men and 104 age-matched university male students to undergo the experiment of the Brentano version of the Muller Lyer illusion and the Zuckerman-Kuhlman Personality Questionnaire (ZKPQ) tests. RESULTS: The military men scored significantly lower than students did on the ZKPQ Impulsive Sensation Seeking test but higher on Aggression-Hostility and Sociality test, and displayed less misperception magnitude to the illusion. The Impulsive Sensation Seeking, Neuroticism-Anxiety and Aggression-Hostility traits in military men, and the Activity in students were respectively correlated with the misperception magnitudes of the illusion in different manners. CONCLUSION: Limited results in our study have indicated that the military men had pronounced personality traits which were correlated with the misperception magnitude of the Muller-Lyer illusion. PMID- 28729914 TI - Effects of mTOR on Neurological Deficits after Transient Global Ischemia. AB - Mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase and activation of its signal pathway plays an important role in regulating protein growth and synthesis as well as cell proliferation and survival. In the present study, we examined the contribution of mTOR and its downstream products to brain injuries and neurological deficiencies after cardiac arrest (CA) induced transient global ischemia. CA was induced by asphyxia followed by cardiopulmonary resuscitation (CPR) in rats. Our results showed that expression of p-mTOR, mTOR mediated phosphorylation of 4E-binding protein 4 (4E-BP1) and p70 ribosomal S6 protein kinase 1 (S6K1) pathways were amplified in CA rats compared to their controls. Blocking mTOR using rapamycin attenuated upregulation of pro inflammatory cytokines (namely IL-1beta, IL-6 and TNF-alpha), and Caspase-3, indicating cell apoptosis and also promoting the levels of vascular endothelial growth factor (VEGF) and its subtype receptor VEGFR-2 in the hippocampus. Moreover, the effects of rapamycin were linked to improvement of neurological deficits and increased brain water content observed in CA rats. In conclusion, activation of mTOR signal is engaged in pathophysiological process during CA induced transient global ischemia and blocking mTOR pathway plays a beneficial role in regulating injured neuronal tissues and neurological deficits via PIC, apoptotic Caspase-3 and VEGF mechanisms. Targeting one or more of these specific mTOR pathways and its downstream signaling molecules may present new opportunities for neural dysfunction and vulnerability related to transient global ischemia. PMID- 28729915 TI - The Concomitant Association of Thyroid Disorders and Myasthenia Gravis. AB - BACKGROUND: Some of the thyroid disorders (TD) and Myasthenia gravis (MG) are autoimmune related disease. The purpose of the study to evaluate the relationship of MG with all morphological and functional thyroid disorders. METHODS: We constructed a population-based cohort study during the period from January 2000 December 2002 by using reimbursement data from the Bureau National Health Insurance (NHI) system in Taiwan. Patients with TD and MG were identified by referring to the ICD-9-CM codes. (ICD-10-CM as reference) .The association of TD with MG occurred only in the same person within the study period. The Q value was used to measure the strength of disease-disease associations. RESULTS: We obtained 520628 TD and 7965 MG records for analysis. Diffuse toxic goiter had highest association rate, followed by nontoxic nodular goiter, simple goiter, chronic lymphocytic thyroiditis, thyroid cancer, and toxic nodular goiter. Female and older patients had a higher rate than their male and younger counterparts, respectively. Functional abnormalities revealed higher incidence of thyrotoxicosis and hypothyroidism in both sexes. We also found the strongest association in men with chronic thyroiditis, diffuse toxic goiter, thyrotoxicosis, acquired hypothyroidism, thyroid cancer, and simple goiter. While an intermediate association was observed in female with diffuse toxic goiter, in a male with toxic and nontoxic nodular/multinodular goiters, in female with thyrotoxicosis, thyroid cancer and acquired hypothyroidism. CONCLUSION: This population based cohort study showed potential association of all types of TD with MG, and observed a higher association rate in female autoimmune TD whereas males showed a higher strength of association. PMID- 28729916 TI - Dynamic Expression of CX36 Protein in Kainic Acid Kindling induced Epilepsy. AB - Connexin (Cx) 36 is known to be a component of gap junctions, and has been suggested to play an important role in epilepsy. In order to determine dynamic changes of Cx36 protein expression in epilepsy and investigate the role of Cx36 in electroencephalographic activity and pathogenesis, we utilized kainic acid (KA) to induce epileptogenesis. We found that epileptic discharges began 71.8 +/- 23.7 s after KA administration. Spike frequency and amplitude of epileptiform activity reached maximal levels at 30 +/- 5.2 min. The maximum level of spike frequency and amplitude of epileptiform activity was 13.9 +/- 0.3 Hz and 198 +/- 14.3mV respectively. Employing Western blotting and immunohistochemistry, we demonstrated that hippocampal Cx36 protein expression was significantly increased 6 h after KA kindling compared to control or sham groups, but decreased in 3 d and 7d groups. Our results suggested that the dynamic change of Cx36 expression may play an important role inepilepsy, and the specific manipulation of Cx36 expression may be a potential target for the treatment of epilepsy. PMID- 28729918 TI - White Matter Sexual Dimorphism of the Adult Human Brain. AB - Sex-biased psychophysiology, behavior, brain function, and conditions are extensive, yet underlying structural brain mechanisms remain unclear. There is contradicting evidence regarding sexual dimorphism when it comes to brain structure, and there is still no consensus on whether or not there exists such a dimorphism for brain white matter. Therefore, we conducted a voxel-based morphometry (VBM) analysis along with global volume analysis for white matter across sex. We analyzed 384 T1-weighted MRI brain images (192 male, 192 female) to investigate any differences in white matter (WM) between males and females. In the VBM analysis, we found males to have larger WM, compared to females, in occipital, temporal, insular, parietal, and frontal brain regions. In contrast, females showed only one WM region to be significantly larger than males: the right postcentral gyrus in the parietal lobe region. Although, on average, males showed larger global WM volume, we did not find any significant difference in global WM volume between males and females. PMID- 28729917 TI - Autophagy, Endoplasmic Reticulum Stress and the Unfolded Protein Response in Intracerebral Hemorrhage. AB - Intracerebral hemorrhage (ICH) is a subtype of stroke that is followed by primary and secondary brain injury. As a result of the injury, cell metabolism is disrupted and a series of stress responses are activated, such as endoplasmic reticulum (ER) stress and the unfolded protein response (UPR), leading to the re establishment of cell homeostasis or cell death. As an important mechanism of cell homeostasis, autophagy has been widely studied, and the associations between autophagy, ER stress, and the UPR have also been demonstrated. Whether these mechanisms are beneficial or detrimental remains a matter of controversy, but there is no doubt as to their vital functions. An understanding of the mechanisms of injury and recovery after ICH is crucial to develop therapeutic strategies. In this review, we summarize the related studies and highlight the roles of autophagy, ER stress, and the UPR in disease, especially in ICH. We also provide an overview of therapeutic approaches that target autophagy, and we discuss the prospects for modulating autophagy, ER stress, and UPR mechanisms in ICH therapy. PMID- 28729920 TI - Annual vaccine-preventable disease report for New South Wales, Australia, 2014. AB - This report provides an epidemiological description of selected vaccine preventable diseases in New South Wales (NSW), Australia, for 2014 to inform ongoing disease monitoring and control efforts. A trend of increasing pertussis notifications was observed, beginning midway through 2014 with the highest disease rates in the 5-9 year age group. Measles notifications increased to 67 cases in 2014 from 34 cases in 2013. Measles cases were associated with travel related importations-predominantly from the Philippines-and secondary transmission increased compared to 2013 involving three main disease clusters. Notifications of invasive meningococcal disease continued to decline across the state with meningococcal B remaining the most common serogroup in NSW. Increasing rates of pertussis notifications from mid-2014 may indicate the beginning of an epidemic, ending the period of low transmission observed in 2013 and the first half of 2014. An increase in measles notifications in 2014, including secondary transmission, indicates the continued need for public health actions including robust follow-up and awareness campaigns. PMID- 28729919 TI - Toward Understanding Non-coding RNA Roles in Intracranial Aneurysms and Subarachnoid Hemorrhage. AB - Subarachnoid hemorrhage (SAH) is a common and frequently life-threatening cerebrovascular disease, which is mostly related with a ruptured intracranial aneurysm. Its complications include rebleeding, early brain injury, cerebral vasospasm, delayed cerebral ischemia, chronic hydrocephalus, and also non neurological problems. Non-coding RNAs (ncRNAs), comprising of microRNAs (miRNAs), small interfering RNAs (siRNAs) and long non-coding RNAs (lncRNAs), play an important role in intracranial aneurysms and SAH. Here, we review the non coding RNAs expression profile and their related mechanisms in intracranial aneurysms and SAH. Moreover, we suggest that these non-coding RNAs function as novel molecular biomarkers to predict intracranial aneurysms and SAH, and may yield new therapies after SAH in the future. PMID- 28729921 TI - An outbreak of foodborne norovirus gastroenteritis linked to a restaurant in Melbourne, Australia, 2014. AB - INTRODUCTION: In May 2014 an outbreak of norovirus occurred among patrons of a restaurant in Melbourne, Australia. Investigations were conducted to identify the infectious agent, mode of transmission and source of illness, and to implement controls to prevent further transmission. METHODS: A retrospective case-control study was conducted to test the hypothesis that food served at the restaurant between 9 and 15 May 2014 was the vehicle for infection. A structured questionnaire was used to collect demographic, illness and food exposure data from study participants. To ascertain whether any food handlers had experienced gastroenteritis symptoms and were a possible source of infection, investigators contacted and interviewed staff who had worked at the restaurant between 9 and 16 May 2014. RESULTS: Forty-six cases (including 16 laboratory-confirmed cases of norovirus) and 49 controls were interviewed and enrolled in the study. Results of the analysis revealed a statistically significant association with illness and consumption of grain salad (OR: 21.6, 95% CI: 1.8-252.7, P = 0.015) and beetroot dip (OR: 22.4, 95% CI: 1.9-267.0, P = 0.014). An interviewed staff member who reported an onset of acute gastrointestinal illness on 12 May 2014 had prepared salads on the day of onset and the previous two days. DISCUSSION: The outbreak was likely caused by person-to-food-to-person transmission. The outbreak emphasizes the importance of the exclusion of symptomatic food handlers and strict hand hygiene practices in the food service industry to prevent contamination of ready-to-eat foods and the kitchen environment. PMID- 28729923 TI - Correlation analysis of the rates of solvolysis of 4-bromopiperidine: a reaction following a Grob fragmentation pathway. AB - A Grunwald-Winstein treatment of the specific rates of solvolysis of 4 bromopiperidine gives for aqueous ethanol, methanol, acetone, and dioxane a very good logarithmic correlation against the YBr solvent ionizing power values with a slope (m value) of 0.46+/-0.02, consistent with the operation of a synchronous Grob fragmentation mechanism. When the organic component of the solvent is 2,2,2 trifluoroethanol (TFE), the data points show a negative deviation, consistent with an appreciable deactivating interaction of the acidic TFE component of the solvent with the lone-pair of electrons present on the nitrogen. PMID- 28729922 TI - Meningococcal disease outbreak related to the World Scout Jamboree in Japan, 2015. AB - PROBLEM: Six invasive meningococcal disease cases occurred among Scottish and Swedish nationals associated with the World Scout Jamboree (WSJ), an international mass gathering, held in Japan. The index case developed symptoms while returning home. The strains from all six cases were identical and seldom seen in Japan. CONTEXT: Over 33 000 participants from 155 countries attended WSJ. At the Jamboree site, participants of the North of Scotland's and Sweden's units camped within the same subcamp and kept the same schedule of events. No information was available about the Swedish and Scottish cases' close personal contact history. ACTION: Health Protection Scotland investigated Scottish cases, conducted active case finding, provided chemoprophylaxis, vaccinated close contacts and advised Scottish WSJ participants and contacts to seek medical care if they developed symptoms. The Public Health Agency of Sweden recommended chemoprophylaxis to all participants in Sweden. In Japan, the Ministry of Health, Labour and Welfare (MHLW) requested the Scout Association of Japan advise all participants to seek medical attention if they developed symptoms. MHLW shared information about the event with local authorities, medical associations, and the Ministry of Education, Culture, Sports, Science and Technology. OUTCOME: No additional case related to WSJ has been reported. This outbreak highlighted the risk for international spread of invasive meningococcal disease at international mass gatherings. DISCUSSION: Assessing risk, educating participants, enhancing surveillance and sharing timely information among related countries are significant for prevention and response against invasive meningococcal disease outbreaks at mass gatherings. PMID- 28729924 TI - Comparison of Injected and Radiated EMC Testing of Active Implanted Cardiac Medical Devices at the Boundary Frequency of 450 MHz. AB - We compared testing via radiated vs. injected susceptibility methods specified in the ISO 14117 standard for electromagnetic compatibility of implantable cardiac medical devices. Injected testing is specified at and below 450 MHz and radiated testing is specified at and above this boundary frequency. Experimental and computational studies were performed to determine voltages induced in a model of an implant. The device under test (DUT) was a model with a metal case (5.0 x 4.5 x 3.4 cm high) containing a diode detector and a fiber optic link plus an insulated wire simulating a unipolar lead. We evaluated induced voltage in the model for radiated versus injected testing. The voltage from experimental measurements agreed with computed values within +/-1.4 dB or less. Radiated testing with 12.25 Watts delivered to the dipole specified in the standard induced the same voltage as the injected test requirement (14 Vp-p). This is in strong contrast to the specified radiated test power of 120 mW or even the optional worst-case radiated test level of 8 Watts. Lateral displacement of the dipole by 2 cm changed the voltage induced in the DUT by 20% or less. For depth changes below saline surface from 5 mm to 10 mm voltage variations were 12.5%. There is poor agreement (by a factor of 9.9 or more) for radiated vs. injected testing at the border frequency of 450 MHz separating the two methods. Our computational model can also be used at other frequencies and for EMC studies of other types of active implants that use the ISO14117 standard's radiated test method, such as neuro-stimulators. PMID- 28729925 TI - Patterns of production of collagen-rich deposits in peripheral nerves in response to injury: A pilot study in a rabbit model. AB - INTRODUCTION: Although collagen-rich deposits are the main component of neural scars, the patterns of their formation are ill defined. Essential to the biosynthesis of collagen fibrils are enzymes catalyzing posttranslational modifications and chaperones that control the formation of the collagen triple helix. Prolyl-4-hydroxylase (P4H) and heat shock protein-47 (HSP47) play a key role, and their production is upregulated during scar formation in human tissues. Alpha smooth muscle actin (alphaSMA) is also produced during fibrotic processes in myofibroblasts that participate in fibrotic response. In injured peripheral nerves, however, the distribution of cells that produce these markers is poorly understood. METHODS: The goal of this study was to determine the distribution of the alphaSMA-positive, HSP47-positive, and the P4H-positive cells to better understand the formation of collagen-rich fibrotic tissue (FT) in response to peripheral nerve injury. To reach this goal, we employed a rabbit model of crush injury and partial-transection injury of the sciatic nerves. RESULTS: Our study demonstrated that alphaSMA is expressed in a relatively small number of cells seen in neural FT. In contrast, cells producing P4H and HSP47 are ubiquitously present in sites of injury of the sciatic nerves. CONCLUSION: We contemplate that these proteins may serve as valuable markers that define fibrotic activities in the injured peripheral nerves. PMID- 28729926 TI - Coherence of BOLD signal and electrical activity in the human brain during deep sevoflurane anesthesia. AB - INTRODUCTION: Changes in neural activity induce changes in functional magnetic resonance (fMRI) blood oxygenation level dependent (BOLD) signal. Commonly, increases in BOLD signal are ascribed to cellular excitation. OBJECTIVE: The relationship between electrical activity and BOLD signal in the human brain was probed on the basis of burst suppression EEG. This condition includes two distinct states of high and low electrical activity. METHODS: Resting-state simultaneous EEG and BOLD measurements were acquired during deep sevoflurane anesthesia with burst suppression EEG in nineteen healthy volunteers. Afterwards, fMRI volumes were assigned to one of the two states (burst or suppression) as defined by the EEG. RESULTS: In the frontal, parietal and temporal lobes as well as in the basal ganglia, BOLD signal increased after burst onset in the EEG and decreased after onset of EEG suppression. In contrast, BOLD signal in the occipital lobe was anticorrelated to electrical activity. This finding was obtained consistently in a general linear model and in raw data. CONCLUSIONS: In human brains exhibiting burst suppression EEG induced by sevoflurane, the positive correlation between BOLD signal and electrical brain activity could be confirmed in most gray matter. The exceptional behavior of the occipital lobe with an anticorrelation of BOLD signal and electrical activity might be due to specific neurovascular coupling mechanisms that are pronounced in the deeply anesthetized brain. PMID- 28729927 TI - Fatigue and cognition: Pupillary responses to problem-solving in early multiple sclerosis patients. AB - INTRODUCTION: In early multiple sclerosis (MS) patients, cognitive changes and fatigue are frequent and troublesome symptoms, probably related to both structural and functional brain changes. Whether there is a common cause of these symptoms in MS is unknown. In theory, an altered regulation of central neuropeptides can lead to changes in regulation of autonomic function, cognitive difficulties, and fatigue. Direct measurements of central neuropeptides are difficult to perform, but measurements of the eye pupil can be used as a reliable proxy of function. METHODS: This study assesses pupil size during problem-solving in early MS patients versus controls. A difference in pupil size to a cognitive challenge could signal altered activity within the autonomic system because of early functional brain changes associated with cognitive load. We recruited MS patients (mean disease duration: 2.6 years, N = 41) and age-matched healthy controls (N = 43) without eye pathology. Neurological impairment, magnetic resonance imaging, visual evoked potentials, depression, and fatigue were assessed in all of the patients. In both groups, we assessed processing speed and retinal imaging. Pupil size was recorded with an eye-tracker during playback of multiplication tasks. RESULTS: Both groups performed well on the cognitive test. The groups showed similar pupillary responses with a mean of 0.55 mm dilation in patients and 0.54 mm dilation in controls for all the tasks collapsed together. However, controls (N = 9) with low cognitive scores (LCS) had an increased pupillary response to cognitive tasks, whereas LCS MS patients (N = 6) did not (p < .05). There was a tendency toward a smaller pupillary response in patients with fatigue. CONCLUSIONS: This is the first study to investigate pupillary responses to cognitive tasks in MS patients. Our results suggest that MS-related changes in cognition and fatigue may be associated with changes in arousal and the autonomic regulation of task-related pupillary responses. This supports the theory of a link between cognition and fatigue in MS. PMID- 28729928 TI - The assessment of laboratory parameters in children with fever and febrile seizures. AB - OBJECTIVE: The aim of the research paper was to assess selected laboratory results in children with fever without seizures and febrile seizure. MATERIALS AND METHODS: The paper presents an analysis of a group of 306 children aged 6 months - 5 years who were admitted with diagnosed fever without seizures and febrile seizures in Specialized Health Care Centre for Mother and Child in Poznan between 1st January 2008 and 31st December 2009. Out of the diagnostics procedures performed in children the following ones were taken into consideration: BCC and CRP. RESULTS: Of the analyzed group of 306 children, 59.48% were boys and 40.52% were girls. In the studied group 61.93% were boys and control group 56.15% were boys. Mean age of admitted children was 22 months. In the study group mean body temperature was 39.0 degrees C and in the control group 38.6 degrees C. A statistically significant difference was found between body temperature of study and control group (p = .005). The mean C-reactive protein level in the study group was 15.73 mg/L and in the control group 58.20 mg/L. There was a statistically significant difference (p < .001). There was a statistically significant difference between the number of lymphocytes and neutrophils (p < .001). There was also a statistically significant difference between the number of hemoglobin, hematocrit and platelets. CONCLUSIONS: The study showed that children with FS, had statistically significant higher neutrophils level compared to those with fever without seizures. The number of lymphocytes was lower in children with FS than in children with fever without seizures. PMID- 28729929 TI - Picture free recall performance linked to the brain's structural connectome. AB - INTRODUCTION: Memory functions are highly variable between healthy humans. The neural correlates of this variability remain largely unknown. METHODS: Here, we investigated how differences in free recall performance are associated with DTI based properties of the brain's structural connectome and with grey matter volumes in 664 healthy young individuals tested in the same MR scanner. RESULTS: Global structural connectivity, but not overall or regional grey matter volumes, positively correlated with recall performance. Moreover, a set of 22 inter regional connections, including some with no previously reported relation to human memory, such as the connection between the temporal pole and the nucleus accumbens, explained 7.8% of phenotypic variance. CONCLUSIONS: In conclusion, this large-scale study indicates that individual memory performance is associated with the level of structural brain connectivity. PMID- 28729930 TI - Structural differences in impaired verbal fluency in essential tremor patients compared to healthy controls. AB - OBJECTIVE: We wanted to identify differences in grey and white matter in essential tremor patients compared to controls in the non-motor domain, using the example of impaired verbal fluency. BACKGROUND: A disturbance of verbal fluency in essential tremor patients compared to healthy controls is behaviorally well described. METHODS: Voxel-based morphometry and tract-based spatial statistics were used to analyze structural differences in grey and white matter in 19 essential tremor patients compared to 23 age- and gender-matched controls. RESULTS: Several significant observations were made. (I) There was less grey matter in the predominantly right precuneus in the essential tremor group compared to controls [p < .001]. (II) In ET patients mean, axial, and radial diffusivity values broadly correlated with the tremor rating scale, pronounced in fronto-parietal regions [p < .05]. (III) In ET patients there was a significant decline in fractional anisotropy values in the corpus callosum in the correlation with verbal fluency results [p < .05]; by inclusion of the tremor rating scale as covariate of no interest this significance was however diminished to a tendency (p < .1). No significant results were found in these within-group correlations in grey matter analyses for ET patients (p > .05). CONCLUSION: The present results indicate that non-motor symptoms such as verbal fluency (VBF) in ET have a structural substrate; their reproduction requires the integration of potential environmental plasticity effects, differentiation into individual clinical subtypes and a careful handling with methodological peculiarities of structural MR imaging. PMID- 28729931 TI - Validity and reliability of the CatWalk system as a static and dynamic gait analysis tool for the assessment of functional nerve recovery in small animal models. AB - INTRODUCTION: A range of behavioral testing paradigms have been developed for the research of central and peripheral nerve injuries with the help of small animal models. Following any nerve repair strategy, improved functional outcome may be the most important evidence of axon regeneration. A novel automated gait analysis system, the CatWalkTM, can measure dynamic as well as static gait patterns of small animals. Of most interest in detecting functional recovery are in particular dynamic gait parameters, coordination measures, and the intensity of the animals paw prints. This article is designed to lead to a more efficient choice of CatWalk parameters in future studies concerning the functional evaluation of nerve regeneration and simultaneously add to better interstudy comparability. METHODS: The aims of the present paper are threefold: (1) to describe the functional method of CatWalk gait analysis, (2) to characterize different parameters acquired by CatWalk gait analysis, and to find the most frequently used parameters as well as (3) to compare their reliability and validity throughout the different studies. RESULTS: In the reviewed articles, the most frequently used parameters were Swing Duration (30), Print Size (27), Stride Length (26), and Max Contact Area (24). Swing Duration was not only frequently used but was also the most reliable and valid parameter. Therefore, we hypothesize that Swing Duration constitutes an important parameter to be chosen for future studies, as it has the highest level of reliability and validity. CONCLUSION: In conclusion, CatWalk can be used as a complementary approach to other behavioral testing paradigms to assess clinically relevant behavioral benefits, with the main advantage that this system demonstrates both static and dynamic gait parameters at the same time. Due to limited reliability and validity of certain parameters, we recommend that only the most frequently assessed parameters should be used in the future. PMID- 28729932 TI - Validity and reliability of the Finnish version of the Multiple Sclerosis Impact Scale-29. AB - BACKGROUND: The Multiple Sclerosis Impact Scale-29 (MSIS-29) has been increasingly used to evaluate the self-perceived impact of multiple sclerosis (MS) on a patient. OBJECTIVES: The aim of this study was to evaluate the psychometric properties of the Finnish version of MSIS-29 in patients with MS. METHODS: A total of 553 patients with MS completed the MSIS-29 and self administered questionnaires capturing information on demographics, disease characteristics and severity, perceived quality of life (EuroQol 5D-3L instrument), and fatigue (Fatigue Severity Scale). RESULTS: The data quality for MSIS-29 was excellent, with 99.5% computable scores for the MSIS-29 physical scale and 99.3% for the MSIS-29 psychological scale. Floor and ceiling effects were minimal. Excellent Cronbach's alpha values of 0.97 and 0.90 were seen for MSIS-29 physical and psychological subscales, respectively. The physical subscale showed highest correlations with measures of physical functioning, such as disease severity and the mobility domain of the quality of life. Similarly, the psychological subscale showed highest correlations with self-reported fatigue and the anxiety/depression domains of the quality of life. MSIS-29 physical scores related strongly to disease severity, whereas the MSIS-29 psychological scores increased in mild disease but declined in more severe disease forms. CONCLUSION: The Finnish version of MSIS-29 has satisfactory psychometric properties. Consistent with the previous recommendations, the use of two MSIS-29 subscale scores instead of a total score was supported. PMID- 28729933 TI - Unprovoked seizures in multiple sclerosis: Why are they rare? AB - INTRODUCTION: The frequency of seizures in patients with multiple sclerosis (MS) ranges from 1.5% to 7.8% and is considerably more common than chance events. The etiopathogenesis of seizures in MS is still poorly understood. METHOD: A review of the literature on seizures and MS using PubMed. RESULTS: Cortical gray matter involvement appears to be an all-too-common pathological finding in MS to play a primary role in the pathogenesis of seizures in MS patients. There is no clear relationship between seizures and the severity of MS. In approximately 10% of cases, a seizure is actually an initial neurological symptom of MS. CONCLUSION: Searching for coherence in the occurrence of unprovoked seizures in MS directs attention to the dichotomy in MS pathology characterized by a complex intertwining of neuroinflammatory and neurodegenerative processes. The appearance (or nonappearance) of seizures in MS in relation to disease activity and disease progression indicates a distinct clinical phenotype of MS that opens up new perspectives in MS research. PMID- 28729934 TI - Effect of lamotrigine on seizure development in a rat pentylenetetrazole kindling model. AB - INTRODUCTION: Epileptogenesis is a process of seizure development. Lamotrigine is a novel antiepileptic drug which is also used for antiepileptogenic research. Kindling models are recommended as potentially useful tools for antiepileptogenic treatment discovery. However, previous studies demonstrated that the antiepileptogenic effect of lamotrigine is controversial in the electrical kindling model. Chemical kindling such as with pentylenetetrazole is another kindling model. The aims of this study were to examine whether lamotrigine could prevent the development of seizure in pentylenetetrazole kindling rats. METHODS: Female rats were kindled by subconvulsive doses of pentylenetetrazole (35 mg/kg) once every other day for 15 times. Thereafter, the kindled rats received different doses of lamotrigine (5, 10 and 20 mg/kg) before pentylenetetrazole to observe the anticonvulsant effect. For the antiepileptogenic experiment, rats were kindled as the same way while pretreated (1 h) with different doses of lamotrigine (5, 10 and 20 mg/kg) before each injection of pentylenetetrazole. After a washout period for 1 week, the rats were administrated with pentylenetetrazole again for 3 times. The seizures were recorded each time. Later it was in vivo electrophysiological experiments followed with histologic analysis. RESULTS: For the anticonvulsant experiment lamotrigine dose-dependently suppressed pentylenetetrazole-induced seizures. Here, 20 mg/kg of lamotrigine pretreatment significantly blocked the seizure development in rats for their seizure stages remained longer in 1-3 during the kindling phase. Mean seizure stages or generalized seizure durations in the 10 and 20 mg/kg lamotrigine pretreated groups were significantly lower or shorter when received 3 times of pentylenetetrazole after the washout period. Electrophysiological study also demonstrated 20 mg/kg of lamotrigine pretreatment obviously eliminated increased population spike amplitude in hippocampus. However, different doses of lamotrigine pretreatment could not alleviate severity of hippocampal neuronal damage. CONCLUSIONS: The results suggest that adequate doses of lamotrigine can prevent seizure development in the pentylenetetrazole kindling rat model. PMID- 28729935 TI - Single-trial EEG-informed fMRI analysis of emotional decision problems in hot executive function. AB - BACKGROUND: Executive function refers to conscious control in psychological process which relates to thinking and action. Emotional decision is a part of hot executive function and contains emotion and logic elements. As a kind of important social adaptation ability, more and more attention has been paid in recent years. OBJECTIVE: Gambling task can be well performed in the study of emotional decision. As fMRI researches focused on gambling task show not completely consistent brain activation regions, this study adopted EEG-fMRI fusion technology to reveal brain neural activity related with feedback stimuli. METHODS: In this study, an EEG-informed fMRI analysis was applied to process simultaneous EEG-fMRI data. First, relative power-spectrum analysis and K-means clustering method were performed separately to extract EEG-fMRI features. Then, Generalized linear models were structured using fMRI data and using different EEG features as regressors. RESULTS: The results showed that in the win versus loss stimuli, the activated regions almost covered the caudate, the ventral striatum (VS), the orbital frontal cortex (OFC), and the cingulate. Wide activation areas associated with reward and punishment were revealed by the EEG-fMRI integration analysis than the conventional fMRI results, such as the posterior cingulate and the OFC. The VS and the medial prefrontal cortex (mPFC) were found when EEG power features were performed as regressors of GLM compared with results entering the amplitudes of feedback-related negativity (FRN) as regressors. Furthermore, the brain region activation intensity was the strongest when theta-band power was used as a regressor compared with the other two fusion results. CONCLUSIONS: The EEG-based fMRI analysis can more accurately depict the whole-brain activation map and analyze emotional decision problems. PMID- 28729936 TI - Are there differences in brain morphology according to handedness? AB - OBJECTIVE: This study aimed to investigate the differences in brain morphology according to handedness. MATERIALS AND METHODS: Forty-two healthy subjects were enrolled (21 right-handers and 21 nonright-handers). The two groups were classified according to the Edinburgh Handedness Inventory. Measures of cortical morphology, such as thickness, surface area, volume, and curvature, and the volumes of subcortical structures, such as the amygdala, caudate, hippocampus, globus pallidus, putamen, and thalamus, were compared between the groups according to handedness using whole-brain 3D T1-weighted MRI. In addition, we investigated the white matter differences between the groups using diffusion tensor imaging. Moreover, we quantified correlations between the handedness scales of the Edinburgh Handedness Inventory and each measure of different brain morphologies. RESULTS: The volumes of the right putamen and left globus pallidus in nonright-handed participants were significantly larger than those who were right-handed (0.3559 vs. 0.3155%, p = .0028; 0.1101 vs. 0.0975%, p = .0025; respectively). Moreover, the volumes of the right putamen and left globus pallidus were negatively correlated with the handedness scales of the Edinburgh Handedness Inventory (r = -.392, p = .0101; r = -.361, p = .0189; respectively). However, the cortex morphology and the other subcortical volumes were not significantly different between the two groups. In addition, we did not find any white matter differences between the groups. CONCLUSIONS: We demonstrated that there were significant differences in brain morphology between right-handers and nonright-handers, especially in the basal ganglia, which could produce differences in motor control according to handedness. PMID- 28729937 TI - Manganese-enhanced magnetic resonance imaging combined with electrophysiology in the evaluation of visual pathway in experimental rat models with monocular blindness. AB - PURPOSE: Our study aimed to explore the feasibility of manganese-enhanced magnetic resonance imaging (MEMRI) combined with visual evoked potentials (VEP) and auditory evoked visual cortex responses (AVR) in evaluating for the establishment of visual/auditory compensatory pathways after monocular blindness. MATERIALS AND METHODS: A total of 14 healthy neonatal male Sprague-Dawley rats were randomly divided into two groups (n = 7 for Groups A and B). Right optic nerve (ON) transection was performed on the 7 rats of Group A to obtain a monocularly blind model, and the 7 rats of Group B were chosen as the control group. Four months later, 400 mmol MnCl2 was injected into the left eye in both groups via intravitreal injection. The changes in the visual pathways projected from the blind eye and the remaining eye in Group A and the normal eyes in Group B were compared to determine if new visual compensatory pathways were established. Additionally, VEP tests were performed to determine complete blindness, and AVR examinations were performed to help identify the generation of auditory compensatory function. RESULTS: The VEP test indicated complete visual loss after ON transection. In the monocularly blind rats, the contrast-to-noise ratio (CNR) of ON, optic tract (OT), lateral geniculate nucleus (LGN), superior colliculus (SC), optic radiation (OR) and visual cortex (VC) of visual pathway projected from the left eye was significantly higher than that of the right pathway (p < .001). Moreover, the CNR of ON, OT, LGN, SC, OR and VC in the visual pathway projected from the left eye of monocularly blind rats was significantly lower than those of normal rats (p < .05). The AVR results revealed that the corresponding bilateral visual cortex in monocularly blind rats did not respond to the auditory stimulus or showed dissimilation with the low frequency. CONCLUSION: MEMRI combined with electrophysiology, including VEP and AVR, may be potentially helpful in the evaluation of the possible generation of new visual/auditory compensatory pathways after monocular blindness. PMID- 28729938 TI - Abnormal resting state effective connectivity within the default mode network in major depressive disorder: A spectral dynamic causal modeling study. AB - INTRODUCTION: Understanding the neural basis underlying major depressive disorder (MDD) is essential for the diagnosis and treatment of this mental disorder. Aberrant activation and functional connectivity of the default mode network (DMN) have been consistently found in patients with MDD. It is not known whether effective connectivity within the DMN is altered in MDD. OBJECTS: The primary object of this study is to investigate the effective connectivity within the DMN during resting state in MDD patients before and after eight weeks of antidepressant treatment. METHODS: We defined four regions of the DMN (medial frontal cortex, posterior cingulate cortex, left parietal cortex, and right parietal cortex) for each participant using a group independent component analysis. The coupling parameters reflecting the causal interactions among the DMN regions were estimated using spectral dynamic causal modeling (DCM). RESULTS: Twenty-seven MDD patients and 27 healthy controls were included in the statistical analysis. Our results showed declined influences from the left parietal cortex to other DMN regions in the pre-treatment patients as compared with healthy controls. After eight weeks of treatment, the influence from the right parietal cortex to the posterior cingulate cortex significantly decreased. CONCLUSION: These findings suggest that the reduced excitatory causal influence of the left parietal cortex is the key alteration of the DMN in patients with MDD, and the disrupted causal influences that parietal cortex exerts on the posterior cingulate cortex is responsive to antidepressant treatment. PMID- 28729939 TI - Feature selective temporal prediction of Alzheimer's disease progression using hippocampus surface morphometry. AB - INTRODUCTION: Prediction of Alzheimer's disease (AD) progression based on baseline measures allows us to understand disease progression and has implications in decisions concerning treatment strategy. To this end, we combine a predictive multi-task machine learning method (cFSGL) with a novel MR-based multivariate morphometric surface map of the hippocampus (mTBM) to predict future cognitive scores of patients. METHODS: Previous work has shown that a multi-task learning framework that performs prediction of all future time points simultaneously (cFSGL) can be used to encode both sparsity as well as temporal smoothness. The authors showed that this method is able to predict cognitive outcomes of ADNI subjects using FreeSurfer-based baseline MRI features, MMSE score demographic information and ApoE status. Whilst volumetric information may hold generalized information on brain status, we hypothesized that hippocampus specific information may be more useful in predictive modeling of AD. To this end, we applied a multivariate tensor-based parametric surface analysis method (mTBM) to extract features from the hippocampal surfaces. RESULTS: We combined mTBM features with traditional surface features such as middle axis distance, the Jacobian determinant as well as 2 of the Jacobian principal eigenvalues to yield 7 normalized hippocampal surface maps of 300 points each. By combining these 7 * 300 = 2100 features together with the previous ~350 features, we illustrate how this type of sparsifying method can be applied to an entire surface map of the hippocampus that yields a feature space that is 2 orders of magnitude larger than what was previously attempted. CONCLUSIONS: By combining the power of the cFSGL multi-task machine learning framework with the addition of AD sensitive mTBM feature maps of the hippocampus surface, we are able to improve the predictive performance of ADAS cognitive scores 6, 12, 24, 36 and 48 months from baseline. PMID- 28729940 TI - Propofol-induced downregulation of NR2B membrane translocation in hippocampus and spatial memory deficits of neonatal mice. AB - BACKGROUND: Thousands of infants and children are undergoing anesthesia around the world every day. But impacts of anesthetics on the developing neural system remain unclear yet. Previous evidence showed that anesthesia might affect the developing neural system. Thus, early-life anesthesia becomes a critical issue in clinical pediatric practice. Hence, propofol, a short-acting and widely applied intravenous anesthetic, has been gaining focus upon neonatal anesthesia. METHODS: Fifty-four male C57BL/6J mice were randomly divided into following three groups: group D6 intraperitoneally (i.p.) injected propofol (100 mg/kg body weight) once a day from postnatal day 6 (P6) to P11, group D1 administrated propofol (100 mg/kg, i.p.) at P6 solely and administrated normal saline (10 ml/kg, i.p.) from P7 to P11, and group N treated with normal saline (10 ml/kg, i.p.) from P6 to P11 as the control (n = 18 per group). Then, at P28, nine mice were collected randomly from each group for NR2B membrane translocation and phosphorylation analysis, and the rest half in each group were assigned to perform Morris water maze tests from P28 to P35. RESULTS: Results showed that total protein expression levels of NR2B increased (p < .001) while its membrane translocation decreased (p < .001, n = 9 per group) in the hippocampus but not in the prefrontal cortex of neonatal mice after repeated propofol administration. Phosphorylation levels of NR2B at serine 1303 (D1: p < .05; D6: p < .001, n = 9 per group) and serine 1480 (D1: p < .01, D6: p < .001, n = 9 per group) increased significantly as well in the hippocampus compared with group N. In addition, memory deficits (p < .05, n = 9 per group) were observed in Morris water maze tests of group D6 mice. CONCLUSIONS: These results suggested that propofol exposure downregulates NR2B membrane translocation and causes spatial memory deficits, with a mediated increased NR2B protein expression and phosphorylation at Ser1303/1480 residues in the hippocampus of neonatal mice. PMID- 28729941 TI - Hippocampal slice preparation in rats acutely suppresses immunoreactivity of microtubule-associated protein (Map2) and glycogen levels without affecting numbers of glia or levels of the glutamate transporter VGlut1. AB - INTRODUCTION: With its preservation of cytoarchitecture and synaptic circuitry, the hippocampal slice preparation has been a critical tool for studying the electrophysiological effects of pharmacological and genetic manipulations. To analyze the maximum number of slices or readouts per dissection, long incubation times postslice preparation are commonly used. We were interested in how slice integrity is affected by incubation postslice preparation. METHODS: Hippocampal slices were prepared by three different methods: a chopper, a vibratome, and a rotary slicer. To test slice integrity, we compared glycogen levels and immunohistochemistry of selected proteins in rat hippocampal slices immediately after dissection and following 2 and 4 hr of incubation. RESULTS: We found that immunoreactivity of the dendritic marker microtubule-associated protein 2 (Map2) drastically decreased during this incubation period, whereas immunoreactivity of the glutamate transporter VGlut1 did not significantly change with incubation time. Astrocytic and microglial cell numbers also did not significantly change with incubation time whereas glycogen levels markedly increased during incubation. CONCLUSION: Immunoreactivity of the dendritic marker Map2 quickly decreased after dissection with all the slicing methods. This work highlights a need for caution when using long incubation periods following slice preparation. PMID- 28729942 TI - Problems related to levodopa-carbidopa intestinal gel treatment in advanced Parkinson's disease. AB - BACKGROUND: Continuous levodopa-carbidopa intestinal gel (LCIG) diminishes daily "off" time and dyskinesia in patients with advanced Parkinson's disease (PD). Complications are common with percutaneous endoscopic gastrostomy with a jejunal extension tube (PEG-J). AIM OF THE STUDY: To report the clinical outcome of LCIG in patients with advanced PD in the years 2006-2014 at Helsinki University Hospital. PATIENTS AND METHODS: Levodopa-carbidopa intestinal gel treatment started following PEG-J placement in patients with advanced PD after successful in-hospital LCIG trial with a nasojejunal tube. Demographics, PEG-J procedures, discontinuation of LCIG, complications and mortality were retrospectively analyzed. RESULTS MEAN SD: Sixty patients with advanced PD [age 68(7) years; duration of PD: 11(4) years] had LCIG treatment for 26(23) months. The majority of patients with advanced PD were satisfied with the LCIG treatment. For 51 patients (85%), the pump was on for 16 hr a day, and for nine patients (15%) it was on for 24 hr a day. After 6 months, the levodopa-equivalent daily dose (LEDD) had increased by 30% compared to pre-LCIG LEDD. Sixty patients underwent a total of 156 PEG-J procedures, and 48 patients (80%) had a total of 143 complications. Forty-six patients (77%) had 119 PEG-J or peristomal complications, and 22 patients (37%) had a total of 25 other complications. The most common complications were accidental removal of the J-tube in 23 patients (38%) and >=5% weight loss in 18 patients (30%). Fifteen patients discontinued the LCIG after 21 (21) months. At the end of the follow-up period of 33(27) months, 38 patients were still on LCIG and nine (15%) had died. CONCLUSION: Most patients were satisfied with LCIG treatment. A few patients lost weight whereas the majority had complications with PEG-J. When LCIG treatment is carried out, neurological and endoscopic units must be prepared for multiple endoscopic procedures. PMID- 28729943 TI - Relationship between cerebellar structure and emotional memory in depression. AB - BACKGROUND: A few studies have been conducted on the relationship between cerebellar volume and emotional memory or clinical severity in major depressive disorder (MDD). In this study, we aimed to compare the volume and density of the cerebellar gray matter (GM) in patients with MDD and in healthy controls (HCs) and explore the association between these cerebellar parameters and measurements of emotional memory and clinical severity. METHOD: Voxel-based morphometry (VBM) and Individual Brain Atlases using Statistical Parametric Mapping (IBASPM) were used to assess GM density and volume in the cerebellum, respectively, in patients with MDD and the HCs. Indicators of emotional memory performance were measured, including the hit rate (HR), rate of false alarm (FA), precision (Pr = HR - FA) and emotional memory enhancement [?Pr = Pr(emotion) - Pr(neutral)] values. Beck Depression Inventory (BDI) scores were used to measure the severity of depression. RESULTS: In the patients with MDD, the GM density was decreased in three cerebellar cortical regions and increased in three cerebellar cortical regions (p < .005). The GM volumes in eight cerebellar cortical regions were significantly smaller in the patients with MDD than in the HC subjects (p < .05). In the patients with MDD, the GM volume was correlated with the ?Pr (p < .05) in two cerebellar cortical regions. The BDI scores were significantly correlated with the relative GM densities (p < .05) in 5 cerebellar cortical regions, and the GM volumes in 13 cerebellar cortical regions were correlated with the BDI scores in patients with MDD. CONCLUSIONS: Emotional memory and the severity of depressive symptoms are associated with structural changes in both the posterior and anterior GM regions in the cerebellum in patients with MDD. These findings could be useful for improving our understanding of the neurobiological mechanisms underlying emotional memory and explaining the abnormalities of the neural correlates that are associated with MDD. PMID- 28729944 TI - The impact of multiple sclerosis onset symptom on cardiac repolarization. AB - INTRODUCTION: Multiple sclerosis is associated with prolonged cardiac repolarization but the underlying physiology has remained unknown. In this study, we compared cardiac repolarization during the relapsing-remitting multiple sclerosis (RRMS) disease course in patients with motor and sensory onset symptom. METHODS: Twenty-five RRMS patients with motor and 33 RRMS patients with sensory onset symptom having 12-lead electrocardiogram (ECG) recorded at the time of the first demyelinating event (ECG1) as well as at the later disease course (ECG2) were identified from the patient records. The average time interval between ECG1 and ECG2 was 8.6 +/- 5.9 y. Heart rate-corrected QT intervals reflecting cardiac repolarization were calculated by Bazett (QTcBaz), Fridericia (QTcFri), and Karjalainen (QTcKar) formulas. RESULTS: Heart rate-corrected QT intervals as well as heart rate were similar in patients with motor and sensory onset symptom in ECG1. However, QTcBaz (p = .002), QTcFri (p = .019), and QTcKar (p = .026) were longer and heart rate was higher (p = .035) in patients with motor than sensory onset symptom in ECG2. Correspondingly, QTcBaz (p = .002), QTcFri (p = .033), and QTcKar (p = .043) prolonged and heart rate tended to increase (p = .060) during the disease course only in the patients with motor onset symptom. CONCLUSIONS: Cardiac repolarization prolonged and heart rate increased during the disease course in RRMS patients with motor but not with sensory onset symptom. This suggests different traits in RRMS according to its initial manifestation and also association of motor onset symptom with more unfavorable cardiovascular prognostic determinants. PMID- 28729945 TI - Validity and reliability of the Fatigue Severity Scale in Finnish multiple sclerosis patients. AB - BACKGROUND: Fatigue is one of the most debilitating symptoms in multiple sclerosis (MS) considerably interfering with patients' daily functioning. Both researchers and clinicians need psychometrically robust methods to evaluate fatigue in MS. OBJECTIVES: The objective of this study was (i) to evaluate the psychometric properties of the Finnish version of the Fatigue Severity Scale (FSS) and (ii) to describe the results among patients with MS. METHODS: In total, 553 patients with MS (mean age, 53.8 years; standard deviation [SD], 11.4; 79% women: mean patient-defined disease severity, Expanded Disability Status Scale [EDSS] 4.0, SD, 2.5) completed the self-administered questionnaires including the FSS. A standard procedure was used for the translation of the FSS. RESULTS: The mean (SD) score for the FSS was 4.5 (1.7); in 65% of the patients, the score was >=4.0. The data quality of the FSS was excellent, with 99.6% of computable scale scores. Floor and ceiling effects were minimal. The FSS showed high internal consistency (Cronbach's alpha, 0.95). Unidimensionality was supported based on confirmatory factor analysis with the comparative fit index being 0.94. The FSS showed moderate/high correlations with the perceived burden of the disease, quality of life and disease severity, whereas, age or gender did not have a significant effect on the FSS score. CONCLUSIONS: The Finnish version of the FSS showed satisfactory reliability and validity and thus can be regarded as a feasible measure of self-reported fatigue. PMID- 28729946 TI - Decrease in short-latency afferent inhibition during corticomotor postexercise depression following repetitive finger movement. AB - INTRODUCTION: This study aimed to clarify cortical circuit mechanisms contributing to corticomotor excitability during postexercise depression (PED) following repetitive nonfatiguing movement. We investigated changes in short latency afferent inhibition (SAI) and short-interval intracortical inhibition (SICI) by paired-pulse transcranial magnetic stimulation (TMS) during PED. METHODS: A total of 16 healthy subjects performed repetitive abduction movements of the right index finger at 2.0 Hz for 6 min at 10% maximum voluntary contraction. We measured SAI evoked by pairing ulnar nerve stimulation with TMS (interstimulus interval, 22 ms) before and during PED (n = 10, experiment 1). We also measured SICI evoked by paired TMS (interstimulus interval, 2 ms) at 80% resting motor threshold (n = 10, experiment 2), and at 80% active motor threshold (n = 8, experiment 3) before and during PED. RESULTS: Single motor evoked potential amplitude significantly decreased 1-2 min after the movement task in all experiments, indicating reliable PED induction. In experiment 1, SAI significantly decreased (disinhibited) 1-2 min during PED, whereas in experiments 2 and 3, SICI showed no significant change during PED. CONCLUSION: This study suggests that cholinergic inhibitory circuit activity decreases during PED following repetitive nonfatiguing movement, whereas GABAA circuit activity remains stable. PMID- 28729948 TI - Algorithms for the Automated Analysis of Age-Related Macular Degeneration Biomarkers on Optical Coherence Tomography: A Systematic Review. AB - PURPOSE: To assess the quality of optical coherence tomography (OCT) grading algorithms for retinal biomarkers of age-related macular degeneration (AMD). METHODS: Following a systematic review of the literature data on detection and quantification of AMD retinal biomarkers by available algorithms were extracted and descriptively synthesized. Algorithm quality was assessed using a modified version of the Quality Assessment of Diagnostic Accuracy Studies 2 checklist with a focus on accuracy against established reference standards and risk of bias. RESULTS: Thirty five studies reporting computer-aided diagnosis (CAD) tools for qualitative analysis or algorithms for quantitative analysis were identified. Compared with manual assessment in reference standards correlation coefficients ranged from 0.54 to 0.97 for drusen, 0.80 to 0.98 for geographic atrophy (GA), and 0.30 to 0.98 for intra- or subretinal fluid and pigment epithelial detachment (PED) detection by automated algorithms. CAD tools achieved area under the curve (AUC) values of 0.94 to 0.99, sensitivity of 0.90 to 1.00, and specificity of 0.89 to 0.92. CONCLUSIONS: Automated analysis of AMD biomarkers on OCT is promising. However, most of the algorithm validation was performed in preselected patients, exhibiting the targeted biomarker only. In addition, type and quality of reported algorithm validation varied substantially. TRANSLATIONAL RELEVANCE: The development of algorithms for combined, simultaneous analysis of multiple AMD biomarkers including AMD staging and the agreement on standardized validation procedures would be of considerable translational value for the clinician and the clinical researcher. PMID- 28729947 TI - Associations between Optic Nerve Head-Related Anatomical Parameters and Refractive Error over the Full Range of Glaucoma Severity. AB - PURPOSE: To evaluate the associations between optic disc (OD)-related anatomical parameters (interartery angle [IAA] between superior and inferior temporal retinal arteries, OD tilt [TL], rotation [ROT], and torsion [TO], OD surface curvature [CUR], and central retinal vessel trunk entry point location [CRVTL] on OD) and the spherical equivalent of refractive error (SE), and to assess the impact of glaucoma severity on these relationships. METHODS: Cirrus optical coherence tomography (OCT) fundus images and 24-2 visual fields of 438 patients were included. Ellipses were fitted to OD borders. IAA was calculated between marked retinal artery locations on a circle around OD. Blood vessel entry point on OD was marked to locate CRVTL. TL was measured as the angle between the lines fitted to OD clinical boundary and the Bruch's membrane edges on the horizontal B scans. Ellipse rotation relative to the vertical axis defined ROT. Angle between the long axis of OD and the interartery line defined TO. CUR was determined by the inner limiting membrane on the horizontal B-scans. Linear regression models evaluated by Bayes Factors (BF) were used to determine the covariance structure between the parameters and SE as well as possible impacts of mean deviation (MD). RESULTS: Our results showed that CRVTL had the strongest relationship with SE, followed by ROT, TL, and IAA (BFs: 3.59 * 107, 2645, 1126, and 248, respectively). MD did not significantly modulate the relationship between ONH parameters and SE. CONCLUSION: Our results suggest that SE should be considered when interpreting the OD and its circumpapillary region for diagnostic purposes. TRANSLATIONAL RELEVANCE: The reported relationships between OD-related parameters and ametropia may help to decrease false-positive clinical diagnoses of optic neuropathies. PMID- 28729949 TI - Modeling the effect of blunt impact on mitochondrial function in cartilage: implications for development of osteoarthritis. AB - OBJECTIVE: Osteoarthritis (OA) is a disease characterized by degeneration of joint cartilage. It is associated with pain and disability and is the result of either age and activity related joint wear or an injury. Non-invasive treatment options are scarce and prevention and early intervention methods are practically non-existent. The modeling effort presented in this article is constructed based on an emerging biological hypothesis-post-impact oxidative stress leads to cartilage cell apoptosis and hence the degeneration observed with the disease. The objective is to quantitatively describe the loss of cell viability and function in cartilage after an injurious impact and identify the key parameters and variables that contribute to this phenomenon. METHODS: We constructed a system of differential equations that tracks cell viability, mitochondrial function, and concentrations of reactive oxygen species (ROS), adenosine triphosphate (ATP), and glycosaminoglycans (GAG). The system was solved using MATLAB and the equations' parameters were fit to existing data using a particle swarm algorithm. RESULTS: The model fits well the available data for cell viability, ATP production, and GAG content. Local sensitivity analysis shows that the initial amount of ROS is the most important parameter. DISCUSSION: The model we constructed is a viable method for producing in silico studies and with a few modifications, and data calibration and validation, may be a powerful predictive tool in the search for a non-invasive treatment for post-traumatic osteoarthritis. PMID- 28729950 TI - Alder and the Golden Fleece: high diversity of Frankia and ectomycorrhizal fungi revealed from Alnus glutinosa subsp. barbata roots close to a Tertiary and glacial refugium. AB - BACKGROUND: Recent climatic history has strongly impacted plant populations, but little is known about its effect on microbes. Alders, which host few and specific symbionts, have high genetic diversity in glacial refugia. Here, we tested the prediction that communities of root symbionts survived in refugia with their host populations. We expected to detect endemic symbionts and a higher species richness in refugia as compared to recolonized areas. METHODS: We sampled ectomycorrhizal (EM) root tips and the nitrogen-fixing actinomycete Frankia communities in eight sites colonized by Alnus glutinosa subsp. barbata close to the Caucasus in Georgia. Three sites were located in the Colchis, one major Eurasian climatic refugia for Arcto-Tertiary flora and alders, and five sites were located in the recolonized zone. Endemic symbionts and plant ITS variants were detected by comparing sequences to published data from Europe and another Tertiary refugium, the Hyrcanian forest. Species richness and community structure were compared between sites from refugia and recolonized areas for each symbionts. RESULTS: For both symbionts, most MOTUs present in Georgia had been found previously elsewhere in Europe. Three endemic Frankia strains were detected in the Colchis vs two in the recolonized zone, and the five endemic EM fungi were detected only in the recolonized zone. Frankia species richness was higher in the Colchis while the contrary was observed for EM fungi. Moreover, the genetic diversity of one alder specialist Alnicola xanthophylla was particularly high in the recolonized zone. The EM communities occurring in the Colchis and the Hyrcanian forests shared closely related endemic species. DISCUSSION: The Colchis did not have the highest alpha diversity and more endemic species, suggesting that our hypothesis based on alder biogeography may not apply to alder's symbionts. Our study in the Caucasus brings new clues to understand symbioses biogeography and their survival in Tertiary and ice-age refugia, and reveals that isolated host populations could be of interest for symbiont diversity conservation. PMID- 28729951 TI - Young children do not require perceptual-motor feedback to solve Aesop's Fable tasks. AB - Aesop's Fable tasks-in which subjects drop objects into a water-filled tube to raise the water level and obtain out-of-reach floating rewards -have been used to test for causal understanding of water displacement in both young children and non-human animals. However, a number of alternative explanations for success on these tasks have yet to be ruled out. One hypothesis is that subjects may respond to perceptual-motor feedback: repeating those actions that bring the reward incrementally closer. Here, we devised a novel, forced-choice version of the Aesop's Fable task to assess whether subjects can solve water displacement tasks when this type of feedback is removed. Subjects had to select only one set of objects, or one type of tube, into which all objects were dropped at once, and the effect the objects had on the water level was visually concealed. In the current experiment, fifty-five 5-9 year old children were tested in six different conditions in which we either varied object properties (floating vs. sinking, hollow vs. solid, large vs. small and too large vs. small objects), the water level (high vs. low) and/or the tube size (narrow vs. wide). We found that children aged 8-9 years old were able to solve most of the water displacement tasks on their first trial, without any opportunity for feedback, suggesting that they mentally simulated the results of their actions before making a choice. Children aged 5-7 years solved two conditions on their first trial (large vs. small objects and high- vs. low-water levels), and learnt to solve most of the remaining conditions over five trials. The developmental pattern shown here is comparable to previous studies using the standard Aesop's Fable task, where eight year olds are typically successful from their first trial and 5-7 year olds learn to pass over five trials. Thus, our results indicate that children do not depend on perceptual-motor feedback to solve these water displacement tasks. The forced choice paradigm we describe could be used comparatively to test whether or not non-human animals require visual feedback to solve water displacement tasks. PMID- 28729952 TI - Nano-sized zeolites as modulators of thiacloprid toxicity on Chironomus riparius. AB - This study investigated whether zeolites of different size (Y30 (nano-sized) and H-Beta(OH)-III (forming large aggregates/agglomerates composed of 50 nm small primary particles)) exerted acute toxicity on larvae of the non-biting midge, Chironomus riparius, and whether such zeolites are able to modulate the toxicity of a common insecticide, thiacloprid, by means of adsorption of a dissolved toxicant. We conducted acute toxicity tests with fourth instar larvae of C. riparius. In these tests, larvae were exposed to zeolites or thiacloprid solely, or to mixtures of both compounds. The mixtures comprised 1.0 ug/L thiacloprid in addition to low (5.2 mg/L), medium (18.2 mg/L), and high (391.7 mg/L) zeolite concentrations, resulting in different adsorption rates of thiacloprid. As biological endpoints, changes in mortality rates and in behavior were monitored every 24 h over a total investigation period of 96 h. Furthermore, we conducted chemical analyses of thiacloprid in the medium and the larvae and located the zeolite particles within the larvae by LA-ICP-MS imaging techniques. Our results demonstrate that both types of zeolites did not exert acute toxicity when applied as single-substances, but led to reduced acute toxicity of thiacloprid when applied together with thiacloprid. These results are in line with the sorption properties of zeolites indicating reduced bioavailability of thiacloprid, although our data indicate that thiacloprid can desorb from zeolites to some extent. While freely dissolved (i.e., non-sorbed) fraction of thiacloprid was a good parameter to roughly estimate toxic effects, it did not correlate with measured internal thiacloprid concentrations. Moreover, it was shown that both zeolite types were ingested by the larvae, but no indication for cellular uptake of them was found. PMID- 28729953 TI - Demographic inference through approximate-Bayesian-computation skyline plots. AB - The skyline plot is a graphical representation of historical effective population sizes as a function of time. Past population sizes for these plots are estimated from genetic data, without a priori assumptions on the mathematical function defining the shape of the demographic trajectory. Because of this flexibility in shape, skyline plots can, in principle, provide realistic descriptions of the complex demographic scenarios that occur in natural populations. Currently, demographic estimates needed for skyline plots are estimated using coalescent samplers or a composite likelihood approach. Here, we provide a way to estimate historical effective population sizes using an Approximate Bayesian Computation (ABC) framework. We assess its performance using simulated and actual microsatellite datasets. Our method correctly retrieves the signal of contracting, constant and expanding populations, although the graphical shape of the plot is not always an accurate representation of the true demographic trajectory, particularly for recent changes in size and contracting populations. Because of the flexibility of ABC, similar approaches can be extended to other types of data, to multiple populations, or to other parameters that can change through time, such as the migration rate. PMID- 28729954 TI - Clinical streptococcal isolates, distinct from Streptococcus pneumoniae, but containing the beta-glucosyltransferase tts gene and expressing serotype 37 capsular polysaccharide. AB - The major virulence factor of the pneumococcus, and target for conjugate vaccines, is the polysaccharide capsule, which is usually encoded by the highly variable cps locus. Serotype 37 is an unusual pneumococcal type in which the single beta-glucosyltransferase gene responsible for serotype capsule production (tts) is located outside of the capsular operon region. Using a previously described automated whole genome sequence (WGS)-based serotyping bioinformatics tool, PneumoCaT, we identified and investigated seven clinical isolates (three from blood cultures) of non-pneumococcal streptococci containing a highly homologous tts and included them in a study panel of 20 isolates which included a 11 further clinical isolates of S. pneumoniae serotype 37, a reference strain of serotype 37 and the S. pseudopneumoniae type strain BAA 960T. The seven non pneumococcal isolates generated novel alleles at all pneumococcal MLST loci and gave low percentage similarity (<45%) to S. pneumoniae or S. pseudopneumoniae species by comparison of short sequence patterns in genomic data (k-mer analysis). The S. pseudopneumoniae BAA-960T isolate generated two novel alleles in the MLST and gave a high similarity (>99%) to the reference sequence for BAA 960T. Twelve isolates gave high similarity (>77%) to the Streptococcus pneumoniae 5652-06 serotype 19A reference genome sequence and had previously reported MLST alleles. Each of the seven clinical non-pneumococcal strains and all of the 12 S. pneumoniae possessed a beta-glycosyltransferase gene (tts) with >95% similarity to the pneumococcal tts reference DNA sequence with 20-22 non-synonymous SNPs. All but two strains in which the tts gene was detected gave positive reactions for serotype 37 in slide agglutination tests with serotype 37 typing sera. Phylogenetic analysis using both SNP and MLST data showed distinct clades corresponding to strains identified as pneumococcus or non-pneumococcus by kmer WGS analysis. Extended k-mer database analysis and ribosomal MLST placed the non pneumococcal isolates within the S. mitis group. Biochemical and bile solubility assays showed differences between the unusual isolates and S. pneumoniae. All isolates had detectable pneumolysin (ply) genes, but only those that identified as pneumococcus contained the genes for autolysin (lytA) or the ABC transporter lipoprotein A (piaA) with >80% coverage and >95% similarity. Here we report the existence of a novel group of strains distinct from S. pneumoniae, but which can express a pneumococcal serotype 37 capsular polysaccharide which can be associated with clinical disease. PMID- 28729955 TI - Identification of four prognostic LncRNAs for survival prediction of patients with hepatocellular carcinoma. AB - BACKGROUND: As the fifth most common cancer worldwide, Hepatocellular carcinoma (HCC) is also the third most common cause of cancer-related death in China. Several lncRNAs have been demonstrated to be associated with occurrence and prognosis of HCC. However, identification of prognostic lncRNA signature for HCC with expression profiling data has not been conducted yet. METHODS: With the reuse of public available TCGA data, expression profiles of lncRNA for 371 patients with HCC were obtained and analyzed to find the independent prognostic lncRNA. Based on the expression of lncRNA, we developed a risk score model, which was evaluated by survival analysis and ROC (receiver operating characteristic) curve. Enrichment analysis was performed to predict the possible role of the identified lncRNA in HCC prognosis. RESULTS: Four lncRNAs (RP11-322E11.5, RP11 150O12.3, AC093609.1, CTC-297N7.9) were found to be significantly and independently associated with survival of HCC patients. We used these four lncRNAs to construct a risk score model, which exhibited a strong ability to distinguish patients with significantly different prognosis (HR = 2.718, 95% CI [2.103-3.514], p = 2.32e-14). Similar results were observed in the subsequent stratification survival analysis for HBV infection status and pathological stage. The ROC curve also implied our risk score as a good indicator for 5-year survival prediction. Furthermore, enrichment analysis revealed that the four signature lncRNAs may be involved in multiple pathways related to tumorigenesis and prognosis. DISCUSSION: Our study recognized four lncRNAs to be significantly associated with prognosis of liver cancer, and could provide novel insights into the potential mechanisms of HCC progression. Additionally, CTC-297N7.9 may influence the downstream TMEM220 gene expression through cis-regualtion. Nevertheless, further well-designed experimental studies are needed to validate our findings. PMID- 28729956 TI - Predicting the host of influenza viruses based on the word vector. AB - Newly emerging influenza viruses continue to threaten public health. A rapid determination of the host range of newly discovered influenza viruses would assist in early assessment of their risk. Here, we attempted to predict the host of influenza viruses using the Support Vector Machine (SVM) classifier based on the word vector, a new representation and feature extraction method for biological sequences. The results show that the length of the word within the word vector, the sequence type (DNA or protein) and the species from which the sequences were derived for generating the word vector all influence the performance of models in predicting the host of influenza viruses. In nearly all cases, the models built on the surface proteins hemagglutinin (HA) and neuraminidase (NA) (or their genes) produced better results than internal influenza proteins (or their genes). The best performance was achieved when the model was built on the HA gene based on word vectors (words of three-letters long) generated from DNA sequences of the influenza virus. This results in accuracies of 99.7% for avian, 96.9% for human and 90.6% for swine influenza viruses. Compared to the method of sequence homology best-hit searches using the Basic Local Alignment Search Tool (BLAST), the word vector-based models still need further improvements in predicting the host of influenza A viruses. PMID- 28729957 TI - Decline of heterozygosity in a large but isolated population: a 45-year examination of moose genetic diversity on Isle Royale. AB - Wildlife conservation and management approaches typically focus on demographic measurements to assess population viability over both short and long periods. However, genetic diversity is an important predictor of long term population vitality. We investigated the pattern of change in genetic diversity in a large and likely isolated moose (Alces alces) population on Isle Royale (Lake Superior) from 1960-2005. We characterized samples, partitioned into five different 5-year periods, using nine microsatellite loci and a portion of the mtDNA control region. We also simulated the moose population to generate a theoretical backdrop of genetic diversity change. In the empirical data, we found that the number of alleles was consistently low and that observed heterozygosity notably declined from 1960 to 2005 (p = 0.08, R2 = 0.70). Furthermore, inbreeding coefficients approximately doubled from 0.08 in 1960-65 to 0.16 in 2000-05. Finally, we found that the empirical rate of observed heterozygosity decline was faster than the rate of observed heterozygosity loss in our simulations. Combined, these data suggest that genetic drift and inbreeding occurred in the Isle Royale moose populations over the study period, leading to significant losses in heterozygosity. Although inbreeding can be mitigated by migration, we found no evidence to support the occurrence of recent migrants into the population using analysis of our mtDNA haplotypes nor microsatellite data. Therefore, the Isle Royale moose population illustrates that even large populations are subjected to inbreeding in the absence of migration. PMID- 28729958 TI - Mutational analysis of driver genes with tumor suppressive and oncogenic roles in gastric cancer. AB - Gastric cancer (GC) is a complex disease with heterogeneous genetic mechanisms. Genomic mutational profiling of gastric cancer not only expands our knowledge about cancer progression at a fundamental genetic level, but also could provide guidance on new treatment decisions, currently based on tumor histology. The fact that precise medicine-based treatment is successful in a subset of tumors indicates the need for better identification of clinically related molecular tumor phenotypes, especially with regard to those driver mutations on tumor suppressor genes (TSGs) and oncogenes (ONGs). We surveyed 313 TSGs and 160 ONGs associated with 48 protein coding and 19 miRNA genes with both TSG and ONG roles. Using public cancer mutational profiles, we confirmed the dual roles of CDKN1A and CDKN1B. In addition to the widely recognized alterations, we identified another 82 frequently mutated genes in public gastric cancer cohort. In summary, these driver mutation profiles of individual GC will form the basis of personalized treatment of gastric cancer, leading to substantial therapeutic improvements. PMID- 28729959 TI - Shot-gun proteome and transcriptome mapping of the jujube floral organ and identification of a pollen-specific S-locus F-box gene. AB - The flower is a plant reproductive organ that forms part of the fruit produced as the flowering season ends. While the number and identity of proteins expressed in a jujube (Ziziphus jujuba Mill.) flower is currently unknown, integrative proteomic and transcriptomic analyses provide a systematic strategy of characterizing the floral biology of plants. We conducted a shotgun proteomic analysis on jujube flowers by using a filter-aided sample preparation tryptic digestion, followed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). In addition, transcriptomics analyses were performed on HiSeq2000 sequencers. In total, 7,853 proteins were identified accounting for nearly 30% of the 'Junzao' gene models (27,443). Genes identified in proteome generally showed higher RPKM (reads per kilobase per million mapped reads) values than undetected genes. Gene ontology categories showed that ribosomes and intracellular organelles were the most dominant classes and accounted for 17.0% and 14.0% of the proteome mass, respectively. The top-ranking proteins with iBAQ >1010 included non-specific lipid transfer proteins, histones, actin-related proteins, fructose-bisphosphate aldolase, Bet v I type allergens, etc. In addition, we identified one pollen specificity S-locus F-box-like gene located on the same chromosome as the S-RNase gene. Both of these may activate the behaviour of gametophyte self incompatibility in jujube. These results reflected the protein profile features of jujube flowers and contributes new information important to the jujube breeding system. PMID- 28729961 TI - Understanding dual precipitation strengthening in ultra-high strength low carbon steel containing nano-sized copper precipitates and carbides. AB - Low carbon ferritic steel alloyed with Ti, Mo and Cu was hot rolled and interrupt cooled to produce nano-sized precipitates of copper and (Ti,Mo)C carbides. The steel had a tensile strength of 840 MPa, an increase in yield strength of 380 MPa over that of the plain carbon steel and reasonable ductility. Transmission electron microscopy and small angle neutron scattering were used to characterize size and volume fraction of the precipitates in the steels designed to form only copper precipitates and only (Ti,Mo)C carbides. The individual and combined precipitation strengthening contributions was calculated using the size and volume fraction of precipitates and compared with the measured values. PMID- 28729960 TI - A Bioengineered Peptide that Localizes to and Illuminates Medulloblastoma: A New Tool with Potential for Fluorescence-Guided Surgical Resection. AB - Tumors of the central nervous system are challenging to treat due to the limited effectiveness and associated toxicities of chemotherapy and radiation therapy. For tumors that can be removed surgically, extent of malignant tissue resection has been shown to correlate with disease progression, recurrence, and survival. Thus, improved technologies for real-time brain tumor imaging are critically needed as tools for guided surgical resection. We previously engineered a novel peptide that binds with high affinity and unique specificity to alphaVbeta3, alphaVbeta5, and alpha5beta1 integrins, which are present on tumor cells, and the vasculature of many cancers, including brain tumors. In the current study, we conjugated this engineered peptide to a near infrared fluorescent dye (Alexa Fluor 680), and used the resulting molecular probe for non-invasive whole body imaging of patient-derived medulloblastoma xenograft tumors implanted in the cerebellum of mice. The engineered peptide exhibited robust targeting and illumination of intracranial medulloblastoma following both intravenous and intraperitoneal injection routes. In contrast, a variant of the engineered peptide containing a scrambled integrin-binding sequence did not localize to brain tumors, demonstrating that tumor-targeting is driven by specific integrin interactions. Ex vivo imaging was used to confirm the presence of tumor and molecular probe localization to the cerebellar region. These results warrant further clinical development of the engineered peptide as a tool for image-guided resection of central nervous system tumors. PMID- 28729962 TI - The Protective Effects of Family Support on the Relationship between Official Intervention and General Delinquency across the Life Course. AB - PURPOSE: Previous research on the labeling perspective has identified mediational processes and the long-term effects of official intervention in the life course. However, it is not yet clear what factors may moderate the relationship between labeling and subsequent offending. The current study integrates Cullen's (1994) social support theory to examine how family social support conditions the criminogenic, stigmatizing effects of official intervention on delinquency and whether such protective effects vary by developmental stage. METHODS: Using longitudinal data from the Rochester Youth Development Study, we estimated negative binomial regression models to investigate the relationships between police arrest, family social support, and criminal offending during both adolescence and young adulthood. RESULTS: Police arrest is a significant predictor of self-reported delinquency in both the adolescent and adult models. Expressive family support exhibits main effects in the adolescent models; instrumental family support exhibits main effects at both developmental stages. Additionally, instrumental family support diminishes some of the predicted adverse effects of official intervention in adulthood. CONCLUSIONS: Perception of family support can be critical in reducing general delinquency as well as buffering against the adverse effects of official intervention on subsequent offending. Policies and programs that work with families subsequent to a criminal justice intervention should emphasize the importance of providing a supportive environment for those who are labeled. PMID- 28729963 TI - Advances in Applications of Metabolomics in Pluripotent Stem Cell Research. AB - Stem cells undergo extensive metabolic rewiring during reprogramming, proliferation and differentiation, and numerous studies have demonstrated a significant role of metabolism in controlling stem cell fates. Recent applications of metabolomics, the study of concentrations and fluxes of small molecules in cells, have advanced efforts to characterize and maturate stem cell fates, assess drug toxicity in stem cell tissue models, identify biomarkers, and study the effects of environment on metabolic pathways in stem cells and their progeny. Looking to the future, combining metabolomics with other -omics approaches will provide a deeper understanding of the complex regulatory mechanisms of stem cells. PMID- 28729964 TI - Are happier people less judgmental of other people's selfish behaviors? Experimental survey evidence from trust and gift exchange games. AB - What determines people's moral judgments of selfish behaviors? Here we study whether people's normative views in trust and gift exchange games, which underlie many situations of economic and social significance, are themselves functions of positive emotions. We use experimental survey methods to investigate the moral judgments of impartial observers empirically, and explore whether we could influence subsequent judgments by deliberately making some individuals happier. We find that moral judgments of selfish behaviors in the economic context depend strongly on the behavior of the interaction partner of the judged person, but their relationships are significantly moderated by an increase in happiness for the person making the judgment. PMID- 28729965 TI - Fluid overload as a major target in management of cardiorenal syndrome: Implications for the practice of peritoneal dialysis. AB - Congestion is an integral component of cardiorenal syndrome and portends an adverse impact on the outcomes. Recent studies suggest that congestion has the ability of modulating the interactions between the kidney and the heart in this setting. Peritoneal dialysis (PD) is a home-based therapeutic modality that is not only offered to patients with end-stage renal disease to provide solute clearance and ultrafiltration, but it has also been used in patients with refractory heart failure and fluid overload to help optimize volume status. Several uncontrolled studies and case series have so far evaluated the role of PD in management of hypervolemia for patients with heart failure. They have generally reported favorable results in this setting. However, the data on the outcomes of patients with end-stage renal disease and concomitant heart failure is mixed, and the proposed theoretical advantages of PD might not translate into improved clinical endpoints. Congestion is prevalent in this patient population and has a significant effect on their survival. As studies suggest that a significant subset of patients with end-stage renal disease who receive PD therapy are hypervolemic, suboptimal management of congestion could at least in part explain these conflicting results. PD is a highly flexible therapeutic modality and the choice of techniques, regimens, and solutions can affect its ability for optimization of fluid status. This article provides an overview of the currently available data on the role and clinical relevance of congestion in patients with cardiorenal syndrome and reviews potential options to enhance decongestion in these patients. PMID- 28729966 TI - Causal relationship between hypoalbuminemia and acute kidney injury. AB - Our meta-analysis published in 2010 provided evidence that low levels of serum albumin (hypoalbuminemia) are a significant independent predictor of acute kidney injury (AKI) and death following AKI. Since then, a large volume of additional data from observational clinical studies has been published further evaluating the relationship between serum albumin and AKI occurrence. This is an updated review of the literature to re-evaluate the hypothesis that hypoalbuminemia is independently associated with increased AKI risk. Eligible studies published from September 2009 to December 2016 were sought in PubMed (MEDLINE) and forty-three were retained, the great majority being retrospective observational cohort studies. These included a total of about 68000 subjects across a diverse range of settings, predominantly cardiac surgery and acute coronary interventions, infectious diseases, transplant surgery, and cancer. Appraisal of this latest data set served to conclusively corroborate and confirm our earlier hypothesis that lower serum albumin is an independent predictor both of AKI and death after AKI, across a range of clinical scenarios. The body of evidence indicates that hypoalbuminemia may causally contribute to development of AKI. Furthermore, administration of human albumin solution has the potential to prevent AKI; a randomized, controlled study provides evidence that correcting hypoalbuminemia may be renal-protective. Therefore, measurement of serum albumin to diagnose hypoalbuminemia may help identify high-risk patients who may benefit from treatment with exogenous human albumin. Multi-center, prospective, randomized, interventional studies are warranted, along with basic research to define the mechanisms through which albumin affords nephroprotection. PMID- 28729967 TI - Tesevatinib ameliorates progression of polycystic kidney disease in rodent models of autosomal recessive polycystic kidney disease. AB - AIM: To investigate the therapeutic potential of tesevatinib (TSV), a unique multi-kinase inhibitor currently in Phase II clinical trials for autosomal dominant polycystic kidney disease (ADPKD), in well-defined rodent models of autosomal recessive polycystic kidney disease (ARPKD). METHODS: We administered TSV in daily doses of 7.5 and 15 mg/kg per day by I.P. to the well characterized bpk model of polycystic kidney disease starting at postnatal day (PN) 4 through PN21 to assess efficacy and toxicity in neonatal mice during postnatal development and still undergoing renal maturation. We administered TSV by oral gavage in the same doses to the orthologous PCK model (from PN30 to PN90) to assess efficacy and toxicity in animals where developmental processes are complete. The following parameters were assessed: Body weight, total kidney weight; kidney weight to body weight ratios; and morphometric determination of a cystic index and a measure of hepatic disease. Renal function was assessed by: Serum BUN; creatinine; and a 12 h urinary concentrating ability. Validation of reported targets including the level of angiogenesis and inhibition of angiogenesis (active VEGFR2/KDR) was assessed by Western analysis. RESULTS: This study demonstrates that: (1) in vivo pharmacological inhibition of multiple kinase cascades with TSV reduced phosphorylation of key mediators of cystogenesis: EGFR, ErbB2, c-Src and KDR; and (2) this reduction of kinase activity resulted in significant reduction of renal and biliary disease in both bpk and PCK models of ARPKD. The amelioration of disease by TSV was not associated with any apparent toxicity. CONCLUSION: The data supports the hypothesis that this multi-kinase inhibitor TSV may provide an effective clinical therapy for human ARPKD. PMID- 28729968 TI - Reproducibility of serial creatinine excretion measurements in peritoneal dialysis. AB - AIM: To test whether muscle mass evaluated by creatinine excretion (EXCr) is maintained in patients with end-stage kidney disease (ESKD) treated by peritoneal dialysis (PD), we evaluated repeated measurements of EXCr in a PD population. METHODS: One hundred and sixty-six PD patients (94 male, 72 female) receiving the same PD dose for the duration of the study (up to approximately 2.5 years) had repeated determinations of total (in urine plus spent dialysate) 24-h EXCr (EXCr T) to assess the adequacy of PD by creatinine clearance. All 166 patients had two EXCr T determinations, 84 of the 166 patients had three EXCr T determinations and 44 of the 166 patients had four EXCr T measurements. EXCr T values were compared using the paired t test in the patients who had two studies and by repeated measures ANOVA in those who were studied three or four times. RESULTS: In patients who were studied twice, with the first and second EXCr T measurements performed at 9.2 +/- 15.2 mo and 17.4 +/- 15.8 mo after onset of PD, respectively, EXCr T did not differ between the first and second study. In patients studied three times and whose final assessment occurred 24.7 +/- 16.3 mo after initiating PD, EXCr T did not differ between the first and second study, but was significantly lower in the third study compared to the first study. In patients who were studied four times and whose fourth measurement was taken 31.9 +/- 16.8 mo after onset of PD, EXCr T did not differ between any of the studies. The average EXCr T value did not change significantly, with the exception of the third study in the patients studied thrice. However, repeated determinations of EXCr T in individuals showed substantial variability, with approximately 50% of the repeated determinations being higher or lower than the first determination by 15% or more. CONCLUSION: The average value of EXCr T remains relatively constant for up to 2.5 years of follow-up in PD patients who adhere to the same PD schedule. However, repeated individual EXCr T values vary considerably in a large proportion of the patients. Further studies are needed to evaluate the clinical significance of varying EXCr T values and the stability of EXCr T beyond 2.5 years of PD follow-up. PMID- 28729969 TI - Exercise-induced albuminuria and circadian blood pressure abnormalities in type 2 diabetes. AB - AIM: To investigate the relationship between circadian variations in blood pressure (BP) and albuminuria at rest, and during exercise in non-hypertensive type 2 diabetes (T2D) patients. METHODS: We conducted a cross-sectional study in well controlled T2D patients, non-hypertensive, without clinical proteinuria and normal creatinine clearance. In each participant, we recorded the BP using ambulatory blood pressure monitoring (ABPM) for 24-h, and albuminuria at rest and after a standardized treadmill exercise. RESULTS: We enrolled 27 type 2 patients with a median age of 52; and a mean duration of diabetes and HbA1c of 3.6 +/- 0.8 years and 6.3% +/- 0.5% respectively. Using a 24-h ABPM, we recorded a mean diurnal systolic blood pressure (SBP) of 128 +/- 17 mmHg vs nocturnal of 123 +/- 19 mmHg (P = 0.004), and mean diurnal diastolic blood pressure (DBP) of 83 +/- 11 mmHg vs nocturnal 78 +/- 14 mmHg (P = 0.002). There was a significant difference between albuminuria at rest [median = 23 mg, interquartile range (IQR) = 10-51] and after exercise (median = 35 mg, IQR = 23-80, P < 0.001). Patients with exercise induced albuminuria had an increase in nocturnal BP values on all three components (128 mmHg vs 110 mmHg, P = 0.03 for SBP; 83 mmHg vs 66 mmHg, P = 0.04; 106 vs 83, P = 0.02 for mean arterial pressure), as well as albuminuric patients at rest. Moreover, exercise induced albuminuria detect a less increase in nocturnal DBP (83 vs 86, P = 0.03) than resting albuminuria. CONCLUSION: Exercise induced albuminuria is associated with an increase in nocturnal BP values in T2D patients. PMID- 28729970 TI - Severe cyclophosphamide-related hyponatremia in a patient with acute glomerulonephritis. AB - Cyclophosphamide is frequently used to treat cancer, autoimmune and renal diseases, such as rapidly progressive glomerulonephritis. Its side effects are well-known, including bone marrow depression, infections, alopecia, sterility, bladder malignancy and hemorrhagic cystitis. Moreover, in some cases cyclophosphamide use has been related to the onset of hyponatremia, by development of a syndrome of inappropriate antidiuresis. Indeed, severe hyponatremia has been previously reported in patients treated with high-dose or moderate-dose of intravenous cyclophosphamide, while only few cases have been reported in patients treated with low dose. Here, we discuss a case of a syndrome of inappropriate antidiuresis followed to a single low-dose of intravenous cyclophosphamide in a patient with a histological diagnosis of acute glomerulonephritis, presenting as acute kidney injury. After cyclophosphamide administration (500 mg IV), while renal function gradually improved, the patient developed confusion and headache. Laboratory examinations showed serum sodium concentration dropped to 122 mmol per liter associated with an elevated urinary osmolality of 199 mOsm/kg, while common causes of acute hyponatremia were excluded. He was successfully treated with water restriction and hypertonic saline solution infusion with the resolution of the electrolyte disorder. This case, together with the previous ones already reported, highlights that electrolyte profile should be strictly monitored in patients undergoing cyclophosphamide therapy in order to early recognize the potentially life threatening complications of acute water retention. PMID- 28729971 TI - Stakeholder consultations on community-based rehabilitation guidelines in Ghana and Uganda. AB - BACKGROUND: The focus of this paper is the new broadened conceptualisation of community-based rehabilitation (CBR), which promotes the empowerment and inclusion of people with disabilities (PWDs) in diverse ways within their communities. New guidelines for CBR were launched in October 2010 by WHO/ILO/UNESCO/IDDC, and this paper describes part of the process by which these were produced using participatory approaches involving International Non Government Organisations (INGOs) and local partners. The paper reviews the evolution of CBR and describes how grassroots consultation by INGOs working with key stakeholders in the disability arena can influence policy on disability issues, and reciprocally how policy change can inform organisations' practice and research activities. This ongoing bidirectional influence is illustrated with data from the participatory consultation process about the new CBR guidelines carried out by Sightsavers in Uganda and Ghana. OBJECTIVES: To consult with key stakeholders in the disability arena in Uganda and Ghana, in order to gain their opinions and suggestions for improvements to the then draft CBR guidelines, as part of a wider global participatory process of consultation on the document. METHODS: The INGO Sightsavers gathered qualitative data through focus group discussions and questionnaires in both countries. RESULTS: The participants' critiques of the draft guidelines carried out in multiagency participatory processes were analysed thematically and fed back to the CBR guidelines editorial team. CONCLUSION: The paper concludes that stakeholders in diverse communities can actively contribute to shaping policy and practice through participatory consultations. Local and national government and non-government organisations and other key informants can inform the development of national and international guidelines and policies. This participatory approach can be successfully facilitated by INGOs. In turn, these processes have prompted organisations to adapt their own policies and programmes in order to be more responsive to the local needs and concerns of PWDs. PMID- 28729972 TI - Designed to deter: Barriers to facilities at secondary schools in Ghana. AB - BACKGROUND: There are varied and complex problems associated with the admission of students with disabilities into secondary (senior high) schools all over the world. This situation is further complicated by difficulties encountered in the built environment of these institutions and, in this, Ghana is no exception. OBJECTIVES: This exploratory study investigated the level of accessibility of the built environment in secondary schools in eight out of the ten regions of Ghana, in order to determine whether they conform to guidelines provided in international building standards and also assess the extent to which they have been designed and constructed to meet the provisions of the Persons with Disability Act 2006, which allows for equal access to public buildings in Ghana. METHOD: In total, 705 building elements in 264 facilities were surveyed using international standards, building codes, regulations and guidelines. These facilities included car parks, classrooms, dormitories, assembly halls, telephone booths and administration blocks. RESULTS: Our findings revealed that most of the building elements were barring and not disability-friendly. Just to name a few: there were obstructions on access routes to and around buildings, absence of designated car parks, unfriendly vertical and horizontal means of circulation in buildings and lack of accessible sanitary accommodations. In addition, the general lighting and signage were poor. As a result, very few students with disabilities are admitted and retained in these schools. CONCLUSION: Mainstreaming of people with disabilities into the Ghanaian educational system remains impossible unless urgent action is taken to alter the facilities at secondary schools. Based on this research outcome, recommendations have been made to the Ghanaian government and the Ghana Education Service, as well as non governmental organisations and relevant professional bodies for the amelioration of the present situation in our secondary schools. PMID- 28729973 TI - Communication training for centre-based carers of children with severe or profound disabilities in the Western Cape, South Africa. AB - The purpose of this paper is to provide a preliminary, qualitative review of an approach to training centre-based carers in supporting basic communication development and providing communication opportunities for the children with severe and profound disabilities in their care. In South Africa, these children are often the most neglected in terms of planning and providing appropriate interventions. For those with severe communication disabilities, an additional lack is in the area of the basic human right to meaningful interactions and communication. Sustainable strategies to provide opportunities for basic communication development of these children are urgently sought. Several effective international and local parent training programmes have been developed, but the urgent need remains to train centre-based carers who are taking care of groups of diversely disabled children in severely under-resourced settings. Non profit organisations (NPOs) have been exploring practical centre-based approaches to skills sharing in physical rehabilitation, activities for daily living, feeding and support for basic communication development. As a freelance speech therapist contracted by four NPOs to implement hands-on training in basic communication for centre-based carers of non-verbal children, the author describes a training approach that evolved over three years, in collaboration with the carers and centre managements. Implications for training (for speech therapists and for community-based rehabilitation workers) and for further research are identified. PMID- 28729974 TI - The implementation of inclusive education in South Africa: Reflections arising from a workshop for teachers and therapists to introduce Universal Design for Learning. AB - South Africa has adopted an inclusive education policy in order to address barriers to learning in the education system. However, the implementation of this policy is hampered by the lack of teachers' skills and knowledge in differentiating the curriculum to address a wide range of learning needs. In this paper we provided a background to inclusive education policy in South Africa and a brief exposition of an instructional design approach, Universal Design for Learning (UDL) that addresses a wide range of learning needs in a single classroom. We reported on a workshop conducted with teachers and therapists in South Africa as a first attempt to introduce UDL in this context. Knowledge of UDL was judged to be appropriate and useful by the course participants in the South African context as a strategy for curriculum differentiation in inclusive classrooms. Furthermore, knowledge of the UDL framework facilitates dialogue between teachers and therapists and provides a relatively simple and comprehensive approach for curriculum differentiation. We therefore conclude that there is potential for this approach that can be expanded through further teacher training. PMID- 28729975 TI - A journey towards inclusive education; a case study from a 'township' in South Africa. AB - The purpose of this case study was to relate part of the journey to appropriate education for two young children with physical disabilities in a low socio economic peri-urban informal settlement - or 'township' - in South Africa. The part of the on-going journey described here spanned four-and-a-half years and included the two children, their families, their teachers, their community and a small team of rehabilitation professionals working for a non-profit organisation in the area. The rehabilitation professionals' goals were to provide support for the children, their families, their current special care centre and the school(s) they would attend in the future. The steps from the special care centre, to a mainstream early childhood development (ECD) centre for both of them, and then on to (a) a school for learners with special educational needs (LSEN) for one child and (b) a mainstream primary school for the other, are described. Challenges encountered on the way included parental fears, community attitudes and physical accessibility. Practical outcomes included different placements for the two children with implications and recommendations for prioritised parent involvement, individual approaches, interdisciplinary and community-based collaborations. Recommendations are given for clinical contexts, curricula and policy matters; for research and for scaling up such a programme through community workers. PMID- 28729976 TI - Journey through the Trials and Triumphs of Disability. AB - One Woman's journey through the Trials and Triumphs of Disability , Disabled Peoples International 8th World Assembly 2011 Durban, South Africa, October 10 13, 2011. When embarking on my career as a teacher at a special school in South Africa, I never thought that a motor vehicle accident would place me in the position where my learners with disabilities suddenly saw me as an ally. Little did I realise the chasm that exists between able-bodied people and people with disabilities, or the remarkable role I would find myself in whilst actively addressing disability and Inclusive Education issues. My experiences with disability in South Africa drew encouraging attention from delegates at the Disabled People's International 8th World Assembly when I shared my story. The resounding positive response affirmed that my experiences are not unique to nationality, gender, race or age, and are typical of the time and country in which I live, where people with disabilities are considered to have little potential, and woman with disabilities are further marginalised. In the infancy of our democracy, we are still in the early days of attending to equity amongst all South Africans. This story comprises both a narrative and a graphic presentation which run parallel, although not always telling an identical story; they complement one another and should be experienced simultaneously. Ultimately, it relates the success that can be achieved by pro-active people with disabilities as members of the South African society within their own spheres of knowledge and skill to change attitudes and practices of people without disabilities in education and local communities. PMID- 28729977 TI - Accessing community health services: challenges faced by poor people with disabilities in a rural community in South Africa. AB - Poor people with disabilities who live in poor rural societies experience unique problems in accessing health services. Their situation is influenced by multiple factors which unfold and interplay throughout the person's life course. The difficulties do not only affect the person with a disability and his or her family, but also impact on the relevant care unit. The barriers are rooted in a life in poverty, upheld and maintained by poverty-reinforcing social forces of the past and the present, and reinforced by the lack of the person's perspective of the health services. This article explores how difficulties may interact and influence access to and utilisation of health services, and how this may render health services out of reach even when they are available. The study reveals that non-compliance is not necessarily about neglect but could as well be a matter of lived poverty. The study was based on in-depth interviews with people with disabilities and family members, and semi-structured interviews with health personnel. The data analysis is contextual and interpretive. When offering health services to people with disabilities living in resource-poor settings, services should take into consideration the person's history, the needs, and the resources and abilities of the family group. Rethinking access to health services should transcend a narrow medical institutionalisation of health professional's training, and include a patient's perspective and a social vision in understanding and practice. Such rethinking requires health service models that integrate the skills of health professionals with the skills of disabled people and their family members. Such skills lie dormant at community level, and need to be recognised and utilised. PMID- 28729978 TI - On the unethicality of disablism: Excluding intellectually impaired individuals from participating in research can be unethical. PMID- 28729979 TI - Family perceptions of intellectual disability: Understanding and support in Dar es Salaam. AB - When attempting to understand the construct of intellectual disability in different contexts, speaking to family members in addition to the individual with the disability may provide new insight about understandings of and responses to intellectual disability in society and may help to identify the forms of support that are available or needed to ensure the quality of life of people with disabilities. This article outlines and discusses interviews that were conducted in Dar es Salaam, Tanzania, with family members of children and adults with intellectual disabilities. These interviews explore how families came to understand that their child had an intellectual disability; the availability of family support; and family hopes and dreams for the future, and were a part of a wider exploratory study that gathered insight from individuals with disabilities, families, and other providers of support to explore understandings and perceptions of disability in Dar es Salaam. Understanding family experiences will help researchers, policy makers, non-governmental organisations, and others to identify family strengths and family support needs which can ultimately improve family quality of life and the quality of life of the member with a disability. PMID- 28729980 TI - Perceived control, academic performance and well-being of Ghanaian college students with disability. AB - BACKGROUND: Empirical evidence abounds showing the impact of perceived control on subjective well-being in several spheres of functioning, including academic performance. At tertiary institutions, such as the Kwame Nkrumah University of Science and Technology, Ghana, little is known about the needs of students with disabilities, as very few persons with disabilities attend institutions of higher learning. OBJECTIVES: This study examined the relationship between perceptions of control and the academic and subjective well-being of students with disabilities. METHOD: A total of 69 students with disabilities participated in this cross sectional descriptive study. Using trusted control and subjective well-being scales, data were subject to descriptive analyses. RESULTS: Consistent with previous works, perceived control increased with increased subjective well-being, moderated by gender. In addition, forms of secondary control appeared to aid primary control in the tenacious pursuit of goals. However, neither perceived control nor self-esteem was predictive of academic performance. CONCLUSION: Limitations of sample size notwithstanding, the findings of the study can be considered provocative. Implications for clinical utility in facilitating context specific interventions for this marginalised group are discussed. Replication with a larger sample size in other tertiary institutions is suggested for future work. PMID- 28729981 TI - Perceptions of caring for children with disabilities: Experiences from Moshi, Tanzania. AB - BACKGROUND: Although there exist laws, policies and standards in Tanzania that serve to protect and improve the lives of children with disabilities, the individual human experiences and feelings of the carers and parents still remain the realities of caring for children with disabilities. There is a lack of qualitative studies examining experiences in a developing context. This research aimed to fill that gap. OBJECTIVES: The objective of this research was to gain an insight into how having a child with a disability impacts upon participants lives and to examine both negative and positive experiences of care through the use of qualitative methods. METHOD: This was a qualitative, exploratory study and followed a phenomenological method. Purposive convenience sampling methods were used to recruit 14 carers in Moshi, Tanzania. Qualitative, semi-structured interviews were undertaken with all 14 participants. RESULTS: Five main themes emerged from the data which shed light on the carers experiences, namely, objective challenges in terms of financial challenges, employment issues and demands of care; subjective challenges in the form of stigma, isolation and pity; positive experiences such as the child's progress, respect and happiness; material and financial needs; and coping mechanisms which included beliefs, support and attitudes. CONCLUSION: The findings of this research were that objective challenges are common and more significant than subjective challenges. Positive experiences were not as easily identified by the participants as the challenges faced. However, having analysed the data, carers do not experience their roles as entirely negative. They simply need the resources to deal with objective challenges which in a developing context are not easily attainable. PMID- 28729982 TI - Barriers to and facilitators of rehabilitation services for people with physical disabilities: A systematic review. AB - BACKGROUND: As health care practitioners, it is important to have an understanding of the common barriers to and facilitators of the rehabilitation services we provide. OBJECTIVES: This article aimed to review the relevant literature regarding barriers to and facilitators of rehabilitation services for people with disabilities. METHOD: Articles for the period 1990-2010 using descriptors related to rehabilitation services, barriers, facilitators and the physically disabled population were retrieved for this review. RESULTS: A total of 19 article titles were identified from references of other articles but following application of the inclusion criteria selected for this review, only six articles were chosen. Five of these articles were qualitative studies and one was a quantitative study. Barriers and facilitators regarding rehabilitation services highlighted by participants in the studies included a perception that health professionals have a lack of understanding of rehabilitation for people with disabilities and there was a lack of information sharing from health professionals about the rehabilitation process. On the other hand some participants reported that health professionals demonstrated confidence in the disability and rehabilitation process during consultation and highlighted that their needs were met by the rehabilitation professionals. CONCLUSION: Even though there were few studies highlighting the barriers to and facilitators of rehabilitation services, they highlighted that there are gaps in the process of rehabilitation services provided. It would be advisable for health professionals to take cognisance of the issues highlighted in this study in order to make rehabilitation services more effective. PMID- 28729983 TI - Disability and HIV: What drives this relationship in Eastern and Southern Africa? AB - The Eastern and Southern Africa (ESA) region is the epicentre of the global HIV epidemic and also home to a large number of people with disabilities. Both HIV and Disability are significant public health issues. While they are generally viewed as distinct and unrelated phenomena data seems to suggest that they are particularly closely intertwined in ESA. For the first time in history, by using the same disability indicator consistently, the publication of the World Report on Disability in 2011 has allowed for the comparison of disability data between countries, and across regions. This has the potential to shed some light on the relationship between disability and socio-economic markers and other health conditions in a way that was not possible previously. In the absence of disability and HIV-specific population-based surveys, this paper uses global socio-economic and HIV datasets and compares them to data contained in the most recent World Report on Disability. The analysis suggests that disability prevalence may be related to HIV-prevalence in ESA (Pearson 0.87). It identifies research and policy gaps and seeks to shed light on the relationship between the two phenomena. It concludes that, more than any other region in the world, ESA needs to ensure better data collection on disability and the inclusion of disability throughout its HIV programmes in order to provide a comprehensive and appropriate response to the epidemic. PMID- 28729984 TI - African indigenous knowledge and research. AB - This paper seeks to heighten awareness about the need to include indigenous knowledge in the design and implementation of research, particularly disability research, in Africa. It affirms the suitability of the Afrocentric paradigm in African research and argues the necessity for an emancipatory and participatory type of research which values and includes indigenous knowledge and peoples. In the predominantly Western-oriented academic circles and investigations, the African voice is either sidelined or suppressed because indigenous knowledge and methods are often ignored or not taken seriously. This paper posits that to be meaningful and empowering, African-based research must, of necessity, include African thought and ideas from inception through completion to the implementation of policies arising from the research. In this way the work is both empowering and meaningful for context-specific lasting impact. PMID- 28729985 TI - Disability and poverty - Reflections on research experiences in Africa and beyond. AB - BACKGROUND: Whilst broadly agreed in the literature that disability and poverty are closely interlinked, the empirical basis for this knowledge is relatively weak. OBJECTIVES: To describe and discuss the current state of knowledge and to suggest the need for further generation of knowledge on disability and poverty. METHOD: Two recent attempts at statistically analysing the situation for disabled people and a series of qualitative studies on disability and poverty are applied in a discussion on the state of current knowledge. RESULTS: Firstly, the surveys confirm substantial gaps in access to services, and a systematic pattern of lower levels of living amongst individuals with disability as compared to non-disabled. Existing surveys are however not originally set up to study the disability - poverty relationship and thus have some important limitations. Secondly, the qualitative studies have shown the relevance of cultural, political and structural phenomena in relation to poverty and disability, but also the complexity and the contextual character of these forces that may sometimes provide or create opportunities either at the individual or the collective level. Whilst not establishing evidence as such, the qualitative studies contribute to illustrating some of the mechanisms that bring individuals with disability into poverty and keep them there. CONCLUSIONS: A longitudinal design including both quantitative and qualitative methods and based on the current conceptual understanding of both disability and poverty is suggested to pursue further knowledge generation on the relationship between disability and poverty. PMID- 28729986 TI - Inclusion of vulnerable groups in health policies: Regional policies on health priorities in Africa. AB - BACKGROUND: If access to equitable health care is to be achieved for all, policy documents must mention and address in some detail different needs of groups vulnerable to not accessing such health care. If these needs are not addressed in the policy documents, there is little chance that they will be addressed at the stage of implementation. OBJECTIVES: This paper reports on an analysis of 11 African Union (AU) policy documents to ascertain the frequency and the extent of mention of 13 core concepts in relation to 12 vulnerable groups, with a specific focus on people with disabilities. METHOD: The paper applied the EquiFrame analytical framework to the 11 AU policy documents. The 11 documents were analysed in terms of how many times a core concept was mentioned and the extent of information on how the core concept should be addressed at the implementation level. Each core concept mention was further analysed in terms of the vulnerable group in referred to. RESULTS: The analysis of regional AU policies highlighted the broad nature of the reference made to vulnerable groups, with a lack of detailed specifications of different needs of different groups. This is confirmed in the highest vulnerable group mention being for 'universal'. The reading of the documents suggests that vulnerable groups are homogeneous in their needs, which is not the case. There is a lack of recognition of different needs of different vulnerable groups in accessing health care. CONCLUSION: The need for more information and knowledge on the needs of all vulnerable groups is evident. The current lack of mention and of any detail on how to address needs of vulnerable groups will significantly impair the access to equitable health care for all. PMID- 28729987 TI - Reading the National Disability and Rehabilitation Policy in the light of Foucault's technologies of power. AB - In the area of disability studies, models have been at the centre of debates, influencing social policies, practices and legal frameworks. The former Ministry of Health and Social Welfare in the Kingdom of Lesotho was not an exception. In its efforts to tackle issues of disability, it produced The National Disability and Rehabilitation Policy: Mainstreaming persons with disabilities into society in 2011. This policy document is rooted in the social model and seeks to address long-standing problems and challenges of people with disabilities in the Kingdom. Using ideas from Foucault, particularly the technologies and regimes of power, which work through language and practice, this article examined ways in which people with disabilities are constituted through state knowledge and government policies, and concluded that these constructions form the basis for alienation and marginalisation in society. PMID- 28729988 TI - Knowledge and use of contraceptive methods amongst deaf people in Ghana. AB - BACKGROUND: Persons with disabilities in general face serious barriers to sexual and reproductive health (SRH) information and services due to institutional and attitudinal barriers. However, because deaf people have unique communication and linguistic needs, which are often misunderstood or ignored, they face greater barriers than other persons with disabilities. Whilst available data indicated that there is a wide gap between knowledge and usage of contraceptive amongst Ghanaians, little is known about the level of contraceptive knowledge and usage amongst deaf people. OBJECTIVES: The objective of the study was to investigate the level of knowledge and use of contraceptive methods amongst deaf people in Ghana with the aim of understanding their contraceptive behaviour and to improve access. METHOD: The study was a participatory SRH needs assessment utilising a two-phase, sequential, mixed methods design. The study included 179 participants, consisting of focus groups with seven executives of Ghana National Association of the Deaf (GNAD), 10 male deaf adults, and 9 deaf female adults. A total of 152 deaf people, made up of students, women, and men participated in a survey, whilst one hearing person served as a key informant. RESULTS: The findings of the study indicated that of the 13 methods shown in the survey, only three were known to about 70% of the adults and 60% of the students. Level of knowledge of the remaining nine methods was low. CONCLUSION: Clear and effective policies are needed to guide the provision of SRH information and services for deaf people in Ghana. PMID- 28729989 TI - Occupational therapy synergy between Comprehensive Community Based Rehabilitation Tanzania and Heifer International to reduce poverty. AB - BACKGROUND: This article describes a partnership between a community-based rehabilitation organisation and a non-governmental organisation (NGO) in Tanzania. The partnership focused on income-generating (IG) activities to tackle the problems of poverty faced by families with a child with a disability (CWD). OBJECTIVES: The aim of this case study was to describe the partnership between Comprehensive Community Based Rehabilitation Tanzania in Moshi (CCBRT-Moshi), a non-governmental organisation, and families to create an income-generating business, namely raising goats. METHOD: This was a team approach between CCBRT Moshi and Heifer International, an organisation that focuses on IG activities to create a synergy or partnership between community-based rehabilitation and IG activities. RESULTS: This partnership between occupational therapy rehabilitation services at CCBRT-Moshi and the NGO resulted in strengthening the effectiveness of occupational therapy services and leaving a more lasting impact on the people they served within the community by helping to reduce poverty in addition to providing rehabilitation and prevention interventions. CONCLUSION: This collaboration was successful as it provided a means for families to generate income from raising goats. Although the results have not been empirically verified, observational and anecdotal evidence suggests that families with CWDs have better quality of life and ultimately improved health through this synergistic partnership. PMID- 28729990 TI - Disabling sexualities: Exploring the impact of the intersection of HIV, disability and gender on the sexualities of women in Zambia. AB - BACKGROUND: Women with a disability are often characterised as a homogenous social group consigned to a cultural stereotype with assumptions of dependence, asexuality and gender neutrality. Furthermore, there is a void of research about the experience of people with disabilities following diagnosis with HIV. Little is known about how HIV diagnosis intersects with disability and gender and how it shapes the experiences of intimacy and gender roles of those negotiating this intersection. OBJECTIVE: The objective of this study was to explore how HIV, disability and gender shape the perspectives of HIV-positive women with disabilities regarding intimacy and gender roles. METHODS: Twelve women in Lusaka, Zambia were recruited for in-depth semi-structured interviews to explore their experiences of having a disability and living with HIV. Interviews were conducted in English, Bemba, Nyanja and Zambian sign language. Descriptive and thematic analyses were conducted, followed by in-depth gender analyses of data relating to intimacy and gender roles. RESULTS: Data analysis led to the identification of two main themes: the impact of HIV diagnosis on intimate relationships amongst the participants; and the disruption and renegotiation of gender roles. These findings demonstrate the loss of intimacy (often decided by the participants) and changes in women's gender roles (infrequently decided by them). CONCLUSIONS: The narrow approaches to sexuality and HIV that reinforce misconceptions and stereotypes need to change. In their place should be inclusive and disability and sex-positive approaches that are informed by the diverse realities of women's lives. Further research is needed to develop stronger evidence of the impact of HIV and disability on gender roles and sexuality. PMID- 28729991 TI - Seeking care for epilepsy and its impacts on households in a rural district in southern Malawi. AB - BACKGROUND: Epilepsy is a disability as defined in the 2012 Disability Act of the Government of Malawi. OBJECTIVES: This article explores the health-seeking behaviour of people with epilepsy in a rural town in southern Malawi and how having a person with epilepsy impacts on the households' productivity. METHOD: A snowball approach was used to identify persons with various forms of disabilities. The article is based on a bigger study carried out in Malawi which explored how persons with disabilities seek health care. In this bigger study, a total of 63 interviews were done with persons with disabilities or their guardians. Eight of the 63 interviews were with persons with epilepsy and this article is based on these interviews. RESULTS: The study found that persons with epilepsy seek both traditional and modern medicines to treat the condition. Informants mentioned that barriers to accessing western treatment include lack of medicines, congestion at health facilities, lack of knowledge about epilepsy, misdiagnosis by health workers and the belief that epilepsy caused by witchcraft cannot be treated by western medicine. The study also highlights the wider impacts of epilepsy on the household such as the failure of children to attend school, children dropping out of school, stigma and discrimination and households being driven deeper into poverty as a result of seeking care for members with epilepsy. CONCLUSION: The existing barriers to accessing treatment for epilepsy can be addressed by using a combination of public education, simple treatments and regular reviews. Ensuring constant availability of drugs for the treatment of epilepsy is key to effective treatment of the condition. This would contribute to closing the treatment gap for epilepsy as advocated by the Global Campaign against Epilepsy. PMID- 28729992 TI - Sexual and reproductive health needs assessment with deaf people in Ghana: Methodological challenges and ethical concerns. AB - BACKGROUND: Deafness is a complex and multifaceted phenomenon. The different ways of perceiving and understanding deafness have practical implications for research with deaf people. Whilst the deaf community is not homogenous, it is generally distinct from the hearing population. Consequently, the appropriateness of applying research methods and informed concern processes designed for the hearing population in research with deaf people has been questioned. OBJECTIVES: This article reflected on some methodological challenges and ethical concerns arising from conducting a sexual and reproductive health needs assessment with deaf people in Ghana. The aim was to provide some perspectives on some of the challenges associated with doing research with deaf people. METHOD: The study was a two phase, sequential, mixed methods design, consisting of three focus groups to assist in the development of a survey and then the implementation of the survey for needs assessment data collection. The number of participants in the study was 179, consisting of 26 focus group participants: 7 executives of the Ghana National Association of the Deaf (GNAD), 10 male adults, and 9 female adults. There were 152 survey respondents (students, women and men) and one key informant. All participants, except the key informant, were deaf people. RESULTS: The application of traditional research methods to studies involving deaf participants presents numerous methodological and ethical dilemmas associated mainly with deaf people's unique cultural and linguistic characteristics. CONCLUSION: Research methods should not be taken as universal guidelines for conducting research in all settings because of differences in settings. PMID- 28729993 TI - Policy implementation in wheelchair service delivery in a rural South African setting. AB - BACKGROUND: Wheelchairs allow users to realise basic human rights and improved quality of life. South African and international documents guide rehabilitation service delivery and thus the provision of wheelchairs. Evidence indicates that rehabilitation policy implementation gaps exist in rural South Africa. OBJECTIVES: The aim of this article was to explore the extent to which wheelchair service delivery in a rural, remote area of South Africa was aligned with the South African National Guidelines on Provision of Assistive Devices, The United Nations Convention on the Rights of Persons with Disabilities and The World Health Organization Guidelines on Provision of Wheelchairs in Less-Resourced Settings. METHOD: Qualitative methods were used. Data were collected through semi structured interviews with 22 participants who were identified through purposive sampling. Content analysis of data was preformed around the construct of wheelchair service delivery. RESULTS: Study findings identified gaps between the guiding documents and wheelchair service delivery. Areas where gaps were identified included service aspects such as referral, assessment, prescription, user and provider training, follow up, maintenance and repair as well as management aspects such as staff support, budget and monitoring. Positive findings related to individual assessments, enthusiastic and caring staff and the provision of wheelchairs at no cost. CONCLUSION: The gaps in policy implementation can have a negative impact on users and the service provider. Inappropriate or no wheelchairs limit user function, participation and quality of life. In addition, an inappropriate wheelchair will have a shorter lifespan, requiring frequent repairs and replacements with cost implications for the service provider. PMID- 28729994 TI - Impact of inaccessible spaces on community participation of people with mobility limitations in Zambia. AB - BACKGROUND: The study investigated the perspective of people with mobility limitations (PWML) in Zambia, firstly of their accessibility to public buildings and spaces, and secondly of how their capacity to participate in a preferred lifestyle has been affected. OBJECTIVES: Firstly to provide insight into the participation experiences of PWML in the social, cultural, economic, political and civic life areas and the relationship of these with disability in Zambia. Secondly to establish how the Zambian disability context shape the experiences of participation by PWML. METHOD: A qualitative design was used to gather data from 75 PWML in five of the nine provinces of Zambia. Focus group discussions and personal interviews were used to examine the accessibility of the built environment and how this impacted on the whole family's participation experiences. The nominal group technique was utilised to rank inaccessible buildings and facilities which posed barriers to opportunities in life areas and how this interfered with the whole family's lifestyle. RESULTS: Inaccessibility of education institutions, workplaces and spaces have contributed to reduced participation with negative implications for personal, family, social and economic aspects of the lives of participants. Government buildings, service buildings, and transportation were universally identified as most important but least accessible. CONCLUSION: Zambians with mobility limitations have been disadvantaged in accessing services and facilities provided to the public, depriving them and their dependants of full and equitable life participation because of reduced economic capacity. This study will assist in informing government of the need to improve environmental access to enable equal rights for all citizens. PMID- 28729995 TI - Disability and masculinity in South African autosomatography. AB - This article examines the representation of disability by disabled black South African men as portrayed in two texts from the autosomatography genre, which encompasses first-person narratives of illness and disability. Drawing on extracts from Musa E. Zulu's The language of me and William Zulu's Spring will come, the article argues that physical disability affects heteronormative concepts of masculinity by altering the body, which is the primary referent for the construction and performance of hegemonic masculinity. In ableist contexts, the male disabled body may be accorded labels of asexuality. This article therefore reveals how male characters with disabilities reconstruct the male self by both reintegrating themselves within the dominant grid of masculinity and reformulating some of the tenets of hegemonic masculinity. PMID- 28729997 TI - Success in the workplace: From the voice of (dis)abled to the voice of enabled. AB - The intention of this article is twofold; first to encourage a shift in seeing 'the disabled' not as people with disabilities but rather as people with unique abilities. Secondly, to explore ways of facilitating gainful employment for these uniquely abled people. The term disability is examined against a backdrop of definitions including the definition postulated by the International Classification of Functioning. In this article, the life experiences of a purposive sample of people with (dis)abilities who have been successful in the world of work are explored. A narrative approach gives voice to their experiences. Quotes from the participants' responses are used to illustrate the common themes that emerged relating to their experiences. These themes are resonated against a backdrop of relevant literature. If disabled people are enabled to recognize and use their unique abilities, as well as develop various self-determination skills, imagine the endless possibilities which could arise for them and society in general. PMID- 28729996 TI - Best practice guidelines for stroke in Cameroon: An innovative and participatory knowledge translation project. AB - BACKGROUND: Although the adherence to stroke guidelines in high-income countries has been shown to be associated with improved patient outcomes, the research, development and implementation of rehabilitation related guidelines in African countries is lacking. OBJECTIVES: The purpose of this article is to describe how a group of front-line practitioners collaborated with academics and students to develop best practice guidelines (BPG) for the management and rehabilitation of stroke in adult patients in Cameroon. METHOD: A working group was established and adapted internationally recognised processes for the development of best practice guidelines. The group determined the scope of the guidelines, documented current practices, and critically appraised evidence to develop guidelines relevant to the Cameroon context. RESULTS: The primary result of this project is best practice guidelines which provided an overview of the provision of stroke rehabilitation services in the region, and made 83 practice recommendations to improve these services. We also report on the successes and challenges encountered during the process, and the working group's recommendations aimed at encouraging others to consider similar projects. CONCLUSION: This project demonstrated that there is interest and capacity for improving stroke rehabilitation practices and for stroke guideline development in Africa. PMID- 28729998 TI - Do disability grants influence adherence to antiretroviral therapy? AB - Anecdotal data suggest that some South Africans living with HIV who receive disability grants from the state deliberately default on their antiretroviral medication in an attempt to lower their CD4 count to remain eligible for grants. No actual empirical data however exist to show that disability grants act as such perverse incentives and are a valid reason for non-adherence. This article examines some of the complexities of antiretroviral adherence in the context of a resource-constrained environment. The multitude of structural barriers, including sometimes difficult patient-doctor conversations about the renewal of disability grants, shape patients' experiences of the clinic environment and influence their adherence to care. PMID- 28729999 TI - Uganda's disability journey: Progress and challenges. PMID- 28730000 TI - A qualitative study: Barriers and support for participation for children with disabilities. AB - BACKGROUND: This qualitative-exploratory study examined the barriers to participation amongst children with disabilities in Lusaka, Zambia, from the mothers' perspective. OBJECTIVES: The objectives of this study were to understand how mothers of children with physical and cognitive disabilities who engaged their children in community-based rehabilitation (CBR) services in Lusaka, Zambia, perceived and described (1) the level of support they received and the barriers they encountered in terms of their child's meaningful social participation; (2) the use and awareness of these barriers to identify and pursue advocacy strategies; and (3) hopes for their child's future. METHODS: Data were collected through semi-structured interviews with each mother in her home. Results: Findings revealed both support and barriers to the child's social participation in relationship to their family, friends and community. Support also came from the CBR programme and mothers' personal resourcefulness. Mothers identified their child's school, their immediate environment and financial burdens as barriers to participation as well as their own personal insecurities and fears. Strategies to overcome barriers included internal and external actions. The mothers involved in the study hope their child's abilities will improve with continued CBR services. Some mothers described a bleak future for their child due to a lack of acceptance and access to education. CONCLUSION: The findings of this study suggest the significant role the mother of a child with a disability plays in her child's social participation. Recommendations include enhancing CBR programming for families, especially for mothers, and advocating on behalf of children with disabilities and their families to attract the attention of policy makers. PMID- 28730001 TI - An innovative approach to reducing pain in patients with peripheral neuropathy related to HIV: A single case study. AB - INTRODUCTION: Peripheral neuropathy (PN) is the most common neurological condition seen in people living with human immunodeficiency virus (HIV) and has been estimated to be present in up to 30% of people with AIDS. Prevalence may be increasing as it appears to be related to the use of antiretroviral therapy in many cases, particularly medication containing stavudine. It is often characterised by burning and numbness in the feet. It can interfere severely with function and sufferers resort to a large number of strategies in an attempt to reduce pain. CASE PRESENTATION: A 50-year-old man presented with severe PN and showed symptoms of extreme weakness and sensitivity of both lower limbs. His symptoms gradually worsened over a period of 18 months to such an extent that he was unable to walk. Medication had no effect on his pain or related symptoms. The authors tested the use of a Vibromat clinical vibrator to treat his PN symptoms. The patient was treated using the same modality for five evenly spaced (monthly) sessions. OUTCOME: The patient showed marked improvement in pain, numbness and pins and needles symptoms after the first session. He was able to walk a short distance with assistance. Treatment was continued and after the third session he was able to walk unaided. Symptom relief was maintained for 4 months. CONCLUSION: This is the first case demonstrating the use of the Vibromat in successfully treating the signs and symptoms of PN. This is important for clinicians who manage patients with HIV-related PN and pain. PMID- 28730002 TI - Accessibility for persons with mobility impairments within an informal trading site: A case study on the markets of Warwick, South Africa. AB - BACKGROUND: There are a number of informal trading sites across cities in sub Saharan Africa, of which the markets of Warwick is one example. Since the informal economy is an important contributor to a city's economy as well as a source of employment, it is important for these sites to be accessible for all persons. Whilst the South African government has put structures in place to identify and remove environmental barriers in order to meet the individual needs of persons with mobility impairments and improve their quality of life, persons with mobility impairments still face barriers and restricting environments that prevent them from participating in society and its social and economic activities. OBJECTIVES: This case study aimed at exploring accessibility within the markets of Warwick for persons with mobility impairments by an ergonomic assessment, augmented by voices of participants within the market. METHOD: A qualitative, instrumental, single case study design was utilised with purposive sampling of the markets of Warwick as the study setting. Multiple sources of data were gathered, such as semi-structured interviews, direct observations of an environmental survey supported by photographs, and the authors' review of relevant documents. Transcriptions were analysed using NVivo 10 software programme with inductive coding. RESULTS: Whilst policies have been in place since 1996 to adjust infrastructure, the markets of Warwick still remain inaccessible to persons with mobility impairments and do not meet the standardised infrastructural design. CONCLUSION: The findings of this study may offer a significant understanding of the complexity of accessibility within an informal trading site and create an awareness of the limitations this has for persons with mobility impairments. Additionally, these findings may assist in effecting a positive change in terms of the infrastructure of the Markets and in continuous advocating for the rights of persons with all disabilities. PMID- 28730003 TI - The other organs. PMID- 28730004 TI - Health-related quality of life of patients six months poststroke living in the Western Cape, South Africa. AB - BACKGROUND: The majority of individuals report a decline in health-related quality of life following a stroke. Quality of life and factors predicting quality of life could differ in individuals from lower income countries. The aim of this study was therefore to determine the quality of life and factors influencing quality of life of community-dwelling stroke patients living in low income, peri-urban areas in the Western Cape, South Africa. METHOD: An observational, longitudinal study was used to collect data from a conveniently selected sample of first-ever stroke patients. The Rivermead Motor Assessment Scale and the Barthel Index were used to determine functional outcome and the EQ 5D was used to collect information relating to quality of life at two months and six months poststroke. Descriptive and inferential statistics were used to analyse the data. RESULTS: The total sample of 100 participants consisted of 50% men and 50% women with a mean age of 61 and a standard deviation of 10.55 years. Six-month quality of life data was analysed for 73 of the 100 participants. Of the 27 who were lost to follow-up, nine participants died, four withdrew from the study after baseline data was collected and eleven could not be followed up as they had either moved or no follow-up telephone numbers were available. A further three participants were excluded from the analysis of the EQ-5D as they were aphasic. Of these, approximately 35% had problems with mobility and self-care, whilst 42% had severe problems with everyday activities and 37.8% expressed having anxiety and depression. Quality of life at two months (p = 0.010) and urinary incontinence (p = 0.002) were significant predictors of quality of life at six months. CONCLUSION: Health-related quality of life was decreased in the South African stroke sample. Functional ability and urinary incontinence were the factors affecting quality of life in the sample. These factors should be considered in the rehabilitation of stroke patients in these settings. PMID- 28730005 TI - The impact of an online Facebook support group for people with multiple sclerosis on non-active users. AB - BACKGROUND: Multiple sclerosis (MS) is a debilitating disease and there is little research on support networks for people with MS (PwMS). More specifically, most studies on online support groups focus on those who actively participate in the group, whereas the majority of those who utilise online support groups do so in a passive way. OBJECTIVES: This study therefore aimed to explore the experiences of non-active users of an online Facebook support group for PwMS. Emphasis was placed on the facilitators and the barriers that were associated with membership to this group. METHOD: An exploratory qualitative research design was implemented, whereby thematic analysis was utilised to examine the ten semi structured interviews that were conducted. RESULTS: Several facilitators were acquired through the online support group; namely emotional support (constant source of support, exposure to negative aspects of the disease), informational support (group as a source of knowledge, quality of information) and social companionship (place of belonging). Some barriers were also identified; namely emotional support (emotions lost online, response to messages, exposure to negative aspects of the disease), informational support (information posted on the group, misuse of group) and social companionship (non-active status). CONCLUSION: These findings demonstrate that the non-active members of the online support group for PwMS have valid reasons for their non-active membership status. More important, the findings suggest that the online Facebook support group provided the group members with an important support network in the form of emotional support, informational support and social companionship, despite their non-active membership status or the barriers that have been identified. PMID- 28730006 TI - Freedom to read: A personal account of the 'book famine'. AB - Even in the digital age, access to literature and other information for people with print impairments remains extremely poor, especially in the developing world. Reading access holds cascading implications for education, economic empowerment, social participation and self-worth. In June 2013 member states of WIPO (the World Intellectual Property Organization) concluded a landmark treaty to reduce copyright impediments to the dissemination of literature to print impaired people. Its effectiveness is not yet clear. Meanwhile, critics hold that disability studies' analyses have too often lacked insight into the personal and psychological ramifications of exclusion. This article provides an account of the 'book famine' from the perspective of a print impaired South African disability researcher, arguing that thorough investigation of the impressions of exclusion is necessary for change. The account highlights the personal, even malignant psychological reverberations of deprivations such as the 'book famine', which may carry traumatic effects which cement the status quo. PMID- 28730008 TI - Development process in Africa: Poverty, politics and indigenous knowledge. AB - BACKGROUND: Persons with disability run the danger of not profiting from the development process due to exclusion from basic services and opportunities. Still, the knowledge base on exclusion mechanisms is relatively weak and there is a danger that important aspects are not addressed as they are hidden behind established understandings that are not critically scrutinised. OBJECTIVES: The main purpose of this article was to highlight critical thoughts on prevailing knowledge of the relationship between disability and poverty, the policy base for addressing the rights of persons with disability, and culture as a key component in continued discrimination. METHOD: This article aimed at integrating three papers on the above topics presented at the 2011 African Network for Evidence-to Action on Disability (AfriNEAD) Symposium. The researchers have therefore thoroughly examined and questioned the relationship between disability and poverty, the influence of policy on action, and the role of culture in reproducing injustice. RESULTS: The article firstly claims that there are limitations in current data collection practice with regards to analysing the relationship between poverty and disability. Secondly, ambitions regarding inclusion of persons with disability in policy processes as well as in implementation of policies are not necessarily implemented in an optimal way. Thirdly, negative aspects of culture in discrimination and bad treatment of disabled need to be highlighted to balance the discussion on disability and culture. CONCLUSION: A critical view of prevailing understandings of disability and development is key to producing the knowledge necessary to eradicate poverty amongst persons with disability and other vulnerable groups. Not only do we need research that is actually designed to reveal the mechanisms behind the disability poverty relationship, we need research that is less tied up with broad political agreements that is not necessarily reflecting the realities at ground level. PMID- 28730007 TI - Perceptions of psychosocial disability amongst psychiatric service users and caregivers in South Africa. AB - BACKGROUND: In many parts of South Africa there is little support for people with psychosocial disability caused by schizophrenia, beyond provision of psychotropic medications. Appropriate community-based psychosocial rehabilitation interventions are a crucial element of mental health service development. OBJECTIVES: This study aimed to use an explanatory model of illness framework to document experiences of illness, disability and recovery amongst service users with schizophrenia and their caregivers in a poorly resourced area in the North West Province. Data were used to provide recommendations for a contextually appropriate non-specialist facilitated group psychosocial rehabilitation intervention. METHOD: Eighteen in-depth individual interviews were conducted: nine with schizophrenia service users and nine with caregivers. Interviews were conducted by two trained field researchers; both clinical psychologists fluent in the first language of participants. All interviews were recorded, translated and transcribed. Data were thematically analysed using NVivo 9. RESULTS: Participants linked the illness to witchcraft, poverty and stress. Family conflict was recognised in the course of the illness, causing stress and challenges for emotional well-being. Knowledge of diagnosis and biomedical treatment was minimal. Key factors recognised by service users as promoting recovery were the ability to work, and the support of traditional healers and religious structures. CONCLUSION: Based on the findings of this study, a group psychosocial rehabilitation intervention emerged as a recommendation, with the incorporation of psycho-education, adherence support, coping skills, and opportunities for income generation and productive activity. The importance of also enlisting the support of religious leaders and traditional healers in supporting recovery is emphasised. PMID- 28730009 TI - With or without us? An audit of disability research in the southern African region. AB - BACKGROUND: Disability research in the global South has not received significant critical consideration as to how it can be used to challenge the oppression and marginalisation of people with disabilities in low-income and middle-income countries. The Southern Africa Federation of the Disabled (SAFOD) embarked on a programme to use research to influence policy and practice relating to people with disabilities in Southern Africa, and commissioned an audit on research expertise in the region. In this article, a research audit is reported on and situated in a framework of emancipatory research. OBJECTIVES: This article sets out to describe a preliminary audit of disability research in the southern African region and to draw conclusions about the current state of disability research in the region and make recommendations. METHOD: The research method entailed working with disability researchers in the ten SAFOD member countries and utilising African disability networks hosted on electronic media. Disability researchers working in the region completed 87 questionnaires, which were reviewed through a thematic analysis. RESULTS: The discussion of results provides a consideration of definitions of disability; the understanding of disability rights, research topics and methodologies; the participation of people with disabilities in research; and the challenges and opportunities for using research to inform disability activism. CONCLUSION: The conclusion highlights critical issues for future research in the region, and considers how a disability researcher database can be used as a tool for disability organisations to prioritise research that serves a disability rights agenda. PMID- 28730010 TI - Building communities of trust: Challenges for disability. AB - This article asks questions about power and partnership in disability research in Africa. Research has been located too much in one type of organisation or another and not sufficiently in the interaction between a range of legitimate stakeholders. Across Africa and Europe, and government and civil society dialogues, the African development research agenda must be owned by Africans. Fully inclusive national and international research partnerships are crucial, but they must be driven from Africa. European constructions of and interventions concerning people with disability have often been inhumane, seeking to eliminate them from society. African cultures have also stigmatised people with disability. I call for a new African-driven research agenda that promotes the human rights of people with disability, and has people with disability not only participating in this research, but directing it. The Southern African Federation of the Disabled (SAFOD) Research Programme (SRP) is breaking new ground in this regard by allowing 'the researched' to become 'the researcher'. PMID- 28730011 TI - Increasing access into higher education: Insights from the 2011 African Network on Evidence-to-Action on Disability Symposium - Education Commission. AB - This article provides some insights into the challenges regarding inclusion in higher education of students with disabilities. It does this by elucidating aspects of the proceedings of the Education Commission at the African Network on Evidence-to-Action on Disability (AfriNEAD) Symposium, which took place in Zimbabwe in November 2011. The presentations specifically focused on the education of people with disabilities from early childhood through to higher education. This article, however, is informed by presentations focusing on increasing access to higher education. The article is focused on the implementation of evidence in practice, research and policies stemming from rigorous debate and scientific foundations, whilst taking into account the dynamic realities of the higher education context. Themes such as the systemic approach needed for inclusion to be successful, increasing access and the dynamic role of students with disabilities are highlighted. PMID- 28730013 TI - Learning from doing the EquitAble project: Content, context, process, and impact of a multi-country research project on vulnerable populations in Africa. AB - BACKGROUND: The 'EquitAble' project carried out content analyses of policies and collected and analysed qualitative and quantitative data concerning access to health services in Sudan, Malawi, Namibia and South Africa. Our particular concern was to address the situation of people with disabilities, although not in isolation from other marginalised or vulnerable groups. OBJECTIVES: This article reports on the content, context, process and impact of project EquitAble, funded by the European Commission Seventh Research Framework Programme, which brought together researchers from Ireland, Norway, South Africa, Namibia, Sudan and Malawi. METHOD: After the 4-year project ended in February 2013, all members of the consortium were asked to anonymously complete a bespoke questionnaire designed by the coordinating team. The purpose of the questionnaire was to capture the views of those who collaborated on the research project in relation to issues of content, context, process and impact of the EquitAble project. RESULTS: Our results indicated some of the successes and challenges encountered by our consortium. CONCLUSION: We identified contextual and process learning points, factors often not discussed in papers, which typically focus on the reporting of the 'content' of results. PMID- 28730012 TI - Surviving spinal cord injury in low income countries. AB - BACKGROUND: Mortality rates from injuries are higher for people from poorer economic backgrounds than those with higher incomes (according to the World Health Organization [WHO]), and health care professionals and organisations dealing with people with disabilities experience that individuals with spinal cord injury (SCI) in low income countries face serious challenges in their daily lives. OBJECTIVES: The aims of this study were to explore life expectancy (life expectancy is the average remaining years of life of an individual) and the situation of persons living with SCI in low income settings. METHOD: Literature studies and qualitative methods were used. Qualitative data was collected through semi-structured interviews with 23 informants from four study sites in Zimbabwe representing persons with SCI, their relatives and rehabilitation professionals. RESULTS: There are few publications available about life expectancy and the daily life of persons with SCI in low income countries. Those few publications identified and the study findings confirm that individuals with SCI are experiencing a high occurrence of pressure sores and urinary tract infections leading to unnecessary suffering, often causing premature death. Pain and depression are frequently reported and stigma and negative attitudes are experienced in society. Lack of appropriate wheelchairs and services, limited knowledge about SCI amongst health care staff, limited access to health care and rehabilitation services, loss of employment and lack of financial resources worsen the daily challenges. CONCLUSION: The study indicates that life expectancy for individuals with SCI in low income settings is shorter than for the average population and also with respect to individuals with SCI in high income countries. Poverty worsened the situation for individuals with SCI, creating barriers that increase the risk of contracting harmful pressure sores and infections leading to premature death. Further explorations on mortality and how individuals with SCI and their families in low income settings are coping in their daily life are required to provide comprehensive evidences. PMID- 28730014 TI - Five challenges for disability-related research in sub-Saharan Africa. AB - Disability research in contemporary sub-Saharan Africa is developing rapidly, and this is something to be celebrated. This article reviews some contemporary developments and suggests that there are five central, and interrelated, challenges for the field. These challenges - experience, expertise, enumeration, evidence, and expectations - go to the heart of thinking about disability research in sub-Saharan Africa. An optimistic but appropriately critical approach to addressing these issues is suggested. PMID- 28730015 TI - Deaf identities in a multicultural setting: The Ugandan context. AB - Often located far apart from each other, deaf and hearing impaired persons face a multiplicity of challenges that evolve around isolation, neglect and the deprivation of essential social services that affect their welfare and survival. Although it is evident that the number of persons born with or acquire hearing impairments in later stages of their lives is increasing in many developing countries, there is limited research on this population. The main objective of this article is to explore the identities and experiences of living as a person who is deaf in Uganda. Using data from semi-structured interviews with 42 deaf persons (aged 19-41) and three focus group discussions, the study findings show that beneath the more pragmatic identities documented in the United States and European discourses there is a matrix of ambiguous, often competing and manifold forms in Uganda that are not necessarily based on the deaf and deaf constructions. The results further show that the country's cultural, religious and ethnic diversity is more of a restraint than an enabler to the aspirations of the deaf community. The study concludes that researchers and policy makers need to be cognisant of the unique issues underlying deaf epistemologies whilst implementing policy and programme initiatives that directly affect them. The upper case 'D' in the term deaf is a convention that has been used since the early 1970s to connote a 'socially constructed visual culture' or a linguistic, social and cultural minority group who use sign language as primary means of communication and identify with the deaf community, whereas the lower case 'd' in deaf refers to 'the audio logical condition of hearing impairment'. However, in this article the lower case has been used consistently. PMID- 28730016 TI - Commuting and communication: An investigation of taxi drivers' experiences, attitudes and beliefs about passengers with communication disorders. AB - BACKGROUND: One of the most popular means of public transport within South Africa is mini-bus taxis. OBJECTIVES: As South Africa is made up of diverse cultures, religions and beliefs, the aim of this study was to explore Johannesburg based taxi drivers' experiences of beliefs about, and attitudes towards passengers who have a communication disability. METHOD: Semi-structured interviews were conducted with 10 mini-bus taxi drivers. RESULTS: Interviews revealed that almost all the taxi drivers had encountered passengers with a communication disability, and had an awareness of passengers with a hearing disability as opposed to a speech disability. Furthermore mini-bus taxi drivers generally held a positive view of their passengers with a communication disability. CONCLUSION: Study findings contribute to existing literature within the fields of speech pathology and audiology, advocacy groups and policy makers, particularly research studies on participation experiences of persons with communication disabilities related to transportation access. The results of the study should also provide a foundation for disability policy development initiatives with the aim of increasing levels of public awareness. PMID- 28730017 TI - Disability, gender, and employment relationships in Africa: The case of Ghana. AB - The exploratory quantitative study sought to develop an understanding about the relationships among disability, gender and employment in Northern Ghana. A total of 110 individuals with disabilities (20-60 years) from various disability groups participated in the study. The results indicate that many persons with disabilities are unemployed, the majority being women. Discrimination is cited as the greatest barrier to the employment of persons with disabilities, particularly women. The majority of persons with disabilities, typically women, live in poverty; given that some are unemployed and those who are employed worked mostly in marginal, seasonal and menial jobs. Persons with disabilities also experience several challenges on the job, including negative perceptions about their capabilities, discrimination and exclusion, irrespective of the employment sector and disability type. Educational interventions such as workshops, documenting and showcasing success stories of persons with disabilities could be helpful to reduce negative perceptions about their capabilities as well as discrimination against them. Government intervention to support persons with disabilities with start-up capital and funding for formal education is also recommended as these two elements were identified respectively as barriers to self-employment and employment in the public/private sectors. Government interventions to create educational opportunities for persons with disabilities are essential given that lower educational attainment affect their employment. PMID- 28730018 TI - Perspectives in musculoskeletal injury management by traditional bone setters in Ashanti, Ghana. AB - BACKGROUND: The popularity of the services of traditional bone setters (TBS) in Ghana as an alternative health care requires exploration and documentation of the perspectives of providers and users. OBJECTIVE: To explore and document the perspectives of providers and users of the services of TBS in the management of musculoskeletal injuries in the Ashanti region, Ghana. METHODS: From the social constructivist and qualitative approach, in-depth interviews were used to explore the perspectives of eight TBS and 16 users of their services, selected purposively through snowballing. Thematic content analysis (TCA) was employed. RESULTS: High recovery rate, warm reception, prompt attention, and the relatively lower charges, are reported to motivate the patronage of the services of TBS for the management of fractures in the legs, arms, ribs, joint bones dislocations, waist and spinal cord problems. The TBS combined traditional and orthodox procedures, using plant and animal-based materials, beliefs, spirituality (God given) and physical therapy in the management of musculoskeletal injuries. No adverse experience was reported by either the providers or users of the traditional management methods. CONCLUSION: With plant and animal-based materials, TBS are observed to combine traditional and orthodox procedures to confidently manage musculoskeletal injuries to the satisfaction of their highly motivated patrons. Although over 60% of the TBS attribute the healing power behind their practice to God, the rest do not discount the role of spiritual therapy. Further studies expanded to include the perspectives of non-users of the services of the TBS will authenticate the findings of this study. PMID- 28730019 TI - Being black in a white skin: Beliefs and stereotypes around albinism at a South African university. AB - Background: Partly because of the legacy of apartheid, and despite being a constitutional democracy, South Africa continues to be a deeply divided society, particularly along racial lines. In this context many people with albinism do not fit neatly into black and white categories and are likely to experience social discrimination and marginalisation. Objectives: The study endeavoured to explore the beliefs and practices regarding albinism within a South African university, and the availability of support services. Method: The research was located within an interpretive qualitative paradigm and was framed within the theories of stigma, discrimination and 'othering'. Interviews were conducted with five students with albinism and 10 students without albinism. Results: Findings confirmed the existence of myths and stereotypes regarding albinism. Students with albinism tended to exclude themselves from the rest of the student community to avoid discrimination and stereotypes around their condition. Conclusion: People with albinism can teach us about social constructions of race, colour and relations between minority groups and the majority culture. Results have implications for schools, disability units at universities, and albinism societies in terms of opening up channels of communication between people with albinism and the general public and fostering knowledge and awareness thereof. PMID- 28730020 TI - Bilateral upper limb amputations in victims of high tension electrical injuries: Three case studies. AB - Bilateral upper limb amputations result in severe disability. High voltage electrical injury is a rare cause of such an outcome and injuries often occur as occupational hazards. We present three case reports of accidental high voltage injuries that occurred in a non-occupational setting. Victims were all initially managed at other centres before referral to our hospital and all subsequently had bilateral upper limb amputations. The high cost of treatment, importance of prevention, and need for rehabilitation are highlighted. PMID- 28730021 TI - The influence of cultural beliefs on the utilisation of rehabilitation services in a rural South African context: Therapists' perspective. PMID- 28730022 TI - The prevalence of self-reported vision difficulty in economically disadvantaged regions of South Africa. AB - BACKGROUND: Vision impairment, resulting in vision difficulties, is a leading cause of disability, and hence one of the key barriers for people to access education and employment, which may force them into poverty. OBJECTIVES: The objective of this study was to determine the prevalence of self-reported vision difficulties as an indicator of vision impairment in economically disadvantaged regions in South Africa, and to examine the relationship between self-reported vision difficulties and socio-economic markers of poverty, namely, income, education and health service needs. METHODS: A cross-sectional study was conducted in economically disadvantaged districts to collect data from households on poverty and health, including vision difficulty. As visual acuity measurements were not conducted, the researchers used the term vision difficulty as an indicator of vision impairment. Data were collected from 27 districts (74 901 respondents). Logistic regression analysis and chi-square tests were used to determine bivariate relationships between variables and self-reported vision difficulty. Kernel density estimators were used for age, categorised by self reported and not reported vision difficulty. RESULTS: Prevalence of self-reported vision difficulty was 11.2% (95% CI, 8.7% - 13.7%). More women (12.7%) compared to men (9.5%) self-reported vision difficulty (p < 0.01). Self-reported vision difficulty was higher (14.2%) for respondents that do not spend any money. A statistically significant relationship was found between the highest level of education and self-reporting of vision difficulty; as completed highest level of education increased, self-reporting of vision difficulty became lower (p < 0.01). A significantly higher prevalence of self-reported vision difficulty was found in respondents who are employed (p < 0.01), 17% (95% CI: 12.8% - 21.1%). CONCLUSION: The evidence from this study suggests associations between socio-economic factors and vision difficulties that have a two-fold relationship (some factors such as education, and access to eye health services are associated with vision difficulty whilst vision difficulty may trap people in their current poverty or deepen their poverty status). The results are thus indicative of the need for further research in South Africa. PMID- 28730023 TI - The need for a Rehabilitation Model to address the disparities of public healthcare for people living with HIV in South Africa. AB - Rehabilitation in the context of HIV management in Africa is still a neglected field which holds great promise for the improvement of the quality of life as well as integration of people living with HIV back into their communities and homes. However, rehabilitation has not been incorporated into HIV care despite the fact that a large number of people living with HIV experience disability. The dearth of literature and lack of models of care to roll out rehabilitation for people living with HIV in Africa are astounding. Well-resourced countries have emerging approaches on the management of disability in the context of HIV. However, epidemic countries are still lacking such an approach neglecting the devastating effects of disability on individual livelihoods and antiretroviral treatment adherence. Thus, rehabilitation needs to be integrated into the response to HIV. This article advocates for the development and implementation of a model of care to guide rehabilitation of people living with HIV in South Africa. PMID- 28730024 TI - Celebrities and spiritual gurus: Comparing two biographical accounts of kidney transplantation and recovery. AB - BACKGROUND: As a kidney transplant recipient I have long been exposed to a shortage of renal narratives and to a dominant theme in those that exist: transplant as restitution or redemption. My lived experience has, however, shown me that post-transplant life is more complex. Even after transplantation, chronic kidney disease requires lifelong health care with varying degrees of impairment, resulting in ongoing liminality for those who experience it. Nonetheless, as a transplant recipient I find the restitution or redemptive narrative pervasive and difficult to escape. OBJECTIVE: I examined two seemingly very dissimilar insider renal biographies, Janet Hermans's Perfect match: A kidney transplant reveals the ultimate second chance, and Steven Cojocaru's Glamour, interrupted: How I became the best-dressed patient in Hollywood, to explore how the narrators treat chronic kidney disease and transplantation. METHODS: In addition to a close textual reading of the biographies, I used my own experience of meaning-making to problematize concepts around restitution or redemptive narratives. RESULTS: I found that the two biographies are, despite appearances and despite the attempts of one author to escape the redemptive form, very much the same type of narrative. The accounts end with the transplant, as is common, but the recipients' lives continue after this, as they learn to live with their transplants, and this is not addressed. CONCLUSIONS: Emphasising restitution or redemption might prevent an understanding of post-transplant liminality that has unique characteristics. The narrator evading this narrative form must come to terms with a changed identity and, sometimes, fight to evade the pervasive narratives others impose. PMID- 28730025 TI - Enabling disability inclusive practices within the University of Cape Town curriculum: A case study. AB - BACKGROUND: Disability inclusion in the curricula of higher education institutions contributes to socially responsive graduates with a capacity to address the cross-cutting issue of disability in development. This article discusses a study conducted at the University of Cape Town (UCT), South Africa, to explore disability inclusion. METHODOLOGY: An instrumental case study approach was adopted and a thematic analysis of data was done. FINDINGS: Academic staff found a variety of ways to include disability, such as discussions in class, practice and service learning, but mainly as part of disciplinary requirements. Including disability as an issue of social justice stems mostly from the personal interest of staff, and is done in an ad hoc manner. CONCLUSION: Disability should be valued, and integrated into the curriculum in a structured manner as a perspective on diversity with which to interrogate our beliefs about ourselves and society. Theorising on disability is needed, as well as the unique perspectives that emerge across interdisciplinary boundaries, especially within the African context. PMID- 28730026 TI - Research Protocol: Development, implementation and evaluation of a cognitive behavioural therapy-based intervention programme for the management of anxiety symptoms in South African children with visual impairments. AB - BACKGROUND: Childhood anxiety presents a serious mental health problem, and it is one of the most common forms of psychological distress reported by youth worldwide. The prevalence of anxiety symptoms amongst South African youth is reported to be significantly higher than in other parts of the world. These high prevalence rates become even more significant when viewed in terms of children with visual impairments, as it is suggested that children with physical disabilities may be more prone, than their non-disabled peers, for the development of psychological difficulties. OBJECTIVES: The main aim of this study is to develop, implement and evaluate a specifically tailored anxiety intervention programme for use with South African children with visual impairments. METHOD: A specifically tailored cognitive-behavioural therapy-based anxiety intervention, for 9-13 year old South African children with visual impairments, will be evaluated in two special schools. The study will employ a randomised wait-list control group design with pre- post- and follow-up intervention measures, with two groups each receiving a 10 session anxiety intervention programme. The main outcome measure relates to the participants' symptoms of anxiety as indicated on the Revised Child Anxiety and Depression Scale. CONCLUSION: If the anxiety intervention programme is found to be effective in reducing symptoms of anxiety, this universal intervention will lay down the foundation upon which future contextually sensitive (South African) anxiety intervention programmes can be built. PMID- 28730027 TI - Experiences of patients and service providers with out-patient rehabilitation services in a rehabilitation centre in the Western Cape Province. AB - BACKGROUND: Rehabilitation is important for persons with disabilities as it contributes to their sense of autonomy, self-worth and social participation, and improves their quality of life. Improving the quality of rehabilitation services requires the dialogue of patients' perceptions with those of service providers, in order to recommend informed reform. OBJECTIVE: The objective was to explore the experiences of persons with physical disabilities and service providers, regarding the multi-disciplinary rehabilitation services provided at a community based out-patient rehabilitation centre. METHODS: A qualitative, exploratory study design was used to collect the data. A focus group was conducted with conveniently selected persons with physical disabilities. Three in-depth interviews were conducted with purposively selected key informants. All ethical considerations were adhered to during the implementation of the study. RESULTS: Patients and service providers had different experiences regarding accessibility to rehabilitation services, and similar experiences with patient education and intensity of rehabilitation. Although the patients experienced that the service providers had sufficient knowledge and skills to manage them, services providers expressed that they lacked certain skills. CONCLUSIONS: The experiences expressed highlighted the need to improve rehabilitation services in terms of increasing the capacity of service providers and providing transport services for persons with disabilities. PMID- 28730028 TI - Initial experiences of family caregivers of survivors of a traumatic brain injury. AB - BACKGROUND: There seems to be a paucity of research on the initial subjective experiences of family caregivers of survivors of a traumatic brain injury (TBI). OBJECTIVE: To explore the challenges that family caregivers face during the initial stages of recovery of a relative who has sustained a TBI. METHODS: Thematic analysis was used to explore the findings from semi-structured interviews that were conducted with 12 female family caregivers of relatives who had sustained a TBI. RESULTS: Family caregivers recalled their initial experiences of the shock at hearing the news about their relative's TBI, negative experiences in hospital and frustrating interactions with healthcare professionals as particularly challenging. CONCLUSION: The findings of this study emphasise caregivers' need for support, information and psycho-education, especially from healthcare professionals, from the very beginning stages of recovery from a TBI. Practical and physical needs with regard to admission to and care in the hospital were also highlighted. This research will hopefully contribute to creating awareness amongst healthcare professionals on how they can contribute to improvement of the services provided by the healthcare system based on the experiences of the caregivers who participated in this study. PMID- 28730029 TI - The complexity of rural contexts experienced by community disability workers in three southern African countries. AB - An understanding of rural communities is fundamental to effective community-based rehabilitation work with persons with disabilities. By removing barriers to community participation, persons with disabilities are enabled to satisfy their fundamental human needs. However, insufficient attention has been paid to the challenges that rural community disability workers (CDWs) face in trying to realise these objectives. This qualitative interpretive study, involving in-depth interviews with 16 community disability workers in Botswana, Malawi and South Africa, revealed the complex ways in which poverty, inappropriately used power and negative attitudes of service providers and communities combine to create formidable barriers to the inclusion of persons with disabilities in families and rural communities. The paper highlights the importance of understanding and working with the concept of 'disability' from a social justice and development perspective. It stresses that by targeting attitudes, actions and relationships, community disability workers can bring about social change in the lives of persons with disabilities and the communities in which they live. PMID- 28730030 TI - Caring for a child with Cerebral Palsy: The experience of Zimbabwean mothers. AB - BACKGROUND: The needs of caregivers of children with disability may not be recognized despite evidence to suggest that they experience increased strain because of their care-giving role. This strain may be exacerbated if they live in under-resourced areas. OBJECTIVES: We set out to establish the well-being of caregivers of children with Cerebral Palsy (CP) living in high-density areas of Harare, Zimbabwe. In addition, we wished to identify factors that might be predictive of caregivers' well-being. Finally, we examined the psychometric properties of the Caregiver Strain Index (CSI) within the context of the study. METHOD: Caregivers of 46 children with CP were assessed twice, at baseline, and after three months, for perceived burden of care and health-related quality of life (HRQoL) using CSI and EQ-5D respectively. The psychometric properties of the CSI were assessed post hoc. RESULTS: The caregivers reported considerable caregiver burden with half of the caregivers reporting CSI scores in the 'clinical distress' range. Many of the caregivers experienced some form of pain, depression and expressed that they were overwhelmed by the care-giving role. No variable was found to be associated with clinical distress. The CSI demonstrated good overall internal consistency (Cronbach's Alpha = 0.8), stability over time (Z = 0.87, p = 0.381) and was significantly and negatively correlated with the EQ 5D VAS (Spearman's rho = -0.33, p = 0.027), demonstrating concurrent validity. CONCLUSION: Caregivers must be monitored routinely for their level of distress and there is an urgent need to provide them with support. The CSI is likely to be a valid measure of distress in this population. PMID- 28730031 TI - Exploring the impact of wheelchair design on user function in a rural South African setting. AB - BACKGROUND: Wheelchairs provide mobility that can enhance function and community integration. Function in a wheelchair is influenced by wheelchair design. OBJECTIVES: To explore the impact of wheelchair design on user function and the variables that guided wheelchair prescription in the study setting. METHOD: A mixed-method, descriptive design using convenience sampling was implemented. Quantitative data were collected from 30 wheelchair users using the functioning every day with a Wheelchair Scale and a Wheelchair Specification Checklist. Qualitative data were collected from ten therapists who prescribed wheelchairs to these users, through interviews. The Kruskal-Wallis test was used to identify relationships, and content analysis was undertaken to identify emerging themes in qualitative data. RESULTS: Wheelchairs with urban designs were issued to 25 (83%) participants. Wheelchair size, fit, support and functional features created challenges concerning transport, operating the wheelchair, performing personal tasks, and indoor and outdoor mobility. Users using wheelchairs designed for use in semi-rural environments achieved significantly better scores regarding the appropriateness of the prescribed wheelchair than those using wheelchairs designed for urban use (p = <0.01). Therapists prescribed the basic, four-wheel folding frame design most often because of a lack of funding, lack of assessment, lack of skills and user choice. CONCLUSION: Issuing urban type wheelchairs to users living in rural settings might have a negative effect on users' functional outcomes. Comprehensive assessments, further training and research, on long term cost and quality of life implications, regarding provision of a suitable wheelchair versus a cheaper less suitable option is recommended. PMID- 28730032 TI - Cognitive rehabilitation groups: A thematic analysis of feasibility and perceived benefits for clients with moderate to severe traumatic brain injury living in the Western Cape. AB - BACKGROUND: Traumatic brain injury (TBI) has a significant impact on the burden of care within the South African setting, impacting on the individual, the family, and the community as a whole. Often the consequences of TBI are permanent, resulting in numerous financial and emotional stressors. OBJECTIVE: This research focusses on the experience of outpatient cognitive rehabilitation groups for individuals who have suffered moderate to severe brain injuries within the South African setting. METHOD: Participants with moderate to severe brain injury were required to attend five cognitive rehabilitation groups and engage in a semistructured interview. Qualitative data were examined via thematic analysis, to determine participants' subjective experiences of group participation. RESULTS: There is a need within the South African setting for cognitive rehabilitation and support groups for individuals who have experienced a TBI. The benefits were notable for both the individuals attending and their support systems. In spite of the benefits there were notable limitations to attendance, including financial restrictions and transport limitations. CONCLUSION: According to participants and their families, there is a scarcity of resources within the Western Cape for clients who have sustained a TBI. Despite limitations in capacity to attend there appears to be a need for structured outpatient cognitive rehabilitation programmes integrating the complex cognitive and emotional challenges faced by individuals with TBI and their families. PMID- 28730033 TI - People with psychogenic non-epileptic seizures: A South African perspective. AB - BACKGROUND: Psychogenic non-epileptic seizures (PNES) is a disabling disorder which has a negative effect on the quality of life of individuals with PNES. A clear understanding of the disorder is necessary, however, to date, research about PNES in South Africa is limited. OBJECTIVES: The aims of this study were to explore the demographic variables of individuals with PNES in South Africa, to review the available body of research on PNES, and to compare it with our results. METHOD: Twenty-two people with PNES, with confirmed video EEG, were recruited by means of convenience sampling from two hospitals. Descriptive statistics were used to describe the demographic variables of the participants. RESULTS: Internationally comparable results revealed misdiagnoses and low treatment delivery amongst a primarily female population. CONCLUSION: This study provided greater insight into individuals with PNES in South Africa, highlighting the need for more information, support, effective treatment and accurate diagnosis of PNES. PMID- 28730034 TI - Inclusive education: A transformation and human rights agenda under spotlight in South Africa. AB - This study investigated the progress made in the implementation of inclusive education as a transformation and human rights tool since its inception in 2001. The study was conducted upon realising that most people underestimate the transformation and human rights value that inclusive education strives to maintain. The total number of participants interviewed was 84. Data was collected using semi-structured interview schedules for the teachers and community members, whereafter it was presented in thematic sections and qualitatively examined for meaning. The results showed that participants comprising teachers and community members do not know or understand the transformational and human rights value of inclusive education. The participants seemed to be equally aware of inclusive education, but they rated its success and value differently. The participants concurred that the philosophy of inclusive education was noble, but they differed regarding the extent to which it had transformed, added value or played an advocacy role in the lives of learners and the community at large over the years. PMID- 28730035 TI - Sharing in the life of the person with disability: A Ghanaian perspective. AB - This thought article was a hermeneutic inquiry into the experiences of informal caregivers of the elderly who are also physically disabled. The experiences of some Ghanaian informal caregivers were examined in three clinical cases and laced with the lived experiences of the author as an informal caregiver and clinician. Two processes were explored. The first relates to how a caregiver is changed through the experience of caregiving by examining the intrapersonal and interpersonal dynamics affecting caregiving. Secondly, the positive 'shifts' that occurred in therapy were explored. In the present Ghanaian society it appears that care for the elderly disabled is compounded by the rapid migration of many Ghanaians to 'greener pastures' in search of a brighter future, with consequent empty homesteads and fragmentation of the socio-cultural practices that hitherto buttressed informal care for the aged. In the absence of well-established professional care facilities, informal caregiving with its numerous challenges has become the norm for many. This article posited that caregiver self-care is the most important, and yet often forgotten, aspect of informal caregiving. When this is neglected, caregiver burnout is sure to occur, which results in poor physical, mental and emotional health for the caregiver. In this state caregivers may injure both themselves and the care recipients. PMID- 28730036 TI - Teaching science and mathematics to students with visual impairments: Reflections of a visually impaired technician. AB - This study reports on factors that limit the participation of blind and partially sighted learners in mathematics and science education. Since the teacher, still remains one of the most crucial factors in any education system, the researcher deemed it important to investigate the role of the teacher as understood by a blind technician in promoting the participation of blind and partially sighted learners in mathematics and science subjects, which few of these learners take beyond primary school. A case study was conducted interrogating a blind technician, who regards himself as an unqualified scientist, in his understanding of various school factors that could entice blind and partially sighted learners to participate in mathematics and science education, and to promote their retention in related professions. The participant thus drew from his own experiences of the school environment and wider concentric social institutions. A semi-structured interview schedule was followed and the responses were recorded by mutual consent. Analysis was conducted based on questions put to the participant. The study revealed that teacher motivation and mentorship in mathematics and science methodologies and the use of tools for learner empowerment are lacking. It further revealed that teachers lack the requisite skills in special education to harness learner potential in mathematics and science. This situation necessitates government action in teacher training and development. PMID- 28730037 TI - Environmental factors influencing participation of stroke survivors in a Western Cape setting. AB - BACKGROUND: Environmental factors compound or diminish the effects of impairments; therefore they have a direct influence on participation of stroke survivors. OBJECTIVES: To determine environmental barriers and facilitators to participation experienced by a group of stroke survivors in the Western Cape province of South Africa. METHODS: A descriptive, mixed methods study was conducted in 2011. Quantitative data was collected with the International Classification for Functioning, Disability and Health core set for stroke (environmental factors), from 53 stroke survivors, sampled through proportional, stratified, random sampling. Data is presented through graphs and tables. Qualitative data was collected from five purposively sampled participants and thematically analysed. RESULTS: Under products and technology, participants regarded assets, food, products and technology for daily living, transportation, mobility and communication, and access to buildings as barriers. The physical geography and attitudes of friends and society created further barriers. With regard to services, systems and policies - housing, communication, transport and social services created barriers. Health services, as well as support from health care service providers and family were considered facilitators. CONCLUSION: A lack of assets compounded barriers with regard to food, products for daily use, communication and transport. Barriers to participation were exacerbated by a lack of services, systems and implementation of policies focused on the inclusion of people with disabilities, as well as minimal access to assistive devices. Recommendations include provision of assistive devices, structural changes to houses, yards, roads and buildings, lobbying for accessible, affordable public transport, access audits of public buildings, and inclusion of non-governmental organisations and home-based care services in a seamless network of care. PMID- 28730038 TI - Is any wheelchair better than no wheelchair? A Zimbabwean perspective. AB - BACKGROUND: Within a rights-based paradigm, wheelchairs are essential in the promotion of user autonomy, dignity, freedom, inclusion and participation. OBJECTIVES: This paper aimed to describe a group of Zimbabwean wheelchair users' satisfaction with wheelchairs, wheelchair services and wheelchair function. METHOD: A mixed method, descriptive study was done. Quantitative data was collected from 94 consecutively sampled wheelchair users, who accessed wheelchair services at 16 clinics in five Zimbabwean provinces between October 2013 and February 2014, using the Quebec User Evaluation of Satisfaction with Assistive Technology for adults and children and Functioning Every day with a Wheelchair questionnaire. Qualitative data were collected through two focus group discussions (22 participants) and two case studies with participants purposively sampled from those who participated in the quantitative phase. RESULTS: More than 60% of participants were dissatisfied with the following wheelchair features: durability (78.6%), weight (75.6%), ease of adjustment (69.1%), effectiveness (69.0%), safety (66.7%), reliability (66.7%), and meeting user needs (60.6%). Similarly, more than 66% of participants were dissatisfied with various services aspects: professional services (69.0%), follow-up (67.0%), and service delivery (68.3%). Although 60% of participants agreed that the wheelchair contributed to specific functions, more than 50% of participants indicated that the features of the wheelchair did not allow in- (53.2%) and outdoor (52.7%) mobility. CONCLUSION: Findings indicate high levels of dissatisfaction with wheelchair features and services, as well as mobility. It is recommended that policy and minimum service standards which incorporate evidence and good practice guidelines for wheelchair services and management of wheelchair donations are developed for Zimbabwe. PMID- 28730039 TI - Graduates' perceptions of prosthetic and orthotic education and clinical practice in Tanzania and Malawi. AB - BACKGROUND: Maintaining and improving the quality of prosthetics and orthotics education at the Tanzania Training Centre for Orthopaedic Technologists is essential for the provision of appropriate prosthetics and orthotics services in African countries. OBJECTIVES: To describe how Tanzanian and Malawian graduates' of the Diploma in Orthopaedic Technology perceive their education and how it could be improved or supplemented to facilitate clinical practice of graduates. METHODS: Nineteen graduates from the diploma course in orthopaedic technology were interviewed and phenomenographic analysis was applied to the data. RESULTS: Seven descriptive categories emerged, namely varied awareness of the profession before starting education, well-equipped teaching facilities, aspects lacking in the learning context, need for changes in the curriculum, enabling people to walk is motivating, obstacles in working conditions and the need for continuous professional development. All participants perceived possible improvements to the content and learning environment. CONCLUSIONS: Prosthetic and orthotic education can be better provided by modifying the content of the diploma programme by dedicating more time to the clinical management of different patient groups and applied biomechanics as well as reducing the programme content focusing on technical aspects of prosthetic and orthotic practice. Graduates were not prepared for the rural working conditions and the graduates desired continued training. PMID- 28730040 TI - Preparation of students with disabilities to graduate into professions in the South African context of higher learning: Obstacles and opportunities. AB - BACKGROUND: Persons with disabilities continue to be excluded from professions in South Africa despite legislation on non-discrimination and equity. OBJECTIVES: We sought to identify both the opportunities and obstacles that students with disabilities face in professional degrees. METHOD: Selected texts from the South African and international literature were analysed and synthesised. RESULTS: Students with disabilities are afforded opportunities to graduate into professions through the current climate of transformation, inclusion and disability policies, various support structures and funding. These opportunities are mitigated by obstacles at both the higher education site and at the workplace. At university, they may experience difficulties in accessing the curriculum, disability units may be limited in the support they can offer, policies may not be implemented, funding is found to be inadequate and the built environment may be inaccessible. Fieldwork poses additional obstacles in terms of public transport which is not accessible to students with disabilities; a lack of higher education support extended to the field sites, and buildings not designed for access by people with disabilities. At both sites, students are impacted by negative attitudes and continued assumptions that disability results from individual deficit, rather than exclusionary practices and pressures. CONCLUSION: It is in the uniqueness of professional preparation, with its high demands of both theory and practice that poses particular obstacles for students with disabilities. We argue for the development of self-advocacy for students with disabilities, ongoing institutional and societal transformation and further research into the experiences of students with disabilities studying for professional degrees. PMID- 28730041 TI - Attitudes of health service providers: The perspective of people with disabilities in the Kumasi Metropolis of Ghana. AB - INTRODUCTION: Awareness of disability issues has gained considerable interest by advocacy groups in recent years. However, it is uncertain whether attitudes and perceptions of all service providers and society have adjusted accordingly towards the health care of people with disabilities. This study sought to examine the attitudes of health providers from the perspective of people with disabilities in the Kumasi Metropolis. METHODS: A cross-sectional study using semi-structured questionnaires was conducted with people with disabilities (with physical, hearing and visual impairments,) in the Kumasi Metropolis. The study used a multi-stage sampling involving cluster and simple random sampling to select 255 respondents split amongst the following five clusters of communities; Oforikrom, Subin, Asewase, Tafo and Asokwa. Data were analysed using STATA 14 and presented in descriptive and inferential statistics. RESULTS: The study found that 71% of the respondents faced some form of discrimination including the use of derogatory remarks, frustration and unavailable required services on the basis of their disability, the type of services they need and the location. Women were 3.89 times more likely to face discrimination; Adjusted odds ratio (AOR) = 3.89 (95% confidence interval [CI]; 1.41, 10.76), and visually impaired was more likely to be discriminated at the facility compared with physical disability; AOR = 5.05 (95% CI; 1.44, 17.65). However, respondents with some educational qualification and those who stayed with their family members were less likely to face discrimination; AOR = 0.08 (95% CI; 0.01, 0.39). CONCLUSION: The study recommends the provision of in-service training for service providers to update their knowledge on disability issues and improve access to services for people with disabilities. PMID- 28730042 TI - Enhancing the public sector's capacity for inclusive economic participation of disabled youth in rural communities. AB - BACKGROUND: The capacity of service providers in the public sector to deliver inclusive services is essential to implement strategies that will allow the full participation of disabled youth in development opportunities in the rural context. OBJECTIVES: This article sets out to describe the capacity of service providers in facilitating the participation of disabled youth in economic development opportunities. METHOD: An instrumental, embedded single case study informed the research design. The sample consisted of five disabled youth, four family members and six service providers. Data was gathered through in depth individual interviews and focus group discussions. Data analysis was done inductively and thematically. In the discussion, the interpretation used organisational capacity elements as a framework. RESULTS: The findings indicate a perception of disability as a multifaceted and challenging issue with different orientations to service delivery, based on the understanding of the impairment and disability. There is a strong focus on impairment and negative attitudes. DISCUSSION: An asset-building approach could facilitate awareness of the capacities of disabled youth and thus shift negative attitudes to enabling attitudes. The vague strategies for youth and women reflect an organisational attitude that seems non-committal to its core agenda of inclusive development, which would ensure equal opportunities for participation by disabled youth. CONCLUSION: An appreciative process of facilitating a deeper understanding of the needs of disabled youth would assist service providers to reconceptualise disability within an expansive framework of equal opportunities and active citizenship. PMID- 28730043 TI - Religion, culture, and discrimination against persons with disabilities in Nigeria. AB - BACKGROUND: There is not a lot in the literature on disability in Nigeria concerning the role that religion, culture and beliefs play in sustaining discriminatory practices against persons with disabilities. OBJECTIVES: Many of these practices are exclusionary in nature and unfair. They are either embedded in or sustained by religion, culture and beliefs about disability and persons with disabilities. METHODS: Drawing on various resources and research on disability, this paper looks at these practices in respect of these sustaining factors. Some of the discriminatory practices that constitute the main focus of the paper are the trafficking and killing of people with mental illness, oculocutaneous albinism and angular kyphosis, raping of women with mental illness and the employment of children with disabilities for alms-begging. RESULTS: The examination of these practices lends some significant weight and substance to the social model of disability, which construes disability in the context of oppression and the failure of social environments and structures to adjust to the needs and aspirations of people with disabilities. CONCLUSION: Given the unfairness and wrongness of these practices they ought to be deplored. Moreover, the Nigerian government needs to push through legislation that targets cultural and religious practices which are discriminatory against persons with disabilities as well as undertake effective and appropriate measures aimed at protecting and advancing the interests of persons with disabilities. PMID- 28730044 TI - Disability inclusion in higher education in Uganda: Status and strategies. AB - BACKGROUND: Uganda has embraced inclusive education and evidently committed itself to bringing about disability inclusion at every level of education. Both legal and non-legal frameworks have been adopted and arguably are in line with the intent of the Convention on the Rights of Persons with Disabilities (CRPD) on education. The CRPD, in Article 24, requires states to attain a right to education for persons with disabilities without discrimination and on the basis of equal opportunities at all levels of education. OBJECTIVES: Despite Uganda's robust disability legal and policy framework on education, there is evidence of exclusion and discrimination of students with disabilities in the higher education institutions. The main objective of this article is to explore the status of disability inclusion in higher education and strategies for its realisation, using evidence from Emong's study, workshop proceedings where the authors facilitated and additional individual interviews with four students with disabilities by the authors. RESULTS: The results show that there are discrimination and exclusion tendencies in matters related to admissions, access to lectures, assessment and examinations, access to library services, halls of residence and other disability support services. CONCLUSION: The article recommends that institutional policies and guidelines on support services for students with disabilities and special needs in higher education be developed, data on students with disabilities collected to help planning, collaboration between Disabled Peoples Organisations (DPO's) strengthened to ensure disability inclusion and the establishment of disability support centres. PMID- 28730045 TI - Use of consumer wireless devices by South Africans with severe communication disability. AB - BACKGROUND: Advancements in wireless technology (e.g. cell phones and tablets) have opened new communication opportunities and environments for individuals with severe communication disabilities. The advancement of these technologies poses challenges to ensuring that these individuals enjoy equal access to this increasingly essential technology. However, a paucity of research exists. OBJECTIVES: To describe the nature and frequency with which South African adults with severe communication disabilities have access to and use wireless devices, as well as the types of activities for which wireless devices are used. METHOD: Survey research was conducted with 30 individuals who use augmentative and alternative communication (AAC) technology using the Survey of User Needs Questionnaire developed in the United States, and localized to the South African context. RESULTS: All participants, despite their limited education, unemployment and low economic status, owned and/or used mainstream wireless devices. Slightly more than half of the participants (53.3%) needed adaptations to their wireless devices. Advantages of using wireless devices were highlighted, including connecting with others (through using text messaging, social networking, making plans with others, sharing photos and videos with friends), for leisure activities (e.g. listening to music, watching videos, playing games), and for safety purposes (e.g. to navigate when lost, using the device when in trouble and needing immediate assistance). CONCLUSION: These wireless devices offer substantial benefits and opportunities to individuals with disabilities who rely on AAC in terms of independence, social participation, education and safety/security. However, they still do not enjoy equal opportunity to access and use wireless devices relative to the non-disabled population. PMID- 28730046 TI - Perceived burden of care and reported coping strategies and needs for family caregivers of people with mental disorders in Zimbabwe. AB - BACKGROUND: Mental health service resources are inadequate in low-income countries, and families are frequently expected to provide care for their relative with a mental disorder. However, research on the consequences of caregiving has been limited in low-income countries, including Zimbabwe. OBJECTIVE: The study explored the perceived impact of mental illness, reported coping strategies and reported needs of the family members of persons diagnosed with bipolar affective disorder or schizophrenia attending a psychiatric hospital in Harare, Zimbabwe. METHODS: A purposive sample of 31 family members participated in in-depth interviews and focus group discussions using standardised study guides. Participants were also screened for common mental disorders (CMDs) using the 14-item Shona Symptom Questionnaire. Qualitative data were analysed thematically using NVivo 8 qualitative data analysis software. Statistical Package for Social Sciences (SPSS version 16) was used for descriptive quantitative data analysis. RESULTS: Caregivers experienced physical, psychological, emotional, social and financial burdens associated with caregiving. They used both emotion-focused and problem-focused coping strategies, depending on the ill family members' behaviours. Seeking spiritual assistance emerged as their most common way of coping. Twenty-one (68%) of the caregivers were at risk of CMDs (including three participants who were suicidal) and were referred to a psychiatrist for further management. Caregivers required support from healthcare professionals to help them cope better. CONCLUSION: Caregivers of patients attending psychiatry hospitals in Zimbabwe carry a substantial and frequently unrecognised burden of caring for a family member with a mental disorder. Better support is needed from health professionals and social services to help them cope better. Further research is required to quantitatively measure caregiver burden and evaluate potential interventions in Zimbabwe. PMID- 28730047 TI - An adult learning perspective on disability and microfinance: The case of Katureebe. AB - BACKGROUND: Despite Uganda's progress in promoting affirmative action for persons with disabilities and its strategy of using microfinance to fight poverty, access to microfinance services by persons with disabilities is still problematic due to barriers, characterised by discrepancies between policies and practices. Regarding education, the affirmative action in favour of learners with disabilities has not translated into actual learning opportunities due to personal and environmental barriers. OBJECTIVES: The study on which this article is based investigated the non-formal and informal adult learning practices regarding microfinance that persons with disabilities engaged in. This article seeks to illuminate the barriers that a person with a visual impairment encountered while learning about and engaging with microfinance and the strategies that he developed to overcome them. METHODS: This was a case study, framed within the social model of disability and critical research paradigm. Data were collected through in-depth interviews of a person with visual impairment and observations of the environment in which adult learning and engagement with Savings and Credit Cooperative Organisations (SACCOs) occurred. RESULTS: Findings indicate that the person with a visual disability faced barriers to learning about microfinance services. He experienced barriers in an integrated manner and developed strategies to overcome these barriers. The barriers and strategies are theorised using the social model of disability. CONCLUSION: The case of a person with visual impairment suggests that persons with disabilities face multiple barriers regarding microfinance, including social, psychological and educational. However, his own agency and attitudes were also of importance as they influenced his learning. Viewing these barriers as blockades can lead to non-participation in learning and engagement with microfinance whereas viewing them as surmountable hurdles can potentially motivate participants to succeed in learning about and engaging with microfinance. PMID- 28730048 TI - Patient perspectives about the healthcare of chronic musculoskeletal pain: Three patient cases. AB - BACKGROUND: Consideration of the patient's perspective in healthcare is important because it may inform holistic and contextually relevant management strategies. OBJECTIVES: The purpose of this study was to explore patients' experiences and perspectives about their chronic musculoskeletal (CMSK) pain and its management in the private healthcare sector in South Africa. This work was done as a pilot study to test, adapt and finalize an interview schedule. METHODS: A descriptive, qualitative study was conducted. The sampling was purposive. Three patients with CMSK pain were recruited to participate in in-depth individual interviews. The interviews were recorded and transcribed ensuring confidentiality. Inductive, thematic content analyses of the transcripts were undertaken. Initial codes were assigned and a code book developed, which was applied to the transcripts to develop categories and themes. RESULTS: Four themes emerged from the data: (1) the participants sought understanding about the pain's origin and the reason for pain persistence; (2) pain impacted their lives in multiple ways; (3) the participants depended on healthcare providers (HCP) for guidance and support; and (4) they had the option of acceptance of chronic pain. CONCLUSION: The participants' knowledge about their health condition had important implications as it influenced their perspectives on pain and its management. The pain presented the participants with several challenges, which included developing an understanding about pain and coping with the impact of pain in their lives. HCPs were perceived to play an important role in empowering or disempowering the participants. PMID- 28730049 TI - Impact of structured wheelchair services on satisfaction and function of wheelchair users in Zimbabwe. AB - BACKGROUND: Providing wheelchairs without comprehensive support services might be detrimental to user satisfaction and function. OBJECTIVES: This paper compares wheelchair user satisfaction and function before and after implementation of comprehensive wheelchair services, based on the World Health Organization guidelines on wheelchair service provision in less resourced settings, in Zimbabwe. METHOD: A pre- and post-test study with a qualitative component was done. Quantitative data were collected with the Quebec User Evaluation of Satisfaction with Assistive Technology for adults and children and the 'Functioning Every day with a Wheelchair Questionnaire'. Data were collected from 55 consecutively sampled wheelchair users, who received a new wheelchair in the study period. Qualitative data were collected through two audio recorded focus groups and two case studies and are presented through narrative examples. RESULTS: The proportion of adult users who were satisfied significantly increased for all wheelchair and service delivery aspects (p = 0.001 - 0.008), except follow-up (p = 0.128). The same was true for children's post-test ratings on all variables assessed (p = 0.001 - 0.04), except training in the use of the device (p = 0.052). The biggest improvement in satisfaction figures were for comfort needs (44.3%), indoor mobility (43.2%), outdoor mobility (37.2%), safe and efficient, independent operation (33.5%) and transport (31.4%). The qualitative data illustrated user satisfaction with wheelchair features and services. CONCLUSION: The wheelchair service programme resulted in significant positive changes in user satisfaction with the wheelchair, wheelchair services and function. It is recommended that the Zimbabwean government and partner organisations continue to support and develop wheelchair services along these guidelines. PMID- 28730050 TI - Early detection of communication delays with the PEDS tools in at-risk South African infants. AB - BACKGROUND: Prevalence of communication delays or disorders is increasing, possibly because of various environmental risk factors. Selection and implementation of effective screening tools are important to detect at-risk infants as early as possible. This study aimed to evaluate the accuracy of the Parents' Evaluation of Developmental Status (PEDS), PEDS-Developmental Milestones and PEDS tools to detect communication delays in infants (6-12 months) in a South African primary healthcare context. METHOD: A comparative study design evaluated the accuracy of the PEDS tools to detect communication delays, using an internationally accepted diagnostic assessment tool, the Rossetti Infant-Toddler Language Scale (RITLS). A convenience sample of 201 infants was selected at primary healthcare clinics. RESULTS: Expressive and receptive language sensitivity scores were low across all three screens (ranging between 14% and 44%). The PEDS tools had high sensitivity (71%) and specificity (73%) ratings for the receptive and expressive language and socio-emotional domain in combination. CONCLUSION: In the sample population, the PEDS tools did not accurately detect receptive and expressive language delays; however, communication delays in general were identified. Future research determining accuracy of the PEDS, PEDS Developmental Milestones and PEDS tools for children aged 2-5 years in detecting communication delays should be prioritised. PMID- 28730051 TI - Parental stress and support of parents of children with spina bifida in Uganda. AB - BACKGROUND: Children with disabilities in Sub-Saharan Africa depend for a large part of their functioning on their parent or caregiver. This study explores parental stress and support of parents of children with spina bifida in Uganda. OBJECTIVES: The study aimed to explore perceived stress and support of parents of children with spina bifida living in Uganda and the factors that influence them. METHODS: A total of 134 parents were interviewed. Focus group discussions were held with four parent support groups in four different regions within the country. The Vineland Adaptive Behaviour Scales, Daily Functioning Subscales and Parental Stress Index Short Form (PSI/SF) were administered to measure the child's daily functioning level and parental stress levels. RESULTS: Parental stress was high in our study population with over half of the parents having a > 90% percentile score on the PSI/SF. Stress outcomes were related to the ability to walk (Spearman's correlation coefficient [rho] = -0.245), continence (rho = 0.182), use of clean intermittent catheterisation (rho = -0.181) and bowel management (rho = -0.213), receiving rehabilitative care (rho = -0.211), household income (rho = -0.178), geographical region (rho = -0.203) and having support from another parent in taking care of the child (rho = -0.234). Linear regression showed parental stress was mostly explained by the child's inability to walk (beta = -0.248), practicing bowel management (beta = -0.468) and having another adult to provide support in caring for the child (beta = -0.228). Parents in northern Uganda had significantly higher scores compared to parents in other regions (Parental Distress, F = 5.467*; Parent-Child Dysfunctional Interaction, F = 8.815**; Difficult Child score, F = 10.489**). CONCLUSION: Parents of children with spina bifida experience high levels of stress. To reduce this stress, rehabilitation services should focus on improving mobility. Advocacy to reduce stigmatisation and peer support networks also need to be strengthened and developed. PMID- 28730052 TI - Communication rehabilitation in sub-Saharan Africa: A workforce profile of speech and language therapists. AB - BACKGROUND: There is an urgent global need to strengthen rehabilitation services for people with disabilities. In sub-Saharan Africa, rehabilitation services for people with communication disabilities continue to be underdeveloped. A first step in strengthening services for people with a communication disabilities is to understand the composition and conditions of the current workforce. OBJECTIVES: This research describes a sample of the speech and language therapists (SLTs) working in SSA (excluding South Africa). This study explores the characteristics of this workforce, including their demographics, education, experience and geographical stability. METHOD: A mixed-methods survey was used to collect data from SLTs within Anglophone countries of SSA. Completed surveys were received from 33 respondents working in 44 jobs across nine countries. Analysis included descriptive and non-parametric inferential statistics. This study reports on a subset of descriptive and quantitative data from the wider survey. RESULTS: A background profile of SLTs across the region is presented. Results indicated that the workforce of SLTs comprised a mix of local and international SLTs, with university-level education. Local SLTs were educated both within and outside of Africa, with more recent graduates trained in Africa. These data reflected the local emergence of speech and language therapy training in SSA. CONCLUSION: This sample comprised a mix of African and international SLTs, with indications of growing localisation of the workforce. Workforce localisation offers potential advantages of linguistic diversity and stability. Challenges including workforce support and developing culturally and contextually relevant SLT practices are discussed. PMID- 28730053 TI - Students with hearing impairment at a South African university: Self-identity and disclosure. AB - BACKGROUND: A growing number of students with hearing loss are being granted access to higher education in South Africa due to the adoption of inclusive educational policies. However, available statistics indicate that participation by students with hearing impairments in higher education remains low and research suggests that support provisioning for those who do gain access is inadequate. OBJECTIVES: This article aims to illustrate that the assumed self-identity of students with hearing impairment influences their choice to disclose their disability. The choice not to disclose their hearing loss prevents them from accessing the necessary reasonable accommodations and this in turn may affect their eventual educational success. METHOD: Reported here is a qualitative descriptive case study at a South African university. Purposive sampling methods were employed. Data were gathered from in-depth interviews with seven students with hearing impairment ranging from moderate to profound, using spoken language. Constructivist grounded theory was used as an approach to the process of generating and transforming the data, as well as the construction of theory. FINDINGS: All the student participants identified as having a hearing rather than a D/deaf identity cultural paradigm and viewed themselves as 'normal'. Linked to this was their unwillingness to disclose their hearing impairment and thus access support. CONCLUSION: It is crucially important for academic, support and administrative staff to be aware of both the assumed 'hearing' identity and therefore subsequent non-disclosure practices of students with a hearing impairment using the oral method of communication. Universities need to put measures in place to encourage students to voluntarily disclose their hearing impairment in order to provide more targeted teaching and learning support. This could lead to improved educational outcomes for students. PMID- 28730054 TI - 'Toning' up hypotonia assessment: A proposal and critique. AB - BACKGROUND: Clinical assessment of hypotonia is challenging due to the subjective nature of the initial clinical evaluation. This poses dilemmas for practitioners in gaining accuracy, given that the presentation of hypotonia can be either a non threatening or malevolent sign. The research question posed was how clinical assessment can be improved, given the current contentions expressed in the scientific literature. OBJECTIVES: This paper describes the development and critique of a clinical algorithm to aid the assessment of hypotonia. METHODS: An initial exploratory sequential phase, consisting of a systematic review, a survey amongst clinicians and a Delphi process, assisted in the development of the algorithm, which is presented within the framework of the International Classification of Functioning, Disability and Health. The ensuing critique followed a qualitative emergent-systematic focus group design with a purposive sample of 59 clinicians. Data were analysed using semantical content analysis and are presented thematically with analytical considerations. RESULTS: This study culminated in the development of an evidence-based clinical algorithm for practice. The qualitative critique of the algorithm considered aspects such as inadequacies, misconceptions and omissions; strengths; clinical use; resource implications; and recommendations. CONCLUSIONS: The first prototype and critique of a clinical algorithm to assist the clinical assessment of hypotonia in children has been described. Barriers highlighted include aspects related to knowledge gaps of clinicians, issues around user-friendliness and formatting concerns. Strengths identified by the critique included aspects related to the evidence-based nature of the criteria within the algorithm, the suitability of the algorithm in being merged or extending current practice, the potential of the algorithm in aiding more accurate decision-making, the suitability of the algorithm across age groups and the logical flow. These findings provide a starting point towards ascertaining the clinical utility of the algorithm as an essential step towards evidence-based praxis. PMID- 28730055 TI - The validation of an educational database for children with profound intellectual disabilities. AB - BACKGROUND: The Western Cape Forum for Intellectual Disability took the South African Government to court in 2010 on its failure to implement the right to education for Children with Severe and Profound Intellectual Disability. Subsequently, multidisciplinary teams were appointed by the Western Cape Education Department to deliver services to the Special Care Centres (SCCs). Initially, minimal information was available on this population. OBJECTIVES: The purpose is to document the process of developing and validating a database for the collection of routine data. METHOD: A descriptive analytical study design was used. A sample of convenience was drawn from individuals under the age of 18 years, enrolled in SCCs in the Western Cape. The team who entered and analysed the data reached consensus regarding the utility and feasibility of each item. RESULTS: Data were collected on 134 children. The omission of certain items from the database was identified. Some information was not reliable or readily available. Of the instruments identified to assess function, the classification systems were found to be reliable and useful, as were the performance scales. The WeeFIM, on the other hand, was lengthy and expensive, and was therefore discarded. DISCUSSION AND CONCLUSIONS: A list of items to be included was identified. Apart from an individual profile, it can be useful for service planning and monitoring, if incorporated into the central information system used to monitor the performance of all children. Without such inclusion, this most vulnerable population, despite court ruling, will not have their right to education adequately addressed. PMID- 28730056 TI - The effect of therapeutic horseback riding on heart rate variability of children with disabilities. AB - BACKGROUND: Heart rate variability (HRV) is the oscillation in the interval between consecutive heart beats, resulting from dynamic interplay between multiple physiologic mechanisms that regulate instantaneous heart rate. Short term heart rate regulation is governed by sympathetic and parasympathetic neural activity and therefore HRV examination can be used as a non-invasive estimate of the functioning of the autonomic nervous system (ANS). AIM: To determine the effects of therapeutic horseback riding (THR) intervention on the HRV of children with disabilities. The objective was to examine if THR intervention improves the HRV of children, hence improving the parasympathetic activity that is associated with a calm and relaxed state. METHODS: This is a quasi-experimental design. Heart rate variability components were measured over six intervention sessions of THR. Heart rate variability measures were recorded from 29 participants with various disabilities, and was assessed in both time and frequency domains. RESULTS: Over the six THR sessions, the time domain showed an increase in HRV for pre-THR indicating improved vagal activation, whereas frequency domain showed both increased sympathetic activity and increased parasympathetic activation during THR based on different components of frequency domain. CONCLUSION: Therapeutic horseback riding intervention of six sessions demonstrated a change in HRV of children with disabilities. However, the changes obtained were not significant to make conclusive measures as to whether sympathetic or parasympathetic activity is predominantly increased after the six sessions. Further research involving more than six sessions of THR is required to yield more significant changes. PMID- 28730057 TI - Living with disabled children in Malawi: Challenges and rewards. AB - BACKGROUND: Rehabilitation personnel need to be sensitive to the cultural aspects that constitute the environment of a disabled child's family life. OBJECTIVES: The aim of this study was to gain insight on how families experience parenting of disabled children and how the families experience the support provided by the rehabilitation system in Malawi. METHOD: An anthropological field study combining interviews and observations was conducted in a rural district of Malawi in 2011. Permission was granted to follow four families, and this study presents the stories of two families, whose children have severe disabilities. We used phenomenological and narrative analyses to make sense of the stories. RESULTS: The findings indicate that families with disabled children invest time and emphasise care for their disabled children. They feel enriched by their experience despite challenging situations with little support from the rehabilitation services. High standards of care demonstrating positive and moral attitudes have earned these families respect in their communities. Storytelling has created an opportunity for the families to understand and interpret their challenging situation with inherent contextual meaning. CONCLUSION: This study shows that families with disabled children draw on cultural and structural strengths that rehabilitation professionals should be aware of in their support to mothers and other caregivers of children with disabilities. PMID- 28730058 TI - Childhood disability population-based surveillance: Assessment of the Ages and Stages Questionnaire Third Edition and Washington Group on Disability Statistics/UNICEF module on child functioning in a rural setting in South Africa. AB - BACKGROUND: Epidemiological information on childhood disability provides the basis for a country to plan, implement and manage the provision of health, educational and social services for these vulnerable children. There is, however, currently no population-based surveillance instrument that is compatible with the International Classification of Functioning, Disability and Health (ICF), internationally comparable, methodologically sound and comprehensively researched, to identify children under 5 years of age who are living with disability in South Africa and internationally. We conducted a descriptive pilot study to investigate the sensitivity and specificity of translated versions of the Ages and Stages Questionnaire Third Edition (ASQ-III) and the Washington Group on Disability Statistics/UNICEF module on child functioning (WG/UNICEF module) as parent-reported measures. The aim of our study was to identify early childhood disabilities in children aged 24-48 months in a rural area of South Africa, to determine the appropriateness of these instruments for population based surveillance in similar contexts internationally. METHODS: This study was conducted in the Xhariep District of the Free State Province in central South Africa, with 50 carers whose children were registered on the South African Social Security Agency (SASSA) database as recipients of a grant for one of the following: Care Dependency, Child Support or Foster Care. The researchers, assisted by community healthcare workers and SASSA staff members, conducted structured interviews using forward-backward translated versions of the ASQ-III and the WG/UNICEF module. RESULTS: Both measurement instruments had a clinically meaningful sensitivity of 60.0%, high specificity of 95.6% for the ASQ-III and 84.4% for the WG/UNICEF module, and the two instruments agreed moderately (Kappa = 0.6). CONCLUSION: Since the WG/UNICEF module is quicker to administer, easier to understand and based on the ICF, it can be considered as an appropriate parent reported measure for large-scale, population-based as well as smaller, community specific contexts. It is, however, recommended that future research and development continues with the WG/UNICEF module to enhance its conceptual equivalence for larger-scale, population-based studies in South Africa and internationally. PMID- 28730059 TI - Slipping and holding minds: A psychosocial analysis of maternal subjectivity in relation to childhood disability. AB - BACKGROUND: This paper elucidates a methodological approach to interview text that tries to acknowledge the psychosocial nature of disability and thereby ensuring that empirical work in disability studies complements theoretical arguments already developed. OBJECTIVES: The aim of this study is to outline a psychosocial conceptualisation of maternal subjectivity in relation to childhood disability and to apply this conceptualisation as an analytic tool to segments of an interview with a mother of a child with physical and developmental disabilities. METHOD: Drawing on psychoanalysis and attachment literature alongside critical social psychology we take readers through the analysis of an interview extract with a particular mother. Through a fine grained analysis, we demonstrate the value of attending to the affective processes in and around the text rooted in the particular intersubjective exchange ('here and how') of the interview and the particular socio-historical context ('there and then') in which the mother, child and researcher are located. FINDINGS: The reading draws attention to discourses that position this particular mother and her children in particular ways while also pointing to investments in these discourses such that these discourses are not purely social but play affective functions. CONCLUSION: This paper demonstrates the value of using multiple lenses to read the text, seeking to understand what is going on from within each lens (discursive/social, interpersonal, intrapsychic), while also seeking to disrupt this understanding as we take up the position of a different lens. This approach enables us to hold onto the complexity and locatedness of maternal subjectivity for mothers of children with disabilities. PMID- 28730060 TI - Access to health care for children with neural tube defects: Experiences of mothers in Zambia. AB - INTRODUCTION: In Zambia, all children born with neural tube defects requiring surgery need to be referred to a tertiary level hospital in Lusaka, the capital city, where the specialists are based. The aim of this study was to explore the experiences of mothers accessing health care who had recently given birth to a child with a neural tube defect. METHODS AND ANALYSIS: In-depth interviews were conducted with a purposively selected sample of 20 mothers at the tertiary level hospital. The interviews were audiotaped, transcribed verbatim and translated. Content analysis was used to identify codes, which were later collapsed into categories and themes. FINDINGS: Five themes emerged: access to health care, access to transport, access to information, concerns about family and support needs. DISCUSSION: Barriers to access to health care included geographical barriers and barriers linked to availability. Geographical barriers were related to distance between home and the health centre, and referral between health facilities. Barriers to availability included the lack of specialist health workers at various levels, and insufficient hospital vehicles to transport mothers and children to the tertiary level hospital. The main barrier to affordability was the cost of transport, which was alleviated by either family or government support. Acceptability of the health services was affected by a lack of information, incorrect advice, the attitude of health workers and the beliefs of the family. CONCLUSION: Access to health care by mothers of children with neural tube defects in Zambia is affected by geographical accessibility, availability, affordability and acceptability. The supply-side barriers and demand-side barriers require different interventions to address them. This suggests that health policy is needed which ensures access to surgery and follow up care. PMID- 28730061 TI - Childhood disability in Turkana, Kenya: Understanding how carers cope in a complex humanitarian setting. AB - BACKGROUND: Although the consequences of disability are magnified in humanitarian contexts, research into the difficulties of caring for children with a disability in such settings has received limited attention. METHODS: Based on in-depth interviews with 31 families, key informants and focus group discussions in Turkana, Kenya, this article explores the lives of families caring for children with a range of impairments (hearing, vision, physical and intellectual) in a complex humanitarian context characterised by drought, flooding, armed conflict, poverty and historical marginalisation. RESULTS: The challenging environmental and social conditions of Turkana magnified not only the impact of impairment on children, but also the burden of caregiving. The remoteness of Turkana, along with the paucity and fragmentation of health, rehabilitation and social services, posed major challenges and created opportunity costs for families. Disability related stigma isolated mothers of children with disabilities, especially, increasing their burden of care and further limiting their access to services and humanitarian programmes. In a context where social systems are already stressed, the combination of these factors compounded the vulnerabilities faced by children with disabilities and their families. CONCLUSION: The needs of children with disabilities and their carers in Turkana are not being met by either community social support systems or humanitarian aid programmes. There is an urgent need to mainstream disability into Turkana services and programmes. PMID- 28730062 TI - Challenges faced by women with disabilities in accessing sexual and reproductive health in Zimbabwe: The case of Chitungwiza town. AB - BACKGROUND: Women with disabilities in Zimbabwe face numerous challenges in accessing sexual and reproductive health. Cultural belief still regards them as not sexually active. The government has also failed to promote policies that facilitate access to sexual and reproductive services by women with disabilities. OBJECTIVES: The reseach objectives were to explore the challenges faced by women with disabilities in accessing sexual and reproductive health in Zimbabwe. METHOD: The data were gathered using in-depth interviews with 23 purposively selected respondents. Thirteen women had physical disabilities, five were visually impaired, three were deaf and two were stammering. The respondents with physical disabilities were using wheelchairs, walking frames, prosthesis, crutches and caliper shoes. The participants' ages ranged from 18 to 45 years. All interviews were transcribed and translated verbatim into English, and passages were extracted from the transcripts. Key themes and concepts were identified and coded to offer a rich framework for analysis, comparisons and presentation of the data. RESULTS: Negative perceptions of health personnel towards people with disabilities, disability-unfriendly infrastructure at health facilities and absence of trained personnel for people with disabilities (sign language) are some of the challenges involved. CONCLUSION: The government, in partnership with other stakeholders, should address challenges faced by women with disabilities when accessing sexual and reproductive health services. Non government, private hospitals and profit-making organisations should join hands with government in funding health requirements for women with disabilities. PMID- 28730063 TI - Community stakeholders' perspectives on the role of occupational therapy in primary healthcare: Implications for practice. AB - BACKGROUND: Primary healthcare (PHC) is central to increased access and transformation in South African healthcare. There is limited literature about services required by occupational therapists in PHC. Despite policy being in place, the implementation of services at grassroots level does not always occur adequately. OBJECTIVES: This study aimed at gaining an understanding of the challenges of being disabled and the services required by occupational therapists (OTs) in rural communities in order to better inform the occupational therapy (OT) training curriculum. METHOD: An exploratory, descriptive qualitative design was implemented using purposive sampling to recruit 23 community healthcare workers from the uGu district. Snowball sampling was used to recruit 37 members of the uGu community, which included people with disability (PWD) and caregivers of PWDs. Audio-recorded focus groups and semi-structured interviews were used to collect data, which were thematically analysed. Ethical approval was obtained from the Biomedical and Research Ethics Committee of the University of KwaZulu Natal (BE248/14). RESULTS: Two main themes emerged namely: firstly, the challenges faced by the disabled community and secondly appropriate opportunities for intervention in PHC. A snapshot of the social and physical inaccessibility challenges experienced by the community was created. Challenges included physical and sexual abuse, discrimination and marginalisation. Community-based rehabilitation and ideas for health promotion and prevention were identified as possible strategies for OT intervention. CONCLUSION: The understanding of the intervention required by OT in PHC was enhanced through obtaining the views of various stakeholders' on the role. This study highlighted the gaps in community based services that OTs should offer in this context. PMID- 28730064 TI - Access to curriculum for students with disabilities at higher education institutions: How does the National University of Lesotho fare? AB - BACKGROUND: Creating access to curricula at institutions of higher education for students with disabilities requires a concerted effort from management and other key stakeholders to identify students' needs and create opportunities for success. OBJECTIVES: This paper presents the findings of a study which examined students with disabilities' access to curricula at a higher education institution in Lesotho. METHOD: Data for this qualitative study were collected using three methods: in-depth interviews, focus group discussions and document analysis. Eleven students with various types of impairments and 15 academic and non academic staff members currently working in close proximity to students with disabilities participated in this study. RESULTS: The findings reveal inconsistencies between the institution's admission policy of non-discrimination according to disability status and its practices. These inconsistencies are discussed under the following themes: (1) access at admission level, (2) management of disability data, (3) support by the special education unit, (4) teaching strategies, (5) support by lecturers, (6) availability of assistive technology, (7) special concessions and (8) students' coping mechanisms. CONCLUSION: We recommend that a clear policy concerning the support of students with disabilities be developed with the following aims: guide decisions on how disability data should be used, define roles that different university departments must play in facilitating access to curricula for all students, influence suitable development of teaching and learning resources, stimulate research on success and completion rates of students with disabilities and mandate restructuring of programmes that are currently inaccessible to students with disabilities. Key stakeholders, including students with disabilities, disabled persons' organisations, disability rights activists, and staff should be involved in such policy design. PMID- 28730065 TI - Exploring structural violence in the context of disability and poverty in Zimbabwe. AB - BACKGROUND: While it is widely assumed that disability, poverty and health are closely linked, research falls short of fully understanding the link. One approach to analysing the links between disability and poverty is through the concept of structural violence, referring to social structures that contribute to the impoverishment of individuals or communities. These structures can be political, ecological, legal and economic, among others. OBJECTIVE: To explore structural violence and how it affects families of children with cerebral palsy among the Tonga ethnic group living in poor rural communities of Binga in Zimbabwe. METHOD: This is a longitudinal, qualitative and ethnographic study. Data were collected over a period of eight years from 2005 to 2013. Data collection techniques were in-depth interviews, participant observation and focus group discussions. Purposive sampling was used to recruit 53 informants. RESULTS: Structural violence was noted through four themes: internal displacement and development, food and politics, water and sanitation, and social services. Poverty was noted in the form of unemployment, lack of education, healthcare, food and shelter. The concept of structural violence inflicted social suffering on the informants. Politics played a major role in activities such as food withdrawal, lack of water, development and allocation of local resources to 'the people of the city', leaving the informants struggling with care. CONCLUSION: Political and economic forces have structured risks and created a situation of extreme human suffering. The capabilities approach brings out the challenges associated with cerebral palsy in the context of development challenges. PMID- 28730066 TI - 'These are not luxuries, it is essential for access to life': Disability related out-of-pocket costs as a driver of economic vulnerability in South Africa. AB - BACKGROUND: With the dawn of the new sustainable development goals, we face not only a world that has seen great successes in alleviating poverty but also a world that has left some groups, such as persons with disabilities, behind. Middle-income countries (MICs) are home to a growing number of persons with disabilities. As these countries strive to achieve the new goals, we have ample opportunity to include persons with disabilities in the emerging poverty alleviation strategies. However, a lack of data and research on the linkages between economic vulnerability and disability in MICs hampers our understanding of the factors increasing economic vulnerability in people with disabilities. METHODS: This article aims to present data related to elements of this vulnerability in one MIC, South Africa. Focusing on out-of-pocket costs, it uses focus group discussions with 73 persons with disabilities and conventional content analysis to describe these costs. RESULTS: A complex and nuanced picture of disability-driven costs evolved on three different areas: care and support for survival and safety, accessibility of services and participation in community. Costs varied depending on care and support needs, accessibility (physical and financial), availability, and knowledge of services and assistive devices. CONCLUSIONS: The development of poverty alleviation and social protection mechanisms in MICs like South Africa needs to better consider diverse disability related care and support needs not only to improve access to services such as education and health (National Health Insurance schemes, accessible clinics) but also to increase the effect of disability-specific benefits and employment equity policies. PMID- 28730067 TI - Practices and discourses of ubuntu: Implications for an African model of disability? AB - BACKGROUND: Southern African scholars and activists working in disability studies have argued that ubuntu or unhu is a part of their world view. OBJECTIVES: Thinking seriously about ubuntu, as a shared collective humanness or social ethics, means to examine how Africans have framed a struggle for this shared humanity in terms of decolonisation and activism. METHOD: Three examples of applications of ubuntu are given, with two mainly linked to making explicit umaka. Firstly, ubuntu is linked to making visible the invisible inequalities for a common humanity in South Africa. Secondly, it becomes correlated to the expression of environmental justice in West and East African countries. RESULTS: An African model of disability that encapsulates ubuntu is correlated to how Africans have illustrated a social ethics of a common humanity in their grassroots struggles against oppression and disablement in the 20th century. Ubuntu also locates disability politically within the wider environment and practices of sustainability which are now important to the post-2105 agenda, Convention on the Rights of Persons with Disabilities (CRPD) and the (UN) Sustainable Development Goals linked to climate change. CONCLUSION: A different kind of political action linked to social justice seems to be evolving in line with ubuntu. This has implications for the future of disability studies. PMID- 28730068 TI - Stroke survivors' levels of community reintegration, quality of life, satisfaction with the physiotherapy services and the level of caregiver strain at community health centres within the Johannesburg area. AB - BACKGROUND: Stroke survivors are discharged home before they are functionally independent and return home with activity limitations that would not be manageable without a caregiver. AIM: To determine stroke survivors' levels of community reintegration, quality of life (QOL), satisfaction with the physiotherapy services and the level of caregiver strain at community health centres within the Johannesburg area. METHOD: This was a cross-sectional study using the following outcome measures: Maleka Stroke Community Reintegration Measure, Stroke-specific quality of life scale, Caregiver strain index and Physical therapy patient satisfaction questionnaire. RESULTS: A total of 108 stroke survivors and 45 caregivers participated in this study. The average age of the stroke survivors was 54 years (standard deviation = 12.73) and 58% (n = 62) had moderate to full community reintegration. They were happy with physiotherapy services but not with parking availability and cost of services. The QOL was poor with the lowest scores for energy and highest scores for vision and language domains. Twenty five (55%) caregivers were strained. A positive correlation was found between community reintegration and satisfaction with services (r = 0.27, p < 0.0001) and QOL (r = 0.51, p < 0.0001). A negative correlation was found between community reintegration and caregiver strain (r = -0.37, p < 0.0001). CONCLUSION: Most stroke survivors are reintegrated into their communities except in the areas of work and education and have poor QOL and most of their caregivers are strained; however, they are satisfied with physiotherapy services. PMID- 28730069 TI - Exploration of the academic lives of students with disabilities at South African universities: Lecturers' perspectives. AB - BACKGROUND: A decade has passed since South Africa signed and ratified the Convention on the Rights of Persons with Disabilities, a human rights treaty that protects the rights and dignity of people with disabilities. However, not much have changed for students with disabilities. OBJECTIVES: The aim of this study was to explore lecturers' experiences with, and perspectives on, disability as well as with students with disabilities. It was hoped that this would contribute to the ongoing policy debates about diversity, inclusion and support for students with disabilities at universities. METHODS: In an effort to understand the lives of students with disabilities better, a study which included students with disabilities, lecturers and disability supporting staff was conducted at two South African universities - University of the Free State and University of Venda. The paper takes a snapshot view of four lecturers and their perceptions of the lives of students with disabilities at their respective universities. RESULTS AND CONCLUSION: Although most disability literature report students with disabilities blaming lecturers for their failure to advance their needs, this paper highlights that the education system needs to be supportive to lecturers for the inclusive agenda to be realised. An argument is made for a more comprehensive approach towards a national disability policy in higher education involving many stakeholders. Without a broader understanding of disability, it will be difficult to engage with the complex ways in which inequalities emerge and are sustained. PMID- 28730070 TI - Inhibition effect of curcumin on UVB-induced secretion of pro-inflammatory cytokines from corneal limbus epithelial cells. AB - AIM: To study the effects of curcumin on the secretion of interleukin (IL)-6 and IL-8 by corneal limbus epithelial cells. METHODS: Human corneal limbus epithelial cells were isolated and cultured from donor eyes and irradiated by UVB at different dosages with or without curcumin. MTT test was used for studying the effects of UVB and curcumin on the cell viability. The role of mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-kappaB) pathways on the UVB induced secretion of IL-6 and IL-8 were tested by addition of their inhibitors to the culture with or without UVB-radiation. Levels of various signal pathways, IL 6 and IL-8 in the cells and in the conditioned culture medium were measured by ELISA analysis. RESULTS: UVB at 20 mJ/cm2 or less and curcumin at 20 umol/L or less did not affect the cell viability of cultured limbus epithelial cells (P>0.05). UVB irradiation at 10 and 20 mJ/cm2 induced a significant increase of secretion of IL-6 and IL-8 and upregulated NF-kappaB and phosphorylated MAPK pathways of cultured limbus epithelial cells (P<0.05). Various signal pathway inhibitors, including SP600125 (JNK inhibitor), SB203580 (p38 MAPK inhibitor) and BAY11-7082 (NF-kappaB inhibitor) significantly decreased the UVB-induced secretion of IL-6 and IL-8 secretion (P<0.05). Curcumin at 5-20 umol/L significantly inhibited UVB-induced secretion of IL-6 and IL-8 by limbus epithelial cells in a dose-dependent manner; while curcumin alone did not affect the secretion of IL-6 and IL-8. The upregulation of NF-kappaB and MAPK pathways induced by UVB treatment was significantly inhibited by curcumin, suggesting that NF-kappaB and MAPK pathways are involved in the inhibitory effect of curcumin on UVB-induced production of IL-6 and IL-8. CONCLUSION: Curcumin may be a promising agent to be explored for the prevention and treatment of pterygium. PMID- 28730071 TI - Effect of sorafenib in a murine high risk penetrating keratoplasty model. AB - AIM: To evaluate the effect of sorafenib in murine high risk keratoplasty model. METHODS: Graft survival, corneal neovascularization, and corneal lymphangiogenesis were compared among the sorafenib, dexamethasone, dimethyl sulfoxide (DMSO), and phosphate buffered saline (PBS) groups following subconjunctival injection in mice that underwent high risk penetrating keratoplasty (HRPK). Real-time polymerase chain reaction was performed to quantify the expression of inflammatory cytokines and vascular endothelial growth factor (VEGF)-A, VEGF-C, vascular endothelial growth factor receptor (VEGFR)-2, VEGFR-3. RESULTS: The two-month graft survival rate for HRPK was 42.86% in sorafenib group, 37.50% in dexamethasone group, 0 in DMSO group, and 0 in PBS group. Sorafenib significantly increased graft survival compared to the DMSO and PBS group (P<0.05). The sorafenib didn't show significant effect in decreasing neovascularization compared with dexamethsone, DMSO, and PBS group. The sorafenib showed less total lymphangiogenesis than the dexamethasone, DMSO, and PBS group (P=0.011, P<0.001, P<0.001, respectively). The sorafenib group showed reduced expression of VEGF-C, tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, VEGFR-2 and VEGFR-3 compared with DMSO group and PBS group (all P<0.05). The sorafenib group didn't show difference in the expression of VEGF-A compared with DMSO, neither with PBS. The sorafenib group showed reduced expression of VEGFR-3 compared with dexamethasone (P=0.051). CONCLUSION: The subconjunctivally administered sorafenib shows significant anti-lymphangiogenic effect, resulting in increased transplant survival in a murine high risk keratoplasty model. We suggest that a close linkage between decreased VEGF-C/VEGFR-2 and -3 signaling and increased corneal graft survival by sorafenib seems to exist. PMID- 28730072 TI - Effects of lens extirpation with anterior vitrectomy on vitreous three dimensional mesh structure. AB - AIM: To investigate the changes in vitreous gel structure after lens extirpation combined with anterior vitrectomy in rabbit eyes. METHODS: Twenty-eight chinchilla rabbits were divided into three groups. The control group (Group I) included 16 eyes from eight rabbits who did not receive any treatment. Group II included 20 eyes from 10 rabbits that underwent lens aspiration only. Group III included 20 eyes from 10 rabbits that underwent lens aspiration combined with posterior capsulotomy and anterior vitrectomy. Eyes were harvested on the 30th and 60th day postoperatively, respectively. Changes in vitreous gel stretch length due to gravity and the rate of vitreous liquefaction were observed. The collagen content in the vitreous body was examined using the L-hydroxyproline test. Electronic microscopic images were obtained from each eyeball. RESULTS: On both the 30th and 60th day postoperatively, the vitreous gel length of group III was significantly shorter than group I and group II (P<0.05), while the rate of liquefaction of the vitreous body in group III was significantly higher than group I and group II (P<0.05). The collagen content in group III was also higher than that in group I and group II (P<0.05). CONCLUSION: Loss of vitreous gel mass is more likely to occur in the eyes of rabbits receiving anterior vitrectomy. Lensectomy combined with anterior vitrectomy may damage the stable three dimensional mesh structure of collagen, which could aggravate vitreous gel liquefaction. PMID- 28730073 TI - A Chinese family with Axenfeld-Rieger syndrome: report of the clinical and genetic findings. AB - AIM: To describe a Chinese family affected by a severe form of Axenfeld-Rieger syndrome (ARS) and characterize the molecular defect in PITX2 in the family. METHODS: Patients presented with typical ARS from a Chinese family were investigated. We performed genome-wide linkage scan and exome sequencing to identify the pathogenic mutations. Candidate mutations were verified for co segregation in the whole pedigree using Sanger sequencing. Real-time polymerase chain reaction (RT-PCR) and Western blotting were performed to verify the expression of the pathogenic gene. RESULTS: Genome-wide linkage and exome sequencing analyses showed PITX2 as the disease candidate gene. A>G substitution at position -11 of 3'ss of exon 5 (IVS5-11A>G) that co-segregated with the disease phenotype was discovered in the family. The PITX2 messenger ribonucleic acid and protein levels were about 50% lower in patients with ARS than in unaffected family members in the family. CONCLUSION: Our findings implicate the first intronic mutation of the PITX2 gene in the pathogenesis of a severe form of ARS in a Chinese family. This study highlights the importance of a systematic search for intronic mutation in ARS cases for which no mutations in the exons of PITX2 have been found. PMID- 28730074 TI - Protection of retinal ganglion cells against optic nerve injury by induction of ischemic preconditioning. AB - AIM: To explore if ischemic preconditioning (IPC) can enhance the survival of retinal ganglion cells (RGCs) after optic nerve axotomy. METHODS: Twenty-four hours prior to retinal ischemia 60min or axotomy, IPC was applied for ten minutes in groups of (n=72) animals. The survival of RGCs, the cellular expression of heat shock protein 27 (HSP27) and heat shock protein 70 (HSP70) and the numbers of retinal microglia in the different groups were quantified at 7 and 14d post injury. The cellular expression of HSP27 and HSP70 and changes in the numbers of retinal microglia were quantified to detect the possible mechanism of the protection of the IPC. RESULTS: Ten minutes of IPC promoted RGC survival in both the optic nerve injury (IPC-ONT) and the retinal ischemia 60min (IPC-IR60) groups, examined at 7d and 14d post-injury. Microglial proliferation showed little correlation with the extent of benefit effects of IPC on the rescue of RGCs. The number of HSP27-positive RGCs was significantly higher in the IPC-ONT group than in the sham IPC-ONT group, although the percentage of HSP27-positive RGCs did not significantly differ between groups. For the IPC-IR60 group, neither the number nor the percentage of the HSP27-positive RGCs differed significantly between the IPC and the sham-operated groups. The number of HSP70-positive RGCs was significantly higher for both the IPC-ONT and the IPC-IR60 experimental groups, but the percentages did not differ. CONCLUSION: The induction of IPC enhances the survival of RGCs against both axotomy and retinal ischemia. PMID- 28730075 TI - CCR7/p-ERK1/2/VEGF signaling promotes retinal neovascularization in a mouse model of oxygen-induced retinopathy. AB - AIM: To investigate the role of CCR7/p-ERK1/2/VEGF signaling in the mouse model of oxygen-induced retinopathy (OIR). METHODS: Neonatal C57BL/6J mice were evenly randomized into four groups: normoxia, OIR, OIR control (treated with scramble siRNA), and OIR treated (treated with CCR7 siRNA). Normoxia group was not specially handled. Postnatal day 7 (P7) mice in the OIR group were exposed to 75%+/-5% oxygen for 5d (P7-P12) and then maintained under normoxic conditions for 5d (P12-P17). Mice in the OIR control and OIR treated groups were given injections of scramble or CCR7 siRNA plasmid on P12 before returning to normoxic conditions for 5d (P12-P17). Retina samples were collected from all mice on P17, stained with adenosine diphosphatase (ADPase), and retinal neovascularization (RNV) was assessed. Retinas were also stained with hematoxylin and eosin (H&E) for RNV quantitation. The distribution and expression of CCR7, p-ERK1/2 and vascular endothelial growth factor (VEGF) were assessed via immunohistochemistry, Western blot, and quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: High oxygen promoted retinal neovascularization (P<0.05) and increased the number of endothelial nuclei in new vessels extending from the retina to the vitreous body; CCR7 promoted this process (P<0.05). CCR7 and VEGF mRNA were expressed at higher levels in the OIR and OIR control groups than in the normoxia and OIR treated groups. CCR7, p-ERK1/2, and VEGF protein were expressed in the retinas of mice in the OIR and OIR control groups. Intravitreal injection of CCR7 siRNA significantly reduced CCR7, p-ERK1/2, and VEGF expression in the OIR mouse model (all P<0.05). CCR7 significantly enhanced the neovascularization and non perfusion areas in the OIR group (P<0.05). CCR7 siRNA significantly reduced levels of p-ERK1/2 and VEGF as compared to OIR controls (P<0.05). CONCLUSION: These results suggest that CCR7/p-ERK 1/2/VEGF signaling plays an important role in OIR. CCR7 may be a potential target for the prevention and treatment of retinopathy of prematurity. PMID- 28730076 TI - Scutellaria barbata attenuates diabetic retinopathy by preventing retinal inflammation and the decreased expression of tight junction protein. AB - AIM: To observe the attenuation of ethanol extract of Herba Scutellaria barbata (SE) against diabetic retinopathy (DR) and its engaged mechanism. METHODS: C57BL/6J mice were intraperitoneally injected with streptozotocin (STZ, 55 mg/kg) for 5 consecutive days to induce diabetes. The diabetic mice were orally given with SE (100, 200 mg/kg) for 1mo at 1mo after STZ injection. Blood-retinal barrier (BRB) breakdown was detected by using Evans blue permeation assay. Real time polymerase chain reaction (RT-PCR), Western blot and immunofluorescence staining were used to detect mRNA and protein expression. Enzyme-linked immunosorbent assay (ELISA) was used to detect serum contents of tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL)-1beta. RESULTS: SE (100, 200 mg/kg) reversed the breakdown of BRB in STZ-induced diabetic mice. The decreased expression of retinal claudin-1 and claudin-19, which are both tight junction (TJ) proteins, was reversed by SE. SE decreased the increased serum contents and retinal mRNA expression of TNF-alpha and IL-1beta. SE also decreased the increased retinal expression of intercellular cell adhesion molecule-1 (ICAM-1). SE reduced the increased phosphorylation of nuclear factor kappa B (NFkappaB) p65 and its subsequent nuclear translocation in retinas from STZ-induced diabetic mice. Results of Western blot and retinal immunofluorescence staining of ionized calcium-binding adapter molecule 1 (Iba1) demonstrated that SE abrogated the activation of microglia cells in STZ-induced diabetic mice. CONCLUSION: SE attenuates the development of DR by inhibiting retinal inflammation and restoring the decreased expression of TJ proteins including claudin-1 and claudin-19. PMID- 28730078 TI - Effect of pyridone agent on blood-retinal barrier in diabetic mice. AB - AIM: To evaluate the therapeutic effect of fluorofenidone on disrupted blood retinal barrier in the diabetic mice and uncover its underlying mechanism. METHODS: db/db mice were randomly chosen for treatment with daily doses of fluorofenidone or placebo at 5-week-old, treatment continued until mice reach 24 week-old. Then, expression of transcriptiona factor insulin gene enhancer binding protein-1 (Islet-1) and vascular endothelial growth factor (VEGF) in murine retinas were evaluated. Retinal vascular permeability was assessed by examining the level of albumin in db/db murine retinas. Furthermore, the retinal vessel tight junction was estimated by checking the level of occludin in the murine retinal tissues. RESULTS: After occurrence of diabetic retinopthy in db/db mice, expressions of transcritpional factor Islet-1 was found to be upregulated in db/db murine retinas compared with non-diabetic controls. Similar to expression pattern of Islet-1, VEGF were also demonstrated to be increased in retinas of db/db mice, which was accompanied by increased retinal vascular leakage and decreased tight junction protein level. Systemetic administration of fluorofenidone repaired broken retinal vascular tight junction by restoring occludin expression in db/db retinal tissue. Consequently, retinal vascular premeability were indicated to be reduced by examining the transudative albumin level in diabetic retinal tissues. Both Islet-1 and VEGF expression were inhibited in the retinas of db/db mice after treatment with fluorofenidone. CONCLUSION: Fluorofenidone significantly protectes retinal tight junction and reduces retinal vascular leakage. The phenomenon can be partially attributed to reducing overexpression of Islet-1 and VEGF in diabetic retinal tissues. PMID- 28730077 TI - Proteomic profiling of early degenerative retina of RCS rats. AB - AIM: To identify the underlying cellular and molecular changes in retinitis pigmentosa (RP). METHODS: Label-free quantification-based proteomics analysis, with its advantages of being more economic and consisting of simpler procedures, has been used with increasing frequency in modern biological research. Dystrophic RCS rats, the first laboratory animal model for the study of RP, possess a similar pathological course as human beings with the diseases. Thus, we employed a comparative proteomics analysis approach for in-depth proteome profiling of retinas from dystrophic RCS rats and non-dystrophic congenic controls through Linear Trap Quadrupole - orbitrap MS/MS, to identify the significant differentially expressed proteins (DEPs). Bioinformatics analyses, including Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway annotation and upstream regulatory analysis, were then performed on these retina proteins. Finally, a Western blotting experiment was carried out to verify the difference in the abundance of transcript factor E2F1. RESULTS: In this study, we identified a total of 2375 protein groups from the retinal protein samples of RCS rats and non-dystrophic congenic controls. Four hundred thirty-four significantly DEPs were selected by Student's t-test. Based on the results of the bioinformatics analysis, we identified mitochondrial dysfunction and transcription factor E2F1 as the key initiation factors in early retinal degenerative process. CONCLUSION: We showed that the mitochondrial dysfunction and the transcription factor E2F1 substantially contribute to the disease etiology of RP. The results provide a new potential therapeutic approach for this retinal degenerative disease. PMID- 28730079 TI - Effect of angiotensin II type 1 receptor blocker and angiotensin converting enzyme inhibitor on the intraocular growth factors and their receptors in streptozotocin-induced diabetic rats. AB - AIM: To investigate the effect of angiotensin II type 1 receptor blocker (ARB) and angiotensin converting enzyme inhibitor (ACEI) on intraocular growth factors and their receptors in streptozotocin-induced diabetic rats. METHODS: Forty Sprague-Dawley rats were divided into 4 groups: control, diabetes mellitus (DM), candesartan-treated DM, and enalapril-treated DM (each group, n=10). After the induction of DM by streptozotocin, candesartan [ARB, 5 mg/(kg.d)] and enalapril [ACEI, 10 mg/(kg.d)] were administered to rats orally for 4wk. Vascular endothelial growth factor (VEGF) and angiotensin II (Ang II) concentrations in the vitreous were measured using enzyme-linked immunosorbent assays, and VEGF receptor 2 and angiotensin II type 1 receptor (AT1R) levels were assessed at week 4 by Western blotting. RESULTS: Vitreous Ang II levels were significantly higher in the DM group and candesartan-treated DM group than in the control (P=0.04 and 0.005, respectively). Vitreous AT1R increased significantly in DM compared to the other three groups (P<0.007). Candesartan-treated DM rats showed higher vitreal AT1R concentration than the enalapril-treated DM group and control (P<0.001 and P=0.005, respectively). No difference in vitreous Ang II and AT1R concentration was found between the enalapril-treated DM group and control. VEGF and its receptor were below the minimum detection limit in all 4 groups. CONCLUSION: Increased Ang II and AT1R in the hyperglycemic state indicate activated the intraocular renin-angiotensin system, which is inhibited more effectively by systemic ACEI than systemic ARB. PMID- 28730080 TI - Old canalicular laceration repair: a retrospective study of the curative effects and prognostic factors. AB - AIM: To investigate the epidemiology and surgical outcomes of old canalicular laceration and analyze the variables impacting on the prognosis of reparation. METHODS: A retrospective review of all old canalicular laceration repairs from Jan. 1, 2008 to Dec. 30, 2015 was performed. Analyzed data included demographics, mechanisms of injury, the time from injury to repair, causes for delayed repair, old associated injuries, the types of surgery, and the effects of repair using canaliculus anastomosis combined with bicanalicular stent intubation. RESULTS: Totally 148 patients with old canalicular laceration received surgical repair and were enrolled. The mean age at presentation was 32.52 years old (ranged from 3 to 63 years old). The 110 patients (74.32%) were male and 127 patients (85.81%) were adults (>=18 years old). The old upper, lower, and bicanalicular lacerations were found in 5 (3.38%), 39 (26.35%), and 104 patients (70.27%), respectively. The mechanism of old injury was primarily due to motor vehicle accidents (n=53, 35.81%). The mean time from injury to repair was 43.61mo (ranged from 1 to 360mo). Associated old ocular and orbit injuries were found in 65 patients (43.92%), and chronic dacryocystitis in 18 patients (12.16%). The main cause of delayed repair was that doctors or patients didn't pay attention to the canalicular laceration because of the concurrent severe injuries (n=71, 47.97%). Totally 136 patients (91.89%) with old canalicular laceration underwent canaliculus anastomosis combined with bicanalicular stent intubation. In all of them, 20 patients (13.51%) were combined with dacryocystorhinostomy. In these cases, 132 patients (97.06%) attained anatomic success, 121 patients (88.97%) reported no epiphora (functional success), 11 patients (8.09%) reported significant epiphora anesis (functional improvement), and 4 (2.94%) reported no significant anesis (functional failure). Rates of anatomic success and functional success were significantly correlated with different canaliculus involved. However, rates of anatomic success and functional success were not significantly affected by the time from injury to repair. CONCLUSION: The canalicular anastomosis combined with bicanalicular stent intubation could act as an effective therapeutics for old canalicular laceration. PMID- 28730081 TI - Effect of human autologous serum and fetal bovine serum on human corneal epithelial cell viability, migration and proliferation in vitro. AB - AIM: To analyze the concentration-dependent effects of autologous serum (AS) and fetal bovine serum (FBS) on human corneal epithelial cell (HCEC) viability, migration and proliferation. METHODS: AS was prepared from 13 patients with non healing epithelial defects Dulbecco's modified eagle medium/Ham's F12 (DMEM/F12) with 5% FBS, 0.5% dimethyl sulphoxide (DMSO), 10 ng/mL human epidermal growth factor, 1% insulin-transferrin-selenium, then were incubated in serum media: DMEM/F12 supplemented by 5%, 10%, 15% or 30% AS or FBS. HCEC viability was analyzed using cell proliferation kit XTT, migration using a wound healing assay, proliferation by the cell proliferation enzyme-linked immunosorbent assay (ELISA) BrdU kit. Statistical analysis was performed using the generalized linear model, the values at 30% AS or 30% FBS were used as the baselines. RESULTS: HCEC viability was the highest at 30% AS or 15% FBS and the lowest at 10% AS or 30% FBS application. HCEC migration was the quickest through 30% AS or 30% FBS and the slowest through 5% AS or 5% FBS concentrations. Proliferation was the most increased through 15% AS or 5% FBS and the least increased through 30% AS or 30% FBS concentrations. HCEC viability at 10% and 15% AS was significantly worse (P=0.001, P=0.023) compared to baseline and significantly better at 15% FBS (P=0.003) concentrations. HCEC migration was significantly worse (P<=0.007) and HCEC proliferation significantly better (P<0.001) in all concentration groups compared to baseline. CONCLUSION: For the best viability of HCEC 30% AS or 15% FBS, for HCEC migration 30% AS or 30% FBS, for proliferation 15% AS or 5% FBS should be used. Therefore, we suggest the use of 30% AS in clinical practice. PMID- 28730082 TI - Evaluation of visual quality of spherical and aspherical intraocular lenses by Optical Quality Analysis System. AB - AIM: To evaluate the impact of spherical and aspherical intraocular lenses on the postoperative visual quality of age-related cataract patients using Optical Quality Analysis System (OQAS). METHODS: Seventy-four eyes with age-related cataracts were randomly divided into spherical and aspherical lens implantation groups. Best-corrected visual acuity (BCVA) was measured preoperatively, one day, one week, two weeks, one month and two months after surgery. A biometric systems analysis using the OQAS objective scattering index (OSI) was performed. RESULTS: There were no significant differences in visual acuity (P>0.05) before and after spherical and aspheric lens implantation. There was a negative linear correction between the OSI value and BCVA (r=-0.634, P=0.000), and positive corrections between the OSI value and the lens LOCUS III value of nucleus color (NC), nucleus opacity (NO), cortex (C) and posterior lens capsular (P) (r=0.704, P=0.000; r=0.514, P=0.000; r=0.276, P=0.020; r=0.417, P=0.000, respectively). OSI values of spherical vs aspherical lenses were 11.5+/-3.6 vs 11.8+/-3.4, 4.1+/-0.9 vs 3.3+/-0.8, 3.5+/-0.9 vs 2.7+/-0.7, 3.3+/-0.8 vs 2.6+/-0.7, 3.2+/-0.7 vs 2.5+/ 0.8, and 3.2+/-0.8 vs 2.5+/-0.8 before and 1d, 1, 2wk, 1 and 2mo after surgery, respectively. All time points varied significantly (P<0.01) between the two groups. CONCLUSION: Aspherical IOLs does not significantly affect visual acuity compared with spherical IOLs. The OSI value, was significantly lower in the aspherical lens group compared with the spherical lens. This study shows that objective visual quality of aspheric IOLs is better than that of the spherical lens by means of OQAS biological measurement method. PMID- 28730083 TI - Viscocanalostomy combined with trabeculotomy and mitomycin C in the treatment of primary congenital glaucoma. AB - AIM: To evaluate the long-term outcome of viscocanalostomy combined with trabeculotomy and mitomycin C in the treatment of primary congenital glaucoma. METHODS: This is a retrospective study. Forty-two eyes of 26 patients with primary congenital glaucoma were enrolled. Intraocular pressure (IOP), corneal diameter (mm) and cup/disc (C/D) were measured before and after the surgery respectively. Follow-up period was 30mo. RESULTS: The mean preoperative IOP was 30.6+/-7.35 mm Hg. Of the 42 eyes, 2 eyes were required conversion to trabeculectomy for the absence of Schlemm's canal. Of remained 40 eyes, 38 eyes (95%) achieved successful IOP control. The average postoperative IOP was 11.69+/ 4.18 mm Hg at 12mo. The mean reduction was 18.91 mm Hg (P<0.0001). Eighteen (75%) eyes presented a reduction in corneal diameter, and 25 (62.5%) eyes presented a C/D ratio reversal after the surgery. There was no serious complication in any patients over the follow-up period. CONCLUSION: Viscocanalostomy combined with trabeculotomy and mitomycin C is useful in the management of primary congenital glaucoma. PMID- 28730084 TI - Analyzing cytokines as biomarkers to evaluate severity of glaucoma. AB - AIM: To analyze cytokines as biomarkers for evaluation of severity of glaucoma. METHODS: This was a prospective case-control study including 29 eyes with glaucoma. Besides, 28 eyes with senile cataract were used as control. Patients were classified into four groups: acute angle closure glaucoma (AACG), chronic angle closure glaucoma (CACG), primary open angle glaucoma (POAG) and senile cataract. Undiluted vitreous samples were collected, then vitreous concentrations of 9 types of cytokines were determined by cytometric bead assay system: gamma interferon (IFNg), interleukin (IL)-10, IL-2, IL-4, IL-5, interferon-gamma inducible protein (IP)-10, monocyte chemoattractant protein (MCP)-1, tumor necrosis factor (TNF)-alpha, and vascular endothelial growth factor (VEGF). We also recorded the intraocular pressure (IOP) of patients in each group and Pearson correlated analysis was performed to analysis the correlation between each type of cytokine with IOP. RESULTS: Vitreous levels of IL-2, IL-5, MCP-1, TNF-alpha and IP-10 were significantly higher (P<0.05) in AACG group. Patients with AACG, CACG and POAG have higher IOP than senile cataract, but we didn't find any significant correlation between IOP with any type of the cytokines. CONCLUSION: Inflammation and immune reaction have a strong link with the pathology of glaucoma especially AACG. Some cytokines may act as biomarkers to evaluate the severity of glaucoma. Anti-inflammatory treatments and controlling of IOP are necessary for the therapy of glaucoma. PMID- 28730085 TI - Ocular surface evaluation in eyes with chronic glaucoma on long term topical antiglaucoma therapy. AB - AIM: To evaluate ocular surface changes and its correlation with the central corneal subbasal nerve fibre layer in chronic glaucoma patients. METHODS: A prospective comparative study of ocular surface evaluation was performed in 50 eyes of 25 patients using two or more antiglaucoma medications for at least 6mo and 50 eyes of 25 normal subjects without any ocular problems as controls. The study parameters evaluated included visual acuity, intraocular pressure, ocular surface evaluation parameters [fluorescein break-up time (FTBUT), Schirmer's I test, ocular surface staining scores and ocular surface disease index score (OSDI)], central corneal sensation (Cochet Bonnett aesthesiometer), central subbasal nerve fiber layer density (SBNFLD) by confocal microscopy. RESULTS: The mean values in the glaucoma cases and control groups respectively were as follows: OSDI score (35.89+/-16.07/6.02+/-3.84; P=0.001), Schirmer's I test score (7.63+/-2.64 mm/12.86+/-1.93 mm; P=0.001), FTBUT (9.44+/-2.76s/11.8+/-1.88s; P=0.001), corneal (5.7+/-2.33/ 1.1+/-0.58; P=0.001) and conjunctival staining score (5.06+/-1.94/0.84+/-0.46; P=0.001), corneal sensitivity (4.68+/-0.44/5.07+/ 0.37; P=0.076), mean subbasal nerve fiber number (3.58+/-0.99/5.40+/-1.70; P=0.001), SBNFL length (1101.44+/-287.56 um/1963.70+/-562.56 um; P=0.001) and density (6883.94+/-1798.03 um/mm2/12 273.15+/-3516.04 um/mm2; P=0.001). Dry eye severity of level 2 and 3 was seen in 66% of glaucoma group. Corneal (R2=0.86) and conjunctival staining (R2=0.71) and OSDI score (R2=0.67) showed statistically significant negative correlation with central corneal SBNFLD while FTBUT (R2=0.84), corneal sensitivity (R2=0.52) showed positive correlation to central corneal SBNFLD in the long term topical antiglaucoma medication group. CONCLUSION: Ocular surface changes and antiglaucoma therapy induced dry eye is found to be associated with decreased SBNFLD in eyes on long term topical antiglaucoma medications. PMID- 28730086 TI - Peptidome profiling of human serum of uveal melanoma patients based on magnetic bead fractionation and mass spectrometry. AB - AIM: To find new biomarkers for uveal melanoma (UM) by analyzing the serum peptidome profile. METHODS: Proteomic spectra in patients with UM before and after operation were analyzed and compared with those of healthy controls. Magnetic affinity beads were used to capture serum peptides and matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometer were used to compile serum peptide profiles. RESULTS: A panel of 49 peptides were differentially expressed between UM patients and controls, of which 33 peptides were of higher intensities in patient group and 16 peptides were of higher intensities in control group. Based on combined use of these potential markers, peptides with mean molecular masses of 1467 and 9289.0 Da provide high sensitivity (83.3%), specificity (100%) and accuracy rate (93.0%) together to differentiate melanoma patients from healthy controls. At the time point of 6mo postoperatively, the levels of many peptides differentially expressed before surgery showed no more statistical difference between the patients and the control group. Fibrinogen alpha-chain precursors were identified as potential UM markers. CONCLUSION: We have shown that a convenient and fast proteomic technique, affinity bead separation and MALDI-TOF analysis combined with bioinformatic software, facilitates the identification of novel biomarkers for UM. PMID- 28730087 TI - Frequency of diabetic retinopathy and associated risk factors in Khartoum, Sudan: population based study. AB - AIM: To assess the frequency and associated risk factors of diabetic retinopathy among Sudanese individuals with diabetes attending Makka Eye complex in Khartoum, Sudan. METHODS: The cross sectional hospital based study recruited 316 individuals with diabetes from Makkah Eye Complex Retina Clinic. Standard questionnaire was used to collect demographic data, medical history and life style characteristics. Blood samples were taken to measure HbA1c and lipid profile. Fundus and slit lamp examination were performed for screening of diabetic retinopathy. RESULTS: Among 316 participants, 187 (59.2%) were males and 129 (40.8%) were females. The mean age of participants was 58.7+/-10.5y. The overall frequency of retinopathy was 261 (82.6%). The percentages of the total participants with proliferative diabetic retinopathy (PDR) were 126 (39.9%) and non-proliferative diabetic retinopathy (NPDR) were 135 (42.7%). Importantly, duration of diabetes mellitus (DM) (72.2% of more than 10y), being on oral hypoglycaemic drugs (versus insulin), and hypertension were all significant risk factors for diabetic retinopathy (P=0.00, 0.01 and 0.00 respectively). Complications of diabetes like diabetic foot (17.7%), history of amputation (6.7%) and clinically significant macular edema (CSME) (47.4%) of the eyes were all significant risk factors (P<0.05). Logistic regression analysis showed that duration of diabetes, hypertension and CSME were found to be absolute risk factors (P=0.007, 0.003 and 0.000 respectively). Duration of DM of more than 10y have more than double risk (OR=2.8), while having hypertension triples the risk of retinopathy (OR=3.1). CONCLUSION: High rates of diabetic retinopathy are noted among individuals with diabetes attending Makkah Eye hospital in capital Khartoum. Urgent strategies are needed to monitor and treat hypertension and optimize diabetes control in individuals with diabetes. More investment in diabetes services is urgently needed. PMID- 28730088 TI - Effect of even and odd-order aberrations on the accommodation response. AB - AIM: To investigate the potential effect that odd and even-order monochromatic aberrations may have on the accommodation response of the human eye. METHODS: Eight healthy subjects with astigmatism below 1 D, best corrected visual acuity 20/20 or better and normal findings in an ophthalmic examination were enrolled. An adaptive optics system was used in order to measure the accommodation response of the subjects' eyes under different conditions: with the natural aberrations being present, and with the odd and even-order aberrations being corrected. Three measurements of accommodation response were monocularly acquired at accommodation demands ranging from 0 to 4 D (0.5 D step). RESULTS: The accommodative lag was greater for the accommodative demands of 1.5, 3, 3.5 and 4 D for the condition in which the even-order aberrations were corrected, in comparison to that obtained for the natural aberrations and corrected odd-order aberrations for the same accommodation demands. No statistically significant differences were found between the accommodation responses under the three conditions. CONCLUSION: The odd and even-order aberrations are not helping the visual system to accommodate, because their partial correction do not affect the accommodation performance. PMID- 28730090 TI - Critical pathway for primary open angle glaucoma diagnosis. AB - AIM: To develop a critical pathway for primary open angle glaucoma (POAG) diagnosis intended to be efficient, to unify criteria, reduce resource use and minimize costs to the health system. METHODS: We performed a systematic search on PubMed, Cochrane, Embase and ClinicalTrials.org databases and classified the quality of evidence from level I through III. RESULTS: A critical pathway was designed by setting a key-decision step by step model on the basis of the best current evidence. CONCLUSION: A critical pathway, evidence-based guideline, may be a useful tool intended to reduce costs while maintaining or even improving the quality of care for diagnosing a highly prevalent pathology such as open angle glaucoma. PMID- 28730089 TI - An international survey of classification and treatment choices for group D retinoblastoma. AB - AIM: To determine which IIRC scheme was used by retinoblastoma centers worldwide and the percentage of D eyes treated primarily with enucleation versus globe salvaging therapies as well as to correlate trends in treatment choice to IIRC version used and geographic region. METHODS: An anonymized electronic survey was offered to 115 physicians at 39 retinoblastoma centers worldwide asking about IIRC classification schemes and treatment patterns used between 2008 and 2012. Participants were asked to record which version of the IIRC was used for classification, how many group D eyes were diagnosed, and how many eyes were treated with enucleation versus globe salvaging therapies. Averages of eyes per treatment modality were calculated and stratified by both IIRC version and geographic region. Statistical significance was determined by Chi-square, ANOVA and Kruskal-Wallis tests using Prism. RESULTS: The survey was completed by 29% of physicians invited to participate. Totally 1807 D eyes were diagnosed. Regarding IIRC system, 27% of centers used the Children's Hospital of Los Angeles (CHLA) version, 33% used the Children's Oncology Group (COG) version, 23% used the Philadelphia version, and 17% were unsure. The rate for primary enucleation varied between 0 and 100% and the mean was 29%. By IIRC version, primary enucleation rates were: Philadelphia, 8%; COG, 34%; and CHLA, 37%. By geographic region, primary enucleation rates were: Latin America, 57%; Asia, 40%; Europe, 36%; Africa, 10%, US, 8%; and Middle East, 8%. However, systemic chemoreduction was used more often than enucleation in all regions except Latin America with a mean of 57% per center (P<0.0001). CONCLUSION: Worldwide there is no consensus on which IIRC version is used, systemic chemoreduction was the most frequently used initial treatment during the study period followed by enucleation and primary treatment modality, especially enucleation, varied greatly with regards to IIRC version used and geographic region. PMID- 28730091 TI - Aberrant expression of genes and proteins in pterygium and their implications in the pathogenesis. AB - Pterygium is a common ocular surface disease induced by a variety of factors. The exact pathogenesis of pterygium remains unclear. Numbers of genes and proteins are discovered in pterygium and they function differently in the occurrence and development of this disease. We searched the Web of Science and PubMed throughout history for literatures about the subject. The keywords we used contain pterygium, gene, protein, angiogenesis, fibrosis, proliferation, inflammation, pathogenesis and therapy. In this review, we summarize the aberrant expression of a range of genes and proteins in pterygium compared with normal conjunctiva or cornea, including growth factors, matrix metalloproteinases and tissue inhibitors of metalloproteinases, interleukins, tumor suppressor genes, proliferation related proteins, apoptosis related proteins, cell adhesion molecules, extracellular matrix proteins, heat shock proteins and tight junction proteins. We illustrate their possible mechanisms in the pathogenesis of pterygium as well as the related intervention based on them for pterygium therapy. PMID- 28730092 TI - Parameters of ocular fundus on spectral-domain optical coherence tomography for glaucoma diagnosis. AB - In this review, we summarize the progression of several parameters assessed by spectral-domain optical coherence tomography (SD-OCT) in recent years for the detection of glaucoma. Monitoring the progression of defects in the retinal nerve fiber layer (RNFL) thickness is essential. Imaging and analysis of retinal ganglion cells (RGCs) and inner plexiform layer (IPL), respectively, have been of great importance. Optic nerve head (ONH) topography obtained from 3D SD-OCT images is another crucial step. Other important assessments involve locating the Bruch's membrane opening (BMO), estimating the optic disc size and rim area, and measuring the lamina cribrosa displacement. Still other parameters found in the past three years for glaucoma diagnosis comprise central retinal artery resistive index, optic disc perfusion in optical coherence tomography angiography (OCTA) study, peripapillary choroidal thickness, and choroidal area in SD-OCT. Recently, several more ocular fundus parameters have been found, and compared with the earlier parameters to judge the accuracy of diagnosis. While a few of these parameters have been widely used in clinical practice, a fair number are still in the experimental stage. PMID- 28730093 TI - A systematic review of pseudophakic monovision for presbyopia correction. AB - A systematic review of the recent literature regarding pseudophakic monovision as a reliable methods for presbyopia correction was performed based on the PubMed, MEDLINE, Nature and the American Academy of Ophthalmology databases in July 2015 and data from 18 descriptive and 12 comparative studies were included in this narrative review. Pseudophakic monosvision seems to be an effective method for presbyopia with high rates of spectacles independence and minimal dysphotopsia side-effects, that should be considered by the modern cataract surgeons. PMID- 28730094 TI - Organ transplantation scandal influencing corneal donation rate. AB - In the majority of countries, there is a shortage of donor corneas for corneal transplantations. This study investigated the impact of organ transplantation scandals on corneal donation rate at the University Hospital Tubingen. Each deceased patient was considered as a potential corneal donor. An ophthalmic resident handled with stable methods of procedures the corneal donor procurement from 2009 to 2015. The rates of corneal donation were examined and analyzed. Among the 5712 hospital deaths, consent for corneal donation was obtained in 711 cases. The mean annual corneal donation rate was 12.4%. Since 2009, the donation rate per year could be increased with exception of 2013 and 2015. In the end of 2012 and 2014 two huge organ donation scandals were known in Germany. In the following years 2013 and 2015 corneal donation rate decreased significantly (P=0.0181 and P=0.0006). We concluded that transplantation scandals have a significant impact on corneal donation rate. Improving professional's performance through full transparency and honesty is very important to earn trust of potential donors and their families. PMID- 28730095 TI - Comparison of surgically induced astigmatism among different surgeons performing the same incision. AB - To compare surgically induced astigmatism (SIA) of different surgeons, who perform the same main incision. Two hundred and seventy eyes underwent cataract surgery with phacoemulsification by four different surgeons (A, B, C, and D). A 3 step, 3.0 mm, superotemporal for the right eye and superonasal for the left eye clear corneal incision was performed. A comparison in SIA among A, B, C and D surgeon was made. No significant difference was found in SIA at both first and sixth postoperative month between different surgeons (P>0.05). SIA is more dependent on incisional characteristics and preoperative astigmatism and less on the surgeon. PMID- 28730096 TI - Retinal detachment repair through multifocal intraocular lens- overcoming visualization challenge of the peripheral retina. PMID- 28730097 TI - Recurrence of keratoconus after deep anterior lamellar keratoplasty following pregnancy. PMID- 28730098 TI - A case of hypermature cataract formation following implantation of an implantable collamer lens with an Aquaport. PMID- 28730099 TI - Hallermann-Streiff syndrome with bilateral microphthalmia, pupillary membranes and cataract absorption. PMID- 28730100 TI - Retinal injury following intravitreal injection of a dexamethasone implant in a vitrectomized eye. PMID- 28730101 TI - Comparative analysis of different feeder layers with 3T3 fibroblasts for culturing rabbits limbal stem cells. AB - AIM: To explore the possibility of human umbilical cord mesenchymal stem cells (hUCMSCs), human umbilical vein endothelial cells (hUVECs), human dental pulp stem cells (hDPSCs) and human periodontal ligament stem cells (hPDLSCs) serving as feeder cells in co-culture systems for the cultivation of limbal stem cells. METHODS: Different feeder layers were cultured in Dulbecco's modified Eagle's medium (DMEM)/F12 and were treated with mitomycin C. Rabbits limbal stem cells (LSCs) were co-cultured on hUCMSCs, hUVECs, hDPSCs, hPDLSCs and NIH-3T3, and then comparative analysis were made between each group to see their respective colony forming efficiency (CFE) assay and immunofluorescence (IPO13,CK3/12). RESULTS: The efficiency of the four type cells in supporting the LSCs morphology and its cellular differentiation was similar to that of NIH-3T3 fibroblasts as demonstrated by the immunostaining properties analysis, with each group exhibiting a similar strong expression pattern of IPO13, but lacking CK3 and CK12 expression in terms of immunostaining. But hUCMSCs, hDPSCs and hPDLSCs feeder layers were superior in promoting colony formation potential of cells when compared to hUVECs and feeder-cell-free culture. CONCLUSION: hUCMSCs, hDPSCs and hPDLSCs can be a suitable alternative to conventional mouse NIH-3T3 feeder cells, so that risk of zoonotic infection can be diminished. PMID- 28730102 TI - Anti-scarring effects of butaprost on human subconjunctival Tenon's fibroblasts. AB - AIM: To investigate the toxicity of the E-prostanoid 2 (EP2) receptor agonist, butaprost against human subconjunctival (Tenon's capsule) fibroblasts, and to determine the underlying mechanism. METHODS: We isolated Tenon's fibroblasts from the subconjunctival area of healthy subjects and evaluated the types of EP receptors expressed using quantitative real-time reverse transcription polymerase chain reaction (RT-PCR). The toxicity of butaprost against the fibroblasts was evaluated using methyl thiazolyl tetrazolium and lactic dehydrogenase assays. The inhibition of conjunctival fibroblast proliferation by butaprost was assessed by measuring alpha-actin levels. The underlying mechanism was assessed by measuring intracellular cyclic adenosine monophosphate (cAMP) levels. Intergroup differences were statistically analyzed using an independent t-test. Densitometry of the Western blot bands was performed using the Image J software. RESULTS: Quantitative real-time RT-PCR revealed that the fibroblast EP2 receptor levels were higher than those of the other EP receptors. Butaprost did not show toxicity against Tenon's tissue, but inhibited conjunctival fibroblast proliferation by reducing collagen synthesis. EP2 receptor activation enhanced the cAMP cascade, which might be an important mechanism underlying this effect. CONCLUSION: Butaprost effectively reduces the subconjunctival scarring response. Given the significance of wound healing modulation in blebs, butaprost's inhibitory effect on subconjunctival Tenon's fibroblasts may be beneficial in managing postoperative scarring in glaucoma surgery. PMID- 28730103 TI - Expressions of TGF-beta2, bFGF and ICAM-1 in lens epithelial cells of complicated cataract with silicone oil tamponade. AB - AIM: To investigate the expression differences of transforming growth factor beta2 (TGF-beta2), basic fibroblast growth factor (bFGF) and intercellular cell adhesion molecule-1 (ICAM-1) in lens epithelial cells (LECs) of complicated cataract with silicone oil tamponade and age-related cataract. METHODS: Totally 150 eyes of 150 patients (aged 35 to 77y) were investigated, including 75 patients with complicated cataract after silicone oil tamponade and 75 patients with age-related cataract. The central piece of anterior capsules was collected during cataract surgery. TGF-beta2, bFGF and ICAM-1 were detected in the 60 specimens of the two groups by immunohistochemistry. The expression levels of the three kinds of messenger ribonucleic acid (mRNA) were determined by real-time quantitative reverse transcription-polymerase chain reaction in the 90 specimens of the two groups. RESULTS: TGF-beta2 was detected in the cytomembrane and cytoplasm of the LECs and bFGF was detected in the nucleus. ICAM-1 was positive in the cytomembrane of the LECs and the distribution of positive cells was uneven. The mRNA genes expression of the TGF-beta2, bFGF and ICAM-1 was significant differences between the two groups and markedly increased in complicated cataract group (P<0.05). CONCLUSION: The up-regulated TGF-beta2, bFGF and ICAM-1 maybe associate with the occurrence and development of complicated cataract with silicone oil tamponade. PMID- 28730104 TI - Down-regulation of protein kinase C alpha/ezrin signals in light-induced phagocytic crisis of retinal pigment epithelium cells. AB - AIM: To investigate the roles of PKC-alpha/ezrin signals in phagocytosis crisis of retinal pigment epithelium (RPE) cells in light damage model. METHODS: Light induced mice RPE injury model was established by continuously irradiating cool white light at different exposure time (0, 4, 8h light intensity: 4.18*10-6 J/cm2). In vitro, human ARPE-19 cells treated with the doses and intensity (1.57*10-6 J/cm2) of laser irradiation. Histology analysis was evaluated by hematoxylin and eosin (HE) staining. In vivo RPE phagocytosis was quantified by measuring the accumulation of photoreceptor outer segments in the sub-retinal space. In vitro RPE phagocytosis was assessed by calculating the relative fluorescence intensity of FITC-labeled microspheres in ARPE-19 cells. To further investigate the molecular mechanism, the activation of PKC-alpha/ezrin signal was evaluated by Western blot in vivo and in vitro. RESULTS: HE staining revealed that the thickness of outer nuclear layer decreased significantly after 4 and 8h light exposure. By immunostaining with rhodopsin, a significant greater accumulation of photoreceptor outer segment was noticed after light injury. In vitro, light injured RPE cells had less phagocytic activity in a dose dependent manner than that of the normal control (P<0.01). Western blot suggested the activation of PKC-alpha/ezrin signaling was down-regulated in a dose-dependent manner after light exposure. CONCLUSION: Our data suggest that light induced phagocytic crisis of RPE cells may result from the down-regulation of PKC alpha/ezrin signaling. PMID- 28730105 TI - Pigment epithelium-derived factor protects retinal ganglion cells from hypoxia induced apoptosis by preventing mitochondrial dysfunction. AB - AIM: To investigate the potential of pigment epithelium-derived factor (PEDF) to protect the immortalized rat retinal ganglion cells-5 (RGC-5) exposed to CoCl2 induced chemical hypoxia. METHODS: After being differentiated with staurosporine (SS), RGC-5 cells were cultured in four conditions: control group cells cultured in Dulbecco's modified eagle medium (DMEM) supplemented with 10% fetal bovine serum, 100 umol/mL streptomycin and penicillin (named as normal conditions); hypoxia group cells cultured in DMEM containing 300 umol/mL CoCl2; cells in the group protected by PEDF were first pretreated with 100 ng/mL PEDF for 2h and then cultured in the same condition as hypoxia group cells; and PEDF group cells that were cultured in the presence of 100 ng/mL PEDF under normal conditions. The cell viability was assessed by MTT assay, the percentage of apoptotic cells was quantified using Annexin V-FITC apoptosis kit, and intra-cellar reactive oxygen species (ROS) was measured by dichloro-dihydro-fluorescein diacetate (DCFH-DA) probe. The mitochondria-mediated apoptosis was also examined to further study the underlying mechanism of the protective effect of PEDF. The opening of mitochondrial permeability transition pores (mPTPs) and membrane potential (Deltapsim) were tested as cellular adenosine triphosphate (ATP) level and glutathione (GSH). Also, the expression and distribution of Cyt C and apoptosis inducing factor (AIF) were observed. RESULTS: SS induced differentiation of RGC-5 cells resulting in elongation of their neurites and establishing contacts between outgrowths. Exposure to 300 umol/mL CoCl2 triggered death of 30% of the total cells in cultures within 24h. At the same time, pretreatment with 100 ng/mL PEDF significantly suppressed the cell death induced by hypoxia (P<0.05). The apoptosis induced by treatment of CoCl2 was that induced cell death accompanied with increasing intra-cellar ROS and decreasing GSH and ATP level. PEDF pre treatment suppressed these effects (P<0.05). Additionally, PEDF treatment inhibited the opening of mPTPs and suppressed decreasing of Deltapsim in RGC-5 cells, resulting in blocking of the mitochondrial apoptotic pathway. CONCLUSION: Pretreatment of RGC-5 cells with 100 ng/mL PEDF significantly decreases the extent of apoptosis. PEDF inhibits the opening of mPTPs and suppresses decreasing of Deltapsim. Moreover, PEDF also reduces ROS production and inhibits cellular ATP level's reduction. Cyt C and AIF activation in PEDF-pretreated cultures are also reduced. These results demonstrate the potential for PEDF to protect RGCs against hypoxic damage in vitro by preventing mitochondrial dysfunction. PMID- 28730106 TI - Mitochondrial expression and activity of P-glycoprotein under oxidative stress in outer blood-retinal barrier. AB - AIM: To investigate the role of oxidative stress in regulating the functional expression of P-glycoprotein (P-gp) in mitochondria of D407 cells. METHODS: D407 cells were exposed to different ranges of concentrations of H2O2. The mitochondrial location of P-gp in the cells subjected to oxidative stress was detected by confocal analysis. Expression of P-gp in isolated mitochondria was assessed by Western blot. The pump activity of P-gp was evaluated by performing the efflux study on isolated mitochondria with Rhodamine 123 (Rho-123) alone and in the presence of P-gp inhibitor (Tariquidar) using flow cytometry analysis. The cells were pretreated with 10 mmol/L N-acetylcysteine (NAC) for 30min before exposing to H2O2, and analyzed the mitochondrial extracts by Western blot and flow cytometry. RESULTS: P-gp was co-localized in the mitochondria by confocal laser scanning microscopy, and it was also detected in the mitochondria of D407 cells using Western blot. Exposure to increasing concentrations of H2O2 led to gradually increased expression and location of P-gp in the mitochondria of cells. Rho-123 efflux assay showed higher uptake of Rho-123 on isolated mitochondria in the presence of Tariquidar both in normal and oxidative stress state. H2O2 up regulated P-gp in D407 cells, which could be reversed by NAC treatment. CONCLUSION: H2O2 could up-regulate the functional expression of P-gp in mitochondria of D407 cells, while antioxidants might suppress oxidative-stress induced over-expression of functional P-gp. It is indicative that limiting the mitochondrial P-gp transport in retinal pigment epithelium cells would be to improve the effect of mitochondria-targeted antioxidant therapy in age-related macular degeneration-like retinopathy. PMID- 28730107 TI - Induction of vascular endothelial growth factor receptor expression in human umbilical vein endothelial cells after repeated bevacizumab treatment in vitro. AB - AIM: To investigate the mechanism underlying the loss of responsiveness to anti vascular endothelial growth factor (VEGF) treatment after repeated injections for choroidal neovascularization, VEGF and VEGF receptor (VEGFR) expressions were evaluated following repeated bevacizumab treatments in hypoxic human umbilical vein endothelial cells (HUVECs) in vitro. METHODS: HUVECs were incubated under hypoxic conditions in two media of different bevacizumab concentrations (1.0 or 2.5 mg/mL) for 17h, and then in a new medium without bevacizumab for 7h. This procedure was repeated twice more. A culture with an identical volume of excipients served as the control. Cytotoxicity and cell proliferation were assessed using 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide and Ki-67 assays, respectively. Levels of VEGF and VEGFR were assessed using enzyme linked immunosorbent assay and Western blot respectively. RESULTS: Cytotoxic effects were not reported for either bevacizumab concentration. Cell proliferation was not reduced after anti-VEGF treatments. VEGF level after single treatment was significantly higher than that of the control and after repeated treatments. Phosphorylated VEGFR-2 expression increased significantly after single and repeated bevacizumab treatments compared with the control. The 1.0 mg/mL bevacizumab induced significantly higher expressions of VEGFR-2 than the 2.5 mg/mL in single and repeated treatment groups. CONCLUSION: Bevacizumab treatment of HUVECs elevated VEGFR expression in both single and repeated treatments, indicating a mechanism for the reduced efficacy of anti-VEGF therapy in ocular neovascular disorders. PMID- 28730108 TI - Transfer of single dose of intravitreal injection of ranibizumab and bevacizumab into milk of sheep. AB - AIM: To investigate whether single-dose intravitreal injections of bevacizumab and ranibizumab transfer into milk. METHODS: This study included lactating 12 sheep and a single 3-month old suckling lamb of each sheep. Two groups consisting of 6 sheep and their lambs were constituted; the ranibizumab group and the bevacizumab group before the administration of intravitreal injections, blood and milk samples were obtained from all sheep and, following the injections, blood and milk samples of all sheep and blood samples of all lambs were collected at regular time points. Serum and milk concentrations of bevacizumab and ranibizumab were measured using an enzyme-linked immunosorbent assay (ELISA) kit. The limit of determination was 0.9 ng/mL for bevacizumab and 0.62 ng/mL for ranibizumab. RESULTS: At 6h after intravitreal injections, bevacizumab concentration was above the limit of determination in the blood of all sheep. At 3wk, when the study was terminated, bevacizumab concentrations were high in 4 sheep. Even though bevacizumab concentrations in milk showed fluctuations, the drug transferred into the milk of all sheep at detectable concentrations. Ranibizumab drug concentrations in the blood and milk of sheep and those in the blood of lambs were below the limit of determination by the ELISA kit. CONCLUSION: This sheep model study demonstrate that intravitreal injection of ranibizumab, which did not transfer into the milk of sheep and suckling lambs, is safer than bevacizumab during lactation period. PMID- 28730109 TI - Human eye ocular component analysis for refractive state and refractive surgery. AB - AIM: To analyze the clinical factors influencing the human vision corrections via the changing of ocular components of human eye in various applications; and to analyze refractive state via a new effective axial length. METHODS: An effective eye model was introduced by the ocular components of human eye including refractive indexes, surface radius (r1, r2, R1, R2) and thickness (t, T) of the cornea and lens, the anterior chamber depth (S1) and the vitreous length (S2). Gaussian optics was used to calculate the change rate of refractive error per unit amount of ocular components of a human eye (the rate function M). A new criterion of myopia was presented via an effective axial length. RESULTS: For typical corneal and lens power of 42 and 21.9 diopters, the rate function Mj (j=1 to 6) were calculated for a 1% change of r1, r2, R1, R2, t, T (in diopters) M1=+0.485, M2=-0.063, M3=+0.053, M4=+0.091, M5=+0.012, and M6=-0.021 diopters. For 1.0 mm increase of S1 and S2, the rate functions were M7=+1.35, and M8=-2.67 diopter/mm, respectively. These rate functions were used to analyze the clinical outcomes in various applications including laser in situ keratomileusis surgery, corneal cross linking procedure, femtosecond laser surgery and scleral ablation for accommodation. CONCLUSION: Using Gaussian optics, analytic formulas are presented for the change of refractive power due to various ocular parameter changes. These formulas provide useful clinical guidance in refractive surgery and other related procedures. PMID- 28730111 TI - Cumulative sum analysis score and phacoemulsification competency learning curve. AB - AIM: To use the cumulative sum analysis score (CUSUM) to construct objectively the learning curve of phacoemulsification competency. METHODS: Three second-year residents and an experienced consultant were monitored for a series of 70 phacoemulsification cases each and had their series analysed by CUSUM regarding posterior capsule rupture (PCR) and best-corrected visual acuity. The acceptable rate for PCR was <5% (lower limit h) and the unacceptable rate was >10% (upper limit h). The acceptable rate for best-corrected visual acuity worse than 20/40 was <10% (lower limit h) and the unacceptable rate was >20% (upper limit h). The area between lower limit h and upper limit h is called the decision interval. RESULTS: There was no statistically significant difference in the mean age, sex or cataract grades between groups. The first trainee achieved PCR CUSUM competency at his 22nd case. His best-corrected visual acuity CUSUM was in the decision interval from his third case and stayed there until the end, never reaching competency. The second trainee achieved PCR CUSUM competency at his 39th case. He could reach best-corrected visual acuity CUSUM competency at his 22nd case. The third trainee achieved PCR CUSUM competency at his 41st case. He reached best-corrected visual acuity CUSUM competency at his 14th case. CONCLUSION: The learning curve of competency in phacoemulsification is constructed by CUSUM and in average took 38 cases for each trainee to achieve it. PMID- 28730110 TI - Incidence of cystoid macular edema after Descemet's stripping automated endothelial keratoplasty. AB - AIM: To determine the incidence of cystoid macular edema (CME) after Descemet's stripping automated endothelial keratoplasty (DSAEK). METHODS: This study included all consecutive patients operated in a Spanish tertiary reference hospital over a period of four years. A total of 55 eyes from 47 patients matched the selection criteria. CME was diagnosed clinically at the slit-lamp and confirmed by optical coherence tomography. RESULTS: Six cases of CME were diagnosed postoperatively, which represented an incidence of 11%. Three patients had previously undergone DSAEK alone (7%; 3/41) and the other three, DSAEK combined with phacoemulsification (21%; 3/14). Five out of six patients with CME responded to standard therapy. CONCLUSION: CME is a possible complication after DSAEK and can be treated with standard therapy. CME appears more frequently when DSAEK is combined with phacoemulsification and posterior chamber (PC) intraocular lens (IOL) implantation. Intraoperative damage to the corneal endothelial cells might play a role in the pathogenesis of CME. As long as the causes remain unclear, we recommend administering prophylaxis when risk factors are present or when combined surgery is planned. PMID- 28730112 TI - Evaluation of antioxidants and argpyrimidine in normal and cataractous lenses in north Indian population. AB - AIM: To assess the level of glutathione, thioltransferase, and argpyrimidine in nuclear and cortical cataractous lenses as well as in the clear lenses in the north Indian population. METHODS: Human cataractous lenses were collected from the patients who underwent extracapsular cataract extraction surgery; clear lenses were collected from the freshly donated eye bank eyes. Antioxidant molecules such as glutathione and thioltransferase enzyme activity were measured; simultaneously in these lenses a blue fluorophore argpyrimidine, an advanced glycation end (AGE) product level was assessed using high performance liquid chromatography (HPLC). RESULTS: The protein concentration was found to be present at higher levels in the control lenses compared to cataract lenses. A significant decrease in the glutathione level was observed in the nuclear cataractous lenses compared to cortical cataractous (P=0.004) and clear lenses (P<=0.005), but no significant change in the level of antioxidant enzyme thioltransferase was observed. Further, argpyrimidine a blue fluorophore (AGE) was found to be significantly higher in the nuclear cataract (P=0.013) compared to cortical cataract lenses. CONCLUSION: Antioxidants such as glutathione significantly decrease in age-related nuclear and cortical cataract and an AGE, argpyrimidine are present at significantly higher levels in nuclear cataract. PMID- 28730113 TI - Increased aquaporin-1 levels in lens epithelial cells with primary angle-closure glaucoma. AB - AIM: To determine the levels of aquaporin-1 (AQP-1) in the lens epithelial cells (LECs) of primary glaucoma and to clarify its correlation with lens thickness. METHODS: This study comprised 64 eyes of 64 patients with primary glaucoma, who were divided into 3 groups: 25 eyes of 25 patients with acute primary angle closure glaucoma (APACG), 19 eyes of 19 patients with chronic primary angle closure glaucoma (CPACG) and 20 eyes of 20 patients with primary open angle glaucoma (POAG). This study also included 12 eyes of 12 patients with senile cataract as controls. The levels of AQP-1 in LECs were examined by real-time quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry. The lens thickness was measured by A-scan ultrasonography. RESULTS: The AQP-1 mRNA levels of LECs were 0.84+/-0.27, 0.69+/-0.34, 0.44+/-0.19 and 0.51+/-0.21 in APACG, CPACG, POAG and senile cataract group, respectively. The levels of AQP-1m RNA were significantly higher in PACG groups compared with those in senile cataract and POAG group (all P<0.05). The immunohistochemistry showed the AQP-1 expression were strong-positive in PACG groups, but weak-positive in senile cataract and POAG group. A positive correlation was found between AQP-1 mRNA levels and the lens thickness (r=0.645, P<0.001). CONCLUSION: These findings show that the higher expression of AQP-1 in LECs may contribute to increased lens thickness, which might be associated with the occurrence and development of PACG. PMID- 28730114 TI - Diagnostic capability of peripapillary retinal nerve fiber layer parameters in time-domain versus spectral-domain optical coherence tomography for assessing glaucoma in high myopia. AB - AIM: To evaluate and compare the diagnostic capabilities of peripapillary retinal nerve fiber layer (p-RNFL) parameters of Spectralis optical coherence tomography (OCT) versus Stratus OCT to detect glaucoma in patients with high myopia. METHODS: This is a retrospective, cross-sectional study. Sixty highly myopic eyes of 60 patients were enrolled, with 30 eyes in the glaucoma group and 30 eyes in the control group. All eyes received peripapillary imaging of the optic disc using Stratus and Spectralis OCT. Areas under the receiver operating characteristic curve (AUROC) and the sensitivity at specificity of >80% and >95% for p-RNFL parameters obtained using the two devices to diagnose glaucoma were analysed and compared. RESULTS: In Spectralis OCT, p-RNFL thickness parameters with the largest AUROC were the temporal-inferior sector (0.974) and the inferior quadrant (0.951), whereas in Stratus OCT, the best parameters were the 7-o'clock sector (0.918) and the inferior quadrant (0.918). Compared to the Stratus OCT parameters, the Spectralis OCT parameters demonstrated generally higher AUROC; however, the difference was not statistically significant. CONCLUSION: The best p RNFL parameters for diagnosing glaucoma in patients with high myopia were the temporal-inferior sector on Spectralis OCT and the 7-o'clock sector on Stratus OCT. There were no significant differences between the AUROCs for Spectralis OCT and Stratus OCT, which suggest that the glaucoma diagnostic capabilities of these two devices in patients with high myopia are similar. PMID- 28730115 TI - Diabetic macular edema in proliferative stage treated with anti-vascular endothelial growth factor agent and triamcinolone acetonide by laser-based strategies. AB - AIM: To appraise the effect of treatment for diabetic macular edema (DME) in proliferative stage with sufficient panrentinal photocoagulation (PRP) therapy and intravitreal injections (IV) Conbercept and posterior subtenon's triamcinolone acetonide (STTA) sequential therapy. METHODS: This prospective clinical randomized controlled trial of cross-over design was conducted in three phases. The participants included cases of DME in proliferative stage. They were divided into two groups and treated with PRP before enrollment. Group A were treated with IV-Conbercept 0.5 mg for one month in the 1st phase. Group B were treated with STTA 40 mg (twice per two weeks). The interventions were exchanged in the second phase (2mo) between the two groups. In the third phase (3-6mo) no other treatment was given. Best corrected visual acuity (BCVA), central macular thickness (CMT) measured by OCT and complications were compared. RESULTS: After phase I: in Group A, BCVA improved from 0.201+/-0.17 to 0.37+/-0.24 (F=5.88, P=0.004). CMT changed from 449+/-155.10 to 304.1+/-84.70 um (F=14.9, P<0.01). In Group B, BCVA changed from 0.195+/-0.19 to 0.26+/-0.20 (F=0.76, P=0.41) while CMT changed from 463.82+/-152.92 to 366.00+/-115.40 um (F=3.70, P<0.03). The improvement of BCVA was better in Group A (P<0.05). After phase II: in Group A, BCVA raised to 0.47+/-0.27 (F=0.26, P<0.01), CMT reduced to 260.67+/-62.97 um (F= 188.3, P<0.01); in Group B, BCVA raised to 0.51+/-0.26 (F=0.31, P<0.01), CMT reduced to 261.93+/-50.15 um (F=-201.9, P<0.01). But there were no difference between two groups (P>0.05). After phase III: in Group A, BCVA maintained 0.42+/ 0.25 (F=0.22, P=0.001), CMT maintained 267.8+/-58.34 um, (F=-0.27, P<0.01); in Group B, BCVA was 0.47+/-0.25 (F=-0.27, P<0.01), CMT was 272.71+/-49.16 um (F= 191.1, P<0.01). No serious complications happened in all phases. CONCLUSION: PRP+Conbercept is better than PRP+STTA in DME with proliferative stage but PRP+Conbercept+STTA sequential therapy may be a wiser choice for persistent effectiveness on anatomical as well as functional status. PMID- 28730116 TI - Factors affecting residual exotropia after two muscle surgery for intermittent exotropia. AB - AIM: To study the factors affecting residual exotropia (>10 PD) at 4-6wk postoperative visit following two rectus muscle surgery for intermittent exotropia [bilateral lateral rectus (LR) recession or unilateral recess resect procedure]. METHODS: A retrospective chart review of patients with intermittent exotropia <=50 PD who underwent two rectus muscle surgery in between Jan. 2011 to Dec. 2013 was performed. Possible factors were compared between patients with residual exotropia (>10 PD) and successful outcome (within 10 PD of orthotropia) at the 4-6wk postoperative visit. Effect/dose ratio was calculated by dividing the effect of surgery by the total amount (mm) of muscle surgery done. RESULTS: One hundred and fifty-seven patients with mean age of 14y (range 3-53y) were included. Twenty-seven patients (17.2%) had residual exotropia at 4-6wk postoperative follow up. Age at surgery (P=0.009) and preoperative deviation for distance (P<=0.001) and near (P=0.001) were identified as important predictors of unsuccessful outcome. The occurrence of residual exotropia was not affected by amblyopia, anisometropia, lateral incomitance, pattern deviation, vertical deviation, type of exotropia or type of surgery done (recess-resect or bilateral LR recession). The effect/dose ratio was more in deviations >40 PD in the both recess-resect and bilateral LR recession type of surgery. The effect/dose ratio was less in patients with residual exotropia as compared to the successful outcome group (1.36 PD/mm vs 2.05 PD/mm in the bilateral LR recession surgery and 1.93 PD/mm vs 2.63 PD/mm in the unilateral recess-resect surgery). CONCLUSION: Residual exotropia is seen in 17% of patients after two muscle surgery for intermittent exotropia. Patients with older age and larger preoperative deviation have greater chances of developing failure of two muscle strabismus surgery for intermittent exotropia. PMID- 28730117 TI - Bevacizumab as adjuvant therapy in the management of pterygium: a systematic review and Meta-analysis. AB - AIM: To evaluate the clinical effect of bevacizumab in pterygium treatment. METHODS: A systematic review and quantitative Meta-analysis was performed. PubMed, EMBASE, Web of Science and Cochrane database were searched for eligible literatures published in English until June 2016. The endpoint was recurrence rate and pooled risk ratio (RR) was calculated. RESULTS: Nine eligible studies were included and Meta-analysis results showed no significantly difference in patients treated with bevacizumab in short term follow-up [3mo: RR=0.70 (0.34, 1.45); 6mo: RR=0.55 (0.23, 1.32)] compared with control groups. No significant effects were observed in favor of bevacizumab in subgroup analyses: patients with subconjunctival injection of bevacizumab [3mo: RR=0.95 (0.70, 1.29); 6mo: RR=0.83 (0.55, 1.28)], primary pterygium [3mo: RR=0.59 (0.23, 1.54; 6mo: RR=0.59 (0.23, 1.53)], simple pterygium excision [3mo: 0.32 (0.05, 2.04), P=0.23; 6mo: 0.27 (0.05, 1.53)] and excision with conjunctival autograft [3mo: 1.51 (0.25, 9.15); 6mo: 1.11 (0.06, 21.69)]. CONCLUSION: In this Meta-analysis, we did not found the significant effect of bevacizumab in pterygium treatment, at least in short term follow-up (3mo and 6mo). PMID- 28730118 TI - Efficiency and safety of laser photocoagulation with or without intravitreal ranibizumab for treatment of diabetic macular edema: a systematic review and Meta analysis. AB - AIM: To compare the therapeutic effect and safety of laser photocoagulation along with intravitreal ranibizumab (IVR) versus laser therapy in treatment of diabetic macular edema (DME). METHODS: Pertinent publications were identified through comprehensive searches of PubMed, EMBASE, Web of Science, Cochrane Library, and ClinicalTrials.gov to identify randomized clinical trials (RCTs) comparing IVR+laser to laser monotherapy in patients with DME. Therapeutic effect estimates were determined by weighted mean differences (WMD) of change from baseline in best corrected visual acuity (BCVA) and central retinal thickness (CRT) at 6, 12, or 24mo after initial treatment, and the risk ratios (RR) for the proportions of patients with at least 10 letters of improvement or reduction at 12mo. Data regarding major ocular and nonocular adverse events (AEs) were collected and analyzed. The Review Manager 5.3.5 was used. RESULTS: Six RCTs involving 2069 patients with DME were selected for this Meta-analysis. The results showed that IVR+laser significantly improved BCVA compared with laser at 6mo (WMD: 6.57; 95% CI: 4.37-8.77; P<0.00001), 12mo (WMD: 5.46; 95% CI: 4.35-6.58; P<0.00001), and 24mo (WMD: 3.42; 95% CI: 0.84-5.99; P=0.009) in patients with DME. IVR+laser was superior to laser in reducing CRT at 12mo from baseline with statistical significance (WMD: -63.46; 95% CI: -101.19 to -25.73; P=0.001). The pooled RR results showed that the proportions of patients with at least 10 letters of improvement or reduction were in favor of IVR+laser arms compared with laser (RR: 2.13; 95% CI: 1.77-2.57; P<0.00001 and RR: 0.37; 95% CI: 0.22-0.62; P=0.0002, respectively). As for AEs, the pooled results showed that a significantly higher proportion of patients suffering from conjunctival hemorrhage (study eye) and diabetic retinal edema (fellow eye) in IVR+laser group compared to laser group (RR: 3.29; 95% CI: 1.53-7.09; P=0.002 and RR: 3.02; 95% CI: 1.24-7.32; P=0.01, respectively). The incidence of other ocular and nonocular AEs considered in this Meta-analysis had no statistical difference between IVR+laser and laser alone. CONCLUSION: The results of our analysis show that IVR+laser has better availability in functional (improving BCVA) and anatomic (reducing CRT) outcomes than laser monotherapy for the treatment of DME. However, the patients who received the treatment of IVR+laser may get a higher risk of suffering from conjunctival hemorrhage (study eye) and diabetic retinal edema (fellow eye). PMID- 28730120 TI - Retraction Notice. AB - [This retracts the article DOI: 10.3980/j.issn.2222-3959.2015.01.27.]. PMID- 28730119 TI - Predictors for attending annual eye screening for diabetic retinopathy amongst patients with diabetes in an urban community of Beijing. AB - AIM: To gain a better understanding of possible factors that may influence the decision of diabetes persons to participate in annual eye screening in an urban community setting of China. METHODS: A structured interview including questions on attendance of eye screening, knowledge and awareness of diabetic retinopathy was conducted. The presence and degree of retinopathy were assessed using two field non-mydriatic retinal photography. RESULTS: Totally 720 diabetes persons were recruited and 519 were enrolled in this cross-sectional study. In this urban setting of Beijing, among diabetes patients of average of 10y duration, 77% confirmed having undergone at least one eye examination and 61% reported having at least one eye examination with dilated pupil. As for the last 12mo, the number decreased to 210 (47%) and 131 (30%) separately. Most of the participants (95%) were aware that diabetes could affect their vision and that regular eye examination was necessary. Very few of them (12%) however were aware that the early stages of diabetic retinopathy presented without symptoms of vision loss. Having attended patient education on diabetes was effective in building awareness about diabetic eye disease and was a significant positive predictor for attending eye screening [education in a year, Adj. OR=0.47 (0.29-0.74), P<0.001, education years ago, Adj. OR=0.56 (0.33-0.96), P=0.036]. The duration of disease also increased the likelihood of having undergone eye screening (Adj. OR=0.96, P<0.05). CONCLUSION: Being exposed to education about the complications of diabetes increases the probability of attending diabetic eye screening. An appropriate patient knowledge building strategy should be made available to patients from the time of diagnosis. PMID- 28730121 TI - Age norms for grating acuity and contrast sensitivity measured by Lea tests in the first three years of life. AB - AIM: To determine age norms in the first three years of life for grating visual acuity and contrast sensitivity obtained with Lea grating test and Hiding Heidi low contrast face test. METHODS: Lea grating test was used to estimate binocular grating acuity and Hiding Heidi low contrast face test was used to estimate contrast sensitivity in 600 healthy infants and children. Age ranged from 3 to 36mo subdivided into 12 groups subjected for full ophthalmologic and pediatric examinations. RESULTS: The grating acuity developed along the first three years of life. It ranged from 1.88+/-0.32 c/d at 3mo to 30.95+/-0.77 c/d at 36mo. The most rapid development was during the first 12mo and the slowest development was from 30 to 36mo. The contrast sensitivity showed rapid development in the first two years of life. Its mean value ranged from 4.23+/-1.17 at 3mo to 78.26+/-8.21 at 24mo. It was constant at the highest score (80) thereafter. CONCLUSION: Age norms for grating acuity along with contrast sensitivity offer a more comprehensive measure of spatial vision and should be incorporated in clinical practice for better visual assessment in preverbal and nonverbal children. PMID- 28730122 TI - Corneal blindness and current major treatment concern-graft scarcity. AB - According to World Health Organization, the global prevalence of blindness in 2010 was 39 million people, among which 4% were due to corneal opacities. Often, the sole resort for visual restoration of patients with damaged corneas is corneal transplantation. However, despite rapid developments of surgical techniques, instrumentations and immunosuppressive agents, corneal blindness remains a prevalent global health issue. This is largely due to the scarcity of good quality corneal grafts. In this review, the causes of corneal blindness, its major treatment options, and the major contributory factors of corneal graft scarcity with potential solutions are discussed. PMID- 28730123 TI - ipRGCs: possible causation accounts for the higher prevalence of sleep disorders in glaucoma patients. AB - Sleep accounts for a third of one's lifetime, partial or complete deprivation of sleep could elicit sever disorders of body function. Previous studies have reported the higher prevalence of sleep disorders in glaucoma patients, but the definite mechanism for this phenomenon is unknown. On the other hand, it is well known by us that the intrinsically photosensitive retinal ganglion cells (ipRGCs) serve additional ocular functions, called non-image-forming (NIF) functions, in the regulation of circadian rhythm, melatonin secretion, sleep, mood and others. Specifically, ipRGCs can directly or indirectly innervate the central areas such as suprachiasmatic nucleus (SCN), downstream pineal gland (the origin of melatonin), sleep and wake-inducing centers and mood regulation areas, making NIF functions of ipRGCs relate to sleep. The more interesting thing is that previous research showed glaucoma not only affected visual functions such as the degeneration of classical retinal ganglion cells (RGCs), but also affected ipRGCs. Therefore, we hypothesize that higher prevalence of sleep disorders in glaucoma patients maybe result from the underlying glaucomatous injuries of ipRGCs leading to the abnormalities of diverse NIF functions corresponding to sleep. PMID- 28730124 TI - Cataract surgery on post radial keratotomy patients. AB - This study aims to evaluate and to compare three different approaches of cataract surgery to patients with previous radial keratotomy (RK), and to analyze the mechanical properties of the cornea after cataract surgery. Three groups of patients, each one including 8 eyes of patients with 16 RK incisions. The first group includes eyes with the first cataract incision superiorly, the second group in the temporal area, the third group in temporal area and a precautionary stabilizing suture across the RK incision adjacent to the main tunnel. In the first group intraoperative dehiscence occurred in three eyes (37.5%): it required immediate application of a suture. In the second group dehiscence occurred intraoperatively in two radial scars (20%): it required immediate application of a suture. In the third group, no intraoperative dehiscences were observed. The stabilizing suture of the RK incision works safer, with a lower risk of dehiscences and less post-operative astigmatism. PMID- 28730125 TI - Hard exudates referral system in eye fundus utilizing speeded up robust features. AB - In the paper a referral system to assist the medical experts in the screening/referral of diabetic retinopathy is suggested. The system has been developed by a sequential use of different existing mathematical techniques. These techniques involve speeded up robust features (SURF), K-means clustering and visual dictionaries (VD). Three databases are mixed to test the working of the system when the sources are dissimilar. When experiments were performed an area under the curve (AUC) of 0.9343 was attained. The results acquired from the system are promising. PMID- 28730126 TI - Pivot concept: achieving a good-quality capsulorrhexis through a 2.2 mm or less clear corneal incision by using standard capsulorhexis forceps. PMID- 28730127 TI - Combined phacoemulsification and anterior vitrectomy in a case of anterior megalophthalmos with open-angle glaucoma and high myopia. PMID- 28730128 TI - Altered perception of floaters in dementia causing self-inflicted injuries. PMID- 28730129 TI - Bilateral uveitis associated with nivolumab therapy for metastatic melanoma: a case report. PMID- 28730130 TI - Nutritional Counseling for Obese Children with Obesity-Related Metabolic Abnormalities in Korea. AB - Child obesity has become a significant health issue in Korea. Prevalence of obesity in school-age children in Korea has been alarmingly rising since 2008. Prevalence of obesity among infants and preschool-age children in Korea has doubled since 2008. Obese children may develop serious health complications. Before nutritional counseling is pursued, several points should be initially considered. The points are modifiable risk factors, assessment for child obesity, and principles of treatment. Motivational interviewing and a multidisciplinary team approach are key principles to consider in managing child obesity effectively in the short-term as well as long-term. Nutritional counseling begins with maintaining a daily log of food and drink intake, which could possibly be causing obesity in a child. Several effective tools for nutritional counseling in practice are the Traffic Light Diet plan, MyPlate, Food Balance Wheel, and 'Food Exchange Table'. Detailed nutritional counseling supported by a qualified dietitian is an art of medicine enabling insulin therapy and hypoglycemic agents to effectively manage diabetes mellitus in obese children. PMID- 28730131 TI - Clinical Study of Congenital Esophageal Stenosis: Comparison according to Association of Esophageal Atresia and Tracheoesophageal Fistula. AB - PURPOSE: Congenital esophageal atresia (CES) is a rare congenital disease. The severity of symptoms is variable; thus, diagnosis is difficult and tends to be delayed. CES is frequently accompanied by esophageal atresia (EA) with/without tracheoesophageal fistula (TEF). We investigated the characteristics of CES by reviewing our experience with CES patients and researched the differences between CES with EA-TEF and isolated CES. METHODS: A total of 31 patients underwent operations for CES were reviewed retrospectively. The patients were divided into two groups according to the association with EA-TEF, and compared the differences. RESULTS: Sixteen boys and 15 girls were included. The mean age at symptom onset was 8 months old, and the mean age at diagnosis was 21 months old. Nine patients with EA-TEF were included group A, whereas the other 22 patients were assigned to group B. There were no differences in sex, gestational age, associated anomalies and pathologic results between the groups. In group A, the age at diagnosis and age at surgery were younger than in group B despite the age at symptom occurrence being similar. Postoperative complications occurred only in group A. CONCLUSION: In this study, symptoms occurred during the weaning period, and vomiting was the most frequent symptom. CES patients with EA-TEF tended to be diagnosed and treated earlier despite the age at symptom occurrence being similar. CES patients with EA-TEF had more postoperative complications; therefore, greater attention should be paid during the postoperative period. PMID- 28730132 TI - Investigation of Efficacy of Lidocaine Spray for Sedated Esophagogastroduodenoscopy in Children. AB - PURPOSE: Our aim in this study is to investigate efficacy of topical lidocaine spray for sedated esophagogastroduodenoscopy (EGD) in children. METHODS: The endoscopy of children aged between 3-18 years who underwent EGD in our endoscopy unit. Intravenous (IV) midazolam and ketamine were used for sedation. Prior to sedation, endoscopy nurse applied topical lidocaine 10% with pump spray at 1 mg/kg dose in group 1, and distilled water via identically scaled pump spray in group 2, in a double blinded fashion. RESULTS: Sedation was not applied in 24.1% of the cases in topical lidocaine spray group (LS group) and in 5.7% of the cases in distilled water spray group (DS group). Gag reflex was observed in 6.5% of cases in LS group and 33.3% of cases in DS group (p=0.024), increased oral secretion was observed in 9.3% of cases in LS group and 51.7% of cases in DS group (p=0.038), sore throat was observed in 3.7% of cases in LS group and 35.6% of cases in DS group (p=0.019) and the difference was statistically significant. CONCLUSION: The study showed that topical pharyngeal lidocaine reduces both requirement and amount of IV sedation before EGD in children and sore throat, gag reflex and decreased oral secretion increase. PMID- 28730133 TI - Cysts of Gastrointestinal Origin in Children: Varied Presentation. AB - PURPOSE: Abdominal cysts of gastrointestinal origin are rare. Their rarity and varied clinical presentations make their pre-operative diagnosis difficult. METHODS: Fourteen patients with histological diagnosis of cysts of gastrointestinal origin admitted between 2009 and 2015 were retrospectively analyzed with respect to age, sex, clinical presentation, diagnostic modality, site and type of cyst, management, outcome and follow-up. RESULTS: The mean age at presentation was 4 years and there were six males and eight females. Abdominal pain was the most common presenting symptom. Five patients had an acute presentation-three had distal ileal mesenteric cysts and two had ileal duplication cyst sharing a common wall with ileum. Six patients presented with chronic abdominal pain and lump-three patients had omental cysts and three had mesenteric cysts-two of these in distal ileum and one in sigmoid colon. Two patients presented with antenatally diagnosed palpable abdominal lump. One had a mesenteric cyst of the ileum and the other had a distal ileal duplication cyst which required excision with resection and anastomosis. One patient had an atypical presentation. He was a known case of sickle cell trait and had presented with vague abdominal pain, recurrent cough and multiple episodes of haemoptysis over a period of one year. At laparotomy, gastric duplication cyst was found which was excised completely. Histopathology confirmed the diagnosis. CONCLUSION: Cysts of gastrointestinal origin are rare and have varied presentation. Surgical excision is the mainstay of treatment. The results and prognosis are good. PMID- 28730134 TI - Innovative Dietary Intervention Answers to Baby Colic. AB - PURPOSE: The purpose of this paper is to evaluate the efficacy of a lactose- reduced synbiotic partial whey hydrolysate in formula fed infants presenting with colic and the impact of this dietary intervention in mean crying time and quality of life. METHODS: Forty infants with infantile colic were treated during one month with parental reassurance and the intervention formula (partial whey hydrolysate, reduced lactose, Bifidobacterium lactis BB12 and galacto oligosaccharides) and were compared to a control group of 20 infants with infantile colic treated with parental reassurance and a standard infant formula. Parents completed a quality of life (QoL) questionnaire assessing the burden of infantile colic. Wilcoxon test, t-test and Mann-Whitney test were used to compare QoL scores before and after intervention as well as between the intervention and control group. RESULTS: At inclusion, duration of crying did not differ between both groups. Crying duration decreased with 2.7 hours (from 3.2 to 0.5 hours) in the intervention group while duration of crying decreased only with 1.2 hours in the control group (p<0.001). Stool composition became looser in the intervention group, but defecation frequency did not change. The median scores of the QoL questionnaire improved significantly in the intervention group for all parameters. In the control group, parameters improved significantly also but not for the parent-child and social interaction. The score changes were significantly greater in the intervention than in the control group. CONCLUSION: The intervention formula (partial whey hydrolysate, synbiotic, reduced lactose) significantly reduced the duration of crying and improved QoL of the parents and infants. PMID- 28730135 TI - Clinical Characteristics and Ultrasonographic Findings of Acute Bacterial Enterocolitis in Children. AB - PURPOSE: This study clarified the bacterial pathogens currently causing acute infectious enterocolitis (AIE) in children and evaluated the clinical characteristics and ultrasonographic findings according to the different pathogens. METHODS: Medical records regarding age, sex, clinical symptoms, laboratory data, identified enteropathogens, ultrasonographic findings, treatment, and outcome of 34 patients who were diagnosed with AIE via stool examination using multiplex polymerase chain reaction (PCR) or culture, were retrospectively reviewed. RESULTS: Twenty-four patients (70.6%) were male. The mean age of the patients was 8.5+/-6.2 (range, 1.1-17.1) years. Six bacterial pathogens were isolated: Salmonella species (spp.) (32.4%), Campylobacter spp. (20.6%), verotoxin-producing Escherichia coli (14.7%), Staphylococcus aureus (11.8%), Clostridium difficile (8.8%), and Shigella spp. (2.9%). Abdominal pain occurred in all patients regardless of pathogen. The patients infected with Salmonella were older than those infected with verotoxin-producing E. coli (p<0.05). C-reactive protein levels were higher in patients with Salmonella and Campylobacter infections than in those with verotoxin-producing E. coli infection (p<0.05), the other clinical and laboratory data were indistinguishable between pathogens. Ultrasonography demonstrated diverse involvement of bowel segments according to pathogen. Wall thickening of both the ileum and the entire colon was the most common lesion site regardless of pathogen. CONCLUSION: Various bacterial agents cause AIE and the symptoms are diverse symptoms, however, all most children recovered spontaneously. Use of multiplex PCR on stool samples warrants improvement of its sensitivity for diagnosis of enteropathogenic bacteria. Ultrasonographic examination is useful for diagnosis of AIE; it can also detect the disease extent and severity. PMID- 28730136 TI - Early Diagnosis of ABCB11 Spectrum Liver Disorders by Next Generation Sequencing. AB - PURPOSE: The goal of this study was the early diagnosis of ABCB11 spectrum liver disorders, especially those focused on benign recurrent intrahepatic cholestasis and progressive familial intrahepatic cholestasis. METHODS: Fifty patients presenting neonatal cholestasis were evaluated to identify underlying etiologies. Genetic analysis was performed on patients suspected to have syndromic diseases or ABCB11 spectrum liver disorders. Two families with proven ABCB11 spectrum liver disorders were subjected to genetic analyses to confirm the diagnosis and were provided genetic counseling. Whole exome sequencing and Sanger sequencing were performed on the patients and the family members. RESULTS: Idiopathic or viral hepatitis was diagnosed in 34%, metabolic disease in 20%, total parenteral nutrition induced cholestasis in 16%, extrahepatic biliary atresia in 14%, genetic disease in 10%, neonatal lupus in 2%, congenital syphilis in 2%, and choledochal cyst in 2% of the patients. The patient with progressive familial intrahepatic cholestasis had novel heterozygous mutations of ABCB11 c.11C>G (p.Ser4*) and c.1543A>G (p.Asn515Asp). The patient with benign recurrent intrahepatic cholestasis had homozygous mutations of ABCB11 c.1331T>C (p.Val444Ala) and heterozygous, c.3084A>G (p.Ala1028Ala). Genetic confirmation of ABCB11 spectrum liver disorder led to early liver transplantation in the progressive familial intrahepatic cholestasis patient. In addition, the atypically severe benign recurrent intrahepatic cholestasis patient was able to avoid unnecessary liver transplantation after genetic analysis. CONCLUSION: ABCB11 spectrum liver disorders can be clinically indistinguishable as they share similar characteristics related to acute episodes. A comprehensive genetic analysis will facilitate optimal diagnosis and treatment. PMID- 28730137 TI - Pediatric Mycoplasma pneumoniae Infection Presenting with Acute Cholestatic Hepatitis and Other Extrapulmonary Manifestations in the Absence of Pneumonia. AB - Mycoplasma pneumoniae infections mainly involve respiratory tract; however, also can manifestate other symptoms by site involved. Extrapulmonary manifestations of M. pneumoniae infection are rarely known to occur without pneumonia. Herein we report a case of a 9-year-old boy who presented with acute cholestatic hepatitis in the absence of pneumonia. Rhabdomyolysis, skin rash, and initial laboratory results suspicious of disseminated intravascular coagulopathy were also observed in this patient. M. pneumoniae infection was identified by a 4-fold increase in immunoglobulin G antibodies to M. pneumoniae between acute and convalescent sera by enzyme-linked immunosorbent assay. This is the first pediatric case in Korea of M. pneumoniae infection presenting with acute cholestatic hepatitis in the absence of pneumonia. PMID- 28730138 TI - Ileal Perforation with Norovirus Gastroenteritis in a 3-Month-Old Infant. AB - Noroviruses have been recognized as the leading cause of epidemic and sporadic gastroenteritis since the advent of molecular diagnostic technique. They have been documented in 5-31% of pediatric patients hospitalized with gastroenteritis. Although norovirus gastroenteritis is typically mild and self-limited, it causes severe, but sometimes fatal, conditions in the vulnerable population such as immunocompromised patients, young children, and the elderly. Bowel perforation due to norovirus infection is rare. We report a case of small bowel perforation with norovirus gastroenteritis in the infant with Down syndrome during the hospitalization with pneumonia. Severe dehydration may cause bowel ischemia and could have triggered bowel perforation in this case. Physicians should be alert to the potential surgical complications followed by severe acute diarrhea, especially in high risk groups. PMID- 28730139 TI - Gastric Hemangioma Treated with Argon Plasma Coagulation in a Newborn Infant. AB - Gastric hemangioma in the neonatal period is a very rare cause of upper gastrointestinal bleeding. We present a case of hemangioma limited to the gastric cavity in a 10-day-old infant. A huge, erythematous mass with bleeding was observed on the lesser curvature side of the upper part of the stomach. Surgical resection was ruled out because the location of the lesion was too close to the gastroesophageal junction. Medical treatment with intravenous H2 blockers, octreotide, packed red blood cell infusions, local epinephrine injection at the lesion site, application of hemoclip, and gel-form embolization of the left gastric artery did not significantly alter the transfusion requirement. Hemostasis was achieved with endoscopic argon plasma coagulation (APC). After two sessions of APC, complete removal of the lesion was achieved. APC was a simple, safe and effective tool for hemostasis and the ablation of gastric hemangioma without significant complications. PMID- 28730140 TI - Current Advances in Checkpoint Inhibitors: Lessons from Non-Central Nervous System Cancers and Potential for Glioblastoma. AB - The adaptive immune system depends on the sequence of antigen presentation, activation, and then inhibition to mount a proportionate response to a threat. Tumors evade the immune response partly by suppressing T-cell activity using immune checkpoints. The use of cytotoxic T-lymphocyte-associated protein 4 (CTLA 4), programmed cell death 1 (PD-1), and programmed cell death ligand 1 (PD-L1) antibodies counteract this suppression, thereby enhancing the antitumor activity of the immune system. This approach has proven efficacy in melanoma, renal cancer, and lung cancer. There is growing evidence that the central nervous system is accessible to the immune system in the diseased state. Moreover, glioblastomas (GBMs) attract CTLA-4-expressing T-cells and express PD-L1, which inhibit activation and continuation of a cytotoxic T-cell response, respectively. This may contribute to the evasion of the host immune response by GBM. Trials are in progress to determine if checkpoint inhibitors will be of benefit in GBM. Radiotherapy could also be helpful in promoting inflammation, enhancing the immunogenicity of tumors, disrupting the blood-brain barrier and creating greater antigen release. The combination of radiotherapy and checkpoint inhibitors has been promising in preclinical trials but is yet to show efficacy in humans. In this review, we summarize the mechanism and current evidence for checkpoint inhibitors in gliomas and other solid tumors, examine the rationale of combining radiotherapy with checkpoint inhibitors, and discuss the potential benefits and pitfalls of this approach. PMID- 28730141 TI - Extracellular Vesicles As Modulators of Tumor Microenvironment and Disease Progression in Glioma. AB - Diffuse gliomas are lethal tumors of the central nervous system (CNS) characterized by infiltrative growth, aggressive nature, and therapeutic resistance. The recent 2016 WHO classification for CNS tumors categorizes diffuse glioma into two major types that include IDH wild-type glioblastoma, which is the predominant type and IDH-mutant glioblastoma, which is less common and displays better prognosis. Recent studies suggest presence of a distinct cell population with stem cell features termed as glioma stem cells (GSCs) to be causal in driving tumor growth in glioblastoma. The presence of a stem and progenitor population possibly makes glioblastoma highly heterogeneous. Significantly, tumor growth is driven by interaction of cells residing within the tumor with the surrounding milieu termed as the tumor microenvironment. It comprises of various cell types such as endothelial cells, secreted factors, and the surrounding extracellular matrix, which altogether help perpetuate the proliferation of GSCs. One of the important mediators critical to the cross talk is extracellular vesicles (EVs). These nano-sized vesicles play important roles in intercellular communication by transporting bioactive molecules into the surrounding milieu, thereby altering cellular functions and/or reprogramming recipient cells. With the growing information on the contribution of EVs in modulation of the tumor microenvironment, it is important to determine their role in both supporting as well as promoting tumor growth in glioma. In this review, we provide a comprehensive overview of the role of EVs in tumor progression and glioma pathogenesis. PMID- 28730142 TI - Taming Parasites by Tailoring Them. AB - The next-generation gene editing based on CRISPR (clustered regularly interspaced short palindromic repeats) has been successfully implemented in a wide range of organisms including some protozoan parasites. However, application of such a versatile game-changing technology in molecular parasitology remains fairly underexplored. Here, we briefly introduce state-of-the-art in human and mouse research and usher new directions to drive the parasitology research in the years to come. In precise, we outline contemporary ways to embolden existing apicomplexan and kinetoplastid parasite models by commissioning front-line gene tailoring methods, and illustrate how we can break the enduring gridlock of gene manipulation in non-model parasitic protists to tackle intriguing questions that remain long unresolved otherwise. We show how a judicious solicitation of the CRISPR technology can eventually balance out the two facets of pathogen-host interplay. PMID- 28730143 TI - Long-Term Temporal Trends of Nosema spp. Infection Prevalence in Northeast Germany: Continuous Spread of Nosema ceranae, an Emerging Pathogen of Honey Bees (Apis mellifera), but No General Replacement of Nosema apis. AB - The Western honey bee (Apis mellifera) is widely used as commercial pollinator in worldwide agriculture and, therefore, plays an important role in global food security. Among the parasites and pathogens threatening health and survival of honey bees are two species of microsporidia, Nosema apis and Nosema ceranae. Nosema ceranae is considered an emerging pathogen of the Western honey bee. Reports on the spread of N. ceranae suggested that this presumably highly virulent species is replacing its more benign congener N. apis in the global A. mellifera population. We here present a 12 year longitudinal cohort study on the prevalence of N. apis and N. ceranae in Northeast Germany. Between 2005 and 2016, a cohort of about 230 honey bee colonies originating from 23 apiaries was sampled twice a year (spring and autumn) resulting in a total of 5,600 bee samples which were subjected to microscopic and molecular analysis for determining the presence of infections with N. apis or/and N. ceranae. Throughout the entire study period, both N. apis- and N. ceranae-infections could be diagnosed within the cohort. Logistic regression analysis of the prevalence data demonstrated a significant increase of N. ceranae-infections over the last 12 years, both in autumn (reflecting the development during the summer) and in spring (reflecting the development over winter) samples. Cell culture experiments confirmed that N. ceranae has a higher proliferative potential than N. apis at 27 degrees and 33 degrees C potentially explaining the increase in N. ceranae prevalence during summer. In autumn, characterized by generally low infection prevalence, this increase was accompanied by a significant decrease in N. apis-infection prevalence. In contrast, in spring, the season with a higher prevalence of infection, no significant decrease of N. apis infections despite a significant increase in N. ceranae infections could be observed. Therefore, our data do not support a general advantage of N. ceranae over N. apis and an overall replacement of N. apis by N. ceranae in the studied honey bee population. PMID- 28730144 TI - Molecular Characterization of the Human Stomach Microbiota in Gastric Cancer Patients. AB - Helicobacter pylori (Hp) is the primary cause of gastric cancer but we know little of its relative abundance and other microbes in the stomach, especially at the time of gastric cancer diagnosis. Here we characterized the taxonomic and derived functional profiles of gastric microbiota in two different sets of gastric cancer patients, and compared them with microbial profiles in other body sites. Paired non-malignant and tumor tissues were sampled from 160 gastric cancer patients with 80 from China and 80 from Mexico. The 16S rRNA gene V3-V4 region was sequenced using MiSeq platform for taxonomic profiles. PICRUSt was used to predict functional profiles. Human Microbiome Project was used for comparison. We showed that Hp is the most abundant member of gastric microbiota in both Chinese and Mexican samples (51 and 24%, respectively), followed by oral associated bacteria. Taxonomic (phylum-level) profiles of stomach microbiota resembled oral microbiota, especially when the Helicobacter reads were removed. The functional profiles of stomach microbiota, however, were distinct from those found in other body sites and had higher inter-subject dissimilarity. Gastric microbiota composition did not differ by Hp colonization status or stomach anatomic sites, but did differ between paired non-malignant and tumor tissues in either Chinese or Mexican samples. Our study showed that Hp is the dominant member of the non-malignant gastric tissue microbiota in many gastric cancer patients. Our results provide insights on the gastric microbiota composition and function in gastric cancer patients, which may have important clinical implications. PMID- 28730145 TI - Prokaryotic RNA Associated to Bacterial Viability Induces Polymorphonuclear Neutrophil Activation. AB - Polymorphonuclear neutrophils (PMN) are the first cellular line of antibacterial host defense. They sense pathogens through recognition of pathogen-associated molecular patterns (PAMPs) by innate pattern recognition receptors, such as Toll like receptors (TLR). The aim of this study was to investigate whether PMN sense bacterial viability and explore which viability factor could be involved in this phenomenon. For this purpose, different functions were evaluated in isolated human PMN using live Escherichia coli (Ec) and heat-killed Ec (HK-Ec). We found that bacterial viability was indispensable to induce PMN activation, as measured by forward-scatter (FSC) increase, CD11b surface expression, chemotaxis, reactive oxygen species (ROS) generation and neutrophil extracellular trap (NET) formation. As uncapped non-polyadenylated prokaryotic mRNA has been recognized as a PAMP associated to bacterial viability by macrophages and dendritic cells, total prokaryotic RNA (pRNA) from live Ec was purified and used as a stimulus for PMN. pRNA triggered similar responses to those observed with live bacteria. No RNA could be isolated from HK-Ec, explaining the lack of effect of dead bacteria. Moreover, the supernatant of dead bacteria was able to induce PMN activation, and this was associated with the presence of pRNA in this supernatant, which is released in the killing process. The induction of bactericidal functions (ROS and NETosis) by pRNA were abolished when the supernatant of dead bacteria or isolated pRNA were treated with RNAse. Moreover, endocytosis was necessary for pRNA induced ROS generation and NETosis, and priming was required for the induction of pRNA-induced ROS in whole blood. However, responses related to movement and degranulation (FSC increase, CD11b up-regulation, and chemotaxis) were still triggered when pRNA was digested with RNase, and were not dependent on pRNA endocytosis or PMN priming. In conclusion, our results indicate that PMN sense live bacteria through recognition of pRNA, and this sensing triggers potent bactericidal mechanisms. PMID- 28730146 TI - Schwannoma of the tongue: a case report with review of literature. AB - BACKGROUND: Schwannomas (or neurilemmomas) of the tongue are benign, usually solitary, encapsulated masses derived from Schwann cells. Clinical evidence indicates that schwannoma is painless and slow growing. In general, schwannoma is treated by surgical excision. Here, we describe a case of schwannoma of the tongue, include a review of the literature from 1955 to 2016, and provide data on age, gender, location, presenting symptoms, size, and treatment methods. CASE PRESENTATION: A 71-year-old female patient presented with a swelling at the base of the tongue of unknown duration. Magnetic resonance images (MRI) showed a large well-circumscribed solid mass and no significant lymph node enlargement. The mass was excised without removing overlying mucosa. CONCLUSIONS: The authors report a case of lingual schwannoma that was completely removed intraorally without preoperative biopsy. No sign or symptoms of recurrence were observed at 12 months postoperatively. PMID- 28730147 TI - Correlation between pain and degenerative bony changes on cone-beam computed tomography images of temporomandibular joints. AB - BACKGROUND: The aim of this study was to assess correlation between pain and degenerative bony changes on cone-beam computed tomography (CBCT) images of temporomandibular joints (TMJs). METHODS: Two hundred eighty-three temporomandibular joints with degenerative bony changes were evaluated. Pain intensity (numeric rating scale, NRS) and pain duration in patients with degenerative joint disease (DJD) were also analyzed. We classified condylar bony changes on CBCT into five types: osteophyte (Osp), erosion (Ero), flattening (Fla), subchondral sclerosis (Scl), and pseudocyst (Pse). RESULTS: Degenerative bony changes were the most frequent in the age groups of 10~19, 20-29, and 50~59 years. The most frequent pain intensity was "none" (NRS 0, 34.6%) followed by "annoying" (NRS 3-5, 29.7%). The most frequent condylar bony change was Fla (219 joints, 77.4%) followed by Ero (169 joints, 59.7%). "Ero + Fla" was the most common combination of the bony changes (12.7%). The frequency of erosion was directly proportional to NRS, but the frequency of osteophyte was inversely proportional. The prevalence of Ero increased from onset until 2 years and gradually decreased thereafter. The prevalence of Osp, Ero, and Pse increased with age. CONCLUSIONS: Osp and Ero can be pain-related variables in degenerative joint disease (DJD) patients. "Six months to 2 years" may be a meaningful time point from the active, unstable phase to the stabilized late phase of DJD. PMID- 28730148 TI - Can Online Discussion Sites Generate Quality Data for Research Purposes? PMID- 28730150 TI - From Electrochemical Biosensors to Biomimetic Sensors Based on Molecularly Imprinted Polymers in Environmental Determination of Heavy Metals. AB - Recent work relevant to heavy metal determination by inhibition-enzyme electrochemical biosensors and by selected biomimetic sensors based on molecularly imprinted polymers has been reviewed. General features and peculiar aspects have been evidenced. The replace of biological component by artificial receptors promises higher selectivity and stability, while biosensors keep their capability of producing an integrated response directly related to biological toxicity of the samples. PMID- 28730149 TI - Review of Antibiotic Resistance in the Indian Ocean Commission: A Human and Animal Health Issue. AB - Antimicrobial resistance (AMR) is a major threat to human, animal health, and environment worldwide. For human, transmission occurred through a variety of routes both in health-care settings and community. In animals, AMR was reported in livestock, pets, and wildlife; transmission of AMR can be zoonotic with the probably most important route being foodborne transmission. The Indian Ocean Commission (IOC), composed of Comoros, Madagascar, Mauritius, Reunion (France), and Seychelles recognized the surveillance of AMR in both animal and human as a main public health priority for the region. Mayotte, French overseas territory, located in Comoros archipelago, was also included in this review. This review summarized our best epidemiological knowledge regarding AMR in Indian Ocean. We documented the prevalence, and phenotypic and genotypic profiles of prone to resistance Gram-positive and Gram-negative bacteria both in animals and humans. Our review clearly pointed out extended-spectrum beta-lactamase and carbapenemase producing Enterobacteriaceae as main human and animal health issue in IOC. However, publications on AMR are scarce, particularly in Comoros, Mayotte, and Seychelles. Thus, research and surveillance priorities were recommended (i) estimating the volume of antimicrobial drugs used in livestock and human medicine in the different territories [mainly third generation cephalosporin (3GC)]; (ii) developing a "One Health" surveillance approach with epidemiological indicators as zoonotic foodborne pathogen (i.e., couple Escherichia coli resistance to 3GC/carbapenems); (iii) screening travelers with a history of hospitalization and consumption of antibiotic drug returning from at risk areas (e.g., mcr-1 transmission with China or hajj pilgrims) allowing an early warning detection of the emergence for quick control measures implementation in IOC. PMID- 28730151 TI - Comparison of Thoracic Radiography and Computed Tomography in Calves with Naturally Occurring Respiratory Disease. AB - OBJECTIVE: To evaluate the severity and extent of lung disease using thoracic computed radiography (CR) compared to contrast-enhanced multi-detector computed tomography (MDCT) of the thorax in calves with naturally occurring respiratory disease and to evaluate the feasibility and safety of performing contrast enhanced thoracic multi-detector MDCT examinations in sedated calves. Furthermore, to evaluate if combining CR or MDCT with respiratory scoring factors will improve prediction of the chronicity of pulmonary disease in calves. ANIMALS: Thirty Jersey heifer calves ranging in age between 25 and 89 days with naturally occurring respiratory disease. PROCEDURES: All calves were evaluated via thoracic CR and contrast-enhanced MDCT. All calves were euthanized immediately following thoracic MDCT and submitted for necropsy. Imaging and histopathology results were compared with each other. RESULTS: Thoracic MDCT was superior for evaluation of pneumonia in calves due to the lack of summation in all areas of the lungs. Intravenously administered sedation provided an adequate plane of sedation for acquiring MDCT images of diagnostic quality, without the need for re-scanning. A diagnosis of pneumonia was made with equal rate on both thoracic CR and MDCT. Although mild differences in classification of lung pattern and extent of lung disease were seen when comparing an experienced and a less experienced evaluator, the overall differences were not statistically significant. The best intra- and inter-observer agreement was noted when evaluating the cranioventral aspects of the lungs in either modality. Clinical respiratory scoring is inadequate for diagnosing chronicity of pneumonia in calves with naturally occurring pneumonia. CONCLUSION AND CLINICAL IMPORTANCE: Both imaging modalities allowed diagnosis of pneumonia in calves. The cranial ventral aspects of the lungs were most commonly affected. Thoracic CR and MDCT provided similar diagnostic effectiveness in diagnosing pneumonia. However, MDCT provided better assessment of subtle details, which may be otherwise obscured due to summation artifact. PMID- 28730153 TI - Assessment of isomiR Discrimination Using Commercial qPCR Methods. AB - We sought to determine whether commercial quantitative polymerase chain reaction (qPCR) methods are capable of distinguishing isomiRs: variants of mature microRNAs (miRNAs) with sequence endpoint differences. We used two commercially available miRNA qPCR methods to quantify miR-21-5p in both synthetic and real cell contexts. We find that although these miRNA qPCR methods possess high sensitivity for specific sequences, they also pick up background signals from closely related isomiRs, which influences the reliable quantification of individual isomiRs. We conclude that these methods do not possess the requisite specificity for reliable isomiR quantification. PMID- 28730154 TI - Linear Temporal Logic (LTL) Based Monitoring of Smart Manufacturing Systems. AB - The vision of Smart Manufacturing Systems (SMS) includes collaborative robots that can adapt to a range of scenarios. This vision requires a classification of multiple system behaviors, or sequences of movement, that can achieve the same high-level tasks. Likewise, this vision presents unique challenges regarding the management of environmental variables in concert with discrete, logic-based programming. Overcoming these challenges requires targeted performance and health monitoring of both the logical controller and the physical components of the robotic system. Prognostics and health management (PHM) defines a field of techniques and methods that enable condition-monitoring, diagnostics, and prognostics of physical elements, functional processes, overall systems, etc. PHM is warranted in this effort given that the controller is vulnerable to program changes, which propagate in unexpected ways, logical runtime exceptions, sensor failure, and even bit rot. The physical component's health is affected by the wear and tear experienced by machines constantly in motion. The controller's source of faults is inherently discrete, while the latter occurs in a manner that builds up continuously over time. Such a disconnect poses unique challenges for PHM. This paper presents a robotic monitoring system that captures and resolves this disconnect. This effort leverages supervisory robotic control and model checking with linear temporal logic (LTL), presenting them as a novel monitoring system for PHM. This methodology has been demonstrated in a MATLAB-based simulator for an industry inspired use-case in the context of PHM. Future work will use the methodology to develop adaptive, intelligent control strategies to evenly distribute wear on the joints of the robotic arms, maximizing the life of the system. PMID- 28730155 TI - Surveillance Study of Influenza Occurrence and Immunity in a Wisconsin Cohort During the 2009 Pandemic. AB - BACKGROUND: Antibody and T-cell immunity to conserved influenza virus antigens can protect animals against infection with diverse influenza strains. Although immunity against conserved antigens occurs in humans, whether such responses provide cross-protection in humans and could be harnessed as the basis for universal influenza vaccines is controversial. The 2009 pandemic provided an opportunity to investigate whether pre-existing cross-reactive immunity affected susceptibility to infection. METHODS: In 2009, we banked sera and peripheral blood mononuclear cells (PBMC) from blood donors, then monitored them for pandemic influenza infection (pH1N1) by polymerase chain reaction or seroconversion. Antibodies to hemagglutinin (HA), neuraminidase (NA), nucleoprotein (NP), matrix 2 (M2), and HA-pseudotypes were measured in sera. T cell inteferon-gamma enzyme-linked immunospot responses were measured in PBMC. RESULTS: There were 13 infections in 117 evaluable donors. Pre-existing T-cell reactivity to pH1N1 was substantial (of 153 donors tested, 146 had >100 spot forming cells/106 cells). Antibodies reactive with pH1N1 were common: anti-NP (all donors) and anti-M2 (44% of donors). Pseudotype-neutralizing antibodies to H1 were detected, but not to highly conserved HA epitopes. Unexpectedly, donors with symptomatic pH1N1 infection had sharp rises in HA pseudotype-neutralizing antibodies, not only pH1N1 but also against multiple seasonal H1s. In addition, an exploratory study of a T-cell marker (response to NP418-426) identified probable infection missed by standard criteria. CONCLUSIONS: Although the number of infections was inadequate for conclusions about mechanisms of protection, this study documents the wide variety of pre-existing, cross-reactive, humoral and cellular immune responses to pandemic influenza virus antigens in humans. These responses can be compared with results of other studies and explored in universal influenza vaccine studies. PMID- 28730156 TI - White Blood Cell Counts, Alcoholism, and Cirrhosis in Pneumococcal Pneumonia. AB - BACKGROUND: An elevated white blood cell (WBC) count is a characteristic finding in pneumococcal pneumonia. Very low WBC counts, occurring in some cases, are often associated with overwhelming pneumonia and have been attributed to alcohol induced suppression of bone marrow. However, a systematic study of neutropenia, leukocytosis, alcohol ingestion, and cirrhosis in pneumococcal pneumonia has not been previously reported. METHODS: Using a database of patients with pneumococcal pneumonia at our medical center, we extracted data on WBC counts at admission, differential counts, alcohol ingestion, and cirrhosis, and we related these to 7 day and 30-day mortality. RESULTS: White blood cell counts were <6000/mm3 in 49 of 481 patients (10.2%) with pneumococcal pneumonia and >25000/mm3 in 40 (8.3%). Mortality at 7 days was 18.4% and 12.5%, respectively, 5-fold and 3-fold greater in patients with WBC <6000 or >25000 than in those with WBC counts between 6000 and 25000 (P < .001). Increased band forms were not associated with a worse outcome (P = .12). Alcohol use and cirrhosis were not associated with WBC counts <6000 (P = .63 and P = .41, respectively). CONCLUSIONS: In a large series of cases of pneumococcal pneumonia, WBC counts <6000 or >25000 correlated significantly with increased 7-day mortality. More than 10% band forms was not associated with a poor outcome. Alcohol abuse was not associated with low WBC or increased mortality. Our findings suggest that greater consideration be given to more intense care for patients with bacterial pneumonia who have very high or very low WBC counts at the time of hospital admission. PMID- 28730152 TI - Zebrafish Get Connected: Investigating Neurotransmission Targets and Alterations in Chemical Toxicity. AB - Neurotransmission is the basis of neuronal communication and is critical for normal brain development, behavior, learning, and memory. Exposure to drugs and chemicals can alter neurotransmission, often through unknown pathways and mechanisms. The zebrafish (Danio rerio) model system is increasingly being used to study the brain and chemical neurotoxicity. In this review, the major neurotransmitter systems, including glutamate, GABA, dopamine, norepinephrine, serotonin, acetylcholine, histamine, and glutamate are surveyed and pathways of synthesis, transport, metabolism, and action are examined. Differences between human and zebrafish neurochemical pathways are highlighted. We also review techniques for evaluating neurological function, including the measurement of neurotransmitter levels, assessment of gene expression through transcriptomic analysis, and the recording of neurobehavior. Finally examples of chemical toxicity studies evaluating alterations in neurotransmitter systems in the zebrafish model are reviewed. PMID- 28730157 TI - Streptobacillus moniliformis Bacteremia in a Pet Shop Employee: Case Report and Literature Review. AB - A 39-year-old pet shop employee who sustained a bite from one of his store's rats developed fever and arthritis. Streptobacillus moniliformis was cultured from the patient's blood, confirming a diagnosis of rat-bite fever. Treatment with standard antibiotics was successful. Although rat-bite fever is commonly considered a zoonosis transmitted by wild or laboratory rats, our case emphasizes that it may be transmitted by pet animals as well. PMID- 28730158 TI - A Rapid Epidemiological Tool to Measure the Burden of Norovirus Infection and Disease in Resource-Limited Settings. AB - BACKGROUND: Rapid, cost-effective tools are needed to estimate the disease burden of acute gastroenteritis (AGE) and norovirus (NoV) in resource-limited settings. METHODS: Households with children (6 weeks-17 years) in rural Guatemala were randomly enrolled into 2 parallel AGE surveillance systems: (1) a prospective cohort, which included an enrollment visit followed by 1 year of prospective observation using a smartphone-based weekly symptom diary; and (2) 2 sequential cross-sectional rapid active sampling (RAS) surveys. Norovirus testing was performed during enrollment (all subjects) and for prospective AGE episodes (prospective cohort only). RESULTS: The prospective cohort enrolled 207 households (469 children) from April to September 2015 followed by 471 person years of observation; RAS survey 1 enrolled 210 households (402 children) during October to November 2015, and RAS survey 2 enrolled 210 separate households (368 children) during January to February 2016. The prospective cohort detected a NoV+ AGE prevalence of 11% and a population-attributable fraction (PAF) of -1.6% at enrollment, followed by an incidence of 1.4 episodes/100 person-years. Rapid active sampling surveys 1 and 2 identified a NoV+ AGE prevalence of 14%-21% and a PAF of 3.2%-12.4%. CONCLUSIONS: Rapid active sampling surveys were practical and identified more cases of NoV infection and disease compared with a parallel prospective cohort in rural Guatemala. PMID- 28730159 TI - Antibiotic Prescribing for Adults Hospitalized in the Etiology of Pneumonia in the Community Study. AB - BACKGROUND: Community-acquired pneumonia (CAP) 2007 guidelines from the Infectious Diseases Society of America (IDSA)/American Thoracic Society (ATS) recommend a respiratory fluoroquinolone or beta-lactam plus macrolide as first line antibiotics for adults hospitalized with CAP. Few studies have assessed guideline-concordant antibiotic use for patients hospitalized with CAP after the 2007 IDSA/ATS guidelines. We examine antibiotics prescribed and associated factors in adults hospitalized with CAP. METHODS: From January 2010 to June 2012, adults hospitalized with clinical and radiographic CAP were enrolled in a prospective Etiology of Pneumonia in the Community study across 5 US hospitals. Patients were interviewed using a standardized questionnaire, and medical charts were reviewed. Antibiotics prescribed were classified according to defined nonrecommended CAP antibiotics. We assessed factors associated with nonrecommended CAP antibiotics using logistic regression. RESULTS: Among enrollees, 1843 of 1874 (98%) ward and 440 of 446 (99%) ICU patients received >=1 antibiotic <=24 hours after admission. Ward patients were prescribed a respiratory fluoroquinolone alone (n = 613; 33%), or beta-lactam plus macrolide (n = 365; 19%), beta-lactam alone (n = 240; 13%), among other antibiotics, including vancomycin (n = 235; 13%) or piperacillin/tazobactam (n = 157; 8%) <=24 hours after admission. Ward patients with known risk for healthcare-associated pneumonia (HCAP), recent outpatient antibiotic use, and in-hospital antibiotic use <6 hours after admission were significantly more likely to receive nonrecommended CAP antibiotics. CONCLUSIONS: Although more than half of ward patients received antibiotics concordant with IDSA/ATS guidelines, a number received nonrecommended CAP antibiotics, including vancomycin and piperacillin/tazobactam; risk factors for HCAP, recent outpatient antibiotic, and rapid inpatient antibiotic use contributed to this. This hypothesis-generating descriptive epidemiology analysis could help inform antibiotic stewardship efforts, reinforces the need to harmonize guidelines for CAP and HCAP, and highlights the need for improved diagnostics to better equip clinicians. PMID- 28730161 TI - Isolation, Culturing, and Differentiation of Primary Myoblasts from Skeletal Muscle of Adult Mice. AB - Myogenesis is a multi-step process that leads to the formation of skeletal muscle during embryonic development and repair of injured myofibers. In this process, myoblasts are the main effector cell type which fuse with each other or to injured myofibers leading to the formation of new myofibers or regeneration of skeletal muscle in adults. Many steps of myogenesis can be recapitulated through in vitro differentiation of myoblasts into myotubes. Most laboratories use immortalized myogenic cells lines that also differentiate into myotubes. Although these cell lines have been found quite useful to delineating the regulatory mechanisms of myogenesis, they often show a great degree of variability depending on the origin of the cells and culture conditions. Primary myoblasts have been suggested as the most physiologically relevant model for studying myogenesis in vitro. However, due to their low abundance in adult skeletal muscle, isolation of primary myoblasts is technically challenging. In this article, we describe an improved protocol for the isolation of primary myoblasts from adult skeletal muscle of mice. We also describe methods for their culturing and differentiation into myotubes. PMID- 28730162 TI - Black Women with Multiple Sex Partners: The Role of Sexual Agency. AB - Motivations of low-income substance using heterosexual Black women in New York City for having multiple sexual partners are explored in this paper. Analysis of in-depth interviews with 50 study participants demonstrates that their relationships consisted of those who had: (1) a main sex partner and a secondary sex partner; or (2) two or more "casual" partners. Individual-level motivations for extra relational sex fell into four dominant themes: sexual pleasure, partner infidelity, sex exchange and past main partners. Using a Black feminist framework, we describe how participants displayed considerable autonomy by actively forming and withdrawing from sexual relationships with men. However, women described low rates of condom use with main partners and inconsistent use of condoms with more casual sexual partners. This contradiction becomes an important area for sexual health interventions. Women who had sexual relations with only one current mate in the past two years were recruited as a monogamous comparison group. PMID- 28730160 TI - Epigenetic Interactions between Alcohol and Cannabinergic Effects: Focus on Histone Modification and DNA Methylation. AB - Epigenetic studies have led to a more profound understanding of the mechanisms involved in chronic conditions. In the case of alcohol addiction, according to the National Institute on Alcohol Abuse and Alcoholism, 16 million adults suffer from Alcohol Use Disorders (AUDs). Even though therapeutic interventions like behavioral therapy and medications to prevent relapse are currently available, no robust cure exists, which stems from the lack of understanding the mechanisms of action of alcohol and the lack of development of precision medicine approaches to treat AUDs. Another common group of addictive substance, cannabinoids, have been studied extensively to reveal they work through cannabinoid receptors. Therapeutic applications have been found for the cannabinoids and a deeper understanding of the endocannabinoid system has been gained over the years. Recent reports of cannabinergic mechanisms in AUDs has opened an exciting realm of research that seeks to elucidate the molecular mechanisms of alcohol-induced end organ diseases and hopefully provide insight into new therapeutic strategies for the treatment of AUDs. To date, several epigenetic mechanisms have been associated with alcohol and cannabinoids independently. Therefore, the scope of this review is to compile the most recent literature regarding alcohol and cannabinoids in terms of a possible epigenetic connection between the endocannabinoid system and alcohol effects. First, we will provide an overview of epigenetics, followed by an overview of alcohol and epigenetic mechanisms with an emphasis on histone modifications and DNA methylations. Then, we will provide an overview of cannabinoids and epigenetic mechanisms. Lastly, we will discuss evidence of interactions between alcohol and cannabinergic pathways and possible insights into the novel epigenetic mechanisms underlying alcohol-cannabinergic pathway activity. Finalizing the review will be a discussion of future directions and therapeutic applications. PMID- 28730163 TI - Brain Strokes Related to Aortic Aneurysma - the Analysis of three Cases. AB - Brain stroke connected with aortic blood flow disturbances is a rare disease and its incidence is difficult to assume. Nevertheless, 10-50% of patients with aortic dissection may not experience any pain. In case of 18-30% patients with aortic dissection neurological signs are first disease presentation and among them ischemic stroke is the most common. The most popular aortic dissection classification is with use of Stanford system. Type A involves the ascending aorta and type B is occurring distal to the subclavian artery. Aortic dissection risk factors include hypertension, cystic medionecrosis, bicuspid aortic valve and Marfan's or Ehlers-Danlos syndrome. PMID- 28730164 TI - Effect of Bicyclol Tablets on Drug Induced Liver Injuries after Kidney Transplantation. AB - Liver injury is one of the most common complications in patients after kidney transplantation. Bicyclol tablets possess obvious anti-inflammatory and liver protective functions. This study aimed to explore the clinical effect of preventive application of Bicyclol on drug induced liver injuries at an early stage after kidney transplantation. A total of 1600 patients who accepted kidney transplantations at our hospital from January 2009 to May 2015 were enrolled in this study, and divided into the prevention group (Bicyclol) and the control group (no hepatic protectors) based on whether or not hepatic protectors were regularly administered after the operation. The occurrence of liver injuries at an early stage after the operation and their influencing factors were analyzed. Total of 745 cases were included in the final analysis of which 82 developed liver injuries post-operation, with 22 in the prevention group (4.82%) as compared to 60 in the control group (20.76%) (P= 0.001). As compared to the control group, OR (95% CI) of the prevention group was 0.197 (0.116, 0.334) after revising HBsAg status, age and maintenance immunosuppression. Prophylactic application of Bicyclol as liver-protective treatment was a protective factor against drug induced liver injuries at an early stage after kidney transplantation. PMID- 28730165 TI - Plasma Free Fatty Acids in Hyperemesis Gravidarum Pregnancy. AB - : We evaluated the free fatty acids differences in plasma between hyperemesis gravidarum(HG) and healthy pregnant in first trimester pregnancy. OBJECTIVE: We aimed to compare the plasma levels of DHA, AA and EPA, between HG patients and healthy pregnant women. DESIGN: Fifty-two pregnants were involved in the study. Twenty-six pregnants of them were HG as study group, and twenty-six pregnants were enrolled as healthy pregnant women at the similar gestational age. The saturated fatty acids C14, C15, C16, C18, C20, C22, and C24; the omega-3 fatty acids eicosapentaenoic acid, (EPA) and docosahexaenoic acid, (DHA); the omega-6 fatty acids linoleic acid, arachidonic acid (AA), and homo-gamma-linolenic acid; and the omega-9 fatty acids oleic acid, erucic acid, and nervonic acid were analysed by gas chromatography. RESULTS: Statistically differences was not seen between the groups with maternal age, gestational age, or plasma levels of EPA, DHA, and AA. Statistically significant difference was seen between the groups with plasma levels of C20 and C22(p<0.05). C20 was declined but C22 was rised in the HG patients. CONCLUSION: EPA, DHA, or AA, which related to placental and fetal neural development are not changing from Hyperemesis gravidarum. PMID- 28730166 TI - Impact of Chromosomal Rearrangement upon DNA Methylation Patterns in Leukemia. AB - Genomic instability, including genetic mutations and chromosomal rearrangements, can lead to cancer development. Aberrant DNA methylation occurs commonly in cancer cells. The aim of this study is to determine the effects of a specific chromosomal lesion the BCR-ABL translocation t(9:22), in establishing DNA methylation profiles in cancer. Materials and methods We compared DNA methylation of 1,505 selected promoter CpGs in chronic myelogenous leukemia (CML), acute lymphoblastic leukemia (ALL) with and without the Philadelphia chromosome t(9:22), CD34+ hematopoietic stem cells transfected with BCR-ABL, and other tumors without BCR-ABL (acute promyelocytic leukemia (APL) and gastrointestinal stromal tumors (GIST). In this study, the DNA methylation profile of CML was more closely related to APL, another myeloid leukemia, than Ph+ ALL. Although DNA methylation profiles were consistent within a specific tumor type, overall DNA methylation profiles were no influenced by BCR-ABL gene translocation in the cancers and tissues studied. We conclude that DNA methylation profiles may reflect the cell of origin in cancers rather than the chromosomal lesions involved in leukemogenesis. PMID- 28730167 TI - The Clinical Characteristics of Patients with Chronic Idiopathic Anal Pain. AB - The aim of this study was to investigate the clinical characteristics, treatment outcomes and psychological distress in patients with chronic idiopathic anal pain. The study was conducted on patients referred to Hangzhou Third Hospital for chronic anal pain from January, 2010 to December, 2014. Patient demographics, clinical history, anorectal physiology, and radiological imaging data were recorded for all patients. The treatment outcome was noted for patients treated and followed up for more than 6 month at the present unit. Ninety-six patients with mean age of 45.1 years (range, 17-82) were studied. Seventy-one patients (74.0%) had functional anorectal pain(FARP). The main complaints were dull, sharp, stabbing, or spasm pain. Among all patients, 34.3% reported that their pain radiated into other locations. Fifty-one patients (53.1%) had bowel dysfunction, while 28.1% patients had urinary dysfunction. The common factors associated with pain relief were day time, lying down and warm water baths; the factors that contributed to aggravated pain were night time, defecation or sitting. 92.7% (89/96) of patients reported symptoms of psychological disturbance. FARP patients exhibited increased depression than non-FARP patients(P<0.05). In addition, female patients were more likely to have depression than male patients (P<0.05). The overall pain treatment success rate was 55.2% (53/96). The pain treatment outcome was better in non-FARP patients than in FARP patients(chi2=3.85, P<0.05). Conclusively, chronic idiopathic anal pain is a complex clinical symptom, involving pelvic floor muscles, the nervous system, endocrine system, and the patients' psychological conditions. Further research is needed to improve diagnosis and treatment for patients with chronic idiopathic anal pain. PMID- 28730168 TI - Bone Tunnel Impaction Reduced the Tibial Tunnel Enlargement. AB - : The purpose of this study was to investigate whether the bone tunnel impaction technique performed by dilators could dwindle the tibial tunnel enlargement after anterior cruciate ligament (ACL) reconstruction with hamstring tendon using both extracortical suspensory fixation devices at femoral and tibial site. Thirty-one consecutive patients undergoing primary ACL reconstruction with the hamstring autograft were enrolled in this research. Patients were randomly allotted to group A (bone tunnel impaction technique using dilators) or group B (regular extraction bone tunnel drilling). RESULTS: The average follow-up was 16.2 months. The mean femoral tunnel widening was 1.05 mm and 1.02 mm respectively in group A and B. The mean tibial tunnel widening was 0.61 mm and 1.08 mm respectively in group A and B. There was no statistical difference for tunnel enlargement between the two groups at the femoral site (P = 0.62) but significant difference at the tibial site (P < 0.0001). CONCLUSION: Bone tunnel impaction technique leaded to a reduction of tibial bone tunnel enlargement after ACL reconstruction with hamstring tendon using both extracortical suspensory fixation devices at femoral and tibial site. PMID- 28730169 TI - Effects of S-1 Combined with Radiotherapy in the Treatment of Nasopharyngeal Cancer: A Meta-analysis Based on Randomized Controlled Trials. AB - The aim of this meta-analysis was to evaluate the effects and toxicity of S-1 combined with radiotherapy in the treatment of nasopharyngeal cancer (NPC). Through a search of the databases of PubMed, Embase, the Chinese Biomedicine Database (CBM), China National Knowledge Infrastructure (CNKI), Wanfang system and Chongqing VIP Information (CQVIP), the efficacy and side effects data of S-1 combined with radiotherapy in the treatment of NPC patients from open published randomized controlled trials (RCTs) were collected. The pooled complete response (CR), partial response (PR), objective response rate (ORR), 2-year survival rate and treatment related toxicity were analyzed by Stata12.0 software. Eight RCTs with 599 cases were included and analyzed in this meta-analysis. The general quality of the 8 studies were deemed as having moderate risk of bias. Adequate sequence generation was reported in 4 studies. Incomplete outcome data address was reported in 7 publications. Five studies indicated to be free of selective reporting. Seven studies reported the treatment complete response (CR) between S 1 combined with radiotherapy and radiotherapy alone. With significant heterogeneity, the data was pooled by random effect model. The pooled results indicated that S-1 combined with radiotherapy can significant increase the CR rate compared to radiotherapy alone (RR=1.52, 95%CI:1.33-1.74, P<0.05). Eight studies reported the partial response (PR) rate between the combined treatment and radiotherapy alone. The pooled results showed that there was no statistical difference for PR between combined treatment and radiotherapy alone (RR=0.85, 95%CI:0.62-1.16, P>0.05). For the effect size of objective response rate (ORR), pooled results indicated that S-1 combined with radiotherapy can significantly increased the ORR by random effect model (RR=1.39, 95%CI:1.23-1.57, P<0.05). The pooled results showed that S-1 combined with radiotherapy significant increase the risk of developing bone marrow suppression (RR=1.94, 95%CI:1.40-2.69, P<0.05) and gastrointestinal reaction (RR=1.81, 95%CI:1.38-2.38, P<0.05) with fixed effect model. However, the pooled oral mucositis (RR=1.22, 95%CI:0.99-1.50, P>0.05) and radiodermatitis (RR=0.93, 95%CI:0.77-1.12, P<0.05) were not statistically different. Two studies reported the 2-year survival rate between the two groups. The pooled results showed the combined treatment significantly increased the 2-year survival rate for patients with nasopharyngeal carcinoma (RR=1.14, 95%CI:1.01-1.28, P<0.05). The funnel plot demonstrated significant publication bias for complete response, partial response, objective response rate and oral mucositis. The egger's line regression test indicated significant publication bias for complete response (t=5.98, P=0.002) and objective response rate(t=6.23, P=0.003). Conclusion S-1 combined with radiotherapy can significant improve the clinical efficacy with more treatment related toxicity compared to radiotherapy alone in the treatment of nasopharyngeal carcinoma. PMID- 28730170 TI - Predictions and Outcomes of Atrial Fibrillation in the Patients with Acute Myocardial Infarction. AB - The large epidemiological studies demonstrated that atrial fibrillation is correlated with high mortality and adverse events in patients with acute myocardial infarction. The aim of this study was to determinate predictors of atrial fibrillation develop during the hospital period in patients with acute myocardial infarction as well as short- and long-term mortality depending on the atrial fibrillation presentation. The 600 patients with an acute myocardial infarction were included in the study and follow-up 84 months. Atrial fibrillation develops during the hospital period was registered in 48 patients (8%). After adjustment by logistic regression model the strongest predictor of atrial fibrillation develop during the hospital period was older age, particularly more than 70 years (odds ratio 2.37, CI 1.23-4.58, p=0.010), followed by increased of Body Mass Index (odds ratio 1.17, CI 1.04-1.33, p=0.012), enlarged diameter of left atrium (LA) (odds ratio 1,18, CI 1,03-1,33, p=0,015) presentation of mitral regurgitation (odds ratio 3.56, CI 1.25-10.32, p=0.018) and B-type natriuretic peptide (odds ratio 2.12, CI 1.24-3.33, p=0.048).Patients with atrial fibrillation develop during the hospital period had a higher mortality during the hospital course (10.4% vs. 5.6%) p=0.179. as well as follow-up period of 84 months than patients without it (64.6% vs. 39.1%) p=0.569, than patients without it, but without statistically significance. Patients with AF develop during the hospital period had higher mortality during the hospital course as well as follow up period of 84 months than patients without it, but without statistically significance. PMID- 28730171 TI - An Accuracy Study of the Intracavitary Electrocardiogram (IC-ECG) Guided Peripherally Inserted Central Catheter Tip Placement among Neonates. AB - OBJECTIVE: To explore the clinical application of the intracavitary electrocardiogram (IC-ECG) guided Peripherally Inserted Central Catheter (PICC) tip placement among neonates. BACKGROUND: the ECGs of neonates are difficult to perform and their wave shapes are of doubtful accuracy due to various interfering factors. METHOD: 115 neonates were admitted to perform PICC guided by IC-ECG. Logistic regression was performed to analyze all possible influencing factors of the accuracy from the tip placement. The puncture site of the PICC, gestational age, height, weight, basal P/R amplitude and positioning P/R amplitude might be related to the accuracy of IC-ECG location. RESULT: The accuracy in the lower extremity was higher than that in the upper extremity. Multivariate logistic regression analysis showed that the weight (Odds Ratio (OR)=1.93, 95%Confidence Interval(CI):1.06-3.50) and positioning P/R amplitude (OR=32.33, 95%CI: 2.02 517.41) are statistically significant risks to the accuracy PICC tip placement. CONCLUSIONS: Possible methods to improve the accuracy might be Catheterizing through lower extremity, keeping the neonates calm, enhancing the electrocardiogram signal and strengthening technical training. Therefore it is practical to perfrom a tip placement by the dynamic change in the P waves from an electrocardiogram (ECG) guided PICC among neonates and as reliable as using X rays. PMID- 28730172 TI - Serum CA125, CA199 and CEA Combined Detection for Epithelial Ovarian Cancer Diagnosis: A Meta-analysis. AB - OBJECTIVE: To evaluate the diagnostic value of combination detection of serum cancer antigen 125 (CA125), carbohydrate antigen 19-9 (CA199) and carci noembryonic antigen(CEA) in patients with epithelial ovarian cancer by pooling the open published studies according to meta-analysis method. METHODS: Diagnostic studies related to combination detection of serum CA125, CA199 and CEA in patients with epithelial ovarian cancer were electronic searched in the databases of PubMed, Cochrane, Google scholar, EMBASE, ISI Web of Knowledge and CNKI by two independent reviewers. The combined diagnostic sensitivity, specificity, positive likely hood ratio (+LR), negative likely hood ratio (-LR), diagnostic odds ratio (DOR), and area under the receiver operating characteristic curve (AUC) were pooled by Med DiSc1.4 software. RESULTS: Twelve prospective diagnostic publications were finally fulfilled the inclusion criteria and were included in this meta-analysis. The pooled diagnostic sensitivity specificity, positive likely hood ratio, negative likely hood ratio, diagnostic odds ratio, and AUC were 0.90 (95%CI: 0.80 to 0.92), 0.83 (95%CI: 0.80 to 0.86), 5.35(95%CI:3.90 to 7.33), 0.13 (95%CI: 0.10 to 0.16), 48.53 (95%CI: 29.91 to 78.72) and 0.92 (95%C: 0.89 to 0.94) respectively by fixed or random effect model. No publication bias was found according to the funnel plot and line regression test (t=-1.34, P=0.21). CONCLUSION: Combination detection serum CA125, CA199 and CEA was a promising biomarker forepithelial ovarian cancer diagnosis with relative high sensitivity and specificity. PMID- 28730173 TI - Surface Coil Intensity Correction in Magnetic Resonance Imaging in Spinal Metastases. AB - OBJECTIVE: To evaluate the clinical application of phased-array surface coil intensity correction in magnetic resonance imaging (MRI) in spinal metastases. METHODS: 3 phantoms and 50 patients with a corresponding total number of 80 spinal metastases were included in this study. Fast spin echo T1- and T2- weighted MRI with and without surface coil intensity correction was routinely performed for all phantoms and patients. Phantoms were evaluated by means of variance to mean ratio of signal intensity on both T1- and T2- weighted MRI obtained with and without surface coil intensity correction. Spinal metastases were evaluated by image quality scores; reading time per case on both T1- and T2- weighted MRI obtained with and without surface coil intensity correction. RESULTS: Spinal metastases were diagnosed more successfully on MRI with surface coil intensity correction than on MRI with conventional surface coil technique. The variance to mean ratio of signal intensity was 53.36% for original T1 weighted MRI and 53.58% for original T2-weighted MRI. The variance to mean ratio of signal intensity was reduced to 18.99% for T1-weighted MRI with surface coil intensity correction and 22.77% for T2-weighted MRI with surface coil intensity correction. The overall image quality scores (interface conspicuity of lesion and details of lesion) were significantly higher than those of the original MRI. The reading time per case was shorter for MRI with surface coil intensity correction than for MRI without surface coil intensity correction. CONCLUSIONS: Phased-array surface coil intensity correction in MRIs of spinal metastases provides improvements in image quality that leads to more successfully detection and assessment of spinal metastases than original MRI. PMID- 28730174 TI - Monitoring Health Inequalities at the Municipal Level: Lithuanian Experience. AB - : This study aimed to assess the attitudes of Lithuanian public health professionals towards health inequality monitoring in municipalities. The survey was conducted in public health bureaus (PHBs) and administrations of municipalities in March 2015. All employees of PHBs, all municipal doctors and all employees of health departments were invited to participate in the study (N=318; response rate, 47.2%). The study participants had positive attitudes towards the importance of health inequality monitoring at the municipal level, meanwhile systematic health inequality monitoring was assessed moderately. The majority of the interviewed professionals working at PHBs and municipalities (91.4% and 88.2%, respectively) declared that health indicators were monitored and analysed in their institutions. The respondents acknowledged the importance of routine monitoring of health indicators for assessment of inequalities, but these indicators were not monitored systematically in every municipality and PHB. Public health professionals identified the following measures for better health inequality monitoring: to strengthen intersectoral collaboration, formulate specific objectives of health programmes, promote actions in reducing health inequalities. CONCLUSIONS: Public health professionals working at the municipal level outlined the importance of monitoring and reducing health inequalities. However, health inequality monitoring at the municipal level was considered as insufficient. PMID- 28730176 TI - Thrombectomy Combined with Indwelling-catheter Thrombolysis is more Effective than Pure Thrombectomy for the Treatment of Lower Extremity Deep Venous Thrombosis. AB - : This study was a retrospective analysis of the efficacy of thrombectomy plus local catheter-directed thrombolysis (CDT) for the treatment of lower extremity deep venous thrombosis (LDVT). The experimental group underwent thrombectomy plus LCDT, whereas the control group underwent thrombectomy plus systemic thrombolysis via the dorsalis pedis vein. Venography and vascular color Doppler ultrasound were performed 7 days after surgery and at follow-up. The differences in the thigh and calf circumferences of normal and affected limbs were compared between groups. The venous patency score and venous patency rate were used for outcome evaluation. Compared with the control group, the experimental group showed a lower venous patency score and higher venous patency rate after treatment (P<0.05). Thirty patients were followed for 3 to 6 months, and according to the last evaluation, the differences in thigh and calf circumference between the normal and affected limbs remained lower in the experimental group than in the control group (P<0.05). Moreover, the venous patency score was lower, and the venous patency rate was higher in the experimental group than in the control group (P<0.05). CONCLUSION: Thrombectomy plus CDT yields a higher venous patency rate and lower recurrence rate than pure thrombectomy for the treatment of LDVT. PMID- 28730175 TI - Role of Epstein-Barr Virus in the Development of Nasopharyngeal Carcinoma. AB - Southern China experiences larger extent of total cancer pathologies, of which nasopharyngeal carcinoma has the highest incidence under otorhinolaryngeal malignant carcinomas. Risk factor of nasopharyngeal carcinoma varies from hereditary causes to virus infection, among which Epstein-Barr virus (EBV) infection is the mostly investigated. The study into mechanism of EBV in occurrence, development and prognosis of nasopharyngeal carcinoma has been studied for several decades. The pathophysiology in making of EBV into a cancerogen includes proteins as latent membrane protein 1 (LMPs) and nucleic acids as micro-RNAs. In this paper, we reviewed till date studies focusing on relationship between EBV and nasopharyngeal carcinoma. PMID- 28730177 TI - Expression of Hepcidin and Neogenin in Colorectal Cancer. AB - OBJECTIVE: To investigate the expression of Hepcidin and Neogenin in tissue from patients with colorectal cancer, to evaluate the relationship between Hepcidin and Neogenin with clinical features, and to study their relationship with anemia. METHODS: Immuno- histochemical method was used to detect the expression of Hepcidin and Neogenin in 62 cases of colorectal cancer. At the same time, the relationship between them and their relationship with clinical characteristics and anemia were analyzed. RESULTS: The expression of Hepcidin was related to T stage (P<0.05), but not with age, gender, lymph node metastasis and distant metastasis. The expression of Neogenin was not correlated with T stage and lymph node metastasis, age, gender, and distant metastasis (P>0.05). There was no significant difference in the expression of Hepcidin and Neogenin between anemia group and non-anemia group. There was no correlation between Hepcidin and Neogenin (r =-0.04, P>0.05). CONCLUSION: The expression of Hepcidin in colorectal cancer was related to the T stage, and had no correlation with Neogenin. The expression of Neogenin could not be used as an objective index to reflect the biological behavior of colorectal cancer. PMID- 28730178 TI - Carnitine and Adiponectin Levels in Breast Cancer after Radiotherapy. AB - : In this study, serum carnitine (CRNT) and adiponectin (APN) levels and the correlation of these parameters in patients with breast cancer before and after treatment with radiotherapy (RT) were determined. MATERIALS AND METHODS: Serum adiponectin and carnitine levels were assessed in 58 patients with breast carcinoma and 30 control subjects. Serum carnitine and APN levels were determined using a specific enzyme-linked immunosorbent assay. RESULTS: While serum carnitine level was significantly lower in the patients with breast cancer after RT compared with the control group and before treatment (p=0.002 and p=0.019, respectively), serum APN level was significantly higher than in the control group and before treatment ( p=0.003 and p=0.027, respectively). Carnitine level showed a negative correlation with APN level in the patients after RT (r= -0.626, p= 0.001). There was no correlation between carnitine and APN levels in subjects of control group and before treatment. Also, neither carnitine nor APN levels demonstrated correlation other parameters. CONCLUSIONS: Results suggest that increased serum adiponectin and decreased carnitine levels in breast cancer after RT than control group. Carnitine level showed a negative correlation with APN level in the patient with breast cancer after RT. While carnitine, HDL-C and total cholesterol levels are decreased, trygliceride and LDL-C levels are increased in patients than control group. In addition, serum APN concentration was inversely correlated with serum carnitine levels. Furthermore, increased serum APN level in breast cancer after RT might be associated with hypocarnitinemia. PMID- 28730180 TI - Measuring Efficiency of Secondary Healthcare Providers in Slovenia. AB - : The chief aim of this study was to analyze secondary healthcare providers' efficiency, focusing on the efficiency analysis of Slovene general hospitals. We intended to present a complete picture of technical, allocative, and cost or economic efficiency of general hospitals. METHODS: We researched the aspects of efficiency with two econometric methods. First, we calculated the necessary quotients of efficiency with the stochastic frontier analyze (SFA), which are realized by econometric evaluation of stochastic frontier functions; then, with the data envelopment analyze (DEA), we calculated the necessary quotients that are based on the linear programming method. RESULTS: Results on measures of efficiency showed that the two chosen methods produced two different conclusions. The SFA method concluded Celje General Hospital is the most efficient general hospital, whereas the DEA method concluded Brezice General Hospital was the hospital to be declared as the most efficient hospital. CONCLUSION: Our results are a useful tool that can aid managers, payers, and designers of healthcare policy to better understand how general hospitals operate. The participants can accordingly decide with less difficulty on any further business operations of general hospitals, having the best practices of general hospitals at their disposal. PMID- 28730179 TI - Causal Neuro-immune Relationships at Patients with Chronic Pyelonephritis and Cholecystitis. Correlations between Parameters EEG, HRV and White Blood Cell Count. AB - : We aim to analyze in bounds KJ Tracey's immunological homunculus conception the relationships between parameters of electroencephalogram (EEG) and heart rate variability (HRV), on the one hand, and the parameters of bhite blood cell count, on the other hand. METHODS: In basal conditions in 23 men, patients with chronic pyelonephritis and cholecystitis in remission, recorded EEG ("NeuroCom Standard", KhAI Medica, Ukraine) and HRV ("Cardiolab+VSR", KhAI Medica, Ukraine). In portion of blood counted up white blood cell count. RESULTS: Revealed that canonical correlation between constellation EEG and HRV parameters form with blood level of leukocytes 0.92 (p<10-5), with relative content in white blood cell count stubnuclear neutrophiles 0.93 (p<10-5), segmentonucleary neutrophiles 0.89 (p<10 3), eosinophiles 0.87 (p=0.003), lymphocytes 0.77 (p<10-3) and with monocytes 0.75 (p=0.003). CONCLUSION: Parameters of white blood cell count significantly modulated by electrical activity some structures of central and autonomic nervous systems. PMID- 28730181 TI - Newborn Screening for Lysosomal Storage Diseases: A Concise Review of the Literature on Screening Methods, Therapeutic Possibilities and Regional Programs. AB - Newborn screening for lysosomal storage diseases (LSDs) is increasingly being considered as an option. The development of analytical screening methods, of second-tier methods, and of therapeutic possibilities, are paving the way for routine screening for LSDs in the coming years. Here, we give a brief description of the current status quo, what screening methods are currently available or are in the pipeline, what is the current status of therapeutic possibilities for LSDs, what LSDs are the most obvious candidates for introduction in screening programs, and what LSDs are already part of regional or national pilot or routine screening programs worldwide. PMID- 28730182 TI - Tracking Deceased-Related Thinking with Neural Pattern Decoding of a Cortical Basal Ganglia Circuit. AB - BACKGROUND: Deceased-related thinking is central to grieving and potentially critical to processing of the loss. Self-report measurements might fail to capture important elements of deceased-related thinking and processing. Here, we used a machine learning approach applied to fMRI - known as neural decoding - to develop a measure of ongoing deceased-related processing. METHODS: 23 subjects grieving the loss of a first-degree relative, spouse or partner within 14 months underwent two fMRI tasks. They first viewed pictures and stories related to the deceased, a living control and a demographic control figure while providing ongoing valence and arousal ratings. Second, they performed a 10-minute Sustained Attention to Response Task (SART) with thought probes every 25-35 seconds to identify deceased, living and self-related thoughts. RESULTS: A conjunction analysis, controlling for valence/arousal, identified neural clusters in basal ganglia, orbital prefrontal cortex and insula associated with both types of deceased-related stimuli vs. the two control conditions in the first task. This pattern was applied to fMRI data collected during the SART, and discriminated deceased-related but not living or self-related thoughts, independently of grief severity and time since loss. Deceased-related thoughts on the SART correlated with self-reported avoidance. The neural model predicted avoidance over and above deceased-related thoughts. CONCLUSIONS: A neural pattern trained to identify mental representations of the deceased tracked deceased-related thinking during a sustained attention task and also predicted subject-level avoidance. This approach provides a new imaging tool to be used as an index of processing the deceased for future studies of complicated grief. PMID- 28730184 TI - Associations between Deceased-Donor Urine MCP-1 and Kidney Transplant Outcomes. AB - INTRODUCTION: Existing methods to predict recipient allograft function during deceased-donor kidney procurement are imprecise. Understanding the potential renal reparative role for monocyte chemoattractant protein-1 (MCP-1), a cytokine involved in macrophage recruitment after injury, might help predict allograft outcomes. METHODS: We conducted a sub-study of the multicenter prospective Deceased Donor Study cohort, which evaluated deceased kidney donors from five organ procurement organizations from May 2010 to December 2013. We measured urine MCP-1 (uMCP-1) concentrations from donor samples collected at nephrectomy to determine associations with donor acute kidney injury (AKI), recipient delayed graft function (DGF), 6-month estimated GFR (eGFR), and graft failure. We also assessed perfusate MCP-1 concentrations from pumped kidneys for associations with DGF and 6-month eGFR. RESULTS: AKI occurred in 111 (9%) donors. Median (interquartile range) uMCP-1 concentration was higher in donors with AKI compared to donors without AKI (1.35 [0.41-3.93] ng/ml vs. 0.32 [0.11-0.80] ng/ml, p<0.001). DGF occurred in 756 (31%) recipients, but uMCP-1 was not independently associated with DGF. Higher donor uMCP-1 concentrations were independently associated with higher 6-month eGFR in those without DGF [0.77 (0.10, 1.45) ml/min/1.73m2 per doubling of uMCP1]. However, there were no independent associations between uMCP-1 and graft failure over a median follow-up of about 2 years. Lastly, perfusate MCP-1 concentrations significantly increased during pump perfusion but were not associated with DGF or 6-month eGFR. CONCLUSION: Donor uMCP-1 concentrations were modestly associated with higher recipient 6-month eGFR in those without DGF. However, the results suggest that donor uMCP-1 has minimal clinical utility given no associations with graft failure. PMID- 28730185 TI - Social networks as predictors of colorectal cancer screening in African Americans. AB - BACKGROUND: Early detection can reduce colorectal cancer (CRC) mortality by 15% 33%, and screening is widely recommended for average-risk adults beginning at age 50 years. Colorectal cancer mortality rates are higher in African Americans than in whites, while screening rates are somewhat lower. Individual social networks can reduce emotional and/or logistical barriers to health-promoting but distasteful procedures such as CRC screening. The aim of this study was to examine social network interactions, and their impact on CRC screening among African Americans. We hypothesized a positive association between social network index (SNI) scores and CRC screening. METHODS: In a community intervention trial with four arms, we previously demonstrated the efficacy of a small group educational intervention to promote CRC screening among African Americans. This intervention outperformed a one-on-one educational intervention, a reduced out-of pocket expense intervention, and a control condition. In the present analysis, we compared the SNI scores for participants in the small group intervention cohort with a comparison group comprised of the other three cohorts. Social networks were assessed using the Social Network Index developed by Cohen. RESULTS: Small group participants had a significantly higher network diversity score (Mean difference 0.71; 95% CI, 0.12-1.31; p=0.0017) than the comparison group. In the second component of the SNI score - the number of people talked to over a two week period - the small group intervention cohort also scored significantly higher than the comparison group. (Mean difference, 9.29; 95% CI, 3.963-14.6266; p=0.0004). CONCLUSIONS: The findings suggest that social interaction and support was at least partially responsible for the relatively high post-intervention screening rate in the small group intervention participants. Education in small groups could foster strong social networks. Strong and positive network diversity and a large number of people in social networks may enhance CRC screening rates among African Americans. PMID- 28730186 TI - STANDARD REFERENCE MATERIALS FOR THE POLYMERS INDUSTRY. AB - The National Institute of Standards and Technology (NIST) provides science, industry, and government with a central source of well-characterized materials certified for chemical composition or for some chemical or physical property. These materials are designated Standard Reference Materials(r) (SRMs) and are used to calibrate measuring instruments, to evaluate methods and systems, or to produce scientific data that can be referred readily to a common base. In this paper, we discuss the history of polymer based SRMs, their current status, and challenges and opportunities to develop new standards to address industrial measurement challenges. PMID- 28730183 TI - Aberrant cerebellar connectivity in bipolar disorder with psychosis. AB - BACKGROUND: The cerebellum, which modulates affect and cognition in addition to motor functions, may contribute substantially to the pathophysiology of mood and psychotic disorders, such as bipolar disorder. A growing literature points to cerebellar abnormalities in bipolar disorder. However, no studies have investigated the topographic representations of resting state cerebellar networks in bipolar disorder, specifically their functional connectivity to cerebral cortical networks. METHODS: Using a well-defined cerebral cortical parcellation scheme as functional connectivity seeds, we compared ten cerebellar resting state networks in 49 patients with bipolar disorder and a lifetime history of psychotic features and 55 healthy control participants matched for age, sex, and image signal-to-noise ratio. RESULTS: Patients with psychotic bipolar disorder showed reduced cerebro-cerebellar functional connectivity in somatomotor A, ventral attention, salience, and frontoparietal control A and B networks relative to healthy control participants. These findings were not significantly correlated with current symptoms. CONCLUSIONS: Patients with psychotic bipolar disorder showed evidence of cerebro-cerebellar dysconnectivity in selective networks. These disease-related changes were substantial and not explained by medication exposure or substance use. Therefore, they may be mechanistically relevant to the underlying susceptibility to mood dysregulation and psychosis. Cerebellar mechanisms deserve further exploration in psychiatric conditions, and this study's findings may have value in guiding future studies on pathophysiology and treatment of mood and psychotic disorders, in particular. PMID- 28730187 TI - Implementing the ISO 15746 Standard for Chemical Process Optimization. AB - This paper proposes an approach to integrating advanced process control solutions with optimization (APC-O) solutions, within any factory, to enable more efficient production processes. Currently, vendors who provide the software applications that implement control solutions are isolated and relatively independent. Each such solution is designed to implement a specific task such as control, simulation, and optimization - and only that task. It is not uncommon for vendors to use different mathematical formalisms and modeling tools that produce different data representations and formats. Moreover, instead of being modeled uniformly only once, the same knowledge is often modeled multiple times - each time using a different, specialized abstraction. As a result, it is extremely difficult to integrate optimization with advanced process control. We believe that a recent standard, International Organization for Standardization (ISO) 15746, describes a data model that can facilitate that integration. In this paper, we demonstrate a novel method of integrating advanced process control using ISO 15746 with numerical optimization. The demonstration is based on a chemical-process-optimization problem, which resides at level 2 of the International Society of Automation (ISA) 95 architecture. The inputs to that optimization problem, which are captured in the ISO 15746 data model, come in two forms: goals from level 3 and feedback from level 1. We map these inputs, using this data model, to a population of a meta-model of the optimization problem for a chemical process. Serialization of the metamodel population provides input to a numerical optimization code of the optimization problem. The results of this integrated process, which is automated, provide the solution to the originally selected, level 2 optimization problem. PMID- 28730188 TI - tert-Butyl nitrite (TBN) as the N atom source for the synthesis of substituted cinnolines with 2-vinylanilines and a relevant mechanism was studied. AB - A green method to synthesize cinnolines by 6pi electrocyclic reaction with alkenyl amines and TBN has been developed. TBN plays a dual role both as a nitrogen atom source and an oxidant in this procedure. Relevant mechanism experiments reveal that the reaction proceeds through electrocyclic reaction and with diazo hydroxide as a key intermediate. PMID- 28730189 TI - Solvent-gated thin-film-transistors. AB - Electrical double layer (EDL) thin film transistors (TFTs) are an interesting class of transistors that use an electrolyte as the gating medium. Recently it has been demonstrated that pure organic solvents can also be used as gating media for TFTs without the addition of exogenous electrolytes. Here we present a systematic study of the performances of TFTs based on two different semiconductors (P3HT and ZnO) gated through nine different solvents either pure or loaded with NaCl. The nature of the solvent impacts the transfer characteristics of the TFT through a change in the gating capacitance while the threshold voltage remains unaffected. Depending on the polarity of solvents, addition of NaCl gives rise to different responses. TFTs gated through highly polar solvents are unaffected by the salt concentration while for low polarity solvents the output current increases with salt up to a plateau. Furthermore, when the semiconductor surface is covered with a high capacitance thin dielectric layer, the TFT output current becomes dependent on the NaCl concentration also for high polarity solvents. This phenomenology was rationalized considering the different contributions of Helmholtz and Guy-Chapman EDLs to the capacitance and the dielectric saturation that decreases the solvent dielectric constant within the Helmholtz EDL. PMID- 28730190 TI - Comparison of halide receptors based on H, halogen, chalcogen, pnicogen, and tetrel bonds. AB - A series of halide receptors are constructed and the geometries and energetics of their binding to F-, Cl-, and Br- assessed by quantum calculations. The dicationic receptors are based on a pair of imidazolium units, connected via a benzene spacer. The imidazoliums each donate a proton to a halide in a pair of H bonds. Replacement of the two bonding protons by Br leads to binding via a pair of halogen bonds. Likewise, chalcogen, pnicogen, and tetrel bonds occur when the protons are replaced, respectively, by Se, As, and Ge. Regardless of the binding group considered, F- is bound much more strongly than are Cl- and Br-. With respect to the latter two halides, the binding energy is not very sensitive to the nature of the binding atom, whether H or some other atom. But there is a great deal of differentiation with respect to F-, where the order varies as tetrel > H ~ pnicogen > halogen > chalcogen. The replacement of the various binding atoms by their analogues in the next row of the periodic table enhances the fluoride binding energy by 22-56%. The strongest fluoride binding agents utilize the tetrel bonds of the Sn atom, whereas it is I-halogen bonds that are preferred for Cl- and Br-. After incorporation of thermal and entropic effects, the halogen, chalcogen, and pnicogen bonding receptors do not represent much of an improvement over H-bonds with regard to this selectivity for F-, even I which binds quite strongly. In stark contrast, the tetrel-bonding derivatives, both Ge and Sn, show by far the greatest selectivity for F- over the other halides, as much as 1013, an enhancement of six orders of magnitude when compared to the H bonding receptor. PMID- 28730191 TI - Processing-structure relationships of poly(ethylene glycol)-modified liposomes. AB - Liposomes with PEG-modified surfaces are amenable to nanocarrier applications and can be prepared via two PEGylated lipid incorporation routes: before and after extrusion (i.e., co-extrusion and post-insertion, respectively). The current study quantifies the processing influence on PEG chain partitioning between the interior and exterior liposome surfaces for the first time using small angle neutron scattering. PMID- 28730192 TI - First stereoselective total synthesis of brevipolide M. AB - The first stereoselective total synthesis of a cytotoxic brevipolide M, which shares a pyrone framework bearing a tetrahydrofuran moiety and a cinnamate group with the readily available (-)-DET, is described. The key steps involved in the synthesis are the epoxide-opening, Brown's allylation, and the RCM reaction to install an alpha,beta-unsaturated lactone ring and the inversion of the C-6' stereogenic hydroxyl group using the Mitsunobu reaction. PMID- 28730193 TI - Using anion recognition to control the folding and unfolding of a single chain phosphorescent polymer. AB - We report here the use of anion recognition to control the folding and unfolding of a single polymeric chain consisting of a PMMA bearing pendant calix[4]pyrrole and Pt(ii) porphyrin subunits. PMID- 28730194 TI - Covalent hybrids based on Re(i) tricarbonyl complexes and polypyridine functionalized polyoxometalate: synthesis, characterization and electronic properties. AB - A series of [Re(CO)3Br(N^N)] (N^N = substituted 2,2'-bipyridine ligand) complexes based on polypyridine-functionalized Dawson polyoxometalate (1-3) has been synthesized. The new hybrids (4-6) were characterized by various analytical techniques, including absorption, vibrational and luminescence spectroscopies as well as electrochemistry. Both units, the polyoxometalate and the transition metal complex, retain their intrinsic properties. Their combination in the newly prepared hybrids results in improved photosensitization in the high-energy visible region. However, a complete quenching of the emission for the [Re(CO)3Br(N^N)] complexes is observed due to formation of a charge separated state, Re(ii) - POM-, as shown by quenching experiments as well as theoretical modelling via DFT. PMID- 28730195 TI - Copper-catalyzed, stereoconvergent, cis-diastereoselective borylative cyclization of omega-mesylate-alpha,beta-unsaturated esters and ketones. AB - The Cu(i)-catalyzed stereoconvergent borylative cyclization of omega-mesylate alpha,beta-unsaturated compounds is facilitated by a simple Cu-bisphosphine catalyst. This reaction provides a novel route to cis-beta-boron-substituted five and six-membered carbocycle and heterocycle esters. Mechanistic studies indicate that stereoconvergence and cis-substitution likely stem from the rapid enolation of the borylcopper adduct with the substrate double bond and the formation of a five-membered intermediate, respectively. PMID- 28730196 TI - Photosensitization mechanism of Cu(ii) porphyrins. AB - This work presents the mechanism of the photoinduced generation of reactive oxygen species (ROS) by paramagnetic copper porphyrins in aqueous solution. Electronic structure calculations within the framework of the (time-dependent) density functional theory, (TD)DFT, reveal the details regarding the development of the atomistic and electronic structures of the copper porphyrin in solution along the set of chemical reactions accessible upon photoactivation. This study identifies the key parameters controlling the feasibility of the various reaction pathways that drive the formation of specific reactive oxygen species, ROS, i.e. superoxide, peroxyl and hydroxyl radicals. An important outcome of our results is the rationalization of how the water solvent molecules play a crucial role in most steps of the overall reaction. The present study is illustrated by focusing on one specific copper porphyrin for which precise experimental data have recently been measured, and can readily be generalized to the whole family of paramagnetic porphyrins. The conclusions of this work shed light on the rational design of metalloporphyrins as photosensitizers for photodynamic therapy. PMID- 28730197 TI - Ionic transport in the amorphous phase of semicrystalline polyethylene oxide thin films. AB - We present a detailed study on the ionic transport properties of polyethylene oxide (PEO) thin films prepared under different conditions. Using a state-of-the art Atomic Force Microscopy (AFM) methodology, we simultaneously acquired the nanostructured topography of these semicrystalline polymer films as well as the corresponding dielectric function; in the latter case by probing the frequency dependent tip-sample electrical interactions. By means of this AFM protocol, we studied the ionic conductivity in the PEO amorphous phase and its dependence on film preparation conditions. In general, for any preparation method, we found a distribution of conductivities ranging from 10-14 to 10-6 S cm-1. Specifically, PEO thin films crystallized from the melt presented relatively high conductivity values, which decreased in the PEO films prepared from solutions at room temperature depending on solvent polarity. We discuss our results by considering the molecular arrangement of the polymer segments in the complex amorphous phase, which is strongly influenced by the PEO crystallization route. PMID- 28730198 TI - Programming shape and tailoring transport: advancing hygromorphic bilayers with aligned nanofibers. AB - Natural systems utilize nanofiber architectures to guide water transport, tune mechanical properties, and actuate in response to their environment. In order to harness these properties, a hygromorphic bilayer composite comprised of a self assembled fiber network and an aligned electrospun fiber network was fabricated. Molecular gel self-assembly was utilized to increase hydrophobicity and strength in one layer, while aligned electrospun poly(vinyl alcohol) (PVA) nanofibers increased the rate of hydration and facilitated tunable actuation in the other. Interfacing these two fiber networks in a poly(ethylene oxide-co-epichlorohydrin) (EO-EPI) matrix led to hydration-driven actuation with tunable curvature. Specifically, variations in fiber alignment were achieved by cutting at 0, 90, and 45 degree angles in relation to the length edge of the composite. Along with the ability to program the natural curvature, the utilization of aligned nanofibers increased water transport compared to random nanofiber systems, resulting in a reduction in response time from 20+ minutes to 2-3 minutes. PMID- 28730199 TI - The amorphous state: first-principles derivation of the Gordon-Taylor equation for direct prediction of the glass transition temperature of mixtures; estimation of the crossover temperature of fragile glass formers; physical basis of the "Rule of 2/3". AB - Predicting the glass transition temperature (Tg) of mixtures has applications that span across industries and scientific disciplines. By plotting experimentally determined Tg values as a function of the glass composition, one can usually apply the Gordon-Taylor (G-T) equation to determine the slope, k, which subsequently can be used in Tg predictions. Traditionally viewed as a phenomenological/empirical model, this work proposes a physical basis for the G-T equation. The proposed equations allow for the calculation of k directly and, hence, they determine/predict the Tg values of mixtures algebraically. Two derivations for k are provided, one for strong glass-formers and the other for fragile mixtures, with the modeled trehalose-water and naproxen-indomethacin systems serving as examples of each. Separately, a new equation is described for the first time that allows for the direct determination of the crossover temperature, Tx, for fragile glass-formers. Lastly, the so-called "Rule of 2/3", which is commonly used to estimate the Tg of a pure amorphous phase based solely on the fusion/melting temperature, Tf, of the corresponding crystalline phase, is shown to be underpinned by the heat capacity ratio of the two phases referenced to a common temperature, as evidenced by the calculations put forth for indomethacin and felodipine. PMID- 28730200 TI - How side chains affect conformation and electrical properties of poly(acrylic acid) in solution? AB - To better understand the effect of side chains on the chain conformation and electrical properties of polyelectrolytes, dielectric measurements were carried out on solutions of poly(acrylic acid) (PAA), poly(acrylic acid)-graft-dodecyl (PAA-g-dodecyl), and poly(acrylic acid)-graft-poly(ethylene oxide) (PAA-g-PEO) over a wide concentration range. Double dielectric relaxations with counterion distribution were observed for these polymers and a refined double-layer polarization model was proposed to analyze these, by which valuable information about conformations and interfacial electrokinetic properties was obtained. The transitional concentrations for the overlapping and entanglement of chains were identified from results for the dielectric increment and relaxation time. The concentration dependences of the ratio of effective charges were estimated from conductivity data. It was shown that effective charges on PAA were greatly influenced by PEO or dodecyl side chains, which caused steric hindrance of counterion binding and further dissociation of carboxylic groups or bound counterions. Moreover, a mutual superposition and offsetting effect of PEO and dodecyl side chains was observed. An enhancement in the interpenetration of counterion atmospheres as a result of side chains was also found. In addition, the rate constant ratio and the distance of counterion fluctuations perpendicular to the chains were estimated. It was demonstrated that the effects of side chains on the effective charges or ionization properties of GCP play an important role in their conformation, counterion distribution, and fluctuation. PMID- 28730201 TI - Copper-catalyzed Mannich-type oxidative beta-functionalization of tertiary amines. AB - A copper-catalyzed Mannich-type oxidative beta-functionalization reaction of amines has been developed. In the presence of an oxidant and a copper catalyst, tertiary amines reacted with N-tosylimines, providing synthetically important 1,3 diamines and enamines, respectively. Preliminary mechanistic studies suggested that the oxidation of the tertiary amine to the enamine intermediate triggers subsequent Mannich-type reactions with N-tosylimines and thus enables the direct beta-functionalization of the tertiary amines. PMID- 28730202 TI - Highly regio-, diastereo- and enantioselective deracemization of axially chiral 3 alkylideneoxindoles. AB - The first catalytic asymmetric dynamic resolution of unprotected racemic 3-(4 alkylcyclohexylidene)indolin-2-ones via a one-step direct vinylogous Michael reaction with chalcones was realized using a chiral N,N'-dioxide/Sc(iii) complex catalytic system. A variety of (Z)-4-alkyl-2-((3-oxo-1,3 diarylpropyl)cyclohexylidene)-indolin-2-ones with three stereogenic centers at xi , gamma- and delta'-positions were obtained in up to 95% yield, 98% ee and 99/1 dr. A possible transition state was proposed to explain the origin of the stereoselectivity. PMID- 28730203 TI - Growth study of hierarchical Ag3PO4/LaCO3OH heterostructures and their efficient photocatalytic activity for RhB degradation. AB - We have demonstrated the synthesis of Ag3PO4/LaCO3OH (APO/LCO) heterostructured photocatalysts by an in situ wet chemical method. From pre-screening evaluations of photocatalysts with APO/(x wt% LCO) composites with mass ratios of x = 5, 10, 15, 20, 25 and 30 wt%, we found that the APO/LCO (20 wt%) exhibited a superior photocatalytic activity for organic pollutant remediation. Therefore, an optimised photocatalyst APO/LCO (20 wt%) is selected for the present study and we investigate the effect of a mixed solvent system (H2O:THF) on the morphology, which has a direct effect on the photocatalytic performance. Interestingly, a profound effect on the morphological features of APO/LCO20 heterostructures was observed with variation in the ratio of the solvent system. From the FESEM study it is observed that the LCO spherical nanoparticles are transformed into nanorods with the variation of THF into the solvent system. Moreover, these LCO nanorods make intimate contact with the APO microstructures which is helpful for the improvement of the photocatalytic activity. The photocatalytic activities of the APO/LCO composites with different solvent ratios were evaluated by the degradation of rhodamine B (RhB) under visible light irradiation. Excellent photocatalytic activity was observed for the APO/LCO-2 (H2O : THF = 60 : 40) sample. This might be due to uniform covering of the APO microstructures by fine LCO rod-like structures offering intimate contact between the APO and LCO and providing proper channels for the degradation reactions. Furthermore, with an increasing THF volume ratio in the reaction system there was an increase of the dimensions of the LCO rod-like structures and also a loose compactness of their uniform intimate contact between the APO/LCO heterostructures. All in all, the enhanced photocatalytic activity of the APO/LCO heterostructures is attributed to the collective co-catalytic effect of LCO, by providing accelerated charge separation through the heterojunction interface, and THF, by helping to tune the unique morphological features which eventually facilitate the photocatalysis process. PMID- 28730204 TI - Electronic and charge transfer properties of bio-inspired flavylium ions for applications in TiO2-based dye-sensitized solar cells. AB - We present here a complete study on four synthetic environmentally friendly flavylium salts employed as sensitizers for dye-sensitized solar cells (DSSCs). The effect of several donor groups on the molecular structure of flavylium ions was investigated by combining electrochemical, spectroscopic and computational means. The computational investigation indicated that these molecules can interact strongly with the TiO2 surface by a single OH group of the dihydroxybenzene moiety, and can efficiently inject electrons into the TiO2 following the excitation of their lowest singlet states exhibiting charge transfer (CT) character. In general, all dyes within the explored series exhibited quite good regeneration efficiencies, often >=70%, in the presence of an iodide electron donor, explaining the high IPCEs and photocurrents recorded in the presence of high lithium content electrolytes. The combination of molecular orbital calculations and electrochemical measurements has also revealed that the introduction of donor groups on the benzopyrylium ring has a generally positive effect resulting in an extended low energy light harvesting and in a potential improvement of the photoinduced charge separation at the semiconductor/dye/electrolyte interface. It also increases the reversibility of the oxidative redox processes of these bio-inspired species, a feature in favour of their long-term stability. At present the best dye within the explored series is 7-(N,N-diethylamino)-3',4'-dihydroxyflavylium chloride based on a dialkylamine donor which is capable of delivering, under optimized conditions, a short-circuit current density of 15 mA cm-2. This is the highest value so far obtained for synthetic analogues of anthocyanins. PMID- 28730205 TI - Dithieno[3,2-b:2',3'-d]pyrrole-benzo[c][1,2,5]thiadiazole conjugate small molecule donors: effect of fluorine content on their photovoltaic properties. AB - Two new small molecule donors, namely ICT4 and ICT6 with D1-A-D2-A-D1 architecture having 2,4-bis(2-ethylhexyl)-4H-dithieno[3,2-b:2',3'-d]pyrrole (EHDTP, D1) and 4,8-bis((2-ethylhexyl)oxy)benzo[1,2-b:4,5-b']dithiophene (OBDT, D2) as the terminal and central donor, and benzo[c][1,2,5]thiadiazole (BT for ICT4) and 5,6-difluorobenzo[c][1,2,5]thiadiazole (F2BT for ICT6) as the acceptor (A) moieties, are synthesized and their optical, electronic and photovoltaic properties are investigated. Both ICT4 and ICT6 have considerable solubility in various solvents and possess efficient light absorption ability [epsilon (*105 mol-1 cm-1) is 0.99 and 1.06, respectively for ICT4 and ICT6] and appropriate frontier molecular orbital energy offsets with [6,6]-phenyl-C71-butyric acid methyl ester (PC71BM). Bulk heterojunction solar cells (BHJSCs) are fabricated using ICT4/ICT6 and PC71BM as donors and acceptors, respectively and BHJSCs with two-step annealed (thermal followed by solvent vapor annealing) active layers of ICT4 and ICT6 show overall power conversion efficiencies (PCEs) of 5.46% and 7.91%, respectively. The superior photovoltaic performance of the ICT6 based BHJSCs is due to the favourable morphology with a nanoscale interpenetrating network in the ICT6:PC71BM active layer induced by the fluorine atoms on the BT acceptor, which significantly enhances the dissociation of excitons, charge transport and the charge collection efficiency, and suppresses bimolecular recombination in the BHJ. The observed higher PCE of 7.91% indicates that ICT6 is one of the best BT based donor material for small molecular BHJSCs. PMID- 28730207 TI - Asymmetric Bronsted acid catalysis with chiral carboxylic acids. AB - Chiral Bronsted acids have found widespread applications as organocatalysts. Weakly acidic species such as diols and (thio)ureas, typically classified as hydrogen bonding catalysts, as well as stronger phosphoric acids, have proven to be highly effective in catalyzing a wide range of asymmetric transformations. In contrast, the use of chiral carboxylic acids as Bronsted acid catalysts is much less developed but has recently garnered increased attention. Given that their pKa's generally lie between those of typical hydrogen bond donors and chiral phosphoric acids, chiral carboxylic acids provide the opportunity to activate a different set of substrates requiring intermediate catalyst acidity. In addition, by taking advantage of judicious catalyst design, the acidity of carboxylic acids can be modulated, for instance by stabilizing the corresponding carboxylate counterion. This review provides an overview of this field, with the aim of highlighting both catalyst design and synthetic applications. PMID- 28730206 TI - Evaluation of dextran(ethylene glycol) hydrogel films for giant unilamellar lipid vesicle production and their application for the encapsulation of polymersomes. AB - Giant Unilamellar Vesicles (GUVs) prepared from phospholipids are becoming popular membrane model systems for use in biophysical studies. The quality, size and yield of GUVs depend on the preparation method used to obtain them. In this study, hydrogels consisting of dextran polymers crosslinked by poly(ethylene glycol) (DexPEG) were used as hydrophilic frameworks for the preparation of vesicle suspensions under physiological ionic strength conditions. A comparative study was conducted using hydrogels with varied physicochemical properties to evaluate their performance for GUV production. The prepared GUVs were quantified by flow cytometry using the Coulter Principle to determine the yield and size distribution. We find that hydrogels of lower mechanical strength, increased swellability and decreased lipid interaction favour GUV production, while their resulting size is determined by the surface roughness of the hydrogel film. Moreover, we embedded polymersomes into the crosslinked hydrogel network, creating a DexPEG - polymersome hybrid film. The re-hydration of lipids on those hybrid substrates led to the production of GUVs and the efficient encapsulation of polymersomes in the lumen of GUVs. PMID- 28730208 TI - Structural diversity of metal-organic self-assembly assisted by chlorine. AB - From the combination of STM imaging and DFT calculations, we show that both alkali metal and halogens interact with different sites of the target molecules resulting in structural formation in a synergistic way. The elementary metal organic motifs are connected by Cl in a variety of fashions demonstrating structural diversity. PMID- 28730209 TI - Geometric and electronic properties of Si-atom doped Al clusters: robustness of binary superatoms against charging. AB - The geometric and electronic properties of silicon-atom-doped aluminum clusters, AlnSim (n = 7-30, m = 0-2), were investigated experimentally. The size dependences of the ionization energy and electron affinity of AlnSim show that the stability of AlnSim is governed by the total number of valence electrons in the clusters, where Al and Si atoms behave as trivalent and tetravalent atoms, respectively. Together with theoretical calculations, it has been revealed that neutral Al10Si and Al12Si have a cage-like geometry with central Si atom encapsulation and closed electronic structures of superatomic orbitals (SAOs), and also that they both exhibit geometric robustness against reductive and oxidative changes as cage-like binary superatoms of Si@Al10 and Si@Al12. As well as the single-atom-doped binary superatoms, the effect of symmetry lowering was examined by doping a second Si atom toward the electron SAO closing of 2P SAO, forming Al11Si2. The corresponding anion and cation clusters keep their geometry of the neutral intact, and the ionization energy is low compared to others, showing that Al11Si2 is characterized to be, Si@Al11Si as an alkaline-like binary superatom. For Al21Si2, a face-sharing bi-icosahedral structure was identified to be the most stable as dimeric superatom clusters. PMID- 28730211 TI - Spring-like motion caused large anisotropic thermal expansion in nonporous M(eim)2 (M = Zn, Cd). AB - Two nonporous coordination polymers were found to possess large anisotropic thermal expansion, which was derived from the flexible structures. A "spring like" thermal motion was proposed to illustrate the mechanism. Compound Cd(eim)2 (eim = 2-ethylimidazole) possesses large linear and reversible thermal expansion properties and the emission intensity shows a linear decrease with temperature, making it a candidate for thermo-responsive materials. PMID- 28730210 TI - A layer-by-layer assembled MoS2 thin film as an efficient platform for laser desorption/ionization mass spectrometry analysis of small molecules. AB - A chip-based platform for laser desorption/ionization mass spectrometry (LDI-MS) analysis of small molecules was developed by utilizing layer-by-layer (LBL) assembly of MoS2 nanoflakes and polyallylamine on an arbitrary substrate. The LDI MS efficiency of small molecules on MoS2 films increased as a function of LBL assembly cycles until reaching a saturation point. The optimized MoS2 nanoflake film exhibits high LDI-MS efficiency, salt tolerance, reusability and uniform ionic signal distribution, and its performance was further enhanced by surface modification with perfluoroalkanes mimicking a clathrate nanostructure. PMID- 28730212 TI - Suspension-based imprint lithography of ZnO-PMMA hybrids. AB - Imprint lithography has been explored as a method to transfer arrays of patterned features onto pure polymers and polymer/metallic nanoparticle composites. Despite the success of this method for those materials, it has never been achieved on the sub-micron scale with polymer-oxide particle hybrids. This study patterns ZnO PMMA (poly(methyl methacrylate)) hybrids via imprint lithography from co suspensions of PMMA and ZnO nanoparticles in anisole from 1 vol% to 20 vol% ZnO solids loading. ZnO nanoparticles are functionalized with nonanoic acid to disperse the nanoparticles in anisole with dissolved PMMA. The feature fidelity of the patterned arrays decreases with increasing ZnO content, indicating an increase in particle agglomeration as the ZnO particle content increases. Feature size, ZnO content, and ZnO nanoparticle agglomeration are critical factors influencing the photoluminescence (PL) intensity. The ZnO solids loading at a 500 nm feature size needs to be 10 vol% or higher for the enhanced PL response. When the ridge size increases to 1 MUm, ZnO solids loading as low as 1 vol% is feasible. This method of lithographic patterning of nanoparticle-polymer suspensions can be applied to a wide variety of hybrid devices and has the potential to open many applications including optical devices and biomedical screening. PMID- 28730213 TI - Magnetic separation: its application in mining, waste purification, medicine, biochemistry and chemistry. AB - The use of strong magnetic field gradients and high magnetic fields generated by permanent magnets or superconducting coils has found applications in many fields such as mining, solid state chemistry, biochemistry and medical research. Lab scale or industrial implementations involve separation of macro- and nanoparticles, cells, proteins, and macromolecules down to small molecules and ions. Most promising are those attempts where the object to be separated is attached to a strong magnetic nanoparticle. Here, all kinds of specific affinity interactions are used to attach magnetic carrier particles to mainly objects of biological interest. Other attempts use a strong paramagnetic suspension for the separation of purely diamagnetic objects, such as bio-macromolecules or heavy metals. The application of magnetic separation to superconducting inorganic phases is of particular interest in combination with ceramic combinatorial chemistry to generate a library of e.g. cuprate superconductors. PMID- 28730214 TI - Palladium(ii) complexes of N,N-diphenylacetamide based thio/selenoethers and flower shaped Pd16S7 and prismatic Pd17Se15 nano-particles tailored as catalysts for C-C and C-O coupling. AB - 2-Bromo-N,N-diphenylacetamide (P1) prepared by reacting diphenylamine with alpha bromoacetyl bromide, on treatment with Na2S and Na2Se generated in situ, has resulted in thio and selenoether ligands, L1 ((Ph2NCOCH2)2S) and L2 ((Ph2NCOCH2)2Se), respectively. Reacting these ligands with Na2PdCl4 in ethanol at room temperature resulted in their complexes [Pd(L1/L2)2Cl2] (C1/C2). P1, L1, L2, C1 and C2 were characterized by 1H, 13C{1H} and 77Se{1H} NMR spectroscopy, IR spectroscopy and High resolution mass spectrometry (HR-MS). Single crystal structures of all the five compounds were determined by X-ray diffraction. In both C1 and C2 the geometry of Pd is nearly square planar. Flower shaped Pd16S7 (size 26-50 nm) and prismatic Pd17Se15 NPs (size 20-55 nm) were synthesized by a single source precursor route (thermolysis at ~280 degrees C in trioctylphosphine) from air and moisture insensitive C1 and C2, respectively. These shapes of the two nanophases were unknown hitherto. They were characterized by powder X-ray diffraction (PXRD), SEM-EDX and HR-TEM and found to show good catalytic activity for Suzuki-Miyaura (Pd loading 0.5 mol%; yield up to 96%) and C-O (Pd loading 0.5 mol%; yield up to 96%) coupling reactions (at 100 degrees C) of aryl bromides with phenylboronic acid and phenol, respectively. The complexes C1 and C2 were found very efficient for Suzuki-Miyaura and C-O coupling as revealed by their optimum loading of 0.0001-0.01 and 0.1 mol% of Pd, respectively, for the two reactions. The reuse of the complexes or NPs as a catalyst is demonstrated. PMID- 28730215 TI - Energetics and diffusion of liquid water and hydrated ions through nanopores in graphene: ab initio molecular dynamics simulation. AB - The energetics and diffusion of water molecules and hydrated ions (Na+, Cl-) passing through nanopores in graphene are addressed by dispersion-corrected density functional theory calculations and ab initio molecular dynamics (MD) simulations. Pores of about 0.8 nm in diameter with different pore-edge passivations, with (H) and (O, H) atoms, were considered. Our MD simulations show a water flux through the hydroxylated pores of about one H2O molecule every three picoseconds, in close agreement with recent experiments that estimated a water flux of three molecules per picosecond through pores of ~1 nm. We also find that both pores are effective in blocking hydrated Na+ and Cl- ions with large energy barriers, ranging from 12 to 15 eV. In addition, pore passivation with O atoms would increase the water transport through hydroxylated pores, due to the formation of hydrogen bonds with nearby water molecules, which is not observed in the hydrogenated pores. PMID- 28730216 TI - The importance of perinatal autopsy. Review of the literature and series of cases. AB - Perinatal autopsy remains the gold-standard procedure used to establish the fetal, neonatal or infant abnormalities. Progressively, perinatal pathology has become a specialized field with important roles of audit for fetal prenatal diagnostic tools, in parents counseling regarding future pregnancies, in scientific research, for epidemiology of congenital abnormalities and teaching. The differences between prenatal ultrasound and autopsy reports represent a strong argument for the autopsy examination following termination of pregnancy. The reasons for such discrepancies are related to the ultrasonographic or pathological examination conditions, the type of the anomalies, the expertise and availability of the operators. Several facts led to an undesirable increase of refusals from parents to consent to a conventional invasive autopsy: the centralization of pathology services, the poor counseling provided by non-experts in fetal medicine and the clinicians' over-appreciation of the importance of the ultrasound diagnostic investigation. Although non-invasive alternatives have been tested with promising results, conventional autopsy remains the gold standard technique for the prenatal diagnosis audit. We report and analyze several cases of prenatally diagnosed malformed fetuses with different particularities that underline the necessity of perinatal autopsy. We discuss the antenatal findings and management and post-mortem autopsies in the respective pregnancies. PMID- 28730217 TI - Novel perspectives on gastrointestinal stromal tumors (GISTs). AB - Since they were described, gastrointestinal stromal tumors (GISTs) are, for pathologists and not only for them, a subject of controversy regarding histological origin, differentiation, nomenclature, malignant potential and prognosis. Before 1998, there were no certainties that GISTs were fundamentally different from other types of abdominal cancers in the big family of mesenchymal tumors. Before the discovery of KIT gene mutations, GISTs were most often classified as leiomyoma, leiomyosarcoma, leiomyoblastoma, and gastrointestinal autonomic nerve tumor. When a tumor is discovered, the first data obtained are initially assessed by one or more imaging tests, such as an ultrasound, computed tomography scan or magnetic resonance imaging. The imaging results define the size of the lesion and its anatomic location, which in the case of GIST is usually within the wall of the stomach or intestine. Depending on the experience of the medical team - radiologist, gastroenterologist or surgeon - reviewing the imagistic tests and correlating them with the general patient profile, the differential diagnostic is reduced and GIST may become the main suspect. PMID- 28730218 TI - The morphogen behind primary congenital glaucoma and the dream of targeting. AB - Glaucoma is a clinical entity with multifactorial etiology, a severe subtype occurs in infancy called primary congenital glaucoma (PCG). Three distinct levels interact sequentially to produce PCG: (i) genetic mutations mainly affecting the CYP1B1 gene, (ii) absence or dysregulation of a morphogen, and (iii) trabecular meshwork pathological changes either in patterning or remodeling. We will discuss these three levels in detail towards further understanding of the morphological basis of the disease, focusing on the missing points, for instance the exact nature and function of the morphogen along with the putative role of CYP1B1 gene. PMID- 28730219 TI - Histological, immunohistochemical and clinical considerations on amniotic membrane transplant for ocular surface reconstruction. AB - Amniotic membrane (AM) transplantation has been used successfully worldwide in ophthalmology plastic surgery for over 100 years. This review presents the histological and the immunohistochemical features of AM compared to those of the conjunctiva and discusses the techniques of processing and preservation, its mechanism of action in ocular reconstruction, its clinical ophthalmic indications, but also advantages and limitations of grafting with this biomaterial. PMID- 28730220 TI - Verner-Morrison syndrome. Literature review. AB - Chronic diarrhea in infants is a common condition for addressability to pediatric gastroenterologists. The causes are multiple and the delay in reaching the final diagnosis can lead to complications in the general condition of the child. The purpose of this review is to present the bio-clinical and histogenetic particularities of a rare clinical entity, characterized by tumoral causes of chronic diarrhea. VIPomas are neuroendocrine tumors that autonomously secrete vasoactive intestinal peptide (VIP). Watery diarrhea, hypokalemia and achlorhydria (WDHA) syndrome caused by VIP-producing tumors only rarely occurs in adult patients with non-pancreatic disease. In pediatric patients, it is extremely rare for a VIPoma to originate in the pancreas; instead, WDHA syndrome is usually associated with VIP-secreting neurogenic tumors involving the retroperitoneum or mediastinum. The majority of VIP secreting tumors in pediatric patients are represented by ganglioneuroblastomas or ganglioneuromas originating in the adrenal medulla or sympathetic neural crest. This syndrome of watery diarrhea associated with hypokalemia and achlorhydria was first described by Verner and Morrison, in 1958, and has been assumed to be due to hypersecretion of VIP. In children, as well as in adult patients, the most likely explanation for persistent secretory diarrhea may be an occult VIPoma. In conclusion, the physicians should be aware that there are some rare tumoral causes of chronic diarrhea, often under-diagnosed. If the diagnosis is not considered, extensive gastrointestinal investigations will be undertaken, delaying the diagnosis and avoidable morbidity will occur. PMID- 28730221 TI - Usefulness of ultrastructure studies for the estimation of the postmortem interval. A systematic review. AB - Establishing the postmortem interval (PMI) is vital in legal medicine as it allows to retrospectively estimate the hour of death, which is essential for the police as a starting point for their inquiries (especially in violent deaths). Ultrastructure studies aimed specifically to detect autolytic changes are scarcely identified in the scientific literature. Moreover, they are performed in a variety of conditions (different temperatures, species, in vitro / in situ, and so on), making the results difficult to interpret for legal medicine purposes. The main aim of this review is to determine the potential usefulness of ultrastructure studies for the estimation of the postmortem interval and to provide a summary of relevant scientific literature in the area, which might be useful as a starting point for more specific and detailed studies in the field. We performed a search on the ISI Thomson Web of Knowledge database using a series of predefined keywords; the articles fulfilling the inclusion criteria were systematically analyzed to identify ultrastructure changes associated with autolysis. Our investigation revealed 20 relevant articles, which detailed ultrastructure changes in the brain, heart, liver, pancreas, kidney, bone, sweat glands, thyroid, skeletal muscle, cartilage and sweat glands. For each organ, we arranged systematically postmortem ultrastructure changes that were described by various authors. Ultrastructure changes appear early and may be useful in determining the time since death in the early postmortem interval. However, most studies published in this area followed methodologies that could not allow a proper reproducibility in forensic circumstances. Therefore, before using ultrastructure for estimating the PMI in practical environments, further studies are needed. They should be performed ideally on human samples, obtained at regular intervals after death, at variable, decreasing temperatures. PMID- 28730222 TI - Tuberculosis and its particularities in Romania and worldwide. AB - Tuberculosis (TB) is a global health issue, with a rising incidence since the beginning of this century. It poses a severe mortality risk and also poses a serious economic risk as it reduces the working capacity of an individual in the most productive part of life. Developing countries face widespread tuberculosis infection - up to 95% of all cases and 98% of deaths, respectively. It is a highly contagious infectious disease caused by Mycobacterium tuberculosis (the Koch bacillus) that can be contracted from either humans or animal hosts. Infection is also associated with immunodepressive conditions and can be contacted through airborne, digestive, cutaneous or other routes of transmission. Pulmonary TB can be either primary - when events follow a first contact between the organism and the bacillus, and secondary - in case of a reactivation of a latent primary infection. One of the aims of this review is to present the current epidemiological data of TB infections in Romania, compared to the rest of the world, with an analysis of associated conditions and extra-respiratory TB infections. One of the main conclusions of our review is that optimal management of this complex disease can only be achieved through a coherent national prevention and treatment program, with centralized financing and sufficient epidemiological, imaging and laboratory support, in conjunction with good patient compliance. PMID- 28730223 TI - Histopathological diagnosis and its correlations with anatomoclinical features, surgical approach and postoperative prognosis in sacral tumors. AB - INTRODUCTION: Sacral tumors encompass numerous histopathological types. They represent an uncommon pathology and, when diagnosed, they are often in advanced stage of the disease, becoming a therapeutic challenge. The correct treatment of a sacral tumor should be established by a multidisciplinary team that will assess the exact anatomical, imagistic and histopathological characteristic of the tumors thus choosing an optimal surgical approach while taking into consideration the risk of recurrence. MATERIAL AND METHODS: We conducted a retrospective analysis of both primitive and metastatic sacral tumors in "Bagdasar-Arseni" Emergency Hospital, Bucharest, Romania, for a period of 10 years, studying demographic data, clinical signs, anatomical and histopathological features as well as surgical approach and postoperative prognosis. RESULTS: Sacral tumors were diagnosed with a peak incidence in the age group 60-69 years, being more frequent in women. Primitive sacral tumor was predominant and, in this subgroup, chordoma was the most frequent. Metastatic tumors appeared in older subjects. None of the histopathological types associated a preferred topography of the resection or increased resectability. Posterior surgical approach was chosen in most cases, total resection being a hard goal to accomplish due to the invasion of vascular and nervous structures. Bleeding was the most frequently reported incident, carcinomas recording the highest blood loss amongst primitive tumors. Overall prognosis was clearly favorable for subjects diagnosed with primitive sacral tumors. CONCLUSIONS: Interpreting imaging data in a clinical context, paying attention to histopathological examination and knowing each histological type characteristics is mandatory in choosing the surgical approach thus obtaining the best postoperative outcome possible. PMID- 28730224 TI - Histopathological and immunohistochemical profile in primary Sjogren's syndrome. AB - Sjogren's syndrome (SS) is an autoimmune disease characterized by hypofunction of the salivary and lachrymal glands. Main clinical features of SS are sicca symptoms, due to the altered glandular function. Also, in advanced stages, bilateral swelling of the parotid glands can be noted, indicative of severe glandular involvement. Phenotypic expression of various mononuclear cells present in the affected tissue offers additional insight into cellular proliferation, survival, migration, antibody secretion and also the potential of forming tertiary lymphoid tissue, i.e., germinal centers. The main objective of the present study was to evaluate various autoimmune activity patterns present in salivary glands by means of immunohistochemistry (IHC) analysis. The study group comprised of 10 primary SS patients, with various degrees of lymphocytic infiltrates confirmed on minor salivary gland (MSG) biopsy. We could identify both morphological changes, i.e., ductal system abnormalities or increased interstitial fibrosis, and immunological patterns associated with SS pathogenesis. CD3+ T-cells displayed a more intense reaction in specimens with mild to intermediate focus score (FS) grade. Specimens with important CD20+ B cell component of lymphocytic infiltrate were associated with intermediate and severe FS grade. Specimens showed varying degrees of CD68+ cells, with more intense IHC reactions in slides displaying a more advanced mononuclear infiltration. Immunoreactivity was strong for both MMP-2 and MMP-8 matrix metalloproteinases, throughout the gland, in areas of acini, without it being linked with proximity of mononuclear cell infiltration. We could also establish some correlations between the degree of lymphocytic infiltration and clinical profile. PMID- 28730225 TI - Purkinje cells pathology in schizophrenia. A morphometric approach. AB - OBJECTIVES: Schizophrenia is a brain disorder that affects more than 21 million people worldwide. Ventricle enlargement and reduction in the volume of the temporal lobe overall and in medial temporal structures constitutes the main macroscopic findings, whilst synaptic and spinal changes as well as gliosis in the hippocampal formation, the prefrontal and the entorhinal cortex stand among cardinal microscopic findings in the schizophrenic brains. In recent years, accumulated evidence comes to light about the role of cerebellum in the pathophysiology of schizophrenia. MATERIALS AND METHODS: The present study is based on the morphological analysis and 3D neuronal reconstruction of the Purkinje cells from 10 schizophrenic brains and 10 normal controls. RESULTS: Significant morphological alterations such as loss of distal and terminal dendritic branches and decrease of the density of the dendritic spines constitute the main morphological findings found in the present study. CONCLUSIONS: The present findings may be added to accumulated evidence on macroscopic and microscopic pathology of the cerebellum in schizophrenia. Morphological alterations of Purkinje cells seem to be a central feature of neuropathology of schizophrenia, reflecting to impairment of neuronal connectivity and functionality, and related to motor and cognitive symptoms. PMID- 28730226 TI - Histopathological aspects of some rare forms of facial basal cell carcinoma. AB - AIM: The main objective of the study was to highlight the histopathological aspects of some rare forms of facial basal cell carcinomas. PATIENTS, MATERIALS AND METHODS: The 65 selected patients were diagnosed with head basal cell carcinoma (BCC), during 2011-2013, and they underwent surgery. The excised tumor tissue fragments were processed for paraffin embedding and stained with Hematoxylin-Eosin (HE), Masson's trichrome with Aniline Blue, and Alcian Blue Periodic Acid Schiff (AB-PAS). RESULTS: The youngest patient was 23 years old, while the oldest was 91 years. The facial BCC there was slightly higher prevalence in males of 34 out of 65 cases. Histopathologically, great varieties of morphological types have been identified in the 65 cases investigated. According to our data, by far the most common are nodular BCCs type, which represented 44.6% from the investigated cases, followed at some distance by morpheiform and superficial subtypes with 13.8% and 10.7%, respectively. The most rare cases of facial BCCs were: cystic, adenoid, fibroepithelial and basal with adnexal differentiation with in one single case each. Relatively rare were the following varieties: pigmented (four cases), combinations of several forms (four cases), metatypical (three cases), keratotic (three cases), and micronodular (two cases). CONCLUSIONS: Within the limits of this study, the data reported here shown that such a lesional pleomorphism very often requires to make a careful differential diagnosis with a number of other tumor or non-tumor entities. PMID- 28730227 TI - HPV genotyping and p16/Ki-67 dual staining in the detection of high-grade cervical lesion in patients with LSIL on Pap smear. AB - p16/Ki-67 dual-stained cytology, either alone or combined with human papillomavirus (HPV) 16/18 genotyping, could be a useful tool for triage for colposcopy of HPV-positive patients. Based on this background, we aimed at comparing the diagnostic performance of the p16/Ki-67 dual staining test, and high-risk HPV test for the detection of high-risk cervical intraepithelial neoplasia (CIN2/3) in patients diagnosed with low-grade squamous intraepithelial lesion (LSIL) on Pap smear. We performed a retrospective study including 184 patients with LSIL cytology on Pap smear, of which 64 were referred for biopsy after colposcopy. Prior biopsy HPV genotyping and dual staining test were performed on all 64 patients. The mean age of the patients selected for conization was 36 years and seven months. The pathological exam showed that 28.13% (18/64) from the patients LSIL on cytology were actually having CIN2/3: 12 cases with CIN2, five cases with CIN3 and one case of in situ cervical carcinoma. HPV positive were 56.25% (36/64) of the patients with LSIL. The p16/Ki-67 dual staining test was positive in 29.69% (19/64) of the patients with LSIL. Among women with LSIL cytology, the sensitivity and specificity of the HPV genotyping test for predicting CIN2/CIN3 were 94.44% (17/18) and 58.7% (27/46), respectively. The sensitivity and specificity of the p16/Ki-67 dual staining test were 66.67% (12/18) and 84.78% (39/46), respectively. Our results agree with other data available in literature and suggest that the p16/Ki-67 dual staining test could be included in the management protocol of patients with modified cytology as a triage test before referring those patients for colposcopy. PMID- 28730228 TI - HER-2/neu expression in different histological subtypes of papillary thyroid carcinoma. AB - The identification and validation of new, complementary prognostic factors represents a challenging issue in thyroid pathology, opening the perspective of papillary thyroid carcinoma (PTC) stratification based on differences of aggressiveness at molecular level. Our study aims to analyze the HER-2/neu expression in different subtypes of PTC and its relationship with the classical clinicopathological factors. We investigated 120 cases of sporadic PTC. The cases were selected based on the histological criteria reported to clinical course and prognosis and distributed in two different subgroups, namely low- and high-risk. HER-2/neu expression was assessed using an adapted semiquantitative score proposed for thyroid carcinomas. The correlations between HER-2/neu expression and clinicopathological prognostic factors were statistically analyzed. HER-2/neu positivity was found in 25 (20.8%) cases, from which 20 cases were classified as subtypes with low-risk and five with high-risk; 95 (79.2%) cases were HER-2/neu negative, 53 cases being included in low- and 42 cases, respectively, in high risk group. HER-2/neu expression was significantly associated with histological subtypes, extrathyroidal extension, and tumor focality. Our results highlight the potential of HER-2/neu as supplementary marker useful for the stratification of PTC in low-risk and high-risk histological groups, along with the well-known clinicopathological prognostic factors. Our data could be considered as new evidences that indicate different involvement of HER-2/neu in tumor development and behavior, possible due to its connection with other factors present in the molecular environment. PMID- 28730229 TI - Molecular analysis of BRCA1 and BRCA2 genes by next generation sequencing and ultrastructural aspects of breast tumor tissue. AB - In this paper, we focus our interest on the dynamics alterations of the tumor stroma interface at the ultrastructural level and to detect BRCA1 and BRCA2 mutations using next generation sequencing (NGS) of breast tumor tissue. Electron microscopic investigation revealed some peculiar infrastructural alterations of the tumor cells per se as well as of the tumor-stroma interface: invadopodia, shedding microvesicles, altered morphology and reduced number of telocytes, different abnormalities of the microvasculature. Tumor suppressor genes BRCA1 and BRCA2 are the genes with most hereditary predisposition to breast and ovarian cancer. An early identification of mutation within these genes is essential for determining classification and therapeutic approach to patients. Genetic tests used to determine mutations in BRCA1 and BRCA2 genes are laborious analysis methods which include, among others, NGS. We analyzed a total of eight samples, in which genomic DNA was amplified using Ion AmpliSeq panel BRCA1 and BRCA2. DNA libraries were created, amplified and sequenced with Ion Torrent Personal Genome Machine. The bio-information data obtained allow us to detect all known pathogenic mutation and uncertain polymorphisms. PMID- 28730230 TI - Magnetic nanoparticles-based therapy for malignant mesothelioma. AB - This work was aimed to analyze the versatility of the chick embryo chorioallantoic membrane (CAM) as in vivo model for the study of the malignant pleural mesothelioma (MPM) and the therapeutic potential of Fe3O4/salicylic acid magnetic nanoparticles (SaMNPs) on MPM cells. The antitumor effects of SaMNPs were studied by in vitro and in vivo tests on CARM-L12 TG3 rat malignant mesothelioma cells and human MPM xenografts implanted on CAMs. In order to assess the human MPM xenograft growth characteristics, calretinin, HBME-1 (Hector Battifora mesothelial epitope-1), and cytokeratins immunohistochemical stainings were performed. The human MPM xenografts continue to develop on the CAMs and xenograft MPM cells showed highly metastatic features and a particular pattern of metastasis. The SaMNPs had a specific uptake by the MPM cells and an antiproliferative effect at therapeutic doses greater than 100 MUg/mL. The results confirmed the possibility to use the CAM as in vivo model to study the biology of MPM and to evaluate the antitumor potential of new therapeutic agents. They highlighted a strong antitumor effect of the SaMNPs on the rat and human MPM cells and open new perspectives in the treatment of MPM. PMID- 28730231 TI - Chondroprotective effects of pulsed shortwave therapy in rabbits with experimental osteoarthritis. AB - INTRODUCTION: Osteoarthritis (OA) represents a public health challenge since the pathogenic treatment, able to induce cartilage regeneration, still remains unknown. Ageing of the population and increasing OA prevalence have led to a lot of research, aiming to identify treatments acting on chondrocytes that play a determinant role in cartilage degeneration/regeneration balance. Pulsed shortwave therapy (with the classical application form - Diapulse) is a physiotherapy method with anabolic effects demonstrated on nervous, conjunctive and vascular tissues, but its effects on OA cartilage are not known. AIM: Our aim was to demonstrate the effects of Diapulse on the cartilage in experimental induced OA. MATERIALS AND METHODS: Experimental OA was induced in 10 mature female rabbits by anterior cruciate ligament transection (ACLT). Ten weeks after ACLT, rabbits were randomized in a treatment group and a control group. Treatment group was exposed to Diapulse at a frequency of 27.12 MHz, pulse length of 65 MUs, pulse frequency of 300 pulses/s (300 Hz) for 10 minutes/day. Control group was exposed to sham therapy. After treatment, rabbits were sacrificed and the cartilage was evaluated by histopathological examinations with Hematoxylin-Eosin (HE) staining and transmission electron microscopy (TEM). RESULTS: OA characteristic changes were found in both groups. In the treatment group, we found that Diapulse influenced the degenerative process in the OA cartilage by improving the chondrocyte viability and the capacity to maintain cellular matrix integrity and structure. CONCLUSIONS: Diapulse can be considered a disease modifying therapeutic procedure and could be a reliable option for treatment of OA patients. PMID- 28730232 TI - Implications of inflammation and remodeling of the enteric glial cells in colorectal adenocarcinoma. AB - AIM: The aim of our study was to assess glial fibrillary acidic protein (GFAP) glial cell phenotype in the enteric nervous system (ENS) in colorectal adenocarcinoma of different tumor grading and, also, to establish correlations between these changes and the tumor proliferative activity and the tumor infiltrating leukocytes. PATIENTS, MATERIALS AND METHODS: We ran an observational, prospective study on a group of 52 patients diagnosed with colorectal adenocarcinoma. They were surgically treated in the 1st Surgery Clinic of the Emergency County Hospital of Craiova, Romania. From the surgically resected pieces, after pathological confirmation and tumor grading, 3-MUm thick seriate sections were cut and processed for immunohistochemistry for detecting GFAP, S100, CD45 and Ki-67. RESULTS: Evaluation of GFAP glial cell type in the ENS of colorectal cancer with different stages of differentiation showed that the density of these nervous elements is higher in well-differentiated (G1) colorectal tumors compared to moderately differentiated (G2) and poorly differentiated (G3) colorectal tumors. For well-differentiated colorectal adenocarcinoma, we did not find any correlations between GFAP glial cell type in the ENS and the tumor proliferative activity or with tumor-infiltrating leukocytes. In what the moderately and poorly differentiated adenocarcinoma are concerned, we found a high inverse variation between GFAP glial cell type in the ENS and the proliferative activity, on one hand, and, between GFAP glial cell type in the ENS and the tumor-infiltrating leukocytes, on the other hand. CONCLUSIONS: The decrease in the density of GFAP glial cell type in the ENS with tumor grading of colorectal cancer and the inverse variation with the tumor proliferative activity and with the tumor-infiltrating leukocytes might serve as putative prognostic factors in colorectal cancer. PMID- 28730233 TI - Assessment of T- and B-lymphocytes and VEGF-A in acute pancreatitis. AB - AIM: Highlighting certain characteristics of T- and B-lymphocytes, as well as of vascular endothelial growth factor-A (VEGF-A) as a prognosis factors for patients suffering from acute pancreatitis, with the scope of establishing diagnosis and therapy. MATERIALS AND METHODS: Pancreatic tissue samples were analyzed, originating from 21 patients deceased due to acute pancreatitis, between the years 2015 and 2016. The study group was subdivided into two subgroups by pathology duration. As control group, pancreatic tissue fragments were sampled from eight patients, deceased due to non-pancreatic acute surgical abdomen (NPASA). RESULTS: By analyzing the immunohistochemical expression of T lymphocytes (immunomarked with the anti-CD3 antibody) and of B-lymphocytes (immunomarked with the anti-CD20 antibody), both on the tissue sections originating from the study patients, as well as the control group patients, we established that these were mostly present in the interstitium, following which the acini, less frequently in the islets, in general with B-lymphocytes being less present than T-lymphocytes. VEGF-A also tends to emerge in the acini periphery, at the border with the stromal connective tissue, while the islets are almost negative for VEGF-A. CONCLUSIONS: We can state that the decreased expression of T- and B-lymphocytes in normal pancreatic tissue, surrounding the necrosis areas, can be used as an aggravated prognosis factor for patients diagnosed with acute pancreatitis. Moreover, the increased immunohistochemical expression of VEGF-A can play an important role in tracking the evolution and pathology of acute pancreatitis. PMID- 28730234 TI - Associated lesions of peri-implant mucosa in immediate versus delayed loading of dental implants. AB - Currently, immediate loading of dental implants is very attractive as a standard protocol for prosthetic restorations in edentulous patients. The aim of this study is to find out the intimate peri-implant mucosa response depending on timing of implant loading, immediate or delayed. Fifty-one screw implants Alpha Bio (Alpha-Bio Tec, Israel) were inserted in 42 partially edentulous patients according to standardized surgical techniques. At six months of loading, samples of peri-implant mucosa were harvested from 27 immediate loaded, respectively 24 delayed loaded implants, and subjected to microscopic examination. Peri-implant mucosa in both loadings revealed a continuous and stable stratified squamous epithelium with moderate acanthosis and slight hyperkeratosis. Severe fibrosis and tendency to scar-like lesions were present mainly in immediate loading. Slight to moderate density of inflammatory chronic cell populations of non uniform feature was common to both loading protocols. As compared to lymphocytes, higher scores of plasma cells were encountered in immediate loading. In immediate and delayed loading, the peri-implant mucosa as a new generated structure does not reveal different tissue responses. After six month of prosthetic loading, the healthy peri-implant mucosa is compatible with fibrosis and minor chronic inflammatory reactions. PMID- 28730235 TI - Histological and immunohistochemical study on the dental pulp of patients with diabetes mellitus. AB - Diabetes mellitus is a disease that brings numerous alterations in the human body, mainly on the blood vessels and nervous system, its complications being difficult to treat most of the time. Oral complications are largely known and studied. Changes that occur in the dental pulp are of importance for the dentists, considering regular procedures outcome. In early stages of the disease, new blood vessels appear especially under the odontoblasts layer as a reaction to stimuli. In later stages, the defense systems of the dental pulp are outnumbered, nervous branches will be destroyed and disorganized. When periodontal disease occurs as well the mortification of the dental pulp will be faster. PMID- 28730236 TI - Root fractures: epidemiological, clinical and radiographic aspects. AB - Chronic root fractures are a relative frequent dental condition, occurring both in vital teeth and in teeth with root canal treatment, with a difficult and frustrating diagnosis. Two clinical forms are described: crown-root fractures with crown origin and vertical root fractures with root origin. The aim of the study was to determine the prevalence of the root fractured extracted teeth in two dental clinics with different profile [oral rehabilitation (OR) and endodontics (E)] and to present some particular aspects of the root fractures. A retrospective study over a period of five years was performed to determine the number of extracted teeth and the motives for extraction. For root fractured extracted teeth were noted: fracture type, tooth vitality, restoration type. Although the number of the patients with tooth extractions in the five years period was significantly higher in OR clinic than in E clinic, the number of tooth extractions was almost similar. Most of the teeth (70.6%) were extracted for caries complications. The prevalence of the root fractured extracted teeth was 17.93%. In OR clinic, women had more root fractured extracted teeth compared with E clinic, where the number of root fractured extracted teeth was higher in men. Most extracted teeth for root fracture were teeth with prosthetic restorations followed by teeth with root canal treatment and dental fillings. The most extracted teeth for root fracture were maxillary premolars, almost similar for both sexes, followed by mandibular molars. The teeth with least extractions for root fractures were mandibular incisors and mandibular canine. PMID- 28730237 TI - Therapeutic potential of certain drug combinations on paclitaxel-induced peripheral neuropathy in rats. AB - BACKGROUND AND AIMS: Experimental research and clinical data support the potential combination therapy for the treatment of neuropathic pain. We aimed to investigate the analgesic effect of the following associations: gabapentin + etifoxine; tramadol + etifoxine; gabapentin + tramadol, in an experimental model of peripheral neuropathy induced by paclitaxel. MATERIALS AND METHODS: Neuropathy was induced in male Wistar rats by the daily administration of 2 mg/kg body weight (bw) paclitaxel intraperitoneally, four days in a row. Analgesics were given concomitantly with paclitaxel, in the following doses: tramadol 15 mg/kg bw, etifoxine 100 mg/kg bw, gabapentin 300 mg/kg bw. Tactile allodynia and mechanical hyperalgesia were assessed using the Dynamic Plantar Aesthesiometer apparatus (Ugo Basile). After 18 days of treatment, the brain and liver tissue susceptibility to lipid peroxidation was evaluated and the sciatic nerve histological examination of the effect on myelin fibers was performed. RESULTS AND CONCLUSIONS: Experimental data have shown a strong analgesic effect of these three tested combinations expressed mainly by the statistically significant increased maximum response time, both in the assessment of allodynia and hyperalgesia. The gabapentin + tramadol combination lead to the maximum analgesic effect, immediately after the discontinuation of paclitaxel (44.94%, p<0.0001) and throughout the study. The treatment associated with tramadol caused a reduction in lipid peroxidation in the brain as compared to paclitaxel group. Combination therapy showed reduced damage to myelinated fiber density in the sciatic nerve. The drug combinations used in the experiment showed therapeutic potential in the fight against neuropathic pain induced by the administration of taxanes. PMID- 28730238 TI - Altered expression of mTOR and autophagy in term normal human placentas. AB - Mammalian target of rapamycin (mTOR) and autophagy have been implied in trophoblast cells proliferation and invasion. This study investigated whether mTOR and autophagy were involved in placental development and fetal programming. A total of 90 term normal placentas (37-42 gestational weeks) were collected from women who underwent elective cesarean section, with large for gestational age (LGA), fetal growth restriction (FGR), and appropriate for gestational age (AGA) infants (n=30, respectively). Capillary volume density within peripheral villi significantly decreased in the FGR placentas compared with the AGA group (p<0.01). Autophagic vacuoles were more prominent in the FGR placentas than in the AGA pregnancies (p<0.001). LC3B-II and Beclin1 in placentas of FGR were increased by 99% and 83%, respectively, while p62 was descended by 39% (p<0.001), compared with that in the AGA group. Whereas, there was no significant differences in these autophagy-related proteins between the LGA and AGA pregnancies. Compared to the AGA pregnancies, placental mTOR was reduced by 30% in the FGR group and raised by 26% in the LGA group (p<0.05). Pearson's correlation analysis showed a significantly inverse correlation between mTOR level and LC3B-II expression (r=-0.456, p<0.01), as well as between mTOR and Beclin1 expression in term human placentas (r=-0.468, p<0.01). These results demonstrate that altered expression of mTOR and autophagy may be associated with the development of placentas and pathophysiology of FGR, and that there may be a reciprocal regulation between mTOR and autophagy in human placentas. PMID- 28730239 TI - Wnt and Nodal signaling simultaneously induces definitive endoderm differentiation of mouse embryonic stem cells. AB - Induced differentiation of definitive endoderm (DE) from embryonic stem cells (ESCs) has been the recent focus of studies investigating regeneration and transplantation of organs of the digestive system. Poor cell survival is the most important challenge to DE differentiation from ESCs. This study aimed to optimize culture conditions to promote the differentiation of mouse ESCs into DE, and to investigate the roles of the Wnt and Nodal signaling pathways in the DE differentiation. The mouse ESCs were treated with or without leukemia inhibitory factor, Wnt3a and Activin A alone or together, and examined the DE differentiation by the DE marker CXCR4 and the ESC marker Oct4. The result showed the optimal induction of differentiation was achieved in cells simultaneously treated with Wnt3a and Activin A. Induction of CXCR4 was also earlier when there was simultaneous activation of Wnt and Nodal signaling compared to the groups treated with only Wnt3a or Activin A alone. These findings provide the basis for the induced differentiation of ESCs for the generation of functional, mature cells of gastrointestinal lineage, which can be potentially used for cell replacement therapy, disease modeling, as well as drug discovery studies. PMID- 28730240 TI - A 16-year retrospective study of dacryocystitis in adult patients in the Moldavia Region, Romania. AB - PURPOSE: Chronic dacryocystitis (CD) is an inflammation of the lacrimal sac and nasolacrimal duct with a long-standing evolution. The aims of this study were to analyze the epidemiology and to evaluate the histopathological features and the chronic inflammation score (CIS) system of chronic dacryocystitis in the region of Moldavia, Romania, over a period of 16 years. METHODS: We conducted a retrospective descriptive analysis of all pathological reports of chronic dacryocystitis from the Department of Pathology, "Prof. Dr. Nicolae Oblu" Emergency Clinical Hospital, Iasi, Romania, between January 1, 1999 and December 31, 2015, with the final application of CIS. We also recorded the demographic information of patients and lesion localizations. RESULTS: Eighteen cases of CD were identified, with a female:male ratio of 8:1. Patient median age was 66.27 years (range 33-83 years), 55.55% being in their eighth and ninth decade of life. A non-systemized growth trend starting with 2002 could be identified. Microscopically, several histopathological features were identified, some of them being associated: epithelial lining hyperplasia with pseudopapillary folds (77.77% of the cases), epithelial invaginations in the submucosa (11.11%), squamous metaplasia (16.66%) or partial denudation (33.33%). The sac wall revealed chronic diffusion (88.88%) or nodular lymphocytic inflammation (11.11%). 5.55% of cases presented fibrosis in the lacrimal sac wall with few lymphocytes. Applying CIS system, the majority of cases (13 patients, 72.22%) were identified with moderate chronic inflammation, only one case (5.55%) pointed out a mild degree of inflammation with a CIS<3, but four (22.22%) cases showed severe inflammatory changes with a CIS>6. CONCLUSIONS: In our region, CD is more frequent in senior women, probably due to their deficient immune system. Histological specimens of CD are not commonly found in practice of pathologists, but when the histological sections are analyzed they reflect a multitude of aspects that need to be known in order to guide ophthalmologists in their practice. In our region, CD is more frequent in senior women, probably due to their deficient immune system and to the specific anatomy of their nasolacrimal duct. The histological appearances varied from patient to patient and even in the same patient varied from one area to another. There were histopathological changes indicating adaptive changes, which could lead to the development of malignant tumors at this level. Therefore, there is a need for patient education with CD both in terms of ophthalmic hygiene and in what regards possible complications in the absence of a regular presentation to the ophthalmologist. PMID- 28730241 TI - Muscle metastases from cervical carcinoma - case report. AB - Muscular metastases are rarely found in medical practice, and the reported cases in literature are not numerous. The diagnosis of these lesions involves an interdisciplinary collaboration. We present a case of secondary determination in the psoas muscle, with a starting point of cervical squamous carcinoma. In establishing the diagnosis, there contributed the clinical, imagistic and magnetic resonance evaluation and computed tomography (CT), the histopathological diagnosis being determined after the CT-guided biopsy puncture. PMID- 28730242 TI - Replaced common hepatic artery originating from the superior mesenteric artery and prepancreatic, anterior course in a patient with cephalic pancreaticoduodenectomy - case report. AB - The presence of hepatic arterial variations is particularly important for patients undergoing cephalic pancreaticoduodenectomy, because it can lead to unnecessary incidents or postoperative complications. We present the case of a patient with pancreatic head neoplasm in which the cephalic pancreaticoduodenectomy was performed and the origin of common hepatic artery from superior mesenteric artery, with an anterior, prepancreatic course. PMID- 28730243 TI - A 52-year-old man with gouty arthritis and erosive lesion in the hip. AB - The case study of peripheral and axial gouty arthritis is described in a 52-year old man without concomitant clinical evidence of tophaceus gout on physical evaluation on admission. Gout is a metabolic disorder related to excess of uric acid in the extracellular compartment, and deposition of monosodium urate crystals in the joints and other sites. Arthritis and tophi are major manifestations, which more often involve the peripheral joints asymmetrically. Chronic tophaceous gout commonly develops after a decade of recurrent polyarticular gout. With lower frequency, the axial skeleton (spine and sacroiliac region) may be affected, condition sometimes associated with additional concerns, diagnostic challenges and pitfalls. Higher suspicion index and utilization of novel radiographic tools can settle these matters. Radiographic imaging exams include plain radiography, computed tomography (CT), magnetic resonance imaging (MRI), and bone scintigraphy to show bone erosion and joint lesions characterizing the spectrum of gouty osteoarthropathy. PMID- 28730244 TI - Keratoacanthoma centrifugum marginatum: an unusual clinical and histopathological diagnostic pitfall. AB - Keratoacanthoma centrifugum marginatum (KCM) is a very rare variant of keratoacanthoma characterized by progressive peripheral growth accompanied by central healing. The tumor has the peculiar ability to involute spontaneously. A careful differential diagnostic with other skin carcinomas or hyperkeratotic lesions is required in order to ensure appropriate clinical management. We report a case of KCM in a 62-year-old man presenting with a solitary, large exophytic, sessile tumor located on the ventral side of the right lower leg, which developed over the course of one year from an initial erythematous papule. The patient presented history of local trauma. To our knowledge, this is the second report in the scientific literature supporting a possible traumatic etiology. Due to its rarity and lack of distinctive histopathological features, KCM poses a difficult diagnostic challenge. Therefore, the importance of an accurate histopathological examination and extensive use of ancillary studies for differential diagnosis is emphasized. PMID- 28730245 TI - Unusual triple combination of prostate, lung and skin cancer. AB - Multiple malignancies are an increasing combination in the recent years in cancer patients, due to prolonged survival rate and to the advances in diagnostic techniques and therapeutic management. We present the case of a patient diagnosed with prostate cancer and metachronous in one year with basal cell carcinoma of the skin and small lung cell carcinoma with lymph nodes and pararectal metastasis. To our best knowledge, this is the only case presented in the medical literature with these three different types of primary malignancy. In conclusion, multiple malignancies in the same patients are a real challenge to the physician, because an early diagnosis and specific treatment modalities are essential for successful patient management and increasing life expectancy. PMID- 28730246 TI - Spontaneous cholecystocutaneous fistula as a primary manifestation of gallbladder adenocarcinoma associated with gallbladder lithiasis - case report. AB - Spontaneous cholecystocutaneous fistula (SCF) is a rare complication of neglected calculous biliary disease and also an extremely rare complication of gallbladder neoplasm. This pathology has become even rarer because of prompt diagnosis and expedient surgical intervention for gallstones. So far, there is one published report of a SCF due to gallbladder adenocarcinoma. We present the case of a woman aged 87 years, admitted to the Vth Department of Surgery, Clinical Municipal Hospital of Cluj-Napoca (Romania) for a tumoral mass located in the epigastrium. In the epigastrium, the patient had three skin orifices of about 1-2 mm each, through which purulent secretion occurred. The abdominal ultrasound highlighted a cholecystocutaneous fistula with the presence of a subcutaneous gallstone. Intraoperatively, we found a cholecystocutaneous fistula, a 1 cm subcutaneous gallstone, gallbladder with thickened walls containing a cylinder-shaped gallstone of 5/3 cm. Fistulectomy, gallstones extraction and cholecystectomy were performed. The histopathological examination highlighted gallbladder adenocarcinoma. In conclusion, SCF can be the first significant manifestation of gallbladder cancer associated with neglected calculous biliary disease. PMID- 28730247 TI - Intramuscular human Dirofilaria repens infection of the temporal region - case report and review of the literature. AB - Dirofilariasis is a zoonotic worldwide-distributed disease, especially in regions with warm to temperate climate, where it recently recorded a significant increase of prevalence. A 61-year-old female, a dog owner, residing in the Southwest of Romania, near a swamp, developed a painless nodule in the left temporal region. The contrast-enhanced computed tomography (CT) scan revealed a temporal intramuscular cystic lesion. The surgical exploration confirmed the lesion as with intramuscular localization. The histopathology and biochemistry investigations established as a cause of the lesion an infestation with Dirofilaria repens species. The patient underwent an anthelmintic treatment with Diethylcarbamazine and the clinical and radiological follow-up did not revealed any recurrences within a period of 15 months after surgery. This is the second case reported in Craiova (Romania), the seventh worldwide reported case with localization in the temporal region, and the second one with intramuscular development in this region. The existence of such cases should alert the clinician to include parasitosis in the differential diagnosis of atypical space occupying lesions of the head regions. PMID- 28730248 TI - Clavicle anatomical osteosynthesis plate breakage - failure analysis report based on patient morphological parameters. AB - Clavicle fracture reported incidence is about 5% of fractures in adult; among them, those located in the middle third of the shaft represent more than 80% from the total of cases. Due to the special morphological and biomechanical constraints of the clavicle, several methods for restoring morphological integrity in these fractures are described, including conservative, non-surgical treatment. The last 10 years of clinical studies in the field have favored the surgical treatment for selected cases; several osteosynthesis implants are in use - mostly anatomical plates with specific advantages and documented complications. A failed anatomical clavicle plate was explanted and analyzed after a protocol using stereomicroscopy, scanning electron microscopy and energy dispersive spectrometry. Based on the computed tomography (CT) scan determination of patient morphological parameters, a finite elements analysis of the failure scenario was completed. The failure analysis has proved that the plate breakage had occurred in the point of maximal elastic stress and minor deformation. The clinical implication is that no hole should remain free of screw during clavicle plate fixation and the implant should be chosen based on patient morphological parameters. In comminuted clavicle fracture, anatomic bridging with locked plate technique may lead to implant failure due to increase of the stress in the midshaft area. Thorough knowledge of anatomy and morphology of complex bones like the clavicle is necessary. Modern osteosynthesis anatomical implants are still to be improved. PMID- 28730249 TI - Sebaceoma associated with seborrheic keratosis. AB - Sebaceoma associated with seborrheic keratosis has only been described once in the literature. Herein, we present an additional case in a 69-year-old woman who complained of a multicolored plaque on the left breast. Dermatoscopy showed a central orange lesion with orange globules suggestive of dilated glands. The periphery of the lesion was brown and gray, with some more pigmented zones. The histopathological study demonstrated a seborrheic keratosis in the peripheral areas, whereas the central part of the lesion was a sebaceoma. We performed an immunohistochemical study with antibodies against MSH6, MSH2, MLH1, and PMS2, which demonstrated preserved nuclear expression of the mismatch repair proteins, therefore ruling out Muir-Torre syndrome. PMID- 28730250 TI - Metastatic high-grade myxofibrosarcoma: review of a clinical case. AB - We present the particular clinical and histological features of a metastatic high grade myxofibrosarcoma (MFS) of the left buttock in a 77-year-old male patient. The tumor was biopsied and surgically removed in order to increase the patient's comfort, due to its increased size and aggressive clinical behavior. Computed tomography (CT) revealed metastases in the pleura and mediastinal lymph nodes, so limb-sparing tumor excision followed by palliative care was the best practice for the patient until the fatal outcome. The histological assessment revealed a tumor composed partly of solid sheets of spindled and pleomorphic cells, partly of areas with prominent myxoid matrix and numerous elongated capillaries. Mitotic figures are frequent, often atypical, followed by numerous giant cells with abundant eosinophilic elongated cytoplasm, resembling myoid cells often multinucleated. A panel of immunohistochemical stainings, including muscle specific actin (MSA), S-100, CD34, desmin and myogenin were performed with a negative result, which aided excluding other soft tissue tumors like rhabdomyosarcoma and leiomyosarcomas, while Ki-67 was highly expressed in more than 70% of the tumor cells. This tumor received 6 points in accordance with the Federation Nationale des Centres de Lutte Contre le Cancer (modified FNCLCC) and was defined as a high-grade MFS [stage IV, G3 pT2bN0M1, according to the 8th edition of TNM Classification of Malignant Tumors, ICD-O 8811/3 in World Health Organization (WHO) Classification 2013]. Due to the clinical findings combined with the histological profile, the fatal prognosis was expected, though the time period was shorter than predicted, confirming the aggressive nature of the tumor. Even if traditionally was considered MFS as a non-metastatic lesion, recent case reports and studies, including our case revealed that this tumors in fact have the potential to be fatal due to metastatic disease. PMID- 28730251 TI - Severe upper gastrointestinal bleeding determined by a gastric lymphoma associated with Helicobacter pylori-positive atrophic gastritis. AB - The pathogenesis of gastric cancer regardless of histological structure is a classic example of gene-environment interaction, and an important epidemiological aspect was the recognized association with Helicobacter pylori infection. This paper describes a case of gastric mucosa-associated lymphoid tissue (MALT) lymphoma in a young patient whose first sign of the disease was upper gastrointestinal bleeding and associated hemorrhagic shock. The patient is a 31 year-old man, diagnosed by endoscopy 10 years ago with H. pylori-positive chronic atrophic gastritis, who refused treatment to eradicate the bacterium and presents currently in the emergency room for serious upper gastrointestinal bleeding. Emergency upper gastrointestinal tract endoscopy highlights the presence of bleeding gastric tumors. It was a surgical emergency and intra-operatively the presence of invasive gastric cancer into the left hepatic lobe was noted which required total gastrectomy with the purpose of hemostasis. Immediate and remote postoperative evolution was favorable and post-operative follow-up at six months, 12 months, and 24 months showed no signs of local or distance occurrence. PMID- 28730252 TI - Morphological, imaging and surgical aspects in a complex case of uterine leiomyosarcoma - case report and review of the literature. AB - Leiomyosarcoma is a rare condition so there are relatively few and small case series and no prospective studies to provide clear guidelines regarding management. We report on a case that presents some particularities that further underline diagnostic and treatment difficulties posed by the affliction of such a rare tumor. This is the case of a 43-year-old woman who had a large tumor arising from the uterus, with a spectacular growth rate over a short period. The patient, with congenital spastic tetraparesis and hydrocephalus, came for belly enlargement with rapid increase in size over the previous two months. Physical exam and ultrasound lead to the conclusion of a large abdominal mass. A computed tomography scan showed a mass arising from the pelvis and a large amount of ascites. An exploratory laparotomy was performed and the histopathology report confirmed the diagnosis of uterine leiomyosarcoma. Leiomyosarcoma poses challenging problems regarding histological grading and, due to its rate of growth, real surgical difficulties. Final diagnosis is done by histopathological examination after surgical excision. Frequently, it is late diagnosed when complete removal of the tumor is often impossible. PMID- 28730253 TI - Fatal hypersensitivity pneumonitis after chemical occupational exposure. AB - Hypersensitivity pneumonitis (HP; extrinsic allergic alveolitis) is a rare non immunoglobulin E (IgE)-mediated inflammatory lung disease caused by inhalation exposure (occupational, recreational or ordinary home exposure). A 36-year-old female patient, without significant medical history, is referred to an outpatient pulmonology clinic for dry cough, shortness of breath, fever, fatigue and weight loss. Chest high-resolution computed tomography (HRCT) was performed, and significant lung fibrosis (especially centrilobular and interlobular in bilateral "thick lines"), traction bronchiectasis and alveolitis in both superior lobes are described. Lung function tests showed severe restrictive dysfunction. Transfer factor of the lung for carbon monoxide (TLCO) being very low, the flexible bronchoscopy was contraindicated. Surgical lung biopsy was performed. Histopathological examination showed characteristic lesions of chronic bilateral hypersensitivity pneumonitis. The patient died four days after the surgical intervention due to post-operative complications. Exposure to various chemical substances can form bonds with human proteins molecules and induce an exaggerated immune response in susceptible individuals. A high index of suspicion of occupational exposure can determine an early diagnosis with a better outcome. PMID- 28730254 TI - Giant abdominal lipofibroma - case presentation. AB - Abdominal lipomas are benign mesenchymal tumors of mature fatty tissue that may appear at any age. We present the case of a 58-year-old patient with a cardiovascular pathology, who presented with diffuse abdominal pains, asthenia, anterior thorax pains and palpitations, abdomen increase, symptoms that had an insidious onset. The clinical and imagistic examinations suggested the diagnosis of giant abdominal lipoma. The surgical intervention allowed the excision of an encapsulated tumor, of 250/220/230 mm, relatively well encapsulated, with a macroscopic aspect of section adipose tissue, with hard whitish areas, with a 12.3 kg weight. The histopathological examination confirmed the diagnosis of lipofibroma. PMID- 28730255 TI - Primary neuroendocrine tumors - an extremely rare cause of obstruction of extrahepatic bile ducts: a case report. AB - Primary neuroendocrine tumors of the extrahepatic bile ducts are extremely rare - up to date, only 77 cases have been reported in the literature, which represents between 0.2-2% of all gastrointestinal carcinoid tumors. The paper focuses on the case of a woman patient, aged 37 years, admitted to the Clinic with the diagnosis of obstructive jaundice, unaccompanied by pain and where imaging indicates a tumor in the third average of the common bile duct (CBD). The surgery involved the excision of CBD, lymphadenectomy and restoring the biliodigestive continuity of Roux-en-Y hepaticojejunostomy. The histopathological and immunohistochemical examinations revealed the presence of a well-differentiated neuroendocrine tumor of CBD. Based on the case report and literature, we attempted to accurately identify and relate this type of tumor to other varieties encountered in the extrahepatic bile ducts, pointing out elements of a positive diagnosis, differential diagnosis, histopathology and immunohistochemistry, and referring to the therapeutic attitude, evolutionary methods and prognosis. PMID- 28730256 TI - Advanced metastatic breast cancer in pregnancy: the imperative of physical breast examination in pregnancy. AB - Breast cancer is the most frequent cancer diagnosed among women; its association with pregnancy is not encountered. As childbearing age is increasing, the diagnosis of breast cancer associated pregnancy tends to be more often than years ago. Here we report a case of a 37-year-old patient, gravida 7, para 7, diagnosed at 30 weeks gestation with metastatic breast cancer. The patient presented to hospital due to an altered performance status. Obstetrical evaluation was within normal range. A metastatic infiltrating breast cancer poorly differentiated (G3) with satellite skin lesions (T4b), ipsilateral axillary and supraclavicular lymph nodes (N3), lung metastasis bilateral with pleural effusion and hepatic metastasis (M1), were diagnosed. The tumor was positive for estrogen receptor (ER) and progesterone receptor (PR) status and negative for human epidermal receptor protein-2 (HER-2)/neu immunostaining. Due to a significant worsening of the patient's dyspnea, a Caesarean section was performed under spinal anesthesia, at 30 + 2 days; and a newborn weighing 1700 g was delivered without malformations. The unsuccessful management of the cancer was inevitable and the patient died two weeks later. Despite her hospitalizations for six prior deliveries (last birth was one year ago), the presence of a palpable tumor was never observed. We aim to highlight the importance of the clinical examination at any given point in pregnancy in order to detect, investigate and treat any suspect tumor of the breast. PMID- 28730257 TI - Apocrine hidrocystoma of the foreskin. A case report and review of the literature. AB - Apocrine hidrocystoma (AH) is an uncommon benign cystic tumor that is rarely located in the genitalia. We present the case of a 52-year-old uncircumcised man who presented an AH on his foreskin. The lesion was non-proliferative. Including the present report, only 10 cases of penile AH have been published to date. Most patients are adult (mean age 39.2 years, range 25-56 years) and only one case in one child and another case in one adolescent have been reported. The lesion involves more commonly the foreskin followed by the shaft. The average maximum diameter was 1.6 cm (range 0.3-3 cm). The majority (70%) of tumors are unilocular. The main differential diagnosis of AH includes eccrine hidrocystoma, epidermal inclusion cyst and male median raphe cyst. Complete excision of the lesion is curative. PMID- 28730258 TI - Morphology with immunohistochemical and genetic profiling of high-grade neuroendocrine carcinoma of colon - a case report with review of literature. AB - Here we present a challenging case of a hepatic flexure colon tumor of 61-year old woman with no primary lesion of lung cancer. Immunohistochemistry was applied and 50 genes were analyzed by next-generation sequencing (NGS) technology. The tumor contained medium to large size neoplastic cells with evident nucleoli to be diagnosed poorly differentiated neuroendocrine predominantly large cell carcinoma of colon [G3: World Health Organization (WHO) 2010] (pT3 N0: 7th edition pTNM). Cytokeratin (CK) AE1/AE3 staining was predominantly membranous with partial distribution in "dot-like" pattern in perinecrotic cancer fields to be reminiscent of small cell carcinoma. Ki67 labeled over 90% of cancer cells with partial positive nuclear staining for thyroid transcription factor-1 (TTF-1). Using NGS, the following mutations were detected: nonsense mutations in four tumor suppressor genes [APC R1114X (molecular argument that the cancer was a primary tumor of colon), TP53 R213X, RB1 E137X and FBWX7 R393X & S282X], mutations in three receptor tyrosine kinases (RET A919V of high transforming activity, EGFR E114K and FLT3 L601I) well known as oncogenes. PMID- 28730259 TI - Clinical manifestations and morphological changes in one case with post-stroke Kluver-Bucy syndrome. AB - We present the case of a 71-year-old right-handed male, admitted to the Department of Neurology, Emergency County Hospital of Arad, Romania, on November 2015, with a rare case of Kluver-Bucy syndrome (KBS), following an ischemic stroke of the right temporal lobe, which was previously diagnosed in December 2014 and was treated accordingly. At the moment of second hospital admission, the patient was found somnolent and confused at home, with traumatic signs of biting of the tongue and urine emission. A couple days after admission, our patient became alert and presented hypersexuality, hypermetamorphosis, increased oral tendency, behavior changes including apathy with loss of anger and fear, and a very increased appetite, transient visual agnosia and right-left disorientation. In the initial phase, the patient could not recognize any members of his family, but he had a tendency to touch everything within his reach and place it into his mouth. The KBS presented in this case, following an ischemic stroke of the right temporal lobe provides distinct and intriguing insights into the possible pathophysiology of this syndrome. Often disruption of consciousness during recovery period may hide the clinical manifestation of the syndrome. PMID- 28730260 TI - Longer survival of a patient with glioblastoma resected with 5-aminolevulinic acid (5-ALA)-guided surgery and foreign body reaction to polyglycolic acid (PGA) suture. AB - In recent years, there is a growing evidence that using 5-aminolevulinic acid (5 ALA)-guided resection of a cerebral glioblastoma, associated with chemoradiotherapy determine a prolonged survival of these patients, even though this period do not exceed 15 months. 5-ALA is a natural biochemical precursor of heme that is metabolized to fluorescent porphyrins, particularly protoporphyrin IX (PPIX) and no foreign reaction were noted until now. However, foreign body reaction developing in neurosurgery is documented in a few number of cases to suture material, surgical hemostatic material, or surgical glove starch, but up to now we could not find any article about granulomatous inflammation to polyglycolic acid (PGA) suture after brain tumor resection. Here we present a case of a delayed foreign body granuloma to PGA suture diagnosed after 10 months following fluorescence-guided surgery with 5-ALA for resection of a cerebral glioblastoma that was difficult to diagnosis both clinically and on magnetic resonance imaging (MRI). Moreover, the survival time was longer. We correlate the appearance of foreign body granuloma with the patient's persistent pre- and postoperative lymphocytosis. We also suggest that the chronic inflammation inhibited the proliferation of any tumoral cells which could remain in the tumor bed because we did not noticed on serial MRI scans a rapidly tumor growth during the first 10 months after the initial surgery as we have expected to be for a glioblastoma. PMID- 28730261 TI - Post-medication Stevens-Johnson syndrome in a girl hospitalized for a norovirus and rotavirus infection. AB - Stevens-Johnson syndrome (SJS) is a cutaneous mucosal disorder characterized by extended necrosis and detachment of the epidermis affecting <10% of the body surface, caused by drugs or infections. The authors report a case of a girl with Depakine resistant epilepsy, who develops a SJS in the third week of introducing lamotrigine. The girl also presents an acute diarrheal disease with double viral etiology - rotavirus and norovirus. The clinical image comprises polymorphic erythematous maculopapular exanthema with vesicular and bullous elements, with ulcerations and desquamations at the level of the eyelids, mouth, anogenital area and tegument denuding at the level of the abdomen and limbs. The SCORTEN score (SCORe of Toxic Epidermal Necrosis) for establishing the seriousness is 1. The evolution of the disease is slowly favorable under conservative treatment, which does not involve the use of corticotherapy or intravenous immunoglobulins. Although there is a low incidence of this syndrome in pediatrics, it may occur as complication of using some drugs - mostly anti-epileptics or antibiotics, corroborated or not with an infectious process. PMID- 28730262 TI - Crypt hyperplastic enteropathy in distal duodenum in Helicobacter pylori infection - report of two cases without evidence of celiac disease. AB - OBJECTIVES: Patients with Helicobacter pylori (HP) infection have been reported to have in addition to duodenitis architectural changes of the duodenal bulb mucosa including villous atrophy and crypt hyperplasia. We here for the first time present two cases of HP-infected adult patients with a crypt hyperplastic enteropathy also in the distal duodenum mimicking celiac disease (CD). METHODS: We evaluated separately the morphology of the anatomical bulb and distal duodenal mucosa using validated quantitative morphometric tools, i.e., the villous height (VH) and crypt depth (CrD) and their ratios. The fresh frozen samples were evaluated for the presence of the CD-specific transglutaminase 2-targeted subepithelial IgA deposits. RESULTS: Both patients had celiac-type crypt hyperplastic mucosal injury in the distal part of the duodenum in the absence of serum autoantibodies and subepithelial IgA deposits. After two years follow-up, having still a normal gluten-containing diet, none of the patients developed CD. Moreover, in the patient re-biopsied two years later, the CD-type enteropathy had healed after HP eradication. CONCLUSIONS: Prospective studies on HP-infected patients are needed in order to confirm our findings. PMID- 28730263 TI - Unicameral bone cyst of the calcaneus - minimally invasive endoscopic surgical treatment. Case report. AB - The role of arthroscopic surgery for the treatment of various orthopedic pathologies has greatly improved during the last years. Recent publications showed that benign bone lesion may benefit from this minimally invasive surgical method, in order to minimize the invasiveness and the period of immobilization and to increase visualization. Unicameral bone cysts may be adequately treated by minimally invasive endoscopic surgery. The purpose of the current paper is to present the case report of a patient with a unicameral bone cyst of the calcaneus that underwent endoscopically assisted treatment with curettage and bone grafting with allograft from a bone bank, with emphasis on the surgical technique. Unicameral bone cyst is a benign bone lesion, which can be adequately treated by endoscopic curettage and percutaneous injection of morselized bone allograft in symptomatic patients. PMID- 28730264 TI - Is the human embryo legally defined and protected? Causes and consequences. AB - "Everyone's right to life shall be protected by law", states the article 2 of the European Convention of Human Rights (1950). This article guarantees the protection of life of all persons. The human embryo, however, does not seem to be under the protection of this article, or, at least not always. The human embryo does not have a nature clearly defined and it is not considered always as person. The law protects only two categories by its ordinary regulations: things and persons. Our main objective is to find out if the human embryo is or not protected, according to the legal framework in Romania. The purpose of the paper is: (1) to familiarize professionals with current debate on the status of the human embryo; (2) to provide main legal standards and regulations concerning this specific area with examples from case reports; (3) to summarize causes and consequences of the human embryo legal interpretations. Our conclusion is that the human embryo is not protected by the law in force at this moment, with very few exceptions. It depends, most of time, on the parent's wishes. From ethical point of view, we are in front of an open and long debate. The law should regulate and define the human embryo in a clear way. Legal standards are extremely necessary for all involved, in the context of the development of the medicine. Embryo's issues have profound implications for medical practice. PMID- 28730265 TI - Letter to the Editor: Medical students and plagiarism. PMID- 28730266 TI - [Malignant melanoma : Current status]. AB - CLINICAL ISSUE: The incidence of malignant melanoma is continuously increasing. The prognosis of metastatic disease is still limited. STANDARD TREATMENT: Until a few years ago palliative chemotherapy with a limited response rate was the standard treatment for metastatic melanoma. TREATMENT INNOVATIONS: Immunotherapy and targeted therapy provide new treatment options. Immune checkpoint inhibitors have significantly improved the prognosis. DIAGNOSTIC WORK-UP: Regional lymph node sonography, computed tomography (CT) of the neck, chest and abdomen and brain magnetic resonance imaging (MRI) are routinely used. As an alternative to CT scans 18 F fluorodeoxyglucose positron emission tomography (FDG-PET) may be used. PERFORMANCE AND ACHIEVEMENTS: Immunotherapy provides the chance of long term disease control in metastatic melanoma. Ipilimumab may provide long-term tumor control in approximately 20% of patients. Median overall survival of approximately 2 years is achieved during therapy with anti-programmed cell death (PD) 1 antibodies. For combined therapy of ipilimumab and nivolumab a response rate of almost 60% is achieved and 2-year survival is also approximately 60%. The range of immune-mediated side effects demands particular consideration. For response evaluation immune-related response criteria were defined. Furthermore, immunotherapeutic approaches, such as talimogene laherparepvec (T-VEC), which is a modified herpes virus can be used for intralesional injection. PRACTICAL RECOMMENDATIONS: An individual definition of the appropriate therapy for each patient is of particular importance. In the context of modern therapy regimens close patient monitoring is crucial. PMID- 28730269 TI - Emergence of Candida glabrata in vulvovaginal candidiasis should be attributed to selective pressure or virulence ability? AB - PURPOSE: Vulvovaginal candidiasis (VVC) is one of the most frequent female genital disorders and Candida glabrata is the second most common agent. Current study was aimed to study the susceptibility to antifungal agents of C. glabrata isolated from vaginal samples and some virulence attributes in order to better understand why this species is emerging as the main VVC agents. METHODS: A total of 60 C. glabrata vaginal isolates were included in this study. Firstly they were screened by susceptibility tests to antifungal agents. The isolates that showed sensitivity or resistance to fluconazole were evaluated for their virulence potential, including ability to adhere to polystyrene and vaginal ring, cell surface hydrophobicity (CSH) and capacity to form biofilm. RESULTS: Candida glabrata isolates varied significantly in adherence capacity, biofilm formation and CSH. However, it was possible to observe that isolates resistant to fluconazole adhered more efficiently to the vaginal ring and were statistically more able to form biofilm. CONCLUSION: These results allow hypothesizing that C. glabrata is an emergent agent in VVC probably because the treatment with fluconazole selects this species. But once adhered, yeasts remain on biotic or abiotic surfaces causing colonization or VVC symptomatology. PMID- 28730267 TI - Phantom-based standardization of CT angiography images for spot sign detection. AB - PURPOSE: The CT angiography (CTA) spot sign is a strong predictor of hematoma expansion in intracerebral hemorrhage (ICH). However, CTA parameters vary widely across centers and may negatively impact spot sign accuracy in predicting ICH expansion. We developed a CT iodine calibration phantom that was scanned at different institutions in a large multicenter ICH clinical trial to determine the effect of image standardization on spot sign detection and performance. METHODS: A custom phantom containing known concentrations of iodine was designed and scanned using the stroke CT protocol at each institution. Custom software was developed to read the CT volume datasets and calculate the Hounsfield unit as a function of iodine concentration for each phantom scan. CTA images obtained within 8 h from symptom onset were analyzed by two trained readers comparing the calibrated vs. uncalibrated density cutoffs for spot sign identification. ICH expansion was defined as hematoma volume growth >33%. RESULTS: A total of 90 subjects qualified for the study, of whom 17/83 (20.5%) experienced ICH expansion. The number of spot sign positive scans was higher in the calibrated analysis (67.8 vs 38.9% p < 0.001). All spot signs identified in the non calibrated analysis remained positive after calibration. Calibrated CTA images had higher sensitivity for ICH expansion (76 vs 52%) but inferior specificity (35 vs 63%) compared with uncalibrated images. CONCLUSION: Normalization of CTA images using phantom data is a feasible strategy to obtain consistent image quantification for spot sign analysis across different sites and may improve sensitivity for identification of ICH expansion. PMID- 28730268 TI - Detection of vessel wall calcifications in vertebral arteries using susceptibility weighted imaging. AB - PURPOSE: Calcification of the brain supplying arteries has been linked to an increased risk for cerebrovascular disease. The purpose of this study was to test the potential of susceptibility weighted MR imaging (SWMR) for the detection of vertebral artery calcifications, based on CT as a reference standard. METHODS: Four hundred seventy-four patients, who had received head CT and 1.5 T MR scans with SWMR, including the distal vertebral artery, between January 2014 and December 2016, were retrospectively evaluated and 389 patients were included. Sensitivity and specificity for the detection of focal calcifications and intra- and interobserver agreement were calculated for SWMR and standard MRI, using CT as a standard of reference. The diameter of vertebral artery calcifications was used to assess correlations between imaging modalities. Furthermore, the degree of vessel stenosis was determined in 30 patients, who had received an additional angiography. RESULTS: On CT scans, 40 patients showed a total of 52 vertebral artery calcifications. While SWMR reached a sensitivity of 94% (95% CI 84-99%) and a specificity of 97% (95% CI 94-98%), standard MRI yielded a sensitivity of 33% (95% CI 20-46%), and a specificity of 93% (95% CI 90-96%). Linear regression analysis of size measurements confirmed a close correlation between SWMR and CT measurements (R 2 = 0.74, p < 0.001). Compared to standard MRI (ICC = 0.52; CI 0.45-0.59), SWMR showed a higher interobserver agreement for calcification measurements (ICC = 0.84; CI 0.81-0.87). CONCLUSIONS: For detection of distal vertebral artery calcifications, SWMR demonstrates a performance comparable to CT and considerably higher than conventional MRI. PMID- 28730270 TI - The patient experience of musculoskeletal imaging tests for investigation of inflammatory arthritis: a mixed-methods study. AB - The objective of this study was to understand the patient experience of musculoskeletal imaging tests for investigation of inflammatory arthritis and factors that contribute to this experience. We conducted a thematic analysis of semi-structured interviews with 33 patients who had a recent peripheral joint musculoskeletal imaging test for investigation of inflammatory arthritis. Data from these interviews were used to generate an 18-item questionnaire which was posted to rheumatology clinic patients within 6 weeks of peripheral joint imaging. Variables associated with the overall experience of the test were analysed using stepwise linear regression. Analysis of the interviews identified six themes: knowledge about the test, awareness of potential harm, the role of imaging in clinical care, discomfort, experience of waiting and 'seeing is believing'. Completed questionnaires were available from 132 patients. In regression analysis, a strong negative association was observed between the 'discomfort during the test' item and the overall experience of the test (standardised beta -0.35, p < 0.001). 'Staff made the experience better' (0.26, p < 0.001) and 'information provided' (0.28, p < 0.001) were positively associated with the overall experience of the test. For those who viewed their images, 'looking at the images with my doctor made me feel more involved in my care' (0.24, p = 0.022) was also associated positively with overall experience. Factors before, during and after a musculoskeletal imaging test contribute to the patient experience. The overall experience is most influenced by patient discomfort and interactions with staff during the test, information provided and viewing images to improve patient involvement in clinical care. PMID- 28730271 TI - Serious adverse events after HPV vaccination: a critical review of randomized trials and post-marketing case series. AB - This article critically reviews HPV vaccine serious adverse events described in pre-licensure randomized trials and in post-marketing case series. HPV vaccine randomized trials were identified in PubMed. Safety data were extracted. Post marketing case series describing HPV immunization adverse events were reviewed. Most HPV vaccine randomized trials did not use inert placebo in the control group. Two of the largest randomized trials found significantly more severe adverse events in the tested HPV vaccine arm of the study. Compared to 2871 women receiving aluminum placebo, the group of 2881 women injected with the bivalent HPV vaccine had more deaths on follow-up (14 vs. 3, p = 0.012). Compared to 7078 girls injected with the 4-valent HPV vaccine, 7071 girls receiving the 9-valent dose had more serious systemic adverse events (3.3 vs. 2.6%, p = 0.01). For the 9 valent dose, our calculated number needed to seriously harm is 140 (95% CI, 79 653) [DOSAGE ERROR CORRECTED] . The number needed to vaccinate is 1757 (95% CI, 131 to infinity). Practically, none of the serious adverse events occurring in any arm of both studies were judged to be vaccine-related. Pre-clinical trials, post-marketing case series, and the global drug adverse reaction database (VigiBase) describe similar post-HPV immunization symptom clusters. Two of the largest randomized HPV vaccine trials unveiled more severe adverse events in the tested HPV vaccine arm of the study. Nine-valent HPV vaccine has a worrisome number needed to vaccinate/number needed to harm quotient. Pre-clinical trials and post-marketing case series describe similar post-HPV immunization symptoms. PMID- 28730273 TI - Glucose as a stimulation agent in the BOLD functional magnetic resonance imaging for liver cirrhosis and hepatocellular carcinoma: a feasibility study. AB - PURPOSE: To explore the role of glucose as a stimulation agent in the blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) for liver cirrhosis and hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Twenty HCC patients with cirrhosis and 10 healthy volunteers were recruited. BOLD fMRI was performed for all participants prior to and 30 min after oral administration of glucose to measure the T2* values of normal liver parenchyma, HCC liver parenchyma, HCC center, and HCC edge. Variations of the T2*(?T2*) before and after administration were calculated. RESULTS: Data from 16 patients and 10 healthy volunteers were reported. Before and after oral administration of glucose, T2* values of the normal liver parenchyma, HCC liver parenchyma, and HCC center were statistically different (p < 0.01), while no statistical difference was found in T2* value of the HCC edge (p = 0.35). ?T2* values of the normal liver parenchyma, HCC liver parenchyma, HCC center, and HCC edge were 2.8 +/- 1.1 ms, -1.3 +/- 1.2 ms, -2.1 +/- 1.8 ms, and 0.8 +/- 3.2 ms before and after administration, respectively. ?T2* value was statistically different in the liver parenchyma between healthy volunteers and HCC patients and between HCC center and HCC edge (both p < 0.01). CONCLUSION: Use of glucose as the stimulation agent in BOLD fMRI may facilitate the assessment of liver function for patients with liver cirrhosis. The potential of ?T2* to correlate with severity of liver cirrhosis, as well as to evaluate hepatic artery perfusion and bioactivity of HCC center should be further investigated. PMID- 28730274 TI - Laparoscopic liver resection of hepatocellular carcinoma located in segments 7 or 8. AB - BACKGROUND: Many centers consider hepatocellular carcinoma (HCC) located in segments 7 or 8 to be unsuitable for laparoscopic liver resection (LLR). We evaluated the safety of LLR of HCC in segments 7 or 8 following the introduction of new laparoscopic techniques. METHODS: This retrospective study included 104 patients who underwent LLR (n = 46) or open liver resection (OLR) (n = 58) for HCC located in segments 7 or 8 between October 2004 and June 2015. The LLR group was subdivided into two subgroups according to whether LLR was performed before (Lap1; n = 29) or after (Lap2; n = 17) the introduction of the Pringle maneuver, intercostal trocars, and semi-lateral patient positioning. RESULTS: Non anatomical resection was more frequent (63.0 vs. 29.3%; P < 0.001) and tumor size was smaller (2.8 vs. 4.7 cm; P < 0.001) in the LLR group than in the OLR group. Blood transfusion (P = 0.526), operation time (P = 0.267), postoperative complications (P = 0.051), and resection margin (P = 0.705) were similar in both groups. LLR was associated with less blood loss (550 vs. 700 ml, P = 0.030) and shorter hospital stay (8 vs. 10 days; P = 0.001). The 3-year overall (90.2 vs. 81.2%, P = 0.096) and disease-free survival (15.1 vs. 12.1%; P = 0.857) rates were similar in both groups. The Lap2 group has less blood loss (230 vs. 500 ml; P = 0.005) and shorter hospital stay (7 vs. 9 days; P = 0.038) compared with the Lap1 group. CONCLUSION: LLR can be safely performed for HCC located in segments 7 or 8 with recent improvements in surgical techniques and accumulated experience. PMID- 28730275 TI - Comparative analysis of open and robotic transversus abdominis release for ventral hernia repair. AB - BACKGROUND: Transversus abdominis release (TAR) is a safe, effective strategy to repair complex ventral incisional hernia (VIH); however, open TAR (o-TAR) often necessitates prolonged hospitalization. Robot-assisted TAR (r-TAR) may benefit short-term outcomes and shorten convalescence. This study compares 90-day outcomes of o-TAR and r-TAR for VIH repair. METHODS: A single-center, retrospective review of patients who underwent o-TAR or r-TAR for VIH from 2015 to 2016 was conducted. Patient and hernia characteristics, operative data, and 90 day outcomes were compared. The primary outcome was hospital length of stay, and secondary metrics were morbidity, surgical site events, and readmission. RESULTS: Overall, 102 patients were identified (76 o-TAR and 26 r-TAR). Patients were comparable regarding age, gender, body mass index, and the presence of co morbidities. Diabetes was more common in the open group (22.3 vs. 0%, P = 0.01). Most VIH defects were midline (89.5 vs. 83%, P = 0.47) and recurrent (52.6 vs. 58.3%, P = 0.65). Hernia characteristics were similar regarding mean defect size (260 +/- 209 vs. 235 +/- 107 cm2, P = 0.55), mesh removal, and type/size mesh implanted. Average operative time was longer in the r-TAR cohort (287 +/- 121 vs. 365 +/- 78 min, P < 0.01) despite most receiving mesh fixation with fibrin sealant alone (18.4 vs. 91.7%, P < 0.01). r-TAR trended toward lower morbidity (39.2 vs. 19.2%, P = 0.09), less severe complications, and similar rates of surgical site events and readmission (6.6 vs. 7.7%, P = 1.00). In addition, r-TAR resulted in a significantly shorter median hospital length of stay compared to o TAR (6 days, 95% CI 5.9-8.3 vs. 3 days, 95% CI 3.2-4.3). CONCLUSIONS: In select patients, the robotic surgical platform facilitates a safe, minimally invasive approach to complex abdominal wall reconstruction, specifically TAR. Robot assisted TAR for VIH offers the short-term benefits of low morbidity and decreased hospital length of stay compared to open TAR. PMID- 28730272 TI - Mitochondria as a target of cardioprotection in models of preconditioning. AB - Over the recent years the view on mitochondria in the heart as a cellular powerhouse providing ATP supply needed to sustain contractile function, basal metabolic processes, and ionic homeostasis has changed radically. At present it is known that dysfunctions of these organelles are essential in the development of a large number of diseases, including cardiovascular diseases. Moreover, mitochondria are considered to be a very promising target of endogenous strategies that are essential in the protection of the myocardium from acute ischemia/reperfusion injury. These strategies including ischemic preconditioning, remote ischemic preconditioning as well as the acute phase of streptozotocin induced diabetes mellitus, provide a similar effect of protection. Alterations observed in the functional and structural properties of heart mitochondria caused by short-term pathological impulses are associated with endogenous cardioprotective processes. It seems that the extent of mitochondrial membrane fluidization could be an active response mechanism to injury with a subtle effect on membrane-associated processes which further affect the environment of the whole organelle, thus inducing metabolic changes in the heart. In this review article, we provide an overview of endogenous protective mechanisms induced by hypoxic, pseudohypoxic and ischemic conditions with special consideration of the role of heart mitochondria in these processes. PMID- 28730276 TI - Effect of patient-reported smoking status on short-term bariatric surgery outcomes. AB - INTRODUCTION: Preoperative patient screening is a major contributor to the remarkable safety of bariatric surgery. Smoking status is a modifiable patient risk factor, and smoking cessation is associated with improved outcomes in surgical patients. However, the length of smoking cessation necessary to optimize bariatric surgery patient outcomes is not yet defined. We sought to explore the relationship between patient-reported smoking status and short-term bariatric surgery outcomes. METHODS: Using prospectively collected data from the MBSC registry, we evaluated the effects of patient-reported length of tobacco abstinence on 30-day surgical outcomes. Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) patients (n = 49,772) were divided into three categories based on smoking status: never smoker, former smoker, and recent smoker. We compared risk-adjusted complication rates using multivariable logistic regression models and compared excess body weight loss using a one-way ANOVA test. RESULTS: The risk-adjusted rate of severe complications among RYGB patients in the recent smoker group was significantly increased relative to patients who had never smoked (OR 1.34; 95% CI, 1.01-1.77), but not among SG patients (OR 1.18; 95% CI 0.87-1.62). In the same populations, differences in overall complication rate were not significant for either RYGB (OR, 1.11; 95% CI 0.94-1.31) or LSG (OR 1.04; 95% CI 0.86-1.25). CONCLUSIONS: Recent smokers suffer detrimental effects of smoking on serious postoperative complications following RYGB surgery, but may not suffer an elevated risk of complications attributable to smoking for sleeve gastrectomy. An evaluation of the effect on long-term outcomes is necessary to further define the risks of smoking on bariatric surgery outcomes. PMID- 28730279 TI - Potentially Inappropriate Antidepressant Prescriptions Among Older Adults in Office-Based Outpatient Settings: National Trends from 2002 to 2012. AB - Using data from 2002 to 2012 National Ambulatory Medical Care Survey, we estimated that the prevalence of overall antidepressant prescriptions increased almost twofold from 5.2% in 2002 to 10.1% in 2012 in office-based outpatient visits made by older adults. In addition, older adults were exposed to the risk of potentially avoidable adverse drug events in approximately one in ten antidepressant-related visits, or 2.2 million visits annually. Amitriptyline and doxepin were the two most frequent disease-independent potentially inappropriate antidepressants. Racial/ethnic minorities, and Medicaid beneficiaries had higher odds of potentially inappropriate antidepressant prescriptions (P < 0.05). Efforts to minimize potentially inappropriate antidepressant prescriptions are needed. PMID- 28730278 TI - Mobilizing Community Health Workers to Address Mental Health Disparities for Underserved Populations: A Systematic Review. AB - This systematic review evaluates efforts to date to involve community health workers (CHWs) in delivering evidence-based mental health interventions to underserved communities in the United States and in low- and middle-income countries. Forty-three articles (39 trials) were reviewed to characterize the background characteristics of CHW, their role in intervention delivery, the types of interventions they delivered, and the implementation supports they received. The majority of trials found that CHW-delivered interventions led to symptom reduction. Training CHWs to support the delivery of evidence-based practices may help to address mental health disparities. Areas for future research as well as clinical and policy implications are discussed. PMID- 28730277 TI - Regulation of class V myosin. AB - Class V myosin (myosin-5) is a molecular motor that functions as an organelle transporter. The activation of myosin-5's motor function has long been known to be associated with a transition from the folded conformation in the off-state to the extended conformation in the on-state, but only recently have we begun to understand the underlying mechanism. The globular tail domain (GTD) of myosin-5 has been identified as the inhibitory domain and has recently been shown to function as a dimer in regulating the motor function. The folded off-state of myosin-5 is stabilized by multiple intramolecular interactions, including head GTD interactions, GTD-GTD interactions, and interactions between the GTD and the C-terminus of the first coiled-coil segment. Any cellular factor that affects these intramolecular interactions and thus the stability of the folded conformation of myosin-5 would be expected to regulate myosin-5 motor function. Both the adaptor proteins of myosin-5 and Ca2+ are potential regulators of myosin 5 motor function, because they can destabilize its folded conformation. A combination of these regulators provides a versatile scheme in regulating myosin 5 motor function in the cell. PMID- 28730280 TI - Evidence for the involvement of the GABAergic, but not serotonergic transmission in the anxiolytic-like effect of bisabolol in the mouse elevated plus maze. AB - Bisabolol (alpha-(-)-bisabolol) is a sesquiterpene which is a part of the essential oil of a variety of plants, but its common source is German chamomile. Several bioactivities including anti-inflammatory, anti-nociceptive, and anti tumor effects were attributed to bisabolol. However, the neuropharmacological properties of bisabolol have not yet been reported. The present study evaluated behavioral effects of bisabolol using elevated plus maze (EPM), open field test (OFT), and rotarod test. Moreover, this study also examined whether the 5-HT1A and GABAA-benzodiazepine receptor systems are involved in the anxiolytic-like effects of bisabolol. After acute intraperitoneal treatment with bisabolol at the doses of 0.5, 1, 2, 5, and 10 mg/kg, OFT, EPM, and rotarod were utilized for investigating behavioral effects. Flumazenil, a benzodiazepine receptor antagonist, and WAY-100635, a 5-HT1A receptor antagonist, were used to determine the action mechanism in the EPM. Bisabolol especially at the dose of 1 mg/kg was effective in increasing the total number of entries and time spent in the open arms of EPM while number of rearing and grooming in OFT was decreased in comparison to the control. In the rotarod, permanence time was decreased in the mice treated with the high doses of bisabolol. Pretreatment with flumazenil, but not WAY-100635, was able to reverse the effect of bisabolol 1 mg/kg in the EPM, indicating that the anxiolytic-like activity of bisabolol occurs via the GABAergic but not serotonergic transmission. The present study supports the idea that bisabolol may mediate its anxiolytic-like and sedative mechanisms involving GABAA receptors. PMID- 28730281 TI - PK/PD studies on non-selective PDE inhibitors in rats using cAMP as a marker of pharmacological response. AB - In recent years, phosphodiesterase (PDE) inhibitors have been frequently tested for the treatment of experimental inflammatory and immune disorders. It is suggested that anti-inflammatory properties of PDE inhibitors are related to their ability to increase cAMP levels. The aim of this study was to verify the hypothesis that cAMP may be a useful marker of pharmacological response following administration of non-selective PDE inhibitors (pentoxifylline and (+/-) lisofylline) to endotoxemic rats. Male Wistar rats were administered LPS (1 mg kg 1, i.v.) simultaneously with either compound given at two doses (40 and 80 mg kg 1, i.v.). Levels of cAMP and both compounds in animal plasma were measured by the validated HPLC methods. Pharmacokinetic-pharmacodynamic analysis was performed using basic and modified indirect response (IDR) models II in Phoenix WinNonlin. The results of this study indicate that, in contrast to pentoxifylline, (+/-) lisofylline demonstrates a non-linear pharmacokinetics in rats with endotoxemia. In vitro study using human recombinant PDE4B and PDE7A revealed the occurrence of additive interaction between studied compounds. Moreover, (+/-)-lisofylline is a more potent inhibitor of PDEs compared to pentoxifylline, as evidenced by lower IC50 values. Following administration of both compounds, levels of cAMP in rat plasma increased in a dose-dependent manner. The modified IDR model II better described cAMP levels over time profiles. The validity of the proposed marker was confirmed by measuring plasma TNF-alpha levels in the studied animals. In conclusion, cAMP may be used in future preclinical and clinical studies of some PDE inhibitors to evaluate the drug concentration-effect relationship. PMID- 28730282 TI - Blockade of alpha2-adrenergic receptors in prelimbic cortex: impact on cocaine self-administration in adult spontaneously hypertensive rats following adolescent atomoxetine treatment. AB - RATIONALE: Research with the spontaneously hypertensive rat (SHR) model of attention deficit/hyperactivity disorder demonstrated that chronic methylphenidate treatment during adolescence increased cocaine self administration established during adulthood under a progressive ratio (PR) schedule. Compared to vehicle, chronic atomoxetine treatment during adolescence failed to increase cocaine self-administration under a PR schedule in adult SHR. OBJECTIVES: We determined if enhanced noradrenergic transmission at alpha2 adrenergic receptors within prefrontal cortex contributes to this neutral effect of adolescent atomoxetine treatment in adult SHR. METHODS: Following treatment from postnatal days 28-55 with atomoxetine (0.3 mg/kg) or vehicle, adult male SHR and control rats from Wistar-Kyoto (WKY) and Wistar (WIS) strains were trained to self-administer 0.3 mg/kg cocaine. Self-administration performance was evaluated under a PR schedule of cocaine delivery following infusion of the alpha2 adrenergic receptor antagonist idazoxan (0 and 10-56 MUg/side) directly into prelimbic cortex. RESULTS: Adult SHR attained higher PR break points and had greater numbers of active lever responses and infusions than WKY and WIS. Idazoxan dose-dependently increased PR break points and active lever responses in SHR following adolescent atomoxetine vs. vehicle treatment. Behavioral changes were negligible after idazoxan pretreatment in SHR following adolescent vehicle or in WKY and WIS following adolescent atomoxetine or vehicle. CONCLUSIONS: alpha2-Adrenergic receptor blockade in prelimbic cortex of SHR masked the expected neutral effect of adolescent atomoxetine on adult cocaine self administration behavior. Moreover, greater efficacy of acute idazoxan challenge in adult SHR after adolescent atomoxetine relative to vehicle is consistent with the idea that chronic atomoxetine may downregulate presynaptic alpha2A-adrenergic autoreceptors in SHR. PMID- 28730283 TI - Blockade of alcohol escalation and "relapse" drinking by pharmacological FAAH inhibition in male and female C57BL/6J mice. AB - BACKGROUND: Anandamide (AEA)-dependent signaling is regulated by the catabolic enzyme fatty acid amide hydrolase (FAAH). Several lines of evidence have demonstrated that FAAH and AEA are involved in the behavioral effects of alcohol. Therefore, we investigated whether a selective FAAH inhibitor, URB597 (cyclohexylcarbamic acid 3'-[aminocarbonyl]-[1,1'-biphenyl]-3-yl ester), altered alcohol intake in mice in a voluntary alcohol drinking model. METHODS: Mice, subjected to 3 weeks of chronic intermittent access (IA) in a two-bottle choice paradigm with 24-h access every other day, developed rapid escalation of alcohol intake and high preference. We evaluated the pharmacological effects of URB597 after both acute (1-day) withdrawal from chronic IA and 1-week withdrawal using the alcohol deprivation effect (ADE) model. AEA and N-acyl ethanolamide (NAE) abundances were determined after chronic IA, acute (1-day), or long-term (1 and 2 weeks) withdrawal in four brain regions. RESULTS: Acute pretreatment with URB597 reduced alcohol intake and preference after acute withdrawal. This effect was blocked by pretreatment with a selective type 1 cannabinoid receptor (CB1) antagonist, suggesting a CB1-mediated mechanism. Both single- and multiple-dosing regimens with an effective dose of URB597 prevented the ADE, with no tolerance development after the multi-dosing regimen. AEA and NAE levels were transiently increased in all brain regions measured after acute withdrawal, indicating that the endocannabinoid system is involved in acute alcohol withdrawal stress response. CONCLUSION: FAAH inhibitors reduce alcohol escalation and "relapse" drinking in mice. PMID- 28730285 TI - An Update on Implants for Minimally Invasive Glaucoma Surgery (MIGS). AB - For several years, the gold standard for surgical treatment of glaucoma has been trabeculectomy. Although very successful at reducing intraocular pressure (IOP), there are several potential complications of trabeculectomy, including sight threatening ones. This has stimulated much research aimed at the development of new and effective procedures to lower IOP with an enhanced safety profile. Minimally invasive glaucoma surgery (MIGS) procedures prioritise patient safety but also demonstrate efficacy in reducing IOP. We performed an online search of peer-reviewed literature using PubMed, entering keywords relevant to this clinical discipline. In summary, there is a lack of long-term safety and efficacy data, a lack of comparative data and a lack of data on standalone (i.e. without simultaneous cataract surgery) procedures. Most implants are not yet FDA approved. Although not exhaustive, since it does not discuss MIGS procedures that are not implants, this article summarises the range of different MIGS implants that are available to the ophthalmic surgeon. PMID- 28730284 TI - A novel interplay between HOTAIR and DNA methylation in osteosarcoma cells indicates a new therapeutic strategy. AB - PURPOSE: Osteosarcoma (OS) is one of the most prevalent primary malignant bone tumors in adolescent. HOTAIR is highly expressed and associated with the epigenetic modifications, especially DNA methylation, in cancer. However, the regulation mechanism between HOTAIR and DNA methylation and the biological effects of them in the pathogenesis of osteosarcoma remains elusive. METHOD: Through RNA-sequencing and computational analysis, followed by a variety of experimental validations, we report a novel interplay between HOTAIR, miR-126, and DNA methylation in OS. RESULTS: We found that HOTAIR is highly expressed in OS cells and the knockdown of HOTAIR leads to the down-regulation of DNMT1, as well as the decrease of global DNA methylation level. RNA-sequencing analysis of HOTAIR-regulated gene shows that CDKN2A is significantly repressed by HOTAIR. A series of experiments show that HOTAIR represses the expression of CDKN2A through inhibiting the promoter activity of CDKN2A by DNA hypermethylation. Further evidence shows that HOTAIR activates the expression of DNMT1 through repressing miR-126, which is the negative regulator of DNMT1. Functionally, HOTAIR depletion increases the sensibility of OS cells to DNMT1 inhibitor through regulating the viability and apoptosis of OS cells via HOTAIR-miR126-DNMT1-CDKN2A axis. CONCLUSION: These results not only enrich our understanding of the regulation relationship between non-coding RNA, DNA methylation, and gene expression, however, also provide a novel direction in developing more sophisticated therapeutic strategies for OS patients. PMID- 28730286 TI - Management of Breast Cancer Risk in Women with Ovarian Cancer and Deleterious BRCA1 or BRCA2 Mutations. PMID- 28730288 TI - [Urology: For all. For each. For us]. PMID- 28730287 TI - [Non-PSA-expressing, solid, and growing mass of the prostate]. PMID- 28730289 TI - Treatment outcome of patients with recurrent glioblastoma multiforme: a retrospective multicenter analysis. AB - Glioblastoma multiforme (GBM) universally recurs with dismal prognosis. We evaluated the efficacy of standard treatment strategies for patients with recurrent GBM (rGBM). From two centers in the Netherlands, 299 patients with rGBM after first-line treatment, diagnosed between 2005 and 2014, were retrospectively evaluated. Four different treatment strategies were defined: systemic treatment (SYST), re-irradiation (RT), re-resection followed by adjuvant treatment (SURG) and best supportive care (BSC). Median OS for all patients was 6.5 months, and median PFS (excluding patients receiving BSC) was 5.5 months. Older age, multifocal lesions and steroid use were significantly associated with a shorter survival. After correction for confounders, patients receiving SYST (34.8%) and SURG (18.7%) had a significantly longer survival than patients receiving BSC (39.5%), 7.3 and 11.0 versus 3.1 months, respectively [HR 0.46 (p < 0.001) and 0.36 (p < 0.001)]. Median survival for patients receiving RT (7.0%) was 9.2 months, but this was not significantly different from patients receiving BSC (p = 0.068). Patients receiving SURG compared to SYST had a longer PFS (9.0 vs. 4.3 months, respectively; p < 0.001), but no difference in OS was observed. After adjustments for confounders, patients with rGBM selected for treatment with SURG or SYST do survive significantly longer than patients who are selected for BSC based on clinical parameters. The value of reoperation versus systemic treatment strategies needs further investigation. PMID- 28730290 TI - A phase I study to investigate the metabolism, excretion, and pharmacokinetics of [14C]fruquintinib, a novel oral selective VEGFR inhibitor, in healthy Chinese male volunteers. AB - PURPOSE: Fruquintinib (HMPL-013) is a novel, potent, and highly selective tyrosine kinase inhibitor targeting the vascular endothelial growth factor receptors (1, 2 and 3). This study was conducted to investigate the metabolism, excretion, and pharmacokinetics of HMPL-013 after a single oral dose to healthy Chinese men. METHODS: Six subjects were administrated an oral suspension containing 5 mg of 14C-labeled HMPL-013 (100 MUCi) in a fasted state. Blood and excreta samples were collected at the designated time points or intervals for pharmacokinetics and radiometric analyses. Safety assessments were conducted throughout the study. RESULTS: Over a 336-h post-dose collection period, mean recovery was 90.11% of the radiolabeled dose, with 60.31% in urine and 29.80% in feces. Mean C max, AUC0-infinity, and T max for HMPL-013 in plasma were 113 ng/mL, 4797 h ng/mL, and 2 h, respectively. Radioactivity and HMPL-013 were cleared from circulation with terminal half-lives of 41.1 and 33.4 h. HMPL-013 was the predominant circulating radioactive component, representing 72.48% of the total radioactivity. M11 was the major circulating metabolite, accounting for 17.31% of the total radioactivity. An additional seven circulating metabolites were identified, each accounting for less than 5% of the total radioactivity. In urine, HMPL-013 accounted for only 0.50% of the administered dose. Three major metabolites M285, M381, and M409-4 were identified in urine accounting for 10.48, 21.16, and 8.92% of the dose, respectively. In feces, HMPL-013 accounted for 5.34% of the dose. M205, M365-2, and M380 were the major metabolites, accounting for 2.29, 3.30, and 2.59% of the dose, respectively. CONCLUSION: HMPL-013 was well tolerated and absorbed rapidly, with parent compound being the predominant circulating component. HMPL-013 was extensively metabolized prior to excretion, and urine was the major route of excretion. PMID- 28730291 TI - Electrolyte disorders with platinum-based chemotherapy: mechanisms, manifestations and management. AB - Platinum chemotherapy, particularly cisplatin, is commonly associated with electrolyte imbalances, including hypomagnesemia, hypokalemia, hypophosphatemia, hypocalcemia and hyponatremia. The corpus of literature on these dyselectrolytemias is large; the objective of this review is to synthesize the literature and summarize the mechanisms responsible for these particular electrolyte disturbances in the context of platinum-based treatment as well as to present the clinical manifestations and current management strategies for oncologists and primary care physicians, since the latter are increasingly called on to provide care for cancer patients with medical comorbidities. Correct diagnosis and effective treatment are essential to improved patient outcomes. PMID- 28730292 TI - Efficacy and safety of taxane monotherapy in advanced gastric cancer refractory to triplet chemotherapy with docetaxel, cisplatin, and S-1: a multicenter retrospective study. AB - PURPOSE: Taxane monotherapy is widely used for advanced gastric cancer (AGC) after failure of standard first-line chemotherapy with fluoropyrimidine and cisplatin. Triplet chemotherapy with docetaxel, cisplatin, and S-1 (DCS) is a promising regimen for first-line chemotherapy of AGC. The aim of this study was to evaluate the efficacy of taxane monotherapy in patients refractory to DCS. METHODS: We retrospectively evaluated the efficacy and safety of taxane monotherapy in patients with AGC refractory to first-line therapy with DCS between January 2010 and April 2015. Selection criteria were as follows: ECOG PS of 0-2, treatment with taxane monotherapy in second-line or third-line therapy after failure of second-line irinotecan, absence of massive ascites, and adequate organ function. RESULTS: A total of 30 patients were included in this study. Of these, 15 patients received paclitaxel while another 15 received nanoparticle albumin-bound paclitaxel in either second- or third-line treatment. Median age for the second/third-line group was 64.0/62.0 (range 27-75/42-75); 14/13 (93.3/86.7%) had ECOG PS of 0 or 1. No patients achieved complete or partial response and stable disease was observed in 37.5/35.7% of the patients in the second/third line. Median progression-free survival and overall survival were 3.4 and 5.8 months in the second-line group, and 2.0 and 4.5 months in the third-line group, respectively. The incidences of any grade >=3 adverse events in the second line group and the third-line group were 60.0 and 33.3%, respectively. There was no treatment-related death. CONCLUSIONS: Taxane monotherapy after DCS failure had acceptable toxicities but was ineffective in AGC patients. PMID- 28730293 TI - Clinical predictors of survival in patients with castration-resistant prostate cancer receiving sipuleucel-T cellular immunotherapy. AB - BACKGROUND: We evaluated the patterns of progression and determined clinical predictors of survival in patients with castration-resistant prostate cancer (CRPCa) who received sipuleucel-T. METHODS: We retrospectively analyzed 56 consecutive patients with asymptomatic or minimally symptomatic CRPCa treated with sipuleucel-T. Age, number of bone metastases, history of prior systemic treatment, and alkaline phosphatase level (ALP) were tested as predictors of survival in a multivariate Cox proportional hazards regression model. The Kaplan Meier method was used to estimate event-free probabilities. RESULTS: The 56 patients were a median age of 67 years (range 51-84 years). After sipuleucel-T treatment, 25 patients developed bone progression after a median of 22 months of follow-up (54% of patients were event free at 2 years) and 10% (6/56 patients) developed rapid progression. Eleven deaths were observed after a median of 28 months of follow-up. Forty-eight patients were included in the multivariate analysis for overall survival. The analysis showed that age >70 years (p = 0.012), number of bone metastases >20 (p = 0.018), prior systemic treatment (p = 0.018), and ALP level >90 IU/L (p = 0.010) significantly predicted worse overall survival. Two-year overall survival was 36% among the 16 patients with two or more of these factors and was 93% among the 32 patients with one or none of these factors (p = 0.0004). CONCLUSIONS: CRPCa patients with age (>70 years), increased tumor burden in bone (>20 metastases and/or elevated ALP level), and/or prior systemic treatment are more likely to experience rapid deterioration after sipuleucel-T. These results need to be prospectively validated. PMID- 28730294 TI - Two-year follow-up study of subchondral surface irregularities of the capitellum on ultrasonography in baseball players under the age of 10 years. AB - OBJECTIVE: To determine whether subchondral surface irregularities of the capitellum on ultrasonography in baseball players under the age of 10 years are indicative of early osteochondritis dissecans (OCD) of the capitellum. MATERIALS AND METHODS: A total of 321 players aged 6-9 years underwent ultrasonographic examination, and the findings for the subchondral bone of the capitellum on the throwing side were graded as 0, 1a, 1b, 2, or 3. Subjects classified as grade 1a or 1b showed irregularities of the subchondral bone surface and were investigated radiographically for OCD. All players continued to throw and were re-examined by ultrasonography after 1 and 2 years. RESULTS: At the first examination, 11/321 (3.4%) had irregularities at the subchondral surface of the capitellum [grade 1a in 7/321 (2.2%); grade 1b in 4/321 (1.2%)]. The seven players with grade 1a showed no evidence of OCD or Panner's disease on radiography and were reclassified as grade 0 at the 2-year follow-up. All four players with grade 1b were reclassified as grade 0 at follow-up 1 and 2 years later. CONCLUSION: Subchondral bone surface irregularities of the capitellum on ultrasonography in children under the age of 10 years may not be indicative of disease, but rather represent variation of ossification during normal development. PMID- 28730295 TI - Incarceration of the medial collateral ligament in the intercondylar notch following proximal avulsion. AB - Intra-articular entrapment of the medial collateral ligament (MCL) is a rare but recognised complication of traumatic injury to the posteromedial corner (PMC) of the knee. Considering the MCL is the most commonly injured ligament of the knee this complication is extremely rare with only a handful of cases describing MCL entrapment following distal avulsion of the MCL. We present the first known case of MCL entrapment following proximal avulsion of the MCL and posterior oblique ligament (POL) with the mid-substance of the MCL becoming entrapped in the joint, lying on the superior surface of the medial meniscus and extending up into the intercondylar notch. In addition, the medial patellar retinaculum was also entrapped in the medial aspect of the medial patellofemoral joint. MCL entrapment is best treated with expeditious surgical intervention and it is therefore crucial that the MRI findings are not overlooked. Details of the clinical assessment, MRI and operative findings are presented with a literature review of MCL entrapment. PMID- 28730296 TI - Early computed tomography or focused assessment with sonography in abdominal trauma: what are the leading opinions? AB - PURPOSE: The initial assessment of severely injured patients in the resuscitation room requires a systematic and quickly performed survey. Whereas the Advanced Trauma Life Support (ATLS(r))-based algorithm recommends focused assessment with sonography in trauma (FAST) among others, recent studies report a survival advantage of early whole-body computed tomography (WBCT) in haemodynamically stable as well as unstable patients. This study assessed the opinions of trauma surgeons about the early use of WBCT in severely injured patients with abdominal trauma, and abdominal CT in patients with isolated abdominal trauma, during resuscitation room treatment. METHODS: An online cross-sectional survey was performed over 8 months. Members of the Swiss Society for Surgery and the Austrian and German associations for trauma surgery were invited to answer nine online questions. RESULTS: Overall, 175 trauma surgeons from 155 departments participated. For haemodynamically stable patients, most considered FAST (77.6%) and early CT (82.3%) to be the ideal diagnostic tools. For haemodynamically unstable patients, 93.4% considered FAST to be mandatory. For CT imaging in unstable patients, 47.5% agreed with the use of CT, whereas 52.5% rated early CT as not essential. For unstable patients with pathological FAST and clinical signs, 86.8% agreed to proceed with immediate laparotomy. CONCLUSIONS: Most surgeons rely on early CT for haemodynamically stable patients with abdominal trauma, whereas FAST is performed with similar frequency and is prioritized in unstable patients. It seems that the results of recent studies supporting early WBCT have not yet found broad acceptance in the surgical community. PMID- 28730297 TI - Trauma to the bladder and ureter: a review of diagnosis, management, and prognosis. AB - BACKGROUND: Injuries to the ureter or bladder are relatively rare. Therefore, a high level of clinical suspicion and knowledge of operative anatomy is of utmost importance for their management. Herein, a review of the literature related to the modern diagnosis, management, and prognosis for bladder and ureteral injuries is presented. METHODS: A literature search was conducted through PubMed. A thorough search of the world's literature published in English was completed. Search terms included "injury, diagnosis, prognosis, and management for ureter and bladder". All years, both genders, as well as penetrating, blunt, and iatrogenic mechanisms were evaluated for inclusion. Following PRISMA guidelines, studies were selected based on relevance and then categorized. RESULTS: 172 potentially relevant studies were identified. Given our focus on modern diagnosis and treatment, we then narrowed the studies in each category to those published within the last 30 years, resulting in a total of 26 studies largely consisting of Level IV retrospective case series. Our review found that bladder ruptures occur from penetrating, blunt, or iatrogenic mechanisms, and most are extraperitoneal (63%). Ureteral injuries are incurred from penetrating mechanisms in 77% of cases. The overall mortality rates for bladder rupture and ureteral injury were 8 and 7%, respectively. LIMITATIONS: Limitations of this article are similar to all PRISMA-guided review articles: the dependence on previously published research and availability of references. CONCLUSION: The bladder is injured far more often than the ureter but ureteral injuries have higher injury severity. Both of these organs can be damaged by penetrating, blunt, or iatrogenic mechanisms and surgical intervention is often required for severe ureter or bladder injuries. Since symptoms of these injuries may not always be apparent, a high level of suspicion is required for appropriate diagnosis and treatment. PMID- 28730299 TI - Prophylactic etanercept treatment in cisplatin ototoxicity. AB - The aim of our study was to evaluate the audiological protective effects of etanercept using distortion product otoacoustic emission (DPOAE) in rats with hearing loss due to cisplatin ototoxicity. The study began with 36 healthy female albino rats; 31 rats had good measurements in DPOAE and were included in the study. On day 0, a single dose of etanercept was given by intraperitoneal administration to 15 rats (etanercept group). No medication was given to the control group. After 24 h, 16 mg/kg cisplatin was given to all rats. DPOAE measurements were performed on the 3rd, 7th, and 21st day. After the DPOAE test on the 21st day, the animals were killed by decapitation. Between-group and intra group comparisons were made using the data of the two groups. A statistically significant difference was observed on the 3rd day at 4921 Hz and higher frequencies, on the 7th day at 6064 Hz and higher frequencies, and on the 21st day at 6494 Hz and higher frequencies (p < 0.05). We observed 10% ototoxicity in the etanercept group and 56% ototoxicity in the control group. A single dose of etanercept 1 day before cisplatin administration decreases cisplatin ototoxicity in the early period. This effect comes to the fore especially over 4500 Hz frequencies at 65 dB and higher. PMID- 28730300 TI - Health-related quality of life in paediatric patients with congenital heart defects: association with the type of heart defect and the surgical technique. AB - : The aim of the study was to investigate the impact of a number of surgical interventions for a various congenital cardiac defects (CHDs) on self-reported HRQoL. METHODS: Patients who had received corrective surgery of several congenital heart defects (surgical VSD closure, Fallot, TGA after atrial or arterial switch or Fontan-type circulation for univentricular AV-connection) were interviewed in the office of their home peadiatric cardiologist. HRQoL in children along 7 dimensions was assessed using a standardised questionnaire (PEDQoL); information on the medical case history of each respondent was also collected. STATISTICS: HRQoL was assessed in the questionnaire by asking about the frequency (never, rarely, often, always) of specific negative experiences; more frequent experiences indicate a lower quality of life. Frequency expressions were transformed into numerical values (25, 50, 75, 100%), and mean values for HRQoL were calculated for each patient and for each domain. Differences in HRQoL among patients with different types of interventions were analysed using the Mann Whitney Test or the Kruskal-Wallis Test as appropriate; p values <0.05 were considered to indicate significant differences, while p values <0.1 were considered to indicate notable trends. RESULTS: Patients: 169 patients (60% male, 40% female) were part of the study. The mean age was 11.6 years; 50 patients had surgical VSD closure, 52 surgeries for Tetralogy of Fallot (22 transannular patch, 18 no transannular patch, 12 inaccurate description), 40 had complete transposition of the great arteries (28 atrial switch, 12 arterial switch), 22 had a Fontan-type procedure for univentricular AV-connection. HRQoL differed little among patients with different CHDs for the items "relation to friends," "interactions in the affected families", and "own body image". For other items, notable differences emerged: patients with univentricular hearts rated their physical capacity worse and showed a tendency towards negative ratings in other domains. On the other hand, patients after Fallot or TGA correction tended to rate their HRQoL in several domains as relatively high. Focusing on the mode of surgery for Fallot repair, respectively, TGA correction the only significant difference was found for "physical capacity" in TGA (atrial vs. arterial repair). Mustard patients tended to rate most items worse. Physical capacity was rated worst by patients with a Fontan circulation. Repeated surgery led to lower ratings for all domains except "physical capacity" and "body image". CONCLUSIONS: Different surgical techniques for CHD do not affect children's and adolescents' self-reported HRQoL to the extent that one would expect. This observation is in line with observations in groups of children with different chronic diseases. Specialised psychosocial support is necessary in order to maintain this positive self-evaluation and to ensure patients are able to lead autonomous personal and professional lives. PMID- 28730301 TI - Biopsychosocial factors predict quality of life in thoracolumbar spine surgery. AB - PURPOSE: Surgical intervention is a treatment option for various spinal pathology but many patients report no improvement or even an exacerbation of symptoms like pain. This study examined the association of preoperative (pre-op) biopsychosocial risk factors with poor quality of life at 2 and 6 months using hierarchical models controlling demographic and medical variables. METHOD: Participants undergoing thoracolumbar spine surgery (N = 214) were provided with questionnaire packages to complete pre-op, at 2 and at 6-month postoperative clinical follow-ups (i.e., demographics, psychosocial measures, SF-12, medical, and clinical measures). The surgeon recorded surgical measures. RESULTS: Examining the pre-op period only, greater age and medication use (for back symptoms) were associated with poorer physical quality of life [physical component summary score (PCS)], while greater catastrophizing, depression, and lower social support were associated with poorer mental QoL [mental component summary score (MCS)]. Lower preoperative PCS, social support, and greater kinesiophobia were associated with diminished PCS at 2-month. Higher pre-op MCS and higher social support was associated with better MCS at 2-month. Poorer PCS at 6-month was associated with older age and low social support, while diminished MCS was associated with lower pre-op social support, MCS, and longer time in the operation room. Preoperative kinesiophobia partially mediated the relationship between pre-op PCS and 2-month PCS. Age partially mediated the relationship between pre-op PCS and at 6-month. For MCS, social support was the lone partial mediator of baseline MCS and both 2 and 6-month MCS. CONCLUSION: These results show that preoperative psychosocial variables are significantly associated with poorer postoperative health-related QoL outcomes following spinal surgeries, supporting a biopsychosocial pre-op care map. PMID- 28730302 TI - Internal resources among informal caregivers: trajectories and associations with well-being. AB - PURPOSE: The experiences, skills, and internal resources that informal caregivers bring into their role may play a critical part in their mental health and well being. This study examined how caregiver internal resources changed over a 10 year period, and how this was related to caregivers' well-being. METHODS: Data are from the Midlife in the United States (MIDUS) study, a national sample of adults, at two time points: 1995-1996 (T1) and 2004-2006 (T2). We identified subjects who reported being a caregiver at T2 and starting care after T1 (mean age = 56; 65% female). We examined internal resources: sense of control (personal mastery); primary and secondary control strategies (persistence in goal striving, positive reappraisal, and lowering expectations); and social support seeking, and psychological and subjective well-being. We evaluated how internal resources changed over time, and how these trajectories were associated with well-being at T2 using multivariable linear regressions. RESULTS: Most caregivers had stable levels of internal resources (between 4 and 13% showed an increase or decrease). Caregivers with increasing or high-stable levels of personal mastery had significantly better well-being scores on 6 out of 8 subscales compared with low stable levels [effect sizes (ES) between 0.39 and 0.79]. Increasing persistence was associated with better personal growth and environmental mastery (ES = 0.96 and 0.91), and increasing and high-stable positive reappraisals were associated with better affect (ES = 0.63 and 0.48) compared with low-stable levels. Lowering aspirations and support seeking were not associated with well-being outcomes. CONCLUSIONS: Practices or interventions that support or improve internal resources could potentially improve caregiver well-being. PMID- 28730303 TI - Exhaled breath online measurement for cervical cancer patients and healthy subjects by proton transfer reaction mass spectrometry. AB - Cervical cancer is a common cancer among women and has a high morbidity and mortality. The traditional clinical methods for cervical cancer screening are invasive and limited in terms of cost and time. There is an unmet clinical need for new methods to aid clinicians in the rapid screening and auxiliary diagnosis of cervical precancer. Recently, breath analysis has become an attractive approach for investigation of cancer biomarkers and shows great potential in cancer screening owing to its high sensitivity, quickness, and non-invasive nature. In this pilot study, breath analysis by proton transfer reaction mass spectrometry (PTR-MS) was utilized for online analysis of the exhaled breath of 13 cervical cancer patients and 34 female healthy volunteers. The Mann-Whitney U test and stepwise forward linear discriminant analysis were performed for data statistics. On the basis of the statistical analysis, four characteristic ions at m/z 76, 87, 93, and 121 were found for discriminating cervical cancer. The sensitivity and specificity were calculated to be 92.3% and 88.2%, respectively, using the stepwise discriminant analysis. The possible identities of characteristic ions were also discussed in detail. Although there are some uncertainties in the identification of these characteristic ions and more participants (including cervical cancer patients and healthy volunteers) are needed to further confirm the results, the results in this study demonstrate that the online breath test using PTR-MS is a promising approach for cervical cancer screening. PMID- 28730304 TI - Novel ribonuclease activity of cusativin from Cucumis sativus for mapping nucleoside modifications in RNA. AB - A recombinant ribonuclease, cusativin, was characterized for its cytidine specific cleavage ability of RNA to map chemical modifications. Following purification of native cusativin protein as described before (Rojo et al. Planta 194:328, 17), partial amino acid sequencing was carried out to identify the corresponding protein coding gene in cucumber genome. Cloning and heterologous expression of the identified gene in Escherichia coli resulted in successful production of active protein as a C-terminal His-tag fusion protein. The ribonuclease activity and cleavage specificity of the fusion protein were confirmed with a variety of tRNA isoacceptors and total tRNA. Characterization of cusativin digestion products by ion-pairing reverse-phase liquid chromatography coupled with mass spectrometry (IP-RP-LC-MS) analysis revealed cleavage of CpA, CpG, and CpU phosphodiester bonds at the 3'-terminus of cytidine under optimal digestion conditions. Ribose methylation or acetylation of cytosine inhibited RNA cleavage. The CpC phosphodiester bond was also resistant to cusativin-mediated RNA cleavage; a feature to our knowledge has not been reported for other nucleobase-specific ribonucleases. Here, we demonstrate the analytical utility of such a novel feature for obtaining high-sequence coverage and accurate mapping of modified residues in substrate RNAs. Graphical abstract Cytidine-specific novel ribonuclease activity of cusativin. PMID- 28730305 TI - Self-assembly of the polymer brush-grafted silica colloidal array for recognition of proteins. AB - Three-dimensional photonic crystal sensors are attractive platforms for autonomous chemical sensing and colorimetric bioassays. At present, the photonic crystal sensors with inverse opal structure were extensively studied, which swells or shrinks in response to the analytes. However, the fabrication of inverse opal sensors still remains a major challenge. Herein, we propose a simple and versatile approach to fabricate 3D opal photonic sensors. This photonic crystal is fabricated via assembly of monodispersed silica particles grafted with linear polymeric ligands (SiO2@LPs). Acrylic acid (negatively charged monomer) and N-tert-butylacrylamide (hydrophobic monomer) were incorporated with N isopropylacrylamide to achieve strong affinity between the designed polymer ligands and proteins. The proposed photonic crystal displays a maximum redshift of 23 nm in response to 2 mg/mL lysozyme, accompanied by the structure color change from blue to green. Compared to the cross-linked polymers, the linear polymer with flexible structure allows the colloidal array to recognize lysozyme with higher sensitivity (as low as 5 MUg/mL) and broader linearity (from 5 to 2000 MUg/mL in aqueous media). In the future, this photonic crystal sensor can be used as universal tools for the detection of a broad range of analytes. Graphical abstract Colloidal array self-assembled by polymer brush-grafted silica for proteins detection. PMID- 28730306 TI - Disposable electrochemical immunosensor for Brettanomyces bruxellensis based on nanogold-reduced graphene oxide hybrid nanomaterial. AB - The assembly of a novel disposable amperometric immunosensor for the detection of the red wine spoilage yeast Brettanomyces bruxellensis is reported. The nanostructured sensing interface was prepared by first coating carbon screen printed electrodes with a gold nanoparticles-reduced graphene oxide hybrid nanomaterial, which was then modified with 3-mercaptopropionic acid to further immobilize specific antibodies for B. bruxellensis via a carbodiimide-coupling reaction. The functionalized electrode allowed the amperometric detection of B. bruxellensis in buffered solutions and red wine samples in the range of 10-106 CFU/mL and 102-106 CFU/mL, with low detection limits of 8 CFU/mL and 56 CFU/mL, respectively. The electrochemical immunosensor also exhibited high reproducibility, selectivity, and storage stability. Graphical abstract A novel disposable electrochemical immunosensor for the detection of the red wine spoilage yeast B. bruxellensis. PMID- 28730307 TI - Experiences and benefits of a career development course for undergraduate chemistry students. PMID- 28730308 TI - TLC surface integrity affects the detection of alkali adduct ions in TLC-MALDI analysis. AB - Direct coupling of thin-layer chromatography (TLC) with matrix-assisted laser desorption ionization (MALDI) mass spectrometry allows fast and detailed characterization of a large variety of analytes. The use of this technique, however, presents great challenges in semiquantitative applications because of the complex phenomena occurring at the TLC surface. In our laboratory, we recently observed that the ion intensities of several alkali adduct ions were significantly different between the top and interior layer of the TLC plate. This indicates that the integrity of the TLC surface can have an important effect on the reproducibility of TLC- MALDI analyses. Graphical Abstract MALDI imaging reveals that surface integrity affects the detection of alkali adductions in TLC MALDI. PMID- 28730309 TI - A simple and rapid infrared-assisted self enzymolysis extraction method for total flavonoid aglycones extraction from Scutellariae Radix and mechanism exploration. AB - A new, simple, and fast infrared-assisted self enzymolysis extraction (IRASEE) approach for the extraction of total flavonoid aglycones (TFA) mainly including baicalein, wogonin, and oroxylin A from Scutellariae Radix is presented to enhance extraction yield. Extraction enzymolysis temperature, enzymolysis liquid to-solid ratio, enzymolysis pH, enzymolysis time and infrared power, the factors affecting IRASEE procedure, were investigated in a newly designed, temperature controlled infrared-assisted extraction (TC-IRAE) system to acquire the optimum analysis conditions. The results illustrated that IRASEE possessed great advantages in terms of efficiency and time compared with other conventional extraction techniques. Furthermore, the mechanism of IRASEE was preliminarily explored by observing the microscopic change of the samples surface structures, studying the main chemical compositions change of the samples before and after extraction and investigating the kinetics and thermodynamics at three temperature levels during the IRASEE process. These findings revealed that IRASEE can destroy the surface microstructures to accelerate the mass transfer and reduce the activation energy to intensify the chemical process. This integrative study presents a simple, rapid, efficient, and environmental IRASEE method for TFA extraction which has promising prospects for other similar herbal medicines. Graphical Abstract ?. PMID- 28730310 TI - Optical biosensor optimized for continuous in-line glucose monitoring in animal cell culture. AB - Biosensors for continuous glucose monitoring in bioreactors could provide a valuable tool for optimizing culture conditions in biotechnological applications. We have developed an optical biosensor for long-term continuous glucose monitoring and demonstrated a tight glucose level control during cell culture in disposable bioreactors. The in-line sensor is based on a commercially available oxygen sensor that is coated with cross-linked glucose oxidase (GOD). The dynamic range of the sensor was tuned by a hydrophilic perforated diffusion membrane with an optimized permeability for glucose and oxygen. The biosensor was thoroughly characterized by experimental data and numerical simulations, which enabled insights into the internal concentration profile of the deactivating by-product hydrogen peroxide. The simulations were carried out with a one-dimensional biosensor model and revealed that, in addition to the internal hydrogen peroxide concentration, the turnover rate of the enzyme GOD plays a crucial role for biosensor stability. In the light of this finding, the glucose sensor was optimized to reach a long functional stability (>52 days) under continuous glucose monitoring conditions with a dynamic range of 0-20 mM and a response time of t 90 <= 10 min. In addition, we demonstrated that the sensor was sterilizable with beta and UV irradiation and only subjected to minor cross sensitivity to oxygen, when an oxygen reference sensor was applied. Graphical abstract Measuring setup of a glucose biosensor in a shake flask for continuous glucose monitoring in mammalian cell culture. PMID- 28730311 TI - Aptamer-based fluorescence-quenching lateral flow strip for rapid detection of mercury (II) ion in water samples. AB - Divalent mercury ion (Hg2+) is one of the most common and stable forms of mercury pollution. In this study, a skillfully designed lateral flow strip (LFS) was developed for sensitive detection of Hg2+ in river water samples. Aptamer, a specific oligonucleotide probe, was used to selectively identify and target Hg2+ instead of antibody in traditional immunechromatographic strips; and the fluorescence-quenching system was used to generate positive and low background florescence signals in the competitive-likely LFS. The linear detection range of the LFS for Hg2+ was 0.13 ng mL-1 to 4 ng mL-1 and the limit of detection (LOD) was 0.13 ng mL-1. This test provided results in 15 min and demonstrated high specificity. For detection of Hg2+ in river water, the results were consistent with inductively coupled plasma-mass spectrometry measurements. The aptamer-based fluorescence-quenching LFS was shown to provide a reliable, accurate method for rapid detection of mercury contamination. Graphical Abstract The principle of the aptamer-based fluorescence-quenching LFS. PMID- 28730312 TI - Hydrophilic interaction liquid chromatography-tandem mass spectrometry for quantitation of paralytic shellfish toxins: validation and application to reference materials. AB - Paralytic shellfish toxins (PSTs) are potent neurotoxins produced by marine dinoflagellates that are responsible for paralytic shellfish poisoning (PSP) in humans. This work highlights our ongoing efforts to develop quantitative methods for PSTs using hydrophilic interaction liquid chromatography-tandem mass spectrometry (HILIC-MS/MS). Compared with the commonly used method of liquid chromatography with post-column oxidation and fluorescence detection (LC-ox-FLD), HILIC-MS/MS has the potential of being more robust, sensitive and straightforward to operate, and provides unequivocal confirmation of toxin identity. The main driving force for the present work was the need for a complementary method to LC ox-FLD to assign values to shellfish tissue matrix reference materials for PSTs. Method parameters that were optimized included LC mobile and stationary phases, electrospray ionization (ESI) conditions, and MS/MS detection parameters. The developed method has been used in the detection and identification of a wide range of PSTs including less common analogues and metabolites in a range of shellfish and algal samples. We have assessed the matrix effects of shellfish samples and have evaluated dilution, standard addition and matrix matched calibration as means of mitigating them. Validation on one LC-MS/MS system for nine common PST analogues (GTX1-4, dcGTX2&3, STX, NEO, and dcSTX) was completed using standard addition. The method was then transferred to a more sensitive LC MS/MS system, expanded to include five more PSTs (C1&2, dcNEO and GTX5&6) and validated using matrix matched calibration. Limits of detection of the validated method ranged between 6 and 280 nmol/kg tissue using standard addition in extracts of blue mussels, with recoveries between 92 and 108%. Finally, this method was used in combination with the AOAC Official Method based on LC-ox-FLD to measure PSTs in a new mussel tissue matrix reference material. PMID- 28730313 TI - Derivatization-free LC-MS/MS method for estrogen quantification in mouse brain highlights a local metabolic regulation after oral versus subcutaneous administration. AB - 17beta-Estradiol (17beta-E2) is a steroid with pleiotropic actions. In addition to being a sexual hormone, it is also produced in the brain where it modulates the reproductive axis. It has been shown that 17beta-E2 also acts on synaptic plasticity and plays a role in neurological pathways and in neurodegenerative diseases. Assaying this steroid in the brain is thus interesting to improve our knowledge of 17beta-E2 effects in the brain. However, 17beta-E2 concentration in the central nervous system has been reported to be of a few nanograms per gram wet weight (nanomolar range concentration); therefore, its quantification requires both an efficient extraction process and a sensitive detection method. Herein is presented a derivatization-free procedure based on solid-phase extraction followed by LC-MS/MS analysis, targeted on 17beta-E2, its isomer17alpha-E2, and its metabolites estrone (E1) and estriol (E3). This extraction process allowed reaching 96% 17beta-E2 recovery from the mouse brain. Limit of detection (LOD) and limit of quantification (LOQ) values of 0.5 and 2.5 pmol mL-1, respectively, were reached for both 17alpha-E2 and 17beta-E2. LOD values for E1 and E3 were 0.01 and 0.025 pmol mL-1, respectively. The variation coefficients for intra- and inter-assays were 6 and 14%, respectively, for both estradiol forms. The method was applied to assess estrogen levels in the mouse brain and hippocampus after 17beta-E2 acute (subcutaneous injection) and chronic (drinking water) physiological administration. Total estrogen levels were determined after enzymatic deconjugation and compared to free estrogen levels. While 17alpha-E2 was not detected in biological samples, 17beta-E2 and metabolite measurements highlight a local biotransformation of estrogens after physiological administration via drinking water. Graphical abstract Method workflow: After oral or subcutaneous Estradiol administration, mouse brain or hippocampus was removed. Samples were homogenized and prepared according to a liquid-liquid extraction, followed by a solid-phase extraction. Then, LC-MS/MS was optimized to quantify 17beta-E2, its isomer17alpha-E2, its metabolites estrone (E1) and estriol (E3) and their conjugates. PMID- 28730314 TI - Spontaneous thrombosis of a giant cerebral varix in a pediatric patient. AB - INTRODUCTION: Cerebral cortical venous aneurysm also known as cerebral varix is a rare entity that usually occurs in relation to high-flow draining veins of arteriovenous fistulas, arteriovenous malformations, and venous angioma. Isolated cerebral varix is an extremely rare entity. CASE REPORT: We present a 1-year-old male with isolated cerebral varix. During follow-up, the varix thrombosed spontaneously without causing any neurological deficits. CONCLUSION: To the best of our knowledge, spontaneous asymptomatic thrombosis of an isolated cerebral varix without any clinical finding was reported for the first time in the literature. PMID- 28730315 TI - Comparison of NellcorTM PM1000N and Masimo Radical-7(r) for detecting apnea in volunteers. AB - PURPOSE: Although capnography is considered the gold standard for monitoring of ventilation, it may not work accurately in some situations. We compared the performance of two non-invasive continuous respiratory rate (RR) monitors that are alternatives for the detection of respiratory depression. METHODS: Fifty healthy volunteers >=20 years old were enrolled in this study. After monitoring of the volunteers was started by the Masimo Radical-7(r) and NellcorTM PM1000N, they breathed at the rate of 12 breaths/min for 3 min and then stopped breathing. As soon as the apnea alarm of either monitor went off, breathing was resumed at the same rate. This entire procedure was repeated three times. The data collected every 30 s included the RR, pulse rate (PR) and oxygen saturation (SpO2). The times of alarm on, alarm off and reappearance of RR on the monitor screens were also recorded. RESULTS: The biases of the RR, PR and SpO2 measurements from the two monitors were 0.5, 0.2 and -0.4, respectively. Of 143 procedures that stopped breathing for more than 30 s, 114 and 15 alarms were shown by the Masimo Radical 7(r) and NellcorTM PM-1000N monitors, respectively. Most alarms of the NellcorTM PM1000N followed from SpO2 <90%. Conversely, most alarms of the Masimo Radical 7(r) were caused by RR <10 breaths/min. Times to alarm on, alarm off and display of RR measured by the Masimo Radical-7(r) monitor were significantly shorter than the NellcorTM PM-1000N monitor. CONCLUSIONS: The Masimo Radical-7(r) monitor provides better detection of apnea in volunteers than the NellcorTM PM-1000N. PMID- 28730316 TI - Locus coeruleus neuronal activity correlates with behavioral response to acute and chronic doses of methylphenidate (Ritalin) in adolescent rats. AB - The objective of this study is to gain insight into the behavioral and neuronal changes induced by acute and chronic methylphenidate (MPD) administration. Specifically, there is limited knowledge of the effects of MPD on the locus coeruleus (LC), the main site of norepinephrine synthesis in the brain. In this study, LC neuronal firing rate was recorded simultaneously with locomotor activity in freely moving adolescent rats. Adolescent rats were chosen to mimic the age group in humans most affected by MPD exposure. Following acute dose of 0.6, 2.5 or 10 mg/kg MPD, all rats showed an increase in locomotor activity. However, in response to chronic MPD doses, individual rats showed either a further increase or decrease in their locomotor activity as compared to the effect initiated by the acute dose-expressing either behavioral sensitization or tolerance, respectively. The LC neuronal recordings from animals expressing behavioral sensitization showed that the majority of units responded to chronic MPD exposure by further increasing firing rates as compared to the initial response to the acute MPD exposure. For the LC neuronal units recorded from animals expressing behavioral tolerance, however, the majority of the units responded to chronic exposure by attenuating or no significant effect on their firing rate as compared to the acute MPD exposure. This observation indicates a correlation between the LC neuronal responses and behavioral activity to chronic MPD exposure. The study shows that LC participates in the effect of MPD and the behavioral expression of sensitization and tolerance to chronic exposure of MPD. PMID- 28730317 TI - Assessment of hepatitis B virus antibody titers in childhood cancer survivors. AB - : Pediatric patients suffering from cancer are at risk of hepatitis B virus (HBV) infection and its related complications even though it is considered a vaccine preventable disease. Little is known of the effects of chemotherapy, and even less is known regarding the impact of HBV booster on HBV antibody titers. It is the purpose of this study to investigate and measure the prevalence of the antihepatitis B surface antibodies (HBsAb) in childhood cancer survivors after completion of their chemotherapy treatment and to further evaluate survivors' response to a single booster dose of HBV vaccine. This observational, cross sectional retrospective study included 43 patients, of which 37 (86%) were found to be seronegative (HBsAb titer <10 mIU/ml). The notable result was that, of the seronegative patients who received a booster dose of HBV vaccine, 90% of the tested cases exhibited a successful raising of HBsAb titers >10 mIU/ml. CONCLUSION: Childhood cancer survivors have high seronegative rates for HBV and the majority of the patients achieved HBsAb titer > 10mIU/ml with a single booster dose of HBV vaccine, which is worth further investigation and research. This study suggests revaccination against HBV post-chemotherapy treatment, as the recommended advice, especially in countries with a high prevalence of HBV infection. What is Known: * There is a variable prevalence of low HBsAb titers measured after the end of chemotherapy in childhood cancer survivors. * There are no universal guidelines for revaccination of these patients. What is New: * This research identified that 86% of childhood cancer survivors treated with standard chemotherapy were seronegative for HBV infection. * A single booster dose HBV vaccine was successful for the majority of patients (90%) to achieve HBsAb titers >10 mIU/ml. PMID- 28730318 TI - Renal function in neonates with twin-twin transfusion syndrome treated with or without fetoscopic laser surgery. AB - : The aim of this study is to investigate the short-term renal function in neonates with twin-twin transfusion syndrome (TTTS), treated with fetoscopic laser surgery (laser group) or conservatively (non-laser group). Creatinine and urea levels and urine output were recorded in the first week after birth. Primary outcome was short-term renal dysfunction, defined as a creatinine level of >100 MUmol/L during the first week postpartum. We evaluated 312 twins (laser group, n = 274; non-laser group, n = 38). Median creatinine and urea levels were lower in the laser group than in the non-laser group (71 versus 82 MUmol/L, p = 0.002). Short-term renal dysfunction was lower in the laser group compared to the non laser group (7.2 versus 34.4%, p < 0.001). Within the laser group, creatinine levels were significantly higher in the subgroup with incomplete laser surgery compared to twins with successful laser surgery (76 versus 69 MUmol/L, p = 0.018). No differences were found between donors and recipients except for a higher incidence of oliguria in donors in the non-laser group on day 1. CONCLUSION: Short-term renal dysfunction occurs less frequently in TTTS twins treated with fetoscopic laser coagulation, particularly after complete surgery, suggesting that laser surgery may have a protective effect on renal function. What is Known: * Antenatally, donor twins in TTTS have severe oliguria due to chronic hypovolemia and impaired renal perfusion * Postnatally, donor twins may suffer from severe renal complications, particularly in TTTS twins treated conservatively. What is New: * The incidence of short-term renal failure in TTTS twins treated with complete laser surgery is low. * After incomplete laser surgery, the incidence of short-term renal dysfunction is increased. PMID- 28730319 TI - Management of postoperative junctional ectopic tachycardia in pediatric patients: a survey of 30 centers in Germany, Austria, and Switzerland. AB - : Postoperative junctional ectopic tachycardia (JET) is a frequent complication after pediatric cardiac surgery. Current recommendations on how and when to treat JET are inconsistent. We evaluated the management strategies of postoperative JET in German-speaking countries. We sent an online survey to 30 centers of pediatric cardiology that perform surgery for congenital heart defects in Germany (24), Austria (4), and Switzerland (2). The survey asked 18 questions about how and in what treatment sequence postoperative JET was managed. All 30 centers completed the survey (100% return rate). There was general agreement that the management of JET is based on administration of antiarrhythmic drugs, body surface cooling, and temporary pacing. Many centers presented treatment algorithms based on published literature, all centers named amiodarone as the first drug of choice. Significant disagreement was found concerning the timing and sequential order of additional therapeutic measures and particularly about the dosing of amiodarone and the role of R-wave synchronized atrial pacing. CONCLUSION: This survey reveals that from center to center, the treatment of postoperative JET may vary substantially. Future work should focus on those treatment modalities where a high rate of variation is found. Such studies may be of value to achieve commonly adopted treatment recommendations. What is known: * Treatment of postoperative junctional ectopic tachycardia is predominantly based on administration of antiarrhythmic drugs, therapeutic cooling, and temporary pacing. * Amiodarone is the antiarrhythmic drug of choice in this context. What is new: * Dosing and duration of administration of amiodarone differ relevantly from center to center. * The sequential order of drug administration, therapeutic cooling, and pacing is not consistent. PMID- 28730320 TI - Esophageal bezoar due to karaya gum granules used as a laxative. AB - Esophageal obstruction from soluble fiber laxatives, such as karaya gum, has been rarely reported in the literature. However, as such preparations are widely commercially available, it is important for gastroenterologists to be aware of their potential to form a bezoar in the esophagus due to swelling on contact with liquid. This report highlights such a case and discusses its challenging management. PMID- 28730321 TI - Age and dressing type as independent predictors of post-operative infection in patients with acute compartment syndrome of the lower leg. AB - PURPOSE: The purpose of this study was to determine independent factors, including timing of fasciotomy, that confer an increased risk of post-operative surgical site infection (SSI) in patients presenting with acute compartment syndrome (ACS) of the lower extremity. METHODS: A retrospective analysis was performed on a consecutive cohort of 53 adult patients requiring fasciotomy for lower-extremity fractures complicated by ACS presenting to a single Level I trauma center over a seven-year study period. The primary outcome measure was the incidence of SSI (as defined by the CDC) occurring within 12 months of fasciotomy. Explanatory variables including site of ACS, time of injury, time of fasciotomy, operative findings, and requirement for additional soft tissue coverage procedures were recorded for all patients. Multivariate regression was used to determine independent predictors of post-operative SSI. RESULTS: post operative SSI was detected in 16 (30.2%) patients. Compared to infection-free patients, patients with post-operative SSI had a significantly higher median age (52.0 vs. 37.0 years, p = 0.010), frequency of intra-operative myonecrosis at time of fasciotomy (31.2% vs. 5.4%, p = 0.021), and requirement for negative pressure wound therapy [NPWT] (93.7% vs. 45.9%, p = 0.002). Multivariate logistic regression analysis confirmed that requirement for NPWT (odds ratio [OR], 17.10; 95% confidence interval [CI], 1.78-164.0; p = 0.014) and increasing age (OR, 1.07; 95% CI, 1.01-1.14; p = 0.037) were independent predictors of post-operative SSI. Timing of fasciotomy following injury was not independently related to the risk of SSI. CONCLUSIONS: ACS occurs on a spectrum of disease severity that evolves variably over time. Increasing age of the patient and requirement for NPWT following fasciotomy are independent predictors of post-operative SSI following emergent fasciotomy for ACS. Further studies are required to inform optimal treatment strategies in such patients. LEVEL OF EVIDENCE: Therapeutic, Level III. PMID- 28730322 TI - Orthopaedic surgeons' opinions surrounding the management of proximal humerus fractures: an international survey. AB - PURPOSE: The purpose of this study was to survey surgeons' preferences surrounding the management and evaluation of proximal humerus fractures internationally. METHODS: A questionnaire was developed using previous literature and input from practicing orthopaedic surgeon opinion leaders. Between November 13, 2014 and December 31, 2014, the questionnaire was posted on the membership section of three major orthopaedic and shoulder surgery association websites. Survey responses were anonymous. RESULTS: The survey was completed by 134 unique practicing orthopaedic surgeons. The majority of respondents (72%) practiced in North America while 28% practiced internationally. For displaced two-part fractures, a preference for open reduction and internal fixation (ORIF) with locking plates was identified (75%). No consensus was reached for preferred treatment of three- and four- part fractures: 37% chose ORIF with locking plates, 26% chose hemi-arthroplasty (HA), and 29% chose reverse shoulder arthroplasty (RSA). Preferred treatment types for three- and four-part fractures were marginally significantly different depending on place of practice (North America vs. international, p = 0.058). A significantly larger proportion of surgeons who had completed an upper extremity fellowship (35%) chose RSA for the treatment of three and four-part fractures, compared to those who had not (9%, p = 0.002). No consensus was observed regarding what outcome measure is best to assess function following proximal humerus fractures. CONCLUSIONS: The management of more complex, displaced proximal humerus fractures remains controversial. Additionally, there are conflicting opinions on what outcome measure is best to assess function following the treatment of proximal humerus fractures. PMID- 28730324 TI - The role of NdgR in glycerol metabolism in Streptomyces coelicolor. AB - Streptomyces, which produces many pharmaceutical antibiotics and anticancer agents, is a genus of soil-dwelling bacteria with numerous regulators that control both primary and secondary metabolism. NdgR is highly conserved in Streptomyces spp. and is known to be involved in antibiotic production, tolerance against shock and physical stress, nitrogen metabolism, leucine metabolism, and N acetylglucosamine metabolism. As another function of NdgR, we report the involvement of NdgR in glycerol metabolism in S. coelicolor. Initially, a glycerol utilization operon containing gylCABX was found to be up-regulated in an ndgR deletion mutant (BG11) grown in N-acetylglucosamine solid minimal media compared with wild-type strain (M145). BG11 produced more antibiotics with a small amount of glycerol and increased glycerol utilization, yielding higher concentrations of lactate and acetate per cell. Moreover, fatty acid production was also changed in BG11 to produce longer chain fatty acids, phenolic compounds, alkanes, and fatty alcohols. Using a gel retardation assay, NdgR was found to bind the upstream region of gylC, working as a repressor. NdgR is a second regulator of a glycerol utilization operon, for which only one regulator, GylR was previously known. PMID- 28730323 TI - The pathogenesis, diagnosis, and management of metastatic tumors to the ovary: a comprehensive review. AB - Secondary tumors of the ovary account for 10-25% of all ovarian malignancies. The most common tumors that give rise to ovarian metastases include breast, colorectal, endometrial, stomach, and appendix cancer. The correct diagnosis of secondary ovarian tumors may be challenging as they are not infrequently misdiagnosed as primary ovarian cancer, particularly in the case of mucinous adenocarcinomas. The distinction from the latter is essential, as it requires different treatment. Immunohistochemistry plays an important role in distinguishing primary ovarian tumors from extra-ovarian metastases and, furthermore, may suggest the primary tumor site. Despite extensive study, some cases remain equivocal even after assessing a broad spectrum of antigens. Therefore, gene expression profiling represents an approach able to further discriminate equivocal findings, and one that has been proven effective in determining the origin of cancer of unknown primary site. The available data concerning secondary ovarian tumors is rather limited owing to the relative heterogeneity of this group and the practical absence of any prospective trials. However, several intriguing questions are encountered in daily practice, including rational diagnostic workup, the role of cytoreductive surgery, and consequent adjuvant chemotherapy. This review seeks to address these issues comprehensively and summarize current knowledge on the epidemiology, pathogenesis, and management of secondary ovarian tumors, including further discussion on the different pathways of metastatisation, metastatic organotropism, and their possible molecular mechanisms. PMID- 28730325 TI - Single-stage photofermentative biohydrogen production from sugar beet molasses by different purple non-sulfur bacteria. AB - Biohydrogen production via fermentative routes offers considerable advantages in waste recycling and sustainable energy production. This can be realized by single stage dark or photofermentative processes, or by a two-stage integrated process; the latter offering the higher production yields due to complete conversion of sugar substrates into H2 and CO2. However, problems arising from the integration of these two processes limit its scale-up and implementation. Hence, high efficiency one-step fermentative biohydrogen production processes from sugar-rich wastes are preferable. In this study, different strains of purple non-sulfur bacteria were investigated for their biohydrogen production capacity on pure sucrose and sugar beet molasses, and the feasibility of single-stage photofermentative biohydrogen production was evaluated. A single-stage photofermentation process was carried out using four different strains of purple non-sulfur bacteria (Rhodobacter capsulatus DSM 1710, R. capsulatus YO3, Rhodobacter sphaeroides O.U.001, and Rhodopseudomonas palustris DSM 127) on different initial sucrose concentrations. The highest hydrogen yield obtained was 10.5 mol H2/mol of sucrose and the maximum hydrogen productivity was 0.78 mmol/L h by Rp. palustris on 5 mM sucrose. A hydrogen yield of 19 mol H2/mol sucrose, which represents 79% of theoretical yield, and a maximum hydrogen productivity of 0.55 mmol/L h were obtained by Rp. palustris from sugar beet molasses. The yield was comparable to those values obtained in two-stage processes. The present study demonstrates that single-stage photofermentation using purple non-sulfur bacteria on sucrose-based wastes is promising. PMID- 28730327 TI - Erratum to: The diagnosis and management of infection following instrumented spinal fusion. PMID- 28730326 TI - Infectious diseases causing autonomic dysfunction. AB - OBJECTIVES: To review infectious diseases that may cause autonomic dysfunction. METHODS: Review of published papers indexed in medline/embase. RESULTS: Autonomic dysfunction has been reported in retrovirus (human immunodeficiency virus (HIV), human T-lymphotropic virus), herpes viruses, flavivirus, enterovirus 71 and lyssavirus infections. Autonomic dysfunction is relatively common in HIV-infected patients and heart rate variability is reduced even in early stages of infection. Orthostatic hypotension, urinary dysfunction and hypohidrosis have been described in tropical spastic paraparesis patients. Varicella zoster reactivation from autonomic ganglia may be involved in visceral disease and chronic intestinal pseudo-obstruction. Autonomic and peripheral nervous system dysfunction may happen in acute tick-borne encephalitis virus infections. Hydrophobia, hypersalivation, dyspnea, photophobia, and piloerection are frequently observed in human rabies. Autonomic dysfunction and vagal denervation is common in Chagas disease. Neuronal depopulation occurs mainly in chagasic heart disease and myenteric plexus, and megacolon, megaesophagus and cardiomyopathy are common complications in the chronic stage of Chagas disease. Parasympathetic autonomic dysfunction precedes left ventricle systolic dysfunction in Chagas disease. A high prevalence of subclinical autonomic neuropathy in leprosy patients has been reported, and autonomic nerve dysfunction may be an early manifestation of the disease. Autonomic dysfunction features in leprosy include anhidrosis, impaired sweating function, localised alopecia ,and reduced heart rate variability. Urinary retention and intestinal pseudo-obstruction have been described in Lyme disease. Diphtheritic polyneuropathy, tetanus and botulism are examples of bacterial infections releasing toxins that affect the autonomic nervous system. CONCLUSIONS: Autonomic dysfunction may be responsible for additional morbidity in some infectious diseases. PMID- 28730328 TI - Comparative study of the efficacy of transdermal buprenorphine patches and prolonged-release tramadol tablets for postoperative pain control after spinal fusion surgery: a prospective, randomized controlled non-inferiority trial. AB - PURPOSE: To compare the efficacy of a transdermal buprenorphine patch (5, 10, 15, and 20 MUg/h) with that of oral tramadol (150, 200, 250, and 300 mg) for postoperative pain control after single level spinal fusion surgery. METHODS: The present study (ClinicalTrials.gov, number NCT02416804) was a prospective, randomized controlled non-inferiority trial designed to determine the efficacy of buprenorphine TDS for alleviating postoperative pain following patient controlled analgesia (PCA) in persons underwent a single level posterior lumbar interbody fusion surgery through 1:1 allocation. The primary outcome was the Visual Analog Pain Scale (VAS) score for postoperative back pain at 7 days after surgery. The non-inferior margin of the VAS was set at delta = 1.5 points. RESULTS: The VAS score (primary outcome) for postoperative back pain at 7 days after surgery in the Buprenorphine group was not inferior compared to the Tramadol group. The overall changes in VAS scores for postoperative pain during follow-up assessments over a 2-week period did not differ between both groups. However, the VAS scores for postoperative pain significantly improved with time after surgery in both groups. The patterns of changes in the VAS scores for postoperative pain during the follow-up period were not significantly different between the both groups. CONCLUSIONS: The efficacy of buprenorphine TDS was not inferior to that of oral tramadol medication for alleviating postoperative pain in the subacute period from 72 h after surgery, following PCA administration. In addition, adverse events were similar between both groups. PMID- 28730329 TI - An Evaluation of the Addition of Critical Congenital Heart Defect Screening in Georgia Newborn Screening Procedures. AB - Objectives Each year in the U.S., approximately 7200 infants are born with a critical congenital heart defect (CCHD). The Georgia Department of Public Health (DPH) mandated routine screening for CCHD starting January 2015. The current study evaluated hospital performance of the mandated CCHD screenings in Georgia. Methods Utilizing the DPH newborn screening surveillance system, data from 6 months before and after the mandate were analyzed for reports submitted and positive CCHD screening results. Chi square tests of independence were performed to examine the association between reporting of results for CCHD screening after the mandate and hospital nursery level [level I (well-baby/newborn); level II (special care); level III (neonatal intensive care unit-NICU)] and NICU submissions. Results In the 6 months following implementation, reports of the screening increased, but the DPH had not received information for approximately 40% of newborns. Hospitals with level III nurseries had poorer reporting rates compared to hospitals with level I or II nurseries. Newborn screening (NBS) cards submitted by NICUs were less likely to contain the CCHD screening results compared to cards submitted by regular Labor and Delivery units. Conclusions for Practice Further attention should focus on improving both CCHD screening and reporting of screening results within hospitals with level III nurseries and from NICUs at all hospital levels. Identifying and addressing the root of the issue, whether it be hospital compliance with CCHD screening or reporting of the results, will help to improve screening rates for all newborns, especially those most vulnerable. PMID- 28730330 TI - Effect of the phosphogypsum amendment of saline and agricultural soils on growth, productivity and antioxidant enzyme activities of tomato (Solanum lycopersicum L.). AB - The objective of this study was to investigate the effects of phosphogypsum (PG) amendment on the physiochemical proprieties of saline and agricultural soils along with the growth, productivity and antioxidant enzyme activities of tomato plants ( Solanum lycopersicum L.) grown on the amended soils under controlled conditions. Obtained results showed that the amendment of saline soil (H) by PG induced a decrease in pH as well as in electrical conductivity. However, for the non saline soil (MC), there was a decrease in pH associated with an increase in electrical conductivity. For both soils, PG amendment led to an increase in Calcium (Ca) and sodium (Na), and a decrease in potassium (K) in plant tissues. Cadmium (Cd), Zinc (Zn) and Chromium (Cr) contents in different parts of plants increased in proportion with PG concentration in the soils. Apart from Cd, all the analyzed metals in tomato fruit were found to be below the recommended maximum allowable concentration (MAC). Our results showed that PG application, at doses not exceeding 20%, seems to be beneficial for growth, photosynthetic activity and productivity of tomato plants as well as in decreasing salinity of saline soils. In these conditions, the use of PG could be a promising project for the rehabilitation of marginalized and saline ecosystems with either ornamental or non-fruit species. For both soils, a significant accumulation of MDA in shoots was detected, reflecting cell membrane damage especially when the PG amendment reached 20%. Beyond 20 and 40% PG, tomato plants developed an enzymatic antioxidant defense system in response to salinity and heavy metal stress. However, at 80% PG, enzymes activities were significantly inhibited. PMID- 28730331 TI - [Early functional passive mobilization of flexor tendon injuries of the hand (zone 2) : Exercise with an exoskeleton compared to physical therapy]. AB - BACKGROUND: These days there are different types of aftercare following flexor tendon injury. Patients in this study received a dynamic Kleinert protocol and additionally two different postoperative treatments. Both treatment groups were compared to each other and results were put into perspective when compared to other treatment options. METHODS: Sixty-two patients presenting with clean lesions of the two flexor tendons in zone 2 received postoperative treatment with a dynamic Kleinert protocol. Patients were randomly divided into either Group I (physical therapy) or Group II (exoskeleton). Range of motion was assessed after 6, 12 and 18 weeks. In addition, we measured the Strickland score and grip strength at the 18-week follow-up. DASH scores were obtained at weeks 12 and 18. RESULTS: Regardless of the received postoperative treatment, range of motion was predominantly limited in the proximal interphalangeal and distal interphalangeal joints after 6 weeks. This deficit decreased with time and almost full range of motion was achieved after 18 weeks. Grip strength measured 75% (Group I) and 78% (Group II) of the healthy hand's level. Good functional outcome was observed in the DASH scores after 12 weeks, which improved further, measuring 7.5 (Group I) and 6.8 (Group II) at the 18-week follow-up. We did not see any clinically relevant differences between the two patient groups. CONCLUSION: Regarding possible reruptures, the Kleinert protocol delivers a safe treatment regime. The possible disadvantage of flexion contractures with the Kleinert protocol was not seen in our measurements. Additional motion exercises using an exoskeleton delivered comparable results to classic physical therapy. PMID- 28730332 TI - [A phase model of trauma rehabilitation : How can we avoid the "rehab-hole"?] AB - Advances in the rescue chain and first aid of polytrauma patients, which have consequently increased their chance of survival, have led to an increase in demands for rehabilitation. However, there is still a large hole in the continuity of rehabilitation between acute patient care and in-patient rehabilitation, the so-called "rehab-hole". The consequences are untapped rehabilitation potential, loss of strength, endurance and motivation as well as impairment of function of the patient.Based on the phase model of neurological/neurosurgical rehabilitation, we propose a step model for the rehabilitation of polytrauma patients that ensures an uninterrupted chain of rehabilitation. After acute patient care (phase a) and a potentially required early patient rehabilitation (phase b), trauma rehabilitation should seamlessly continue on to phase c. The implementation of phase c after acute patient rehabilitation requires changes in the structure of "orthopaedic" rehabilitation clinics and financial support due the large consumption of resources by more complexly injured patients in this phase. The subsequent rehabilitation in phase d is well established and complies with current rehabilitation measures (AHB, BGSW). Further rehabilitation measures may be essential for social and occupational reintegration of the patient (phase e), depending on the complexity of their injuries after the accident. For patients with long-lasting results after an accident, it is crucial to implement continuous follow-ups (phase f) to ensure a better long-term outcome.In order to implement this phase model it is necessary to establish specialized facilities that meet the particular requirements needed for phase c. This tri-phased treatment model in trauma centres can therefore be used in trauma rehabilitation. In addition to the already established local and regional rehabilitation centres, nationwide trauma rehabilitation centres have adopted phase c rehabilitation. PMID- 28730333 TI - Identification of a novel leukemic-specific splice variant of DNMT3B and its stability. AB - DNA methyltransferases make use of alternative splicing mechanism to generate various splice variants, but their role(s) in modulating DNA methylation patterns in the cells is unclear. Notably, DNMT3B alone contains nearly 40 different splice variants. In this study, we have identified a novel splice variant of DNMT3B, which lacks exon 7 and 10 from leukemic cell lines which we termed as DNMT3B9. The exon 7 codes for the major part of PWWP domain, and exon 10 inclusion serves as a pluripotent marker. By quantitative RT-PCR using exon-exon junction-specific primers, we showed higher level of DNMT3B9 transcripts in several leukemic cell lines. However, DNMT3B9 expression was less in other tested cancer cell lines indicating that DNMT3B9 might serve as a leukemic-specific biomarker. Surprisingly, endogenous protein for DNMT3B9 was not detected in leukemic cells suggesting the unidentified RNA-related function(s) for DNMT3B9. In addition, we showed that DNMT3B9 protein lacks PWWP domain is less stable compared to other DNMT3B variants which contain PWWP domain through computational predictions and by cycloheximide half-life experiment. Taken together, we demonstrated the existence of novel leukemic-specific splice variant of DNMT3B and provide the evidence for the role of PWWP domain in the stability of DNMT3B. The findings reported here have relevance in epigenetic therapy, which is aimed to target the DNMT3B in cancer cells. PMID- 28730334 TI - miR-181a-2 downregulates the E3 ubiquitin ligase CUL4A transcript and promotes cell proliferation. AB - MiR-181a-2 plays a major role in cell proliferation both positively and negatively depending on tissue type by targeting several regulators 3'UTR regions. We have predicted several targets for miR-181a-2 through computational approaches and characterized one its interesting target, CUL4A, an E3 ubiquitin ligase. CUL4A regulates diverse functions in the cells including DNA repair, DNA replication, cell cycle, genomic stability through polyubiquitination of target proteins. Deregulation of both miR-181a-2 and CUL4A are reported in many cancerous cells, but the functional link between them is unknown. We show that miR-181a-5p binds to 3'UTR of CUL4A and regulates its transcripts levels in HEK293 cells through overexpression studies. In addition, by using MTT and Neutral red assays, we showed that miR-181a-2 overexpression increased the proliferation in HEK293 cells. Moreover, cell cycle analysis using flow cytometer revealed that an increase in S-phase cells upon the overexpression of miR-181a-2. Though several miRNAs are known to downregulate the CUL4A levels, here we show that miR-181a-2 also participates in the downregulation of CUL4A. Taken together, our data demonstrated that miR-181a-2 increases the cell proliferation in HEK293 cells possibly through the downregulation of CUL4A. PMID- 28730335 TI - Clinical and prognosis value of the CIMP status combined with MLH1 or p16 INK4a methylation in colorectal cancer. AB - Aberrant DNA methylation of CpG islands occurred frequently in CRC and associated with transcriptional silencing of key genes. In this study, the CIMP combined with MLH1 or p16 INK4a methylation status was determined in CRC patients and correlated with clinicopathological parameters and overall survival. Our data showed that CIMP+ CRCs were identified in 32.9% of cases and that CACNAG1 is the most frequently methylated promoter. When we combined the CIMP with the MLH1 or the p16 INK4a methylation status, we found that CIMP-/MLH1-U (37.8%) and CIMP /p16 INK4a -U (35.4%) tumors were the most frequent among the four subtypes. Statistical analysis showed that tumor location, lymphovascular invasion, TNM stage, and MSI differed among the group of patients. Kaplan-Meier analyses revealed differences in overall survival according to the CIMP combined with MLH1 or p16 INK4a methylation status. In a multivariate analysis, CIMP/MLH1 and CIMP/p16 INK4a methylation statuses were predictive of prognosis, and the OS was longer for patients with tumors CIMP-/MLH1-M, as well as CIMP-/p16 INK4a -M. Furthermore, DNMT1 is significantly overexpressed in tumors than in normal tissues as well as in CIMP+ than CIMP- tumors. Our results suggest that tumor classification based on the CIMP status combined with MLH1 or p16 INK4a methylation is useful to predict prognosis in CRC patients. PMID- 28730336 TI - Serologic Markers of Autism Spectrum Disorder. AB - According to WHO data, about 67 million people worldwide are affected by autism, and this number grows by 14% annually. Among the possible causes of autism are genetic modifications, organic lesions of the central nervous system, metabolic disorders, influence of viral and bacterial infections, chemical influence to the mother's body during pregnancy, etc. The conducted research shows that research papers published until today do not name any potential protein markers that meet the requirements of the basic parameters for evaluating the efficiency of disease diagnostics, in particular high sensitivity, specificity, and accuracy. Conducting proteomic research on a big scale in order to detect serologic markers of protein nature associated with development of autism spectrum disorders seems to be highly relevant. PMID- 28730337 TI - Memantine Can Reduce Ethanol-Induced Caspase-3 Activity and Apoptosis in H4 Cells by Decreasing Intracellular Calcium. AB - Caspase-3 activation and apoptosis are associated with various neurodegenerative disorders. Calcium activation is an important factor in promoting apoptosis. We, therefore, assessed the role of intracellular calcium in ethanol-induced activation of caspase-3 in H4 human neuroglioma cells and the protective effect of the NMDA receptor antagonist, memantine, on ethanol-induced apoptosis in H4 cells. H4 cells were treated with 100 mM EtOH (in culture medium) for 2 days. For interaction studies, cells were treated with memantine (4 MUM), EDTA (1 mM), or BAPTA-AM (10 MUM) before treatment with EtOH. Knockdown of the gene encoding the NR1 subunit of the NMDA receptor was performed using RNAi. Apoptosis was detected by Annexin V-FITC/PI staining and flow cytometry. Cell viability was detected using an MTS cell proliferation kit. Fluorescence dual wavelength spectrophotometry was used to determine the intracellular calcium concentration. The levels of NR1, caspase-3, IP3R1, and SERCA1 proteins were detected by western blotting. NR1, IP3R1, and SERCA1 mRNA levels were detected by qPCR. We observed increased expression of NR1, IP3R1, SERCA1, and increased intracellular levels of calcium ions in H4 cells exposed to ethanol. In addition, the calcium chelators, EDTA and BAPTA, and RNAi disruption of the NMDA receptor reduced ethanol-induced caspase-3 activation in H4 cells. Memantine treatment reduced the ethanol-induced increase of intracellular calcium, caspase-3 activation, apoptosis, and the ethanol-induced decrease in cell viability. Our results indicate that ethanol induced caspase-3 activation and apoptosis are likely to be dependent on cytosolic calcium levels and that they can be reduced by memantine treatment. PMID- 28730338 TI - Jagged1 promotes aromatase inhibitor resistance by modulating tumor-associated macrophage differentiation in breast cancer patients. AB - PURPOSE: Endocrine resistance limits the efficacy of anti-estrogen therapies. Notch signaling is involved in modulating tumor-associated macrophage (TAM) differentiation and is upregulated in endocrine-resistant breast cancer cells. Here, we analyzed the role of Jagged1 in the regulation of TAM polarization to investigate whether the Jagged1-Notch pathway promotes the acquisition of aromatase inhibitor (AI) resistance by upregulating TAM infiltration. METHODS: The Jagged1 expression levels and M2 TAM infiltration density, in 203 tumor samples from ER-positive postmenopausal patients, who received AI treatment, were evaluated by immunohistochemical staining and the results were compared with clincopathological parameters and survival. The Jagged1 protein and mRNA levels were analyzed in MCF-7 and long-term endocrine-depleted (LTED) cell lines. The phenotypes of macrophage after macrophages were co-cultured with either MCF-7 or LTED cells, were evaluated using flow cytometry. Cell migration assay was performed to evaluate the mobility of cancer cells. Notch gama secretase inhibitor (GSI) RO4929097 was employed to investigate whether modulation of Notch signaling affects M2 polarization. RESULTS: In the tumor samples, Jagged1 expression was found to be associated with a large tumor size, high histological grade, lymphatic invasion, and high Ki67 expression. Jagged1 expression was also correlated with reduced disease-free and overall survival and was positively associated with the stromal M2 TAM infiltration density in primary tumor tissues. In AI-resistance patients, M2 TAM infiltration was denser in metastatic lesions than in primary tumors. Higher Jagged1 protein and mRNA levels were also found in LTED cells, which model AI-resistant conditions in patients, compared with MCF-7 cells. Macrophages co-cultured with LTED cells expressed higher levels of M2 marker and IL-10. M2 TAM proportion was reduced when macrophages were pre-treated with GSI before co-culture. CONCLUSIONS: The Jagged1-Notch pathway showed elevated expression in AI-resistant breast cancer cells, resulting in macrophage differentiation towards M2 TAMs and there contributing to the acquisition of AI resistance. PMID- 28730339 TI - Breast cancer neoplastic seeding in the setting of image-guided needle biopsies of the breast. AB - PURPOSE: To identify clinicopathologic, technical, and imaging features associated with neoplastic seeding (NS) following image-guided needle breast biopsy. METHODS: We performed an institutional review board-approved retrospective review of patients presenting with a new diagnosis of breast cancer or suspicious breast findings requiring biopsy with subsequent diagnosis of NS. The time from biopsy to NS diagnosis was calculated. Histology, grade, estrogen receptor (ER) status, progesterone receptor (PR) status, HER2 status, T category, and N category were recorded. Biopsy guidance method, needle gauge, and number of passes were reviewed in addition to the mammographic and sonographic features of the primary tumors and the NS. RESULTS: Eight cases of NS were identified in 4010 patients. The mean time from biopsy to NS diagnosis was 60.8 days. The most frequent histology was invasive ductal carcinoma (7/8). Six cases were grade 3 (75.0%). Five primary breast cancers were ER, PR, and HER2 negative (62.5%). Seven patients underwent biopsy with ultrasound guidance. Multiple-insertion, non coaxial ultrasound-guided core-needle biopsy was done in 6 cases. Mammographic presentation of NS was focal asymmetry (3/7 cases), mass (1/7), calcifications only (1/7), or occult (2/7). Sonographic presentation of NS was most often a mass (7/8) with irregular shape (5/7) and without circumscribed margins (6/7) and was occult in 1 case (1/8). NS distribution was subdermal and intradermal. CONCLUSION: High-grade, triple-negative breast cancers and multiple-insertion, non-coaxial biopsies may be risk factors for NS. NS should be suspected on the basis of the superficial and linear pattern of disease progression in these patients. PMID- 28730341 TI - Erratum to: The clinical and genetic characteristics in children with mitochondrial disease in China. PMID- 28730342 TI - Transcriptome analysis of three cotton pests reveals features of gene expressions in the mesophyll feeder Apolygus lucorum. AB - The green mirid bug Apolygus lucorum is an agricultural pest that is known to cause damage to more than 150 plant species. Here, we report the transcriptomes of A. lucorum at three different developmental stages (the second and fifth instar nymphs and adults). A total of 98,236 unigenes with an average length of 1,335 nt was obtained, of which 50,640 were annotated, including those encoding digestive enzymes and cytochrome P450s. Comparisons with cotton bollworm and cotton aphid transcriptomes revealed distinct features of A. lucorum as a mesophyll feeder. The gene expression dynamics varied during development from young nymphs to adults. The high-quality transcriptome data and the gene expression dynamics reported here provide valuable data for a more comprehensive understanding of the physiology and development of mirid bugs, and for mining targets for their control. PMID- 28730340 TI - CYP2D6 genotype is not associated with survival in breast cancer patients treated with tamoxifen: results from a population-based study. AB - PURPOSE: A number of studies have tested the hypothesis that breast cancer patients with low-activity CYP2D6 genotypes achieve inferior benefit from tamoxifen treatment, putatively due to lack of metabolic activation to endoxifen. Studies have provided conflicting data, and meta-analyses suggest a small but significant increase in cancer recurrence, necessitating additional studies to allow for accurate effect assessment. We conducted a retrospective pharmacogenomic analysis of a prospectively collected community-based cohort of patients with estrogen receptor-positive breast cancer to test for associations between low-activity CYP2D6 genotype and disease outcome in 500 patients treated with adjuvant tamoxifen monotherapy and 500 who did not receive any systemic adjuvant therapy. METHODS: Tumor-derived DNA was genotyped for common, functionally consequential CYP2D6 polymorphisms (*2, *3, *4, *6, *10, *41, and copy number variants) and assigned a CYP2D6 activity score (AS) ranging from none (0) to full (2). Patients with poor metabolizer (AS = 0) phenotype were compared to patients with AS > 0 and in secondary analyses AS was analyzed quantitatively. Clinical outcome of interest was recurrence free survival (RFS) and analyses using long-rank test were adjusted for relevant clinical covariates (nodal status, tumor size, etc.). RESULTS: CYP2D6 AS was not associated with RFS in tamoxifen treated patients in univariate analyses (p > 0.2). In adjusted analyses, increasing AS was associated with inferior RFS (Hazard ratio 1.43, 95% confidence interval 1.00-2.04, p = 0.05). In patients that did not receive tamoxifen treatment, increasing CYP2D6 AS, and AS > 0, were associated with superior RFS (each p = 0.0015). CONCLUSIONS: This population-based study does not support the hypothesis that patients with diminished CYP2D6 activity achieve inferior tamoxifen benefit. These contradictory findings suggest that the association between CYP2D6 genotype and tamoxifen treatment efficacy is null or near null, and unlikely to be useful in clinical practice. PMID- 28730343 TI - Age at maturation has sex- and temperature-specific effects on telomere length in a fish. AB - Telomeres are highly conserved nucleoprotein structures which protect genome integrity. The length of telomeres is influenced by both genetic and environmental factors, but relatively little is known about how different hereditary and environmental factors interact in determining telomere length. We manipulated growth rates and timing of maturation by exposing full-sib nine spined sticklebacks (Pungitius pungitius) to two different temperature treatments and quantified the effects of temperature treatments, sex, timing of maturation, growth rate and family (genetic influences) on telomere length. We did not find the overall effect of temperature treatment on the relative telomere length. However, we found that variation in telomere length was related to timing of maturation in a sex- and temperature-dependent manner. Telomere length was negatively related to age at maturation in elevated temperature and early maturing males and females differed in telomere length. Variation in growth rate did not explain any variation in telomere length. The broad sense heritability (h 2) of telomere length was estimated at h 2 = 0.31 - 0.47, suggesting predominance of environmental over genetic determinants of telomere length variability. This study provides the first evidence that age at maturation together with factors associated with it are influencing telomere length in an ectotherm. Future studies are encouraged to identify the extent to which these results can be replicated in other ectotherms. PMID- 28730344 TI - Bearing fruit: flower removal reveals the trade-offs associated with high reproductive effort for lowbush blueberry. AB - Past studies have shown that taxa from disparate groups often respond similarly to reduced reproductive effort. These common responses imply that high reproductive effort trades off with a consistent set of other life functions for most angiosperms, albeit modulated by their growth form and life history. However, many questions remain about reproductive trade-offs in plants, including just how many other life functions they involve, how diverse these functions may be, and how the severity of these trade-offs may vary through time. To address these questions in a long-lived, iteroparous shrub, we performed flower removal on plots of lowbush blueberry, Vaccinium angustifolium (Ericaceae), over 3 years. We found significant physiological differences between removal and control plots for ten diverse traits. Vegetative phenology was shifted earlier by about 20% in removal plots, and removal plots had about 15% more vegetative biomass by mid season as well. Removal plots produced about 10% more ripe fruit per reproductive node by harvest than control plots, and reproductive nodes in removal plots produced at least one fruit by harvest about 6% more often. While fruit water content and titratable acidity were increased by removal, other fruit traits, such as sugar content and fresh mass, were not. The strength of the removal effect varied significantly by year for seven traits; for many, such as vegetative mass/stem and ripe fruit production/node, the effect was stronger in years with more stressful abiotic conditions. Our results demonstrate that there are tangible but variable costs to high reproductive effort for flowering plants. PMID- 28730345 TI - Does fear beget fear? Risk-mediated habitat selection triggers predator avoidance at lower trophic levels. AB - Non-consumptive effects (NCEs) of predators are ubiquitous in food webs with well detailed impacts on trophic cascades over multiple levels. However, integrating NCEs with other predator-mediated interactions, like intraguild predation, as well as context-specific habitat factors that shape top-down pressure, remains a challenge. Focusing on two common seed predators, mice (Peromyscus spp.) and carabid beetles (Coleoptera: Carabidae), we quantify trophic and behavioral consequences of predation risk and availability of refuge vegetation on both intraguild predators (mice) and intraguild prey (beetles). In a 2-year field experiment, we manipulated refuge habitat (red clover), small mammal access, and moonlight, which small mammals use as an indirect cue of predation risk. We found that avoidance of predation risk by mice in simulated moonlight reduced carabid activity density in vegetation by up to 50% compared to exposed habitat, but had no cascading effects on seed predation. We linked patterns observed in the field with behavioral mechanisms by observing beetle foraging activity, and found that exposure to both indirect and direct vertebrate predator cues reduced movement by 50%, consistent with predator-mediated activity reductions observed in the field. However, predation risk increased carabid seed consumption by 43%. Thus, weak effects of predation risk on seed removal in the field may be explained by overcompensatory seed feeding by beetles. This work demonstrates that predators elicit responses that cascade over multiple trophic levels, triggering behavioral changes in species lower on the food chain. These behavior-mediated cascades are controlled by their spatiotemporal context and have important downstream impacts on predator-prey dynamics. PMID- 28730346 TI - Gyrfalcons Falco rusticolus adjust CTNS expression to food abundance: a possible contribution to cysteine homeostasis. AB - Melanins form the basis of animal pigmentation. When the sulphurated form of melanin, termed pheomelanin, is synthesized, the sulfhydryl group of cysteine is incorporated to the pigment structure. This may constrain physiological performance because it consumes the most important intracellular antioxidant (i.e., glutathione, GSH), of which cysteine is a constitutive amino acid. However, this may also help avoid excess cysteine, which is toxic. Pheomelanin synthesis is regulated by several genes, some of them exerting this regulation by controlling the transport of cysteine in melanocytes. We investigated the possibility that these genes are epigenetically labile regarding protein intake and thus contribute to cysteine homeostasis. We found in the Icelandic population of gyrfalcon Falco rusticolus, a species that pigments its plumage with pheomelanin, that the expression of a gene regulating the export of cystine out of melanosomes (CTNS) in feather melanocytes of developing nestlings increases with food abundance in the breeding territories where they were reared. The expression of other genes regulating pheomelanin synthesis by different mechanisms of influence on cysteine availability (Slc7a11 and Slc45a2) or by other processes (MC1R and AGRP) was not affected by food abundance. As the gyrfalcon is a strict carnivore and variation in food abundance mainly reflects variation in protein intake, we suggest that epigenetic lability in CTNS has evolved in some species because of its potential benefits contributing to cysteine homeostasis. Potential applications of our results should now be investigated in the context of renal failure and other disorders associated with cystinosis caused by CTNS dysfunction. PMID- 28730347 TI - [Gastric signet ring cell carcinoma : New aspects for long-range prognosis]. PMID- 28730348 TI - [Pharyngoesophageal diverticulum]. AB - Over the last 20-30 years, treatment of pharyngoesophageal diverticula was subject to a number of fundamental changes. Considering the classical open transcervical approaches, the necessity for myotomy of the upper esophageal sphincter with the goal of interrupting the pathogenesis of the disease has become a standard component of the operation. On the other hand, with the growing popularity of rigid and flexible endoscopic techniques, pharyngoesophageal diverticula are increasingly being treated by gastroenterologists and otorhinolaryngologists, often with the argument of a technically easier and less invasive procedure; however, it remains unclear whether this shift towards endoscopic techniques truly translates into better outcome quality. This aim of this CME article is to summarize the available scientific evidence on the complex pathophysiology, diagnostics and treatment of pharyngoesophageal diverticula and to provide the reader with an updated guide to best clinical practice for diagnostics and treatment. PMID- 28730350 TI - [On the diagnosis of Meniere's disease : Discussion of the new criteria]. PMID- 28730349 TI - Manganese-Mediated Decrease in Levels of c-RET and Tyrosine Hydroxylase Expression In Vitro. AB - Previous studies showed that overexposure to manganese causes parkinsonism, a disorder of dopaminergic neurons. Previous studies also showed that activity of c RET kinase controls dopamine production through regulation of tyrosine hydroxylase (TH) expression, suggesting the involvement of c-RET in the development of parkinsonism. To our knowledge, however, there is no report showing a correlation between manganese-mediated parkinsonism and c-RET. In this study, we examined the effect of manganese on the expression and/or activation levels of c-RET and TH in human TH-expressing cells (TGW cells). We first found that treatment with 30 and 100 MUM manganese resulted in reduction of c-RET transcript level and degradation of c-RET protein through promotion of ubiquitination. We then examined the biological significance of manganese mediated decrease of c-RET protein expression. Decreased TH expression with decreased c-RET kinase activity was observed in c-RET protein-depleted TGW cells by treatment with manganese (30 MUM) as well as by c-RET siRNA transfection. Since TH protein has been shown to be involved in the dopamine-producing pathway in previous studies, our results indicate the possibility that manganese-mediated reduction of TH expression and phosphorylation via decreased expression of c-RET protein in neural cells is involved in parkinsonism induced by manganese. PMID- 28730351 TI - Insight into pi-hole interactions containing the inorganic heterocyclic compounds S2N2/SN2P2. AB - Similar to sigma-hole interactions, the pi-hole interaction has attracted much attention in recent years. According to the positive electrostatic potentials above and below the surface of inorganic heterocyclic compounds S2N2 and three SN2P2 isomers (heterocyclic compounds 1-4), and the negative electrostatic potential outside the X atom of XH3 (X = N, P, As), S2N2/SN2P2?XH3 (X = N, P, As) complexes were constructed and optimized at the MP2/aug-cc-pVTZ level. The X atom of XH3 (X = N, P, As) is almost perpendicular to the ring of the heterocyclic compounds. The pi-hole interaction energy becomes greater as the trend goes from 1?XH3 to 4?XH3. These pi-hole interactions are weak and belong to "closed-shell" noncovalent interactions. According to the energy decomposition analysis, of the three attractive terms, the dispersion energy contributes more than the electrostatic energy. The polarization effect also plays an important role in the formation of pi-hole complexes, with the contrasting phenomena of decreasing electronic density in the pi-hole region and increasing electric density outside the X atom of XH3 (X = N, P, As). Graphical abstract Computed density difference plots for the complexes 3?NH 3 (a 1), 3?PH 3 (b 1), 3?AsH 3 (c 1) and electron density shifts for the complexes 3?NH 3 (a 2), 3?PH 3 (b 2),3?AsH 3 (c 2) on the 0.001 a.u. contour. PMID- 28730352 TI - Exploring the potential energy surface of novel [H, S, Se, Br] species: a high level first principle study. AB - The characterization of the seleno-sulfide-bromo systems and the isomerization process on the [H, S, Se, Br] potential energy surface were investigated using state-of-the-art theoretical methods. The CCSD(T) and the MP2 levels of theory were employed along with the series of correlation consistent basis sets extrapolated to the complete basis set (CBS) limit in the optimization of the geometrical parameters and computation of electronic energies. The relative stability, in kcal mol-1, at the CCSD(T)/CBS follows the trend: HSSeBr (0) > HSeSBr (9.51) > SSeHBr (24.02) > SeSHBr (25.42). This order was observed in the previous study of the [H, S, Se, Cl] species. The structural parameters and vibrational frequencies of the [H, S, Se, Br] species are reported. This research work should be helpful to experimentalists in order to gain insights into these novel heteroatom molecules. Graphical abstract Relative energy profile (in kcal mol-1) using the CCSD(T)/CBS and MP2/CBS (in parentheses) method of the stationary states on the [H, S, Se, Br] PES. PMID- 28730353 TI - An Exploration into the Bacterial Community under Different Pasteurization Conditions during Substrate Preparation (Composting-Phase II) for Agaricus bisporus Cultivation. AB - Substrate preparation (i.e., composting) for Agaricus bisporus cultivation is the most critical point of mushroom production. Among many factors involved in the composting process, the microbial ecology of the system is the underlying drive of composting and can be influenced by composting management techniques. Pasteurization temperature at the beginning of phase II, in theory, may influence the bacterial community and subsequently the "selectivity" and nutrition of the final substrate. Therefore, this hypothesis was tested by simulation in bioreactors under different pasteurization conditions (57 degrees C/6 h, 60 degrees C/2 h, and 68 degrees C/2 h), simulating conditions adopted by many producers. Bacterial diversity, based on 16S ribosomal RNA obtained by high throughput sequencing and classified in operational taxonomic units (OTUs), was greater than previously reported using culture-dependent methods. Alpha diversity estimators show a lower diversity of OTUs under a high-temperature pasteurization condition. Bacillales order shows a relatively higher OTU abundance under a high pasteurization temperature, which also was related to high ammonia emission measurements. On the other hand, beta diversity analysis showed no significantly changes in the bacterial community structure under different conditions. Agaricus bisporus mycelium growth during a standard spawn run period was significantly slower in the compost pasteurized at high temperature. Since the bacterial community structure was not greatly affected by different pasteurization conditions but by-products left (e.g., ammonia) at the end of compost conditioning varied, further studies need to be conducted to determine the functional role of the microbial communities found during substrate preparation for Agaricus bisporus cultivation. PMID- 28730355 TI - Charge transport in DNA model with vibrational and rotational coupling motions. AB - The dynamics of the Peyrard-Bishop model for vibrational motion of DNA dynamics, which has been extended by taking into account the rotational motion for the nucleotides (Silva et al., J. Biol. Phys. 34, 511-519, 2018) is studied. We report on the presence of the modulational instability (MI) of a plane wave for charge migration in DNA and the generation of soliton-like excitations in DNA nucleotides. We show that the original differential-difference equation for the DNA dynamics can be reduced in the continuum approximation to a set of three coupled nonlinear equations. The linear stability analysis of continuous wave solutions of the coupled systems is performed and the growth rate of instability is found numerically. Numerical simulations show the validity of the analytical approach with the generation of wave packets provided that the wave numbers fall in the instability domain. PMID- 28730354 TI - Early Recurrence of Neuroendocrine Liver Metastasis After Curative Hepatectomy: Risk Factors, Prognosis, and Treatment. AB - BACKGROUND: Early tumor recurrence after curative resection typically indicates a poor prognosis. The objective of the current study was to investigate the risk factors, treatment, and prognosis of early recurrence of neuroendocrine tumor (NET) liver metastasis (NELM) after hepatic resection. METHODS: A total of 481 patients who underwent curative-intent resection for NELM were identified from a multi-institutional database. Data on clinicopathological characteristics, intraoperative details, and outcomes were documented. The optimal cutoff value to differentiate early and late recurrence was determined to be 3 years based on linear regression. RESULTS: With a median follow-up of 60 months, 223 (46.4%) patients developed a recurrence, including 158 (70.9%) early and 65 (29.1%) late recurrences. On multivariable analysis, pancreatic NET, primary tumor lymph node metastasis, and a microscopic positive surgical margin were independent risk factors for early intrahepatic recurrence. While recurrence patterns and treatments were comparable among patients with early and late recurrences, early recurrence was associated with worse disease-specific survival than late recurrences (10-year NELM-specific survival, 44.5 vs 75.8%, p < 0.001). Among the 34 (21.5%) patients who underwent curative treatment for early recurrence, post recurrence disease-specific survival was better than non-curatively treated patients (10-year NELM-specific survival, 54.2 vs 26.3%, p = 0.028), yet similar to patients with late recurrences treated with curative intent (10-year NELM specific survival, 54.2 vs 37.4%, p = 0.519). CONCLUSIONS: Early recurrence after surgery for NELM was associated with the pancreatic type, primary lymph node metastasis, and extrahepatic disease. Re-treatment with curative intent prolonged survival after recurrence, and therefore, operative intervention even for early recurrences of NELM should be considered. PMID- 28730356 TI - Seasonal variation of chemical composition and source apportionment of PM2.5 in Pune, India. AB - Particulate matter with size less than or equal to 2.5 MUm (PM2.5) samples were collected from an urban site Pune, India, during April 2015 to April 2016. The samples were analyzed for various chemical constituents, including water soluble inorganic ions, organic carbon (OC), and elemental carbon (EC). The yearly mean total mass concentration of PM2.5 at Pune was 37.3 MUg/m3, which is almost four times higher than the annual WHO standard (10 MUg/m3), and almost equal to that recommended by the Central Pollution Control Board, India (40 MUg/m3). Measured (OC, EC) and estimated organic matter (OM) were the dominant component (56 +/- 11%) in the total particulate matter which play major role in the regional atmospheric chemistry. Total measured inorganic components formed about 35% of PM2.5. Major chemical contributors to PM2.5 mass were OC (30%), SO42- (13%), and Cl- and EC (9% each). The high ratios of OC/EC demonstrated the existence of secondary organic carbon. The air mass origin and correlations between the various components indicate that long range transport of pollutants from Indo Gangetic Plain (IGP) and Southern part of the Arabian Peninsula might have contributed to the high aerosol mass during the dry and winter seasons. To our knowledge, this is the first systematic study that comprehensively explores the chemical characterization and source apportionment of PM2.5 aerosol speciation in Pune by applying multiple approaches based on a seasonal perspective. This study is broadly applicable to understanding the differences in anthropogenic and natural sources in the urban environment of particle air pollution over this region. PMID- 28730357 TI - Biosynthesis of silver nanoparticles from Spirulina microalgae and its antibacterial activity. AB - The present work focuses on a low-cost, simple, and green synthesis of silver nanoparticles (AgNPs) by mixing AgNO3 solution with the extract of Spirulina platensis (SP) without any chemical reducing and/or capping agents. The green synthesis of AgNPs was confirmed by the color change from colorless to yellowish brown. The biosynthesis of AgNPs was further confirmed by UV-visible spectroscopy (UV-vis), Fourier transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD), biological transmission electron microscopy (Bio-TEM), and energy dispersive X-ray analysis (EDX). The UV-vis spectroscopy results showed the surface plasmon resonance (SPR) of AgNPs around 450 nm. Bio-TEM analysis revealed that the Ag nanoparticles were well dispersed with average range of 5-50 nm. XRD results indicated that the green synthetic process produced face-centered cubic structure of AgNPs. FT-IR spectroscopy analysis showed that the bioactive molecules from the SP extract believed to be the responsible for the reduction of Ag ions. Furthermore, the synthesized AgNPs were evaluated against pathogens such as Staphylococcus sp. and Klebsiella sp. The AgNPs (1-4 mM) extensively reduced the growth rate of the pathogens. PMID- 28730358 TI - Hydrogeochemical characterization and groundwater quality assessment in intruded coastal brine aquifers (Laizhou Bay, China). AB - The aquifer in the coastal area of the Laizhou Bay is affected by salinization processes related to intense groundwater exploitation for brine resource and for agriculture irrigation during the last three decades. As a result, the dynamic balances among freshwater, brine, and seawater have been disturbed and the quality of groundwater has deteriorated. To fully understand the groundwater chemical distribution and evolution in the regional aquifers, hydrogeochemical and isotopic studies have been conducted based on the water samples from 102 observation wells. Groundwater levels and salinities in four monitoring wells are as well measured to inspect the general groundwater flow and chemical patterns and seasonal variations. Chemical components such as Na+, K+, Ca2+, Mg2+, Sr2+, Cl-, SO42-, HCO3-, NO3-, F-, and TDS during the same period are analyzed to explore geochemical evolution, water-rock interactions, sources of salt, nitrate, and fluoride pollution in fresh, brackish, saline, and brine waters. The decreased water levels without typical seasonal variation in the southeast of the study area confirm an over-exploitation of groundwater. The hydrogeochemical characteristics indicate fresh-saline-brine-saline transition pattern from inland to coast where evaporation is a vital factor to control the chemical evolution. The cation exchange processes are occurred at fresh-saline interfaces of mixtures along the hydraulic gradient. Meanwhile, isotopic data indicate that the brine in aquifers was either originated from older meteoric water with mineral dissolution and evaporation or repeatedly evaporation of retained seawater with fresher water recharge and mixing in geological time. Groundwater suitability for drinking is further evaluated according to water quality standard of China. Results reveal high risks of nitrate and fluoride contamination. The elevated nitrate concentration of 560 mg/L, which as high as 28 times of the standard content in drinking water is identified in the south region. In addition, the nitrate and ammonia data of the Wei River suggests decreasing nitrification rate in the study area from inland to estuary. High fluoride concentration, larger than 1 mg/L, is also detected in an area of about 50% of the study region. The saltwater intrusion is analyzed to be responsible for part of dissolution of minerals containing fluoride. Therefore, water treatment before drinking is needed in urgent to reduce the health expose risk. PMID- 28730359 TI - Improving Cu(II) sorption by biochar via pyrolyzation under CO2: the importance of inherent inorganic species. AB - Biochar from Spartina alterniflora (SA) and rice straw (RS) under N2/CO2 were evaluated for Cu(II) removal from aqueous solution. The result indicates SA biochar prepared at 700 degrees C under CO2 can achieve a Cu(II) sorption capacity of 89.12 +/- 2.77 mg/g, which is higher than that from N2 by about 50%. CO2 can promote the development of multi-porous structure, enhance specific surface area, and increase the amounts of hydroxyl and carboxyl groups on biochar. In addition, CO2 can inhibit the thermal decomposition of inorganic carbonate, such as MgCO3 and CaCO3 in biochar. These matters facilitate Cu(II) removal via the formation of chemical precipitation of Cu2(OH)2CO3. The dissolution of inherent inorganic matter makes Cu(II) transformed into hydrolyzed species or amorphous precipitation, which contributes to about 75% (w/w) of Cu(II) removal. Metal exchange with complexed cations and the formation of basic cupric carbonate are time-consuming and responsible for about 24% (w/w) of Cu(II) removal. Graphical abstract ?. PMID- 28730360 TI - Characterization of extracellular polymeric substance (EPS) fractions produced by Microcystis aeruginosa under the stress of linoleic acid sustained-release microspheres. AB - This paper focuses on the characterization of extracellular polymeric substances (EPS), which are composed of soluble EPS (SL-EPS), loosely bound EPS (LB-EPS), and tightly bound EPS (TB-EPS) produced by Microcystis aeruginosa under the stress of linoleic acid (LA) and LA sustained-release microspheres. Three dimensional excitation-emission matrix (3D-EEM) fluorescence spectroscopy and Fourier transform infrared (FTIR) spectrometry were used to characterize three forms of EPS while the content of polysaccharide and protein was tested, respectively. The results showed that the highest inhibitor rate (IR) occurred when M. aeruginosa were exposed to LA sustained-release microspheres of 0.3 g L 1. The 3D-EEM contour demonstrated that tryptophan and protein-like substances were detected in all three EPS fractions, whereas humic acid-like substance was only distributed in SL-EPS, and aromatic proteins merely existed in LB-EPS and TB EPS. The infrared spectrum showed that functional groups in three EPS fractions had no obvious change in all experimental groups. Polysaccharide (1120-1270 cm-1, C-O-C and C-O stretching vibration) and protein (1384-1670 cm-1, C-N and N-H stretching) were detected in three forms of EPS. Graphical abstract ?. PMID- 28730361 TI - The effect of different surface materials on runoff quality in permeable pavement systems. AB - To investigate the effect of different permeable pavement surface materials on the removal of pollutants from urban storm-runoff, six commonly surface materials (porous asphalt, porous concrete, cement brick, ceramic brick, sand base brick, and shale brick) were selected in this study and the research was carried out by column experiments. Except the concentrations of total suspended solids (TSS), chemical oxygen demand (COD), ammonia nitrogen (NH4-N), nitrate nitrogen (NO3-N), total nitrogen (TN), and total phosphorus (TP) in the influent and effluent that were measured, the removal mechanism of pollutants was discussed further. The results indicate that the surface materials influence the removal efficiency of pollutants greatly and have different effects on certain pollutant. Furthermore, the physical interception and adsorption would be the main mechanism for the removal of pollutants from runoff. For example, for all surface materials, the average removal efficiency of TSS is nearly about 90.0% because of physical interception. Due to the amount of iron oxide, the removal efficiency of COD, NO3 N, and TN of shale brick was 88.2, 35.1, and 17.5%, respectively. NH4-N and TN can be easily removed by porous asphalt due to the high content of organic matter. By lacking of useful adsorption sites, all the surface materials had little effect on the removal of TP from runoff. This research could offer useful guidelines for the better design of permeable pavement system and promote the insight into the removal mechanism of pollutants in permeable pavement system. Graphical abstract Different types of materials for the different types of pollutants in the runoff purification capacity were significantly different, overall, shale brick and porous asphalt Shale bricks and porous asphalt have a better purification effect according to the six kinds of materials. PMID- 28730362 TI - Removal of Cr(VI) from aqueous solution using electrosynthesized 4-amino-3 hydroxynaphthalene-1-sulfonic acid doped polypyrrole as adsorbent. AB - Polypyrrole (PPy) conducting films, doped with 4-amino-3-hydroxynaphthalene sulfonic acid (AHNSA), were electrosynthesized by anodic oxidation of pyrrole on Pt and steel electrodes in aqueous medium (0.01 M AHNSA +0.007 M NaOH, using cyclic voltammetry (CV), and their electrochemical properties were studied. Fourier-transform infrared (FT-IR) spectroscopy confirmed the formation of AHNSA PPy films. Their morphology was characterized by scanning electron microscopy (SEM), and their optical properties, including UV-VIS absorption and fluorescence spectra, were also investigated. AHNSA-PPy films were used for the removal of chromium(VI) from aqueous solution, by means of the immersion method and the Cr(VI) electro-reduction method. The effect of various experimental parameters, including the adsorbent (polymer) mass, pH, type of electrodes, and current intensity, on the adsorption of chromium by the polymer was performed and optimized. The adsorption and electro-reduction of (Cr VI) on the AHNSA-PPy film surface were found to be highly pH-dependent, and the kinetics of Cr(VI) adsorption and electro-reduction followed second-order kinetic curves. Apparent second-order rate constants were about three times higher for the Cr(VI) electro reduction method than for the immersion method, indicating that the use of electro-reduction method significantly accelerated the chromium adsorption process on polymer. The maximum adsorption capacity of the AHNSA-PPy film for chromium was 224 mg g-1. A 96% chromium removal from pure aqueous solution was reached within about 48 h by the immersion method, but only within about 6 h by the Cr(VI) electro-reduction method. Application of both methods to Cr(VI) fortified natural waters of Senegal led to chromium removal efficiency high values (93 to 96% according to the type of natural water). PMID- 28730363 TI - Leaching of Cu, Cd, Pb, and phosphorus and their availability in the phosphate amended contaminated soils under simulated acid rain. AB - Phosphate amendments have been used to immobilize heavy metal-contaminated soils. However, phosphate amendments contain large amounts of phosphorus, which could leach out to potentially contaminate groundwater and surface water. A laboratory column leaching experiment was designed to study the effects of simulated acid rain (SAR) on the potential release of copper (Cu), lead (Pb), cadmium (Cd), and phosphorus (P), and their availability after immobilizing with hydroxyapatite (HAP) and potassium dihydrogen phosphate (PDP). The application of HAP and PDP enhanced the leachate electrical conductivity, total organic carbon, and pH. Higher P was found in the PDP- (>4.29 mg L-1) and HAP-treated (>1.69 mg L-1) columns than that in untreated (<0.2 mg L-1) columns, and they were both over the class V limit (0.4 mg L-1) mandated by the Chinese National Quality Standards for Surface Waters (GB 3838-2002). PDP application decreased the leachate Cu, Pb, and Cd effectively; however, HAP addition increased leachate Cu and Pb. HAP and PDP applications decreased the soil CaCl2-extractable and exchangeable fraction of Cu, Pb, and Cd, and increased resin P. However, eluviations transformed the heavy metals from inactive to active fractions and reduced soil labile P. These findings showed that HAP and PDP had a potential risk of excessive P-induced eutrophication. Meanwhile, more attention should be paid to the leaching loss of multiple metals because phosphate amendments might promote the leaching of some metals while immobilizing others. PMID- 28730364 TI - Water resources vulnerability assessment in the Adriatic Sea region: the case of Corfu Island. AB - Cross-border water resources management and protection is a complicated task to achieve, lacking a common methodological framework. Especially in the Adriatic region, water used for drinking water supply purposes pass from many different countries, turning its management into a hard task to achieve. During the DRINKADRIA project, a common methodological framework has been developed, for efficient and effective cross-border water supply and resources management, taking into consideration different resources types (surface and groundwater) emphasizing in drinking water supply intake. The common methodology for water resources management is based on four pillars: climate characteristics and climate change, water resources availability, quality, and security. The present paper assesses both present and future vulnerability of water resources in the Adriatic region, with special focus on Corfu Island, Greece. The results showed that climate change is expected to impact negatively on water resources availability while at the same time, water demand is expected to increase. Water quality problems will be intensified especially due to land use changes and salt water intrusion. The analysis identified areas where water resources are more vulnerable, allowing decision makers develop management strategies. PMID- 28730365 TI - Cd, Pb, and Zn mobility and (bio)availability in contaminated soils from a former smelting site amended with biochar. AB - Biochar is a potential candidate for the remediation of metal(loid)-contaminated soils. However, the mechanisms of contaminant-biochar retention and release depend on the amount of soil contaminants and physicochemical characteristics, as well as the durability of the biochar contaminant complex, which may be related to the pyrolysis process parameters. The objective of the present study was to evaluate, in a former contaminated smelting site, the impact of two doses of wood biochar (2 and 5% w/w) on metal immobilization and/or phytoavailability and their effectiveness in promoting plant growth in mesocosm experiments. Different soil mixtures were investigated. The main physicochemical parameters and the Cd, Pb, and Zn contents were determined in soil and in soil pore water. Additionally, the growth, dry weight, and metal concentrations were analyzed in the different dwarf bean plant (Phaseolus vulgaris L.) organs tested. Results showed that the addition of biochar at two doses (2 and 5%) improved soil conditions by increasing soil pH, electrical conductivity, and water holding capacity. Furthermore, the application of biochar (5%) to metal-contaminated soil reduced Cd, Pb, and Zn mobility and availability, and hence their accumulation in the different P. vulgaris L. organs. In conclusion, the data clearly demonstrated that biochar application can be effectively used for Cd, Pb, and Zn immobilization, thereby reducing their bioavailability and phytotoxicity. PMID- 28730366 TI - To coil or not to coil: application practices, perception and efficacy of mosquito coils in a malaria-endemic community in Ghana. AB - Although evidence of mosquito coils' impact on disease epidemiology is limited, they are popularized as mosquito-borne disease prevention devices. Their usage affects the environment, human and mosquito health. This study investigated the perception, usage pattern and efficacy of coils in a predominantly poor malaria endemic Ghanaian peri-urban area. Information on protection methods, perception and usage pattern was garnered using questionnaires. The efficacy of commonly used coils in the area was then assessed on the malaria vector, Anopheles gambiae, in a glass chamber. Sole or co-application of mosquito control methods and risky usage practices were reported. Coils were deemed harmful to humans and mosquitoes, and their perceived effectiveness varied, with several factors influencing their purchase. High d-allethrin concentration coils induced quicker mosquito knockdown; however, mortality was less than 85%. The coil usage pattern compromises users' health and can enhance mosquito tolerance to d-allethrin. The coils were ineffective against the vector, outlining a dichotomy between the users' perception of efficacy and the observed efficacy. Hence, the usage of other safer and more effective vector control methods should be encouraged to protect households. PMID- 28730367 TI - Prevalence of chromosomal aberrations in Argentinean agricultural workers. AB - Little is known about biosecurity measures and toxic effects during pesticide application in the province of Jujuy, Argentina, particularly concerning the protective measures and mixture of pesticides used by rural workers. We carried out an observational study of agricultural workers from Jujuy (76 exposed subjects and 53 controls) to investigate the prevalence of chromosomal aberrations (CAs) in human lymphocytes as well as the activity level of acetylcholinesterase (AChE) in red blood cell erythrocytes. Whole blood samples (5 mL) were collected in heparinized Vacutainer tubes for cytogenetic analysis and erythrocyte cholinesterase activity determination according to Ellman's method. Cytogenetic results showed a significant CA increase in pesticide-exposed individuals as compared with controls (4.20 +/- 0.15 vs. 1.00 +/- 0.05, respectively; p < 0.001), suggesting that pesticides are clastogenic agents causing DNA damage. Erythrocyte cholinesterase activity was significantly lower in exposed individuals, evidencing the possible occurrence of perturbations in blood as well as neurotoxicity in pesticide sprayers. These results suggest the need for periodic biomonitoring of these biomarkers together with education and training of occupational workers for the safe application of potentially harmful pesticides. PMID- 28730368 TI - Safety of cold polypectomy for small colorectal neoplastic lesions: a prospective cohort study in Japan. AB - BACKGROUND: Cold polypectomy has been widely accepted for removal of small colorectal polyps. However, no large-scale prospective study exists as for its safety in Japan. We investigated this issue in this single-center, prospective cohort study in a total of 1198 colorectal polyps resected with cold polypectomy. PATIENTS AND METHODS: Four hundred and seventy-four patients who underwent cold polypectomy for colorectal neoplastic lesions less than 10-mm diameter between September 2014 and October 2016 were enrolled. Primary outcome was the incidence of delayed bleeding within 2 weeks after the procedure. Secondary outcomes were the rate of immediate bleeding, perforation, endoscopic en bloc resection, and advanced histology. RESULTS: Cold polypectomy was performed on 1198 polyps in the 474 patients. No delayed bleeding or colonic perforation was observed. Immediate bleeding during the procedure, requiring endoscopic hemostasis, occurred in 97 lesions (8.1%), and all of them were successfully managed endoscopically. The endoscopic en bloc resection rate was 97.2%. Twenty-eight lesions (2.3%) were histologically diagnosed as advanced neoplasia; among them, three lesions were well-differentiated adenocarcinomas, and in two of them, a negative margin was not histologically confirmed. CONCLUSIONS: Cold polypectomy for small colorectal polyps is a safe technique without significant complication, but careful endoscopic diagnosis at cold polypectomy is necessary to identify advanced neoplasia. The reliability of cold polypectomy in excision of polyps with high grade neoplasia should be established before the procedure becomes standard in the excision of small colorectal polyps. CLINICAL TRIAL REGISTRATION NUMBER: UMIN000014812. PMID- 28730370 TI - The N-terminal and central domain of colicin A enables phage lysin to lyse Escherichia coli extracellularly. AB - Multidrug-resistant Escherichia coli has seriously threatened antibiotic resources and international public health. Bacteriophage lysin preparations have been widely considered as valid agents for solving multidrug resistances. Many lysins have been derived to treat diseases caused by Gram-positive bacteria, but only a few lysin preparations have been found that successively treat diseases caused by Gram-negative bacteria. The outer membrane of Gram-negative bacteria effectively blocks the interactions between peptidoglycan in the periplasmic space and bacteriophage lysins, which therefore hampers the antimicrobial effects of bacteriophage lysins. In this study, a new fusion protein (Colicin-Lysep3) was constructed by fusing the translocation and receptor binding domains of colicin A with an E. coli phage lysin, which endows Colicin-Lysep3 bactericidal activity against E. coli from outside of Gram-negative bacteria. These results show that Colicin-Lysep3 could lyse the E. coli broadly in vitro and significantly reduce the number of E. coli in an intestinal infection mouse model. Overall, our findings first demonstrated that a colicin A fragment could enable a bacteriophage lysin to lyse E. coli from the outside, promoting the application of phage lysin preparations in control of Gram-negative bacteria. PMID- 28730369 TI - Survival analysis in rectal carcinoma after neoadjuvant chemoradiation: various methods with different results. AB - PURPOSE: Survival is an important indicator of outcome quality in rectal carcinoma. The 5-year survival rate is the typical outcome measurement. In patients with neoadjuvant chemoradiation followed by curative surgery, 7 years of follow-up is recommended. Different methods of survival analysis lead to different results. Here, we compared four different methods. METHODS: The data of 439 patients with rectal carcinoma treated with neoadjuvant chemoradiation followed by curative total mesorectal excision (TME) surgery between 1995 and 2010 were analysed. After stratifying by stage, relative survival (RS), cancer related survival (CRS), overall survival (OS) and disease-free survival (DFS) were compared. In particular, the 3-year disease-free survival rate was compared to the 5- and 7-year overall survival rates. RESULTS: In the total cohort, the 5 year survival rates ranged from 90% (RS), over 84% (CRS) and 83% (OS) to 72% (DFS). Depending on the stage of disease, the differences between the 5-year survival rates varied between 10 and 32 percentage points. The differences were lowest in UICC stage y0 and highest in UICC stage yIV. The 3-year DFS-rate was always lower (worse) than the 5-year OS rate and higher (better) than the 7-year OS rate, with the exception of stage yIV. CONCLUSIONS: Comparisons of survival are only meaningful if the same methods are applied. The 3-year rate of DFS was always worse than the rate of 5-year OS. Therefore, the 3-year rate of DFS appears to be a useful surrogate indicator in rectal carcinoma treatment studies. PMID- 28730371 TI - Idiomarina andamanensis sp. nov., an alkalitolerant bacterium isolated from Andaman Sea water. AB - Two closely related aerobic, Gram-negative rod shaped bacteria (strain W5T and W3) were isolated from Andaman Sea. Heterotrophic growth on marine agar was observed at 15-45 degrees C and pH 6-10. Strain W5T showed maximum 16S rRNA sequence similarity of 99.58% with Idiomarina marina JCM 15083T. DNA fingerprinting analysis by ERIC-REP PCR, PFGE and MLSA revealed differences in banding patterns, also DNA-DNA hybridization values were well below 70% confirming W5T to be a new species. DNA G+C content was 46.7 mol%. Major fatty acids were iso-C15:0, iso-C17:0, iso-C17:1 omega9c, iso-C13:0 3OH, iso-C11:0 3OH and C16:0. Polar lipids included phosphatidylglycerol (PG) and phosphatidylethanolamine (PE) diphosphatidylglycerol (DPG) phospholipid (PL) two aminolipids (AL) and two unidentified lipids (L1-2). Q-8 is the predominant ubiquinone. On the basis of polyphasic taxonomic study, strain W5T is considered to be representative of a new species of the genus Idiomarina, for which the name Idiomarina andamanensis sp. nov. is being proposed. The type strain W5T (= LMG 29773T = JCM 31645T) was isolated from Andaman Sea. PMID- 28730372 TI - Ultrasound picture in a case of fibular neuropathy at knee. PMID- 28730373 TI - Disadvantages of having a shortening of the proximal radius. PMID- 28730374 TI - Is tensiomyography a useful assessment tool in sports medicine? PMID- 28730375 TI - Higher dietary glycemic index, but not glycemic load, is associated with a lower prevalence of depressive symptoms in a cross-sectional study of young and middle aged Japanese women. AB - OBJECTIVE: Epidemiologic evidence on the associations between dietary glycemic index (GI) and glycemic load (GL) and depressive symptoms is not only limited, particularly in Asian populations where dietary GI and GL are typically higher than in Western countries, but also inconclusive. This cross-sectional study examined these associations in Japanese women. METHODS: Subjects were 3963 young (age 18-years) and 3826 middle-aged (mean age 47.8 years) Japanese women. Dietary GI and GL were assessed using a validated diet history questionnaire. Depression symptoms were defined as present when subjects had a Center for Epidemiologic Studies Depression score >=16. RESULTS: The prevalence of depressive symptoms was 50.2% for young women and 27.3% for middle-aged women. The mean (SD) values of energy-adjusted dietary GI and GL (GI for glucose = 100) were, respectively, 64.9 (4.3) and 142.0 (27.4) for young women and 65.0 (4.1) and 142.2 (29.5) for middle aged women. After adjustment for potential confounding factors, higher dietary GI was associated with a lower prevalence of depressive symptoms. Adjusted OR (95% CI) for depressive symptoms in the highest compared to lowest quintiles of dietary GI was 0.66 (0.52, 0.82) for young women (P for trend = 0.001) and 0.75 (0.60, 0.96) for middle-aged women (P for trend = 0.046). Conversely, there was no association between dietary GL and depressive symptoms in either age group. CONCLUSIONS: Dietary GI, but not GL, was inversely associated with depressive symptoms in a group of young and middle-aged Japanese women with relatively high dietary GI and GL. PMID- 28730377 TI - Influence of Vitamin D and Cotinine on T-Regulatory Cells and Asthma Severity in Children. AB - Asthma is a common chronic respiratory diseases in children. Understanding the immune mechanisms of epigenetic factors may contribute to a better control of asthma. This study seeks to determine the effects of serum vitamin D and urine cotinine on asthma severity and on T regulatory cells (Tregs) and other immune related factors such as CD3, CD4, CD8, CD19, CD16/56, and anti-CD3 HLA-DR3. The study involved 34 children with asthma. Disease severity was assessed with the Asthma Control Test, spirometry, and the fractional exhaled nitric oxide (FeNO). The control group consisted of 18 healthy children. We found a significantly lower proportion of Tregs in the serum of asthmatic children compared with the control group (p < 0.002). There were no significant differences in the other immunological factors investigated. Nor was there any appreciable association between vitamin D or cotinine and the course of asthma, FeNO, Tregs, and the other immune factors. However, the percentage of Tregs was positively associated with the level of FeNO (p < 0.02). In conclusion, the study shows a role of T regulatory cells in the pathogenesis of asthma in children, but fails to show any influence of serum vitamin D or urine cotinine on disease course. PMID- 28730376 TI - Lower urinary tract obstruction: fetal intervention based on prenatal staging. AB - The authors present an overview of lower urinary tract obstruction (LUTO) in the fetus with a particular focus on the insult to the developing renal system. Diagnostic criteria along with the challenges in estimating long-term prognosis are reviewed. A proposed prenatal LUTO disease severity classification to guide management decisions with fetal intervention to maintain or salvage in utero and neonatal pulmonary and renal function is also discussed. Stage I LUTO (mild form) is characterized by normal amniotic fluid index after 18 weeks, normal kidney echogenicity, no renal cortical cysts, no evidence of renal dysplasia, and favorable urinary biochemistries when sampled between 18 and 30 weeks; prenatal surveillance is recommended. Stage II LUTO is characterized by oligohydramnios/anhydramnios, hyperechogenic kidneys but absent renal cortical cysts or apparent signs of renal dysplasia and favorable fetal urinary biochemistry; fetal vesicoamniotic shunting (VAS) or fetal cystoscopy is indicated to prevent pulmonary hypoplasia and renal failure. Stage III LUTO is oligohydramnios/anhydramnios, hyperechogenic kidneys with cortical cysts and renal dysplasia and unfavorable fetal urinary biochemistry after serial evaluation; fetal vesicoamniotic shunt may prevent severe pulmonary hypoplasia but not renal failure. Stage IV is characterized by intrauterine fetal renal failure, defined by anhydramnios and ultrasound (US) findings suggestive of severe renal dysplasia, and is associated with death in 24 h of life or end-stage renal disease (ESRD) within the first week of life; fetal vesicoamniotic shunt and fetal cystoscopy are not indicated. PMID- 28730378 TI - Enzymatic Activity of Candida spp. from Oral Cavity and Urine in Children with Nephrotic Syndrome. AB - Oral colonization with Candida spp. is not synonymous with a systemic active infection. The aim of the study was to evaluate enzymatic activity of Candida strains isolated from the oral cavity in patients with nephrotic syndrome (NS) and to compare it with the activity determined in urine. We studied 32 children with NS and 26 control healthy children. Children with NS were treated with glucocorticosteroids, cyclosporin A, mycophenolate mofetil or azathioprine. In all children, API-ZYM enzymatic tests were performed to evaluate hydrolytic enzymes of Candida isolated from the oral cavity and in urine. Candida spp. were isolated from the oral cavity in 11 patients with NS (34.4%), all receiving immunosuppressive treatment. All strains produced valine arylamidase, 9 alpha glucosidase (E16), and 9 N-acetyl-beta-glucosaminidase (E18). A positive correlation between the presence of Candida in the oral cavity and E16 and E18 enzymatic activity in both oral cavity and urine was found. A dose of cyclosporin A had an effect on the enzymatic activity (p < 0.05). We conclude that immunosuppressive treatment of NS in children may predispose to systemic Candida invasion. The results of this study suggest that oral candida infection should be monitored in children with nephrotic syndrome, particularly those treated with immunosuppressive agents. PMID- 28730379 TI - Vaccine Effectiveness against Influenza in 2015/16 in Hospital and Ambulatory Medical Care Facilities: Polish Results of the European I-MOVE+ Multicenter Study. AB - Influenza vaccination is the best measure available to prevent seasonal influenza infection. The majority of studies on vaccine effectiveness in the 2015/16 season conducted in the European I-MOVE+ Project, show that a match between the circulating influenza strains in the general public and those included in the vaccine for the Northern Hemisphere was low to moderate. As part of I-MOVE+, Poland has implemented a case control negative study design and molecular biology methods, such as real time RT-PCR, to assess the vaccine match and effectiveness. The research described herein consisted of two major influenza vaccine effectiveness investigations conducted in Poland in the 2015/16 season. The general practice part of the study included 228 cases consisting of 159 type A, 65 type B, and 4 coinfections (types A + B), and 312 negative control cases. The hospital study part included 26 cases consisting of 21 type A, 2 type B, and 3 coinfections, and 13 negative control cases. The data were collected from patients of all ages recruited by 46 volunteering doctors in 15 Poland's provinces and three hospitals, respectively. In both study parts, only were seven patients and 12 control subjects vaccinated. Low vaccine coverage, a major limitation of the Polish study, makes the calculation of vaccine effectiveness for the Polish population hardly applicable statistically. Despite the crudeness of data, they were included into the common European analysis. The overall vaccine effectiveness amounted to 21.0% (95% CI: 74-122). It was somehow better for type B virus: 53.9% (95% CI: 47-87) and type A virus: 23.6% (95% CI: 83-185). A larger sample size is needed to achieve a desired interpretation of results on influenza vaccine effectiveness in Poland. PMID- 28730381 TI - Pooled Human Serum Increases Regenerative Potential of In Vitro Expanded Stem Cells from Human Extracted Deciduous Teeth. AB - In regenerative therapy, in vitro expansion of stem cells is critical to obtain a significantly higher number of cells for successful engraftment after transplantation. However, stem cells lose its regenerative potential and enter senescence during in vitro expansion. In this study, the influence of foetal bovine serum (FBS) and pooled human serum (pHS) on the proliferation, morphology and migration of stem cells from human extracted deciduous teeth (SHED) was compared. SHED (n = 3) was expanded in KnockOut DMEM supplemented with either pHS (pHS-SM) or FBS (FBS-SM). pHS was prepared using peripheral blood serum of six healthy male adults, aged between 21 and 35 years old. The number of live SHED was significantly higher, from passage 5 to 7, when cultured in pHS-SM compared to those cultured in FBS-SM ( p < 0.05). Number of cells having flattened morphology, characteristics of partially differentiated and senescent cells, was significantly lower ( p < 0.05) in pHS-SM (3%) compared to those in FBS-SM (7%). Furthermore, migration of SHED in pHS-SM was found to be more directional. The presence of selected ten paracrine factors known for their proliferation and migration potential was detected in all six individual human sera, used to produce pHS, none of which were detected in FBS. Ingenuity Pathway Analysis showed the possible involvement of the 'ephrin receptor signalling pathway' to regulate the proliferation and migration of SHED in pHS-SM. In conclusion, pHS-SM showed significantly higher proliferation rate and could maintain significantly lower number of senescent cells and support directional migration of cells. PMID- 28730380 TI - Acute and Chronic Effects of Oral Erdosteine on Ciliary Beat Frequency, Cough Sensitivity and Airway Reactivity. AB - Erdosteine as a mucolytic agent that decreases mucus viscosity and facilitates mucus expulsion from the airways by cough or ciliary movement. Our objective was to determine whether erdosteine can directly contribute to mucus clearance. We addressed the issue by monitoring acute and chronic effects of erdosteine on ciliary beat frequency (CBF), cough sensitivity, and airway smooth muscle reactivity. The experiments were performed in healthy guinea pigs. Erdosteine (10 mg/kg) was administrated orally in a single dose or daily through 7 days. The cough reflex and specific airway resistance were evaluated in vivo. The CBF in tracheal brushed samples and the contractile response of tracheal smooth muscle stripes to bronchoconstrictive mediators were evaluated in vitro. We found that neither acute nor chronic erdosteine treatment had a significant effect on cough sensitivity and airway reactivity. However, in the vitro condition, erdosteine increased CBF and reduced tracheal smooth muscle contractility; the effects were more pronounced after chronic treatment. We conclude that erdosteine may directly contribute to mucus clearance by CBF stimulation. Although erdosteine has no effect on cough reflex sensitivity, its mild bronchodilator and mucolytic properties may promote effective cough. PMID- 28730382 TI - Role of Mesenchymal Stem Cells in Cancer Development and Their Use in Cancer Therapy. AB - Stem cells have the ability to perpetuate themselves through self-renewal and generate mature cells of a particular tissue through differentiation. Mesenchymal stem cells (MSCs) play an important role in tissue homeostasis - supporting tissue regeneration. MSCs are rare pluripotent cells supporting hematopoietic and mesenchymal cell lineages. MSCs have a great therapeutic potential in cancer therapy, as well as stem cell exosome and/or microvesicle-mediated tissue regeneration. In this review, the use of hMSCs in stem cell-mediated cancer therapy is discussed. PMID- 28730383 TI - Consensus modeling to develop the farmers' market readiness assessment and decision instrument. AB - Nutrition-related policy, system, and environmental (PSE) interventions such as farmers' markets have been recommended as effective strategies for promoting healthy diet for chronic disease prevention. Tools are needed to assess community readiness and capacity factors influencing successful farmers' market implementation among diverse practitioners in different community contexts. We describe a multiphase consensus modeling approach used to develop a diagnostic tool for assessing readiness and capacity to implement farmers' market interventions among public health and community nutrition practitioners working with low-income populations in diverse contexts. Modeling methods included the following: phase 1, qualitative study with community stakeholders to explore facilitators and barriers influencing successful implementation of farmers' market interventions in low-income communities; phase 2, development of indicators based on operationalization of qualitative findings; phase 3, assessment of relevance and importance of indicators and themes through consensus conference with expert panel; phase 4, refinement of indicators based on consensus conference; and phase 5, pilot test of the assessment tool. Findings illuminate a range of implementation factors influencing farmers' market PSE interventions and offer guidance for tailoring intervention delivery based on levels of community, practitioner, and organizational readiness and capacity. PMID- 28730384 TI - Verifying Identities of Plant-Based Multivitamins Using Phytochemical Fingerprinting in Combination with Multiple Bioassays. AB - Sales of multivitamins have been growing rapidly and the concept of natural multivitamin, plant-based multivitamin, or both has been introduced in the market, leading consumers to anticipate additional health benefits from phytochemicals that accompany the vitamins. However, the lack of labeling requirements might lead to fraudulent claims. Therefore, the objective of this study was to develop a strategy to verify identity of plant-based multivitamins. Phytochemical fingerprinting was used to discriminate identities. In addition, multiple bioassays were performed to determine total antioxidant capacity. A statistical computation model was then used to measure contributions of phytochemicals and vitamins to antioxidant activities. Fifteen multivitamins were purchased from the local markets in Seoul, Korea and classified into three groups according to the number of plant ingredients. Pearson correlation analysis among antioxidant capacities, amount phenols, and number of plant ingredients revealed that ferric reducing antioxidant power (FRAP) and 2,2-diphenyl-1-picryhydrazyl (DPPH) assay results had the highest correlation with total phenol content. This suggests that FRAP and DPPH assays are useful for characterizing plant-derived multivitamins. Furthermore, net effect linear regression analysis confirmed that the contribution of phytochemicals to total antioxidant capacities was always relatively higher than that of vitamins. Taken together, the results suggest that phytochemical fingerprinting in combination with multiple bioassays could be used as a strategy to determine whether plant-derived multivitamins could provide additional health benefits beyond their nutritional value. PMID- 28730385 TI - The role of F-actin in the transport and secretion of chromaffin granules: an historic perspective. AB - Actin is one of the most ubiquitous protein playing fundamental roles in a variety of cellular processes. Since early in the 1980s, it was evident that filamentous actin (F-actin) formed a peripheral cortical barrier that prevented vesicles to access secretory sites in chromaffin cells in culture. Later, around 2000, it was described that the F-actin structure accomplishes a dual role serving both vesicle transport and retentive purposes and undergoing dynamic transient changes during cell stimulation. The complex role of the F-actin cytoskeleton in neuroendocrine secretion was further evidenced when it has been proved to participate in the scaffold structure holding together the secretory machinery at active sites and participate in the generation of mechanical forces that drive the opening of the fusion pore, during the first decade of the present century. The complex vision of the multiple roles of F-actin in secretion we have acquired to date comes largely from studies performed on traditional 2D cultures of primary cells; however, recent evidences suggest that these may not accurately mimic the 3D in vivo environment, and thus, more work is now needed on adrenomedullary cells kept in a more "native" configuration to fully understand the role of F-actin in regulating chromaffin granule transport and secretion under physiological conditions. PMID- 28730386 TI - Erratum to: Changes of myocardial gene expression and protein composition in patients with dilated cardiomyopathy after immunoadsorption with subsequent immunoglobulin substitution. PMID- 28730387 TI - Dynamics of the Pro-Oxidant/Antioxidant System Parameters in Wound Discharge and Plasma in Experimental Purulent Wound during Its Technological Liquid Phase Treatment. AB - The dynamics of the pro-oxidant/antioxidant system of rabbits was studied at the local (in exudate) and systemic (blood) levels during therapy of purulent wounds in liquid medium with the use of a programmed device and the efficiency of the proposed technological method was compared with that of classical methods for the treatment of these wounds. More rapid recovery of the indicators of the pro oxidant/antioxidant system to physiological values in the postoperative period was observed after treatment by the proposed method (7 days vs. 10 days after standard treatment), these results attest to strengthening of the adaptation potential in laboratory animals. The intensity of free radical oxidation in the exudate decreased by 26.6% in animals treated by the technological method. These data indicated acceleration of the regenerative processes at the local level. PMID- 28730388 TI - Assessment of Oxidative Status of the Brain and Blood Plasma in Rats with Modeled Focal Cerebral Ischemia/Reperfusion Injury. AB - Parameters of the oxidative status of the brain and blood plasma were measured in rats 24 h after 1-h focal cerebral ischemia. In the brain of rats exposed to cerebral ischemia, activities of superoxide dismutase and catalase were elevated. Ischemia reduced the total antioxidant activity of the brain and the levels of malonic dialdehyde and protein carbonyl derivatives. In the blood plasma of experimental rats, superoxide dismutase activity and malonic dialdehyde level increased and total antioxidant activity decreased, i.e. the shifts were similar to those in the brain. The ischemia-induced changes in the brain and blood were not always co-directed. PMID- 28730389 TI - Cardiovascular Effects of High-Molecular-Weight Compounds of Humic Nature. AB - The active ingredient extracted from the peat humic substances was characterized by physicochemical parameters evaluated by UV- and IR-spectroscopy, titration, and elemental (C, H, N) analysis. The cardiovascular effects of this ingredient were examined on isolated Langendorff-perfused rat heart. It was found that the active substance in a concentration range of 0.01-0.1 mg/ml produced a vasodilating effect; in addition, it decreased the end-diastolic and left ventricular developed pressures. PMID- 28730390 TI - Expression of Type I Cannabinoid Receptors at Different Stages of Neuronal Differentiation of Human Fibroblasts. AB - Differential expression of type 1 cannabinoid receptors (CR1) was evaluated at different stages of human skin fibroblast transformation into terminally differentiated neurons. Immunocytochemical staining detected no CR1 on fibroblasts, but their transformation into induced pluripotent stem cells was accompanied by marked stimulation of CR1 expression. In neuronal precursors, the receptors were located mainly on cell bodies and at the base of their processes. This distribution was retained at the terminal stage of differentiation of induced pluripotent stem cells into neurons. PMID- 28730392 TI - [Can online therapy meaningfully complement psychotherapy? Con]. PMID- 28730391 TI - Short-term outcomes in minimally invasive versus open gastrectomy: the differences between East and West. A systematic review of the literature. AB - OBJECTIVE: Minimally invasive surgical techniques for gastric cancer are gaining more interest worldwide. Several Asian studies have proven the benefits of minimally invasive techniques over the open techniques. Nevertheless, implementation of this technique in Western countries is gradual. The aim of this systematic review is to give insight in the differences in outcomes and patient characteristics in Asian countries in comparison to Western countries. METHODOLOGY: An extensive systematic search was conducted using the Medline, Embase, and Cochrane databases. Analysis of the outcomes was performed regarding operative results, postoperative recovery, complications, mortality, lymph node yield, radicality of the resected specimen, and survival. A total of 12 Asian and 8 Western studies were included. RESULTS: Minimally invasive gastrectomy shows faster postoperative recovery, fewer complications, and similar outcomes regarding mortality in both the Eastern and Western studies. However, patient characteristics such as age and BMI differ between these populations. Comparison of overall outcomes in minimally invasive and open procedures between East and West showed differences in complications, mortality, and number of resected lymph nodes in favor of the Asian population. CONCLUSION: Improved outcomes are observed following minimally invasive gastrectomy in comparison to open procedures in both Western and Asian studies. There are differences in patient characteristics between the Western and Asian populations. Overall outcomes seem to be in favor of the Asian population. These differences may fade with centralization of care for gastric cancer patients in the West and increasing surgical experience. PMID- 28730393 TI - [Fulminant EBV meningoencephalitis : Good clinical outcome in a young, immunocompetent female]. PMID- 28730394 TI - Helical Polyacetylenes Induced via Noncovalent Chiral Interactions and Their Applications as Chiral Materials. AB - Construction of predominantly one-handed helical polyacetylenes with a desired helix sense utilizing noncovalent chiral interactions with nonracemic chiral guest compounds based on a supramolecular approach is described. As with the conventional dynamic helical polymers possessing optically active pendant groups covalently bonded to the polymer chains, this noncovalent helicity induction system can show significant chiral amplification phenomena, in which the chiral information of the nonracemic guests can transfer with high cooperativity through noncovalent bonding interactions to induce an almost single-handed helical conformation in the polymer backbone. An intriguing "memory effect" of the induced macromolecular helicity is observed for some polyacetylenes, which means that the helical conformations induced in dynamic helical polyacetylene can be transformed into metastable static ones by tuning their helix-inversion barriers. Potential applications of helical polyacetylenes with controlled helix sense constructed by the "noncovalent helicity induction and/or memory effect" as chiral materials are also described. PMID- 28730395 TI - Dynamic hip screw and fibular strut graft for fixation of fresh femoral neck fracture with posterior comminution. AB - INTRODUCTION: Posterior comminution of the femoral neck fracture is a major cause of delayed and non-union owing to the loss of the buttressing effect against the posterior rotation. When a femoral neck fracture with posterior comminution is anatomically reduced, only the anterior portions of the femoral neck fracture surfaces are brought into contact leaving a posterior defect. The purpose of this study was to evaluate the use of fibular strut grafting and dynamic hip screw (DHS) for fresh femoral neck fractures with posterior comminution in young patient less than 50 years. MATERIALS AND METHODS: Between October 2012 and March 2016, 35 patients aged 20-50 years, 30 men and 5 women underwent fixation using DHS and fibular strut grafts for Garden grades III (25 patients) and IV (10 patients) femoral neck fractures with posterior comminution. All fractures were reduced by closed methods, and no hip was aspirated. Clinical and radiological outcomes were evaluated. RESULTS: All patients were in the age group of 20-50 years (mean 37 years). The mean delay in presentation after injury was 1 day. The mean final follow-up for these 35 patients was 27.2 months. Healing of the femoral neck was attained in 34 cases, with an average time to union of 4.8 months (range 4-8 months). One patient underwent arthroplasty due to failure of fixation. According to the Harris hip score, outcome was good to excellent in 30 patients, fair in 4, and poor in 1. CONCLUSIONS: In our study, only one patient developed non-union and no patients had avascular necrosis of the femoral head. Closed reduction, fibular strut grafts, and DHS fixation is a reliable procedure for femoral neck fractures with posterior comminution in young adults. PMID- 28730396 TI - Prevention of Anxiety and Depression in Swedish School Children: a Cluster Randomized Effectiveness Study. AB - Our study aimed at evaluating FRIENDS for Life, an intervention to prevent anxiety and depression in Swedish school children. A total of 695 children between the ages of 8 and 11 were recruited from 17 schools in Stockholm, Sweden, and cluster-randomized to either the intervention or control group. Teachers in the intervention group received a full day of training and administered FRIENDS for Life in their classrooms. We assessed the children's anxiety and depressive symptoms, general mental health, and academic performance at pre- and post intervention as well as at the 12-month follow-up. A multi-informant approach was used with data collected from children, parents, and teachers. Assessment was done with the Spence Children's Anxiety Scale, Children's Depression Inventory, and the Strengths and Difficulties Questionnaire. Children's baseline symptoms, gender, and age as well as their teacher's use of supervision were examined as moderators of effect. Our study found no short- or long-term effects of the intervention for any outcome with regard to the entire sample. We found an enhanced effect of the intervention regarding children with elevated depressive symptoms at baseline. We found a decrease in anxiety symptoms among children whose teachers attended a larger number of supervision sessions, compared to children whose teachers attended fewer supervised sessions or the control group. Mediation analyses showed that this effect was driven by change in the last phase of the intervention, suggesting that supervision might play an important role in enhancing teachers' ability to administer the intervention effectively. PMID- 28730397 TI - "People Give Opinions, but the Decision Belongs to the Patient": Examining Cancer Treatment Decisions Among Latinos/as in Central Florida. AB - Latinos/as, the fastest-growing ethnic group in the United States, experience high cancer rates. Factors contributing to treatment decisions among Latinos diagnosed with cancer must be studied. This paper aims to identify treatment decisions among Latinos with cancer and examine factors influencing these decisions. A qualitative exploratory study using semi-structured interviews of 60 Latino/as diagnosed with cancer was conducted. Close-ended responses were analyzed using percentages and frequency distributions, while open-ended responses were analyzed using open coding and thematic categorization. Surgery was the most commonly chosen treatment among participants because it was perceived as providing the highest chance of prolonging life. Only 57% of participants were provided with treatment options. Latinos/as typically prefer modest, paternalistic patient-physician relationships. Therefore, providing culturally appropriate information is valuable. This study underscores the need for health providers to present all available treatment options to enhance cancer treatment outcomes. PMID- 28730398 TI - Prevalence and Correlates of Psychological Distress and Psychiatric Disorders in Asylum Seekers and Refugees Resettled in an Italian Catchment Area. AB - In recent years there has been a progressive rise in the number of asylum seekers and refugees displaced from their country of origin, with significant social, economic, humanitarian and public health implications. The aim of this study is to describe the frequency and correlates of psychological distress and psychiatric disorders in asylum seekers and refugees resettled in an Italian catchment area. In the catchment area of Verona, all male asylum seekers and refugees aged 18 or above included in the Italian protection system for asylum seekers and refugees during a period of 1 year were screened for psychological distress and psychiatric disorders using validated questionnaires. During the study period, 109 asylum seekers or refugees were recruited. The frequency of traumatic events experienced was very high. More than one-third of the participants (36%) showed clinically relevant psychological distress, and one fourth (25%), met the criteria for a psychiatric diagnosis, mainly PTSD and depressive disorders. In multivariate analyses, time after departure, length of stay in the host country and number of traumatic events were independent factors associated with psychological distress and psychiatric disorders. In an unselected sample of male asylum seekers and refugees, after around 1 year of resettlement in an Italian catchment area, the frequency of psychological distress and psychiatric disorders was substantial and clinically relevant. Health care systems should include a mental health component to recognise and effectively treat mental health conditions. PMID- 28730399 TI - Optical coherence tomography angiography findings in Susac's syndrome: a case report. AB - PURPOSE: To report clinical features of Susac's syndrome (SS) using optical coherence tomography angiography (OCTA). METHODS: Case report. RESULTS: A 25-year old Caucasian female with a history of non-pulsatile migraine, tinnitus, and verbal apraxia complaining of peripheral scotoma in left eye due to branch retinal arteriole occlusion (BRAO) was diagnosed as having SS after audiometric test, brain magnetic resonance imaging, and multimodal retinal imaging. Fundus biomicroscopy and fluorescein angiography (FA) revealed the presence of retinal ischemia in the area of BRAO. The OCTA images showed decreased vascular perfusion of both superficial and deep plexuses in the area of the occluded arteriole with increase of vascular density values after treatment with intravenous glucocorticoids, cyclophosphamide, and aspirin. CONCLUSIONS: OCTA offers a valid alternative to the standard invasive FA, evaluating vascular perfusion in all capillary plexuses, and monitoring retinal microvascular flow changes during the course of BRAO, without dye injection. PMID- 28730400 TI - Evaluation of retrobulbar blood flow and choroidal thickness in patients with rheumatoid arthritis. AB - PURPOSE: To evaluate whether retrobulbar blood flow and choroidal thickness (CT) are affected in patients with rheumatoid arthritis (RA), and the relationship between these values. METHODS: We evaluated 40 eyes of 20 RA patients and 40 eyes of 20 healthy controls. The enhanced depth imaging optical coherence tomography, color Doppler imaging, was held. Statistical analysis was performed. RESULTS: Peak systolic velocity (PSV) of ophthalmic (OA) and central retinal artery (CRA) were significantly higher in RA. No significant difference was observed when end diastolic velocity (EDV) of OA and CRA was compared between the groups. The resistivity index (RI) of OA and CRA was higher in RA. Perifoveal/subfoveal CT was lower in RA. Negative correlation was detected between the RI of OA and the perifoveal CT, and a positive correlation was detected between RI of CRA and CT. CONCLUSIONS: Ocular hemodynamics is effected by RA and can exaggerate ocular complications of various vascular diseases such as diabetes mellitus, hypertension, retinal vascular occlusions. PMID- 28730401 TI - Hypertensive phase and its association with surgical outcomes in Baerveldt implantation. AB - PURPOSE: To evaluate the rate of the hypertensive phase (HP) post-Baerveldt implantation and association between HP and surgical outcomes. METHODS: This is a retrospective observational study of glaucoma patients who had Baerveldt implantation in 2004 and completed 18 months of follow-up. At 18 months of follow up, medical records for HP and its associated factors, and surgical outcomes such as rate of failures, intraocular pressure (IOP), numbers of medications administered, and complications were reviewed and identified. RESULTS: Thirty seven patients were eligible. Mean (SD) preoperative IOP was 30.5 (7.9) mmHg which significantly lowered to 13.1 (7.0) mmHg post-operation. Mean numbers of medications (SD) significantly decreased from 3.6 (0.7) to 1.3 (1.3). Failure rate at 18 months was 10.8% (4/37 patients). HP was noted in 18/37 patients (48.6%) with the onset between 1 and 3 months post-surgery. Preoperative IOP and one previous glaucoma surgery were associated with presence of HP (p = 0.010, OR 0.82, 95% CI 0.71-0.96 and p = 0.003, OR 26.12, 95% CI 2.95-231.41, respectively). The presence of HP was predictive of postoperative numbers of medications administered (p = 0.001). None of those with HP were from the failure group. CONCLUSION: Baerveldt implantation is an effective procedure with high success rate. HP was common after Baerveldt implantation. Preoperative IOP and numbers of previous glaucoma surgery are risk factors for developing HP. Presence of HP can predict whether long-term anti-glaucoma medication(s) are needed or not. PMID- 28730402 TI - Theoretical Perspectives of Adherence to Web-Based Interventions: a Scoping Review. AB - PURPOSE: The purpose of this paper is to review the literature as this relates to theoretical perspectives of adherence to web-based interventions, drawing upon empirical evidence from the fields of psychology, business, information technology and health care. METHODS: A scoping review of the literature utilising principles outlined by Arksey and O'Malley was undertaken. RESULTS: Several relevant theoretical perspectives have emerged, eight of which are charted and discussed in this review. These are the Internet Intervention Model, Persuasive Systems Design, the 'PERMA' framework, the Support Accountability Model, the Model of User Engagement, the Technology Acceptance Model, the Unified Theory of Acceptance and Use of IT and the Conceptual Model of User Engagement. CONCLUSIONS: The findings of the review indicate that an interdisciplinary approach, incorporating a range of technological, environmental and individual factors, may be needed in order to comprehensively explain user adherence to web based interventions. PMID- 28730403 TI - Functional Characterization of Potential Probiotic Lactic Acid Bacteria Isolated from Kalarei and Development of Probiotic Fermented Oat Flour. AB - Considerable variations among probiotics with respect to their health benefitting attributes fuel the research on bioprospecting of proficient probiotic strains from various ecological niches especially the poorly unexplored ones. In the current study, kalarei, an indigenous cheese-like fermented milk product, and other dairy-based sources like curd and raw milk were used for isolation of lactic acid bacteria (LAB). Among 34 LAB isolates, 7 that could withstand simulated gastrointestinal (GI) conditions were characterized for functional probiotic attributes, viz. adhesion ability, aggregation and coaggregation, extracellular enzyme producing capability, antibacterial activity against pathogens and antibiotic resistance. The isolate M-13 (from kalarei) which exhibited most of the desirable probiotic functional properties was identified as Lactobacillus plantarum based on 16S ribosomal DNA sequence analysis and designated as L. plantarum M-13. The sequence was submitted to GenBank (accession number KT592509). The study presents the first ever report of isolation of potential probiotic LAB, i.e. L. plantarum M-13 from indigenous food kalarei, and its application for development of potential probiotic fermented oat flour (PFOF). PFOF was analysed for parameters like viability of L. plantarum M-13, acidity and pH. Results show that PFOF serves as a good matrix for potential probiotic L. plantarum M-13 as it supported adequate growth of the organism (14.4 log cfu/ml after 72 h of fermentation). In addition, appreciable acid production by L. plantarum M-13 and consequential pH reduction indicates the vigorous and active metabolic status of the potential probiotic organism in the food matrix. Thus, study shows that fermented oat flour may possibly be developed as a potential probiotic carrier especially in view of the problems associated with dairy products as probiotic vehicles. PMID- 28730404 TI - Efficacy of thromboprophylaxis during pregnancy in women with a previous cerebral vein thrombosis. PMID- 28730405 TI - Non-neurogenic Chronic Urinary Retention: What Are We Treating? AB - PURPOSE OF REVIEW: This review examines current terminology used to define non neurogenic chronic urinary retention (CUR), describes the pathophysiology of urinary retention, and highlights contemporary diagnostic and treatment algorithms. RECENT FINDINGS: There is no standardized definition for the condition, but volumes >300 ml are commonly used to describe CUR. It is a clinical diagnosis which does not require urodynamics. Pathophysiologic causes of CUR be from myogenic, neurogenic, bladder outlet obstruction, or a combination of these sources. Treatment algorithms recommend stratifying patients with chronic urinary retention by risk and by symptoms before initiating treatment. Common CUR outcome endpoints need to be better utilized so that treatment modalities can be compared. Non-neurogenic CUR is a heterogeneous condition that has multiple definitions, underlying physiologies, and possible endpoints. Standardization is needed to better understand and treat CUR. PMID- 28730406 TI - Benefits and risks of P2Y12 inhibitor preloading in patients with acute coronary syndrome and stable angina. AB - Treatment with P2Y12 inhibitors is an integral part of the standard of care for patients undergoing percutaneous coronary intervention. However, the most appropriate timing for P2Y12 inhibitor administration remains unclear, and the value of "preloading" with P2Y12 inhibitors prior to cardiac catheterization is controversial. While pre-catheterization treatment with P2Y12 inhibitors is performed with the goal of decreasing adverse cardiovascular events, this potential benefit must be weighed against the increased risk of bleeding complications and operative delay if coronary artery bypass graft surgery is indicated. A number of studies have been conducted to evaluate the utility of preloading with P2Y12 inhibitors prior to cardiac catheterization for varying indications including stable angina and acute coronary syndrome (ACS). In this article, we review the literature and discuss the advantages and disadvantages of the preloading strategy. Several individual studies offer inconclusive and even conflicting findings. However, when taken in sum, these studies allow for several conclusions about the utility of P2Y12 inhibitor pretreatment. The existing literature demonstrate that preloading is associated with some degree of reduction in adverse ischemic events, although this benefit comes with an increased risk of bleeding complications. The appropriateness of preloading therefore varies based on the indication for catheterization, likely justified in patients with ACS but unlikely to benefit patients with stable angina. PMID- 28730407 TI - Venous thromboembolism: thrombosis, inflammation, and immunothrombosis for clinicians. AB - Venous thromboembolism (VTE) is a worldwide disease related with mortality, cardiovascular disability, impaired quality of life and, cause major long-term complications. Clinicians related to the acute and long-term patients care must be involved in the molecular mechanisms of thrombosis. The vessel wall and its inner lining of the endothelium are critical to the maintenance of a patent vasculature. After endothelial disruption, collagen (first line of endothelial defense) and intravascular tissue factor (second line of endothelial defense) are exposed to blood flow, starting the formation of a thrombus. Anticoagulant endovascular proteins and endogenous fibrinolysis have an active role in hemostasis. Currently, the process of coagulation is a cell surface-based model that includes three overlapping phases: initiation, amplification, and propagation. From a simple view, inflammation is one of the first responses of the immune system to infection; inflammation is driven by eicosanoids and cytokines, which are released by injured or infected cells. Common cytokines, which regulate inflammatory response, include interleukins (mainly interleukin-6) that are responsible for communication among white blood cells, chemokines that promote chemotaxis, and interferons that have anti-viral effects. Acute infections have been associated with a transient increase in the risk of myocardial infarction, stroke and recently with venous thrombosis, supporting the notion that systemic and respiratory infections increase the risk of thromboembolic events. Recently, immunothrombosis, another thrombosis mechanism that includes innate immune mechanisms, the neutrophil extracellular genetic traps, and the immunothrombosis dysregulation, could explain some cases of "unprovoked" VTE especially in elderly, a high-risk population for thrombosis. PMID- 28730408 TI - Evolution of the HIV-1 transgenic rat: utility in assessing the progression of HIV-1-associated neurocognitive disorders. AB - Understanding the progression of HIV-1-associated neurocognitive disorders (HAND) is a critical need as the prevalence of HIV-1 in older individuals (>50 years) is markedly increasing due to the great success of combination antiretroviral therapy (cART). Longitudinal experimental designs, in comparison to cross sectional studies, provide an opportunity to establish age-related disease progression in HAND. The HIV-1 transgenic (Tg) rat, which has been promoted for investigating the effect of long-term HIV-1 viral protein exposure, was used to examine two interrelated goals. First, to establish the integrity of sensory and motor systems through the majority of the animal's functional lifespan. Strong evidence for intact sensory and motor system function through advancing age in HIV-1 Tg and control animals was observed in cross-modal prepulse inhibition (PPI) and locomotor activity. The integrity of sensory and motor system function suggested the utility of the HIV-1 Tg rat in investigating the progression of HAND. Second, to assess the progression of neurocognitive impairment, including temporal processing and long-term episodic memory, in the HIV-1 Tg rat; the factor of biological sex was integral to the experimental design. Cross-modal PPI revealed significant alterations in the development of temporal processing in HIV 1 Tg animals relative to controls; alterations which were more pronounced in female HIV-1 Tg rats relative to male HIV-1 Tg rats. Locomotor activity revealed deficits in intrasession habituation, suggestive of a disruption in long-term episodic memory, in HIV-1 Tg animals. Understanding the progression of HAND heralds an opportunity for the development of an advantageous model of progressive neurocognitive deficits in HIV-1 and establishes fundamental groundwork for the development of neurorestorative treatments. PMID- 28730410 TI - Engineering of the cytochrome P450 monooxygenase system for benzyl maltol hydroxylation. AB - Maltol derivatives are utilized in a variety of fields due to their metal chelating abilities, and modification of the 2-methyl side chain is known to effectively expand their functional diversity. In the present study, microbial enzymes were screened for hydroxylating activity towards the 2-methyl group in a maltol derivative, 3-benzyloxy-2-methyl-4-pyrone (BMAL). Novosphingobium sp. SB32149 was found to have the ability to convert BMAL into 3-benzyloxy-2 hydroxymethyl-4-pyrone (BMAL-OH). The enzymes responsible, a cytochrome P450 monooxygenase (P450nov), a ferredoxin (FDXnov), and a ferredoxin reductase (FDRnov), were identified in the SB32149 strain. In the reaction with recombinant Escherichia coli expressing P450nov, FDXnov, and FDRnov, BMAL-OH was successfully produced from BMAL. Moreover, using the directed evolution approach, four amino acid substitutions, L188P/F218L/L237M in P450nov and A10T in FDXnov, were found to enhance BMAL-OH production. Consequently, up to 5.2 g/L BMAL-OH was obtained from 8.0 g/L BMAL by bioconversion using a 250-mL jar fermenter, indicating that this strain may be useful for synthesis of maltol derivatives which could have potential applications in various fields. PMID- 28730409 TI - Iron oxides alter methanogenic pathways of acetate in production water of high temperature petroleum reservoir. AB - Acetate is a key intermediate in anaerobic crude oil biodegradation and also a precursor for methanogenesis in petroleum reservoirs. The impact of iron oxides, viz. beta-FeOOH (akaganeite) and magnetite (Fe3O4), on the methanogenic acetate metabolism in production water of a high-temperature petroleum reservoir was investigated. Methane production was observed in all the treatments amended with acetate. In the microcosms amended with acetate solely about 30% of the acetate utilized was converted to methane, whereas methane production was stimulated in the presence of magnetite (Fe3O4) resulting in a 48.34% conversion to methane. Methane production in acetate-amended, beta-FeOOH (akaganeite)-supplemented microcosms was much faster and acetate consumption was greatly improved compared to the other conditions in which the stoichiometric expected amounts of methane were not produced. Microbial community analysis showed that Thermacetogenium spp. (known syntrophic acetate oxidizers) and hydrogenotrophic methanogens closely related to Methanothermobacter spp. were enriched in acetate and acetate/magnetite (Fe3O4) microcosms suggesting that methanogenic acetate metabolism was through hydrogenotrophic methanogenesis fueled by syntrophic acetate oxidizers. The acetate/beta-FeOOH (akaganeite) microcosms, however, differed by the dominance of archaea closely related to the acetoclastic Methanosaeta thermophila. These observations suggest that supplementation of beta FeOOH (akaganeite) accelerated the production of methane further, driven the alteration of the methanogenic community, and changed the pathway of acetate methanogenesis from hydrogenotrophic methanogenesis fueled by syntrophic acetate oxidizers to acetoclastic. PMID- 28730411 TI - Sugary Endosperm is Modulated by Starch Branching Enzyme IIa in Rice (Oryza sativa L.). AB - BACKGROUND: Starch biosynthesis is one of the most important pathways that determine both grain quality and yield in rice (Oryza sativa L.). Sugary endosperm, sugary-1 (sug-1), is a mutant trait for starch biosynthesis. Rice plants carrying sug-1 produce grains that accumulate water-soluble carbohydrates instead of starch, even after maturity. Although this trait enhances the diversity of grain quality, sugary endosperm rice has hardly been commercialized due to the severely wrinkled grains and subsequent problems in milling. This study was conducted to identify the genes responsible for the sug-h phenotype through a map-based cloning technology. RESULTS: We induced a mild sugary mutant, sugary-h (sug-h) through the chemical mutagenesis on the Korean japonica cultivar Hwacheong. Grains of the sug-h mutant were translucent and amber-colored, and the endosperm appeared less wrinkled than sug-1, whereas the soluble sugar content was fairly high. These characteristics confer greater marketability to the sug-h mutant. Genetic analyses indicated that the sug-h mutant phenotype was controlled by a complementary interaction of two recessive genes, Isoamylase1 (OsISA1), which was reported previously, and Starch branching enzyme IIa (OsBEIIa), which was newly identified in this study. Complementation tests indicated that OsBEIIa regulated the properties of sugary endosperm. CONCLUSIONS: Complementary interactions between the starch biosynthesis genes OsISA1 and OsBEIIa determine the mild sugary endosperm mutant, sugary-h, in rice. Our finding may facilitate the breeding of sugaryendosperm rice for commercial benefit. PMID- 28730412 TI - GNS4, a novel allele of DWARF11, regulates grain number and grain size in a high yield rice variety. AB - BACKGROUND: Rice plays an extremely important role in food safety because it feeds more than half of the world's population. Rice grain yield depends on biomass and the harvest index. An important strategy to break through the rice grain yield ceiling is to increase the biological yield. Therefore, genes associated with organ size are important targets for rice breeding. RESULTS: We characterized a rice mutant gns4 (grain number and size on chromosome 4) with reduced organ size, fewer grains per panicle, and smaller grains compared with those of WT. Map-based cloning indicated that the GNS4 gene, encoding a cytochrome P450 protein, is a novel allele of DWARF11 (D11). A single nucleotide polymorphism (deletion) in the promoter region of GNS4 reduced its expression level in the mutant, leading to reduced grain number and smaller grains. Morphological and cellular analyses suggested that GNS4 positively regulates grain size by promoting cell elongation. Overexpression of GNS4 significantly increased organ size, 1000-grain weight, and panicle size, and subsequently enhanced grain yields in both the Nipponbare and Wuyunjing7 (a high-yielding cultivar) backgrounds. These results suggest that GNS4 is key target gene with possible applications in rice yield breeding. CONCLUSION: GNS4 was identified as a positive regulator of grain number and grain size in rice. Increasing the expression level of this gene in a high-yielding rice variety enhanced grain yield. GNS4 can be targeted in breeding programs to increase yields. PMID- 28730413 TI - Updating the elite rice variety Kongyu 131 by improving the Gn1a locus. AB - BACKGROUND: Kongyu 131 is an elite japonica rice variety of Heilongjiang Province, China. It has the characteristics of early maturity, superior quality, high yield, cold tolerance and wide adaptability. However, there is potential to improve the yield of Kongyu 131 because of the relatively few grains per panicle compared with other varieties. Hence, we rebuilt the genome of Kongyu 131 by replacing the GRAIN NUMBER1a (Gn1a) locus with a high-yielding allele from a big panicle indica rice variety, GKBR. High-resolution melting (HRM) analysis was used for single nucleotide polymorphism (SNP) genotyping. RESULTS: Quantitative trait locus (QTL) analysis of the BC3F2 population showed that the introgressed segment carrying the Gn1a allele of GKBR significantly increased the branch number and grain number per panicle. Using 5 SNP markers designed against the sequence within and around Gn1a, the introgressed chromosome segment was shortened to approximately 430 Kb to minimize the linkage drag by screening recombinants in the target region. Genomic components of the new Kongyu 131 were detected using 220 SNP markers evenly distributed across 12 chromosomes, suggesting that the recovery ratio of the recurrent parent genome (RRPG) was 99.89%. Compared with Kongyu 131, the yield per plant of the new Kongyu 131 increased by 8.3% and 11.9% at Changchun and Jiamusi, respectively. CONCLUSIONS: To achieve the high yield potential of Kongyu 131, a minute chromosome fragment carrying the favorable Gn1a allele from the donor parent was introgressed into the genome of Kongyu 131, which resulted in a larger panicle and subsequent yield increase in the new Kongyu 131. These results indicate the feasibility of improving an undesirable trait of an elite variety by replacing only a small chromosome segment carrying a favorable allele. PMID- 28730414 TI - Erratum to: Cytopathology of pericardial effusions : Experience from a tertiary center of cardiology. PMID- 28730415 TI - SPECT: Workhorse of state of the art nuclear cardiology. PMID- 28730416 TI - Quality of Life, Coping Styles, Stress Levels, and Time Use in Mothers of Children with Autism Spectrum Disorders: Comparing Single Versus Coupled Households. AB - This study aimed to examine the influence of differences in household status on the parental stress, coping, time use and quality of life (QoL) among mothers of children with autism spectrum disorders. Forty-three single and 164 coupled mothers completed the survey. Data were analysed using multivariate logistic regression. We found that single mothers were 1.05 times more likely to report lower levels of environmental QoL. Whilst they were 1.73 times more likely to use acceptance coping style, this association did not persist after adjusting for total number of children, household income and employment status. There was no difference in time use and stress between these mothers. Possible environmental issues for single mothers and implications for future research are discussed. PMID- 28730417 TI - Patterns of Age-Related Cognitive Differences in Adults with Autism Spectrum Disorder. AB - Little is known about age-related cognitive differences in autism spectrum disorder (ASD). However, given the overlap in cognitive impairments in ASD to those seen in typical aging, it is possible that adults with ASD will face even greater cognitive difficulties as they age. The current study used a cross sectional design to examine age-related cognitive differences in adults with ASD and age and IQ-matched adults with typical development (age range 30-67 years). Results indicated that both age and diagnosis were related to poorer cognitive performance. However, adults with ASD exhibited pronounced age effects on measures related to executive functioning compared to adults with typical development, suggesting that aging in ASD may disproportionately affect specific cognitive processes. PMID- 28730418 TI - Total and free cortisol levels during 1 MUg, 25 MUg, and 250 MUg cosyntropin stimulation tests compared to insulin tolerance test: results of a randomized, prospective, pilot study. AB - PURPOSE: The appropriate cosyntropin dose during cosyntropin stimulation tests remains uncertain. We conducted a prospective, randomized pilot study to compare 1 MUg IV low dose cosyntropin test, 25 MUg IM medium dose cosyntropin test, and 250 MUg IM standard dose cosyntropin test to evaluate secondary adrenal insufficiency. Insulin tolerance test was used as the gold standard. METHOD: The study included patients with hypothalamic/pituitary disease (n = 10) with at least one pituitary axis deficiency other than ACTH deficiency and controls (n = 12). All tests were done in random order. Sensitivity and specificity were calculated for total cortisol and serum free cortisol cut-off levels during cosyntropin stimulation tests. RESULTS: The median (range) age and F/M sex ratios for patients and controls were 54 years (23-62), 2/8, and 33 years (21-51), 6/6, respectively. The best total cortisol cut-off during low dose cosyntropin test, medium dose cosyntropin test, 30 min and 60 min standard dose cosyntropin test were 14.6 MUg/dL (100% sensitivity & specificity), 18.7 MUg/dL (100% sensitivity, 88% specificity), 16.1 (100% sensitivity & specificity), and 19.5 MUg/dL (100% sensitivity & specificity), respectively. There was no difference in the ROC curve for cortisol values between the cosyntropin stimulation tests (p > 0.41). Using a cortisol cut-off of 18 MUg/dL during cosyntropin stimulation tests, only cortisol level at 30 min during standard dose cosyntropin test provided discrimination similar to insulin tolerance test. The best peak free cortisol cut off levels were 1 MUg/dL for insulin tolerance test, 0.9 MUg/dL for low dose cosyntropin test, 0.9 MUg/dL for medium dose cosyntropin test, and 0.9 MUg/dL and 1.3 MUg/dL for 30 min and 60 min standard dose cosyntropin test, respectively. CONCLUSION: All cosyntropin stimulation tests had excellent correlations with insulin tolerance test, when appropriate cut-offs were used. This pilot study does not suggest an advantage in using 25 MUg cosyntropin dose during the cosyntropin stimulation test. A serum free cortisol cut-off of 0.9 MUg/dL may be used as pass criterion during low dose cosyntropin test, standard dose cosyntropin test cosyntropin test, and 30 min standard dose cosyntropin test. PMID- 28730419 TI - The intriguing connections of leptin to hyperparathyroidism. AB - PURPOSE: Leptin has been implicated in bone metabolism, but the association with parathyroid gland function has not been fully clarified. This review aimed to summarize evidence of the association between leptin and hyperparathyroidism, both primary and secondary, elucidating the potential pathophysiologic and therapeutic consequences between leptin and parathyroid hormone, hopefully prompting the design of new studies. RESULTS: Experimental studies indicate a positive loop between leptin and parathyroid hormone in primary hyperparathyroidism. Dissimilar, parathyroid hormone seems to inhibit leptin expression in severe secondary hyperparathyroidism. Data from clinical studies indicate higher leptin levels in patients with primary hyperparathyroidism than controls, but no association between parathyroid hormone and leptin levels, as well as a minimal or neutral effect of parathyroidectomy on leptin levels in patients with primary hyperparathyroidism. Clinical data on secondary hyperparathyroidism, mainly derived from patients with chronic kidney disease, indicate a potential inverse association between leptin and parathyroid hormone in some, but not all studies. This relationship may be affected by the diversity of morbidity among these patients. CONCLUSIONS: Data from experimental studies suggest a different association between leptin and parathyroid hormone in primary and secondary hyperparathyroidism. Data from clinical studies are conflicting and potentially affected by confounders. More focused, well-designed studies are warranted to elucidate a potential association between leptin and parathyroid hormone, which may have specific clinical implications, i.e., targeting obesity and hyperleptinemia in patients with hyperparathyroidism. PMID- 28730421 TI - [Documentation of decisions to withhold or withdraw life-sustaining therapies : Recommendation of the Ethics Section of the German Interdisciplinary Association of Critical Care and Emergency Medicine (DIVI) in collaboration with the Ethics Section of the German Society for Medical Intensive Care and Emergency Medicine (DGIIN)]. PMID- 28730423 TI - [Female prostate cancer?] AB - We present a case of a female patient who had a clinically suspected advanced urothelial carcinoma of the urethra. Histopathological examination surprisingly revealed a malignant tumor with morphological and immunohistochemical features of prostate cancer, leading to the diagnosis of the extremely rare entity of Skene's gland adenocarcinoma. PMID- 28730420 TI - Inappropriate implantable cardioverter defibrillator shocks-incidence, effect, and implications for driver licensing. AB - PURPOSE: Patients with implantable cardioverter defibrillators (ICDs) have an ongoing risk of sudden incapacitation that may cause traffic accidents. However, there are limited data on the magnitude of this risk after inappropriate ICD therapies. We studied the rate of syncope associated with inappropriate ICD therapies to provide a scientific basis for formulating driving restrictions. METHODS: Inappropriate ICD therapy event data between 1997 and 2014 from 50 Japanese institutions were analyzed retrospectively. The annual risk of harm (RH) to others posed by a driver with an ICD was calculated for private driving habits. We used a commonly employed annual RH to others of 5 in 100,000 (0.005%) as an acceptable risk threshold. RESULTS: Of the 4089 patients, 772 inappropriate ICD therapies occurred in 417 patients (age 61 +/- 15 years, 74% male, and 65% secondary prevention). Patients experiencing inappropriate therapies had a mean number of 1.8 +/- 1.5 therapy episodes during a median follow-up period of 3.9 years. No significant differences were found in the age, sex, or number of inappropriate therapies between patients receiving ICDs for primary or secondary prevention. Only three patients (0.7%) experienced syncope associated with inappropriate therapies. The maximum annual RH to others after the first therapy in primary and secondary prevention patients was calculated to be 0.11 in 100,000 and 0.12 in 100,000, respectively. CONCLUSIONS: We found that the annual RH from driving was far below the commonly cited acceptable risk threshold. Our data provide useful information to supplement current recommendations on driving restrictions in ICD patients with private driving habits. PMID- 28730424 TI - Possible Immunomodulating Effect of Retinol on Cytokines Secretion in Patients with Recurrent Furunculosis. AB - Recurrent furunculosis is an infection of hair follicles which results in formation of abscesses. Previous studies showed that the pathogenesis of the disease may include an immune-mediated component as the proliferative response of peripheral blood lymphocytes to staphylococcal antigen is depressed. The aim of our study was to evaluate cytokines concentration in the plasma of patients with recurrent furunculosis and to determine whether retinol affects the secretion of those cytokines in patients with recurrent furunculosis and healthy subjects. Blood samples were taken from 15 patients with recurrent furunculosis and 15 age matched healthy subjects. A quantitative determination of selected cytokines (IL 17, 13, 2, 10, 4, IFN-gamma, TNF-alpha) was performed in the plasma at baseline and after 72-h culture of peripheral blood mononuclear cells with and without retinol in both groups. In the plasma of patients with recurrent furunculosis, concentration of IL-10, 2, and TNF-alpha was significantly higher, whereas IL-13 significantly lower when compared with healthy subjects. After retinol stimulation, the concentration of IL-17 and IFN-gamma increased significantly in both groups. Secretion of anti-inflammatory cytokines, especially IL-10 (p < 0.002) and 13 (p < 0.01), achieved lower levels in recurrent furunculosis samples than in those of healthy controls. Network of cytokines differs in patients with recurrent furunculosis from healthy subjects. Retinol stimulation affects secretion of both pro-inflammatory and anti-inflammatory cytokines. Further studies are recommended for better understanding the pathomechanism of recurrent furunculosis and potential clinical use of retinol in patients affected by recurrent furunculosis. PMID- 28730425 TI - AT-101 acts as anti-proliferative and hormone suppressive agent in mouse pituitary corticotroph tumor cells. AB - PURPOSE: Gossypol, a naturally occurring compound in cottonseeds, has anticancer effects against several tumor cell lines. It has been extensively studied in clinical trials and is well tolerated with a favorable safety profile. AT-101, a derivative of R (-)-gossypol, binds to Bcl-2 family proteins and induces apoptosis in vitro. Although transsphenoidal surgical excision of the pituitary corticotroph adenoma is the gold standard of care, it is not successful all the time. Medical therapy for Cushing's disease still remains a challenge for the clinicians. We aimed to investigate the cytotoxic and apoptotic effects of AT-101 in mouse pituitary corticotroph tumor AtT20 cells. METHODS: Cytotoxic effect of AT-101 was assessed by XTT cell viability assay. Apoptosis was shown by measuring DNA fragmentation and Caspase-3/7 activity. Changes in mRNA expressions of apoptosis-related genes were investigated by qPCR array after treatment with AT 101. ACTH was measured by ACTH-EIA Kit. RESULTS: AT-101 induced cytotoxicity and apoptosis in AtT20 cells. mRNA levels of pro-apoptotic genes such as TNFR-SF-10B, Bid, PYCARD, Caspase-8, Caspase-3, and Caspase-7 were induced by 2.0-, 1.5-, 1.7 , 1.5-, 1.6-, and 2-fold, respectively, in AtT20 cells by AT-101 treatment. Moreover, some of the anti-apoptotic genes such as BCL2L10, NAIP1, and PAK-7 were reduced by 2.1-, 2.3-, 4.0-fold, respectively, in AtT20 cells. AT-101 also decreased ACTH secretion significantly. CONCLUSION: AT-101 induces apoptosis in mouse pituitary corticotroph tumor cells. PMID- 28730426 TI - Phytaspase-loaded, Mn-doped ZnS quantum dots when embedded into chitosan nanoparticles leads to improved chemotherapy of HeLa cells using in cisplatin. AB - OBJECTIVES: To investigate the potential of recombinant phytaspase loaded manganese (Mn) doped zinc sulphide (ZnS) quantum dots embedded chitosan nanoparticles for augmenting cisplatin induced chemotherapy of HeLa cells. RESULTS: The recombinant phytaspase was cloned into bacterial expression vector PGEX-4T-2. The expressed and purified recombinant plant phytaspase protein from Escherichia coli BL21 was immobilized onto the cationic nanocomposite. Confocal microscopy elucidated the delivery of these luminescent nanocomposites inside cervical cancer HeLa cells. A 50% reduction in the viability of HeLa cells was achieved only in the case of phytaspase-nanocomposites-cisplatin combination at a dose of phytaspase (42 nM), nanocomposites (56.3 MUg/ml) and cisplatin (0.44 MUg/ml). CONCLUSION: Luminescent cationic nanocomposites were developed for intracellular delivery of recombinant phytaspase, which due to its caspase-like activity assisted in substantiating the chemotherapeutic activity of apoptosis inducing drug-cisplatin. PMID- 28730428 TI - Need for a more developmental perspective: QTc prolongation under psychotropic medication. PMID- 28730427 TI - [Basic research in ophthalmology in Germany and its international context]. AB - BACKGROUND: Experimental basic research provides the foundations for the elucidation of pathophysiological mechanisms of diseases and the development of novel diagnostic and therapeutic strategies for ophthalmological diseases. The objective of this contribution is to provide an overview of the international interconnection of basic research in ophthalmology in Germany. METHODS: The international context of ophthalmological research conducted in Germany is presented by means of personal experiences and data published by the German Ophthalmological Society (DOG), the German Research Foundation (DFG) and the European Union (EU). Due to the lack of organized databases this article lays no claim to completeness. RESULTS: Basic research in ophthalmology in Germany is mainly conducted in university eye departments and is mainly related to the etiology, pathophysiology and therapy development for various ophthalmic diseases. It is primarily funded by the DFG, the Federal Ministry of Education and Research (BMBF) and the EU plays an increasingly important role. Thus, ophthalmological research is integrated into numerous European research networks and beyond that into many international interconnections and relationships. CONCLUSION: In Germany, both clinical and basic research in ophthalmology is integrated into many international networks and is only functionally viable in an international context; however, given the increasing impact of ophthalmological research in Asian countries, future strategies require a continued focus on career development, research infrastructure, working environment and international cooperation. PMID- 28730429 TI - A New Method to Predict Ion Effects in RNA Folding. AB - The strong interaction between metal ions in solution and highly charged RNA molecules is critical for RNA structure formation and stabilization. Metal ions binding to RNA can induce RNA structural changes that are important for RNA cellular functions. Therefore, quantitative modeling of the ion effects is essential for RNA structure prediction and RNA-based molecular design. Recently, inspired by the increasing experimental evidence that supports the importance of ion correlation and fluctuation in ion-RNA interactions, we developed a new computational model, Monte Carlo Tightly Bound Ion (MCTBI) model. The validity of the model is shown by the improved accuracy in the predictions for ion binding properties and ion-dependent free energies for RNA structures. In this chapter, using homodimeric tetraloop-receptor docking as an illustrative example, we showcase the MCTBI method for the computational prediction of the ion effects in RNA folding. PMID- 28730430 TI - Computational Generation of RNA Nanorings. AB - A variety of designed RNA ring structures (ranging from triangles to hexagonal rings) have been reported in the scientific literature. Designing self-assembling RNA ring structures from structural motifs is, however, a nontrivial problem as there are many combinations of motifs and linking helices. Moreover, most combinations of motifs and linker helices will not lead to ring closure. A solution to this problem was recently published using a "design-by-catalog" approach where motif combinations that lead to rings are precomputed and tabulated. Here we present a web-browser based workflow for creating RNA rings using Galaxy, a web-based platform that can be used for workflow management. An example of how these RNA rings are generated and processed to create a 3D model of the ring is discussed. PMID- 28730431 TI - Protocols for Molecular Dynamics Simulations of RNA Nanostructures. AB - Molecular dynamics (MD) simulations have been used as one of the main research tools to study a wide range of biological systems and bridge the gap between X ray crystallography or NMR structures and biological mechanism. In the field of RNA nanostructures, MD simulations have been used to fix steric clashes in computationally designed RNA nanostructures, characterize the dynamics, and investigate the interaction between RNA and other biomolecules such as delivery agents and membranes.In this chapter we present examples of computational protocols for molecular dynamics simulations in explicit and implicit solvent using the Amber Molecular Dynamics Package. We also show examples of post simulation analysis steps and briefly mention selected tools beyond the Amber package. Limitations of the methods, tools, and protocols are also discussed. Most of the examples are illustrated for a small RNA duplex (helix), but the protocols are applicable to any nucleic acid structure, subject only to the computational speed and memory limitations of the hardware available to the user. PMID- 28730432 TI - Rolling Circle Transcription for the Self-Assembly of Multimeric RNAi Structures and Its Applications in Nanomedicine. AB - The enzymatic process of rolling circle transcription (RCT) enables self-assembly of multimeric RNAi structures from a circular DNA template. The self-assembled RNAi structures can be manipulated easily by simple base pairing rules with short DNA fragments for constructing multifunctional nanoparticles in the field of nanomedicine. Here we describe the method to generate multifunctional RNAi nanoparticles applicable in nanomedicine. PMID- 28730433 TI - Computational Prediction of the Immunomodulatory Potential of RNA Sequences. AB - Advances in the knowledge of various roles played by non-coding RNAs have stimulated the application of RNA molecules as therapeutics. Among these molecules, miRNA, siRNA, and CRISPR-Cas9 associated gRNA have been identified as the most potent RNA molecule classes with diverse therapeutic applications. One of the major limitations of RNA-based therapeutics is immunotoxicity of RNA molecules as it may induce the innate immune system. In contrast, RNA molecules that are potent immunostimulators are strong candidates for use in vaccine adjuvants. Thus, it is important to understand the immunotoxic or immunostimulatory potential of these RNA molecules. The experimental techniques for determining immunostimulatory potential of siRNAs are time- and resource consuming. To overcome this limitation, recently our group has developed a web based server "imRNA" for predicting the immunomodulatory potential of RNA sequences. This server integrates a number of modules that allow users to perform various tasks including (1) generation of RNA analogs with reduced immunotoxicity, (2) identification of highly immunostimulatory regions in RNA sequence, and (3) virtual screening. This server may also assist users in the identification of minimum mutations required in a given RNA sequence to minimize its immunomodulatory potential that is required for designing RNA-based therapeutics. Besides, the server can be used for designing RNA-based vaccine adjuvants as it may assist users in the identification of mutations required for increasing immunomodulatory potential of a given RNA sequence. In summary, this chapter describes major applications of the "imRNA" server in designing RNA-based therapeutics and vaccine adjuvants (http://www.imtech.res.in/raghava/imrna/). PMID- 28730434 TI - Cotranscriptional Production of Chemically Modified RNA Nanoparticles. AB - RNA nanoparticles consisting of multiple RNA strands of different sequences forming various three-dimensional structures emerge as promising carriers of siRNAs, RNA aptamers, and ribozymes. In vitro transcription of a mixture of dsDNA templates encoding all the subunits of the RNA nanoparticle may result in cotranscriptional self-assembly of the nanoparticle. Based on our experience with production of RNA nanorings, RNA nanocubes, and RNA three-way junctions, we propose a strategy for optimization of the cotranscriptional production of chemically modified ribonuclease-resistant RNA nanoparticles. PMID- 28730435 TI - Supported Fluid Lipid Bilayer as a Scaffold to Direct Assembly of RNA Nanostructures. AB - RNA architectonics offers the possibility to design and assemble RNA into specific shapes, such as nanoscale 3D solids or nanogrids. Combining the minute size of these programmable shapes with precise positioning on a surface further enhances their potential as building blocks in nanotechnology and nanomedicine. Here we describe a bottom-up approach to direct the arrangement of nucleic acid nanostructures by using a supported fluid lipid bilayer as a surface scaffold. The strong attractive electrostatic interactions between RNA polyanions and cationic lipids promote RNA adsorption and self-assembly. Protocol steps for the characterization of assembled RNA complexes via several complementary methods (QCM-D, ellipsometry, confocal fluorescence microscopy, AFM) are also provided. Due to their tunable nature, lipid bilayers can be used to organize RNA laterally on the micrometer scale and thus facilitate the building of more complex 3D structures. The bilayer-based approach can be extended to other programmable RNA or DNA objects to construct intricate structures, such as 2D grids or 3D cages, with high precision. PMID- 28730436 TI - Evaluation of Thermal Stability of RNA Nanoparticles by Temperature Gradient Gel Electrophoresis (TGGE) in Native Condition. AB - Temperature gradient gel electrophoresis (TGGE) is a powerful tool used to analyze the thermal stabilities of nucleic acids. While TGGE is a decades-old technique, it has recently gained favor in the field of RNA nanotechnology, notably in assessing the thermal stabilities of RNA nanoparticles (NPs). With TGGE, an electrical current and a linear temperature gradient are applied simultaneously to NP-loaded polyacrylamide gel, separating the negatively charged NPs based on their thermal behavior (a more stable RNA complex will remain intact through higher temperature ranges). The linear temperature gradient can be set either perpendicular or parallel to the electrical current, as either will make the NPs undergo a transition from native to denatured conformations. Often, the melting transition is influenced by sequence variations, secondary/tertiary structures, concentrations, and external factors such as the presence of a denaturing agent (e.g., urea), the presence of monovalent or divalent metal ions, and the pH of the solvent. In this chapter, we describe the experimental setup and the analysis of the thermal stability of RNA NPs in native conditions using a modified version of a commercially available TGGE system. PMID- 28730437 TI - Design and Crystallography of Self-Assembling RNA Nanostructures. AB - Biological RNA architectures are composed of autonomously folding modules which can be tailored as building blocks for the construction of RNA nanostructures. Designed base pair interactions allow complex nano-objects to self-assemble from simple RNA motifs. X-ray crystallography plays an important role in both the design and analysis of such RNA nanostructures. Here, we describe methods for the design and X-ray crystallographic structure analysis of an RNA square and two different triangles, which self-assemble from short oligonucleotides and serve as a platform for building functional nano-sized nucleic acid architectures. PMID- 28730438 TI - X-Aptamer Selection and Validation. AB - Aptamers and second generation analogs, such as X-Aptamers (XAs), SOMAmers, locked nucleic acids (LNAs), and others are increasingly being used for molecular pathway targeting, biomarker discovery, or disease diagnosis by interacting with protein targets on the surface of cells or in solution. Such targeting is being used for imaging, diagnostic evaluation, interference of protein function, or delivery of therapeutic agents. Selection of aptamers using the original SELEX method is cumbersome and time-consuming, often requiring 10-15 rounds of selection, and provides aptamers with a limited number of functional groups, namely four bases of DNA or RNA, although newer SELEX methods have increased this diversity. In contrast, X-Aptamers provide an unlimited number of functional groups and thus are superior targeting agents. Here, we discuss the X-Aptamer selection process. PMID- 28730439 TI - Design and Preparation of Aptamer-siRNA Chimeras (AsiCs) for Targeted Cancer Therapy. AB - Conjugation of cell-internalizing DNA or RNA aptamers to tumor-suppressing siRNAs represents a novel promising approach for cancer therapy. Here we describe how to employ RNA aptamers that bind to cell surface receptors as carriers for cell targeted siRNA (or miRNA) delivery. This protocol was optimized to improve the efficiency of the aptamer-siRNA/miRNA conjugates and facilitate its implementation in most molecular biology labs. The single working steps include (1) outlining the optimal sequences of the RNA strands bearing the aptamer and siRNA sequence, for which further (2) a dsDNA template is synthesized and then (3) transcribed into an RNA that will be (4) folded and annealed to a chemically synthesized siRNA complementary strand. Moreover, we reference recent examples and advances in the aptamer delivery field. PMID- 28730440 TI - Cellular Delivery of siRNAs Using Bolaamphiphiles. AB - Discovery of RNA interference (RNAi) has opened up a new arena of therapeutic intervention for the treatment of cancerous as well as noncancerous diseases. The RNAi pathway utilizes RNAi inducers such as small interfering RNAs (siRNAs) to target and silence disease causing genes. However, efficient delivery of siRNAs for eliciting efficacious RNAi has remained a daunting challenge. Nonviral vectors such as lipids have shown great promise in delivering siRNAs. Recently, a novel class of cationic lipid molecules "bolaamphiphile lipids" or "bola lipids" has been shown to deliver siRNAs to cause effective gene silencing in cells. The present chapter showcases the ability of bola lipids to form micelles, bind with nucleic acids and protect nucleic acids against nucleases. Also, high in vitro transfection efficiency for silencing green fluorescent protein (GFP) using Dicer substrate siRNAs (dsiRNAs) designed against GFP at nontoxic dose in a human breast cancer model is demonstrated. Our results showed that these cationic bola lipids are promising siRNA delivery agents. PMID- 28730441 TI - Preparation and Optimization of Lipid-Like Nanoparticles for mRNA Delivery. AB - Lipid-like nanoparticles (LLNs) have shown great promise for nucleic acid delivery. Recently, we have developed N 1,N 3,N 5-tris(2-aminoethyl)benzene-1,3,5 tricarboxamide (TT) derived lipid-like compounds, formulated them into TT LLNs for mRNA delivery, and applied an orthogonal array design to facilitate formulation optimization. This chapter focuses on the following contents relevant to lipid-like nanoparticles: formulation method, particle characterization, orthogonal array design, and in vitro assays. PMID- 28730442 TI - Chitosan Nanoparticles for miRNA Delivery. AB - RNA interference techniques represent a promising strategy for therapeutic applications. In addition to small interfering RNA-based approaches, which have been widely studied and translated into clinical investigations, microRNA-based approaches are attractive owing to their "one hit, multiple targets" concept. To overcome challenges with in vivo delivery of microRNAs related to stability, cellular uptake, and specific delivery, our group has developed and characterized chitosan nanoparticles for nucleotide delivery. This platform allows for robust target modulation and antitumor activity following intravenous administration. PMID- 28730443 TI - Synthesis of PLGA-Lipid Hybrid Nanoparticles for siRNA Delivery Using the Emulsion Method PLGA-PEG-Lipid Nanoparticles for siRNA Delivery. AB - The effective delivery of small interfering RNA (siRNA) to tumor cells remains a challenge for applications in cancer therapy. The development of polymeric nanoparticles with high siRNA loading efficacy has shown great potential for cancer targets. Double emulsion solvent evaporation technique is a useful tool for encapsulation of hydrophilic molecules (e.g., siRNA). Here we describe a versatile platform for siRNA delivery based on PLGA-PEG-cationic lipid nanoparticles by using the double emulsion method. The resulting nanoparticles show high encapsulation efficiency for siRNA (up to 90%) and demonstrate effective downregulation of the target genes in vitro and vivo. PMID- 28730444 TI - Oxime Ether Lipids as Transfection Agents: Assembly and Complexation with siRNA. AB - RNAi-based therapeutic approaches to combat cancer and other diseases are currently an area of great interest. However, practical applications of this approach rely on optimal tools to carry and deliver siRNA to the desired site. Oxime ether lipids (OELs) are a class of molecules among other various carriers being examined for siRNA delivery. OELs, relatively new candidates, belong to a class of non-glycerol based lipids and have begun to claim their place as an siRNA delivery carrier in the field of RNAi therapy. Chemical synthesis steps of OELs are considered relatively simple with the ability to modify the functionalities as desired. OEL-siRNA complexes can be assembled in the presence of serum-containing buffers (or cell culture media) and recent data from our and other groups have demonstrated that OELs are viable carriers for siRNA delivery in the cell culture systems. In this chapter, we provide the details of experimental protocols routinely used in our laboratory to examine OEL-siRNA complexes including their assembly, stability, and transfection efficiencies. PMID- 28730446 TI - Intracellular Reassociation of RNA-DNA Hybrids that Activates RNAi in HIV Infected Cells. AB - Human immunodeficiency virus Type 1 (HIV-1) is the major cause of acquired immune deficiency syndrome (AIDS). In 2014, it was estimated that 1.2 million people died from AIDS-related illnesses. RNA interference-based therapy to block HIV replication is a field that, as of now, is without any FDA-approved drugs available for clinical use. In this chapter we describe a protocol for testing and utilizing a new approach that relies on reassociation of RNA-DNA hybrids activating RNAi and blocking HIV replication in human cells. PMID- 28730445 TI - Polycationic Probe-Guided Nanopore Single-Molecule Counter for Selective miRNA Detection. AB - MicroRNAs (miRNAs) are a class of noncoding RNAs that are being explored as a new type of disease biomarkers. The nanopore single-molecule sensor offers a potential noninvasive tool to detect miRNAs for diagnostics and prognosis applications. However, one of the challenges that limits its clinical applications is the presence of a large variety of nontarget nucleic acids in the biofluid extracts. Upon interacting with the nanopore, nontarget nucleic acids produce "contaminative" nanopore signals that interfere with target miRNA discrimination, thus severely lowering the accuracy in target miRNA detection. We have reported a novel method that utilizes a designed polycationic peptide-PNA probe to specifically guide the target miRNA migration toward the nanopore, whereas any nontarget nucleic acids without the probe bound is rejected by the nanopore. Consequently, nontarget species are driven away from the nanopore and only the target miRNA can be detected at low concentration. This method is also able to discriminate miRNAs with single-nucleotide difference by using PNA to capture miRNA. Considering the significance and impact of this substantial advance for the future miRNA detection in biofluid samples, we prepared this detailed protocol, by which the readers can view the experimental procedure, data analysis, and resulting explanation. PMID- 28730447 TI - Construction and In Vivo Testing of Prokaryotic Riboregulators. AB - RNAs that are transcribed and self-assemble within living cells are valuable tools for regulating and organizing cellular activities. Riboregulators, in particular, have been widely used for modulating translation and transcription in response to cognate transactivating or trigger RNAs, enabling cells to evaluate logic operations and to respond to environmental cues. Herein we detail a set of methods for the rapid construction and testing of prokaryotic riboregulators in Escherichia coli. These methods enable construction of dozens of riboregulator plasmids at the same time without the use of restriction enzymes. Furthermore, they facilitate rapid screening of devices and can be applied to a variety of other self-assembling in vivo RNA systems. PMID- 28730448 TI - Preparation of a Conditional RNA Switch. AB - RNA has gained great interest for use in biomedical and therapeutic applications. This is due in part to RNA's ability to perform multiple functions, including the regulation of endogenously expressed genes. However, the ability of RNA based drugs to distinguish target diseased cells from healthy tissue remains challenging. Here we present methods for the production of a recently developed conditional RNA switch that releases a Dicer substrate RNA in response to interaction with a specific RNA biomarker. PMID- 28730449 TI - Rational Engineering of a Modular Group I Ribozyme to Control Its Activity by Self-Dimerization. AB - We designed and constructed a dimer of the Tetrahymena group I ribozyme the activity of which is regulated by self-dimerization. This dimer was rationally designed by utilizing the P5abc and DeltaP5abc domains as large RNA motifs. This strategy enabled us to install large ribozyme functions into an RNA structure. This is a step toward expanding the field of RNA nanotechnology beyond the limitation of using only relatively small functional motifs. Self-dimerization can also be rationally programmed by modular engineering of RNA interaction motifs. In this chapter, we present the procedure for the rational design and construction of large ribozyme domains based on RNA tertiary structures. We also describe the electrophoresis mobility shift assay (EMS) and several ribozyme activity assays to confirm the ribozyme function and its regulation. We have succeeded in construction of tecto-GIRz. PMID- 28730450 TI - CRISPR-Cas RNA Scaffolds for Transcriptional Programming in Yeast. AB - CRISPR scaffold RNAs (scRNAs) provide a modular system for locus-specific transcriptional programming. scRNAs are generated by extending CRISPR guide RNA sequences with domains that recruit RNA-binding proteins, thus physically linking DNA binding and protein recruitment activities. A single scRNA molecule encodes information about the target locus and instructions about what regulatory function to execute at that locus. Sets of scRNA constructs can be used to generate synthetic multigene transcriptional programs in which some genes are activated and others are repressed. Such programs can be executed by inducing expression of the dCas9 protein, which acts as a single master regulatory control point, and this approach has been recently applied to flexibly redirect flux through a complex branched metabolic pathway in yeast. This protocol describes how to construct multi-scRNA transcriptional programs in yeast, including target site selection, cloning strategies, and yeast engineering. PMID- 28730451 TI - Using Planar Phi29 pRNA Three-Way Junction to Control Size and Shape of RNA Nanoparticles for Biodistribution Profiling in Mice. AB - RNA is rapidly emerging as a versatile building block for nanoparticle assembly due to its simplicity in base pairing, while exhibiting diversity in function such as enzymatic activity similar to some proteins. Recent advances in RNA nanotechnology have generated significant interests in applying RNA nanoparticles for various applications in nanotechnology and nanomedicine. In particular, assessing the effect of size and shape on cell entry and intracellular trafficking as well as in vivo biodistribution of nanoparticles is challenging due to the lack of nanoparticles rich in structure while varying in size and shape. RNA nanotechnology exemplified by the packaging RNA (pRNA) of bacteriophage phi29 DNA packaging motor has provided a different prospect in nanoparticle designs. Of note, there is a robust three-way junction (3WJ) motif in pRNA which can serve as an adaptable scaffold to construct thermodynamically stable 2D planar and 3D globular RNA architectures with tunable shapes and sizes, and harboring various targeting, therapeutic, and imaging modules. This chapter focuses on the methods for constructing pRNA-3WJ based nanoparticles with controllable sizes and shapes, and assessment of their biodistribution profiles in cancer mouse models after systemic injection and ocular mouse models following subconjunctival injection. PMID- 28730452 TI - Transcranial color Doppler in stroke-free adult patients with sickle cell disease. AB - The threshold velocity >=200 cm/s at transcranial Doppler (TCD) evaluation is a useful cut-off for preventing the stroke (STOP trial) in pediatric patients with sickle cell disease (SCD), term including different types of sickle genotypes. Scanty data are available for adult SCD patients. We compared intracranial blood flow velocities between adult SCD patients and controls using transcranial color Doppler (TCCD), measuring the peak of systolic velocity (PSV) with the insonation angle correction and the pulsatility index (PI), an indicator of endothelial elasticity. Fifty-three adult SCD patients (aged >18 years) were enrolled (15 sickle cell anemia, 26 sickle cell thalassemia, and 12 HbS/HbC). None of the patients presented neurological signs. PSVs in middle cerebral artery (MCA) were higher in SCD patients than in controls (p = 0.001). In sickle cell anemia patients, PSVs were higher when compared to HbS/betaThal (p < 0.0060) and HbS/HbC patients (p < 0.0139). PI was within the lower range of normality in SCD patients compared to controls. Moreover, MCA-PSV was higher with lower Hb levels and higher HbS%; PI did not change with variation of Hb levels and HbS%.PSV and PI in SCD adult patients could be a relevant index to indicate the abnormal cerebral blood flow and to detect the sickle endothelial damage, in order to prevent cerebrovascular accidents. PMID- 28730453 TI - Pregnancy in patients with thrombocytopenia and absent radii (TAR) syndrome. PMID- 28730454 TI - Erratum to: Hidden burden of non-medical spending associated with inpatient care among the poor in Afghanistan. PMID- 28730455 TI - Does professional experience save teeth? A survey among prosthodontists. AB - OBJECTIVES: The aim of this study is to investigate the effect of clinical experience and educational background on clinical decision-making of dentists presented with two prosthodontic cases. METHODS: A questionnaire-based survey was performed among 66 prosthodontists who were divided into two groups. The first group included clinicians from Belgium, Germany, and the Netherlands covering a wide spectrum of dental experience. The second (specialized) group consisted of German dentists performing their last module of a 3-year postgraduate master program in prosthodontics. Two patient scenarios of different complexities were presented to the participants who were asked to make an educated choice among seven therapeutic options. RESULTS: Sixty-six dentists participated. For case #1, 22 therapeutic suggestions were offered within the international group (variation 54%), while 17 options were chosen in the specialized group (variation 68%). For case #2, five (variation 12%) and four (variation 16%) different therapeutic options were planned in the groups, respectively. Treatment planning in combination with implants was clearly preferred by dentists with an experience of 20 years or less. Conversely, participants with more experience favored more conventional treatments. All differences were statistically significant (p < 0.05). CONCLUSION: Clinicians' experience and educational background had a clinically relevant influence on decision-making and treatment planning. A clear preference for implant-free therapies was noted for dentists with more than two decades of professional experience. CLINICAL SIGNIFICANCE: In complex cases, clinicians with more than 20 years of professional experience tend to save questionable teeth rather than to resort to implants. This interindividual variation might less likely occur when more external evidence is taken into account during the decision-making process. PMID- 28730456 TI - Photofunctionalization and non-thermal plasma activation of titanium surfaces. AB - OBJECTIVE: The aim of this study was to compare UV light and non-thermal plasma (NTP) treatment regarding the improvement of physical material characteristics and cell reaction on titanium surfaces in vitro after short-term functionalization. MATERIALS AND METHODS: Moderately rough (Ra 1.8-2.0 MUm) sandblasted and acid-etched titanium disks were treated by UV light (0.05 mW/cm2 at lambda = 360 nm and 2 mW/cm2 at lambda = 250 nm) or by NTP (24 W, -0.5 mbar) of argon or oxygen for 12 min each. Surface structure was investigated by scanning electron microscopy, confocal microscopy and X-ray photoelectron spectroscopy (XPS). Hydrophilicity was assessed by dynamic contact angle measurement. Cell attachment, viability, cell proliferation and cytotoxicity were assessed in vitro using murine osteoblast-like cells. RESULTS: UV irradiation or NTP treatment of titanium surfaces did not alter the surface structure. XPS analysis revealed a significantly increased oxidation of the surface and a decrease of carbon after the use of either method. NTP and UV light led to a significant better cell attachment of murine osteoblasts; significantly more osteoblasts grew on the treated surfaces at each time point (p < 0.001). CONCLUSIONS: UV light as well as NTP modified the surface of titanium and significantly improved the conditions for murine osteoblast cells in vitro. However, results indicate a slight advantage for NTP of argon and oxygen in a short time interval of surface functionalization compared to UV. CLINICAL RELEVANCE: UV light and NTP are able to improve surface conditions of dental implants made of titanium. PMID- 28730457 TI - Efficacy, safety, and clinical outcome of modern mechanical thrombectomy in elderly patients with acute ischemic stroke. AB - BACKGROUND: The average life expectancy is increasing worldwide, surpassing 80 years in some countries. Recently, mechanical thrombectomy (MT) using modern devices and techniques has led to improved clinical outcomes following acute ischemic stroke. However, thus far, it remains uncertain whether MT is effective in elderly patients aged over 80 years. METHODS: Between July 2013 and June 2016, 207 patients with acute ischemic stroke in the anterior circulation received MT at our center. The applied MT strategies were forced arterial suction thrombectomy (FAST) and stent retriever thrombectomy. Patients were divided into those <80 years (n = 173) and those >=80 years (n = 34). We compared clinical and angiographic parameters between groups. RESULTS: The median age was 67.5 in the younger group and 82 in the elderly group; 92.5% of the younger group and 70.6% of the elderly group received MT via the FAST technique. Angiographic outcomes, including procedural time, mTICI 2b-3 reperfusion (85.5% vs. 82.4%, p = 0.633), and symptomatic intracranial hemorrhage, were not different between the groups. A favorable clinical outcome rate was significantly higher in the younger group (62.4% vs. 44.1%, p = 0.047). Younger age, a low NIHSS score, and fast onset to reperfusion time were favorable prognostic factors in elderly patients. CONCLUSION: Modern MT in elderly patients with acute ischemic stroke is safe and effective compared to younger patients despite a lower favorable clinical outcome. Our findings may suggest that an appropriate MT strategy with respect to the location of the target occlusion and vascular tortuosity might be helpful to achieve fast reperfusion and improved outcomes for elderly patients. PMID- 28730458 TI - Generation and Screening of T-DNA Insertion Mutants Mediated by Agrobacterium tumefaciens in the Garden Asparagus Stem Blight Pathogen Phomopsis asparagi. AB - The garden asparagus stem blight caused by filamentous fungus Phomopsis asparagi exposes a serious threat on asparagus production globally. However, to present, we understand poorly about the molecular mechanisms of fungal pathogenicity. To facilitate functional genomics research of P. asparagi, here we developed a highly efficient and stable Agrobacterium tumefaciens-mediated transformation approach which yielded 150-200 transformants per 1 * 106 conidia. Our results indicated that 25 degrees C, acetosyringone concentration of 150 MUmol/L, and 72 h were recommended as optimal co-cultivation conditions for the transformation. Using this transformation approach, we constructed a T-DNA insertion mutant library containing 1253 strains. Twenty randomly selected T-DNA insertion mutants were able to grow on 0.2 * PDA selective media after five successive subcultures without selective pressure, indicating that the exogenous T-DNA was stably integrated into the P. asparagi genome. We confirmed several randomly selected mutants using PCR with primers specific to the hph gene. Southern blots suggested that three out of the five selected mutants have a single T-DNA insertion. Interestingly, multiple mutant candidates with growth defects were obtained from the growth assay. Moreover, several mutants were selected for further analysis on the T-DNA flanking sequences through TAIL-PCR analysis. A sequence comparison of total junction fragments implied that the insertion of T-DNA within P. asparagi genome appeared to be a random event. The transformation technology and genetic resources developed here will facilitate studies of pathogenic mechanisms in this devastating filamentous fungal pathogen of garden asparagus. PMID- 28730460 TI - Impact of safety warnings on domperidone prescribing in Ireland. AB - AIM: This study aimed to investigate the impact of the 2014 safety warnings on use of domperidone, on subsequent prescribing patterns in Ireland. METHODS: The Irish HSE-PCRS pharmacy claims database was used to identify the study cohort (aged 18+), prescribed domperidone from Jan 2014 to Oct 2015. Dosage was available for each claim; concomitant prescription with the following drug classes was identified and calculated as a percentage of the total number of claims: anti-arrhythmics, macrolide antimicrobials and the selective serotonin receptor inhibitors (SSRIs) citalopram and escitalopram. Segmented regression analysis was used to examine the changes in prescribing before and after the issue of safety warnings in May 2014. RESULTS: A total of 397,572 claims for domperidone were identified from Jan 2014 to Oct 2015. Overall, there was a significant decline in numbers receiving domperidone during the study period (from 22,226 to 15,691 claims, p = 0.012), with no significant change over time. In addition, no significant change in co-prescribed SSRIs or anti-arrhythmic agents was observed over time; co-prescribed macrolide antimicrobials significantly increased after the safety advisory compared to trends before (p = 0.031). In those aged 60+ years, 10% of claims (n = 1332) were for doses >30 mg/day at the start of the study with no significant change in dose after the May advisory. CONCLUSIONS: Safety warnings concerning domperidone appeared to have had little effect on prescribing patterns in Ireland. Of concern is the continuing co-prescription with drugs known to increase the risk of QT prolongation, in all ages, including the 60+ year age group. PMID- 28730459 TI - Fetal programming as a predictor of adult health or disease: the need to reevaluate fetal heart function. AB - Epidemiologic and experimental evidence suggests that adverse stimuli during critical periods in utero permanently alters organ structure and function and may have persistent consequences for the long-term health of the offspring. Fetal hypoxia, maternal malnutrition, or ventricular overloading are among the major adverse conditions that can compromise cardiovascular development in early life. With the heart as a central organ in fetal adaptive mechanisms, a deeper understanding of the fetal cardiovascular physiology and of the echocardiographic tools to assess both normal and stressed pregnancies would give precious information on fetal well-being and hopefully may help in early identification of special risk groups for cardiovascular diseases later in life. Assessment of cardiac function in the fetus represents an additional challenge when comparing to children and adults, requiring advanced training and a critical approach to properly acquire and interpret functional parameters. This review summarizes the basic fetal cardiovascular physiology and the main differences from the mature postnatal circulation, provides an overview of the particularities of echocardiographic evaluation in the fetus, and finally proposes an integrated view of in utero programming of cardiovascular diseases later in life, highlighting priorities for future clinical research. PMID- 28730461 TI - Low salinity affects cellularity, DNA methylation, and mRNA expression of igf1 in the liver of half smooth tongue sole (Cynoglossus semilaevis). AB - Animal growth depends on feedback regulation of hormone levels and environmental conditions. Insulin-like growth factor-1 (Igf1) promotes cell growth and differentiation and represses apoptosis and is highly regulated by the environment. Moreover, animals modify physiological homeostasis under stressful conditions through epigenetics and genetic regulatory mechanisms. Therefore, a comprehensive understanding of the effects of salt on fish growth is needed. In this study, half smooth tongue sole (Cynoglossus semilaevis) were subjected to 150/00 salinity for 0, 7, and 60 days (D) to assess the effects of low salinity on liver cellularity and growth. The results show that low salinity changed liver morphology, suggesting an increase in energy expenditure to recover from the osmotic disruption. igf1 was upregulated in female fish under 150/00 salinity after 7D and may participate in molecular repair. igf1 was downregulated after 60D of salt stress, resulting in retarded growth. Methylation levels were opposite to those of gene expression, suggesting inhibited regulation. Furthermore, three exons in the igf1 gene had significantly different methylation levels in fish under salt stress. Notably, more putative transcription factor binding sites were located in CpG sites at higher methylation levels. igf1 is not a sex-related gene, as no difference in methylation level was detected between males and females in the control group. These results clarify liver damage and changes in DNA methylation and mRNA expression of igf1, providing insight into the adverse effects of low salt on growth of C. semilaevis and the epigenetics and regulatory mechanisms involved in stressful conditions. PMID- 28730462 TI - Nd-induced honeycomb structure of intermetallic phase enhances the corrosion resistance of Mg alloys for bone implants. AB - Mg-5.6Zn-0.5Zr alloy (ZK60) tends to degrade too rapid for orthopedic application, in spite of its natural degradation, suitable strength and good biocompatibility. In this study, Nd was alloyed with ZK60 via laser melting method to enhance its corrosion resistance. The microstructure features, mechanical properties and corrosion behaviors of ZK60-xNd (x = 0, 1.8, 3.6, 5.4 wt.%) were investigated. Results showed that laser melted ZK60-xNd were composed of fine alpha-Mg grains and intermetallic phases along grain boundaries. And the precipitated intermetallic phases experienced successive changes: divorced island like MgZn phase -> honeycomb-like T phase -> coarsened and agglomerated W phase with Nd increasing. It was worth noting that ZK60-3.6Nd with honeycomb-like T phase exhibited an optimal corrosion behavior with a corrosion rate of 1.56 mm year-1. The improved corrosion behavior was ascribed to: (I) dense surface film caused by the formation of Nd2O3 hindered the invasion of immersion solution; (II) the three-dimensional honeycomb structure of intermetallic phases formed a tight barrier to restrain the propagation of corrosion. Moreover, ZK60-3.6Nd exhibited good biocompatibility. It was suggested that ZK60-3.6Nd was a preferable candidate for biodegradable bone implant. PMID- 28730463 TI - Exploring new alleles for frost tolerance in winter rye. AB - KEY MESSAGE: Rye genetic resources provide a valuable source of new alleles for the improvement of frost tolerance in rye breeding programs. Frost tolerance is a must-have trait for winter cereal production in northern and continental cropping areas. Genetic resources should harbor promising alleles for the improvement of frost tolerance of winter rye elite lines. For frost tolerance breeding, the identification of quantitative trait loci (QTL) and the choice of optimum genome based selection methods are essential. We identified genomic regions involved in frost tolerance of winter rye by QTL mapping in a biparental population derived from a highly frost tolerant selection from the Canadian cultivar Puma and the European elite line Lo157. Lines per se and their testcrosses were phenotyped in a controlled freeze test and in multi-location field trials in Russia and Canada. Three QTL on chromosomes 4R, 5R, and 7R were consistently detected across environments. The QTL on 5R is congruent with the genomic region harboring the Frost resistance locus 2 (Fr-2) in Triticeae. The Puma allele at the Fr-R2 locus was found to significantly increase frost tolerance. A comparison of predictive ability obtained from the QTL-based model with different whole-genome prediction models revealed that besides a few large, also small QTL effects contribute to the genomic variance of frost tolerance in rye. Genomic prediction models assigning a high weight to the Fr-R2 locus allow increasing the selection intensity for frost tolerance by genome-based pre-selection of promising candidates. PMID- 28730464 TI - Genome-wide association mapping of canopy wilting in diverse soybean genotypes. AB - KEY MESSAGE: Genome-wide association analysis identified 61 SNP markers for canopy wilting, which likely tagged 51 different loci. Based on the allelic effects of the significant SNPs, the slowest and fastest wilting genotypes were identified. Drought stress is a major global constraint for crop production, and slow canopy wilting is a promising trait for improving drought tolerance. The objective of this study was to identify genetic loci associated with canopy wilting and to confirm those loci with previously reported canopy wilting QTLs. A panel of 373 maturity group (MG) IV soybean genotypes was grown in four environments to evaluate canopy wilting. Statistical analysis of phenotype indicated wide variation for the trait, with significant effects of genotype (G), environment (E), and G * E interaction. Over 42,000 SNP markers were obtained from the Illumina Infinium SoySNP50K iSelect SNP Beadchip. After filtration for quality control, 31,260 SNPs with a minor allele frequency (MAF) >=5% were used for association mapping using the Fixed and random model Circulating Probability Unification (FarmCPU) model. There were 61 environment-specific significant SNP canopy wilting associations, and 21 SNPs that associated with canopy wilting in more than one environment. There were 34 significant SNPs associated with canopy wilting when averaged across environments. Together, these SNPs tagged 23 putative loci associated with canopy wilting. Six of the putative loci were located within previously reported chromosomal regions that were associated with canopy wilting through bi-parental mapping. Several significant SNPs were located within a gene or very close to genes that had a reported biological connection to transpiration or water transport. Favorable alleles from significant SNPs may be an important resource for pyramiding genes to improve drought tolerance and for identifying parental genotypes for use in breeding programs. PMID- 28730466 TI - Simon Wong, MD. PMID- 28730465 TI - Time-varying decision boundaries: insights from optimality analysis. AB - The most widely used account of decision-making proposes that people choose between alternatives by accumulating evidence in favor of each alternative until this evidence reaches a decision boundary. It is frequently assumed that this decision boundary stays constant during a decision, depending on the evidence collected but not on time. Recent experimental and theoretical work has challenged this assumption, showing that constant decision boundaries are, in some circumstances, sub-optimal. We introduce a theoretical model that facilitates identification of the optimal decision boundaries under a wide range of conditions. Time-varying optimal decision boundaries for our model are a result only of uncertainty over the difficulty of each trial and do not require decision deadlines or costs associated with collecting evidence, as assumed by previous authors. Furthermore, the shape of optimal decision boundaries depends on the difficulties of different decisions. When some trials are very difficult, optimal boundaries decrease with time, but for tasks that only include a mixture of easy and medium difficulty trials, the optimal boundaries increase or stay constant. We also show how this simple model can be extended to more complex decision-making tasks such as when people have unequal priors or when they can choose to opt out of decisions. The theoretical model presented here provides an important framework to understand how, why, and whether decision boundaries should change over time in experiments on decision-making. PMID- 28730468 TI - Methods for optimizing the display conditions of brain magnetic resonance images. AB - PURPOSE: To investigate a method for optimizing the display conditions of brain magnetic resonance (MR) images. MATERIALS AND METHODS: We retrospectively analyzed brain MR images of 120 adults classified into screening, acute cerebral infarction, and brain tumor groups (n = 40 each). Two observers independently displayed the images on a monitor and optimized the display conditions using the W/L and U/L methods. In the W/L method, the observers manipulated the width and level of the display window, while in the U/L method they manipulated the upper and lower levels of the window. The times required were compared between the two methods. Additionally, the appropriateness of the determined window setting was evaluated visually by the respective observer to exclude the possibility that rough, suboptimal adjustment shortened the adjustment time. RESULTS: For both observers and all groups, the time required for optimization was significantly shorter for the U/L method than for the W/L method. The appropriateness of the window setting for the U/L method was equal to or better than that for the W/L method. CONCLUSION: Manipulating the upper and lower levels of the display window appears to improve the efficiency of interpreting brain MR images through rapid optimization of the display condition. PMID- 28730467 TI - Organ retention of gadolinium in mother and pup mice: effect of pregnancy and type of gadolinium-based contrast agents. AB - PURPOSE: To investigate the effect of pregnancy and type of gadolinium (Gd)-based contrast agents (GBCAs) on organ retention of Gd in mother and pup mice after maternal administration. MATERIALS AND METHODS: Gd-DTPA-BMA (gadodiamide) or Gd DOTA (gadoterate dimeglumine) was administered (2.0 mmol/kg of maternal weight) four times to pregnant Balb/c mice from gestational day 16-19, respectively. At 28 days after birth, they were euthanized and their organs (blood, brain, liver, kidney, spleen, and bone) were removed for the measurement of Gd by inductively coupled plasma mass spectrometry. RESULTS: Gd retention in maternal organs was generally lower than that in the organs of non-pregnant mice in both Gd-DTPA-BMA and Gd-DOTA groups. Significantly higher Gd retention was observed in the organs of pups whose mothers were administered Gd-DTPA-BMA as compared to those whose mothers were administered Gd-DOTA. Tissue-to-muscle ratio in the brains of pups was higher than that of mothers. CONCLUSION: We demonstrated in utero transplacental Gd retention in pups. In various organs in both mothers and pups, Gd retention was consistently higher for Gd-DTPA-BMA than Gd-DOTA administration. Pregnancy affected Gd retention in many maternal organs. PMID- 28730469 TI - Optogenetic Control of Ras/Erk Signaling Using the Phy-PIF System. AB - The Ras/Erk signaling pathway plays a central role in diverse cellular processes ranging from development to immune cell activation to neural plasticity to cancer. In recent years, this pathway has been widely studied using live-cell fluorescent biosensors, revealing complex Erk dynamics that arise in many cellular contexts. Yet despite these high-resolution tools for measurement, the field has lacked analogous tools for control over Ras/Erk signaling in live cells. Here, we provide detailed methods for one such tool based on the optical control of Ras activity, which we call "Opto-SOS." Expression of the Opto-SOS constructs can be coupled with a live-cell reporter of Erk activity to reveal highly quantitative input-to-output maps of the pathway. Detailed herein are protocols for expressing the Opto-SOS system in cultured cells, purifying the small molecule cofactor necessary for optical stimulation, imaging Erk responses using live-cell microscopy, and processing the imaging data to quantify Ras/Erk signaling dynamics. PMID- 28730470 TI - Dissecting Kinase Effector Signaling Using the RapRTAP Methodology. AB - Kinases are involved in a broad spectrum of cell behaviors. A single kinase can interact with different ligands each eliciting a specific cellular response. Dissecting downstream signaling pathways of kinases is a key step to understanding physiological and pathological cell process. However, directing kinase activity to specific substrates remains challenging. Here, we present a new tool to selectively activate a kinase in a specific protein complex in living cells. This technology uses a rapamycin-inducible kinase activation coupled to interaction with FKBP12-binding domain (FRB) tagged protein. Here, we demonstrate application of this method by targeting Src to either p130Cas or FAK and discriminating cell mophodynamic changes downstream each of these signaling complexes. PMID- 28730471 TI - Single-Cell Imaging of ERK Signaling Using Fluorescent Biosensors. AB - Single-cell analysis of the mitogen-activated protein kinase (MAPK) extracellular signal-regulated kinase (ERK) provides a means to perform highly detailed kinetic studies, assess heterogeneity between cells, and distinguish the subcellular localization of ERK activity. We describe here the methods needed to perform such measurements in a cell type of the investigator's choosing. We discuss the selection of appropriate reporters and provide detailed methods for stably introducing reporters, collecting live-cell data, and automatically extracting quantitative information from individual cells. PMID- 28730472 TI - Quantification of Cell Signaling Networks Using Kinase Activity Chemosensors. AB - The ability to directly determine endogenous kinase activity in tissue homogenates provides valuable insights into signaling aberrations that underlie disease phenotypes. When activity data is collected across a panel of kinases, a unique "signaling fingerprint" is generated that allows for discrimination between diseased and normal tissue. Here we describe the use of peptide-based kinase activity sensors to fingerprint the signaling changes associated with disease states. This approach leverages the phosphorylation-sensitive sulfonamido oxine (Sox) fluorophore to provide a direct readout of kinase enzymatic activity in unfractionated tissue homogenates from animal models or clinical samples. To demonstrate the application of this technology, we focus on a rat model of nonalcoholic fatty liver disease (NAFLD). Sox-based activity probes allow for the rapid and straightforward analysis of changes in kinase enzymatic activity associated with disease states, providing leads for further investigation using traditional biochemical approaches. PMID- 28730473 TI - Expression of Recombinant Phosphoproteins for Signal Transduction Studies. AB - Complex signaling cascades are difficult to study in vitro without phosphorylated proteins. Here, we describe a technique for the routine production of recombinant phosphoproteins by directly incorporating phosphoserine as a nonstandard amino acid. This protocol utilizes an optimized phosphoserine orthogonal translation system and an engineered strain of E. coli containing no genomic amber codons. This approach has been used to generate a variety of phosphorylated proteins to understand the role of protein phosphorylation in cell signaling. PMID- 28730474 TI - Allosteric Modulation of Src Family Kinases with ATP-Competitive Inhibitors. AB - The Src family kinases (SFKs) are an important family of tyrosine kinases that are allosterically regulated by their SH2 and SH3 domains. Engagement of SFK SH2 and SH3 domains with their intramolecular ligands leads to reduced kinase activity by stabilizing an inactive ATP-binding site conformation. Disruption of these intramolecular interactions stabilizes a more active ATP-binding site conformation and restores SFK activity. Interestingly, this allosteric relationship is bidirectional in that ATP-competitive ligands that stabilize distinct active site conformations can divergently modulate the abilities of the regulatory SH2 and SH3 domains to participate in intermolecular interactions. Here, we describe a series of assays that profile the bidirectional relationship between the ATP-binding sites and regulatory domains of SFKs. These methods can be used to discover ATP-competitive inhibitors that are selective for distinct ATP-binding site conformations of SFKs and for characterizing the effects that ATP-competitive inhibitors of SFKs have on domains that are distal to their site of interaction. PMID- 28730475 TI - Characterization of Ligand Binding to Pseudokinases Using a Thermal Shift Assay. AB - The protocol herein describes a robust and proven method for the measurement of pseudokinase-ligand interaction using a fluorescence-based thermal shift assay (TSA). Pseudokinases are kinase-like proteins that have recently emerged as crucial regulatory modules of signal transduction pathways and may well represent a novel class of drug targets. However, unlike kinases, the regulatory activity of pseudokinases is mainly conferred through protein-protein interactions. Understanding the mechanisms that underlie pseudokinase conformational changes through ligand binding and how such conformational changes can tune signaling pathways is a necessary step to unravel their biological functions.Thermal denaturation-based methods have proven to be a powerful method for determining the capacity of purified recombinant pseudokinases to bind ligands and can simultaneously inform on the potential druggability of the nucleotide-binding site. This assay takes advantage of a change in fluorescence arising when the dye, SYPRO Orange, binds to hydrophobic patches that become exposed when a protein undergoes thermal unfolding. Ligand binding to a protein is known to increase its thermal stability, which is reflected by a shift between the thermal denaturation curves of the unliganded protein and the liganded protein. Here, we illustrate the utility of the method with the pseudokinases, ErbB3/HER3, ILK, ROP5Bi, JAK1, JAK2, TYK2, MLKL, STRAD, TRIB1, VRK3, and ROR1. This method can also be used to determine optimal buffer conditions that may increase protein stability and can be tailored to other protein families. PMID- 28730476 TI - Proteomic Profiling of Protein Kinase Inhibitor Targets by Mass Spectrometry. AB - Identifying cellular targets of bioactive small molecules from large-scale screening campaigns can be a significant bottleneck in developing novel therapeutics. Our rapid small-molecule target profiling protocol combines affinity enrichment and SILAC for proteomic identification of small molecule protein interactions. Selective interactions are easily discernable from nonspecific protein binding by quantitative ratios. Using kinase inhibitors as an example, we provide an optimized protocol featuring on-bead protein digestion and single nano-flow liquid chromatographic-mass spectrometric (LC-MS) analyses, consequently increasing analytical throughput and sensitivity over gel-based sample preparation methods for rapid profiling of kinase inhibitor targets. PMID- 28730477 TI - Utilizing the Luminex Magnetic Bead-Based Suspension Array for Rapid Multiplexed Phosphoprotein Quantification. AB - The study of protein phosphorylation is critical for the advancement of our understanding of cellular responses to external and internal stimuli. Phosphorylation, the addition of phosphate groups, most often occurs on serine, threonine, or tyrosine residues due to the action of protein kinases. This structural change causes the protein to become activated (or deactivated) and enables it in turn to initiate the phosphorylation of other proteins in a cascade, eventually causing cell-wide changes such as apoptosis, cell differentiation, and growth (among others). Cellular phosphoprotein pathway dysregulation by mutation or chromosomal instability can often give the cell a selective advantage and lead to cancer. Obviously the understanding of these systems is of huge importance to the field of oncology.This chapter aims to provide a "how to" manual for one such technology, the 96-well plate-based xMAP(r) platform from Luminex. The system utilizes antibody-bound free-floating magnetic spheres which can easily be removed from suspension via magnetization. There are 100 unique bead sets (moving up to 500 bead sets for the most recent system) identified by the ratio of two dyes coating the microsphere. Each bead set is conjugated to a specific antibody which allows targeted protein extraction from low-concentration lysate solution. Biotinylated secondary antibodies/streptavidin-R-phycoerythrin (SAPE) complexes provide the quantification mechanism for the phosphoprotein of interest. PMID- 28730478 TI - High-Content Imaging and RNAi Screens for Investigating Kinase Network Plasticity. AB - High-content imaging connects the information-rich method of microscopy with the systematic objective principles of software-driven analysis. Suited to automation and, therefore, considerable scale-up of study size, this approach can deliver multiparametric data over cell populations or at the level of the individual cell and has found considerable utility in reverse genetic and pharmacological screens. Here we present a method to screen small interfering RNA (siRNA) libraries allowing subsequent observation of the impact of each knockdown on two interlinked, high-content, G1-/S-phase cell cycle transition assays related to cyclin-dependent kinase (CDK) 2 activity. We show how plasticity within the network governing the activity of this kinase can be detected by combining modifier siRNAs with a siRNA library. The method uses fluorescent immunostaining of a nuclear antigen, CyclinA, following cell fixation while also preserving the fluorescence of a stably expressed fluorescent protein-tagged reporter for CDK2 activity. We provide methodology for data extraction and handling including an R script that converts the multidimensional data into four simple binary outcomes, on which a hit-mining strategy can be built. The workflow described can in principle be adopted to yield quantitative single-cell-resolved data and mining for outcomes relating to a broad range of other similar readouts and signaling contexts. PMID- 28730479 TI - Analysis of Drug Resistance Using Kinome-Wide Functional Screens. AB - The clinical success of tyrosine kinase inhibitors specific for BCR-ABL-, EGFR-, ALK-, and ROS1-driven cancers continues to spur the quest to match specific oncogene-defined tumor types with an appropriate molecularly targeted therapy. Unfortunately, responses to these agents are not durable with intrinsic or acquired resistance limiting benefit. Additionally, efforts to identify the appropriate targets of new drugs have focused on nonfunctional assays such as large-scale sequencing for somatic mutations or analysis of gene copy number. Acknowledging both the problem of resistance and the shortcomings of the current methods for detecting appropriate drug targets, much interest has been focused on RNAi-based screens. These screens utilize a library of shRNAs targeting the whole genome or a subset of genes and provide a high-throughput and unbiased means to functionally assess genes impacting various aspects of tumor biology, especially proliferation and survival. The function of genes can be measured in the context of a specific drug treatment, termed a synthetic lethal screen, or genes may be assessed for their individual dependency, termed an essential gene screen. Here, we describe a method for performing both of these types of screens using a kinome targeted shRNA library in human cancer cell lines. PMID- 28730480 TI - Identification and Validation of Driver Kinases from Next-Generation Sequencing Data. AB - It is well appreciated that activating mutations in kinase genes result in kinome reprogramming that leads to altered downstream signaling networks that drive tumor progression. Indeed small-molecule inhibition of activated kinases has heralded the wave of precision medicine in the past decade. The advent of next generation sequencing has identified a plethora of potentially activating mutations and fusion genes in previously unreported kinase genes that can potentially be developed as targeted therapies. However, the bottleneck in the translation of these alterations into clinically useful therapies lies in their functional validation. Here we describe a set of in vitro functional assays we have optimized to assess whether mutations in kinases are activating. Through overexpression of wild-type and mutant kinase cDNA constructs, we described growth assays in two and three dimensions to ascribe functionality using breast cancer as a model system. PMID- 28730481 TI - Label-Free Phosphoproteomic Approach for Kinase Signaling Analysis. AB - Phosphoproteomics is a powerful platform for the unbiased profiling of kinase driven signaling pathways. Quantitation of phosphorylation can be performed by means of either labeling or label-free mass spectrometry (MS) methods. Because of their simplicity and universality, label-free methodology is gaining acceptance and popularity in molecular biology research. Analytical workflows for label-free quantification of phosphorylation, however, need to overcome several hurdles for the technique to be accurate and precise. These include the use of biochemical extraction procedures that efficiently and reproducibly isolate phosphopeptides from complex peptide matrices and an analytical strategy that can cope with missing MS/MS phosphopeptide spectra in a subset of the samples being compared. Testing the accuracy of the developed workflows is an essential prerequisite in the analysis of small molecules by MS, and this is achieved by constructing calibration curves to demonstrate linearity of quantification for each analyte. This level of analytical rigor is rarely shown in large-scale quantification of proteins using either label-based or label-free techniques. In this chapter we show an approach to test linearity of quantification of each phosphopeptide quantified by liquid chromatography (LC)-MS without the need to synthesize standards or label proteins. We further describe the appropriate sample handling techniques required for the reproducible recovery of phosphopeptides and explore the essential algorithmic features that enable the handling of missing MS/MS spectra and thus make label-free data suitable for such analyses. The combined technology described in this chapter expands the applicability of phosphoproteomics to questions not previously tractable with other methodologies. PMID- 28730482 TI - Cell-Specific Labeling for Analyzing Bidirectional Signaling by Mass Spectrometry. AB - Cell-specific proteome labeling enables global proteome-wide analysis of cell signaling in heterotypic co-cultures. Such approaches have provided unique insight in contact-initiated receptor tyrosine kinase signaling, transfer of proteomic material between heterotypic cells, and interactions between normal and oncogenic cells. Here we describe current methods for cell-specific labeling of heterotypic cells with isotopic labeled amino acids (e.g., SILAC and CTAP). We outline the advantages and disadvantages of individual approaches, describe typical experimental scenarios, and discuss where each experimental approach is optimally applied. PMID- 28730483 TI - Characterization of the Phospho-Adhesome by Mass Spectrometry-Based Proteomics. AB - Integrin adhesion receptors engage with their extracellular matrix (ECM) ligands, initiating intracellular signaling pathways that regulate a range of fundamental cell functions. Protein kinases and phosphatases play an integral role in integrin adhesion-mediated signaling. However, until recently, knowledge of the phosphorylation sites regulated downstream of integrin ligation was limited to candidate-based approaches and did not support a system-level understanding of the molecular mechanisms through which ECM engagement influences cell behavior. Here, we describe a mass spectrometry (MS)-based phosphoproteomic protocol that enables the global characterization of phosphorylation-based signaling networks activated by integrin-mediated adhesion. To analyze specifically integrin proximal signaling, the phosphoproteomic workflow involves the affinity-based isolation and analysis of integrin-associated complexes (IACs) rather than proteins solubilized from whole-cell lysates , which are typically used for global phosphoproteomic studies. The detection of phosphorylation sites from IAC proteins was optimized at various stages of the workflow, including IAC isolation, proteolytic digestion, and MS-based data acquisition strategies. The protocol permits the identification and quantification of IAC components by both Western blotting and MS. Notably, compared to phosphoproteomic analyses of cell lysates, the workflow described here enables an improved detection of phosphorylation sites from well-defined IAC proteins, including many known components of the signaling pathways activated by adhesion to the ECM. PMID- 28730484 TI - Analysis of Phosphotyrosine Signaling Networks in Lung Cancer Cell Lines. AB - Robust isolation and identification of peptides phosphorylated at their tyrosine residues are key steps in deciphering complex signaling networks governed by protein tyrosine kinases, including kinases involved in oncogenesis. Phosphotyrosine (pY)-containing peptides are commonly isolated from cellular lysates by means of antibody and/or metal affinity-based enrichment followed by their identification by mass spectrometry. Herein, we describe robust two-stage isolation of phosphotyrosine peptides and mass spectrometry-aided identification of phosphosites to characterize basal signaling networks in unstimulated non small cell lung cancer (NSCLC) cell lines. PMID- 28730485 TI - Targeted Analysis of Phosphotyrosine Signaling by Multiple Reaction Monitoring Mass Spectrometry. AB - Phosphoproteomics is an important tool for the unbiased investigation of signaling network activation and has particular application to unraveling aberrant signaling driving cancer progression. However, validating the behavior of specific phosphosites across multiple experimental conditions remains challenging, due to limitations inherent in discovery-based proteomic workflows and the limited availability of high-quality antibodies required for alternative, immunoaffinity-based methods. Targeted phosphoproteomics enables specific phosphosites to be quantified reproducibly across multiple experimental conditions. Importantly, targeted phosphoproteomic assays can be designed rapidly on the basis of data acquired in discovery proteomic experiments and circumvent the requirement of immunoaffinity techniques for reliable antibodies raised to specific, potentially poorly immunogenic phosphopeptides. In the following protocol, we present a method for the relative quantification of phosphosites across multiple experimental conditions and/or technical and biological replicates. PMID- 28730486 TI - Phosphoproteomic Analysis of Isolated Mitochondria in Yeast. AB - Mitochondria play a central role in cellular energy metabolism and cell death. Deregulation of mitochondrial functions is associated with several human pathologies (neurodegenerative diseases, neuromuscular diseases, type II diabetes, obesity, cancer). The steadily increasing number of identified mitochondrial phosphoproteins, kinases, and phosphatases in recent years suggests that reversible protein phosphorylation plays an important part in the control of mitochondrial processes. In addition, many mitochondrial phosphoproteins probably still remain to be identified, considering that 30% of proteins are expected to be phosphorylated in eukaryotes. In this chapter, we describe two procedures for the analysis of the mitochondrial phosphoproteome. The first one is a qualitative method that combines blue native and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (2D-BN/SDS-PAGE) and specific phosphoprotein staining. The second one is a quantitative approach that associates mitochondrial peptide labeling, phosphopeptide enrichment, and mass spectrometry. PMID- 28730487 TI - A Methodology for Comprehensive Analysis of Toll-Like Receptor Signaling in Macrophages. AB - A combination of high-throughput, multiplexed, quantitative methods with computational modeling and statistical approaches is required to obtain system level understanding of biological function. Mass spectrometry (MS)-based proteomics has emerged as a preferred tool for the analysis of changes in protein abundance and their post-translational modification (PTM) levels at a global scale, comparable with genomic experiments and generating data suitable for use in mathematical modeling of signaling pathways. Here we describe a set of parallel bottom-up proteomic approaches to detect and quantify the global protein changes in total intracellular proteins, their phosphorylation, and the proteins released by active and passive secretion or shedding mechanisms (referred to as the secretome as reviewed in Makridakis and Vlahou, J Proteome 73:2291-2305, 2010) in response to the stimulation of Toll-like receptors (TLRs) with specific ligands in cultured macrophages. The method includes protocols for metabolic labeling of cells (SILAC: stable isotope labeling by amino acids in cell culture; Ong et al., Mol Cell Proteomics 1:376-386, 2002), ligand stimulation, cell lysis and media collection, in-gel and in-solution modification and digestion of proteins, phosphopeptide enrichment for phosphoproteomics, and LC-MS/MS analysis. With these methods, we can not only reliably quantify the relative changes in the TLR signaling components (Sjoelund et al., J Proteome Res 13:5185-5197, 2014) but also use the data as constraints for mathematical modeling. PMID- 28730488 TI - Absolute Phosphorylation Stoichiometry Analysis by Motif-Targeting Quantitative Mass Spectrometry. AB - Direct measurement of site-specific phosphorylation stoichiometry can unambiguously distinguish whether the degree of phosphorylation is regulated by upstream kinase/phosphatase activity or by transcriptional regulation to alter protein expression level. Here, we describe a motif-targeting quantitative proteomic approach that integrates dephosphorylation, isotope tag labeling, and enzymatic kinase reaction for large-scale phosphorylation stoichiometry measurement of the human proteome. PMID- 28730489 TI - Identification of Plant Kinase Substrates Based on Kinase Assay-Linked Phosphoproteomics. AB - Protein phosphorylation is one of the key events in the regulation of plant physiological responses to diverse environmental stimuli. As crucial regulators of phosphorylation, protein kinases have been linked to the control of seed germination, flowering, and stress responses. Identifying downstream substrates of kinases is important for dissecting kinase-substrate networks as well as delineating the underlying defense mechanisms in response to extracellular stimulation. Despite the fact that thousands of kinase-substrate networks have been identified in mammalian cells, the downstream substrates of important plant kinases are still elusive. Moreover, it remains challenging to identify bona fide kinase substrates from proteome-wide analyses. Thus, developing methodologies with high sensitivity and specificity is imperative for understanding plant kinase-substrate cascades. Here, we describe a proteomic strategy termed kinase assay-linked phosphoproteomics (KALIP) approach for large-scale identification of the direct substrates of plant kinases with high sensitivity and a low false positive rate. PMID- 28730490 TI - Mass Spectrometry Analysis of Spatial Protein Networks by Colocalization Analysis (COLA). AB - A major challenge in systems biology is comprehensive mapping of protein interaction networks. Crucially, such interactions are often dynamic in nature, necessitating methods that can rapidly mine the interactome across varied conditions and treatments to reveal change in the interaction networks. Recently, we described a fast mass spectrometry-based method to reveal functional interactions in mammalian cells on a global scale, by revealing spatial colocalizations between proteins (COLA) (Mardakheh et al., Mol Biosyst 13:92-105, 2017). As protein localization and function are inherently linked, significant colocalization between two proteins is a strong indication for their functional interaction. COLA uses rapid complete subcellular fractionation, coupled with quantitative proteomics to generate a subcellular localization profile for each protein quantified by the mass spectrometer. Robust clustering is then applied to reveal significant similarities in protein localization profiles, indicative of colocalization. PMID- 28730491 TI - Development of Selected Reaction Monitoring Methods to Systematically Quantify Kinase Abundance and Phosphorylation Stoichiometry in Human Samples. AB - Protein phosphorylation, one of the most common types of post-translational modifications, is the central regulatory mechanism of cellular signaling networks. In human cells, thousands of proteins are continuously and dynamically phosphorylated and dephosphorylated at specific sites and times in response to external and internal stimuli. Reversible phosphorylation is facilitated by the action of two protein superfamilies: kinases and phosphatases. Kinases play an essential role in almost every relevant physiological process in human cells and their deregulation is linked to pathologies ranging from cancer to autoimmune diseases.Systematic identification of kinases expressed in a particular cell type, quantification of their abundance, and precise determination of their phosphorylation stoichiometry are essential to understand the cellular signaling networks and physiology of a sample. Our protocol outlines the steps to build and use a high-throughput, comprehensive, modular, and robust selected reaction monitoring (SRM) proteomics framework to facilitate quantification of the kinome state in research or clinical human samples. PMID- 28730492 TI - Analysis of Signaling Networks at the Single-Cell Level Using Mass Cytometry. AB - Mass cytometry is a powerful technology that enables the measurement of >40 parameters at the single-cell level. The inherent spectral limitations of fluorescent flow cytometry are circumvented by the use of antibodies conjugated to metal isotope reporters, which are measured quantitatively using a CyTOF mass cytometer. The high dimensionality of mass cytometry is particularly useful for the analysis of cell signaling networks in complex biological samples. We describe here methods for cell preparation, antibody staining, data acquisition, and analysis of multidimensional data from a mass cytometry experiment. PMID- 28730493 TI - Magnetic Resonance Spectroscopy (MRS)-Based Methods for Examining Cancer Metabolism in Response to Oncogenic Kinase Drug Treatment. AB - Magnetic resonance spectroscopy (MRS) is an analytical technique that has been extensively used to examine reprogrammed metabolism and treatment response in cancer cells and solid tumors both in vivo and ex vivo. High-resolution MRS (HR MRS) is one of the best methods for metabolic profiling, as it is highly quantitative, robust, and reproducible. The protocols for dual-phase extraction of cancer cells and tumors and sample preparations for high-resolution 1H and 31P HR-MRS analysis are described here. Descriptions of spectra acquisition and analysis are also included in this chapter. PMID- 28730494 TI - Deconstructing the Metabolic Networks of Oncogenic Signaling Using Targeted Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS). AB - Metabolic reprogramming is recognized as an emerging hallmark of oncogenic signaling and cancer development. Hence the need to identify novel quantitative analytical platforms for studying metabolism in vitro and in vivo has dramatically increased. Here, we describe the experimental workflow for a targeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) approach involving positive/negative ion switching to analyze >250 metabolites of central carbon metabolism, nucleotides, and amino acids. PMID- 28730495 TI - Modeling of Receptor Tyrosine Kinase Signaling: Computational and Experimental Protocols. AB - The advent of systems biology has convincingly demonstrated that the integration of experiments and dynamic modelling is a powerful approach to understand the cellular network biology. Here we present experimental and computational protocols that are necessary for applying this integrative approach to the quantitative studies of receptor tyrosine kinase (RTK) signaling networks. Signaling by RTKs controls multiple cellular processes, including the regulation of cell survival, motility, proliferation, differentiation, glucose metabolism, and apoptosis. We describe methods of model building and training on experimentally obtained quantitative datasets, as well as experimental methods of obtaining quantitative dose-response and temporal dependencies of protein phosphorylation and activities. The presented methods make possible (1) both the fine-grained modeling of complex signaling dynamics and identification of salient, course-grained network structures (such as feedback loops) that bring about intricate dynamics, and (2) experimental validation of dynamic models. PMID- 28730496 TI - An Interdisciplinary Approach for Designing Kinetic Models of the Ras/MAPK Signaling Pathway. AB - We present in this article a methodology for designing kinetic models of molecular signaling networks, which was exemplarily applied for modeling one of the Ras/MAPK signaling pathways in the mouse Y1 adrenocortical cell line. The methodology is interdisciplinary, that is, it was developed in a way that both dry and wet lab teams worked together along the whole modeling process. PMID- 28730497 TI - Databases and Computational Tools for Evolutionary Analysis of Protein Phosphorylation. AB - Advancements in MS-based phospho-proteomics techniques have helped uncover hundred thousands of protein phosphorylation sites in human and various model organisms. The majority of these sites are uncharacterized. The sheer number of uncharacterized sites necessitates systematic approaches to prioritize sites for more in-depth annotation. Analyzing the phosphorylation and sequence conservation of uncharacterized sites across species can help reveal a subset of the functionally important phosphorylation events. Here, we outline the workflow and provide an overview of publicly available computational resources for conservation analysis of novel phosphorylation sites. PMID- 28730498 TI - Informatics Approaches for Predicting, Understanding, and Testing Cancer Drug Combinations. AB - Making cancer treatment more effective is one of the grand challenges in our health care system. However, many drugs have entered clinical trials but so far showed limited efficacy or induced rapid development of resistance. We urgently need multi-targeted drug combinations, which shall selectively inhibit the cancer cells and block the emergence of drug resistance. The book chapter focuses on mathematical and computational tools to facilitate the discovery of the most promising drug combinations to improve efficacy and prevent resistance. Data integration approaches that leverage drug-target interactions, cancer molecular features, and signaling pathways for predicting, understanding, and testing drug combinations are critically reviewed. PMID- 28730499 TI - Target Inhibition Maps Based on Responses to Kinase Inhibitors. AB - The prediction of tumor sensitivity to targeted drugs remains a major challenge in the design of optimal therapeutic strategies. This chapter presents a computational modeling approach to infer target inhibition maps based on responses of the tumor culture to a range of kinase inhibitors. The kinase inhibition profiles of the targeted drugs and the functional responses are utilized to infer potential tumor proliferation circuits that can assist in generation of synergistic drug combinations. PMID- 28730500 TI - Partial Least Squares Regression Models for the Analysis of Kinase Signaling. AB - Partial least squares regression (PLSR) is a data-driven modeling approach that can be used to analyze multivariate relationships between kinase networks and cellular decisions or patient outcomes. In PLSR, a linear model relating an X matrix of dependent variables and a Y matrix of independent variables is generated by extracting the factors with the strongest covariation. While the identified relationship is correlative, PLSR models can be used to generate quantitative predictions for new conditions or perturbations to the network, allowing for mechanisms to be identified. This chapter will provide a brief explanation of PLSR and provide an instructive example to demonstrate the use of PLSR to analyze kinase signaling. PMID- 28730501 TI - The pseudo-SAH sign: an imaging pitfall in postmortem computed tomography. AB - Postmortem computed tomography (PMCT) of the brain has an important role in detection of subarachnoid hemorrhage (SAH), which has a high mortality rate. However, a phenomenon known as "pseudo-SAH," or high-attenuation areas along the cisterns mimicking SAH, may be seen on CT. The aim of this study was to evaluate the diagnostic accuracy of brain PMCT for SAH and to identify the characteristics of pseudo-SAH. Findings on PMCT (sulcal effacement, asymmetry, maximum thickness of SAH signs, presence of acute/subacute intraventricular/intraparenchymal hemorrhage) and clinical history (left ventricular assist device [LVAD] implantation, anticoagulation therapy/coagulation disorder, global ischemia) were compared between subjects with true SAH and those with pseudo-SAH. Twenty eight of 128 enrolled subjects had positive signs of SAH on PMCT, 20 (71.4%) had SAH on autopsy, and 8 (28.6%) did not. The sensitivity, specificity, positive predictive value, and negative predictive value of SAH signs seen on PMCT were 95.2, 94.6, 71.4, and 99.3%, respectively. Asymmetry of SAH signs and acute/subacute intraventricular and intraparenchymal hemorrhage were significantly more common in true SAH cases than in pseudo-SAH cases. The maximum thickness of SAH signs was significantly greater in true SAH cases. A history of LVAD implantation, anticoagulation therapy, and/or a coagulation disorder were more common in true SAH cases but not significantly so. A history of global ischemia was significantly more common in pseudo-SAH cases. If signs of SAH are observed on PMCT, it is important to look for other signs on PMCT and carefully review the clinical history to avoid a diagnostic error. PMID- 28730502 TI - Establishment of 11 linked X-STR loci within 1.1 Mb to assist with kinship testing. AB - This report identifies and characterizes 10 novel short tandem repeat (STR) loci on the human X chromosome, all of which are within a range of 1.1 Mb. These newly characterized loci were developed to aid in kinship assignment when the X chromosome is specifically required. The repeat DNA sequences were identified initially using data in GenBank and are located immediately upstream and downstream from the previously described locus DXS6807. Only those loci with seven or more observed alleles were used for further study resulting in the identification of 10 new loci. The distance between each pair of loci ranged from 24,998 to 244,701 bp with an average of approximately 110.8 kb. The number of observed alleles ranged from 7 to 30 for these 10 loci with a polymorphic information content ranging from 0.593 to 0.930. The LOD score from a pairwise linkage study ranged from 4.40 to 23.73, indicating that these 11 loci were highly linked, as expected. In line with standard forensic practice, all 11 loci can be amplified in one multiplex reaction, and comprehensive allelic ladders for all the loci have been constructed. These newly established 11 linked STR loci on the human X chromosome were found to be highly polymorphic and have the potential to aid in kinship testing where the X chromosome loci currently plays a role. PMID- 28730503 TI - Chicago Classification of Esophageal Motility Disorders: Lessons Learned. AB - PURPOSE OF REVIEW: High-resolution manometry (HRM) is increasingly performed worldwide, to study esophageal motility. The Chicago classification is subsequently applied to interpret the manometric findings and facilitate a diagnosis of esophageal motility disorders. This review will discuss new insights regarding the diagnosis and management using the Chicago classification. RECENT FINDINGS: Recent studies have demonstrated that high-resolution manometry is superior to conventional manometry, and has a higher sensitivity to diagnose achalasia. Furthermore, the subclassification of achalasia as used in the Chicago classification has prognostic value and can be used to direct treatment. Diagnosis of esophageal spasm has been improved by using the distal latency as diagnostic criterion. Recently, criteria for minor disorders of peristalsis have been sharpened, leading to a lower rate of patients with abnormal results, thereby increasing the relevance of a diagnosis. High-resolution manometry is now considered the gold standard for diagnosis of esophageal motility disorders. The Chicago classification provides a standardized approach for analysis and categorization of abnormalities that has led to a significant increase in our knowledge regarding the diagnosis and management of motility disorders. Further refinement of the classification will be required. PMID- 28730504 TI - Changing Trends in Stomach Cancer Throughout the World. AB - PURPOSE OF REVIEW: The paper aims to discuss the global trends in gastric cancer incidence in relation to important factors involved in the pathogenesis of gastric cancer. RECENT FINDINGS: Despite a significant worldwide decline, gastric cancer remains a common cause of cancer death. The decline has been multifactorial and preceded the fall in Helicobacter pylori prevalence. The initial decline was associated with changes in food preservation and availability, especially of fresh fruits and vegetables, followed by a decline in the primary etiologic factor, H. pylori. Gastric cancer incidence remains high in East Asia, intermediate in Latin America, and low in developed countries. Significant racial/ethnic variability exists. The rapid decline in incidence in East Asia will continue as primary and secondary prevention strategies are implemented. The incidence in Latin America is unlikely to decline significantly over the next few decades given high H. pylori prevalence in the young. Ultimately, global H. pylori eradication will be needed to largely eliminate gastric cancer. PMID- 28730505 TI - Stool Based Testing for Colorectal Cancer: an Overview of Available Evidence. AB - PURPOSE OF REVIEW: The goal of this review is to summarize stool-based testing for colorectal cancer (CRC). The key questions answered in this review were the advantages and limitations of each available stool-based test for CRC and to examine their comparative efficacy. RECENT FINDINGS: Guaiac-based fecal occult blood testing (gFOBT) is no longer a relevant test for CRC screening. fecal immunochemical testing (FIT) tests, especially quantitative assays, are clearly a reliable stool-based test. Multitarget DNA (mtsDNA) stool testing may represent a viable option as well, although cost and test characteristics are yet fully defined. FIT and mtsDNA represent the options for stool-based CRC screening. In larger screening centers, quantitative FIT assays represent an attractive option for stool-based testing. Qualitative FIT has applicability in smaller centers. Although a large validation trial showed promising results for mtsDNA, further head-to-head trials with FIT will help define the ultimate role of mtsDNA. Ultimately, however, the best test for CRC screening is the one performed stool based CRC screening as an initial or alternative option can increase participation in CRC screening. PMID- 28730506 TI - Hiatus Hernia as a Cause of Dysphagia. AB - PURPOSE OF REVIEW: This review aims to discuss the putative relationship between hiatus hernia and dysphagia. RECENT FINDINGS: Proposed mechanisms of dysphagia in patients with hiatus hernia are usually difficult to identify, but recent advances in technology (high-resolution manometry with or without concomitant impedance, ambulatory pH with impedance, videofluoroscopy, and the endoluminal functional lumen imaging probe (EndoFLIP)) and methodology (inclusion of swallows of various consistencies and volumes or shifting position during the manometry protocol) can help induce symptoms and identify the underlying disorder. Chronic reflux disease is often associated with hiatus hernia and is the most common underlying etiology. Dysmotility because of impaired contractility and vigor can occur as a consequence of repeated acid exposure from the acid pocket within the hernia, and the resultant poor clearance subsequently worsens this insult. As such, dysphagia appears to be more common with increasing hiatus hernia size. Furthermore, mucosal inflammation can lead to fibrotic stricture formation and in turn obstruction. On the other hand, there appears to be a difference in the pathophysiology of smaller sliding hernias, in that those with dysphagia are more likely to have extrinsic compression at the crural diaphragm as compared to those with reflux symptoms only. Sliding hiatus hernia, especially when small, does not commonly lead to dysmotility and dysphagia; however, in those patients with symptoms, the underlying etiology can be sought with new technologies and, in particular, the reproduction of normal eating and drinking during testing. PMID- 28730508 TI - Quality Improvement Initiatives in Inflammatory Bowel Disease. AB - PURPOSE OF REVIEW: This article serves as an overview of several quality improvement initiatives in inflammatory bowel disease (IBD). RECENT FINDINGS: IBD is associated with significant variation in care, suggesting poor quality of care. There have been several efforts to improve the quality of care for patients with IBD. Quality improvement (QI) initiatives in IBD are intended to be patient centric, improve outcomes for individuals and populations, and reduce costs-all consistent with "the triple aim" put forth by the Institute for Healthcare Improvement (IHI). Current QI initiatives include the development of quality measure sets to standardize processes and outcomes, learning health systems to foster collaborative improvement, and patient-centered medical homes specific to patients with IBD in shared risk models of care. Some of these programs have demonstrated early success in improving patient outcomes, reducing costs, improving patient satisfaction, and facilitating patient engagement. However, further studies are needed to evaluate and compare the effects of these programs over time on clinical outcomes in order to demonstrate long-term value and sustainability. PMID- 28730507 TI - Can We Use Diet to Effectively Treat Esophageal Disease? A Review of the Current Literature. AB - PURPOSE OF REVIEW: Esophageal diseases represent a wide variety of conditions affecting esophageal anatomy, physiology, and motility. Therapy focuses on pharmacotherapy and endoscopic or surgical management. Dietary therapy can be considered in management algorithms for specific esophageal diseases. This review focuses on outlining the literature related to dietary therapy in gastroesophageal reflux disease, eosinophilic esophagitis, Barrett's esophagus, and esophageal adenocarcinoma. RECENT FINDINGS: Currently, data are strongest for dietary manipulation in eosinophilic esophagitis, specifically the six-food elimination diet. Dietary effects on gastroesophageal reflux disease are less clear, though newer research indicates that increased fiber with reduction in simple sugar intake may improve symptoms. In terms of Barrett's esophagus and esophageal adenocarcinoma, antioxidant intake may affect carcinogenesis, though to an unknown degree. Outcomes data regarding dietary manipulation for the management of esophageal diseases is heterogeneous. Given the rising interest in non-pharmacological treatment options for these patients, continued research is warranted. PMID- 28730509 TI - Effect of a 2000-m running test on antioxidant and cytokine response in plasma and circulating cells. AB - Exercise intensity usually correlates with increased oxidative stress and enhanced cytokine production. However, it is unknown if all types of exercise that induce muscle damage can cause a parallel response in the oxidation balance and cytokine production. To this end, the effect of a 2000-m running test in a group of volunteers that regularly train in aerobic routines was studied. Different circulating parameters were measured, oxidative stress markers (protein carbonyls and malondialdehyde), antioxidant enzyme activity, and cytokine levels in plasma as well as in the main circulating cells of blood samples obtained in basal conditions and after test execution. As a result, the test caused muscle damage evidenced by an increase in circulating creatine kinase and myoglobin. This was accompanied by an increase in protein carbonyls in plasma and peripheral blood mononuclear cells. Activities of antioxidant enzymes (catalase, glutathione peroxidase and reductase, superoxide dismutase) were elevated in peripheral blood mononuclear cells, neutrophils, and erythrocytes after the test. Regarding cytokine production, interleukin-6, interleukin-8, interleukin-10, and tumor necrosis factor-alpha exhibited no significant changes after the test. Results suggest that this short but intense running exercise (2000 m) can induce muscle damage and elicit a good balance between oxidant/antioxidant responses with no changes in the circulating concentration of pro-inflammatory cytokines. PMID- 28730510 TI - Antiinflammation and Antioxidant Effects of Thalidomide on Pulmonary Fibrosis in Mice and Human Lung Fibroblasts. AB - In this study, the potential effects of thalidomide (Thal) on bleomycin (BLM) induced pulmonary fibrosis were investigated. BALB/C mice model of pulmonary fibrosis induced by an intratracheal instillation of BLM was adopted, and then was intraperitoneally injected with Thal (10, 20, 50 mg/kg) daily for 8 days, while the control and BLM-treated mouse groups were injected with a saline solution. The effects of Thal on pulmonary injury were evaluated by the lung wet/dry weight ratios and histopathological examination. Inflammation of lung tissues was assessed by measuring the levels of interleukin (IL)-6, IL-8, tumor necrosis factor (TNF)-alpha, and transforming growth factor (TGF)-beta in bronchoalveolar lavage fluid. Oxidative stress was evaluated by detecting the levels of reactive oxygen species (ROS), superoxide dismutase (SOD), total antioxidant capacity (T-AOC), and malondialdehyde (MDA) in lung tissue. The results indicated that Thal treatment remarkably attenuated pulmonary fibrosis, oxidative stress, and inflammation in mouse lungs. The antiinflammatory and antioxidant effects of Thal were also found in human lung fibroblasts. Thal administration significantly enhanced the activity of thioredoxin reductase; however, the other enzymes or proteins involved in biologic oxidation-reduction equilibrium were not affected. Our findings indicate that Thal-mediated suppression of pulmonary fibrosis is related to the inhibition of oxidative stress and inflammatory response. In summary, these results may provide a rationale to explore clinical application of Thal for the prevention of pulmonary fibrosis. PMID- 28730511 TI - Intermediate Molecular Mass Hyaluronan and CD44 Receptor Interactions Enhance Neutrophil Phagocytosis and IL-8 Production via p38- and ERK1/2-MAPK Signalling Pathways. AB - CD44 is a common leukocyte adhesion molecule expressed on the surface of various cells. Hyaluronan (HA), the natural ligand of CD44, is a simple repeated disaccharide with variable molecular mass that is widely distributed on cell surfaces and the connective tissue matrix. The binding of small molecular mass HA (SMM-HA, MW < 80 kDa) to CD44 on immune-related cells elicits cell proliferation, differentiation, and cytokine production. However, the effects and molecular basis of intermediate molecular mass HA (IMM-HA, MW ~ 500 kDa)-CD44 interactions on polymorphonuclear neutrophil (PMN) functions have not been elucidated. We hypothesised that IMM-HA would potentiate immune functions as well as SMM-HA. In the present study, we demonstrated IMM-HA and CD44 interactions enhanced normal PMN phagocytosis and IL-8 production compared to those with LPS or anti-CD45 treatment via F-actin cytoskeleton polymerization and subsequent ERK1/2- and p38 MAPK phosphorylation. Antibody-based inhibition of CD44 did not affect PMN function; however, F-actin aggregation was induced without MAPK phosphorylation. Enhanced PMN function via IMM-HA was determined to be CD44-dependent since this effect was abolished in DMSO-induced CD44(-) PMN-like cells obtained from HL-60 cells. In conclusion, we demonstrated that IMM-HA and CD44 interactions on PMNs potently elicit F-actin cytoskeleton polymerization and p38- and ERK1/2-MAPK phosphorylation to enhance PMN function. PMID- 28730513 TI - Element repetition rates encode functionally distinct information in pied babbler 'clucks' and 'purrs'. AB - Human language is a recombinant system that achieves its productivity through the combination of a limited set of sounds. Research investigating the evolutionary origin of this generative capacity has generally focused on the capacity of non human animals to combine different types of discrete sounds to encode new meaning, with less emphasis on meaning-differentiating mechanisms achieved through potentially simpler temporal modifications within a sequence of repeated sounds. Here we show that pied babblers (Turdoides bicolor) generate two functionally distinct vocalisations composed of the same sound type, which can only be distinguished by the number of repeated elements. Specifically, babblers produce extended 'purrs' composed of, on average, around 17 element repetitions when drawing young offspring to a food source and truncated 'clucks' composed of a fixed number of 2-3 elements when collectively mediating imminent changes in foraging site. We propose that meaning-differentiating temporal structuring might be a much more widespread combinatorial mechanism than currently recognised and is likely of particular value for species with limited vocal repertoires in order to increase their communicative output. PMID- 28730512 TI - NLRP3 Deletion Inhibits the Non-alcoholic Steatohepatitis Development and Inflammation in Kupffer Cells Induced by Palmitic Acid. AB - The cleavage and secretion of pro-inflammatory cytokines IL-1beta and IL-18 is regulated by NLRP3 (NACHT, LRR, and PYD domain-containing protein 3) inflammasome activation. Kupffer cells (KCs) are implicated in the pathogenesis of various liver diseases, such as non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease, and liver fibrosis. However, the role of NLRP3 played in the non alcoholic steatohepatitis (NASH) has yet to be evaluated. In the present study, methionine-choline-deficient (MCD) diet was used to establish the mice NASH model. The expression levels of F4/80 and NLRP3 in liver tissues were evaluated, and the IL-1beta and IL-18 in serum were also evaluated. KCs were isolated from wild-type (WT) mice and NLRP3 knockout (NLRP3-/-) mice and then randomly divided into two groups: the control and palmitic acid (PA) groups. The expression levels of NLRP3, ASC, and caspase-1 in KCs were determined by RT-PCR, western blotting, and immunofluorescence. The levels of IL-1beta and IL-18 in the supernatant (SN) of KCs were evaluated by enzyme-linked immunosorbent assay (ELISA). We found that KCs and NLRP3 play pro-inflammatory roles in the progression of NASH, probably through secretions of IL-1beta and IL-18 by KCs induced by PA. PA could act as a kind of damage-associated molecular patterns to elevate the messenger RNA and protein expression levels of NLRP3, ASC, and caspase-1 in KCs from WT mice. In the contrast, NLRP3 deletion could inhibit the NLRP3 inflammasome upregulation and activation in KCs induced by PA. Furthermore, the levels of pro-inflammatory cytokines IL-1beta and IL-18 in the SN of KCs from WT mice were all elevated with the stimulation of PA, and the increase of these cytokines in the SN was blocked by NLRP3 deletion. In conclusion, our novel findings demonstrate that NLRP3 plays a pivotal role in NASH development and pro-inflammatory cytokines IL-1beta and IL 18 secretion induced by PA stimulation, and NLRP3 might be an effective potential target for the treatment of liver inflammatory diseases associated with NLRP3 inflammasome activation. PMID- 28730514 TI - Fostering responsible research with genome editing technologies: a European perspective. AB - In this consensus paper resulting from a meeting that involved representatives from more than 20 European partners, we recommend the foundation of an expert group (European Steering Committee) to assess the potential benefits and draw backs of genome editing (off-targets, mosaicisms, etc.), and to design risk matrices and scenarios for a responsible use of this promising technology. In addition, this European steering committee will contribute in promoting an open debate on societal aspects prior to a translation into national and international legislation. PMID- 28730515 TI - Selective induction of DNA damage, G2 abrogation, and mitochondrial apoptosis by leaf extract of traditional medicinal plant Wrightia arborea in K562 cells. AB - Plants have proved to be an important source of anti-cancer drugs. Wrightia arborea, an Indian Ayurvedic medicinal plant, is used traditionally to treat a variety of ailments. This study evaluates the antiproliferative/apoptotic potential of Wrightia arborea leaf extracts, prepared in different organic solvents, on cancer cell lines. MTT assay, light and fluorescence microscopy, flow cytometry, DNA laddering, alkaline comet assay, and western blotting were some of the techniques used for evaluation. Combinations of camptothecin, either with CHK1 inhibitor-PD407824 or with W. arborea leaf extract, were deployed to determine the G2 abrogating potential of the extract. The chloroform extract (WAC) selectively killed K562 cells, without affecting cancerous MCF-7, Hep G2 cells, and normal human peripheral blood lymphocytes. Cell death was characterized by observation of apoptotic bodies, increased Ca2+ and ROS, phosphatidyl serine externalization, mitochondrial membrane depolarization, DNA laddering, increased sub-G1 population, and altered expression of caspase 3, -9, and PARP. WAC also induced DNA damage, alterations in key G2/M phase protein expression, cell cycle perturbation, and potent G2 abrogation. The present study showed that W. arborea leaf extract, WAC, is capable of selectively killing leukemic cancer cells leaving normal lymphocytes unaffected. Our results indicate that this is effectuated through DNA damage and G2 abrogation leading to mitochondrial apoptosis. Taken together, this report contributes toward a better understanding of the anticancer properties of this traditional medicinal plant extract possessing valuable bioactive constituents which can serve as a bioresource for promising complimentary/alternative/chemopreventive therapeutics. PMID- 28730516 TI - Cryptosporidium infection in children with cancer undergoing chemotherapy: how important is the prevention of opportunistic parasitic infections in patients with malignancies? AB - Cryptosporidiosis is a relatively uncommon disease in healthy individuals but could be potentially worrisome in immunocompromised patients. This study aimed to evaluate Cryptosporidium infection in children with cancer undergoing chemotherapy. A case-control study was conducted in 132 children with cancer undergoing chemotherapy and 132 non-cancer controls. The modified Ziehl-Neelsen (MZN) staining and polymerase chain reaction methods were used for the detection of Cryptosporidium parasite. All positive isolates were sequenced for phylogenetic analysis. Statistical analysis was performed using the SPSS version 16 and Fisher exact test. The rate of cryptosporidiosis in children with cancer undergoing chemotherapy was 3.8%, which was higher than that of the control group. Other intestinal parasites detected in patients with cancer included Giardia lamblia (3%), Entamoeba coli (1.5%), and Chilomastix mesnili (0.8%). In the control group, only two (1.5%) cases were positive for G. lamblia. No significant difference was observed between the gender, age, residency, contact with domestic animals, stool appearance, neutropenia, chemotherapy period, and type of malignancy with regard to cryptosporidiosis. Phylogenetic analysis revealed that Cryptosporidium parvum isolates in this study relied on a branch that represents similar sequences from Iran and other countries. Although the rate of Cryptosporidium infection was relatively higher in children with cancer undergoing chemotherapy compared to the control group, any statistically significant difference has not been found between them. These findings should not be contrary to the need for healthcare to prevent opportunistic parasitic infections in malignant and immunocompromised patients. PMID- 28730518 TI - The Case for Enrolling High-Cost Patients in an ACO. AB - Though accountable care organizations (ACOs) are increasingly important to American healthcare, ethical inquiry into ACOs remains in its nascent stages. Several articles have raised the concern that ACOs have an incentive to avoid enrolling high-cost patients and, thereby, have an incentive to deny care to those who need it the most. This concern is borne out by the reports of consultants working with newly formed ACOs. This paper argues that, contra initial appearances, there is no financial incentive for ACOs to avoid enrolling high-cost patients. PMID- 28730517 TI - Selective IgM Deficiency: Clinical and Laboratory Features of 17 Patients and a Review of the Literature. AB - PURPOSE: Primary selective IgM deficiency (sIgMD) is a primary immunodeficiency with unclear pathogenesis and a low number of published cases. METHODS: We reviewed clinical and laboratory manifestations of 17 sIgMD patients. Serum IgM, IgG, and its subclasses, IgA, IgE, antibodies against tetanus toxoid, pneumococcal polysaccharides and Haemophilus influenzae type b, isohemagglutinins, and T and B lymphocyte subsets, expressions of IgM on B cells and B lymphocyte production of IgM were compared with previously reported case reports and a small series of patients, which included 81 subjects in total. RESULTS: We found that some patients in our cohort (OC) and published cases (PC) had increased IgE levels (OC 7/15; PC 21/37), decreased IgG4 levels (OC 5/14), very low titers of isohemagglutinins (OC 8/8; PC 18/21), increased transitional B cell counts (OC 8/9), decreased marginal zone B cell counts (OC 8/9), and increased 21low B cell counts (OC 7/9). Compared with the PC (20/20), only two of five OC patients showed very low or undetectable production of IgM after stimulation. A majority of the patients had normal antibody production to protein and polysaccharide antigens, basic lymphocyte subset counts, and expression of surface IgM molecules on B cells. CONCLUSIONS: Low IgM levels are associated with various immunopathological disorders; however, pathogenic mechanisms leading to decreased IgM serum level in selective IgM deficiency remain unclear. Moreover, it is difficult to elucidate how strong these associations are and if these immunopathological conditions are primary or secondary. PMID- 28730519 TI - Left atrial appendage aneurysm presenting with chronic cough. PMID- 28730520 TI - A betabaculovirus DNA polymerase cannot substitute for the DNA polymerase of the alphabaculovirus Autographa californica nucleopolyhedrovirus. AB - DNA polymerase (DNApol) is present in all baculoviruses and plays a crucial role in viral DNA replication. Previously we showed that the DNApol of the alphabaculovirus group II Spodoptera litura nucleopolyhedrovirus (SpltNPV) could partially substitute for the DNApol of a group I alphabaculovirus, Autographa californica multiple nucleopolyhedrovirus (AcMNPV). However, it is not known if a betabaculovirus DNApol could subsititute for the alphabaculovirus DNApol in AcMNPV. In this report, DNApol of the betabaculovirus Pieris rapae granulovirus (PiraGV) was inserted into a dnapol-null AcMNPV bacmid, creating Bac AcDeltapol:PrPol. The repair virus did not spread to neighboring cells; virus growth curve and real-time PCR revealed that the PiraGV dnapol substitution abrogated AcMNPV DNA replication and virus production. Immunofluorescence microscopy showed that PiraGV DNApol could be expressed and localized to the nucleus. Collectively, our results suggested that the alphabaculovirus AcMNPV DNApol could not be replaced by a DNApol from the betabaculovirus, PiraGV. PMID- 28730521 TI - Complete genomic sequence of a duck enteritis virus attenuated via serial passage in chick embryos. AB - Here, we present the complete genomic sequence of an attenuated duck enteritis virus (DEV). The Chinese standard challenge strain of DEV (DEV CSC) was serially passaged 20 times in chick embryo fibroblasts and then 85 times in chick embryos. The virus was attenuated and was avirulent to 2-month-old ducks. The attenuated DEV genome is 162,131 base pairs (bp) in length and as long as the parental genomic sequence. There are only 22 nucleotide substitutions, resulting in single amino acid changes in open reading frames LORF5, LORF4, UL41, UL39, UL32, UL13, UL10, UL3, US3, US4 and US7. The genome sequence has been deposited in the GenBank database under accession number KU216226. This study provides genetic information about DEV attenuation and further advances our understanding of the molecular basis of DEV pathogenesis. PMID- 28730522 TI - Characterization of reassortant H1-subtype avian influenza viruses isolated from poultry in Zhejiang Province in China from 2013 to 2015. AB - From 2013 to 2015, 32 H1-subtype avian influenza viruses (AIVs), H1N2 (n = 12), H1N3 (n = 14), H1N4 (n = 4) and H1N9 (n = 2), were isolated from poultry in Zhejiang Province in eastern China. These strains were characterized by whole genome sequencing with subsequent phylogenetic analysis and genetic comparison. Phylogenetic analysis of all eight viral genes showed that these strains clustered in the AIV Eurasian lineage. These strains were found to be minimally pathogenic in mice and were able to replicate in mice without prior adaptation. Continued surveillance is needed, considering the important role of poultry in AIV reassortment. PMID- 28730523 TI - Antibody-dependent enhancement of serotype II feline enteric coronavirus infection in primary feline monocytes. AB - Feline coronavirus (FCoV) has been classified into two biotypes: avirulent feline coronavirus (feline enteric coronavirus: FECV) and virulent feline coronavirus (feline infectious peritonitis virus: FIPV). In FIPV infection, antibody dependent enhancement (ADE) has been reported and was shown to be associated with severe clinical disease. On the other hand, the potential role of ADE in FECV infection has not been examined. In this study, using laboratory strains of serotype II FIPV WSU 79-1146 (FIPV 79-1146) and serotype II FECV WSU 79-1683 (FECV 79-1683), we investigated the relationship between ADE and induction of inflammatory cytokines, which are pathogenesis-related factors, for each strain. As with ADE of FIPV 79-1146 infection, a monoclonal antibody against the spike protein of FCoV (mAb 6-4-2) enhanced FECV 79-1683 replication in U937 cells and primary feline monocytes. However, the ADE activity of FECV 79-1683 was lower than that of FIPV 79-1146. Moreover, mRNA levels of inflammatory cytokines (TNF alpha, IL-1beta, and IL-6) significantly increased with ADE of FIPV 79-1146 infection in primary feline monocytes, but FECV 79-1683 did not demonstrate an increase in these levels. In conclusion, infection of monocytes by FECV was enhanced by antibodies, but the efficiency of infection was lower than that of FIPV. PMID- 28730524 TI - Genetic characterization of novel reassortant H5N6-subtype influenza viruses isolated from cats in eastern China. AB - Cats are susceptible to influenza A viruses and therefore may act as transmission vectors within households, posing a potential public health concern. Two novel reassortant H5N6 influenza viruses were isolated from cats in Zhejiang Province, Eastern China, in 2016. Both viruses were characterized by whole-genome sequencing with subsequent phylogenetic analysis and genetic comparison. Phylogenetic analysis showed that these viruses received their genes from H5N6, H9N2, and H7N9 influenza viruses isolated from China. These H5N6 viruses were able to replicate in mice without prior adaptation. Our results show that continued circulation of these viruses could endanger humans. PMID- 28730526 TI - Direct Oral Anticoagulants Use in Antiphospholipid Syndrome: Are These Drugs an Effective and Safe Alternative to Warfarin? A Systematic Review of the Literature: Comment. AB - We respond to comments by Dufrost et al. about the RAPS trial, in particular, showing that the trial did achieve its target sample size; pointing out that thrombin potential is not synonymous with overall thrombin generation; confirming that overall, no increased thrombotic risk was evident comparing rivaroxaban with warfarin; and that high-risk patients (28% were triple positive, representative of patients with venous thromboembolism requiring standard-intensity anticoagulation) were included; and clarifying our rationale for using a laboratory surrogate primary outcome measure instead of a clinical one. PMID- 28730525 TI - Identification of a seed coat-specific promoter fragment from the Arabidopsis MUCILAGE-MODIFIED4 gene. AB - KEY MESSAGE: The Arabidopsis seed coat-specific promoter fragment described is an important tool for basic and applied research in Brassicaceae species. During differentiation, the epidermal cells of the Arabidopsis seed coat produce and secrete large quantities of mucilage. On hydration of mature seeds, this mucilage becomes easily accessible as it is extruded to form a tightly attached halo at the seed surface. Mucilage is composed mainly of pectin, and also contains the key cell wall components cellulose, hemicellulose, and proteins, making it a valuable model for studying numerous aspects of cell wall biology. Seed coat specific promoters are an important tool that can be used to assess the effects of expressing biosynthetic enzymes and diverse cell wall-modifying proteins on mucilage structure and function. Additionally, they can be used for production of easily accessible recombinant proteins of commercial interest. The MUCILAGE MODIFIED4 (MUM4) gene is expressed in a wide variety of plant tissues and is strongly up-regulated in the seed coat during mucilage synthesis, implying the presence of a seed coat-specific region in its promoter. Promoter deletion analysis facilitated isolation of a 308 base pair sequence (MUM4 0.3Pro ) that directs reporter gene expression in the seed coat cells of both Arabidopsis and Camelina sativa, and is regulated by the same transcription factor cascade as endogenous MUM4. Therefore, MUM4 0.3Pro is a promoter fragment that serves as a new tool for seed coat biology research. PMID- 28730527 TI - Characterization of the complete mitochondrial genome of Acanthoscelides obtectus (Coleoptera: Chrysomelidae: Bruchinae) with phylogenetic analysis. AB - Acanthoscelides obtectus is a common species of the subfamily Bruchinae and a worldwide-distributed seed-feeding beetle. The complete mitochondrial genome of A. obtectus is 16,130 bp in length with an A + T content of 76.4%. It contains a positive AT skew and a negative GC skew. The mitogenome of A. obtectus contains 13 protein-coding genes (PCGs), 22 tRNA genes, two rRNA genes and a non-coding region (D-loop). All PCGs start with an ATN codon, and seven (ND3, ATP6, COIII, ND3, ND4L, ND6, and Cytb) of them terminate with TAA, while the remaining five (COI, COII, ND1, ND4, and ND5) terminate with a single T, ATP8 terminates with TGA. Except tRNA Ser , the secondary structures of 21 tRNAs that can be folded into a typical clover-leaf structure were identified. The secondary structures of lrRNA and srRNA were also predicted in this study. There are six domains with 48 helices in lrRNA and three domains with 32 helices in srRNA. The control region of A. obtectus is 1354 bp in size with the highest A + T content (83.5%) in a mitochondrial gene. Thirteen PCGs in 19 species have been used to infer their phylogenetic relationships. Our results show that A. obtectus belongs to the family Chrysomelidae (subfamily-Bruchinae). This is the first study on phylogenetic analyses involving the mitochondrial genes of A. obtectus and could provide basic data for future studies of mitochondrial genome diversities and the evolution of related insect lineages. PMID- 28730528 TI - Sulforaphane Promotes Mitochondrial Protection in SH-SY5Y Cells Exposed to Hydrogen Peroxide by an Nrf2-Dependent Mechanism. AB - Sulforaphane (SFN; C6H11NOS2) is an isothiocyanate found in cruciferous vegetables, such as broccoli, kale, and radish. SFN exhibits antioxidant, anti apoptotic, anti-tumor, and anti-inflammatory activities in different cell types. However, it was not previously demonstrated whether and how this natural compound would exert mitochondrial protection experimentally. Therefore, we investigated here the effects of a pretreatment (for 30 min) with SFN at 5 MUM on mitochondria obtained from human neuroblastoma SH-SY5Y cells exposed to hydrogen peroxide (H2O2) at 300 MUM for 24 h. We found that SFN prevented loss of viability in H2O2 treated SH-SY5Y cells. Furthermore, SFN decreased lipid peroxidation, protein carbonylation, and protein nitration in mitochondrial membranes of H2O2-exposed cells. Importantly, SFN enhanced the levels of both cellular and mitochondrial glutathione (GSH). SFN also suppressed the H2O2-mediated inhibition of mitochondrial components involved in the maintenance of the bioenergetics state, such as aconitase, alpha-ketoglutarate dehydrogenase, and succinate dehydrogenase, as well as complexes I and V. Consequently, SFN prevented the decline induced by H2O2 on the levels of ATP in SH-SY5Y cells. Silencing of the nuclear factor erythroid 2-related factor 2 (Nrf2) transcription factor by using small interfering RNA (siRNA) abolished the mitochondrial and cellular protection elicited by SFN. Therefore, SFN abrogated the H2O2-induced mitochondrial impairment by an Nrf2-dependent manner. PMID- 28730530 TI - Spastic paretic hemifacial contracture related to multiple sclerosis: a rare and under-recognized entity. AB - We describe an additional case of spastic paretic hemifacial contracture, an uncommon condition characterized by sustained unilateral contraction of the facial muscles associated with mild ipsilateral facial paresis. This entity has only rarely been associated with multiple sclerosis (MS) and can be mistaken for hemifacial spasm. Early consideration of MS in the differential diagnosis of young patients admitted with these symptoms is essential. PMID- 28730529 TI - Role of the Golgi Apparatus in the Blood-Brain Barrier: Golgi Protection May Be a Targeted Therapy for Neurological Diseases. AB - The blood-brain barrier (BBB) protects the brain from toxic material in the blood, provides nutrients for brain tissues, and screens harmful substances from the brain. The specific brain microvascular endothelial cells (BMVECs), tight junction between endothelial cells, and astrocytes ensure proper function of the central nervous system (CNS). Pathological factors disrupt the integrity of the BBB by destroying the normal function of endothelial cells and decreasing the production of tight junction proteins or the expression of proteins specifically localized on astrocytes. Interestingly, fragmentation of the Golgi apparatus is observed in neurological diseases and is involved in the destruction of the BBB function. The Golgi acts as a processing center in which proteins are transported after being processed in the endoplasmic reticulum. Besides reprocessing, classifying, and packaging proteins, the Golgi apparatus (GA) also acts as a signaling platform and calcium pool. In this review, we summarized the current literature on the potential relationship between the Golgi and endothelial cells, tight junction, and astrocytes. The normal function of the BBB is maintained as long as the normal function and morphology of the GA are not disturbed. Furthermore, we speculate that protecting the Golgi may be a novel therapeutic approach to protect the BBB and treat neurological diseases due to BBB dysfunction. PMID- 28730533 TI - Capsule Commentary on Jackson et al., Tricyclic and Tetracyclic Antidepressants for the Prevention of Frequent Episodic or Chronic Tension-Type Headache in Adults: A Systematic Review and Meta-Analysis. PMID- 28730532 TI - Survey of primary care providers' knowledge of screening for, diagnosing and managing prediabetes. AB - BACKGROUND: Prediabetes affects 86 million US adults, but primary care providers' (PCPs') knowledge, practices, attitudes and beliefs toward prediabetes are unclear. OBJECTIVE: Assess PCPs' (1) knowledge of risk factors that should prompt prediabetes screening, laboratory criteria for diagnosing prediabetes and guidelines for management of prediabetes; (2) management practices around prediabetes; (3) attitudes and beliefs about prediabetes. DESIGN: Self administered written survey of PCPs. PARTICIPANTS: One hundred forty of 155 PCPs (90%) attending an annual provider retreat for academically affiliated multispecialty practices in the mid-Atlantic region. MAIN MEASURES: Descriptive analyses of survey questions on knowledge, management, and attitudes and beliefs related to prediabetes. Multivariate logistic regression was used to determine the association between provider characteristics (gender, race/ethnicity, years since training, specialty and provider type) and knowledge, management, and attitudes and beliefs about prediabetes. KEY RESULTS: Six percent of PCPs correctly identified all of the risk factors that should prompt prediabetes screening. Only 17% of PCPs correctly identified the laboratory parameters for diagnosing prediabetes based on both fasting glucose and hemoglobin A1c. Nearly 90% of PCPs reported close follow-up (within 6 months) of patients with prediabetes. Few PCPs (11%) selected referral to a behavioral weight loss program as the recommended initial management approach to prediabetes. PCPs agreed that patient-related factors are important barriers to lifestyle change and metformin use. Provider characteristics were generally not associated with knowledge, management, attitudes and beliefs about prediabetes in multivariate analyses. CONCLUSIONS: Addressing gaps in knowledge and the underutilization of behavioral weight loss programs in prediabetes are two essential areas where PCPs could take a lead in curbing the diabetes epidemic. PMID- 28730531 TI - Comparing different tissue-engineered repair materials for the treatment of pelvic organ prolapse and urinary incontinence: which material is better? AB - INTRODUCTION AND HYPOTHESIS: Synthetic non-absorbable meshes are widely used to augment surgical repair of pelvic organ prolapse (POP) and stress urinary incontinence (SUI), but these meshes are associated with serious complications. This study compares the attachment and extracellular matrix (ECM) production of adipose-derived stem cells (ADSCs) on different biodegradable nanomaterials to develop tissue engineered repair materials. METHODS: Rat ADSCs were isolated and cultured on electrospun poly-L-lactic acid (PLA) and electrospun poly(L-lactide) trimethylene carbonate-gycolide (PLTG) terpolymers for 1 and 2 weeks. Samples were tested for cell proliferation (cell counting kit-8), microstructure, and morphology (scanning electron microscopy), production of ECM components (immunostaining for collagen I, collagen III, and elastin) and biomechanical properties (uniaxial tensile methods). RESULTS: The ADSCs showed good attachment and proliferation on both PLA and PLTG scaffolds. The production of collagen I and collagen III on both scaffolds was greater at 14 days than at 7 days and was greater on PLTG scaffolds than on PLA scaffolds, but these differences were not significant. The addition of ADSCs onto scaffolds led to a significant increase in the biomechanical properties of both PLA and PLTG scaffolds compared with unseeded scaffolds. CONCLUSION: These data support the use of both PLA and PLTG as tissue-engineered repair materials for POP or SUI. PMID- 28730534 TI - Tracheal Cartilage Isolation and Decellularization. AB - Tissue decellularization allows isolation of tissue extracellular matrix components, enabling bioengineering of native tissue microenvironments with minimal antigenic components. Here we describe a method to harvest decellularized cartilage tissue from donor trachea using a series of chemical and enzymatic washes and incorporating the extracellular matrix in gelatin methacrylate hydrogels. This decellularized cartilage tissue is easily incorporated into a variety of hydrogels to create a cartilage tissue scaffold. PMID- 28730535 TI - The recomBead Borrelia antibody index, CXCL13 and total IgM index for laboratory diagnosis of Lyme neuroborreliosis in children. AB - For laboratory diagnostics of Lyme neuroborreliosis (LNB), the recomBead Borrelia antibody index (AI) assay has shown promising results in a mixed age population, but has not previously been evaluated with specific focus on paediatric patients. The aim of the study was to evaluate the recomBead Borrelia AI assay in cerebrospinal fluid (CSF) for the laboratory diagnosis of LNB in children. We also wanted to explore whether early markers, such as CXCL13 in CSF and/or total IgM index could be useful as complementary diagnostic tools. Children being evaluated for LNB in a Swedish Lyme endemic area were included in the study (n = 146). Serum and CSF were collected on admission. Patients with other specific diagnoses were controls (n = 15). The recomBead Borrelia AI assay and the recomBead CXCL13 assay (Mikrogen) were applied together with total IgM index. The overall sensitivity for recomBead Borrelia AI (IgM and IgG together) was 74% and the specificity was 97%. However, the highest sensitivity (91%) at an acceptable level of specificity (90%) was obtained by recomBead Borrelia AI together with CXCL13 and total IgM index, showing a positive predictive value of 84% and a negative predictive value of 95%. Thus, the recomBead Borrelia AI assay performs with moderate sensitivity and high specificity in paediatric LNB patients. The major advantage seems to be increased sensitivity in the possible LNB group compared to the IDEIA assay. The diagnostic sensitivity may be further increased by using a combination of early markers, such as CXCL13 in CSF and total IgM index. PMID- 28730536 TI - Effectiveness and feasibility of robotic gastric neurostimulator placement in patients with refractory gastroparesis. AB - Gastric neurostimulation (GNS) with Enterra(r) therapy device (Medtronic, Minneapolis, MN) appears as the last resort for patients with refractory gastroparesis. Currently, the device has Humanitarian Use status by Food and Drug Administration, thereby requiring further investigation. We aim to describe its feasibility and clinical outcomes using robotic technique. From June 2014 to September 2016, 15 consecutive patients underwent robotic insertion of Enterra(r) device. Patient demographics, comorbidities, and clinical outcomes including mortality, length of stay, readmission rates, reoperation and complications were retrospectively collected. Patients were also assessed based on a validated 14 point questionnaire regarding satisfaction with the operation, quality of life and symptomatic relief. Mean age was 41.6 years +/- 13.8 and there were 11 females (73.3%). No mortality was reported. The annual hospital admissions were reduced after GNS (2.5 +/- 4.1 vs. 3.6 +/- 4.4, p = 0.004). The frequency of bloating (p = 0.029) and severity of emesis (p = 0.038), early satiety (p = 0.042) and bloating (p = 0.031) were reduced after GNS. The severity and frequency total scores were also improved after GNS (12.6 +/- 1.4 vs. 18.1 +/- 2.7, p = 0.008 and 12.9 +/- 2.2 vs. 16.1 +/- 1.1, p = 0.016, respectively). This is the first report describing the clinical experience with robotic insertion of GNS device. This approach is safe and feasible and seems to have similar long term outcomes as laparoscopic technique. Potential advantages to robotic technique include enhanced dexterity and suturing of the device within gastric wall. Further experience with large prospective studies and randomized clinical trials may be warranted. PMID- 28730538 TI - Spectrum of lesions derived from branchial arches occurring in the thyroid: from solid cell nests to tumors. AB - There is a group of lesions in the head and neck region derived from branchial arches and related structures which, when inflamed, are characterized by the formation of cysts lined by squamous or glandular epithelium and surrounded by a heavy inflammatory infiltrate rich in germinal centers. In the thyroid, the main source of various structures which may cause diagnostic dilemma is the ultimobranchial body. To investigate the spectrum of such thyroid lesions, the consultation files were reviewed for thyroid samples containing pathological structures regarded to arise from the ultimobranchial body. Positive reaction with antibodies against CK5/6, p63, galectin 3, and CEA, and negative reaction with antibodies against thyroglobulin, TTF-1, and calcitonin were used to confirm the diagnosis. The specific subtype of the ultimobranchial body-derived lesion was then determined based on histological examination of H&E-stained slides. Twenty-one cases of ultimobranchial body-derived lesions were retrieved from the consultation files, 20 of them along with clinical information (M/F = 6/14, mean age 55 years, range 36-68 years). Lesions derived from the ultimobranchial body were classified as follows: (hyperplastic) solid cell nests (nine cases), solid cell nests with focal cystic change (five cases), cystic solid cell nests (two cases), branchial cleft-like cyst (four cases), and finally a peculiar Warthin tumor-like lesion (one case). We suggest that the common denominator of these structures is that they all arise due to activation of inflammatory cells around the vestigial structures, which leads to cystic dilatation and proliferation of the epithelial component. PMID- 28730539 TI - CORR Insights(r): Is the Clavicula Pro Humero Technique of Value for Reconstruction After Resection of the Proximal Humerus in Children? PMID- 28730537 TI - Lung cancer as a paradigm for precision oncology in solid tumours. AB - Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death in the western world. However, the combination of molecular genotyping and subsequent systematic treatment of decoded target structures is a prime example of precision oncology in solid tumours. In this review, current targets of approved therapeutics and potential targets in clinical and preclinical trials are outlined. Furthermore, immune checkpoint inhibitors, as promising new therapeutic options, which have already been applied successfully in cases of lung cancer, are introduced. A major issue of targeted treatment of lung tumours is the persistent development of resistance. The underlying mechanisms and established and potentially applicable alternative therapeutic approaches are described. In this process of precision oncology, immunohistochemistry, fluorescence in situ hybridization, and parallel sequencing are crucial diagnostic tools. PMID- 28730540 TI - Gigaspora margarita with and without its endobacterium shows adaptive responses to oxidative stress. AB - Arbuscular mycorrhizal (AM) fungi experience oxidative stress during the plant fungal interaction, due to endogenous reactive oxygen species (ROS) produced by fungal metabolism and exogenous ROS produced by plant cells. Here, we examine the responses to H2O2 in Gigaspora margarita, an AM fungus containing the endobacterial symbiont Candidatus Glomeribacter gigasporarum (CaGg). Previous studies revealed that G. margarita with its endobacterium produces more ATP and has higher respiratory activity than a cured line that lacks the endobacterium. This higher bioenergetic potential leads to higher production of ROS and to a higher ROS-detoxifying capacity, suggesting a direct or indirect role of the endobacterium in modulating fungal antioxidant responses. To test the hypothesis that the fungal-endobacterial symbiosis may enhance the fitness of the AM fungus in the presence of oxidative stress, we treated the fungus with a sublethal concentration of H2O2 and performed RNA-seq analysis. Our results demonstrate that (i) irrespective of the endobacterium presence, G. margarita faces oxidative stress by activating multiple metabolic processes (methionine oxidation, sulfur uptake, the pentose phosphate pathway, activation of ROS-scavenger genes); (ii) in the presence of its endobacterium, G. margarita upregulates some metabolic pathways, like chromatin status modifications and iron metabolism; and (iii) contrary to our hypothesis, the cured line responds to H2O2 by activating the transcription of specific ROS scavengers. We confirmed the RNA-seq findings by measuring the glutathione and ascorbate concentration, which was the same in both lines after H2O2 treatment. We conclude that both fungal lines may face oxidative stress, but they activate alternative strategies. PMID- 28730541 TI - Increased sequencing depth does not increase captured diversity of arbuscular mycorrhizal fungi. AB - The arrival of 454 sequencing represented a major breakthrough by allowing deeper sequencing of environmental samples than was possible with existing Sanger approaches. Illumina MiSeq provides a further increase in sequencing depth but shorter read length compared with 454 sequencing. We explored whether Illumina sequencing improves estimates of arbuscular mycorrhizal (AM) fungal richness in plant root samples, compared with 454 sequencing. We identified AM fungi in root samples by sequencing amplicons of the SSU rRNA gene with 454 and Illumina MiSeq paired-end sequencing. In addition, we sequenced metagenomic DNA without prior PCR amplification. Amplicon-based Illumina sequencing yielded two orders of magnitude higher sequencing depth per sample than 454 sequencing. Initial analysis with minimal quality control recorded five times higher AM fungal richness per sample with Illumina sequencing. Additional quality control of Illumina samples, including restriction of the marker region to the most variable amplicon fragment, revealed AM fungal richness values close to those produced by 454 sequencing. Furthermore, AM fungal richness estimates were not correlated with sequencing depth between 300 and 30,000 reads per sample, suggesting that the lower end of this range is sufficient for adequate description of AM fungal communities. By contrast, metagenomic Illumina sequencing yielded very few AM fungal reads and taxa and was dominated by plant DNA, suggesting that AM fungal DNA is present at prohibitively low abundance in colonised root samples. In conclusion, Illumina MiSeq sequencing yielded higher sequencing depth, but similar richness of AM fungi in root samples, compared with 454 sequencing. PMID- 28730542 TI - Physically Demanding Labor and Health Among Indigenous Women in the Ecuadorian Highlands. AB - Physically demanding work carried out during long workdays affects women's health. In rural and agrarian societies, women perform a variety of domestic and productive tasks, often from dawn to dusk, with little or no leisure time. This paper presents the results of a survey of indigenous women in six rural communities in the Ecuadorian highlands. It was conducted to measure the amount of time women spend on physically demanding work in the context of food security, parity outcomes, and access to prenatal health care. The findings demonstrate that these women work very long workdays and also experience food insecurity and poor access to prenatal health care. PMID- 28730543 TI - Method for Continuous Monitoring of Electrospray Ion Formation. AB - A method for continuously monitoring the performance of electrospray ionization without the addition of hardware or chemistry to the system is demonstrated. In the method, which we refer to as SprayDx, cluster ions with solvent vapor natively formed by electrospray are followed throughout the collection of liquid chromatography-selected reaction monitoring data. The cluster ion extracted ion chromatograms report on the consistency of the ion formation and detection system. The data collected by the SprayDx method resemble the data collected for postcolumn infusion of analyte. The response of the cluster ions monitored reports on changes in the physical parameters of the ion source such as voltage and gas flow. SprayDx is also observed to report on ion suppression in a fashion very similar to a postcolumn infusion of analyte. We anticipate the method finding utility as a continuous readout on the performance of electrospray and other atmospheric pressure ionization processes. Graphical Abstract ?. PMID- 28730544 TI - Sleep duration and cognitive impairment in older adults: response. PMID- 28730546 TI - Mammalian mitochondrial RNAs are degraded in the mitochondrial intermembrane space by RNASET2. AB - Mammalian mitochondrial genome encodes a small set of tRNAs, rRNAs, and mRNAs. The RNA synthesis process has been well characterized. How the RNAs are degraded, however, is poorly understood. It was long assumed that the degradation happens in the matrix where transcription and translation machineries reside. Here we show that contrary to the assumption, mammalian mitochondrial RNA degradation occurs in the mitochondrial intermembrane space (IMS) and the IMS-localized RNASET2 is the enzyme that degrades the RNAs. This provides a new paradigm for understanding mitochondrial RNA metabolism and transport. PMID- 28730548 TI - Orthopedic infections caused by obligatory anaerobic Gram-negative rods: report of two cases. AB - Anaerobic bone and joint infections are uncommon, although the number of anaerobic infections is presumably underestimated because of difficulties with isolation and identification of obligate anaerobes. This study describes two cases of complicated Bacteroides fragilis peri-implant infection of the lumbar spine, infection of the hip and osteomyelitis. Bacteria were identified with the use of a mass spectrometer, VITEK MS system. Drug susceptibility was performed with the use of E-test. The EUCAST breakpoints were used for interpretation with B. fragilis ATCC 25285 as a control. In the two described cases clinical samples were collected for microbiological examination intraoperatively and simultaneously empirical treatment was applied. B. fragilis was isolated in monoculture or in a combination with other bacteria. The treatment was continued according to the susceptibility tests. In a case one clindamycin failure was observed and clindamycin resistance of the isolate was likely due to inadequate time of therapy. Difficulties in collecting an adequate samples and culturing anaerobic bacteria cause that not all infections are properly recognized. In a successful therapy, identification and determination of the susceptibility of the pathogen are essential as well as an appropriate surgical debridement. PMID- 28730547 TI - Sideways fall-induced impact force and its effect on hip fracture risk: a review. AB - : Osteoporotic hip fracture, mostly induced in falls among the elderly, is a major health burden over the world. The impact force applied to the hip is an important factor in determining the risk of hip fracture. However, biomechanical researches have yielded conflicting conclusions about whether the fall-induced impact force can be accurately predicted by the available models. It also has been debated whether or not the effect of impact force has been considered appropriately in hip fracture risk assessment tools. This study aimed to provide a state-of-the-art review of the available methods for predicting the impact force, investigate their strengths/limitations, and suggest further improvements in modeling of human body falling. METHODS: We divided the effective parameters on impact force to two categories: (1) the parameters that can be determined subject-specifically and (2) the parameters that may significantly vary from fall to fall for an individual and cannot be considered subject-specifically. RESULTS: The parameters in the first category can be investigated in human body fall experiments. Video capture of real-life falls was reported as a valuable method to investigate the parameters in the second category that significantly affect the impact force and cannot be determined in human body fall experiments. CONCLUSIONS: The analysis of the gathered data revealed that there is a need to develop modified biomechanical models for more accurate prediction of the impact force and appropriately adopt them in hip fracture risk assessment tools in order to achieve a better precision in identifying high-risk patients. Graphical abstract Impact force to the hip induced in sideways falls is affected by many parameters and may remarkably vary from subject to subject. PMID- 28730549 TI - Creation and Curation of the Society of Imaging Informatics in Medicine Hackathon Dataset. AB - In order to support innovation, the Society of Imaging Informatics in Medicine (SIIM) elected to create a collaborative computing experience called a "hackathon." The SIIM Hackathon has always consisted of two components, the event itself and the infrastructure and resources provided to the participants. In 2014, SIIM provided a collection of servers to participants during the annual meeting. After initial server setup, it was clear that clinical and imaging "test" data were also needed in order to create useful applications. We outline the goals, thought process, and execution behind the creation and maintenance of the clinical and imaging data used to create DICOM and FHIR Hackathon resources. PMID- 28730550 TI - Disease management of tomato through PGPB: current trends and future perspective. AB - Tomato is the world's second most cultivated vegetable. During cultivation or post-harvest storage, it is susceptible to more than 200 diseases caused by an array of pathogenic fungi, nematodes, bacteria, and viruses. Although wide range of chemical pesticides are currently available to manage plant diseases, continuous application of pesticides not only affect the nutritional contents of tomato but also the texture or productivity of soil. In this context, plant growth promoting bacteria (PGPB) are one of the nature friendly, safe, and effective alternatives for the management of diseases and pathogens of tomato. Currently, numbers of microbes have been used as soil or plant inoculants in different plants including tomato as biocontrol. Besides disease inhibition, these inoculants also act as growth modulators. The present article describes the biocontrol potential of PGPB strains and mechanisms for the diseases management in tomato. PMID- 28730551 TI - Pseudomonas fluorescens R68 assisted enhancement in growth and fertilizer utilization of Amaranthus tricolor (L.). AB - Plant probiotic potential of rhizosphere microbiome and its role in phytofertilizer mobilization are largely unexplored. In the current study, the rhizobacterium Pseudomonas fluorescens R68 (PFR68) isolated from Western Ghat was analyzed for its growth enhancement effect on the leafy vegetable Amaranthus tricolor (L.). One month of field growth of PFR68 inoculated A. tricolor has found to have enhanced growth parameters such as leaf number (1.57 fold), root number (1.76 fold), shoot length (1.28 fold) and fresh weight (2.31 fold). The treatment also improved soil fertility in terms of Nitrogen, Phosphorus and Potassium content. Most remarkably, application of PFR68 alone and 50% of recommended NPK dose along with PFR68 has resulted in enhanced growth of A. tricolor comparable to plants treated with full dose of NPK. In addition to this, application of PFR68 along with 50% NPK augmented the available Nitrogen and Phosphorus content in soil. This indicates the potential of selected organism in enrichment of soil health and enhancement of crop productivity. In conclusion, field performance of PFR68 on growth of A. tricolor confirms its promises to develop into plant probiotic formulation. PMID- 28730545 TI - Platelet "first responders" in wound response, cancer, and metastasis. AB - Platelets serve as "first responders" during normal wounding and homeostasis. Arising from bone marrow stem cell lineage megakaryocytes, anucleate platelets can influence inflammation and immune regulation. Biophysically, platelets are optimized due to size and discoid morphology to distribute near vessel walls, monitor vascular integrity, and initiate quick responses to vascular lesions. Adhesion receptors linked to a highly reactive filopodia-generating cytoskeleton maximizes their vascular surface contact allowing rapid response capabilities. Functionally, platelets normally initiate rapid clotting, vasoconstriction, inflammation, and wound biology that leads to sterilization, tissue repair, and resolution. Platelets also are among the first to sense, phagocytize, decorate, or react to pathogens in the circulation. These platelet first responder properties are commandeered during chronic inflammation, cancer progression, and metastasis. Leaky or inflammatory reaction blood vessel genesis during carcinogenesis provides opportunities for platelet invasion into tumors. Cancer is thought of as a non-healing or chronic wound that can be actively aided by platelet mitogenic properties to stimulate tumor growth. This growth ultimately outstrips circulatory support leads to angiogenesis and intravasation of tumor cells into the blood stream. Circulating tumor cells reengage additional platelets, which facilitates tumor cell adhesion, arrest and extravasation, and metastasis. This process, along with the hypercoagulable states associated with malignancy, is amplified by IL6 production in tumors that stimulate liver thrombopoietin production and elevates circulating platelet numbers by thrombopoiesis in the bone marrow. These complex interactions and the "first responder" role of platelets during diverse physiologic stresses provide a useful therapeutic target that deserves further exploration. PMID- 28730552 TI - The Usefulness of Patch Repair Using the Repermeabilized Umbilical Vein of the Round Ligament for Hepatobiliary Malignancies. AB - BACKGROUND: Patients with tumors invading major veins may require combined resection and reconstruction. However, venous reconstruction often demands complex hepatobiliary and vascular surgical procedures. In this study, we report a simple patch repair technique for venous reconstruction using the repermeabilized umbilical vein of the round ligament. METHODS: We reviewed the outcomes of eleven patients who underwent venous wedge resection and patch repair using the repermeabilized umbilical vein of the round ligament at our institution. RESULTS: Procurement of the round ligament and method of making a patch is simple. The duration of anastomosis was approximately 15 min. Eight patients (73%) underwent hepatic resection followed by hepatic vein reconstruction; two (18%) pancreaticoduodenectomy followed by inferior vena cava (IVC) reconstruction; one (9%) hepatic resection followed by IVC reconstruction. Although one reconstructed vein became narrowed, the other ten veins were patent after surgery. CONCLUSIONS: Patch repair using the repermeabilized umbilical vein of the round ligament is a simple and useful technique. PMID- 28730553 TI - Younger Age is an Independent Factor for Graft Weight Overestimation: Analysis of the Clinical Impact on Recipient Outcomes in 340 Japanese Living Liver Donors. AB - BACKGROUND: Accurate preoperative estimation of graft weight is essential for improving outcomes in living donor liver transplantation. METHODS: This retrospective study sought to identify factors associated with graft weight overestimation. From April 2006 to August 2015, 340 living donors were assigned to no-overestimate (n = 284) or overestimate (n = 56) groups. We defined graft weight overestimation as a discrepancy >=15% between estimated graft volume and actual graft weight. Donor data were compared, and associated factors for graft weight overestimation were analyzed. Recipient outcomes were compared between the groups according to identified factors. RESULTS: Donors were significantly younger in the overestimate group than in the no-overestimate group (35.0 vs. 46.0 years; p < 0.001). Multivariate analysis identified donor age <45 years as an independent risk factor for graft weight overestimation (odds ratio 2.068; 95% confidence interval 1.114-3.839; p = 0.021). Among recipients with donors <45 years (n = 168), incidence of small-for-size dysfunction (SFSD) was significantly higher in the overestimate group than in the no-overestimate group (7/37 patients vs. 7/131 patients; p = 0.016); no significant difference was observed among recipients with donors >=45 years (n = 172). First-year mortality was lower in SFSD recipients with donors <45 years (14.3 vs. 60.9%, p = 0.007). Among recipients with younger donors, graft survival was not significantly different between overestimate and no-overestimate groups. CONCLUSIONS: Younger donor age was an independent risk factor for graft weight overestimation leading to SFSD in recipients, but did not impair graft survival. PMID- 28730554 TI - Bedside selection of positive end-expiratory pressure by electrical impedance tomography in hypoxemic patients: a feasibility study. AB - BACKGROUND: Positive end-expiratory pressure (PEEP) is a key element of mechanical ventilation. It should optimize recruitment, without causing excessive overdistension, but controversy exists on the best method to set it. The purpose of the study was to test the feasibility of setting PEEP with electrical impedance tomography in order to prevent lung de-recruitment following a recruitment maneuver. We enrolled 16 patients undergoing mechanical ventilation with PaO2/FiO2 <300 mmHg. In all patients, under constant tidal volume (6-8 ml/kg) PEEP was set based on the PEEP/FiO2 table proposed by the ARDS network (PEEPARDSnet). We performed a recruitment maneuver and monitored the end expiratory lung impedance (EELI) over 10 min. If the EELI signal decreased during this period, the recruitment maneuver was repeated and PEEP increased by 2 cmH2O. This procedure was repeated until the EELI maintained a stability over time (PEEPEIT). RESULTS: The procedure was feasible in 87% patients. PEEPEIT was higher than PEEPARDSnet (13 +/- 3 vs. 9 +/- 2 cmH2O, p < 0.001). PaO2/FiO2 improved during PEEPEIT and driving pressure decreased. Recruited volume correlated with the decrease in driving pressure but not with oxygenation improvement. Finally, regional alveolar hyperdistention and collapse was reduced in dependent lung layers and increased in non-dependent lung layers. CONCLUSIONS: In hypoxemic patients, a PEEP selection strategy aimed at stabilizing alveolar recruitment guided by EIT at the bedside was feasible and safe. This strategy led, in comparison with the ARDSnet table, to higher PEEP, improved oxygenation and reduced driving pressure, allowing to estimate the relative weight of overdistension and recruitment. PMID- 28730555 TI - Intermittent versus continuous renal replacement therapy in acute methanol poisoning: comparison of clinical effectiveness in mass poisoning outbreaks. AB - BACKGROUND: Intermittent hemodialysis (IHD) is the modality of choice in the extracorporeal treatment (ECTR) of acute methanol poisoning. However, the comparative clinical effectiveness of intermittent versus continuous modalities (CRRT) is unknown. During an outbreak of mass methanol poisoning, we therefore studied the effect of IHD versus CRRT on mortality and the prevalence of visual/central nervous system (CNS) sequelae in survivors. METHODS: The study was designed as prospective observational cohort study. Patients hospitalized with a diagnosis of acute methanol poisoning were identified for the study. Exploratory factor analysis and multivariate logistic regression were applied to determine the effect of ECTR modality on the outcome. RESULTS: Data were obtained from 41 patients treated with IHD and 40 patients with CRRT. The follow-up time in survivors was two years. Both groups of patients were comparable by age, time to presentation, laboratory data, clinical features, and other treatment applied. The CRRT group was more acidemic (arterial blood pH 6.96 +/- 0.08 vs. 7.17 +/- 0.07; p < 0.001) and more severely poisoned (25/40 vs. 9/41 patients with Glasgow Coma Scale (GCS) <= 8; p < 0.001). The median intensive care unit length of stay (4 (range 1-16) days vs. 4 (1-22) days; p = 0.703) and the number of patients with complications during the treatment (11/41 vs. 13/40 patients; p = 0.576) did not differ between the groups. The mortality was higher in the CRRT group (15/40 vs. 5/41; p = 0.008). The number of survivors without sequelae of poisoning was higher in the IHD group (23/41 vs. 10/40; p = 0.004). There was a significant association of ECTR modality with both mortality and the number of survivors with visual and CNS sequelae of poisoning, but this association was not present after adjustment for arterial blood pH and GCS on admission (all p > 0.05). CONCLUSIONS: In spite of the faster correction of the acidosis and the quicker removal of the toxic metabolite in intermittent dialysis, we did not find significant differences in the treatment outcomes between the two groups after adjusting for the degree of acidemia and the severity of poisoning on admission. These findings support the strategy of "use what you have" in situations with large outbreaks and limited dialysis capacity. PMID- 28730557 TI - Extrinsic Religious Orientation and Disordered Eating Pathology Among Modern Orthodox Israeli Adolescents: The Mediating Role of Adherence to the Superwoman Ideal and Body Dissatisfaction. AB - The role of religious and spiritual factors has been recognized with regard to risk factors for disordered eating pathology (DEP). Specifically, religious orientation, or underlying religious motivation, has been associated with DEP among a variety of religious groups. Extrinsic religious orientation has consistently been found to be associated with increased levels of DEP among Christians and Jews in the USA. However, this paradigm has not been investigated cross-culturally. The current study is the first to examine the association of extrinsic religious orientation and DEP among Modern Orthodox Israeli adolescents. Furthermore, the mediating mechanisms of adherence to the Superwoman Ideal and body dissatisfaction are explored to further elucidate the mechanisms generating the association between religious orientation and DEP. A sample of 120 Modern Orthodox Israeli adolescent females participated in an anonymous survey which asked about DEP, body dissatisfaction, adherence to the Superwoman Ideal and religious orientation. Mediation models revealed a significant association between extrinsic religious orientation and DEP. Furthermore, adherence to the Superwoman Ideal and body dissatisfaction serially mediated the association between religious orientation and DEP. Findings suggest that a pathway through which extrinsic orientation influences DEP is through greater adherence to the Superwoman Ideal which leads to higher levels of body dissatisfaction, which is known to be a proximal risk factor for DEP. This finding is discussed in light of specific cultural pressures within the Modern Orthodox population and related clinical implications. PMID- 28730556 TI - Stem Cell Derived Retinal Pigment Epithelium: The Role of Pigmentation as Maturation Marker and Gene Expression Profile Comparison with Human Endogenous Retinal Pigment Epithelium. AB - In age-related macular degeneration (AMD) the retinal pigment epithelium (RPE) deteriorates, leading to photoreceptor decay and severe vision loss. New therapeutic strategies aim at RPE replacement by transplantation of pluripotent stem cell (PSC)-derived RPE. Several protocols to generate RPE have been developed where appearance of pigmentation is commonly used as indicator of RPE differentiation and maturation. It is, however, unclear how different pigmentation stages reflect developmental stages and functionality of PSC-derived RPE cells. We generated human embryonic stem cell-derived RPE (hESC-RPE) cells and investigated their gene expression profiles at early pigmentation (EP) and late pigmentation (LP) stages. In addition, we compared the hESC-RPE samples with human endogenous RPE. We used a common reference design microarray (44 K). Our analysis showed that maturing hESC-RPE, upon acquiring pigmentation, expresses markers specific for human RPE. Interestingly, our analysis revealed that EP and LP hESC-RPE do not differ much in gene expression. Our data further showed that pigmented hESC-RPE has a significant lower expression than human endogenous RPE in the visual cycle and oxidative stress pathways. In contrast, we observed a significantly higher expression of pathways related to the process adhesion-to polarity model that is typical of developing epithelial cells. We conclude that, in vitro, the first appearance of pigmentation hallmarks differentiated RPE. However, further increase in pigmentation does not result in much significant gene expression changes and does not add important RPE functionalities. Consequently, our results suggest that the time span for obtaining differentiated hESC-RPE cells, that are suitable for transplantation, may be greatly reduced. PMID- 28730558 TI - Transplantation sites for porcine islets. AB - AIMS/HYPOTHESIS: Xenotransplantation has great potential to provide beta cell replacement and thereby provide a cure for large numbers of people with type 1 diabetes. Crucial to the success of xenotransplantation is establishment of the most viable sites for transplantation. METHODS: We compared porcine islet tissue transplanted into kidney, liver and spleen in pig recipients as assessed by blood glucose levels and IVGTT. RESULTS: Kidney was the superior site for porcine islet tissue transplantation, followed by liver then spleen. This was demonstrated by IVGTTs showing significant difference between the peak glucose levels: 22.8 +/- 2.9 mmol/l for kidney compared with 26.8 +/- 1.3 mmol/l for spleen and 24.7 +/- 1.7 mmol/l for liver. CONCLUSIONS/INTERPRETATION: Kidney grafts are not as feasible in humans and liver results were relatively poorer than spleen. For islet transplantation to be viable and successful in the longer term, there remains a need for future investigation of alternative sites. PMID- 28730559 TI - Fathers Know Best: Inner-City African American Fathers' Perceptions Regarding Their Involvement in the Pediatric Medical Home. AB - OBJECTIVE: Despite nearly three in four African American (AA) children being born to unwed mothers, AA fathers maintain relatively high levels of parenting engagement, whether or not they live with their children. While father involvement correlates with decreased adverse child health outcomes, the nature of AA father involvement in child health-including engagement in the pediatric medical home-remains largely unexplored. Our study aimed to assess perceptions of pediatric medical home participation among a cohort of urban, AA fathers. METHODS: Group level assessments (GLA; N = 17) were conducted among AA fathers in an urban, Midwestern neighborhood to examine perceptions regarding pediatric medical home involvement. Study participants generated themes based on GLA responses, and study staff used grounded theory as a framework for qualitative analysis of thematic data. RESULTS: Fathers desired to have their parental role acknowledged by mothers and pediatricians. They perceived unrecognized parenting strengths, including being role models, teachers, and providers for their children. Respondents endorsed uncertainty navigating the pediatric health care system, unawareness of their children's pediatric appointments, and feeling excluded from health care decision-making by their children's mothers and pediatric providers. CONCLUSIONS: In our cohort, AA fathers have a strong desire to be involved in their children's healthy development, but feel marginalized in their parenting role. AA fathers want improved communication with physicians and their children's mothers and to be actively included in health care decision making. Enhanced efforts to engage fathers in the pediatric medical home may lead to improved health outcomes and reduced disparities for minority children. PMID- 28730560 TI - Impairment of ntcA gene revealed its role in regulating iron homeostasis, ROS production and cellular phenotype under iron deficiency in cyanobacterium Anabaena sp. PCC 7120. AB - Iron deficiency ends up into several unavoidable consequences including damaging oxidative stress in cyanobacteria. NtcA is a global nitrogen regulator controls wide range of metabolisms in addition to regulation of nitrogen metabolism. In present communication, NtcA based regulation of iron homeostasis, ROS production and cellular phenotype under iron deficiency in Anabaena 7120 has been investigated. NtcA regulates the concentration dependent iron uptake by controlling the expression of furA gene. NtcA also regulated pigment synthesis and phenotypic alterations in Anabaena 7120. A significant increase in ROS production and corresponding reduction in the activities of antioxidative enzymes (SOD, CAT, APX and GR) in CSE2 mutant strain in contrast to wild type Anabaena 7120 also suggested the possible involvement of NtcA in protection against oxidative stress in iron deficiency. NtcA has no impact on the expression of furB and furC in spite of presence of consensus NtcA binding site (NBS) and -10 boxes in their promoter. NtcA also regulates the thylakoid arrangement as well as related photosynthetic and respiration rates under iron deficiency in Anabaena 7120. Overall results suggested that NtcA regulates iron acquisition and in turn protect Anabaena cells from the damaging effects of oxidative stress induced under iron deficiency. PMID- 28730561 TI - Men Experience Higher Risk of Pneumonia and Death After Intracerebral Hemorrhage. AB - BACKGROUND: Infectious complications worsen outcome after intracerebral hemorrhage (ICH). We investigated the impact of sex on post-ICH infections and mortality. METHODS: Consecutive ICH patients (admitted to a single hospital between 1994 and 2015) were retrospectively assessed via chart review to ascertain the following in-hospital infections: urinary tract infection (UTI), pneumonia, and sepsis. Adjusted logistic regression was performed to identify associations between sex, infection, and mortality at 90 days. RESULTS: Two thousand and four patients were investigated, 1071 (53.7%) males. Men were more likely to develop pneumonia (21.9 vs 15.5% p < 0.001) and sepsis (3.4 vs 1.6%, p = 0.009), whereas women had higher risk of UTI (19.9 vs 11.7% p < 0.001). Multivariate analyses confirmed association between male sex and pneumonia (Odds Ratio (OR) 1.37, 95% confidence interval (CI) 1.08-1.74, p = 0.011). Male sex (OR 1.40; CI 1.07-1.85; p = 0.015) and infection (OR 1.56; CI 1.11-1.85; p = 0.011) were independently associated with higher 90-day mortality. CONCLUSIONS: Types and rates of infection following ICH differ by sex. Male sex independently increases pneumonia risk, which subsequently increases 90-day mortality. Sex specific preventive strategies to reduce the risk of these complications may be one strategy to improve ICH outcomes. PMID- 28730563 TI - Functional connectivity and cognitive impairment in migraine with and without aura. AB - BACKGROUND: Several fMRI studies in migraine assessed resting state functional connectivity in different networks suggesting that this neurological condition was associated with brain functional alteration. The aim of present study was to explore the association between cognitive functions and cerebral functional connectivity, in default mode network, in migraine patients without and with aura, during interictal episodic attack. METHODS: Twenty-eight migraine patients (14 without and 14 with aura) and 14 matched normal controls, were consecutively recruited. A battery of standardized neuropsychological test was administered to evaluate cognitive functions and all subjects underwent a resting state with high field fMRI examination. RESULTS: Migraine patients did not show abnormalities in neuropsychological evaluation, while, we found a specific alteration in cortical network, if we compared migraine with and without aura. We observed, in migraine with aura, an increased connectivity in left angular gyrus, left supramarginal gyrus, right precentral gyrus, right postcentral gyrus, right insular cortex. CONCLUSION: Our findings showed in migraine patients an alteration in functional connectivity architecture. We think that our results could be useful to better understand migraine pathogenesis. PMID- 28730565 TI - Landmark and longitudinal exposure-response analyses in drug development. PMID- 28730564 TI - A new approach to assess occupational exposure to airborne fungal contamination and mycotoxins of forklift drivers in waste sorting facilities. AB - The waste management industry is an important employer, and exposure of waste handling workers to microorganisms is considered an occupational health problem. Besides fungal contamination, it is important to consider the co-occurrence of mycotoxins in this setting. Forklifts with closed cabinet and air conditioner are commonly used in waste industry to transport waste and other products within the facilities, possibly increasing the risk of exposure under certain conditions. The aim of this study was to assess the fungal contamination and mycotoxin levels in filters from the air conditioning system of forklift cabinets, as an indicator to assess occupational exposure of the drivers working in a waste sorting facility. Cytotoxicity was also assessed to understand and characterize the toxicity of the complex mixtures as present in the forklift filters. Aqueous extracts of filters from 11 vehicles were streaked onto 2% malt extract agar (MEA) with chloramphenicol (0.05 g/L) media, and in dichloran glycerol (DG18) agar-based media for morphological identification of the mycobiota. Real-time quantitative PCR amplification of genes from Aspergillus sections Fumigati, Flavi, Circumdati, and Versicolores was also performed. Mycotoxins were analyzed using LC-MS/MS system. Cytotoxicity of filter extracts was analyzed by using a MTT cell culture test. Aspergillus species were found most frequently, namely Aspergillus sections Circumdati (MEA 48%; DG18 41%) and Nigri (MEA 32%; DG18 17.3%). By qPCR, only Aspergillus section Fumigati species were found, but positive results were obtained for all assessed filters. No mycotoxins were detected in aqueous filter extracts, but most extracts were highly cytotoxic (n = 6) or medium cytotoxic (n = 4). Although filter service life and cytotoxicity were not clearly correlated, the results suggest that observing air conditioner filter replacement frequency may be a critical aspect to avoid worker's exposure. Further research is required to check if the environmental conditions as present in the filters could allow the production of mycotoxins and their dissemination in the cabinet during the normal use of the vehicles. PMID- 28730562 TI - Therapeutical approaches to paroxysmal hemicrania, hemicrania continua and short lasting unilateral neuralgiform headache attacks: a critical appraisal. AB - BACKGROUND: Hemicrania continua (HC), paroxysmal hemicrania (PH) and short lasting neuralgiform headache attacks (SUNCT and SUNA) are rare syndromes with a difficult therapeutic approach. The aim of this review is to summarize all articles dealing with treatments for HC, PH, SUNCT and SUNA, comparing them in terms of effectiveness and safety. METHODS: A survey was performed using the pubmed database for documents published from the 1st January 1989 onwards. All types of articles were considered, those ones dealing with symptomatic cases and non-English written ones were excluded. RESULTS: Indomethacin is the best treatment both for HC and PH. For the acute treatment of HC, piroxicam and celecoxib have shown good results, whilst for the prolonged treatment celecoxib, topiramate and gabapentin are good options besides indomethacin. For PH the best drug besides indomethacin is piroxicam, both for acute and prolonged treatment. For SUNCT and SUNA the most effective treatments are intravenous or subcutaneous lidocaine for the acute treatment of active phases and lamotrigine for the their prevention. Other effective therapeutic options are intravenous steroids for acute treatment and topiramate for prolonged treatment. Non-pharmacological techniques have shown good results in SUNCT and SUNA but, since they have been tried on a small number of patients, the reliability of their efficacy is poor and their safety profile mostly unknown. CONCLUSIONS: Besides a great number of treatments tried, HC, PH, SUNCT and SUNA management remains difficult, according with their unknown pathogenesis and their rarity, which strongly limits the studies upon these conditions. Further studies are needed to better define the treatment of choice for these conditions. PMID- 28730566 TI - Acute esophageal necrosis (black esophagus): a case report and literature review. PMID- 28730567 TI - Kidney disease measures are associated with the burden of coronary atherosclerosis, independently of diabetes. PMID- 28730568 TI - Anemia: an independent risk factor of diabetic peripheral neuropathy in type 2 diabetic patients. AB - AIMS: Recently, the association between anemia and diabetic microvascular complications has been studied. Diabetic peripheral neuropathy (DPN) is also a common complication of type 2 diabetes mellitus (T2DM), while the relationship between anemia and DPN is rarely investigated. The aim of this study is to evaluate the association between anemia and DPN in T2DM. METHODS: In this cross sectional study, 1134 T2DM inpatients were enrolled. The diagnosis of DPN was based on neuropathy system score (NSS) and neuropathy disability score (NDS). Logistic regression was conducted to analyze the association between anemia and DPN. RESULTS: The proportions of anemia in DPN and non-DPN group were 25.4 and 15.2%, respectively. Compared with non-anemia group, the proportions of moderate/severe NSS (42.7 vs. 24.5%, P < 0.001) and moderate/severe NDS (51.5 vs. 38.0%, P < 0.001) were higher while the nerve conduction velocity (NCV) was lower in anemia group. Univariate logistic regression analysis showed patients with anemia possessed an increased risk of DPN [OR = 1.906, 95%CI: 1.416, 2.567, P < 0.001]. Multivariate logistic regression analysis suggested anemia was an independent risk factor of DPN in model 1 and model 2 [model 1: OR = 1.472, 95%CI: 1.047, 2.070, P = 0.026; model 2: OR = 1.448, 95%CI: 1.013, 2.071, P = 0.043]. CONCLUSIONS: Anemia is an independent risk factor of DPN in T2DM patients. PMID- 28730569 TI - Immune Escape Mechanism is Impaired in the Microenvironment of Thyroid Lymph Node Metastasis. AB - We previously identified the infiltration of CD8+ lymphocytes and COX2 expression as an independent factor of risk for recurrence in papillary thyroid carcinoma (PTC) patients. However, the presence of lymph node (LN) metastasis at diagnosis lost its significance in a multivariate model analysis. These results encouraged us to compare the immune cells arrangement in the microenvironment of the LN metastasis and the primary tumor. We studied 104 consecutive PTC patients. Tissue specimens of both primary tumor and LN metastasis at the time of diagnosis were available in 19 out of them. These 19 patients were followed up for 32 to 81 months (64.7 +/- 47.5 months). Immune cell markers were investigated using immunohistochemistry and included tumor infiltrating lymphocytes subsets such as CD3, CD4, CD8, CD16, CD20, CD45RO, GRANZYME B, CD69, and CD25. We also investigated the expression of COX2 in tumor cells. Paired t test showed an increase of GRANZYME-B+ lymphocytes density in LN metastasis compared to the corresponding primary tumor, suggesting that LN metastasis is enriched with activated immune cells. In addition, we observed a decrease in COX2 expression levels in LN metastasis compared to the corresponding primary tumors, reinforcing the idea that the immune escape mechanism is impaired in the microenvironment of thyroid LN metastasis. In conclusion, our data demonstrated that the microenvironment of PTC LN metastasis present features that favor an anti-tumor immune response. This may help to explain why the presence of LN metastasis at diagnosis is not a good predictor of PTC patients' survival or disease progression. PMID- 28730570 TI - Structural connectivity differences in essential tremor with and without resting tremor. AB - In this work, we investigated motor network structure in patients affected by essential tremor (ET) with or without resting tremor, using probabilistic tractography of the cerebello-thalamo-basal ganglia-cortical loop. Twenty-five patients with ET, twenty-two patients with ET associated with resting tremor (rET), and twenty-five age- and sex-matched healthy controls were included in the study. All participants underwent whole-brain 3D T1-weighted and diffusion weighted MRI, and DAT-SPECT. Probabilistic tractography was performed on diffusion data in network mode, reconstructing connections between the different structures of the cerebello-thalamo-basal ganglia-cortical loop. All patients with ET, regardless of the presence of resting tremor, had normal DAT-SPECT, but showed significantly decreased connectivity in the cerebello-thalamo-precentral cortex network bilaterally, compared to healthy controls. In addition, patients with rET showed reduced connectivity in a pathway connecting globus pallidus, caudate, and supplementary motor area, compared to ET and controls. This latter circuit was significantly damaged in the hemisphere contralateral to the side clinically most affected by resting tremor. These findings provide insights upon structural changes underlying the different clinical presentations of ET. Our study demonstrates that ET and rET share common alterations in the cerebello thalamo-precentral cortex circuit, while rET patients are characterized by specific damage to additional structures of motor network, such as globus pallidus, caudate nucleus, and supplementary motor area. Our findings suggest that ET and rET are different subtypes of the same neurodegenerative disorder. PMID- 28730572 TI - Hypomagnesaemia as a trigger of relapsing non-alcoholic Wernicke encephalopathy: a case report. PMID- 28730571 TI - Early trigeminal nerve involvement in Listeria monocytogenes rhombencephalitis: case series and systematic review. AB - Listeria monocytogenes is associated with rhombencephalitis. However, the exact mechanisms of brainstem invasion remains poorly understood. Here, we demonstrate clinical and radiological data suggesting that Listeria may invade the brainstem via the trigeminal nerve. Three females (41, 64 and 70 years) with culture proven L. monocytogenes bacteremia and rhombencephalitis were investigated in the period of 2014-16. T2-weighted and contrast-enhanced T1-weighted MRI revealed a cerebellopontine abscess in all three patients, including the involvement of the trigeminal nerve root. In two patients, MRI also revealed selective contrast enhancement of the sensory trigeminal tract in the pons and medulla oblongata. Prior to any other neurological symptoms, two patients complained of hypoesthesia and a tingling sensation in the ipsilateral half of the face, consistent with sensory trigeminal nerve dysfunction on that side. In addition, we identified another 120 cases of Listeria rhombencephalitis following a systematic review. Cranial nerves VII, V, IX, and X, respectively, medulla oblongata, cerebellum and pons, were the most frequently involved brain structures. The present clinical and radiological findings corroborate earlier data from animal experiments, indicating that L. monocytogenes may be capable of retrograde intra-axonal migration along the cranial nerves. We suggest that in a subset of patients with rhombencephalitis L. monocytogenes enters the cerebellopontine angle through the trigeminal nerve, invading the brainstem via the sensory trigeminal nuclei. PMID- 28730573 TI - A "wavering puff of smoke": a rare case of moyamoya disease. PMID- 28730574 TI - Mechanical ventilation guided by electrical impedance tomography in pediatric acute respiratory distress syndrome. AB - Mechanical ventilation strategies in pediatric acute respiratory distress syndrome (pARDS) continue to advance. Optimizing positive end expiratory pressure (PEEP) and ventilation to recruitable lung can be difficult to clinically achieve. This is in part, due to disease evolution, unpredictable changes in lung compliance, and the inability to assess regional tidal volumes in real time at the bedside. Here we report the utilization of thoracic electrical impedance tomography to guide daily PEEP settings and recruitment maneuvers in a child with pARDS. PMID- 28730575 TI - The Effect of Chronic Fluorosis on Calcium Ions and CaMKIIalpha, and c-fos Expression in the Rat Hippocampus. AB - This study investigated neurotoxicity of chronic fluorosis in the rat hippocampus. Newly weaning, male, Sprague-Dawley (SD) rats were administered 15, 30, and 60 mg/L sodium fluoride (NaF) solution (fluorine ion concentration 8.25, 16.50, and 33.00 mg/L, respectively), and tap water, for 18 months. The neurotoxicological mechanism was examined with a focus on intracellular calcium overload. Results showed that as the fluoride concentration increased, calcium ion concentration [Ca2+], the expression of calcium/calmodulin-dependent protein kinase II alpha (CaMKIIalpha), and the expression of catus proto-oncogene protein c-fos (c-fos) all tend to increase. Compared to the control group, Ca2+, CaMKIIalpha, and c-fos significantly increased (P < 0.05) in the moderate fluoride and the high-fluoride groups. These results indicate that Ca2+/CaMKIIalpha/c-fos channel signal may be the molecular mechanism of central nervous system damage caused by chronic fluoride intoxication. Moreover, elevated Ca2+ concentration in the hippocampus may be the initiating factor of neuronal apoptosis induced by fluoride. PMID- 28730576 TI - Effects of Boron Supplementation on Expression of Hsp70 in the Spleen of African Ostrich. AB - Increased synthesis of heat shock protein 70 (Hsp70) occurs in prokaryotes and eukaryotes in response to physiological, environmental, and chemical exposures, thus allowing the cell survival from fatal conditions. Hsp70 cytoprotective properties may be clarified by its anti-apoptotic function. Boron has been reported to play an essential role in various organ developments and metabolisms. However, it is not known if boron is also able to modulate the Hsp70. In the present study, the actions of boron on ostrich spleen and expression level of Hsp70 were investigated. Thirty healthy ostrich chicks were randomly assigned to six groups: groups I, II, III, IV, V, and VI and fed the basal diet spiked with 0 , 40-, 80-, 160-, 320-, and 640-mg boric acid (BA)/L, respectively, in drinking water. The histomorphological examination in the spleen was done by hematoxylin and eosin (HE) staining. The expression level of Hsp70 was analyzed by immunohistochemistry (IHC) and western blotting, and mRNA expression of Hsp70 was investigated by quantitative real-time PCR (qPCR). In order to investigate apoptosis, TUNEL assay reaction in all treatment groups was analyzed. Our results showed that the histological structure of spleen up to 160 mg/L BA supplementation groups well developed. The Hsp70 expression level first induced at low-dose groups (up to group IV) and then inhibited dramatically in high-dose groups (V and VI) while comparing with the group I (0 mg BA). The TUNEL assay reaction revealed that the cell apoptosis amount was decreased in group IV, but in group V and especially in group VI, it was significantly increased (P < 0.01). Taken altogether, proper dietary boron treatment might stimulate ostrich chick spleen development by promoting the Hsp70 expression level and inhibiting apoptosis, while a high amount of boron supplementation would impair the ostrich spleen structure by inhibiting Hsp70 expression level and promoting cell apoptosis. PMID- 28730577 TI - A case of successful conversion from everolimus to surgical resection of a giant pancreatic neuroendocrine tumor. AB - BACKGROUND: Although pancreatic neuroendocrine tumors generally have a far better prognosis relative to pancreatic cancer, the varied manifestations lead to treatment-related challenges. Everolimus therapy is generally recommended for patients with advanced pancreatic neuroendocrine tumors; however, its efficacy in a neoadjuvant setting remains unclear. Here we present a case of a giant pancreatic neuroendocrine tumor with a portal tumor thrombus that became resectable after everolimus therapy. CASE PRESENTATION: A 62-year-old woman was admitted to our hospital for surgical resection of a giant pancreatic neuroendocrine tumor in the left upper abdomen. Unfortunately, she was ineligible for surgery because the tumor had extended near the hepatic hilus in the portal vein, and she was administered everolimus (10 mg/day). After 2 years of this therapy, the extent of portal vein involvement had decreased, despite the lack of significant changes in the tumor size, and the hepatic hilus became free of disease. She was subsequently referred to us for resection via distal pancreatectomy with portal vein reconstruction because the tumor had begun to grow slowly. Pathological review identified a grade 2 neuroendocrine tumor with no lymph node metastasis. The patient's postoperative course was uneventful, and she has remained recurrence-free for 27 months, despite a lack of additional treatment. CONCLUSIONS: Our experience suggests that everolimus could be useful for neoadjuvant therapy in cases of locally advanced pancreatic neuroendocrine tumor. PMID- 28730578 TI - A Multi-tiered Model for Clinical Scholarship. PMID- 28730579 TI - pH Meter. PMID- 28730580 TI - A case study characterizing animal fecal sources in surface water using a mitochondrial DNA marker. AB - Water quality impairment by fecal waste in coastal watersheds is a public health issue. The present study provided evidence for the use of a mitochondrial (mtDNA) marker to detect animal fecal sources in surface water. The accurate identification of fecal pollution is based on the notion that fecal microorganisms preferentially inhabit a host animal's gut environment. In contrast, mtDNA host-specific markers are inherent to eukaryotic host cells, which offers the advantage by detecting DNA from the host rather than its fecal bacteria. The present study focused on sampling water presumably from non-point sources (NPS), which can increase bacterial and nitrogen concentrations to receiving water bodies. Stream sampling sites located within the Piscataqua River Watershed (PRW), New Hampshire, USA, were sampled from a range of sites that experienced nitrogen inputs such as sewer and septic systems and suburban runoff. Three mitochondrial (mtDNA) gene marker assays (human, bovine, and canine) were tested from surface water. Nineteen sites were sampled during an 18-month period. Analyses of the combined single and multiplex assay results showed that the proportion of occurrence was highest for bovine (15.6%; n = 77) compared to canine (5.6%; n = 70) and human (5.7%; n = 107) mtDNA gene markers. For the human mtDNA marker, there was a statistically significant relationship between presence vs. absence and land use (Fisher's test p = 0.0031). This result was evident particularly for rural suburban septic, which showed the highest proportion of presence (19.2%) compared to the urban sewered (3.3%), suburban sewered (0%), and agricultural (0%) as well as forested septic (0%) sites. Although further testing across varied land use is needed, our study provides evidence for using the mtDNA marker in large watersheds. PMID- 28730581 TI - Biogas from poultry waste-production and energy potential. AB - The objective of this study was to evaluate the effect of heat treatment on poultry litter with different levels of reutilisation for potential generation of biogas in experimental biodigesters. Chicken litter used was obtained from two small-scale poultry houses where 14 birds m-2 were housed for a period of 42 days per cycle. Litter from aviary 1 received no heat treatment while each batch of litter produced from aviary 2 underwent a fermentation process. For each batch taken, two biodigesters were set for each aviary, with hydraulic retention time of 35 days. The efficiency of the biodigestion process was evaluated by biogas production in relation to total solids (TS) added, as well as the potential for power generation. Quantified volumes ranged from 8.9 to 41.1 L of biogas for aviary 1, and 6.7 to 33.9 L of biogas for aviary 2, with the sixth bed reused from both aviaries registering the largest biogas potential. Average potential biogas in m3 kg-1 of TS added were 0.022 to 0.034 for aviary 1 and 0.015 to 0.022 for aviary 2. Energy values of biogas produced were calculated based on calorific value and ranged from 0.06 to 0.33 kWh for chicken litter without fermentation and from 0.05 to 0.27 kWh for chicken litter with fermentation. It was concluded that the re-use of poultry litter resulted in an increase in biogas production, and the use of fermentation in the microbiological treatment of poultry litter seems to have negatively influenced production of biogas. PMID- 28730582 TI - The biochemical and histological analysis of subcutaneous calcitonin and intramedullary methylprednisolone on bone repair after bone marrow ablation: an experimental comparative study in rats. AB - BACKGROUND: Although, glucocorticoid (GC) and calcitonin-induced changes in bone repair have been studied previously, the exact effects of these on fracture healing remain controversial. Hence, the purpose of this experimental study is to determine biochemical and histological effects of locally administrated GC and systemically administrated calcitonin on the kinetics of healing response after bone marrow ablation in rats. METHODS: After having undergone marrow ablation, a steroid-treated group of rats (n = 24) received a single dose of intramedullary methylprednisolone (2 mg/kg), a calcitonin-treated group (n = 24) received intermittently administrated subcutaneous salmon calcitonin (16 IU/kg), and a control group (n = 24) received intramedullary saline (25 MUl). RESULTS: Blood samples taken on days 1, 3, 7, 9, and 15 after ablation showed an increase in serum calcium, alkaline phosphatase (ALP), and phosphate levels in the Calcitonin and Control groups. Levels of calcium and ALP peaked on day 7 after ablation. However, an increase in phosphate levels indicated a biphasic reaction that peaked on the third and ninth day after ablation. Hypercalcemia was not observed in Steroid group because of the inhibition of osteoclastic bone resorption. In that group, the serum levels of ALP and phosphate were lower than baseline levels. The levels of urinary calcium excretion peaked 3 to 7 days after marrow ablation in the control group and 7 to 9 days after that procedure in the steroid group. Histologic evaluation showed that the rats in the control group demonstrated the expected healing period according to the histological grades and that a delay in healing occurred in the calcitonin group after day 9 because of the inhibition of osteoclastic bone resorption. All rats in the steroid group exhibited a decrease and delayed healing response. CONCLUSION: Total serum calcium, phosphate, and ALP levels increased after bilateral tibial bone marrow ablation and urine calcium and hydroxyproline excretion also increased as a factor of bone resorption. Subcutaneously administrated salmon calcitonin did not affect biochemical changes after marrow ablation. Single-dose intramedullary methylprednisolone inhibited extra-tibial bone resorption induced by cytokines after bone marrow ablation. PMID- 28730584 TI - Roadmap 2017-2021: Stronger organization and better response to the needs of Member States in the Eastern Mediterranean Region. PMID- 28730585 TI - Occult hepatitis B infection in Egyptian health care workers. AB - We tested the frequency of occult hepatitis B infection (OBI) among Egyptian healthcare workers (HCWs). We tested 132 HCWs for hepatitis B virus (HBV) DNA by nested polymerase chain reaction (PCR), and hepatitis C virus antibody (anti-HCV) by ELISA. HCV RNA was measured by nested PCR in anti-HCV-positive HCWs. HBV-DNA positive HCWs were subjected to HBV genotyping. We included 132 HCWs who were negative for hepatitis B surface antigen and positive for hepatitis B core antibody (anti-HBc). OBI was detected in 7 male HCWs, and HBV E genotype was detected in 3, HBV D in 2 and HBV D and E in 2. Two OBI-positive HCWs had a history of neonatal hepatitis B vaccination. Anti-HCV seropositivity was detected in 17 HCWs who were positive for anti-HBc; 15 of whom were positive for HCV RNA by nested PCR. HCV infection was confirmed by anti-HCV and HCV RNA in 1 of 7 HCWs with OBI. In conclusion, Egyptian HCWs have a significant rate of OBI and HBV E genotype is prevalent. PMID- 28730583 TI - Genetics in an isolated population like Finland: a different basis for genomic medicine? AB - A unique genetic background in an isolated population like that of Finland offers special opportunities for genetic research as well as for applying the genetic developments to the health care. On the other hand, the different genetic background may require local attempts to develop diagnostics and treatment as the selection of diseases and mutations differs from that in the other populations. In this review, we describe the experiences of research and health care in this genetic isolate starting from the identification of specific monogenic diseases enriched in the Finnish population all the way to implementing the knowledge of the unique genetic background to genomic medicine at population level. PMID- 28730586 TI - Mediator role of experiential avoidance in relationship of perceived stress and alexithymia with mental health. AB - This cross-sectional study investigated the mediatory role of experiential avoidance in the relationship between perceived stress and alexithymia with mental health. We enrolled 440 students (age 18-30 years) at Kermanshah University of Medical Sciences through stratified random sampling method. The study tools were demographic checklist, GHQ-28, Toronto Alexithymia Scale-20 and Perceived Stress Scale. Data were analysed by SPSS-18 and AMOS-18 using Pearson correlation, hierarchical regression analysis and structural equation modelling (SEM). There was a significant positive correlation between perceived stress and experiential avoidance, and alexithymia and mental health problems (P < 0.001). SEM showed that the relationship between perceived stress and mental health problems by experiential avoidance was 0.19 [(beta = 0.19; standard error (SE) = 0.09; P = 0.001], and the relationship between alexithymia and mental health problems through experiential avoidance was 0.09 (beta = 0.09; SE = 0.43; P = 0.01). The mediatory role of experiential avoidance was confirmed in such a way that the effects of alexithymia and perceived stress decreased. PMID- 28730587 TI - Coverage of tobacco control in Jordanian newspapers: implications for strengthening the role of news media. AB - News media play a critical role in tobacco control. To strengthen this role in Jordan, four newspapers were searched and 1 145 articles between 2011 and 2015 were coded for mention of MPOWER topics and for tone of coverage (neutral, pro-, or anti-tobacco control). Monthly counts, mention of tobacco control topics and the tones were examined. The monthly count of tobacco control-related news items showed an upward trend with an average monthly growth of 16%. Peaks in coverage were observed in synchrony with national tobacco control developments. 'Warn' was the topic most frequently mentioned (46%). 'Protect' was the only topic that showed a statistically significant upward trend over time. A pro-tobacco control tone was more prevalent than an antitobacco control or neutral tone. Thus, efforts are needed to enhance the newsworthiness of certain topics, boost influence on decision-makers and pre-empt industry interference. PMID- 28730588 TI - Awareness among a Saudi Arabian university community of Middle East respiratory syndrome coronavirus following an outbreak. AB - This study aimed to measure the level of awareness of faculty members, staff and students in a female Saudi Arabian university community towards Middle East respiratory syndrome coronvirus (MERS-CoV) following an outbreak. A self administered questionnaire containing knowledge questions was distributed and completed by the 1541 participants. The overall knowledge score was 43.2%. It was only significantly higher in participants from the health colleges (50.6%). The majority (78.9%) of the respondents recognized the typical symptoms of MERS-CoV but only 67.1% knew the recommended preventive hygiene practices. Awareness of disease epidemiology, severity, fatality rate and treatment was very low. The knowledge of health care workers/ students of the recommended precautions that should be applied when dealing with patients was poor (55.5%). Significant improvement in educational programmes for both the health care and non-health care professionals is warranted, particularly in crowded educational institutions or workplaces. PMID- 28730589 TI - Medical students' perceptions of supporting pharmacology learning in English by key information prepared in Arabic. AB - We explored medical students' perceptions of supporting pharmacology self learning in English by focused materials prepared in Arabic. This study targeted third-year medical students at the Arabian Gulf University in Bahrain (n= 183). During the endocrine and metabolism subunit, which is taught in English, slides containing focused information in Arabic preceded detailed English ones. At the end of the subunit, students' perceptions were explored by a questionnaire and focus group discussions. Most participants reported that this intervention made pharmacology learning easier, improved confidence in drug selection, knowledge of adverse drug reactions, detection of response to medications and occurrence of adverse reactions. Most respondents thought that this intervention would help them during the clinical phase of their study and in communicating drug therapy to patients in Arabic. Supporting pharmacology learning in a foreign language with instructional materials prepared in a native language improved students self reported learning and satisfaction. PMID- 28730590 TI - Health production and determinants of health systems performance in WHO Eastern Mediterranean Region. AB - This descriptive-analytical study used data envelopment analysis to evaluated the technical efficiency (TE) of health systems in Member States of the World Health Organization Eastern Mediterranean Region during 2004-2011. Life expectancy and infant mortality were used as outputs. Per capita total expenditure on health, and number of physicians, nurses and midwives and hospital beds per 1000 people were used as inputs. The determinants of TE of the health systems were examined using a regression model. United Arab Emirates and Somalia had the most efficient health systems with a TE score of 1. Djibouti and Libya had the most inefficient health systems, with TE scores of 0.346 and 0.435, respectively. The most important determinants of TE were the level of education and gross domestic product per capita. The relationship between unemployment and out-of-pocket health expenditure was not significantly associated with TE of the health systems. To improve TE of the health systems, countries should focus on individuals' empowerment in education and income level, rather than only on providing healthcare services. PMID- 28730591 TI - Use of traditional medicine among type 2 diabetic Libyans. AB - The use of traditional medicines is common among patients with chronic illnesses and this practice might pose health risks. The use among Libyan patients with diabetes is unknown. Therefore, this study aimed to estimate the prevalence of traditional medicine use in the previous year among Libyans with type 2 diabetes and to examine the association between its use and sociodemographic and clinical characteristics of the patients. A cross-sectional study was conducted at a large diabetes centre in Tripoli. A self-reported questionnaire was used for data collection. Of the 523 respondents, 28.9% used traditional remedies. Sex was the only variable significantly associated with traditional medicine use; more women used traditional medicines (P = 0.01). A total of 77 traditional medicine items were reported to be used, of which herbs were the most common. The use of traditional medicine for diabetes is prevalent and some of the reported items could pose health risks. Health education programmes are suggested to raise the awareness of the health risks of this practice. PMID- 28730592 TI - Audit sur la qualite de la vaccination en milieu scolaire dans la region de Monastir (Tunisie). AB - We conducted a clinical audit by observing 55 vaccinators in schools in the governorate of Monastir in 2014. We used a set of criteria by referring to the national immunization programme. The cold chain was respected in most cases. Accumulators, the collector of syringes and needles, cotton balls soaked in alcohol and emergency box were available in 85.5%, 76.4%, 98.2% and 41.8% of cases respectively. Hand washing before immunization session was performed in 29.1% of cases. Waste disposal according to the hygiene rules was done by 40 agents. Health education of students regarding the interest of vaccination was done in 67.3% of cases. Therefore, improvements in hand hygiene practice and education are recommended. PMID- 28730593 TI - Blunted cerebral vascular responsiveness to hypercapnia in obese individuals. AB - NEW FINDINGS: What is the central question of this study? Is there a difference in the cerebral vascular response to rebreathing-induced hypercapnia between obese and lean individuals? What is the main finding and its importance? The main finding is that obese individuals have an attenuated increase in cerebral vascular conductance during hypercapnia relative to lean individuals. This finding suggests cerebral vascular dysfunction in this population, which might contribute to the greater prevalence of cerebral vascular and neurocognitive disease in this population. Obesity increases the risk of cardiovascular disease by >45%. Furthermore, obesity is a contributory factor to cognitive impairment and Alzheimer's disease. The mechanisms accounting for this increased disease risk have not been clarified. This study tested the hypothesis that the total range of change (a) in cerebral blood velocity (CBV) and cerebral vascular conductance (CVCI) and the maximal (y0) CBV and CVCI achieved during rebreathing induced hypercapnia would be attenuated in obese individuals. Sixteen lean and 15 obese individuals participated. The magnitude of rebreathing-induced hypercapnia was similar between groups (lean, ?15 +/- 3 mmHg versus obese, ?15 +/- 2 mmHg; P = 0.82). The total range of change in CBV during rebreathing (a; expressed as a percentage) was similar between groups (lean, 91 +/- 24% versus obese, 76 +/- 19%, P = 0.07), whereas the total range of change in CVCI during rebreathing (a; expressed as a percentage) was attenuated in the obese individuals (lean, 71 +/- 20% versus obese, 51 +/- 15%, P < 0.01). Likewise, the maximal increase in CBV during rebreathing (y0; expressed as a percentage) was similar between groups (lean, 189 +/- 22% versus obese, 179 +/- 20%, P = 0.20), whereas the maximal increase in CVCI during rebreathing (y0; expressed as a percentage) was attenuated in the obese individuals (lean, 172 +/- 19% versus obese, 155 +/- 17 %, P = 0.01). These data indicate that the cerebral vascular response to rebreathing-induced hypercapnia is attenuated in obese individuals. This impairment might be a factor contributing to the elevated cerebral vascular and neurocognitive disease risk in this population. PMID- 28730594 TI - Seed desiccation mechanisms co-opted for vegetative desiccation in the resurrection grass Oropetium thomaeum. AB - Resurrection plants desiccate during periods of prolonged drought stress, then resume normal cellular metabolism upon water availability. Desiccation tolerance has multiple origins in flowering plants, and it likely evolved through rewiring seed desiccation pathways. Oropetium thomaeum is an emerging model for extreme drought tolerance, and its genome, which is the smallest among surveyed grasses, was recently sequenced. Combining RNA-seq, targeted metabolite analysis and comparative genomics, we show evidence for co-option of seed-specific pathways during vegetative desiccation. Desiccation-related gene co-expression clusters are enriched in functions related to seed development including several seed specific transcription factors. Across the metabolic network, pathways involved in programmed cell death inhibition, ABA signalling and others are activated during dehydration. Oleosins and oil bodies that typically function in seed storage are highly abundant in desiccated leaves and may function for membrane stability and storage. Orthologs to seed-specific LEA proteins from rice and maize have neofunctionalized in Oropetium with high expression during desiccation. Accumulation of sucrose, raffinose and stachyose in drying leaves mirrors sugar accumulation patterns in maturing seeds. Together, these results connect vegetative desiccation with existing seed desiccation and drought responsive pathways and provide some key candidate genes for engineering improved drought tolerance in crop plants. PMID- 28730595 TI - CD155, an onco-immunologic molecule in human tumors. AB - CD155 is the fifth member in the nectin-like molecule family, and functions as the receptor of poliovirus; therefore, CD155 is also referred to as necl-5, or PVR. As an immunoglobulin-like adhesion molecule, CD155 is involved in cell motility, and natural killer and T cell-mediated immunity. CD155 is barely or weakly expressed in various normal human tissues, but frequently overexpressed in human malignant tumors. CD155 overexpression promotes tumor cell invasion and migration, and is associated with tumor progression and poor prognosis. As the ligand for both costimulatory receptor CD226 and coinhibitory receptor TIGIT and CD96 on natural killer and T cells, CD155 seems to play a dual role in oncoimmunity. However, some recent studies indicate that CD155 overexpression may induce tumor immune escape. Taken together, CD155 may be considered as a target for the treatment of tumors with CD155 overexpression. PMID- 28730596 TI - Current treatment preferences in chronic myeloid leukemia: The Mayo Clinic Physicians' survey. PMID- 28730597 TI - Evidence of unique genetic diversity in Aspergillus fumigatus isolates from Cameroon. AB - Aspergillus fumigatus is a saprophytic fungus that can cause lethal invasive aspergillosis in immunocompromised patients. Recent studies have shown that Eurasian and North American populations of A. fumigatus often consist of genetically diverse strains. However, very little is known about African populations of A. fumigatus. Here, we characterise the genetic diversity and triazole susceptibility of A. fumigatus in Cameroon, West Africa. A total of 495 soil samples were obtained from nine collection sites in three Cameroonian regions. Nine microsatellite markers were used to genotype all 51 identified A. fumigatus isolates. In vitro susceptibility to itraconazole and voriconazole was tested using micro broth dilution. The 51 Cameroonian A. fumigatus isolates belonged to 45 genotypes. Consistent with recombination, 32 of 36 possible pairwise loci combinations are phylogenetically incompatible. Interestingly, evidence for geographic sub-structuring was found within Cameroon and the sub population with the most evidence of recombination was also the least susceptible sub-population to the triazole antifungals tested. Furthermore, the Cameroonian sample was significantly differentiated from those in Eurasia and North America. Overall, our results indicate the genetic uniqueness of Cameroonian A. fumigatus populations and that additional novel genetic diversity likely exist in other parts of Africa. PMID- 28730598 TI - Do new tools help us identify substrate to target for ablation in ventricular tachycardia? PMID- 28730599 TI - Modulated Structure Calculated for Superconducting Hydrogen Sulfide. AB - Compression of hydrogen sulfide using first principles metadynamics and molecular dynamics calculations revealed a modulated structure with high proton mobility which exhibits a diffraction pattern matching well with experiment. The structure consists of a sublattice of rectangular meandering SH- chains and molecular-like H3 S+ stacked alternately in tetragonal and cubic slabs forming a long-period modulation. The novel structure offers a new perspective on the possible origin of the superconductivity at very high temperatures in which the conducting electrons in the SH chains are perturbed by the fluxional motions of the H3 S resulting in strong electron-phonon coupling. PMID- 28730600 TI - Transcriptomic insights into the alternative splicing-mediated adaptation of the entomopathogenic fungus Beauveria bassiana to host niches: autophagy-related gene 8 as an example. AB - Alternative splicing (AS) regulates various biological processes in fungi by extending the cellular proteome. However, comprehensive studies investigating AS in entomopathogenic fungi are lacking. Based on transcriptome data obtained via dual RNA-seq, the first overview of AS events was developed for Beauveria bassiana growing in an insect haemocoel. The AS was demonstrated for 556 of 8840 expressed genes, accounting for 5.4% of the total genes in B. bassiana. Intron retention was the most abundant type of AS, accounting for 87.1% of all splicing events and exon skipping events were rare, only accounting for 2.0% of all events. Functional distribution analysis indicated an association between alternatively spliced genes and several physiological processes. Notably, B. bassiana autophagy-related gene 8 (BbATG8), an indispensable gene for autophagy, was spliced at an alternative 5' splice site to generate two transcripts (BbATG8 alpha and BbATG8-beta). The BbATG8-alpha transcript was necessary for fungal autophagy and oxidation tolerance, while the BbATG8-beta transcript was not. These two transcripts differentially contributed to the formation of conidia or blastospores as well as fungal virulence. Thus, AS acts as a powerful post transcriptional regulatory strategy in insect mycopathogens and significantly mediates fungal transcriptional adaption to host niches. PMID- 28730601 TI - Benthic iron cycling in a high-oxygen environment: Implications for interpreting the Archean sedimentary iron isotope record. AB - The most notable trend in the sedimentary iron isotope record is a shift at the end of the Archean from highly variable delta56 Fe values with large negative excursions to less variable delta56 Fe values with more limited negative values. The mechanistic explanation behind this trend has been extensively debated, with two main competing hypotheses: (i) a shift in marine redox conditions and the transition to quantitative iron oxidation; and (ii) a decrease in the signature of microbial iron reduction in the sedimentary record because of increased bacterial sulfate reduction (BSR). Here, we provide new insights into this debate and attempt to assess these two hypotheses by analyzing the iron isotope composition of siderite concretions from the Carboniferous Mazon Creek fossil site. These concretions precipitated in an environment with water column oxygenation, extensive sediment pile dissimilatory iron reduction (DIR) but limited bacterial sulfate reduction (BSR). Most of the concretions have slightly positive iron isotope values, with a mean of 0.150/00 and limited iron isotope variability compared to the Archean sedimentary record. This limited variability in an environment with high DIR and low BSR suggests that these conditions alone are insufficient to explain Archean iron isotope compositions. Therefore, these results support the idea that the unusually variable and negative iron isotope values in the Archean are due to dissimilatory iron reduction (DIR) coupled with extensive water column iron cycling. PMID- 28730602 TI - Deep learning of the sectional appearances of 3D CT images for anatomical structure segmentation based on an FCN voting method. AB - PURPOSE: We propose a single network trained by pixel-to-label deep learning to address the general issue of automatic multiple organ segmentation in three dimensional (3D) computed tomography (CT) images. Our method can be described as a voxel-wise multiple-class classification scheme for automatically assigning labels to each pixel/voxel in a 2D/3D CT image. METHODS: We simplify the segmentation algorithms of anatomical structures (including multiple organs) in a CT image (generally in 3D) to a majority voting scheme over the semantic segmentation of multiple 2D slices drawn from different viewpoints with redundancy. The proposed method inherits the spirit of fully convolutional networks (FCNs) that consist of "convolution" and "deconvolution" layers for 2D semantic image segmentation, and expands the core structure with 3D-2D-3D transformations to adapt to 3D CT image segmentation. All parameters in the proposed network are trained pixel-to-label from a small number of CT cases with human annotations as the ground truth. The proposed network naturally fulfills the requirements of multiple organ segmentations in CT cases of different sizes that cover arbitrary scan regions without any adjustment. RESULTS: The proposed network was trained and validated using the simultaneous segmentation of 19 anatomical structures in the human torso, including 17 major organs and two special regions (lumen and content inside of stomach). Some of these structures have never been reported in previous research on CT segmentation. A database consisting of 240 (95% for training and 5% for testing) 3D CT scans, together with their manually annotated ground-truth segmentations, was used in our experiments. The results show that the 19 structures of interest were segmented with acceptable accuracy (88.1% and 87.9% voxels in the training and testing datasets, respectively, were labeled correctly) against the ground truth. CONCLUSIONS: We propose a single network based on pixel-to-label deep learning to address the challenging issue of anatomical structure segmentation in 3D CT cases. The novelty of this work is the policy of deep learning of the different 2D sectional appearances of 3D anatomical structures for CT cases and the majority voting of the 3D segmentation results from multiple crossed 2D sections to achieve availability and reliability with better efficiency, generality, and flexibility than conventional segmentation methods, which must be guided by human expertise. PMID- 28730603 TI - Hidradenitis Suppurativa in Children Treated with Finasteride-A Case Series. AB - BACKGROUND: Hidradenitis suppurativa (HS) is rare in childhood, with only 2% of cases in patients younger than 11 years. It is a chronic, recurrent, debilitating condition for which no universally effective treatment has been developed. We present five cases of children with HS diagnosed between the ages of 6 and 11 years. METHODS: Patients were treated with oral finasteride 1 to 5 mg/day. All had entered puberty at the time of treatment initiation. All had normal laboratory results before starting treatment. The maximum duration of treatment was 24 months. RESULTS: Four patients were female. Two were overweight. Three had been previously treated with oral antibiotics, and two of these with oral isotretinoin, with partial or no improvement. Overall improvement of the disease was observed in all patients, with a reduction of the frequency and intensity of the flares. No adverse effects were observed or reported during treatment. CONCLUSION: Treatment of HS can be challenging. The options available include antimicrobials, immunosuppressants, hormonal therapies, lasers, and surgery. The authors report the largest series of children with HS treated with finasteride. The results support the use of finasteride as monotherapy for the treatment of this disease in children. Further studies are necessary to fully understand the role of this drug in the management of this disease. PMID- 28730604 TI - Structural basis for intramolecular interaction of post-translationally modified H-Ras*GTP prepared by protein ligation. AB - Ras undergoes post-translational modifications including farnesylation, proteolysis, and carboxymethylation at the C terminus, which are necessary for membrane recruitment and effector recognition. Full activation of c-Raf-1 requires cooperative interaction of the farnesylated C terminus and the activator region of Ras with its cysteine-rich domain (CRD). However, the molecular basis for this interaction remains unclear because of difficulties in preparing modified Ras in amounts sufficient for structural studies. Here, we use Sortase A catalyzed protein ligation to prepare modified Ras in sufficient amounts for NMR and X-ray crystallographic analyses. The results show that the farnesylated C terminus establishes an intramolecular interaction with the catalytic domain and brings the farnesyl moiety to the proximity of the activator region, which may be responsible for their cooperative recognition of c-Raf-1-CRD. PMID- 28730606 TI - Technical Note: Empirical altitude correction factors for well chamber measurements of permanent prostate and breast seed implant sources. AB - PURPOSE: Previous studies in the literature have measured an altitude effect for low-energy brachytherapy seeds; a correction factor applied in addition to PTP to account for the breakdown of Bragg-Gray cavity theory at low energies in well type ionization chambers. In clinical practice, many centers use altitude correction factors that are not seed-model-specific. The purpose of this work is to present altitude correction factors for several seed models without documented factors in the literature. METHODS: An in-house constructed pressure vessel was used with a well-type ionization chamber to measure the air-kerma strength of the IsoAid Advantage (Pd-103), Theragenics AgX100 (I-125), and Nucletron selectSeed (I-125) at a pressure range representative of those encountered worldwide. The TheraSeed 200 (Pd-103) was also measured for comparison to the originally published correction factor for validation of the experimental process. When correction factors derived in this work were within experimental uncertainties of those published, no new correction factors were proposed. RESULTS: The three seed models measured herein all demonstrated a similar response to change in pressure as previously documented in the literature with the HDR 1000 Plus well-type ionization chamber. Correction factors of the functional form PA=k1(P[torr])k2, consistent with those previously published, were found to be appropriate for these seed models. A new correction factor is proposed for the Theragenics AgX100 and Nucletron selectSeed (k1 = 0.0417, k2 = 0.479). The IsoAid Advantage, however, agreed to within uncertainty with the published altitude correction factor for the TheraSeed 200; thus the application of the same correction factor is appropriate (k1 = 0.0241, k2 = 0.562). CONCLUSIONS: This work presents altitude correction factors for three permanent implant brachytherapy seed models in clinical use. This will allow clinics to utilize model-specific factors, reducing systematic errors in their air-kerma strength verifications. PMID- 28730605 TI - Contributions of Interleukin-33 and TSLP in a papain-soaked contact lens-induced mouse conjunctival inflammation model. AB - INTRODUCTION: Pathological changes of severe chronic allergic conjunctivitis are driven not only via acquired immunity but also via innate immunity. Type 2 immune response-initiating cytokines may play some roles as innate immunity-dependent components of the ocular surface inflammation. To investigate the involvement of type 2 immune response-initiating cytokines in innate immunity-dependent, papain induced conjunctival inflammation model using IL-25-, IL-33-, and TSLP receptor (TSLPR)-knockout (KO) mice with reference to basophils and ILC2. METHODS: Papain soaked contact lenses (papain-CLs) were installed in the conjunctival sacs of C57BL/6-IL-25 KO, IL-33 KO, TSLPR KO, Rag2 KO, Bas-TRECK, and wild-type mice and their eyes were sampled at day 5. The eosinophil and basophil infiltration in papain-CL model was evaluated histologically and cytokine expression was examined. To clarify the roles of basophils and ILC2, basophil/ILC2-depletion experiments were carried out. RESULTS: Papain-induced conjunctival inflammation exhibited eosinophil infiltration and upregulation of Th2 cytokine expression. Reduction of eosinophil and basophil infiltration and attenuated Th2 cytokine expression were observed in the papain-CL model using IL-33 KO and TSLPR KO mice. Depletion of basophils or ILC2s in the conjunctivae of the papain-CL model reduced eosinophil infiltration. CONCLUSIONS: Innate immunity-driven type 2 immune responses of the ocular surface are dependent on IL-33, TSLP, basophils, and ILC2. These components may be possible therapeutic targets for refractory allergic keratoconjunctivitis. PMID- 28730607 TI - Concurrent Chondrodysplasia Punctata Type 2 (Conradi-Hunermann-Happle Syndrome) and Ichthyosis Vulgaris in Teenaged Twin Girls. AB - We present concurrent X-linked chondrodysplasia punctata and ichthyosis vulgaris in adolescent fraternal twin girls, notable for initial presentation with dry skin in adolescence, characterized by dark-brown scale typical of ichthyosis vulgaris and blaschkolinear, atrophic, scaly plaques. This constellation of findings prompted further genetic investigation. Using a multigene approach to examine 39 genes associated with congenital ichthyosis, next-generation sequencing revealed a novel heterozygous missense mutation at a mutational hotspot in the EBP gene c.439C>T (p.R147C) in conjunction with a single nonsense mutation in the FLG gene (p.R501X) in both sisters. These individuals highlight the clinical variability of Conradi-Hunermann-Happle syndrome, illustrate the possibility of co-occurrence of rare and common forms of ichthyosis, and demonstrate the utility of multigene analysis. PMID- 28730608 TI - In/ex copula ejaculatory activities of aqueous and methanolic extracts of Aframomum melegueta (Zingiberaceae) in sexually experienced male rat. AB - This study was undertaken to evaluate the effects of Aframomum melegueta on male rat ejaculation using in/ex copula techniques. For the in copula experiment, rats were orally treated with aqueous or methanolic extract (20 and 100 mg/kg) of A. melegueta for 14 days. Each rat was mated with a primed receptive female on days 0, 7 and 14 of treatment, and the ejaculatory latency and post-ejaculatory interval were measured. In the ex copula experiment, the electromyography of the bulbospongiosus muscles and intraseminal pressure were recorded in spinal rats after mechanical (urethral and penile) and pharmacological stimulations (intravenous injection of dopamine (5 mg/kg) and, aqueous or methanolic extract of A. melegueta, 2.5; 5; 10 and 20 mg/kg). Furthermore, the effect of dopamine on fictive ejaculation was monitored in rats orally pre-treated with A. melegueta extracts (20 and 100 mg/kg) for 7 or 14 days. Treatment with the aqueous or methanolic extract of A. melegueta significantly decreased the ejaculatory latency (p < .05) and post-ejaculatory interval (p < .01) after 14 days. In spinal rats, mechanical or pharmacological stimulations triggered fictive ejaculation. In animals orally pre-treated with A. melegueta extracts, the pro ejaculatory effect of dopamine was more expressed. Present findings show that A. melegueta possesses pro-ejaculatory effects. PMID- 28730609 TI - Discrepancy Between Experimental and Theoretical Predictions of the Adiabaticity of Ti+ +CH3 OH. AB - The reaction between Ti+ and methanol (CH3 OH) is a model system for competition between activation of C-O, C-H, and O-H bonds and of the role of excited electronic pathways in catalytic processes. Herein, we use experimental kinetics, quantum chemical calculations, and statistical modeling to identify the critical features of the reaction's potential energy surface. Experimental kinetics data between 300 and 600 K shows the reaction largely proceeds through C-O bond activation, yielding TiOH+ and TiO+ . Products of the O-H activation pathway, TiOCH2+ and TiOCH3+ are minor, whereas C-H bond activation is not observed at thermal energies. Statistical modeling well-reproduces the experimental results and offers insight into the reaction mechanism. Notably, efficient spin-crossing along the C-O activation pathway is required to produce the observed product distribution, in contrast to a previous estimate of inefficient crossing based on calculation of a small spin-orbit coupling constant. This discrepancy highlights a potential limitation of simple models within the Landau-Zener framework, which are commonly used to calculate surface-crossing probabilities in reactive systems. PMID- 28730610 TI - Effect of excessive gestational weight gain on trial of labour after caesarean: A retrospective cohort study. AB - BACKGROUND: Counselling women for and managing birth after caesarean section are important. Research is needed on evaluation of antenatal factors that predict likelihood of successful trial of labour after caesarean section (TOLAC). AIM: To evaluate the effect of gestational weight gain on mode of delivery in women having TOLAC. MATERIALS AND METHODS: A retrospective cohort study of eligible women who underwent TOLAC (January 2012 to July 2015) at a large urban hospital. Gestational weight gain was classified as 'excessive' or 'not excessive' based on calculated pre-pregnancy body mass index. Multivariable logistic regression analysis was performed to estimate the association of gestational weight gain and vaginal birth, adjusting for socio-demographic and pregnancy-related factors. RESULTS: Of 534 women, those who gained excessive weight were less likely to have a vaginal birth as women who did not (adjusted odds ratio (aOR) 0.48, 95% confidence interval (CI) 0.29-0.81)). Women with previous vaginal birth were more likely to have a vaginal birth (aOR 3.74, 95% CI 1.90-7.36), while women >=35, women who had an epidural, and women who delivered at 40 weeks, were less likely (aOR 0.58, 95% CI 0.35-0.97, aOR 0.12, 95% CI 0.07-0.22, and aOR 0.53, 95% CI 0.31-0.91, respectively). CONCLUSIONS: Gaining excessive weight in pregnancy is potentially modifiable, and can be incorporated into individual antenatal counselling, and into risk prediction models, to assist with informed decision making around planned mode of delivery in women with previous caesarean section. Future research could focus on interventions to reduce gestational weight gain in women planning TOLAC. PMID- 28730611 TI - Adjuvant irradiation to prevent keloidal fibroproliferative growth should be standard of care. PMID- 28730612 TI - Herpes gestationis and oral contraceptive: Case report and review of the literature. PMID- 28730614 TI - Synchrotron tomographic images from human lung adenocarcinoma: Three-dimensional reconstruction and histologic correlations. AB - High-resolution tomographic images using synchrotron X-rays are expected to provide detailed reflection of microstructures, thereby allowing for the examination of histologic structures without destruction of the specimen. This study aims to evaluate the synchrotron tomographic images of mixed ground-glass opacity excised on 5-mm sections in comparison to pathologic examination. The Institutional Review Board of our institute approved this retrospective study, and written informed consent was obtained from each patient whose lung tissue would be used. Obtained lung cancer specimens were brought to the multiple Wiggler 6C beam line at the Pohang Light Source (PLS-II) in Korea, and phase contrast X-ray images were obtained in November 2016. The X-ray emanated from a bending magnet of the electron storage ring with electron energy of 3 GeV, and a typical beam current was 320 mA. Reconstructed tomographic images were compared with images from histologic slides obtained from the same samples. Pulmonary microstructures including terminal bronchioles, alveolar sacs, and vasculature were identified with phase contrast X-ray images. Images from normal lung tissue and mixed ground-glass opacity were clearly distinguishable. Hyperplasia of the interalveolar septum and dysplasia of microstructure were clearly identified. The imaging findings correlated well with hematoxylin-eosin stained specimens. Tomographic images using synchrotron radiation have the potential for clinical applications. With refinement, this technique may become a diagnostic tool for detection of lung cancer. PMID- 28730615 TI - Vulvar cancer in high-income countries: Increasing burden of disease. AB - The aim of this study was to assess trends in the age-specific incidence of vulvar cancer in 13 high-income countries satisfying a priori conditions regarding the availability of cancer registry data over a 20-year period; these were Canada, the United States, nine European countries, Australia and Japan. Five-yearly incidence and population at risk were obtained from the International Agency for Research on Cancer's Cancer Incidence in Five Continents for the years 1988-1992 (Volume 7) to 2003-2007 (Volume 10). The 5-yearly average percent change (AvPC) over the period and standardised rate ratios (SRRs) for 2003-2007 versus 1988-1992 were used to assess changes in the age-standardised incidence rates of vulvar cancer for all ages, and for <60 years and 60+ years. During the study period, the 5-yearly AvPC across the 13 countries increased by 4.6% (p = 0.005) in women of all ages, and 11.6% (p = 0.02) in those <60 years. No change was observed in women aged 60+ years (5-yearly AvPC = 0.1%, p = 0.94). The SRR for 2003-2007 versus 1988-1992 was significantly elevated in women <60 years of age (SRR = 1.38, 95% CI: 1.30-1.46), but not in women of 60+ years (SRR = 1.01, 95% CI: 0.97-1.05). The increase in incidence in women <60 years of age drove a significant increase in the overall SRR in women of all ages (SRR = 1.14, 95% CI: 1.11-1.18). Some differences in the specific findings at the individual country level were observed. The findings are consistent with changing sexual behaviours and increasing levels of exposure to human papillomavirus (HPV) in cohorts born around/after about 1950, but younger cohorts offered HPV vaccination are likely to receive some protection against developing vulvar cancer in the future. PMID- 28730613 TI - Overweight but unseen: a review of the underestimation of weight status and a visual normalization theory. AB - Although overweight and obesity are widespread across most of the developed world, a considerable body of research has now accumulated, which suggests that adiposity often goes undetected. A substantial proportion of individuals with overweight or obesity do not identify they are overweight, and large numbers of parents of children with overweight or obesity fail to identify their child as being overweight. Lay people and medical practitioners are also now poor at identifying overweight and obesity in others. A visual normalization theory of the under-detection of overweight and obesity is proposed. This theory is based on the notion that weight status is judged relative to visual body size norms. Because larger body sizes are now common, this has caused a recalibration to the range of body sizes that are perceived as being 'normal' and increased the visual threshold for what constitutes 'overweight'. Evidence is reviewed that indicates this process has played a significant role in the under-detection of overweight and obesity. The public health relevance of the under-detection of overweight and obesity is also discussed. PMID- 28730616 TI - Acute Genital Swelling Heralding C1 Esterase Inhibitor Deficiency in a Child. AB - A healthy 5-year-old boy presented to the emergency department with an acute genital swelling. He had no relevant family history. His presentation and blood investigations were consistent with C1 esterase inhibitor deficiency, mostly likely arising de novo. A rare cause of acute genital swelling and its management are discussed. PMID- 28730618 TI - Undiagnosed, chronic temporomandibular joint pain: making a case for FDG-PET/CT. PMID- 28730617 TI - Methotrexate for Severe Childhood Atopic Dermatitis: Clinical Experience in a Tertiary Center. AB - BACKGROUND/OBJECTIVES: Atopic dermatitis (AD) affects up to 20% of children. Although the majority of patients are adequately controlled using emollients, topical corticosteroids, topical calcineurin inhibitors, or phototherapy, children with moderate to severe AD may require systemic treatment for control. The objective of the current study was to evaluate the efficacy and safety of methotrexate in children with severe AD attending a tertiary referral center. METHODS: A retrospective chart review was undertaken of all children who received methotrexate for severe AD at our tertiary referral center from November 2010 to August 2015. RESULTS: Forty-seven children were started on methotrexate for AD during this period. The mean Investigator Global Assessment (IGA) at the 3- to 5 month follow-up improved from 4.25 to 2.8, with further improvement to 1.9 in the patients that continued therapy beyond 10 months. Changes in the Children's Dermatology Life Quality Index (CDLQI) mirrored changes in the IGA, with improvement in the mean CDLQI from 14.4 at the start of the treatment to 7.5 at the 3- to 5-month follow-up. Further improvement in the CDLQI to 6.6 in patients who continued methotrexate beyond 10 months confirmed continued improvement in disease control beyond medium-term therapy. The treatment was well tolerated. CONCLUSIONS: Methotrexate appears to be an effective, safe treatment for severe pediatric AD. Its therapeutic effects continue beyond the medium-term treatment period, as reflected by further improvement in IGA and CDLQI scores in patients who continued methotrexate therapy beyond 10 months. PMID- 28730619 TI - Real-World Adherence and Persistence with Direct Oral Anticoagulants in Adults with Atrial Fibrillation. AB - BACKGROUND: Evidence of adherence and persistence patterns in anticoagulation (AC) therapy comparing treatment-naive and non-naive patients is lacking. The objective of this study was to evaluate patterns of medication adherence and persistence in a real-world setting among AC-naive and AC-experienced patients with atrial fibrillation (AF) who were treated with direct oral anticoagulants (DOACs). METHODS: AF patients newly initiating a DOAC with a minimum of 6 months of continuous health plan enrollment pre and postindex date (first DOAC prescription) were identified from the Truven Health MarketScan Commercial and Medicare Supplemental databases (2009-2013). DOAC adherence (proportion of days covered [PDC]), persistence, and predictors of adherence were assessed at 6 and 12 months postindex. RESULTS: Of 66,090 AF patients included, 46.6% (n=30,826) were AC naive and 53.4% (n=35,264) were AC experienced (age: 66.9 +/- 12.7 vs 70.4 +/- 11.4 yrs, p<0.001; male: n=19,132 [62.1%] vs n=21,691 [61.5%], p=0.14, respectively). A majority of patients received dabigatran as their index DOAC (n=49,210; 74.5%). The mean PDC in AC-naive versus AC-experienced patients at 6 and 12 months of follow-up was 72.3% versus 83.3% (p<0.001) and 63.7% versus 79.9% (p<0.001), respectively. Persistence with DOAC therapy in AC-naive and AC experienced patients at 6 and 12 months ranged from 59.3% and 76.3% (p<0.0001) to 31.6% and 50.2% (p<0.0001), respectively. Predictors of higher DOAC adherence were older age and higher number of concomitant medications. Predictors of lower adherence were higher number of comorbidities and AC-naive user status. CONCLUSION: Medication adherence and persistence with DOACs declined over time and both were suboptimal and lower (at 6 and 12 mo postindex) in AC-naive compared to AC-experienced patients. These findings can help target future strategies or interventions for patient education and long-term AC management especially in those patients naive to DOAC therapy. Future investigation should examine potential reasons for differences in DOAC adherence and persistence between AC-experienced versus AC-naive patients and the implications for patient outcomes. PMID- 28730620 TI - Laparoscopic repair of a left paraduodenal hernia. PMID- 28730621 TI - Multiple homonuclear band-selective decoupling NMR: Fast and unambiguous determination of diastereomeric excess. AB - Discrimination and quantification of chiral stereoisomers have been studied by different analytical methods, and NMR has emerged as a powerful one with the advancements in pure-shift NMR methods. In the present manuscript, an al-F1F2 MHOBS-DIAG NMR method for the quantification of diastereomeric excess ratio (dr) has been proposed and demonstrated, using hesperidin and naringin mixtures. This method enables simultaneous quantification of dr at multiple resonances, in a single experiment, and it takes only 10 min to record. The present method uses spectral aliasing and thus demands only very few indirect dwell increments. Further, the measured dr values are very reliable, because we consider several spins for the quantification. PMID- 28730622 TI - Susceptibility to HIV-1 infection is influenced by toll like receptor-2 (-196 to 174) polymorphism in a north Indian population. AB - BACKGROUND: Toll like receptors (TLRs) are pattern recognition receptors that recognize molecular patterns of pathogens and play an important role in innate immunity. Recent studies have identified that a single nucleotide polymorphism (SNP) in the TLR gene impairs the response to TLR ligands in some individuals and is associated with susceptibility to various infectious diseases. The present study aimed to investigate the role of four SNPs in the TLR2 gene [-196 to -174 Ins/Del, 2258 G/A (Arg753Gln), 2029 C/T (Arg677Trp) and 1892 C/A (Pro631His)] with respect to susceptibility and progression to HIV-1 in North Indian individuals. METHODS: The study population consisted of 160 HIV-1 seropositive patients stratified on the basis of disease severity (stages I, II and III) and 270 HIV-1 seronegative individuals. The subjects were genotyped for TLR2 gene polymorphism by polymerase chain reaction restriction fragment length polymorphism. RESULTS: In the present study, we found that the TLR2 Del mutant genotype [odds ratio (OR) = 2.138; p = 0.001] and allele (OR = 1.562; p = 0.002) was at a higher frequency in patients with HIV-1 infection compared to healthy controls and was significantly associated with the risk of HIV-1 infection and disease susceptibility. Furthermore, we also found that TLR2 Del homozygous genotype was at a lower frequency in stage III (19.35%) compared to stage I (50.87%; OR = 1.901) and stage II (43.05%; OR = 1.514) and was associated with a reduced risk of HIV-1 disease progression. CONCLUSIONS: The present study reports for the first time that the TLR2-196 to -174 Ins/Del polymorphism is a risk factor for HIV-1 transmission in HIV-1 infected North Indian individuals. PMID- 28730623 TI - Effects of fluoride-modified titanium surfaces with the similar roughness on RUNX2 gene expression of osteoblast-like MG63 cells. AB - Chemical modification of titanium surfaces by hydrofluoric acid (HF) is an effective method to improve bone responses on titanium implant surfaces. In this study, titanium disks were sandblasted with titanium oxide grits and modified with 0.2% and 0.4% of diluted HF under different exposure times of 40 and 60 s. Surface characteristics, such as surface chemical composition, surface topography, and surface wettability, were investigated. To examine MG63 osteoblast-like cell responses to fluoride-modified titanium surfaces with roughness similar to that of nonmodified surfaces, a cell proliferation assay was performed and gene expression levels of Runx2 were evaluated using real-time PCR. Fluoride-modified titanium surfaces revealed no significant roughness difference but with hydrophilic properties than control group SB. Moreover, the relative atomic concentration percentages of fluoride were 0.7, 1.5, and 2.8. As fluoride concentrations increased, surface wettability increased and cell proliferation began earlier. However, the gene expression levels of Runx2 increased earlier on surfaces with 1.5% fluoride, with significantly high surface skewness. There seems to be an optimal fluoride concentration percentage when gene expression levels of Runx2 were taken into consideration. In addition, surface parameters, such as surface wettability and surface skewness, seem to be important factors in the enhancement of osteoblast differentiation by HF. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 3102-3109, 2017. PMID- 28730624 TI - Prevalence of nickel allergy in Europe following the EU Nickel Directive - a review. AB - Nickel contact allergy remains a problem in EU countries, despite the EU Nickel Directive. To study the prevalence of nickel allergy in EU countries following the implementation of the EU Nickel Directive, we performed a systematic search in PubMed for studies that examined the prevalence of nickel allergy in EU countries published during 2005-2016. We identified 46 studies: 10 in the general population and 36 in patch tested dermatitis patients. A significantly lower prevalence of nickel allergy after than before the implementation of the EU Nickel Directive was found in women aged 18-35 years (11.4% versus 19.8%) (p = 0.02), in female dermatitis patients aged <=17 years (14.3% versus 29.2%) (p < 0.0001), and in dermatitis patients aged 18-30 years (women: 20.2% versus 36.6%) (p < 0.0001) (men: 4.9% versus 6.6%) (p < 0.0001). Overall, the prevalence was higher in southern than in northern EU countries, and generally remained high, affecting 8-18% of the general population. A consistent pattern of decreasing prevalence of nickel allergy in some EU countries was observed, although the prevalence among young women remains high. Steps should be taken for better prevention of nickel allergy in EU countries. PMID- 28730625 TI - FGF9 mutation causes craniosynostosis along with multiple synostoses. AB - Craniosynostosis is commonly caused by mutations in fibroblast growth factor receptors (FGFRs), highlighting the essential role of FGF-mediated signaling in skeletal development. We set out to identify the molecular defect in a family referred for craniosynostosis and in whom no mutation was previously detected. Using next-generation sequencing, we identified a novel missense mutation in FGF9. Modeling based upon the crystal structure and functional studies confirmed its pathogenicity showing that it impaired homodimerization and FGFR3 binding. Only one FGF9 mutation has been previously reported in a multigeneration family with multiple synostoses (SYNS3) but no signs of craniosynostosis. In contrast, our family has a greater phenotypic resemblance to that observed in the Fgf9 spontaneous mouse mutant, elbow-knee-synostosis, Eks, with both multiple synostoses and craniosynostosis. We have demonstrated for the first time that mutations in FGF9 cause craniosynostosis in humans and confirm that FGF9 mutations cause multiple synostoses. PMID- 28730627 TI - Will we all be replaced by machines? PMID- 28730626 TI - Adverse reactions to fillers should be published - on the consensus statement on adverse effects following hyaluronic acid-based fillers. PMID- 28730628 TI - Acute hepatic porphyria and cancer risk: a nationwide cohort study. AB - BACKGROUND: Acute hepatic porphyria (AHP) is considered to be a risk factor for primary liver cancer (PLC), but varying risk estimates have been published. OBJECTIVES: Our aim was to investigate the risk of PLC and other cancers in persons with AHP using a nationwide cohort design. Given that greater numbers of women than men tend to have manifest and more severe AHP, a further aim was to investigate sex differences in this risk. METHODS: The study sample consisted of all Norwegian residents aged 18 years or older during the period 2000-2011. Persons with AHP (n = 251) were identified through the Norwegian Porphyria Centre, and patients with a cancer diagnosis were identified by linkage to the Cancer Registry of Norway. RESULTS: For persons with AHP, the annual incidence rate of PLC was 0.35%. PLC risk was substantially higher for individuals with an AHP diagnosis compared to the reference population [adjusted hazard ratio (aHR) 108, 95% confidence interval (CI) 56-207]. In a meta-analysis of published studies on PLC and AHP, including ours, women had a higher risk than men. In addition, our results suggested that persons with AHP may have increased risks of kidney (aHR 7.4, 95% CI 2.4-23.1) and endometrial cancers (aHR 6.2, 95% CI 2.0 19.3). CONCLUSIONS: Our findings confirmed a substantially higher risk of PLC associated with AHP compared to the general population. In a meta-analysis, the risk was shown to be greater for women than men. The novel findings of a moderate to substantial association between AHP and kidney and endometrial cancers should be investigated further. PMID- 28730629 TI - Emergency department use for acute rhinosinusitis: Insurance dependent for children and adults. AB - OBJECTIVES/HYPOTHESIS: Patients with Medicaid or self-pay insurance status are more likely to present to the emergency department (ED) for uncomplicated acute rhinosinusitis (ARS). Our aim was to determine if this pattern holds true for both pediatric and adult visits. STUDY DESIGN: Cross-sectional study using the 2005 to 2012 National Hospital Ambulatory Medical Care Surveys and National Ambulatory Medical Care Surveys. METHODS: We included all visits with International Classification of Diseases, Ninth Revision codes for ARS and without codes for ARS complications. We tested for associations between insurance type and presentation to an ED versus a primary care physician (PCP), stratifying children versus adults. We used univariate and multivariable logistic regression modeling, controlling for clinical and demographic characteristics for analysis. RESULTS: There were 51,579,977 uncomplicated ARS visits to PCPs (48,213,335 visits) and EDs (3,366,642 visits). Medicaid and uninsured patients were under represented for ARS visits. Medicaid insurance was significantly associated with ED presentation for ARS for both children (adjusted odds ratio [OR] = 7.0, P < 0.001) and adults (adjusted OR = 6.8, P < 0.001). Children with ARS and self-pay insurance status were much more likely to present to the ED (adjusted OR = 48.8, P < 0.001) than adults (adjusted OR = 5.2, P < 0.001); this difference between children and adults with self-pay insurance was significant (P = 0.001). CONCLUSION: With respect to absolute numbers of visits, patients with Medicaid or no insurance use less care overall for uncomplicated ARS than do privately insured patients. Medicaid is associated with ED presentation for ARS for pediatric and adult visits. Self-pay insurance status is strongly associated with ED presentation for adult and pediatric visits, and is significantly more common for children. These results suggest limitations in primary care access for uncomplicated ARS based on insurance status, particularly for uninsured pediatric patients. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:299-303, 2018. PMID- 28730630 TI - Hartmann's reversal: a comparative study between laparoscopic and open approaches. AB - BACKGROUND: A reversal of Hartmann's procedure can be performed using either a laparoscopic or open approach. However, laparoscopic reversal (LR) of Hartmann's procedure is challenging. This study was designed to compare the results between open and laparoscopic approaches. METHODS: This was a retrospective study of prospectively collected data. We analysed 29 patients who received Hartmann's reversal at Korea University Anam Hospital between April 2007 and September 2014. All patients underwent either LR (n = 17) or open reversal (OR, n = 12). RESULTS: Patient characteristics were similar between the LR and OR groups. There was also no difference in mean operation time (212.5 versus 251.8 min), diversion ileostomy, length of hospital stay, postoperative analgesic days, time to diet resumption (3.9 versus 6.2 days) or complication rate. Although the time to resuming a solid diet was not different between the two groups (P = 0.053), bowel movement occurred faster in LR patients (LR versus OR, 1.8 versus 2.8 days, P = 0.020). Patients in the LR group also had less blood loss during surgery (114.1 versus 594.2 mL, P = 0.026). There were no mortalities in this study. CONCLUSION: LR of Hartmann's procedure resulted in faster bowel function recovery than the open method. Laparoscopic approaches are feasible even for patients who received an open Hartmann's procedure. PMID- 28730631 TI - Attractiveness of working in home care: An online focus group study among nurses. AB - Many western countries are experiencing a substantial shortage of home-care nurses due to the increasing numbers of care-dependent people living at home. In depth knowledge is needed about what home-care nurses find attractive about their work in order to make recommendations for the recruitment and retention of home care nursing staff. The aims of this explorative, qualitative study were to gain in-depth knowledge about which aspects home-care nurses find attractive about their work and to explore whether these aspects vary for home-care nurses with different levels of education. Discussions were conducted with six online focus groups in 2016 with a total of 38 Dutch home-care nurses. The transcripts were analysed using the principles of thematic analysis. The findings showed that home care nurses find it attractive that they are a "linchpin", in the sense of being the leading professional and with the patient as the centre of care. Home-care nurses also find having autonomy attractive: autonomy over decision-making about care, freedom in work scheduling and working in a self-directed team. Variety in patient situations and activities also makes their work attractive. Home-care nurses with a bachelor's degree did not differ much in what they found attractive aspects from those with an associate degree (a nursing qualification after completing senior secondary vocational education). It is concluded that autonomy, variety and being a "linchpin" are the attractive aspects of working in home care. To help recruit and retain home-care nursing staff, these attractive aspects should be emphasised in nursing education and practice, in recruitment programmes and in publicity material. PMID- 28730632 TI - Apparent and standardized ileal digestibility of amino acids in diverse barley cultivars fed to growing pigs. AB - The objectives of this study were to determine the chemical composition, ileal amino acid (AA) digestibility of barley varieties and to develop equations to predict the AA digestibility based on the chemical characteristics of individual barley. A wide selection of nine barley varieties in the main growing regions of China was used in the experiment. Ten crossbred pigs (30.9 +/- 1.8 kg) were allotted to a 6 * 10 Youden Square. The treatments included a nitrogen-free diet and nine barley test diets. Considerable variation was observed in the content of neutral detergent fiber, acid detergent fiber, crude protein (CP) and all AAs among the barley samples. The standardized ileal digestibility (SID) of indispensable AAs with the exception of arginine, phenylalanine and threonine were different (P < 0.05) among the nine barley sources tested. With R2 values exceeding 0.50, significant linear regression equations for CP and threonine were obtained. In conclusion, significant differences existed in the ileal digestibility of CP and AAs among barley varieties. It is difficult to predict the SID of most of the amino acids in barely based upon chemical characteristics. PMID- 28730634 TI - Does perceived stress moderate the association between depressive symptoms and socioemotional and behavioural strengths and difficulties in adolescence? AB - More and more students report high level of perceived stress during childhood and adolescence, which is associated with socioemotional and behavioural strengths and difficulties. This study aims-based on the cognitive vulnerability transactional stress theory-to examine perceived stress in early adolescence as a potential moderator in the association between depressive symptoms and socioemotional and behavioural strengths and difficulties from early to middle adolescence. Results of latent moderated structural equations with questionnaire data from a longitudinal study with 1,088 German students (Time 1: Mage = 13.70, SD = 0.53; Time 2: N = 845, Mage = 15.32, SD = 0.49) indicate that perceived stress functions as a moderator in the above-mentioned association and dominates the interaction if perceived strongly. PMID- 28730633 TI - PD-1 expression on CD8+ T cells regulates their differentiation within lung allografts and is critical for tolerance induction. AB - Immunological requirements for rejection and tolerance induction differ between various organs. While memory CD8+ T cells are considered a barrier to immunosuppression-mediated acceptance of most tissues and organs, tolerance induction after lung transplantation is critically dependent on central memory CD8+ T lymphocytes. Here we demonstrate that costimulation blockade-mediated tolerance after lung transplantation is dependent on programmed cell death 1 (PD 1) expression on CD8+ T cells. In the absence of PD-1 expression, CD8+ T cells form prolonged interactions with graft-infiltrating CD11c+ cells; their differentiation is skewed towards an effector memory phenotype and grafts are rejected acutely. These findings extend the notion that requirements for tolerance induction after lung transplantation differ from other organs. Thus, immunosuppressive strategies for lung transplant recipients need to be tailored based on the unique immunological properties of this organ. PMID- 28730635 TI - Lamellar ichthyosis associated bilateral pseudoainhum of fingers and toes successfully treated with tazarotene. PMID- 28730637 TI - Identification and functional characterization of an odorant receptor in pea aphid, Acyrthosiphon pisum. AB - The sensitive olfactory system is necessary for survival of insects. Odorant receptors (ORs) are located on the dendrites of olfactory receptor neurons and play a critical role in odor detection. Insect ORs are functionally analyzed via heterologous expression in a Xenopus oocyte system using a two-electrode voltage clamp (TEVC) electrophysiological recording. Here, we have identified a novel OR in the pea aphid, Acyrthosiphon pisum, then we cloned and named it ApisOR4. We analyzed the ApisOR4 tissue expression patterns and found expression only in antennae tissues. Further functional analysis using TEVC revealed that ApisOR4 is broadly tuned to eight volatiles, which elicit electrophysiological response in pea aphid antennae. This study provides an initial functional analysis of aphid ORs and identifies candidate volatiles to be used in developing new strategies for aphid control. PMID- 28730636 TI - The reduction in maize leaf growth under mild drought affects the transition between cell division and cell expansion and cannot be restored by elevated gibberellic acid levels. AB - Growth is characterized by the interplay between cell division and cell expansion, two processes that occur separated along the growth zone at the maize leaf. To gain further insight into the transition between cell division and cell expansion, conditions were investigated in which the position of this transition zone was positively or negatively affected. High levels of gibberellic acid (GA) in plants overexpressing the GA biosynthesis gene GA20-OXIDASE (GA20OX-1OE ) shifted the transition zone more distally, whereas mild drought, which is associated with lowered GA biosynthesis, resulted in a more basal positioning. However, the increased levels of GA in the GA20OX-1OE line were insufficient to convey tolerance to the mild drought treatment, indicating that another mechanism in addition to lowered GA levels is restricting growth during drought. Transcriptome analysis with high spatial resolution indicated that mild drought specifically induces a reprogramming of transcriptional regulation in the division zone. 'Leaf Growth Viewer' was developed as an online searchable tool containing the high-resolution data. PMID- 28730638 TI - Plasma pharmacokinetics of quinocetone in ducks after oral and intravenous administration. AB - Quinocetone (QCT), an antimicrobial growth promoter, is widely used in food producing animals. However, information about pharmacokinetics (PK) of QCT in ducks still remains unavailable up to now. In this study, QCT and its major metabolites (1-desoxyquinocetone, di-desoxyquinocetone and 3-methyl-quinoxaline-2 carboxylic) in ducks were studied using a simple and sensitive UHPLC-MS/MS assay. Twenty ducks were divided into two groups. (n = 10/group). One group received QCT by oral administration at dose of 40 mg/kg while another group received QCT intravenously at 10 mg/kg. Plasma samples were collected at various time points from 0 to 96 hr. QCT and its major metabolites in duck plasma samples were extracted by 1 ml acetonitrile and detected by UHPLC-MS/MS, with the gradient mobile phase that consisted of 0.1% formic acid in water (A) and acetonitrile (B). A noncompartment analysis was used to calculate the PK parameters. The results showed that following oral dosing, the peak plasma concentration (Cmax ) of QCT was 32.14 ng/ml and the area under the curve (AUCINF_obs) was 233.63 (h ng)/ ml. Following intravenous dosing, the Cmax , AUCINF_obs and Vss_obs were 96.70 ng/ml, 152.34 (h ng)/ ml and 807.00 L/kg, respectively. These data indicated that the QCT was less absorbed in vivo following oral administration, with low bioavailability (38.43%). QCT and its major metabolites such as 1 desoxyquinocetone and 3-methyl-quinoxaline-2-carboxylic were detected at individual time points in individual ducks, while the di-desoxyquinocetone was not detected in all time points in all ducks. This study enriches basic scientific data about pharmacokinetics of QCT in ducks after oral and intravenous administration and will be beneficial for clinical application in ducks. PMID- 28730639 TI - Corrigendum: Synthesis of alpha-Dawson-Type Silicotungstate [alpha-Si2 W18 O62 ]8 and Protonation and Deprotonation Inside the Aperture through Intramolecular Hydrogen Bonds. PMID- 28730640 TI - 2016 updated Thai Rheumatism Association Recommendations for the use of biologic and targeted synthetic disease-modifying anti-rheumatic drugs in patients with rheumatoid arthritis. AB - AIM: In June 2015, the Thai Rheumatism Association (TRA) approved an update of its recommendation for the use of biologic disease-modifying anti-rheumatic drugs (bDMARDs) and targeted synthetic (tsDMARD) in the treatment of rheumatoid arthritis (RA) to cover those currently available in Thailand (etanercept, infliximab, golimumab, rituximab, tocilizumab, abatacept and tofacitinib). METHOD: A search of the literature was performed between January 2000 and June 2015. Existing RA recommendations, in relation to the use of bDMARDs and tsDMARD, were identified and evaluated by the AGREE II instrument prior to their use as a 'guide' for developing this TRA recommendation. An additional literature search was performed in order to answer specific clinical questions that could not be found in existing guidelines. RESULT: Thirteen recommendations were developed. They covered the use of RA classification criteria, the aim of RA treatment, when to initiate bDMARDs/tsDMARD or taper or switch them to other medications, as well as monitoring these drugs during their use. In addition, specific issues including their use and vaccination, malignancies, pregnancy and lactation, and perioperative period also were addressed. Public hearings were performed at the annual meeting of the TRA and of the Royal College of Physicians of Thailand. The recommendations were distributed to other professional associations related to RA management, as well as government sectors associated with the reimbursement policy, prior to development of the final version. CONCLUSION: These recommendations will help Thai rheumatologists prescribe bDMARDs and tsDMARD more appropriately when treating RA patients. PMID- 28730641 TI - Basal ganglia and autism - a translational perspective. AB - : The basal ganglia are a collection of nuclei below the cortical surface that are involved in both motor and non-motor functions, including higher order cognition, social interactions, speech, and repetitive behaviors. Motor development milestones that are delayed in autism such as gross motor, fine motor and walking can aid in early diagnosis of autism. Neuropathology and neuroimaging findings in autism cases revealed volumetric changes and altered cell density in select basal ganglia nuclei. Interestingly, in autism, both the basal ganglia and the cerebellum are impacted both in their motor and non-motor domains and recently, found to be connected via the pons through a short disynaptic pathway. In typically developing individuals, the basal ganglia plays an important role in: eye movement, movement coordination, sensory modulation and processing, eye hand coordination, action chaining, and inhibition control. Genetic models have proved to be useful toward understanding cellular and molecular changes at the synaptic level in the basal ganglia that may in part contribute to these autism related behaviors. In autism, basal ganglia functions in motor skill acquisition and development are altered, thus disrupting the normal flow of feedback to the cortex. Taken together, there is an abundance of emerging evidence that the basal ganglia likely plays critical roles in maintaining an inhibitory balance between cortical and subcortical structures, critical for normal motor actions and cognitive functions. In autism, this inhibitory balance is disturbed thus impacting key pathways that affect normal cortical network activity. Autism Res 2017, 10: 1751-1775. (c) 2017 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Habit learning, action selection and performance are modulated by the basal ganglia, a collection of groups of neurons located below the cerebral cortex in the brain. In autism, there is emerging evidence that parts of the basal ganglia are structurally and functionally altered disrupting normal information flow. The basal ganglia through its interconnected circuits with the cerebral cortex and the cerebellum can potentially impact various motor and cognitive functions in the autism brain. PMID- 28730642 TI - MYC expression and translocation analyses in low-grade and transformed follicular lymphoma. AB - AIMS: Low-grade follicular lymphoma (FL) (grade 1/2, FL1/2) has an annual risk of transformation of ~3%, which is associated with aberrations in CDKN2A/B, TP53, and MYC. As in diffuse large B-cell lymphoma, high MYC expression in transformed FL (tFL) might predict a MYC breakpoint. METHODS AND RESULTS: We quantified MYC expression by immunohistochemistry and digital analysis in 41 paired biopsies from 20 patients with FL1/2 with subsequent transformation and in four isolated biopsies of tFL. As controls, 28 biopsies of FL1/2 without transformation (median follow-up of 105 months) and nine biopsies of FL3A/B were analysed. In the 20 FL1/2-tFL pairs, MYC expression was significantly higher in tFL than in the initial FL1/2 biopsies (median 54% versus 6%; 7% in FL3A, and 35% in FL3B). MYC breaks (MYC-R) were detected in eight of 21 (38%) tFLs analysed by fluorescence in-situ hybridization (FISH), with a median MYC score of 86%. In two of the analysed tFL cases, the translocation was already detected in antecedent FL1/2. MYC partners were immunoglobulin (IG) loci in three of eight cases (one IGL, one IGH, and one IGK) and non-IG in five of eight cases (two PAX5, one BCL6, and two unknown). Of the eight MYC-R+ cases, six were BCL2+/MYC+ double-hit, one was BCL2+/BCL6+/MYC+ triple-hit, and one was MYC+ single-hit. All three IG-MYC+ cases showed a MYC expression level of >85%, whereas the five cases with a non-IG MYC partner had a wider range of expression (median 68%, range 13-86%). Among the 13 MYC-R- tFLs, two groups with almost dichotomous MYC expression could be observed (three cases showed >=90% MYC expression), suggesting alternative mechanisms of MYC activation. CONCLUSIONS: we show an increase in MYC expression from FL1/2 to tFL. MYC breakpoints were present in ~40% of the cases, which is markedly higher than in de novo DLBCL. MYC expression was uniformly high in cases with an IG-MYC translocation but much more heterogeneous and in part independent of the presence of a MYC break in non-IG-MYC and MYC-negative cases. PMID- 28730643 TI - Differences in gadolinium retention after repeated injections of macrocyclic MR contrast agents to rats. AB - PURPOSE: To compare the levels of gadolinium in the blood, cerebrum, cerebellum, liver, femur, kidneys, and skin after multiple exposure of rats to the macrocyclic gadolinium-based contrast agents (GBCAs) gadoterate, gadobutrol, and gadoteridol. MATERIALS AND METHODS: Fifty male Wistar Han rats were randomized to three exposure groups (n = 15 per group) and one control group (n = 5). Animals in the exposure groups received a total of 20 GBCA administrations (four administrations per week for 5 consecutive weeks) at a dose of 0.6 mmol/kg bodyweight. After a 28-day recovery period animals were sacrificed and the blood and tissues harvested for determination of gadolinium (Gd) levels. Gd determination was performed by inductively coupled plasma mass spectrometry (ICP MS). RESULTS: After 28 days' recovery no Gd was found in the blood, liver, or skin of any animal in any group. Significantly lower levels of Gd were noted with gadoteridol compared to gadoterate and gadobutrol in the cerebellum (0.150 +/- 0.022 vs. 0.292 +/- 0.057 and 0.287 +/- 0.056 nmol/g, respectively; P < 0.001), cerebrum (0.116 +/- 0.036 vs. 0.250 +/- 0.032 and 0.263 +/- 0.045 nmol/g, respectively; P < 0.001), and kidneys (25 +/- 13 vs. 139 +/- 88 [P < 0.01] and 204 +/- 109 [P < 0.001], respectively). Higher levels of Gd were noted in the femur (7.48 +/- 1.37 vs. 5.69 +/- 1.75 and 8.60 +/- 2.04 nmol/g, respectively) with significantly less Gd determined for gadoterate than for gadobutrol (P < 0.001) and gadoteridol (P < 0.05). CONCLUSION: Differences exist between macrocyclic agents in terms of their propensity to accumulate in tissues. The observed differences in Gd concentration point to differences in GBCA washout rates in this setting and in this experimental model, with gadoteridol being the GBCA that is most efficiently removed from both cerebral and renal tissues. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 5 J. Magn. Reson. Imaging 2018;47:746 752. PMID- 28730644 TI - FungiScopeTM -Global Emerging Fungal Infection Registry. AB - Rare invasive fungal diseases (IFD) are challenging for the treating physicians because of their unspecific clinical presentation, as well as the lack of standardised diagnostic and effective treatment strategies. Late onset of treatment and inappropriate medication is associated with high mortality, thus, urging the need for a better understanding of these diseases. The purpose of FungiScopeTM is to continuously collect clinical information and specimens to improve the knowledge on epidemiology and eventually improve patient management of these orphan diseases. FungiScopeTM was founded in 2003, and today, collaborators from 66 countries support the registry. So far, clinical data of 794 cases have been entered using a web-based approach. Within the growing network of experts, new collaborations developed, leading to several publications of comprehensive analyses of patient subgroups identified from the registry. Data extracted from FungiScopeTM have also been used as the sole control group for the approval of a new antifungal drug. Due to the rarity of these diseases, a global registry is an appropriate method of pooling the scarce and scattered information. Joining efforts across medical specialities and geographical borders is key for researching rare IFD. Here, we describe the structure and management of the FungiScopeTM registry. PMID- 28730645 TI - Effect of metformin on germ cell-specific apoptosis, oxidative stress and epididymal sperm quality after testicular torsion/detorsion in rats. AB - The study was designed to evaluate the effects of metformin on apoptosis and epididymal sperm quality in a rat testicular ischaemia/reperfusion (I/R) injury model. A total of 72 male rats were divided into four groups (n = 18 for each group): group 1 (sham-operated group), group 2 (metformin group), group 3 (torsion/detorsion [T/D] + saline) and group 4 (T/D + 300 mg kg-1 metformin). Testicular torsion was achieved by rotating the right testis 720 degrees in a clockwise direction for 1 hr. Tissue malondialdehyde (MDA) level and caspase-3 activity increased and the activities of catalase, superoxide dismutase and glutathione peroxidase decreased in comparison with sham-operated group 4 hr after detorsion (p < .001). In six rats of each group 24 hr after detorsion, histopathological changes and germ cell apoptosis were significantly deteriorated by measuring mean of seminiferous tubule diameters (MSTD) and TUNEL test. Moreover, 30 days after T/D, sperm concentration and motility were examined in six animals per group. Metformin pre-treatment reduced MDA and caspase-3 levels and normalised antioxidant enzyme activities 4 hr after detorsion, and germ cell apoptosis was significantly decreased, and the MSTD, as well as sperm functions, was significantly improved. Reduction in oxidative stress and apoptosis may have a major role in cytoprotective effects of metformin. PMID- 28730647 TI - Swimming pools and fungi: An epidemiology survey in Polish indoor swimming facilities. AB - Environmental conditions for swimming facilities may support fungal growth and also may represent a biological risk for users. However, since previously published studies both cleaning procedures and sanitary regulations are likely to have been improved. The aim of the study was to examine whether attendance to public swimming pools was still a risk factor for fungal infection of the skin in Poland. We investigated the occurrence of mycotic species, in a sample from Polish swimming pools. Detection and identification of isolated species were achieved by cultural and morphological methods. Study revealed high incidence of yeast and yeast-like fungi. Candida spp. and Rhodotorula rubra were commonly detected, followed by Aspergillus spp. and Trichophyton mentagrophytes. Surprisingly, the prevalence of clinically important species isolated from swimming pool environments did not reflect prevalence of those species in Polish population. The present results are in agreement with previous research and support that swimming pools remain an important reservoir of clinically important fungi, yet the exposure associated with swimming pools may not be a major source of dermatophytic infection in Poland. PMID- 28730646 TI - Prospective observational study of carbon-ion radiotherapy for non-squamous cell carcinoma of the head and neck. AB - To evaluate the efficacy and safety of carbon-ion radiotherapy for non-squamous cell carcinoma of the head and neck, 35 patients were enrolled in this prospective study. The primary end-point was the 3-year local control rate, and the secondary end-points included the 3-year overall survival rate and adverse events. Acute and late adverse events were evaluated according to the Common Terminology Criteria for Adverse Events, version 4.0. The median follow-up time for all patients was 39 months. Thirty-two and three patients received 64.0 Gy (relative biological effectiveness) and 57.6 Gy (relative biological effectiveness) in 16 fractions, respectively. Adenoid cystic carcinoma was dominant (60%). Four patients had local recurrence and five patients died. The 3 year local control and overall survival rates were 93% and 88%, respectively. Acute grade 2-3 radiation mucositis (65%) and dermatitis (31%) was common, which improved immediately with conservative therapy. Late mucositis of grade 2, grade 3, and grade 4 were observed in 11, one, and no patients, respectively. There were no adverse events of grade 5. Carbon-ion radiotherapy achieved excellent local control and overall survival rates for non-squamous cell carcinoma. However, the late mucosal adverse events were not rare, and meticulous treatment planning is required. Trial registration no. UMIN000007886. PMID- 28730648 TI - Calcineurin inhibitor withdrawal or tapering for kidney transplant recipients. AB - BACKGROUND: Calcineurin inhibitors (CNI) can reduce acute transplant rejection and immediate graft loss but are associated with significant adverse effects such as hypertension and nephrotoxicity which may contribute to chronic rejection. CNI toxicity has led to numerous studies investigating CNI withdrawal and tapering strategies. Despite this, uncertainty remains about minimisation or withdrawal of CNI. OBJECTIVES: This review aimed to look at the benefits and harms of CNI tapering or withdrawal in terms of graft function and loss, incidence of acute rejection episodes, treatment-related side effects (hypertension, hyperlipidaemia) and death. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Specialised Register to 11 October 2016 through contact with the Information Specialist using search terms relevant to this review. Studies contained in the Specialised Register are identified through search strategies specifically designed for CENTRAL, MEDLINE, and EMBASE; handsearching conference proceedings; and searching the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: All randomised controlled trials (RCTs) where drug regimens containing CNI were compared to alternative drug regimens (CNI withdrawal, tapering or low dose) in the post transplant period were included, without age or dosage restriction. DATA COLLECTION AND ANALYSIS: Two authors independently assessed studies for eligibility, risk of bias, and extracted data. Results were expressed as risk ratio (RR) or mean difference (MD) with 95% confidence intervals (CI). MAIN RESULTS: We included 83 studies that involved 16,156 participants. Most were open label studies; less than 30% of studies reported randomisation method and allocation concealment. Studies were analysed as intent-to-treat in 60% and all pre-specified outcomes were reported in 54 studies. The attrition and reporting bias were unclear in the remainder of the studies as factors used to judge bias were reported inconsistently. We also noted that 50% (47 studies) of studies were funded by the pharmaceutical industry.We classified studies into four groups: CNI withdrawal or avoidance with or without substitution with mammalian target of rapamycin inhibitors (mTOR-I); and low dose CNI with or without mTOR-I. The withdrawal groups were further stratified as avoidance and withdrawal subgroups for major outcomes.CNI withdrawal may lead to rejection (RR 2.54, 95% CI 1.56 to 4.12; moderate certainty evidence), may make little or no difference to death (RR 1.09, 95% CI 0.96 to 1.24; moderate certainty), and probably slightly reduces graft loss (RR 0.85, 95% CI 0.74 to 0.98; low quality evidence). Hypertension was probably reduced in the CNI withdrawal group (RR 0.82, 95% CI 0.71 to 0.95; low certainty), while CNI withdrawal may make little or no difference to malignancy (RR 1.10, 95% CI 0.93 to 1.30; low certainty), and probably makes little or no difference to cytomegalovirus (CMV) (RR 0.87, 95% CI 0.52 to 1.45; low certainty)CNI avoidance may result in increased acute rejection (RR 2.16, 95% CI 0.85 to 5.49; low certainty) but little or no difference in graft loss (RR 0.96, 95% CI 0.79 to 1.16; low certainty). Late CNI withdrawal increased acute rejection (RR 3.21, 95% CI 1.59 to 6.48; moderate certainty) but probably reduced graft loss (RR 0.84, 95% CI 0.72 to 0.97, low certainty).Results were similar when CNI avoidance or withdrawal was combined with the introduction of mTOR-I; acute rejection was probably increased (RR 1.43; 95% CI 1.15 to 1.78; moderate certainty) and there was probably little or no difference in death (RR 0.96; 95% CI 0.69 to 1.36, moderate certainty). mTOR-I substitution may make little or no difference to graft loss (RR 0.94, 95% CI 0.75 to 1.19; low certainty), probably makes little of no difference to hypertension (RR 0.86, 95% CI 0.64 to 1.15; moderate), and probably reduced the risk of cytomegalovirus (CMV) (RR 0.60, 95% CI 0.44 to 0.82; moderate certainty) and malignancy (RR 0.69, 95% CI 0.47 to 1.00; low certainty). Lymphoceles were increased with mTOR-I substitution (RR 1.45, 95% CI 0.95 to 2.21; low certainty).Low dose CNI combined with mTOR-I probably increased glomerular filtration rate (GFR) (MD 6.24 mL/min, 95% CI 3.28 to 9.119; moderate certainty), reduced graft loss (RR 0.75, 95% CI 0.55 to 1.02; moderate certainty), and made little or no difference to acute rejection (RR 1.13 ; 95% CI 0.91 to 1.40; moderate certainty). Hypertension was decreased (RR 0.98, 95% CI 0.80 to 1.20; low certainty) as was CMV (RR 0.41, 95% CI 0.16 to 1.06; low certainty). Low dose CNI plus mTOR-I makes probably makes little of no difference to malignancy (RR 1.22, 95% CI 0.42 to 3.53; low certainty) and may make little of no difference to death (RR 1.16, 95% CI 0.71 to 1.90; moderate certainty). AUTHORS' CONCLUSIONS: CNI avoidance increased acute rejection and CNI withdrawal increases acute rejection but reduced graft loss at least over the short-term. Low dose CNI with induction regimens reduced acute rejection and graft loss with no major adverse events, also in the short-term. The use of mTOR-I reduced CMV infections but increased the risk of acute rejection. These conclusions must be tempered by the lack of long-term data in most of the studies, particularly with regards to chronic antibody-mediated rejection, and the suboptimal methodological quality of the included studies. PMID- 28730649 TI - Focal atrial tachycardia from extremely high level of superior vena cava. PMID- 28730650 TI - Regulatory roles of introns in fungicide sensitivity of Fusarium graminearum. AB - Although the roles of introns have been much debated in eukaryotic organisms, none of them have been functionally characterized in Fusarium graminearum. In this study, we characterized the roles of introns in regulation of fungicide sensitivity of F. graminearum. beta2 tub, cyp51A and myosin-5 are important target genes of benzimidazoles, triazoles and cyanoacrylates respectively. To explore the sensitivity regulation functions of introns in target genes, several detailed deletion studies were completed on the intronic regions of beta2 tub, cyp51A and myosin-5. Phenotypic analyses showed that deletion of the fourth intron from beta2 tub gene (designated beta2 Deltai4), the sole intron from cyp51A gene (cyp51A-Deltai) and the second intron from myosin-5 gene (myo5 Deltai2) exhibited an increased sensitivity to corresponding fungicides. In contrast, deletion of the first or second intron from beta2 tub gene exhibited a decreased sensitivity to carbendazim. qRT-PCR showed that the mRNA transcript levels of target genes were significantly downregulated in beta2 Deltai4, cyp51A Deltai and myo5-Deltai2 respectively. Meanwhile, Western blot assays revealed that the protein expression levels of beta2 tub was also dramatically reduced in beta2 Deltai4, but accumulated in beta2 Deltai1 and beta2 Deltai2. Overall, our results indicate that introns in target genes significantly regulate the fungicide-sensitivity by influencing expression of the corresponding resident genes in F. graminearum. PMID- 28730651 TI - A comparison of the electrophysiologic and electroanatomic characteristics between the right and left atrium in persistent atrial fibrillation: Is the right atrium a window into the left? AB - INTRODUCTION: The right atrium (RA) is readily accessible; however, it is unclear whether changes in the RA are representative of the LA. We performed detailed biatrial electroanatomic mapping to determine the electrophysiological relationship between the atria. METHODS AND RESULTS: Consecutive patients with persistent AF underwent biatrial electroanatomical mapping with a contact force catheter acquiring points with a CF >10 g prior to ablation. Points were analyzed for tissue voltage, complex electrograms, low voltage (<0.5 mV), scar (<0.05 mV), and conduction velocity (CV). Forty patients (mean age 59 +/- 9.2 years, AF duration 12.9 +/- 9.2 months, LA area: 28 +/- 5.2, RA area: 25 +/- 6.4 mm2 , LVEF: 44 +/- 15%) underwent mapping during CS pacing. Bipolar voltage (R = 0.57, P <0.001), unipolar voltage (R = 0.68, P <0.001), low voltage (<0.5 nV) (R = 0.48, P = 0.002), fractionation (R = 0.73, P <0.001), and CV (R = 0.49, P = 0.001) correlated well between atria. There was no difference in global bipolar voltage (LA 1.89 +/- 0.77 vs. RA 1.77 +/- 0.57 mV, P = 0.57); complex electrograms (LA 20% vs. RA 20%, P = 0.99) or low voltage (LA 15% vs. RA 16%, P = 0.84). Global unipolar voltage was significantly higher in the LA compared to the RA (2.95 +/- 1.14 vs. 2.28 +/- 0.65 mV, P = 0.002) and CV was significantly slower in the RA compared to the LA (0.93 +/- 0.15 m/s vs. 1.01 +/- 0.19 m/s, P = 0.001). CONCLUSION: AF is associated with remodeling processes affecting both atria. The more accessible RA provides an insight into the biatrial process associated with AF in various disease states without trans-septal access. PMID- 28730653 TI - Dermatitis of the Foot: Epidemiologic and Clinical Features in 389 Children. AB - BACKGROUND/OBJECTIVES: Footwear dermatitis is a form of contact dermatitis resulting from exposure to shoes. There have been only small studies regarding foot contact dermatitis in children. The present study was undertaken to define the prevalence and epidemiologic and clinical features of shoe dermatitis in children. METHODS: A retrospective study was undertaken of all children referred for patch testing between 1996 and 2015. Children with dermatitis limited to the feet were selected. RESULTS: We collected data from 389 children younger than 16 years, 52 of whom (13.4%) were referred with dermatitis exclusively on the feet. Diagnosis after patch testing was allergic contact dermatitis in 23 children (44.2%), atopic eczema in 12 (23.1%), juvenile plantar dermatosis in 8 (15.4%), dyshidrotic eczema in 6 (11.5%), irritant contact dermatitis in 2 (3.8%), and tinea pedis in 1 (1.9%). The most frequent allergens were potassium dichromate, thimerosal, cobalt chloride, mercapto mix, colophonium, mercury, and nickel(II) sulfate. CONCLUSION: Allergic contact dermatitis caused by footwear is a common cause of foot dermatitis in children. Children with foot dermatitis should be referred for patch testing when an allergic origin is suspected. PMID- 28730652 TI - Effects of collimator angle, couch angle, and starting phase on motion-tracking dynamic conformal arc therapy (4D DCAT). AB - PURPOSE: The aim of this study was to find an optimized configuration of collimator angle, couch angle, and starting tracking phase to improve the delivery performance in terms of MLC position errors, maximal MLC leaf speed, and total beam-on time of DCAT plans with motion tracking (4D DCAT). METHOD AND MATERIALS: Nontracking conformal arc plans were first created based on a single phase (maximal exhalation phase) of a respiratory motion phantom with a spherical target. An ideal model was used to simulate the target motion in superior inferior (SI), anterior-posterior (AP), and left-right (LR) dimensions. The motion was decomposed to the MLC leaf position coordinates for motion compensation and generating 4D DCAT plans. The plans were studied with collimator angle ranged from 0 degrees to 90 degrees ; couch angle ranged from 350 degrees (-10 degrees ) to 10 degrees ; and starting tracking phases at maximal inhalation (theta=pi/2) and exhalation (theta=0) phases. Plan performance score (PPS) evaluates the plan complexity including the variability in MLC leaf positions, degree of irregularity in field shape and area. PPS ranges from 0 to 1, where low PPS indicates a plan with high complexity. The 4D DCAT plans with the maximal and the minimal PPS were selected and delivered on a Varian TrueBeam linear accelerator. Gafchromic-EBT3 dosimetry films were used to measure the dose delivered to the target in the phantom. Gamma analysis for film measurements with 90% passing rate threshold using 3%/3 mm criteria and trajectory log files were analyzed for plan delivery accuracy evaluation. RESULTS: The maximal PPS of all the plans was 0.554, achieved with collimator angle at 87 degrees , couch angle at 350 degrees , and starting phase at maximal inhalation (theta=pi/2). The maximal MLC leaf speed, MLC leaf errors, total leaf travel distance, and beam-on time were 20 mm/s, 0.39 +/- 0.16 mm, 1385 cm, and 157 s, respectively. The starting phase, whether at maximal inhalation or exhalation had a relatively small contribution to PPS (0.01 +/- 0.05). CONCLUSIONS: By selecting collimator angle, couch angle, and starting tracking phase, 4D DCAT plans with the maximal PPS demonstrated less MLC leaf position errors, lower maximal MLC leaf speed, and shorter beam-on time which improved the performance of 4D motion-tracking DCAT delivery. PMID- 28730654 TI - Extensive wildfires, climate change, and an abrupt state change in subalpine ribbon forests, Colorado. AB - Ecosystems may shift abruptly when the effects of climate change and disturbance interact, and landscapes with regularly patterned vegetation may be especially vulnerable to abrupt shifts. Here we use a fossil pollen record from a regularly patterned ribbon forest (alternating bands of forests and meadows) in Colorado to examine whether past changes in wildfire and climate produced abrupt vegetation shifts. Comparing the percentages of conifer pollen with sedimentary delta18 O data (interpreted as an indicator of temperature or snow accumulation) indicates a first-order linear relationship between vegetation composition and climate change with no detectable lags over the past 2,500 yr (r = 0.55, P < 0.001). Additionally, however, we find that the vegetation changed abruptly within a century of extensive wildfires, which were recognized in a previous study to have burned approximately 80% of the surrounding 1,000 km2 landscape 1,000 yr ago when temperatures rose ~0.5 degrees C. The vegetation change was larger than expected from the effects of climate change alone. Pollen assemblages changed from a composition associated with closed subalpine forests to one similar to modern ribbon forests. Fossil pollen assemblages then remained like those from modern ribbon forests for the following ~1,000 yr, providing a clear example of how extensive disturbances can trigger persistent new vegetation states and alter how vegetation responds to climate. PMID- 28730655 TI - High-intensity interval training vs. moderate interval training: the lack of equalisation, an ongoing problem. PMID- 28730656 TI - Spontaneous pregnancy during ulipristal acetate treatment of giant uterine leiomyoma. AB - WHAT IS KNOWN AND OBJECTIVE: Ulipristal acetate, a progesterone receptor modulator, pharmacologically inhibits endometrial proliferation and thereby prevents pregnancy. It is primarily used as emergency contraception, but also for the treatment of fibroids in women of reproductive age. There have been no published cases of pregnancy, while on therapy with ulipristal acetate. CASE DESCRIPTION: In this article, we present a case report of spontaneous pregnancy during ulipristal acetate therapy. WHAT IS NEW AND CONCLUSION: To our knowledge, this is the first patient with spontaneous conception, while on ulipristal acetate treatment. There were no drug-related complications, and the pregnancy resulted in the delivery of a healthy baby. PMID- 28730657 TI - Higher levels of cardiorespiratory fitness keep liver mitochondria happy! PMID- 28730658 TI - Ferroelectrics as Smart Mechanical Materials. AB - The mechanical properties of materials are insensitive to space inversion, even when they are crystallographically asymmetric. In practice, this means that turning a piezoelectric crystal upside down or switching the polarization of a ferroelectric should not change its mechanical response. Strain gradients, however, introduce an additional source of asymmetry that has mechanical consequences. Using nanoindentation and contact-resonance force microscopy, this study demonstrates that the mechanical response to indentation of a uniaxial ferroelectric (LiNbO3 ) does change when its polarity is switched, and use this mechanical asymmetry both to quantify its flexoelectricity and to mechanically read the sign of its ferroelectric domains. PMID- 28730659 TI - Reply to letter to the editor: high-intensity interval training vs. moderate intensity continuous training: the lack of equalization, an ongoing problem. PMID- 28730661 TI - Patch testing in non-immediate cutaneous adverse drug reactions: value of extemporaneous patch tests. AB - BACKGROUND: Patch testing following a standardized protocol is reliable for identifying the culprit drug in cutaneous adverse drug reactions (CADRs). However, these patch tests (PTs) require pharmaceutical material and staff, which are not always easily available. OBJECTIVES: To evaluate an extemporaneous PT method in CADRs. METHODS: We retrospectively analysed data for all patients referred to our department between March 2009 and June 2013 for patch testing after a non-immediate CADR. The patients who supplied their own suspected drugs were tested both with extemporaneous PTs and with conventional PTs. Extemporaneous PTs involved a nurse crushing and diluting the drug in pet. in a ratio of approximately one-third to two-thirds. Standardized PTs were performed according to guidelines, with commercial drugs diluted to 30% or with active ingredients diluted to 10%. We analysed the data for the two PT methods in terms of the number of positive test reactions, drugs tested, and type of CADR for patients in whom the two PT methods were used. RESULTS: In total, 75 of 156 patients underwent the two PT procedures, including 91 double tests. Overall, 21 tests gave positive reactions with the two methods, and 69 other tests gave negative results with the two methods. CONCLUSION: Our series yielded results similar to those of published series concerning the types of CADR and the drugs responsible. Our results suggest that, for CADRs, if a patient supplies a suspected drug but if the pharmaceutical material and staff are not available for conventional PTs, extemporaneous PTs performed by the nurse with the commercial drug used by the patient can be useful and reliable. PMID- 28730660 TI - Bezlotoxumab: A Novel Agent for the Prevention of Recurrent Clostridium difficile Infection. AB - During the past decade, the incidence and severity of Clostridium difficile infection (CDI) have significantly increased, leading to a rise in CDI-associated hospitalizations, health care costs, and mortality. Although treatment options exist for CDI, recurrence is frequent following treatment. Furthermore, patients with at least one CDI recurrence are at an increased risk of developing additional recurrences. A novel approach to the prevention of recurrent CDI is the use of monoclonal antibodies directed against the toxins responsible for CDI as an adjunct to antibiotic treatment. Bezlotoxumab, a human monoclonal antibody that binds and neutralizes C. difficile toxin B, is the first therapeutic agent to receive United States Food and Drug Administration approval for the prevention of CDI recurrence. Clinical studies have demonstrated superior efficacy of bezlotoxumab in adults receiving antibiotic therapy for CDI compared with antibiotic therapy alone for the prevention of CDI recurrence. Bezlotoxumab was well tolerated in clinical trials, with the most common adverse effects being nausea, vomiting, fatigue, pyrexia, headache, and diarrhea. The demonstrated efficacy, safety, and characteristics of bezlotoxumab present an advance in prevention of CDI recurrence. PMID- 28730662 TI - Telomere length and angiogenic cytokines in knee osteoarthritis. PMID- 28730663 TI - Acceptance of a structured diagnostic interview in children, parents, and interviewers. AB - The objective of this study was to investigate the satisfaction and acceptance of a structured diagnostic interview in clinical practice and in a research setting. Using the Structured Diagnostic Interview for Mental Disorders in Children and Adolescents (Kinder-DIPS), 28 certified interviewers conducted 202 interviews (115 with parents, 87 with children). After each interview, children, parents, and interviewers completed a questionnaire assessing the overall satisfaction (0 = not at all satisfied to 100 = totally satisfied) and acceptance (0 = completely disagree to 3 = completely agree) with the interview. Satisfaction ratings were highly positive, all means >82. The mean of the overall acceptance for children was 2.43 (standard deviation [SD] = 0.41), 2.54 (SD = 0.33) of the parents, 2.30 (SD = 0.43) of the children's interviewers, and 2.46 (SD = 0.32) of the parents' interviewers. Using separate univariate regression models, significant predictors for higher satisfaction and acceptance with the interview are higher children's Global Assessment of Functioning, fewer number of children's diagnoses, shorter duration of the interview, a research setting, female sex of the interviewer, and older age of the interviewer. Results indicate that structured diagnostic interviews are highly accepted by children, parents, and interviewers. Importantly, this is true for different treatment settings. PMID- 28730664 TI - Exploring approaches to dietetic assessment of a common task across different universities through assessment moderation. AB - BACKGROUND: Assessment presents one of the greatest challenges to evaluating health professional trainee performance, as a result of the subjectivity of judgements and variability in assessor standards. The present study aimed to test a moderation procedure for assessment across four independent universities and explore approaches to assessment and the factors that influence assessment decisions. METHODS: Assessment tasks designed independently by each of the four universities to assess student readiness for placement were chosen for the present study. Each university provided four student performance recordings for moderation. Eight different academic assessors viewed the student performances and assessed them using the corresponding university assessment instrument. Assessment results were collated and presented back to the assessors, together with the original university assessment results. Results were discussed with assessors to explore variations. The discussion was recorded, transcribed, thematically analysed and presented back to all assessors to achieve consensus on the emerging major learnings. RESULTS: Although there were differences in absolute scores, there was consistency (12 out of 16 performances) in overall judgement decisions regarding placement readiness. Proficient communication skills were considered a key factor when determining placement readiness. The discussion revealed: (i) assessment instruments; (ii) assessor factors; and (iii) the subjectivity of judgement as the major factors influencing assessment. CONCLUSIONS: Assessment moderation is a useful method for improving the quality of assessment decisions by sharing understanding and aligning standards of performance. PMID- 28730665 TI - Is DNA ploidy related to smoking? AB - BACKGROUND: In the oral cavity, genomic instability is caused by long-term exposure to carcinogens. The aim of this study was to evaluate the relationship between smoking and DNA ploidy. METHODS: Cytological material was obtained from patients participating in the Outpatient Smoking Treatment Program of the Heart Institute (INCOR-HCFMUSP), and of the Discipline of Oral Medicine (ICT-UNESP). The inclusion criteria for all groups were the absence of a history of malignant tumors, absence of clinical signs of changes in the selected area, and alcohol consumption of less than 3 units per week. Group 1:30 smokers before smoking cessation treatment; Group 2:30 non-smokers; Group 3:30 ex-smokers abstinent for at least 1 year. Cytological smears were collected from the floor of the mouth and border of the tongue and stained by Feulgen. Aneuploidy was evaluated using the ACIS(r) III system. RESULTS: The Kruskal-Wallis test showed no statistically significant difference (P = .4383) between the groups studied. No association between tobacco consumption and aneuploidy was observed in group 1 (P = 1) or group 2 (P = .68; Fisher's exact test). CONCLUSION: Smoking was not associated with changes in DNA content or the incidence of aneuploidy in normal oral mucosa. PMID- 28730666 TI - Weaning of proton pump inhibitors in patients with suspected laryngopharyngeal reflux disease. AB - OBJECTIVE: To evaluate the feasibility of a proton pump inhibitor (PPI) weaning protocol in a cohort of patients following successful empiric treatment for suspected laryngopharyngeal reflux disease (LPRD). STUDY DESIGN: Retrospective chart review. METHODS: LPRD patients were weaned from PPIs using a standardized weaning protocol. Symptom recurrence rate following PPI wean and present PPI use were determined. All numeric data were analyzed. The setting was a tertiary laryngology practice. The subjects were patients who had a positive response to empiric treatment for LPRD and subsequently were weaned from PPI therapy. RESULTS: Thirty-five patients with suspected LPRD were instructed to wean from PPI after successful empiric treatment of their LPRD symptoms from July 2013 to September 2015. Twenty-three patients (66%) remained symptom-free post-wean. Twelve patients (34%) had symptom recurrence post-wean; of those, 11 of them (92%) needed to go back on a PPI. Median durations of follow-up for the unsuccessful wean group and the successful wean group were 13 (range 6-29) months and 18 (range 6-38) months, respectively. Pre-wean and post-wean reflux symptom index (RSI) scores in the unsuccessful wean group were 7.7 +/- 5.6 and 12.9 +/- 6 (P = .11). Pre-wean and post-wean RSI scores in the successful wean group were 8.1 +/- 6.5 and 8.1 +/- 9.0 (P < .99). Body mass index (BMI) was found to be a significant predictor of failure to wean (odds ratio = 0.72, 95% confidence interval = 0.55-0.95) after controlling for age, sex, PPI treatment duration, and PPI regime. None of the other covariates were found to be significant predictors of failure of PPI wean. CONCLUSION: Approximately 66% of patients who were on PPIs for LPRD were successfully weaned. High BMI was significantly predictive of failure to wean. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:133-137, 2018. PMID- 28730667 TI - Role of plasma exchange, leukocytapheresis, and plasma diafiltration in management of refractory macrophage activation syndrome. AB - Macrophage activation syndrome (MAS) is a life-threating complication of systemic juvenile idiopathic arthritis (s-JIA). Steroid and cyclosporine (CsA) are effective for MAS, but, treatment for steroid- and CsA-resistant patients is still challenging. We report the case of steroid and CsA resistant s-JIA associated MAS misdiagnosed as Kawasaki disease (KD), who was successfully treated with the combination of plasma exchange (PE) and leukocytapheresis (LCAP) followed by plasma diafiltration (PDF). PE + LCAP effectively removed proinflammatory cytokines and reduced the number of peripheral white blood cells. Furthermore, PDF also removed proinflammatory cytokines as effectively as PE + LCAP. Early diagnosis of s-JIA is necessary to avoid developing MAS. The measurement of serum ferritin and IL-18 levels are useful for differentiating s JIA from KD. Apheresis therapies are an alternative option to induce remission for severe patients with steroid- or CsA-resistant MAS. PMID- 28730668 TI - Recurrent triploid digynic conceptions and mature ovarian teratomas: Are they different manifestations of the same genetic defect? AB - Miscarriages affect 15% of clinically recognized pregnancies. Recurrent miscarriage (RM) is defined by the occurrence of at least two consecutive pregnancy losses and affects 1%-5% of couples trying to conceive. In an attempt to categorize patients with RM and identify the mechanisms leading to their miscarriages, we first used flow cytometry to assess the ploidy of 93 products of conception (POCs) from 53 patients with RM (>=3 miscarriages). We identified a single patient with four triploid POCs. We then used fluorescent in situ hybridization to confirm the triploidies and fluorescent microsatellite genotyping with distal and pericentromeric markers to determine their parental origin and the mechanisms leading to their formation. We found that all four triploidies were digynic and due to a failure in meiosis II (MII), suggesting a genetic predisposition. Upon further investigation into the family, we found a remarkable history of ovarian cysts and dysfunctions on the maternal side. Notably, one maternal cousin had a mature ovarian teratoma that we analyzed and found an identical mechanism at its origin, a failure in MII. The identification of two patients in the same family with two different manifestations-digynic triploid conceptions and mature ovarian teratomas, both resulting from the failure of MII-suggests an inherited genetic susceptibility toward an error in MII segregating in the family that may manifest in the form of a triploid digynic miscarriage or a mature ovarian teratoma. Our findings may facilitate the future identification of causative mutations for MII defects. PMID- 28730670 TI - Molluscum Contagiosum-Like Presentation of Langerhans Cell Histiocytosis: A Case and Review. AB - Langerhans cell histiocytosis (LCH) is a rare disorder characterized by clonal proliferation of Langerhans cells in the skin. A molluscum-like presentation of cutaneous LCH is rare but important to consider for examination and management. We present an atypical molluscum-like LCH case and review the literature for common features of this unusual presentation. PMID- 28730669 TI - Primary prevention implantable cardioverter-defibrillator therapy: a matter not yet adequately explored waiting for guidelines update. PMID- 28730671 TI - Many faces of rationality: Implications of the great rationality debate for clinical decision-making. AB - Given that more than 30% of healthcare costs are wasted on inappropriate care, suboptimal care is increasingly connected to the quality of medical decisions. It has been argued that personal decisions are the leading cause of death, and 80% of healthcare expenditures result from physicians' decisions. Therefore, improving healthcare necessitates improving medical decisions, ie, making decisions (more) rational. Drawing on writings from The Great Rationality Debate from the fields of philosophy, economics, and psychology, we identify core ingredients of rationality commonly encountered across various theoretical models. Rationality is typically classified under umbrella of normative (addressing the question how people "should" or "ought to" make their decisions) and descriptive theories of decision-making (which portray how people actually make their decisions). Normative theories of rational thought of relevance to medicine include epistemic theories that direct practice of evidence-based medicine and expected utility theory, which provides the basis for widely used clinical decision analyses. Descriptive theories of rationality of direct relevance to medical decision-making include bounded rationality, argumentative theory of reasoning, adaptive rationality, dual processing model of rationality, regret-based rationality, pragmatic/substantive rationality, and meta rationality. For the first time, we provide a review of wide range of theories and models of rationality. We showed that what is "rational" behaviour under one rationality theory may be irrational under the other theory. We also showed that context is of paramount importance to rationality and that no one model of rationality can possibly fit all contexts. We suggest that in context-poor situations, such as policy decision-making, normative theories based on expected utility informed by best research evidence may provide the optimal approach to medical decision-making, whereas in the context-rich circumstances other types of rationality, informed by human cognitive architecture and driven by intuition and emotions such as the aim to minimize regret, may provide better solution to the problem at hand. The choice of theory under which we operate is important as it determines both policy and our individual decision-making. PMID- 28730672 TI - Lipid-lowering therapy of everolimus-related severe hypertriglyceridaemia in a pancreatic neuroendocrine tumour (pNET). AB - WHAT IS KNOWN AND OBJECTIVE: Hypertriglyceridaemia (HTG) is a potentially serious side effect of everolimus therapy. We here report a case of severe HTG in an everolimus-treated patient and provide recommendations for its management. CASE SUMMARY: The patient was a 70-year-old woman, being treated with everolimus for a pancreatic neuroendocrine tumour (pNET). She developed severe HTG to a maximum of 969 mg/dL after 22 months of therapy. Treatment with fenofibrate rapidly normalized triglyceride (TG) levels. WHAT IS NEW AND CONCLUSION: Severe HTG may occur in everolimus-treated patients. Prescription of the appropriate therapy can allow patients to continue this medication. PMID- 28730673 TI - Autonomic dysfunction as a mechanism of intradialytic blood pressure instability. AB - The autonomic nervous system (ANS) is the principal endogenous defense mechanism that maintains blood pressure in the setting of hypotension. Disruption of the ANS impairs this ability and can contribute to blood pressure instability, including hypotension and hypertension. In this narrative review, we provide an overview of the ANS and the consequences of its dysfunction in patients with end stage kidney disease treated with dialysis. We also discuss possible mechanisms of this autonomic dysfunction that may need future investigation. PMID- 28730674 TI - Long-term therapy with ustekinumab for psoriasis in a patient with a history of malignant melanoma. PMID- 28730675 TI - Hierarchical Hybrids Integrated by Dual Polypyrrole-Based Porous Carbons for Enhanced Capacitive Performance. AB - Architectural design of nitrogenous polymer-based carbons represents a facile and efficient strategy to improve performance because of their morphological diversity, tailorability, and N-containing structure. In this research, 0D and 1D forms of polypyrrole-derived porous carbons (A-PCS and A-PCT, respectively) are first integrated into nitrogen-doped hierarchically porous A-PCS/PCT hybrids by applying an easy multistep method. This integration, along with chemical activation, prevents serious agglomeration of carbon particles or tubes and creates a connected porous network structure, leading to improved textural properties (high surface area of 1684 m2 g-1 , high pore volume of 1.57 cm3 g-1 , and hierarchical porosity). Thus, A-PCS/PCT hybrids in a three-electrode setup reach high specific capacitances of 224 and 206 F g-1 at 1 and 20 A g-1 , respectively, with high rate capability (92 % capacitance retention). A symmetrical supercapacitor with A-PCS/PCT electrodes presents the highest power and energy densities of 12.6 kW kg-1 and 8.58 Wh kg-1 , respectively, and exceptional cycling life and stability with 92.4 % retention for up to 20 000 cycles. This study on conductive polymer-based hybrid materials may guide the design of architectures with new structures for applications in energy storage and conversion technologies. PMID- 28730676 TI - Evaluation of the specific effects of intranasal glucagon on glucose production and lipid concentration in healthy men during a pancreatic clamp. AB - AIM: To investigate the specific effects of intranasal glucagon (ING) on plasma glucose, endogenous glucose production (EGP) and lipid concentration. METHODS: We conducted a single-blind, randomized, crossover study at our academic investigation unit. Under pancreatic clamp conditions with tracer infusion, 1 mg ING or intranasal placebo (INP) was administered to 10 healthy men. As pilot studies showed that ING transiently increased plasma glucagon, we infused intravenous glucagon for 30 minutes along with INP to ensure similar plasma glucagon concentrations between interventions. The main outcome measures were plasma glucose, EGP, free fatty acid (FFA) and triglyceride (TG) concentrations. RESULTS: In the presence of similar plasma glucagon concentrations, the increase in plasma glucose under these experimental conditions was attenuated with ING (mean plasma glucose analysis of variance P < .001) with reduction in EGP (P = .027). No significant differences were seen in plasma FFA and TG concentrations. CONCLUSION: ING raises plasma glucose but this route of administration attenuates the gluco-stimulatory effect of glucagon by reducing EGP. This observation invites speculation about a potential central nervous system effect of glucagon, which requires further investigation. If ING is developed as a treatment for hypoglycaemia, this attenuated effect on plasma glucose should be taken into account. PMID- 28730677 TI - Discovery and Total Synthesis of Natural Cystobactamid Derivatives with Superior Activity against Gram-Negative Pathogens. AB - Antibiotic discovery and development is challenging as chemical scaffolds of synthetic origin often lack the required pharmaceutical properties, and the discovery of novel ones from natural sources is tedious. Herein, we report the discovery of new cystobactamids with a significantly improved antibacterial profile in a detailed screening of myxobacterial producer strains. Some of these new derivatives display antibacterial activities in the low-MUg mL-1 range against Gram-negative pathogens, including clinical isolates of Klebsiella oxytoca, Pseudomonas aeruginosa, and fluoroquinolone-resistant Enterobacteriaceae, which were not observed for previously reported cystobactamids. Our findings provide structure-activity relationships and show how pathogen resistance can be overcome by natural scaffold diversity. The most promising derivative 861-2 was prepared by total synthesis, enabling further chemical optimization of this privileged scaffold. PMID- 28730678 TI - Prognosis following cancer surgery during holiday periods. AB - Surgery is the mainstay curative treatment in most cancer. We aimed to test the new hypothesis that cancer surgery performed during holiday periods is associated with worse long-term prognosis than for non-holiday periods. This nationwide Swedish population-based cohort study included 228,927 patients during 1997-2014 who underwent elective resectional surgery for a cancer where the annual number of resections was over 100. The 16 eligible cancer sites were grouped into 10 cancer groups. The exposure, holiday periods, was classified as wide (14-weeks) or narrow (7-weeks). Surgery conducted inside versus outside holiday periods was compared regarding overall disease-specific (main outcome) and overall all-cause (secondary outcome) mortality. Cox regression provided hazard ratios (HR) with 95% confidence intervals (CI) adjusted for age, sex, comorbidity, hospital volume, calendar period and tumor stage. Surgery conducted during wide and narrow holiday periods were associated with increased HRs of disease-specific mortality for cancer of the breast (HR 1.08, 95% CI 1.03-1.13 and HR 1.06, 95% CI 1.01 1.12) and possibly of cancer of the liver-pancreas-bile ducts (HR 1.09, 95% CI 0.99-1.20 and HR 1.12, 95% CI 0.99-1.26). Sub-groups with cancer of the colon rectum, head-and-neck, prostate, kidney-urine bladder and thyroid also experienced statistically significantly worse prognosis following surgery conducted during holiday periods. No influence of surgery during holiday was detected for cancer of the esophagus-stomach, lung or ovary-uterus. All-cause HRs were similar to the disease-specific HRs. The prognosis following cancer surgery might not be fully maintained during holiday periods for all cancer sites. PMID- 28730679 TI - Weighing in on international growth standards: testing the case in Australian preschool children. AB - Overweight and obesity in preschool-aged children are major health concerns. Accurate and reliable estimates of prevalence are necessary to direct public health and clinical interventions. There are currently three international growth standards used to determine prevalence of overweight and obesity, each using different methodologies: Center for Disease Control (CDC), World Health Organization (WHO) and International Obesity Task Force (IOTF). Adoption and use of each method were examined through a systematic review of Australian population studies (2006-2017). For this period, systematically identified population studies (N = 20) reported prevalence of overweight and obesity ranging between 15 and 38% with most (n = 16) applying the IOTF standards. To demonstrate the differences in prevalence estimates yielded by the IOTF in comparison to the WHO and CDC standards, methods were applied to a sample of N = 1,926 Australian children, aged 3-5 years. As expected, the three standards yielded significantly different estimates when applied to this single population. Prevalence of overweight/obesity was WHO - 9.3%, IOTF - 21.7% and CDC - 33.1%. Judicious selection of growth standards, taking account of their underpinning methodologies and provisions of access to study data sets to allow prevalence comparisons, is recommended. PMID- 28730680 TI - Cervical stability training with and without core stability training for patients with cervical disc herniation: A randomized, single-blind study. AB - BACKGROUND: This study aims at evaluating and comparing the effects of cervical stability training to combined cervical and core stability training in patients with neck pain and cervical disc herniation. METHODS: Fifty patients with neck pain and cervical disc herniation were included in the study, randomly divided into two groups as cervical stability and cervical-core stability. Training was applied three times a week in three phases, and lasted for a total duration of 8 weeks. Pain, activation and static endurance of deep cervical flexor muscles, static endurance of neck muscles, cross-sectional diameter of M. Longus Colli, static endurance of trunk muscles, disability and kinesiophobia were assessed. RESULTS: Pain, activation and static endurance of deep cervical flexors, static endurance of neck muscles, cross-sectional diameter of M. Longus Colli, static endurance of trunk muscles, disability and kinesiophobia improved in both groups following the training sessions (p < 0.05). Comparison of the effectiveness of these two training methods revealed that the cervical stability group produced a greater increase in the right transverse diameter of M. Longus Colli (p < 0.05). However, static endurance of trunk muscles and kinesiophobia displayed better improvement in the cervical-core stability group (p < 0.05). CONCLUSIONS: Cervical stability training provided benefit to patients with cervical disc herniation. The addition of core stability training did not provide any additional significant benefit. Further research is required to investigate the efficacy of combining other techniques with cervical stability training in patients with cervical disc herniation. SIGNIFICANCE: Both cervical stability training and its combination with core stability training were significantly and similarly effective on neck pain and neck muscle endurance in patients with cervical disc herniation. PMID- 28730681 TI - Histone variants expression in peripheral blood mononuclear cells of patients with rheumatoid arthritis. AB - AIM: The purpose of the present study was to analyze the expression of four histone variants, implicated in the regulation of gene expression, in peripheral blood mononuclear cell (PBMC) samples of patients with rheumatoid arthritis and healthy controls. METHOD: We analyzed the expression of three genes encoding histone variants H3.3, H2A.Z, macroH2A1.1 and macroH2A1.2 in PBMC samples of 50 patients with RA, diagnosed according to American College of Rheumatology (ACR) criteria, and 51 matched healthy controls using SYBR green real-time polymerase chain reaction. Mann-Whitney U-test and Spearman correlation were used for data analysis. RESULTS: The expression of H2A.Z was increased by 1.51-fold (P < 0.001) and the expression of H3.3 was increased by 1.13-fold (P = 0.048) in PBMCs of patients with RA compared to healthy controls. Furthermore, we found a positive correlation between Disease Activity Score (DAS-28) based on erythrocyte sedimentation rate and the expression of H2A.Z. CONCLUSIONS: Given the role of H3.3 and H2A.Z in nucleosome positioning, chromatin structure and transcription regulation, we suggest that lymphocytes and monocytes, the main cell subtypes in PBMCs of RA patients, possess a more accessible chromatin. PMID- 28730683 TI - Ectopic fat accumulation in the pancreas and its biomarkers: A systematic review and meta-analysis. AB - Presence of fat in the pancreas increases the risk of metabolic co-morbidities. Detection and quantification of pancreatic fat is not a routine clinical practice, at least in part because of need to use expensive imaging techniques. We aimed to systematically review common markers of pancreatic fat in blood and to investigate differences in these markers associated with fatty pancreas. The search was conducted in 3 databases (EMBASE, Scopus, and MEDLINE). Studies in humans were eligible for inclusion if they reported on biological markers and percentage of pancreatic fat or fatty pancreas prevalence. Data were pooled for correlation and effect size meta-analysis. A total of 17 studies including 11 967 individuals were eligible for meta-analysis. Markers of lipid metabolism, including circulating triglycerides (r = 0.38 [95% confidence interval (CI) 0.31, 0.46]) and high-density lipoprotein cholesterol (r = -0.33 [95% CI -0.35, 0.31]), and markers of glucose metabolism, including glycated haemoglobin (r = 0.39 [95% CI 0.30, 0.48], insulin (r = 0.38 [95% CI 0.33, 0.43]), and homeostasis model assessment-insulin resistance (r = 0.37 [95% CI 0.30, 0.44], yielded the best correlations with percentage of pancreatic fat. Further, effect size analysis showed large and medium effects for the above markers of lipid and glucose metabolism. Circulating levels of triglycerides and glycated haemoglobin appear to be the best currently available markers of pancreatic fat. The approach of non-invasive and accurate detection of pancreatic fat by blood analysis should be further explored in the future, by investigating other potential biological markers of pancreatic fat. PMID- 28730684 TI - Chest wall lymphomas: Fine needle aspiration cytodiagnosis and review of the literature. AB - OBJECTIVE: Compared to other chest wall malignancies, lymphoma is a common disease. However, published literature on a series of lymphoma cases involving the chest wall is scarce. The aim of the present study, was to describe experience with chest wall swellings diagnosed as lymphoid neoplasms on fine needle aspiration (FNA) cytology. METHODS: Eleven chest wall swellings were diagnosed as lymphoid neoplasms on FNA over a period of 15 years (January 2000 December 2014). The age of patients ranged from 19 to 73 years (median, 46). The male-to -emale ratio was 7:4. Ten cases had an anterior or lateral chest wall mass, and one swelling was in the scapular region. Six cases had concurrent lymphadenopathy, and one had bone involvement. The FNA smears were reviewed and classified under WHO Classification of Hematopoietic Neoplasms. The histopathological diagnoses were available in eight cases. RESULTS: The preliminary cytodiagnoses in 11 cases of chest wall lymphoid neoplasms were anaplastic large cell lymphoma (ALCL) in two cases, and ALCL/malignant melanoma, ALCL/T-cell-rich-B-cell lymphoma (TCRBCL)/Hodgkin's lymphoma (HL), plasmacytoma/neuroendocrine carcinoma, Hodgkin's lymphoma, small cell NHL/CLL, NHL, suggestive of NHL, post-transplant peripheral T-cell lymphoma (PTCL), and a malignant plasma cell tumour in one case each. The reviewed cytodiagnoses of lymphoid neoplasms were as follows: ALCL ( five cases), centroblastic lymphoma (two cases), and small cell lymphoma/CLL, post-transplant peripheral T-cell lymphoma, Hodgkin's lymphoma and plasmacytoma (one case each). Histopathological diagnoses available in eight cases confirmed the presence of lymphoid neoplasms. CONCLUSION: A variety of lymphoid neoplasms involved the chest wall, and among them, ALCL was a common form. PMID- 28730682 TI - Structure and development of the subesophageal zone of the Drosophila brain. I. Segmental architecture, compartmentalization, and lineage anatomy. AB - The subesophageal zone (SEZ) of the Drosophila brain houses the circuitry underlying feeding behavior and is involved in many other aspects of sensory processing and locomotor control. Formed by the merging of four neuromeres, the internal architecture of the SEZ can be best understood by identifying segmentally reiterated landmarks emerging in the embryo and larva, and following the gradual changes by which these landmarks become integrated into the mature SEZ during metamorphosis. In previous works, the system of longitudinal fibers (connectives) and transverse axons (commissures) has been used as a scaffold that provides internal landmarks for the neuromeres of the larval ventral nerve cord. We have extended the analysis of this scaffold to the SEZ and, in addition, reconstructed the tracts formed by lineages and nerves in relationship to the connectives and commissures. As a result, we establish reliable criteria that define boundaries between the four neuromeres (tritocerebrum, mandibular neuromere, maxillary neuromere, labial neuromere) of the SEZ at all stages of development. Fascicles and lineage tracts also demarcate seven columnar neuropil domains (ventromedial, ventro-lateral, centromedial, central, centrolateral, dorsomedial, dorsolateral) identifiable throughout development. These anatomical subdivisions, presented in the form of an atlas including confocal sections and 3D digital models for the larval, pupal and adult stage, allowed us to describe the morphogenetic changes shaping the adult SEZ. Finally, we mapped MARCM-labeled clones of all secondary lineages of the SEZ to the newly established neuropil subdivisions. Our work will facilitate future studies of function and comparative anatomy of the SEZ. PMID- 28730686 TI - High-resolution manometry assessment of the lower esophageal sphincter after contraction: Normative values and clinical correlation. AB - BACKGROUND: The Chicago Classification v3.0 proposed extending the distal contractile integral (DCI) measurement domain to include the lower esophageal sphincter (LES) to enhance the detection of esophageal hypercontractility. However, normative and clinical data for this approach are unreported. We aimed to describe the application of an extended DCI measurement in asymptomatic controls and patients. METHODS: High-resolution manometry (HRM) of 65 asymptomatic controls and 72 patients with normal motility were evaluated retrospectively. Dysphagia and chest pain symptoms were assessed using the brief esophageal dysphagia questionnaire (BEDQ); >=10 was considered abnormal. HRM studies of 10 supine swallows were evaluated via the standard DCI and an extended DCI measurement domain (DCI+) to include the lower esophageal sphincter (LES) during and after the peristaltic wave. The DCI-increment was calculated as the DCI+ minus DCI. KEY RESULTS: Among controls, the median (5-95th percentile) DCI+ was 1915 (1359-6921) mm Hg/cm/s and DCI-increment was 534 (126-1488) mm Hg/cm/s. Two patients (3%) had >=2 swallows with DCI+ >8000 mm Hg/cm/s and seven (10%) patients had at least one swallow with DCI+ >8000 mm Hg/cm/s, ie, had potential motility reclassification by application of DCI+. Seven of these nine patients (78%) were evaluated for dysphagia or chest pain, but only 3/9 (33%) had an abnormal BEDQ. CONCLUSIONS AND INFERENCES: Extension of the DCI measurement domain may aid quantifying hypercontractility that involves the LES. However, adjusting management strategies based on reclassification of patients with otherwise normal motility should be cautiously considered. PMID- 28730685 TI - TEX15: A DNA repair gene associated with prostate cancer risk in Han Chinese. AB - BACKGROUND: Both common and rare genetic variants may contribute to risk of developing prostate cancer. Genome-wide association studies (GWASs) have identified ~100 independent, common variants associated with prostate cancer risk. However, little is known about the association of rare variants (minor allele frequency [MAF] <1%) in the genome with prostate cancer risk. METHODS: A two-stage study was used to test the association of rare, deleterious coding variants, annotated using predictive algorithms, with prostate cancer risk in Chinese men. Predicted rare, deleterious coding variants in the Illumina HumanExome-12 v1.1 beadchip were first evaluated in 1343 prostate cancer patients and 1008 controls. Significant variants were then validated in an additional 1816 prostate cancer patients and 1549 controls. RESULTS: In the discovery stage, 14 predicted rare, deleterious coding variants were significantly associated with prostate cancer risk (P < 0.01). In the confirmation stage, Q1631H in TEX15 (rs142485241), a DNA repair gene, was significantly associated with prostate cancer risk (P = 0.0069). The estimated odds ratio (OR) of the variant in the combined analysis was 3.24 (95% Confidence Interval 1.85-6.06), P = 8.81 * 10-5 . Additionally, rs28756990 (V741F) at MLH3 (P = 0.06) and rs2961144 (I126V) at OR2A5 (P = 0.065) were marginally associated with prostate cancer risk in the replication stage. CONCLUSIONS: Our study provided preliminary evidence that the rare variant Q1631H in DNA repair gene TEX15 is associated with prostate cancer risk. This finding complements known common prostate cancer risk-associated variants and suggests the possible role of DNA repair genes in prostate cancer development. PMID- 28730687 TI - Efficacy of abatacept in patients with rheumatoid arthritis, as assessed by magnetic resonance imaging of bilateral hands. AB - AIM: To examine the efficacy of abatacept in patients with rheumatoid arthritis (RA) using magnetic resonance imaging (MRI) of bilateral hands. METHOD: This prospective study included 35 RA patients. MRI of bilateral hands was performed at baseline and after 12 months of treatment with intravenous abatacept. MRI images were scored for synovitis, osteitis, erosion and joint space narrowing (JSN) according to the RA MRI Scoring System (RAMRIS). The primary endpoint was the change in RAMRIS score from baseline. Repair of erosion was defined as a negative change in the erosion score that was greater than the smallest detectable changes (SDCs). RESULTS: Thirty-one patients completed the study. Median synovitis and osteitis scores showed statistically significant reductions at Month 12 when compared to baseline (synovitis score, -5.5 [P < 0.0001]; osteitis score, -0.5 [P = 0.03]). However, median erosion and JSN scores did not significantly change. At Month 12, 83% of patients showed no progression of erosion scores and repair of erosion was observed in 11% of patients. All patients with repair of erosion achieved functional remission (Health Assessment Questionnaire-Disability Index <= 0.5). The Simplified Disease Activity Index response rate at Month 1 was identified as an independent factor predicting changes in the erosion scores at Month 12. CONCLUSION: Abatacept treatment reduced synovitis and osteitis scores and did not worsen erosion and JSN scores at Month 12. Over 10% of patients experienced repair of erosion. PMID- 28730688 TI - Sense and Simplicity in HADDOCK Scoring: Lessons from CASP-CAPRI (page 418). PMID- 28730689 TI - Relationships among muscle fiber type composition, fiber diameter and MRF gene expression in different skeletal muscles of naturally grazing Wuzhumuqin sheep during postnatal development. AB - The aim of this study was to determine the relationships among muscle fiber-type composition, fiber diameter, and myogenic regulatory factor (MRF) gene expression in different skeletal muscles during development in naturally grazing Wuzhumuqin sheep. Three major muscles (i.e. the Longissimus dorsi (LD), Biceps femoris (BF) and Triceps brachii (TB)) were obtained from 20 Wuzhumuqin sheep and 20 castrated rams at each of the following ages: 1, 3, 6, 9, 12 and 18 months. Muscle fiber type composition and fiber diameter were measured using histochemistry and morphological analysis, and MRF gene expression levels were determined using real time PCR. In the LD muscle, changes in the proportion of each of different types of fiber (I, IIA and IIB) were relatively small. In the BF muscle, a higher proportion of type I and a 6.19-fold lower proportion of type IIA fibers were observed (P < 0.05). In addition, the compositions of type I and IIA fibers continuously changed in the TB muscle (P < 0.05). Moreover, muscle diameter gradually increased throughout development (P < 0.05). Almost no significant difference was found in MRF gene expression patterns, which appeared to be relatively stable. These results suggest that changes in fiber-type composition and increases in fiber size may be mutually interacting processes during muscle development. PMID- 28730690 TI - Incorporating Comprehensive Management of Direct Oral Anticoagulants into Anticoagulation Clinics. AB - Anticoagulation clinics emerged as a means to optimize warfarin effectiveness and minimize bleeding risks. Anticoagulation clinics have traditionally been warfarin based models due to the need for frequent blood-level monitoring, drug interactions, dietary considerations, and periprocedural management with warfarin. These models have demonstrated improved anticoagulation control and reduced bleeding complications for patients taking warfarin. Direct oral anticoagulants (DOACs) emerged with the perception of improved convenience due to the lack of blood-level monitoring and lack of dietary considerations. Despite the advantages of DOAC therapy, new challenges exist with their management, warranting ongoing monitoring. Such challenges include prescribing and dosing issues, drug adherence, drug interactions, and high drug cost. Comprehensive anticoagulation centers are needed to manage and monitor all oral anticoagulants including DOACs. The objectives of this review are to describe the challenges and opportunities that exist in the management of DOACs and to describe a practice model that integrates a DOAC management service into the traditional anticoagulation clinic. PMID- 28730691 TI - Effect of Abrupt Discontinuation of Antidepressants in Critically Ill Hospitalized Adults. AB - OBJECTIVES: To determine whether discontinuation of chronic antidepressant therapy is associated with a higher risk of antidepressant discontinuation syndrome (ADS) symptoms in patients admitted to the intensive care unit (ICU) when compared with those who were continued on therapy and to identify factors associated with increased risk of ADS in this population. DESIGN: Single-center retrospective observational cohort study. SETTING: ICUs in a tertiary care hospital. PATIENTS: A total of 106 adult patients, admitted to the ICU between September 2013 and August 2014, who had a length of stay of 72 hours or longer and who were receiving chronic selective serotonin inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) before admission. MEASUREMENTS AND MAIN RESULTS: Patients were classified as continued or discontinued from therapy based on initiation of home SSRI/SNRI therapy within 48 hours of admission. The primary end point was incidence of ADS symptoms. Type of symptoms, receipt of symptom-related therapies, and length of stay were also assessed. Sequential logistic regression analysis was used to determine the impact of discontinuation while controlling for other risk factors. Therapy was discontinued in 38.7% of patients. The risk of developing ADS symptoms was higher in discontinued patients (unadjusted odds ratio [OR] 2.6, 95% confidence interval [CI] 1.12-6.07, p=0.024). After adjusting for covariates, the odds of ADS increased (adjusted OR 3.8, 95% CI 1.3-11.7, p=0.018). Female sex was associated with an increase in risk of ADS (OR 3.4, 95% CI 1.2-10.0, p=0.026). Affective symptoms were the most prevalent type reported (34.1% vs 10.8%, p=0.005). Use of symptom-related therapies and length of stay did not differ between groups. CONCLUSION: Abrupt discontinuation of SSRI/SNRI therapy increases the risk of ADS symptoms in critically ill patients, particularly in females. These results underscore the importance of continuation of home antidepressant therapy even in the setting of critical illness. PMID- 28730692 TI - Self-perception of voice in transgender persons during cross-sex hormone therapy. AB - OBJECTIVE: Self-perception of voice has a significant psychosocial impact on transgender persons. Research about the evolution of self-perception of voice during cross-sex hormone therapy (CSHT) is lacking. The aim of this study was to examine if self-perception of voice changes during CSHT, and if a change of serum testosterone levels as a result of CSHT can predict a change of self-perception of voice. STUDY DESIGN: Prospective longitudinal study. METHODS: The Transsexual Voice Questionnaire (TVQ), consisting of three factors-anxiety and avoidance (AA), gender identity (GI), and voice quality (VQ)-was used. Transgender persons completed the TVQ at baseline (80 trans men and 103 trans women), after 3 and 12 months of CSHT follow-up. RESULTS: Trans men: From 0 to 3 months, 0 to 12 months, and 3 to 2 months of CSHT, the AA and GI scores improved. From 0 to 3 months of CSHT, the increasing testosterone level was predictive for the improvements of AA and GI scores. Trans women: From 0 to 3 months, the GI score improved. From 0 to 12 months, the AA, GI, and VQ scores improved. Improvements of self-perception of voice could not be predicted by changing serum testosterone levels. CONCLUSION: During CSHT, self-perception of voice improves in both trans men and trans women. In trans men only, the improving self-perception of voice during the first 3 months can be attributed to the CSHT. For trans women, this study supports that testosterone has acted irreversibly virializing to the voice before CSHT, if they already went through male puberty. LEVEL OF EVIDENCE: 4. Laryngoscope, 127:2796 2804, 2017. PMID- 28730693 TI - Fiber characteristics of pork muscle exhibiting different levels of drip loss. AB - The present study aimed to investigate the fiber characteristics of pork muscle exhibiting different levels of drip loss during storage. The samples were taken from Longissimus dorsi muscle to evaluate drip loss (n = 100). Fifteen muscles per group (low and high drip loss) were selected to evaluate the histological characteristics at 0 and 72 h of storage time. The statistical analysis revealed that a high drip loss group had greater endomysium thickness than a low drip loss group at 0 h of storage time (P < 0.05). There were no significant differences in total number of fibers, fiber diameter, fiber area and perimysium thickness at 0 h of storage time (P > 0.05). At 72 h of storage time, a high drip loss was evident in higher total number of fibers (P < 0.01), but smaller fiber diameter (P < 0.05), fiber area (P < 0.01) and endomysium thickness (P < 0.01) than a low drip loss group. There was no significant difference in perimysium thickness (P > 0.05). In conclusion, drip loss might be affected by muscle structural characteristics during storage. PMID- 28730694 TI - Pharmacodynamics, pharmacokinetics and safety of multiple ascending doses of the novel dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 agonist RG7697 in people with type 2 diabetes mellitus. AB - AIMS: To investigate the pharmacodynamics, pharmacokinetics and safety of multiple ascending doses of RG7697, a dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 agonist, in patients with type 2 diabetes mellitus (T2D). METHODS: A total of 56 patients with T2D received once-daily subcutaneous (s.c.) injection of RG7697 (0.25-2.5 mg) or placebo for 14 days in a randomized, double-blind, dose-escalation study. Adverse events (AEs), vital signs, ECGs and routine laboratory variables were intensively monitored. Drug concentrations, fasting glycaemic variables, 24-hour glucose profiles, glycated haemoglobin (HbA1c) and antibody formation were measured. Several meal tolerance and gastric emptying tests were performed during the study. RESULTS: Daily s.c. injections of RG7697 were well tolerated by the majority of participants with T2D. The most frequently reported AEs with RG7697 were diarrhoea, nausea and decreased appetite. Asymptomatic events of hypoglycaemia were relatively uniformly distributed across dose groups including placebo. Pharmacokinetic steady-state was achieved within 1 week. Meaningful reductions in fasting, postprandial and 24-hour plasma glucose profile were observed at doses >=0.75 mg, and were associated with numerical decreases in HbA1c (-0.67% [2.5-mg dose] vs 0.21% [placebo]). Decrease in postprandial insulin at doses >=1.1 mg suggested improvement in insulin sensitivity. Minimum delay in gastric emptying and body weight reductions numerically greater than placebo (- 3.0 kg vs -0.9 kg) were seen at the highest dose of 2.5 mg. CONCLUSIONS: Daily doses of RG7697 for 2 weeks were well tolerated by the majority of patients with T2D. Pharmacokinetic data supported once-daily dosing and pharmacodynamic effect displayed dose dependent reductions in fasting and postprandial plasma glucose, without increasing the risk of hypoglycaemia. PMID- 28730695 TI - Concurrent electrical cervicomedullary stimulation and cervical transcutaneous spinal direct current stimulation result in a stimulus interaction. AB - NEW FINDINGS: What is the central question of this study? We previously showed that the motor pathway is not modified after cervical transcutaneous spinal direct current stimulation (tsDCS) applied using anterior-posterior electrodes. Here, we examine the motor pathway during stimulation. What is the main finding and its importance? We show that electrically elicited muscle responses to cervicomedullary stimulation are modified during tsDCS, whereas magnetically elicited responses are not. Modelling reveals electrical field modifications during concurrent tsDCS and electrical cervicomedullary stimulation. Changes in muscle response probably result from electrical field modifications rather than physiological changes. Care should be taken when applying electrical stimuli simultaneously. Transcutaneous spinal direct current stimulation (tsDCS) can modulate neuronal excitability within the human spinal cord; however, few studies have used tsDCS at a cervical level. This study aimed to characterize cervical tsDCS further by observing its acute effects on motor responses to transcranial magnetic stimulation and cervicomedullary stimulation. In both studies 1 and 2, participants (study 1, n = 8, four female; and study 2, n = 8, three female) received two periods of 10 min, 3 mA cervical tsDCS on the same day through electrodes placed in an anterior-posterior configuration over the neck; one period with the cathode posterior (c-tsDCS) and the other with the anode posterior (a-tsDCS). In study 1, electrically elicited cervicomedullary motor evoked potentials (eCMEPs) and transcranial magnetic stimulation-elicited motor evoked potentials (MEPs) were measured in biceps brachii and flexor carpi radialis before, during and after each tsDCS period. In study 2, eCMEPs and magnetically elicited CMEPs (mCMEPs) were measured before, during and after each tsDCS period. For study 3, computational modelling was used to observe possible interactions of cervical tsDCS and electrical cervicomedullary stimulation. Studies 1 and 2 revealed that eCMEPs were larger during c-tsDCS and smaller during a-tsDCS compared with those elicited when tsDCS was off (P < 0.05), with no changes in MEPs or mCMEPs. Modelling revealed that eCMEP changes might result from modifications of the electrical field direction and magnitude when combined with cervical tsDCS. Bidirectional eCMEP changes are likely to be caused by an interaction between cervical tsDCS and electrical cervicomedullary stimulation; therefore, care should be taken when combining such electrical stimuli in close proximity. PMID- 28730696 TI - CD34+ cells seeded in collagen scaffolds promote bone formation in a mouse calvarial defect model. AB - Bone tissue engineering (BTE) holds promise for managing the clinical problem of large bone defects. However, clinical adoption of BTE is limited due to limited vascularization of constructs, which could be circumvented by pre-cultivation of osteogenic and endothelial derived cells in natural-based polymer scaffolds. However, until now not many studies compared the effect of mono- and cocultures pre-seeded in collagen before implantation. We utilized a mouse calvarial defect model and compared five groups of collagen scaffolds: a negative control of a collagen scaffold alone, a positive control treated with BMP-7, monocultures of either human osteoblasts (hOBs) or CD34+ cells, and a coculture of hOB and CD34+ cells. Each pre-seeded collagen scaffold was implanted in mice. After 6 weeks mice were sacrificed and their skulls prepared for volumetric and histologic analysis. We found that a monoculture of CD34+ cells and a coculture of hOB and CD34+ cells pre-cultured in the collagen scaffold increased bone regeneration to a similar extend. In these groups, greater amounts of new bone were found compared with hOB monocultures. Interestingly, monoculture of CD34+ cells demonstrated better fracture healing than monoculture of hOBs, emphasizing the possible role of angiogenesis. Our results are promising regarding a cellular based collagen BTE construct, but more work is needed to understand the complex interaction between the osteogenic and endothelial cells. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1505-1516, 2018. PMID- 28730697 TI - Impact of simultaneous glutamate dehydrogenase and toxin A/B rapid immunoassay on Clostridium difficile diagnosis and treatment in hospitalized patients with antibiotic-associated diarrhea in a university hospital of Brazil. AB - BACKGROUND AND AIM: Clostridium difficile is a major cause of health care associated infection, but disagreement between diagnostic tests is an ongoing barrier to clinical decision-making. Conventional enzyme immunoassay (EIA) for toxin detection is currently the most frequently used technique for C. difficile infection (CDI) diagnosis, but its low sensitivity makes the development of an alternative strategy necessary for improving the diagnosis in developing countries. METHODS: Between years 2011 and 2015, 154 stool samples from patients with antibiotic-associated diarrhea were examined by toxigenic culture and EIA for the diagnosis of CDI. In the year 2015, when glutamate dehydrogenase (GDH) test was first available in Brazil, 53 of those fecal specimens were also tested by the C. diff Quik Chek Complete rapid immunoassay. At this time, we prospectively assessed the impact of this test on CDI treatment rates before and after it was introduced in clinical practice. RESULTS: The GDH component of C. diff Quik Chek Complete test had a sensitivity of 100% and specificity of 95.1% compared with toxigenic culture, with 89.8% concordance. The Tox A/B II EIA and the toxin portion of C. diff Quik Chek Complete yielded sensitivities between values of 50-58.3%, with 100% specificities. The introduction of GDH test increased the number of treated patients with CDI from 57.7% to 100%. CONCLUSIONS: Glutamate dehydrogenase test is a reliable method for the diagnosis of CDI and greatly increases the number of properly treated patients with CDI. Therefore, this exam should be considered the mainstay for the laboratory diagnosis of CDI in developing countries. PMID- 28730698 TI - Boar sperm quality after supplementation of diets with omega-3 polyunsaturated fatty acids extracted from microalgae. AB - This study evaluated effects of diet supplementation with omega-3 polyunsaturated fatty acids (PUFA) from microalgae on boar sperm quality. Two groups of boars (n = 3 each) were fed during 75 days either a commercial diet (control), or the same diet supplemented with omega-3 PUFA from the heterotrophic microalgae Schizochytrium sp. (120 g/kg). Sixteen ejaculates were collected per boar. Some sperm kinetics parameters were inferior for supplemented than for control boars (p < .05): distance average path; distance in both curved and straight line; velocity average path, velocity in both curved and straight line; and amplitude of lateral head displacement. Spermatozoa from supplemented boars presented lower mitochondrial functionality, but greater membrane fluidity compared to the control group (p < .01). Membrane and acrosome integrity, production of reactive oxygen species and lipid peroxidation did not differ (p > .05). Serum cholesterol levels were greater (p < .05) for supplemented than for control boars at the 30th and 60th d of supplementation, but levels of triglycerides and IGF-1 did not differ (p > .05). Compared to the control, spermatozoa of supplemented boars were slower, travelled shorter distances and presented impaired energy metabolism, but their greater membrane fluidity may potentially favour their cryopreservation. PMID- 28730699 TI - Elevated cardiac troponin T in cirrhotic patients with emergency care admissions: Associations with mortality. AB - BACKGROUND AND AIM: Mortality of cirrhotic patients after emergency care admission is high, and prognostic factors can help in prioritizing patients. The aim of our study was to assess the association between levels of cardiac troponin T (cTnT) and 1-year mortality in patients with liver cirrhosis without known cardiac disease, who were admitted to the emergency department (ED). METHODS: All patients with cirrhosis presented to the ED from October 2009 until August 2015 who had an initial cTnT value measured with the first lab panel were retrospectively analyzed with a follow-up of 365 days. RESULTS: Of a total of 237 cirrhotic ED patients, cTnT measurements were available for 87 (63% men, mean age 58.9 +/- 11.0 years, and median Model for End-stage Liver Disease score was 15 [25th-75th percentile: 10-19]). Chronic Liver Failure Consortium acute-on-chronic liver failure (CLIF-C-ACLF) score was 33. Forty-three patients (49%) had cTnT values above the normal range (14 ng/L), of which 19 (22%) had values over 30 ng/L. Two patients were lost to follow-up. In multivariable analysis, both CLIF-C ACLF (hazard ratio 1.072 per point increase; 95% confidence interval 1.029-1.117; P < 0.001) and cTnT (hazard ratio 1.014 per ng/L increase; 95% confidence interval 1.004-1.024; P = 0.008) emerged as independently associated with mortality. CONCLUSIONS: A large proportion of cirrhotic patients in the ED have elevated levels of cTnT even if there is no evidence of cardiac disease. Elevated cTnT is associated with increased mortality during 1 year after correcting for Model for End-stage Liver Disease and CLIF-C-ACLF scores. PMID- 28730701 TI - Ultrahigh Carrier Mobility Achieved in Photoresponsive Hybrid Perovskite Films via Coupling with Single-Walled Carbon Nanotubes. PMID- 28730702 TI - High Performance Graphene/Ni2 P Hybrid Anodes for Lithium and Sodium Storage through 3D Yolk-Shell-Like Nanostructural Design. PMID- 28730700 TI - Relating switching rates between normal and persister cells to substrate and antibiotic concentrations: a mathematical modelling approach supported by experiments. AB - We developed and compared two mathematical models of variable phenotypic switching rates between normal and persister cells that depend on substrate concentration and antibiotic presence. They could be used to simulate the formation of persisters in environments with concentration gradients such as biofilms. Our models are extensions of a previous model of the dynamics of normal and persistent cell populations developed by Balaban et al. (2004, Science 305: 1622). We calibrated the models' parameters with experimental killing curves obtained after ciprofloxacin treatment of samples regularly harvested from planktonic batch cultures of Klebsiella pneumoniae. Our switching models accurately reproduced the dynamics of normal and persistent populations in planktonic batch cultures and under antibiotic treatment. Results showed that the models are valid for a large range of substrate concentrations and for zero or high doses of antibiotics. PMID- 28730703 TI - Synthesis, Structure, and Properties of Near-Infrared [b]Phenanthrene-Fused BF2 Azadipyrromethenes. AB - A new class of phenanthrene-fused BF2 azadipyrromethene (azaBODIPY) dyes have been synthesized through a tandem Suzuki reaction and oxidative ring-fusion reaction, or a palladium-catalyzed intramolecular C-H activation reaction. These phenanthrene-fused azaBODIPY dyes are highly photostable and display markedly redshifted absorption (up to lambda=771 nm) and emission bands (lambda~800 nm) in the near-infrared region. DFT calculations and cyclic voltammetry studies indicate that, upon annulation, more pronounced stabilization of the LUMO is the origin of the bathochromic shift of the absorption and high photostability. PMID- 28730704 TI - The ATHENA HPV study underrepresents "other" high-risk HPV genotypes when compared with a diverse New York City population. AB - OBJECTIVE: Persistent infection with oncogenic high risk HPV (hrHPV) types causes virtually all cases of cervical cancer. HPV 16 and 18 have been targeted for individual genotyping and vaccination because of their presence in 71% of invasive cervical cancers worldwide. Montefiore Medical Center, Bronx, New York serves a population known for ethnic and racial diversity. Given this diversity it is possible that HPV genotypes not individually detected by current testing are causing significant disease. METHODS: We conducted a retrospective analysis of liquid based cervicovaginal cytology and Cobas HPV results reported between October 5, 2015 and March 30, 2016. This included 20 483 samples from patients aged 16-95 (average age 42), with racial distribution including: African-American 32.4%, Other (includes denied, unknown, mixed, Hispanic) 52.1%, Caucasian 14.5%, Asian 0.7%, American Indian/Alaskan Native 0.3%. In all, 14 938 samples (72.9%) were submitted for clinically requested COBAS 4800 HPV testing, which separately reports HPV 16, 18 and a pool of 12 other hrHPV. RESULTS: A total of 3180 (21.5%) tested hrHPV positive. The percentage of patients with cytologic diagnosis of HSIL (high-grade squamous intraepithelial lesion) that were positive only for HPV 16 was 19.4% vs 1.8% for all cytologic diagnoses. However, only one of the HSIL cases was HPV 18 positive along with other hrHPV (OHR). Surprisingly, a majority (64.5%) was positive for only OHR. CONCLUSIONS: Further evaluation is needed to determine if this pool of other hrHPV includes individual genotypes that in our population carry a higher risk of persistence and progression to cancer. PMID- 28730705 TI - "Those who care much, understand much." Maternal perceptions of children's appetite: Perspectives from urban and rural caregivers of diverse parenting experience in Bangladesh. AB - Appetite in children is an important determinant of nutritional intake and growth. The information used by caregivers to understand children's appetite can help inform infant and young child feeding promotion and appetite assessment. We conducted a qualitative study to (a) explore maternal perceptions and responses to children's appetite and (b) to identify how these factors differ by type of caregiver, level of maternal experience, and urban versus rural context. We used purposive sampling to recruit mothers and alternate caregivers into 14 total focus group discussions (six to eight participants in each group; N = 95) in both urban and rural settings in Bangladesh. To understand children's appetite, caregivers monitor children's dietary patterns, emotional signs, and physical and verbal cues. Healthy appetite was observed by willingness to eat diverse foods, finish offered portions, and by acceptance of foods without excessive prompting. Child illness was cited for a cause of low appetite, which was manifested through fussiness, and avoiding commonly consumed foods. Mothers described a limited set of feeding practices (offering diverse foods, playing, and cheering children with videos) to encourage consumption when children lacked appetite. Mothers' stress related to work was noted as a barrier to identifying appetite cues. Urban mothers described a lower access to instrumental social support for child feeding but informational support than mothers in the rural setting. Understanding caregivers' perceptions of children's appetite may inform strategies to improve responsive feeding and tool development to assess changes in appetite as early indicators of change in health or nutrition status among high-risk children. PMID- 28730706 TI - Chromatographic profiles of tryptophan and kynurenine enantiomers derivatized with (S)-4-(3-isothiocyanatopyrrolidin-1-yl)-7-(N,N-dimethylaminosulfonyl)-2,1,3 benzoxadiazole using LC-MS/MS on a triazole-bonded column. AB - d- and l-Tryptophan (Trp) and d- and l-kynurenine (KYN) were derivatized with a chiral reagent, (S)-4-(3-isothiocyanatopyrrolidin-1-yl)-7-(N,N dimethylaminosulfonyl)-2,1,3-benzoxadiazole (DBD-PyNCS), and were separated enantiomerically by high-performance liquid chromatography (HPLC) equipped with a triazole-bonded column (Cosmosil HILIC) using tandem mass spectrometric (MS/MS) detection. Effects of column temperature, salt (HCO2 NH4 ) concentration, and pH of the mobile phase in the enantiomeric separation, followed by MS detection of (S)-DBD-PyNCS-d,l-Trp and -d,l-KYN, were investigated. The mobile phase consisting of CH3 CN/10 mM ammonium formate in H2 O (pH 5.0) (90/10) with a column temperature of 50-60 degrees C gave satisfactory resolution (Rs) and mass spectrometric detection. The enantiomeric separation of d,l-Trp and d,l-KYN produced Rs values of 2.22 and 2.13, and separation factors (alpha) of 1.08 and 1.08, for the Trp and KYN enantiomers, respectively. The proposed LC-MS/MS method provided excellent detection sensitivity of both enantiomers of Trp and KYN (5.1 19 nM). PMID- 28730708 TI - Evaluation of the hypocholesterolemic effect and prebiotic activity of a lentil (Lens culinaris Medik) extract. AB - SCOPE: The aim of our work was to produce a hydroalcoholic extract of lentils and to examine (a) the hypocholesterolemic action in an animal model, by studying the plasma cholesterol level and the concentration of bile acids in the feces; (b) the potential prebiotic effect, by conducting an in vitro culture fermentation experiment and assessing the level of SCFAs in the feces of rats. METHODS AND RESULTS: Lentil extract (LE) was obtained by extracting lentils with a solution of H2 0/EtOH (70/30 v/v) for 3 h, and the content of main nutrients was determined. After 71 days of diet-induced hypercholesterolemia in rats, LE reduced the cholesterol level of rats of 16.8% (p < 0.05) and increased the level of bile acids in the feces of rats (p < 0.01). LE revealed the same prebiotic activity of inulin and good bifidogenic activity, inasmuch as it enhanced the growth of Bifidobacterium spp. by 3 log (p < 0.05). The concentration of SCFAs in the feces of rats fed with LE increased during the time of the study. CONCLUSION: This new hydroalcoholic extract obtained from lentils was shown to possess hypocholesterolemic and prebiotic properties, and could have interesting applications in the field of nutraceuticals. PMID- 28730707 TI - Establishment and characterization of a novel murine model of pancreatic cancer cachexia. AB - BACKGROUND: Cachexia is a complex metabolic and behavioural syndrome lacking effective therapies. Pancreatic ductal adenocarcinoma (PDAC) is one of the most important conditions associated with cachexia, with >80% of PDAC patients suffering from the condition. To establish the cardinal features of a murine model of PDAC-associated cachexia, we characterized the effects of implanting a pancreatic tumour cell line from a syngeneic C57BL/6 KRASG12D P53R172H Pdx-Cre+/+ (KPC) mouse. METHODS: Male and female C57BL/6 mice were inoculated subcutaneously, intraperitoneally, or orthotopically with KPC tumour cells. We performed rigorous phenotypic, metabolic, and behavioural analysis of animals over the course of tumour development. RESULTS: All routes of administration produced rapidly growing tumours histologically consistent with moderate to poorly differentiated PDAC. The phenotype of this model was dependent on route of administration, with orthotopic and intraperitoneal implantation inducing more severe cachexia than subcutaneous implantation. KPC tumour growth decreased food intake, decreased adiposity and lean body mass, and decreased locomotor activity. Muscle catabolism was observed in both skeletal and cardiac muscles, but the dominant catabolic pathway differed between these tissues. The wasting syndrome in this model was accompanied by hypothalamic inflammation, progressively decreasing brown and white adipose tissue uncoupling protein 1 (Ucp1) expression, and increased peripheral inflammation. Haematological and endocrine abnormalities included neutrophil-dominant leukocytosis and anaemia, and decreased serum testosterone. CONCLUSIONS: Syngeneic KPC allografts are a robust model for studying cachexia, which recapitulate key features of the PDAC disease process and induce a wide array of cachexia manifestations. This model is therefore ideally suited for future studies exploring the physiological systems involved in cachexia and for preclinical studies of novel therapies. PMID- 28730710 TI - The molecular ecology of Microcystis sp. blooms in the San Francisco Estuary. AB - Harmful blooms of the cyanobacterium Microcystis sp. have become increasingly pervasive in the San Francisco Estuary Delta (USA) since the early 2000s and their rise has coincided with substantial decreases in several important fish species. Direct and indirect effects Microcystis blooms may have on the Delta food web were investigated. The Microcystis population was tracked for 2 years at six sites throughout the Delta using quantitative PCR. High-throughput amplicon sequencing and colony PCR sequencing revealed the presence of 10 different strains of Microcystis, including 6 different microcystin-producing strains. Shotgun metagenomic analysis identified a variety of Microcystis secondary metabolite pathways, including those for the biosynthesis of: aeruginosin, cyanopeptolin, microginin, microviridin and piricyclamide. A sizable reduction was observed in microbial community diversity during a large Microcystis bloom (H' = 0.61) relative to periods preceding (H' = 2.32) or following (H' = 3.71) the bloom. Physicochemical conditions of the water column were stable throughout the bloom period. The elevated abundance of a cyanomyophage with high similarity to previously sequenced isolates known to infect Microcystis sp. was implicated in the bloom's collapse. Network analysis was employed to elucidate synergistic and antagonistic relationships between Microcystis and other bacteria and indicated that only very few taxa were positively correlated with Microcystis. PMID- 28730709 TI - The role of the cytopathologist in subtyping and epidermal growth factor receptor testing in non-small cell lung cancer: An institutional experience. AB - OBJECTIVE: Approximately 10% of non-small-cell lung cancer (NSCLC) remains unclassifiable as NSCLC-not otherwise specified (NOS), after using a panel of immunomarkers. The present study was undertaken to assess sensitivity and specificity of immunomarkers in sub-typing NSCLC on fine needle aspiration cytology (FNAC). Epidermal growth factor receptor (EGFR) mutations were also detected in these samples. METHODS: Sixty cases of NSCLC including 15 squamous cell carcinoma (SCC), 15 adenocarcinomas (ADC) and 30 NSCLC-NOS reported on FNAC were included in the study. A panel of CK7, CK5/6, TTF-1 and p63 was applied in these cases. DNA was extracted from 54 cases including 14 effusion samples, and EGFR mutations were detected. RESULTS: Classic ADC cases (n=15) showed 73.3% TTF 1 positivity and 100% CK7 positivity. Two cases of ADC showed aberrant expression of p63 and 2 cases showed CK5/6 positivity. 80% of classic SCC cases (n=15) showed strong nuclear p63 positivity and 86.6% were positive for CK5/6. TTF-1 was seen exclusively in ADC cases. Immunohistochemistry (IHC) using two immunomarkers (TTF-1 and p63) helped in subtyping 24/30(80%) cases of NSCLC. EGFR mutations were detected in 9/54 (16.7%) cases, and the most common mutation was short in frame deletion in Exon 19. CONCLUSIONS: More than 90% of NSCLC can be sub-typed on cytology samples with the help of immunochemistry. The sensitivity of TTF-1, p63, CK5/6 and CK7 was 73.3%, 80%, 100% and 100%, respectively. The specificity of TTF-1, p63, CK5/6 and CK7 was 100%, 86.6%, 86.6% and 93.3%, respectively. TTF 1 is highly specific, and almost 80% of NSCLC-NOS cases can be sub-typed using TTF-1 and p63. EGFR mutations can be detected in cytology samples, and 16.7% samples were positive for EGFR mutations. PMID- 28730711 TI - Supplementation of protease, alone and in combination with fructooligosaccharide to low protein diet for finishing pigs. AB - Effects of adding protease with or without fructooligosaccharide (FOS) to low protein diet on growth performance, nutrient digestibility and fecal noxious gas emission were evaluated in 160 finishing pigs (57.70 +/- 1.16 kg) in a 9-week study. Pigs were randomly divided into four dietary treatments, PC: positive control diet (15.97% crude protein (CP)); NC: negative control diet (12.94% CP); PRO: NC supplemented with 0.05% protease; PROFOS: NC supplemented with 0.05% protease and 0.1% FOS. During weeks 4-9 and weeks 0-9, gain : feed ratio was impaired (P < 0.05) in pigs fed NC diet compared with those fed PC, PRO and PROFOS diets. Pigs fed PC, PRO and PROFOS diets had higher (P < 0.05) apparent total tract digestibility (ATTD) of CP than pigs fed NC diet. Pigs fed PROFOS diet had reduced (P < 0.05) ammonia emissions compared to pigs fed NC and PRO diets. These data indicate that reducing dietary CP concentrations impaired growth performance, decreased ATTD of CP and reduced ammonia emissions. Supplementation of protease in low CP diet improved growth performance and increased ATTD of CP. Dietary supplementation with protease and FOS in low CP diet improved growth performance, increased ATTD of CP and decreased fecal ammonia emission. PMID- 28730712 TI - Slow conduction through an arc of block: A basis for arrhythmia formation postmyocardial infarction. AB - INTRODUCTION: The electrophysiologic basis for characteristic rate-dependent, constant-late-coupled (390 + 54 milliseconds) premature ventricular beats (PVBs) present 4-5 days following coronary artery occlusion were examined in 108 anesthetized dogs. METHODS AND RESULTS: Fractionated/double potentials were observed in injured zone bipolar and composite electrograms at prolonged sinus cycle lengths (1,296 +/- 396 milliseconds). At shorter cycle lengths, conduction of the delayed potential decremented, separating from the initial electrogram by a progressively prolonged isoelectric interval. With sufficient delay of the second potential following an isoelectric interval, a PVB was initiated. Both metastable and stable constant-coupled PVBs were associated with Wenckebach-like patterns of delayed activation following an isoelectric interval. Signal averaging from the infarct border confirmed the presence of an isoelectric interval preceding the PVBs (N = 15). Pacing from the site of double potential formation accurately reproduced the surface ECG morphology (N = 15) of spontaneous PVBs. Closely-spaced epicardial mapping demonstrated delayed activation across an isoelectric interval representing "an arc of conduction block." Rate-dependent very slow antegrade conduction through a zone of apparent conduction block (N = 8) produced decremental activation delays until the delay was sufficient to excite epicardium distal to the original "arc of conduction block," resulting in PVB formation. CONCLUSION: The present experiments demonstrate double potential formation and rate-dependent constant-coupled late PVB formation in infarcted dog hearts. Electrode recordings demonstrate a prolonged isoelectric period preceding PVB formation consistent with very slow conduction (<70 mm/s) across a line of apparent conduction block and may represent a new mechanism of PVB formation following myocardial infarction. PMID- 28730713 TI - Investigation of genetic diversity and inbreeding in a Japanese native horse breed for suggestions on its conservation. AB - Because native breeds can serve as genetic resources for adapting to environment changes, their conservation is important for future agroecosystems. Using pedigree analysis, we investigated genetic diversity and inbreeding in Japanese Hokkaido native horses, which have adapted to a cold climate and roughage diet. Genetic diversity was measured as the number of founders and the effective number of founders, ancestors and genomes. All metrics imply a decrease in genetic diversity. A comparison of these metrics suggested that pedigree bottlenecks contributed more than did random gene losses to the reduction of genetic diversity. Estimates of marginal contributions of ancestors suggest that the bottlenecks arose mainly because related stallions had been used for breeding. A tendency for an increase in inbreeding coefficients was observed. F-statistics revealed that a small effective population size majorly contributed to this increase, although non-random mating in particular regions also contributed. Because the bottlenecks are thought to have reduced the effective population size, our results imply that mitigation of bottlenecks is important for conservation. To this end, breeding should involve genetically diverse stallions. In addition, to prevent non-random mating observed in particular regions, efforts should be made to plan mating with consideration of kinships. PMID- 28730714 TI - Alkaloid profiling of herbal drugs using high resolution mass spectrometry. AB - Herbal infusions are consumed worldwide thanks to their "natural" beneficial effects, also due to the presence of alkaloids, although these compounds can have poisonous effects. A method combining online solid-phase purification with high resolution mass spectrometry was used to define the alkaloid profiles of 117 herbs and 7 commercial blends. Forty-one alkaloids were quantified in reference to analytical standards, while the presence of a further 116 was confirmed based on accurate mass, retention time, and fragmentation profile. The targeted study showed that 52% of herbs and 42% of commercial blends contained at least one alkaloid. Pyrrolizidines were the most commonly present (26% of samples), with concentrations generally ranging from the quantification limit to roughly 100 MUg kg-1 . Moreover, a homemade infusion was studied, finding on average 45% and 6% lower extraction for pyrrolizidine and steroidal alkaloids, respectively. Nevertheless, the migration of pyrrolizidines was confirmed. The study confirmed the frequent presence, natural or accidental, of alkaloids in commercial infusion herbs, highlighting the urgent need for routine and accurate controls. PMID- 28730715 TI - Different thermotolerances in in vitro-produced embryos derived from different maternal and paternal genetic backgrounds. AB - The present study evaluated the effects of genetic backgrounds on the developmental competence and thermotolerance of bovine in vitro-produced (IVP) embryos. First, Holstein (Hol) and Japanese Black (JB) oocytes were fertilized with sperm from Hol, JB and a thermotolerant breed (Brahman), and in vitro development was evaluated when the embryos were exposed to heat shock on Day 2 (Day 0 = day of fertilization). Sperm genetic backgrounds affected the developmental competence in controls (P < 0.05). Second, the effect of sperm pre incubation for 4 h on subsequent in vitro fertilization was assessed using different sperm genetic backgrounds. The pre-incubation of sperm did not decrease the embryonic development regardless of the breed of the sperm. A milder heat shock (40.0 degrees C) effect on parthenotes (Hol and JB) and IVP embryos were evaluated. JB parthenotes showed developmental arrest after Day 4, and the rate of development to the blastocyst stage decreased by heat shock, but not in Hol parthenotes. Heat shock decreased developmental competence after cleavage of IVP embryos regardless of genetic background. The thermotolerance of IVP embryos would be controlled by both maternal and paternal factors but genetic involvement was still unclear. Further evaluation is needed to reveal the genetic contribution to thermotolerance. PMID- 28730716 TI - Manganese(I)-Catalyzed Enantioselective Hydrogenation of Ketones Using a Defined Chiral PNP Pincer Ligand. AB - A new chiral manganese PNP pincer complex is described. The asymmetric hydrogenation of several prochiral ketones with molecular hydrogen in the presence of this complex proceeds under mild conditions (30-40 degrees C, 4 h, 30 bar H2 ). Besides high catalytic activity for aromatic substrates, aliphatic ketones are hydrogenated with remarkable selectivity (e.r. up to 92:8). DFT calculations support an outer sphere hydrogenation mechanism as well as the experimentally determined stereochemistry. PMID- 28730717 TI - Measuring the contribution of art therapy in multidisciplinary treatment of personality disorders: The construction of the Self-expression and Emotion Regulation in Art Therapy Scale (SERATS). AB - Despite the use of art therapy in clinical practice, its appreciation and reported beneficial results, no instruments are available to measure specific effects of art therapy among patients with personality disorders cluster B/C in multidisciplinary treatment. In the present study, we described the development and psychometric evaluation of the Self-expression and Emotion Regulation in Art Therapy Scale (SERATS). Structural validity (exploratory and confirmatory factor analysis), reliability, construct validity and sensitivity to change were examined using two independent databases (n = 335; n = 34) of patients diagnosed with personality disorders cluster B/C. This resulted in a nine-item effect scale with a single factor with a high internal reliability and high test-retest reliability; it demonstrated discriminant validity and sensitivity to change. In conclusion, the SERATS is brief and content-valid and offers objective and reliable information on self-expression and emotion regulation in art therapy among patients with personality disorders cluster B/C. Although more research on construct validity is needed, the SERATS is a promising tool to be applied as an effect scale and as a monitoring tool during art therapy treatment. (c) 2017 The Authors Personality and Mental Health Published by John Wiley & Sons Ltd. PMID- 28730718 TI - Impact of binding mechanism on selective inhibition of histone deacetylase isoforms. AB - Industrialized drug screening campaigns usually deliver hundreds of compounds that are active on a particular pharmaceutical target. In light of high failure rates of drug candidates due to unforeseeable off-target toxicity, the early identification of the most promising compounds with high potential for target selectivity is an urgent need to improve the quality of lead compounds and lower attrition rates in the drug development process. The reliable prediction of the selectivity of active substances for a target protein is a challenging task. A comprehensive study of the binding kinetics, thermodynamics, and selectivity of chemically related ligands of histone deacetylase (HDAC) like amidohydrolase from Pseudomonas aeruginosa (HDAHpa ) reveals one general binding mechanism for all analyzed compounds consisting of a preceding conformational selection step followed by an optional subsequent induced fit. Depending on the chemical structure, the ligands bind to one or two of at least three protein conformations with different rate constants. Although these kinetic and mechanistic differences hamper the predictability of selectivity for the HDAC inhibitors, we demonstrate that the enthalpy-weighted binding constant KdDeltaH is a useful metric to predict isoform selectivity of inhibitors against HDAC enzymes and relatively robust toward different but related binding mechanisms. PMID- 28730719 TI - Anticandidal Activity of Extracts and a Novel Compound, Amnomopin, Isolated From Petriella setifera. AB - A novel triterpenoidal compound named 'amnomopin' (3beta-diglucoside-5,12-28-oic acid), which is named IUPAC as 3-O-(2' ? 1"diglucoside)1,2,3,4,4a,5,6,6a,6b,7,9,10,11,12,12a,12b,13,14b-octadecahydro-10 hydroxy-2,2,6a,6b,9,9,12a-heptamethylpicene-4a-carboxylic acid, was isolated from the extract Petriella setifera. The total alcoholic extract of P. setifera showed a great activity against clinically isolated Candida species, including Candida albicans, Candida dubliniensis, Candida famata, Candida glabrata, Candida inconspicua, Candida kefyr, Candida krusei, Candida norvegensis, Candida parapsilosis and Candida tropicalis. Also, the new compound amnomopin was active against all the investigated Candida species. The highest anticandidal activity of P. setifera extract was obtained against C. kefyr (22.6 +/- 1.5 mm), C. albicans and C. norvegensis (21.3 +/- 0.63 mm) and C. krusei (20.6 +/- 1.5 mm). Moreover, the minimum inhibitory concentrations of both the total extract and the isolated compound were low. The minimum inhibitory concentration of the compound isolated from P. setifera was 0.49 MUg/mL against C. kefyr, 0.98 MUg/mL against C. albicans and C. norvegensis and 1.95 MUg/mL against C. krusei. The oral dosing of the extract and the isolated compound did not show any significant effect on the activity of alanine aminotransferase, aspirate aminotransferase and the levels of blood urea and serum creatinine. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28730720 TI - Microstructural white matter brain abnormalities in patients with idiopathic fecal incontinence. AB - BACKGROUND: Abnormal central nervous system processing of visceral sensation may be a part of the pathogenesis behind idiopathic fecal incontinence (IFI). Our aim was to characterize brain differences in patients with IFI and healthy controls by means of structural magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI). METHODS: In 21 female patients with IFI and 15 female healthy controls, whole-brain structural differences in gray matter volume (GMV), cortical thickness, and white matter tracts fractional anisotropy (FA) were quantified. For this purpose, we used voxel-based morphometry, surface based morphometry and tract-based spatial statistic, respectively. Furthermore, associations between structural brain characteristics and latencies of rectal sensory evoked electroencephalography potentials were determined. KEY RESULTS: Compared to healthy controls, IFI patients had significantly reduced FA values, reflecting reduced white matter tract integrity, in the left hemisphere superior longitudinal fasciculus (SLF), posterior thalamic radiation, and middle frontal gyrus (MFG), all P<.05. No differences were observed in GMV or in cortical thickness. The reduced FA values in the SLF and MFG were correlated with prolonged latencies of cortical potentials evoked by rectal stimuli (all P<.05). CONCLUSIONS & INFERENCES: This explorative study suggests that IFI patients have no macrostructural brain changes, but exhibit microstructural changes in white matter tracts relevant for sensory processing. The clinical relevance of this finding is supported by its correlations with prolonged latencies of cortical potentials evoked by rectal stimulation. This supports the theories of central nervous system changes as part of the pathogenesis in IFI patients. PMID- 28730721 TI - EPHB4 Mutation Implicated in Capillary Malformation-Arteriovenous Malformation Syndrome: A Case Report. AB - Capillary malformation-arteriovenous malformation (CM-AVM) syndrome, due to inactivating mutations in RASA1 in 68% of cases, is characterized by the development of cutaneous capillary malformations and arteriovenous malformations or fistulas; no known genetic etiology has been identified in patients with CM AVM syndrome without RASA1 mutations. We present the case of a child with RASA1 negative CM-AVM syndrome with a de novo missense mutation in EPHB4, a transmembrane tyrosine kinase receptor essential for vasculogenesis. Inactivating the mutation in EPHB4 has been shown to upregulate the mitogen-activated protein kinase pathway and the mammalian target of rapamycin complex 1, possibly contributing to the development of vascular malformations. PMID- 28730722 TI - Metagenome-based surveillance and diagnostic approaches to studying the microbial ecology of food production and processing environments. AB - Metagenomic-based analyses have the potential to revolutionize our understanding of the microbiology of food production and processing environments. By adopting such approaches, it will be possible to more accurately determine sources of microbial contamination, identify critical control points for such contaminants, and select practices that optimize quality and safety. This mini-review will discuss the merits of adopting metagenostic-based approaches, highlight novel insights that they have provided to date and consider how they could be further implemented. PMID- 28730723 TI - Do assortative mating and immigrant inviability help maintain population genetic structuring of an herbivore on a crop and a wild relative? AB - Population genetic structuring is common among herbivorous insects and frequently is associated with divergent host plants, such as crops and their wild relatives. Previous studies showed population genetic structuring in corn leafhopper Dalbulus maidis in Mexico, such that the species consists of two sympatric, host plant-associated populations: an abundant and widespread "pestiferous" population on maize (Zea mays mays), and a small and localized "wild" population on perennial teosinte (Zea diploperennis), a maize wild relative with a limited distribution. This study addressed whether assortative mating and immigrant inviability mediate genetic structuring of corn leafhopper by comparing the mating and reproductive successes of pestiferous and wild females that colonize their nonassociated host plants against the successes of females colonizing their associated host plants. Assortative mating was assessed by comparing mating frequencies and premating and mating times among females of each population on each host plant; immigrant inviability was assessed by comparing, across two generations, the fecundity, survival, development time, sex ratio, and population growth rate among leafhopper populations and host plants. Our results showed that on maize, and compared to resident, pestiferous females, wild females were more likely to mate, and greater proportions of their offspring survived to adult stage and were daughters; consequently, the per-generation population growth rate on maize was greater for immigrant, wild leafhoppers compared to resident, pestiferous leafhoppers. Our results suggested that wild leafhoppers emigrating to maize have a fitness advantage over resident, pestiferous leafhoppers, while immigrant pestiferous and resident wild leafhoppers on teosinte have similar fitnesses. PMID- 28730724 TI - Dynamic loop gain increases upon adopting the supine body position during sleep in patients with obstructive sleep apnoea. AB - BACKGROUND AND OBJECTIVE: Obstructive sleep apnoea (OSA) is typically worse in the supine versus lateral sleeping position. One potential factor driving this observation is a decrease in lung volume in the supine position which is expected by theory to increase a key OSA pathogenic factor: dynamic ventilatory control instability (i.e. loop gain). We aimed to quantify dynamic loop gain in OSA patients in the lateral and supine positions, and to explore the relationship between change in dynamic loop gain and change in lung volume with position. METHODS: Data from 20 patients enrolled in previous studies on the effect of body position on OSA pathogenesis were retrospectively analysed. Dynamic loop gain was calculated from routinely collected polysomnographic signals using a previously validated mathematical model. Lung volumes were measured in the awake state with a nitrogen washout technique. RESULTS: Dynamic loop gain was significantly higher in the supine than in the lateral position (0.77 +/- 0.15 vs 0.68 +/- 0.14, P = 0.012). Supine functional residual capacity (FRC) was significantly lower than lateral FRC (81.0 +/- 15.4% vs 87.3 +/- 18.4% of the seated FRC, P = 0.021). The reduced FRC we observed on moving to the supine position was predicted by theory to increase loop gain by 10.2 (0.6, 17.1)%, a value similar to the observed increase of 8.4 (-1.5, 31.0)%. CONCLUSION: Dynamic loop gain increased by a small but statistically significant amount when moving from the lateral to supine position and this may, in part, contribute to the worsening of OSA in the supine sleeping position. PMID- 28730725 TI - Targeting nano drug delivery to cancer cells using tunable, multi-layer, silver decorated gold nanorods. AB - Multifunctional nanoparticles have high potential as targeting delivery vehicles for cancer chemotherapy. In this study, silver-decorated gold nanorods (AuNR?Ag) have been successfully used to deliver specific, targeted chemotherapy against breast cancer (MCF7) and prostate carcinoma (PC3) cell lines. Doxorubicin, a commonly used chemotherapy, and anti-Epithelial cell adhesion molecule (anti EpCAM) antibodies were covalently bonded to thiolated polyethylene glycol-coated AuNR?Ag, and the resultant system was used to deliver the drugs to cancer cells in vitro. Furthermore, these nanoparticles have a unique spectral signature by surface enhanced Raman spectroscopy (SERS), which enables reliable detection and monitoring of the distribution of these chemotherapy constructs inside cells. The development of interest in a plasmonic nano drugs system with unique spectroscopic signatures could result in a clinical approach to the precise targeting and visualization of cells and solid tumors while delivering molecules for the enhanced treatment of cancerous tumors. PMID- 28730726 TI - Changes in the extracellular matrix surrounding human chronic wounds revealed by 2-photon imaging. AB - Chronic wounds are a growing problem worldwide with no effective therapeutic treatments available. Our objective was to understand the composition of the dermal tissue surrounding venous leg ulcers and diabetic foot ulcers (DFU). We used novel 2-photon imaging techniques alongside classical histology to examine biopsies from the edges of two common types of chronic wound, venous leg ulcers and DFU. Compared to normal intact skin, we found that collagen levels are significantly reduced throughout the dermis of venous leg ulcer biopsies and DFU, with a reduction in both fibril thickness and abundance. Both wound types showed a significant reduction in elastin in the upper dermis, but in DFU, the loss was throughout the dermis. Loss of extracellular matrix correlated with high levels of CD68- and CD18-positive leukocytes. 2-photon imaging of the extracellular matrix in the intact tissue surrounding a chronic wound with a hand-held device may provide a useful clinical indicator on the healing progression or deterioration of these wounds. PMID- 28730727 TI - Better arthritis care: Patients' expectations and priorities, the competencies that community-based health professionals need to improve their care of people with arthritis? AB - OBJECTIVE: The aim of the present study was to identify the competencies that patients think non-specialist community-based nurses and allied health professionals (AHPs) need to enable them to assess, care for and manage arthritis appropriately. METHODS: Four face-to-face focus groups were held with a total of 16 women and nine men with arthritis, to discuss the care they received from community-based health professionals, the skills and knowledge they expected from community-based health professionals and what they prioritized. RESULTS: People with arthritis wanted health providers to have an understanding of the difference between inflammatory arthritis (IA) and osteoarthritis (OA), of how serious OA can be, and of the unpredictability of IA and flares. They emphasized the need for nurses and AHPs to understand the psychosocial impact of arthritis on individuals, family and friends, and the psychological adjustment needed when diagnosed with IA. They wanted community-based health professionals to have some knowledge of the types of drug treatments that people with IA receive and the implications of taking immunosuppressive drugs. They also wanted them to understand the pain associated with arthritis, particularly OA, which participants felt was not taken seriously enough. They wanted nurses and AHPs in the community to be able to give basic advice on pacing and pain management, to make multidisciplinary referrals, to communicate effectively between referral points and to be able to signpost people to sources of help and good, reliable sources of education and information (especially for OA). They also wanted them to understand that patients who have had a diagnosis for a long time are the experts in their own disease. Other areas which were emphasized as being important were good communication skills and taking a holistic approach to caring for people with arthritis. CONCLUSIONS: OA and IA differ significantly, both in their nature and their management. However, patients with arthritis want health professionals working in the community to be able to take a holistic approach to arthritis, with an understanding not just of the physical effects, but also their impact on the lives of patients, their family and their wider social circle, and on their ability to participate. People with OA want their condition to be taken seriously and to be offered appropriate management options, while people with IA want professionals to understand the unpredictability of their condition and to have a basic understanding of the drugs used for its treatment. PMID- 28730728 TI - Beneficial long-term antidiabetic actions of N- and C-terminally modified analogues of apelin-13 in diet-induced obese diabetic mice. AB - AIMS: To investigate the chronic effects of twice-daily administration of stable apelin analogues, apelin-13 amide and pyroglutamyl (pGlu) apelin-13 amide, on metabolic variables in glucose-intolerant and insulin-resistant diet-induced obese mice fed a high-fat diet for 150 days. METHODS: Groups of mice received twice-daily (9 am and 5 pm) injections of saline vehicle, apelin-13 amide, (pGlu)apelin-13 amide or exendin-4(1-39) for 28 days (all at 25 nmol/kg). Energy intake, body weight, non-fasting blood glucose, plasma insulin, glucose tolerance, metabolic response to feeding and insulin sensitivity, together with pancreatic hormone content and biochemical variables such as lipids and total GLP 1 were monitored. Dual-energy X-ray absorptiometry analysis and indirect calorimetry were also performed. RESULTS: Administration of apelin-13 amide, (pGlu)apelin-13 amide or exendin-4 significantly decreased body weight, food intake and blood glucose and increased plasma insulin compared with high-fat-fed saline-treated controls (P < .05 and P < .001), Additionally, all peptide-treated groups exhibited improved glucose tolerance (oral and intraperitoneal), metabolic responses to feeding and associated insulin secretion. (pGlu)apelin-13 amide also significantly improved glycated haemoglobin and insulin sensitivity after 28 days. Both (pGlu)apelin-13 amide and exendin-4 increased bone mineral content and decreased respiratory exchange ratio, whereas only (pGlu)apelin-13 amide increased energy expenditure. All treatment groups displayed reduced circulating triglycerides and increased glucagon-like peptide-1 concentrations, although only (pGlu)apelin-13 amide significantly reduced LDL cholesterol and total body fat, and increased pancreatic insulin content. CONCLUSION: These data indicate the therapeutic potential of stable apelin-13 analogues, with effects equivalent to or better than those of exendin-4. PMID- 28730729 TI - Traffic-related air pollution associations with cytokeratin-18, a marker of hepatocellular apoptosis, in an overweight and obese paediatric population. AB - INTRODUCTION: Traffic-related air pollution causes fatty liver, inflammation and fibrosis in animal models, but there have been few studies in humans. OBJECTIVES: To test the hypothesis that traffic-related air pollution causes non-alcoholic fatty liver disease (NAFLD) and increased markers for non-alcoholic steatohepatitis (NASH); and that NAFLD increases liver susceptibility to increased NASH risk. METHODS: Data collected prospectively from 74 overweight or obese children were obtained from the Yale Pediatric Obesity Clinic. Traffic related air pollution was characterized as vehicle traffic volume on major roads within a 1 km residential buffer, and as residential nitrogen dioxide (NO2 ) exposure. Outcomes were hepatic fat fraction (HFF) measured by magnetic resonance imaging, liver enzymes using standard assays and plasma cytokeratin-18 (CK-18) by immunosorbent assays. RESULTS: Significant non-linear relationships with air pollution and CK-18 were found. Plasma CK-18 at follow-up increased from approximately 150 U/L to almost 200 U/L as residential traffic volume increased from 220 000 vehicle-km to 330 000 vehicle-km, after adjustment for baseline CK 18, age and gender. Among patients with NAFLD at baseline, CK-18 increased from 140 U/L to 200 U/L (a 1.5 standard deviation increase in CK-18) as NO2 increased from 8 to 10 ppb. CONCLUSIONS: Traffic-related air pollution was associated with CK-18. Effects were larger in children with pre-existing NAFLD at study entry. PMID- 28730731 TI - Induction of stress- and immune-associated genes in the Indian meal moth Plodia interpunctella against envenomation by the ectoparasitoid Bracon hebetor. AB - Envenomation is an important process in parasitism by parasitic wasps; it suppresses the immune and development of host insects. However, the molecular mechanisms of host responses to envenomation are not yet clear. This study aimed to determine the transcription-level responses of the Indian meal moth Plodia interpunctella against envenomation of the ectoparasitoid Bracon hebetor. Quantitative real-time reverse-transcription PCR was used to determine the transcriptional changes of 13 selected genes, which are associated with development, metabolism, stress, or immunity, in the feeding and wandering fifth instar larvae over a 4-day period after envenomation. The effects of envenomation on the feeding-stage larvae were compared with those of starvation in the transcriptional levels of the 13 genes. Most selected genes were altered in their expression by either envenomation or starvation. In particular, a heat shock protein, hsp70, was highly upregulated in envenomated larvae in both the feeding and wandering stages as well as in starved larvae. Further, some genes were upregulated by envenomation in a stage-specific manner. For example, hsp25 was upregulated after envenomation in the feeding larvae, but hsp90 and an immune associated gene, hemolin, were upregulated in the wandering larvae. However, both envenomation and starvation resulted in the downregulation of genes associated with development and metabolism. Taken together, P. interpunctella upregulated stress- and immune-responsive genes, but downregulated genes associated with development and metabolism after envenomation. This study provides important information for understanding the molecular mechanisms of host responses to parasitism. PMID- 28730730 TI - Renal Impairment Hampers Bisphosphonate Treatment in a Quarter of Lung Cancer Patients with Bone Metastasis. AB - Renal function impairment in lung cancer patients with bone metastases was investigated, as this can limit the application of bisphosphonates representing the gold standard in the management of such cases. Clinicopathological data of 570 lung cancer patients were retrospectively analysed for changes in renal function parameters. Comorbidities included hypertension (50%), COPD (33%) and diabetes mellitus (15%). Statistical analysis was performed with Fisher's exact tests and a Cox proportional hazards model. In patients suffering from hypertension, both median serum creatinine and blood urea nitrogen (BUN) were higher (81.9 versus 75.8 MUmol/L, p < 0.001 and 6.0 versus 5.7 mmol/L, p = 0.005, respectively). Such a difference could not be observed in patients with diabetes. In patients with COPD, only serum creatinine was higher (81.1 versus 77.3 MUmol/L, p = 0.004). In the whole cohort, we found that while at the time of lung cancer diagnosis the ratio of patients in the pathological range (PRR) was 8.67% for serum creatinine (median: 75 MUmol/L) and 14.16% for BUN (median: 5.4 mmol/L), at the time of bone metastasis the PRR for serum creatinine increased to 16.11% (median: 77.0 MUmol/L) and for BUN to 24.07% (median: 6.0 mmol/L), which is a significant increase for both parameters (p < 0.001). For the whole cohort, the last laboratory results showed a 26.37% PRR for serum creatinine and 45.66% PRR for BUN (significant increase for both, p < 0.001). Multivariate analysis revealed that patients with hypertension had a higher chance for switching to the pathological range sooner (p = 0.033, HR: 1.372, CI: 1.025-1.835). Also, the appearance of the bone metastasis correlated with an acceleration of the onset of such a switch (p < 0.001, HR: 2.655, CI: 1.581-4.456). Our results suggest that renal function is impaired in a significant proportion of patients with lung cancer and highlight the importance of non-nephrotoxic drug in the management of bone metastases. PMID- 28730732 TI - Shared atypical default mode and salience network functional connectivity between autism and schizophrenia. AB - : Schizophrenia and autism spectrum disorder (ASD) are two prevalent neurodevelopmental disorders sharing some similar genetic basis and clinical features. The extent to which they share common neural substrates remains unclear. Resting-state fMRI data were collected from 35 drug-naive adolescent participants with first-episode schizophrenia (15.6 +/- 1.8 years old) and 31 healthy controls (15.4 +/- 1.6 years old). Data from 22 participants with ASD (13.1 +/- 3.1 years old) and 21 healthy controls (12.9 +/- 2.9 years old) were downloaded from the Autism Brain Imaging Data Exchange. Resting-state functional networks were constructed using predefined regions of interest. Multivariate pattern analysis combined with multi-task regression feature selection methods were conducted in two datasets separately. Classification between individuals with disorders and controls was achieved with high accuracy (schizophrenia dataset: accuracy = 83%; ASD dataset: accuracy = 80%). Shared atypical brain connections contributing to classification were mostly present in the default mode network (DMN) and salience network (SN). These functional connections were further related to severity of social deficits in ASD (p = 0.002). Distinct atypical connections were also more related to the DMN and SN, but showed different atypical connectivity patterns between the two disorders. These results suggest some common neural mechanisms contributing to schizophrenia and ASD, and may aid in understanding the pathology of these two neurodevelopmental disorders. Autism Res 2017, 10: 1776-1786. (c) 2017 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Autism spectrum disorder (ASD) and schizophrenia are two common neurodevelopmental disorders which share several genetic and behavioral features. The present study identified common neural mechanisms contributing to ASD and schizophrenia using resting-state functional MRI data. The results may help to understand the pathology of these two neurodevelopmental disorders. PMID- 28730733 TI - The Potential Impact of Radix Paeoniae Alba in Embryonic Development of Mice. AB - Although Radix Paeoniae Alba (RPA) has been ranked as one of the top 6 herbs used frequently to prevent and treat miscarriages clinically, there is no clear evidence regarding its safety in embryonic development. This study aims to evaluate the potential impacts of RPA on embryonic stem cells (ESCs) and pregnant mice. Cytotoxicity assays of the extract were performed in ESCs and 3T3 cells. Pregnant ICR mice were orally treated with RPA extracts at dosages of 0 (G1 group as negative controls), 2, 8 and 32 g/kg/day (G2, G3 and G4 groups) respectively from the gestation day (Gd) 6-15. On Gd 18, there was no significant difference in the IC50 values between ESCs and 3T3 cells (p > 0.05). There was no significant difference in the maternal and fetal evaluations among four groups (p > 0.05). Fetal IL-2, IL-2r, TNF-alpha, TNF-alphar, IL-4, IL-4r, IL-10r, IL-17 and IL-17r of G4 group were significantly lower than G1 group (p < 0.05). In conclusion, RPA at dosage of 32 g/kg/day (16-folds of human daily dosage) did not cause adverse impact in cultured ESCs and pregnant mice. RPA might down-regulate fetal Th1/Th2/Th17 cytokines and receptors maybe beneficial to embryonic survival and development. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28730734 TI - Efficacy and safety of sugarcane policosanol on dyslipidemia: A meta-analysis of randomized controlled trials. AB - SCOPE: This study aimed to systematically investigate whether sugarcane policosanol was effective and safe on dyslipidemia. METHODS AND RESULTS: A total of 11 databases including the PubMed, Web of science, Embase, Scopus, the Cochrane library and SinoMed databases were searched for available studies investigating the effects of policosanol on dyslipidemia. A total of 22 studies including 1886 subjects were included in the analysis. The pooled results showed that compared with placebo, sugarcane policosanol could significantly reduce total cholesterol (TC, 95% CI: -0.87 to -0.30 mmol/L) and low density lipoprotein cholesterol (LDL-c, 95% CI: -1.02 to -0.40 mmol/L) and increase high density lipoprotein cholesterol; however, no significant effects were observed on triglyceride (TG) and body weight. Subgroup analysis suggested the studies from Cuba obtained more effective data than those outside this country, and the effects were not proportional to the dose. The adverse effects analysis demonstrated that sugarcane policosanol was safer than the control agents. CONCLUSION: The pooled results supported the lipid-lowering effects and safety of policosanol. Because of the high heterogeneity, the better treatment effects observed in the Cuban studies and the inconsistent dose-response relationship, more clinical trials are needed to further confirm the efficacy of policosanol on dyslipidemia. PMID- 28730735 TI - Effectiveness, safety and comfort of StatLock securement for peripherally inserted central catheters: A systematic review and meta-analysis. AB - In this systematic review and meta-analysis, we evaluated the effectiveness, safety and comfort of StatLock for the securement of peripherally-inserted central catheters. PubMed, EMBASE, Cochrane Library, China National Knowledge Infrastructure, WanFang Database, and China Science and Technology Journal Database were searched. Randomized, controlled trials comparing StatLock with tape or suture on the performance of securing peripherally-inserted central catheters were selected. Meta-analysis was performed using Review Manager 5.3 software. Thirteen randomized, controlled trials involving 1970 patients were included. Our results showed that StatLock reduced the incidence of catheter dislodgement and unplanned removal. Moreover, patients in the StatLock group had lower incidence of skin ulceration, phlebitis, catheter-related bloodstream infection, and cellulitis, and felt more comfortable compared with those in the control group. Current evidence suggests that the StatLock securement device offer advantages over tape and suture in preventing catheter-related complications and improving patient comfort. However, as considerable heterogeneity was found among the included studies, and the quality of evidence for main outcomes was relatively low, the results should be viewed with caution. PMID- 28730736 TI - The importance of moral emotions for effective collaboration in culturally diverse healthcare teams. AB - Moral emotions shape the effectiveness of culturally diverse teams. However, these emotions, which are integral to determining ethically responsive patient care and team relationships, typically go unrecognised. The contribution of emotions to moral deliberation is subjugated within the technorational environment of healthcare decision-making. Contemporary healthcare organisations rely on a multicultural workforce charged with the ethical care of vulnerable people. Limited extant literature examines the role of moral emotions in ethical decision-making among culturally diverse healthcare teams. Moral emotions are evident in ethnocentric moral perspectives that construct some colleagues' practices as 'other'. This article examines how moral emotions are evoked when cultural dissonance influences nurses' moral perceptions. We use a qualitative investigation of teamwork within culturally diverse healthcare organisations. We use Haidt's () account of moral emotions to examine practice-based accounts of 36 internationally educated and 17 New Zealand educated nurses practising in New Zealand. The study provides evidence that moral emotions are frequently elicited by communication and care practices considered 'foreign'. The main implication is that although safe practice in healthcare organisations is reliant on highly functioning teams, collaboration is challenged by interprofessional power relations of contested culturally shaped values. We address practice-based strategies that enable engagement with moral emotions to enhance effective teamwork. PMID- 28730737 TI - Vinylation of Aryl Ether (Lignin beta-O-4 Linkage) and Epoxides with Calcium Carbide through C-O Bond Cleavage. AB - Calcium carbide has been increasingly used as a sustainable, easy-to-handle, and low-cost feedstock in organic synthesis. Currently, methodologies of using calcium carbide as "solid acetylene" in synthesis are strictly limited to activation and reaction with X-H (X=C, N, O, S) bonds. Herein, a mild and transition-metal-free protocol was developed for the vinylation of epoxides and aryl ether linkage (beta-O-4 lignin model compound) with calcium carbide through C-O bond cleavage, forming valuable vinyl ether products. Calcium carbide plays a vital role in the C-O bond activation and cleavage, and in providing acetylide source for the formation of vinylated products. These exciting results may provide new methodologies for organic synthesis and new insights toward lignin- or biomassrelated degradation to useful products. PMID- 28730738 TI - The effects of aspirated thickened water on survival and pulmonary injury in a rabbit model. AB - OBJECTIVES/HYPOTHESIS: Liquid thickeners are one of the most frequently utilized treatment strategies for persons with oropharyngeal swallowing dysfunction. The effect of commercially available thickeners on lung injury is uncertain. The purpose of this study was to compare the effects of aspiration of water alone, xanthan gum (XG)-thickened water, and cornstarch (CS)-thickened water on survival and lung morphology in a rabbit model. STUDY DESIGN: Animal model. Prospective small animal clinical trial. METHODS: Adult New Zealand White rabbits (n = 24) were divided into three groups of eight rabbits. The groups underwent 3 consecutive days of 1.5 mL/kg intratracheal instillation of water (n = 8), XG thickened water (n = 8), and CS-thickened water (n = 8). The animals were euthanized on day 4, and survival and pulmonary histopathology were compared between groups. RESULTS: In all, 12.5% of rabbits (n = 8) instilled with CS thickened water survived until the endpoint of the study (day 4). All animals instilled with water (n = 8) or XG-thickened water (n = 8) survived. A mild increase in intra-alveolar hemorrhage was observed for the animals instilled with CS-thickened water compared to the other groups (P < .05). In the groups that survived to the endpoint of the study, instillation of water thickened with XG resulted in greater pulmonary inflammation, pulmonary interstitial congestion, and alveolar edema than water alone (P < .05). CONCLUSIONS: These data suggest that 3 consecutive days of 1.5 mg/kg of aspirated CS-thickened water are fatal, and that XG-thickened water is more injurious than aspirated water alone. Additional research is necessary to further delineate the dangers of aspirated thickened liquids. LEVEL OF EVIDENCE: NA. Laryngoscope, 128:327-331, 2018. PMID- 28730739 TI - Effect of the age of broodstock males on sperm function during cold storage in the trout (Oncorhynchus mykiss). AB - The knowledge of sperm quality in the broodstock males of different ages is a prerequisite to identify the reproductive ability of cultivated fish for the hatchery management. Thus, in this work, we analysed sperm function of the semen stored of broodstock males of rainbow trout (Oncorhychus mykiss) in different reproductive ages (2, 3 and 4 years old). Sperm samples of each reproductive age were stored in Storfish(r) during 10 days at 4 degrees C, and then, motility, viability, mitochondrial function (MMP), superoxide anion (O2-) level and DNA fragmentation (DNAfrag ) were assessed. The results demonstrated that sperm function parameters were affected significantly by the age of the males and the time of storage. Motility, viability and MMP significantly decreased, and DNAfrag and O2- level increased with the age increment and the time of storage. In conclusion, sperm quality of 2 and 3 years old were superior to those of 4 years old, based on higher quality of various sperm functions such as motility, viability, MMP, DNA integrity and level O2- during short-term storage. This information must be considered for optimum utilization of broodstock males in aquaculture. PMID- 28730740 TI - Statistical process control and verifying positional accuracy of a cobra motion couch using step-wedge quality assurance tool. AB - This study utilizes process control techniques to identify action limits for TomoTherapy couch positioning quality assurance tests. A test was introduced to monitor accuracy of the applied couch offset detection in the TomoTherapy Hi-Art treatment system using the TQA "Step-Wedge Helical" module and MVCT detector. Individual X-charts, process capability (cp), probability (P), and acceptability (cpk) indices were used to monitor a 4-year couch IEC offset data to detect systematic and random errors in the couch positional accuracy for different action levels. Process capability tests were also performed on the retrospective data to define tolerances based on user-specified levels. A second study was carried out whereby physical couch offsets were applied using the TQA module and the MVCT detector was used to detect the observed variations. Random and systematic variations were observed for the SPC-based upper and lower control limits, and investigations were carried out to maintain the ongoing stability of the process for a 4-year and a three-monthly period. Local trend analysis showed mean variations up to +/-0.5 mm in the three-monthly analysis period for all IEC offset measurements. Variations were also observed in the detected versus applied offsets using the MVCT detector in the second study largely in the vertical direction, and actions were taken to remediate this error. Based on the results, it was recommended that imaging shifts in each coordinate direction be only applied after assessing the machine for applied versus detected test results using the step helical module. User-specified tolerance levels of at least +/-2 mm were recommended for a test frequency of once every 3 months to improve couch positional accuracy. SPC enables detection of systematic variations prior to reaching machine tolerance levels. Couch encoding system recalibrations reduced variations to user-specified levels and a monitoring period of 3 months using SPC facilitated in detecting systematic and random variations. SPC analysis for couch positional accuracy enabled greater control in the identification of errors, thereby increasing confidence levels in daily treatment setups. PMID- 28730741 TI - The power of competence support: The impact of coaches and athlete leaders on intrinsic motivation and performance. AB - Grounded in the Cognitive Evaluation Theory, a mini-theory of Self-Determination Theory, this experimental field study sought to examine the impact of competence support of both coaches and athlete leaders on athletes' competence satisfaction, intrinsic motivation, and subjective as well as objective performance. Male basketball players (N = 120) were allocated to groups of 5 players. These groups were then randomly assigned to a control group or to 1 of 3 experimental conditions. In these experimental conditions, either the coach, the athlete leader, or both provided motivational feedback to their team. The provision of motivational feedback by either the coach or the athlete leader was sufficient to increase athletes' competence satisfaction, intrinsic motivation, and objective performance (i.e., enhanced execution time without a decrease in scoring percentage) relative to the control group. Interestingly, when both the coach and the athlete leader provided competence support, a surplus effect was observed on objective performance compared with when only the coach provided competence support. Furthermore, structural equation modeling revealed that players' competence satisfaction mediated the relationship between the provided competence support and players' intrinsic motivation, while a direct effect was observed on objective performance. In conclusion, the study findings indicate that also athlete leaders can adopt a motivating role, and that by doing so, their impact is as strong as the impact of the coach. Both coaches and athlete leaders can thus boost athletes' objective performance and foster competence satisfaction, with the latter resulting in increased intrinsic motivation. PMID- 28730742 TI - Microenvironment modulation and enhancement of antilymphoma therapy by the heparanase inhibitor roneparstat. PMID- 28730743 TI - Inulin-type fructans and whey protein both modulate appetite but only fructans alter gut microbiota in adults with overweight/obesity: A randomized controlled trial. AB - SCOPE: Independently, prebiotics and dietary protein have been shown to improve weight loss and/or alter appetite. Our objective was to determine the effect of combined prebiotic and whey protein on appetite, body composition and gut microbiota in adults with overweight/obesity. METHODS AND RESULTS: In a 12 week, placebo-controlled, double-blind study, 125 adults with overweight/obesity were randomly assigned to receive isocaloric snack bars of: (1) Control; (2) Inulin type fructans (ITF); (3) Whey protein; (4) ITF + Whey protein. Appetite, body composition and gut microbiota composition/genetic potential were assessed. Compared to Control, body fat was significantly reduced in the Whey protein group at 12 wks. Hunger, desire to eat and prospective food consumption were all lower with ITF, Whey protein and ITF + Whey protein compared to Control at 12 wks. Microbial community structure differed from 0 to 12 wks in the ITF and ITF +Whey Protein groups (i.e. increased Bifidobacterium) but not Whey Protein or Control. Changes in microbial genetic potential were seen between Control and ITF containing treatments. CONCLUSION: Adding ITF, whey protein or both to snack bars improved several aspects of appetite control. Changes in gut microbiota may explain in part the effects of ITF but likely not whey protein. PMID- 28730744 TI - Improving hospital discharge arrangements for people who are homeless: A realist synthesis of the intermediate care literature. AB - This review presents a realist synthesis of "what works and why" in intermediate care for people who are homeless. The overall aim was to update an earlier synthesis of intermediate care by capturing new evidence from a recent UK government funding initiative (the "Homeless Hospital Discharge Fund"). The initiative made resources available to the charitable sector to enable partnership working with the National Health Service (NHS) in order to improve hospital discharge arrangements for people who are homeless. The synthesis adopted the RAMESES guidelines and reporting standards. Electronic searches were carried out for peer-reviewed articles published in English from 2000 to 2016. Local evaluations and the grey literature were also included. The inclusion criteria was that articles and reports should describe "interventions" that encompassed most of the key characteristics of intermediate care as previously defined in the academic literature. Searches yielded 47 articles and reports. Most of these originated in the UK or the USA and fell within the realist quality rating of "thick description". The synthesis involved using this new evidence to interrogate the utility of earlier programme theories. Overall, the results confirmed the importance of (i) collaborative care planning, (ii) reablement and (iii) integrated working as key to effective intermediate care delivery. However, the additional evidence drawn from the field of homelessness highlighted the potential for some theory refinements. First, that "psychologically informed" approaches to relationship building may be necessary to ensure that service users are meaningfully engaged in collaborative care planning and second, that integrated working could be managed differently so that people are not "handed over" at the point at which the intermediate care episode ends. This was theorised as key to ensuring that ongoing care arrangements do not break down and that gains are not lost to the person or the system vis-a-vis the prevention of readmission to hospital. PMID- 28730745 TI - Influence of minor deterioration of renal function after PCI on outcome in patients with ST-elevation myocardial infarction. AB - OBJECTIVES: Our aim was to assess the possible impact of a deterioration of renal function (DRF) not fulfilling the criteria for acute kidney injury after percutaneous coronary intervention (PCI) on outcome in patients with ST-elevation myocardial infarction (STEMI) on 30-day and long-term outcomes. BACKGROUND: Data is lacking on the influence of DRF after PCI on outcome in patients with STEMI. METHODS: The present study is an analysis of 2572 STEMI patients who underwent PCI. The group with DRF (1022 patients) and the group without DRF (1550 patients) were compared. Thirty-day and long-term all-cause mortality were observed. Data was analyzed using descriptive statistics. RESULTS: Similar mortality was observed in both groups at day 30 (4.2% patients with DRF died vs 3.2% without DRF; ns) but more patients had died in the DRF group (18.9% patients with DRF vs 14.0% without DRF; P = 0.001) by the end of the observation period. After adjustments, DRF did not independently predict long-term mortality. Age more than 70 years, bleeding, hyperlipidemia, renal dysfunction on admission, anemia on admission, diabetes, PCI of LAD, the use of more than 200 mL contrast, but not DRF after PCI, were identified as independent prognostic factors for increased long-term mortality. Renal dysfunction, bleeding, contrast >200 mL, hyperlipidemia, age >70 years, anemia, and PCI LAD predicted DRF. CONCLUSION: DRF identified patients at increased risk of higher long-term mortality but was not independently associated with mortality. PMID- 28730746 TI - Management and prevalence of long-term conditions in primary health care for adults with intellectual disabilities compared with the general population: A population-based cohort study. AB - BACKGROUND: In the UK, general practitioners/family physicians receive pay for performance on management of long-term conditions, according to best-practice indicators. METHOD: Management of long-term conditions was compared between 721 adults with intellectual disabilities and the general population (n = 764,672). Prevalence of long-term conditions was determined, and associated factors were investigated via logistic regression analyses. RESULTS: Adults with intellectual disabilities received significantly poorer management of all long-term conditions on 38/57 (66.7%) indicators. Achievement was high (75.1%-100%) for only 19.6% of adults with intellectual disabilities, compared with 76.8% of the general population. Adults with intellectual disabilities had higher rates of epilepsy, psychosis, hypothyroidism, asthma, diabetes and heart failure. There were no clear associations with neighbourhood deprivation. CONCLUSIONS: Adults with intellectual disabilities receive poorer care, despite conditions being more prevalent. The imperative now is to find practical, implementable means of supporting the challenges that general practices face in delivering equitable care. PMID- 28730747 TI - Study of the prevalence of 5 HT-2C receptor gene polymorphisms in Egyptian patients with lifelong premature ejaculation. AB - We investigated the prevalence of 5HT2C receptor gene polymorphisms in Egyptian patients with lifelong premature ejaculation. A total of 350 participants were enrolled in a prospective study. Two hundred and forty-five cases with lifelong premature ejaculation joined this study, in addition to 105 controls. We instructed the partners of the cases to measure the IELT of the first intercourse only using a stopwatch for 1 month. Genotyping was carried out at the end of the study. The results showed that the majority of the patients and controls were Cys/Cys. A highly significant statistical association was found between the studied gene polymorphisms and IELT among cases (p-values = .009). The study emphasised the potential role of 5HT2C receptor gene polymorphisms in patients with lifelong premature ejaculation. PMID- 28730748 TI - Extracellular signal-regulated kinase activation in the spinal cord contributes to visceral hypersensitivity induced by craniofacial injury followed by stress. AB - BACKGROUND: We previously developed an animal model to examine mechanisms that underlie the emergence of visceral hypersensitivity modeling pain characteristics of temporomandibular disorder (TMD) patients with comorbid irritable bowel syndrome (IBS). In ovariectomized (OVx) rats with estradiol (E2) replacement, visceral hypersensitivity developed subsequent to masseter muscle inflammation followed by repeated forced swim (FS) stress. The purpose of this study was to investigate whether activation of extracellular signal-regulated kinase (ERK) in the spinal cord contributes to visceral hypersensitivity in this overlapping pain model. METHODS: In OVx with E2 replacement rats masseter muscle inflammation was followed by 3 day FS (comorbid condition). Depression-like behaviors were assessed by sucrose preference and in the elevated plus maze, and visceral sensitivity was measured by the visceromotor response (VMR) to colorectal distention. The protein level of ERK1/2 and phosphorylated ERK1/2 (p-ERK1/2) in the L6-S2 dorsal spinal cord was analyzed by western blot. KEY RESULTS: FS stress decreased sucrose consumption in E2 replaced rats in sucrose preference test. The expression of p-ERK1/2 in the L6-S2 dorsal spinal cord increased significantly in E2 with comorbid rats. Intrathecal injection of mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitor PD98059 blocked the visceral hypersensitivity induced by masseter muscle inflammation combined with FS stress. CONCLUSIONS & INFERENCES: These data indicate that ERK1/2 activation contributes to the visceral hypersensitivity evoked by craniofacial inflammation pain combined with stress. The results may provide a new therapeutic avenue for alleviating overlapping pain conditions. PMID- 28730749 TI - Impact of the dynamic and static component of the sport practised for electrocardiogram analysis in screening athletes. AB - To interpret the electrocardiogram (ECG) of athletes, the recommendations of the ESC and the Seattle criteria define type 1 peculiarities, those induced by training, and type 2, those not induced by training, to rule out cardiomyopathy. The specificity of the screening was improved by Sheikh who defined "Refined Criteria," which includes a group of intermediate peculiarities. The aim of our study was to investigate the influence of static and dynamic components on the prevalence of different types of abnormalities. The ECGs of 1030 athletes performed during preparticipation screening were interpreted using these three classifications. Our work revealed 62/16%, 69/13%, and 71/7% of type 1 peculiarities and type 2 abnormalities for the ESC, Seattle, and Refined Criteria algorithms, respectively(P<.001). For type 2 abnormalities, three independent factors were found for the ESC and Seattle criteria: age, Afro-Caribbean origin, and the dynamic component with, for the latter, an OR[95% CI] of 2.35[1.28-4.33] (P=.006) and 1.90[1.03-3.51] (P=.041), respectively. In contrast, only the Afro Caribbean origin was associated with type 2 abnormalities using the Refined Criteria: OR[95% CI] 2.67[1.60-4.46] (P<.0001). The Refined Criteria classified more athletes in the type 1 category and fewer in the type 2 category compared with the ESC and Seattle algorithms. Contrary to previous studies, a high dynamic component was not associated with type 2 abnormalities when the Refined Criteria were used; only the Afro-Caribbean origin remained associated. Further research is necessary to better understand adaptations with regard to duration and thus improve the modern criteria for ECG screening in athletes. PMID- 28730750 TI - Improving type 2 diabetes mellitus glycaemic outcomes is possible without spending more on medication: Lessons from the UK National Diabetes Audit. AB - AIMS: To determine the factors at general practice level that relate to glycaemic control outcomes in people with type 2 diabetes (T2DM). METHODS: Data were accessed from 4050 general practices (50% of total) covering 1.6 million patients with T2DM in the UK National Diabetes Audit 2013 to 2014 and 2014 to 2015. This audit reported characteristics, services and outcomes in the T2DM population, including percentage of patients who had total glycaemic control (TGC), defined as glycated haemoglobin (HbA1c) <=7.5% (58 mmol/mol), and the percentage who were at higher glycaemic risk (HGR), defined as HbA1c >10% (86 mmol/mol); the respective figures were 67.2% and 6.2%. The medication data were examined in terms of annual defined daily doses (DDDs). Multivariate linear regression analysis was used to identify associations between DDD and patient and practice characteristics. RESULTS: Over the period 2012/2013 to 2015/2016, patient numbers grew 4% annually and annual medication expenditure by 8%, but glycaemic control outcomes did not improve. The main findings were that practices with better outcomes: had a higher percentage of patients aged >65 years; provided more effective diabetes services (including case identification, care checks, patient education, percentage of patients with blood pressure and cholesterol under control and more patients with type 1 diabetes achieving target HbA1c levels); spent less overall on prescribing per patient with T2DM; and on average, prescribed fewer sulphonylureas, less insulin (for patients with T2DM), fewer glucagon-like peptide-1 agonists, more metformin, more dipeptidyl peptidase-4 inhibitors, and more blood glucose monitoring strips. Ethnicity and social disadvantage and levels of thiazolidinedione (glitazone) prescribing had no significant impact on outcomes. Sodium-glucose co-transporter-2 inhibitor use was too low for an effect to be observed in the period examined. CONCLUSIONS: If all practices brought their service and medication to the level of the top decile practices, they could achieve 74.7% compared with the median of 67.3% of patients achieving TGC, showing an increase of 213 000 in patients achieving TGC, while reducing the number at HGR to 3.8% compared with 6.1%, benefiting 62 000 patients. This could have a major impact on the overall consequent healthcare costs of managing diabetes complications with their attendant mortality risks. PMID- 28730751 TI - Tuberculosis and biologics in rheumatology: A special situation. AB - India has a huge patient burden of rheumatic diseases (RDs) including rheumatoid arthritis. The use of biologics has transformed the treatment paradigm for RD; however, biologic treatment-related infections (especially tuberculosis [TB]) are an area of potential concern for TB-endemic nations like India. Anti-tumor necrosis factor (TNF) therapy impairs the physiological TNF-mediated signaling and may cause reactivation and dissemination of latent TB infection (LTBI). Careful screening is, thus, crucial in RD patients who are about to commence anti TNF treatment. To date, there is no consensus available for the screening, evaluation and treatment of LTBI as well as on the drug dosage and duration regimen (monotherapy or combination therapy) in the Indian population. An evidence-based algorithm for LTBI screening and management in RD patients undergoing biologic disease-modifying anti-rheumatic drug therapy is suggested in this review for Indian rheumatologists. The proposed algorithm guides physicians through a step-wise screening approach, including medical history, tuberculin skin test, interferon gamma release assay, chest radiograph and management of LTBI with isoniazid therapy or its combination with rifampicin. Further, the provided algorithm can aid the national bodies (such as National TB Control Program) in formulating recommendations for LTBI in this high-risk population. PMID- 28730752 TI - Targeted Nanotherapeutics Encapsulating Liver X Receptor Agonist GW3965 Enhance Antiatherogenic Effects without Adverse Effects on Hepatic Lipid Metabolism in Ldlr-/- Mice. AB - The pharmacological manipulation of liver X receptors (LXRs) has been an attractive therapeutic strategy for atherosclerosis treatment as they control reverse cholesterol transport and inflammatory response. This study presents the development and efficacy of nanoparticles (NPs) incorporating the synthetic LXR agonist GW3965 (GW) in targeting atherosclerotic lesions. Collagen IV (Col IV) targeting ligands are employed to functionalize the NPs to improve targeting to the atherosclerotic plaque, and formulation parameters such as the length of the polyethylene glycol (PEG) coating molecules are systematically optimized. In vitro studies indicate that the GW-encapsulated NPs upregulate the LXR target genes and downregulate proinflammatory mediator in macrophages. The Col IV targeted NPs encapsulating GW (Col IV-GW-NPs) successfully reaches atherosclerotic lesions when administered for 5 weeks to mice with preexisting lesions, substantially reducing macrophage content (~30%) compared to the PBS group, which is with greater efficacy versus nontargeting NPs encapsulating GW (GW-NPs) (~18%). In addition, mice administered the Col IV-GW-NPs do not demonstrate increased hepatic lipid biosynthesis or hyperlipidemia during the treatment period, unlike mice injected with the free GW. These findings suggest a new form of LXR-based therapeutics capable of enhanced delivery of the LXR agonist to atherosclerotic lesions without altering hepatic lipid metabolism. PMID- 28730754 TI - Diffuse Hepatic Hemangiomas Successfully Treated Using Sirolimus and High-Dose Propranolol. AB - Diffuse hepatic hemangiomas are a challenging disease that can be life threatening. We present the case of an infant with diffuse hepatic hemangiomas who failed first-line therapies but later responded to sirolimus and high-dose propranolol. PMID- 28730753 TI - Randomized clinical trial of Appendicitis Inflammatory Response score-based management of patients with suspected appendicitis. AB - BACKGROUND: The role of imaging in the diagnosis of appendicitis is controversial. This prospective interventional study and nested randomized trial analysed the impact of implementing a risk stratification algorithm based on the Appendicitis Inflammatory Response (AIR) score, and compared routine imaging with selective imaging after clinical reassessment. METHOD: Patients presenting with suspicion of appendicitis between September 2009 and January 2012 from age 10 years were included at 21 emergency surgical centres and from age 5 years at three university paediatric centres. Registration of clinical characteristics, treatments and outcomes started during the baseline period. The AIR score-based algorithm was implemented during the intervention period. Intermediate-risk patients were randomized to routine imaging or selective imaging after clinical reassessment. RESULTS: The baseline period included 1152 patients, and the intervention period 2639, of whom 1068 intermediate-risk patients were randomized. In low-risk patients, use of the AIR score-based algorithm resulted in less imaging (19.2 versus 34.5 per cent; P < 0.001), fewer admissions (29.5 versus 42.8 per cent; P < 0.001), and fewer negative explorations (1.6 versus 3.2 per cent; P = 0.030) and operations for non-perforated appendicitis (6.8 versus 9.7 per cent; P = 0.034). Intermediate-risk patients randomized to the imaging and observation groups had the same proportion of negative appendicectomies (6.4 versus 6.7 per cent respectively; P = 0.884), number of admissions, number of perforations and length of hospital stay, but routine imaging was associated with an increased proportion of patients treated for appendicitis (53.4 versus 46.3 per cent; P = 0.020). CONCLUSION: AIR score-based risk classification can safely reduce the use of diagnostic imaging and hospital admissions in patients with suspicion of appendicitis. Registration number: NCT00971438 ( http://www.clinicaltrials.gov). PMID- 28730755 TI - The Unusual Role of Aromatic Solvent in Single-Site AluminumI Chemistry: Insights from Theory. AB - The single-site activation of strong sigma bonds (such as that of H-H, P-H, and N H) remains a significant challenge in main-group chemistry, with only a few cases reported to date. In this regard, recent exciting experiments performed with aluminumI complexes hold significance because they have been seen to activate a variety of strong sigma bonds. Such chemistry is generally seen to occur in aromatic solvents. Current computational studies with DFT reveal the interesting reason for this: an explicit aromatic solvent molecule acts as a catalyst by converting the aluminumI complex into aluminumIII during the process. Different cases of sigma-bond activation by aluminumI complexes have been investigated and the efficiency of H-X (X=H, NHtBu, PPh2 ) bond activation in the presence of an explicit benzene solvent molecule is orders of magnitude higher than that in its absence. The current work therefore reveals the chemistry of aluminumI complexes to be richer and more complex than that previously realized, and shows it to be dependent on metal-solvent cooperativity; the first known example of its kind in main-group chemistry. PMID- 28730756 TI - Animal-assisted psychotherapy for young people with behavioural problems in residential care. AB - The aim of this study was to evaluate the impact of an animal-assisted psychotherapy (AAP) programme on clinical symptoms, personal adjustment, and adaptive skills in a group of adolescents in residential care who had experienced childhood trauma and who presented mental health problems and difficulties adapting to the care home environment. The 87 participants (Mage = 15.17, SD = 1.53) were divided into two groups: a treatment group (25 girls and 27 boys; Mage = 15.00, SD = 1.55) and a control group (9 girls and 26 boys; Mage = 15.42, SD = 1.50). The programme consisted of 34 sessions involving both group (23 sessions) and individual (11 sessions) AAP. The Behaviour Assessment System for Children was used to evaluate clinical and adaptive dimensions of behaviour and personality. The results indicated that, in comparison with controls, the young people who took part in the AAP programme reported a significant improvement on two measures of internalizing symptoms, namely, depression and sense of inadequacy. Although no significant differences were observed in relation to externalizing symptoms, the adolescents who received the AAP programme showed improved social skills in terms of their ability to interact satisfactorily with peers and adults in the care home environment, as well as a more positive attitude towards teachers at school. These results suggest that AAP may be a promising treatment for young people who have experienced childhood trauma and who subsequently find it difficult to adapt to the residential care setting. PMID- 28730757 TI - Psoriatic arthritis treatment regimens, therapy duration and reasons for cessation in the biologics era: a multi-centre Australian study. AB - AIM: To describe the treatment regimens, duration of therapy and reasons for disease-modifying antirheumatic drug (DMARD) cessation in a large psoriatic arthritis (PsA) cohort. METHODS: A retrospective non-interventional multi-centre study using Audit4 electronic medical records, with de-identified, routinely collected clinical data from rheumatology practices in the OPAL consortium (Optimising Patient outcomes in Australian rheumatoLogy) during November 2015. Baseline characteristics, type and duration of conventional and biologic DMARDs (cDMARD and bDMARD, respectively), disease activity (Disease Activity Score of 28 joints C-reactive protein [DAS28-CRP]), and reasons for treatment cessation were recorded. RESULTS: A total of 3422 rheumatologist-diagnosed PsA patients were included: 60% female, mean age 54 years and disease duration 10 years. Of patients with treatment recorded (n = 2948), 46% were on cDMARD monotherapy, 19% bDMARD monotherapy, 13% combination bDMARD and cDMARDs, 11% combination cDMARDs and 10% no DMARDs. Of those with DAS28-CRP results (n = 494), the highest mean DAS28-CRP was 3.32 on combination cDMARDs, and the lowest was 2.19 on bDMARD monotherapy. Median duration on cDMARD monotherapy was 33.5 months (n = 2232), on bDMARD monotherapy 110.1 months (n = 751), on combination bDMARD and cDMARDs 68.5 months (n = 559). The most common reasons for cessation of cDMARD monotherapy was adverse reactions (41%), for bDMARD monotherapy lack of efficacy (26%), and for combination bDMARD and cDMARDs treatment completed or no longer required (37%). CONCLUSION: Most PsA patients were prescribed DMARD therapies with a large proportion receiving cDMARDs. Patients on combination cDMARD therapies had the highest DAS28-CRP results. Adverse reactions were the most common reason for cessation of cDMARD monotherapy, whereas for bDMARD monotherapy it was lack of efficacy. PMID- 28730758 TI - Platinum derivatives: a multidisciplinary approach. AB - Cancer is one of the most difficult diseases to be treated. The particularities regarding the tumors' occurrence mechanism, their evolution under chemotherapy, disease-free interval, but also the increasing number of patients make cancer an intensively studied health domain. Although introduced in therapy since the early 80s, platinum derivatives play an essential role in anticancer therapy. Their use in therapy resulted in improving the patient quality of life and prolonging disease-free interval, which makes them still a benchmark for other anticancer compounds. However, adverse reactions and allergic reactions are a major impediment in therapy with platinum derivatives. This paper summarizes data about platinum derivatives through a multidisciplinary approach, starting from a chemical point of view and on to their mechanism of action, mechanism of cellular resistance, predictive factors for the outcome of chemotherapy such as micro RNAs (miRNAs), tumor suppressor protein p53, and the excision repair cross complementing 1 protein (ERCC1). PMID- 28730759 TI - Surgical treatment for colorectal cancer in octogenarians and nonagenarians. AB - Advances in surgical techniques and perioperative care have improved cancer related outcomes. However, there are still concerns regarding the safety of octogenarian and nonagenarian patients during surgery. Clinicians may be reluctant to perform a radical resection for colorectal cancer and administer adjuvant or palliative cytotoxic chemotherapy to octogenarian and nonagenarian patients. In the elderly, setting a primary goal based on multidisciplinary team discussions prior to treatment is important. The overall treatment scheme, risks, and potential benefits should be discussed with elderly patients and their families. In this review, we will discuss multidimensional aspects of colorectal cancer surgery for octogenarian and nonagenarian patients with respect to age related physiological declines, preoperative assessments, appropriate surgical procedures, and short-term and oncologic outcomes. In this era of an aging society, clinicians should provide objective evidence to octogenarian and nonagenarian patients regarding estimated short-term and oncologic outcomes. However, there is a limited number of studies concerning outcomes following colorectal cancer surgery in octogenarians and nonagenarians. In the future, a prospective study with a larger cohort would be helpful to collect objective data on octogenarian and nonagenarian patients. PMID- 28730760 TI - Targeted therapy with anaplastic lymphoma kinase inhibitors in non-small cell lung cancer even with brain metastasis. AB - The incidence of brain metastases has increased as a result of improved systemic disease control and advances in imaging. Brain metastasis can occur approximately in 25-40% of the patients with non-small cell lung cancer (NSCLC) and it is a frequent cause of death. Stereotactic radiosurgery, whole-brain radiotherapy (WBRT) or surgical resection are the local treatment modalities for brain metastases which are feasible either alone, in combination, or as sequential treatments. Resistance to systemic therapy for brain metastasis poses significant clinical problems. In anaplastic lymphoma kinase (ALK)-positive NSCLC patients; ALK inhibitors may provide a new treatment option for brain metastasis and could improve overall survival (OS). Even in patients with crizotinib-resistant disease, second generation ALK inhibitors display prominent clinical activity. There is rapidly emerging preclinical and clinical data showing improvement in this issue. In this article we reviewed the latest literature data concerning the brain metastases and intracranial efficacy of ALK inhibitors in patients with ALK positive NSCLC. PMID- 28730761 TI - Tumor infiltrating lymphocytes as a prognostic factor in malignant melanoma. Review of the literature. AB - Malignant melanoma represents the major cause of mortality among skin cancers, with increasing incidence and mortality rates worldwide. Despite the numerous public health campaigns and the efforts undertaken in the last decade regarding the establishment of a rapid diagnostic and an efficient treatment for these patients, the long-term prognosis has not been significantly improved. Thus, numerous studies were conducted in order to establish a more accurate prognosis, tumor infiltrating lymphocytes (TILs) being considered in many studies as independent prognostic factors of lymph node metastasis and overall survival in patients with melanoma. Moreover, immunotherapy has been intensively studied and evolved in recent times, and represents a promising treatment option for patients with advanced stage (metastatic) malignant melanoma. In this review article, we provided a literature overview on the histological classification, the history and the essential role of TILs, as well as the implications of regulatory T (Treg) cells and FOX P3 transcription factor in malignant melanoma. PMID- 28730762 TI - Review of the three-field techniques in breast cancer radiotherapy. AB - Breast cancer is often treated with radiotherapy (RT), with two opposing tangential fields. When indicated, supraclavicular lymph nodes have to be irradiated, and a third anterior field is applied. The junction region has the potential to be over or underdosed. To overcome this problem, many techniques have been proposed. A literature review of 3 Dimensional Conformal RT (3D CRT) and older 3-field techniques was carried out. Intensity Modulated RT (IMRT) techniques are also briefly discussed. Techniques are categorized, few characteristic examples are presented and a comparison is attempted. Three-field techniques can be divided in monoisocentric and two-isocentric. Two-isocentric techniques can be further divided in full field and half field techniques. Monoisocentric techniques show certain great advantages over two-isocentric techniques. However, they are not always applicable and they require extra caution as they are characterized by high dose gradient in the junction region. IMRT has been proved to give better dosimetric results. Three-field matching is a complicated procedure, with potential of over or undredosage in the junction region. Many techniques have been proposed, each with advantages and disadvantages. Among them, monoisocentric techniques, when carefully applied, are the ideal choice, provided IMRT facility is not available. Otherwise, a two isocentric half beam technique is recommended. PMID- 28730763 TI - DNA mismatch repair deficiency in lung and oral cavity carcinomas: the role of histogenetic origin. AB - DNA mismatch repair system (DNA MMR) is a crucial genetic mechanism for DNA homeostasis in prokaryotic and eukaryotic cells. During DNA replication and also recombination, point intra-nucleotide errors including base deletion, insertion, and mis-incorporation happen. These raised abnormalities in the newly synthesized DNA strand could affect negatively the stability of the molecule and the function of the corresponding genes. DNA MMR proteins prevent these errors by recognizing and repairing them, securing directly the normal anatomy of the DNA double strand and indirectly the expression of the genes. Specific genomic alterations - mutations, loss of heterozygosity (LOH), or promoter hypermethylation - regarding the MMR genes (human homologues) hMLH1, hMSH2, hMSH3, hMSH6, hPMS1 and hPMS2 modify negatively their expression leading to loss of their function in repairing the corresponding base to base errors. The result known as microsatellite instability (MSI) was initially recognized in colonic carcinoma, especially in its inherited aspect - the Lynch syndrome -, the most common form of hereditary colon carcinoma. Since then, acquired deficiencies in specific DNA MMR genes have been detected in a broad spectrum of malignancies including different anatomic regions and histologies such as stomach, prostate, esophageal, endometrial, lung and head & neck. In the current special review we explored the role of DNA MMR deficiency in lung and oral cavity carcinomas in order to identify similarities and differences regarding the corresponding genes alterations. PMID- 28730764 TI - mTOR deregulation in oral cavity squamous cell carcinoma. AB - Signal transduction pathways consist of a variety of inter- and intra-cellular molecules. They act as supporting mechanisms for cell survival and homeostasis. Among them, the phosphatidylinositol 3-kinase (PI3K)/tumor suppressor phosphatase and tensin homologue deleted on chromosome ten (PTEN)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway plays a crucial role in regulating normal cell growth based on growth factor receptors (GFRs) interaction, including epidermal GFR (type II-HER2) and insulin GFR (IGF). mTOR protein acts as a serine-threonine kinase that belongs to the PI3K-related kinase family. It mediates protein and lipid synthesis, mitochondrial metabolism, biogenesis, proliferation and also negatively regulates autophagy. Two distinct multiprotein complexes have been mainly identified and cloned: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). mTOR is deregulated predominantly due to mutations, deletions, loss of heterozygosity (LOH) or abnormal phosphorylation of the upstream molecules inside the current pathway. Pure mTOR mutations are very rare. Development of specific inhibitors at the basis of targeted therapeutic strategies such as rapamycin (rapalogs) is an evolution in handling patients with mTOR abnormal overactivity. In the current special article we explored the role of the gene deregulation leading to abnormal protein expression in oral cavity squamous cell carcinoma (SCC). PMID- 28730765 TI - Prognostic role of inflammatory biomarkers in metastatic breast cancer. AB - PURPOSE: The effects of inflammation on the prognosis, life expectancy and several parameters such as response to treatment of breast cancer have been previously studied. The purpose of this study was to investigate the effect of inflammatory markers on prognosis in patients with metastatic breast cancer. METHODS: This study was conducted on 81 patients with metastatic breast cancer who have been followed up at the Department of Medical Oncology, Hacettepe University Institute of Oncology, between December, 2009 and March, 2014. For all studied parameters Kaplan-Meier survival estimates and p values computed by log rank test were calculated. A p value < 0.05 was considered statistically significant. RESULTS: Median follow-up time was 26 months. There were 38 deaths due to disease progression during the follow up. The levels of serum albumin, and erythrocyte sedimentation rate (ESR) were not associated with a significant effect on overall survival (OS). Among patients with a higher serum C-reactive protein (CRP), the estimated mean survival was 84+/-36 months, compared to 278+/ 113 months among patients with a normal serum CRP (p=0.032). When patients with higher and normal lactate dehydrogenase (LDH) levels were compared, their 2-year OS survival rates were 68.2 and 87.7%, respectively (p=0.034). Among patients with higher serum ferritin levels, the estimated mean survival was 29+/-10 months, compared to 212+/-113 months for normal serum ferritin (p=0.01). Among patients with higher serum beta-2 microglobulin (beta2-M), the estimated mean OS survival was 28+/-8 months, compared to 84+/-57 months for those with normal levels (p<0.01). CONCLUSION: Serum CRP, ferritin and beta2-M can be useful prognostic factors for OS in patients with metastatic breast cancer. PMID- 28730766 TI - Comparison of prognosis and clinical features between synchronous bilateral and unilateral breast cancers. AB - PURPOSE: The clinical significance of synchronous bilateral breast cancer (SBBC) is unclear and its influence on prognosis is controversial. Our study objective was to determine the epidemiological features, tumor characteristics, and prognosis of SBBC in comparison with those of unilateral breast cancer (UBC). METHODS: A total of 3675 breast cancer patients diagnosed and treated between 2000 and 2014 were evaluated. Of these patients, 132 (3.6%) had bilateral breast cancer, including 55 patients (1.5%) with SBBC and 77 (2.1%) with metachronous bilateral breast cancer (MBBC). The patient demographic characteristics, including survival data and clinicopathological tumor characteristics, were obtained from medical charts and compared between the patients with SBBC and those with UBC. RESULTS: The median age in the SBBC group was 51 years (range 32 77). The mastectomy rate was higher in the SBBC group (72.7%) than in the UBC group (66.6%) (p=0.08). In both the SBBC and UBC groups, the baseline clinicopathological features and the history of treatment with radiotherapy and chemotherapy were similar. Infiltrating ductal carcinoma was the most common histology in both groups. Lobular histology was more frequent in the SBBC group (36.3%) than in the UBC group (17.1%; p<0.001). Stage IV disease at initial presentation was more frequent in the SBBC group than in the UBC group (34.5 vs 8.7%, p<0.001). The 5-year disease-free survival (DFS) rates were 90% and 82% in the SBBC and UBC groups, respectively (p=0.99). The 5-year overall survival (OS) rates were 83% and 88%, respectively (p=0.357). The multivariate Cox regression analysis, including stage, hormone receptor status, grade, and SBBC, revealed that the presence of SBBC was not associated with OS (hazard ratio 0.929; 95% confidence interval, 0.455-0.1894, p=0.839). CONCLUSION: Despite the differences in histology, initial stage, and other characteristics, the prognoses of UBC and SBBC were similar. PMID- 28730767 TI - The role of interleukin 8 and matrix metalloproteinases 2 and 9 in breast cancer treated with tamoxifen AB - PURPOSE: To evaluate the role of interleukin 8 (IL8) and matrix metalloproteinase (MMP) 2 and 9 as potential parameters of response to adjuvant tamoxifen and to examine possible associations between biomarkers that might imply possible biological dependence. METHODS: The study included 59 postmenopausal breast cancer patients who received adjuvant tamoxifen. Biomarker levels were determined by ELISA in cytosol tumor extracts. RESULTS: Estrogen receptor (ER) proved as a reliable parameter of response to tamoxifen; patients with ER+ status had significantly longer median relapse-free survival (RFS) compared to those with ER status (p=0.04). Patients with IL8-status had longer median RFS compared to those with IL8+ status (77 and 53 months, respectively) but without significant difference. Patients with MMP9+ status had longer median RFS compared to those with MMP9-status (92 and 66 months, respectively) but without significant difference. There was no significant difference in RFS between the subgroups formed according to MMP2 median value. A significant positive correlation was found between IL8 and MMP9 levels (p<0.001). Expression of MMP9 was significantly higher in patients with IL8 levels higher than the median (p=0.001). CONCLUSIONS: IL8 showed a tendency to act as an unfavorable parameter while MMP9 showed a tendency to act as a favorable parameter of response to tamoxifen, whereas the role of MMP2 as a potential predictive parameter is more complex. The results indicate that possible existence of positive feedback between IL8 and MMP9 might contribute to progression of breast cancer. PMID- 28730768 TI - Modulatory effect of neoadjuvant chemotherapy on the prognosis of patients with breast cancer. AB - PURPOSE: To evaluate the changes in biological markers ER, PR, HER2 and Ki67 in residual tumor after surgery for locally advanced breast cancer (LABC), and also to evaluate the outcome of breast cancer patients treated with neoadjuvant chemotherapy (NAC). METHODS: 144 breast cancer patients treated with NAC at the Oncology Institute of Vojvodina, Serbia from 2011 to 2015 were included in this study. Changes in biologic markers ER,PR, HER2/neu and Ki-67 were evaluated at diagnostic core biopsy and at the final surgery tissue specimens. RESULTS: Of 144 patients pathological complete response was achieved in 17 (12%) and these were excluded from the study. Evaluated were 127 patients with residual tumor after the final surgery. A change in hormone receptor status (ER,PR) occurred in 9.4% of the patients (ER in 5%, PR in 14.5%) and HER2 status in 4.7% of the patients. ER and PR status change from negative to positive was associated with better overall survival (OS), but without statistical significance (p=0.16). Patients with conversion of HER2 status from negative to positive lived longer (65 vs 42 months). Furthermore, it was determined that HER2 change from negative to positive was associated with better OS (p=0.03). Ki-67 changed in 17 (11.8%) patients. The decrease of Ki-67 expression after NAC was associated with better outcome. Median follow up was 37.5 months (range 16.2-76.8). CONCLUSION: Changes in hormone receptor status, HER2 status and Ki-67 occurred after NAC in patients with LABC. A change from negative to positive hormone receptor status and HER2 status offers new treatment options, like endocrine therapy, and/or trastuzumab therapy for breast cancer patients. The decrease of Ki-67 expression after NAC was associated with better outcome. PMID- 28730769 TI - Downregulation and subcellular distribution of HER2 involved in MDA-MB-453 breast cancer cell apoptosis induced by lapatinib/celastrol combination. AB - PURPOSE: To investigate the effect and related molecular mechanisms of lapatinib/celastrol combination or single-agent treatment in HER2/neu overexpressing MDA-MB-453 breast cancer cells. METHODS: The effects of treatment with lapatinib, celastrol or their combination on cell growth were determined using MTT assay. Drug synergy was determined using the combination index (CI) methods derived from Chou-Talalay equations using CalcuSyn software. Apoptotic morphology was observed by fluorescence microscope with Hoechst 33258 staining. Changes of apoptotic and growth pathways-related proteins were analysed by Western blot. The expression of HER2 of cell surface was performed by flow cytometry. Subcellular distribution of HER2 was observed by immunofluorescence study. RESULTS: Combination celastrol and lapatinib produced strong synergy in growth inhibition and apoptosis in comparison to single-agent treatment in HER2/neu-overexpressing MDA-MB-453 cells. Interestingly, compared with celastrol treatment alone, lapatinib/celastrol combination induced more HER2 membrane protein downregulation and ectopic to cytoplasm and nucleus in MDA-MB-453 cells. CONCLUSION: The combination of celastrol and lapatinib could be used as a novel combination regimen which provides a strong anticancer synergy in the treatment of HER2/neu-overexpressing cancer cells. PMID- 28730770 TI - Characteristics and outcomes of patients with multifocal/multicentric and unifocal breast cancer. AB - PURPOSE: The clinical behavior and outcome of multifocal (MF) and multicentric (MC) breast tumors are not well characterized. The purpose of this study was to compare the prognosis of MF/MC tumors with unifocal (UF)tumors and its correlation with other pathological characteristics and patient outcomes. METHODS: Eighty-three patients with MC/MF breast cancer and 501 with UF breast cancer treated at the Surgical Clinic Nis were studied. We compared MC/MF and UF breast cancer patients with respect to demographics, tumor characteristics- adjuvant systemic therapy, local recurrence-free survival (LRFS) and overall survival (OS). RESULTS: There was no significant statistical difference between the two groups with respect to mean age at diagnosis, tumor grade, nodal status, estrogen receptor status, lymphovascular invasion (LVI) and adjuvant systemic therapy. The MC/MF group had more patients with modified radical mastectomy and the UF group had more patients with breast-conserving surgery. Cox multivariate regression analysis showed that the regional lymph node metastases and LVI were the most important predictors of 5-year OS rate. During this period, locoregional recurrence was registered in 29 (5.78%) patients in the UF group and in 5 (6.02%) patients in the MF/MC group (p=0.48). No statistically significant differences in the 5-year LRFS and OS between the two groups were noticed. CONCLUSION: The prognostic value of MF/MC disease is still not well known, although some studies have suggested that it is associated with a worse prognosis. This study showed no statistically significant difference in the 5-year LRFS and OS between UF and MF/MC groups. PMID- 28730771 TI - Biomarkers for the early detection of relapses in metastatic colorectal cancers. AB - PURPOSE: To assess prognostic/predictive value of carcinoembryonic antigen (CEA), transthyretin (TRT), alphaenolase (NNE), beta2-microglobulin (beta2-micro), B cell activating factor (BAFF) and circulating tumor cells (CTCs) in metastatic colorectal cancer (mCRC) patients treated with chemotherapy with or without bevacizumab. METHODS: 72 histologically confirmed mCRC patients treated at Oncology Institute Cluj were included. Biomarker levels were measured through validated methods. A manual method was used for CTCs, involving hemolysis, cytospin centrifugation and immunocytochemical staining for pan-cytokeratin. Statistical endpoints were response, progression- free survival (PFS) and overall survival (OS). RESULTS: Initial chemotherapy was fluoropyrimidine/oxaliplatin based in 93.1%; bevacizumab was added in 58.3% of the patients. Median PFS and OS were 16.4 and 24.4 months. Two-year OS for CR & PR vs SD vs PD were 90% vs 48% vs 12%, respectively (p<0.01). Two-year OS for chemo/ bevacizumab vs chemotherapy: 65% vs 42% (p=0.09). Baseline CEA >=5 ng/ml had a negative prognostic impact on OS and PFS (p<0.01). High baseline CEA was predictive of improved OS when adding bevacizumab (2-year OS chemo/bevacizumab vs chemo: 60% vs 17%, p<0.01); adding bevacizumab in patients with normal CEA did not improve OS (p=0.29). Higher than cut-off values for TRT had a positive OS prognostic value (p<0.01); higher levels for NNE, beta2-microglobulin and BAFF had a negative impact (p<0.01). Two-year OS for baseline <1 CTC/ml vs >=1 CTC/ ml was 74% vs 64% respectively (p=0.15). CONCLUSIONS: The evaluated biomarkers could be useful prognostic factors for survival. Baseline CEA also has predictive value, suggesting that patients with low levels do not benefit from bevacizumab. A non-statistically significant correlation was observed between the number of CTCs and outcome. PMID- 28730772 TI - A comparative study of laparoscopic microwave ablation with laparoscopic radiofrequency ablation for colorectal liver metastasis. AB - PURPOSE: Laparoscopic thermal ablation is a common alternative to surgical resection for treating colorectal liver metastasis, particularly for metastases located in difficult-to-reach regions. This study aimed to compare the short- and longterm outcomes of laparoscopic radiofrequency ablation (LRFA) and laparoscopic microwave ablation (LMWA) used for treating colorectal liver metastasis. METHODS: Data from patients with colorectal liver metastasis who had undergone LRFA or LMWA from January 2010 to January 2016 were examined. Baseline data, postoperative 30-day complications, complete ablation rates, local tumor progression rates, and disease-free (DFS) and overall survival (OS) rates were compared between the two treatment groups. RESULTS: A total of 179 patients with colorectal liver metastasis (71 with LMWA and 108 with LRFA) were treated via the laparoscopic approach. Major postoperative 30-day complication rates were 11.1% and 12.7% in the LRFA and LMWA groups, respectively (p=0.046). No perioperative or postoperative 30-day deaths occurred. Local tumor progression (LTP) rates were 10.2% (11/108) and 1.4% (1/71) in the LRFA and LMWA groups (p=0.046), respectively. Fiveyear OS rates were 56% and 58% (p=0.498) and 5-year DFS rates were 41% and 39% (p=0.557) in the LRFA and LMWA groups, respectively. CONCLUSIONS: LRFA and LMWA appear to be safe for treating colorectal liver metastasis. The OS and DFS rates were similar, although LTP rates were lower in the LMWA group than in the LRFA group. PMID- 28730773 TI - Thermal ablation may improve outcomes in patients with colorectal liver metastasis: a case-control study. AB - PURPOSE: Local thermal ablation may extend the scope of palliative therapy in patients with colorectal liver metastasis. We performed a retrospective, case controlled study to compare patients with colorectal liver metastases that were treated with percutaneous radiofrequency (RF) or microwave (MW) thermal ablation, against the control group of chemotherapy alone. METHODS: We described baseline demographics, ablation sessions, procedure duration and related complications. We compared outcomes of percutaneous thermal ablation versus chemotherapy alone (controls) in patients with colorectal liver metastasis. The control group assigned (non-ablated patients) had similar demographics and prior treatment profile when compared to ablated patients. Progression-free survival (PFS) and overall survival (OS) were estimated for the two groups. RESULTS: Twenty-eight cases with 57 baseline hepatic lesions (median age 68 years; male to female ratio 2:1) were evaluated and compared with 48 controls. A total of 55 sessions (52 RF, 3 MW) were performed among the cases, with minimal procedural time (median 8 min), zero mortality and no severe complications (3 cases of local hepatic hematoma not requiring hospitalization). Ablated patients had prolonged median PFS (19.4 months) and OS (27.5 months) when compared against controls (14.0 and 21.4 months, respectively). After adjusting for hepatic involvement, PFS estimates were comparable and OS was better for the ablated group. One and 2-year survival estimates were 0.96 and 0.79 for thermal ablation patients compared with 0.82 and 0.52 for controls (p=0.05 and p=0.07, respectively). CONCLUSION: Percutaneous thermal ablation may delay progression and death in colorectal cancer patients with metastatic liver disease. PMID- 28730774 TI - Laparoscopic colectomy for serosa-positive colon cancer (pT4a) in patients with preoperative diagnosis of cancer without serosal invasion. AB - PURPOSE: Although general surgeons normally perform laparoscopic colectomies in patients with colon cancer, the procedure is also indicated for serosa-negative tumors (<= cT3). Serosal invasion (T4a) is regarded as a potential risk factor for peritoneal dissemination due to pneumoperitoneum effects and tumor manipulation during laparoscopic colectomy. We compared short- and long-term outcomes of patients who underwent laparoscopic and open colectomies for serosa involving colon cancer (pT4a) and had a preoperative diagnosis of cancer without serosal invasion (<=cT3). METHODS: A total of 179 patients (102 patients treated with laparoscopic colectomies and 77 with open colectomies) who were treated between 2009 and 2015 were included. These patients were first diagnosed preoperatively with <= cT3 disease based on computed tomography, endoscopy, or endoscopic ultrasound, but they were diagnosed with pT4a disease based on final pathology results. Recurrence and survival rates between the two groups were compared. RESULTS: Baseline characteristics, clinical stage, type of colectomy, and short-term outcome did not differ between the groups. Five-year overall survival (OS) (p=0.248) and disease- free survival (DFS) rates (p=0.113) were comparable between the laparoscopic and open groups. Recurrence patterns did not differ between groups. Moreover, laparoscopic colectomy did not increase peritoneal recurrence compared to open colectomy. By multivariate analysis, surgical approach was not an independent prognostic factor for OS or DFS. CONCLUSION: Similar survival and recurrence patterns were observed in patients with serosa-involving colon cancer (pT4a) who were preoperatively diagnosed with serosa negative disease (<=cT3) and underwent either laparoscopic or open colectomies. Laparoscopic colectomy may be safely performed in patients with serosa-positive tumors. PMID- 28730775 TI - Charlson comorbidity index for evaluatiomicronn omicronf the outcomes of elderly patients undergoing laparoscopic surgery for colon cancer. AB - PURPOSE: We investigated the effectiveness of the Charlson comorbidity index (CCI) for predicting postoperative 30-day complications and long-term survival outcomes of elderly patients who underwent laparoscopic surgery for colon cancer with radical intent. METHODS: We reviewed 178 patients aged >=70 years who underwent laparoscopic surgery for colon cancer with radical intent between January 2008 and December 2015. Patients were divided into high CCI (CCI >= 3; n=71) and low CCI (CCI < 3; n=107) groups for comparative analyses of differences in their short- and long-term outcomes. RESULTS: Postoperative 30-day complications were more frequent in the high CCI group than in the low CCI group. Logistic regression analysis revealed that a high CCI was significantly predictive of postoperative 30-day complications. The 5-year overall survival (OS) rates were 65% and 54% for the low and high CCI groups, respectively (p=0.034) and their 5-year disease-free survival (DFS) rates were 60% and 47%, respectively (p=0.030). CONCLUSION: CCI predicted the likelihood of postoperative 30-day complications and long-term survival outcomes of elderly patients who underwent laparoscopic surgery for colon cancer with radical intent. PMID- 28730776 TI - Institutional variations in nutritional aspects of enhanced recovery pathways after elective surgery for colon cancer. AB - PURPOSE: Perioperative nutritional optimisation is one of the key aspects of the Enhanced Recovery after Surgery (ERAS) pathway after elective colorectal cancer resections. Despite the general acceptance of ERAS as a safe and cost-effective perioperative care bundle, significant variations in terms of nutritional support exist among colorectal units. METHODS: To assess these variations, we performed a cross-sectional online survey among colorectal surgical residents within a UK region. RESULTS: Our survey of practice demonstrated that despite the international recommendations, a considerable percentage of colorectal units would still advocate prolonged fasting prior to surgery without routine use of carbohydrate loading, as well as delaying resumption of oral intake postoperatively. In addition, in almost one in five colorectal units, the patients would not be assessed by the specialist nutrition team for potential support during their hospitalisation. CONCLUSION: Therefore, we believe that further education of the medical and allied health professional staff is required regarding the correct implementation of ERAS pathway guidelines after elective surgery for colorectal cancer. PMID- 28730777 TI - Long non-coding RNA XIST functions as an oncogene in human colorectal cancer by targeting miR-132-3p. AB - PURPOSE: Colorectal cancer (CRC) is a frequent malignant tumor with high death rate and poor prognosis. Few reports have explored the association between CRC development and long non-coding (lnc) RNAs expression. This study focused on the important role of a novel lncRNA XIST in the development of CRC. METHODS: To investigate the function of long lncRNA XIST in CRC, its expression level was monitored in both CRC cells and 50 pairs of human CRC tissues and adjacent tissues by RT-qPCR. Moreover, the associations between lncRNA XIST expression level and clinicopathological characteristics and 5-year survival rate of CRC patients were evaluated. Furthermore, function assays containing cell proliferation assay, flow cytometry and colony formation were conducted to investigate the role of lncRNA XIST in CRC. Western blotting assay and luciferase assay were used to explore the regulation mechanism of lncRNA XIST in the development. RESULTS: The expression level of XIST was significantly increased in both CRC tissues sample and CRC cells. XIST promoted CRC cell proliferation by affecting the cell cycle. In addition, XIST and miR-132-3p were inhibited by each other reciprocally. MAPK1 was proved to be a direct target spot of miR-132-3p. We claim that XIST was responsible for CRC cell proliferation working by the miR-132 3p/MAPK1 axis. CONCLUSION: The present study suggests that lncRNA XIST is a potential oncogene in CRC, and could promote CRC cell proliferation through inhibiting miR-132-3p, which may provide a new therapeutic target of CRC. PMID- 28730778 TI - Study on the effect of integrin alphanubeta6 on the proliferation and apoptosis of thyroid carcinoma cells. AB - PURPOSE: To study the effect of integrin alphavbeta6 on the proliferation and apoptosis of thyroid carcinoma cells. METHODS: The experiment was conducted on 3 groups : the control group, the positive observation group (in which the alphanubeta6 on the surface of the thyroid carcinoma cell line SW579 was blocked by monoclonal antibody 10D5) and the negative observation group (in which the alphanubeta6 was dealt with the negative placebo of 10D5-the IgG2a). Cell proliferation was detected by MTT assay, apoptosis by flow cytometry and the protein levels in Caspase-3, CyclinB1 and Bcl-xl as well as the protein levels in ERK, p-ERK, JNK, p-JNK, p38 and p-p38 were detected by Western blot. RESULTS: The cell survival rates of the control group and the negative observation group were prominently higher than those of the positive observation group, following decrease in the apoptosis rates, and the differences were statistically significant (p<0.05). The protein levels in CyclinB1 and Bcl-x1 of the control group and the negative observation group were prominently higher than those of the positive observation group, whereas the levels in Caspase-3 were decreased; the differences were statistically significant (p<0.05). The protein levels in p ERK, p-JNK and p-p38 of the control group and the negative observation group were prominently higher than those of the positive observation group, while the protein levels of ERK, JNK and p38 showed no difference. CONCLUSION: Integrin alphanubeta6 can mediate the MAPK signal pathway of the cells and regulate the expression of CyclinB1 and the apoptosis-related proteins like Bcl-x1 and Caspase 2, thus affecting the process of the proliferation and apoptosis of thyroid carcinoma cells. PMID- 28730779 TI - A comparative study on postoperative mortality prediction of SFLI scoring system and Child-Pugh classification in patients with hepatocellular carcinoma. AB - PURPOSE: In our previous study, we have established the clinical significance of the SFLI (scoring formula of liver injury), the purpose of this study was to compare the SFLI system and the Child-Pugh grading system in the prediction of postoperative mortality in patients with hepatocellular carcinoma (HCC). METHODS: 114 patients with HCC who underwent surgical treatment were enrolled. According to the requirement of the indicators for the Child-Pugh classification, various indices (including albumin [ALB], total bilirubin [TBIL], prothrombin time [PT], ascites, and hepatic encephalopathy) were considered in these patients before surgery, and then Child-Pugh grading was performed. Similarly, the serum biochemical markers including ALB, pre-albumin (PA), TBIL, serum creatining (SCR), international normalized ratio (INR), alanine transminase (ALT), aspartate transaminase (AST), gamma-glutamyl transpeptidase (ggr;-GT), alkaline phosphatase (ALP), PT, activated partial thromboplastin time (APTT), and thrombine time (TT) were collected before surgery for SFLI analysis. The predicted postoperative mortality rates of these two scoring models and their diagnostic efficacy were analyzed and compared. RESULTS: According to the Child-Pugh grading system, in level A, B and C were 75, 35, and 4 cases respectively, and the corresponding mortality rates were 1.3% (1/75), 17.1% (6/35) and 75% (3/4). Meanwhile, according to the SLFI classification, the number of patients in the grade I, I+, II, and III were 36, 29, 28, and 21, respectively, and the corresponding mortality rates were 0, 0, 14.3% (4/28), and 28.6% (6/21), respectively. The patient mortality rate increased significantly with increasing grading (p<0.01). These two classification methods were further compared using ROC analysis, in which the area under the curve (AUC) for the Child-Pugh method was 10.2% with a 95% confidence interval (95% CI) 17-18, and the AUC of SFLI was 88.2% with a 95% CI 80-96. CONCLUSION: The SFLI scoring system is very useful in the assessment of liver function and postoperative mortality, and its grading standard is much better than the traditional Child-Pugh classification in many aspects. PMID- 28730780 TI - Vascular endothelial growth factor gene polymorphisms and gastric cancer risk: a meta-analysis. AB - PURPOSE: Vascular endothelial growth factor (VEGF) plays important roles in the process of tumor growth and metastasis. Although the association between VEGF polymorphisms and gastric cancer risk has been extensively studied, available results remain controversial. To derive a convincing estimation of the relationship, a meta-analysis containing 6 VEGF (+936C/T, -634G/C, -460T/C, +1612G/A, -2578C/A and -1154G/A) gene polymorphisms was performed. METHODS: We conducted a systematic search of PubMed and Chinese National Knowledge Infrastructure (CNKI) to select relevant articles. Nine available case-control studies with 2,281 gastric cancer cases and 2,820 healthy controls met the inclusion criteria. The odds ratio (OR) and 95% confidence interval (95% CI) were used to evaluate the strength of the association. RESULTS: This meta-analysis indicated that the VEGF-634 G allele carrier represented a risk factor for gastric cancer (GG+GC vs CC: OR=1.23, 95% CI=1.02-1.49, p=0.03). The VEGF +1612G/A polymorphism was associated with risk of gastric cancer (G allele vs A allele: OR=0.62, 95% CI=0.49- 0.79, p<0.0001; GG+GA vs AA: OR=0.16, 95% CI=0.05 0.51, p=0.002 and GA+AA vs GG: OR=1.57, 95% CI=1.21-2.04, p=0.008). For polymorphisms of VEGF +936C/T, -460C/T, -2578C/A , -1154G/A, no association was found with gastric cancer risk. CONCLUSION: Our meta-analysis suggests that VEGF 634 G allele carrier may increase gastric cancer risk, whereas the VEGF +1612 G/A G allele and G allele carrier may decrease the risk. No association between+936C/T, -460C/T, -2578C/A, -1154G/A polymorphisms and susceptibility to gastric cancer was found. PMID- 28730781 TI - Feasibility research of treating advanced gastric carcinoma with laparoscopy. AB - PURPOSE: To determine the feasibility and safety of treating patients with advanced gastric cancer with laparoscopy. METHODS: We retrospectively analyzed 180 patients with advanced gastric carcinoma and divided them into either the laparoscopy group (96 cases) or the laparotomy group (84 cases). RESULTS: The number of lymph nodes dissected during surgery and the surgical time were similar in both groups. The incision length, total amount of bleeding during the operation, postoperative exhaust recovery time, and the length of hospital stay were significantly improved in the laparoscopy group when compared to the laparotomy group. The rate of postoperative complications was also significantly lower in the laparoscopy group. The levels of C-reactive protein (CRP) at 1, 7, and 10 days after surgery were significantly lower in the laparoscopy group. CONCLUSION: Overall, the laparoscopic radical operation for advanced gastric carcinoma demonstrated higher safety, shorter incision less bleeding, faster postoperative recovery, and lower rate of postoperative complications compared to the laparotomy group. Thus, this study has shown clear advantages for shifting to laparoscopy for the treatment of advanced gastric carcinoma. PMID- 28730782 TI - Human glioma cells-conditioned medium promotes proliferation and migration of human bone marrow mesenchymal stromal cells in vitro. AB - PURPOSE: To investigate changes in cell proliferation and migration of human bone marrow-derived mesenchymal stromal cells (hMSCs) in glioma environment, in order to assess the tumorigenic risk of hMSCs in the clinical application to treat human gliomas. METHODS: hMSCs were obtained from normal adult persons and identified by their morphological characteristics and test of their stemness. The U251 glioma cell-conditioned medium (U251-CM) was obtained to simulate the human glioma environment in vitro. hMSCs were cultured in the U251-CM or the control medium in the same conditionzs and changes in cell proliferation and migration were detected by MTT assay and wound healing assay. RESULTS: The results of MTT assay showed that, compared with the control group, the proliferation of hMSCs cultured in U251-CM increased significantly, and the results of wound healing assay showed that the migration of hMSCs cultured in U251-CM also increased significantly. CONCLUSIONS: Human glioma cell-conditioned medium may promote the proliferation and migration of hMSCs, and we are concerned about the tumorigenic risk of hMSCs in glioma environment before their clinical application. PMID- 28730783 TI - Analysis of related risk factors and reversal value of renal injury in elderly patients with multiple myeloma. AB - PURPOSE: To study risk factors associated with renal injuries in elderly patients with multiple myeloma. METHODS: From January 2012 to January 2015 135 elderly patients with multiple myeloma who were treated in Xuzhou No.1 People's Hospital were enrolled in this study. Risk factors associated with their renal function, such as gender, serum levels of hemoglobin, uric acid, serum calcium and phosphorus, serum and urinary levels of beta2 microglobulin, diastolic blood pressure and light chain protein distribution were assessed before and after relative treatments. RESULTS: Compared with patients with normal renal function, the proportion of severe anemia, serum uric acid, calcium, and phosphorus levels were significantly higher in patients with abnormal renal function. Also, serum and urinary beta2 microglobulin levels and diastolic blood pressure were significantly higher in patients with abnormal renal function. Light chain protein of patients with abnormal renal function (mostly lambda protein), severe anemia, abnormally increased calcium and high diastolic blood pressure were independent risk factors in renal injuries. Blood urea nitrogen (BUN) and creatinine levels in both groups returned to normal after the anemia was corrected. Compared with the abnormal renal function group, one-year survival rate in the normal renal function group with myeloma was significantly higher. CONCLUSION: Increased diastolic blood pressure, moderate and severe anemia as well as elevated level of serum calcium were independent risk factors for renal injuries in multiple myeloma. Blood pressure control (especially diastolic blood pressure) and correcting the anemia were proved to be effective means for reversing the disturbed renal function and ameliorating patients' quality of life . PMID- 28730784 TI - Single-center retrospective analysis of 162 cases with thymoma complicating myasthenia gravis. AB - PURPOSE: We conducted this study to retrospectively analyze the clinical effects of surgical resection for patients with myasthenia gravis (MG) complicated with thymoma. METHODS: 162 patients with myasthenia gravis complicated with thymoma, that were admitted to our hospital and underwent surgical disease resection from Nov. 1993 to Nov. 2015, were selected for this study. Analyzed were the pathology (2004 WHO), Masaoka clinical stage, myasthenia gravis types (Osserman types), myasthenic crisis during the perioperative period, and the relationship between recurrence and survival rates during follow-up visits. Operational methods included thymusectomy by sternal incision or video-assisted thoracoscopic thymusectomy. RESULTS: There were significant differences regarding distribution of clinical stages among different types of pathology. The operation time, efficacy rate, 5 and 10-year survival rates and complication rates during the perioperative period of video-assisted thoracoscopy were compared to those of the conventional surgery group. Among these groups, hemorrhage during operation, postoperative drainage and recurrence rate were significantly lower in the thoracoscopy group than in those of the conventional surgery group (p<0.05). CONCLUSION: The pathology type and clinical stages of thymoma complicating myasthenia gravis are related to the types of myasthenia gravis and the myasthenic crisis during perioperative period. Therefore, our results indicate that the thoracoscope treatment is safe and effective. PMID- 28730785 TI - PDCD1 strengthens the sensitivity of ovarian cancer to cisplatin chemotherapy by promoting apoptosis. AB - PURPOSE: The primary purpose of this study was to make clear the role of PDCD1 in the occurrence and progression of ovarian cancer, and explain its mechanism. METHODS: RT-PCR, westem blot, MTT and immunohistochemistry were used to detect the expression levels of PDCD1 mRNA and protein in human ovarian cancer cell lines (SKOV3, 3AO, CAOV3 and OVCAR3), human normal ovary, serous cystadenoma, and serous cystadenocarcinoma tissue. SKOV3, SKOV3-MOCK, and SKOV3-PDCD1 cells were subcutaneously injected into the armpit of nude mice to observe the effect of PDCD1 expression on tumorigenic ability. Cisplatin, carboplatin, cyclophosphamide, etoposide and paclitaxel were used in the experiments. RESULTS: PDCD1 was lowly expressed in SKOV3 and 3AO, moderately expressed in CAOV3, and highly expressed in OVCAR3. PDCD1 significantly inhibited the proliferation and clone formation ability of the ovarian carcinoma cell line SKOV3. In the SKOV3 PDCD1 group, the tumor formation rate decreased significantly and the tumor formation time prolonged significantly. The CAOV3 and OVCAR3 cells with high expression of PDCD1 were more sensitive to cisplatin. The SKOV3 and 3AO cells with low expression of PDCD1 were less sensitive to cisplatin. Compared with the SKOV3- MOCK control group, the apoptosis rate and the expression levels of the caspase-3/8 proteins activity increased significantly in the PDCD1 overexpression group. The expression levels of caspase-9 and Bax increased slightly. No significant changes were observed in the expression of Bcl-2. CONCLUSION: The expression of PDCD1 decreased significantly in human ovarian cancer. Overexpression of PDCD1 can inhibit the proliferation capacity of ovarian cancer. PDCD1 strengthens the sensitivity of ovarian cancer to cisplatin by promoting cisplatin-induced apoptosis. PMID- 28730786 TI - Clinical significance of microvessel density and proliferation in prostate cancer core biopsy. AB - PURPOSE: To investigate the microvessel density (MVD) and proliferation in prostate cancer (PC) core biopsies. METHODS: Core biopsy samples of PC tissue from 45 patients were routinely processed and embedded in paraffin. The samples of PC formed the investigated group (n=25), while samples of benign prostatic hyperplasia (BPH) served as controls (n=20). From paraffin blocks, 3-5 MUm-thick sections were made and routine hematoxylin-eosin method and immunohistochemical ABC method with Ki67 and CD34 antibodies were applied. Immunohistochemical expression of Ki67 and CD34 was stereometrically quantified. RESULTS: The median number of Ki67 and CD34 positive cells per mm2 in PC were significantly higher in comparison to the median of these cells in BHP. The average age and Gleason score in patients with high proliferation index (proIDX) and MVD index (mvdIDX) was significantly greater in comparison to those with low proIDX and low mvdIDX. The absolute values of Ki67 expression were in highly positive and significant correlation with the absolute values of CD34 expression. Highly significant correlation was found between Gleason score and proIDX and mvdIDX. CONCLUSION: This study showed that PC expressed significantly higher values of Ki67 and CD34 in comparison to BPH. The values of proIDX and mvdIDX obtained by core biopsy could clearly show the level of cancer progression expressed through highly correlated Gleason score. In this way it is possible to identify the patients at high risk for disease progression. PMID- 28730787 TI - Association of ferritin with prostate cancer. AB - PURPOSE: Prostate specific antigen (PSA) has been widely used as the unique serum biomarker for the diagnosis and/ or pre-diagnosis of prostate cancer (PCa). However, the diagnostic value of PSA is a subject of ongoing debate owing to its lack of specificity, especially when the PSA level is moderately increased (e.g., 4-10 ng/ml). Thus, we suggest the need for identification of a new biomarker to discriminate PCa cases from benign prostatic hyperplasia (BPH) and normal controls (N). METHODS: Urine or tissue samples of PCa patients, BPH patients, and normal controls were systematically collected. The expression of ferritin light chain (FTL) and ferritin heavy chain (FTH) was verified by immunohistochemistry in the tissue. The concentration of urinary ferritin was measured by Access Immunoassay. The level of creatinine in the urine was detected on a HITACHI 7080 system to calculate the ferritin-creatinine ratio (FCR). The data were statistically analyzed using the rank sum test. RESULTS: Immunohistochemical characterization of tissues in patients with PCa and BPH was conducted. We found representative immunohistochemical expression of FTL and FTH, with strong staining intensity in PCa and weak staining intensity in BPH. Furthermore, there were differences in urinary FCR among the three groups, with significant differences in the PCa group (134.46+/-47.01) compared to both the BPH (24.18+/ 3.17, p = 0.009) and control (6.42+/-0.82, p = 0.003) groups. In contrast, there was no significant difference between the BPH and N groups (p = 0.649). CONCLUSIONS: Ferritin is a potential urinary biomarker to discriminate between PCa and BPH patients. PMID- 28730788 TI - Topoisomerase I deregulation in laryngeal squamous cell carcinomas based on tissue microarray analysis. AB - PURPOSE: Topoisomerases (types: I/IIa-b/IIIa-b) represent a super-family of nucleic enzymes involved in the DNA replication, transcription, recombination, and also chromosome topological formation. Topoisomerase's I (Topo I- gene location: 20q12) aberrant expression is a frequent genetic event in a variety of solid malignancies. Topo I inhibition promotes cell death due to DNA damage and for this reason it is a target for specific targeted chemotherapy (camptothecin, topotecan, irinotecan). Our aim was to investigate the role of abnormal Topo I protein expression in laryngeal squamous cell carcinomas (LSCC) in which there are very limited data regarding the influence of the marker. METHODS: Using tissue microarray (TMA) technology, 50 formalin-fixed, paraffin-embedded primary laryngeal SCCs were cored and re-pembedded into one recipient block. Immunohistochemistry was performed using anti- Topo I antibody. Digital image analysis was also implemented for evaluating objectively the protein expression levels on the corresponding stained nuclei. RESULTS: Topo I protein overexpression (moderate to high staining intensity values) was observed in 32/50 (64%) tissue cores, whereas low expression rates were detected in 18/50 (36%) cases. Topo I overall expression was strongly associated with the differentiation grade of the examined tumors (p=0.021). No other statistical correlations were identified. CONCLUSIONS: Topo I overexpression is observed in a significant subset of LSCCs affecting the level of differentiation in them. Additional molecular studies focused on the mechanism of Topo I gene/protein deregulation (i.e. amplification, abnormal epigenetic promoter methylation, mRNA aberrant expression) are necessary discriminating the eligible patients for applying specific chemotherapeutic strategies based on anti-Topo I agents. PMID- 28730789 TI - Quality of nursing care as perceived by cancer patients: A cross-sectional survey in four European countries. AB - PURPOSE: To explore and compare cancer patients' perceptions on the quality of nursing care in four European countries. METHODS: Data were collected in Cyprus, Finland, Greece and Sweden. The sample comprised 596 hospitalized cancer patients. The quality of nursing care was measured using the "Oncology Patients' Perceptions of the Quality of Nursing Care Scale" (OPPQNCS). Patient characteristics were also collected. Analysis of variance was used to examine the effects of country on the perceptions of the quality of nursing care. RESULTS: Patients' age ranged from 18 to 86 years, and 58% were male. The comparison of cancer patients' perceptions regarding the quality of nursing care between the four countries showed a statistically significant difference in the total OPPQNCS scores (p<0.001) as well as in the subscales responsiveness (p<0.001), individualization (p<0.001), coordination (p<0.001) and proficiency (p<0.001). The Cronbach's alpha coefficient for the OPPQNCS ranged between 0.89 and 0.95. A multivariate analysis of variance for the OPPQNCS controlled by respondents' demographic characteristics revealed that only the patient's country was significantly related with the patients' perceptions of quality care. CONCLUSION: Quality of nursing care as perceived by cancer patients was high, but differed between the four countries. The impact of the clinical status of cancer patients on the quality of nursing care and managerial factors such as staffing/nursing care delivery models that influence the ability of nurses to offer high quality care should also be explored by more focused studies. PMID- 28730790 TI - Perioperative systemic chemotherapy for peritoneal mucinous appendiceal carcinomas treated with cytoreductive surgery & HIPEC. AB - PURPOSE: To identify the role of systemic chemotherapy in the management of appendiceal malignancies. METHODS: Over a 10-year period (2005 -2014), 52 patients with appendiceal neoplasms were treated at our Peritoneal Surface Malignancy Unit [14 (26.9%) disseminated peritoneal adenomucinosis (DPAM), 30 (57.7%) peritoneal mucinous carcinomatosis of appendiceal origin (PMCA) and 8 (15.4%) PMCA-I]. All patients (100%) underwent cytoreductive surgery (CRS) & hyperthermic intraperitoneal chemotherapy (HIPEC), while 20 (38.5%) of them also received perioperative systemic chemotherapy. RESULTS: Mean peritoneal cancer index (PCI) was 23.6. Completeness of cytoreduction score (CC-S) was: CC-0 in 26 patients (50%), CC-1 in 20 patients (38.5%) and CC-2 in 6 patients (11.5%). High grade malignancy was reported in 27 patients (51.9%) and low grade malignancy in 25 patients (48.1%). More than half of the patients developed recurrence (n=36, 69.2%), while death was reported in 40.4% (n=21). Median overall survival (OS) in all histologic groups was 24 months for patients who received perioperative systemic chemotherapy and 14 months for patients who did not (p=0.048). Median disease free survival (DFS) in all histologic groups was 19 months for patients who received perioperative systemic chemotherapy and 10 months for patients who did not (p=0.034). CONCLUSION: We suggest that perioperative systemic chemotherapy serves as a helpful therapeutic tool in the management of peritoneal mucinous appendiceal carcinomas treated with cytoreductive surgery & HIPEC. PMID- 28730791 TI - A mathematical optimization model for efficient assignment of inpatients in an oncology center in China. AB - This paper addresses a problem for assignment of chemo-receiving inpatients in an oncology care center, which has not been addressed in the literature. Chemotherapy is regarded as one of the most effective treatments for cancer. In recent years, as cancer incidence increased, the number of patients admitted to a cancer treatment center has also been rising. How to balance the workload of medical service resources by planning admission of patients has become an essential problem that must be given consideration by policy- makers. The allocation of chemotherapy patients, different from that of the routine inpatients, is restrained by treatment agreements of patients and presents periodic features. Therefore, the allocation of chemotherapy patients is much more difficult than that of routine patients. A mixed integer programming (MIP) model was first formulated for this problem in order to maximize the usage of beds. Specific features of chemotherapy, such as chemotherapy protocols, were integrated into this model. The inpatient assignment problem was proved to be non deterministic polynomial- complete and we propose an exact method to solve it. Numerical experiments on suitable use-case scenarios and a practical Chinese oncology center were performed to test and evaluate this model. The obtained results demonstrated the effectiveness of our method. Some useful managerial implication are provided for policy-makers through the analysis of obtained results. The models and methods suggested here can be effectively applied in similar departments of other countries and regions. PMID- 28730792 TI - Predictive markers for trastuzumab-associated cardiac dysfunction in patients with early-stage human epidermal growth factor receptor 2-positive breast cancer receiving trastuzumab. PMID- 28730794 TI - Athens Eye Hospital Ocular Oncology multidisciplinary team providing combined treatments for patients with choroidal melanoma: 3 years results. PMID- 28730795 TI - Preliminary study on the role of secondary surgery in ovarian cancer patients. Experience of a tertiary institution. PMID- 28730797 TI - Ileal perforation following cetuximab and FOLFIRI chemotherapy in a patient with ascending colon cancer with peritoneal carcinomatosis. PMID- 28730796 TI - Histopathological definition of medullary breast cancer should be revisited. PMID- 28730798 TI - A young woman with metastatic colon cancer presenting with elevated serum beta human chorionic gonadotropin. PMID- 28730799 TI - A historical overview of laryngeal carcinoma and the first total laryngectomies. AB - Laryngeal cancer was a well known entity since antiquity and its treatment evolved through several phases. The lack of knowledge in anatomy and pathology as well as the absence of anesthesia and proper instrumentation made the treatment almost impossible. Ancient physicians were performing laryngotomy or tracheotomy in an attempt to prevent the suffocation symptoms produced by tumoral masses. In 19th century the invention of laryngoscope and the advent of pathology and anesthesiology encouraged surgeons to operate on man. In 1873 Theodor Billroth (1829-1894) performed the first laryngectomy followed by several other colleagues among which Enrico Bottini (1837-1903) and Themistocles Gluck (1853-1942). Thanks to their contribution a new era came in laryngeal cancer treatment: the conservation laryngeal surgery. PMID- 28730800 TI - Optimizing the role of transthoracic echocardiography to improve the cardiovascular risk stratification: the dream of subclinical coronary artery disease detection. AB - Detecting coronary artery disease at a subclinical level has always been a challenging task for cardiologists. Various non-invasive echocardiographic approaches such as measurements of left ventricular hypertrophy, diastolic function, left atrial enlargement, valve sclerosis and calcification, epicardial fat thickness, and pulse wave velocity have been proposed to integrate the available risk-charts. The present review is a collection of evidence that supports the role of the above mentioned features in cardiac risk stratification, summarizing the state of the art in non-invasive echocardiographic coronary risk assessment. Each parameter is presented with its strengths and weaknesses, aiming to trace the future directions for the development of a reliable non-invasive approach. PMID- 28730801 TI - Impact of Metal Contacts on the Performance of Multilayer HfS2 Field-Effect Transistors. AB - HfS2 is one of the emerging transition metal dichalcogenides and is very promising for low-power nanoelectronics and high-sensitivity optoelectronic device applications. We studied the band structures of 1T-HfS2 with different thicknesses by first principles simulation, and the impact of different metal contacts to the HfS2 device performance has been experimentally studied. Back gate and top-gate HfS2 field-effect transistors (FETs) were fabricated, and better electrical characteristics have been achieved with the FETs with the Ti/Au contact as compared with the Pt-contacted FETs. Thin layers of Pt and Ti/Au films were deposited on HfS2 flakes to investigate the metal/HfS2 interface by using scanning electron microscopy, atomic force microscopy, and Raman spectroscopy. A smoother Ti/Au film was formed on HfS2, resulting in higher carrier injection and transport efficiency. The phonon behavior being dominated by the interface chemical bonding at the Ti/Au contact region has been confirmed with the more sensitive A1g phonon mode from the bilayer HfS2. PMID- 28730802 TI - Sensing Single Molecule Penetration into Nanopores: Pushing the Time Resolution to the Diffusion Limit. AB - To quantify small molecule penetration into and eventually permeation through nanopores, we applied an improved excess-noise analysis of the ion current fluctuation caused by entering molecules. The kinetic parameters of substrate entry and exit are derived from a two-state Markov model, analyzing the substrate concentration dependence of the average ion current and its variance. Including filter corrections allows one to detect the transition rates beyond the cutoff frequency, fc, of the instrumental ion-current filter. As an application of the method, we performed an analysis of the single-channel ion current of Meropenem, an antibiotic of the carbapenem family, interacting with OmpF, the major general outer membrane channel of Escherichia coli bacteria. At 40 degrees C we detected the residence time of Meropenem inside OmpF of about 500 ns-more than 2 orders of magnitude smaller than fc-1 and close to the diffusion limit of few hundred nanoseconds. We also have established theoretical limit conditions under which the substrate-induced channel blockages can be detected and suggest that submicrosecond-scale gating kinetic parameters are accessible with existing experimental equipment. PMID- 28730803 TI - Three-Dimensional Graphene Foam-Filled Elastomer Composites with High Thermal and Mechanical Properties. AB - To meet the increasing demands for effective heat management of electronic devices, a graphene-based polymeric composite is considered to be one of the candidate materials owing to the ultrahigh thermal conductivity (TC) of graphene. However, poor graphene dispersion, low quality of exfoliated graphene, and strong phonon scattering at the graphene/matrix interface restrict the heat dissipation ability of graphene-filled composites. Here, a facile and versatile approach to bond graphene foam (GF) with polydimethylsiloxane (PDMS) is proposed, and the corresponding composite with considerable improvement in TC and insulativity is fabricated. First, three-dimensional GF was coated with polydopamine (PDA) via pi pi stack and functional groups from PDA reacted with 3-aminopropyltriethoxysilane (APTS). Then, the modified GF was compressed (c-GF) to enhance density and infiltrated with PDMS to get the c-GF/PDA/APTS/PDMS composite. As a result, these processes endow the composite with high TC of in-plane 28.77 W m-1 K-1 and out-of plane 1.62 W m-1 K-1 at 11.62 wt % GF loading. Besides, the composite manifests obvious improvement in mechanical properties, thermal stability, and insulativity compared to neat PDMS and GF/PDMS composite. An attempt to use the composite for cooling a ceramic heater is found to be successful. Above results open a way for such composites to be applied for the heat management of electronic devices. PMID- 28730804 TI - Wearable and Transparent Capacitive Strain Sensor with High Sensitivity Based on Patterned Ag Nanowire Networks. AB - In this study, a transparent and stretchable thin-film capacitive strain sensor based on patterned Ag nanowire networks (AgNWs) was successfully fabricated. The AgNWs were patterned using a capillary force lithography (CFL) method and were embedded onto the surface of the polydimethylsiloxane substrate. The strain (epsilon) sensitivity of the capacitive strain sensor was controlled and enhanced by patterning the AgNWs into electrodes with an interdigitated shape. The interdigitated capacitive strain sensor (ICSS) is expected to have -1.57 gauge factor (GF) at 30% epsilon by calculation, which is much higher than the sensitivity of typical parallel-plate-type capacitive strain sensors. Because of the interdigitated pattern of the electrodes, the GF of the ICSS was increased up to -2.0. The ICSS had no hysteresis behavior up to epsilon values of 15% and showed stable epsilon sensing performance during the repeated stretching test at epsilon values of 10% for 1000 cycles. Furthermore, there was no cross talk between epsilon and pressure sensing in the AgNW-based ICSS, which was found to be insensitive to externally applied pressure. The ICSS was then used to detect the finger and wrist muscle motions of the human body to simulate its application to large and small epsilon sensing. PMID- 28730805 TI - Integrating Discovery-driven Proteomics and Selected Reaction Monitoring To Develop a Noninvasive Assay for Geoduck Reproductive Maturation. AB - Geoduck clams (Panopea generosa) are an increasingly important fishery and aquaculture product along the eastern Pacific coast from Baja California, Mexico, to Alaska. These long-lived clams are highly fecund, although sustainable hatchery production of genetically diverse larvae is hindered by the lack of sexual dimorphism, resulting in asynchronous spawning of broodstock, unequal sex ratios, and low numbers of breeders. The development of assays of gonad physiology could indicate sex and maturation stage as well as be used to assess the status of natural populations. Proteomic profiles were determined for three reproductive maturation stages in both male and female clams using data-dependent acquisition (DDA) of gonad proteins. Gonad proteomes became increasingly divergent between males and females as maturation progressed. The DDA data were used to develop targets analyzed with selected reaction monitoring (SRM) in gonad tissue as well as hemolymph. The SRM assay yielded a suite of indicator peptides that can be used as an efficient assay to determine geoduck gonad maturation status. Application of SRM in hemolymph samples demonstrates that this procedure could effectively be used to assess reproductive status in marine mollusks in a nonlethal manner. PMID- 28730806 TI - Investigation of Exciton Recombination Zone in Quantum Dot Light-Emitting Diodes Using a Fluorescent Probe. AB - Exciton recombination zone, where the photons are generated, can greatly affect the performance, such as the efficiency and color purity, of the quantum dot (QD) light-emitting diodes (QLEDs). To probe the exciton recombination zone, 4 (dicyanomethylene)-2-t-butyl-6(1,1,7,7-tetramethyljulolidyl-9-enyl)-4H-pyran (DCJTB) is doped into the charge transport layer as a fluorescent sensor; by monitoring the Forster resonant energy transfer (FRET) between QD and DCJTB, the location of the recombination zone can be determined. It is found that the electron transport layer (ETL) has a great impact on the recombination zone. For example, in QLEDs with ZnMgO ETL, the recombination zone is near the interface of the QD/hole transport layer (HTL) and is shifted to the interface of the QD/ETL as the driving voltage is increased, whereas in devices with 1,3,5-tris(2-N phenylbenzimidazolyl) benzene (TPBi) ETL, the recombination zone is close to the interface of the QD/ETL and moved to the interface of the QD/HTL with the increase in the driving voltage. Our results can also clarify the light emission mechanism in QLEDs. In devices with ZnMgO ETL, the emission is dominated by the direct charge recombination, whereas in devices with TPBi ETL, the emission is contributed by both FRET and direct charge recombination. Our studies suggest that fluorescent probe can be a powerful tool for investigating the exciton recombination zone, light emission mechanism, and other fundamental processes in QLEDs. PMID- 28730807 TI - Cationic Carbon Dots for Modification-Free Detection of Hyaluronidase via an Electrostatic-Controlled Ratiometric Fluorescence Assay. AB - Carbon dots (CDs) emerge as excellent fluorescent nanomaterials, but the full exploitation and application of their exceptional properties in the development of fluorescence assay are still rare. In this work, cationic carbon dots (C-CDs) covered with plenty of positive charges on the surface were synthesized through a facile ultrasonic method. Negatively charged hyaluronic acid (HA) caused the aggregation of positively charged C-CDs and neutral red (NR) along its linear chain via electrostatic adsorption, leading to a remarkable Forster resonance energy transfer (FRET) from C-CDs to NR. However, the presence of hyaluronidase (HAase) resulted in the enzymolysis of HA, as well as the liberation of C-CDs and NR. The corresponding change of fluorescence color from red to green-yellow afforded a reliable ratiometric assay for HAase. Also the ratio of fluorescence intensity for C-CDs (I525) to that for NR (I630) was used for quantitative detection of HAase. The proposed sensing system was easily operated in aqueous media with a detection limit of 0.05 U/mL. This strategy provides a new approach for the wider application of some special CDs in detecting biomolecules. PMID- 28730808 TI - Determination of the Relationship between Expression and Functional Activity of Multidrug Resistance-Associated Protein 1 using Scanning Electrochemical Microscopy. AB - Cancer cells can develop multidrug resistance (MDR) after prolonged exposure to chemotherapeutic drugs, which is a severe impediment to successful treatment. MDR is typically associated with transmembrane proteins mediating efflux of administered drugs, thereby keeping their intracellular concentration below the threshold required to kill cells. Although expression assays based on flow cytometry and immunostaining have shown that multidrug resistance-associated protein 1 (MRP1) is prevalent in many cancer types, the functional activity of this efflux pump is more difficult to elucidate, especially at the single-cell level. Herein, we report the measurement of MRP1 functional activity in individual cancer cells using scanning electrochemical microscopy (SECM). Cells were cultured onto plastic substrates containing selective adhesion sites. Optical microscopy and SECM revealed that cells adapt to the underlying surface, while MRP1 functional activity increases once the dimensions of the adhesive islands become smaller than those of the cell itself. Time-lapse SECM imaging revealed a suitable window of 30 min to complete each measurement before the cell undergoes blebbing, which is associated with a considerable increase in functional activity. Distinct cell populations were produced by performing a doxorubicin drug challenge on two parental cell lines (e.g., wild-type HeLa cells and MRP1-overexpressing HeLa-R cells). Expression and functional activity of MRP1 were determined using flow cytometry and SECM, and our findings show that these parameters do not directly correlate. This suggests that functional activity may represent a powerful indicator of a cancer cell's response to chemotherapeutic treatment and should improve our understanding of efflux mechanisms based on MRP1. PMID- 28730809 TI - Ruthenium-Catalyzed 1,6-Aromatic Enamide-Silylalkyne Cycloisomerization: Approach to 2,3-Disubstituted Indoles. AB - Cycloisomerization is an atom economic procedure that converts dienes and enynes into cyclic molecules. To date, cycloisomerization between enamides and silylalkynes has not been explored. We found that N-acyl-N-vinyl-2 silylalkynylaniline derivatives undergo a cycloisomerization in the presence of a well-defined ruthenium hydride to give a 2,3-disubstitued indole. The vinyl and silylmethyl substituents on the 2- and 3-positions of the indole can be easily converted to other functional groups. PMID- 28730810 TI - Static and Dynamic Water Motion-Induced Instability in Oxide Thin-Film Transistors and Its Suppression by Using Low-k Fluoropolymer Passivation. AB - Here, we report static and dynamic water motion-induced instability in indium gallium-zinc-oxide (IGZO) thin-film transistors (TFTs) and its effective suppression with the use of a simple, solution-processed low-k (epsilon ~ 1.9) fluoroplastic resin (FPR) passivation layer. The liquid-contact electrification effect, in which an undesirable drain current modulation is induced by a dynamic motion of a charged liquid such as water, can cause a significant instability in IGZO TFTs. It was found that by adopting a thin (~44 nm) FPR passivation layer for IGZO TFTs, the current modulation induced by the water-contact electrification was greatly reduced in both off- and on-states of the device. In addition, the FPR-passivated IGZO TFTs exhibited an excellent stability to static water exposure (a threshold voltage shift of +0.8 V upon 3600 s of water soaking), which is attributed to the hydrophobicity of the FPR passivation layer. Here, we discuss the origin of the current instability caused by the liquid contact electrification as well as various static and dynamic stability tests for IGZO TFTs. On the basis of our findings, we believe that the use of a thin, solution-processed FPR passivation layer is effective in suppressing the static and dynamic water motion-induced instabilities, which may enable the realization of high-performance and environment-stable oxide TFTs for emerging wearable and skin-like electronics. PMID- 28730811 TI - Atomic Mechanism of Hybridization-Dependent Surface Reconstruction with Tailored Functionality in Hexagonal Multiferroics. AB - The broken symmetry along with anomalous defect structures and charging conditions at multiferroics surface can alter both crystal structures and electronic configurations, bringing in emergent physical properties. Extraordinary surface states are induced into original mutually coupled order parameters in such strongly correlated oxides, which flourish in diverse properties but remain less explored. Here, we report the peculiar surface ferroelectric states and reconfigurable functionalities driven by the relaxation of surface and consequent changes in O 2p and Y 4d orbital (p-d) hybridization within a representative hexagonal multiferroics, YMnO3. An unprecedented surface reconstruction is achieved by tailored p-d hybridization coupling with in-plane oxygen vacancies, which is atomically revealed on the basis of the advantages of state-of-the-art aberration-corrected (scanning) transmission electron microscopy. Further ab initio density functional theory calculations verify the key roles of in-plane oxygen vacancies in modulating polarization properties and electronic structure, which should be regarded as the atomic multiferroic element. This surface configuration is found to induce tunable functionalities, such as surface ferromagnetism and conductivity. Meanwhile, the controversial origin of improper ferroelectricity that is unexpectedly free from critical size has also been atomically unraveled. Our findings provide new insights into the design and implementation of surface chemistry devices by simply controlling the oxygen stoichiometry, greatly advance our understandings of surface science in strongly correlated oxides, and enable exciting innovations and new technological functionality paradigms. PMID- 28730812 TI - Potential-Scanning Localized Plasmon Sensing with Single and Coupled Gold Nanorods. AB - Single plasmonic nanoparticles can potentially serve as optical sensors for detecting local refractive index changes. However, simultaneous monitoring of the scattering spectra from multiple nanoparticles is not practical. Here we perform potential-scanning localized surface plasmon resonance (LSPR) sensing. Gold nanorods are immobilized on an ITO electrode. Instead of collecting the full spectrum, as is done in conventional LSPR sensing, the electrode potential is scanned while the rod spectra are monitored at a single wavelength. We demonstrate that refractive index changes can be determined from single wavelength experiments and we further find that gold nanorod (NR) dimers exhibit higher refractive index sensitivities than single NRs in both potential-scanning and conventional wavelength-scanning based LSPR sensing. PMID- 28730813 TI - Nanoneedle-Based Sensing in Biological Systems. AB - Nanoneedles are high aspect ratio nanostructures with a unique biointerface. Thanks to their peculiar yet poorly understood interaction with cells, they very effectively sense intracellular conditions, typically with lower toxicity and perturbation than traditionally available probes. Through long-term, reversible interfacing with cells, nanoneedles can monitor biological functions over the course of several days. Their nanoscale dimension and the assembly into large scale, ordered, dense arrays enable monitoring the functions of large cell populations, to provide functional maps with submicron spatial resolution. Intracellularly, they sense electrical activity of complex excitable networks, as well as concentration, function, and interaction of biomolecules in situ, while extracellularly they can measure the forces exerted by cells with piconewton detection limits, or efficiently sort rare cells based on their membrane receptors. Nanoneedles can investigate the function of many biological systems, ranging from cells, to biological fluids, to tissues and living organisms. This review examines the devices, strategies, and workflows developed to use nanoneedles for sensing in biological systems. PMID- 28730814 TI - Persistent Urban Influence on Surface Water Quality via Impacted Groundwater. AB - Growing urban environments stress hydrologic systems and impact downstream water quality. We examined a third-order catchment that transitions from an undisturbed mountain environment into urban Salt Lake City, Utah. We performed synoptic surveys during a range of seasonal baseflow conditions and utilized multiple lines of evidence to identify mechanisms by which urbanization impacts water quality. Surface water chemistry did not change appreciably until several kilometers into the urban environment, where concentrations of solutes such as chloride and nitrate increase quickly in a gaining reach. Groundwater springs discharging in this gaining system demonstrate the role of contaminated baseflow from an aquifer in driving stream chemistry. Hydrometric and hydrochemical observations were used to estimate that the aquifer contains approximately 18% water sourced from the urban area. The carbon and nitrogen dynamics indicated the urban aquifer also serves as a biogeochemical reactor. The evidence of surface water-groundwater exchange on a spatial scale of kilometers and time scale of months to years suggests a need to evolve the hydrologic model of anthropogenic impacts to urban water quality to include exchange with the subsurface. This has implications on the space and time scales of water quality mitigation efforts. PMID- 28730815 TI - Biofouling Removal and Protein Detection Using a Hypersonic Resonator. AB - Nonspecific binding (NSB) is a general issue for surface based biosensors. Various approaches have been developed to prevent or remove the NSBs. However, these approaches either increased the background signals of the sensors or limited to specific transducers interface. In this work, we developed a hydrodynamic approach to selectively remove the NSBs using a microfabricated hypersonic resonator with 2.5 gigahertz (GHz) resonant frequency. The high frequency device facilitates generation of multiple controlled microvortexes which then create cleaning forces at the solid-liquid interfaces. The competitive adhesive and cleaning forces have been investigated using the finite element method (FEM) simulation, identifying the feasibility of the vortex-induced NSB removal. NSB proteins have been selectively removed experimentally both on the surface of the resonator and on other substrates which contact the vortexes. Thus, the developed hydrodynamic approach is believed to be a simple and versatile tool for NSB removal and compatible to many sensor systems. The unique feature of the hypersonic resonator is that it can be used as a gravimetric sensor as well; thus a combined NSB removal and protein detection dual functional biosensor system is developed. PMID- 28730816 TI - Multifunctional Octamethyltetrasila[2.2]cyclophanes: Conformational Variations, Circularly Polarized Luminescence, and Organic Electroluminescence. AB - Both symmetrical and unsymmetrical cyclophanes containing disilane units, tetrasila[2.2]cyclophanes 1-9, were synthesized. The syn and anti conformations and the kinetics of inversion between two anti-isomers were investigated by X-ray diffraction and variable-temperature NMR analysis, respectively. The flipping motion of two aromatic rings was affected by the bulkiness of the aromatic moiety (1 vs 6), the phase (solid vs solution), and the inclusion by host molecules (1 vs 1?[Ag2L]2+). The photophysical, electrochemical, and structural properties of the compounds were thoroughly investigated. Unsymmetrical tetrasila[2.2]cyclophanes 5-8 displayed blue-green emission arising from intramolecular charge transfer. Compound 6 emitted a brilliant green light in the solid state under 365 nm irradiation and showed a higher fluorescence quantum yield in the solid state (Phi = 0.49) than in solution (Phi = 0.05). We also obtained planar chiral tetrasila[2.2]cyclophane 9, which showed interesting chiroptical properties, such as a circularly polarized luminescence (CPL) with a dissymmetry factor of |glum| = ca. 2 * 10-3 at 500 nm. Moreover, an organic green light-emitting diode that showed a maximum external quantum efficiency (etaext) of ca. 0.4% was fabricated by doping 4,4'-bis(2,2'-diphenylvinyl)-1,1'-biphenyl with 6. PMID- 28730817 TI - Efficient Solid-State Electrochemiluminescence from High-Quality Perovskite Quantum Dot Films. AB - Halide perovskite materials have emerged as a new class of revolutionary photovoltaic and optoelectronic nanomaterials. However, the study on electrochemiluminescence (ECL) from halide perovskite nanomaterials is still in its infancy due to their instability, sensitivity, and difficulties in purification and film formation. Here, we propose a scraping coating method for the fabrication of high-quality halide perovskite quantum dot (QD) film on electrode, which shows dense and uniform packing with minimum grain size. When CsPbBr3 QDs are taken as model materials, highly efficient ECL can be obtained from such perovskite QD film with anhydrous ethyl acetate as both electrolyte and coreactant. The CsPbBr3 QD film displays intense and stable ECL with ultranarrow emission spectrum bandwidth (24 nm). The CsPbBr3 QD film shows an extremely high ECL efficiency which is up to 5 times relative to the standard Ru(bpy)32+/tri-n propylamine system. This approach is universal and also applies to hybrid organic inorganic halide perovskite QDs. This work not only extends the properties and applications of halide perovskite materials but also provides a new method for the in-depth study on the structure and properties of these kinds of materials. PMID- 28730818 TI - Nanoscale Mechanics of the Solid Electrolyte Interphase on Lithiated-Silicon Electrodes. AB - The ~300% volume changes of lithiated silicon electrodes (LixSi) during electrochemical cycling lead to cracking of the solid electrolyte interface (SEI). Here, we report how strain is transferred from LixSi to two primary inorganic SEI components: LiF and Li2O. Our first principle calculations show that LiF, effectively bonded on LixSi at x > 1, enables the entire interface structure to deform plastically by forming delocalized stable voids. In contrast, Li2O tightly bonded to LixSi is stiffer, and deforms rigidly across all x. Our results explain the significantly improved ductility of SEI with higher LiF versus Li2O content observed experimentally. PMID- 28730819 TI - Hypervalent Iodine Reagent Mediated Oxidative Heterocyclization of Aldoximes with Heterocyclic Alkenes. AB - An efficient cycloaddition of heterocyclic alkenes with nitrile oxides generated in situ from the corresponding aldoximes using organohypervalent iodine(III) reagent, [hydroxy(tosyloxy)iodo]benzene (Koser's reagent), has been developed. The oxidative cyclization of various aldoximes with 1-propene-1,3-sultone affords the respective isoxazoline-ring-fused heterobicyclic products in moderate to good yields. Furthermore, the reaction of aldoxime with a cyclic phospholene-oxide under similar conditions produces the corresponding heterobicyclic phospholene oxides in moderate yields. The structures of bicyclic phospholene oxide and two sultones were established by single-crystal X-ray crystallography. PMID- 28730820 TI - Tryptic Peptides Bearing C-Terminal Dimethyllysine Need to Be Considered during the Analysis of Lysine Dimethylation in Proteomic Study. AB - Lysine methylation plays important roles in structural and functional regulation of chromatin. Although trypsin is the most widely used protease in mass spectrometry-based proteomic analysis for lysine methylation substrates, the proteolytic activity of trypsin on dimethylated lysine residues remains an arguable issue. In this study, we tested the ability of trypsin to cleave dimethylated lysine residues in synthetic peptides, purified albumin, and whole cell lysate, and found that the C-terminal of dimethylated lysine residue could be cleaved in a protein sequence-dependent manner. Kinetic studies revealed that the optimal digestion time and enzyme-to-substrate ratio for the cleavage of dimethylated lysine by trypsin was around 16 h and 1:50, respectively. We further showed the tryptic C-terminal lysine-dimethylated (C-Kme2) peptides could contribute to a significant portion of substrate identification in the proteomic study, which utilizes the chemical dimethylation labeling approach. More than 120 tryptic C-Kme2 peptides (7% of total peptides identified) were identified in chemically lysine-dimethyl-labeled HeLa whole cell lysate by a single-shot nanoflow high performance liquid chromatography with tandem mass spectrometry (nano-HPLC-MS/MS) analysis. Moreover, in an assay for substrate identification of protease Glu-C using stable isotope dimethyl labeling approach, our data showed the tryptic C-Kme2 peptides accounted for more than 13% of total tryptic peptides. Additionally, our in vivo methylome profiling data revealed some C-Kme2 peptides, which is of importance to identification and quantification of biologically relevant protein and lysine-methylated site. Therefore, we reason that the tryptic peptides bearing C-terminal dimethylated lysine need to be considered in the mass spectrometric analysis of lysine dimethylation. PMID- 28730821 TI - Efficient Carrier-to-Exciton Conversion in Field Emission Tunnel Diodes Based on MIS-Type van der Waals Heterostack. AB - We report on efficient carrier-to-exciton conversion and planar electroluminescence from tunnel diodes based on a metal-insulator-semiconductor (MIS) van der Waals heterostack consisting of few-layer graphene (FLG), hexagonal boron nitride (hBN), and monolayer tungsten disulfide (WS2). These devices exhibit excitonic electroluminescence with extremely low threshold current density of a few pA.MUm-2, which is several orders of magnitude lower compared to the previously reported values for the best planar EL devices. Using a reference dye, we estimate the EL quantum efficiency to be ~1% at low current density limit, which is of the same order of magnitude as photoluminescence quantum yield at the equivalent excitation rate. Our observations reveal that the efficiency of our devices is not limited by carrier-to-exciton conversion efficiency but by the inherent exciton-to-photon yield of the material. The device characteristics indicate that the light emission is triggered by injection of hot minority carriers (holes) to n-doped WS2 by Fowler-Nordheim tunneling and that hBN serves as an efficient hole-transport and electron-blocking layer. Our findings offer insight into the intelligent design of van der Waals heterostructures and avenues for realizing efficient excitonic devices. PMID- 28730822 TI - Distributions of Polycyclic Aromatic Hydrocarbons, Aromatic Ketones, Carboxylic Acids, and Trace Metals in Arctic Aerosols: Long-Range Atmospheric Transport, Photochemical Degradation/Production at Polar Sunrise. AB - The distributions, correlations, and source apportionment of aromatic acids, aromatic ketones, polycyclic aromatic hydrocarbons (PAHs), and trace metals were studied in Canadian high Arctic aerosols. Nineteen PAHs including minor sulfur containing heterocyclic PAH (dibenzothiophene) and major 6 carcinogenic PAHs were detected with a high proportion of fluoranthene followed by benzo[k]fluoranthene, pyrene, and chrysene. However, in the sunlit period of spring, their concentrations significantly declined likely due to photochemical decomposition. During the polar sunrise from mid-March to mid-April, benzo[a]pyrene to benzo[e]pyrene ratios significantly dropped, and the ratios diminished further from late April to May onward. These results suggest that PAHs transported over the Arctic are subjected to strong photochemical degradation at polar sunrise. Although aromatic ketones decreased in spring, concentrations of some aromatic acids such as benzoic and phthalic acids increased during the course of polar sunrise, suggesting that aromatic hydrocarbons are oxidized to result in aromatic acids. However, PAHs do not act as the major source for low molecular weight (LMW) diacids such as oxalic acid that are largely formed at polar sunrise in the arctic atmosphere because PAHs are 1 to 2 orders of magnitude less abundant than LMW diacids. Correlations of trace metals with organics, their sources, and the possible role of trace transition metals are explained. PMID- 28730823 TI - Pathophysiological analysis of the progression of hepatic lesions in STAM mice. AB - Nonalcoholic steatohepatitis (NASH) is a current health issue since the disease often leads to hepatocellular carcinoma; however, the pathogenesis of the disease has still not been fully elucidated. In this study, we investigated the pathophysiological changes observed in hepatic lesions in STAM mice, a novel NASH model. STAM mice, high fat-diet (HFD) fed mice, and streptozotocin (STZ) treated mice were prepared, and changes over time, such as biological parameters, mRNA expression, and histopathological findings, were evaluated once animal reached 5, 7, and 10 weeks of age. STZ mice presented with hyperglycemia and an increase in oxidative stress in immunohistochemical analyses of Hexanoyl-lysine: HEL from 5 weeks, with fibrosis in the liver also being observed from 5 weeks. HFD mice presented with hyperinsulinemia from 7 weeks and the slight hepatosteatosis was observed at 5 weeks, with changes significantly increasing until 10 weeks. STAM mice at 10 weeks showed significant hepatic changes, including hepatosteatosis, hypertrophic hepatocytes, and fibrosis, indicating pathological changes associated with NASH. These results suggested that the increase in oxidative stress with hyperglycemia triggered hepatic lesions in STAM mice, and insulin resistance promoted lesion formation with hepatic lipid accumulation. STAM mice may be a useful model for elucidating the pathogenesis of NASH with diabetes. PMID- 28730824 TI - Glucagon-like peptide-1 analogues exenatide and liraglutide exert inhibitory effect on the early phase of liver regeneration after partial hepatectomy in rats. AB - Glucagon-like peptide-1 (GLP-1) is an incretin known for proliferative and antiapoptotic effects on various tissues. Exenatide and Liraglutide are GLP-1 analogues used in clinical practice as antidiabetic drugs. Since GLP-1 and its analogues exert significant effect on liver metabolism and since changes in intermediary metabolism play an important role in the process of liver regeneration, we decided to determine the effect of Exenatide and Liraglutide on the early phase of liver regeneration and selected metabolic parameters in a model of 2/3 partial hepatectomy (PHx) in rats. Animals were submitted either to PHx or laparotomy and received 3 doses of either GLP-1 analogues (Exenatide - 42 microg/kg b.w., Liraglutide - 0.75 mg/kg b.w.) or saline intraperitoneally. We analyzed body and liver weight, liver bromodeoxyuridine incorporation, liver content of DNA, triacylglycerols and cholesterol and biochemical serum parameters. Bromodeoxyuridine labeling was significantly lower in hepatectomized rats receiving either type of GLP-1 analogues when compared to hepatectomized controls. This effect was more pronounced in the Liraglutide group compared to Exenatide (p<0.001). In addition, liver DNA content was lower in hepatectomized rats receiving Liraglutide than in hepatectomized control rats (p<0.001). In conclusion, GLP-1 analogues Exenatide and Liraglutide significantly inhibited an early phase of liver regeneration after PHx in rats. This inhibitory effect was more pronounced in rats receiving Liraglutide. PMID- 28730825 TI - The implication of AMPA receptor in synaptic plasticity impairment and intellectual disability in fragile X syndrome. AB - Fragile X syndrome (FXS) is the most frequently inherited form of intellectual disability and prevalent single-gene cause of autism. A priority of FXS research is to determine the molecular mechanisms underlying the cognitive and social functioning impairments in humans and the FXS mouse model. Glutamate ionotropic alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors (AMPARs) mediate a majority of fast excitatory neurotransmission in the central nervous system and are critically important for nearly all aspects of brain function, including neuronal development, synaptic plasticity, and learning and memory. Both preclinical and clinical studies have indicated that expression, trafficking, and functions of AMPARs are altered and result in altered synapse development and plasticity, cognitive impairment, and poor mental health in FXS. In this review, we discuss the contribution of AMPARs to disorders of FXS by highlighting recent research advances with a specific focus on change in AMPARs expression, trafficking, and dependent synaptic plasticity. Since changes in synaptic strength underlie the basis of learning, development, and disease, we suggest that the current knowledge base of AMPARs has reached a unique point to permit a comprehensive re-evaluation of their roles in FXS. PMID- 28730826 TI - Effect of carcinogen 1,2-dimethylhydrazine treatment on fiber types in skeletal muscles of male Wistar rats. AB - The cancerogen 1,2-dimethylhydrazine (DMH), widely used in the experimental animal model of carcinogenesis, affects various organs, but its effect on muscle fibers is unknown. To evaluate the effect of 15-week DMH treatment on the fiber size and myosin heavy chain (MyHC) isoforms, which substantially determine fiber types and their contractile characteristics, pure and hybrid fiber types were immunohistochemically determined according to the MyHC isoform expression in soleus, extensor digitorum longus, gastrocnemius medialis and lateralis muscles of DMH-treated and control male Wistar rats. Whereas the size of fibers was mostly unaffected, the MyHC isoform expression was partially affected in both gastrocnemius samples, but not in the soleus and extensor digitorum longus of DMH treated rats. The lower proportions of hybrid fiber types and especially that of type 1/2x in most gastrocnemius samples of DMH-treated rats resulted in a shift towards a single MyHC isoform expression, but the extent and pattern of the MyHC isoform shift varied across the different gastrocnemius samples. Such variable response to DMH treatment across muscles indicates that each muscle possesses its own adaptive range. These findings are essential for an accurate evaluation of skeletal muscle characteristics in DMH animal model. PMID- 28730827 TI - Glucose added to a fat load suppresses the postprandial triglyceridemia response in carriers of the -1131C and 56G variants of the APOA5 gene. AB - Apolipoprotein A-V plays an important role in the determination of plasma triglyceride (TG) concentration. We aimed to determine whether polymorphisms 1131T>C (rs662799) and 56C>G (rs3135506) of the APOA5 gene have an impact on the course of postprandial lipemia induced by a fat load and a fat load with added glucose. Thirty healthy male volunteers, seven heterozygous for the -1131C variant and three for the 56G variant (HT) carriers, and 20 wild-type (WT) carriers underwent two 8-hour tests of postprandial lipemia - one after an experimental breakfast consisting of 75 g of fat and second after a breakfast consisting of 75 g of fat and 25 g of glucose. HT carriers had a higher postprandial response after fat load than WT carriers (AUC TG: 14.01+/-4.27 vs. 9.84+/-3.32 mmol*h/l, respectively, p=0.016). Glucose added to the test meal suppressed such a difference. Heterozygous carriers of the variants of APOA5 ( 1131C and 56G) display more pronounced postprandial lipemia after pure fat load than WT carriers. This statistically significant difference disappears when glucose is added to a fat load, suggesting that meal composition modulates the effect of these polymorphisms on the magnitude of postprandial lipemia. PMID- 28730828 TI - The effect of hypertension on adult hippocampal neurogenesis in young adult spontaneously hypertensive rats and Dahl rats. AB - The dentate gyrus of the hippocampus is one of the few places in the brain where neurogenesis occurs in adulthood. Nowadays, an increasing number of children and young adults are affected by hypertension, one of the factors in the development of cerebrovascular diseases and age-related cognitive deficits. Since these cognitive deficits are often hippocampus-dependent, it is possible that hypertension exerts this effect via decreasing adult neurogenesis which has been shown to be essential for a range of cognitive tasks. We used spontaneously hypertensive rats, which develop hypertension in the first weeks of life. Half of them were treated with the antihypertensive drug captopril. We found that the drug-induced lowering of blood pressure in this period did not affect the rate of adult neurogenesis. In a second experiment, we used another animal model of hypertension - salt-sensitive and salt-resistant strains of Dahl rats. A high salt diet induces hypertension in the salt-sensitive strain, but not in the salt resistant strain. The high-salt diet led to salt-induced hypertension, but did not affect the level of adult neurogenesis in the dentate gyrus of the hippocampus. We conclude that hypertension does not significantly affect the rate of hippocampal neurogenesis in young adult rats. PMID- 28730829 TI - Mechanism of electrocardiographic T-wave flattening in diabetes mellitus: experimental and simulation study. AB - In the present study we investigated the contribution of ventricular repolarization time (RT) dispersion (the maximal difference in RT) and RT gradients (the differences in RT in apicobasal, anteroposterior and interventricular directions) to T-wave flattening in a setting of experimental diabetes mellitus. In 9 healthy and 11 diabetic (alloxan model) open-chest rabbits, we measured RT in ventricular epicardial electrograms. To specify the contributions of apicobasal, interventricular and anteroposterior RT gradients and RT dispersion to the body surface potentials we determined T-wave voltage differences between modified upper- and lower-chest precordial leads (T-wave amplitude dispersions, TWAD). Expression of RT gradients and RT dispersion in the correspondent TWAD parameters was studied by computer simulations. Diabetic rabbits demonstrated flattened T-waves in precordial leads associated with increased anteroposterior and decreased apicobasal RT gradients (P<0.05) due to RT prolongation at the apex. For diabetics, simulations predicted the preserved T vector length and altered sagittal and longitudinal TWAD proven by experimental measurements. T-wave flattening in the diabetic rabbits was not due to changes in RT dispersion, but reflected the redistributed ventricular repolarization pattern with prolonged apical repolarization resulting in increased anteroposterior and decreased apicobasal RT gradients. PMID- 28730830 TI - Preventive effect of L-carnitine on the disorder of lipid metabolism and circadian clock of mice subjected to chronic jet-lag. AB - Circadian clock plays an essential role in orchestrating daily physiology, and its disruption can evoke metabolic diseases such as obesity. L-Carnitine can reduce blood lipid levels, and ameliorate fatty liver through regulating lipid metabolism. However, whether L-Carnitine administration may affect the disturbance of lipid metabolism and circadian rhythm of mice induced by prolonged circadian disruption is still unknown. Herein, we investigated the effects of L Carnitine on conditions of circadian clock and lipid metabolism through a chronic jet-lag mice model which was developed by reversing 12 h light/12 h dark cycle every 4 days for a continuous 12 weeks. Results showed that L-Carnitine administration significantly decreased levels of serum glutamic-oxaloacetic transaminase (GOT) and triglycerides (TG), which were remarkably elevated by chronic jet-lag. More importantly, quantitative real-time polymerase chain reaction (qRT-PCR) analysis indicated that L-Carnitine supplementation would effectively counteract the negative alterations in gene expression which related to lipid metabolism (Srebp1, Acaca, Fasn, and Scd1), metabolic regulator (mTOR) and circadian rhythm (Bmal1, Per1, Cry1 and Dec1) in the liver of mice subjected to the chronic jet-lag. As a conclusion, L-Carnitine was partly effective in preventing the disruption of circadian clock and lipid metabolic disorders induced by the chronic jet-lag. PMID- 28730831 TI - The galanin and galanin receptor subtypes, its regulatory role in the biological and pathological functions. AB - The multitalented neuropeptide galanin was first discovered 30 years ago but initially no biologic activity was found. Further research studies discovered the presence of galanin in the brain and some peripheral tissues, and galanin was identified as a modulator of neurotransmission in the central and peripheral nervous system. Over the last decade there were performed very intensive studies of the neuronal actions and also of nonneuronal actions of galanin. Other galanin family peptides have been described, namely galanin, galanin-like peptide, galanin-message associated peptide and alarin. The effect of these peptides is mediated through three galanin receptors subtypes, GalR1, GalR2 and GalR3 belonging to G protein coupled receptors, and signaling via multiple transduction pathways, including inhibition of cyclic AMP/protein kinase A (GalR1, GalR3) and stimulation of phospholipase C (GalR2). This also explains why one specific molecule of galanin can be responsible for different roles in different tissues. The present review summarizes the information currently available on the relationship between the galaninergic system and known pathological states. The research of novel galanin receptor specific agonists and antagonists is also very promising for its future role in pharmacological treatment. The galaninergic system is important target for current and future biomedical research. PMID- 28730832 TI - Liraglutide preserves intracellular calcium handling in isolated murine myocytes exposed to oxidative stress. AB - In ischemic/reperfusion (I/R) injured hearts, severe oxidative stress occurs and is associated with intracellular calcium (Ca(2+)) overload. Glucagon-Like Peptide 1 (GLP-1) analogues have been shown to exert cardioprotection in I/R heart. However, there is little information regarding the effects of GLP-1 analogue on the intracellular Ca(2+) regulation in the presence of oxidative stress. Therefore, we investigated the effects of GLP-1 analogue, (liraglutide, 10 microM) applied before or after hydrogen peroxide (H(2)O(2), 50 microM) treatment on intracellular Ca(2+) regulation in isolated cardiomyocytes. We hypothesized that liraglutide can attenuate intracellular Ca(2+) overload in cardiomyocytes under H(2)O(2)-induced cardiomyocyte injury. Cardiomyocytes were isolated from the hearts of male Wistar rats. Isolated cardiomyocytes were loaded with Fura 2/AM and fluorescence intensity was recorded. Intracellular Ca(2+) transient decay rate, intracellular Ca(2+) transient amplitude and intracellular diastolic Ca(2+) levels were recorded before and after treatment with liraglutide. In H(2)O(2) induced severe oxidative stressed cardiomyocytes (which mimic cardiac I/R) injury, liraglutide given prior to or after H(2)O(2) administration effectively increased both intracellular Ca(2+) transient amplitude and intracellular Ca(2+) transient decay rate, without altering the intracellular diastolic Ca(2+) level. Liraglutide attenuated intracellular Ca(2+) overload in H(2)O(2)-induced cardiomyocyte injury and may be responsible for cardioprotection during cardiac I/R injury by preserving physiological levels of calcium handling during the systolic and diastolic phases of myocyte activation. PMID- 28730833 TI - Short-term administration of melatonin or ghrelin on diabetic rats: effects on angiotensin II and vasopressin-induced uterine contractility. AB - The glycosaminoglycan (GAG) molecules are a group of high molecular weight, negatively charged polysaccharides present abundantly in the mammalian organism. By their virtue of ion and water binding capacity, they may affect the redistribution of body fluids and ultimately the blood pressure. Data from the literature suggests that the mitogens Vascular Endothelial Growth Factor (VEGF)-A and VEGF-C are able to regulate the amount and charge density of GAGs and their detachment from the cell surface. Based on these findings we investigated the relationship between the level of dietary sodium intake, the expression levels of VEGF-A and VEGF-C, and the amount of the skin GAGs hyaluronic acid and chondroitin sulphate in an in vivo rat model. Significant correlation between dietary sodium intake, skin sodium levels and GAG content was found. We confirmed the GAG synthesizing role of VEGF-C but failed to prove that GAGs are degraded by VEGF-A. No significant difference in blood pressure was registered between the different dietary groups. A quotient calculated form the ion and water content of the skin tissue samples suggests that - in contrast to previous findings - the osmotically inactive ions and bound water fractions are proportional. PMID- 28730834 TI - Resveratrol alleviates ethanol-induced hormonal and metabolic disturbances in the rat. AB - Brain-specific link protein Bral2 represents a substantial component of perineuronal nets (PNNs) enwrapping neurons in the central nervous system. To elucidate the role of Bral2 in auditory signal processing, the hearing function in knockout Bral2(-/-) (KO) mice was investigated using behavioral and electrophysiological methods and compared with wild type Bral2(+/+) (WT) mice. The amplitudes of the acoustic startle reflex (ASR) and the efficiency of the prepulse inhibition of ASR (PPI of ASR), produced by prepulse noise stimulus or gap in continuous noise, was similar in 2-week-old WT and KO mice. Over the 2 month postnatal period the increase of ASR amplitudes was significantly more evident in WT mice than in KO mice. The efficiency of the PPI of ASR significantly increased in the 2-month postnatal period in WT mice, whereas in KO mice the PPI efficiency did not change. Hearing thresholds in 2-month-old WT mice, based on the auditory brainstem response (ABR) recordings, were significantly lower at high frequencies than in KO mice. However, amplitudes and peak latencies of individual waves of click-evoked ABR did not differ significantly between WT and KO mice. Temporal resolution and neural adaptation were significantly better in 2-month-old WT mice than in age-matched KO mice. These results support a hypothesis that the absence of perineuronal net formation at the end of the developmental period in the KO mice results in higher hearing threshold at high frequencies and weaker temporal resolution ability in adult KO animals compared to WT mice. PMID- 28730835 TI - The effect of very-low-calorie diet on mitochondrial dysfunction in subcutaneous adipose tissue and peripheral monocytes of obese subjects with type 2 diabetes mellitus. AB - Mitochondrial dysfunction is a potentially important player in the development of insulin resistance and type 2 diabetes mellitus (T2DM). We investigated the changes of mRNA expression of genes encoding main enzymatic complexes of mitochondrial respiratory chain in subcutaneous adipose tissue (SCAT) and peripheral monocytes (PM) of 11 subjects with simple obesity (OB), 16 obese patients with T2DM and 17 healthy lean subjects (C) before and after very low calorie diet (VLCD) using quantitative real time PCR. At baseline in SCAT, both T2DM and OB group had decreased mRNA expression of all investigated mitochondrial genes with the exception of 2 complex I (NDUFA 12) and complex IV (COX 4/1) enzymes in OB subjects. In contrast, in PM only the expression of complex I enzymes NDUFA 12 and MT-ND5 was reduced in both T2DM and OB subjects along with decreased expression of citrate synthase (CS) in T2DM group. Additionally, T2DM subjects showed reduced activity of pyruvate dehydrogenase and complex IV in peripheral blood elements. VLCD further decreased mRNA expression of CS and complex I (NT-ND5) and II (SDHA) enzymes in SCAT and complex IV (COX4/1) and ATP synthase in PM of T2DM group, while increasing the activity of complex IV in their peripheral blood elements. We conclude that impaired mitochondrial biogenesis and decreased activity of respiratory chain enzymatic complexes was present in SCAT and PM of obese and diabetic patients. VLCD improved metabolic parameters and ameliorated mitochondrial oxidative function in peripheral blood elements of T2DM subjects but had only minor and inconsistent effect on mitochondrial gene mRNA expression in SCAT and PM. PMID- 28730836 TI - Effects of rapid or slow body weight reduction on intramuscular protein degradation pathways during equivalent weight loss on rats. AB - The purpose of this study was to compare the effects of short-term fasting induced rapid weight loss with those of slower but equivalent body weight loss induced by daily calorie restriction on muscle protein degradation pathways and muscle protein content. Male Fischer rats were subjected to either 30 % calorie restriction for 2 weeks to slowly decrease body weight (Slow) or 3-day fasting to rapidly decrease body weight by a comparable level of that of the Slow group (Rapid). The final body weights were about 15 % lower in both the Slow and Rapid groups than in the Con group (p<0.001). The total protein content and wet weight of fast-twitch plantaris muscle, but not slow-twitch soleus muscle, were significantly lower in the Rapid group compared with the control rats fed ad libitum. Substantial increases in the expression ratio of autophagosomal membrane proteins (LC3-II/-I ratio) and polyubiquitinated protein concentration, used as biomarkers of autophagy-lysosome and ubiquitin-proteasome activities, respectively, were observed in the plantaris muscle of the Rapid group. Moreover, the LC3-II/-I ratio and polyubiquitinated protein concentration were negatively correlated with the total protein content and wet weight of plantaris muscle. These results suggest that short-term fasting-induced rapid body weight loss activates autophagy-lysosome and ubiquitin-proteasome systems more strongly than calorie restriction-induced slower weight reduction, resulting in muscular atrophy in fast-twitch muscle. PMID- 28730837 TI - Molecular basis of TRPA1 regulation in nociceptive neurons. A review. AB - Transient receptor potential A1 (TRPA1) is an excitatory ion channel that functions as a cellular sensor, detecting a wide range of proalgesic agents such as environmental irritants and endogenous products of inflammation and oxidative stress. Topical application of TRPA1 agonists produces an acute nociceptive response through peripheral release of neuropeptides, purines and other transmitters from activated sensory nerve endings. This, in turn, further regulates TRPA1 activity downstream of G-protein and phospholipase C-coupled signaling cascades. Despite the important physiological relevance of such regulation leading to nociceptor sensitization and consequent pain hypersensitivity, the specific domains through which TRPA1 undergoes post translational modifications that affect its activation properties are yet to be determined at a molecular level. This review aims at providing an account of our current knowledge on molecular basis of regulation by neuronal inflammatory signaling pathways that converge on the TRPA1 channel protein and through modification of its specific residues influence the extent to which this channel may contribute to pain. PMID- 28730838 TI - Adult neurogenesis in the hippocampus from a perspective of discrimination and generalization: a hypothesis. AB - The function of adult neurogenesis in the dentate gyrus is not yet completely understood, though many competing theories have attempted to explain the function of these newly-generated neurons. Most theories give adult neurogenesis a role in aiding known hippocampal/dentate gyrus functions. Other theories offer a novel role for these new cells based on their unique physiological qualities, such as their low excitability threshold. Many behavioral tests have been used to test these theories, but results have been inconsistent and often contradictory. Substantial variability in tests and protocols may be at least partially responsible for the mixed results. On the other hand, conflicting results arising from the same tests can serve as aids in elucidating the function of adult neurogenesis. Here, we offer a hypothesis that considers the cognitive nature of tasks commonly used to assess the function of adult neurogenesis, and introduce a dichotomy between tasks focused on discrimination vs. generalization. We view these two aspects as opposite ends of the continuous spectrum onto which traditional tests can be mapped. We propose that high neurogenesis favors behavioral discrimination while low adult neurogenesis favors behavioral generalization of a knowledge or rule. Since many tasks require both, the effects of neurogenesis could be cancelled out in many cases. Although speculative, we hope that our view presents an interesting and testable hypothesis of the effect of adult neurogenesis in traditional behavioral tasks. We conclude that new, carefully designed behavioral tests may be necessary to reach a final consensus on the role of adult neurogenesis in behavior. PMID- 28730839 TI - TRPV1 receptors contribute to mediate paclitaxel-induced c-Fos expression in spinal cord dorsal horn neurons. AB - Transient receptor potential vanilloid type 1 (TRPV1) receptors are important in the development of different pathological chronic pain states. Here we examined the role of spinal cord TRPV1 receptors in the mechanisms leading to activation of dorsal horn neurons after paclitaxel (PAC) treatment. PAC is a widely used chemotherapeutic drug that often leads to development of painful neuropathy. Immunohistochemical analysis of c-Fos protein expression in dorsal horn neurons was used as a marker of neuronal activation. Rat spinal cord slices were processed for in vitro incubation with PAC (100 nM) and TRPV1 receptor antagonists (SB366791 and AMG9810; 10 microM). PAC treatment induced significant upregulation of c-Fos nuclear expression in superficial dorsal horn neurons that was diminished by TRPV1 receptor antagonists pre-incubation. These results further substantiated the role of spinal TRPV1 receptors in the development of paclitaxel-induced neuropathic pain and contribute to better understanding of the pathological mechanisms involved. PMID- 28730840 TI - The safety of available and emerging options for emergency contraception. AB - INTRODUCTION: Emergency contraception (EC) is a way to significantly reduce the chance of becoming pregnant after an episode of unprotected intercourse. Considerable data support the safety of all available and emerging options for EC. Areas covered: This review presents a comprehensive summary of the literature regarding the safety of EC as well as directions for further study. PubMed was searched for all relevant studies published prior to June 2017. Expertopinion: All available methods of EC (i.e., ulipristal acetate pills, levonorgestrel pills, and the copper-IUD), carry only mild side effects and serious adverse events are essentially unknown. The copper IUD has the highest efficacy of EC methods. Given the excellent safety profiles of mifepristone and the levonorgestrel IUD, research is ongoing related to use of these products for EC. PMID- 28730841 TI - Effectiveness of a Worksite Intervention for Male Construction Workers on Dietary and Physical Activity Behaviors, Body Mass Index, and Health Outcomes: Results of a Randomized Controlled Trial. AB - PURPOSE: To evaluate the effectiveness of an individually tailored intervention for improvement in lifestyle behavior, health indicators, and prevention and reduction of overweight among construction workers. DESIGN: Randomized controlled trial. SETTING: Various blue-collar departments of a large construction company in the Netherlands. PARTICIPANTS: Blue-collar workers randomized to an intervention (n = 162) or a control group (n = 152). INTERVENTION: The intervention group received individual coaching sessions, tailored information, and materials to improve lifestyle behavior during a 6-month period, and the control group received usual care. MEASURES: Body weight, body mass index (BMI), waist circumference, physical activity (PA) levels, dietary behavior, blood pressure, and blood cholesterol were assessed. ANALYSIS: Effectiveness of the intervention on outcome measures at 6- and 12-month follow-up was assessed by using linear and logistic regression models adjusting for baseline levels. RESULTS: After 6 months, a statistically significant intervention effect was found on body weight ( B = -1.06, P = .010), BMI ( B = -0.32, P = .010), and waist circumference ( B = -1.38, P = .032). At 6 months, the percentage of those meeting public health guidelines for PA increased significantly in the intervention group compared to the control group ( B = 2.06, P = .032), and for sugar-sweetened beverages, an intervention effect was found at 6 months as well ( B = -2.82, P = .003). At 12 months, for weight-related outcomes, these differences were slightly smaller and no longer statistically significant. The intervention was not effective on the total amount of moderate to vigorous PA and other dietary and health outcomes. CONCLUSION: Intervention participants showed positive changes in vigorous PA and intake of sugar-sweetened beverages compared to controls, as well as effects on weight-related outcomes at 6 months. Long-term effects were still promising but not statistically significant. PMID- 28730842 TI - Comparison of distinctive clinical and cardiac magnetic resonance features between ST elevation myocardial infarction patients with incomplete myocardial rupture and those with moderate to severe pericardial effusion. AB - BACKGROUND: Whether patients with incomplete myocardial rupture (IMR) present distinctive clinical and cardiac magnetic resonance features from those with moderate-severe pericardial effusion (?10 mm (PE)) remains unknown Methods: We compared the clinical, angiographic and cardiac magnetic resonance characteristics of nine patients with IMR (diagnosed angiographically and/or by cardiac magnetic resonance) with 29 with PE, and also with 38 without IMR or PE with evidence of transmural necrosis (reference group) matched for age, gender and year of admission. RESULTS: Patients with IMR were younger than those with PE ( p<0.001) but the two groups shared a higher rate of admission delay (78% and 41%) than those without IMR/PE (5%, p<0.001) and lower frequency of reperfusion therapy (44%, 55% and 100%, respectively, p<0.001). Thirteen patients with PE (45%) but only one IMR (11%) presented recurrent chest pain. IMR patients tended to present smaller infarct size at cardiac magnetic resonance ( p=0.153 and 0.036) and number of segments with ?75% necrosis than PE patients and those without IMR/PE ( p=0.098 and 0.029, respectively). Ten PE patients presented cardiac tamponade (35%). A control 2D-echocardiogram performed within two years in 71 patients (93%) documented a pseudoaneurysm in one PE and in one IMR patient. CONCLUSIONS: IMR is generally silent and occurs in younger patients with smaller infarct size than those with PE although both present late and are often untreated with reperfusion therapy. These findings may warrant imaging assessment in ST elevation myocardial infarction patients with delayed admission, particularly in absence of reperfusion, to rule out an IMR. PMID- 28730843 TI - Clinical value of ST-segment change after return of spontaneous cardiac arrest and emergent coronary angiography in patients with out-of-hospital cardiac arrest: Diagnostic and therapeutic importance of vasospastic angina. AB - BACKGROUND: We investigated the association between initial ST-segment change after return of spontaneous circulation (ROSC) and the incidence of acute coronary lesions in patients with out-of-hospital cardiac arrest (OHCA), and clinical outcomes of patients with OHCA caused by vasospastic angina pectoris (VSA). METHODS: Among 2779 OHCA patients in our institution, all patients with ROSC underwent emergent coronary angiography (CAG) except for those with an obvious extra-cardiac cause of OHCA. Initial ST-segment changes after ROSC were reviewed, and 30-day survival and neurological outcome (Cerebral Performance Category) were evaluated. RESULTS: Of the 155 patients, 52 (34%) had ST-segment elevation (STE) and 103 (66%) had non-STE. Significant coronary culprit lesions were present in 81% of patients with STE and in 33% of patients with non-STE ( P<.001). Percutaneous coronary intervention (PCI) was successful in 60 patients (93.8%) and failed in 4 patients (6.2%). Among 155 patients, 74 patients (47.7%) had favorable neurological prognosis, and 104 patients (67.1%) were alive at 30 days. ST-segment analysis showed good positive predictive value (81%) but low negative predictive value (68%) in diagnosing the presence of acute coronary lesions. VSA was found in 5 patients (9.6%) in the STE group and in 12 patients (11.7%) in the non-STE group. Of these 17 patients, 9 (52.9%) had favorable neurological outcome and 14 (82.4%) were alive at 30 days. CONCLUSION: An acute culprit lesion may be the cause of OHCA even in the absence of STE. In survivors of OHCA with normal coronary arteries, spasm provocation testing should be performed to detect VSA as a cause of the arrest. PMID- 28730844 TI - Correlation between uterine artery Doppler indices and menstrual irregularities among levonorgestrel releasing intrauterine system and depot medroxyprogesterone acetate users: a prospective observational study. AB - OBJECTIVE: To ascertain whether menstrual irregularities among users of levonorgestrel releasing intrauterine system (LNG-IUS) and depot medroxyprogesterone acetate (DMPA), were associated with changes in uterine artery Doppler indices or not. METHODS: This three-year prospective observational study included 102 women using LNG-IUS and 104 women using DMPA for contraception. Participants were followed at regular intervals over three years with performance of transvaginal ultrasound to measure uterine artery pulsatility index (PI) and resistance index (RI) before starting the method and at six months, 12 months, two and three years thereafter. Data was collected and tabulated. RESULTS: Significant changes in uterine artery PI and RI were detected. PI indices were reduced after six months of use in both groups and elevated significantly at 12 months in both groups compared to initial values (p < .001) while RI significantly reduced after six months in both groups and elevated significantly at 12 months, two and three years in both groups compared to initial values (p < .001). Both PI and RI significantly reduced in women suffered abnormal uterine bleeding and significantly elevated in women experienced amenorrhea irrespective of the method used (p < .001). CONCLUSIONS: LNG-IUS and DMPA induce hemodynamic changes in the uterine arteries denoting positive correlation with menstrual irregularities. Larger multicentre studies are warranted to potentiate our findings. PMID- 28730845 TI - Evaluation of toxicity after acute accidental methotrexate ingestions in children under 6 years old: a 16-year multi-center review. AB - CONTEXT: There is little data on the frequency of adverse events following acute methotrexate ingestions in pediatric patients. Likewise, recommendations for observation length, site and management strategies in this population are not well established. Therefore, most recommendations are modeled after management of chronic overdose in patients with underlying medical conditions. OBJECTIVE: The primary objective of this study is to determine the frequency of acute toxicity after acute methotrexate accidental unsupervised ingestions in patients less than six years. In addition, we describe the frequency of late toxicity and characterize the management site and approaches. MATERIALS AND METHODS: This is a retrospective cohort study of pediatric accidental unsupervised methotrexate ingestions reported to six poison centers in the United States over a 16 year period. Demographic information, exposure details, signs, symptoms, treatments, length and location of observation and outcomes were collected. RESULTS: 103 patients met inclusion criteria. Methotrexate dose was reported in 86 patients (84%) and ranged from 1.3 mg-75 mg. The majority of cases (97%) ingested a dose <=20 mg. The significant majority of cases experienced no clinical effects (99 of 103 cases; 96%). Three children experienced minor outcome (3%). There were no patients with a major outcome or death. CONCLUSIONS: The incidence of toxicity from pediatric single, acute ingestions of methotrexate is rare and when it occurs is generally limited to no or only minimally concerning effects. Because concentrations from single ingestions were consistent with low subtoxic exposures, we believe that home monitoring without hospital referral and without methotrexate specific therapy is reasonable in those with acute ingestions up to 20 mg. PMID- 28730846 TI - Spectral Behavior of White Pigment Mixtures Using Reflectance, Ultraviolet Fluorescence Spectroscopy, and Multispectral Imaging. AB - Reflectance spectroscopy, ultraviolet (UV)-fluorescence spectroscopy, and multispectral imaging have been widely employed for pigment identification on paintings. From ancient times to the present, lead white, zinc white, and titanium white have been the most important white pigments used for paintings and they are used as pigment markers for dating a work of art. The spectral behavior of these pigments is reported in several scientific papers and websites, but those of their mixtures are quite unknown. We present a combined nondestructive approach for identifying mixtures of lead white, zinc white, and titanium white as powder and dispersed in two different binder media (egg yolk and linseed oil) by using reflectance spectroscopy, spectrofluorimetry, multispectral reflectance and UV-fluorescence imaging. We propose a novel approach for mapping the presence of white pigments in paintings by false color images obtained from multispectral reflectance and UV-fluorescence images. We found that the presence of lead white mixed with either zinc white or titanium white is highly detectable. Zinc white mixed with lead white or titanium white can be identified due to its UV fluorescence emission, whereas titanium white in association with lead white or zinc white is distinguishable by its reflectance spectral features. In most cases, the UV-fluorescence analyses also permit the recognition of the binder media in which the pigments are dispersed. PMID- 28730847 TI - Canadian Guidelines for the Assessment and Diagnosis of Patients with Schizophrenia Spectrum and Other Psychotic Disorders. AB - OBJECTIVE: The objective of this article is to identify best practices in the diagnosis and assessment of patients with schizophrenia spectrum and other psychotic disorders. The diagnosis and assessment may occur in a range of situations from the emergency room to the outpatient clinic and at different stages of the disorder. The focus may be on acute exacerbations of illness, residual symptoms, levels of function, or changes in the response to treatment. METHODS: A systematic search was conducted for guidelines published in the last 5 years for schizophrenia and schizophrenia spectrum disorders. The guidelines were rated by at least 2 raters, and recommendations adopted on the diagnosis and assessment were primarily drawn from the American Psychiatric Association practice guidelines for the psychiatric evaluation of adults and the National Institute for Health and Care Excellence guideline on psychosis and schizophrenia in adults. A number of de novo recommendations were also developed. RESULTS: Eleven recommendations were identified that cover a range of assessment situations from diagnosis to the involvement of families in assessments. CONCLUSIONS: An accurate assessment establishes the baseline for treatment planning based on clinical decision making for both pharmacotherapy and psychosocial treatments. PMID- 28730848 TI - Canadian Treatment Guidelines for Individuals at Clinical High Risk of Psychosis. AB - OBJECTIVE: Young people who are at clinical high risk (CHR) of developing psychosis are often help seeking and have significant distress and dysfunction. There are limited guidelines for the assessment and treatment for this population. The aim of this guideline was to develop treatment recommendations for this at-risk group. METHOD: A systematic search was conducted for published guidelines for CHR. All current guidelines for schizophrenia were reviewed for treatment guidelines on individuals at CHR. The recommendations adopted were primarily drawn from the European Psychiatric Association (EPA) guidance on the early intervention in clinical high-risk states of psychoses and the 2014 National Institute for Health and Care Excellence (NICE) guidelines on the treatment and management of those at CHR for psychosis. RESULTS: After the guideline development process described, 9 recommendations were developed based on the quality of evidence, appropriateness for the Canadian health care system, and clinical expert consensus. CONCLUSIONS: Assessment by an expert in the field was the first recommendation. It was recommended that treatment follow a staged approach with psychological treatments being the first-line treatment and pharmacotherapy reserved for adults, those who did not respond to psychological interventions, and those who had more severe symptoms. PMID- 28730850 TI - Development and Validation of the Heidelberg Form for Emotion Regulation Strategies (HFERST): Factor Structure, Reliability, and Validity. AB - The Heidelberg Form for Emotion Regulation Strategies (HFERST) was developed to complement previous emotion regulation (ER) questionnaires and addresses some of their limitations by measuring eight ER strategies. An initial item pool was developed in German following expert discussions and adaptation of the items from existing ER scales. Following a stepwise selection based on the experts' judgments, 32 items with the best content validity were chosen. Results of an exploratory factor analysis in Study 1 ( N = 399) and two confirmatory factor analyses in Studies 2 ( N = 715) and 3 ( N = 408) supported the eight-factor structure of the HFERST and provided evidence for its internal consistency, construct and criterion validity, and clinical utility. Study 4 supported a 2 week stability of the HFERST and Study 5 showed that, following an ER intervention, the HFERST captured a reduction in dysfunctional and an improvement in functional ER strategies, which again supports the clinical utility of the HFERST. PMID- 28730849 TI - Treadmill training to improve mobility for people with sub-acute stroke: a phase II feasibility randomized controlled trial. AB - OBJECTIVE: This phase II study investigated the feasibility and potential effectiveness of treadmill training versus normal gait re-education for ambulant and non-ambulant people with sub-acute stroke delivered as part of normal clinical practice. DESIGN: A single-blind, feasibility randomized controlled trial. SETTING: Four hospital-based stroke units. SUBJECTS: Participants within three months of stroke onset. INTERVENTIONS: Participants were randomized to treadmill training (minimum twice weekly) plus normal gait re-education or normal gait re-education only (control) for up to eight weeks. MAIN MEASURES: Measures were taken at baseline, after eight weeks of intervention and at six-month follow up. The primary outcome was the Rivermead Mobility Index. Other measures included the Functional Ambulation Category, 10-metre walk, 6-minute walk, Barthel Index, Motor Assessment Scale, Stroke Impact Scale and a measure of confidence in walking. RESULTS: In all, 77 patients were randomized, 39 to treadmill and 38 to control. It was feasible to deliver treadmill training to people with sub-acute stroke. Only two adverse events occurred. No statistically significant differences were found between groups. For example, Rivermead Mobility Index, median (interquartile range (IQR)): after eight weeks treadmill 5 (4-9), control 6 (4-11) p = 0.33; or six-month follow-up treadmill 8.5 (3-12), control 8 (6 12.5) p = 0.42. The frequency and intensity of intervention was low. CONCLUSION: Treadmill training in sub-acute stroke patients was feasible but showed no significant difference in outcomes when compared to normal gait re-education. A large definitive randomized trial is now required to explore treadmill training in normal clinical practice. PMID- 28730851 TI - Agomelatine for the treatment of generalized anxiety disorder. AB - INTRODUCTION: Agomelatine is a melatonergic antidepressant, approved for the treatment of Major Depressive Disorder (MDD) in Europe and Australia, but not in the United States. This compound seems to be promising in the short-term and maintenance treatment of Generalized Anxiety Disorder (GAD). Areas covered: This paper presents an evaluation of the available data about the clinical efficacy and tolerability of agomelatine in the treatment of GAD. Expert opinion: First line GAD treatments are limited by high rates of lack of clinical response. Preliminary data would indicate agomelatine as a safe compound, and with a higher rate of clinical response in the short-term and an earlier improvement of symptoms with respect to Selective Serotonine Reuptake Inhibitors (SSRIs) and Selective Serotonin Noradrenaline Reuptake Inhibitors (SNRIs). In addition, agomelatine has not been associated with potential risk of abuse as in case of pregabalin and with long-term metabolic side effects similar to quetiapine. The major limitation of the results presented is that little data has come from long term or comparative trials. Furthermore, some caution should be reserved in case of liver impairment (e.g. in subjects with alcohol abuse). PMID- 28730852 TI - Cannabinoid hyperemesis syndrome and topical capsaicin: treating smoke with fire? - the authors reply. PMID- 28730853 TI - Dengue in the elderly: a review. AB - INTRODUCTION: Changing dengue epidemiological trends have resulted in a shift in the disease burden to the adult population. Older adults suffer from poorer outcomes as compared to their younger counterparts, making clinical management of this sub-population particularly challenging. Areas covered: We present a review of the current literature on the changing epidemiology of dengue in the elderly, the atypical features of the clinical disease in this population with emphasis on severe disease presentations and challenges in the current management strategies. Expert commentary: Dengue in the elderly is an increasingly important yet greatly understudied area. There is an urgent need to refine the current diagnostic criteria to improve diagnosis, classification of disease severity and identify individuals in this population who are likely to progress to severe disease. Management strategies in this population would have to be adjusted to account for the increased number of co-morbidities. The role of the available dengue vaccines in this group is uncertain, and more studies into their safety and efficacy are critically needed. PMID- 28730855 TI - Relationship Intervention for Inmates and Their Partners: Bringing Couples Together Before Release. AB - The aim of this intervention study was to examine the impact of the Prevention and Relationship Enhancement Program on inmates and their partners with the programming goal to reduce the negative impact of incarceration on families. This study was conducted in a prison facility in the Northeast United States, and data were collected on 40 couples (40 male inmates and 40 female partners) that completed the program. This study used a self-report pre and post survey to collect data on relationship satisfaction, relationship confidence, types of interactions, as well as program satisfaction. Results demonstrated that inmates and their partners improved their positive interactions and relationship confidence. Different trends were found for men and women in marital satisfaction and negative interactions. Both groups reported that the program was beneficial for improving communication; however, listening techniques and setting ground rules during discussions were still issues both groups struggled with at the end of the intervention. PMID- 28730854 TI - Physical activity, body mass index and waist circumference change, and normal range glycated hemoglobin on incident diabetes: Jackson Heart Study. AB - OBJECTIVES: The purpose of this study was to 1) evaluate whether physical activity has a protective effect on incident diabetes among African Americans across combinations of body mass index (BMI) and waist circumference (WC), 2) evaluate the effect of changes on BMI and WC on incident diabetes, and 3) evaluate the effect of 'normal range' glycated hemoglobin (A1C) on incident diabetes. METHODS: Data from the prospective Jackson Heart Study were evaluated, with baseline data assessed between 2001 and 2004 and follow-up data occurring between 2009 and 2013. Physical activity was assessed via a validated questionnaire, with measured BMI, WC and A1C assessed via standard procedures. RESULTS: The sample included 2,450 adults who did not have evidence of diabetes at the baseline assessment, with 286 incident diabetes cases occurring at the follow-up assessment. Physical activity did not have a protective effect against incident diabetes across different BMI and WC combinations. Notably, BMI change from baseline to follow-up was associated with incident diabetes (HR = 1.08; 95% CI: 1.03-1.13). Further, higher levels of A1C within the 'normal-range' was associated with incident diabetes (HR = 7.51, 95% CI = 2.66-21.25). CONCLUSION: Increases in BMI over time and higher A1C within the normal range were associated with incident diabetes. Serial monitoring of BMI, as well as A1C, even among those with a 'normal' A1C, may be warranted by clinicians. Future work evaluating this novel three-way model (physical activity, BMI and WC) should consider utilizing an objective measure of physical activity. PMID- 28730856 TI - In vitro drug-drug interactions of budesonide: inhibition and induction of transporters and cytochrome P450 enzymes. AB - 1. Budesonide is a glucocorticoid used in the treatment of several respiratory and gastrointestinal inflammatory diseases. Glucocorticoids have been demonstrated to induce cytochrome P450 (CYP) 3A and the efflux transporter P glycoprotein (P-gp). This study aimed to evaluate the potential of budesonide to act as a perpetrator or a victim of transporter- or CYP-mediated drug-drug interactions (DDIs). 2. In vitro studies were conducted for P-gp, breast cancer resistance protein and organic anion and cation transporters (OATP1B1, OATP1B3, OAT1, OAT3, OCT2) in transporter-transfected cells. Changes in mRNA expression in human hepatocytes and enzyme activity in human liver microsomes by budesonide were determined for CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A. 3. The data indicated that budesonide is a substrate of P-gp but is not a substrate or an inhibitor of the other transporters investigated. Budesonide is neither an inducer nor an inhibitor of major CYP enzymes. The effect of P-gp on budesonide disposition is anticipated to be low owing to CYP3A-mediated clearance. 4. Collectively, our data indicate there is a low risk of budesonide perpetrating clinical DDIs mediated by the transporters or CYPs studied. PMID- 28730857 TI - Controversies in complex percutaneous coronary intervention: radial versus femoral. AB - INTRODUCTION: Evolution in the technology used in the cardiac catheterization laboratory has permitted a migration from the femoral to radial artery access for many interventional procedures while concurrently improving outcomes. As a disruptive technology, transradial access has been associated with several controversies including a dichotomous relationship with femoral access. Areas covered: Several different patient subsets along with perceived technical challenges in interventional cardiology are reviewed with regard to the issue of access site. Evolving technological improvements germane to transradial techniques are also discussed as garnered from the literature of recent clinical trials and reports. Expert commentary: Radial techniques have been enhanced by newer technology and the spread of knowledge. Fusion of radial techniques with those of the femoral approach is evolving into a unifying concept of using the access that is most appropriate for the patient. No one access technique can cover all clinical subsets of patients. There is a need for complimentary access skillsets for even the most advanced cardiovascular technology used in the cardiac catheterization laboratory if the patients' outcomes are to be idealized. PMID- 28730858 TI - Management of children with persistent group A streptococcal carriage. AB - INTRODUCTION: Chronic GAS carrier state is best defined as the prolonged presence of group A beta-haemolytic Streptococcus (GAS) in the pharynx without evidence of infection or inflammation. Chronic GAS carriers have a low risk of immune mediated complications. Persistent pharyngeal carriage often raises management issues. In this study, we review the evidence on the management of persistent GAS carriage in children and propose a management algorithm. Areas covered: Chronic GAS pharyngeal carriage is quite common affecting 10-20% of school-aged children. Pathogenesis of carriage has been related to the pharynx microflora and to special properties of GAS, but several aspects are yet to be elucidated. Management greatly depends on whether the individual child belongs to a 'high risk' group and might benefit from eradication regimens or not, when observation only and reassurance are enough. Penicillin plus rifampin and clindamycin monotherapy have been recommended for eradication; limited evidence of effectiveness of azithromycin has been reported. Surgical intervention is not indicated. Expert commentary: GAS infection is a common reason for antibiotic use and abuse in children and asymptomatic carriers constitute the major reservoir of GAS in the community. Several aspects are yet to be elucidated and well-designed studies are needed for firm conclusions to be drawn. PMID- 28730859 TI - Molecular targeting of inosine-5'-monophosphate dehydrogenase by FF-10501 promotes erythropoiesis via ROS/MAPK pathway. AB - One of the major symptoms of myelodysplastic syndromes (MDS) is severe cytopenia. Despite cytokine therapies, such as erythropoiesis-stimulating agents, many patients still require blood transfusions, and the development of new therapeutic approaches is needed. In this work, we studied the effects of the inosine-5' monophosphate (IMP) dehydrogenase (IMPDH) inhibitor FF-10501 on erythropoiesis of human hematopoietic cells. Differentiation of K562 chronic myeloid leukemia cells to an erythroid lineage was promoted by FF-10501 in a dose-dependent manner. Interestingly, we found that metabolic conversion of IMP to hypoxanthine leads to elevation of reactive oxygen species (ROS). The differentiative effects of FF 10501 were abolished by the ROS scavenger dimethylthiourea or the p38 MAPK inhibitor SB203580. Furthermore, FF-10501 promoted erythropoiesis from CD34+ hematopoietic stem/progenitor cells, accompanied with ROS accumulation, while high-dose FF-10501 mainly showed cytotoxic effects. These findings denote the potential of IMPDH inhibition therapy with FF-10501 in amelioration of anemia in MDS patients. PMID- 28730860 TI - Prevalence of attention-deficit/hyperactivity and other disruptive behaviour disorder symptoms among primary school-age children in Kayseri, Turkey. AB - Objectives This study aimed to determine the prevalence of attention deficit/hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), and conduct disorder (CD), and their influencing factors on primary school-age children. Methods This cross-sectional study was conducted among 2045 students, 7 15 years old, who were randomly selected from seven schools in Kayseri, Turkey, in 2012. Participants were stratified by socioeconomic status. Data were collected using the Turgay DSM-IV-Based Child and Adolescent Behavioural Disorders Screening and Rating Scale (T-DSM-IV-S). For statistical analyses, the t-test and analysis of variance were used. Results Rates of disruptive behaviour disorders (DBDs) among children were as follows: ADHD, 6.2%; CD, 14.4%; and ODD, 6.7%. The prevalence of ADHD was higher in boys and children whose mothers were homemakers and from poorly-educated and low-income families, compared with their peers. CD was more prevalent among boys and children 13-15 years old, whose parents had low income levels and were separated. ODD was higher in boys and children whose mothers were homemakers. Conclusions Our findings suggest that the overall prevalence of DBDs in our study area is 27.4%, which is similar to the pooled worldwide prevalence. Adverse family factors are closely associated with the prevalence of DBDs. PMID- 28730861 TI - Comparative Outcomes in Children and Adults With Anti- N-Methyl-D-Aspartate (anti NMDA) Receptor Encephalitis. AB - This study compared neurologic disability and adaptive function in children and adults >1 year following anti- N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis diagnosis. Retrospective record review identified 12 patients with anti-NMDAR encephalitis. At last follow-up, all surviving patients had "good" modified Rankin Score (0-2). Four children, 6 adults, and their families participated in a telephone interview. Median duration since diagnosis was similar for children (2.42 years, interquartile range 2.12-3.32) and adults (3.55 years, interquartile range 2.08-5.50 years). 3/4 (75%) pediatric and 3/5 (60%) adult patients reported neuropsychiatric symptoms (fatigue, emotional lability, short-term memory deficits or concentration deficits). On the Adaptive Behavior Assessment System (ABAS-3), although overall adaptive function was intact for adults (general adaptive composite standard score: median 104.5, interquartile range 98.8-112.5), the median for children was below average (General Adaptive Composite Standard Score: median 82.0, interquartile range 79.0-89.0). Children with anti-NDMAR encephalitis may have long-term effects impacting daily life while adults regain normal function. PMID- 28730862 TI - Correctional Officers and Workplace Adversity: Identifying Interpersonal, Cognitive, and Behavioral Response Tendencies. AB - This study explored correctional officers' response tendencies (i.e., cognitive, interpersonal, and behavioral response patterns they engage in) when managing workplace adversity. In total, 53 Australian correctional officers participated in the study. Eight exploratory focus group discussions ( n = 42) were conducted to identify a set of officer-endorsed response tendencies. Thematic analysis of group data revealed that correctional officers engage in a range of response tendencies when facing workplace adversity and that these tendencies may be categorized as interpersonally, cognitively, or behaviorally based. Semistructured interviews ( n = 11) were then conducted to provide further depth of information regarding officer response tendency usage. Results are discussed in terms of common themes, future research, and implications for developing training programs designed to ameliorate the effects of workplace adversity. PMID- 28730863 TI - Non-operative management of ulnar collateral ligament injuries in the throwing athlete. AB - Medial ulnar collateral ligament (UCL) injuries have become increasingly prevalent in overhead athletes. The orthopaedic literature contains a wealth of information on operative management of these injuries. However, there are few high-quality longitudinal studies on non-operative care of UCL injuries. The purpose of this review is to describe the non-operative approach to managing UCL injuries, including recommended rehabilitation strategies and predictors of successful non-operative treatment. PMID- 28730864 TI - Automatic RBG-depth-pressure anthropometric analysis and individualised sleep solution prescription. AB - INTRODUCTION: Sleep surfaces must adapt to individual somatotypic features to maintain a comfortable, convenient and healthy sleep, preventing diseases and injuries. Individually determining the most adequate rest surface can often be a complex and subjective question. OBJECTIVES: To design and validate an automatic multimodal somatotype determination model to automatically recommend an individually designed mattress-topper-pillow combination. METHODS: Design and validation of an automated prescription model for an individualised sleep system is performed through a single-image 2 D-3 D analysis and body pressure distribution, to objectively determine optimal individual sleep surfaces combining five different mattress densities, three different toppers and three cervical pillows. RESULTS: A final study (n = 151) and re-analysis (n = 117) defined and validated the model, showing high correlations between calculated and real data (>85% in height and body circumferences, 89.9% in weight, 80.4% in body mass index and more than 70% in morphotype categorisation). CONCLUSIONS: Somatotype determination model can accurately prescribe an individualised sleep solution. This can be useful for healthy people and for health centres that need to adapt sleep surfaces to people with special needs. Next steps will increase model's accuracy and analise, if this prescribed individualised sleep solution can improve sleep quantity and quality; additionally, future studies will adapt the model to mattresses with technological improvements, tailor-made production and will define interfaces for people with special needs. PMID- 28730866 TI - Managing acute coronary syndrome caused by plaque erosion without stent implantation: a word of caution. PMID- 28730865 TI - Psychological assessment of children and adolescents with obesity. AB - Objective This study aimed to analyse the psychological conditions and behaviour of a group of Chinese children and adolescents with obesity, and to develop an intervention for these young patients. Methods A group of 72 patients aged from 4 to 15 years were recruited from an obesity clinic. Patients, or the parents of children younger than 12 years, filled out a series of self-report questionnaires, and the responses were recorded and analysed. Results The 72 children and adolescents with obesity had a mean age of 9.14 +/- 2.18 years. The body mass index-z scores of children with obesity showed a significant positive correlation with the level of impulsive behaviour, motivational impulses, and cognitive instability (inattention). Children with obesity quickly responded with extreme emotions, and these responses were positively correlated with the degree of obesity (slight, intermediate, or severe obesity). Conclusion Children and adolescents being treated for obesity have many underlying psychological problems, including emotional instability and impulsivity, and are prone to extreme emotional-psychological problems. These difficulties are positively correlated with the degree of obesity. Therefore, clinical treatment of these problems requires not only use of medication, improved nutrition, and healthy exercise, but also addressing underlying psychologic problems. PMID- 28730867 TI - External load training does not alter balance performance in well-trained women. AB - This study investigated the influence of external load training (ELT) on static and dynamic balance. Nineteen females stratified into two groups (ELT = 9, control = 10) completed three testing sessions over 6 weeks. The ELT group wore weighted vests (WV) of ~8% body mass for 32 h/week during daily living and three training sessions/week for 3 weeks. Following completion of ELT, a 3 week detraining (DET) phase was completed. Bilateral and unilateral static balance were assessed with eyes open and closed. Dynamic balance was assessed using the star excursion balance test (SEBT). Static and dynamic balance variables were analysed using a 2 (group) x 3 (time) between participants repeated measures ANOVA (p < 0.05). Results revealed significant reductions in average centre of pressure (COP) velocity in the control group on the non-dominant limb with eyes closed, and significantly greater reach distances in the ELT group on the SEBT for the posteromedial and medial directions on the dominant limb (p < 0.05). These findings suggest the ELT group did not significantly improve their balance in comparison to the control group. However, future research should further examine this unique, supplemental training method and the impact on balance performance. PMID- 28730868 TI - Intercontinental validation of brain volume measurements using MSmetrix. AB - Background Brain volume assessment has become an important outcome within research and treatment of multiple sclerosis (MS). MSmetrix (Icometrix) has been developed specifically for patients with MS. The original healthy, 'normal' population used for determination of the acceptable brain volume data consisted mainly of Europeans. Methods In the present study, results from 295 completely normal magnetic resonance imaging scans from Brazilian subjects were plotted against the original results in MSmetrix. Results With regard to whole brain volume, only 2% of the healthy adult subjects from Brazil were below the 5th percentile of the graph, and for grey matter volume, only 3% of the subjects were below the 5th percentile of MSmetrix standards. Conclusion MSmetrix may be used across different populations. PMID- 28730869 TI - Impact of iron deficiency on exercise capacity and outcome in heart failure with reduced, mid-range and preserved ejection fraction. AB - BACKGROUND: Little information is available about the prevalence and impact on exercise capacity and outcome of iron deficiency in heart failure with mid-range (HFmrEF) and preserved (HFpEF) ejection fraction in comparison to heart failure with reduced ejection-fraction (HFrEF). Furthermore, no data is available about the progression of ID in patients without baseline anaemia. METHODS: We evaluated baseline iron and haemoglobin-status in a single-centre, prospective heart failure database. Baseline functional status, VO2max, echocardiography and clinical-outcome (all-cause mortality and heart failure admissions) were evaluated. ID, anaemia, HFrEF, HFmrEF and HFpEF were defined according to established criteria. RESULTS: A total of 1197 patients (71% male) were evaluated (HFrEF, n = 897; HFmrEF, n = 229; HFpEF, n = 72). The overall prevalence of ID was 53% (50% in HFrEF; 61% in HFmrEF; 64% in HFpEF) and 36% for anaemia. ID was associated with a lower VO2max in patients with HFrEF, HFmrEF and HFpEF (p < .001 in all). Iron status more closely related to a poor VO2max than anaemia status (p < .001). Furthermore, poor clinical-outcome was more strongly associated with iron status than anaemia status. Exposing eight patients without anaemia to iron deficiency for 39 months resulted in one patient developing new-onset anaemia (defined as progression of ID). Patients with progression of ID exhibited a significant higher risk of heart failure hospitalisation and all-cause mortality (HR = 1.4; CI = 1.01-1.94; p = .046) than patients without progression. CONCLUSIONS: Iron deficiency is common in patients with HFrEF, HFmrEF and HFpEF, and negatively affects VO2max and clinical-outcome. Progression of iron deficiency parallels an increased risk for worsening of heart failure. PMID- 28730870 TI - Cardiac autonomic recovery after strength exercise in lower and upper limbs. AB - Introduction Strength exercises influence the cardiovascular system by promoting autonomic adjustments induced by the increased metabolic demand and consequent increase in local blood flow. However, it is unclear whether there are differences between upper and lower limbs. We aimedto evaluate recovery of cardiac autonomic modulation afterstrengthexercise in upper and lower limbs. Methods We analysed 29 healthy male subjects physically active but not professional athletes aged between 20 and 35 years old. We analysed heart rate variability (HRV) in the time and frequency domain 0-10 minutes before exercise (T1), 0-10 minutes after exercise (T2), 10-20 minutes after exercise (T3) and 20 30 minutes after exercise (T4). Results Regarding the time domain we observed that the SDNN, pNN50 and RMSSD were reduced (P < 0.0001) in T2, T3, T4 in relation to T1 with no difference between upper and lower limbs. In the frequency domain analysis, we observed stronger significancefor the increased values of LF (nu) (P = 0.0008) and LF/HF ratio (P = 0.0008) and for reduction in HF (nu) (P = 0.0008) in the lower limbs compared to upper limbs (LF (nu) - P = 0.0015, LF/HF ratio - P = 0.0028 and HF (nu) - P = 0.0028). Conclusion Strength exercise acutely induced more pronounced cardiac autonomic responses in lower limbs compared to upper limbs. PMID- 28730871 TI - Effects of timing of signal indicating jump directions on knee biomechanics in jump-landing-jump tasks. AB - A variety of the available time to react (ATR) has been utilised to study knee biomechanics during reactive jump-landing tasks. The purpose was to quantify knee kinematics and kinetics during a jump-land-jump task of three possible directions as the ATR was reduced. Thirty-four recreational athletes performed 45 trials of a jump-land-jump task, during which the direction of the second jump (lateral, medial or vertical) was indicated before they initiated the first jump, the instant they initiated the first jump, 300 ms before landing, 150 ms before landing or at the instant of landing. Knee joint angles and moments close to the instant of landing were significantly different when the ATR was equal to or more than 300 ms before landing, but became similar when the ATR was 150 ms or 0 ms before landing. As the ATR was decreased, knee moments decreased for the medial jump direction, but increased for the lateral jump direction. When the ATR is shorter than an individual's reaction time, the movement pattern cannot be pre planned before landing. Knee biomechanics are dependent on the timing of the signal and the subsequent jump direction. Precise control of timing and screening athletes with low ATR are suggested. PMID- 28730872 TI - A dual-label time-resolved fluorescence immunoassay for the simultaneous determination of cystatin C and beta2-microglobulin in urine. AB - BACKGROUND: Contrast media is widely used in clinical diagnostic and interventional procedures, but may cause damage to the kidney, that is, contrast induced nephropathy. This study was to establish a dual-label time-resolved fluorescence immunoassay (TRFIA) for the simultaneous determination of renal function markers cystatin-C (Cys-C) and beta2-microglobulin (beta2-MG) for the early diagnosis and follow-up surveillance of contrast-induced nephropathy. METHODS: A sandwich immunoassay was used to detect the concentration of Cys-C, and the competitive immunoassay was used to detect the concentration of beta2-MG in 50 samples of urine. The performance of this dual-label TRFIA was evaluated and compared with commercial assays. RESULTS: The sensitivity for Cys-C detection was 1.26 ng/ml, the average recovery was 99.36%; The sensitivity for beta2-MG detection was 2.13 ng/ml, the average recovery was 100.18%. Bland-Altman analysis showed that the dual-label TRFIA method and the commercial kits had a good agreement, suggesting they can be used interchangeably in clinical urine analysis. CONCLUSION: The present dual-label TRFIA has high sensitivity, specificity and accuracy in clinical sample analysis. This method can be used for the early diagnosis and follow-up surveillance of the contrast-induced nephropathy. PMID- 28730873 TI - Physiological Traits Determining Yield Tolerance of Wheat to Foliar Diseases. AB - Tolerance is defined as the ability of one cultivar to yield more than another cultivar under similar disease severity. If both cultivars suffer an equal loss in healthy (green) leaf area duration (HAD) over the grain filling period due to disease presence, then the yield loss per unit HAD loss is smaller for a more tolerant cultivar. Little is understood of what physiological and developmental traits of cultivars determine disease tolerance. In this study, we use a mathematical model of wheat to investigate the effect of a wide range of wheat phenotypes on tolerance. During the phase from stem extension to anthesis, the model calculates the assimilate source and sink potential, allowing for dynamic changes to the source-sink balance by partitioning assimilates between ear development and storage of water-soluble carbon (WSC) reserves, according to assimilate availability. To quantify tolerance, rates of epidemic progress were varied on each phenotype, leading to different levels of HAD loss during the postanthesis, grain-filling period. Model outputs show that the main determinant of tolerance is the total amount of assimilate produced per grain during the rapid grain-fill period, leading to a strong positive correlation between HAD per grain and tolerance. Reductions in traits that affect carbon assimilation rate and increases in traits that determine the amount of structural biomass in the plant increase disease tolerance through their associated reduction in number of grains per ear. Some of the most influential traits are the canopy green area index, carbon use efficiency, and leaf specific weight. Increased WSC accumulation can either increase or decrease tolerance. Furthermore, a cultivar is shown to be maximally tolerant when a crop is able to just fill its total sink size in the presence of disease. The model has identified influential functional traits and established that their associations with tolerance have a mechanistic basis. PMID- 28730874 TI - Abortion politics in Cambodia social history, local forms and transnational issues. AB - Cambodia's current abortion rate and ratio could be among the highest in Southeast Asia. In 1997, the Cambodian parliament passed the first law regulating abortions. This law was adopted to contribute to reduce the high maternal mortality ratio, as a significant number of maternal deaths were believed to be related to complications of unsafe abortion. A decade later, the Ministry of Health had not yet established medical protocols for safe abortion access and women often continued to induce their own terminations or seek unsafe services. However, in 2009, the Cambodian authorities approved the importation and distribution of one manufactured abortion pill. In addition, manual vacuum abortions and medical abortion training programmes were implemented at the referral hospital level. How has this situation come about? What do we know about the local agencies of the transnational reproductive health policies related to safe abortion access in this country? This paper aims to analyse how history and intersections between global interventions, state policies, local moralities and individual strategies shape abortion policies, practices and technologies. Finally, our findings raise some issues for public health programming. PMID- 28730875 TI - The influence of fatalistic beliefs on health beliefs among diabetics in Khartoum, Sudan: a comparison between Coptic Christians and Sunni Muslims. AB - Although there are many studies assessing the influence of religious beliefs on health they do not agree on whether the impact is positive or negative. More so, there is no consensus in the available literature on the definition of fatalism and what it means to individuals. In this phenomenological study we attempt to define what religious fatalism means to people living with diabetes in Khartoum, and how it affects their health beliefs, and how those beliefs affect their sense of coherence and generalized resistance resources, since salutogenesis is the guiding theory in this study. Three Copts and five Sunnis living with diabetes were interviewed, as well as a Coptic clergyman and a Sunni scholar. The semi structured interviews were recorded and transcribed verbatim for analysis. Thematic network analysis was used to code salient concepts into basic themes, organizing themes and global themes. The empirical findings are thus structured as the three global themes: (1) fatalism and free will; (2) health responsibility; (3) acceptance and coping. Fatalism was defined as events beyond an individual's control where it is then the individual's free will to seek healthy behavior. Thus health responsibility was stressed upon by the participants in this study as well as the clergyman and scholar. There is also the concept of 'God doesn't give one what one cannot handle' that the participants relate to coping and acceptance. This study finds that the meaning of religious fatalism held by participants and religious clergy is not disempowering. The participants believe that they are responsible for their health. The meaning derived from fatalism is related to how they can accept what is beyond their control and cope with their health condition. Religious fatalism contributed to comprehensibility, manageability and meaningfulness in our participants' response to diabetes. PMID- 28730876 TI - Epipericardial fat necrosis: an atypical cause of acute chest pain. PMID- 28730877 TI - From mental hygiene to mental health: ideology, discourses and practices in Franco's Spain (1939-75). AB - Based on an analysis of the discourses, the ideological appropriation and the practical influence of mental hygiene in Spanish psychiatry during the early years of the Francoist regime, this article examines its decline and subsequent replacement by the new concept of mental health promoted by the World Health Organization and other international bodies from the mid-twentieth century. The old approach, essentially focused on the prophylaxis of insanity within the framework of a set of interventionist policies of social defence, was thus transformed from the beginning of the 1960s into a much more ambitious and comprehensive project which sought to promote the psychosocial balance and performance of individuals in the context of increasingly socialized health related discourses and networks of care. PMID- 28730878 TI - Investigational drugs in development for Hepatitis D. AB - INTRODUCTION: Treatment of chronic hepatitis D still relies on Interferon. To improve efficacy, new therapeutic strategies are in development which aim to deprive the Hepatitis D Virus (HDV) of functions of the Hepatitis B Virus and of the host required for its life-cycle. Areas covered: The therapeutic options are; 1) The inhibition of the farnesylation of the large HD-protein permissive of virion assembly with Lonafarnib, 2) The blocking of HBsAg entry into cells with Myrcludex B via the inhibition of the Sodium Taurocholate Cotransporting Receptor, to prevent the spreading of HDV to uninfected hepatocytes, 3) The reduction of subviral HBsAg particles by REP 2139, leading to diminished virion morphogenesis . Expert opinion: Lonafarnib and Myrcludex reduced serum HVD-RNA; neither diminished serum HBsAg. NAP REP-2139 diminished both HDV-RNA and HBsAg in serum; a full report is awaited. In combination with Peg-Interferon, these new drugs may provide additional efficacy. PMID- 28730879 TI - RGRNA: prediction of RNA secondary structure based on replacement and growth of stems. AB - Owing to their structural diversity, RNAs perform many diverse biological functions in the cell. RNA secondary structure is thus important for predicting RNA function. Here, we propose a new combinatorial optimization algorithm, named RGRNA, to improve the accuracy of predicting RNA secondary structure. Following the establishment of a stempool, the stems are sorted by length, and chosen from largest to smallest. If the stem selected is the true stem, the secondary structure of this stem when combined with another stem selected at random will have low free energy, and the free energy will tend to gradually diminish. The free energy is considered as a parameter and the structure is converted into binary numbers to determine stem compatibility, for step-by-step prediction of the secondary structure for all combinations of stems. The RNA secondary structure can be predicted by the RGRNA method. Our experimental results show that the proposed algorithm outperforms RNAfold in terms of sensitivity, specificity, and Matthews correlation coefficient value. PMID- 28730880 TI - Response of narrow QRS tachycardia to a premature ventricular ectopic rhythm. What is the mechanism? PMID- 28730881 TI - Comparison of jump-landing protocols with Biodex Balance System as measures of dynamic postural stability in athletes. AB - The objective of the study was to determine whether a relationship exists between the two common methods for assessing postural stability in athletes: the time-to stabilisation (TTS) via force-plate and the Biodex Balance System (BBS). The conditions under which these measurements assess dynamic postural control may not provide sufficient feedback to practitioners. Fourty-four amateur soccer players with no history of musculoskeletal disorders volunteered for the study. Pearson correlation was used to compare the anterior-posterior (AP), medio-lateral (ML), and the overall stability indexes measured by BBS, with the corresponding parameters of TTS assessed via force plate. There was no significant correlation between any parameters of dynamic stability measured by force-plate and the stability indexes. However, there was a significant correlation between the resulting vectors and the AP component of TTS for each jump protocol. Furthermore, forward drop landing exhibited shortest TTS in AP direction, while lateral drop landing resulted in longer ML TTS relative to both forward jumps (p < 0.001). These results demonstrate that the TTS and BBS stability indexes should be used as distinct measures of dynamic postural stability. TTS protocols may be modified to target a specific training conditions or athletic population. PMID- 28730882 TI - Retraction Notice. PMID- 28730883 TI - Affected Aspects Regarding Literacy and Numeracy in Children Treated for Brain Tumors. AB - The aim of this study was to investigate the test results of reading speed, reading comprehension, word comprehension, spelling, basic arithmetic skills, and number sense (intuitive understanding of numbers) by children treated for brain tumors. This is a retrospective study based on medical records, including standardized academic tests. In the years of 2010 to 2014, all children in the area of Stockholm between 7 and 18 years (IQ <70) who had no major linguistic or motor difficulties after they had undergone treatment for brain tumors were offered a special education assessment one year after treatment, at school start, or the year before a transition from one stage to another. Our results indicate that children treated for a brain tumor are at risk of having difficulties in spelling, reading speed, and arithmetic and that the test performance may decline over years in arithmetic and spelling. Children diagnosed at age 0 to 6 years may need extra tutoring at school start, especially in basic arithmetic skills. In both reading and mathematics, many children perform better on tests focused on understanding than on tests focused on speed. Continuous special needs assessments including different aspects of literacy and numeracy, are important for understanding each child's specific needs. PMID- 28730884 TI - The Effect of Financial Compensation on Willingness to Supply a Child's Blood Sample: A Randomized Controlled Trial. AB - Medical researchers frequently need to collect blood samples from study participants. The determination of whether and how much compensation to provide to the participants is challenging. Institutional review boards typically allow researchers to provide a compensation that reimburses participants for their time and effort but is not so large as to be coercive. Using a randomized controlled trial, we estimate parents' responsiveness to financial compensation in terms of their willingness to provide their child's blood sample. We find that an additional dollar of compensation raises the willingness to provide a child's blood sample by about 0.5 percentage point at a base of 65%. This corresponds to an elasticity of .33. Using the findings, we provide general guidance on how compensation can be structured to strike a balance between appropriate compensation for participation and coercion. PMID- 28730885 TI - Ataluren in cystic fibrosis: development, clinical studies and where are we now? AB - INTRODUCTION: Cystic fibrosis (CF) is one of the most common genetically-acquired life-limiting conditions worldwide. The underlying defect is dysfunction of the cystic fibrosis transmembrane-conductance regulator (CFTR) which leads to progressive lung disease and other multi-system effects. Around 10% of people with CF have a class I nonsense mutation that leads to production of shortened CFTR due to a premature termination codon (PTC). Areas covered: We discuss the discovery of the small-molecule drug ataluren, which in vitro has been shown to allow read-through of PTCs and facilitate synthesis of full-length protein. We review clinical studies that have been performed involving ataluren in CF. Early phase short-term cross-over studies showed improvement in nasal potential difference. A follow-up phase III randomised controlled trial did not show a significant difference for the primary outcome of lung function, however a post hoc analysis suggested possible benefit in patients not receiving tobramycin. A further randomised controlled trial in patients not receiving tobramycin has been reported as showing no benefit but has not yet been published in full peer reviewed form. Expert opinion: A small-molecule approach to facilitate read through of PTCs in nonsense mutations makes intuitive sense. However, at present there is no high-quality evidence of clinical efficacy for ataluren in people with CF. PMID- 28730886 TI - Is the 10 m incremental shuttle walk test a useful test of exercise capacity for patients referred to cardiac rehabilitation? AB - BACKGROUND: Field exercise tests are a feasible alternative to the symptom limited exercise test for measuring exercise capacity in patients attending cardiac rehabilitation. AIMS: To evaluate the criterion validity of the 10 m incremental shuttle walk test (ISWT) as a useful tool for measurement of exercise capacity for patients eligible for cardiac rehabilitation. METHODS: Fifteen patients eligible for cardiac rehabilitation completed a treadmill symptom limited exercise test and two ISWTs with the order of testing randomised. Associations between the symptom-limited exercise test and the ISWT were explored and the ability of the ISWT to predict symptom-limited exercise test duration estimated. RESULTS: There was a moderate to high association ( r2 ?0.72) between ISWT duration and distance, and symptom-limited exercise test duration; and a moderate association between ISWT peak heart rate and end of test oxygen saturation and these outcomes on the symptom-limited exercise test (0.47? r2 ?0.67). However, prediction of symptom-limited exercise test duration based on the ISWT produced wide 95% confidence intervals, for example, ranging from 9.1 to 16.3 minutes for an individual who completes the ISWT. Order of testing did not affect the results and the association between the ISWT and symptom-limited exercise test was similar for both the first (ISWT 1) and second test (ISWT 2) ISWT. CONCLUSIONS: The results provide support for the ISWT as a convenient field test of exercise capacity in a cardiac rehabilitation population, but not as a surrogate to predict symptom-limited exercise test duration for individuals. A single ISWT may provide as good an estimate of exercise capacity as repeating the test. PMID- 28730887 TI - A systematic review and meta-analysis of pneumonia associated with thin liquid vs. thickened liquid intake in patients who aspirate. AB - OBJECTIVE: To investigate whether drinking thin liquids with safety strategies increases the risk for pneumonia as compared with thickened liquids in patients who have demonstrated aspiration of thin liquids. DATA SOURCES: Seven electronic databases, one clinical register, and three conference archives were searched. No language or publication date restrictions were imposed. Reference lists were scanned and authors and experts in the field were contacted. REVIEW METHODS: A blind review was performed by two reviewers for published or unpublished randomized controlled trials and prospective non-randomized trials comparing the incidence of pneumonia with intake of thin liquids plus safety strategies vs. thickened liquids in adult patients who aspirated on thin liquids. The data were extracted from included studies. Odds ratios (OR) for pneumonia were calculated from the extracted data. Risk of bias was also assessed with the included published trials. RESULTS: Seven studies out of 2465 studies including 650 patients met the inclusion criteria. All of the seven studies excluded patients with more than one known risk factor for pneumonia. Six studies compared thin water protocols to thickened liquids for pneumonia prevention. A meta-analysis was done on the six studies, showing no significant difference for pneumonia risk (OR = 0.82; 95% CI = 0.05-13.42; p = 0.89). CONCLUSIONS: There was no significant difference in the risk of pneumonia in aspirating patients who took thin liquids with safety strategies compared with those who took thickened liquids only. This result, however, is generalizable only for patients with low risk of pneumonia. PMID- 28730888 TI - Preoperative exercise training prevents functional decline after lung resection surgery: a randomized, single-blind controlled trial. AB - OBJECTIVES: To investigate the effects of a preoperative pulmonary rehabilitation programme in patients with lung cancer undergoing video-assisted thoracic surgery. DESIGN: Randomized, single-blind controlled trial. SETTING: Teaching hospital. SUBJECTS: Patients with suspected or confirmed lung cancer undergoing video-assisted thoracic surgery. INTERVENTION: Participants were randomized to either a prehabilitation group or a control group. Participants in the prehabilitation group underwent a combination of moderate endurance and resistance training plus breathing exercises three to five times per week. MAIN MEASURES: The primary outcome of the study was exercise capacity. Secondary outcomes were muscle strength (Senior Fitness Test), health-related quality of life (Short-Form 36) and the postoperative outcomes. Patients were evaluated at baseline (before randomization), presurgery (only the prehabilitation group), after surgery and three months post-operatively. RESULTS: A total of 40 patients were randomized and 22 finished the study (10 in the prehabilitation group and 12 in the control group). Three patients were lost to follow-up at three months. After the training, there was a statistically significant improvement in exercise tolerance (+397 seconds, p = 0.0001), the physical summary component of the SF-36 (+4.4 points, p = 0.008) and muscle strength ( p < 0.01). There were no significant differences between groups after surgery. However, three months postoperatively, significant differences were found in the mean change of exercise capacity ( p = 0.005), physical summary component ( p = 0.001) and upper and lower body strength ( p = 0.045 and p = 0.002). CONCLUSIONS: A pulmonary rehabilitation programme before video-assisted thoracic surgery seems to improve patients' preoperative condition and may prevent functional decline after surgery. Clinical Registration Number: NCT01963923 (Registration date 10/10/2013). PMID- 28730889 TI - Purposefulness as a critical factor in functioning, disability and health. AB - Guided by theoretical frameworks of health and illness such as the International Classification of Functioning, Disability, and Health (ICF), we seek to describe the importance of purposefulness in the context of rehabilitation. We argue that ascribing meaning to life events, particularly changes in health, and acting in a manner that is driven by purpose is a universal characteristic of human beings. The ability to contextualize purposefulness within the broader biopsychosocial model of illness may provide a greater understanding of the relationship of purpose in the process of rehabilitation. We support the notion that purposefulness is an ever-present component throughout our lives and it exists as a convergence of personal factors, past experiences, and our personal narrative. Having a sense of purposefulness and being able to understand the meaning of different aspects of our lives is what allows us to find purpose while experiencing a health condition. More importantly, and in the context of rehabilitation efforts, we believe that if purposefulness can be identified or collectively defined by the individual, then rehabilitation outcomes may be enhanced. In a variety of contexts ranging from disease, aging, severe trauma, and even war, purposefulness and its component elements consistently distinguish themselves as being essential for regaining a sense of direction and facilitating one's response to any health condition. PMID- 28730891 TI - Introductory paragraph. PMID- 28730890 TI - The biopsychosocial model of illness: a model whose time has come. AB - The biopsychosocial model outlined in Engel's classic Science paper four decades ago emerged from dissatisfaction with the biomedical model of illness, which remains the dominant healthcare model. Engel's call to arms for a biopsychosocial model has been taken up in several healthcare fields, but it has not been accepted in the more economically dominant and politically powerful acute medical and surgical domains. It is widely used in research into complex healthcare interventions, it is the basis of the World Health Organisation's International Classification of Functioning (WHO ICF), it is used clinically, and it is used to structure clinical guidelines. Critically, it is now generally accepted that illness and health are the result of an interaction between biological, psychological, and social factors. Despite the evidence supporting its validity and utility, the biopsychosocial model has had little influence on the larger scale organization and funding of healthcare provision. With chronic diseases now accounting for most morbidity and many deaths in Western countries, healthcare systems designed around acute biomedical care models are struggling to improve patient-reported outcomes and reduce healthcare costs. Consequently, there is now a greater need to apply the biopsychological model to healthcare management. The increasing proportion of healthcare resource devoted to chronic disorders and the accompanying need to improve patient outcomes requires action; better understanding and employment of the biopsychosocial model by those charged with healthcare funding could help improve healthcare outcome while also controlling costs. PMID- 28730892 TI - A systematic review of peer mentoring interventions for people with traumatic brain injury. AB - OBJECTIVE: This systematic review sought evidence concerning the effectiveness of peer mentoring for people with traumatic brain injury. DATA SOURCES: Fourteen electronic databases were searched, including PsycINFO, MEDLINE, CINAHL, EMBASE and the Cochrane Library, from inception to September 21 2016. Ten grey literature databases, PROSPERO, two trials registers, reference lists and author citations were also searched. REVIEW METHODS: Studies which employed a model of one-to-one peer mentoring between traumatic brain injury survivors were included. Two reviewers independently screened all titles and abstracts before screening full texts of shortlisted studies. A third reviewer resolved disagreements. Two reviewers independently extracted data and assessed studies for quality and risk of bias. RESULTS: The search returned 753 records, including one identified through hand searching. 495 records remained after removal of duplicates and 459 were excluded after screening. Full texts were assessed for the remaining 36 studies and six met the inclusion criteria. All were conducted in the United States between 1996 and 2012 and employed a variety of designs including two randomised controlled trials. A total of 288 people with traumatic brain injury participated in the studies. No significant improvements in social activity level or social network size were found, but significant improvements were shown in areas including behavioural control, mood, coping and quality of life. CONCLUSION: There is limited evidence for the effectiveness of peer mentoring after traumatic brain injury. The available evidence comes from small-scale studies, of variable quality, without detailed information on the content of sessions or the 'active ingredient' of the interventions. PMID- 28730893 TI - Multicenter study of genetic abnormalities associated with severe oligospermia and non-obstructive azoospermia. AB - Objective * Chong Xie, Xiangfeng Chen, and Yulin Liu contributed equally to this work. Genetic defects are identified in nearly 20% of infertile males. Determining the frequency and types of major genetic abnormalities in severe male infertility helps inform appropriate genetic counseling before assisted reproductive techniques. Methods Cytogenetic results of 912 patients with non obstructive azoospermia (NOA) and severe oligozoospermia (SOS) in Eastern China were reviewed in this multicenter study from January 2011 to December 2015. Controls were 215 normozoospermic men with offspring. Results Among all patients, 22.6% (206/912) had genetic abnormalities, including 27.3% (146/534) of NOA patients and 15.9% (60/378) of SOS patients. Chromosomal abnormalities (all autosomal) were detected in only 1.9% (4 /215) of controls. In NOA patients, sex chromosomal abnormalities were identified in 25.8% (138/534), of which 8% (43/534) had a 47,XXY karyotype or its mosaic; higher than the SOS group prevalence (1.1%; 4/378). The incidence of Y chromosome microdeletions was lower in the SOS group (13.2%; 50/378) than in the NOA group (17.8%; 95/534). Conclusions The high prevalence of genetic abnormalities in our study indicates the importance of routine genetic testing in severe male infertility diagnosis. This may help determine the choice of assisted reproductive technique and allow specific pre-implantation genetic testing to minimize the risk of transmitting genetic defects. PMID- 28730894 TI - Low 5-HT1B receptor binding in the migraine brain: A PET study. AB - Background The pathophysiology of migraine may involve dysfunction of serotonergic signaling. In particular, the 5-HT1B receptor is considered a key player due to the efficacy of 5-HT1B receptor agonists for treatment of migraine attacks. Aim To examine the cerebral 5-HT1B receptor binding in interictal migraine patients without aura compared to controls. Methods Eighteen migraine patients, who had been migraine free for >48 hours, and 16 controls were scanned after injection of the 5-HT1B receptor specific radioligand [11C]AZ10419369 for quantification of cerebral 5-HT1B receptor binding. Patients who reported migraine <48 hours after the PET examination were excluded from the final analysis. We defined seven brain regions involved in pain modulation as regions of interest and applied a latent variable model (LVM) to assess the group effect on binding across these regions. Results Our data support a model wherein group status predicts the latent variable ( p = 0.038), with migraine patients having lower 5-HT1B receptor binding across regions compared to controls. Further, in a whole-brain voxel-based analysis, time since last migraine attack correlated positively with 5-HT1B receptor binding in the dorsal raphe and in the midbrain. Conclusion We report here for the first time that migraine patients have low 5 HT1B receptor binding in pain modulating regions, reflecting decreased receptor density. This is either a primary constitutive trait of the migraine brain or secondary to repeated exposure to migraine attacks. We also provide indirect support for the dorsal raphe 5-HT1B receptors being temporarily downregulated during the migraine attack, presumably in response to higher cerebral serotonin levels in the ictal phase. PMID- 28730895 TI - Incidence, treatment strategies and outcomes of acute coronary syndrome with and without ongoing myocardial ischaemia: results from the CZECH-3 registry. AB - BACKGROUND: Patients with acute coronary syndrome with signs of ongoing myocardial ischaemia at first medical contact should be indicated for immediate invasive treatment. AIM: To assess the incidence, treatment strategies and outcomes of acute coronary syndrome in a large unselected cohort of patients with respect to the signs of ongoing myocardial ischaemia. METHODS: The CZECH-3 registry included 1754 consecutive patients admitted for suspected acute coronary syndrome to 43 hospitals during a 2-month period in the autumn of 2015. Acute coronary syndrome with ongoing myocardial ischaemia was defined by the presence of persistent/recurrent chest pain/dyspnoea and at least one of the following: persistent ST-segment elevation or depression, bundle branch block, haemodynamic or electric instability due to suspected ischaemia. Major adverse cardiac events (death, reinfarction, stroke, unexpected revascularisation, stent thrombosis) and severe bleeding according to Bleeding Academic Research Consortium criteria were evaluated at 30 days. RESULTS: Acute coronary syndrome was ruled out during the hospital stay in 434 (24.7%) patients. Out of 1280 patients with confirmed acute coronary syndrome, 732 (57%) had clinical signs of ongoing myocardial ischaemia at first medical contact. Coronary angiography was performed in 94.7% of patients with confirmed acute coronary syndrome with ongoing myocardial ischaemia and 89% of patients with confirmed acute coronary syndrome without ongoing myocardial ischaemia ( P<0.001). The major adverse cardiac event rate was 9.8% for patients with confirmed acute coronary syndrome with ongoing myocardial ischaemia and 5.5% for patients without ongoing myocardial ischaemia ( P=0.005), the 30-day severe bleeding rate was 1.6% and 1.5% ( P=1.0). Patients with ongoing myocardial ischaemia admitted to regional hospitals had higher major adverse cardiac event rates compared with patients admitted directly to cardiocentres with percutaneous coronary intervention capability (13.3% vs. 8.2%, P=0.034). CONCLUSIONS: Ongoing myocardial ischaemia was present in more than half of patients hospitalised with acute coronary syndrome. These very high-risk patients may benefit from direct admission to percutaneous coronary intervention-capable centres. PMID- 28730896 TI - Cannabinoid hyperemesis syndrome: potential mechanisms for the benefit of capsaicin and hot water hydrotherapy in treatment. AB - INTRODUCTION: Cannabinoid hyperemesis syndrome is a clinical disorder that has become more prevalent with increasing use of cannabis and synthetic cannabinoids, and which is difficult to treat. Standard antiemetics commonly fail to alleviate the severe nausea and vomiting characteristic of the syndrome. Curiously, cannabinoid hyperemesis syndrome patients often report dramatic relief of symptoms with hot showers and baths, and topical capsaicin. OBJECTIVES: In this review, we detail the pharmacokinetics and pharmacodynamics of capsaicin and explore possible mechanisms for its beneficial effect, including activation of transient receptor potential vanilloid 1 and neurohumoral regulation. Putative mechanisms responsible for the benefit of hot water hydrotherapy are also investigated. METHODS: An extensive search of PubMed, OpenGrey, and Google Scholar from inception to April 2017 was performed to identify known and theoretical thermoregulatory mechanisms associated with the endocannabinoid system. The searches resulted in 2417 articles. These articles were screened for relevant mechanisms behind capsaicin and heat activation having potential antiemetic effects. References from the selected articles were also hand searched. A total of 137 articles were considered relevant and included. Capsaicin: Topical capsaicin is primarily used for treatment of neuropathic pain, but it has also been used successfully in some 20 cases of cannabinoid hyperemesis syndrome. The pharmacokinetics and pharmacodynamics of capsaicin as a transient receptor potential vanilloid 1 agonist may explain this effect. Topical capsaicin has a longer half-life than oral administration, thus its potential duration of benefit is longer. Capsaicin and transient receptor potential vanilloid 1: Topical capsaicin binds and activates the transient receptor potential vanilloid 1 receptor, triggering influx of calcium and sodium, as well as release of inflammatory neuropeptides leading to transient burning, stinging, and itching. This elicits a novel type of desensitization analgesia. Transient receptor potential vanilloid 1 receptors also respond to noxious stimuli, such as heat (>43 degrees C), acids (pH <6), pain, change in osmolarity, and endovanilloids. The action of topical capsaicin may mimic the effect of heat activation of transient receptor potential vanilloid 1. Endocannabinoid system and transient receptor potential vanilloid 1: Cannabinoid hyperemesis syndrome may result from a derangement in the endocannabinoid system secondary to chronic exogenous stimulation. The relief of cannabinoid hyperemesis syndrome symptoms from heat and use of transient receptor potential vanilloid 1 agonists suggests a complex interrelation between the endocannabinoid system and transient receptor potential vanilloid 1. Temperature regulation: Hot water hydrotherapy is a mainstay of self-treatment for cannabinoid hyperemesis syndrome patients. This may be explained by heat-induced transient receptor potential vanilloid 1 activation. "Sensocrine" antiemetic effects: Transient receptor potential vanilloid 1 activation by heat or capsaicin results in modulation of tachykinins, somatostatin, pituitary adenylate-cyclase activating polypeptide, and calcitonin gene-related peptide as well as histaminergic, cholinergic, and serotonergic transmission. These downstream effects represent further possible explanations for transient receptor potential vanilloid 1-associated antiemesis. CONCLUSIONS: These complex interactions between the endocannabinoid systems and transient receptor potential vanilloid 1, in the setting of cannabinoid receptor desensitization, may yield important clues into the pathophysiology and treatment of cannabinoid hyperemesis syndrome. This knowledge can provide clinicians caring for these patients with additional treatment options that may reduce length of stay, avoid unnecessary imaging and laboratory testing, and decrease the use of potentially harmful medications such as opioids. PMID- 28730897 TI - Intervention and management of developmental coordination disorder: Are we providing evidence-based services?: Intervention et traitement d'un trouble du developpement de la coordination : Les ergotherapeutes fournissent-ils des services fondes sur les faits scientifiques? AB - BACKGROUND: Occupational therapists are well positioned to provide intervention to improve outcomes for children with developmental coordination disorder. However, little is known about what occupational therapy services are provided for these children. PURPOSE: As part of a larger study exploring service provision for children with developmental coordination disorder, the purpose of this study was to examine intervention and referral practices of occupational therapists in British Columbia, Canada. METHOD: An online survey was e-mailed to a convenience and snowball sample of paediatric occupational therapists, with 165 therapists responding. Descriptive statistics were used for the data analysis. FINDINGS: Results show that the type and duration of intervention varied greatly throughout the province, as well as within health regions. Although 70% (87/124) of therapists reported being at least moderately familiar with current evidence, only 47% to 59% selected task-based methods as their primary intervention approach. IMPLICATIONS: Findings provide a baseline for current intervention and an opportunity for targeted knowledge translation initiatives. PMID- 28730899 TI - Rethinking enabling occupational performance: Can the self-driving car be our road map? PMID- 28730900 TI - Falls prevention interventions for older adults with low vision: A scoping review: Etude de portee sur les interventions visant a prevenir les chutes chez les aines ayant une basse vision. AB - BACKGROUND: Older adults with low vision are especially vulnerable to falls. There are no comprehensive reviews of fall prevention interventions for older adults with vision loss who live in the community. PURPOSE: The aim of this study was to review the evidence regarding community-based falls prevention interventions that appear inclusive of and/or accessible to individuals with low vision. METHOD: A scoping review was completed using the framework developed by Arksey and O'Malley, and the charted data were analyzed using sums and percentages and qualitative content analysis. FINDINGS: Seventeen publications were selected for this review. The analysis allowed for a thorough description of the types of falls prevention interventions (multiple components, home safety/modification, tai chi, the Alexander Technique, improvement of vision through vision assessment and referral, vision/agility training, and yoga), how each intervention addresses vision impairment, and the relation of results to falls risk. IMPLICATIONS: Falls prevention research targeting individuals with visual impairment is limited, and the intervention approaches available may not be effective for older adults with permanent vision loss. PMID- 28730902 TI - Relationships between adolescent body mass index, physical activity, and sensory processing patterns: Relations entre l'indice de masse corporelle, l'activite physique et les schemes d'integration sensorielle des adolescents. AB - BACKGROUND: Trends show a significant decline with adolescent physical activity (PA). Knowledge regarding how sensory-processing patterns and body mass index (BMI) relate to adolescents' PA participation is scarce. PURPOSE: This study investigated if relationships exist between adolescent BMI, sensory processing, and PA participation. METHOD: This correlational study collected data from 141 adolescents who completed the Adolescent/Adult Sensory Profile and the Physical Activity Questionnaire-Adolescent. Their BMIs were calculated using self-reported age, height, and weight. The data were analyzed using descriptive statistics and two-tailed Spearman's rank correlation coefficients. FINDINGS: Adolescents with different sensory-processing patterns reported participation in both similar and distinct PAs. Participation in PA and BMI shared no significant correlation. Sensory sensitivity and BMI total ( rs = -.171, p = .044) and BMI percentile ( rs = -.191, p = .024) demonstrated significant correlations. Analysis revealed a correlation between sensory seeking patterns and PA ( rs = .224, p = .008) as well as correlations among sensory quadrants and participation in specific PAs. IMPLICATIONS: Occupational therapists should consider an adolescent's sensory preferences when recommending PA interventions. PMID- 28730904 TI - Occupational therapists' awareness of guidelines for assessment and diagnosis of developmental coordination disorder: Mesure selon laquelle les ergotherapeutes connaissent les lignes directrices relatives a l'evaluation et au diagnostic du trouble du developpement de la coordination. AB - BACKGROUND: Developmental coordination disorder (DCD) is a motor skills disorder that can have negative lifelong psychosocial impacts if not diagnosed. Occupational therapists have a role in facilitating a diagnosis for children with DCD through assessment. PURPOSE: The purpose of this study was to determine the level of understanding of current DCD guidelines for assessment and diagnosis among occupational therapists working in paediatric settings in British Columbia, Canada. METHOD: An online survey was e-mailed to occupational therapists who consented to be contacted for research purposes; 169 paediatric therapists responded. Data were reported using percentage, mean, and standard deviation of responses for each answer. FINDINGS: Although many occupational therapists are aware of DCD and the diagnostic criteria, most are unaware of current guidelines for assessment and diagnosis. Many are using cutoff scores inconsistent with current recommendations and thus may not be facilitating a diagnosis when one may be appropriate. IMPLICATIONS: Occupational therapists may benefit from targeted education regarding DCD assessment and diagnosis. PMID- 28730906 TI - Mortality, intensive care treatment, and cost evaluation: Role of a polymerase chain reaction assay in patients with sepsis. AB - Objective We examined whether patients with a positive SeptiFast (SF) assay (LightCycler SeptiFast; Roche Diagnostics, Basel, Switzerland) developed higher long-term mortality, a more difficult course of treatment, and a higher antimicrobial treatment cost than patients with a negative SF assay. Methods We performed a post-hoc analysis of data collected in a 1-year prospective interventional study of adults with severe sepsis and septic shock. In addition to the standard treatment, an additional 5 ml of blood was obtained for an SF assay, and the antimicrobial treatment was changed according to the SF results. Results We included 57 patients, and the SF assay was positive (SF+) in 10 (17.5%) and negative (SF-) in 47 (82.5%) patients. A trend toward a higher 6 month, 1-year, and 2-year mortality rate was observed in the SF+ group. In the SF+ group, we observed a significantly greater need for second-line vasopressor therapy, a higher initial procalcitonin concentration, and higher maximum C reactive protein and lactate concentrations. We found no significant differences in cost of antimicrobial treatment between the SF+ and SF- groups. Conclusions We observed a trend toward higher long-term mortality and a more difficult course of treatment but no difference in the cost of antimicrobial treatment. PMID- 28730907 TI - The rs10229583 polymorphism near paired box gene 4 is associated with gestational diabetes mellitus in Chinese women. AB - Objective The rs10229583 polymorphism near paired box gene 4 ( PAX4) is associated with insulin resistance and type 2 diabetes. Mutations in the PAX4 gene may be associated with impaired differentiation/development of pancreatic islet beta cells during fetal development and, consequently, a compromised insulin response to high blood glucose. To ascertain whether this polymorphism plays a role in gestational diabetes mellitus (GDM), we investigated the genotypic and allele frequency differences between GDM and normal pregnancies. Methods A total of 310 GDM and 440 normal pregnancies were evaluated. Allele and genotype frequencies of rs10229583 were determined for all participants with Sanger sequencing and SNaPshot. Association of the allele and genotypes of the single nucleotide polymorphism with the disease was analyzed using Pearson's chi2 test and OR (odds ratio). Results The G allele was more frequent in patients with GDM compared with controls (OR = 1.47, 95% confidence interval (CI): 1.12-1.939). The GG genotype frequency of rs10229583 was significantly different between subjects with GDM and normal controls (OR = 1.411, 95% CI: 1.032-1.928). The OR of the GA + GG genotype was 3.182 (95% CI: 1.294-7.826) for patients with GDM compared with controls. Conclusion The present study suggests that rs10229583 is associated with GDM. PMID- 28730908 TI - Electrical stimulation for the treatment of obstructive sleep apnoea: a review of the evidence. AB - INTRODUCTION: Obstructive sleep apnoea is an increasingly prevalent clinical condition with significant impact on individuals and public health. Continuous positive airway pressure therapy is the standard treatment, but adherence is limited and alternative treatments are needed. In this context, non-invasive and invasive methods for the electrical stimulation of upper airway dilator muscles have been demonstrated to be effective in selected patients. Areas covered: This review will cover investigations on the clinical effects, safety, and tolerability of non-invasive and invasive electrical stimulation of the upper airway for the management of obstructive sleep apnoea. Following a search of the relevant literature published on PubMed this review is focused mainly on data obtained from randomized clinical trials and clinical studies. Expert commentary: The available evidence provides a rationale to consider upper airway electrical stimulation as treatment for selected patients with obstructive sleep apnoea, who have poor adherence or experience difficulties with continuous positive airway pressure therapy. Non-invasive stimulation using transcutaneous electrodes and implantable hypoglossal nerve stimulator technologies may provide an alternative to continuous positive airway pressure for the treatment of obstructive sleep apnoea via restoration of neuromuscular tone and improved upper airway patency. PMID- 28730910 TI - The Brief Peer Conflict Scale: Psychometric Properties Among a Sample of Incarcerated Male Juvenile Offenders. AB - Aggression can be considered a multidimensional construct that influences various forms of antisocial behavior, including juvenile delinquency and conduct problems. The aim of the present study was to assess the psychometric properties of the Brief Peer Conflict Scale-20 item version (PCS-20) among a Portuguese forensic sample (N = 192) of incarcerated male juvenile offenders ( M = 16.62 years; SD = 1.52 years; age range = 13-18 years). The PCS-20 demonstrated good psychometric properties in terms of its four-factor structure, internal consistency, convergent validity, and discriminant validity that generally justify its use among incarcerated male youth. The findings provide additional support for the extension of the PCS-20 across different cultures, ethnic groups, and samples. PMID- 28730909 TI - Dramatic response of acute disseminated intravascular coagulation to erlotinib in a patient with lung adenocarcinoma with activating EGFR mutation. AB - Disseminated intravascular coagulation (DIC) is a commonly encountered clinical situation characterized by thrombotic occlusion or bleeding in patients with lung cancer. DIC in patients with cancer is usually asymptomatic, taking a chronic form as a compensatory mechanism. Although acute DIC in patients with lung cancer is rarely reported, it can be fatal. We herein describe a patient with lung adenocarcinoma with an activating mutation of the epidermal growth factor receptor (EGFR) gene who developed acute DIC after minor surgical excision. The patient's condition dramatically improved immediately after administration of erlotinib. This report alerts physicians to the occurrence of acute DIC and serves as a reference in treating EGFR mutation-positive lung cancer in patients with DIC. PMID- 28730911 TI - Important learning factors in high- and low-achieving students in undergraduate biomechanics. AB - The purpose of the present study was to document crucial factors associated with students' learning of biomechanical concepts, particularly between high- and-low achieving students. Students (N = 113) from three introductory biomechanics classes at two public universities volunteered for the study. Two measures of students' learning were obtained, final course grade and improvement on the Biomechanics Concept Inventory version 3 administered before and after the course. Participants also completed a 15-item questionnaire documenting student learning characteristics, effort, and confidence. Partial correlations controlling for all other variables in the study, confirmed previous studies that students' grade point average (p < 0.01), interest in biomechanics, (p < 0.05), and physics credits passed (p < 0.05) are factors uniquely associated with learning biomechanics concepts. Students' confidence when encountering difficult biomechanics concepts was also significantly (p < 0.05) associated with final grade. There were significant differences between top 15% and bottom 15% achievers on these variables (p < 0.05), as well as on readings completed, work to pay for college per week, and learning epistemology. Consequently, instructors should consider strategies to promote students' interest in biomechanics and confidence in solving relevant professional problems in order to improve learning for both low- and high-ability students. PMID- 28730912 TI - RHD-specific microRNA for regulation of the DEL blood group: integration of computational and experimental approaches. AB - OBJECTIVE: The discovery of specific microRNAs (miRNA) mediates a better understanding of molecular mechanisms, diagnosis and prognosis of complex phenotypes. Synthesis of the RhD blood group involves multiple factors causing variation in the expression of RHD antigens. The mechanism underlying the extremely weak expression of RHD antigen associated with the RHD variant called DEL (D-elute) is incompletely understood. Down-regulation of gene expression through miRNA is a guide to the potential involvement of miRNAs in the DEL blood group. In order to determine the association of miRNAs and Rh-DEL blood donors with DEL variant, we investigated the expression level RHD-specific miRNA. METHODS: Blood samples were serologically tested for RhD blood group determination. DNA was analysed using SSP-PCR for the Asian-type DEL allele (RHD 1227 G>A). Bioinformatics analyses were applied for prediction of candidate RHD specific miRNA. The RHD-specific miRNA expression level was quantitated using a real-time-qPCR approach. The miRNA expression levels of various RhD blood groups were compared and statistically analysed. RESULTS: The bioinformatics tools (n = 3) for prediction of miRNA targeting on RHD identified miR-98 as the miRNA potentially specific for the 3' UTR of RHD. The relative expression levels of miR 98 among D-positive (n = 50), D-negative (n = 49) and DEL (n = 63) subjects showed no statistically significant differences (P-values = 0.58). CONCLUSION: This is the first attempt to determine whether miR-98 is involved in RHD expression using computational and experimental approaches. Further investigations are necessary to fully characterize the miRNA genetics in DEL blood group regulation. PMID- 28730913 TI - Delta HR/BT as a possible predictor of severity or mortality, not a predictor of bacterial infection. PMID- 28730914 TI - The health-economic studies of HPV vaccination in Southeast Asian countries: a systematic review. AB - INTRODUCTION: The cervical cancer-related burden is an important problem in Southeast Asian (SEA) countries. However, only 3 out of 11 countries implement the comprehensive prevention program. Areas covered: This is a retrospective review from all relevant studies until 2015 from two main databases, MEDLINE/Pubmed and Embase in order to provide an evidence on the health economics of HPV vaccination in the region. Expert commentary: The implementation of HPV vaccination will generate substantial health and economic benefit in SEA countries since the number of cervical cancer cases in this region are generally high. Therefore, a clear recommendation on how HPV vaccination should be implemented in a country, for example on how many doses will be used, how much cost is required or is it a school based- or clinical based-delivery, is critically required. PMID- 28730916 TI - Left main coronary artery stenosis due to a protruding calcified nodule. PMID- 28730915 TI - Burnout among Danish prison personnel: A question of quantitative and emotional demands. AB - : Objectives The objective of this follow-up study was to investigate associations between individual, occupational and work environment factors and burnout among both uniformed and non-uniformed personnel working in the Danish Prison and Probation Service. Methods The participants (N = 4808) with client contact received a questionnaire in 2010 and again in 2011. In 2010, 2843 participants responded to the questionnaire (59.1%), and in 2011, 1741 responded to the questionnaire, yielding a response rate of 61.2% of the baseline population, and 36.2% of the invited population. Burnout and work characteristics were measured with validated scales from the Copenhagen Psychosocial Questionnaire, and data was analysed by logistic regression. Results Risk factors with the highest impact on burnout were work environmental factors: quantitative demands, emotional demands, involvement in and meaning of work. Role conflict, role clarity, social support and demands for hiding emotions had borderline significance. Besides cohabitation, there was no association between individual factors and burnout or between occupational characteristics and burnout. Moreover, there was no association between exposure to threats and violence and burnout. CONCLUSIONS: Efforts for preventing burnout ought to be concentrated on reducing the quantitative job-demands, on easing and improving staff-inmate relationships, but also on involvement in and meaning of work. Most work in prison is invisible and the overall goals are in conflict with each other. Management must provide solutions to problems of role conflict and support groups for social support. There is a risk of burnout among both uniformed personnel and non-uniformed personnel working in both open and closed facilities. PMID- 28730917 TI - Novice runners show greater changes in kinematics with fatigue compared with competitive runners. AB - Fatigue, developed over the course of a run, may cause changes in running kinematics. Training status may influence the effect of fatigue on running kinematics, since well trained, competitive runners are used to running until exhaustion, whereas novice runners are not. This study aimed to determine changes in running kinematics during an exhaustive run in both novice (NOVICE) and competitive (COMP) long-distance runners. About 15 NOVICE and 15 COMP runners performed a treadmill run, until voluntary exhaustion at 3,200 m time trial pace. Joint angles and global trunk and pelvis angles were recorded at the beginning and at the end of the run. In both groups, peak pelvic anterior tilt, pelvic rotation range of motion (both during stance phase) and ankle plantar flexion during swing phase increased after the exhaustive run. There was a significant interaction effect between group and exhaustion for peak forward trunk lean, which increased only in the NOVICE group, and for hip abduction during mid-swing, which increased in NOVICE and decreased in COMP runners. In conclusion, NOVICE runners showed larger kinematic adjustments when exhausted than COMP runners. This may affect their running performance and should be taken into account when assessing a runner's injury risk. PMID- 28730918 TI - Clinical and economic implications of urinary tract infections. AB - INTRODUCTION: Urinary tract infections represent one of the most frequent reasons for hospitalization. As a result of their prevalence from community-based origins as well as those which develop in hospital setting, this constellation of infections represents a tremendous burden to the global healthcare system. Areas covered: Over the last several decades the management of these infections has become more complicated due to the underlying comorbid conditions of the patients as well as escalating antimicrobial resistance to many of the most frequently used oral and parenteral agents. One such example is the emergence of extend spectrum beta-lactamase-producing (ESBL) bacteria that render many of the most frequently utilized oral and parenteral penicillin and cephalosporin based regimens of little clinical utility. As such new treatment strategies are required to effectively manage the growing population of patients with multi-drug resistant bacteria. Expert commentary: Herein, we review some of the current literature which reveals the challenges associated with the contemporary management of UTIs, while presenting strategies such as the implementation of clinical pathways that have the potential to enhance the quality and efficiency of care while reducing the overall cost of care. PMID- 28730919 TI - An update on biomarker discovery and use in systemic sclerosis. AB - INTRODUCTION: Systemic sclerosis (SSc) is an autoimmune disease characterized by excessive extracellular matrix deposition in the skin and internal organs. Three major abnormalities, autoimmunity, vasculopathy, and fibrosis, are considered to play important roles in the pathophysiology of SSc. SSc is a heterogeneous disease with clinical features, disease progress, therapeutic response, and prognosis. Therefore, identification of biomarkers, which can predict the course of the disease, is required for the progress of clinical practice. Areas covered: This review focuses on various SSc biomarkers for diagnosis, disease severity, and activity, as well as newly emerging and promising SSc biomarkers. Search was through PubMed and we focus on the papers in the last 5 years. Expert commentary: Biomarkers for SSc can be categorized into several groups: activity biomarker, severity biomarker, predictive biomarker, and biomarkers for specific clinical features (skin fibrosis, lung fibrosis, pulmonary arterial hypertension, peripheral vasculopathy, gastrointestinal, and malignancy). Some chemokines, such as CCL2 and CXCL4, have been identified as biomarkers of skin and lung fibrosis in SSc. In addition, anti-RNA polymerase III antibody has been noted to be a predictive biomarker of gastric antral vascular ectasia and malignancy. PMID- 28730920 TI - Validity of a device designed to measure braking power in bicycle disc brakes. AB - Real-world cycling performance depends not only on exercise capacities, but also on efficiently traversing the bicycle through the terrain. The aim of this study was to determine if it was possible to quantify the braking done by a cyclist in the field. One cyclist performed 408 braking trials (348 on a flat road; 60 on a flat dirt path) over 5 days on a bicycle fitted with brake torque and angular velocity sensors to measure brake power. Based on Newtonian physics, the sum of brake work, aerodynamic drag and rolling resistance was compared with the change in kinetic energy in each braking event. Strong linear relationships between the total energy removed from the bicycle-rider system through braking and the change in kinetic energy were observed on the tar-sealed road (r2 = 0.989; p < 0.0001) and the dirt path (r2 = 0.952; p < 0.0001). T-tests revealed no difference between the total energy removed and the change in kinetic energy on the road (p = 0.715) or dirt (p = 0.128). This study highlights that brake torque and angular velocity sensors are valid for calculating brake power on the disc brakes of a bicycle in field conditions. Such a device may be useful for investigating cyclists' ability to traverse through various terrains. PMID- 28730921 TI - Kinematic repeatability of a multi-segment foot model for dance. AB - The purpose of this study was to determine the intra and inter-assessor repeatability of a modified Rizzoli Foot Model for analysing the foot kinematics of ballet dancers. Six university-level ballet dancers performed the movements; parallel stance, turnout plie, turnout stance, turnout rise and flex-point-flex. The three-dimensional (3D) position of individual reflective markers and marker triads was used to model the movement of the dancers' tibia, entire foot, hindfoot, midfoot, forefoot and hallux. Intra and inter-assessor reliability demonstrated excellent (ICC >= 0.75) repeatability for the first metatarsophalangeal joint in the sagittal plane. Intra-assessor reliability demonstrated excellent (ICC >= 0.75) repeatability during flex-point-flex across all inter-segmental angles except for the tibia-hindfoot and hindfoot-midfoot frontal planes. Inter-assessor repeatability ranged from poor to excellent (0.5 > ICC >= 0.75) for the 3D segment rotations. The most repeatable measure was the tibia-foot dorsiflexion/plantar flexion articulation whereas the least repeatable measure was the hindfoot-midfoot adduction/abduction articulation. The variation found in the inter-assessor results is likely due to inconsistencies in marker placement. This 3D dance specific multi-segment foot model provides insight into which kinematic measures can be reliably used to ascertain in vivo technical errors and/or biomechanical abnormalities in a dancer's foot motion. PMID- 28730922 TI - Investigating the ways in which health information technology can promote antimicrobial stewardship: a conceptual overview. AB - Antimicrobial resistance is now recognised as a threat to health worldwide. Antimicrobial stewardship aims to promote the responsible use of antibiotics and is high on international and national policy agendas. Health information technology has the potential to support antimicrobial stewardship in a number of ways, but this field is still poorly characterised and understood. Building on a recent systematic review and expert roundtable discussions, we take a lifecycle perspective of antibiotic use in hospitals and identify potential targets for health information technology-based interventions to support antimicrobial stewardship. We aim for this work to help chart a future research agenda in this critically important area. PMID- 28730923 TI - An epidemic of overdiagnosis and overtreatment: getting to the heart of the problem. PMID- 28730924 TI - What lessons can the National Health Service learn from an 'upside-down' management style? PMID- 28730925 TI - Leadership of population healthcare. PMID- 28730926 TI - Value of CHA2DS2-VASc score and gender in predicting PCI outcomes in ST segment elevation myocardial infarction. PMID- 28730927 TI - Pathways to experiencing mental problems and need for mental support in patients with pulmonary arterial hypertension. AB - Pulmonary arterial hypertension (PAH) affects the physical and emotional wellbeing of patients. More information is needed regarding mental problems and preferences for support. Qualitative interviews were used to explore mental problems and preference for support of PAH patients. Additionally, a survey was used to assess the presence of mental problems (Problem List), distress (Distress Thermometer) and the need for mental support. In 24 semi-structured interviews, the following problem themes were identified: energy balance; loss of abilities; feeling misunderstood; and handling of worries and emotions. Need for support was based on an interplay between resilience to psychological distress, additional life problems, age, disease status, attitude towards professional help, and experienced support from significant others. The results from the survey highlight the need for professional support, as 50.8% of the 67 patients who completed the survey would consider support when offered, specifically when offered by a pulmonary hypertension (PH) professional. Younger age (odds ratio [OR] = 0.97, P = 0.04), depression (OR = 11.435, P = 0.001) and possibly anxiety (OR = 3.831, P = 0.069) were related to need for support. In conclusion, many patients with PAH are in need of mental support, which should be offered by a PH professional and tailored to phase of the disease and personal characteristics. PMID- 28730928 TI - Feasibility of Na18F PET/CT and MRI for Noninvasive In Vivo Quantification of Knee Pathophysiological Bone Metabolism in a Canine Model of Post-traumatic Osteoarthritis. AB - PURPOSE: To assess and quantify by molecular imaging knee osseous metabolic changes serially in an in vivo canine model of posttraumatic osteoarthritis (PTOA) of the knee utilizing sodium fluoride (Na18F) positron emission tomography (PET)/computed tomography (CT) coregistered with magnetic resonance imaging (MRI). MATERIALS AND METHODS: Sodium fluoride PET imaging of 5 canines was performed prior to anterior cruciate ligament transection (ACLT) and 2 times post ACLT (3 and 12 weeks). The PET/CT was coregistered with MRI, enabling serial anatomically guided visual and quantitative three-dimensional (3D) region of interest (ROI) assessment by maximum standardized uptake value. RESULTS: Prior to ACLT, every 3D ROI assessed in both knees showed no Na18F uptake above background. The uptake of Na18F in the bone of the ACLT knees increased exponentially, presenting significantly higher uptake at 12 weeks in every region compared to the ACLT knees at baseline. Furthermore, the uninjured contralateral limb and the ipsilateral distal bones and joints presented Na18F uptake at 3 and 12 weeks post-ACLT. CONCLUSION: This study demonstrated that Na18F PET/CT coregistered with MRI is a feasible molecular imaging biomarker to assess knee osseous metabolic changes serially in an in vivo canine model of knee PTOA. Moreover, it brings a novel musculoskeletal preclinical imaging methodology that can provide unique insights into PTOA pathophysiology. PMID- 28730930 TI - Empowerment: challenges in measurement. AB - Empowerment is core to health promotion; however, there is a lack of consensus in the wider literature as to how to define it and at what level it may occur. Definitional inconsistency inevitably leads to challenges in measuring empowerment; yet if it is as important as is claimed, this must be addressed. This paper discusses the complexities of measuring empowerment and puts forward a number of recommendations for researchers and policy makers as to how this can be achieved noting some of the tensions that may arise between theoretical considerations, research and practice. We argue that empowerment is a culturally and socially defined construct and that this should be taken into account in attempts to measure it. Finally we conclude that, in order to build up the evidence base for empowerment, there is a need for research clearly defining what it is and how it is being measured. PMID- 28730929 TI - Development of a screening tool to predict malnutrition among children under two years old in Zambia. AB - BACKGROUND: Maternal and child undernutrition is an important issue, particularly in low- and middle-income countries. Children at high risk of malnutrition should be prioritized to receive necessary interventions to minimize such risk. Several risk factors have been proposed; however, until now, there has been no appropriate evaluation method to identify these children. In sub-Saharan Africa, children commonly receive regular check-ups from community health workers. A simple and easy nutrition assessment method is therefore needed for use by semi professional health workers. OBJECTIVES: The aim of this study was to develop and test a practical screening tool for community use in predicting growth stunting in children under two years in rural Zambia. METHODS: Field research was conducted from July to August 2014 in Southern Province, Zambia. Two hundred and sixty-four mother-child pairs participated in the study. Anthropometric measurements were performed on all children and mothers, and all mothers were interviewed. Risk factors for the screening test were estimated by using least absolute shrinkage and selection operator analysis. After re-evaluating all participants using the new screening tool, a receiver operating characteristic curve was drawn to set the cut-off value. Sensitivity and specificity were also calculated. RESULTS: The screening tool included age, weight-for-age Z-score status, birth weight, feeding status, history of sibling death, multiple birth, and maternal education level. The total score ranged from 0 to 22, and the cut off value was eight. Sensitivity and specificity were 0.963 and 0.697 respectively. CONCLUSIONS: A screening tool was developed to predict children at high risk of malnutrition living in Zambia. Further longitudinal studies are needed to confirm the test's validity in detecting future stunting and to investigate the effectiveness of malnutrition treatment. PMID- 28730931 TI - A Reading Model from the Perspective of Japanese Orthography: Connectionist Approach to the Hypothesis of Granularity and Transparency. AB - This study presents a computer simulation model of reading in Japanese syllabic kana and morphographic kanji. The model was based on the simulation model developed by Harm and Seidenberg for reading in English. The purpose of building the current model was to verify the validity of the hypothesis of granularity and transparency (HGT) postulated by Wydell and Butterworth, focusing on the granularity dimension. The HGT was developed in order to explain the behavioral dissociation between excellent reading skills in Japanese and poor reading skills in English of an English-Japanese bilingual individual as well as the relatively low incidence of developmental dyslexia in Japan. The current model was successful in simulating the granularity dimension of the HGT. The study also identified several limitations, which need to be addressed in future research. PMID- 28730933 TI - Drug delivery to the lungs: challenges and opportunities. AB - Pulmonary drug delivery is relatively complex because the respiratory tract has evolved defense mechanisms to keep inhaled drug particles out of the lungs and to remove or inactivate them once deposited. In addition to these mechanical, chemical and immunological barriers, pulmonary drug delivery is adversely affected by the behavioral barriers of poor adherence and poor inhaler technique. Strategies to mitigate the effects of these barriers include use of inhaler devices and formulations that deliver drug to the lungs efficiently, appropriate inhaler technique and improved education of patients. Owing to the advantages offered by the pulmonary route, the challenges that the route poses are worth addressing, and if successfully addressed, the pulmonary route offers huge opportunities, often fulfilling unmet clinical needs. PMID- 28730932 TI - Effect-site concentration of remifentanil required to blunt haemodynamic responses during tracheal intubation: A randomized comparison between single- and double-lumen tubes. AB - Objective To investigate the effect-site concentration of remifentanil required to blunt haemodynamic responses during tracheal intubation with a single-lumen tube (SLT) or a double-lumen tube (DLT). Methods Patients scheduled for thoracic surgery requiring one-lung ventilation were randomly allocated to either the SLT or DLT group. All patients received a target-controlled infusion of propofol and a predetermined concentration of remifentanil. Haemodynamic parameters during intubation were recorded. The effect-site concentration of remifentanil was determined using a delayed up-and-down sequential allocation method. Results A total of 92 patients were enrolled in the study. The effective effect-site concentrations of remifentanil required to blunt haemodynamic responses in 50% of patients (EC50) estimated by isotonic regression with bootstrapping was higher in the DLT than the SLT group (8.5 ng/ml [95% confidence interval (CI) 8.0-9.5 ng/ml] versus 6.5 ng/ml [95% CI 5.6-6.7 ng/ml], respectively). Similarly, the effective effect-site concentrations of remifentanil in 95% of patients in the DLT group was higher than the SLT group (9.9 ng/ml [95% CI 9.8-10.0 ng/ml] versus 7.0 ng/ml [95% CI 6.9-7.0 ng/ml], respectively). Conclusions This study demonstrated that a DLT requires a 30% higher EC50 of remifentanil than does an SLT to blunt haemodynamic responses during tracheal intubation when combined with a target-controlled infusion of propofol. Trial registration Clinicaltrials.gov identifier: NCT01542099. PMID- 28730934 TI - Challenges in oral peptide delivery: lessons learnt from the clinic and future prospects. AB - Therapeutic peptides have become very successful drugs due to their specificity, potency and low toxicity, but they show challenges for their delivery, due to their short half-life and rapid plasma clearance. For these reasons, peptides are usually administered using injectable sustained-release formulations. Oral peptide route is highly compelling from a patient and commercial point of view. However, poor peptide stability and low permeability across the intestinal epithelium still make it very challenging to effectively deliver peptides by the oral route. In this paper, biopharmaceutical and formulation features of oral peptides, as well as key clinical outcomes, are reviewed and discussed in the perspective of designing next generation of oral peptide formulations for a true paradigm shift. PMID- 28730935 TI - Effect of directly compressible excipient and treated agar on drug release of clopidogrel oral disintegrating tablets. AB - AIM: In the present investigation, oral dissolving/dispersible/disintegrating tablets (ODTs) of clopidogrel were designed with a view to enhance the bioavailability and patient compliance by two different methods, namely, direct compression and effervescent methods using directly compressible excipient and treated agar (TAG). MATERIALS & METHODS: In the direct compression method, TAG was used as a disintegrant and another method used a mixture of sodium bicarbonate and tartaric acid along with TAG as disintegrants. RESULTS: Among the directly compressed tablets, treated agar formulation 3 and among the effervescent tablets, treated agar and effervescent formulation 4 was found to be promising. CONCLUSION: Treated agar formulation 3 prepared by direct compression method emerged as an overall best formulation based on the in vitro drug release characteristics. PMID- 28730936 TI - An industry update: what is the latest news in therapeutic delivery? AB - This Industry Update covers the period from 1 through 30 April 2017, and is based on information sourced from company press releases, scientific literature, patents and various news websites. Biogen expanded its portfolio of developmental drugs targeting neurological diseases by licensing a drug from Bristol-Myers Squibb which is currently under investigation for the treatment of progressive supranuclear palsy. Takeda announced a deal with NuBiyota focused on developing treatments for gastrointestinal disorders, based on the manipulation of microbes living in the gut. Novartis announced an expansion of its neuroscience collaboration with Amgen as well as licensing of a developmental compound to treat dry eye. EmulateBio announced a collaboration with the US FDA to explore and evaluate its organs-on-chip technology in toxicological testing of food products, but which has wider opportunities in drug development. In the treatment of pulmonary hypertension, Vectura announced the commercial launch of its Fox nebulizer technology to deliver a Bayer drug and Respira announced a deal in which it exclusively licensed an inhaled drug-device product to United Therapeutics. Published research suggested that the benefit of pumps over multiple injections in the treatment of diabetes maybe more due to training than technology, and a group from the University of Pennsylvania showed that electrical stimulation of the brain can improve memory function but only when applied at the right time. Alzheon published work that explains the mechanism behind its developmental Alzheimer's drug. PMID- 28730937 TI - Clay-based drug-delivery systems: what does the future hold? AB - Clays for drug delivery have been used from ancient time due to the large availability of clay minerals and their unprecedented properties. The empirical use of nanoclays from the past is converted in a stimulating scientific task aimed at building up nanoarchitectonic vehicles for drug delivery in a targeted and stimuli-responsive fashion. Here the historical aspects are discussed; next the modern examples of applications of different clay-based materials are discussed. A special focus is given to halloysite clay nanotubes, which are an emerging and very promising nanomaterial for drug-delivery purposes due to its special morphology and unique chemical properties. Advantages and limitations of these natural nanomaterials are critically discussed pointing out the future perspectives and directions for further research. PMID- 28730938 TI - Stratum corneum modulation by chemical enhancers and lipid nanostructures: implications for transdermal drug delivery. AB - Skin is the outermost and largest protective covering of the body. The uppermost layer of the skin, stratum corneum also called the horny layer is composed of keratin-filled cells covered by a lipid matrix which shields the skin from physical and chemical entrants. The lipid lamellar structure comprises of ceramides, cholesterol, fatty acids and proteins. Chemical enhancers that mimic the lamellar chemistry, reversibly fluidize the latter can be utilized for enhancing transport of cargo across the epidermis into the dermis. This review deals with the stratum corneum chemistry, mechanisms to modulate its packing with the aid of chemical enhancers, biophysical techniques for characterization and applications in the design of nature-inspired biocompatible lipid nanostructures for transdermal delivery of drugs and bioactive agents. PMID- 28730939 TI - Drug delivery to the brain: how can nanoencapsulated statins be used in the clinic? AB - Statins are used for the primary and secondary prevention of cardiovascular disease by inhibiting cholesterol synthesis in the liver. Statins have also noncholesterol-related effects, called pleiotropic effects, which arise from statins' anti-inflammatory, immunomodulatory and antioxidant properties. These effects are especially attractive for the treatment of various brain diseases ranging from stroke to neurodegenerative diseases. Still, low brain concentrations after oral drug administration hinder the clinical application of statins in these pathologies. Pharmaceutical nanotechnologies may offer a solution to this problem, as local or targeted delivery of nanoencapsulated statins may increase brain availability. This special report rapidly summarizes the potential of statins in the treatment of brain diseases and the pharmaceutical nanotechnologies that could provide a viable approach to enable these indications. PMID- 28730940 TI - Nanomicrobicides for HIV vaginal transmission prevention: where do we stand? PMID- 28730941 TI - How can we fine-tune nanoparticles to improve drug delivery? PMID- 28730942 TI - Posterior drug delivery via periocular route: challenges and opportunities. AB - Drug delivery to the posterior segment via the periocular route is a promising route for delivery of a range of formulations. In this review, we have highlighted the challenges and opportunities of posterior segment drug delivery via the periocular route. Consequently, we have discussed different types of periocular routes, physiological barriers that limit effective drug delivery, practical challenges regarding patient compliance and acceptability and recent advances in developing innovative strategies to enhance periocular drug delivery. We conclude with a perspective on how we envisage the importance of understanding complex barrier functions so as to continue to develop innovative drug-delivery systems. PMID- 28730943 TI - Collective in exile: Utilizing terror management theory to understand women's wailing performance. AB - Although women's wailing at death rites in various cultures typically amplifies mortality salience, this ritual phenomenon is absent in the research literature on terror management theory (TMT). This study explored Yemenite-Jewish wailing in Israel as an example of how a traditional performance manages death anxiety in a community context. Observations of wailing events and interviews with Yemenite Jewish wailers and mourners in Israel were analyzed to understand respondents' perceptions of the experience of wailing as well as the anxiety-oriented psychotherapeutic expertise involved. The findings are discussed to propose an alternative outlook on the intersubjective adaptive value of death anxiety. After describing TMT's view on the role of culture in coping with death anxiety, I consider the extent to which Yemenite-Jewish wailing is consistent with the premises of TMT. PMID- 28730944 TI - Integrating bioassays and analytical chemistry as an improved approach to support safety assessment of food contact materials. AB - Food contact materials (FCM) contain chemicals which can migrate into food and result in human exposure. Although it is mandatory to ensure that migration does not endanger human health, there is still no consensus on how to pragmatically assess the safety of FCM since traditional approaches would require extensive toxicological and analytical testing which are expensive and time consuming. Recently, the combination of bioassays, analytical chemistry and risk assessment has been promoted as a new paradigm to identify toxicologically relevant molecules and address safety issues. However, there has been debate on the actual value of bioassays in that framework. In the present work, a FCM anticipated to release the endocrine active chemical 4-nonyphenol (4NP) was used as a model. In a migration study, the leaching of 4NP was confirmed by LC-MS/MS and GC-MS. This was correlated with an increase in both estrogenic and anti-androgenic activities as measured with bioassays. A standard risk assessment indicated that according to the food intake scenario applied, the level of 4NP measured was lower, close or slightly above the acceptable daily intake. Altogether these results show that bioassays could reveal the presence of an endocrine active chemical in a real case FCM migration study. The levels reported were relevant for safety assessment. In addition, this work also highlighted that bioactivity measured in migrate does not necessarily represent a safety issue. In conclusion, together with analytics, bioassays contribute to identify toxicologically relevant molecules leaching from FCM and enable improved safety assessment. PMID- 28730945 TI - Perspectives. PMID- 28730946 TI - Contribution of upper limb muscles to two different gripping styles in elite indoor tug of war athletes. AB - To investigate characteristic upper limb muscle use between two common tug of war (TOW) gripping styles, 20 elite athletes from two high school TOW teams were recruited. Under conditioned attack pulling (with 90% maximal force) on a tug machine, participants used their own habitual gripping style to pull for five 15 s trials. Force and kinematic measurements showed a significantly better force performance and higher centre-of-gravity tilting angle with the gripping style one than with the gripping style two (GS2) (both p < 0.05). However, an overall higher and more symmetrical muscle activation detected by normalised surface electromyography signal amplitude was found in the GS2 group (both p < 0.05). In both groups, the distal and flexor muscles were more activated than the proximal and extensor muscles, respectively (p < 0.05). Higher co-contraction ratio was found in the wrist joints of the latter arm in both groups (p < 0.05). As higher muscle activation level and co-contraction indicate higher muscle and joint injury incidences, we suggest that gripping style factors should be considered in training to prevent muscle and joint injury. Future study concerning segmental kinematics, ground reaction force, moment arm and muscle endurance during the defence phase are warranted. PMID- 28730947 TI - Safety of nitric oxide added to the ECMO circuit: a pilot study in children. AB - We describe our experience of 30 consecutive children supported with ECMO and receiving 20 ppm of nitric oxide in the oxygenator of the ECMO circuit. Administration of nitric oxide into the ECMO circuit is safe and could potentially mitigate ischaemia reperfusion injury and end-organ dysfunction of children requiring mechanical support. PMID- 28730948 TI - Nonvitamin-K-antagonist oral anticoagulants versus warfarin in patients with atrial fibrillation and previous stroke or transient ischemic attack: An updated systematic review and meta-analysis of randomized controlled trials. AB - Background In a previous systematic review and meta-analysis, we assessed the efficacy and safety of nonvitamin-K antagonist oral anticoagulants versus warfarin in patients with atrial fibrillation and stroke or transient ischemic attack. Since then, new information became available. Aim The aim of the present work was to update the results of the previous systematic review and meta analysis. Methods We searched PubMed until 24 August 2016 for randomized controlled trials using the following search items: "atrial fibrillation" and "anticoagulation" and "warfarin" and "previous stroke or transient ischemic attack." Eligible studies had to be phase III trials in patients with atrial fibrillation comparing warfarin with nonvitamin-K antagonist oral anticoagulants currently on the market or with the intention to be brought to the market in North America or Europe. The outcomes assessed in the efficacy analysis included stroke or systemic embolism, stroke, ischemic or unknown stroke, disabling or fatal stroke, hemorrhagic stroke, cardiovascular death, death from any cause, and myocardial infarction. The outcomes assessed in the safety analysis included major bleeding, intracranial bleeding, and major gastrointestinal bleeding. We performed fixed effects analyses on intention-to-treat basis. Results Among 183 potentially eligible articles, four were included in the meta-analysis. In 20,500 patients, compared to warfarin, nonvitamin-K antagonist oral anticoagulants were associated with a significant reduction of stroke/systemic embolism (relative risk reduction: 13.7%, absolute risk reduction: 0.78%, number needed to treat to prevent one event: 127), hemorrhagic stroke (relative risk reduction: 50.0%, absolute risk reduction: 0.63%, number needed to treat: 157), any stroke (relative risk reduction: 13.1%, absolute risk reduction: 0.7%, number needed to treat: 142), and intracranial hemorrhage (relative risk reduction: 46.1%, absolute risk reduction: 0.88%, number needed to treat: 113) over 1.8-2.8 years. Conclusions This updated meta-analysis in 20,500 atrial fibrillation patients with previous stroke or transient ischemic attack shows that compared to warfarin non-vitamin-K antagonist oral anticoagulants are associated with a significant reduction of stroke, stroke or systemic embolism, hemorrhagic stroke, and intracranial bleeding. PMID- 28730949 TI - ERic Acute StrokE Recanalization: A study using predictive analytics to assess a new device for mechanical thrombectomy. AB - Aim and hypothesis Using a new study design, we investigate whether next generation mechanical thrombectomy devices improve clinical outcomes in ischemic stroke patients. We hypothesize that this new methodology is superior to intravenous tissue plasminogen activator therapy alone. Methods and design ERic Acute StrokE Recanalization is an investigator-initiated prospective single-arm, multicenter, controlled, open label study to compare the safety and effectiveness of a new recanalization device and distal access catheter in acute ischemic stroke patients with symptoms attributable to acute ischemic stroke and vessel occlusion of the internal cerebral artery or middle cerebral artery. Study outcome The primary effectiveness endpoint is the volume of saved tissue. Volume of saved tissue is defined as difference of the actual infarct volume and the brain volume that is predicted to develop infarction by using an optimized high level machine learning model that is trained on data from a historical cohort treated with IV tissue plasminogen activator. Sample size estimates Based on own preliminary data, 45 patients fulfilling all inclusion criteria need to complete the study to show an efficacy >38% with a power of 80% and a one-sided alpha error risk of 0.05 (based on a one sample t-test). Discussion ERic Acute StrokE Recanalization is the first prospective study in interventional stroke therapy to use predictive analytics as primary and secondary endpoint. Such trial design cannot replace randomized controlled trials with clinical endpoints. However, ERic Acute StrokE Recanalization could serve as an exemplary trial design for evaluating nonpivotal neurovascular interventions. PMID- 28730950 TI - Statistical analysis plan for the Head Position in Stroke Trial (HeadPoST): An international cluster cross-over randomized trial. AB - Background There is evidence to indicate that the lying flat head position increases cerebral blood flow and oxygenation in patients with acute ischemic stroke, but how these physiological effects translate into clinical outcomes is uncertain. The Head Position in Stroke Trial aims to determine the comparative effectiveness of lying flat (0 degrees ) compared to sitting up (>=30 degrees ) head positioning, initiated within 24 h of hospital admission for patients with acute stroke. Design An international, pragmatic, cluster-randomized, crossover, open, blinded outcome assessed clinical trial. Each hospital with an established acute stroke unit (cluster) site was required to recruit up to 140 consecutive cases of acute stroke (one phase of head positioning before immediately crossing over to the other phase of head positioning), including both acute ischemic stroke and intracerebral hemorrhage, in each randomized head position as a 'business as usual' policy. Objective To outline in detail the predetermined statistical analysis plan for the study. Methods All accumulated data will be reviewed and formally assessed. Information regarding baseline characteristics of patients, their process of care and management will be outlined, and for each item, statistically relevant descriptive elements will be described. For the trial outcomes, the most appropriate statistical comparisons are described. Results A statistical analysis plan was developed that is transparent, verifiable, and predetermined before completion of data collection. Conclusions We developed a predetermined statistical analysis plan for Head Position in Stroke Trial to avoid analysis bias arising from prior knowledge of the findings, in order to reliably quantify the benefits and harms of lying flat versus sitting up early after the onset of acute stroke. Trial registration ClinicalTrials.gov identifier NCT02162017; ANZCTR identifier ACTRN12614000483651. PMID- 28730951 TI - Penumbra and re-canalization acute computed tomography in ischemic stroke evaluation: PRACTISE study protocol. AB - Rationale Multimodal imaging, including computed tomography angiography and computed tomography perfusion imaging, yields additional information on intracranial vessels and brain perfusion and can differentiate between ischemic core and penumbra which may affect patient selection for intravenous thrombolysis. Hypothesis The use of multimodal imaging will increase the number of patients receiving intravenous thrombolysis and lead to better treatment outcomes. Sample size 400 patients. Methods and design PRACTISE is a prospective, multicenter, randomized, controlled trial in which patients presenting within 4.5 h of symptom onset are randomized to either the current evidence-based imaging (NCCT alone) or additional multimodal computed tomography imaging (NCCT + computed tomography angiography + computed tomography perfusion). Clinical decisions on intravenous recombinant tissue plasminogen activator are documented. Total imaging time in both arms and time to initiation of treatment delivery in those treated with intravenous recombinant tissue plasminogen activator, is recorded. Follow-up will include brain imaging at 24 h to document infarct size, the presence of edema and the presence of intra-cerebral hemorrhage. Clinical evaluations include NIHSS score at baseline, 24 h and day 7 +/- 2, and mRS at day 90 to define functional outcomes. Study outcomes The primary outcome is the proportion of patients receiving intravenous recombinant tissue plasminogen activator. Secondary end-points evaluate times to decision-making, comparison of different image processing software and clinical outcomes at three months. Discussion Multimodal computed tomography is a widely available tool for patient selection for revascularization therapy, but it is currently unknown whether the use of additional imaging in all stroke patients is beneficial. The study opened for recruitment in March 2015 and will provide data on the value of multimodal imaging in treatment decisions for acute stroke. PMID- 28730952 TI - Editorial. PMID- 28730954 TI - Evaluation of in vitro Anti-psoriatic Activity of a Novel Polyherbal Formulation by Multiparametric Analysis. AB - BACKGROUND: We have developed a novel aqueous polyherbal formulation (SIRB-001) consisting of 3 herbs; Rheum palmatum L., Lonicera Japonica and Rehmannia glutinosa Libosch in the ratio 1:1:3. SIRB-001 has demonstrated efficacious effects in psoriasis patients. OBJECTIVE: This study was aimed at scientifically evaluating the in vitro antipsoriatic activity of SIRB-001. METHOD: The in vitro anti-psoriatic properties of SIRB-001 were assessed in human keratinocyte cell line; HaCaT. Anti-proliferative effect was studied using MTT assay. Apoptosis was examined by flow cytometry and colorimetric methods. Inflammatory markers and VEGF were determined by ELISA. IL-17/IL-23 secretion was assessed in immune cells. Signaling markers (kinases) by enzymatic assay and Topoisomerase-II activity by Kinetoplast DNA Cleavage assay was tested. RESULTS: SIRB-001 significantly inhibited (p<0.01) proliferation of HaCaT cells and induced apoptosis. Significant (p<0.01) downregulation of pro-inflammatory markers (TNF- alpha, IFN-gamma, IL-6, NO, sPLA2) and VEGF was observed. IL-17/IL-23 secretion was significantly (p<0.01) alleviated in immune cells (RAW264.7 and THP-1). Inhibition of signaling markers (AKT1, FLT3, MAPK1, PRKCA, MAP2K) was observed. SIRB-001 demonstrated inhibition of Topoisomerase-II activity. High Performance Liquid Chromatography (HPLC) analysis of SIRB-001 was carried out using standard marker compounds chlorogenic acid (tR=13.98min), Acteoside (tR=24.22 min) and Rhein (tR=53.76 min). CONCLUSION: The in vitro results substantiate the anti psoriatic effect of SIRB-001 in patients. SIRB-001 exerted anti-psoriatic effects at cellular level via multiple arms (antiproliferative, pro-apoptotic, anti inflammatory, anti-angiogenic). This study provides insight into mechanism of action of SIRB-001 and highlights its promising potential for development as a herbal therapeutic agent for psoriasis, emphasizing the need of further pharmacological evaluation and toxicological studies. PMID- 28730956 TI - Review on Bioorganometallic Chemistry and New Outcomes in the Synthesis and Substitution of Tetracarbonyl(pyrrolylimine) Complexes of Rhenium with Organophosphorus Ligands. AB - : After a short review dealing with bioorganometallic chemistry, the synthesis of tetracarbonyl (pyrrolylimine) complexes of rhenium bearing chirality on the pyrrolyl ligands was reported.The reactivity of these compounds towards the substitution of one carbonyl ligand with triphenyl phosphine, tricyclohexyl phosphine and trimethyl phosphite was studied. The rhenium becoming a stereogenic center in that transformation, the resulting tricarbonyl species were obtained as mixtures of diastereomers, with diastereomeric excesses varying from 8 to 84%, according to the reaction conditions and the relative steric hindrances of the pyrrolylimine and the organophosphorus ligands. These bioorganometallics are potential CO releasing molecules that could be used in the field of medicinal chemistry. PMID- 28730957 TI - Design, Preparation and Characterization of Modular Squalene-based Nanosystems for Controlled Drug Release. AB - This article reviews the innovative and original concept the "squalenoylation", a technology allowing the formulation of a wide range of drug molecules (both hydrophilic and lipophilic) as nanoparticles. The "squalenoylation" approach is based on the covalent linkage between the squalene, a natural and biocompatible lipid belonging to the terpenoid family, and a drug, in order to increase its pharmacological efficacy. Fundamentally, the dynamically folded conformation of squalene triggers the resulting squalene-drug bioconjugates to self-assemble as nanoparticles of 100-300 nm. In general, these nanoparticles showed long blood circulation times after intravenous administration and improved pharmacological activity with reduced side effects and toxicity. This flexible and generic technique opens exciting perspectives in the drug delivery field. PMID- 28730955 TI - iTRAQ-based Proteomic Analysis of APPSw,Ind Mice Provides Insights into the Early Changes in Alzheimer's Disease. AB - BACKGROUND: Several proteins have been identified as potential diagnostic biomarkers in imaging, genetic, or proteomic studies in Alzheimer disease (AD) patients and mouse models. However, biomarkers for presymptom diagnosis of AD are still under investigation, as are the presymptom molecular changes in AD pathogenesis. OBJECTIVE: In this study, we aim to analyzed the early proteomic changes in APPSw,Ind mice and to conduct further functional studies on interesting proteins. METHODS: We used the isobaric tags for relative and absolute quantitation (iTRAQ) approach combined with mass spectrometry to examine the early proteomic changes in hippocampi of APPSw,Ind mice. Quantitative reverse transcription polymerase chain reaction (RT-PCR) and immuno-blotting were performed for further validation. Finally, the functions of interesting proteins beta-spectrin and Rab3a in APP trafficking and processing were tested by shRNA knockdown, in N2A cells stably expressing beta-amyloid precursor protein (APP). RESULTS: The iTRAQ and RT-PCR results revealed the detailed molecular changes in oxidative stress, myelination, astrocyte activation, mTOR signaling and Rab3 dependent APP trafficking in the early stage of AD progression. Knock down of beta -spectrin and Rab3a finally led to increased APP fragment production, indicating key roles of beta-spectrin and Rab3a in regulating APP processing. CONCLUSION: Our study provides the first insights into the proteomic changes that occur in the hippocampus in the early stages of the AD mouse model. In addition to improving the understanding of molecular alterations and functional cascades involved in early AD pathogenesis, our findings raise the possibility of developing potential biomarkers and therapeutic targets for early AD. PMID- 28730958 TI - Engineering Synergistically Active and Bioavailable Cost-effective Medicines for Neglected Tropical Diseases; The Role of Excipients. AB - Leishmaniasis is a neglected tropical disease responsible for the ninth largest disease burden in the world threatening 350 million people mostly in developing countries. The lack of efficacy, severe adverse effects, long duration, high cost and parenteral administration of the current therapies result in poor patient compliance and emergence of resistance. Leishmaniasis' unmet need for safer, affordable and more effective treatments is only partly addressed by today's global health product pipeline that focuses on products amenable to rapid clinical development, mainly by reformulating or repurposing existing drugs for new uses. Excipients are necessary for ensuring the stability and bioavailability of currently available antileishmaniasis drugs which in their majority are poorly soluble or have severe side-effects. Thus, selection of excipients that can ensure bioavailability and safety as well as elicit a synergistic effect against the Leishmania parasites without compromising safety will result in a more efficacious, safe and fast to market medicine. We have evaluated the in vitro activity of 30 commercially available generally regarded as safe (GRAS) excipients against different Leishmania spp., their cytotoxicity and potential use for inclusion in novel formulations. Amongst the tested excipients, the compounds with higher selectivity index were Eudragit E100 (cationic triblock copolymer of dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate), CTAB (cetyltrimethylammonium bromide, cationic), lauric acid, Labrasol(non-ionic, caprylocaproyl polyoxyl- 8 glycerides) and sodium deoxycholate. An ideal excipient need to possess amphiphilic nature with ionic/polar groups and possess a short or medium fatty acid chain such as lauric (C12), capric C10) or caprylicacid (C8). Inclusion of these excipients and identification of the optimal combination of drug and excipients would lead to a more effective and safer antileishmanial therapies. PMID- 28730959 TI - Chemometric Analysis Of Inter- And Intra-Molecular Diversification Factors By A Machine Learning Simplex Approach. A Review And Research On Astragalus Saponins. AB - Metabolisms represent highly organized systems characterized by strong regulations satisfying the mass conservation principle. This makes a whole chemical resource to be competitively shared between several ways at both intra and inter-molecular scales. Whole resource sharing can be statistically associated with a constant sum-unit constraint which represents the basis of simplex mixture rule. In this work, a new simplex-based simulation approach was developed to learn scaffold information on metabolic processes controlling molecular diversity from a wide set of observed chemical structures. Starting from a dataset of chemical structures classified into p clusters, a machine learning process was applied by linearly combining the p clusters j and randomly sampling a constant number (n) of molecules according to different clusters' weights (wj/w) given by Scheffe's mixture matrix. At the output of mixture design, molecular linear combinations lead to calculate barycentric molecules integrating the characteristics of the different weighted clusters. The N mixtures-design was iterated by bootstrap technique leading to extensive exploration of chemical variability between and within clusters. Finally, the K response matrices issued from K iterated mixture designs were averaged to calculate a smoothed matrix containing scaffold information on regulation processes responsible for molecular diversification at inter- and intra-molecular (atomic) scales. This matrix was used as a backbone for graphical analysis of positive and negative trends between atomic characteristics (chemical substitutions) at both mentioned scales. This new simplex approach was illustrated by cycloartane-based saponins of Astragalus genus by combining three desmosylation clusters characterized by relative glycosylation levels of different aglycones' carbons. PMID- 28730961 TI - Novel Fluorinated Porphyrins Sensitize Tumor Cells to Photodamage in Normoxia and Hypoxia: Synthesis and Biocompatible Formulations. AB - BACKGROUND: Hypoxia renders tumor cells refractory to treatment. One way to overcome this problem is the design of drug delivery systems that contain the antitumor agent within an oxygen supply medium. OBJECTIVE: to evaluate whether the perfluorocarbon liquids (capable of retaining up to 50% v/v amounts of O2 gas) can be tools for delivery of photosensitizers to hypoxic tumors. METHOD: We synthesized a series of compounds in which fluoroaliphatic or fluoroaromatic moieties were conjugated to the porphyrin ring in meso-positions. Two derivatives were tested as the solutions prepared either from a dimethylformamide stock ('free' formulation) or from a perfluorocarbon emulsion in which the photosensitizer is entrapped in the oxygenated medium. RESULTS: In the emulsion the hydrophobic photosensitizer and the gas transporting liquid represented a biocompatible composition. Free formulations or perfluorocarbon emulsions of fluorinated porphyrins evoked little-to-null dark cytotoxicity. In contrast, each formulation triggered cell death upon light activation. Photodamage in the presence of fluorinated porphyrins was achievable not only at normoxic (20.9% O2 v/v) conditions but also in hypoxia (0.5% O2). With new compounds dissolved in the medium the cell photodamage in hypoxia was negligible whereas a significant photodamage was achieved with the emulsions of fluorinated porphyrins. The derivative with the fluoroalkyl substituent was more potent than its structurally close analog carrying the fluoroaryl moiety. CONCLUSION: Our new fluorinated porphyrin derivatives, especially their emulsions in which the photosensitizer and the oxygenated medium are coupled into one phase, can be perspective for photoelimination of hypoxic tumor cells. PMID- 28730960 TI - Protein Kinases as Tumor Biomarkers and Therapeutic Targets. AB - Over the last three decades, neoplasms have become the largest cause of human mortality due to both high tumor incidence and mortality. Chemotherapy is one of the main therapies employed to treat neoplasms. Although classical genotoxic drugs, such as cyclophosphamide, 5-FU, cisplatin and doxorubicin have been applied in clinical settings and have achieved very good treatment efficacy, many cancer patients died of tumor metastasis, drug toxicity or drug resistance due to tumor heterogeneity. Targeted molecular treatments based on the genes, receptors, and kinases expressed by a tumor make individualized treatment possible. Protein kinases catalyze the phosphorylation of proteins and are involved in multiple cellular processes. In many cancers, mutation or abnormal expression of protein kinases is correlated with tumorigenesis, metastasis and resistance to chemotherapy. Tumor-related protein kinases have become important molecular targets and biomarkers. The use of protein kinases as tumor biomarkers primarily focuses on tyrosine and serine/threonine kinases. Many tumor drugs targeting protein kinases, such as monoclonal antibody and tyrosine kinase inhibitors (TKIs), are widely utilized in clinic. Additional drugs aimed at combating drug resistance and metastasis should be developed targeting protein kinases. In this review, we summarize several important protein kinases involved in cancer and analyze why these kinases can be used as biomarkers or targets for cancer diagnosis and/or treatment. Furthermore, numerous drugs targeting protein kinases as well as their development and activity are discussed. PMID- 28730962 TI - Phosphonium Salt Displays Cytotoxic Effects Against Human Cancer Cell Lines. AB - : Aims/Objective: Phosphonium salts are compounds whose structural characteristics enable them to cross the plasma and mitochondrial membrane with ease. Cancer cells have higher plasma membrane potentials than normal cells; phosphonium salts selectively accumulate in the mitochondria of neoplastic cells and inhibit mitochondrial function. METHOD: In the present work, we investigated the cytotoxic activity of lipophilic phosphonium salt (11- methoxy11-oxo-undecyl) triphenylphosphonium bromide (MUTP) as well as of the two new phosphine oxide salts, 3,3'-(methylphosphoryl) dibenzenaminium chloride (SBAMPO) and 3,3' (phenylphosphoryl) dibenzenaminium chloride (SBAPPO) on the proliferation of breast cancer cell line (MCF-7) and human uterin cervix adenocarcinoma cells (HeLa). RESULT: We showed that only MUTP exhibits antiproliferative effects on both cell lines, without affecting the normal breast epithelial cell proliferation. More specifically, we demonstrated that MUTP treatment of breast cancer cells is associated with impaired cell-cycle progression and metabolically induces mitochondrial damage and triggers apoptotic cell death in MCF-7 and HeLa cells. Taken together, these findings suggest that MUTP may be capable of selectively targeting neoplastic cell growth and therefore has potential applications as anticancer agent. PMID- 28730963 TI - Increased Expression of IRE1alpha Associates with the Resistant Mechanism of Osimertinib (AZD9291)-resistant non-small Cell Lung Cancer HCC827/OSIR Cells. AB - BACKGROUND: Osimertinib (OSI), also known as AZD9291, is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that has been approved for the treatment of non-small cell lung cancer (NSCLC) patients. OBJECTIVE: Establishment of the OSI-resistant HCC827/OSIR cell line and study of its resistant mechanism. METHOD: The anti-proliferative effect was studied through MTT and colony formation assays. The protein expression was detected by Western blot assay. The gene was silenced by small interfering RNA. The cellular morphology was observed by using an optical microscope. The viable cell numbers were counted by trypan blue staining assay. RESULTS: The OSI-resistant HCC827/OSIR cells were established on HCC827 cells with naive EGFR-sensitive mutation, and the resistant effects of HCC827/OSIR cells were confirmed through MTT and colony formation assays. The IC50s of HCC827/OSIR cells to other EGFR TKIs, such as gefitinib, erlotinib, afatinib, and rociletinib was higher than that of the HCC827 cells. The anti-proliferative effects of paclitaxel, pemetrexed, doxorubicin, and fluorouracil in HCC827 and HCC827/OSIR cells were similar. The expression of inositolrequiring enzyme 1alpha (IRE1alpha) was increased after the cells developed resistance to OSI. The number of viable cells in both cell lines, particularly in HCC827/OSIR cells, was decreased through knockdown of IRE1alpha or pretreatment with STF-083010, an IRE1alpha inhibitor. CONCLUSION: An increased expression of IRE1alpha may be one of the resistant mechanisms for OSI-resistant NSCLC. PMID- 28730964 TI - CCL2 is Modulated by Cytokines and PPAR-gamma in Anaplastic Thyroid Cancer. AB - BACKGROUND AND OBJECTIVE: Chemokine (C-C motif) ligand (CCL)2, the prototype Th2 chemokine, is secreted by tumor cells, and has growth promoting effects. Whether CCL2 protumorigenic activities will be validated, then CCL2 and its receptor CCR2 may be therapeutic targets in cancer. METHODS: We tested in "primary human anaplastic thyroid carcinoma (ATC) cells" (ANA) versus "normal thyroid follicular cells" (TFC): a) CCL2 secretion basally, after IFN-gamma and/or TNF-alpha stimulation; b) PPARgamma activation by thiazolidinediones (TZDs), rosiglitazone or pioglitazone, on CCL2 secretion, and on proliferation and apoptosis in ANA. RESULTS: ANA produced basally CCL2, at a higher level versus TFC. IFN-gamma or TNF-alpha dose-dependently induced the CCL2 release in 3/6 or 5/6 ANA, respectively, but in all TFC. IFN-gamma+TNF-alpha induced a synergistic release of CCL2 in all TFC, but only in 1/6 ATC. TZDs exerted an inhibition of CCL2 release in 3/6 ANA, while had no effect in TFC. Pioglitazone inhibition of ANA proliferation was not associated with the effect on CCL2; NF-kappaB and ERK1/2 were basally activated in ANA, increased by IFN-gamma+TNF-alpha, and pioglitazone inhibited IFN- gamma+TNF-alpha activation. CCL2 serum levels were higher in 6 ATC patients than in 5 controls (813+/-345 versus 345+/-212, pg/mL; respectively; P<0.01, ANOVA). CONCLUSION: ANA produce CCL2 basally and after cytokines stimulation, with an extremely variable pattern of modulation, suggesting different types of deregulation in the chemokine modulation. Serum CCL2 is increased in ATC patients. Further studies will be necessary to evaluate if CCL2 might be used as a marker in the followup of ATC patients. PMID- 28730965 TI - Efficient Non-Invasive Plasmid-DNA Administration into Tibialis Cranialis Muscle of "Little" Mice. AB - BACKGROUND: An alternative treatment for growth hormone deficiency based on hGH DNA administration, followed by electro gene transfer, was investigated by injecting the plasmid into surgically exposed or non-exposed quadriceps or tibialis muscle of immunodeficient "little" mice. METHODS: An optimization of electrotransfer conditions via a new combination of high/low voltage pulses is presented. After 3 days, serum hGH was determined and in a 28-day assay, the relative growth parameters were compared. RESULTS: Both groups exhibited similar results: 5.0 +/- 2.2 (SD) and 3.5 +/- 0.9 ng hGH/ml (P>0.05; n=7) for the exposed quadriceps and non-exposed tibialis treatments, respectively. The final body weight increases were 16.1% for the quadriceps and 18.9% for the tibialis group. The tail and nose-to-tail length increases were 4.5% and 7.1% for the quadriceps and 4.8 and 4.6% for the tibialis group. The right and left femur length increases, obtained from radiographic measurements, were 16.9% and 12.7% for the quadriceps and 19.4% and 12.3% for the tibialis, respectively. A non-significant difference between exposed quadriceps and non-exposed tibialis treatments (P=0.48) was confirmed via a completely integrated statistical analysis. Circulating mIGF-1 levels were 126 +/- 47, 106 +/- 93 (P>0.05) and 38 +/- 15 ng/ml for the quadriceps, tibialis and saline treatments, respectively. CONCLUSION: These results show that hGH-DNA administration into non-exposed tibialis muscle followed by the new HV/LV electrotransfer protocol was an equally efficient, less traumatic treatment, much more suitable for pre-clinical testing than administration into exposed quadriceps. PMID- 28730969 TI - The Battle for Iron between Humans and Microbes. AB - BACKGROUND: Iron is an essential micronutrient for bacteria, fungi, and humans; as such, each has evolved specialized iron uptake systems to acquire iron from the extracellular environment. OBJECTIVE: To describe complex 'tug of war' for iron that has evolved between human hosts and pathogenic microorganisms in the battle for this vital nutrient. METHODS: A review of current literature was performed, to assess current approaches and controversies in iron therapy and chelation in humans. RESULTS: In humans, sequestration (hiding) of iron from invading pathogens is often successful; however, many pathogens have evolved mechanisms to circumvent this approach. CONCLUSION: Clinically, controversy continues whether iron overload or administration of iron results in an increased risk of infection. The administration of iron chelating agents and siderophore- conjugate drugs to infected hosts seems a biologically plausible approach as adjunctive therapy in the treatment of infections caused by pathogens dependent on host iron supply (e.g. tuberculosis, malaria, and many bacterial and fungal pathogens); however, thus far, studies in humans have proved unsuccessful. PMID- 28730966 TI - Nicotinic Cholinergic System in the Hypothalamus Modulates the Activity of the Hypothalamic Neuropeptides During the Stress Response. AB - BACKGROUND: The hypothalamus harbors high levels of cholinergic neurons and axon terminals. Nicotinic acetylcholine receptors, which play an important role in cholinergic neurotransmission, are expressed abundantly in the hypothalamus. Accumulating evidence reveals a regulatory role for nicotine in the regulation of the stress responses. The present review will discuss the hypothalamic neuropeptides and their interaction with the nicotinic cholinergic system. The anatomical distribution of the cholinergic neurons, axon terminals and nicotinic receptors in discrete hypothalamic nuclei will be described. The effect of nicotinic cholinergic neurotransmission and nicotine exposure on hypothalamic pituitaryadrenal (HPA) axis regulation at the hypothalamic level will be analyzed in view of the different neuropeptides involved. METHODS: Published research related to nicotinic cholinergic regulation of the HPA axis activity at the hypothalamic level is reviewed. RESULTS: The nicotinic cholinergic system is one of the major modulators of the HPA axis activity. There is substantial evidence supporting the regulation of hypothalamic neuropeptides by nicotinic acetylcholine receptors. However, most of the studies showing the nicotinic regulation of hypothalamic neuropeptides have employed systemic administration of nicotine. Additionally, we know little about the nicotinic receptor distribution on neuropeptide-synthesizing neurons in the hypothalamus and the physiological responses they trigger in these neurons. CONCLUSION: Disturbed functioning of the HPA axis and hypothalamic neuropeptides results in pathologies such as depression, anxiety disorders and obesity, which are common and significant health problems. A better understanding of the nicotinic regulation of hypothalamic neuropeptides will aid in drug development and provide means to cope with these diseases. Considering that nicotine is also an abused substance, a better understanding of the role of the nicotinic cholinergic system on the HPA axis will aid in developing improved therapeutic strategies for smoking cessation. PMID- 28730970 TI - Healthy Diet And Reduction Of Chronic Disease Risks Of Night Shift Workers. AB - BACKGROUND: The large increase in epidemiological studies on night shift work is due to the important effects of night shift work on workers' health and psychophysical wellbeing. The short-term effects-insomnia, difficulties in managing work and private life, lower work performance, and more work and extra work accidents-are easily studied. However, there are several long-term effects that are difficult to study because of the need for detailed exposure assessment and the long latency periods of these diseases. OBJECTIVE: The aim was to collect epidemiologic evidence of diseases in night shift workers, describing their biological pathways and a set of dietary guidelines. METHOD: This is a review on diet and health effects in night shift workers. RESULTS: Significant increases in the rate ratios and hazard ratios of different diseases were associated with modified eating behaviours and poor eating habits among night shift workers. Night shift work is a risk factor for disruption of the circadian rhythms and for some genetic deregulation because it produces the inversion of the sleep/wake cycle and modifies the alternation between activity and rest. CONCLUSION: A healthy diet and improved dietary practices, together with other factors, can reduce shift workers' chronic disease risk. The literature showed the importance of eating behaviour in order to prevent diseases in these workers; therefore, educational programmes are necessary to encourage several important lifestyle changes. The target of our future research will be the role of food components in some dietetic habits for the prevention of disease in night shift workers. PMID- 28730967 TI - Microglia and Astrocytes in Alzheimer's Disease: Implications for Therapy. AB - BACKGROUND: Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by the progressive loss of neurons, which typically leads to severe impairments in cognitive functions including memory and learning. Key pathological features of this disease include the deposition of highly insoluble amyloid beta peptides and the formation of neurofibrillary tangles (NFTs) in the brain. Mounting evidence also implicates sustained glial-mediated inflammation as a major contributor of the neurodegenerative processes and cognitive deficits observed in AD. METHODS: This paper provides an overview of findings from both human and animal studies investigating the role of microglia and astrocytes in AD, and discusses potential avenues for therapeutic intervention. RESULTS: Glial mediated inflammation is a 'double-edged sword', performing both detrimental and beneficial functions in AD. Despite tremendous effort in elucidating the molecular and cellular mechanisms underlying AD pathology, to date, there is no treatment that could prevent or cure this disease. Current treatments are only useful in slowing down the progression of AD and helping patients manage some of their behavioral and cognitive symptoms. CONCLUSION: A better understanding of the role of microglia and astrocytes in the regulation of AD pathology is needed as this could pave the way for new therapeutic strategies. PMID- 28730968 TI - Modulation of the Immune System for the Treatment of Glaucoma. AB - BACKGROUND: At present intraocular pressure (IOP) lowering therapies are the only approach to treat glaucoma. Neuroprotective strategies to protect the retinal ganglion cells (RGC) from apoptosis are lacking to date. Substantial amount of research concerning the role of the immune system in glaucoma has been performed in the recent years. This review aims to analyse changes found in the peripheral immune system, as well as selected local changes of retina immune cells in the glaucomatous retina. METHODS: By dividing the immune system into the innate and the adaptive immune system, a systematic literature research was performed to find recent approaches concerning the modulation of the immune system in the context of glaucoma. Also ClinicalTrials.gov was assessed to identify studies with a translational context. RESULTS: We found that some aspects of the immune system, such as changes in antibody levels, changes in toll like receptor signalling, T cells and retinal microglial cells, experience more research activity than other areas such as changes in dendritic cells or macrophages. Briefly, results from clinical studies revealed altered immunoreactivities against retinal and optic nerve antigens in sera and aqueous humor of glaucoma patients and point toward an autoimmune involvement in glaucomatous neurodegeneration and RGC death. IgG accumulations along with plasma cells were found localised in human glaucomatous retinae in a pro-inflammatory environment possibly maintained by microglia. Animal studies show that antibodies (e.g. anti- heat shock protein 60 and anti-myelin basic protein) elevated in glaucoma patients provoke autoaggressive RGC loss and are associated with IgG depositions and increased microglial cells. Also, studies addressing changes in T lymphocytes, macrophages but also local immune responses in the retina have been performed and also hold promising results. CONCLUSIONS: This recapitulation of recent literature demonstrates that the immune system definitely plays a role in the pathogenesis of glaucoma. Multiple changes in the peripheral innate as well as adaptive immune system have been detected and give room for further research concerning valuable therapeutic targets. We conclude that there still is a great need to bring together the results derived from basic research analysing different aspects of the immune system in glaucoma to understand the immune context of the disease. Furthermore local immune changes in the retina of glaucoma patients still leave room for further therapeutic targets. PMID- 28730971 TI - Apoptosis and anti-cancer drug discovery: the power of medicinal fungi and plants. AB - The purpose of this account is to review the compounds capable of eliciting mitochondria-mediated apoptosis in cancer cells produced by medicinal fungi and plants. The medicinal fungi discussed encompass Cordyceps, Ganoderma species, Coriolus versicolor and Hypsizygus marmoreus. The medicinal plants discussed comprise Astragalus complanatus , Dendrobium spp,Dioscorea spp, Glycyrrhiza spp, Panax notoginseng, Panax ginseng, and Momordica charantia. These compounds have the potential of development into anticancer drugs. PMID- 28730973 TI - Determination of Ethanol in Kombucha Products: Single-Laboratory Validation, First Action 2016.12. PMID- 28730972 TI - AOAC SMPR(r) 2017.011. Standard Method Performance Requirements (SMPRs) for Identification and Quantitation of Free Alpha Amino Acids in Dietary Ingredients and Supplements. PMID- 28730974 TI - Dual-Laboratory Validation of a Method for the Determination of Fructans in Infant Formula and Adult Nutritionals: First Action 2016.14. PMID- 28730975 TI - Quantitative Analysis of Aloins and Aloin-Emodin in Aloe Vera Raw Materials and Finished Products Using High-Performance Liquid Chromatography: Single-Laboratory Validation, First Action 2016.09. PMID- 28730976 TI - Salmonella Intracellular Lifestyles and Their Impact on Host-to-Host Transmission. AB - More than a century ago, infections by Salmonella were already associated with foodborne enteric diseases with high morbidity in humans and cattle. Intestinal inflammation and diarrhea are hallmarks of infections caused by nontyphoidal Salmonella serovars, and these pathologies facilitate pathogen transmission to the environment. In those early times, physicians and microbiologists also realized that typhoid and paratyphoid fever caused by some Salmonella serovars could be transmitted by "carriers," individuals outwardly healthy or at most suffering from some minor chronic complaint. In his pioneering study of the nontyphoidal serovar Typhimurium in 1967, Takeuchi published the first images of intracellular bacteria enclosed by membrane-bound vacuoles in the initial stages of the intestinal epithelium penetration. These compartments, called Salmonella containing vacuoles, are highly dynamic phagosomes with differing biogenesis depending on the host cell type. Single-cell studies involving real-time imaging and gene expression profiling, together with new approaches based on genetic reporters sensitive to growth rate, have uncovered unprecedented heterogeneous responses in intracellular bacteria. Subpopulations of intracellular bacteria displaying fast, reduced, or no growth, as well as cytosolic and intravacuolar bacteria, have been reported in both in vitro and in vivo infection models. Recent investigations, most of them focused on the serovar Typhimurium, point to the selection of persisting bacteria inside macrophages or following an autophagy attack in fibroblasts. Here, we discuss these heterogeneous intracellular lifestyles and speculate on how these disparate behaviors may impact host-to-host transmissibility of Salmonella serovars. PMID- 28730977 TI - Determination of Lutein and beta-Carotene in Infant Formula and Adult Nutritionals by Ultra-High-Performance Liquid Chromatography: Single-Laboratory Validation, First Action 2016.13. PMID- 28730978 TI - Determination of Biotin in Infant, Pediatric, and Adult Nutritionals by High Performance Liquid Chromatography and Fluorescence Detection: Single-Laboratory Validation, First Action 2016.11. PMID- 28730979 TI - Adsorption of Staphylococcus viruses S13' and S24-1 on Staphylococcus aureus strains with different glycosidic linkage patterns of wall teichoic acids. AB - The group of phages belonging to the family Podoviridae, genus P68virus, including Staphylococcus viruses S13' and S24-1, are important because of their benefits in phage therapy against Staphylococcus aureus infections. The O glycosidic linkage patterns of wall teichoic acids (WTAs) in S. aureus cell walls seem to be important for adsorption of this phage group. In this study, the adsorption of Staphylococcus viruses S13' and S24-1 to S. aureus was examined using strains with modified WTA glycosidic linkage patterns. We found that the beta-O-N-acetylglucosamine of WTAs was essential for S13' adsorption, while N acetylglucosamine, regardless of the alpha- and beta-O-glycosidic linkages of the WTAs, was essential for S24-1 adsorption. Next, examining the binding activities of their receptor-binding proteins (RBPs) to cell walls with different WTA glycosidic patterns, the beta-O-N-acetylglucosamine of the WTAs was essential for S13' RBP binding, while N-acetylglucosamine, regardless of the alpha- and beta-O glycosidic linkages of the WTAs, was essential for S24-1 RBP binding. Therefore, the results of the RBP binding assays were consistent with those of the phage adsorption assays. Bioinformatic analysis suggested that the RBPs of Staphylococcus viruses S13' and S24-1 were structurally similar to the RBPs of phage phi11 of thefamily Siphoviridae. Phylogenetic analysis of the RBPs indicated that two phylogenetic subclusters in the family Podoviridae were related to the glycosidic linkage patterns required for phage adsorption, possibly mediated by RBPs. We hope that this study will encourage the future development of therapeutic phages. PMID- 28730980 TI - Validation of Spectrophotometric Methods for the Determination of Total Polyphenol and Total Flavonoid Content. AB - The aim of this study was to validate spectrophotometric methods for the measurement of total polyphenol (TP; via the Folin-Ciocalteu method) and total flavonoid (TF) content [via the aluminum chloride (AlCl3) method]. Validation parameters of these methods were determined, including linearity, sensitivity, precision (intra-assay and intermediate), accuracy, LOD, and LOQ. For the validation process, groups of polyphenol standards were used, including phenolic acids (gallic, p-coumaric, caffeic, and chlorogenic acids), flavan-3-ols [(+) catechin and procyanidins B1 and B2], flavonols (quercetin and quercetin-3 rutinoside), and dihydrochalcones (phloretin and phloretin-2-glucoside). Obtained validation parameters were within acceptable ranges with high determination coefficients, reasonably low LODs and LOQs, and high slopes in the calibration curves for both methods, except for phloretin and phloretin-2-glucoside, for which there were low slopes in the calibration curves for the AlCl3 method. To evaluate differences in polyphenol content, the validated spectrophotometric methods were used to determine TP and TF content in wines (Plavac, Grasevina, and Vranac) and juices (blueberry, strawberry, and blackcurrant juice) according to the polyphenol calibration curves. Polyphenol contents were different for both methods in all wines and juices. PMID- 28730981 TI - Bartonella quintana, an Unrecognized Cause of Infective Endocarditis in Children in Ethiopia. AB - Bartonella quintana endocarditis, a common cause of culture-negative endocarditis in adults, has rarely been reported in children. We describe 5 patients 7-16 years of age from Ethiopia with heart defects and endocarditis; 4 cases were caused by infection with B. quintana and 1 by Bartonella of undetermined species. All 5 patients were afebrile and oligosymptomatic, although 3 had heart failure. C-reactive protein was normal or slightly elevated, and erythrocyte sedimentation rate was high. The diagnosis was confirmed by echocardiographic demonstration of vegetations, the presence of high Bartonella IgG titers, and identification of B. quintana DNA in excised vegetations. Embolic events were diagnosed in 2 patients. Our data suggest that B. quintana is not an uncommon cause of native valve endocarditis in children in Ethiopia with heart defects and that possible B. quintana infection should be suspected and pursued among residents of and immigrants from East Africa, including Ethiopia, with culture-negative endocarditis. PMID- 28730982 TI - Toward a "New School" of surgical research. PMID- 28730984 TI - Bariatric surgery tourism hidden costs? How Canada is not doing its part in covering bariatric surgery under the Canada Health Act. AB - SUMMARY: Many Canadians seek medical treatment outside our borders. Waiting times, rather than lack of expertise, are the number one culprit, and with globalization of health care, the number of patients who travel to obtain medical care will continue to rise. Though the provinces have covered the costs of complications from surgeries performed abroad for many years, complications from bariatric surgery performed abroad have been receiving negative attention. This commentary discusses associated costs and questions how the Canada Health Act should be covering bariatric procedures. PMID- 28730985 TI - A uniquely Canadian military moment: Sam Hughes and the No. 7 General Hospital, 1915-1916. AB - SUMMARY: Universities across Canada actively supported the call to arms in 1914, and Queen's University in Kingston, Ontario, was no different. Though a myriad of units composed of Queen's faculty and students were created, the university perceived the military hospital raised by the school's medical faculty to be among its most vital contributions to the First World War. This commentary describes the engagement of the No. 7 General Hospital with the Minister of Militia, Sam Hughes, which has become an almost unknown footnote to its illustrious story. This commentary has an Appendix, available at canjsurg.ca. PMID- 28730987 TI - Evaluation of an advanced-practice physiotherapist in triaging patients with lumbar spine pain: surgeon-physiotherapist level of agreement and patient satisfaction. AB - BACKGROUND: Surgery for lumbar spine pain is indicated for specific etiologies. Given the majority of individuals referred to spine surgeons are not surgical candidates, care delivery is inefficient, with consultations being of limited value for most. Using specially trained physiotherapists in triage is a human resource strategy that may optimize surgeons' time and the patient experience. METHODS: An advanced-practice physiotherapist (APP) and a surgeon assessed consecutive patients with lumbar spine pain presenting at an academic health centre's spine surgery clinic. The second assessor was blinded to the outcome of the first. We used the kappa statistic to evaluate surgeon-APP level of chance corrected agreement concerning patients' need for a surgical consultation. To assess satisfaction with the APP, patients completed a modified version of the validated Visit-specific Questionnaire. RESULTS: The sample included 102 participants (54 women) with a mean age of 54.3 +/- 14.3 years and a mean Oswestry Disability Index score of 35.4 +/- 16.6. The assessors' overall agreement was 86%. The kappa coefficient for the need for a surgical consultation was 0.69 (95% confidence interval 0.54-0.84). The APP identified that 77% of patients did not require a surgical consultation. Twenty-one patients underwent surgery. Satisfaction scores for the APP were very high (mean score 92 out of 100). CONCLUSION: In triaging patients with lumbar spine pain, the APP and surgeon had a high level of agreement. An APP performing triage at a surgical centre can effectively reduce wait lists by 70%, reserving surgical consultations for those patients in whom they are indicated. PMID- 28730986 TI - Long-term use of left ventricular assist devices: a report on clinical outcomes. AB - BACKGROUND: The literature examining clinical outcomes and readmissions during extended (> 1 yr) left ventricular assist device (LVAD) support is scarce, particularly in the era of continuous-flow LVADs. METHODS: We completed a retrospective cohort study on consecutive LVAD patients from June 2006 to March 2015, focusing on those who received more than 1 year of total LVAD support time. Demographic characteristics, clinical outcomes and readmissions were analyzed using standard statistical methods. All readmissions were categorized as per the Interagency Registry for Mechanically Assisted Circulatory Support 2015 guidelines. RESULTS: Of the 103 patients who received LVADs during the study period, 37 received LVAD support for more than 1 year, with 18 receiving support for more than 2 years. Average support time was 786 +/- 381 days, with total support time reaching 80 patient-years. During a median follow-up of 2 years, 27 patients died, with 1-year conditional survival of 74%. Median freedom from first readmission was 106 days (range 1-603 d), with an average length of stay of 6 days. Readmissions resulted in an average of 41 +/- 76 days in hospital per patient. Reasons for readmission were major infection (24%), major bleeding (19%) and device malfunction/thrombus (13%). There were a total of 112 procedures completed during the readmissions, with 60% of procedures being done in 13% (n = 5) of patients. CONCLUSION: Continuous-flow LVADs provide excellent long-term survival. The present study describes marked differences in reasons for readmissions between the general LVAD population and those supported for more than 1 year. Prolonged LVAD support resulted in decreased susceptibility to major bleeds and increased susceptibility to infection. PMID- 28730988 TI - Radiostereometric analysis of keeled versus pegged glenoid components in total shoulder arthroplasty: a randomized feasibility study. AB - BACKGROUND: This study aimed to assess differences in the fixation and functional outcomes between pegged and keeled all-polyethylene glenoid components for standard total shoulder arthroplasty. METHODS: Patients were randomized to receive a keeled or pegged all-polyethylene glenoid component. We used model based radiostereometric analysis (RSA) to assess glenoid fixation and subjective outcome measures to assess patient function. Follow-up examinations were completed at 6 weeks and 6, 12 and 24 months after surgery. Modifications to the RSA surgical, imaging and analytical techniques were required throughout the study to improve the viability of the data. RESULTS: Stymied enrolment resulted in only 16 patients being included in our analyses. The RSA data indicated statistically greater coronal plane migration in the keeled glenoid group than in the pegged group at 12 and 24 months. Functional outcome scores did not differ significantly between the groups at any follow-up. One patient with a keeled glenoid showed high component migration after 24 months and subsequently required revision surgery 7 years postoperatively. CONCLUSION: Despite a small sample size, we found significant differences in migration between glenoid device designs. Although clinically these findings are not robust, we have shown the feasibility of RSA in total shoulder arthroplasty as well as the value of a high precision metric to achieve objective results in a small group of patients. PMID- 28730989 TI - Users' guide to the surgical literature: how to assess an article using surrogate end points. AB - SUMMARY: Phase 3 randomized controlled trials are the widely accepted gold standard through which treatment decisions are made, as they assess the efficacy of a novel treatment against the control on the relevant patient population. The effectiveness of the novel treatment should be derived by measuring patient important outcomes; however, to accurately assess these outcomes, clinical trials often require extensive patient follow-up and large sample sizes that can incur substantial expense. For this reason, investigators substitute surrogate end points to reduce the sample size and duration of a trial, ultimately reducing cost. The purpose of this article is to help surgeons appraise the surgical literature that use surrogate end points for patient-important outcomes. PMID- 28730990 TI - In memoriam of Dr. David White, PhD, FRCPath (1946-2017). PMID- 28730991 TI - 2017 Canadian Surgery Forum Abstracts. PMID- 28730992 TI - An illustrated guide for characters and terminology used in descriptions of Phlebotominae (Diptera, Psychodidae). AB - Phlebotomine (Diptera, Psychodidae, Phlebotominae) taxonomy has been studied extensively, primarily due to the role of these flies as vectors of various parasites, including species of Leishmania, Bartonella and arboviruses that cause diseases in humans and other vertebrates. We present some topics discussed at a round-table on phlebotomine taxonomy held at the Ninth International Symposium on Phlebotomine Sandflies (ISOPS IX) in Reims, France, in June 2016. To date, approximately one thousand phlebotomine species have been described worldwide, although in varying languages and mostly without standardization of characters and terminology. In the interest of standardization, we list the characters that should minimally be considered in the description of new phlebotomine taxa as well as annotated illustrations of several characters. For these characters, multiple illustrations are provided to show some of the variations. The preferred terms for all pertinent characters are listed as well as their synonyms in English, Portuguese, and French. Finally, we offer an updated list of abbreviations to be used for generic and subgeneric names. PMID- 28730993 TI - Seroepidemiology of Sarcocystis neurona and Neospora hughesi infections in domestic donkeys (Equus asinus) in Durango, Mexico. AB - There is currently no information regarding Sarcocystis neurona and Neospora hughesi infections in donkeys in Mexico. Here, we determined the presence of antibodies against S. neurona and N. hughesi in donkeys in the northern Mexican state of Durango. Serum samples of 239 domestic donkeys (Equus asinus) were assayed for S. neurona and N. hughesi antibodies using home-made enzyme-linked immunoassays; six (2.5%) of the 239 donkeys tested seropositive for S. neurona. The seroprevalence of S. neurona infection was comparable among donkeys regardless of their origin, health status, or sex. Multivariate analysis showed that seropositivity to S. neurona was associated with increased age (OR = 2.95; 95% CI: 1.11-7.82; p = 0.02). Antibodies to N. hughesi were found in two (0.8%) of the 239 donkeys. Both exposed donkeys were healthy, 3- and 6-year-old females. This is the first evidence of S. neurona and N. hughesi infections in donkeys in Mexico. PMID- 28730995 TI - Decoding human mental states by whole-head EEG+fNIRS during category fluency task performance. AB - OBJECTIVE: Concurrent scalp electroencephalography (EEG) and functional near infrared spectroscopy (fNIRS), which we refer to as EEG+fNIRS, promises greater accuracy than the individual modalities while remaining nearly as convenient as EEG. We sought to quantify the hybrid system's ability to decode mental states and compare it with its unimodal components. APPROACH: We recorded from healthy volunteers taking the category fluency test and applied machine learning techniques to the data. MAIN RESULTS: EEG+fNIRS's decoding accuracy was greater than that of its subsystems, partly due to the new type of neurovascular features made available by hybrid data. SIGNIFICANCE: Availability of an accurate and practical decoding method has potential implications for medical diagnosis, brain computer interface design, and neuroergonomics. PMID- 28730996 TI - Correspondence between the electronic structure and phase separation in a K-doped FeSe system. AB - Phase separated potassium intercalated FeSe thin films have been synthesized by pulsed laser deposition. The coexistence of FeSe phase and 245 phase was investigated both by x-ray photoemission spectroscopy (XPS) and x-ray diffraction. The volume ratio of these two phases is sensitive to temperatures and amount of extra potassium dosing. The XPS and ultraviolet photoelectron spectroscopy results indicated that these two phases shows the different hybridization strength between adjacent Fe layer and Se layer. We infer that the layered electronic structure is the necessary condition of superconductivity in potassium-doped FeSe system, and the phase separation is driven by competition between quasi-2D and 3D bonding mode within FeSe layer. Similar competition may also be able to interpret the phase seperation in K x Fe2-y Se2 bulk single crystal. PMID- 28730994 TI - Baseline and post-treatment hepatitis C NS5A resistance in relapsed patients from a multicentric real-life cohort. AB - BACKGROUND: Recent data have suggested that failure to achieve sustained virological response with direct-acting antiviral therapy is usually due to relapse and is primarily associated with the emergence of resistance-associated substitutions. The aim of this study was to investigate the prevalence and characterization of non-structural-5A resistance-associated substitutions in patients infected with HCV genotypes 1, 3 and 4 treated by direct-acting antiviral therapy, including anti-non-structural-5A, and to characterize the pre existing resistance-associated substitutions in subjects treated with anti-non structural-5A inhibitors. METHODS: From January 2014 to March 2016, 2,995 patients infected with HCV genotypes 1, 3 and 4 were exposed to non-structural-5A inhibitors. Sequencing results at the time of virological failure were available for 61 patients; sequencing at baseline was available for 35 of these patients. RESULTS: Among the 35 patients with sequencing results available at baseline, 15 had no resistance-associated substitution, 16 had only one resistance-associated substitution, and 4 had more than one resistance-associated substitution. Resistance-associated substitutions were harbored in 57% of the sequences in the non-structural-5A region. Among the 61 patients sequenced at virological failure, 50 (82%) patients presented at least one resistance-associated substitutions inducing a high level of resistance to non-structural-5A inhibitors (>10-fold resistance). CONCLUSIONS: This pooled analysis suggests that non-structural-5A resistance-associated substitutions screening should be recommended when considering retreatment with a non-structural-5A inhibitor regimen in patients who have previously experienced failed non-structural-5A treatment. PMID- 28730997 TI - Improving the electrical contact at a Pt/TiO2 nanowire interface by selective application of focused femtosecond laser irradiation. AB - In this paper, we show that tightly focused femtosecond laser irradiation is effective in improving nanojoining of an oxide nanowire (NW) (TiO2) to a metal electrode (Pt), and how this process can be used to modify contact states. Enhanced chemical bondings are created due to localized plasmonically enhanced optical absorption at the Pt/TiO2 interface as confirmed by finite element simulations of the localized field distribution during irradiation. Nano Auger electron spectroscopy shows that the resulting heterojunction is depleted in oxygen, suggesting that a TiO2-x layer is formed between the Pt electrode and the TiO2 NW. The presence of this redox layer at the metal/oxide interface plays an important role in decreasing the Schottky barrier height and in facilitating chemical bonding. After laser irradiation at the cathode for 10 s at a fluence of 5.02 mJ cm-2, the Pt/TiO2 NW/Pt structure displays different electrical properties under forward and reverse bias voltage, respectively. The creation of this asymmetric electrical characteristic shows the way in which modification of the electronic interface by laser engineering can replace the electroforming process in resistive switching devices and how it can be used to control contact states in a metal/oxide interface. PMID- 28730998 TI - Identifying Predatory or Pseudo-journals. PMID- 28730999 TI - Surgery for benign prostatic hyperplasia: Profile of patients in a tertiary care institution. AB - BACKGROUND: Medical therapy is widely used for managing benign prostatic hyperplasia (BPH) and has made an impact on the profile of patients who ultimately undergo surgery. This changing profile may impact outcomes of surgery and associated complications. To assess the impact of medical management, we evaluated the profile of patients who had surgery for BPH at our institution. METHODS: A retrospective chart-review was performed of patient demographics, indications for surgery, preoperative comorbid conditions and postoperative course in patients who underwent surgery for BPH over a 5-year period. The data were analysed for demographic trends in comparison with historical cohorts. RESULTS: A total of 327 patients underwent surgery for BPH between 2008 and 2012. Their mean age was 66.4 years, the mean prostate gland weight was 59.2 g and the mean duration of symptoms was 35.3 months; 34% had a prostate gland weight of >60 g; 1 59 (48.6%) patients had an absolute indication for surgery; 139 (42.5%) of these were catheterized and 6.1% of patients presented with azotaemia or upper tract changes without urinary retention. CONCLUSIONS: In comparison with historical cohorts, more patients are undergoing surgery for absolute indications including retention of urine and hydroureteronephrosis. However, the patients are younger, they have fewer comorbid conditions and have a similar rate of complications after the procedure. PMID- 28731000 TI - Appropriateness-based reimbursement of elective invasive coronary procedures in low- and middle-income countries: Preliminary assessment of feasibility in India. AB - BACKGROUND: Elective coronary interventional procedures are often overused and sometimes inappropriately used. The incentives for overuse are greater in low- and middle-income countries, where much of healthcare is provided by poorly regulated, fee-for-service systems. Overuse and inappropriate use increase healthcare costs and are potentially harmful to patients. Linking appropriate use of elective procedures to their reimbursement might deter overuse. METHODS: We explored the feasibility of introducing appropriateness criteria as a precondition to settling reimbursement claims in a publicly funded health insurance scheme in Maharashtra, India. Clinical algorithms were developed from the current best-practice criteria and used to determine appropriateness at the time of obtaining pre-authorization for elective percutaneous coronary intervention (PCI) and coronary artery bypass graft (CABG) surgeries. The number of PCIs as a proportion of the total number of procedures reimbursed under the scheme was the primary outcome measure. This proportion was compared for 1-year periods before and after implementation of appropriateness-based reimbursement, using the chi-square test. Comparisons were also made separately for public and private hospitals. The change in the proportion of CABG surgeries over the same time periods was used as a comparator (as they are less subject to inappropriate use). RESULTS: The insurance scheme provided cover to a population of 20 424 585 (18.2% of the population of Maharashtra) in 8 districts, through 106 hospitals (73 private and 33 public). There was a 12.3% (95% CI 8.9%-15.5%, p=0.0001) reduction in the proportion of PCIs performed in the 1-year period after the introduction of appropriateness-based reimbursement. The reduction was similar for public and private hospitals. There was no significant change in the proportion of CABG surgeries (2.3% v. 2.2%, p=0.20). At current rates, use of appropriateness-based reimbursement would result in approximately 783 (95% CI 483 1099) less PCIs with potential annual savings of about ? 57 million (US$ 0.93 million; 95% CI 0.57-1.3) to the government scheme. CONCLUSIONS: It seems feasible to implement an appropriateness-based system for reimbursement of elective coronary interventional procedures in a government-funded health insurance scheme in a developing country. This potentially cost-saving approach may reduce inappropriate use. PMID- 28731001 TI - Economic and social impact of out-of-pocket expenditure on households of patients attending public hospitals. AB - BACKGROUND: We aimed to generate evidence on the social and economic impact of out-of-pocket expenses incurred by households on illness. METHODS: We did a hospital-based cross-sectional study including a convenience sample of 374 inpatients and outpatients. RESULTS: The median illness expenditure was the same (?62 500) for inpatients and outpatients. Of all respondents, 51.3% among the rural and 65.5% among the urban patients were employed before illness, but after illness only 24.4% among the rural and 23.4% among the urban patients remained in employment. The proportion of rural households of different socioeconomic categories that experienced decrease in expenditure on food, education and health, and those who had to sell land or cattle, and the education of whose children suffered was statistically significant. The proportion of indebted families in different socioeconomic classes was also statistically significant among both rural and urban patients. The lowest socioeconomic strata depended mostly upon the financial support of their friends to tide over the financial crisis of an illness. CONCLUSION: Our study shows that out-of-pocket expenses on healthcare are a burden not only for the poor but also the middle classes. PMID- 28731002 TI - Neuropathogenesis by Chandipura virus: An acute encephalitis syndrome in India. AB - Chandipura virus (CHPV) has been contributing to the rising number of premature deaths due to acute encephalitis syndrome for over a decade in India. CHPV belongs to the family Rhabdoviridae. Neuropathogenesis of CHPV has been well established but the exact route of entry into the central nervous system (CNS) and the triggering factor for neuronal death are still unknown. Rabies virus and vesicular stomatitis virus, which are related closely to CHPV, enter the CNS retrogradely from peripheral or olfactory neurons. Disruption of the blood-brain barrier has also been connoted in the entry of CHPV into the CNS. CHPV upon entering the neurons triggers cellular stress factors and release of reactive oxygen species (ROS). The stress granules produced in response to cellular stress have been implicated in viral replication and ROS generation, which stimulates neuronal death. Both these phenomena cohesively explain the neuropathogenesis and neurodegeneration following CHPV infection. PMID- 28731003 TI - Consolidation chemotherapy after concurrent chemoradiotherapy in locally advanced nonsquamous non-small cell lung cancer: When, in whom and how much? PMID- 28731004 TI - Early mobilization in surgical ICU: Not a chimera anymore? PMID- 28731005 TI - Preparing medical students with congenital colour vision deficiency for safe practice. AB - BACKGROUND: Colour vision of candidates is tested in many medical colleges in India at the time of admission to undergraduate courses; however, there are no guidelines, and therefore no counselling, on how students with congenital colour vision deficiency (CCVD) should negotiate the medical course, and how best they can practise safely after graduation. Problems in interpreting coloured signs may lead to misdiagnosis. This study aimed to explore difficulties during clinical work that requires colour discrimination, and to offer suggestions on safe practice based on the findings and a review of the literature. METHODS: We did a cross-sectional study after obtaining institutional ethical clearance and written informed consent. Thirty volunteer medical students with CCVD (>=3 errors on Ishihara chart) were matched with 30 volunteers from their own batch who made no errors. All participants interpreted colour-dependent clinical and laboratory photographs. RESULTS: Students with CCVD made more errors (range 5-26; mean [SD] 13.17 [5.873] out of 75 items in 35 colour-dependent photographs) than colour normal students (range 2-13; mean [SD] 5.53 [3.037], p<0.001). The nature of the errors suggested that medical students with CCVD could have problems in learning histology, pathology, haematology, microbiology, dermatology, paediatrics, medicine, biochemistry and during ophthalmoscopy. CONCLUSIONS: Screening at the time of admission will make students aware of their CCVD status and, through conscious practice thereafter, they may understand their limitations. Faculty could guide and prepare such students for safe practice. PMID- 28731006 TI - Fifth Dr Ida S. Scudder Humanitarian Oration. PMID- 28731008 TI - Letter from Mumbai. PMID- 28731007 TI - Research in India. PMID- 28731009 TI - Interlesional 'flip-flop' between 68Ga-DOTATATE and FDG-PET/CT in thyroglobulin elevated negative iodine scintigraphy (TENIS) syndrome. PMID- 28731011 TI - Erratum. PMID- 28731012 TI - Livedo reticularis after intra-articular hyaluronic acid injection. PMID- 28731013 TI - Cholinergic urticaria: Clinicoepidemiological paradigms from a tertiary care center in North India. PMID- 28731014 TI - Unilateral striate-punctate keratoderma: An extremely rare presentation of punctate keratoderma. PMID- 28731015 TI - Vitiligo developing in congenital segmental speckled lentiginous nevus: Another example of immunocompromised cutaneous district due to immunological assault on aberrant melanocytes? PMID- 28731016 TI - Hidradenitis suppurativa unresponsive to canakinumab treatment: A case report. PMID- 28731017 TI - Methotrexate iontophoresis versus coal tar ointment in palmoplantar psoriasis: A pilot study. AB - BACKGROUND: Palmoplantar psoriasis is often disabling and refractory to conventional therapy. Systemic drugs are indicated in its severe form, but side effects are a concern with their use. Methotrexate is one such systemic drug which is effective and cheap. To reduce systemic toxicity, methotrexate has been tried topically but results have been inconsistent due to poor drug penetration into the skin by passive diffusion. Iontophoresis may enhance its absorption and efficacy. AIM: To evaluate the efficacy and safety of topical methotrexate iontophoresis in comparison with coal tar ointment in the treatment of palmoplantar psoriasis. METHODS: Thirty-one patients with palmar and/or plantar psoriasis were selected for the study and 28 patients completed it. The side having more severe involvement was treated while the other palm/sole served as a control. Iontophoresis using methotrexate solution was carried out on the study palm/sole with the injectable preparation of methotrexate (50 mg/2 ml) once a week for the first 4 weeks and subsequently every two weeks, for a total of six sittings. The control palm/sole was treated with coal tar ointment on other days. Erythema, scaling, induration and fissuring scores were noted in both groups before and after treatment. RESULTS: Both study and control groups showed decreases in scores but the reduction was more in the study group, the difference being statistically significant. LIMITATIONS: Drawbacks of our study include the small sample size and the lack of follow-up. The study and control arms were not exactly matched and the study was not blinded. CONCLUSION: Methotrexate iontophoresis was safe and more effective than coal tar ointmentin palmoplantarpsoriasis. PMID- 28731018 TI - Palmoplantar aquagenic urticaria: A case report. PMID- 28731019 TI - Dermatomyositis revealing both a metastatic linitis plastica and hepatitis C virus infection. PMID- 28731020 TI - Long-term result of hair transplantation for therapy resistant alopecia areata of eyebrows. PMID- 28731021 TI - Wickham's striae-like appearance in a case of nodular Kaposi's sarcoma: A dermoscopic pitfall. PMID- 28731022 TI - The growing clinical importance of functional tricuspid valve regurgitation. PMID- 28731023 TI - An "extinct volcano": a stable ruptured coronary plaque shown by OCT imaging. PMID- 28731024 TI - Permanent pacemaker implantation and Takotsubo syndrome: should we revise our modus operandi? PMID- 28731025 TI - Long-term changes in ventricular repolarization induced by coronary artery bridging in primary hypertrophic cardiomyopathy. PMID- 28731026 TI - The novel gene HA117 promotes in vitro and in vivo drug resistance in mouse colon tumor cells. AB - In this study, we characterized the role of HA117, a novel gene we previously identified, in drug resistance in vitro and in vivo. Briefly, CT26 cells expressing HA117 were obtained by infection with a recombinant adenovirus, and tested for drug sensitivity by methyl thiazolyl tetrazolium assay. In addition, the effect of HA117 on drug sensitivity was assessed in CT26 colon tumors transplanted into nude mice. In vitro, expression of HA117 increased the resistance of CT26 cells to 5-fluorouracil 2.75 times (P<0.05). Similarly, expression of HA117 in subcutaneously xenografted CT26 colon cancer significantly lowered its sensitivity to 5-fluorouracil (P<0.05). Collectively, the results suggest that HA117 regulates the development of drug resistance in CT26 cells in vitro and in vivo. PMID- 28731027 TI - PTENP1 acts as a ceRNA to regulate PTEN by sponging miR-19b and explores the biological role of PTENP1 in breast cancer. AB - This study aimed to investigate role of long noncoding RNA PTENP1 regulating PTEN expression via miR-19b to affect breast cancer (BC) progression. We measured expressions of PTENP1, miR-19b and PTEN in 65 matched BC cancerous and noncancerous tissues by quantitative real-time fluorescence PCR (qRT-PCR) and investigated the biological effects of PTENP1 in BC MDA-MB-231 cells by several in vitro experiments including CCK8, wound healing, transwell and Annexin V FITC/PI analysis. Besides, the competing endogenous RNA (ceRNA) activity of PTENP1 on miR-19b was detected by luciferase reporter assay, and the expressions of related genes and proteins were determined by western blot assay and qRT-PCR. Increased PTENP1 and PTEN and decreased miR-19b were observed in BC tissues and cell lines. Further, PTENP1 and PTEN are direct targets of miR-19b, and overexpressed PTENP1 in MDA-MB-231 cells could supress cell proliferation, migration and invasion and promote cell apoptosis. Moreover, PTENP1 could upregulate PTEN via its ceRNA interaction on miR-19b, as well as induced the upregulation of p53 and downregulation of p-AKT. Enhanced PTENP1 could inhibit BC cell growth, metastasis and tumourigenicity by inhibiting miR-19b and facilitating PTEN in BC, thereby may represent a novel target for diagnosis and treatment of BC. PMID- 28731028 TI - Corrigendum: A UK wide cohort study describing management and outcomes for infants with surgical Necrotising Enterocolitis. AB - This corrects the article DOI: 10.1038/srep41149. PMID- 28731029 TI - Nrp2 is sufficient to instruct circuit formation of mitral-cells to mediate odour induced attractive social responses. AB - Odour information induces various innate responses that are critical to the survival of the individual and for the species. An axon guidance molecule, Neuropilin 2 (Nrp2), is known to mediate targeting of olfactory sensory neurons (primary neurons), to the posteroventral main olfactory bulb (PV MOB) in mice. Here we report that Nrp2-positive (Nrp2+) mitral cells (MCs, second-order neurons) play crucial roles in transmitting attractive social signals from the PV MOB to the anterior part of medial amygdala (MeA). Semaphorin 3F, a repulsive ligand to Nrp2, regulates both migration of Nrp2+ MCs to the PV MOB and their axonal projection to the anterior MeA. In the MC-specific Nrp2 knockout mice, circuit formation of Nrp2+ MCs and odour-induced attractive social responses are impaired. In utero, electroporation demonstrates that activation of the Nrp2 gene in MCs is sufficient to instruct their circuit formation from the PV MOB to the anterior MeA. PMID- 28731030 TI - Cryo-EM structure and biochemical analysis reveal the basis of the functional difference between human PI3KC3-C1 and -C2. AB - Phosphatidylinositol 3-phosphate (PI3P) plays essential roles in vesicular trafficking, organelle biogenesis and autophagy. Two class III phosphatidylinositol 3-kinase (PI3KC3) complexes have been identified in mammals, the ATG14L complex (PI3KC3-C1) and the UVRAG complex (PI3KC3-C2). PI3KC3-C1 is crucial for autophagosome biogenesis, and PI3KC3-C2 is involved in various membrane trafficking events. Here we report the cryo-EM structures of human PI3KC3-C1 and PI3KC3-C2 at sub-nanometer resolution. The two structures share a common L-shaped overall architecture with distinct features. EM examination revealed that PI3KC3-C1 "stands up" on lipid monolayers, with the ATG14L BATs domain and the VPS34 C-terminal domain (CTD) directly contacting the membrane. Biochemical dissection indicated that the ATG14L BATs domain is responsible for membrane anchoring, whereas the CTD of VPS34 determines the orientation. Furthermore, PI3KC3-C2 binds much more weakly than PI3KC3-C1 to both PI containing liposomes and purified endoplasmic reticulum (ER) vesicles, a property that is specifically determined by the ATG14L BATs domain. The in vivo ER localization analysis indicated that the BATs domain was required for ER localization of PI3KC3. We propose that the different lipid binding capacity is the key factor that differentiates the functions of PI3KC3-C1 and PI3KC3-C2 in autophagy. PMID- 28731031 TI - NLRP9b: a novel RNA-sensing inflammasome complex. AB - Inflammasome sensors recognize pathogens and danger signals and assemble an immune signaling complex, which induces the secretion of pro-inflammatory cytokines IL-1beta and IL-18, and pyroptosis. A new study published in Nature now describes a new inflammasome sensor NLRP9b in intestinal epithelial cells, which in concert with the RNA sensor DHX9, recognize short dsRNA from Rotavirus. PMID- 28731032 TI - Corrigendum: Asymmetric parental genome engineering by Cas9 during mouse meiotic exit. AB - This corrects the article DOI: 10.1038/srep07621. PMID- 28731033 TI - Linking brain connectivity and behavior after acute and chronic alcohol exposure. PMID- 28731035 TI - Growth and development: Dwarfism linked to hypertension treatment. PMID- 28731034 TI - Regulation of hepatic glucose metabolism in health and disease. AB - The liver is crucial for the maintenance of normal glucose homeostasis - it produces glucose during fasting and stores glucose postprandially. However, these hepatic processes are dysregulated in type 1 and type 2 diabetes mellitus, and this imbalance contributes to hyperglycaemia in the fasted and postprandial states. Net hepatic glucose production is the summation of glucose fluxes from gluconeogenesis, glycogenolysis, glycogen synthesis, glycolysis and other pathways. In this Review, we discuss the in vivo regulation of these hepatic glucose fluxes. In particular, we highlight the importance of indirect (extrahepatic) control of hepatic gluconeogenesis and direct (hepatic) control of hepatic glycogen metabolism. We also propose a mechanism for the progression of subclinical hepatic insulin resistance to overt fasting hyperglycaemia in type 2 diabetes mellitus. Insights into the control of hepatic gluconeogenesis by metformin and insulin and into the role of lipid-induced hepatic insulin resistance in modifying gluconeogenic and net hepatic glycogen synthetic flux are also discussed. Finally, we consider the therapeutic potential of strategies that target hepatosteatosis, hyperglucagonaemia and adipose lipolysis. PMID- 28731037 TI - Dementia: Skin alpha-synuclein deposits - a new biomarker for DLB? PMID- 28731038 TI - Alzheimer disease: Tau pathology in atomic detail. PMID- 28731036 TI - Stroke in women - from evidence to inequalities. AB - Stroke is the second largest cause of disability-adjusted life-years lost worldwide. The prevalence of stroke in women is predicted to rise rapidly, owing to the increasing average age of the global female population. Vascular risk factors differ between women and men in terms of prevalence, and evidence increasingly supports the clinical importance of sex differences in stroke. The influence of some risk factors for stroke - including diabetes mellitus and atrial fibrillation - are stronger in women, and hypertensive disorders of pregnancy also affect the risk of stroke decades after pregnancy. However, in an era of evidence-based medicine, women are notably under-represented in clinical trials - despite governmental actions highlighting the need to include both men and women in clinical trials - resulting in a reduced generalizability of study results to women. The aim of this Review is to highlight new insights into specificities of stroke in women, to plan future research priorities, and to influence public health policies to decrease the worldwide burden of stroke in women. PMID- 28731039 TI - Peripheral neuropathies: Long-term opioid therapy in neuropathy: benefit or harm? PMID- 28731041 TI - Risk assessment in solitary fibrous tumors: validation and refinement of a risk stratification model. AB - Solitary fibrous tumors are an uncommon sarcoma type characterized by NAB2-STAT6 gene fusion. While solitary fibrous tumors metastasize in 5-25% of cases, it has historically been challenging to determine which specific tumor and patient characteristics predict aggressive behavior. We previously reported on a novel risk stratification scheme for solitary fibrous tumors incorporating patient age, tumor size, and mitotic activity to predict risk of metastasis. Herein we validate this risk stratification scheme in an independent, lower-risk population of 79 patients with primary non-meningeal solitary fibrous tumors, and propose incorporating tumor necrosis as a fourth variable to further improve the risk score. Fifty-seven percent of cases were considered low risk, 29% intermediate risk, and 14% high risk for metastasis. Of 50 patients with sufficient clinical follow-up data, no metastases developed in the low-risk patients (n=23), while there was a 7% 10-year metastatic risk in the intermediate risk group (n=17), and a 49% 5-year metastatic risk for the high-risk patients (n=10). When tumor necrosis was added as a fourth variable to the model, predictive power was enhanced. Under the revised stratification, the proportion of tumors identified as low risk increased to 66%, with no metastasis at 10 years, intermediate risk cases comprised 24% with 10% risk of metastasis at 10 years, and high risk comprised 10% of cases with 73% risk of metastasis at 5 years. In Kaplan-Meier analysis, this fourth-variable stratification provided significant discrimination between the risk groups (P=0.0005). These findings confirmed the clinical utility of our previously published risk stratification model and support the inclusion of necrosis as a fourth variable in the model. PMID- 28731040 TI - ER stress and the unfolded protein response in neurodegeneration. AB - The clinical manifestation of neurodegenerative diseases is initiated by the selective alteration in the functionality of distinct neuronal populations. The pathology of many neurodegenerative diseases includes accumulation of misfolded proteins in the brain. In physiological conditions, the proteostasis network maintains normal protein folding, trafficking and degradation; alterations in this network - particularly disturbances to the function of endoplasmic reticulum (ER) - are thought to contribute to abnormal protein aggregation. ER stress triggers a signalling reaction known as the unfolded protein response (UPR), which induces adaptive programmes that improve protein folding and promote quality control mechanisms and degradative pathways or can activate apoptosis when damage is irreversible. In this Review, we discuss the latest advances in defining the functional contribution of ER stress to brain diseases, including novel evidence that relates the UPR to synaptic function, which has implications for cognition and memory. A complex concept is emerging wherein the consequences of ER stress can differ drastically depending on the disease context and the UPR signalling pathway that is altered. Strategies to target specific components of the UPR using small molecules and gene therapy are in development, and promise interesting avenues for future interventions to delay or stop neurodegeneration. PMID- 28731042 TI - Molecular alterations of coexisting thyroid papillary carcinoma and anaplastic carcinoma: identification of TERT mutation as an independent risk factor for transformation. AB - Thyroid papillary carcinoma is the most common endocrine neoplasm and generally carries a favorable prognosis. However, a small subset of papillary carcinomas transforms into anaplastic carcinoma, an undifferentiated cancer with a dismal prognosis. Recent studies using next-generation sequencing revealed the genomic landscape of papillary carcinoma and anaplastic carcinoma. However, risk factors for anaplastic transformation in papillary carcinoma remain obscure. In the present study, we investigated molecular alterations of papillary carcinoma and anaplastic carcinoma components in 27 tumors in which anaplastic carcinoma coexisted with antecedent papillary carcinoma. We conducted direct sequencing for BRAF, TERT promoter and PIK3CA, and immunohistochemistry for p53, TTF-1 and subunits of the SWI/SNF complex (ARID1A, ARID1B, ATRX, SMARCA2, SMARCA4, SMARCB1, and PBRM1). BRAFV600E and TERT promoter mutated at the rate of 90% and 95%, respectively, and these mutational statuses were almost identical between the papillary carcinoma and anaplastic carcinoma components. PIK3CA mutation was positive in 33% of our samples with a heterogeneous mutation pattern of the papillary carcinoma and anaplastic carcinoma components. Aberrant expression of p53 and loss of TTF-1 were present in 63 and 59%, respectively, and these two alterations were confined to the anaplastic carcinoma components. There was a loss of the SWI/SNF complex in a subset of the tumors with a heterogeneous pattern of the papillary carcinoma and anaplastic carcinoma components: SMARCA4 in 4% and PBRM1 in 4%. In a multivariate comparison between the antecedent papillary carcinoma components and control papillary carcinomas without anaplastic transformation, TERT promoter mutation was independently associated with anaplastic transformation. Collectively, papillary carcinoma-derived anaplastic carcinomas are characterized by BRAF and TERT promoter mutations, and these mutations occur prior to anaplastic transformation. Alterations of PIK3CA and the SWI/SNF complex are relatively rare and temporally heterogeneous. Of note, a papillary carcinoma harboring TERT promoter mutation is at higher risk for anaplastic transformation. PMID- 28731043 TI - Gastroblastoma harbors a recurrent somatic MALAT1-GLI1 fusion gene. AB - Gastroblastoma is a rare distinctive biphasic tumor of the stomach. The molecular biology of gastroblastoma has not been studied, and no affirmative diagnostic markers have been developed. We retrieved two gastroblastomas from the consultation practices of the authors and performed transcriptome sequencing on formalin-fixed paraffin-embedded tissue. Recurrent predicted fusion genes were validated at genomic and RNA levels. The presence of the fusion gene was confirmed on two additional paraffin-embedded cases of gastroblastoma. Control cases of histologic mimics (biphasic synovial sarcoma, leiomyoma, leiomyosarcoma, desmoid-type fibromatosis, EWSR1-FLI1-positive Ewing sarcoma, Wilms' tumor, gastrointestinal stromal tumor, plexiform fibromyxoma, Sonic hedgehog-type medulloblastomas, and normal gastric mucosa and muscularis propria were also analyzed. The gastroblastomas affected two males and two females aged 9-56 years. Transcriptome sequencing identified recurrent somatic MALAT1-GLI1 fusion genes, which were predicted to retain the key domains of GLI1. The MALAT1-GLI1 fusion gene was validated by break-apart and dual-fusion FISH and RT-PCR. The additional two gastroblastomas were also positive for the MALAT1-GLI1 fusion gene. None of the other control cases harbored MALAT1-GLI1. Overexpression of GLI1 in the cases of gastroblastomas was confirmed at RNA and protein levels. Pathway analysis revealed activation of the Sonic hedgehog pathway in gastroblastoma and gene expression profiling showed that gastroblastomas grouped together and were most similar to Sonic hedgehog-type medulloblastomas. In summary, we have identified an oncogenic MALAT1-GLI1 fusion gene in all cases of gastroblastoma that may serve as a diagnostic biomarker. The fusion gene is predicted to encode a protein that includes the zinc finger domains of GLI1 and results in overexpression of GLI1 protein and activation of the Sonic hedgehog pathway. PMID- 28731044 TI - Computer-assisted measurement of primary tumor area is prognostic of recurrence free survival in stage IB melanoma patients. AB - Current staging guidelines are insufficient to predict which patients with thin primary melanoma are at high risk of recurrence. Computer-assisted image analysis may allow for more practical and objective histopathological analysis of primary tumors than traditional light microscopy. We studied a prospective cohort of stage IB melanoma patients treated at NYU Langone Medical Center from 2002 to 2014. Primary tumor width, manual area, digital area, and conformation were evaluated in a patient subset via computer-assisted image analysis. The associations between histologic variables and survival were evaluated using Cox proportional hazards model. Logistic regressions were used to build a classifier with clinicopathological characteristics to predict recurrence status. Of the 655 patients with stage IB melanoma studied, a subset of 149 patient tumors (63 recurred, 86 did not recur) underwent computer-assisted histopathological analysis. Increasing tumor width (hazard ratios (HR): 1.17, P=0.01) and digital area (HR: 1.08, P<0.01) were significantly associated with worse recurrence-free survival, whereas non-contiguous conformation (HR: 0.57, P=0.05) was significantly associated with better recurrence-free survival. The novel histopathological classifier composed of digital area, conformation, and baseline variables effectively distinguished recurrent cases from non-recurrent cases (AUC: 0.733, 95% confidence interval (CI): 0.647-0.818), compared to the baseline classifier alone (AUC: 0.635, 95% CI: 0.545-0.724). Primary tumor cross-sectional area, width, and conformation measured via computer-assisted analysis may help identify high-risk patients with stage IB melanoma. PMID- 28731045 TI - Renal cell tumors with clear cell histology and intact VHL and chromosome 3p: a histological review of tumors from the Cancer Genome Atlas database. AB - Clear cell renal cell carcinoma is by far the most common form of kidney cancer; however, a number of histologically similar tumors are now recognized and considered distinct entities. The Cancer Genome Atlas published data set was queried (http://cbioportal.org) for clear cell renal cell carcinoma tumors lacking VHL gene mutation and chromosome 3p loss, for which whole-slide images were reviewed. Of the 418 tumors in the published Cancer Genome Atlas clear cell renal cell carcinoma database, 387 had VHL mutation, copy number loss for chromosome 3p, or both (93%). Of the remaining, 27/31 had whole-slide images for review. One had 3p loss based on karyotype but not sequencing, and three demonstrated VHL promoter hypermethylation. Nine could be reclassified as distinct or emerging entities: translocation renal cell carcinoma (n=3), TCEB1 mutant renal cell carcinoma (n=3), papillary renal cell carcinoma (n=2), and clear cell papillary renal cell carcinoma (n=1). Of the remaining, 6 had other clear cell renal cell carcinoma-associated gene alterations (PBRM1, SMARCA4, BAP1, SETD2), leaving 11 specimens, including 2 high-grade or sarcomatoid renal cell carcinomas and 2 with prominent fibromuscular stroma (not TCEB1 mutant). One of the remaining tumors exhibited gain of chromosome 7 but lacked histological features of papillary renal cell carcinoma. Two tumors previously reported to harbor TFE3 gene fusions also exhibited VHL mutation, chromosome 3p loss, and morphology indistinguishable from clear cell renal cell carcinoma, the significance of which is uncertain. In summary, almost all clear cell renal cell carcinomas harbor VHL mutation, 3p copy number loss, or both. Of tumors with clear cell histology that lack these alterations, a subset can now be reclassified as other entities. Further study will determine whether additional entities exist, based on distinct genetic pathways that may have implications for treatment. PMID- 28731046 TI - PD-L1 expression and the immune microenvironment in primary invasive lobular carcinomas of the breast. AB - Tumor-infiltrating lymphocytes and immune checkpoint proteins such as PD-L1 are potential prognostic factors and therapeutic targets in breast cancer. Most studies characterizing the breast tumor immune microenvironment have focused on ductal carcinomas. Here we investigate the tumor microenvironment of primary invasive lobular carcinomas. Previously constructed tissue microarrays of 47 lobular carcinomas were labeled by immunohistochemistry for PD-L1, CD8, CD20, and FoxP3. The stromal immune infiltrate density was qualitatively scored as a percentage of tumor area: 1+ (<5%); 2+ (5-10%); 3+ (10-15%); or 4+ (>50%). The average immune cell subtype per high-power field was quantitatively scored. The percentage PD-L1 labeling on tumor-infiltrating lymphocytes was scored as none, focal (<5%), moderate (10-24%), or diffuse (50-100%). The percentage of membranous carcinoma cell PD-L1 labeling was also recorded, with <5% considered negative. All lobular carcinomas contained PD-L1+ tumor-infiltrating lymphocytes with the majority showing 1+ immune infiltrates with focal-moderate PD-L1 labeling. PD-L1 was expressed by tumor cells in 17% of lobular carcinomas. In contrast to ductal carcinomas, there was no correlation between the immune infiltrate density, the PD-L1 expression by lobular carcinoma cells, tumor grade, or the expression of estrogen receptor or human epidermal growth factor receptor 2. However, both the tumor-infiltrating lymphocyte density and the average CD8+ T cell counts correlated with immune cell PD-L1 status (P=0.004 and 0.03, respectively). Similar to breast ductal carcinomas, PD-L1+ lobular breast carcinomas had higher numbers of PD-L1+ tumor-infiltrating lymphocytes (63%) than PD-L1- lobular carcinomas (23%; P=0.04). These data show that a subset of primary breast lobular carcinomas both express PD-L1 on tumor cells and contain PD-L1+ tumor-infiltrating lymphocytes, suggesting the possibility of both constitutive and adaptive PD-L1 expression. Together, these results support immunotherapy as a potential treatment for a subset of patients with primary invasive lobular breast carcinomas. PMID- 28731047 TI - Targeted next-generation sequencing supports epidermoid metaplasia of the esophagus as a precursor to esophageal squamous neoplasia. AB - Esophageal epidermoid metaplasia is a rare condition that involves the proximal to-middle third of the esophagus. It is sharply demarcated and defined histologically by epithelial hyperplasia, a prominent granular cell layer, and superficial hyperorthokeratosis. In addition, preliminary studies have suggested an association between esophageal epidermoid metaplasia and esophageal squamous neoplasia (squamous dysplasia and esophageal squamous cell carcinoma). To further characterize esophageal epidermoid metaplasia and better define its relationship to squamous neoplasia of the esophagus, we performed targeted next-generation sequencing on uninvolved esophageal squamous mucosa and matching esophageal epidermoid metaplasia specimens from 18 patients. Further, we evaluated both synchronous and metachronous high-grade squamous dysplasia/esophageal squamous cell carcinoma by next-generation sequencing from 5 of the 18 (28%) patients, and compared these findings to corresponding esophageal epidermoid metaplasia specimens. Targeted next-generation sequencing revealed 12 of 18 (67%) esophageal epidermoid metaplasia specimens' harbored alterations in genes often associated with esophageal squamous cell carcinoma. The most frequently mutated genes consisted of TP53 (n=10), PIK3CA (n=2), EGFR (n=2), MYCN (n=1), HRAS (n=1), and the TERT promoter (n=1). Sequencing of synchronous and metachronous high-grade squamous dysplasia/esophageal squamous cell carcinoma identified shared genetic alterations with corresponding esophageal epidermoid metaplasia specimens that suggests a clonal relationship between these entities. In addition, the presence of a TP53 mutation in esophageal epidermoid metaplasia specimens correlated with concurrent or progression to high-grade squamous dysplasia/esophageal squamous cell carcinoma. No genetic alterations were detected in uninvolved esophageal squamous mucosa. On the basis of these findings, we conclude esophageal epidermoid metaplasia is a precursor to in situ and invasive esophageal squamous neoplasia. Further, the detection of TP53 mutations in esophageal epidermoid metaplasia specimens may serve as an early detection biomarker for high-grade squamous dysplasia/esophageal squamous cell carcinoma. PMID- 28731048 TI - Altered peritumoral microRNA expression predicts head and neck cancer patients with a high risk of recurrence. AB - Head and neck squamous cell carcinoma is typically characterized by a high incidence of local recurrences. It has been extensively shown that mucosa from head and neck squamous cell carcinoma patients carries both genetic and gene expression alterations, which are mostly attributable to major etiologic agents of head and neck squamous cell carcinoma. We previously identified a signature of microRNAs (miRNAs) whose high expression in tumors is predictive of recurrence. Here, we investigated whether the deregulation of miRNA expression in the tumor surrounding mucosa is correlated to disease recurrence. Specifically, comparing the miRNA expression in matched tumoral, peritumoral, and normal tissues collected from head and neck squamous cell carcinoma patients, we identified 35 miRNAs that are deregulated in both tumoral and peritumoral tissues as compared with normal matched samples. Four of these composed a miRNA signature that predicts head and neck squamous cell carcinoma local recurrence independently from prognostic clinical variables. The predictive power of the miRNA signature increased when using the expression levels derived from both the peritumoral and the tumoral tissues. The expression signal of the miRNAs composing the predictive signature correlated with the transcriptional levels of genes mostly associated with proliferation. Our results show that expression of miRNAs in tumor surrounding mucosa may strongly contribute to the identification of head and neck squamous cell carcinoma patients at high risk of local recurrence. PMID- 28731049 TI - Composite hemangioendothelioma with neuroendocrine marker expression: an aggressive variant. AB - Aberrant expression of neuroendocrine markers is extremely rare in endothelial neoplasms, with only a single report describing three cases. Although originally classified as conventional angiosarcoma, further assessment of these tumors revealed a strikingly composite morphology composed of retiform and epithelioid elements reminiscent of composite hemangioendothelioma, a rare subtype of hemangioendothelioma. To further investigate these findings, available materials from 11 morphologically distinctive endothelial tumors showing neuroendocrine marker expression were retrieved from our archives. Immunohistochemistry for CD31, CD34, FLI-1, synaptophysin, chromogranin, D2-40, ERG, keratin (OSCAR), and CAMTA1 was performed. Total RNA from five cases were extracted and subjected to whole transcriptome sequencing. Clinical follow-up was obtained. These tumors were found to arise in five males and six females in patients from 9 to 55 years in age (median 47 years). They arose both in superficial (wrist, ankle, scalp, hip, and foot) and deep (periaortic tissues, C5 vertebra, pulmonary vein, and liver) locations. All contained elongated, retiform vascular channels lined by hyperchromatic 'hobnail' endothelial cells and a solid growth of uniform epithelioid cells reminiscent of epithelioid hemangioendothelioma. Hemangioma like foci also lined by hobnail endothelial cells were frequently present. Mitotic activity was typically <1/10 HPF, and necrosis or areas of conventional angiosarcoma was absent. The results of immunohistochemistry were: CD31 (10/10), FLI-1 (10/10), ERG (9/9), CD34 (5/10), D2-40 (7/10), synaptophysin (11/11), chromogranin A (1/11), CD56 (5/11), keratin (0/11), and CAMTA1 (0/6). Sequencing analysis showed one case with PTBP1-MAML2 and one case with EPC1-PHC2 fusion transcripts; fusion transcripts were not identified in the remaining cases. Follow-up (8 cases) revealed local recurrence in one patient and metastatic spread in four individuals (bone, lung, liver, and brain). One person died of disease. Although the morphological features of these tumors are characteristic of composite hemangioendothelioma, this distinctive subset with neuroendocrine differentiation more often involves deep locations and displays more aggressive behavior than typically described in other cases of composite hemangioendothelioma. PMID- 28731050 TI - Genomic abnormalities in invasive endocervical adenocarcinoma correlate with pattern of invasion: biologic and clinical implications. AB - The pattern-based classification system for HPV-related endocervical adenocarcinoma, which classifies tumors based on the destructiveness of stromal invasion, is predictive of the risk of nodal metastases and adverse outcome. Previous studies have demonstrated clinically important molecular alterations in endocervical adenocarcinoma, including KRAS and PIK3CA mutations; however, correlation between the molecular landscape and pathological variables including pattern of invasion has not been thoroughly explored. In this study, 20 endocervical adenocarcinomas were classified using the pattern-based classification system and were subjected to targeted sequencing using the Ion AmpliSeq Cancer Hotspot Panel v2 (ThermoFisher Scientific, Waltham, MA, USA) that surveys hotspot regions of 50 oncogenes and tumor suppressor genes. Single nucleotide polymorphisms were correlated with clinical and pathologic variables including pattern of invasion. Five (25%), six (30%), and nine (45%) cases were classified as patterns A, B, and C respectively. Lymph node metastases, advanced stage at presentation and mortality from disease were exclusively seen in destructively invasive tumors (patterns B or C). Prevalent mutations in the cohort involved PIK3CA (30%), KRAS (30%), MET (15%), and RB1 (10%). Most (94%) relevant genomic alterations were present in destructively invasive tumors with PIK3CA, KRAS, and RB1 mutations seen exclusively in pattern B or C subgroups. KRAS mutations correlated with advanced stage at presentation (FIGO stage II or higher). Our findings indicate that the pattern of stromal invasion correlates with genomic abnormalities detected by next-generation sequencing, suggesting that tumors without destructive growth (pattern A) are biologically distinct from those with destructive invasion (patterns B and C), and that pattern B endocervical adenocarcinoma is more closely related to its pattern C counterpart. The pattern-based classification may be used as a triage tool when considering molecular testing for prognostic or therapeutic purposes. PMID- 28731051 TI - Neurotropic melanoma: an analysis of the clinicopathological features, management strategies and survival outcomes for 671 patients treated at a tertiary referral center. AB - Neurotropic cutaneous melanoma is a rare melanoma subtype that invades nerves and is often associated with desmoplastic melanoma. Limited data suggest that it has a greater propensity to recur locally, but it is unknown whether its behavior differs from that of other melanoma subtypes, including desmoplastic melanoma. We investigated clinicopathological predictors of outcome in a cohort of 671 patients with neurotropic melanoma to develop evidence-based management recommendations. Patients with primary neurotropic melanoma diagnosed from 1985 to 2013 were identified from the Melanoma Institute Australia database, along with a control cohort of 718 non-neurotropic melanoma patients. Features predictive of sentinel lymph node status, recurrence, melanoma-specific survival and response to adjuvant radiotherapy were sought. Neither local recurrence (hazard ratio: 1.28 (0.73-2.25) P=0.39) nor melanoma-specific survival (hazard ratio: 0.79 (0.55-1.15) P=0.22) were significantly affected by the presence of neurotropism on multivariate analysis. However, there was a markedly reduced likelihood of sentinel node positivity (hazard ratio: 0.61 (0.41-0.89) P=0.01) in neurotropic melanoma patients. Surgical margins >=8mm halved the recurrence risk compared with <2 mm margins (hazard ratio: 0.46 (0.31-0.68) P<0.001). Additionally, in neurotropic melanoma patients with <8 mm margins, adjuvant radiotherapy halved the recurrence risk (hazard ratio: 0.48 (0.27-0.87) P=0.02). This, the largest study of neurotropic melanoma reported to date, has demonstrated that the presence of neurotropism does not alter the risk of melanoma recurrence or survival but does reduce the likelihood of sentinel node positivity. For successful treatment of neurotropic melanoma, adequate excision margins are of paramount importance. However, when adequate margins cannot be achieved, adjuvant radiotherapy reduces the risk of recurrence. PMID- 28731052 TI - Real-world visual acuity outcomes between ranibizumab and aflibercept in treatment of neovascular AMD in a large US data set. AB - PurposeTo examine 12-month real-world visual acuity outcomes and treatment patterns in neovascular age-related macular degeneration (nAMD) eyes, including those with pigment epithelial detachment (PED), receiving ranibizumab or aflibercept.Patients and methodsElectronic medical records were used to identify ranibizumab or aflibercept-treated nAMD eyes with 12 months follow-up from first prescription. The primary objective was to compare mean change in visual acuity (VA) between index and month 12, in eyes treated with ranibizumab and aflibercept to assess the non-inferiority of ranibizumab vs aflibercept using a -5 letter non inferiority margin. The number of injections and non-injection visits during follow-up were key secondary objectives.ResultsA total of 3350 ranibizumab and 4300 aflibercept treatment-naive eyes were included. At month 12, mean change from index in VA letter score was -0.30 for ranibizumab and -0.19 for aflibercept (P=0.81). The adjusted difference of mean change was -0.14 (-0.79 to 0.51) (P=0.67) (generalized estimating equations method) confirming the non-inferiority of ranibizumab. Eyes received a similar number of injections during follow-up. The mean (+/-SD) number of ranibizumab and aflibercept injections were 6.70 (+/ 2.54) and 7.00 (+/-2.40), respectively (P<0.0001). In PED eyes, the mean (+/-SD) change between baseline to month 12 was 1.25 (+/-11.3) for ranibizumab and -0.39 (+/-13.3) for aflibercept (adjusted between-group difference 1.80 (-0.71 to 4.30; P=0.16)) achieved with a mean (+/-SD) 7.85 (+/-2.68) ranibizumab and 7.47 (+/ 2.45) aflibercept injections, (P=0.11).ConclusionsRanibizumab and aflibercept treatment yielded comparable VA outcomes in nAMD eyes, including those with PED, with similar treatment patterns over 12 months in real-world clinical practice. PMID- 28731053 TI - OCT angiography documented reperfusion of translocated autologous full thickness RPE-choroid graft for complicated neovascular age-related macular degeneration. AB - PurposeThe purpose of this study is to investigate the reperfusion of translocated retinal pigment epithelium (RPE)-choroid graft in the treatment of patients with neovascular age-related macular degeneration (nAMD), using OCT angiography (OCTA), a novel non-invasive, high-resolution imaging modality.Patients and methodsEighteen eyes of 18 consecutive patients suffering from complicated nAMD underwent RPE-choroid patch graft translocation surgery using a peripheral retinotomy and flap-over technique. We analyzed functional and anatomical outcome using visual acuity, Spectral Domain OCT and OCTA.ResultsWith a mean follow-up of 11 months, out of 18 patients, 15 gained vision, 1 remained stable, and 2 lost vision. Overall, the visual acuity improved with a mean of 30 letters. Perfusion of the graft tissue was confirmed in all patients. Two patients developed signs of a recurrent neovascular membrane during follow-up. No cases of proliferative vitreoretinopathy occurred in this series.ConclusionsOCTA images show signs of perfusion in all grafts. Encouraging functional results and low risk of severe complications suggest that RPE-choroid graft translocation is a valid option in patients with complicated nAMD. PMID- 28731054 TI - Does bariatric surgery prevent progression of diabetic retinopathy? AB - PurposeTo assess the changes in diabetic retinopathy (DR) in type 2 diabetes (T2DM) patients post bariatric surgery and report on the risk factors that may be associated with it.Patients and methodsRetrospective observational study of T2DM patients who underwent bariatric surgery in a UK specialist bariatric unit between 2009 and 2015. Preoperative and postoperative weight, HbA1c, and annual DR screening results were collected from medical records. Patients with preoperative retinal screening and at least one postoperative retinal screening were eligible for analysis. Multivariate analysis was used to explore significant clinical predictors on postoperative worsening in DR.ResultsA total of 102 patients were eligible for analysis and were followed up for 4 years. Preoperatively, 68% of patients had no DR compared to 30% with background retinopathy, 1% pre-proliferative retinopathy, and 1% proliferative retinopathy. In the first postoperative visit, 19% of patients developed new DR compared to 70% stable and 11% improved. These proportions remained similar for each postoperative visit over time. Young age, male gender, high preoperative HbA1c, and presence of preoperative retinopathy were the significant predictors of worsening postoperatively.ConclusionBariatric surgery does not prevent progression of DR. Young male patients with pre-existing DR and poor preoperative glycaemic control are most at risk of progression. All diabetic patients should attend regular DR screening post bariatric surgery to allow early detection of potentially sight-threatening changes, particularly among those with identifiable risk factors. Future prospective studies with prolonged follow-up are required to clarify the duration of risk. PMID- 28731055 TI - Choroidal excavation in choroidal osteoma complicated by choroidal neovascularization. AB - PurposeTo describe multimodal imaging features of choroidal osteoma (CO) complicated by choroidal neovascularization (CNV) and focal choroidal excavation (FCE).MethodsPatients presenting with CO and CNV between January and October 2016 were considered for this study. Diagnosis of CO was confirmed by ultrasound examination. All patients underwent multimodal imaging including optical coherence tomography (OCT), swept-source OCT angiography (DRI OCT Triton, Topcon, Inc., Tokyo, Japan) and fluorescein angiography (Spectralis HRA+OCT; Heidelberg Engineering, Heidelberg, Germany).ResultsTwo patients (one with bilateral CO) were included in the study. OCT showed a FCE in two eyes of two patients (one in correspondence of the CNV and the other adjacent to the CNV). OCT-A demonstrated presence of microvascular flow within neovascular network of the CNVs. Decalcification of the tumor was noted in correspondence of one eye with FCE.ConclusionsFCE may be found in eyes with choroidal osteoma and CNV. OCT-A was a valuable tool for detection of CNV complicating choroidal osteoma. Decalcification of choroidal osteoma may represent a common pathogenic pathway for development of FCE and CNV in choroidal osteoma. PMID- 28731056 TI - Universal newborn eye screening: an effective strategy to improve ocular health? PMID- 28731057 TI - Idiopathic macular holes and direction of vitreomacular traction: structural changes and surgical outcomes. AB - PurposeTo compare the structural changes, clinical course, and treatment outcomes of vertical and horizontal vitreomacular traction (VMT) induced impending macular holes (IMHs) and full-thickness macular holes (FTMHs).MethodsIn this retrospective study, 23 and 32 cases of IMHs and FTMHs, respectively, were analyzed. The IMH cases were divided into two subgroups: IMH with and without foveal detachment. Vitreofoveal traction angles (TAs) between the inner retinal surface and posterior hyaloid were measured from horizontal and vertical optical coherence tomography (OCT) images by using the trigonometric function (the angle equals the arctangent of the height over the base) after adjustments for magnification factors. The largest angle was defined as the vitreomacular TA for the examined case. The critical angle-the TA differentiating cases with (vertical traction) or without (horizontal traction) foveal detachment (vertical traction) was determined using regression analysis. Pretreatment and posttreatment OCT images, clinical courses, and treatment outcomes were compared between the two groups.ResultsThe critical angle was 27.2 degrees . Cases of vertical traction had higher foveal height in the IMH group and wider bases in the FTMH group (P<0.05 respectively). IMHs with vertical traction had greater VM attachment than those with horizontal traction. In the FTMH group, postoperative visual improvement was lower (P=0.002); in the vertical traction group, inner segment:outer segment defects persisted longer (P=0.02).ConclusionsThe critical angle separating vertical from horizontal traction was 27.2 degrees . Vertical VMT results in greater foveal structural changes in IMHs and possibly less favorable surgical outcomes in FTMHs. PMID- 28731058 TI - Multicenter study of pars plana vitrectomy for optic disc pit maculopathy: MACPIT study. AB - PurposeTo evaluate surgical intervention with pars plana vitrectomy (PPV) for correction of optic disc pit maculopathy (ODP-M).Patients and methodsRetrospective chart review from 13 centres of 51 eyes of 50 patients with ODP-M who underwent PPV between 2002-2014. Anatomic and final best-corrected visual acuity (BCVA) outcomes were evaluated for all cases with different adjuvant techniques.ResultsThere were 23 males and 27 females with median age 25.5 (6-68) years. Preoperative median foveal thickness was 694.5 (331-1384) MUm and improved to 252.5 (153-1405) MUm. Median BCVA improved from 20/200 (20/20000 to 20/40) to 20/40 (20/2000 to 20/20) with 20/40 or better in 31 eyes. Complete retinal reattachment was achieved in 44 eyes (86.3%) at 7.1 (5.9) months. The good surgical outcomes were achieved in different adjuvant groups. Median follow up was 24 (6 to 120) months.ConclusionsThese results confirm the long-term effectiveness of PPV for ODP-M. Prospective studies are needed to determine the effectiveness of any adjuvant technique in improving the success of PPV for ODP M. PMID- 28731060 TI - A juiced-up joint implant. PMID- 28731059 TI - Optical coherence tomography detection of characteristic retinal nerve fiber layer thinning in nasal hypoplasia of the optic disc. AB - PurposeTo determine the clinical usefulness of optical coherence tomography (OCT) for detecting thinning of the retinal nerve fiber layer (RNFL) in eyes with nasal hypoplasia of the optic discs (NHOD).Patients and methodsThe medical records of five patients (eight eyes) with NHOD were reviewed. The ratio of the disc-macula distance to the disc diameter (DM/DD) and the disc ovality ratio of the minimal to maximal DD were assessed using fundus photographs. The RNFL thicknesses of the temporal, superior, nasal, and inferior quadrants were evaluated using OCT quadrant maps.ResultsAll eight eyes had temporal visual field defects that respected the vertical meridians that needed to be differentiated from those related to chiasmal compression. The mean DM/DD ratio was 3.1 and the mean disc ovality ratio was 0.81. The mean RNFL thicknesses of the temporal, superior, nasal, and inferior quadrants were 90.3, 103.1, 34.8, and 112.8 microns, respectively.ConclusionSmall optic discs and tilted discs might be associated with NHOD. Measurement of the RNFL thickness around the optic disc using OCT scans clearly visualized the characteristic RNFL thinning of the nasal quadrants corresponding to the temporal sector visual field defects in eyes with NHOD. OCT confirmed the presence of NHOD and might differentiate eyes with NHOD from those with chiasmal compression. PMID- 28731064 TI - Response to Protocol Review Scenario: A need for more justification. PMID- 28731065 TI - A mini-microscope that moves with mice. PMID- 28731066 TI - Response to Protocol Review Scenario: If it's only an opinion, it won't fly. PMID- 28731067 TI - To the heart of cardiac injury. PMID- 28731068 TI - How should a PI justify the use of vertebrate species when asked about invertebrate alternatives? PMID- 28731069 TI - Response to Protocol Review Scenario: It's all in the questions. PMID- 28731070 TI - All eyes on zebrafish. PMID- 28731071 TI - [Potential impact of colors of filters used in sunglasses on the melatonin suppression process]. AB - BACKGROUND: In this article the methods for determining spectral transmittance of optical radiation in the visible waveband range through selected materials used as optical filters against solar glare were described. MATERIAL AND METHODS: Transmittance coefficients specified for the fraction of light passing through tested filters, taking into account the mechanism of eye adaptation to daylight and night vision and the melatonin suppression process were compared for 4 dyed sunglass filters. RESULTS: The values of transmittance coefficients specified for wavelength bands, 380-780 nm (for visible range) and 425-560 nm (for blue light range affecting the melatonin suppression process) were determined. CONCLUSIONS: The use of sunglasses with different color filters modifies the spectral characteristics of transmittance (spectrum) of visible light reaching the eye (including blue radiation) in such a way that it may have a potential impact on the melatonin suppression process. Med Pr 2017;68(5):629-637. PMID- 28731072 TI - [Evaluation of the results of the prevention program "Protect your voice" implemented by The Greater Poland Center of Occupational Medicine of Poznan]. AB - BACKGROUND: The aim of the study was to evaluate the rationale for training in voice emission and voice prophylaxis among teachers and to assess the effects of voice disorders rehabilitation in the selected group of teachers participating in the program "Protect your voice." MATERIAL AND METHODS: An anonymous survey was conducted among 463 teachers participating in the training part of the program. The effectivness of rehabilitation of teachers with occupational voice disorders was evaluated among 51 subjects (average age: 43 years) taking part in diagnostic and rehabilitation part of the program. Phonation voice exercises with speech therapist and physiotherapy (iontophoresis, inhalations and elektrostimulation) were administered. Evaluation of rehabilitation was based on phoniatric examination, including videostroboscopy and statistical calculations. RESULTS: The survey showed that among teachers there is high demand (98%) for training in proper voice emission, hygiene and prevention of voice. The effectiveness of rehabilitation has been confirmed by the observed improvements in phonatory activities of larynx, proper breathing during phonation (p = 0.0000), the voice quality (p = 0.0022), prolonged phonation time (an average of 1.39 s), increased number of people who correctly activated resonators (p = 0.0000) and increased number of people with phonation without excesive muscle tension of the neck. CONCLUSIONS: The results indicate that among all the professionally active teachers, there is a need for regular training of proper voice emission and vocal hygiene and then conduct individually phonation and breathing exercises, supported by the physiotherapy. This should be an effective method of voice disorders prevention in teachers. Med Pr 2017;68(5):593-603. PMID- 28731073 TI - [Effect of stress and intesity of mobile phone using on the health and subjective symptoms in GSM workers]. AB - BACKGROUND: There are no available data on the health consequences that may result from the synergistic effects of electromagnetic fields (EMF) and stress. Understanding the mechanisms of the simultaneous exposure will make it possible to develop procedures to minimize adverse health effects in professionals using mobile phones. MATERIAL AND METHODS: A questionnaire survey was conducted in 600 randomly selected people to obtain data on their health status and the prevalence of subjective symptoms related to the mobile phones using. Among them, there were 208 GSM Network employees, to whom the Perceived Stress Scale and Assessment of Stress at Work Questionnaire were sent. Eighty-nine completed questionnaires were returned (response rate - 42.8%). RESULTS: The mean age of respondents was 30.3 years (standard deviation (SD) = 7.7), time of occupational use of mobile phone - 4.1 years (SD = 1.7), the level of occupational stress - 95.3 (SD = 19.1). A significant percentage of people (62.8%) complained of the frequent difficulties in coping with problems of everyday life, and 57.4% had a fairly frequent problems with managing their own affairs. Significant differences in the life stress were detected between groups with different time of phone use (p = 0.03), and in occupational stress level, significant differences were noted between the 2 groups differing in the length of the conversation (p = 0.05). The risk of headache, associated (odds ratio (OR) = 4.2, p = 0.008) or not associated (OR = 2.97, p = 0.04) with calls on mobile phone, adjusted for stress, was significantly higher in people speaking via mobile more than 60 min/day than in those talking less. CONCLUSIONS: The study indicates that both stressors acting at the same time (EMF from cell phone and stress) adversely affect the well-being of workers and increase the risk of subjective symptoms. Med Pr 2017;68(5):617 628. PMID- 28731074 TI - Left hippocampus sparing whole brain radiotherapy (WBRT): A planning study. AB - AIMS: Unilateral sparing of the dominant (left) hippocampus during whole brain radiotherapy (WBRT) could mitigate cognitive decline, especially verbal memory, similar to the widely investigated bilateral hippocampus avoidance (HA-WBRT). The aim of this planning study is dosimetrical comparison of HA-WBRT with only left hippocampus sparing (LHA-WBRT) plans. METHODS: HA-WBRT plans for 10 patients were prepared in accordance with RTOG 0933 trial and served as baseline for comparisons with several LHA-WBRT plans prepared with an effort: 1) to maintain the same left hippocampus dosimetry ("BEST PTV") and 2) to maintain same dosimetry in planning target volume as in HA-WBRT ("BEST LH"). RESULTS: All HA WBRT plans met RTOG 0933 protocol criteria with a mean Conformity index 1.09 and mean Homogeneity index (HI) 0.21. Mean right and left hippocampal D100% was 7.8 Gy and 8.5 Gy and mean Dmax 14.0 Gy and 13.8 Gy, respectively. "BEST PTV" plans reduced HI by 31.2% (P=0.005) which is mirrored by lower PTV_D2% (-0.8 Gy, P=0.005) and higher PTV_D98% (+1.3 Gy, P=0.005) as well as decreased optic pathway's Dmax by 1 Gy. In "BEST LH", mean D100% and Dmax for the left hippocampus were significantly reduced by 11.2% (P=0.005) and 10.9% (P=0.005) respectively. CONCLUSIONS: LHA-WBRT could improve target coverage and/or further decrease in dose to spared hippocampus. Future clinical trials must confirm whether statistically significant reduction in left hippocampal dose is also clinically significant. PMID- 28731075 TI - A simple supramolecular assay for drug detection in urine. AB - A supramolecular colorimetric assay utilising the macrocyclic host cucurbit[7]uril (CB[7]) with a commercial dye molecule, neutral red (NR), was evaluated as a novel method for drug detection in urine of a model therapeutic peptide drug Octreotide. PMID- 28731076 TI - Simple Gd3+-Neu5NAc complexation results in NMR chemical shift asymmetries of structurally equivalent complex-type N-glycan branches. AB - In the present Communication, we propose a quite simple but previously overlooked approach for conveniently analyzing, assigning, and extracting sialic acid containing N-glycan structures using high-resolution NMR spectroscopy without pre installing metal chelators. Paramagnetic metals, such as Gd3+, appear to bind to the carboxyl groups of N-acetylneuraminic acid when introduced at room temperature, leading to the measurement of nonequivalent proton and carbon NMR spectral signals among otherwise "identical" glycan branched structures. PMID- 28731077 TI - High-performance adsorption and separation of anionic dyes in water using a chemically stable graphene-like metal-organic framework. AB - A highly stable graphene-like metal-organic framework (BUC-17) was prepared and used as an adsorbent to carry out the adsorption of anionic dyes from simulated wastewater, which exhibited excellent adsorption performance, particularly towards Congo red (CR) up to 4923.7 mg g-1 at room temperature. It was used to fix a SPE column to conduct rapid separation of anionic dyes from an organic dye matrix. A related mechanism was also proposed. PMID- 28731078 TI - A mononuclear iron carbonyl complex [Fe(MU-bdt)(CO)2(PTA)2] with bulky phosphine ligands: a model for the [FeFe] hydrogenase enzyme active site with an inverted redox potential. AB - A mononuclear hexa-coordinated iron carbonyl complex [Fe(MU-bdt)(CO)2(PTA)2] 1 (bdt = 1,2-benzenedithiolate; PTA = 1,3,5-triaza-7-phosphaadamantane) with two bulky phosphine ligands in the trans position was synthesized and characterized by X-ray structural analysis coulometry data, FTIR, electrochemistry and electronic structure calculations. The complex undergoes a facilitated two electron reduction 1/12- and shows an inverted one-electron reduction for 1/1- at higher potentials. Electrochemical investigations of 1 are compared to the closely related [Fe(bdt)(CO)2(PMe3)2] compound. A mechanistic suggestion for the hydrogen evolution reaction upon proton reduction from acid media is derived. The stability of 1 in both weak and strong acids is monitored by cyclic voltammetry. PMID- 28731079 TI - A polymeric temozolomide nanocomposite against orthotopic glioblastoma xenograft: tumor-specific homing directed by nestin. AB - The development of effective therapeutic strategies for glioblastoma faces challenges such as modulating the blood brain barrier (BBB) for drug influx and selectively targeting tumor cells. Nanocarrier drug delivery strategies are functionalized to enhance vascular permeability. We engineered superparamagnetic iron oxide nanoparticle (SPION) based polymeric nanocomposites (84.37 +/- 12.37 nm / 101.56 +/- 7.42 nm) embedding temozolomide (TMZ) targeted against glioblastoma by tagging an antibody against nestin, a stem cell marker, and transferrin / polysorbate-80 to permeate the BBB. The targeting and therapeutic efficacy of the nanocomposite resulted in enhanced permeability across the BBB in an orthotopic glioblastoma xenograft model. Sustained release of TMZ from the nanocomposite contributed to enhanced tumor cell death while sparing normal brain cells as evidenced through micro SPECT/CT analysis. The functionalized nanocomposites showed significant reductions in tumor volume compared to pure TMZ, as substantiated by reduced proliferation markers such as proliferating cell nuclear antigen (PCNA) and Ki-67. We report here a novel targeted TMZ delivery strategy using a potent homing moiety, nestin, tagged to a polymeric nanocomposite to target glioblastoma. In addition to tumor targeting, this study constitutes a broad horizon for enhanced therapeutic efficacy with further scope for capitalizing on the magnetic properties of SPION for targeted killing of cancer cells while sparing normal tissues. PMID- 28731081 TI - Metal-mediated reactions between dialkylcyanamides and acetamidoxime generate unusual (nitrosoguanidinate)nickel(ii) complexes. AB - The nitrosoguanidinate complexes [Ni{NH[double bond, length as m dash]C(NR2)NN(O)}2] (R2 = Me21, (CH2)4O 2, (CH2)43, (CH2)54, (Me)Ph 5, Ph26, (p MeC6H4)27) were obtained in low-to-moderate (12-26%) yields but reproducible yields in an unexpected metal-mediated reaction in MeOH between the nickel salt NiCl2.2H2O, N,N-disubstituted cyanamides NCNR2, and the amidoxime MeC([double bond, length as m-dash]NOH)NH2. These complexes were formed along with a spectrum of cyanamide-oxime coupling products. The IR and X-ray data indicate the delocalization within the NNO and NCN systems of the nitrosoguanidinate ligand. This delocalization was additionally confirmed by inspection of Wiberg bond indices for the selected bonds. In the X-ray structure of 5, the rare metallophilic contacts NiNi between stacks of the square-planar complexes were detected and these non-covalent interactions were studied by non-relativistic and relativistic DFT calculations and topological analysis of the electron density distribution within the framework of Bader's theory (QTAIM method). The estimated strength of the NiNi interactions is 1.3-1.9 kcal mol-1 and they are mostly determined by crystal packing effects and weak attractive interactions between adjacent metal centers due to the overlapping of their dz2 and pz orbitals. PMID- 28731082 TI - From the metal to the channel: a study of carrier injection through the metal/2D MoS2 interface. AB - Despite the fact that two-dimensional MoS2 films continue to be of interest for novel device concepts and beyond silicon technologies, there is still a lack of understanding on the carrier injection at metal/MoS2 interface and effective mitigation of the contact resistance. In this work, we develop a semi-classical model to identify the main mechanisms and trajectories for carrier injection at MoS2 contacts. The proposed model successfully captures the experimentally observed contact behavior and the overall electrical behavior of MoS2 field effect transistors. Using this model, we evaluate the injection trajectories for different MoS2 thicknesses and bias conditions. We find for multilayer (>2) MoS2, the contribution of injection at the contact edge and injection under the contact increase with lateral and perpendicular fields, respectively. Furthermore, we identify that the carriers are predominantly injected at the edge of the contact metal for monolayer and bilayer MoS2. Following these insights, we have found that the transmission line model could significantly overestimate the transfer length and hence the contact resistivity for monolayer and bilayer MoS2. Finally, we evaluate different contact strategies to improve the contact resistance considering the limiting injection trajectory. PMID- 28731080 TI - A tumor-targeted polymer theranostics platform for positron emission tomography and fluorescence imaging. AB - Here, we describe a novel polymer platform suitable for efficient diagnostics and potential theranostics based on 89Zr-labeled N-(2-hydroxypropyl)methacrylamide (HPMA)-based copolymer conjugates. A set of polymers differing in molecular weight with either low dispersity or high dispersity were designed and synthesized and their biodistribution in vivo was successfully and precisely observed over 72 h. Moreover, the feasibility of two imaging techniques, fluorescence imaging (FI) and positron emission tomography (PET), was compared using labeled polymer conjugates. Both methods gave comparable results thus showing the enhanced diagnostic potential of the prepared polymer-dye or polymer chelator-89Zr constructs. The in vivo and ex vivo PET/FI studies indicated that the dispersity and molecular weight of the linear HPMA polymers have a significant influence on the pharmacokinetics of the polymer conjugates. The higher molecular weight and narrower distribution of molecular weights of the polymer carriers improve their pharmacokinetic profile for highly prolonged blood circulation and enhanced tumor uptake. Moreover, the same polymer carrier with the anticancer drug doxorubicin bound by a pH-sensitive hydrazone bond showed higher cytotoxicity and cellular uptake in vitro. Therefore, HPMA copolymers with low dispersity and a molecular weight near the limit of renal filtration can be used as highly efficient polymer carriers of tumor-targeted therapeutics or for theranostics with minimal side effects. PMID- 28731083 TI - Mutable polyelectrolyte tube arrays: mesoscale modeling and lateral force microscopy. AB - In this study, the pH-dependent friction of layer-by-layer assemblies of poly(allylamine hydrochloride) and poly(acrylic acid) (PAH/PAA) are quantified for microtube array structures via experimental and simulated lateral force microscopy (LFM). A novel coarse-grain tube model is developed, utilizing a molecular dynamics (MD) framework with a Hertzian soft contact potential (such that F ~ delta3/2) to allow the efficient dynamic simulation of 3D arrays consisting of hundreds of tubes at micrometer length scales. By quantitatively comparing experimental LFM and computational results, the coupling between geometry (tube spacing and swelling) and material properties (intrinsic stiffness) results in a transition from bending dominated deformation to bending combined with inter-tube contact, independent of material adhesion assumptions. Variation of tube spacing (and thus control of contact) can be used to exploit the normal and lateral resistance of the tube arrays as a function of pH (2.0/5.5), beyond the effect of areal tube density, with increased resistances (potential mutability) up to a factor of ~60. This study provides a novel modeling platform to assess and design dynamic polyelectrolyte-based substrates/coatings with tailorable stimulus-responsive surface friction. Our results show that micro-geometry can be used alongside stimulus-responsive material changes to amplify and systematically tune mutability. PMID- 28731084 TI - Selective synthesis of pyrrolo[1,2-a]azepines or 4,6-dicarbonyl indoles via tandem reactions of alkynones with pyrrole derivatives. AB - Novel methodologies for the selective synthesis of pyrrolo[1,2-a]azepines or 4,6 dicarbonyl indoles starting from pyrrole derivatives and alkynones are described. When reactions were carried out with 1,2,4-trisubstituted N-propargyl pyrroles using a ZnI2 catalyst, pyrrolo[1,2-a]azepines were obtained. Whereas 4,6 dicarbonyl indoles were produced selectively with 1,2-disubstituted pyrroles in the presence of silica gel. The reaction outcomes depend on the substituent pattern of the substrates and the nature of the catalysts chosen. Control reactions suggested that the formation of a conjugated enamine intermediate was crucial for both the processes. With easily accessible starting materials, inexpensive catalysts and an easy-to-handle procedure, this reaction has the potential to become a general protocol for the synthesis of pyrrolo[1,2 a]azepines or indoles. PMID- 28731085 TI - Heptafluoroisopropyl diazomethane (i-C3F7CHN2): in situ generation and synthesis of pyrazoles. AB - A novel chemical reagent - heptafluoroisopropyl diazomethane (i-C3F7CHN2) - has been generated in situ in aqueous media. It readily reacts with electron deficient alkynes towards polyfluorinated pyrazoles that are important in agrochemistry. PMID- 28731086 TI - Microfluidic and nanofluidic phase behaviour characterization for industrial CO2, oil and gas. AB - Microfluidic systems that leverage unique micro-scale phenomena have been developed to provide rapid, accurate and robust analysis, predominantly for biomedical applications. These attributes, in addition to the ability to access high temperatures and pressures, have motivated recent expanded applications in phase measurements relevant to industrial CO2, oil and gas applications. We here present a comprehensive review of this exciting new field, separating microfluidic and nanofluidic approaches. Microfluidics is practical, and provides similar phase properties analysis to established bulk methods with advantages in speed, control and sample size. Nanofluidic phase behaviour can deviate from bulk measurements, which is of particular relevance to emerging unconventional oil and gas production from nanoporous shale. In short, microfluidics offers a practical, compelling replacement of current bulk phase measurement systems, whereas nanofluidics is not practical, but uniquely provides insight into phase change phenomena at nanoscales. Challenges, trends and opportunities for phase measurements at both scales are highlighted. PMID- 28731087 TI - Chiral two bladed ML2 metallamacrocycles: design, structures and solution behavior. AB - Chiral two bladed complexes of [Co(L)2][BF4]2 (1) and [Zn(L)2][BF4]2 (2) containing an atropoisomeric semi-rigid bidentate ligand L were synthesized and characterized. They are obtained as homochiral species but in a racemic mixture via a ligand self-sorting mechanism. These enantiomers can be differentiated in solution using optically active anions. PMID- 28731088 TI - Laser-engraved carbon nanotube paper for instilling high sensitivity, high stretchability, and high linearity in strain sensors. AB - There is an increasing demand for strain sensors with high sensitivity and high stretchability for new applications such as robotics or wearable electronics. However, for the available technologies, the sensitivity of the sensors varies widely. These sensors are also highly nonlinear, making reliable measurement challenging. Here we introduce a new family of sensors composed of a laser engraved carbon nanotube paper embedded in an elastomer. A roll-to-roll pressing of these sensors activates a pre-defined fragmentation process, which results in a well-controlled, fragmented microstructure. Such sensors are reproducible and durable and can attain ultrahigh sensitivity and high stretchability (with a gauge factor of over 4.2 * 104 at 150% strain). Moreover, they can attain high linearity from 0% to 15% and from 22% to 150% strain. They are good candidates for stretchable electronic applications that require high sensitivity and linearity at large strains. PMID- 28731089 TI - Unveiling the synergistic effect of polysulfide additive and MnO2 hollow spheres in evolving a stable cyclic performance in Li-S batteries. AB - Herein, we demonstrate a synergistic approach involving polar-based oxide and polysulfide additives for effectively suppressing polysulfide dissolution during cycling. The MnO2 hollow spheres not only provide physical confinement for the polysulfide species but also enable strong chemical interactions between polysulfide species and oxides, while the added polysulfide furnishes a mass buffering effect and compensates for the capacity losses due to partial cathode dissolution during discharge. The capacity retentions of S/KB, S/KB/LiPS, S/KB/MnO2, and S/KB/MnO2/LiPS composite cathodes are 31%, 45%, 59%, and 91% respectively. The remarkable capacity retention of the S/KB/LiPS/MnO2 composite electrode is mainly attributed to the synergistic effect between MnO2 and polysulfide additives. PMID- 28731090 TI - Octahedral Yb(iii) complexes embedded in [CoIII(CN)6]-bridged coordination chains: combining sensitized near-infrared fluorescence with slow magnetic relaxation. AB - Ytterbium (3+) ions combined with 3-pyridone and hexacyanido-cobaltate(iii) anions in a concentrated aqueous solution produce cyanido-bridged {[YbIII(3 pyridone)2(H2O)2][CoIII(CN)6]} (1) chains. The resulting YbIII complexes of an elongated octahedral geometry reveal two coexisting functionalities: a field induced slow magnetic relaxation with an energy barrier of DeltaE/kB = 45(1) K at Hdc = 1 kOe, and an YbIII-centered near-infrared fluorescence in the 950-1100 nm range sensitized by 3-pyridone and [CoIII(CN)6]3-. PMID- 28731091 TI - Developing force fields when experimental data is sparse: AMBER/GAFF-compatible parameters for inorganic and alkyl oxoanions. AB - We present a set of Lennard-Jones parameters for classical, all-atom models of acetate and various alkylated and non-alkylated forms of sulfate, sulfonate and phosphate ions, optimized to reproduce their interactions with water and with the physiologically relevant sodium, ammonium and methylammonium cations. The parameters are internally consistent and are fully compatible with the Generalized Amber Force Field (GAFF), the AMBER force field for proteins, the accompanying TIP3P water model and the sodium model of Joung and Cheatham. The parameters were developed primarily relying on experimental information - hydration free energies and solution activity derivatives at 0.5 m concentration with ab initio, gas phase calculations being used for the cases where experimental information is missing. The ab initio parameterization scheme presented here is distinct from other approaches because it explicitly connects gas phase binding energies to intermolecular interactions in solution. We demonstrate that the original GAFF/AMBER parameters often overestimate anion cation interactions, leading to an excessive number of contact ion pairs in solutions of carboxylate ions, and to aggregation in solutions of divalent ions. GAFF/AMBER parameters lead to excessive numbers of salt bridges in proteins and of contact ion pairs between sodium and acidic protein groups, issues that are resolved by using the optimized parameters presented here. PMID- 28731092 TI - A Ni-P@NiCo LDH core-shell nanorod-decorated nickel foam with enhanced areal specific capacitance for high-performance supercapacitors. AB - Recently, transition metal-based nanomaterials have played a key role in the applications of supercapacitors. In this study, nickel phosphide (Ni-P) was simply combined with NiCo LDH via facile phosphorization of Ni foam and subsequent electrodeposition to form core-shell nanorod arrays on the Ni foam; the Ni-P@NiCo LDH was then directly used for a pseudocapacitive electrode. Owing to the splendid synergistic effect between Ni-P and NiCo LDH nanosheets as well as the hierarchical structure of 1D nanorods, 2D nanosheets, and 3D Ni foam, the hybrid electrode exhibited significantly enhanced electrochemical performances. The Ni-P@NiCo LDH electrode showed a high specific capacitance of 12.9 F cm-2 at 5 mA cm-2 (3470.5 F g-1 at a current density of 1.3 A g-1) that remained as high as 6.4 F cm-2 at a high current density of 100 mA cm-2 (1700 F g-1 at 27 A g-1) and excellent cycling stability (96% capacity retention after 10 000 cycles at 40 mA cm-2). Furthermore, the asymmetric supercapacitors (ASCs) were assembled using Ni-P@NiCo LDH as a positive electrode and activated carbon (AC) as a negative electrode. The obtained ASCs delivered remarkable energy density and power density as well as good cycling performance. The enhanced electrochemical activities open a new avenue for the development of supercapacitors. PMID- 28731093 TI - Rapid and selective synthesis of spiropyrazolines and pyrazolylphthalides employing Seyferth-Gilbert reagent. AB - An unexpected product-selectivity in the reaction of 2-arylideneindane-1,3-dione with dimethyl diazomethylphosphonate leading to the formation of two different types of products is reported. The reaction carried out in acetone in the presence of catalytic amount of cesium fluoride afforded spiropyrazoline phosphonates via 1,3-dipolar cycloaddition reaction, whereas the reaction in methanol yielded an interesting class of pyrazolylphthalides. This strategy provides an efficient alternative method for the construction of pyrazolylphthalides, and moreover, the process is general, works under mild conditions, and exhibits high functional group compatibility. PMID- 28731094 TI - Assembly and dichroism of a four-component halogen-bonded metal-organic cocrystal salt solvate involving dicyanoaurate(I) acceptors. AB - We describe the use of dicyanoaurate ions as linear ditopic metal-organic acceptors for the halogen bond-driven assembly of a dichroic metal-organic cocrystal based on azobenzene chromophores. Structural analysis by single crystal X-ray diffraction revealed that the material is a four-component solid, consisting of anticipated anionic metal-organic halogen-bonded chains based on dicyanoaurate ions, as well as complex potassium-based cations and discrete molecules of the crown ether 15-crown-5. Importantly, the structural analysis revealed the parallel alignment of the halogen-bonded chains required for dichroic behaviour, confirming that crystal engineering principles developed for the design of halogen-bonded dichroic organic cocrystals are also applicable to metal-based structures. In the broader context of crystal engineering, the structure of the herein reported dichroic material is additionally interesting as the presence of an ion pair, a neutral azobenzene and a molecule of a room temperature liquid make it an example of a solid that simultaneously conforms to definitions of a salt, a cocrystal, and a solvate. PMID- 28731095 TI - Polarization driven conductance variations at charged ferroelectric domain walls. AB - Conducting domain walls (CDWs) in ferroelectric materials are promising candidates for applications in a manifold of nanoscale, optoelectronic devices. Characterization of their microscopic properties, however, remains challenging due to their small dimension and highly insulating environment. Here, we inspect individual CDWs in single-crystalline LiNbO3 by the combination of photoemission electron microscopy (PEEM) and second harmonic generation (SHG) microscopy. While SHG unveils the overall domain wall inclination angle alpha, PEEM is sensitive to local conductance variations, both at and away from the domain wall. Thus, the two imaging techniques deliver complementary information over a large field of view. In agreement with earlier theoretical predictions we find that the local conductance is dictated by alpha and reveal a quantitative connection between them. Our results help to elucidate the electronic structure of CDWs and underline the value of PEEM as a non-contact characterization tool for mapping local conductance variations in highly resistive environments. PMID- 28731096 TI - A CuI/CuIII prototypical organometallic mechanism for the deactivation of an active pincer-like CuI catalyst in Ullmann-type couplings. AB - Unraveling the mechanistic details of copper-catalyzed arylation of nucleophiles (Ullmann-type couplings) is a very challenging task. It is a matter of intense debate whether it is a radical-based process or an organometallic redox-based process. The ancillary ligand choice in Ullmann-type couplings plays a key role in such transformations and can strongly influence the catalytic efficiency as well as the mechanism. Here, we show how a predesigned tridentate pincer-like catalyst undergoes a deactivation pathway through a CuI/CuIII prototypical mechanism as demonstrated by helium-tagging infrared photodissociation (IRPD) spectroscopy and DFT studies, lending a strong support to the existence of an aryl-CuIII species in the Ullmann couplings using this tridentate ligand. PMID- 28731097 TI - DBA-induced caspase-3-dependent apoptosis occurs through mitochondrial translocation of cyt-c in the rat hippocampus. AB - Dibromoacetic acid (DBA), a by-product of disinfection, develops in drinking water during chlorination or ozonation processes. Water intake is the main source of DBA exposure in humans, which is potentially neurotoxic. The present study investigated the neurotoxic effects of DBA by assessing the behavioral and biochemical characteristics of Sprague Dawley rats intragastrically treated with DBA at concentrations of 20, 50 and 125 mg kg-1 body weight for 28 consecutive days. The results indicated that animal weight gain and food consumption were not significantly affected by DBA. However, shuttle box tests showed increases in mistake frequency and reaction latency between the control and high-dose group. We found significant changes in hippocampal neurons by histomorphological observation. Additionally, biochemical analysis indicated enhanced production of reactive oxygen species (ROS) resulting in disruption of cellular antioxidant defense systems including decreased mitochondrial superoxide dismutase (SOD) activity and release of cytochrome c (cyt-c) from mitochondria into the cytosol, which can induce neuronal apoptosis. Furthermore, the increase of cyt-c in the cytosol enhanced caspase-3 and caspase-9 activity, which was confirmed by poly ADP-ribose polymerase-1 (PARP-1) cleavage to its signature fragment of 85 kDa and decreased levels of protein kinase C-delta (PKC-delta) in the hippocampus. Meanwhile, DBA treatment caused differential modulation of apoptosis-associated proteins and mRNAs for phosphorylated apoptosis signal regulating kinase 1 (p-ASK 1), phosphorylated c-jun N-terminal kinase (p-JNK), cyt-c, Bax, Bcl-2, caspase-9 and cleaved caspase-3 accompanied by DNA damage. Taken together, these data indicate that DBA may induce neurotoxicity via caspase-3-dependent apoptosis involving mitochondrial translocation of cyt-c in the rat hippocampus. PMID- 28731098 TI - A reaction model on the self-assembly process of octahedron-shaped coordination capsules. AB - Herein, the self-assembly process of an octahedron-shaped coordination capsule was analyzed based on a master equation approach using a reaction network model. This model was found to adequately reproduce the overall experimentally observed time evolutions and enabled us to trace the real-time evolution of transient intermediates, ranging from milli-second to hours. The time evolution of the distribution of individual intermediates species was obtained; a few linear oligomers located near the reactant were produced at first, followed by an explosive increase in several types of intermediates. All of them were then consolidated into a few species just before the formation of the final product. A long-lived [Pd618Py]12+ is a key compound, which acts as a kinetic trap in the reaction dynamics. PMID- 28731099 TI - Novel phosphorescent cationic iridium(iii) complexes with o-carboranylation on the ancillary N^N ligand. AB - A novel series of heteroleptic iridium complexes with 2-phenyl-pyridine as a main ligand and carborane-functionalized 2,2'-bipyridine as an ancillary ligand were synthesized, and characterized as [Ir(ppy)2(By)]PF6 (where ppy is 2-phenyl pyridine, By is 5-(2-R-Cb)-2,2'-bipyridine, R = H (2a), CH3 (2b), Ph (2c), iPr (2d) and iBu (2e), or By is 4-(2-R-Cb)-2,2'-bipyridine while R = H (3a), CH3 (3b), Ph (3c), iPr (3d) and iBu (3e), Cb = o-carboran-1-yl). The R groups and the substitution sites of carborane on the pyridine ring have caused differences in the emission properties of these complexes. In addition, the quantum efficiency of [Ir(ppy)2(By)]PF6 complexes has been tuned as well through the introduction of various 2-R-substituted o-carboranes into the ancillary ligand 2,2'-bipyridine, no matter in the solid state (from 0.12 to 0.25) or in solution (from 0.04 to 0.25). The emission color was tuned from yellow to red by the o-carboranyl unit because of its inductive effect. Density functional theory (DFT) and time dependent DFT (TD-DFT) calculations have been applied to investigate excited state electronic structures of the newly synthesized complexes, which are consistent with the observed red-shift emissions. PMID- 28731100 TI - The 15N NMR chemical shift in the characterization of weak halogen bonding in solution. AB - We have studied the applicability of 15N NMR spectroscopy in the characterization of the very weak halogen bonds of nonfluorinated halogen bond donors with a nitrogenous Lewis base in solution. The ability of the technique to detect the relative strength of iodine-, bromine- and chlorine-centered halogen bonds, as well as solvent and substituent effects was evaluated. Whereas computations on the DFT level indicate that 15N NMR chemical shifts reflect the diamagnetic deshielding associated with the formation of a weak halogen bond, the experimentally observed chemical shift differences were on the edge of detectability due to the low molar fraction of halogen-bonded complexes in solution. The formation of the analogous yet stronger hydrogen bond of phenols have induced approximately ten times larger chemical shift changes, and could be detected and correlated to the electronic properties of substituents of the hydrogen bond donors. Overall, 15N NMR is shown to be a suitable tool for the characterization of comparably strong secondary interactions in solution, but not sufficiently accurate for the detection of the formation of thermodynamically labile, weak halogen bonded complexes. PMID- 28731101 TI - Selective molecular annealing: in situ small angle X-ray scattering study of microwave-assisted annealing of block copolymers. AB - Microwave annealing has emerged as an alternative to traditional thermal annealing approaches for optimising block copolymer self-assembly. A novel sample environment enabling small angle X-ray scattering to be performed in situ during microwave annealing is demonstrated, which has enabled, for the first time, the direct study of the effects of microwave annealing upon the self-assembly behavior of a model, commercial triblock copolymer system [polystyrene-block poly(ethylene-co-butylene)-block-polystyrene]. Results show that the block copolymer is a poor microwave absorber, resulting in no change in the block copolymer morphology upon application of microwave energy. The block copolymer species may only indirectly interact with the microwave energy when a small molecule microwave-interactive species [diethylene glycol dibenzoate (DEGDB)] is incorporated directly into the polymer matrix. Then significant morphological development is observed at DEGDB loadings >=6 wt%. Through spatial localisation of the microwave-interactive species, we demonstrate targeted annealing of specific regions of a multi-component system, opening routes for the development of "smart" manufacturing methodologies. PMID- 28731102 TI - Halogen bonds and sigma-holes. AB - The models behind simple bonding theory and the origins of some components often proposed to be involved in weak intermolecular bonds are described with special reference to sigma-hole bonding, of which halogen bonds are a subset. A protocol for the analysis of weak intermolecular interactions is proposed on the basis of sound physical principles. This protocol uses three different levels of interaction; "permanent" Coulomb interactions between unperturbed monomers, relaxed Coulomb interactions and dispersion. Of the three, only dispersion is not a real, measurable quantity. It is, however, included in order to describe interactions that cannot be treated entirely by the first two levels. PMID- 28731103 TI - Hollow and microporous triphenylamine networks post-modified with TCNE for enhanced organocathode performance. AB - Hollow microporous triphenylamine networks (H-MTPN) were post-modified with tetracyanoethylene (TCNE) to generate tetracyanobutadiene moieties in H-MTPN TCNE. The H-MTPN-TCNE showed the improved electrochemical performance of cathode materials for lithium ion batteries, compared to the original H-MTPN. PMID- 28731104 TI - A new droplet-forming fluidic junction for the generation of highly compartmentalised capsules. AB - A new oscillatory microfluidic junction is described, which enables the consistent formation of highly uniform and complex double emulsions, and is demonstrated for the encapsulation of four different reagents within the inner droplets (called cores) of the double emulsion droplets. Once the double emulsion droplets had attained a spherical form, the cores assumed specific 3D arrangements, the orchestration of which appeared to depend upon the specific emulsion morphology. Such double emulsion droplets were used as templates to produce highly compartmentalised microcapsules and multisomes. Based on these construct models, we numerically demonstrated a model chemical reaction sequence between and within the liquid cores. This work could provide a platform to perform space/time-dependent applications, such as programmed experiments, synthesis, and delivery systems. PMID- 28731105 TI - A comparative VUV absorption mass-spectroscopy study on protonated peptides of different size. AB - The ionization of gas-phase protonated peptides and proteins can induce molecular responses ranging from purely non-dissociative ionization to extensive multifragmentation of the system. In the case of soft X-ray photoionization, a monotonic transition between both regimes occurs in the mass range between 0.5 and 10 kDa. Despite the localized nature of the photoabsorption, excitation energy equilibrates before fragmentation sets in and the transition reflects the increase of the heat capacity with protein size. Here, we have investigated the influence of peptide size on vacuum ultraviolet (VUV) photoionization of protonated proteins, where photoexcitation and ionization are limited to valence electrons rather than inner shell electrons and the photoexcitation contribution is markedly lower. Gas phase protonated peptides with masses ranging from 0.6-2.8 kDa were trapped in a radiofrequency ion trap and exposed to synchrotron radiation. Time of flight mass spectrometry was employed for the investigation of the photoionization and photofragmentation processes. The relationship between peptide fragmentation and peptide size exhibits a similar trend as observed for soft X-ray absorption. Due to the lower excitation energies involved, however, dissociation is already quenched at smaller masses and peptide amino acid compositions, protonation states and ionization potentials lead to deviations from the general trend. PMID- 28731106 TI - Building new discrete supramolecular assemblies through the interaction of iso tellurazole N-oxides with Lewis acids and bases. AB - The supramolecular macrocycles spontaneously assembled by iso-tellurazole N oxides are stable towards Lewis bases as strong as N-heterocyclic carbenes (NHC) but readily react with Lewis acids such as BR3 (R = Ph, F). The electron acceptor ability of the tellurium atom is greatly enhanced in the resulting O-bonded adducts, which consequently enables binding to a variety of Lewis bases that includes acetonitrile, 4-dimethylaminopyridine, 4,4'-bipyridine, triphenyl phosphine, a N-heterocyclic carbene and a second molecule of iso-tellurazole N oxide. PMID- 28731107 TI - A fluorescent turn on nanoprobe for simultaneous visualization of dual-targets involved in cell apoptosis and drug screening in living cells. AB - Herein, a novel dual-responsive two-color fluorescent nanoprobe has been designed for the fluorescence activation imaging of cell apoptosis in living cells. The nanoprobe consists of a gold nanoparticle core functionalized with a dense layer of DNA aptamers and peptides, which shows high affinity and specific response to cytochrome c (Cyt c) and caspase-3, respectively. The formation of the aptamer Cyt c complex and the cleavage of the specific peptide by caspase-3 can liberate the dye labelled aptamers and peptides from the surface of gold nanoparticles, and then recover their fluorescence. The turn-on and specific recognition properties of our nanoprobe allow for the sensitive and selective detection of Cyt c concentration and caspase-3 activity both in solutions and in living cells. The here proposed nanoprobe with the abilities of real-time monitoring the cell apoptosis and evaluating the apoptosis-related drug efficacy might serve as a potential interesting tool for studying the molecular mechanisms of apoptosis regulation or screening the apoptosis-based drugs. PMID- 28731108 TI - Manganese-mediated synthesis of an NHC core non-symmetric pincer ligand and evaluation of its coordination properties. AB - The alkylation of N-(2-pyridyl)imidazole by the MnI methylene-phosphonium complex [Cp(CO)2Mn(eta2-P,C-Ph2P[double bond, length as m-dash]C(H)Ph)]BF4 offers a straightforward route to a tridentate pro-ligand featuring an NHC core and phosphine/pyridine arms. The ability of this PCN ligand to coordinate in a pincer mode was recognized in RhI, RhIII, and NiII complexes. PMID- 28731109 TI - The preference for dual-gold(i) catalysis in the hydro(alkoxylation vs. phenoxylation) of alkynes. AB - Dinuclear gold complexes and their use in catalysis have received significant recent attention, but there are few critical comparisons of mono- versus dual gold-catalysed pathways. Herein we study the hydroalkoxylation and hydrophenoxylation of alkynes using density functional theory calculations, and compare two possible mechanisms that have been proposed previously on the basis of theoretical and experimental studies, which unravel different preferences because of both the nature of the alkyne and alcohol and the non-innocent role of the counter-anion of a dual gold based catalyst. Entropy is found to have a significant effect, rendering the nucleophilic attack of the monoaurated intermediate [Au(L)(eta2-alkyne)]+ difficult both kinetically and thermodynamically; this mechanism cannot easily form only the trans-alkene product that is observed experimentally. Instead, a reaction via a dual gold catalysed mechanism presents much lower barriers. In addition, for the sake of direct comparison with recent results by Belanzoni and Zuccaccia, oversimplification of the N-heterocyclic carbene (NHC) ligand in the calculations might decrease the enthalpy barrier and lead to results that are not directly applicable to experiments. Moreover, the alkylic or arylic nature of the alkyne and/or alcohol is also tested. PMID- 28731110 TI - A redox-controlled electrolyte for plasmonic enhanced dye-sensitized solar cells. AB - Plasmonic enhanced dye-sensitized solar cells (DSSCs) with metallic nanostructures suffer from corrosion problems, especially with the presence of the iodine/triiodide redox couple in the electrolyte. Herein, we introduce an alternative approach by compensating the corrosion with a modified liquid electrolyte. In contrast to the existing method of surface preservation for plasmonic nanostructures, the redox-controlled electrolyte (RCE) contains iodoaurate intermediates, i.e. gold(i) diiodide (AuI2-) and gold(iii) tetraiodide (AuI4-) with optimal concentrations, such that these intermediates are readily reduced to gold nanoparticles during the operation of DSSCs. As corrosion and redeposition of gold occur simultaneously, it effectively provides corrosion compensation to the plasmonic gold nanostructures embedded in the photoanode. Cycling tests of the specific amount of gold contents in the RCE of DSSCs support the fact that the dissolution and deposition of gold are reversible and repeatable. This gold deposition on the TiO2 photoanode results in forming a Schottky barrier (SB) at the metal-semiconductor interface and effectively inhibits the recombination of electron-hole pairs. Therefore, the RCE increases the short-circuit current, amplifies the open-circuit voltage, and reduces the impedance of the TiO2/dye interface. The power conversion efficiency of DSSCs was improved by 57% after incorporating the RCE. PMID- 28731113 TI - Correction: Facile synthesis of stable, water soluble, dendron-coated gold nanoparticles. AB - Correction for 'Facile synthesis of stable, water soluble, dendron-coated gold nanoparticles' by Alan E. Enciso, et al., Nanoscale, 2017, 9, 3128-3132. PMID- 28731112 TI - Carrier-free, self-assembled pure drug nanorods composed of 10 hydroxycamptothecin and chlorin e6 for combinatorial chemo-photodynamic antitumor therapy in vivo. AB - Carrier-free nanodrugs formulated from the supramolecular self-assembly of pure drug molecules have emerged as an innovative and promising strategy for tumor therapy. We report herein a new and simple method to directly assemble a small hydrophobic anticancer drug, 10-hydroxycamptothecin (HCPT), with a photosensitizer chlorin e6 (Ce6) to form stable, discrete nanorods (NRs), which not only circumvent the extreme hydrophobicity of HCPT but also incorporate two different modalities into one delivery system for combination therapy. Different ratios of HCPT to Ce6 were evaluated to afford the optimal nanoformulation. The as-prepared HCPT/Ce6 NRs were fully characterized, indicating a relatively uniform size of about 360 nm in length and 135 nm in width, and a surface charge of about -33 mV. Efficient internalization of the NRs by cancer cells was observed by using a confocal microscope and the generation of singlet oxygen species arising from the NRs under 655 nm laser irradiation was detected by DCFH DA. As a result, very potent in vitro efficacy against several kinds of cancer cell lines was achieved through chemo-photodynamic dual therapy. The in vivo tumor suppression effect of HCPT/Ce6 NRs was verified on a subcutaneous xenograft mouse model, achieving almost complete inhibition of the tumor growth, which may benefit from the superiority of nanomedicine and combination therapy. The rationale of this facile and green strategy for carrier-free nanodrug formulation via the self-assembly approach might provide new opportunities for the development of combinatorial therapeutics for tumors. PMID- 28731115 TI - The synthesis of cycloalka[b]furans via an Au(i)-catalyzed tandem reaction of 3 yne-1,2-diols. AB - An Au(i)-catalyzed cyclization/1,2-rearrangement/aromatization cascade of 3-yne 1,2-diols has been successfully realized. This reaction not only provides a new and efficient strategy for the synthesis of substituted cycloalka[b]furan compounds as well as their derivatives, but might also facilitate related biological studies. PMID- 28731114 TI - Ru(ii)-(PTA) and -mPTA complexes with N2-donor ligands bipyridyl and phenanthroline and their antiproliferative activities on human multiple myeloma cell lines. AB - A series of novel ruthenium(ii) 2,2'-bipyridyl (bpy) and 1,10-phenanthroline (phen) derivatives containing PTA (1,3,5-triaza-7-phosphaadamantane) or mPTA (N methyl-1,3,5-triaza-7-phosphaadamantane cation) have been synthesized and fully characterized. Three types of complexes have been obtained, neutral [Ru(N N)(PTA)2Cl2] (1, N-N = bpy and 4, N-N = phen), monocationic [Ru(N-N)(PTA)3Cl][Cl] (2, N-N = bpy and 5, N-N = phen) and dicationic [Ru(N-N)(mPTA)Cl2][BF4]2 (3, N-N = bpy and 6, N-N = phen). The solid-state structures of four complexes have been determined by single-crystal X-ray diffraction. The cytotoxicity of the complexes has been evaluated in vitro against U266 and RPMI human multiple myeloma cells. PMID- 28731116 TI - Liquid exfoliation of 2D MoS2 nanosheets and their utilization as a label-free electrochemical immunoassay for subclinical ketosis. AB - We report the step-by-step fabrication of a 2D MoS2 nanostructure-based disposable electrochemical immunosensor to detect beta-hydroxybutyrate (betaHBA), a novel subclinical ketosis biomarker. The MoS2 nanosheets were exfoliated in the liquid phase by ultrasonication, and then followed by deposition on gold colloid modified screen-printed electrodes (Au-SPE). The MoS2-modified electrodes were thoroughly characterized by physical, electrochemical as well as spectroscopic techniques, and the obtained results indicate the successful and irreversible electrodeposition of MoS2 nanosheets. These MoS2-modified disposable electrodes were subsequently bioconjugated with anti-betaHBA antibodies and then employed for the label-free immunosensing of the betaHBA biomarker to detect subclinical ketosis. A simple electrochemical Differential Pulse Voltammetry (DPV) technique based immunodetection was realized for the sensing of varying concentrations of betaHBA antigen. The bioassay demonstrated remarkable sensitivity and specificity having a dynamic linear response range of 0.7 mM to 10 mM for betaHBA in standard antigen solutions, spiked serum, blood, milk and clinical samples, with linear results being obtained with R2 ~ 0.9923. The sensor electrodes were also studied with other relative interferents to investigate cross reactivity and non specificity. These electrodes showed a linear, specific, reproducible and stable response towards the betaHBA antigen over a wide range of concentrations. PMID- 28731117 TI - Close contacts and noncovalent interactions in crystals. AB - Close contacts, defined as interatomic separations less than the sum of the respective van der Waals radii, are commonly invoked to identify attractive nonbonded interactions in crystal lattices. While this is often effective, it can also be misleading because (a) there are significant uncertainties associated with van der Waals radii, and (b) it may not be valid to attribute the interactions solely to specific pairs of atoms. The interactions within crystal lattices are Coulombic, and the strongest positive and/or negative regions do not always correspond to the positions of atoms; they are sometimes located between atoms. Examples of both types are given and discussed, focusing in particular upon sigma-hole interactions. PMID- 28731118 TI - Correction: Photoinduced electron transfer across an organic molecular wall: octa acid encapsulated ESIPT dyes as electron donors. AB - Correction for 'Photoinduced electron transfer across an organic molecular wall: octa acid encapsulated ESIPT dyes as electron donors' by Fabiano S. Santos et al., Photochem. Photobiol. Sci., 2017, 16, 840-844. PMID- 28731119 TI - Non-invasively improving the Schottky barriers of metal-MoS2 interfaces: effects of atomic vacancies in a BN buffer layer. AB - Using first-principles calculations within density functional theory, vacancies in the BN buffer layer have been predicted to improve the Schottky barrier of the metal-MoS2 interface without deteriorating the intrinsic properties of the MoS2 layer. Here, the effects of concentrations, sizes and types of vacancies on the contact properties of metal/BN-MoS2 sandwich interfaces are comparatively studied. The results show that vacancies in the BN buffer layer not only don't deteriorate the charge scatterings and electronic properties of the MoS2 layer at the metal/BN-MoS2 interface, but also improve the charge density and contact resistance between the metal surface and the BN layer. Although these vacancies have a negligible influence on the Fermi level pinning effect of the metal/BN MoS2 interface, both N-vacancies and B-vacancies significantly change the position of the Fermi level of the metal/BN-MoS2 interface and then tune the Schottky barriers. Moreover, the Schottky barriers of metal/BN-MoS2 interfaces can decrease at first with the increasing concentrations and sizes of vacancies. When the concentration of vacancies increases to 4%, the Schottky barriers of metal/BN-MoS2 interfaces can reduce to the minimum value. The lowest n-type and p type Schottky barriers of Au/BN-MoS2 and Pt/BN-MoS2 interfaces can reduce to 0.16 and 0.28 eV, respectively. However, the Schottky barriers are deteriorated when the sizes and concentrations of vacancies continue to increase because vacancies with large sizes and concentrations obviously change the interfacial structures of metal/BN-MoS2 interfaces and disarrange the directions of interface dipoles. The predictions in this work provide a non-invasive method to achieve high performance metal-MoS2 interfaces with low Schottky barriers. PMID- 28731120 TI - Na3V2(PO4)3 coated by N-doped carbon from ionic liquid as cathode materials for high rate and long-life Na-ion batteries. AB - A facile and simple hydrothermal assisted sol-gel route was developed to prepare nitrogen doped carbon coated Na3V2(PO4)3 nanocomposites (denoted as NVP@C-N) as cathodes for sodium ion batteries (NIBs). An ionic liquid (EMIm-dca) was used as the nitrogen doped carbon source. The optimized N-doped carbon coated Na3V2(PO4)3 (denoted as NVP@C-N150) displays a very thin and uniform N-doped carbon coating layer (thickness: ~2 nm), showing an excellent sodium storage performance (85 mA h g-1 at 20 C after 5000 cycles) and high rate capability (71 mA h g-1 at 80 C). Such a superior sodium storage performance derives from the nitrogen doping carbon coating, triggering amounts of extrinsical defects and active sites in the N-doped amorphous carbon layer, which highly accelerates Na-ion and electron transport. This approach is simple, facile and shows easy scale-up. It could be extended to other materials for energy storage. PMID- 28731121 TI - Unified total synthesis of (+)-chinensiolide B and (+)-8-epigrosheimin. AB - An expedient synthetic approach has been developed for the unified total synthesis of (+)-chinensiolide B and (+)-8-epigrosheimin. The point of divergence was provided by the lactone aldehyde 6, in which four contiguous stereocenters were achieved by a stereocontrolled Evans syn-aldol reaction of a R-carvone derived enantiopure aldehyde and chiral N-succinyl-oxazolidinone. The lactone aldehyde 6 was synthesized in multigram quantity in three steps. Highly optimized chemo- and stereoselective reactions and functional group interconversion enabled us to assemble (+)-chinensiolide B and (+)-8-epigrosheimin from 6. PMID- 28731122 TI - Ligand effect on the rhodium porphyrin catalyzed hydrogenation of [2.2]paracyclophane with water: key bimetallic hydrogenation. AB - Rhodium porphyrin catalyzed hydrogenation of the aliphatic carbon-carbon sigma bond of [2.2]paracyclophane with water has been examined with a variety of tetraarylporphyrins and axial ligands. Mechanistic investigations show that RhIII(ttp)H, which can be derived from the reaction of [RhII(ttp)]2 with water without a sacrificial reductant, plays an important role in promoting bimetallic reductive elimination to give the hydrogenation product. PMID- 28731123 TI - Lasiodiplactone A, a novel lactone from the mangrove endophytic fungus Lasiodiplodia theobromae ZJ-HQ1. AB - Lasiodiplactone A (1), an unprecedented lactone, was obtained from the mangrove endophytic fungus Lasiodiplodia theobromae ZJ-HQ1. The structure of 1 was established by analysis of NMR spectroscopic data and electronic circular dichroism (ECD) spectra. Lasiodiplactone A (1) was the first example of lactone that possesses a unique tetracyclic system (12/6/6/5) of RAL12 (12-membered beta resorcylic acid lactone) with a pyran ring and a furan ring. A possible biogenetic pathway for 1 was proposed. Compound 1 showed anti-inflammatory activity by inhibiting nitric oxide (NO) production in lipopolysaccharide activated in RAW264.7 cells with IC50 value of 23.5 MUM and exhibited potential alpha-glucosidase inhibitory activity with IC50 values of 29.4 MUM. PMID- 28731124 TI - BMP7 mediates the anticancer effect of honokiol by upregulating p53 in HCT116 cells. AB - Colorectal cancer (CRC) is the second leading cause of cancer death. Hence, there is a great need to explore new efficacious drugs for the treatment of CRC. Honokiol (HNK), a natural product extracted from magnolia bark, processes various biological activities, including anticancer. In this study, we introduced cell viability assay, western blotting, real-time PCR and immunofluorescent staining to determine the anticancer effect of HNK, and the possible mechanism underlying this biological process. We found that HNK can inhibit the proliferation and induce apoptosis in HCT116 cells in a concentration- and time-dependent manner. HNK activates p53 in HCT116 and other colon cancer cells. Exogenous p53 potentiates the anticancer of HNK, while p53 inhibitor decreases this effect of HNK. Moreover, HNK upregulates the expression of bone morphogenetic protein 7 (BMP7) in colon cancer cells; Exogenous BMP7 enhances the anticancer activity of HNK and BMP7 specific antibody reduces this effect of HNK. For mechanism, we found that HNK cannot increase the level of Smad1/5/8; Exogenous BMP7 potentiates the HNK-induced activation of p53. On the contrary, BMP7 specific antibody inhibits the HNK-induced activation of p53 in colon cancer cells and partly decreases the total level of p53. Our findings suggested that HNK may be a promising anticancer drug for CRC; activation of p53 plays an important role in the anticancer activity of HNK, which may be initialized partly by the HNK induced upregulation of BMP7. PMID- 28731125 TI - N-peptide of vMIP-II reverses paclitaxel-resistance by regulating miRNA-335 in breast cancer. AB - Acquisition of resistance to paclitaxel is one of the most important problems in treatment of breast cancer patients, but the molecular mechanisms underlying sensitivity to paclitaxel remains elusive. Emerging evidence has demonstrated that microRNAs (miRNAs) play important roles in regulation of cell growth, migration and invasion through inhibiting the expression of its target genes. In our previous studies, we have shown that microRNA-335 (miR-335) decreased obviously between paclitaxel-resistant (PR) and parental breast cancer cells through miRNA microarray. However, the roles of miR-335 in breast cancer progression and metastasis are still largely unknown. NT21MP was designed and synthesized as an antagonist with CXCR4 to inhibit cellular proliferation and induce apoptosis. Therefore, the aim of this study was to explore the underlying mechanism of miR-335 and NT21MP in reverse PR in breast cancer cells. In this study, we found that miR-335 expression is significantly lower in PR MCF-7 and SKBR-3 cells (MCF-7/PR and SKBR-3/PR) compared with their parental MCF-7 and SKBR 3 cells. Functional experiments showed that overexpression of miR-335 and NT21MP increased the number of apoptosis cells, arrested cells in G0/G1 phase transition, and suppressed cell migration and invasion in vitro. Dual luciferase assays revealed that SETD8 is a direct target gene of miR-335. Furthermore, miR 335 markedly inhibited expression of SETD8 via Wnt/beta-catenin signaling and subsequently inhibited the expression of its downstream genes cyclin D1, and c Myc. Additionally, ectopic expression of miR-335 or depletion of its target gene SETD8 could enhance the sensitivity of PR cells to paclitaxel. Taken together, these date elucidated that NT21MP and miR-335 mediated PR of breast cancer cells partly through regulation of Wnt/beta-catenin signaling pathway. Activation of miR-335 or inactivation of SETD8 could be a novel approach for the treatment of breast cancer. PMID- 28731126 TI - miR-132 in atrial fibrillation directly targets connective tissue growth factor. AB - Atrial fibrillation (AF) is the most frequently occurring, persistent cardiac arrhythmia, and the hallmark of AF-dependent structural remodeling is atrial fibrosis. Connective tissue growth factor (CTGF) is important in the process of fibrosis. The association between miRNA and CTGF in AF-dependent fibrosis remains to be elucidated. The present study aimed to determine if microRNA (miR)-132 was able to regulate CTGF with an anti-fibrotic effect in AF. A total of ten dogs or patients were assigned to control (n=4) and AF groups (n=6). The left atrium of dogs or right atrial appendage of patients was observed. Following this, cardiac fibroblasts of adult rats were treated with or without angiotensin II (Ang II). Furthermore, cardiac fibroblasts were transfected with miR-132 mimics, inhibitor or negative control. The expression of miR-132 and CTGF were analyzed by reverse transcription-quantitative polymerase chain reaction or western blotting. These analyses demonstrated that miR-132 expression was decreased and CTGF increased in the human and canine models with AF. The expression of miR-132 and CTGF protein levels were upregulated in Ang II stimulated cardiac fibroblasts of adult rats. Furthermore, when miR-132 was introduced into cardiac fibroblasts, the expression of miR-132 increased significantly whereas the expression of CTGF decreased. Inverse results were observed when cardiac fibroblasts were transfected with miR 132 inhibitor. The luciferase reporter assay was then performed to confirm that miR-132 may suppress CTGF expression by binding to its 3'-untranslated region. In conclusion, miR-132 may target CTGF in regulating fibrosis in Ang II-treated cardiac fibroblasts. These findings may aid in providing potential therapeutic targets in the treatment of AF. PMID- 28731127 TI - Pidotimod exacerbates allergic pulmonary infection in an OVA mouse model of asthma. AB - Pidotimod is a synthetic dipeptide with biological and immuno-modulatory properties. It has been widely used for treatment and prevention of recurrent respiratory infections. However, its impact on the regulation of allergic pulmonary inflammation is still not clear. In the current study, an ovalbumin (OVA)-induced allergic asthma model was used to investigate the immune-modulating effects of pidotimod on airway eosinophilia, mucus metaplasia and inflammatory factor expression compared with dexamethasone (positive control). The authors determined that treatment with pidotimod exacerbated pulmonary inflammation as demonstrated by significantly increased eosinophil infiltration, dramatically elevated immunoglobulin E production, and enhanced T helper 2 response. Moreover, treatment failed to attenuate mucus production in lung tissue, and did not reduce OVA-induced high levels of FIZZ1 and Arg1 expression in asthmatic mice. In contrast, administration of dexamethasone was efficient in alleviating allergic airway inflammation in OVA-induced asthmatic mice. These data indicated that pidotimod as an immunotherapeutic agent should be used cautiously and the effectiveness for controlling allergic asthma needs further evaluation and research. PMID- 28731128 TI - lncRNA expression character associated with ischemic reperfusion injury. AB - Ischemic reperfusion injury (IRI) contributes to morbidity and mortality worldwide and results in a poor outcome for patients suffering from myocardial infarction. Ischemic post-conditioning (IPostC), consisting of one or several brief periods of ischemia and reperfusion, generates powerful protection against IRI. The mechanism of IPostC initiation and development has previously been investigated, however still remains to be fully elucidated. Notably, long non coding (lnc) RNAs have previously been demonstrated to be important in cardiovascular diseases. However, there is little information about the systematic analysis of IRI-associated lncRNA expression signature. The present study used microarrays to analyze the lncRNA expression characters of ischemic IPostc (corresponding to IRI), and demonstrated that 2,292 lncRNAs were observed to be upregulated and 1,848 lncRNAs downregulated. Gene ontology (GO) and Pathway analysis subsequently demonstrated that dysregulated lncRNAs participated in various biological processes, which are upregulated or downregulated in IPostC tissues. Finally, the present study verified that AK144818, ENSMUST00000156637, ENSMUST00000118342, ENSMUST00000118149, uc008ane.1, ENSMUST00000164933, ENSMUST00000162347, ENSMUST00000135945, and ENSMUST00000176338, ENSMUST00000120587, ENDMUST00000155271, ENSMUST00000125121 and Uc008thl.1 were associated with the initiation and development of IPostC. The present study may aid in the understanding of the initiation and development mechanisms of IPostC and provide novel and potential biomarkers that may be used in the diagnosis or as therapeutic targets in the treatment of IRI. PMID- 28731130 TI - Effects of reduced beta2 glycoprotein I on high glucose-induced cell death in HUVECs. AB - Reduced beta2 glycoprotein I (beta2GPI) has been demonstrated to exhibit a beneficial effect in diabetic atherosclerosis and retinal neovascularization. However, the effect of reduced beta2GPI on vascular disorders in diabetic mellitus (DM) remains to be elucidated. The present study established a high glucose-induced injury model using human umbilical cords veins (HUVECs) and evaluated the protective effects of reduced beta2GPI against the injury. The data demonstrated that a low concentration of reduced beta2GPI (0.5 uM) mitigated high glucose-induced cell loss, decreased nitric oxide (NO) production and resulted in calcium overloading. Mechanically, reduced beta2GPI additionally reversed high glucose-induced phosphatase and tensin homolog (PTEN) accumulation, decrease of protein kinase B phosphorylation and nitric oxide synthase activity, and increase of cyclooxygenase-2 activity. It was further confirmed that PTEN inhibitor-bpV (1 uM) exhibited similar effects to those resulting from reduced beta2GPI. Overall, the data revealed that reduced beta2GPI exerts protective effects from glucose induced injury in HUVECs, potentially via decreasing PTEN levels. The present study suggests reduced beta2GPI may act as a novel therapeutic strategy for the treatment of vascular disorders in DM. PMID- 28731129 TI - Expression profile of C19MC microRNAs in placental tissue of patients with preterm prelabor rupture of membranes and spontaneous preterm birth. AB - The aim of the study was to demonstrate that preterm birth (PTB) is associated with altered C19MC microRNA expression profile in placental tissues. Gene expression of 15 placental specific microRNAs (miR-512-5p, miR-515-5p, miR-516 5p, miR-517-5p, miR-518b, miR-518f-5p, miR-519a, miR-519d, miR-519e-5p, miR-520a 5p, miR-520h, miR-524-5p, miR-525-5p, miR-526a and miR-526b-5p) was compared between groups: 34 spontaneous PTB, 108 preterm prelabor rupture of membranes (PPROM) and 20 term in labor pregnancies. Correlation between variables including relative microRNA quantification in placental tissues and the gestational age at delivery, white blood cell (WBC) count at admission and serum levels of C reactive protein at admission in patients with PPROM and PTB was determined. Expression profile of microRNAs was different between PPROM and term in labor pregnancies, PTB and term in labor pregnancies, and between gestational age matched PPROM and PTB groups. When compared with term in labor pregnancies, while C19MC microRNAs showed a downregulation in PPROM pregnancies (miR-525-5p), in PTB pregnancies C19MC microRNAs were upregulated (miR-515-5p, miR-516-5p, miR-518b, miR-518f-5p, miR-519a, miR-519e-5p, miR-520a-5p, miR-520h, and miR-526b-5p) or showed a trend to upregulation (miR-519d and miR-526a). In comparison to PTB pregnancies, the PPROM group demonstrated a significant portion of downregulated C19MC microRNAs (miR-516-5p, miR-517-5p, miR-518b, miR-518f-5p, miR-519a, miR 519d, miR-519e-5p, miR-520a-5p, miR-520h, miR-525-5p, miR-526a and miR-526b-5p). In the group of PPROM pregnancies, a weak negative correlation between the gestational age at delivery and microRNA gene expression in placental tissue for all examined C19MC microRNAs was observed. PTB pregnancies showed a positive correlation (miR-512-5p, miR-515-5p, miR-519e-5p) or a trend to positive correlation (miR-516-5p, miR-518b, miR-520h) between particular C19MC microRNAs and maternal WBC count at admission. Our study demonstrates that upregulation of C19MC microRNAs is a characteristic phenomenon of PTB. PPROM pregnancies have a tendency to produce lower levels of miR-525-5p. All examined C19MC microRNAs displayed decreased expression with advancing gestational age in PPROM group. PMID- 28731133 TI - Irrelevance of anti-nAChR cytoplasmic loop antibody in the degree of myasthenia gravis. AB - Anti-nicotinic acetylcholine receptor (nAChR) antibody in myasthenia gravis (MG) usually refers to that against the extracellular domain (ECD) of nAChR. However, growing evidence has indicated that there also exists the nAChR antibody against the nAChR cytoplasmic loop (CL) in patients with MG. Some studies have demonstrated that the anti-CL antibody may play a protective role in animal models of experimental autoimmune MG. However, to date, limited or no information is available as to whether anti-CL antibody plays a beneficial role in patients with MG. In this, we examined the levels of anti-CL and anti-ECD antibodies in the sera of 76 patients with MG from the MG sample bank of our department, including 29 generalized MG (gMG) and 47 ocular MG (OMG) cases, as well as 40 healthy controls by radioimmunoassay. We also analyzed the correlation between anti-CL antibody levels and the degree of severity in patients with MG. Our results revealed that among the 76 patients with MG, 61 serum samples (80.3%) were positive for anti-ECD nAChR antibody, among which 38 (38/61, 62.3%) were positive for anti-CL antibody. The levels of anti-ECD antibodies in gMG were higher than those in OMG; however, the levels of anti-CL antibodies in gMG were comparable with those in OMG. No clear correlation was observed between the anti ECD antibody levels and those of anti-CL antibody. Taken together, our findings provide the first clinical evidence of the possibly different role of anti-CL antibody in patients with MG compared to its role in animal models of MG. Anti-CL antibody may not exert a beneficial effect in patients with MG, but may play an as yet udetermined role in the development of MG. PMID- 28731132 TI - miR-374 mediates the malignant transformation of gastric cancer-associated mesenchymal stem cells in an experimental rat model. AB - Mesenchymal stem cells (MSCs) are a critical component of the tumor microenvironment. Upon distinct pathological stimulus, MSCs show phenotypic and functional changes. Gastric cancer is one of the leading causes of cancer-related deaths worldwide. The roles and mechanisms of MSCs in gastric cancer have not been well characterized. In the present study, we investigated the roles of MSCs in the malignant transformation from gastritis to gastric cancer using an N methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced gastric cancer model. We isolated MSCs from the gastric tissues of normal (RGN-MSCs) and MNNG-exposed rats (RGI-MSCs), and compared the biological properties of RGI-MSCs with RGN-MSCs. We found that RGI-MSCs had increased proliferative and migratory capabilities than these capacities noted in the RGN-MSCs. In addition, RGI-MSCs produced higher levels of IL-6, CXCL10 and MCP-1 than RGN-MSCs. Moreover, RGI-MSCs promoted the migration of normal gastric mucosa epithelial cells by inducing epithelial mesenchymal transition (EMT). The upregulation of miR-374 in RGI-MSCs was partially responsible for their increased proliferative and migratory capabilities. Collectively, our findings provide new evidence for the roles of MSCs in gastric carcinogenesis, suggesting that targeting gastric cancer associated MSCs may represent a novel avenue for gastric cancer therapy. PMID- 28731131 TI - Assessment of the antioxidant activity of an olive oil total polyphenolic fraction and hydroxytyrosol from a Greek Olea europea variety in endothelial cells and myoblasts. AB - Olive oil (OO) constitutes the basis of the Mediterranean diet, and it seems that its biophenols, such as hydroxytyrosol (HT) may scavenge free radicals, attracting distinct attention due to their beneficial effects in many pathological conditions, such as cancer. To the best of our knowedge, this is the first study in which the functional properties of an OO total polyphenolic fraction (TPF) and pure HT were examined in order to determine their antioxidant effects at a cellular level in endothelial cells and myoblasts. The test compounds were isolated using a green gradient-elution centrifugal partition chromatography-based method that allows the isolation of large volumes of OO in a continuous extraction procedure and with extremely low solvent consumption. For the isolation of HT, a combination of two chromatographic techniques was used, which is effective for the recovery of pure compounds from complex natural extracts. Moreover, TPF and HT exhibited potent free radical scavenging activity in vitro. The cells were treated with non-cytotoxic concentrations and their redox status [in terms of glutathione (GSH) and reactive oxygen species (ROS) levels] was assessed. TPF extract was less cytotoxic than HT, and the observed differences between the two cell lines used suggest a tissue-specific activity. Finally, flow cytometric analysis revealed that both TPF and HT improved the redox status by increasing the levels of GSH, one of the most important antioxidant molecules, in both endothelial cells and myoblasts, while the ROS levels were not significantly affected. PMID- 28731134 TI - A novel gene expression scoring system for accurate diagnosis of basaloid squamous cell carcinoma of the esophagus. AB - Basaloid squamous cell carcinoma of the esophagus (BSCE) is a rare variant of squamous cell carcinoma that is difficult to distinguish from other carcinomas by preoperative endoscopic biopsy because of its histological varieties. Accurate diagnosis is essential for adequate treatment, and the methods proposed so far (e.g., immunohistochemical staining) have limitations. In this study, we tried to identify the characteristic bundles of gene expression in BSCE using comprehensive gene expression analysis (CGEA). Subsequently, we constructed a gene expression scoring system for the proper diagnosis of BSCE. Fifty-seven surgical specimens, including seven BSCEs, obtained from 30 patients who underwent esophagectomy were used for constructing the scoring system. Three hundred and twelve biopsy specimens, including eight BSCEs, obtained from 80 patients and 20 commercially available formalin-fixed paraffin-embedded (FFPE) specimens diagnosed as esophageal cancer, including 13 BSCEs, were used for validation. After our original mathematical extraction algorithm, 75 genes were extracted to distinguish BSCE from non-BSCE. The cumulative converted values (gene expression score) of the respective 75 genes from each specimen were obtained and lined up in ascending order to assess the optimal gene expression cut-off score for a definitive diagnosis of BSCE. The validation of this scoring system showed high prediction of the biopsy specimens [area under the curve (AUC)=0.981; 95% confidence interval (CI): 0.952-1.000] and the commercially available FFPE specimens (AUC=0.901; 95% CI: 0.750-1.000). In conclusion, using CGEA in a gene expression scoring system helps in differentiating BSCE from non BSCE with high accuracy and may contribute in improving BSCE treatment. PMID- 28731135 TI - Multi-glycoside of Tripterygium wilfordii Hook. f. attenuates glomerulosclerosis in a rat model of diabetic nephropathy by exerting anti-microinflammatory effects without affecting hyperglycemia. AB - Multi-glycoside of Tripterygium wilfordii Hook. f. (GTW) has been proven to be clinically effective in relieving microinflammation in patients with early diabetic nephropathy (DN). However, the therapeutic mechanisms involved in vivo remain unclear. In the process of early DN, microinflammation and activation of p38 mitogen-activated protein kinase (MAPK) and canonical nuclear factor (NF) kappaB signaling pathways are the important mechanisms by which hyperglycemia contributes to glomerulosclerosis (GS). Therefore, this study aimed to examine the ameliorative effects of GTW on GS, and then to clarify its anti microinflammatory mechanisms by inhibiting p38 MAPK and NF-kappaB signaling activities in the kidney. All rats were divided into 4 groups: the sham group, the sham + GTW group, the vehicle group and the GTW group. The suitable dose of GTW and vehicle were daily administered for 8 weeks after the induction of DN by unilateral nephrectomy combined with intraperitoneal injections of streptozotocin (STZ). The general status of the rats, biochemical parameters, renal histological changes and macrophages in glomeruli, as well as expression of the key proteins in the p38 MAPK and canonical NF-kappaB signaling pathways and inflammatory cytokines including tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta and transforming growth factor (TGF)-beta1 in the kidney were examined, respectively. The results revealed that, GTW improved the general cond-ition and biochemical parameters of the rats, but did not lower blood glucose; GTW attenuated GS and suppressed glomerular microinflammation including the infiltration of ED1+ cells in glomeruli and the protein overexpression of TNF-alpha, IL-1beta and TGF-beta1 in the kidney; GTW inhibited the protein overexpression of key signaling molecules of p38 MAPK and canonical NF-kappaB pathways in the kidney including phosphorylated p38 MAPK, phosphorylated inhibitor protein IkappaB and NF-kappaB (p65). On the whole, we expounded that GTW, as a natural regulator in vivo, alleviates GS without affecting hyperglycemia, by exerting anti-microinflammatory effects, including reducing macrophage infiltration in glomeruli, suppressing TNF alpha, IL-1beta and TGF-beta1 overexpression in the kidney and inhibiting p38 MAPK and NF-kappaB signaling activities. PMID- 28731136 TI - MHY451 induces cell cycle arrest and apoptosis by ROS generation in HCT116 human colorectal cancer cells. AB - Colorectal cancer (CRC) is the third most frequently diagnosed cancer and cause of cancer-related deaths. Despite advancements in conventional therapeutic approaches to CRC, most patients with CRC die of their disease. There is a need to develop novel therapeutic agents for this malignancy. Therefore, the present study aimed to examine the anticancer effects and elucidate the underlying mechanism of MHY451 in HCT116 human colorectal cancer cells. Treatment with MHY451 inhibited cell growth in a time- and concentration-dependent manner. MHY451 increased the accumulation of cell cycle progression at the G2/M phase. This agent decreased the protein level of cyclin B1 and its activating partners, Cdc25c and Cdc2, whereas it increased the cell cycle inhibitor p21WAF/CIP. The induction of apoptosis was observed by decreased viability, cleavage of poly(ADP ribose) polymerase (PARP), alteration in the ratio of Bax/Bcl-2 protein expression and reduction of procaspase-8 and -9. Pretreatment with Z-VAD-FMK, a pan-caspase inhibitor, inhibited MHY451-induced apoptosis, indicating that apoptotic cell death by MHY451 was mediated through caspases. Moreover, the apoptotic effect of MHY451 was reactive oxygen species (ROS)-dependent, evidenced by the inhibition of MHY451-induced PARP cleavage and ROS generation by N acetylcysteine-induced ROS scavenging. Taken together, these results demonstrate that MHY451 exerts anticancer effects by regulating the cell cycle, inducing apoptosis through caspase activation and generating ROS. These results suggest that MHY451 has considerable potential for chemoprevention or treatment of CRC or both. PMID- 28731137 TI - Phosphorylation of Bcl-2 plays an important role in glycochenodeoxycholate induced survival and chemoresistance in HCC. AB - Hepatocellular carcinoma (HCC) is a highly malignant tumor and can evolve rapidly to resistance to chemotherapies. Glycochenodeoxycholate (GCDA), which is toxic and hydrophobic, is the main ingredient in the bile and associated with carcinogenesis of gastrointenstinal tumors. Bcl-2 is the most important anti apoptotic protein and overexpressed in various human tumors. In the present study, we found that GCDA can induce the chemoresistance of human liver cancer cells and specific depletion of Bcl-2 by RNA interference blocks GCDA-stimulated chemoresistance, which indicate the pivotal role of Bcl-2 in such process. Mechanistically, GCDA simultaneously stimulates phosphorylation of Bcl-2 at Ser70 site and activates extracellular signal-regulated kinase 1/2 (ERK1/2), and inhibition of ERK1/2 by PD98059 (MAPK/ERK1/2 inhibitor) or siRNA (targeting ERK1/2) suppresses GCDA-stimulated phosphorylation of Bcl-2 and significantly attenuates the survival and chemoresistance induced by GCDA in liver cancer cells. Thus, GCDA-induced survival and chemoresistance of liver cancer cells may occur through activation of Bcl-2 by phosphorylation at Ser70 site through MAPK/ERK1/2 pathway, which may contribute to the development of human liver cancer and chemoresistance. PMID- 28731138 TI - Upregulation of long non-coding RNA DQ786243 promotes the progression of gastric cancer. AB - Long non-coding RNAs (lncRNAs) have been identified as key regulatory factors in various biological processes. Their dysregulation has been observed in several types of human cancer, including gastric cancer (GC). The aim of the present study was to investigate the putative roles of the lncRNA DQ786243 in the progression of GC, as well as evaluate its diagnostic and therapeutic potential in GC. The expression of DQ786243 in 82 pairs of GC tissues and adjacent healthy tissues, as well as in three GC cell lines and a human normal gastric epithelial cell line, was assessed using reverse transcription-quantitative polymerase chain reaction. In addition, the putative correlation between the expression of DQ786243 and various clinicopathological features of GC was investigated. Furthermore, the effects of silencing DQ786243 in GC cells were examined using RNA interference. Colony formation and Cell Counting kit-8 assays were used to evaluate the effects of DQ786243 on GC cell proliferation, and Transwell and wound healing assays were used to examine GC cell migration and invasion. The results of the present study demonstrated that the expression of DQ786243 was significantly upregulated in GC tissues and cell lines compared with healthy control tissues and cells. Correlation analysis revealed a significant association between the expression of DQ786243 and the TNM stage, tumor size, depth of invasion and presence of lymph node metastasis in patients with GC. Furthermore, silencing the DQ786243 was demonstrated to inhibit proliferation, and impair the migration and invasion of GC cells. The present results suggested that DQ786243 may function as an oncogenic regulator via promoting the proliferation and metastasis of GC cells. Therefore, DQ786243 may have potential as a novel biomarker for the diagnosis of GC, and may also be a promising candidate for the development of novel therapeutic approaches for the treatment of patients with GC. PMID- 28731139 TI - Inhibitory effects of FKBP14 on human cervical cancer cells. AB - The FK506-binding protein 14 (FKBP14), which belongs to a subfamily of immunophilins, has been implicated in various biochemical processes. However, its effects on human cervical cancer remain to be elucidated. The present study aimed to determine the exact role of FKBP14 in human cervical cancer cell proliferation, cell cycle progression, apoptosis, invasion and migration. Cell proliferation was measured by Cell Counting Kit-8 assay. Flow cytometry was conducted to determine the effects of FKBP14 on cell cycle progression and apoptosis. Cell invasion and migration were determined by Transwell assay. The results of the present study demonstrated that silencing FKBP14 expression using short hairpin (sh)RNA suppressed proliferation, invasion and migration of HeLa and C-33A cells, and also induced apoptosis and cell cycle arrest. Furthermore, silencing FKBP14 expression decreased the protein expression levels of B-cell lymphoma 2 (Bcl-2), matrix metalloproteinase (MMP)2 and MMP9, and increased the levels of caspase-3 and Bcl-2-associated X protein in FKBP14 shRNA-infected HeLa and C-33A cells. In conclusion, FKBP14 may act as an oncogene through suppressing apoptosis and promoting motility in human cervical carcinogenesis; therefore, it may be considered a potential therapeutic target for the treatment of cervical cancer. PMID- 28731140 TI - Integrated analysis of genome-wide gene expression and DNA methylation microarray of diffuse large B-cell lymphoma with TET mutations. AB - Diffuse large B-cell lymphoma (DLBCL), the most frequently occurring type of lymphoid malignancy, has been demonstrated to be associated with mutations of Ten Eleven Translocation (TET). In order to explore the association between DLBCL and TET mutations, the present study analyzed the gene expression and methylation profiles in human DLBCL biopsy tissues with wildtype and mutated TET2. The microarray dataset GSE37365, containing two subseries: the genome-wide gene expression dataset GSE37362 and the DNA methylation microarray dataset GSE37363, was downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were identified using the limma package of R. Furthermore, differentially methylated sites and differentially methylated regions were identified. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed via GO stats and GSEABase packages respectively. Finally, the Pathview package was used to construct the network of enriched pathways. A total of 198 DEGs (106 up- and 92 downregulated) were obtained. A total of 602 shared differentially methylated genes (DMGs) were identified according to differentially methylated levels. A total of 12 overlapping genes were identified in DEGs and DMGs. It was observed that 9 of the 12 overlapped genes were downregulated and hypermethylated, with 24 GO terms and one KEGG pathway significantly enriched. The results of the present study demonstrated that the genes cryptochrome circadian clock 1, zinc finger protein (ZNF) interacting with K protein 1, ZNF134, ZNF256 and ZNF615, which were hypermethylated and downregulated in DLBCL patients with TET2 mutations, were the key genes in the association between DLBCL and TET mutations. These genes may act as potential biomarkers for the diagnosis of DLBCL in the future. PMID- 28731141 TI - Botulinum toxin A improves adipose tissue engraftment by promoting cell proliferation, adipogenesis and angiogenesis. AB - Adipose tissue engraftment has become a well-established therapy in plastic and reconstructive surgery used to restore age-related or injury-related soft tissue loss. However, the unpredictable absorption rates limit its further application. Some clinicians have noted that more optimal aesthetic results are achieved when botulinum toxin A (BoNTA) is applied prior to adipose tissue grafting. In the present study, we transplanted allogeneic adipose tissue treated with or without BoNTA in SD rats in vivo. We subsequently evaluated the survival rate (weight, volume, apoptosis and cellular integrity) and revascularization of the adipose tissue. The results revealed that BoNTA improved the long-term weight and volume retention of the graft, and preserved cellular integrity. BoNTA significantly increased the expression levels of CD31 and vascular endothelial growth factor (VEGF), suggesting enhanced vasodilation and endothelial cell proliferation. In vitro, adipose-derived stem cells (ASCs) were isolated, identified and induced to proliferate and differentiate with or without BoNTA. Furthermore, to evaluate the proliferative, adipogenic and angiogenic ability of the ASCs, CCK-8 assay and Oil Red O staining were conducted. Gene and protein expression levels were analyzed by RT-qPCR and western blot analysis. The results revealed that 8x10-2 U/ml BoNTA as the optimal dose increased ASC proliferation and adipogenic differentiation capacity, as well as the expression level of the key cytokine of angiogenesis. On the whole, our findings indicate that BoNTA improves adipose tissue engraftment and promotes ASC regeneration, which could benefit future clinical applications. PMID- 28731142 TI - NLRC3 promotes host resistance against Pseudomonas aeruginosa-induced keratitis by promoting the degradation of IRAK1. AB - Pseudomonas aeruginosa (PA)-induced keratitis is one of the most common and destructive bacterial diseases. The pathogenesis of PA infections is closely associated with excessive inflammatory responses. Nucleotide oligomerization domain (NOD)-like receptor (NLR) family with caspase activation and recruitment domain (CARD) containing 3 (NLRC3) protein has been implicated as a negative regulator of inflammation and antiviral response, but the role of NLRC3 in PA induced keratitis has not been described. In the present study, we investigated the effects of NLRC3 in PA-induced keratitis and explored the underlying mechanism. We found that the expression of NLRC3 was decreased in mouse corneas and macrophages after PA infection. Overexpr-ession of NLRC3 significantly attenuated disease progression, inhibited the activation of nuclear factor-kappaB signaling and decreased the production of pro-inflammatory cytokines after PA infection. Furthermore, overexpression of NLRC3 promoted K48-linked polyubiquitination and degradation of interleukin-1 receptor-associated kinase 1 (IRAK1). Taken together, we demonstrated that NLRC3 has an anti-inflammatory effect on PA-induced keratitis, which may provide an improved understanding of host resistance to PA infection. PMID- 28731143 TI - Suppression of hepatic dysfunction in tenascin-X-deficient mice fed a high-fat diet. AB - Extracellular matrix glycoprotein tenascin-X (TNX) is the largest member of the tenascin family. In the present study, the contribution of TNX to liver dysfunction was investigated by administration of high-fat and high-cholesterol diet with high levels of phosphorus and calcium (HFCD) to wild-type (WT) and TNX knockout (KO) mice. After 16 weeks of HFCD administration, the ratio of liver weight to body weight was approximately 22% higher in the HFCD-fed WT mice compared with the HFCD-fed TNX-KO mice, indicating hepatomegaly in HFCD-fed WT mice. Histological analyses with hematoxylin and eosin staining at 21 weeks revealed that hepatocyte hypertrophy in HFCD-fed TNX-KO mice was suppressed to 85% of that in HFCD-fed WT mice. By contrast, there was a 1.2-fold increase in lipid deposition in hepatocytes from HFCD-fed TNX-KO mice compared with HFCD-fed WT mice at 18 weeks, as demonstrated by Oil Red O staining. In addition, TNX-KO mice at 21 weeks and 27 weeks post-HFCD administration exhibited significant suppression of inflammatory cell infiltrate to 51 and 24% of that in WT mice, respectively. Immunofluorescence analysis for type I collagen and Elastica van Gieson staining demonstrated a clear hepatic fibrosis progression in HFCD-fed WT mice at 27 weeks, whereas hepatic fibrosis was undetected in HFCD-fed TNX-KO mice. The present findings indicated that TNX deficiency suppressed hepatic dysfunction induced by HFCD administration. PMID- 28731145 TI - Piezo1 protein induces the apoptosis of human osteoarthritis-derived chondrocytes by activating caspase-12, the signaling marker of ER stress. AB - The present study was carried out to determine whether the mechanically activated cation channel Piezo1 protein plays a role as a signaling pathway which causes the apoptosis of human chondrocytes. The chondrocytes were isolated, cultured, and then subjected to mechanical stretch force for 0, 2, 12, 24 and 48 h, respectively. The expression levels of Piezo1 and the apoptosis-related protein caspase-12 were assessed by reverse transcription-quantitative polymerase chain reaction, as well as the apoptosis-related genes, B cell lymphoma/leukemia-2 (Bcl 2), Bcl-associated X protein (Bax) and Bcl-2-associated death promoter (BAD). Lactate dehydrogenase (LDH) activity was used to discern dead cells. Piezo1 expression was determined by immunofluorescence. In addition, Piezo1 inhibitor, GsMTx4, was used to block the mechanically activated (MA) cation channel Piezo1, and served as a positive control. The results showed that the osteoarthritis (OA) derived chondrocytes showed a tendency to undergo late-stage apoptosis under compressive loading. Piezo1 and caspase-12 were significantly upregulated under static compressive stimuli and the expression was related to the rate of apoptosis of the OA-derived chondrocytes during compressive loading. The expression of caspase-12 and late-stage apoptosis of the human OA-derived chondrocytes were repressed by GsMTx4, the specific inhibitor of Piezo1, while the expression of Piezo1 and the induction of the apoptosis of the OA-derived chondrocytes during compressive loading was not totally blocked. Thus, we conclude that Piezo1 plays an important role in the apoptosis of human OA-derived chondrocytes through a caspase-12-dependent pathway. The expression of Piezo1 protein was not totally inhibited by GsMTx4. PMID- 28731146 TI - Aberrant expression of RSK4 in breast cancer and its role in the regulation of tumorigenicity. AB - Breast cancer is the most frequently diagnosed cancer in both more and less economically developed countries and remains the leading cause of cancer-related death in women worldwide. In this study, to explore the expression and pathological role of RSK4 in breast cancer progression, we demonstrated that RSK4 expression was significantly decreased in breast cancer cells and tissues, and the overexpression of RSK4 in MDA-MB-231 cells inhibited cell migration and invasion. In a mouse model experiment, overexpression of RSK4 in mice further confirmed its critical role in regulating breast cancer tumorigenicity. The regulatory role of RSK4 in breast cancer development was mediated by AKT and extracellular signal-regulated kinase (ERK) signaling pathways and the expression of RSK4 was altered by DNA methylation in promoter regions. These results provide important insight into the role of RSK4 in cancerogenesis and may help to improve the prevention, diagnosis and treatment of breast cancer. PMID- 28731144 TI - Dietary fiber in irritable bowel syndrome (Review). AB - Irritable bowel syndrome (IBS) is a common chronic gastrointestinal disorder. It is widely believed that IBS is caused by a deficient intake of dietary fiber, and most physicians recommend that patients with IBS increase their intake of dietary fiber in order to relieve their symptoms. However, different types of dietary fiber exhibit marked differences in physical and chemical properties, and the associated health benefits are specific for each fiber type. Short-chain soluble and highly fermentable dietary fiber, such as oligosaccharides results in rapid gas production that can cause abdominal pain/discomfort, abdominal bloating/distension and flatulence in patients with IBS. By contrast, long-chain, intermediate viscous, soluble and moderately fermentable dietary fiber, such as psyllium results in a low gas production and the absence of the symptoms related to excessive gas production. The effects of type of fiber have been documented in the management of IBS, and it is known to improve the overall symptoms in patients with IBS. Dietary fiber acts on the gastrointestinal tract through several mechanisms, including increased fecal mass with mechanical stimulation/irritation of the colonic mucosa with increasing secretion and peristalsis, and the actions of fermentation byproducts, particularly short-chain fatty acids, on the intestinal microbiota, immune system and the neuroendocrine system of the gastrointestinal tract. Fiber supplementation, particularly psyllium, is both safe and effective in improving IBS symptoms globally. Dietary fiber also has other health benefits, such as lowering blood cholesterol levels, improving glycemic control and body weight management. PMID- 28731147 TI - Beclin 1 overexpression inhibits chondrocyte apoptosis and downregulates extracellular matrix metabolism in osteoarthritis. AB - In the present study, the expression of Beclin 1 in osteoarthritis (OA) cartilage tissue was investigated, and also its role in proliferation, apoptosis and expression of matrix metalloproteinases (MMPs) in chondrocytes obtained from patients with OA. Beclin 1 expression in cartilage tissue from OA patients, and in the age- and sex-matched controls, was detected by immunohistochemistry, semi quantitative polymerase chain reaction and western blotting. Chondrocytes were divided into control and Beclin 1-overexpressed groups. After transfection for 48, 72 and 96 h, cell viability, apoptosis, the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway and MMPs were examined. The mRNA and protein expression levels of Beclin 1 were significantly decreased in cartilage tissue from OA patients compared with the sex- and age-matched controls (P<0.05). In chondrocytes from OA patients, Beclin 1 overexpression significantly increased cell viability (P<0.05). Beclin 1 overexpression additionally decreased the degree of apoptosis, as demonstrated by Hoechst staining and flow cytometric analysis. B-cell lymphoma-2 (Bcl-2) was upregulated, and Bcl-2 associated X was downregulated, following Beclin 1 overexpression (P<0.05). The PI3K/Akt/mTOR signaling pathway was mitigated following Beclin 1 overexpression (P<0.05). In addition, MMP1, MMP3 and MMP13 were downregulated after Beclin 1 overexpression (P<0.05). Taken together, low expression levels of Beclin 1 may contribute towards the degeneration of chondrocytes. Beclin 1 overexpression increased cell viability, inhibited apoptosis and MMPs, likely via the PI3K/Akt/mTOR signaling pathway. PMID- 28731149 TI - The role of T helper 17 cells in the pathogenesis of hepatitis B virus-related liver cirrhosis (Review). AB - In chronic hepatitis B virus (HBV)-infected patients, T helper 17 (Th17) cells are significantly elevated. Th17 cells initiate immune-mediated pathogenesis and have a critical role in the process of HBV-related liver cirrhosis (HBV-LC). The mechanisms underlying this process are attributed to Th17-secreted cytokines, which include interleukin (IL)-17, IL-21 and IL-22; however, a systemic analysis regarding these mechanisms has yet to be conducted. Therefore, the present study aimed to investigate the role of Th17 cells in the pathogenesis of HBV-LC. All randomized clinical trials, case series, case reports and meta-analyses that contained the aforementioned keywords were included in the review process. In addition, unpublished information from the Food and Drug Administration was included. The findings indicated that Th17-secreted cytokines, including IL-17, IL-21 and IL-22, function by activating or silencing hepatic stellate cells, modulating proinflammatory and pro- or antifibrogenic effectors, regulating extracellular matrix formation, upregulating chemokine expression, and inducing hepatocellular damage or hepatoprotection during the HBV-LC process. In addition, Th17 cells and Th17-secreted cytokines may be considered a potential tool in the diagnosis or treatment of HBV-LC. The present review summarized the role of Th17 cells in the pathogenesis of HBV-LC in order to deepen the clinical understanding of the role of Th17 cells and also to support the development of effective therapies for patients with HBV-LC. PMID- 28731150 TI - miR-4262 inhibits colon cancer cell proliferation via targeting of GALNT4. AB - MicroRNAs (miRs) have been demonstrated to be important in the establishment and progression of colon cancer. However the underlying molecular mechanisms remain to be fully elucidated. Polypeptide N-acetylgalactosaminyltransferase4 (GALNT4) participates in numerous cellular processes, including tumorigenesis. The present study used reverse transcription-quantitative polymerase chain reaction and western blotting to investigate the expression levels of miR-4262 and GALNT4 in tissues and cells. In addition, MTS and colony formation assays, and cell cycle analysis were performed to evaluate the effect of miR-4262 on cell proliferation and the cell cycle. The findings demonstrated that miR-4262 was a direct target of GALNT4 mRNA. Overexpression of miR-4262 was demonstrated to decrease GALNT4 mRNA and protein expression levels, and thereby suppressed cell viability, growth and cell-cycle progression in SW480 and SW620 colon cancer cells. In addition, knockdown of miR-4262 significantly increased the cell viability, growth, and cell-cycle progression of SW480 and SW620 cells. The expression level of miR-4262 was observed to be downregulated as the expression of GALNT4 was upregulated in colon cancer tissues and cell lines. In conclusion, the results demonstrated that miR-4262 may be involved in the development of colon cancer via targeting of GALNT4. The miR-4262/GALNT4 axis may be a novel target for diagnosing and understanding the underlying molecular mechanism of colon cancer. PMID- 28731151 TI - MEG3 is a prognostic factor for CRC and promotes chemosensitivity by enhancing oxaliplatin-induced cell apoptosis. AB - A major reason for the failure of advanced colorectal cancer (CRC) treatment is the occurrence of chemoresistance to oxaliplatin-based chemotherapy. Recently, studies have shown that long non-coding RNAs (lncRNAs) play an important role in drug resistance. Using HiSeq sequencing methods, we identified that lncRNAs show differential expression levels in oxaliplatin-resistant (OxR) and non-resistant CRC patients. RT-qPCR was then performed in tissues and serum samples, and lncRNA MEG3 was verified to be downregulated in non-responding patients and to have considerable discriminating potential to identify responding patients from non responding patients. Moreover, decreased serum MEG3 expression was associated with poor chemoresponse and low survival rate in CRC patients receiving oxaliplatin treatment. Subsequently, OxR cell lines were established, and MEG3 was significantly downregulated in HT29 OxR and SW480 OxR cells. In addition, overexpression of MEG3 with pMEG3 reversed oxaliplatin resistance in both CRC cell lines. Flow cytometric apoptosis analysis indicated that MEG3 promoted CRC cell apoptosis. More importantly, MEG3 enhanced oxaliplatin-induced cell cytotoxicity in CRC. In conclusion, our integrated approach demonstrated that decreased expression of lncRNA MEG3 in CRC confers potent poor therapeutic efficacy, and that MEG3 promotes chemosensitivity by enhancing oxaliplatin induced cell apoptosis. Thus, overexpression of MEG3 may be a future direction by which to develop a novel therapeutic strategy to overcome oxaliplatin resistance of CRC patients. PMID- 28731148 TI - Molecular genetics and targeted therapy of WNT-related human diseases (Review). AB - Canonical WNT signaling through Frizzled and LRP5/6 receptors is transduced to the WNT/beta-catenin and WNT/stabilization of proteins (STOP) signaling cascades to regulate cell fate and proliferation, whereas non-canonical WNT signaling through Frizzled or ROR receptors is transduced to the WNT/planar cell polarity (PCP), WNT/G protein-coupled receptor (GPCR) and WNT/receptor tyrosine kinase (RTK) signaling cascades to regulate cytoskeletal dynamics and directional cell movement. WNT/beta-catenin signaling cascade crosstalks with RTK/SRK and GPCR cAMP-PKA signaling cascades to regulate beta-catenin phosphorylation and beta catenin-dependent transcription. Germline mutations in WNT signaling molecules cause hereditary colorectal cancer, bone diseases, exudative vitreoretinopathy, intellectual disability syndrome and PCP-related diseases. APC or CTNNB1 mutations in colorectal, endometrial and prostate cancers activate the WNT/beta catenin signaling cascade. RNF43, ZNRF3, RSPO2 or RSPO3 alterations in breast, colorectal, gastric, pancreatic and other cancers activate the WNT/beta-catenin, WNT/STOP and other WNT signaling cascades. ROR1 upregulation in B-cell leukemia and solid tumors and ROR2 upregulation in melanoma induce invasion, metastasis and therapeutic resistance through Rho-ROCK, Rac-JNK, PI3K-AKT and YAP signaling activation. WNT signaling in cancer, stromal and immune cells dynamically orchestrate immune evasion and antitumor immunity in a cell context-dependent manner. Porcupine (PORCN), RSPO3, WNT2B, FZD5, FZD10, ROR1, tankyrase and beta catenin are targets of anti-WNT signaling therapy, and ETC-159, LGK974, OMP-18R5 (vantictumab), OMP-54F28 (ipafricept), OMP-131R10 (rosmantuzumab), PRI-724 and UC 961 (cirmtuzumab) are in clinical trials for cancer patients. Different classes of anti-WNT signaling therapeutics are necessary for the treatment of APC/CTNNB1 , RNF43/ZNRF3/RSPO2/RSPO3- and ROR1-types of human cancers. By contrast, Dickkopf related protein 1 (DKK1), SOST and glycogen synthase kinase 3beta (GSK3beta) are targets of pro-WNT signaling therapy, and anti-DKK1 (BHQ880 and DKN-01) and anti SOST (blosozumab, BPS804 and romosozumab) monoclonal antibodies are being tested in clinical trials for cancer patients and osteoporotic post-menopausal women. WNT-targeting therapeutics have also been applied as reagents for in vitro stem cell processing in the field of regenerative medicine. PMID- 28731152 TI - AEG-1 associates with metastasis in papillary thyroid cancer through upregulation of MMP2/9. AB - Astrocyte elevated gene-1 (AEG-1), known as an oncogene, is overexpressed in various cancers and implicated in tumor progression and metastasis. However, its functional significance and underlying molecular mechanisms in thyroid cancer remain to be elucidated. In the present study, we detected the potential function of AEG-1 in papillary thyroid cancer (PTC). We also investigated the relation between AEG-1 and matrix metalloproteases (MMP)2 and 9 through immunohistochemistry, western blotting, real-time PCR, immunofluorescence staining, zymography and co-immunoprecipitation (Co-IP). We found that overexpression of AEG-1 in PTC was positively correlated with lymph node metastasis and MMP2/9 expression. Knockdown of AEG-1 reduced the capacity of migration and invasion through downregulation of MMP2/9 in thyroid cancer cells. Furthermore, we firstly found that AEG-1 interacted with MMP9 in thyroid cancer cells. AEG-1 was associated with the activation of the nuclear factor kappaB (NF kappaB) signaling pathways in thyroid cancer cells. Overall, our results for the first time showed that AEG-1 interacted with MMP9 in thyroid cancer cells and AEG 1 expression was closely associated with progression and metastasis of papillary thyroid cancer. AEG-1 might be a potential therapeutic target in papillary thyroid cancer. PMID- 28731154 TI - SYPL1 overexpression predicts poor prognosis of hepatocellular carcinoma and associates with epithelial-mesenchymal transition. AB - Hepatocellular carcinoma (HCC) is the second leading cause of cancer mortality worldwide, which is mainly due to relapse and metastasis. Synaptophysin-like 1 (SYPL1), a member of SYP family proteins, exerts complicated functions, which prompted us to wonder whether SYPL1 contributed to HCC progress. Herein, we performed integrative experiments of quantitative real-time polymerase chain reaction (qRT-PCR), western blot analysis and immunohistochemistry (IHC), and found that SYPL1 overexpression in HCC tissues was closely correlated with several malignant clinicopathologic features of HCC. The results from IHC in serial sections of HCC tissues further indicated that SYPL1 expression was associated with epithelial-mesenchymal transition (EMT) biomarkers of HCC cells. Additionally, Kaplan-Meier survival analysis showed that SYPL1 overexpression was significantly associated with reduced overall survival (OS) (p<0.001) and disease free survival (DFS) (p=0.002). Furthermore, univariate and multivariate Cox proportional hazards analysis identified SYPL1 as an independent prognostic factor for OS [hazard ratio (HR), 2.443, 95% confidence interval (CI), 1.429 4.177, p=0.001] and DFS (HR, 1.680, 95% CI=1.012-2.788, p=0.045) of HCC patients. Collectively, SYPL1 overexpression predicts poor prognosis of HCC and may associate with EMT of HCC cells. Therefore, SYPL1 could serve as a future novel biomarker and potential therapy target for HCC. PMID- 28731153 TI - Altered profile of mRNA expression in atrioventricular node of streptozotocin induced diabetic rats. AB - Prolonged action potential duration, reduced action potential firing rate, upstroke velocity and rate of diastolic depolarization have been demonstrated in atrioventricular node (AVN) cells from streptozotocin (STZ)-induced diabetic rats. To further clarify the molecular basis of these electrical disturbances, the mRNA profiles encoding a variety of proteins associated with the generation and conduction of electrical activity in the AVN, were evaluated in the STZ induced diabetic rat heart. Expression of mRNA was measured in AVN biopsies using reverse transcription-quantitative polymerase chain reaction techniques. Notable differences in mRNA expression included upregulation of genes encoding membrane and intracellular Ca2+ transport, including solute carrier family 8 member A1, transient receptor potential channel 1, ryanodine receptor 2/3, hyperpolarization activated cyclic-nucleotide 2 and 3, calcium channel voltage-dependent, beta2 subunit and sodium channels 3a, 4a, 7a and 3b. In addition to this, potassium channels potassium voltage-gated channel subfamily A member 4, potassium channel calcium activated intermediate/small conductance subfamily N alpha member 2, potassium voltage-gated channel subfamily J members 3, 5, and 11, potassium channel subfamily K members 1, 2, 3 and natriuretic peptide B (BNP) were upregulated in AVN of STZ heart, compared with controls. Alterations in gene expression were associated with upregulation of various proteins including the inwardly rectifying, potassium channel Kir3.4, NCX1 and BNP. The present study demonstrated notable differences in the profile of mRNA encoding proteins associated with the generation, conduction and regulation of electrical signals in the AVN of the STZ-induced diabetic rat heart. These data will provide a basis for a substantial range of future studies to investigate whether variations in mRNA translate into alterations in electrophysiological function. PMID- 28731155 TI - Marine collagen peptides reduce endothelial cell injury in diabetic rats by inhibiting apoptosis and the expression of coupling factor 6 and microparticles. AB - The present study aimed to elucidate the role of marine collagen peptides (MCPs) in protection of carotid artery vascular endothelial cells (CAVECs) in type 2 diabetes mellitus (T2DM), and the mechanism underlying this process. In an in vivo experiment, diabetic Wistar rats were divided randomly into four groups (n=10/group): Diabetes control, and three diabetes groups administered low, medium and high doses of MCPs (2.25, 4.5 and 9.0 g/kg body weight/day, respectively). Another 10 healthy rats served as the control. In an in vitro experiment, human umbilical-vein endothelial cells (HUVECs) were incubated in normal and high concentrations of glucose with or without MCPs (3.0, 15.0 and 30.0 mg/ml, respectively) for 24, 48 or 72 h. Blood vessel/endothelial construction, inflammatory exudation and associated molecular biomarkers in CAVECs were detected and analyzed. The results of the present study demonstrated that in rats, MCP treatment for 4 weeks significantly lowered blood glucose and attenuated endothelial thinning and inflammatory exudation in carotid-artery vascular endothelial cells. In vitro, the high-glucose intervention significantly increased cell apoptosis in HUVECs, and medium and high doses of MCPs (4.5 and 9.0 g/kg body weight/day, respectively) partially ameliorated this high glucose mediated apoptosis and decreased levels of apoptosis biomarkers. In conclusion, a moderate oral MCP dose (>=4.5 g/kg body weight/day) may be a novel therapeutic tool to protect against early cardiovascular complications associated with T2DM by inhibiting apoptosis and reducing the expression of coupling factor 6 and microparticles. PMID- 28731156 TI - Protein interacting with C-kinase 1 modulates exocytosis and KATP conductance in pancreatic beta cells. AB - It has been previously identified that alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) are expressed in pancreatic beta cells and regulate exocytosis and insulin release. It is known that protein interacting with C-kinase 1 (PICK1) regulates trafficking and synaptic targeting of AMPARs in the central nervous system. However, it is unknown whether PICK1 regulates glutamate-induced insulin release in beta cells. The present study demonstrated that glutamate-induced exocytosis was increased in beta cells derived from PICK1 knockout mice. In agreement with this result, adding PICK1 in beta cells reduced glutamate-induced exocytosis, whereas adding EVKI, a peptide that interrupts the interaction between AMPARs and PICK1, increased the exocytosis of beta cells with the application of glutamate. Furthermore, the conductance of ATP-sensitive potassium (KATP) channels was reduced in PICK1-knockout mice, which was reversed by the overexpression of PICK1. In addition, PICK1 application reduced voltage oscillation induced by the closure of KATP. Taken together, the results indicate that PICK1 regulates glutamate-induced exocytosis in beta cells. PMID- 28731157 TI - Curcumin prevents lipopolysaccharide-induced matrix metalloproteinase-2 activity via the Ras/MEK1/2 signaling pathway in rat vascular smooth muscle cells. AB - The aim of the present study was to examine the effect of curcumin treatment on lipopolysaccharide (LPS)-induced matrix metalloproteinase-2 (MMP-2) activity, and assess whether the effects are mediated by the Ras/mitogen-activated protein kinase kinase 1/2 (MEK1/2) signaling pathway in vascular smooth muscle cells (VSMCs). VSMCs were isolated from male Sprague-Dawley rats. Protein expression levels were analyzed by western blotting. The activity of MMP-2 was measured with gelatin zymography, and an electrophoretic mobility shift assay was used to detect the DNA binding activity of nuclear factor-kappaB (NF-kappaB). Curcumin treatment was demonstrated to inhibit LPS-induced MMP-2 activity in rat VSMCs. This inhibitory effect was partially blocked by ammonium pyrrolidinedithiocarbamate, an inhibitor of NF-kappaB activation, and farnesylthiosalicylic acid, an inhibitor of Ras. In addition, the results of the present study indicated that LPS-induced phosphorylation of Ras homolog family member A and MEK1/2 was significantly decreased by curcumin. Furthermore, NF kappaB p65 expression in the nucleus and the DNA binding activity of NF-kappaB in rat LPS-exposed VSMCs was decreased by curcumin. Taken together, these findings suggest that curcumin prevents of LPS-induced MMP-2 activity through Ras/MEK1/2 and NF-kappaB signaling. PMID- 28731158 TI - The long non-coding RNA SNHG3 functions as a competing endogenous RNA to promote malignant development of colorectal cancer. AB - Accumulating evidence has revealed that aberrantly expressed long non-coding transcripts are involved in the development and progression of colorectal cancer (CRC). Small nucleolar RNA host gene 3 (SNHG3) is a newly identified lncRNA, and little is known about its clinical significance and biological functions in the development of CRC. In the present study, we found that the expression of SNHG3 was significantly upregulated in CRC, and upregulation of SNHG3 predicted poor prognosis for patients with CRC as determined through analysis of the data obtained from TCGA database. Gain-of function and loss-of function assays revealed that SNHG3 markedly promoted cellular proliferation of CRC cells. Gene Set Enrichment Analysis (GSEA) suggested that high expression of SNHG3 was positively associated with c-Myc and its targets genes. Furthermore, ectopic overexpression of SNHG3 increased the expression of c-Myc and its target genes, whereas inhibition of SNHG3 had opposite effect on the expression of c-Myc and its targets. Mechanistic investigations demonstrated that SNHG3 functioned as a competing endogenous RNA (ceRNA) to 'sponge' miR-182-5p, thus leading to the release of c-Myc from miR-182-5p and modulating the expression of c-Myc. In conclusion, SNHG3 promoted CRC progression via sponging miR-182-5p and upregulating c-Myc and its target genes. PMID- 28731159 TI - Ganoderic acid A inhibits proliferation and invasion, and promotes apoptosis in human hepatocellular carcinoma cells. AB - Ganoderic acid A (GA-A), a triterpenoid, has been demonstrated to suppress cell proliferation in various cancers, including breast cancer and osteosarcoma. However, its effect on human hepatocellular carcinoma (HCC) remains to be elucidated. The present study aimed to investigate the effect of GA-A on HCC cells in vitro. The HepG2 and SMMC7721 human HCC cell lines were treated with differing concentrations of GA-A for 24, 48 and 72 h. The cell growth rate, cell cycle and apoptosis, migration and invasion were determined using a Cell Counting Kit-8, flow cytometry and transwell assays, respectively. The expression of apoptosis-associated proteins was detected via western blot analysis. GA-A significantly inhibited the proliferation of human HCC HepG2 and SMMC7721 cells in a dose-dependent manner. Furthermore, GA-A induced cell cycle arrest at the G0/G1 phase and apoptosis, and suppressed the migration and invasion of HCC cells. Furthermore, GA-A decreased the expression of cyclin D1 and increased the expression of p21 and cleaved caspase-3. In conclusion, GA-A suppressed the proliferation of human HCC cells in vitro and may act as a promising natural therapeutic reagent in the treatment of HCC. PMID- 28731160 TI - Adipose-derived stem cells and hyaluronic acid based gel compatibility, studied in vitro. AB - Minimally invasive aesthetic and cosmetic procedures have increased in popularity. Injectable dermal fillers provide soft tissue augmentation, improve facial rejuvenation and wrinkles, and correct tissue defects. To investigate the use of adipose-derived stem cells integrated with a hyaluronic acid based gel as a dermal filler, the present study used cytotoxicity studies, proliferation studies, adipogenic and osteogenic differentiation, apoptosis assays and scanning electron microscopy. Although hyaluronic acid induced low levels of apoptosis in adipose-derived stem cells, its significantly promoted proliferation of adipose derived stem cells. Hyaluronic acid demonstrates little toxicity against adipose derived stem cells. Adipose-derived stem cells were able to differentiate into adipocytes and osteoblasts. Furthermore, scanning electron microscopy revealed that adipose-derived stem cells maintained intact structures on the surface of hyaluronic acid as well as in it, and demonstrated abundant cell attachments. The present study demonstrated the compatibility of adipose-derived stem cells and hyaluronic acid based gels in vitro. PMID- 28731161 TI - Investigation of the molecular mechanisms underlying myotonic dystrophy types 1 and 2 cataracts using microRNA-target gene networks. AB - The purpose of the present study was to investigate the molecular mechanisms of myotonic dystrophy (DM) 1 and 2 cataracts using bioinformatics methods. A microarray dataset (E-MEXP-3365) downloaded from the Array Express database included lens epithelial samples of DM1 and DM2 cataract patients (n=3/group) and non-DM lens epithelial samples as a control (n=4). Differentially expressed genes (DEGs) were identified between DM1 and control samples, and between DM2 and control samples. Pathway enrichment analyses were performed for the DEGs. Potential micro (mi)RNAs regulating these DEGs were predicted. An miRNA-target gene network was constructed for DM1 and DM2. The study identified 223 DEGs in DM1, and 303 DEGs in DM2. DM1 and DM2 shared 172 DEGs. The DEGs in DM1 were enriched with calcium, Wnt and axon guidance signaling pathways. The DEGs in DM2 were linked by adherens junction signaling pathways. miRNA (miR)-197, miR-29b and miR-29c were included in the network modules of DM1. miR-197, miR-29c and miR-29a were involved in the network modules of DM2. It is therefore hypothesized that these signaling pathways and miRNAs underlie DM1 and DM2 cataracts, and may represent potential therapeutic targets for the treatment of this disorder. PMID- 28731162 TI - A homozygous MYO7A mutation associated to Usher syndrome and unilateral auditory neuropathy spectrum disorder. AB - Usher syndrome (USH) is an autosomal recessive disorder characterized by sensorineural hearing loss, progressive visual loss and night blindness due to retinitis pigmentosa (RP), with or without vestibular dysfunction. The purpose of this study was to detect the causative gene in a consanguineous Chinese family with USH. A c.3696_3706del (p.R1232Sfs*72) variant in the myosin VIIa gene (MYO7A) was identified in the homozygous state by exome sequencing. The co segregation of the MYO7A c.3696_3706del variant with the phenotype of deafness and progressive visual loss in the USH family was confirmed by Sanger sequencing. The variant was absent in 200 healthy controls. Therefore, the c.3696_3706del variant may disrupt the interaction between myosin VIIa and other USH1 proteins, and impair melanosome transport in retinal pigment epithelial cells. Notably, bilateral auditory brainstem responses were absent in two patients of the USH family, while distortion product otoacoustic emissions were elicited in the right ears of the two patients, consistent with clinical diagnosis of unilateral auditory neuropathy spectrum disorder. These data suggested that the homozygous c.3696_3706del variant in the MYO7A gene may be the disease-causing mutation for the disorder in this family. These findings broaden the phenotype spectrum of the MYO7A gene, and may facilitate understanding of the molecular pathogenesis of the disease, and genetic counseling for the family. PMID- 28731163 TI - [Corrigendum] FUCA1 is induced by wild-type p53 and expressed at different levels in thyroid cancers depending on p53 status. AB - Subsequent to the publication of the above paper, the authors noted that: 1) there was an error on Fig. 4, page 2046, in which the symbols of alpha-L fucosidase 1 (FUCA 1) and fucosyltransferase 8 (FUT 8) had been mistakenly labelled the wrong way around (FUCA 1 should have been represented by the blue bars, and FUT 8 by the red), and 2) the sentence 'Average levels of FUCA1 mRNA were low in ATC s while expression levels in PTC samples were comparable or slightly higher than those present in normal thyroid tissues (Fig. 4)', page 2046, left column, 4th line from the bottom, was not appropriate to explain the result of Fig. 4. Therefore, this sentence is replaced by: 'FUCA1 RNA expression levels were found to be lower in anaplastic thyroid cancer samples (ATC s), while they were higher in papillary thyroid cancer samples (PTC s) and in normal thyroid tissues (Fig. 4)'. The corrected version of Fig. 4 is shown below, which now accurately shows how FUCA1 RNA expression levels were found to be lower in anaplastic thyroid cancer samples (ATC s), while they were higher in papillary thyroid cancer samples (PTC s) and in normal thyroid tissues. We sincerely apologize for the mistake and the inappropriate explanation in the text, and thank the reader of our article who drew this matter to our attention. Furthermore, we regret any inconvenience these chages have caused. [the original article was published in the International Journal of Oncology 50: 2043-2048, 2017; DOI: 10.3892/ijo.2017.3968]. PMID- 28731164 TI - Active targeting co-delivery system based on hollow mesoporous silica nanoparticles for antitumor therapy in ovarian cancer stem-like cells. AB - The combination of nanocarriers and chemotherapy drugs can release the chemotherapy drugs to the tumor tissue, which can enhance the antitumor effect and reduce the adverse reactions at the same time. In this study, a co-delivery system based on hollow mesoporous silica nanoparticles (HMSN) was developed and characterized. We also investigated the in vitro effect of this system on CD117+CD44+A2780 cell line. HMSN was selected as the nanocarrier, with -COOH modified on the surface and doxorubicin (DOX), NVP-AEW 541 (NVP) loaded inside. IGF-1R was chosen as the drug target, apoptosis rate and expression of cyclin B1, Bax, Bcl-xl, p-Akt were used to evaluate the antitumor effect of HMSN-COOH@DOX fluorescence NVP. The HMSN co-delivery system was successfully synthesized with encapsulation efficiency of 37% (DOX) and 44% (NVP), and high PH-sensitive property was observed. The apoptosis rate of CD117+CD44+A2780 ovarian cancer stem like cells treated by HMSN co-delivery system were almost 3 times higher than those of the free drugs group. The expression of Bax was significantly increased while Bcl-xl, and p-Akt reduced (P<=0.05). These data indicate that the co delivery system demonstrated a high efficiency in promoting apoptosis in ovarian cancer stem-like cells by targeting IGF-1R, but further study is still needed. PMID- 28731165 TI - Homeobox-containing protein 1 loss is associated with clinicopathological performance in glioma. AB - Homeobox-containing protein 1 (HMBOX1) is a novel member of the homeobox family, and abnormal expression of HMBOX1 has been observed in several types of carcinoma. A total of 144 cases of confirmed glioma diagnoses were included in the present study. Grading was performed according to the World Health Organization (WHO) grading system for central nervous system neoplasm. Immunohistochemical staining of HMBOX1, proliferation marker protein Ki-67 (Ki 67) and microvessel density (MVD) was performed, and scores were calculated. HMBOX1 mRNA levels were detected using the reverse transcription quantitative polymerase chain reaction. It was identified that the expression of HMBOX1 was reduced in glioma tissue compared with normal brain tissue (P<0.05). The expression of HMBOX1 was downregulated significantly in WHO grade IV tumors compared with WHO grades II and III (P<0.05). HMBOX1 expression was significantly correlated with WHO grade, Karnofsky Performance Score, MVD and Ki-67 expression; however, not associated with age or gender. Log-rank testing did not demonstrate that HMBOX1 expression was associated with prognosis. In conclusion, HMBOX1 may be a potential diagnostic marker in glioma. PMID- 28731166 TI - Screening of the prognostic targets for breast cancer based co-expression modules analysis. AB - The purpose of the present study was to screen the prognostic targets for breast cancer based on a co-expression modules analysis. The microarray dataset GSE73383 was downloaded from the Gene Expression Omnibus (GEO) database, including 15 breast cancer samples with good prognosis and 9 breast cancer samples with poor prognosis. The differentially expressed genes (DEGs) were identified with the limma package. The Database for Annotation, Visualization and Integrated Discovery was used to perform Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Furthermore, the co-expression analysis of DEGs was conducted with weighted correlation analysis. The interaction associations were analyzed with the Human Protein Reference Database and BioGRID. The protein-protein interactions (PPI) network was constructed and visualized by Cytoscape software. A total of 491 DEGs were identified in breast cancer samples with poor prognosis compared with those with good prognosis, and they were enriched in 85 GO terms and 4 KEGG pathways. 368 DEGs were co-expressed with others, and they were clustered into 10 modules. Module 6 was the most relevant to the clinical features, and 21 genes and 273 interaction pairs were selected out. Abnormal expression levels of required for meiotic nuclear division 5 homolog A (RMND5A) and angiopoietin-like protein 1 (ANGPTL1) were associated with a poor prognosis. It was indicated that SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily D, member 1, SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily D, member 1, dihydropyrimidinase-like 2, RMND5A and ANGPTL1 were potential prognostic markers in breast cancer, and the cell cycle may be involved in the regulation of breast cancer. PMID- 28731167 TI - High expression of TRIM29 (ATDC) contributes to poor prognosis and tumor metastasis by inducing epithelial-mesenchymal transition in osteosarcoma. AB - The association of TRIM29 overexpression with cancer progression and poor clinical prognosis has been reported in the context of several types of cancers. In the present study, we investigated the prognostic relevance of TRIM29 and its involvement in the progression of human osteosarcoma. To the best of our knowledge, this is the first study to demonstrate a major role of TRIM29 in osteosarcoma. Our results showed that the expression of TRIM29 in osteosarcoma tissues was much higher than that in normal bone tissues. Furthermore, TRIM29 expression was significantly correlated with tumor size, recurrence, metastasis and overall survival time. High expression of TRIM29 and presence of metastasis were independent predictors of poor prognosis in these patients. Both protein and mRNA expression of TRIM29 in osteosarcoma cell lines were significantly higher than those in osteoblast cell line, hFOB1.19. Moreover, the results indicated that TRIM29 promoted migration and invasive growth of osteosarcoma cells by inducing epithelial-mesenchymal transition. Therefore, ectopic expression of TRIM29 potentially contributes to metastasis and poor prognosis in patients with osteosarcoma. In summary, TRIM29 is a potential prognostic biomarker and a therapeutic target for patients with osteosarcoma. PMID- 28731168 TI - Osteoclast regulation of osteoblasts via RANK-RANKL reverse signal transduction in vitro. AB - The treatment of osteoporosis typically inhibits the activity of osteoclasts, which subsequently results in the suppression of bone formation and maintenance, however the underlying mechanism remains to be elucidated. The receptor activator of nuclear factor kappa-B ligand (RANKL)-receptor activator of nuclear factor kappa-B (RANK) signaling axis is important in the osteoblast regulation of osteoclasts. RANKL surface-bound molecules expressed on T cells stimulate a reverse signaling transduction in order to regulate the T cells, therefore the present study hypothesized that RANKL expressed on osteoblasts may transfer reverse signals to regulate osteoblasts. A series of experiments were designed to test the hypothesis, using MTT, stealth RNA interference, reverse transcription quantitative polymerase chain reaction, western blot analysis, alkaline phosphatase activity assay and alizarin red staining. The present study observed the role of RANK-RANKL reverse signaling on osteoblasts, regulated by osteoclasts. Osteoblasts were treated with recombinant RANK proteins. The soluble RANK enhanced the mineralization of osteoblasts. When the RANKL was knocked down in the osteoblast, RANK demonstrated a weak osteogenic effect on the RANKL deficient osteoblast compared with the wild-type osteoblast which served as a control. Addition of soluble RANK activated the p38 mitogen activated protein kinase (MAPK) signaling pathway in the osteoblast and blocking this same pathway in E1 cells reduced the effect of RANK. In the co-culture system of osteoblasts and osteoclasts, p38 MAPK in E1 cells was phosphorylated a short time following co-culture and the phosphorylation then blocked by abundant soluble RANKL. The findings suggested that RANKL expressed on osteoblasts transferred reverse signals from the exterior of the cell to the interior, which regulated the osteoblasts. PMID- 28731169 TI - In vivo and in vitro inhibition of human gastric cancer progress by upregulating Kank1 gene. AB - Recent research has found that Kank1 gene, as one of the important members of the Kank gene family, plays an important role in the occurrence and development of malignant tumors. As a brand new cancer suppressor gene, its expression is significantly downregulated or missing in various kinds of malignant tumors. However, no report on the specific role of Kank1 in the genesis and development of gastric cancer is available yet. In the present study, we found significantly lower expression of Kank1 gene in human gastric cancer cells. When Kank1 gene was upregulated, it was found that the proliferation of gastric cancer cells was obviously inhibited, cell apoptosis occurred and caspase family expression changed with mainly activation of caspase-3 and caspase-9 as well as the apparent imbalance in Bcl-2/Bax ratio. we also found that upregulating Kank1 gene may result in the inhibition of the ability of the invasion and metastasis of tumor cells and the significant change in the expression level of MMP-7 of MMP family, which were confirmed by the in vivo nude mouse experiment, as upregulating Kank1 gene expression may result in decline in the nude mouse tumor formation rate and the significant reduction in the transplanted tumor size. The results above indicate that upregulating the Kank1 gene can inhibit the progress of gastric cancer in vivo and in vitro and its mechanism is closely relevant to apoptosis and the tumor invasion and metastasis. PMID- 28731170 TI - Isorhamnetin inhibits IL-1beta-induced expression of inflammatory mediators in human chondrocytes. AB - Isorhamnetin (ISH) is a flavonoid primarily obtained from the fruit of Hippophae rhamnoides L., which possesses anti-inflammatory properties. However, the effect of ISH on the expression of inflammatory mediators in response to interleukin (IL)-1beta stimulation has not been elucidated. The present study investigated the effects of ISH on the expression of inflammatory mediators in human chondrocytes, induced by IL-1beta. The results of the present study demonstrated that pretreatment with ISH inhibited the expression of stromelysin-1 and collagenase 3 in chondrocytes, induced by IL-1beta. Pretreatment with ISH inhibited the IL-1beta-stimulated synthesis of NO and prostaglandin E2 induced by IL-1beta, in addition to the expression of inducible nitric oxide synthase and prostaglandin G/H synthase 2 in chondrocytes. Additionally, ISH inhibited the expression of nuclear factor (NF)-kappaB and transcription factor p65, and the degradation of NF-kappaB inhibitor alpha induced by IL-1beta in chondrocytes. In conclusion, the results of the present study indicated that ISH exhibited anti inflammatory and chondroprotective effects in IL-1beta-stimulated chondrocytes. The results of the present study suggest that ISH may be a potential agent in the future treatment of osteoarthritis. PMID- 28731171 TI - Protective role of Pollen Typhae total flavone against the palmitic acid-induced impairment of glucose-stimulated insulin secretion involving GPR40 signaling in INS-1 cells. AB - Prolonged elevated levels of free fatty acids (FFAs) contribute to the impairment of insulin secretion function of pancreatic beta cells, a hallmark of type 2 diabetes, which is partly attributed to the dysfunction of G-protein-coupled receptor 40 (GPR40) signaling. Pollen Typhae total flavone (PTF), an extract from a Chinese herbal medicine named Pollen Typhae, has been reported to effectively treat type 2 diabetes, but the underlying mechanisms remain to be fully elucidated. In the present study, palmitic acid (PA), a saturated fatty acid, severely impaired glucose-stimulated insulin secretion (GSIS) in a time-dependent manner in INS-1 cells, and PTF treatment prevented the impairment in a dose dependent manner. Moreover, PTF improved insulin secretion function in rats presenting with type 2 diabetes induced by a high-fat diet and low-dose streptozotocin. Furthermore, PA exposure for 24 h decreased the protein expression of GPR40, phospholipase C (PLC)beta1, PLCbeta3, and protein kinase C (PKC), and inhibited the activity of PLC and PKC stimulated by GW9508, a GPR40 agonist. In addition, PTF enhanced the protein expression of GPR40 and to a certain extent strengthened the protein expression of PKC, increased cellular levels of triphosphoinositide (IP3) and diacylglycerol (DAG), and promoted GW9508 stimulated activity of PLC and PKC reduced by PA in INS-1 cells, which were blocked by PLC inhibitor U-73122 and PKC inhibitor staurosporine, respectively. Additionally, the improvement in PA-induced impairment of GSIS by PTF in INS-1 cells was restrained by U-73122, staurosporine, and calcium channel inhibitor nifedipine, respectively. The results indicate that PTF exerts a protective role against PA-induced impairment of GSIS involving GPR40 signaling in INS-1 cells. PMID- 28731172 TI - Comparison of the neuronal differentiation abilities of bone marrow-derived and adipose tissue-derived mesenchymal stem cells. AB - Bone marrow-derived mesenchymal stem cells (BMSCs) and adipose tissue-derived mesenchymal stem cells (ADSCs) are able to differentiate into neuron-like cells when exposed to small molecule compounds, however the specific differences in their neuronal differentiation abilities remain to be fully elucidated. The present study aimed to compare the neuronal differentiation abilities of BMSCs and ADSCs. BMSCs and ADSCs from the same Sprague Dawley rats were isolated and cultured for use. The proliferation capacity was revealed using a cell counting method. Following BMSCs and ADSCs induction by four types of small-molecular compounds, the expression of various neuronal markers and the secretion of several neurotrophic factors were detected by immunofluorescence, western blotting, reverse transcription-quantitative polymerase chain reaction and ELISA. It was demonstrated that the ADSCs exhibited an increased proliferation capacity compared with BMSCs, according to cumulative population doubling analyses. Following a 7-day neuronal induction period, BMSCs and ADSCs exhibited a neuron like morphology, and were termed neuronal induced (NI)-BMSCs and NI-ADSCs. They expressed neuronal markers including beta-tubulin III, microtubule associated protein 2 and choline acetyltransferase. The number of NI-BMSCs that positively expressed the neuronal markers was significantly decreased compared with NI ADSCs, and the expression and secretion of the neurotrophic factors nerve growth factor and 3'-nucleotidase in NI-BMSCs were additionally decreased compared with NI-ADSCs. The findings of the present study indicated that the neuronal differentiation abilities and neurotrophic factor secretion abilities of ADSCs were increased compared with BMSCs. ADSCs may therefore act as efficient candidates in cell transplantation therapy for diseases and injuries of the nervous system. PMID- 28731173 TI - Anacardic acid induces cell apoptosis of prostatic cancer through autophagy by ER stress/DAPK3/Akt signaling pathway. AB - Anacardic acid, which is commonly seen in plants of Anacardiaceae, is an important composition of cashew, ginkgo leaf and fruit, and it has been suggested in previous research to show antitumor activity. The main aim of the present study was to evaluate the anticancer effects of anacardic acid on cell apoptosis of prostatic cancer and molecular mechanisms of this phenomenon. In this study we found that anacardic acid inhibited cell proliferation, induced apoptosis and caspase-3/9 activities and Bax protein expression of prostatic cancer. Anacardic acid induced the ER stress inducing factors (BiP, CHOP, p-eIF2alpha), autophagy, LC3, Beclin-1, Atg 7 and DAPK3 protein expression, and suppressed p-Akt and p mTOR protein expression of prostatic cancer. Si-CHOP was used to inhibit ER stress in prostatic cancer by anacardic acid, which showed that the cell proliferation was increased, apoptosis, and caspase-3/9 activities and Bax protein expression was suppressed, autophagy, LC3, Beclin-1, Atg 7 and DAPK3 protein expression was reduced, and p-Akt and p-mTOR protein expression was promoted. DAPK3 inhibited p-Akt and p-mTOR protein expression, enhanced the anticancer effects of anacardic acid on prostatic cancer through autophagy. For the first time, the present study showed that anacardic acid induces cell apoptosis of prostatic cancer through autophagy by ER stress/DAPK3/Akt signaling pathway. PMID- 28731174 TI - LHX3 is an early stage and radiosensitivity prognostic biomarker in lung adenocarcinoma. AB - Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. We previously identified LHX3 as a new preferentially expressed gene in NSCLC. In the present study, we sought to determine its expression, the clinical relevance and the functional roles in NSCLC. LHX3 expression is sharply increased in carcinoma tissues compared to non-carcinoma tissues. Relational analysis reveals a significant association between LHX3 expression and clinical stage (n=172, p=0.032) or radiotherapy (n=167, p=0.022) of patients. LHX3 expression is much higher in the patients at advanced stages (stage III-IV) than in the patients at early stages (stage I-II, p=0.0304), and LHX3 expression is remarkably increased in the patients with radiotherapy treatment (p=0.0002). Survival analyses indicate that LHX3 is associated with unfavorable survival (n=180, p=0.002) and represents an independent prognostic factor [hazard ratio (HR)=1.834, p=0.004] of the NSCLC patients. Furthermore, LHX3 is associated with unfavorable overall survival (n=866, p=0.004) and represents an independent prognostic factor (HR=2.36, p=0.000) in lung adenocarcinoma (ADC) patients, but is not associated with overall survival of squamous cell carcinoma (SCC) patients (n=524, p=0.27). Further analyses found that LHX3 is an early-stage (n=94, p=0.003) and radiosensitivity (n=45, p=0.002) prognostic factor in ADC patients. The patients without radiotherapy have a significantly prolonged survival compared to those with radiotherapy (p=0.0069). Further functional studies show that forced expression of LHX3 in lung cancer cells obviously promotes cell proliferation and invasion, whereas inhibits cell apoptosis. In summary, LHX3 is an early-stage and radiosensitivity prognostic biomarker, and a novel potential oncogene in ADC. PMID- 28731175 TI - Heat shock-induced HIKESHI protects cell viability via nuclear translocation of heat shock protein 70. AB - Heat shock proteins (HSPs), particularly HSP70, help restore normal cellular function following damage caused by stressors. HSP expression in tumor tissues indicates cancer progression, and while the development of HSP inhibitors is progressing, these substances are not widely used to treat cancer. HIKESHI (C11orf73) does not control the intracellular movement of HSP70 at normal temperatures; however, it does regulate the function and movements of HSP70 during heat shock. In this study, we examined the intracellular movement of HSP70 during heat shock to investigate the significance of HIKESHI expression in gastric cancer (GC) and determine if HIKESHI inhibition has cytotoxic effects. We examined HIKESHI using GC cell lines and immunostaining in 207 GC tissue samples. HIKESHI expression in GC tissues was associated with the progression of lymphatic invasion. Suppressing HIKESHI using siRNA did not affect cell viability at normal temperatures. However, suppressing HIKESHI during heat shock inhibited HSP70 nuclear transport and suppressed cell viability. Our results suggest that HIKESHI is a marker of cancer progression and that the combination of HIKESHI inhibition and hyperthermia is a therapeutic tool for refractory GC. PMID- 28731176 TI - Hypotonic contrast media is more toxic than isotonic contrast media on endothelial cells in vivo and in vitro. AB - The aim of the current study was to investigate the cytotoxic effects of hypotonic (iopamidol) and isotonic (iodixanol) contract media (CMs) in vitro and in vivo. A total of 60 Wistar rats were included and were randomly divided into three groups (20 rats per group). Iodixanol (4 g iodine/kg), iopamidol (4 g iodine/kg) or equal volume of normal saline was injected via tail vein. HUVEC and H5V cell viability was determined by Cell Counting Kit-8 agents. Western blotting was performed to detect ATP-binding cassette subfamily G member 1 (ABCG1) expression. For histological analysis, hematoxylin and eosin staining was performed. Plasma endothelin, von Willebrand factor, tissue type plasminogen activator, plasminogen activator inhibitor, D-Dimer, fibrinogen, anti-thrombin III, plasminogen and nitric oxide synthase (NOS) were measured by using ELISA. Both iopamidol and iodixanol treatments deceased cell viability and increased apoptosis of HUVEC and H5V cells, along with downregulated NOS and ABCG1. The injection of iopamidol or iodixanol into rats changed the endothelium-related plasma levels of biomarkers, including endothelin, von Willebrand factor, tissue type plasminogen activator, plasminogen activator inhibitor, D-Dimer, fibrinogen and anti-thrombin III. However, endothelia isolated from rat abdominal aorta in the iodixanol group retained their normal structure, whereas endothelial structure in the iopamidol group was injured and disrupted. The findings in the present study suggested that both hypotonic and isotonic CMs may lead to endothelial dysfunction and thrombin and fibrinolytic system disorder. However, hypotonic CMs may be more toxic than isotonic CMs. Therefore, additional cautions should be taken when selecting hypotonic CMs and their dosages during cardioangiography. PMID- 28731177 TI - Co-expression of Axin and APC gene fragments inhibits colorectal cancer cell growth via regulation of the Wnt signaling pathway. AB - Adenomatous polyposis coli (APC) and Axin interactions serve an important role in colorectal cancer (CRC) pathogenesis. The aim of the present study was to assess the combined effects of Axin and APC co-expression in CRC cells, and to determine the underlying mechanisms involved. SW480 cells were divided into the following groups: Untransfected (SW480 group), transfected with pEGFP-N3plus pCS2-MT (SW480/vector-vector), transfected with pEGFP-N3-APC5 (SW480/APC5), and transfected with pEGFP-N3-APC5 pluspCS2-MT-Axin (SW480/APC5-Axin). APC5 and Axin mRNA levels were determined by reverse transcription-polymerase chain reaction. MTT assays and flow cytometry analysis were performed to assess cell growth and cell cycle distribution, respectively. Quantitative PCR and western blot analyses were conducted to evaluate the mRNA and protein levels, respectively, of Wnt signaling effectors, including beta-catenin, c-myc and survivin. Successful transfection of SW480 cells was determined with APC and APC-Axin plasmids as indicated by the green fluorescence signals. Notably, SW480/APC5 cell growth was inhibited by 40.33%, and cells co-expressing APC5 and Axin demonstrated 61.27% inhibition of cell growth compared with SW480 control cells. The results demonstrate that APC5 may induce G1/S arrest in SW480 cells, and Axin may enhance cell growth arrest induced by APC5. The mRNA and protein levels of beta-catenin, c-myc and survivin were significantly reduced in SW480/APC-Axin cells when compared with the SW480/APC group. In conclusion, co-expression of APC5 and Axin genes significantly downregulated Wnt signaling in human SW480 CRC cells and inhibited cell growth, when compared with cells transfected with APC5 alone. These results may provide experimental evidence to support combined gene therapy in CRC. PMID- 28731178 TI - MicroRNA-379 acts as a tumor suppressor in non-small cell lung cancer by targeting the IGF-1R-mediated AKT and ERK pathways. AB - Lung cancer is one of the most common types of malignancy in humans and is a leading cause of cancer-related deaths among men and women worldwide. Aberrantly expressed microRNAs in non-small cell lung cancer (NSCLC) contribute to tumor occurrence and development as either tumor suppressors or promoters. MicroRNA-379 (miR-379) is dysregulated in several types of human cancer. However, its expression pattern, role and underlying mechanism in NSCLC progression and metastasis are poorly understood. In this study, assay of reverse transcription quantitative polymerase chain reaction showed that miR-379 was downregulated in both NSCLC tissue and cell lines. Low miR-379 expression in NSCLC tissues was significantly correlated with TNM stage and lymph node metastasis. In addition, functional experiments revealed that restoring the expression of miR-379 inhibited cell proliferation, migration and invasion of NSCLC. The insulin-like growth factor receptor-1 (IGF-1R) was identified as a direct target of miR-379 in NSCLC. IGF-1R was highly expressed in NSCLC tissues and inversely correlated with miR-379 expression. Downregulation of IGF-1R had tumor suppressive roles similar to that of miR-379 overexpression on NSCLC cell proliferation, migration and invasion. Moreover, the upregulation of IGF-1R effectively rescued the tumor suppressive roles induced by miR-379 overexpression in NSCLC. The resumption of the expression of miR-379 inhibited the activation of AKT and ERK signaling pathways in NSCLC. These findings suggested that miR-379 acts as a tumor suppressor in NSCLC by directly targeting IGF-1R and indirectly regulating AKT and ERK signaling pathways. miR-379 provides novel therapeutic targets for the treatment of patients with this disease. PMID- 28731179 TI - Clinical significance of miR-138 in patients with malignant melanoma through targeting of PDK1 in the PI3K/AKT autophagy signaling pathway. AB - The present study investigated the clinical significance of miR-138 in patients with malignant melanoma (MM), which has previously been associated with tumor growth. In patients with MM, we found that the expression of miR-138 was significantly downregulated when compared with healthy control subjects. Overexpression of miR-138 in the human melanoma cell line A2058 inhibited cell proliferation and induced cell apoptosis, and increased caspase-3 and Bax protein expression when compared with a negative control group. Meanwhile, miR-138 overexpression promoted cell autophagy, induced LC3 protein expression, and suppressed the PI3K/AKT/mTOR signaling pathway and PDK1 protein expression in A2058 cells. LY294002, an inhibitor of PI3K, suppressed PI3K/AKT/mTOR signaling, induced apoptosis, inhibited cell proliferation, increased caspase-3 and Bax protein expression, and decreased PDK1 protein expression in A2058 cells following miR-138 overexpression. Collectively, our findings indicate the clinical significance of miR-138 in patients with MM through its targeting of PDK1 expression in the PI3K/AKT/mTOR autophagy signaling pathway. PMID- 28731180 TI - miR-216b inhibits glioma cell migration and invasion through suppression of FoxM1. AB - MicroRNAs (miRNAs) play a vital role in tumour biological and pathologic processes. In the present study, we aimed to detect the expression and biological role of miR-216b in glioma. Our data showed that miR-216b was significantly downregulated in human glioma tissues and cells. Ectopic expression of miR-216b inhibited the proliferation and invasion of U87 and U251 cells and suppressed the growth of xenograft tumours in vivo. Bioinformatic and luciferase reporter analyses identified Forkhead box protein M1 (FoxM1) as a direct target of miR 216b. Overexpression of miR-216b inhibited the expression of FoxM1 in glioma cells. Rescue experiments demonstrated that co-transfection of FoxM1 lacking the 3'-untranslated region partially prevented miR-216b-induced inhibition of glioma cell growth and invasion. In vivo studies indicated that ectopic expression of miR-216b impeded the proliferation of glioma xenograft tumours in nude mice, coupled with a decreased in FoxM1 protein expression and the percentage of Ki-67 positive tumour cells. Taken together, our results provide evidence of the suppressive activity of miR-216b in glioma, which is largely ascribed to downregulation of FoxM1. Restoration of miR-216b may provide a novel potential therapeutic agent for glioma. PMID- 28731181 TI - miR-21 promotes alpha-SMA and collagen I expression in hepatic stellate cells via the Smad7 signaling pathway. AB - The aim of the present study was to investigate the role of microRNA (miR)-21 in regulating collagen I and Smad7 expression in activated rat hepatic stellate cells (HSCs). Rat HSCs were isolated by single-step density gradient centrifugation with Nycodenz. Cellular content of miR-21, SMAD7, alpha-smooth muscle actin (alpha-SMA), collagen type I alpha 1 (COLLA1) and COLL alpha 2 (A2) mRNA was examined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and cellular content of Smad7 and alpha-SMA protein was detected by western blotting. Binding of miR-21 to the 3'-untranslated region (UTR) of Smad7 was verified by dual-luciferase assay. The authors observed that, in activated HSCs, expression of miR-21 was significantly increased in a time-dependent manner, while expression of Smad7 mRNA and protein was significantly reduced. In addition, miR-21 mimics significantly enhanced cellular alpha-SMA mRNA and protein content, while miR-21 inhibitor significantly reduced alpha-SMA mRNA and protein levels. Similarly, cellular content of COLLA1 and COLLA2 mRNA was significantly elevated by miR-21 mimics, but reduced by miR-21 inhibitor, in activated HSCs. Moreover, cellular content of Smad7 mRNA and protein was significantly reduced by miR-21 mimics, but significantly increased by miR-21 inhibitor. Furthermore, miR-21 mimics activated firefly luciferase in HEK293 cells transfected with the wild type 3'-UTR of Smad7. miR-21 regulates expression of alpha-SMA and collagen I in activated rat HSCs by directly targeting Smad7. PMID- 28731182 TI - IL-6/STAT3/miR-34a protects against neonatal lung injury patients. AB - The present study aimed to investigate the protective role of the interleukin (IL)-6/signal transducer and activator of transcription 3 (STAT3)/microRNA (miR) 34a signaling pathway in patients with neonatal lung injury (NLI) and the underlying molecular mechanisms of these effects. It was demonstrated that miR 34a serum expression was significantly upregulated in patients and mice with NLI. Meanwhile, IL-6 and phosphorylated-STAT3 protein expression, and tumor necrosis factor (TNF)-alpha, IL-1beta and IL-18 activity levels in NLI mice were significantly induced compared with the normal control group. The promotion of IL 6 protein expression resulted in significantly increased TNF-alpha, IL-1beta and IL-18 activity levels, phosphorylated-STAT3 and p65 protein expression, and miR 34a expression in NLI mice compared with the corresponding normal control groups. In A549 cells treated with lipopolysaccharides, the promotion of miR-34a protein expression significantly increased TNF-alpha, IL-1beta and IL-18 activity levels, and induced transcription factor p65 protein expression compared with the corresponding negative control groups. Collectively, the data of the present study indicate that IL-6R/STAT3/miR-34a possesses a protective role in patients with neonatal lung injury. PMID- 28731183 TI - Paeoniflorin exerts neuroprotective effects against glutamate-induced PC12 cellular cytotoxicity by inhibiting apoptosis. AB - Paeoniflorin (PF) is an active ingredient of Radix Paeoniae, which is known to exert neuroprotective effects. However, the mechanims behind the neuroprotective effects of PF are not yet fully understood. The apoptosis of neurons plays an important role in the cerebral ischemia-induced cascade response. This study aimed to investigate neuroprotective effects of PF against glutamate-induced PC12 cellular cytotoxicity and to determine whether these effects are mediated via the inhibition of apoptosis in vitro and the activity of mitochondrial apoptosis associated proteins in PC12 cells. Exposure of the PC12 cells to glutamate induced cell morphological changes, significantly decreased cell viability and induced apoptosis, with similar results being observed from the Hoechst 33342 staining and Annexin V/PI staining experiments. Glutamate also increased the lactate dehydrogenase release by the PC12 cells. However, treatment with PF prevented these effects. Furthermore, PF inhibited Bax and Bad expression and increased Bcl-2 and Bcl-xL expression; it also decreased the levels of downstream protein (caspase-3 and caspase-9). Collectively, our results indicate that PF protects PC12 cells against glutamate-induced neurotoxicity possibly through the inhibition of the expression of mitochondrial apoptosis-associated proteins. PMID- 28731184 TI - Bufalin reverses acquired drug resistance by inhibiting stemness in colorectal cancer cells. AB - Drug resistance is an obstacle to chemotherapy in tumor patients. Recent studies have shown that the high stemness of cancer cells may be induced by chemotherapeutic drugs, which is correlated with drug resistance. In the present study, we investigated the effects of bufalin on the stemness of colorectal cancer. We found that cisplatin could induce high stemness through the tumorsphere formation assay in vitro and in vivo in the colorectal cancer cell lines HCT116 and LoVo. In addition, cisplatin-treated tumorsphere cells showed drug-resistant properties. These results suggested that acquired drug resistance induced by cisplatin in colorectal cancer cells occurred via high stemness. On assessing the effects of bufalin, a traditional Chinese medicine monomer, we found that it could reverse the high stemness and drug resistance induced by cisplatin in colorectal cancer. These findings suggest that bufalin plays an adjuvant role in colorectal cancer chemotherapy and may help reverse acquired drug resistance. These findings may aid in the development of new therapeutic strategies. PMID- 28731185 TI - Snail maintains metastatic potential, cancer stem-like properties, and chemoresistance in mesenchymal mouse breast cancer TUBO-P2J cells. AB - Snail, a zinc-finger transcriptional repressor of E-cadherin expression, is one of the key inducers of epithelial-mesenchymal transition (EMT) in epithelial cancer. In breast cancer, EMT has been associated with malignancies, including metastasis, cancer stem-like properties, and resistance to chemotherapy and radiotherapy. In this study, we analysed the role of Snail in the highly metastatic mesenchymal TUBO-P2J mouse breast cancer cells, by loss of function using short hairpin RNA. Though silencing Snail did not restore the E-cadherin expression or induce morphological changes, Snail silencing significantly ablated in vitro and in vivo metastatic potentials. In addition, Snail silencing also reduced resistance to chemotherapy drugs and cancer stem-like properties, such as CD44 expression, aldehyde dehydrogenase (ALDH) activity, colony formation, and in vivo tumour formation and growth. However, radioresistance was not decreased by silencing Snail. Collectively, this study suggested that Snail is a main regulator of the maintenance of malignancy potentials and is a good target to prevent cancer metastasis and to increase chemotherapy susceptibility. PMID- 28731186 TI - Let-7c-5p inhibits cell proliferation and induces cell apoptosis by targeting ERCC6 in breast cancer. AB - In this study, we found that let-7c-5p expression was clearly downregulated in breast cancer tissues compared with that of corresponding adjacent tissues. Furthermore, overexpression of let-7c-5p in MCF-7 breast cancer cells could significantly inhibit cell proliferation and induce cell apoptosis. The target genes of let-7c-5p were predicted by the way of bioinformatics, and validated by dual luciferase reporter assay and western blotting demonstrating that excision repair cross complementing 6 (ERCC6) gene was a direct target. Collectively, the present study suggested that let-7c-5p acted as a tumor suppressor in breast cancer possibly by negatively regulating ERCC6, which took an important part in nucleotide excision repair and it may provide a new potential strategy for breast cancer therapy. PMID- 28731187 TI - Isolation and purification of novel peptides derived from Sepia ink: Effects on apoptosis of prostate cancer cell PC-3. AB - Novel prostate cancer therapeutics are in high demand. In order to identify potential therapeutic targets, protein from sepia ink was hydrolyzed by utilizing pepsin in an orthogonal array design. Pepsin hydrolysate (SH) obtained at optimal conditions exhibited the highest antitumor activity. Subsequently, a novel antitumor peptide, which was termed SHP, was isolated through ultrafiltration, gel filtration chromatography and reversed phase high-performance liquid chromatography. The amino acid sequence of SHP was identified as Leu-Lys-Glu-Glu Asn-Arg-Arg-Arg-Arg-Asp with a molecular mass of 1371.53 Da. The results of the proliferation assay revealed that SHP significantly inhibited the proliferation of PC-3 cells in a time- and dose-dependent manner. Acridine orange/ethidium bromide staining indicated significant SHP-induced apoptosis. Furthermore, Annexin V/PI double-staining assays revealed that the percentage of early- stage apoptotic cells increased from 8.85 to 29% following PC-3 exposure to 5, 10 and 15 mg/ml SHP for 24 h. SHP-induced apoptosis was accompanied by the activation of cellular tumor antigen p53 and caspase-3, the upregulation of apoptosis regulator BAX, and the downregulation of apoptosis regulator Bcl-2. These findings suggest that SHP is a novel inducer of apoptosis in vitro and merits further investigation as a possible therapeutic agent for the treatment of cancer. PMID- 28731188 TI - Hispidin rescues palmitate-induced insulin resistance in C2C12 myotubes. AB - Skeletal muscle serves an important role in the utilization of glucose during insulin-stimulated conditions. Excessive saturated fatty acids are considered to be a major contributing factor to insulin resistance in skeletal muscle cells. The present study investigated the effects of hispidin on palmitate-induced insulin resistance in C2C12 skeletal muscle myotubes via an MTT assay, glucose uptake assay, Oil-Red-O staining and western blot analysis. Hispidin reversed the palmitate-induced inhibition of glucose uptake, and inhibited palmitate-induced intracellular lipid accumulation. Hispidin suppressed insulin receptor substrate 1 Ser307 phosphorylation, and significantly promoted the activation of phosphatidylinositol-3-kinase and Akt, via inhibition of protein kinase C theta. Furthermore, hispidin treatment of C2C12 muscle cells increased glucose uptake via activation of adenosine monophosphate-activated protein kinase. These findings indicated that hispidin may improve palmitate-induced insulin resistance in skeletal muscle myotubes, and therefore hispidin treatment may be beneficial for patients with diabetes. PMID- 28731189 TI - Identification of pivotal genes and pathways for spinal cord injury via bioinformatics analysis. AB - The present study aimed to identify key genes and pathways associated with spinal cord injury (SCI) and subsequently investigate possible therapeutic targets for the condition. The array data of GSE20907 was downloaded from the Gene Expression Omnibus database and 24 gene chips, including 3-day, 4-day, 1-week, 2-week and 1 month post-SCI together with control propriospinal neurons, were used for the analysis. The raw data was normalized and then the differentially expressed genes (DEGs) in the (A) 2-week post-SCI group vs. control group, (B) 1-month post-SCI group vs. control group, (C) 1-month and 2-week post-SCI group vs. control group, and (D) all post-SCI groups vs. all control groups, were analyzed with a limma package. Gene Ontology annotation and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses for DEGs were performed. Cluster analysis was performed using ClusterOne plugins. All the DEGs identified were associated with immune and inflammatory responses. Signal transducer and activator of transcription 3 (STAT3), erb-B2 receptor tyrosine kinase 4 (ERBB4) and cytochrome B-245, alpha polypeptide (CYBA) were in the network diagrams of (A), (C) and (D), respectively. The enrichment analysis of DEGs identified in all samples demonstrated that the DEGs were also enriched in the chemokine signaling pathway (enriched in STAT3) and the high-affinity immunoglobulin E receptor (FcepsilonRI) signaling pathway [enriched in proto-oncogene, src family tyrosine kinase (LYN)]. Immune and inflammatory responses serve significant roles in SCI. STAT3, ERBB4 and CYBA may be key genes associated with SCI at certain stages. Furthermore, STAT3 and LYN may be involved in the development of SCI via the chemokine and FcepsilonRI signaling pathways, respectively. PMID- 28731190 TI - Lutein protects against severe traumatic brain injury through anti-inflammation and antioxidative effects via ICAM-1/Nrf-2. AB - Many studies have reported that lutein may exert its biological activities, including anti-inflammation, anti-oxidase and anti-apoptosis, through effects on reactive oxygen species (ROS). Thus, lutein may prevent the damaging activities of ROS in cells. The current study investigated the effect of lutein against severe traumatic brain injury (STBI) and examined the mechanism of this protective effect. Sprague-Dawley rats were randomly divided into 5 groups: Control group, STBI model group, 40 mg/kg lutein-treated group, 80 mg/kg lutein treated group and 160 mg/kg lutein-treated group. In this study, lutein protects against STBI, suppressed, interleukin (IL)-1beta, IL-6 and monocyte chemoattractant protein-1 expression, reduced serum ROS levels, and reduced superoxide dismutase and glutathione peroxidase activities in STBI rats. Treatment with lutein effectively downregulated the expression of NF-kappaB p65 and cyclooxygenase-2, intercellular adhesion molecule (ICAM)-1 protein, and upregulated nuclear factor erythroid 2 like 2 (Nrf-2) and endothelin-1 protein levels in STBI rats. These findings demonstrated that lutein protects against STBI, has anti-inflammation and antioxidative effects and alters ICAM-1/Nrf-2 expression, which may be a novel therapeutic for STBI the clinic. PMID- 28731191 TI - Carboxy-terminus Hsc70 interacting protein exerts a tumor inhibition function in head and neck cancer. AB - Several independent studies have reported the roles of the E3 ubiquitin ligase, carboxy-terminus Hsc70 interacting protein (CHIP) in various types of cancers. However, the biological effects of CHIP vary in regards to different cancers, and the role of CHIP in head and neck cancers (HNCs) remains unknown. In the present study, CHIP overexpression plasmids and CHIP knockdown lentivirus were constructed to affect the expression levels of CHIP protein and biological behaviors in HNC cell lines bilaterally. The biological behaviors regulated by CHIP in HNCs were investigated both in vivo and in vitro with a series of assays and analyses. A tissue microarray was stained and analyzed for the clinical significance of CHIP expression in HNCs. We identified that CHIP suppressed the malignant behaviors of HNCs in a series of in vitro and in vivo experiments, but not its two loss-of-function mutants. However, we observed an altered expression pattern of CHIP from a well, moderate, to poor differentiation pathological status in HNC specimens. In a retrospective cohort of HNCs, lower expression of CHIP indicated a poor differentiation status in tumors and a lower overall survival rate. The present study demonstrated that CHIP functions as a tumor suppressor in HNCs. In conclusion, we demonstrated that suppressed expression of CHIP may result in the progression of HNCs. PMID- 28731192 TI - ANP32A modulates cell growth by regulating p38 and Akt activity in colorectal cancer. AB - Acidic leucine-rich nuclear phosphoprotein-32A (ANP32A) possesses multiple biochemical activities, has been found to be decreased or absent in malignant tumors. However, new findings have shown that it is expressed in greater amounts in advanced cancers than in early-stage tumors. The role and clinical significance of ANP32A in colorectal cancer (CRC) is still unknown. In the present study, the expression of ANP32A was assessed in 68 CRC patients by IHC, and then the correlation of its expression with clinicopathological factors was investigated using the Allred, Klein and immune response scoring system analysis. Western blot and real-time PCR analyses were used to assess ANP32A expression and the activity of Akt and p38 in cancer and normal tissues. These data indicated a significant association between ANP32A expression and the activity of Akt and p38, besides the tumor differentiation status in CRC patients. IHC and western blotting data revealed that ANP32A was overexpressed in CRC patients, and ANP32A levels were higher in poorly differentiated tumors. Protein and mRNA analysis revealed that with a high expression of ANP32A, the activation of Akt was enhanced, while the p-38 phosphorylation level was decreased in CRC tissues. MTT assay and functional studies revealed that knockdown of ANP32A inhibited cell growth and induced p38 phosphorylation and Akt dephosphorylation. The present study indicated that ANP32A promoted CRC proliferation by inhibition of p38 and activation of Akt signaling pathways and suggested that ANP32A may play a potential role in CRC diagnosis and therapy. PMID- 28731193 TI - Promotion of glycolysis by HOTAIR through GLUT1 upregulation via mTOR signaling. AB - The long non-coding RNA HOX transcript antisense RNA (HOTAIR) plays a key role in the progression of various carcinomas. However, whether or not HOTAIR influences glucose metabolism and the specific underlying mechanism in hepatocellular carcinoma (HCC) cells remain unclear. In the present study, we found markedly increased HOTAIR expression in 84 HCC tissues and demonstrated that HOTAIR overexpression promoted cell proliferation using Cell Counting Kit-8. The effect on glucose metabolism regulated by HOTAIR in HCC cells was determined by detecting lactate and glucose levels: HOTAIR promoted glycolysis by upregulating glucose transporter isoform 1 (GLUT1) and activating mammalian target of rapamycin (mTOR) signaling, whereas knockdown of HOTAIR suppressed this effect. Our research reveals a novel relationship between HOTAIR and glucose metabolism in HCC cells, and it may be a therapeutic target for diagnosing and treating HCC. PMID- 28731194 TI - SMURF1 promotes the proliferation, migration and invasion of gastric cancer cells. AB - Smad ubiquitin regulatory factor 1 (SMURF1), a well-known E3 ubiquitin ligase, targets substrate proteins for ubiquitination and proteasomal degradation. Accumulating studies have shown that SMURF1 acts as an oncogenic factor in human malignancies. However, the clinical significance of SMURF1 and its role in gastric cancer (GC) remain unclear. The expression of SMURF1 was detected in 68 cases of GC and corresponding tumor-adjacent specimens. Our results revealed that SMURF1 was prominently overexpressed in GC specimens compared to corresponding tumor-adjacent tissues. Furthermore, increased levels of SMURF1 mRNA were also observed in GC cell lines. Clinicopathological detection ascertained that SMURF1 positive expression was associated with large tumor size, more lymph nodes and distant metastasis as well as advanced tumor-node-metastasis (TNM) stage of GC. Notably, GC patients with SMURF1 positive-expressing tumors exhibited a significant decreased survival. Further experiments illustrated that SMURF1 knockdown significantly inhibited proliferation, migration and invasion of MGC 803 cells, while SMURF1 overexpression prominently promoted these behaviors in SGC-7901 cells. In vivo studies revealed that SMURF1 knockdown markedly inhibited tumor growth and liver metastasis of GC. Mechanically, SMURF1 inversely regulated the expression of DOC-2/DAB2 interactive protein (DAB2IP) in GC tissues and cells. Furthermore, DAB2IP restoration revealed similar effects to SMURF1 knockdown on MGC-803 cells with decreased proliferation, migration and invasion. In addition, the PI3K/Akt pathway and its downstream targets including c-Myc and ZEB1 were potentially involved in the oncogenic role of the SMURF1/DABIP axis. Collectively, the present study revealed the first evidence that SMURF1 can be potentially used as a clinical biomarker and target for novel treatment of human GC. PMID- 28731195 TI - Inhibition of ARC promoting the apoptosis of rat pulmonary arterial smooth muscle cells after serum deprivation in vitro. AB - Apoptosis has important pathophysiological consequences contributing to pulmonary arterial hypertension (PAH). However, the mechanism underlying apoptosis in PAH remains unknown. Apoptosis repressor with caspase recruitment domain (ARC) is an essential factor in cell apoptosis, and regulates intrinsic and extrinsic apoptosis signaling pathways. It is hypothesized that ARC may be involved in the apoptotic responses of pulmonary arterial smooth muscle cells (PASMCs) following mild chronic injury. In the present study, serum deprivation (SD) was used to induce apoptosis of PASMCs. It was demonstrated that the expression of ARC in PASMCs was significantly increased following SD stimulation within 24 h, and ARC downregulation using small interfering RNA significantly enhanced the apoptosis of PASMCs following SD stimulation. In addition, the results demonstrated that ARC downregulation significantly increased the expression of proapoptotic factors and the level of reactive oxygen species (ROS), and decreased the mitochondrial membrane potential following SD exposure, suggesting ARC regulates the apoptosis of PASMCs via modulating mitochondrial function and ROS accumulation. The results of the present study revealed that ARC inhibition promotes the apoptosis of PASMCs following SD stimulation, and that ARC expression increases in the early stages of SD injury. PMID- 28731196 TI - MicroRNA-106a promotes cell migration and invasion by targeting tissue inhibitor of matrix metalloproteinase 2 in cervical cancer. AB - Increasing evidence has demonstrated that miRNAs play a critical role in tumor development and progression. Previous studies have revealed that miR-106a is abnormally expressed in various cancers. However, its function and underlying mechanism in cervical cancer (CC) remains unknown. In this study, we confirmed that the expression of miR-106a was significantly upregulated in both CC cell lines and tissues by qRT-PCR. The increased expression of miR-106a was obviously associated with adverse prognostic features. Moreover, we demonstrated that miR 106a was a novel independent prognostic marker for predicting the 5-year survival of CC patients. The ectopic overexpression of miR-106a promoted cell migration, invasion and invasion-related gene expression, while downregulated miR-106a reversed the effect. In addition, miR-106a regulated tissue inhibitor of metalloproteinase (TIMP)2 by directly binding to its 3'-UTR, leading to the indution of the expression of matrix metalloproteinases (MMPs). In clinical samples of CC, miR-106a was inversely correlated with TIMP2, which was downregulated in CC. Alteration of TIMP2 expression at least partially abolished the migration, invasion and MMP expression of miR-106a in CC cells. In conclusion, our data indicated that miR-106a promoted the migration, invasion and MMP expression of CC by targeting TIMP2, and may represent a novel potential therapeutic target and prognostic marker for CC. PMID- 28731197 TI - Metastatic Gallbladder Carcinoma in Meningioma: A Case Report. AB - Metastases from tumors to systemic cancers are rare. The most common intracranial recipient tumor is meningioma. Metastasis from gallbladder cancer has been previously reported from only one patient during autopsy. We present the case of a 72-year-old woman who underwent surgery for right frontal skull base meningioma.The tumor was completely removed. Histological specimens showed gallbladder carcinomatous metastasis with diffuse neuroendocrine differentiation in meningothelial meningioma. The Ki-67 proliferation index of the meningioma was 3%. Further, 60% positive immunoreactivity with the progesterone receptor was observed in meningioma cells. In carcinoma cells, diffuse positive immunoreactivity with chromogranin, CDX2, CEA, panCK, cytokeratin 7, and synaptophysin was observed. A combination of molecular, metabolic, immunological, and/or hormonal factors may contribute to the pathogenesis of this lesion. It cannot be ruled out that it is more common than expected. PMID- 28731199 TI - Achilles: A Homeric hero enamoured with the absolute. AB - This article explores through a psychoanalytical lens the character of Achilles in Homer's Iliad, the matrix behind the Western conception of heroism. The contribution reveals the psychological link binding the words and acts of the most valiant of warriors in Antiquity, which is situated in myth and termed "the Eros of the absolute." The paroxystic ideality underlying the aforementioned myth, which is rooted in the anthropological need to believe, is at the origin of Achilles' legendary MUnnuiotasigma, that is, the flood of rage triggered by contests for supremacy, aggravated by the loss of his war comrade, aroused by the drama of aging and death, and then transfigured through song and memory. The main claim of the author is that Iliad, despite its seeming lack of attention to interiority, is launched by the archetypal emotion of wrath and owes its appeal to its hero's embrace of heroic idealism in an excessive, radical and absolute way that results in a captivating narcissism and sadomasochistic antithesis of ideality. This argument leads to the conclusion that Homer is the Father of the "primitive horde" of affects. PMID- 28731200 TI - Suicidal Self-Directed Violence Among Homeless US Veterans: A Systematic Review. AB - A systematic review of the literature was conducted to investigate suicidal self directed violence and homelessness among US military veterans, and identify existing suicide prevention strategies. In November 2015, MEDLINE, EMBASE, PsycInfo, CINAHL, Web of Science, Cochrane Library, Google, and Google Scholar were searched. Articles published since 1990 investigating self-directed violence among homeless veterans were identified. Data were extracted and synthesized qualitatively. Nineteen observational studies were included. Suicide ideation rates were 1.3% (current), 7.0% (past week), 12.1%-18% (past 30 days), and 74% (lifetime). Suicide attempt rates were 0%-6% (past 30 days), 30.7%-31.5% (past 5 years), and 15%-46.6% (lifetime). Death by suicide rate was 81.0 per 100,000. No interventional studies to prevent self-directed violence among homeless veterans were identified. Homeless veterans are at risk for self-directed violence, suggesting the need for research to examine preventive strategies. A comprehensive public health approach to suicide prevention needs to focus on vulnerable populations, including homeless veterans. PMID- 28731198 TI - GSK-3beta inhibition suppresses instability-induced osteolysis by a dual action on osteoblast and osteoclast differentiation. AB - Currently, there are no medications available to treat aseptic loosening of orthopedic implants. Using osteoprotegerin fusion protein (OPG-Fc), we previously blocked instability-induced osteoclast differentiation and peri-prosthetic osteolysis. Wnt/beta-catenin signaling, which regulates OPG secretion from osteoblasts, also modulates the bone tissue response to mechanical loading. We hypothesized that activating Wnt/beta-catenin signaling by inhibiting glycogen synthase kinase-3beta (GSK-3beta) would reduce instability-induced bone loss through regulation of both osteoblast and osteoclast differentiation. We examined effects of GSK-3beta inhibition on regulation of RANKL and OPG in a rat model of mechanical instability-induced peri-implant osteolysis. The rats were treated daily with a GSK-3beta inhibitor, AR28 (20 mg/kg bw), for up to 5 days. Bone tissue and blood serum were assessed by qRT-PCR, immunohistochemistry, and ELISA on days 3 and 5, and by micro-CT on day 5. After 3 days of treatment with AR28, mRNA levels of beta-catenin, Runx2, Osterix, Col1alpha1, and ALP were increased leading to higher osteoblast numbers compared to vehicle-treated animals. BMP-2 and Wnt16 mRNA levels were downregulated by mechanical instability and this was rescued by GSK-3beta inhibition. Osteoclast numbers were decreased significantly after 3 days of GSK-3beta inhibition, which correlated with enhanced OPG mRNA expression. This was accompanied by decreased serum levels of TRAP5b on days 3 and 5. Treatment with AR28 upregulated osteoblast differentiation, while osteoclastogenesis was blunted, leading to increased bone mass by day 5. These data suggest that GSK-3beta inactivation suppresses osteolysis through regulating both osteoblast and osteoclast differentiation in a rat model of instability induced osteolysis. PMID- 28731201 TI - A technological and regulatory outlook on CRISPR crop editing. AB - Generating plants with increased yields while maintaining low production and maintenance costs is highly important since plants are the major food source for humans and animals, as well as important producers of chemicals, pharmaceuticals, and fuels. Gene editing approaches, particularly the CRISPR-Cas system, are the preferred methods for improving crops, enabling quick, robust, and accurate gene manipulation. Nevertheless, new breeds of genetically modified crops have initiated substantial debates concerning their biosafety, commercial use, and regulation. Here, we discuss the challenges facing genetic engineering of crops by CRISPR-cas, and highlight the pros and cons of using this tool. PMID- 28731202 TI - On the brink: the highly reduced plastomes of nonphotosynthetic Ericaceae. AB - Ericaceae (the heather family) is a large and diverse group of plants that forms elaborate symbiotic relationships with mycorrhizal fungi, and includes several nonphotosynthetic lineages. Using an extensive sample of fully mycoheterotrophic (MH) species, we explored inter- and intraspecific variation as well as selective constraints acting on the plastomes of these unusual plants. The plastomes of seven MH genera were analysed in a phylogenetic context with two geographically disparate individuals sequenced for Allotropa, Monotropa, and Pityopus. The plastomes of nonphotosynthetic Ericaceae are highly reduced in size (c. 33-41 kbp) and content, having lost all photosynthesis-related genes, and are reduced to encoding housekeeping genes as well as a protease subunit (clpP)-like and acetyl-CoA carboxylase subunit D (accD)-like open reading frames. Despite an increase in the rate of their nucleotide substitutions, the remaining protein coding genes are typically under purifying selection in full MHs. We also identified ribosomal proteins under relaxed or neutral selection. These plastomes also exhibit striking structural rearrangements. Intraspecific variation within MH Ericaceae ranges from a few differences (Allotropa) to extensive population divergences (Monotropa, Hypopitys), which indicates that cryptic speciation may be occurring in several lineages. The pattern of gene loss within fully MH Ericaceae plastomes suggests an advanced state of degradation. PMID- 28731204 TI - Urban-Rural Differences in Tubal Ligation Incidence in the State of Georgia, USA. AB - PURPOSE: To evaluate the difference in tubal ligation use between rural and urban counties in the state of Georgia, USA. METHODS: The study population included 2,160 women aged 22-45. All participants completed a detailed interview on their reproductive histories. County of residence was categorized using the National Center for Health Statistics Urban-Rural Classification Scheme. We estimated the association between urbanization of county of residence and tubal ligation using Cox regression. Among women with a tubal ligation, we examined factors associated with prior contraception use and the desire for more children. FINDINGS: After adjustment for covariates, women residing in rural counties had twice the incidence rate of tubal ligation compared with women in large metropolitan counties (adjusted hazard ratio [aHR] = 2.0, 95% CI = 1.4-2.9) and were on average 3 years younger at the time of the procedure. No differences were observed between small metropolitan and large metropolitan counties (aHR = 1.1, CI = 0.9-1.5). Our data suggest that women from large metropolitan counties are slightly more likely than women from rural counties to use hormonal contraception or long-acting reversible contraception prior to tubal ligation and to desire more children after tubal ligation. CONCLUSIONS: Women from rural counties are more likely to undergo a tubal ligation than their urban counterparts. Our results suggest that circumstances regarding opting for tubal ligation may differ between urban and rural areas, and recommendations of alternative contraceptive options may need to be tailored differently for rural areas. PMID- 28731203 TI - PTENP1 inhibits the growth of esophageal squamous cell carcinoma by regulating SOCS6 expression and correlates with disease prognosis. AB - PTEN pseudogene (PTENP1) has a tumor suppressive role in multiple cancers. However, its involvement in esophageal squamous cell carcinoma (ESCC) remains largely unknown. In this study, we set out to identify the role of PTENP1 in the development of ESCC. Gene Expression Omnibus database was employed to investigate the expression of PTENP1 in ESCC. sRNA target Database (StarBase v2.0) was used to query the downstream of PTENP1. Next, both in vitro and in vivo experiments were employed to explore the function. Cell proliferation was evaluated by CCK-8, soft agar, and colony formation assays. Expression of relative genes was assessed by quantitative real-time PCR (qRT-PCR) and Western blotting. 3'UTR luciferase assay was used to confirm the miRNA binding. The clinical significance of PTENP1 was further validated by immunohistochemistry (IHC) and correlation with clinicopathological indicators in additional samples (n = 93). We found expression of PTENP1 in ESCC was lower than that in the corresponding adjacent normal tissues (n = 17). Overexpression of PTENP1 in Eca109 and TE-1 cells resulted in inhibited proliferation and altered expression of SOCS6-p-STAT3-HIF 1alpha pathway both in vitro and in vivo. Subsequent IHC reported a similar trend in human ESCC samples. 3'UTR luciferase assay demonstrated that PTENP1 3'UTR decoyed miR-17-5p from binding to SOCS6. Moreover, PTENP1 expression was correlated with clinicopathological indicators to varying degrees, including histological grade, TNM stage, infiltration depth, lymph node metastasis, and overall survival. Taken together, these results suggested an anti-oncogenic role of PTENP1. Meanwhile, PTENP1 may also serve as a candidate of prognostic indicator for ESCC patients. PMID- 28731205 TI - Construction of Nitrogen-Doped Carbon-Coated MoSe2 Microspheres with Enhanced Performance for Lithium Storage. AB - Exploring advanced anode materials with highly reversible capacity have gained great interests for large-scale lithium storage. A facile two-step method is developed to synthesize nitrogen-doped carbon coated MoSe2 microspheres via hydrothermal plus thermal polymerization. The MoSe2 microspheres composed of interconnected nanoflakes are homogeneously coated by a thin nitrogen-doped carbon (N-C) layer. As an anode for lithium ion batteries, the MoSe2 /N-C composite shows better reversibility, smaller polarization, and higher electrochemical reactivity as compared to the unmodified MoSe2 microspheres. The MoSe2 /N-C electrode delivers a high specific capacity of 698 mAh g-1 after 100 cycles at a current density of 100 mA g-1 and good high rate performance (471 mAh g-1 at a high current density of 2000 mA g-1 ). The improved electrochemical performance is attributed to the conductive N-C coating and hierarchical microsphere structure with fast ion/electron transfer characteristics. PMID- 28731206 TI - Comparative plasma and interstitial fluid pharmacokinetics of flunixin meglumine and ceftiofur hydrochloride following individual and co-administration in dairy cows. AB - Ceftiofur (CEF) and flunixin meglumine (FLU) are two drugs approved for use in beef and dairy cattle that are frequently used in combination for many diseases. These two drugs are the most commonly used drugs in dairy cattle in their respective drug classes. Two research groups have recently published manuscripts demonstrating altered pharmacokinetics of FLU and CEF in cows affected with naturally occurring mastitis. The objective of this study was to determine whether pharmacokinetics of flunixin meglumine administered intravenously or intramuscularly administered ceftiofur hydrochloride would be altered when co administered versus individual administration to healthy dairy cattle. Ten cows were utilized in a three-period, three-treatment crossover design, with all cows receiving each treatment one time with a 10-day washout period between treatments. Following treatment, plasma and interstitial fluid samples were collected and stored for later analysis. Additionally, plasma ultrafiltrate was collected using microcentrifugation to determine plasma protein binding of each drug. Drug concentrations in plasma, plasma ultrafiltrate, and interstitial fluid were determined using high-pressure liquid chromatography coupled with mass spectrometry. The results of this trial indicate that drug interactions between FLU and CEF do not occur when the two drugs are administered simultaneously in healthy cattle. Further work is needed to determine whether this relationship is maintained in the presence of severe disease. PMID- 28731207 TI - Polyclonal and monoclonal antibodies for treating acute rejection episodes in kidney transplant recipients. AB - BACKGROUND: Registry data shows that the incidence of acute rejection has been steadily falling. Approximately 10% to 35% of kidney recipients will undergo treatment for at least one episode of acute rejection within the first post transplant year. Treatment options include pulsed steroid therapy, the use of an antibody preparation, the alteration of background immunosuppression, or combinations of these options. Over recent years, new treatment strategies have evolved, and in many parts of the world there has been an increase in use of tacrolimus and mycophenolate and a reduction in the use of cyclosporin and azathioprine use as baseline immunosuppression to prevent acute rejection. There are also global variations in use of polyclonal and monoclonal antibodies to treat acute rejection. This is an update of a review published in 2006. OBJECTIVES: The aim of this systematic review was to: (1) to evaluate the relative and absolute effects of different classes of antibody preparation in preventing graft loss and resolving cellular or humoral rejection episodes when used as a treatment for first episode of rejection in kidney transplant recipients; (2) evaluate the relative and absolute effects of different classes of antibody preparation in preventing graft loss and resolving cellular or humoral rejection episodes when used as a treatment for steroid-resistant rejection in kidney transplant recipients; (3) determine how the benefits and adverse events vary for each type of antibody preparation; and (4) determine how the benefits and harms vary for different formulations of antibody within each type. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Specialised Register to 18 April 2017 through contact with the Information Specialist using search terms relevant to this review. SELECTION CRITERIA: Randomised controlled trials (RCTs) in all languages comparing all mono- and polyclonal antibody preparations, given in combination with any other immunosuppressive agents, for the treatment of cellular or humoral graft rejection, when compared to any other treatment for acute rejection were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two authors independently assessed the risk of bias of the included studies and extracted data. Statistical analyses were performed using a random effects model and results expressed as risk ratio (RR) or mean difference (MD) with 95% confidence intervals (CI). MAIN RESULTS: We included 11 new studies (18 reports, 346 participants) in this update, bring the total number of included studies to 31 (76 reports, 1680 participants). Studies were generally small, incompletely reported, especially for potential harms, and did not define outcome measures adequately. The risk of bias was inadequate or unclear risk for random sequence generation (81%), allocation concealment (87%) and other bias (87%). There were, however, a predominance of low risk of bias for blinding (75%) and incomplete outcome data (80%) across all the studies. Selective reporting had a mixture of low (58%), high (29%), and unclear (13%) risk of bias.Seventeen studies (1005 participants) compared therapies for first acute cellular rejection episodes. Antibody therapy was probably better than steroid in reversing acute cellular rejection (RR 0.50, 95% CI 0.30 to 0.82; moderate certainty) and preventing subsequent rejection (RR 0.70, 95% CI 0.50 to 0.99; moderate certainty), may be better for preventing graft loss (death censored: (RR 0.80, 95% CI 0.57 to 1.12; low certainty) but there was little or no difference in death at one year. Adverse effects of treatment (including fever, chills and malaise following drug administration) were probably reduced with steroid therapy (RR 23.88, 95% CI 5.10 to 111.86; I2 = 16%; moderate certainty).Twelve studies (576 patients) investigated antibody treatment for steroid-resistant rejection. There was little or no benefit of muromonab-CD3 over ATG or ALG in reversing rejection, preventing subsequent rejection, or preventing graft loss or death. Two studies compared the use of rituximab for treatment of acute humoral rejection (58 patients). Muromonab-CD3 treated patients suffered three times more than those receiving either ATG or T10B9, from a syndrome of fever, chills and malaise following drug administration (RR 3.12, 95% CI 1.87 to 5.21; I2 = 31%), and experienced more neurological side effects (RR 13.10 95% CI 1.43 to 120.05; I2 = 36%) (low certainty evidence).There was no evidence of additional benefit from rituximab in terms of either reversal of rejection (RR 0.94, 95% CI 0.54 to 1.64), or graft loss or death 12 months (RR 1.0, 95% CI 0.23 to 4.35). Rituximab plus steroids probably increases the risk of urinary tract infection/pyelonephritis (RR 5.73, 95% CI 1.80 to 18.21). AUTHORS' CONCLUSIONS: In reversing first acute cellular rejection and preventing graft loss, any antibody is probably better than steroid, but there is little or no difference in subsequent rejection and patient survival. In reversing steroid-resistant rejection there was little or no difference between different antibodies over a period of 12 months, with limited data beyond that time frame. In treating acute humoral rejection, there was no evidence that the use of antibody therapy conferred additional benefit in terms of reversal of rejection, or death or graft loss.Although this is an updated review, the majority of newer included studies provide additional evidence from the cyclosporin/azathioprine era of kidney transplantation and therefore conclusions cannot necessarily be extrapolated to patients treated with more contemporary immunosuppressive regimens which include tacrolimus/mycophenolate or sirolimus. However, many kidney transplant centres around the world continue to use older immunosuppressive regimes and the findings of this review remain strongly relevant to their clinical practice.Larger studies with standardised reproducible outcome criteria are needed to investigate the outcomes and risks of antibody treatments for acute rejection in kidney transplant recipients receiving contemporary immunosuppressive regimes. PMID- 28731208 TI - Super-Strong, Super-Stiff Macrofibers with Aligned, Long Bacterial Cellulose Nanofibers. AB - With their impressive properties such as remarkable unit tensile strength, modulus, and resistance to heat, flame, and chemical agents that normally degrade conventional macrofibers, high-performance macrofibers are now widely used in various fields including aerospace, biomedical, civil engineering, construction, protective apparel, geotextile, and electronic areas. Those macrofibers with a diameter of tens to hundreds of micrometers are typically derived from polymers, gel spun fibers, modified carbon fibers, carbon-nanotube fibers, ceramic fibers, and synthetic vitreous fibers. Cellulose nanofibers are promising building blocks for future high-performance biomaterials and textiles due to their high ultimate strength and stiffness resulting from a highly ordered orientation along the fiber axis. For the first time, an effective fabrication method is successfully applied for high-performance macrofibers involving a wet-drawing and wet-twisting process of ultralong bacterial cellulose nanofibers. The resulting bacterial cellulose macrofibers yield record high tensile strength (826 MPa) and Young's modulus (65.7 GPa) owing to the large length and the alignment of nanofibers along fiber axis. When normalized by weight, the specific tensile strength of the macrofiber is as high as 598 MPa g-1 cm3 , which is even substantially stronger than the novel lightweight steel (227 MPa g-1 cm3 ). PMID- 28731209 TI - Evaluating Atypical Features of Femur Fractures: How Change in Radiological Criteria Influenced Incidence and Demography of Atypical Femur Fractures in a Community Setting. AB - Identification of atypical femoral fractures (AFFs) can be challenging. To assist in the radiological assessment, an American Society for Bone and Mineral Research (ASBMR) Task Force developed a case definition for AFFs in 2010, revising it in 2013. How the revised definition performs in a community setting compared with the 2010 definition is unknown. We applied the 2013 criteria to 372 femoral fractures that occurred between January 1, 1996, and June 30, 2009, employing two independent expert physician reviewers. We used radiographs that had been categorized in a previous study on the incidence of atypical fractures using 2010 ASMBR criteria (BEAK1). In this follow-up study (BEAK2), the same reviewers reviewed all previously identified femoral shaft fractures (FSFs) (n = 197) and distal femur fractures (n = 131) plus a 15% random sample of intertrochanteric fractures (n = 49). After initial review, agreement between the two reviewers ranged from 63% to 100% for specific features, and 84% of radiographs received the same overall classification. Fewer fractures met the 2013 compared with 2010 ASMBR case definition of AFFs (37 per 2013 criteria versus 74 per 2010 criteria). Forty-three radiographs (58%) categorized as AFFs according to 2010 criteria were no longer AFFs when 2013 criteria were applied, and an additional 12 non-atypical FSFs according to 2010 criteria were reclassified as AFFs according to 2013 criteria. The major cause of AFF reclassification was the change in the definition of transverse configuration. The modification of the comminution, non traumatic, and periosteal/endosteal thickness criteria resulted in the reclassification of non-atypical FSFs to AFFs. Incidence rate of AFFs according to 2013 ASBMR criteria was lower overall during the 13 years of observation than when the 2010 ASBMR criteria were applied, although we saw a slight increase starting in 2000. As in BEAK1, we found that those with AFFs were younger, more often female, and had a higher exposure rate to bisphosphonates than those with non-atypical FSFs. As we continue to unravel the demographics of those who suffer from AFFs, our study adds information about how the change in criteria influences epidemiological work. (c) 2017 American Society for Bone and Mineral Research. PMID- 28731210 TI - Ecological guild and enzyme activities of rhizosphere soil microbial communities associated with Bt-maize cultivation under field conditions in North West Province of South Africa. AB - Insecticidal proteins expressed by genetically modified Bt maize may alter the enzymatic and microbial communities associated with rhizosphere soil. This study investigated the structure and enzymatic activity of rhizosphere soil microbial communities associated with field grown Bt and non-Bt maize. Rhizosphere soil samples were collected from Bt and non-Bt fields under dryland and irrigated conditions. Samples were subjected to chemical tests, enzyme analyses, and next generation sequencing. Results showed that nitrate and phosphorus concentrations were significantly higher in non-Bt maize dryland soils, while organic carbon was significantly higher in non-Bt maize irrigated field soil. Acid phosphatase and beta-glucosidase activities were significantly reduced in soils under Bt maize cultivation. The species diversity differed between fields and Bt and non-Bt maize soils. Results revealed that Actinobacteria, Proteobacteria, and Acidobacteria were the dominant phyla present in these soils. Redundancy analyses indicated that some chemical properties and enzyme activities could explain differences in bacterial community structures. Variances existed in microbial community structures between Bt and non-Bt maize fields. There were also differences between the chemical and biochemical properties of rhizosphere soils under Bt and non-Bt maize cultivation. These differences could be related to agricultural practices and cultivar type. PMID- 28731211 TI - Comparative pathogenicity of Vibrio spp., Photobacterium damselae ssp. damselae and five isolates of Aeromonas salmonicida ssp. achromogenes in juvenile Atlantic halibut (Hippoglossus hippoglossus). AB - Juvenile Atlantic halibut (~100 mg, Hippoglossus hippoglossus) were exposed to Vibrio proteolyticus, a Vibrio spp. isolate, Photobacterium damselae ssp. damselae and five different isolates of Aeromonas salmonicida ssp. achromogenes via an hour-long bath immersion to ascertain their variation in pathogenicity to this fish species. Results were analysed using Kaplan-Meier survival analysis. Analysis of the data from challenges using A. salmonicida ssp. achromogenes revealed three survival values of zero and a spread of values from 0 to 28.43. Challenges using a Vibrio spp isolate, V. proteolyticus and P. damselae resulted in Kaplan-Meier survival estimates of 31.21, 50.41 and 57.21, respectively. As all bacterial species tested could induce juvenile halibut mortalities, they must all be considered as potential pathogens. However, the degree of pathogenicity of A. salmonicida is isolate dependent. PMID- 28731212 TI - Cross-validation of commercial enzyme-linked immunosorbent assay and radioimmunoassay for porcine C-peptide concentration measurements in non-human primate serum. AB - BACKGROUND: C-peptide concentration is widely used as a marker of insulin secretion and is especially relevant in evaluating islet graft function following transplantation, because its measurement is not confounded by the presence of exogenous insulin. To address the shortage of human islet donors, the use of porcine islets has been proposed as a possible solution and the stringent pig-to non-human primate (NHP) model is often the most relevant for pre-clinical evaluation of the potential for diabetes reversal resulting from an islet xenograft. The Millipore radioimmunoassay (RIA) was exclusively used to measure porcine C-peptide (PCP) until 2013 when the assay was discontinued and subsequently a commercially available enzyme-linked immunosorbent assay (ELISA) from Mercodia has been widely adopted. Both assays have been used in pre-clinical trials evaluating the therapeutic potential of xenograft products in reversing diabetes in the pig-to-NHP model, to interpret data in a comparable way it may be useful to perform a harmonization of C-peptide measurements. METHODS: We performed a method comparison by determining the PCP concentration in 620 serum samples collected from 20 diabetic cynomolgus macaques transplanted with adult porcine islets. All analyses were performed according to manufacturer instructions. RESULTS: With both assays, we demonstrated an acceptable detection limit, precision, and recovery. Linearity of the ELISA met acceptance criteria at all concentrations tested while linearity of the RIA only met acceptance criteria at five of the eight concentrations tested. The RIA had a detection limit of 0.16 ng/mL, and recovery ranged from 82% to 96% and met linearity acceptance criteria at 0.35 ng/mL and from 0.78 to 2.33 ng/mL. The ELISA had a detection limit of 0.03 ng/mL, and recovery ranged from 81% to 115% and met linearity acceptance criteria from 0.08 to 0.85 ng/mL. Both assays had intra-assay precision <11% and inter-assay precision <14%. PCP concentration measured by ELISA demonstrated a significant correlation with RIA (R2 =.9721, P<.0001). This strong correlation supports use of the regression equation y=2.029x+0.0897 to transform ELISA data to RIA or inversely y=0.4930x-0.0456 to convert RIA data to ELISA for direct comparison between assays in the concentration range of 0-3.0 ng/mL. Measured C peptide concentration was lower with the ELISA than with the RIA; individual measurements plotted against the averages of the pair demonstrated that the variability from the mean strongly depended on increasing concentration. CONCLUSIONS: Porcine C-peptide can be reliably measured in NHP serum using the Mercodia ELISA, making this assay interchangeable with the Millipore RIA. Inherent differences in antibody affinity and calibration factors may explain the lower ELISA values as compared to the RIA; however without access to a traceable reference standard, it is not possible to determine which assay is most accurate. Regression modeling resulted in a correction factor appropriate for conversion of ELISA data to RIA-equivalent data facilitating comparison of assay results longitudinally and between groups. PMID- 28731214 TI - From positive psychology to psychopathology: the continuum of attention-deficit hyperactivity disorder. AB - BACKGROUND: Integration of positive psychology into clinical research and treatment has been slow. This integration can be facilitated by the conceptualisation of mental disorders as the high, symptomatic extreme of continuous normal variation. This assumes that there is also a low, positive extreme, which is, however, unchartered territory. This study aims to examine how well current measures capture the low extreme of mental disorder continua, using attention-deficit hyperactivity disorder (ADHD) as an example. METHODS: The ability of three validated scales to capture ADHD as a continuous trait was examined using Item Response Theory in a sample of 9,882 adolescents from the UK population-representative Twins Early Development Study. These scales were: the Strengths and Weakness of ADHD Symptoms and Normal behaviour scale (SWAN), Strength and Difficulties Questionnaire (SDQ - hyperactivity subscale), and Conners' Parent Rating Scale (Conners). RESULTS: Only the SWAN reliably differentiated interindividual differences between participants lying at any level of the continuous ADHD latent trait, including the extreme low, positive end (z-scores from -3 to +3). The SDQ showed low reliability across the ADHD latent trait. In contrast, the Conners performed best at differentiating individuals scoring at or above the mean to the high symptomatic range (z-scores from 0 to +3). The SWAN was the only measure to provide indicators of 'positive mental health', endorsed in the presence of particularly good attentive abilities. CONCLUSIONS: Scales such as the SWAN that reliably capture ADHD as a continuous trait, including the positive end, are important for not missing meaningful variation in population-based studies. Indicators of positive mental health may be helpful in clinical practice, as positive attributes have been shown to directly influence as well as buffer negative effects of psychiatric symptoms. PMID- 28731213 TI - Immunomodulatory properties of Olea europaea leaf extract in intestinal inflammation. AB - SCOPE: Extracts from olive (Olea europaea) leaves are used in Mediterranean traditional medicine as anti-inflammatory agents. They contain antioxidant phenolic compounds, such as oleuropeoside, which could be interesting for the treatment of inflammatory conditions associated with oxidative stress in humans, including inflammatory bowel disease. METHODS AND RESULTS: The anti-inflammatory effects of olive leaf extract (0.5-25 mg/kg) were studied in two mice models of colitis (DSS and DNBS). Olive leaf extract (0.1-100 MUg/mL) immunomodulatory effects were also investigated in different cell types and in ex vivo organ cultures of mucosal explants of healthy donors and Crohn's disease (CD) patients. The extract showed effect in both colitis models reducing the expression of proinflammatory mediators (IL-1beta, TNF-alpha, and iNOS), and improving the intestinal epithelial barrier integrity restoring the expression of ZO-1, MUC-2, and TFF-3. These effects were confirmed in vitro. Furthermore, it reduced the production of proinflammatory mediators (IL-1beta, IL-6, IL-8, and TNF-alpha) in intestinal mucosal samples from CD patients. CONCLUSION: Olive leaf extract presented intestinal anti-inflammatory activity in colitis mouse models, maybe be related to its immunomodulatory properties and the capacity to restore the intestinal epithelial barrier. Besides, the extract could also regulate the activity of cells involved in the inflammatory response. PMID- 28731215 TI - Hypophosphatasia in Adults: Clinical Assessment and Treatment Considerations. AB - Hypophosphatasia (HPP) is a rare inherited disorder of bone affecting approximately 500 to 600 known individuals in the United States. HPP is the result of mutations involving the gene for tissue nonspecific alkaline phosphatase. Five clinical types of HPP are recognized. The clinical presentation of HPP varies from devastating prenatal intrauterine disease to mild manifestations in adulthood. In adults, main clinical involvement includes early loss of primary or secondary teeth, osteoporosis, bone pain, chondrocalcinosis, and fractures. Treatment for HPP is limited. Asfotase alfa is a subcutaneously administered synthetic human alkaline phosphatase that is approved for treatment of patients, including adults, with perinatal/infantile- and juvenile-onset HPP. However, guidelines for the treatment of adults with HPP are not available. This discussion addresses diagnostic and treatment considerations for adults with HPP. (c) 2017 American Society for Bone and Mineral Research. PMID- 28731216 TI - Indigenous food ingredients for complementary food formulations to combat infant malnutrition in Benin: a review. AB - This paper reviews indigenous Beninese food resources as potential ingredients for complementary infant foods with the aim to develop affordable formulations for low-income households in each agro-ecological zone of the country. Potential ingredients were selected on their documented nutritional value. The selected foods encompass 347 food resources, namely 297 plant products from home gardens or collected from natural vegetation and 50 animals, either domesticated or from the wild. The compiled data reveal that the distribution of the available food resources was unbalanced between agro-ecological zones. Only a few animal ingredients are obtainable in northern Benin. Most resources are seasonal, but their availability may be extended. A high variation was observed in energy and nutrient contents. Antinutritional factors were identified in some resources, but processing techniques were reported to reduce their presence in meals. In general, ingredients from local tree foods (Adansonia digitata, Parkia biglobosa) were adequate as sources of nutrients for complementary infant foods. Based on this review, local foods for the development of complementary food formulas for Beninese infants and children may be selected for each agro-ecological zone. The approach used is exemplary for other sub-Saharan African countries in need of complementary infant foods. (c) 2017 Society of Chemical Industry. PMID- 28731217 TI - Small RNAs in regulating temperature stress response in plants. AB - Due to global climate change, temperature stress has become one of the primary causes of crop losses worldwide. Much progress has been made in unraveling the complex stress response mechanisms in plants, particularly in the identification of temperature stress responsive protein-coding genes. Recently discovered microRNAs (miRNAs) and endogenous small-interfering RNAs (siRN As) have also been demonstrated as important players in plant temperature stress response. Using high-throughput sequencing, many small RNAs, especially miRNAs, have been identified to be triggered by cold or heat. Subsequently, several studies have shown an important functional role for these small RNAs in cold or heat tolerance. These findings greatly broaden our understanding of endogenous small RNAs in plant stress response control. Here, we highlight new findings regarding the roles of miRNAs and siRNAs in plant temperature stress response and acclimation. We also review the current understanding of the regulatory mechanisms of small RNAs in temperature stress response, and explore the outlook for the use of these small RNAs in molecular breeding for improvement of temperature stress tolerance in plants. PMID- 28731218 TI - Explosives in the Cage: Metal-Organic Frameworks for High-Energy Materials Sensing and Desensitization. AB - An overview of the current status of coordination polymers and metal-organic frameworks (MOFs) pertaining to the field of energetic materials is provided. The explosive applications of MOFs are discussed from two aspects: one for detection of explosives, and the other for explosive desensitization. By virtue of their adjustable pore/cage sizes, high surface area, tunable functional sites, and rich host-guest chemistry, MOFs have emerged as promising candidates for both explosive sensing and desensitization. The challenges and perspectives in these two areas are thoroughly discussed, and the processing methods for practical applications are also discussed briefly. PMID- 28731219 TI - Daylight effect on melatonin secretion in adult female guanacos (Lama guanicoe). AB - The wild South American camelids developed a strategy of seasonal reproduction during spring and summer with singleton birth. The photoperiod is one of the factors that may modulate this seasonality where light would be translated into a hormonal signal. This study evaluated the influence of changes in daily light intensity on melatonin concentration in captive guanacos under a long-day photoperiod (16 hr light/8 hr dark; 33 '28'S). Mean melatonin concentration was 28.3 +/- 20.3 pg/ml, with a maximum of 52.14 +/- 17.19 pg/ml at 23:30 and minimum of 14.29 +/- 6.64 pg/ml at 08:30 (p < .001). There was a negative association between light intensity and melatonin concentration (r = -0.57; p < .001). The results indicate that guanacos respond to variation in daily environmental light with a hormonal response and point to a circannual rhythm as a function of the photoperiod. PMID- 28731220 TI - Mechanically Tunable Bioink for 3D Bioprinting of Human Cells. AB - This study introduces a thermogelling bioink based on carboxylated agarose (CA) for bioprinting of mechanically defined microenvironments mimicking natural tissues. In CA system, by adjusting the degree of carboxylation, the elastic modulus of printed gels can be tuned over several orders of magnitudes (5-230 Pa) while ensuring almost no change to the shear viscosity (10-17 mPa) of the bioink solution; thus enabling the fabrication of 3D structures made of different mechanical domains under identical printing parameters and low nozzle shear stress. Human mesenchymal stem cells printed using CA as a bioink show significantly higher survival (95%) in comparison to when printed using native agarose (62%), a commonly used thermogelling hydrogel for 3D-bioprinting applications. This work paves the way toward the printing of complex tissue-like structures composed of a range of mechanically discrete microdomains that could potentially reproduce natural mechanical aspects of functional tissues. PMID- 28731221 TI - Evaluating the Renal Safety of Investigational New Drugs: Where Should We Be Going? AB - We the authors work in the US Food and Drug Administration (FDA) review division responsible for the therapeutic agents for primary renal disease. We also field consultative inquiries regarding off-target adverse renal effects of drugs intended to treat other diseases. We do neither basic science research on renal diseases nor clinical studies of new drugs, but we are professional spectators of both. We offer here our thoughts on the challenge of identifying renal safety signals in the preclinical space and in the earliest phases of clinical development. PMID- 28731222 TI - Bio-nano interface and environment: A critical review. AB - The bio-nano interface is the boundary where engineered nanomaterials (ENMs) meet the biological system, exerting the biological function for which they have been designed or inducing adverse effects on other cells or organisms when they reach nontarget scenarios (i.e., the natural environment). Research has been performed to determine the fate, transport, and toxic properties of ENMs, but much of it is focused on pristine or so-called as-manufactured ENMs, or else modifications of the materials were not assessed. We review the most recent progress regarding the bio-nano interface and the transformations that ENMs undergo in the environment, paying special attention to the adsorption of environmental biomolecules on the surface of ENMs. Whereas the protein corona has received considerable attention in the fields of biomedics and human toxicology, its environmental analogue (the eco-corona) has been much less studied. A section dedicated to the analytical methods for studying and characterizing the eco-corona is also presented. We conclude by presenting and discussing the key problems and knowledge gaps that need to be resolved in the near future regarding the bio-nano interface and the eco-corona. Environ Toxicol Chem 2017;36:3181-3193. (c) 2017 SETAC. PMID- 28731223 TI - Neferine modulates IGF-1R/Nrf2 signaling in doxorubicin treated H9c2 cardiomyoblasts. AB - Doxorubicin (DOX) induced cardiotoxicity is a major problem during chemotherapy of cancers. DOX-mediated suppression of type 1 IGF receptor (IGF-1R) signaling leads to cardiac dysfunction. Neferine, a bisbezylisoquinoline alkaloid from the seed embryos of Nelumbo nucifera Gaertn possesses a distinct range of pharmacological properties. Herewith, the present study attempts to elucidate the protective role of neferine against DOX induced toxicity in H9c2 rat cardiomyoblast cell line model. DOX-treated H9c2 cells significantly increased mitochondrial superoxide generation, depleted cellular antioxidant status, suppressed the activation of IGF-1R signaling via PI3K/Akt/mTOR and induced autophagy by the activation of ULK1, Beclin1, Atg7, and LC3B. Neferine pre treatment activated IGF-1R signaling, improved cellular antioxidant pool, increased the expression of down-stream targets of IGF-1R, such as PI3K/Akt/mTOR, inhibited mitochondrial superoxide generation and autophagy significantly with the induction of Nrf2 translocation and expressions of HO1 and SOD1. Our study suggests the use of neferine for amelioration of DOX-mediated cardiotoxicity. PMID- 28731224 TI - Extremely Low Density and Super-Compressible Graphene Cellular Materials. AB - Development of extremely low density graphene elastomer (GE) holds the potential to enable new properties that traditional cellular materials cannot offer, which are promising for a range of emerging applications, ranging from flexible electronics to multifunctional scaffolds. However, existing graphene foams with extremely low density are generally found to have very poor mechanical resilience. It is scientifically intriguing but remains unresolved whether and how the density limit of this class of cellular materials can be further pushed down while their mechanical resilience is being retained. In this work, a simple annealing strategy is developed to investigate the role of intersheet interactions in the formation of extreme-low-density of graphene-based cellular materials. It is discovered that the density limit of mechanically resilient cellular GEs can be further pushed down as low as 0.16 mg cm-3 through thermal annealing. The resultant extremely low density GEs reveal a range of unprecedented properties, including complete recovery from 98% compression in both of liquid and air, ultrahigh solvent adsorption capacity, ultrahigh pressure sensitivity, and light transmittance. PMID- 28731225 TI - Decreased levels of PDI and P5 in oligodendrocytes in Alzheimer's disease. AB - Protein disulfide isomerase (PDI) is a chaperone protein located in the endoplasmic reticulum (ER). Nitric oxide-induced S-nitrosylation of PDI inhibits its enzymatic activity, leading to protein accumulation and activation of the unfolded protein response. Protein disulfide isomerase P5 (P5) is a member of the PDI family that mostly localizes to the ER lumen. Both S-nitrosylated PDI and S nitrosylated P5 are found in Alzheimer's disease (AD) brain. Previously, we showed that expression of the ER stress marker, growth arrest, and DNA damage protein (GADD34) was significantly increased in neurons and oligodendrocytes in AD brain. In the present study, we showed that PDI and P5 levels were significantly decreased in oligodendrocytes in the brains of AD patients and an AD mouse model. Interestingly, these decreases were evident before the animals displayed typical AD pathology. Because we previously showed that small short interfering RNA knockdown of PDI or P5 could affect the viability of neuronal cells under ER stress, dysfunction of PDI and P5 under ER stress could cause apoptosis of neuronal cells. In summary, we showed that the levels of PDI and P5 were significantly decreased in the oligodendrocytes of AD patients. This phenomenon was also found in an AD mouse model before the animals displayed AD pathology. The overall findings suggest that oligodendrocytes may play important roles in AD pathogenesis. PMID- 28731226 TI - Curcumin converts Foxp3+ regulatory T cells to T helper 1 cells in patients with lung cancer. AB - The regulatory T cells (Treg) play an important role in the tumor tolerance. The methods to regulate the Treg population in cancer-bearing hosts are limited currently. The effect of curcumin on inhibiting cancer has been recognized, but the mechanism remains elusive. This study tests a hypothesis that administration of curcumin down regulates Tregs in lung cancer (LC) patients. In this study, a group of LC patients was treated with curcumin. The peripheral Tregs and T helper (Th) 1 cells were analyzed by flow cytometry. The mechanism by which curcumin regulated the Tregs was observed by cell culture approaches. The results showed that the frequency of peripheral Treg was markedly higher in LC patients than that in healthy subjects, which was suppressed after treating with curcumin for 2 weeks. The peripheral Th1 cells were increased in LC patients after the curcumin therapy. The data of the in vitro experiments showed that curcumin converted the LC patient-isolated Tregs to Th1 cells via repressing the gene transcription of forkhead protein-3 and increasing the expression of interferon-gamma. In conclusion, curcumin can convert LC patient-isolated Tregs to Th1 cells. The results suggest that curcumin may improve the antitumor immunity by regulating the tumor specific immune tolerance. PMID- 28731228 TI - Erratum. PMID- 28731227 TI - Dithiopheneindenofluorene (TIF) Semiconducting Polymers with Very High Mobility in Field-Effect Transistors. AB - The charge-carrier mobility of organic semiconducting polymers is known to be enhanced when the energetic disorder of the polymer is minimized. Fused, planar aromatic ring structures contribute to reducing the polymer conformational disorder, as demonstrated by polymers containing the indacenodithiophene (IDT) repeat unit, which have both a low Urbach energy and a high mobility in thin-film transistor (TFT) devices. Expanding on this design motif, copolymers containing the dithiopheneindenofluorene repeat unit are synthesized, which extends the fused aromatic structure with two additional phenyl rings, further rigidifying the polymer backbone. A range of copolymers are prepared and their electrical properties and thin-film morphology evaluated, with the co-benzothiadiazole polymer having a twofold increase in hole mobility when compared to the IDT analog, reaching values of almost 3 cm2 V-1 s-1 in bottom-gate top-contact organic field-effect transistors. PMID- 28731229 TI - Macroscopic Polarization Enhancement Promoting Photo- and Piezoelectric-Induced Charge Separation and Molecular Oxygen Activation. AB - Efficient photo- and piezoelectric-induced molecular oxygen activation are both achieved by macroscopic polarization enhancement on a noncentrosymmetric piezoelectric semiconductor BiOIO3 . The replacement of V5+ ions for I5+ in IO3 polyhedra gives rise to strengthened macroscopic polarization of BiOIO3 , which facilitates the charge separation in the photocatalytic and piezoelectric catalytic process, and renders largely promoted photo- and piezoelectric induced reactive oxygen species (ROS) evolution, such as superoxide radicals (. O2- ) and hydroxyl radicals (. OH). This work advances piezoelectricity as a new route to efficient ROS generation, and also discloses macroscopic polarization engineering on improvement of multi-responsive catalysis. PMID- 28731230 TI - Effects of spray drift of glyphosate on nontarget terrestrial plants-A critical review. AB - Glyphosate is a widely used broad-spectrum postemergent herbicide used for weed control in both agricultural and nonagricultural settings. Spray drift of glyphosate can pose a risk to nontarget terrestrial plants and plant communities outside the intended area of application, but the lack of a well-established predicted-no-effect drift rate makes properly assessing such risk difficult. For this reason, a literature review and meta-analysis was carried out with the aim to determine the level of drift that is likely to cause harm to plants and to explore what spray-reducing targets would be sufficiently protective. No-observed adverse effect rates, lowest-observed-adverse effect rates, and effect rates giving 10, 25, and 50% effects were extracted from a total of 39 different publications. The data were combined per species, and species sensitivity distributions were constructed and fitted with a log-logistic model to assess protectiveness. No systematic differences were detected between the responses of monocotyledons or dicotyledons, but wild plants were found to be generally less sensitive to glyphosate drift than domesticated plants. The results indicate that restricting spray drift to a level below 5 g a.e./ha would protect approximately 95% of all higher plant species against minor adverse effects of glyphosate drift and that rates below 1 to 2 g a.e./ha would be almost completely protective. No studies were encountered that evaluated effects of spray drift against nonvascular plants, and therefore, the conclusions are only valid for vascular plants. Environ Toxicol Chem 2017;36:2879-2886. (c) 2017 SETAC. PMID- 28731231 TI - Comparative analysis of juice volatiles in selected mandarins, mandarin relatives and other citrus genotypes. AB - BACKGROUND: Citrus fruit flavor is an important attribute prioritized in variety improvement. The present study compared juice volatiles compositions from 13 selected citrus genotypes, including six mandarins (Citrus reticulata), three sour oranges (Citrus aurantium), one blood orange (Citrus sinensis), one lime (Citrus limonia), one Clementine (Citrus clementina) and one satsuma (Citrus unshiu). RESULTS: Large differences were observed with respect to volatile compositions among the citrus genotypes. 'Goutou' sour orange contained the greatest number of volatile compounds and the largest volatile production level. 'Ponkan' mandarin had the smallest number of volatiles and 'Owari' satsuma yielded the lowest volatile production level. 'Goutou' sour orange and 'Moro' blood orange were clearly distinguished from other citrus genotypes based on the analysis of volatile compositions, even though they were assigned into one single group with two other sour oranges by the molecular marker profiles. CONCLUSIONS: The clustering analysis based on the aroma volatile compositions was able to differentiate mandarin varieties and natural sub-groups, and was also supported by the molecular marker study. The gas chromatography-mass spectrometry analysis of citrus juice aroma volatiles can be used as a tool to distinguish citrus genotypes and assist in the assessment of future citrus breeding programs. The aroma volatile profiles of the different citrus genotypes and inter-relationships detected among volatile compounds and among citrus genotypes will provide fundamental information on the development of marker-assisted selection in citrus breeding. (c) 2017 Society of Chemical Industry. PMID- 28731232 TI - A comprehensive review of agrimoniin. AB - Plant tannins are a unique class of polyphenols with relatively high molecular weights. Within the ellagitannins group, agrimoniin--dimeric ellagitannin--is one of the most representative compounds found in many plant materials belonging to the Rosaceae family. Agrimoniin was first isolated in 1982 from roots of Agrimonia pilosa Ledeb. (Rosaceae), a plant traditionally used in Japan and China as an antidiarrheal, hemostatic, and antiparasitic agent. Agrimoniin is a constituent of medicinal plants, which are often applied orally in the form of infusions, decoctions, or tinctures. It is also present in commonly consumed food products, such as strawberries and raspberries. It is metabolized by human gut microbiota into a series of low-molecular-weight urolithins with proven anti inflammatory and anticancer in vivo and in vitro bioactivities. The compound has received widespread interest owing to some interesting biological effects and therapeutic activities, which we elaborate in the present review. Additionally, we present an overview of the techniques used for the analysis, isolation, and separation of agrimoniin from the practical perspective. PMID- 28731233 TI - Integration of cellular and molecular endpoints to assess the toxicity of polycyclic aromatic hydrocarbons in HepG2 cell line. AB - Polycyclic aromatic hydrocarbons (PAHs) are persistent pollutants present in the environment with known mutagenic and carcinogenic properties. In the present study the effects of exposure to single or multiple doses of benzo[a]anthracene (BaA), pyrene (Pyr), and 3 halogenated derivatives of these compounds (1 chloropyrene, 1-bromopyrene [1-BrPyr], and 7-chlorobenzo[a]anthracene [7-ClBaA]) were evaluated in a liver-derived human cell line (HepG2). Cytotoxicity as assessed by the classic 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and neutral red assays showed a mild toxic effect in response to single or multiple dose exposure for up to 72 h, except for multiple dose exposure to BaA and 7-ClBaA (1 MUM/d for 4 d) and single exposure to 10 MUM BaA. Furthermore, selective mitochondrial and lysosomal toxicity was observed for Pyr and BaA series, respectively. To understand the underlying molecular mechanisms responsible for this effect, reactive oxygen species production, mitochondrial membrane depolarization, lysosomal pH, DNA fragmentation, and early and late apoptosis mediators were evaluated after exposure to single doses of the compounds. All compounds were able to trigger oxidative stress after 24 h as measured by catalase activity, and a good correlation was found between mitochondrial membrane depolarization, lysosomal pH increase, and MTT and neutral red assays. Evaluation of cell death mediators showed that caspase-3/7, but not annexin-V, pathways were involved in toxicity triggered by the studied compounds. The integration of all results showed that 1-BrPyr and BaA have a higher toxicity potential. Environ Toxicol Chem 2017;36:3404-3414. (c) 2017 SETAC. PMID- 28731235 TI - What progress have we made in the treatment of atopic eczema? Putting the new biological therapies into a wider context. PMID- 28731236 TI - Cover image: Intralymphatic histiocytosis with giant blanching violaceous plaques. PMID- 28731237 TI - Pathogenesis of morphoea: knowledge gaps in subtypes and comparisons to systemic sclerosis. PMID- 28731238 TI - A critical eye on registry data in psoriasis. PMID- 28731239 TI - New technology discloses the tumour margin of extramammary Paget disease? PMID- 28731241 TI - A new potential option for topical treatment of basal cell carcinoma? PMID- 28731242 TI - Antimalarials in cutaneous lupus erythematous subtypes. PMID- 28731243 TI - Biologics for psoriasis: more drugs, new patient categories, but fresh challenges for clinical dermatologists. PMID- 28731244 TI - Candida infections and interleukin-17 inhibitors used in dermatology. PMID- 28731246 TI - To learn more about sickle cell ulcers. PMID- 28731247 TI - Positive about negative: no need for a pink cloud of fluff and justifications. PMID- 28731248 TI - Lessons to be learned from type 1 segmental Gorlin syndrome. PMID- 28731249 TI - Image Gallery: Never miss the details: the importance of dermoscopy in the differential diagnosis of coexistent inflammatory disorders. PMID- 28731250 TI - Providing dermatological care in resource-limited settings: barriers and potential solutions. PMID- 28731251 TI - A practical approach to the initial dose and subsequent increments for ultraviolet A1 phototherapy. PMID- 28731252 TI - Percutaneous absorption risks in atopic dermatitis. PMID- 28731254 TI - Prognostic factors of patients with linear IgA bullous dermatosis. PMID- 28731255 TI - Mild classical xeroderma pigmentosum. PMID- 28731256 TI - Image Gallery: Pink papules within a tattoo linked to Mycobacterium chelonae infection. PMID- 28731257 TI - Clinical significance of immunoglobulin E in bullous pemphigoid. PMID- 28731258 TI - Image Gallery: Congenital onychodysplasia of the toenails. PMID- 28731259 TI - Folliculotropic mycosis fungoides is a heterogenous group. PMID- 28731261 TI - Structural Insights into Borates with an Anion-Templated Open-Framework Configuration: Asymmetric K2 BaB16 O26 versus Centrosymmetric K3 CsB20 O32 and Na2 M2 NB18 O30 (M=Rb, Cs; N=Ba, Pb). AB - Five new mixed-metal borate crystals, namely, K2 BaB16 O26 , K3 CsB20 O32 , Na2 Cs2 BaB18 O30 , Na2 Rb2 PbB18 O30 , and Na2 Cs2 PbB18 O30 , have been synthesized by the high-temperature solution method. These structures were characterized by single-crystal X-ray diffraction and their B-O configurations are shown to feature complicated three-dimensional (3D) open-framework structures incorporating different types of channels. For all five compounds, the frameworks can be reduced to four-connected (4-c) uninodal nets with sra-, dia- and nbo-type topologies by assigning the [B5 O10 ]5- and [B3 O7 ]5- clusters as basic nodes. First-principles calculations have shown that the multiple cations in mixed-metal borates influence the ground-state electronic structures and associated optical absorptions. In addition, the crystal structures, thermal stabilities, and IR spectra of the title compounds have also been performed. PMID- 28731260 TI - Transcriptional regulation of APP by apoE: To boldly go where no isoform has gone before: ApoE, APP transcription and AD: Hypothesised mechanisms and existing knowledge gaps. AB - Alzheimer's disease (AD) is the most common form of dementia that gradually disrupts the brain network to impair memory, language and cognition. While the amyloid hypothesis remains the leading proposed mechanism to explain AD pathophysiology, anti-amyloid therapeutic strategies have yet to translate into useful therapies, suggesting that amyloid beta-protein and its precursor, the amyloid precursor protein (APP) are but a part of the disease cascade. Further, risk of AD can be modulated by a number of factors, the most impactful being the E4 isoform of apolipoprotein E (apoE). A recent study reported a novel isoform dependent transcriptional regulation of APP by apoE. These interesting new results add to the myriad of mechanisms that have been proposed to explain how apoE4 enhances AD risk, highlighting the complexities of not only apoE and AD pathophysiology, but also of disease itself. Also see the video abstract here: https://youtu.be/yd14MBdPkCY. PMID- 28731262 TI - Nephroprotective Effects of Anthocyanin from the Fruits of Panax ginseng (GFA) on Cisplatin-Induced Acute Kidney Injury in Mice. AB - Cisplatin is an effective anticancer chemotherapeutic agent, but the use of cisplatin in the clinic is severely limited by side effects. Nephrotoxicity is a major factor that contributes to the side effects of cisplatin chemotherapy. The aim of this research was to survey the nephroprotective effects of anthocyanin from the fruits of Panax ginseng (GFA) in a murine model of cisplatin-induced acute kidney injury. We observed that pretreatment with GFA attenuated cisplatin induced elevations in blood urea nitrogen and creatinine levels and histopathological injury induced by cisplatin. The formation of kidney malondialdehyde, heme oxygenase-1, cytochrome P450 E1 and 4-hydroxynonenal with a concomitant reduction in reduced glutathione was also inhibited by GFA, while the activities of kidney superoxide dismutase and catalase were all increased. GFA also inhibited the increase in serum tumour necrosis factor-alpha and interleukin 1beta induced by cisplatin. In addition, the levels of induced nitric oxide synthase and cyclooxygenase-2 were suppressed by GFA. Furthermore, GFA supplementation inhibited the activation of apoptotic pathways by increasing B cell lymphoma 2 and decreasing Bcl2-associated X protein expression. In conclusion, the findings from the present investigation demonstrate that GFA pre administration can significantly prevent cisplatin-induced nephrotoxicity, which may be related to its antioxidant, anti-apoptotic and antiinflammatory effects. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28731263 TI - Commercial strain-derived clinical Saccharomyces cerevisiae can evolve new phenotypes without higher pathogenicity. AB - SCOPE: Saccharomyces cerevisiae is one of the most important microbes in food industry, but there is growing evidence on its potential pathogenicity as well. Its status as a member of human mycobiome is still not fully understood. METHODS AND RESULTS: In this study, we characterize clinical S. cerevisiae isolates from Hungarian hospitals along with commercial baking and probiotic strains, and determine their phenotypic parameters, virulence factors, interactions with human macrophages, and pathogenicity. Four of the clinical isolates could be traced back to commercial strains based on genetic fingerprinting. Our observations indicate that the commercial-derived clinical isolates have evolved new phenotypes and show similar, or in two cases, significantly decreased pathogenicity. Furthermore, immunological experiments revealed that the variability in human primary macrophage activation after coincubation with yeasts is largely donor and not isolate dependent. CONCLUSION: Isolates in this study offer an interesting insight into the potential microevolution of probiotic and food strains in human hosts. These commensal yeasts display various changes in their phenotypes, indicating that the colonization of the host does not necessarily impose a selective pressure toward higher virulence/pathogenicity. PMID- 28731264 TI - High-Yield Synthesis of Crystal-Phase-Heterostructured 4H/fcc Au@Pd Core-Shell Nanorods for Electrocatalytic Ethanol Oxidation. AB - Noble-metal nanomaterials are attracting increasing research interest due to their promising applications in electrochemical catalysis, for example. Although great efforts have been devoted to the size-, shape-, and architecture-controlled synthesis of noble-metal nanomaterials, their crystal-phase-controlled synthesis is still in its infancy. Here, for the first time, this study reports high-yield synthesis of Au nanorods (NRs) with alternating 4H/face-centered cubic (fcc) crystal-phase heterostructures via a one-pot wet-chemical method. The coexistence of 4H and fcc phases is relatively stable, and the 4H/fcc Au NRs can serve as templates for crystal-phase-controlled epitaxial growth of other metals. As an example, bimetallic 4H/fcc Au@Pd core-shell NRs are synthesized via the epitaxial growth of Pd on 4H/fcc Au NRs. Significantly, the 4H/fcc Au@Pd NRs show superior mass activity toward the ethanol oxidation reaction, i.e., 6.2 and 4.9 times those of commercial Pd black and Pt/C catalysts, respectively. It is believed that this new synthetic strategy can be used to prepare other novel catalysts for various promising applications. PMID- 28731265 TI - Application of dead end-knockout zebrafish as recipients of germ cell transplantation. AB - Germ cell transplantation is a promising technology for the propagation of endangered or valuable fishes. In this technique, sterile male and female recipient fish are injected with donor germ cells so they can produce viable gametes derived from the donor cells. The dead end (dnd) gene is involved in the migration of primordial germ cells; therefore, dnd-knockout zebrafish are expected to be germ-cell-free, making them suitable recipients for germ cell transplantation. dnd mutants were produced by microinjecting 2 nl of 10 ng/MUl cRNAs encoding zinc finger nucleases against dnd into the blastodisc of zebrafish embryos before the cell- cleavage stage. One of the resulting founder males was mated with a wild-type female, and produced heterozygous mutants in the F1 generation. Mating of these F1 mutants produced an F2 generation with approximately 25% of the clutch being homozygous mutant (dnd-knockout) male, and lacking germ cells (as confirmed by expression analyses of vasa). The resulting dnd-knockout zebrafish males were tested for suitability as germ cell transplantation recipients by intraperitoneal transplantation of testicular cells prepared from vasa-gfp zebrafish. GFP-positive germ cells incorporated into the germ-cell-free gonads of the dnd-knockout recipients matured into functional sperm. Progeny tests revealed that the sperm from these dnd-knockout recipients were derived entirely from donor cells. Thus, we demonstrated that homozygous dnd mutants became germ-cell-free males that are able to nurse donor-derived germ cells. PMID- 28731266 TI - A randomized, double-blind, placebo-controlled crossover study of the effects of levetiracetam on cognition, mood, and balance in healthy older adults. AB - OBJECTIVE: The cognitive and mood effects of levetiracetam (LEV) in older adults are not known. This study compared the cognitive and mood effects of LEV to placebo in healthy older adults. METHODS: Cognitive, mood, and balance variables were compared between LEV and placebo using a randomized, double-blind, placebo controlled crossover study with two 5-week treatment periods. Healthy volunteers (n = 20) aged 65-80 (mean age 72.4) received either LEV or placebo in which the LEV target dose was 1,000 mg/day. Volunteers, aged 65-80, were without epilepsy to limit potentially confounding the impact of seizures and/or underlying neuropathology on outcomes. LEV was initiated at 250 mg twice a day for 2 weeks, then increased to 500 mg twice a day for 2 weeks, and then tapered to 250 mg twice a day for 1 week. This was randomized with placebo for the two treatment arms. Measures included standardized neuropsychological, mood, and balance tests yielding 32 variables. Balance was assessed using subjective report (e.g., A-B neurotoxicity scale) and objective data (e.g., Berg Balance Scale). RESULTS: Average LEV serum concentration was 16.9 (standard deviation [SD} 7.7). Repeated measures analysis of variance (ANOVA) found no differences between LEV and placebo phases for 29 (90.6%) of 32 variables including no change in balance. Performance on LEV was better than placebo on a visual memory (MCG Complex Figure Recall; p = 0.007) and two attention tests (Trail Making Test, Part A, p = 0.009; Stroop Interference, p = 0.004). There was a trend for greater irritability and fatigue (POMS Anger and Fatigue) during the LEV phase (p = 0.029, p = 0.035). Effect-size changes were generally small (Cohen d < 0.5). SIGNIFICANCE: LEV was well tolerated in this elderly population in terms of cognition, mood, and balance. When anticonvulsant medication is indicated for older adults, LEV has pharmacokinetic advantages, and these data indicate no adverse impact on cognition or balance. PMID- 28731267 TI - Heuristic knowledge-based planning for single-isocenter stereotactic radiosurgery to multiple brain metastases. AB - PURPOSE: Single-isocenter, volumetric-modulated arc therapy (VMAT) stereotactic radiosurgery (SRS) for multiple brain metastases (multimets) can deliver highly conformal dose distributions and reduce overall patient treatment time compared to other techniques. However, treatment planning for multimet cases is highly complex due to variability in numbers and sizes of brain metastases, as well as their relative proximity to organs-at-risk (OARs). The purpose of this study was to automate the VMAT planning of multimet cases through a knowledge-based planning (KBP) approach that adapts single-target SRS dose predictions to multiple target predictions. METHODS: Using a previously published artificial neural network (ANN) KBP system trained on single-target, linac-based SRS plans, 3D dose distribution predictions for multimet patients were obtained by treating each brain lesion as a solitary target and subsequently combining individual dose predictions into a single distribution. Spatial dose distributions di(r->) for each of the i = 1...N lesions were merged using the combination function d(r >)=?iNdin(r->)1/n. The optimal value of n was determined by minimizing root-mean squared (RMS) difference between clinical multimet plans and predicted dose per unit length along the line profile joining each lesion in the clinical cohort. The gradient measure GM=[3/4pi]1/3V50%1/3-V100%1/3 is the primary quality metric for SRS plan evaluation at our institution and served as the main comparative metric between clinical plans and the KBP results. A total of 41 previously treated multimet plans, with target numbers ranging from N = 2-10, were used to validate the ANN predictions and subsequent KBP auto-planning routine. Fully deliverable KBP plans were developed by converting predicted dose distribution into patient-specific optimization objectives for the clinical treatment planning system (TPS). Plan parity was maintained through identical arc configuration and target normalization. Overall plan quality improvements were quantified by calculating the difference between SRS quality metrics (QMs): DeltaQM = QMclinical - QMKBP . In addition to GM, investigated QMs were: volume of brain receiving >= 10 Gy (V10 Gy ), volume of brain receiving >= 5 Gy (DeltaV5 Gy ), heterogeneity index (HI), dose to 0.1 cc of the brainstem (D0.1 cc ), dose to 1% of the optic chiasm (D1% ), and interlesion dose (DIL ). In addition to this quantitative analysis, overall plan quality was assessed via blinded plan comparison of the manual and KBP treatment plans by SRS-specializing physicians. RESULTS: A dose combination factor of n = 8 yielded an integrated dose profile RMS difference of 2.9% across the 41-patient cohort. Multimet dose predictions exhibited DeltaGM = 0.07 +/- 0.10 cm against the clinical sample, implying either further normal tissue sparing was possible or that dose predictions were slightly overestimating achievable dose gradients. The latter is the more likely explanation, as this bias vanished when dose predictions were converted to deliverable KBP plans DeltaGM = 0.00 +/- 0.08 cm. Remaining QMs were nearly identical or showed modest improvements in the KBP sample. Equivalent QMs included: DeltaV10 Gy = 0.37 +/- 3.78 cc, DeltaHI = 0.02 +/- 0.08 and DeltaDIL = -2.22 +/- 171.4 cGy. The KBP plans showed a greater degree of normal tissue sparing as indicated by brain DeltaV5 Gy = 4.11+/- 24.05 cc, brainstem DeltaD0.1 cc = 42.8 +/- 121.4 cGy, and chiasm DeltaD1% = 50.8 +/- 83.0 cGy. In blinded review by SRS-specializing physicians, KBP-generated plans were deemed equivalent or superior in 32/41(78.1%) of the cases. CONCLUSION: Heuristic KBP-driven automated planning in linac-based, single-isocenter treatments for multiple brain metastases maintained or exceeded overall plan quality. PMID- 28731268 TI - 13 C metabolic flux profiling of Pichia pastoris grown in aerobic batch cultures on glucose revealed high relative anabolic use of TCA cycle and limited incorporation of provided precursors of branched-chain amino acids. AB - : Carbon metabolism of Crabtree-negative yeast Pichia pastoris was profiled using 13 C nuclear magnetic resonance (NMR) to delineate regulation during exponential growth and to study the import of two precursors for branched-chain amino acid biosynthesis, alpha-ketoisovalerate and alpha-ketobutyrate. Cells were grown in aerobic batch cultures containing (a) only glucose, (b) glucose along with the precursors, or (c) glucose and Val. The study provided the following new insights. First, 13 C flux ratio analyses of central metabolism reveal an unexpectedly high anaplerotic supply of the tricarboxylic acid cycle for a Crabtree-negative yeast, and show that a substantial fraction of glucose catabolism proceeds through the pentose phosphate pathway. A comparison with previous flux ratio analyses for batch cultures of Crabtree-negative Pichia stipitis and Crabtree-positive Saccharomyces cerevisiae indicate that the overall regulation of central carbon metabolism in P. pastoris is intermediate in between P. stipitis and S. cerevisiae. Second, excess alpha-ketoisovalerate in the medium is not transported into the cytoplasm indicating that P. pastoris lacks a suitable transporter. In contrast, excess Val is efficiently taken up and largely fulfills demands for both Val and Leu for protein synthesis. Third, excess alpha ketobutyrate is transported into the mitochondria for Ile biosynthesis. However, the import does not efficiently inhibit the synthesis of alpha-ketobutyrate from pyruvate indicating that P. pastoris has not been optimized evolutionarily to take full advantage of this carbon source. These findings have direct implications for preparing uniformly 2 H,13 C,15 N-labeled proteins containing protonated Ile, Val, and Leu methyl groups in P. pastoris for NMR-based structural biology. ENZYMES: Acetohydroxy acid isomeroreductase (EC 1.1.1.86), branched-chain amino acid aminotransferase (BCAT, EC 2.6.1.42), fumarase (EC 4.2.1.2), malic enzyme (EC 1.1.1.39/1.1.1.40), phosphoenolpyruvate carboxykinase (EC 4.1.1.49), pyruvate carboxylase (EC 6.4.1.1), pyruvate kinase (EC 2.7.1.40), l-serine hydroxymethyltransferase (EC 2.1.2.1), threonine aldolase (EC 4.1.2.5), threonine dehydratase (EC 4.3.1.19); transketolase (EC 2.2.1.1), transaldolase (EC 2.2.1.2). PMID- 28731269 TI - Biofilm formation and antibiotic resistance in Klebsiella pneumoniae urinary strains. AB - AIMS: Multidrug-resistant Klebsiella pneumoniae has become a relevant healthcare associated pathogen. Capsule, type 1 and 3 fimbriae (mrkA gene), type 2 quorum sensing system (luxS), synthesis of D-galactan I (wbbM), LPS transport (wzm) and poly-beta-1,6-N-acetyl-D-glucosamine (pgaA) seem involved in K. pneumoniae biofilm. Nonenzymatic antibiotic resistance is related to nonexpression or mutation of porins (OmpK35 and OmpK36), and efflux pump (acrB) overexpression. The aim of this study was to analyse some virulence factors of K. pneumoniae isolates, and to evaluate possible correlations between their antibiotic resistance profile and ability to form biofilm. METHODS AND RESULTS: Quantitative biofilm production assay, congo red agar test and string test were performed on 120 isolates clustered in 56 extensively drug-resistant (XDR), 40 MDR and 24 susceptible (S) strains. Nine representative strains were analysed by real-time RT-PCR for the expression of antibiotic resistance (OmpK35, OmpK36, acrB) and biofilm production genes (mrkA, luxS, pga, wbbM, wzm) during planktonic and sessile growth. XDR isolates showed a higher ability to form biofilm (91.07%) and to produce polysaccharides (78.57%) when compared to MDR and S strains. In biofilm-growing XDR strains, seven of eight genes were upregulated, with the only exception of OmpK36. CONCLUSIONS: XDR strains exhibited phenotypic and genotypic features supporting a significant growth as biofilm. SIGNIFICANCE AND IMPACT OF THE STUDY: This study produces new findings that highlight a positive correlation between antibiotic resistance profile and biofilm-forming ability in XDR K. pneumoniae strains. These new evidences might contribute to the progress in selection of therapeutic treatments of infections caused by K. pneumoniae resistant also to the 'last line of defence' antibiotics, that is, carbapenems. PMID- 28731270 TI - Polarized Light-Emitting Diodes Based on Patterned MoS2 Nanosheet Hole Transport Layer. AB - Here, this study successfully fabricates few-layer MoS2 nanosheets from (NH4 )2 MoS4 and applies them as the hole transport layer as well as the template for highly polarized organic light-emitting diodes (OLEDs). The obtained material consists of polycrystalline MoS2 nanosheets with thicknesses of 2 nm. The MoS2 nanosheets are patterned by rubbing/ion-beam treatment. The Raman spectra shows that {poly(9,9-dioctylfluorene-alt-benzothiadiazole), poly[(9,9-di-n octylfluorenyl-2,7-diyl)-alt-(benzo[2,1,3]thiadiazol-4,8-diyl)]} (F8BT) on patterned MoS2 exhibits distinctive polarization behavior. It is discovered that patterned MoS2 not only improves the device efficiency but also changes the polarization behavior of the devices owing to the alignment of F8BT. This work demonstrates a highly efficient polarized OLED with a polarization ratio of 62.5:1 in the emission spectrum (166.7:1 at the peak intensity of 540 nm), which meets the manufacturing requirement. In addition, the use of patterned MoS2 nanosheets not only tunes the polarization of the OLEDs but also dramatically improves the device performance as compared with that of devices using untreated MoS2 . PMID- 28731271 TI - Ultrasound elastography for carpal tunnel pressure measurement: A cadaveric validation study. AB - Carpal tunnel pressure is a key factor in the etiology of carpal tunnel syndrome. Numerous approaches have been conducted to measure carpal tunnel pressure. However, most techniques are invasive and take time and effort. We have developed an innovative approach to noninvasively assess the tunnel pressure by using the ultrasound surface wave elastography (USWE) technique. In a previous study it was shown that the shear wave speed in a tendon increased linearly with increasing tunnel pressure enclosed the tendon in a simple tendon model. This study aimed to examine the relationship between the carpal tunnel pressure and the shear wave speeds inside and outside the carpal tunnel in a human cadaveric model. The result showed that the shear wave speed inside the carpal tunnel increased linearly with created carpal tunnel pressure, while the shear wave speed outside the carpal tunnel remained constant. These findings suggest that noninvasive measurement of carpal tunnel pressure is possible by measuring the shear wave speed in the tendon. After fully establishing this technology and being applicable in clinic, it would be useful in the diagnosis of carpal tunnel syndrome. For that reason, further validation with this technique in both healthy controls and patients with carpal tunnel syndrome is required. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:477-483, 2018. PMID- 28731272 TI - Short-term toxicity of 1-methylnaphthalene to Americamysis bahia and 5 deep-sea crustaceans. AB - There are few studies that have evaluated hydrocarbon toxicity to vertically migrating deep-sea micronekton. Crustaceans were collected alive using a 9-m2 Tucker trawl with a thermally insulated cod end and returned to the laboratory in 10 degrees C seawater. Toxicity of the polycyclic aromatic hydrocarbon 1 methylnaphthalene to Americamysis bahia, Janicella spinacauda, Systellaspis debilis, Sergestes sp., Sergia sp., and a euphausiid species was assessed in a constant exposure toxicity test utilizing a novel passive dosing toxicity testing protocol. The endpoint of the median lethal concentration tests was mortality, and the results revealed high sensitivity of the deep-sea micronekton compared with other species for which these data are available. Threshold concentrations were also used to calculate critical target lipid body burdens using the target lipid model. Environ Toxicol Chem 2017;36:3415-3423. (c) 2017 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals, Inc. on behalf of SETAC. PMID- 28731273 TI - Scaffold-Free Liver-On-A-Chip with Multiscale Organotypic Cultures. AB - The considerable advances that have been made in the development of organotypic cultures have failed to overcome the challenges of expressing tissue-specific functions and complexities, especially for organs that require multitasking and complex biological processes, such as the liver. Primary liver cells are ideal biological building blocks for functional organotypic reconstruction, but are limited by their rapid loss of physiological integrity in vitro. Here the concept of lattice growth used in material science is applied to develop a tissue incubator, which provides physiological cues and controls the 3D assembly of primary cells. The cues include a biological growing template, spatial coculture, biomimetic radial flow, and circulation in a scaffold-free condition. The feasibility of recapitulating a multiscale physiological structural hierarchy, complex drug clearance, and zonal physiology from the cell to tissue level in long-term cultured liver-on-a-chip is demonstrated. These methods are promising for future applications in pharmacodynamics and personal medicine. PMID- 28731274 TI - Synthesis and Characterization of 2,2'-Dinitramino-5,5'-bi(1-oxa-3,4-diazole) and Derivatives as Economic and Highly Dense Energetic Materials. AB - 2,2'-Dinitramino-5,5'-bi(1-oxa-3,4-diazole) (2) is a new highly energetic material with superior calculated detonation performance in comparison to cyclo 1,3,5-trimethylene-2,4,6-trinitramine (RDX) and penta-erythritoltetranitrate (PETN) and can be prepared by an economical and practical two-step synthesis. The starting material 2,2'-diamino-5,5'-bi(1-oxa-3,4-diazole) (1) is synthesized by the reaction of oxalyl dihydrazide with cyanogen bromide. Nitration of 1 yields the title compound in perfect yield and purity. The combination of its high density of 1.986 g cm-3 , the positive heat of formation (+190 kJ mol-1 ), and a slightly positive oxygen balance (+6.2 %) results in ideal calculated detonation parameters (e.g. detonation velocity 9296 m s-1 ). The sensitivities toward impact and friction can be adjusted by deprotonation and formation of corresponding nitrogen-rich salts, for example, ammonium (3), hydroxylammonium (4), and guanidinium (5) salts. PMID- 28731275 TI - Exceptionally Strong Electron-Donating Ability of Bora-Ylide Substituent vis-a vis Silylene and Silylium Ion. AB - Electropositive boron-based substituent (phosphonium bora-ylide) with an exceptionally strong pi- and sigma-electron donating character dramatically increases the stability of a new type of N-heterocyclic silylene 2 featuring amino- and bora-ylide-substituents. Moreover, the related silylium ion 4 and transition-metal-silylene complexes, with trigonal-planar geometries around the silicon center, are also well stabilized. Therefore, the N,B-heterocyclic silylene 2 can be used as a strongly electron-donating innocent ligand in coordination chemistry similarly to N-heterocyclic carbenes. PMID- 28731276 TI - Attempt to Harvest a Sufficient Number of Mononuclear Cells in an Appropriate Blood Product Volume By Modification of the Default Apheresis Setting. AB - To harvest for T cell therapy, a 1.6-fold higher number of CD3+ T cells was collected with MNC mode (N = 10) compared with Auto PBSC mode (N = 5) in COBE Spectra cell separator, but the blood product volume was increased by 3.5-fold. For therapeutic angiogenesis therapy, apheresis was initially performed using Auto PBSC mode (N = 4) to fine tune the blood product volume to omit cell concentration, but the collected number of mononuclear cells was lower than expected. However, an increase of the harvest cycle number from 3.8 +/- 0.5 to 7.4 +/- 2.0 cycles (N = 19) resulted in a 2.1-fold higher number of collected mononuclear cells (8.7 +/- 4.1 * 109 vs. 4.1 +/- 1.0 * 109 cells, P < 0.05). The increase in blood product volume by this modification appeared to be lower than that expected with MNC mode. These data show that optimal harvesting can be achieved by modification of default collection settings. PMID- 28731277 TI - TNF-alpha-induced NF-kappaB activation promotes myofibroblast differentiation of LR-MSCs and exacerbates bleomycin-induced pulmonary fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and irreversible lung disease of unknown cause. It has been reported that both lung resident mesenchymal stem cells (LR-MSCs) and tumor necrosis factor-alpha (TNF-alpha) play important roles in the development of pulmonary fibrosis. However, the underlying connections between LR-MSCs and TNF-alpha in the pathogenesis of pulmonary fibrosis are still elusive. In this study, we found that the pro-inflammatory cytokine TNF-alpha and the transcription factor nuclear factor kappa B (NF kappaB) p65 subunit were both upregulated in bleomycin-induced fibrotic lung tissue. In addition, we discovered that TNF-alpha promotes myofibroblast differentiation of LR-MSCs through activating NF-kappaB signaling. Interestingly, we also found that TNF-alpha promotes the expression of beta-catenin. Moreover, we demonstrated that suppression of the NF-kappaB signaling could attenuate myofibroblast differentiation of LR-MSCs and bleomycin-induced pulmonary fibrosis which were accompanied with decreased expression of beta-catenin. Our data implicates that inhibition of the NF-kappaB signaling pathway may provide a therapeutic strategy for pulmonary fibrosis, a disease that warrants more effective treatment approaches. PMID- 28731278 TI - Knockdown of long non-coding RNA MEG3 protects H9c2 cells from hypoxia-induced injury by targeting microRNA-183. AB - Acute myocardial infarction (AMI) occurs when blood supply to the heart is diminished (ischemia) for long time, and ischemia is primarily caused due to hypoxia. This study evaluated the effects of long non-coding RNA maternally expressed gene 3 (MEG3) on hypoxic rat cardiomyocyte-drived H9c2 cells. Hypoxic injury was confirmed by alterations of cell viability, migration, invasion, apoptosis, and hypoxia-inducible factor 1alpha (HIF-1alpha) expression. MEG3 level in hypoxic cells and effects of its knockdown on hypoxic cells were assessed. The interactions between MEG3 and miR-183 as well as miR-183 and p27 were investigated. In addition, the effects of aberrantly expressed MEG3, miR 183, and p27 on hypoxic cells along with the activation of PI3K/AKT/FOXO3a signaling pathway were all assessed. Results showed that hypoxia induced decreases of cell viability, migration and invasion, and increases of apoptosis and expressions of HIF-1alpha and MEG3. Knockdown of MEG3 decreased hypoxia induced injury in H9c2 cells. Knockdown of MEG3 also increased miR-183 expression, which was identified as a target of MEG3. The effects of MEG3 knockdown on the hypoxic cells were reversed by miR-183 silence. p27 was identified as a target gene of miR-183, and its expression negatively regulated by miR-183. The mechanistic studies revealed that knockdown of p27 decreased hypoxia-induced H9c2 cell injury by activating PI3K/AKT/FOXO3a signal pathways. These findings suggest that knockdown of MEG3 alleviates hypoxia-induced H9c2 cell injury by miR-183-mediated suppression of p27 through activation of PI3K/AKT/FOXO3a signaling pathway. PMID- 28731279 TI - Influence of l-amino acids on aggregation and biofilm formation in Azotobacter chroococcum and Trichoderma viride. AB - AIM: The effects of l-amino acids on growth and biofilm formation in Azotobacter chroococcum (Az) and Trichoderma viride (Tv) as single (Az, Tv) and staggered inoculated cultures (Az-Tv, Tv-Az) were investigated. METHODS AND RESULTS: A preliminary study using a set of 20 l-amino acids, identified 6 amino acids (l Glu, l-Gln, l-His, l-Ser, l-Thr and l-Trp) which significantly enhanced growth and biofilm formation. Supplementation of these amino acids at different concentrations revealed that 40 mmol l-1 was most effective. l-Glu and l-Gln favoured planktonic growth in both single and in staggered inoculated cultures, while l-Trp and l-Thr, enhanced aggregation and biofilm formation. Addition of l Glu or l-Gln increased carbohydrate content and planktonic population. Principal component analysis revealed the significant role of proteins in growth and biofilm formation, particularly with supplementation of l-Trp, l-Thr and l-Ser. Azotobacter was found to function better as biofilm under staggered inoculated culture with Trichoderma. CONCLUSIONS: The results illustrate that amino acids play crucial roles in microbial biofilm formation, by influencing growth, aggregation and carbohydrates synthesized. SIGNIFICANCE AND IMPACT OF THE STUDY: The differential and specific roles of amino acids on biofilm formation are of significance for agriculturally important micro-organisms that grow as biofilms, colonize and benefit the plants more effectively. PMID- 28731280 TI - Methodologies and approaches for the analysis of cell-nanoparticle interactions. AB - How to study nanoparticle-cell interactions is the key question that puzzles researchers in the fields of nanomedicine as well as in nanotoxicology. In nanotoxicology, the amount of nanoparticles internalized by the cells or bound to the external surfaces of cells determines the toxic profile of those particles. In medical applications, cellular uptake and binding of medically effective nanoparticles decides their efficacy. Despite the importance of understanding the extent and mode of nanoparticle-cell interactions, these processes are underinvestigated, mainly due to the lack of suitable user-friendly methodologies. Here we discuss the advantages and limitations of currently available (and most advanced) microscopic, spectroscopic, and other bioanalytical methods that could be used to assess cell-nanoparticle interactions either qualitatively or quantitatively. Special emphasis is given to the methods that enable analysis and identification of nanoparticles at single-cell level, and allow intracellular localization and speciation analysis of nanoparticles. This article is categorized under: Nanotechnology Approaches to Biology > Cells at the Nanoscale Toxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials. PMID- 28731281 TI - Glycaemia control and the risk of hospitalisation for infection in patients with type 2 diabetes: Hong Kong Diabetes Registry. AB - BACKGROUND: Infection occurs more commonly in diabetic patients compared with the general population and is an under-recognised but important morbidity in patients with diabetes. We examined the impact of glycaemic control on hospitalisation for infection in a large prospective cohort of Chinese adults with type 2 diabetes. METHODS: Between July 1994 and June 2014, 22 846 patients with type 2 diabetes underwent detailed assessment of metabolic control and diabetes complications. Patients were followed for occurrence of infection requiring hospitalisation as identified using discharge diagnosis codes. RESULTS: Over a median follow-up of 4.8 years, 20.3% of patients were hospitalised for any infection type, with respiratory tract, genitourinary tract, and skin being the most commonly affected sites. In multivariate Cox regression, time-dependent HbA1c was associated with all-site infection (hazard ratio [HR] 1.07 [95% confidence interval {CI}:1.05 1.09, P < 0.001]), genitourinary tract infection (HR 1.09 [95% CI: 1.04-1.14], P < 0.001), and skin infection (HR 1.16 [95% CI 1.12-1.21]. P < 0.001), but not infection of respiratory tract, and was independent of age, gender, disease duration, smoking, body mass index, glomerular filtration rate, haemoglobin, history of stroke, congestive heart failure, coronary heart disease, peripheral artery disease, diabetic neuropathy and cancer, and baseline drug use. Against an arbitrary HbA1c interval of >7.0-8.0% (53-64 mmol/mol), patients with HbA1c <=6.0% (42 mmol/mol) and >8.0% (64 mmol/mol) had excess risks of infection related hospitalisation adjusted for other factors. CONCLUSIONS: In patients with type 2 diabetes, burden of serious infection is high. In the diabetic population, a U-shape relationship between glycaemia and infection-related hospitalisation was detected. PMID- 28731282 TI - Altered signaling associated with chronic arsenic exposure in human skin keratinocytes. AB - Modulation of signaling pathways upon chronic arsenic exposure remains poorly studied. Here, we carried out SILAC-based quantitative phosphoproteomics analysis to dissect the signaling induced upon chronic arsenic exposure in human skin keratinocyte cell line, HaCaT. We identified 4171 unique phosphosites derived from 2000 proteins. We observed differential phosphorylation of 406 phosphosites (twofold) corresponding to 305 proteins. Several pathways involved in cytoskeleton maintenance and organization were found to be significantly enriched (p<0.05). Our data revealed altered phosphorylation of proteins associated with adherens junction remodeling and actin polymerization. Kinases such as protein kinase C iota type (PRKCI), mitogen-activated protein kinase kinase kinase 1 (MAP3K1), tyrosine-protein kinase BAZ1B (BAZ1B) and STE20 like kinase (SLK) were found to be hyperphosphorylated. Our study provides novel insights into signaling perturbations associated with chronic arsenic exposure in human skin keratinocytes. All MS/MS data have been deposited to the ProteomeXchange with identifier PXD004868. PMID- 28731283 TI - Covalent Functionalization of Graphene by Nucleophilic Addition Reaction: Synthesis and Optical-Limiting Properties. AB - Covalent functionalization of reduced graphene oxide (rGO) was performed by using conjugated polymers with different monomers through nucleophilic addition of nitrogen anions to rGO. Three conjugated polymers containing tetraphenylethylene, carbazole, and phenyl groups were used, and as a result of pi-pi interactions and the "polymer-wrapping" effect, the dispersion stability of rGO was improved. Even if the reaction site in the polymers was the same, there were great differences in the reactivities of the polymers, the dispersion stabilities of the resultant composites, and also the optical limiting (OL) performances of the resultant composites. The differences may be attributed to the pi-conjugated structure and steric hindrance of the moiety in the polymer skeleton, which has scarcely been reported. Besides, the resultant rGO-P1 and rGO-P3 materials both showed excellent OL responses, even at 4 MUJ. This behavior should enable their potential application in photonic and optoelectronic devices to protect human eyes or optical sensors from damage by intense laser irradiation. PMID- 28731284 TI - The RNA-binding protein HuR inhibits expression of CCL5 and limits recruitment of macrophages into tumors. AB - The RNA-binding protein HuR promotes tumor growth by affecting proliferation, metastasis, apoptosis, and angiogenesis. Although immune cells, especially tumor associated macrophages, are critical components of the tumor stroma, the influence of HuR in tumors on the recruitment of immune cells remains poorly understood. In the present study, we, therefore, aimed to elucidate the impact of tumor cell HuR on the interaction between tumor cells and macrophages. To this end, we stably depleted HuR in human MCF-7 breast cancer cells. We found that HuR deficient cells not only showed reduced proliferation, they further expressed elevated levels of the chemokine CCL5. HuR-dependent repression of CCL5 was neither caused by altered CCL5 mRNA stability, nor by changes in CCL5 translation. Instead, loss of HuR augmented transcription of CCL5, which was mediated via an interferon-stimulated response element in the CCL5 promoter. Furthermore, HuR depletion enhanced macrophage recruitment into MCF-7 tumor spheroids, an effect which was completely lost upon neutralization of CCL5. HuR expression further negatively correlated with CCL5 expression and macrophage appearance in a cohort of breast tumors. Thus, while HuR is well-characterized to support various pro-tumorigenic features in tumor cells, we provide evidence that it limits the recruitment of macrophages into tumors by repressing CCL5. As macrophage infiltration is associated with poor prognosis, our findings underline the highly cell-type and context specific role of HuR in tumorigenesis. PMID- 28731285 TI - Plant infection by two different viruses induce contrasting changes of vectors fitness and behavior. AB - Insect-vectored plant viruses can induce changes in plant phenotypes, thus influencing plant-vector interactions in a way that may promote their dispersal according to their mode of transmission (i.e., circulative vs. noncirculative). This indirect vector manipulation requires host-virus-vector coevolution and would thus be effective solely in very specific plant-virus-vector species associations. Some studies suggest this manipulation may depend on multiple factors relative to various intrinsic characteristics of vectors such as transmission efficiency. In anintegrative study, we tested the effects of infection of the Brassicaceae Camelina sativa with the noncirculative Cauliflower mosaic virus (CaMV) or the circulative Turnip yellows virus (TuYV) on the host plant colonization of two aphid species differing in their virus transmission efficiency: the polyphagous Myzus persicae, efficient vector of both viruses, and the Brassicaceae specialist Brevicoryne brassicae, poor vector of TuYV and efficient vector of CaMV. Results confirmed the important role of virus mode of transmission as plant-mediated effects of CaMV on the two aphid species induced negative alterations of feeding behavior (i.e., decreased phloem sap ingestion) and performance that were both conducive for virus fitness by promoting dispersion after a rapid acquisition. In addition, virus transmission efficiency may also play a role in vector manipulation by viruses as only the responses of the efficient vector to plant-mediated effects of TuYV, that is, enhanced feeding behavior and performances, were favorable to their acquisition and further dispersal. Altogether, this work demonstrated that vector transmission efficiency also has to be considered when studying the mechanisms underlying vector manipulation by viruses. Our results also reinforce the idea that vector manipulation requires coevolution between plant, virus and vector. PMID- 28731286 TI - Impact of Fluorine Atoms on Perylene Diimide Derivative for Fullerene-Free Organic Photovoltaics. AB - The incorporation of fluorine atoms in organic semiconducting materials has attracted much attention recently due to its unique function to manipulate the molecular packing, film morphology and molecular energy levels. In this work, two perylenediimide (PDI) derivatives FPDI-CDTph and FPDI-CDTph2F were designed and synthesized to investigate the impact of fluorination on non-fullerene acceptors. Both FPDI-CDTph and FPDI-CDTph2F exhibited strong and broad absorption profiles, suitable lowest unoccupied molecular orbital (LUMO) and highest occupied molecular orbital (HOMO) energy levels, and good electron transport ability. Compared with FPDI-CDTph, the fluorinated acceptor (FPDI-CDTph2F) afforded an optimal bulk heterojunction morphology with an interconnected and nanoscale phase separated structure that allowed more efficient exciton dissociation and balanced charge transport. Consequently, organic solar cells based on FPDI-CDTph2F showed a much higher power conversion efficiency (PCE) of 6.03 % than that of FPDI-CDTph based devices (4.10 %) without any post-fabrication treatment. PMID- 28731287 TI - Tricetin suppresses human oral cancer cell migration by reducing matrix metalloproteinase-9 expression through the mitogen-activated protein kinase signaling pathway. AB - Tricetin is a flavonoid derivative and a potent anti-inflammatory and anticancer agent. However, the molecular mechanism underlying the effects of tricetin on human oral cancer cell migration remains unclear. The cell migration and invasion abilities of three oral cancer cell lines (SCC-9, HSC-3, and OECM-1) were analyzed using Boyden chamber migration assays. Our results demonstrated that tricetin attenuates 12-O-tetradecanoylphorbol-13-acetate-induced SCC-9, HSC-3, and OECM-1 cell invasiveness and migration by reducing matrix metalloproteinase (MMP)-9 enzyme activity. The reverse transcription polymerase chain reaction and luciferase reporter assay revealed that tricetin downregulates the mRNA expression and promoter activity of MMP-9. In addition, Western blot analysis revealed that tricetin significantly reduced the levels of phosphorylated c-Jun N terminal kinase (JNK) 1/2 and p38 levels but not those of extracellular signal regulated kinase 1/2. In conclusion, this study demonstrated that tricetin suppresses MMP-9 enzymatic activity by downregulating the p38/JNK1/2 pathway and might be a beneficial chemopreventive agent. PMID- 28731288 TI - Radiation therapists' perspectives on participating in research. AB - INTRODUCTION: The objectives of this research were to: (1) determine the extent of Australian radiation therapists (RTs) research participation; (2) evaluate the impact of research involvement on career perceptions (3) explore which research topics require investigation and (4) identify benefits and barriers to research participation. METHODS: This study used mixed methods to collect qualitative and quantitative data using an online survey from a larger workforce study of RTs and radiation oncology medical physicists. Participants practising in Australia completed questions about their research involvement. Chi-square tests and logistic regression were used to analyse quantitative data and content analysis was used to explore qualitative data. RESULTS: Two hundred and ninety-six RTs answered the research questions. Forty-six percent had been involved in research. Of these, 91% had been involved in departmental, 28% in national, 14% in international and 29% in informal or self-directed research studies. Eleven RTs (8%) had received funding as a chief/principal investigator. Involvement in research was associated with a desire to make a career change. However, it also appeared to be associated with greater satisfaction with career progression and staying in the career. Respondents identified a range of potential research topics, benefits of participating in research and barriers which included lack of time, support and cost. CONCLUSION: Almost half of the RT participants identified that they were participating in research. Our data suggest that continued involvement in research, and opportunities to participate, improve RT job satisfaction. RTs' research activities are likely to be extended through provision of additional time and support. PMID- 28731289 TI - Current status of achieving blood pressure target and its clinical correlates in Japanese type 2 diabetes. AB - AIMS/INTRODUCTION: To investigate the current status of achieved blood pressure levels in association with the number of antihypertensive drug classes as of 2013, and to explore the clinical correlates with achievement of target blood pressure in a large-scale cohort of Japanese subjects with type 2 diabetes. MATERIALS AND METHODS: A nationwide survey was conducted including 12,811 subjects with type 2 diabetes. Subjects were divided by achieved blood pressure, <130/80 or 140/90 mmHg, and the number of drug classes taken. RESULTS: The percentages achieving a blood pressure of <130/80 or 140/90 mmHg were 52.0% and 86.1%, respectively. The prevalence of hypertension, if defined as >=130/80 mmHg or treated, became 67.9%. Among subjects taking antihypertensive drugs, a blood pressure of <130/80 or <140/90 mmHg was 46.7% and 83.2%, respectively. The percentages of <130/80 mmHg were 55.9% without drugs, 47.1% on 1, 42.5% on 2, 47.2% on 3, and 56.8% on >=4 drugs, respectively. The most prescribed drugs were renin-angiotensin system inhibitors, followed by calcium channel blockers, diuretics, and beta-blockers. The multiple logistic regression analysis indicated that a blood pressure <130/80 mmHg was associated with lower values in age, body mass index, albuminuria, and glomerular filtration rate, higher proportions on targets for HbA1C and lipids, and less retinopathy. CONCLUSIONS: In type 2 diabetes, hypertension is common and only 52% achieved <130/80 mmHg, indicating a difficulty in blood pressure lowering. This was correlated with difficulties in glycemic and lipid management, obesity, and vascular complications, implying these clustering to be a serious problem. This article is protected by copyright. All rights reserved. PMID- 28731290 TI - Autoantibodies against PFDN2 are associated with an increased risk of type 2 diabetes: A case-control study. AB - BACKGROUND: The adaptive immune system is involved in type 2 diabetes mellitus (T2DM), indicating the presence of unidentified autoantibodies that might be useful biomarkers for emerging immunomodulatory therapy. A prior microarray study with a small number of participants suggested the association of novel autoantibodies with T2DM in Southwest American Indians. We therefore sought to determine whether antibodies against 14 target proteins are associated with T2DM in a large case-control study. METHODS: Participants were adults (age 20-59 y) of Southwest American Indian heritage. Plasma antibodies against 14 possible target proteins were measured in 476 cases with T2DM of less than 5 years duration and compared with 424 controls with normal glucose regulation. RESULTS: Higher levels of antibodies against prefoldin subunit 2 (PFDN2) were associated with T2DM (P = .0001; Bonferroni-corrected threshold for multiple tests = 0.0036 [alpha = 0.05]). The association between anti-PFDN2 antibodies and T2DM remained in multivariable logistic regression (odds ratio 1.27; 95% confidence interval, 1.09 1.49; per one SD difference in anti-PFDN2 antibody). The odds of T2DM were increased in the highest anti-PFDN2 antibody quintile by 66% compared with the lowest quintile. Differences in anti-PFDN2 antibodies were most prominent among cases with earlier onset of disease (ie, age 20-39 y) compared with controls. CONCLUSIONS: Anti-PFDN2 antibodies are associated with T2DM and might be a useful biomarker. These findings indicate that autoimmunity may play a role in T2DM in Southwest American Indians, especially among adults presenting with young onset of disease. PMID- 28731291 TI - Critical questions: Advancing the health of female Veterans. AB - PURPOSE: Women are the fastest growing Veteran population in the United States and many receive all or part of their health care outside of the Department of Veterans Affairs (VA). The purpose of this article is to review the healthcare issues of women Veterans and discuss implications for care. DATA SOURCES: Review of selected literature, VA resources and guidelines, and expert opinion. CONCLUSIONS: Few providers are aware of the impact military service has on the health of women and fail to ask the all-important question, "Have you served in the military?" Recognizing women's military service can reveal important information that can answer perplexing clinical questions, aid in designing comprehensive plans of care, and enable women to receive the assistance needed to address complex physical and psychosocial issues to improve the quality of their lives. IMPLICATIONS FOR PRACTICE: There are gender disparities related to physical health conditions, mental health issues, environmental exposures, and socioeconomic factors that contribute to female Veterans' vulnerabilities. Many of the health conditions, if recognized in a timely manner, can be ameliorated and shift the health trajectory of this population. Clinicians play a critical role in identifying health risk and helping female Veterans start the sometimes arduous journey toward wellness. Discovering and acknowledging women's military history is critical in ensuring quality care and appropriate decision making. PMID- 28731292 TI - Retraction: 'Attitudes on intimate touch during nursing care in China' by Nan Lu, Xiaoyan Gao and Shuang Zhang. PMID- 28731293 TI - The influence of resilience on mental health: The role of general well-being: Methodological issues to avoid prediction fallacy in a cross-sectional study. PMID- 28731294 TI - The Bioinorganic Chemistry of Lead in the Context of Its Toxicity. AB - Owing to its abundance on earth and its multiple uses by humans, lead (Pb) is a major toxicant that has threatened human health for millennia and continues to do so. There is no safe level of exposure, necessitating a nuanced approach to its control in the food we consume, the water we drink, and the air we breathe. Turnover in soft tissues is within days. In contrast, lead accumulates in bone and turns over with a half-life of about 30 years, though it can be mobilized from bone under physiological and pathophysiological conditions of bone resorption. Children are particularly vulnerable to lead exposure and suffer irreversible neurological deficits affecting learning ability and behavior. In adults, chronic effects of exposure to lead include elevated blood pressure, development of cancers, and, as suggested more recently, neurodegeneration. Some pathways of systemic and cellular metabolism of Pb(II) are known. However, except for its action in delta-aminolevulinate dehydratase, its molecular toxicology remains largely speculative in terms of specific targets. One major molecular mechanism seems to be the replacement of zinc with lead in zinc proteins with functional consequences. Calcium binding proteins are also being discussed as possible targets. However, the affinities of lead for calcium sites in proteins are orders of magnitude lower than those for zinc sites. Therefore, it remains to be shown whether lead at the concentrations occurring in tissues can replace calcium in proteins in vivo. Despite humans having recognized the hazards of lead exposure for a very long time, uncertainties remain as to the threshold for adverse effects on our health and the low levels of exposure during our lives as a risk factor for chronic disease. PMID- 28731295 TI - Biogeochemistry of Lead. Its Release to the Environment and Chemical Speciation. AB - Lead (Pb) is a metal that is not essential for life processes and proves acutely toxic to most organisms. Compared to other metals Pb is rather immobile in the environment but still its biogeochemical cycling is greatly perturbed by human activities. In this review we present a summary of information describing the physical and chemical properties of Pb, its distribution in crustal materials, and the processes, both natural and anthropogenic, that contribute to the metal's mobilization in the biosphere. The relatively high volatility of Pb metal, low melting point, its large ionic radius, and its chemical speciation in aquatic systems contributes to its redistribution by anthropogenic and natural processes. The biogeochemical cycle of Pb is significantly altered by anthropogenic inputs. This alteration began in antiquity but accelerated during the industrial revolution, which sparked increases in both mining activities and fossil fuel combustion. Estimates of the flux of Pb to the atmosphere, its deposition and processing in soils and freshwater systems are presented. Finally, the basin scale distribution of dissolved Pb in the ocean is interpreted in light of the chemical speciation and association with inorganic and organic particulate matter. The utility of stable radiogenic Pb isotopes, as a complement to concentration data, to trace inputs to the ocean, better understand the biogeochemical cycling of Pb and track water mass circulation in the ocean is discussed. An ongoing international survey of trace elements and their isotopes in seawater will undoubtedly increase our understanding of the deposition, biogeochemical cycling and fate of this infamous toxic metal. PMID- 28731296 TI - Analytical Methods for the Determination of Lead in the Environment. AB - A survey of the methods for the determination of lead in environmental samples is given. These are mainly based on sensitive atomic spectrometry, but alternatives, such as electrochemical and separation methods are also possible. Discussed are also sample preparation and speciation for differentiation between different organometallic forms as well as applications of isotope-selective determinations. PMID- 28731297 TI - Smart Capsules for Lead Removal from Industrial Wastewater. AB - Ground and especially drinking water could be contaminated by heavy metal ions such as lead and chromium, or the metalloid arsenic, discarded from industrial wastewater. These heavy metal ions are regarded as highly toxic pollutants which could cause a wide range of health problems in case of a long-term accumulation in the body. Thus, there have been many efforts to reduce the concentration of lead ions in effluent wastewater. They have included the establishment of stringent permissible discharge levels and management policies, the application of various pollution-control technologies, and the development of adsorbent materials for lead reduction. According to Science [1] encapsulation, developed approximately 65 years ago, has been defined as a major interdisciplinary research technology. Encapsulation has been used to deliver almost everything from advanced drugs to unique consumer sensory experiences. In this chapter we review the art of encapsulation technology as a potential breakthrough solution for a recyclable removal system for lead ions. Moreover, in order to provide the readers with a comprehensive and in-depth understanding of recent developments and innovative applications in this field, we highlight some remarkable advantages of encapsulation for heavy metal remove, such as simplicity of preparation, applicability for a wide range of selective extractants, large special interfacial area, ability for concentration of metal ions from dilute solutions, and less leakage of harmful components to the environment. PMID- 28731298 TI - Lead Speciation in Microorganisms. AB - The biogeochemical cycles of lead (Pb) have been largely affected by anthropogenic activities as a result of its high natural abundance and use over the centuries [1]. At sites more strongly impacted by urbanization [2] and mining [3], Pb is found at high nano to low micromolar concentrations in surface waters, and can be significantly higher in soil and sediment [4]. Microorganisms are found everywhere and their responses to Pb exposure can range from resistant to highly sensitive [5, 6]. These varying levels of toxicity can be attributed to the cellular handling of Pb, making it important to understand the role of intracellular Pb speciation for more accurate toxicity predictions. PMID- 28731299 TI - Human Biomonitoring of Lead Exposure. AB - After a chronic exposure, lead accumulates in the human body, especially in bones and teeth. Critical effects of lead affect the nervous system, reproduction, fertility as well as genotoxicity and carcinogenicity [1]. Analyses of lead concentrations in human biological material are performed using inductively coupled plasma mass spectrometry and atomic absorption spectrometry, but also electrochemical methods and X-ray fluorescence spectroscopy. The predominant sample matrices include blood and bone, as well as urine, hair, nail, and saliva. To characterize first biological effects, diverse parameters are discussed as "biomarkers of effect". These include delta-aminolevulinic acid dehydratase (ALAD) and erythrocyte porphyrins (EPs) in blood as well as delta-aminolevulinic acid (ALA) in urine and plasma and coproporphyrin in urine. However, biomarkers of effect alone are not sufficiently sensitive for an early detection of a health impairment caused by lead. In summary, lead in blood is the most prominent and best validated biomarker for a lead exposure. A recommended diagnostic strategy for revealing lead-induced effects is the determination of lead in whole blood combined with the analysis of different effect parameters like ALA and coproporphyrin in urine and ALAD and zinc protoporphyrin (ZPP) in blood. PMID- 28731300 TI - Solid State Structures of Lead Complexes with Relevance for Biological Systems. AB - Structural information on the interaction between lead ion and its targeting biological substances is important not only for enriching coordination chemistry of lead but for successfully treating lead poisoning that is a present-day problem. This chapter provides structural data, mainly metal binding sites/modes, observed in crystal structures of lead complexes with biorelevant molecules, obtained from the Cambridge Structural Database (the CSD version 5.36 updated to May 2015) and the Protein Data Bank (PDB updated to February 2016). Ligands include (i) amino acids and small peptides, (ii) proteins, (iii) nucleic acid constituents, (iv) nucleic acids, (v) simple saccharides, and (vi) other biorelevant molecules involving lead-detoxification agents. For representative complexes of these ligands, some details on the environment of the metal coordination and structural characteristics are described. PMID- 28731301 TI - Lead(II) Complexes of Amino Acids, Peptides, and Other Related Ligands of Biological Interest. AB - Lead(II) forms (NH2,COO-)-chelated mono- and bis-complexes with simple amino acids, while mono-complexes with pH-dependent coordination modes exist with simple dipeptides. These mostly hemidirected complexes have moderate stability. While a weak interaction of side chain imidazole and carboxylate in lead(II) aminoacidato complexes is found, the thiolate group has an exceptionally high affinity to this metal ion. For example, tridentate (NH2,COO-,S-)-coordination of penicillamine (Pen) and cysteine (Cys) results in an extremely strong interaction with lead(II), but, owing to the sterical effect of the 6s2 pair, a second ligand is not able to coordinate in the above mentioned tridentate way. Although there is no example for a lead(II)-induced deprotonation and coordination of a peptide amide and the side-chain thiolate in oligopeptides has a somewhat lower basicity compared to that of Pen or Cys, still the Cys-containing peptides interact rather strongly with lead(II). Interestingly, the position of Cys in the peptide influences significantly both the lead-binding ability via different bonding modes and the selectivity for lead(II) against other metal ions, like zinc(II) or cadmium(II). At high ligand excess, however, coordination of three sulfur donors to lead(II) is found with thiolate-containing amino acids and oligopeptides. High basicity oxygens of hydroxamates, hydroxypyronates, and hydroxypyridinonates are also effective lead-binding donors. Some factors affecting the complexation of these ligands with lead(II) are: (i) A larger extent of delocalization along the ring in hydroxypyridinonate results in a more favored metal-binding ability over hydroxypyronate. (ii) Even monohydroxamates are good ligands and form mono- and bis-complexes with lead(II). (iii) In general, dihydroxamates and trihydroxamate based siderophores, like desferrioxamine B (DFB) and desferricoprogen (DFC), are better binding agents for Pb(II) than the monohydroxamates, but the length and structure of linkers connecting the hydroxamate moieties have a significant impact on the complexation and selectivity for lead(II). (iv) The corresponding thio derivatives are significantly better ligands for lead than their parent oxo molecules, but polymeric complexes with poor water solubility are formed in most cases. (v) Out of the hydroxamate derivatives of amino acids the alpha-ones are the most effective ligands, provided polynuclear species involving the hydroxamate-oxygens, amino-N and hydroxamate-N can be formed. PMID- 28731302 TI - Lead(II) Binding in Metallothioneins. AB - Heavy metal exposure has long been associated with metallothionein (MT) regulation and its functions. MT is a ubiquitous, cysteine-rich protein that is involved in homeostatic metal response for the essential metals zinc and copper, as well as detoxification of heavy metals; the most commonly proposed being cadmium. MT binds in vivo to a number of metals in addition to zinc, cadmium and copper, such as bismuth. In vitro, metallation with a wide range of metals (especially mercury, arsenic, and lead) has been reported using a variety of analytical methods. To fully understand MT and its role with lead metabolism, we will describe how MT interacts with a wide variety of metals that bind in vitro. In general, affinity to the metal-binding cysteine residues of MT follows that of metal binding to thiols: Zn(II) < Pb(II) < Cd (II) < Cu(I) < Ag(I) < Hg(II) < Bi(III). To introduce the metal binding properties that we feel directly relate to the metallation of metallothionein by Pb(II), we will explore MT's interactions with metals long known as toxic, particularly, Cd(II), Hg(II), and As(III), along with xenobiotic metals, and how these metal-binding studies complement those of lead binding. Lead's effects on an organism's physiological functions are not fully understood, but it is known that chronic exposure inflicts amongst other factors pernicious anemia and developmental issues in the brain, especially in children who are more vulnerable to its toxic effects. Understanding the interaction of lead with metallothioneins throughout the biosphere, from bacteria, to algae, to fish, to humans, is important in determining pathways for lead to enter and damage physiologically significant protein function, and thereby its toxicity. PMID- 28731304 TI - Complex Formation of Lead(II) with Nucleotides and Their Constituents. AB - Lead is widely distributed in the environment; it is known to mankind for thousands of years and its toxicity is nowadays (again) well recognized, though on the molecular level only partly understood. One of the reasons for this shortcoming is that the coordination chemistry of the biologically important lead(II) is complicated due to the various coordination numbers it can adopt (CN = 4 to 10) as well as by the 6s2 electron lone pair which, with CN = 4, can shield one side of the Pb2+ coordination sphere. The chapter focuses on the properties of Pb2+ complexes formed with nucleotides and their constituents and derivatives. Covered are (among others) the complexes formed with hydroxy groups and sugar residues, the interactions with the various nucleobases occurring in nucleic acids, as well as complexes of phosphates. It is expeced that such interactions, next to those like with lipids and proteins, are responsible for the toxic properties of lead. To emphasize the special properties of Pb2+ complexes, these are compared as far as possible with the corresponding properties of the Ca2+, Fe2+, Cu2+, Zn2+, and Cd2+ species. It needs to be mentioned that the hard-soft rule fails with Pb2+. This metal ion forms complexes with ligands offering O donors of a stability comparable to that of Cu2+. In contrast, with aromatic N ligands, like imidazole or N7 sites of purines, complex stability is comparable to that of the corresponding Fe2+ complexes. The properties of Pb2+ towards S donor sites are difficult to generalize: On the one hand Pb2+ forms very stable complexes with nucleoside 5'-O-thiomonophosphates by coordinating to nearly 100% at S in the thiophosphate group; however, on the other hand, once a sulfur atom replaces one of the terminal oxygen atoms in the phosphodiester linkage, macrochelate formation of the phosphate-bound Pb2+ occurs with the O and not the S site. Quite generally, the phosphodiester linkage is a relatively weak binding site, but the affinity increases further to the mono- and then to the di- and triphosphate. The same holds for the corresponding nucleotides, though the Pb2+ affinity had to be estimated via that of the Cu2+ complexes for some of these ligands. Complex stability of the pyrimidine nucleotides (due to their anti conformation) is solely determined by the coordinating tendency of the phosphate group(s); this also holds for the Pb2+ complex of adenosine 5'-monophosphate. For the other purinenucleotides macrochelate formation takes place by the interaction of the phosphate coordinated Pb2+ with the N7/(C6)O site of, e.g., the guanine residue. The extents of the formation degrees of these chelates are summarized. Unfortunately, information about mixed ligand (ternary) or other higher order comlexes is missing, but still it is hoped that the present overview will help to understand the interaction of Pb2+ with nucleotides and nucleic acids, and especially that it will facilitate further research in this fascinating area. PMID- 28731305 TI - The Role of Lead(II) in Nucleic Acids. AB - Although lead(II) is naturally not associated with nucleic acids, this metal ions has been applied with DNA and RNA in various contexts. Pb2+ is an excellent hydrolytic metal ion for nucleic acids, which is why it is mainly used as probing agent for secondary structure and to determine metal ion binding sites both in vitro and in vivo. A further application of lead(II) is in structural studies, i.e., NMR, but also in X-ray crystallography, mostly using this heavy metal to solve the phase problem in the latter method. The structures of tRNAPhe, RNase P, HIV-1 DIS, and the leadzyme are discussed here in detail. A major part of this review is devoted to the cleavage properties of lead(II) with RNA because of its excellence in catalyzing phosphodiester cleavage. Metal ion binding sites in large naturally occurring ribozymes are regularly determined by Pb2+ cleavage, and also in the in vitro selected socalled leadzyme, this metal ion is the decisive key to backbone cleavage at a specific site. Lead(II) was used in the first in vitro selection that yielded a catalytic DNA, i.e., the DNAzyme named GR5. Next to the GR5, the so-called 8-17E is the second most prominent DNAzyme today. Derivatives of these two lead(II)-dependent DNAzymes, as well as the G quadruplex forming PS2.M have been applied to detect lead(II) in the lower nanomolar range not only in the test tube but also in body fluids. Due to the toxicity of lead(II) for living beings, this is a highly active research field. Finally, further applications of lead(II)-dependent DNAzymes, e.g., in the construction of nanocomputers, are also discussed. PMID- 28731303 TI - Lead(II) Binding in Natural and Artificial Proteins. AB - This article describes recent attempts to understand the biological chemistry of lead using a synthetic biology approach. Lead binds to a variety of different biomolecules ranging from enzymes to regulatory and signaling proteins to bone matrix. We have focused on the interactions of this element in thiolate-rich sites that are found in metalloregulatory proteins such as Pbr, Znt, and CadC and in enzymes such as delta-aminolevulinic acid dehydratase (ALAD). In these proteins, Pb(II) is often found as a homoleptic and hemidirectic Pb(II)(SR)3- complex. Using first principles of biophysics, we have developed relatively short peptides that can associate into three-stranded coiled coils (3SCCs), in which a cysteine group is incorporated into the hydrophobic core to generate a (cysteine)3 binding site. We describe how lead may be sequestered into these sites, the characteristic spectral features may be observed for such systems and we provide crystallographic insight on metal binding. The Pb(II)(SR)3- that is revealed within these alpha-helical assemblies forms a trigonal pyramidal structure (having an endo orientation) with distinct conformations than are also found in natural proteins (having an exo conformation). This structural insight, combined with 207Pb NMR spectroscopy, suggests that while Pb(II) prefers hemidirected Pb(II)(SR)3- scaffolds regardless of the protein fold, the way this is achieved within alpha-helical systems is different than in beta-sheet or loop regions of proteins. These interactions between metal coordination preference and protein structural preference undoubtedly are exploited in natural systems to allow for protein conformation changes that define function. Thus, using a design approach that separates the numerous factors that lead to stable natural proteins allows us to extract fundamental concepts on how metals behave in biological systems. PMID- 28731306 TI - Historical View on Lead: Guidelines and Regulations. AB - Lead has been used in many commodities for centuries. As a result, human exposure has occurred through the production and use of these lead-containing products. For example, leaded gasoline, lead-based paint, and lead solder/pipes in water distribution systems have been important in terms of exposure potential to the general population. Worker exposures occur in various industrial activities such as lead smelting and refining, battery manufacturing, steel welding or cutting operations, printing, and construction. Some industrial locations have also been a source of exposure to the surrounding communities. While the toxicity of relatively high lead exposures has been recognized for centuries, modern scientific studies have shown adverse health effects at very low doses, particularly in the developing nervous system of fetuses and children. This chapter reflects on historical and current views on lead toxicity. It also addresses the development and evolution of exposure prevention policies. As discussed here, these lead policies target a variety of potential exposure routes and sources. The changes reflect our better understanding of lead toxicity. The chapter provides lead-related guidelines and regulations currently valid in the U. S. and in many countries around the world. The reader will learn about the significant progress that has been made through regulations and guidelines to reduce exposure and prevent lead toxicity. PMID- 28731307 TI - Environmental Impact of Alkyl Lead(IV) Derivatives: Perspective after Their Phase out. AB - The use of alkyl lead derivatives as antiknock agents in gasoline can be considered as one of the main pollution disasters of the 20th century because of both the global character of the pollution emitted and the seriousness of the impact on human health. Alkyl lead derivatives in themselves cannot be considered to be persistent pollutants because they readily degrade either before being released from the tailpipes or soon afterwards in the atmosphere. However, the inorganic lead they produced has been deposited in soils all over the planet, largely, but not exclusively in urban areas and along motorways, since the direct emission of lead into the atmosphere favored its dispersal over great distances: The signal of the massive use of alkyl lead derivatives has been found all over the world, including in remote sites such as polar areas. The short residence time of lead in the atmosphere implies that this compartment is highly responsive to changes in emissions. This was demonstrated when leaded gasoline was phased out and is in striking contrast to the very long permanence of inorganic lead in soils, where resuspension is a permanent source of toxic lead. PMID- 28731308 TI - Lead Toxicity in Plants. AB - This review looks critically at the relevance of lead (Pb2+) toxicity and proposed mechanisms of Pb2+ -induced stress in algae and higher plants. As a basis, the current main sources of Pb2+ contamination in the environment are presented, which include agriculture, industry, and road traffic. Further, bioavailability of lead is discussed as a basis for evaluating the environmental relevance of the many studies on lead toxicity that have been published in the past decades. These studies suggest three main mechanisms of toxicity of Pb2+: inhibition of photosynthesis, oxidative stress, and "genotoxicity" including DNA damage and defects in mitosis. Looking at the applied concentration ranges in these studies reveals that likely the defects in mitosis are the environmentally most relevant effects. In contrast, inhibition of photosynthetic light reactions is far less efficient with Pb2+ compared to other metal ions, so that for Pb2+ toxicity it seems environmentally not relevant. As a conclusion and outlook, a direction of future studies towards establishment of reliable concentration thresholds of the various toxic effects and their causal interconnection is suggested. PMID- 28731309 TI - Toxicology of Lead and Its Damage to Mammalian Organs. AB - The toxicity of lead has been appreciated for centuries. Lead is a commonly used metal in industrialized nations, which results in the release of lead into the environment. Governmental agencies regulate the amount of lead permissible for workers to be exposed to; however, unregulated environmental lead exposure is a high concern. While essential metals have physiologic roles, there are no health benefits from lead intake. In this chapter, we discuss sources of lead exposure, the absorption, distribution, and elimination of lead from the human body, and molecular mechanisms of lead-induced toxicity. We also discuss the evidence on the association between lead exposure and blood pressure, and the influence of sociodemographic, lifestyle and environmental determinants of lead exposure in the general population. We highlight the effects on the nervous system, kidney, immune system, blood, reproductive system, and bones. PMID- 28731310 TI - Erratum PMID- 28731311 TI - Erratum PMID- 28731312 TI - Gentiana kurroo Royle attenuates the metabolic aberrations in diabetic rats; Swertiamarin, swertisin and lupeol being the possible bioactive principles. AB - Background Gentiana kuroo Royle is a medicinally important plant of north-western Himalayas used for various ailments. In the present study, the plant extracts were investigated for the antidiabetic effects in streptozotocin-induced diabetic rats. Methods The impact of the extracts on serum glucose levels of diabetic rats was compared with reference drug - glibenclamide-treated diabetic rats. Streptozotocin injection was used to induce diabetes in fasted rats. Various biochemical, physiological and histopathological parameters in diabetic rats were observed for assessing the antidiabetic activity. Results The serum glucose concentrations in diabetic rats were significantly lowered by the extracts (methanolic and hydroethanolic at the doses of 250 and 500 mg/kg body weight). Several related biochemical parameters like creatinine, low-density lipoproteins, triglycerides, cholesterol, alkaline phosphatase, serum glutamate oxaloacetate transaminase and serum glutamate pyruvate transaminase were likewise decreased by the concentrates. The extracts also showed reduction in feed and water consumption of diabetic rats when compared with the diabetic control. The extracts were found to demonstrate regenerative/protective effect on beta-cells of pancreas in diabetic rats. The methanolic and hydroethanolic extracts also exhibited hypoglycaemic effect in normal glucose-fed rats (oral glucose tolerance tests). LC-MS characterization of this extract showed the presence of these compounds - Swertiamarin, swertisin, lupeol, etc. Conclusions The current study demonstrated the counter diabetic capability of G. kuroo Royle being powerful in hyperglycaemia and can viably ensure against other metabolic deviations created by diabetes in rats. The possible bioactive principles responsible for the antidiabetic activity of G. kurroo Royle are Swertiamarin, swertisin and lupeol. PMID- 28731313 TI - An innovative mindfulness and educational care approach in an adult patient affected by gastroesophageal reflux: the IARA model. AB - Patients affected by gastroesophageal reflux disease (GERD) have a poor quality of life caused by several manifestations such as cough, asthma, laryngitis and dental erosion. The clinical conditions are highly disabling for patients and symptoms are difficult to manage. These conditions lead to many discomforts which contribute to an increase of the disease perception. For these reasons, it is important to improve the interventions on psychological aspects that ameliorate the patients' quality of life. The application of IARA model has proven useful to decrease GERD symptoms, distress and medication intake and to increase adherence to care, improving the patient's quality of life. PMID- 28731314 TI - Desensitization to chemical and food sensitivities by low-dose immunotherapy ascertained by provocation neutralization is associated with reduced influx of calcium ions into lymphocytes. AB - Background Food and chemical sensitivities have detrimental effects on health and the quality of life. The natural course of such sensitivities can potentially be altered through various types of allergen-specific immunotherapy, including low dose immunotherapy. The molecular mechanism by which low-dose immunotherapy causes desensitization has not thus far been elucidated. While resting lymphocytes maintain a low cytosolic calcium ion concentration, antigen receptor signaling results in calcium ion influx, predominantly via store-operated calcium channels. We therefore hypothesized that desensitization by low-dose immunotherapy is associated with reduced influx of calcium ions into lymphocytes. The aim of this study was to test this hypothesis. Methods Intracellular lymphocytic calcium ion concentrations were assayed in a total of 47 patients, following incubation with picogram amounts of the test allergens, using a cell permeable calcium-sensing ratiometric fluorescent dye and fluorescence spectroscopy, both at baseline and following successful provocation neutralization treatment with low-dose immunotherapy. Results Low-dose immunotherapy was associated with a reduction in lymphocytic intracellular calcium ion concentration following treatment of: 23 % for metabisulfite sensitivity (p<0.0004); 12 % for salicylate sensitivity (p<0.01); 23 % for benzoate sensitivity (p<0.01); 30 % for formaldehyde sensitivity (p<0.0001); 16 % for sensitivity to petrol exhaust (p<0.003); 16 % for natural gas sensitivity (p<0.001); 13 % for nickel sensitivity (p<0.05); 30 % for sensitivity to organophosphates (p<0.01); and 24 % for sensitivity to nitrosamines (p<0.05). Conclusions Low-dose immunotherapy may affect baseline levels of intracellular calcium in lymphocytes, supporting the premise that allergens affect cell signaling in immune cells and provocation neutralization immunotherapy helps to promote more normal immune cell signaling. PMID- 28731315 TI - Hypocholesterolemic activity of cornelian cherry (Cornus mas L.) fruits. AB - Background Lipid profile disturbances are important risk factors for cardiovascular events in patients with diabetes mellitus and finding safe and multifaceted agents is persuaded in this regard. This study aimed to evaluate the effect of cornelian cherry dried powder (CCDP) on serum lipid profile as well as liver antioxidant capacity, HMG-CoA reductase level and activity, and LDL receptor level in streptozotocin-induced diabetic rats. Methods Forty-eight male adult Wistar rats were randomly allocated into eight equal groups and were treated for 4 weeks as follows: negative control (normal rats, basic diet); positive control (diabetic rats, basic diet), T1 to T4 groups: diabetic rats fed with basic diet containing 0.25, 0.5, 1 and 2 g/ 100 g BW CCDP, respectively; T5: diabetic rats fed with basic diet plus 10 mg/kg lovastatin in drinking water and T6: normal rats fed with basic diet containing 1 g/ 100 g BW CCDP. Results Administration of CCDP had no significant effect on serum glucose levels in diabetic rats however decreased total cholesterol, low-density lipoprotein cholesterol (LDL-C) and increased high-density lipoprotein cholesterol (HDL-C) levels and liver antioxidant capacity as compared to positive control rats (p<0.05). Although HMG-CoA reductase level showed a significant decrease only in T3 group, its activity was reduced in all diabetic CCDP and lovastatin-treated groups as compared to positive control. LDL receptor level remained statistically the same among positive control and CCDP-treated groups. Conclusions In conclusion, the present study confirms hypocholesterolemic effect of CCDP in diabetic rats and demonstrated that this effect was at least partly due to inhibition of liver HMG-CoA reductase activity. PMID- 28731316 TI - Phytochemical analysis of Myrtus communis plant: Conventional versus microwave assisted-extraction procedures. AB - Background Myrtle (Myrtus communis L) may constitute an interesting dietary source of health protective compounds. Microwave-assisted extraction (MAE) of total phenolic compounds (TPC) from myrtle leaf, stems, pericarp, and seeds was studied and the results were compared with those of the conventional method extraction (CME) in terms of extraction time. Methods Extraction yield/efficiency and antioxidant activity were measured using radical scavenging assay (DPPH*) and reducing power. Results The results show that the MAE was higher in terms of saving energy, extraction time (62 s) and extraction efficiency of bioactive compound compared to CME (2 h). Leaf presented the optimum content of total phenols (250 mg GAE.g-1 DW) and flavonoids (13.65 mg GAE.g-1 DW). However, the anthocyanin content was most important in pericarp extract (176.50+/-2.17 mg Cyd 3-glu g-1 DW). The antioxidant activity was important in all parts, mainly in leaves. The results indicated that appropriate microwave treatment could be an efficient process to phenolic compounds recovery and thus, better the antioxidant activity of myrtle extract. Conclusions Principal component analysis (PCA) applied to the experimental data shows that the distribution of the myrtle phenolic compounds depended on their plant part localization as well as the extraction method. PMID- 28731317 TI - Air-Stable, Self-Bleaching Electrochromic Device Based on Viologen- and Ferrocene Containing Triflimide Redox Ionic Liquids. AB - We demonstrate an electrochromic device with self-bleaching ability that uses ethyl viologen- ([EV]2+) and ferrocene-based redox ionic liquids ([FcNTf]-) as the electroactive species. These electroactive compounds are insensitive to atmospheric O2 and H2O in both their oxidized and reduced states once dissolved in a typical ionic liquid electrolyte ([BMIm][NTf2]), allowing for the device to be assembled outside a glovebox without any encapsulation. This device could generate a deep blue color by the application of a 2.0 V potential between two fluorine-doped tin oxide (FTO) substrates to oxidize the ferrocenyl centers to [FcNTf]0 while reducing viologen to [EV]+*. Self-bleaching occurs at OCP as [EV]+* and [FcNTf]0 undergo homogeneous electron transfer in the electrolyte. The mass transport of ethyl viologen and ferrocenylsulfonyl(trifluoromethylsulfonyl)imide ([FcNTf]-) anion was evaluated by double potential step chronoamperometry to study the impact of the diffusion coefficient on the self-bleaching mechanism. The electrochromic device demonstrated here shows a contrast DeltaT (610 nm) around 40% at 2.0 V as colored cell voltage, a switching time in the order of few seconds for coloration and bleaching, coloration efficiency of 105.4 to 146.2 cm2 C1- at 610 nm, and very high stability (94.8% DeltaT after 1000 cycles) despite the presence of O2 and H2O in the electrolyte. PMID- 28731318 TI - Ultrafast Ionic Liquid-Assisted Microwave Synthesis of SnO Microflowers and Their Superior Sodium-Ion Storage Performance. AB - Tin oxide (SnO) is considered one of the most promising metal oxides for utilization as anode material in sodium ion batteries (SIBs), because of its ease of synthesis, high specific gravimetric capacity, and satisfactory cycling performance. However, to aim at practical applications, the Coulombic efficiency during cycling needs to be further improved, which requires a deeper knowledge of its working mechanism. Here, a microflower-shaped SnO material is synthesized by means of an ultrafast ionic liquid-assisted microwave method. The as-prepared SnO anode active material exhibits excellent cycling performance, good Coulombic efficiency as well as a large capacity delivered at low potential, which is fundamental to maximize the energy output of SIBs. These overall merits were never reported before for pure SnO anodes (i.e., not in a composite with, for example, graphene). Additionally, by combining ex situ XRD and XPS, it is clearly demonstrated for the first time that the Sn-Na alloy, which is formed during the initial sodium sodiation, desodiates in two successive but fully separated steps. Totally different from the previous report, the pristine SnO phase is not regenerated upon desodiation up to 3 V vs Na/Na+. The newly disclosed reaction route provides an alternative view of the complex reaction mechanism of these families of metal oxides for sodium ion batteries. PMID- 28731319 TI - Few-Layered Mo(1-x)WxS2 Hollow Nanospheres on Ni3S2 Nanorod Heterostructure as Robust Electrocatalysts for Overall Water Splitting. AB - Owing to unique optical, electronic, and catalytic properties, MoS2 have received increasing interest in electrochemical water splitting. Herein, few-layered Mo(1 x)WxS2 hollow nanospheres-modified Ni3S2 heterostructures are prepared through a facile hydrothermal method to further enhance the electrocatalytic performance of MoS2. The doping of W element optimizes the electronic structure of MoS2@Ni3S2 thus improving the conductivity and charge-transfer ability of MoS2@Ni3S2. In addition, benefitting from the few-layered hollow structure of Mo(1-x)WxS2, the strong electronic interactions between Mo(1-x)WxS2 and Ni3S2 and the hierarchical structure of one-dimensional nanorods and three-dimensional Ni foam, massive active sites and fast ion and charge transportation are obtained. As a result, the optimized Mo(1-x)WxS2@Ni3S2 heterostructure (Mo-W-S-2@Ni3S2) achieves an extremely low overpotential of 98 mV for hydrogen evolution reaction and 285 mV for oxygen evolution reaction at 10 mA cm-2 in alkaline electrolyte. Particularly, using Mo-W-S-2@Ni3S2 heterostructure as a bifunctional electrocatalyst, a cell voltage of 1.62 V is required to deliver a 10 mA cm-2 water splitting current density. In addition, the electrode can be maintained at 10 mA cm-2 for at least 50 h, indicating the excellent stability of Mo-W-S 2@Ni3S2 heterostructure. Therefore, this development demonstrates an effective and feasible strategy to prepare highly efficient bifunctional electrocatalysts for overall water splitting. PMID- 28731320 TI - Fabrication of Nanostructured Omniphobic and Superomniphobic Surfaces with Inexpensive CO2 Laser Engraver. AB - Superomniphobic surfaces (i.e., surfaces that are extremely repellent to both high surface tension liquids like water and low surface tension liquid like oils) can be fabricated through a combination of surface chemistry that imparts low solid surface energy with a re-entrant surface texture. Recently, surface texturing with lasers has received significant attention because laser texturing is scalable, solvent-free, and can produce a monolithic texture on virtually any material. In this work, we fabricated nanostructured omniphobic and superomniphobic surfaces with a variety of materials using a simple, inexpensive and commercially available CO2 laser engraver. Further, we demonstrated that the nanostructured omniphobic and superomniphobic surfaces fabricated using our laser texturing technique can be used to design patterned surfaces, surfaces with discrete domains of the desired wettability, and on-surface microfluidic devices. PMID- 28731321 TI - Conjugation Dependent Interaction of Folic Acid with Folate Binding Protein. AB - Serum proteins play a critical role in the transport, uptake, and efficacy of targeted drug therapies, and here we investigate the interactions between folic acid-polymer conjugates and serum folate binding protein (FBP), the soluble form of the cellular membrane-bound folate receptor. We demonstrate that both choice of polymer and method of ligand conjugation affect the interactions between folic acid-polymer conjugates and serum FBP, resulting in changes in the folic acid induced protein aggregation process. We have previously demonstrated that individual FBP molecules self-aggregate into nanoparticles at physiological concentrations. When poly(amidoamine) dendrimer-folic acid conjugates bound to FBP, the distribution of nanoparticles was preserved. However, the dendritic conjugates produced larger nanoparticles than those formed in the presence of physiologically normal human levels of folic acid, and the conjugation method affected particle size distribution. In contrast, poly(ethylene glycol)-folic acid conjugates demonstrated substantially reduced binding to FBP, did not cause folic acid-induced aggregation, and fully disrupted FBP self-aggregation. On the basis of these results, we discuss the potential implications for biodistribution, trafficking, and therapeutic efficacy of targeted nanoscale therapeutics, especially considering the widespread clinical use of poly(ethylene glycol) conjugates. We highlight the importance of considering specific serum protein interactions in the rational design of similar nanocarrier systems. Our results suggest that prebinding therapeutic nanocarriers to serum FBP may allow folate-specific metabolic pathways to be exploited for delivery while also affording benefits of utilizing an endogenous protein as a vector. PMID- 28731322 TI - Large-Scale Stretchable Semiembedded Copper Nanowire Transparent Conductive Films by an Electrospinning Template. AB - With recent emergence of wearable electronic devices, flexible and stretchable transparent electrodes are the core components to realize innovative devices. The copper nanowire (CuNW) network is commonly chosen because of its high conductivity and transparency. However, the junction resistances and low aspect ratios still limit its further stretchable performance. Herein, a large-scale stretchable semiembedded CuNW transparent conductive film (TCF) was fabricated by electrolessly depositing Cu on the electrospun poly(4-vinylpyridine) polymer template semiembedded in polydimethylsiloxane. Compared with traditional CuNWs, which are as-coated on the flexible substrate, the semiembedded CuNW TCFs showed low sheet resistance (15.6 Omega.sq-1 at ~82% transmittance) as well as outstanding stretchability and mechanical stability. The light-emitting diode connected the stretchable semiembedded CuNW TCFs in the electric circuit still lighted up even after stretching with 25% strain. Moreover, this semiembedded CuNW TCF was successfully applied in polymer solar cells as a stretchable conductive electrode, which yielded a power conversion efficiency of 4.6% with 0.1 cm2 effective area. The large-scale stretchable CuNW TCFs show potential for the development of wearable electronic devices. PMID- 28731323 TI - Analyzing Liposomal Drug Delivery Systems in Three-Dimensional Cell Culture Models Using MALDI Imaging Mass Spectrometry. AB - Cancer chemotherapeutics often fail to reach all diseased cells. To help solve this problem, researchers are investigating novel drug delivery systems. Liposomes are an attractive option due to their low toxicity, high biocompatibility, and potential to carry a large amount of a drug to the tumor site, all while avoiding being eliminated from the body. This study evaluates the penetration of doxorubicin-encased liposomes into three-dimensional cell cultures, or spheroids. Liposomes composed of lipids containing head groups of phosphatidylcholine (PC), phosphatidylethanolamine (PE), and cholesterol were created by extrusion. Doxorubicin is encapsulated within the hydrophilic core of the liposome. The drug is actively released in the spheroid as the lipids bind to cellular lipid bilayers. Spheroids were dosed with liposomal doxorubicin, free doxorubicin, or media control to assess drug distribution over the course of 72 h. Drug penetration was visualized by Matrix-Assisted Laser Desorption/Ionization Imaging Mass Spectrometry (MALDI-IMS) with confirmation by steady state fluorescence microscopy, creating a comprehensive picture of drug distribution. This technique is able to identify both free and liposomal doxorubicin throughout the spheroid after just 12 hours of treatment. Additionally, MALDI-IMS is able to detect three metabolites of doxorubicin, indicating that cells actively metabolize the drug during treatment. Steady state fluorescence microscopy cannot distinguish the drug from its metabolites as they have the same emission spectra. This report summarizes the first study to use MALDI-IMS to analyze drug penetration of a liposomal drug carrier as well as its metabolites. PMID- 28731324 TI - Using Infrared Spectroscopy and Multivariate Analysis to Detect Antibiotics' Resistant Escherichia coli Bacteria. AB - Bacterial pathogens are one of the primary causes of human morbidity worldwide. Historically, antibiotics have been highly effective against most bacterial pathogens; however, the increasing resistance of bacteria to a broad spectrum of commonly used antibiotics has become a global health-care problem. Early and rapid determination of bacterial susceptibility to antibiotics has become essential in many clinical settings and, sometimes, can save lives. Currently classical procedures require at least 48 h for determining bacterial susceptibility, which can constitute a life-threatening delay for effective treatment. Infrared (IR) microscopy is a rapid and inexpensive technique, which has been used successfully for the detection and identification of various biological samples; nonetheless, its true potential in routine clinical diagnosis has not yet been established. In this study, we evaluated the potential of this technique for rapid identification of bacterial susceptibility to specific antibiotics based on the IR spectra of the bacteria. IR spectroscopy was conducted on bacterial colonies, obtained after 24 h culture from patients' samples. An IR microscope was utilized, and a computational classification method was developed to analyze the IR spectra by novel pattern-recognition and statistical tools, to determine E. coli susceptibility within a few minutes to different antibiotics, gentamicin, ceftazidime, nitrofurantoin, nalidixic acid, ofloxacin. Our results show that it was possible to classify the tested bacteria into sensitive and resistant types, with success rates as high as 85% for a number of examined antibiotics. These promising results open the potential of this technique for faster determination of bacterial susceptibility to certain antibiotics. PMID- 28731325 TI - Bioinspired and Biomimetic AgNPs/Gentamicin-Embedded Silk Fibroin Coatings for Robust Antibacterial and Osteogenetic Applications. AB - With the progressively increasing demand for orthopedic Ti implants, the balance between two primary complications restricting implant applications is needed to be solved: the lack of bone tissue integration and biomedical device-associated infections (BAI), where emergence of multiresistance bacteria make it worse. Notably, a combination of silver nanoparticles (AgNPs) and a kind of antibiotic can synergistically inhibit bacterial growth, where a low concentration of AgNPs has been confirmed to promote the proliferation and osteogenesis of osteoblasts. In this work, we built AgNPs/gentamicin (Gen)-embedded silk fibroin (SF)-based biomimetic coatings on orthopedic titanium by a facile dipping-drying circular process and with the assistance of polydopamine (PD). Ag+ was reduced to AgNPs by SF under ultraviolet (UV) irradiation, and then they were detected by transmission electron microscope (TEM) images and UV-visible (UV-vis) analyses. Intriguingly, the addition of Gen highly improved the reduction efficiency of Ag+. The antibacterial efficiency of SF-based coatings was examined by challenging them with pathogenic Staphylococcus aureus (S. aureus) bacteria which produced biofilms, and consequently, we found that low concentration loading, durable release of Ag+ (28 days), and 10-fold improvement of antibacterial efficiency were achieved for our novel AgNPs- and Gen-embeded silk fibroin coatings. In bacteria and a cells cocultured system, AgNPs/Gen-embedded coatings strongly inhibited adhesion and proliferation of S. aureus, simultaneously improving cell adhesion and growth. To investigate cytocompatibility and osteogenic potential, different coatings were cultured with MC3T3 cells; AgNPs/Gen-embedded coatings showed generally acceptable biocompatibility (cell adhesion, proliferation, and viability) and accelerated osteoblast maturation (alkaline phosphatase production, matrix secretion, and calcification). Expectantly, this novel biofunctional coating will have promising applications in orthopedic and dental titanium implants thanks to its excellently antibacterial, biocompatible, and osteogenic activities. PMID- 28731326 TI - Oxygen Partial Pressure during Pulsed Laser Deposition: Deterministic Role on Thermodynamic Stability of Atomic Termination Sequence at SrRuO3/BaTiO3 Interface. AB - With recent trends on miniaturizing oxide-based devices, the need for atomic scale control of surface/interface structures by pulsed laser deposition (PLD) has increased. In particular, realizing uniform atomic termination at the surface/interface is highly desirable. However, a lack of understanding on the surface formation mechanism in PLD has limited a deliberate control of surface/interface atomic stacking sequences. Here, taking the prototypical SrRuO3/BaTiO3/SrRuO3 (SRO/BTO/SRO) heterostructure as a model system, we investigated the formation of different interfacial termination sequences (BaO RuO2 or TiO2-SrO) with oxygen partial pressure (PO2) during PLD. We found that a uniform SrO-TiO2 termination sequence at the SRO/BTO interface can be achieved by lowering the PO2 to 5 mTorr, regardless of the total background gas pressure (Ptotal), growth mode, or growth rate. Our results indicate that the thermodynamic stability of the BTO surface at the low-energy kinetics stage of PLD can play an important role in surface/interface termination formation. This work paves the way for realizing termination engineering in functional oxide heterostructures. PMID- 28731327 TI - Donor-Acceptor Properties of a Single-Molecule Altered by On-Surface Complex Formation. AB - Electron donor-acceptor molecules are of outstanding interest in molecular electronics and organic solar cells for their intramolecular charge transfer controlled via electrical or optical excitation. The preservation of their electronic character in the ground state upon adsorption on a surface is cardinal for their implementation in such single-molecule devices. Here, we investigate by atomic force microscopy and scanning tunneling microscopy a prototypical system consisting of a pi-conjugated tetrathiafulvalene-fused dipyridophenazine molecule adsorbed on thin NaCl films on Cu(111). Depending on the adsorption site, the molecule is found either in a nearly undisturbed free state or in a bound state. In the latter case, the molecule adopts a specific adsorption site, leading to the formation of a chelate complex with a single Na+ alkali cation pulled out from the insulating film. Although expected to be electronically decoupled, the charge distribution of the complex is drastically modified, leading to the loss of the intrinsic donor-acceptor character. The chelate complex formation is reversible with respect to lateral manipulations, enabling tunable donor-acceptor molecular switches activated by on-surface coordination. PMID- 28731328 TI - Bisphosphonate-Functionalized Hydroxyapatite Nanoparticles for the Delivery of the Bromodomain Inhibitor JQ1 in the Treatment of Osteosarcoma. AB - Osteosarcoma (OS) is one of the most common neoplasia among children, and its survival statistics have been stagnating since the combinatorial anticancer therapy triad was first introduced. Here, we report on the assessment of the effect of hydroxyapatite (HAp) nanoparticles loaded with medronate, the simplest bisphosphonate, as a bone-targeting agent and JQ1, a small-molecule bromodomain inhibitor, as a chemotherapeutic in different 2D and 3D K7M2 OS in vitro models. Both additives decreased the crystallinity of HAp, but the effect was more intense for medronate because of its higher affinity for HAp. As the result of PO43--NH+ binding, JQ1 shielded the surface phosphates of HAp and pushed its surface charge to more positive values, exhibiting the opposite effect from calcium-blocking medronate. In contrast to the faster and more exponential release of JQ1 from monetite, its release from HAp nanoparticles followed a zero order kinetics, but 98% of the payload was released after 48 h. The apoptotic effect of HAp nanoparticles loaded with JQ1, with medronate and with both JQ1 and medronate, was selective in 2D culture: pronounced against the OS cells and nonexistent against the healthy fibroblasts. While OS cell invasion was significantly inhibited by all of the JQ1-containing HAp formulations, that is, with and without medronate, all of the combinations of the targeting compound, medronate, and the chemotherapeutic, JQ1, delivered using HAp, but not HAp alone, inhibited OS cell migration from the tumor spheroids. JQ1 delivered using HAp had an effect on tumor migration, invasion, and apoptosis even at extremely low, subnanomolar concentrations, at which no effect of JQ1 per se was observed, meaning that this form of delivery could help achieve a multifold increase of this drug's efficacy. More than 80% of OS cells internalized JQ1-loaded HAp nanoparticles after 24 h of coincubation, suggesting that this augmentation of the activity of JQ1 may be due to the intracellular delivery and sustained release of the drug enabled by HAp. In addition to the reduction of the OS cell viability, the reduction of the migration and invasion radii was observed in OS tumor spheroids challenged with even JQ1-free medronate-functionalized HAp nanoparticles, demonstrating a definite anticancer activity of medronate alone when combined with HAp. The effect of medronate-functionalized JQ1-loaded HAp nanoparticles was most noticeable against OS cells differentiated into an osteoblastic lineage, in which case they surpassed in effect pure JQ1 and medronate-free compositions. The activity of JQ1 was mediated through increased Ezrin expression and decreased RUNX2 expression and was MYC and FOSL1 independent, but these patterns of gene expression changed in cells challenged with the nanoparticulate form of delivery, having been accompanied by the upregulation of RUNX2 and downregulation of Ezrin in OS cells treated with medronate-functionalized JQ1-loaded HAp nanoparticles. PMID- 28731329 TI - Generation and Characterization of Anti-VGLUT Nanobodies Acting as Inhibitors of Transport. AB - The uptake of glutamate by synaptic vesicles is mediated by vesicular glutamate transporters (VGLUTs). The central role of these transporters in excitatory neurotransmission underpins their importance as pharmacological targets. Although several compounds inhibit VGLUTs, highly specific inhibitors were so far unavailable, thus limiting applications to in vitro experiments. Besides their potential in pharmacology, specific inhibitors would also be beneficial for the elucidation of transport mechanisms. To overcome this shortage, we generated nanobodies (Nbs) by immunization of a llama with purified rat VGLUT1 and subsequent selection of binders from a phage display library. All identified Nbs recognize cytosolic epitopes, and two of the binders greatly reduced the rate of uptake of glutamate by reconstituted liposomes and subcellular fractions enriched with synaptic vesicles. These Nbs can be expressed as functional green fluorescent protein fusion proteins in the cytosol of HEK cells for intracellular applications as immunocytochemical and biochemical agents. The selected binders thus provide valuable tools for cell biology and neuroscience. PMID- 28731331 TI - Highly Efficient Catalytic Route for the Synthesis of Functionalized Silsesquioxanes. AB - Silsesquioxanes (POSS) have recently become the subject of growing interest in many branches of materials chemistry. Despite this great interest, no direct metal-catalyzed method to cap the corner of the POSS molecules has yet been proposed. In this report, we present a highly efficient method for the synthesis of functionalized silsesquioxanes mediated by scandium(III) triflate, which opens up the possibility of introducing a wide variety of functional groups into this class of organosilicon compounds under mild conditions with excellent yields. We also investigated the differences in the activity of the Lewis acid (Sc(OTf)3) and the hidden Bronsted acid (TfOH) generated in situ from triflates as catalysts in the functionalization of silsesquioxanes. What is more, this solution provides an efficient corner-capping reaction and other functionalizations to obtain silsesquioxane derivatives which are often not possible to synthesize with good yields, efficiency, and chemoselectivity using conventional methods. PMID- 28731330 TI - Mapping Functionally Important Residues in the Na+/Dicarboxylate Cotransporter, NaDC1. AB - Transporters from the SLC13 family couple the transport of two to four Na+ ions with a di- or tricarboxylate, such as succinate or citrate. We have previously modeled mammalian members of the SLC13 family, including the Na+/dicarboxylate cotransporter NaDC1 (SLC13A2), based on a structure of the bacterial homologue VcINDY in an inward-facing conformation with one sodium ion bound at the Na1 site. In the study presented here, we modeled the outward-facing conformation of rabbit and human NaDC1 (rbNaDC1 and hNaDC1, respectively) using an outward-facing model of VcINDY as a template and identified residues in or near the putative Na2 and Na3 cation binding sites. Guided by the structural models in both conformations, we performed site-directed mutagenesis in rbNaDC1 for residues proposed to be in the Na+ or substrate binding sites. Cysteine substitution of T474 in the predicted Na2 binding site results in an inactive protein. The M539C mutant has a low apparent affinity for both sodium and lithium cations, suggesting that M539 may form part of the putative Na3 binding site. The Y432C and T86C mutants have increased Km values for succinate, supporting their proposed location in the outward-facing substrate binding site. In addition, cysteine labeling by MTSEA-biotin shows that Y432C is accessible from the outside of the cell, and the accessibility changes in the presence or absence of Na+. The results of this study improve our understanding of substrate and ion recognition in the mammalian members of the SLC13 family and provide a framework for developing conformationally specific inhibitors against these transporters. PMID- 28731332 TI - Tuning the Cavity Size and Chirality of Self-Assembling 3D DNA Crystals. AB - The foundational goal of structural DNA nanotechnology-the field that uses oligonucleotides as a molecular building block for the programmable self-assembly of nanostructured systems-was to use DNA to construct three-dimensional (3D) lattices for solving macromolecular structures. The programmable nature of DNA makes it an ideal system for rationally constructing self-assembled crystals and immobilizing guest molecules in a repeating 3D array through their specific stereospatial interactions with the scaffold. In this work, we have extended a previously described motif (4 * 5) by expanding the structure to a system that links four double-helical layers; we use a central weaving oligonucleotide containing a sequence of four six-base repeats (4 * 6), forming a matrix of layers that are organized and dictated by a series of Holliday junctions. In addition, we have assembled mirror image crystals (l-DNA) with the identical sequence that are completely resistant to nucleases. Bromine and selenium derivatives were obtained for the l- and d-DNA forms, respectively, allowing phase determination for both forms and solution of the resulting structures to 3.0 and 3.05 A resolution. Both right- and left-handed forms crystallized in the trigonal space groups with mirror image 3-fold helical screw axes P32 and P31 for each motif, respectively. The structures reveal a highly organized array of discrete and well-defined cavities that are suitable for hosting guest molecules and allow us to dictate a priori the assembly of guest-DNA conjugates with a specified crystalline hand. PMID- 28731333 TI - Livestock Housing and Manure Storage Need to Be Improved in China. PMID- 28731334 TI - Optical Spectra and Magnetic Behavior of a Wide Range of Europium(III) Oxo Compounds: Analysis of the Ligand-Field Effects. AB - The europium-oxygen interaction in nine different europium(III) oxo-compounds (including C-type Eu2O3) was investigated on the basis of powder reflectance spectra (near-IR/vis/UV) and temperature-dependent magnetic measurements. Computation of the transition energies and of the effective Bohr magneton numbers for Eu3+ in the different ligand fields were performed within the framework of the angular overlap model (AOM) using the computer program BonnMag. These calculations show that all electronic transition energies in the optical spectra, the magnetic susceptibilities as well as their temperature dependence, are very well-accounted for by AOM. BonnMag provides a facile way to perform these calculations. Analysis of the obtained "best fit" AOM parameters esigma(EuIII-O) shows that these are significantly influenced by the further bonding partners of oxygen ("second-sphere ligand-field effect"). An increase of esigma, max(EuIII-O) from 404 cm-1 (EuPO4) to 687 cm-1 (EuSbO4), both normalized to d(EuIII-O) = 2.38 A, is found. Correlation of this variation to oxide polarizability and optical basicity of the oxo-compounds is discussed. PMID- 28731336 TI - Triple Reuptake Inhibitors as Potential Therapeutics for Depression and Other Disorders: Design Paradigm and Developmental Challenges. AB - Although first-line antidepressants offer therapeutic benefit, about 35% of depressed patients are not adequately treated, creating a large unmet medical need. These medicines mostly enhance the synaptic levels of serotonin and/or norepinephrine. Evidence from preclinical and clinical studies implicate dopamine hypofunction in the pathophysiology of depression. Triple reuptake inhibitors (TRIs), which elevate dopamine in addition to serotonin and norepinephrine, may demonstrate greater efficacy, with the reversal of anhedonia and improved tolerability. Medicinal chemistry efforts have resulted in more than 10 clinical candidates, although clinical candidates have failed to demonstrate superior efficacy compared to placebo or existing antidepressants. Hence, the successful development of future TRIs for depression will demand strong translational evidence, an optimal dosing regimen, and better tolerability. TRIs also hold therapeutic potential for other indications, with four candidates under clinical development for attention deficit hyperactivity disorder, binge eating disorder, cocaine addiction, obesity, and type 2 diabetes. Clinical studies have indicated a lower abuse potential for TRIs than psychostimulants. PMID- 28731337 TI - Sky-Blue-Emitting Dendritic Alkynylgold(III) Complexes for Solution-Processable Organic Light-Emitting Devices. AB - A new class of tridentate ligand-containing cyclometalated gold(III) complexes featuring dendritic alkynyl ligands with carbazole moieties as dendrons and peripheral groups has been synthesized up to the third generation. High performance solution-processable organic light-emitting devices (OLEDs) with maximum current efficiency of up to 23.7 cd A-1 and external quantum efficiency of up to 6.9% have been realized by a simple spin-coating technique. With the incorporation of bulky carbazole moieties to form higher generation dendrimers, the undesirable excimeric emission could be effectively reduced, allowing the fine-tuning of the emission color toward the blue region. This represents the first successful demonstration of sky-blue-emitting alkynylgold(III) complexes and its application in solution-processable OLEDs. PMID- 28731335 TI - A Simple Representation of Three-Dimensional Molecular Structure. AB - Statistical and machine learning approaches predict drug-to-target relationships from 2D small-molecule topology patterns. One might expect 3D information to improve these calculations. Here we apply the logic of the extended connectivity fingerprint (ECFP) to develop a rapid, alignment-invariant 3D representation of molecular conformers, the extended three-dimensional fingerprint (E3FP). By integrating E3FP with the similarity ensemble approach (SEA), we achieve higher precision-recall performance relative to SEA with ECFP on ChEMBL20 and equivalent receiver operating characteristic performance. We identify classes of molecules for which E3FP is a better predictor of similarity in bioactivity than is ECFP. Finally, we report novel drug-to-target binding predictions inaccessible by 2D fingerprints and confirm three of them experimentally with ligand efficiencies from 0.442-0.637 kcal/mol/heavy atom. PMID- 28731338 TI - Tunable Magnetism and Extraordinary Sunlight Absorbance in Indium Triphosphide Monolayer. AB - Atomically thin two-dimensional (2D) materials have received considerable research interest due to their extraordinary properties and promising applications. Here we predict the monolayered indium triphosphide (InP3) as a new semiconducting 2D material with a range of favorable functional properties by means of ab initio calculations. The 2D InP3 crystal shows high stability and promise of experimental synthesis. It possesses an indirect band gap of 1.14 eV and a high electron mobility of 1919 cm2 V-1 s-1, which can be strongly manipulated with applied strain. Remarkably, the InP3 monolayer suggests tunable magnetism and half-metallicity under hole doping or defect engineering, which is attributed to the novel Mexican-hat-like bands and van Hove singularities in its electronic structure. A semiconductor-metal transition is also revealed by doping 2D InP3 with electrons. Furthermore, monolayered InP3 exhibits extraordinary optical absorption with significant excitonic effects in the entire range of the visible light spectrum. All these desired properties render 2D InP3 a promising candidate for future applications in a wide variety of technologies, in particular for electronic, spintronic, and photovoltaic devices. PMID- 28731339 TI - Colloidal-Bound Polyphosphates and Organic Phosphates Are Bioavailable: A Nutrient Solution Study. AB - Colloidal forms of Fe(III) minerals can be stabilized in solution by coatings of organic or poly-phosphate (P), which reduce the zeta-potential. This opens up a route toward the development of nanoforms of P fertilizers. However, it is unclear if such P forms are bioavailable. To address this question, spinach (Spinacia oleracea) was grown in nutrient solutions, at equal total P, using three different forms of P (orthophosphate = Pi; hexametaphosphate = HMP; myo inositol hexaphosphate = IHP), free or bound to goethite/ferrihydrite colloids. After 10 days, P uptake was determined with a dose-response curve using colloid free Pi as a reference treatment. The Pi concentration generating equal P uptake as in colloidal P treatments was used to calculate the relative bioavailability of colloidal P (RBAcolloid). The RBAcolloid was about 60% for Pi-loaded goethite, stabilized with natural organic matter. For HMP/IHP-Pi-loaded colloids, RBAcolloid ranged between 10 and 50%, in line with their higher sorption strength. In conclusion, colloidal organic P or poly-P can stabilize Fe(III) colloids in solution and can contribute to plant-available P. Soil experiments are required to assess their potential as nanofertilizers. PMID- 28731340 TI - Chemistry of Sputter-Deposited Lithium Sulfide Films. AB - Lithium sulfide (Li2S) is under intense study because it is the insulating discharge product of ultrahigh energy density lithium-sulfur (Li-S) batteries and a candidate cathode material for lithium-metal-free Li-S cells. In this work, we report the fabrication of an apparatus for sputter deposition of Li2S films ranging in thickness from a few nanometers to several micrometers at rates over 2 nm min-1. High-temperature annealing of the films is shown to produce crystalline films of high chemical purity Li2S for the first time. We provide evidence via complementary X-ray photoelectron and Raman spectroscopy that sputter deposition produces a unique sulfide structure composed of polymer-like chains of Li2S units. The electrochemistry of these films is markedly different from annealed crystalline Li2S, which is shown to be electrochemically inactive. The full theoretical capacity of the as-deposited sulfide structure could be realized during galvanostatic charge, suggesting a facile, solid-state charge process. Finally, we explore trends in the plasma chemistry that lead to nonstoichiometry and depth inhomogeneity during Li2S sputter deposition. PMID- 28731341 TI - A 2D Coordination Network That Detects Nitro Explosives in Water, Catalyzes Baylis-Hillman Reactions, and Undergoes Unusual 2D->3D Single-Crystal to Single Crystal Transformation. AB - The solvothermal reaction of Zn(NO3)2.6H2O and a linear dicarboxylate ligand H2L, in the presence of urotropine in N,N'-dimethylformamide (DMF), gives rise to a new porous two-dimensional (2D) coordination network, {[Zn3(L)3(urotropine)2].2DMF.3H2O}n (1), with hxl topology. Interestingly, framework 1 exhibits excellent emission properties owing to the presence of naphthalene moiety in the linker H2L, that can be efficiently suppressed by subtle quantity of nitro explosives in aqueous medium. Furthermore, presence of urotropine molecules bound to the metal centers, 1 is found to be an excellent heterogeneous catalyst meant for atom-economical C-C bond-forming Baylis-Hillman reactions. Additionally, crystals of 1 undergo complete transmetalation with Cu(II) to afford isostructural 1Cu. Moreover, the 2D framework of 1 allows replacement of urotropine molecules by 4,4'-azopyridine (azp) linker resulting in a three-dimensional (3D) metal-organic framework, {[Zn(L)(azp)].4DMF 2H2O}n (2). The 1->2 transformation takes place in single-crystal-to-single crystal manner supported by powder X-ray diffraction, atomic force microscopy, high-resolution transmission electron microscopy, and morphological studies. Remarkably, during this 2D->3D transformation, the original trinuclear [Zn3(COO)6] secondary building unit changes to a mononuclear node, which is unprecedented. PMID- 28731342 TI - A Formal Synthesis of (-)-Perhydrohistrionicotoxin Using a Cross Metathesis Hydrogenation Approach. AB - The development of an efficient, high yielding six-step convergent synthesis of the semisynthetic alkaloid (-)-perhydrohistrionicotoxin is described. The key transformations include the cross metathesis of a Bronsted-acid masked primary homoallylic amine with a vinyl cyclohexenone and a regioselective palladium catalyzed hydrogenation. This sequence generated the advanced Winterfeldt spirocyclic precursor in 47% overall yield, with a longest linear sequence of five steps. PMID- 28731343 TI - "Roller-Wheel"-Type Pt-Containing Small Molecules and the Impact of "Rollers" on Material Crystallinity, Electronic Properties, and Solar Cell Performance. AB - We report the synthesis, characterization, and detailed comparison of a series of novel Pt-bisacetylide containing conjugated small molecules possessing an unconventional "roller-wheel" shaped structure that is distinctly different from the "dumbbell" designs in traditional Pt-bisacetylide containing conjugated polymers and small molecules. The relationships between the chemical nature and length of the "rollers" and the electronic and physical properties of the materials are carefully studied by steady-state spectroscopy, cyclic voltammetry, differential scanning calorimetry, single-crystal X-ray diffraction, transient absorption spectroscopy, theoretical calculation, and device application. It was revealed that if the roller are long enough, these molecules can "slip-stack" in the solid state, leading to high crystallinity and charge mobility. Organic solar cells were fabricated and showed power conversion efficiencies up to 5.9%, out performing all existing Pt-containing materials. The device performance was also found to be sensitive to optimization conditions and blend morphologies, which are a result of the intricate interplay among materials crystallinity, phase separation, and the relative positions of the lowest singlet and triplet excited states. PMID- 28731344 TI - Correction to "Rational Design and Synthesis of Carboxylate Gemini Surfactants with an Excellent Aggregate Behavior for Nano-La2O3 Morphology-Controllable Preparation". PMID- 28731345 TI - Asymmetric alpha-Sulfonyl- and alpha-Phosphoryl-Oxylation of Ketones by a Chiral Hypervalent Iodine(III). AB - An enantioselective direct oxygenation of propiophenone derivatives mediated by a catalytic or stoichiometric amount of new chiral non-C2-symmetric iodoarenes(III) is reported. The reaction gives an easy entry to optically active alpha-sulfonyl- and alpha-phosphoryl oxyketones in respectable yields and enantioselectivities. PMID- 28731346 TI - Kinetics of Light-Induced Intramolecular Energy Transfer in Different Conformational States of NADH. AB - When bound to a protein, the coenzyme NAD+/NADH typically exists in an extended conformation, while in aqueous solutions it can be characterized by an equilibrium of folded and unfolded structures. It was recognized long ago that in the folded conformation light absorption at the adenine ring initiates an effective energy transfer (ET) toward the nicotinamide group, but the mechanism of this process is still unexplored. Here we apply ultrafast transient absorption measurements on NADH combined with compartmental model analysis for following the kinetics of the ET. We find that the actual ET is extremely rapid (~70 fs). The high rate can be well described by a Forster-type mechanism, promoted by both the special photophysical properties of adenine and the subnanometer inter-ring distance. The rapid ET creates a vibrationally hot excited state on nicotinamide, the vibrational and electronic relaxation of which is characterized by 1.7 and 650 ps, respectively. PMID- 28731347 TI - Integrated Venomics and Venom Gland Transcriptome Analysis of Juvenile and Adult Mexican Rattlesnakes Crotalus simus, C. tzabcan, and C. culminatus Revealed miRNA modulated Ontogenetic Shifts. AB - Adult rattlesnakes within genus Crotalus express one of two distinct venom phenotypes, type I (hemorrhagic) and type II (neurotoxic). In Costa Rican Central American rattlesnake, ontogenetic changes in the concentration of miRNAs modulate venom type II to type I transition. Venomics and venom gland transcriptome analyses showed that adult C. simus and C. tzabcan expressed intermediate patterns between type II and type I venoms, whereas C. culminatus had a canonical type I venom. Neonate/juvenile and adult Mexican rattlesnakes showed notable inter- and intraspecific variability in the number, type, abundance and ontogenetic shifts of the transcriptional and translational venom gland activities. These results support a role for miRNAs in the ontogenetic venom compositional changes in the three congeneric Mexican rattlesnakes. It is worth noting the finding of dual-action miRNAs, which silence the translation of neurotoxic heterodimeric PLA2 crotoxin and acidic PLA2 mRNAs while simultaneously up-regulating SVMP-targeting mRNAs. Dual transcriptional regulation potentially explains the existence of mutually exclusive crotoxin-rich (type-II) and SVMP rich (type-I) venom phenotypic dichotomy among rattlesnakes. Our results support the hypothesis that alterations of the distribution of miRNAs, modulating the translational activity of venom gland toxin-encoding mRNAs in response to an external cue, may contribute to the mechanism generating adaptive venom variability. PMID- 28731348 TI - Proton Transport in Hierarchical-Structured Nafion Membranes: A NMR Study. AB - It is known that hierarchical structure plays a key role in many unique material properties such as self-cleaning effect of lotus leaves and the antifogging property of the compound eyes of mosquitoes. This study reports a series of highly ordered mesoporous Nafion membranes with unique hierarchical structural features at the nanometer scale. Using NMR, we show for the first time that, at low RH conditions, the proton in the ionic domains migrates via a surface diffusion mechanism and exhibits approximately 2 orders of magnitude faster transport than that in the nanopores, whereas the nanopores play a role of reservoir and maintain water and thereby conductivity at higher temperature and lower humidities. Thereby creating hierarchical nanoscale structures is a feasible and promising strategy to develop PEMs that would enable efficient electrochemical performance in devices such as fuel cells, even in the absence of high humidity and at elevated temperatures. PMID- 28731349 TI - Improved Metrological Traceability of Particle Size Values Measured with Line Start Incremental Centrifugal Liquid Sedimentation. AB - Line-start incremental centrifugal liquid sedimentation (disc-CLS) is a powerful method to determine particle size based on the principles of Stokes' law. Because several of the input quantities of the Stokes equation cannot be easily determined for this case of a rotating disc, the disc-CLS approach relies on calibrating the sedimentation time scale with reference particles. To use these calibrant particles for establishing metrological traceability, they must fulfill the same requirements as those imposed on a certified reference material, i.e., their certified Stokes diameter and density value must come with a realistic measurement uncertainty and with a traceability statement. As is the case for several other techniques, the calibrants do not always come with uncertainties for the assigned modal diameter and effective particle density. The lack of such information and the absence of a traceability statement make it difficult for the end-user to estimate the uncertainty of the measurement results and to compare them with results obtained by others. We present the results of a collaborative study that aimed at demonstrating the traceability of particle size results obtained with disc-CLS. For this purpose, the particle size and effective particle density of polyvinyl chloride calibrants were measured using different validated methods, and measurement uncertainties were estimated according to the Guide to the Expression of Uncertainty in Measurement. The results indicate that the modal Stokes diameter and effective particle density that are assigned to the calibrants are accurate within 5% and 3.5%, respectively, and that they can be used to establish traceability of particle size results obtained with disc-CLS. This conclusion has a great impact on the traceability statement of certified particle size reference materials, for which the traceability is limited to the size and density values of the calibrant particles. PMID- 28731351 TI - Theory of Light-Modulated Emission Spectroscopy. AB - Perovskite solar cells and fluorescent collectors formed by a dispersion of quantum dots in a transparent solid are paradigmatic devices for photon capture and utilization that involve the coupling of photon displacement, absorption and regeneration. In order to obtain information about the coupled photonic processes in systems involving photon recycling, we analyze the transfer function for modulated outgoing to incoming photon flux. We show the physical features of light-to-light impedance that reveals a trap-limited diffusion of photons coupled with the nonradiative recombination. The spectral shapes allow one to distinguish readily photonic recombination and diffusion kinetic phenomena and consequently to determine the physical parameters that control the system's quantum yield for photoluminescence. PMID- 28731350 TI - Gastric and Duodenal Ethanol Concentrations after Intake of Alcoholic Beverages in Postprandial Conditions. AB - This study determined intraluminal ethanol concentrations (stomach and duodenum) in fed healthy volunteers after the consumption of common alcoholic beverages (beer, wine, and whisky). The results of this study were compared with a previous study in fasted volunteers. Five healthy volunteers were recruited in a crossover study. The fed state was simulated by ingestion of 250 mL of Nutridrink Compact Neutral. Volunteers subsequently consumed two standard units of beer (Stella Artois, 500 mL, 5.2% ethanol), wine (Blanc du Blanc, 200 mL, 11% ethanol), or whisky (Gallantry Whisky, 80 mL, 40% ethanol). Gastric and duodenal fluids were aspirated through two catheters over time and analyzed for ethanol content by head space gas chromatography. The capability of ethanol to permeate gastric and duodenal rat mucosa was examined in an Ussing chambers setup. A similar average gastric Cmax was observed in the beer and the wine conditions: 3.3% and 3.7% ethanol, respectively. The gastric Cmax in the whisky condition amounted to 8.5% ethanol. Lower ethanol concentrations were observed in the duodenum compared to the stomach. The duodenal Cmax was similar in all three conditions: 1.3%, 1.2%, and 1.6% ethanol for beer, wine, and whisky, respectively. Compared to the fasted state (reported in a previous study), higher gastric ethanol concentrations were observed during a longer time period. In the beer and wine conditions, similar concentrations were observed in the intestine regardless of the prandial state. After intake of whisky, however, the ethanol concentration was lower in the fed intestine. Alcohol was observed to permeate both gastric and duodenal rat mucosa. Higher intragastric ethanol concentrations were maintained for a longer period of time in fed compared to fasted state conditions. However, the observed concentration profiles were not in line with current FDA guidelines for alcohol resistance testing of formulations, stating that in vitro tests should investigate the impact of up to 40% ethanol for 2 h. The presented intraluminal ethanol concentrations may serve as reference data for the further development of relevant in vitro models to assess ethanol effects on formulation performance. PMID- 28731352 TI - Exploiting the Marangoni Effect To Initiate Instabilities and Direct the Assembly of Liquid Metal Filaments. AB - Utilization of the Marangoni effect in a liquid metal is investigated, focusing on initiating instabilities to direct material assembly via the Rayleigh-Plateau instability. Thin (2 nm) copper (Cu) films are lithographically patterned onto thick (12 nm) nickel (Ni) strips to induce a surface energy gradient at the maximum wavelength of the filament instability predicted by Rayleigh-Plateau instability analysis. The pattern is irradiated with an 18 ns pulsed laser such that the pattern melts and the resultant Ni-Cu surface tension gradient induces Marangoni flows due to the difference in surface energies. The experimental results, supported by extensive direct numerical simulations, demonstrate that the Marangoni flow exceeds the capillary flow induced by the initial geometry, guiding instabilities such that final nanoparticle location is directed toward the regions of higher surface energy (Ni regions). Our work shows a route for manipulation, by means of the Marangoni effect, to direct the evolution of the surface instabilities and the resulting pattern formation. PMID- 28731353 TI - Altering DNA-Programmable Colloidal Crystallization Paths by Modulating Particle Repulsion. AB - Colloidal crystal engineering with DNA can be used to realize precise control over nanoparticle (NP) arrangement. Here, we investigate a case of DNA-based assembly where the properties of DNA as a polyelectrolyte brush are employed to alter a hybridization-driven NP crystallization pathway. Using the coassembly of DNA-conjugated proteins and spherical gold nanoparticles (AuNPs) as a model system, we explore how steric repulsion between noncomplementary, neighboring NPs due to overlapping DNA shells can influence their ligand-directed behavior. Specifically, our experimental data coupled with coarse-grained molecular dynamics (MD) simulations reveal that, by changing factors related to NP repulsion, two structurally distinct outcomes can be achieved. When steric repulsion between DNA-AuNPs is significantly greater than that between DNA proteins, a lower packing density crystal lattice is favored over the structure that is predicted by design rules based on DNA hybridization considerations alone. This is enabled by the large difference in DNA density on AuNPs versus proteins and can be tuned by modulating the flexibility, and thus conformational entropy, of the DNA on the constituent particles. At intermediate ligand flexibility, the crystallization pathways are energetically similar, and the structural outcome can be adjusted using the density of DNA duplexes on DNA-AuNPs and by screening the Coulomb potential between them. Such lattices are shown to undergo dynamic reorganization upon changing the salt concentration. These data help elucidate the structural considerations necessary for understanding repulsive forces in DNA-mediated assembly and lay the groundwork for using them to increase architectural diversity in engineering colloidal crystals. PMID- 28731354 TI - An Anionic Surfactant on an Anionic Substrate: Monovalent Cation Binding. AB - Neutron reflectometry has been used to study the adsorption of the anionic surfactant bis(2-ethylhexyl) sulfosuccinate cesium salt on the anionic surface of mica. Evidence of significant adsorption is reported. The adsorption is reversible and changes little with pH. This unexpected adsorption behavior of an anionic molecule on an anionic surface is discussed in terms of recent models for surfactant adsorption such as cation bridging, where adsorption has been reported with the divalent ion calcium but not previously observed with monovalent ions. PMID- 28731355 TI - Luminescent, Fire-Resistant, and Water-Proof Ultralong Hydroxyapatite Nanowire Based Paper for Multimode Anticounterfeiting Applications. AB - Counterfeiting of valuable certificates, documents, and banknotes is a serious issue worldwide. As a result, the need for developing novel anticounterfeiting materials is greatly increasing. Herein, we report a new kind of ultralong hydroxyapatite nanowire (HAPNW)-based paper with luminescence, fire resistance, and waterproofness properties that may be exploited for anticounterfeiting applications. In this work, lanthanide-ion-doped HAPNWs (HAPNW:Ln3+) with lengths over 100 MUm have been synthesized and used as a raw material to fabricating a free-standing luminescent, fire-resistant, water-proof paper through a simple vacuum filtration process. It is interesting to find that the luminescence intensity, structure, and morphology of HAPNW:Ln3+ highly depend on the experimental conditions. The as-prepared HAPNW:Ln3+ paper has a unique combination of properties, such as high flexibility, good processability, writing and printing abilities, luminescence, tunable emission color, waterproofness, and fire resistance. In addition, a well-designed pattern can be embedded in the paper that is invisible under ambient light but viewable as a luminescent color under ultraviolet light. Moreover, the HAPNW:Ln3+ paper can be well-preserved without any damage after being burned by fire or soaked in water. The unique combination of luminescence, fire resistance, and waterproofness properties and the nanowire structure of the as-prepared HAPNW:Ln3+ paper may be exploited toward developing a new kind of multimode anticounterfeiting technology for various high-level security antiforgery applications, such as in making forgery proof documents, certificates, labels, and tags and in packaging. PMID- 28731356 TI - Preparation of Colloidal Organosilica Spheres through Spontaneous Emulsification. AB - Colloidal particles of controlled size are promising building blocks for the self assembly of functional materials. Here, we systematically study a method to synthesize monodisperse, micrometer-sized spheres from 3-(trimethoxysilyl)propyl methacrylate (TPM) in a benchtop experiment. Their ease of preparation, smoothness, and physical properties provide distinct advantages over other widely employed materials such as silica, polystyrene, and poly(methyl methacrylate). We describe that the spontaneous emulsification of TPM droplets in water is caused by base-catalyzed hydrolysis, self-condensation, and the deprotonation of TPM. By studying the time-dependent size evolution, we find that the droplet size increases without any detectable secondary nucleation. Resulting TPM droplets are polymerized to form solid particles. The particle diameter can be controlled in the range of 0.4 to 2.8 MUm by adjusting the volume fraction of added monomer and the pH of the solution. Droplets can be grown to diameters of up to 4 MUm by adding TPM monomer after the initial emulsification. Additionally, we characterize various physical parameters of the TPM particles, and we describe methods to incorporate several fluorescent dyes. PMID- 28731357 TI - Visible-Light Induced and Oxygen-Promoted Oxidative Cyclization of Aromatic Enamines for the Synthesis of Quinolines Derivatives. AB - The dual transition metal-visible light photoredox catalysis for the synthesis of quinoline derivatives by using dioxygen as an oxygen source is developed. By using visible light, the direct oxidative cyclization of aromatic enamines with alkynes or alkenes can be achieved at mild conditions with an aid of copper or palladium catalysts, and a variety of multisubstituted quinoline derivatives could be obtained in good to moderate yields under mild reaction conditions. PMID- 28731358 TI - Toward Early Identification of Clinically Relevant Interstitial Lung Disease. PMID- 28731359 TI - Western Dietary Pattern Is Associated With Severe Coronary Artery Disease. AB - The independent predictive value of an unhealthy diet on the severity of coronary artery disease (CAD) requires further investigation. We assessed the impact of dietary pattern on CAD severity. In this cohort study, we included 188 symptomatic stable patients with CAD. Patients were categorized as having severe CAD or nonsevere CAD by coronary angiography. Among several demographics and clinical characteristics, all patients were tested using a semiquantitative food frequency questionnaire. Concerning baseline demographic characteristics, there was no difference between patients with severe CAD and nonsevere CAD. Principal component analysis revealed 8 distinct dietary patterns. The first component Western dietary pattern (increased intake of fat, red meat, and carbohydrates and minimal consumption of fruits and green leafy vegetables) was predictive of severe CAD (area under the curve: 0.73, 95% confidence intervals: 0.64-0.83, P < .001). In conclusion, an unhealthy Western type of diet is associated with the severity of coronary artery lesions in patients with stable CAD. These findings highlight the role of dietary patterns when estimating cardiovascular risk for the management of patients with CAD. PMID- 28731360 TI - Communications between Pulmonary Airways and Blood Vessels. A New Mechanism? PMID- 28731361 TI - The Impact of Teaching Prognostication at the End of Life: A Pre-Post Interventional Study. AB - BACKGROUND: Providing accurate and valid prognostic information significantly influences end-of-life care. Disclosing a poor prognosis can be among the most difficult of physician responsibilities, thus having appropriate knowledge during training is crucial for appropriate prognostication. OBJECTIVE: To provide internal medicine (IM) house staff with a pre- and posteducational survey to determine their ability to accurately prognosticate 5 common end-stage diseases. DESIGN: We conducted a pre- and posteducational intervention survey-based study. A preintervention survey was administered to IM postgraduate year 1 (PGY-1) and PGY-2-4 house staff. The survey consisted of case scenarios for 5 common end stage diseases, containing 1 question on comfort level and 2 on prognostication (totaling 10 points). A 30-minute educational intervention was presented immediately after the initial survey. The same survey was readministered 4 weeks thereafter. An identical survey was administered once to palliative care faculty. RESULTS: Forty house staff completed pre- and posteducational surveys. Eight palliative care faculty completed the survey. No difference was found between all house staff pre- and postscores (mean 2.70 [1.45] vs 2.78 [1.59], P = .141). There was no significant difference between PGY-1 and PGY-2-4 pretest scores (mean 2.63 [1.71] vs 2.81 [1.42], P = .72). The PGY-2-4 posttest score was significantly greater than PGY-1 posttest score (3.38 [1.58] vs 2.38 [1.58], P = .05). Total house staff posttest score was significantly lower than gold standard palliative care faculty (mean 4.71 [1.98] vs 2.78 [1.59], P = .006). CONCLUSIONS: Our pre-post intervention survey-based study demonstrates no significant increases in all house staff scores. The PGY-2-4 postintervention scores improved significantly. We speculate the optimal time for prognostication education may be after the PGY-1 year when house staff have had sufficient exposure to common conditions. PMID- 28731363 TI - Fifty Years of Research in ARDS. ARDS: How It All Began. PMID- 28731362 TI - Greater Cognitive Deficits with Sleep-disordered Breathing among Individuals with Genetic Susceptibility to Alzheimer Disease. The Multi-Ethnic Study of Atherosclerosis. AB - RATIONALE: There are conflicting findings regarding the link between sleep apnea and cognitive dysfunction. OBJECTIVES: Investigate associations between indicators of sleep-disordered breathing (SDB) and cognitive function in the Multi-Ethnic Study of Atherosclerosis and assess effect modification by the apolipoprotein epsilon-4 (APOE-epsilon4) allele. METHODS: A diverse population (N = 1,752) underwent type 2 in-home polysomnography, which included measurement of percentage sleep time less than 90% oxyhemoglobin saturation (%Sat < 90%) and apnea-hypopnea index (AHI). Epworth Sleepiness Scale score (ESS) and sleep apnea syndrome (SAS; AHI >= 5 and ESS > 10) were also analyzed. Cognitive outcomes included the Cognitive Abilities Screening Instrument; Digit Symbol Coding (DSC) test; and Digit Span Tests (DST) Forward and Backward. RESULTS: Participants were 45.4% men, aged 68.1 years (SD, 9.1 yr) with a median AHI of 9.0 and mean ESS of 6.0. Approximately 9.7% had SAS, and 26.8% had at least one copy of the APOE epsilon4 allele. In adjusted analyses, a 1-SD increase in %Sat < 90% and ESS score were associated with a poorer attention and memory assessed by the DST Forward score (beta = -0.12 [SE, 0.06] and beta = -0.13 [SE, 0.06], respectively; P <= 0.05). SAS and higher ESS scores were also associated with poorer attention and processing speed as measured by the DSC (beta = -0.69 [SE, 0.35] and beta = 1.42 [SE, 0.35], respectively; P < 0.05). The presence of APOE-epsilon4 allele modified the associations of %Sat < 90% with DST forward and of ESS with DSC (Pinteraction <= 0.05). CONCLUSIONS: Overnight hypoxemia and sleepiness were associated with cognition. The average effect estimates were small, similar to effect estimates for several other individual dementia risk factors. Associations were strongest in APOE-epsilon4 risk allele carriers. Our results (1) suggest that SDB be considered among a group of modifiable dementia risk factors, and (2) highlight the potential vulnerability of APOE-epsilon4 risk allele carriers with SDB. PMID- 28731364 TI - Synthesis of a new insulin-mimetic anti-diabetic drug containing vitamin A and vanadium(IV) salt: Chemico-biological characterizations. AB - Diabetes patients suffer from chronic disorders in the metabolism due to high blood sugar caused by anomalies in insulin excretion. Recently, vanadium compounds have been prepared and functionalized to decrease the level of hyperglycemia. Vitamin A boosts beta cell activity; therefore, the lack of this vitamin plays a role in the development of type 2 diabetes. The aim of this article focused on the synthesis of a new anti-diabetic drug formed from the complexation of a vanadium(IV) salt with vitamin A. Vitamin A acts as a unidentate chelate through the oxygen of its -OH group. The vanadium(IV) compound is surrounded by two vitamin A molecules. The [VO(vitamin A)2(H2O)2] compound was synthesized in a binary solvent system consisting of MeOH/H2O (1:1 ratio) in alkaline media at pH = 8. This compound was characterized using Fourier transform infrared spectra (FT-IR), electronic spectra (UV-vis), effective magnetic moment, electron spin resonance (ESR), scanning electron microscopy (SEM), transmission electron microscopy (TEM), and thermal analysis (thermogravimetry (TG) differential thermal analysis (DTA)). Anti-diabetic efficiency for the vanadium(IV) compound was assessed in streptozotocin (STZ)-induced diabetic mice. The results of the animal studies demonstrate the ability of the vanadium(IV) complex to act as an anti-diabetic agent, as measured by improvements of lipid profile, antioxidant activity (superoxide dismutase), malondialdehyde (MDA), glutathione, methionine synthase, and kidney and liver functions. PMID- 28731365 TI - Chemical Composition and Antimigraine Activity of Essential Oil of Angelicae dahuricae Radix. AB - The aim of this study was to explore the chemical composition and the effect of essential oil of Angelicae dahuricae radix on a nitroglycerin (NTG)-induced rat model of migraine. The CO2 supercritical fluid extraction method was optimized for the extraction of essential oil of A. dahuricae radix (EOAD) and its chemical composition was determined. The migraine model was established by subcutaneous injection of NTG (10 mg/kg) 1 h after the last administration of EOAD. The therapeutic effect of EOAD and its underlying mechanism were assessed by monitoring behavioral changes, levels of nitric oxide (NO) in serum and brain tissues, plasma levels of calcitonin gene-related peptide (CGRP) and endothelin (ET), and ET/NO ratio. The optimal conditions for CO2 supercritical fluid extraction of EOAD, as determined by orthogonal test [L9(34)], were as follows: 2 h extraction time, 20 MPa pressure, 40 degrees C temperature, and 30 mesh. The yield of EOAD was 1.8%. On gas chromatography-mass spectrometry, 45 peaks were found in EOAD, and 22 compounds were identified and quantified. The main constituents of EOAD were 1-dodecanol (13.71%), elemene (7.54%), palmitic acid ethyl ester (7.32%), alpha-pinene (6.25%), and 1-pentadecanol (6.08%). Compared with rat migraine model controls, EOAD (35, 70, and 140 mg/kg) significantly reduced the number of head shaking, head scratching, and hind leg shooting events, decreased serum and brain NO levels, decreased plasma CGRP, and increased ET levels in rats. ET/NO ratio was elevated to 28.68 in the EOAD high-dose group. EOAD ameliorates NTG-induced migraine in rats likely by modulating the levels of vasoactive substances. PMID- 28731366 TI - Chondromyxoid fibroma of the distal fibula treated by percutaneous radiofrequency ablation. AB - BACKGROUND: Percutaneous radiofrequency ablation (RFA) has been shown to be an effective treatment for soft tissue lesions and also benign bone tumors, especially osteoid osteoma. There are limited data regarding this technique in other bone tumors, specifically larger and more aggressive ones. PURPOSES: To describe the use of RFA as a definitive treatment and an alternative to traditional open surgery for the treatment of chondromyxoid fibroma (CMF), a benign but locally aggressive bone tumor. CASE PRESENTATION: An 11.5-year-old girl was diagnosed with a 4-cm lytic bone lesion of the distal fibula. Evaluation, including biopsy, revealed CMF. It was managed by fluoroscopy-guided RFA only. Six-year follow-up demonstrated complete healing without damage to the adjacent distal fibular growth plate. DISCUSSION AND CONCLUSIONS: RFA induces local heat in the ablation field and causes tissue necrosis. The depth of heat penetration and the size of heated sphere are accurately controlled by modern types of ablation probes and accurate positioning. The current report demonstrates the ability to use this percutaneous technique for larger and more aggressive bone tumors than has been indicated previously. PMID- 28731367 TI - Methamphetamine Causes Photoreceptor Cell Damage Through Promoting Polarization of Macrophages and Inducing Inflammatory Response. AB - Classically activated macrophages (M1) are proinflammatory effectors and closely related to the progression of neurotoxicity. As a powerful psychostimulant and addictive drug, methamphetamine (Meth) abuse could result in long-lasting abnormalities in retina. This study investigated the effect of Meth at nontoxic concentration on macrophage activation state and its resultant toxicity to photoreceptor cells. Results showed that cytotoxicity was caused by Meth on 661 W cells after coculturing with RAW264.7 macrophage. RAW264.7 cells tended to switch to the M1 phenotype, releasing more proinflammatory cytokines after treatment with Meth. Meth could also upregulate the M1-related gene and protein expression. Our study demonstrated that Meth promoted macrophage polarization from M0 to M1 and induced inflammatory response, providing the scientific rationale for the photoreceptor cell damage caused by the Meth abuse. PMID- 28731368 TI - Computerized Planning of Prostate Cryosurgery and Shape Considerations. AB - The current study aims to explore possible relationships between various prostate shapes and the difficulty in creating a computer-based plan for cryosurgery. This research effort is a part of an ongoing study to develop computational means in order to improve cryosurgery training and education. This study uses a computerized planner-a key building block of a recently developed prototype for cryosurgery training. The quality of planning is measured by the overall defect volume, a proprietary concept which refers to undercooled areas internal to the target region and overcooled areas external to it. Results of this study numerically confirm that the overall defect volume decreases with an increasing number of cryoprobes, regardless of the geometry of the prostate. However, the number of cryoprobes required to achieve the smallest possible defect may be unrealistically high (<30). Results of this study also demonstrate that the optimal cryoprobe layout is associated with a smaller defect for symmetric prostate geometries and, independently, for prostate models that better resemble a sphere. Furthermore, a smaller defect is typically achieved when the urethra passes through the center of the prostate model. This study proposes to create a cryoprobe convex hull for the purpose of initial planning, which is a subdomain similar in shape to the prostate but at a reduced size. Parametric studies indicate that a cryoprobe convex hull contracted by 7 to 9 mm in all directions from the prostate capsule serves as a quasi-optimal initial condition for planning, that is, a preselected number of cryoprobes placed in the cryoprobe convex hull yields favorable results for optimization. The cryoprobe convex hull could accelerate computer-based planning, while also being adopted as a concept for traditional cryosurgery training, when computerized means are absent. PMID- 28731369 TI - Experimental Evaluation of Tranexamic Acid-Loaded Porous Starch as a Hemostatic Powder. AB - We evaluated the effectiveness of a novel hemostatic powder called Tranexamic Acid-loaded Porous Starch (TAPS) developed recently on blood clotting activity and hemostasis. The effectiveness of TAPS was evaluated by comparing hemostatic properties with those of Quick-acting Styptic Powder (QSP) and Compound Microporous Polysaccharide Haemostatic powder (CMPHP). The blood clotting activities of human blood were analyzed by thromboela-stogram (TEG) assays in vitro. The hemostatic effectiveness in vivo was evaluated using a rat model with hepatic traumatic hemorrhage. The blood loss and standardized bleeding score, which reflects the degree of bleeding after treatment with styptic powder, were used to evaluate hemostatic efficacy. In vitro, the values of TEG parameters in TAPS group were significantly different, compared with untreated controls or CMPHP group (p < 0.05). In vivo, the application of QSP, CMPHP and TAPS led to significantly decreased post-treatment blood loss than in the control group (p < 0.01). The scores of the groups treated with QSP, CMPHP and TAPS (0, 0.2+/-0.422, 0.3+/-0.483, respectively) were significant lower than with gauze control (1.6+/ 0.516) which success hemostatic was achieved at 5 minutes (p < 0.01). Hemostasis was achieved successfully within approximately 4 minutes after the application of TAPS. TAPS could help blood to form an artificial scab on a wound and to seal injuries for hemostasis to reduce blood loss in rats with hepatic trauma and hemorrhage. It was safe to use with no impact on blood clotting function or other apparent side effects. PMID- 28731370 TI - An Evaluation of a Factor Xa-Based Clotting Time Test for Enoxaparin: A Proof-of Concept Study. AB - A well-accepted test for monitoring anticoagulation by enoxaparin is not currently available. As inadequate dosing may result in thrombosis or bleeding, a clinical need exists for a suitable test. Previous in silico and in vitro studies have identified factor Xa as an appropriate activating agent, and the phospholipid Actin FS as a cofactor for a Xa clotting time (TenaCT) test. A proof of-concept study was designed to (1) explore the reproducibility of the TenaCT test and (2) explore factors that could affect the performance of the test. In vitro clotting time tests were carried out using plasma from 20 healthy volunteers. The effect of enoxaparin was determined at concentrations of 0.25, 0.50, and 1.0 IU/mL. Clotting times for the volunteers were significantly prolonged with increasing enoxaparin concentrations. Clotting times were significantly shortened for frozen plasma samples. No significant differences in prolongation of clotting times were observed between male and female volunteers or between the 2 evaluated age groups. The clotting times were consistent between 2 separate occasions. The TenaCT test was able to distinguish between the subtherapeutic and therapeutic concentrations of enoxaparin. Plasma should not be frozen prior to performing the test, without defining a frozen plasma reference range. This study provided proof-of-concept for a Xa-based test that can detect enoxaparin dose effects, but additional studies are needed to further develop the test. PMID- 28731371 TI - Determinants of Infection Outcome in HCV-Genotype 4. AB - Hepatitis C virus (HCV) infection represents a worldwide health problem and has been for long an attractive point of research due to diversity among different genotypes regarding unique geographical distribution and diverse treatment outcome. HCV is considered a major cause of chronic liver disease and cirrhosis, which leads to liver failure and hepatocellular carcinoma requiring liver transplantation. Of the HCV genotypes identified, HCV genotype 4 (HCV-4) is the least studied. HCV-4 is responsible for ~10% of HCV infections and is common in the Middle East and Africa; recently it is increasingly prevalent in European Countries. HCV-4 is a continuing epidemic in Egypt, having the highest prevalence of HCV worldwide. "Know your epidemic, know your response" concept necessitates better understanding of HCV-4 characteristics to control disease dissemination and progression, which compromises the life quality of chronic HCV-infected patients. In this review, we discuss the epidemiology, natural history, and treatment options for patients with HCV-4 infection. PMID- 28731372 TI - Exploring the effect of vitamin D3 supplementation on the anti-EBV antibody response in relapsing-remitting multiple sclerosis. AB - BACKGROUND: Epstein-Barr virus (EBV) infection and vitamin D insufficiency are potentially interacting risk factors for multiple sclerosis (MS). OBJECTIVES: To investigate the effect of high-dose vitamin D3 supplements on antibody levels against the EBV nuclear antigen-1 (EBNA-1) in patients with relapsing-remitting multiple sclerosis (RRMS) and to explore any underlying mechanism affecting anti EBNA-1 antibody levels. METHODS: This study utilized blood samples from a randomized controlled trial in RRMS patients receiving either vitamin D3 (14,000 IU/day; n = 30) or placebo ( n = 23) over 48 weeks. Circulating levels of 25 hydroxyvitamin-D, and anti-EBNA-1, anti-EBV viral capsid antigen (VCA), and anti cytomegalovirus (CMV) antibodies were measured. EBV load in leukocytes, EBV specific cytotoxic T-cell responses, and anti-EBNA-1 antibody production in vitro were also explored. RESULTS: The median antibody levels against EBNA-1, but not VCA and CMV, significantly reduced in the vitamin D3 group (526 (368-1683) to 455 (380-1148) U/mL) compared to the placebo group (432 (351-1280) to 429 (297-1290) U/mL; p = 0.023). EBV load and cytotoxic T-cell responses were unaffected. Anti EBNA-1 antibody levels remained below detection limits in B-cell cultures. CONCLUSION: High-dose vitamin D3 supplementation selectively reduces anti-EBNA-1 antibody levels in RRMS patients. Our exploratory studies do not implicate a promoted immune response against EBV as the underlying mechanism. PMID- 28731373 TI - Efficacy of 1% Metformin Gel in Patients With Moderate and Severe Chronic Periodontitis: A Randomized Controlled Clinical Trial. AB - BACKGROUND: The aim of this study is to investigate efficacy of metformin (MF) 1% gel as an adjunct to scaling and root planing (SRP) in the treatment of moderate and severe chronic periodontitis (CP). METHODS: Seventy patients were categorized into two treatment groups: 1) SRP plus 1% MF and 2) SRP plus placebo. Clinical parameters were recorded at baseline and 3, 6, and 9 months. They included plaque index (PI), modified sulcus bleeding index (mSBI), probing depth (PD), and clinical attachment level (CAL). Radiologic assessment of intrabony defects (IBDs) and percentage defect depth reduction (DDR%) was done at baseline and 6- and 9-month intervals using computer-aided software. PD, CAL, and DDR% were evaluated in two subgroups in both the placebo and MF group: 1) initial PD of 5 to 7 mm and 2) initial PD of >7 mm. RESULTS: Mean PD reduction and mean CAL gain was found to be greater in the MF group than the placebo group at all visits. Clinical parameters (PD, CAL) in both subgroups, with initial PDs of 5 to 7 and >7 mm, showed significant improvement in the 1% MF group compared with the placebo group. A significantly greater mean DDR% was found in the MF group than the placebo group at 6 and 9 months in both subgroups, 5 to 7 and >7 mm of initial PD. CONCLUSION: There was a greater decrease in PD and more CAL gain with significant IBD depth reduction at sites treated with SRP plus locally delivered MF in patients with CP in both initial PD = 5 to 7 and >7 mm subgroups compared with placebo. PMID- 28731374 TI - Trait Emotional Intelligence Related to Bullying in Elementary School Children and to Victimization in Boys. AB - While Healthy People 2020 calls for a reduction of bullying among high school students as a public health priority, earlier intervention supported by Occupational Therapists may be warranted. The current study investigated the prevalence of bullying behaviors within an elementary school, compared the experiences of victims with those of perpetrators, and determined when and for whom Trait Emotional Intelligence is a predictor of bullying and victimization. Elementary school children ( n = 235) in Grades 3 to 5 completed the Forms of Bullying Scale-Victim, the Forms of Bullying Scale-Perpetrator, and the Trait Emotional Intelligence Questionnaire-Child Short Form. The prevalence of bully only perpetration was 3.0%, of victimization-only was 48.5%, and of bully victimization was 10.4%. Trait Emotional Intelligence was negatively associated with bullying. Trait Emotional Intelligence was negatively associated with victimization in boys, but not girls. The findings are discussed within the need to provide instruction and services to students at an early age. PMID- 28731376 TI - Welcome to the Focused Scientific Sessions at the 2017 ACVP and ASVCP Concurrent Annual Meeting in Vancouver. PMID- 28731375 TI - Notice of Withdrawal: No Incidence of Nephrogenic Systemic Fibrosis after Gadobenate Dimeglumine Administration in Patients Undergoing Dialysis or Those with Severe Chronic Kidney Disease. AB - The authors have requested to withdraw this manuscript from publication because the study was not conducted in full accordance with the relevant institutional IRB protocol. (c) RSNA, 2018. PMID- 28731377 TI - Pathologic Changes and Autophagy: New Insights for the Pathogenesis of Animal Diseases. PMID- 28731378 TI - Experimental Infection of Cattle With a Novel Prion Derived From Atypical H-Type Bovine Spongiform Encephalopathy. AB - H-type bovine spongiform encephalopathy (H-BSE) is an atypical form of BSE in cattle. During passaging of H-BSE in transgenic bovinized (TgBoPrP) mice, a novel phenotype of BSE, termed BSE-SW emerged and was characterized by a short incubation time and host weight loss. To investigate the biological and biochemical properties of the BSE-SW prion, a transmission study was conducted in cattle, which were inoculated intracerebrally with brain homogenate from BSE-SW infected TgBoPrP mice. The disease incubation period was approximately 15 months. The animals showed characteristic neurological signs of dullness, and severe spongiform changes and a widespread, uniform distribution of disease-associated prion protein (PrPSc) were observed throughout the brain of infected cattle. Immunohistochemical PrPSc staining of the brain revealed the presence of intraglial accumulations and plaque-like deposits. No remarkable differences were identified in vacuolar lesion scores, topographical distribution patterns, and staining types of PrPSc in the brains of BSE-SW- vs H-BSE-infected cattle. PrPSc deposition was detected in the ganglia, vagus nerve, spinal nerve, cauda equina, adrenal medulla, and ocular muscle. Western blot analysis revealed that the specific biochemical properties of the BSE-SW prion, with an additional 10- to 12 kDa fragment, were well maintained after transmission. These findings indicated that the BSE-SW prion has biochemical properties distinct from those of H-BSE in cattle, although clinical and pathologic features of BSW-SW in cattle are indistinguishable from those of H-BSE. The results suggest that the 2 infectious agents, BSE-SW and H-BSE, are closely related strains. PMID- 28731379 TI - Quasi-experimental evaluation of a multifaceted intervention to improve quality of end-of-life care and quality of dying for patients with advanced dementia in long-term care institutions. AB - BACKGROUND: Improvement in the quality of end-of-life care for advanced dementia is increasingly recognized as a priority in palliative care. AIM: To evaluate the impact of a multidimensional intervention to improve quality of care and quality of dying in advanced dementia in long-term care facilities. DESIGN: Quasi experimental study with the intervention taking place in two long-term care facilities versus usual care in two others over a 1-year period. The intervention had five components: (1) training program to physicians and nursing staff, (2) clinical monitoring of pain using an observational pain scale, (3) implementation of a regular mouth care routine, (4) early and systematic communication with families about end-of-life care issues with provision of an information booklet, and (5) involvement of a nurse facilitator to implement and monitor the intervention. Quality of care was assessed with the Family Perception of Care Scale. The Symptom Management for End-of-Life Care in Dementia and the Comfort Assessment in Dying scales were used to assess the quality of dying. PARTICIPANTS: A total of 193 residents with advanced dementia and their close family members were included (97 in the intervention group and 96 in the usual care group). RESULTS: The Family Perception of Care score was significantly higher in the intervention group than in the usual care group (157.3 vs 149.1; p = 0.04). The Comfort Assessment and Symptom Management scores were also significantly higher in the intervention group. CONCLUSIONS: Our multidimensional intervention in long-term care facilities for patients with terminal dementia resulted in improved quality of care and quality of dying when compared to usual care. PMID- 28731380 TI - First Experience of Performing Hybrid Operations in Chronic Venous Obstructions of Iliofemoral Segments in Patients With Postthrombotic Syndrome. AB - OBJECTIVE: To assess the first results of hybrid operations in chronic venous obstructions of iliofemoral segments in patients with postthrombotic syndrome (PTS). METHODS: Hybrid operations (open endovenectomy from the common femoral vein with arteriovenous fistula creation and iliac vein stenting) were performed in 12 patients diagnosed with PTS. All of the patients were diagnosed with severe chronic venous insufficiency. The degree of manifestations of PTS was assessed by means of the Villalta score 7 months before and after the surgical intervention. Diagnostic methods of study included ultrasound duplex scanning, magnetic resonance and/or multispiral computed venography, and contrast venography. RESULTS: Technical success of the procedure was 92%. The outcomes of hybrid operations after 7 months were followed up in 6 patients and in 4 patients in 3 months. Secondary patency rates of the stented iliac veins amounted to 100%. No recurrences of venous ulcers were observed. Median Villalta scores improved from 15 to 7 ( P = .012). CONCLUSION: The first experience of hybrid operations for obstructive lesions of veins of the iliofemoral segments demonstrated their high efficacy and safety. PMID- 28731381 TI - Reperfusion after ischemic stroke is associated with reduced brain edema. AB - Rapid revascularization is highly effective for acute stroke, but animal studies suggest that reperfusion edema may attenuate its beneficial effects. We investigated the relationship between reperfusion and edema in patients from the Echoplanar Imaging Thrombolysis Evaluation Trial (EPITHET) and Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy (MR RESCUE) cohorts. Reperfusion percentage was measured as the difference in perfusion weighted imaging lesion volume between baseline and follow-up (day 3-5 for EPITHET; day 6-8 for MR RESCUE). Midline shift (MLS) and swelling volume were quantified on follow-up MRI. We found that reperfusion was associated with less MLS (EPITHET: Spearman rho = -0.46; P < 0.001, and MR RESCUE: Spearman rho = 0.49; P < 0.001) and lower swelling volume (EPITHET: Spearman rho = -0.56; P < 0.001, and MR RESCUE: Spearman rho = -0.27; P = 0.026). Multivariable analyses performed in EPITHET and MR RESCUE demonstrated that reperfusion independently predicted both less MLS (beta coefficient = -0.056; P = 0.025, and beta coefficient = -0.38; P = 0.028, respectively) and lower swelling volumes (beta coefficient = -4.7; P = 0.007, and beta coefficient = -10.7; P = 0.009, respectively), after adjusting for age, sex, NIHSS, admission glucose and follow up lesion size. Taken together, our data suggest that even modest improvement in perfusion is associated with less brain edema in EPITHET and MR RESCUE. PMID- 28731382 TI - External validation and clinical utility of a prediction model for 6-month mortality in patients undergoing hemodialysis for end-stage kidney disease. AB - BACKGROUND: End-stage kidney disease is associated with poor prognosis. Health care professionals must be prepared to address end-of-life issues and identify those at high risk for dying. A 6-month mortality prediction model for patients on dialysis derived in the United States is used but has not been externally validated. AIM: We aimed to assess the external validity and clinical utility in an independent cohort in Canada. DESIGN: We examined the performance of the published 6-month mortality prediction model, using discrimination, calibration, and decision curve analyses. SETTING/PARTICIPANTS: Data were derived from a cohort of 374 prevalent dialysis patients in two regions of British Columbia, Canada, which included serum albumin, age, peripheral vascular disease, dementia, and answers to the "the surprise question" ("Would I be surprised if this patient died within the next year?"). RESULTS: The observed mortality in the validation cohort was 11.5% at 6 months. The prediction model had reasonable discrimination (c-stat = 0.70) but poor calibration (calibration-in-the-large = -0.53 (95% confidence interval: -0.88, -0.18); calibration slope = 0.57 (95% confidence interval: 0.31, 0.83)) in our data. Decision curve analysis showed the model only has added value in guiding clinical decision in a small range of threshold probabilities: 8%-20%. CONCLUSION: Despite reasonable discrimination, the prediction model has poor calibration in this external study cohort; thus, it may have limited clinical utility in settings outside of where it was derived. Decision curve analysis clarifies limitations in clinical utility not apparent by receiver operating characteristic curve analysis. This study highlights the importance of external validation of prediction models prior to routine use in clinical practice. PMID- 28731383 TI - Training Employers to Implement Health Promotion Programs: Results From the CDC Work@Health(r) Program. AB - PURPOSE: Centers for Disease Control and Prevention (CDC) initiated the Work@Health Program to teach employers how to improve worker health using evidence-based strategies. Program goals included (1) determining the best way(s) to deliver employer training, (2) increasing employers' knowledge of workplace health promotion (WHP), and (3) increasing the number of evidence-based WHP interventions at employers' worksites. This study is one of the few to examine the effectiveness of a program designed to train employers how to implement WHP programs. DESIGN: Pre- and posttest design. SETTING: Training via 1 of 3 formats hands-on, online, or blended. PARTICIPANTS: Two hundred six individual participants from 173 employers of all sizes. INTERVENTION: Eight-module training curriculum to guide participants through building an evidence-based WHP program, followed by 6 to 10 months of technical assistance. MEASURES: The CDC Worksite Health ScoreCard and knowledge, attitudes, and behavior survey. ANALYSIS: Descriptive statistics, paired t tests, and mixed linear models. RESULTS: Participants' posttraining mean knowledge scores were significantly greater than the pretraining scores (61.1 vs 53.2, P < .001). A year after training, employers had significantly increased the number of evidence-based interventions in place (47.7 vs 35.5, P < .001). Employers' improvements did not significantly differ among the 3 training delivery formats. CONCLUSION: The Work@Health Program provided employers with knowledge to implement WHP interventions. The training and technical assistance provided structure, practical guidance, and tools to assess needs and select, implement, and evaluate interventions. PMID- 28731384 TI - Current Use of E-Cigarettes and Conventional Cigarettes Among US High School Students in Urban and Rural Locations: 2014 National Youth Tobacco Survey. AB - PURPOSE: Adolescent tobacco use is higher in rural than in urban areas. While e cigarette use is increasing rapidly among this age group, differences in prevalence between rural versus urban populations for this relatively novel product have not been explored. The purpose is to investigate whether location of school (rural-urban) is associated with e-cigarette use and dual use (defined as the use of both e-cigarettes and conventional cigarettes) among high school students. DESIGN: Cross-sectional survey obtained using a stratified, 3-stage cluster sample design. SETTING: United States. PARTICIPANTS: A nationally representative sample of US high school students (N = 11 053) who completed the 2014 National Youth Tobacco Survey (NYTS); slightly more than half were urban (54%). MEASURES: The NYTS measures tobacco-related knowledge, attitudes, and use behavior and demographics of students in the United States. ANALYSIS: Weighted logistic regression assessed the relationships of urban-rural location with current e-cigarette use and dual use, adjusting for demographic factors, perceived risk, and social norms. RESULTS: There were clear differences in patterns of adolescent e-cigarette and cigarette use in rural versus urban areas. Social norms and perceptions may play a role in understanding these differences. CONCLUSION: Urban youth current cigarette smokers were nearly twice as likely as rural cigarette smokers to also use e-cigarettes. Reasons for urban-rural differences need to be taken into account when designing prevention programs and policy changes. PMID- 28731386 TI - Impact of Childhood Adversity and Out-of-Home Placement for Male Adolescents Who Have Engaged in Sexually Abusive Behavior. AB - Child maltreatment and household dysfunction have long been linked to delinquency, adult criminality, and sexual offending. However, the association between adverse childhood experiences (ACEs), factors related to out-of-home placement, and the onset of maladaptive behaviors has not thoroughly been explored in adolescents who have engaged in sexually abusive behavior. In the present study, we examined archival records of 120 male youths who have received treatment for sexually abusive behavior. As expected, the male adolescents in this sample have experienced higher rates of ACEs than samples of adult males in the community, adult males who committed sexual offenses, and juvenile justice involved males as reported in the literature. Discrete-time survival analyses yielded increased risks of onset of aggression and sexually abusive behavior during early childhood and mid-to-late childhood, with significant associations between higher ACE scores and a greater number of out-of-home placements. Implications and future directions are discussed. PMID- 28731385 TI - Kids SIP smartER: A Feasibility Study to Reduce Sugar-Sweetened Beverage Consumption Among Middle School Youth in Central Appalachia. AB - PURPOSE: To test the feasibility of Kids SIP smartER, a school-based intervention to reduce consumption of sugar-sweetened beverages (SSBs). DESIGN: Matched contact randomized crossover study with mixed-methods analysis. SETTING: One middle school in rural, Appalachian Virginia. PARTICIPANTS: Seventy-four sixth and seventh graders (5 classrooms) received Kids SIP smartER in random order over 2 intervention periods. Feasibility outcomes were assessed among 2 teachers. INTERVENTION: Kids SIP smartER consisted of 6 lessons grounded in the Theory of Planned Behavior, media literacy, and public health literacy and aimed to improve individual SSB behaviors and understanding of media literacy and prevalent regional disparities. The matched-contact intervention promoted physical activity. MEASURES: Beverage Intake Questionnaire-15 (SSB consumption), validated theory questionnaires, feasibility questionnaires (student and teacher), student focus groups, teacher interviews, and process data (eg, attendance). ANALYSIS: Repeated measures analysis of variances across 3 time points, descriptive statistics, and deductive analysis of qualitative data. RESULTS: During the first intervention period, students receiving Kids SIP smartER (n = 43) significantly reduced SSBs by 11 ounces/day ( P = .01) and improved media ( P < .001) and public health literacy ( P < .01) understanding; however, only media literacy showed between-group differences ( P < .01). Students and teachers found Kids SIP smartER acceptable, in-demand, practical, and implementable within existing resources. CONCLUSION: Kids SIP smartER is feasible in an underresourced, rural school setting. Results will inform further development and large-scale testing of Kids SIP smartER to reduce SSBs among rural adolescents. PMID- 28731387 TI - A Comparative Analysis of Pulmonary and Critical Care Medicine Guideline Development Methodologies. AB - RATIONALE: The Institute of Medicine (IOM) standards for guideline development have had unintended negative consequences. A more efficient approach is desirable. OBJECTIVES: To determine whether a modified Delphi process early during guideline development discriminates recommendations that should be informed by a systematic review from those that can be based upon expert consensus. METHODS: The same questions addressed by IOM-compliant pulmonary or critical care guidelines were addressed by expert panels using a modified Delphi process, termed the Convergence of Opinion on Recommendations and Evidence (CORE) process. The resulting recommendations were compared. Concordance of the course of action, strength of recommendation, and quality of evidence, as well as the duration of recommendation development, were measured. MEASUREMENTS AND MAIN RESULTS: When 50% agreement was required to make a recommendation, all questions yielded recommendations, and the recommended courses of action were 89.6% concordant. When 70% agreement was required, 17.9% of questions did not yield recommendations, but for those that did, the recommended courses of action were 98.2% concordant. The time to completion was shorter for the CORE process (median, 19.3 vs. 1,309.0 d; P = 0.0002). CONCLUSIONS: We propose the CORE process as an early step in guideline creation. Questions for which 70% agreement on a recommendation cannot be achieved should go through an IOM-compliant process; however, questions for which 70% agreement on a recommendation can be achieved can be accepted, avoiding a lengthy systematic review. PMID- 28731388 TI - Electronic Visits for Minor Acute Illnesses: Analysis of Patient Demographics, Prescription Rates, and Follow-Up Care Within an Asynchronous Text-Based Online Visit. AB - INTRODUCTION: Patients can obtain medical advice and treatment from a healthcare provider asynchronously through an electronic visit (eVisit) within a secure online portal. METHODS: We conducted a retrospective record review of Mayo Clinic Rochester primary care empaneled patients who had an eVisit for a minor acute illness and were reviewed for 30-day outcomes of follow-up. RESULTS: Of the 1,009 eVisits analyzed, a total of 340 (34%) had follow-up within 30 days, with a follow-up rate of 154 (20%) when those who were advised to follow-up were excluded. Factors significantly associated with any type of follow-up care included specific advice for follow-up given by the eVisit provider and lack of a prescription given at the eVisit. The majority of eVisits were requested by females (88%), although gender was not associated with likelihood of having follow-up care. Fourteen patients received follow-up care in the emergency department, one patient was hospitalized, and zero deaths occurred within 30 days of the eVisit. Most eVisits (70%) were requested during regular clinic hours. Four diagnoses (urinary tract infection, sinusitis, upper respiratory infection, and conjunctivitis) comprised 87% of all eVisits. CONCLUSION: Most eVisits for minor acute illnesses can be completed without any further interaction with the healthcare system. PMID- 28731389 TI - Protease Hydrolysates of Filefish (Thamnaconus modestus) Byproducts Effectively Inhibit Foodborne Pathogens. AB - In this study, novel antimicrobial peptides had been derived by enzymatic hydrolysis of filefish (Thamnaconus modestus) byproduct (HFBP). Different proteases, (papain [P], trypsin [T], neutrase [N], pepsin [PE], and the mixture I [PN] and mixture II [PT]) and different hydrolysis time (60, 120, 180, and 240 min), have been used to generate peptides with different lengths and amino acid sequences. The antimicrobial properties of HFBPs were tested, against Gram positive and Gram-negative strains, using disc diffusion method. HFBP prepared after 120 min of the enzymatic hydrolysis by trypsin (HFBP-T) exhibited greatest antibacterial activities. Bacillus cereus 10451 (BC) and Salmonella enteritidis 10982 (SE) strains were most sensitive to HFBP-T with an inhibitory zone of 24.68 and 29.67 mm diameter and minimum inhibitory concentration of 1.25 and 2.5 mg/mL, respectively. Moreover, the antimicrobial activities of tested HFBPs increased significantly at low pH and temperature. The amino acid analysis showed that HFBP T protein hydrolysate is high in an amino acid of proline, which probably contributes to the antimicrobial activity. The results obtained from scanning electron microscopy suggested that HFBPs might kill bacteria by acting on the cell wall of bacteria. Conclusively, the HFBP derived from filefish byproduct with biological activates is an interesting alternative to the use of waste from the fishing industry as natural antimicrobials in food stuff. PMID- 28731390 TI - Letter to the Editor. Limitation of the Orthopedic System Inc. Cervical Spine Base Unit. PMID- 28731391 TI - Malpractice litigation following spine surgery. AB - OBJECTIVE Adverse events related to spine surgery sometimes lead to litigation. Few studies have evaluated the association between spine surgical complications and medical malpractice proceedings, outcomes, and awards. The aim of this study was to identify the most frequent causes of alleged malpractice in spine surgery and to gain insight into patient demographic and clinical characteristics associated with medical negligence litigation. METHODS A search for "spine surgery" spanning February 1988 to May 2015 was conducted utilizing the medicolegal research service VerdictSearch (ALM Media Properties, LLC). Demographic data for the plaintiff and defendant in addition to clinical data for the procedure and legal outcomes were examined. Spinal cord injury, anoxic/hypoxic brain injury, and death were classified as catastrophic complications; all other complications were classified as noncatastrophic. Both chi-square and t-tests were used to evaluate the effect of these variables on case outcomes and awards granted. RESULTS A total of 569 legal cases were examined; 335 cases were excluded due to irrelevance or insufficient information. Of the 234 cases included in this investigation, 54.2% (127 cases) resulted in a defendant ruling, 26.1% (61) in a plaintiff ruling, and 19.6% (46) in a settlement. The awards granted for plaintiff rulings ranged from $134,000 to $38,323,196 (mean $4,045,205 +/- $6,804,647). Awards for settlements ranged from $125,000 to $9,000,000 (mean $1,930,278 +/- $2,113,593), which was significantly less than plaintiff rulings (p = 0.022). Compared with cases without a delay in diagnosis of the complication, the cases with a diagnostic delay were more likely to result in a plaintiff verdict or settlement (42.9% vs 72.7%, p = 0.007) than a defense verdict, and were more likely to settle out of court (17.5% vs 40.9%, p = 0.008). Similarly, compared with cases without a delay in treatment of the complication, those with a therapeutic delay were more likely to result in a plaintiff verdict or settlement (43.7% vs 68.4%, p = 0.03) than a defense verdict, and were more likely to settle out of court (18.1% vs 36.8%, p = 0.04). Overall, 28% of cases (66/234) involved catastrophic complications. Physicians were more likely to lose cases (plaintiff verdict or settlement) with catastrophic complications (66.7% vs 37.5%, p < 0.001). In cases with a plaintiff ruling, catastrophic complications resulted in significantly larger mean awards than noncatastrophic complications ($6.1M vs $2.9M, p = 0.04). The medical specialty of the provider and the age or sex of the patient were not associated with the case outcome or award granted (p > 0.05). The average time to a decision for defendant verdicts was 5.1 years; for plaintiff rulings, 5.0 years; and for settlements, 3.4 years. CONCLUSIONS Delays in the diagnosis and the treatment of a surgical complication predict legal case outcomes favoring the plaintiff. Catastrophic complications are linked to large sums awarded to the plaintiff and are predictive of rulings against the physician. For physician defendants, the costs of settlements are significantly less than those of losing in court. Although this study provides potentially valuable data from a large series of postoperative litigation cases, it may not provide a true representation of all jurisdictions, each of which has variable malpractice laws and medicolegal environments. PMID- 28731392 TI - Editorial. Spine professionals must critically examine the impact of medicolegal pressures on delivering care. PMID- 28731394 TI - Letter to the Editor. Percutaneous posterior cervical transfacet fixation. PMID- 28731393 TI - The impact of decompression with instrumentation on local failure following spine stereotactic radiosurgery. AB - OBJECTIVE Spine stereotactic radiosurgery (SRS) is a safe and effective treatment for spinal metastases. However, it is unknown whether this highly conformal radiation technique is suitable at instrumented sites given the potential for microscopic disease seeding. The authors hypothesized that spinal decompression with instrumentation is not associated with increased local failure (LF) following SRS. METHODS A 2:1 propensity-matched retrospective cohort study of patients undergoing SRS for spinal metastasis was conducted. Patients with less than 1 month of radiographic follow-up were excluded. Each SRS treatment with spinal decompression and instrumentation was propensity matched to 2 controls without decompression or instrumentation on the basis of demographic, disease related, dosimetric, and treatment-site characteristics. Standardized differences were used to assess for balance between matched cohorts. The primary outcome was the 12-month cumulative incidence of LF, with death as a competing risk. Lesions demonstrating any in-field progression were considered LFs. Secondary outcomes of interest were post-SRS pain flare, vertebral compression fracture, instrumentation failure, and any Grade >= 3 toxicity. Cumulative incidences analysis was used to estimate LF in each cohort, which were compared via Gray's test. Multivariate competing-risks regression was then used to adjust for prespecified covariates. RESULTS Of 650 candidates for the control group, 166 were propensity matched to 83 patients with instrumentation. Baseline characteristics were well balanced. The median prescription dose was 16 Gy in each cohort. The 12-month cumulative incidence of LF was not statistically significantly different between cohorts (22.8% [instrumentation] vs 15.8% [control], p = 0.25). After adjusting for the prespecified covariates in a multivariate competing-risks model, decompression with instrumentation did not contribute to a greater risk of LF (HR 1.21, 95% CI 0.74-1.98, p = 0.45). The incidences of post-SRS pain flare (11% vs 14%, p = 0.55), vertebral compression fracture (12% vs 22%, p = 0.04), and Grade >= 3 toxicity (1% vs 1%, p = 1.00) were not increased at instrumented sites. No instrumentation failures were observed. CONCLUSIONS In this propensity-matched analysis, LF and toxicity were similar among cohorts, suggesting that decompression with instrumentation does not significantly impact the efficacy or safety of spine SRS. Accordingly, spinal instrumentation may not be a contraindication to SRS. Future studies comparing SRS to conventional radiotherapy at instrumented sites in matched populations are warranted. PMID- 28731395 TI - Nasoseptal flap necrosis: a rare complication of endoscopic endonasal surgery. AB - OBJECTIVE The vascularized nasoseptal flap (NSF) has become the workhorse for skull base reconstruction during endoscopic endonasal surgery (EES) of the ventral skull base. Although infrequently reported, as with any vascularized flap the NSF may undergo ischemic necrosis and become a nidus for infection. The University of Pittsburgh Medical Center's experience with NSF was reviewed to determine the incidence of necrotic NSF in patients following EES and describe the clinical presentation, imaging characteristics, and risk factors associated with this complication. METHODS The electronic medical records of 1285 consecutive patients who underwent EES at the University of Pittsburgh Medical Center between January 2010 and December 2014 were retrospectively reviewed. From this first group, a list of all patients in whom NSF was used for reconstruction was generated and further refined to determine if the patient returned to the operating room and the cause of this reexploration. Patients were included in the final analysis if they underwent endoscopic reexploration for suspected CSF leak or meningitis. Those patients who returned to the operating room for staged surgery or hematoma were excluded. Two neurosurgeons and a neuroradiologist, who were blinded to each other's results, assessed the MRI characteristics of the included patients. RESULTS In total, 601 patients underwent NSF reconstruction during the study period, and 49 patients met the criteria for inclusion in the final analysis. On endoscopic exploration, 8 patients had a necrotic, nonviable NSF, while 41 patients had a viable NSF with a CSF leak. The group of patients with a necrotic, nonviable NSF was then compared with the group with viable NSF. All 8 patients with a necrotic NSF had clinical and laboratory evidence indicative of meningitis compared with 9 of 41 patients with a viable NSF (p < 0.001). Four patients with necrotic flaps developed epidural empyema compared with 2 of 41 patients in the viable NSF group (p = 0.02). The lack of NSF enhancement on MR (p < 0.001), prior surgery (p = 0.043), and the use of a fat graft (p = 0.004) were associated with necrotic NSF. CONCLUSIONS The signs of meningitis after EES in the absence of a clear CSF leak with the lack of NSF enhancement on MRI should raise the suspicion of necrotic NSF. These patients should undergo prompt exploration and debridement of nonviable tissue with revision of skull base reconstruction. PMID- 28731396 TI - Contralateral posterior interhemispheric approach to deep medial parietooccipital vascular malformations: surgical technique and results. AB - OBJECTIVE Deep medial parietooccipital arteriovenous malformations (AVMs) and cerebral cavernous malformations (CCMs) are traditionally resected through an ipsilateral posterior interhemispheric approach (IPIA), which creates a deep, perpendicular perspective with limited access to the lateral margins of the lesion. The contralateral posterior interhemispheric approach (CPIA) flips the positioning, with the midline positioned horizontally for retraction due to gravity, but with the AVM on the upper side and the approach from the contralateral, lower side. The aim of this paper was to analyze whether the perpendicular angle of attack that is used in IPIA would convert to a parallel angle of attack with the CPIA, with less retraction, improved working angles, and no significant increase in risk. METHODS A retrospective review of pre- and postoperative clinical and radiographic data was performed in 8 patients who underwent a CPIA. RESULTS Three AVMs and 5 CCMs were resected using the CPIA, with an average nidus size of 2.3 cm and CCM diameter of 1.7 cm. All lesions were resected completely, as confirmed on postoperative catheter angiography or MRI. All patients had good neurological outcomes, with either stable or improved modified Rankin Scale scores at last follow-up. CONCLUSIONS The CPIA is a safe alternative approach to the IPIA for deep medial parietooccipital vascular malformations that extend 2 cm or more off the midline. Contralaterality and retraction due to gravity optimize the interhemispheric corridor, the surgical trajectory to the lesion, and the visualization of the lateral margin, without resection or retraction of adjacent normal cortex. Although the falx is a physical barrier to accessing the lesion, it stabilizes the ipsilateral hemisphere while gravity delivers the dissected lesion through the transfalcine window. Patient positioning, CSF drainage, venous preservation, and meticulous dissection of the deep margins are critical to the safety of this approach. PMID- 28731397 TI - Anaplastic meningioma: an analysis of the National Cancer Database from 2004 to 2012. AB - OBJECTIVE Anaplastic meningiomas represent 1%-2% of meningioma diagnoses and portend a poor prognosis. Limited information is available on practice patterns and optimal management. The purpose of this study was to define treatment patterns and outcomes by treatment modality using a large national cancer registry. METHODS The National Cancer Database was used to identify patients diagnosed with anaplastic meningioma from 2004 to 2012. Log-rank statistics were used to compare survival outcomes by extent of resection, use of adjuvant radiotherapy (RT), and use of adjuvant chemotherapy. Least-squares linear regression was used to evaluate the utilization of RT over time. Logistic regression modeling was used to identify predictors of receipt of RT. Cox proportional hazards modeling was used to evaluate the effect of RT, gross-total resection (GTR), and chemotherapy on survival. RESULTS A total of 755 adults with anaplastic meningioma were identified. The 5-year overall survival rate was 41.4%. Fifty-two percent of patients received RT, 7% received chemotherapy, and 58% underwent GTR. Older patients were less likely to receive RT (OR 0.98, p < 0.01). Older age (HR 1.04, p < 0.01), high comorbidity score (HR 1.33, p = 0.02), and subtotal resection (HR 1.57, p = 0.02) were associated with increased risk of death on multivariate modeling, while RT receipt was associated with decreased risk of death (HR 0.79, p = 0.04). Chemotherapy did not have a demonstrable effect on survival (HR 1.33, p = 0.18). CONCLUSIONS Anaplastic meningioma portends a poor prognosis. Gross-total resection and RT are associated with improved survival, but utilization of RT is low. Unless medically contraindicated, patients with anaplastic meningioma should be offered RT. PMID- 28731398 TI - Management of multiple meningiomas. AB - OBJECTIVE Multiple meningiomas account for 1%-10% of meningiomas. This study describes epidemiological aspects of the disease and its management, which is more challenging than for single tumors. METHODS A consecutive series of adult patients with >= 2 spatially separated meningiomas was reviewed. Patients with neurofibromatosis Type 2 were excluded. The authors collected clinical, imaging, histological, and treatment data to obtain information on epidemiology, management options, and outcomes of active treatment and surveillance. RESULTS A total of 133 consecutive patients were included over 25 years, with a total of 395 synchronous and 53 metachronous meningiomas, and a median of 2 tumors per patient. One hundred six patients had sporadic disease, 26 had radiation-induced disease, and 1 had familial meningiomatosis. At presentation, half of the patients were asymptomatic. In terms of their maximum cross-sectional diameter, the tumors were small (<= 2 cm) in 67% and large (> 4 cm) in 11% of the meningiomas. Fifty-four patients had upfront treatment, and 31 had delayed treatment after an observation period (mean 4 years). One in 4 patients had >= 2 meningiomas treated. Overall, 64% of patients had treatment for 142 tumors-67 with surgery and 18 with radiotherapy alone. The mean follow-up was 7 years, with 13% of treated patients receiving salvage therapy. Approximately 1 in 4 patients who underwent surgery had >= 1 WHO Grade II or III meningioma. Meningiomas of different histological subtypes and grades in the same patient were not uncommon. CONCLUSIONS Multiple meningiomas are often asymptomatic, probably because the majority are small and a significant proportion are induced by radiation. Approximately two-thirds of patients with multiple meningiomas require therapy, but only one-third of all meningiomas need active treatment. The authors recommend surveillance for stable and asymptomatic meningiomas and therapy for those that are symptomatic or growing. PMID- 28731399 TI - Expanding the endoscopic transpterygoid corridor to the petroclival region: anatomical study and volumetric comparative analysis. AB - OBJECTIVE The endoscopic endonasal transmaxillary transpterygoid (TMTP) approach has been the gateway for lateral skull base exposure. Removal of the cartilaginous eustachian tube (ET) and lateral mobilization of the internal carotid artery (ICA) are technically demanding adjunctive steps that are used to access the petroclival region. The gained expansion of the deep working corridor provided by these maneuvers has yet to be quantified. METHODS The TMTP approach with cartilaginous ET removal and ICA mobilization was performed in 5 adult cadaveric heads (10 sides). Accessible portions of the petrous apex were drilled during the following 3 stages: 1) before ET removal, 2) after ET removal but before ICA mobilization, and 3) after ET removal and ICA repositioning. Resection volumes were calculated using 3D reconstructions generated from thin-slice CT scans obtained before and after each step of the dissection. RESULTS The average petrous temporal bone resection volumes at each stage were 0.21 cm3, 0.71 cm3, and 1.32 cm3 (p < 0.05, paired t-test). Without ET removal, inferior and superior access to the petrous apex was limited. Furthermore, without ICA mobilization, drilling was confined to the inferior two-thirds of the petrous apex. After mobilization, the resection was extended superiorly through the upper extent of the petrous apex. CONCLUSIONS The transpterygoid corridor to the petroclival region is maximally expanded by the resection of the cartilaginous ET and mobilization of the paraclival ICA. These added maneuvers expanded the deep window almost 6 times and provided more lateral access to the petroclival region with a maximum volume of 1.5 cm3. This may result in the ability to resect small to-moderate sized intradural petroclival lesions up to that volume. Larger lesions may better be approached through an open transcranial approach. PMID- 28731400 TI - Letter to the Editor. Expression of tissue (pro)renin receptor and concentrations of its soluble form in CSF in adult diffuse gliomas. PMID- 28731401 TI - Intraoperative perception and estimates on extent of resection during awake glioma surgery: overcoming the learning curve. AB - OBJECTIVE There is ample evidence that extent of resection (EOR) is associated with improved outcomes for glioma surgery. However, it is often difficult to accurately estimate EOR intraoperatively, and surgeon accuracy has yet to be reviewed. In this study, the authors quantitatively assessed the accuracy of intraoperative perception of EOR during awake craniotomy for tumor resection. METHODS A single-surgeon experience of performing awake craniotomies for tumor resection over a 17-year period was examined. Retrospective review of operative reports for quantitative estimation of EOR was recorded. Definitive EOR was based on postoperative MRI. Analysis of accuracy of EOR estimation was examined both as a general outcome (gross-total resection [GTR] or subtotal resection [STR]), and quantitatively (5% within EOR on postoperative MRI). Patient demographics, tumor characteristics, and surgeon experience were examined. The effects of accuracy on motor and language outcomes were assessed. RESULTS A total of 451 patients were included in the study. Overall accuracy of intraoperative perception of whether GTR or STR was achieved was 79.6%, and overall accuracy of quantitative perception of resection (within 5% of postoperative MRI) was 81.4%. There was a significant difference (p = 0.049) in accuracy for gross perception over the 17 year period, with improvement over the later years: 1997-2000 (72.6%), 2001-2004 (78.5%), 2005-2008 (80.7%), and 2009-2013 (84.4%). Similarly, there was a significant improvement (p = 0.015) in accuracy of quantitative perception of EOR over the 17-year period: 1997-2000 (72.2%), 2001-2004 (69.8%), 2005-2008 (84.8%), and 2009-2013 (93.4%). This improvement in accuracy is demonstrated by the significantly higher odds of correctly estimating quantitative EOR in the later years of the series on multivariate logistic regression. Insular tumors were associated with the highest accuracy of gross perception (89.3%; p = 0.034), but lowest accuracy of quantitative perception (61.1% correct; p < 0.001) compared with tumors in other locations. Even after adjusting for surgeon experience, this particular trend for insular tumors remained true. The absence of 1p19q co deletion was associated with higher quantitative perception accuracy (96.9% vs 81.5%; p = 0.051). Tumor grade, recurrence, diagnosis, and isocitrate dehydrogenase-1 (IDH-1) status were not associated with accurate perception of EOR. Overall, new neurological deficits occurred in 8.4% of cases, and 42.1% of those new neurological deficits persisted after the 3-month follow-up. Correct quantitative perception was associated with lower postoperative motor deficits (2.4%) compared with incorrect perceptions (8.0%; p = 0.029). There were no detectable differences in language outcomes based on perception of EOR. CONCLUSIONS The findings from this study suggest that there is a learning curve associated with the ability to accurately assess intraoperative EOR during glioma surgery, and it may take more than a decade to be truly proficient. Understanding the factors associated with this ability to accurately assess EOR will provide safer surgeries while maximizing tumor resection. PMID- 28731402 TI - Twenty-four-hour emergency intervention versus early intervention in aneurysmal subarachnoid hemorrhage. AB - OBJECTIVE Recent observational data suggest that ultra-early treatment of ruptured aneurysms prevents rebleeding, thus improving clinical outcomes. However, advances in critical care management of patients with ruptured aneurysms may reduce the rate of rebleeding in comparison with earlier trials, such as the International Cooperative Study on the Timing of Aneurysm Surgery. The objective of the present study was to determine if an ultra-early aneurysm repair protocol will or will not significantly reduce the number of incidents of rebleeding following aneurysmal subarachnoid hemorrhage (SAH). METHODS A retrospective analysis of data from a prospectively collected cohort of patients with SAH was performed. Rebleeding was diagnosed as new or expanded hemorrhage on CT, which was determined by independent review conducted by multiple physicians. Preventability of rebleeding by ultra-early aneurysm clipping or coiling was also independently reviewed. Standard statistics were used to determine statistically significant differences between the demographic characteristics of those with rebleeding compared with those without. RESULTS Of 317 patients with aneurysmal SAH, 24 (7.6%, 95% CI 4.7-10.5) experienced rebleeding at any time point following initial aneurysm rupture. Only 1/24 (4.2%, 95% CI -3.8 to 12.2) incidents of rebleeding could have been prevented by a 24-hour ultra-early aneurysm repair protocol. The other 23 incidents could not have been prevented for the following reasons: rebleeding prior to admission to the authors' institution (14/23, 60.9%); initial diagnostic angiography negative for aneurysm (4/23, 17.4%); postoperative rebleeding (2/23, 8.7%); patient unable to undergo operation due to medical instability (2/23, 8.7%); intraoperative rebleeding (1/23, 4.3%). CONCLUSIONS At a single tertiary academic center, the overall rebleeding rate was 7.6% (95% CI 4.7-10.5) for those presenting with ruptured aneurysms. Implementation of a 24-hour ultra-early aneurysm repair protocol would only result in, at most, a 0.3% (95% CI -0.3 to 0.9) reduction in the incidence of rebleeding. PMID- 28731403 TI - Safe and sustainable: the extracranial approach toward frontoethmoidal meningoencephalocele repair. AB - OBJECTIVE Although rare, frontoethmoidal meningoencephaloceles continue to pose a challenge to neurosurgeons and plastic reconstructive surgeons. Especially when faced with limited infrastructure and resources, establishing reliable and safe surgical techniques is of paramount importance. The authors present a case series in order to evaluate a previously proposed concise approach for meningoencephalocele repair, with a focus on sustainability of internationally driven surgical efforts. METHODS Between 2001 and 2016, a total of 246 patients with frontoethmoidal meningoencephaloceles were treated using a 1-stage extracranial approach by a single surgeon in the Department of Neurosurgery of the Yangon General Hospital in Yangon, Myanmar, initially assisted by European surgeons. Outcomes and complications were evaluated. RESULTS A total of 246 patients (138 male and 108 female) were treated. Their ages ranged from 75 days to 32 years (median 8 years). The duration of follow-up ranged between 4 weeks and 16 years (median 4 months). Eighteen patients (7.3%) showed signs of increased intracranial pressure postoperatively, and early CSF rhinorrhea was observed in 27 patients (11%), with 5 (2%) of them requiring operative dural repair. In 8 patients, a decompressive lumbar puncture was performed. There were 8 postoperative deaths (3.3%) due to meningitis. In 15 patients (6.1%), recurrent herniation of brain tissue was observed; this herniation led to blindness in 1 case. The remaining patients all showed good to very good aesthetic and functional results. CONCLUSIONS A minimally invasive, purely extracranial approach to frontoethmoidal meningoencephalocele repair may serve well, especially in middle- and low-income countries. This case series points out how the frequently critiqued lack of sustainability in the field of humanitarian surgical missions, as well as the often-cited missing aftercare and dependence on foreign supporters, can be circumvented by meticulous training of local surgeons. PMID- 28731404 TI - Jackson-Pratt drainage in pediatric craniofacial reconstructive surgery: is it helping or hurting? AB - OBJECTIVE Jackson-Pratt drains (JPDs) are commonly employed in pediatric craniofacial reconstructive surgery (CRFS) to reduce postoperative wound complications, but their risk profile remains unknown. Perioperative blood loss and volume shifts are major risks of CFRS. The goal of this study was to evaluate the risks of JPD usage in CFRS, particularly with regard to perioperative blood loss, hyponatremia, intensive care unit (ICU) length of stay, and postoperative wound complications. METHODS The authors performed a retrospective review of data obtained in pediatric patients who underwent CFRS at a single institution, as performed by multiple surgeons between January 2010 and December 2014. Data were gathered from patients who did and did not receive JPDs at the time of surgery. Outcome measures were compared between the JPD and no-JPD groups. RESULTS The overall population 179 pediatric patients: 128 who received JPDs and 51 who did not. In their analysis, the authors found no significant differences in baseline patient characteristics between the two groups. The average JPD output over the first 48 hours was 222 +/- 142 ml. When examining the immediate preoperative to immediate postoperative time period, no significant differences were noted between the groups with regard to the need for blood transfusion or changes in hemoglobin, hematocrit, or serum sodium levels. These differences were also not significant when examining the 48-hour postoperative period. Finally, no significant differences in hospital length of stay, ICU length of stay, or emergency department visits at 60 days were noted between the two groups. CONCLUSIONS In this retrospective study, the use of JPDs in pediatric CFRS was not associated with an increased risk of serious perioperative complications, although the benefits of this practice remain unclear. PMID- 28731406 TI - Reconstructing human pancreatic differentiation by mapping specific cell populations during development. AB - Information remains scarce on human development compared to animal models. Here, we reconstructed human fetal pancreatic differentiation using cell surface markers. We demonstrate that at 7weeks of development, the glycoprotein 2 (GP2) marks a multipotent cell population that will differentiate into the acinar, ductal or endocrine lineages. Development towards the acinar lineage is paralleled by an increase in GP2 expression. Conversely, a subset of the GP2+ population undergoes endocrine differentiation by down-regulating GP2 and CD142 and turning on NEUROG3, a marker of endocrine differentiation. Endocrine maturation progresses by up-regulating SUSD2 and lowering ECAD levels. Finally, in vitro differentiation of pancreatic endocrine cells derived from human pluripotent stem cells mimics key in vivo events. Our work paves the way to extend our understanding of the origin of mature human pancreatic cell types and how such lineage decisions are regulated. PMID- 28731405 TI - Pro-death NMDA receptor signaling is promoted by the GluN2B C-terminus independently of Dapk1. AB - Aberrant NMDA receptor (NMDAR) activity contributes to several neurological disorders, but direct antagonism is poorly tolerated therapeutically. The GluN2B cytoplasmic C-terminal domain (CTD) represents an alternative therapeutic target since it potentiates excitotoxic signaling. The key GluN2B CTD-centred event in excitotoxicity is proposed to involve its phosphorylation at Ser-1303 by Dapk1, that is blocked by a neuroprotective cell-permeable peptide mimetic of the region. Contrary to this model, we find that excitotoxicity can proceed without increased Ser-1303 phosphorylation, and is unaffected by Dapk1 deficiency in vitro or following ischemia in vivo. Pharmacological analysis of the aforementioned neuroprotective peptide revealed that it acts in a sequence independent manner as an open-channel NMDAR antagonist at or near the Mg2+ site, due to its high net positive charge. Thus, GluN2B-driven excitotoxic signaling can proceed independently of Dapk1 or altered Ser-1303 phosphorylation. PMID- 28731407 TI - T cell receptor repertoires of mice and humans are clustered in similarity networks around conserved public CDR3 sequences. AB - Diversity of T cell receptor (TCR) repertoires, generated by somatic DNA rearrangements, is central to immune system function. However, the level of sequence similarity of TCR repertoires within and between species has not been characterized. Using network analysis of high-throughput TCR sequencing data, we found that abundant CDR3-TCRbeta sequences were clustered within networks generated by sequence similarity. We discovered a substantial number of public CDR3-TCRbeta segments that were identical in mice and humans. These conserved public sequences were central within TCR sequence-similarity networks. Annotated TCR sequences, previously associated with self-specificities such as autoimmunity and cancer, were linked to network clusters. Mechanistically, CDR3 networks were promoted by MHC-mediated selection, and were reduced following immunization, immune checkpoint blockade or aging. Our findings provide a new view of T cell repertoire organization and physiology, and suggest that the immune system distributes its TCR sequences unevenly, attending to specific foci of reactivity. PMID- 28731410 TI - Infectious and Noninfectious Pulmonary Complications in Patients With Primary Immunodeficiency Disorders. AB - Primary immunodeficiency disorders (PIDs) are caused by 1 or more defects of the immune system. Patients are more likely to experience recurrent and/or severe infections and tend to develop a wide range of complications. Respiratory diseases are the main and initial manifestation in most cases and the most common complication. Pulmonary complications cause significant morbidity and mortality in patients with PIDs. Early diagnosis and appropriate treatment can prevent or at least slow the development of respiratory complications. Since the spectrum of pulmonary complications in PIDs is broad, we divided pulmonary complications into upper respiratory complications (eg, sinusitis, otitis media, and laryngeal angioedema) and lower respiratory complications (eg, pneumonia, bronchitis, bronchiectasis, interstitial lung diseases, organizing pneumonia, pulmonary adenopathies and malignancies, hyperreactive airway diseases, pulmonary dysgenesis, and adverse reactions to treatment). This review covers the main respiratory manifestations in patients with PIDs. PMID- 28731409 TI - Assessment of the Probability of Autochthonous Transmission of Chikungunya Virus in Canada under Recent and Projected Climate Change. AB - BACKGROUND: Chikungunya virus (CHIKV) is a reemerging pathogen transmitted by Aedes aegypti and Aedes albopictus mosquitoes. The ongoing Caribbean outbreak is of concern due to the potential for infected travelers to spread the virus to countries where vectors are present and the population is susceptible. Although there has been no autochthonous transmission of CHIKV in Canada, there is concern that both Ae. albopictus and CHIKV will become established, particularly under projected climate change. We developed risk maps for autochthonous CHIKV transmission in Canada under recent (1981-2010) and projected climate (2011-2040 and 2041-2070). METHODS: The risk for CHIKV transmission was the combination of the climatic suitability for CHIKV transmission potential and the climatic suitability for the presence of Ae. albopictus; the former was assessed using a stochastic model to calculate R0 and the latter was assessed by deriving a suitability indicator (SIG) that captures a set of climatic conditions known to influence the ecology of Ae. albopictus. R0 and SIG were calculated for each grid cell in Canada south of 60 degrees N, for each time period and for two emission scenarios, and combined to produce overall risk categories that were mapped to identify areas suitable for transmission and the duration of transmissibility. FINDINGS: The risk for autochthonous CHIKV transmission under recent climate is very low with all of Canada classified as unsuitable or rather unsuitable for transmission. Small parts of southern coastal British Columbia become progressively suitable with short-term and long-term projected climate; the duration of potential transmission is limited to 1-2 months of the year. INTERPRETATION: Although the current risk for autochthonous CHIKV transmission in Canada is very low, our study could be further supported by the routine surveillance of Ae. albopictus in areas identified as potentially suitable for transmission given our uncertainty on the current distribution of this species in Canada. https://doi.org/10.1289/EHP669 PMID- 28731408 TI - Defining the biological basis of radiomic phenotypes in lung cancer. AB - Medical imaging can visualize characteristics of human cancer noninvasively. Radiomics is an emerging field that translates these medical images into quantitative data to enable phenotypic profiling of tumors. While radiomics has been associated with several clinical endpoints, the complex relationships of radiomics, clinical factors, and tumor biology are largely unknown. To this end, we analyzed two independent cohorts of respectively 262 North American and 89 European patients with lung cancer, and consistently identified previously undescribed associations between radiomic imaging features, molecular pathways, and clinical factors. In particular, we found a relationship between imaging features, immune response, inflammation, and survival, which was further validated by immunohistochemical staining. Moreover, a number of imaging features showed predictive value for specific pathways; for example, intra-tumor heterogeneity features predicted activity of RNA polymerase transcription (AUC = 0.62, p=0.03) and intensity dispersion was predictive of the autodegration pathway of a ubiquitin ligase (AUC = 0.69, p<10-4). Finally, we observed that prognostic biomarkers performed highest when combining radiomic, genetic, and clinical information (CI = 0.73, p<10-9) indicating complementary value of these data. In conclusion, we demonstrate that radiomic approaches permit noninvasive assessment of both molecular and clinical characteristics of tumors, and therefore have the potential to advance clinical decision-making by systematically analyzing standard-of-care medical images. PMID- 28731411 TI - Oral Immunotherapy for Food Allergy: A Spanish Guideline. Immunotherapy Egg and Milk Spanish Guide (ITEMS Guide). Part I: Cow Milk and Egg Oral Immunotherapy: Introduction, Methodology, Rationale, Current State, Indications, Contraindications, and Oral Immunotherapy Build-up Phase. AB - BACKGROUND AND OBJECTIVE: Cow milk and egg are the most frequent causes of food allergy in the first years of life. Oral immunotherapy (OIT) has been investigated as an alternative to avoidance diets. No clinical practice guidelines on the management of OIT with milk and egg are currently available. Objectives: To develop clinical guidelines for OIT based on available scientific evidence and the opinions of experts. METHODS: A review was made of studies published between 1984 and June 2016, doctoral theses published in Spain, summaries of communications at scientific meetings (SEAIC, SEICAP, EAACI, and AAAAI), and the consensus of opinion established by a group of experts from the scientific societies SEICAP and SEAIC. RESULTS: Recommendations were established regarding the indications, requirements and practical aspects of the different phases of OIT, as well as special protocols for patients at high risk of adverse reactions. CONCLUSIONS: Clinical practice guidelines based on the consensus reached between Spanish experts are presented for the management of OIT with milk and egg. PMID- 28731412 TI - Lung Sound Analysis Is Useful for Monitoring Therapy in Patients With Bronchial Asthma. AB - BACKGROUND AND OBJECTIVE: Lung sound analysis (LSA) has been reported to be useful for predicting airway obstruction and inflammation in patients with bronchial asthma. Objectives: We examined whether the exhalation-to-inhalation sound pressure ratio in the middle frequency range (200-400 Hz) (E/I MF) is useful for monitoring therapy in patients with asthma. METHODS: The study population comprised 84 patients with mild to moderate asthma whose LSA data were available before and after 1 year of daily treatment with (budesonide 800 MUg). We analyzed whether the E/I MF before and after treatment was associated with the fractional exhaled nitric oxide (FeNO) level, sputum eosinophil percentage, respiratory function, and airway hyperresponsiveness. RESULTS: Prior to treatment with budesonide, the E/I MF was significantly correlated with respiratory function, airway hyperresponsiveness, FeNO, and sputum eosinophil percentage. The cutoff values for the E/I MF to detect the abnormalities of respiratory function, FeNO, and sputum eosinophil percentage were 0.367, 0.358, and 0.363, respectively. With respect to the reference value, the E/I MF improved significantly in patients whose respiratory function and FeNO benefited from therapy with budesonide compared with patients whose respiratory function did not benefit from budesonide (odds ratios of 6.39 and 4.78, respectively). According to the multivariate analysis, patients whose E/I MF did not improve had a longer history of smoking (P=.038), poorer posttreatment respiratory function (P=.028), and higher posttreatment FeNO (P=.0095). CONCLUSIONS: Similar to respiratory function and FeNO, E/I MF based on LSA is a useful indicator for monitoring the efficacy of therapy in asthmatic patients. PMID- 28731413 TI - Association Between Pollen Exposure and Nasal Cytokines in Grass Pollen-Allergic Children. PMID- 28731414 TI - Identification of a Lipid Transfer Protein as a New Allergen From Morus alba Pollen. PMID- 28731415 TI - Eosinophilic Esophagitis After Egg Oral Immunotherapy in an Adult With Egg Allergy and Egg-Bird Syndrome. PMID- 28731416 TI - Physician, Beware! Drug Fever Without Skin Rashes Can Be Caused by Minocycline. PMID- 28731417 TI - Donkey's Milk Is Well Accepted and Tolerated by Infants With Cow's Milk Food Protein-Induced Enterocolitis Syndrome: A Preliminary Study. PMID- 28731418 TI - An Unusual Case of Contact Dermatitis Caused by a Pacemaker Implanted for Neurostimulation. PMID- 28731419 TI - Stevens-Johnson Syndrome After Influenza Vaccine Injection. PMID- 28731420 TI - Adult Atopic Dermatitis: Less Certainty, More Challenges. PMID- 28731421 TI - Reply to "Adult Atopic Dermatitis: Less Certainty, More Challenges". PMID- 28731422 TI - Frailty in men living with HIV: a cross-sectional comparison of three frailty instruments. AB - BACKGROUND: Potent antiretroviral treatment has resulted in near normal life expectancy for people living with HIV. Consequently, there is an increased focus on comorbidities, frailty and quality of life. METHODS: We assessed and compared the prevalence of frailty, associated factors and relationship with quality of life in older Australian men living with HIV in a cross-sectional study using three frailty measurements. The Frailty Phenotype, Frailty Index and Edmonton Frail Scale were applied to 93 HIV-infected men aged over 50 years, on antiretroviral therapy. Multivariable ordinal logistic regression was used to analyse the associations of frailty with covariates and quality of life. RESULTS: The prevalence of frailty was 10.8% (n=10) using the Frailty Phenotype; 22.6% (n=21) using the Frailty Index and 15.1% (n=14) using the Edmonton Frail Scale. Frailty Phenotype-defined pre-frailty/frailty was associated with pre-1996 ART initiation (OR, 3.56; CI, 1.23, 10.36; P=0.020) and depression (OR, 3.74; CI, 1.24, 11.27; P=0.019). Osteoporosis, serious non-AIDS events and AIDS were associated with Frailty Index-defined frailty (OR, 4.84, CI, 1.27, 18.43, P=0.021; OR, 4.27, CI, 1.25, 14.58, P=0.020; OR, 4.62, CI, 1.30, 16.45, P=0.018, respectively) and Edmonton Frail Scale-defined frailty (OR, 7.51; CI, 1.55, 36.42; P=0.012; OR, 7.71; CI, 1.62, 36.75; P=0.010; OR, 8.53; CI, 1.70, 42.73; P=0.009, respectively), independent of age and current CD4+ T-cell count. Frailty, defined by any of the instruments, was significantly associated with poorer quality of life (P<0.001). CONCLUSIONS: Identifying frailty is an increasingly important contemporary consideration of HIV care related to ageing and quality of life. PMID- 28731423 TI - Magnetic properties of monoclinic lanthanide metaborates, Ln(BO2)3, Ln = Pr, Nd, Gd, Tb. AB - The bulk magnetic properties of the lanthanide metaborates, Ln(BO2)3, Ln = Pr, Nd, Gd, Tb are studied using magnetic susceptibility, heat capacity and isothermal magnetisation measurements. They are found to crystallise in a monoclinic structure containing chains of magnetic Ln 3+ and could therefore exhibit features of low-dimensional magnetism and frustration. Pr(BO2)3 is found to have a non-magnetic singlet ground state. No magnetic ordering is observed down to 0.4 K for Nd(BO2)3. Gd(BO2)3 exhibits a sharp magnetic transition at 1.1 K, corresponding to 3D magnetic ordering. Tb(BO2)3 shows two magnetic ordering features at 1.05 K and 1.95 K. A magnetisation plateau at a third of the saturation magnetisation is seen at 2 K for both Nd(BO2)3 and Tb(BO2)3, which persists in an applied field of 14 T. This is proposed to be a signature of quasi 1D behaviour in Nd(BO2)3 and Tb(BO2)3. PMID- 28731424 TI - Separation of atomic-scale spin contrast on NiO(0 0 1) by magnetic resonance force microscopy. AB - In magnetic exchange force microscopy, images contain the topographic contrast mixed with the spin contrast on the sample surface. In this study, we propose a new method of magnetic resonance force microscopy using ferromagnetic resonance to extract only the spin contrast. In this method, the magnetization of a magnetic cantilever is modulated by ferromagnetic resonance to separate the spin contrast and topographic contrast. We succeeded in obtaining a spin image of Ni atoms on a NiO (0 0 1) surface. Furthermore, we successfully detected the superexchange interaction between the tip apex atom and the second layer of Ni atoms. PMID- 28731425 TI - High-performance electronic transport in the plane of 3D type-II Dirac semimetals. AB - Recently, the type-II Dirac fermion, a new topological state, has been proposed in the Al3V family. It breaks Lorentz symmetry and has unique physical properties. We use first-principles calculations to investigate electronic transport limited by phonon scattering. The electronic resistivity in the xy plane is estimated to be 24.1 [Formula: see text] cm for Al3V and is much lower than that along the z direction. The heavy electronic effective mass along the z direction and the main electron-phonon coupling, originating from the phonon modes vibrating along the z direction, lead to anisotropic electronic transport, which is also found in other members of the Al3V family. PMID- 28731426 TI - Hydroxylated graphene-based flexible carbon film with ultrahigh electrical and thermal conductivity. AB - Graphene-based films are widely used in the electronics industry. Here, surface hydroxylated graphene sheets (HGS) have been synthesized from natural graphite (NG) by a rapid and efficient molten hydroxide-assisted exfoliation technique. This method enables preparation of aqueous dispersible graphene sheets with a high dispersed concentration (~10.0 mg ml-1) and an extraordinary production yield (~100%). The HGS dispersion was processed into graphene flexible film (HGCF) through fast filtration, annealing treatment and mechanical compression. The HGS endows graphene flexible film with a high electrical conductivity of 11.5 * 104 S m-1 and a superior thermal conductivity of 1842 W m-1 K-1. Simultaneously, the superflexible HGCF could endure 3000 repeated cycles of bending or folding. As a result, this graphene flexible film is expected to be integrated into electronic packaging and high-power electronics applications. PMID- 28731428 TI - Development of Nasal Lipid Nanocarriers Containing Curcumin for Brain Targeting. AB - BACKGROUND: Curcumin (CUR) has properties that can be useful for the treatment of Alzheimer's disease. Such properties are the inhibition of amyloid-beta-protein (Abeta) aggregation, Abeta-induced inflammation, and activities of beta-secretase and acetylcholinesterase. However, previous studies have revealed that CUR exhibited low bioavailability and difficulties in reaching the brain. OBJECTIVE: To overcome such drawbacks, this study aims at developing nasal lipid nanocarriers loaded with CUR to effectively target the brain. METHODS: The lipid nanocarriers (NE) were prepared using the hot solvent diffusion associated with the phase inversion temperature methods. Physico-chemical and morphological characterizations and in vitro drug release of the nanocarriers were carried out. The CUR permeation/retention was analyzed in Franz-type diffusion cell using porcine nasal mucosa. Confocal laser scan and histopathological studies were also performed. RESULTS: The results showed that the NE sizes ranged between 18 nm and 44 nm with negative zeta potential. The CUR content ranged from 0.24 to 1.50 mg/mL with an encapsulation efficiency of 99%. The profiles of CUR release indicated a biphasic kinetics. CUR-NE permeation across the porcine nasal mucosa was higher when compared to free CUR. These results have also been validated through an analysis on a confocal microscopy. In addition, no toxicity on the nasal mucosa has been observed in a histopathological analysis. CONCLUSION: These results suggest that it is possible to develop NEs with a high content of CUR and small particle size. Such an encapsulation increases the potential of CUR permeation across the porcine nasal mucosa. PMID- 28731429 TI - Severity of Depression Impacts Imminent Conversion from Mild Cognitive Impairment to Alzheimer's Disease. AB - BACKGROUND: Mild cognitive impairment (MCI) has been suggested to represent a prodromal stage of dementia and to confer a high risk for conversion to dementia Alzheimer's type (DAT). OBJECTIVES: In this study, we examined the predictive value of depressive symptoms and neuropsychological variables on conversion of MCI to DAT. METHODS: Neuropsychological and clinical follow-up data of 260 MCI patients seen at the Psychiatric Memory Clinic of the Medical University of Innsbruck between 2005 and 2015 were analyzed retrospectively. Depression was assessed using the Geriatric Depression Scale (GDS). Potential predictors of conversion from MCI to DAT were analyzed by logistic regression analyses and additional survival-analytic methods. RESULTS: Of the 260 patients (mean age 71.5+/-7.7 years), 83 (32%) converted to DAT within a mean follow-up time of 3.2+/-2.2 years and estimated one-year conversion rate of 10.1%. The univariate analysis showed with few exceptions (gender, use of antidepressants, low GDS score) group differences at baseline in patients converted to DAT compared to stable MCI patients. Logistic regression analysis as well as survival analysis revealed moderate to severe depression together with higher age and specific cognitive deficits as predictors of conversion from MCI to DAT. CONCLUSION: Our results support the predictive value of different neuropsychological measures on the progression of DAT. In addition, we found a strong negative influence of depression on conversion to DAT in MCI patients. These results emphasize the importance of assessing depressive symptoms in the early stages of DAT when evaluating the conversion from MCI to DAT. PMID- 28731430 TI - Neuroimaging Feature Terminology: A Controlled Terminology for the Annotation of Brain Imaging Features. AB - Ontologies and terminologies are used for interoperability of knowledge and data in a standard manner among interdisciplinary research groups. Existing imaging ontologies capture general aspects of the imaging domain as a whole such as methodological concepts or calibrations of imaging instruments. However, none of the existing ontologies covers the diagnostic features measured by imaging technologies in the context of neurodegenerative diseases. Therefore, the Neuro Imaging Feature Terminology (NIFT) was developed to organize the knowledge domain of measured brain features in association with neurodegenerative diseases by imaging technologies. The purpose is to identify quantitative imaging biomarkers that can be extracted from multi-modal brain imaging data. This terminology attempts to cover measured features and parameters in brain scans relevant to disease progression. In this paper, we demonstrate the systematic retrieval of measured indices from literature and how the extracted knowledge can be further used for disease modeling that integrates neuroimaging features with molecular processes. PMID- 28731431 TI - Association between Cholesterol Exposure and Neuropathological Findings: The ACT Study. AB - We characterized the relationship between late life cholesterol exposure and neuropathological outcomes in a community-based, older adult cohort. Adult Changes in Thought (ACT) is a cohort study that enrolls consenting, randomly selected, non-demented people aged >=65 from a healthcare delivery system. We used late life HDL and total cholesterol lab values from Group Health computerized records, and calculated HDL and non-HDL levels. We evaluated neuropathological outcomes of Alzheimer's disease, cerebral amyloid angiopathy, vascular brain injury, and Lewy body disease. Using linear mixed models with age and antilipemic medication as predictors, we obtained predicted cholesterol values at age 70 and 10 years prior to death for individuals with available cholesterol data in 10-year exposure windows. We used logistic regression to determine whether predicted late life cholesterol levels were associated with neuropathological outcomes controlling for age at death, APOE genotype, sex, and their interactions with cholesterol levels. 525 decedents came to autopsy by 08/2014. Of these, plasma cholesterol concentration was available for 318 (age 70, model 1) and 396 (10 years prior to death, model 2) participants. We did not find associations between late life cholesterol and Alzheimer's disease neuropathological changes, and there were no associations between cholesterol levels and amyloid angiopathy or vascular brain injury. We observed an association between predicted non-HDL cholesterol at age 70 and Lewy body disease. Our study suggests an association between late life non-HDL cholesterol exposure and Lewy body disease. We did not observe associations between late life cholesterol levels and Braak stage or CERAD score. PMID- 28731432 TI - Multivariate Approach for Alzheimer's Disease Detection Using Stationary Wavelet Entropy and Predator-Prey Particle Swarm Optimization. AB - BACKGROUND: The number of patients with Alzheimer's disease is increasing rapidly every year. Scholars often use computer vision and machine learning methods to develop an automatic diagnosis system. OBJECTIVE: In this study, we developed a novel machine learning system that can make diagnoses automatically from brain magnetic resonance images. METHODS: First, the brain imaging was processed, including skull stripping and spatial normalization. Second, one axial slice was selected from the volumetric image, and stationary wavelet entropy (SWE) was done to extract the texture features. Third, a single-hidden-layer neural network was used as the classifier. Finally, a predator-prey particle swarm optimization was proposed to train the weights and biases of the classifier. RESULTS: Our method used 4-level decomposition and yielded 13 SWE features. The classification yielded an overall accuracy of 92.73+/-1.03%, a sensitivity of 92.69+/-1.29%, and a specificity of 92.78+/-1.51%. The area under the curve is 0.95+/-0.02. Additionally, this method only cost 0.88 s to identify a subject in online stage, after its volumetric image is preprocessed. CONCLUSION: In terms of classification performance, our method performs better than 10 state-of-the-art approaches and the performance of human observers. Therefore, this proposed method is effective in the detection of Alzheimer's disease. PMID- 28731433 TI - The Effects of Cardiotrophin-1 on Early Synaptic Mitochondrial Dysfunction and Synaptic Pathology in APPswe/PS1dE9 Mice. AB - The coexistence of neuronal mitochondrial pathology and synaptic dysfunction is an early pathological feature of Alzheimer's disease (AD). Cardiotrophin-1 (CT-1) has been shown to exhibit impressive neuroprotective effects. Previous studies have shown positive effects of CT-1 on brain glucose metabolism and cognition in APPswe/PS1dE9 transgenic mice; however, little is known about the effects of CT-1 on early synaptic mitochondrial dysfunction and resultant synaptic pathology in the brain. In this study, 4-month-old transgenic mice with brain tissue-specific CT-1 expression were used alone or in combination with APPswe/PS1dE9 transgenic mice to evaluate the effect of CT-1 on synaptic mitochondrial dysfunction and resultant synaptic pathology, and cryptic memory deficits in the APPswe/PS1dE9 transgenic mice. The potential mechanism of action of CT-1 was also examined. Young CT-1*APPswe/PS1dE9 transgenic mice exhibited improvements in long-term learning and memory ability and ameliorations of synaptic mitochondrial/synaptic impairments compared to young APPswe/PS1dE9 transgenic mice. Moreover, CT-1 upregulated the expression of AMPAR and increased AMP-activated protein kinase (AMPK) activity in the hippocampus of APPswe/PS1dE9 transgenic mice. However, AMPK inhibition through shRNA knockdown of AMPKalpha blocked the neuroprotective effects of CT-1 on the expression of AMPAR and mitochondrial/synaptic dysfunction in Abeta-treated mouse neurons. These results suggest that CT-1 may be a potent candidate for the early prevention and treatment of AD. PMID- 28731434 TI - Passive Assessment of Routine Driving with Unobtrusive Sensors: A New Approach for Identifying and Monitoring Functional Level in Normal Aging and Mild Cognitive Impairment. AB - BACKGROUND: Driving is a key functional activity for many older adults, and changes in routine driving may be associated with emerging cognitive decline due to early neurodegenerative disease. Current methods for assessing driving such as self-report are inadequate for identifying and monitoring subtle changes in driving patterns that may be the earliest signals of functional change in developing mild cognitive impairment (MCI). OBJECTIVE: This proof of concept study aimed to establish the feasibility of continuous driving monitoring in a sample of cognitively normal and MCI older adults for an average of 206 days using an unobtrusive driving sensor and demonstrate that derived sensor-based driving metrics could effectively discriminate between MCI and cognitively intact groups. METHODS: Novel objective driving measures derived from 6 months of routine driving monitoring were examined in older adults with intact cognition (n = 21) and MCI (n = 7) who were enrolled in the Oregon Center for Aging and Technology (ORCATECH) longitudinal assessment program. RESULTS: Unobtrusive continuous monitoring of older adults' routine driving using a driving sensor was feasible and well accepted. MCI participants drove fewer miles and spent less time on the highway per day than cognitively intact participants. MCI drivers showed less day-to-day fluctuations in their driving habits than cognitively intact drivers. CONCLUSION: Sensor-based driving measures are objective, unobtrusive, and can be assessed every time a person drives his or her vehicle to identify clinically meaningful changes in daily driving. This novel methodology has the potential to be useful for the early detection and monitoring of changes in daily functioning within individuals. PMID- 28731435 TI - Identification of Circulating miR-125b as a Potential Biomarker of Alzheimer's Disease in APP/PS1 Transgenic Mouse. AB - Alzheimer's disease (AD) is the most common form of dementia, characterized by progressive decline in cognitive abilities of the affected individuals. Biological markers are essential to identify individuals at early stages of the disease for timely therapeutic intervention. Currently, pathological biomarkers are detected either through cerebrospinal fluid analysis or brain imaging, or postmortem, all of which are expensive, invasive, or time consuming. Recently, some studies have shown that circulating miR-125b, miR-181c, miR-9, miR-191-5p, miR-26b-3p, and miR-28-3p may be biomarkers of AD. However, those potential biomarkers are not validated in an AD mouse model. In the current study, we found that circulating miR-125b, miR-9, and miR-191-5p are downregulated, and miR-28-3p is upregulated in an APP/PS1 transgenic mouse model of AD. Furthermore, the correlation analysis shows a positive correlation between the expression of miR 125b and cognitive function of the APP/PS1 transgenic mouse. Moreover, we also determined that the level of serum miR-125b, miR-9, and miR-191-5p were reversed in EGCG-treated APP/PS1 transgenic mouse models. Finally, the expression of miR 125b was significantly downregulated in EGCG-treated SH-SY5Y cells. PMID- 28731436 TI - Impaired Processing of Serial Order Determines Working Memory Impairments in Alzheimer's Disease. AB - BACKGROUND: Working memory (WM) problems are commonly observed in Alzheimer's disease (AD), but the affected mechanisms leading to impaired WM are still insufficiently understood. The ability to efficiently process serial order in WM has been demonstrated to be fundamental to fluent daily life functioning. The decreased capability to mentally process serial position in WM has been put forward as the underlying explanation for generally compromised WM performance. OBJECTIVE: Determine which mechanisms, such as order processing, are responsible for deficient WM functioning in AD. METHOD: A group of AD patients (n = 32) and their partners (n = 25), assigned to the control group, were submitted to an extensive battery of neuropsychological and experimental tasks, assessing general cognitive state and functioning of several aspects related to serial order WM. RESULTS: The results revealed an impaired ability to bind item information to serial position within WM in AD patients compared to controls. It was additionally observed that AD patients experienced specific difficulties with directing spatial attention when searching for item information stored in WM. CONCLUSION: The processing of serial order and the allocation of attentional resources are both disrupted, explaining the generally reduced WM functioning in AD patients. Further studies should now clarify whether this observation could explain disease-related problems for other cognitive functions such as verbal expression, auditory comprehension, or planning. PMID- 28731437 TI - Computerized Cognitive Screen (CoCoSc): A Self-Administered Computerized Test for Screening for Cognitive Impairment in Community Social Centers. AB - BACKGROUND: Computerized cognitive tests may serve as a preliminary, low-cost method to identify individuals with suspected cognitive impairment in the community. OBJECTIVE: To develop a self-administered computerized test, namely the "Computerized Cognitive Screen (CoCoSc), Hong Kong version", for screening of individuals with cognitive impairment (CI) in community settings. METHODS: The CoCoSc is a 15-min computerized cognitive screen covering memory, executive functions, orientation, attention and working memory, and prospective memory administered on a touchscreen computer. Individuals with CI and cognitively normal controls were administered the CoCoSc and the Montreal Cognitive Assessment (MoCA). Validity of the CoCoSc was assessed based on the relationship with the MoCA using Pearson correlation. Receiver operating characteristic curve (ROC) was used to examine the ability of the CoCoSc to differentiate CI from controls. RESULTS: Fifty-nine individuals with CI and 101 controls were recruited. Seventy-five (46.9%) participants had <=6 years of education. Performance on the CoCoSc differed between normal and CI groups in both low and high education subgroups. Total scores of the CoCoSc and MoCA were significantly correlated (r = 0.71, p < 0.001). The area under ROC was 0.78, p < 0.001 for the CoCoSc total score in differentiating the CI group from the cognitively normal group. A cut-off of <=30 on the CoCoSc was associated with a sensitivity of 0.78 and specificity of 0.69. The CoCoSc was well accepted by attendees of community social centers. CONCLUSION: The CoCoSc is a promising computerized cognitive screen for self-administration in community social centers. It is feasible for testing individuals with high or low education levels. PMID- 28731438 TI - Evidence that the Human Innate Immune Peptide LL-37 may be a Binding Partner of Amyloid-beta and Inhibitor of Fibril Assembly. AB - BACKGROUND: Identifying physiologically relevant binding partners of amyloid-beta (Abeta) that modulate in vivo fibril formation may yield new insights into Alzheimer's disease (AD) etiology. Human cathelicidin peptide, LL-37, is an innate immune effector and modulator, ubiquitous in human tissues and expressed in myriad cell types. OBJECTIVE: We present in vitro experimental evidence and discuss findings supporting a novel hypothesis that LL-37 binds to Abeta42 and can modulate Abeta fibril formation. METHODS: Specific interactions between LL-37 and Abeta (with Abeta in different aggregation states, assessed by capillary electrophoresis) were demonstrated by surface plasmon resonance imaging (SPRi). Morphological and structural changes were investigated by transmission electron microscopy (TEM) and circular dichroism (CD) spectroscopy. Neuroinflammatory and cytotoxic effects of LL-37 alone, Abeta42 alone, and LL-37/Abeta complexes were evaluated in human microglia and neuroblastoma cell lines (SH-SY5Y). RESULTS: SPRi shows binding specificity between LL-37 and Abeta, while TEM shows that LL 37 inhibits Abeta42 fibril formation, particularly Abeta's ability to form long, straight fibrils characteristic of AD. CD reveals that LL-37 prevents Abeta42 from adopting its typical beta-type secondary structure. Microglia-mediated toxicities of LL-37 and Abeta42 to neurons are greatly attenuated when the two peptides are co-incubated prior to addition. We discuss the complementary biophysical characteristics and AD-related biological activities of these two peptides. CONCLUSION: Based on this body of evidence, we propose that LL-37 and Abeta42 may be natural binding partners, which implies that balanced (or unbalanced) spatiotemporal expression of the two peptides could impact AD initiation and progression. PMID- 28731439 TI - Antihypertensive Treatment is associated with MRI-Derived Markers of Neurodegeneration and Impaired Cognition: A Propensity-Weighted Cohort Study. AB - BACKGROUND: Hypertension is an important risk factor for Alzheimer's disease (AD) and cerebral small vessel disease. Angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are common anti-hypertensive treatments, but have differential effects on cortical amyloid. OBJECTIVE: The objective of this study was to evaluate associations between anti-hypertensive treatment, brain volume, and cognition, using a propensity-weighted analysis to account for confounding by indication. METHODS: We identified a cohort of normal elderly adults and individuals with mild cognitive impairment (MCI) or AD (N = 886; mean age = 75.0) from the Alzheimer's Disease Neuroimaging Initiative. Primary outcomes were brain parenchymal fraction, total hippocampal volume, and white matter hyperintensity (WMH) volume. Secondary outcomes were standardized scores on neuropsychological tests. Propensity-weighted adjusted multivariate linear regression was used to estimate associations between anti-hypertensive treatment class and MRI volumes and cognition. RESULTS: Individuals treated with ARBs showed larger hippocampal volumes (R2 = 0.83, p = 0.05) and brain parenchymal fraction (R2 = 0.83, p = 0.01) than those treated with ACEIs. When stratified by diagnosis, this effect remained only in normal elderly adults and MCI patients, and a significant association between ARBs and lower WMH volume (R2 = 0.83, p = 0.03) emerged for AD patients only. ARBs were also associated with significantly better performance on tests of episodic and verbal memory, language, and executive function (all p < 0.05). CONCLUSIONS: Findings are consistent with evidence for a neuroprotective effect of treatment with ARBs for brain structure and cognition. This study has potential implications for the treatment of hypertension, particularly in elderly adults at risk of cognitive decline and AD. PMID- 28731440 TI - Challenges and Considerations Related to Studying Dementia in Blacks/African Americans. AB - Blacks/African Americans have been reported to be ~2-4 times more likely to develop clinical Alzheimer's disease (AD) compared to Whites. Unfortunately, study design challenges (e.g., recruitment bias), racism, mistrust of healthcare providers and biomedical researchers, confounders related to socioeconomic status, and other sources of bias are often ignored when interpreting differences in human subjects categorized by race. Failure to account for these factors can lead to misinterpretation of results, reification of race as biology, discrimination, and missed or delayed diagnoses. Here we provide a selected historical background, discuss challenges, present opportunities, and suggest considerations for studying health outcomes among racial/ethnic groups. We encourage neuroscientists to consider shifting away from using biologic determination to interpret data, and work instead toward a paradigm of incorporating both biological and socio-environmental factors known to affect health outcomes with the goal of understanding and improving dementia treatments for Blacks/African Americans and other underserved populations. PMID- 28731441 TI - The Distinction of Amyloid-beta Protein Precursor (AbetaPP) Ratio in Platelet Between Alzheimer's Disease Patients and Controls: A Systematic Review and Meta Analysis. AB - To systematically assess the clinical significance of platelet amyloid-beta protein precursor (AbetaPP) ratio between Alzheimer's disease (AD) patients and controls. 14 articles were selected in this analysis by search of databases including PubMed and Web of Science up to December 2016. Random effects models were used to calculate the standardized mean difference (SMD). Subgroup analyses were used to detect the cause of heterogeneity. The result showed a significant drop in platelet AbetaPP ratio in AD patients compared to controls [SMD: -1.871; 95% CI: (-2.33, -1.41); p < 0.001; I2 = 88.0% ]. Subgroup analysis revealed races or the quality of studies may be the cause of high heterogeneity. This meta analysis concluded that there is a close association between platelet AbetaPP ratio and AD. It is necessary to design a sizable sample study to further support that platelet AbetaPP ratio can be a biomarker of AD. PMID- 28731442 TI - Of Mice and Men: Comparative Analysis of Neuro-Inflammatory Mechanisms in Human and Mouse Using Cause-and-Effect Models. AB - Perturbance in inflammatory pathways have been identified as one of the major factors which leads to neurodegenerative diseases (NDD). Owing to the limited access of human brain tissues and the immense complexity of the brain, animal models, specifically mouse models, play a key role in advancing the NDD field. However, many of these mouse models fail to reproduce the clinical manifestations and end points of the disease. NDD drugs, which passed the efficacy test in mice, were repeatedly not successful in clinical trials. There are numerous studies which are supporting and opposing the applicability of mouse models in neuroinflammation and NDD. In this paper, we assessed to what extend a mouse can mimic the cellular and molecular interactions in humans at a mechanism level. Based on our mechanistic modeling approach, we investigate the failure of a neuroinflammation targeted drug in the late phases of clinical trials based on the comparative analyses between the two species. PMID- 28731443 TI - Accuracy of Clinical Diagnosis of Dementia with Lewy Bodies versus Neuropathology. AB - BACKGROUND: The first consensus criteria for dementia with Lewy bodies (DLB) published in 1996 were revised in 2005, partly because the original clinical criteria had suboptimal sensitivity. Few studies have assessed the accuracy of the 2005 criteria applied prospectively in newly diagnosed patients who have been followed longitudinally. OBJECTIVE: To explore the correlation between clinical and pathological diagnoses in patients with DLB and Parkinson's disease with dementia (PDD). METHODS: From a prospective referral cohort study with enriched recruitment of patients with DLB and PDD, we included the first 56 patients coming to autopsy. Patients had mild dementia at inclusion and were followed annually until death with standardized clinical assessments. Pathological assessment was performed blind to clinical information according to standardized protocols and consensus criteria for DLB. RESULTS: 20 patients received a pathological diagnosis of Lewy body disease; the corresponding clinical diagnoses were probable DLB (n = 11), PDD (n = 5), probable (n = 2) or possible (n = 2) Alzheimer's disease (AD). Of 14 patients with a clinical diagnosis of probable DLB, 11 had DLB/PDD and 3 had AD at pathology. One patient with clinically possible DLB fulfilled criteria for pathological AD. Sensitivity, specificity, positive predictive value, and negative predictive values for probable DLB were 73%, 93%, 79%, and 90%. CONCLUSION: Our findings suggest that the international clinical consensus criteria for DLB perform reasonably well. However, false positive and false negative diagnoses still occur, indicating that the criteria need to be improved, that biomarkers may be needed, and that neuropathological feedback is vital to improve accuracy. PMID- 28731444 TI - The Relationship of Brain Amyloid Load and APOE Status to Regional Cortical Thinning and Cognition in the ADNI Cohort. AB - BACKGROUND: Both amyloid (Abeta) load and APOE4 allele are associated with neurodegenerative changes in Alzheimer's disease (AD) prone regions and with risk for cognitive impairment. OBJECTIVE: To evaluate the unique and independent contribution of APOE4 allele status (E4+?E4-), Abeta status (Amy+?Amy-), and combined APOE4 and Abeta status on regional cortical thickness (CoTh) and cognition among participants diagnosed as cognitively normal (CN, n = 251), early mild cognitive impairment (EMCI, n = 207), late mild cognitive impairment (LMCI, n = 196), and mild AD (n = 162) from the ADNI. METHODS: A series of two-way ANCOVAs with post-hoc Tukey HSD tests, controlling independently for Abeta and APOE4 status and age were examined. RESULTS: Among LMCI and AD participants, cortical thinning was widespread in association with Amy+ status, whereas in association with E4+ status only in the inferior temporal and medial orbito frontal regions. Among CN and EMCI participants, E4+ status, but not Amy+ status, was independently associated with increased CoTh, especially in limbic regions [e.g., in the entorhinal cortex, CoTh was 0.123 mm greater (p = 0.002) among E4+ than E4-participants]. Among CN and EMCI, both E4+ and Amy+ status were independently associated with cognitive impairment, which was greatest among those with combined E4 + and Amy+ status. CONCLUSION: Decreased CoTh is independently associated with Amy+ status in many brain regions, but with E4+ status in very restricted number of brain regions. Among CN and EMCI participants, E4 + status is associated with increased CoTh, in medial and inferior temporal regions, although cognitive impairment at this state is independently associated with Amy+ and E4 + status. These findings imply a unique pathophysiological mechanism for E4 + status in AD and its progression. PMID- 28731445 TI - Colivelin Ameliorates Impairments in Cognitive Behaviors and Synaptic Plasticity in APP/PS1 Transgenic Mice. AB - Alzheimer's disease (AD) is the most common cause of dementia, and effective therapeutics are lacking. Colivelin (CLN), a novel, strong humanin derivative, is effective in vitro in preventing cell death induced by AD-causative genes and amyloid-beta protein (Abeta) even at a low concentration. We recently demonstrated that intrahippocampal injection of CLN prevents Abeta25-35-induced deficits in spatial memory and synaptic plasticity in normal rats. Here, we further observed the effects of chronically intranasally (i.n.) administered CLN on cognitive behaviors and pathological hallmarks in 9-month-old APPswe/PS1dE9 (APP/PS1) AD mice using multiple behavioral tests and immunochemistry. The electrophysiological mechanism of CLN neuroprotection was also investigated by recording in vivo hippocampal long-term potentiation (LTP). CLN pretreatment effectively prevented impairments in new object recognition, working memory, and long-term spatial memory and reversed the depression of in vivo hippocampal LTP in APP/PS1 mice. Additionally, chronic application of CLN obviously reduced Abeta deposition in the hippocampus in APP/PS1 mice. These results indicate that CLN has strong neuroprotective effects on learning and memory behaviors in APP/PS1 mice and that this behavioral improvement is closely associated with the reduction of Abeta deposition and alleviation of LTP suppression in the hippocampus, supporting the potential of CLN for the prevention and treatment of AD. PMID- 28731446 TI - Effect of APOE Genotype on Synaptic Proteins in Earlier Adult Life. AB - BACKGROUND: Possession of APOEE4 is a strong risk factor for late-onset Alzheimer's disease and is associated with loss of synaptic proteins in the elderly even in the absence of Alzheimer's disease. OBJECTIVE: We hypothesized that E4 allele possession in non-demented adults aged under-75 would also be associated with alterations in the levels of synaptic proteins. METHODS: We measured synaptophysin, PSD95, drebrin, SNAP-25, and septin 7 by ELISA in hippocampus and superior temporal gyrus from 103 adults aged <75 without dementia. Corresponding gene expression was measured by RT-PCR. RESULTS: There was no evidence that E4 affected levels of the proteins measured. Instead we found an increase in post-synaptic proteins in the hippocampi of those with an E32 genotype. The evidence was strongest for drebrin (p = 0.011). There was some evidence of increased synaptic protein gene expression in E4 carriers. CONCLUSIONS: People with an APOEE32 genotype have a reduced risk of Alzheimer's disease. It may be relevant that they have a higher level of post-synaptic proteins in the hippocampus even in earlier adulthood. PMID- 28731447 TI - Chromatin-Bound Oxidized alpha-Synuclein Causes Strand Breaks in Neuronal Genomes in in vitro Models of Parkinson's Disease. AB - Alpha-synuclein (alpha-Syn) overexpression and misfolding/aggregation in degenerating dopaminergic neurons have long been implicated in Parkinson's disease (PD). The neurotoxicity of alpha-Syn is enhanced by iron (Fe) and other pro-oxidant metals, leading to generation of reactive oxygen species in PD brain. Although alpha-Syn is predominantly localized in presynaptic nerve terminals, a small fraction exists in neuronal nuclei. However, the functional and/or pathological role of nuclear alpha-Syn is unclear. Following up on our earlier report that alpha-Syn directly binds DNA in vitro, here we confirm the nuclear localization and chromatin association of alpha-Syn in neurons using proximity ligation and chromatin immunoprecipitation analysis. Moderate (~2-fold) increase in alpha-Syn expression in neural lineage progenitor cells (NPC) derived from induced pluripotent human stem cells (iPSCs) or differentiated SHSY-5Y cells caused DNA strand breaks in the nuclear genome, which was further enhanced synergistically by Fe salts. Furthermore, alpha-Syn required nuclear localization for inducing genome damage as revealed by the effect of nucleus versus cytosol specific mutants. Enhanced DNA damage by oxidized and misfolded/oligomeric alpha Syn suggests that DNA nicking activity is mediated by the chemical nuclease activity of an oxidized peptide segment in the misfolded alpha-Syn. Consistent with this finding, a marked increase in Fe-dependent DNA breaks was observed in NPCs from a PD patient-derived iPSC line harboring triplication of the SNCA gene. Finally, alpha-Syn combined with Fe significantly promoted neuronal cell death. Together, these findings provide a novel molecular insight into the direct role of alpha-Syn in inducing neuronal genome damage, which could possibly contribute to neurodegeneration in PD. PMID- 28731449 TI - Cerebrospinal Fluid Neurogranin as a Biomarker of Neurodegenerative Diseases: A Cross-Sectional Study. AB - We investigated cerebrospinal fluid (CSF) concentrations of the postsynaptic biomarker neurogranin at baseline in cognitively healthy controls (HC) compared to individuals with mild cognitive impairment (MCI), patients with Alzheimer's disease (AD) dementia, and patients with frontotemporal dementia (FTD). CSF neurogranin was quantified using an in-house immunoassay in a cross-sectional multicenter study of 108 participants [AD dementia (n = 35), FTD (n = 9), MCI (n = 41), cognitively HC (n = 23)]. CSF neurogranin concentrations were significantly higher in AD patients compared with both HC subjects and FTD patients, suggesting that increased CSF neurogranin concentrations may indicate AD-related pathophysiology. CSF neurogranin was independently associated with both total tau and hyperphosphorylated tau proteins, whereas a non-significant correlation with the 42-amino acid-long amyloid-beta peptide was evident. CSF neurogranin, however, was not superior to core AD biomarkers in differentiating HC from the three diagnostic groups, and it did not improve their diagnostic accuracy. We conclude that further classification and longitudinal studies are required to shed more light into the potential role of neurogranin as a pathophysiological biomarker of neurodegenerative diseases. PMID- 28731448 TI - Left Frontal Hub Connectivity during Memory Performance Supports Reserve in Aging and Mild Cognitive Impairment. AB - Reserve in aging and Alzheimer's disease (AD) is defined as maintaining cognition at a relatively high level in the presence of neurodegeneration, an ability often associated with higher education among other life factors. Recent evidence suggests that higher resting-state functional connectivity within the frontoparietal control network, specifically the left frontal cortex (LFC) hub, contributes to higher reserve. Following up these previous resting-state fMRI findings, we probed memory-task related functional connectivity of the LFC hub as a neural substrate of reserve. In elderly controls (CN, n = 37) and patients with mild cognitive impairment (MCI, n = 17), we assessed global connectivity of the LFC hub during successful face-name association learning, using generalized psychophysiological interaction analyses. Reserve was quantified as residualized memory performance, accounted for gender and proxies of neurodegeneration (age, hippocampus atrophy, and APOE genotype). We found that greater education was associated with higher LFC-connectivity in both CN and MCI during successful memory. Furthermore, higher LFC-connectivity predicted higher residualized memory (i.e., reserve). These results suggest that higher LFC-connectivity contributes to reserve in both healthy and pathological aging. PMID- 28731450 TI - The Experiences of People with Dementia and Their Caregivers in Dementia Diagnosis. AB - BACKGROUND: People can live well with dementia if they are diagnosed early and receive early interventions and appropriate dementia management and care. However, dementia is currently under-detected and under-diagnosed. The diagnosis rate is around 50% only in higher-income countries and 5-10% only in low- and middle-income countries. Studies on consumers' experiences in engaging in dementia diagnosis in a socio-cultural context are much needed in order to generate research evidence to inform person-centered dementia care and services. OBJECTIVE: The aim of the study was to understand the experiences of people with dementia and their caregivers in engaging in dementia diagnosis. METHODS: An interpretative study design informed by Gadamer's hermeneutic principles was applied to the present study to achieve the aim of the study. The study was strengthened by applying a social ecological framework to the study design. In total, 23 participants contributed to the interviews or focus group. Thematic analysis was applied to data analysis. RESULTS: Four themes were determined from data and described as: capabilities to detect the memory loss in an early stage, perceptions and beliefs of dementia in the community, different journeys toward the diagnosis and expectations of a smooth journey for others. These findings illuminate a social ecological perspective of improving early detection and timely diagnosis of dementia in the community settings. CONCLUSION: The findings of this study have implications for policy, resource, and practice development. Consumers expect that government subsidized dementia care services in primary care and specialist care settings are needed in order to enable consumer-driven timely diagnosis and dementia management in home care settings. PMID- 28731451 TI - Novel Blood-Based Biomarkers of Cognition, Stress, and Physical or Cognitive Training in Older Adults at Risk of Dementia: Preliminary Evidence for a Role of BDNF, Irisin, and the Kynurenine Pathway. AB - Psychosocial stress and physical, cognitive, and social activity predict the risk of cognitive decline and dementia. The aim of this study was to elucidate brain-derived neurotrophic factor (BDNF), irisin, and the kynurenine pathway (KP) as potential underlying biological correlates. We evaluated associations of irisin and the KP with BDNF in serum and with cognition, stress, and activities. Furthermore, changes in serum concentrations of BDNF, irisin, and KP metabolites were investigated after physical or cognitive training. Forty-seven older adults at risk of dementia were assigned to 10 weeks of physical training, cognitive training, or a wait-list control condition. Previous physical, cognitive, and social activities and stressful life events were recorded; global cognition, episodic memory, and executive functions were assessed. Serum levels of L kynurenine, kynurenic acid, 3-hydroxykynurenine (3-HK), and quinolinic acid (QUIN) were determined by validated assays based on liquid chromatography coupled to tandem mass spectrometry. BDNF and irisin serum levels were determined with enzyme-linked immunosorbent assays. BDNF and irisin correlated positively with global cognition and episodic memory, while the neurotoxic metabolite QUIN correlated negatively with executive functions. Stressful life events were associated with reduced BDNF and increased 3-HK. 3-HK decreased after cognitive training, while BDNF tended to increase after physical training. This suggests that psychosocial stress as well as cognitive and physical training may impact BDNF serum levels and the KP. Irisin and QUIN may constitute novel serum biomarkers of cognitive impairment, in addition to BDNF. Larger scale trials are needed to replicate and extend these novel findings. PMID- 28731453 TI - Topological Alterations and Symptom-Relevant Modules in the Whole-Brain Structural Network in Semantic Dementia. AB - BACKGROUND: Semantic dementia (SD) is characterized by a selective decline in semantic processing. Although the neuropsychological pattern of this disease has been identified, its topological global alterations and symptom-relevant modules in the whole-brain anatomical network have not been fully elucidated. OBJECTIVE: This study aims to explore the topological alteration of anatomical network in SD and reveal the modules associated with semantic deficits in this disease. METHODS: We first constructed the whole-brain white-matter networks of 20 healthy controls and 19 patients with SD. Then, the network metrics of graph theory were compared between these two groups. Finally, we separated the network of SD patients into different modules and correlated the structural integrity of each module with the severity of the semantic deficits across patients. RESULTS: The network of the SD patients presented a significantly reduced global efficiency, indicating that the long-distance connections were damaged. The network was divided into the following four distinctive modules: the left temporal/occipital/parietal, frontal, right temporal/occipital, and frontal/parietal modules. The first two modules were associated with the semantic deficits of SD. CONCLUSION: These findings illustrate the skeleton of the neuroanatomical network of SD patients and highlight the key role of the left temporal/occipital/parietal module and the left frontal module in semantic processing. PMID- 28731452 TI - Temporal Order of Alzheimer's Disease-Related Cognitive Marker Changes in BLSA and WRAP Longitudinal Studies. AB - Investigation of the temporal trajectories of currently used neuropsychological tests is critical to identifying earliest changing measures on the path to dementia due to Alzheimer's disease (AD). We used the Progression Score (PS) method to characterize the temporal trajectories of measures of verbal memory, executive function, attention, processing speed, language, and mental status using data spanning normal cognition, mild cognitive impairment, and AD from 1,661 participants with a total of 7,839 visits (age at last visit 77.6 SD 9.2) in the Baltimore Longitudinal Study of Aging (BLSA) and 1510 participants with a total of 3,473 visits (age at last visit 59.5 SD 7.4) in the Wisconsin Registry for Alzheimer's Prevention (WRAP). This method aligns individuals in time based on the similarity of their longitudinal measurements to reveal temporal trajectories. As a validation of our methodology, we explored the associations between the individualized cognitive progression scores (Cog-PS) computed by our method and clinical diagnosis. Digit span tests were the first to show declines in both data sets, and were detected mainly among cognitively normal individuals. These were followed by tests of verbal memory, which were in turn followed by Trail Making Tests, Boston Naming Test, and Mini-Mental State Examination. Differences in Cog-PS across the clinical diagnosis and APOEE4 groups were statistically significant, highlighting the potential use of Cog-PS as individualized indicators of disease progression. Identifying cognitive measures that are changing in preclinical AD can lead to the development of novel cognitive tests that are finely tuned to detecting earliest changes. PMID- 28731454 TI - Shi-Jiang Li, PhD, Recipient of 2017 Alzheimer Award. PMID- 28731455 TI - Corrigendum: Cassava foliage affects the microbial diversity of Chinese indigenous geese caecum using 16S rRNA sequencing. AB - This corrects the article DOI: 10.1038/srep45697. PMID- 28731456 TI - Upregulation of TET activity with ascorbic acid induces epigenetic modulation of lymphoma cells. AB - The Ten Eleven Translocation (TET) enzymes have been found to be mutated in both diffuse large B-cell (DLBCL) and peripheral T-cell (PTCL) lymphomas resulting in DNA hypermethylation. Recent studies in embryonal stem cells showed that ascorbic acid (AA) is a cofactor for TET with a binding site at the catalytic domain, and enhances TET activity. We hypothesized that AA could potentially enhance TET activity in lymphoma cells to cause DNA demethylation, reactivate expression of tumor suppressor genes and enhance chemosensitivity. We demonstrate in vitro that AA treatment of DLBCL and PTCL cells using AA concentrations achievable intravenously increased TET activity leading to DNA demethylation. This epigenetic effect is independent of hydrogen peroxide. AA treatment increased the expression of SMAD1, a tumor suppressor gene known to be suppressed by methylation, and increased chemosensitivity of lymphoma cells. Twenty-nine percent (10/34) of unselected lymphoma patients had plasma AA levels that were deficient suggesting an additional clinical mechanism of TET hypofunction. These data indicate that AA has the potential to modify TET function in lymphoma and enhance chemosensitivity. In addition, the AA deficiency seen in some patients may further impair TET function and contribute to resistance. Clinical trials testing intravenous AA with chemotherapy are warranted. PMID- 28731457 TI - MiR-155/miR-150 network regulates progression through the disease phases of chronic lymphocytic leukemia. PMID- 28731458 TI - Flow cytometry based monocyte subset analysis accurately distinguishes chronic myelomonocytic leukemia from myeloproliferative neoplasms with associated monocytosis. PMID- 28731459 TI - Malignant T cells activate endothelial cells via IL-17 F. PMID- 28731460 TI - Corrigendum: Effect of age on pro-inflammatory miRNAs contained in mesenchymal stem cell-derived extracellular vesicles. AB - This corrects the article DOI: 10.1038/srep43923. PMID- 28731461 TI - Corrigendum: Inorganic Photocatalytic Enhancement: Activated RhB Photodegradation by Surface Modification of SnO2 Nanocrystals with V2O5-like species. AB - This corrects the article DOI: 10.1038/srep44763. PMID- 28731462 TI - Corrigendum: Characterization of the first double-stranded RNA bacteriophage infecting Pseudomonas aeruginosa. AB - This corrects the article DOI: 10.1038/srep38795. PMID- 28731463 TI - Peroxisomes protect lymphoma cells from HDAC inhibitor-mediated apoptosis. AB - Peroxisomes are a critical rheostat of reactive oxygen species (ROS), yet their role in drug sensitivity and resistance remains unexplored. Gene expression analysis of clinical lymphoma samples suggests that peroxisomes are involved in mediating drug resistance to the histone deacetylase inhibitor (HDACi) Vorinostat (Vor), which promotes ROS-mediated apoptosis. Vor augments peroxisome numbers in cultured lymphoma cells, concomitant with increased levels of peroxisomal proteins PEX3, PEX11B, and PMP70. Genetic inhibition of peroxisomes, using PEX3 knockdown, reveals that peroxisomes protect lymphoma cells against Vor-mediated cell death. Conversely, Vor-resistant cells were tolerant to elevated ROS levels and possess upregulated levels of (1) catalase, a peroxisomal antioxidant, and (2) plasmalogens, ether glycerophospholipids that represent peroxisome function and serve as antioxidants. Catalase knockdown induces apoptosis in Vor-resistant cells and potentiates ROS-mediated apoptosis in Vor-sensitive cells. These findings highlight the role of peroxisomes in resistance to therapeutic intervention in cancer, and provide a novel modality to circumvent drug resistance. PMID- 28731464 TI - Trophoblast survival signaling during human placentation requires HSP70 activation of MMP2-mediated HBEGF shedding. AB - Survival of trophoblast cells in the low oxygen environment of human placentation requires metalloproteinase-mediated shedding of HBEGF and downstream signaling. A matrix metalloproteinase (MMP) antibody array and quantitative RT-PCR revealed upregulation of MMP2 post-transcriptionally in human first trimester HTR-8/SVneo trophoblast cells and placental villous explants exposed to 2% O2. Specific MMP inhibitors established the requirement for MMP2 in HBEGF shedding and upregulation. Because alpha-amanitin inhibited the upregulation of HBEGF, differentially expressed genes were identified by next-generation sequencing of RNA from trophoblast cells cultured at 2% O2 for 0, 1, 2 and 4 h. Nine genes, all containing HIF-response elements, were upregulated at 1 h, but only HSPA6 (HSP70B') remained elevated at 2-4 h. The HSP70 chaperone inhibitor VER 155008 blocked upregulation of both MMP2 and HBEGF at 2% O2, and increased apoptosis. However, both HBEGF upregulation and apoptosis were rescued by exogenous MMP2. Proximity ligation assays demonstrated interactions between HSP70 and MMP2, and between MMP2 and HBEGF, supporting the concept that MMP2-mediated shedding of HBEGF, initiated by HSP70, contributes to trophoblast survival at the low O2 concentrations encountered during the first trimester, and is essential for successful pregnancy outcomes. Trophoblast survival during human placentation, when oxygenation is minimal, required HSP70 activity, which mediated MMP2 accumulation and the transactivation of anti-apoptotic ERBB signaling by HBEGF shedding. PMID- 28731465 TI - PR-Set7 deficiency limits uterine epithelial population growth hampering postnatal gland formation in mice. AB - Formation of secretary endometrial glands in the uterus known as adenogenesis is a typical process of branching morphogenesis involving dynamic epithelial growth and differentiation. Unsuccessful adenogenesis often leads to female infertility. However, it remains largely unexplored so far regarding the epigenetic machinery governing normal endometrial gland formation. Here, we demonstrated that PR-Set7, an epigenetic regulator for H4K20me1 modification, was extensively expressed in the postnatal uteri, and its conditional deletion resulted in a complete lack of endometrial glands and infertility in mice. Subsequent analysis revealed that uterine PR-Set7 deficiency abolishes the dynamic endometrial epithelial population growth during the short span of gland formation from postnatal days 3 to 9. This markedly reduced epithelial population growth in PR-Set7-null mutant uteri is well associated with DNA damage accumulation and massive apoptotic death in the epithelium, due to blockade of 53BP1 recruitment to DNA damage sites upon reduced levels of H4K20me1/2. Using PgrCre/+/Rosa26DTA/+ mouse line and postnatal progesterone injection mouse model, we further confirmed that an impaired epithelial cell population growth either by inducing epithelial death in the diphtheria toxin-A (DTA)-mouse model or attenuating epithelial growth upon postnatal progesterone treatment similarly hampers uterine adenogenesis. Collectively, we establish here a novel 'epithelial population growth threshold' model for successful gland development. Besides further shedding light on the regulatory machinery governing uterine gland formation, our findings raise a safety concern on progesterone supplementation to prevent preterm birth in women bearing a female fetus, as exogenous progesterone may hamper uterine adenogenesis via attenuating epithelial population growth. PMID- 28731466 TI - Interaction of galectin-3 with MUC1 on cell surface promotes EGFR dimerization and activation in human epithelial cancer cells. AB - Epidermal growth factor receptor (EGFR) is an important regulator of epithelial cell growth and survival in normal and cancerous tissues and is a principal therapeutic target for cancer treatment. EGFR is associated in epithelial cells with the heavily glycosylated transmembrane mucin protein MUC1, a natural ligand of galectin-3 that is overexpressed in cancer. This study reveals that the expression of cell surface MUC1 is a critical enhancer of EGF-induced EGFR activation in human breast and colon cancer cells. Both the MUC1 extracellular and intracellular domains are involved in EGFR activation but the predominant influence comes from its extracellular domain. Binding of galectin-3 to the MUC1 extracellular domain induces MUC1 cell surface polarization and increases MUC1 EGFR association. This leads to a rapid increase of EGFR homo-/hetero dimerization and subsequently increased, and also prolonged, EGFR activation and signalling. This effect requires both the galectin-3 C-terminal carbohydrate recognition domain and its N-terminal ligand multi-merization domain. Thus, interaction of galectin-3 with MUC1 on cell surface promotes EGFR dimerization and activation in epithelial cancer cells. As MUC1 and galectin-3 are both commonly overexpressed in most types of epithelial cancers, their interaction and impact on EGFR activation likely makes important contribution to EGFR-associated tumorigenesis and cancer progression and may also influence the effectiveness of EGFR-targeted cancer therapy. PMID- 28731467 TI - Uncultivated microbes in need of their own taxonomy. AB - The great majority of microbial species remains uncultured, severely limiting their taxonomic characterization and thus communication among scientists. Although Candidatus was devised as a provisional category to classify uncultured taxa, it has not been widely accepted owing to technical limitations and lack of priority of Candidatus names in the official nomenclature. High-throughput sequencing provides the potential for data-rich taxonomic descriptions of uncultivated microbes, comparable in quality to those of cultured organisms. In order to fully realize this potential, standards and guidelines on how to perform these descriptions are needed. Here we aimed to outline these standards and draw the roadmap for a new genome-based taxonomy that, at least initially, would be parallel but highly convergent to the one in existence for isolates. In particular, we recommend the use of DNA genome sequences, recovered by population binning or single-cell techniques, as the basis for (i) identification and phylogenetic placement, (ii) bioinformatics-based functional and thus phenotypic predictions, as well as (iii) type material. We also recommend the implementation of an independent nomenclatural system for uncultivated taxa, following the same nomenclature rules as those for cultured Bacteria and Archaea but with its own list of validly published names. If widely adopted, this system will not only facilitate a comprehensive characterization of the 'uncultivated majority', but also provide a unified catalogue of validly published names, thereby avoiding synonyms and confusion. We also suggest that a committee of experts, supported by an international microbiological society, should be formed to govern the new classification system. PMID- 28731468 TI - A role for the cell-wall protein silacidin in cell size of the diatom Thalassiosira pseudonana. AB - Diatoms contribute 20% of global primary production and form the basis of many marine food webs. Although their species diversity correlates with broad diversity in cell size, there is also an intraspecific cell-size plasticity owing to sexual reproduction and varying environmental conditions. However, despite the ecological significance of the diatom cell size for food-web structure and global biogeochemical cycles, our knowledge about genes underpinning the size of diatom cells remains elusive. Here, a combination of reverse genetics, experimental evolution and comparative RNA-sequencing analyses enabled us to identify a previously unknown genetic control of cell size in the diatom Thalassiosira pseudonana. In particular, the targeted deregulation of the expression of the cell-wall protein silacidin caused a significant increase in valve diameter. Remarkably, the natural downregulation of the silacidin gene transcript due to experimental evolution under low temperature also correlated with cell-size increase. Our data give first evidence for a genetically controlled regulation of cell size in T. pseudonana and possibly other centric diatoms as they also encode the silacidin gene in their genomes. PMID- 28731469 TI - Novel chaperonins are prevalent in the virioplankton and demonstrate links to viral biology and ecology. AB - Chaperonins are protein-folding machinery found in all cellular life. Chaperonin genes have been documented within a few viruses, yet, surprisingly, analysis of metagenome sequence data indicated that chaperonin-carrying viruses are common and geographically widespread in marine ecosystems. Also unexpected was the discovery of viral chaperonin sequences related to thermosome proteins of archaea, indicating the presence of virioplankton populations infecting marine archaeal hosts. Virioplankton large subunit chaperonin sequences (GroELs) were divergent from bacterial sequences, indicating that viruses have carried this gene over long evolutionary time. Analysis of viral metagenome contigs indicated that: the order of large and small subunit genes was linked to the phylogeny of GroEL; both lytic and temperate phages may carry group I chaperonin genes; and viruses carrying a GroEL gene likely have large double-stranded DNA (dsDNA) genomes (>70 kb). Given these connections, it is likely that chaperonins are critical to the biology and ecology of virioplankton populations that carry these genes. Moreover, these discoveries raise the intriguing possibility that viral chaperonins may more broadly alter the structure and function of viral and cellular proteins in infected host cells. PMID- 28731470 TI - A genomic perspective on stoichiometric regulation of soil carbon cycling. AB - Similar to plant growth, soil carbon (C) cycling is constrained by the availability of nitrogen (N) and phosphorus (P). We hypothesized that stoichiometric control over soil microbial C cycling may be shaped by functional guilds with distinct nutrient substrate preferences. Across a series of rice fields spanning 5-25% soil C (N:P from 1:12 to 1:70), C turnover was best correlated with P availability and increased with experimental N addition only in lower C (mineral) soils with N:P?16. Microbial community membership also varied with soil stoichiometry but not with N addition. Shotgun metagenome data revealed changes in community functions with increasing C turnover, including a shift from aromatic C to carbohydrate utilization accompanied by lower N uptake and P scavenging. Similar patterns of C, N and P acquisition, along with higher ribosomal RNA operon copy numbers, distinguished that microbial taxa positively correlated with C turnover. Considering such tradeoffs in genomic resource allocation patterns among taxa strengthened correlations between microbial community composition and C cycling, suggesting simplified guilds amenable to ecosystem modeling. Our results suggest that patterns of soil C turnover may reflect community-dependent metabolic shifts driven by resource allocation strategies, analogous to growth rate-stoichiometry coupling in animal and plant communities. PMID- 28731471 TI - Changes in nutrient stoichiometry, elemental homeostasis and growth rate of aquatic litter-associated fungi in response to inorganic nutrient supply. AB - Aquatic fungi mediate important energy and nutrient transfers in freshwater ecosystems, a role potentially altered by widespread eutrophication. We studied the effects of dissolved nitrogen (N) and phosphorus (P) concentrations and ratios on fungal stoichiometry, elemental homeostasis, nutrient uptake and growth rate in two experiments that used (1) liquid media and a relatively recalcitrant carbon (C) source and (2) fungi grown on leaf litter in microcosms. Two monospecific fungal cultures and a multi-species assemblage were assessed in each experiment. Combining a radioactive tracer to estimate fungal production (C accrual) with N and P uptake measurements provided an ecologically relevant estimate of mean fungal C:N:P of 107:9:1 in litter-associated fungi, similar to the 92:9:1 obtained from liquid cultures. Aquatic fungi were found to be relatively homeostatic with respect to their C:N ratio (~11:1), but non homeostatic with respect to C:P and N:P. Dissolved N greatly affected fungal growth rate and production, with little effect on C:nutrient stoichiometry. Conversely, dissolved P did not affect fungal growth and production but controlled biomass C:P and N:P, probably via luxury P uptake and storage. The ability of fungi to immobilize and store excess P may alter nutrient flow through aquatic food webs and affect ecosystem functioning. PMID- 28731472 TI - High abundance and expression of transposases in bacteria from the Baltic Sea. AB - Transposases are mobile genetic elements suggested to have an important role in bacterial genome plasticity and host adaptation but their transcriptional activity in natural bacterial communities is largely unexplored. Here we analyzed metagenomes and -transcriptomes of size fractionated (0.1-0.8, 0.8-3.0 and 3.0 200 MUm) bacterial communities from the brackish Baltic Sea, and adjacent marine waters. The Baltic Sea transposase levels, up to 1.7% of bacterial genes and 2% of bacterial transcripts, were considerably higher than in marine waters and similar to levels reported for extreme environments. Large variations in expression were found between transposase families and groups of bacteria, with a two-fold higher transcription in Cyanobacteria than in any other phylum. The community-level results were corroborated at the genus level by Synechococcus transposases reaching up to 5.2% of genes and 6.9% of transcripts, which is in contrast to marine Synechococcus that largely lack these genes. Levels peaked in Synechococcus from the largest size fraction, suggesting high frequencies of lateral gene transfer and high genome plasticity in colony-forming picocyanobacteria. Together, the results support an elevated rate of transposition-based genome change and adaptation in bacterial populations of the Baltic Sea, and possibly also of other highly dynamic estuarine waters. PMID- 28731473 TI - Ninety-nine de novo assembled genomes from the moose (Alces alces) rumen microbiome provide new insights into microbial plant biomass degradation. AB - The moose (Alces alces) is a ruminant that harvests energy from fiber-rich lignocellulose material through carbohydrate-active enzymes (CAZymes) produced by its rumen microbes. We applied shotgun metagenomics to rumen contents from six moose to obtain insights into this microbiome. Following binning, 99 metagenome assembled genomes (MAGs) belonging to 11 prokaryotic phyla were reconstructed and characterized based on phylogeny and CAZyme profile. The taxonomy of these MAGs reflected the overall composition of the metagenome, with dominance of the phyla Bacteroidetes and Firmicutes. Unlike in other ruminants, Spirochaetes constituted a significant proportion of the community and our analyses indicate that the corresponding strains are primarily pectin digesters. Pectin-degrading genes were also common in MAGs of Ruminococcus, Fibrobacteres and Bacteroidetes and were overall overrepresented in the moose microbiome compared with other ruminants. Phylogenomic analyses revealed several clades within the Bacteriodetes without previously characterized genomes. Several of these MAGs encoded a large numbers of dockerins, a module usually associated with cellulosomes. The Bacteroidetes dockerins were often linked to CAZymes and sometimes encoded inside polysaccharide utilization loci, which has never been reported before. The almost 100 CAZyme-annotated genomes reconstructed in this study provide an in-depth view of an efficient lignocellulose-degrading microbiome and prospects for developing enzyme technology for biorefineries. PMID- 28731474 TI - Bacterial transcriptome remodeling during sequential co-culture with a marine dinoflagellate and diatom. AB - In their role as primary producers, marine phytoplankton modulate heterotrophic bacterial activities through differences in the types and amounts of organic matter they release. This study investigates the transcriptional response of bacterium Ruegeria pomeroyi, a member of the Roseobacter clade known to affiliate with diverse phytoplankton groups in the ocean, during a shift in phytoplankton taxonomy. The bacterium was initially introduced into a culture of the dinoflagellate Alexandrium tamarense, and then experienced a change in phytoplankton community composition as the diatom Thalassiosira pseudonana gradually outcompeted the dinoflagellate. Samples were taken throughout the 30 day experiment to track shifts in bacterial gene expression informative of metabolic and ecological interactions. Transcriptome data indicate fundamental differences in the exometabolites released by the two phytoplankton. During growth with the dinoflagellate, gene expression patterns indicated that the main sources of carbon and energy for R. pomeroyi were dimethysulfoniopropionate (DMSP), taurine, methylated amines, and polyamines. During growth with the diatom, dihydroxypropanesulfonate (DHPS), xylose, ectoine, and glycolate instead appeared to fuel the bulk of bacterial metabolism. Expression patterns of genes for quorum sensing, gene transfer agent, and motility suggest that bacterial processes related to cell communication and signaling differed depending on which phytoplankton species dominated the co-culture. A remodeling of the R. pomeroyi transcriptome implicating more than a quarter of the genome occurred through the change in phytoplankton regime. PMID- 28731475 TI - Unusual metabolic diversity of hyperalkaliphilic microbial communities associated with subterranean serpentinization at The Cedars. AB - Water from The Cedars springs that discharge from serpentinized ultramafic rocks feature highly basic (pH=~12), highly reducing (Eh<-550 mV) conditions with low ionic concentrations. These conditions make the springs exceptionally challenging for life. Here, we report the metagenomic data and recovered draft genomes from two different springs, GPS1 and BS5. GPS1, which was fed solely by a deep groundwater source within the serpentinizing system, was dominated by several bacterial taxa from the phyla OD1 ('Parcubacteria') and Chloroflexi. Members of the GPS1 community had, for the most part, the smallest genomes reported for their respective taxa, and encoded only archaeal (A-type) ATP synthases or no ATP synthases at all. Furthermore, none of the members encoded respiration-related genes and some of the members also did not encode key biosynthesis-related genes. In contrast, BS5, fed by shallow water, appears to have a community driven by hydrogen metabolism and was dominated by a diverse group of Proteobacteria similar to those seen in many terrestrial serpentinization sites. Our findings indicated that the harsh ultrabasic geological setting supported unexpectedly diverse microbial metabolic strategies and that the deep-water-fed springs supported a community that was remarkable in its unusual metagenomic and genomic constitution. PMID- 28731476 TI - Exact sequence variants should replace operational taxonomic units in marker-gene data analysis. AB - Recent advances have made it possible to analyze high-throughput marker-gene sequencing data without resorting to the customary construction of molecular operational taxonomic units (OTUs): clusters of sequencing reads that differ by less than a fixed dissimilarity threshold. New methods control errors sufficiently such that amplicon sequence variants (ASVs) can be resolved exactly, down to the level of single-nucleotide differences over the sequenced gene region. The benefits of finer resolution are immediately apparent, and arguments for ASV methods have focused on their improved resolution. Less obvious, but we believe more important, are the broad benefits that derive from the status of ASVs as consistent labels with intrinsic biological meaning identified independently from a reference database. Here we discuss how these features grant ASVs the combined advantages of closed-reference OTUs-including computational costs that scale linearly with study size, simple merging between independently processed data sets, and forward prediction-and of de novo OTUs-including accurate measurement of diversity and applicability to communities lacking deep coverage in reference databases. We argue that the improvements in reusability, reproducibility and comprehensiveness are sufficiently great that ASVs should replace OTUs as the standard unit of marker-gene analysis and reporting. PMID- 28731477 TI - Cohesion: a method for quantifying the connectivity of microbial communities. AB - The ability to predict microbial community dynamics lags behind the quantity of data available in these systems. Most predictive models use only environmental parameters, although a long history of ecological literature suggests that community complexity should also be an informative parameter. Thus, we hypothesize that incorporating information about a community's complexity might improve predictive power in microbial models. Here, we present a new metric, called community 'cohesion,' that quantifies the degree of connectivity of a microbial community. We analyze six long-term (10+ years) microbial data sets using the cohesion metrics and validate our approach using data sets where absolute abundances of taxa are available. As a case study of our metrics' utility, we show that community cohesion is a strong predictor of Bray-Curtis dissimilarity (R2=0.47) between phytoplankton communities in Lake Mendota, WI, USA. Our cohesion metrics outperform a model built using all available environmental data collected during a long-term sampling program. The result that cohesion corresponds strongly to Bray-Curtis dissimilarity is consistent across the six long-term time series, including five phytoplankton data sets and one bacterial 16S rRNA gene sequencing data set. We explain here the calculation of our cohesion metrics and their potential uses in microbial ecology. PMID- 28731478 TI - Role of plant-fungal nutrient trading and host control in determining the competitive success of ectomycorrhizal fungi. AB - Multiple ectomycorrhizal fungi (EMF) compete to colonise the roots of a host plant, but it is not known whether their success is under plant or fungal control, or a combination of both. We assessed whether plants control EMF colonisation by preferentially allocating more carbon to more beneficial partners in terms of nitrogen supply or if other factors drive competitive success. We combined stable isotope labelling and RNA-sequencing approaches to characterise nutrient exchange between the plant host Eucalyptus grandis and three Pisolithus isolates when growing alone and when competing either indirectly (with a physical barrier) or directly. Overall, we found that nitrogen provision to the plant does not explain the amount of carbon that an isolate receives nor the number of roots that it colonises. Differences in nutrient exchange among isolates were related to differences in expression of key fungal and plant nitrogen and carbon transporter genes. When given a choice of partners, the plant was able to limit colonisation by the least cooperative isolate. This was not explained by a reduction in allocated carbon. Instead, our results suggest that partner choice in EMF could operate through the upregulation of defence-related genes against those fungi providing fewer nutrients. PMID- 28731480 TI - Erratum: Intrinsic cardiovascular autonomic regulatory system of astronauts exposed long-term to microgravity in space: observational study. AB - [This corrects the article DOI: 10.1038/npjmgrav.2015.18.]. PMID- 28731479 TI - Marine archaeal dynamics and interactions with the microbial community over 5 years from surface to seafloor. AB - Marine archaea are critical contributors to global carbon and nitrogen redox cycles, but their temporal variability and microbial associations across the water column are poorly known. We evaluated seasonal variability of free living (0.2-1 MUm size fraction) Thaumarchaea Marine Group I (MGI) and Euryarchaea Marine Group II (MGII) communities and their associations with the microbial community from surface to seafloor (890 m) over 5 years by 16S rRNA V4-V5 gene sequencing. MGI and MGII communities demonstrated distinct compositions at different depths, and seasonality at all depths. Microbial association networks at 150 m, 500 m and 890 m, revealed diverse assemblages of MGI (presumed ammonia oxidizers) and Nitrospina taxa (presumed dominant nitrite oxidizers, completing the nitrification process), suggesting distinct MGI-Nitrospina OTUs are responsible for nitrification at different depths and seasons, and depth- related and seasonal variability in nitrification could be affected by alternating MGI Nitrospina assemblages. MGII taxa also showed distinct correlations to possibly heterotrophic bacteria, most commonly to members of Marine Group A, Chloroflexi, Marine Group B, and SAR86. Thus, both MGI and MGII likely have dynamic associations with bacteria based on similarities in activity or other interactions that select for distinct microbial assemblages over time. The importance of MGII taxa as members of the heterotrophic community previously reported for photic zone appears to apply throughout the water column. PMID- 28731481 TI - Corrigendum: Pathway on demand: automated reconstruction of human signaling networks. AB - [This corrects the article DOI: 10.1038/npjsba.2016.2.]. PMID- 28731482 TI - Radiofluorination of a NHC-PF5 adduct: toward new probes for 18F PET imaging. AB - The radiofluorination of N-heterocyclic carbene (NHC) phosphorus(v) fluoride adducts has been investigated. The results show that the IMe-PF5 derivative (IMe = 1,3-dimethylimidazol-2-ylidene) undergoes a Lewis acid promoted 18F-19F isotopic exchange. The resulting radiofluorinated probe is remarkably resistant to hydrolysis both in vitro as well as in vivo. PMID- 28731483 TI - The role of laminins in cartilaginous tissues: from development to regeneration. AB - As a key molecule of the extracellular matrix, laminin provides a delicate microenvironment for cell functions. Recent findings suggest that laminins expressed by cartilage-forming cells (chondrocytes, progenitor cells and stem cells) could promote chondrogenesis. However, few papers outline the effect of laminins on providing a favorable matrix microenvironment for cartilage regeneration. In this review, we delineated the expression of laminins in hyaline cartilage, fibrocartilage and cartilage-like tissue (nucleus pulposus) throughout several developmental stages. We also examined the effect of laminins on the biological activities of chondrocytes, including adhesion, migration and survival. Furthermore, we scrutinized the potential influence of various laminin isoforms on cartilage-forming cells' proliferation and chondrogenic differentiation. With this information, we hope to facilitate the understanding of the spatial and temporal interactions between cartilage-forming cells and laminin microenvironment to eventually advance cell-based cartilage engineering and regeneration. PMID- 28731484 TI - CPR, ECLS, BVAD and successful heart transplantation within 2 months: a single centre case series in two young, high-urgency listed patients. AB - INTRODUCTION: In times of organ shortage, death while on the heart waiting-list still represents a major problem. As a consequence, bridging to transplant as well as the decision when to escalate therapy play a very important role. METHODS AND RESULTS: We report on two young patients with dilated cardiomyopathy and acute decompensation who were successfully bridged to heart transplantation with both left and temporary right ventricular assist devices in just 2 months. CONCLUSIONS: As a permanent biventricular assist device (BVAD) would have definitely impaired the patients' outcome after HTX, we decided to implant an LVAD with a temporary RVAD. In our opinion, this represents a suitable strategy to reduce mortality in HU-listed patients with acute deterioration of cardiac pump function and should be further evaluated in future studies. PMID- 28731485 TI - Th17/regulatory T cell imbalance in sepsis patients with multiple organ dysfunction syndrome: attenuated by high-volume hemofiltration. AB - BACKGROUND: We assessed the Th17 (T-helper cell)/Treg (Regulatory T cell) imbalance in sepsis patients with multiple organ dysfunction syndrome (MODS) and the clinical benefits of continuous high-volume hemofiltration (HVHF). METHODS: 48 sepsis patients, including 22 patients with MODS (MODS group, n = 22) and 26 without (non-MODS group, n = 26), and 20 healthy volunteer controls were enrolled. The patients in MODS group were randomly divided into the continuous blood purification (CBP) group (n = 11) receiving conventional comprehensive treatment plus high-volume hemofiltration and the non-CBP group (n = 11) receiving conventional comprehensive treatment only. At day 28, all 48 patients were divided into the survival group (n = 36) and the non-survival group (n = 12). Venous blood samples, collected at 0, 6, 12 and 24 hours during hemofiltration (or equivalent times in the non-CBP group), were assessed by flow cytometry to detect the Th17 and Treg cells in peripheral blood. Serum cytokines (such as IL-6, IL-17, IL-23, IL-10 and TGF-beta1) were detected by enzyme-linked immune sorbent assay (ELISA). RESULTS: Th17%, Treg%, Th17/Treg, IL-6, IL-17, IL 23, IL-10 and TGF-beta1 were significantly higher in MODS and non-MODS group than in the health control (p<0.05), while Th17%, Treg%, Th17/Treg and measured cytokines were significantly higher in the MODS group compared to the non-MODS group (p<0.05). After HVHF treatment, Th17%, Treg%, Th17/Treg, IL-6, IL-17, and IL-10 were significantly reduced (p<0.05), while there were no significant changes in the non-CBP group (p>0.05). In addition, APACHE II and SOFA scores decreased markedly after HVHF treatment. Baseline Th17%, Treg%, Th17/Treg, IL-6, IL-17, IL-23, IL-10 and TGF-beta1 were significantly higher in the non-survival group compared to the survival group. Both Th17% and Th17/Treg were positivity correlated with concentration of IL-6 and APACHE II score (p<0.01). CONCLUSIONS: The level of Th17/Treg imbalance in sepsis is related to the occurrence and prognosis of MODS. High-volume hemofiltration can attenuate the Th17/Treg imbalance in sepsis patients, possibly by removing inflammatory mediators. PMID- 28731486 TI - Demineralized dentin and enamel matrices as suitable substrates for bone regeneration. AB - BACKGROUND: In recent decades, tooth derivatives such as dentin (D) and enamel (E) have been considered as potential graft biomaterials to treat bone defects. This study aimed to investigate the effects of demineralization on the physical chemical and biological behavior of D and E. METHODS: Human D and E were minced into particles (O<1 mm), demineralized and sterilized. Thorough physical-chemical and biochemical characterizations of native and demineralized materials were performed by SEM and EDS analysis and ELISA kits to determine mineral, collagen type I and BMP-2 contents. In addition, MG63 and SAOS-2 cells were seeded on tooth-derived materials and Bio-Oss(r), and a comparison of cell responses in terms of adhesion and proliferation was carried out. RESULTS: The sterilization process, as a combination of chemical and thermal treatments, was found to be effective for all materials. On the other hand, D demineralization allowed preserving the collagen content, while increasing BMP-2 bioavailability. D and demineralized D (dD) displayed excellent biocompatibility, even greater than Bio Oss(r). Conversely, the high mineral content displayed by E, as confirmed by EDS analysis, inhibited cell proliferation. Of note, even though the demineralization process was somehow less effective in E than in D, demineralized E (dE) displayed increased BMP-2 bioavailability and improved performance in vitro compared with native E. CONCLUSIONS: Our results substantiate the idea that the demineralization process lead to an increase of BMP-2 bioavailability, thus paving the way toward development of more effective, osteoinductive tooth-derived materials for bone regeneration and replacement. PMID- 28731487 TI - Intraoperative fluoroscopy with a direct anterior approach reduces variation in acetabular cup abduction angle. AB - INTRODUCTION: The purpose of this study was to compare acetabular cup position for 2 cohorts of total hip arthroplasty (THA) patients who had a direct anterior approach. METHODS: 100 THA cases were performed with an anterior approach using intraoperative fluoroscopy (IF) to aid in cup positioning. Another group of 100 cases underwent THA with an anterior approach without the use of any fluoroscopy. Postoperative abduction and anteversion angles were measured using Martell's hip analysis software. RESULTS: Mean abduction angle was 43.2 degrees (standard deviation (SD) = 4.5 degrees ) for the IF group versus 37.5 degrees (SD = 7.4 degrees ) for cases without IF (p<0.001). 18% more cases with IF fell within the Lewinnek safe zone (p<0.001); however, a similar number of cases had over 50 degrees of abduction. The mean anteversion angles of the two groups were also significantly different (IF 21.8 degrees vs. 24.9 degrees ) (p<0.01). CONCLUSIONS: There was significantly less variation in cup position among the cases using IF with regards to abduction. PMID- 28731488 TI - Contamination risk of synovial biopsy cultures in total hip arthroplasty: a prospective review of 100 cases. AB - INTRODUCTION: Cultures of deep synovial biopsies remain an important tool in diagnosing periprosthetic joint infection, a devastating complication following total hip arthroplasty (THA). Recent reports of unexpected positive intraoperative cultures in aseptic revision arthroplasty, however, challenge the validity and interpretation of these cultures. The aim of this study was to evaluate the contamination risk of synovial biopsy cultures collected intraoperatively during primary THA of healthy subjects. METHODS: Synovial biopsies for culture were collected during primary total hip arthroplasty procedures from 100 consecutive cases. The synovial biopsies were taken within the first 15 minutes after skin incision. Biopsy specimen were cultured on 4 different media for 8 or 15 days. Positive cultures were identified using Maldi Tof spectrometry. RESULTS: 16 cultures yielded a bacterium, suggesting a false positive result of 16%. The mean time for the cultures to become positive was 6.29 days (standard deviation [SD] 3.90) with a maximum of 15 days. Proprionibacterium acnes and Staphylococcus epidermidis were most commonly cultured with 6 positive results for both bacteria. CONCLUSIONS: Our study yielded a 16% false positive rate in cultures of synovial biopsy taken during primary total hip arthroplasty of healthy subjects, suggesting that contamination risk of these synovial biopsy cultures may be larger than assumed by clinicians. PMID- 28731489 TI - Sexual health, adherence to Mediterranean diet, body weight, physical activity and mental state: factors correlated to each other. AB - INTRODUCTION: Mediterranean diet has shown a protective role against cardiovascular disease, diabetes, cancer onset, microvascular damage and dementia in many trials. Our purpose is the assessment of a correlation between physical activity, Mediterranean diet, body mass index (BMI), depression and erection disorder (ED). METHODS: After having signed disclaimer to the study participation, we administered the IIEF 15 questionnaire (International Index of Erectil Function), the Hamilton questionnaire for major depression, the Med-Diet Questionnaire, the Ipaq Questionnaire (International Index of Physical Activity) to 245 patients and calculated the BMI. Only 141 were eligible. We excluded patients with a history of smoking, with obesity from the second grade to rise, anorexia, hyperlipidemia, Induratio Penis Plastica, diabetes, cardiovascular and neurological disease, hypogonadism, prostatitis, diabetes, hypertension, psychiatric diseases and the history of radical prostatectomy and finally age >72 and <50 years or who were taking cholesterol-lowering medication. Patients were divided into two groups: 65 patients without ED and 76 patients with ED. RESULTS: We found a statistically difference in BMI between the groups. Adherence to Med Diet showed a significant difference between the two groups at Student t-test and the Chi-square test. The Ipaq test and Hamilton test did not show statistical differences between the two groups neither for Student t-test nor for Chi-square test, but high levels seem to be protective factors. CONCLUSIONS: Body weight and a healthy diet are protective factors against the ED, more than a sufficient physical activity. Depression has shown only a worsening tendency of the erection. PMID- 28731490 TI - Lancisi's sign and central venous catheter tip position: a case report. AB - INTRODUCTION: Valvular disease and pulmonary hypertension are common conditions in haemodialysis patients. In presence of tricuspid regurgitation, an increased retrograde blood flow into the right atrium during ventricle systole results in a typical modification of the normal venous waveform, creating a giant c-v wave. This condition clinically appears as a venous palpable pulsation within the internal jugular vein, also known as Lancisi's sign. CASE REPORT: An 83-year-old woman underwent haemodialysis for 9 years. After arteriovenous fistula thrombosis, a right internal jugular vein non-tunnelled central venous catheter (CVC) was placed. About one month later, the patient was referred to our facility for the placement of a tunnelled CVC. Neck examination revealed an elevated jugular venous pulse, the Lancisi's sign. Surprisingly, chest x-ray posteroanterior view showed the non-tunnelled catheter tip in correspondence with the right ventricle. She underwent surgery for temporary to tunnelled CVC conversion using the same venous insertion site (Bellcath(r)10Fr-length 25 cm to Mahurkar(r)13.5Fr-length 19 cm). In the postoperative period, we observed a significant reduction of the jugular venous pulse. DISCUSSION: The inappropriate placement of a 25-cm temporary CVC in the right internal jugular vein worsened the tricuspid valve regurgitation, which became evident by the Lancisi's sign. Removal of the temporary CVC from the right ventricle resulted in improved right cardiac function. Safe approaches recommended by guidelines for the CVC insertion technique and for checking the tip position should be applied in order to avoid complications. PMID- 28731493 TI - Lower extremity dialysis arteriovenous graft patency preservation due to traumatic fistula to adjacent vein. PMID- 28731491 TI - Patient satisfaction and acceptance of their totally implanted central venous catheter: a French prospective multicenter study. AB - INTRODUCTION: Most cancer patients require a totally implanted central venous catheter (TIVAD) for their treatment. In a previous study, we developed and validated a questionnaire dubbed QASICC (Questionnaire for Acceptance of, and Satisfaction with, Implanted Central Venous Catheter) assessing patient satisfaction with, and acceptance of, their TIVAD. In the present study, we conducted a large, prospective, multicenter study in cancer patients aimed to analyze factors that could influence patients' acceptance of, and satisfaction with, their device. METHODS: The QASICC is composed of 22 items assessing 5 dimensions. The construction and validation of the questionnaire was achieved using validated methodology to determine its psychometric characteristics. The questionnaire was submitted to 720 patients in 11 French institutions; 567 answers were analyzed. RESULTS: Younger patients had the most difficulties in coping with their TIVAD, especially regarding daily activities and their body image and private life compared to older patients. Sex was significantly related to patient satisfaction, with worse scores in women. Breast tumor location was also correlated with low TIVAD acceptance. TIVAD on the right side also positively influenced satisfaction and acceptance of the device. CONCLUSIONS: QASICC has proved to be efficient, and to detect known issues regarding daily activities and body image. As our population was mostly composed of women with breast cancer, our results reflect specific aspects of this population. The TIVAD remains generally well-accepted and our questionnaire should help health-care workers to better address the specific needs of their patients based on the answers provided. PMID- 28731492 TI - Factors causing loss of normal Doppler waveform of the left internal jugular vein: evaluation on chest computed tomography. AB - PURPOSE: To evaluate the presence and causes of left brachiocephalic vein (LBCV) steno-occlusive lesions in patients with loss of normal waveform in Doppler ultrasound of the left internal jugular vein (LIJV). MATERIALS AND METHODS: We performed Doppler ultrasound of both internal jugular veins in 1912 patients who received an implantable venous access port from August 2013 to January 2016. Among them, 106 patients showed loss of normal Doppler waveforms of the LIJV (56 men and 50 women; mean age, 61.4 +/- 11.6 years). We retrospectively analyzed the presence and causes of the LBCV steno-occlusive lesions on contrast-enhanced chest computed tomography (CT) images. RESULTS: LBCV steno-occlusive lesions were present in 82 patients (77.4%). The causes of these lesions were anatomic structures (n = 70, 85.4%), tumorous lesions (n = 11, 13.4%), and thrombus (n = 1, 1.2%). The anterior anatomic structures to the LBCV causing stenosis were bony structures (n = 50), right upper lobe (n = 11), and mediastinal fat (n = 9). The posterior anatomic structures to the LBCV resulting in stenosis were right brachiocephalic artery (n = 58), left common carotid artery (n = 7), and aortic arch (n = 5). The tumorous lesions resulting in stenosis were mediastinal lymph node (n = 5), thymic lesions (n = 3), lymphoma (n = 1), lung cancer (n = 1), and bone tumor (n = 1). CONCLUSIONS: It is necessary to suspect steno-occlusive lesion of the LBCV from various causes and to use caution when performing central venous catheterization in cases with loss of a normal Doppler waveform. PMID- 28731494 TI - Subthreshold micropulse laser reduces anti-VEGF injection burden in patients with diabetic macular edema. AB - PURPOSE: To evaluate the efficacy of micropulse laser in the early treatment of diabetic macular edema (DME) and its associated burden of anti-vascular endothelial growth factor (VEGF) injections. METHODS: This retrospective comparative study compared a group of 19 eyes with DME treated with micropulse laser to a matched control group of 19 eyes with DME treated with ranibizumab injections without micropulse laser. Recorded parameters included previous medical and ocular history, previous and subsequent ranibizumab injections administered for DME, visual acuity (VA), central macular thickness throughout the follow-up period, and the occurrence of any complications. RESULTS: The improvement in VA was comparable in both groups, at 12 months and at the final follow-up. Patients treated with micropulse laser required significantly fewer ranibizumab injections than their controls, both at 12 months (1.7 +/- 2.3 vs 5.6 +/- 2.1) and by the end of the follow-up (2.6 +/- 3.3 vs 9.3 +/- 5.1) (p<0.001 for both). No complications related to the micropulse laser were encountered. CONCLUSIONS: Micropulse laser is a safe and effective treatment for DME, which may achieve comparable improvement in VA along with a significant reduction in the burden of anti-VEGF injections. We suggest a treatment approach for its inclusion in the early stages of DME. PMID- 28731495 TI - Significance of neutrophil-to-lymphocyte ratio in Western advanced EGFR-mutated non-small cell lung cancer receiving a targeted therapy. AB - PURPOSE: Lung cancer is one of the leading causes of cancer-related death worldwide and, although targeted therapy with tyrosine kinase inhibitors has dramatically improved the rates of response and survival in advanced EGFR-mutated adenocarcinoma, the overall outcome remains unsatisfactory. Therefore, new prognostic factors, preferably simple, inexpensive, and easy to reproduce on a large scale, are needed. We performed a retrospective analysis of our database including 63 western Caucasian patients with advanced EGFR-mutated lung adenocarcinoma and receiving gefitinib, erlotinib, or afatinib as first- or second-line therapy. Several studies demonstrated a strong link between elevated neutrophil-to-lymphocyte ratio (NLR) and poor prognosis both in early and advanced stages of non-small-cell lung cancer (NSCLC). METHODS: From January 2011 to December 2015, 63 consecutive elegible patients with advanced EGFR-mutated NSCLC were included in this analysis from 5 institutions. The NLR was derived from the absolute neutrophil and the absolute lymphocyte counts of a full blood count and the cutoff value was determined according to the mean NLR level. RESULTS: Despite the small sample analyzed, we found that NLR has a prognostic role for progression-free survival (PFS) and overall survival (OS), reaching a statistically significant difference with a better PFS and OS in the lower NLR group. CONCLUSIONS: Pretreatment NLR seems to represent a reliable, simple, and easy to reproduce laboratory tool to predict outcome and response to cancer therapies in this setting of Western Caucasian patients with EGFR-mutated NSCLC. PMID- 28731496 TI - Prognostic Factors for Survival in Metastatic Renal Cell Carcinoma Patients with Brain Metastases Receiving Targeted Therapy. AB - Background The primary objective of our study was to examine the clinical outcomes and prognosis of patients with metastatic renal cell carcinoma (mRCC) with brain metastases (BMs) receiving targeted therapy. Patients and methods Fifty-eight patients from 16 oncology centers for whom complete clinical data were available were retrospectively reviewed. Results The median age was 57 years (range 30-80). Most patients underwent a nephrectomy (n = 41; 70.7%), were male (n = 42; 72.4%) and had clear-cell (CC) RCC (n = 51; 87.9%). Patients were treated with first-line sunitinib (n = 45; 77.6%) or pazopanib (n = 13; 22.4%). The median time from the initial RCC diagnosis to the diagnosis of BMs was 9 months. The median time from the first occurrence of metastasis to the development of BMs was 7 months. The median overall survival (OS) of mRCC patients with BMs was 13 months. Time from the initial diagnosis of systemic metastasis to the development of BMs (<12 months; p = 0.001), histological subtype (non-CC; p<0.05) and number of BMs (>=2; p<0.05) were significantly associated with OS in multivariate analysis. There were no cases of toxic death. One mRCC patient with BMs (1.7%) experienced treatment-related cerebral necrosis. All other toxicities included those commonly observed with VEGF-TKI therapy. Conclusions The time from the initial diagnosis of systemic metastasis to the development of BMs (<12 months), a non-CC histological subtype, and a greater number of BMs (>=2) were independent risk factors for a poor prognosis. PMID- 28731497 TI - The effect of frailty on short-term outcomes after head and neck cancer surgery. AB - OBJECTIVE: To determine the relationship between frailty and comorbidity, in hospital mortality, postoperative complications, length of hospital stay (LOS), and costs in head and neck cancer (HNCA) surgery. STUDY DESIGN: Cross-sectional analysis. METHODS: Discharge data from the Nationwide Inpatient Sample for 159,301 patients who underwent ablative surgery for a malignant oral cavity, laryngeal, hypopharyngeal, or oropharyngeal neoplasm in 2001 to 2010 was analyzed using cross-tabulations and multivariate regression modeling. Frailty was defined based on frailty-defining diagnosis clusters from the Johns Hopkins Adjusted Clinical Groups frailty-defining diagnosis indicator. RESULTS: Frailty was identified in 7.4% of patients and was significantly associated with advanced comorbidity (odds ratio [OR] = 1.5[1.3-1.8]), Medicaid (OR = 1.5[1.3-1.8]), major procedures (OR = 1.6[1.4-1.8]), flap reconstruction (OR = 1.7[1.3-2.1]), high volume hospitals (OR = 0.7[0.5-1.0]), discharge to a short-term facility (OR = 4.4[2.9-6.7]), or other facility (OR = 5.4[4.5-6.6]). Frailty was a significant predictor of in-hospital death (OR = 1.6[1.1-2.4]), postoperative surgical complications (OR = 2.0[1.7-2.3]), acute medical complications (OR = 3.9[3.2 4.9]), increased LOS (mean, 4.9 days), and increased mean incremental costs ($11,839), and was associated with higher odds of surgical complications and increased costs than advanced comorbidity. There was a significant interaction between frailty and comorbidity for acute medical complications and length of hospitalization, with a synergistic effect on the odds of medical complications and LOS in patients with comorbidity who were also frail. CONCLUSION: Frailty is an independent predictor of postoperative morbidity, mortality, LOS, and costs in HNCA surgery patients, and has a synergistic interaction with comorbidity that is associated with an increased likelihood of medical complications and greater LOS in patients with comorbidity who are also frail. LEVEL OF EVIDENCE: 2c. Laryngoscope, 128:102-110, 2018. PMID- 28731498 TI - Adult morphea en coup de sabre with accompanying regional polymyositis: A separate entity? PMID- 28731499 TI - The Frontal Sinus Cavity Exhibits Sexual Dimorphism in 3D Cone-beam CT Images and can be Used for Sex Determination. AB - Few studies have assessed the use of the frontal sinus cavities for sex differentiation. In this study, a new methodology was used to assess the reliability of CBCT images of the frontal sinus cavity for determining sex based on the sexual dimorphism found in this anatomical structure. The survey sample consisted of 130 scans that were reconstructed three-dimensionally. 3D images of the cavity volume in the frontal, lateral, and basal views were exported in TIFF. The following variables were measured in a second program: area, perimeter, bounding rectangle, ellipse fit, circularity, aspect ratio, roundness, solidity, and Feret's diameter. The methodology demonstrated the existence of sexual dimorphism with an accuracy of 80.0% in the logistic regression model. The basal view had the greatest explanatory power in the final model. This methodology may be used as an alternative way of determining a reliable biological profile during the analysis of skeletal remains. PMID- 28731500 TI - A case of disfiguring primary cutaneous squamous cell carcinoma of the nasal tip. PMID- 28731501 TI - Eyeball Position in Facial Approximation: Accuracy of Methods for Predicting Globe Positioning in Lateral View. AB - This study measured the accuracy of traditional and validated newly proposed methods for globe positioning in lateral view. Eighty lateral head cephalograms of adult subjects from Central Europe were taken, and the actual and predicted dimensions were compared. The anteroposterior eyeball position was estimated as the most accurate method based on the proportion of the orbital height (SEE = 1.9 mm) and was followed by the "tangent to the iris method" showing SEE = 2.4 mm. The traditional "tangent to the cornea method" underestimated the eyeball projection by SEE = 5.8 mm. Concerning the superoinferior eyeball position, the results showed a deviation from a central to a more superior position by 0.3 mm, on average, and the traditional method of central positioning of the globe could not be rejected as inaccurate (SEE = 0.3 mm). Based on regression analyzes or proportionality of the orbital height, the SEE = 2.1 mm. PMID- 28731502 TI - Histologic scoring indices for evaluation of disease activity in Crohn's disease. AB - BACKGROUND: Histologic assessment of mucosal disease activity has been increasingly used in clinical trials of treatment for Crohn's disease. However, the operating properties of the currently existing histologic scoring indices remain unclear. OBJECTIVES: A systematic review was undertaken to evaluate the development and operating characteristics of available histologic disease activity indices in Crohn's disease. SEARCH METHODS: Electronic searches of MEDLINE, EMBASE, PubMed, and the Cochrane Library (CENTRAL) databases from inception to 20 July 2016 were supplemented by manual reviews of bibliographies and abstracts submitted to major gastroenterology meetings (Digestive Disease Week, United European Gastroenterology Week, European Crohn's and Colitis Organisation). SELECTION CRITERIA: Any study design (e.g. randomised controlled trial, cohort study, case series) that evaluated a histologic disease activity index in patients with Crohn's disease was considered for inclusion. Study participants included adult patients (> 16 years), diagnosed with Crohn's disease using conventional clinical, radiographic or endoscopic criteria. DATA COLLECTION AND ANALYSIS: Two authors independently reviewed the titles and abstracts of the studies identified from the literature search. The full text of potentially relevant citations were reviewed for inclusion and the study investigators were contacted as needed for clarification. Any disagreements regarding study eligibility were resolved by discussion and consensus with a third author.Two authors independently extracted and recorded data using a standard form. The following data were recorded from each eligible study: number of patients enrolled; number of patients per treatment arm; patient characteristics: age and gender distribution; description of histologic disease activity index utilized; and outcomes such as content validity, construct validity, criterion validity, responsiveness, intra-rater reliability, inter-rater reliability, and feasibility. MAIN RESULTS: Sixteen reports of 14 studies describing 14 different numerical histological indices fulfilled the inclusion criteria.Inter-rater reliability was assessed in one study. For the Naini and Cortina Score, estimates of correlation were 'almost perfect', ranging from r = 0.94 to 0.96. The methodological quality of this study with respect to reliability was 'good'.With respect to validity, correlation estimates between various histological scoring systems and Crohn's disease activity as measured by objective markers of inflammation (including C-reactive protein, erythrocyte sedimentation rate, fecal calprotectin and fecal lactoferrin); endoscopic disease activity scores; clinical disease activity scores; and quality of life questionnaires were reported. Comparisons between histologic scoring indices and endoscopic scoring indices ranged from no correlation to 'substantial' (r = 0.779). The methodological quality of the studies that explored validity ranged form 'poor' to 'good'.Responsiveness data were available in seven studies. After subjects were administered a treatment of known efficacy, statistically significant change in the index score was demonstrated in five studies with respect to six indices. Two studies failed to indicate whether there was statistically significant change in the index score post-treatment. With regard to methodological quality, six of the studies were rated as 'poor' and one of the studies was rated as 'fair'.Feasibility was assessed by one study. The Naini and Cortina Score was shown to be simple to use and feasible for every given case. AUTHORS' CONCLUSIONS: Currently there is no fully validated histological scoring index for evaluation of Crohn's disease activity. Development of a validated histological scoring index for Crohn's disease is a clinical and research priority. PMID- 28731503 TI - Impact of soybean aging conditions on tofu sensory characteristics and acceptance. AB - BACKGROUND: Tofu from aged soybeans is of poor quality, mainly with respect to texture. Texture defects described in the literature are contradictory. No study has investigated all sensory properties simultaneously. The objective of the present study was to evaluate the effect of soybean aging conditions [natural: ambient temperature and RH, 18 months, and accelerated: 30 degrees C, 84% relative humidity (RH), 6 months] on all of the sensory characteristics and the acceptance of tofu. Texture and color were also evaluated via an instrumental method. The control condition was -20 degrees C and 47% RH. Coodetec 214 and BRS 267 cultivars were studied. RESULTS: The effect of soybean accelerated aging on tofu sensory characteristics and acceptance was more pronounced compared to the natural condition. The two cultivars had a similar behavior. Tofu control exhibited a light, uniform and bright color, cohesive appearance, sweet aroma and flavor, as well as a firm and elastic texture. Tofu made from both aged cultivars showed a gray color with dark spots, a rough appearance, fermented aroma, rancid flavor, an astringent and bitter taste, a fracturable texture and adherence to the oral cavity after chewing. These characteristics of tofu from aged soybeans implied a low acceptance by consumers. CONCLUSION: Tofu from natural and accelerated aged soybeans has sensory attributes of appearance, as well as aroma, flavor and damaged texture, that are unacceptable by consumers. (c) 2017 Society of Chemical Industry. PMID- 28731504 TI - Authors' Response. PMID- 28731506 TI - An Australian Mohs external quality assurance program. PMID- 28731505 TI - Calcium/calmodulin-dependent kinase 2 mediates Epac-induced spontaneous transient outward currents in rat vascular smooth muscle. AB - KEY POINTS: The Ca2+ and redox-sensing enzyme Ca2+ /calmodulin-dependent kinase 2 (CaMKII) is a crucial and well-established signalling molecule in the heart and brain. In vascular smooth muscle, which controls blood flow by contracting and relaxing in response to complex Ca2+ signals and oxidative stress, surprisingly little is known about the role of CaMKII. The vasodilator-induced second messenger cAMP can relax vascular smooth muscle via its effector, exchange protein directly activated by cAMP (Epac), by activating spontaneous transient outward currents (STOCs) that hyperpolarize the cell membrane and reduce voltage dependent Ca2+ influx. How Epac activates STOCs is unknown. In the present study, we map the pathway by which Epac increases STOC activity in contractile vascular smooth muscle and show that a critical step is the activation of CaMKII. To our knowledge, this is the first report of CaMKII activation triggering cellular activity known to induce vasorelaxation. ABSTRACT: Activation of the major cAMP effector, exchange protein directly activated by cAMP (Epac), induces vascular smooth muscle relaxation by increasing the activity of ryanodine (RyR)-sensitive release channels on the peripheral sarcoplasmic reticulum. Resultant Ca2+ sparks activate plasma membrane Ca2+ -activated K+ (BKCa ) channels, evoking spontaneous transient outward currents (STOCs) that hyperpolarize the cell and reduce voltage dependent Ca2+ entry. In the present study, we investigate the mechanism by which Epac increases STOC activity. We show that the selective Epac activator 8-(4 chloro-phenylthio)-2'-O-methyladenosine-3', 5-cyclic monophosphate-AM (8-pCPT-AM) induces autophosphorylation (activation) of calcium/calmodulin-dependent kinase 2 (CaMKII) and also that inhibition of CaMKII abolishes 8-pCPT-AM-induced increases in STOC activity. Epac-induced CaMKII activation is probably initiated by inositol 1,4,5-trisphosphate (IP3 )-mobilized Ca2+ : 8-pCPT-AM fails to induce CaMKII activation following intracellular Ca2+ store depletion and inhibition of IP3 receptors blocks both 8-pCPT-AM-mediated CaMKII phosphorylation and STOC activity. 8-pCPT-AM does not directly activate BKCa channels, but STOCs cannot be generated by 8-pCPT-AM in the presence of ryanodine. Furthermore, exposure to 8 pCPT-AM significantly slows the initial rate of [Ca2+ ]i rise induced by the RyR activator caffeine without significantly affecting the caffeine-induced Ca2+ transient amplitude, a measure of Ca2+ store content. We conclude that Epac mediated STOC activity (i) occurs via activation of CaMKII and (ii) is driven by changes in the underlying behaviour of RyR channels. To our knowledge, this is the first report of CaMKII initiating cellular activity linked to vasorelaxation and suggests novel roles for this Ca2+ and redox-sensing enzyme in the regulation of vascular tone and blood flow. PMID- 28731507 TI - Folliculotropic mycosis fungoides associated with atopic dermatitis. PMID- 28731508 TI - A re-examination of Montreal Cognitive Assessment (MoCA) cutoff scores. AB - OBJECTIVE: The Montreal Cognitive Assessment (MoCA; Nasreddine et al., 2005) is a cognitive screening tool that aims to differentiate healthy cognitive aging from Mild Cognitive Impairment (MCI). Several validation studies have been conducted on the MoCA, in a variety of clinical populations. Some studies have indicated that the originally suggested cutoff score of 26/30 leads to an inflated rate of false positives, particularly for those of older age and/or lower education. We conducted a systematic review and meta-analysis of the literature to determine the diagnostic accuracy of the MoCA for differentiating healthy cognitive aging from possible MCI. METHODS: Of the 304 studies identified, nine met inclusion criteria for the meta-analysis. These studies were assessed across a range of cutoff scores to determine the respective sensitivities, specificities, positive and negative predictive accuracies, likelihood ratios for positive and negative results, classification accuracies, and Youden indices. RESULTS: Meta-analysis revealed a cutoff score of 23/30 yielded the best diagnostic accuracy across a range of parameters. CONCLUSIONS: A MoCA cutoff score of 23, rather than the initially recommended score of 26, lowers the false positive rate and shows overall better diagnostic accuracy. We recommend the use of this cutoff score going forward. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28731509 TI - Keeping safe. Continuous glucose monitoring (CGM) in persons with Type 1 diabetes and impaired awareness of hypoglycaemia: a qualitative study. AB - AIM: To further our understanding of individual use and experience of continuous glucose monitoring (CGM) in adults with Type 1 diabetes and impaired awareness of hypoglycaemia, we conducted a qualitative study supplementary to a randomized controlled trial, using semi-structured interviews. METHODS: Twenty-three participants of the IN CONTROL trial were interviewed within 4 weeks after the last study visit. The interview centred around experiences of CGM, taking into account the person's expectations prior to the trial. The interview was semi structured, using open-ended questions and, if needed, prompts were offered to elicit further responses. Using thematic analysis, the interview transcripts were coded independently by three members of the research team. The consolidated criteria for reporting qualitative research (COREQ) were followed. RESULTS: Overall, CGM was experienced as helpful in gaining more insight into glucose variability, and temporarily improved sense of control, reduced distress and made participants less dependent on others. However, some participants experienced confrontation with CGM output as intrusive, while some reported frustration due to failing technique and difficulty trusting the device. Participants reported active and passive self-management behaviours mirroring individual differences in attitudes and coping styles. CONCLUSIONS: In adults with Type 1 diabetes at risk of recurrent hypoglycaemia due to impaired awareness of hypoglycaemia, CGM use enhances a sense of control and safety for most, but not all. Future studies should further explore differential use of CGM in this population in the context of active and passive self-management styles. PMID- 28731510 TI - The association of lower urinary tract symptoms with incidental falls and fear of falling in later life: The Community Health Survey. AB - AIM: To evaluate the association between lower urinary tract symptoms (LUTS) and incidental falls and fear of falling. METHODS: We used data obtained from the 2011 Korean Community Health Survey (KCHS) conducted between August and October 2011 in South Korea. The survey was carried out to estimate patterns of disease prevalence and morbidity in men >40 years old. The trained interviewers performed face-to-face sociodemographic questionnaires using computer-assisted personal interviewing (CAPI) software, the International Prostate Symptom Score (IPSS), the Quality of Life score (EQ-5D), and a questionnaire about past falls and fear of falling. RESULTS: Data from 67 457 men were collected and analyzed. The subjects who had previously experienced a fall had slightly higher scores for IPSS, severity of LUTS, voiding LUTS, and storage LUTS than subjects with no prior fall history. A multivariate model of the relationship between falls and LUTS severity indicated that the relationship between the IPSS components and fall history was significant (mild, moderate, severe: OR = 1.00, 2.53, 3.91, respectively, P < 0.0001). A multivariate model of fear of falling and LUTS also showed a significant relationship between severity, voiding, and storage symptoms (severe IPSS: OR = 2.411, 95%CI: 2.2-2.642, P < 0.001; voiding symptoms: OR = 1.766, 95%CI: 1.681-1.856, P < 0.001; storage symptoms: OR = 1.705, 95%CI: 1.625 1.789, P < 0.001). CONCLUSION: This study emphasizes the relationship between LUTS and falling. Furthermore, increased LUTS severity led to a higher risk of incidental falls. A high correlation between fear of falling and LUTS was also observed in this study. PMID- 28731511 TI - Hypothermia at neonatal intensive care unit admission was not associated with respiratory disease or death in very preterm infants. AB - AIM: This study investigated the association between hypothermia and respiratory distress syndrome (RDS), bronchopulmonary dysplasia (BPD) or death in very preterm infants admitted to a Danish neonatal intensive care unit (NICU). METHODS: We studied 675 infants born at Aalborg University Hospital before 32 weeks and admitted to the NICU from April 1997 to December 2011. Hypothermia was defined as a core temperature of <36.5 degrees C on admission. The primary outcome was severe RDS or death within the first three days of life, and the secondary outcome was BPD or death before 36 postmenstrual weeks. The multivariable logistic regression was adjusted for early-onset infection, gestational age, Apgar score, sex, treatment year and birth weight. RESULTS: Infants with hypothermia had a twofold increase (OR) in the odds for RDS or death (2.03), but the adjusted OR was not statistically significant (1.36). They also demonstrated a twofold increase (OR) in the odds for BPD or death (2.28), but again the adjusted OR was not statistically significant (1.03). CONCLUSION: After adjusting for confounders, we found that the association between hypothermia on admission to the NICU and RDS or death, or BPD or death was statistically insignificant. PMID- 28731512 TI - Fast and simultaneous determination of 1 H-1 H and 1 H-19 F scalar couplings in complex spin systems: Application of PSYCHE homonuclear broadband decoupling. AB - The present manuscript focuses on fast and simultaneous determination of 1 H-1 H and 1 H-19 F scalar couplings in fluorinated complex steroid molecules. Incorporation of broadband PSYCHE homonuclear decoupling in the indirect dimension of zero-quantum filtered diagonal experiments (F1-PSYCHE-DIAG) suppresses 1 H-1 H scalar couplings; however, it retains 1 H-19 F scalar couplings (along F1 dimension) for the 19 F coupled protons while preserving the pure-shift nature for 1 H resonances uncoupled to 19 F. In such cases, along the direct dimensions, 1 H-1 H scalar coupling multiplets deconvolute and they appear as duplicated multiplets for the 19 F coupled protons, which facilitates unambiguous discrimination of 19 F coupled 1 H chemical sites from the others. Further, as an added advantage, data acquisition has been accelerated by invoking the known ideas of spectral aliasing in the F1-PSYCHE-DIAG scheme and experiments demand only ~10 min of spectrometer times. PMID- 28731514 TI - With or without you: Effects of the concurrent range expansion of an herbivore and its natural enemy on native species interactions. AB - Global climatic changes may lead to the arrival of multiple range-expanding species from different trophic levels into new habitats, either simultaneously or in quick succession, potentially causing the introduction of manifold novel interactions into native food webs. Unraveling the complex biotic interactions between native and range-expanding species is critical to understand the impact of climate change on community ecology, but experimental evidence is lacking. In a series of laboratory experiments that simulated direct and indirect species interactions, we investigated the effects of the concurrent arrival of a range expanding insect herbivore in Europe, Spodoptera littoralis, and its associated parasitoid Microplitis rufiventris, on the native herbivore Mamestra brassicae, and its associated parasitoid Microplitis mediator, when co-occurring on a native plant, Brassica rapa. Overall, direct interactions between the herbivores were beneficial for the exotic herbivore (higher pupal weight than the native herbivore), and negative for the native herbivore (higher mortality than the exotic herbivore). At the third trophic level, both parasitoids were unable to parasitize the herbivore they did not coexist with, but the presence of the exotic parasitoid still negatively affected the native herbivore (increased mortality) and the native parasitoid (decreased parasitism rate), through failed parasitism attempts and interference effects. Our results suggest different interaction scenarios depending on whether S. littoralis and its parasitoid arrive to the native tritrophic system separately or concurrently, as the negative effects associated with the presence of the parasitoid were dependent on the presence of the exotic herbivore. These findings illustrate the complexity and interconnectedness of multitrophic changes resulting from concurrent species arrival to new environments, and the need for integrating the ecological effects of such arrivals into the general theoretical framework of global invasion patterns driven by climatic change. PMID- 28731515 TI - Analysis of structure-function network decoupling in the brain systems of spastic diplegic cerebral palsy. AB - Manifestation of the functionalities from the structural brain network is becoming increasingly important to understand a brain disease. With the aim of investigating the differential structure-function couplings according to network systems, we investigated the structural and functional brain networks of patients with spastic diplegic cerebral palsy with periventricular leukomalacia compared to healthy controls. The structural and functional networks of the whole brain and motor system, constructed using deterministic and probabilistic tractography of diffusion tensor magnetic resonance images and Pearson and partial correlation analyses of resting-state functional magnetic resonance images, showed differential embedding of functional networks in the structural networks in patients. In the whole-brain network of patients, significantly reduced global network efficiency compared to healthy controls were found in the structural networks but not in the functional networks, resulting in reduced structural functional coupling. On the contrary, the motor network of patients had a significantly lower functional network efficiency over the intact structural network and a lower structure-function coupling than the control group. This reduced coupling but reverse directionality in the whole-brain and motor networks of patients was prominent particularly between the probabilistic structural and partial correlation-based functional networks. Intact (or less deficient) functional network over impaired structural networks of the whole brain and highly impaired functional network topology over the intact structural motor network might subserve relatively preserved cognitions and impaired motor functions in cerebral palsy. This study suggests that the structure-function relationship, evaluated specifically using sparse functional connectivity, may reveal important clues to functional reorganization in cerebral palsy. Hum Brain Mapp 38:5292-5306, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28731516 TI - miR-181d regulates human dendritic cell maturation through NF-kappaB pathway. AB - OBJECTIVES: MicroRNAs (miRNAs) are considered as the cellular regulators which post-transcriptionally modulate gene expression in diverse biological processes including cell development and immunity. In this study, we investigated functions of miR-181d in dendritic cells (DCs) maturation, and the underlying mechanisms were also explored. MATERIALS AND METHODS: Here we did the miRNA screening in human DCs in response to lipopolysaccharides (LPS) by quantitative real-time PCR (qRT-PCR). The expressions of DCs maturation markers were measured after miRNA mimics transfections. The pharmacological inhibitors of signalling pathways were applied to examine miR-181d effect on DCs maturation by Western blot. Luciferase assay and mixed lymphocyte reaction (MLR) were also performed to reveal the target gene of miR-181d and test the viability of T cells treated with miR-181d transfected DCs. RESULTS: Overexpression of miR-181d per se is sufficient to promote DCs maturation, and up-regulate CD80 and CD83 expressions without LPS. Besides, we showed that miR-181d activated NF-kappaB pathway and also promoted the expression of pro-inflammatory cytokine IL12 and TNF-alpha. Inhibition of NF kappaB pathway suppressed DCs maturation. Luciferase reporter assay and target gene knockdown assay indicated that miR-181d targets regulator cylindromatosis (CYLD), a primary negative regulator of NF-kappaB pathway. MLR assay showed that miR-181d-transfected DCs could promote T-cell proliferation than iDCs in vitro. CONCLUSION: Our study demonstrates that miR-181d is required for DCs maturation through the activation of NF-kappaB pathway by targeting CYLD. PMID- 28731517 TI - Mental steps: Differential activation of internal pacemakers in motor imagery and in mental imitation of gait. AB - Gait imagery and gait observation can boost the recovery of locomotion dysfunctions; yet, a neurologically justified rationale for their clinical application is lacking as much as a direct comparison of their neural correlates. Using functional magnetic resonance imaging, we measured the neural correlates of explicit motor imagery of gait during observation of in-motion videos shot in a park with a steady cam (Virtual Walking task). In a 2 * 2 factorial design, we assessed the modulatory effect of gait observation and of foot movement execution on the neural correlates of the Virtual Walking task: in half of the trials, the participants were asked to mentally imitate a human model shown while walking along the same route (mental imitation condition); moreover, for half of all the trials, the participants also performed rhythmic ankle dorsiflexion as a proxy for stepping movements. We found that, beyond the areas associated with the execution of lower limb movements (the paracentral lobule, the supplementary motor area, and the cerebellum), gait imagery also recruited dorsal premotor and posterior parietal areas known to contribute to the adaptation of walking patterns to environmental cues. When compared with mental imitation, motor imagery recruited a more extensive network, including a brainstem area compatible with the human mesencephalic locomotor region (MLR). Reduced activation of the MLR in mental imitation indicates that this more visually guided task poses less demand on subcortical structures crucial for internally generated gait patterns. This finding may explain why patients with subcortical degeneration benefit from rehabilitation protocols based on gait observation. Hum Brain Mapp 38:5195-5216, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28731518 TI - Enzymatic Synthesis of Homogeneous Chondroitin Sulfate Oligosaccharides. AB - Chondroitin sulfate (CS) is a sulfated polysaccharide that plays essential physiological roles. Here, we report an enzyme-based method for the synthesis of a library of 15 different CS oligosaccharides. This library covers 4-O-sulfated and 6-O-sulfated oligosaccharides ranging from trisaccharides to nonasaccharides. We also describe the synthesis of unnatural 6-O-sulfated CS pentasaccharides containing either a 6-O-sulfo-2-azidogalactosamine or a 6-O-sulfogalactosamine residue. The availability of structurally defined CS oligosaccharides offers a novel approach to investigate the biological functions of CS. PMID- 28731519 TI - Citizen's Charter in a primary health-care setting of Nepal: An accountability tool or a "mere wall poster"? AB - BACKGROUND: Despite some empirical findings on the usefulness of citizen's charters on awareness of rights and services, there is a dearth of literature about charter implementation and impact on health service delivery in low-income settings. OBJECTIVE: To gauge the level of awareness of the Charter within Nepal's primary health-care (PHC) system, perceived impact and factors affecting Charter implementation. METHOD: Using a case study design, a quantitative survey was administered to 400 participants from 22 of 39 PHC facilities in the Dang District to gauge awareness of the Charter. Additionally, qualitative interviews with 39 key informants were conducted to explore the perceived impact of the Charter and factors affecting its implementation. RESULTS: Few service users (15%) were aware of the existence of the Charter. Among these, a greater proportion were literate, and there were also differences according to ethnicity and occupational group. The Charter was usually not properly displayed and had been implemented with no prior public consultation. It contained information that provided awareness of health facility services, particularly the more educated public, but had limited potential for increasing transparency and holding service providers accountable to citizens. Proper display, consultation with stakeholders, orientation or training and educational factors, follow-up and monitoring, and provision of sanctions were all lacking, negatively influencing the implementation of the Charter. CONCLUSION: Poor implementation and low public awareness of the Charter limit its usefulness. Provision of sanctions and consultation with citizens in Charter development are needed to expand the scope of Charters from information brochures to tools for accountability. PMID- 28731520 TI - Lichenified papules: An unusual cutaneous presentation of metastatic breast cancer. PMID- 28731522 TI - Wildlife species benefitting from a greener Arctic are most sensitive to shrub cover at leading range edges. AB - Widespread expansion of shrubs is occurring across the Arctic. Shrub expansion will substantially alter arctic wildlife habitats. Identifying which wildlife species are most affected by shrubification is central to predicting future arctic community composition. Through meta-analysis, we synthesized the published evidence for effects of canopy-forming shrubs on birds and mammals in the Arctic and Subarctic. We examined variation in species behaviour, distribution and population dynamics in birds and mammals in response to shrub cover (including shrub cover indicators such as shrub occurrence, extent, density and height). We also assessed the degree of heterogeneity in wildlife responses to shrub cover and synthesized the remaining literature that did not fit the criteria for our quantitative meta-analyses. Species from higher green vegetation biomass habitats (high Normalized Difference Vegetation Index, NDVI, across their distribution) were more likely to respond positively to shrub cover, demonstrating the potential for species to expand from boreal to arctic habitats under shrubification. Wildlife populations located in the lowest vegetation biomass (low NDVI) areas of their species' range had the greatest proportion of positive responses to shrub cover, highlighting how increases in performance at leading edges of invaders distributions may be particularly rapid. This demonstrates the need to study species at these leading edges to accurately predict expansion potential. Arctic specialists were poorly represented across studies (limited to 5 bird and 0 mammal species), this knowledge gap potentially explains the few reported negative effects of shrub cover (3 of 29 species). Species responses to shrub cover showed substantial heterogeneity and varied among sites and years in all studies with sufficient replication to detect such variation. Our study highlights the importance of responses at species range edges in determining outcomes of shrubification for arctic birds and mammals and the need for greater examination of potential wildlife losers under shrubification. PMID- 28731523 TI - Erythema annulare centrifugum: remission during two pregnancies and exacerbation in between. PMID- 28731524 TI - Chronic cheilitis: Faecal calprotectin test a way to diagnose oral Crohn's disease. PMID- 28731525 TI - Differences in Stem Cell Processing Lead to Distinct Secretomes Secretion Implications for Differential Results of Previous Clinical Trials of Stem Cell Therapy for Myocardial Infarction. AB - Stem cell therapy for acute myocardial infarction (AMI) seemed to be a promising therapy, however, large clinical trials brought differential outcome. It has been shown that paracrine effects of secretomes of stem cells rather than cell therapy might play a fundamental role. The present study seeks to compare cell processing protocols of clinical trials and investigate effects of differential cell culture conditions on chemokine secretion and functional effects. Different secretomes are compared regarding IL-8, VEGF, MCP-1, and TNF-alpha secretion. Secretome mediated effects are evaluated on endothelial cell (HUVEC) tube formation and migration. Cardioprotective signaling kinases in human cardiomyocytes are determined by Western immunoblotting. Cells processed according to the REPAIR-AMI protocol secrete significantly higher amounts of IL-8 (487.3 +/- 1231.1 vs 9.1 +/ 8.2 pg mL-1 ; p < 0.05). REAPIR-AMI supernatants lead to significantly pronounced tube formation and migration on HUVEC and enhance the phosphorylation of Akt, ERK, and CREB. Cell processing conditions have a major impact on the composition of the secretome. The REPAIR-AMI secretome significantly enhances proangiogenic chemokine secretion, angiogenesis, cell migration, and cardioprotective signaling pathways. These results might explain differential outcomes between clinical trials. Optimizing cell processing protocols with special regards to paracrine factors, might open a new therapeutic concept for improving patient outcome. PMID- 28731528 TI - Improving Succinate Productivity by Engineering a Cyanobacterial CO2 Concentrating System (CCM) in Escherichia coli. AB - Biologically fixation of CO2 has great potential as a significant carbon source for biosynthesis, which is also a major way to reduce CO2 accumulation in atmosphere. Phosphoenolpyruvate (PEP) carboxylation is the key step of anaerobic succinate production in Escherichia coli. In this reaction, one mole CO2 is assimilated with PEP to form oxaloacetate by PEP carboxykinase (PCK). The preferred substrate of PCK is CO2 , which is very limited in cytoplasm. In this study, the carbon concentration mechanism (CCM) of cyanobacteria was introduced into Escherichia coli to enhance the intracellular inorganic carbon concentration for improving carboxylation velocity. Overexpression of the bicarbonate transporter (BT) or carbonic anhydrase (CA) gene from Synechococcus sp. PCC7002 led to a 22 or 35% increase in succinate titer at 36 h, respectively. The carboxylation rate of PCK increased from 2.46 to 3.92 umol min-1 mg-1 protein by overexpression of the CA gene. In addition, co-overexpression of BT and CA genes had a synergetic effect, leading to a 44% increase in succinate titer at 36 h. This work is the first attempt to increase carbon fixation involved in microbial biosynthesis by engineering a biological CO2 delivery system, which provides new direction and strategies for improving industrial fermentations based on biological CO2 assimilation pathways. PMID- 28731526 TI - Drug discovery and development for rare genetic disorders. AB - Approximately 7,000 rare diseases affect millions of individuals in the United States. Although rare diseases taken together have an enormous impact, there is a significant gap between basic research and clinical interventions. Opportunities now exist to accelerate drug development for the treatment of rare diseases. Disease foundations and research centers worldwide focus on better understanding rare disorders. Here, the state-of-the-art drug discovery strategies for small molecules and biological approaches for orphan diseases are reviewed. Rare diseases are usually genetic diseases; hence, employing pharmacogenetics to develop treatments and using whole genome sequencing to identify the etiologies for such diseases are appropriate strategies to exploit. Beginning with high throughput screening of small molecules, the benefits and challenges of target based and phenotypic screens are discussed. Explanations and examples of drug repurposing are given; drug repurposing as an approach to quickly move programs to clinical trials is evaluated. Consideration is given to the category of biologics which include gene therapy, recombinant proteins, and autologous transplants. Disease models, including animal models and induced pluripotent stem cells (iPSCs) derived from patients, are surveyed. Finally, the role of biomarkers in drug discovery and development, as well as clinical trials, is elucidated. PMID- 28731529 TI - Association between systemic antibiotic and corticosteroid use for chronic rhinosinusitis and quality of life. AB - OBJECTIVE: We sought to establish the significance of querying chronic rhinosinusitis (CRS) patients about their past CRS-related oral antibiotic and corticosteroid usage by determining the association between these metrics and patients' quality of life (QoL). STUDY DESIGN: Cross-sectional study. METHODS: A total of 157 patients with CRS were prospectively recruited. CRS-specific QoL was measured using the 22-item Sinonasal Outcome Test (SNOT-22). General health related QoL was measured using the EuroQoL five-dimensional questionnaire visual analog scale. Associations were sought between these measures of QoL and frequency of CRS-related oral antibiotic and corticosteroid usage reported by the participants in the prior 3 and 12 months. RESULTS: More frequent antibiotic and corticosteroid use was significantly associated with worse CRS-specific and general health-related QoL, whether querying medication use over the prior 3 months or over the prior 12 months (P < 0.001 in all cases). The effect size of CRS-related antibiotic use during the prior 3 months on CRS-specific QoL (SNOT-22 score) was significantly greater than for use during the prior 12 months. However, there was no other statistically significant difference in effect size for association between QoL and CRS-related antibiotic or corticosteroid use in the prior 3 months versus prior 12 months. These results were independent of the presence or absence of polyps. CONCLUSION: More frequent past CRS-related oral antibiotic and corticosteroid use, regardless of time period queried (3 months or 12 months) is associated with significant decrease in CRS-specific and general health-related QoL. CRS-related systemic medication use is an important indicator of CRS patients' QOL that easily can be queried and utilized in both clinical and research settings. LEVEL OF EVIDENCE: 2c. Laryngoscope, 128:37-42, 2018. PMID- 28731527 TI - Mechanotransduction Effects on Endothelial Cell Proliferation via CD31 and VEGFR2: Implications for Immunomagnetic Separation. AB - Immunomagnetic separation is used to isolate circulating endothelial cells (ECs) and endothelial progenitor cells (EPCs) for diagnostics and tissue engineering. However, potentially detrimental changes in cell properties have been observed post-separation. Here, the effect of mechanical force, which is naturally applied during immunomagnetic separation, on proliferation of human umbilical vein endothelial cells (HUVEC), kinase insert domain-positive receptor (KDR) cells, and peripheral blood mononuclear cells (PBMCs). Cells are exposed to CD31 or Vascular Endothelial Growth Factor Receptor-2 (VEGFR2) targeted MACSi beads at varying bead to cell ratios and compared to free antibody and unconjugated beads. A vertical magnetic gradient is applied to static 2D cultures, and a magnetic cell sorter is used to analyze cells in dynamic flow. No significant difference in EC proliferation is observed for controls or VEGFR2-targeting beads, whereas CD31-conjugated beads increase proliferation in a dose dependent manner in static 2-D cultures. This effect occurs in the absence of magnetic field, but is more pronounced with magnetic force. After flow sorting, similar increases in proliferation are seen for CD31 targeting beads. Thus, the effects of targeting antibody and magnetic force applied should be considered when designing immunomagnetic separation protocols for ECs. PMID- 28731530 TI - Diagnostic accuracy of nasal cannula versus microphone for detection of snoring. AB - OBJECTIVE: Snoring is a common reason for referral to a sleep unit. Although there are several instruments to measure snoring, there is no gold standard for this purpose. In this study, we determine the diagnostic accuracy of the cannula as compared with the microphone, which are the two most commonly used tools. STUDY DESIGN: We performed a cross-sectional study of 75 patients who underwent baseline home sleep apnea testing for any reason. METHODS: Snore intensity and percentage were assessed during Home sleep-apnea testing via nasal cannula and microphone in all patients. We performed a complete diagnostic accuracy analysis, assuming the microphone to be the reference instrument use in order to compare it with the cannula. RESULTS: The intra-class correlation coefficient between the cannula and microphone for the percentage of snoring was 0.25. The Bland Bland Altman analysis to determine the agreement regarding the percentage of snoring showed a lower limit of -57.73 and an upper limit of 20.30. A linear regression analysis of the differences produced a negative slope of -0.86. The receiver operating characteristic curve for severe snoring using the cannula produced an area under the curve of 0.67 (P = 0.019). The cannula showed a sensitivity of 57.89 and a specificity of 73.21. CONCLUSION: The nasal cannula showed poor reliability and accuracy for measuring snoring. LEVEL OF EVIDENCE: 2b. Laryngoscope, 127:2886-2890, 2017. PMID- 28731532 TI - Formate and Nitrate Utilization in Enterobacter aerogenes for Semi-Anaerobic Production of Isobutanol. AB - Anaerobic bioprocessing is preferred because of its economic advantages. However, low productivity and decreased growth of the host strain have limited the use of the anaerobic process. Anaerobic respiration can be applied to anoxic processing using formate and nitrate metabolism to improve the productivity of value-added metabolites. A isobutanol-producing strains is constructed using Enterobacter aerogenes as a host strain by metabolic engineering approaches. The byproduct pathway (ldhA, budA, and pflB) is knocked out, and heterologous keto-acid decarboxylase (kivD) and alcohol dehydrogenase (adhA) are expressed along with the L-valine synthesis pathway (ilvCD and budB). The pyruvate formate-lyase mutant shows decreased growth rates when cultivated in semi-anaerobic conditions, which results in a decline in productivity. When formate and nitrate are supplied in the culture medium, the growth rates and amount of isobutanol production is restored (4.4 g L-1 , 0.23 g g-1 glucose, 0.18 g L-1 h-1 ). To determine the function of the formate and nitrate coupling reaction system, the mutant strains that could not utilize formate or nitrate is contructed. Decreased growth and productivity are observed in the nitrate reductase (narG) mutant strain. This is the first report of engineering isobutanol-producing E. aerogenes to increase strain fitness via augmentation of formate and nitrate metabolism during anaerobic cultivation. PMID- 28731531 TI - Solitary splenic metastasis from lung adenocarcinoma: A case report. AB - Solitary splenic metastasis is extremely rare, with only 27 reported cases in the literature. An 81-year-old woman was referred to our hospital for treatment of pulmonary and splenic lesions. Chest computed tomography showed a small lung nodule in the right upper lobe, abdominal computed tomography showed an 8 cm splenic mass with abnormal accumulation, and positron emission tomography revealed a maximum standardized uptake value of 7.9. She had elevated serum cancer antigen 19-9 (1847 U/mL) and carcinoembryonic antigen concentrations (17.9 ng/mL). She underwent laparoscopic splenectomy. Pathological examination revealed poorly differentiated adenocarcinoma. We performed partial lung resection and diagnosed the small lung lesion as lung adenocarcinoma. Both lesions were positive for thyroid transcription factor 1. Thus, primary lung adenocarcinoma and solitary splenic metastasis were diagnosed. The patient was still alive without recurrence four years postoperatively. Herein, we report a rare case of lung adenocarcinoma with solitary splenic metastasis and review the literature. PMID- 28731533 TI - Improvement of d-Lactic Acid Production in Saccharomyces cerevisiae Under Acidic Conditions by Evolutionary and Rational Metabolic Engineering. AB - Microbial lactic acid (LA) production under acidic fermentation conditions is favorable to reduce the production cost, but circumventing LA toxicity is a major challenge. A d-LA-producing Saccharomyces cerevisiae strain JHY5610 is generated by expressing d-lactate dehydrogenase gene (Lm. ldhA) from Leuconostoc mesenteroides, while deleting genes involved in ethanol production (ADH1, ADH2, ADH3, ADH4, and ADH5), glycerol production (GPD1 and GPD2), and degradation of d LA (DLD1). Adaptive laboratory evolution of JHY5610 lead to a strain JHY5710 having higher LA tolerance and d-LA-production capability. Genome sequencing of JHY5710 reveal that SUR1I245S mutation increases LA tolerance and d-LA production, whereas a loss-of-function mutation of ERF2 only contributes to increasing d-LA production. Introduction of both SUR1I245S and erf2Delta mutations into JHY5610 largely mimic the d-LA-production capability of JHY5710, suggesting that these two mutations, which could modulate sphingolipid production and protein palmitoylation, are mainly responsible for the improved d-LA production in JHY5710. JHY5710 is further improved by deleting PDC1 encoding pyruvate decarboxylase and additional integration of Lm. ldhA gene. The resulting strain JHY5730 produce up to 82.6 g L-1 of d-LA with a yield of 0.83 g g-1 glucose and a productivity of 1.50 g/(L . h) in fed-batch fermentation at pH 3.5. PMID- 28731534 TI - Internal quality control in an academic cytopathology laboratory for the introduction of a new reporting system for endometrial cytology. AB - BACKGROUND: To evaluate reproducibility of a reporting system for endometrial cytology. METHODS: Cytologic slides from 49 patients, prepared via liquid based cytology, were blindly examined by five cytopathologists of various experience levels, applying a recently introduced reporting system as previously reported. The agreement among cytopathologists was evaluated via Kappa (kappa) statistics and the Kendall's Coefficient of Variation (W); cytologic results were compared with the relevant histologic report. RESULTS: Substantial agreement among all five raters was found in the benign, ACE-L and malignant categories, fair agreement in inadequate and ACE-H categories, whereas only slight agreement in ACE-U. For the three more experienced cytopathologists, an almost perfect agreement was found in inadequate, benign, and ACE-L categories, substantial agreement in ACE-H and malignant categories and fair agreement in ACE-U category. Overall agreement for all five cytopathologists and for all categories was moderate, whereas it was very high for the three senior raters. Using the Kendall's test, both five cytopathologists (W = 0.81) and the three senior ones (W = 0.93) had very high agreement. Sensitivity: 83.33-92.59%, specificity: 83.33 94.74%, ROC area: 71.72-90.3%. CONCLUSION: Application of appropriate statistical tests shows that integration of a new reporting cytologic system is effective with an overall accuracy around 90%. Both statistical tests applied disclosed lower agreement rates among both all five raters and the three most experienced ones in the intermediate categories constituting the gray zone, thus delineating the need for better training of cytopathologists to correctly identify diagnostic criteria for classification of a given case into these categories. PMID- 28731536 TI - Commentary on: Lockhart JJ, Satya-murti S. Diagnosing crime and diagnosing disease: bias reduction strategies in the forensic and clinical sciences. J Forensic Sci https://doi.org/10.1111/1556-4029.13453. Epub 2017 Feb 23. PMID- 28731535 TI - Ultrasound-Guided Drainage for Pediatric Soft Tissue Abscesses Decreases Clinical Failure Rates Compared to Drainage Without Ultrasound: A Retrospective Study. AB - OBJECTIVES: Soft tissue abscesses are common in the pediatric emergency department (ED). Ultrasound (US) can be used to both diagnose soft tissue abscesses as well as guide drainage. We hypothesized that clinical failure rates would be less in pediatric patients with suspected skin abscesses when evaluated with US. METHODS: We performed a retrospective review of suspected pediatric skin abscesses at 4 EDs over a 22-month period. Cases were identified through electronic medical record descriptions, discharge diagnoses, and US database records. Data on US use, findings, and outcomes were abstracted to an electronic database. Comparisons between groups included US versus non-US (primary outcome) as well as surgical drainage vs nonsurgical drainage (secondary outcome). RESULTS: A total of 377 patients were seen with concern for a potential skin abscess; 141 patients (37.4%) underwent US imaging during their visit, and 239 (63.4%) underwent incision and drainage (I&D) during their ED stay: 90 with US and 149 without. The failure rate for patients evaluated with US was significantly lower than that for those evaluated without US (4.4% versus 15.6%; P < .005). Thirty-four (11.3%) of the 302 patients with a diagnosis of an abscess failed therapy: 19 (8.2%) after I&D and 15 (21.1%) after nonsurgical management. Failure after I&D was associated with a smaller abscess cavity on US imaging (17.2 versus 44.8 mm3 ; P < .05). CONCLUSIONS: The use of US for patients with a suspected skin abscess was associated with a reduction in the amount of clinical failure rates after both surgical drainage and nonsurgical therapy. Ultrasound should be used when evaluating or treating patients with abscesses. PMID- 28731537 TI - Frailty and cancer: Implications for oncology surgery, medical oncology, and radiation oncology. AB - Answer questions and earn CME/CNE The concept of frailty has become increasingly recognized as one of the most important issues in health care and health outcomes and is of particular importance in patients with cancer who are receiving treatment with surgery, chemotherapy, and radiotherapy. Because both cancer itself, as well as the therapies offered, can be significant additional stressors that challenge a patient's physiologic reserve, the incidence of frailty in older patients with cancer is especially high-it is estimated that over one-half of older patients with cancer have frailty or prefrailty. Defining frailty can be challenging, however. Put simply, frailty is a state of extreme vulnerability to stressors that leads to adverse health outcomes. In reality, frailty is a complex, multidimensional, and cyclical state of diminished physiologic reserve that results in decreased resiliency and adaptive capacity and increased vulnerability to stressors. In addition, over 70 different measures of frailty have been proposed. Still, it has been demonstrated that frail patients are at increased risk of postoperative complications, chemotherapy intolerance, disease progression, and death. Although international standardization of frailty cutoff points are needed, continued efforts by oncology physicians and surgeons to identify frailty and promote multidisciplinary decision making will help to develop more individualized management strategies and optimize care for patients with cancer. CA Cancer J Clin 2017;67:362-377. (c) 2017 American Cancer Society. PMID- 28731538 TI - Meta-analysis of quality-of-life improvement after cochlear implantation and associations with speech recognition abilities. AB - OBJECTIVES: Determine the impact of cochlear implantation on quality of life (QOL) and determine the correlation between QOL and speech recognition ability. STUDY DESIGN: Two authors independently searched PubMed, Medline, Scopus, and the Cumulative Index to Nursing and Allied Health Literature to identify studies reporting hearing-specific or cochlear implant (CI)-specific QOL outcomes before and after cochlear implantation, and studies reporting correlations between QOL and speech recognition after cochlear implantation. Data from the included articles were obtained independently by two authors. Standardized mean difference (SMD) for each measure and pooled effects were determined to assess improvement in QOL before and after cochlear implantation. RESULTS: From 14 articles with 679 CI patients who met the inclusion criteria, pooled analyses of all hearing specific QOL measures revealed a very strong improvement in QOL after cochlear implantation (SMD = 1.77). Subset analysis of CI-specific QOL measures also showed very strong improvement (SMD = 1.69). Thirteen articles with 715 patients met the criteria to evaluate associations between QOL and speech recognition. Pooled analyses showed a low positive correlation between hearing-specific QOL and word recognition in quiet (r = 0.213), sentence recognition in quiet (r = 0.241), and sentence recognition in noise (r = 0.238). Subset analysis of CI specific QOL showed similarly low positive correlations with word recognition in quiet (r = 0.213), word recognition in noise (r = 0.241), and sentence recognition in noise (r = 0.255). CONCLUSIONS: Using hearing-specific and CI specific measures of QOL, patients report significantly improved QOL after cochlear implantation. However, widely used clinical measures of speech recognition are poor predictors of patient-reported QOL with CIs. Laryngoscope, 128:982-990, 2018. PMID- 28731539 TI - Interleukin 17A gene polymorphism rs2275913 is associated with osteitis after the Bacillus Calmette-Guerin vaccination. AB - AIM: Interleukin-17 (IL-17) appears to promote the host's defence against mycobacterial infections. This study evaluated the association between IL17A gene polymorphism and the risk of Bacillus Calmette-Guerin (BCG) osteitis after newborn vaccination and between IL17A gene polymorphism and IL-17A concentrations in serum. METHODS: IL17A rs2275913 gene polymorphisms and serum IL-17A concentrations were studied in 132 adults aged 21-49 years from across Finland, who had BCG osteitis in infancy after a newborn BCG vaccination. The subjects were recruited in 2007-2008, and their whole-blood samples were sent to the National Institute for Health and Welfare, Turku, Finland. Their genotypes and minor allele frequencies were compared with 405 population-based unvaccinated controls aged two to three months from a prospective birth cohort study. RESULTS: The genotypes and allele frequencies of IL17A rs2275913 differed significantly between the former BCG osteitis patients and controls. The genotype was variant in 75.8% of cases and 64.0% of controls (p = 0.012), and the minor allele frequency was 50.0% in the cases and 41.6% of the controls (p = 0.009). Serum IL 17 concentrations did not differ significantly between the cases with wild or variant genotypes. CONCLUSION: IL17A rs2275913 gene polymorphism was associated with a risk of BCG osteitis after vaccination. PMID- 28731540 TI - Participation of osteoclastogenic factors in immunopathogenesis of human chronic periapical lesions. AB - BACKGROUND: Chronic periapical lesions (CPLs) are common lesions of the oral cavity and are the result of caries, tooth fracture, iatrogenic causes, or factors causing contamination and pulp necrosis. Inflammatory cells participate in the expansion of CPLs by releasing factors that stimulate or inhibit osteolytic activity. The objective of this study was to investigate the participation of RANKL, TNF-alpha, cathepsin K, IL-33, and OPG in the development of radicular cysts (RCs) and periapical granulomas (PGs). METHODS: Paraffin embedded sections of 30 RCs and 22 PGs were submitted to immunohistochemistry. RESULTS: Immunoexpression of the proteins studied was observed in the epithelium and capsule of RCs, as well as in connective tissue of PGs. The expression of the osteoclastogenic factors studied differed significantly in RCs and PGs (P < .001), with lower expression of OPG in RCs. In PGs, the lowest expression was observed for cathepsin K. Comparison of the 2 lesions showed a similar participation of RANKL and IL33, while a significant difference was observed for OPG (P < .001), TNF-alpha (P = .002), and cathepsin K (P = .016). No association of the expression of the proteins with lesions size was observed. CONCLUSIONS: This study demonstrated the participation of RANKL, TNF-alpha, IL-33, cathepsin K, and OPG in the development of RCs and PGs, with emphasis on the highest immunoreactivity of cathepsin in RCs and TNF-alpha and OPG in PGs. OPG possibly determines the slower growth of PGs compared to RCs. PMID- 28731541 TI - Demography and genome divergence of lake and stream populations of an East African cichlid fish. AB - Disentangling the processes and mechanisms underlying adaptive diversification is facilitated by the comparative study of replicate population pairs that have diverged along a similar environmental gradient. Such a setting is realized in a cichlid fish from southern Lake Tanganyika, Astatotilapia burtoni, which occurs within the lake proper as well as in various affluent rivers. Previously, we demonstrated that independent lake and stream populations show similar adaptations to the two habitat regimes. However, little is known about the evolutionary and demographic history of the A. burtoni populations in question and the patterns of genome divergence among them. Here, we apply restriction site associated DNA sequencing (RADseq) to examine the evolutionary history, the population structure and genomic differentiation of lake and stream populations in A. burtoni. A phylogenetic reconstruction based on genome-wide molecular data largely resolved the evolutionary relationships among populations, allowing us to re-evaluate the independence of replicate lake-stream population clusters. Further, we detected a strong pattern of isolation by distance, with baseline genomic divergence increasing with geographic distance and decreasing with the level of gene flow between lake and stream populations. Genome divergence patterns were heterogeneous and inconsistent among lake-stream population clusters, which is explained by differences in divergence times, levels of gene flow and local selection regimes. In line with the latter, we only detected consistent outlier loci when the most divergent lake-stream population pair was excluded. Several of the thus identified candidate genes have inferred functions in immune and neuronal systems and show differences in gene expression between lake and stream populations. PMID- 28731542 TI - Total Syntheses of Cystobactamids and Structural Confirmation of Cystobactamid 919-2. AB - The cystobactamids are a family of antibacterial natural products with unprecedented chemical scaffolds that are active against both Gram-positive and Gram-negative pathogens. Herein, we describe the first total synthesis of cystobactamid 919-2 from three fragments. Our convergent synthesis enabled both the confirmation of the correct structure and the determination of the absolute configuration of cystobactamid 919-2. PMID- 28731543 TI - Pollen grains as contaminants in cytopathology. PMID- 28731544 TI - Localized MRS reliability of in vivo glutamate at 3 T in shortened scan times: a feasibility study. AB - Glutamate is the prime excitatory neurotransmitter in the mammalian brain and has been implicated in a wide range of psychiatric conditions. To improve the applicability and clinical reach of magnetic resonance spectroscopy (MRS), research is needed to develop shortened, yet reliable, MRS scanning procedures for standard 1.5-3-T clinical magnetic resonance imaging (MRI) systems, particularly with young or vulnerable populations unable to tolerate longer protocols. To this end, we evaluated the test-retest reliability of a shortened J resolved MRS sequence in healthy adolescents (n = 22) aged 12-14 years. Participants underwent a series of sequential 6-min MRS scans, with the participants remaining in situ between successive scans. Glutamate and other metabolites were acquired from the rostral anterior cingulate cortex, as glutamatergic function in this region has been implicated in a number of psychiatric illnesses. Thirteen neurochemicals were quantified as ratios to total creatine, and reliability scores were expressed as the percentage difference between the two scans for each metabolite. Test-retest assessment of glutamate was reliable, as scores were less than 10% different (7.1 +/- 4.2%), and glutamate values across scans were significantly correlated (Pearson r = 0.680, p < 10-4 ). Several other neurochemicals demonstrated satisfactory reliability, including choline (Cho) (7.4 +/- 5.6%), glutathione (GSH) (8.6 +/- 4.1%), myo inositol (mI) (6.5 +/- 7.1%) and N-acetylaspartate (NAA) (3.5 +/- 3.6%), with test-retest correlations ranging from 0.747 to 0.953. A number of metabolites, however, did not demonstrate acceptable test-retest reliability using the current J-resolved MRS sequence, ranging from 13.8 +/- 13.7% (aspartate, Asp) to 45.9 +/- 38.3% (glycine, Gly). Collectively, test-retest analyses suggest that clinically viable quantitative data can be obtained on standard MRI systems for glutamate, as well as the other metabolites, during short scan times in a traditionally challenging brain region. PMID- 28731546 TI - Stereoselective Synthesis of Piperidines by Iridium-Catalyzed Cyclocondensation. AB - An iridium-catalyzed cyclocondensation of amino alcohols and aldehydes is reported. Intramolecular allylic substitution by an enamine intermediate and subsequent in situ reduction furnishes 3,4-disubstituted piperidines with high enantiospecificity and good diastereoselectivity. The modular approach and the broad functional group tolerance provide access to diverse piperidine derivatives, which were further functionalized to give a versatile set of products. PMID- 28731545 TI - Genome-scale data reveal that endemic Poecilia populations from small sulphidic springs display no evidence of inbreeding. AB - Populations with limited ranges can be highly vulnerable to changes in their environment and are, thus, of high conservation concern. Populations that experience human-induced range reductions are often highly inbred and lack genetic diversity, but it is unknown whether this is also the case for populations with naturally small ranges. The fishes Poecilia sulphuraria (listed as critically endangered) and Poecilia thermalis, which are endemic to small hydrogen sulphide-rich springs in southern Mexico, are examples of such populations with inherently small habitats. We used geometric morphometrics and population genetics to quantify phenotypic and genetic variation within and among two populations of P. sulphuraria and one population of P. thermalis. Principal component analyses revealed phenotypic and genetic differences among the populations. Evidence for inbreeding was low compared to populations that have undergone habitat reduction. The genetic data were also used to infer the demographic history of these populations to obtain estimates for effective population sizes and migration rates. Effective population sizes were large given the small habitats of these populations. Our results imply that these three endemic extremophile populations should each be considered separately for conservation purposes. Additionally, this study suggests that populations in naturally small habitats may have lower rates of inbreeding and higher genetic diversity than expected, and therefore may be better equipped to handle environmental perturbations than anticipated. We caution, however, that the inferred lack of inbreeding and the large effective population sizes could potentially be a result of colonization by genetically diverse ancestors. PMID- 28731547 TI - Does hospital ownership influence hospital referral region health rankings in the United States. AB - Extensive evidence demonstrates that a hospital's organizational ownership structure impacts its overall performance, but little is known concerning the influence of hospital structure on the health of its community. This paper explores the association between US hospital referral region (HRR) health rankings and hospital ownership and performance. Data from the 2016 Commonwealth Fund Scorecard on Local Health System Performance, the American Hospital Association dataset, and the Hospital Value-Based Purchasing dataset are utilized to conduct a cross-sectional analysis of 36 quality measures across 306 HRRs. Multivariate regression analysis was used to estimate the association among hospital ownership, system performance measures-access and affordability, prevention and treatment, avoidable hospital use and cost, and healthy lives-and performance as measured by value-based purchasing total performance scores. We found that indicators of access and affordability, as well as prevention and treatment, were significantly associated across all 3 hospitals' organizational structures. Hospital referral regions with a greater number of not-for-profit hospitals demonstrated greater indications of access and affordability, as well as better prevention and treatment rankings than for-profit and government hospitals. Hospital referral regions with a greater number of government, nonfederal hospitals had worse scores for healthy lives. Furthermore, the greater the total performance scores score, the better the HRR score on prevention and treatment rankings. The greater the per capita income, the better the score across all 4 dimensions. As such, this inquiry supports the assertion that performance of a local health system is dependent on its community's resources of health care delivery entities and their structure. PMID- 28731548 TI - Oral lacerations during motocross: A case report. AB - Motocross is a high-risk sport that can cause serious injuries including oral injuries. However, mouthguard use is not mandatory in motocross. This report describes a case of an oral laceration with exposure of bilateral inferior alveolar nerves as a result of a motocross accident in which the patient was not wearing a mouthguard. PMID- 28731549 TI - Development and validation of the Dietetic Confidence Scale for working with clients experiencing psychological issues. AB - AIM: A standardised tool was needed to measure a generalist dietitian's confidence about working with clients experiencing psychological issues in order to effectively evaluate mental health-related professional development activities. The aim of this study was to develop, pilot and validate a robust instrument that measures a generalist dietitian's professional confidence for working with clients experiencing psychological issues. METHODS: The Dietetic Confidence Scale (DCS) was developed. Two cross-sectional samples of practicing dietitians (n = 185; 458) from various settings and locations were recruited. Study 1: principal components analysis (PCA) helped refine scale items and derive a model, which was then validated using confirmatory factor analysis (CFA, Study 2). Cronbach's alpha estimated scale reliability. Correlations assessed associations between factors. RESULTS: Study 1: A 13-item, two-factor solution accounted for 69.1% of the total variance. Total Cronbach's alpha = 0.92. Dietetic confidence was associated with: (i) Confidence using the Nutrition Care Process and (ii) Confidence Advocating for Self care and Client care. Study 2: The CFA supported the proposed scale and model. A Good Fit Index of 0.95 indicated a strong fit. Item-factor correlations ranged from r = 0.50 to 0.91. The final scale showed good reliability (alpha = 0.93). CONCLUSIONS: This is the first self-efficacy scale for dietetic practitioners subjected to PCA and CFA using two independent samples. The DCS is a psychometrically robust instrument with strong internal consistency. It can be used to measure dietetic confidence about working with clients experiencing psychological issues and to highlight areas where additional support or training may be needed. Further validity and reliability testing is needed to enhance scale generalisability and use. PMID- 28731550 TI - Food allergy in schools: The importance of government involvement. AB - AIM: Children have the highest rates of food-related allergic reactions. While 85% of children outgrow allergies including cow's milk and eggs by five years of age, allergies to peanuts and seafood continue into adulthood. The school setting poses a high-risk environment for allergen exposure. The aim of the present study was to examine the availability, drivers and communication of school food allergy awareness and management policies/guidelines in one Australian education jurisdiction. METHODS: A cross-sectional study comprising an online survey of principals on school allergy awareness (n = 100) was conducted in public, catholic and independent primary and high schools in an Australian education jurisdiction between August 2011 and November 2012. RESULTS: Sixty-three per cent (17/27) of schools responding to the survey reported using food allergy management guidelines. An average of 13 students per school were reported to have a food allergy with 93% of schools reported having students with at least one food allergy. Parents, not government policy, were identified as primary drivers of food allergy guideline implementation and a third of schools provided anaphylaxis training annually. Communication of food allergy management was limited with only 42 school websites either providing access to policies/guidelines or providing a food allergy statement. CONCLUSIONS: Detailed awareness and management guidelines are integral for schools to adequately manage food-induced allergic reactions, including anaphylaxis, in the school environment. To enable this, national government support through legislation and policy is needed to ensure a consistent, up-to-date and policed approach to food allergy management in the Australian education sector. PMID- 28731551 TI - Sarcopenia and hospitalisation costs in older adults: a cross-sectional study. AB - AIM: The impact of sarcopenia on hospitalisation has been under intense investigation; however, little is known about the association between sarcopenia and their costs among hospitalised patients. The aim of the present study was to quantify the association between sarcopenia and hospitalisation costs among older adults. METHODS: A cross-sectional study was conducted in 201 hospitalised older adults in a general hospital. Sarcopenia was identified according to the European Working Group on Sarcopenia in Older People (EWGSOP) criteria. Muscle mass was assessed by anthropometric measurements, muscle strength through handgrip strength evaluation and physical performance by Timed Up and Go Test. Nutritional status was evaluated using the Mini Nutritional Assessment-Short Form (MNA-SF), and hospital costs were assessed with the Diagnosis Related Groups (DRGs) system. Multivariable logistic regression models were fitted to quantify the association between sarcopenia and hospital costs. Increased hospital costs were considered when a patients' cost was higher than the mean cost of an average patient (?2396.24). RESULTS: Within this sample, 10.4% sarcopenic, 43.8% at nutritional risk and 14.9% undernourished older adults were identified. After adjustment, sarcopenia (OR = 5.70, 95% CI 1.57-20.71) and low muscle strength (OR = 2.40, 95% CI 1.12-5.15) were associated with increased hospital costs. CONCLUSIONS: Sarcopenia and low muscle strength at hospital admission were independently associated with increased hospital costs. PMID- 28731552 TI - Development of food lists as a first step to develop a food frequency questionnaire for toddlers in a multi-ethnic population. AB - AIM: Toddlerhood is an important stage of growth, thus understanding the food intake of children in this age group is important. In Singapore, there is currently no simple tool, such as Food Frequency Questionnaire (FFQ), to collect dietary information from this ethnically diverse age group. Generating an appropriate food list is a crucial step in the development of a FFQ and this step is not clearly documented in the literature. The purpose of this study is to generate food lists and portion sizes for toddlers from three major ethnic groups in Singapore and document the processes involved in this first stage. METHODS: A total of 30 mothers (equal number of Malays, Indians and Chinese) of 11-24-month old children completed three-day food records and participated in the focus group discussion. The reported food items were then categorised into food groups. RESULTS: The food lists varied by ethnic groups with the longest list obtained from Chinese toddlers. There were also other foods that were then classified as common foods for all ethnicities. Commonly used utensils among the three ethnic groups were small-sized bowls, plates, cups and spoons. For portion sizes, these utensils were typically half-filled for the toddlers. CONCLUSIONS: As all Singaporeans have access to the same foods, the ethnic-specific food lists generated in this study could be combined into one list. Together with portion sizes, this information can be used for developing a semi-quantitative FFQ. PMID- 28731553 TI - Trends in fluid consumption and beverage choices among adults reveal preferences for ayran and black tea in central Turkey. AB - AIM: Beverages are globally significant sources of water in the diet. There is a lack of knowledge about fluid intake from beverage and water consumption in Turkey. Thus, the aim of this study was to examine the type of drinks preferred at meals and snacks as well as the daily fluid, beverage and water intakes based on age and gender. METHODS: A cross-sectional survey was administered to 3411 randomly chosen adult participants (n = 1522 male, n = 1919 female) representing the general profile of central Turkey. The survey consisted of a demographic/personal information questionnaire, 24-hour dietary recalls and mealtime-based beverage frequency questionnaires. Body weights and heights were measured. RESULTS: Daily average total fluid consumption was 2270 mL/day, of which water was 1470 mL/day, and other beverages were 800 mL/day. More than 90% of the participants drank black tea at breakfast and snacks. For lunch and dinner, young participants' major choices were carbonated soft drinks followed by ayran (diluted salty plain yoghurt); middle aged and older participants' choices were ayran followed by black tea. Carbonated soft drinks were preferred over ayran in subjects aged 19-39 years. CONCLUSIONS: Older participants prefer healthy, traditional choices such as ayran and black tea, but younger participants prefer high energy-containing drinks with low nutritional value. Thus, this unique information contributes to the data on beverage consumption patterns in different countries and might be useful for increasing consumption of nutritious fluids and decreasing sugar usage in Turkey. PMID- 28731554 TI - Evaluation of a 'healthiness' rating system for food outlet types in Australian residential communities. AB - AIM: To obtain expert consensus to develop and evaluate a rating system on the relative healthiness of Australian suburbs' food outlet types. METHODS: Twenty four food outlet types and 10 local suburbs were identified from previous mapping studies and based on a scan of suburbs across one large Australian geographical region. Initial food outlet 'scores' for relative healthiness were proposed based on available literature, classified into five categories, from 'most' to 'least' healthy. In round 1 of a modified Delphi survey, participants, Australian public health and nutrition experts, were given each outlet type's definition and the proposed scores and invited to modify the scores based on their perceived 'healthiness'. In round 2, participants were able to revise or adjust their scores. RESULTS: Median scores for food outlet types from both rounds highly correlated with the originally proposed scores (two-tailed Pearson's correlation coefficient 0.97 and 0.96, respectively, P = 0.01), and scores from round 1 highly correlated with those from round 2 (Pearson's coefficient 0.998, P = 0.01). Round 2 scores were used to calculate suburbs' overall food environment score, healthiness score, unhealthiness score and a ratio of unhealthiness to healthiness scores. There was strong positive correlation between suburbs' ratio of unhealthiness to healthiness scores and a previously recognised scoring ratio, Retail Food Environment Index (Spearman's rho 0.847, P < 0.01). CONCLUSIONS: The study generated experts' consensus about relative healthiness of food outlet types found in Australian neighbourhoods. Proposed scores can be used to assess and compare healthiness of community food environments and to explore their associations with area characteristics, population's diet and health outcomes. PMID- 28731555 TI - Who does nutrition prevention work in Queensland? An investigation of structural and political workforce reforms. AB - AIM: This study aimed (i) to determine the change in the number of government funded nutrition positions following structural and political reforms and (ii) to describe the remaining workforce available to do nutrition prevention work, including student placements, in Queensland. METHODS: Positions funded by the Queensland government were counted using departmental human resource data and compared with data collected 4 years earlier. Positions not funded by the government were identified using formal professional networks and governance group lists. Both groups were sent an online survey that explored their position name, funding source, employer, qualifications, years of experience, work in prevention and ability to supervise students. RESULTS: There was a 90% reduction in the number of nutrition prevention positions funded by the government between 2009 (137 full time equivalents (FTE)) and 2013 (14 FTE). In 2013, 313 specialist (n = 92) and generalist (n = 221) practitioners were identified as potentially working in nutrition prevention throughout Queensland. A total of 30 permanent FTEs indicated over 75% of their work focused on prevention. This included the 14 FTE funded by the Queensland government and an additional 16 FTE from other sectors. Generalists did not consider themselves part of the nutrition workforce. CONCLUSIONS: Queensland experienced an extreme reduction in its nutrition prevention workforce as a result of political and structural reforms. This disinvestment by the Queensland government was not compensated for by other sectors, and has left marked deficits in public health nutrition capacity, including student placements. PMID- 28731556 TI - Dietetic management of gestational diabetes in New Zealand: A cross-sectional survey. AB - AIM: The aim of this study was to evaluate dietetic practice in the management of gestational diabetes in New Zealand, compare this with evidence-based guidelines and determine the need for New Zealand-specific evidence-based nutrition practice guidelines for gestational diabetes. METHODS: A 64-item cross-sectional online survey of New Zealand-registered dietitians providing care to women with gestational diabetes was undertaken. Participants were recruited through Dietitians New Zealand, District Health Boards and private practices across New Zealand. The survey examined dietetic service provision, management recommendations, guideline use, service evaluation, compliance with national and international guidelines and the perceived need for New Zealand-specific evidence based guidelines for the nutritional management of gestational diabetes. RESULTS: Thirty-three (62%) eligible dietitians participated in the survey. There was significant variation in dietetic services and management recommendations. Nine (28%) dietitians felt the service within which they worked did not offer adequate dietetic services for women with gestational diabetes. Compliance with national and international evidence-based guidelines ranged from 28 to 100% depending on the recommendation. Twenty-five (76%) respondents felt there was a need for New Zealand-specific evidence-based nutrition practice guidelines for gestational diabetes. CONCLUSIONS: These results highlight differences in dietetic services and practice in New Zealand and variations in compliance with local and international evidence-based guidelines. The development of New Zealand-specific evidence-based nutrition practice guidelines for gestational diabetes is supported. PMID- 28731557 TI - Data mining: Potential applications in research on nutrition and health. AB - AIM: Data mining enables further insights from nutrition-related research, but caution is required. The aim of this analysis was to demonstrate and compare the utility of data mining methods in classifying a categorical outcome derived from a nutrition-related intervention. METHODS: Baseline data (23 variables, 8 categorical) on participants (n = 295) in an intervention trial were used to classify participants in terms of meeting the criteria of achieving 10 000 steps per day. Results from classification and regression trees (CARTs), random forests, adaptive boosting, logistic regression, support vector machines and neural networks were compared using area under the curve (AUC) and error assessments. RESULTS: The CART produced the best model when considering the AUC (0.703), overall error (18%) and within class error (28%). Logistic regression also performed reasonably well compared to the other models (AUC 0.675, overall error 23%, within class error 36%). All the methods gave different rankings of variables' importance. CART found that body fat, quality of life using the SF-12 Physical Component Summary (PCS) and the cholesterol: HDL ratio were the most important predictors of meeting the 10 000 steps criteria, while logistic regression showed the SF-12PCS, glucose levels and level of education to be the most significant predictors (P <= 0.01). CONCLUSIONS: Differing outcomes suggest caution is required with a single data mining method, particularly in a dataset with nonlinear relationships and outliers and when exploring relationships that were not the primary outcomes of the research. PMID- 28731558 TI - Food provision in early childhood education and care services: Exploring how staff determine nutritional adequacy. AB - AIM: The aim of this study was to explore the methods, processes and strategies used by early childhood education and care (ECEC) services when determining the nutritional adequacy of food provided to children in their care. METHODS: Semi structured interviews (n = 22) were conducted with directors, educators and cooks at long day care services (LDCS) (n = 12) regarding nutritional adequacy, the use of tools, guidelines and checklists, menu planning and identification and management of unhealthy foods. A qualitative thematic approach was used to identify anticipated and emergent themes. Case-by-case comparisons were then made, and tables and models were created to allow for comparative analysis. RESULTS: LDCS relied on personal knowledge, experience and 'common sense' when determining the nutritional adequacy of the food provided to children. LDCS demonstrated a lack of awareness and use of current regulatory requirements, nutrition guidelines and recommendations, although the services were confident in providing nutrition advice to parents/carers. CONCLUSIONS: LDCS staff use personal knowledge and experience over evidence-based nutrition guidelines and recommendations when determining if the food provided to children is nutritionally adequate. ECEC services are recognised as important settings for obesity prevention and the development of lifetime healthy eating habits. This study highlights the complexities and inconsistencies in providing food that is nutritious and appropriate to children in care while highlighting the need to improve the use and accessibility of nutrition guidelines. PMID- 28731559 TI - Association between anthropometric measures of regional fat mass and heart rate variability in obese women. AB - AIM: Impaired autonomic function could be the mechanism for the development of cardiometabolic diseases in obesity. Hence, simple anthropometric measures of overall and central obesity could be screening markers for autonomic imbalance. We analysed the relationship between heart rate variability (HRV) parameters and obesity indicators. METHODS: Sixty-three obese women underwent blood pressure, lipids and anthropometric measurements, body composition assessment, HOMA (homeostasis model assessment) index calculation and short-term HRV analysis. RESULTS: The correlation between obesity indicators and HRV parameters was influenced by age. In the multiple regression model, sagittal abdominal diameter (SAD) was a significant negative predictor of lnLF/HF (logarithmically transformed ratio of low to high frequencies) and lnLFnorm, and positive predictor of HFnorm (normalized high frequencies); the significant relationship remained even after adjustment for age, HOMA, blood pressure, lipid profile, menopause, body mass index (BMI) and body fat percentage (FAT). Anterior forearm skinfold showed inverse association with HRV. Correlation between waist circumference and waist-to-height ratio (WHtR) with lnLF/HF, as well as between anterior thigh skinfold with lnLF/HF, LFnorm (normalised low frequencies) and HFnorm was lost after further adjustments. CONCLUSION: Among all anthropometric measures, SAD and anterior forearm skinfold thickness showed the highest predictive ability for HRV. Markers of lower sympathetic and higher cardiac parasympathetic activity corresponded with indicator of central obesity, while indicators of peripheral obesity showed completely opposite relationship with markers of cardiac autonomic activity. PMID- 28731560 TI - Food insecure student clients of a university-based food bank have compromised health, dietary intake and academic quality. AB - AIM: University and college students in wealthy countries may be vulnerable to financial food insecurity. If food insecure students have suboptimal health, their ability to learn and excel in their education could be compromised. This Canadian study examined the relationship of food security status to diet and self perceived health and academic quality among students receiving emergency food hampers from the Campus Food Bank at University of Alberta. METHODS: A convenience sample of 58 students completed a survey. RESULTS: Of participating students, 10.3% were food secure, 44.8% were moderately food insecure and 44.8% were severely food insecure. Overall, 32.8% rated their general health as fair/poor, 27.6% rated their mental health as fair/poor and 60.3% indicated at least one adverse academic outcome of not having enough money for food. Compared to other participating students, students with severe food insecurity had a greater likelihood of fair/poor general health (odds ratios (OR) 4.03, 95% confidence intervals (CI) 1.10-14.78); fair/poor mental health (OR 4.96, 95% CI 1.28-19.19); being unable to concentrate in class or during an exam (73.1% vs 40.6%, chi2 = 6.12, P = 0.013); relying on food hampers (34.6% vs 9.7%, chi2 = 5.57, P = 0.018); and, consuming fewer daily fruits, vegetables and legumes (2.12 vs 2.97 cup equivalents, P = 0.009). CONCLUSIONS: Food insecurity compromises students' health, diet and academic quality. Campus food banks are not the solution to student hunger. Governmental and university-based programmes and policies are needed to improve the food security situation of university students. PMID- 28731561 TI - Association of glycaemic index and glycaemic load with metabolic syndrome in an Iranian adult population: Isfahan Healthy Heart Program. AB - AIM: There is controversy around the clinical effects of the dietary glycaemic index (GI) and glycaemic load (GL) on cardiovascular diseases risk factors such as metabolic syndrome (MetS). So, the present study was performed to evaluate the relationship between GI or GL and metabolic syndrome in an Iranian adult population in 2007. METHODS: The study was based on data from a sub-sample of the Isfahan Healthy Heart Program (IHHP), collected across three cities in central Iran, in the year 2007. This was a cross-sectional survey of 1618 randomly selected adults aged >=19 years. Nutritional assessment was conducted by a single 24-hour recall questionnaire. Fasting serum lipids, anthropometric indicators and blood pressure were measured by standard methods. Analysis of covariance was used to compare metabolic syndrome components according to energy-adjusted GI and GL levels. To expose the effect of potential confounders, hierarchical logistic regression models were utilised to determine adjusted odds ratios (OR) and 95% CI. RESULTS: After adjustment for age, gender, body mass index and energy intake, high GI was found to be significantly associated with MetS (OR 95% CI) (1.46 (1.01-2.12)). This was attenuated marginally by excluding the confounding effects of dietary fibre intake (1.29 (1.01-1.74)). All hierarchical models illustrated no significant association between energy-adjusted GL and the risk of MetS adjusted for confounders. CONCLUSIONS: There is a positive relationship between dietary GI, but not GL, and the presence of MetS after adjustment for potential confounders. However, studies with long duration of follow up and experimental studies are still required to confirm this relationship. PMID- 28731562 TI - Relative validity of a brief Fat and Fibre Behaviour Questionnaire in a population of overweight and obese breast cancer survivors: A note of caution. AB - AIM: Dietary intake assessment is often difficult in research contexts because of time and resource constraints and participant burden. Valid, reliable and brief assessments of dietary behaviour are needed. Additionally, examination of instrument performance in a variety of populations is needed. This study assessed relative validity and responsiveness to change of the Fat and Fibre Behaviour Questionnaire (FFBQ) in a population of breast cancer survivors compared with dietary intake measured by 24-hour recalls. METHODS: Data were collected at baseline and six months after baseline of a six-month, randomised controlled trial that evaluated a telephone-based behavioural weight loss intervention (n = 45) compared to usual care (n = 45) among overweight and obese breast cancer survivors. The FFBQ's total index, fat index and fibre index were assessed for relative validity against two 24-hour recalls (Pearson's correlations). Responsiveness to change was assessed as intervention group change divided by standard deviation of usual care group change. RESULTS: Pearson's correlations of the fat index with fat intake measures ranged from -0.09 to -0.30 (P < 0.05) at baseline and from -0.19 to -0.28 (P < 0.05) for dietary change. Correlations of the fibre index with unadjusted and energy-adjusted fibre intake measures (0.25 0.32, P < 0.05) were significant at baseline only. Both the FFBQ and 24-hour recall were responsive to fat-related dietary changes and not responsive to fibre related changes. CONCLUSIONS: The FFBQ showed small to medium relative validity against 24-hour dietary recall for assessing fat and fibre dietary behaviours and changes in dietary fat, and was responsive to fat-related dietary changes in this population. PMID- 28731563 TI - Improving Fructose Utilization and Butanol Production by Clostridium acetobutylicum via Extracellular Redox Potential Regulation and Intracellular Metabolite Analysis. AB - Jerusalem artichoke (JA) can grow well in marginal lands with high biomass yield, and thus is a potential energy crop for biorefinery. The major biomass of JA is from tubers, which contain inulin that can be easily hydrolyzed into a mixture of fructose and glucose, but fructose utilization for producing butanol as an advanced biofuel is poor compared to glucose-based ABE fermentation by Clostridium acetobutylicum. In this article, the impact of extracellular redox potential (ORP) on the process is studied using a mixture of fructose and glucose to simulate the hydrolysate of JA tubers. When the extracellular ORP is controlled above -460 mV, 13.2 g L-1 butanol is produced from 51.0 g L-1 total sugars (40.1 g L-1 fructose and 10.9 g L-1 glucose), leading to dramatically increased butanol yield and butanol/ABE ratio of 0.26 g g-1 and 0.67, respectively. Intracellular metabolite and q-PCR analysis further indicate that intracellular ATP and NADH availabilities are significantly improved together with the fructose-specific PTS expression at the lag phase, which consequently facilitate fructose transport, metabolic shift toward solventogenesis and carbon flux redistribution for butanol biosynthesis. Therefore, the extracellular ORP control can be an effective strategy to improve butanol production from fructose based feedstock. PMID- 28731564 TI - Alcohol-Related Knowledge and Alcohol-Related Norms in 4- to 6-Year-Olds-Evidence from the Dutch Electronic Appropriate Beverage Task. AB - BACKGROUND: Limited research is available on children's alcohol-related knowledge and alcohol-related norms, yet a better comprehension of these factors may be crucial in explaining alcohol use later in life. This study provides insights into alcohol-related knowledge and alcohol-related norms in 4- to 6-year-olds. METHODS: Participating children (N = 329; 48.9% boys) were shown, on a tablet, 18 drawings depicting 72 male and female adults and/or children in various situations, and were asked to indicate what the depicted persons drank by touching 1 of 12 depicted beverages (4 alcoholic; 8 nonalcoholic). Subsequently, the children were asked to name the beverages and indicate whether they contained alcohol. RESULTS: Children identified 30.7% of the alcoholic beverages (i.e., beer, champagne, red wine, and white wine) correctly by name, and they identified 41.6% of the alcoholic beverages correctly as alcohol containing. Children more often correctly identified the name and nonalcoholic content of nonalcoholic beverages compared to the name and alcoholic content of alcoholic beverages. No sex differences emerged in the correct identification of the name and the content of both alcoholic beverages and nonalcoholic beverages. However, alcohol-related knowledge was age graded. Alcoholic beverages were more often assigned to male adults (39.2%) than to female adults (24.8%) or to children (13.2%). Additionally, alcoholic beverages were more often assigned to adults depicted in the presumably more appropriate situations (e.g., "when having an indoor party": 37.0%) than to those depicted in the presumably more inappropriate situations (e.g., "when driving a car": 28.6%). CONCLUSIONS: Four- to 6-year-olds already have knowledge about alcohol and its norms in adult culture. Insight into the development of children's alcohol-related knowledge and alcohol-related norms over time is required to investigate the transitions to alcohol expectancies, drinking motives, and alcohol initiation often occurring in adolescence. PMID- 28731565 TI - A Narrative Synthesis of Women's Out-of-Body Experiences During Childbirth. AB - INTRODUCTION: Some women have a dissociated, out-of-body experience (OBE) during childbirth, which may be described as seeing the body from above or floating above the body. This review examines this phenomenon using narratives from women who have experienced intrapartum OBEs. METHODS: A narrative synthesis of qualitative research was employed to systematically synthesize OBE narratives from existing studies. Strict inclusion and exclusion criteria were applied. The included papers were critiqued by 2 of the authors to determine the appropriateness of the narrative synthesis method, procedural transparency, and soundness of the interpretive approach. RESULTS: Women experiencing OBEs during labor and birth report a disembodied state in the presence of stress or trauma. Three forms of OBEs are described: floating above the scene, remaining close to the scene, or full separation of a body part from the main body. Women had clear recall of OBEs, describing the experience and point of occurrence. Women who reported OBEs had experienced current or previous traumatic childbirth, or trauma in a non-birth situation. OBEs as prosaic experiences were not identified. DISCUSSION: OBEs are part of the lived experience of some women giving birth. The OBEs in this review were trauma related with some women disclosing previous posttraumatic stress disorder (PTSD). It is not evident whether there is a connection between PTSD and OBEs at present, and OBEs may serve as a potential coping mechanism in the presence of trauma. Clinicians should legitimize women's disclosure of OBEs and explore and ascertain their impact, either as a normal coping mechanism or a precursor to perinatal mental illness. Research into the function of OBEs and any relationship to PTSD may assist in early interventions for childbearing women. PMID- 28731566 TI - Heterogeneity in kinesin function. AB - The kinesin family proteins are often studied as prototypical molecular motors; a deeper understanding of them can illuminate regulation of intracellular transport. It is typically assumed that they function identically. Here we find that this assumption of homogeneous function appears incorrect: variation among motors' velocities in vivo and in vitro is larger than the stochastic variation expected for an ensemble of "identical" motors. When moving on microtubules, slow and fast motors are persistently slow, and fast, respectively. We develop theory that provides quantitative criteria to determine whether the observed single molecule variation is too large to be generated from an ensemble of identical molecules. To analyze such heterogeneity, we group traces into homogeneous sub ensembles. Motility studies varying the temperature, pH and glycerol concentration suggest at least 2 distinct functional states that are independently affected by external conditions. We end by investigating the functional ramifications of such heterogeneity through Monte-Carlo multi-motor simulations. PMID- 28731567 TI - Integration of white matter network is associated with interindividual differences in psychologically mediated placebo response in migraine patients. AB - Individual differences of brain changes of neural communication and integration in the modular architecture of the human brain network exist for the repeated migraine attack and physical or psychological stressors. However, whether the interindividual variability in the migraine brain connectome predicts placebo response to placebo treatment is still unclear. Using DTI and graph theory approaches, we systematically investigated the topological organization of white matter networks in 71 patients with migraine without aura (MO) and 50 matched healthy controls at three levels: global network measure, nodal efficiency, and nodal intramodule/intermodule efficiency. All patients participated in an 8-week sham acupuncture treatment to induce analgesia. In our results, 30% (n = 21) of patients had 50% change in migraine days from baseline after placebo treatment. At baseline, abnormal increased network integration was found in MO patients as compared with the HC group, and the increased global efficiency before starting clinical treatment was associated with their following placebo response. For nodal efficiency, significantly increased within-subnetwork nodal efficiency and intersubnetwork connectivity of the hippocampus and middle frontal gyrus in patients' white matter network were correlated with the responses of follow-up placebo treatment. Our findings suggested that the trait-like individual differences in pain-related maladaptive stress interfered with and diminished the capacity of chronic pain modulation differently, and the placebo response for treatment could be predicted from a prior white matter network modular structure in migraineurs. Hum Brain Mapp 38:5250-5259, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28731568 TI - A Strong Hybrid Fatty Acid Inducible Transcriptional Sensor Built From Yarrowia lipolytica Upstream Activating and Regulatory Sequences. AB - The engineering of Yarrowia lipolytica to accumulate lipids with high titers and productivities has been enabled with a handful of constitutive promoters for pathway engineering. However, the development of promoters that are both strong and lipid responsive could greatly benefit the bioproduction efficiency of lipid derived oleochemicals in oleaginous yeast. In this study, a fatty acid regulated hybrid promoter for use in Y. lipolytica is engineered. A 200 bp upstream regulatory sequence in the peroxisomal acyl CoA oxidase 2 (POX2) promoter is identified. Further analysis of the promoter sequence reveal a regulatory sequence, that when used in tandem repeats, lead to a 48-fold induction of gene expression relative to glucose and fourfold higher than the native POX2 promoter. To date, this is the strongest inducible promoter reported in Y. lipolytica. Taken together, the results show that it is possible to engineer strong promoters that retain strong inducibility. These types of promoters will be useful in controlling metabolism and as fatty acid sensors. PMID- 28731569 TI - Diversity in thermal affinity among key piscivores buffers impacts of ocean warming on predator-prey interactions. AB - Asymmetries in responses to climate change have the potential to alter important predator-prey interactions, in part by altering the location and size of spatial refugia for prey. We evaluated the effect of ocean warming on interactions between four important piscivores and four of their prey in the U.S. Northeast Shelf by examining species overlap under historical conditions (1968-2014) and with a doubling in CO2 . Because both predator and prey shift their distributions in response to changing ocean conditions, the net impact of warming or cooling on predator-prey interactions was not determined a priori from the range extent of either predator or prey alone. For Atlantic cod, an historically dominant piscivore in the region, we found that both historical and future warming led to a decline in the proportion of prey species' range it occupied and caused a potential reduction in its ability to exert top-down control on these prey. In contrast, the potential for overlap of spiny dogfish with prey species was enhanced by warming, expanding their importance as predators in this system. In sum, the decline in the ecological role for cod that began with overfishing in this ecosystem will likely be exacerbated by warming, but this loss may be counteracted by the rise in dominance of other piscivores with contrasting thermal preferences. Functional diversity in thermal affinity within the piscivore guild may therefore buffer against the impact of warming on marine ecosystems, suggesting a novel mechanism by which diversity confers resilience. PMID- 28731570 TI - Susceptibility weighted imaging and quantitative susceptibility mapping of the cerebral vasculature using ferumoxytol. AB - PURPOSE: To demonstrate the potential of imaging cerebral arteries and veins with ferumoxytol using susceptibility weighted imaging (SWI) and quantitative susceptibility mapping (QSM). MATERIALS AND METHODS: The relationships between ferumoxytol concentration and the apparent susceptibility at 1.5T, 3T, and 7T were determined using phantom data; the ability of visualizing subvoxel vessels was evaluated using simulations; and the feasibility of using ferumoxytol to enhance the visibility of small vessels was confirmed in three healthy volunteers at 7T(with doses 1 mg/kg to 4 mg/kg). The visualization of the lenticulostriate arteries and the medullary veins was assessed by two raters and the contrast-to noise ratios (CNRs) of these vessels were measured. RESULTS: The relationship between ferumoxytol concentration and susceptibility was linear with a slope 13.3 +/- 0.2 ppm.mg-1 .mL at 7T. Simulations showed that SWI data with an increased dose of ferumoxytol, higher echo time (TE), and higher imaging resolution improved the detection of smaller vessels. With 4 mg/kg ferumoxytol, voxel aspect ratio = 1:8, TE = 10 ms, the diameter of the smallest detectable artery was approximately 50MUm. The rating score for arteries was improved from 1.5 +/- 0.5 (precontrast) to 3.0 +/- 0.0 (post-4 mg/kg) in the in vivo data and the apparent susceptibilities of the arteries (0.65 +/- 0.02 ppm at 4 mg/kg) agreed well with the expected susceptibility (0.71 +/- 0.05 ppm). CONCLUSION: The CNR for cerebral vessels with ferumoxytol can be enhanced using SWI, and the apparent susceptibilities of the arteries can be reliably quantified using QSM. This approach improves the imaging of the entire vascular system outside the capillaries and may be valuable for a variety of neurodegenerative diseases which involve the microvasculature. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;47:621-633. PMID- 28731571 TI - Model-Based Investigation on the Mass Transfer and Adsorption Mechanisms of Mono Pegylated Lysozyme in Ion-Exchange Chromatography. AB - Recent studies highlighted the potential of PEGylated proteins to improve stabilities and pharmacokinetics of protein drugs. Ion-exchange chromatography (IEX) is among the most frequently used purification methods for PEGylated proteins. However, the underlying physical mechanisms allowing for a separation of different PEGamers (proteins with a varying number of attached PEG molecules) are not yet fully understood. In this work, mechanistic chromatography modeling is applied to gain a deeper understanding of the mass transfer and adsorption/desorption mechanisms of mono-PEGylated proteins in IEX. Using a combination of the general rate model (GRM) and the steric mass action (SMA) isotherm, simulation results in good agreement with the experimental data are achieved. During linear gradient elution of proteins attached with PEG of different molecular weight, similar peak heights, and peak shapes at constant gradient length are observed. A superimposed effect of increased desorption rate and reduced diffusion rate as a function of the hydrodynamic radius of PEGylated proteins is identified to be the reason of this anomaly. That is why the concept of the diffusion-desorption-compensation effect is proposed. In addition to the altered elution orders, PEGylation results in a considerable decrease of maximum binding capacity. By using the SMA model in a kinetic formulation, the adsorption behavior of PEGylated proteins in the highly concentrated state is described mechanistically. An exponential increase in the steric hindrance effect with increasing PEG molecular weight is observed. This suggests the formation of multiple PEG layers in the interstitial space between bound proteins and an associated shielding of ligands on the adsorber surface to be the cause of the reduced maximum binding capacity. The presented in silico approach thus complements the hitherto proposed theories on the binding mechanisms of PEGylated proteins in IEX. PMID- 28731572 TI - Endoscopic surgical technique for benign fibrotic strictures of the upper esophageal sphincter. AB - A 43-year-old man with complaints of increased difficulty swallowing and weight loss underwent videofluorographic examination of swallowing, which revealed severely reduced cricopharyngeal opening. Endoscopic cricopharyngeal myotomy was carried out using a modified technique (mECPM). A benign fibrotic stricture of the upper esophageal sphincter (UES) was identified under visualization of a distending operating laryngoscope. A vertical midline incision in the strictured mucosa and submucosal resection of the cricopharyngeal muscle were done using a CO2 laser. The initial vertical mucosal incision was tightly sutured in the horizontal direction with absorbable surgical sutures. Histopathological examination of the cricopharyngeal muscle revealed infiltration of inflammatory cells. The patient started oral intake on postoperative day 7. He has been symptom free for 2 years with an improved body mass index, and postoperative laryngoscopy revealed no salivary retention in the piriform sinuses. The technique presented here provides sufficient opening of the UES by eliminating the problem of restenosis. mECPM will be useful for treating benign fibrotic strictures of the UES. PMID- 28731573 TI - Effect of alcohol dehydrogenase-1B and -7 polymorphisms on blood ethanol and acetaldehyde concentrations in healthy subjects with a history of moderate alcohol consumption. AB - This study aims to evaluate the effect of ADH1B and ADH7 genotypes on blood acetaldehyde and ethanol levels after alcohol ingestion, and to measure the genotoxic effect of smoking and ethanol on the buccal cells, also controlling for ADH variants. We recruited healthy Italian subjects with at least a moderate history of alcohol consumption. All subjects were given an alcoholic drink of 0.4 g ethanol /kg of body weight. Blood venous samples were collected at baseline, and 30, 60, 90, and 120 minutes after ingestion. Buccal cells were collected before ethanol ingestion. Sixty subjects were enrolled in the study. Individuals with the ADH1B GG genotype had median ethanol levels of 5.0mM (IQR 3.4-7.2), and those with the ADH1B GT/TT genotype had 4.7mM (IQR 4.2-4.8). Corresponding acetaldehyde levels were 1.5MUM (IQR 0.7-2.6) for ADH1B GG genotype and 1.6MUM (IQR 1.5-1.7) for ADH1B CG/GG genotype. Individuals with the ADH7 CC genotype had median ethanol levels of 5.0mM (IQR 3.3-7.2), while 5.0mM (IQR 4.7-5.6) was in those with the ADH7 CG/GG genotype. Corresponding acetaldehyde levels were 1.5 MUM (IQR 0.7-2.6) for ADH7 CC genotype and 1.5 MUM (IQR 1.4-1.6) for ADH7 CG/GG genotypes. A non-significant increase in the frequency of karyolitic and pyknotic cells was found in the group of heavy drinkers and current smokers, when compared to the moderate drinkers and the non-smokers. Our study does not support the hypothesis that ADH1B and ADH7 genotypes affect blood ethanol and acetaldehyde concentration. PMID- 28731574 TI - Rapid Buffer and Ligand Screening for Affinity Chromatography by Multiplexed Surface Plasmon Resonance Imaging. AB - Protein purifications are often based on the principle of affinity chromatography, where the protein of interest selectively binds to an immobilized ligand. The development of affinity purification requires selecting proper wash and elution conditions. In recent years, miniaturization of the purification process is applied to speed up the development (e.g., microtiterplates, robocolumns). The application of surface plasmon resonance imaging (SPRi) as a tool to simultaneously screen many buffer conditions for wash and elution steps in an affinity-based purification process is studied. Additionally, the protein A ligand stability after exposure to harsh cleaning conditions often limits the reuse of resins and is determined at lab scale. The SPRi technology to screen ligand life-time with respect to alkali stability is used. It is also demonstrated that SPRi can successfully be applied in screening experiments for process developments in a miniaturized approach. The amount of resin, protein and buffer in these studies is reduced 30-300-fold compared to 1 mL column scale, and approximately 10-1000-fold compared to filter plate experiments. The overall development time can be decreased from several months towards days. The multiplexed SPRi can be applied in screening affinity chromatography conditions in early stage development for ligand development and recombinant protein production. PMID- 28731575 TI - The Automation of Regression Modeling in Osteometric Sorting: An Ordination Approach. AB - This study compares the original osteometric sorting association method with an ordination approach across all combinations of the humerus, ulna, radius, femur, tibia, and fibula. This includes both the original prediction interval and t statistic approaches. Standard measurements are utilized in the models with full measurements combined and without length measurements. The sample is the osteometric sorting reference from the Defense POW/MIA Accounting Agency. A full set of performance statistics is provided. Results indicate the ordination approach outperforms the original in the majority of bone combinations. Models with length measurements have more exclusion power than those without. It is recommended for the ordination approach to supersede the original when applied to large commingled assemblages. PMID- 28731577 TI - Commentary on: Gibbons J, Mojica A, Peele M. Human electrical muscular incapacitation and effects on QTc interval. J Forensic Sci https://doi.org/10.1111/1556-4029.13490. Epub 2017 April 17. PMID- 28731576 TI - Influence of trainee involvement on procedural characteristics for linear endobronchial ultrasound. AB - BACKGROUND: Linear endobronchial ultrasound (EBUS) is a safe and effective method for the diagnostic sampling of mediastinal lymph nodes. However, there is a learning curve associated with the procedure and operator experience influences diagnostic yield. We sought to determine if trainee involvement during EBUS influences procedural characteristics, complication rate, and diagnostic yield. METHODS: We performed a retrospective analysis of 220 subjects who underwent an EBUS procedure at our center from December 2012 to June 2013. Procedures were performed by six different interventional pulmonologists with substantial experience with EBUS or by a trainee under their direct supervision. Procedural characteristics and complications were recorded. Diagnostic yield and specimen adequacy were compared between groups. RESULTS: EBUS was performed in 220 patients with a trainee involved (n = 116) or by staff physician alone (n = 104). Patient characteristics, and the number and size of lymph node stations sampled were similar. EBUS duration was longer (16.0 vs. 13.7 minutes; P = 0.002) and the total dose of lidocaine used was higher (322.3 vs. 304.2 mg; P = 0.045) when a trainee was involved. The rate of adequate specimens sampled was comparable between the groups (92.0 vs. 92.0%; P = 0.60). Diagnostic yield was lower when a trainee was involved in the EBUS procedure (52.6 vs. 68.3%; P = 0.02). CONCLUSION: Trainee involvement significantly increased EBUS duration and the dose of local anesthesia used for the procedure. Diagnostic yield was lower when a trainee was involved. Factors accounting for this difference in yield, despite adequate samples being obtained, warrant further investigation. PMID- 28731578 TI - Tinea corporis presenting as disseminated verrucous plaques caused by Arthroderma incurvatum in a young Indian boy. PMID- 28731579 TI - Residual dynamic and risk assessment of dimethomorph in Swiss chard grown at two different sites. AB - Residue analysis of dimethomorph in Swiss chard cultivated at two different locations under greenhouse conditions was conducted using high-performance liquid chromatography-ultraviolet detection and confirmed by tandem mass spectrometry. The randomly collected samples (over 14 days) were extracted with acetonitrile and purified using a Florisil solid-phase extraction cartridge. Linearity over a concentration range of 0.05-50.0 mg/L had an excellent coefficient of determination of 0.9996. Recovery rate ranged from 82.98 to 95.43% with relative standard deviations <=5.12% and limits of detection and quantification of 0.003 and 0.01 mg/kg, respectively. The initial deposits [day 0 (2 h post-application)] were considerably lower (7.57 and 8.55 mg/kg for sites 1 and 2, respectively) than the maximum residue limit (30 mg/kg) set by the Korean Ministry of Food and Drug Safety. The dissipation half-life was approximately the same, being 5.0 and 5.1 days for sites 1 and 2, respectively. Risk assessment estimated as acceptable daily intake revealed a value of 0.084 or 0.094% (day 0) and 0.014% (10 days post application), for sites 1 and 2, respectively. The values indicated that dimethomorph can be safely used on Swiss chard, with no hazardous effects expected for Korean consumers. PMID- 28731580 TI - Rewiring the Glucose Transportation and Central Metabolic Pathways for Overproduction of N-Acetylglucosamine in Bacillus subtilis. AB - N-acetylglucosamine (GlcNAc) is an important amino sugar extensively used in the healthcare field. In a previous study, the recombinant Bacillus subtilis strain BSGN6-PxylA -glmS-pP43NMK-GNA1 (BN0-GNA1) had been constructed for microbial production of GlcNAc by pathway design and modular optimization. Here, the production of GlcNAc is further improved by rewiring both the glucose transportation and central metabolic pathways. First, the phosphotransferase system (PTS) is blocked by deletion of three genes, yyzE (encoding the PTS system transporter subunit IIA YyzE), ypqE (encoding the PTS system transporter subunit IIA YpqE), and ptsG (encoding the PTS system glucose-specific EIICBA component), resulting in 47.6% increase in the GlcNAc titer (from 6.5 +/- 0.25 to 9.6 +/- 0.16 g L-1 ) in shake flasks. Then, reinforcement of the expression of the glcP and glcK genes and optimization of glucose facilitator proteins are performed to promote glucose import and phosphorylation. Next, the competitive pathways for GlcNAc synthesis, namely glycolysis, peptidoglycan synthesis pathway, pentose phosphate pathway, and tricarboxylic acid cycle, are repressed by initiation codon-optimization strategies, and the GlcNAc titer in shake flasks is improved from 10.8 +/- 0.25 to 13.2 +/- 0.31 g L-1 . Finally, the GlcNAc titer is further increased to 42.1 +/- 1.1 g L-1 in a 3-L fed-batch bioreactor, which is 1.72-fold that of the original strain, BN0-GNA1. This study shows considerably enhanced GlcNAc production, and the metabolic engineering strategy described here will be useful for engineering other prokaryotic microorganisms for the production of GlcNAc and related molecules. PMID- 28731581 TI - The inherited risk of retained placenta: a population based cohort study. AB - OBJECTIVE: To investigate whether retained placenta in the first generation is associated with an increased risk of retained placenta in the second generation. DESIGN: Population-based cohort study. SETTING: Sweden. POPULATION: Using linked generational data from the Swedish Medical Birth Register 1973-2012, we identified 494 000 second-generation births with information on the birth of the mother (first-generation index birth). For 292 897 of these births there was information also on the birth of the father. METHODS: Risk of retained placenta in the second generation was calculated as adjusted odds ratios (aOR) by unconditional logistic regression with 95% confidence intervals (95% CI) according to whether retained placenta occurred in a first generation birth or not. MAIN OUTCOME: Retained placenta in the second generation. RESULTS: The risk of retained placenta in a second-generation birth was increased if retained placenta had occurred at the mother's own birth (aOR 1.66, 95% CI 1.52-1.82), at the birth of one of her siblings (aOR 1.58, 95% CI 1.43-1.76) or both (aOR 2.75, 95% CI 2.18-3.46). The risk was slightly increased if retained placenta had occurred at the birth of the father (aOR 1.23, 95% CI 1.07-1.41). For preterm births in both generations, the risk of retained placenta in the second generation was increased six-fold if retained placenta had occurred at the mother's birth (OR 6.55, 95% CI 2.68-16.02). CONCLUSION: There is an intergenerational recurrence of retained placenta on the maternal and most likely also on the paternal side. The recurrence risk seems strongest in preterm pregnancies. TWEETABLE ABSTRACT: A population-based cohort study suggests that there is an intergenerational recurrence of retained placenta. PMID- 28731582 TI - Episodic foresight beyond the very next event in 3- and 4-year-old children. AB - Testing episodic foresight in children generally involves presenting them with a problem in one location (e.g., Room A) and, after a spending a delay in a different location, telling them they will be returning to Room A. Before they go, children are presented with a number of items, one of which will allow them to solve the problem in Room A. At around 3 to 4 years of age children display episodic foresight, selecting the item that will allow them to solve the problem. To date, however, no study has assessed whether 3- and 4-year-old children can plan beyond the very next event, selecting the correct item when there is a delay before returning to Room A. Here, we show that 3- and 4-year-old children can pass when a delay is imposed but that their performance is significantly worse than when they are planning for an immediate event. PMID- 28731583 TI - The effectiveness of transcutaneous tibial nerve stimulation (TTNS) for adults with overactive bladder syndrome: A systematic review. AB - AIMS: To evaluate effectiveness of transcutaneous tibial nerve stimulation (TTNS) for treating adults with overactive bladder (OAB) of idiopathic or neurogenic origin, using a systematic review of the literature. METHODS: Systematic searches of four databases were undertaken between 1980 and 2017. Included studies investigated effects of TTNS on OAB. Study selection, data extraction, quality appraisal was performed by two independent reviewers. Narrative analysis was undertaken where meta-analysis was not possible due to study heterogeneity. Meta analysis of RCTs was performed using a fixed effects model. RESULTS: Ten RCTs and three prospective cohort studies involving 629 participants were reviewed. Meta analysis of two trials comparing TTNS with sham showed mean reduction in total ICIQ Urinary Incontinence Short Form (ICIQ-UI SF) associated with TTNS of -3.79 (95% CI -5.82, -1.76; P = 0.0003, I2 = 25%). Narrative review showed TTNS and antimuscarinic treatment were equally effective (four trials), TTNS provided greater benefit for OAB symptoms than behavioral interventions (two trials), tibial nerve, and sacral foramen stimulation were equally effective but combined stimulation was most effective (one trial). Significant improvements in OAB symptoms were reported by 48-93% participants and UI cure rates of 25-45%. No adverse events were reported. CONCLUSIONS: Limited evidence is provided that TTNS is an effective, safe intervention for idiopathic OAB in adults and may be of benefit in those with neurogenic OAB. Further studies are essential to confirm these results as well as to determine efficacy and associated costs for specific patient groups, most effective stimulation dosage, duration of effect, and stimulation regimes for longer-term maintenance. PMID- 28731584 TI - Insulin secretion and action in North Indian women during pregnancy. AB - AIM: The relative roles(s) of impaired insulin secretion vs. insulin resistance in the development of gestational diabetes mellitus depend upon multiple risk factors and diagnostic criteria. Here, we explored their relative contribution to gestational diabetes as defined by the WHO 1999 (GDM1999) and adapted WHO 2013 (GDM2013) criteria, excluding the 1-h glucose value, in a high-risk Indian population from Punjab. METHODS: Insulin secretion (HOMA2-B) and insulin action (HOMA2-IR) were assessed in 4665 Indian women with or without gestational diabetes defined by the GDM1999 or adapted GDM2013 criteria. RESULTS: Gestational diabetes defined using both criteria was associated with decreased insulin secretion compared with pregnant women with normal glucose tolerance. Women with gestational diabetes defined by the adapted GDM2013, but not GDM1999 criteria, were more insulin resistant than pregnant women with normal glucose tolerance, and furthermore displayed lower insulin secretion than GDM1999 women. Urban habitat, illiteracy, high age and low BMI were independently associated with reduced insulin secretion, whereas Sikh religion, increasing age and BMI, as well as a family history of diabetes were independently associated with increased insulin resistance. CONCLUSIONS: Gestational diabetes risk factors influence insulin secretion and action in North Indian women in a differential manner. Gestational diabetes classified using the adapted GDM2013 compared with GDM1999 criteria is associated with more severe impairments of insulin secretion and action. PMID- 28731585 TI - Bacterial invertases: Occurrence, production, biochemical characterization, and significance of transfructosylation. AB - Invertase or beta-D-fructofuranoside fructohydrolase (EC 3.2.1.26) was one of the foremost enzyme biocatalysts and established the primary concepts of most enzyme kinetic principles. Invertases are glycoside hydrolases and occur mostly in microorganisms. Among microbial strains, for many decades yeast species have been extensively researched for invertase production, characterization, and applications in industries. Besides, limited literature is available on invertases from bacterial strains. The enzymic and molecular biological reports from bacterial invertases are scarce. In this minireview, occurrence, production, biochemical properties, and significance of transfructosylation of bacterial invertases are reported. PMID- 28731586 TI - Pregnancy in women with nonclassic congenital adrenal hyperplasia: Time to conceive and outcome. AB - OBJECTIVE: Nonclassic congenital adrenal hyperplasia (NCAH) is common among Ashkenazi Jews (1:400). It is associated with various degrees of postnatal virilization, irregular menses and infertility. Therapy of symptomatic subjects consists of physiologic doses of glucocorticoids. The objective of this study was to evaluate the effect of glucocorticoid treatment on fertility and on pregnancy outcome in women with NCAH. DESIGN, SETTING AND PATIENTS: This retrospective study included 75 women diagnosed with NCAH who were followed in our clinic and sought fertility between 2008 and 2015. RESULTS: Seventy-two women succeeded in conceiving (187 pregnancies). Time to conception was 4.0 +/- 7 months without and 3.3 +/- 3 months with glucocorticoid therapy (P = .43). Seventeen pregnancies were achieved by glucocorticoid therapy after failure to conceive spontaneously. Time to conception before therapy initiation was 10.2 +/- 11.4 months compared to 3.3 +/- 3.4 months after therapy initiation (P = .02). Of 187 pregnancies, 135 (72%) resulted in live births, 38 (20.3%) ended in spontaneous miscarriages during the first trimester, seven (3.7%) were electively terminated, three (1.6%) were ectopic and four (2.1%) were ongoing during the study with similar rate in glucocorticoid treated and untreated pregnancies. CONCLUSIONS: The 96% pregnancy rate among our cohort of NCAH females was similar to the 95% rate reported for the normal population. Glucocorticoid therapy may shorten the time to conceive in a subgroup of women with NCAH. Glucocorticoid therapy did not affect the rate of first trimester miscarriage. Our 77% live birth rate was similar to the 72% live birth rate in the current healthy US population. PMID- 28731587 TI - Reversible Pressure-Controlled Depolymerization of a Copper(II)-Containing Coordination Polymer. AB - A unique pressure-induced Cu-N bond breaking/bond forming reaction is reported. The variation of pressure on a single crystal of a one-dimensional copper- (II) containing coordination polymer (Cu2 L2 (1-methylpiperazine)2 ]n , where H2 L is 1,1'-(1,3-phenylene)-bis(4,4-dimethylpentane-1,3-dione)), was monitored using single crystal X-ray diffraction with the aid of a diamond anvil cell. At a very low elevated pressure (~0.05 GPa) a remarkable reversible phase change was observed. The phase change results in the depolymerization of the material through the cleavage and formation of axial Cu-N bonds as well as "ring flips" of individual axially coordinated 1-methylpiperazine ligands. Overall, the pressure induced phase change is associated with a surprising (and non-intuitive) shift in structure-from a 1-dimensional coordination polymer to a discrete dinuclear complex. PMID- 28731588 TI - Human leukocyte antigen distribution and genomic ancestry in Brazilian patients with sickle cell disease. AB - Hematopoietic stem-cell transplantation (HSCT) is currently the only established curative treatment for sickle cell disease (SCD), but is limited by donor availability. Ethnicity is thought to have an impact on the complications experienced by patients that undergo HSCT and on the likelihood of identifying an human leukocyte antigen (HLA) matched donor. In the present study, we investigated the genomic ancestry and the distribution of HLA allele groups in Brazilian patients with SCD, compared these HLA profiles to worldwide populations and evaluate the availability of HLA-matched donors. A broad intercontinental admixture of patients with SCD was observed, with African ancestry ranging from 6.7% to 93.4%. In a dendrogram based on HLA frequencies, Brazilian patients with SCD were included in a branch containing only populations with a significant African component. Among the 126 patients evaluated, 10 (8%) found a HLA-matched unrelated donor in a database of 18 134 donors. Self-reported white, brown and black matched donors were identified, and no significant difference in the percentage of compatible donors was observed between these ethnic groups. Our results show that Brazilian patients with SCD are very admixed, indicating that this group is a promising target for admixture mapping of genes involved in complications after HSCT. Additional studies may help to clarify the impact of the genetic diversity and admixture of these patients on the donor availability. PMID- 28731589 TI - Effects of nitric oxide on large-conductance Ca2+ -activated K+ currents in human cardiac fibroblasts through PKA and PKG-related pathways. AB - The human cardiac fibroblast (HCF) is the most abundant cell type in the myocardium, and HCFs play critical roles in maintaining normal cardiac function. However, unlike cardiomyocytes, the electrophysiology of HCFs is not well established. In the cardiovascular system, Ca2+ -activated K+ (KCa) channels have distinct physiological and pathological functions, and nitric oxide (NO) plays a key role. In this study, we investigated the potential effects of NO on KCa channels in HCFs. We recorded strong oscillating, well-maintained outward K+ currents without marked inactivation throughout the test pulse period and detected outward rectification in the I-V curve; these are all characteristics that are typical of KCa currents. These currents were blocked with iberiotoxin (IBTX, a BKCa blocker) but not with TRAM-34 (an IKCa blocker). The amplitudes of the currents were increased with SNAP (an NO donor), and these increases were inhibited with IBTX. The SNAP-stimulating effect on the BKCa currents was blocked by pretreatment with KT5823 (a protein kinase G [PKG] inhibitor) or 1 H-[1,-2, 4] oxadiazolo-[4,-3-a] quinoxalin-1-one (ODQ; a soluble guanylate cyclase inhibitor). Additionally, 8-bromo-cyclic guanosine 3',5'-monophosphate (8-Br cGMP) stimulated the BKCa currents, and pretreatment with KT5720 (a protein kinase A [PKA] inhibitor) and SQ22536 (an adenylyl cyclase inhibitor) blocked the NO-stimulating effect on the BKCa currents. Furthermore, 8-bromo-cyclic adenosine 3',5'-monophosphate (8-Br-cAMP) activated the BKCa currents. These data suggest that BKCa current is the main subtype of the KCa current in HCFs and that NO enhances these currents through the PKG and PKA pathways. PMID- 28731590 TI - Handheld fetal Doppler device for assessing heart rate in neonatal resuscitation. AB - BACKGROUND: The use of neonatal three-lead electrocardiograms (Neo-ECG) is suggested for the assessment of heart rate (HR) in neonatal resuscitation, but primary childbirth facilities (i.e. maternity clinics or maternity homes) are not sufficiently equipped for this. The aim of this study was to therefore to confirm the potential of a handheld fetal Doppler device (FDD), widely used to assess HR in labor room resuscitation, and to compare its equivalency to Neo-ECG. METHODS: In low-risk full-term infants, HR was measured five times per minute in minutes 1 5 after delivery using the FDD and Neo-ECG, and their equivalence compared. The equivalence margin was set at a HR difference of <+/-5 beats/min and <+/-5%. Moreover, the times at which HR was displayed were measured for both methods. RESULTS: FDD and Neo-ECG HR correlated strongly (r = 0.977) in 155 measurements in 33 cases. The mean HR difference was -0.123 beats/min (95%CI: -0.594 to +0.345), and the logarithmic transformation of the HR ratio was -0.0003 (95%CI: 0.0020 to +0.0015). The mean HR difference and HR ratio were within the equivalence margin. For HR assessment using the FDD, 155 of 165 measurements (93.9%) could be obtained in <10 s. CONCLUSIONS: In HR assessment, FDD is a valid substitute for Neo-ECG in primary childbirth facilities that are not sufficiently equipped for Neo-ECG. PMID- 28731591 TI - Sedation protocol with fasting and shorter sleep leads to magnetic resonance imaging success. AB - BACKGROUND: Young children undergoing magnetic resonance imaging (MRI) require sedation. In June 2013, Tokyo Metropolitan Ohtsuka Hospital (TMOH) introduced an oral sedation protocol for young children undergoing MRI; the protocol included instructions on fasting before sedation, and recommended a shorter duration of sleep the night before MRI. We compared the MRI success rate before and after the introduction of this protocol. METHODS: The eligible subjects were children under 3 years old who underwent MRI by appointment at TMOH between October 2012 and March 2014, under sedation with triclofos sodium. All those who underwent MRI in or after June 2013 were enrolled prospectively as a post-protocol group. All patients who underwent MRI before June 2013 were enrolled retrospectively as a pre-protocol group, with data collected from chart review. RESULTS: Seventy-four patients were enrolled in the post-protocol group, and 42 in the pre-protocol group. The MRI success rate was significantly higher in the post-protocol group than in the pre-protocol group (98.7% vs 88.1%), as was the rate of on-time starting of MRI (86.5% vs 71.4%). The post-protocol group woke up earlier on the day of examination (6:18 a.m. vs 6:43 a.m.), resulting in a significantly longer time between awakening and the beginning of sedation (289.8 min vs 265.9 min), and a significantly shorter average duration of sleep on the previous night (504.8 min vs 532.3 min). CONCLUSIONS: Implementation of a hospital-wide sedation protocol for young children undergoing MRI significantly improved the MRI success rate. PMID- 28731592 TI - Arginase activity of Leishmania isolated from patients with cutaneous leishmaniasis. AB - Cutaneous leishmaniasis (CL) is one of the most important vector-borne parasitic diseases, highly endemic in Iran, and its prevalence is increasing all over the country. Arginase (ARG) activity in isolated Leishmania parasites from CL patients is yet to be explored. This study aimed to compare the ARG activity of isolated Leishmania promastigotes from CL patients with a standard strain of Leishmania major and its influences on the disease pathogenesis. We recruited 16 confirmed CL patients from Qom Province, in central Iran; after detection of Leishmania species using PCR-RFLP, we assessed the levels of ARG in the isolated promastigotes and determined the parasites' growth rate. Only L. major was identified from CL patients. The level of ARG activity in the isolated Leishmania promastigotes from CL patients was significantly higher than that obtained from the standard strain of L. major. No significant correlations between ARG activity and lesion size, number or duration were observed; in contrast, a significant negative correlation was seen between ARG level and Leishmania' growth rate. The obtained results suggest that increased ARG expression and activity in the isolated Leishmania promastigotes might contribute to the higher parasite infectivity and play a major role in the pathogenicity of the CL. PMID- 28731593 TI - Synthesis, Characterization, and Efficient Catalytic Activities of a Nickel(II) Porphyrin: Remarkable Solvent and Substrate Effects on Participation of Multiple Active Oxidants. AB - A new nickel(II) porphyrin complex, [NiII (porp)] (1), has been synthesized and characterized by 1 H NMR, 13 C NMR and mass spectrometry analysis. This NiII porphyrin complex 1 quantitatively catalyzed the epoxidation reaction of a wide range of olefins with meta-chloroperoxybenzoic acid (m-CPBA) under mild conditions. Reactivity and Hammett studies, H218 O-exchange experiments, and the use of PPAA (peroxyphenylacetic acid) as a mechanistic probe suggested that participation of multiple active oxidants NiII -OOC(O)R 2, NiIV -Oxo 3, and NiIII -Oxo 4 within olefin epoxidation reactions by the nickel porphyrin complex is markedly affected by solvent polarity, concentration, and type of substrate. In aprotic solvent systems, such as toluene, CH2 Cl2 , and CH3 CN, multiple oxidants, NiII -(O)R 2, NiIV -Oxo 3, and NiIII -Oxo 4, operate simultaneously as the key active intermediates responsible for epoxidation reactions of easy-to oxidize substrate cyclohexene, whereas NiIV -Oxo 3 and NiIII -Oxo 4 species become the common reactive oxidant for the difficult-to-oxidize substrate 1 octene. In a protic solvent system, a mixture of CH3 CN and H2 O (95:5), the NiII -OOC(O)R 2 undergoes heterolytic or homolytic O-O bond cleavage to afford NiIV Oxo 3 and NiIII -Oxo 4 species by general acid catalysis prior to direct interaction between 2 and olefin, regardless of the type of substrate. In this case, only NiIV -Oxo 3 and NiIII -Oxo 4 species were the common reactive oxidant responsible for olefin epoxidation reactions. PMID- 28731594 TI - Duplex Doppler Sonographic Assessment of the Superior Mesenteric Artery in Patients With Mesenteric Panniculitis. AB - OBJECTIVES: We aimed to determine how the hemodynamic parameters of the superior mesenteric artery are affected in mesenteric panniculitis. METHODS: Twenty-one patients with a diagnosis of mesenteric panniculitis on computed tomography were evaluated with duplex Doppler sonography. The control group consisted 20 asymptomatic volunteers. The peak systolic velocity, end-diastolic velocity (EDV), resistive index (RI), pulsatility index (PI), blood flow volume, and body mass index were measured in the group of patients with mesenteric panniculitis, and the findings were compared with those of the control group. RESULTS: The mean blood flow volume and EDV were significantly higher in the patient group: The mean superior mesenteric artery blood flow volume +/- SD was 917.86 +/- 228.97 mL/min in the patient group versus 389.73 +/- 92.72 mL/min in the control group (P < .001). The mean EDV was 31.56 +/- 8.44 m/s in the patient group versus 19.27 +/- 4.19 m/s in the control group (P < .001). The mean RI and PI were significantly lower in the patient group: The mean RI was 0.81 +/- 0.04 in the patient group versus 0.85 +/- 0.03 in the control group (P = .001). The mean PI was 2.69 +/- 0.68 in the patient group versus 3.81 +/- 1.13 in the control group (P = .001). the mean superior mesenteric artery diameter was 7.30 +/- 0.67 mm in the patient group versus and 6.46 +/- 0.66 mm in the control group (P < .001). The mean BMI was 27.95 +/- 3.80 kg/m2 in the patient group versus 23.16 +/- 3.47 kg/m2 in the control group (P < .001). CONCLUSIONS: In patients with mesenteric panniculitis, the Doppler spectrum of the superior mesenteric artery shows detectable changes, which are characterized by decreased vascular resistance and increased blood flow. PMID- 28731595 TI - Identification of carboxylesterase genes associated with pyrethroid resistance in the malaria vector Anopheles sinensis (Diptera: Culicidae). AB - BACKGROUND: Carboxylesterases (CCEs) are one of three large detoxification enzyme families. Some CCEs are active on synthetic insecticides with ester structures. Anopheles sinensis is an important malaria vector in eastern Asia. This study identified and characterized the CCE genes in the A. sinensis genome and determined CCE genes associated with pyrethroid resistance using RNA sequencing (RNA-seq) and quantitative reverse transcription - polymerase chain reaction (qRT PCR), in A. sinensis from Anhui, Chongqing, and Yunnan in China. RESULTS: Fifty seven putative CCEs were identified and placed into three classes, 12 subfamilies and 14 clades through phylogenetic and homology analyses. Exon sizes ranged from 31 to 4317 bp, with 49 CCEs having two to five exons and eight having six to 11 exons. A total of 183 introns were recognized with sizes ranging from 31 to 4317 bp. The 57 CCEs were located on 14 scaffolds, with 70% located on four scaffolds. The alpha-esterase subfamily was significantly expanded compared with that of Anopheles gambiae. In a pyrethroid-resistant strain, RNA-seq detected five upregulated CCE genes and qRT-PCR detected 12 upregulated CCE genes. The alpha esterase 10 (AsAe10) and acetylcholinesterase 1 (AsAce1) genes were the main CCE genes associated with pyrethroid resistance. CONCLUSION: This information will be useful for further study of the CCE gene family and pyrethroid resistance mechanisms mediated by CCEs. (c) 2017 Society of Chemical Industry. PMID- 28731596 TI - Mapping neuronal density in peri-infarct cortex with PET. PMID- 28731597 TI - Reliability and relative validity of a diet index score for adults derived from a self-reported short food survey. AB - AIM: Assess the reliability and relative validity of a diet index score for adults derived using a 38-item online survey. METHODS: The short food survey (SFS) measured 'usual' intake of seven food groups, three food choice indicators and variety; and was completed by 61 adults aged 19-50 years from Adelaide, Australia. A score was applied to assess compliance with the 2013 Australian Dietary Guidelines. Reliability of the survey was measured between two administrations one week apart; and validity by comparing the first administration to the average of three 24-hour dietary recalls. Statistical analyses included paired samples t-tests, intra-class correlation coefficient (ICC), percentage agreement, Cohen's kappa coefficients and Bland-Altman plots. RESULTS: Estimates of daily food group servings were reliable (within 0.3 servings, P > 0.05) but not valid for all foods groups. The mean total index score was approximately 70 points (out of 100) on both SFS administrations (ICC = 0.71 (95% CI 0.56:0.81). Relative validity analysis showed moderate correlation between SFS#1 and 24-hour recalls (ICC = 0.43 (0.21:0.62, P < 0.001)), with 51% agreement in allocation to tertiles of diet quality between methods (k = 0.262, P = 0.004). The survey overestimated the diet index score by an average of 12.7 points out of 100 [-20.11:42.94] in comparison to recalls. CONCLUSIONS: The survey overestimated compliance with guidelines relative to dietary recalls. It demonstrated good reliability; however, the validity of estimating intake of some food groups needs improvement. Future refinement will provide a valuable online tool to assess compliance with the Australian dietary recommendations. PMID- 28731598 TI - Comparison of malnutrition inflammation score, anthropometry and biochemical parameters in assessing the difference in protein-energy wasting between normal weight and obese patients undergoing haemodialysis. AB - AIM: Protein-energy wasting (PEW) is prevalent in haemodialysis. Obesity is an independent risk factor of kidney insufficiency, but it is proposed to have beneficial roles in better outcomes in the final stage of disease. Better nutritional status and body reserves are among probable mechanisms, but direct examinations are limited. The present study aimed to investigate whether obese patients have preferable nutritional status compared to normal weight patients based on malnutrition inflammation score (MIS) and other PEW parameters in haemodialysis. METHODS: This case-control study investigated 52 normal weight (18.5 < body mass index (BMI) < 25 kg/m2 ) and 48 obese (BMI>=30 kg/m2 ) patients on regular haemodialysis. PEW was assessed based on anthropometric and biochemical factors, recent weight changes, appetite, anorexia, dietary intake and MIS. RESULTS: Obese patients had better MIS compared with the normal weight group (P < 0.001), although varying degrees of wasting were prevalent among this group too (75% mild and 25% moderate wasting). The obese group had less significant weight loss (4.2 vs 8%) and anorexia and better appetite. However, a considerable percentage of patients in both groups showed muscle (94.6% of normal weight and 19.5% of obese) and peripheral fat tissue (89.2% of normal weight and 31.7% of obese) losses compared to the 50th percentile. Biochemical parameters were not significantly different between groups except for triglyceride (P = 0.001), transferrin and total iron-binding capacity (P = 0.028). CONCLUSIONS: MIS was significantly better in obese patients; however, both groups showed degrees of wasting based on MIS and other PEW parameters. Nutritional status of obese haemodialysis patients should be monitored regularly because of high risk of PEW like other BMI categories. PMID- 28731599 TI - Does eating environment have an impact on the protein and energy intake in the hospitalised elderly? AB - AIM: This pilot study aimed to examine the difference in energy and protein intake of the midday meal in two different eating environments-the communal dining room and patient bedside-and to obtain feedback on patient preference at each location. METHODS: Elderly patients in two rehabilitation wards were observed consuming the midday meal on two consecutive days: day 1 in the dining room and day 2 at the bedside. The patients' intake was recorded by a visual 5 point assessment scale and analysed for protein and energy content using the hospital food services nutrient analysis of the menu. Patients were also surveyed on preference of eating environment through a written survey. RESULTS: This study found that patients consumed 20% more energy and protein when dining in a communal environment (P = 0.006 and 0.01, respectively). Patients with a body mass index of less than 22 (P = 0.01 and 0.01, respectively) and those with significant cognitive impairment (P = 0.001 and 0.007, respectively) ate 30% more protein and energy in the dining room, and those identified at risk of malnutrition (Malnutrition Screening Tool (MST) >= 2) ate 42% more energy and 27% more protein in the dining room, although this was not statistically significant (P = 0.05 and 0.16). A total of 86% of surveyed patients favoured eating their midday meal in the dining room. CONCLUSIONS: This study supports the contention that a dining room environment can increase food intake, increase patients' opportunities to enjoy the social aspect of meal times, and potentially lead to weight gain and reduced malnutrition risk in the rehabilitation setting. PMID- 28731600 TI - Spot-testing urine pH, a novel dietary biomarker? A randomised cross-over trial. AB - AIM: Spot-tests of urine pH are claimed to be an accessible biomarker of net acid excretion (NAE), and as such, they may be able to determine changes in an individual's intake of acid- or base-forming foods. To test this hypothesis, we aimed to determine if spot-tests of urine pH could index NAE and relay the consumption of a fruit and vegetable (F&V) concentrate whilst determining this concentrate's capacity to modulate NAE. METHODS: In a double blind, placebo controlled, cross-over trial, healthy adults (n = 13) were allocated by simple randomisation to receive a F&V concentrate or placebo for three days each, with diet standardised throughout. Measurements of 24-hour NAE, 24-hour urine pH and spot-tests of urine pH were taken throughout the study. RESULTS: The 24-hour urine pH predicted 24-hour NAE (P = <0.0001). However, spot-tested urine pH displayed prediction intervals too wide to infer 24-hour NAE and inconsistent ability to reflect concentrate ingestion, despite 24-hour NAE and 24-hour urine pH decreasing (-25.8 mEq, 95% CI -44.3 to -7.4, P = 0.01, d = 0.94) and increasing (+0.51, 95% CI 0.25-0.79, P = 0.002, d = 1.3), respectively, following supplementation. CONCLUSIONS: Spot-tests of urine pH are not a valid dietary biomarker of daily NAE and were unable to reliably track changes, despite a F&V concentrate clearly modulating the daily rate of NAE. PMID- 28731601 TI - Telephone-delivered weight management services in the hospital outpatient setting: Decision-makers' perceptions of their use in routine practice. AB - AIM: Providing effective weight management services to the growing number of overweight or obese hospital patients necessitates long-term service provision; however, it is arguably not within the acute-care hospital remit to provide such extended services. Referral to community-based programs is required to provide continuing weight management services. The Get Healthy Service is a free six month, telephone-delivered lifestyle program, now offered in several states of Australia with potential for wide population reach. However, health practitioner referral into the service has been low. The study aimed to examine awareness and suitability of the Get Healthy Service for referral of hospital outpatients for weight management, among key health-care decision-makers. METHODS: Nine key decision-makers from metropolitan and rural Queensland Health hospitals took part in semi-structured telephone interviews that were audio-recorded (January-July 2014), transcribed verbatim and thematically analysed. RESULTS: Interviews revealed that most decision-makers had limited awareness of the Get Healthy Service but perceived the telephone service to be suitable for patient referrals. Incorporating Get Healthy Service referrals into patient care was seen to be potentially valuable and relatively easy to implement, with most interviewees suggesting that they would provide a Get Healthy Service brochure to patients who could then self-refer into the service. CONCLUSIONS: The Get Healthy Service provides a referral model for weight management service provision that appears feasible for use in Queensland hospital settings. Increased awareness and a more integrated approach to referrals would likely result in improved enrolment to the service, with future research needed to demonstrate this. PMID- 28731603 TI - Disease-related malnutrition in the twenty-first century: From best evidence to best practice. PMID- 28731602 TI - Accuracy and precision of estimation equations to predict net endogenous acid excretion using the Australian food database. AB - AIM: The gold standard of measurement for net endogenous acid production (NEAP) is net acid excretion (NAE), a test that is not readily available, and consequently, estimative equations by Remer and Manz and Frassetto et al. are often used. These equations rely on nutrient databases and it is recommended that their validity be assessed using a country's database before their application in research in that country. We sought to delineate the accuracy and precision of these estimation equations using the Australian food database. METHODS: In a double blind, randomised, cross-over fashion, healthy participants (n = 13) residing in regional Australia were exposed to varying net acid loads while they collected weighted food diaries and 24-hour urine samples for measurement of NAE. RESULTS: In comparison to the Frassetto et al. equations (equation one bias = 57.1 mEq/day, equation two bias = -32.8 mEq/day), only the Remer and Manz equation was accurate (bias = -5.4 mEq/day); however, all equations were imprecise. CONCLUSIONS: Using the Australian database, the performance of these equations to predict NEAP appears equal to other databases; however, caveats apply in their application. For future research, the equation by Remer and Manz is preferential for group estimates. None of the equations are recommended for individual estimates. PMID- 28731604 TI - Nutritional status, management and clinical outcomes in patients with esophageal and gastro-oesophageal cancers: A descriptive study. AB - AIM: The aims of this study were to investigate the nutritional management practice and nutritional status of patients with oesophageal and gastro oesophageal cancers, and to propose strategies for improving their nutritional and clinical outcomes. METHODS: All patients diagnosed with oesophageal and gastro-oesophageal cancers and treated with chemotherapy and/or radiotherapy at the Liverpool Cancer Therapy Centre (between August 2010 and February 2014) were included in this retrospective study. Patient and tumour characteristics, nutritional status and management were compared to clinical outcomes. RESULTS: A total of 69 patients met the inclusion criteria. The median weight loss prior to treatment commencement was 10.5% (Interquartile Range (IQR) = 6.6-15.4). A decline in nutritional status continued throughout the treatment course. The median percentage of weight loss during treatment was 3.53% (IQR = 0.00-6.84). Seven and 19 patients required nutrition intervention using a feeding tube or stent insertion to manage dysphagia, respectively. In patients treated with a curative intent, radiotherapy was completed in 100% of those with a nasogastric tube insertion as compared to 80% who had a stent insertion. There was a higher percentage of patients from culturally and linguistically diverse (CALD) background, experiencing significant weight loss when compared with their non CALD counterparts (P = 0.04). CONCLUSIONS: Patients with oesophageal and gastro oesophageal cancers commonly present with significant weight loss and this continues during the course of their anti-cancer treatment. A standardised protocol of nutrition management for these cancer patients is recommended, focusing on assisting patients from CALD backgrounds. PMID- 28731605 TI - Optimising the effectiveness of diabetes education in an East Asian population. AB - AIM: To explore the collective patterns of learning behaviours and preferences of Chinese people during diabetes education. The study was carried out across three countries and aimed to identify strategies that could be used to tailor diabetes education to Chinese people. METHODS: A case study approach was undertaken in three countries (Australia, China and Singapore) using participant observations and qualitative interviews. Purposive sampling was used to select field sites before a snowball technique was employed to identify relevant interviewees. Thematic analysis with pattern matching was used for data analysis. RESULTS: A total of 39 participant observations and 22 interviews were conducted. Chinese people with diabetes were observed seeking advice and recommendations from health professionals. When told clearly what to do, they strived for full compliance. They tended to be submissive during diabetes education and were not likely to raise concerns, negotiate or participate in making medical decisions. They appeared to prefer prescriptive concrete instructions rather than more flexible conceptual education and to believe that behavioural change should be achieved by individual willpower and determination, resulting in an 'all-or-nothing' approach. Regular repeated information sessions were reported to establish rapport and trust. CONCLUSIONS: For diabetes education to be culturally modified for Chinese people, there is a need to consider their unique philosophies and behaviours during education to support lifestyle changes. Building trust from the early stages of education was achieved by encouraging rapport through the provision of clear and precise instructions. This should be done before engaging in an open discussion of implementation strategies. Once the trust is built, healthy behaviour change may follow. PMID- 28731606 TI - Feasibility of home-based dietetic intervention to improve the nutritional status of older adults post-hospital discharge. AB - AIM: To determine if a model of home-based dietetic care improves dietary intake and weight status in a specific group of older adults post-hospitalisation. METHODS: The Department of Veterans' Affairs clients aged 65 years and over were recruited from hospitals in a regional area of New South Wales, Australia (n = 32 men, n = 36 women). Nutritional status was assessed at home at baseline (within two weeks post-discharge) and three months post-discharge using a diet history, a food frequency checklist and Mini Nutritional Assessment (MNA). Personalised dietary advice was provided by a single dietitian according to participants' nutritional status. RESULTS: Mean body weight improved significantly (P = 0.048), as well as mean MNA score (21.9 +/- 3.5 vs 25.2 +/- 3.1) (P < 0.001). Mean energy, protein and micronutrient intakes were adequate at baseline and three months, except for vitamin D. At three months, the underweight group (body mass index (BMI) < 23 kg/m2 ) had significantly higher mean protein intake per body weight (1.7 +/- 0.4 g/kg) compared to those who were a desirable weight (BMI 23 27 kg/m2 ) (1.4 +/- 0.3 g/kg) or overweight (BMI>27 kg/m2 ) (1.1 +/- 0.3 g/kg) peers (P < 0.001). There was significant improvement in energy intake contributed from oral nutrition supplements (+95.5 +/- 388.2 kJ/day) and milk (+259.6 +/- 659.8 kJ/day). CONCLUSIONS: Dietetic intervention improved nutritional status 3 months after hospital discharge in older adults living in the community. PMID- 28731607 TI - Process evaluation of a patient-centred, patient-directed, group-based education program for the management of type 2 diabetes mellitus. AB - AIM: The present study developed and evaluated a patient-centred, patient directed, group-based education program for the management of type 2 diabetes mellitus. METHODS: Two frameworks, the Medical Research Council (MRC) framework for developing and evaluating complex interventions and the RE-AIM framework were followed. Data to develop the intervention were sourced from scoping of the literature and formative evaluation. Program evaluation comprised analysis of primary recruitment of participants through general practitioners, baseline and end-point measures of anthropometry, four validated questionnaires, contemporaneous facilitator notes and telephone interviews with participants. RESULTS: A total of 16 participants enrolled in the intervention. Post intervention results were obtained from 13 participants, with an estimated mean change from baseline in weight of -0.72 kg (95%CI -1.44 to -0.01), body mass index of -0.25 kg/m2 (95%CI -0.49 to -0.01) and waist circumference of -1.04 cm (95%CI -4.52 to 2.44). The group education program was acceptable to participants. The results suggest that recruitment through general practitioners is ineffective, and alternative recruitment strategies are required. CONCLUSIONS: This patient-centred, patient-directed, group-based intervention for the management of type 2 diabetes mellitus was both feasible and acceptable to patients. Health professionals should consider the combined use of the MRC and RE AIM frameworks in the development of interventions to ensure a rigorous design process and to enable the evaluation of all phases of the intervention, which will facilitate translation to other settings. Further research with a larger sample trialling additional recruitment strategies, evaluating further measures of effectiveness and utilising lengthier follow-up periods is required. PMID- 28731608 TI - Dietetic and educational interventions improve clinical outcomes of diabetic and obese clients with mental impairment. AB - AIM: The aim of this study was to evaluate the effect of dietetic and educational interventions provided to clients with type 2 diabetes (with or without obesity) or obesity-only residing in supported residential facilities and characterised by mental impairment. METHODS: A retrospective audit involving the retrieval of information from medical records and databases was undertaken to evaluate the effect of dietetic and educational interventions. Clinical outcomes were weight, body mass index and glycosylated haemoglobin (HbA1c) levels. RESULTS: A total of 91 clients were included, 47 with type 2 diabetes (with or without obesity) and 44 with obesity-only. All but one had schizophrenia, an intellectual disability or another psychological condition. After interventions, the diabetic subgroup demonstrated significant decreases in weight (mean [SD] initial = 101.5 [20.7], final = 97.8 [20.6] kg, P = 0.001) and body mass index (mean [SD] initial = 35.8 [8.1], final = 34.4 [7.8] kg/m2 , P = 0.001) and a non-significant decrease in HbA1c over time. The obesity-only subgroup showed no significant change in outcomes. Factors significantly negatively impacting at least one outcome included the presence of schizophrenia (P <= 0.017) and refusal of intervention(s) (P <= 0.048), whereas a significant positive impact was seen for a greater total number of visits to a dietitian or diabetes educator (P <= 0.024). CONCLUSIONS: These results provide evidence to support the effectiveness of dietetic and educational interventions for this vulnerable client group. PMID- 28731609 TI - Dietary sodium and potassium intake and their association with blood pressure in a non-hypertensive Iranian adult population: Isfahan salt study. AB - AIM: The association of sodium (Na) and potassium (K) intake with blood pressure (BP) is an ongoing debate, especially in central Iran. We aimed to examine the mean Na and K intake, major sources of Na and the relationship between BP and dietary and urinary Na and K. METHODS: This cross-sectional study was performed in central Iran in 2013-2014. A total of 796 non-hypertensive adults aged >18 years were randomly recruited. The semi-quantitative food frequency questionnaire was used to assess dietary Na and K intake. Moreover, 24-hour urine samples were collected to measure 24-hour urinary Na (UNa) and K (UK) as biomarkers. BP was measured twice on each arm using a standard protocol. RESULTS: The mean Na and K intake were 4309.6 +/- 1344.4 and 2732.7 +/- 1050.5 mg/day, respectively. Table and cooking salt were the main sources of Na. Odds ratio (OR) (95% confidence interval (CI)) of the crude model in the highest quartile of UNa indicated a significant association with the higher risk of prehypertension (OR (95% CI): 2.09 (1.09-4.05); P for trend = 0.007). After adjustment for potential confounders, prehypertension was significantly associated with increasing dietary Na/K ratio (OR (95% CI): 1.28 (1.01-1.57); P for trend = 0.046) and UNa/UK ratio (OR (95% CI): 2.15(1.08-4.55); P for trend = 0.029). CONCLUSIONS: Increasing dietary and urinary Na/K ratios and UNa were associated with elevated BP and prehypertension occurrence. These findings support the necessity of developing a salt reduction programme in our country. PMID- 28731610 TI - Relative validity of a 2-day 24-hour dietary recall compared with a 2-day weighed dietary record among adults in South China. AB - AIM: To determine the relative validity of a 2-day 24-hour dietary recall (HR) designed to assess energy and nutrient intake among Chinese adults compared with a 2-day weighed dietary record (WD). METHODS: Data were obtained from an ongoing population-based, prospective cohort study of adults aged 18-65 years in South China. A total of 41 adults completing a HR and a WD within 14 days were included in the present analysis. Estimations of individual mean differences, Spearman's correlation coefficients, cross-classifications and Bland-Altman plots were used to assess the agreement between the intakes of energy and 18 nutrients obtained from the HR and the WD. RESULTS: With the exception of total fat, saturated fatty acids, thiamine, potassium and magnesium, the energy and nutrient intakes between the HR and WD showed no significant differences. All dietary intakes that were evaluated by the HR were correlated significantly with the dietary intake from the WD (de-attenuated correlation coefficients ranged from 0.10 to 0.87). The proportion of participants classified into quartiles correctly ranged from 61% for tocopherol intake to 90% for energy intake. The weighted k values ranking the participants ranged from 0.11 for tocopherol intake to 0.41 for the intakes of energy and calcium. The Bland-Altman plots showed moderate/good agreement among all the dietary intakes that were estimated from the HR and WD, except for total fat. CONCLUSIONS: This study suggests that an HR could be a valid tool for estimating the energy and nutrient intakes among adults in South China at the group level. PMID- 28731611 TI - Energy drink consumption is associated with reduced sleep quality among college students: a cross-sectional study. AB - AIM: Intake of caffeinated energy drinks has significantly increased, specifically among young adults and adolescents. College students are prone to developing unhealthy eating habits and dependence on stimulants, which puts them at a greater risk of sleep problems. This study aims to investigate the prevalence of caffeinated energy drink consumption and its association with sleep quality in college students. METHODS: A sample of 919 randomly selected adults (237 males and 682 females) from various colleges at the University of Sharjah/United Arab Emirates participated in this cross-sectional study. Data were collected using an online validated questionnaire. RESULTS: The current study revealed that 376 students (41%) were consuming energy drinks on a regular basis. Approximately half of the students had normal sleep patterns; the other half had sleep problems (anxiety and intermittent sleep). Results of the present study revealed a significant (r = -0.10, P < 0.05) relationship between the consumption of energy drinks and sleep quality and patterns. CONCLUSIONS: Moderate consumption of energy drinks was reported among college students. Consumption of energy drinks was significantly associated with changes in sleep quality and patterns of students. PMID- 28731612 TI - Mesoderm Lineage 3D Tissue Constructs Are Produced at Large-Scale in a 3D Stem Cell Bioprocess. AB - Various studies have presented different approaches to direct pluripotent stem cell differentiation such as applying defined sets of exogenous biochemical signals and genetic/epigenetic modifications. Although differentiation to target lineages can be successfully regulated, such conventional methods are often complicated, laborious, and not cost-effective to be employed to the large-scale production of 3D stem cell-based tissue constructs. A 3D-culture platform that could realize the large-scale production of mesoderm lineage tissue constructs from embryonic stem cells (ESCs) is developed. ESCs are cultured using our previously established 3D-bioprocess platform which is amenable to mass production of 3D ESC-based tissue constructs. Hepatocarcinoma cell line conditioned medium is introduced to the large-scale 3D culture to provide a specific biomolecular microenvironment to mimic in vivo mesoderm formation process. After 5 days of spontaneous differentiation period, the resulting 3D tissue constructs are composed of multipotent mesodermal progenitor cells verified by gene and molecular expression profiles. Subsequently the optimal time points to trigger terminal differentiation towards cardiomyogenesis or osteogenesis from the mesodermal tissue constructs is found. A simple and affordable 3D ESC-bioprocess that can reach the scalable production of mesoderm origin tissues with significantly improved correspondent tissue properties is demonstrated. PMID- 28731613 TI - Polyol Structure Influences Enzymatic Hydrolysis of Bio-Based 2,5 Furandicarboxylic Acid (FDCA) Polyesters. AB - Polyesters of 2,5-furandicarboxylic acid (FDCA) have gained attention as they can be regarded as the bio-based alternatives to the petroleum-based polyesters of terephthalic acid. However, only little is known about the biodegradation and enzymatic hydrolysis of FDCA-based polyesters. This work aims to investigate the influence of different polyols on enzymatic hydrolysis of FDCA-based polyesters. A series of polyesters containing various polyols are synthesized and analyzed regarding susceptibility to enzymatic hydrolysis by cutinase 1 from Thermobifida cellulosilytica (Thc_Cut1). FDCA-based polyesters' number average molecular weight (Mn ) ranged from 9360-35 800 g mol-1 according to gel permeation chromatography (GPC) analysis. Differential scanning calorimetry (DSC) analyses show decreasing glass transition temperature (Tg ) with increasing diol chain length. Crystallinity of all polyesters is below 1% except for polyesters containing 1,6-hexanediol, 1,8-octanediol, and 1,12-dodecanediol for which calculated crystallinities are 27, 37, and 30%, respectively. Thc_Cut1 hydrolyzes all tested polyesters with preference for polyesters containing 1,5-pentanediol and 1,9-nonanediol (57.7 +/- 7.5 and 52.8 +/- 4.0% released FDCA). Enzyme activity increases when the linear diol 1,3-propanediol is replaced by the branched analog 1,2-propanediol or ethoxy units are introduced into the polyester chain. The results will contribute to expand the knowledge of microbial biodegradation of FDCA-based polyesters. PMID- 28731614 TI - Economic injury levels and economic thresholds for Leptoglossus zonatus (Dallas) (Hemiptera: Coreidae) infesting seed maize. AB - BACKGROUND: Although Leptoglossus zonatus is considered a secondary pest of maize grown for grain, when grown for seed, this pest can cause significant economic damage. There are no records of management recommendations for this pest. The objectives of this work were to quantify losses caused by L. zonatus to different genotypes used for seed maize production and to estimate the acute toxicity of selected insecticides to L. zonatus using different application technologies. The ultimate goal was to calculate economic injury levels (EILs) and develop economic thresholds (ETs) for L. zonatus infesting seed maize. RESULTS: EILs and ETs varied, respectively, from 3 to 8 and from 2 to 6 adults per 1000 plants, depending on the genotype, insecticide and application technology. Effective control was obtained by using aerial or ground application of lambda-cyhalothrin (10.6%) + thiametoxan (14.1%) or permethrin (38.4%) at the rates of 1.48 mL ha-1 and 27.10 mL ha-1 , respectively, or ground application of methomyl (21.5%) at the rate of 244.06 mL ha-1 . CONCLUSION: Maize grown for seed is susceptible to L. zonatus damage during reproductive stages, and the pest densities requiring management vary with genotype, insecticide, and application technology. These results contribute significantly to integrated pest management (IPM) for seed maize. (c) 2017 Society of Chemical Industry. PMID- 28731615 TI - The prevalence of CCR5-Delta32 mutation in a cohort of Saudi stem cell donors. AB - CCR5 is a chemokine receptor that was found to be used by HIV as a co-receptor for entering target cells. A 32 bp deletion was described in certain people that rendered CCR5 non-functional. The mutant allele CCR5-Delta32 has been shown to prevent HIV infection. In addition, stem cell transplantation with the CCR5 Delta32 homozygous genotype can lead to clearance of HIV infection. In this study, our aim was to investigate the frequency of CCR5-Delta32 mutation in a cohort of stem cell donors from cord blood bank and stem cell donor registry. A total of 3025 samples were collected from healthy stem cell donors (2625) and from cord blood units (400). DNA was extracted and the CCR5 gene was amplified by polymerase chain reaction (PCR) in a light cycler system using SYBR Green dye. The mutated gene was further confirmed by direct gene sequencing. We found 38 heterozygous for CCR5-Delta32 and one homozygous CCR5 mutation (Delta32/Delta32) out of the 3025 tested individuals. We conclude that the protective CCR5-Delta32 allele appears to be rarely present in Saudi Arabia. PMID- 28731617 TI - In vivo diagnosis of early-stage gastric cancer found after Helicobacter pylori eradication using probe-based confocal laser endomicroscopy. AB - BACKGROUND AND AIM: Early-stage gastric cancer (EGC) found after Helicobacter pylori (Hp) eradication often displays non-tumorous regenerative epithelium and/or maturated tumorous epithelium overlying the cancerous tissue, which may confuse endoscopic and histological diagnosis. Probe-based confocal laser endomicroscopy (pCLE) enables in vivo real-time optical biopsy. We compared the diagnostic yields for these EGC cases using conventional white light endoscopy (WL), magnifying endoscopy with narrow-band imaging (ME-NBI), pCLE, and endoscopic biopsy; we also compared the accuracy of the horizontal extent diagnosis between ME-NBI and pCLE. METHODS: This study enrolled 30 patients with 36 EGC lesions after successful Hp eradication. Diagnostic yields of WL, ME-NBI, pCLE, and endoscopic biopsy were prospectively compared. Four points of cancerous margins (oral, anal, anterior, and posterior sites) were also prospectively evaluated with M-NBI and pCLE to determine the horizontal extent of the EGC. RESULTS: Diagnostic yield was significantly higher with pCLE than with WL and endoscopic biopsy (97 vs 72%, 97 vs 72%, P = 0.0159, 0.0077, respectively), whereas it did not differ from ME-NBI (88.9%, P = 0.371). Height of non-tumorous regenerative epithelium or maturated atypical glands was 104.7 +/- 34.2 MUm in the pCLE-positive cases, whereas it was 188.3 +/- 27.1 MUm in a pCLE-negative case (P = 0.0004). Diagnostic accuracy of the horizontal margin of EGC was significantly higher with pCLE than with ME-NBI (92 vs 70%, P = 0.0159). CONCLUSION: pCLE may be helpful for the diagnosis of ambiguous ECG found after Hp eradication because it enables real-time scanning throughout the lesion and detection of subsurface microstructure. PMID- 28731616 TI - Inversion recovery ultrashort echo time imaging of ultrashort T2 tissue components in ovine brain at 3 T: a sequential D2 O exchange study. AB - Inversion recovery ultrashort echo time (IR-UTE) imaging holds the potential to directly characterize MR signals from ultrashort T2 tissue components (STCs), such as collagen in cartilage and myelin in brain. The application of IR-UTE for myelin imaging has been challenging because of the high water content in brain and the possibility that the ultrashort T2 * signals are contaminated by water protons, including those associated with myelin sheaths. This study investigated such a possibility in an ovine brain D2 O exchange model and explored the potential of IR-UTE imaging for the quantification of ultrashort T2 * signals in both white and gray matter at 3 T. Six specimens were examined before and after sequential immersion in 99.9% D2 O. Long T2 MR signals were measured using a clinical proton density-weighted fast spin echo (PD-FSE) sequence. IR-UTE images were first acquired with different inversion times to determine the optimal inversion time to null the long T2 signals (TInull ). Then, at this TInull , images with echo times (TEs) of 0.01-4 ms were acquired to measure the T2 * values of STCs. The PD-FSE signal dropped to near zero after 24 h of immersion in D2 O. A wide range of TInull values were used at different time points (240-330 ms for white matter and 320-350 ms for gray matter at TR = 1000 ms) because the T1 values of the long T2 tissue components changed significantly. The T2 * values of STCs were 200-300 MUs in both white and gray matter (comparable with the values obtained from myelin powder and its mixture with D2 O or H2 O), and showed minimal changes after sequential immersion. The ultrashort T2 * signals seen on IR-UTE images are unlikely to be from water protons as they are exchangeable with deuterons in D2 O. The source is more likely to be myelin itself in white matter, and might also be associated with other membranous structures in gray matter. PMID- 28731618 TI - Controlling the near-infrared transparency of costal cartilage by impregnation with clearing agents and magnetite nanoparticles. AB - Penetration depth of near-infrared laser radiation to costal cartilage is controlled by the tissue absorption and scattering, and it is the critical parameter to provide the relaxation of mechanical stress throughout the whole thickness of cartilage implant. To enhance the penetration for the laser radiation on 1.56 MUm, the optical clearing solutions of glycerol and fructose of various concentrations are tested. The effective and reversible tissue clearance was achieved. However, the increasing absorption of radiation should be concerned: 5 degrees C-8 degrees C increase of tissue temperature was detected. Laser parameters used for stress relaxation in cartilage should be optimized when applying optical clearing agents. To concentrate the absorption in the superficial tissue layers, magnetite nanoparticle (NP) dispersions with the mean size 95 +/- 5 nm and concentration 3.9 +/- 1.1 * 1011 particles/mL are applied. The significant increase in the tissue heating rate was observed along with the decrease in its transparency. Using NPs the respective laser power can be decreased, allowing us to obtain the working temperature locally with reduced thermal effect on the surrounding tissue. PMID- 28731619 TI - New onset diabetes after kidney transplantation is associated with increased mortality-A retrospective cohort study. AB - OBJECTIVE: Clinical outcomes in individuals with new onset diabetes after transplantation (NODAT) and the optimal treatment for this complication are poorly characterized. This study was intended to better define these issues. METHODS: Patients who underwent kidney transplantation and did not have diabetes prior to transplantation were included in the study. Clinical outcomes were compared between those who developed NODAT and those who did not. In those who developed NODAT, oral therapy was compared with insulin based therapy. RESULTS: A total of 266 kidney transplant recipients were included, of which 71 (27%) developed NODAT during the time of the follow-up. Using Cox multivariate analysis adjusted for age and gender, hazard ratio for overall mortality among patients with NODAT versus those without NODAT was 2.69 (95% CI 1.04-7.01). Among patients who developed NODAT, 29 patients (40%) were treated with an insulin-based regimen. At the end of follow-up, no difference was found in mean HbA1c, and therapy regimen was not associated with greater mortality. CONCLUSIONS: New onset diabetes in kidney transplanted patients is associated with increased mortality compared with kidney transplanted patients without NODAT. PMID- 28731620 TI - Solvent-Free Off-On Detection of the Improvised Explosive Triacetone Triperoxide (TATP) with Fluorogenic Materials. AB - A fluorogenic perylenediimide-functionalized polyacrylate capable of generating color and fluorescence changes in the presence of triacetone triperoxide TATP), an improvised explosive used in terrorist attacks, under solvent-free, solid state conditions has been developed. The material works by accumulating volatile TATP until it reaches a threshold; therefore, triggering colorimetric and fluorescent responses. PMID- 28731621 TI - Metabolic Engineering for Advanced Biofuels Production and Recent Advances Toward Commercialization. AB - Research on renewable biofuels produced by microorganisms has enjoyed considerable advances in academic and industrial settings. As the renewable ethanol market approaches maturity, the demand is rising for the commercialization of more energy-dense fuel targets. Many strategies implemented in recent years have considerably increased the diversity and number of fuel targets that can be produced by microorganisms. Moreover, strain optimization for some of these fuel targets has ultimately led to their production at industrial scale. In this review, the recent metabolic engineering approaches for augmenting biofuel production derived from alcohols, isoprenoids, and fatty acids in several microorganisms are discussed. In addition, the successful commercialization ventures for each class of biofuel targets are discussed. PMID- 28731622 TI - Mechanistic Modeling Based PAT Implementation for Ion-Exchange Process Chromatography of Charge Variants of Monoclonal Antibody Products. AB - Process chromatography is typically used to remove product related impurities and variants that have very similar physicochemical properties to the product. Baseline separation may not be achieved in most cases due to high protein loading and thus, pooling of the elution peak can be challenging for maximizing yield and achieving consistency in product quality. Batch-to-batch variability in quality of the feed material also occurs in commercial manufacturing. Mechanistic modeling of process chromatography, though non-trivial, can be an enabler for implementation of Process Analytical Technology. This paper presents one such application involving prediction of the impact of variability in feed quality and in gradient shape on separation of charge variants by cation exchange process chromatography and thereby facilitating feed forward control. Five batches having different compositions of charge variants have been used to demonstrate the proposed pooling strategy based on simulated chromatograms and the outcome has been compared to offline pooling based on fractionation. For all the conditions examined and for the desired target of main product (67%), the proposed approach resulted in remarkable consistency in product quality (67 +/- 2%) while delivering a yield of greater than 90%. PMID- 28731623 TI - Concentric photothermal coagulation with basket-integrated optical device for treatment of tracheal stenosis. AB - A basket-integrated optical device is developed to consistently treat tubular tissue by centering an optical diffuser in the lumen. Four nitinol arms in conjunction with the optical diffusing applicator are deployed to induce homogeneous circumferential light emission and concentric photothermal coagulation on tracheal tissue. A 1470-nm laser light is employed for the tissue testing at various irradiation conditions and evaluated in terms of thermal gradient and temperature evolution. Preliminary experiments on liver tissue demonstrate the concentric development of the radial thermal coagulation in the tissue (eccentric ratio = ~5.5%). The interstitial tissue temperature increases with the total amount of energy delivery (around 65 degrees C). Ex vivo trachea testing yields up to 16.5% tissue shrinkage due to dehydration as well as uniform ablation of the cilia and goblet cells in a mucosa layer under 7-W irradiation for 10 s. The proposed optical device may be a feasible therapeutic method to entail the circumferential coagulation in the tubular tissues in a reliable manner. PMID- 28731625 TI - Dietitians Association of Australia 34th National Conference, "Cultivating Fresh Evidence", Hobart, Tasmania, Australia, 18-20 May 2017. PMID- 28731626 TI - Editorial. PMID- 28731624 TI - Risk For Postpartum Depression Among Immigrant Arabic Women in the United States: A Feasibility Study. AB - INTRODUCTION: Postpartum depression (PPD) affects approximately 14% of women in the United States and 10% to 37% of Arabic women in the Middle East. Evidence suggests that immigrant women experience higher rates, but information on PPD among immigrant women of Arabic descent in the United States is nonexistent. METHODS: A cross-sectional descriptive feasibility study was conducted to assess the practicality of implementing a larger proposed research study to examine predictors of PPD in US immigrant women of Arabic descent residing in Dearborn, Michigan. Fifty women were recruited from an Arab community center and completed demographic data, the Arabic version of the Edinburgh Postpartum Depression Scale (EPDS), and the Postpartum Depression Predictors Inventory-Revised (PDPI-R). RESULTS: Among participants, 36% were considered at high risk for developing PPD. Lack of social support, antenatal anxiety, antenatal depression, maternity blues (feeling depressed during the first 4 weeks postpartum), and life stress were significantly related to risk for PPD. Multiple regression analysis revealed that social support (t = -3.77, P < .0001) and maternity blues (t = 2.19, P = .03) were the only significant predictors for postpartum depressive symptoms. DISCUSSION: Findings of this study describe the prevalence of PPD in a sample of US immigrant women of Arabic descent and support the feasibility of a larger and more in-depth understanding of their immigration and acculturation experiences. Study participants reported high risk for PPD. Maternity blues and lack of social support were significant predictors to the risk for PPD. Future research tailored to this minority group is recommended. PMID- 28731627 TI - His-Tag Immobilization of Cutinase 1 From Thermobifida cellulosilytica for Solvent-Free Synthesis of Polyesters. AB - For many years, lipase B from Candida antarctica (CaLB) was the primary biocatalyst used for enzymatic esterification and polycondensation reactions. More recently, the need for novel biocatalysts with different selectivity has arisen in the biotechnology and biocatalysis fields. The present work describes how the catalytic potential of Thermobifida cellulosilytica cutinase 1 (Thc_Cut1) was exploited for polyester synthesis. In a first step, Thc_Cut1 was immobilized on three different carriers, namely Opal, Coral, and Amber, using a novel non toxic His-tag method based on chelated Fe(III) ions (>99% protein bounded). In a second step, the biocatalyzed synthesis of an array of aliphatic polyesters was conducted. A selectivity chain study in a solvent-free reaction environment showed how, in contrast to CaLB, Thc_Cut1 presents a certain preference for C6 C4 ester-diol combinations reaching monomer conversions up to 78% and Mw of 878 g mol-1 when the Amber immobilized Thc_Cut1 was used. The synthetic potential of this cutinase was also tested in organic solvents, showing a marked activity decrease in polar media like that observed for CaLB. Finally, recyclability studies were performed, which showed an excellent stability of the immobilized Thc_Cut1 (retained activity >94%) over 24 h reaction cycles when a solvent-free workup was used. Concerning a practical application of the biocatalyst's preparation, the production of oligomers with Mn values below 10 kDa is usually desired for the production of nanoparticles and for the synthesis of functional pre-polymers for coating applications that can be crosslinked in a second reaction step. PMID- 28731628 TI - Aerial release of Rhinoncomimus latipes (Coleoptera: Curculionidae) to control Persicaria perfoliata (Polygonaceae) using an unmanned aerial system. AB - BACKGROUND: Rhinoncomimus latipes (Coleoptera: Curculionidae) is a major biological control agent against the invasive plant Persicaria perfoliata. Release of R. latipes is challenging with the current visit-and-hand release approach because P. perfoliata shows a high degree of patchiness in the landscape, possesses recurved barbs on its stems, and often spreads into hard-to access areas. This 3-year study developed and evaluated unmanned aerial systems (UAS) for precise aerial release of R. latipes to control P. perfoliata. RESULTS: We have developed two UAS (i.e. quad-rotor and tri-rotor) and an aerial release system to disseminate R. latipes. These include pods containing R. latipes and a dispenser to accommodate eight pods. Results of field tests to evaluate the systems showed no significant (P > 0.05) effects on survivorship and feeding ability of R. latipes after aerial release. CONCLUSION: Our study demonstrates the potential of UAS for precision aerial release of biological control agents to control invasive plants. The aerial deployment systems we have developed, including both pods and a dispenser, are low cost, logistically practical, and effective with no negative effects on aerially released R. latipes. (c) 2017 Society of Chemical Industry. PMID- 28731629 TI - Stabilizing the Performance of High-Capacity Sulfur Composite Electrodes by a New Gel Polymer Electrolyte Configuration. AB - Increased pollution and the resulting increase in global warming are drawing attention to boosting the use of renewable energy sources such as solar or wind. However, the production of energy from most renewable sources is intermittent and thus relies on the availability of electrical energy-storage systems with high capacity and at competitive cost. Lithium-sulfur batteries are among the most promising technologies in this respect due to a very high theoretical energy density (1675 mAh g-1 ) and that the active material, sulfur, is abundant and inexpensive. However, a so far limited practical energy density, life time, and the scaleup of materials and production processes prevent their introduction into commercial applications. In this work, we report on a simple strategy to address these issues by using a new gel polymer electrolyte (GPE) that enables stable performance close to the theoretical capacity of a low cost sulfur-carbon composite with high loading of active material, that is, 70 % sulfur. We show that the GPE prevents sulfur dissolution and reduces migration of polysulfide species to the anode. This functional mechanism of the GPE membranes is revealed by investigating both its morphology and the Li-anode/GPE interface at various states of discharge/charge using Raman spectroscopy. PMID- 28731630 TI - Improved PKS Gene Expression With Strong Endogenous Promoter Resulted in Geldanamycin Yield Increase. AB - The type I polyketide geldanamycin is a potent anti-tumor reagent. Its biosynthesis includes three steps: the biosynthesis of precursors, such as 3 amino-5-hydroxybenzoic acid (AHBA), the polyketide synthase (PKS) chain extension, and the post-PKS modifications. According to the genomic and transcriptomic analysis, the PKS chain extension was deduced to be the rate limiting step for geldanamycin production in Streptomyces hygroscopicus XM201. In order to improve the expression of PKS genes, a strong endogenous promoter 5063p was obtained based on the transcriptomic analysis and XylE enzymatic assay. By replacing the native PKS promoter gdmA1p with 5063p, the expression of the PKS genes during geldanamycin fermentation was increased by 4-141-folds, and the geldanamycin yield was increased by 39%. Interestingly, AHBA feeding experiment showed that the supply of AHBA in turn become a new rate-limiting factor for geldanamycin production. Further combined overexpression of the 6-gene AHBA biosynthetic cassette and PKS genes increased the yield of geldanamycin by 88%, from 773 mg L-1 of the wild-type to 1450 mg L-1 in the derived strain. Our results suggested that improved expression of all PKS genes in a particular biosynthetic gene cluster is important for the yield increase of the corresponding polyketide natural product. PMID- 28731631 TI - Substrate Curvature Restricts Spreading and Induces Differentiation of Human Mesenchymal Stem Cells. AB - While cells attach, spread, migrate, proliferate, and differentiate in three dimensional (3D) micromechanical environments, the mechanical factors of these environments influence the shapes, sizes, and adhesion forces of the cells. Here, the authors culture human mesenchymal stem cells (hMSCs) on a unique class of curvature-defined substrates, micro glass ball embedded polyacrylamide gels, prepared with an improved protocol, and investigate the spreading responses of the hMSCs on the glass balls to study the effects of substrate curvature on the spreading of hMSCs. The authors find that, among the used diameters of glass balls, the minimum diameter of a glass ball on which an hMSC can attach and spread is 500 MUm. In contrast to the well-spread morphologies with randomly multiple lamellipodia for the hMSCs growing on the flat glass plates, the morphologies of the hMSCs growing on the glass balls are almost uniformly spindle shaped with two lamellipodia. The sensitivities of the attachment and spreading morphology of an hMSC to substrate curvature are very different from those of a fibroblast. The RT-PCR analysis reveals that the substrate curvature alone can induce adipogenesis of the hMSCs. These findings imply that substrate curvature has profound effects on stem cell behaviors, and detailed and in-depth studies on these effects and their underlying biophysical mechanisms are necessary. PMID- 28731632 TI - Macrophages of Different Phenotypes Influence the Migration of BMSCs in PLGA Scaffolds with Different Pore Size. AB - Immune modulation of the scaffolds not only reduces the host immunological rejection response, but also improves the regenerative cell migration into the scaffolds. Herein a convenient immune modulation of poly(lactide-co-glycolide) (PLGA) scaffold is applied with macrophages of different phenotypes to evaluate its influence on the migration behavior of bone marrow mesenchymal stem cells (BMSCs). With pro-inflammatory macrophages (M1) pre-loading, BMSCs migrate significantly faster into the PLGA scaffold, compared with those in the control scaffold or pre-seeded with inactivated macrophages (M0). The pore size of PLGA scaffolds is found to take a more important role, as the one with a larger pore size significantly enhance migration of BMSCs no matter the pre-seeding of macrophages. The enhanced cell migration in the macrophage-modulated scaffold can provide a new protocol for in situ tissue regeneration by recruiting endogenous cells. PMID- 28731633 TI - Australian consumer awareness of health benefits associated with vegetable consumption. AB - AIM: The present study investigated the perceived health benefits of specific vegetable consumption to guide the use of nutrition and health claims on vegetable marketing collateral. METHODS: Free elicitation and consumer ranking data were collected through an online survey of 1000 adults from across Australia and analysed for the perceived importance of vegetables in the daily diet, number of serves consumed per day, knowledge about health-related benefits of specific vegetables and perceived health benefits of vegetable consumption. RESULTS: The importance of vegetables in the diet and daily vegetable consumption was higher in people from an English-speaking background, females, people aged 45 years and over and people living in non-metropolitan areas. Digestion was selected as the major health benefit from consumption of specific vegetables. However, understanding of the health benefits of specific vegetable consumption was relatively low among consumers. Half of the respondents were not sure of the health benefits associated with specific vegetables, except for carrots and spinach. Some respondents volunteered nutrient content or other information. CONCLUSIONS: There was no clear indication that consumers understand the specific health benefits conferred by consumption of vegetables. Nutrient and health benefit labelling therefore has the capacity to enhance knowledge of vegetable consumers. It is recommended that health benefit labelling be tailored to promote greater consumption of vegetables in those demographic groups where vegetable consumption was lower. The present study assists the Australian vegetable industry in helping consumers make more informed consumption choices. PMID- 28731634 TI - Measuring the quality of Hospital Food Services: Development and reliability of a Meal Quality Audit Tool. AB - AIM: To develop and test the reliability of a Meal Quality Audit Tool (MQAT) to audit the quality of hospital meals to assist food service managers and dietitians in identifying areas for improvement. METHODS: The MQAT was developed using expert opinion and was modified over time with extensive use and feedback. A phased approach was used to assess content validity and test reliability: (i) trial with 60 dietetic students, (ii) trial with 12 food service dietitians in practice and (iii) interrater reliability study. Phases 1 and 2 confirmed content validity and informed minor revision of scoring, language and formatting of the MQAT. To assess reliability of the final MQAT, eight separate meal quality audits of five identical meals were conducted over several weeks in the hospital setting. Each audit comprised an 'expert' team and four 'test' teams (dietitians, food services and ward staff). Interrater reliability was determined using intra class correlation analysis. RESULTS: There was statistically significant interrater reliability for dimensions of Temperature and Accuracy (P < 0.001) but not for Appearance or Sensory. Composition of the 'test' team appeared to influence results for Appearance and Sensory, with food service-led teams scoring higher on these dimensions. 'Test' teams reported that MQAT was clear and easy to use. CONCLUSIONS: MQAT was found to be reliable for Temperature and Accuracy domains, with further work required to improve the reliability of the Appearance and Sensory dimensions. The systematic use of the tool, used in conjunction with patient satisfaction, could provide pertinent and useful information regarding the quality of food services and areas for improvement. PMID- 28731635 TI - University foodservices' potential for providing environmental education to students. AB - AIMS: University foodservices are potentially well placed to foster environmental education in a non-classroom setting and so could have the power to benefit communities through producing environmentally literate graduates. Buy-in from foodservice staff is critical for realising this potential, so understanding what foodservice staff think about their foodservice engaging in the provision of environmental education is essential. The aim of this study was to identify the dominant perspectives held by university foodservice staff about the desirability and realities of fostering environmental education in their workplaces. METHODS: The study design integrated two phases: (i) 36 foodservice staff conducted a card sorting activity that revealed four dominant viewpoints; (ii) 60 foodservice staff completed a survey where they identified with one of these viewpoints. The study was conducted in Dunedin, New Zealand. RESULTS: The four main perspectives were The 'Believer', the 'Relatively Positive Integrator', the 'Uncertain Contender' and the 'Sceptic'. All of the perspective groups, except for Sceptic, believed environmental education in their workplace was desirable. In the survey, 25% of the 60 participants self-identified with the Believer narrative, 40% with the Relatively Positive Integrator, 25% with the Uncertain Contender and 10% with the Sceptic. There were no significant differences between factors for sociodemographic characteristics. CONCLUSIONS: A paradigm shift in foodservice framework thinking could unlock the potential university foodservice has to assist universities whose strategic mission is to embed environmental education in both curricular and co-/extracurricula activities. PMID- 28731636 TI - Foodservice management returns: The need to rejuvenate the superhero contribution of dietetics. PMID- 28731637 TI - Do low-income Cypriots experience food stress? The cost of a healthy food basket relative to guaranteed minimum income in Nicosia, Cyprus. AB - AIM: The aim of the present study was to assess the cost, acceptability and affordability of the healthy food basket (HFB) among low-income families in Cyprus. METHODS: HFBs were constructed based on the National Guidelines for Nutrition and Exercise for six different types of households. Acceptability was tested through focus groups. Affordability was defined as the cost of the HFB as a percentage of the guaranteed minimum income (GMI). The value of the GMI is set to be equal to ?480 for a single individual and increases with the size of the recipient unit in accordance with the Organization for Economic Co-operation and Development equivalence scales. The Ministry of Labour estimates that, on average, nearly 50% of the GMI is required for food. RESULTS: The total monthly budget for HFB is 0.80, 1.11, 1.27, 1.28, 1.44 and 1.48 times higher than the GMI budget for food among different types of households in Cyprus (a single woman, a single man, a couple, a single woman with two children, a single man with two children and a couple with two children, respectively). In particular, a family with two children on GMI would need to spend a large proportion of their income on the HFB (71.68%). CONCLUSIONS: The GMI scheme appears not to consider the cost of healthy food, and thus, families on welfare payments in Cyprus are at a high risk of experiencing food stress. Therefore, additional research is required to measure the cost of the six HFBs in various settings. PMID- 28731638 TI - Factors influencing hospital foodservice staff's capacity to deliver a nutrition intervention. AB - AIM: Implementation of an intervention can result in a discrepancy between what was planned and what is delivered, affecting outcomes for recipients. The aim was to explore, from the perspective of hospital foodservice staff, their experiences delivering a nutrition intervention and the barriers and enablers to its implementation. METHODS: A process evaluation of a pilot study was undertaken using qualitative description. A purposive sample (n = 15) of hospital foodservice supervisors and foodservice assistants responsible for delivering a higher energy menu to hospital patients participated in focus groups and semistructured interviews. Theoretical frameworks of behaviour underpinned the method. Content analysis elicited factors (sub-themes) influencing foodservice staff's capability, opportunity and motivation to provide the nutrition intervention. Thematic analysis (by two independent researchers) further explored factors (themes) related to the process of the intervention's implementation. RESULTS: Five key themes (and 15 sub-themes) explained factors effecting implementation of the nutrition intervention. Aspects of the foodservice environment and patients' resistance were barriers to implementation and perceived sustainability. Teamwork, problem solving, leadership and job satisfaction were enablers. There was an opportunity to optimise training and feedback. Characteristics of foodservice staff, including their: knowledge, beliefs and perceptions of diet, health and their job role, had the potential to influence their behaviours and decision making. CONCLUSIONS: A number of interacting factors influenced foodservice staff's delivery of a higher energy menu as planned. Addressing the challenges of time, foodservice structure, patients' resistance, gaps in knowledge and misconceptions among foodservice staff may enhance similar nutrition interventions in the future. PMID- 28731639 TI - Exploring family home food environments: Household resources needed to utilise weekly deliveries of free fruits and vegetables. AB - AIM: An adapted ethnographic approach was used to explore household factors that influence family fruit and vegetable consumption when access and cost barriers are removed. 'Structural' barriers, such as food affordability and accessibility, are likely to influence fruit and vegetable consumption in disadvantaged households, but households may require additional resources (human and social) to increase consumption. METHODS: Five low-income and five high-income households with children (N = 39 individuals) were observed in their home environment for three months. Including both advantaged and disadvantaged families allowed exploration of socioeconomic factors influencing these households. Each household received a free box of fresh fruit and vegetables each week for 10-12 weeks, delivered to their home, and were home-visited twice a week by a researcher (40+ hours per household). An inductive analysis of rich observational and discussion data revealed themes describing factors influencing household fruit and vegetable consumption. RESULTS: Household food cultures were dynamic and influenced by available resources. Even when free produce was delivered to homes, these households required human resource (personal drivers influenced by early life exposure and household dynamics) and external social networks to make use of them. When household finances and/or labour were limited, there was greater dependence on external organisations for tangible support. CONCLUSIONS: Even when structural barriers were removed, disadvantaged families needed a range of resources across the life course to improve eating behaviours, including sufficient, motivated and skilled labour and harmonious family relationships. Strategies targeting these households must consider structural, social, cultural and intra-familial influences on food choice. PMID- 28731640 TI - Are products sold in university vending machines nutritionally poor? A food environment audit. AB - AIM: (i) To audit the nutritional composition, promotion and cost of products available from vending machines available to young adults; and (ii) to examine the relationship between product availability and sales. METHODS: A cross sectional analysis of snacks and beverages available and purchased at a large urban university was conducted between March and September 2014. Sales were electronically tracked for nine months. RESULTS: A total of 61 vending machines were identified; 95% (n = 864) of the available snacks and 49% of beverages (n = 455) were less-healthy items. The mean (SD) nutrient value of snacks sold was: energy 1173 kJ (437.5), saturated fat 5.36 g (3.6), sodium 251 mg (219), fibre 1.56 g (1.29) and energy density 20.16 kJ/g (2.34) per portion vended. There was a strong correlation between the availability of food and beverages and purchases (R2 = 0.98, P < 0.001). CONCLUSIONS: Vending machines market and sell less healthy food and beverages to university students. Efforts to improve the nutritional quality are indicated and afford an opportunity to improve the diet quality of young adults, a group at risk of obesity. PMID- 28731641 TI - Macronutrient content and food exchanges for 48 Greek Mediterranean dishes. AB - AIM: The purpose of the present study was to facilitate the translation of traditional Greek Mediterranean recipes into food exchanges for diabetes. Moreover, it provides a useful food list for meal planning, which can be used by health professionals and nutritionists, as well as researchers and the public. METHODS: A total of 48 traditional Greek Mediterranean dishes were selected in order to include appetisers, sauces, salads, pies, dishes with vegetables and legumes as well as egg, pasta, rice, meat, fish and poultry-based dishes. The macronutrient content of each recipe (carbohydrate, fat, protein and dietary fibre) was estimated with the use of the USDA database and Greek food composition tables. Then, in order to calculate the food exchanges per serve, an approximation method was followed as suggested in the literature. RESULTS: The Mediterranean Greek dishes contain a considerable amount of vegetables and dietary fibre, and their energy content mainly derives from olive oil. For each serve, carbohydrate, non-starchy vegetable, protein (lean, medium or high fat), milk and fat exchanges are provided. Moreover, the type of fat that each recipe contains is reported. CONCLUSIONS: The presented data offer a chance for health professionals to efficiently plan Mediterranean-type meals, ensuring more sophisticated dietetic advice, higher standards of medical nutrition therapy and greater patient self-efficacy. PMID- 28731642 TI - Utility of a brief index to measure diet quality of Australian preschoolers in the Feeding Healthy Food to Kids Randomised Controlled Trial. AB - AIM: The aim was to evaluate the utility of a brief dietary intake assessment tool in measuring nutritional adequacy of preschoolers and differences in food and nutrient intake between quartiles stratified by overall diet quality. METHODS: Dietary intakes of preschoolers (n = 146) from the Feeding Healthy Food to Kids trial were reported by parents/caregivers using a 120-item food frequency questionnaire (FFQ). Diet quality was assessed using the Australian Recommended Food Score for Preschoolers. Analyses were performed using Kruskal-Wallis one-way analysis of variance, adjusted for Type 1 error. Participants were grouped into quartiles by total food score for comparison of subscale scores, food groups and nutrient intakes from the FFQ. RESULTS: Participants who scored less than the median total food score of 36 were more likely to have suboptimal micronutrient intakes. Median fruit (9 vs 5, P < 0.0001) and vegetable (14 vs 7, P < 0.0001) subscale scores for preschoolers in the highest quartile were significantly higher than the lowest quartile, indicating much greater fruit and vegetable variety. Statistically significant differences in diet quality score by quartiles (P < 0.05) were found for total energy and percentage energy from core foods, protein, fibre and 11 micronutrients. CONCLUSIONS: The Australian Recommended Food Score for Preschoolers is a practical brief diet quality assessment tool to measure food variety and nutritional adequacy in Australian preschoolers. Stratifying children by baseline diet quality in future nutrition interventions is recommended in order to identify those who are likely to benefit or require more targeted approaches to address specific nutritional needs in order to optimise food and nutrient intakes. PMID- 28731643 TI - Transcriptome-Based Identification of the Optimal Reference CHO Genes for Normalisation of qPCR Data. AB - Real-time quantitative PCR (qPCR) is the standard method for determination of relative changes in mRNA transcript abundance. Analytical accuracy, precision and reliability are critically dependent on the selection of internal control reference genes. In this study, the authors have identified optimal reference genes that can be utilised universally for qPCR analysis of CHO cell mRNAs. Initially, transcriptomic datasets were analysed to identify eight endogenous genes that exhibited high expression stability across four distinct CHO cell lines sampled in different culture phases. The relative transcript abundance of each gene in 20 diverse, commonly applied experimental conditions was then determined by qPCR analysis. Utilizing GeNorm, BestKeeper and NormFinder algorithms, the authors identified four mRNAs (Gnb1, Fkbp1a, Tmed2 and Mmadhc) that exhibited a highly stable level of expression across all conditions, validating their utility as universally applicable reference genes. Whilst any combination of only two genes can be generally used for normalisation of qPCR data, the authors show that specific combinations of reference genes are particularly suited to discrete experimental conditions. In summary, the authors report the identification of fully validated universal reference genes, optimised primer sequences robust to genomic mutations and simple reference gene pair selection guidelines that enable streamlined qPCR analyses of mRNA abundance in CHO cells with maximum accuracy and precision. PMID- 28731644 TI - Detection of a novel allele, HLA-A*24:198, by sequence-based typing in a Chinese individual. AB - HLA-A*24:198 has one nucleotide change from HLA-A*24:02:01 where aspartic acid (29) is changed to asparagine. PMID- 28731674 TI - [Leukemia cutis]. PMID- 28731676 TI - Enabling Efficient Creation of Long-Lived Charge-Separation on Dye-Sensitized NiO Photocathodes. AB - The hole-injection and recombination photophysics for NiO sensitized with RuP ([RuII(bpy)2(4,4'-(PO3H2)2-bpy)]2+) are explored. Ultrafast transient absorption (TA) measurements performed with an external electrochemical bias reveal the efficiency for productive hole-injection, that is, quenching of the dye excited state that results in a detectable charge-separated electron-hole pair, is linearly dependent on the electronic occupation of intragap states in the NiO film. Population of these states via a negative applied potential increases the efficiency from 0% to 100%. The results indicate the primary loss mechanism for dye-sensitized NiO is rapid nongeminate recombination enabled by the presence of latent holes in the surface of the NiO film. Our findings suggest a new design paradigm for NiO photocathodes and devices centered on the avoidance of this recombination pathway. PMID- 28731675 TI - Sustained Release of a Peptide-Based Matrix Metalloproteinase-2 Inhibitor to Attenuate Adverse Cardiac Remodeling and Improve Cardiac Function Following Myocardial Infarction. AB - Following myocardial infarction (MI), degradation of extracellular matrix (ECM) by upregulated matrix metalloproteinases (MMPs) especially MMP-2 decreases tissue mechanical properties, leading to cardiac function deterioration. Attenuation of cardiac ECM degradation at the early stage of MI has the potential to preserve tissue mechanical properties, resulting in cardiac function increase. Yet the strategy for efficiently preventing cardiac ECM degradation remains to be established. Current preclinical approaches have shown limited efficacy because of low drug dosage allocated to the heart tissue, dose-limiting side effects, and cardiac fibrosis. To address these limitations, we have developed a MMP-2 inhibitor delivery system that can be specifically delivered into infarcted hearts at early stage of MI to efficiently prevent MMP-2-mediated ECM degradation. The system was based on an injectable, degradable, fast gelation, and thermosensitive hydrogel, and a MMP-2 specific inhibitor, peptide CTTHWGFTLC (CTT). The use of fast gelation hydrogel allowed to completely retain CTT in the heart tissue. The system was able to release low molecular weight CTT over 4 weeks possibly due to the strong hydrogen bonding between the hydrogel and CTT. The release kinetics was modulated by amount of CTT loaded into the hydrogel, and using chondroitin sulfate and heparin that can interact with CTT and the hydrogel. Both glycosaminoglycans augmented CTT release, while heparin more greatly accelerated the release. After it was injected into the infarcted hearts for 4 weeks, the released CTT efficiently prevented cardiac ECM degradation as it not only increased tissue thickness but also preserved collagen composition similar to that in the normal heart tissue. In addition, the delivery system significantly improved cardiac function. Importantly, the delivery system did not induce cardiac fibrosis. These results demonstrate that the developed MMP-2 inhibitor delivery system has potential to efficiently reduce adverse myocardial remodeling and improve cardiac function. PMID- 28731677 TI - An Evaluation of Optimal PEGylation Strategies for Maximizing the Lymphatic Exposure and Antiviral Activity of Interferon after Subcutaneous Administration. AB - Interferon alpha2 is an antiviral/antiproliferative protein that is currently used to treat hepatitis C infections and several forms of cancer. Two PEGylated variants of interferon alpha2 (containing 12 and 40 kDa PEGs) are currently marketed and display longer plasma circulation times than that of unmodified interferon. With increasing realization that the lymphatic system plays an important role in the extrahepatic replication of the hepatitis C virus and in the metastatic dissemination of cancers, this study sought to evaluate PEGylation strategies to optimally enhance the antiviral activity and plasma and lymphatic exposure of interferon after subcutaneous administration in rats. The results showed that conjugation with a linear 20 kDa PEG provided the most ideal balance between activity and plasma and lymph exposure. A linear 5 kDa PEG variant also exhibited excellent plasma and lymph exposure to interferon activity when compared to those of unmodified interferon and the clinically available linear 12 kDa PEGylated construct. PMID- 28731678 TI - Stable and Efficient CuO Based Photocathode through Oxygen-Rich Composition and Au-Pd Nanostructure Incorporation for Solar-Hydrogen Production. AB - Enhancing stability against photocorrosion and improving photocurrent response are the main challenges toward the development of cupric oxide (CuO) based photocathodes for solar-driven hydrogen production. In this paper, stable and efficient CuO-photocathodes have been developed using in situ materials engineering and through gold-palladium (Au-Pd) nanoparticles deposition on the CuO surface. The CuO photocathode exhibits a photocurrent generation of ~3 mA/cm2 at 0 V v/s RHE. Time-of-flight secondary ion mass spectrometry (TOF-SIMS) analysis and X-ray spectroscopy (XPS) confirm the formation of oxygen-rich (O rich) CuO film which demonstrates a highly stable photocathode with retained photocurrent of ~90% for 20 min. The influence of chemical composition on the photocathode performance and stability has been discussed in detail. In addition, O-rich CuO photocathodes deposited with Au-Pd nanostructures have shown enhanced photoelectrochemical performance. Linear scan voltammetry characteristic shows ~25% enhancement in photocurrent after Au-Pd deposition and reaches ~4 mA/cm2 at "0" V v/s RHE. Hydrogen evolution rate significantly depends on the elemental composition of CuO and metal nanostructure. The present work has demonstrated a stable photocathode with high photocurrent for visible-light-driven water splitting and hydrogen production. PMID- 28731679 TI - Binding of Bacteria to Poly(N-isopropylacrylamide) Modified with Vancomycin: Comparison of Behavior of Linear and Highly Branched Polymers. AB - The behavior of a linear copolymer of N-isopropylacrylamide with pendant vancomycin functionality was compared to an analogous highly branched copolymer with vancomycin functionality at the chain ends. Highly branched poly(N isopropylacrylamide) modified with vancomycin (HB-PNIPAM-van) was synthesized by functionalization of the HB-PNIPAM, prepared using reversible addition fragmentation chain transfer polymerization. Linear PNIPAM with pendant vancomycin functionality (L-PNIPAM-van) was synthesized by functionalization of poly(N-isopropylacrylamide-co-vinyl benzoic acid). HB-PNIPAM-van aggregated S. aureus effectively, whereas the L-PNIPAM-van polymer did not. It was found that when the HB-PNIPAM-van was incubated with S. aureus the resultant phase transition provided an increase in the intensity of fluorescence of a solvatochromic dye, nile red, added to the system. In contrast, a significantly lower increase in fluorescence intensity was obtained when L-PNIPAM-van was incubated with S. aureus. These data showed that the degree of desolvation of HB PNIPAM-van was much greater than the desolvation of the linear version. Using microcalorimetry, it was shown that there were no significant differences in the affinities of the polymer ligands for d-Ala-d-Ala and therefore differences in the interactions with bacteria were associated with changes in the probability of access of the polymer bound ligands to the d-Ala-d-Ala dipeptide. The data support the hypothesis that generation of polymer systems that respond to cellular targets, for applications such as cell targeting, detection of pathogens etc., requires the use of branched polymers with ligands situated at the chain ends. PMID- 28731680 TI - Nitrilotriacetic Amine-Functionalized Polymeric Core-Shell Nanoparticles as Enzyme Immobilization Supports. AB - Nitrilotriacetic amine (NTA)-functionalized nanoparticles obtained by aqueous polymerization-induced self-assembly (PISA) are introduced as immobilization supports for polyhistidine-functionalized (His-tagged) enzymes. A novel initiator for nitroxide-mediated polymerization based on the nitroxide SG1 and carrying a protected NTA moiety was first synthesized. Size-exclusion chromatography (SEC) and electrospray ionization mass spectrometry (ESI-MS) proved the ability of this initiator to produce well-defined end-functional vinyl polymers. Subsequently, oligo(ethylene glycol) methacrylate-based macroinitiators were synthesized and chain-extended to form amphiphilic block copolymer nanoparticles, either by nanoprecipitation or by PISA. The latter method yielded spherical nanoparticles with a higher definition, as demonstrated by dynamic light scattering (DLS). Deprotection of the NTA moiety and complexation with nickel ions were assessed by DLS and inductively coupled plasma optical emission spectroscopy/mass spectrometry (ICP-OES/MS). Finally, immobilization of His-tagged horseradish peroxidase and ester hydrolase were successfully carried out, leading to catalytically active nanobiocatalysts, as shown by UV-vis measurements. PMID- 28731681 TI - First N-Borylated Emitters Displaying Highly Efficient Thermally Activated Delayed Fluorescence and High-Performance OLEDs. AB - Despite the fast boom of thermally activated delayed fluorescence (TADF) emitters bearing borane-based acceptor, so far, no TADF emitter with a direct B-N linkage between N-donor and boryl acceptor has been reported. The latter should simplify the molecular architecture and hence facilitate the synthetic design and versatility. We report here the preparation and characterization of a new series of N-borylated compounds with functional acridine donor unit; namely: ACBM, PACBM, and SACBM. Spectroscopic studies were performed to explore their photophysical properties that exhibited prominent solvatochromism and thermally activated delayed fluorescence. The time-dependent DFT calculation indicated the involvement of substantial intramolecular charge transfer character for which HOMO and LUMO are spatially separated. For compound SACBM, fabrication of green emitting OLED gave CIE chromaticity of (0.22, 0.59) and maximum external quantum efficiency, luminance efficiency and power efficiency of 19.1%, 60.9 cd/A, and 43.6 lm/W, respectively, demonstrating for the first time the highly efficient OLEDs using N-borylated TADF emitters. PMID- 28731682 TI - Cold Adaptation of Triosephosphate Isomerase. AB - The main problem for enzymes from psychrophilic species, which need to work near the freezing point of liquid water, is the exponential decay of reaction rates as the temperature is decreased. Cold-adapted enzymes have solved this problem by shifting the activation enthalpy-entropy balance for the catalyzed reaction compared to those of their mesophilic orthologs. To understand the structural basis of this universal feature, it is necessary to examine pairs of such orthologous enzymes, with known three-dimensional structures, at the microscopic level. Here, we use molecular dynamics free energy calculations in combination with the empirical valence bond method to evaluate the temperature dependence of the activation free energy for differently adapted triosephosphate isomerases. The results show that the enzyme from the psychrophilic bacterium Vibrio marinus indeed displays the characteristic shift in enthalpy-entropy balance, compared to that of the yeast ortholog. The origin of this effect is found to be located in a few surface-exposed protein loops that show differential mobilities in the two enzymes. Key mutations render these loops more mobile in the cold-adapted triosephosphate isomerase, which explains both the reduced activation enthalpy contribution from the protein surface and the lower thermostability. PMID- 28731683 TI - Synthesis and Optical Properties of [Cu6E6(SnPh)2(PPh2Et)6] (E = S, Se, Te) Cluster Molecules. AB - A homologous series of three copper-tin-chalcogenide cluster molecules [Cu6E6(SnPh)2(PPh2Et)6] (E = S, Se, Te) was synthesized by reactions of CuO(O)CCH3 and PhSnCl3 with E(SiMe3)2 in the presence of PPh2Et. The cluster cage structures are similar, with slight differences in the bridging modes of the respective chalcogenide ligands E. The onset of the optical absorption displays a significant decrease of ca. 1.1 eV on going from sulfur to tellurium. The differences in bonding and electronic excitations can be rationalized by DFT and TDDFT calculations. All complexes display near-infrared phosphorescence at cryogenic temperatures. In parallel with the absorption, the emission maximum shifts to lower energies in a series of sulfur, selenium, and tellurium compounds. In particular, the copper-tin-tellurium complex emits at an energy as low as ca. 0.97 eV (1280 nm). PMID- 28731684 TI - The Binding Mode of N-Hydroxyamidines to Indoleamine 2,3-Dioxygenase 1 (IDO1). AB - Indoleamine 2,3-dioxygenase 1 (IDO1) is an important target in cancer immunotherapy. The most advanced clinical compound, epacadostat (INCB024360), binds to the heme cofactor of IDO1 through an N-hydroxyamidine function. Conflicting binding modes have recently been proposed, reporting iron binding either through the hydroxyamidine oxygen or through the hydroxyamidine nitrogen atom. Here, we use quantum chemical calculations, docking, and quantum mechanics/molecular mechanics calculations based on available X-ray data to resolve this issue and to propose a physically meaningful binding mode. Our findings will aid the design of novel IDO1 ligands based on this pharmacophore. PMID- 28731685 TI - Lipophilic Polycation Vehicles Display High Plasmid DNA Delivery to Multiple Cell Types. AB - A class of cationic poly(alkylamidoamine)s (PAAAs) containing lipophilic methylene linkers were designed and examined as in vitro plasmid DNA (pDNA) delivery agents. The PAAAs were synthesized via step-growth polymerization between a diamine monomer and each of four different diacid chloride monomers with varying methylene linker lengths, including glutaryl chloride, adipoyl chloride, pimeloyl chloride, and suberoyl chloride, which served to systematically increase the lipophilicity of the polymers. The synthesized polymers successfully complexed with pDNA in reduced serum medium at N/P ratios of 5 and greater, resulting in polyplexes with hydrodynamic diameters of approximately 1 MUm. These polyplexes were tested for in vitro transgene expression and cytotoxicity using HDFa (human dermal fibroblast), HeLa (human cervical carcinoma), HMEC (human mammary epithelial), and HUVEC (human umbilical vein endothelial) cells. Interestingly, select PAAA polyplex formulations were found to be more effective than Lipofectamine 2000 at promoting transgene expression (GFP) while maintaining comparable or higher cell viability. Transgene expression was highest in HeLa cells (~90% for most formulations) and lowest in HDFa cells (up to ~20%) as measured by GFP fluorescence. In addition, the cytotoxicity of PAAA polyplex formulations was significantly increased as the molecular weight, N/P ratio, and methylene linker length were increased. The PAAA vehicles developed herein provide a new delivery vehicle design strategy of displaying attributes of both polycations and lipids, which show promise as a tunable scaffold for refining the structure-activity-toxicity profiles for future genome editing studies. PMID- 28731686 TI - Pyrethroid Insecticide Cypermethrin Accelerates Pubertal Onset in Male Mice via Disrupting Hypothalamic-Pituitary-Gonadal Axis. AB - Pyrethroids, a class of insecticides that are widely used worldwide, have been identified as endocrine-disrupting chemicals (EDCs). Our recent epidemiological study reported on an association of increased pyrethroids exposure with elevated gonadotropins levels and earlier pubertal development in Chinese boys. In this study, we further investigated the effects of cypermethrin (CP), one of the most ubiquitous pyrethroid insecticides, on hypothalamic-pituitary-gonadal (HPG) axis and pubertal onset in male animal models. Early postnatal exposure to CP at environmentally relevant doses (0.5, 5, and 50 MUg/kg CP) significantly accelerated the age of puberty onset in male mice. Administration of CP induced a dose-dependent increase in serum levels of luteinizing hormone (LH), follicle stimulating hormone (FSH) and testosterone in male mice. CP did not affect gonadotropin-releasing hormone (GnRH) gene expression in the hypothalamus, but CP at higher concentrations stimulated GnRH pulse frequency. CP could induce the secretion of LH and FSH, as well as the expression of gonadotropin subunit genes [chorionic gonadotropin alpha (CGalpha), LHbeta, and FSHbeta] in pituitary gonadotropes. CP stimulated testosterone production and the expression of steroidogenesis-related genes [steroidogenic acute regulatory (StAR) and Cytochrome p 450, family 11, subfamily A, polypeptide 1 (CYP11A1)] in testicular Leydig cells. The interference with hypothalamic sodium channels as well as calcium channels in pituitary gonadotropes and testicular Leydig cells was responsible for CP-induced HPG axis maturation. Our findings established in animal models provide further evidence for the biological plausibility of pyrethroid exposure as a potentially environmental contributor to earlier puberty in males. PMID- 28731687 TI - Intramolecular C-H and C-F Bond Oxygenation by Site-Differentiated Tetranuclear Manganese Models of the OEC. AB - The dangler manganese center in the oxygen-evolving complex (OEC) of photosystem II plays an important role in the oxidation of water to dioxygen. Inspired by the structure of the OEC, we synthesized a series of site-differentiated tetra manganese clusters [LMn3(PhPz)3OMn][OTf]x (2: x = 2; 3: x = 1) that features an apical manganese ion-distinct from the others-that is appended to a trinuclear manganese core through an MU4-oxygen atom bridge. This cluster design was targeted to facilitate studies of high-valent Mn-oxo formation, which is a proposed step in the mechanism for water oxidation by the OEC. Terminal Mn-oxo species-supported by a multinuclear motif-were targeted by treating 2 and 3 with iodosobenzene. Akin to our previously reported iron complexes, intramolecular arene hydroxylation was observed to yield the C-H bond oxygenated complexes [LMn3(PhPz)2(OArPz)OMn][OTf]x (5: x = 2; 6: x = 1). The fluorinated series [LMn3(F2ArPz)3OMn][OTf]x (8: x = 2; 9: x = 1) was also synthesized to mitigate the observed intramolecular hydroxylation. Treatment of 8 and 9 with iodosobenzene results in intramolecular arene C-F bond oxygenation as judged by electrospray ionization mass spectrometry. The observed aromatic C-H and C-F hydroxylation is suggestive of a putative high-valent terminal metal-oxo species, and it is one of the very few examples capable of oxygenating C-F bonds. PMID- 28731688 TI - The pi Configuration of the WWW Motif of a Short Trp-Rich Peptide Is Critical for Targeting Bacterial Membranes, Disrupting Preformed Biofilms, and Killing Methicillin-Resistant Staphylococcus aureus. AB - Tryptophan-rich peptides, being short and suitable for large-scale chemical synthesis, are attractive candidates for developing a new generation of antimicrobials to combat antibiotic-resistant bacteria (superbugs). Although there are numerous pictures of the membrane-bound structure of a single tryptophan (W), how multiple Trp amino acids assemble themselves and interact with bacterial membranes is poorly understood. This communication presents the three-dimensional structure of an eight-residue Trp-rich peptide (WWWLRKIW-NH2 with 50% W) determined by the improved two-dimensional nuclear magnetic resonance method, which includes the measurements of 13C and 15N chemical shifts at natural abundance. This peptide forms the shortest two-turn helix with a distinct amphipathic feature. A unique structural arrangement is identified for the Trp triplet, WWW, that forms a pi configuration with W2 as the horizontal bar and W1/W3 forming the two legs. An arginine scan reveals that the WWW motif is essential for killing methicillin-resistant Staphylococcus aureus USA300 and disrupting preformed bacterial biofilms. This unique pi configuration for the WWW motif is stabilized by aromatic-aromatic interactions as evidenced by ring current shifts as well as nuclear Overhauser effects. Because the WWW motif is maintained, a change of I7 to R led to a potent antimicrobial and antibiofilm peptide with 4-fold improvement in cell selectivity. Collectively, this study elucidated the structural basis of antibiofilm activity of the peptide, identified a better peptide candidate via structure-activity relationship studies, and laid the foundation for engineering future antibiotics based on the WWW motif. PMID- 28731689 TI - Dinuclear Coordination Compounds Based on a 5-Nitropicolinic Carboxylate Ligand with Single-Molecule Magnet Behavior. AB - Isostructural dinuclear dysprosium and yttrium coordination compounds based on the 5-nitropicolinic carboxylate ligand were synthesized and characterized. The formation of these air-stable complexes is achieved via solvothermal routes employing water as the reaction solvent. The dysprosium-based complex exhibits single-molecule magnet behavior with frequency dependence of the out-of-phase susceptibility at zero direct-current field. High-resolution mass spectrometry (electrospray ionization) experiments and advanced NMR methods including diffusion NMR techniques were applied on the diamagnetic yttrium analogue and established that these species retained their solid-state structure in solution with hydrodynamic radii of 6.5 A. Full 1H, 13C, 15N, 89Y, Delta1Hcoord, Delta13Ccoord, and Delta15Ncoord NMR data are given, and through the analysis of the Ramsey equation, the first electronic insights of these derivatives are provided. PMID- 28731691 TI - Singlet Oxygen Photophysics in Liquid Solvents: Converging on a Unified Picture. AB - Singlet oxygen, O2(a1Deltag), the lowest excited electronic state of molecular oxygen, is an omnipresent part of life on earth. It is readily formed through a variety of chemical and photochemical processes, and its unique reactions are important not just as a tool in chemical syntheses but also in processes that range from polymer degradation to signaling in biological cells. For these reasons, O2(a1Deltag) has been the subject of intense activity in a broad distribution of scientific fields for the past ~50 years. The characteristic reactions of O2(a1Deltag) kinetically compete with processes that deactivate this excited state to the ground state of oxygen, O2(X3Sigmag-). Moreover, O2(a1Deltag) is ideally monitored using one of these deactivation channels: O2(a1Deltag) -> O2(X3Sigmag-) phosphorescence at 1270 nm. Thus, there is ample justification to study and control these competing processes, including those mediated by solvents, and the chemistry community has likewise actively tackled this issue. In themselves, the solvent-mediated radiative and nonradiative transitions between the three lowest-lying electronic states of oxygen [O2(X3Sigmag-), O2(a1Deltag), and O2(b1Sigmag+)] are relevant to issues at the core of modern chemistry. In the isolated oxygen molecule, these transitions are forbidden by quantum-mechanical selection rules. However, solvent molecules perturb oxygen in such a way as to make these transitions more probable. Most interestingly, the effect of a series of solvents on the O2(X3Sigmag-) O2(b1Sigmag+) transition, for example, can be totally different from the effect of the same series of solvents on the O2(X3Sigmag-)-O2(a1Deltag) transition. Moreover, a given solvent that appreciably increases the probability of a radiative transition generally does not provide a correspondingly viable pathway for nonradiative energy loss, and vice versa. The ~50 years of experimental work leading to these conclusions were not easy; spectroscopically monitoring such weak and low-energy transitions in time-resolved experiments is challenging. Consequently, results obtained from different laboratories often were not consistent. In turn, attempts to interpret molecular events were often simplistic and/or misguided. However, over the recent past, increasingly accurate experiments have converged on a base of credible data, finally forming a consistent picture of this system that is resonant with theoretical models. The concepts involved encompass a large fraction of chemistry's fundamental lexicon, e.g., spin-orbit coupling, state mixing, quantum tunneling, electronic-to vibrational energy transfer, activation barriers, collision complexes, and charge transfer interactions. In this Account, we provide an explanatory overview of the ways in which a given solvent will perturb the radiative and nonradiative transitions between the O2(X3Sigmag-), O2(a1Deltag), and O2(b1Sigmag+) states. PMID- 28731692 TI - Quinolinyl Nitrone RP19 Induces Neuroprotection after Transient Brain Ischemia. AB - There is a need to develop additional effective therapies for ischemic stroke. Nitrones, which were first developed as reactive oxygen species (ROS)-trapping compounds, have been proposed as neuroprotective agents for ischemic stroke, a ROS-related disorder. The previous reported ROS-trapping compound, quinolyl nitrone RP19, is here being assayed to induce neuroprotection to ischemia reperfusion injury in three experimental ischemia models: (i) oxygen-glucose deprivation (OGD) on primary neuronal cultures; (ii) transient global cerebral ischemia in four-vessel occlusion model; and (iii) transient focal cerebral ischemia in middle cerebral artery occlusion (tMCAO) model. RP19 (50 MUM) induced long-term neuroprotection at 5 days of recovery after OGD in primary neuronal cultures, evaluated by cell viability assay, and decreased both ROS formation and lipid peroxidation upon recovery after OGD. Furthermore, treatment of animals with RP19 at the onset of reperfusion after either global or focal ischemia, at the dose range that was demonstrated to be neuroprotective in neuronal cultures, decreased neuronal death and apoptosis induction, reduced the size of infarct, and improved the neurological deficit scores after 48 h or 5 days of reperfusion after ischemia. The molecule proposed, quinolyl nitrone RP19, induced substantial neuroprotection on experimental ischemia in neuronal cells, and against ischemic injury following transient brain ischemia in treated animals. This molecule may have potential therapeutic interest in ischemic stroke and to reduce the reoxygenation-induced injury after induced reperfusion. PMID- 28731693 TI - Isolable Bis(triarylamine) Dications: Analogues of Thiele's, Chichibabin's, and Muller's Hydrocarbons. AB - Since the pioneering work by Thiele and Chichibabin, who synthesized the first diradicals bridged by phenylene and biphenylene groups in 1904 and 1907, respectively, numerous efforts have been devoted to synthesizing stable diradicals during the last few decades, and several strategies have been developed to stabilize these highly reactive diradicals. In this Account, we describe the synthesis and characterization of isolable bis(triarylamine) dications, nitrogen analogues of Thiele's, Chichibabin's, and Muller's hydrocarbons, which represent facilely accessible, stable diradicals by replacing carbinyl centers with isoelectronic aminium centers. Along with discussing the molecular structures and electronic structures of the isolated bis(triarylamine) dications, their spectroscopic and magnetic properties are also introduced. Since 2011, we have reported the stabilization of a variety of radical cations bearing the weakly coordinating anion Al(ORF)4- (RF = polyfluorinated alkyl group), which we have recently successfully applied for the stabilization and crystallization of bis(triarylamine) dications, analogues of Thiele's, Chichibabin's, and Muller's hydrocarbons. Prior to our and Kamada's work, there have been only three stable bis(triarylamine) dications isolated in the solid state. The facile access of bis(triarylamine) dications in their crystalline forms allowed us to pursue a deep investigation of their solid-state structures, electronic structures, and physical properties. Similar to their hydrocarbon analogues, bis(triarylamine) dications possess characteristic resonance structures between open-shell singlet (OS) diradicals and closed-shell (CS) quinoidal forms. The combination of single crystal X-ray diffraction (XRD) analysis and density functional theory (DFT) calculations has proved to be a robust strategy to gain a better understanding of the electronic structures of the obtained diradicals. The structural parameters obtained from XRD analysis reflect the overall contribution of each resonance structure to the crystal structure. The comparison of the parameters from the crystal structures with those from DFT calculations for the pure electronic configurations (CS, OS, and triplet states) affords an overview of the ground state structures of the diradicals. To justify the "degree" of singlet diradical character, the diradical parameter y is applied, which is estimated by the occupancy of the lowest unoccupied natural orbital (LUNO) having antibonding nature (y = 0 for the closed-shell and y = 1 for the pure singlet diradical). In addition, magnetic susceptibility measurements serve as a practical experimental method to determine the singlet-triplet energy gaps of the isolable diradical dications. Through detailed studies on isolable bis(triarylamine) dications, magnetic bistability caused by intramolecular electron-exchange interactions was observed. Moreover, we also found that the singlet-triplet energy gaps of the diradicals could be thermally controlled. These investigations highlight the potential of bis(triarylamine) dications as building blocks for functional materials. PMID- 28731690 TI - The Metal Drives the Chemistry: Dual Functions of Acireductone Dioxygenase. AB - Acireductone dioxygenase (ARD) from the methionine salvage pathway (MSP) is a unique enzyme that exhibits dual chemistry determined solely by the identity of the divalent transition-metal ion (Fe2+ or Ni2+) in the active site. The Fe2+ containing isozyme catalyzes the on-pathway reaction using substrates 1,2 dihydroxy-3-keto-5-methylthiopent-1-ene (acireductone) and dioxygen to generate formate and the ketoacid precursor of methionine, 2-keto-4-methylthiobutyrate, whereas the Ni2+-containing isozyme catalyzes an off-pathway shunt with the same substrates, generating methylthiopropionate, carbon monoxide, and formate. The dual chemistry of ARD was originally discovered in the bacterium Klebsiella oxytoca, but it has recently been shown that mammalian ARD enzymes (mouse and human) are also capable of catalyzing metal-dependent dual chemistry in vitro. This is particularly interesting, since carbon monoxide, one of the products of off-pathway reaction, has been identified as an antiapoptotic molecule in mammals. In addition, several biochemical and genetic studies have indicated an inhibitory role of human ARD in cancer. This comprehensive review describes the biochemical and structural characterization of the ARD family, the proposed experimental and theoretical approaches to establishing mechanisms for the dual chemistry, insights into the mechanism based on comparison with structurally and functionally similar enzymes, and the applications of this research to the field of artificial metalloenzymes and synthetic biology. PMID- 28731694 TI - Foliar Desiccators Glyphosate, Carfentrazone, and Paraquat Affect the Technological and Chemical Properties of Cowpea Grains. AB - The effects of the use of glyphosate (GLY), glyphosate plus carfentrazone (GLY/CAR), and paraquat (PAR) as plant desiccators on the technological and chemical properties of cowpea grains were investigated. All studied desiccants provided lower cooking time to freshly harvested cowpea. However, the coat color of PAR- and GLY/CAR-treated cowpea was reddish in comparison to the control treatment. Principal component analysis (PCA) from liquid chromatography-mass spectrometry (LC-MS) data sets showed a clear distinction among cowpea from the different treatments. Catechin-3-glucoside and epicatechin significantly contributed for discriminating GLY-treated cowpea, while citric acid was responsible for discriminating GLY/CAR-treated cowpea. Quercetin derivative and gluconic acid were responsible for discriminating control treatment. Residual glyphosate and paraquat content was higher than the maximum limits allowed by Codex Alimentarius and the European Union Commission. Improvements in the technological and chemical properties of cowpea may not be overlapped by the risks that those desiccants exhibit when exceeding the maximum limits of tolerance in food. PMID- 28731695 TI - How Rhodopsin Tunes the Equilibrium between Protonated and Deprotonated Forms of the Retinal Chromophore. AB - Rhodopsin is a photoactive G-protein-coupled receptor (GPCR) that converts dim light into a signal for the brain, leading to eyesight. Full activation of this GPCR is achieved after passing through several steps of the protein's photoactivation pathway. Key events of rhodopsin activation are the initial cis trans photoisomerization of the covalently bound retinal moiety followed by conformational rearrangements and deprotonation of the chromophore's protonated Schiff base (PSB), which ultimately lead to full activation in the meta II state. PSB deprotonation is crucial for achieving full activation of rhodopsin; however, the specific structural rearrangements that have to take place to induce this pKa shift are not well understood. Classical molecular dynamics (MD) simulations were employed to identify intermediate states after the cis-trans isomerization of rhodopsin's retinal moiety. In order to select the intermediate state in which PSB deprotonation is experimentally known to occur, the validity of the intermediate configurations was checked through an evaluation of the optical properties in comparison with experiment. Subsequently, the selected state was used to investigate the molecular factors that enable PSB deprotonation at body temperature to obtain a better understanding of the difference between the protonated and the deprotonated state of the chromophore. To this end, the deprotonation reaction has been investigated by applying QM/MM MD simulations in combination with thermodynamic integration. The study shows that, compared to the inactive 11-cis-retinal case, trans-retinal rhodopsin is able to undergo PSB deprotonation due to a change in the conformation of the retinal and a consequent alteration in the hydrogen-bond (HB) network in which PSB and the counterion Glu113 are embedded. Besides the retinal moiety and Glu113, also two water molecules as well as Thr94 and Gly90 that are related to congenital night blindness are part of this essential HB network. PMID- 28731696 TI - Tuning Nonradiative Lifetimes via Molecular Aggregation. AB - We show that molecular aggregation can strongly influence the nonradiative decay (NRD) lifetime of an electronic excitation. As a demonstrative example, we consider a transition-dipole-dipole-interacting dimer whose monomers have harmonic potential energy surfaces (PESs). Depending on the position of the NRD channel (qnr), we find that the NRD lifetime (taunrdim) can exhibit a completely different dependence on the intermolecular-interaction strength. We observe that (i) for qnr near the Franck-Condon region, taunrdim increases with the interaction strength; (ii) for qnr near the minimum of the monomer excited PES, the intermolecular interaction has little influence on taunrdim; and (iii) for qnr near the classical turning point of the monomer nuclear dynamics, on the other side of the minimum, taunrdim decreases with the interaction strength. Our findings suggest design principles for molecular systems where a specific fluorescence quantum yield is desired. PMID- 28731697 TI - Total Synthesis of Bruceolline I. AB - The first total synthesis of the natural product bruceolline I, isolated in small quantities from the ethanol extract of Brucea mollis stems, was achieved in 29% yield over nine steps and with high enantiomeric purity (>98%). The key step of the process is the tandem gold-catalyzed rearrangement/Nazarov reaction of a propargylic acetate derivative. This synthesis provides a sufficient amount of synthesized bruceolline I for further bioassays. PMID- 28731698 TI - Regiocontrolled Electrosynthesis of [60]Fullerene Bisadducts: Photovoltaic Performance and Crystal Structures of C60 o-Quinodimethane Bisadducts. AB - C60 o-quinodimethane bisadducts [C60(QM)2] are promising electron acceptors for bulk heterojuction (BHJ) organic solar cells (OSCs). However, previous production of C60(QM)2 often resulted in excessive regioisomers, which were difficult to purify and might consequently obscure the structure-performance study of the organofullerene acceptors. Herein, the electrosynthesis of C60(QM)2 is reported. The reaction exhibits a strong regiocontrol with generation of fewer regioisomers. Pure regioisomers of cis-2, trans-3, and e C60(QM)2 are obtained, and the structures are solved with single-crystal X-ray diffraction. Interestingly, the cis-2 and trans-3 regioisomers exhibit better photovoltaic performance than the e regioisomer in the OSCs based on poly(3-hexylthiophene) (P3HT), which can be correlated with their structural difference. PMID- 28731700 TI - Nanomanipulation of Individual DNA Molecules Covered by Single-Layered Reduced Graphene Oxide Sheets on a Solid Substrate. AB - Nanomanipulation of single DNA molecules has great potential in fundamental genetic research and clinical analysis, and is a good model system for studying the interfacial effects on physiochemical processes, which occur when manipulating the linear DNA molecules with an atomic force microscope (AFM) tip. Here, we demonstrate that AFM nanomanipulation can be carried out on DNA molecules covered by a single-layered reduced graphene oxide sheet. Nanomanipulation, which includes cutting, pushing, and sweeping operations, specific to the covered DNA molecules can be achieved in a well-controlled manner using AFM in the PeakForce Quantitative Nano-Mechanics mode. It was found that the normal force required to cut covered DNA strands is over five times greater than that required for naked strands. This technique provides a distinctive method for the construction of graphene architecture by tailoring the underlying artificial DNA nanostructures. PMID- 28731701 TI - Model for the Enantioselectivity of Asymmetric Intramolecular Alkylations by Bis Quaternized Cinchona Alkaloid-Derived Catalysts. AB - A model for the stereoselectivity of intramolecular alkylations by N,N' disubstituted cinchona alkaloids reported by Xiang et al. was established using density functional theory (DFT) calculations. The stereocontrol is based on the minimal distortion of the transition state (TS) and catalyst required to achieve favorable electrostatic interactions in the favored TS. Counterions must be included in computational modeling of ion-paired catalysis in order to reproduce experimental enantioselectivity. PMID- 28731703 TI - Natural Poly- and Oligosaccharides as Novel Delivery Systems for Plant Protection Compounds. AB - To increase the bioavailability of plant protection products, we have applied a new approach based on noncovalent association with natural water-soluble polysaccharides and oligosaccharides as delivery systems (DSs). The mechanochemical technique has been applied to prepare the solid-state nanodispersed compositions of antidote 1,8-naphthalic anhydride (NA) with arabinogalactan, sodium salt of carboxymethylcellulose, and glycyrrhizin as DSs. The effect of DSs on the solubility and the penetration of NA into the seeds of barley and wheat has been investigated by various physicochemical techniques. All DSs considerably enhance the solubility of NA and improve its penetration into the grain. The influence of polysaccharides and oligosaccharides on artificial lipid membranes was studied by the NMR relaxation method. It was concluded that the effect of polysaccharides and oligosaccharides on the penetration efficacy of plant protection products might be associated with the detected solubility enhancement and the affinity of DSs to the surface of cell membranes. PMID- 28731704 TI - Preparation of Spiro[indene-1,1'-isoindolin]-3'-ones via Sulfuric Acid-Promoted Cascade Cyclization. AB - The sulfuric acid-promoted cascade cyclization of 2-(3-hydroxyprop-1 ynyl)benzonitriles led to an efficient synthesis of spiro[indene-1,1'-isoindolin] 3'-ones. This class of spiro compounds could also be prepared by the sulfuric acid-catalyzed cyclization of 2-(phenylacryloyl)benzonitriles, which were readily derived from 2-(3-hydroxyprop-1-ynyl)benzamides using trifluoroacetic acid as a catalyst. PMID- 28731702 TI - Drude Polarizable Force Field for Molecular Dynamics Simulations of Saturated and Unsaturated Zwitterionic Lipids. AB - Additive force fields are designed to account for induced electronic polarization in a mean-field average way, using effective empirical fixed charges. The limitation of this approximation is cause for serious concerns, particularly in the case of lipid membranes, where the molecular environment undergoes dramatic variations over microscopic length scales. A polarizable force field based on the classical Drude oscillator offers a practical and computationally efficient framework for an improved representation of electrostatic interactions in molecular simulations. Building on the first-generation Drude polarizable force field for the dipalmitoylphosphatidylcholine 1,2-dipalmitoyl-sn-glycero-3 phosphocholine (DPPC) molecule, the present effort was undertaken to improve this initial model and expand the force field to a wider range of phospholipid molecules. New lipids parametrized include dimyristoylphosphatidylcholine (DMPC), dilauroylphosphatidylcholine (DLPC), 1-palmitoyl-2-oleoyl-sn-glycero-3 phosphocholine (POPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), dipalmitoylphosphatidylethanolamine (DPPE), 1-palmitoyl-2-oleoyl-sn-glycero-3 phosphoethanolamine (POPE), and 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE). The iterative optimization protocol employed in this effort led to lipid models that achieve a good balance between reproducing quantum mechanical data on model compound representative of phospholipids and reproducing a range of experimental condensed phase properties of bilayers. A parametrization strategy based on a restrained ensemble-maximum entropy methodology was used to help accurately match the experimental NMR order parameters in the polar headgroup region. All the parameters were developed to be compatible with the remainder of the Drude polarizable force field, which includes water, ions, proteins, DNA, and selected carbohydrates. PMID- 28731705 TI - Reversible Self-Assembly of Degradable Polymersomes with Upper Critical Solution Temperature in Water. AB - Temperature-induced self-assembly of block copolymers allows the formation of smart nanodimensional structures. Mostly, nondegradable lower critical solution temperature (LCST) segments are applied to prepare such dynamic aggregates. However, degradable upper critical phase separation (UCST) block copolymers that would allow the swelling or disassembly at elevated temperatures with eventual backbone hydrolysis have not been reported to date. We present the first well defined degradable poly(phosphonate)s with adjustable UCST. The organocatalytic anionic ring-opening copolymerization of 2-alkyl-2-oxo-1,3,2-dioxaphospholanes provided functional polymers with excellent control over molecular weight and copolymer composition. The prepolymers were turned into thermoresponsive polymers by thiol-ene modification to introduce pendant carboxylic acids. By this means, non cell-toxic, degradable polymers exhibiting UCST behavior in water between 43 and 71 degrees C were produced. Block copolymers with PEG as a nonresponsive water-soluble block can self-assemble into well-defined polymersomes with narrow size distribution. Depending on the responsive block, these structures either swell or disassemble completely upon an increased temperature. PMID- 28731706 TI - Automated Construction of Molecular Active Spaces from Atomic Valence Orbitals. AB - We introduce the atomic valence active space (AVAS), a simple and well-defined automated technique for constructing active orbital spaces for use in multiconfiguration and multireference (MR) electronic structure calculations. Concretely, the technique constructs active molecular orbitals capable of describing all relevant electronic configurations emerging from a targeted set of atomic valence orbitals (e.g., the metal d orbitals in a coordination complex). This is achieved via a linear transformation of the occupied and unoccupied orbital spaces from an easily obtainable single-reference wave function (such as from a Hartree-Fock or Kohn-Sham calculations) based on projectors to targeted atomic valence orbitals. We discuss the premises, theory, and implementation of the idea, and several of its variations are tested. To investigate the performance and accuracy, we calculate the excitation energies for various transition-metal complexes in typical application scenarios. Additionally, we follow the homolytic bond breaking process of a Fenton reaction along its reaction coordinate. While the described AVAS technique is not a universal solution to the active space problem, its premises are fulfilled in many application scenarios of transition-metal chemistry and bond dissociation processes. In these cases the technique makes MR calculations easier to execute, easier to reproduce by any user, and simplifies the determination of the appropriate size of the active space required for accurate results. PMID- 28731707 TI - Dynamic Effects of Biochar on the Bacterial Community Structure in Soil Contaminated with Polycyclic Aromatic Hydrocarbons. AB - Amending soil with biochar is an effective soil remediation strategy for organic contaminants. This study investigated the dynamic effects of wheat straw biochar on the bacterial community structure during remediation by high-throughput sequencing. The wheat straw biochar amended into the soil significantly reduced the bioavailability and toxicity of polycyclic aromatic hydrocarbons (PAHs). Biochar amendment helped to maintain the bacterial diversity in the PAH contaminated soil. The relationship between the immobilization of PAHs and the soil bacterial diversity fit a quadratic model. Before week 12 of the incubation, the incubation time was the main factor contributing to the changes in the soil bacterial community structure. However, biochar greatly affected the bacterial community structure after 12 weeks of amendment, and the effects were dependent upon the biochar type. Amendment with biochar mainly facilitated the growth of rare bacterial genera (relative abundance of 0.01-1%) in the studied soil. Therefore, the application of wheat straw biochar into PAH-contaminated soil can reduce the environmental risks of PAHs and benefit the soil microbial ecology. PMID- 28731708 TI - Argon Plasma Induced Phase Transition in Monolayer MoS2. AB - In this work, we report a facile, clean, controllable and scalable phase engineering technique for monolayer MoS2. We found that weak Ar-plasma bombardment can locally induce 2H->1T phase transition in monolayer MoS2 to form mosaic structures. These 2H->1T phase transitions are stabilized by point defects (single S-vacancies) and the sizes of induced 1T domains are typically a few nanometers, as revealed by scanning tunneling microscopy measurements. On the basis of a selected-area phase patterning process, we fabricated MoS2 FETs inducing 1T phase transition within the metal contact areas, which exhibit substantially improved device performances. Our results open up a new route for phase engineering in monolayer MoS2 and other transition metal dichalcogenide (TMD) materials. PMID- 28731709 TI - Agronomic Effectiveness of Granulated and Powdered P-Exchanged Mg-Al LDH Relative to Struvite and MAP. AB - Layered double hydroxides (LDHs) used to recover P from wastewater have recently been proposed as new slow-release fertilizers. Here, the use of P-exchanged Mg-Al LDHs as powdered or granulated fertilizer is explored and compared with monoammonium phosphate (MAP), a fully water-soluble fertilizer, and with struvite, a recycled phosphate fertilizer with lower solubility. First, these three fertilizers were compared in a 100-day incubation experiment using P diffusion visualization and chemical analysis to assess P release from either granules or powdered fertilizer in three different soils. By the end of the incubation, 74-90% of P remained within the LDH granule, confirming a slow release. Second, a pot experiment was performed with wheat (Triticum aestivum) in an acid and a calcareous soil. The granular treatment resulted in a considerably higher P uptake for MAP compared to LDH and struvite. For the powder treatments, the P uptake was less than for granular MAP and was largely unaffected by the chemical form. The LDHs and struvite showed a lower agronomic effectiveness than granular MAP, but the benefits of their use in P recycling, potential residual value, and environmental benefits may render these slow-release fertilizers attractive. PMID- 28731710 TI - Computational Calorimetry of PNIPAM Cononsolvency in Water/Methanol Mixtures. AB - We revisit the mechanism for cononsolvency of PNIPAM in water/methanol mixtures. Using extensive molecular dynamics simulations, we calculate the calorimetric enthalpy of the PNIPAM collapse transition and observe a unique fingerprint of PNIPAM cononsolvency which is analyzed in terms of microscopic interactions. We find that polymer hydration is the determining factor for PNIPAM collapse in the cononsolvency regime. In particular, it is shown that methanol frustrates the ability of water to form hydrogen bonds with the amide proton and therefore causes polymer collapse. PMID- 28731711 TI - Identification of Proteomic Features To Distinguish Benign Pulmonary Nodules from Lung Adenocarcinoma. AB - We hypothesized that distinct protein expression features of benign and malignant pulmonary nodules may reveal novel candidate biomarkers for the early detection of lung cancer. We performed proteome profiling by liquid chromatography-tandem mass spectrometry to characterize 34 resected benign lung nodules, 24 untreated lung adenocarcinomas (ADCs), and biopsies of bronchial epithelium. Group comparisons identified 65 proteins that differentiate nodules from ADCs and normal bronchial epithelium and 66 proteins that differentiate ADCs from nodules and normal bronchial epithelium. We developed a multiplexed parallel reaction monitoring (PRM) assay to quantify a subset of 43 of these candidate biomarkers in an independent cohort of 20 benign nodules, 21 ADCs, and 20 normal bronchial biopsies. PRM analyses confirmed significant nodule-specific abundance of 10 proteins including ALOX5, ALOX5AP, CCL19, CILP1, COL5A2, ITGB2, ITGAX, PTPRE, S100A12, and SLC2A3 and significant ADC-specific abundance of CEACAM6, CRABP2, LAD1, PLOD2, and TMEM110-MUSTN1. Immunohistochemistry analyses for seven selected proteins performed on an independent set of tissue microarrays confirmed nodule specific expression of ALOX5, ALOX5AP, ITGAX, and SLC2A3 and cancer-specific expression of CEACAM6. These studies illustrate the value of global and targeted proteomics in a systematic process to identify and qualify candidate biomarkers for noninvasive molecular diagnosis of lung cancer. PMID- 28731712 TI - Associated Lattice and Electronic Structural Evolutions in Compressed Multilayer ReS2. AB - The transition metal dichalcogenide (TMD) ReS2 is a promising material for optoelectronic devices because of its remarkable quantum yield. Pressure can effectively tune the optoelectronic properties of TMDs through control of the atomic displacement. Here, we systematically investigated the lattice and electronic structural evolutions of compressed multilayer ReS2. Both Raman spectra and first-principles calculations suggest the occurrence of an intralayer phase transition followed by an interlayer transition. A transition from one indirect to another indirect bandgap at 2.7 GPa was revealed by both high pressure photoluminescence (PL) measurements and first-principles calculations, this behavior was elucidated by considering the fundamental relationship between lattice variation and electronic evolution. Moreover, by comparing the high pressure behavior of MoS2 and ReS2, we demonstrated interlayer coupling plays a critical role in determining the lattice and electronic structures in compressed TMDs. Our findings suggest the potential application of ReS2 in fabricating various stacking devices with tailored properties. PMID- 28731713 TI - Revealing the Electrochemical Charging Mechanism of Nanosized Li2S by in Situ and Operando X-ray Absorption Spectroscopy. AB - Lithium sulfide (Li2S) is a promising cathode material for lithium-sulfur (Li/S) cells due to its high theoretical specific capacity (1166 mAh g-1) and ability to pair with nonmetallic lithium anodes to avoid potential safety issues. However, when used as the cathode, a high charging voltage (~4 V versus Li+/Li) is always necessary to activate Li2S in the first charge process, and the voltage profile becomes similar to that of a common sulfur electrode in the following charge processes. In this report, we have prepared an electrode of nanosphere Li2S particles and investigated its charging mechanism of the initial two charge processes by in situ and operando X-ray absorption spectroscopy. The results indicate that Li2S is directly converted to elemental sulfur through a two-phase transformation in the first charge process, while it is oxidized first to polysulfides and then to sulfur in the second charge process. The origin of the different charging mechanisms and corresponding charge-voltage profiles of the first and second charge processes is found to be related to the remaining polysulfides at the end of the first discharge process: they can not only facilitate the charge-transfer process at the Li2S/electrolyte interface but also chemically react with Li2S and act as the polysulfide facilitator for the electrochemical oxidation of Li2S in the following charge processes. Our present study provides a new fundamental understanding of the charging mechanism of the Li2S electrode, which should be of help for the further development of high performance Li/S cells. PMID- 28731714 TI - Total Synthesis and Structural Revision of Chaetoviridins A. AB - The first synthesis of the proposed structures of chaetoviridins A 1-4 has been achieved in 10 steps by controlling the syn- or anti-aldol side chain. The angular lactone has been regioselectively introduced by condensation of a chiral dioxin-4-one to cazisochromene. Comparison of the NMR and circular dichroism data of the synthesized and reported natural products led to the complete reassignment and renaming of the chaetoviridins. PMID- 28731715 TI - Tandem Oxidative Dearomatizing Spirocyclizations of Propargyl Guanidines and Ureas. AB - Treatment of propargyl ureas or guanidines with iodosobenzene diacetate results in an oxidative tandem amination/etherification dearomatizing spirocyclization. This transformation leads directly to the complete framework of the Leucetta alkaloids, spirocalcaridine A and B. PMID- 28731716 TI - The Inheritance Angle: A Determinant for the Number of Members in the Substituted Cucurbit[n]uril Family. AB - Two new glycoluril diethers have been prepared, bearing strained cyclobutene and cyclobutane rings at the fused junction of the two imidazolidinone rings. The wide angle of the concave face of the cyclobutano derivative enabled the synthesis of cyclobutanocucurbit[5-8]uril, the largest member being the most significant achievement. A limited binding affinity study compared the new substituted family to classical cucurbit[5-8]uril. Surprisingly lower affinities were found, except for cyclobutanocucurbit[6]uril, which was 3.3-fold higher. PMID- 28731717 TI - Hydrogen Bond Direction Enables Palladium-Catalyzed Branch- and Enantioselective Allylic Aminations and Beyond. AB - The palladium-catalyzed branch- and enantioselective allylic amination of vinyl benzoxazinones was accomplished through controlling the hydrogen bond direction. This protocol provides a rapid and efficient route for synthesizing an important building block, chiral amino alkene, from widely available aliphatic amines in 64 -> 99% yields with up to 99% ee. Furthermore, this transformation and the accompanying products were utilized to develop one-pot reactions through dual catalysis, affording chiral indolines with good synthetic efficiency and excellent enantiocontrol. PMID- 28731718 TI - Correction to "beta-Cyclodextrin Polymer Network Sequesters Perfluorooctanoic Acid at Environmentally Relevant Concentrations". PMID- 28731720 TI - Analytic Energy Gradients for Variational Two-Electron Reduced-Density-Matrix Driven Complete Active Space Self-Consistent Field Theory. AB - Analytic energy gradients are presented for a variational two-electron reduced density-matrix (2-RDM)-driven complete active space self-consistent field (CASSCF) method. The active-space 2-RDM is determined using a semidefinite programing (SDP) algorithm built upon an augmented Lagrangian formalism. Expressions for analytic gradients are simplified by the fact that the Lagrangian is stationary with respect to variations in both the primal and the dual solutions to the SDP problem. Orbital response contributions to the gradient are identical to those that arise in conventional CASSCF methods in which the electronic structure of the active space is described by a full configuration interaction (CI) wave function. We explore the relative performance of variational 2-RDM (v2RDM)- and CI-driven CASSCF for the equilibrium geometries of 20 small molecules. When enforcing two-particle N-representability conditions, full-valence v2RDM-CASSCF-optimized bond lengths display a mean unsigned error of 0.0060 A and a maximum unsigned error of 0.0265 A, relative to those obtained from full-valence CI-CASSCF. When enforcing partial three-particle N representability conditions, the mean and maximum unsigned errors are reduced to only 0.0006 and 0.0054 A, respectively. For these same molecules, full-valence v2RDM-CASSCF bond lengths computed in the cc-pVQZ basis set deviate from experimentally determined ones on average by 0.017 and 0.011 A when enforcing two and three-particle conditions, respectively, whereas CI-CASSCF displays an average deviation of 0.010 A. The v2RDM-CASSCF approach with two-particle conditions is also applied to the equilibrium geometry of pentacene; optimized bond lengths deviate from those derived from experiment, on average, by 0.015 A when using a cc-pVDZ basis set and a (22e,22o) active space. PMID- 28731719 TI - Discovery, Structure-Activity Relationship, and Binding Mode of an Imidazo[1,2 a]pyridine Series of Autotaxin Inhibitors. AB - Autotaxin (ATX) is a secreted enzyme playing a major role in the production of lysophosphatidic acid (LPA) in blood through hydrolysis of lysophosphatidyl choline (LPC). The ATX-LPA signaling axis arouses a high interest in the drug discovery industry as it has been implicated in several diseases including cancer, fibrotic diseases, and inflammation, among others. An imidazo[1,2 a]pyridine series of ATX inhibitors was identified out of a high-throughput screening (HTS). A cocrystal structure with one of these compounds and ATX revealed a novel binding mode with occupancy of the hydrophobic pocket and channel of ATX but no interaction with zinc ions of the catalytic site. Exploration of the structure-activity relationship led to compounds displaying high activity in biochemical and plasma assays, exemplified by compound 40. Compound 40 was also able to decrease the plasma LPA levels upon oral administration to rats. PMID- 28731721 TI - Enantioselective Synthesis of Spiro[indolizidine-1,3'-oxindoles]. AB - A three-step procedure for the enantioselective synthesis of spiro[indolizidine 1,3'-oxindoles], consisting of a stereoselective cyclocondensation reaction between (S)-tryptophanol and a prochiral or racemic delta-oxoester, bromination of the resulting oxazolopiperidone lactam, and a final stereoselective spirocyclization, is reported. PMID- 28731722 TI - Dynamically Reconfigurable Metadevice Employing Nanostructured Phase-Change Materials. AB - Mastering dynamic free-space spectral control and modulation in the near-infrared (NIR) and optical regimes remains a challenging task that is hindered by the available functional materials at high frequencies. In this work, we have realized an efficient metadevice capable of spectral control by minimizing the thermal mass of a vanadium dioxide phase-change material (PCM) and placing the PCM at the feed gap of a bow-tie field antenna. The device has an experimentally measured tuning range of up to 360 nm in the NIR and a modulation depth of 33% at the resonant wavelength. The metadevice is configured for integrated and local heating, leading to faster switching and more precise spatial control compared with devices based on phase-change thin films. We envisage that the combined advantages of this device will open new opportunities for signal processing, memory, security, and holography at optical frequencies. PMID- 28731724 TI - Concurrent Hydrogenation of Three Functional Groups Enables Synthesis of C3' Homologated Nucleoside Amino Acids. AB - Internucleoside amide linkages are excellent mimics of phosphodiesters in RNA and may be used to optimize the properties of short interfering RNAs. Herein we report a remarkably straightforward, efficient and step economic synthesis of C3' homologated uridine and adenosine amino acids starting from nucleosides in six steps (31% overall yield) and eight steps (16% overall yield), respectively. The key enabling step is a one-pot multifunctional group transformation including a stereoselective hydrogenation, termed "Global Hydrogenation". PMID- 28731723 TI - DFT-Assisted Polymorph Identification from Lattice Raman Fingerprinting. AB - A combined experimental and theoretical approach, consisting of lattice phonon Raman spectroscopy and density functional theory (DFT) calculations, is proposed as a tool for lattice dynamics characterization and polymorph phase identification. To illustrate the reliability of the method, the lattice phonon Raman spectra of two polymorphs of the molecule 2,7-dioctyloxy[1]benzothieno[3,2 b]benzothiophene are investigated. We show that DFT calculations of the lattice vibrations based on the known crystal structures, including many-body dispersion van der Waals (MBD-vdW) corrections, predict experimental data within an accuracy of ?5 cm-1 (?0.6 meV). Due to the high accuracy of the simulations, they can be used to unambiguously identify different polymorphs and to characterize the nature of the lattice vibrations and their relationship to the structural properties. More generally, this work implies that DFT-MBD-vdW is a promising method to describe also other physical properties that depend on lattice dynamics like charge transport. PMID- 28731725 TI - Skin and soft tissue infections, active component, U.S. Armed Forces, 2013-2016. AB - During the 4-year surveillance period, there were 282,571 incident cases of skin and soft tissue infection (SSTI) among active component U.S. military members diagnosed in inpatient or outpatient settings, corresponding to an overall incidence of 558.2 per 10,000 person-years (p-yrs). An additional 10,904 cases occurred in theater of operations (460.0 per 10,000 p-yrs). Approximately half (49.4%) were classified as "other SSTI" (e.g., folliculitis, impetigo); 45.9% were cellulitis/abscess; 4.6% were carbuncles/furuncles; and 0.1% were erysipelas. Annual incidence rates declined by 46.6% over the surveillance period. In general, higher rates of SSTIs were associated with younger age, recruit trainee status, and junior enlisted rank. During the surveillance period, 238,924 service members were treated for SSTIs in outpatient or inpatient settings, which accounted for 395,361 medical encounters and 19,213 hospital bed days. The history of operational significance of skin infections in the military, the high healthcare costs associated with evaluating and treating skin infections, and the risk of infections by antibiotic-resistant organisms highlight the importance of prevention, early diagnosis, and definitive treatment of skin infections, particularly in high-risk settings such as new recruit/basic training populations. PMID- 28731726 TI - Age-period-cohort analysis of colorectal cancer, service members aged 20-59 years, active component, U.S. Armed Forces, 1997-2016. AB - In the U.S. general population, incidence of colorectal cancer appears to be increasing in younger age groups since the mid-1980s. The objective of this report was to better understand the time-varying elements (age, period, and birth cohort effects) in the epidemiology of colorectal cancer among the active component of the U.S. Armed Forces. During 1997-2016, there were 1,108 incident cases of colorectal cancer among service members aged 20-59 years, corresponding to an overall incidence rate of 4.3 per 100,000 person-years (p-yrs). Rates were particularly high among men (4.4 per 100,000 p-yrs) and non- Hispanic black service members (5.3 per 100,000 p-yrs). Overall crude incidence of colorectal cancer increased in an exponential fashion with increasing age groups until the oldest age group (55-59 years), in which the increase was attenuated. No birth cohort or period effects were identified in the age-period-cohort analysis. This finding could be due to limited power, selection bias, better screening practices in the Military Health System (MHS) compared with the general population, or true lack of effects. Continued population-based screening for colorectal cancer in the MHS is recommended to maintain low and decreasing incidence in the U.S. Armed Forces. PMID- 28731727 TI - Incidence of gastrointestinal infections among U.S. active component service members stationed in the U.S. compared to U.S. civilians, 2012-2014. AB - Gastrointestinal (GI) infections in the U.S. Armed Forces have consistently been among the most frequent disease and non-battle injury diagnoses. A retrospective analysis of surveillance data categorized as GI infections among active component service members during 2012-2014 was performed. During the study period, 99% of inpatient and outpatient GI encounters were reported as nonspecific GI infection (13,331 cases per 100,000 people), leaving only a small percentage of cases attributed to specific causes. The five most common organisms associated with GI infections were Campylobacter (10.30 per 100,000 people), nontyphoidal Salmonella (7.43), Giardia (3.15), Shigella (2.11), and norovirus (1.25). The civilian population incidence rates of foodborne diseases during the same time period are significantly greater than incidence rates within the U.S. active component for all select bacterial and parasitic pathogens, except Campylobacter. Nonspecific gastroenteritis incidence increased during winter months, which is similar to the seasonal pattern for viruses such as norovirus. The preponderance of nonspecific infections highlights the need for increased testing and a more in-depth review of the impact of GI infections on operational effectiveness within the U.S. PMID- 28731728 TI - Brief report: Laboratory characterization of noroviruses identified in specimens from Military Health System beneficiaries during an outbreak in Germany, 2016 2017. PMID- 28731729 TI - Surveillance snapshot: Norovirus outbreaks among military forces, 2008-2016. PMID- 28731730 TI - Uhlmann Connection in Fermionic Systems Undergoing Phase Transitions. AB - We study the behavior of the Uhlmann connection in systems of fermions undergoing phase transitions. In particular, we analyze some of the paradigmatic cases of topological insulators and superconductors in one dimension, as well as the BCS theory of superconductivity in three dimensions. We show that the Uhlmann connection signals phase transitions in which the eigenbasis of the state of the system changes. Moreover, using the established fidelity approach and the study of the edge states, we show the absence of thermally driven phase transitions in the case of topological insulators and superconductors. We clarify what is the relevant parameter space associated with the Uhlmann connection so that it signals the existence of order in mixed states. In addition, the study of Majorana modes at finite temperature opens the possibility of applications in realistic stable quantum memories. Finally, the analysis of the different behavior of the BCS model and the Kitaev chain, with respect to the Uhlmann connection, suggested that in realistic scenarios the gap of topological superconductors could also, generically, be temperature dependent. PMID- 28731731 TI - Current-Driven Instability of the Quantum Anomalous Hall Effect in Ferromagnetic Topological Insulators. AB - The instability of the quantum anomalous Hall (QAH) effect has been studied as a function of the electric current and temperature in ferromagnetic topological insulator thin films. We find that a characteristic current for the breakdown of the QAH effect is roughly proportional to the Hall-bar width, indicating that the Hall electric field is relevant to the breakdown. We also find that electron transport is dominated by variable range hopping (VRH) at low temperatures. Combining the current and temperature dependences of the conductivity in the VRH regime, the localization length of the QAH state is evaluated to be about 5 MUm. The long localization length suggests a marginally insulating nature of the QAH state due to a large number of in-gap states. PMID- 28731732 TI - Observation of Flat Electron Temperature Profiles in the Lithium Tokamak Experiment. AB - It has been predicted for over a decade that low-recycling plasma-facing components in fusion devices would allow high edge temperatures and flat or nearly flat temperature profiles. In recent experiments with lithium wall coatings in the Lithium Tokamak Experiment (LTX), a hot edge (>200 eV) and flat electron temperature profiles have been measured following the termination of external fueling. Reduced recycling was demonstrated by retention of ~60% of the injected hydrogen in the walls following the discharge. Electron energy confinement followed typical Ohmic confinement scaling during fueling, but did not decrease with density after fueling terminated, ultimately exceeding the scaling by ~200%. Achievement of the low-recycling, hot edge regime has been an important goal of LTX and lithium plasma-facing component research in general, as it has potentially significant implications for the operation, design, and cost of fusion devices. PMID- 28731733 TI - Experimental Realization of Type-II Dirac Fermions in a PdTe_{2} Superconductor. AB - A Dirac fermion in a topological Dirac semimetal is a quadruple-degenerate quasiparticle state with a relativistic linear dispersion. Breaking either time reversal or inversion symmetry turns this system into a Weyl semimetal that hosts double-degenerate Weyl fermion states with opposite chiralities. These two kinds of quasiparticles, although described by a relativistic Dirac equation, do not necessarily obey Lorentz invariance, allowing the existence of so-called type-II fermions. The recent theoretical discovery of type-II Weyl fermions evokes the prediction of type-II Dirac fermions in PtSe_{2}-type transition metal dichalcogenides, expecting experimental confirmation. Here, we report an experimental realization of type-II Dirac fermions in PdTe_{2} by angle-resolved photoemission spectroscopy combined with ab initio band calculations. Our experimental finding shows the first example that has both superconductivity and type-II Dirac fermions, which turns the topological material research into a new phase. PMID- 28731734 TI - Determining Potentials of Zero Charge of Metal Electrodes versus the Standard Hydrogen Electrode from Density-Functional-Theory-Based Molecular Dynamics. AB - We develop a computationally efficient scheme to determine the potentials of zero charge (PZC) of metal-water interfaces with respect to the standard hydrogen electrode. We calculate the PZC of Pt(111), Au(111), Pd(111) and Ag(111) at a good accuracy using this scheme. Moreover, we find that the interface dipole potentials are almost entirely caused by charge transfer from water to the surfaces, the magnitude of which depends on the bonding strength between water and the metals, while water orientation hardly contributes at the PZC conditions. PMID- 28731735 TI - Critical Time Crystals in Dipolar Systems. AB - We analyze the quantum dynamics of periodically driven, disordered systems in the presence of long-range interactions. Focusing on the stability of discrete time crystalline (DTC) order in such systems, we use a perturbative procedure to evaluate its lifetime. For 3D systems with dipolar interactions, we show that the corresponding decay is parametrically slow, implying that robust, long-lived DTC order can be obtained. We further predict a sharp crossover from the stable DTC regime into a regime where DTC order is lost, reminiscent of a phase transition. These results are in good agreement with the recent experiments utilizing a dense, dipolar spin ensemble in diamond [Nature (London) 543, 221 (2017)NATUAS0028-083610.1038/nature21426]. They demonstrate the existence of a novel, critical DTC regime that is stabilized not by many-body localization but rather by slow, critical dynamics. Our analysis shows that the DTC response can be used as a sensitive probe of nonequilibrium quantum matter. PMID- 28731736 TI - Enhancing Entropy and Enthalpy Fluctuations to Drive Crystallization in Atomistic Simulations. AB - Crystallization is a process of great practical relevance in which rare but crucial fluctuations lead to the formation of a solid phase starting from the liquid. As in all first order first transitions, there is an interplay between enthalpy and entropy. Based on this idea, in order to drive crystallization in molecular simulations, we introduce two collective variables, one enthalpic and the other entropic. Defined in this way, these collective variables do not prejudge the structure into which the system is going to crystallize. We show the usefulness of this approach by studying the cases of sodium and aluminum that crystallize in the bcc and fcc crystalline structures, respectively. Using these two generic collective variables, we perform variationally enhanced sampling and well tempered metadynamics simulations and find that the systems transform spontaneously and reversibly between the liquid and the solid phases. PMID- 28731737 TI - Robust Single-Shot Spin Measurement with 99.5% Fidelity in a Quantum Dot Array. AB - We demonstrate a new method for projective single-shot measurement of two electron spin states (singlet versus triplet) in an array of gate-defined lateral quantum dots in GaAs. The measurement has very high fidelity and is robust with respect to electric and magnetic fluctuations in the environment. It exploits a long-lived metastable charge state, which increases both the contrast and the duration of the charge signal distinguishing the two measurement outcomes. This method allows us to evaluate the charge measurement error and the spin-to-charge conversion error separately. We specify conditions under which this method can be used, and project its general applicability to scalable quantum dot arrays in GaAs or silicon. PMID- 28731738 TI - Spin-Orbital Correlated Dynamics in the Spinel-Type Vanadium Oxide MnV_{2}O_{4}. AB - We investigate the magnetic dynamics in the spinel-type vanadium oxide MnV_{2}O_{4}. Inelastic neutron scattering around 10 meV and a Heisenberg model analysis have revealed that V^{3+} spin-wave modes exist at a lower-energy region than previously reported. The scattering around 20 meV cannot be reproduced with the spin-wave analysis. We propose that this scattering could originate from the spin-orbital coupled excitation. This scattering is most likely attributable to V^{3+} spin-wave modes, entangled with the orbital hybridization between t_{2g} orbitals. PMID- 28731739 TI - Prethermalization at Low Temperature: The Scent of Long-Range Order. AB - Nonequilibrium time evolution in isolated many-body quantum systems generally results in thermalization. However, the relaxation process can be very slow, and quasistationary nonthermal plateaux are often observed at intermediate times. The paradigmatic example is a quantum quench in an integrable model with weak integrability breaking; for a long time, the state cannot escape the constraints imposed by the approximate integrability. We unveil a new mechanism of prethermalization, based on the presence of a symmetry of the prequench Hamiltonian, which is spontaneously broken at zero temperature and is explicitly broken by the postquench Hamiltonian. The typical time scale of the phenomenon is proportional to the thermal correlation length of the initial state, which diverges as the temperature is lowered. We show that the prethermal quasistationary state can be approximated by a mixed state that violates cluster decomposition property. We consider two examples: the transverse-field Ising chain, where the full-time evolution is computed analytically, and the (nonintegrable) anisotropic next-nearest-neighbor Ising model, which is investigated numerically. PMID- 28731740 TI - Quasicontinuous-Variable Quantum Computation with Collective Spins in Multipath Interferometers. AB - Collective spins of large atomic samples trapped inside optical resonators can carry quantum information that can be processed in a way similar to quantum computation with continuous variables. It is shown here that by combining the resonators in multipath interferometers one can realize coupling between different samples, and that polynomial Hamiltonians can be constructed by repeated spin rotations and twisting induced by dispersive interaction of the atoms with light. Application can be expected in the efficient simulation of quantum systems. PMID- 28731741 TI - Nonlinear Conductivity and Collective Charge Excitations in the Lowest Landau Level. AB - For weakly disordered fractional quantum Hall phases, the nonlinear photoconductivity is related to the charge susceptibility of the clean system by a Floquet boost. Thus, it may be possible to probe collective charge modes at finite wave vectors by electrical transport. Incompressible phases, irradiated at slightly above the magnetoroton gap, are predicted to exhibit negative photoconductivity and zero resistance states with spontaneous internal electric fields. Nonlinear conductivity can probe composite fermions' charge excitations in compressible filling factors. PMID- 28731742 TI - Semiclassical "Divide-and-Conquer" Method for Spectroscopic Calculations of High Dimensional Molecular Systems. AB - A new semiclassical "divide-and-conquer" method is presented with the aim of demonstrating that quantum dynamics simulations of high dimensional molecular systems are doable. The method is first tested by calculating the quantum vibrational power spectra of water, methane, and benzene-three molecules of increasing dimensionality for which benchmark quantum results are available-and then applied to C_{60}, a system characterized by 174 vibrational degrees of freedom. Results show that the approach can accurately account for quantum anharmonicities, purely quantum features like overtones, and the removal of degeneracy when the molecular symmetry is broken. PMID- 28731743 TI - Nonadiabatic Kohn Anomaly in Heavily Boron-Doped Diamond. AB - We report evidence of a nonadiabatic Kohn anomaly in boron-doped diamond, using a joint theoretical and experimental analysis of the phonon dispersion relations. We demonstrate that standard calculations of phonons using density-functional perturbation theory are unable to reproduce the dispersion relations of the high energy phonons measured by high-resolution inelastic x-ray scattering. On the contrary, by taking into account nonadiabatic effects within a many-body field theoretic framework, we obtain excellent agreement with our experimental data. This result indicates a breakdown of the Born-Oppenheimer approximation in the phonon dispersion relations of boron-doped diamond. PMID- 28731744 TI - Quantum Zeno Suppression of Intramolecular Forces. AB - We show that Born-Oppenheimer surfaces can intrinsically decohere, implying loss of coherence among constituent electronic basis states. We consider the example of interatomic forces due to resonant dipole-dipole interactions within a dimer of highly excited Rydberg atoms, embedded in an ultracold gas. These forces rely on a coherent superposition of two-atom electronic states, which is destroyed by continuous monitoring of the dimer state through a detection scheme utilizing the background gas atoms. We show that this intrinsic decoherence of the molecular energy surface can gradually deteriorate a repulsive dimer state, causing a mixing of attractive and repulsive character. For sufficiently strong decoherence, a Zeno-like effect causes a complete cessation of interatomic forces. We finally show how short decohering pulses can controllably redistribute population between the different molecular energy surfaces. PMID- 28731745 TI - Event-Ready Bell Test Using Entangled Atoms Simultaneously Closing Detection and Locality Loopholes. AB - An experimental test of Bell's inequality allows ruling out any local-realistic description of nature by measuring correlations between distant systems. While such tests are conceptually simple, there are strict requirements concerning the detection efficiency of the involved measurements, as well as the enforcement of spacelike separation between the measurement events. Only very recently could both loopholes be closed simultaneously. Here we present a statistically significant, event-ready Bell test based on combining heralded entanglement of atoms separated by 398 m with fast and efficient measurements of the atomic spin states closing essential loopholes. We obtain a violation with S=2.221+/-0.033 (compared to the maximal value of 2 achievable with models based on local hidden variables) which allows us to refute the hypothesis of local realism with a significance level P<2.57*10^{-9}. PMID- 28731746 TI - Transference of Fermi Contour Anisotropy to Composite Fermions. AB - There has been a surge of recent interest in the role of anisotropy in interaction-induced phenomena in two-dimensional (2D) charged carrier systems. A fundamental question is how an anisotropy in the energy-band structure of the carriers at zero magnetic field affects the properties of the interacting particles at high fields, in particular of the composite fermions (CFs) and the fractional quantum Hall states (FQHSs). We demonstrate here tunable anisotropy for holes and hole-flux CFs confined to GaAs quantum wells, via applying in situ in-plane strain and measuring their Fermi wave vector anisotropy through commensurability oscillations. For strains on the order of 10^{-4} we observe significant deformations of the shapes of the Fermi contours for both holes and CFs. The measured Fermi contour anisotropy for CFs at high magnetic field (alpha_{CF}) is less than the anisotropy of their low-field hole (fermion) counterparts (alpha_{F}), and closely follows the relation alpha_{CF}=sqrt[alpha_{F}]. The energy gap measured for the nu=2/3 FQHS, on the other hand, is nearly unaffected by the Fermi contour anisotropy up to alpha_{F}~3.3, the highest anisotropy achieved in our experiments. PMID- 28731747 TI - Tuning Paramagnetic Spin Excitations of Single Adatoms. AB - We predict the existence of paramagnetic spin excitations (PSE) in nonmagnetic single adatoms. Our calculations demonstrate that PSE develop a well-defined structure in the meV region when the adatom's Stoner criterion for magnetism is close to the critical point. We further reveal a subtle tunability and enhancement of PSE by external magnetic fields. Finally, we show how PSE can be detected as moving steps in the dI/dV signal of inelastic scanning tunneling spectroscopy, opening a potential route for experimentally accessing electronic properties of nonmagnetic adatoms, such as the Stoner parameter. PMID- 28731748 TI - Characterizing Time Irreversibility in Disordered Fermionic Systems by the Effect of Local Perturbations. AB - We study the effects of local perturbations on the dynamics of disordered fermionic systems in order to characterize time irreversibility. We focus on three different systems: the noninteracting Anderson and Aubry-Andre-Harper (AAH) models and the interacting spinless disordered t-V chain. First, we consider the effect on the full many-body wave functions by measuring the Loschmidt echo (LE). We show that in the extended or ergodic phase the LE decays exponentially fast with time, while in the localized phase the decay is algebraic. We demonstrate that the exponent of the decay of the LE in the localized phase diverges proportionally to the single-particle localization length as we approach the metal-insulator transition in the AAH model. Second, we probe different phases of disordered systems by studying the time expectation value of local observables evolved with two Hamiltonians that differ by a spatially local perturbation. Remarkably, we find that many-body localized systems could lose memory of the initial state in the long-time limit, in contrast to the noninteracting localized phase where some memory is always preserved. PMID- 28731749 TI - Computational Power of Symmetry-Protected Topological Phases. AB - We consider ground states of quantum spin chains with symmetry-protected topological (SPT) order as resources for measurement-based quantum computation (MBQC). We show that, for a wide range of SPT phases, the computational power of ground states is uniform throughout each phase. This computational power, defined as the Lie group of executable gates in MBQC, is determined by the same algebraic information that labels the SPT phase itself. We prove that these Lie groups always contain a full set of single-qubit gates, thereby affirming the long standing conjecture that general SPT phases can serve as computationally useful phases of matter. PMID- 28731750 TI - Coupling Constant Corrections in a Holographic Model of Heavy Ion Collisions. AB - We initiate a holographic study of coupling-dependent heavy ion collisions by analyzing, for the first time, the effects of leading-order, inverse coupling constant corrections. In the dual description, this amounts to colliding gravitational shock waves in a theory with curvature-squared terms. We find that, at intermediate coupling, nuclei experience less stopping and have more energy deposited near the light cone. When the decreased coupling results in an 80% larger shear viscosity, the time at which hydrodynamics becomes a good description of the plasma created from high energy collisions increases by 25%. The hydrodynamic phase of the evolution starts with a wider rapidity profile and smaller entropy. PMID- 28731751 TI - Inferences about Supernova Physics from Gravitational-Wave Measurements: GW151226 Spin Misalignment as an Indicator of Strong Black-Hole Natal Kicks. AB - The inferred parameters of the binary black hole GW151226 are consistent with nonzero spin for the most massive black hole, misaligned from the binary's orbital angular momentum. If the black holes formed through isolated binary evolution from an initially aligned binary star, this misalignment would then arise from a natal kick imparted to the first-born black hole at its birth during stellar collapse. We use simple kinematic arguments to constrain the characteristic magnitude of this kick, and find that a natal kick v_{k}?50 km/s must be imparted to the black hole at birth to produce misalignments consistent with GW151226. Such large natal kicks exceed those adopted by default in most of the current supernova and binary evolution models. PMID- 28731752 TI - Novel Pd_{2}Se_{3} Two-Dimensional Phase Driven by Interlayer Fusion in Layered PdSe_{2}. AB - Two-dimensional (2D) materials are easily fabricated when their bulk form has a layered structure. The monolayer form in layered transition-metal dichalcogenides is typically the same as a single layer of the bulk material. However, PdSe_{2} presents a puzzle. Its monolayer form has been theoretically shown to be stable, but there have been no reports that monolayer PdSe_{2} has been fabricated. Here, combining atomic-scale imaging in a scanning transmission electron microscope and density functional theory, we demonstrate that the preferred monolayer form of this material amounts to a melding of two bulk monolayers accompanied by the emission of Se atoms so that the resulting stoichiometry is Pd_{2}Se_{3}. We further verify the interlayer melding mechanism by creating Se vacancies in situ in the layered PdSe_{2} matrix using electron irradiation. The discovery that strong interlayer interactions can be induced by defects and lead to the formation of new 2D materials opens a new venue for the exploration of defect engineering and novel 2D structures. PMID- 28731753 TI - New Measurements of the Beam Normal Spin Asymmetries at Large Backward Angles with Hydrogen and Deuterium Targets. AB - New measurements of the beam normal single spin asymmetry in the electron elastic and quasielastic scattering on the proton and deuteron, respectively, at large backward angles and at ?Q^{2}?=0.22 (GeV/c)^{2} and ?Q^{2}?=0.35 ( GeV/c)^{2} are reported. The experimentally observed asymmetries are compared with the theoretical calculation of Pasquini and Vanderhaeghen [Phys. Rev. C 70, 045206 (2004).PRVCAN0556-281310.1103/PhysRevC.70.045206]. The agreement of the measurements with the theoretical calculations shows a dominance of the inelastic intermediate excited states of the nucleon, piN and the Delta resonance. The measurements explore a new, important parameter region of the exchanged virtual photon virtualities. PMID- 28731754 TI - Accidental Peccei-Quinn Symmetry Protected to Arbitrary Order. AB - A SU(N)_{L}*SU(N)_{R} gauge theory for a scalar multiplet Y transforming in the bifundamental representation (N,N[over -]) preserves, for N>4, an accidental U(1) symmetry first broken at operator dimension N. A vacuum expectation value for Y can break the symmetry to H_{s}=SU(N)_{L+R} or to H_{h}=SU(N-1)_{L}*SU(N 1)_{R}*U(1)_{L+R}. In the first case the accidental U(1) gets also broken, yielding a pseudo-Nambu-Goldstone boson with mass suppression controlled by N. In the second case a global U(1) remains unbroken. The strong CP problem is solved by coupling Y to new fermions carrying color. The first case allows for a Peccei Quinn solution with U(1)_{PQ} protected by the gauge symmetry up to order N. In the second case U(1) can get broken by condensates of the new strong dynamics, resulting in a composite axion. By coupling Y to fermions carrying only weak isospin, models for axionlike particles can be constructed. PMID- 28731755 TI - Spacetime Symmetries and Conformal Data in the Continuous Multiscale Entanglement Renormalization Ansatz. AB - The generalization of the multiscale entanglement renormalization ansatz (MERA) to continuous systems, or cMERA [Haegeman et al., Phys. Rev. Lett. 110, 100402 (2013)PRLTAO0031-900710.1103/PhysRevLett.110.100402], is expected to become a powerful variational ansatz for the ground state of strongly interacting quantum field theories. In this Letter, we investigate, in the simpler context of Gaussian cMERA for free theories, the extent to which the cMERA state |Psi^{Lambda}? with finite UV cutoff Lambda can capture the spacetime symmetries of the ground state |Psi?. For a free boson conformal field theory (CFT) in 1+1 dimensions, as a concrete example, we build a quasilocal unitary transformation V that maps |Psi? into |Psi^{Lambda}? and show two main results. (i) Any spacetime symmetry of the ground state |Psi? is also mapped by V into a spacetime symmetry of the cMERA |Psi^{Lambda}?. However, while in the CFT, the stress-energy tensor T_{MUnu}(x) (in terms of which all the spacetime symmetry generators are expressed) is local, and the corresponding cMERA stress-energy tensor T_{MUnu}^{Lambda}(x)=VT_{MUnu}(x)V^{?} is quasilocal. (ii) From the cMERA, we can extract quasilocal scaling operators O_{alpha}^{Lambda}(x) characterized by the exact same scaling dimensions Delta_{alpha}, conformal spins s_{alpha}, operator product expansion coefficients C_{alphabetagamma}, and central charge c as the original CFT. Finally, we argue that these results should also apply to interacting theories. PMID- 28731756 TI - Stochastic Chaos in a Turbulent Swirling Flow. AB - We report the experimental evidence of the existence of a random attractor in a fully developed turbulent swirling flow. By defining a global observable which tracks the asymmetry in the flux of angular momentum imparted to the flow, we can first reconstruct the associated turbulent attractor and then follow its route towards chaos. We further show that the experimental attractor can be modeled by stochastic Duffing equations, that match the quantitative properties of the experimental flow, namely, the number of quasistationary states and transition rates among them, the effective dimensions, and the continuity of the first Lyapunov exponents. Such properties can be recovered neither using deterministic models nor using stochastic differential equations based on effective potentials obtained by inverting the probability distributions of the experimental global observables. Our findings open the way to low-dimensional modeling of systems featuring a large number of degrees of freedom and multiple quasistationary states. PMID- 28731760 TI - Steady States of Infinite-Size Dissipative Quantum Chains via Imaginary Time Evolution. AB - Directly in the thermodynamic limit, we show how to combine local imaginary and real-time evolution of tensor networks to efficiently and accurately find the nonequilibrium steady states (NESSs) of one-dimensional dissipative quantum lattices governed by a local Lindblad master equation. The imaginary time evolution first bypasses any highly correlated portions of the real-time evolution trajectory by directly converging to the weakly correlated subspace of the NESS, after which, real-time evolution completes the convergence to the NESS with high accuracy. We demonstrate the power of the method with the dissipative transverse field quantum Ising chain. We show that a crossover of an order parameter shown to be smooth in previous finite-size studies remains smooth in the thermodynamic limit. PMID- 28731758 TI - Noncontact Cohesive Swimming of Bacteria in Two-Dimensional Liquid Films. AB - Bacterial swimming in confined two-dimensional environments is ubiquitous in nature and in clinical settings. Characterizing individual interactions between swimming bacteria in 2D confinement will help to understand diverse microbial processes, such as bacterial swarming and biofilm formation. Here we report a novel motion pattern displayed by flagellated bacteria in 2D confinement: When two nearby cells align their moving directions, they tend to engage in cohesive swimming without direct cell body contact, as a result of hydrodynamic interaction but not flagellar intertwining. We further found that cells in cohesive swimming move with higher directional persistence, which can increase the effective diffusivity of cells by ~3 times as predicted by computational modeling. As a conserved behavior for peritrichously flagellated bacteria, cohesive swimming in 2D confinement may be key to collective motion and self organization in bacterial swarms; it may also promote bacterial dispersal in unsaturated soils and in interstitial space during infections. PMID- 28731757 TI - Phase Locking the Spin Precession in a Storage Ring. AB - This Letter reports the successful use of feedback from a spin polarization measurement to the revolution frequency of a 0.97 GeV/c bunched and polarized deuteron beam in the Cooler Synchrotron (COSY) storage ring in order to control both the precession rate (~121 kHz) and the phase of the horizontal polarization component. Real time synchronization with a radio frequency (rf) solenoid made possible the rotation of the polarization out of the horizontal plane, yielding a demonstration of the feedback method to manipulate the polarization. In particular, the rotation rate shows a sinusoidal function of the horizontal polarization phase (relative to the rf solenoid), which was controlled to within a 1 standard deviation range of sigma=0.21 rad. The minimum possible adjustment was 3.7 mHz out of a revolution frequency of 753 kHz, which changes the precession rate by 26 mrad/s. Such a capability meets a requirement for the use of storage rings to look for an intrinsic electric dipole moment of charged particles. PMID- 28731759 TI - Single-Molecule Investigation of Energy Dynamics in a Coupled Plasmon-Exciton System. AB - We investigate the near-field interaction between an isolated free-base phthalocyanine molecule and a plasmon localized in the gap between an NaCl covered Ag(111) surface and the tip apex of a scanning tunneling microscope. When the tip is located in the close proximity of the molecule, asymmetric dips emerge in the broad luminescence spectrum of the plasmon generated by the tunneling current. The origin of the dips is explained by energy transfer between the plasmon and molecular excitons and a quantum mechanical interference effect, where molecular vibrations provide additional degrees of freedom in the dynamic process. PMID- 28731761 TI - Dissipatively Stabilized Quantum Sensor Based on Indirect Nuclear-Nuclear Interactions. AB - We propose to use a dissipatively stabilized nitrogen vacancy (NV) center as a mediator of interaction between two nuclear spins that are protected from decoherence and relaxation of the NV due to the periodical resets of the NV center. Under ambient conditions this scheme achieves highly selective high fidelity quantum gates between nuclear spins in a quantum register even at large NV-nuclear distances. Importantly, this method allows for the use of nuclear spins as a sensor rather than a memory, while the NV spin acts as an ancillary system for the initialization and readout of the sensor. The immunity to the decoherence and relaxation of the NV center leads to a tunable sharp frequency filter while allowing at the same time the continuous collection of the signal to achieve simultaneously high spectral selectivity and high signal-to-noise ratio. PMID- 28731763 TI - Measurement-Induced Strong Kerr Nonlinearity for Weak Quantum States of Light. AB - Strong nonlinearity at the single photon level represents a crucial enabling tool for optical quantum technologies. Here we report on experimental implementation of a strong Kerr nonlinearity by measurement-induced quantum operations on weak quantum states of light. Our scheme coherently combines two sequences of single photon addition and subtraction to induce a nonlinear phase shift at the single photon level. We probe the induced nonlinearity with weak coherent states and characterize the output non-Gaussian states with quantum state tomography. The strong nonlinearity is clearly witnessed as a change of sign of specific off diagonal density matrix elements in the Fock basis. PMID- 28731764 TI - Phase-Tuned Entangled State Generation between Distant Spin Qubits. AB - Quantum entanglement between distant qubits is an important feature of quantum networks. Distribution of entanglement over long distances can be enabled through coherently interfacing qubit pairs via photonic channels. Here, we report the realization of optically generated quantum entanglement between electron spin qubits confined in two distant semiconductor quantum dots. The protocol relies on spin-photon entanglement in the trionic Lambda system and quantum erasure of the Raman-photon path information. The measurement of a single Raman photon is used to project the spin qubits into a joint quantum state with an interferometrically stabilized and tunable relative phase. We report an average Bell-state fidelity for |psi^{(+)}? and |psi^{(-)}? states of 61.6+/-2.3% and a record-high entanglement generation rate of 7.3 kHz between distant qubits. PMID- 28731762 TI - Measurement of Neutral-Current K^{+} Production by Neutrinos using MINERvA. AB - Neutral-current production of K^{+} by atmospheric neutrinos is a background in searches for the proton decay p->K^{+}nu[over -]. Reactions such as nup >nuK^{+}Lambda are indistinguishable from proton decays when the decay products of the Lambda are below detection threshold. Events with K^{+} are identified in MINERvA by reconstructing the timing signature of a K^{+} decay at rest. A sample of 201 neutrino-induced neutral-current K^{+} events is used to measure differential cross sections with respect to the K^{+} kinetic energy, and the non K^{+} hadronic visible energy. An excess of events at low hadronic visible energy is observed relative to the prediction of the neut event generator. Good agreement is observed with the cross section prediction of the genie generator. A search for photons from pi^{0} decay, which would veto a neutral-current K^{+} event in a proton decay search, is performed, and a 2sigma deficit of detached photons is observed relative to the genie prediction. PMID- 28731765 TI - Critical Role of Monoclinic Polarization Rotation in High-Performance Perovskite Piezoelectric Materials. AB - High-performance piezoelectric materials constantly attract interest for both technological applications and fundamental research. The understanding of the origin of the high-performance piezoelectric property remains a challenge mainly due to the lack of direct experimental evidence. We perform in situ high-energy x ray diffraction combined with 2D geometry scattering technology to reveal the underlying mechanism for the perovskite-type lead-based high-performance piezoelectric materials. The direct structural evidence reveals that the electric field-driven continuous polarization rotation within the monoclinic plane plays a critical role to achieve the giant piezoelectric response. An intrinsic relationship between the crystal structure and piezoelectric performance in perovskite ferroelectrics has been established: A strong tendency of electric field-driven polarization rotation generates peak piezoelectric performance and vice versa. Furthermore, the monoclinic M_{A} structure is the key feature to superior piezoelectric properties as compared to other structures such as monoclinic M_{B}, rhombohedral, and tetragonal. A high piezoelectric response originates from intrinsic lattice strain, but little from extrinsic domain switching. The present results will facilitate designing high-performance perovskite piezoelectric materials by enhancing the intrinsic lattice contribution with easy and continuous polarization rotation. PMID- 28731766 TI - Observing Dissipative Topological Defects with Coupled Lasers. AB - Topological defects have been observed and studied in a wide range of systems, such as cosmology, spin systems, cold atoms, and optics, as they are quenched across a phase transition into an ordered state. These defects limit the coherence of the system and its ability to approach a fully ordered state, so revealing their origin and control is becoming an increasingly important field of research. We observe dissipative topological defects in a one-dimensional ring of phased-locked lasers, and show how their formation is related to the Kibble-Zurek mechanism and is governed in a universal manner by two competing time scales. The ratio between these two time scales depends on the system parameters, and thus offers the possibility of enabling the system to dissipate to a fully ordered, defect-free state that can be exploited for solving hard computational problems in various fields. PMID- 28731767 TI - Measurement of a Richtmyer-Meshkov Instability at an Air-SF_{6} Interface in a Semiannular Shock Tube. AB - We report the first measurements of the perturbation amplitude in the converging Richtmyer-Meshkov instability in a semiannular shock tube. At early stages, the amplitude growth agrees well with the impulsive model considering the geometrical convergence effect. A quick decrease of the growth rate at late time, even to be negative, before the reshock is observed for the first time. The reduction of the growth rate is ascribed to the Rayleigh-Taylor stabilization caused by the interface deceleration motion only presented in the converging circumstance. By reasonably evaluating the Rayleigh-Taylor stabilization, a modified model based on the Bell equation is proposed, which well predicts the perturbation growth in a converging geometry from early to late stages before the reshock. It is also found that the flow compressibility is significant in the converging Richtmyer Meshkov instability. PMID- 28731768 TI - Self-Organized Velocity Pulses of Dense Colloidal Suspensions in Microchannel Flow. AB - We present a numerical study of dense colloidal suspensions in a pressure-driven microchannel flow in two dimensions. The colloids are modeled as elastic and frictional spheres suspended in a Newtonian fluid, which we simulate using the method of multiparticle collision dynamics. The model reproduces periodic velocity and density pulse trains, traveling upstream in the microchannel, which are found in experiments conducted by Isa et al. [Phys. Rev. Lett. 102, 058302 (2009)PRLTAO0031-900710.1103/PhysRevLett.102.058302]. We show that colloid-wall friction and the resultant force chains are crucial for the formation of these pulses. With an increasing colloid density, first solitary jams occur, which become periodic pulse trains at intermediate densities and unstable solitary pulses at high densities. We formulate a phenomenological continuum model and show how these spatiotemporal flow and density profiles can be understood as homoclinic and periodic orbits in traveling-wave equations. PMID- 28731769 TI - First-Principles Prediction of Spin-Polarized Multiple Dirac Rings in Manganese Fluoride. AB - Spin-polarized materials with Dirac features have sparked great scientific interest due to their potential applications in spintronics. But such a type of structure is very rare and none has been fabricated. Here, we investigate the already experimentally synthesized manganese fluoride (MnF_{3}) as a novel spin polarized Dirac material by using first-principles calculations. MnF_{3} exhibits multiple Dirac cones in one spin orientation, while it behaves like a large gap semiconductor in the other spin channel. The estimated Fermi velocity for each cone is of the same order of magnitude as that in graphene. The 3D band structure further reveals that MnF_{3} possesses rings of Dirac nodes in the Brillouin zone. Such a spin-polarized multiple Dirac ring feature is reported for the first time in an experimentally realized material. Moreover, similar band dispersions can be also found in other transition metal fluorides (e.g., CoF_{3}, CrF_{3}, and FeF_{3}). Our results highlight a new interesting single-spin Dirac material with promising applications in spintronics and information technologies. PMID- 28731770 TI - Transient Magnetophotoinduced Absorption Studies of Photoexcitations in pi Conjugated Donor-Acceptor Copolymers. AB - We have utilized a plethora of transient and steady state optical and magneto optical spectroscopies in a broad spectral range (0.25-2.5 eV) for elucidating the primary and long-lived photoexcitations in a low band-gap pi-conjugated donor acceptor (DA) copolymer used for efficient photovoltaic solar cells. We show that both singlet excitons (SE) and intrachain triplet-triplet (TT) pairs are photogenerated in the DA-copolymer chains. From the picosecond transient magnetic field response of these species we conclude that the SE and TT spin states are coupled. The TT decomposition into two intrachain geminate triplet excitons maintains spin coherence and thus their spin entanglement lasts into the microsecond time domain. PMID- 28731771 TI - Colloidal Spherocylinders at an Interface: Flipper Dynamics and Bilayer Formation. AB - We study the response of a film of colloidal spherocylinders to compression by combining pressure-area isotherm measurements, microscopy, and computer simulations. We find that the behavior of the film depends strongly on the geometry of the particles. For a small aspect ratio, a uniform monolayer forms and then buckles. For a higher aspect ratio, particles flip to orient perpendicular to the interface; we show that flipping occurs in locations where the nematic ordering is low. Our experiments and simulations further demonstrate that the longest particles rearrange to self-assemble a colloidal bilayer, which is stable due to the unique geometry of spherocylinders at an interface. PMID- 28731772 TI - Publisher's Note: Infrared Topological Plasmons in Graphene [Phys. Rev. Lett. 118, 245301 (2017)]. AB - This corrects the article DOI: 10.1103/PhysRevLett.118.245301. PMID- 28731773 TI - Visualizing the Efimov Correlation in Bose Polarons. AB - The Bose polaron is a quasiparticle of an impurity dressed by surrounding bosons. In few-body physics, it is known that two identical bosons and a third distinguishable particle can form a sequence of Efimov bound states in the vicinity of interspecies scattering resonance. On the other hand, in the Bose polaron system with an impurity atom embedded in many bosons, no signature of Efimov physics has been reported in the existing spectroscopy measurements to date. In this Letter, we propose that a large mass imbalance between a light impurity and heavy bosons can help produce visible signatures of Efimov physics in such a spectroscopy measurement. Using the diagrammatic approach in the virial expansion to include three-body effects from pair-wise interactions, we determine the impurity self-energy and its spectral function. Taking the ^{6}Li-^{133}Cs system as a concrete example, we find two visible Efimov branches in the polaron spectrum, as well as their hybridizations with the attractive polaron branch. We also discuss the general scenarios for observing the signature of Efimov physics in polaron systems. This work paves the way for experimentally exploring intriguing few-body correlations in a many-body system in the near future. PMID- 28731774 TI - Femtosecond Spin Current Pulses Generated by the Nonthermal Spin-Dependent Seebeck Effect and Interacting with Ferromagnets in Spin Valves. AB - Using the sensitivity of optical second harmonic generation to currents, we demonstrate the generation of 250-fs long spin current pulses in Fe/Au/Fe/MgO(001) spin valves. The temporal profile of these pulses indicates ballistic transport of hot electrons across a sub-100 nm Au layer. The pulse duration is primarily determined by the thermalization time of laser-excited hot carriers in Fe. Considering the calculated spin-dependent Fe/Au interface transmittance we conclude that a nonthermal spin-dependent Seebeck effect is responsible for the generation of ultrashort spin current pulses. The demonstrated rotation of spin polarization of hot electrons upon interaction with noncollinear magnetization at Au/Fe interfaces holds high potential for future spintronic devices. PMID- 28731775 TI - Nonlinear Quantum Metrology of Many-Body Open Systems. AB - We introduce general bounds for the parameter estimation error in nonlinear quantum metrology of many-body open systems in the Markovian limit. Given a k body Hamiltonian and p-body Lindblad operators, the estimation error of a Hamiltonian parameter using a Greenberger-Horne-Zeilinger state as a probe is shown to scale as N^{-[k-(p/2)]}, surpassing the shot-noise limit for 2k>p+1. Metrology equivalence between initial product states and maximally entangled states is established for p>=1. We further show that one can estimate the system environment coupling parameter with precision N^{-(p/2)}, while many-body decoherence enhances the precision to N^{-k} in the noise-amplitude estimation of a fluctuating k-body Hamiltonian. For the long-range Ising model, we show that the precision of this parameter beats the shot-noise limit when the range of interactions is below a threshold value. PMID- 28731776 TI - Predicting Flory-Huggins chi from Simulations. AB - We introduce a method, based on a novel thermodynamic integration scheme, to extract the Flory-Huggins chi parameter as small as 10^{-3}kT for polymer blends from molecular dynamics (MD) simulations. We obtain chi for the archetypical coarse-grained model of nonpolar polymer blends: flexible bead-spring chains with different Lennard-Jones interactions between A and B monomers. Using these chi values and a lattice version of self-consistent field theory (SCFT), we predict the shape of planar interfaces for phase-separated binary blends. Our SCFT results agree with MD simulations, validating both the predicted chi values and our thermodynamic integration method. Combined with atomistic simulations, our method can be applied to predict chi for new polymers from their chemical structures. PMID- 28731777 TI - Induction and Maintenance Adjuvant Mitomycin C Topical Therapy for Upper Tract Urothelial Carcinoma: Tolerability and Intermediate Term Outcomes. AB - PURPOSE: Endoscopic management of upper tract urothelial carcinoma (UTUC) is associated with higher recurrences, which could be reduced by application of topical therapy. Adjuvant induction Bacillus Calmette-Guerin has shown inferior outcomes for UTUC compared to bladder cancer, and maintenance regimens for UTUC are unexplored. We report on the efficacy, safety, and tolerability of Mitomycin C (MMC) induction and maintenance adjuvant topical therapy for UTUC. MATERIALS AND METHODS: Patients with UTUC who received adjuvant topical therapy after complete endoscopic control of Ta/T1 tumors were retrospectively reviewed. Patients were treated using percutaneous nephrostomy tube (NT) or cystoscopically placed weekly ureteral catheters, per patient preference, and all patients were offered induction and maintenance. Standardized follow-up of every 3 months in the first year, then at a minimum every 6 months, with ureteroscopy and at least annual CT, was performed. Primary outcomes were recurrence-free, progression free, nephroureterectomy-free rate and cancer-specific and overall survival. Secondary outcomes were safety and treatment tolerability. RESULTS: Twenty-seven patients with 28 renal units received adjuvant topical therapy from January 2008 to March 2015. Median follow-up was 19 months (range 7-92). Three year recurrence free, progression-free, and nephroureterectomy-free survival rates were 60% [confidence interval (95% CI): 42, 86%], 80% [95% CI: 64, 100%], and 76% [95% CI: 60, 97%]. Cancer-specific mortality rate was 0%, and 3-year overall survival was 92.9%. Nine patients experienced adverse outcomes, all related to interventions and none related to systemic toxicity. CONCLUSIONS: Induction and maintenance adjuvant topical MMC for endoscopically resected UTUC is feasible, well tolerated and shows promising intermediate term data on recurrence, progression, and nephroureterectomy-free survival. PMID- 28731780 TI - Evaluation of Turmeric Chip Compared with Chlorhexidine Chip as a Local Drug Delivery Agent in the Treatment of Chronic Periodontitis: A Split Mouth Randomized Controlled Clinical Trial. AB - AIMS AND OBJECTIVE: The aim of this study was to evaluate and compare the effect of chlorhexidine (CHX) chip and turmeric chip as a local drug delivery (LDD) agent in the treatment of patients with chronic periodontitis. MATERIALS AND METHODS: A total of 120 sites with pocket depths 5-8 mm were chosen as a split mouth design at 3 sites in the same patient. Selected sites were randomly divided into three groups to receive CHX chip in addition to scaling and root planing (SRP) in group A, turmeric chip in addition to SRP in group B, and SRP only in group C. Clinical parameters, that is, plaque index (PI), gingival index (GI), probing pocket depth (PPD), and relative attachment level (RAL) were recorded at baseline, 1 month, and 3 months interval. RESULT: On applying statistical analysis, results revealed that there was a significant reduction in all the clinical parameters, that is, PI, GI, PPD, and gain in RAL from baseline to 1 month and 3 months in all the three groups. These results were found to be significantly high in the CHX group and turmeric group than in the SRP group. Also, the results in both the test groups were maintained till the end of the study periods, but SRP group showed a significant deterioration after 1 month as was seen by increase in PPD and decrease in RAL scores after 3 months in the SRP group. CONCLUSION: Both the treatment modalities with the application of LDD as an adjunct to SRP proved to be equally beneficial in the treatment of chronic periodontitis. PMID- 28731778 TI - A Pharmacologic Algorithm for Youth Who Are at High Risk for Bipolar Disorder. AB - OBJECTIVE: Depression and brief periods of manic symptoms are linked to a significant risk of progression to bipolar disorder (BD) in children who have a first-degree relative with BD I or II. However, little evidence exists to guide the pharmacologic management of children with these high-risk phenotypes. We propose a pharmacological treatment algorithm for high-risk youth and present results on its use in a study of children with a first-degree relative with BD. METHODS: Subjects were 40 youth (mean 12.7 years, range 9-17 years) who had (1) a first-degree relative with lifetime history of BD I or II, (2) DSM-IV-TR diagnoses of BD not otherwise specified, major depressive disorder or cyclothymic disorder, and (3) active symptoms of depression, mania, or hypomania. Participants and their families were enrolled in a randomized trial examining the effects of two psychosocial interventions on the 1-year course of mood disorder. At study intake, participants received a psychiatric evaluation and were offered medications or had existing medications optimized to decrease symptom severity. During the 1-year study, psychiatrists treated participants using a medication algorithm to treat depressive or manic symptoms as well as comorbid anxiety and/or attention-deficit/hyperactivity disorder. RESULTS: At study entry, 25 of 40 (62.5%) of the participants were taking at least one psychiatric medication. At 1 year, nearly an identical proportion were taking medications (22 of 35, 63%). Independent ratings indicated that in 84.7% of the study visits, physicians maintained adherence to the algorithm. No patients experienced antidepressant- or stimulant-induced mania during the study. CONCLUSIONS: An algorithmic approach to pharmacologic interventions may aid in the management of youth (i.e., age <18) at high risk for BD. Future studies should compare outcomes in high-risk patients receiving algorithm-prescribed treatment versus those receiving treatment as usual. CLINICAL TRIAL REGISTRATION INFORMATION: Early Family-Focused Treatment for Youth at Risk for Bipolar Disorder; www.clinicaltrials.gov/ ; NCT00943085. PMID- 28731779 TI - Arthroscopic Labral Base Repair in the Hip: 5-Year Minimum Clinical Outcomes. AB - BACKGROUND: Arthroscopic labral base repair (LBR) in the hip is a previously described technique designed to restore the native functional anatomy of the labrum by reproducing its seal against the femoral head. LBR has been shown to have good short-term outcomes. Hypothesis/Purpose: The purpose was to evaluate clinical outcomes of an LBR cohort with a minimum 5-year follow-up. It was hypothesized that patients who underwent LBR would continue to have significant improvement from their preoperative scores and maintain scores similar to their 2 year outcomes. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Data for patients undergoing primary hip arthroscopic surgery with LBR from February 2008 to May 2011 with a minimum 5-year follow-up were prospectively collected and retrospectively reviewed. Patients with preoperative Tonnis osteoarthritis grade >=2, previous hip conditions (slipped capital femoral epiphysis, avascular necrosis, Legg-Calv-Perthes disease), severe dysplasia (lateral center-edge angle <18 degrees ), or previous ipsilateral hip surgery were excluded. Statistical equivalence tests evaluated patient-reported outcomes (PROs) including the modified Harris Hip Score (mHHS), Non-Arthritic Hip Score (NAHS), Hip Outcome Score-Sport-Specific Subscale (HOS-SSS), visual analog scale (VAS) for pain, and patient satisfaction (0-10 scale; 10 = very satisfied). RESULTS: Of the 70 patients (74 hips) who met inclusion and exclusion criteria, 60 (85.7%) patients (64 hips) were available at a minimum 5-year follow-up. All PRO scores significantly improved from preoperative values with a mean follow-up of 67.8 +/- 7.4 months (range, 60.0-89.7 months). The mean mHHS increased from 64.4 +/-13.8 to 85.3 +/- 17.7 ( P < .001), the mean NAHS from 63.7 +/- 17.0 to 87.0 +/- 14.7 ( P < .001), and the mean HOS-SSS from 47.1 +/- 23.2 to 76.5 +/- 25.9 ( P < .001). The mean VAS score decreased from 5.9 +/- 2.4 to 2.0 +/- 2.1 ( P < .001). The mean patient satisfaction score was 8.1 +/- 2.0. The improvement in PRO scores was sustained from 2- to 5-year follow-up. At 2 and 5 years, survivorship rates were 96.9% and 90.6%, respectively, and the respective secondary arthroscopic surgery rates were 10.9% (7/64) and 17.2% (11/64). CONCLUSION: At a minimum 5 year follow-up, arthroscopic LBR continued to be a successful procedure and valid technique based on 3 PROs, the VAS, patient satisfaction, and survivorship. Significantly improved outcome scores were maintained compared with preoperative values and showed no signs of deterioration from the 2-year scores. The long-term survivorship of hip arthroscopic surgery has yet to be determined; however, these midterm results demonstrate the rates of additional procedures (both secondary arthroscopic surgery and conversion to total hip arthroplasty), that may be necessary after 2 years. PMID- 28731781 TI - lncRNA-PVT1 Facilitates Invasion Through Upregulation of MMP9 in Nonsmall Cell Lung Cancer Cell. AB - Lung cancer is the most common solid tumor around the world. It has been reported that upregulation of long noncoding RNA (lncRNA) plasmacytoma variant translocation 1 (lncRNA-PVT1) is closely associated with tumor metastasis. However, the function and underlying molecular mechanism of lncRNA-PVT1 in nonsmall cell lung cancer (NSCLC) invasion remain unknown. In this study, we found that overexpression of lncRNA-PVT1 promoted the invasive ability of NSCLC cells, whereas silence of lncRNA-PVT1 suppressed cell invasion. Furthermore, we found that lncRNA-PVT1 upregulated MMP9 expression in a post-transcriptional manner. Specifically, lncRNA-PVT1 directly interacted with miR-200a and miR-200b, which suppressed MMP9 expression. Taken together, lncRNA-PVT1 functions as a competitive endogenous RNA to regulate MMP9 expression through competitively binding the common microRNAs, miR-200a and miR-200b. These findings suggest that lncRNA-PVT1 could predispose NSCLC patients to metastases and may serve as a promising target for antimetastatic therapies. PMID- 28731782 TI - Identifiability of Components of Complex Interventions Using Factorial Designs. AB - OBJECTIVE: The aim of this contribution is to demonstrate how the component structure of a complex intervention (CI) can be efficiently exploited for study design and statistical analysis by using concepts of factorial designs. Many studies on CIs in complementary and alternative medicine exhibit the structure of factorial designs, where all possible combinations of the levels of two or more treatments occur together. In this contribution, the treatment arms of CI studies are explicitly viewed as factorial combinations of their components. Experimental design offers the general concept of identifiability of effects, that is, unique estimability of the components' effects from the observed data. For factorial designs, a simple cross table representation of the treatment arms can show the components or sums or interactions of components that are identifiable within a given study design. The question of identifiability arises particularly if some combinations of components are not observed (e.g., individualized homeopathic prescription without consultation). Study designs from published homeopathy studies are used for demonstration. CONCLUSIONS: CI studies should explicitly use an intervention's factorial component structure if it is inherent in the treatment arms being compared. In this way, investigators can avoid study designs from which the effects of interest cannot be uniquely estimated and improve the interpretation of estimated effects. PMID- 28731783 TI - Identification of SPPL2a Inhibitors by Multiparametric Analysis of a High-Content Ultra-High-Throughput Screen. AB - The intramembrane protease signal peptide peptidase-like 2a (SPPL2a) is a potential drug target for the treatment of autoimmune diseases due to an essential role in B cells and dendritic cells. To screen a library of 1.4 million compounds for inhibitors of SPPL2a, we developed an imaging assay detecting nuclear translocation of the proteolytically released cytosolic substrate fragment. The state-of-the-art hit calling approach based on nuclear translocation resulted in numerous false-positive hits, mainly interrupting intracellular protein trafficking. To filter the false positives, we extracted 340 image-based readouts and developed a novel multiparametric analysis method that successfully triaged the primary hit list. The identified scaffolds were validated by demonstrating activity on endogenous SPPL2a and substrate CD74/p8 in B cells. The multiparametric analysis discovered diverse cellular phenotypes and provided profiles for the whole library. The principle of the presented imaging assay, the screening strategy, and multiparametric analysis are potentially applicable in future screening campaigns. PMID- 28731784 TI - Response to the Article "Overall Survival among Cancer Patients Undergoing Opioid Rotation to Methadone Compared to Other Opioids". PMID- 28731785 TI - Networks of Transcription Factors for Oct4 Expression in Mice. AB - The present review aimed to assess the networks of transcription factors regulating the Oct4 expression in mice. Through a comprehensive analysis of the binding sites and the interrelationships of the transcription factors of Oct4, it is found that transcription factors of Oct4 form three regulating complexes centered by Oct4-Sox2, Nanog, and Lrh1. They bind on CR4, CR2, and CR1 regions of Oct4 promoter/enhancer, respectively, to activate Oct4 transcription synergistically. This article also discusses the mechanisms of fine-tuning the Oct4 expression. These findings have important implications in the field of stem cell and developmental biology. PMID- 28731786 TI - High Post-treatment alpha-Fetoprotein Levels and Aspartate Aminotransferase-to Platelet Ratio Index Predict Hepatocellular Carcinoma in Hepatitis C Virus Decompensated Cirrhotic Patients with Sustained Virological Response After Antiviral Therapy. AB - Although eradication of hepatitis C virus (HCV) decreases the risk of hepatocellular carcinoma (HCC) development, a considerable level of risk remains in cirrhotic patients with advanced liver disease. Yet, data for the effect of serum markers on HCC development in this population after viral eradication are still lacking. Seventy-eight consecutive patients with HCV infection and decompensated cirrhosis were administered interferon-based regimens at our hospital between August 2008 and December 2013. Thirty-four achieved sustained virological response and were enrolled in the study. Occurrence of HCC was evaluated every 3-6 months post-treatment. The mean age of the 34 patients was 55.7 +/- 8.3 years (range: 39-70) old. Compared with baseline, at 24 weeks post treatment the serum levels were significantly decreased for alpha-fetoprotein (AFP) (12.20 +/- 4.12 versus 8.37 +/- 2.75 ng/mL, P < 0.001), aspartate aminotransferase (AST) (58.44 +/- 15.12 versus 36.59 +/- 11.22 IU/L, P < 0.001), and AST-to-platelet ratio index (APRI) (2.21 +/- 0.74 versus 1.35 +/- 0.61, P < 0.001) but significantly increased for platelet count (69.65 +/- 17.46 versus 73.65 +/- 18.0 * 103/MUL, P = 0.022). Median follow-up time was 41.4 +/- 16.8 (range: 9-71) months, and 5 patients (14.7%) developed HCC. Post-treatment APRI >=1.5 and AFP >=10 ng/mL were associated with HCC development (both P < 0.01). Post-treatment AFP and APRI maybe are useful markers to further classify HCC risk in HCV-decompensated cirrhotic patients after viral eradication. PMID- 28731787 TI - Effect of Euterpe oleracea Mart. (Acai) Oil on Dyslipidemia Caused by Cocos nucifera L. Saturated Fat in Wistar Rats. AB - Dyslipidemia is caused by disturbances in lipid metabolism that lead to chronic elevations of serum lipids, especially low-density lipoprotein (LDL)-cholesterol and triglycerides, increasing the risk of metabolic syndrome, obesity, diabetes, atherogenic processes, and cardiovascular diseases. The oil from the fruits of Euterpe oleracea (OFEO) is rich in unsaturated fatty acids with potential for treating alterations in lipid metabolism. In this study, we aimed to investigate the effect of OFEO on hyperlipidemia induced by Cocos nucifera L. saturated fat (GSC) in Wistar rats. Chromatographic profile showed that unsaturated fatty acids account for 66.08% in OFEO, predominately oleic acid (54.30%), and saturated fatty acids (palmitic acid 31.6%) account for 33.92%. GSC-induced dyslipidemia resulted in an increase in total cholesterol, LDL-cholesterol, triglycerides, glucose, and liver and abdominal fat, as well as atherogenic processes in the thoracic aorta. OFEO treatment did not reduce hypertriglyceridemia, but did reduce total cholesterol and LDL-cholesterol, thus contributing to the antiatherogenic action of OFEO. OFEO treatment inhibited the formation of atheromatous plaques in the vascular endothelium of the treated rats, as well as those who were treated with simvastatin. The results obtained suggest that OFEO has an antiatherogenic effect in a rat model of dyslipidemia. PMID- 28731788 TI - Identification of Osr2 Transcriptional Target Genes in Palate Development. AB - Previous studies have identified the odd-skipped related 2 (Osr2) transcription factor as a key intrinsic regulator of palatal shelf growth and morphogenesis. However, little is known about the molecular program acting downstream of Osr2 in the regulation of palatogenesis. In this study, we isolated palatal mesenchyme cells from embryonic day 12.5 (E12.5) and E13.5 Osr2RFP/+ and Osr2RFP/- mutant mouse embryos and performed whole transcriptome RNA sequencing analyses. Differential expression analysis of the RNA sequencing datasets revealed that expression of 70 genes was upregulated and expression of 61 genes was downregulated by >1.5-fold at both E12.5 and E13.5 in the Osr2RFP/- palatal mesenchyme cells, in comparison with Osr2RFP/+ littermates. Gene ontology analysis revealed enrichment of signaling molecules and transcription factors crucial for skeletal development and osteoblast differentiation among those significantly upregulated in the Osr2 mutant palatal mesenchyme. Using quantitative real-time polymerase chain reaction (RT-PCR)and in situ hybridization assays, we validated that the Osr2-/- embryos exhibit significantly increased and expanded expression of many osteogenic pathway genes, including Bmp3, Bmp5, Bmp7, Mef2c, Sox6, and Sp7 in the developing palatal mesenchyme. Furthermore, we demonstrate that expression of Sema3a, Sema3d, and Sema3e, is ectopically activated in the developing palatal mesenchyme in Osr2-/- embryos. Through chromatin immunoprecipitation, followed by RT-PCR analysis, we demonstrate that endogenous Osr2 protein binds to the promoter regions of the Sema3a and Sema3d genes in the embryonic palatal mesenchyme. Moreover, Osr2 expression repressed the transcription from the Sema3a and Sema3d promoters in cotransfected cells. Since the Sema3 subfamily of signaling molecules plays diverse roles in the regulation of cell proliferation, migration, and differentiation, these data reveal a novel role for Osr2 in regulation of palatal morphogenesis through preventing aberrant activation of Sema3 signaling. Together, these data indicate that Osr2 controls multiple molecular pathways, including BMP and Sema3 signaling, in palate development. PMID- 28731789 TI - Age and Cancer Treatment Are Related to Receiving Treatment Summaries and Survivorship Care Plans in Female Young Adult Cancer Survivors. AB - The study determined factors associated with patient-reported receipt of survivorship care plans and/or treatment summaries (SCP/TS). Two hundred forty female young adult cancer survivors ages 18-44 completed a web-based survey that included self-report on receiving SCP/TS. Mean age was 32.8 (standard deviation 5.8) years; 20% were diagnosed with cancer at age <21. Only 47% reported receipt of SCP/TS. Age <21 at diagnosis (odds ratio [OR] 2.0, 95% confidence interval [CI] 1.0-3.9), chemotherapy (OR 2.3, 95% CI 1.2-4.6), central nervous system radiation (OR 2.5, 95% CI 1.1-5.6), and bone marrow transplantation (OR 7.2, 95% CI 1.5-33.3) were significantly associated with higher odds of SCP/TS receipt. Improved integration of TS and SCP into cancer survivorship care is needed. PMID- 28731790 TI - The Biased Evolution of Generation Time. AB - Many life-history traits are important determinants of the generation time. For instance, semelparous species whose adults reproduce only once have shorter generation times than iteroparous species that reproduce on several occasions, assuming equal development duration. A shorter generation time ensures a higher growth rate in stable environments where resources are in excess and is therefore a positively selected feature in this situation. In a stable and limiting environment, all combinations of traits that produce the same number of viable offspring are selectively equivalent. Here we study the neutral evolution of life history strategies with different generation times and show that the slowest strategy represents the most likely evolutionary outcome when mutation is considered. Indeed, strategies with longer generation times generate fewer mutants per time unit, which makes them less likely to be replaced within a given time period. This turnover bias favors the evolution of strategies with long generation times. Its real impact, however, depends on both the population size and the nature of selection on life-history strategies. The latter is primarily impacted by the relationships between life-history traits whose estimation will be crucial to understanding the evolution of life-history strategies. PMID- 28731791 TI - Sensory Drive, Color, and Color Vision. AB - Colors often appear to differ in arbitrary ways among related species. However, a fraction of color diversity may be explained because some signals are more easily perceived in one environment rather than another. Models show that not only signals but also the perception of signals should regularly evolve in response to different environments, whether these primarily involve detection of conspecifics or detection of predators and prey. Thus, a deeper understanding of how perception of color correlates with environmental attributes should help generate more predictive models of color divergence. Here, I briefly review our understanding of color vision in vertebrates. Then I focus on opsin spectral tuning and opsin expression, two traits involved in color perception that have become amenable to study. I ask how opsin tuning is correlated with ecological differences, notably the light environment, and how this potentially affects perception of conspecific colors. Although opsin tuning appears to evolve slowly, opsin expression levels are more evolutionarily labile but have been difficult to connect to color perception. The challenge going forward will be to identify how physiological differences involved in color vision, such as opsin expression levels, translate into perceptual differences, the selection pressures that have driven those differences, and ultimately how this may drive evolution of conspecific colors. PMID- 28731792 TI - The Evolution of Energetic Scaling across the Vertebrate Tree of Life. AB - Metabolism is the link between ecology and physiology-it dictates the flow of energy through individuals and across trophic levels. Much of the predictive power of metabolic theories of ecology derives from the scaling relationship between organismal size and metabolic rate. There is growing evidence that this scaling relationship is not universal, but we have little knowledge of how it has evolved over macroevolutionary time. Here we develop a novel phylogenetic comparative method to investigate how often and in which clades the macroevolutionary dynamics of the metabolic scaling have changed. We find strong evidence that the metabolic scaling relationship has shifted multiple times across the vertebrate phylogeny. However, shifts are rare and otherwise strongly constrained. Importantly, both the estimated slope and intercept values vary widely across regimes, with slopes that spanned across theoretically predicted values such as 2/3 or 3/4. We further tested whether traits such as ecto /endothermy, genome size, and quadratic curvature with body mass (i.e., energetic constraints at extreme body sizes) could explain the observed pattern of shifts. Though these factors help explain some of the variation in scaling parameters, much of the remaining variation remains elusive. Our results lay the groundwork for further exploration of the evolutionary and ecological drivers of major transitions in metabolic strategy and for harnessing this information to improve macroecological predictions. PMID- 28731793 TI - Phylogeny, Traits, and Biodiversity of a Neotropical Bat Assemblage: Close Relatives Show Similar Responses to Local Deforestation. AB - If species' evolutionary pasts predetermine their responses to evolutionarily novel stressors, then phylogeny could predict species survival in an increasingly human-dominated world. To understand the role of phylogenetic relatedness in structuring responses to rapid environmental change, we focused on assemblages of Neotropical bats, an ecologically diverse and functionally important group. We examined how taxonomic and phylogenetic diversity shift between tropical forest and farmland. We then explored the importance of evolutionary history by ascertaining whether close relatives share similar responses to environmental change and which species traits might mediate these trends. We analyzed a 5-year data set (5,011 captures) from 18 sites in a countryside landscape in southern Costa Rica using statistical models that account and correct for imperfect detection of species across sites, spatial autocorrelation, and consideration of spatial scale. Taxonomic and phylogenetic diversity decreased with deforestation, and assemblages became more phylogenetically clustered. Species' responses to deforestation were strongly phylogenetically correlated. Body mass and absolute wing loading explained a substantial portion of species variation in species' habitat preferences, likely related to these traits' influence on maneuverability in cluttered forest environments. Our findings highlight the role that evolutionary history plays in determining which species will survive human impacts and the need to consider diversity metrics, evolutionary history, and traits together when making predictions about species persistence for conservation or ecosystem functioning. PMID- 28731794 TI - A Neutral Model for the Evolution of Diet Breadth. AB - Variation in diet breadth among organisms is a pervasive feature of the natural world that has resisted general explanation. In particular, trade-offs in the ability to use one resource at the expense of another have been expected but rarely detected. We explore a spatial model for the evolution of specialization, motivated by studies of plant-feeding insects. The model is neutral with respect to the causes and consequences of diet breadth: the number of hosts utilized is not constrained by trade-offs, and specialization or generalization does not confer a direct advantage with respect to the persistence of populations or the probability of diversification. We find that diet breadth evolves in ways that resemble reports from natural communities. Simulated communities are dominated by specialized species, with a predictable but less species-rich component of generalized taxa. These results raise the possibility that specialization might be a consequence of stochastic diversification dynamics acting on spatially segregated consumer-resource associations rather than a trait either favored or constrained directly by natural selection. Finally, our model generates hypotheses for global patterns of herbivore diet breadth, including a positive effect of host richness and a negative effect of evenness in host plant abundance on the number of specialized taxa. PMID- 28731795 TI - Plant Size and Competitive Dynamics along Nutrient Gradients. AB - Resource competition theory in plants has focused largely on resource acquisition traits that are independent of size, such as traits of individual leaves or roots or proportional allocation to different functions. However, plants also differ in maximum potential size, which could outweigh differences in module-level traits. We used a community ecosystem model called mondrian to investigate whether larger size inevitably increases competitive ability and how size interacts with nitrogen supply. Contrary to the conventional wisdom that bigger is better, we found that invader success and competitive ability are unimodal functions of maximum potential size, such that plants that are too large (or too small) are disproportionately suppressed by competition. Optimal size increases with nitrogen supply, even when plants compete for nitrogen only in a size-symmetric manner, although adding size-asymmetric competition for light does substantially increase the advantage of larger size at high nitrogen. These complex interactions of plant size and nitrogen supply lead to strong nonlinearities such that small differences in nitrogen can result in large differences in plant invasion success and the influence of competition along productivity gradients. PMID- 28731796 TI - Bees without Flowers: Before Peak Bloom, Diverse Native Bees Find Insect-Produced Honeydew Sugars. AB - Bee foragers respond to complex visual, olfactory, and extrasensory cues to optimize searches for floral rewards. Their abilities to detect and distinguish floral colors, shapes, volatiles, and ultraviolet signals and even gauge nectar availability from changes in floral humidity or electric fields are well studied. Bee foraging behaviors in the absence of floral cues, however, are rarely considered. We observed 42 species of wild bees visiting inconspicuous, nonflowering shrubs during early spring in a protected Mediterranean habitat. We determined experimentally that these bees were accessing sugary honeydew secretions from scale insects without the aid of standard cues. While honeydew use is known among some social Hymenoptera, its use across a diverse community of solitary bees is a novel observation. The widespread ability of native bees to locate and use unadvertised, nonfloral sugars suggests unappreciated sensory mechanisms and/or the existence of an interspecific foraging network among solitary bees that may influence how native bees cope with scarcity of floral resources and increasing environmental change. PMID- 28731797 TI - Quantitative Genetic Variation in, and Environmental Effects on, Pathogen Resistance and Temperature-Dependent Disease Severity in a Wild Trout. AB - Health after pathogen contact varies among individuals because of differences in pathogen load (which is limited by resistance) and disease severity in response to pathogen load (which is limited by tolerance). To understand pathogen-induced host evolution, it is critical to know not only the relative contributions of nongenetic and genetic variation to resistance and tolerance but also how they change environmentally. We quantified nongenetic and genetic variation in parasite load and the associated temperature-dependent disease among trout siblings from two rivers. We detected a genetic variance for parasite load 6.6 times as large in the colder river. By contrast, genetic variance for disease traits tended to be larger in the warmer river, where the disease was manifested more severely. The relationships between disease severity and pathogen load (tolerance) exhibited plateaus at low pathogen load and stronger steepening slopes at high pathogen load in the warmer river. Our study demonstrates the environmental influence on disease severity, nongenetic and genetic variance for health-damage-limiting host abilities, and the shape of tolerance curves. Environmental variability is predicted to govern the presence and intensity of selection, change the relative contributions of nongenetic and genetic variance, and therefore hamper evolution toward more resistant and tolerant hosts. PMID- 28731798 TI - Most Colorful Example of Genetic Assimilation? Exploring the Evolutionary Destiny of Recurrent Phenotypic Accommodation. AB - Evolution of adaptation requires both generation of novel phenotypic variation and retention of a locally beneficial subset of this variation. Such retention can be facilitated by genetic assimilation, the accumulation of genetic and molecular mechanisms that stabilize induced phenotypes and assume progressively greater control over their reliable production. A particularly strong inference into genetic assimilation as an evolutionary process requires a system where it is possible to directly evaluate the extent to which an induced phenotype is progressively incorporated into preexisting developmental pathways. Evolution of diet-dependent pigmentation in birds-where external carotenoids are coopted into internal metabolism to a variable degree before being integrated with a feather's developmental processes-provides such an opportunity. Here we combine a metabolic network view of carotenoid evolution with detailed empirical study of feather modifications to show that the effect of physical properties of carotenoids on feather structure depends on their metabolic modification, their environmental recurrence, and biochemical redundancy, as predicted by the genetic assimilation hypothesis. Metabolized carotenoids caused less stochastic variation in feather structure and were more closely integrated with feather growth than were dietary carotenoids of the same molecular weight. These patterns were driven by the recurrence of organism-carotenoid associations: commonly used dietary carotenoids and biochemically redundant derived carotenoids caused less stochastic variation in feather structure than did rarely used or biochemically unique compounds. We discuss implications of genetic assimilation processes for the evolutionary diversification of diet-dependent animal coloration. PMID- 28731799 TI - Multispecies Coexistence without Diffuse Competition; or, Why Phylogenetic Signal and Trait Clustering Weaken Coexistence. AB - Related and phenotypically similar species often compete more strongly than unrelated and dissimilar species. Much is unknown about the community-level implications of such complex interactions. Here, we study how they affect community dynamics differently from diffuse interactions (competing equally with all heterospecifics). We derive results for a model that applies to many forms of density dependence and also examine specific cases using a site-occupancy model of forest dynamics. The results indicate that nondiffuse competition produces three effects that will not occur under diffuse competition: first, the central niche effect-if a species has high niche overlap with several competitors, then its average fitness is reduced; second, the common competitor effect-if a species has high niche overlap with more common species, then its average fitness is reduced (these two effects are usually equalizing, because more favorable niches are likely to contain more species and more abundant species); and, finally, the community redistribution effect-when a species falls to low density, the relative abundance of its competitors will change, altering its ability to recover. The community redistribution effect usually undermines coexistence, because the community will usually become dominated by an invader's closest competitors. This study provides both instructions for measuring these effects in the field and a framework for analyzing how phylogenetic signal, trait-based niche axes, and other forms of nondiffuse competition affect coexistence. PMID- 28731800 TI - Natural History Constrains the Macroevolution of Foot Morphology in European Plethodontid Salamanders. AB - The natural history of organisms can have major effects on the tempo and mode of evolution, but few examples show how unique natural histories affect rates of evolution at macroevolutionary scales. European plethodontid salamanders (Plethodontidae: Hydromantes) display a particular natural history relative to other members of the family. Hydromantes commonly occupy caves and small crevices, where they cling to the walls and ceilings. On the basis of this unique and strongly selected behavior, we test the prediction that rates of phenotypic evolution will be lower in traits associated with climbing. We find that, within Hydromantes, foot morphological traits evolve at significantly lower rates than do other phenotypic traits. Additionally, Hydromantes displays a lower rate of foot morphology evolution than does a nonclimbing genus, Plethodon. Our findings suggest that macroevolutionary trends of phenotypic diversification can be mediated by the unique behavioral responses in taxa related to particular attributes of their natural history. PMID- 28731801 TI - Diversification of Trait Combinations in Coevolving Plant and Insect Lineages. AB - Closely related species often have similar traits and sometimes interact with the same species. A crucial problem in evolutionary ecology is therefore to understand how coevolving species diverge when they interact with a set of closely related species from another lineage rather than with a single species. We evaluated geographic differences in the floral morphology of all woodland star plant species (Lithophragma, Saxifragaceae) that are pollinated by Greya (Prodoxidae) moths. Flowers of each woodland star species differed depending on whether plants interact locally with one, two, or no pollinating moth species. Plants of one species grown in six different environments showed few differences in floral traits, suggesting that the geographic differences are not due significantly to trait plasticity. Greya moth populations also showed significant geographic divergence in morphology, depending on the local host and on whether the moth species co-occurred locally. Divergence in the plants and the moths involved shifts in combinations of partially correlated traits, rather than any one trait. The results indicate that the geographic mosaic of coevolution can be amplified as coevolving lineages diversify into separate species and come together in different combinations in different ecosystems. PMID- 28731802 TI - Neurovascular Structures at Risk With Curved Retrograde TTC Fusion Nails. AB - BACKGROUND: The purpose of this study was to assess the risk of iatrogenic injury to plantar neurovascular structures of the foot during insertion of a curved retrograde tibiotalocalcaneal (TTC) fusion nail. MATERIAL AND METHODS: Ten below knee thawed fresh-frozen cadaveric specimens underwent curved retrograde nailing of the ankle. The shortest distance between the nail and the main plantar neurovascular branches and injured structures were recorded during dissection. We also evaluated the relative position of these structures along 2 lines (AB, connecting the calcaneus to the first metatarsal, and BC, connecting the first and fifth metatarsal). RESULTS: The lateral plantar artery was found to be in direct contact with the nail 70% of the time, with a macroscopic laceration 30% of the time. The Baxter nerve was injured 20% of the time, as was the lateral plantar nerve. The medial plantar artery and nerve were never injured. The most proximal structure to cross line AB was the Baxter nerve followed by the lateral plantar artery, the nail, the lateral plantar nerve, and the medial plantar nerve. CONCLUSION: Our cadaveric anatomic study found that the most common structures at risk for iatrogenic injury by lateral curved retrograde TTC fusion nails were the lateral plantar artery and nerve, and the Baxter nerve. CLINICAL RELEVANCE: Determination of a true neurovascular safe zone is challenging and therefore warrants careful operative dissection to minimize neurovascular injuries. PMID- 28731803 TI - Finding the Best Recall and Cancer Detection Rates for Screening Mammography. PMID- 28731804 TI - Nuclear Medicine and Molecular Imaging-An Impactful Decade of Contributions to Patient Care and Driving Precision Medicine. PMID- 28731805 TI - Reply to "Finding the Best Recall and Cancer Detection Rates for Screening Mammography". PMID- 28731806 TI - Digital Breast Tomosynthesis Assists in Differentiating Vascular Calcification From Malignant Calcification. PMID- 28731807 TI - Distribution of Citations Received by Scientific Papers Published in the Imaging Literature From 2001 to 2010: Decreasing Inequality and Polarization. AB - OBJECTIVE: The objective of this study was to assess the distribution of citations received by scientific papers published in the imaging literature between 2001 and 2010. MATERIALS AND METHODS: We extracted the number of citations of all articles and reviews for 5 years after publication using the Scopus (Elsevier) citation database of imaging journals between 2001 and 2010. We quantitatively analyzed article and review citations from each journal and each year, including the number, proportion, and annual number of citations of the most- (>= 20 citations) and least-cited (three or fewer citations) papers; ratio of most-cited to least-cited papers; 75/25 percentile citation ratio; 90/10 percentile citation ratio; Gini coefficient; and Kolkata index. RESULTS: Our analysis of 124,331 articles and 13,575 reviews from 121 journals showed that the proportion of most-cited articles (from 19.6% to 27.1%) and reviews (from 19.1% to 37.2%) increased from 2001 to 2010, whereas the proportion of least-cited articles (from 32.3% to 23.0%) and reviews (from 31.9% to 15.8%) declined over the same period. The annual numbers of citations of most-cited articles and reviews both reached a peak in the fourth year after publication, whereas those of least-cited articles and reviews reached a peak in the second and fist years, respectively, after publication and thereafter decreased. The 75/25 percentile ratio for articles declined from 41.1 to 27.5 between 2001 and 2010. Over the same time, the 75/25 percentile ratio for reviews declined from 47.4 to 22.9. The 90/10 percentile ratio for articles declined from 1730.8 to 188.7; for reviews, the 90/10 percentile ratio declined from 5788.0 to 100.7. The Gini coefficient of articles and reviews also declined from 0.6116 to 0.5721 for articles and from 0.6507 to 0.5649 for reviews; the k index, from 0.7260 to 0.7088 for articles from 0.7409 to 0.7072 for reviews. CONCLUSION: Inequality and polarization of citations consistently decreased in the imaging literature from 2001 to 2010. PMID- 28731808 TI - Clinical Practice in PET/CT for the Management of Head and Neck Squamous Cell Cancer. AB - OBJECTIVE: The purpose of this article is to summarize the evidence for the value of PET/CT for the management of patients with head and neck squamous cell cancer and suggest best clinical practices. CONCLUSION: FDG PET/CT is a valuable imaging tool for identifying unknown primary tumors in patients with known cervical node metastases leading to management change and is the standard of care for the initial staging of stage III and IV head and neck squamous cell carcinomas (HNSCCs), for assessing therapy response when performed at least 12 weeks after chemoradiation therapy, and for avoiding unnecessary planned neck dissection. Neck dissection is avoided if PET/CT findings are negative-regardless of the size of the residual neck nodes-because survival outcomes are not compromised. FDG PET/CT is valuable in detecting recurrences and metastases during follow-up when suspected because of clinical symptoms and serves as a prognostic marker for patient survival outcomes, for 5 years. Using FDG PET/CT for routine surveillance of HNSCC after 6 months of treatment without any clinical suspicion should be discouraged. PMID- 28731809 TI - Reply to "Digital Breast Tomosynthesis Assists in Differentiating Vascular Calcification From Malignant Calcification". PMID- 28731810 TI - Medicolegal-Malpractice and Ethical Issues in RadiologyAmended Versus Addended Versus Addendum Reports. PMID- 28731811 TI - Correction. PMID- 28731812 TI - 3D-Printed Visceral Aneurysm Models Based on CT Data for Simulations of Endovascular Embolization: Evaluation of Size and Shape Accuracy. AB - OBJECTIVE: The objective of this study is to verify the accuracy of 3D-printed hollow models of visceral aneurysms created from CT angiography (CTA) data, by evaluating the sizes and shapes of aneurysms and related arteries. SUBJECTS AND METHODS: From March 2006 to August 2015, 19 true visceral aneurysms were embolized via interventional radiologic treatment provided by the radiology department at our institution; aneurysms with bleeding (n = 3) or without thin slice (< 1 mm) preembolization CT data (n = 1) were excluded. A total of 15 consecutive true visceral aneurysms from 11 patients (eight women and three men; mean age, 61 years; range, 53-72 years) whose aneurysms were embolized via endovascular procedures were included in this study. Three-dimensional-printed hollow models of aneurysms and related arteries were fabricated from CTA data. The accuracies of the sizes and shapes of the 3D-printed hollow models were evaluated using the nonparametric Wilcoxon signed rank test and the Dice coefficient index. RESULTS: Aneurysm sizes ranged from 138 to 18,691 mm3 (diameter, 6.1-35.7 mm), and no statistically significant difference was noted between patient data and 3D-printed models (p = 0.56). Shape analysis of whole aneurysms and related arteries indicated a high level of accuracy (Dice coefficient index value, 84.2-95.8%; mean [+/- SD], 91.1 +/- 4.1%). CONCLUSION: The sizes and shapes of 3D-printed hollow visceral aneurysm models created from CTA data were accurate. These models can be used for simulations of endovascular treatment and precise anatomic information. PMID- 28731813 TI - Reply to "Relative Utility or Marginal Positive Predictive Values Accounting for Overdiagnosis Should Guide Optimal Recall Rates". PMID- 28731814 TI - Biliopancreatic Reflux Shown on Gadoxetic Acid-Enhanced MRI. PMID- 28731815 TI - Reply to "Biliopancreatic Reflux Shown on Gadoxetic Acid-Enhanced MRI". PMID- 28731816 TI - Relative Utility or Marginal Positive Predictive Values Accounting for Overdiagnosis Should Guide Optimal Recall Rates. PMID- 28731817 TI - Infrared Spectrometer for ExoMars: A Mast-Mounted Instrument for the Rover. AB - ISEM (Infrared Spectrometer for ExoMars) is a pencil-beam infrared spectrometer that will measure reflected solar radiation in the near infrared range for context assessment of the surface mineralogy in the vicinity of the ExoMars rover. The instrument will be accommodated on the mast of the rover and will be operated together with the panoramic camera (PanCam), high-resolution camera (HRC). ISEM will study the mineralogical and petrographic composition of the martian surface in the vicinity of the rover, and in combination with the other remote sensing instruments, it will aid in the selection of potential targets for close-up investigations and drilling sites. Of particular scientific interest are water-bearing minerals, such as phyllosilicates, sulfates, carbonates, and minerals indicative of astrobiological potential, such as borates, nitrates, and ammonium-bearing minerals. The instrument has an ~1 degrees field of view and covers the spectral range between 1.15 and 3.30 MUm with a spectral resolution varying from 3.3 nm at 1.15 MUm to 28 nm at 3.30 MUm. The ISEM optical head is mounted on the mast, and its electronics box is located inside the rover's body. The spectrometer uses an acousto-optic tunable filter and a Peltier-cooled InAs detector. The mass of ISEM is 1.74 kg, including the electronics and harness. The science objectives of the experiment, the instrument design, and operational scenarios are described. Key Words: ExoMars-ISEM-Mars-Surface-Mineralogy Spectroscopy-AOTF-Infrared. Astrobiology 17, 542-564. PMID- 28731818 TI - The ADRON-RM Instrument Onboard the ExoMars Rover. AB - This overview presents the physical principles, design, measurement capabilities, and summary of planned operations of the autonomous detector of radiation of neutrons onboard rover at Mars (ADRON-RM) on the surface of Mars. ADRON-RM is a Russian project selected for the joint European Space Agency-Roscosmos ExoMars 2020 landing mission. A compact passive neutron spectrometer, ADRON-RM, was designed to study the abundance and distribution of water and neutron absorption elements (such as Cl, Fe, and others) in the martian subsurface along the path of the ExoMars rover. Key Words: Mars exploration-Surface-Neutron Spectroscopy Water. Astrobiology 17, 585-594. PMID- 28731819 TI - The Close-Up Imager Onboard the ESA ExoMars Rover: Objectives, Description, Operations, and Science Validation Activities. AB - The Close-Up Imager (CLUPI) onboard the ESA ExoMars Rover is a powerful high resolution color camera specifically designed for close-up observations. Its accommodation on the movable drill allows multiple positioning. The science objectives of the instrument are geological characterization of rocks in terms of texture, structure, and color and the search for potential morphological biosignatures. We present the CLUPI science objectives, performance, and technical description, followed by a description of the instrument's planned operations strategy during the mission on Mars. CLUPI will contribute to the rover mission by surveying the geological environment, acquiring close-up images of outcrops, observing the drilling area, inspecting the top portion of the drill borehole (and deposited fines), monitoring drilling operations, and imaging samples collected by the drill. A status of the current development and planned science validation activities is also given. Key Words: Mars-Biosignatures Planetary Instrumentation. Astrobiology 17, 595-611. PMID- 28731820 TI - Uncommon neoplasms of the biliary tract: radiological findings. AB - OBJECTIVE: To report our cancer centre experience in the biliary tumours incidence other than cholangiocellular-carcinoma, emphasizing the radiological features. METHODS: 197 patients with biliary disease undergoing Gd-EOB-DTPA enhanced MRI were reviewed. Four radiologists evaluated retrospectively size, structure, anatomical site and signal intensity of lesions on MRI. Enhancement pattern during the arterial-, portal- and late-phase on ultrasound, CT and MR study was assessed as well as the enhancement pattern during the hepatobiliary phase on MRI. RESULTS: 23 patients were selected. The lesion was intraductal in 5 cases, periductal in 14 and intrahepatic in 4. 16 lesions were solid, 5 uniloculated cystic and 2 complex cystic. In five patients the lesion was simple cyst, with a signal intensity in T1 weighted (T1W) and T2 weighted (T2W) similar to the gallbladder. In two patients with complex cystic lesion, the solid component was heterogeneously hypointense in T1 W, hyperintense in T2 W with a restricted diffusion. The solid component showed heterogeneous contrast enhancement on CT, MR and ultrasound. The tumour was intrahepatic in two patients, with signal hypointense in T1 W and hyperintense in T2 W. Diffusion was restricted. The lesions showed heterogeneous contrast-enhancement. The periductal lesions were hypointense in T1 W, hyperintense in T2 W with restricted diffusion. The lesion showed progressive contrast-enhancement. Peribiliary melanoma was hyperintense in T1 W, hyperintense in T2 W with restricted diffusion and progressively contrast-enhanced. CONCLUSION: Biliary tumours can have a wide spectrum of radiologic appearances and consequently represent a diagnostic challenge for the radiologist. Advances in knowledge: MRI is the technique of choice in diagnosing biliary tumours, including rare (non-CCC) tumours. PMID- 28731821 TI - Trust in Physicians, Continuity and Coordination of Care, and Quality of Death in Patients with Advanced Cancer. AB - BACKGROUND: Provider-centered factors contribute to unexplained variation in the quality of death (QOD). The relationship between healthcare providers (HCPs) and patients, bidirectional communication, and consistency of longitudinal care planning are important provider-centered factors. OBJECTIVE: To explore whether the level of trust in HCPs, the quality of continuity of care, and the level of coordination of care among home HCPs are associated with the QOD for cancer patients dying at home. DESIGN: This study was a part of a nationwide multicenter questionnaire survey of bereaved family members of cancer patients evaluating the quality of end-of-life care in Japan. SETTING/SUBJECTS: We investigated 702 family members of cancer patients who died at home. MEASUREMENTS: The QOD was evaluated from nine core domains of the short version of the Good Death Inventory (GDI). We measured five factors on a Likert scale, including patient and family trust in HCPs, continuity of care by home hospice and hospital physicians, and coordination of care among home hospice staff. RESULTS: A total of 538 responses (77%) were obtained and 486 responses were analyzed. Trust in HCPs was correlated with the GDI score (r = 0.300-0.387, p < 0.001). The quality of care coordination was associated with the GDI score (r = 0.242, p < 0.001). CONCLUSIONS: Trust of the patient and family in home hospice staff, as well as coordination of care among hospice staff, are associated with the QOD for cancer patients dying at home. PMID- 28731822 TI - Treatments for Idiopathic Granulomatous Mastitis: Systematic Review and Meta Analysis. AB - OBJECTIVES: Idiopathic granulomatous mastitis (IGM) is a benign breast disease with no ideal treatment regimen so far. This study aimed to evaluate the complete remission/resolution (CR) rate and recurrence rate of different treatment options. METHODS: We systematically searched and identified eligible studies from January 1, 2010, to December 31, 2015, in PubMed, EMBASE, Cochrane Central Register of Controlled Trials, and Medline databases. We included original studies reporting the CR and/or recurrence rate of each treatment used. The pooled incidence and 95% confidence interval (95% CI) for CR and recurrence rate were calculated using Stata 13.0. RESULTS: Fifteen eligible studies were included in our study. Six, nine, and five studies with 138, 358, and 106 patients were analyzed for surgical managements, oral steroids, and oral steroids+surgical managements, respectively. The pooled estimates for CR rate of them were 90.6% (95% CI 83.8%, 95.7%), 71.8% (95% CI 67.1%, 76.3%), and 94.5% (95% CI 88.9%, 98.3%). The pooled estimates for recurrence rate were 6.8% (95% CI 3.3%, 11.5%), 20.9% (95% CI 9.2%, 16.1%), and 4.0% (95% CI 1.5%, 8.4%), respectively. Other interventions analyzed were topical steroids, observation, oral steroids+MTX, and steroids+prolactin lowering agent, with varied pooled estimates for CR and recurrence rate. CONCLUSION: Surgical managements had high CR rate with relatively low recurrence rate, with or without steroids. Thus, it was suitable for patients requiring rapid remission. However, for patients with concerns about surgical scarring, oral steroids could be an acceptable option. Further investigations are still needed to better understand the managements of IGM. PMID- 28731823 TI - Maternal-Fetal Outcomes in 34 Pregnant Women with Type 1 Diabetes in Sensor Augmented Insulin Pump Therapy. AB - BACKGROUND: Pregnancy in women with type 1 diabetes (T1D) is associated with increased risk of maternal complications and neonatal morbidity and mortality. Optimizing glycemic control improves these outcomes. OBJECTIVE: To describe the experience of using sensor-augmented insulin pump therapy (SAPT) and SAPT + low glucose suspension (LGS) on pregnant women with T1D, including neonatal and maternal outcomes. METHODS: A prospective observational study was conducted in women with T1D who started SAPT and SAPT + LGS before or during pregnancy at the San Ignacio University Hospital Diabetes Center in Bogota, Colombia. The main indication was severe hypoglycemia (SH) and poor glycemic control. Glycated hemoglobin (A1c), hypoglycemia, and maternal and fetal outcomes were assessed. RESULTS: Thirty-four pregnant women with T1D on SAPT and SAPT + LGS were included. Sixteen patients started therapy during pregnancy at a mean gestational age of 17.6 +/- 8.3 weeks. Mean preconceptional A1c was 8.24% +/- 2.02%. Absolute reduction of A1c level from prepregnancy to third trimester was -1.63% (P < 0.0001), with a significant clinical and statistical reduction in both groups, women who initiated SAPT before or during pregnancy. 52.9% of patients in second trimester and 66.6% in third trimester achieved A1c <6.5%, respectively. 91.1% underwent cesarean section. The main reasons were iterative cesarean (30%), fetal distress (20%), and preeclampsia (16%). The median gestational age at delivery was 37 weeks and 15 pregnancies resulted in preterm delivery. There was neither maternal-fetal mortality nor severe hypoglycemic episodes. Two patients had diabetic ketoacidosis. CONCLUSIONS: In pregnant patients with T1D and high risk of hypoglycemia, SAPT and SAPT + LGS should be considered as a therapeutic alternative for A1c reduction with a low risk of SH. However, additional studies are required to evaluate the efficacy and safety of this therapy during pregnancy. PMID- 28731824 TI - Evolutionary Scenarios and Primate Natural History. AB - Scenarios summarize evolutionary patterns and processes by interpreting organismal traits and their natural history correlates in a phylogenetic context. They are constructed by (1) describing phenotypes (including physiology and behavior), ideally with attention to formative roles of development, experience, and culture; (2) inferring homologies, homoplasies, ancestral character states, and their transformations with phylogenetic analyses; and (3) integrating those components with ecological and other ancillary data. At their best, evolutionary scenarios are factually dense narratives that entail no known falsehoods; their empirical and methodological shortcomings are transparent, they might be rejected based on new discoveries, and their potential ideological pitfalls are flagged for scrutiny. They are exemplified here by homoplastic foraging with percussive tools by humans, chimpanzees, capuchins, and macaques; homoplastic hunting with spears by humans and chimpanzees; and private experiences (e.g., sense of fairness, grief) among diverse animals, the homologous or homoplastic status of which often remains unexplored. Although scenarios are problematic when used to bolster political agendas, if constructed carefully and regarded skeptically, they can synthesize knowledge, inspire research, engender public understanding of evolution, enrich ethical debates, and provide a deeper historical context for conservation, including nature appreciation. PMID- 28731825 TI - Convergent Phenotypic Evolution despite Contrasting Demographic Histories in the Fauna of White Sands. AB - When are evolutionary outcomes predictable? Cases of convergent evolution can shed light on when, why, and how different species exhibit shared evolutionary trajectories. In particular, studying diverse species in a common environment can illuminate how different factors facilitate or constrain adaptive evolution. Here we integrate studies of pattern and process in the fauna at White Sands (New Mexico) to understand the determinants of convergent evolution. Numerous animal species at White Sands exhibit phenotypic convergence in response to a novel-and shared-selective environment: geologically young gypsum dunes. We synthesize 15 years of research on White Sands lizards to assess the contribution of natural selection, genetic architecture, and population demography to patterns of phenotypic evolution. We also present new data for two species of White Sands arthropods, Ammobaenetes arenicolus and Habronattus ustulatus. Overall, we find dramatic phenotypic convergence across diverse species at White Sands. Although the direction of phenotypic response is parallel, the magnitude of phenotypic response varies among species. We also find that species exhibit strikingly different demographic patterns across the ecotone. The species with the most genetic structure between White Sands and dark-soil populations generally exhibit the least phenotypic divergence, suggesting population demography as a key modulator of adaptation. Comparative studies are particularly important for understanding the determinants of convergence in natural systems. PMID- 28731826 TI - Convergently Evolved Toxic Secondary Metabolites in Plants Drive the Parallel Molecular Evolution of Insect Resistance. AB - Natural selection imposed by natural toxins has led to striking levels of convergent evolution at the molecular level. Cardiac glycosides represent a group of plant toxins that block the Na,K-ATPase, a vital membrane protein in animals. Several herbivorous insects have convergently evolved resistant Na,K-ATPases, and in some species, convergent gene duplications have also arisen, likely to cope with pleiotropic costs of resistance. To understand the genetic basis and predictability of these adaptations, we studied five independent lineages of leaf mining flies (Diptera: Agromyzidae). These flies have colonized host plants in four botanical families that convergently evolved cardiac glycosides of two structural types: cardenolides and bufadienolides. We compared each of six fly species feeding on such plants to a phylogenetically related but nonadapted species. Irrespective of the type of cardiac glycoside in the host plant, five out of six exposed species displayed substitutions in the cardiac glycoside binding site of the Na,K-ATPase that were previously described in other insect orders; in only one species was the gene duplicated. In vitro assays of nervous tissue extractions confirmed that the substitutions lead to increased resistance of the Na,K-ATPase. Our results demonstrate that target site insensitivity of Na,K-ATPase is a common response to dietary cardiac glycosides leading to highly predictable amino acid changes; nonetheless, convergent evolution of gene duplication for this multifunctional enzyme appears more constrained. PMID- 28731827 TI - Convergence, Consilience, and the Evolution of Temperate Deciduous Forests. AB - The deciduous habit of northern temperate trees and shrubs provides one of the most obvious examples of convergent evolution, but how did it evolve? Hypotheses based on the fossil record posit that deciduousness evolved first in response to drought or darkness and preadapted certain lineages as cold climates spread. An alternative is that evergreens first established in freezing environments and later evolved the deciduous habit. We monitored phenological patterns of 20 species of Viburnum spanning tropical, lucidophyllous (subtropical montane and warm temperate), and cool temperate Asian forests. In lucidophyllous forests, all viburnums were evergreen plants that exhibited coordinated leaf flushes with the onset of the rainy season but varied greatly in the timing of leaf senescence. In contrast, deciduous species exhibited tight coordination of both flushing and senescence, and we found a perfect correlation between the deciduous habit and prolonged annual freezing. In contrast to previous stepwise hypotheses, a consilience of independent lines of evidence supports a lockstep model in which deciduousness evolved in situ, in parallel, and concurrent with a gradual cooling climate. A pervasive selective force combined with the elevated evolutionary accessibility of a particular response may explain the massive convergence of adaptive strategies that characterizes the world's biomes. PMID- 28731828 TI - Geographical Variation in Community Divergence: Insights from Tropical Forest Monodominance by Ectomycorrhizal Trees. AB - Convergence occurs in both species traits and community structure, but how convergence at the two scales influences each other remains unclear. To address this question, we focus on tropical forest monodominance, in which a single, often ectomycorrhizal (EM) tree species occasionally dominates forest stands within a landscape otherwise characterized by diverse communities of arbuscular mycorrhizal (AM) trees. Such monodominance is a striking potential example of community divergence resulting in alternative stable states. However, it is observed only in some tropical regions. A diverse suite of AM and EM trees locally codominate forest stands elsewhere. We develop a hypothesis to explain this geographical difference using a simulation model of plant community assembly. Simulation results suggest that in a region with a few EM species (e.g., South America), EM trees experience strong selection for convergent traits that match the abiotic conditions of the environment. Consequently, EM species successfully compete against other species to form monodominant stands via positive plant-soil feedbacks. By contrast, in a region with many EM species (e.g., Southeast Asia), species maintain divergent traits because of complex plant-soil feedbacks, with no species having traits that enable monodominance. An analysis of plant trait data from Borneo and Peruvian Amazon was inconclusive. Overall, this work highlights the utility of geographical comparison in understanding the relationship between trait convergence and community convergence. PMID- 28731829 TI - Pattern and Process in the Comparative Study of Convergent Evolution. AB - Understanding processes that have shaped broad-scale biodiversity patterns is a fundamental goal in evolutionary biology. The development of phylogenetic comparative methods has yielded a tool kit for analyzing contemporary patterns by explicitly modeling processes of change in the past, providing neontologists tools for asking questions previously accessible only for select taxa via the fossil record or laboratory experimentation. The comparative approach, however, differs operationally from alternative approaches to studying convergence in that, for studies of only extant species, convergence must be inferred using evolutionary process models rather than being directly measured. As a result, investigation of evolutionary pattern and process cannot be decoupled in comparative studies of convergence, even though such a decoupling could in theory guard against adaptationist bias. Assumptions about evolutionary process underlying comparative tools can shape the inference of convergent pattern in sometimes profound ways and can color interpretation of such patterns. We discuss these issues and other limitations common to most phylogenetic comparative approaches and suggest ways that they can be avoided in practice. We conclude by promoting a multipronged approach to studying convergence that integrates comparative methods with complementary tests of evolutionary mechanisms and includes ecological and biogeographical perspectives. Carefully employed, the comparative method remains a powerful tool for enriching our understanding of convergence in macroevolution, especially for investigation of why convergence occurs in some settings but not others. PMID- 28731830 TI - Convergence and Divergence in a Long-Term Experiment with Bacteria. AB - Suitably designed experiments offer the possibility of quantifying evolutionary convergence because the fraction of replicate populations that converge is known. Here I review an experiment with Escherichia coli, in which 12 populations were founded from the same ancestral strain and have evolved for almost 30 years and more than 65,000 generations under the same conditions. The tension between divergence and convergence has been a major focus of this experiment. I summarize analyses of competitive fitness, correlated responses to different environments, cell morphology, the capacity to use a previously untapped resource, mutation rates, genomic changes, and within-population polymorphisms. These analyses reveal convergence, divergence, and often a complicated mix thereof. Complications include concordance in the direction of evolutionary change with sustained quantitative variation among populations, and the potential for a given trait to exhibit divergence on one timescale and convergence on another. Despite these complications, which also occur in nature, experiments provide a powerful way to study evolutionary convergence based on analyzing replicate lineages that experience the same environment. PMID- 28731831 TI - Toward a Predictive Framework for Convergent Evolution: Integrating Natural History, Genetic Mechanisms, and Consequences for the Diversity of Life. AB - A charm of biology as a scientific discipline is the diversity of life. Although this diversity can make laws of biology challenging to discover, several repeated patterns and general principles govern evolutionary diversification. Convergent evolution, the independent evolution of similar phenotypes, has been at the heart of one approach to understand generality in the evolutionary process. Yet understanding when and why organismal traits and strategies repeatedly evolve has been a central challenge. These issues were the focus of the American Society of Naturalists Vice Presidential Symposium in 2016 and are the subject of this collection of articles. Although naturalists have long made inferences about convergent evolution and its importance, there has been confusion in the interpretation of the pattern of convergence. Does convergence primarily indicate adaptation or constraint? How often should convergence be expected? Are there general principles that would allow us to predict where and when and by what mechanisms convergent evolution should occur? What role does natural history play in advancing our understanding of general evolutionary principles? In this introductory article, I address these questions, review several generalizations about convergent evolution that have emerged over the past 15 years, and present a framework for advancing the study and interpretation of convergence. Perhaps the most important emerging conclusion is that the genetic mechanisms of convergent evolution are phylogenetically conserved; that is, more closely related species tend to share the same genetic basis of traits, even when independently evolved. Finally, I highlight how the articles in this special issue further develop concepts, methodologies, and case studies at the frontier of our understanding of the causes and consequences of convergent evolution. PMID- 28731832 TI - Effects of Cervical High-Velocity Low-Amplitude Techniques on Range of Motion, Strength Performance, and Cardiovascular Outcomes: A Review. AB - BACKGROUND: Cervical high-velocity low-amplitude (HVLA) manipulation technique is among the oldest and most frequently used chiropractic manual therapy, but the physiologic and biomechanics effects were not completely clear. OBJECTIVE: This review aims to describe the effects of cervical HVLA manipulation techniques on range of motion, strength, and cardiovascular performance. METHODS/DESIGN: A systematic search was conducted of the electronic databases from January 2000 to August 2016: PubMed (n = 131), ScienceDirect (n = 101), Scopus (n = 991), PEDro (n = 33), CINAHL (n = 884), and SciELO (n = 5). Two independent reviewers conducted the screening process to determine article eligibility. The intervention that included randomized controlled trials was thrust, or HVLA, manipulative therapy directed to the cervical spine. Methodological quality was assessed using the Cochrane risk-of-bias tool. The initial search rendered 2145 articles. After screening titles and abstracts, 11 articles remained for full text review. RESULTS: The review shows that cervical HVLA manipulation treatment results in a large effect size (d > 0.80) on increasing cervical range of motion and mouth opening. In patients with lateral epicondylalgia, cervical HVLA manipulation resulted in increased pain-free handgrip strength, with large effect sizes (1.44 and 0.78, respectively). Finally, in subjects with hypertension the blood pressure seemed to decrease after cervical HVLA manipulation. Higher quality studies are needed to develop a stronger evidence-based foundation for HVLA manipulation techniques as a treatment for cervical conditions. PMID- 28731833 TI - The Dishwater Menace: Healthy Drinking Spaces and the Public Good in Post Prohibition Ontario. AB - This paper examines inter-bureaucracy tension, negotiation, and resolution in the case of the oversight of beverage room sanitation in Ontario in the 1930s and 1940s. Both the Liquor Control Board of Ontario (LCBO) and various public health authorities claimed authority over the health status of public drinking spaces. But the LCBO had legislative priority. The ensuing debates regarding health and cleanliness linked issues of beverage room glass sanitation to a biopolitical approach to public drinking. Developing a more scientifically sophisticated approach to beverage glass cleaning required a balancing of administrative priorities. Perfect sanitation was expensive and complicated, and the LCBO's mandate demanded attention to the financial viability of beverage rooms. The LCBO needed to forge a trade off between safety and viability, while maintaining a public drinking system that dissuaded illegal drinking. The subsequent compromise in beverage room glass sanitation tied contemporary chemical sanitizers to the challenging economics of depression-era beverage room management. PMID- 28731834 TI - The Essential Oil of Hyptis mutabilis in Ichthyophthirius multifiliis Infection and its Effect on Hematological, Biochemical, and Immunological Parameters in Silver Catfish, Rhamdia quelen. AB - This study evaluated the activity of leaf essential oil (EO) from Hyptis mutabilis as well as its major constituent, (-)-globulol, in infections by the parasite Ichthyophthirius multifiliis (ich). Effects on hematological, biochemical, and immunological parameters of silver catfish, Rhamdia quelen, exposed to the same samples also were evaluated. In the first experiment, naturally infected fish were treated with EO (0, 10, and 20 mg . L-1) and ethanol, using several methods of exposure. Fish mortality and the number of trophonts per fish were assessed after 48 and 96 hr. Hour-long daily baths resulted in optimal survival, so this methodology was used for the second experiment, in which infected animals were exposed to (-)-globulol at 2.5 and 5 mg . L-1. The most effective concentrations in Experiments 1 and 2 were chosen for Experiment 3, in which healthy animals were subjected to hour-long daily baths with EO (20 mg . L-1) or (-)-globulol (2.5 mg . L-1). Additionally, an in vitro experiment was performed with EO and globulol at the same concentrations of the in vivo test. EO and (-)-globulol increased the survival of fish infected with ich and altered certain hematological and biochemical parameters. After 4 days, levels of hematocrit, erythrocytes, and leukocytes increased significantly in healthy animals exposed to EO. Exposure to (-)-globulol increased leukocyte number alone. No significant differences in nonspecific immunological parameters were detected when treated groups were compared to controls, but the leukocytosis observed in EO- and globulol-treated healthy animals indicates that EO and (-) globulol increased innate immunity in these fish. An in vitro antiparasitic effect was observed in both samples. PMID- 28731835 TI - Alternative Facts. PMID- 28731836 TI - Mortality Rate and Antibiotic Resistance in Complicated Diverticulitis: Report of 272 Consecutive Patients Worldwide: A Prospective Cohort Study. AB - BACKGROUND: Complicated diverticulitis (CD) is a common problem for surgeons. In treating it, as a general principle, every verified source of infection should be controlled. Supplementary antimicrobial management involves a delicate balance of optimizing empirical therapy while reducing unnecessary antibiotic use. The necessity to know the most frequent infecting pathogens and their spectra of resistance is becoming pivotal. The aim of this study was to determine the microbiologic profile of complicated intra-abdominal infections (IAIs) secondary to CD, to analyze the role of empirical antimicrobial therapy, and to describe the clinical aspects of CD worldwide. MATERIAL AND METHODS: The study derives from two multicenter prospective observational studies: CIAO (Complicated Intra Abdominal infection Observational study) and CIAOW (Complicated Intra-Abdominal infection Observational World" study). The aim of the study was to analyze the intra-abdominal bacteriology in complicated diverticulitis and its relation to the clinical outcome. RESULTS: The 272 patients had a mean/median age of 66.3 +/- 14.9 (standard deviation; SD) and 69 (range 18-99). Patients >70 years old totaled 122 (44.9%). Conditions at admission were sepsis in 113 patients (41.5%) and severe sepsis and septic shock in 37 (13.6%) and 21 (7.7%), respectively; and localized peritonitis in 148 patients (54.4%), whereas in 124 (45.6%), the condition was generalized. Some 94 patients (34.6%) experienced a delay in initial intervention (>24 h). The mean and median duration of antimicrobial therapy were 12.3 +/- 8.7 (standard deviation) and 10 (range 1-59) days. A total of 162 patients (59.6%) obtained adequate empirical antibiotic therapy, and 96 patients (35.3%) were admitted to the intensive care unit (ICU). The 30-day mortality rate was 12.1%. A total of 311 bacteria were isolated: 136 (43.7%) gram negative, 76 (24.4%) gram-positive, 22 (7%) fungi, and 77 (24.7%) anaerobes. Of the 363 bacteria isolated, 22 (7%) were drug resistant. Four of these infections (22.2%) were health-care-associated and 18 (5.7%) community-acquired. By univariable analysis, the only statistically significant factor associated with resistant bacteria was inadequacy of the empirical antimicrobial therapy (p = 0.004). The factors associated with death were delay in initial intervention (p = 0.006) and ICU admission because of severe sepsis on admission (p = 0.004). CONCLUSION: Early source control is mandatory to reduce the mortality rate in complicated diverticulitis. Effective empirical antimicrobial agent therapy is necessary to reduce resistance and improve the clinical outcome. PMID- 28731837 TI - Surrogate Decision Making When Patients Cannot Decide within the Veterans Health Administration System. PMID- 28731838 TI - Neuroprotection in Glaucoma: Animal Models and Clinical Trials. AB - Glaucoma is a progressive neurodegenerative disease that frequently results in irreversible blindness. Glaucoma causes death of retinal ganglion cells (RGCs) and their axons in the optic nerve, resulting in visual field deficits and eventual loss of visual acuity. Glaucoma is a complex optic neuropathy, and a successful strategy for its treatment requires not only better management of known risk factors such as elevated intraocular pressure and the development of improved tools for detecting RGC injury but also treatments that address this injury (i.e., neuroprotection). Experimental models of glaucoma provide insight into the cellular and molecular mechanisms of glaucomatous optic neuropathy and aid the development of neuroprotective therapies. PMID- 28731839 TI - Cost-Benefit Arbitration Between Multiple Reinforcement-Learning Systems. AB - Human behavior is sometimes determined by habit and other times by goal-directed planning. Modern reinforcement-learning theories formalize this distinction as a competition between a computationally cheap but inaccurate model-free system that gives rise to habits and a computationally expensive but accurate model-based system that implements planning. It is unclear, however, how people choose to allocate control between these systems. Here, we propose that arbitration occurs by comparing each system's task-specific costs and benefits. To investigate this proposal, we conducted two experiments showing that people increase model-based control when it achieves greater accuracy than model-free control, and especially when the rewards of accurate performance are amplified. In contrast, they are insensitive to reward amplification when model-based and model-free control yield equivalent accuracy. This suggests that humans adaptively balance habitual and planned action through on-line cost-benefit analysis. PMID- 28731840 TI - Clinical Effect of Rebound Hyperthermia After Cooling Postcardiac Arrest: A Meta Analysis. AB - Rebound hyperthermia (RH) is frequently seen after completion of targeted temperature management (TTM) in comatose survivors of cardiac arrest. However, its clinical significance is not well understood. Previous studies analyzing the association of RH with clinical outcome have reported conflicting results. The purpose of this meta-analysis is to examine the impact of RH after completion of TTM in patients postcardiac arrest. We reviewed six studies that evaluated the incidence of RH (T > 38 degrees C) with documentation of outcome based on the presence of hyperthermia. We reviewed all six articles and extracted the data for mortality and neurological outcome. A total of 729 patients were analyzed for neurological outcome and 950 patients were analyzed for mortality. RH was found to be associated with a significantly worse neurological outcome (odds ratio [OR] 1.55; 95% confidence interval [CI] 1.13-2.14). RH was not significantly associated with a higher mortality (OR 1.31; 95% CI 1.00-1.72). We also analyzed three studies totaling 206 patients for neurological outcomes and mortality that included patients with severe RH (T > 38.5 degrees C). Severe RH was found to be associated with significantly worse neurological outcome (OR 1.92, 95% CI 1.28 1.90) and significantly worse mortality (OR 2.22, 95% CI 1.50-3.29). RH is common after completion of TTM in comatose patients because of cardiac arrest and is associated with poor neurological outcomes. The clinical impact of RH is likely proportional to the magnitude of RH. PMID- 28731841 TI - Survey of Nutrition Management Practices in Centers for Pediatric Intestinal Rehabilitation. AB - BACKGROUND: Nutrition management of pediatric intestinal failure (IF) requires interdisciplinary coordination of parenteral nutrition (PN) and enteral nutrition (EN) support. Nutrition strategies used by specialists in pediatric intestinal rehabilitation to promote gut adaptation and manage complications have not been previously summarized. METHODS: A practice survey was distributed to members of the dietitian subgroup of the American Society for Parenteral and Enteral Nutrition Pediatric Intestinal Failure Section. The survey included 24 open-ended questions related to PN and enteral feeding strategies, nutrition management of PN-associated liver disease, and laboratory monitoring. RESULTS: Dietitians from 14 centers completed the survey. Management components for patients at risk for cholestasis were consistent and included fat minimization, trace element modification, avoiding PN overfeeding, and providing EN. Parenteral amino acid solutions designed for infants/young children are used in patients <1 or 2 years of age. Trace minerals are dosed individually in 10 of 14 centers. Eleven centers prescribe a continuous infusion of breast milk or elemental formula 1-2 weeks after resection while 3 centers determine the formula type by the extent of resection. Most (86%) centers do not have a protocol for initiating oral/motor therapy. Laboratory panel composition varied widely by center. The selection and frequency of use depended on clinical variables, including cholestatic status, exclusive vs partial PN dependence, postrepletion verification vs routine monitoring, intestinal anatomy, and acuity of care. CONCLUSION: EN and PN management strategies are relatively consistent among U.S. centers. Collaborative initiatives are necessary to define better practices and establish laboratory monitoring guidelines. PMID- 28731842 TI - Role of Pepsin and Oropharyngeal pH-Monitoring to Assess the Postoperative Outcome of Patients with Laryngopharyngeal Reflux: Results of a Pilot Trial. AB - BACKGROUND: The aim of this study was to evaluate the value of salivary pepsin and oropharyngeal pH-monitoring to assess the surgical outcome of patients with laryngopharyngeal reflux (LPR). MATERIALS AND METHODS: Twenty consecutive patients with LPR despite proton pump inhibitor treatment received laparoscopic antireflux surgery. Twenty-four hour esophageal pH-monitoring (multichannel intraluminal impedance monitoring [MII]-pH) and esophageal manometry (high resolution manometry) data were documented preoperatively and at 3-month follow up. An ears, nose and throat (ENT) examination was performed, including assessment of Belafsky Reflux Finding Score (RFS). Clinical symptoms were evaluated with the Belafsky Reflux Symptom Index (RSI) and the Gastrointestinal Quality of Life Index (GIQLI). Simultaneous to the MII-pH and collection of saliva samples, detection of oropharyngeal reflux events was performed. Treatment failure was defined as postoperative pathologic RFS or RSI score and improvement of GIQLI of <10 points, despite showing a normal DeMeester score. RESULTS: At baseline, all patients had a pathological ENT examination, RSI score, and MII-pH data. All patients showed postoperatively a normal DeMeester score (mean 6.39 +/- 4.87). Five patients were defined as treatment failures with a change of pepsin concentration from median 157.0 (95% confidence interval [CI]: 0-422) to 180.7 (95% CI: 0-500). In patients defined as treatment success, median pepsin value decreased from 206.3 (95% CI: 89-278) to 76.0 (95% CI: 55-205); (P = .093). Oropharyngeal pH-monitoring data showed no significant change in both groups. CONCLUSION: Salivary pepsin could be a marker for treatment success, while oropharyngeal pH-monitoring seems to be inadequate in these terms. However, larger studies are required to reach firm conclusions. PMID- 28731843 TI - Telemedicine Use Decreases Rural Emergency Department Length of Stay for Transferred North Dakota Trauma Patients. AB - BACKGROUND: Telemedicine has been proposed as one strategy to improve local trauma care and decrease disparities between rural and urban trauma outcomes. OBJECTIVES: This study was conducted to describe the effect of telemedicine on management and clinical outcomes for trauma patients in North Dakota. METHODS: Cohort study of adult (age >=18 years) trauma patients treated in North Dakota Critical Access Hospital (CAH) Emergency Departments (EDs) from 2008 to 2014. Records were linked to a telemedicine network's call records, indicating whether telemedicine was available and/or used at the institution at the time of the care. Multivariable generalized estimating equations were developed to identify associations between telemedicine consultation and availability and outcomes such as transfer, timeliness of care, trauma imaging, and mortality. RESULTS: Of the 7,500 North Dakota trauma patients seen in CAH, telemedicine was consulted for 11% of patients in telemedicine-capable EDs and 4% of total trauma patients. Telemedicine utilization was independently associated with decreased initial ED length of stay (LOS) (30 min, 95% confidence interval [CI] 14-45 min) for transferred patients. Telemedicine availability was associated with an increase in the probability of interhospital transfer (adjusted odds ratio [aOR] 1.2, 95% CI 1.1-1.4). Telemedicine availability was associated with increased total ED LOS (15 min, 95% CI 10-21 min), and computed tomography scans (aOR 1.6, 95% CI 1.3 1.9). CONCLUSIONS: ED-based telemedicine consultation is requested for the most severely injured rural trauma patients. Telemedicine consultation was associated with more rapid interhospital transfer, and telemedicine availability is associated with increased radiography use and transfer. Future work should evaluate how telemedicine could target patients likely to benefit from telemedicine consultation. PMID- 28731845 TI - Rho Protein: Roles and Mechanisms. AB - At the end of the multistep transcription process, the elongating RNA polymerase (RNAP) is dislodged from the DNA template either at specific DNA sequences, called the terminators, or by a nascent RNA-dependent helicase, Rho. In Escherichia coli, about half of the transcription events are terminated by the Rho protein. Rho utilizes its RNA-dependent ATPase activities to translocate along the mRNA and eventually dislodges the RNAP via an unknown mechanism. The transcription elongation factor NusG facilitates this termination process by directly interacting with Rho. In this review, we discuss current models describing the mechanism of action of this hexameric transcription terminator, its regulation by different cis and trans factors, and the effects of the termination process on physiological processes in bacterial cells, particularly E. coli and Salmonella enterica Typhimurium. PMID- 28731844 TI - Outcome by Gender in the Veterans Health Administration Motivating Overweight/Obese Veterans Everywhere Weight Management Program. AB - BACKGROUND: Few evaluations of the Veterans Health Administration Motivating Overweight/Obese Veterans Everywhere (MOVE!) weight management program have assessed 6-month weight change or factors associated with weight change by gender. MATERIALS AND METHODS: Analysis of administrative data from a national sample of veterans in the VA MOVE! PROGRAM: RESULTS: A total of 62,882 participants were included, 14.6% were women. Compared with men, women were younger (49.6 years [standard deviation, SD, 10.8] vs. 59.3 years [SD, 9.8], p < 0.0001), less likely to be married (34.1% vs. 56.0%, p < 0.0001), and had higher rates of post-traumatic stress disorder (26.0% vs. 22.4%, p < 0.0001) and depression (49.3% vs. 32.9%, p < 0.001). The mean number of MOVE! visits attended by women was lower than men (5.6 [SD, 5.3] vs. 6.0 [SD, 5.9], p < 0.0001). Women, compared with men, reported lower rates of being able to rely on family or friends (35.7% vs. 40.8%, p < 0.0001). Observed mean percent change in weight for women was -1.5% (SD, 5.2) and for men was -1.9% (SD, 4.8, p < 0.0001). The odds of >=5% weight loss were no different for women (body-mass index [BMI] >25 kg/m2) compared with men (BMI >25 kg/m2; odds ratio, 1.05 [95% confidence interval, 0.99 1.11; p = 0.13]). CONCLUSIONS: Women veterans lost less weight overall compared with men. There was no difference in the odds of achieving clinically significant weight loss by gender. The majority of women and men enrolled lost <5% weight despite being enrolled in a lifestyle intervention. Future studies should focus on identifying program- and participant-level barriers to weight loss. PMID- 28731846 TI - Present and Future of Culturing Bacteria. AB - The cultivation of bacteria is highly biased toward a few phylogenetic groups. Many of the currently underexplored bacterial lineages likely have novel biosynthetic pathways and unknown biochemical features. New cultivation concepts have been developed based on an improved understanding of the ecology of previously not-cultured bacteria. Particularly successful were improved media that mimic the natural types and concentrations of substrates and nutrients, high throughput cultivation techniques, and approaches that exploit biofilm formation and bacterial interactions. Metagenomics and single-cell genomics can reveal unknown metabolic features of not-yet-cultured bacteria and, if complemented by culture-independent physiological analyses, will help to target functional novelty more efficiently. However, numerous novel types of bacteria that were initially enriched subsequently escaped isolation. Future cultivation work will therefore need to focus on improved subcultivation, purification, and preservation techniques to recover and utilize a larger fraction of microbial diversity. PMID- 28731848 TI - Usability, Acceptability, and Impact of a Pediatric Teledermatology Mobile Health Application. AB - OBJECTIVE: Pediatric dermatology appointment wait times often exceed several months. We evaluated the usability, acceptability, and clinical impact of a store and-forward teledermatology mobile application (app) linking families with pediatric dermatologists. METHODS: Parents of children age 6 weeks to 17 years or individuals 18-21 years old were invited (by e-mail or referral) to participate in this single group, prospective study. Within the app, users photographed the skin condition, answered questions, and submitted their case for review. One pediatric dermatologist viewed cases, diagnosed conditions, and provided instructions and prescriptions. User surveys immediately following app use and 1 week later, supplemented by electronic logs, assessed usability, acceptability, and impact. RESULTS: One hundred ninety-seven parents and one adolescent submitted cases within 39 days of invitation. App users were more likely to be white than those in the population invited (67% vs. 34%, p < 0.001) and their children were slightly younger (mean 7.3 vs. 9.0 years, p < 0.001). A majority, 83% found the app easy to use, 97% felt that submitting a case took "the right amount of time," 87% were satisfied, and 93% would use the app again. Prescription receipt was associated with increased app satisfaction (p = 0.008). The median user received a response in 2.8 h (interquartile range 1.1-6.4). Had the app been unavailable, 44% reported that they would have waited for primary care, 32% for a dermatology appointment, and 7% would have gone to an urgent care clinic. CONCLUSIONS: A mobile health app allowing families to directly consult a pediatric dermatologist was usable, acceptable, and expedited care. PMID- 28731849 TI - A multicenter effort to improve comparability of vitamin B6 assays in whole blood. PMID- 28731847 TI - The Colorful World of Extracellular Electron Shuttles. AB - Descriptions of the changeable, striking colors associated with secreted natural products date back well over a century. These molecules can serve as extracellular electron shuttles (EESs) that permit microbes to access substrates at a distance. In this review, we argue that the colorful world of EESs has been too long neglected. Rather than simply serving as a diagnostic attribute of a particular microbial strain, redox-active natural products likely play fundamental, underappreciated roles in the biology of their producers, particularly those that inhabit biofilms. Here, we describe the chemical diversity and potential distribution of EES producers and users, discuss the costs associated with their biosynthesis, and critically evaluate strategies for their economical usage. We hope this review will inspire efforts to identify and explore the importance of EES cycling by a wide range of microorganisms so that their contributions to shaping microbial communities can be better assessed and exploited. PMID- 28731850 TI - The diagnostic accuracy of biomarkers for diagnosis of primary biliary cholangitis (PBC) in anti-mitochondrial antibody (AMA)-negative PBC patients: a review of literature. AB - Primary biliary cholangitis (PBC), also known as primary biliary cirrhosis, is an autoimmune disease of the liver characterized by anti-mitochondrial antibodies (AMA) in 90%-95% of patients. The aim of this study was to evaluate the diagnostic value of several serum biomarkers in patients with PBC but negative for AMA. Some antinuclear antibodies (ANA) pattern, detected by indirect immunofluorescence (IIF), such as multiple nuclear dot (MND) and rim-like patterns are well-known to be specific for PBC. The corresponding nuclear antigens are the components of the nuclear pore complex (Gp210 for rim-like pattern) and Sp100, PML proteins (for MND pattern) detectable by immunoblotting and ELISA methods. More recently, new biomarkers have been evaluated in order to improve the diagnostic sensitivity, such as kelch-like 12 (KLHL12) and hexokinase 1. Considering these different serum biomarkers, studies evaluating their diagnostic role in AMA-negative PBC patients compared to AMA-positive ones and controls were included in this review. Pooled sensitivity and specificity were 37% and 85%, respectively. The overall PPV and NPV mean values were 45% and 83%. Even if all biomarkers are very specific for PBC, the overall sensitivity was poor and therefore is necessary to identify a marker with a greater sensitivity for PBC in AMA-negative patients. PMID- 28731851 TI - The frequency of occurrence of fish-shaped red blood cells in different haematologic disorders. AB - BACKGROUND: Red blood cells (RBC) resembling the silhouette of a fish are rarely observed in peripheral blood (PB) smears. In this study, we determined the frequency of occurrence of fish-shaped RBC in different haematologic diseases. METHODS: We examined PB smears of patients with iron deficiency anaemia (IDA) (n=23), beta-thalassaemia minor (BTM) (n=30), sickle cell disease (SCD) (n=7), autoimmune haemolytic anaemia (AIHA) (n=13), microangiopathic haemolytic anaemia (MAHA) (n=11), hereditary sphaerocytosis (HS) (n=4), hereditary elliptocytosis (HE) (n=3), vitamin B12 and folate deficiency (n=15), anaemia in liver disease (LD) (n=17), myelodysplastic syndrome (MDS) (n=15), acute myeloid leukaemia (AML) (n=29), chronic myeloid leukaemia (CML) (n=18), primary myelofibrosis (PMF) (n=12), chronic myelo-monocytic leukaemia (CMML) (n=15) and 21 healthy controls by light microscopy for the occurrence of fish-shaped erythrocytes. The fish shaped RBC were counted as cells per 20 high-power fields (HPF) at 1000-fold magnification, and slides containing >=1 fish-shaped RBC/20 HPF were regarded as positive. RESULTS: Fish-shaped RBC were significantly found in HE, iron deficiency, vitamin B12/folate deficiency, LD and PMF. The highest numbers of fish-shaped RBC were seen in HE and vitamin B12/folate deficiency. In patients with BTM, MDS, AML and CMML, this RBC anomaly was only occasionally observed. Furthermore, a statistically significant negative correlation of haemoglobin with the occurrence of fish-shaped RBC was apparent (p<0.014). CONCLUSIONS: Our data show that the occurrence of fish-shaped RBC is suggestive of a pathologic condition, especially IDA, HE, vitamin B12 or folate deficiency, primary mylofibrosis or LD, and is significantly associated with severity of anaemia. PMID- 28731852 TI - Sweat travels: the issue of sweat chloride transportation. PMID- 28731853 TI - Hormonal factors in the control of the browning of white adipose tissue. AB - Adipose tissue has been historically classified into anabolic white adipose tissue (WAT) and catabolic brown adipose tissue (BAT). Recent studies have revealed the plasticity of WAT, where white adipocytes can be induced into 'brown like' heat-producing adipocytes (BRITE or beige adipocytes). Recruiting and activating BRITE adipocytes in WAT (so-called 'browning') is believed to provide new avenues for the treatment of obesity-related diseases. A number of hormonal factors have been found to regulate BRITE adipose development and activity through autocrine, paracrine and systemic mechanisms. In this mini-review we will discuss the impact of these factors on the browning process, especially those hormonal factors identified with direct effects on white adipocytes. PMID- 28731854 TI - Oral submucous fibrosis in a school-going Indian adolescent boy. AB - A 14-year-old boy presented to our hospital with a chief complaint of difficulty in opening his mouth and a burning sensation on eating spicy food. The oral mucosa showed generalized diffused blanching and he was unable to protrude his tongue. For 6 years he had habitually chewed gutkha - a mixture of betel nut and tobacco for several minutes a day. This oral submucous fibrosis condition is very rare in young patients. The case highlights the link between oral submucous fibrosis and the regular use of areca nut (gutkha) products in a young boy. PMID- 28731855 TI - Seeking sexual health information? Professionals' novel experiences of the barriers that prevent female adolescents seeking sexual health information. AB - Objective Sexual health professionals are key stakeholders in implementing sexual health intervention programmes, yet their views are largely absent from the literature. Sexual health professionals provide a unique perspective on teen sexual health issues as they engage in confidential discussions with a wide range of teenagers. This study aimed to provide an in-depth exploration of professionals' perceptions of teenagers' sexual health information seeking practices and barriers. Furthermore, the research provided a unique re examination of key predictors of risky sexual behaviours, which have been highlighted by previous research. Methods Nine semi-structured interviews were undertaken with sexual health professionals to explore their perceptions of teenagers' sexual health information seeking practises and barriers. Subsequently the professionals rank ordered the 57 factors identified in previous research in terms of their perceived importance in predicting risky sexual behaviours. Results Four themes emerged: "society and media"; "environment and family"; "peer influences"; and "the self". The rank order task confirmed that 33 of the 57 factors were perceived as highly important by sexual health professionals. Conclusion Society, peers, environment and family are perceived as barriers to teenagers seeking reliable sexual health information, but these are dependent on the individual person. An individual with higher self-esteem is more confident in seeking sexual health information and applying this knowledge appropriately. Self esteem was also identified as a key perceived predictor of risky sexual behaviours. Therefore, there is scope for intervention programmes targeting self esteem and knowledge, so teenagers have the confidence to seek out sexual health information and to make their own informed sexual health decisions. PMID- 28731856 TI - Bullying, its effects on attitude towards class attendance and the contribution of physical and dentofacial features among adolescents in Northern Nigeria. AB - Background Bullying is a worldwide problem with varying consequences. Victims of school bullying may be targeted for many reasons including their appearance. They may also fear school and have difficulties in concentration. Objective This study aimed to determine the prevalence of bullying amongst adolescents in Kano, Northern Nigeria, the contribution of physical features and the perceived effect of bullying on their academic performance and school attendance. Subjects and methods Eight hundred and thirty-five students aged between 12 years and 17 years from eight randomly selected secondary schools in Kano, Nigeria took part in this study. Data collection was by self-administered questionnaires and analysis was by SPSS version 17. Results The pupils' mean age and standard deviation was 14.79 + 1.53 years. There were more male and private school pupils with 55.1% and 62%, respectively. About 43% of respondents reported being victims of bullying while about 32% had bullied someone else. There was more bullying in public schools than in private schools (p-value = 0.003). However, there was no significant gender difference (p > 0.05). More bullied pupils hated being in or outside the classroom (p < 0.05). Similarly, significantly higher number of bullied pupils played truant than non-bullied (p < 0.001). One-fifth of the victims of bullying felt it had consequences on their academic performance. Bullies frequently targeted general physical and dento-facial appearance. Conclusion The prevalence of bullying was high among the sampled population especially within public schools. This also had a significant negative effect on the students' academic performance. PMID- 28731857 TI - CytoMCS: A Multiple Maximum Common Subgraph Detection Tool for Cytoscape. AB - Comparative analysis of biological networks is a major problem in computational integrative systems biology. By computing the maximum common edge subgraph between a set of networks, one is able to detect conserved substructures between them and quantify their topological similarity. To aid such analyses we have developed CytoMCS, a Cytoscape app for computing inexact solutions to the maximum common edge subgraph problem for two or more graphs. Our algorithm uses an iterative local search heuristic for computing conserved subgraphs, optimizing a squared edge conservation score that is able to detect not only fully conserved edges but also partially conserved edges. It can be applied to any set of directed or undirected, simple graphs loaded as networks into Cytoscape, e.g. protein-protein interaction networks or gene regulatory networks. CytoMCS is available as a Cytoscape app at http://apps.cytoscape.org/apps/cytomcs. PMID- 28731858 TI - A Generalized Approach for Measuring Relationships Among Genes. AB - Several methods for identifying relationships among pairs of genes have been developed. In this article, we present a generalized approach for measuring relationships between any pairs of genes, which is based on statistical prediction. We derive two particular versions of the generalized approach, least squares estimation (LSE) and nearest neighbors prediction (NNP). According to mathematical proof, LSE is equivalent to the methods based on correlation; and NNP is approximate to one popular method called the maximal information coefficient (MIC) according to the performances in simulations and real dataset. Moreover, the approach based on statistical prediction can be extended from two genes relationships to multi-genes relationships. This application would help to identify relationships among multi-genes. PMID- 28731859 TI - Air pollution and Parkinson's disease - evidence and future directions. AB - Parkinson's disease (PD) is a neurodegenerative disease of unknown etiology that is thought to be caused by a complex combination of environmental and/or genetic factors. Air pollution exposure is linked to numerous adverse effects on human health, including brain inflammation and oxidative stress, processes that are believed to contribute to the development and progression of PD. This review provides an overview of recent advances in the epidemiology of air pollution and PD, including evidence of the effects of various pollutants (ozone, PM10, PM2.5, PM2.5-10, NOx, NO2, CO, traffic air pollution, second-hand smoking) on PD risk. Based on this evidence, promising opportunities for future research are outlined, including: (1) studies of smaller particle sizes that cross the blood-brain barrier, (2) studies of the effects of air pollution on PD mortality and/or progression; (3) studies of interactions of air pollution with gene environment and other environmental factors. PMID- 28731860 TI - The Case of Total Parenteral Nutrition Precipitated Neuroleptic Malignant-Like Syndrome in Advanced Stage Parkinson Disease. PMID- 28731862 TI - Muscle, neuromuscular junction and peripheral nerve diseases. PMID- 28731861 TI - Genetic control of apoprotein A-I and atheroprotection: some insights from inbred strains of mice. AB - PURPOSE OF REVIEW: Previous epidemiological studies and studies in experimental animals have provided strong evidence for the atheroprotective effect of HDL and its major apoprotein, apolipoprotein A-I (apoA-I). Identification of genetic loci associating apoA-I/HDL with cardiovascular disease is needed to establish a causal relationship. RECENT FINDINGS: Pharmacological interventions to increase apoA-I or HDL cholesterol levels in humans are not associated with reduction in atherosclerosis. Genome wide association study (GWAS) studies in humans and hybrid mouse diversity panel (HMDP) studies looking for genetic variants associated with apoA-I or HDL cholesterol levels with cardiovascular disease and atherosclerosis have not provided strong evidence for their atheroprotective function. SUMMARY: These findings indicate that GWAS and HMDP studies identifying possible genetic determinants of HDL and apoA-I function are needed. PMID- 28731863 TI - Screening Adolescents for Alcohol Use: Tracking Practice Trends of Massachusetts Pediatricians. AB - OBJECTIVES: Substance use screening is a recommended component of routine healthcare for adolescents. A 2008 survey of Massachusetts primary care physicians found high rates of screening, but low rates of validated tool use, leading to the concern that physicians may be missing substance use-related problems and disorders. In an effort to improve practice, a cross-disciplinary group developed and distributed an adolescent screening, brief intervention, and referral to treatment toolkit in 2009. A new survey of Massachusetts primary care physicians was conducted in 2014; this report describes its findings, and compares them to those from 2008. METHODS: A survey was mailed to a randomly selected sample of Massachusetts primary care physicians listed in the state Board of Registration in Medicine database. Item response frequencies were computed. Multiple logistic regression modeling was used to compare 2008 and 2014 responses, while controlling for any demographic differences between samples. RESULTS: Pediatrician respondents in 2014 (analysis N = 130) reported a high rate of annually screening patients for alcohol use (96.2%), but only 56.2% reported using a validated screening tool. Rates of screening and validated tool use were higher in 2014 than 2008. Insufficient knowledge as a reported barrier to screening decreased from 2008 to 2014. However, lack of time or staff resources remained key perceived barriers to screening. CONCLUSIONS: Our findings suggest that adolescent alcohol use screening practices among Massachusetts pediatricians have improved in recent years, during a time of national and statewide efforts to educate physicians. However, opportunities for practice improvement remain. PMID- 28731864 TI - Minimal Detectable Change Thresholds and Responsiveness of Zephyr Bioharness & Fitbit Charge Devices. AB - The aim of the current study was to define the MDC thresholds for Zephyr Bioharness (ZB) and Fitbit Charge (FC-HR) heart rate variables, and to establish the internal responsiveness of ZB and FC-HR devices in terms of their heart rate, respiratory rate variables and number of steps taken variables, in a healthy sample of males and females at resting, sub-maximal activity and throughout recovery phases. A total of sixty participants (30 females, 48 +/- 15) and (30 males, 48 +/- 15) were recruited using stratified convenience and snowball sampling approaches from our university student, staff and faculty population. At rest, MDC90 values of +/- 4.89 and +/- 5.15 were noted for ZB and FC-HR devices respectively. Throughout the recovery, thresholds of +/-8.14 for ZB and +/- 8.74 for FC-HR were reported. During the sub-maximal phases, scores of +/- 8.18 and +/ 9.35 were established for ZB and FC-HR respectively. From a resting to a sub maximal state, the Standardized Response Means for ZB and FC-HR heart rate variables exhibited large responsiveness of SRMZB-HR=4.42; SRMFC-HR=4.04. In addition, the ZB respiratory rate variable showed the largest effect size of SRMZB-RR= 2.55. Similarly, large effect size of SRMFC-ST=1.76 were reported for the FC-HR steps taken variable. From a sub-maximal to a recovery state, he Standardized Response Means for ZB and FC-HR heart rate variables demonstrated effect sizes of SRMZBHR= -3.10; SRMFC-HR= -3.12). Furthermore, the ZB respiratory rate variable displayed similar internal responsiveness measures of SRMZB-RR= 2.45. To conclude, Similar MDC heart rate thresholds can be expected using the ZB and FC-HR devices, and that the two devices demonstrated large internal responsiveness in our healthy male and female cohort when transitioning from resting to submaximal states and vice-versa. Our findings suggest that the ZB and FC-HR devices can be used in monitoring performance improvements or deterioration over time, and would allow qualified personnel in assessing the effectiveness of exercise programs in healthy individuals. PMID- 28731865 TI - "Joining the Spots in Adults and Young Tots": A Clinicopathological Study of Henoch-Schonlein Purpura (IgA Vasculitis). AB - INTRODUCTION: Henoch-Schonlein Purpura (HSP; IgA vasculitis), the most common vasculitis of childhood, has a wide spectrum of clinical manifestations ranging from palpable purpura with abdominal pain and arthritis to the more morbid renal involvement. AIMS AND OBJECTIVES: To study and correlate the clinical presentation, laboratory values, skin and renal histopathology and immunofluoroscence findings in HSP. MATERIAL AND METHODS: A total of 44 cases of HSP from March 2011 to February 2014 were studied for the above features along with their clinical outcomes. RESULTS: The mean age of the patients at presentation was 28.4 years (range 4.5-69 years) with 26.2% being children younger than 15 years. Purpura at presentation was seen in all with 77.1% cases exhibiting extracutaneous involvement. Skin biopsy revealed leukocytoclastic vasculitis in all cases, dominant IgA deposition in the papillary dermal vessels in 43 cases (97.7%), associated C3 in 10 cases (23.3%), and full-house positivity in 1 case. One case without skin immunofluorescence had renal mesangial IgA deposits. Nine cases (20.9%) with an average age of 39 years had renal symptoms and displayed varied histology from focal mesangioproliferative glomerulonephritis to crescentic. All of them had dominant mesangial IgA deposits, majority falling into International Study of Kidney Disease in Children (ISKDC) class IIIb. Peritubular capillaritis was noted in 3 cases. Two patients (4.5%) progressed to end stage renal disease, one of whom had cellular crescents at presentation. CONCLUSIONS: HSP was seen both in children and adults. Renal involvement was seen in 20.9% cases, all older than 14 years, and 66.7% with extracutaneous manifestations. The outcome in this series was favorable in 96% cases. PMID- 28731866 TI - Refractory Intertrigo in the Right Inguinal Crease: Answer. PMID- 28731867 TI - Specific Skin Lesions of Sarcoidosis Located at Venipuncture Points for Blood Sample Collection. AB - It has been suggested that the predilection of sarcoidosis to affect scars is due to the presence of antigens or foreign bodies that can serve as a stimulus for granuloma formation. Several patients with sarcoidosis-specific skin lesions in venous puncture sites have been reported. However, in these patients the pathogenesis of the cutaneous lesions is not clear because the presence of foreign bodies is not to be expected. Our objective was to describe 3 patients who developed specific lesions of sarcoidosis in areas of venipuncture and to discuss their possible pathogenesis. The database of the Sarcoid Clinic of Bellvitge Hospital (an 800-bed university referral center providing tertiary care to approximately 1 million people in Barcelona, Spain) was reviewed to detect those patients with specific cutaneous lesions of systemic sarcoidosis in areas of venipuncture. Three patients with biopsy-proven specific cutaneous lesions of systemic sarcoidosis in areas of venipuncture for blood collection were detected (3 women, mean age 56 years). In one case, the histopathological image shows the hypothetical path of a needle through the skin. In 2 cases, an amorphous birefringent material was detected under polarized light. This material was consistent with silicone. In patients who are developing sarcoidosis, the smallest amount of oil used as lubricant in the needle for sample blood collection may induce the formation of granulomas. In addition to exploring scars, it is advisable to explore the cubital folds to detect specific cutaneous lesions of sarcoidosis. PMID- 28731868 TI - Inflammatory Myofibroblastic Tumors of the Female Genital Tract Are Under recognized: A Low Threshold for ALK Immunohistochemistry Is Required. AB - Inflammatory myofibroblastic tumor (IMT) of the female genital tract is under recognized. We investigated the prevalence of ALK-positive IMT in lesions previously diagnosed as gynecologic smooth muscle tumors. Immunohistochemistry (IHC) for ALK was performed on tissue microarrays of unselected tumors resected from 2009 to 2013. Three of 1176 (0.26%) "leiomyomas" and 1 of 44 (2.3%) "leiomyosarcomas" were ALK IHC positive, confirmed translocated by fluorescence in situ hybridization (FISH) and therefore more appropriately classified as IMT. On review significant areas of all 4 tumors closely mimicked smooth muscle tumors morphologically, but all showed at least subtle/focal features suggesting IMT. Recognizing that the distinction between IMT and leiomyoma/leiomyosarcoma can be subtle, we then reviewed 1 hematoxylin and eosin slide from each patient undergoing surgery for "leiomyoma" from 2014 to 2017 and selected cases for ALK IHC with a low threshold. Of these, 30 of 571 (5.3%) underwent IHC. Two were confirmed to be IHC positive and FISH rearranged. Of the 6 IMTs, only 1 tumor with a previous diagnosis of leiomyosarcoma, an infiltrative margin and equivocal necrosis, metastasized. Of note it demonstrated a less aggressive clinical course compared with most metastatic leiomyosarcomas (alive with disease at 6 y). The patient was subsequently offered crizotinib to which she responded rapidly. In conclusion, IMTs may closely mimic gynecologic smooth muscle tumors. IMTs account for at least 5 of 1747 (0.3%) tumors previously diagnosed as leiomyoma and 1 of 44 (2.3%) as leiomyosarcoma. These tumors may be recognized prospectively with awareness of subtle/focal histologic clues, coupled with a low threshold for ALK IHC. PMID- 28731869 TI - Individual- and Population-Level Impacts of Traumatic Brain Injury and Maternal Characteristics on Subsequent Offending Behavior. AB - OBJECTIVE: To evaluate the individual- and population-level impact of a combination of factors, including traumatic brain injury (TBI) and certain maternal characteristics, on subsequent criminal conviction. DESIGN AND PARTICIPANTS: A retrospective record linkage study involving a cohort of 30 599 individuals born between 1980 and 1985, with ratio of 1 (with TBI): 3 (no TBI), matched by sex and the year of birth. METHODS AND PROCEDURES: Cox proportional hazard regression models and population attributable risk percentages (PAR%) were used to assess the contribution of TBI and other risk factors on subsequent criminal convictions. MAIN OUTCOMES AND RESULTS: Overall, individuals born to the teenaged mothers (<20 years) have significantly higher proportion of TBI than those born to older mothers (35% vs 22%; P < .001). In the gender-specific analyses, a history of TBI was associated with increased risk for criminal convictions (adjusted hazard ratio [aHR]: 1.48, 95% confidence interval [CI]: 1.36-1.60, and aHR: 1.45, 95% CI: 1.22-1.73, for men and women, respectively). Maternal characteristics (maternal age, single parent, multiparity) were identified as the greater contributor to the criminal convictions (PAR%: 57% and 67% for men and women, respectively). The combined impact of mental illness, maternal factors, and TBI was estimated to be 67% and 74% (for men and women, respectively); with nonoverlapping 95% CIs for PAR%, these factors were estimated to have had a higher impact among females than among males. CONCLUSION: More than half of the criminal convictions were associated with a relatively small number of risk factors, including poor mental health, low socioeconomic status, and TBI as well as certain maternal characteristics. PMID- 28731870 TI - The Association of Cognitive Reserve in Chronic-Phase Functional and Neuropsychological Outcomes Following Traumatic Brain Injury. AB - OBJECTIVE: Examine the association of cognitive reserve (CR) factors (estimated premorbid intelligence quotient [IQ], years of education, and occupational attainment) and traumatic brain injury (TBI) severity with functional and neuropsychological outcomes 1 to 5 years following TBI. PARTICIPANTS: Patients with mild (N = 58), moderate (N = 25), or severe (N = 17) TBI. MAIN MEASURES: Cognitive reserve factors (estimated premorbid IQ, years of education, and occupational attainment); neuropsychological test battery; Glasgow Outcome Scale Extended; Short Form-36 Health Survey. ANALYSES: Spearman-Brown correlations, linear regression models, and analyses of covariance were used to analyze the relation between CR factors and outcome measures. RESULTS: Analyses revealed significant relations between estimated premorbid IQ and neuropsychological outcomes (P < .004): California Verbal Learning Test, Wechsler Adult Intelligence Scale-Fourth Edition working memory, Booklet Category Test, Trail Making Test B, and Grooved Pegboard Test. There was also a significant correlation between estimated premorbid IQ and Wechsler Adult Intelligence Scale-Fourth Edition processing speed. Years of education had significant relations with California Verbal Learning Test and Wechsler Adult Intelligence Scale-Fourth Edition working memory and processing speed scores. There were significant differences between TBI severity groups and performance on the Trail Making Test A, Grooved Pegboard Test, and Finger Tapping Test. CONCLUSIONS: Cognitive reserve factors may be associated with outcomes following TBI. Additional alternatives to TBI severity are needed to help guide rehabilitative planning postinjury. PMID- 28731871 TI - Online Family Problem Solving for Pediatric Traumatic Brain Injury: Influences of Parental Marital Status and Participation on Adolescent Outcomes. AB - OBJECTIVE: To examine the moderating effects of parent marital status and participation on efficacy of an online family problem-solving intervention for pediatric traumatic brain injury (TBI). METHODS: Participants were 132 adolescents (12-17 years) who had sustained a recent (<6 months) TBI and their parents. Participants were randomly assigned to the intervention (Counselor Assisted Problem Solving, CAPS) or an Internet resource comparison (IRC) condition. CAPS was designed to support families in the initial phase following TBI, by teaching problem-solving skills and addressing common challenges. To examine the moderating effect of parent marital status, participants were divided into 4 groups (ie, CAPS married household, CAPS unmarried household, IRC married household, and IRC unmarried household). Family income and caregiver education were controlled in analyses. RESULTS: Parent marital status moderated treatment effects on adolescent externalizing behavior problems. Adolescents from married households in CAPS displayed fewer behavior problems at 6 and 18 months postbaseline compared with adolescents from unmarried households in CAPS. Among married CAPS families, there were no differences in outcomes among families where 1 or 2 parents actively participated. CONCLUSIONS: Web-based interventions for pediatric TBI, such as CAPS, are a viable option for some although not all families. Further research is needed to investigate factors that influence efficacy to match families to the most beneficial treatments. PMID- 28731872 TI - Bleeding risk assessment in hemophilia A carriers from Dakar, Senegal. AB - : Hemophilia A carriers have an abnormal X chromosome with a molecular abnormality of FVIII gene. These carriers, long considered to be free of bleeding risk, could have the same symptoms as mild hemophiliacs. This study aim to assess bleeding risk of hemophilia A carriers monitored at the Clinical Hematology Department of Dakar. This is a prospective study of a period of 6 months including 22 hemophilia A carriers aged between 8 and 48 years. Hemophilia carriers were recruited using the genealogical tree of hemophiliacs followed in the service. Their diagnosis was carried out by long range PCR and Sanger sequencing method searching the molecular abnormality responsible for hemophilia in their family. Bleeding risk was determined using a questionnaire consisting of different bleeding symptoms quoted from -1 to 4 according to the severity. Total of different values allow to determine the bleeding score which was pathological if it was greater than or equal to 1. Medium age was 22.5 years (8-48) (SD = 9.28). Four hemophilia A carriers (18.1%) presented bleeding symptoms and had a bleeding score at least 1 (P = 0.02). Menorrhagia was predominant (13.6%) followed by epistaxis (9%), gingivorrhagia (9%), and prolonged bleeding after tooth extraction (9%). Factor VIII level was lower in hemophilia carriers who presented bleeding (42 +/- 8.61 UI/l) versus hemophilia carriers without bleeding (100 +/- 50.95 UI/l) (P = 0.001). There was no significant correlation between bleeding occurrence and age (P = 0.81), activated patial thromboplastin time value (P = 0.97) and FVIII/Von Willebrand Factor ratio (P = 0.12). One in five hemophilia carriers presented bleeding and the questionnaire was effective to identify hemophilia carriers who had a risk of bleeding. PMID- 28731873 TI - Health-related quality of life in Iranian adult men with severe hemophilia. AB - : Health-related quality of life (HRQOL) assessment should be part of the regular clinical assessment of persons with hemophilia. This study assessed quality of life of severe hemophilia patients (Type A) in Tehran comprehensive hemophilia care center. This cross-sectional study was done in 2016 and 84 men aged over 20 years with severe hemophilia (Type A) were assessed. All patients have been treated over 10 years at the comprehensive hemophilia care center, Iran. The HRQOL assessment includes the A36 Hemophilia-QOL questionnaire, sociodemographical and clinical characteristics. The overall HRQOL mean (+/-SD) in the present sample was 69.1 +/- 26.0 (A36Hemofilia-QoL Global Index). The mean (+/-SD) scores according the domains were: physical health (15.0 +/- 5.7), daily activities (6.7 +/- 3.8), joint damage (4.2 +/- 2.9), pain (3.0 +/- 1.9), social activities and relationships (10.7 +/- 5.8) and emotional function (9.2 +/- 5.0) classified moderate-to-poor state. In contrast with treatment satisfaction (4.8 +/- 1.6), treatment difficulties (9.5 +/- 3.4) and mental health (6.2 +/- 3.3), those were all in moderate-to-good state. Patients with higher education levels had better quality of life in the area of anxiety (P = 0.034), mental health (P = 0.007), social activities and personal relationships (P = 0.002). In general, poor quality of life of patients was 13.1%, 42.9% weak-to-moderate, 38.1% moderate-to-good and 6% good. It was shown that over 50% of patients had low-to moderate HRQOL in the domains, such as physical health, daily activities, joint damage, pain, social activities and personal relationships. Efforts are necessary to improve their HRQOL. PMID- 28731874 TI - Novel targets for anticoagulants lacking bleeding risk. AB - PURPOSE OF REVIEW: Arterial and venous thromboembolic diseases are associated with significant morbidity and mortality and present a major medical burden. Currently used anticoagulants for the prevention or treatment of thromboembolic events including heparins, vitamin K-antagonists and inhibitors of thrombin or factor Xa target enzymes of the coagulation cascade that are critical for fibrin formation. However, fibrin is also necessary for hemostatic mechanisms to terminate blood loss at injury sites. As a result currently used anticoagulants substantially raise the risk of bleeding and are associated with an increase in potentially life-threatening hemorrhage, partially offsetting the benefits of reduced thrombosis. RECENT FINDINGS: Within the last decade, experimental and preclinical data have revealed the existence of coagulation mechanisms that principally differ in thrombosis and haemostasis. Some coagulation proteins including, XI and XII have a differential role in haemostasis and thrombosis. Targeting these proteins may provide an opportunity to prevent thromboembolic disease without causing bleeding. SUMMARY: This review summarizes recent studies on selective targeting of coagulation proteins that may allow prevention and treatment of thrombosis without causing bleeding. These novel approaches present a possibility for selective interference with fibrin formation in pathologic thrombosis that may lead to a new generation of safe anticoagulant drugs. PMID- 28731875 TI - Management of complex spine surgery. AB - PURPOSE OF REVIEW: The main objective of this article is to present the updated data regarding the perioperative management of patients undergoing major spine surgery in an era where the surgical techniques are changing and there is a high demand for these surgeries in older and high-risk patients. RECENT FINDINGS: Preoperative assessment and stabilization is now more structured protocol and it is based on a multidisciplinary approach to the patient. The Enhanced Recovery After Surgery (ERAS) programs and the Perioperative Surgical Home on major spine surgery are not yet fully evidence based but it seems that the use of a perioperative optimization of patients and use of a drugs' bundle is more effective than using single drugs or interventions on the postoperative pain reduction and faster recovery from surgery. Fluid and pain-control protocols combined with an accurate blood management represent the key to success. SUMMARY: A tailored approach to patients undergoing major spine surgeries seems to be effective improving the outcome and quality of life of patients. Future studies should aim to understand which elements of the ERAS can be improved to allow the patient to have a long-term good outcome. VIDEO ABSTRACT. PMID- 28731876 TI - Neuraxial drug delivery for the management of cancer pain: cost, updates, and society guidelines. AB - PURPOSE OF REVIEW: The present study discusses the utilization of neuraxial drug delivery (NDD) for the management of cancer pain, based on recent trials, reviews, and guidelines with a focus on cost analysis. RECENT FINDINGS: Almost all recent publications suggest that more stringent research is needed to improve evidence on NDD, particularly as conflicting reports exist regarding cost effectiveness of drug delivery systems. The combination of local anesthetics and opioids, with or without clonidine, continues to be reported as beneficial with the utilization of patient controlled systems providing an advantage over continuous ones. Interestingly, the use of opioids as an adjunct to local anesthetics may not enhance analgesia but the addition of dexamethasone is useful for incident cancer-related bone pain. Ziconitide remains supported as first-line therapy in districts where it is available - United States and Europe. Although new targeted drugs are being designed for cancer pain management, none have seen human clinical trials in the last year. SUMMARY: The ability to demonstrate cost effectiveness of NDD is variable from region to region. Less expensive externalized systems may pose a viable alternative. With the exception of dexamethasone, no new drugs have been shown to provide any benefit to conventional medications. PMID- 28731877 TI - Simple Preoperative Ink Test as a Novel Adjunct to Intrastromal Keratopigmentation for Post-laser Peripheral Iridotomy Dysphotopsias. AB - PURPOSE: To describe a simple preoperative ink test as a novel adjunct to intrastromal keratopigmentation for post-laser peripheral iridotomy (LPI) dysphotopsias. METHODS: A surgical marking pen is applied to the area over a peripheral iridotomy before intrastromal keratopigmentation. The patient can then assess whether there is any improvement in their symptoms of dysphotopsias. Manual intrastromal keratopigmentation can then be performed using a crescent blade into the clear cornea at 50% depth and tunneled centrally to create a pocket ensuring that the peripheral iridotomy is fully occluded. The crescent blade is coated with an alcohol-based commercially available black tattoo pigment, and the pocket is filled. RESULTS: We have used the preoperative ink marker test on 5 eyes in patients with post-LPI (4 temporal and 1 superior) dysphotopsias before performing intrastromal keratopigmentation, with good patient satisfaction. Patients report immediate symptomatic relief after the procedure. This ink marking technique can also be extended to help identify which iris defect is symptomatic in patients with multiple iris defects. CONCLUSIONS: The preoperative ink test before intrastromal keratopigmentation is a novel adjunct to the treatment of post-LPI dysphotopsias. PMID- 28731878 TI - Correlation of Corneal Biomechanical Stiffness With Refractive Error and Ocular Biometry in a Pediatric Population. AB - PURPOSE: To assess the correlation between corneal biomechanical stiffness and refractive error (RE) in the pediatric population. METHODS: A total of 733 pediatric eyes were included in the study retrospectively. All eyes underwent corneal tomography (Pentacam), RE assessment, and air-puff deformation (Corvis ST). Waveform analyses of deformation provided corneal stiffness (CS) and extraocular tissue stiffness (EOS). Eyes were subgrouped into emmetropia [manifest refraction spherical equivalent (MRSE) ~ 0 D], hyperopia (MRSE > 0 D), myopia I (MRSE between 0 D and -3 D), myopia II (MRSE between -3 D and -6 D), and myopia III (MRSE greater than -6 D) for multivariate analyses. Ocular biometry variables [age, intraocular pressure (IOP), central corneal thickness (CCT), corneal astigmatism, anterior chamber depth, and RE] were used as covariates. The apparent elastic modulus (E) was defined as the ratio of CS and CCT. RESULTS: All groups had similar age, CCT, and IOP (P > 0.05). CS was the only parameter to differ between all the grades of myopia (P < 0.0001). CS was lower by 3.72%, 6.84%, and 10.68% in myopia I, II, and III eyes, respectively, relative to emmetropic eyes. EOS increased by 11.15%, 22.60%, and 28.5%, respectively. Multivariate regression revealed age, IOP, CCT, corneal astigmatism, anterior chamber depth, and RE as significant predictors of CS, with a high coefficient of regression (R = 0.66). Corneal E negatively correlated with the grade of myopia. CONCLUSIONS: CS and EOS correlated negatively and positively with the grade of myopia, respectively. Ocular biometry variables were significant predictors of both CS and EOS. The decrease in CS was attributed to that in elastic modulus. PMID- 28731879 TI - Peripheral Endothelial Cell Count Is a Predictor of Disease Severity in Advanced Fuchs Endothelial Corneal Dystrophy. AB - PURPOSE: In advanced Fuchs endothelial corneal dystrophy (FECD), central endothelial changes do not correlate with disease severity. The peripheral endothelial cell count (ECC) has not been studied as a marker of FECD severity. The goal of this study was to determine the relationship between the peripheral ECC and known clinical markers of FECD in advanced cases. METHODS: Patients with FECD examined between January 1, 2013, and September 1, 2016, by 1 cornea specialist were identified. Medical records from all previous visits were reviewed to include eyes with high-quality central and peripheral in vivo confocal microscopy images performed on the same day as a clinical evaluation. Endothelial photographs were used to perform manual cell counts centrally and peripherally. Clinical grading of FECD from 1 to 4 was performed at the slit lamp. RESULTS: We identified 154 eyes of 126 patients that met criteria for inclusion. With higher disease grades, central ECC and peripheral ECC decreased, visual acuity worsened, and central corneal thickness (CCT) increased (all P < 0.05). In patients with advanced disease (defined as either grade 3 or 4, CCT >700, or central ECC <350), the peripheral ECC was the best predictor of disease severity and had the highest number of statistically significant correlations with other clinical markers compared with competing variables. CONCLUSIONS: In advanced FECD, severity is best determined by the peripheral ECC compared with the central ECC, visual acuity, clinical disease grade, and CCT. The peripheral ECC should be added to the clinical parameters used to evaluate FECD severity. PMID- 28731880 TI - Refractive Surgery: Malpractice Litigation Outcomes. AB - PURPOSE: To review data on malpractice claims related to refractive surgery to identify common allegations and injuries and financial outcomes. METHODS: The WestlawNext database was reviewed for all malpractice lawsuits/settlements related to refractive eye surgery. Data evaluated included patient demographics, type of operation performed, plaintiff allegation, nature of injury, and litigation outcomes. RESULTS: A total of 167 cases met the inclusion criteria, of which 108 cases (64.7%) were found to be favorable and 59 cases (35.3%) unfavorable to the defendant. A total of 141 cases were tried by a jury with 108 cases (76.4%) favorable and 33 cases (23.6%) unfavorable to the defendant. Laser in situ keratomileusis was performed in 127 cases (76%). The most common allegations were negligence in treatment or surgery in 127 cases (76%) and lack of informed consent in 83 cases (49.7%). For all cases, the need for future surgery (P = 0.0001) and surgery resulting in keratoconus (P = 0.05) were more likely to favor the plaintiff. In jury verdict decisions, cases in which failure to diagnose a preoperative condition was alleged favored the defendant (P = 0.03), whereas machine malfunction (P = 0.05) favored the plaintiff. After adjustment for inflation, the overall mean award was $1,287,872. Jury verdicts and settlements led to mean awards of $1,604,801 and $826,883, respectively. CONCLUSIONS: Malpractice litigation in refractive surgery tends to favor the defendant. However, large awards and settlements were given in cases that were favorable to the plaintiff. The need for future surgery and surgery leading to keratoconus increased the chance of an unfavorable outcome. PMID- 28731881 TI - Implementation of a Nurse-driven Educational Program Improves Management of Sorafenib's Toxicities in Hepatocellular Carcinoma. AB - BACKGROUND: Sorafenib is the standard treatment of advanced hepatocellular carcinoma. Because of its unique toxicities, improving patients' tolerance merits close follow-up. Nurses can play a crucial role by leading a patient educational program (EP). OBJECTIVES: The aim of this study was to assess whether adding EP to usual care (UC) improves patient's care. METHODS: Since 2011, oncologists referred patients treated by sorafenib to the EP led by clinical nurses. The EP included a visit before the first administration, weekly telephone calls, and a visit with the nurse before each oncologist consultation. We retrospectively compared patients in the EP with those in UC followed by an oncologist and patients included in a clinical trial. RESULTS: Since 2005, 129 patients were treated with sorafenib for hepatocellular carcinoma: 31 in the EP (24%), 22 in a clinical trial (17%), and 76 with UC (59%). Seventy-one percent of the patients in the EP had toxicities identified during a telephone call, which prompted symptomatic measures in 65% of the patients, leading to treatment modification before the planned on-site visit in 29% of the patients. Educational program patients required fewer dose reductions (39% vs 61% for UC, P = .04), and median time to first dose reduction was shorter with EP than with UC (25 vs 45 days, P = .036). CONCLUSIONS: This study suggests a clinical benefit of EP related to improved toxicity management of sorafenib that resulted in fewer dose reductions. IMPLICATIONS FOR PRACTICE: Patients treated with sorafenib may benefit from an EP. Different types of EP should be compared prospectively, focusing on patients' quality of life. PMID- 28731882 TI - The Effect on Bone Outcomes of Home-based Exercise Intervention for Prostate Cancer Survivors Receiving Androgen Deprivation Therapy: A Pilot Randomized Controlled Trial. AB - BACKGROUND: Cancer treatment-induced bone loss has important long-term effects in prostate cancer survivors (PCSs) receiving androgen deprivation therapy (ADT), but little is known about preventive interventions. OBJECTIVE: The aim of this study was to examine the feasibility and preliminary effectiveness of a 6-month home-based exercise intervention in PCSs. METHODS: In this pilot, randomized controlled trial, 51 men (mean age, 70.8 years) were randomized to a 6-month home based exercise intervention for preventing osteoporosis group (n = 26) or an exercise placebo intervention of stretching exercise group (n = 25). Primary outcomes were bone mineral density and bone turnover markers. Secondary outcomes were physical performance (level of physical activity, muscle strength, and balance) and health-related quality of life. RESULTS: The patient retention rate for 6 months was 80.4%. The mean adherence rate was 84.7% for weight-bearing exercise and 64.8% for resistance exercise. No adverse events during the study period were reported. Although primary outcomes did not differ significantly between the 2 groups, the home-based exercise intervention for preventing osteoporosis group demonstrated significantly greater increased muscle strength than the stretching exercise group. CONCLUSIONS: A home-based exercise program is relatively feasible and safe and may improve muscle strength but not bone outcomes. IMPLICATIONS FOR PRACTICE: Given the importance of preventing cancer treatment-induced bone loss among PCSs receiving ADT, a home-based exercise intervention can be considered, but further trials with a larger sample are required to determine its effect for bone outcomes. PMID- 28731883 TI - The Effects on Children's Anxiety and Quality of Life of a Psychoeducational Program for Families Living With Parental Cancer and Their Network: A Randomized Controlled Trial Study. AB - BACKGROUND: Families living with parental cancer report lack of social support. The Cancer PEPSONE Program (CPP) was developed to bridge the gap between the families and their network. OBJECTIVE: The aims of this study were to study the effect of the CPP on children's anxiety and quality of life (QOL) and examine the association between the CPP's effect on their well parents' received social support, QOL, and psychological distress and the children's anxiety and QOL. METHODS: The CPP, a psychoeducational program for the families and their social network, was evaluated using a randomized controlled trial design. The children and their well parents completed questionnaires measuring QOL, psychological distress, and social support at baseline and after 3 and 6 months. RESULTS: Thirty-five families were enrolled (18 intervention, 17 controls). The CPP stabilized the children's family function, although the family function largely (d = 0.86) decreased in the control group (P = .018). No significant effects were found on anxiety, overall QOL, or QOL subdimensions. Significant correlations were documented between the children's levels of anxiety and the well parents' received social support (r = -0.196, P < .001), QOL (r = -0.138, P < .05), and psychological distress (r = 0.166, P < .05). CONCLUSIONS: The CPP seems to stabilize the children's perceived family function but did not target the other outcomes. Further studies with larger samples are needed. IMPLICATIONS FOR CLINICAL PRACTICE: Optimizing social network for families living with parental cancer may support the family's function. Actions should be initiated to increase the well parents' social support, QOL, and psychological distress, which may also benefit the children. PMID- 28731884 TI - Determination of Colorectal Cancer Risk Levels, Colorectal Cancer Screening Rates, and Factors Affecting Screening Participation of Individuals Working in Agriculture in Turkey. AB - BACKGROUND: Colorectal cancer (CRC) is the fourth ranked malignancy leading to death in Turkey. Agricultural workers with low socioeconomic level are particularly at risk due to the intense use of pesticides. OBJECTIVE: The aim of this study was to determine CRC risk levels, status of participation in CRC screenings, and the factors affecting participation in screenings among individuals between 50 and 70 years old working in agriculture. METHODS: Data in this cross-sectional study were collected from 244 agricultural workers in Turkey. RESULTS: The rate of participation in CRC screenings among these workers at high risk was low. Their knowledge and health beliefs did not affect their participation in CRC screenings. Having a friend or neighbor with CRC and knowing which doctor to consult increased participation in CRC screenings 10 times, and having abdominal pain increased participation in CRC screenings 4 times. CONCLUSIONS: The rate of participation in CRC screenings is low in this group of workers, but rates may increase when these individuals are directed to be screened. IMPLICATIONS FOR PRACTICE: Health professionals should advise agricultural workers to participate in CRC screenings and should inform workers about the locations where screenings are conducted. PMID- 28731885 TI - Effectiveness of a Posterior Shoulder Stretching Program on University-Level Overhead Athletes: Randomized Controlled Trial. AB - OBJECTIVE: To determine whether a posterior shoulder stretch was effective in increasing internal rotation (IR) and horizontal adduction (HAd) range of motion (ROM) in overhead athletes identified as having reduced mobility. DESIGN: Randomized controlled trial (parallel design). SETTING: University-based sports medicine clinic. PARTICIPANTS: Thirty-seven university-level athletes in volleyball, swimming, and tennis, with IR ROM deficits >=15 degrees , were randomized into intervention or control groups. No subjects withdrew or were lost to follow-up. INTERVENTION: The intervention group performed the "sleeper stretch" daily for 8 weeks, whereas the control group performed usual activities. MAIN OUTCOME MEASURES: Independent t tests determined whether IR and HAd ROM differences between groups were significant at 8 weeks and 2-way repeated measures analysis of variance tests measured the rate of shoulder ROM change. Subject-reported shoulder pain and function were obtained at each evaluation. RESULTS: Significant differences were found between the intervention and control groups' IR and HAd ROM at 8 weeks (P < 0.001 and P = 0.003, respectively) compared with baseline (zero weeks) (P = 0.19 and P = 0.82, respectively). Significant improvements in IR were detected in the intervention group at 4 weeks (P < 0.001), whereas HAd demonstrated significant changes only at 8 weeks (P = 0.003). Reported shoulder function (P = 0.002) was different between study groups at 8 weeks. CONCLUSION: Overhead, university-level athletes with an IR deficit >=15 degrees significantly increased their IR and HAd ROM after performing a posterior shoulder stretch for 8 weeks. CLINICAL RELEVANCE: Effective management of posterior shoulder tightness through stretching may reduce the incidence of shoulder pathology in overhead athletes. PMID- 28731886 TI - Collegiate Student Athletes With History of ADHD or Academic Difficulties Are More Likely to Produce an Invalid Protocol on Baseline ImPACT Testing. AB - OBJECTIVE: Attention deficit hyperactivity disorder (ADHD) and other academically relevant diagnoses have been suggested as modifiers of neurocognitive testing in sport-related concussion, such as Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT). These preexisting conditions may suppress ImPACT scores to the extent that they are indistinguishable from low scores because of poor effort. The present study hypothesized that student athletes with history of ADHD or academic difficulties produce lower ImPACT composite scores and are more likely to produce invalid protocols than those without such conditions. DESIGN: Cross-sectional study. SETTING: Midsized public university. PARTICIPANTS: Nine hundred forty-nine National College Athletic Association athletes (average age = 19.2 years; 6.8% ADHD, 5.6% Academic Difficulties, 2.0% comorbid ADHD/Academic Difficulties). INDEPENDENT VARIABLES: Three seasons of baseline ImPACT protocols were analyzed. Student athletes were grouped using self-reported histories of ADHD or academic difficulties taken from ImPACT demographic questions. DEPENDENT VARIABLES: ImPACT composite scores and protocol validity. RESULTS: Student athletes in the academic difficulties and comorbid groups performed worse on ImPACT composite scores (Pillai's Trace = 0.05), though this pattern did not emerge for those with ADHD. Student athletes with comorbid history were more likely to produce an invalid baseline (10.5% invalid) (chi (2) = 11.08, P = 0.004). Those with ADHD were also more likely to produce an invalid protocol (7.7% invalid, compared with 2.6% in student athletes with no history) (chi (2) = 10.70, P = 0.005). CONCLUSIONS: These findings suggest that student athletes reporting comorbid histories or histories of academic difficulties alone produce lower ImPACT composite scores, and that those with comorbid histories or histories of ADHD alone produce invalid protocol warnings more frequently than student athletes without such histories. Future studies should further examine invalid score thresholds on the ImPACT, especially in student athletes with conditions that may influence test performance. CLINICAL RELEVANCE: Student athletes with history of ADHD or academic difficulties may more frequently fall below validity score thresholds, suggesting caution in interpreting test performance. PMID- 28731887 TI - Risk of anaphylaxis in complementary and alternative medicine. AB - PURPOSE OF REVIEW: Complementary and alternative medicine (CAM) use is widespread across the world. Patients with asthma and allergy regularly use CAM therapies. Allergic and anaphylactic reactions to CAM have been reported. RECENT FINDINGS: Recent attempts to regulate and monitor adverse reaction to these therapies have given us further insight into potential causes of severe allergic reactions. Several culprits identified including Andrographis paniculata, Echinacea species, bee products, Ginkgo biloba and Ginseng are discussed here. SUMMARY: Knowing the factors that increase the risk of anaphylaxis allows reactions to be recognized, reported and further investigated. Research to identify key causative allergens is necessary in the future. Collaboration between the allergy community and CAM practitioners can allow better understanding of allergy to these therapies. PMID- 28731888 TI - Elevated plasma levels of Mac-2 binding protein predict poor cardiovascular outcomes in patients with acute coronary syndrome. AB - BACKGROUND: Mac-2 binding protein (M2BP) is an inflammatory glycoprotein associated with carotid atherosclerosis and all-cause mortality in patients with suspected coronary artery diseases. We aimed to explore the potential association of plasma M2BP levels with unstable plaque morphology and cardiovascular outcomes in patients with acute coronary syndrome (ACS). PATIENTS AND METHODS: We compared plasma M2BP levels among three groups: 216 patients with ACS, 82 patients with stable angina pectoris, and 50 controls. Angiographic analyses of complex lesions were carried out in patients with ACS and they were followed up prospectively for 12 months for the occurrence of major adverse cardiovascular outcomes (MACEs). RESULTS: Patients with ACS showed significantly higher plasma levels of M2BP than patients with stable angina pectoris (P<0.001) and controls (P<0.001). M2BP levels correlated positively with the presence (P<0.001) and extent (P=0.005) of complex lesions. During follow-up, 45 (20.8%) cases of MACEs occurred. Survival analysis indicated that high M2BP levels were associated with a poor prognosis (log-rank P=0.008). After Cox multivariate adjustment, plasma M2BP levels remained an independent predictor of MACEs either as a continuous variable (hazard ratio: 1.178, 95% confidence interval: 1.093-1.270, P<0.001) or as a categorical variable (hazard ratio: 2.783, 95% confidence interval: 1.433-5.404, P=0.002). CONCLUSION: Plasma M2BP levels might be predictive of unstable plaque and were associated independently with poor cardiovascular outcomes in patients with ACS. PMID- 28731889 TI - Stent thrombosis with bioabsorbable polymer drug-eluting stents: insights from the Food and Drug Administration database. AB - BACKGROUND: SYNERGY, a bioabsorbable polymer-based, everolimus-eluting stent (BP DES), recently received regulatory approval in the USA for use in percutaneous coronary interventions. Yet, information on the safety of BP-DES in routine clinical practice is limited. Our aim was to compare the safety of the recently approved BP-DES with current durable polymer drug-eluting stents (DP-DES) by analyzing adverse events, namely, stent thrombosis (ST), reported to the Manufacturer and User Facility Device Experience (MAUDE) database. MATERIALS AND METHODS: The MAUDE database requires nationwide mandatory notification for adverse events on devices approved for clinical use. This database was searched for adverse events reported between 1 October 2015 and 25 December 2016, encountered after the placement of either BP-DES or DP-DES. Only those adverse events were included where the exposure period to the stents was comparable after the index procedure. Of all the adverse events reported, the event of interest was ST. RESULTS: A total of 951 adverse events were reported. ST occurred in 48/951 of all events, 31/309 and 17/642 when BP-DES or DP-DES were used, respectively (P=0.00001). Of the 31 ST events with BP-DES, 68% (21/31) occurred within less than or equal to 24 h of the index procedure and 52% (16/31) occurred within less than or equal to 2 h. CONCLUSION: Our results raise the possibility of an increased risk of ST, particularly early ST (within 24 h), with the recently approved BP-DES. However, because of the inherent limitations of reporting within the MAUDE database, these data merely highlight a potential need for additional surveillance and randomized trials to assess further the safety of the bioabsorbable platform. PMID- 28731890 TI - Metformin Exposure During Pregnancy and Lactation Did Not Cause Vascular Reactivity Alteration in Adult Male Offsprings. AB - Metformin has been used for the treatment of some metabolic diseases during gestation and the beneficial effects of metformin to the vascular system have been described in diabetic and obese animal models. Nevertheless, the long-term consequences to the vascular system of offsprings maternally exposed to metformin have not yet been characterized. Therefore, we want to test the hypothesis that gestational and lactational exposure to metformin would be safe for the vascular reactivity of male adult offsprings. Wistar female rats were treated with metformin 293 mg.kg.d, by gavage, from gestational day (GD) 0 to GD 21 (METG) or GD 0 until postnatal day 21 (METGL). Control dams received water by gavage in the same periods (CTRG and CTRGL). In male offsprings (75 days), the aortic reactivity to phenylephrine, acetylcholine, and sodium nitroprusside in the presence or absence of endothelium were evaluated. The results demonstrated that aortic contraction and relaxation were similar between groups. These data showed that metformin exposure during pregnancy and lactation did not interfere with aortic reactivity, suggesting that metformin exposure during gestational and lactation are safe for the offsprings' vascular system. PMID- 28731891 TI - White Wine Consumption Influences Inflammatory Phase of Repair After Myocardial Infarction in Rats. AB - Effects of white wine (WW) consumption on the expression of inflammatory markers/mediators (MMP-2, MMP-9, NF-KB p65 and TGF-beta1) in myocardial tissue after experimentally induced permanent myocardial ischemia was investigated. Male Sprague-Dawley rats were given either a combination of WW and water or only water, for 28 days. After coronary ligation, animals were left to survive for 24 hours. Three representative areas: infarct/ischemic, peri-infarct/border zone, and control/non-ischemic zones were analyzed for expression of immunoreactivity by measuring the threshold area % of signal density. For MMP-9, significantly smaller expression was found in all 3 zones of wine drinking animals (P < 0.001). There was no difference in MMP-2 immunoreactivity between the 2 groups, except in peri-infarct zones, where the signal was significantly decreased (P < 0.001). The same pattern of expression was found for the NF-kappaB p65 signal, although no differences between experimental groups were observed for TGF-beta1. White wine consumption decreases the expression of the 3 investigated inflammatory markers/mediators in the peri-infarct zone, suggesting its significant modulatory effect. For MMP-9 and MMP-2, expression was similar to the effect of postischemic reperfusion. No effect on TGF-beta1 was observed, highlighting its role in being the master-switch, changing from the inflammatory to the proliferative stage of infarct healing. PMID- 28731892 TI - Racial Differences in Geographic Access to Medical Care as Measured by Patient Report and Geographic Information Systems. AB - BACKGROUND: Geographic access-the travel burden required to reach medical care-is an important aspect of care. Studies, which typically rely on geographic information system (GIS) calculated travel times, have found some evidence of racial disparities in spatial access to care. However, the validity of these studies depends on the accuracy of travel times by patient race. OBJECTIVES: To determine if there are racial differences when comparing patient-reported and GIS calculated travel times. RESEARCH DESIGN: Data came from the Philadelphia Area Prostate Cancer Access Study (P Access), a cohort study of men diagnosed with localized prostate cancer. We conducted cross-sectional analysis of 2136 men using multivariable linear mixed-effects models to examine the effect of race on differences in patient-reported and GIS-calculated travel times to urology and radiation oncology cancer providers. RESULTS: Patient-reported travel times were, on an average, longer than GIS-calculated times. For urology practices, median patient-reported travel times were 12.7 minutes longer than GIS-calculated travel times for blacks versus 7.2 minutes longer for whites. After adjusting for potential confounders, including socioeconomic status and car access, the difference was significantly greater for black patients than white patients (2.0 min; 95% confidence interval, 0.58-3.44). CONCLUSIONS: GIS-calculated travel time may underestimate access to care, especially for black patients. Future studies that use GIS-calculated travel times to examine racial disparities in spatial access to care might consider including patient-reported travel times and controlling for factors that might affect the accuracy of GIS-calculated travel times. PMID- 28731893 TI - Validity of Administrative Data in Identifying Cancer-related Events in Adolescents and Young Adults: A Population-based Study Using the IMPACT Cohort. AB - BACKGROUND: Despite the importance of estimating population level cancer outcomes, most registries do not collect critical events such as relapse. Attempts to use health administrative data to identify these events have focused on older adults and have been mostly unsuccessful. We developed and tested administrative data-based algorithms in a population-based cohort of adolescents and young adults with cancer. METHODS: We identified all Ontario adolescents and young adults 15-21 years old diagnosed with leukemia, lymphoma, sarcoma, or testicular cancer between 1992-2012. Chart abstraction determined the end of initial treatment (EOIT) date and subsequent cancer-related events (progression, relapse, second cancer). Linkage to population-based administrative databases identified fee and procedure codes indicating cancer treatment or palliative care. Algorithms determining EOIT based on a time interval free of treatment associated codes, and new cancer-related events based on billing codes, were compared with chart-abstracted data. RESULTS: The cohort comprised 1404 patients. Time periods free of treatment-associated codes did not validly identify EOIT dates; using subsequent codes to identify new cancer events was thus associated with low sensitivity (56.2%). However, using administrative data codes that occurred after the EOIT date based on chart abstraction, the first cancer-related event was identified with excellent validity (sensitivity, 87.0%; specificity, 93.3%; positive predictive value, 81.5%; negative predictive value, 95.5%). CONCLUSIONS: Although administrative data alone did not validly identify cancer related events, administrative data in combination with chart collected EOIT dates was associated with excellent validity. The collection of EOIT dates by cancer registries would significantly expand the potential of administrative data linkage to assess cancer outcomes. PMID- 28731895 TI - Our Senior Editorial Reviewers: A Centerpiece. PMID- 28731894 TI - Ralph V. McKinney, Jr. Award in Basic and Clinical Research for 2017. PMID- 28731896 TI - Freehand Versus Guided Surgery: Factors Influencing Accuracy of Dental Implant Placement. AB - INTRODUCTION: Patient anatomy, practitioner experience, and surgical approach are all factors that influence implant accuracy. However, the relative importance of each factor is poorly understood. The present study aimed to identify which factors most critically determine implant accuracy to aid the practitioner in case selection for guided versus freehand surgery. METHODS: One practitioner's ideal implant angulation and position was compared with his achieved position radiographically for 450 implants placed using a conventional freehand method. The relative contribution of 11 demographic, anatomical, and surgical factors to the accuracy of implant placement was systematically quantified. DISCUSSION: The most important predictors of angulation and position accuracy were the number of adjacent implants placed and the tooth-borne status of the site. Immediate placement also significantly increased position accuracy, whereas cases with narrow sites were significantly more accurate in angulation. Accuracy also improved with the practitioner's experience. CONCLUSION: These results suggest tooth-borne, single-implant cases performed later in the practitioner's experience are most appropriate for freehand placement, whereas guided surgery should be considered to improve accuracy for multiple-implant cases in edentulous or partially edentulous sites. PMID- 28731897 TI - Marginal Bone Loss Around Early-Loaded SLA and SLActive Implants: Radiological Follow-Up Evaluation Up to 6.5 Years. AB - PURPOSE: The aim of this study was to compare marginal bone loss around early loaded SLA and SLActive tissue-level implants (Straumann Dental Implants; Institut Straumann AG, Basel, Switzerland) after a mean of 81-month follow-up period. MATERIAL AND METHODS: One hundred seven SLA and 68 SLActive implants were placed in 55 patients and loaded with final restoration after 8 and 3 weeks of healing time, respectively. Marginal bone loss around implants was determined radiographically at initial and after a mean observation time ranging between 20 and 81 months. The effect of location (mandible vs maxilla), smoking habit, sex, implant length and diameter, and the type of prosthesis on the marginal bone loss was evaluated. RESULTS: The overall cumulative survival rate was 98.2% being 99% for SLA implants and 97% for SLActive implants. After 20-month follow-up period, mean marginal bone loss values for the SLA and SLActive implants were 0.24 and 0.17 mm, respectively. After 81 months, mean marginal bone loss for the SLA and SLActive implants reached 0.71 and 0.53 mm, respectively. Marginal bone loss was affected by the length and type of implant and patients' smoking habit after a mean observation time of 20 months. However, none of the parameters had any significant effect on the marginal bone loss after a follow-up period of 81 months. CONCLUSION: With both SLA and SLActive implants, successful clinical results could be achieved up to 6.5 years of follow-up period. PMID- 28731898 TI - Steady progress toward a malaria vaccine. AB - PURPOSE OF REVIEW: Great progress has been made in reducing malaria morbidity and mortality, yet the parasite continues to cause a startling 200 million infections and 500 000 deaths annually. Malaria vaccine development is pushing new boundaries by steady advancement toward a licensed product. RECENT FINDINGS: Despite 50 years of research, the complexity of Plasmoidum falciparum confounds all attempts to eradicate the organism. This very complexity has pushed the boundaries of vaccine development to new heights, yet it remains to be seen if an affordable vaccine can provide durable and high-level protection. Novel vaccines such as RTS,S/AS01E are on the edge of licensure, but old techniques have resurged with the ability to deliver vialed, whole organism vaccines. Novel adjuvants, multistage/multiantigen approaches and transmission blocking vaccines all contribute to a multipronged battle plan to conquer malaria. SUMMARY: Vaccines are the most cost-effective tools to control infectious diseases, yet the complexity of malaria has frustrated all attempts to develop an effective product. This review concentrates on recent advances in malaria vaccine development that lend hope that a vaccine can be produced and malaria eradicated. PMID- 28731899 TI - Current perspectives on invasive nontyphoidal Salmonella disease. AB - PURPOSE OF REVIEW: We searched PubMed for scientific literature published in the past 2 years for relevant information regarding the burden of invasive nontyphoidal Salmonella disease and host factors associated with nontyphoidal Salmonella infection and discuss current knowledge on vaccine development. The following search terms were used: Salmonella, non typhoidal/nontyphoidal, NTS, disease, bloodstream infection, invasive, sepsis/septicaemia/septicemia, bacteraemia/bacteremia, gastroenteritis, incidence, prevalence, morbidity, mortality, case fatality, host/risk factor, vaccination, and prevention/control. RECENT FINDINGS: Estimates of the global invasive nontyphoidal Salmonella disease burden have been recently updated; additional data from Africa, Asia, and Latin America are now available. New data bridge various knowledge gaps, particularly with respect to host risk factors and the geographical distribution of iNTS serovars. It has also been observed that Salmonella Typhimurium sequence type 313 is emergent in several African countries. Available data suggest that genetic variation in the sequence type 313 strain has led to increased pathogenicity and human host adaptation. A bivalent efficacious vaccine, targeting Salmonella serovars Typhimurium and Enteritidis, would significantly lower the disease burden in high-risk populations. SUMMARY: The mobilization of surveillance networks, especially in Asia and Latin America, may provide missing data regarding the invasive nontyphoidal Salmonella disease burden and their corresponding antimicrobial susceptibility profiles. Efforts and resources should be directed toward invasive nontyphoidal Salmonella disease vaccine development. PMID- 28731900 TI - Micro- and Macrocirculatory Changes During Sepsis and Septic Shock in a Rat Model. AB - Microcirculation is the motor of sepsis. In the present study, we investigated whether microcirculatory alterations occur before changes of systemic hemodynamics in a rat model of cecum ligation and puncture (CLP)-induced sepsis. We further investigated renal microcirculatory changes during sepsis and compared those with buccal microcirculation. Twelve male Sprague-Dawley rats were randomized into a sham control group (n = 6) and a CLP group (n = 6). Perfused microvessel density (PVD) and microvascular flow index (MFI) were evaluated using sidestream dark field (SDF) video microscopy at baseline-60, 120, 180, 240, 300, and 360 min following CLP. A semiquantitative score was calculated for vessels of less than 20 MUm, primarily representing the capillaries. Hemodynamic measurements such as cardiac output (CO), aortic pressure (AP), heart rate (HR), end-tidal CO2 (ETCO2), blood pH, and lactate were measured simultaneously. The serum cytokine interleukin 6 (IL-6) was measured at baseline-120, 240, and 360 min. In the CLP group, buccal PVD and MFI were reduced at 180 min (P < 0.05 vs. baseline); renal PVD and MFI were reduced at 180 min (P < 0.05 vs. baseline), but MAP and CO did not change until 300 min after CLP. In the rat model of peritonitis-induced sepsis, microcirculatory alterations of both peripheral mucosa and kidney occurred earlier than global hemodynamics. Monitoring the microcirculation may provide a means of early detection of circulatory failure during sepsis. The changes of renal microcirculation correlate with that of buccal during sepsis and septic shock. PMID- 28731901 TI - Should First-line Empiric Treatment Strategies for Neonates Cover Coagulase negative Staphylococcal Infections in Kenya? AB - BACKGROUND: Neonatal mortality remains high in sub-Saharan Africa, and a third of deaths are estimated to result from infection. While coagulase-negative staphylococci (CoNS) are leading neonatal pathogens in resource-rich settings, their role, and the need for early anti-Staphylococcal treatment in empiric antibiotic guidelines, is unknown in sub-Saharan Africa. METHODS: We examined systematic clinical and microbiologic surveillance data from all neonatal admissions to Kilifi County Hospital (1998-2013) to determine associated case fatality and/or prolonged duration of admission associated with CoNS in neonates treated according to standard World Health Organization guidelines. RESULTS: CoNS was isolated from blood culture in 995 of 9552 (10%) neonates. Case fatality among neonates with CoNS isolated from blood did not differ from other neonatal admissions (P = 0.2), and duration of admission was not prolonged [odds ratio (OR) = 0.9 (0.7-1.0), P = 0.040]. Neonates with CoNS were more likely to have convulsions [OR = 1.4 (1.0-1.8), P = 0.031] but less likely to have impaired consciousness or severe indrawing [OR = 0.8 (0.7-0.9), P = 0.025; OR = 0.9 (0.7 1.0), P = 0.065]. CONCLUSIONS: CoNS isolation in blood cultures at admission was not associated with adverse clinical outcomes in neonates treated according to standard World Health Organization guidelines for hospital care in this setting. There is no evidence that first-line antimicrobial treatment guidelines should be altered to increase cover for CoNS infections in neonates in this setting. PMID- 28731902 TI - Terasaki Epitope Mismatch Burden Predicts the Development of De Novo DQ Donor Specific Antibodies and are Associated With Adverse Allograft Outcomes. AB - BACKGROUND: De novo DQ donor-specific antibody (DSA) are associated with antibody mediated rejection and allograft loss. Given the lack of effective treatment of de novo DQ DSA, their prevention is vital if there is to be an improvement of long-term allograft survival. Using the HLA Matchmaker program, DQ epitope matching has been shown to be superior to HLA antigen mismatching in predicting de novo DQ DSA development. Whether DQ epitopes determined by Terasaki may more accurately predict de novo DQ development over HLA antigen matching is not known. METHODS: We retrospectively analyzed the immunogenicity of the different HLA antigens, DQB1 alleles and DQB1 Teraskai epitopes (TerEp) in a large cohort of renal transplant recipients, by comparing patient mismatches with de novo DSA development. RESULTS: Patients mismatched at a DQB1 allele were at significantly higher risk of developing de novo DSA compared with other mismatched HLA antigens. Patients mismatched at the DQ7 allele appear to be at specific risk. For patients mismatched at a single DQB1 allele, the risk of de novo DQ DSA development increases with the number of TerEp mismatches. However, the immunogenicity of the different DQ TerEps does not appear to be equal. Patients who develop antibodies against TerEps are at increased risk of adverse allograft outcomes, specifically antibody-mediated rejection. CONCLUSIONS: Epitope mismatch burden, determined by TerEps, helps predict risk of de novo DQ DSA development and offers an alternative approach to predict an alloimmune response. PMID- 28731903 TI - Hepatitis Transmission Risk in Kidney Transplantation (the HINT study): A Cross Sectional Survey of Transplant Clinicians in Australia and New Zealand. AB - BACKGROUND: Interpreting hepatitis serology and virus transmission risk in transplantation can be challenging. Decisions must balance opportunity to transplant against potential infection transmission. We aimed to survey understanding among the Australian and New Zealand medical transplant workforce of hepatitis risk in kidney donors and recipients. METHODS: An anonymous, self completed, cross-sectional survey was distributed via electronic mailing lists to Australian and New Zealand clinicians involved in kidney transplantation (2014 2015). We compared interpretation of clinical scenarios with paired donor and recipient hepatitis B virus and hepatitis C virus serology to recommendations in clinical practice guidelines. We used logistic regression modeling to investigate characteristics associated with decisions on transplant suitability in scenarios with poor (<50%) guideline concordance (odds ratios [OR]). RESULTS: One hundred ten respondents had representative workforce demographics: most were male (63%) nephrologists (74%) aged 40 to 49 years. Although donor and recipient hepatitis status was largely well understood, transplant suitability responses varied among respondents. For a hepatitis B virus surface antigen-positive donor and vaccinated recipient, 44% suggested this was unsuitable for transplant (guideline concordant) but 35% suggested this was suitable with prophylaxis (guideline divergent). In 4 scenarios with transplant suitability guideline concordance less than 50%, acute transplant care involvement predicted guideline concordant responses (OR, 1.69; P = 0.04). Guideline concordant responses were chosen less by hepatologists, intensive care doctors (OR, 0.23, 0.35, respectively; P = 0.01), and New Zealanders (guideline concordant responses OR, 0.17; P < 0.01; alternative responses OR, 4.31; P < 0.01). CONCLUSIONS: Despite broadly consistent interpretations of hepatitis serology, transplant suitability decisions varied and often diverged from guidelines. Improved decision support may reduce clinician variability. PMID- 28731904 TI - Monoclonal Gammopathy of Undetermined Significance After Kidney Transplantation: Single-Center Experience. AB - BACKGROUND: Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic premalignant plasma cell disorder. Prevalence and clinical outcomes of MGUS in kidney transplant (KT) recipients have been previously reported in few studies with conflicting results. METHODS: We conducted a retrospective study in a population of 548 KT recipients transplanted between 1998 and 2015. RESULTS: Thirty-nine (8.1%) subjects developed MGUS after KT. At diagnosis of MGUS, the average age was 52 +/- 9.2 years, and 23% of the patients were younger than 50 years. Occurrence of MGUS was not influenced by age and sex. After a mean follow up of 7.8 years, only 1 (2.5%) patient progressed to multiple myeloma. We found no differences in the incidence of solid and hematological malignancies, serious infections, graft failure, and mortality between KT patients with MGUS and a matched cohort of KT recipients without MGUS. The MGUS group had a significantly higher prevalence of monoclonal B cell lymphocytosis, premalignant condition poorly described in KT recipients. Prior history of glomerulonephritis or interstitial nephritis, as cause of renal failure, represented the only predictive factor for MGUS development. CONCLUSIONS: MGUS is a premalignant disorder frequently encountered in KT recipients. We found no differences in clinical outcomes between MGUS patients and KT controls. PMID- 28731905 TI - Validation of the Prognostic Kidney Donor Risk Index Scoring System of Deceased Donors for Renal Transplantation in the Netherlands. AB - BACKGROUND: The prognostic Kidney Donor Risk Index (KDRI)-developed and internally validated in the United States-is a widely used tool to predict transplant outcome of a deceased donor kidney. The KDRI is currently used for longevity matching between donors and recipients in the United States. METHODS: We aimed to externally validate the KDRIdonor-only and KDRIfull as proposed by Rao et al (2009). KDRIdonor-only consist of 10 donor factors, and KDRIfull with an additional 4 transplant factors. We used the Dutch Organ Transplantation Registry to include 3201 adult recipients transplanted from 2002 to 2012. RESULTS: The median Dutch KDRI was 1.21 and comparable with the year 2012 in the United States (median of 1.24). The calibration-slope was 0.98 and 0.96 for the KDRIfull and KDRIdonor-only, respectively, indicating that predictions of graft failure were on average similar. The discriminative ability (Harrell C) of the KDRIfull and the KDRIdonor-only at 5 years was 0.63 (95% confidence interval [CI], 0.62-0.64), and 0.62 (95% CI, 0.61-0.63), respectively. We found misspecification of 3 KDRI factors: age (P = 0.002), weight (P = 0.017), and cold ischemia time (P < 0.001). Adding the use of inotropic drugs before donation (P = 0.040) and the interaction between circulatory-death donor kidneys and prolonged cold ischemic time (>24 hours vs 12 hours; P = 0.059) could improve predictive ability. CONCLUSIONS: The KDRI performs equal in the Dutch population. Discriminative ability of the KDRI indicates limited clinical use for adequate individualized decisions. An updated KDRI may contribute to a standardized policy meeting the growing demand of donor kidneys in the Eurotransplant region. PMID- 28731906 TI - C1-Inhibitor Treatment Decreases Renal Injury in an Established Brain-Dead Rat Model. AB - BACKGROUND: Kidneys derived from brain-dead (BD) donors have lower graft survival rates compared with kidneys from living donors. Complement activation plays an important role in brain death. The aim of our study was therefore to investigate the effect of C1-inhibitor (C1-INH) on BD-induced renal injury. METHODS: Brain death was induced in rats by inflating a subdurally placed balloon catheter. Thirty minutes after BD, rats were treated with saline, low-dose or high-dose C1 INH. Sham-operated rats served as controls. After 4 hours of brain death, renal function, injury, inflammation, and complement activation were assessed. RESULTS: High-dose C1-INH treatment of BD donors resulted in significantly lower renal gene expression and serum levels of IL-6. Treatment with C1-INH also improved renal function and reduced renal injury, reflected by the significantly lower kidney injury marker 1 gene expression and lower serum levels of lactate dehydrogenase and creatinine. Furthermore, C1-INH effectively reduced complement activation by brain death and significantly increased functional levels. However, C1-INH treatment did not prevent renal cellular influx. CONCLUSIONS: Targeting complement activation after the induction of brain death reduced renal inflammation and improved renal function before transplantation. Therefore, strategies targeting complement activation in human BD donors might clinically improve donor organ viability and renal allograft survival. PMID- 28731907 TI - Oral Nucleos(t)ide Analogs Alone After Liver Transplantation in Chronic Hepatitis B With Preexisting rt204 Mutation. AB - BACKGROUND: There is currently limited data regarding the use of oral antiviral therapy alone without hepatitis B immune globulin for chronic hepatitis B patients with preexisting lamivudine (LAM) resistance (LAM-R) undergoing liver transplantation. METHODS: This is a cohort study determining the effectiveness and long-term outcome in this group of patients. RESULTS: Fifty-seven consecutive chronic hepatitis B patients with preexisting rt204 LAM-R mutations or virological load refractory to LAM undergoing liver transplantation were included, with a median follow-up of 73 months. Fifty-five (96.5%) patients received a regimen that included the use of nucleotide analogs. The cumulative rate of hepatitis B surface antigen seroclearance at 1, 5, and 10 years was 82%, 88%, and 91%, respectively. At the time of transplantation, 39 (72%) patients had detectable hepatitis B virus (HBV) DNA, with a median of 4.5 log copies/mL. The cumulative rate of HBV undetectability was 91% at 1 year, increasing to 100% by 5 years. After 1 year of liver transplantation, over 90% of the patients had undetectable HBV DNA, and from 8 years onward, 100% had undetectable HBV DNA. The overall long-term survival was excellent, with a 12-year survival of 87%. There was no HBV-related graft loss, and no retransplantation or deaths due to HBV reactivation. CONCLUSION: Oral antiviral therapy alone without hepatitis B immune globulin is highly effective in preventing HBV reactivation and graft loss from recurrent hepatitis B after liver transplantation in patients with preexisting LAM resistance HBV. The long-term outcome was excellent, with survival of 87% at 12 years after transplantation, without any mortality related to HBV reactivation. PMID- 28731908 TI - Prognostic Factors in Lung Transplantation After Hematopoietic Stem Cell Transplantation. AB - BACKGROUND: Lung transplantation is the final lifesaving option for patients with pulmonary complications after hematopoietic stem cell transplantation (HSCT). Patients undergoing HSCT for hematologic diseases are thought to be high-risk candidates for lung transplantation; therefore, few lung transplants are performed for these patients, and few studies have been reported. This study aimed to describe the characteristics and outcomes of lung transplantation in patients with pulmonary complications after HSCT. METHODS: We retrospectively investigated 62 patients who underwent lung transplantation after HSCT. All data were collected from 6 lung transplant centers in Japan. RESULTS: Seventeen patients underwent cadaveric lung transplantation, whereas 45 underwent living donor lobar lung transplantation (LDLLT). In the LDLLT group, 18 patients underwent LDLLT after HSCT in which one of the donors had also served as a donor for HSCT. Seven patients underwent single LDLLT for which the donor was the same as the patient from whom stem cells were obtained for HSCT. Preoperative hypercapnia was observed in 52 patients (84%). Thirteen patients (21%) required mechanical ventilation preoperatively. Fifty-five patients underwent HSCT for hematologic malignancies, and 4 (7%) relapsed after lung transplantation. The 5 year survival rate was 64.2%. In a multivariable analysis, patients younger than 45 years and those with the same donor for both procedures exhibited significantly better survival (P = 0.012 and 0.041, respectively). CONCLUSIONS: Lung transplantation for pulmonary complications after HSCT was performed safely and yielded better survival, especially in younger recipients for whom both lung transplantation and HSCT involved the same donor. PMID- 28731909 TI - Trichodysplasia Spinulosa. PMID- 28731910 TI - New Answers to Old Conundrums: What Antibodies, Exosomes and Inflammasomes Bring to the Conversation. Canadian National Transplant Research Program International Summit Report. AB - Antibody-mediated injury is a major cause of allograft dysfunction and loss. Antibodies to ABH(O) blood group antigens are classic mediators of ABO incompatible graft rejection, whereas donor-specific anti-HLA antibodies and, more recently, autoantibodies are appreciated as important contributors to allograft inflammation and dysfunction. In August 2016, the International Summit of the Canadian National Transplant Research Program focused on recent advances in the field of antibody-mediated rejection. Here, we describe work presented and discussed at the meeting, with a focus on 3 major themes: the importance of (1) natural antibodies and autoantibodies, (2) tissue injury-derived exosomes and autoimmunity, (3) inflammasome activation and innate immune responses in regulating allograft inflammation and dysfunction. Finally, we explore novel areas of therapeutic intervention that have recently emerged from these 3 major and overlapping fields of transplantation research. PMID- 28731912 TI - Assessing infant and maternal readiness for newborn discharge. AB - PURPOSE OF REVIEW: The review highlights the shift from prescribed length of stay (LOS) to mother-infant dyad readiness as the basis for making discharge decisions for healthy term newborns. We describe the components of readiness that should be considered in making the decision, focusing on infant clinical readiness, and maternal and familial readiness. RECENT FINDINGS: Although the Newborns' and Mothers' Health Protection Act of 1996 aimed to protect infants and mothers by establishing a minimum LOS, the American Academy of Pediatrics 2015 policy on newborn discharge acknowledges the shift from LOS-based to readiness-based discharge decision-making. Healthcare providers must consider a variety of infant and maternal characteristics in determining the appropriate time to discharge a dyad, and mothers should be actively involved in the decision-making process. Criteria for infant clinical readiness include the following: establishment of effective feeding, evaluation of jaundice risk, review and discussion of infant and household vaccination status, obtainment of specimen for metabolic screening, tests of hearing ability, assessment of sepsis risk factors, screening for congenital heart disease, and evaluation of parental knowledge about infant safety measures. Important consideration should also be given to the mother's sociodemographic vulnerabilities, maternal confidence and perception of discharge readiness, and availability of postdischarge care continuity. SUMMARY: The timing of newborn discharge should be a joint decision made by the mother and healthcare providers based on readiness. The decision should consider the infant's health status, the mother's health status, the mother's perception of readiness, and the availability of social and familial support for the mother and infant. Accessible and comprehensive support postdischarge is also important for helping infants achieve optimal health outcomes. PMID- 28731911 TI - Expert and self-assessment of lifetime symptoms and diagnosis of major depressive disorder in large-scale genetic studies in the general population: comparison of a clinical interview and a self-administered checklist. AB - Major depression disorder (MDD) is a complex neuropsychiatric disorder and an increasing number of genetic risk variants are being identified. Investigation of their influence in the general population requires accurate and efficient assessment of depressive symptoms. Here, clinical interviews conducted by clinicians are the gold standard. We investigated whether valid and reliable clinical phenotypes can be obtained efficiently using self-administered instruments. Lifetime depressive symptoms and lifetime MDD diagnosis were assessed in 464 population-based individuals using a clinical interview and a structured, self-administered checklist. Analyses were carried out of the following: (i) intraclass correlations (ICC) between checklist and interview; (ii) sensitivity/specificity of the checklist; and (iii) the association of interview and checklist with a positive family history of MDD (FH-MDD+). The correspondence of the self-administered checklist with the clinical interview was good for most depressive symptoms (ICC=0.60-0.80) and moderate for MDD diagnosis (ICC=0.45). With the consecutive inclusion of MDD diagnostic criteria, sensitivity decreased from 0.67 to 0.46, whereas specificity remained high (0.95). For checklist and interview, strong associations were found between FH MDD+ and most depressive symptoms and MDD diagnosis (all odds ratio>=1.83). The self-administered checklist showed high reliability for both the assessment of lifetime depressive symptoms and screening for individuals with no lifetime diagnosis of MDD. However, attention is warranted when the aim is to identify MDD cases. The positive association between depressive symptomatology and FH-MDD+ indicates the usefulness of both instruments to assess patients in genetic studies. Our data suggest that the more time-efficient and cost-efficient self administered instruments also allow for the assessment of depressive symptoms accurate enough to investigate the influence of MDD genetic risk variants in the general population. PMID- 28731913 TI - Response to the Letter: Predictors for Airway Complications Following Single or Multilevel Anterior Cervical Discectomy and Fusion. PMID- 28731914 TI - Phenotype of Same-Day-Discharge Patients After Percutaneous Coronary Intervention. AB - BACKGROUND: Overnight observation is the standard of care for uncomplicated elective percutaneous coronary intervention (PCI). However, same-day discharge (SDD) is reportedly safe using predetermined criteria and patient risk categories. Characteristics of patients with SDD have not yet been described. OBJECTIVE: The purpose of this study was to describe the phenotype of patients appropriate for SDD after PCI without predetermined criteria and patient risk categories. METHODS: Analysis of PCI registry data was conducted on patients (n = 2174) who underwent elective and nonelective PCI between January 2012 and June 2014. Preliminary analysis included descriptive statistics, t tests, and chi tests. All variables were analyzed using random forest plot to determine importance of predictors of SDD followed by confirmatory logistic regression. RESULTS: Random forest plot indicated 6 predictors of SDD. Confirmatory logistic regression using a model with all 6 predictors indicated that the model was able to distinguish between patients with SDD and overnight observation after PCI and was statistically significant (chi(7.12, N = 2174) = 511.12, P < .005). Strongest predictors of SDD were stable angina (odds ratio, 5.93 [95% confidence interval, 1.316-26.712]; P = .020) followed by non-ST elevation myocardial infarction/high risk unstable angina (odds ratio, 1.66 [95% confidence interval, 1.239-2.225]; P = .001). Readmission within 24 hours of SDD after PCI was low at 0.91%. CONCLUSIONS: Age, access site, complexity, and number of lesions stented did not preclude SDD. A broader range of patients, particularly patients in higher risk categories (non-ST elevation myocardial infarction and unstable angina), are candidates for SDD. PMID- 28731915 TI - Cross-cultural Adaptation of the Self-care of Hypertension Inventory Into Brazilian Portuguese. AB - BACKGROUND: Lifestyle changes and treatment adherence still constitute a challenge to healthcare providers involved in the care of persons with hypertension. The lack of validated instruments measuring the ability of hypertensive patients to manage their disease has slowed research progress in this area. The Self-care of Hypertension Inventory, originally developed in the United States, consists of 23 items divided across 3 scales: Self-care Maintenance, Self-care Management, and Self-care Confidence. These scales measure how well patients with hypertension adhere to treatment and manage elevated blood pressure, as well as their confidence in their ability to perform self-care. A rigorous cross-cultural adaptation and validation process is required before this instrument can be used in other countries. OBJECTIVE: The aims of this study were to translate the Self-care of Hypertension Inventory into Brazilian Portuguese with cross-cultural adaptation and to evaluate interobserver reliability and temporal stability. METHODS: This methodological study involved forward translation, synthesis of forward translations, back-translation, synthesis of back-translations, expert committee review, and pretesting. Interobserver agreement and the temporal stability of the scales were assessed. RESULTS: The expert committee proposed semantic and cultural modifications to some items and the addition of guidance statements to facilitate administration of the scale. Interobserver analysis demonstrated substantial agreement. Analysis of temporal stability showed near-perfect agreement. CONCLUSIONS: Cross-cultural adaptation of the Self-care of Hypertension Inventory successfully produced a Portuguese language version of the instrument for further evaluation of psychometric properties. Once that step is completed, the scale can be used in Brazil. PMID- 28731916 TI - Central Nervous System Fungal Infection and Acute Lymphoblastic Leukemia in Children: What is the Optimal Duration of Antifungal Therapy? AB - Invasive fungal infections are rare in children with acute lymphoblastic leukemia. It compromises the antileukemia therapy should it happen. Central nervous system fungal infections carry high mortality. We here report the case of a 6.5-year-old girl who developed multiple central nervous system fungal abscesses possibly due to Aspergillus infection during induction therapy for acute lymphoblastic leukemia who has been successfully managed without compromising antileukemia therapy. She has been receiving antifungal therapy and maintenance chemotherapy for 20 months from diagnosis. We reviewed literature about the optimal duration of therapy for such children as the reported cases duration ranged between 4 and 24 months. PMID- 28731917 TI - The Impact of Iron Overload in Acute Leukemia: Chronic Inflammation, But Not the Presence of Nontransferrin Bound Iron is a Determinant of Oxidative Stress. AB - In the literature, studies on the oxidant effects of nontransferrin bound iron [NTBI (eLPI assay)] during chemotherapy of acute lymphoblastic leukemia and acute myeloblastic leukemia are lacking. We established NTBI and oxidative stress determinants (OSD), iron parameters, high-sensitive C-reactive protein (hs-CRP) levels, liver tests, cumulative chemotherapeutic doses, and transfused blood in 36 children with acute leukemia throughout chemotherapy. These parameters were determined at the beginning and end of chemotherapy blocks (11 time points) and in 20 healthy children using enzyme-linked immunosorbent assay, and colorimetric and fluorometric enzymatic methods. In acute lymphoblastic leukemia, NTBI, OSD, and hs-CRP were higher than controls at 4/11, 7/11, and 9/11 time points (P<0.05). At 3 time points, NTBI and OSD concurrently increased. Ferritin, soluble transferrin receptor, serum iron, and transferrin saturation were higher than in controls at 5 to 11/11 time points (P<0.05). Those with NTBI had higher iron parameters than those without NTBI (P<0.05), but showed similar OSD, hs-CRP, liver enzymes, cumulative chemotherapeutics, and transfused blood (P>0.05). OSD did not correlate with NTBI, but correlated with hs-CRP. In conclusion, NTBI is a poor predictor of OSD in acute leukemia possibly because of the heterogeneity of NTBI and chronic inflammation. Further studies are needed to delineate the pathophysiology of these diseases. PMID- 28731919 TI - A Case Presentation: Rare Occurrence of an Adolescent Male Presenting With an ATRT and Simultaneous Low-grade Glioneuronal Tumor. AB - Atypical rhabdoid/teratoid tumor (ATRT) is an uncommon and highly malignant tumor of the central nervous system. The majority of ATRT tumors occur in infancy and young children located in the posterior fossa. The ideal treatment for cure remains controversial and prognosis is typically unfavorable. We present a case of an atypical presentation of ATRT, presenting in adolescence with an additional low-grade glioneuronal tumor discovered at diagnosis. PMID- 28731920 TI - Eye Movement Disorders Following Allogeneic Bone Marrow Transplantation on FK506 (Tacrolimus) and Ganciclovir. AB - FK506 (tacrolimus) is an immunosuppressive drug and more potent than cyclosporine. FK506 is widely used for immunosuppression in the prevention and treatment of graft-versus-host disease after allogeneic bone marrow transplantation and solid organ transplantation. Neurotoxicity is a recognized complication of FK506 therapy, but ptosis and weakness of eye abduction unilaterally has not been reported in association with FK506 administration to date. We discuss a 13-year-old male patient who developed ptosis and weakness of eye abduction unilaterally 90 days after transplantation with bone marrow from an unrelated donor, for acute lymphoblastic leukemia in this case report. FK506 therapy was administered for graft-versus-host disease prophylaxis and CMV infection was treated with ganciclovir. The physical examination findings completely resolved 72 to 96 hours after concomitant FK506 and ganciclovir treatment were terminated. PMID- 28731921 TI - Loss of CDKN1C in a Recurrent Atypical Teratoid/Rhabdoid Tumor. AB - Atypical teratoid/rhabdoid tumor (AT/RT) is a malignant tumor that is commonly associated with biallelic alterations of SMARCB1. Recurrent or refractory AT/RT has not been molecularly characterized as well. We present the case of a child with recurrent AT/RT who underwent clinically integrated molecular profiling (germline DNA and tumor DNA/RNA sequencing). This demonstrated a somatic lesion in CDKN1C alongside hallmark loss of SMARCB1. This data allowed us to explore potential personalized therapies for this patient and expose a molecular driver that may be involved in similar cases. PMID- 28731922 TI - A Novel g.55040074delT in ALAS2 Gene Resulting in a Monomeric Protein and Severe Sideroblastic Anemia Phenotype. AB - Sideroblastic anemias are a rare group of disorders resulting from defective iron incorporation during heme synthesis and hence characterized by anemia and presence of ringed sideroblasts in bone marrow. The most common form is an X linked disorder caused by mutations in ALAS2 gene. In the current paper, a case of X-linked sideroblastic anemia caused by a novel homozygous deletional mutation in exon 10 of ALAS2 gene is presented. The female infant developed moderately severe anemia at 6 months of age, which did not improve despite adequate nutritional support. The diagnosis was suspected considering a high plasma ferritin of 740.9 MUg/L. The protein structure as predicted by SWISS model was a monomeric form rather than wild-type homodimer, resulting in marked loss of function and protein instability. PMID- 28731923 TI - Human Bocavirus: Can It Trigger Hemophagocytic Lymphohistiocytosis? AB - With improvements in molecular diagnostic methods, report of Human bocavirus (HBoV) as an etiologic agent in many studies on viral respiratory and gastrointestinal infections has been increasing. Two pediatric patients who presented with secondary hemophagocytic lymphohistiocytosis were examined for etiologic causes, including viruses. Whole bacterial and fungal cultures and viral serological studies were negative. Viral polymerase chain reaction of nasopharyngeal secretions showed HBoV. One was successfully treated with intravenous immunoglobulins, whereas the other died with multiorgan failure. Here we report 2 pediatric patients with secondary hemophagocytic lymphohistiocytosis and detection of HBoV as the sole agent, predicting an association. PMID- 28731924 TI - Clinical trial registry use in anaesthesiology systematic reviews: A cross sectional study of systematic reviews published in anaesthesiology journals and the Cochrane Library. AB - BACKGROUND: Publication bias within systematic reviews may result in incorrect conclusions leading to inappropriate clinical decisions and a decreased quality of patient care. Searching clinical trial registries for unpublished studies is one possible solution to minimise publication bias. OBJECTIVES: To examine rates of clinical trial registry searches in systematic reviews published in respected anaesthesiology journals and whether these searches found trials (or data) eligible for inclusion; to compare rates of registry searches between published reviews and similar reviews within the Cochrane Anaesthesia, Critical and Emergency Care Group; to conduct trial registry searches for a subset of reviews, determining whether eligible studies were overlooked; to investigate whether reporting of results in completed anaesthesia trials on ClinicalTrials.gov followed guidelines. DESIGN: A cross-sectional study of systematic reviews published in 10 anaesthesiology journals and the Cochrane Library. SETTING AND PARTICIPANTS: PubMed and the Cochrane Library were searched for systematic reviews or meta-analyses. MAIN OUTCOME MEASURES: The primary outcome was the number of systematic reviews that searched clinical trial registries for unpublished trials. Secondary outcomes included the number of registered trials in the ClinicalTrial.gov registry and the number of trials reporting trial results which were available on the ClinicalTrials.gov database and which should have been considered in a systematic review. RESULTS: The PubMed search yielded 507 records, and 415 remained after exclusions. Of these, 49 (11.8%) included a search of clinical trial registries. In total, 12 systematic reviews reported finding unpublished data but only five incorporated the data into their analyses. Of the Cochrane reviews, 58.9% (43/73) reported registry searches. Among a sample of 30 systematic reviews that omitted registry searches, we found many studies within the registries that were probably eligible to be included in the systematic reviews. For completed trials within the ClinicalTrials.gov database, only 15.4% reported results. CONCLUSION: The majority of systematic reviews in anaesthesiology did not include data from clinical trial registries. Exclusion of statistically nonsignificant data may lead to a biased interpretation of the data and hence inappropriate clinical interventions. TRIAL REGISTRATION: Registered in University hospital Medical Information Network (UMIN) Clinical Trials Registry (UMIN000021932). PMID- 28731925 TI - Thoracic paravertebral block for postoperative pain management after renal surgery: A randomised controlled trial. AB - BACKGROUND: Thoracic paravertebral block (ThPVB) combined with general anaesthesia is used in thoracic and general surgery. It provides effective analgesia, reduces surgical stress response and the incidence of chronic postoperative pain. OBJECTIVE: To assess the efficacy of ThPVB in reducing opioid requirements and decreasing the intensity of pain after renal surgery. DESIGN: A randomised, open label study. SETTING: A single university hospital. Study conducted from August 2013 to February 2014. PARTICIPANTS: In total, 68 patients scheduled for elective renal surgery (open nephrectomy or open nephron-sparing surgery). INTERVENTIONS: Preoperative ThPVB with 0.5% bupivacaine combined with general anaesthesia, followed by postoperative oxycodone combined with nonopioid analgesics as rescue drugs. Follow-up period: 48 h. MAIN OUTCOME MEASURES: Total dose of postoperative oxycodone required, pain intensity, occurrence of opioid related adverse events, ThPVB-related adverse events and patient satisfaction. RESULTS: A total of 68 patients were randomised into two groups and, of these, 10 were subsequently excluded from analysis. Patients in group paravertebral block (PVB; n = 27) had general anaesthesia and ThPVB, and those in group general (anaesthesia) (GEN) (n = 31) formed a control group receiving general anaesthesia only. Compared with patients in group GEN, patients who received ThPVB required 39% less i.v. oxycodone over the first 48 h and had less pain at rest (P < 0.01) throughout the first 24 h. Group PVB patients also experienced fewer opioid related adverse events and were less sedated during the first 12 postoperative hours. Patients in the PVB group had higher satisfaction scores at 48 h compared with the control group. There were no serious adverse events. CONCLUSION: In our study, preoperative ThPVB was an effective part of a multimodal analgesia regimen for reducing opioid consumption and pain intensity. Methods and drugs used in both groups were well tolerated with no serious adverse events. Compared with the control group, patients in the ThPVB group reported increased satisfaction. TRIAL REGISTRATION: Clinical Trials NCT02840526. PMID- 28731926 TI - History of anaesthesia: The ketamine story - past, present and future. PMID- 28731927 TI - Injectate spread following anterior sub-costal and posterior approaches to the quadratus lumborum block: A comparative cadaveric study. AB - BACKGROUND: The dermatomal level of analgesia achieved with quadratus lumborum blocks varies according to the location of injection. The most commonly used approaches are either at the postero-lateral aspect or anterior to the quadratus lumborum muscle. OBJECTIVE: To determine whether the site of injection of contrast dye around the quadratus lumborum muscle of cadavers affects the extent and mechanism of dye spread. DESIGN: Observational human cadaver study. SETTING: Cleveland Clinic cadaveric laboratory. PARTICIPANTS: Six fresh human cadavers. INTERVENTIONS: The cadavers received either a posterior quadratus lumborum block or an anterior subcostal quadratus lumborum block on each side. MAIN OUTCOME MEASURES: Cadavers were dissected to determine the extent of dye spread. RESULTS: The posterior quadratus lumborum block approach revealed consistently deep staining of the iliohypogastric, ilioinguinal, subcostal nerve, T11 to 12 and L1 nerve roots. In addition, staining of the middle thoracolumbar fascia was seen in all specimens but only variable staining of T10 nerve roots. The anterior subcostal quadratus lumborum block approach in all specimens demonstrated predictable deep staining of the iliohypogastric and ilioinguinal nerves, subcostal nerves, T11 to 12 and L1 nerve roots, and in addition traversing the arcuate ligaments to involve T9 to 12 nerve roots with variable staining of higher thoracic nerve roots. CONCLUSIONS: Our cadaveric study demonstrates that injection of dye on the posterior aspect of quadratus lumborum muscle led to injectate spread through the lateral and posterior abdominal wall but with limited cranial spread, whereas the anterior approach produced broader coverage of the lower to mid-thoracic region. Clinical translation of these findings to determine the practical significance is warranted. PMID- 28731928 TI - Serious game versus online course for pretraining medical students before a simulation-based mastery learning course on cardiopulmonary resuscitation: A randomised controlled study. AB - BACKGROUND: Although both recorded lectures and serious games have been used to pretrain health professionals before simulation training on cardiopulmonary resuscitation, they have never been compared. OBJECTIVE: The aim of this study was to compare an online course and a serious game for pretraining medical students before simulation-based mastery learning on the management of sudden cardiac arrest. DESIGN: A randomised controlled trial. Participants were pretrained using the online course or the serious game on day 1 and day 7. On day 8, each participant was evaluated repeatedly on a scenario of cardiac arrest until reaching a minimum passing score. SETTING: Department of Simulation in Healthcare in a French medical faculty. PARTICIPANTS: Eighty-two volunteer second year medical students participated between June and October 2016 and 79 were assessed for primary outcome. INTERVENTIONS: The serious game used was Staying Alive, which involved a 3D realistic environment, and the online course involved a PowerPoint lecture. MAIN OUTCOME MEASURES: The median total training time needed for students to reach the minimum passing score on day 8. This same outcome was also assessed 4 months later. RESULTS: The median training time (interquartile range) necessary for students to reach the minimum passing score was similar between the two groups: 20.5 (15.8 to 30.3) minutes in the serious game group versus 23 (15 to 32) minutes in the online course group, P = 0.51. Achieving an appropriate degree of chest compression was the most difficult requirement to fulfil for students in both groups. Four months later, the median training time decreased significantly in both groups, but no correlation was found at an individual level with the training times observed on day 8. CONCLUSION: The serious game used in this study was not superior to an online course to pretrain medical students in the management of a cardiac arrest. The absence of any correlation between the performances of students evaluated during two training sessions separated by 4 months suggests that some elements in the management of cardiac arrest such as compression depth can only be partially learned and retained after a simulation-based training. TRIAL REGISTRATION: ClinicalTrials.gov-NCT02758119. PMID- 28731929 TI - Impact of aortic rather than brachial pulsatile haemodynamics on variations in end-organ measures across the full adult blood pressure range. AB - AIMS: To determine the extent to which the adverse effects of blood pressure (BP) are mediated by pulsatile haemodynamic changes across the normotensive as compared with the hypertensive adult brachial BP range, and whether aortic rather than brachial pulsatile changes best index these effects. METHODS: In 1307 community participants, the contribution of pulsatile haemodynamics (applanation tonometry and SphygmoCor software) to variations in left ventricular mass index (LVMI) (echocardiography) (n = 920), carotid intima-media thickness (IMT) (n = 712) and estimated glomerular filtration rate (eGFR) (n = 1164) were assessed. RESULTS: In normotensive participants (50.5%) independent of steady-state pressure (mean arterial pressure), significant relations between aortic backward wave pressure and LVMI (partial r = 0.16, P < 0.001) or IMT (partial r = 0.15, P < 0.005) and between aortic pulse wave velocity and eGFR (partial r = -0.18, P < 0.0001) were noted, effects which in hypertensive participants were observed for LVMI and eGFR, but not IMT. With adjustments for brachial pulse pressure (PP) or SBP and confounders, aortic backward wave pressure and aortic pulse wave velocity showed independent relations with LVMI, IMT or eGFR in normotensive participants, but only with LVMI or eGFR in hypertensive participants. In normotensive participants, as compared with brachial PP or SBP, aortic backward wave pressure showed a greater slope (beta-coefficient) of the relation with LVMI (0.99 +/- 0.24 versus 0.47 +/- 0.10 and 0.41 +/- 0.09 mmHg, P < 0.05) and IMT (0.0045 +/- 0.0013 versus 0.0013 +/- 0.0006 and 0.0013 +/- 0.0005 mmHg, P < 0.05) and a stronger association with left ventricular hypertrophy [odds ratios (95% confidence interval), 1.125 (1.059-1.195) versus 1.054 (1.027-1.082) and 1.042 (1.020-1.066), P < 0.05]. However, in hypertensive participants, only the slope of the aortic backward wave pressure-LVMI relationship was greater than that of PP-LVMI and SBP-LVMI relations. CONCLUSION: Beyond brachial BP, pulsatile haemodynamics rather than steady-state pressures account for end-organ effects more consistently across the normotensive than the hypertensive BP range. Hence, targeting aortic pulsatile haemodynamic changes may best limit BP-related cardiovascular risk within the normotensive BP range. PMID- 28731930 TI - Early life exposure to Chinese famine modifies the association between hypertension and cardiovascular disease. AB - OBJECTIVE: Studies have shown that famine exposure during early life may increase the risk of cardiovascular disease (CVD), hypertension, and diabetes during adulthood. We aimed to assess whether exposure to the Chinese famine (1959-1961) modifies the association between hypertension and CVD. METHODS: We investigated data of 5772 adults born between 1954 and 1964 from the China Health and Retirement Longitudinal Study. CVD was based on self-reported doctor's diagnosis of heart problems (heart attack, coronary heart disease, angina, congestive heart failure, or other heart problems) and stroke. RESULTS: Overall, hypertension was associated with a doubling of CVD risk (odds ratio 1.97, 1.56-2.48, P < 0.001). There was a significant interaction between hypertension and famine exposure for CVD (P = 0.04). The odds ratio of hypertension for CVD were: 1.69 [95% confidence interval (CI) 1.06-2.72, P = 0.03], 2.35 (95%CI 1.44-3.83, P = 0.001), 2.48 (95%CI 1.49-4.11, P < 0.001), 3.35 (95%CI 1.54-7.27, P = 0.002), and 1.40 (95%CI 0.82-2.38, P = 0.215) among adults in late childhood, mid childhood, early childhood, fetal, and nonexposed cohorts, respectively. The risk gradient between hypertension and CVD across famine cohorts was mainly seen among women, those living in urban areas and those with central obesity. CONCLUSION: Early life exposure to the Chinese famine exacerbated the association between hypertension and CVD, especially among women and those living in urban areas or those with central obesity. PMID- 28731932 TI - Investing in Physicians Is Investing in Patients: Enhancing Patient Safety Through Physician Health and Well-being Research. AB - Keeping medical practitioners healthy is an important consideration for workforce satisfaction and retention, as well as public safety. However, there is limited evidence demonstrating how to best care for this group. The absence of data is related to the lack of available funding in this area of research. Supporting investigations that examine physician health often "fall through the cracks" of traditional funding opportunities, landing somewhere between patient safety and workforce development priorities. To address this, funders must extend the scope of current grant opportunities by broadening the scope of patient safety and its relationship to physician health. Other considerations are allocating a portion of doctors' licensing fees to support physician health research and encourage researchers to collaborate with interested stakeholders who can underwrite the costs of studies. Ultimately, funding studies of physician health benefits not only the community of doctors but also the millions of patients receiving care each year. PMID- 28731931 TI - Renal function and its association with blood pressure in Middle Eastern immigrants and native Swedes. AB - BACKGROUND: Iraqi-born immigrants residing in Sweden are at high risk for type 2 diabetes, obesity and hyperlipidemia compared with native Swedes. Paradoxically, hypertension is less prevalent in this immigrant population. The aim of this study was to investigate differences in renal function and further if differences in blood pressure (BP) levels were associated with differences across ethnicities in renal function as a possible explanation to the paradox. METHODS: A population based, cross-sectional study of men and women, born in Iraq or Sweden, aged 30-75 years was conducted in Malmo, Sweden, from 2010 to 2012. Blood samples were drawn, physical examinations performed and self-administrated questionnaires were assessed. Estimated glomerular filtration rate (eGFR) was calculated from the Caucasian Asian Pediatric Adult cohort formula based on cystatin C. RESULTS: Participants without history of cardiovascular disease born in Iraq (n = 1214), irrespective of age and sex, presented with higher eGFR than participants born in Sweden (n = 659), (96.5 ml/min per 1.73 m vs. 93.6, P = 0.009). Furthermore, eGFR showed weaker association with BP in Iraqis than in Swedes, especially for SBP. The relationship was confirmed by a significant interaction between eGFR and country of birth (Pinteraction country of birth * eGFRcystatinC = 0.004). CONCLUSION: The current study shows differences across ethnicities in renal function and its associations with BP. More studies are needed to understand mechanisms contributing to BP regulation and renal function in populations of different ethnic backgrounds. PMID- 28731933 TI - Continuous Capnography Reduces the Incidence of Opioid-Induced Respiratory Rescue by Hospital Rapid Resuscitation Team. AB - OBJECTIVE: The aim of this study was to determine the impact of end tidal carbon dioxide or capnography monitoring in patients requiring patient-controlled analgesia (PCA) on the incidence of opioid-induced respiratory depression (OIRD) in the setting of rapid response. METHODS: A retrospective analysis was conducted in an urban tertiary care facility on the incidence of OIRD in the setting of rapid response as defined by a positive response to naloxone from January 2012 to December 2015. In March 2013, continuous capnography monitoring was implemented for all patients using PCA. RESULTS: The preintervention incidence of OIRD in the setting of rapid response was 0.04% of patients receiving opioids. After the implementation of capnography, the incidence of OIRD in the setting of rapid response was reduced to 0.02%, which was statistically significant (chi = 46.246; df, 1; P < 0.0001). The rate of transfers to a higher level of care associated with these events was also reduced by 79% (baseline, 7.6 transfers/month; postintervention, 1.6 transfers/month). CONCLUSIONS: Continuous capnography monitoring in patients receiving PCA significantly reduces the incidence of OIRD in the setting of rapid response and unplanned transfers to a higher level of care. PMID- 28731934 TI - Long-Term Evaluation of Specular Microscopic Changes Following Nd: YAG Iridotomy in Chronic Primary Angle-Closure Glaucoma Eyes. AB - AIM: The aim of this study was to evaluate specular microscopy of chronic primary angle-closure glaucoma (CPACG) eyes at least 1 year after Nd:YAG iridotomy, and compare them with CPACG eyes without an iridotomy and age-matched, normal eyes. PATIENTS AND METHOD: Consecutive patients of CPACG at the Glaucoma service were screened. All patients underwent slit-lamp biomicroscopy, +90 D examination, and applanation tonometry. A total of 100 eyes of 100 consecutive patients of CPACG with an Nd:YAG iridotomy performed >=1 year before, who met all inclusion/exclusion criteria, 60 consecutive CPACG eyes without an iridotomy, and 60 age and refraction-matched control eyes were enrolled. A specular microscopy was performed in one eye of each patient by an observer masked to diagnosis. RESULTS: CPACG patients had a mean age of 62+/-8 years, a mean intraocular pressure of 18+/-5.3 mm Hg, a mean specular count of 2536+/-224 cells/mm, and mean duration after iridotomy of 3.2+/-2 years. There was a significant correlation of specular endothelial counts with age (r=-0.39; P<0.001) and interval after iridotomy (r=-0.25; P=0.01). CPACG eyes without an iridotomy had a mean age of 62+/-5 years and a mean specular count of 2469+/-199 cells/mm. Normal control eyes with a mean age of 61+/-6 years had a mean specular count of 2729+/ 299 cells/mm. There was no significant difference in specular count between CPACG eyes with or without an iridotomy (P=0.19); however, both CPACG groups had a specular count significantly lower than controls (P=0.01 and 0.02, respectively). There was no statistically significant difference seen in polymegathism (coefficient of variation) and pleomorphism (% of hexagonal cells) in endothelial cells among the 3 groups. CONCLUSIONS: An Nd:YAG iridotomy in CPACG eyes did not lead to any significant changes in central corneal specular microscopy in the long term as compared with patients who did not undergo iridotomy. Eyes with CPACG, without and after an iridotomy, had a lower specular count compared with age-matched controls. PMID- 28731935 TI - Predictive Value of the Water Drinking Test and the Risk of Glaucomatous Visual Field Progression. AB - PURPOSE: The purpose of this is to test the hypothesis the intraocular pressure (IOP) peaks during a stress test [the water drinking test (WDT)] can estimate the risk of future visual field progression in treated primary open-angle glaucoma (POAG) patients. PATIENTS AND METHODS: Design: Prospective, longitudinal study. SETTING: Clinical practice. STUDY POPULATION: Treated POAG patients whose IOP was <=18 mm Hg and who had no IOP-lowering interventions between the date of the WDT and the last eligible visual field. INTERVENTION: At baseline examination, patients underwent the WDT and were then followed at regular intervals with office-based IOP measurements and visual field testing. MAIN OUTCOME MEASURE: Cox proportional hazards survival analysis testing the predictive value of IOP peaks during the WDT versus IOP measurements during office hours on visual field progression. RESULTS: A total of 144 eyes of 96 patients with baseline visual field damage ranging from mild to severe followed for a mean of 28 months were analyzed. In the multivariable analysis adjusting for potential confounders, higher IOP peaks during the WDT were predictive of future visual field progression (hazard ratio=1.11; 95% confidence interval, 1.02 to 1.21; P=0.013). The average and peak IOP during office hours over the same follow-up period were not significantly associated with progression (P=0.651 and 0.569, respectively). CONCLUSIONS: IOP peaks detected with the WDT were predictive of future visual field progression in a treated POAG population. This stress test could be a useful tool for risk assessment in daily practice. PMID- 28731936 TI - Case Series: Keratolimbal Allograft as a Patch Graft for Glaucoma Drainage Devices. AB - PURPOSE: Tube exposure remains one of the most common complications after glaucoma drainage device (GDD) implantation, despite various types of patch grafts available today. We present a 4 patient case series following the effectivity of the keratolimbal allograft (KLAL) as a patch graft for cases of tube exposure. Given its inherent population of stem cells, our hypothesis was that this highly replicative, biological tissue would provide an adequate means of glaucoma tube coverage. The subset of patients chosen for the KLAL patch graft all had a history of abnormally scarred conjunctiva or thin sclera. The aim of utilizing the KLAL patch with its associated donor conjunctival and scleral ring was also to provide additional reinforcement and adequate tube coverage in the setting of compromised native tissue. OBSERVATIONS: Four patients comprised of 2 males and 2 females with a minimum postoperative period of 12 months. All GDDs were initially implanted with a limbal-based incision using either Ahmed glaucoma valve or Baerveldt drainage implant. Three of the 4 patients received the KLAL patch graft after tube exposure with scleral patch graft and 1 patient received KLAL as the primary graft during initial tube placement. CONCLUSIONS: Two of the 4 eyes experienced tube re-exposure postoperatively at 2 and 3 months, respectively. Both of these cases had a history of prior tube exposure after scleral patch graft and both were tubes placed in the pars plana. Interestingly, the patients with failed grafts were younger with a history of more ocular surgeries as compared with the patients with graft viable eyes. RELEVANCE: Through our case series, we found that the KLAL utilized as a patch graft over GDD tubes has the potential for favorable outcomes in certain subtypes of eyes. Although further large scale investigation will be necessary to better define the risk factors associated with graft failure, proving the graft's viability is a crucial first step. PMID- 28731938 TI - Featured Articles for CME Credit August 2017. PMID- 28731940 TI - Introduction: Decision Making With Older Cancer Patients. PMID- 28731937 TI - An adapted Clavien-Dindo scoring system in trauma as a clinically meaningful nonmortality endpoint. AB - BACKGROUND: There is no consensus on reporting nonmortality trauma complications in a graded manner. The Clavien-Dindo scale of complications was originally for elective surgery and requires adaptation to provide meaningful data for trauma patients. In particular, the original score does not account for those treated without surgery. We report an adapted Clavien-Dindo in trauma (ACDiT) scale and apply it to patients managed operatively and nonoperatively. METHODS: A combined prospective and retrospective international multicenter observational study was undertaken to apply the ACDiT scale to 484 trauma patients at three university teaching hospitals (Birmingham, England (n = 303); Houston, Texas (n = 113); and Glasgow, Scotland (n = 68)). These included both intensive care unit (ICU) and non-ICU-managed patients. The Clavien-Dindo scoring system was adapted for trauma patients based on consensus amongst an international collaboration of trauma specialists at these sites. Data included whether initial patients were managed operatively or nonoperatively. Complication grades were compared with hospital free and ICU-free days as other outcome measures of patient morbidity. RESULTS: Two hundred seventeen (44.8%) of 484 patients experienced complications, of whom 61 (28.1%) of 217 died (grade V). The remainder consisted of grades I (n = 20), II (n = 60), III (n = 24), and IV (n = 52). There was a strong association between higher ACDiT grade category and lower number of hospital-free and ICU free days (p < 0.01). Eighty-eight patients with complications did not require surgery, validating the score's usefulness in patients managed nonoperatively. CONCLUSION: The ACDiT scale can be used to grade the severity of posttrauma complications in patients managed both operatively and nonoperatively. It provides clinically meaningful data for morbidity and mortality meetings and other quality improvement exercises. LEVEL OF EVIDENCE: Prognostic, level IV. PMID- 28731941 TI - The Biology of Aging and Cancer: Frailty, Inflammation, and Immunity. AB - The majority of patients with common malignancies are older adults. Intrinsic complex biological changes of aging along with inflammation, immunosenescence, age-associated chronic diseases, and extrinsic environmental and psychosocial factors have significant impact on not only development and behavior of individual malignancies, but also physiologic reserve and vulnerability of older patients who suffer from them. As a result, clinical practice of geriatric oncology demands integration of careful geriatric assessment and management. This article provides an overview of basic biology of aging and its relationship with cancer. After a brief introduction about the definition and mechanisms of aging, as well as age-related biological and physiological changes, the discussion mainly focuses on recent development and insights into the relationship of frailty, inflammation, and immunity with cancer, highlighting how the new knowledge can help further improve assessment and treatment of older patients with malignancies and promote cancer research. PMID- 28731942 TI - Geriatric Assessment and Tools for Predicting Treatment Toxicity in Older Adults With Cancer. AB - Cancer is a disease of older adults, and the majority of new cancer cases and deaths occur in people 65 years or older. However, fewer data are available regarding the risks and benefits of cancer treatment in older adults, and commonly used assessments in oncology fail to adequately evaluate factors that affect treatment efficacy and outcomes in the older patients. The geriatric assessment is a multidisciplinary evaluation that provides detailed information about a patient's functional status, comorbidities, psychological state, social support, nutritional status, and cognitive function. Among older patients with cancer, geriatric assessment has been shown to identify patients at risk of poorer overall survival, and geriatric assessment-based tools are significantly more effective in predicting chemotherapy toxicity than other currently utilized measures. In this review, we summarize the components of the geriatric assessment and provide information about existing tools used to predict treatment toxicity in older patients with cancer. PMID- 28731943 TI - The Impact of Polypharmacy on Patient Outcomes in Older Adults With Cancer. AB - Polypharmacy is prevalent in older adults with cancer and may be advantageous for the management of certain chronic disease states, but uncertainty exists regarding potential hazards and consequences. Cancer-related therapy adds to the prevalence of polypharmacy, which can lead to compromised cancer management plans (i.e., postoperative complications, treatment delays, and/or premature treatment discontinuation). Polypharmacy has been identified as one of the domains commonly included in the Comprehensive Geriatric Assessment likely because of the potential influence on health outcomes. This review summarizes existing evidence regarding health outcomes associated with polypharmacy in older adults with cancer. Preliminary evidence demonstrated that relationships exist between polypharmacy and health outcomes including adverse drug events, falls, frailty, hospitalization, postoperative complications, and mortality. This research is limited by study confounders, inconsistent definitions for polypharmacy, heterogeneous cancer types and stages, and the complex relationship between medication regimens and outcomes. Additional studies are needed to enhance the accuracy and replicability of this research. PMID- 28731944 TI - Cancer Immunotherapy in Older Patients. AB - Advancing age remains one of the most significant risk factors for cancer development. Changes in the immune system occur with aging, and likely play a role in the increased incidence of malignancy in older patients. With the advent of immune checkpoint inhibitors, and their use in a variety of malignancies, there has been an explosion of clinical trials evaluating their use. Unfortunately, these trials have not shown consistent results in elderly patients, nor have age-specific outcomes been consistently reported. Further evaluation of the efficacy and toxicity of these agents in the elderly is needed, as they are now in frequent clinical use. By investigating how age-related changes in the immune system occur and intersect with use of immune checkpoint inhibitors, their use can be optimized in a clear and safe manner. Further study of age-related changes in the immune system can also lead to effective combination immunotherapeutic approaches, maximizing the efficacy of immune checkpoint inhibitors across tumor types and across the age spectrum of cancer patients. PMID- 28731945 TI - The Changing Paradigm of Radiotherapy in the Elderly Population. AB - There is increasing awareness of the special needs for care of the elderly cancer patient. Newer precise conformal radiotherapy techniques allow the safe delivery of higher doses of radiotherapy to the target tumor while reducing the dose to surrounding critical organs. This has led to a shortening of radiotherapy protocols for both curative and palliative indications. We review these novel techniques and protocols and the published clinical studies that include elderly patients treated with these techniques. Despite the fact that the elderly are a growing significant proportion of cancer patients, and the need for radiotherapy in the elderly is expected to rise with increasing life expectancy, they are underrepresented in most clinical studies of radiotherapy, and there are few studies specifically investigating radiotherapy in the elderly. The treatment of early-stage primary lung cancer with stereotactic body radiotherapy is a prime example how new highly conformal techniques and shortened treatment protocols are changing the approach to radiotherapy in the elderly. With improved imaging and radiotherapy treatment precision, it is expected that such techniques will become increasingly used in other cancer sites. It is important for radiation oncologists to be aware of the special needs of the elderly cancer patient and in particular to assess these patients based on functional status and not only chronological age. In addition, geriatric oncologists should be aware of modern radiotherapy techniques that can be particularly appropriate for the elderly patient. PMID- 28731946 TI - Treatment Minimization in Older Patients With Early-Stage Breast Cancer. AB - The management of early-stage breast cancer in older patients is complex and requires a careful balance of the risk of cancer death with the competing risks of comorbidities and treatment-related toxicity in women with largely favorable disease. As the US population continues to age, oncologists will increasingly encounter this clinical challenge. Several strategies involving each core component of breast cancer therapy have been investigated to minimize treatment in these patients while still maintaining acceptable outcomes. These include omission of primary tumor resection, surgical axillary evaluation, systemic chemotherapy, and/or radiotherapy, as well as reduction in radiotherapy treatment volume (partial breast irradiation) or total treatment time (hypofractionation). We review these strategies and the literature supporting their use, as well as future directions for treatment minimization. PMID- 28731947 TI - Early Stage Cancer in Older Adults: Prostate-Avoiding Overtreatment and Undertreatment. AB - The diagnosis of prostate cancer in elderly men is likely to increase over the next several decades, owing to changing demographics and a rising population of men older than 65 years. Given the heterogeneity and well-documented challenges in screening, diagnosing, and managing indolent versus aggressive prostate cancer, the geriatric patient population is particularly vulnerable to prostate cancer treatment nuances. Clinicians must become familiar with geriatric assessment tools to better answer life-expectancy questions prior to counseling patients on treatment options. The preferences and values of patients and their families must always be considered when making screening and treatment decisions. Careful selection of patients following a holistic evaluation will not only minimize overtreatment and undertreatment of prostate cancer, but may also allow for the early identification of unique geriatric vulnerabilities and permit quicker interventions to improve the quality of life of these men during their elderly years. PMID- 28731948 TI - Managing Cancer Pain in Older Adults. AB - Managing cancer pain in older adults can be complex and challenging. Understanding the unique needs of older patients with cancer is important to safe and effective pain management. The goals of this review are to discuss the assessment of older adults with cancer-related pain, treatment of cancer pain, and adverse effects or potential risks from treatment that are unique to older patients. A detailed pain assessment and when possible utilizing the geriatric assessment are vital to developing a cancer pain management plan. The geriatric assessment can help clinicians uncover problems not routinely assessed in the standard oncologic evaluation. Opioid pain medications are safe and effective for older adults with cancer pain as long as these medications are closely monitored and titrated slowly. In addition to the well-known adverse effects of opioid medications, clinicians need to be aware of the unique risks in older adults, which could include delirium, polypharmacy, and falls. PMID- 28731950 TI - Totally Laparoscopic Resection for Low Sigmoid and Rectal Cancer Using Natural Orifice Specimen Extraction Techniques. AB - BACKGROUND: A minilaparotomy for specimen extraction during laparoscopy occasionally results in postoperative wound complications. We have performed a totally laparoscopic resection for early colorectal cancer using the natural orifice specimen extraction technique. METHODS: From 2008 to 2013, we have performed a totally laparoscopic resection for clinical stage I and IIA low sigmoid colon and rectal cancers. A prospectively maintained database was reviewed to assess the outcomes after surgery. RESULTS: In total, 40 patients had high anterior resections using transanal specimen extraction, and 32 patients had low anterior resections with transanal pull-through. Eight patients (11%) reported conversion to conventional laparoscopic colorectal resections; anastomotic leakages occurred in 4 patients (5.6%). No mortality or cancer recurrence was observed during 42.5+/-16.2 months of follow-up. CONCLUSIONS: One natural orifice specimen extraction technique, known as transanal specimen extraction, has emerged as a promising form of totally laparoscopic surgical intervention for early-stage cancers of the low sigmoid colon and rectum. PMID- 28731951 TI - Does Sugammadex Administration Affect Postoperative Nausea and Vomiting After Laparoscopic Cholecystectomy: A Prospective, Double-Blind, Randomized Study. AB - BACKGROUND: The aim of this study is to assess the effect of sugammadex on postoperative nausea and vomiting (PONV) in patients undergoing laparoscopic cholecystectomy. METHODS: Eighty patients who were scheduled for elective laparoscopic cholecystectomy surgery were enrolled in this prospective study. Patients were randomly assigned to neostigmine (group N) or sugammadex (group S) for neuromuscular antagonism at the end of anesthesia. The incidence of PONV and antiemetic consumption were recorded. RESULTS: Nausea and vomiting were observed in 60% of the patients given sugammadex and 77.5% given neostigmine during the initial 24 hours postoperatively. The incidence of nausea and the need for rescue antiemetic were lower in group S than group N during all time intervals but there were no significant differences between the groups. CONCLUSIONS: Sugammadex seems to be effective in decreasing the incidence of PONV, severity of nausea, number of patients who suffered from nausea and vomiting, and need for rescue antiemetic, although there were no significant differences. PMID- 28731949 TI - Cancer Screening in the Elderly: A Review of Breast, Colorectal, Lung, and Prostate Cancer Screening. AB - There are relatively limited data on outcomes of screening older adults for cancer; therefore, the decision to screen older adults requires balancing the potential harms of screening and follow-up diagnostic tests with the possibility of benefit. Harms of screening can be amplified in older and frail adults and include discomfort from undergoing the test itself, anxiety, potential complications from diagnostic procedures resulting from a false-positive test, false reassurance from a false-negative test, and overdiagnosis of tumors that are of no threat and may result in overtreatment. In this paper, we review the evidence and guidelines on breast, colorectal, lung and prostate cancer as applied to older adults. We also provide a general framework for approaching cancer screening in older adults by incorporating evidence-based guidelines, patient preferences, and patient life expectancy estimates into shared screening decisions. PMID- 28731952 TI - Open Colectomies of Shorter Operative Time Do Not Result in Improved Outcomes Compared With Prolonged Laparoscopic Operations. AB - BACKGROUND: Laparoscopic colectomies are associated with reduced perioperative morbidity and mortality compared with open surgery. Nevertheless, many surgeons continue to utilize an open surgical approach due to the perceived benefits of shorter operative times. This study aims to compare the outcomes of laparoscopic versus open colectomies of equal or shorter operative duration. METHODS: All patients undergoing elective laparoscopic or open colectomy in the American College of Surgeons National Surgical Quality Improvement Project (ACS-NSQIP) were identified from the years 2005 through 2012. Patients were stratified first by operative procedure including partial colectomy, total colectomy, or low anterior resection. Each surgical group was then divided into 4 groups according to operative time: <90 minutes, >=90 minutes and <3 hours, >=3 hours and <6 hours, and >=6 hours. In total, 30-day outcomes were compared between laparoscopic operations and open procedures of shorter or equivalent durations within each surgical group. Multivariate logistic regression was utilized to account for differences in patient demographics and comorbidities between the surgical groups. RESULTS: In total, 156,503 patients met inclusion criteria; 112,053 (71.6%) patients underwent a partial colectomy, 13,838 (8.8%) patients underwent a total colectomy, and 30,612 (19.6%) patients underwent a low anterior resection. A laparoscopic approach was used in 34% (37,789 patients) of the partial colectomies performed, 31% (4285 patients) of the total colectomies performed, and 45% (13,850 patients) of the low anterior resections performed. For all procedures, laparoscopic operations <6 hours were associated with superior outcomes compared with shorter open procedures. The benefit of laparoscopic operations was lost when operative time exceeded 6 hours. CONCLUSIONS: Laparoscopic colectomies are associated with improved outcomes compared with open operations that do not exceed an operative time of 6 hours. Given the potential to improve patient outcomes, consideration should be given to the laparoscopic approach for all colon surgeries expected to be completed in <6 hours. PMID- 28731953 TI - Assessment of Weight Loss With the Intragastric Balloon in Patients With Different Degrees of Obesity. AB - INTRODUCTION: The intragastric balloon (IGB) is an endoscopic device for the treatment of obesity. Best results are observed in patients who follow a dietary program but few studies have assessed the results of this treatment in patients with different degrees of obesity. AIM: The aim of this study is to compare the efficacy of IGB in patients with different degrees of obesity. METHOD: A total of 2002 patients with IGB were retrospectively evaluated and were divided into groups according to initial body mass index (BMI) range, as follows: group 1, 27 to 29.9 kg/m; group 2, 30 to 34.9 kg/m; group 3, 35 to 39.9 kg/m; group 4, 40 to 44.9 kg/m; group 5, >=45 kg/m. Weight was assessed in 3 different times: before (T0), 1 month (T1), 6 months (T2), and 6 months after removal of the IGB (T3). RESULTS: A total of 946 patients lost follow-up. Overall, 40 (3.78%) removed the device before programmed by intolerance, and 1016 patients completed the 6-month treatment. The mean weight loss was 18.9%, excess weight loss 60.1% and an BMI reduction of 6.76 points. 6 months after removal of the balloon 842 patients had continued follow-up (82.8%). At this time, weight loss was 19.84%, excess weight loss was 59.49%, and BMI reduction of 7.06 points. In all groups there was statistical difference between the times T0 and T1 and between T1 and T2 (P<0.001). There was no statistical difference between T2 and T3, in any group. CONCLUSION: IGB provided sustained weight loss in patients who remained in dietary follow-up for 1 year. PMID- 28731954 TI - Laparoscopic Pancreaticoduodenectomy: A Single Team Preliminary Experience. AB - OBJECTIVE: The present study aimed to describe the authors' experience and the perioperative outcome for laparoscopic pancreaticoduodenectomy (LPD). MATERIALS AND METHODS: Perioperative clinical data of 57 consecutive pancreaticoduodenectomy (PD) procedures performed from January 2014 to May 2016 in the Department of Hepatobiliary Surgery, Hunan Provincial People's Hospital were retrospectively analyzed. RESULTS: The median of operative time was 315 minutes (range, 220 to 575 min) and the median of intraoperative estimated blood loss was 200 mL (range, 100 to 550 mL). Conversion to open PD was required in 3 patients (5.3%) as a result of difficult dissection. Hand-assisted LPD was used in 2 patients (3.5%). Mean length of hospital stay was 14.8 days (8 to 29 d). Cumulative surgery-related morbidity was 28.1%, included bleeding (n=4), pancreatic fistula (n=3), biliary fistula (n=1), delayed gastric emptying (n=1), intra-abdominal infection (n=3), pulmonary infection (n=3), and ileus (n=1). Postoperative severe complications (Clavien>=III) were detected in 4 patients (7.0%) including 1 intra-abdominal infection, 2 postoperative bleeding event, and 1 afferent delayed gastric emptying. Three patients required reoperation. There was no 30-day or in-hospital mortality. Pathologic diagnoses were pancreatic ductal adenocarcinoma (n=5), ampullary adenocarcinoma (n=10), duodenal adenocarcinoma (n=24), distal common bile duct cancer (n=13), atypical hyperplasia of bile duct (n=2), and chronic pancreatitis (n=3). No patient had margin positive resection; the number of harvested lymph nodes were (16.7+/-4.2), the number of positive lymph nodes were (1.3+/-1.1). CONCLUSIONS: LPD, although complicated and difficult, serve as a safe and effective method for experienced surgeons. PMID- 28731955 TI - Clinical Outcomes of Esophagojejunostomy in Totally Laparoscopic Total Gastrectomy: A Multicenter Study. AB - PURPOSE: To examine the short-term outcomes of intracorporeal anastomosis during totally laparoscopic total gastrectomy retrospectively at multiple institutions. PATIENTS AND METHODS: We collected data of the patients who had undergone totally laparoscopic total gastrectomy at 4 institutions. All patients received an intracorporeal esophagojejunostomy. RESULTS: Of the 215 patients evaluated, 147 underwent functional end-to-end anastomosis (FEEA) as the intracorporeal esophagojejunostomy (FEEA group), and 68 patients received a circular stapler anastomosis (Circular group). The rate of tumor invasion to the esophagus was significantly higher in the Circular group than in the FEEA group (33% vs. 6%, respectively; P<0.0001). Univariate and multivariate analyses revealed that the circular stapler anastomosis and high preoperative BMI were statistically significant risk factors for postoperative leakage. However, the rates of complications and mortality were not significantly different between groups. CONSIDERATION: Our results showed that each type of esophagojejunostomy is safe and feasible for patients with gastric cancer with acceptable morbidity and mortality. PMID- 28731956 TI - Laparoscopic Intragastric Surgery With Endoscopic Assistance: A 2 Gastrostomy Approach With Multiple Applications. AB - PURPOSE: Laparoscopic intragastric resection is a surgical modality with acceptable oncologic outcomes for gastrointestinal stromal tumors and leiomyomas, particularly for masses located near the gastroesophageal junction (GEJ). We describe our technique of 2 gastrostomy laparoscopic, intragastric resection with endoscopic assistance. METHODS: We detail our technique and report a unique application of this versatile approach. RESULTS: Between December 2015 and July 2016, 4 patients underwent our combined technique of intragastric surgery. Complete resection was performed in the 2 patients who had gastrointestinal stromal tumors and 1 patient with a leiomyoma without complications. One patient had the unique diagnosis of gastritis cystica profunda. This mass could not be resected, but an effective Tru-cut core needle biopsy was obtained, and the mass was able to be diagnosed and decompressed. CONCLUSIONS: Our technique of 2 gastrostomy laparoscopic intragastric surgery is feasible and offers an effective oncologic approach for resection of tumors near the GEJ. PMID- 28731957 TI - Longitudinal Postoperative Course of Pain and Dysfunction Following Total Knee Arthroplasty. AB - OBJECTIVES: Although the majority of patients undergoing total knee arthroplasty (TKA) report substantial improvement in pain and function, a significant subset experience persistent postsurgical pain and dysfunction. Better understanding of the longitudinal postoperative course is needed, including the association between patient status following physical rehabilitation at 6-weeks post-TKA, to 6-months outcomes. This study aims to described the postoperative course of TKA and examine variables associated with change in pain and functioning between 6 weeks and 6-months post-TKA. METHODS: In this longitudinal study of 223 participants, assessments of analgesic intake, depression, anxiety, pain catastrophizing, dysfunction, resting and range of motion pain, and pain sensitivity were completed at 6-weeks post-TKA. Analgesic intake, pain ratings, and dysfunction data were also collected at 6-months post-TKA. Pain and dysfunction ratings were divided into none-mild and moderate-severe categories. RESULTS: Between 6-weeks and 6-months post-TKA, 75% of the sample stayed in the same pain category, 20% improved, and 5% worsened. In terms of functional changes between 6 weeks and 6 months, 65% of the sample stayed in the same functional category, whereas 31% improved and 5% worsened. DISCUSSION: These findings demonstrate that the majority of patients' pain and functioning remains stable between 6 weeks and 6 months post-TKA. However, a notable subset continues to improve or worsen in pain and functioning and the current study identifies variables associated with these changes. PMID- 28731958 TI - Pain Catastrophizing and Pain Health-Related Quality-of-Life in Endometriosis. AB - OBJECTIVES: To determine if pain catastrophizing is independently associated with pain health-related quality-of-life (HRQoL) in women with endometriosis, independent of potential confounders. MATERIALS AND METHODS: Analysis of cross sectional baseline data from a prospective database at a tertiary referral center for endometriosis/pelvic pain. Referrals to the center were recruited between December 2013 to April 2015, with data collected from online patient questionnaires, physical examination, and review of medical records. The primary outcome was HRQoL as measured by the 11-item pain subscale of the Endometriosis Health Profile-30 questionnaire. The Pain Catastrophizing Scale was the independent variable of interest. Other independent variables (potential confounders) included other psychological measures, pain severity, comorbid pain conditions, and social-behavioral and demographic variables. Multivariable linear regression was used to control for these potential confounders and assess independent associations with the primary outcome. RESULTS: In total, 236 women were included (87% consent rate). The mean age was 35.0+/-7.3 years, and 98 (42%) had stage I to II endometriosis, 110 (47%) had stage III to IV endometriosis, and 28 (11%) were of unknown stage after review of operative records. Regression analysis demonstrated that higher pain catastrophizing (P<0.001), more severe chronic pelvic pain (P<0.001), more severe dysmenorrhea (P<0.001), and abdominal wall pain (positive Carnett test) (P=0.033) were independently associated with worse pain HRQoL. DISCUSSION: Higher pain catastrophizing was associated with a reduced pain HRQoL in women with endometriosis at a tertiary referral center, independent of pain severity and other potential confounders. PMID- 28731959 TI - Efficacy of Intra-Articular Botulinum Toxin in Osteoarticular Joint Pain: A Meta Analysis of Randomized Controlled Trials. AB - OBJECTIVE: This study was conducted with the aim of evaluating the efficacy of intra-articular injections of botulinum toxin type A (BT-A) into the painful joint diseases through a systematic review of the literature and a meta-analysis of controlled randomized trials. Intra-articular therapies (corticosteroids, hyaluronic acid) have limited efficacy and run a risk of toxicity in patients with joint pain. New therapeutic options are needed to treat painful osteoarticular disease. METHODS: We searched via Pubmed, American College of Rheumatology, and European League Against Rheumatism congresses, and gray literature for the studies reported until June 2016 and addressing the issue of BT intra-articular injections in patients with refractory joint pain. Randomized trials were included. For the meta-analysis, we compared a numeric rating scale (NRS) from 0 to 10 before treatment and at 1 or 2 months and 6 months after in the BT-A and the control groups for each study. We also compared separately low dose and high dose of BT at 1 or 2 months' evaluation. RESULTS: In a total of 269 selected articles, 8 were analyzed and 6 studies were included in the meta analysis involving a total of 382 patients. On comparing the NRS rating for 5 trials, at 1 or 2 months irrespective of the dose of BT, 4 trials showed a positive effect of BT compared with the control on the NRS and 1 found no effect; the overall weighted mean difference [95% confidence interval (CI)] was -1.10 ( 1.62, -0.58) (P<0.0001, I=63%). Among the 4 trials with a low dose of BT (100 U), comparing NRS at 1 or 2 months, 3 trials showed significant results with a positive effect of BT-A injection compared with the control on the NRS; the fourth study failed to find any effect. The overall weighted mean difference (95% CI) was -0.95 (-0.02, -1.88) (P=0.05, I=67%). In the 2 trials using a high dose of BT (200 U) comparing NRS at 1 or 2 months, there was an almost zero effect of BT, with an overall weighted mean difference (95% CI) of 0.13 (-0.55, 0.81) (P=0.71, I=0%). In the 3 trials comparing NRS at 6 months there was an overall weighted mean difference (95% CI) of -0.57 (-1.98, 0.83) (P=0.42, I=73%). CONCLUSIONS: BT-A intra-articular injections have short-term benefits with a statistically significant decrease in the NRS pain score of around 1 point in patients with refractory joint pain. A decrease in the pain score was also observed at 6 months but with a nonsignificant result. PMID- 28731960 TI - Perceived Pain Extent is Not Associated With Widespread Pressure Pain Sensitivity, Clinical Features, Related Disability, Anxiety, or Depression in Women With Episodic Migraine. AB - OBJECTIVE: People with migraine present with varying pain extent and an expanded distribution of perceived pain may reflect central sensitization. The relationship between pain extent and clinical features, psychological outcomes, related disability, and pressure pain sensitivity in migraine has been poorly investigated. Our aim was to investigate whether the perceived pain extent, assessed from pain drawings, relates to measures of pressure pain sensitivity, clinical, psychological outcomes, and related disability in women with episodic migraine. METHODS: A total of 72 women with episodic migraine completed pain drawings, which were subsequently digitized allowing pain extent to be calculated utilising novel software. Pressure pain thresholds were assessed bilaterally over the temporalis muscle (trigeminal area), the cervical spine (extratrigeminal area), and tibialis anterior muscle (distant pain-free area). Clinical features of migraine, migraine-related disability (migraine disability assessment questionnaire [MIDAS]), and anxiety and depression (Hospital Anxiety-Depression Scale [HADS]) were also assessed. Spearman rho correlation coefficients were computed to reveal correlations between pain extent and the remaining outcomes. RESULTS: No significant associations were observed between pain extent and pressure pain thresholds in trigeminal, extratrigeminal or distant pain-free areas, migraine pain features, or psychological variables including anxiety or depression, and migraine-related disability. CONCLUSIONS: Pain extent within the trigeminocervical area was not associated with any of the measured clinical outcomes and not related to the degree of pressure pain sensitization in women with episodic migraine. Further research is needed to determine if the presence of expanded pain areas outside of the trigeminal area can play a relevant role in the sensitization processes in migraine. PMID- 28731961 TI - Joint Effect of Alcohol Consumption and Educational Level on Alcohol-related Medical Events: A Danish Register-based Cohort Study. AB - BACKGROUND: Alcohol-related mortality is more pronounced in lower than in higher socioeconomic groups in Western countries. Part of the explanation is differences in drinking patterns. However, differences in vulnerability to health consequences of alcohol consumption across socioeconomic groups may also play a role. We investigated the joint effect of alcohol consumption and educational level on the rate of alcohol-related medical events. METHODS: We pooled seven prospective cohorts from Denmark that enrolled 74,278 men and women age 30-70 years (study period, 1981 to 2009). We measured alcohol consumption at baseline using self-administrated questionnaires. Information on highest attained education 1 year before study entry and hospital and mortality data on alcohol related medical events were obtained through linkage to nationwide registries. We performed analyses using the Aalen additive hazards model. RESULTS: During follow up (1,085,049 person-years), a total of 1718 alcohol-related events occurred. The joint effect of very high alcohol consumption (>21 [>28] drinks per week in women [men]) and low education on alcohol-related events exceeded the sum of their separate effects. Among men, we observed 289 (95% confidence interval = 123, 457) extra events per 100,000 person-years owing to education-alcohol interaction (P < 0.001). Similarly, among women, we observed 239 (95% confidence interval = 90, 388) extra events per 100,000 person-years owing to this interaction (P < 0.001). CONCLUSIONS: High alcohol consumption is associated with a higher risk of alcohol related medical events among those with low compared with high education. This interaction may be explained by differences in vulnerability and drinking patterns across educational groups.See video abstract at, http://links.lww.com/EDE/B267. PMID- 28731962 TI - Polymorphisms in cytochrome P450 oxidoreductase and its effect on drug metabolism and efficacy. AB - Cytochrome P450 oxidoreductase (POR) has played a potential role in the metabolism of drugs and steroids by supplying electrons to microsomal cytochrome P450 (CYP) enzymes. More than 200 different POR mutations and polymorphisms causing more than 130 amino acid changes in the POR protein have been reported since 2004. A503V is a common amino acid sequence variant encoded by POR*28, whereas A287P and R457H are the most common disease-causing mutations in Europeans and Asians, respectively. Polymorphisms in the POR gene can affect POR activity, CYP-mediated drug metabolism activities, and the efficacy of several clinically used drugs. The effects of POR variants on CYP activities are substrate dependent. In this review, recent research on the effects of POR genetic polymorphisms on drug metabolism and therapy has been summarized and discussed, which can contribute to the rational use of drugs in clinic and the development of personalized medicine. PMID- 28731963 TI - Audiologic Gain of Incus Short Process Vibroplasty With Conventional Incus Long Process Vibroplasty: A Retrospective Analysis of 36 Patients. AB - OBJECTIVE: To compare the audiological and non-audiological benefits of incus short process (SP) vibroplasty with those of conventional incus long process (LP) vibroplasty. STUDY DESIGN: Retrospective analysis. SETTING: Tertiary referral center. PATIENTS: Thirty-six patients with sensorineural hearing loss were treated with the semi-implantable middle ear hearing device. Of these, 22 were treated with conventional LP vibroplasty, and 14 were treated with SP vibroplasty using SP couplers. INTERVENTIONS: Implantation with the semi-implantable middle ear hearing device by different methods. MAIN OUTCOME MEASURES: Pre- and postoperative hearing level, word recognition score, operation time, and duration of hospital stay were compared. We also surveyed a questionnaire to assess postoperative complications. RESULTS: The improvement in hearing gain was comparable between SP vibroplasty and conventional LP vibroplasty, except at 8 kHz, at which LP vibroplasty showed better hearing gain (p < 0.05). Patients undergoing SP vibroplasty had shorter operation time (p < 0.01) and duration of hospital stay (p < 0.01). While four patients who underwent incus LP vibroplasty experienced taste changes, none who underwent incus SP vibroplasty experienced any complications. CONCLUSIONS: SP vibroplasty with the newly invented SP coupler could be a good alternative to conventional LP vibroplasty for treating patients with sensorineural hearing loss. Although both SP vibroplasty and LP vibroplasty produce good results, the former is associated with a shorter operation time and duration of hospital stay as well as fewer complications. PMID- 28731964 TI - The Relationship Between Environmental Sound Awareness and Speech Recognition Skills in Experienced Cochlear Implant Users. AB - HYPOTHESIS: 1) Environmental sound awareness (ESA) and speech recognition skills in experienced, adult cochlear implant (CI) users will be highly correlated, and, 2) ESA skills of CI users will be significantly lower than those of age-matched adults with normal hearing. BACKGROUND: Enhancement of ESA is often discussed with patients with sensorineural hearing loss as a potential benefit of implantation and, in some cases, ESA may be a major motivating factor. Despite its ecological validity and patients' expectations, ESA remains largely a presumed skill. The relationship between ESA and speech recognition is not well understood. METHODS: ESA was assessed in 35 postlingually deaf, experienced CI users and a control group of 41 age-matched, normal hearing listeners using the validated, computerized familiar environmental sounds test-identification (FEST I) and a diverse speech recognition battery. Demographic and audiological factors as well as nonverbal intelligence quotient (IQ)/nonverbal reasoning and spectral resolution were assessed. RESULTS: Six of the 35 experienced CI users (17%) demonstrated FEST-I accuracy within the range of the NH controls. Among CI users all correlations between FEST-I accuracy and speech recognition scores were strong. Chronological age at the time of testing, duration of deafness, spectral resolution, and nonverbal IQ/nonverbal reasoning were strongly correlated with FEST-I accuracy. Partial correlation analysis showed that correlations between FEST-I and speech recognition measures remained significant when controlling for the demographic and audiological factors. CONCLUSION: Our findings reinforce the hypothesis that ESA and speech perception share common underlying processes rather than reflecting truly separate auditory domains. PMID- 28731965 TI - Functional Outcomes Post Lisfranc Injury-Transarticular Screws, Dorsal Bridge Plating or Combination Treatment? AB - OBJECTIVE: To identify whether transarticular screws, dorsal bridging plates or a combination of the 2 result in the best functional outcome after Lisfranc injury. DESIGN: Case series. SETTING: Level one trauma center. PATIENTS: Fifty patients who underwent surgical fixation of Lisfranc injuries over a 6-year period were retrospectively reviewed. INTERVENTION: One of 3 treatment arms: transarticular screw fixation alone, dorsal bridge plating alone or a combination of dorsal bridge and transarticular screw fixation. MAIN OUTCOME MEASURES: The primary outcome measures were 1 of 2 midfoot scores-the American Orthopaedic Foot and Ankle Society (AOFAS) Midfoot Score and the Foot Function Index (FFI) Score. Secondary results included postoperative complications. RESULTS: Quality anatomical reduction is the best predictor of functional outcomes (FFI-P = 0.008, AOFAS-P = 0.02). Functional outcomes with both FFI and AOFAS scores were not significantly associated with any of the fixation groups (FFI-P = 0.495, AOFAS-P = 0.654) on univariate analysis. Injury type by Myerson classification systems or open versus closed status was also not significantly associated with any fixation group. Open exposures were more likely to result in soft-tissue complications, but there was no significant difference in metalware failure or need for removal. CONCLUSION: Functional outcomes after Lisfranc fractures are most dependant on the quality of anatomical reduction and not the choice of fixation implant used. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 28731966 TI - Re: Response to the Analysis of Patient Outcomes in Two-Screw Versus Single-Screw Cephalomedullary Nail. PMID- 28731968 TI - A Silent Killer: Insights Into Venous Thromboembolism Formation and Prevention. PMID- 28731967 TI - Reply re: Response to the Analysis of Patient Outcomes in Two-Screw Versus Single Screw Cephalomedullary Nail. PMID- 28731969 TI - Ischemic Leg, Perfused Lung: A Trial of Remote Ischemic Preconditioning. PMID- 28731970 TI - Fasting Before Anesthesia: An Unsettled Dilemma. PMID- 28731971 TI - Time Is Money. PMID- 28731972 TI - Inhaled Pulmonary Vasodilators in Cardiac Surgery Patients: Correct Answer Is "NO". PMID- 28731973 TI - Professionalism: The "Forgotten" Core Competency. PMID- 28731974 TI - Two Minutes to Improve Cardiac Surgery Outcomes. PMID- 28731975 TI - The Consensus Bundle on Hypertension in Pregnancy and the Anesthesiologist: Doing All the Right Things for All the Patients All of the Time. PMID- 28731977 TI - Interventions for Neuropathic Pain: An Overview of Systematic Reviews. AB - Numerous interventions for neuropathic pain (NeuP) are available, but its treatment remains unsatisfactory. We systematically summarized evidence from systematic reviews (SRs) of randomized controlled trials on interventions for NeuP. Five electronic databases were searched up to March 2015. Study quality was analyzed using A Measurement Tool to Assess Systematic Reviews. The most common interventions in 97 included SRs were pharmacologic (59%) and surgical (15%). The majority of analyzed SRs were of medium quality. More than 50% of conclusions from abstracts on efficacy and approximately 80% on safety were inconclusive. Effective interventions were described for painful diabetic neuropathy (pregabalin, gabapentin, certain tricyclic antidepressants [TCAs], opioids, antidepressants, and anticonvulsants), postherpetic neuralgia (gabapentin, pregabalin, certain TCAs, antidepressants and anticonvulsants, opioids, sodium valproate, topical capsaicin, and lidocaine), lumbar radicular pain (epidural corticosteroids, repetitive transcranial magnetic stimulation [rTMS], and discectomy), cervical radicular pain (rTMS), carpal tunnel syndrome (carpal tunnel release), cubital tunnel syndrome (simple decompression and ulnar nerve transposition), trigeminal neuralgia (carbamazepine, lamotrigine, and pimozide for refractory cases, rTMS), HIV-related neuropathy (topical capsaicin), and central NeuP (certain TCAs, pregabalin, cannabinoids, and rTMS). Evidence about interventions for NeuP is frequently inconclusive or completely lacking. New randomized controlled trials about interventions for NeuP are necessary; they should address safety and use clear diagnostic criteria. PMID- 28731978 TI - Differences in Spatiotemporal Parameters Between Trained Runners and Untrained Participants. AB - Gomez-Molina, J, Ogueta-Alday, A, Stickley, C, Tobalina, JC, Cabrejas-Ugartondo, J, and Garcia-Lopez, J. Differences in spatiotemporal parameters between trained runners and untrained participants. J Strength Cond Res 31(8): 2169-2175, 2017 The aim of this study was to compare the spatiotemporal parameters of trained runners and untrained participants with the same foot strike pattern (rearfoot) during running at controlled speeds. Twenty-one participants were classified in 2 groups according to their training experience: Trained (n = 10, amateur runners with long distance training experience) and Untrained (n = 11, healthy untrained participants). Anthropometric variables were recorded, and the participants performed both a submaximal (between 9 and 15 km.h) and a graded exercise running test (from 6 km.h until exhaustion) on a treadmill. Physiological (V[Combining Dot Above]O2max, heart rate, running economy [RE], peak speed ...) and biomechanical variables (contact and flight times, step rate, and length) were simultaneously registered. Trained runners showed higher step rate and shorter step length than the Untrained group at the same running speeds (between 4 and 7%, p <= 0.05) and at the same physiological intensities (between 7 and 11%, p <= 0.05). However, there were no differences in contact and flight times between groups. Significant differences (p <= 0.05) and large effect sizes (Cohen's d) between groups were found for body mass, sum of 6 skinfolds, V[Combining Dot Above]O2max, peak speed, and ventilatory threshold and respiratory compensation threshold speeds. The Trained group also showed a ~7% better RE (ml.kg.km) than the Untrained group. In conclusion, adopting higher step rate and shorter step length may be an adaptive mechanism of the Trained group to reduce injury risk and possibly improve RE. However, contact and flight times were consistent regardless of training level. PMID- 28731979 TI - Global Positioning System Analysis of a High School Football Scrimmage. AB - Gleason, BH, Sams, M, Salley, JT, Pustina, A, and Stone, MH. Global positioning system analysis of a high school football scrimmage. J Strength Cond Res 31(8): 2183-2188, 2017-The purpose of this study was to examine the physical demands of a high school American football scrimmage. Male high school football players (N = 25) participated in a spring scrimmage. Global positioning system data and game film were recorded throughout the entirety of the scrimmage to determine the total distance covered, the distance covered in different velocity bands, the number of accelerations and decelerations performed, and the work-to-rest ratio of the scrimmage. The athletes were divided into 2 groups: linemen (L) (N = 7) vs. nonlinemen (NL) (N = 8) for statistical analysis, and independent T-tests with Holm's sequential Bonferroni adjustment were used to determine differences in movement characteristics between the L and NL groups. Average play duration was 5.7 +/- 2.1 seconds, whereas the rest interval was 33.4 +/- 13.6 seconds between plays, for an overall exercise-to-rest ratio of 1:5.9. Total distance, standing and walking distance, running distance, striding distance, sprinting distance, and total high-speed running distance covered by NL was greater than L (statistically significant at p <= 0.05). Distances traveled in each velocity band by position and by play are also included to provide context of our findings. Data from the present study add to the pool of support for the use of position-specific training in preparing high school football players for competition. PMID- 28731980 TI - Running Performance, Nationality, Sex, and Age in the 10-km, Half-Marathon, Marathon, and the 100-km Ultramarathon IAAF 1999-2015. AB - Nikolaidis PT, Onywera VO, and Knechtle B. Running performance, nationality, sex, and age in the 10-km, half-marathon, marathon, and the 100-km ultramarathon IAAF 1999-2015. J Strength Cond Res 31(8): 2189-2207, 2017-The aim of this study was to examine the performance of the world's best runners in the 10-km, half marathon, marathon, and 100-km races by age, sex, and nationality during 1999 2015, using data from the International Association of Athletics Federations (IAAF). A total of 38,895 runners (17,136 women and 21,759 men) were evaluated, with 2,594 (1,360 women and 1,234 men) in the 10-km; 11,595 (5,225 women and 6,370 men) in the half-marathon; 23,973 (10,208 women and 13,765 men) in the marathon; and 733 (343 women and 390 men) in 100-km events. Most runners in the 10-km event (women 40%, men 67%) and the half-marathon (women 30%, men 57%) were Kenyans. In the marathon, most female and male runners were Ethiopians (women 17%, men 14%) and Kenyans (women 15%, men 43%), respectively. In the 100-km event, most runners were Japanese (20% women, and 80% men). Women were older than the men in the 10-km (32.0 +/- 6.0 vs. 25.3 +/- 4.3 years, p < 0.001), half marathon (27.5 +/- 4.7 vs. 25.9 +/- 4.1 years, p < 0.001), and marathon events (29.5 +/- 5.5 vs. 29.1 +/- 4.3 years, p < 0.001), but not in 100-km event (36.6 +/- 6.1 vs. 35.9 +/- 5.5 years, p = 0.097). Men were faster than the women in the 10-km (28:04 +/- 0:17 vs. 32:08 +/- 0.31 (minutes:seconds), p < 0.001), half marathon (1:01:58 +/- 0:00:52 vs. 1:11:21 +/- 0:01:18 (hours:minutes:seconds), p < 0.001), marathon (2:13:42 +/- 0:03:01 vs. 2:35:04 +/- 0:05:21 (hours:minutes:seconds), p < 0.001), and 100-km events (6:48:01 +/- 0:11:29 vs. 7:53:51 +/- 0:16:37 (hours:minutes:seconds), p < 0.001). East Africans were not the fastest compared with athletes originating from other countries where only the Ethiopian men were faster than all other men in the marathon. In summary, (a) in the 10-km, half-marathon and marathon events, most runners were from Kenya and Ethiopia, and from Japan and Russia in the 100-km event; (b) women were older than the men in all distance events except the 100-km event; PMID- 28731981 TI - Technology in Strength and Conditioning: Assessing Bodyweight Squat Technique With Wearable Sensors. AB - O'Reilly, MA, Whelan, DF, Ward, TE, Delahunt, E, and Caulfield, BM. Technology in strength and conditioning: assessing bodyweight squat technique with wearable sensors. J Strength Cond Res 31(8): 2303-2312, 2017-Strength and conditioning (S&C) coaches offer expert guidance to help those they work with achieve their personal fitness goals. However, it is not always practical to operate under the direct supervision of an S&C coach and consequently individuals are often left training without expert oversight. Recent developments in inertial measurement units (IMUs) and mobile computing platforms have allowed for the possibility of unobtrusive motion tracking systems and the provision of real-time individualized feedback regarding exercise performance. These systems could enable S&C coaches to remotely monitor sessions and help individuals record their workout performance. One aspect of such technologies is the ability to assess exercise technique and detect common deviations from acceptable exercise form. In this study, we investigate this ability in the context of a bodyweight (BW) squat exercise. Inertial measurement units were positioned on the lumbar spine, thighs, and shanks of 77 healthy participants. Participants completed repetitions of BW squats with acceptable form and 5 common deviations from acceptable BW squatting technique. Descriptive features were extracted from the IMU signals for each BW squat repetition, and these were used to train a technique classifier. Acceptable or aberrant BW squat technique can be detected with 98% accuracy, 96% sensitivity, and 99% specificity when using features derived from all 5 IMUs. A single IMU system can also distinguish between acceptable and aberrant BW squat biomechanics with excellent accuracy, sensitivity, and specificity. Detecting exact deviations from acceptable BW squatting technique can be achieved with 80% accuracy using a 5 IMU system and 72% accuracy when using a single IMU positioned on the right shank. These results suggest that IMU-based systems can distinguish between acceptable and aberrant BW squat technique with excellent accuracy with a single IMU system. Identification of exact deviations is also possible but multi IMU systems outperform single IMU systems. PMID- 28731982 TI - Peripheral oxytocin receptors inhibit the nociceptive input signal to spinal dorsal horn wide-dynamic-range neurons. AB - Oxytocin (OT) has emerged as a mediator of endogenous analgesia in behavioral and electrophysiological experiments. In fact, OT receptors (OTRs) in the spinal dorsal horn participate in a selective inhibition of the neuronal activity mediated by Adelta and C fibers but not Abeta fibers. This study shows that OTRs are expressed in the terminal nerve endings and are able to inhibit nociceptive neuronal firing. Indeed, local peripheral OT blocked the first sensorial activity of Adelta and C fibers recorded in the spinal cord neurons. Furthermore, using the formalin behavioral nociceptive test, we demonstrated that only ipsilateral OTR activation inhibits pain behavior. Our data are reinforced by the fact that the OTR protein is expressed in the sciatic nerve. Consistent with this, immunofluorescence of primary afferent fibers suggest that OTRs could be located in nociceptive-specific terminals of the skin. Taken together, our results suggest that OTRs could be found in nociceptive terminals and that on activation they are able to inhibit nociceptive input. PMID- 28731983 TI - A Systematic Review and Meta-analysis of the Effort-Reward Imbalance Model of Workplace Stress and Hypothalamic-Pituitary-Adrenal Axis Measures of Stress. AB - OBJECTIVE: The association between effort-reward imbalance (ERI) and various health outcomes has been well documented over the past 20 years, but the mechanisms responsible for this association remain unclear. The present meta analysis assessed the associations of ERI and overcommitment (OC) in the workplace with hypothalamic-pituitary-adrenal (HPA) axis measures. METHODS: Electronic databases were searched with the phrase "effort*reward*imbalance," which yielded 319 studies leading to 56 full-text studies being screened. Thirty two studies within 14 articles met inclusion criteria and were meta-analyzed using mixed and random effects models. RESULTS: Greater ERI was associated with increased HPA axis activity (r = .09, p < .001, k = 14, N = 2541). The cortisol awakening response (r = .14, p < .001, k = 9, N = 584) and cortisol waking concentrations (r = .12, p = .01, k = 6, N = 493) were the only HPA measures associated with ERI. OC was also associated with greater HPA axis activity (r = .06, p < .01, k = 10, N = 1918). Cortisol (PM) (r = .13, p = .02, k = 3, N = 295) was the only HPA measure associated with OC. CONCLUSIONS: ERI and OC were similarly related with HPA responsivity. However, because OC moderated the relationship between ERI and HPA axis markers, the importance of OC should not be overlooked. Because OC is likely more malleable than ERI to intervention, this may be a promising avenue for future research. PMID- 28731984 TI - The Association of Cigarette Smoking With High-Frequency Heart Rate Variability: An Ecological Momentary Assessment Study. AB - OBJECTIVE: Evidence from both laboratory and observational studies suggests that acute and chronic smoking leads to reduced high-frequency heart rate variability (HF-HRV), a measure of cardiac vagal regulation. We used ecological momentary assessment (EMA) to study the effect of smoking on concurrent HF-HRV in a trial measuring the effects of hostility reduction and compared 24-hour HF-HRV in smokers and nonsmokers. METHOD: Ambulatory electrocardiogram data were collected before randomization from 149 healthy individuals with high hostility levels (20 45 years, body mass index <= 32 kg/m) and paired with concurrent EMA ratings of smoking and physical position during waking hours. A multilevel mixed model was estimated associating ln(HF-HRV) from smoking status (between-person factor) and person-centered momentary smoking (within-person factor, treated as a random effect), adjusting for momentary physical position, medication use, and consumption of alcohol and caffeine. RESULTS: Thirty-five smokers and 114 nonsmokers provided both EMA and HF-HRV data. Within smokers, ln HF-HRV was reduced by 0.31 millisecond (p = .04) when participants reported having recently smoked cigarettes, compared with when they had not. The 24-hour HF-HRV was significantly lower in smokers (M [SD] = 5.24 [0.14] milliseconds) than nonsmokers (5.63 +/- 0.07 milliseconds, p = .01). CONCLUSIONS: In healthy smokers with high hostility levels used as their own controls during daily living, smoking acutely reduced HF-HRV. HF-HRV was also reduced in smokers as compared with nonsmokers. Although limited by a small sample of individuals with high hostility levels, these findings nonetheless provide additional evidence that cardiac vagal regulation is lowered by cigarette smoking, which may be one of the numerous pathophysiological effects of smoking. PMID- 28731985 TI - Accelerated DNA Methylation Age: Associations with PTSD and Mortality. AB - OBJECTIVE: Recently-developed indices of cellular age based on DNA methylation (DNAm) data, referred to as DNAm age, are being used to study factors that influence the rate of aging and the health correlates of these metrics of the epigenetic clock. This study evaluated associations between trauma exposure, posttraumatic stress disorder (PTSD) symptoms, and accelerated versus decelerated DNAm age among military veterans. We also examined if accelerated DNAm age predicted mortality over the course of a 6.5-year medical record review period. METHODS: 339 genotype-confirmed white, non-Hispanic, middle-aged, trauma-exposed veterans underwent psychiatric assessment and genome-wide DNAm analysis. DNAm age was calculated using a previously validated algorithm. Medical records were available for a subset of 241 veterans and were reviewed approximately 6.5 years after DNA collection and PTSD assessment. RESULTS: PTSD hyperarousal symptoms were associated with accelerated DNAm age (beta = .20, p = .009) but trauma exposure and total PTSD severity were not. Accelerated DNAm age was also associated with 13% increased risk for all-cause mortality (HR: 1.13, 95% CI: 1.01 - 1.26) during the medical record review period. CONCLUSIONS: Findings of this study replicate the association between PTSD and accelerated DNAm age and suggest this effect may be specific to the hyperarousal symptom cluster. Results point to the potential utility of DNAm age algorithms for identifying individuals who are aging at an accelerated rate and for determining the factors that influence this process. PMID- 28731986 TI - The Effect of Sex on Heart Rate Variability at High Altitude. AB - : There is evidence suggesting that high altitude (HA) exposure leads to a fall in heart rate variability (HRV) that is linked to the development of acute mountain sickness (AMS). The effects of sex on changes in HRV at HA and its relationship to AMS are unknown. METHODS: HRV (5-min single-lead ECG) was measured in 63 healthy adults (41 men and 22 women) 18-56 yr of age at sea level (SL) and during a HA trek at 3619, 4600, and 5140 m, respectively. The main effects of altitude (SL, 3619 m, 4600 m, and 5140 m) and sex (men vs women) and their potential interaction were assessed using a factorial repeated-measures ANOVA. Logistic regression analyses were performed to assess the ability of HRV to predict AMS. RESULTS: Men and women were of similar age (31.2 +/- 9.3 vs 31.7 +/- 7.5 yr), ethnicity, and body and mass index. There was main effect for altitude on heart rate, SD of normal-to-normal (NN) intervals (SDNN), root mean square of successive differences (RMSSD), number of pairs of successive NN differing by >50 ms (NN50), NN50/total number of NN, very low-frequency power, low-frequency (LF) power, high-frequency (HF) power, and total power (TP). The most consistent effect on post hoc analysis was reduction in these HRV measures between 3619 and 5140 m at HA. Heart rate was significantly lower and SDNN, RMSSD, LF power, HF power, and TP were higher in men compared with women at HA. There was no interaction between sex and altitude for any of the HRV indices measured. HRV was not predictive of AMS development. CONCLUSIONS: Increasing HA leads to a reduction in HRV. Significant differences between men and women emerge at HA. HRV was not predictive of AMS. PMID- 28731987 TI - Evidence of Heritable Determinants of Decompression Sickness in Rats. AB - INTRODUCTION: Decompression sickness (DCS) is a complex and poorly understood systemic disease caused by inadequate desaturation after a decrease of ambient pressure. Strong variability between individuals is observed for DCS occurrence. This raises questions concerning factors that may be involved in the interindividual variability of DCS occurrence. This study aimed to experimentally assess the existence of heritable factors involved in DCS occurrence by selectively breeding individuals resistant to DCS from a population stock of Wistar rats. METHODS: Fifty-two male and 52 female Wistar rats were submitted to a simulated air dive known to reliably induce about 63% DCS: compression was performed at 100 kPa.min up to 1000 kPa absolute pressure before a 45-min long stay. Decompression was performed at 100 kPa.min with three decompression stops: 5 min at 200 kPa, 5 min at 160 kPa, and 10 min at 130 kPa. Animals were observed for 1 h to detect DCS symptoms. Individuals without DCS were selected and bred to create a new generation, subsequently subjected to the same hyperbaric protocol. This procedure was repeated up to the third generation of rats. RESULTS: As reported previously, this diving profile induced 67% of DCS, and 33% asymptomatic animals in the founding population. DCS/asymptomatic ratio was not initially different between sexes, although males were heavier than females. In three generations, the outcome of the dive significantly changed from 33% to 67% asymptomatic rats, for both sexes. Interestingly, survival in females increased sooner than in males. CONCLUSIONS: This study offers evidence suggesting the inheritance of DCS resistance. Future research will focus on genetic and physiological comparisons between the initial strain and the new resistant population. PMID- 28731988 TI - Roles of Mitogen-Activating Protein Kinase Kinase Kinase Kinase-3 (MAP4K3) in Preterm Skeletal Muscle Satellite Cell Myogenesis and Mammalian Target of Rapamycin Complex 1 (mTORC1) Activation Regulation. AB - BACKGROUND Preterm skeletal muscle genesis is a paradigm for myogenesis. The role of mitogen-activating protein kinase kinase kinase kinase-3 (MAP4K3) in preterm skeletal muscle satellite cells myogenesis or its relationship to mammalian target of rapamycin complex 1 (mTORC1) activity have not been previously elaborated. MATERIAL AND METHODS Small interfering RNA (siRNA) interference technology was used to inhibit MAP4K3 expression. Leucine stimulation experiments were performed following MAP4K3-siRNA interference. The differentiation of primary preterm skeletal muscle satellite cells was observed after siRNA-MAP4K3 interference. Western blot analysis was used to determine the expression of MAP4K3, MyHC, MyoD, myogenin, p-mTOR, and p-S6K1. The immunofluorescence fusion index of MyHC and myogenin were detected. MAP4K3 effects on preterm rat satellite cells differentiation and its relationship to mTORC1 activity are reported. RESULTS MAP4K3 siRNA knockdown inhibited myotube formation and both MyoD and myogenin expression in primary preterm rat skeletal muscle satellite cells, but MAP4K3 siRNA had no effect on the activity of mTORC1. In primary preterm rat skeletal muscle satellite cells, MAP4K3 knockdown resulted in significantly weaker, but not entirely blunted, leucine-induced mTORC1 signaling. CONCLUSIONS MAP4K3 positively regulates preterm skeletal muscle satellite cell myogenesis, but may not regulate mTORC1 activity. MAP4K3 may play a role in mTORC1 full activation in response to leucine. PMID- 28731989 TI - [New opportunities towards gastroenterology training]. PMID- 28731990 TI - [Performance of ASGE predictive criteria in diagnosis of choledocholithiasis in the Edgardo Rebagliati Martins Hospital]. AB - BACKGROUND: In Peru, there are still no local studies designed for evaluating the performance of clinical guidelines designed to stratify patients according to probability of choledocholithiasis. OBJECTIVES: To evaluate the performance of predictive criteria proposed by the American Society for Gastrointestinal Endoscopy (ASGE) in diagnosis of choledocholithiasis. MATERIALS AND METHODS: A retrospective cohort study conducted in a hospital in Lima (Rebagliati hospital). Were included all patients with suspected choledocholithiasis who underwent endoscopic retrograde cholangiopancreatography (ERCP) between July 2014 and June 2015. Predictors of choledocholithiasis proposed by the ASGE and the diagnostic performance of the risk categories were evaluated. RESULTS: 118 patients met the inclusion criteria. In multivariate analysis, only age >55 years (OR: 3.07 [95: 1.14-8.31], p = 0.027) and the finding of stones in the common bile duct by abdominal ultrasound (OR: 1.68 [95% CI: 1.09-2.59], p = 0.018) were associated with the presence of choledocholithiasis on ERCP. The performance of the high and intermediate risk categories were 75.82% and 70.37% respectively. The performance of the high-risk category improved to 85.90% using a second set of biochemical markers. CONCLUSIONS: The performance of the predictors and risk categories proposed by the ASGE in diagnosis of choledocholithiasis is acceptable in our hospital, according to the proposed standards; however, it must be further improved to prevent the use of diagnostic ERCP. PMID- 28731991 TI - Endoscopic prediction of tumor invasion depth in early gastric neoplasia: a prospective study in Peru. AB - INTRODUCTION: Endoscopic resection is the first option treatment of early gastric cancer with invasion to mucosa or superficial submucosa, because the risk of nodal metastasis is negligible. Then the prediction of tumor invasion is cardinal. OBJECTIVES: Determine the accuracy of endoscopic prediction for tumor invasion depth in early gastric neoplasia and define endoscopic characteristics associated with massive submucosal invasion. MATERIALS AND METHODS: Prospective sudy of diagnostic test validation. We included patients with early gastric neoplasias that were endoscopically or surgically resected from January 2012 to May 2016. Every lesion was looked for the presence of these features: margin elevation, central elevation, irregular surface, enlarged folds, size > 30mm and rigidity. The invasion prediction was categorized in: M-Sm1 when none feature was present, Sm2 when 2 or more features were present, and indeterminated when only one feature was present. We compared endoscopic prediction to pathological staging and determined diagnostic accuracy. RESULTS: The global accuracy for endoscopic prediction was 98.2%. Sensitivity, specificity, positive and negative predictive values for M-Sm1 prediction were 97.6, 100, 100 y 92.8%, and for Sm2 prediction were 100, 97.6, 92.8 y 97.6%, respectively. Rigidity, irregular Surface, margin elevation and enlarged folds were associated with Sm2 invasion. CONCLUSIONS: Endoscopic prediction of tumor invasion depth in early gastric neoplasia is very accurate. The main endoscopic feature associated with Sm2 invasion is rigidity. PMID- 28731992 TI - [Effect of Sacha Inchi oil (Plukenetiavolubilis L.) on 1,2-dimethylhydrazine induced colon carcinogenesis in Holtzman rats]. AB - OBJECTIVES: To evaluate the preventive effect of Sacha Inchi oil (SIO) on 1,2 dimethylhydrazine (DMH)-induced colon carcinogenesis (CC) in Holtzman rats. MATERIALS AND METHODS: Experimental study with 28 Holtzman male albino rats randomly distributed into 4 groups: a positive control group exposed to DMH (C1), a negative control group exposed to SIO at 150 uL/kg/day (C2), and two experimental groups exposed to DMH with SIO at 150 uL/kg/day (E1) and SIO at 300 uL/kg/day (E2). The DMH was applied for 8 weeks and the total induction time was 22 weeks. Pathological examination was performed by identifying cancerous tumor lesions in the guts. The preventive effect was evaluated based on proportions of lack of lesion in the groups exposed to DMH. RESULTS: Cancerous tumor lesions were identified in: two specimens of group C1, one specimen of group E1 and two specimens of group E2. No intestinal lesions were identified in group C2. The proportions of lack of lesion were: in group C1 of 75%, in group E1 of 87.5% and group E2 of 75%. No significant differences were found (p>0.05). CONCLUSIONS: It was not found a significant protective effect of SIO on DMH-induced CC in Holtzman rats, compared to control group. PMID- 28731993 TI - [Colorectal cancer in young adults: clinical and epidemiological features in the Peruvian population]. AB - OBJECTIVES: To determine the clinical epidemiological characteristics of young adult patients with colorectal cancer. MATERIALS AND METHODS: Information collected by the Direccion General de Epidemiologia by the surveillance strategy in non-communicable diseases for the period 2006-2014 was requested. The rate of age-adjusted incidence and a descriptive statistical analysis of the variables studied were calculated. RESULTS: 1261 CRC cases were reported in patients between 20-49 years of age. The annual percentage change (APC) for the incidence is declining -0.09% (p=0.004). The CPA for CRC cases was -3.9% in men (p=0.009) and -5.22% in women (p=0.014). 640 women and 621 men were reported. Most cases of CRC in the studied population is the group of 40-49 years with 60.3% of cases. Lima was the region with the highest number of reported cases (42.6%). 63.7% of CRC cases were represented by colon tumors. CONCLUSIONS: Based on case reports provided by the DGE, there is a trend of decrease in the incidence of CRC cases in young adults Peruvian in the last 10 years. PMID- 28731994 TI - [The frequency and clinical profile of gallbladder cancer in patients undergoing cholecystectomy in 3 reference hospitals in Chiclayo between 2011-2015]. AB - OBJECTIVES: To describe the frequency and clinical profile of gallbladder cancer in patients undergoing cholecystectomy in 3 reference hospitals in Chiclayo between 2011-2015. MATERIALS AND METHODS: A retrospective cross-sectional study. The study is divided into 2 phases, the first was to count the total number of reports of gallbladder pathology and select positive cases for cancer; the second phase was to collect data from the medical records of patients positive for cancer. RESULTS: From 5720 pathology reports gallbladder, 58 (1.01%) were positive for vesicular neoplasia. 42 cases (72.4%) were women and only 16 (27.6%) were men. The most common symptom was abdominal pain in 41 cases (70.7%). 18 patients (31%) reported other symptoms, the hyporexia was the most frequent with 8 cases (13.8%). 41 cases (70.7%) had gallstone. The predominant type of cancer was adenocarcinoma in 48 cases (82.8%) followed by mucinous carcinoma in 3 cases (5.2%). CONCLUSIONS: In the department of Lambayeque frequency of gallbladder cancer was 1.01% with predominance in females and sixth decade of life, being Adenocarcinoma, the most common type. Likewise, patients had more frequent abdominal pain and jaundice. PMID- 28731995 TI - [Update on chronic pancreatitis: review article]. AB - Chronic pancreatitis is a progressive fibro-inflammatory disease of the pancreas characterized by irreversible fibrosis of the gland with eventual failure of exocrine and endocrine functions and hallmark features of abdominal pain, malabsorption, malnutrition, diabetes mellitus and pancreatic calcifications. In many patients this disease results from a complex mix of environmental (eg, alcohol, cigarettes, and occupational chemicals), genetic factors and a few patients with hereditary or autoimmune disease. The management includes medical, endoscopic and surgical approaches with the need for interaction between various specialties, calling for a concerted multidisciplinary approach. This review provides the reader with a comprehensive overview of the studies summarizing the epidemiology, etiology, physiopatology, clinical manifestation, diagnosis and treatments of the disease. PMID- 28731996 TI - [Pancreatitis, genes and islet cells auto transplant; updates and new horizons]. AB - Pancreatitis is an inflammation of the pancreas that can progress from an acute presentation to an acute recurring presentation and eventually to chronic pancreatitis, which is characterized by irreversible morphological changes and scarring of the pancreas. The entity known as hereditary pancreatitis has been recognized in the literature for years and certainly the discovery of the PRSS1 gene in 1996 marked the beginning of a new era of genetic discoveries associated with the disease. Since then, multiple genes have been described as the causing agents of pancreatitis or disease modifiers, some of the most important ones being the PRSS1, SPINK1, CFTR, CASR, CTRC, CLDN2, and CPA1. The patient selection process for genetic testing should be guided by the current experts' recommendations and should meet specific corresponding criteria. Once the diagnosis has been made, treatment should be tailored to each patient's particular needs. Certainly, the advent of the total pancreatectomy with auto islet cell transplantation, which has the main goal to improve the pain caused by the chronic pancreatitis and simultaneously reduce the severity of the pancreatectomy induced diabetes, is an attractive alternative in the treatment and management of patient with a diagnosis of hereditary pancreatitis. However, strict criteria and an interdisciplinary management are essential since this surgery is irreversible and carries lifetime health consequences that all patients must be aware of and the medical team must be able to early recognize these and treat accordingly. However, there are many potential areas in this field for more, better and forefront research to be developed aiming for a better understanding of the disease process and for the development of a cure. PMID- 28731997 TI - Perforated Meckel's diverticulum. AB - We report a patient with diffuse peritonitis due to perforation of Meckel's diverticulum. This patient was referred to the operating room and underwent bowel resection segment encompassing the area of the diverticulum and terminoterminal primary enteroanastomosis on two levels with good evolution. The diverticulum complications are often related to the presence of ectopic mucosa, specially the gastric and pancreatic type. Since preoperative diagnosis is difficult and infrequent, in most cases this anomaly is confirmed only during surgery. Surgical resection of the affected intestinal segment is the mainstay of treatment in both diverticula diagnosed incidentally, as the complicated by inflammation, bleeding, obstruction or perforation. We conclude that in cases of acute abdomen punctured, the diagnosis of Meckel's diverticulum should be considered. PMID- 28731998 TI - Laparoendoscopic rendez-vous: a safe alternative to the treatment of choledocholithiasis. AB - The choice treatment for choledocholithiasis when associated with lithiasic cholecystitis is endoscopic retrograde cholangiopancreatography (ERCP). However, in some cases this therapeutic fails, which requires an alternative method to extract the stones. The surgical approach tends to be the next step, but it is related to greater complexity of achievement and higher complications rates. In 1993, Deslandres et al. developed the combined treatment called laparoendoscopic rendez-vous, that unites in a single stage the endoscopic treatment of choledocholithiasis and laparoscopic removal of the gallbladder. We report the case of a patient diagnosed with common bile duct (CBD) stones, in which the conventional CPRE was not successful, and was taken to treatment by laparoendoscopic approach. We conclude, based on this case and on other published studies, that this therapeutic modality has advantages for being feasible, presenting low complications rate, shorter hospital stay and acceptable cost. PMID- 28731999 TI - [Duodenal Linphoma asociated to Strongyloides stercoralis infection. Two types of HTLV-1 infection]. AB - Infection by the Human T- Lymphotropic virus I (HTLV-1) causes Adult T cell Leukemia-lymphoma (ATLL), being the duodenal involvement rare. Commonly, patients co-infected with HTLV-1 and Strongyloides stercoralis are seen due to the lack of TH2 response found on these patients. We describe a 48-year- old woman, from the jungle of Peru, with a family history of HTLV-1 infection, who presented with a History of chronic diarrhea and weight loss. HTLV-1 infection with ATLL and strongyloidiasis were diagnosed. Ivermectin treatment and chemotherapy were initiated, being stabilized, and discharged. We report this case because of the unusual coexistence in the duodenum of ATLL and strongyloidiasis. PMID- 28732000 TI - Biliary ileus: case report. AB - Biliary ileusis a uncommon cause of mechanical bowel obstruction, affecting older adult patients who often have other significant medical conditions. It is caused by intestinal impaction of a gallstone that enters the bowel via a cholecysto enteric fistula. The mortality rate is considerable, ranging between 12 and 27%. Treatment in most cases is surgical, aimed at the resolution of the intestinal obstruction. We report the case of a 55 year old patient diagnosed with biliary ileus, wich evolved without complications after a enterolithotomy. We have concluded, based on the literature that an early diagnosis associated with appropriate therapy can lead to a better prognosis. PMID- 28732001 TI - [Eosinophilic gastroenteritis. A case report and a review of the literature]. AB - Eosinophilic gastroenteritis is a rare primary disease distinguished by abundant eosinophilic infiltration of the intestinal mucosa. It concerns variable and nonspecific gastrointestinal symptoms according to the depth of infiltration and may cause severe complications. We reported a case of a 52-year- old woman without prior diseases with 8-month history of diarrhea, abdominal pain, ascites and weight loss. After having performed routine tests and rolled out most common diseases, we get to the diagnosis. Eosinophilic gastroenteritis requires a high suspicion for the diagnosis; because of chronic symptoms, it shows a burden on the nutritional status and quality of life of patients. Therefore, it is imperative that physicians should review this topic and consider it within differential diagnosis of chronic diarrhea and abdominal pain. PMID- 28732002 TI - [Gastrointestinal stromal tumor in young pregnant woman: case report]. AB - Female patient, 28 years old, with a gestation of 14 weeks, natural and from Ilo Moquegua. Came with a time of disease 4 days with hematemesis, melena, epigastric pain and syncope. Background of colonic resection for peritonitis due to trauma 20 years ago; upper gastrointestinal bleeding three years ago; paternal grandparents died of gastric cancer; chronic gastritis diagnosed from 19 year old. In laboratory studies hemoglobin of 9.2. In the upper gastrointestinal endoscopy was found absence of active upper gastrointestinal bleeding, a large tumor in proximal body toward greater curvature and posterior wall, 8 cm in diameter approximately, lobed appearance, with most of the mucosal surface unscathed is evidence, areas of ulceration of 2-3 mm covered with fibrin (biopsies taken), hard consistency, tent sign (positive) and cushionsign (negative). Imaging studies such as MRI or CT were not possible due to the pregnancy. In the complete abdominal ultrasound only grade I hepatic steatosis was reported. The results of endoscopic biopsy showed cell proliferation ofepithelioid characteristics with atypia. Immunohistochemistry was performed indicating CD117 (positive), CD 34 (negative), Ki 67 (positive 1%). The final diagnosis was a gastrointestinal stromal tumor epithelioid type with mitotic rate lower of 1%. Finally, surgical resection of the tumor was performed in which addition of 3 implants was found up to 1 cm in diameter in pancreatic peritoneum covering surface. We present the case as this is an unusual presentation of this tumor. PMID- 28732003 TI - [Diffuse type of gastric cancer adenocarcinoma in 10 years old boy: report of a case]. AB - We report a rare case of diffuse type of gastric cancer with signet ring cells in 10 years old boy who was admitted with a 12 months history with weight loss, dysphagia to solids first and to liquids later, anorexia, fatigue, dizziness, vomiting and later, with pain in the left upper quadrant. On examination, he appeared pale, malnourished, with cafe-au- lait spots over the trunk and extremities. Laboratory tests showed; Hb 7.5 g, albumin 2.62 g, Thevenon positive on stools. Abdominal ultrasound examination showed periaortic masses and diffuse space occupying lesions in the liver. Endoscopic examination of the stomach showed multiple elevated tumor lesions. One located at 3 cm on the subcardial region presented irregular borders, partially eroded, that bleed easily when rubbing its surface. Multiple biopsy samples were taken. They showed a diffuse gastric signet cell type carcinoma of the stomach. Immunohistochemistry was positive to CK 8. The patient died a year later with wide spread metastasis. The boy was born through a normal delivery after a normal pregnancy to a primipara mother. His family history recorded a grandmother aunt dying of gastric cancer. PMID- 28732004 TI - [Irritable bowel syndrome in medical students from Latin America: an overlooked problem?] PMID- 28732005 TI - Filamin actin-binding and titin-binding fulfill distinct functions in Z-disc cohesion. AB - Many proteins contribute to the contractile properties of muscles, most notably myosin thick filaments, which are anchored at the M-line, and actin thin filaments, which are anchored at the Z-discs that border each sarcomere. In humans, mutations in the actin-binding protein Filamin-C result in myopathies, but the underlying molecular function is not well understood. Here we show using Drosophila indirect flight muscle that the filamin ortholog Cheerio in conjunction with the giant elastic protein titin plays a crucial role in keeping thin filaments stably anchored at the Z-disc. We identify the filamin domains required for interaction with the titin ortholog Sallimus, and we demonstrate a genetic interaction of filamin with titin and actin. Filamin mutants disrupting the actin- or the titin-binding domain display distinct phenotypes, with Z-discs breaking up in parallel or perpendicularly to the myofibril, respectively. Thus, Z-discs require filamin to withstand the strong contractile forces acting on them. PMID- 28732006 TI - Drivers for Rift Valley fever emergence in Mayotte: A Bayesian modelling approach. AB - Rift Valley fever (RVF) is a major zoonotic and arboviral hemorrhagic fever. The conditions leading to RVF epidemics are still unclear, and the relative role of climatic and anthropogenic factors may vary between ecosystems. Here, we estimate the most likely scenario that led to RVF emergence on the island of Mayotte, following the 2006-2007 African epidemic. We developed the first mathematical model for RVF that accounts for climate, animal imports and livestock susceptibility, which is fitted to a 12-years dataset. RVF emergence was found to be triggered by the import of infectious animals, whilst transmissibility was approximated as a linear or exponential function of vegetation density. Model forecasts indicated a very low probability of virus endemicity in 2017, and therefore of re-emergence in a closed system (i.e. without import of infected animals). However, the very high proportion of naive animals reached in 2016 implies that the island remains vulnerable to the import of infectious animals. We recommend reinforcing surveillance in livestock, should RVF be reported is neighbouring territories. Our model should be tested elsewhere, with ecosystem specific data. PMID- 28732007 TI - A data-driven modeling approach to identify disease-specific multi-organ networks driving physiological dysregulation. AB - Multiple physiological systems interact throughout the development of a complex disease. Knowledge of the dynamics and connectivity of interactions across physiological systems could facilitate the prevention or mitigation of organ damage underlying complex diseases, many of which are currently refractory to available therapeutics (e.g., hypertension). We studied the regulatory interactions operating within and across organs throughout disease development by integrating in vivo analysis of gene expression dynamics with a reverse engineering approach to infer data-driven dynamic network models of multi-organ gene regulatory influences. We obtained experimental data on the expression of 22 genes across five organs, over a time span that encompassed the development of autonomic nervous system dysfunction and hypertension. We pursued a unique approach for identification of continuous-time models that jointly described the dynamics and structure of multi-organ networks by estimating a sparse subset of ~12,000 possible gene regulatory interactions. Our analyses revealed that an autonomic dysfunction-specific multi-organ sequence of gene expression activation patterns was associated with a distinct gene regulatory network. We analyzed the model structures for adaptation motifs, and identified disease-specific network motifs involving genes that exhibited aberrant temporal dynamics. Bioinformatic analyses identified disease-specific single nucleotide variants within or near transcription factor binding sites upstream of key genes implicated in maintaining physiological homeostasis. Our approach illustrates a novel framework for investigating the pathogenesis through model-based analysis of multi-organ system dynamics and network properties. Our results yielded novel candidate molecular targets driving the development of cardiovascular disease, metabolic syndrome, and immune dysfunction. PMID- 28732008 TI - Falls, non-accidental falls and syncope in community-dwelling adults aged 50 years and older: Implications for cardiovascular assessment. AB - OBJECTIVES: To calculate the prevalence of all falls, non-accidental falls and syncope in an older population and characterize cardiovascular risk profiles. DESIGN: Prospective, longitudinal cohort study. SETTING: The first two waves of data from the Irish Longitudinal Study on Ageing (TILDA). PARTICIPANTS: 8172 community-dwelling adults aged 50 years and older resident in the Republic of Ireland. MEASUREMENTS: Self-reported history of all falls, non-accidental falls and syncope in the year preceding the first two waves of data collection. Demographic factors and self-reported cardiovascular conditions were used to characterize cardiovascular risk profiles. RESULTS: The prevalence of all falls in the past year was 19.2% or 192 per thousand persons and increased with age (50 64 years 17.5%; 65-74 years 19.4%; 75+ years 24.4%). Non-accidental falls had an estimated prevalence of 5.1% or 51 falls per thousand persons and accounted for 26.5% of all falls reported and also increased with age (50-64 years 4.0%; 65-74 years 5.5%; 75+ years 8.0%). The prevalence for syncope was estimated to be 4.4% or 44per thousand persons but did not show a similar age gradient. Participants with at least 5 cardiovascular conditions were more likely to report all falls (OR = 2.07, 95% CI 1.18-3.64, p<0.05) and NAF (OR = 2.89, 95%CI 1.28-6.52, p<0.05). CONCLUSIONS: The prevalence of all falls and non-accidental falls increases with age but the same pattern was not consistently observed for syncope. There is an increased odds of reporting all three outcomes with increasing number of self-reported cardiovascular conditions. Further work is needed to uncover the interplay between cardiovascular disease and subsequent falls. PMID- 28732009 TI - Effects of local cardiac denervation on cardiac innervation and ventricular arrhythmia after chronic myocardial infarction. AB - BACKGROUND: Modulation of the autonomic nervous system (ANS) has already been demonstrated to display antiarrhythmic effects in patients and animals with MI. In this study, we investigated whether local cardiac denervation has any beneficial effects on ventricular electrical stability and cardiac function in the chronic phase of MI. METHODS: Twenty-one anesthetized dogs were randomly assigned into the sham-operated, MI and MI-ablation groups, respectively. Four weeks after local cardiac denervation, LSG stimulation was used to induce VPCs and VAs. The ventricular fibrillation threshold (VFT) and the incidence of inducible VPCs were measured with electrophysiological protocol. Cardiac innervation was determined with immunohistochemical staining of growth associated protein-43 (GAP43) and tyrosine hydroxylase (TH). The global cardiac and regional ventricular function was evaluated with doppler echocardiography in this study. RESULTS: Four weeks after operation, the incidence of inducible VPC and VF in MI ablation group were significantly reduced compared to the MI dogs (p<0.05). Moreover, local cardiac denervation significantly improved VFT in the infarcted border zone (p<0.05). The densities of GAP43 and TH-positive nerve fibers in the infarcted border zone in the MI-ablation group were lower than those in the MI group (p<0.05). However, the local cardiac denervation did not significantly improve cardiac function in the chronic phase of MI, determined by the left ventricle diameter (LV), left atrial diameter (LA), ejection fraction (EF). CONCLUSIONS: Summarily, in the chronic phase of MI, local cardiac denervation reduces the ventricular electrical instability, and attenuates spatial heterogeneity of sympathetic nerve reconstruction. Our study suggests that this methodology might decrease malignant ventricular arrhythmia in chronic MI, and has a great potential for clinical application. PMID- 28732010 TI - Biofilm imaging in porous media by laboratory X-Ray tomography: Combining a non destructive contrast agent with propagation-based phase-contrast imaging tools. AB - X-ray tomography is a powerful tool giving access to the morphology of biofilms, in 3D porous media, at the mesoscale. Due to the high water content of biofilms, the attenuation coefficient of biofilms and water are very close, hindering the distinction between biofilms and water without the use of contrast agents. Until now, the use of contrast agents such as barium sulfate, silver-coated micro particles or 1-chloronaphtalene added to the liquid phase allowed imaging the biofilm 3D morphology. However, these contrast agents are not passive and potentially interact with the biofilm when injected into the sample. Here, we use a natural inorganic compound, namely iron sulfate, as a contrast agent progressively bounded in dilute or colloidal form into the EPS matrix during biofilm growth. By combining a very long source-to-detector distance on a X-ray laboratory source with a Lorentzian filter implemented prior to tomographic reconstruction, we substantially increase the contrast between the biofilm and the surrounding liquid, which allows revealing the 3D biofilm morphology. A comparison of this new method with the method proposed by Davit et al (Davit et al., 2011), which uses barium sulfate as a contrast agent to mark the liquid phase was performed. Quantitative evaluations between the methods revealed substantial differences for the volumetric fractions obtained from both methods. Namely, contrast agent-biofilm interactions (e.g. biofilm detachment) occurring during barium sulfate injection caused a reduction of the biofilm volumetric fraction of more than 50% and displacement of biofilm patches elsewhere in the column. Two key advantages of the newly proposed method are that passive addition of iron sulfate maintains the integrity of the biofilm prior to imaging, and that the biofilm itself is marked by the contrast agent, rather than the liquid phase as in other available methods. The iron sulfate method presented can be applied to understand biofilm development and bioclogging mechanisms in porous materials and the obtained biofilm morphology could be an ideal basis for 3D numerical calculations of hydrodynamic conditions to investigate biofilm-flow coupling. PMID- 28732011 TI - Proteomics analysis reveals a dynamic diurnal pattern of photosynthesis-related pathways in maize leaves. AB - Plant leaves exhibit differentiated patterns of photosynthesis rates under diurnal light regulation. Maize leaves show a single-peak pattern without photoinhibition at midday when the light intensity is maximized. This mechanism contributes to highly efficient photosynthesis in maize leaves. To understand the molecular basis of this process, an isobaric tag for relative and absolute quantitation (iTRAQ)-based proteomics analysis was performed to reveal the dynamic pattern of proteins related to photosynthetic reactions. Steady, single peak and double-peak protein expression patterns were discovered in maize leaves, and antenna proteins in these leaves displayed a steady pattern. In contrast, the photosystem, carbon fixation and citrate pathways were highly controlled by diurnal light intensity. Most enzymes in the limiting steps of these pathways were major sites of regulation. Thus, maize leaves optimize photosynthesis and carbon fixation outside of light harvesting to adapt to the changes in diurnal light intensity at the protein level. PMID- 28732012 TI - Multi-approach metabolomics analysis and artificial simplified phytocomplexes reveal cultivar-dependent synergy between polyphenols and ascorbic acid in fruits of the sweet cherry (Prunus avium L.). AB - Fruits of the sweet cherry (Prunus avium L.) accumulate a range of antioxidants that can help to prevent cardiovascular disease, inflammation and cancer. We tested the in vitro antioxidant activity of 18 sweet cherry cultivars collected from 12 farms in the protected geographical indication region of Marostica (Vicenza, Italy) during two growing seasons. Multiple targeted and untargeted metabolomics approaches (NMR, LC-MS, HPLC-DAD, HPLC-UV) as well as artificial simplified phytocomplexes representing the cultivars Sandra Tardiva, Sandra and Grace Star were then used to determine whether the total antioxidant activity reflected the additive effects of each compound or resulted from synergistic interactions. We found that the composition of each cultivar depended more on genetic variability than environmental factors. Furthermore, phenolic compounds were the principal source of antioxidant activity and experiments with artificial simplified phytocomplexes indicated strong synergy between the anthocyanins and quercetins/ascorbic acid specifically in the cultivar Sandra Tardiva. Our data therefore indicate that the total antioxidant activity of sweet cherry fruits may originate from cultivar-dependent interactions among different classes of metabolite. PMID- 28732013 TI - The KP1_4563 gene is regulated by the cAMP receptor protein and controls type 3 fimbrial function in Klebsiella pneumoniae NTUH-K2044. AB - Klebsiella pneumoniae (K. pneumoniae) is an opportunistic pathogen that can adhere to host cells or extracellular matrix via type 1 and type 3 fimbriae. KP1_4563 is a gene encoding a hypothetical protein in K. pneumoniae NTUH-K2044. KP1_4563 is located between the type 1 and type 3 fimbrial gene clusters and is likely associated with fimbrial function given its putative conserved domains of unknown function (DUF1471). Cyclic AMP receptor protein (CRP) regulates virulence related gene expression and is a crucial transcriptional regulator in many bacteria. The predicted DNA recognition motif of CRP is present in the KP1_4563 promoter region. This study aimed to investigate the function of KP1_4563 in fimbriae and its transcriptional regulation mechanism by CRP. We generated Kp Delta4563 mutant and complementation strains. We utilized phenotype and adhesion assays to evaluate the role of KP1_4563 in fimbriae. We conducted quantitative RT PCR (qRT-PCR), LacZ fusion, electrophoretic mobility shift, and DNase I footprinting assays to study the transcriptional regulation of KP1_4563 gene by CRP. We found that KP1_4563 negatively regulates the function of type 3 fimbriae. Compared with NTUH-K2044, the absence of KP1_4563 enhanced the ability of Kp Delta4563 to adhere to A549 cells. CRP negatively regulates KP1_4563 by directly binding to its promoter region. KP1_4563 plays an important role in type 3 fimbrial function. This novel insight will assist in the development of strategies for preventing K. pneumoniae infection. PMID- 28732014 TI - Association of time-serial changes in ambient particulate matters (PMs) with respiratory emergency cases in Taipei's Wenshan District. AB - Ambient air pollution poses a significant risk for a group of common and often debilitating respiratory diseases, but its direct impact on cause-specific respiratory diseases using emergency room visit (ERV) as an indicator remains to be fully explored. In this study, we conducted a time-series study of ambient PM2.5, NO2, SO2 and their association with ERV for asthma, COPD and pneumonia in a four-year time span. Relative risks for ERV as per log increase in the level of ambient pollutants with time lags of up to 10 days were calculated, using a generalized additive model of Poisson regression. Daily 24-h average concentrations of PM2.5 and pollutant gases were obtained from a local Gutting air quality monitoring station. Results showed that the ERVs for pneumonia and asthma were associated with the level of PM2.5. The effects of PM2.5 on the risk of ERV for asthma were found to be significant at lag days 1 and 2 with increasing risk of 4.34% [RR: 1.091; CI: 1.020-1.166 (95%)] and 3.58% [RR: 1.074; CI: 1.007-1.146 (95%)], respectively. The ERV for pneumonia was associated with the level of PM2.5 at lag days 5, 6 and 7, with increasing risk of 1.92% [RR: 1.039; CI: 1.009-1.070 (95%)], 2.03% [RR: 1.041; CI: 1.009-1.075 (95%)], and 1.82% [RR: 1.037; CI: 1.001-1.075 (95%)], respectively. Further, PM2.5, but not NO2 and SO2, posed a significant risk of ERV for asthma during spring at lag days 0, 1 and 2 (17.12%, RR: 1.408, CI: 1.075-1.238; 15.30%, RR: 1.358 CI: 1.158 1.166; 11.94%, RR: 1.165, CI: 1.004-1.121), which was particularly evident for those who were younger than 75 years of age. In contrast, only PM2.5 was a significant risk of ERV for COPD, which was primarily for those who were younger than 75 years of age during summer season at lag days 3, 4 and 5. (26.66%, RR: 1.704, CI: 1.104-2.632; 26.99%; RR: 1.716, CI: 1.151-2.557; 24.09%; RR: 1.619, CI: 1.111-2.360). Collectively, these results suggested significant seasonal variation and differential time lag effects of PM2.5 on ERV for asthma, COPD and pneumonia. PMID- 28732015 TI - Maintenance costs of serotiny in a variably serotinous pine: The role of water supply. AB - Serotiny is an important adaptation for plants in fire-prone environments. However, different mechanisms also induce the opening of serotinous cones in the absence of fire in variably serotinous species. Xeriscence -cone opening driven by dry and hot conditions- is considered to be mediated only by the external environment, but endogenous factors could also play a significant role. Using the variably serotinous Pinus halepensis as our model species, we determined the effects of cone age and scales density in cone opening, and using in-situ and ex situ manipulative experiments we investigated the role of water availability in the opening of serotinous cones. We hypothesized that loss of connection between the cones and the branch through the peduncles or the absence of water supply could induce a faster cone opening. Results showed that older cones lost more water and opened at lower temperatures, with no influence of scales density. Both field and chamber manipulative experiments (using paired cones of the same whorl) confirmed that water intake through the peduncles affected significantly the pace of cone opening, such that lack of water supply speeded up cone dehiscence. However, this was true for weakly serotinous provenances-more common in this species-, while highly serotinous provenances were indifferent to this effect in the field test. All our results support that cone serotiny in P. halepensis involves the allocation of water to the cones, which is highly consistent with the previously observed environmental effects. Importantly, the existence of maintenance costs of serotinous cones has strong implications on the effects of climate change in the resilience of natural populations, via modifications of the canopy seed banks and recruitment after stand-replacing fires. Moreover, evolutionary models for serotiny in P. halepensis must take into account the significant contribution of maintenance costs to the complex interaction between genotype and the environment. PMID- 28732016 TI - Maternal residential proximity to unconventional gas development and perinatal outcomes among a diverse urban population in Texas. AB - OBJECTIVE: To assess associations between unconventional natural gas development (UGD) and perinatal outcomes. METHODS: We conducted a retrospective birth cohort study among 158,894 women with a birth or fetal death from November 30, 2010 November 29, 2012 in the Barnett Shale, in North Texas. We constructed three UGD activity metrics by calculating the inverse distance-weighted sum of active wells within three separate geographic buffers surrounding the maternal residence: <=1/2, 2, or 10-miles. We excluded women if the nearest well to her residence was >20 miles. Metrics were categorized by tertiles among women with >=1 well within the respective buffer; women with zero wells <=10 miles (the largest buffer) served as a common referent group. We used logistic or linear regression with generalized estimating equations to assess associations between UGD-activity and preterm birth, small-for-gestational age (SGA), fetal death, or birthweight. Adjusted models of fetal death and birthweight included: maternal age, race/ethnicity, education, pre-pregnancy body mass index, parity, smoking, adequacy of prenatal care, previous poor pregnancy outcome, and infant sex. Preterm birth models included all of the above except parity; SGA models included all of the above except previous poor pregnancy outcome. RESULTS: We found increased adjusted odds of preterm birth associated with UGD-activity in the highest tertiles of the 1/2- (odds ratio (OR) = 1.14; 95% confidence interval 1.03, 1.25), 2- (1.14; 1.07, 1.22), and 10-mile (1.15; 1.08, 1.22) metrics. Increased adjusted odds of fetal death were found in the second tertile of the 2 mile metric (1.56; 1.16, 2.11) and the highest tertile of the 10-mile metric (1.34; 1.04-1.72). We found little indication of an association with SGA or term birthweight. CONCLUSIONS: Our results are suggestive of an association between maternal residential proximity to UGD-activity and preterm birth and fetal death. Quantifying chemical and non-chemical stressors among residents near UGD should be prioritized. PMID- 28732020 TI - Setting strategy of delay-optimization-oriented SMAC contention window size. AB - Some frame components, such as SYNC (frame synchronization) and RTS/CTS (Ready to Send/Clear to Send), are not taken into consideration when the traditional setting strategies conduct the optimization of SMAC (Sensor MAC) contention window size. This paper proposes mathematical models that allow the analysis of data packets forwarding delay within one SMAC virtual cluster. Simulation results in OMNeT++ show good agreements with the proposed mathematical models, validating the models' correctness. The curve analyses of the models confirm the existence of delay-optimization-oriented contention window size that is closely related to the number of simultaneously contending nodes. Afterwards, it is shown that SYNC, RTS/CTS and EIFS (Extended InterFrame Space) have impacts on the optimal contention window size and expected delivery delay to various degrees, as well as throughput and energy efficiency. One ideal setting strategy of delay optimization-oriented SMAC contention window size requires the combination of the network scale, SYNC, RTS/CTS and EIFS. Additionally, it is demonstrated that the proposed setting strategy makes contributions to the improvement in the existing SMAC extensions when they are integrated with each other, in terms of the end-to end delay, throughput and energy consumption. PMID- 28732018 TI - Carboplatin with intravenous and subsequent oral administration of vinorelbine in resected non-small-cell-lung cancer in real-world set-up. AB - OBJECTIVES: Adjuvant cisplatin-based chemotherapy is recommended for routine use in patients with Stage IIA, IIB or IIIA non-small cell lung cancer (NSCLC) after complete resection. Results obtained for Stage IB were not conclusive. While vinorelbine plus cisplatin is the preferred choice after resection, combining vinorelbine with carboplatin promises improved compliance and delivery of drugs due to lower toxicity. We evaluated the impact of this option on treatment compliance and survival under real-world conditions. MATERIAL AND METHODS: A prospective, single-arm, multicenter, non-interventional study evaluated the tolerability, dose intensity and survival resulting from adjuvant use of intravenous carboplatin (AUC 5 on day 1) with vinorelbine administered both intravenously (25 mg/m2 on day 1) and orally (60 mg/m2 on day 8) within four cycles of 21 days each. A total of 74 patients with a median age of 64 years were observed. RESULTS: The mean number of accomplished cycles was 3.78, and 62 patients (83.7%) completed all four planned cycles. Relative dose intensity for carboplatin was 88.9%, for intravenous vinorelbine 93.1%, and for oral vinorelbine 83.2%. Median follow-up was 4.73 years. Median disease-specific survival (DSS) was 7.63 years, median overall survival (OS) was 5.90 years, median disease-free survival (DFS0) was 4.43 years, and five-year survival was 56.2%. TNM stage of disease significantly affected DSS and OS. Favorable survival was observed in females, nonsmokers, patients aged over 65 years, patient with prior lobectomy, patients with tumor of squamous histology, and those who finished the planned therapy, but the differences were non-significant. CONCLUSION: Adjuvant carboplatin with vinorelbine switched from intravenous to oral administration was shown to be a favorable regimen with regard to tolerability and safety. Compliance to therapy was high, and survival parameters were promising, showing that applied regimen can be another potential option for adjuvant chemotherapy in patients with NSCLC. PMID- 28732017 TI - Disease severity in patients with visceral leishmaniasis is not altered by co infection with intestinal parasites. AB - Visceral leishmaniasis (VL) is a neglected tropical disease that affects the poorest communities and can cause substantial morbidity and mortality. Visceral leishmaniasis is characterized by the presence of Leishmania parasites in the spleen, liver and bone marrow, hepatosplenomegaly, pancytopenia, prolonged fever, systemic inflammation and low body mass index (BMI). The factors impacting on the severity of VL are poorly characterized. Here we performed a cross-sectional study to assess whether co-infection of VL patients with intestinal parasites influences disease severity, assessed with clinical and haematological data, inflammation, cytokine profiles and BMI. Data from VL patients was similar to VL patients co-infected with intestinal parasites, suggesting that co-infection of VL patients with intestinal parasites does not alter disease severity. PMID- 28732023 TI - Correction: A Chemical-Genomic Screen of Neglected Antibiotics Reveals Illicit Transport of Kasugamycin and Blasticidin S. AB - [This corrects the article DOI: 10.1371/journal.pgen.1006124.]. PMID- 28732019 TI - Rate of hepatitis C viral clearance by human livers in human patients: Liver transplantation modeling primary infection and implications for studying entry inhibition. AB - : To better understand the dynamics of early hepatitis C virus (HCV) infection, we determined how rapidly non-cirrhotic HCV-uninfected liver allografts clear HCV from the circulation of cirrhotic HCV-infected patients at the time of transplantation but before administration of immunosuppression. Specifically, we characterized serum HCV kinetics during the first 90 min of reperfusion for 19 chronically HCV-infected patients transplanted with an HCV-uninfected liver by measuring serum viral load immediately prior to reperfusion (t = 0) and then every 15 min for a total of 90 min (t = 90). Immunosuppression was withheld until all samples were taken to better model primary infection. During this period, rates of viral clearance varied more than 20-fold with a median rate constant of 0.0357 1/min, range 0.0089-0.2169; half-life (minutes) median 19.4, range 3.2 77.8. The majority of viral clearance occurred within the first 60 min. The amount of blood transfused during this 90-min period (a potential confounding variable of this human liver transplant model of primary infection) accounted for 53% and 59% of k (r = 0.53, p = 0.05) and half-life (r = 0.59, p = 0.03) variability, respectively. No other clinical variables tested (age, allograft weight, and degree of reperfusion injury as assessed by peak postoperative ALT or AST) accounted for the remaining variability (p>0.05). CONCLUSION: In a human liver transplant model of primary infection, HCV rapidly clears the bloodstream. With approximately 90% of clearance occurring in the first 90 minutes of reperfusion, studies of HCV entry inhibition could utilize rate of clearance during this early period as an outcome measure. PMID- 28732021 TI - In Vitro comparison of 213Bi- and 177Lu-radiation for peptide receptor radionuclide therapy. AB - BACKGROUND: Absorbed doses for alpha-emitters are different from those for beta emitters, as the high linear energy transfer (LET) nature of alpha-particles results in a very dense energy deposition over a relatively short path length near the point of emission. This highly localized and therefore high energy deposition can lead to enhanced cell-killing effects at absorbed doses that are non-lethal in low-LET type of exposure. Affinities of DOTA-DPhe1-Tyr3-octreotate (DOTATATE), 115In-DOTATATE, 175Lu-DOTATATE and 209Bi-DOTATATE were determined in the K562-SST2 cell line. Two other cell lines were used for radiation response assessment; BON and CA20948, with a low and high expression of somatostatin receptors, respectively. Cellular uptake kinetics of 111In-DOTATATE were determined in CA20948 cells. CA20948 and BON were irradiated with 137Cs, 177Lu DTPA, 177Lu-DOTATATE, 213Bi-DTPA and 213Bi-DOTATATE. Absorbed doses were calculated using the MIRDcell dosimetry method for the specific binding and a Monte Carlo model of a cylindrical 6-well plate geometry for the exposure by the radioactive incubation medium. Absorbed doses were compared to conventional irradiation of cells with 137Cs and the relative biological effect (RBE) at 10% survival was calculated. RESULTS: IC50 of (labelled) DOTATATE was in the nM range. Absorbed doses up to 7 Gy were obtained by 5.2 MBq 213Bi-DOTATATE, in majority the dose was caused by alpha-particle radiation. Cellular internalization determined with 111In-DOTATATE showed a linear relation with incubation time. Cell survival after exposure of 213Bi-DTPA and 213Bi-DOTATATE to BON or CA20948 cells showed a linear-exponential relation with the absorbed dose, confirming the high LET character of 213Bi. The survival of CA20948 after exposure to 177Lu-DOTATATE and the reference 137Cs irradiation showed the typical curvature of the linear-quadratic model. 10% Cell survival of CA20948 was reached at 3 Gy with 213Bi-DOTATATE, a factor 6 lower than the 18 Gy found for 177Lu DOTATATE and also below the 5 Gy after 137Cs external exposure. CONCLUSION: 213Bi DTPA and 213Bi-DOTATATE lead to a factor 6 advantage in cell killing compared to 177Lu-DOTATATE. The RBE at 10% survival by 213Bi-ligand compared to 137Cs was 2.0 whereas the RBE for 177Lu-DOTATATE was 0.3 in the CA20948 in vitro model. PMID- 28732022 TI - Global economic trade-offs between wild nature and tropical agriculture. AB - Global demands for agricultural and forestry products provide economic incentives for deforestation across the tropics. Much of this deforestation occurs with a lack of information on the spatial distribution of benefits and costs of deforestation. To inform global sustainable land-use policies, we combine geographic information systems (GIS) with a meta-analysis of ecosystem services (ES) studies to perform a spatially explicit analysis of the trade-offs between agricultural benefits, carbon emissions, and losses of multiple ecosystem services because of tropical deforestation from 2000 to 2012. Even though the value of ecosystem services presents large inherent uncertainties, we find a pattern supporting the argument that the externalities of destroying tropical forests are greater than the current direct economic benefits derived from agriculture in all cases bar one: when yield and rent potentials of high-value crops could be realized in the future. Our analysis identifies the Atlantic Forest, areas around the Gulf of Guinea, and Thailand as areas where agricultural conversion appears economically efficient, indicating a major impediment to the long-term financial sustainability of Reducing Emissions from Deforestation and forest Degradation (REDD+) schemes in those countries. By contrast, Latin America, insular Southeast Asia, and Madagascar present areas with low agricultural rents (ARs) and high values in carbon stocks and ES, suggesting that they are economically viable conservation targets. Our study helps identify optimal areas for conservation and agriculture together with their associated uncertainties, which could enhance the efficiency and sustainability of pantropical land-use policies and help direct future research efforts. PMID- 28732024 TI - 4-(Nitrophenylsulfonyl)piperazines mitigate radiation damage to multiple tissues. AB - Our ability to use ionizing radiation as an energy source, as a therapeutic agent, and, unfortunately, as a weapon, has evolved tremendously over the past 120 years, yet our tool box to handle the consequences of accidental and unwanted radiation exposure remains very limited. We have identified a novel group of small molecule compounds with a 4-nitrophenylsulfonamide (NPS) backbone in common that dramatically decrease mortality from the hematopoietic acute radiation syndrome (hARS). The group emerged from an in vitro high throughput screen (HTS) for inhibitors of radiation-induced apoptosis. The lead compound also mitigates against death after local abdominal irradiation and after local thoracic irradiation (LTI) in models of subacute radiation pneumonitis and late radiation fibrosis. Mitigation of hARS is through activation of radiation-induced CD11b+Ly6G+Ly6C+ immature myeloid cells. This is consistent with the notion that myeloerythroid-restricted progenitors protect against WBI-induced lethality and extends the possible involvement of the myeloid lineage in radiation effects. The lead compound was active if given to mice before or after WBI and had some anti tumor action, suggesting that these compounds may find broader applications to cancer radiation therapy. PMID- 28732026 TI - Investigation of opioid use and long-term oncologic outcomes for non-small cell lung cancer patients treated with surgery. AB - Opioids are commonly used for postoperative pain control in cancer patients. In addition to pain control, an association between opioid use and long-term oncologic outcomes, such as recurrence or overall survival, has been postulated. The aim of this study was to determine whether postoperative opioid use in patients with non-small cell lung cancer is associated with long-term oncologic outcomes, including recurrence and death. Data obtained from 1009 medical records of patients who underwent curative resection at the National Cancer Center, Korea between January 2006 and December 2010 were retrospectively analyzed. Seven-day opioid use was divided into four quartiles to analyze probability of recurrence and death. Multivariate regression analyses of recurrence and death was conducted, including the calculation of odds ratios. A total of 871 patients were analyzed. When opioid dosage was examined by quartiles, the probability of death and recurrence increased gradually with increasing opioid use. However, in the multivariate regression analysis, the amount of opioid usage did not affect the risk of recurrence or death of lung cancer (P = 0.520 for recurrence; P = 0.659 for death). Opioid use was correlated with outcome when stratified by lung cancer stage (P = 0.004 for recurrence; P = 0.049 for death); however, the odds ratios only slightly increased (1.001 for stage IA-IIIA) for both outcomes. In non-small cell lung cancer patients, the amount of opioid usage does not affect the risk of recurrence and death of lung cancer. There was an association with stage (IA IIIA), but the effect was negligible. A well-designed prospective study is needed. PMID- 28732025 TI - Hand factor ablation causes defective left ventricular chamber development and compromised adult cardiac function. AB - Coordinated cardiomyocyte growth, differentiation, and morphogenesis are essential for heart formation. We demonstrate that the bHLH transcription factors Hand1 and Hand2 play critical regulatory roles for left ventricle (LV) cardiomyocyte proliferation and morphogenesis. Using an LV-specific Cre allele (Hand1LV-Cre), we ablate Hand1-lineage cardiomyocytes, revealing that DTA mediated cardiomyocyte death results in a hypoplastic LV by E10.5. Once Hand1 linage cells are removed from the LV, and Hand1 expression is switched off, embryonic hearts recover by E16.5. In contrast, conditional LV loss-of-function of both Hand1 and Hand2 results in aberrant trabeculation and thickened compact zone myocardium resulting from enhanced proliferation and a breakdown of compact zone/trabecular/ventricular septal identity. Surviving Hand1;Hand2 mutants display diminished cardiac function that is rescued by concurrent ablation of Hand-null cardiomyocytes. Collectively, we conclude that, within a mixed cardiomyocyte population, removal of defective myocardium and replacement with healthy endogenous cardiomyocytes may provide an effective strategy for cardiac repair. PMID- 28732029 TI - The tonic immobility test: Do wild and captive golden mantella frogs (Mantella aurantiaca) have the same response? AB - Adaptations to captivity that reduce fitness are one of many reasons, which explain the low success rate of reintroductions. One way of testing this hypothesis is to compare an important behavioural response in captive and wild members of the same species. Thanatosis, is an anti-predator strategy that reduces the risk of death from predation, which is a common behavioral response in frogs. The study subjects for this investigation were captive and wild populations of Mantella aurantiaca. Thanatosis reaction was measured using the Tonic Immobility (TI) test, a method that consists of placing a frog on its back, restraining it in this position for a short period of time and then releasing it and measuring how much time was spent feigning death. To understand the pattern of reaction time, morphometric data were also collected as body condition can affect the duration of thanatosis. The significantly different TI times found in this study, one captive population with shorter responses, were principally an effect of body condition rather than being a result of rearing environment. However, this does not mean that we can always dismiss the importance of rearing environment in terms of behavioural skills expressed. PMID- 28732028 TI - The individual and contextual determinants of the use of telemedicine: A descriptive study of the perceptions of Senegal's physicians and telemedicine projects managers. AB - Telemedicine is considered to be an effective strategy to aid in the recruitment and retention of physicians in underserved areas and, in doing so, improve access to healthcare. Telemedicine's use, however, depends on individual and contextual factors. Using a mixed methods design, we studied these factors in Senegal based on a micro, meso and macro framework. A quantitative questionnaire administered to 165 physicians working in public hospitals and 151 physicians working in district health centres was used to identify individual (micro) factors. This was augmented with qualitative descriptive data involving individual interviews with 30 physicians working in public hospitals, 36 physicians working in district health centres and 10 telemedicine project managers to identify contextual (meso and macro) factors. Physicians were selected using purposeful random sampling; managers through snowball sampling. Quantitative data were analyzed descriptively using SPSS 23 and qualitative data thematically using NVivo 10. At the micro level, we found that 72.1% of the physicians working in public hospitals and 82.1% of the physicians working in district health centres were likely to use telemedicine in their professional activities. At the meso level, we identified several technical, organizational and ethical factors, while at the macro level the study revealed a number of financial, political, legal, socioeconomic and cultural factors. We conclude that better awareness of the interplay between factors can assist health authorities to develop telemedicine in ways that will attract use by physicians, thus improving physicians' recruitment and retention in underserved areas. PMID- 28732027 TI - Serum irisin and myostatin levels after 2 weeks of high-altitude climbing. AB - Exposure to high-altitude hypoxia causes physiological and metabolic adaptive changes by disturbing homeostasis. Hypoxia-related changes in skeletal muscle affect the closely interconnected energy and regeneration processes. The balance between protein synthesis and degradation in the skeletal muscle is regulated by several molecules such as myostatin, cytokines, vitamin D, and irisin. This study investigates changes in irisin and myostatin levels in male climbers after a 2 week high-altitude expedition, and their association with 25(OH)D and indices of inflammatory processes. The study was performed in 8 men aged between 23 and 31 years, who participated in a 2-week climbing expedition in the Alps. The measurements of body composition and serum concentrations of irisin, myostatin, 25(OH)D, interleukin-6, myoglobin, high-sensitivity C-reactive protein, osteoprotegerin, and high-sensitivity soluble receptor activator of NF-kappaB ligand (sRANKL) were performed before and after expedition. A 2-week exposure to hypobaric hypoxia caused significant decrease in body mass, body mass index (BMI), free fat mass and irisin, 25-Hydroxyvitamin D levels. On the other hand, significant increase in the levels of myoglobin, high-sensitivity C-reactive protein, interleukin-6, and osteoprotegerin were noted. The observed correlations of irisin with 25(OH)D levels, as well as myostatin levels with inflammatory markers and the OPG/RANKL ratio indicate that these myokines may be involved in the energy-related processes and skeletal muscle regeneration in response to 2 week exposure to hypobaric hypoxia. PMID- 28732034 TI - Neglecting the call of the wild: Captive frogs like the sound of their own voice. AB - Acoustic communication is highly influential in the expression of social behavior by anuran amphibians, transmitting information about the individual's physical condition and motivation. We studied the phonotactic (approach movements) responses of wild and captive male golden mantella frogs to conspecific wild and captive playback calls to determine the impact of captivity on social behaviour mediated by vocalisations. Calls were recorded from one wild and two captive populations. Phonotaxis experiments were then conducted by attracting M. aurantiaca males across a PVC grid on the forest floor or enclosure floor to a speaker. For each playback, the following parameters were recorded to define the accuracy of phonotaxis: (1) number of jumps; (2) jump angles; (3) jump distances; (4) path straightness. During this experiment we observed that wild frogs had a similar behavioural (phonotaxis) response to calls independent of their source while frogs from Chester Zoo had a significantly stronger response to calls of other conspecifics held separately at Chester Zoo. The lack of appropriate phonotaxis response by captive bred frogs to the calls of wild conspecifics could have serious negative conservation implications, if the captive bred individuals were released back to the wild. PMID- 28732032 TI - Individual- and area-level characteristics associated with alcohol-related mortality among adult Lithuanian males: A multilevel analysis based on census linked data. AB - BACKGROUND: Although excessive alcohol-related mortality in the post-Soviet countries remains the major public health threat, determinants of this phenomenon are still poorly understood. AIMS: We assess simultaneously individual- and area level factors associated with an elevated risk of alcohol-related mortality among Lithuanian males aged 30-64. METHODS: Our analysis is based on a census-linked dataset containing information on individual- and area-level characteristics and death events which occurred between March 1st, 2011 and December 31st, 2013. We limit the analysis to a few causes of death which are directly linked to excessive alcohol consumption: accidental poisonings by alcohol (X45) and liver cirrhosis (K70 and K74). Multilevel Poisson regression models with random intercepts are applied to estimate mortality rate ratios (MRR). RESULTS: The selected individual-level characteristics are important predictors of alcohol related mortality, whereas area-level variables show much less pronounced or insignificant effects. Compared to married men, never married (MRR = 1.9, CI:1.6 2.2), divorced (MRR = 2.6, CI:2.3-2.9), and widowed (MRR = 2.4, CI: 1.8-3.1) men are disadvantaged groups. Men who have the lowest level of educational attainment have the highest mortality risk (MRR = 1.7 CI:1.4-2.1). Being unemployed is associated with a five-fold risk of alcohol-related death (MRR = 5.1, CI: 4.4 5.9), even after adjusting for all other individual variables. Lithuanian males have an advantage over Russian (MRR = 1.3, CI:1.1-1.6) and Polish (MRR = 1.8, CI: 1.5-2.2) males. After adjusting for all individual characteristics, only two out of seven area-level variables-i.e., the share of ethnic minorities in the population and the election turnout-have statistically significant direct associations. These variables contribute to a higher risk of alcohol-related mortality at the individual level. CONCLUSIONS: The huge and increasing socio economic disparities in alcohol-related mortality indicate that recently implemented anti-alcohol measures in Lithuania should be reinforced by specific measures targeting the most disadvantaged population groups and geographical areas. PMID- 28732031 TI - Breast tissue ablation with irreversible electroporation in rabbits: A safety and feasibility study. AB - BACKGROUND AND AIM: Irreversible electroporation (IRE) was confirmed to control several solid tumors effectively in vivo. Our preclinical study aimed to assess the feasibility and safety of IRE in the breast of rabbit. METHODS: Thirty New Zealand white rabbits were randomly divided into 3 groups of 10 rabbits (control group, IRE group A, and B). Two mono-electrode needles were inserted into the breast tissue by percutaneous puncture. Electrocardiogram and vital signs were monitored before, during, and after ablation. Histopathology, immunohistochemistry, and transmission electron microscopy were examined at 0 hours, 12 hours, 24 hours, 4 days, 7 days, 14 days, and 28 days after ablation. RESULTS: All the rabbits survived the procedure with no significant adverse effects. Intra-operative ventricular arrhythmias occurred in 1 rabbit from IRE group B and was immediately relieved after ablation. Reversible subcutaneous hemorrhage was observed in 8 rabbits from IRE group A and 7 rabbits from IRE group B. No skin was burnt, however, pectoralis major muscle injuries were found in all rabbits. Histopathological and ultrastructural examination revealed the coexistence of cell necrosis and apoptosis. HE, TUNEL, and Masson staining revealed breast tissue injury and the recovery of damage by fibrous tissue and granulation tissue. Notably, the structures of mammary gland lobules and interstitial components of the breasts were well preserved. CONCLUSIONS: Our study suggests that IRE destroys breast cancer while effectively preserving the skin, the structure of mammary gland lobules, and interstitial components. IRE may be a promising technique to locally control breast cancer and to maintain the esthetic of the breast. PMID- 28732036 TI - An accurate coarse-grained model for chitosan polysaccharides in aqueous solution. AB - Computational models can provide detailed information about molecular conformations and interactions in solution, which is currently inaccessible by other means in many cases. Here we describe an efficient and precise coarse grained model for long polysaccharides in aqueous solution at different physico chemical conditions such as pH and ionic strength. The Model is carefully constructed based on all-atom simulations of small saccharides and metadynamics sampling of the dihedral angles in the glycosidic links, which represent the most flexible degrees of freedom of the polysaccharides. The model is validated against experimental data for Chitosan molecules in solution with various degree of deacetylation, and is shown to closely reproduce the available experimental data. For long polymers, subtle differences of the free energy maps of the glycosidic links are found to significantly affect the measurable polymer properties. Therefore, for titratable monomers the free energy maps of the corresponding links are updated according to the current charge of the monomers. We then characterize the microscopic and mesoscopic structural properties of large chitosan polysaccharides in solution for a wide range of solvent pH and ionic strength, and investigate the effect of polymer length and degree and pattern of deacetylation on the polymer properties. PMID- 28732030 TI - Identification of odorant binding proteins and chemosensory proteins in Microplitis mediator as well as functional characterization of chemosensory protein 3. AB - Odorant binding proteins (OBPs) and chemosensory proteins (CSPs) play important roles in transporting semiochemicals through the sensillar lymph to olfactory receptors in insect antennae. In the present study, twenty OBPs and three CSPs were identified from the antennal transcriptome of Microplitis mediator. Ten OBPs (MmedOBP11-20) and two CSPs (MmedCSP2-3) were newly identified. The expression patterns of these new genes in olfactory and non-olfactory tissues were investigated by real-time quantitative PCR (qPCR) measurement. The results indicated that MmedOBP14, MmedOBP18, MmedCSP2 and MmedCSP3 were primarily expressed in antennae suggesting potential olfactory roles in M. mediator. However, other genes including MmedOBP11-13, 15-17, 19-20 appeared to be expressed at higher levels in body parts than in antennae. Focusing on the functional characterization of MmedCSP3, immunocytochemistry and fluorescent competitive binding assays were conducted indoors. It was found that MmedCSP3 was specifically located in the sensillum lymph of olfactory sensilla basiconca type 2. The recombinant MmedCSP3 could bind several types of host insects odors and plant volatiles. Interestingly, three sex pheromone components of Noctuidae insects, cis-11-hexadecenyl aldehyde (Z11-16: Ald), cis-11-hexadecanol (Z11-16: OH), and trans-11-tetradecenyl acetate (E11-14: Ac), showed high binding affinities (Ki = 17.24-18.77 MUM). The MmedCSP3 may be involved in locating host insects. Our data provide a base for further investigating the physiological roles of OBPs and CSPs in M. mediator, and extend the function of MmedCSP3 in chemoreception of M. mediator. PMID- 28732037 TI - Integrating cervical cancer with HIV healthcare services: A systematic review. AB - BACKGROUND: Cervical cancer is a major public health problem. Even though readily preventable, it is the fourth leading cause of death in women globally. Women living with HIV are at increased risk of invasive cervical cancer, highlighting the need for access to screening and treatment for this population. Integration of services has been proposed as an effective way of improving access to cervical cancer screening especially in areas of high HIV prevalence as well as lower resourced settings. This paper presents the results of a systematic review of programs integrating cervical cancer and HIV services globally, including feasibility, acceptability, clinical outcomes and facilitators for service delivery. METHODS: This is part of a larger systematic review on integration of services for HIV and non-communicable diseases. To be considered for inclusion studies had to report on programs to integrate cervical cancer and HIV services at the level of service delivery. We searched multiple databases including Global Health, Medline and Embase from inception until December 2015. Articles were screened independently by two reviewers for inclusion and data were extracted and assessed for risk of bias. MAIN RESULTS: 11,057 records were identified initially. 7,616 articles were screened by title and abstract for inclusion. A total of 21 papers reporting interventions integrating cervical cancer care and HIV services met the criteria for inclusion. All but one study described integration of cervical cancer screening services into existing HIV services. Most programs also offered treatment of minor lesions, a 'screen-and-treat' approach, with some also offering treatment of larger lesions within the same visit. Three distinct models of integration were identified. One model described integration within the same clinic through training of existing staff. Another model described integration through co-location of services, with the third model describing programs of integration through complex coordination across the care pathway. The studies suggested that integration of cervical cancer services with HIV services using all models was feasible and acceptable to patients. However, several barriers were reported, including high loss to follow up for further treatment, limited human-resources, and logistical and chain management support. Using visual screening methods can facilitate screening and treatment of minor to larger lesions in a single 'screen-and-treat' visit. Complex integration in a single-visit was shown to reduce loss to follow up. The use of existing health infrastructure and funding together with comprehensive staff training and supervision, community engagement and digital technology were some of the many other facilitators for integration reported across models. CONCLUSIONS: This review shows that integration of cervical cancer screening and treatment with HIV services using different models of service delivery is feasible as well as acceptable to women living with HIV. However, the descriptive nature of most papers and lack of data on the effect on long-term outcomes for HIV or cervical cancer limits the inference on the effectiveness of the integrated programs. There is a need for strengthening of health systems across the care continuum and for high quality studies evaluating the effect of integration on HIV as well as on cervical cancer outcomes. PMID- 28732033 TI - Spatial and simultaneous representative seroprevalence of anti-Toxoplasma gondii antibodies in owners and their domiciled dogs in a major city of southern Brazil. AB - Toxoplasmosis, caused by Toxoplasma gondii, has traditionally been considered an important water and foodborne protozoonosis with important public health considerations. Although felids play a well-established role as definitive hosts, canine epidemiological involvement in the parasite's life cycle remains questionable and controversial. The increasing closeness of the human-dog bond, particularly seen in urban settings, has been recognized as a historically unprecedented worldwide movement. Sharing daily lives in the same households, dogs may be exposed to similar associated risks of T. gondii infection as their owners. Thus, epidemiological assessment of the intra-domiciled environment, especially among socio-economically different human populations, may provide novel information regarding the actual role of dogs in animal and human toxoplasmosis. Despite spatial approaches being recently used for other water and foodborne diseases, no study has been conducted on the simultaneous spatial seroprevalence of both human and animal IgG anti-T. gondii antibodies in urban areas of major cities. Accordingly, the aim of the present study was to assess the seroprevalence and associated variables of Toxoplasma infection in owners and their domiciled dogs in Londrina, southern Brazil. Human and canine seroprevalence rates and variables associated with seroprevalence were investigated through representative random sampling among 564 households, which included 597 owners and 729 dogs. Overall, statistically significant differences between the seroprevalence of human and dog anti-T. gondii antibodies were found by Immunofluorescence Antibody Testing in 248/597 (41.54%) owners and 119/729 (16.32%) dogs. Through multiple analysis, significant concomitant variables for seropositivity of household individuals (people and dogs) were determined, including public sewer service, yard cleaning frequency, and having a dirty yard. Although no statistically significant multiple logistic model was observed among owners, univariate analysis detected associations with monthly income, soil contact, and occupation. Among dogs, the absence of other dogs and the absence of a dirty yard were concomitant significantly protective associated factors. Age differences between seropositive and seronegative individuals was significant only for human beings, with the median age of negative individuals significantly higher than positive individuals. Although no spatial clusters were identified for humans or residences, a significant cluster was identified for dogs. In conclusion, characteristics of urban toxoplasmosis may include significantly higher owner seroprevalence than their owned dogs, with canine seroprevalence directly associated with having more dogs and a dirty backyard, and spatial differences in both human and dog exposures. Although not a good indicator for human foodborne diseases, dogs may be a reliable sentinel for environmental infection. Moreover, such a holistic approach may provide crucial information for more focused prevention and monitoring programs, particularly in households with multiple pets and trash-filled backyards. PMID- 28732039 TI - Abnormal meiosis in an intersectional allotriploid of Populus L. and segregation of ploidy levels in 2x * 3x progeny. AB - Triploid plants are usually highly aborted owing to unbalanced meiotic chromosome segregation, but limited viable gametes can participate in the transition to different ploidy levels. In this study, numerous meiotic abnormalities were found with high frequency in an intersectional allotriploid poplar (Populus alba * P. berolinensis 'Yinzhong'), including univalents, precocious chromosome migration, lagging chromosomes, chromosome bridges, micronuclei, and precocious cytokinesis, indicating high genetic imbalance in this allotriploid. Some micronuclei trigger mini-spindle formation in metaphase II and participate in cytokinesis to form polyads with microcytes. Unbalanced chromosome segregation and chromosome elimination resulted in the formation of microspores with aneuploid chromosome sets. Fusion of sister nuclei occurs in microsporocytes with precocious cytokinesis, which could form second meiotic division restitution (SDR)-type gametes. However, SDR-type gametes likely contain incomplete chromosome sets due to unbalanced segregation of homologous chromosomes during the first meiotic division in triploids. Misorientation of spindles during the second meiotic division, such as fused and tripolar spindles with low frequency, could result in the formation of first meiotic division restitution (FDR)-type unreduced gametes, which most likely contain three complete chromosome sets. Although 'Yinzhong' yields 88.7% stainable pollen grains with wide diameter variation from 23.9 to 61.3 MUm, the pollen viability is poor (2.78% +/- 0.38). A cross of 'Yinzhong' pollen with a diploid female clone produced progeny with extensive segregation of ploidy levels, including 29 diploids, 18 triploids, 4 tetraploids, and 48 aneuploids, suggesting the formation of viable aneuploidy and unreduced pollen in 'Yinzhong'. Individuals with different chromosome compositions are potential to analyze chromosomal function and to integrate the chromosomal dosage variation into breeding programs of Populus. PMID- 28732042 TI - Numerical study on the lubrication performance of compression ring-cylinder liner system with spherical dimples. AB - The effects of surface texture on the lubrication performance of a compression ring-cylinder liner system are studied in this paper. By considering the surface roughness of the compression ring and cylinder liner, a mixed lubrication model is presented to investigate the tribological behaviors of a barrel-shaped compression ring-cylinder liner system with spherical dimples on the liner. In order to determine the rupture and reformulation positions of fluid film accurately, the Jacoboson-Floberg-Olsson (JFO) cavitation boundary condition is applied to the mixed lubrication model for ensuring the mass-conservative law. On this basis, the minimum oil film thickness and average friction forces in the compression ring-cylinder liner system are investigated under the engine-like conditions by changing the dimple area density, radius, and depth. The wear load, average friction forces, and power loss of the compression ring-cylinder liner system with and without dimples are also compared for different compression ring face profiles. The results show that the spherical dimples can produce a larger reduction of friction in mixed lubrication region, and reduce power loss significantly in the middle of the strokes. In addition, higher reduction percentages of average friction forces and wear are obtained for smaller crown height or larger axial width. PMID- 28732040 TI - Perceptions of Arab men regarding female breast cancer screening examinations Findings from a Middle East study. AB - OBJECTIVES: In the Middle East, Qatar in particular, the incidence of breast cancer has substantially increased in recent years, and is expected to double by 2030. This diagnosis also occurs at a later stage in the disease. Early detection along with proper treatment reduces radical mastectomy and mortality rates, yet only one-third of Arab women in Qatar participate in breast cancer screening (BCS) activities of any sort. Many women in the conservative Qatari society rely on male family members for support and protection. This study investigates the attitudes and perceptions of Arab men in regards to breast cancer screening and what they see as both incentives and barriers to women's participation in BCS activities. DESIGN: A qualitative methodology using purposive sampling technique was chosen in order to explore participant's attitudes, beliefs and health related actions. Individual in-depth interviews with open-ended questions were conducted with 50 Arab men during October 2011 to May 2012. Data collection, analysis, and interpretation occurred simultaneously. NVivo 9, a qualitative data analysis software program was used to organize themes and subthemes. RESULTS: It was found that most men understood the importance of regular BCS in early detection of breast cancer. They felt they had an important role in encouraging the women in their lives to participate in BCS activities, but were adamant that any examination must be done by a female health care professional. Few knew details about screening guidelines in Qatar, but most had a basic knowledge of some screening activities. Most indicated an interest in learning more about BC and screening activities in order to better help and inform their female family members. CONCLUSION: Because Arab men perceive that their opinions and support are a major factor influencing female family members' participation in breast cancer screening, it is important that any program instituted to increase such screening participation be aimed at both men and women. More information is needed by both sexes as to the need for and benefits of regular screening activities, the techniques used, and the newly revised guidelines in Qatar. Such a program needs to be introduced in the near future in order to avert, at least partially, the expected doubling in breast cancer cases by 2030 in the Middle East. PMID- 28732035 TI - Vaccine-induced immune responses against both Gag and Env improve control of simian immunodeficiency virus replication in rectally challenged rhesus macaques. AB - The ability to control lentivirus replication may be determined, in part, by the extent to which individual viral proteins are targeted by the immune system. Consequently, defining the antigens that elicit the most protective immune responses may facilitate the design of effective HIV-1 vaccines. Here we vaccinated four groups of rhesus macaques with a heterologous vector prime/boost/boost/boost (PBBB) regimen expressing the following simian immunodeficiency virus (SIV) genes: env, gag, vif, rev, tat, and nef (Group 1); env, vif, rev, tat, and nef (Group 2); gag, vif, rev, tat, and nef (Group 3); or vif, rev, tat, and nef (Group 4). Following repeated intrarectal challenges with a marginal dose of the neutralization-resistant SIVmac239 clone, vaccinees in Groups 1-3 became infected at similar rates compared to control animals. Unexpectedly, vaccinees in Group 4 became infected at a slower pace than the other animals, although this difference was not statistically significant. Group 1 exhibited the best post-acquisition virologic control of SIV infection, with significant reductions in both peak and chronic phase viremia. Indeed, 5/8 Group 1 vaccinees had viral loads of less than 2,000 vRNA copies/mL of plasma in the chronic phase. Vaccine regimens that did not contain gag (Group 2), env (Group 3), or both of these inserts (Group 4) were largely ineffective at decreasing viremia. Thus, vaccine-induced immune responses against both Gag and Env appeared to maximize control of immunodeficiency virus replication. Collectively, these findings are relevant for HIV-1 vaccine design as they provide additional insights into which of the lentiviral proteins might serve as the best vaccine immunogens. PMID- 28732038 TI - Analysis of patient data from laboratories during the Ebola virus disease outbreak in Liberia, April 2014 to March 2015. AB - An outbreak of Ebola virus disease (EVD) in Liberia began in March 2014 and ended in January 2016. Epidemiological information on the EVD cases was collected and managed nationally; however, collection and management of the data were challenging at the time because surveillance and reporting systems malfunctioned during the outbreak. EVD diagnostic laboratories, however, were able to register basic demographic and clinical information of patients more systematically. Here we present data on 16,370 laboratory samples that were tested between April 4, 2014 and March 29, 2015. A total of 10,536 traceable individuals were identified, of whom 3,897 were confirmed cases (positive for Ebola virus RNA). There were significant differences in sex, age, and place of residence between confirmed and suspected cases that tested negative for Ebola virus RNA. Age (young children and the elderly) and place of residence (rural areas) were the risk factors for death due to the disease. The case fatality rate of confirmed cases decreased from 80% to 63% during the study period. These findings may help support future investigations and lead to a fuller understanding of the outbreak in Liberia. PMID- 28732044 TI - The prognostic impact of human papillomavirus status following treatment failure in oropharyngeal cancer. AB - INTRODUCTION: Despite the human papillomavirus conferring a better prognosis in the primary treatment setting, the prognostic impact of viral status after treatment failure in oropharyngeal squamous cell carcinoma patients is poorly understood. METHODS: We retrospectively identified 33 oropharyngeal squamous cell carcinoma (OPC) patients with local and/or distant disease recurrence post treatment, and looked at metastatic patterns, time to failure and survival patterns by HPV status. RESULTS: Median overall survival following local failure was not significantly different by HPV status (17 months for HPV+ vs. 14 months for HPV-, p = 0.23). However, following distant failures, HPV+ patients lived significantly longer than HPV- patients (median 42 months vs. 11 months, p = 0.004). HPV- patients were more likely to have locoregional failures as compared to HPV+ patients (p = 0.005), but the difference in distant failure between both groups was not significant (p = 0.09). HPV+ patients were more likely to develop metastases to sites other than the lung and bones. CONCLUSION: HPV positivity predicts a favorable prognosis with the potential for long-term survival following distant, not locoregional, failures. These results have important implications for the aggressiveness of treatment and type of surveillance imaging performed. PMID- 28732043 TI - Investigation of horizontal gene transfer of pathogenicity islands in Escherichia coli using next-generation sequencing. AB - Horizontal gene transfer (HGT) contributes to the evolution of bacteria. All extraintestinal pathogenic Escherichia coli (ExPEC) harbour pathogenicity islands (PAIs), however relatively little is known about the acquisition of these PAIs. Due to these islands, ExPEC have properties to colonize and invade its hosts efficiently. Even though these PAIs are known to be acquired by HGT, only very few PAIs do carry mobilization and transfer genes required for the transmission by HGT. In this study, we apply for the first time next-generation sequencing (NGS) and in silico analyses in combination with in vitro experiments to decipher the mechanisms of PAI acquisition in ExPEC. For this, we investigated three neighbouring E. coli PAIs, namely the high-pathogenicity island (HPI), the pks and the serU island. As these PAIs contain no mobilization and transfer genes, they are immobile and dependent on transfer vehicles. By whole genome sequencing of the entire E. coli reference (ECOR) collection and by applying a phylogenetic approach we could unambiguously demonstrate that these PAIs are transmitted not only vertically, but also horizontally. Furthermore, we could prove in silico that distinct groups of PAIs were transferred "en bloc" in conjunction with the neighbouring chromosomal backbone. We traced this PAI transfer in vitro using an F' plasmid. Different lengths of transferred DNA were exactly detectable in the sequenced transconjugants indicating NGS as a powerful tool for determination of PAI transfer. PMID- 28732041 TI - Understanding Russell's viper venom factor V activator's substrate specificity by surface plasmon resonance and in-silico studies. AB - Blood coagulation factor V (FV) is activated either by Factor X or thrombin, cleaving at three different sites viz., Site I (Arg709-Ser710), site II (Arg1018 Thr1019), and site III (Arg1545-Ser1546). Russell's viper venom factor V activator (RVV-V) is a thrombin-like serine proteinase that activates FV with selective, single cleavage at site III. A long lasting effort is being pending in understanding the 'selective' binding specificity of the RVV-V towards site III. Here, we present the binding kinetic study of RVV-V with two designed peptides corresponding to the regions from site I (Gln699-Asn713) and site II (1008Lys Pro1022), respectively, that include 15 amino acids. Our investigation for justifying the binding efficacy and kinetics of peptides includes SPR method, protein-peptide docking, molecular dynamics simulation, and principal component analysis (PCA). Surprisingly, the SPR experiment disclosed that the Peptide II showed a lower binding affinity with KD of 2.775 mM while the Peptide I showed none. Docking and simulation of both the peptides with RVV-V engaged either rooted or shallow binding for Peptide II and Peptide I respectively. The peptide binding resulted in global conformational changes in the native fold of RVV-V, whereas the similar studies for thrombin failed to make major changes in the native fold. In support, the PCA analysis for RVV-V showed the dislocation of catalytic triad upon binding both the peptides. Hence, RVV-V, a serine protease, is incompetent in cleaving these two sites. This study suggests a transition in RVV-V from the native rigid to the distorted flexible structure and paves a way to design a new peptide substrate/inhibitor. PMID- 28732050 TI - A Heckman selection model for the safety analysis of signalized intersections. AB - PURPOSE: The objective of this paper is to provide a new method for estimating crash rate and severity simultaneously. METHODS: This study explores a Heckman selection model of the crash rate and severity simultaneously at different levels and a two-step procedure is used to investigate the crash rate and severity levels. The first step uses a probit regression model to determine the sample selection process, and the second step develops a multiple regression model to simultaneously evaluate the crash rate and severity for slight injury/kill or serious injury (KSI), respectively. The model uses 555 observations from 262 signalized intersections in the Hong Kong metropolitan area, integrated with information on the traffic flow, geometric road design, road environment, traffic control and any crashes that occurred during two years. RESULTS: The results of the proposed two-step Heckman selection model illustrate the necessity of different crash rates for different crash severity levels. CONCLUSIONS: A comparison with the existing approaches suggests that the Heckman selection model offers an efficient and convenient alternative method for evaluating the safety performance at signalized intersections. PMID- 28732049 TI - Testing the optimal defense hypothesis in nature: Variation for glucosinolate profiles within plants. AB - Plants employ highly variable chemical defenses against a broad community of herbivores, which vary in their susceptibilities to specific compounds. Variation in chemical defenses within the plant has been found in many species; the ecological and evolutionary influences on this variation, however, are less well understood. One central theory describing the allocation of defenses in the plant is the Optimal Defense Hypothesis (ODH), which predicts that defenses will be concentrated in tissues that are of high fitness value to the plant. Although the ODH has been repeatedly supported within vegetative tissues, few studies have compared vegetative and reproductive tissues, and the results have not been conclusive. We quantified variation in glucosinolate profile and tissue value between vegetative and reproductive tissues in Boechera stricta, a close relative of Arabidopsis. B. stricta manufactures glucosinolates, a set of defensive compounds that vary genetically and are straightforward to quantify. Genetic diversity in glucosinolate profile has been previously demonstrated to be important to both herbivory and fitness in B. stricta; however, the importance of glucosinolate variation among tissues has not. Here, we investigate whether allocation of glucosinolates within the plant is consistent with the ODH. We used both clipping experiments on endogenous plants and ambient herbivory in a large scale transplant experiment at three sites to quantify fitness effects of loss of rosette leaves, cauline leaves, and flowers and fruits. We measured glucosinolate concentration in leaves and fruits in the transplant experiment, and asked whether more valuable tissues were more defended. We also investigated within plant variation in other aspects of the glucosinolate profile. Our results indicated that damage to fruits had a significantly larger effect on overall fitness than damage to leaves, and that fruits had much higher concentrations of glucosinolates, supporting the ODH. This is, to the best of our knowledge, the first study to explicitly compare both tissue value and chemical defense concentrations between vegetative and reproductive tissues under natural conditions. PMID- 28732048 TI - Wolbachia and dengue virus infection in the mosquito Aedes fluviatilis (Diptera: Culicidae). AB - Dengue represents a serious threat to human health, with billions of people living at risk of the disease. Wolbachia pipientis is a bacterial endosymbiont common to many insect species. Wolbachia transinfections in mosquito disease vectors have great value for disease control given the bacterium's ability to spread into wild mosquito populations, and to interfere with infections of pathogens, such as dengue virus. Aedes fluviatilis is a mosquito with a widespread distribution in Latin America, but its status as a dengue vector has not been clarified. Ae. fluviatilis is also naturally infected by the wFlu Wolbachia strain, which has been demonstrated to enhance infection with the avian malarial parasite Plasmodium gallinaceum. We performed experimental infections of Ae. fluviatilis with DENV-2 and DENV-3 isolates from Brazil via injection or oral feeding to provide insight into its competence for the virus. We also examined the effect of the native Wolbachia infection on the virus using a mosquito line where the wFlu infection had been cleared by antibiotic treatment. Through RT qPCR, we observed that Ae. fluviatilis could become infected with both viruses via either method of infection, although at a lower rate than Aedes aegypti, the primary dengue vector. We then detected DENV-2 and DENV-3 in the saliva of injected mosquitoes, and observed that injection of DENV-3-infected saliva produced subsequent infections in naive Ae. aegypti. However, across our data we observed no difference in prevalence of infection and viral load between Wolbachia-infected and -uninfected mosquitoes, suggesting that there is no effect of wFlu on dengue virus. Our results highlight that Ae. fluviatilis could potentially serve as a dengue vector under the right circumstances, although further testing is required to determine if this occurs in the field. PMID- 28732047 TI - In vivo analysis of glaucoma-related features within the optic nerve head using enhanced depth imaging optical coherence tomography. AB - Structural differences between optic nerve head (ONH) parameters in glaucomatous and non-glaucomatous eyes has been documented, however the association between such parameters in patients with different disease stages is yet to be elucidated. We investigated the relationship between different laminar and prelaminar ONH structures using enhanced depth imaging spectral-domain optical coherence tomography (EDI OCT) in a population with and without glaucoma. In this observational case-control study, we prospectively enrolled healthy individuals and glaucomatous patients with different disease stages. All participants underwent EDI OCT imaging (Heidelberg Engineering). Following ONH parameters were measured on serial vertical B-scans by two examiners masked to patient's clinical data: lamina cribrosa (LC) and prelaminar neural tissue (PLNT) thicknesses, Bruch's membrane opening (BMO) and cup depth. Associations between cup depth, and laminar and prelaminar parameters were evaluated controlling for possible confounding factors such as axial length and disc size. Sixty-four eyes of 64 patients were included (30 with glaucoma and 34 controls). Eyes with glaucoma had significantly lower mean LC and PLNT thickness, and greater mean cup depth than controls (p<0.01). There was a significant negative association between PLNT thickness and cup depth in glaucomatous eyes (R2 = 0.158, p = 0.029). In addition, LC thickness correlated significantly with cup depth (R2 = 0.135, p = 0.045). Eyes with thinner LCs presented deeper cups. Overall, cup depth and BMO had the best and LC thickness had the worst intraobserver and interobserver reproducibility grading. In conclusion, significant associations were seen between cup depth, LC and PLNT thickness. Eyes with deeper cups not only had less neural tissue, but also thinner LCs, independent of disc size and axial length. Best reproducibility was found for prelaminar parameters compared to deeper ONH structures. PMID- 28732045 TI - The exported chaperone Hsp70-x supports virulence functions for Plasmodium falciparum blood stage parasites. AB - Malaria is caused by five different Plasmodium spp. in humans each of which modifies the host erythrocyte to survive and replicate. The two main causes of malaria, P. falciparum and P. vivax, differ in their ability to cause severe disease, mainly due to differences in the cytoadhesion of infected erythrocytes (IE) in the microvasculature. Cytoadhesion of P. falciparum in the brain leads to a large number of deaths each year and is a consequence of exported parasite proteins, some of which modify the erythrocyte cytoskeleton while others such as PfEMP1 project onto the erythrocyte surface where they bind to endothelial cells. Here we investigate the effects of knocking out an exported Hsp70-type chaperone termed Hsp70-x that is present in P. falciparum but not P. vivax. Although the growth of Deltahsp70-x parasites was unaffected, the export of PfEMP1 cytoadherence proteins was delayed and Deltahsp70-x IE had reduced adhesion. The Deltahsp70-x IE were also more rigid than wild-type controls indicating changes in the way the parasites modified their host erythrocyte. To investigate the cause of this, transcriptional and translational changes in exported and chaperone proteins were monitored and some changes were observed. We propose that PfHsp70-x is not essential for survival in vitro, but may be required for the efficient export and functioning of some P. falciparum exported proteins. PMID- 28732052 TI - Protein asparagine deamidation prediction based on structures with machine learning methods. AB - Chemical stability is a major concern in the development of protein therapeutics due to its impact on both efficacy and safety. Protein "hotspots" are amino acid residues that are subject to various chemical modifications, including deamidation, isomerization, glycosylation, oxidation etc. A more accurate prediction method for potential hotspot residues would allow their elimination or reduction as early as possible in the drug discovery process. In this work, we focus on prediction models for asparagine (Asn) deamidation. Sequence-based prediction method simply identifies the NG motif (amino acid asparagine followed by a glycine) to be liable to deamidation. It still dominates deamidation evaluation process in most pharmaceutical setup due to its convenience. However, the simple sequence-based method is less accurate and often causes over engineering a protein. We introduce structure-based prediction models by mining available experimental and structural data of deamidated proteins. Our training set contains 194 Asn residues from 25 proteins that all have available high resolution crystal structures. Experimentally measured deamidation half-life of Asn in penta-peptides as well as 3D structure-based properties, such as solvent exposure, crystallographic B-factors, local secondary structure and dihedral angles etc., were used to train prediction models with several machine learning algorithms. The prediction tools were cross-validated as well as tested with an external test data set. The random forest model had high enrichment in ranking deamidated residues higher than non-deamidated residues while effectively eliminated false positive predictions. It is possible that such quantitative protein structure-function relationship tools can also be applied to other protein hotspot predictions. In addition, we extensively discussed metrics being used to evaluate the performance of predicting unbalanced data sets such as the deamidation case. PMID- 28732046 TI - Qualitative differences in cellular immunogenicity elicited by hepatitis C virus T-Cell vaccines employing prime-boost regimens. AB - T-cell based vaccines have been considered as attractive candidates for prevention of hepatitis C virus (HCV) infections. In this study we compared the magnitude and phenotypic characteristics of CD8+ T-cells induced by three commonly used viral vectors, Adenovirus-5 (Ad5), Vaccinia virus (VV) and Modified Vaccinia Ankara (MVA) expressing the HCV NS3/4A protein. C57/BL6 mice were primed with DNA expressing NS3/4A and boosted with each of the viral vectors in individual groups of mice. We then tracked the vaccine-induced CD8+ T-cell responses using pentamer binding and cytokine production analysis. Overall, our data indicate that the memory cells induced by Ad5 were inferior to those induced by VV or MVA. We found that Ad5 boosting resulted in rapid expansion and significantly higher frequencies of NS3-specific T-cells compared to VV and MVA boosting. However, the functional profiles, assessed through analysis of the memory cell marker CD127 and the anti-apoptotic molecule Bcl-2 in the blood, spleen, and liver; and measurements of interferon-gamma, tumor necrosis factor alpha, and interleukin-2 production indicated significantly lower frequencies of long-lived memory T-cells following Ad5 boosting compared to VV and MVA. This same set of analyses suggested that the memory cells induced following boosting with MVA were superior to those induced by both Ad5 and VV. This superiority of the MVA-induced CD8+ T-cells was confirmed following surrogate challenge of mice with a recombinant mouse herpes virus expressing the HCV NS3 protein. Higher levels of NS3-specific CD8+ T-cells displaying the functional markers CD69, Ki67 and Granzyme B were found in the spleens of mice boosted with MVA compared to VV and Ad5, both alone and in combination. These data suggest that MVA may be a more successful viral vector for induction of effective CD8+ T-cell responses against hepatitis C virus. PMID- 28732051 TI - CD4 is expressed on a heterogeneous subset of hematopoietic progenitors, which persistently harbor CXCR4 and CCR5-tropic HIV proviral genomes in vivo. AB - Latent HIV infection of long-lived cells is a barrier to viral clearance. Hematopoietic stem and progenitor cells are a heterogeneous population of cells, some of which are long-lived. CXCR4-tropic HIVs infect a broad range of HSPC subtypes, including hematopoietic stem cells, which are multi-potent and long lived. However, CCR5-tropic HIV infection is limited to more differentiated progenitor cells with life spans that are less well understood. Consistent with emerging data that restricted progenitor cells can be long-lived, we detected persistent HIV in restricted HSPC populations from optimally treated people. Further, genotypic and phenotypic analysis of amplified env alleles from donor samples indicated that both CXCR4- and CCR5-tropic viruses persisted in HSPCs. RNA profiling confirmed expression of HIV receptor RNA in a pattern that was consistent with in vitro and in vivo results. In addition, we characterized a CD4high HSPC sub-population that was preferentially targeted by a variety of CXCR4- and CCR5-tropic HIVs in vitro. Finally, we present strong evidence that HIV proviral genomes of both tropisms can be transmitted to CD4-negative daughter cells of multiple lineages in vivo. In some cases, the transmitted proviral genomes contained signature deletions that inactivated the virus, eliminating the possibility that coincidental infection explains the results. These data support a model in which both stem and non-stem cell progenitors serve as persistent reservoirs for CXCR4- and CCR5-tropic HIV proviral genomes that can be passed to daughter cells. PMID- 28732054 TI - Types of devices used in ridge split procedure for alveolar bone expansion: A systematic review. AB - The aim of this systematic review was to evaluate instrumentation procedures of the alveolar ridge expansion technique (ARST) with or without Guided Bone Regeneration (GBR) and to identify the most used instruments for successful outcome. An electronic as well as manual literature search was conducted in several databases including Medline, Embase, and Cochrane Central Register of Controlled Trials, for articles written in English up to September 2016. The question in focus was to identify the type of device for ridge expansion that is most frequently used and provides adequate bone expansion and implant success rate. To meet the inclusion criteria, the studies were analysed for the following parameters: prospective or retrospective studies, cohort or case studies/series, cases with 5 or more human subjects, type of device used for surgery, location of defect, and minimum follow up period. The frequency of osteotome usage in this study was approximately 65%, and on average, the implant success was 97%. The motorized expanders and ultrasonic surgery system are easier to use and cause less trauma to the bone compared to the traditional/conventional instruments like mallets and osteotomes. However, their cost is a limiting factor; hence, osteotomes remain a popular mode of instrumentation. PMID- 28732055 TI - Role of HTRA1 in bone formation and regeneration: In vitro and in vivo evaluation. AB - The role of mammalian high temperature requirement protease A1 (HTRA1) in somatic stem cell differentiation and mineralized matrix formation remains controversial, having been demonstrated to impart either anti- or pro-osteogenic effects, depending on the in vitro cell model used. The aim of this study was therefore to further evaluate the role of HTRA1 in regulating the differentiation potential and lineage commitment of murine mesenchymal stem cells in vitro, and to assess its influence on bone structure and regeneration in vivo. Our results demonstrated that short hairpin RNA-mediated ablation of Htra1 in the murine mesenchymal cell line C3H10T1/2 increased the expression of several osteogenic gene markers, and significantly enhanced matrix mineralization in response to BMP 2 stimulation. These effects were concomitant with decreases in the expression of chondrogenic gene markers, and increases in adipogenic gene expression and lipid accrual. Despite the profound effects of loss-of-function of HTRA1 on this in vitro osteochondral model, these were not reproduced in vivo, where bone microarchitecture and regeneration in 16-week-old Htra1-knockout mice remained unaltered as compared to wild-type controls. By comparison, analysis of femurs from 52-week-old mice revealed that bone structure was better preserved in Htra1 knockout mice than age-matched wild-type controls. These findings therefore provide additional insights into the role played by HTRA1 in regulating mesenchymal stem cell differentiation, and offer opportunities for improving our understanding of how this multifunctional protease may act to influence bone quality. PMID- 28732056 TI - Inferring microbial interactions in thermophilic and mesophilic anaerobic digestion of hog waste. AB - Anaerobic digestion (AnD) is a microbiological process that converts organic waste materials into biogas. Because of its high methane content, biogas is a combustible energy source and serves as an important environmental technology commonly used in the management of animal waste generated on large animal farms. Much work has been done on hardware design and process engineering for the generation of biogas. However, little is known about the complexity of the microbiology in this process. In particular, how microbes interact in the digester and eventually breakdown and convert organic matter into biogas is still regarded as a "black box." We used 16S rRNA sequencing as a tool to study the microbial community in laboratory hog waste digesters under tightly controlled conditions, and systematically unraveled the distinct interaction networks of two microbial communities from mesophilic (MAnD) and thermophilic anaerobic digestion (TAnD). Under thermophilic conditions, the well-known association between hydrogen-producing bacteria, e.g., Ruminococcaceae and Prevotellaceae, and hydrotrophic methanogens, Methanomicrobiaceae, was reverse engineered by their interactive topological niches. The inferred interaction network provides a sketch enabling the determination of microbial interactive relationships that conventional strategy of finding differential taxa was hard to achieve. This research is still in its infancy, but it can help to depict the dynamics of microbial ecosystems and to lay the groundwork for understanding how microorganisms cohabit in the anaerobic digester. PMID- 28732053 TI - Dysregulation of pulmonary endothelial protein C receptor and thrombomodulin in severe falciparum malaria-associated ARDS relevant to hemozoin. AB - To investigate the role of the protein C system, endothelial protein C receptor (EPCR) and thrombomodulin (TM) in the pathogenesis of malaria-associated acute respiratory distress syndrome (ARDS) in relation to hemozoin and proinflammatory cytokines-induced type II pneumocyte injury and -aggravated pulmonary resolution. A total of 29 left-over lung specimens that were obtained from patients who died from severe falciparum malaria were examined. Histopathological, immunohistochemical and electron microscopic analyses revealed that ARDS coexisted with pulmonary edema and systemic bleeding; the severity was dependent on the level of hemozoin deposition in the lung and internal alveolar hemorrhaging. The loss of EPCR and TM was primarily identified in ARDS patients and was related to the level of hemozoin, parasitized red blood cell (PRBC) and white blood cell accumulation in the lung. Moreover, an in vitro analysis demonstrated that interleukin-13 and -31 and hemozoin induced pneumocytic cell injury and apoptosis, as assessed by EB/AO staining, electron microscopy and the up-regulation of CARD-9 mRNA (caspase recruitment domain-9 messenger-ribonucleic acid). The dysregulation of EPCR and TM in the lung, especially in those with increased levels of hemozoin, may play an important role in the pathogenesis of malaria-associated ARDS through an apoptotic pathway. PMID- 28732059 TI - ECIS technology reveals that monocytes isolated by CD14+ve selection mediate greater loss of BBB integrity than untouched monocytes, which occurs to a greater extent with IL-1beta activated endothelium in comparison to TNFalpha. AB - BACKGROUND: We have previously shown that TNFalpha and IL-1beta differentially regulate the inflammatory phenotype of human brain endothelial cells (hCMVECs). In this regard, IL-1beta treatment was considerably more potent than TNFalpha at increasing expression of inflammatory chemokines and leukocyte adhesion molecules. We therefore hypothesised that interaction of the hCMVECs with human monocytes would also be dependent on the activation status of the endothelium. Therefore, the primary aim of this study was to assess whether brain endothelial cells activated by IL-1beta or TNFalpha differed in their interaction with monocytes. METHODS: Monocyte interaction was measured using the real time, label free impedance based ECIS technology, to evaluate endothelial barrier integrity during monocyte attachment and transendothelial migration. RESULTS: ECIS technology revealed that there was a greater loss of barrier integrity with IL 1beta activation and this loss lasted for longer. This was expected and consistent with our hypothesis. However, more striking and concerning was the observation that the method of monocyte enrichment greatly influenced the extent of endothelial barrier compromise. Importantly, we observed that positively isolated monocytes (CD14+ve) caused greater reduction in barrier resistance, than the negatively selected monocytes (untouched). Analysis of the isolated monocyte populations revealed that the CD14+ve isolation consistently yields highly pure monocytes (>92%), whereas the untouched isolation was much more variable, yielding ~70% enrichment on average. These two enrichment methods were compared as it was thought that the presence of non-classical CD16hi monocytes in the untouched enrichment may mediate greater compromise than the classical CD14hi monocytes. This however, was not the case and these observations raise a number of important considerations pertaining to the enrichment strategy, which are essential for generating reliable and consistent data. CONCLUSIONS: We conclude that IL-1beta and TNFalpha differentially influence monocyte interaction with brain endothelial cells and moreover, the enrichment method also influences the monocyte response as revealed using ECIS technology. PMID- 28732057 TI - Structural basis of Zn(II) induced metal detoxification and antibiotic resistance by histidine kinase CzcS in Pseudomonas aeruginosa. AB - Pseudomonas aeruginosa (P. aeruginosa) is a major opportunistic human pathogen, causing serious nosocomial infections among immunocompromised patients by multi determinant virulence and high antibiotic resistance. The CzcR-CzcS signal transduction system in P. aeruginosa is primarily involved in metal detoxification and antibiotic resistance through co-regulating cross-resistance between Zn(II) and carbapenem antibiotics. Although the intracellular regulatory pathway is well-established, the mechanism by which extracellular sensor domain of histidine kinase (HK) CzcS responds to Zn(II) stimulus to trigger downstream signal transduction remains unclear. Here we determined the crystal structure of the CzcS sensor domain (CzcS SD) in complex with Zn(II) at 1.7 A resolution. This is the first three-dimensional structural view of Zn(II)-sensor domain of the two component system (TCS). The CzcS SD is of alpha/beta-fold in nature, and it senses the Zn(II) stimulus at micromole level in a tetrahedral geometry through its symmetry-related residues (His55 and Asp60) on the dimer interface. Though the CzcS SD resembles the PhoQ-DcuS-CitA (PDC) superfamily member, it interacts with the effector in a novel domain with the N-terminal alpha-helices rather than the conserved beta-sheets pocket. The dimerization of the N-terminal H1 and H1' alpha-helices is of primary importance for the activity of HK CzcS. This study provides preliminary insight into the molecular mechanism of Zn(II) sensing and signaling transduction by the HK CzcS, which will be beneficial to understand how the pathogen P. aeruginosa resists to high levels of heavy metals and antimicrobial agents. PMID- 28732060 TI - Formation of singlet oxygen by decomposition of protein hydroperoxide in photosystem II. AB - Singlet oxygen (1O2) is formed by triplet-triplet energy transfer from triplet chlorophyll to O2 via Type II photosensitization reaction in photosystem II (PSII). Formation of triplet chlorophyll is associated with the change in spin state of the excited electron and recombination of triplet radical pair in the PSII antenna complex and reaction center, respectively. Here, we have provided evidence for the formation of 1O2 by decomposition of protein hydroperoxide in PSII membranes deprived of Mn4O5Ca complex. Protein hydroperoxide is formed by protein oxidation initiated by highly oxidizing chlorophyll cation radical and hydroxyl radical formed by Type I photosensitization reaction. Under highly oxidizing conditions, protein hydroperoxide is oxidized to protein peroxyl radical which either cyclizes to dioxetane or recombines with another protein peroxyl radical to tetroxide. These highly unstable intermediates decompose to triplet carbonyls which transfer energy to O2 forming 1O2. Data presented in this study show for the first time that 1O2 is formed by decomposition of protein hydroperoxide in PSII membranes deprived of Mn4O5Ca complex. PMID- 28732064 TI - Mechanisms of aggregation in an ant-tended treehopper: Attraction to mutualists is balanced by conspecific competition. AB - Understanding the spatial structure of populations and communities has been a dominant focus of ecological research, and spatial structure is increasingly seen as critical for understanding population dynamics. Habitat (or host) preference is a proximate mechanism that can generate aggregation or overdispersion, lending insight into the ultimate consequences of observed spatial distributions. Publilia concava is a univoltine phloem-feeding insect that forms mutualistic associations with ants, which consume honeydew and protect treehoppers from predation. Treehopper adults and nymphs are aggregated at the scale of goldenrod plant stems, and previous studies have suggested that this aggregation is an adaptive response that increases feeding performance or maximizes benefits of ant tending. Previous studies have also shown experimentally that individual treehoppers preferentially oviposit on plants with ants present, but a complimentary hypothesis that treehoppers prefer to oviposit near conspecifics (e.g., to take advantage of density-dependent ant attraction) remains untested. We show that, as expected, the probability of treehopper oviposition increases with ant-presence and relative ant abundance. However, we also find that treehopper oviposition decreases with increasing treehopper density. Thus our results are inconsistent with the hypothesis that treehopper aggregation is a socially cooperative strategy to attract ants; we suggest that aggregation is a form of conflict and an unavoidable by-product of individual responses to ant tending levels. PMID- 28732062 TI - A Drosophila model for toxicogenomics: Genetic variation in susceptibility to heavy metal exposure. AB - The genetic factors that give rise to variation in susceptibility to environmental toxins remain largely unexplored. Studies on genetic variation in susceptibility to environmental toxins are challenging in human populations, due to the variety of clinical symptoms and difficulty in determining which symptoms causally result from toxic exposure; uncontrolled environments, often with exposure to multiple toxicants; and difficulty in relating phenotypic effect size to toxic dose, especially when symptoms become manifest with a substantial time lag. Drosophila melanogaster is a powerful model that enables genome-wide studies for the identification of allelic variants that contribute to variation in susceptibility to environmental toxins, since the genetic background, environmental rearing conditions and toxic exposure can be precisely controlled. Here, we used extreme QTL mapping in an outbred population derived from the D. melanogaster Genetic Reference Panel to identify alleles associated with resistance to lead and/or cadmium, two ubiquitous environmental toxins that present serious health risks. We identified single nucleotide polymorphisms (SNPs) associated with variation in resistance to both heavy metals as well as SNPs associated with resistance specific to each of them. The effects of these SNPs were largely sex-specific. We applied mutational and RNAi analyses to 33 candidate genes and functionally validated 28 of them. We constructed networks of candidate genes as blueprints for orthologous networks of human genes. The latter not only provided functional contexts for known human targets of heavy metal toxicity, but also implicated novel candidate susceptibility genes. These studies validate Drosophila as a translational toxicogenomics gene discovery system. PMID- 28732058 TI - The role of a FADS1 polymorphism in the association of fatty acid blood levels, BMI and blood pressure in young children-Analyses based on path models. AB - BACKGROUND: The recent obesity epidemic in children also showed an increase in the prevalence of hypertension. As blood pressure (BP) is associated with (long chain) polyunsaturated fatty acids (LC PUFA), genetic variation in desaturase enzymes being involved in the synthesis of LC PUFA may be associated with BP. This study aimed to investigate the direct effects (independent of mediating variables) and indirect effects (mediated through intermediate variables) of a common variant in the FADS1 gene, rs174546, known to affect delta-5 desaturase (D5D) activity on PUFA level, body mass index (BMI) and BP. METHODS: A subsample of the IDEFICS (Identification and prevention of dietary- and lifestyle-induced health effects in children and infants) baseline survey including 520 children aged 2 to <10 years from six European countries was included. The association between rs174546 (T100kb from the nearest TSS. The majority of pSTAT5 peaks contain a central palindromic GAS element, TTCYXRGAA. There was significant enrichment for GATA motifs and CACCC box motifs within the neighbourhood of pSTAT5-bound peaks, and GATA1 and/or KLF1 co-occupancy at many sites. Using 4sU-RNA-seq we determined the EPO-induced transcriptome and validated differentially expressed genes using dynamic CAGE data and qRT-PCR. We identified known direct pSTAT5 target genes such as Bcl2l1, Pim1 and Cish, and many new targets likely to be involved in driving erythroid cell differentiation including those involved in mRNA splicing (Rbm25), epigenetic regulation (Suv420h2), and EpoR turnover (Clint1/EpsinR). Some of these new EpoR-JAK2-pSTAT5 target genes could be used as biomarkers for monitoring disease activity in polycythaemia vera, and for monitoring responses to JAK inhibitors. PMID- 28732073 TI - First-trimester fetal growth restriction and the occurrence of miscarriage in rural Bangladesh: A prospective cohort study. AB - Fetal growth restriction in early pregnancy increases the risk of adverse pregnancy outcome, which has a significant social and psychological impact on women. There is limited information related to community-based study to evaluate early indicators related to miscarriage. The aim of this study is to examine the relationship between fetal growth restriction, measured by ultrasound crown-rump length (CRL), and subsequent occurrence of miscarriage in pregnant women in rural Bangladesh. The study was conducted within the Maternal and Infant Nutrition Interventions Trial in Matlab (MINIMat study), Bangladesh. A total of 4436 pregnant women were enrolled in the study when they were at less than 14 gestational weeks. The expected CRL was determined based on an established growth curve of gestational age and CRL, and deviation from this curve of CRL was expressed as a z-score. After identifying related covariates, the multiple Poisson regression model was used to determine the independent contribution from the CRL to miscarriage. A total of 3058 singleton pregnant women were included in analyses, with 92 miscarriages and 2966 continued pregnancies. The occurrence of miscarriages was significantly higher in the smaller categories of CRL z-score after adjustments for maternal age, parity, early pregnancy BMI, gestational age at CRL measurement and socioeconomic status (adjusted relative risk [95% confidence interval]: 1.03 [1.02-1.05] for less than -2 z-score). In a rural Bangladesh population, smaller than expected CRL for the gestational age was related to subsequent miscarriage. Ultrasound biometry information together with careful clinical assessment should provide much needed attention and care for pregnant women. PMID- 28732074 TI - Who uses running apps and sports watches? Determinants and consumer profiles of event runners' usage of running-related smartphone applications and sports watches. AB - Individual and unorganized sports with a health-related focus, such as recreational running, have grown extensively in the last decade. Consistent with this development, there has been an exponential increase in the availability and use of electronic monitoring devices such as smartphone applications (apps) and sports watches. These electronic devices could provide support and monitoring for unorganized runners, who have no access to professional trainers and coaches. The purpose of this paper is to gain insight into the characteristics of event runners who use running-related apps and sports watches. This knowledge is useful from research, design, and marketing perspectives to adequately address unorganized runners' needs, and to support them in healthy and sustainable running through personalized technology. Data used in this study are drawn from the standardized online Eindhoven Running Survey 2014 (ERS14). In total, 2,172 participants in the Half Marathon Eindhoven 2014 completed the questionnaire (a response rate of 40.0%). Binary logistic regressions were used to analyze the impact of socio-demographic variables, running-related variables, and psychographic characteristics on the use of running-related apps and sports watches. Next, consumer profiles were identified. The results indicate that the use of monitoring devices is affected by socio-demographics as well as sports related and psychographic variables, and this relationship depends on the type of monitoring device. Therefore, distinctive consumer profiles have been developed to provide a tool for designers and manufacturers of electronic running-related devices to better target (unorganized) runners' needs through personalized and differentiated approaches. Apps are more likely to be used by younger, less experienced and involved runners. Hence, apps have the potential to target this group of novice, less trained, and unorganized runners. In contrast, sports watches are more likely to be used by a different group of runners, older and more experienced runners with higher involvement. Although apps and sports watches may potentially promote and stimulate sports participation, these electronic devices do require a more differentiated approach to target specific needs of runners. Considerable efforts in terms of personalization and tailoring have to be made to develop the full potential of these electronic devices as drivers for healthy and sustainable sports participation. PMID- 28732070 TI - Characterization of human enterovirus71 virus-like particles used for vaccine antigens. AB - Human enterovirus 71 (EV71) is a major causative pathogen of hand, foot and mouth disease (HFMD) and has caused outbreaks with significant mortality among young children in the Asia-Pacific region in recent years. Towards developing a vaccine for this disease, we have expressed and purified EV71 virus-like particles (VLPs), which resemble the authentic virus in appearance, capsid structure and protein sequence, from insect cells (Sf9) using a multistep chromatography process. We demonstrated intracellular localization of the VLPs in host cells by in situ immunogold detection, electron microscopy and immunofluorescence. Characteristics of these EV71 VLPs were studied using a variety of immunological and physicochemical techniques, which aimed to reveal that the purified EV71 VLPs have good morphology and structure consistent with natural EV71 empty capsids. Results of the amino acid analysis, SDS-PAGE, Western blotting and high performance liquid chromatography confirmed the high purity of the EV71 VLPs. However the sedimentation coefficient of the VLPs showed that they were smaller than that of secreted EV71 VLPs purified by discontinuous cesium chloride density gradients, they were similar to the empty capsids of natural EV71 virions reported previously. Combined with the previous study that EV71 VLPs purified by a multistep chromatography process were able to elicit strong humoral immune responses in mice, our results further supported the conclusion that our EV71 VLPs had well-preserved molecular and structural characteristics. The EV71 VLPs produced from the baculovirus expression system and purified by a multistep chromatography process displayed key structural and immunological features, which would contribute to their efficacy as a HFMD vaccine. PMID- 28732075 TI - Comprehensive selection of reference genes for quantitative RT-PCR analysis of murine extramedullary hematopoiesis during development. AB - The purpose of this study was to perform a comprehensive evaluation and selection of reference genes for the study of extramedullary hematopoiesis during development and the early post-natal period. A total of six candidate reference genes (ACTB, GAPDH, HPRT1, PPID, TBP, TUBB3) in four organs (heart, liver, spleen, and thymus) over five perinatal time points (Embryonic days 14.5, 16.5, 18.5, Post-natal days 0, 21) were evaluated by quantitative real-time PCR. The expression stability of the candidate reference genes were analyzed using geNorm, NormFinder, Bestkeeper, Delta CT method, and RefFinder software packages. Detailed methodology for isolation of high quality/purity RNA and analysis is presented. Detailed analysis demonstrated that TBP is the best single reference gene for embryonic samples and HPRT1 is the best single reference gene for post natal and pooled embryonic and post-natal samples. Organ-level analysis demonstrated that HPRT1 was the most suitable reference gene for heart, liver and thymus samples, while TBP was the best candidate for spleen samples. In general, TUBB3 was consistently the least stable gene for normalization. This is the first study to describe a systematic comprehensive selection of reference genes for murine extramedullary hematopoietic tissues over a developmental time course. We provide suggested reference genes for individual tissues and developmental stages and propose that a combination of reference genes affords flexibility in experimental design and analysis. PMID- 28732069 TI - Saccharomyces boulardii CNCM I-745 supplementation reduces gastrointestinal dysfunction in an animal model of IBS. AB - BACKGROUND: We evaluated the effect of Saccharomyces boulardii CNCM I-745 on intestinal neuromuscular anomalies in an IBS-type mouse model of gastrointestinal motor dysfunctions elicited by Herpes Simplex Virus type 1 (HSV-1) exposure. METHODS: Mice were inoculated intranasally with HSV-1 (102 PFU) or vehicle at time 0 and 4 weeks later by the intragastric (IG) route (108 PFU). Six weeks after IG inoculum, mice were randomly allocated to receive oral gavage with either S. boulardii (107 CFU/day) or vehicle. After 4 weeks the following were determined: a) intestinal motility using fluorescein-isothiocyanate dextran distribution in the gut, fecal pellet expulsion, stool water content, and distal colonic transit of glass beads; b) integrity of the enteric nervous system (ENS) by immunohistochemistry on ileal whole-mount preparations and western blot of protein lysates from ileal longitudinal muscle and myenteric plexus; c) isometric muscle tension with electric field and pharmacological (carbachol) stimulation of ileal segments; and d) intestinal inflammation by levels of tumor necrosis factor alpha, interleukin(IL)-1beta, IL-10 and IL-4. RESULTS: S. boulardii CNCM I-745 improved HSV-1 induced intestinal dysmotility and alteration of intestinal transit observed ten weeks after IG inoculum of the virus. Also, the probiotic yeast ameliorated the structural alterations of the ENS induced by HSV-1 (i.e., reduced peripherin immunoreactivity and expression, increased glial S100beta protein immunoreactivity and neuronal nitric oxide synthase level, reduced substance P-positive fibers). Moreover, S. boulardii CNCM I-745 diminished the production of HSV-1 associated pro-inflammatory cytokines in the myenteric plexus and increased levels of anti-inflammatory interleukins. CONCLUSIONS: S. boulardii CNCM I-745 ameliorated gastrointestinal neuromuscular anomalies in a mouse model of gut dysfunctions typically observed with irritable bowel syndrome. PMID- 28732071 TI - The ideas about advanced life support and affecting factors at the end-stage of life in a hospital in Turkey. AB - BACKGROUND: The participation of the people in health decisions may be structured in various levels. One of these is participation in decisions for the treatment. "Advanced directives" is one of the examples for the participation in decisions for the treatment. AIM: We wanted to determine the decisions on advanced life support at the end-stage of life in case of a life-threatening illness for the people themselves and their first degree relatives and the factors effecting these decisions. DESIGN AND SETTING: The cross-sectional study was conducted with volunteers among patients and patient relatives who applied to all polyclinics of the Ankara Numune Training and Research Hospital except the emergency, oncology and psychiatry polyclinics between 15.12.2012 and 15.03.2013. METHOD: A questionnaire, the Hospital Anxiety Depression (HAD) scale, and Templer's Death Anxiety Scale (TDA) were applied to all individuals. SPSS for Win. Ver. 17.0 and MS-Excel 2010 Starter software bundles were used for all statistical analysis and calculations. RESULTS: The participants want both themselves and their first degree relatives included in end-stage decision-making process. Therefore, the patients and their families should be informed adequately during decision making process and quality communication must be provided. CONCLUSION: Participants who have given their end-stage decisions previously want to be treated according to these decisions. This desire can just be possible by advanced directives.When moral and material loads of end-stage process are taken into consideration, countries, in which advanced directives are practiced, should be examined well and participants' desire should be evaluated in terms of practicability. PMID- 28732067 TI - Thromboembolic adverse event study of combined estrogen-progestin preparations using Japanese Adverse Drug Event Report database. AB - Combined estrogen-progestin preparations (CEPs) are associated with thromboembolic (TE) side effects. The aim of this study was to evaluate the incidence of TE using the Japanese Adverse Drug Event Report (JADER) database. Adverse events recorded from April 2004 to November 2014 in the JADER database were obtained from the Pharmaceuticals and Medical Devices Agency (PMDA) website (www.pmda.go.jp). We calculated the reporting odds ratios (RORs) of suspected CEPs, analyzed the time-to-onset profile, and assessed the hazard type using Weibull shape parameter (WSP). Furthermore, we used the applied association rule mining technique to discover undetected relationships such as the possible risk factors. The total number of reported cases in the JADER contained was 338,224. The RORs (95% confidential interval, CI) of drospirenone combined with ethinyl estradiol (EE, Dro-EE), norethisterone with EE (Ne-EE), levonorgestrel with EE (Lev-EE), desogestrel with EE (Des-EE), and norgestrel with EE (Nor-EE) were 56.2 (44.3-71.4), 29.1 (23.5-35.9), 42.9 (32.3-57.0), 44.7 (32.7-61.1), and 38.6 (26.3 56.7), respectively. The medians (25%-75%) of the time-to-onset of Dro-EE, Ne-EE, Lev-EE, Des-EE, and Nor-EE were 150.0 (75.3-314.0), 128.0 (27.0-279.0), 204.0 (44.0-660.0), 142.0 (41.3-344.0), and 16.5 (8.8-32.0) days, respectively. The 95% CIs of the WSP-beta for Ne-EE, Lev-EE, and Nor-EE were lower and excluded 1. Association rule mining indicated that patients with anemia had a potential risk of developing a TE when using CEPs. Our results suggest that it is important to monitor patients administered CEP for TE. Careful observation is recommended, especially for those using Nor-EE, and this information may be useful for efficient therapeutic planning. PMID- 28732068 TI - Effects of liver-stage clearance by Primaquine on gametocyte carriage of Plasmodium vivax and P. falciparum. AB - BACKGROUND: Primaquine (PQ) is the only currently licensed antimalarial that prevents Plasmodium vivax (Pv) relapses. It also clears mature P. falciparum (Pf) gametocytes, thereby reducing post-treatment transmission. Randomized PQ treatment in a treatment-to-reinfection cohort in Papua New Guinean children permitted the study of Pv and Pf gametocyte carriage after radical cure and to investigate the contribution of Pv relapses. METHODS: Children received radical cure with Chloroquine, Artemether-Lumefantrine plus either PQ or placebo. Blood samples were subsequently collected in 2-to 4-weekly intervals over 8 months. Gametocytes were detected by quantitative reverse transcription-PCR targeting pvs25 and pfs25. RESULTS: PQ treatment reduced the incidence of Pv gametocytes by 73%, which was comparable to the effect of PQ on incidence of blood-stage infections. 92% of Pv and 79% of Pf gametocyte-positive infections were asymptomatic. Pv and to a lesser extent Pf gametocyte positivity and density were associated with high blood-stage parasite densities. Multivariate analysis revealed that the odds of gametocytes were significantly reduced in mixed-species infections compared to single-species infections for both species (ORPv = 0.39 [95% CI 0.25-0.62], ORPf = 0.33 [95% CI 0.18-0.60], p<0.001). No difference between the PQ and placebo treatment arms was observed in density of Pv gametocytes or in the proportion of Pv infections that carried gametocytes. First infections after blood-stage and placebo treatment, likely caused by a relapsing hypnozoite, were equally likely to carry gametocytes than first infections after PQ treatment, likely caused by an infective mosquito bite. CONCLUSION: Pv relapses and new infections are associated with similar levels of gametocytaemia. Relapses thus contribute considerably to the Pv reservoir highlighting the importance of effective anti-hypnozoite treatment for efficient control of Pv. TRIAL REGISTRATION: ClinicalTrials.gov NCT02143934. PMID- 28732072 TI - Placental peptides metabolism and maternal factors as predictors of risk of gestational diabetes in pregnant women. A case-control study. AB - BACKGROUND: Gestational diabetes is a risk factor for perinatal complications; include shoulder dystocia, birth injuries such as bone fractures and nerve palsies. It is associated with later development of type 2 diabetes, the risk of macrosomia and other long-term health effects of infants born to diabetic mothers. The study assesses placental peptides and maternal factors as potential predictors of gestational diabetes among pregnant women. MATERIAL AND METHODS: A total of 200 pregnant women were recruited for the study, 150 pregnant women without pre gestational diabetes including 50 women with low risk factors of diabetes as controls and 50 other pregnant women with pregestational diabetes as control. Fasting blood glucose and the lipid profile were determined by enzymatic methods using Envoy(r) 500 reagents (Vital Diagnostics, USA). Glycated haemoglobin was assessed using the Cation Exchange resin method. Leptin and the Human Placenta Lactogen were assayed using the Sandwich-ELISA technique. Beta chorionic gonadotrophin, insulin, progesterone and estradiol were determined using chemilumiscence imunoassay technique on MAGLUMI 600 analyzer. Anthropometry, including BMI and blood pressure were also measured. RESULTS: Fasting plasma glucose (FBG), insulin, insulin resistance, glycated haemoglobin and Human Placenta Lactogen(HPL)were significantly (p<0.0001) increased in the pregestational diabetic women whereas progesterone and estradiol were significantly decreased. In the second trimester however, there was no significant difference (p>0.05) in estradiol, insulin, insulin resistance and HPL between the pregnant women who developed gestational diabetes and those who did not. Leptin, progesterone and FBG were significantly increased in those who developed GDM. The risk of developing gestational diabetes increased with overweight (OR = 1.76, P = 0.370) and family history of diabetes (OR = 2.18, P = 0.282). CONCLUSION: Leptin, progesterone, estradiol estimated in this study were increased in the gestational diabetes mellitus women and fairly predicted gestational diabetes in the non-diabetics pregnant women. Obesity, aging and family history of diabetes were strongly predictive of gestational diabetes. PMID- 28732076 TI - EINCR1 is an EGF inducible lincRNA overexpressed in lung adenocarcinomas. AB - Long non-coding RNAs are being increasingly recognised as important molecules involved in regulating a diverse array of biological functions. For example, many long non-coding RNAs have been associated with tumourigenesis and in this context their molecular functions often involves impacting on chromatin and transcriptional control processes. One important cellular control system that is often deregulated in cancer cells is the ERK MAP kinase pathway. Here we have investigated whether ERK pathway signaling in response to EGF stimulation, leads to changes in the production of long non-coding RNAs. We identify several different classes of EGF pathway-regulated lncRNAs. We focus on one of the inducible lincRNAs, EGF inducible long intergenic non-coding RNA 1 (EINCR1). EINCR1 is predominantly nuclear and shows delayed activation kinetics compared to other immediate-early EGF-inducible genes. In humans it is expressed in a tissue specific manner and is mainly confined to the heart but it exhibits little evolutionary conservation. Importantly, in several cancers EINCR1 shows elevated expression levels which correlate with poor survival in lung adenocarcinoma patients. In the context of lung adenocarcinomas, EINCR1 expression is anti correlated with the expression of several protein coding EGF-regulated genes. A potential functional connection is demonstrated as EINCR1 overexpression is shown to reduce the expression of EGF-regulated protein coding genes including FOS and FOSB. PMID- 28732077 TI - Mutations in the Caenorhabditis elegans orthologs of human genes required for mitochondrial tRNA modification cause similar electron transport chain defects but different nuclear responses. AB - Several oxidative phosphorylation (OXPHOS) diseases are caused by defects in the post-transcriptional modification of mitochondrial tRNAs (mt-tRNAs). Mutations in MTO1 or GTPBP3 impair the modification of the wobble uridine at position 5 of the pyrimidine ring and cause heart failure. Mutations in TRMU affect modification at position 2 and cause liver disease. Presently, the molecular basis of the diseases and why mutations in the different genes lead to such different clinical symptoms is poorly understood. Here we use Caenorhabditis elegans as a model organism to investigate how defects in the TRMU, GTPBP3 and MTO1 orthologues (designated as mttu-1, mtcu-1, and mtcu-2, respectively) exert their effects. We found that whereas the inactivation of each C. elegans gene is associated with a mild OXPHOS dysfunction, mutations in mtcu-1 or mtcu-2 cause changes in the expression of metabolic and mitochondrial stress response genes that are quite different from those caused by mttu-1 mutations. Our data suggest that retrograde signaling promotes defect-specific metabolic reprogramming, which is able to rescue the OXPHOS dysfunction in the single mutants by stimulating the oxidative tricarboxylic acid cycle flux through complex II. This adaptive response, however, appears to be associated with a biological cost since the single mutant worms exhibit thermosensitivity and decreased fertility and, in the case of mttu 1, longer reproductive cycle. Notably, mttu-1 worms also exhibit increased lifespan. We further show that mtcu-1; mttu-1 and mtcu-2; mttu-1 double mutants display severe growth defects and sterility. The animal models presented here support the idea that the pathological states in humans may initially develop not as a direct consequence of a bioenergetic defect, but from the cell's maladaptive response to the hypomodification status of mt-tRNAs. Our work highlights the important association of the defect-specific metabolic rewiring with the pathological phenotype, which must be taken into consideration in exploring specific therapeutic interventions. PMID- 28732078 TI - Impact of diabetes mellitus on indeterminate results of the QuantiFERON TB Gold In-Tube test: A propensity score matching analysis. AB - BACKGROUND: The sensitivity of interferon-gamma release assays (IGRAs) in the detection of Mycobacterium tuberculosis infection could be affected by conditions of immune dysregulation. For this reason, diabetes mellitus (DM) may increase the frequency of indeterminate results of IGRAs. However, there have been inconsistent reports of role of DM on indeterminate IGRA results. METHODS: We retrospectively reviewed all patients who underwent QuantiFERON-TB Gold In-Tube testing (QFT-GIT) at Chonnam National University Hospital. We collected the clinical and laboratory data of these patients. RESULTS: Of all 3,391 subjects, 1,265 (37.3%) had a positive QFT-GIT result, 266 (7.8%) had an indeterminate result, and 1,860 (54.9%) had a negative result. The mean age was 54.8 +/- 18.1 years and 55.0% of the patients were male. There were 512 (15.1%) patients with DM. Multivariable analysis revealed that systemic corticosteroid use, tuberculosis, lymphocytopenia, low serum albumin, and high serum C-reactive protein (CRP) levels were significantly associated with indeterminate QFT-GIT results. However, DM was not associated with indeterminate QFT-GIT results (adjusted odds ratio, 0.98; 95% confidence interval, 0.69-1.41; P = 0.939). After propensity score matching, DM was not associated with indeterminate results of QFT-GIT. CONCLUSION: In this large cohort study, DM does not affect the incidence of indeterminate results of QFT-GIT. PMID- 28732080 TI - Age-related decrements in dual-task performance: Comparison of different mobility and cognitive tasks. A cross sectional study. AB - This cross-sectional study investigated the age-related differences in dual-task performance both in mobility and cognitive tasks and the additive dual-task costs in a sample of older, middle-aged and young adults. 74 older adults (M = 72.63+/ 5.57 years), 58 middle-aged adults (M = 46.69+/-4.68 years) and 63 young adults (M = 25.34+/-3.00 years) participated in the study. Participants performed different mobility and subtraction tasks under both single- and dual-task conditions. Linear regressions, repeated-measures and one-way analyses of covariance were used, The results showed: significant effects of the age on the dual and mobility tasks (p<0.05) and differences among the age-groups in the combined dual-task costs (p<0.05); significant decreases in mobility performance under dual-task conditions in all groups (p<0.05) and a decrease in cognitive performance in the older group (p<0.05). Dual-task activity affected mobility and cognitive performance, especially in older adults who showed a higher dual-task cost, suggesting that dual-tasks activities are affected by the age and consequently also mobility and cognitive tasks are negatively influenced. PMID- 28732079 TI - LMP1-mediated glycolysis induces myeloid-derived suppressor cell expansion in nasopharyngeal carcinoma. AB - Myeloid-derived suppressor cells (MDSCs) are expanded in tumor microenvironments, including that of Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC). The link between MDSC expansion and EBV infection in NPC is unclear. Here, we show that EBV latent membrane protein 1 (LMP1) promotes MDSC expansion in the tumor microenvironment by promoting extra-mitochondrial glycolysis in malignant cells, which is a scenario for immune escape initially suggested by the frequent, concomitant detection of abundant LMP1, glucose transporter 1 (GLUT1) and CD33+ MDSCs in tumor sections. The full process has been reconstituted in vitro. LMP1 promotes the expression of multiple glycolytic genes, including GLUT1. This metabolic reprogramming results in increased expression of the Nod-like receptor family protein 3 (NLRP3) inflammasome, COX-2 and P-p65 and, consequently, increased production of IL-1beta, IL-6 and GM-CSF. Finally, these changes in the environment of malignant cells result in enhanced NPC-derived MDSC induction. One key step is the physical interaction of LMP1 with GLUT1 to stabilize the GLUT1 protein by blocking its K48-ubiquitination and p62-dependent autolysosomal degradation. This work indicates that LMP1-mediated glycolysis regulates IL 1beta, IL-6 and GM-CSF production through the NLRP3 inflammasome, COX-2 and P-p65 signaling pathways to enhance tumor-associated MDSC expansion, which leads to tumor immunosuppression in NPC. PMID- 28732082 TI - Osteosarcoma enters a post genomic era with in silico opportunities: Generation of the High Dimensional Database for facilitating sarcoma biology research: A report from the Children's Oncology Group and the QuadW Foundation. AB - The prospective banking of osteosarcoma tissue samples to promote research endeavors has been realized through the establishment of a nationally centralized biospecimen repository, the Children's Oncology Group (COG) biospecimen bank located at the Biopathology Center (BPC)/Nationwide Children's Hospital in Columbus, Ohio. Although the physical inventory of osteosarcoma biospecimens is substantive (>15,000 sample specimens), the nature of these resources remains exhaustible. Despite judicious allocation of these high-value biospecimens for conducting sarcoma-related research, a deeper understanding of osteosarcoma biology, in particular metastases, remains unrealized. In addition the identification and development of novel diagnostics and effective therapeutics remain elusive. The QuadW-COG Childhood Sarcoma Biostatistics and Annotation Office (CSBAO) has developed the High Dimensional Data (HDD) platform to complement the existing physical inventory and to promote in silico hypothesis testing in sarcoma biology. The HDD is a relational biologic database derived from matched osteosarcoma biospecimens in which diverse experimental readouts have been generated and digitally deposited. As proof-of-concept, we demonstrate that the HDD platform can be utilized to address previously unrealized biologic questions though the systematic juxtaposition of diverse datasets derived from shared biospecimens. The continued population of the HDD platform with high value, high-throughput and mineable datasets allows a shared and reusable resource for researchers, both experimentalists and bioinformatics investigators, to propose and answer questions in silico that advance our understanding of osteosarcoma biology. PMID- 28732081 TI - IL-6 variant is associated with metastasis in breast cancer patients. AB - INTRODUCTION: Although tumor metastases remain significant drivers of mortality, the genetic factors that increase the risks of metastases are not fully identified. Interleukin 6 (IL-6) has emerged as an important factor in breast cancer progression with IL-6 single nucleotide polymorphism (SNP) variants shown to affect survival. We hypothesized that SNPs of the IL-6 promoter at rs1800795 in breast cancer patients are associated with distant metastases. METHODS: We performed an initial case-control study using Vanderbilt University Medical Center's BioVU, a genomic biobank linked to de-identified electronic medical records in the Synthetic Derivative database, to identify germline SNPs that may predict the development of metastatic disease to any site from any solid tumor including breast cancer. We identified a SNP in IL-6: rs1800795 to be of significance and evaluated this finding using a separate, matched-pair cohort of breast cancer patients with and without metastases from The Ohio State University Wexner Medical Center. RESULTS: The initial study suggested that GG relative to CG at rs1800795 (OR 1.52; 95% CI 1.14-2.02; p = 0.004) was significantly associated with the development of metastases. This association was also observed in the Ohio State University cohort (OR 2.23; 95% CI 1.06-4.71; p = 0.001). There were no significant relationships between rs1800795 status and any patient or tumor characteristics, including estrogen receptor status. CONCLUSIONS: These findings suggest that GG SNP at IL-6: rs1800795 may indicate an increased risk of metastasis of primary breast cancer. Further studies in larger population sets are warranted as advanced screening and prophylactic intervention might be employed in GG carriers. PMID- 28732083 TI - APOL1 risk alleles among individuals with CKD in Northern Tanzania: A pilot study. AB - INTRODUCTION: In sub-Saharan Africa, approximately 100 million people have CKD, yet genetic risk factors are not well-understood. Despite the potential importance of understanding APOL1 risk allele status among individuals with CKD, little genetic research has been conducted. Therefore, we conducted a pilot study evaluating the feasibility of and willingness to participate in genetic research on kidney disease, and we estimated APOL1 risk allele frequencies among individuals with CKD. METHODS: In 2014, we conducted a community-based field study evaluating CKD epidemiology in northern Tanzania. We assessed for CKD using urine albumin and serum creatinine to estimate GFR. We invited participants with CKD to enroll in an additional genetic study. We obtained dried-blood spots on filter cards, from which we extracted DNA using sterile punch biopsies. We genotyped for two single nucleotide polymorphisms (SNPs) defining the APOL1 G1 risk allele and an insertion/deletion polymorphism defining the G2 risk allele. Genotyping was performed in duplicate. RESULTS: We enrolled 481 participant, 57 (12%) of whom had CKD. Among these, enrollment for genotyping was high (n = 48; 84%). We extracted a median of 19.4 ng of DNA from each dried-blood spot sample, and we genotyped the two APOL1 G1 SNPs and the APOL1 G2 polymorphism. Genotyping quality was high, with all duplicated samples showing perfect concordance. The frequency of APOL1 risk variants ranged from 7.0% to 11.0%, which was similar to previously-reported frequencies from the general population of northern Tanzania (p>0.2). DISCUSSION: In individuals with CKD from northern Tanzania, we demonstrated feasibility of genotyping APOL1 risk alleles. We successfully genotyped three risk variants from DNA extracted from filter cards, and we demonstrated a high enrollment for participation. In this population, more extensive genetic studies of kidney disease may be well-received and will be feasible. PMID- 28732086 TI - Risk of stomach cancer in Aotearoa/New Zealand: A Maori population based case control study. AB - Maori, the indigenous people of New Zealand, experience disproportionate rates of stomach cancer, compared to non-Maori. The overall aim of the study was to better understand the reasons for the considerable excess of stomach cancer in Maori and to identify priorities for prevention. Maori stomach cancer cases from the New Zealand Cancer Registry between 1 February 2009 and 31 October 2013 and Maori controls, randomly selected from the New Zealand electoral roll were matched by 5 year age bands to cases. Logistic regression was used to estimate odd ratios (OR) and 95% confidence intervals (CI) between exposures and stomach cancer risk. Post stratification weighting of controls was used to account for differential non response by deprivation category. The study comprised 165 cases and 480 controls. Nearly half (47.9%) of cases were of the diffuse subtype. There were differences in the distribution of risk factors between cases and controls. Of interest were the strong relationships seen with increased stomach risk and having >2 people sharing a bedroom in childhood (OR 3.30, 95%CI 1.95-5.59), testing for H pylori (OR 12.17, 95%CI 6.15-24.08), being an ex-smoker (OR 2.26, 95%CI 1.44-3.54) and exposure to environmental tobacco smoke in adulthood (OR 3.29, 95%CI 1.94-5.59). Some results were attenuated following post-stratification weighting. This is the first national study of stomach cancer in any indigenous population and the first Maori-only population-based study of stomach cancer undertaken in New Zealand. We emphasize caution in interpreting the findings given the possibility of selection bias. Population-level strategies to reduce the incidence of stomach cancer in Maori include expanding measures to screen and treat those infected with H pylori and a continued policy focus on reducing tobacco consumption and uptake. PMID- 28732084 TI - Increased ParB level affects expression of stress response, adaptation and virulence operons and potentiates repression of promoters adjacent to the high affinity binding sites parS3 and parS4 in Pseudomonas aeruginosa. AB - Similarly to its homologs in other bacteria, Pseudomonas aeruginosa partitioning protein ParB facilitates segregation of newly replicated chromosomes. Lack of ParB is not lethal but results in increased frequency of anucleate cells production, longer division time, cell elongation, altered colony morphology and defective swarming and swimming motility. Unlike in other bacteria, inactivation of parB leads to major changes of the transcriptome, suggesting that, directly or indirectly, ParB plays a role in regulation of gene expression in this organism. ParB overproduction affects growth rate, cell division and motility in a similar way as ParB deficiency. To identify primary ParB targets, here we analysed the impact of a slight increase in ParB level on P. aeruginosa transcriptome. ParB excess, which does not cause changes in growth rate and chromosome segregation, significantly alters the expression of 176 loci. Most notably, the mRNA level of genes adjacent to high affinity ParB binding sites parS1-4 close to oriC is reduced. Conversely, in cells lacking either parB or functional parS sequences the orfs adjacent to parS3 and parS4 are upregulated, indicating that direct ParB parS3/parS4 interactions repress the transcription in this region. In addition, increased ParB level brings about repression or activation of numerous genes including several transcriptional regulators involved in SOS response, virulence and adaptation. Overall, our data support the role of partitioning protein ParB as a transcriptional regulator in Pseudomonas aeruginosa. PMID- 28732085 TI - Point-of-care screening for hepatitis B virus infection in pregnant women at an antenatal clinic: A South African experience. AB - BACKGROUND & AIMS: Elimination of HIV and syphilis mother-to-child transmission (MTCT) has received much attention but little consideration has been given to the possibility of elimination of HBV MTCT. In sub-Saharan Africa, HBV vertical transmission continues to be reported and it remains an important public health problem. This study aimed to assess the feasibility of screening pregnant women for HBV using a point-of-care (POC) test and implementing interventions to prevent HBV MTCT. METHODS: In this observational prospective cohort study, HIV uninfected pregnant women who consented to testing were screened for HBV using a rapid POC test for HBsAg. Positive results were laboratory-confirmed and tested for HBV DNA and serological markers. Women with viral loads >= 20 000 IU/ml received tenofovir (TDF) treatment and all infants received birth-dose HBV vaccine. Two blood samples collected six months apart from HBV-exposed infants within their first year of life were tested for HBV DNA. RESULTS: Of 144 women who were approached, 134 consented to participating (93% acceptance rate of HBV POC test). Six women tested positive for HBsAg (4.5%; 95% CI 0.99%-8.01%), all confirmed by laboratory testing. Two mothers, M1 and M4, were treated with TDF during their third trimester of pregnancy. Six HBV-exposed infants received the HBV vaccine within 24 hours of birth, of whom two were lost to follow-up and four (including the two born to M1 and M4) had undetectable levels of HBV DNA when tested at the two time points. CONCLUSION: We found that HBV screening using POC testing fulfilled the criteria considered necessary for implementation. It has acceptable performance, is inexpensive, reliable, and was well accepted by the study participants. Screening pregnant women as part of the HBV MTCT prevention strategy is therefore feasible in a South African clinical setting. PMID- 28732087 TI - A dissociation between engagement and learning: Enthusiastic instructions fail to reliably improve performance on a memory task. AB - Despite widespread assertions that enthusiasm is an important quality of effective teaching, empirical research on the effect of enthusiasm on learning and memory is mixed and largely inconclusive. To help resolve these inconsistencies, we conducted a carefully-controlled laboratory experiment, investigating whether enthusiastic instructions for a memory task would improve recall accuracy. Scripted videos, either enthusiastic or neutral, were used to manipulate the delivery of task instructions. We also manipulated the sequence of learning items, replicating the spacing effect, a known cognitive technique for memory improvement. Although spaced study reliably improved test performance, we found no reliable effect of enthusiasm on memory performance across two experiments. We did, however, find that enthusiastic instructions caused participants to respond to more item prompts, leaving fewer test questions blank, an outcome typically associated with increased task motivation. We find no support for the popular claim that enthusiastic instruction will improve learning, although it may still improve engagement. This dissociation between motivation and learning is discussed, as well as its implications for education and future research on student learning. PMID- 28732088 TI - Patient and doctor perspectives on HIV screening in the emergency department: A prospective cross-sectional study. AB - BACKGROUND: The emergency department (ED) is mentioned specifically in the Swiss HIV testing recommendations as a site at which patients can benefit from expanded HIV testing to optimise early HIV diagnosis. At our centre, where local HIV seroprevalence is 0.2-0.4%, 1% of all patients presenting to the ED are tested for HIV. Barriers to HIV testing, from the patient and doctor perspective, and patient acceptability of rapid HIV testing were examined in this study. METHODS: Between October 2014 and May 2015, 100 discrete patient-doctor encounter pairs undertook a survey in the ED of Lausanne University Hospital, Switzerland. Patients completed a questionnaire on HIV risk factors and were offered free rapid HIV testing (INSTITM). For every patient included, the treating doctor was asked if HIV testing had 1) been indicated according to the national testing recommendations, 2) mentioned, and 3) offered during the consultation. RESULTS: Of 100 patients, 30 had indications for HIV testing through risk factors or a suggestive presenting complaint (PC). Fifty patients accepted rapid testing; no test was reactive. Of 50 patients declining testing, 82% considered themselves not at risk or had recently tested negative and 16% wished to focus on their PC. ED doctors identified 20 patients with testing indications, mentioned testing to nine and offered testing to six. The main reason for doctors not mentioning or not offering testing was the wish to focus on the PC. DISCUSSION: Patients and doctors at our ED share the testing barrier of wishing to focus on the PC. Rapid HIV testing offered in parallel to the patient-doctor consultation increased the testing rate from 6% (offered by doctors) to 50%. Introducing this service would enable testing of patients not offered tests by their doctors and reduce missed opportunities for early HIV diagnosis. PMID- 28732090 TI - Incidence, predictors and severity of adverse events among whole blood donors. AB - BACKGROUND: Adverse events have been reported post blood donation. Donors might refrain from donating again due to such events which lowers the blood supply in collection centers. AIM: This study measured the incidence, predictors and severity of adverse events among donors of a single whole blood unit at one of the largest donation centers in Saudi Arabia. METHODS: A retrospective cohort was conducted in 2015 to investigate the adverse events immediately post donation. Donor characteristics such as age, blood pressure, hemoglobin level, weight and history of donation were described and tested as potential risk predictors. Eligible blood donors were 18,936/24,634 (76.8%). RESULTS: Incidence of adverse events found 1.1% (208 donors), of which 0.65% had mild symptoms (chills; nausea; pallor; dizziness; nervousness; headache), while 0.45% had severe symptoms (hypotension; convulsions; syncope; respiratory distress; emesis). Multiple logistic regression showed that, the incidence of adverse events was significantly higher among young age donors <30 years RR[95%CI] = 1.58[1.18 2.12], p < 0.002, higher hemoglobin levels RR[95%CI] = 1.30[1.15-1.46], lower weight donors <75kg RR[95%CI] = 1.71[1.29-2.27], p <0.001 and first time donors RR[95%CI] = 2.21[1.64-2.97], p < 0.001 compared to older age donors >=30, lower hemoglobin levels, heavier weight donors >= 75, and previous donors, respectively. More severe adverse events were observed among older and heavier donors, previous donors, lower hemoglobin levels and hypertensive donors but with no statistical significance. CONCLUSION: Young blood donors, donors with lower weight and first time donors are at higher risk of contracting adverse events. Higher hemoglobin level is also a potential risk predictor of adverse events post whole blood donation. PMID- 28732089 TI - Cx47 fine-tunes the handling of serum lipids but is dispensable for lymphatic vascular function. AB - Mutations in the gap junction protein connexin47 (Cx47) are associated with lymphedema. However, the role of Cx47 in lymphatic pathophysiology is unknown. We demonstrate that Cx47 is expressed in lymphatic endothelial cells by whole-mount immunostaining and qPCR. To determine if Cx47 plays a role in lymphatic vessel function we analysed Cx47-/- mice. Cx47-deficiency did not affect lymphatic contractility (contractile amplitude or frequency) or lymphatic morphology (vessel diameter or number of valves). Interstitial fluid drainage or dendritic cell migration through lymphatic vessels was also not affected by Cx47 deficiency. Cx47 is dispensable for long-chain fatty acid absorption from the gut but rather promotes serum lipid handling as prolonged elevated triglyceride levels were observed in Cx47-deficient mice after oral lipid tolerance tests. When crossed with Apolipoprotein E-deficient (Apoe-/-) mice, LDL-cholesterol was decreased in young Cx47-/-Apoe-/- adults as compared to Apoe-/- mice, which was inverted later in life. Finally, advanced atherosclerotic plaques in thoracic abdominal aortas of 15 months-old mice tended to be larger in Cx47-/-Apoe-/- mice. These plaques contained fewer macrophages but similar amounts of T lymphocytes, collagen and lipids than plaques of Apoe-/- mice. In conclusion, Cx47 is expressed in lymphatic endothelium and seems modestly implicated in multiple aspects of lymphatic pathophysiology. PMID- 28732091 TI - Perfusion of surgical cavity wall enhancement in early post-treatment MR imaging may stratify the time-to-progression in glioblastoma. AB - OBJECTIVE: To determine if perfusion in surgical cavity wall enhancement (SCWE) obtained in early post-treatment MR imaging can stratify time-to-progression (TTP) in glioblastoma. MATERIALS AND METHODS: This study enrolled 60 glioblastoma patients with more than 5-mm-thick SCWEs as detected on contrast-enhanced MR imaging after concurrent chemoradiation therapy. Two independent readers categorized the shape and perfusion state of SCWEs as nodular or non-nodular and as having positive or negative perfusion compared with the contralateral grey matter on arterial spin labeling (ASL). The perfusion fraction on ASL within the contrast-enhancing lesion was calculated. The independent predictability of TTP was analyzed using the Kaplan-Meier method and Cox proportional hazards modelling. RESULTS: The perfusion fraction was higher in the non-progression group, significantly for reader 2 (P = 0.03) and borderline significantly for reader 1 (P = 0.08). A positive perfusion state and (P = 0.02) a higher perfusion fraction of the SCWE were found to become an independent predictor of longer TTP (P = 0.001 for reader 1 and P < 0.001 for reader 2). The contrast enhancement pattern did not become a TTP predictor. CONCLUSION: Assessment of perfusion in early post-treatment MR imaging can stratify TTP in patients with glioblastoma for adjuvant temozolomide therapy. Positive perfusion in SCWEs can become a predictor of a longer TTP. PMID- 28732092 TI - Dietary oleic acid regulates hepatic lipogenesis through a liver X receptor dependent signaling. AB - Olive oil consumption is beneficial for health as it is associated with a decreased prevalence of cancer and cardiovascular diseases. Oleic acid is, by far, the most abundant component of olive oil. Since it can be made through de novo synthesis in animals, it is not an essential fatty acid. While it has become clear that dietary oleic acid regulates many biological processes, the signaling pathway involved in these regulations remains poorly defined. In this work we tested the impact of an oleic acid-rich diet on hepatic gene expression. We were particularly interested in addressing the contribution of Liver X Receptors (LXR) in the control of genes involved in hepatic lipogenesis, an essential process in whole body energy homeostasis. We used wild-type mice and transgenic mice deficient for both alpha and beta Liver X Receptor isoforms (LXR-/-) fed a control or an oleate enriched diet. We observed that hepatic-lipid accumulation was enhanced as well as the expression of lipogenic genes in the liver of wild type mice fed the oleate enriched diet. In contrast, none of these changes occurred in the liver of LXR-/- mice. Strikingly, oleate-rich diet reduced cholesterolemia in wild-type mice and induced signs of liver inflammation and damage in LXR-/- mice but not in wild-type mice. This work suggests that dietary oleic acid reduces cholesterolemia while promoting LXR-dependent hepatic lipogenesis without detrimental effects to the liver. PMID- 28732093 TI - Attitudes among transplant professionals regarding shifting paradigms in eligibility criteria for live kidney donation. AB - BACKGROUND: The transplant community increasingly accepts extended criteria live kidney donors, however, great (geographical) differences are present in policies regarding the acceptance of these donors, and guidelines do not offer clarity. The aim of this survey was to reveal these differences and to get an insight in both centre policies as well as personal beliefs of transplant professionals. METHODS: An online survey was sent to 1128 ESOT-members. Questions were included about several extended donor criteria; overweight/obesity, older age, vascular multiplicity, minors as donors and comorbidities; hypertension, impaired fasting glucose, kidney stones, malignancies and renal cysts. Comparisons were made between transplant centres of three regions in Europe and between Europe and other countries worldwide. RESULTS: 331 questionnaires were completed by professionals from 55 countries. Significant differences exist between regions in Europe in acceptance of donors with several extended criteria. Median refusal rate for potential live donors is 15%. Furthermore, differences are seen regarding pre-operative work-up, both in specialists who perform screening as in preoperative imaging. CONCLUSIONS: Remarkably, 23.4% of transplant professionals sometimes deviate from their centre policy, resulting in more or less comparable personal beliefs regarding extended criteria. Variety is seen, proving the need for a standardized approach in selection, preferably evidence based. PMID- 28732095 TI - Automated framework for intraretinal cystoid macular edema segmentation in three dimensional optical coherence tomography images with macular hole. AB - Cystoid macular edema (CME) and macular hole (MH) are the leading causes for visual loss in retinal diseases. The volume of the CMEs can be an accurate predictor for visual prognosis. This paper presents an automatic method to segment the CMEs from the abnormal retina with coexistence of MH in three dimensional-optical coherence tomography images. The proposed framework consists of preprocessing and CMEs segmentation. The preprocessing part includes denoising, intraretinal layers segmentation and flattening, and MH and vessel silhouettes exclusion. In the CMEs segmentation, a three-step strategy is applied. First, an AdaBoost classifier trained with 57 features is employed to generate the initialization results. Second, an automated shape-constrained graph cut algorithm is applied to obtain the refined results. Finally, cyst area information is used to remove false positives (FPs). The method was evaluated on 19 eyes with coexistence of CMEs and MH from 18 subjects. The true positive volume fraction, FP volume fraction, dice similarity coefficient, and accuracy rate for CMEs segmentation were 81.0%+/-7.8%, 0.80%+/-0.63%, 80.9%+/-5.7%, and 99.7%+/-0.1%, respectively. PMID- 28732094 TI - Surface-enhanced Raman spectroscopy competitive binding biosensor development utilizing surface modification of silver nanocubes and a citrulline aptamer. AB - A point-of-care (PoC) device with the ability to detect biomarkers at low concentrations in bodily fluids would have an enormous potential for medical diagnostics outside the central laboratory. One method to monitor analytes at low concentrations is by using surface-enhanced Raman spectroscopy (SERS). In this preliminary study toward using SERS for PoC biosensing, the surface of colloidal silver (Ag) nanocubes has been modified to test the feasibility of a competitive binding SERS assay utilizing aptamers against citrulline. Specifically, Ag nanocubes were functionalized with mercaptobenzoic acid, as well as a heterobifunctional polyethylene glycol linker that forms an amide bond with the amino acid citrulline. After the functionalization, the nanocubes were characterized by zeta-potential, transmission electron microscopy images, ultraviolet/visible spectroscopy, and by SERS. The citrulline aptamers were developed and tested using backscattering interferometry. The data show that our surface modification method does work and that the functionalized nanoparticles can be detected using SERS down to a 24.5 picomolar level. Last, we used microscale thermophoresis to show that the aptamers bind to citrulline with at least a 50 times stronger affinity than other amino acids.Download PDFSAVE FOR LATER PMID- 28732096 TI - Determination of three optical properties from subdiffusive spatially resolved reflectance calculations. AB - We report a theoretical study on the determination of three optical properties from spatially resolved reflectance calculations. In particular, the reduced scattering coefficient MUs', the absorption coefficient MUa, and the recently defined phase function parameter sigma are identified. The solution of the inverse problem is based on the principal component analysis of a large set of reflectance profiles that were calculated using an analytical solution of the radiative transfer equation. Different phase function types were studied to test the method in the range of 0.63 mm-1<=MUs'<=4.2 mm-1 and 0.002 mm-1<=MUa<=0.1 mm-1. For curves impaired with noise, we were able to reconstruct MUs' and MUa with relative median errors of 2.5% and 12%, respectively, and sigma with an absolute median error of 0.04. PMID- 28732097 TI - Resources for LSHSS Authors. AB - Purpose: In this article, the Editor-in-Chief of Language, Speech, and Hearing Services in Schools (LSHSS) highlights key resources for authors wishing to publish their work in LSHSS. PMID- 28732098 TI - Variability of the Pressure Measurements Exerted by the Tip of Laryngoscope During Laryngeal Sensory Testing: A Clinical Demonstration. AB - Purpose: Clinicians often test laryngeal sensation by touching the laryngeal mucosa with the tip of a flexible laryngoscope. However, the pressure applied to the larynx by using this touch method is unknown, and the expected responses elicited by this method are uncertain. The variability in pressure delivered by clinicians using the touch method was investigated, and the subject responses to the touches were also reported. Methods: A fiberoptic pressure sensor passed through the working channel of a laryngoscope, with its tip positioned at the distal port of the channel. Two examiners each tested 8 healthy adults. Each examiner touched the mucosa covering the left arytenoid 3 times. The sensor recorded the pressure exerted by each touch. An investigator noted subject responses to the touches. From the recorded videos, the absence or presence of the laryngeal adductor reflex in response to touch was judged. Results: Pressure values obtained for 46 of the 48 possible samples ranged from 17.9 mmHg to the measurement ceiling of 350.0 mmHg. The most frequently observed response was positive subject report followed by the laryngeal adductor reflex. Conclusion: Pressure applied to the larynx by using the touch method was highly variable, indicating potential diagnostic inaccuracy in determining laryngeal sensory function. PMID- 28732099 TI - Expression of Concern: Schietroma M, Cecilia EM, Carlei F, Sista F, De Santis G, Lancione L, Amicucci G. Dexamethasone for the Prevention of Recurrent Laryngeal Nerve Palsy and Other Complications After Thyroid Surgery: A Randomized Double blind Placebo-Controlled Trial. JAMA Otolaryngol Head Neck Surg. 2013;139(5):471 478. doi:10.1001/jamaoto.2013.2821. PMID- 28732101 TI - The Conundrum of Digital Medicine. PMID- 28732100 TI - Nerve Conduction Studies for Carpal Tunnel Syndrome: Gold Standard or Unnecessary Evil? PMID- 28732102 TI - Erratum for Periprosthetic Fractures in Megaprostheses: Algorithmic Approach to Treatment. PMID- 28732103 TI - Denosumab: Current Use in the Treatment of Primary Bone Tumors. AB - Denosumab, a human monoclonal antibody that inhibits bone resorption by binding on the receptor activator of the nuclear factor kappa-beta ligand, has recently emerged as an additional option in the treatment of musculoskeletal osteolytic tumors. This article focuses on the recent literature regarding the effectiveness of denosumab in the management of giant cell tumor, multiple myeloma, aneurysmal bone cyst, and osteosarcoma. The mechanism of action of denosumab in the management of these tumors and the associated side effects are discussed in detail. [ Orthopedics. 2017; 40(4):204-210.]. PMID- 28732104 TI - Reciprocal feedback between self-concept and goal pursuit in daily life. AB - OBJECTIVE: We hypothesized that self-knowledge and goal perseverance are mutually reinforcing because of the roles of self-knowledge in directing goal pursuit, and of goal pursuit in structuring the self-concept. METHOD: To test this hypothesis, we used a daily diary design with 97 college-aged participants for 40 days to assess whether daily self-concept clarity and grit predict one another's next-day levels. Data were analyzed using multilevel cross-lagged panel modeling. RESULTS: Results indicated that daily self-concept clarity and grit had positive and symmetric associations with each other across time, while controlling for their respective previous values. Similar crossed results were also found when testing the model using individual daily self-concept clarity and grit items. CONCLUSIONS: The results are the first to indicate the existence of reinforcing feedback loops between self-concept clarity and grit, such that fluctuations in the clarity of self-knowledge are associated with fluctuations in goal resolve, and vice versa. Discussion centers on the implications of these results for the functional link between mind and action and on the study's heuristic value for subsequent research. PMID- 28732105 TI - Shining a light on the Arabidopsis circadian clock. AB - The circadian clock provides essential timing information to ensure optimal growth to prevailing external environmental conditions. A major time-setting mechanism (zeitgeber) in clock synchronization is light. Differing light wavelengths, intensities, and photoperiodic duration are processed for the clock setting mechanism. Many studies on light-input pathways to the clock have focused on Arabidopsis thaliana. Photoreceptors are specific chromic proteins that detect light signals and transmit this information to the central circadian oscillator through a number of different signalling mechanisms. The most well-characterized clock-mediating photoreceptors are cryptochromes and phytochromes, detecting blue, red, and far-red wavelengths of light. Ultraviolet and shaded light are also processed signals to the oscillator. Notably, the clock reciprocally generates rhythms of photoreceptor action leading to so-called gating of light responses. Intermediate proteins, such as Phytochrome interacting factors (PIFs), constitutive photomorphogenic 1 (COP1) and EARLY FLOWERING 3 (ELF3), have been established in signalling pathways downstream of photoreceptor activation. However, the precise details for these signalling mechanisms are not fully established. This review highlights both historical and recent efforts made to understand overall light input to the oscillator, first looking at how each wavelength of light is detected, this is then related to known input mechanisms and their interactions. PMID- 28732106 TI - Specific alpha7 nicotinic acetylcholine receptor agonist ameliorates isoproterenol-induced cardiac remodelling in mice through TGF-beta1/Smad3 pathway. AB - It is well-accepted that inflammation plays an important role in the development of cardiac remodelling and that therapeutic approaches targeting inflammation can inhibit cardiac remodelling. Although a large amount of evidence indicates that activation of alpha7 nicotinic acetylcholine receptor (alpha7nAChR) causes an anti-inflammatory effect, the role of alpha7nAChR in cardiac remodelling and the underlying mechanism have not been established. To investigate the effect of the specific alpha7nAChR agonist, PNU282987, on cardiac remodelling induced by isoproterenol (ISO 60 mg/kg per day) in mice, the cardiomyocyte cross-sectional area (CSA) and collagen volume fraction were evaluated by hematoxylin and eosin (HE) and Masson staining, respectively. Cardiac function and ventricular wall thickness were measured by echocardiography. The protein expressions of collagen I, matrix metalloproteinase 9 (MMP-9), transforming growth factor beta1 (TGF beta1), and Smad3 were analyzed by Western blot. ISO-induced cardiac hypertrophy, characterized by an increase in the heart weight/body weight ratio, CSA and ventricular wall thickness. Moreover, cardiac fibrosis indices, such as collagen volume fraction, MMP-9 and collagen I protein expression, were also increased by ISO. PNU282987 not only attenuated cardiac hypertrophy but also decreased the cardiac fibrosis induced by ISO. Furthermore, PNU282987 suppressed TGF-beta1 protein expression and the phosphorylation of Smad3 induced by ISO. In conclusion, PNU282987 ameliorated the cardiac remodelling induced by ISO, which may be related to the TGF-beta1/Smad3 pathway. These data imply that the alpha7nAChR may represent a novel therapeutic target for cardiac remodelling in many cardiovascular diseases. PMID- 28732107 TI - Characteristic Flavor of Traditional Soup Made by Stewing Chinese Yellow-Feather Chickens. AB - The traditional recipe for Chinese chicken soup creates a popular taste of particular umami and aroma. The present study investigated the effects of stewing time (1, 2, and 3 h) on the principal taste-active and volatile compounds and the overall flavor profile of traditional Chinese chicken soup by measuring the contents of free amino acids (FAAs), 5'-nucleotides, minerals and volatile compounds and by evaluating the taste and aroma profiles using an electronic nose, an electronic tongue and a human panel. Results showed that the major umami related compounds in the chicken soup were inosine 5'-monophosphate (IMP) and chloride, both of which increased significantly (P < 0.05) during stewing. The taste active values (TAVs) of the equivalent umami concentration (EUC) increased from 4.08 to 9.93 (P < 0.05) after stewing for 3 h. Although the FAA and mineral contents increased significantly (P < 0.05), their TAVs were less than 1. The volatile compounds were mainly hexanal, heptanal, octanal, nonanal, (E)-2 nonanal, (E)-2-decenal, (E,E)-2,4-decadienal, 1-hexanol, and 2-pentyl furan. With the prolonged stewing time, the aldehydes first increased and then decreased significantly (P < 0.05), while 1-hexanol and 2-pentyl furan increased steadily (P < 0.05). The aroma scores of the chicken soup reached the maximum after stewing for 3 h. The discrepancy in overall flavor characteristics tended to stabilize after 2 h of stewing. In general, stewing time has a positive effect on improving the flavor profiles of chicken soup, especially within the first 2 h. PMID- 28732109 TI - The Present State and Future Application of Cloud Computing for Numerical Groundwater Modeling. PMID- 28732108 TI - Prospective Interest of Deep Learning for Hydrological Inference. PMID- 28732110 TI - Growth inhibitory effect of beta-eudesmol on cholangiocarcinoma cells and its potential suppressive effect on heme oxygenase-1 production, STAT1/3 activation, and NF-kappaB downregulation. AB - Cholangiocarcinoma (CCA) is a progressively fatal form of cancer originating from the malignant transformation of hepatic biliary cholangiocytes. The present study reports for the first time in vitro growth inhibitory activities of beta eudesmol, the bioactive sesquiterpenoid present in the rhizome of Atractylodes lancea (Thunb) DC., with respect to its underlying potential effects on heme oxygenase-1 (HO-1) production, STAT1/3 phosphorylation, and NF-kappaB protein expression in human CCA cell line CL-6. The cytotoxic effect of beta-eudesmol on CL-6 cells was evaluated by MTT assay using normal human embryonic fibroblast (OUMS) as a control cell line. Results indicated that beta-eudesmol exhibited selective cytotoxicity towards CL-6 compared to OUMS with mean (+/-SD) IC50 (concentration that inhibits cell growth by 50%) values of 166.75 +/- 3.69 and 240.01 +/- 16.54 MUmol/L, respectively. In addition, it also significantly suppressed colony forming and wound healing ability of CL-6 cells in a concentration-dependent manner. Western blot analysis indicated that beta eudesmol treatment resulted in significant suppression of HO-1 production in CL-6 cells. Its inhibitory effects on the phosphorylation of STAT1/3 proteins and expression of NF-kappaB (p65 and p50) proteins were concentration-dependent. Taken together, these results suggest that beta-eudesmol exerts significant growth inhibitory activity on CL-6 cells that may be linked to its inhibitory effect on the production of HO-1, phosphorylation of STAT1/3, and expression of major NF-kappaB proteins. PMID- 28732111 TI - Characterization of Metabolic Pathways and Absorption of Sea Cucumber Saponins, Holothurin A and Echinoside A, in Vitro and in Vivo. AB - Sea cucumber saponins (SCSs) exhibit a wide spectrum of bioactivities, but their metabolic characteristics are not well elucidated. In this study, the metabolism of holothurin A (HA) and echinoside A (EA), 2 major saponins in sea cucumber, by gut microflora were investigated. First, we conducted an in vitro study, where in the SCSs were incubated with intestinal microflora and the metabolites were detected by high pressure liquid chromatography-high resolution mass spectrometry. We also conducted an in vivo study on rats, where in the intestinal contents, serum, urine, and feces were collected and evaluated after oral administration of SCSs. In the in vitro study, we identified 6 deglycosylated metabolites of HA and EA, assigned M1-M6. In the in vivo study, we found all the deglycosylated metabolites in the intestinal contents after oral administration, and both the metabolites and their prototype components could be absorbed. Four metabolites were identified in the serum, 6 in the urine, and 4 in the feces. The saponins with different structures showed different absorption characteristics in rats. According to our results, deglycosylation is the main intestinal microflora mediated metabolic pathway for SCSs, and both the SCSs and deglycosylated metabolites can be absorbed by intestine. This study improves the understanding of the metabolism of HA and EA by gut flora, which will be useful for further analysis of the bioactivity mechanism of SCSs. PMID- 28732112 TI - Identifying mechanisms for cancer cell chemoresistance. PMID- 28732114 TI - Harnessing harmful by-product as the driving force. PMID- 28732116 TI - Strategies for preventing antibody light chain truncation. PMID- 28732115 TI - Biotechnology and Bioengineering: Volume 114, Number 9, September 2017. PMID- 28732117 TI - Identification by phenotypic and genetic approaches of an indigenous Saccharomyces cerevisiae wine strain with high desiccation tolerance. AB - During active dry yeast (ADY) production process, cells are exposed to multiple stresses, such as thermal, oxidative and hyperosmotic shock. Previously, by analysing cells in exponential growth phase, we selected an indigenous Saccharomyces cerevisiae wine strain, namely CD-6Sc, for its higher tolerance to desiccation and higher expression of specific desiccation stress-related genes in comparison to other yeast strains. In this study, we performed a desiccation treatment on stationary phase cells by comparing the efficacy of two different methods: a 'laboratory dry test' on a small scale (mild stress) and a treatment by spray-drying (severe stress), one of the most appropriate preservation method for yeasts and other micro-organisms. The expression of selected desiccation related genes has been also assessed in order to validate predictive markers for desiccation tolerance. Our data demonstrate that the 'mild' and the 'severe' desiccation treatments give similar results in terms of cell recovery, but the choice of marker genes strictly depends on the growth phase in which cells undergo desiccation. The indigenous CD-6Sc was ultimately identified as a high dehydration stress-tolerant indigenous strain suitable for ADY production. This study highlights the exploitation of natural yeast biodiversity as a source of hidden technological features and as an alternative approach to strain improvement by genetic modifications. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28732118 TI - Programmed cell death-1 (PD-1) checkpoint blockade in combination with a mammalian target of rapamycin inhibitor restrains hepatocellular carcinoma growth induced by hepatoma cell-intrinsic PD-1. AB - : Inhibitors of programmed cell death 1 (PD-1) administered as single agents have resulted in durable tumor regression in advanced cancer patients. However, only a minority of cancer patients respond to anti-PD-1 immunotherapy. Here, we show that PD-1 expression in hepatocellular carcinoma promotes tumor growth independently of adaptive immunity. Knockdown of PD-1 suppresses tumor growth, whereas PD-1 overexpression enhances tumorigenesis in immunodeficient xenografted mice. Mechanistically, PD-1 binds the downstream mammalian target of rapamycin effectors eukaryotic initiation factor 4E and ribosomal protein S6, thus promoting their phosphorylation. Moreover, combining mammalian target of rapamycin inhibition with anti-PD-1 antibody treatment results in more durable and synergistic tumor regression than either single agent alone, each of which presents only modest efficacy. CONCLUSION: Targeting mammalian target of rapamycin pathways in combination with PD-1 may result in increased antitumor efficacy in cancer patients. (Hepatology 2017;66:1920-1933). PMID- 28732119 TI - Association between PM2.5 and PM2.5 Constituents and Preterm Delivery in California, 2000-2006. AB - BACKGROUND: Particulate matter (PM) has been documented to contribute to preterm delivery. However, few studies have investigated the relationships between individual constituents of fine PM (PM2.5 ) and preterm delivery, and factors that may modify their associations. METHODS: In this study, we examined the associations between several prenatal exposure metrics to PM2.5 and 23 constituents of PM2.5 and preterm delivery in California from 2000 to 2006. In a retrospective cohort study including 231 637 births, we conducted logistic regression analyses adjusting for maternal, infant, temporal, geographic, and neighbourhood characteristics. RESULTS: We observed increased risk for preterm delivery with full-gestational exposure for several PM2.5 constituents. Per interquartile range increase, ammonium (21.2%, 95% confidence interval (CI) 17.1, 25.4), nitrate (18.1%, 95% CI 14.9, 21.4) and bromine (16.7%, 95% CI 13.2, 20.3) had some of the largest increased risks. Alternatively, some PM2.5 constituents were inversely associated with preterm delivery, including chlorine (-8.2%, 95% CI -10.3, -6.0), sodium (-13.2%, 95% CI -15.2, -11.3), sodium ion (-11.9%, 95% CI -14.1, -9.6) and vanadium (-19.2%, 95% CI -25.3, -12.6). Greater associations between PM2.5 constituents and preterm delivery were observed for Blacks and Asians, older mothers, and those with some college education compared to their reference groups, as well as for births with gestational ages from 32 to 34 weeks. CONCLUSIONS: PM2.5 constituents ammonium, nitrate and bromine, often linked to traffic and biomass combustion, were most associated with increased risk of preterm delivery in California. Certain demographic subgroups may be particularly impacted. PMID- 28732120 TI - The prevalence of molar incisor hypomineralization: evidence from 70 studies. AB - OBJECTIVE: A growing number of studies have investigated the prevalence of Molar Incisor Hypomineralization (MIH) around the world. The aim of this study was to systematically estimate the pooled prevalence of MIH. METHODS: A comprehensive literature research was completed in English and Chinese databases. Random effect models were used to calculate the pooled prevalence. To address the heterogeneity, meta-regression, and sensitivity analyzes were conducted. Publication bias was estimated by trim and fill method. RESULTS: Seventy eligible studies were included. The pooled prevalence of MIH was 14.2% globally. In subgroup analysis, South America (18.0%, 95% CI: 13.8-22.2) and Spain (21.1%, 95% CI: 17.7-24.6) had the highest prevalence. There was no significant difference between males (14.3%, 95% CI: 12.0-16.6) and females (14.4%, 95% CI: 12.8-15.9). The prevalence of MIH among children 10 years of age or younger (15.1%, 95% CI: 12.1-18.2) was much higher than the prevalence of MIH among older children (12.1%, 95% CI: 8.0-16.3). Sample size explained 15.7% heterogeneity. CONCLUSION: MIH has a high incidence globally, especially among children <10 years old. It is, therefore, imperative to develop more appropriate dental healthcare strategies to care for these children and to identify the etiology of MIH to prevent it occurring. PMID- 28732121 TI - Sequencing the gut metagenome as a noninvasive diagnosis for advanced nonalcoholic steatohepatitis. PMID- 28732122 TI - Human Preferences and Belief Patterns Mimic Ecosystem Hysteresis. PMID- 28732123 TI - Toward Increased Use of Data Worth Analyses in Groundwater Studies. PMID- 28732125 TI - Birth preparedness and complication readiness among prenatal attendees in a teaching hospital in South West Nigeria. AB - OBJECTIVE: To assess birth preparedness and complication readiness (BPCR) as well as knowledge of danger signs during pregnancy, labor/delivery, and the postpartum period. METHODS: A cross-sectional study was undertaken of pregnant women attending the prenatal clinic at a tertiary hospital in Nigeria between October and December 2016. A pretested and structured questionnaire was used to collect data on BPCR, and logistic regression was performed to determine factors affecting BPCR. RESULTS: Of 325 participants, 274 (84.3%) had knowledge of BPCR components, and 265 (81.5%) were well prepared for birth and its complications. However, only 89 (27.4%) knew key danger signs during labor/delivery and 81 (24.9%) knew those in the first 2 days after delivery. Older age, higher parity, tertiary education of women, paid employment of women and their spouses, higher social class, frequent prenatal visits, and knowledge of danger signs were significantly associated with BPCR (P<0.05). Higher parity, maternal government employment, and knowledge of danger signs during pregnancy remained determinants of BPCR on logistic regression (P<0.05). CONCLUSION: Although there was a high level of knowledge and practice of BPCR, knowledge of key danger signs was low. Therefore, prenatal education needs to be improved with an emphasis on teaching pregnant women to recognize key danger signs. PMID- 28732126 TI - Chinese isms dimensions in mainland China and Taiwan: Convergence and extension of American isms dimensions. AB - OBJECTIVE: Previous studies of American English isms terms have uncovered as many as five broad factors: tradition-oriented religiousness (TR), subjective spirituality (SS), communal rationalism (CR), unmitigated self-interest (USI), and inequality aversion (IA). The present studies took a similar lexical approach to investigate the Chinese-language isms structures in both mainland China and Taiwan. METHOD AND RESULTS: In Study 1, exploratory factor analyses with 915 mainland Chinese subjects uncovered four interpretable factors dimensionalizing 165 mainland Chinese dictionary isms terms. These factors represented contents of a combination of TR and SS, USI, CR, and a culturally unique Communist Party of China (CPC) ideology factor. In Study 2, exploratory factor analyses with 467 Taiwan Chinese subjects revealed four interpretable factors categorizing 291 Taiwan Chinese dictionary isms terms. These factors represented contents of a combination of TR and SS, USI, CR, and a culturally unique dimension expressing aspirations for happiness. CONCLUSIONS: The results gave evidence for the existence of the isms factors TR and SS, USI, and CR in Chinese culture. Cultural uniqueness was reflected in the merging of TR and SS into the factor Syncretic Religiousness and the culture-specific factors of CPC ideology in China and Happiness/Peace Promotion in Taiwan. PMID- 28732127 TI - Editorial. PMID- 28732128 TI - Inhibition of Shigella sonnei and Shigella flexneri in Hummus Using Citric Acid and Garlic Extract. AB - Hummus (chickpea dip) is a ready-to-eat product that may pose a significant risk to human if pathogens are present. Several organisms including Shigella spp. have been isolated from hummus. However, studies on the survival and inhibition of Shigella spp. in food are scarce. This study investigated the growth pattern of Sh. sonnei and Sh. flexneri in hummus at different temperatures (4, 10, and 24 degrees C). Additionally, the inhibitory activity of different concentrations of citric acid (CA) (0.5%, 1.0%, and 2.0%) and garlic extract (GE) (1.0%, 2.0%, and 3.0%) against Sh. sonnei and Sh. flexneri inoculated into hummus and stored at 4 and 10 degrees C was investigated. Both Shigella spp. survived well at 4 degrees C, while both grew to >7.0 log10 after 4 d at 10 degrees C or 1 d at 24 degrees C. At 4 degrees C, CA at 0.5% and 1.0% resulted in a slight reduction in the count (approximately 1.0 log10 ); a complete elimination of Sh. sonnei was attained by using 2.0% CA. However, approximately 3.0 log10 reduction in Sh. sonnei was obtained at 10 degrees C. For Sh. flexneri, CA at 0.5% and 1.0% resulted in a bacteriostatic inhibition. GE at 1.0% and 2.0% resulted in approximately 1.0 to 2.0 log10 reduction in Sh. sonnei count at 4 degrees C, while at 3.0% GE, approximately 4.0 and 3.0 log10 reductions were obtained at 4 and 10 degrees C, respectively. In comparison, the 2.0% and 3.0% GE resulted in a bacteriostatic effect against Sh. flexneri at 4 and 10 degrees C. PMID- 28732129 TI - beta-1,6-glucan synthesis-associated genes are required for proper spore wall formation in Saccharomyces cerevisiae. AB - The yeast spore wall is an excellent model to study the assembly of an extracellular macromolecule structure. In the present study, mutants defective in beta-1,6-glucan synthesis, including kre1?, kre6?, kre9? and big1?, were sporulated to analyse the effect of beta-1,6-glucan defects on the spore wall. Except for kre6?, these mutant spores were sensitive to treatment with ether, suggesting that the mutations perturb the integrity of the spore wall. Morphologically, the mutant spores were indistinguishable from wild-type spores. They lacked significant sporulation defects partly because the chitosan layer, which covers the glucan layer, compensated for the damage. The proof for this model was obtained from the effect of the additional deletion of CHS3 that resulted in the absence of the chitosan layer. Among the double mutants, the most severe spore wall deficiency was observed in big1? spores. The majority of the big1?chs3? mutants failed to form visible spores at a higher temperature. Given that the big1? mutation caused a failure to attach a GPI-anchored reporter, Cwp2 GFP, to the spore wall, beta-1,6-glucan is involved in tethering of GPI-anchored proteins in the spore wall as well as in the vegetative cell wall. Thus, beta-1,6 glucan is required for proper organization of the spore wall. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28732130 TI - Abnormalities in the 24-hour rhythm of skin temperature in cirrhosis: Sleep-wake and general clinical implications. AB - BACKGROUND & AIMS: Sleep preparation/onset are associated with peripheral vasodilatation and a decrease in body temperature. The hyperdynamic syndrome exhibited by patients with cirrhosis may impinge on sleep preparation, thus contributing to their difficulties falling asleep. The aim of this study was the assessment of skin temperature, in relation to sleep-wake patterns, in patients with cirrhosis. METHODS: Fifty-three subjects were initially recruited, and 46 completed the study. Of the final 46, 12 were outpatients with cirrhosis, 13 inpatients with cirrhosis, 11 inpatients without cirrhosis and 10 healthy volunteers. All underwent baseline sleep-wake evaluation and blood sampling for inflammatory markers and morning melatonin levels. Distal/proximal skin temperature and their gradient (DPG) were recorded for 24 hours by a wireless device. Over this period subjects kept a sleep-wake diary. RESULTS: Inpatients with cirrhosis slept significantly less well than the other groups. Inpatients and outpatients with cirrhosis had higher proximal temperature and blunted rhythmicity compared to the other groups. Inpatients with/without cirrhosis had higher distal temperature values and blunted rhythmicity compared to the other groups. Inpatients and outpatients with cirrhosis had significantly lower DPG values compared to the other groups, and DPG reached near-zero values several hours later. Significant correlations were observed between temperature and sleep wake variables and inflammatory markers. CONCLUSIONS: Alterations of distal/proximal skin temperature, their gradient and their time-course were observed in patients with cirrhosis, which may contribute to their sleep disturbances. PMID- 28732132 TI - Entrapment of amino acids in gas phase surfactant assemblies: The case of tryptophan confined in positively charged (1R,2S)-dodecyl (2-hydroxy-1-methyl-2 phenylethyl) dimethylammonium bromide aggregates. AB - The ability of positively charged aggregates of the surfactant (1R,2S)-dodecyl(2 hydroxy-1-methyl-2-phenylethyl)dimethylammonium bromide (DMEB) to incorporate D tryptophan or L-tryptophan in the gas phase has been investigated by electrospray ion mobility mass spectrometry (ESI-IM-MS). Strongly impacted by the pH of the electrosprayed solutions, both protonated (T+ ) and deprotonated (T- ) tryptophan are effectively included into the aggregates, whereas, tryptophan in zwitterionic (T0 ) form is practically absent in singly charged DMEB aggregates but can be found in multiply charged ones. The ability to incorporate tryptophan increases with the aggregation number and charge state of aggregates. More than 1 tryptophan species can be entrapped (aggregates including up to 5 tryptophan are observed). Collision induced dissociation experiments performed on the positively singly charged DMEB hexamer containing 1 T- show that at low collision energies the loss of a DMEB molecule is preferred with respect to the loss of the DMEB cation plus T- species which, in turn, is preferred with respect to the loss of mere tryptophan, suggesting that the deprotonated amino acid is preferentially located in proximity of a DMEB head group and with the ionic moiety pointing towards the core of the aggregate. The analysis of the collision cross sections (CCS) of bare and tryptophan containing aggregates allowed evaluating the contributions of tryptophan and bromide ions to the total aggregate CCS. No significant discrimination between D-tryptophan and L-tryptophan by the chiral DMEB aggregates has been evidenced by mass spectra data, CID experiments, and CCS values. PMID- 28732131 TI - The Evolving Landscape for Complement Therapeutics in Rheumatic and Autoimmune Diseases. AB - The complement system is increasingly understood to play major roles in the pathogenesis of human inflammatory and autoimmune diseases. Because of this situation, there are rapidly expanding commercial efforts to develop novel complement inhibitors and effector pathway-modulating drugs. This review provides insights into the evolving understanding of the complement system components, mechanisms of activation within and across the 3 pathways (classical, alternative, and lectin), how the pathways are normally controlled and then dysregulated in target tissues, and what diseases are known to be, in large part, complement-dependent through the successful development and approval of complement therapeutics in patients. Mechanisms of complement activation in rheumatoid arthritis, lupus, and thrombotic microangiopathies are also illustrated. In addition, the specific therapeutic drugs that are both approved and under development are discussed in the context of both nonrheumatic and rheumatic diseases. Finally, the methods by which the complement system can be assessed in humans through biomarker studies are outlined, with the goal of understanding, in specific patients, how the system is functioning. PMID- 28732133 TI - Ionization and collision induced dissociation of steroid bisglucuronides. AB - Studies on steroid metabolism are of utmost importance to improve the detection capabilities of anabolic androgenic steroids (AASs) misuse in sports drug testing. In humans, glucuronoconjugates are the most abundant phase II metabolites of AAS. Bisglucuronidation is a reaction where two separated functional groups on the same molecule are conjugated with glucuronic acid. These metabolites have not been studied in depth for steroids and could be interesting markers for doping control. The aim of the present work was to study the ionization and collision-induced dissociation of steroid bisglucuronides to be able to develop mass spectrometric analytical strategies for their detection in urine samples after AAS administration. Because steroid bisglucuronides are not commercially available, 19 of them were qualitatively synthesized to study their mass spectrometric behavior. Bisglucuronides ionized as [M+NH4 ]+ in positive mode, and as [M-H]- and [M-2H]2- in negative mode. The most specific product ions of steroid bisglucuronides in positive mode resulted from the neutral losses of 387 and 405 Da (corresponding to [M+NH4 -NH3 -2gluc-H2 O]+ and [M+NH4 -NH3 -2gluc 2H2 O]+ , respectively, being "gluc" a dehydrated glucuronide moiety), and in negative mode, the fragmentation of [M-2H]2- showed ion losses of m/z 175 and 75 (gluc- and HOCH2 CO2- , respectively). On the basis of the common behavior, a selected reaction monitoring method was developed to detect bisglucuronide metabolites in urine samples. As a proof of concept, urines obtained after administration of norandrostenediol were studied, and a bisglucuronide metabolite was detected in those urines. The results demonstrate the usefulness of the analytical strategy to detect bisglucuronide metabolites in urine samples, and the formation of these metabolites after administration of AAS. PMID- 28732134 TI - Physical Functioning, Pain, and Health-Related Quality of Life in Adults With Juvenile Idiopathic Arthritis: A Longitudinal 30-Year Followup Study. AB - OBJECTIVE: To describe physical functioning, pain, and health-related quality of life (HRQoL) in adults with juvenile idiopathic arthritis (JIA), investigate changes over time, and identify predictors of poorer HRQoL after 30 years of disease. METHODS: Patients (n = 176) clinically examined after 15 years were reassessed using the Health Assessment Questionnaire disability index (HAQ DI), the visual analog scale pain subscale (VAS pain), and the Medical Outcomes Study Short Form 36 (SF-36) after 23 years and 30 years. Patients with signs of active disease after a minimum of 15 years were clinically examined again at 30 years. Patients were compared to matched controls. RESULTS: At the 30-year followup, 82 patients (47%) had HAQ DI scores >0, and the median VAS pain score in patients was 0.6 (range 0-10). Patients had lower SF-36 physical component summary (PCS) scores compared with controls (P < 0.001), and this was evident for patients both with and without clinical remission (P <= 0.01). No group differences were found in SF-36 mental component summary scores. Patients also scored worse than controls on all SF-36 subscales (P <= 0.01) except mental health. PCS scores worsened significantly between the 15- and 30-year followup time points (P = 0.001). Worse HAQ DI, VAS pain, and patient's global assessment of well-being scores, and receiving disability/social living allowance at 30 years, were correlated with lower PCS scores. Worse HAQ DI, patient's global assessment of well-being, and VAS fatigue scores at 15-year followup predicted lower PCS scores at 30-year followup. CONCLUSION: JIA had a detrimental effect on physical HRQoL as measured by the PCS of the SF-36. The strongest correlates were physical disability, pain, fatigue, well-being, and receiving disability/social living allowance. PMID- 28732136 TI - An approach to estimate the activation energies of fragmentation occurring in quadrupole collision cell of the mass spectrometer. AB - The classical semi-quantitative Rice-Ramsperger-Kassel (RRK) theory was used for the calculation of the internal energy dependent reaction rate coefficient of the collision-induced dissociation (CID) reaction in tandem mass spectrometry (MS/MS). The survival yield (SY) was determined by the reaction rate equation for the unimolecular dissociation of the precursor ion. The parameters of the rate equation and the RRK model were approximated based on the instrumental conditions. We used the RRK equation for the description of the basic behavior of the fragmentation reactions and for the estimation of the internal energy of the precursor ion. The critical energies for fragmentation (Eo ) of various molecules were estimated and compared with those reported in the literature. The model was extended by taking into account the initial internal energy distribution of the ions created in the ion source. It must be emphasized that our approach provides only a crude estimate for Eo . PMID- 28732135 TI - Synovial Immunophenotype and Anti-Citrullinated Peptide Antibodies in Rheumatoid Arthritis Patients: Relationship to Treatment Response and Radiologic Prognosis. AB - OBJECTIVE: Serum anti-citrullinated peptide antibodies (ACPAs) may be present before the development of rheumatoid arthritis (RA) and may be predictive of more severe, erosive disease. This study was undertaken to examine the synovial tissue immunophenotype according to ACPA status in patients with RA, as well as the response to treatment and erosion status. METHODS: Consecutive RA patients were prospectively recruited and underwent clinical and serologic assessments before and after treatment. Radiologic assessment was performed at the time of clinical follow-up. Synovial tissue was immunostained for specific markers of B cells (CD19), T cells (CD3, CD4, and CD8), macrophages (CD68), and blood vessels (factor VIII). Serum CXCL13 levels were quantified by enzyme-linked immunosorbent assay. Synovial tissue sections were analyzed for immunophenotype according to ACPA status, using a validated semiquantitative scoring method, and also analyzed for the presence of lymphoid aggregates. Response to treatment with nonbiologic or biologic disease-modifying antirheumatic drugs was assessed using the European League Against Rheumatism (EULAR) response criteria. RESULTS: In total, 123 subjects (78 ACPA+) were included. Compared to ACPA- RA patients, synovium from ACPA+ RA patients was characterized by significantly higher levels of CD19+ B cells and CD3+ and CD8+ T cells (each P < 0.05), and CD19+ B cell levels were significantly higher in patients who were naive to treatment. The CD19+ B cell infiltrate level was higher in patients with erosions at follow-up (P = 0.0128). Levels of lymphoid aggregates of CD19+ B cells were significantly higher in ACPA+ patients (P < 0.05), and this was associated with increased serum CXCL13 levels. The EULAR response was significantly associated with the level of CD3+ T cell infiltrates (P < 0.05), while CD68+ macrophage and CD8+ T cell levels were predictive of the response to tumor necrosis factor inhibitors (P < 0.05). CONCLUSION: The results of this prospective study demonstrate that the levels of synovial B cell infiltrates and lymphoid aggregates were significantly higher in ACPA+ RA patients, especially those who were naive to treatment. In addition, ACPA+ subjects developed more erosions during progression of the disease and had higher serum levels of CXCL13. The EULAR response to therapy in ACPA+ RA patients was associated with increased levels of T cell and macrophage markers. PMID- 28732137 TI - Prevalence of Sacroiliitis in Inflammatory Bowel Disease Using a Standardized Computed Tomography Scoring System. AB - OBJECTIVE: There is an increasing emphasis on the early identification and treatment of ankylosing spondylitis (AS) of which the hallmark is sacroiliitis. Patients with inflammatory bowel disease (IBD) are at increased risk of AS and often receive computed tomography (CT) scans of their abdomen, affording clinicians the opportunity to determine the presence of sacroiliitis. Previous studies using CT have relied only on the radiologist's gestalt or a nonvalidated adaptation of the modified New York criteria. Our aim is to assess the prevalence of sacroiliitis in IBD using a validated screening tool and to determine how frequently these patients are referred for rheumatologic evaluation. METHODS: Patients with IBD were recruited from an IBD clinic. Control patients were recruited from a urology clinic and were confirmed to be without back pain, spondylitis, psoriasis, colitis, or uveitis by chart review. CT scans were read by 2 blinded readers and sacroiliitis was defined by the presence of ankylosis or a total erosion score of >=3. RESULTS: CT scans were available in 233 Crohn's disease (CD) patients, 83 ulcerative colitis (UC) patients, and 108 control patients, and sacroiliitis was seen in 15%, 16.9%, and 5.6% of patients, respectively. The prevalence was higher in patients with IBD than in controls (P = 0.007), with no significant difference between CD and UC patients. Of the 49 IBD patients found to have sacroiliitis by CT scan, only 5 had been referred to a rheumatologist. CONCLUSION: There is a 3-fold higher prevalence of sacroiliitis in IBD compared with controls. Despite a growing awareness of this increased prevalence, many patients are not referred to a rheumatologist. PMID- 28732138 TI - Involving citizens in priority setting for public health research: Implementation in infection research. AB - BACKGROUND: Public sources fund the majority of UK infection research, but citizens currently have no formal role in resource allocation. To explore the feasibility and willingness of citizens to engage in strategic decision making, we developed and tested a practical tool to capture public priorities for research. METHOD: A scenario including six infection themes for funding was developed to assess citizen priorities for research funding. This was tested over two days at a university public festival. Votes were cast anonymously along with rationale for selection. The scenario was then implemented during a three-hour focus group exploring views on engagement in strategic decisions and in-depth evaluation of the tool. RESULTS: 188/491(38%) prioritized funding research into drug-resistant infections followed by emerging infections(18%). Results were similar between both days. Focus groups contained a total of 20 citizens with an equal gender split, range of ethnicities and ages ranging from 18 to >70 years. The tool was perceived as clear with participants able to make informed comparisons. Rationale for funding choices provided by voters and focus group participants are grouped into three major themes: (i) Information processing; (ii) Knowledge of the problem; (iii) Responsibility; and a unique theme within the focus groups (iv) The potential role of citizens in decision making. Divergent perceptions of relevance and confidence of "non-experts" as decision makers were expressed. CONCLUSION: Voting scenarios can be used to collect, en masse, citizens' choices and rationale for research priorities. Ensuring adequate levels of citizen information and confidence is important to allow deployment in other formats. PMID- 28732139 TI - Advances in Electrocatalysis for Energy Conversion and Synthesis of Organic Molecules. AB - Ubiquitous electrochemistry is expected to play a major role for reliable energy supply as well as for production of sustainable fuels and chemicals. The fundamental understanding of organics-based electrocatalysis in alkaline media at the solid-liquid interface involves complex mechanisms and performance descriptors (from the electrolyte and reaction intermediates), which undermine the roads towards advance and breakthroughs. Here, we review and diagnose recently designed strategies for the electrochemical conversion of organics into electricity and/or higher-value chemicals. To tune the mysterious workings of nanocatalysts in electrochemical devices, we examine the guiding principles by which the performance of a particular electrode material is governed, thus highlighting various tactics for the development of synthesis methods for nanomaterials with specific properties. We end by examining the production of chemicals by using electrochemical methods, from selective oxidation to reduction reactions. The intricate relationship between electrode and selectivity encourages both of the communities of electrocatalysis and organic synthesis to move forward together toward the renaissance of electrosynthesis methods. PMID- 28732141 TI - Intraoperative ultrasound for prediction of hepatocellular carcinoma biological behaviour: Prospective comparison with pathology. AB - BACKGROUND & AIMS: Preoperative prediction of both microinvasive hepatocellular carcinoma and histological grade of hepatocellular carcinoma is pivotal to treatment planning and prognostication. The aim of this study was to evaluate whether some intraoperative ultrasound features correlate with both the presence of same histological patterns and differentiation grade of hepatocellular carcinoma on the histological features of the primary resected tumour. METHODS: All patients with single, small hepatocellular carcinoma that underwent hepatic resection were included in this prospective double-blind study: the intraoperative ultrasound patterns of nodule were registered and compared with similar histological features. RESULTS: A total of 179 patients were enclosed in this study: 97 (54%) patients (34% in HCC <=2 cm) had a microinvasive hepatocellular carcinoma at ultrasound examination, while 82 (46%) patients (41% in HCC <=2 cm) at histological evaluation. Statistical analysis showed that diameters <=2 cm, presence of satellites and microinvasive hepatocellular carcinoma at ultrasound examination were the variables with the strongest association with the histological findings. In the multivariate analysis, the vascular microinfiltration and infiltrative hepatocellular carcinoma aspect were independent predictors for grading. CONCLUSIONS: In patients with cirrhosis and hepatocellular carcinoma, the prevalence of microinvasive hepatocellular carcinoma is high, even in cases of HCC <=2 cm. Intraoperative ultrasound findings strongly correlated with histopathological criteria in detecting microinvasive patterns and are useful to predict neoplastic differentiation. The knowledge of these features prior to treatment are highly desired (this can be obtained by an intraoperative ultrasound examination), as they could help in providing optimal management of patients with hepatocellular carcinoma. PMID- 28732140 TI - Fibroblast growth factor 2 (FGF2) is present in human spermatozoa and is related with sperm motility. The use of recombinant FGF2 to improve motile sperm recovery. AB - Fibroblast growth factors (FGFs) and their receptors (FGFRs) regulate several functions of somatic cells. In a previous work, we reported FGFR expression in human spermatozoa and their involvement in motility. This study aimed to evaluate the presence and localization of fibroblast growth factor 2 (FGF2) in human spermatozoa, to determine the relationship of FGF2 levels with conventional semen parameters and to assess the effect of recombinant FGF2 (rFGF2) on sperm recovery in a selection procedure. Western immunoblotting analysis using an antibody against FGF2 revealed an 18-kDa band in sperm protein extracts. The protein was immunolocalized in the sperm flagellum and acrosomal region, as well as in all germ cells. Sperm FGF2 levels, assessed by flow cytometry, showed a positive (p < 0.05) correlation with sperm concentration, motility, total sperm number and total motile cells per ejaculate. Moreover, samples with abnormal motility depicted diminished (p < 0.01) FGF2 levels compared to those with normal motility. Spermatozoa exposed to rFGF2 bound the protein, exhibited higher (p < 0.05) total and motile sperm recoveries, and increased (p < 0.01) kinematic parameters after the swim-up. Findings herein presented lead to consider sperm FGF2 level as a potential marker of sperm quality, and rFGF2 as a supplement for improving sperm recovery in selection techniques. PMID- 28732142 TI - Network meta-analysis including treatment by covariate interactions: Consistency can vary across covariate values. AB - BACKGROUND: Many reviews aim to compare numerous treatments and report results stratified by subgroups (eg, by disease severity). In such cases, a network meta analysis model including treatment by covariate interactions can estimate the relative effects of all treatment pairings for each subgroup of patients. Two key assumptions underlie such models: consistency of treatment effects and consistency of the regression coefficients for the interactions. Consistency may differ depending on the covariate value at which consistency is assessed. For valid inference, we need to be confident of consistency for the relevant range of covariate values. In this paper, we demonstrate how to assess consistency of treatment effects from direct and indirect evidence at various covariate values. METHODS: Consistency is assessed using visual inspection, inconsistency estimates, and probabilities. The method is applied to an individual patient dataset comparing artemisinin combination therapies for treating uncomplicated malaria in children using the covariate age. RESULTS: The magnitude of the inconsistency appears to be decreasing with increasing age for each comparison. For one comparison, direct and indirect evidence differ for age 1 (P = .05), and this brings results for age 1 for all comparisons into question. CONCLUSION: When fitting models including interactions, the consistency of direct and indirect evidence must be assessed across the range of covariates included in the trials. Clinical inferences are only valid for covariate values for which results are consistent. PMID- 28732143 TI - IFNL4 rs368234815 and rs117648444 variants predict off-treatment HBsAg seroclearance in IFN-treated HBeAg-negative chronic hepatitis B patients. AB - BACKGROUND & AIM: Robust baseline predictors of interferon (IFN) response in HBeAg-negative chronic hepatitis B (CHB) patients are not currently available. The recently described rs368234815 TT/DeltaG dinucleotide and rs117648444 nonsynonymous P70S polymorphisms in IFN lambda 4 (IFNL4) gene, which are strongly associated with response to IFN in hepatitis C virus (HCV) infection, could be also useful in IFN-treated CHB patients. Here we assessed whether IFNL4 rs368234815 and rs117648444 polymorphisms predict IFN-induced HBsAg clearance in CHB patients. METHODS: We sequenced the IFNL4 gene on genomic DNA collected from 126 HBeAg-negative CHB patients treated with IFN and followed up for a median of 11 (1-23) years. RESULTS: The 15-year cumulative probability of HBsAg loss in the 62 carriers of the rs368234815 TT/TT genotype, which abolishes the IFNlambda4 protein production, was comparable to that of 19 patients carrying the rs117648444 T allele predicted to produce an impaired IFNlambda4-S70 protein (39% vs 42%, P = .827). In contrast, these 81 patients, either not producing IFNlambda4 or producing an impaired IFNlambda4-S70 protein, had a significantly higher 15-year probability of HBsAg loss compared to the 45 subjects predicted to encode only the fully functional IFNlambda4-P70 (42% vs 11% P = .003). At multivariate analysis, combination of the rs368234815 and rs117648444 genotypes strongly predicted HBsAg clearance (HR 5.90, 95% CI 1.70-20.9, P = .006) together with pretreatment serum HBV DNA levels (HR 0.57, 95% CI 0.39-0.83, P = .003). CONCLUSION: IFNL4 rs368234815 and rs117648444 functional variants are worth to be investigated as pretreatment combined predictors of IFN response in HBeAg negative CHB patients. PMID- 28732144 TI - Influence of high latitude light conditions on sensory quality and contents of health and sensory-related compounds in swede roots (Brassica napus L. ssp. rapifera Metzg.). AB - BACKGROUND: Vegetable growers in Arctic areas must increasingly rely on market strategies based on regional origin and product quality. Swede roots (rutabaga) were grown in a phytotron to investigate the effect of high latitude light conditions on sensory quality and some health and sensory-related compounds. Experimental treatments included modifications of 24 h natural day length (69 degrees 39' N) by moving plants at daily intervals to dark chambers with either no light, fluorescent growth light and/or low intensity photoperiod extension. RESULTS: Shortening the photosynthetic light period to 12 h produced smaller roots than 15.7 h and 18 h, with highest scores for bitter and sulfur taste, and lowest scores for sweetness, acidic taste and fibrousness. The photoperiod in combination with the photosynthetic light period also had an influence on glucosinolate (GLS) contents, with lowest concentrations in 24 h natural light and highest in 12 h natural light. Concentrations of vitamin C, glucose, fructose and sucrose were not significantly influenced by any of the treatments. CONCLUSION: High latitude light conditions, with long photosynthetic light periods and 24 h photoperiod, can enhance sweet/less bitter taste and reduce GLS contents in swede roots, compared to growth under short day conditions. This influence of light conditions on eating quality may benefit marketing of regional products from high latitudes. (c) 2017 Society of Chemical Industry. PMID- 28732145 TI - Evaluation of primary mediastinal large B cell lymphoma by flow cytometry. AB - BACKGROUND: Primary mediastinal large B cell lymphoma (PMLBCL) is a B cell non Hodgkin lymphoma (B-NHL) that shows morphologic, immunophenotypic, and genetic similarities to classical Hodgkin lymphoma (CHL). We evaluated the neoplastic and reactive infiltrate of PMLBCL by flow cytometry (FC). METHODS: A total of 24 cases of PMLBCL were retrospectively characterized using FC combinations for B NHL, T-NHL, and CHL. RESULTS: The CHL assay identified the neoplastic population (NP) in all cases, while the B-NHL assay identified the NP in 18 of 24 cases. In four cases, the neoplastic population was retrospectively identified in the B-NHL tube, given the CHL tube-derived immunophenotype. Neoplastic cells of PMLBCL displayed a B cell immunophenotype (CD19/CD20+ ), with CD40 consistently and brightly expressed. Most cases lacked immunoglobulin light chains, CD10, and CD15; CD30 was frequently expressed. All cases showed expression of CD71 and CD95. The reactive infiltrate in PMLBCL showed increases in T cells relative to reactive tissues. Lower CD4/CD8 ratios in PMLBCL relative to CHL and reactive tissues were also observed. Although not seen as commonly as with CHL, 41% of cases showed a reactive CD3/CD4/CD7bright /CD45bright+ T cell population. Reactive populations seen in PMLBCL were similar to that seen in diffuse large B cell lymphoma, not otherwise specified. CONCLUSIONS: FC can detect the NP of PMLBCL and a FC assay for CHL performed better than a B-NHL assay in this regard. The neoplastic cells showed a B cell immunophenotype with over-expression of CD40. The reactive infiltrate in PMLBCL shows unique features including a prominent CD8+ T cell infiltrate. (c) 2017 International Clinical Cytometry Society. PMID- 28732146 TI - Medicago truncatula Zinc-Iron Permease6 provides zinc to rhizobia-infected nodule cells. AB - Zinc is a micronutrient required for symbiotic nitrogen fixation. It has been proposed that in model legume Medicago truncatula, zinc is delivered by the root vasculature into the nodule and released in the infection/differentiation zone. There, transporters must introduce this element into rhizobia-infected cells to metallate the apoproteins that use zinc as a cofactor. MtZIP6 (Medtr4g083570) is an M. truncatula Zinc-Iron Permease (ZIP) that is expressed only in roots and nodules, with the highest expression levels in the infection/differentiation zone. Immunolocalization studies indicate that it is located in the plasma membrane of nodule rhizobia-infected cells. Down-regulating MtZIP6 expression levels with RNAi does not result in any strong phenotype when plants are fed mineral nitrogen. However, these plants displayed severe growth defects when they depended on nitrogen fixed by their nodules, losing of 80% of their nitrogenase activity. The reduction of this activity was likely an indirect effect of zinc being retained in the infection/differentiation zone and not reaching the cytosol of rhizobia-infected cells. These data are consistent with a model in which MtZIP6 would be responsible for zinc uptake by rhizobia-infected nodule cells in the infection/differentiation zone. PMID- 28732147 TI - Financial Incentives and Health Coaching to Improve Physical Activity Following Total Knee Replacement: A Randomized Controlled Trial. AB - OBJECTIVE: Most persons who undergo total knee replacement (TKR) do not increase their physical activity following surgery. We assessed whether financial incentives and health coaching would improve physical activity in persons undergoing TKR. METHODS: We designed a factorial randomized controlled trial among persons undergoing TKR for osteoarthritis. Subjects underwent normal perioperative procedures, including postoperative physical therapy, and were assigned to 1 of 4 arms: attention control, telephonic health coaching (THC), financial incentives (FI), or THC + FI. We objectively measured step counts and minutes of physical activity using a commercial accelerometer (Fitbit Zip) and compared the changes from pre-TKR to 6 months post-TKR across the 4 study arms. RESULTS: Of the 202 randomized subjects, 150 (74%) provided both pre-TKR and 6 months post-TKR accelerometer data. Among completers, the mean +/- SE daily step count at 6 months ranged from 5,619 +/- 381 in the THC arm to 7,152 +/- 407 in the THC + FI arm (adjusting for baseline values). Daily step count 6 months post TKR increased by 680 (95% confidence interval [95% CI] -94, 1,454) in the control arm, 274 (95% CI -473, 1,021) in the THC arm, 826 (95% CI 89, 1,563) in the FI arm, and 1,808 (95% CI 1,010, 2,606) in the THC + FI arm. Weekly physical activity increased by mean +/- SE 14 +/- 10, 14 +/- 10, 16 +/- 10, and 39 +/- 11 minutes in the control, THC, FI, and THC + FI arms, respectively. CONCLUSION: A dual THC + FI intervention led to substantial improvements in step count and physical activity following TKR. PMID- 28732148 TI - Trends in Hospitalizations for Serious Infections in Patients With Rheumatoid Arthritis in the US Between 1993 and 2013. AB - OBJECTIVE: The epidemiology of hospitalizations with infections among patients with rheumatoid arthritis (RA) is unknown, despite an increase in RA treatments that confer a risk of infection. METHODS: We examined National Inpatient Sample data from 1993-2013. We identified hospitalizations among adults with RA, defined by International Classification of Diseases, Ninth Revision, Clinical Modification codes (714.xx) in any secondary diagnosis field. We evaluated 5 infections as the primary diagnosis: pneumonia, sepsis, urinary tract infection (UTI), skin and soft tissue infections (SSTIs), and opportunistic infections (OIs). The primary outcome was the proportion of hospitalizations for each infection among all hospitalizations with a secondary diagnosis of RA. RESULTS: There were 792,921 hospitalizations for infection with a secondary diagnosis of RA, with the rates increasing from 90 to 206 per 100,000 persons from 1993-2013. The proportion of hospitalizations decreased for pneumonia (from 5.4% to 4.6%), UTI (from 0.4% to 0.38%), and OIs (from 0.44% to 0.26%). The proportion of hospitalizations for SSTIs increased slightly (from 2.3% to 2.5%), while hospitalizations for sepsis more than tripled (from 1.9% to 6.4%). CONCLUSION: Between 1993 and 2013, the proportion of hospitalizations for infections among RA patients appeared to decline for pneumonia and OIs, with a slight decrease in UTI, a slight increase in SSTIs, and a substantial increase in hospitalizations with sepsis. Our results are consistent with previous reports that the sensitivity of sepsis coding has increased over time. PMID- 28732149 TI - Beware of the origin of numbers: Standard scoring of the SF-12 and SF-36 summary measures distorts measurement and score interpretations. AB - The 12-item Short Form Health Survey (SF-12) is a generic health rating scale developed to reproduce the Physical and Mental Component Summary scores (PCS and MCS, respectively) of a longer survey, the SF-36. The standard PCS/MCS scoring algorithm has been criticized because its expected dimensionality often lacks empirical support, scoring is based on the assumption that physical and mental health are uncorrelated, and because scores on physical health items influence MCS scores, and vice versa. In this paper, we review the standard PCS/MCS scoring algorithm for the SF-12 and consider alternative scoring procedures: the RAND-12 Health Status Inventory (HSI) and raw sum scores. We corroborate that the SF-12 reproduces SF-36 scores but also inherits its problems. In simulations, good physical health scores reduce mental health scores, and vice versa. This may explain results of clinical studies in which, for example, poor physical health scores result in good MCS scores despite compromised mental health. When applied to empirical data from people with Parkinson's disease (PD) and stroke, standard SF-12 scores suggest a weak correlation between physical and mental health (rs .16), whereas RAND-12 HSI and raw sum scores show a much stronger correlation (rs .67-.68). Furthermore, standard PCS scores yield a different statistical conclusion regarding the association between physical health and age than do RAND 12 HSI and raw sum scores. We recommend that the standard SF-12 scoring algorithm be abandoned in favor of alternatives that provide more valid representations of physical and mental health, of which raw sum scores appear the simplest. PMID- 28732150 TI - Research in Nursing & Health Author Guidelines. PMID- 28732151 TI - Patients' Attitudes and Experiences of Disease-Modifying Antirheumatic Drugs in Rheumatoid Arthritis and Spondyloarthritis: A Qualitative Synthesis. AB - OBJECTIVE: Nonadherence to disease-modifying antirheumatic drugs (DMARDS) in rheumatoid arthritis (RA) and spondyloarthritis (SpA) results in increased disease activity and symptoms and poorer quality of life. We aimed to describe patients' attitudes and experiences of DMARDs in RA and SpA to inform strategies to improve medication adherence. METHODS: Databases (MEDLINE, Embase, PsycINFO, and CINAHL) were searched to January 2016. Thematic synthesis was used to analyze the findings. RESULTS: From 56 studies involving 1,383 adult patients (RA [n = 1,149], SpA [n = 191], not specified [n = 43]), we identified 6 themes (with subthemes): intensifying disease identity (severity of sudden pharmacotherapy, signifying deteriorating health, daunting lifelong therapy), distressing uncertainties and consequences (poisoning the body, doubting efficacy, conflicting and confusing advice, prognostic uncertainty with changing treatment regimens), powerful social influences (swayed by others' experiences, partnering with physicians, maintaining roles, confidence in comprehensive and ongoing care, valuing peer support), privilege and right of access to biologic agents (expensive medications must be better, right to receive a biologic agent, fearing dispossession), maintaining control (complete ownership of decision, taking extreme risks, minimizing lifestyle intrusion), and negotiating treatment expectations (miraculous recovery, mediocre benefit, reaching the end of the line). CONCLUSION: Patients perceive DMARDs as strong medications with alarming side effects that intensify their disease identity. Trust and confidence in medical care, positive experiences with DMARDS among other patients, and an expectation that medications will help maintain participation in life can motivate patients to use DMARDs. Creating a supportive environment for patients to voice their concerns may improve treatment satisfaction, adherence, and health outcomes. PMID- 28732152 TI - Secukinumab in the Treatment of Psoriasis and Psoriatic Arthritis: A Review of the Literature. AB - While there are several commercially available treatment options for psoriasis and psoriatic arthritis, there remains a large number of individuals who are refractory to current modalities. In the recent past, there has been increasing evidence that interleukin (IL)-17 plays a vital role in the pathophysiology of psoriasis. Preclinical, phase II, and phase III studies of secukinumab (Cosentyx(r)) targeting IL-17 and its receptor have thus far proved to be promising. We reviewed the results of phase II and phase III clinical trials for secukinumab in the treatment of psoriasis and psoriatic arthritis. Only published studies were considered in the present review. We also performed an English language literature search from January 2003 to September 2015 using PubMed with any of the following key words: (secukinumab OR AIN457) AND (psoriasis OR psoriatic arthritis). In our review of the literature, seven phase III and five phase II clinical trials, as well as open-label extension studies with unpublished findings were found. Results from phase III clinical trials indicated secukinumab to be efficacious and safe for the treatment of psoriasis and psoriatic arthritis according to Psoriasis Area and Severity Index (PASI) and American College of Rheumatology (ACR) scores. The safety profile of this agent was similar across all studies, with the most frequently reported adverse events of nasopharyngitis, upper respiratory infections, headache, and injection site reaction. Secukinumab demonstrates rapid and robust clinical improvement accompanied by a favorable short- term safety profile. The results of the phase III trials continue to reinforce the theory that the IL-17 pathway is an essential target in psoriasis and psoriatic arthritis treatment. Additional extension studies of lower level evidence are needed to further understand the safety profile of the drug. PMID- 28732153 TI - Hepatitis B and C Viruses and Biologics. AB - Hepatitis B virus (HBV) and hepatitis C virus (HCV) are common, worldwide viral illnesses that potentially impact the clinician's ability to manage patients with immunosuppressive medications such as biological therapy. In light of recent literature reviews, patients with HBV and HCV should be referred to a hepatologist or infectious disease expert prior to initiation of biological therapy. PMID- 28732154 TI - Ironing Out Genes in the Environment: An Experimental Study of the DNA-Goethite Interface. AB - DNA fate in soil plays an important role in the cycling of genetic information in the environment. Adsorption onto mineral surfaces has great impact on this function. This study probes the kinetics, equilibrium behavior and bonding mechanisms associated with adsorption of DNA onto goethite, a common soil mineral. Surface sensitive ATR-FTIR and XPS approaches are applied to directly characterize the DNA-goethite interface. Adsorption kinetics follow a pseudo first-order model, suggesting adsorption rate is surface limited. Adsorption rate constants increase with DNA concentration, ranging from 3.29 * 10-3 to 3.55 * 10 1 min-1. Equilibrium adsorption, as monitored by ATR-FTIR and XPS, follows the Langmuir model, with a high affinity of DNA for goethite observed (K = 1.25 * 103 and 9.48 * 102 mL/mg for ATR-FTIR and XPS, respectively). ATR-FTIR and XPS characterization of the structure of surface adsorbed DNA demonstrates inner sphere coordination between backbone phosphate groups of DNA and goethite. Furthermore, adsorbed DNA retains a B-form, suggesting the DNA helix adsorbs on goethite without degradation or alteration to helical structure, despite binding of backbone phosphate groups. This work advances our understanding of the environmental behavior of DNA by characterizing the mechanism of adsorption onto a prominent soil mineral. PMID- 28732155 TI - Relating Redox Properties of Polyvinylamine-g-TEMPO/Laccase Hydrogel Complexes to Cellulose Oxidation. AB - The structure and electrochemical properties of adsorbed complexes based on mixtures of polyvinylamine-g-TEMPO (PVAm-T) and laccase were related to the ability of the adsorbed complexes to oxidize cellulose. PVAm-T10 with 10% of the amines bearing TEMPO moieties (i.e., DS = 10%), adsorbed onto gold sulfonate EQCM D sensor surfaces giving a hydrogel film that was 7 nm thick, 89% water, and encasing laccase (200 mM) and TEMPO moieties (33 mM). For DS values >10%, all of the TEMPOs in the hydrogel film were redox-active in that they could be oxidized by the electrode. With hydrogel layers made with lower-DS PVAm-Ts, only about half of the TEMPOs were redox-active; 10% DS appears to be a percolation threshold for complete TEMPO-to-TEMPO electron transport. In parallel experiments with hydrogel complexes adsorbed onto regenerated cellulose films, the aldehyde concentrations increased monotonically with the density of redox-active TEMPO moieties in the adsorbed hydrogel. The maximum density of aldehydes was 0.24 MUmol/m2, about 10 times less than the theoretical concentration of primary hydroxyl groups exposed on crystalline cellulose surfaces. Previous work showed that PVAm-T/laccase complexes are effective adhesives between wet cellulose surfaces when the DS is >10%. This work supports the explanation that TEMPO-to TEMPO electron transport is required for the generation of aldehydes necessary for wet adhesion to PVAm. PMID- 28732156 TI - Fixed Bed Modeling of Nonsteroidal Anti-Inflammatory Drug Removal by Ion-Exchange in Synthetic Urine: Mass Removal or Toxicity Reduction? AB - Ion-exchange removal of nonsteroidal anti-inflammatory drugs (NSAIDs) in synthetic urine can selectively remove pharmaceuticals with minimal coremoval of nutrients to enhance nutrient recovery efforts. However, the effect of endogenous metabolites in urine on ion-exchange removal, and the corresponding reduction in ecotoxicity potential of pharmaceuticals in treated urine entering the environment, is unknown. To assess treatment efficacy, this work paired predicted breakthrough curves determined by the homogeneous surface diffusion model to an in vitro bioassay to evaluate COX-1 inhibition. The presence of endogenous metabolites in urine significantly impacted pharmaceutical removal, by competing for ion-exchange sites on the resin and reducing the resin capacity for pharmaceuticals. This indicates ion-exchange would be ineffective at removing NSAIDs and other negatively charged compounds in urine. Due to hydrolysis of pharmaceutical metabolites back to the parent compound, treatment systems should be designed based on the ultimate pharmaceutical concentration in ureolyzed urine. Mass removal and COX-1 inhibition followed a nonlinear correlation and mixture toxicity followed the generalized concentration addition model. This work demonstrates the importance of evaluating removal of contaminants of emerging concern, such as pharmaceuticals, using a risk-based approach to ecotoxicity end points in conjunction with mass removal. PMID- 28732157 TI - Large-Scale Statistics for Threshold Optimization of Optically Pumped Nanowire Lasers. AB - Single nanowire lasers based on bottom-up III-V materials have been shown to exhibit room-temperature near-infrared lasing, making them highly promising for use as nanoscale, silicon-integrable, and coherent light sources. While lasing behavior is reproducible, small variations in growth conditions across a substrate arising from the use of bottom-up growth techniques can introduce interwire disorder, either through geometric or material inhomogeneity. Nanolasers critically depend on both high material quality and tight dimensional tolerances, and as such, lasing threshold is both sensitive to and a sensitive probe of such inhomogeneity. We present an all-optical characterization technique coupled to statistical analysis to correlate geometrical and material parameters with lasing threshold. For these multiple-quantum-well nanolasers, it is found that low threshold is closely linked to longer lasing wavelength caused by losses in the core, providing a route to optimized future low-threshold devices. A best in-group room temperature lasing threshold of ~43 MUJ cm-2 under pulsed excitation was found, and overall device yields in excess of 50% are measured, demonstrating a promising future for the nanolaser architecture. PMID- 28732159 TI - Remote Single-Molecule Switching: Identification and Nanoengineering of Hot Electron-Induced Tautomerization. AB - Molecular electronics where single molecules perform basic functionalities of digital circuits is a fascinating concept that one day may augment or even replace nowadays semiconductor technologies. The tautomerization of molecules, that is, the bistable functional position of hydrogen protons within an organic frame, has recently been intensively discussed as a potential avenue toward nanoscale switches. It has been shown that tautomerization can be triggered locally or nonlocally, that is, by a scanning tunneling microscope (STM) tip positioned directly above or in close vicinity to the molecule. Whereas consensus exists that local switching is caused by inelastic electrons that excite vibrational molecular modes, the detailed processes responsible for nonlocal tautomerization switching and, even more important in the context of this work, methods to control, engineer, and potentially utilize this process are largely unknown. Here, we demonstrate for dehydrogenated H2Pc molecules on Ag(111) how to controllably decrease or increase the probability of nonlocal, hot electron induced tautomerization by atom-by-atom designed Ag nanostructures. We show that Ag atom walls act as potential barriers that exponentially damp the hot electron current between the injection point and the molecule, reducing the switching probability by up to 83% for a four-atom wide wall. By placing the molecule in one and the STM tip in the other focal point of an elliptical nanostructure, we could coherently focus hot electrons onto the molecule that led to an almost tripled switching probability. Furthermore, single and double slit experiment based on silver atom structures were used to characterize the spatial extension of hot electron packets. The absence of any detectable interference pattern suggests that the coherence length of the hot electrons that trigger tautomerization processes is rather short. Our results demonstrate that the tautomerization switching of single molecules can remotely be controlled by utilizing suitable nanostructures and may pave the way for designing new tautomerization-based switches. PMID- 28732158 TI - Deleterious Consequences of UDP-Galactopyranose Mutase Inhibition for Nematodes. AB - Parasitic nematodes pose a serious threat to agriculture, livestock, and human health. Increasing resistance to antiparasitic agents underscores the need to replenish our anthelmintic arsenal. The nonpathogenic Caenorhabditis elegans, which serves as an effective model of parasitic helminths, has been used to search for new anthelmintic leads. We previously reported small-molecule inhibitors of the essential C. elegans protein UDP-galactopyranose mutase (UGM or Glf). This enzyme is required for the generation of galactofuranose (Galf) containing glycans and is needed in nematodes for proper cuticle formation. Though our first-generation inhibitors were effective in vitro, they elicited no phenotypic effects. These findings are consistent with the known difficulty of targeting nematodes. C. elegans is recalcitrant to pharmacological modulation; typically, less than 0.02% of small molecules elicit a phenotypic effect, even at 40 MUM. We postulated that the lack of activity of the UGM inhibitors was due to their carboxylic acid group, which can be exploited by nematodes for detoxification. We therefore tested whether replacement of the carboxylate with an N-acylsulfonamide surrogate would result in active compounds. UGM inhibitors with the carboxylate mimetic can phenocopy the deleterious consequences of UGM depletion in C. elegans. These findings support the use of UGM inhibitors as anthelmintic agents. They also outline a strategy to render small-molecule carboxylates more effective against nematodes. PMID- 28732160 TI - Color-Encoded Assays for the Simultaneous Quantification of Dual Cancer Biomarkers. AB - For the first time, the scattering light of noble nanoparticles was applied for the simultaneous detection of dual cancer biomarkers. Two nanoprobes with dual scattering light colors were used for the simultaneous imaging of alpha fetoprotein (AFP) and carcinoembryonic antigen (CEA) based on the sandwich-type immunoassay. Since AFP can combine anti-AFP-modified gold nanoparticles, which have green scattering light under the dark-field microscopic imaging (iDFM) technique, while CEA can conjugate anti-CEA-immobilized silver nanoparticles, which have blue scattering light, the simultaneous determination of AFP and CEA can be achieved by separately counting the number of green and blue light spots in iDFM. The mutual interference between the detection processes of AFP and CEA in the dual detection was investigated, and a negligible interference was found when the concentration of the antigen was in the range of 0.5-10 ng/mL, indicating the practicability of the simultaneous sensitive detection of dual targets. Furthermore, AFP and CEA in serum samples were also quantified directly without additional sample pretreatment, demonstrating the potential applications of the developed method in clinical diagnosis. PMID- 28732161 TI - Elegant pH-Responsive Nanovehicle for Drug Delivery Based on Triazine Dendrimer Modified Magnetic Nanoparticles. AB - Owing to properties of magnetic nanoparticles and elegant three-dimensional macromolecule architectural features, dendrimeric structures have been investigated as nanoscale drug delivery systems. In this work, a novel magnetic nanocarrier, generation two (G2) triazine dendrimer modified Fe3O4@SiO2 magnetic nanoparticles (MNP-G2), was designed, fabricated, and characterized by Fourier transform infrared (FT-IR), thermal gravimetric analysis (TGA), vibrating sample magnetometer (VSM), field emission scanning electron microscopy (FE-SEM), transmission electron microscopy (TEM), and dynamic light scattering (DLS). The prepared MNP-G2 nanosystem offers a new formulation that combines the unique properties of MNPs and triazine dendrimer as a biocompatible material for biomedical applications. To demonstrate the potential of MNP-G2, the nanoparticles were loaded with methotrexate (MTX), a proven chemotherapy drug. The MTX-loaded MNP-G2 (MNP-G2/MTX) exhibited a high drug-loading capacity of MTX and the excellent ability for controlled drug release. The cytotoxicity of MNP G2/MTX using an 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide based assay and MCF-7, HeLa, and Caov-4 cell lines revealed that MNP-G2/MTX was more active against the tumor cells than the free drug in a mildly acidic environment. The results of hemolysis, hemagglutination, and coagulation assays confirmed the good blood safety of MNP-G2/MTX. Moreover, the cell uptake and intracellular distribution of MNP-G2/MTX were studied by flow cytometry analysis and confocal laser scanning microscopy (CLSM). This research suggests that MNP G2/MTX with good biocompatibility and degradability can be selected as an ideal and effective drug carrier in targeted biomedicine studies especially anticancer applications. PMID- 28732162 TI - Dynamic Design of Spatial Patterns of Colloidal Suspensions. AB - We study the collective dynamics of colloidal suspensions in the presence of a time-dependent potential by means of dynamic density functional theory. We consider a nonlinear diffusion equation for the density and show that spatial patterns emerge from a sinusoidal external potential with a time-dependent wavelength. These patterns are characterized by a sinusoidal density with the average wavelength and a Bessel-function envelope with an induced wavelength that depends only on the amplitude of the temporal oscillations. As a generalization of this result, we propose a design strategy to obtain a family of spatial patterns using time-dependent potentials of practically arbitrary shape. PMID- 28732163 TI - Diamines Can Initiate New Particle Formation in the Atmosphere. AB - Recent experimental evidence suggests that diamines can enhance atmospheric new particle formation more efficiently compared to monoamines such as dimethylamine. Here we investigate the molecular interactions between sulfuric acid (sa) and the diamine putrescine (put) using computational methods. The molecular structure of up to four sulfuric acid molecules and up to four putrescine molecules were obtained at the omegaB97X-D/6-31++G(d,p) level of theory. We utilized a domain local pair natural orbital coupled cluster method (DLPNO-CCSD(T)/aug-cc-pVTZ) to obtain highly accurate binding energies of the clusters. We find that the (sa)1 4(put)1-4 clusters show more ionic character than clusters consisting of sulfuric acid and dimethylamine (dma) by readily forming several sulfate ions in the cluster. To estimate the stability of the clusters, we calculate the evaporation rates and compare them to ESI-APi-TOF measurements. Using the atmospheric cluster dynamics code (ACDC), we simulate and compare the new particle formation rates between the (sa)1-4(put)1-4 and (sa)1-4(dma)1-4 cluster systems. We find that putrescine significantly enhances the formation of new particles compared to dimethylamine. Our findings suggest that a large range of amines with different basicity is capable of explaining various regions of the observed new particle formation events. These results indicate that diamines, or related compounds with high basicity, might be important species in forming the initial cluster with sulfuric acid and subsequently more abundant amines with lower basicity can assist in the new particle formation process by attaching to the sulfuric acid diamine nucleus. PMID- 28732164 TI - Electrochemical Intercalation of Mg2+ into Anhydrous and Hydrated Crystalline Tungsten Oxides. AB - The reversible intercalation of multivalent cations, especially Mg2+, into a solid-state electrode is an attractive mechanism for next-generation energy storage devices. These reactions typically exhibit poor kinetics due to a high activation energy for interfacial charge-transfer and slow solid-state diffusion. Interlayer water in V2O5 and MnO2 has been shown to improve Mg2+ intercalation kinetics in nonaqueous electrolytes. Here, the effect of structural water on Mg2+ intercalation in nonaqueous electrolytes is examined in crystalline WO3 and the related hydrated and layered WO3.nH2O (n = 1, 2). Using thin film electrodes, cyclic voltammetry, Raman spectroscopy, X-ray diffraction, and electron microscopy, the energy storage in these materials is determined to involve reversible Mg2+ intercalation. It is found that the anhydrous WO3 can intercalate up to ~0.3 Mg2+ (75 mAh g-1) and can maintain the monoclinic structure for at least 50 cycles at a cyclic voltammetry sweep rate of 0.1 mV s-1. The kinetics of Mg2+ storage in WO3 are limited by solid-state diffusion, which is similar to its behavior in a Li+ electrolyte. On the other hand, the maximum capacity for Mg2+ storage in WO3.nH2O is approximately half that of WO3 (35 mAh g-1). However, the kinetics of both Mg2+ and Li+ storage in WO3.nH2O are primarily limited by the interface and are thus pseudocapacitive. The stability of the structural water in WO3.nH2O varies: the interlayer water of WO3.2H2O is removed upon exposure to a nonaqueous electrolyte, while the water directly coordinated to W is stable during electrochemical cycling. These results demonstrate that tungsten oxides are potential candidates for Mg2+ cathodes, that in these materials structural water can lead to improved Mg2+ kinetics at the expense of capacity, and that the type of structural water affects stability. PMID- 28732165 TI - Complexity Reduction in Large Quantum Systems: Fragment Identification and Population Analysis via a Local Optimized Minimal Basis. AB - We present, within Kohn-Sham density functional theory calculations, a quantitative method to identify and assess the partitioning of a large quantum mechanical system into fragments. We then show how within this framework simple generalizations of other well-known population analyses can be used to extract, from first-principles, reliable electrostatic multipoles for the identified fragments. Our approach reduces arbitrariness in the fragmentation procedure and enables the possibility to assess quantitatively whether the corresponding fragment multipoles can be interpreted as observable quantities associated with a system moiety. By applying our formalism within the code BigDFT, we show that the use of a minimal set of in situ-optimized basis functions allows at the same time a proper fragment definition and an accurate description of the electronic structure. PMID- 28732166 TI - MEL-N16: A Series of Novel Endomorphin Analogs with Good Analgesic Activity and a Favorable Side Effect Profile. AB - Opioid peptides are neuromodulators that bind to opioid receptors and reduce pain sensitivity. Endomorphins are among the most active endogenous opioid peptides, and they have good affinity and selectivity toward the MU opioid receptor. However, their clinical usage is hindered by their inability to cross the blood brain barrier and their poor in vivo activity after peripheral injection. In order to overcome these defects, we have designed and synthesized a series of novel endomorphin analogs with multiple site modifications. Radioligand binding, cAMP accumulation, and beta-arrestin-2 recruitment assays were employed to determine the activity of synthesized endomorphin analogs toward opioid receptors. The blood-brain barrier permeability and antinociceptive effect of these analogs were determined in several rodent models of acute and persistent pain. In addition, the side effects of the analogs were examined. The radioligand binding assay and functional activity examination indicated that the MEL-N16 series of compounds were more active agonists against MU opioid receptor than were the parent peptides. Notably, the analogs displayed biased downstream signaling toward G-protein pathways over beta-arrestin-2 recruitment. The analogs showed highly potent antinociceptive effects in the tested nociceptive models. In comparison with endomorphins, the synthesized analogs were better able to penetrate the blood-brain barrier and exerted their pain regulatory activity in the central nervous system after peripheral injection. These analogs also have lower tendency to cause side effects than morphine does at similar or equal antinociceptive doses. The MEL-N16 compounds have highly potent and efficacious analgesic effects in various pain models with a favorable side effect profile. PMID- 28732167 TI - Quantum Transport and Sub-Band Structure of Modulation-Doped GaAs/AlAs Core Superlattice Nanowires. AB - Modulation-doped III-V semiconductor nanowire (NW) heterostructures have recently emerged as promising candidates to host high-mobility electron channels for future high-frequency, low-energy transistor technologies. The one-dimensional geometry of NWs also makes them attractive for studying quantum confinement effects. Here, we report correlated investigations into the discrete electronic sub-band structure of confined electrons in the channel of Si delta-doped GaAs GaAs/AlAs core-superlattice NW heterostructures and the associated signatures in low-temperature transport. On the basis of accurate structural and dopant analysis using scanning transmission electron microscopy and atom probe tomography, we calculated the sub-band structure of electrons confined in the NW core and employ a labeling system inspired by atomic orbital notation. Electron transport measurements on top-gated NW transistors at cryogenic temperatures revealed signatures consistent with the depopulation of the quasi-one-dimensional sub-bands, as well as confinement in zero-dimensional-like states due to an impurity-defined background disorder potential. These findings are instructive toward reaching the ballistic transport regime in GaAs-AlGaAs based NW systems. PMID- 28732168 TI - Inland Sea Spray Aerosol Transport and Incomplete Chloride Depletion: Varying Degrees of Reactive Processing Observed during SOAS. AB - Multiphase reactions involving sea spray aerosol (SSA) impact trace gas budgets in coastal regions by acting as a reservoir for oxidized nitrogen and sulfur species, as well as being a source of halogen gases (HCl, ClNO2, etc.). Whereas most studies of multiphase reactions on SSA have focused on marine environments, far less is known about SSA transported inland. Herein, single-particle measurements of SSA are reported at a site >320 km from the Gulf of Mexico, with transport times of 7-68 h. Samples were collected during the Southern Oxidant and Aerosol Study (SOAS) in June-July 2013 near Centreville, Alabama. SSA was observed in 93% of 42 time periods analyzed. During two marine air mass periods, SSA represented significant number fractions of particles in the accumulation (0.2-1.0 MUm, 11%) and coarse (1.0-10.0 MUm, 35%) modes. Chloride content of SSA particles ranged from full to partial depletion, with 24% of SSA particles containing chloride (mole fraction of Cl/Na >= 0.1, 90% chloride depletion). Both the frequent observation of SSA at an inland site and the range of chloride depletion observed suggest that SSA may represent an underappreciated inland sink for NOx/SO2 oxidation products and a source of halogen gases. PMID- 28732169 TI - Design of Modular Peptide Surfactants and Their Surface Activity. AB - Designed peptide surfactants offer a number of advanced properties over conventional petrochemical surfactants, including biocompatibility, sustainability, and tailorability of the chemical and physical properties through peptide design. Their biocompatibility and degradability make them attractive for various applications, particularly for food and pharmaceutical applications. In this work, two new peptide surfactants derived from an amphiphilic peptide surfactant (AM1) were designed (AM-S and C8-AM) to better understand links between structure, interfacial activity, and emulsification. Based on AM1, which has an interfacial alpha-helical structure, AM-S and C8-AM were designed to have two modules, that is, the alpha-helical AM1 module and an additional hydrophobic moiety to provide for better anchoring at the oil-water interface. Both AM-S and C8-AM at low bulk concentration of 20 MUM were able to adsorb rapidly at the oil water interface and reduced interfacial tension to equilibrium values of 17.0 and 8.4 mN/m within 400 s, respectively. Their relatively quick adsorption kinetics allowed the formation of nanoemulsions with smaller droplet sizes and narrower size distribution. AM-S and C8-AM at 800 MUM bulk concentration could make nanoemulsions of average diameters 180 and 147 nm, respectively, by simple sonication. With respect to the long-term stability, a minimum peptide concentration of 400 MUM for AM-S and a lower concentration of 100 MUM for C8-AM were demonstrated to effectively stabilize nanoemulsions over 3 weeks. Compared to AM1, the AM-S nanoemulsion retained its stimuli-responsive function triggered by metal ions, whereas the C8-AM nanoemulsions did not respond to the stimuli as efficiently as AM-S because of the strong anchoring ability of the hydrophobic C8 module. The two-module design of AM-S and C8-AM represents a new strategy in tuning the surface activity of peptide surfactants, offering useful information and guidance of future designs. PMID- 28732170 TI - Angiotensin II receptors' modulation of calcium homeostasis in human vascular endothelial cells. AB - Angiotensin II (AngII) plays an important role in the regulation of vascular smooth muscle function. However, little is known about AngII and its receptors AT1 (AT1R) and AT2 (AT2R) and their modulation of intracellular calcium in vascular endothelial cells (VECs) in general and more particularly of human origin. Using western blots, our results showed that AT1Rs and AT2Rs are present in human VECs (hVECs). Using quantitative 3D confocal imaging, our results showed that AngII is present at the cytoplasmic and nucleoplasmic levels and its relative density is lower in the nucleoplasm. However, both AngII receptors AT1 and AT2 are present at both the plasma and the nuclear envelope membranes (NEMs). AngII (10-10 mol/L) induces a transient decrease of the relative density of cytosolic and nuclear AT1Rs. Blockade of AT1Rs with losartan or blocking protein synthesis with cycloheximide does not prevent internalization and nuclear translocation of AT1Rs but prevents de novo AT1R synthesis. In addition, AngII induces cytosolic and nuclear increases (EC50 near 5 * 10-14 mol/L) of calcium via the activation of AT1Rs. These results demonstrate that both AT1 and AT2 receptors are present in hVECs, and that only AT1Rs seem to undergo transcellular trafficking and modulate cytosolic and nuclear calcium homeostasis. PMID- 28732171 TI - Using metagenomics to show the efficacy of forest restoration in the New Jersey Pine Barrens. AB - The Franklin Parker Preserve within the New Jersey Pine Barrens contains 5000 acres of wetlands habitat, including old-growth Atlantic white cedar (or AWC; Chamaecyparis thyoides) swamps, cranberry bogs, and former cranberry bogs undergoing restoration into AWC forests. This study showed that the C-use efficiency was greater in the old-growth AWC soils than in soils from 8-year-old mid-stage restored AWC stands, which were greater than found in soil from 4-year old AWC stands-the latter two stands being restored from long-term cranberry bogs. A metagenomic analysis of eDNA extracted from these soils showed that the C cycle trends were associated with increases in the relative numbers of DNA sequences from several copiotrophic bacterial groups (Bacteroidetes and Proteobacteria), complex C-decomposing fungal groups (Sordiomycetes, Mortierellales, and Thelephorales), and collembolan and formicid invertebrates. All groups are indicators of successionally more advanced soils, and critical for soil C-cycle activities. These data suggest that the restoration activities studied are enhancing critical guilds of soil biota, and increasing C-use efficiency in the soils of restored habitats, and that the use of metagenomic analysis of soil eDNA can be used in the development of assessment models for soil recovery of wetlands following restoration. PMID- 28732172 TI - Role of endothelin-1 and its receptors, ETA and ETB, in the survival of human vascular endothelial cells. AB - Our previous work showed the presence of endothelin-1 (ET-1) receptors, ETA and ETB, in human vascular endothelial cells (hVECs). In this study, we wanted to verify whether ET-1 plays a role in the survival of hVECs via the activation of its receptors ETA and (or) ETB (ETAR and ETBR, respectively). Our results showed that treatment of hVECs with ET-1 prevented apoptosis induced by genistein, an effect that was mimicked by treatment with ETBR-specific agonist IRL1620. Furthermore, blockade of ETBR with the selective ETBR antagonist A-192621 prevented the anti-apoptotic effect of ET-1 in hVECs. However, activation of ETA receptor alone did not seem to contribute to the anti-apoptotic effect of ET-1. In addition, the anti-apoptotic effect of ETBR was found to be associated with caspase 3 inhibition and does not depend on the density of this type of receptor. In conclusion, our results showed that ET-1 possesses an anti-apoptotic effect in hVECs and that this effect is mediated, to a great extent, via the activation of ETBR. This study revealed a new role for ETBR in the survival of hVECs. PMID- 28732173 TI - Exploring the potential of gametic reconstruction of parental genotypes by F1 hybrids as a bridge for rapid introgression. AB - Interspecific hybridization and genetic introgression are commonly observed in natural populations of many species, especially trees. Among oaks, gene flow between closely related species has been well documented. And yet, hybridization does not lead to a "melting pot", i.e., the homogenization of phenotypic traits. Here, we explore how the combination of several common reproductive and genomic traits could create an avenue for interspecific gene flow that partially explains this apparent paradox. During meiosis, F1 hybrids will produce approximately (1/2)n "reconstructed" parental gametes, where n equals the number of chromosomes. Crossing over would introduce a small amount of introgressive material. The resulting parental-type gametophytes would probably possess a similar fertilization advantage as conspecific pollen. The resulting "backcross" would actually be the genetic equivalent of a conspecific out-cross, with a small amount of heterospecific DNA captured through crossing over. Even with detailed genomic analysis, the resulting offspring would not appear to be a backcross. This avenue for rapid introgression between species through the F1 hybrid will be viable for organisms that meet certain conditions: low base chromosome number, conserved genomic structure and size, production of billions of gametes/gametophytes during each reproductive event, and conspecific fertilization advantage. PMID- 28732174 TI - Spatial organization of fibroblast and spermatocyte nuclei with different B chromosome content in Korean field mouse, Apodemus peninsulae (Rodentia, Muridae). AB - Korean field mouse (Apodemus peninsulae) shows a wide variation in the number of B chromosomes composed of constitutive heterochromatin. For this reason, it provides a good model to study the influence of the number of centromeres and amount of heterochromatin on spatial organization of interphase nuclei. We analyzed the three-dimensional organization of fibroblast and spermatocyte nuclei of the field mice carrying a different number of B chromosomes using laser scanning microscopy and 3D fluorescence in situ hybridization. We detected a co localization of the B chromosomes with constitutive heterochromatin of the chromosomes of the basic set. We showed a non-random distribution of B chromosomes in the spermatocyte nuclei. Unpaired B chromosomes showed a tendency to occur in the compartment formed by the unpaired part of the XY bivalent. PMID- 28732175 TI - Genome-wide identification, functional prediction, and evolutionary analysis of the R2R3-MYB superfamily in Brassica napus. AB - R2R3-MYB transcription factors (TFs) have been shown to play important roles in plants, including in development and in various stress conditions. Phylogenetic analysis showed the presence of 249 R2R3-MYB TFs in Brassica napus, called BnaR2R3-MYB TFs, clustered into 38 clades. BnaR2R3-MYB TFs were distributed on 19 chromosomes of B. napus. Sixteen gene clusters were identified. BnaR2R3-MYB TFs were characterized by motif prediction, gene structure analysis, and gene ontology. Evolutionary analysis revealed that BnaR2R3-MYB TFs are mainly formed as a result of whole-genome duplication. Orthologs and paralogs of BnaR2R3-MYB TFs were identified in B. napus, B. rapa, B. oleracea, and Arabidopsis thaliana using synteny-based methods. Purifying selection was pervasive within R2R3-MYB TFs. Kn/Ks values lower than 0.3 indicated that BnaR2R3-MYB TFs are being functionally converged. The role of gene conversion in the formation of BnaR2R3 MYB TFs was significant. Cis-regulatory elements in the upstream regions of BnaR2R3-MYB genes, miRNA targeting BnaR2R3MYB TFs, and post translational modifications were identified. Digital expression data revealed that BnaR2R3-MYB genes were highly expressed in the roots and under high salinity treatment after 24 h. BnaMYB21, BnaMYB141, and BnaMYB148 have been suggested for improving salt tolerant B. napus. BnaR2R3-MYB genes were mostly up regulated on the 14th day post inoculation with Leptosphaeria biglobosa and L. maculan. BnaMYB150 is a candidate for increased tolerance to Leptospheria in B. napus. PMID- 28732176 TI - A Comprehensive Craniofacial Study of 22q11.2 Deletion Syndrome. AB - The 22q11.2 deletion syndrome (22q11.2DS) is one of the most frequent microdeletion syndromes and presents with a highly variable phenotype. In most affected individuals, specific but subtle facial features can be seen. In this observational study, we aim to investigate the craniofacial and dental features of 20 children with a confirmed diagnosis of 22q11.2DS by analyzing 3-dimensional (3D) facial surface scans, 2-dimensional (2D) clinical photographs, panoramic and cephalometric radiographs, and dental casts. The 3D facial scans were compared to scans of a healthy control group and analyzed using a spatially dense geometric morphometric approach. Cephalometric radiographs were digitally traced, and measurements were compared to existing standards. Occlusal and dental features were studied on dental casts and panoramic radiographs. Interestingly, a general trend of facial hypoplasia in the lower part of the face could be evidenced with the 3D facial analysis in children with 22q11.2DS compared to controls. Cephalometric analysis confirmed a dorsal position of the mandible to the maxilla in 2D and showed an enlarged cranial base angle. Measurements for occlusion did not differ significantly from standards. Despite individual variability, we observed a retruded lower part of the face as a common feature, and we also found a significantly higher prevalence of tooth agenesis in our cohort of 20 children with 22q11.2DS (20%). Furthermore, 3D facial surface scanning proved to be an important noninvasive, diagnostic tool to investigate external features and the underlying skeletal pattern. PMID- 28732178 TI - Reproductive Plasticity in the Nematode Gyrinicola batrachiensis: Does an Intermediate Reproductive Strategy Exist in Sexually Reproducing, Didelphic Pinworms? AB - Phenotypic plasticity is a process in which multiple phenotypes arise from 1 genotype because of environmental selection pressures. Gyrinicola batrachiensis has a heterogeneous reproductive strategy such that females reproduce either via parthogenesis with thick-shelled eggs in a single uterus or sexual reproduction with thick- and thin-shelled eggs in separate uterine horns. No evidence exists that strains of G. batrachiensis are able to switch between parthenogenetic and sexual reproduction. Thin-shelled eggs are autoinfective, and thick-shelled eggs act as transmission agents once shed into the aquatic environment. Our primary goal was to determine whether dioecious, didelphic pinworms that infect Rana sphenocephala, a slow-developing tadpole, and Osteopilus septentrionalis, a quick developing tadpole, display reproductive plasticity with concern to thick- and thin-egg development. We performed experimental cross-infections in aquatic mesocosms to determine if dioecious, didelphic worms vary (based on tadpole host) in their ability to produce thin-shelled eggs: O. septentrionalis (hylid) egg masses were exposed to infected R. sphenocephala (ranid) tadpoles, ranid egg masses to infected hylid tadpoles, and a fully crossed infection that exposed ranid and hylid egg masses to infected tadpoles of both anuran families. Results indicated that worms reproduced via didelphic haplodiploidy in experimental ranid and hylid hosts, but that worms from hylids produced only thick-shelled eggs, which supports an intermediate reproductive strategy in O. septentrionalis. There was a significant difference in the mean intensities of ranid and hylid hosts, supporting our assertion that females infecting ranids are capable of producing autoinfective, thin-shelled eggs, and females infecting hylids do not produce such thin-shelled, autoinfective eggs because of the host microenvironment. PMID- 28732177 TI - Inguinal Hernia in Athletes: Role of Dynamic Ultrasound. AB - BACKGROUND: Inguinal hernia is a commonly encountered cause of pain in athletes. Because of the anatomic complexity, lack of standard imaging, and the dynamic condition, there is no unified opinion explaining its underlying pathology. HYPOTHESIS: Athletes with persistent groin pain would have a high prevalence of inguinal hernia with dynamic ultrasound, and herniorrhaphy would successfully return athletes to activity. STUDY DESIGN: Case-control study. LEVEL OF EVIDENCE: Level 3. METHODS: Forty-seven amateur and professional athletes with sports related groin pain who underwent ultrasound were selected based on history and examination. Patients with prior groin surgery or hip pathology were excluded. Clinical and surgical documentation were correlated with imaging. The study group was compared with 41 age-matched asymptomatic athletes. RESULTS: Ultrasound was positive for hernia with movement of bowel, bladder, or omental tissue anterior to the inferior epigastric vessels during Valsalva maneuver. The 47-patient symptomatic study group included 41 patients with direct inguinal hernias, 1 with indirect inguinal hernia, and 5 with negative ultrasound. Of 42 patients with hernia, 39 significantly improved with herniorrhaphy, 2 failed to improve after surgery and were diagnosed with adductor longus tears, and 1 improved with physical therapy. Five patients with negative ultrasound underwent magnetic resonance imaging and were diagnosed with hip labral tear or osteitis pubis. The 41-patient asymptomatic control group included 3 patients with direct inguinal hernias, 2 with indirect inguinal hernias, and 3 with femoral hernias. CONCLUSION: Inguinal hernias are a major component of groin pain in athletes. Prevalence of direct inguinal hernia in symptomatic athletes was greater than that for controls ( P < 0.001). Surgery was successful in returning these athletes to sport: 39 of 42 (93%) athletes with groin pain and inguinal hernia became asymptomatic. CLINICAL RELEVANCE: Persistent groin pain in the athlete may relate to inguinal hernia, which can be diagnosed with dynamic ultrasound imaging. Herniorrhaphy is successful at returning athletes to sports activity. PMID- 28732180 TI - The Role of Noncoding Genetic Variation in Isolated Orofacial Clefts. AB - In the past decade, medical genetic research has generated multiple discoveries, many of which were obtained via genome-wide association studies (GWASs). A major GWAS finding is that the majority of risk variants for complex traits map to noncoding regions. This has resulted in a paradigm shift in terms of the interpretation of human genomic sequence variation, with more attention now being paid to what was previously termed "junk DNA." Translation of genetic findings into biologically meaningful results requires 1) large-scale and cell-specific efforts to annotate non-protein-coding regions and 2) the integration of comprehensive genomic data sets. However, this represents an enormous challenge, particularly in the case of human traits that arise during embryonic development, such as orofacial clefts (OFCs). OFC is a multifactorial trait and ranks among the most common of all human congenital malformations. These 2 attributes apply in particular to its isolated forms (nonsyndromic OFC [nsOFC]). Although genetic studies (including GWASs) have yielded novel insights into the genetic architecture of nsOFC, few data are available concerning causality and affected biological pathways. Reasons for this deficiency include the complex genetic architecture at risk loci and the limited availability of functional data sets from human tissues that represent relevant embryonic sites and time points. The present review summarizes current knowledge of the role of noncoding regions in nsOFC etiology. We describe the identification of genetic risk factors for nsOFC and several of the approaches used to identify causal variants at these loci. These strategies include the use of biological and genetic information from public databases, the assessment of the full spectrum of genetic variability within 1 locus, and comprehensive in vitro and in vivo experiments. This review also highlights the role of the emerging research field "functional genomics" and its increasing contribution to our biological understanding of nsOFC. PMID- 28732179 TI - KGF Enhances Oral Epithelial Adhesion and Rete Peg Elongation via Integrins. AB - Oral epithelial adhesion to the lamina propria underlies the physiologic function of the oral mucosa and contributes to resisting bacterial invasion, preventing body fluid loss, and maintaining routine chewing; thus, understanding the factors that positively influence oral epithelial adhesion is a research topic of great interest. Rete pegs contribute to oral epithelial adhesion by enlarging the contact areas, whereas integrins are the major molecules that mediate epithelial cell adhesion to the basement membrane. Keratinocyte growth factor (KGF) can promote both rete peg elongation in the skin and the expression of integrins in various cell types. Herein, we tested the effects of submucosal injection of KGF in the ventral surfaces of rat tongues on oral epithelial adhesion. The data confirmed that topical injection of KGF elevated the adhesive forces, elongated the rete pegs, and increased the abundance of integrins, KGF, and KGF receptor on the rat tongue ventral surface. However, HYD-1 (Lys-Ile-Lys-Met-Val-Ile-Ser-Trp Lys-Gly), an integrin antagonist, inhibited the KGF-enhanced epithelial adhesion and rete peg elongation. Moreover, KGF promoted the expression of integrin subunits alpha6, beta4, alpha3, and beta1 in human immortalized oral epithelial cells in 2- and 3-dimensional culture systems. In vitro cell attachment assays demonstrated that HYD-1 inhibited the adhesion of human immortalized oral epithelial cells on Matrigel. Strikingly, the expression of integrins, KGF, and KGFR in human masticatory mucosae with longer rete pegs was more abundant than that in the lining mucosae with shorter rete pegs. In addition, rete peg lengths were positively correlated with the expression levels of integrins, KGF, and KGF receptor. These findings indicate that KGF strengthens oral epithelial adhesion and rete peg elongation via integrins. PMID- 28732181 TI - IRF6 and SPRY4 Signaling Interact in Periderm Development. AB - Rare mutations in IRF6 and GRHL3 cause Van der Woude syndrome, an autosomal dominant orofacial clefting disorder. Common variants in IRF6 and GRHL3 also contribute risk for isolated orofacial clefting. Similarly, variants within genes that encode receptor tyrosine kinase (RTK) signaling components, including members of the FGF pathway, EPHA3 and SPRY2, also contribute risk for isolated orofacial clefting. In the mouse, loss of Irf6 or perturbation of Fgf signaling leads to abnormal oral epithelial adhesions and cleft palate. Oral adhesions can result from a disruption of periderm formation. Here, we find that IRF6 and SPRY4 signaling interact in periderm function. We crossed Irf6 heterozygous ( Irf6+/-) mice with transgenic mice that express Spry4 in the basal epithelial layer ( TgKRT14::Spry4). While embryos with either of these mutations can have abnormal oral adhesions, using a new quantitative assay, we observed a nonadditive effect of abnormal oral epithelial adhesions in the most severely affected double mutant embryos ( Irf6+/-;TgKRT14::Spry4). At the molecular level, the sites of abnormal oral adhesions maintained periderm-like cells that express keratin 6, but we observed abnormal expression of GRHL3. Together, these data suggest that Irf6 and RTK signaling interact in regulating periderm differentiation and function, as well as provide a rationale to screen for epistatic interactions between variants in IRF6 and RTK signaling pathway genes in human orofacial clefting populations. PMID- 28732182 TI - Stim1 Regulates Enamel Mineralization and Ameloblast Modulation. AB - Loss-of-function mutations in the Ca2+ release-activated Ca2+ channel genes ORAI1 and STIM1 abolish store-operated Ca2+ entry (SOCE) and result in ectodermal dysplasia with amelogenesis imperfecta. However, because of the limited availability of patient tissue, analyses of enamel mineralization or possible changes in ameloblast function or morphology have not been possible. Here, we generated mice with ectodermal tissue-specific deletion of Stim1 ( Stim1 cKO [conditional knockout]), Stim2 ( Stim2 cKO), and Stim1 and Stim2 ( Stim1/2 cKO) and analyzed their enamel phenotypes as compared with those of control ( Stim1/2fl/fl) animals. Ablation of Stim1 and Stim1/2 but not Stim2 expression resulted in chalky enamel and severe attrition at the incisor tips and molar cusps. Stim1 and Stim1/2 cKO, but not Stim2 cKO, demonstrated inferior enamel mineralization with impaired structural integrity, whereas the shape of the teeth and enamel thickness appeared to be normal in all animals. The gene expression levels of the enamel matrix proteins Amelx and Ambn and the enamel matrix proteases Mmp20 and Klk4 were not altered by the abrogation of SOCE in Stim1/2 cKO mice. The morphology of ameloblasts during the secretory and maturation stages was not significantly altered in either the incisors or molars of the cKO animals. However, in Stim1 and Stim1/2 cKO incisors, the alternating modulation of maturation-stage ameloblasts between the smooth- and ruffle-ended cell types continued beyond the regular cycle and extended to the areas corresponding to the zone of postmodulation ameloblasts in the teeth of control animals. These results indicate that SOCE is essential for proper enamel mineralization, in which Stim1 plays a critical role during the maturation process. PMID- 28732183 TI - New Resins for Dental Composites. AB - Restorative composites have evolved significantly since they were first introduced in the early 1960s, with most of the development concentrating on the filler technology. This has led to improved mechanical properties, notably wear resistance, and has expanded the use of composites to larger posterior restorations. On the organic matrix side, concerns over the polymerization stress and the potential damage to the bonded interface have dominated research in the past 20 y, with many "low-shrinkage" composites being launched commercially. The lack of clinical correlation between the use of these materials and improved restoration outcomes has shifted the focus more recently to improving materials' resistance to degradation in the oral environment, caused by aqueous solvents and salivary enzymes, as well as biofilm development. Antimicrobial and ester-free monomers have been developed in the recent past, and evidence is mounting for their potential benefit. This article reviews literature on the newest materials currently on the market and provides an outlook for the future developments needed to improve restoration longevity past the average 10 y. PMID- 28732184 TI - High-Throughput Identification of miR-596 Inducing p53-Mediated Apoptosis in HeLa and HCT116 Cells Using Cell Microarray. AB - miRNAs play a key role in the regulation of gene networks in mammalian cells. However, little is known about their roles and functions in the apoptosis pathway. Here, we conducted a whole-genome miRNA screening for apoptosis and identified more than 100 miRNAs as apoptosis inducers. To further explain the roles of these mRNAs in apoptosis, a second round of screening was conducted between p53 +/+ and -/- cells. Among the hits, miR-596 was identified as a regulator of p53. The overexpression of miR-596 significantly increased p53 at the protein level, thereby inducing apoptosis. We also demonstrated that Smurf1 was the direct target of miR-596. Previously, Smurf1 was reported to attenuate the level of p53 through binding and stabilizing MDM2, a p53 inhibitor. Consequently, by targeting Smurf1, miR-596 indirectly increased the p53 level in mammalian cells. Moreover, our study demonstrated that miR-596 had other antitumor characteristics, such as inhibiting migration and proliferation. The data from the GEO dataset revealed that the high expression of miR-596 contributed to survival benefits among cancer patients. These results make miR 596 a potential antitumor factor for future biomedical applications. PMID- 28732185 TI - Chronotype, Sleep Characteristics, and Musculoskeletal Disorders Among Hospital Nurses. AB - Work-related musculoskeletal disorders (WMSDs) persist as the leading occupational injury, accounting for nearly half of nurses' total occupational injuries. Musculoskeletal pain is a known cause of sleep disruption, and individuals with WMSDs that interfere with sleep often report more pain. Evening chronotype has been associated with poor sleep among nurses. However, the associations among chronotype, sleep, and WMSDs are still unclear, and were explored in the present study. A cross-sectional survey was administered to 397 nurses, with 47.4% reporting WMSDs. Robust Poisson regression modeling suggested that evening type (PR = 1.32, p < .05), prolonged sleep onset latency (PR = 1.37, p < .05), and using sleep-promoting substances (PR = 1.35, p < .01) were associated with increased risk of WMSDs among nurses, after adjusting for shift work, regular exercise, body mass index, and other covariates. This study suggests that well-designed evidence-based nonpharmacological interventions to improve sleep may reduce the risk of WMSDs among nurses. PMID- 28732186 TI - Assessing the Impact of Surgeon Experience on Urinary Continence Recovery After Robot-Assisted Radical Prostatectomy: Results of Four High-Volume Surgeons. AB - PURPOSE: To test the impact of surgeon experience on urinary continence (UC) recovery after robot-assisted radical prostatectomy (RARP). MATERIALS AND METHODS: The study included 1477 consecutive patients treated with RARP by four surgeons between 2006 and 2014. UC recovery was defined as being completely dry over a 24-hour period at follow-up. Surgeon experience was coded as the total number of RARP performed by the surgeon before the patient's operation. Multivariable analysis tested the association between surgeon experience and UC recovery. Covariates consisted of patient age, Charlson comorbidity index, preoperative International Index of Erectile Function-Erectile Function domain (IIEF-EF), nerve-sparing surgery (none vs unilateral vs bilateral), and preoperative risk groups (low- vs intermediate- vs high risk). RESULTS: The number of cases performed by each surgeon was 541, 413, 411, and 112, respectively. Median follow-up was 24 months (inter-quartile range: 18, 40). The UC recovery rate at 1 year after surgery was 82%. At multivariable analyses, surgeon experience represented an independent predictor of UC recovery (hazard ratio: 1.02, p < 0.001). The surgical learning curve was similar among surgeons, moving linearly from ~60% of UC rate at the initial cases to almost 90% after more than 400 procedures. CONCLUSIONS: In patients undergoing RARP, surgeon experience is a significant predictor of UC recovery. The surgical learning curve of UC recovery does not reach a plateau even after more than 100 cases, suggesting a continuous improvement of the surgical technique. These findings deserve attention for patient counseling and future comparative studies evaluating functional outcomes after RARP. PMID- 28732187 TI - Do Genetic Markers of Inflammation Modify the Relationship between Periodontitis and Nonalcoholic Fatty Liver Disease? Findings from the SHIP Study. AB - An association between periodontitis and nonalcoholic fatty liver disease (NAFLD) has been reported by experimental animal and epidemiologic studies. This study investigated whether circulating levels of serum C-reactive protein (CRP) and a weighted genetic CRP score representing markers of inflammatory burden modify the association between periodontitis and NAFLD. Data came from 2,481 participants of the Study of Health in Pomerania who attended baseline examination that occurred between 1997 and 2001. Periodontitis was defined as the percentage of sites (0%, <30%, >=30%) with probing pocket depth (PD) >=4 mm, and NAFLD status was determined using liver ultrasound assessment. Serum CRP levels were assayed at a central laboratory, and single-nucleotide polymorphisms previously identified through genome-wide association studies as robustly associated with serum CRP were combined into a weighted genetic CRP score (wGSCRP). Logistic regression models estimated the association between periodontitis and NAFLD within strata of serum CRP and separately within strata of the wGSCRP. The prevalence of NAFLD was 26.4% (95% confidence interval [CI], 24.6, 28.1) while 17.8% (95% CI, 16.0-19.6) had >=30% of sites with PD >=4 mm. Whereas the wGSCRP was not a modifier ( Pinteraction = 0.8) on the multiplicative scale, serum CRP modified the relationship between periodontitis and NAFLD ( Pinteraction = 0.01). The covariate-adjusted prevalence odds ratio of NAFLD comparing participants with >=30% of sites with PD >=4 mm to those with no site affected was 2.39 (95% CI, 1.32-4.31) among participants with serum CRP <1 mg/L. The corresponding estimate was 0.97 (95% CI, 0.57-1.66) for participants with serum CRP levels of 1 to 3 mg/L and 1.12 (95% CI, 0.65-1.93) for participants with serum CRP >3 mg/L. Periodontitis was positively associated with higher prevalence odds of NAFLD, and this relationship was modified by serum CRP levels. PMID- 28732188 TI - Adapted methods for scanning electron microscopy (SEM) in assessment of human sperm morphology. AB - Infertility is a widespread problem, and in some cases, the routine basic semen analysis is not sufficient to detect the cause of male infertility. The use of the scanning electron microscope (SEM) could provide a detailed insight into spermatozoa morphology, but it requires specific sample preparation techniques. The purpose of this study was to select, adjust, and optimize a method for the preparation of spermatozoa samples prior to SEM analysis, and to establish the protocol required for its use in clinical practice. We examined sperm samples of 50 men. The samples were fixed with modified iso-osmolar aldehyde solution followed by osmium post-fixation. In the first method, dehydration of the cells and subsequent critical point drying (CPD) were performed on a coverslip. In the second method, the samples were dehydrated in centrifuge tubes; hexamethyldisilazane (HMDS) was used as a drying agent instead of CPD, and the samples were air-dried. The third procedure was based on a membrane filter. The samples were dehydrated and dried with HMDS in a Gooch crucible, continuously, without centrifugation or redispersion of the sample. Our results showed that the fixation with modified iso-osmolar aldehyde solution followed by osmium post fixation, and combined with dehydration and CPD on a coverslip, is the most convenient procedure for SEM sample preparation. In the case of small-size samples or low sperm concentration, dehydration and drying with HMDS on the membrane filter enabled the best reliability, repeatability, and comparability of the results. The presented procedures are suitable for routine use, and they can be applied to confirm as well as to correct a diagnosis. PMID- 28732189 TI - Erratum to "BLOS2 maintains hematopoietic stem cells in the fetal liver via repressing Notch signaling". PMID- 28732190 TI - Comparison of the ACC/AHA and Framingham algorithms to assess cardiovascular risk in HIV-infected patients. AB - The aim of this study was to compare the predictions of Framingham cardiovascular (CV) risk score (FRS) and the American College of Cardiology/American Heart Association (ACC/AHA) risk score in an HIV outpatient clinic in the city of Vitoria, Espirito Santo, Brazil. In a cross-sectional study 341 HIV infected patients over 40 years old consecutively recruited were interviewed. Cohen's kappa coefficient was used to assess agreement between the two algorithms. 61.3% were stratified as low risk by Framingham score, compared with 54% by ACC/AHA score (Spearman correlation 0.845; p<0.000). Only 26.1% were classified as cardiovascular high risk by Framingham compared to 46% by ACC/AHA score (Kappa=0.745; p<0.039). Only one out of eight patients had cardiovascular high risk by Framingham at the time of a myocardial infarction event registered up to five years before the study period. Both cardiovascular risk scores but especially Framingham underestimated high-risk patients in this HIV-infected population. PMID- 28732191 TI - A cardinal sin when researching neuropsin/KLK8: Thou shalt validate antibodies. PMID- 28732192 TI - Cost and quality issues in establishing hematopoietic cell transplant program in developing countries. AB - The hematopoietic cell transplant (HCT) activity has grown significantly over the past two decades in both developing and developed countries. Many challenges arise in establishing new HCT programs in developing countries, due to scarcity of resources and manpower in expertise in HCT. While cost issues can potentially hinder establishment of new HCT programs in certain regions, the focus on quality and value should be included in the general vision of leadership before establishing an HCT program. The main challenge in most developing countries is the lack of trained/qualified personnel, enormous start-up costs for a tertiary care center, and quality maintenance. Herein, we discuss the main challenges from a cost and quality perspective which occur at initiation of a new HCT program. We give real world examples of two developing countries that have recently started new HCT programs despite significant financial constraints. We also portray recommendations from the Worldwide Network of Blood and Marrow Transplantation for levels of requirements for a new HCT program. We hope that this review will serve as a general guide for new transplant program leadership with respect to the concerns of balancing high quality with concurrently lowering costs. PMID- 28732194 TI - Principles of Chemical Biology: APEX, Cell-Free Enzyme Systems, New Antibiotics, Epigenetic-Membrane Relationship, and Metastable Transcription. AB - This month: GPCR signaling and networks in APEX, making terpenes via biocatalysis in a cell-free system, antibiotics for Gram-negative bugs, the role of membranes in epigenetics, and the role of metastability in transcription. PMID- 28732193 TI - What should a website dedicated to the postnatal period contain? A Delphi survey among parents and professionals. AB - OBJECTIVES: Mothers have a great need for information during the postnatal period. Trying to meet this need, mothers are increasingly turning to the Internet. Nevertheless, many women have stated that they often or always found that the information that they found on the Internet was incomplete or wrong. Many women therefore believe that health professionals should suggest reliable Internet websites for new mothers. The aim of this study was therefore to find a consensus on the content of a reliable and centralized website dedicated to mothers from the end of pregnancy to 1 year after childbirth. DESIGN: Two rounds of an online Delphi survey were used in this study. SETTING AND PARTICIPANTS: The panel of participants involved in the survey included parents (both mothers and fathers) and professionals (health professionals and professionals of early childhood for mothers of children aged 0 to 2 years). FINDINGS: Ninety-six parents and professionals participated in the first round (37.7 +/- 9.76 years; 84.4% of women) and 78 in the second round. The majority of participants (94.6%) thought that a centralized website could help mothers from pregnancy to one year after childbirth. The content that the experts would like to find on a website were themed into five categories: "infants' information", "parents' information", "administrative information", "professionals' information" and "type of resources". In each category, experts highlighted the key words that they found important and should be reported on the website. The most important items highlighted by participants were baby's feeding/breastfeeding (92.8%), babies' needs (84.1%), baby blues (77.9%), postpartum depression (72.1%), management of the couple's relationship (72.1%), women's right to postnatal care (83.6%), links to reliable documents (63.9%) and a list of useful contacts (52.5%). CONCLUSIONS: This study helped to understand the questions that mothers ask themselves during the postpartum period and provided priorities to respond to their questions in the process of developing a website. PMID- 28732195 TI - Fake Inhibitors: AMPK Activation Trumps Inhibition. AB - Protein kinase inhibitors have become increasingly important therapeutic drugs for the treatment of human diseases; however, resistance and off-target effects can limit their use. In this issue of Cell Chemical Biology, Ross et al. (2017) reveal a novel off-target mechanism where the Src kinase inhibitor SU6656 paradoxically primes AMPK for phosphorylation and activation by the upstream kinase LKB1. PMID- 28732196 TI - Sam68 Offers Selectively Aimed Modulation of Transcription in Cancer Stem Cells. AB - In this issue of Cell Chemical Biology,Benoit et al. (2017) report the selective targeting of cancer stem cells (CSCs) by the ICG-001/CWP family of molecules. Their findings reveal that Sam68 is a transcriptional modulator uniquely required for the dysregulated Wnt/beta-catenin signaling in CSCs over healthy stem cells. PMID- 28732197 TI - Wrecking Staph's Rafts: Staphylococcus aureus No Longer Unsinkable? AB - Functional membrane microdomains (FMMs) serve to spatially restrict and coordinate a diversity of cellular functions. Flotillins serve as scaffolds within FMMs, and in this issue of Cell Chemical Biology, Koch et al. (2017) show that disrupting Staphylococcus aureus scaffolds via small molecules perturbs virulence gene expression and attenuates S. aureus virulence. PMID- 28732198 TI - Primary Cell Phenotypic Screening Illuminates ADRs and AOPs. AB - Preclinical, in vitro screening for adverse drug reactions continues to present challenges in the field of drug development. In this issue of Cell Chemical Biology, Shah et al. (2017) employ a phenotypic screening strategy using a panel of human primary cells to define a signature response and an adverse outcome pathway for delayed type IV skin hypersensitivity. PMID- 28732199 TI - Catch Shiny Droplets in Suspension-Finding the Needle in a Haystack. AB - In a recent issue of Cell Chemical Biology, Chaipan et al. (2017) described a high-throughput screening methodology to identify epitopes on HIV-1 particles recognized by broadly neutralizing antibodies. The approach utilizes a droplet based microfluidics platform combining robust phenotypic single-virus sorting with next-generation sequencing of viral quasispecies. PMID- 28732200 TI - Systematic Metrics Depicting Cell Death Kinetics. AB - In a recent issue of Cell Systems, Forcina et al. (2017) developed a scalable time-lapse analysis of cell death kinetics (STACK) method and combined it with a "lag exponential death" model to quantitatively characterize the onset and rate of cell death. STACK provides a useful quantitative tool to determine how cell death kinetics may be modulated pharmacologically in cell culture systems. PMID- 28732202 TI - Retraction Notice to: An ATP-Competitive Inhibitor Modulates the Allosteric Function of the HER3 Pseudokinase. PMID- 28732201 TI - Small Molecules for Early Endosome-Specific Patch Clamping. AB - To resolve the subcellular distribution of endolysosomal ion channels, we have established a novel experimental approach to selectively patch clamp Rab5 positive early endosomes (EE) versus Rab7/LAMP1-positive late endosomes/lysosomes (LE/LY). To functionally characterize ion channels in endolysosomal membranes with the patch-clamp technique, it is important to develop techniques to selectively enlarge the respective organelles. We found here that two small molecules, wortmannin and latrunculin B, enlarge Rab5-positive EE when combined but not Rab7-, LAMP1-, or Rab11 (RE)-positive vesicles. The two compounds act rapidly, specifically, and are readily applicable in contrast to genetic approaches or previously used compounds such as vacuolin, which enlarges EE, RE, and LE/LY. We apply this approach here to measure currents mediated by TRPML channels, in particular TRPML3, which we found to be functionally active in both EE and LE/LY in overexpressing cells as well as in endogenously expressing CD11b+ lung-tissue macrophages. PMID- 28732203 TI - Antiviral Immunity and Circular RNA: No End in Sight. AB - In this issue of Molecular Cell, two papers by Chen et al. (2017) and Li et al. (2017) describe new insights into circRNA biogenesis and function, connecting circRNAs to innate immune pathways. PMID- 28732204 TI - Put Your Mark Where Your Damage Is: Acetyl-CoA Production by ACLY Promotes DNA Repair. AB - In this issue of Molecular Cell, Sivanand et al. (2017) describe the importance for nuclear ACLY-mediated production of acetyl-CoA, which promotes histone acetylation, BRCA1 recruitment, and subsequent HR-mediated DNA repair in response to DNA damage, thus drawing a direct link between DNA repair and cellular metabolism. PMID- 28732205 TI - Unique Roles of the Non-identical MCM Subunits in DNA Replication Licensing. AB - A family of six homologous subunits, Mcm2, -3, -4, -5, -6, and -7, each with its own unique features, forms the catalytic core of the eukaryotic replicative helicase. The necessity of six similar but non-identical subunits has been a mystery since its initial discovery. Recent cryo-EM structures of the Mcm2-7 (MCM) double hexamer, its precursors, and the origin recognition complex (ORC) Cdc6-Cdt1-Mcm2-7 (OCCM) intermediate showed that each of these subunits plays a distinct role in orchestrating the assembly of the pre-replication complex (pre RC) by ORC-Cdc6 and Cdt1. PMID- 28732207 TI - A CRISPR Resource for Individual, Combinatorial, or Multiplexed Gene Knockout. AB - We have combined a machine-learning approach with other strategies to optimize knockout efficiency with the CRISPR/Cas9 system. In addition, we have developed a multiplexed sgRNA expression strategy that promotes the functional ablation of single genes and allows for combinatorial targeting. These strategies have been combined to design and construct a genome-wide, sequence-verified, arrayed CRISPR library. This resource allows single-target or combinatorial genetic screens to be carried out at scale in a multiplexed or arrayed format. By conducting parallel loss-of-function screens, we compare our approach to existing sgRNA design and expression strategies. PMID- 28732206 TI - A UTX-MLL4-p300 Transcriptional Regulatory Network Coordinately Shapes Active Enhancer Landscapes for Eliciting Transcription. AB - Enhancer activation is a critical step for gene activation. Here we report an epigenetic crosstalk at enhancers between the UTX (H3K27 demethylase)-MLL4 (H3K4 methyltransferase) complex and the histone acetyltransferase p300. We demonstrate that UTX, in a demethylase activity-independent manner, facilitates conversion of inactive enhancers in embryonic stem cells to an active (H3K4me1+/H3K27ac+) state by recruiting and coupling the enzymatic functions of MLL4 and p300. Loss of UTX leads to attenuated enhancer activity, characterized by reduced levels of H3K4me1 and H3K27ac as well as impaired transcription. The UTX-MLL4 complex enhances p300 dependent H3K27 acetylation through UTX-dependent stimulation of p300 recruitment, while MLL4-mediated H3K4 monomethylation, reciprocally, requires p300 function. Importantly, MLL4-generated H3K4me1 further enhances p300 dependent transcription. This work reveals a previously unrecognized cooperativity among enhancer-associated chromatin modulators, including a unique function for UTX, in establishing an "active enhancer landscape" and defines a detailed mechanism for the joint deposition of H3K4me1 and H3K27ac. PMID- 28732208 TI - Longitudinal investigation of the parietal lobe anatomy in bipolar disorder and its association with general functioning. AB - The parietal lobe (PL) supports cognitive domains, including attention and memory, which are impaired in bipolar disorder (BD). Although cross-sectional voxel-based morphometry studies found reduced PL grey matter (GM) in BD, none has longitudinally focused on PL anatomy in BD, relating it to patients' functioning. Thirty-eight right-handed BD patients and 42 matched healthy subjects (HS) underwent a Magnetic Resonance Imaging (MRI) scan at baseline. Seventeen BD patients and 16 matched HS underwent a follow-up MRI. PL white matter (WM) and GM volumes were measured. The trajectory of parietal volumes over time and the possible relation with the global functioning were investigated in both BD patients and HS. At baseline, BD patients showed significant reduced PL WM and GM and different WM laterality compared with HS. Furthermore, smaller PL WM volumes predicted lower global functioning in BD, but not in HS. At follow-up, although BD patients reported reduced PL WM compared with HS, no different pattern of volume changes over time was detected between groups. This study suggests the involvement of the PL in the pathophysiology of BD. In particular, PL WM reductions seem to predict an impairment in general functioning in BD and might represent a marker of functional outcome. PMID- 28732209 TI - The effect of a peer education program on combating violence against women: A randomized controlled study. AB - BACKGROUND: Student nurses in Turkey need to be exposed to appropriate undergraduate training if they are to acquire the required knowledge, attitudes and skills that will help them to fight the issue of violence against women (VAW). OBJECTIVES: The aim of this research study was to assess the effect of a peer education program about combating VAW on the knowledge, attitudes and skills of nursing students. DESIGN: The study was designed as a randomized controlled trial. SETTINGS: The participants in the intervention group received peer education on combating VAW. PARTICIPANTS: 136 nursing students (intervention group: n=63, control group: n=73) were included in the study. RESULTS: Participants in both the intervention and control groups were assessed at pre training and at two months post-training. Pre-training and post-training knowledge and attitudes were significantly different in the intervention group (p<0.001). Moreover, the intervention group displayed a statistically significant difference in their ability to explain the correct interventions in a case study about VAW (p<0.001). CONCLUSIONS: Our results indicate that peer education should be used as a part of undergraduate nursing education on VAW. PMID- 28732210 TI - Nursing as universal and recognisable: Nursing students'perceptions of learning outcomes from intercultural peer learning webinars: A qualitative study. AB - BACKGROUND: Nursing students need to be prepared for the increasingly culturally diverse health care. Therefore, providing students with international perspectives remains the mission of higher education. However, given the logistic and financial constraints, not all students will be able to travel overseas for their international experiences. A feasible alternative to study abroad is internationalisation-at-home where intercultural dimensions are incorporated into curriculum, without students leaving their home universities. This paper presents findings from a collaboration between nursing programmes in Sweden and Hong Kong. The aim of the project was to explore how undergraduate nursing students' perceived achieved learning outcomes after participating in a web-based intercultural peer-learning intervention. PMID- 28732211 TI - Psychological Health and Pediatric Urology: The Missing Chapter in Our Surgical Atlas. PMID- 28732213 TI - Comparison of Blood Collection Tubes from Three Different Manufacturers for the Collection of Cell-Free DNA for Liquid Biopsy Mutation Testing. AB - The improvement in sensitive techniques has allowed the detection of tumor specific aberrations in circulating tumor (ct) DNA. Amplification-refractory mutation system PCR has been used for the analysis of ctDNA to detect resistance causing mutations in the epidermal growth factor receptor gene (eg, EGFR T790M) in lung cancer patients. So far, Streck tubes have been widely used as standard blood collection tubes. Here, we compared blood collection tubes manufactured by Streck with tubes from Roche and Qiagen regarding their utility in stabilizing ctDNA in plasma samples. Venous blood from healthy donors was collected in tubes from Streck, Roche, and Qiagen. Samples were spiked with artificially fragmented EGFR T790M-mutated DNA and stored for different periods of time or spiked with different DNA amounts before plasma preparation. Extracted ctDNA was analyzed by amplification-refractory mutation system PCR. Mutant DNA, spiked into blood samples from healthy donors at quantities of 1 or 3 ng, was still reliably detectable in all samples after 7 days. EGFR T790M could be detected when spiking was performed with an amount of artificial ctDNA of 0.5 ng when tubes from Roche and Qiagen were used. Blood collection tubes from Roche and Qiagen are highly suitable for ctDNA stabilization and subsequent liquid biopsy testing. Even low ctDNA concentrations allow the detection of somatic mutations. PMID- 28732214 TI - CRISPR/Cas9 Technology-Based Xenograft Tumors as Candidate Reference Materials for Multiple EML4-ALK Rearrangements Testing. AB - The echinoderm microtubule-associated protein-like 4 and anaplastic lymphoma kinase (ALK) receptor tyrosine kinase (EML4-ALK) rearrangement is an important biomarker that plays a pivotal role in therapeutic decision making for non-small cell lung cancer (NSCLC) patients. Ensuring accuracy and reproducibility of EML4 ALK testing by fluorescence in situ hybridization, immunohistochemistry, RT-PCR, and next-generation sequencing requires reliable reference materials for monitoring assay sensitivity and specificity. Herein, we developed novel reference materials for various kinds of EML4-ALK testing. CRISPR/Cas9 was used to edit various NSCLC cell lines containing EML4-ALK rearrangement variants 1, 2, and 3a/b. After s.c. inoculation, the formalin-fixed, paraffin-embedded (FFPE) samples from xenografts were prepared and tested for suitability as candidate reference materials by fluorescence in situ hybridization, immunohistochemistry, RT-PCR, and next-generation sequencing. Sample validation and commutability assessments showed that all types of FFPE samples derived from xenograft tumors have typical histological structures, and EML4-ALK testing results were similar to the clinical ALK-positive NSCLC specimens. Among the four methods for EML4-ALK detection, the validation test showed 100% concordance. Furthermore, these novel FFPE reference materials showed good stability and homogeneity. Without limitations on variant types and production, our novel FFPE samples based on CRISPR/Cas9 editing and xenografts are suitable as candidate reference materials for the validation, verification, internal quality control, and proficiency testing of EML4-ALK detection. PMID- 28732212 TI - UALCAN: A Portal for Facilitating Tumor Subgroup Gene Expression and Survival Analyses. AB - Genomics data from The Cancer Genome Atlas (TCGA) project has led to the comprehensive molecular characterization of multiple cancer types. The large sample numbers in TCGA offer an excellent opportunity to address questions associated with tumo heterogeneity. Exploration of the data by cancer researchers and clinicians is imperative to unearth novel therapeutic/diagnostic biomarkers. Various computational tools have been developed to aid researchers in carrying out specific TCGA data analyses; however there is need for resources to facilitate the study of gene expression variations and survival associations across tumors. Here, we report UALCAN, an easy to use, interactive web-portal to perform to in-depth analyses of TCGA gene expression data. UALCAN uses TCGA level 3 RNA-seq and clinical data from 31 cancer types. The portal's user-friendly features allow to perform: 1) analyze relative expression of a query gene(s) across tumor and normal samples, as well as in various tumor sub-groups based on individual cancer stages, tumor grade, race, body weight or other clinicopathologic features, 2) estimate the effect of gene expression level and clinicopathologic features on patient survival; and 3) identify the top over- and under-expressed (up and down-regulated) genes in individual cancer types. This resource serves as a platform for in silico validation of target genes and for identifying tumor sub-group specific candidate biomarkers. Thus, UALCAN web portal could be extremely helpful in accelerating cancer research. UALCAN is publicly available at http://ualcan.path.uab.edu. PMID- 28732215 TI - A Method for Next-Generation Sequencing of Paired Diagnostic and Remission Samples to Detect Mitochondrial DNA Mutations Associated with Leukemia. AB - Somatic mitochondrial DNA (mtDNA) mutations have been identified in many human cancers, including leukemia. To identify somatic mutations, it is necessary to have a control tissue from the same individual for comparison. When patients with leukemia achieve remission, the remission peripheral blood may be a suitable and easily accessible control tissue, but this approach has not previously been applied to the study of mtDNA mutations. We have developed and validated a next generation sequencing approach for the identification of leukemia-associated mtDNA mutations in 26 chronic myeloid leukemia patients at diagnosis using either nonhematopoietic or remission blood samples as the control. The entire mt genome was amplified by long-range PCR and sequenced using Illumina technology. Variant caller software was used to detect mtDNA somatic mutations, and an empirically determined threshold of 2% was applied to minimize false-positive results because of sequencing errors. Mutations were called against both nonhematopoietic and remission controls: the overall concordance between the two approaches was 81% (73/90 mutations). Some discordant results were because of the presence of somatic mutations in remission samples, because of either minimal residual disease or nonleukemic hematopoietic clones. This method could be applied to study somatic mtDNA mutations in leukemia patients who achieve minimal residual disease, and in patients with nonhematopoietic cancers who have a matched uninvolved tissue available. PMID- 28732216 TI - Development of HLA-B*57:01 Genotyping Real-Time PCR with Optimized Hydrolysis Probe Design. AB - HLA-B*57:01 genotyping before abacavir (ABC) administration is a standard of care to avoid ABC-driven hypersensitivity reactions. Several HLA-B*57:01 tests have been developed, each with advantages and disadvantages. Some have limited accuracy, require special instrumentation, and/or are labor intensive and expensive. We developed a novel hydrolysis probe-based real-time PCR method of HLA-B*57:01 genotyping. Primer and probes were designed based on published sequence variations in exon 3 of HLA-B that distinguish HLA-B*57:01 from ABC insensitive alleles such as HLA-B*57:03 and HLA-B*58:01. We designed PCR primers to amplify HLA-B*57:01 along with closely related alleles, such as HLA-B*57:03, directly from genomic DNA. Most ABC-insensitive alleles, including HLA-B*58:01, would not produce any products in the PCR reaction. Our hydrolysis probes enable differentiation of HLA-B*57:01 from the other amplified, but ABC-insensitive, alleles. In addition to using real-time PCR, we used restriction enzymes to generate differential digestion patterns that led to the development of an HLA B*57:01 PCR-restriction fragment length polymorphism marker. When used to genotype a set of 75 selected clinical samples, our real-time PCR assay demonstrated 100% accuracy in distinguishing between the HLA-B*57:01-positive and -negative alleles when results were compared to those of sequence-specific oligonucleotide probe typing and reference laboratory testing. Our newly developed test will allow clinical laboratories with real-time PCR capabilities to perform HLA-B*57:01 genotyping in a timely and economical manner. PMID- 28732217 TI - Finite Element Evaluation of Stable Fixation in Combined Mandibular Fractures. AB - PURPOSE: The fixation of combined mandibular fractures, especially symphyseal condylar fractures, although occurring commonly and having a higher complication rate in the clinic, is rarely investigated regarding predictable therapeutic approaches. Thus this study's aim was to assess different forms of condylar fixation when combined with symphyseal fracture fixation. MATERIALS AND METHODS: Using finite element models, we analyzed the stress distribution that occurs when a condylar fracture is fixed with 1 miniplate, 2 miniplates, or a trapezoidal condylar miniplate and when a symphyseal fracture is fixed with 2 parallel plates, 2 perpendicular plates, or 2 lag screws. The null hypothesis was that there would be no differences among the different fixation techniques. RESULTS: The results showed a stress concentration in the anterior region of the condyle, close to the sigmoid notch. Moreover, adequate fixation in the symphysis could result in less tension at the condylar region. Therefore, when the symphysis was fixed with a lag-screw technique, condylar fixation was less required, showing a more adequate stress distribution when the condyle was fixed with 1 or 2 plates. Conversely, when the symphyseal fixation was less effective, by use of perpendicular plates, there was a change in the stress distribution at the condylar region, altering fixation behavior and resulting in more tension and displacement in the condyle, especially when a trapezoidal plate was used. CONCLUSIONS: A lag screw and parallel double plates appear to be suitable for symphyseal fixation, whereas 2 straightly positioned plates and a trapezoidal plate are suitable for condylar fixation. However, the combination of perpendicular plates in symphyseal fixation and a trapezoidal plate in condylar fixation showed an altered stress distribution. PMID- 28732218 TI - Invasiveness of Tibial Bone Graft Harvesting for Secondary Alveolar Bone Grafting: Can Harvesting Be Performed at the Age of Less Than 10 Years Without Complications? AB - PURPOSE: In this study, particulate cancellous bone marrow was harvested from the tibia for alveolar bone grafting, and postoperative complications at the donor site were compared between patients aged 10 years or older (29 tibias) and those aged younger than 10 years (42 tibias). PATIENTS AND METHODS: Enrolled patients were those who underwent tibial bone graft harvesting at the Department of Oral and Maxillofacial Surgery, Aichi Gakuin University, during a period of 3 years and 1 month from March 2012 through March 2015. We examined clinical findings at the time of harvesting and changes in symptoms during hospital admission in study 1. Follow-up examinations and survey questionnaires on symptoms also were investigated to clarify medium- to long-term postoperative outcomes in study 2. RESULTS: In both age groups, medium- to long-term postoperative findings showed no apparent adverse events, except for acceptable levels of scar tissue. Clinical findings on harvesting and early postoperative findings showed that intraoperative blood loss, early postoperative pain, and gait disorders were similar between the group aged younger than 10 years and the group aged 10 years or older. However, the latter group needed a considerably longer time for ambulation and weight-bearing pain to disappear and for every movement in daily activities to return to normal. Regarding patients with a bilateral alveolar cleft, we found no significant difference between the first and second harvesting in the factors affecting postoperative morbidity. CONCLUSIONS: Our findings suggest that tibial bone graft harvesting is safe and requires a shorter recovery period even in patients aged between 8 and 10 years. PMID- 28732219 TI - Perioperative Systemic Corticosteroids in Orthognathic Surgery: A Systematic Review and Meta-Analysis. AB - PURPOSE: Perioperative systemic corticosteroids are broadly used in orthognathic surgery to prevent postoperative complications, but it is unclear whether this practice is beneficial and concerns about potential side effects have been raised. The purpose of this systematic review and meta-analysis was to assess the effects of perioperative systemic corticosteroids on clinically important outcomes in patients undergoing orthognathic surgery. MATERIALS AND METHODS: The authors conducted a systematic review of randomized controlled trials evaluating the effect of systemic corticosteroids in orthognathic surgery compared with placebo or any other intervention. The authors searched Medline, Embase, Cochrane Central, CINAHL, Lilacs, Scopus, and Web of Science and references of included trials. The primary outcome was the incidence of postoperative reintubation during the index hospitalization. The secondary outcomes were hospital length of stay, decreases in facial edema, and adverse events. Data were summarized using Mantel-Haenszel random-effects models. RESULTS: Of the 1,098 trials retrieved, 8 were included (n = 234). No trial evaluated the risk of postoperative reintubation. One trial evaluated the duration of hospital stay and showed no difference associated with the intervention. There was a decrease in facial edema with the use of systemic corticosteroids (n = 80; standardized mean difference, 1.07; 95% confidence interval, -1.99 to -0.16; I2 = 67%). Three trials reported side effects, such as postoperative surgical site bleeding, hypersensitivity, and stomach discomfort with intake of corticosteroids. The 8 trials had an unclear risk of bias. CONCLUSION: The authors observed no evidence of effect of systemic corticosteroids on the risk of reintubation and hospital length of stay in orthognathic surgery. Although facial edema decrease was observed to be improved with the intervention, adverse effects were inconsistently screened and reported. Thus, the use of systemic steroids in orthognathic surgery is not supported by strong evidence. PMID- 28732220 TI - Short-Term Evaluation of Gustatory Changes After Surgical Removal of Mandibular Third Molar-A Prospective Randomized Control Trial. AB - PURPOSE: The present study was carried out to prospectively determine the incidence and severity of suprathreshold taste changes after surgical removal of mandibular third molars. MATERIALS AND METHODS: Sixty patients who required removal of impacted third molars were included in the study. Based on the Winter criteria of angulation of impacted mandibular third molars, 15 patients each with mesioangular, distoangular, horizontal, and vertical impacted third molars were selected. The chemo-gustometry chart in pentagon scheme was used to represent the results of gustometry and to establish a correlation between the difficulty index of impacted third molar removal and the incidence of gustatory changes. All patients underwent spatial taste testing preoperatively and 1 week postoperatively. RESULTS: The highest incidence of taste changes was noted in category 3 (difficulty score, 7 to 8) and mostly for distoangular and vertically impacted teeth. CONCLUSION: In their extensive patient analysis of 4 different taste sensations, the authors found that suprathreshold taste changes do occur after surgical removal of an impacted mandibular third molar, with a high difficulty index score indicating the highest prevalence for altered taste sensations for distoangular and vertical impactions. PMID- 28732221 TI - Atrophic Mandible Fractures: Are Bone Grafts Necessary? An Update. AB - PURPOSE: The management of atrophic mandibular fractures poses a challenge because of anatomic variations and medical comorbidities associated with elderly patients. The purpose of this article is to review and update the literature regarding the management of atrophic mandible fractures using load-bearing reconstruction plates placed without bone grafts. MATERIALS AND METHODS: We performed a review of the English-language literature looking for atrophic mandibular fractures with or without continuity defects and reconstruction without bone grafts. Included are 2 new patients from our institution who presented with fractures of their atrophic mandibles and had continuity defects and infections. Both patients underwent reconstruction with a combination of a reconstruction plate, recombinant human bone morphogenetic protein 2, and tricalcium phosphate. This study was approved as an "exempt study" by the Institutional Review Board at the University of Kentucky. This investigation observed the Declaration of Helsinki on medical protocol and ethics. RESULTS: Currently, the standard of care to manage atrophic mandibular fractures with or without a continuity defect is a combination of a reconstruction plate plus autogenous bone graft. However, there is a need for an alternative option for patients with substantial comorbidities. Bone morphogenetic proteins, with or without additional substances, appear to be a choice. In our experience, successful healing occurred in patients with a combination of a reconstruction plate, recombinant human bone morphogenetic protein 2, and tricalcium phosphate. CONCLUSIONS: Whereas primary reconstruction of atrophic mandibular fractures with reconstruction plates supplemented with autogenous bone graft is the standard of care, in selected cases in which multiple comorbidities may influence local and/or systemic outcomes, bone morphogenetic proteins and tricalcium phosphate can be used as a predictable alternative to autogenous grafts. PMID- 28732222 TI - Orthodontic Extraction and Third Molar Eruption. PMID- 28732223 TI - Safety concerns of Piezoelectric Units in Implantable Cardioverter Defibrillator. AB - PURPOSE: Evidence-based research appears to conflict on the potential risk of electromagnetic interference (EMI) between piezoelectric units (Pzs) and implantable cardioverters and defibrillators (ICDs). The purpose of this study was to observe whether the EMI produced by Pzs is hazardous for ICDs. MATERIALS AND METHODS: A cross-sectional study of 6 Pzs was conducted in vitro for EMI using an ICD system. To simulate the human body's electrical resistance, electrographic recordings were made of the ICD and lead that were immersed in a bath of saline solution. The variables investigated were the presence of EMI, the distance between the ICD and the Pz, and signal intensity, damage, and type of damage to the ICD and lead. Each series of tests was repeated 3 times, beginning with a 15-second baseline recording (control), until all recording conditions had been covered. Each Pz was recorded under the following conditions: less than 2 cm from the tip of the ICD lead; less than 2 cm from the ICD; less than 2 cm from the lead body and coils; and 15 cm from the lead or the ICD (R4). RESULTS: In the positive control (direct contact between the lead or the ICD with the Pz switched on), the ICD detected electrical activity as false heart activity. However, after covering all test conditions, no EMI was produced by the Pzs. CONCLUSION: No EMI or permanent changes in the functioning of the ICD were detected in vitro. PMID- 28732224 TI - Three-Dimensional Changes in the Upper Airway of Skeletal Class III Patients After Different Orthognathic Surgical Procedures. AB - PURPOSE: We hypothesized that 3-dimensional changes in the upper airway of patients with skeletal Class III malocclusion are different after mandibular setback and maxillary advancement (MSMA) compared with mandibular setback (MS) and that upper airway changes and the amount of jaw movement are correlated. PATIENTS AND METHODS: Skeletal Class III patients who underwent MS surgery or MSMA surgery were included in this retrospective cohort study. Cone beam computed tomography scans were acquired before and 3 months after surgery. Changes in the upper airway space were assessed as primary outcome variables. All cone beam computed tomography scans were imported into Dolphin Imaging software (version 11.7; Dolphin Imaging & Management Solutions, Chatsworth, CA) for reconstruction. SPSS software (version 22.0; IBM, Armonk, NY) was used for comparisons of the preoperative and postoperative changes within and between the groups, with analysis of correlations between upper airway changes and the amount of jaw movement. RESULTS: The study included 29 patients (13 in MS group and 16 in MSMA group). In the MS group, the velopharynx, glossopharynx, laryngopharynx, and total upper airway were significantly narrower after orthognathic surgery (P < .05). In the MSMA group, the velopharynx was significantly narrower after surgery (P < .05) whereas no statistically significant constriction was found in the other parts of the upper airway (P > .05). The velopharyngeal, glossopharyngeal, laryngopharyngeal, and total upper airway space in the MS group decreased significantly more than that in the MSMA group (P < .05). CONCLUSIONS: The upper airway was constricted more after MS surgery than after MSMA surgery. From the perspective of upper airway changes, MSMA leads to better outcomes than solely MS. PMID- 28732225 TI - Influence of hypo- and hyperthermia on death time estimation - A simulation study. AB - Numerous physiological and pathological mechanisms can cause elevated or lowered body core temperatures. Deviations from the physiological level of about 37 degrees C can influence temperature based death time estimations. However, it has not been investigated by means of thermodynamics, to which extent hypo- and hyperthermia bias death time estimates. Using numerical simulation, the present study investigates the errors inherent in temperature based death time estimation in case of elevated or lowered body core temperatures before death. The most considerable errors with regard to the normothermic model occur in the first few hours post-mortem. With decreasing body core temperature and increasing post mortem time the error diminishes and stagnates at a nearly constant level. PMID- 28732226 TI - Intermittent administration of parathyroid hormone ameliorated alveolar bone loss in experimental periodontitis in streptozotocin-induced diabetic rats. AB - OBJECTIVE: Intermittent administration of parathyroid hormone (PTH) has been demonstrated to have anabolic effects on bone metabolism and is approved for use in the treatment of osteoporosis. This study evaluates the role of intermittent PTH administration on alveolar bone loss in streptozotocin (STZ)-induced diabetic rats. DESIGN: Fifty male Sprague Dawley rats were randomly divided into the following five groups: (1) a control group (saline placebo without ligature and STZ injection), (2) a PTH group (PTH administration without ligature and STZ injection), (3) an L group (saline placebo with ligature), (4) an L+STZ group (saline placebo with ligature and STZ injection), and (5) an L+STZ+PTH group (PTH administration with ligature and STZ injection). PTH was administered at 75MUg/kg per dose four times a week for 28days. Subsequently, all rats were sacrificed, and their mandibles were extracted for micro-computed tomography (micro-CT) scanning, as well as histological and immunochemical evaluation. RESULTS: Micro CT scanning demonstrated the anabolic effect of PTH on alveolar bone metabolism in STZ-induced diabetic rats (P<0.05), and histomorphometry indicated that PTH inhibited inflammation of the periodontium and increased the level of osteoblastic activity (P<0.05). Immunochemical evaluation showed that rats subjected to both ligature placement and STZ injection had the highest receptor activator of nuclear factor kappa B ligand (RANKL)/osteoprotegerin (OPG) ratio and that PTH administration decreased this ratio. CONCLUSION: Intermittent systemic PTH administration effectively reduced alveolar bone loss and ameliorated the manifestation of experimental periodontitis in STZ-induced diabetic rats. PMID- 28732228 TI - A facile method for preparation of emulsion using the high gravity technique. AB - This study demonstrates a new process for preparation of oil-in-water (O/W) emulsion using the high gravity technique. This involves a mixture of oil and water that are passed through a rotating packed bed, under a high shear force, from which oil is emulsified into tiny droplets and subsequently dispersed in water. The process is cycled in order to break the droplets repeatedly and achieve an emulsion with small size and low polydispersity index (PDI). The advantage of the high gravity technique is that the emulsions with a desired size and polydispersity can be rapidly obtained by tuning experimental parameters, such as relative centrifugal force (RCF), cycle times (CT), liquid flow rate (VL) and surfactant concentration (Csurfactant). The size of emulsions is shown to decrease with increasing RCF, CT, VL and Csurfactant. The PDI of emulsion prepared by high gravity technique is also much improved in comparison to that prepared by conventional sonication, which is further confirmed with dynamic light scattering and confocal imaging characterization. To provide an additional perspective on the high gravity technique as a tool to make O/W emulsions, uniformly distributed liquid crystal droplets were prepared by using the high gravity technique, which have been well studied for their in situ chemical and biological detection. In short, the high gravity technique for preparing emulsions is facile, fast and can be potentially applied for large scale industry applications. PMID- 28732227 TI - ATM supports gammaherpesvirus replication by attenuating type I interferon pathway. AB - Ataxia-Telangiectasia mutated (ATM) kinase participates in multiple networks, including DNA damage response, oxidative stress, and mitophagy. ATM also supports replication of diverse DNA and RNA viruses. Gammaherpesviruses are prevalent cancer-associated viruses that benefit from ATM expression during replication. This proviral role of ATM had been ascribed to its signaling within the DNA damage response network; other functions of ATM have not been considered. In this study increased type I interferon (IFN) responses were observed in ATM deficient gammaherpesvirus-infected macrophages. Using a mouse model that combines ATM and type I IFN receptor deficiencies we show that increased type I IFN response in the absence of ATM fully accounts for the proviral role of ATM during gammaherpesvirus replication. Further, increased type I IFN response rendered ATM deficient macrophages more susceptible to antiviral effects of type II IFN. This study identifies attenuation of type I IFN responses as the primary mechanism underlying proviral function of ATM during gammaherpesvirus infection. PMID- 28732229 TI - A novel approach to fabricate dye-encapsulated polymeric micro- and nanoparticles by thin film dewetting technique. AB - A new method is reported for fabrication of polymeric micro- and nanoparticles from an intermediate patterned surface originated by dewetting of a polymeric thin film. Poly (d, l-lactide-co-glycolide) or PLGA, a biocompatible polymer is used to develop a thin film over a clean glass substrate which dewets spontaneously in the micro-/nano-patterned surface of size range 50nm to 3.5um. Since another water-soluble polymer, poly vinyl alcohol (PVA) is coated on the same glass substrate before PLGA thin film formation, developed micro-/nano patterns are easily extracted in water in the form of micro- and nanoparticle mixture of size range 50nm to 3.0um. This simplified method is also used to effectively encapsulate a dye molecule, rhodamine B inside the PLGA micro /nanoparticles. The developed dye-encapsulated nanoparticles, PLGA-rhodamine are separated from the mixture and tested for in-vitro delivery application of external molecules inside human lung cancer cells. For the first time, the use of thin film dewetting technique is reported as a potential route for the synthesis of polymeric micro-/nanoparticles and effective encapsulation of external species therein. PMID- 28732230 TI - Maximum likelihood optimal and robust Support Vector Regression with lncosh loss function. AB - In this paper, a novel and continuously differentiable convex loss function based on natural logarithm of hyperbolic cosine function, namely lncosh loss, is introduced to obtain Support Vector Regression (SVR) models which are optimal in the maximum likelihood sense for the hyper-secant error distributions. Most of the current regression models assume that the distribution of error is Gaussian, which corresponds to the squared loss function and has helpful analytical properties such as easy computation and analysis. However, in many real world applications, most observations are subject to unknown noise distributions, so the Gaussian distribution may not be a useful choice. The developed SVR model with the parameterized lncosh loss provides a possibility of learning a loss function leading to a regression model which is maximum likelihood optimal for a specific input-output data. The SVR models obtained with different parameter choices of lncosh loss with epsilon-insensitiveness feature, possess most of the desirable characteristics of well-known loss functions such as Vapnik's loss, the Squared loss, and Huber's loss function as special cases. In other words, it is observed in the extensive simulations that the mentioned lncosh loss function is entirely controlled by a single adjustable lambda parameter and as a result, it allows switching between different losses depending on the choice of lambda. The effectiveness and feasibility of lncosh loss function are validated through a number of synthetic and real world benchmark data sets for various types of additive noise distributions. PMID- 28732231 TI - Kernel dynamic policy programming: Applicable reinforcement learning to robot systems with high dimensional states. AB - We propose a new value function approach for model-free reinforcement learning in Markov decision processes involving high dimensional states that addresses the issues of brittleness and intractable computational complexity, therefore rendering the value function approach based reinforcement learning algorithms applicable to high dimensional systems. Our new algorithm, Kernel Dynamic Policy Programming (KDPP) smoothly updates the value function in accordance to the Kullback-Leibler divergence between current and updated policies. Stabilizing the learning in this manner enables the application of the kernel trick to value function approximation, which greatly reduces computational requirements for learning in high dimensional state spaces. The performance of KDPP against other kernel trick based value function approaches is first investigated in a simulated n DOF manipulator reaching task, where only KDPP efficiently learned a viable policy at n=40. As an application to a real world high dimensional robot system, KDPP successfully learned the task of unscrewing a bottle cap via a Pneumatic Artificial Muscle (PAM) driven robotic hand with tactile sensors; a system with a state space of 32 dimensions, while given limited samples and with ordinary computing resources. PMID- 28732232 TI - Periodicity and stability for variable-time impulsive neural networks. AB - The paper considers a general neural networks model with variable-time impulses. It is shown that each solution of the system intersects with every discontinuous surface exactly once via several new well-proposed assumptions. Moreover, based on the comparison principle, this paper shows that neural networks with variable time impulse can be reduced to the corresponding neural network with fixed-time impulses under well-selected conditions. Meanwhile, the fixed-time impulsive systems can be regarded as the comparison system of the variable-time impulsive neural networks. Furthermore, a series of sufficient criteria are derived to ensure the existence and global exponential stability of periodic solution of variable-time impulsive neural networks, and to illustrate the same stability properties between variable-time impulsive neural networks and the fixed-time ones. The new criteria are established by applying Schaefer's fixed point theorem combined with the use of inequality technique. Finally, a numerical example is presented to show the effectiveness of the proposed results. PMID- 28732233 TI - Piecewise convexity of artificial neural networks. AB - Although artificial neural networks have shown great promise in applications including computer vision and speech recognition, there remains considerable practical and theoretical difficulty in optimizing their parameters. The seemingly unreasonable success of gradient descent methods in minimizing these non-convex functions remains poorly understood. In this work we offer some theoretical guarantees for networks with piecewise affine activation functions, which have in recent years become the norm. We prove three main results. First, that the network is piecewise convex as a function of the input data. Second, that the network, considered as a function of the parameters in a single layer, all others held constant, is again piecewise convex. Third, that the network as a function of all its parameters is piecewise multi-convex, a generalization of biconvexity. From here we characterize the local minima and stationary points of the training objective, showing that they minimize the objective on certain subsets of the parameter space. We then analyze the performance of two optimization algorithms on multi-convex problems: gradient descent, and a method which repeatedly solves a number of convex sub-problems. We prove necessary convergence conditions for the first algorithm and both necessary and sufficient conditions for the second, after introducing regularization to the objective. Finally, we remark on the remaining difficulty of the global optimization problem. Under the squared error objective, we show that by varying the training data, a single rectifier neuron admits local minima arbitrarily far apart, both in objective value and parameter space. PMID- 28732234 TI - Computational modelling of genome-scale metabolic networks and its application to CHO cell cultures. AB - Genome-scale metabolic models (GEMs) have become increasingly important in recent years. Currently, GEMs are the most accurate in silico representation of the genotype-phenotype link. They allow us to study complex networks from the systems perspective. Their application may drastically reduce the amount of experimental and clinical work, improve diagnostic tools and increase our understanding of complex biological phenomena. GEMs have also demonstrated high potential for the optimisation of bio-based production of recombinant proteins. Herein, we review the basic concepts, methods, resources and software tools used for the reconstruction and application of GEMs. We overview the evolution of the modelling efforts devoted to the metabolism of Chinese Hamster Ovary (CHO) cells. We present a case study on CHO cell metabolism under different amino acid depletions. This leads us to the identification of the most influential as well as essential amino acids in selected CHO cell lines. PMID- 28732235 TI - Medication takeovers: Covert druggings and behavioral control in Alzheimer's. AB - Older adults consume the most prescription medication in the U.S. For those who develop Alzheimer's disease, risk of medication misuse increases with the progression of the disease. Family members commonly intervene to lessen risks by taking over the management and administering of a medication regimen. Despite the potential for grave harm around the misuse of powerful drugs, few studies provide insight into the household social context of medication use for this disease. Drawing on 60 in-depth interviews conducted in four waves over 2.5 years, this study investigates how family members administered prescription and over-the counter medications to elders with Alzheimer's. The findings detail how family members initially created and enacted the role of proxy-administrator to avoid self-administration errors and then expanded the role to manage disruptive behaviors. During this process, family members perceived themselves as working in partnership with doctors, especially in the effort to craft a regimen that controlled the affected individual's mood and sleep/wake cycle. The paper concludes by discussing the implications that family members used medications to improve conformity to a preferred household social order. The study offers conceptual advances in understanding 1) the process of proxy-administration in Alzheimer's care and 2) the role of proxy-administrators in the medicalization of deviant behavior. PMID- 28732236 TI - Neighborhood SES is particularly important to the cardiovascular health of low SES individuals. AB - RATIONALE: Health disparities defined by neighborhood socioeconomic status (SES) are well established; it is less well understood whether neighborhood SES is differentially associated with health depending on one's own SES. OBJECTIVE: The double jeopardy hypothesis, collective resources model, fundamental cause theory, and relative deprivation hypothesis support differential patterns of association between neighborhood and individual SES with health. The first three models suggest that higher neighborhood SES predicts health more strongly among lower, as compared to higher, SES individuals. The relative deprivation hypothesis suggests that higher SES neighborhoods bring no extra health benefit to low SES individuals and could even bring a health deficit. This study examined competing hypotheses with prospective associations between cardiovascular (CV) health and individual SES, neighborhood SES, and their interaction. METHOD: Data were from two waves of the Midlife in the United States (MIDUS) Study (N = 1012), a national survey of adults ages 25 and older at baseline. Neighborhood SES was a composite of five census tract-level SES indicators from the 1990 census. Individual SES was a composite of educational attainment and household income at wave one (1995-1996). CV health at wave two (2004-2008), was computed as a composite based on smoking status, body mass index, physical activity, diet, total cholesterol, blood pressure, and glucose. RESULTS: Individual and neighborhood SES were each associated with CV health net of baseline health status and other covariates. Interactions between individual and neighborhood SES showed that higher neighborhood SES was associated with better CV health for those of lower, not higher, individual SES. CONCLUSION: Results are consistent with the double jeopardy hypothesis, the collective resources model, and the fundamental cause theory, but not with a relative deprivation hypothesis. Results suggest that additional attention to the neighborhood socioeconomic context of lower SES individuals may reduce SES disparities in cardiovascular health. PMID- 28732237 TI - Decentralization of health care systems and health outcomes: Evidence from a natural experiment. AB - While many countries worldwide are shifting responsibilities for their health systems to local levels of government, there is to date insufficient evidence about the potential impact of these policy reforms. We estimate the impact of decentralization of the health services on infant and neonatal mortality using a natural experiment: the devolution of health care decision making powers to Spanish regions. The devolution was implemented gradually and asymmetrically over a twenty-year period (1981-2002). The order in which the regions were decentralized was driven by political factors and hence can be considered exogenous to health outcomes. In addition, we exploit the dynamic effect of decentralization of health services and allow for heterogeneous effects by the two main types of decentralization implemented across regions: full decentralization (political and fiscal powers) versus political decentralization only. Our difference in differences results based on a panel dataset for the 50 Spanish provinces over the period 1980 to 2010 show that the lasting benefit of decentralization accrues only to regions which enjoy almost full fiscal and political powers and which are also among the richest regions. PMID- 28732238 TI - Community Action for Health in India's National Rural Health Mission: One policy, many paths. AB - Community participation as a strategy for health system strengthening and accountability is an almost ubiquitous policy prescription. In 2005, with the election of a new Government in India, the National Rural Health Mission was launched. This was aimed at 'architectural correction' of the health care system, and enshrined 'communitization' as one of its pillars. The mission also provided unique policy spaces and opportunity structures that enabled civil society groups to attempt to bring on to the policy agenda as well as implement a more collective action and social justice based approach to community based accountability. Despite receiving a lot of support and funding from the central ministry in the pilot phase, the subsequent roll out of the process, led in the post-pilot phase by the individual state governments, showed very varied outcomes. This paper using both documentary and interview based data is the first study to document the roll out of this ambitious process. Looking critically at what varied and why, the paper attempts to derive lessons for future implementation of such contested concepts. PMID- 28732239 TI - Effects of antiepileptic drugs on mitochondrial functions, morphology, kinetics, biogenesis, and survival. AB - OBJECTIVES: Antiepileptic drugs (AEDs) exhibit adverse and beneficial effects on mitochondria, which have a strong impact on the treatment of patients with a mitochondrial disorder (MID) with epilepsy (mitochondrial epilepsy). This review aims at summarizing and discussing recent findings concerning the effect of AEDs on mitochondrial functions and the clinical consequences with regard to therapy of mitochondrial epilepsy and of MIDs in general. METHODS: Literature review. RESULTS: AEDs may interfere with the respiratory chain, with non-respiratory chain enzymes, carrier proteins, or mitochondrial biogenesis, with carrier proteins, membrane-bound channels or receptors and the membrane potential, with anti-oxidative defense mechanisms, with morphology, dynamics and survival of mitochondria, and with the mtDNA. There are AEDs of which adverse effects outweigh beneficial effects, such as valproic acid, carbamazepine, phenytoin, or phenobarbital and there are AEDs in which beneficial effects dominate over mitochondrial toxic effects, such as lamotrigine, levetiracetam, gabapentin, or zonisamide. However, from most AEDs only little is known about their interference with mitochondria. CONCLUSIONS: Mitochondrial epilepsy might be initially treated with AEDs with low mitochondrial toxic potential. Only in case mitochondrial epilepsy is refractory to these AEDs, AEDs with higher mitochondrial toxic potential might be tried. In patients carrying POLG1 mutations AEDs with high mitochondrial toxic potential are contraindicated. PMID- 28732240 TI - Constitutive transgene expression of Stem Cell Antigen-1 in the hair follicle alters the sensitivity to tumor formation and progression. AB - The cell surface protein Stem Cell Antigen-1 (Sca-1) marks stem or progenitor cells in several murine tissues and is normally upregulated during cancer development. Although the specific function of Sca-1 remains unknown, Sca-1 seems to play a role in proliferation, differentiation and cell migration in a number of tissues. In the skin epithelium, Sca-1 is highly expressed in the interfollicular epidermis but is absent in most compartments of the hair follicle; however, the function of Sca-1 in the skin has not been investigated. To explore the role of Sca-1 in normal and malignant skin development we generated transgenic mice that express Sca-1 in the hair follicle stem cells that are normally Sca-1 negative. Development of hair follicles and interfollicular epidermis appeared normal in Sca-1 mutant mice; however, follicular induction of Sca-1 expression in bulge region and isthmus stem cells reduced the overall yield of papillomas in a chemical carcinogenesis protocol. Despite that fewer papillomas developed in transgenic mice a higher proportion of the papillomas underwent malignant conversion. These findings suggest that overexpression of Sca 1 in the hair follicle stem cells contributes at different stages of tumour development. In early stages, overexpression of Sca-1 decreases tumour formation while at later stages overexpression of Sca-1 seems to drive tumours towards malignant progression. PMID- 28732241 TI - Generation of skeletal myogenic progenitors from human pluripotent stem cells using non-viral delivery of minicircle DNA. AB - Currently, the most efficient and promising approach for generating large numbers of engraftable human skeletal myogenic progenitors from pluripotent stem cells requires the conditional in vitro overexpression of PAX7 using lentiviral vectors. Because a non-integrating approach would be preferable to eliminate or minimize the risk associated with random genomic integration, here we investigate whether transient expression of PAX7 using minicircle DNA would enable the generation of functional pluripotent stem cell-derived myogenic progenitors, equivalent to those generated by lentivirus. Our results demonstrate that upon multiple transfections, the minicircle approach allows for the scalable generation of myogenic progenitors and these undergo efficient terminal differentiation in vitro. However, transplantation of minicircle-generated myogenic progenitors resulted in limited engraftment. This is probably due to less efficient delivery and more transient PAX7 expression in these cultures since PAX7 downregulation is accompanied by high level of spontaneous differentiation. Thus, although the in vitro data shows that the minicircle approach could potentially replace the use of lentivirus, improvements in the transfection/expression system will be necessary before it will be a feasible strategy for the generation of myogenic progenitors for cell replacement therapy. PMID- 28732242 TI - The depression and marital status relationship is modified by both age and gender. AB - BACKGROUND: Marital status is associated with major depression prevalence, however, the strength of association may be modified by age and gender. METHODS: The data sources were a series of cross sectional national health surveys of the Canadian population carried out by Statistics Canada during 1996-2013. These were cross-sectional files from the National Population Health Survey of 1996, together with the Canadian Community Health Surveys from 2000 to 2013; the respondents were 18 years and older. The data was analyzed with meta-analytic techniques and logistic regression. RESULTS: In terms of gender, the odds ratios of depression were smaller for females (vs males) who were single, widowed or separated compared to married people. Regarding age, the odds ratios for depression showed a steady rise with increasing age for those in single and in common-law relationships compared to married people. In contrast the odds ratios for depression declined with age for those widowed, separated and divorced compared to married people. The strength of the interaction terms used to quantify these moderating effects showed no change from 1996 to 2013. LIMITATIONS: Only one member of each household was included, so that relationship issues could not be studied. The generalizability of our findings requires international data. Also the diagnostic interviews used are not as accurate as clinical assessments. CONCLUSION: Use of large numbers of participants has revealed some robust modifying effects of both gender and age on the depression/marital status relationship. The clinical significance of our findings is that the vulnerability to development of depression is not only related to marital status, but that this relationship is modified by age and gender. PMID- 28732243 TI - Modeling trait depression amplifies the effect of childbearing on postpartum depression. AB - BACKGROUND: The literature on the relative risk for depression in the postpartum period has largely focused on state (or episodic) depression, and has not addressed trait depression (a woman's general tendency to experience depressed mood). The present study evaluates the association between childbirth and depression in the postpartum period, taking into account the role of stable differences in women's vulnerability for depression across a 10-year span. METHODS: Data from the National Longitudinal Survey of Youth 1997 Cohort (N = 4385) were used. The recency of childbirth was used as a predictor of state depression in two models: one that modeled stable depressive symptoms over time (a multi-state single-trait model; LST), and one that did not (an autoregressive cross-lagged model; ARM). RESULTS: Modeling trait depression, in addition to state depression, improved model fit and had the effect of increasing the magnitude of the association between childbirth and state depression in the postpartum period. LIMITATIONS: The secondary nature of the data limited the complexity of analyses (e.g., models with multivariate predictors were not possible), as the data were not collected with the present study in mind. CONCLUSIONS: These findings may reflect the fact that some of the covariance between childbirth and episodic depression is obscured by the effect of trait depression, and it is not until trait depression is explicitly modeled that the magnitude of the relationship between childbirth and depression becomes clear. PMID- 28732244 TI - Thyroglossal duct cysts in children: Sonographic features every radiologist should know and their histopathological correlation. AB - Distinguishing between thyroglossal duct cysts (TGDC) and dermoid cysts (DC) sonographically can be challenging. We illustrate the three sonographic features in neck masses in children recently identified as being most suggestive of TGDC (septa, irregular wall and solid elements) and their corresponding histopathology. These three variables form a proposed predictive model for TGDC as a guide to surgical intervention. Pediatric radiologists should be familiar with these key imaging features, as compared with other imaging features described in TGDC also illustrated here, which are less discriminating. PMID- 28732245 TI - Interleukin-4 receptor-targeted delivery of Bcl-xL siRNA sensitizes tumors to chemotherapy and inhibits tumor growth. AB - IL-4 receptor (IL-4R) is commonly up-regulated on tumor cells, and interactions between the receptor and Interleukin-4 (IL-4) can induce the expression of anti apoptotic proteins, including Bcl-xL. This contributes to tumor cell survival and their resistance to chemotherapy. In this study, we exploited IL-4R-targeted delivery of Bcl-xL siRNA to IL-4R-expressing tumor cells in order to sensitize them to chemotherapy. To target IL-4R, an IL-4R-binding peptide, IL4RPep-1, was attached to branched polyethyleneimine-superparamagnetic iron oxide nanoparticles (BPEI-SPION). These nanoparticles were then complexed with Bcl-xL-targeting siRNA. IL-4R-targeted BPEI-SPION/Bcl-xL siRNA more efficiently reduced Bcl-xL gene expression and enhanced cytotoxicity of doxorubicin in MDA-MB231 breast tumor cells compared to untargeted BPEI-SPION/Bcl-xL siRNA. The siRNA was released from the complexes after 15 h of incubation at pH 5.5 and was stable in the complexes up to 72 h in the serum. The IL-4R-targeted BPEI-SPION/siRNA was internalized by cells through IL-4R, successfully escaped the endosomes, and was dispersed into the cytoplasm. Near-infrared fluorescence and magnetic resonance imaging demonstrated that in vivo tumor homing and accumulation of IL-4R-targeted BPEI-SPION/siRNA were both higher than untargeted BPEI-SPION/siRNA. The IL-4R targeted BPEI-SPION/Bcl-xL siRNA, in combination with doxorubicin, significantly inhibited tumor growth in mice compared to untargeted BPEI-SPION/Bcl-xL siRNA. These results suggest that the IL-4R-targeted delivery of Bcl-xL siRNA to IL-4R expressing tumors can sensitize tumors to chemotherapy and enhance the efficacy of anti-tumor therapeutics. PMID- 28732247 TI - Repairing sciatic nerve injury with an EPO-loaded nerve conduit and sandwiched-in strategy of transplanting mesenchymal stem cells. AB - Transplantation of a biosynthetic nerve conduit carrying neuro-protective cytokines is promising for treating peripheral nerve injury. Here we developed a novel strategy for repairing sciatic nerve injury by EPO-loaded Chitosan nerve conduit (EPO/Chi) and sandwiched-in transplantation of mesenchymal stem cells (MSCs). Then, the beneficial effect of EPO/Chi + MSCs on nerve regeneration was also further investigated by in vitro cellular experiments. In vivo experiment showed that combination of EPO-loaded Chitosan nerve conduit with MSCs could significantly accelerate nerve healing and improve morphological repair. Furthermore, the in vitro cellular experiments results demonstrated that the loaded EPO in nerve conduit could significantly reinforce the repair performance of both MSCs and Schwann cells, which may also contribute to the therapeutic outcome of the EPO/Chi + MSCs strategy. Collectively, the EPO-loaded nerve conduit and sandwiched-in transplantation of MSCs we reported in the study may represent a new potential strategy for peripheral nerve reconstruction. PMID- 28732248 TI - Effects of adults' contingent responding on infants' behavior in ambiguous situations. AB - We examined the effect of adults' contingency in responding to infants' behavior in an ambiguous situation in two experiments. In Experiment 1, forty-four 12 month-old infants were exposed to an ambiguous toy. An unfamiliar adult responded either contingently or non-contingently to the infant's bids and then presented the toy and provided positive information. During toy presentation, infants in the non-contingent condition looked less at the experimenter than infants in the contingent condition. In a concluding free-play situation infants in the non contingent condition played less and tended to touch the toy less. In Experiment 2 (forty-four 12-month-old infants), the parent either responded promptly or with a delay each time the infant made contact initiatives and then presented an ambiguous toy and delivered the positive information. The infants in the non contingent condition tended to look less at the parent during toy presentation and also tended to play less with the toy during the concluding free-play situation. The findings show that adults' contingency in responding influences infants' behavior in ambiguous situations. PMID- 28732246 TI - Inspiration from heart development: Biomimetic development of functional human cardiac organoids. AB - Recent progress in human organoids has provided 3D tissue systems to model human development, diseases, as well as develop cell delivery systems for regenerative therapies. While direct differentiation of human embryoid bodies holds great promise for cardiac organoid production, intramyocardial cell organization during heart development provides biological foundation to fabricate human cardiac organoids with defined cell types. Inspired by the intramyocardial organization events in coronary vasculogenesis, where a diverse, yet defined, mixture of cardiac cell types self-organizes into functional myocardium in the absence of blood flow, we have developed a defined method to produce scaffold-free human cardiac organoids that structurally and functionally resembled the lumenized vascular network in the developing myocardium, supported hiPSC-CM development and possessed fundamental cardiac tissue-level functions. In particular, this development-driven strategy offers a robust, tunable system to examine the contributions of individual cell types, matrix materials and additional factors for developmental insight, biomimetic matrix composition to advance biomaterial design, tissue/organ-level drug screening, and cell therapy for heart repair. PMID- 28732249 TI - Evaluating Alzheimer's disease biomarkers as mediators of age-related cognitive decline. AB - Age-related changes in cognition are partially mediated by the presence of neuropathology and neurodegeneration. This manuscript evaluates the degree to which biomarkers of Alzheimer's disease, (AD) neuropathology and longitudinal changes in brain structure, account for age-related differences in cognition. Data from the AD Neuroimaging Initiative (n = 1012) were analyzed, including individuals with normal cognition and mild cognitive impairment. Parallel process mixed effects regression models characterized longitudinal trajectories of cognitive variables and time-varying changes in brain volumes. Baseline age was associated with both memory and executive function at baseline (p's < 0.001) and change in memory and executive function performances over time (p's < 0.05). After adjusting for clinical diagnosis, baseline, and longitudinal changes in brain volume, and baseline levels of cerebrospinal fluid biomarkers, age effects on change in episodic memory and executive function were fully attenuated, age effects on baseline memory were substantially attenuated, but an association remained between age and baseline executive function. Results support previous studies that show that age effects on cognitive decline are fully mediated by disease and neurodegeneration variables but also show domain-specific age effects on baseline cognition, specifically an age pathway to executive function that is independent of brain and disease pathways. PMID- 28732251 TI - Nutrient deficiency and obstetrical outcomes in pregnant women following Roux-en Y gastric bypass: A retrospective Danish cohort study with a matched comparison group. AB - OBJECTIVE: Roux-en-Y gastric bypass surgery and small-for-gestational-age births are known to be associated although the etiology is not fully understood. This study aimed to investigate pregnancy outcomes and maternal nutritional status among pregnant women with a history of Roux-en-Y gastric bypass using maternal anemia and gestational weight gain as indicators of micronutrient and macronutrient deficiency in pregnancy. STUDY DESIGN: The study was designed as a retrospective matched cohort study. All Roux-en-Y-gastric-bypass-operated pregnant women (n=151) who were followed in the outpatient obstetric clinic at Aalborg University Hospital in Denmark and gave birth between 1 January 2010 and 31 December 2013 were included. Each Roux-en-Y-gastric-bypass-operated woman was closely matched with a non-Roux-en-Y-gastric-bypass-operated woman. Primary outcomes were small-for-gestational-age birth, maternal anemia and gestational weight gain. The two groups (matched 1:1) were compared by paired tests on all measures, conditional logistic regression for paired binary data and the paired t test or Wilcoxon signed-rank test for paired continuous data. RESULTS: The risk of small-for-gestational-age birth (odds ratio (OR)=2.67, 95% confidence interval (CI); 1.04-6.82) and maternal anemia (OR=3.0, 95% CI; 1.09-8.25) were significantly increased for the Roux-en-Y gastric bypass group compared to the non-Roux-en-Y gastric bypass group. No significant difference was found in gestational weight gain (p=0.169) between women with a history of Roux-en-Y gastric bypass (11.51kg+/-8.97 standard deviation (SD)) and non- Roux-en-Y gastric-bypass-operated women (12.18kg+/-6.28 SD). CONCLUSION: A history of Roux en-Y gastric bypass surgery increases the risk of small-for-gestational-age birth and anemia, while a finding of differences in gestational weight gain is uncorroborated. Our findings suggest a role of micronutrient deficiency rather than reduced gestational weight gain in the etiology of small-for-gestational-age birth among women with a history of Roux-en-Y gastric bypass surgery. PMID- 28732250 TI - Structural biology of telomerase and its interaction at telomeres. AB - Telomerase is an RNP that synthesizes the 3' ends of linear chromosomes and is an important regulator of telomere length. It contains a single long non-coding telomerase RNA (TER), telomerase reverse transcriptase (TERT), and other proteins that vary among organisms. Recent progress in structural biology of telomerase includes reports of the first cryo-electron microscopy structure of telomerase, from Tetrahymena, new crystal structures of TERT domains, telomerase RNA structures and models, and identification in Tetrahymena telomerase holoenzyme of human homologues of telomere-associated proteins that have provided a more unified view of telomerase interaction at telomeres as well as insights into the role of telomerase RNA in activity and assembly. PMID- 28732252 TI - Update on medical treatment of uterine fibroids. AB - OBJECTIVES: In this review paper, the pros and cons of the available pharmacological options for the treatment of uterine fibroids are explored, including oral progestogens, levonorgestrel intra-uterine device, gonadotropin releasing hormone analogs and progesterone receptor modulators with an emphasis on ulipristal acetate. STUDY DESIGN: The choice of the appropriate therapeutic approach for uterine fibroids depends on several factors, including women's age, parity, childbearing aspirations and wish to preserve fertility, extent and severity of symptoms, size, number and location of myomas, risk of malignancy and proximity to menopause. Some treatment algorithms have been proposed for uterine fibroids, considering both efficacy and safety data from clinical trials, and women characteristics and choices. Therefore, we propose two optimized treatment algorithms for the treatment of uterine fibroids, one for the treatment of uterine fibroids in women of reproductive age with the desire to spare reproductive capacity, and another for the treatment of uterine fibroids in women >40years with no desire for pregnancy. RESULTS: Symptoms associated with uterine fibroids may significantly impair a patient quality of life. Therapy includes surgery, which may range from a hysterectomy to several other uterus-sparing techniques and several different types of pharmacological therapies. Studies with ulipristal acetate have provided a change of paradigm in the treatment of uterine fibroids, demonstrating the efficacy and favorable tolerability profile, not only for the preoperative treatment of moderate to severe fibroid-associated symptoms, but also, and very importantly, for the long-term medical management of patients with symptomatic fibroids. PMID- 28732253 TI - Diminished ovarian reserve in women with transfusion-dependent beta-thalassemia major: Is iron gonadotoxic? AB - OBJECTIVE: Iron accumulation in the endocrine glands has been implicated in the aetiopathogenesis of decreased reproductive capacity in patients with beta thalassemia major (beta-TM). The aim of the current study was to investigate the serum concentration of anti-Mullerian hormone (AMH), a marker of ovarian reserve, in women with transfusion-dependent beta-TM. STUDY DESIGN: In this case-control study, we recruited 43 women with transfusion-dependent TM and 44 age-matched healthy controls. Hormonal and haematological parameters, serum level of AMH, antral follicle count, and ovarian volume were assessed. RESULTS: Twenty-two of the 43 women were hypogonadotropic, 8 with primary amenorrhea and 14 with secondary amenorrhea. FSH, LH, estradiol, prolactin, and AMH levels; antral follicle count; and ovarian volume were significantly lower in women with TM compared with the control group (p<0.05 for all). CONCLUSION: AMH level and other ovarian reserve markers are significantly diminished in women with transfusion dependent TM compared to age-matched controls. Our findings support a deleterious effect of iron overload on ovarian tissue. PMID- 28732254 TI - Going down the tubes! Impact on seizure control of antiepileptic medication given via percutaneous feeding tubes. AB - BACKGROUND: Long-term feeding by percutaneous endoscopic gastrostomy tube (PEG) is uncommon but can present significant issues when both nutrition and medication have to be fed down the same tube. This is especially important in people with epilepsy where the dose and bioavailability of antiepileptic drugs are critical to maintain adequate seizure control. This group with long-term PEG tubes is particularly vulnerable and dependent on their carers to provide high standard of care. Indeed, approximately half of the people with long-term feeding tubes suffer from severe intellectual disability which requires careful coordination of all members of the multidisciplinary team. It is all the more important when consideration is given that around 50% of people with severe ID have seizures, mostly treatment resistant. METHOD: A detailed literature review was conducted with the focus on the numerous factors that can affect medication delivery and absorption with the potential to destabilize seizure control in people with PEG. Issues concerning the site of drug absorption, excipients and dilution, interaction between antiepileptic drugs and the nutritional feed, bioavailability, and problems with the PEG tube are considered. RESULTS: There is limited research in this area and the studies are often based on small numbers, healthy volunteers or in vitro findings. CONCLUSION: In the absence of sound research data, seizure control in each patient with a PEG needs to be considered on an individual basis. Establishing a baseline by measuring the serum levels prior to the tube insertion may be helpful, followed by checking the levels after PEG insertion. PMID- 28732255 TI - Can head trauma trigger adult-onset Rasmussen's encephalitis? AB - Rasmussen's encephalitis (RE) is a rare unilateral inflammatory brain disorder that causes progressive neurocognitive deterioration and refractory epilepsy including epilepsia partialis continua (EPC). We describe a patient with a unique presentation, where right upper limb EPC due to RE began within 2weeks of a concussive left frontal head injury, in a 36-year-old female without other identifiable etiology, no prior neurological deficit nor suggestion of intracranial pathology or infection, and no preceding seizures. The diagnosis of RE followed extensive investigation, excluding confounding diagnoses, with supportive histopathology, and her EPC has proven refractory to treatment. In the absence of a satisfactory alternative etiology and exclusion of differential diagnoses, the most likely cause or precipitant of this patient's RE was head trauma. PMID- 28732256 TI - Using the Theory of Planned Behavior incorporated with perceived barriers to explore sexual counseling services delivered by healthcare professionals in individuals suffering from epilepsy. AB - People with epilepsy (PWE) are highly likely to suffer from sexual dysfunction, and dealing with this issue is a challenge for healthcare providers. Unfortunately, there is no theory-driven study that has investigated the counseling practice of healthcare providers for sexual problems in PWE. Therefore, we decided to apply the well-established Theory of Planned Behavior (TPB) to examine factors associated with healthcare providers' sexual counseling in PWE. Apart from TPB, perceived barriers toward providing counseling could be a possible factor that needs to be investigated as well. Therefore, two models explaining sexual counseling practice were proposed. Model 1 included only TPB and Model 2 included TPB incorporated with perceived barriers. Five hundred fifty nine Iranian healthcare professionals responsible for PWE were recruited across several neurology clinics and asked to complete TPB-specific questionnaires. The same healthcare professionals were asked to complete an additional questionnaire on their attitudes toward sexual counseling 18months later. Structural equation modeling suggested Model 2 to be more useful in explaining sexual counseling practice compared with Model 1. Moreover, attitude and perceived behavioral control showed stronger associations with behavioral intention, whereas subjective norm showed weaker associations. The associations were similar across different healthcare professionals (i.e., medical doctors vs. nurses). In conclusion, TPB incorporated with perceived barriers might be a useful theory for different types of healthcare providers to improve and enhance sexual counseling practice. PMID- 28732257 TI - Epileptiform discharges in EEG and seizure risk in adolescent children of women with epilepsy. AB - We aimed to study the epileptiform discharges (ED) and seizure risk in EEG of 12 18-year-old children of women with epilepsy (WWE). Children of WWE who were prospectively followed up in the Kerala registry of epilepsy and pregnancy (KREP), aged 12-16years (n=92; males 48, females 44) underwent clinical evaluation and a 30-min digital 18-channel EEG. The EEG showed epileptiform discharges in 13 children (5 males and 8 females). The EDs were generalized in 9 and focal in 4 (occipital 2, frontal 1, and centroparietal 1). They had significantly higher risk of ED (odds ratio 4.02, 95% CI 1.04-15.51) when compared to published prevalence of ED in healthy children. There were 2 children with epilepsy (one with localization-related epilepsy and the other generalized epilepsy). The children under study had a trend towards higher prevalence of epilepsy (odds ratio 3.39, 95% CI 0.82-13.77) when compared to age specific prevalence of epilepsy from community surveys in same region. Children of WWE showed increased risk of ED in EEG and trend towards increased seizure risk when compared to healthy children. PMID- 28732258 TI - Areca catechu (palm tree) nut chewing and seizures: An observational study. AB - OBJECTIVE: The objective of this study was to report the impact of chronic abuse of Areca catechu nut wrapped in leaf (also known as doma, quid, paan), the fourth most commonly abused psychoactive substance worldwide, on the frequency of seizures among people with epilepsy. METHODS: People with clinically diagnosed epilepsy (>14years old) residing in the Kingdom of Bhutan were surveyed for self reported Areca catechu use, demographic variables, epilepsy characteristics, and seizure frequency. The relationship between seizure frequency in the prior month and chewing Areca catechu, adjusted for various confounders, was analyzed using multivariable regression models. RESULTS: There were 152 people with epilepsy, including 50 chewers (33%) and 102 (67%) nonchewers. The median duration of chewing A. catechu was 62months (25th, 75th percentiles: 24, 120months). Chewers consumed an average of three nuts daily. There was no significant difference between chewers and nonchewers in the mean age, proportion of male vs. female, age at first epileptic seizure, or number of antiepileptic drugs presently taken; chewers were more likely to be rural dwellers (p=0.042). After adjustment for all of the above variables, on average, chewers had 58.7% fewer [95%CI: (-79.4, 17.0)] seizures in the prior month, equating to 2.1 fewer [95% CI: (-3.9, -0.3)] seizures. CONCLUSIONS: Our observational study suggests that the social custom of chewing Areca catechu nut is associated with reduced seizure frequency among people with epilepsy. This association may be due to its natural stimulant properties, a novel antiepileptic property of the nut, or has another, yet unknown explanation. PMID- 28732259 TI - Dravet syndrome: Characteristics, comorbidities, and caregiver concerns. AB - The Dravet Syndrome Foundation (DSF) conducted the largest in-depth survey of parents and caregivers of patients with Dravet syndrome (DS) to date, in order to (1) identify top concerns among caregivers, (2) establish an approximate frequency of characteristics and comorbidities of DS beyond seizures, and (3) provide direction for clinicians and researchers looking to study the effects of DS on the patient and family unit. Two hundred fifty-six responses were received representing a patient age range of 9months to 32years with a median age group of 7-10years (IQR=8). In an open response, caregivers ranked speech/communication, impacts on siblings, and cognitive impairment as their top concerns after seizure control, and nearly two-thirds of caregivers reported having suffered from depression. Some characteristics of DS such as gait issues increased with patient age, while others, including photosensitivity, hypotonia, and ataxia, were present from a young age. Comorbidities such as sleep disturbances and cardiac abnormalities were more frequently reported than in previous studies and some (including bradycardia) were correlated with SCN1A mutation status. This survey supports the concept of Dravet syndrome as a disease of the central nervous system with far-reaching effects and highlights the importance of the patient voice in determining appropriate research objectives. While seizure frequency is a relatively well-understood objective, seizures represent only a portion of parent and caregiver concerns. Studying the characteristics of DS described herein may identify additional outcomes significant for research. PMID- 28732260 TI - Differences in emotional stimuli processing in subjects with MTLE with and without depression. AB - In healthy people, a preference in attention maintenance and memory for words with emotional valence comparing to neutral words has been shown. The pattern of emotional stimuli processing may be different in people with mesial temporal lobe epilepsy (MTLE) and it may be sensitive to the presence of depressive symptoms. In order to explore these possibilities, we applied the emotional spatial cueing attentional task and the free recall memory task to participants (N=39) with MTLE and compared them with healthy controls. We hypothesized that the pattern of maintaining attention and remembering emotional words is different in people with MTLE. Current literature indicates that this pattern will change from positive bias in the controls, though no emotional bias in the participants with MTLE without depression (MTLE-d), and in this work we examined this pattern in the participants with MTLE with depressive symptoms (MTLE+d). Our results show that in both attention and memory, control subjects exhibit positive emotional bias, the subjects with MTLE-d show nonemotional bias and the subjects with MTLE+d have bias away from positive words. Participants with MTLE+d maintained attention for positive words shorter than others. Participants with MTLE+d had worse recall for positive words than the participants with MTLE-d and for all words when compared to controls. We found that faster attention disengagement from positive words and worse memory for positive words is associated with elevated levels of depressive symptoms. PMID- 28732261 TI - Predictors of disclosure management behavior at the end of 1-year follow-up in Korean adults with newly diagnosed epilepsy. AB - PURPOSE: Epilepsy is a concealable stigmatizing condition. We investigated the factors predicting disclosure management behavior in Korean adults with newly diagnosed epilepsy. METHODS: This longitudinal multicenter study included Korean adults with newly diagnosed epilepsy. Using statistical analyses, we determined at the end of a 1-year follow-up whether Disclosure Management Scale (DMS) scores were predicted by demographic, clinical, and psychosocial variables, including felt stigma, stress coping style, personality traits, social support, and experienced discrimination from society. RESULTS: Of a total of 121 participants, 69% reported that they often or sometimes kept their diagnosis a secret from others and rarely or never talked to others about their epilepsy. The average DMS score was 5.8 (SD=2.9, range 0-11). In univariate analyses, DMS scores were significantly associated with an emotion-focused coping style (r=0.320, p<0.001), social support (r=-0.185, p<0.05), and experienced discrimination (p<0.05). Emotion-focused coping was the only independent predictor of a higher DMS score. Felt stigma, personality traits, and seizure freedom were not related to the DMS score. CONCLUSIONS: Two-thirds of Korean adults with newly diagnosed epilepsy often or sometimes keep their epilepsy a secret. Emotion-focused coping is the most important predictor of concealment of epilepsy diagnosis at the end of a 1 year follow-up, although social support and episodes of experienced discrimination are also associated with disclosure management strategies. PMID- 28732262 TI - Attitudes toward epilepsy and perceptions of epilepsy-related stigma in Korean evangelical Christians. AB - PURPOSE: The scriptural description of Jesus driving out an evil spirit from a boy with epilepsy supported the idea of the spiritual nature of epilepsy for centuries. Korea has a shorter history of Christianity than the Western world. We determined whether there are differences in attitudes toward epilepsy and perception of epilepsy-related stigma between people with and without belief in evangelical Christianity in Korea. METHODS: Data were collected from evangelical churches and theological colleges. People without religious beliefs were enrolled as a control group through convenience sampling. The Public Attitudes Toward Epilepsy (PATE) scale and the modified Stigma Scale for epilepsy were used. Familiarity with and knowledge of epilepsy were also assessed. Evangelical Christians were categorized as professional or nonprofessional depending on whether they had received professional education in Christian theology. RESULTS: A total of 227 evangelical Christians and 139 controls were included. The scores on the Stigma Scale and in the two PATE domains were significantly lower in the professional Christian group than in the controls or the nonprofessional group (p<0.05) but did not differ between the nonprofessional group and controls. After controlling for confounders, only the professional group was independently associated with lower scores on the Stigma Scale and in the PATE personal domain (p<0.05). The remaining associations lost their significance. CONCLUSIONS: We found no differences in attitudes toward epilepsy and perception of stigma between people with and without belief in evangelical Christianity in Korea. PMID- 28732263 TI - Proteomic analysis of naturally occurring boron tolerant plant Gypsophila sphaerocephala L. in response to high boron concentration. AB - Gypsophila sphaerocephala is a naturally Boron (B) tolerant species that can grow around the B mining areas in Turkey, where the B concentration in soil reaches a lethal dose for plants (up to ~8900mgkg-1 (~140mM). While its interesting survival capacity in extremely B containing soils, any molecular research has been conducted to understand its high tolerance mechanism yet. In the present study, we have performed a proteomic analysis of this plant to understand its high tolerance towards B-stress. Seedlings of G. sphaerocephala were collected from B mining area and were adapted to greenhouse conditions. An excessive level of Boric acid (3mM)was applied to the plantlets for 24h. Total proteins were precipitated by using TCA/Acetone method. 2D-PAGE (two-dimensional polyacrylamide gel electrophoresis) analysis of the proteins was carried out. Out of 121 protein spots, 14 were differentially expressed between the control and B-exposed G. sphaerocephala roots. The peptide profile of each protein was determined by MALDI TOF mass spectrometer after in-gel trypsin digestion. The identified proteins are involved in different mechanisms in the cell such as in antioxidant mechanism, energy metabolism, protein degradation, lipid biosynthesis and signaling pathways, indicating that G. sphaerocephala has multiple cooperating mechanisms to protect itself from high B levels. Overall, this study sheds light on to the possible regulatory switches (gene/s) controlling the B-tolerance proteins and their possible roles in plant's defense mechanism. PMID- 28732264 TI - Insights into plant phosphate sensing and signaling. AB - Phosphorus (P) is a macronutrient essential for plant growth, therefore, soil P level is critical to crop yield potential in agriculture. As Pi levels limit crop yield under many soil conditions, it is crucial to understand the mechanisms by which plants adapt to low-phosphate (Pi) soil conditions and interact with their soil microbiome to improve crop P use efficiency, in order to ensure global food security. Recent advances have been made towards achieving this goal through advancing our understanding of the plant's response to limiting Pi conditions to maintain P homeostasis. In this review, we assess advances made in local and systemic Pi sensing and signaling, and in the molecular events for Pi absorption, redistribution and plant-symbiont interactions. These findings offer important avenues for bio-engineering of agricultural crops with traits for enhanced Pi acquisition and utilization. PMID- 28732265 TI - Chronic work stress and decreased vagal tone impairs decision making and reaction time in jockeys. AB - The inverse relationship between acute stress and decision-making is well documented, but few studies have investigated the impact of chronic stress. Jockeys work exhaustive schedules and have extremely dangerous occupations, with safe performance requiring quick reaction time and accurate decision-making. We used the effort reward imbalance (ERI) occupational stress model to assess the relationship of work stress with indices of stress physiology and decision-making and reaction time. Jockeys (N=32) completed computerised cognitive tasks (Cogstate) on two occasions; September and November (naturally occurring lower and higher stress periods), either side of an acute stress test. Higher ERI was correlated with the cortisol awakening responses (high stress r=-0.37; low stress r=0.36), and with decrements in decision-making comparable to having a blood alcohol concentration of 0.08 in the high stress period (p<0.001) The LF/HF ratio of heart rate variability impacted the association of ERI with decision-making. Potentially, this may be attributed to a 'tipping point' whereby the higher ERI reported by jockeys in the high stress period decreases vagal tone, which may contribute to reduced decision-making abilities. PMID- 28732266 TI - Effect of heat treatments on the microstructure and formability of Al-Mg-Mn-Sc-Zr alloy. AB - Microstructures and formability of scandium and zirconium added Al-Mg-Mn alloy sheets with various heating conditions were examined to improve their mechanical properties. Formability of these samples were judged by the Lankford value, r value. It was possible to fabricate mechanically balanced Al-Mg-Mn-Sc-Zr alloy with high hardness 76.2 Hv and with high formability with r=1.2, by not only adding scandium and zirconium but also optimizing the heat treatment conditions. PMID- 28732267 TI - Understanding the holobiont: the interdependence of plants and their microbiome. AB - The holobiont is composed by the plant and its microbiome. In a similar way to ecological systems of higher organisms, the holobiont shows interdependent and complex dynamics [1,2]. While plants originate from seeds, the microbiome has a multitude of sources. The assemblage of these communities depends on the interaction between the emerging seedling and its surrounding environment, with soil being the main source. These microbial communities are controlled by the plant through different strategies, such as the specific profile of root exudates and its immune system. Despite this control, the microbiome is still able to adapt and thrive. The molecular knowledge behind these interactions and microbial '-omic' technologies are developing to the point of enabling holobiont engineering. For a long time microorganisms were in the background of plant biology but new multidisciplinary approaches have led to an appreciation of the importance of the holobiont, where plants and microbes are interdependent. PMID- 28732268 TI - Validation, comparison, and combination of algorithms for automatic detection of pulmonary nodules in computed tomography images: The LUNA16 challenge. AB - Automatic detection of pulmonary nodules in thoracic computed tomography (CT) scans has been an active area of research for the last two decades. However, there have only been few studies that provide a comparative performance evaluation of different systems on a common database. We have therefore set up the LUNA16 challenge, an objective evaluation framework for automatic nodule detection algorithms using the largest publicly available reference database of chest CT scans, the LIDC-IDRI data set. In LUNA16, participants develop their algorithm and upload their predictions on 888 CT scans in one of the two tracks: 1) the complete nodule detection track where a complete CAD system should be developed, or 2) the false positive reduction track where a provided set of nodule candidates should be classified. This paper describes the setup of LUNA16 and presents the results of the challenge so far. Moreover, the impact of combining individual systems on the detection performance was also investigated. It was observed that the leading solutions employed convolutional networks and used the provided set of nodule candidates. The combination of these solutions achieved an excellent sensitivity of over 95% at fewer than 1.0 false positives per scan. This highlights the potential of combining algorithms to improve the detection performance. Our observer study with four expert readers has shown that the best system detects nodules that were missed by expert readers who originally annotated the LIDC-IDRI data. We released this set of additional nodules for further development of CAD systems. PMID- 28732270 TI - Unexpected histopathology of acute appendicitis. AB - INTRODUCTION: Appendicular diverticula and associated diverticulitis is a rare disease. Patients present commonly with symptoms of acute appendicitis and require laparoscopic or open surgery. Diagnosis is usually made only on histology. Here, we present a rare case of acute diverticulitis of the appendix. CASE PRESENTATION: A 33-year old gentleman presented with right iliac fossa pain of 3 days duration. On admission, appendicitis was diagnosed on Computerized Tomography (CT) scan and laparoscopic appendicectomy was subsequently performed. Intra-operative findings were unremarkable and recovery was uneventful. Histopathology however revealed diverticulitis of appendix with acellular mucin. DISCUSSION: Acute diverticulitis of the appendix is an exceptionally rare condition and reported in 0.004%-2% of appendicectomies. It presents usually when complicated with perforation and bleeding. There is however a strong association with certain malignancies such as mucinous neoplasm, carcinoid and Pseudomyxoma peritoneii. Radiological proven appendicular diverticulum requires early intervention due to higher chance of diverticulitis related complication. Surgeons should be aware about this rare disease and may consider elective surgery in view of potential risk of complications and malignancy. CONCLUSION: We concluded that because of strong malignant association, it would be recommended that all appendix specimens should inspect during and after surgery and concurrent examination of peritoneal cavity is recommended. PMID- 28732271 TI - A rare anomaly of the right superior pulmonary vein: Report of a case. AB - INTRODUCTION: Although there are a lot of variations of pulmonary veins (PVs) including dangerous type that could cause serous complications during the surgery, limited information has been reported about these variations. We have experienced an extremely rare anomaly of the right superior PV. PRESENTATION OF CASE: A 74-year-old man patient with right lung cancer visited our hospital. Chest computed tomography (CT) revealed a pulmonary nodule in the right lower lobe. Contrast-enhanced three-dimensional CT (3D-CT) showed that the right superior PV ran abnormally between the right main pulmonary artery (PA) and the right main bronchus. We performed right lower lobectomy and systematic nodal dissection. The operative findings confirmed that the right superior PV ran abnormally same as 3D-CT. DISCUSSION: In most reported cases, anomalous PVs pass behind the right bronchi or into the roof of the left atrium. The anomaly reported in the present case has been reported in only one case report. This case suggests that the space between the right main PA and the right main bronchus is not always safe for dissection. CONCLUSION: Preoperative 3D-CT is useful for avoiding unexpected bleeding. PMID- 28732269 TI - Gyral net: A new representation of cortical folding organization. AB - One distinct feature of the cerebral cortex is its convex (gyri) and concave (sulci) folding patterns. Due to the remarkable complexity and variability of gyral/sulcal shapes, it has been challenging to quantitatively model their organization patterns. Inspired by the observation that the lines of gyral crests can form a connected graph on each brain hemisphere, we propose a new representation of cortical gyri/sulci organization pattern - gyral net, which models cortical architecture from a graph perspective, starting with nodes and edges obtained from the reconstructed cortical surfaces. A novel computational framework is developed to efficiently and automatically construct gyral nets from surface meshes, and four measurements are devised to quantify the folding patterns. Using an MRI dataset for autism study as a test bed, we identified reduced local connectivity cost and increased curviness of gyral net bilaterally on the parietal lobe, occipital lobe, and temporal lobe in autistic patients. Additionally, we found that the cortical thickness and the gyral straightness of gyral joints are higher than the rest of gyral crest regions. The proposed representation offers a new tool for a comprehensive and reliable characterization of the cortical folding organization. This novel computational framework will enable large-scale analyses of cortical folding patterns in the future. PMID- 28732273 TI - Using computational theory to constrain statistical models of neural data. AB - Computational neuroscience is, to first order, dominated by two approaches: the 'bottom-up' approach, which searches for statistical patterns in large-scale neural recordings, and the 'top-down' approach, which begins with a theory of computation and considers plausible neural implementations. While this division is not clear-cut, we argue that these approaches should be much more intimately linked. From a Bayesian perspective, computational theories provide constrained prior distributions on neural data-albeit highly sophisticated ones. By connecting theory to observation via a probabilistic model, we provide the link necessary to test, evaluate, and revise our theories in a data-driven and statistically rigorous fashion. This review highlights examples of this theory driven pipeline for neural data analysis in recent literature and illustrates it with a worked example based on the temporal difference learning model of dopamine. PMID- 28732274 TI - New source models to represent the irradiation process in panoramic gamma irradiator. AB - The use of gamma irradiation technologies generates a number of complex scientific and technical problems; for example, the target is manually loaded onto turntables and is rotated during the entire irradiation process and the MCNPX three-dimensional geometry simulation is kept static. For this, it is necessary to introduce additional approaches. In this paper, two new methodologies are proposed for the simulation of irradiation process in panoramic gamma irradiator. The study was performed at the gamma irradiation facility at the Nuclear Technology Development Center of the National Nuclear Energy Commission, Brazil. The source can be reproduced with a homogenized geometry. Validation of MCNPX calculations of gamma doses were performed by thorough comparison with the experimental measurements. The contribution of this proposed source models has opened new lines of research. The results of this study showed that the proposed source models effectively represent the irradiation process. PMID- 28732272 TI - Screening of the 'Open Scaffolds' collection from Compounds Australia identifies a new chemical entity with anthelmintic activities against different developmental stages of the barber's pole worm and other parasitic nematodes. AB - The discovery and development of novel anthelmintic classes is essential to sustain the control of socioeconomically important parasitic worms of humans and animals. With the aim of offering novel, lead-like scaffolds for drug discovery, Compounds Australia released the 'Open Scaffolds' collection containing 33,999 compounds, with extensive information available on the physicochemical properties of these chemicals. In the present study, we screened 14,464 prioritised compounds from the 'Open Scaffolds' collection against the exsheathed third-stage larvae (xL3s) of Haemonchus contortus using recently developed whole-organism screening assays. We identified a hit compound, called SN00797439, which was shown to reproducibly reduce xL3 motility by >= 70%; this compound induced a characteristic, "coiled" xL3 phenotype (IC50 = 3.46-5.93 MUM), inhibited motility of fourth-stage larvae (L4s; IC50 = 0.31-12.5 MUM) and caused considerable cuticular damage to L4s in vitro. When tested on other parasitic nematodes in vitro, SN00797439 was shown to inhibit (IC50 = 3-50 MUM) adults of Ancylostoma ceylanicum (hookworm) and first-stage larvae of Trichuris muris (whipworm) and eventually kill (>90%) these stages. Furthermore, this compound completely inhibited the motility of female and male adults of Brugia malayi (50-100 MUM) as well as microfilariae of both B. malayi and Dirofilaria immitis (heartworm). Overall, these results show that SN00797439 acts against genetically (evolutionarily) distant parasitic nematodes i.e. H. contortus and A. ceylanicum [strongyloids] vs. B. malayi and D. immitis [filarioids] vs. T. muris [enoplid], and, thus, might offer a novel, lead-like scaffold for the development of a relatively broad-spectrum anthelmintic. Our future work will focus on assessing the activity of SN00797439 against other pathogens that cause neglected tropical diseases, optimising analogs with improved biological activities and characterising their targets. PMID- 28732275 TI - Plot-, farm-, and watershed-scale effects of coffee cultivation in runoff and sediment production in western Puerto Rico. AB - The combination of a topographically abrupt wet-tropical setting with the high level of soil exposure that typifies many sun-grown coffee farms represents optimal conditions for high erosion rates. Although traditionally considered as a main cause for water resource degradation, limited empirical evidence has existed to document its true contribution. This study relies on plot-scale experimental results conducted in western Puerto Rico to assess the impact of cultivated surfaces and farm access roads on runoff and sediment production from the plot to the farm and watershed scales. Results show that unsurfaced and graveled road surfaces produce one- to two-orders of magnitude more per unit area runoff than cultivated lands. Similarly, erosion rates from unsurfaced roads are about 102 g m-2 per cm of rainfall and these are two-orders of magnitude greater than from actively cultivated surfaces. Mitigation practices such as uncompacting road surfaces by ripping and gravel application reduce onsite erosion rates to 0.6% and 8% of unsurfaced conditions, respectively. At the farm scale, coffee farms are estimated to produce sediment at a rate of 12-18 Mg ha-1 yr-1, and roads are undoubtedly the dominant sediment source responsible for 59-95% of the total sediment produced. The costs associated to ameliorating erosion problems through road graveling are high. Therefore, a combined approach that treats road erosion onsite with one that traps sediment before it reaches river networks is the viable solution to this problem. PMID- 28732276 TI - Sampling and single particle analysis for the chemical characterisation of fine atmospheric particulates: A review. AB - To better understand the potential environmental and human health impacts of fine airborne particulate matter (APM), detailed physical and chemical characterisation is required. The only means to accurately distinguish between the multiple compositions in APM is by single particle analysis. A variety of methods and instruments are available, which range from filter-based sample collection for off-line laboratory analysis to on-line instruments that detect the airborne particles and generate size distribution and chemical data in real time. There are many reasons for sampling particulates in the ambient atmosphere and as a consequence, different measurement strategies and sampling devices are used depending on the scientific objectives and subsequent analytical techniques. This review is designed as a guide to some of the techniques available for the sampling and subsequent chemical analysis of individual inorganic particles. PMID- 28732277 TI - Assessment of metal and PAH profiles in SUDS soil based on an improved experimental procedure. AB - The increasing use of infiltration-based systems for stormwater management questions the soil's ability to act as a long-term filter for runoff contaminants, and brings about operational matters regarding the most effective maintenance practices to enhance contaminant retention in SUDS. This paper reports the vertical extent of metal and PAH contamination in the soil of seven source-control devices in operation for more than 10 years, assessed via a two step sampling strategy to optimize the representativeness of the contamination profiles. Metal distribution was typically characterized by a significant surface buildup, followed by a decrease in concentrations with increasing depth, usually coming close to the background values. PAH were more heterogeneously distributed with depth, but their accumulation was globally restricted to the upper 10-40 cm. This indicates an interesting potential for pollution interception by the upper horizons of soil, but does not necessarily prevent from downward fluxes, even while measuring low surface contents, as deeper strata may have lesser retention capacities. Specific amendments of the surface soil may help prevent this problem. Surface soil renewal - which would be necessary over 2.5-30 cm in four sites, according to the "strictest" standards for soil remediation - may regenerate the soil's sorption potential, but such a practice could disrupt the interactions with the local ecosystem, so this should be carried out exceptionally and not as a preventive measure. PMID- 28732278 TI - Advances of small molecule targeting of kinases. AB - Reversible protein phosphorylation regulates virtually all aspects of life in the cell. As a result, dysregulation of protein kinases, the enzymes responsible for transferring phosphate groups from ATP to proteins, are often the cause or consequence of many human diseases including cancer. Almost three dozen protein kinase inhibitors (PKIs) have been approved for clinical applications since 1995, the vast majority of them for the treatment of cancer. According to the NCI, there are more than 100 types of cancer. However, FDA-approved PKIs only target 14 of them. Importantly, of the more than 500 protein kinases encoded by the human genome, only 22 are targets for currently approved PKIs, suggesting that the reservoir of PKIs still has room to grow significantly. In this short review we will discuss the most recent advances, challenges, and alternatives to currently adopted strategies in this burgeoning field. PMID- 28732281 TI - Epileptic seizure detection in EEGs signals based on the weighted visibility graph entropy. AB - PURPOSE: Epileptic seizure detection has been a complex task for both researchers and specialist in that the assessment of epilepsy is difficult because, electroencephalogram (EEG) signals are chaotic and non-stationary. METHOD: This paper proposes a new method based on weighted visibility graph entropy (WVGE) to identify seizure from EEG signals. Single channel EEG signals are mapped onto the WVGs and WVGEs are calculated from these WVGs. Then some features are extracted of WVGEs and given to classifiers to investigate the performance of these features to classify the brain signals into three groups of normal (healthy), seizure free (interictal) and during a seizure (ictal) groups. Four popular classifiers namely Support Vector Machine (SVM), K-Nearest Neighbor (KNN), Decision tree (DT) and, Naive Bayes (NB) are used in this work. RESULT: Experimental results show that the proposed method can classify normal, ictal and interictal groups with a high accuracy of 97%. CONCLUSIONS: This high accuracy index, which is obtained using just three features, is higher than those obtained by several previous works in which more nonlinear features were employed. Also, our method is fast and easy and may be helpful in different applications of automatic seizure detection such as online epileptic seizure detection. PMID- 28732279 TI - Turbocharging vaccines: emerging adjuvants for dendritic cell based therapeutic cancer vaccines. AB - Development of therapeutic cancer vaccines has been hindered by the many pro tumorigenic mechanisms at play in cancer patients that serve to suppress both antigen presenting cells and T cells. In face of these obstacles, cancer vaccines are most likely to promote anti-tumorigenic immune responses only when formulated with strong adjuvants, and in combination with new immune interventions designed to reverse immune suppression and exhaustion of T cells in the tumor microenvironment. Dendritic cells (DCs) are often termed 'nature's adjuvant' due to their exceptional capacity for initiating both innate and adaptive immune responses. Hence, the past decade has witnessed a flurry of activity in testing DC based immunotherapies for cancer intervention. In this review we will discuss advances in conventional adjuvants and provide insight into new adjuvants as they pertain to DC cancer therapy. PMID- 28732280 TI - Evaluation of a novel median power spectrogram for seizure detection by non neurophysiologists. AB - PURPOSE: (1) To evaluate how well resident physicians use a novel EEG spectral analysis tool (the median power spectrogram; MPS) to detect seizures. (2) To assess the capability of the MPS to identify different seizure types. METHODS: 120 EEG records from children with intractable seizures were converted to MPS by taking the median power across leads and using multi-taper spectral estimation. Twelve blinded neurology residents were trained to interpret the spectrogram with a five-minute video tutorial and post-test. Two residents independently assessed each set for presence of seizures. Their performance was compared to seizures identified using conventional EEG. Two blinded neurologists separately reviewed the EEGs and spectrograms to independently categorize the seizures. Their results were used to determine the spectrogram's capability to reveal seizures and visualize different seizure types for the user. RESULTS: Three key MPS features distinguished seizures from inter-ictal background: power difference relative to background, down-sloping resonance bands, and power in high frequencies. Using these features, residents identified seizures with 77% sensitivity and 72% specificity. 86% (51/59) of focal seizures and 81% (22/27) of generalized seizures were detected by at least one resident. Missed seizures included brief (<60s) seizures, tonic seizures, seizures with predominant delta (0-4Hz) activity, and seizures evident primarily in supplementary low temporal leads. CONCLUSIONS: The MPS is a novel qEEG modality that requires minimal training to interpret. It enables physicians without extensive neurophysiology training to identify seizures with sensitivity and specificity comparable to more complex multi-modal qEEG displays. PMID- 28732282 TI - Proficient use of low spatial frequencies facilitates face memory but shows protracted maturation throughout adolescence. AB - Face perception is characterized by configural processing, which depends on visual information in the low spatial frequency (LSF) ranges. However, it is unclear whether LSF content is equally important for face memory. The present study investigated how face information in the low and high SF range plays a role in the configural encoding of faces for short-term and long-term recall. Moreover, we examined how SF-dependent face memorization develops in female adolescence, by comparing children (9-10-year-olds), adolescents (12-13-year-olds and 15-16-year-olds), and young adults (21-32-year-olds). Results show that similar to face perception, delayed face recognition was consistently facilitated by LSF content. However, only adults were able to adequately employ configural LSF cues for short-term recall, analogous to the slow maturation of LSF-driven configural face perception reported by previous studies. Moreover, the insensitivity to face inversion of early adolescents revealed their inadequate use of configural face cues regardless of SF availability, corroborating previous reports on an adolescent "dip" in face recognition. Like face perception, face recognition has a protracted maturational course. In (female) adolescence, sensitivity to configural LSF cues is developed, which aids not only configural face perception but also face memorization. PMID- 28732283 TI - Deciphering the mechanism of interaction of edifenphos with calf thymus DNA. AB - Edifenphos is an important organophosphate pesticide with many antifungal and anti-insecticidal properties but it may cause potential hazards to human health. In this work, we have tried to explore the binding mode of action and mechanism of edifenphos to calf thymus DNA (CT-DNA). Several experiments such as ultraviolet-visible absorption spectra and emission spectroscopy showed complex formation between edifenphos and CT-DNA and low binding constant values supporting groove binding mode. These results were further confirmed by circular dichroism (CD), CT-DNA melting studies, viscosity measurements, density functional theory and molecular docking. CD study suggests that edifenphos does not alter native structure of CT-DNA. Isothermal calorimetry reveals that binding of edifenphos with CT-DNA is enthalpy driven process. Competitive binding assay and effect of ionic strength showed that edifenphos binds to CT-DNA via groove binding manner. Hence, edifenphos is a minor groove binder preferably interacting with A-T regions with docking score -6.84kJ/mol. PMID- 28732284 TI - Field-free molecular orientation by delayed elliptically polarised laser pulses. AB - A theoretical model of NAREX (non-adiabatic rotational excitation) and field-free molecular orientation by a short specific elliptically polarised laser pulses (EPLPs) driving a polar molecule is presented. By choosing the proper value of elliptically polarised field parameters, efficient field-free orientation could be achieved. It is demonstrated that NAREX can be controlled by various laser parameters, out of which pulse shape plays the most significant role. The effect of elliptic parameter on the rotational excitation and orientation dynamics is also under concern. PMID- 28732285 TI - Infrared dispersion analysis and Raman scattering spectra of taurine single crystals. AB - A comprehensive set of optical vibrational modes of monoclinic taurine crystals was determined by Raman scattering, and infrared reflectivity and transmission spectroscopies. By using appropriate scattering/reflection geometries, the vibrational modes were resolved by polarization and the most relevant modes of the crystal could be assigned. In particular, we were able to review the symmetry of the gerade modes and to resolve ambiguities in the literature. Owing to the non-orthogonal character of Bu modes in monoclinic crystals (lying on the optic axial plane), we carried out a generalized Lorentz dispersion analysis consisting of simultaneous adjust of infrared-reflectivity spectra at various light polarization angles. The Au modes (parallel to the C2-axis) were treated within the classical Lorentz model. The behavior of off-diagonal and diagonal terms of the complex dielectric tensors and the presence of anomalous dispersion were discussed as consequences of the low symmetry of the crystal. PMID- 28732286 TI - Development of liquid chromatographic methods for enantioseparation and sensitive detection of beta-adrenolytics/beta2-agonists in human plasma using a single enantiomer reagent. AB - Enantioseparation of four commonly used beta-adrenolytics (bisoprolol, salbutamol, and carvedilol, marketed as racemic mixtures) has been achieved by both TLC and RPHPLC via an indirect approach. A new chiral reagent, (S)-naproxen benzotriazole ester, was synthesized and it was characterized by UV, IR, 1HNMR, elemental analysis and polarimetry. It was used to synthesize diastereomeric derivatives of the three beta-adrenolytics under microwave irradiation. TLC separation of diastereomeric derivatives was achieved which were then isolated by preparative approach; these were characterized and were used as standard reference for determining absolute configuration of diastereomeric derivatives and for establishing validated HPLC method for enantioseparation and sensitive detection of the three beta-adrenolytics in human plasma. Mobile phase in gradient mode containing methanol and aqueous triethylaminephosphate (TEAP) was successful for HPLC separation; conditions with respect to pH, flow rate, and buffer concentration were optimized. The method is capable to accurately quantitate beta-adrenolytics in human plasma with minimal sample clean-up and rapid separation by TLC and RPHPLC. The limit of detection values were 0.97 and 0.87ng/mL for diastereomeric derivatives of (S)- and (R)-bisoprolol, respectively, which are very low in comparison to literature reports. PMID- 28732287 TI - Factors affecting the interaction between carbon nanotubes and redox enzymes in direct electron transfer-type bioelectrocatalysis. AB - The effects of three types of water-soluble carbon nanotubes (CNTs) of different lengths on the direct electron transfer (DET)-type bioelectrocatalysis of redox enzymes were investigated. Bilirubin oxidase (BOD), copper efflux oxidase (CueO), and a membrane-bound NiFe hydrogenase (H2ase) were used as model redox enzymes for four-electron dioxygen (O2) reduction (in the case of BOD and CueO) and two electron dihydrogen (H2) oxidation (in the case of H2ase). As a result, diffusion controlled O2 reduction in an O2-saturated neutral buffer was realized by BOD on CNTs of a length of 1MUm, but the catalytic current densities decreased as the length of CNTs increased. However, almost opposite trends were obtained when CueO and H2ase were utilized as the biocatalysts. Factors of the CNTs and the enzymes affecting the characteristics of the DET-type bioelectrocatalysis of the three enzymes were discussed. Finally, the electrostatic interaction between an enzyme (especially the portion near the redox active center) and CNTs is proposed as one of the most important factors governing the performance of DET-type bioelectrocatalysis. PMID- 28732288 TI - LncRNA HOTAIR alleviates rheumatoid arthritis by targeting miR-138 and inactivating NF-kappaB pathway. AB - Rheumatoid arthritis (RA) is a chronic and autoimmune-mediated inflammatory disease. We aimed to investigate the regulation of lncRNA HOTAIR in LPS-treated chondrocytes and RA mouse. Our results showed that HOTAIR expression was significantly reduced in LPS-treated chondrocytes. The HOTAIR was then over expressed in chondrocytes by transfecting recombinant lentivirus carrying sequences encoding HOTAIR. The LPS-induced reduction of cell proliferation rate and production of two inflammatory factors interleukin (IL)-17, IL-23 were markedly inhibited. Enforced expression of HOTAIR also led to the upregulation of proliferation-related protein Ki67 and proliferating cell nuclear antigen (PCNA). Moreover, a negative correlation was detected between the expression of HOTAIR and microRNA (miR)-138, and the expression of miR-138 was significantly increased in LPS-induced chondrocytes. The effects of HOTAIR over-expression on the proliferation and inflammation were partly reversed by miR-138 overexpression. Furthermore, the overexpression of HOTAIR significantly inhibited the activation of nuclear transcription factor-kappaB (NF-kappaB) in LPS-treated chondrocytes by suppressing p65 to cell nucleus, resulting in the down-regulation of IL-1beta and tumor necrosis factor (TNF)-alpha. In addition, the in vivo experiments exhibited that overexpression of HOTAIR increased cell proliferation and inhibited inflammation in RA rats, which were demonstrated by upregulation of Ki67 and PCNA, reduced CD4+IL-17+,CD4+IL-23+ cells, and down-regulation of p-p65, IL-1beta and TNF-alpha. In summary, our study suggests HOTAIR plays a protective role in RA by increasing proliferation rate and inhibiting inflammation, which may be related with the regulation of miR-138 expression and NF-kappaB signaling pathway. These results suggest that the regulation of HOTAIR may be a promising therapeutic strategy for RA. PMID- 28732289 TI - Effects of psychotherapies for posttraumatic stress disorder on sleep disturbances: Results from a randomized clinical trial. AB - The effectiveness and mechanisms of psychotherapies for posttraumatic stress disorder (PTSD) in treating sleep problems is of interest. This study compared the effects of a trauma-focused and a non-trauma-focused psychotherapy on sleep, to investigate whether 1) sleep improves with psychotherapy for PTSD; 2) the degree of sleep improvement depends on whether the intervention is trauma or nontrauma-focused; 3) the memory-updating procedure in cognitive therapy for PTSD (CT-PTSD) is associated with sleep improvements; 4) initial sleep duration affects PTSD treatment outcome; and 5) which symptom changes are associated with sleep duration improvements. Self-reported sleep was assessed during a randomized controlled trial (Ehlers et al., 2014) comparing CT-PTSD (delivered weekly or intensively over 7-days) with emotion-focused supportive therapy, and a waitlist. Sleep duration was reported daily in sleep diaries during intensive CT-PTSD. CT PTSD led to greater increases in sleep duration (55.2 min) and reductions in insomnia symptoms and nightmares than supportive therapy and the waitlist. In intensive CT-PTSD, sleep duration improved within 7 days, and sleep diaries indicated a 40-min sleep duration increase after updating trauma memories. Initial sleep duration was not related to CT-PTSD treatment outcome when initial PTSD symptom severity was controlled. The results suggest that trauma-focused psychotherapy for PTSD is more effective than nontrauma-focused therapy in improving self-reported sleep, and that CT-PTSD can still be effective in the presence of reduced sleep duration. PMID- 28732290 TI - Synergistic effect of UV pretreated Fe-ZSM-5 catalysts for heterogeneous catalytic complete oxidation of VOC: A technology development for sustainable use. AB - In this work, the performance of benzene, toluene, ethylbenzene, and xylene (BTEX) removal and degradation from gas, air streams on UV pretreated Fe-ZSM-5 in a batch reactor at room temperature were studied. The Fe-ZSM-5 zeolite catalyst was prepared by hydrothermal reaction method. The influence of UV pre-irradiation time on the removal of BTEX were assessed by varying the time, ranging from 15min to 60smin. Then, sustainability of the activation of the catalyst resulted by UV pretreatment was studied by the four-cycle experiment with one time UV irradiation and after each cycle irradiation followed by BTEX removal after every cycle respectively. The results of BTEX removal depicted that 30min of UV pretreatment was sufficient for complete organics removal. The UV pretreatment effect on the catalytic oxidation and the stability of the catalyst were studied by modern instrumental techniques. The novelty of the process was the sustainable reuse of catalyst with persistent VOC removal, which works on the -adsorption oxidation-regeneration-adsorption- cycle, which was confirmed by the characterization studies of the catalyst after four runs. The results revealed that the change in the structure, stability, morphology, and removal efficiency of the catalyst during the experiments was negligible. The VOC degradation mechanism studies showed that the oxidation occurs due to the formation of free radicals as well as hydroxyl ions, so named it heterogeneous photo-Fenton oxidation. The residual materials analysis showed the complete mineralization of VOC except small amount of acetone as oxidation product. Lastly, the kinetics of the VOC removal was studied. PMID- 28732291 TI - Comments on "Radiofrequency electromagnetic fields and some cancers of unknown etiology: An ecological study". AB - This correspondence refers to the Science of the Total Environment article by Gonzalez-Rubio et al. entitled "Radiofrequency electromagnetic fields and some cancers of unknown etiology: An ecological study". Authors of this paper have presented the findings of their preliminary epidemiological study which combined epidemiology, statistics and geographical information systems (GIS). Gonzalez Rubio et al. have analyzed the possible link between exposure to Radiofrequency Electromagnetic Fields (RF-EMF) in the city of Albacete, Spain and the incidence of cancers such as lymphomas, and brain tumors. The shortcomings of this study are discussed. PMID- 28732292 TI - Influence of rainfall duration and intensity on particulate matter removal from plant leaves. AB - Rainfall influences removal of airborne particulate matter (PM) from leaf surfaces through a process called wash off resulting in throughfall that carries PM to the ground. The present study examined the effects of rainfall characteristics on PM wash-off mass and rate from the foliage of four broadleaf species, to investigate retention of PM pollution. In a controlled rainfall simulation experiment, rainfall intensity was set to 15, 30, and 50mmh-1, and sampling intervals for the three rainfall intensities were divided into 10, 5, and 3min, respectively. Of the plants examined, the evergreen shrub Euonymus japonicus had the greatest surface PM accumulation before rainfall (165MUgcm-2), maximum wash-off during the first 2.5mm of rain (30MUgcm-2), and maximum surface PM retention after rainfall (24MUgcm-2). Fitting observations with the Box Lucas regression model, cumulative PM wash-off rates increased with cumulative rainfall amount, until the curves tended to become steady after rain exceeded 12.5mm. Wash off removed 51 to 70% of surface PM accumulation. As rainfall intensity increased, the duration of PM wash-off decreased, and wash-off rates were highest during the first rainfall interval. However, there was no significant difference between PM wash-off rates for rainfall intensities of 30 and 50mmh-1 in each rainfall interval. In addition, rain did not remove all PM completely, and PM retention following rainfall differed with rainfall intensity, except for Populus tomentosa. PMID- 28732293 TI - Investigation of the wash-off process using an innovative portable rainfall simulator allowing continuous monitoring of flow and turbidity at the urban surface outlet. AB - Development of appropriate models, based on an in-depth understanding of the wash off process, is essential to accurately estimating pollutant loads transported by stormwater, thereby minimizing environmental contamination. To this end, we developed an innovative rainfall simulator, which simulated an intense rainfall (120mm/h) and permitted the acquisition of runoff samples as well as the in situ monitoring of continuous flow and turbidity dynamics. Relationships between deposited sediments and total suspended solids in simulated runoff were thus investigated on two different types of surfaces within the Paris region in terms of loads and particle size distribution. Results demonstrate the occurrence of first flush phenomenon on the sidewalks even under constant flow. Results also show that the highest fraction conveyed by runoff consisted of fine (<16MUm) and medium-sized (<100MUm) particles, whose detachment was more favorable from smooth surfaces than from rougher ones. In terms of stormwater quality modelling, results suggest that the integration of a wash-off fraction based on both particle size and rainfall intensity could be an entrance for a better prediction of stormwater pollution. PMID- 28732294 TI - Soil bacterial community response to vegetation succession after fencing in the grassland of China. AB - Natural succession is an important process in terrestrial system, playing an important role in enhancing soil quality and plant diversity. Soil bacteria is the linkage between soil and plant, has an important role in aboveground community dynamics and ecosystem functioning in terrestrial ecosystems, driving the decomposition of soil organic matter and plant litter. However, the role of soil bacteria in the secondary succession has not been well understood, particularly in the degraded soil of Loess Plateau. In this study, we investigated soil nutrients and soil bacterial community during the secondary succession after a long-term fencing in the grassland, in the Yuwu Mountain, northwest China. The chronosequence included 1year, 12years, 20years and 30years. The soil bacterial community composition was determined by the Illumina HiSeq sequencing method. The data showed that soil bacterial diversity had no significant changes along the chronosequence, but soil bacterial community compositions significantly changed. Proteobacteria, Acidobacteria and Actinobacteria were the main phyla in all the samples across succession. With the accumulation of soil organic matter and nutrients, the relative abundance of Actinobacteria decreased, whereas Proteobacteria increased. These shifts may be caused by the increase of the available nutrients across the secondary succession. In the younger sites, soils were dominated by oligotrophic groups, whereas soil in the late-succession site were dominated by copiotrophic groups, indicating the dependence of soil bacterial community composition on the contents of soil available nutrients. PMID- 28732295 TI - Determination of 54 pesticides in waters of the Iberian Douro River estuary and risk assessment of environmentally relevant mixtures using theoretical approaches and Artemia salina and Daphnia magna bioassays. AB - As a case study, the estuary of the international Douro River (Iberian Peninsula) was sampled over a year (2010) at six sampling sites to determine the presence of 56 pesticides of different categories (insecticides, herbicides, and fungicides). 96% of measured pesticides were detected in 79% of the quantified samples. Individual average pesticide concentrations ranged from 39 to 1 265ng/L, indicating a ubiquitous presence of the selected compounds; moreover, twelve pesticides were above the 2013/39/EU Directive limits. Due to its highly impacted profile, a theoretical hazard assessment was done considering the average and maximum environmental mixtures of all measured pesticides to identify the most sensitive trophic level. For both environmental mixtures, the theoretical approach suggested that invertebrates were the most sensitive group. Therefore, short-time exposure assays using both invertebrates Artemia salina and Daphnia magna, were done using the referred mixtures. Data demonstrated significant toxic effects ? high mortality rate and abnormal swimming behaviour ? of the exposed animals. Both approaches (theoretical and experimental) support the analytical results, alerting for an intervention on this estuarine environment and of other comparable. PMID- 28732296 TI - Contribution of waste water treatment plants to pesticide toxicity in agriculture catchments. AB - Pesticide residues are frequently found in water bodies and may threaten freshwater ecosystems and biodiversity. In addition to runoff or leaching from treated agricultural fields, pesticides may enter streams via effluents from wastewater treatment plants (WWTPs). We compared the pesticide toxicity in terms of log maximum Toxic Unit (log mTU) of sampling sites in small agricultural streams of Germany with and without WWTPs in the upstream catchments. We found an approximately half log unit higher pesticide toxicity for sampling sites with WWTPs (p < 0.001). Compared to fungicides and insecticides, herbicides contributed most to the total pesticide toxicity in streams with WWTPs. A few compounds (diuron, terbuthylazin, isoproturon, terbutryn and Metazachlor) dominated the herbicide toxicity. Pesticide toxicity was not correlated with upstream distance to WWTP (Spearman's rank correlation, rho = - 0.11, p > 0.05) suggesting that other context variables are more important to explain WWTP-driven pesticide toxicity. Our results suggest that WWTPs contribute to pesticide toxicity in German streams. PMID- 28732297 TI - Influence of environmental conditions on the toxicokinetics of cadmium in the marine copepod Acartia tonsa. AB - mMarine and estuarine ecosystems are highly productive areas that often act as a final sink for several pollutants, such as cadmium. Environmental conditions in these habitats can affect metal speciation, as well as its uptake and depuration by living organisms. The aim of this study was to assess cadmium uptake and depuration rates in the euryhaline calanoid copepod Acartia tonsa under different pH, salinity and temperature conditions. Cadmium speciation did not vary with changing pH or temperature, but varied with salinity. Free Cd2+ ion activity increased with decreasing salinities resulting in increased cadmium concentrations in A. tonsa. However, uptake rate, derived using free Cd2+ ion activity, showed no significant differences at different salinities indicating a simultaneous combined effect of Cd2+ speciation and metabolic rates for osmoregulation. Cadmium concentration in A. tonsa and uptake rate increased with increasing pH, showing a peak at the intermediate pH of 7.5, while depuration rate fluctuated, thus suggesting that both parameters are mediated by metabolic processes (to maintain homeostasis at pH levels lower than normal) and ion competition at membrane binding sites. Cadmium concentration in A. tonsa, uptake and depuration rates increased with increasing temperature, a trend that can be attributed to an increase in metabolic energy demand at higher temperatures. The present study shows that cadmium uptake and depuration rates in the marine copepod A. tonsa is mostly affected by biological processes, mainly driven by metabolic mechanisms, and to a lesser extent by metal speciation in the exposure medium. PMID- 28732298 TI - Stomatal and non-stomatal factors regulated the photosynthesis of soybean seedlings in the present of exogenous bisphenol A. AB - Bisphenol A (BPA) is an emerging environmental endocrine disruptor that has toxic effects on plants growth. Photosynthesis supplies the substances and energy required for plant growth, and regulated by stomatal and non-stomatal factors. Therefore, in this study, to reveal how BPA affects photosynthesis in soybean seedlings (Glycine max L.) from the perspective of stomatal and non-stomatal factors, the stomatal factors (stomatal conductance and behaviours) and non stomatal factors (Hill reaction, apparent quantum efficiency, Rubisco activity, carboxylation efficiency, the maximum Rubisco carboxylation velocity, ribulose 1,5-bisphospate regeneration capacities mediated by maximum electron transport rates, and triose phosphate utilization rate) were investigated using a portable photosynthesis system. Moreover, the pollution of BPA in the environment was simulated. The results indicate that low-dose BPA enhanced net photosynthetic rate (Pn) primarily by promoting stomatal factors, resulting in increased relative growth rates and accelerated soybean seedling growth. High-dose BPA decreases the Pn by simultaneously inhibiting stomatal and non-stomatal factors, and this inhibition decreases the relative growth rates further reducing soybean seedling growth. Following the withdrawal of BPA, all of the indices were restored to varying degrees. In conclusion, low-dose BPA increased the Pn by promoting stomatal factors while high-dose BPA decreased the Pn by simultaneously inhibiting stomatal and non-stomatal factors. These findings provide a model (or, hypothesis) for the effects of BPA on plant photosynthesis. PMID- 28732299 TI - Enterovesical fistula, a rare complication of Meckel's diverticulum: A case report. AB - INTRODUCTION: Enterovesical fistulas usually result from diverticulitis, Crohn's disease, or colorectal cancer. A perforated Meckel's diverticulum can exceptionally result in an vesico-diverticulum fistula, as noted in only seven previously reported cases. CASE REPORT: A 35-year old Arabic male, quadriplegic,who presented epigastralgia evolving for a week, associated with abdominal distension and cloudy urine. On examination he was feverish (38.5 degrees C), dehydrated with tenderness in the entire distended abdomen; rectal examination revealed a hypotonic sphincter with no other abnormality. After investigations, acute peritonitis diagnosis was retained. Exploratory laparotomy revealed a vesico-diverticular fistula resulting from a performed Meckel's diverticulum. Diverticulectomy, ileostomy and bladder sutures were performed after peritoneal cleansing. The postoperative course was uneventful. The anatomo pathological examination confirmed the diagnosis of a perforated Meckel's diverticulum that did not contain ectopic gastric or pancreatic tissue. CONCLUSION: Vesico-diverticular fistula resulting from a perforated Meckel's diverticulum is a rare complication. To our knowledge, this is only the fourth reported case which is not associated to inflammatory bowel disease. PMID- 28732300 TI - Complete torsion of gallbladder following laparoscopic cholecystectomy: A case study. AB - INTRODUCTION: Gallbladder torsion is mainly associated with a floating gallbladder. From an anatomical perspective, laparoscopic cholecystectomy is a more optimal treatment than open cholecystectomy. PRESENTATION OF CASE: An 84 year-old woman visited the Onomichi General Hospital because of progressive pain in the right upper quadrant of her abdomen. Physical examination revealed a positive Murphy sign and peritoneal irritation. Laboratory data demonstrated that inflammatory marker levels were increased. Abdominal ultrasonography showed that blood flow in the cystic artery was reduced and the gallbladder was swollen. Abdominal contrast-enhanced computerized tomography indicated that the swollen gallbladder was modestly enhanced and the fundus was displaced under the midline and detached from the gallbladder bed. The cystic duct was twisted. Magnetic resonance cholangiopancreatography showed that the root of the cystic duct was unclear and the extrahepatic bile duct had V-shaped distortion. The gallbladder neck showed a tapering interruption with the common biliary duct. We made a preoperative diagnosis of gallbladder torsion. Accordingly, emergency laparoscopic cholecystectomy was performed. The intraoperative findings included a dark swollen gallbladder that was twisted in the counterclockwise direction. The patient was discharged without any postoperative complications on day 7. DISCUSSION: Combined acute onset of abdominal pain with characteristic radiological findings made it possible to precisely diagnose gallbladder torsion. CONCLUSION: Laparoscopic cholecystectomy can be the gold standard treatment for gallbladder torsion after a preoperative diagnosis is made. PMID- 28732301 TI - A case of multiple inflammatory hepatic pseudotumor protruding from the liver surface after colonic cancer. AB - INTRODUCTION: Inflammatory hepatic pseudotumor (IHPT) is an important benign liver disease because it is difficult to clinically and radiologically distinguish from malignant tumors. PRESENTATION OF CASE: Here, we describe a case of a 67-year-old male patient diagnosed with multiple inflammatory hepatic pseudotumors. The patient had undergone left hemicolectomy for descending colonic cancer (T3 N0 M0 stage IIA) 2 years prior. He underwent segment 6 and segment 7 partial hepatectomy because of suspected liver metastasis. The patient had an unremarkable postoperative course and was discharged 7days after surgery. Marked infiltration of inflammatory cells was observed on histological examination. The patient was finally diagnosed with IHPT of the fibrohistiocytic type. DISCUSSION: Repeated imaging studies over 1 month showed the spontaneous regression of the hepatic tumors. Therefore, knowledge regarding this condition is necessary to allow for treatment, even in the absence of experience. During examination, it may be important to ascertain lesion size. Moreover, percutaneous needle biopsy and follow-up examinations are necessary for cases of suspected IHPT. CONCLUSION: Hepatectomy should be considered if the lesion is suspected to be an IHPT. PMID- 28732302 TI - A familiar-size Stroop effect in the absence of basic-level recognition. AB - When we view a picture of an object, we automatically recognize what the object is and know how big it typically is in the world (Konkle & Oliva, 2012). Is information about an object's size activated only after we've identified the object, or can this size information be activated before object recognition even occurs? We previously found that big and small objects differ in mid-level perceptual features (Long, Konkle, Cohen, & Alvarez, 2016). Here we asked whether these perceptual features can automatically trigger real-world size processing, bypassing the need for basic-level object recognition. To test this hypothesis, we used an image synthesis algorithm to generate "texform" images, which are unrecognizable versions of big and small objects that still preserve some textural and form information from the original images. Across two experiments, we find that even though these synthesized stimuli cannot be identified, they automatically trigger familiar size processing and give rise to a Size-Stroop effect. Furthermore, we isolate perceived curvature as one feature the visual system uses to infer real-world size. These results suggest that mid-level perceptual features can automatically feed forward to facilitate object processing, and challenge the idea that we must first identify an object before we can access its higher-level properties. PMID- 28732303 TI - Do analog number representations underlie the meanings of young children's verbal numerals? AB - Children learn to count, and even learn the cardinal meanings of the first three or four verbal numerals ("one" through "three" or "four"), before they master the numerical significance of counting. If so, it follows that the cardinal meanings of those first few numerals cannot be derived, initially, from their place in the count list and the counting routine. What non-verbal representations, then, support the cardinal meanings of verbal numerals before children have mastered how counting does so? Four experiments addressed the commonly adopted assumption that in the earliest period of learning the meanings of number words, children map verbal numerals to regions of the analog number system (ANS), a system of representation with numerical content that is widely attested in animals and in human infants. Experiment 1 confirmed that children who know what "three" means, but who do not yet know what "four" means, and do not yet know how counting represents number, can be easily taught the meaning of "four," if they are trained to indicate sets of four when they are paired with a series of sets that contrast numerically with four. If children learn "four" by mapping the word to an ANS representation of sets of four, and if such ANS value-to-word mappings underlie the meanings of other known numerals early in development, then analogous teaching should enable young children to establish a ANS value-to-word mapping for between "ten" and sets of 10 as specified by the ANS. Furthermore, the ease of learning should be a function of the ratio of the number of individuals in the comparison set to 10. Three further experiments tested these hypotheses by attempting to teach young Cardinal Principle-knowers the meaning of the word "ten," under the same training conditions "three-"knowers are easily taught the meaning of "four". The children learned which picture in each training pair had "ten." However, test trials with novel animals and spatial configurations showed that they had failed to learn what set sizes should be labeled "ten", even when, after training, they were asked to indicate a set of 10 vs. a set of 20 or 30 (well within the ratio sensitivity of the ANS even early in infancy). Furthermore, there was no effect of ratio on success during test trials. These data provide new evidence that ANS value-to-word mappings do not underlie the meanings of number words early in development. We discuss what other non-verbal representations might do so, and discuss other ways the ANS may support learning how counting represents number. PMID- 28732304 TI - Outbreak of Salmonella enteritidis PT14b gastroenteritis at a restaurant in England: the use of molecular typing to achieve a successful prosecution. AB - OBJECTIVES: To describe an outbreak of Salmonella enteritidis phage type (PT) 14b in people who had eaten at a restaurant, and the investigation and subsequent prosecution of the food business operator (FBO). STUDY DESIGN: The local health protection team and environmental health department formed an outbreak control team to investigate the outbreak. METHODS: Epidemiological, microbiological, and environmental investigations were undertaken. Epidemiological investigations involved case finding and interviews. Microbiological investigation: stool samples from the suspected cases and environmental samples from the implicated food business were investigated. Salmonella isolates obtained were subjected to multiple locus variable-number tandem repeat analysis (MLVA) profiling and whole genome sequencing. In addition, adenosine triphosphate (ATP) hygiene swab tests were used to verify the quality of cleaning procedures and data loggers were used to determine the water temperature of the mechanical dishwasher. RESULTS: Fifteen cases of illness where the causative agent was shown to be S. enteritidis PT14b were identified, all of whom had eaten at the same restaurant. S. enteritidis PT14b was also identified from three of the 11 food and environmental samples taken at the restaurant and found to have the same MLVA profile as the cases. A case for prosecution was built and the FBO was successfully prosecuted in July 2015. CONCLUSIONS: This investigation highlighted that the use of molecular typing as part of thorough epidemiological, microbiological, and environmental investigations can present a robust case for prosecution against restaurants which pose a risk to public health. PMID- 28732306 TI - Photostability testing using online reactor HPLC hyphenation and mass spectrometric compound identification illustrated by ketoprofen as model compound. AB - Investigations on the photochemical stability of pharmaceutical substances are mandatory in drug development and licensing as photo-induced degradation of an active pharmaceutical ingredient (API) may not only lead to decreased API concentrations but also to toxic or reactive products. Thus, the US Food and Drug Administration (FDA) and the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) issued Guidance for Industry Q1B "Photostability Testing of New Drug Substances and Products" for testing of pure but also packed drugs. However, photoproducts are also known to be generated in vivo under sunlight exposure of the skin and lead to considerable amounts of adverse drug effects. Herein we present an alternative system that may be used for photostability testing mimicking both situations. It combines a tailored photoreactor with an exchangeable pen light source and a modified HPLC system with online-SPE. Identification of photoproducts may be performed using mass spectrometry. The potential of accurate mass spectrometry as a tool for identification of photoproducts was demonstrated as well. A comparison of the online photoreactor system and the traditional photochamber irradiation was performed using ketoprofen for proof of concept. In both designs acetylbenzophenone and ethylbenzophenone were detected as main photoproducts. The new device allows for fast and easy photostability studies that may help to reduce time consuming in vitro experiments and animal trials. Using state of the art instruments kinetic studies could also easily be performed with qualitative and quantitative perspectives combined into one experimental design with only very low amounts of API needed. This may be useful in early drug development, where only small amounts of API are available. Scale-up may also be easily realized for the generation of reference material for quantification and quality control (QC) processes as well as for toxicity testing. PMID- 28732305 TI - Association between gaseous air pollutants and inflammatory, hemostatic and lipid markers in a cohort of midlife women. AB - BACKGROUND: Exposures to ambient gaseous pollutants have been linked to cardiovascular diseases (CVDs), but the biological mechanisms remain uncertain. OBJECTIVES: This study examined the changes in CVD marker levels resulting from elevated exposure to ambient gaseous pollutants in midlife women. METHODS: Annual repeated measurements of several inflammatory, hemostatic and lipid makers were obtained from 2306 midlife women enrolled in the longitudinal Study of Women's Health Across the Nation (SWAN) between 1999 and 2004. Ambient carbon monoxide (CO), nitrogen dioxide (NO2), and sulfur dioxide (SO2) data were assigned to each woman based on proximity of the monitoring station to her residential address. Short- and long-term exposures were calculated, and their associations with markers were examined using linear mixed-effects regression models, adjusted for demographic, health and other factors. RESULTS: Short-term CO exposure was associated with increased fibrinogen, i.e., every interquartile increase of average prior one-week exposure to CO was associated with 1.3% (95% CI: 0.6%, 2.0%) increase in fibrinogen. Long-term exposures to NO2 and SO2 were associated with reduced high-density lipoproteins and apolipoprotein A1, e.g., 4.0% (1.7%, 6.3%) and 4.7% (2.8%, 6.6%) decrease per interquartile increment in prior one year average NO2 concentration, respectively. Fine particle (PM2.5) exposure confounded associations between CO/NO2 and inflammatory/hemostatic markers, while associations with lipoproteins were generally robust to PM2.5 adjustment. CONCLUSIONS: Exposures to these gas pollutants at current ambient levels may increase thrombotic potential and disrupt cholesterol metabolism, contributing to greater risk of CVDs in midlife women. Caution should be exercised in evaluating the confounding by PM2.5 exposure. PMID- 28732307 TI - A multisite audit to assess how women with complex social factors access and engage with maternity services. AB - OBJECTIVE: to audit women with socially complex lives' documented access to and engagement with antenatal care provided by three inner city, UK maternity services in relation to birth and neonatal outcomes, and referral processes. BACKGROUND: women living socially complex lives, including young mothers, recently arrived immigrants, non-English speaking, and those experiencing domestic violence, poor mental health, drug and alcohol abuse, and poverty experience high rates of morbidity, mortality and poor birth outcomes. This is associated with late access to and poor engagement with antenatal care. METHOD: data was collected from three separate NHS trusts data management systems for a total of 182 women living socially complex lives, between January and December 2015. Data was presented by individual trust and compared to standards derived from NICE guidelines, local trust policy and national statistic using Excel and SPSS Version 22. Tests of correlation were carried out to minimise risks of confounding factors in characteristic differences. FINDINGS: non-English speaking women were much less likely to have accessed care within the recommended timeframes, with over 70% of the sample not booked for maternity care by 12 weeks gestation. On average 89% primiparous women across all samples had less than the recommended number of antenatal appointments. No sample met the audit criteria in terms of number of antenatal appointments attended. Data held on the perinatal data management systems for a number of outcomes and processes was largely incomplete and appeared unreliable. CONCLUSION: this data forms a baseline against which to assess the impact of future service developments aimed at improving access and engagement with services for women living with complex social factors. The audit identified issues with the completeness and reliability of data on the perinatal data management system. PMID- 28732308 TI - Ripk3 induces mitochondrial apoptosis via inhibition of FUNDC1 mitophagy in cardiac IR injury. AB - Ripk3-required necroptosis and mitochondria-mediated apoptosis are the predominant types of cell death that largely account for the development of cardiac ischemia reperfusion injury (IRI). Here, we explored the effect of Ripk3 on mitochondrial apoptosis. Compared with wild-type mice, the infarcted area in Ripk3-deficient (Ripk3-/-) mice had a relatively low abundance of apoptotic cells. Moreover, the loss of Ripk3 protected the mitochondria against IRI and inhibited caspase9 apoptotic pathways. These protective effects of Ripk3 deficiency were relied on mitophagy activation. However, inhibition of mitophagy under Ripk3 deficiency enhanced cardiomyocyte and endothelia apoptosis, augmented infarcted area and induced microvascular dysfunction. Furthermore, ischemia activated mitophagy by modifying FUNDC1 dephosphorylation, which substantively engulfed mitochondria debris and cytochrome-c, thus blocking apoptosis signal. However, reperfusion injury elevated the expression of Ripk3 which disrupted FUNDC1 activation and abated mitophagy, increasing the likelihood of apoptosis. In summary, this study confirms the promotive effect of Ripk3 on mitochondria mediated apoptosis via inhibition of FUNDC1-dependent mitophagy in cardiac IRI. These findings provide new insight into the roles of Ripk3-related necroptosis, mitochondria-mediated apoptosis and FUNDC1-required mitophagy in cardiac IRI. PMID- 28732310 TI - Achieving directional propagation of elastic waves via topology optimization. AB - This paper presents a study on topology optimization of novel material microstructural configurations to achieve directional elastic wave propagation through maximization of partial band gaps. A waveguide incorporating a periodic microstructure material may exhibit different propagation properties for the plane elastic waves incident from different inlets. A topology optimization problem is formulated to enhance such a property with a gradient-based mathematical programming algorithm. For alleviating the issue of local optimum traps, the random morphology description functions (RMDFs) are introduced to generate random initial designs for the optimization process. The optimized designs finally converge to the orderly material distribution and numerical validation shows improved directional propagation property as expected. The utilization of linear two-dimension phononic crystal with efficient partial band gap is suitable for directional propagation with a broad frequency range. PMID- 28732309 TI - Zebularine induces replication-dependent double-strand breaks which are preferentially repaired by homologous recombination. AB - Zebularine is a second-generation, highly stable hydrophilic inhibitor of DNA methylation with oral bioavailability that preferentially target cancer cells. It acts primarily as a trap for DNA methyl transferases (DNMTs) protein by forming covalent complexes between DNMT protein and zebularine-substrate DNA. It's well documented that replication-blocking DNA lesions can cause replication fork collapse and thereby to the formation of DNA double-strand breaks (DSB). DSB are dangerous lesions that can lead to potentially oncogenic genomic rearrangements or cell death. The two major pathways for repair of DSB are non-homologous end joining (NHEJ) and homologous recombination (HR). Recently, multiple functions for the HR machinery have been identified at arrested forks. Here we investigate in more detail the importance of the lesions induced by zebularine in terms of DNA damage and cytotoxicity as well as the role of HR in the repair of these lesions. When we examined the contribution of NHEJ and HR in the repair of DSB induced by zebularine we found that these breaks were preferentially repaired by HR. Also we show that the production of DSB is dependent on active replication. To test this, we determined chromosome damage by zebularine while transiently inhibiting DNA synthesis. Here we report that cells deficient in single-strand break (SSB) repair are hypersensitive to zebularine. We have observed more DSB induced by zebularine in XRCC1 deficient cells, likely to be the result of conversion of SSB into toxic DSB when encountered by a replication fork. Furthermore we demonstrate that HR is required for the repair of these breaks. Overall, our data suggest that zebularine induces replication-dependent DSB which are preferentially repaired by HR. PMID- 28732311 TI - Solid and aqueous magnetoliposomes as nanocarriers for a new potential drug active against breast cancer. AB - Iron oxide nanoparticles, with diameters around 12nm, were synthesized by coprecipitation method. The magnetic properties indicate a superparamagnetic behavior with a coercive field of 9.7Oe and a blocking temperature of 118K. Both aqueous and solid magnetoliposomes containing magnetite nanoparticles have sizes below 150nm, suitable for biomedical applications. Interaction between both types of magnetoliposomes and models of biological membranes was proven. A new antitumor compound, a diarylurea derivative of thienopyridine, active against breast cancer, was incorporated in both aqueous and solid magnetoliposomes, being mainly located in the lipid membrane. A promising application of these magnetoliposomes in oncology is anticipated, allowing a combined therapeutic approach, using both chemotherapy and magnetic hyperthermia. PMID- 28732312 TI - Drug-eluting scaffold inhibited in vivo pancreatic tumorigenesis by engaging murine CCR4+CD8+ T cells. AB - CCL17 is well known for its ability to engage CCR4+CD8+ T cells, which have been shown to play a critical role in preventing tumorigenesis. In this study, we attempted to inhibit in vivo pancreatic tumorigenesis by engaging murine CCR4+CD8+ T cells through a drug-eluting scaffold with a payload of CCL17. The drug-eluting scaffold was fabricated by electrospinning polyglyconate and porcine gelatin. The electrospun scaffold featured randomly distributed non-woven fibers with diameters ranging from 1MUm to 4MUm. The in vitro study confirmed that scaffolding materials were non-cytotoxic to pancreatic cancer cells. The in vivo study showed an increased presence of murine CCR4+CD8+ T cells into the tumor mass treated with drug-eluting scaffold compared to those with non-eluting scaffold or the control groups. The weights of tumor masses were 132.04mg+/ 12.25mg in the control group, 158.12mg+/-18.98mg in the NES group and 96.22mg+/ 14.56mg in the DES group, respectively. The volumes of tumor masses were 1035.21mm3+/-128.97mm3 in the control group, 978.56mm3+/-110.19mm3 in the NES group and 634.35mm3+/-87.12mm3 in the DES group, respectively. Further study showed that the increased presence of CCR4+CD8+ T cells also inhibited the hepatic metastasis of pancreatic cancer cells. Our study shed a new light on the post-operative treatment of pancreatic cancer to prevent the recurrence. PMID- 28732313 TI - Biomechanics of cell rearrangements in Drosophila. AB - To acquire their adequate size and shape, living tissues grow and substantially deform as they develop. To do so, the cells making up the tissue can grow and deform as well, but they can also divide, intercalate and die. Among those cell behaviors, cell intercalation, also named cell rearrangement, is a major contributor to the morphogenesis of many cohesive tissues since it enables tissues to drastically deform as they develop while keeping their cohesiveness and avoiding extreme deformation of their cells. Here we review the mechanical principles and biological regulations at play during cell rearrangements in Drosophila tissues by first describing them in other cellular materials and by categorizing them. We then briefly discuss their quantifications and their interplay with other cell processes. PMID- 28732314 TI - The effect of low-dose furosemide in critically ill patients with early acute kidney injury: A pilot randomized blinded controlled trial (the SPARK study). AB - PURPOSE: Furosemide is commonly prescribed in acute kidney injury (AKI). Prior studies have found conflicting findings on whether furosemide modifies the course and outcome of AKI. METHODS: Pilot multi-center randomized blinded placebo controlled trial in adult patients with AKI admitted to three intensive care units. Participants were randomly allocated to furosemide bolus and infusion or 0.9% saline placebo. Primary endpoint was worsening AKI, defined by the RIFLE criteria. Secondary endpoints were kidney recovery, renal replacement therapy (RRT) and adverse events. RESULTS: The trial was terminated after enrollment of 73 participants (37 to furosemide and 36 to placebo). Mean (SD) age was 61.7 (14.3), 79.5% were medical admissions, mean (SD) APACHE II score was 26.6 (7.8), 90.4% received mechanical ventilation and 61.6% received vasoactives. Groups were similar at baseline. No differences were found in the proportion with worsening AKI (43.2% vs. 37.1%, p=0.6), kidney recovery (29.7% vs. 42.9%, p=0.3), or RRT (27.0% s. 28.6%, p=0.8). Adverse events, mostly electrolyte abnormalities, were more common in furosemide-treated patients (p<0.001). Protocol deviations were common, due often to supplementary furosemide. CONCLUSIONS: In this pilot trial, furosemide did not reduce the rate of worsening AKI, improve recovery or reduce RRT; however, was associated with greater electrolyte abnormalities. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00978354 registered September 9, 2014. PMID- 28732315 TI - Total and ionized magnesium testing in the surgical intensive care unit - Opportunities for improved laboratory and pharmacy utilization. AB - PURPOSE: Ionized fraction (iMg) is the physiologically active form of magnesium (Mg); total Mg may not accurately reflect iMg status. Erroneously "low" Mg levels may result in unnecessary repetitive testing. MATERIALS AND METHODS: From 11/2015 to 01/2016, patients ordered for Mg from a pilot ICU also had iMg tested. Weighted kappa statistic was used to assess agreement between Mg categories (low, normal, high). Predictors of unnecessary repeated Mg testing and repletion using data were explored through logistic regression models using GEE techniques to account for repeated measurements in both bivariate and multivariable analyses. RESULTS: There were 470Mg/iMg paired measurements from 173 patients. The weighted kappa statistic was 0.35 (95%CI 0.27-0.43) indicating poor agreement in assessment of magnesium status. Of the 34Mg samples reported as "low", only 6 (18%) were considered "low" using concurrent iMg testing. In the multivariable models, history of atrial fibrillation (aOR=1.61, 95%CI 1.16-2.21, p=0.004) and concomitant metoclopramide (aOR=1.71, 95%CI 1.03-2.81, p=0.036) were significant predictors of unnecessary repeat Mg testing. CONCLUSIONS: In the surgical ICU, categorical agreement (low, normal, high) was poor between Mg and iMg. Over 80% of "low" total Mg values are erroneous and may result in unnecessary additional measurements and repletion. PMID- 28732316 TI - A user-friendly technical set-up for infrared photography of forensic findings. AB - Infrared photography is interesting for a use in forensic science and forensic medicine since it reveals findings that normally are almost invisible to the human eye. Originally, infrared photography has been made possible by the placement of an infrared light transmission filter screwed in front of the camera objective lens. However, this set-up is associated with many drawbacks such as the loss of the autofocus function, the need of an external infrared source, and long exposure times which make the use of a tripod necessary. These limitations prevented up to now the routine application of infrared photography in forensics. In this study the use of a professional modification inside the digital camera body was evaluated regarding camera handling and image quality. This permanent modification consisted of the replacement of the in-built infrared blocking filter by an infrared transmission filter of 700nm and 830nm, respectively. The application of this camera set-up for the photo-documentation of forensically relevant post-mortem findings was investigated in examples of trace evidence such as gunshot residues on the skin, in external findings, e.g. hematomas, as well as in an exemplary internal finding, i.e., Wischnewski spots in a putrefied stomach. The application of scattered light created by indirect flashlight yielded a more uniform illumination of the object, and the use of the 700nm filter resulted in better pictures than the 830nm filter. Compared to pictures taken under visible light, infrared photographs generally yielded better contrast. This allowed for discerning more details and revealed findings which were not visible otherwise, such as imprints on a fabric and tattoos in mummified skin. The permanent modification of a digital camera by building in a 700nm infrared transmission filter resulted in a user-friendly and efficient set-up which qualified for the use in daily forensic routine. Main advantages were a clear picture in the viewfinder, an auto-focus usable over the whole range of infrared light, and the possibility of using short shutter speeds which allows taking infrared pictures free-hand. The proposed set-up with a modification of the camera allows a user friendly application of infrared photography in post-mortem settings. PMID- 28732317 TI - Cross-lagged relations between motives and substance use: Can use strengthen your motivation over time? AB - Motives for substance use have garnered considerable attention due to the strong predictive utility of this construct, both in terms of use and problems associated with use. The current study examined the cross-lagged relations between alcohol use and motives, and marijuana use and motives over three yearly assessment periods in a large sample (N=526, 48% male) of college students. The relations between substance use and motives were assessed at each time point, allowing for the examination of these inter-relations over time. Results indicated different trends based on the type of substance. For alcohol use, cross lagged trends were found between freshman and sophomore year for coping, social, and conformity motives with cross-lagged relations between enhancement motives and alcohol use across all years. However, outside of enhancement motives, cross lagged relations were not found between sophomore and junior year. In contrast, cross-lagged effects were found for marijuana use and coping, enhancement, and expansion motives between sophomore and junior year, but not freshman year. These results suggest that people's expectations that drinking or smoking marijuana makes activities more reinforcing and helps them cope with distress may perpetuate use. In turn, use itself may enhance these expectations over time. Results have direct implications for treatment, with recommended focus on motives, behavior activation, and healthy coping skills in order to interrupt the cycle of substance use. PMID- 28732318 TI - The Experimental Tobacco Marketplace II: Substitutability and sex effects in dual electronic cigarette and conventional cigarette users. AB - AIM: The aim of the current study was to evaluate tobacco product purchasing in the Experimental: Tobacco Marketplace (ETM) among male and female smokers who also use e-cigarettes. We hypothesized a high substitution profile for e cigarettes and that males would purchase more Snus than females. METHODS: The ETM is an online market used in clinical abuse liability research to mimic real-world purchasing patterns. Tobacco products, including each participant's usual choice of conventional and e-cigarettes, were presented along with a price and description of nicotine content. Participants were endowed with an account balance based on the number of cigarettes and e-cigarettes consumed per week. Each participant was exposed to four ETM sessions in random order during which the price of conventional cigarettes was manipulated. RESULTS: Cigarette consumption decreased as price increased. A mixed factor three-way ANOVA revealed a significant main effect of price (i.e., more alternative products were purchased at higher cigarette prices), product (i.e., more e-cigarettes were purchased than gum, lozenges, and Snus), and sex (i.e., males purchased more than females). A significant three-way interaction indicated that males purchased more e-cigarettes, Snus, and dip than females at higher cigarette prices. CONCLUSION: This study suggests that the user profile of cigarette smokers is associated with behavioral economic measures of alternative product substitution and indicates that the evaluation of nicotine replacement products should be considered for both males and females separately. PMID- 28732319 TI - Did the dependent coverage expansion increase risky substance use among young adults? AB - BACKGROUND: The dependent coverage expansion (DCE) enacted through the Affordable Care Act increased health insurance coverage among young adults. Increasing insurance coverage in this age group has the potential for unintended consequences on risky substance use. METHODS: Repeated cross-sectional surveys were used to compare change in substance use during the period the DCE was implemented in the 19-25year old target age group (Pre-DCE n=15,772, Post-DCE n=22,719) with contemporaneous change in a slightly older age group that was not targeted by the policy (Pre-DCE=19,851, Post-DCE n=28,157). Outcomes include 11 measures of alcohol, illicit drug and cigarette use. Statistical controls were included for demographic and socioeconomic factors and for early initiation of substance use to adjust for historical trends in developmental trajectories. RESULTS: Risky substance use decreased in young adults relative to the older age group over the period that the DCE was implemented. However, statistical adjustment for initiation of substance use prior to age 18, which is prior to exposure to the DCE, accounted for the differences between the age groups. In adjusted models, associations between the DCE and substance use outcomes range from 0.96 to 1.08 with p-values ranging from 0.330 to 0.963. CONCLUSIONS: Historical trends in initiation of substance use prior to age 18, not the DCE, account for change in risky substance use among 19-25year olds relative to 26 34year olds. The evidence does not support the suggestion that health insurance coverage would increase risky substance use among young adults. PMID- 28732320 TI - Do cyclists make better drivers? Associations between cycling experience and change detection in road scenes. AB - Efficient processing of visual information is crucial to safe driving. Previous research has demonstrated that driving experience strongly affects attentional allocation, with large differences between novice and experienced drivers. Expanding on this, we explored the influence of non-driving experiences on attentional allocation by comparing drivers with and without cycling experience. Based on situation awareness field studies, we predicted cyclist-drivers would demonstrate superior performance. Participants were 42 experienced drivers (17 female, 25 male) aged 30-50 years (M=39.8): 20 drivers and 22 cyclist-drivers. The experiment used a change detection flicker task, in which participants must determine whether two alternating images are identical (change-absent) or differ in a single detail (change-present). The changed object was either a road sign, car, pedestrian, or bicycle. Change target significantly affected both accuracy and response time: all participants were slower and less accurate at detecting changes to road signs, compared with when the change was a moving road user (i.e., car, pedestrian, bicycle). Accuracy did not differ significantly between groups, but cyclist-drivers were significantly faster than drivers at identifying changes, with the effect being largest for bicycle and sign changes. The results suggest that cycling experience is associated with more efficient attentional processing for road scenes. PMID- 28732321 TI - Aggregating exposures & cumulating risk for semivolatile organic compounds: A review. AB - Increasingly, health risk assessment is addressing multiple pathway exposures to multiple contaminants. We reviewed aggregated exposure and cumulative risk approaches for contemporary and ubiquitous semivolatile organic compounds (SVOC). We identified 22 studies aggregating exposure pathways, and 31 cumulating risk. Exposure aggregation is based on the addition of pathway-specific doses, using kinetic modeling where it exists, and classic external dose equations otherwise. In most cases, exposure is dominated by a single route or source of exposure - mainly the oral pathway - via dietary or non-dietary exposure. Preferential routes and sources of exposure are influenced by SVOC physical-chemical properties such as vapor pressure. The cumulative risk approach for contaminants is based on dose addition. Simple sum of hazard quotient (Hazard Index: HI) is the most commonly used cumulative risk assessment approach, while Relative Potency Factor (RPF) appeared to the best suited - although this calls for a level of toxicological information that limits the number of compounds that can be studied simultaneously. Where both were performed, moving from HI to more refined approach produced similar results. In conclusion, both approaches - exposure aggregation and cumulative risk - rely on simple assumptions. Nevertheless, they allow uncertainty to be reduced, in comparison with source-by source or chemical-by-chemical approaches. PMID- 28732322 TI - Effects of environmental pollutants on signaling pathways in rat pituitary GH3 adenoma cells. AB - An increased rate of acromegaly was reported in industrialized areas, suggesting an involvement of environmental pollutants in the pathogenesis and behavior of GH secreting pituitary adenomas. Based on these premises, the aim of the study was to evaluate the effects of some widely diffused pollutants (i.e. benzene, BZ; bis(2-ethylhexyl) phthalate, DEHP and polychlorinated biphenyls, PCB) on growth hormone secretion, the somatostatin and estrogenic pathways, viability and proliferation of rat GH-producing pituitary adenoma (GH3) cells. All the pollutants induced a statistically significant increase in GH secretion and interfered with cell signaling. They all modulated the expression of SSTR2 and ZAC1, involved in the somatostatin signaling, and the expression of the transcription factor FOXA1, involved in the estrogen receptor signaling. Moreover, all the pollutants increased the expression of the CYP1A1, suggesting AHR pathway activation. None of the pollutants impacted on cell proliferation or viability. Present data demonstrate that exposure to different pollutants, used at in vivo relevant concentrations, plays an important role in the behavior of GH3 pituitary adenoma cells, by increasing GH secretion and modulating several cellular signaling pathways. These observations support a possible influence of different pollutants in vivo on the GH-adenoma aggressiveness and biological behavior. PMID- 28732323 TI - Evaluation of an online training for improving self-reported evidence-based decision-making skills in cancer control among public health professionals. AB - OBJECTIVES: The purpose of this evaluation was to assess the effect of the online evidence-based cancer control (EBCC) training on improving the self-reported evidence-based decision-making (EBDM) skills in cancer control among Nebraska public health professionals. STUDY DESIGN: Cross-sectional group comparison. METHODS: Previously developed EBDM measures were administered via online surveys to 201 public health professionals at baseline (comparison group) and 123 professionals who took part in the training. Respondents rated the importance of and their skill level in 18 EBCC skills. Differences were examined using analysis of variance models adjusted for gender, age, years at agency, and years in position, and stratified by respondent educational attainment. RESULTS: Among professionals without an advanced degree, training participants reported higher overall skill scores (P = .016) than the baseline non-participant group, primarily driven by differences in the partnerships and collaboration and evaluation domains. No differences in importance ratings were observed. Among professionals with advanced degrees, there were no differences in skill scores and small differences in importance scores in the expected direction (P < .05). Respondents at baseline rated the following facilitators for EBDM as important: expectations from agency leaders and community partners, high priority placed on EBDM by leadership, trainings, and positive feedback. They also reported using a variety of materials for making decisions about programs and policies, though few used individual scientific studies. CONCLUSIONS: EBCC led to improved self reported EBDM skills among public health professionals without an advanced degree, though a gap remained between the self-reported skills and the perceived importance of the skills. Further research on training content and modalities for professionals with higher educational attainment and baseline skill scores is needed. PMID- 28732324 TI - Anti-Mullerian hormone (AMH) levels in premenopausal breast cancer patients treated with taxane-based adjuvant chemotherapy - A translational research project of the SUCCESS A study. AB - BACKGROUND: Premenopausal women undergoing chemotherapy are at high risk for premature ovarian failure and its long-term consequences. Data on potential markers to evaluate ovarian reserve pre- and posttreatment are limited. Anti Mullerian hormone (AMH) known for ovarian reserve in reproductive medicine could be a surrogate marker and was assessed in premenopausal breast cancer patients of the SUCCESS A study (EUDRA-CT no. 2005-000490-21). METHODS: We identified 170 premenopausal patients, age <= 40 years at trial entry, who received FEC-Doc as taxane-anthracylince based chemotherapy. Blood samples were taken at three time points: Before, four weeks after and two years after adjuvant chemotherapy. Serum AMH-levels were evaluated in a central laboratory by a quantitative immunoassay AMH Gen II ELISA (Beckman Coulter, Brea, USA). RESULTS: Median age was 36 years (21-40 years). Median serum AMH-level before chemotherapy was 1.37 ng/ml (range < 0.1-11.3 ng/ml). Four weeks after chemotherapy AMH-levels dropped in 98.6% of the patients to <0.1 ng/ml (range < 0.1-0.21 ng/ml). After two years, 73.3% (n = 101) showed no evidence of ovarian function recovery (AMH <0.1 ng/ml, range < 0.1-3.9 ng/ml). Permanent chemotherapy induced amenorrhea occurred only in 50.6% of the patients. CONCLUSIONS: In this analysis, premenopausal patients showed a high rate of ovarian impairment reflected by low AMH-levels after chemotherapy. PMID- 28732325 TI - Epidemiology and pathophysiology of pregnancy-associated breast cancer: A review. AB - The interactions between pregnancy and breast cancer (BC) are complex. Overall, parity is associated with long-term protective effects against BC, however in a small group of susceptible patients, pregnancy can lead to the development of a form of BC with a particularly poor prognosis. Pregnancy-associated breast cancer (PABC) remains an under-studied but important and growing clinical problem worldwide. Several aspects of PABC, including risk factors and mechanisms involved in its occurrence and aggressiveness, are incompletely understood. This review aims to summarize the epidemiology, biology, patho-physiology and clinical characteristics of PABC. We emphasize that age at first pregnancy, absence of breastfeeding and family history stand out as possible risk factors for developing PABC that ought to be incorporated into clinical tools for assessing a woman's risk of developing PABC. Also, improved methods for identifying women at risk of developing PABC in the general population are needed. PMID- 28732327 TI - Prediagnostic serum calcium and albumin and ovarian cancer: A nested case-control study in the Norwegian Janus Serum Bank Cohort. AB - BACKGROUND: Women with higher serum calcium may be more likely to be diagnosed and die of ovarian cancer. We evaluated that finding in a large, prospective cohort. METHODS: We conducted a nested case-control study using a population based biobank from Norway. We compared 202 ovarian cancer cases and 202 controls, matched for age, date at blood draw, and county of residence, with respect to serum calcium and albumin, adjusted for anthropometric variables. We evaluated risks using the entire follow-up period as well as 2-15 years and 16-25 years ("early" and "late", respectively). RESULTS: For the entire follow-up, risk was significantly increased in the highest tertile of albumin and for high albumin and calcium jointly. Risks for ovarian cancer differed markedly by follow-up time. In early follow-up, women in the highest tertile of serum calcium had a 2.5 fold increased risk, adjusted for height and body mass index (OR=2.47, 95% C.I. 1.12-5.45) with a significant dose-response (p=0.024). Risk was not elevated in late follow-up (OR=0.62, 95% C.I. 0.27-1.36). Similarly, in early follow-up, women in the highest tertile of serum albumin had an increased risk (OR=2.55, 95% C.I.1.22-5.49) with a significant dose-response (p=0.009). Conversely, risk was not increased in late follow-up (OR=1.36, 95% C.I. 0.65-2.83). CONCLUSIONS: These data confirm a prospective association between higher serum calcium and ovarian cancer. An association in early, but not late, follow-up suggests that the higher calcium reflects the presence of existing cancer. A positive association with serum albumin is novel and should be interpreted cautiously. PMID- 28732328 TI - Spectroscopic descriptors for dynamic changes of soluble microbial products from activated sludge at different biomass growth phases under prolonged starvation. AB - In this study, the spectroscopic indices of soluble microbial products (SMP) were explored using absorption and fluorescence spectroscopy to identify different distinctive biomass growth phases (i.e., exponential phase, pseudo-endogenous phase, and endogenous phase) and to describe the microbial activity of activated sludge in a batch type bioreactor under prolonged starvation. The optical descriptors, including UV absorption at 254 nm (UVA254), spectral slope, absorbance slope index (ASI), biological index (BIX), humification index (HIX), and the ratio of tryptophan-like to humic-like components (C1/C2), were examined to describe the dynamic changes in SMP. These indices were mostly associated with dissolved organic carbon (DOC) of SMPs and specific oxygen uptake rate (SOUR). Among those, ASI was the most strongly correlated with the SOUR data for the pseudo-endogenous and the endogenous periods. Although the three microbial phases were well discriminated using the spectral slope, BIX, and the C1/C2 ratio, the C1/C2 ratio can be suggested as the most preferable indicator as it can also trace the changes of the relative abundance of proteins to humic-like substances in SMPs. The suggested spectroscopic descriptors were reasonably explained by the general trends of decreased large-sized biopolymer fractions (e.g., proteins) and increased humic substrates (HS) with starvation time, which were detected by size exclusion chromatography. This study provides a novel insight into the strong potential of using optical descriptors to easily probe microbial status in biological treatment systems. PMID- 28732326 TI - Therapeutic applications of histone deacetylase inhibitors in sarcoma. AB - Sarcomas are a rare group of malignant tumors originating from mesenchymal stem cells. Surgery, radiation and chemotherapy are currently the only standard treatments for sarcoma. However, their response rates to chemotherapy are quite low. Toxic side effects and multi-drug chemoresistance make treatment even more challenging. Therefore, better drugs to treat sarcomas are needed. Histone deacetylase inhibitors (HDAC inhibitors, HDACi, HDIs) are epigenetic modifying agents that can inhibit sarcoma growth in vitro and in vivo through a variety of pathways, including inducing tumor cell apoptosis, causing cell cycle arrest, impairing tumor invasion and preventing metastasis. Importantly, preclinical studies have revealed that HDIs can not only sensitize sarcomas to chemotherapy and radiotherapy, but also increase treatment responses when combined with other chemotherapeutic drugs. Several phase I and II clinical trials have been conducted to assess the efficacy of HDIs either as monotherapy or in combination with standard chemotherapeutic agents or targeted therapeutic drugs for sarcomas. Combination regimen for sarcomas appear to be more promising than monotherapy when using HDIs. This review summarizes our current understanding and therapeutic applications of HDIs in sarcomas. PMID- 28732329 TI - An experimental study on the influence of water stagnation and temperature change on water quality in a full-scale domestic drinking water system. AB - The drinking water quality changes during the transport through distribution systems. Domestic drinking water systems (DDWSs), which include the plumbing between the water meter and consumer's taps, are the most critical points in which water quality may be affected. In distribution networks, the drinking water temperature and water residence time are regarded as indicators of the drinking water quality. This paper describes an experimental research on the influence of stagnation time and temperature change on drinking water quality in a full-scale DDWS. Two sets of stagnation experiments, during winter and summer months, with various stagnation intervals (up to 168 h of stagnation) were carried out. Water and biofilms were sampled at two different taps, a kitchen and a shower tap. Results from this study indicate that temperature and water stagnation affect both chemical and microbial quality in DDWSs, whereas microbial parameters in stagnant water appear to be driven by the temperature of fresh water. Biofilm formed in the shower pipe contained more total and intact cells than the kitchen pipe biofilm. Alphaproteobacteria were found to dominate in the shower biofilm (78% of all Proteobacteria), while in the kitchen tap biofilm Alphaproteobacteria, Betaproteobacteria and Gammaproteobacteria were evenly distributed. PMID- 28732330 TI - Legacy persistent organic pollutants including PBDEs in the trophic web of the Ross Sea (Antarctica). AB - The ecological features of the Ross Sea trophic web are peculiar and different from other polar food webs, with respect to the use of habitat and species interactions; due to its ecosystem integrity, it is the world's largest Marine Protected Area, established in 2016. Polar organisms are reported to bioaccumulate lipophilic contaminant, viz persistent organic pollutants (POPs). Legacy POPs and flame retardants (polybrominated diphenyl ethers, PBDEs) were studied in key species of the Ross Sea (Euphausia superba, Pleuragramma antarctica) and their predators (Dissostichus mawsoni, Pygoscelis adeliae, Aptenodytes forsteri, Catharacta maccormicki, Leptonychotes weddellii). Gaschromatography revealed the presence of PCBs, HCB, DDTs, PBDEs in most of the samples; HCHs, dieldrin, Eldrin, non-ortho PCBs, PCDDs, PCDFs were detected only in some species. The average ?PBDEs was 0.19-1.35 pg/g wet wt in the key-species and one-two order of magnitude higher in the predators. Penguins and skuas from an area where a long-term field camp is located showed higher BDE concentrations. The SigmaDDTs was higher in the Antarctic toothfish (20 +/- 6.73 ng/g wet wt) and in the South Polar skua (5.911 +/- 3.425 ng/g wet wt). The TEQs were evaluated and the highest concentration was found in the Weddell seal, due to PCB169, 1,2,3,4,7,8-HxCDF, and 2,3,4,6,7,8-HxCDF. There was no significant relationship between the trophic level and the POP concentrations. Although low concentrations, organisms of the Ross Sea trophic web should be further studied: lack of information on some ecotoxicological features and human impacts including global change may distress the ecosystem with unpredictable effects. PMID- 28732331 TI - An evaluation of DNA damage in human lymphocytes and sperm exposed to methyl methanesulfonate involving the regulation pathways associated with apoptosis. AB - Exposure to DNA-damaging agents produces a range of stress-related responses. These change the expression of genes leading to mutations that cause cell cycle arrest, induction of apoptosis and cancer. We have examined the contribution of haploid and diploid DNA damage and genes involved in the regulation of the apoptotic process associated with exposure, The Comet assay was used to detect DNA damage and quantitative RT-PCR analysis (qPCR) to detect gene expression changes in lymphocytes and sperm in response to methyl methanesulfonate. In the Comet assay, cells were administered 0-1.2 mM of MMS at 37 degrees C for 30 min for lymphocytes and 32 degrees C for 60 min for sperm to obtain optimal survival for both cell types. In the Comet assay a significant increase in Olive tail moment (OTM) and % tail DNA indicated DNA damage at increasing concentrations compared to the control group. In the qPCR study, cells were treated for 4 h, and RNA was isolated at the end of the treatment. qPCR analysis of genes associated with DNA stress responses showed that TP53 and CDKN1A are upregulated, while BCL2 is downregulated compared with the control. Thus, MMS caused DNA damage in lymphocytes at increasing concentrations, but appeared not to have the same effect in sperm at the low concentrations. These results indicate that exposure to MMS increased DNA damage and triggered the apoptotic response by activating TP53, CDKN1A and BCL2. These findings of the processing of DNA damage in human lymphocytes and sperm should be taken into account when genotoxic alterations in both cell types are produced when monitoring human exposure. PMID- 28732332 TI - Heavy metal partitioning of suspended particulate matter-water and sediment-water in the Yangtze Estuary. AB - The partitioning of ten heavy metals (As, Cd, Co, Cr, Cu, Hg, Ni, Pb, Sb, and Zn) between the water, suspended particulate matter (SPM), and sediments in seven channel sections during three hydrologic seasons in the Yangtze Estuary was comprehensively investigated. Special attention was paid to the role of tides, influential factors (concentrations of SPM and dissolved organic carbon, and particle size), and heavy metal speciation. The SPM-water and sediment-water partition coefficients (Kp) of the heavy metals exhibited similar changes along the channel sections, though the former were larger throughout the estuary. Because of the higher salinity, the Kp values of most of the metals were higher in the north branch than in the south branch. The Kp values of Cd, Co, and As generally decreased from the wet season to the dry season. Both the diagonal line method and paired samples t-test showed that no specific phase transfer of heavy metals existed during the flood and ebb tides, but the sediment-water Kp was more concentrated for the diagonal line method, owing to the relatively smaller tidal influences on the sediment. The partition coefficients (especially the Kp for SPM water) had negative correlations with the dissolved organic carbon (DOC) but positive correlations were noted with the particle size for most of the heavy metals in sediment. Two types of significant correlations were observed between Kp and metal speciation (i.e., exchangeable, carbonate, reducible, organic, and residual fractions), which can be used to identify the dominant phase-partition mechanisms (e.g., adsorption or desorption) of heavy metals. PMID- 28732333 TI - p-Nitrophenol degradation by electro-Fenton process: Pathway, kinetic model and optimization using central composite design. AB - The chemical process scale-up, from lab studies to industrial production, is challenging and requires deep knowledge of the kinetic model and the reactions that take place in the system. This knowledge is also useful in order to be employed for the reactor design and the determination of the optimal operational conditions. In this study, a model substituted phenol such as p-nitrophenol was degraded by electro-Fenton process and the reaction products yielded along the treatment were recorded. The kinetic model was developed using Matlab software and was based on main reactions that occurred until total mineralization which allowed predicting the degradation pathway under this advanced oxidation process. The predicted concentration profiles of p-nitrophenol, their intermediates and by products in electro-Fenton process were validated with experimental assays and the results were consistent. Finally, based on the developed kinetic model the degradation process was optimized using central composite design taking as key parameters the ferrous ion concentration and current density. PMID- 28732334 TI - Does laser phototherapy influence the proliferation of myoepithelial cells in the salivary gland of hypothyroid rats? AB - Thyroid hormones influence both development and growth of organs and tissues and guarantee metabolic demands that interfere with the quality of digestive secretions, including those of the salivary glands. Laser phototherapy - LPT can modulate various biological phenomena and its diverse effects permit the action on different cell types. The aim of this study was to evaluate the influence of laser phototherapy on myoepithelial cells of salivary glands of hypothyroid rats. Forty-two albino Wistar rats were divided into two main groups: euthyroid (EU) and hypothyroid (HYPO). Hypothyroidism was induced using propylthiouracil (PTU) for 4weeks. Each group was divided into subgroups: control (without laser) and laser groups (Red/infrared - IR). LPT was used on the submandibular gland and was carried out using a diode laser (lambda660 or lambda780nm, 40mW, spot size 0.04cm2, irradiation area 1cm2, 300s, 6J/cm2 per gland, 12J/cm2 per session) and started two weeks after PTU treatment. LPT was repeated every other day for two weeks. After animal death, the glands were removed, dissected and processed for immunohistochemical analysis. It was observed an increase in the number of myoepithelial cells of hypothyroid control rats in comparison to euthyroid controls (p=0.001). Visible LPT (lambda660nm) caused significant higher proliferation of myoepithelial cells in EU rats when compared to IR LPT (lambda 780nm)(p<=0.001).It is concluded that, despite the LPT protocol used did not influence myoepithelial proliferation on hypothyroid rats it significantly increased the proliferation on euthyroid animals. PMID- 28732335 TI - Characteristics and source apportionment of PM2.5 during persistent extreme haze events in Chengdu, southwest China. AB - Based on detailed data from Chengdu Plain (CP) from 6 January to 16 January, two typical haze episodes were analyzed to clarify the haze formation mechanism in winter. Weather conditions, chemical compositions, secondary pollutant transformation, optical properties of aerosols, the potential source contribution function (PSCF) and source apportionment were studied. The planetary boundary layer (PBL) height decreased distinctly during the haze episodes and restrained air pollutant vertical dispersion. As the haze worsened, the value of PBL * PM2.5 increased notably. The [NO3-]/[SO42-] ratio was 0.61, 0.76 and 0.88 during a non haze period, episode 1 and episode 2, respectively, indicating that the mobile source of the air pollution is increasingly predominant in Chengdu. Water vapor also played a vital role in the formation of haze by accelerating the chemical transformation of secondary pollutants, leading to the hygroscopic growth of aerosols. The PSCF and backward trajectories of the air masses indicated that the pollution mainly came from the south. The secondary inorganic aerosols, vehicle emissions, coal combustion, biomass burning, industry, and dust contributed 34.1%, 24.1%, 12.7%, 12.3%, 7.6%, and 7.2% to PM2.5 masses in episode 1 and 28.9%, 23.1%, 9.4%, 9.5%, 20.3% and 7.5% in episode 2. PMID- 28732336 TI - Using machine learning to identify air pollution exposure profiles associated with early cognitive skills among U.S. children. AB - Data-driven machine learning methods present an opportunity to simultaneously assess the impact of multiple air pollutants on health outcomes. The goal of this study was to apply a two-stage, data-driven approach to identify associations between air pollutant exposure profiles and children's cognitive skills. Data from 6900 children enrolled in the Early Childhood Longitudinal Study, Birth Cohort, a national study of children born in 2001 and followed through kindergarten, were linked to estimated concentrations of 104 ambient air toxics in the 2002 National Air Toxics Assessment using ZIP code of residence at age 9 months. In the first-stage, 100 regression trees were learned to identify ambient air pollutant exposure profiles most closely associated with scores on a standardized mathematics test administered to children in kindergarten. In the second-stage, the exposure profiles frequently predicting lower math scores were included within linear regression models and adjusted for confounders in order to estimate the magnitude of their effect on math scores. This approach was applied to the full population, and then to the populations living in urban and highly populated urban areas. Our first-stage results in the full population suggested children with low trichloroethylene exposure had significantly lower math scores. This association was not observed for children living in urban communities, suggesting that confounding related to urbanicity needs to be considered within the first-stage. When restricting our analysis to populations living in urban and highly-populated urban areas, high isophorone levels were found to predict lower math scores. Within adjusted regression models of children in highly-populated urban areas, the estimated effect of higher isophorone exposure on math scores was -1.19 points (95% CI -1.94, -0.44). Similar results were observed for the overall population of urban children. This data-driven, two-stage approach can be applied to other populations, exposures and outcomes to generate hypotheses within high-dimensional exposure data. PMID- 28732337 TI - Critical review of soil contamination by polybrominated diphenyl ethers (PBDEs) and novel brominated flame retardants (NBFRs); concentrations, sources and congener profiles. AB - Polybrominated diphenyl ethers (PBDEs) have been used in a broad array of polymeric materials such as plastics, foams, resins and adhesives to inhibit the spread of fires since the 1970s. The widespread environmental contamination and well documented toxic effects of PBDEs have led to bans and voluntary withdrawals in many jurisdictions. Replacement novel brominated flame retardants (NBFRs) have, however, exhibited many of the same toxic characteristics as PBDEs and appear to share similar environmental fate. This paper presents a critical review of the scientific literature regarding PBDE and NBFR contamination of surface soils internationally, with the secondary objective of identifying probable pollution sources. An evaluation of NBFR distribution in soil was also conducted to assess the suitability of the newer compounds as replacements for PBDEs, with respect to their land contamination potential. Principle production of PBDEs and NBFRs and their consequent use in secondary polymer manufacture appear to be processes with strong potential to contaminate surrounding soils. Evidence suggests that PBDEs and NBFRs are also released from flame retarded products during disposal via landfill, dumping, incineration and recycling. While the land application of sewage sludge represents another major pathway of soil contamination it is not considered in this review as it is extensively covered elsewhere. Both PBDEs and NBFRs were commonly detected at background locations including Antarctica and northern polar regions. PBDE congener profiles in soil were broadly representative of the major constituents in Penta-, Octa- and Deca BDE commercial mixtures and related to predicted market place demand. BDE-209 dominated soil profiles, followed by BDE-99 and BDE-47. Although further research is required to gain baseline data on NBFRs in soil, the current state of scientific literature suggests that NBFRs pose a similar risk to land contamination as PBDEs. PMID- 28732338 TI - Toxic organic substances and marker compounds in size-segregated urban particulate matter - Implications for involvement in the in vitro bioactivity of the extractable organic matter. AB - Toxic organic substances and polar organic marker compounds, i.e. polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs), polybrominated diphenyl ethers (PBDEs), polycyclic aromatic hydrocarbons (PAHs) and their nitro derivatives (N-PAHs), as well as dicarboxylic acids (DCAs) and sugars/sugar anhydrites (S/SAs) were analyzed in size-segregated PM samples (<0.49, 0.49-0.97, 0.97-3 and >3 MUm) collected at two urban sites (urban traffic and urban background) during the cold and the warm season. The potential associations between the organic PM determinants and the adverse cellular effects (i.e. cytotoxicity, genotoxicity, DNA damage, oxidative DNA adduct formation, and inflammatory response) induced by the extractable organic matter (EOM) of PM, previously measured in Velali et al. (2016b), were investigated by bivariate correlations and Principal Component Analysis (PCA). Partial Least Square regression analysis (PLS) was also employed in order to identify the chemical classes mainly involved in the EOM-induced toxicological endpoints in the various particle size fractions. Results indicated that particle size range <0.49 MUm was the major carrier of PM mass and organic compounds at both sites. All toxic organic compounds exhibited higher concentrations at the urban traffic site, except PCBs and OCPs that did not exhibit intra-urban variations. Conversely, wintertime levels of levoglucosan were significantly higher at the urban background site as a result of residential biomass burning. The PLS regression analysis allowed quite good prediction of the EOM-induced cytotoxicity and genotoxicity based on the determined organic chemical classes, particularly for the finest size fraction of PM. Nevertheless, it is expected that other chemical constituents, not determined here, also contribute to the measured toxicological responses. PMID- 28732339 TI - Aryl- and alkyl-phosphorus-containing flame retardants induced mitochondrial impairment and cell death in Chinese hamster ovary (CHO-k1) cells. AB - Phosphorus-containing flame retardants (PFRs) are increasingly in demand worldwide as replacements for brominated flame retardants (BFRs), but insufficient available toxicological information on PFRs makes assessing their health risks challenging. Mitochondria are important targets of various environmental pollutants, and mitochondrial dysfunction may lead to many common diseases. In the present study, mitochondria impairment-related endpoints were measured by a high content screening (HCS) assay for 11 selected non-halogen PFRs in Chinese hamster ovary (CHO-k1) cells. A cluster analysis was used to categorize these PFRs into three groups according to their structural characteristics and results from the HCS assay. Two groups, containing long-chain alkyl-PFRs and all aryl-PFRs, were found to cause mitochondrial impairment but showed different mechanisms of toxicity. Due to the high correlation between cell death and mitochondrial impairment, two PFRs with different structures, trihexyl phosphate (THP) and cresyl diphenyl phosphate (CDP), were selected and compared with chlorpyrifos (CPF) to elucidate their mechanism of inducing cell death. THP (an alkyl-PFR) was found to utilize a similar pathway as CPF to induce apoptosis. However, cell death induced by CDP (an aryl-PFR) was different from classical necrosis based on experiments to discriminate among the different modes of cell death. These results confirm that mitochondria might be important targets for some PFRs and that differently structured PFRs could function via distinct mechanisms of toxicity. PMID- 28732340 TI - Vascular regulation of glioma stem-like cells: a balancing act. AB - Glioblastoma (GBM) are aggressive and therapy-resistant brain tumours driven by glioma stem-like cells (GSCs). GSC behaviour is controlled by the microenvironment, or niche, in which the cells reside. It is well-established that the vasculature is a key component of the GSC niche, which drives maintenance in the tumour bulk and invasion at the margin. Emerging evidence now indicates that the specific properties of the vasculature within these two regions impose different functional states on resident GSCs, generating distinct subpopulations. Here, we review these recent findings, focusing on the mechanisms that underlie GSC/vascular communication. We further discuss how plasticity enables GSCs to respond to vascular changes by interconverting bidirectionally between states, and address the therapeutic implications of this dynamic response. PMID- 28732341 TI - Chirp excitation. AB - The paper describes the design of broadband chirp excitation pulses. We first develop a three stage model for understanding chirp excitation in NMR. We then show how a chirp pi pulse can be used to refocus the phase of the chirp excitation pulse. The resulting magnetization still has some phase dispersion in it. We show how a combination of two chirp pi pulses instead of one can be used to eliminate this dispersion, leaving behind a small residual phase dispersion. The excitation pulse sequence presented here allows exciting arbitrary large bandwidths without increasing the peak rf-amplitude. Experimental excitation profiles for the residual HDO signal in a sample of 99.5% D2O are displayed as a function of resonance offset. Although methods presented in this paper have appeared elsewhere, we present complete analytical treatment that elucidates the working of these methods. PMID- 28732342 TI - SCOPE-mTL: A non-invasive tool for identifying and lateralizing mesial temporal lobe seizures prior to scalp EEG ictal onset. AB - OBJECTIVE: In mesial temporal lobe (mTL) epilepsy, seizure onset can precede the appearance of a scalp EEG ictal pattern by many seconds. The ability to identify this early, occult mTL seizure activity could improve lateralization and localization of mTL seizures on scalp EEG. METHODS: Using scalp EEG spectral features and machine learning approaches on a dataset of combined scalp EEG and foramen ovale electrode recordings in patients with mTL epilepsy, we developed an algorithm, SCOPE-mTL, to detect and lateralize early, occult mTL seizure activity, prior to the appearance of a scalp EEG ictal pattern. RESULTS: Using SCOPE-mTL, 73% of seizures with occult mTL onset were identified as such, and no seizures that lacked an occult mTL onset were identified as having one. Predicted mTL seizure onset times were highly correlated with actual mTL seizure onset times (r=0.69). 50% of seizures with early mTL onset were lateralizable prior to scalp ictal onset, with 94% accuracy. CONCLUSIONS: SCOPE-mTL can identify and lateralize mTL seizures prior to scalp EEG ictal onset, with high sensitivity, specificity, and accuracy. SIGNIFICANCE: Quantitative analysis of scalp EEG can provide important information about mTL seizures, even in the absence of a visible scalp EEG ictal correlate. PMID- 28732343 TI - An ultrasensitive electrochemical biosensor for polynucleotide kinase assay based on gold nanoparticle-mediated lambda exonuclease cleavage-induced signal amplification. AB - Polynucleotide kinase (PNK) plays an essential role in cellular nucleic acid metabolism and the cellular response to DNA damage. However, conventional methods for PNK assay suffer from low sensitivity and involve multiple steps. Herein, we develop a simply electrochemical method for sensitive detection of PNK activity on the basis of Au nanoparticle (AuNP)-mediated lambda exonuclease cleavage induced signal amplification. We use [Ru(NH3)6]3+ as the electrochemically active indicator and design two DNA strands (i.e., strand 1 and strand 2) to sense PNK. The assembly of strand 2 on the AuNP surface leads to the formation of AuNP strand 2 conjugates which can be subsequently immobilized on the gold electrode through the hybridization of strand 1 with strand 2 for the generation of a high electrochemical signal. The presence of PNK induces the phosphorylation of the strand 2-strand 1 hybrid and the subsequent cleavage of double-stranded DNA (dsDNA) by lambda exonuclease, resulting in the release of AuNP-strand 2 conjugates and [Ru(NH3)6]3+ from the gold electrode surface and consequently the decrease of electrochemical signal. The PNK activity can be simply monitored by the measurement of [Ru(NH3)6]3+ peak current signal. This assay is very sensitive with a detection limit of as low as 7.762 * 10-4UmL-1 and exhibits a large dynamic range from 0.001 to 10UmL-1. Moreover, this method can be used to screen the PNK inhibitors, and it shows excellent performance in real sample analysis, thus holding great potential for further applications in biological researches and clinic diagnosis. PMID- 28732344 TI - Visible-light driven label-free photoelectrochemical immunosensor based on TiO2/S BiVO4@Ag2S nanocomposites for sensitive detection OTA. AB - A label-free photoelectrochemical (PEC) platform with high visible-light activity for quantitative detection of the ochratoxin A (OTA) was developed by assembly of Ag2S nanoparticles (NPs) sensitized on titanium dioxide/red blood cell-like shape bismuth vanadate (TiO2/S-BiVO4) electrode via layer-by-layer (LBL) strategy. In this protocol, ascorbic acid was used as an efficient electron donor for scavenging photo-generated holes and inhibiting light driven electron-hole pair recombination. TiO2 has good photoelectric activity and large surface area. The S BiVO4 with porous structure surfaces can contribute to the high photocurrent intensity under visible-light irradiation. Moreover, the Ag2S NPs were in-situ growth on surfaces of thioglycolic acid modified S-BiVO4, which enhanced photocurrent response and further improved the photocurrent conversion efficiency. Under optimal conditions, the PEC immunosensor exhibited a wide linear concentration range from 5pgmL-1 to 750ngmL-1, with a low detection limit of 1.7pgmL-1 (S/N = 3) for OTA. Additionally, the designed immunosensor was performed with good stability, reproducibility and selectivity, thus opening up a new promising PEC platform for some other small molecules analysis. PMID- 28732346 TI - Multiplexed aptasensor for simultaneous detection of carcinoembryonic antigen and mucin-1 based on metal ion electrochemical labels and Ru(NH3)63+ electronic wires. AB - In this paper, a dual-target electrochemical aptasensor has been developed for simultaneous detection of carcinoembryonic antigen and mucin-1 based on metal ion electrochemical labels and Ru(NH3)63+ electronic wires. When targets are present, the interaction between targets and their respective aptamers leads to the dissociation of double-strand DNA because the targets have higher affinity to its aptamer than the complementary strand. And the qualitative and quantitative analyses of the two targets are realized by the differential pulse voltammetry (DPV) peaks generated by metal ion electrochemical labels. For the effective loading of a large number of metal ions, Au/bovine serum albumin (Au/BSA) nanospheres are employed as carriers to develop Au/BSA-metal ions. After Ru(NH3)63+ complexes are embedded into double-strand DNA to form the electronic wires, the electrical conductivity and the electron transfer of the detection system are greatly improved. The detection limit of the proposed assay was calculated as 3.33fM ranging from 0.01pM to 100nM. Therefore, this novel sensing assay provides a new and sensitive platform for detecting several targets simultaneously in biochemical research and clinical diagnosis. PMID- 28732345 TI - Multichannel electroanalytical devices for competitive ELISA of phenylethanolamine A. AB - Herein, we reported a disposable electroanalytical device for competitive enzyme linked immunosorbent assay (ELISA) of phenylethanolamine A (PA). Conductive carbon tape coated with gold cluster served as the working electrode, while the counter and reference electrodes were fabricated on the filter paper by the screen-printing technique. Separating fabrication of the working electrode from other electrodes could make it possible for full utilization of the working electrode modification in bulk and no contamination of the immune-reagents on the counter and reference electrodes. The gold cluster played an important role in both immobilizing antigen and accelerating electron transfer. The eight-channel devices were utilized to detect PA on the strategy of competitive ELISA. The detection range and the limit of detection (LOD) using differential pulse voltammetry for PA were 0.005-60ngmL-1 and 2.6pgmL-1, respectively. And also, the linear range for PA performed by square wave voltammetry was 0.05-60ngmL-1 with the LOD value as 0.028ngmL-1. The results clearly demonstrated that the proposed electroanalytical devices could be successfully applied in immunoassay and might be further developed for determination of different analytes based on ELISA format. PMID- 28732390 TI - A novel "hitch-and-ride" deep biliary cannulation method during rendezvous endoscopic ultrasound-guided ERCP technique. AB - Background and study aim Endoscopic ultrasound-guided rendezvous (EUS-RV) is increasingly reported as a treatment option after failed endoscopic retrograde cholangiopancreatography. We developed a novel "hitch-and-ride" catheter for biliary cannulation to reduce the risk of guidewire loss during EUS-RV. Patients and methods We retrospectively evaluated safety and technical success of EUS-RV between June 2011 and May 2016. Biliary cannulation during EUS-RV using three methods - over-the-wire, along-the-wire, and hitch-and-ride - were compared. Results A total of 30 EUS-RVs were attempted and the technical success rate was 93.3 %, with two failures (one bile duct puncture and one guidewire insertion). After 28 cases of successful guidewire passage, cannulation was attempted by the over-the-wire (n = 13), along-the-wire (n = 4) or hitch-and-ride (n = 11) method. Only the hitch-and-ride method achieved biliary cannulation without guidewire loss or conversion to the other methods. Time to cannulation was shorter with the hitch-and-ride method (4 minutes) than with over-the-wire and along-the-wire methods (9 and 13 minutes, respectively). The adverse event rate of EUS-RV was 23.3 %. Conclusion A novel hitch-and-ride catheter was feasible for biliary cannulation after EUS-RV. PMID- 28732391 TI - A new intraductal radiofrequency ablation device for inoperable biliopancreatic tumors complicated by obstructive jaundice: the IGNITE-1 study. AB - Background and study aims Biliary stenting of unresectable malignant bile duct obstruction is generally accepted as the standard of care but it can be hampered by tumor ingrowth and stent dysfunction. We aimed to test the feasibility, safety, and biliary patency rate of a new endoscopically applied intraductal radiofrequency ablation (RFA) device. Patients and methods Eighteen patients with inoperable malignant biliary obstruction underwent endoscopic retrograde cholangiopancreatography (ERCP)-directed RFA and stenting. Results Between December 2014 and November 2015, 18 patients underwent RFA to the intended region, with no complications within 3 months of the procedure. Bilirubin levels post-RFA and stenting decreased significantly (7.8 +/- 1 mg/dL to 1.7 +/- 0.4 mg/dL; P < 0.001). At 90 and 180 days post-intervention, biliary patency was maintained in 80 % and 69 % of patients still alive at that time, respectively. The median overall stent patency was 110 days (range 16 - 374), with a median patient survival of 227 days (range 16 - 374). Conclusion Intraductal RFA using a new device in patients with inoperable biliopancreatic cancer complicated by jaundice appeared feasible and safe with acceptable biliary patency. Randomized trials with prolonged follow-up are warranted.ClinTrials.gov: NCT02468076. PMID- 28732392 TI - Systematic assessment with I-SCAN magnification endoscopy and acetic acid improves dysplasia detection in patients with Barrett's esophagus. AB - Background and study aims Enhanced endoscopic imaging with chromoendoscopy may improve dysplasia recognition in patients undergoing assessment of Barrett's esophagus (BE). This may reduce the need for random biopsies to detect more dysplasia. The aim of this study was to assess the effect of magnification endoscopy with I-SCAN (Pentax, Tokyo, Japan) and acetic acid (ACA) on dysplasia detection in BE using a novel mucosal and vascular classification system. Methods BE segments and suspicious lesions were recorded with high definition white-light and magnification endoscopy enhanced using all I-SCAN modes in combination. We created a novel mucosal and vascular classification system based on similar previously validated classifications for narrow-band imaging (NBI). A total of 27 videos were rated before and after ACA application. Following validation, a further 20 patients had their full endoscopies recorded and analyzed to model use of the system to detect dysplasia in a routine clinical scenario. Results The accuracy of the I-SCAN classification system for BE dysplasia improved with I SCAN magnification from 69 % to 79 % post-ACA (P = 0.01). In the routine clinical scenario model in 20 new patients, accuracy of dysplasia detection increased from 76 % using a "pull-through" alone to 83 % when ACA and magnification endoscopy were combined (P = 0.047). Overall interobserver agreement between experts for dysplasia detection was substantial (0.69). Conclusions A new I-SCAN classification system for BE was validated against similar systems for NBI with similar outcomes. When used in combination with magnification and ACA, the classification detected BE dysplasia in clinical practice with good accuracy.Trials registered at ISRCTN (58235785). PMID- 28732393 TI - MicroRNA-30a suppresses tumor progression by blocking Ras/Raf/MEK/ERK signaling pathway in hepatocellular carcinoma. AB - Emerging reports suggest microRNAs (miRNAs) play a vital role in the progression of malignant tumors. MiR-30a is downregulated in a variety of cancers and acts as a tumor suppressing gene. However, the molecular mechanisms of miRNA-30a in hepatocellular carcinoma (HCC) are still unclear. Hereby, in this study, we detected that miR-30a expression was significantly down-regulated in both HCC tissues compared with adjacent non-cancerous liver tissues, and we also observed that miR-30a expression was lower in HCC cell lines than that of normal controls. By overexpression of miRNA-30a, we evaluated cell growth with CCK-8 assay and cell apoptosis by flow cytometry. The function of miR-30a on cellular migration in HCC cells was assessed. The potential target genes of miR-30a were analyzed with luciferase activity assay. Our data displayed that miR-30a mimic markedly inhibited HCC cell growth, induced cell apoptosis, and upregulated the expression of apoptotic proteins in HepG2 and MHCC976L cells. We also found that upregulation of miR-30a significantly inhibited HCC cells migration and invasion. Bioinformatics analysis revealed K-Ras was a regulative target gene of miR-30a, and further dual luciferase reporter assay showed that miR-30a directly binds to the 3'-untranslated region (3'-UTR) of K-Ras mRNA. Furthermore, we found that in HepG2 and MHCC97L cancer cells, miR-30a overexpression completely blocked the K Ras/c-Raf/MEK/ERK pathway activation. Overall, these findings demonstrated that miR-30a might play a certain role in the cell growth, apoptosis and metastasis of HCC cells, partially via regulating K-Ras/c-Raf/MEK/ERK signaling pathway, potentially, it is therefore a candidate targeting biomarker for HCC therapy. PMID- 28732394 TI - Surface-charge effects on the electro-orientation of insulating boron-nitride nanotubes in aqueous suspension. AB - The alignment of hexagonal boron-nitride nanotubes (BNNTs) in aqueous KCl solutions under spatially uniform electric fields was examined experimentally, using direct optical visualization to probe the orientation dynamics of individual BNNTs for different electric-field frequencies. Different from most previously studied nanowires and nanotubes, BNNTs are wide-bandgap materials which are essentially insulating at room temperature. We analyze the electro orientation of BNNTs in the general context of polarizable cylindrical particles in liquid suspensions, whose behavior can fall into different regimes, including alignment due to Maxwell-Wagner induced dipoles at high frequencies, and alignment due to fluid motion of the electrical double layer around the particles at lower frequencies. For BNNTs, the variation of the crossover frequencies in the electro-orientation spectra was studied in electrolytes of different conductivity. The effect of BNNT surface charge on electro-orientation was further studied by changing the pH of the aqueous solution. We find that the electric-field alignment of the BNNTs in the low-frequency regime is associated with the charging and motion of the electrical double layer around the particle. However, as BNNTs are non-conducting particles, the reasons for the formation of the electrical double layer are likely to be different than that of conducting particles. We discuss two possible mechanisms for the double-layer formation and alignment of 1D dielectric particles, and make comparison to those for the more commonly studied conducting particles. PMID- 28732395 TI - Microalgae-bacteria models evolution: From microalgae steady-state to integrated microalgae-bacteria wastewater treatment models - A comparative review. AB - The search for environmentally neutral alternative fuels had revived the interest for microalgae-bacteria wastewater treatment systems. The potential achieving of bioproducts from microalgae biomass has also greatly contributed. The reactions that occur in these systems are complex, and the degree of scientific knowledge is still scarce compared to that of conventional bacteria wastewater treatments. Mathematical models offer a great opportunity to study the simultaneous effect of the multiple factors affecting microalgae and bacteria, thus allowing for the prediction of final biomass production, and contributing to the system design optimization in terms of operation and control. During the last decades, numerous models describing microalgae growth have been proposed. However, a lower number of integral models considering microalgae as well as bacteria is available. In this paper, the evolution of microalgae models from simple steady-state models (usually dependent on one factor) to more complex dynamic models (with two or more factors) has been revised. A summary of integrated microalgae-bacteria models has been reviewed, outlining their main features and presenting their processes and value parameters. Eventually, a critical discussion on integrated models has been put forward. PMID- 28732396 TI - Role of dams in the phase transfer of antibiotics in an urban river receiving wastewater treatment plant effluent. AB - Dams are universally constructed to change hydrodynamic forces and impound water in urban rivers, but few efforts have been made to expound the impact of dams on the transport of antibiotics in rivers. In this study, the main object and focus was to elucidate the intercept effect of rubber dam and the gate dam on the sediment-water phase redistribution of eight typical antibiotics along an urban river with the water replenished from wastewater treatment plants (WWTPs). The results show that the eight antibiotics were widely detected in the whole river segment, and the WWTPs were found to be the main sources. Among the eight antibiotics, fluoroquinolones had the highest concentrations in the surface water, while tetracyclines constituted the dominant composition in the sediments. Due to the retention effect, the rubber dam encouraged the enrichment and degradation of the antibiotics in the river. However, the role of gate dams depended mainly on the opening and closing of the sluice gate. For all eight antibiotics, each dam or WWTP exhibited a generally consistent impact on the changes (e.g., an increase or decrease) of the sediment-water partitioning coefficients, although obvious differences existed between effect degree. Moreover, the changes in the coefficients caused by the rubber dam were completely opposite to those affected by gate dams. Contrary to the other six antibiotics, the two sulfonamides showed significant relationships with the dissolved organic matter in the surface water but had no significant relationships with the organic matter in the sediments. PMID- 28732397 TI - Combined sewer overflow events and childhood emergency department visits: A case crossover study. AB - In localities with combined sewer systems, combined sewer overflow (CSO) events frequently occur following high precipitation and can result in the release of untreated sewage and industrial wastewater into surface waters. We hypothesized that either direct contact with or proximity to aerosolized CSO effluent would increase the risk for childhood emergency department (ED) visits for asthma, gastrointestinal (GI) illnesses, and skin and soft tissue infections (SSTIs) in Cincinnati, OH, USA. ED visits for 2010-2014 due to GI diseases, asthma, and SSTIs were extracted from the Cincinnati Children's Hospital Medical Center electronic health records. The location and timing of CSO events were obtained from the Metropolitan Sewer District (MSD) of Greater Cincinnati. ED visits with a residential address within 500m of a CSO site were used in a case-control crossover study with two bi-directional control periods. Conditional logistic regression models were used to estimate the risk of an ED visit associated with a CSO event at lag periods of 0 to 7days. Statistically significant elevated risks for GI-related ED visits was observed two (OR: 1.16 [95% CI 1.04,1.30]) days after CSO events. CSO events were not significantly associated with asthma- or SSTI-related ED visits, but show similar trends. Our findings suggest an increased risk for GI-related ED visits following CSO events among children who reside near CSO sites. PMID- 28732398 TI - Simulation of targeted pollutant-mitigation-strategies to reduce nitrate and sediment hotspots in agricultural watershed. AB - About 50% of U.S. water pollution problems are caused by non-point source (NPS) pollution, primarily sediment and nutrients from agricultural areas, despite the widespread implementation of agricultural Best Management Practices (BMPs). However, the effectiveness of implementation strategies and type of BMPs at watershed scale are still not well understood. In this study, the Soil and Water Assessment Tool (SWAT) ecohydrological model was used to assess the effectiveness of pollutant mitigation strategies in the Raccoon River watershed (RRW) in west central Iowa, USA. We analyzed fourteen management scenarios based on systematic combinations of five strategies: fertilizer/manure management, changing row-crop land to perennial grass, vegetative filter strips, cover crops and shallower tile drainage systems, specifically aimed at reducing nitrate and total suspended sediment yields from hotspot areas in the RRW. Moreover, we assessed implications of climate change on management practices, and the impacts of management practices on water availability, row crop yield, and total agricultural production. Our results indicate that sufficient reduction of nitrate load may require either implementation of multiple management practices (38.5% with current setup) or conversion of extensive areas into perennial grass (up to 49.7%) to meet and maintain the drinking water standard. However, climate change may undermine the effectiveness of management practices, especially late in the 21st century, cutting the reduction by up to 65% for nitrate and more for sediment loads. Further, though our approach is targeted, it resulted in a slight decrease (~5%) in watershed average crop yield and hence an overall reduction in total crop production, mainly due to the conversion of row-crop lands to perennial grass. Such yield reductions could be quite spatially heterogeneously distributed (0 to 40%). PMID- 28732399 TI - Analysis of emerging organic contaminants in water, fish and suspended particulate matter (SPM) in the Joint Danube Survey using solid-phase extraction followed by UHPLC-MS-MS and GC-MS analysis. AB - In the third Joint Danube Survey (JDS3), emerging organic contaminants were analysed in the dissolved water phase of samples from the Danube River and its major tributaries. Analyses were performed using solid-phase extraction (SPE) followed by ultra-high-pressure liquid chromatography triple-quadrupole mass spectrometry (UHPLC-MS-MS) and gas chromatography-mass spectrometry (GC-MS). The polar organic compounds analysed by UHPLC-MS-MS were 1H-benzotriazole, methylbenzotriazoles, carbamazepine, 10,11-dihydro-10,11-dihydroxy-carbamazepine, diclofenac, sulfamethox-azole, 2,4-D (2,4-dichlorophenoxyacetic acid), MCPA (2 methyl-4-chlorophenoxyacetic acid), metolachlor, cybutryne (irgarol), terbutryn, DEET (N,N-diethyl-m-toluamide), and several perfluoroalkyl acids (C6-C9; C8=perfluorooctanoic acid (PFOA)) and perfluorooctansulfonic acid (PFOS). In addition, several organophosphorus flame retardants were analysed by GC-MS. The most relevant compounds identified in the 71 water samples, in terms of highest median and maximum concentrations, were 1H-benzotriazole, tris(1-chloro-2 propyl)phosphate (TCPP), methylbenzotriazoles, carbama-zepine and its metabolite, DEET, sulfamethoxazole, tris(isobutyl)phosphate (TiBP), tris(2 chloroethyl)phosphate (TCEP), PFOA, PFOS and diclofenac. The concentrations of these compounds in the samples were generally below the environmental quality standard (EQS) threshold values, with the exception of PFOS, the concentration of which exceeded the annual average water EQS limit of 0.65ng/L along the whole river, and also exceeded the fish biota EQS of 9.1MUg/kg. In addition, the proposed EQS for diclofenac, of 0.1MUg/L, was exceeded in the Arges River in Romania (255ng/L). PMID- 28732401 TI - Can brook trout survive climate change in large rivers? If it rains. AB - We provide an assessment of thermal characteristics and climate change vulnerability for brook trout (Salvelinus fontinalis) habitats in the upper Shavers Fork sub-watershed, West Virginia. Spatial and temporal (2001-2015) variability in observed summer (6/1-8/31) stream temperatures was quantified in 23 (9 tributary, 14 main-stem) reaches. We developed a mixed effects model to predict site-specific mean daily stream temperature from air temperature and discharge and coupled this model with a hydrologic model to predict future (2016 2100) changes in stream temperature under low (RCP 4.5) and high (RCP 8.5) emissions scenarios. Observed mean daily stream temperature exceeded the 21 degrees C brook trout physiological threshold in all but one main-stem site, and 3 sites exceeded proposed thermal limits for either 63- and 7-day mean stream temperature. We modeled mean daily stream temperature with a high degree of certainty (R2=0.93; RMSE=0.76 degrees C). Predicted increases in mean daily stream temperature in main-stem and tributary reaches ranged from 0.2 degrees C (RCP 4.5) to 1.2 degrees C (RCP 8.5). Between 2091 and 2100, the average number of days with mean daily stream temperature>21 degrees C increased within main stem sites under the RCP 4.5 (0-1.2days) and 8.5 (0-13) scenarios; however, no site is expected to exceed 63- or 7-day thermal limits. During the warmest 10years, >=5 main-stem sites exceeded the 63- or 7-day thermal tolerance limits under both climate emissions scenarios. Years with the greatest increases in stream temperature were characterized by low mean daily discharge. Main-stem reaches below major tributaries never exceed thermal limits, despite neighboring reaches having among the highest observed and predicted stream temperatures. Persistence of thermal refugia within upper Shavers Fork would enable persistence of metapopulation structure and life history processes. However, this will only be possible if projected increases in discharge are realized and offset expected increases in air temperature. PMID- 28732400 TI - Solar photocatalytic disinfection of agricultural pathogenic fungi (Curvularia sp.) in real urban wastewater. AB - The interest in developing alternative water disinfection methods that increase the access to irrigation water free of pathogens for agricultural purposes is increasing in the last decades. Advanced Oxidation Processes (AOPs) have been demonstrated to be very efficient for the abatement of several kind of pathogens in contaminated water. The purpose of the current study was to evaluate and compare the capability of several solar AOPs for the inactivation of resistant spores of agricultural fungi. Solar photoassisted H2O2, solar photo-Fenton at acid and near-neutral pH, and solar heterogeneous photocatalysis using TiO2, with and without H2O2, have been studied for the inactivation of spores of Curvularia sp., a phytopathogenic fungi worldwide found in soils and crops. Different concentrations of reagents and catalysts were evaluated at bench scale (solar vessel reactors, 200mL) and at pilot plant scale (solar Compound Parabolic Collector-CPC reactor, 20L) under natural solar radiation using distilled water (DW) and real secondary effluents (SE) from a municipal wastewater treatment plant. Inactivation order of Curvularia sp. in distilled water was determined, i.e. TiO2/H2O2/sunlight (100/50mgL-1)>H2O2/sunlight (40mgL-1)>TiO2/sunlight (100mgL-1)>photo-Fenton with 5/10mgL-1 of Fe2+/H2O2 at pH3 and near-neutral pH. For the case of SE, at near neutral pH, the most efficient solar process was H2O2/Solar (60mgL-1); nevertheless, the best Curvularia sp. inactivation rate was obtained with photo-Fenton (10/20mgL-1 of Fe2+/H2O2) requiring a previous water adicification to pH3, within 300 and 210min of solar treatment, respectively. These results show the efficiency of solar AOPs as a feasible option for the inactivation of resistant pathogens in water for crops irrigation, even in the presence of organic matter (average Dissolved Organic Carbon (DOC): 24mgL-1), and open a window for future wastewater reclamation and irrigation use. PMID- 28732402 TI - Characteristics of black carbon in snow from Laohugou No. 12 glacier on the northern Tibetan Plateau. AB - Black carbon (BC) emitted from the incomplete combustion of biomass and fossil fuel impacts the climate system, cryospheric change, and human health. This study documents black carbon deposition in snow from a benchmark glacier on the northern Tibetan Plateau. Significant seasonality of BC concentrations indicates different input or post-depositional processes. BC particles deposited in snow had a mass volume median diameter slightly larger than that of black carbon particles typically found in the atmosphere. Also, unlike black carbon particles in the atmosphere, the particles deposited in snow did not exhibit highly fractal morphology by Scanning Transmission Electron Microscope. Footprint analysis indicated BC deposited on the glacier in summer originated mainly from Central Asia; in winter, the depositing air masses generally originated from Central Asia and Pakistan. Anthropogenic emissions play an important role on black carbon deposition in glacial snow, especially in winter. The mass absorption efficiency of BC in snow at 632nm exhibited significantly seasonality, with higher values in summer and lower values in winter. The information on black carbon deposition in glacial snow provided in this study could be used to help mitigate the impacts of BC on glacier melting on the northern Tibetan Plateau. PMID- 28732403 TI - Ecosystem service trade-offs and their influencing factors: A case study in the Loess Plateau of China. AB - Soil erosion control (SEC), carbon sequestration (CAS), and soil moisture (SMO) strongly interact in the semi-arid Loess Plateau. Since SMO has supportive effects on SEC and CAS, it can be considered as ecosystem service (ES), and there is an immediate need to coordinate the relationships among these ecosystem services (ESs) to promote the sustainability of vegetation recovery. In this study, we quantified the ESs, ES trade-offs, and the environmental factors in 151 sample plots in the Ansai watershed, and we used a redundancy analysis (RDA) to clarify the effects of environmental factors on these ESs and their trade-offs. The results were as follows: (1) the general trend in the SEC of vegetation types was Robinia pseudoacacia (CH)>native grass (NG)>small arbor (ST)>Hippophae rhamnoides (SJ)>artificial grass (AG)>Caragana korshinskii (NT)>apple orchard (GY)>crop (CP); the CAS trend was CH>SJ>NT>AG>CP>ST>GY>NG; and the SMO trend was CP>NG>GY>AG>SJ>ST>CH>NT. (2) For SEC-SMO trade-offs, the influence of vegetation type, altitude, silt and sand composition was dominant. The arrangement of NG, AG, and SJ could decrease the extent of the trade-offs. (3) For CAS-SMO trade offs, vegetation coverage and types were the dominant factors, but the effects were not complex. The extent of these trade-offs was lowest for NT, and that for SJ was the second lowest. (4) Considering the relationships among the three ESs, SJ was the most appropriate afforestation plant. Combing the vegetation types, slope position, slope gradient, and soil properties could regulate these ES relationships. The dominant factors influencing ES trade-offs varied among the different soil layers, so we must consider the corresponding influencing factors to regulate ESs. Moreover, manual management measures were also important for coordinating the ES relationships. Our research provides a better understanding of the mechanisms influencing the relationships among ESs. PMID- 28732404 TI - Influence of the stabilizers on the toxicity of metallic nanomaterials in aquatic organisms and human cell lines. AB - In this study, following a systematic approach, we used aquatic species (bacteria Vibrio fischeri and microalgae Raphidocelis subcapitata) and different human cell lines (Caco-2, HepG2, SV-80 and HaCaT) representing different tissues and exposure pathways, to investigate how two organic stabilizers (PVA and DMSO) used for NMs dispersion influence their physicochemical properties, the persistence of metals in suspension and the toxicity/ecotoxicity of two metallic NMs (nano-Ag and nano-Cu). Although the stabilizers are expected to contribute to improve the dispersion and stability of NMs, the results obtained clearly showed that no similar changes in toxicity and morphological properties of the nano-Ag can be expected after its stabilization with PVA. Thus, regarding human cell lines, the reduction in the average size of the PVA-nano-Ag was followed by a reduction or maintenance of its toxicity, but the opposite was observed for the aquatic species tested since an increase in the average size enhanced its toxicity. As far as nano-Cu is considered DMSO contributed for a better dispersion of this nanomaterial, however this was not translated in a similar toxicity/ecotoxicity modification. In summary, even for nano-Cu, for which few or no data exists regarding its toxicity after stabilization with organic compounds, it was confirmed with consistent data, that the toxicity of metallic NMs is a complex combination of average size, chemical composition, solubilization or persistence in suspension of the metallic forms, interaction with test medium components and sensitivity of test species and cell lines. The combination of all of these factors makes the toxicity of metallic NMs unpredictable and points for the need of an extensive evaluation of each new formulation. PMID- 28732405 TI - Increased N2O emission by inhibited plant growth in the CO2 leaked soil environment: Simulation of CO2 leakage from carbon capture and storage (CCS) site. AB - Atmospheric carbon dioxide (CO2) concentrations is continuing to increase due to anthropogenic activity, and geological CO2 storage via carbon capture and storage (CCS) technology can be an effective way to mitigate global warming due to CO2 emission. However, the possibility of CO2 leakage from reservoirs and pipelines exists, and such leakage could negatively affect organisms in the soil environment. Therefore, to determine the impacts of geological CO2 leakage on plant and soil processes, we conducted a greenhouse study in which plants and soils were exposed to high levels of soil CO2. Cabbage, which has been reported to be vulnerable to high soil CO2, was grown under BI (no injection), NI (99.99% N2 injection), and CI (99.99% CO2 injection). Mean soil CO2 concentration for CI was 66.8-76.9% and the mean O2 concentrations in NI and CI were 6.6-12.7%, which could be observed in the CO2 leaked soil from the pipelines connected to the CCS sites. The soil N2O emission was increased by 286% in the CI, where NO3--N concentration was 160% higher compared to that in the control. This indicates that higher N2O emission from CO2 leakage could be due to enhanced nitrification process. Higher NO3--N content in soil was related to inhibited plant metabolism. In the CI treatment, chlorophyll content decreased and chlorosis appeared after 8th day of injection. Due to the inhibited root growth, leaf water and nitrogen contents were consistently lowered by 15% under CI treatment. Our results imply that N2O emission could be increased by the secondary effects of CO2 leakage on plant metabolism. Hence, monitoring the environmental changes in rhizosphere would be very useful for impact assessment of CCS technology. PMID- 28732406 TI - Quantifying deforestation and forest degradation with thermal response. AB - Deforestation and forest degradation cause the deterioration of resources and ecosystem services. However, there are still no operational indicators to measure forest status, especially for forest degradation. In the present study, we analysed the thermal response number (TRN, calculated by daily total net radiation divided by daily temperature range) of 163 sites including mature forest, disturbed forest, planted forest, shrubland, grassland, savanna vegetation and cropland. TRN generally increased with latitude, however the regression of TRN against latitude differed among vegetation types. Mature forests are superior as thermal buffers, and had significantly higher TRN than disturbed and planted forests. There was a clear boundary between TRN of forest and non-forest vegetation (i.e. grassland and savanna) with the exception of shrubland, whose TRN overlapped with that of forest vegetation. We propose to use the TRN of local mature forest as the optimal TRN (TRNopt). A forest with lower than 75% of TRNopt was identified as subjected to significant disturbance, and forests with 66% of TRNopt was the threshold for deforestation within the absolute latitude from 30 degrees to 55 degrees . Our results emphasized the irreplaceable thermal buffer capacity of mature forest. TRN can be used for early warning of deforestation and degradation risk. It is therefore a valuable tool in the effort to protect forests and prevent deforestation. PMID- 28732407 TI - A synergistic combination of nutrient reclamation from manure and resultant hydrochar upgradation by acid-supported hydrothermal carbonization. AB - Cattle manure was hydrothermally carbonized in acid solutions (0-2% HCl), then nutrient concentration in liquid product and physicochemical properties of hydrochar were characterized to investigate the effects of acid addition on hydrochar properties and nutrient recovery from manure. Results showed that hydrothermal carbonization (HTC) in 2% HCl extracted almost 100% and 63.38% of phosphorus and nitrogen, respectively; specifically, >90% of the extracted phosphorus was PO4-P in liquid from HTC with acid addition, and increasing amount of extracted nitrogen was NH4-N with increasing acid addition. Generally, higher heating value, surface area, total pore volume, fixed carbon, atomic ratios of H/C and O/C were increased in hydrochars from HTC with acid addition, while yield, volatile matter, contents of nitrogen, sulfur and oxygen of these hydrochars were decreased. These results indicated that HTC with acid addition could simultaneously facilitate nutrient recovery from manure and resulting hydrochar upgradation. PMID- 28732408 TI - Is Internal Maxillary Artery Bypass Feasible without Zygomatic Osteotomy? PMID- 28732409 TI - In Reply to "Is Internal Maxillary Artery Bypass Feasible without Zygomatic Osteotomy?" PMID- 28732410 TI - Craniopharyngioma: Surgical Outcome as Related to the Degree of Hypothalamic Involvement. PMID- 28732411 TI - In Reply to "Craniopharyngioma: Surgical Outcome as Related to the Degree of Hypothalamic Involvement". PMID- 28732412 TI - Letter to the Editor Regarding "Six Walls of the Cavernous Sinus Identified by Sectioned Images and Three-Dimensional Models: Anatomic Report". PMID- 28732413 TI - In Reply to the Letter to the Editor Regarding "Six Walls of the Cavernous Sinus Identified by Sectioned Images and Three-Dimensional Models: Anatomic Report". PMID- 28732414 TI - Risk Factors for Poor Outcome in Hypertensive Intraventricular Hemorrhage Treated by External Ventricular Drainage with Intraventricular Fibrinolysis: Statistical and Methodologic Issues. PMID- 28732415 TI - In Reply to "Risk Factors for Poor Outcome in Hypertensive Intraventricular Hemorrhage Treated by External Ventricular Drainage with Intraventricular Fibrinolysis: Statistical and Methodologic Issues". PMID- 28732416 TI - Primary Spinal Cord Glioblastoma Multiforme: A Rare but Uniformly Fatal Neoplasm. PMID- 28732417 TI - Expanding Spectrum and Diversifying Role of Laser Beam from Intraoperative Cranial Surgery Adjunct to Magnetic Resonance-Guided Minimally Invasive Thermal Laser Ablation Therapy for Intracranial Tumor. PMID- 28732418 TI - Expanding Horizon of Neuroendoscopic Procedure from Endoscopic-Assisted Tumor Resection, Vascular Surgery, and Management of Hydrocephalus to Diagnostic and Therapeutic Management of Pyogenic Ventriculitis. PMID- 28732419 TI - Evolution of Different Surgical Treatment Techniques for Management and Improving Outcome of Chiari Malformation Type 1. PMID- 28732420 TI - Letter to the Editor Regarding "Impact of Intraoperative Monitoring During Elective Complex Spinal Fusions (>=4 Levels) on 30-Day Complication and Readmission Rates: A Single Institutional Study of 643 Adult Spinal Deformity Patients". PMID- 28732421 TI - Neuroendoscope: Evolving Spectrum of Utility in the Management of Hydrocephalus, Biopsy, and Resection of Ventricular Tumors and Cyst Fenestration. PMID- 28732422 TI - Syringostomy Using Myringostomy Tube. PMID- 28732423 TI - Statin Use in Patients with Aneurysmal Subarachnoid Hemorrhage May not Significantly Reduce the Occurrence of Delayed Ischemic Neurological Deficit. PMID- 28732424 TI - Letter to the Editor Regarding "Acute Spinal Epidural Hematoma After Acupuncture: Case Report and Literature Review". PMID- 28732425 TI - In Reply to the Letter to the Editor Regarding "Acute Spinal Epidural Hematoma After Acupuncture: Case Report and Literature Review". PMID- 28732426 TI - Moyamoya Disease: From Hypoperfusion to Network Disruption. PMID- 28732427 TI - In Reply To "Moyamoya Disease: From Hypoperfusion to Network Disruption". PMID- 28732428 TI - Physicians, Ethics, and Hospital Management. PMID- 28732429 TI - The Fringes. PMID- 28732430 TI - Bee Pollen Flavonoids as a Therapeutic Agent in Allergic and Immunological Disorders. AB - Bee pollen grains, as the male reproductive part of seed-bearing plants contain considerable concentrations of various phytochemicals and nutrients. Since antiquity, people throughout the world used pollens to cure colds, flu, ulcers, premature aging, anemia and colitis. It is now well-documented that some bee pollen secondary metabolites (e.g. flavonoid) may have positive health effects. In recent years, the flavonoids have attracted much interest because of their wide range of biological properties and their beneficial effects on human health. The current review, points out potential therapeutic effects of bee pollen flavonoids as one of the main bee pollen bioactive compounds in allergic and immunological diseases. Due to the fact that some types of flavonoid components in bee pollen have anti-allergic, anti-oxidant and anti-inflammatory properties, bee pollen flavonoids can be excellent candidates for future studies including phytotherapy, molecular pharmacology and substitutes for chemicals used in treating allergic and immunological disorders. PMID- 28732431 TI - The Efficacy of Oral Immunotherapy in Patients with Cow's Milk Allergy. AB - Cow's milk allergy is the most common type of food allergy that decrease the quality of life of patients and their families. The aim of this study was to evaluate the efficacy of oral immunotherapy in patients with cow's milk allergy. 14 patients above 3 years of age with a history of cow's milk allergy confirmed by positive double blind placebo controlled food challenge (DBPCFC) test, presence of serum IgE against cow's milk and positive SPT (skin prick test) were enrolled in this study. During the immunotherapy all patients received increasing amounts of cow's milk during three phases. The type and severity of allergic reactions were recorded after each dose. The serum IgE and SPT were measured at the beginning and at the end of study. Since February 2014 to March 2015, 14 patients with the median age of 4.75 (3.7-7) years were studied. 13 patients (92.9%) completed the build up and maintenance phase successfully and became desensitized to cow's milk. During the build up and maintenance phase, 24 (2.0%) and 11 (0.9%) episodes of allergic reactions occurred, respectively. The median serum IgE level against cow's milk proteins and casein decreased from 39.3 to 10.4 and 7.72 to 2.83 (ku/L), respectively. The median of the difference of the wheal diameter in SPT with the control, decreased from 10 to 6 mm during the immunotherapy protocol. Oral immunotherapy is effective to decrease the frequency and the severity of allergic reactions but due to high rate of allergic reactions and possible anaphylaxis, it must be done under strict supervision of both clinicians and caregivers. PMID- 28732432 TI - Intradermal Skin Testing in Allergic Rhinitis and Asthma with Negative Skin Prick Tests. AB - Taking medical history, physical examination, and performing some in vivo and in vitro tests are necessary for the diagnosis of allergy. Skin prick test (SPT) is considered as the standard method and first-line approach for the detection of allergic sensitization. Although mainly SPT is used for the detection of allergic sensitization, intradermal skin test (IDST) may be necessary, especially in patients with a negative SPT result. IDST is quite safe; however, is nowadays seldom used for detection of inhalant allergy and its value remains controversial. We aimed to investigate whether IDST is useful and necessary in diagnosis of respiratory allergies or not. This study involved 4223 patients with allergic rhinitis (AR) and/or bronchial asthma (BA). SPT results were positive in 2419 patients (57%) and negative in 1804 (43%). IDST was applied to 344 patients with marked allergic symptoms and with negative SPT results. Out of 344 patients, 152 (44%) showed allergic sensitization to IDST. The most commonly encountered allergic response was against the house dust mite (HDM) (32.6%). Allergic response against fungal spores was also relatively high (22%), while the pollen allergy rate (4.3%) was quite low. In BA patients with negative prick test, IDST made a significant contribution to the diagnosis of HDM allergy (p=0.003). To avoid missed diagnosis of AR and BA, particularly regarding the HDM allergy, application of IDST may be beneficial; therefore, IDST should be considered as the next step after SPT for diagnosis of allergy prior to in vitro or provocation tests. PMID- 28732433 TI - The Effect of Salt Space on Clinical Findings and Peak Expiratory Flow in Children with Mild to Moderate Asthma: A Randomized Crossover Trial. AB - The asthma treatment and control might be associated with significant burden on family and community' thus exploring other therapeutic plans could be desirable. The aim of this study was to investigate the effect of salt space on clinical findings and peak expiratory flow rate among children with asthma. In this randomized crossover trial, 34 patients aged 6-14 years old with mild to moderate asthma were selected and randomly divided into two groups. The first group went through a period of salt therapy by staying in the salt room for one hour, three times a week for 3 consecutive weeks and then was under observation for three weeks. This process was reversed for the second group (three weeks under observation followed by salt therapy). The wash-out period was one week. During the study, the morning and evening peak expiratory flow (PEF), the frequency of coughing, wheezing, dyspnea and use of rescue medications were measured. Salt therapy had a significant effect on raising the morning and evening PEF in the second week in both groups (p=0.028 and p=0.032, respectively). However, there was no significant effect on PEF variabilities' cough' wheezing, dyspnea, and the frequency of rescue medication (p>0.05). No side effect was observed during salt therapy. This study showed the significant effect of salt therapy on PEF rate of the patients in the second week. However, further studies with different frequency and time of salt therapy on respiratory disorders are recommended. PMID- 28732434 TI - Effects of Intraperitoneal Injection of Allogeneic Bone Marrow-derived Mesenchymal Stem Cells on Bronchiolitis Obliterans in Mice Model. AB - Bone marrow-derived mesenchymal stem cells (BMSCs) can ameliorate a variety of lung diseases such as asthma, lung fibrosis, and acute lung injury by its anti inflammatory and immunmodulatory effects. In this study, we developed a mouse model of bronchiolitis obliterans (BO) and evaluated the effects of the intraperitoneal administration of BMSCs on lung histopathology and cytokine levels. 25 BALB/c mice were divided into four groups; control group (Group I), BO developed and 1x106 BMSCs-injected group (Group II), non-BO, 1x106 BMSCs-injected group (Group III), and BO developed and saline-injected group (Group IV). Histological and immunohistochemical findings of the lung tissue and the migration of BMSCs to the lung were evaluated using light and confocal microscopy techniques. Confocal microscopy evaluations showed that there was no noteworthy amount of BMSCs in the lung tissue of group III while significant amount of BMSCs was detected in group II. Wall thicknesses of terminal bronchiole and periterminal bronchiolar collagen deposition were significantly lower in group II compared to the group IV (p<0.05). Furthermore, according to the immunohistochemical staining results, CD3, CD4, CD8, CD20, CD68 and neutrophil elastase positive immune cells of group II were stained more positive than group IV cells (p<0.05). IFN-gamma IL-2 and TNF-alpha levels in bronchoalveolar lavage fluid (BALF) were significantly lower in group II compared to group IV (p<0.05). The findings of this study indicate that intraperitoneally administered BMSCs have potent effects on histopatological changes of the lung tissue and cytokine levels in the murine model of BO. PMID- 28732435 TI - The Effect of Oral Levamisole Co-administration on the Level of Immune Response to Hepatitis B Vaccine in Healthy Individuals: A Randomized Clinical Trial. AB - Despite its proven efficacy, the hepatitis B vaccine requires improvements in immune enhancement and durability, especially in the elderly. Levamisole, an immune modulator, has been tested as an adjuvant to hepatitis B vaccine in several studies in immune-compromised populations. However, we aimed to evaluate the effect of levamisole on the immune response to hepatitis B vaccine in healthy subjects. In this randomized clinical trial, healthy family members of chronic hepatitis B patients were given twenty-microgram intramuscular injections of hepatitis B vaccine at 0, 1, and 6 months and 50 miligrams of oral levamisole twice a day for two weeks with every vaccination dose. Serum hepatitis B surface antibody (HBsAb) levels of ultimately 98 individuals were measured one month after the final vaccination dose and compared to those of 119 subjects that received placebo and vaccine with an identical regimen. HBsAb levels >10 mIU/mL were considered protective. The Student's t-test, Mann-Whitney test, Kruskal Wallis analysis (quantitative comparison in age groups), Chi-square test, and the Pearson correlation were used to analyze data. p<0.05 was considered significant. Serum HBsAb levels were significantly higher in the test group (p<0.001). All test subjects had levels above 50 mIU/mL (86.7% exceeding 100 mIU/mL). The quantitative response according to age groups was remarkable (p=0.01 and p<0.001 for placebo and levamisole, respectively), while that of gender was insignificant (p=0.9). Unlike HBsAb titers amongst controls, levels in the levamisole group were affected by smoking (p=0.79 and p=0.006, respectively). We conclude that oral levamisole as an adjuvant to the hepatitis B vaccine enhances the anti-HBs antibody in healthy vaccinees. PMID- 28732436 TI - Downregulation of Aquaporin3 in Systemic Sclerosis Dermal Fibroblasts. AB - Skin dryness and thickening are hallmarks of systemic sclerosis (SSc) disease. Aquaporins (AQPs) are plasma membrane proteins that transport glycerol and water, resulting in water retention and skin hydration. Expression of AQPs has been evaluated in human normal skin. However, expression of these proteins in SSc dermal fibroblasts has not yet been reported. The aim of this study was to assess the expression profile of AQPs in dermal fibroblasts of SSc patients. Fibroblast cells were extracted from SSc and healthy skin biopsies and characterized using fibroblast surface protein antibody. The SYBR Green Real-time PCR was used to evaluate the mRNA expression of AQP1, 3, 5, 7, 9, and 10 in dermal fibroblasts. Immunoblotting was performed to confirm the results of Real-time PCR. Our data demonstrated that only AQP1, AQP3, and AQP9 were expressed in human skin fibroblasts. Moreover, the expression of AQP3 mRNA and protein were significantly decreased in SSc dermal fibroblasts compare to healthy fibroblasts. AQP3, which involves in skin hydration and wound healing through water and glycerol transmission, is downregulated in SSc fibroblasts. Based on previous studies and our results, it seems that SSc manifestations like skin dryness, abnormal wound healing, and fibrotic lesions may be related to downregulation of AQP3 in SSc fibroblasts. Therefore, induction of AQP3 expression can be a potential treatment to relieve SSc skin thickness in the future. PMID- 28732437 TI - Effect of MicroRNA-21 Transfection on In-vitro Differentiation of Human Naive CD4+ T Cells to Regulatory T Cells. AB - Regulatory T cells (Tregs) are important components of the immune system that modulate responses of other cells. These cells are involved in peripheral tolerance mechanisms, so defect in development and function of these cells can result in autoimmune disease. Increasing evidence supports the role of microRNAs 21 (miR-21) in the regulation of forkhead box P3 (Foxp3) expression in Tregs. We aimed to determine whether miR-21 transfection to naive CD4+ T cells can be useful in generation of iTregs in-vitro. We investigated in-vitro differentiation of miR-21-transfected naive CD4+ T cells to iTregs and compared these iTregs to cytokine-differentiated iTregs and control group. We showed that expression of Foxp3, transforming growth factor beta (TGF-beta), and interleukin-10 (IL-10) are increased in iTregs generated after miR-21 transfection in comparison with cytokine-differentiated iTregs and control group. Our findings demonstrate that miR-21 has positive role in in-vitro generation of induced regulatory T-cells (iTregs). PMID- 28732438 TI - Investigation of Killer Immunoglobulin-like Receptor (KIR) and HLA Genotypes to Predict the Occurrence of Acute Allograft Rejection after Kidney Transplantation. AB - After kidney transplantation, natural killer (NK) cells play a pivotal role in triggering the immune response to the allogeneic grafts primarily by their killer cell immunoglobulin-like receptors (KIR). This process may be one mechanism that contributes to graft rejection. In this study, we have evaluated whether acute rejection after kidney transplantation was associated with predicted NK cell alloreactivity based on KIR gene and ligand along with KIR/HLA compound genotype analysis. After kidney transplantation, natural killer (NK) cells play a pivotal role in triggering the immune response to the allogeneic grafts primarily by their killer-cell immunoglobulin-like receptors (KIR). This process may be one mechanism that contributes to graft rejection. In this study, we have evaluated whether acute rejection after kidney transplantation was associated with predicted NK cell alloreactivity based on KIR gene and ligand along with KIR/HLA compound genotype analysis. DNA from 65 patients with biopsy-proven acute kidney allograft rejection (AKAR), 61 clinically stable graft function (SGF) recipients and 176 healthy subjects were identified for the presence or absence of 10 variable KIR genes (both activating and inhibitory receptors) and their HLA ligands using polymerase chain reaction-sequence specific primers (PCR-SSP) assay. Although no significant difference in the frequency of individual KIR genes, was found the gene content, and the haplotypic distribution between the three categories were detected, the frequency of the KIR3DL1+HLA-Bw4*A allele combination was significantly lower in AKAR patients compared to SGF recipients (p=0.004, OR=0.34, CI=0.16-0.72) and healthy subjects (p=0.019, OR=0.47, CI=0.25 0.89). Kaplan-Meier survival test showed that the KIR3DL1+HLA-Bw4*A allele combination could be considered protective for AKAR (p=0.04 by log-rank). The results of this study suggest that KIR/HLA polymorphism may be a genetic susceptibility factor to alloreactivity dysfunction in the NK cells of patients with AKAR. It is likely that a KIR/HLA combinatorial study can be beneficial in predicting AKAR occurrence for the purpose of selecting donors appropriately. PMID- 28732439 TI - The Extract of Portulaca oleracea and Its Constituent, Alpha Linolenic Acid Affects Serum Oxidant Levels and Inflammatory Cells in Sensitized Rats. AB - The effects of Portulaca oleracea and its constituent, alpha linolenic acid on serum oxidant levels and inflammatory cells in sensitized rats were examined. Eight groups of rats including control, sensitized, sensitized rats treated with 1, 2 and 4 mg/mL extract of P. oleracea, 0.2 and 0.4 mg/mL alpha linolenic acid (ALA) and 1.25 MUg/mL dexamethaswere studied serum levels of superoxide dismutase (SOD), catalase (CAT, thiol groups, NO2, NO3, and Malondialdehyde (MDA) as well as total and differential WBC in blood were measured. Serum concentrations of SOD, CAT and thiol were significantly decreased but NO2, NO3 and MDA as well as total WBC number and percentages of eosinophil and neutrophil were increased in sensitized group (p<0.001 for all cases).Treatment of sensitized animals with dexamethasone, high concentrations of the extract and ALA improved all measured variables except monocyte for all three treatment groups and eosinophil for dexamethasone treatment (p<0.01 to p<0.001). In addition, treatment with low and medium extract and low ALA concentrations improved serum levels of NO2, NO3 and total WBC count (p<0.001 for all cases). Neutrophil and lymphocyte percentages and serum level of thiol also improved due to treatment with medium extract and low ALA concentration (p<0.01 to p<0.001). Medium extract and low ALA treatment also caused improvement of serum level of CAT and eosinophil percentage as well as SOD level respectively (p<0.01 to p<0.001). The effect of the extract of P. oleracea and ALA on serum oxidants and inflammatory cells were demonstrated in sensitized rats, which was comparable with dexamethasone effects at used concentrations. PMID- 28732440 TI - Intravenous Injection of Myelin Oligodendrocyte Glycoprotein-coated PLGA Microparticles Have Tolerogenic Effects in Experimental Autoimmune Encephalomyelitis. AB - The abnormal function of the T lymphocytes causes a range of autoimmune diseases, particularly multiple sclerosis; hence, several methods have been used to treat these disorders through the induction of antigen-specific tolerance in T cells. The present study aims to use a simple and low-cost method to produce poly (lactic-co-glycolic acid) (PLGA) nanoparticles for carrying antigens and inducing antigen-specific tolerance. In this study, PLGA nanoparticles were produced using the water/oil/water (W/O/W) method. The myelin oligodendrocyte glycoprotein (MOG) peptide and ovalbumin peptide(OVA) were covalently bound to the synthetic PLGA nanoparticles in the presence of 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDCI) and were injected to six groups of C57BL/6 mice one week before the induction of the experimental autoimmune encephalomyelitis (EAE) intravenously or subcutaneously; one group was considered as control; finally, immunologic responses including delayed-type hypersensitivity (DTH) response and lymphocyte proliferation were investigated. The results showed that the intravenous injection of microparticles containing MOG peptides before the development of the EAE model, not only could delay the incidence of syndrome, but also increase the antigen-specific tolerance. Moreover, a reduced delayed-type hypersensitivity response was observed in the mice primed with microparticles containing MOG peptides. In addition, a reduced spleen lymphocyte proliferation was found in the same mice when challenged with antigens. The present study proposes a simple, inexpensive, effective and safe method for preparing MOG-conjugated PLGA microparticles with immune tolerance properties that can be used in the treatment or reducing clinical syndromes of EAE model. PMID- 28732441 TI - Determination of the Residual Entropy of Simple Mixtures by Monte Carlo Simulation. AB - Extensive Monte Carlo simulations were performed for (neon + krypton) mixtures for temperatures between 200 K and 600 K and pressures up to 1 GPa, using Lennard Jones potentials to describe the intermolecular interactions. The residual entropies were obtained via Widom's insertion method, as well as via an integration technique. At high pressures, the residual entropy is, to a very good approximation, a linear function of lambdaa-1, which is the reciprocal value of the average Monte Carlo displacement parameter that gives the acceptance ratio a for translational moves. The slope of this linear function varies linearly with the mole fraction and is related to the effective collision diameters of the molecules. As the displacement parameter is available during Monte Carlo simulations of fluids, its linearity with the residual entropy can be used to compute this properties with negligible computational effort at high densities, when particle insertion methods become unreliable. PMID- 28732442 TI - Dipeptides Embedded in a Lipid Bilayer Membrane as Synthetic Water Channels. AB - Water channels are essential to life sciences and many biological processes. We report a molecular simulation study on dipeptides embedded in a lipid (dipalmitoylphosphatidylcholine) membrane as synthetic water channels. Five dipeptides are examined including FF, FL, LF, and LL (with hydrophilic channels) and AV (with hydrophobic channel). It is found that AV is unstable in the lipid membrane due to incompatible interaction between the hydrophilic external surface of AV and the hydrophobic lipid tails; whereas FF, FL, LF, and LL with hydrophobic external surface exhibit good stability. In the four hydrophilic channels FF, FL, LF, and LL, water chains are formed; the number of chains ranges from multiple, two to one depending on channel diameter; moreover, water undergoes single-file diffusion and the mobility is enhanced with increasing channel diameter. The permeation rate of water in the FF channel is 9.20/ns, about three times that in aquaporin; however, the rate in FL, LF, and LL is much slower. Intriguingly, the rate can be tuned by a lateral stress/strain on the lipid membrane. The simulation study provides fundamental understanding on the stability of dipeptide channels embedded in a lipid membrane, quantitatively characterizing water structure, dynamics, and permeation in the channels. These microscopic insights are useful for the development of new water channels. PMID- 28732443 TI - First-Principles Study on O2 Adsorption and Dissociation Processes over Rh(100) and Rh(111) Surfaces. AB - Through DFT calculations, a systematic description of O2 adsorption and dissociation processes over Rh(100) and Rh(111) surfaces has been provided. The dominance of parallel orientation in molecularly adsorbed states and during the impinging processes has been identified, along with the explicit adsorption configurations and preferred impinging trajectories on both surfaces. The dissociation of O2 is found to occur either by precursor-mediated adsorption or by direct dissociation. O2 in its initial precursor state dissociates facilely on Rh(100), but this is a little harder on Rh(111) by going through a two-step process. The latter can be described as a preliminary rotation and subsequent dissociation, with the final locations of two O atoms disturbed easily by coadsorbed O atoms surrounding the dissociating O2 molecule due to the existence of a relatively flat potential energy surface stage along the way. The present work may provide the basis for kinetic modeling to investigate the catalytic properties on a realistic scale. PMID- 28732444 TI - Adsorption of Water and Ammonia on Graphene: Evidence for Chemisorption from X ray Absorption Spectra. AB - While the bonding of molecular adsorbates to graphene has so far been characterized as physisorption, our study of adsorbed ammonia and water using near-edge X-ray absorption spectroscopy provides unambiguous evidence for a chemical contribution to the adsorption bond. We use the situation, unique to graphene, to characterize the unoccupied valence band states of the partners in the bond on the basis of the complementary adsorbate and substrate X-ray absorption K edges. New adsorbate-induced features on the substrate (carbon) K edge are interpreted as hybrid states in terms of a simple model of chemical interaction. PMID- 28732445 TI - Photoelectron Spectroscopy Study of Quinonimides. AB - Structures and energetics of o-, m-, and p-quinonimide anions (OC6H4N-) and quinoniminyl radicals have been investigated by using negative ion photoelectron spectroscopy. Modeling of the photoelectron spectrum of the ortho isomer shows that the ground state of the anion is a triplet, while the quinoniminyl radical has a doublet ground state with a doublet-quartet splitting of 35.5 kcal/mol. The para radical has doublet ground state, but a band for a quartet state is missing from the photoelectron spectrum indicating that the anion has a singlet ground state, in contrast to previously reported calculations. The theoretical modeling is revisited here, and it is shown that accurate predictions for the electronic structure of the para-quinonimide anion require both an accurate account of electron correlation and a sufficiently diffuse basis set. Electron affinities of o- and p-quinoniminyl radicals are measured to be 1.715 +/- 0.010 and 1.675 +/- 0.010 eV, respectively. The photoelectron spectrum of the m-quinonimide anion shows that the ion undergoes several different rearrangements, including a rearrangement to the energetically favorable para isomer. Such rearrangements preclude a meaningful analysis of the experimental spectrum. PMID- 28732446 TI - Mesoscale Structures in the Adlayer of A-B2 Heterogeneous Catalysis. AB - This article explores the adsorbate distributions in the adlayer for a model A-B2 system of heterogeneous catalysis, i.e., A + 1/2B2 -> AB, via kinetic Monte Carlo (KMC) simulations. In comparison with our previous work on the A-B model (Sun, F.; Huang, W.; Li, J. Structural characteristics of the adlayer in heterogeneous catalysis. Chem. Eng. Sci. 2016, 153, 87-92), species B2 here brings about significant new features due to its special site requirement during adsorption and desorption and a different stoichiometric ratio in reactions. The effects of various kinetic processes on the adsorbate distribution are found to be similar to those in the A-B system; that is, both desorption and diffusion (besides adsorption) processes contribute to the adlayer uniformity while reactions account for clustering. However, desorption exhibits a stronger role than diffusion in homogenizing the adlayer, which is opposite to the finding in the previous A-B model. Under a fixed partial pressure, different reaction and desorption rate constants can lead to steady states with different dominant species, which has not been observed in the A-B system. The regime of species B poisoning shrinks as well, leading to the spreading of the coexisting regime, in comparison with the A-B model. PMID- 28732447 TI - DNA Polymerase lambda Active Site Favors a Mutagenic Mispair between the Enol Form of Deoxyguanosine Triphosphate Substrate and the Keto Form of Thymidine Template: A Free Energy Perturbation Study. AB - Human DNA polymerase lambda is an intermediate fidelity member of the X family, which plays a role in DNA repair. Recent X-ray diffraction structures of a ternary complex of a loop-deletion mutant of polymerase lambda, a deoxyguanosine triphosphate analogue, and a gapped DNA show that guanine and thymine form a mutagenic mispair with an unexpected Watson-Crick-like geometry rather than a wobble geometry. Hence, there is an intriguing possibility that either thymine in the DNA or guanine in the deoxyguanosine triphosphate analogue may spend a substantial fraction of time in a deprotonated or enol form (both are minor species in aqueous solution) in the active site of the polymerase lambda mutant. The experiments do not determine particular forms of the nucleobases that contribute to this mutagenic mispair. Thus, we investigate the thermodynamics of formation of various mispairs between guanine and thymine in the ternary complex at a neutral pH using classical molecular dynamics simulations and the free energy perturbation method. Our free energy calculations, as well as a comparison of the experimental and computed structures of mispairs, indicate that the Watson Crick-like mispair between the enol tautomer of guanine and the keto tautomer of thymine is dominant. The wobble mispair between the keto forms of guanine and thymine and the Watson-Crick-like mispair between the keto tautomer of guanine and the enol tautomer of thymine are less prevalent, and mispairs that involve deprotonated guanine or thymine are thermodynamically unlikely. These findings are consistent with the experiment and relevant for understanding mechanisms of spontaneous mutagenesis. PMID- 28732450 TI - Molecular Dynamics Simulations for Loading-Dependent Diffusion of CO2, SO2, CH4, and Their Binary Mixtures in ZIF-10: The Role of Hydrogen Bond. AB - The loading-dependent diffusion behavior of CH4, CO2, SO2, and their binary mixtures in ZIF-10 has been investigated in detail by using classical molecular dynamics simulations. Our simulation results demonstrate that the self-diffusion coefficient Di of CH4 molecules decreases sharply and monotonically with the loading while those of both CO2 and SO2 molecules initially display a slight increase at low uptakes and follow a slow decrease at high uptakes. Accordingly, the interaction energies between CH4 molecules and ZIF-10 remain nearly constant regardless of the loading due to the absence of hydrogen bonds (HBs), while the interaction energies between CO2 (or SO2) and ZIF-10 decease rapidly with the loading, especially at small amounts of gas molecules. Such different loading dependent diffusion and interaction mechanisms can be attributed to the relevant HB behavior between gas molecules and ZIF-10. At low loadings, both the number and strength of HBs between CO2 (or SO2) molecules and ZIF-10 decrease obviously as the loading increases, which is responsible for the slight increase of their diffusion coefficients. However, at high loadings, their HB strength increases with the loading. Similar loading-dependent phenomena of diffusion, interaction, and HB behavior can be observed for CH4, CO2, and SO2 binary mixtures in ZIF-10, only associated with some HB competition between CO2 and SO2 molecules in the case of the CO2/SO2 mixture. PMID- 28732451 TI - Dapsone and azole interactions: A clinical perspective. AB - An understanding of the clinical significance of dapsone-drug interactions is essential for optimal use of this agent. This review aims to provide clinicians with an overview of this topic. PMID- 28732448 TI - Synthesis of a Bicyclic Azetidine with In Vivo Antimalarial Activity Enabled by Stereospecific, Directed C(sp3)-H Arylation. AB - The development of new antimalarial therapeutics is necessary to address the increasing resistance to current drugs. Bicyclic azetidines targeting Plasmodium falciparum phenylalanyl-tRNA synthetase comprise one promising new class of antimalarials, especially due to their activities against three stages of the parasite's life cycle, but a lengthy synthetic route to these compounds may affect the feasibility of delivering new therapeutic agents within the cost constraints of antimalarial drugs. Here, we report an efficient synthesis of antimalarial compound BRD3914 (EC50 = 15 nM) that hinges on a Pd-catalyzed, directed C(sp3)-H arylation of azetidines at the C3 position. This newly developed protocol exhibits a broad substrate scope and provides access to valuable, stereochemically defined building blocks. BRD3914 was evaluated in P. falciparum-infected mice, providing a cure after four oral doses. PMID- 28732452 TI - Assessment of the potential impact of dose rounding parenteral chemotherapy agents on cost savings and drug waste minimization. AB - Background Fiscally responsible utilization of anticancer treatments is necessary to combat their continually increasing cost. Dose rounding is one strategy that has been explored to minimize cost and waste without losing clinical effectiveness. Objectives To determine if dose rounding chemotherapy agents is a feasible cost-containment strategy at an institution with a small oncology clinic. Methods This study is a retrospective chart review of all body surface area dosed parenteral chemotherapy prescribed for an oncological diagnosis over a 12-month period (1 October 2015-30 September 2016). Chemotherapy doses were rounded down by 5%. Doses for patients with metastatic diagnoses were also rounded down by 10%. Rounded doses were evaluated for a potential decrease in vial size. Cost was represented as dollar/milligram of drug. Potential for drug waste minimization was also calculated. Results There were 877 total doses of chemotherapy administered to 70 unique patients throughout the 12-month duration of the study. When doses were rounded down by 5%, 140 doses qualified for a decrease in vial number. The potential for cost savings was $22,849 with 83,802 mg saved from wastage. A 10% decrease resulted in the reduction of vials for 248 doses, a potential savings of $30,911 with 129,011 milligrams saved. The targeted agents accounted for the majority of savings, $16,920 of the $22,849 with 5% rounding and $20,086 of the $30,911 with 10% rounding. Conclusion Dose rounding has the potential to be an effective cost-containment strategy in low volume oncology clinics. PMID- 28732449 TI - Dependence of the Linker Histone and Chromatin Condensation on the Nucleosome Environment. AB - The linker histone (LH), an auxiliary protein that can bind to chromatin and interact with the linker DNA to form stem motifs, is a key element of chromatin compaction. By affecting the chromatin condensation level, it also plays an active role in gene expression. However, the presence and variable concentration of LH in chromatin fibers with different DNA linker lengths indicate that its folding and condensation are highly adaptable and dependent on the immediate nucleosome environment. Recent experimental studies revealed that the behavior of LH in mononucleosomes markedly differs from that in small nucleosome arrays, but the associated mechanism is unknown. Here we report a structural analysis of the behavior of LH in mononucleosomes and oligonucleosomes (2-6 nucleosomes) using mesoscale chromatin simulations. We show that the adapted stem configuration heavily depends on the strength of electrostatic interactions between LH and its parental DNA linkers, and that those interactions tend to be asymmetric in small oligonucleosome systems. Namely, LH in oligonucleosomes dominantly interacts with one DNA linker only, as opposed to mononucleosomes where LH has similar interactions with both linkers and forms a highly stable nucleosome stem. Although we show that the LH condensation depends sensitively on the electrostatic interactions with entering and exiting DNA linkers, other interactions, especially by nonparental cores and nonparental linkers, modulate the structural condensation by softening LH and thus making oligonucleosomes more flexible, in comparison to to mono- and dinucleosomes. We also find that the overall LH/chromatin interactions sensitively depend on the linker length because the linker length determines the maximal nucleosome stem length. For mononucleosomes with DNA linkers shorter than LH, LH condenses fully, while for DNA linkers comparable or longer than LH, the LH extension in mononucleosomes strongly follows the length of DNA linkers, unhampered by neighboring linker histones. Thus, LH is more condensed for mononucleosomes with short linkers, compared to oligonucleosomes, and its orientation is variable and highly environment-dependent. More generally, the work underscores the agility of LH whose folding dynamics critically controls genomic packaging and gene expression. PMID- 28732453 TI - Real-world chart review study of adverse events management in patients taking tyrosine kinase inhibitors to treat metastatic renal cell carcinoma. AB - PURPOSE: The purpose is to describe management of adverse events of special interest across tyrosine kinase inhibitors approved for metastatic renal cell carcinoma. METHODS: We conducted a retrospective chart review in metastatic renal cell carcinoma patients initiating tyrosine kinase inhibitor monotherapy between 15 November 2010 and 15 November 2013, and experiencing >= 1 adverse events of special interest (diarrhea, fatigue, hand-foot syndrome, hypertension, or stomatitis/mucositis) within 3 months of initiation. Demographics, medical history, treatment regimens, and adverse events of special interest management data for 3.5 months postonset were collected. RESULTS: In 220 charts from 27 centers, tyrosine kinase inhibitors prescribed included sunitinib (55%), pazopanib (27%), axitinib (9%), and sorafenib (8%). During the study period, patients experienced 376 adverse events of special interest (13% serious). Fatigue was most common (62% of patients), followed by hypertension (37%), diarrhea (30%), stomatitis/mucositis (29%), and hand-foot syndrome (12%). Over half (56%) the adverse events of special interest were resolved or resolving. Treatment discontinuation due to adverse events of special interest occurred in 15% of patients. Prophylaxis was rarely provided (8%), whereas 59% of patients received adverse events of special interest treatment (pharmacologic (55%) and/or nonpharmacologic (7%)), 27% received tyrosine kinase inhibitor dose management, 23% received both adverse events of special interest treatment and dose management, and 31% received neither. Hypertension was the most treated (72% of all events), and fatigue was the least treated (9%); only 4% of patients received pharmacologic treatment for fatigue. CONCLUSIONS: Most adverse events of special interest were nonserious and more than half of the patients received pharmacologic and/or nonpharmacologic treatment. Fatigue was the most common yet least frequently treated adverse event of special interest, and few patients received prophylaxis or nonpharmacologic treatment. More emphasis on treatment and prophylaxis options for bothersome adverse events is warranted. PMID- 28732454 TI - Leaching behaviour of municipal solid waste incineration bottom ash: From granular material to monolithic concrete. AB - The aim of this work was to assess the leaching behaviour of the bottom ash derived from municipal solid waste incineration (MSWI) used in concrete production. In particular, the release of pollutants was evaluated by the application of different leaching tests, both on granular materials and monolithic samples (concrete mixtures cast with bottom ash). The results confirmed that, according to Italian regulations, unwashed bottom ashes present critical issues for the use as alternative aggregates in the construction sector due to the excessive release of pollutants; instead, the leachate from washed bottom ashes was similar to natural aggregates. The concentration of pollutants in the leachate from concrete mixtures was lower than regulation limits for reuse. The crushing process significantly influenced the release of pollutants: this behaviour was due both to the increase in surface area and the release of contaminants from cement. Moreover, the increase in contact time (up to 64 days) involved more heavy metals to be released. PMID- 28732455 TI - Comparison of Births by Provider, Place, and Payer in New Hampshire. AB - This study examines maternity care in a rural state by birth attendant, place of birth, and payer of birth. It is a secondary analysis of birth certificate data in New Hampshire between the years 2005 and 2012. Results revealed that in New Hampshire, the majority of births occurred in the hospital setting (98.6%). Physicians attended 75.8% of births, certified nurse midwives attended 17%, and certified professional midwives attended 1%. Medicaid coverage was the payer source for 28% of all births, compared with 44.9% nationally. Women with a private payer source were more likely than women with Medicaid or other payer sources to have a cesarean section. The findings demonstrate quality of care outcomes among a range of clinicians and settings, providing a policy argument for expanding maternity care options. PMID- 28732456 TI - Introduced Rats and an Endemic Roundworm: Does Rattus rattus Contribute to Baylisascaris procyonis Transmission in California? AB - The introduced black rat, Rattus rattus, occurs throughout the native range of the raccoon roundworm, Baylisascaris procyonis, and might incorporate into its life cycle if rats consume parasite eggs, acquire viable infections, and are eaten by raccoons. Although rats forage at raccoon latrines, their role in B. procyonis transmission remains unknown. Here I tested the potential for rats to amplify B. procyonis transmission in California by surveying wild rodents for B. procyonis and conducting scavenger trials with the use of motion-activated cameras. Rattus rattus were infected with B. procyonis at intensities more than 100 times greater than that of co-occurring native Reithrodontomys megalotis and Peromyscus maniculatus. Rodent carcasses were scavenged by opossums, skunks, and raccoons, suggesting that these rodents, particularly R. rattus, contribute to B. procyonis transmission in this coastal California ecosystem. PMID- 28732457 TI - Long-term recurrence of venous thromboembolism after short-term treatment of symptomatic isolated distal deep vein thrombosis: A cohort study. AB - Isolated distal deep vein thrombosis (IDDVT) is a common clinical manifestation of venous thromboembolism (VTE). However, there are only scant and heterogeneous data available on the long-term risk of recurrent VTE after IDDVT, and the optimal therapeutic management remains uncertain. We carried out a retrospective cohort study of consecutive patients diagnosed with symptomatic IDDVT between 2004 and 2011, according to a predefined short-term treatment protocol (low molecular weight heparin (LMWH) for 4-6 weeks). The primary outcome was the occurrence of recurrent VTE. A total of 321 patients were enrolled. IDDVT was associated with a transient risk factor or cancer in 165 (51.4%) and 56 (17.4%) patients, respectively. LMWH was administered for 4-6 weeks to 280 patients (87.2%), who were included in the primary analysis. Overall, during a mean follow up of 42.3 months, 42 patients (15%) developed recurrent VTE, which occurred as proximal DVT or PE in 21 cases. The recurrence rate of VTE per 100 patient-years was 3.5 in patients with transient risk factors, 7.2 in patients with unprovoked IDDVT, and 5.9 in patients with cancer ( p=0.018). At multivariable analysis, unprovoked IDDVT and previous VTE were significantly associated with recurrent VTE (HR 2.16, 95% CI 1.12-4.16 and HR 1.97, 95% CI 1.01-3.86, respectively). In conclusion, the long-term risk of recurrent VTE after IDDVT treated for 4-6 weeks is not negligible, in particular in patients with unprovoked IDDVT or cancer. Further studies are needed to clarify whether a longer, but definite treatment duration effectively prevents these recurrences. PMID- 28732458 TI - Use of a complete autologous blood recovery system (the Sorin Xtra(r) Autotransfusion System) during mechanical thrombectomy of extensive cerebral venous sinus thrombosis. AB - Background The endovascular therapy for cerebral venous sinus thrombosis (CVST) is currently accepted as a second-line treatment for patients who have failed or those in whom systemic anticoagulation is contraindicated or in a subgroup of patients presenting with rapid neurologic deterioration. A number of different mechanical and pharmacologic endovascular strategies have been reported, either as separate or combined approaches. These new catheters and aspiration systems have a high power and vacuum capacity, which carries a risk of anemization of the patient and hypovolemic shock, being necessitating the transfusion of the patient. Material and methods Because of the problems that donor blood transfusion can bring, we describe the use of a Sorin Xtra(r) Autotransfusion System (ATS). This complete autologous blood recovery system was designed for use in procedures where medium- to high-volume blood loss occurs, such as major surgeries. We have adapted it to recover all the blood aspirated during the mechanical thrombectomy procedures of the dural cerebral venous sinuses, since they are procedures that can cause a significant loss of blood. One advantage to this is the patient receives his or her own blood instead of donor blood, so there is no risk of contracting outside diseases or transfusion reactions. Conclusions This technical note describes a novel and previously unpublished technical approach to CVST that can be immediately applied to clinical practice. It also raises awareness among the interventional neuroradiologist and anesthesiologist communities about novel, potentially lifesaving endovascular treatments in patients with extensive CVST. PMID- 28732459 TI - CRISPulator: a discrete simulation tool for pooled genetic screens. AB - BACKGROUND: The rapid adoption of CRISPR technology has enabled biomedical researchers to conduct CRISPR-based genetic screens in a pooled format. The quality of results from such screens is heavily dependent on the selection of optimal screen design parameters, which also affects cost and scalability. However, the cost and effort of implementing pooled screens prohibits experimental testing of a large number of parameters. RESULTS: We present CRISPulator, a Monte Carlo method-based computational tool that simulates the impact of screen parameters on the robustness of screen results, thereby enabling users to build intuition and insights that will inform their experimental strategy. CRISPulator enables the simulation of screens relying on either CRISPR interference (CRISPRi) or CRISPR nuclease (CRISPRn). Pooled screens based on cell growth/survival, as well as fluorescence-activated cell sorting according to fluorescent reporter phenotypes are supported. CRISPulator is freely available online ( http://crispulator.ucsf.edu ). CONCLUSIONS: CRISPulator facilitates the design of pooled genetic screens by enabling the exploration of a large space of experimental parameters in silico, rather than through costly experimental trial and error. We illustrate its power by deriving non-obvious rules for optimal screen design. PMID- 28732460 TI - Novel efficient genome-wide SNP panels for the conservation of the highly endangered Iberian lynx. AB - BACKGROUND: The Iberian lynx (Lynx pardinus) has been acknowledged as the most endangered felid species in the world. An intense contraction and fragmentation during the twentieth century left less than 100 individuals split in two isolated and genetically eroded populations by 2002. Genetic monitoring and management so far have been based on 36 STRs, but their limited variability and the more complex situation of current populations demand more efficient molecular markers. The recent characterization of the Iberian lynx genome identified more than 1.6 million SNPs, of which 1536 were selected and genotyped in an extended Iberian lynx sample. METHODS: We validated 1492 SNPs and analysed their heterozygosity, Hardy-Weinberg equilibrium, and linkage disequilibrium. We then selected a panel of 343 minimally linked autosomal SNPs from which we extracted subsets optimized for four different typical tasks in conservation applications: individual identification, parentage assignment, relatedness estimation, and admixture classification, and compared their power to currently used STR panels. RESULTS: We ascribed 21 SNPs to chromosome X based on their segregation patterns, and identified one additional marker that showed significant differentiation between sexes. For all applications considered, panels of autosomal SNPs showed higher power than the currently used STR set with only a very modest increase in the number of markers. CONCLUSIONS: These novel panels of highly informative genome wide SNPs provide more powerful, efficient, and flexible tools for the genetic management and non-invasive monitoring of Iberian lynx populations. This example highlights an important outcome of whole-genome studies in genetically threatened species. PMID- 28732461 TI - A deep convolutional neural network approach to single-particle recognition in cryo-electron microscopy. AB - BACKGROUND: Single-particle cryo-electron microscopy (cryo-EM) has become a mainstream tool for the structural determination of biological macromolecular complexes. However, high-resolution cryo-EM reconstruction often requires hundreds of thousands of single-particle images. Particle extraction from experimental micrographs thus can be laborious and presents a major practical bottleneck in cryo-EM structural determination. Existing computational methods for particle picking often use low-resolution templates for particle matching, making them susceptible to reference-dependent bias. It is critical to develop a highly efficient template-free method for the automatic recognition of particle images from cryo-EM micrographs. RESULTS: We developed a deep learning-based algorithmic framework, DeepEM, for single-particle recognition from noisy cryo-EM micrographs, enabling automated particle picking, selection and verification in an integrated fashion. The kernel of DeepEM is built upon a convolutional neural network (CNN) composed of eight layers, which can be recursively trained to be highly "knowledgeable". Our approach exhibits an improved performance and accuracy when tested on the standard KLH dataset. Application of DeepEM to several challenging experimental cryo-EM datasets demonstrated its ability to avoid the selection of un-wanted particles and non-particles even when true particles contain fewer features. CONCLUSIONS: The DeepEM methodology, derived from a deep CNN, allows automated particle extraction from raw cryo-EM micrographs in the absence of a template. It demonstrates an improved performance, objectivity and accuracy. Application of this novel method is expected to free the labor involved in single-particle verification, significantly improving the efficiency of cryo-EM data processing. PMID- 28732462 TI - Exploring general-purpose protein features for distinguishing enzymes and non enzymes within the twilight zone. PMID- 28732464 TI - Erratum to: Positive selection neighboring functionally essential sites and disease-implicated regions of mammalian reproductive proteins. PMID- 28732463 TI - Common and phylogenetically widespread coding for peptides by bacterial small RNAs. AB - BACKGROUND: While eukaryotic noncoding RNAs have recently received intense scrutiny, it is becoming clear that bacterial transcription is at least as pervasive. Bacterial small RNAs and antisense RNAs (sRNAs) are often assumed to be noncoding, due to their lack of long open reading frames (ORFs). However, there are numerous examples of sRNAs encoding for small proteins, whether or not they also have a regulatory role at the RNA level. METHODS: Here, we apply flexible machine learning techniques based on sequence features and comparative genomics to quantify the prevalence of sRNA ORFs under natural selection to maintain protein-coding function in 14 phylogenetically diverse bacteria. Importantly, we quantify uncertainty in our predictions, and follow up on them using mass spectrometry proteomics and comparison to datasets including ribosome profiling. RESULTS: A majority of annotated sRNAs have at least one ORF between 10 and 50 amino acids long, and we conservatively predict that 409+/-191.7 unannotated sRNA ORFs are under selection to maintain coding (mean estimate and 95% confidence interval), an average of 29 per species considered here. This implies that overall at least 10.3+/-0.5% of sRNAs have a coding ORF, and in some species around 20% do. 165+/-69 of these novel coding ORFs have some antisense overlap to annotated ORFs. As experimental validation, many of our predictions are translated in published ribosome profiling data and are identified via mass spectrometry shotgun proteomics. B. subtilis sRNAs with coding ORFs are enriched for high expression in biofilms and confluent growth, and S. pneumoniae sRNAs with coding ORFs are involved in virulence. sRNA coding ORFs are enriched for transmembrane domains and many are predicted novel components of type I toxin/antitoxin systems. CONCLUSIONS: We predict over two dozen new protein coding genes per bacterial species, but crucially also quantified the uncertainty in this estimate. Our predictions for sRNA coding ORFs, along with predicted novel type I toxins and tools for sorting and visualizing genomic context, are freely available in a user-friendly format at http://disco-bac.web.pasteur.fr. We expect these easily-accessible predictions to be a valuable tool for the study not only of bacterial sRNAs and type I toxin-antitoxin systems, but also of bacterial genetics and genomics. PMID- 28732466 TI - Estimation of linkage disequilibrium and effective population size in New Zealand sheep using three different methods to create genetic maps. AB - BACKGROUND: Investments in genetic selection have played a major role in the New Zealand sheep industry competitiveness. Selection may erode genetic diversity, which is a crucial factor for the success of breeding programs. Better understanding of linkage disequilibrium (LD) and ancestral effective population size (Ne) through quantifying this diversity and comparison between populations allows for more informed decisions with regards to selective breeding taking population genetic diversity into account. The estimation of N e can be determined via genetic markers and requires knowledge of genetic distances between these markers. Single nucleotide polymorphisms (SNP) data from a sample of 12,597 New Zealand crossbred and purebred sheep genotyped with the Illumina Ovine SNP50 BeadChip was used to perform a genome-wide scan of LD and N e . Three methods to estimate genetic distances were investigated: 1) M1: a ratio fixed across the whole genome of one Megabase per centiMorgan; 2) M2: the ratios of genetic distance (using M3, below) over physical distance fixed for each chromosome; and, 3) M3: a genetic map of inter-SNP distances estimated using CRIMAP software (v2.503). RESULTS: The estimates obtained with M2 and M3 showed much less variability between autosomes than those with M1, which tended to give lower N e results and higher LD decay. The results suggest that N e has decreased since the development of sheep breeds in Europe and this reduction in Ne has been accelerated in the last three decades. The N e estimated for five generations in the past ranged from 71 to 237 for Texel and Romney breeds, respectively. A low level of genetic kinship and inbreeding was estimated in those breeds suggesting avoidance of mating close relatives. CONCLUSIONS: M3 was considered the most accurate method to create genetic maps for the estimation of LD and Ne. The findings of this study highlight the history of genetic selection in New Zealand crossbred and purebred sheep and these results will be very useful to understand genetic diversity of the population with respect to genetic selection. In addition, it will help geneticists to identify genomic regions which have been preferentially selected within a variety of breeds and populations. PMID- 28732465 TI - Genome-wide signals of positive selection in strongylocentrotid sea urchins. AB - BACKGROUND: Comparative genomics studies investigating the signals of positive selection among groups of closely related species are still rare and limited in taxonomic breadth. Such studies show great promise in advancing our knowledge about the proportion and the identity of genes experiencing diversifying selection. However, methodological challenges have led to high levels of false positives in past studies. Here, we use the well-annotated genome of the purple sea urchin, Strongylocentrotus purpuratus, as a reference to investigate the signals of positive selection at 6520 single-copy orthologs from nine sea urchin species belonging to the family Strongylocentrotidae paying careful attention to minimizing false positives. RESULTS: We identified 1008 (15.5%) candidate positive selection genes (PSGs). Tests for positive selection along the nine terminal branches of the phylogeny identified 824 genes that showed lineage specific adaptive diversification (1.67% of branch-sites tests performed). Positively selected codons were not enriched at exon borders or near regions containing missing data, suggesting a limited contribution of false positives caused by alignment or annotation errors. Alignments were validated at 10 loci with re-sequencing using Sanger methods. No differences were observed in the rates of synonymous substitution (d S), GC content, and codon bias between the candidate PSGs and those not showing positive selection. However, the candidate PSGs had 68% higher rates of nonsynonymous substitution (d N) and 33% lower levels of heterozygosity, consistent with selective sweeps and opposite to that expected by a relaxation of selective constraint. Although positive selection was identified at reproductive proteins and innate immunity genes, the strongest signals of adaptive diversification were observed at extracellular matrix proteins, cell adhesion molecules, membrane receptors, and ion channels. Many candidate PSGs have been widely implicated as targets of pathogen binding, inactivation, mimicry, or exploitation in other groups (notably mammals). CONCLUSIONS: Our study confirmed the widespread action of positive selection across sea urchin genomes and allowed us to reject the possibility that annotation and alignment errors (including paralogs) were responsible for creating false signals of adaptive molecular divergence. The candidate PSGs identified in our study represent promising targets for future research into the selective agents responsible for their adaptive diversification and their contribution to speciation. PMID- 28732468 TI - NoGOA: predicting noisy GO annotations using evidences and sparse representation. AB - BACKGROUND: Gene Ontology (GO) is a community effort to represent functional features of gene products. GO annotations (GOA) provide functional associations between GO terms and gene products. Due to resources limitation, only a small portion of annotations are manually checked by curators, and the others are electronically inferred. Although quality control techniques have been applied to ensure the quality of annotations, the community consistently report that there are still considerable noisy (or incorrect) annotations. Given the wide application of annotations, however, how to identify noisy annotations is an important but yet seldom studied open problem. RESULTS: We introduce a novel approach called NoGOA to predict noisy annotations. NoGOA applies sparse representation on the gene-term association matrix to reduce the impact of noisy annotations, and takes advantage of sparse representation coefficients to measure the semantic similarity between genes. Secondly, it preliminarily predicts noisy annotations of a gene based on aggregated votes from semantic neighborhood genes of that gene. Next, NoGOA estimates the ratio of noisy annotations for each evidence code based on direct annotations in GOA files archived on different periods, and then weights entries of the association matrix via estimated ratios and propagates weights to ancestors of direct annotations using GO hierarchy. Finally, it integrates evidence-weighted association matrix and aggregated votes to predict noisy annotations. Experiments on archived GOA files of six model species (H. sapiens, A. thaliana, S. cerevisiae, G. gallus, B. Taurus and M. musculus) demonstrate that NoGOA achieves significantly better results than other related methods and removing noisy annotations improves the performance of gene function prediction. CONCLUSIONS: The comparative study justifies the effectiveness of integrating evidence codes with sparse representation for predicting noisy GO annotations. Codes and datasets are available at http://mlda.swu.edu.cn/codes.php?name=NoGOA . PMID- 28732467 TI - Minimal tool set for a prokaryotic circadian clock. AB - BACKGROUND: Circadian clocks are found in organisms of almost all domains including photosynthetic Cyanobacteria, whereby large diversity exists within the protein components involved. In the model cyanobacterium Synechococcus elongatus PCC 7942 circadian rhythms are driven by a unique KaiABC protein clock, which is embedded in a network of input and output factors. Homologous proteins to the KaiABC clock have been observed in Bacteria and Archaea, where evidence for circadian behavior in these domains is accumulating. However, interaction and function of non-cyanobacterial Kai-proteins as well as homologous input and output components remain mainly unclear. RESULTS: Using a universal BLAST analyses, we identified putative KaiC-based timing systems in organisms outside as well as variations within Cyanobacteria. A systematic analyses of publicly available microarray data elucidated interesting variations in circadian gene expression between different cyanobacterial strains, which might be correlated to the diversity of genome encoded clock components. Based on statistical analyses of co-occurrences of the clock components homologous to Synechococcus elongatus PCC 7942, we propose putative networks of reduced and fully functional clock systems. Further, we studied KaiC sequence conservation to determine functionally important regions of diverged KaiC homologs. Biochemical characterization of exemplary cyanobacterial KaiC proteins as well as homologs from two thermophilic Archaea demonstrated that kinase activity is always present. However, a KaiA mediated phosphorylation is only detectable in KaiC1 orthologs. CONCLUSION: Our analysis of 11,264 genomes clearly demonstrates that components of the Synechococcus elongatus PCC 7942 circadian clock are present in Bacteria and Archaea. However, all components are less abundant in other organisms than Cyanobacteria and KaiA, Pex, LdpA, and CdpA are only present in the latter. Thus, only reduced KaiBC-based or even simpler, solely KaiC-based timing systems might exist outside of the cyanobacterial phylum, which might be capable of driving diurnal oscillations. PMID- 28732469 TI - Microsatellite marker development by partial sequencing of the sour passion fruit genome (Passiflora edulis Sims). AB - BACKGROUND: The Passiflora genus comprises hundreds of wild and cultivated species of passion fruit used for food, industrial, ornamental and medicinal purposes. Efforts to develop genomic tools for genetic analysis of P. edulis, the most important commercial Passiflora species, are still incipient. In spite of many recognized applications of microsatellite markers in genetics and breeding, their availability for passion fruit research remains restricted. Microsatellite markers in P. edulis are usually limited in number, show reduced polymorphism, and are mostly based on compound or imperfect repeats. Furthermore, they are confined to only a few Passiflora species. We describe the use of NGS technology to partially assemble the P. edulis genome in order to develop hundreds of new microsatellite markers. RESULTS: A total of 14.11 Gbp of Illumina paired-end sequence reads were analyzed to detect simple sequence repeat sites in the sour passion fruit genome. A sample of 1300 contigs containing perfect repeat microsatellite sequences was selected for PCR primer development. Panels of di- and tri-nucleotide repeat markers were then tested in P. edulis germplasm accessions for validation. DNA polymorphism was detected in 74% of the markers (PIC = 0.16 to 0.77; number of alleles/locus = 2 to 7). A core panel of highly polymorphic markers (PIC = 0.46 to 0.77) was used to cross-amplify PCR products in 79 species of Passiflora (including P. edulis), belonging to four subgenera (Astrophea, Decaloba, Distephana and Passiflora). Approximately 71% of the marker/species combinations resulted in positive amplicons in all species tested. DNA polymorphism was detected in germplasm accessions of six closely related Passiflora species (P. edulis, P. alata, P. maliformis, P. nitida, P. quadrangularis and P. setacea) and the data used for accession discrimination and species assignment. CONCLUSION: A database of P. edulis DNA sequences obtained by NGS technology was examined to identify microsatellite repeats in the sour passion fruit genome. Markers were submitted to evaluation using accessions of cultivated and wild Passiflora species. The new microsatellite markers detected high levels of DNA polymorphism in sour passion fruit and can potentially be used in genetic analysis of P. edulis and other Passiflora species. PMID- 28732470 TI - Erratum to: Comparative transcriptome analyses on silk glands of six silkmoths imply the genetic basis of silk structure and coloration. PMID- 28732471 TI - Gene expression patterns of chicken neuregulin 3 in association with copy number variation and frameshift deletion. AB - BACKGROUND: Neuregulin 3 (NRG3) plays a key role in central nervous system development and is a strong candidate for human mental disorders. Thus, genetic variation in NRG3 may have some impact on a variety of phenotypes in non mammalian vertebrates. Recently, genome-wide screening for short insertions and deletions in chicken (Gallus gallus) genomes has provided useful information about structural variation in functionally important genes. NRG3 is one such gene that has a putative frameshift deletion in exon 2, resulting in premature termination of translation. Our aims were to characterize the structure of chicken NRG3 and to compare expression patterns between NRG3 isoforms. RESULTS: Depending on the presence or absence of the 2-bp deletion in chicken NRG3, 3 breeds (red junglefowl [RJF], Boris Brown [BB], and Hinai-jidori [HJ]) were genotyped using flanking primers. In the commercial breeds (BB and HJ), approximately 45% of individuals had at least one exon 2 allele with the 2-bp deletion, whereas there was no deletion allele in RJF. The lack of a homozygous mutant indicated the existence of duplicated NRG3 segments in the chicken genome. Indeed, highly conserved elements consisting of exon 1, intron 1, exon 2, and part of intron 2 were found in the reference RJF genome, and quantitative PCR detected copy number variation (CNV) between breeds as well as between individuals. The copy number of conserved elements was significantly higher in chicks harboring the 2-bp deletion in exon 2. We identified 7 novel transcript variants using total mRNA isolated from the amygdala. Novel isoforms were found to lack the exon 2 cassette, which probably harbored the premature termination codon. The relative transcription levels of the newly identified isoforms were almost the same between chick groups with and without the 2-bp deletion, while chicks with the deletion showed significant suppression of the expression of previously reported isoforms. CONCLUSIONS: A putative frameshift deletion and CNV in chicken NRG3 are structural mutations that occurred before the establishment of commercial chicken lines. Our results further suggest that the putative frameshift deletion in exon 2 may potentially affect the expression level of particular isoforms of chicken NRG3. PMID- 28732472 TI - GeneXpert HIV-1 quant assay, a new tool for scale up of viral load monitoring in the success of ART programme in India. AB - BACKGROUND: Recent WHO guidelines identify virologic monitoring for diagnosing and confirming ART failure. In view of this, validation and scale up of point of care viral load technologies is essential in resource limited settings. METHODS: A systematic validation of the GeneXpert(r) HIV-1 Quant assay (a point-of-care technology) in view of scaling up HIV-1 viral load in India to monitor the success of national ART programme was carried out. Two hundred nineteen plasma specimens falling in nine viral load ranges (<40 to >5 L copies/ml) were tested by the Abbott m2000rt Real Time and GeneXpert HIV-1 Quant assays. Additionally, 20 seronegative; 16 stored specimens and 10 spiked controls were also tested. Statistical analysis was done using Stata/IC and sensitivity, specificity, PPV, NPV and %misclassification rates were calculated as per DHSs/AISs, WHO, NACO cut offs for virological failure. RESULTS: The GeneXpert assay compared well with the Abbott assay with a higher sensitivity (97%), specificity (97-100%) and concordance (91.32%). The correlation between two assays (r = 0.886) was statistically significant (p < 0.01), the linear regression showed a moderate fit (R2 = 0.784) and differences were within limits of agreement. Reproducibility showed an average variation of 4.15 and 3.52% while Lower limit of detection (LLD) and Upper limit of detection (ULD) were 42 and 1,740,000 copies/ml respectively. The misclassification rates for three viral load cut offs were not statistically different (p = 0.736). All seronegative samples were negative and viral loads of the stored samples showed a good fit (R2 = 0.896 to 0.982). CONCLUSION: The viral load results of GeneXpert HIV-1 Quant assay compared well with Abbott HIV-1 m2000 Real Time PCR; suggesting its use as a Point of care assay for viral load estimation in resource limited settings. Its ease of performance and rapidity will aid in timely diagnosis of ART failures, integrated HIV-TB management and will facilitate the UNAIDS 90-90-90 target. PMID- 28732473 TI - Patterns of instrumental activities of daily living and association with predictors among community-dwelling older women: A latent class analysis. AB - BACKGROUND: The purpose of this study was to classify patterns of instrumental activities of daily living (IADL) among community-dwelling older women, to examine difference in characteristics among the classes, and to explore predictors of class membership. METHODS: This study was a secondary analysis of nationwide data from the 2014 Actual Living Condition of the Elderly and Welfare Need Survey. A total of 10,451 individuals aged 65 years or older were interviewed for the 2014 dataset, but we only selected the female participants (n = 6095) for this study. For statistical analyses, latent class analysis was applied to identify different latent classes of IADL and then the effects of predictors on IADL patterns were analyzed by using multinomial logistic regression. RESULTS: The 5-class model was the best fit for the data. The size of class 1was the biggest (n = 5093, 83.6%), followed by class 5 (n = 401, 6.6%), class 3 (n = 308, 5.1%), class 2 (n = 181, 3.0%), and class 4 (n = 113, 1.8%). The largest class had total independency on all items of IADL. In the multinomial regression, members in the classes 2, 3, 4 and 5 were significantly more likely to have older age and decreased cognitive status compared with the class of total independency on all items of IADL (class1). CONCLUSIONS: The predictors of the classes identified in this study can be used for tailored and targeted interventions to increased old adults' independency on IADL. PMID- 28732474 TI - Clinical and epidemiological characteristics of pyogenic liver abscess in people 65 years or older versus people under 65: a retrospective study. AB - BACKGROUND: To analyse the clinical, epidemiological, microbiological and prognostic differences of pyogenic liver abscess (PLA) in older (>= 65 years of age) versus younger patients (< 65 years). METHODS: Multicentre, retrospective cohort study in all patients with PLA admitted to two Spanish hospitals from January 2000 to January 2014. Cases were divided into two age groups (< 65 years and >=65 years) for comparison of clinical, epidemiological and microbiological characteristics as well as treatment. RESULTS: Of 98 patients analysed, 40 patients were younger than 65, and 58 were aged 65 or older. Significant associations in the older group were found with female sex (adjusted odds ratio [ORa] 9.0; 95% CI 1.4, 56), non-cryptogenic origin (ORa 14.5; 95% CI 1.6, 129), absence of chronic liver disease (ORa 14; 95% CI 1.3, 155), Escherichia coli infection (ORa 7.7; 95% CI 1.03, 58), and incidence of complications (ORa 2.3; 95% CI 1.04, 5.4). Mortality was 8.2% overall, although all deaths occurred in the older group (8/58; 13.8%) (p = 0.02). DISCUSSION: Our results are in consonance with other published studies. Older patients with PLA tend to present more anomalies in the biliary tract (Kai et. al, World J Gastroenterol 18: 2948 295, 2012, Rahimian et. al, Clin Infect Dis 39:1654-9, 2004, Seeto, Medicine (Baltimore) 75:99-113, 1996, Kao et.al, Aliment Pharmacol Ther 36:467-76, 2012, Lai et. al, Gastroenterology 146:129-37, 2014), while younger patients are more often male and present more commonly with previous liver disease (especially related to alcohol) and cryptogenic PLA. CONCLUSION: In patients aged 65 or older, PLA was more common in women and in those with a history of biliary disease, and E. coli was the most frequent bacterium. Mortality was also higher in the older group. PMID- 28732475 TI - Associations between childhood overweight, obesity, abdominal obesity and obesogenic behaviors and practices in Australian homes. AB - BACKGROUND: Despite emerging research about the role of the family and home environment on early childhood obesity, little is known on how weight-related behaviors, parent practices and the home environment influence overweight/obesity in older children and adolescents. METHODS: This analysis used data from a cross sectional, representative population survey of Australian children age 5-16 years conducted in 2015. Data included measured anthropometry to calculate body mass index (BMI; kg/m2) and waist-to-height ratio (WHtR; waist circumference/height). Information on home-based weight-related behaviors (individual eating and screen time behaviors, parent influences including rules and home environment factors) were measured using established short questions, with parental proxy reporting for children in up to grade 4, and self-report for students in grades 6, 8 and 10. Logistic regression models were used to examine associations between weight status and home-based weight-related behaviors. RESULTS: Both children and adolescents who did not consume breakfast daily were more likely to be overweight/obese OR (95% CI) = 1.39 (1.07-1.81) p = 0.015, OR (95% CI) =1.42 (1.16-1.74) p = 0.001, respectively, adjusted for age, gender, socio-economic status, rural/urban residence and physical activity. There was also a significant positive association with higher waist-to-height ratio in both children and adolescents. Among children, having a TV in the bedroom was also associated with overweight and obesity OR (95% CI) = 1.54 (1.13-2.09) p = 0.006 and higher waist to-height ratio. For adolescents, parenting practices such as having no rules on screen-time, OR (95% CI) = 1.29 (1.07-1.55) p = 0.008, and rewarding good behavior with sweets, OR (95% CI) = 2.18 (1.05-4.52) p = 0.036, were significant factors associated with overweight and obesity. The prevalence of these obesogenic behaviors were higher in certain sub-groups of children and adolescents, specifically those from social disadvantage and non-English-speaking backgrounds. CONCLUSIONS: Interventions to reduce the prevalence of obesity and overweight should include promoting daily breakfast, reducing screen-time, and encouraging health-promoting parenting practices. Interventions should particularly focus on those at some social disadvantage and from non-English speaking backgrounds. PMID- 28732476 TI - Evaluation of creatine kinase and liver enzymes in identification of severe dengue. AB - BACKGROUND: Existing biomarkers such as AST, ALT and hematocrit have been associated with severe dengue but evidence are mixed. Recently, interests in creatine kinase as a dengue biomarker have risen. These biomarkers represent several underlying pathophysiological processes in dengue. Hence, we aimed to assess AST, ALT, CK and hematocrit in identification of severe dengue and to assess the correlational relationship amongst common biomarkers of dengue. METHODS: This was a retrospective cohort study of confirmed dengue patients who were warded in Kuala Lumpur Hospital between December 2014 and January 2015. CK, AST, ALT, hematocrit, platelet count, WBC and serum albumin were taken upon ward admission and repeated at timed intervals. Composite indices based on admission AST and ALT were analyzed. Correlation coefficients and coefficients of determination were computed. RESULTS: Among the 365 cases reviewed, twenty-two (6%) patients had severe dengue. AST and ALT were found to be good at identification of severe dengue. The AST2/ALT composite index was the most accurate (AUC 0.83; 95% CI 0.73 - 0.93). Optimal cutoff was 402 with a sensitivity of 59.1% (95% CI: 36.4 - 79.3%) and specificity of 92.4% (95% CI: 89.1 - 95.0%). Modified cutoff of 653 had a sensitivity of 40.9% (95% CI: 20.7 - 63.7%) and specificity of 97.4% (95% CI: 95.1 - 98.8%). Our analyses also suggested that several underlying biological processes represented by biomarkers tested were unrelated despite occurring in the same disease entity. Also, markers of plasma leakage were discordant and AST was likely hepatic in origin. CONCLUSIONS: The composite index AST2/ALT may be used as a marker for identification of severe dengue based on admission AST and ALT, with two choices of cutoff values, 402 and 653. AST is most likely of liver origin and CK does not provide additional value. PMID- 28732477 TI - A web-based clinical decision tool to support treatment decision-making in psychiatry: a pilot focus group study with clinicians, patients and carers. AB - BACKGROUND: Treatment decision tools have been developed in many fields of medicine, including psychiatry, however benefits for patients have not been sustained once the support is withdrawn. We have developed a web-based computerised clinical decision support tool (CDST), which can provide patients and clinicians with continuous, up-to-date, personalised information about the efficacy and tolerability of competing interventions. To test the feasibility and acceptability of the CDST we conducted a focus group study, aimed to explore the views of clinicians, patients and carers. METHODS: The CDST was developed in Oxford. To tailor treatments at an individual level, the CDST combines the best available evidence from the scientific literature with patient preferences and values, and with patient medical profile to generate personalised clinical recommendations. We conducted three focus groups comprising of three different participant types: consultant psychiatrists, participants with a mental health diagnosis and/or experience of caring for someone with a mental health diagnosis, and primary care practitioners and nurses. Each 1-h focus group started with a short visual demonstration of the CDST. To standardise the discussion during the focus groups, we used the same topic guide that covered themes relating to the acceptability and usability of the CDST. Focus groups were recorded and any identifying participant details were anonymised. Data were analysed thematically and managed using the Framework method and the constant comparative method. RESULTS: The focus groups took place in Oxford between October 2016 and January 2017. Overall 31 participants attended (12 consultants, 11 primary care practitioners and 8 patients or carers). The main themes that emerged related to CDST applications in clinical practice, communication, conflicting priorities, record keeping and data management. CDST was considered a useful clinical decision support, with recognised value in promoting clinician-patient collaboration and contributing to the development of personalised medicine. One major benefit of the CDST was perceived to be the open discussion about the possible side-effects of medications. Participants from all the three groups, however, universally commented that the terminology and language presented on the CDST were too medicalised, potentially leading to ethical issues around consent to treatment. CONCLUSIONS: The CDST can improve communication pathways between patients, carers and clinicians, identifying care priorities and providing an up to-date platform for implementing evidence-based practice, with regard to prescribing practices. PMID- 28732478 TI - Comparative assessment of clinical rating scales in Wilson's disease. AB - BACKGROUND: Wilson's disease (WD) is an autosomal recessive disorder of copper metabolism resulting in multifaceted neurological, hepatic, and psychiatric symptoms. The objective of the study was to comparatively assess two clinical rating scales for WD, the Unified Wilson's Disease Rating Scale (UWDRS) and the Global Assessment Scale for Wilson's disease (GAS for WD), and to test the feasibility of the patient reported part of the UWDRS neurological subscale (termed the "minimal UWDRS"). METHODS: In this prospective, monocentric, cross sectional study, 65 patients (median age 35 [range: 15-62] years; 33 female, 32 male) with treated WD were scored according to the two rating scales. RESULTS: The UWDRS neurological subscore correlated with the GAS for WD Tier 2 score (r = 0.80; p < 0.001). Correlations of the UWDRS hepatic subscore and the GAS for WD Tier 1 score with both the Model for End Stage Liver Disease (MELD) score (r = 0.44/r = 0.28; p < 0.001/p = 0.027) and the Child-Pugh score (r = 0.32/r = 0.12; p = 0.015/p = 0.376) were weak. The "minimal UWDRS" score significantly correlated with the UWDRS total score (r = 0.86), the UWDRS neurological subscore (r = 0.89), and the GAS for WD Tier 2 score (r = 0.86). CONCLUSIONS: The UWDRS neurological and psychiatric subscales and the GAS for WD Tier 2 score are valuable tools for the clinical assessment of WD patients. The "minimal UWDRS" is a practical prescreening tool outside scientific trials. PMID- 28732479 TI - An integrated computational-experimental approach reveals Yersinia pestis genes essential across a narrow or a broad range of environmental conditions. AB - BACKGROUND: The World Health Organization has categorized plague as a re-emerging disease and the potential for Yersinia pestis to also be used as a bioweapon makes the identification of new drug targets against this pathogen a priority. Environmental temperature is a key signal which regulates virulence of the bacterium. The bacterium normally grows outside the human host at 28 degrees C. Therefore, understanding the mechanisms that the bacterium used to adapt to a mammalian host at 37 degrees C is central to the development of vaccines or drugs for the prevention or treatment of human disease. RESULTS: Using a library of over 1 million Y. pestis CO92 random mutants and transposon-directed insertion site sequencing, we identified 530 essential genes when the bacteria were cultured at 28 degrees C. When the library of mutants was subsequently cultured at 37 degrees C we identified 19 genes that were essential at 37 degrees C but not at 28 degrees C, including genes which encode proteins that play a role in enabling functioning of the type III secretion and in DNA replication and maintenance. Using genome-scale metabolic network reconstruction we showed that growth conditions profoundly influence the physiology of the bacterium, and by combining computational and experimental approaches we were able to identify 54 genes that are essential under a broad range of conditions. CONCLUSIONS: Using an integrated computational-experimental approach we identify genes which are required for growth at 37 degrees C and under a broad range of environments may be the best targets for the development of new interventions to prevent or treat plague in humans. PMID- 28732480 TI - Metformin and longevity (METAL): a window of opportunity study investigating the biological effects of metformin in localised prostate cancer. AB - BACKGROUND: Metformin is a biguanide oral hypoglycaemic agent commonly used for the treatment of type 2 diabetes mellitus. In addition to its anti-diabetic effect, metformin has also been associated with a reduced risk of cancer incidence of a number of solid tumours, including prostate cancer (PCa). However, the underlying biological mechanisms for these observations have not been fully characterised in PCa. One hypothesis is that the indirect insulin lowering effect may have an anti-neoplastic action as elevated insulin and insulin like growth factor - 1 (IGF-1) levels play a role in PCa development and progression. In addition, metformin is a potent activator of activated protein kinase (AMPK) which in turn inhibits the mammalian target of rapamycin (mTOR) and other signal transduction mechanisms. These direct effects can lead to reduced cell proliferation. Given its wide availability and tolerable side effect profile, metformin represents an attractive potential therapeutic option for men with PCa. Hence, the need for a clinical trial investigating its biological mechanisms in PCa. METHODS: METAL is a randomised, placebo-controlled, double-blind, window of opportunity study investigating the biological mechanism of metformin in PCa. 100 patients with newly-diagnosed, localised PCa scheduled for radical prostatectomy will be randomised 1:1 to receive metformin (1 g b.d.) or placebo for four weeks (+/- 1 week) prior to prostatectomy. Tissue will be collected from both diagnostic biopsy and prostatectomy specimens. The primary endpoint is the difference in expression levels of markers of the Fatty acid synthase (FASN)/AMPK pathway pre and post treatment between the placebo and metformin arms. Secondary endpoints include the difference in expression levels of indicators of proliferation (ki67 and TUNEL) pre and post treatment between the placebo and metformin arms. METAL is currently open to recruitment at Guy's and St Thomas' Hospital and the Royal Marsden Hospital, London. DISCUSSION: This randomised placebo-controlled double blinded trial of metformin vs. placebo in men with localised PCa due to undergo radical prostatectomy, aims to elucidate the mechanism of action of metformin in PCa cells, which should then enable further larger stratification trials to take place. TRIAL REGISTRATION: EudraCT number 2014-005193-11 . Registered on September 09, 2015. PMID- 28732481 TI - Central and peripheral fatigue development in the shoulder muscle with obesity during an isometric endurance task. AB - BACKGROUND: Fatigue increases the likelihood of developing work-related musculoskeletal disorders and injury. Due to the physiological and neuromuscular changes that accompany obesity, it may alter the fatigue development mechanism and exacerbate injury risk. The upper extremities have the highest incidence rates for work-related musculoskeletal disorders. Therefore, the goals of this study were to investigate the effect of obesity on central vs. peripheral fatigue as well as on the physical signs of fatigue on the middle deltoid muscle. METHODS: A measure of central activation ratio was used to quantify central fatigue by considering the increment in the torque output by superimposed twitch relative to its corresponding maximum voluntary contraction. For this purpose, electrical stimulation was delivered at the middle deltoid muscles of 22 non obese (18 < body mass index (BMI) < 25 kg/m2) and 17 obese (30 < BMI < 40 kg/m2) individuals aged 18-32 years old. Participants completed superimposed maximum voluntary isometric contractions of shoulder abduction before and after a sustained isometric fatiguing task at either 30 or 60% of the muscle capacity. Differences in endurance time, torque fluctuation, torque loss, and muscle activity measured by an electromyography sensor were also investigated. RESULTS: A greater reduction of voluntary activation of motor units (p = 0.001) with fatigue was observed for individuals who are obese. Contrary to the effect of obesity on central fatigue, a trend toward reduced peripheral fatigue (p = 0.06) was observed for the obese group compared to the non-obese group. On average, a 14% higher rate of torque loss per second was observed among individuals with obesity in comparison to non-obese participants. CONCLUSIONS: The observed greater contribution of central fatigue during the sustained endurance tasks suggests that among young healthy obese individuals, the faster fatigue development with obesity, commonly reported in the literature, is most likely due to the central elements rather than the peripheral factors. This finding has implications for fatigue prevention programs during sustained exertions and can help to develop training, work, and rest schedules considering obesity. PMID- 28732482 TI - Treatment outcomes in schizophrenia: qualitative study of the views of family carers. AB - BACKGROUND: Schizophrenia is a complex, heterogeneous disorder, with highly variable treatment outcomes, and relatively little is known about what is important to patients. The aim of the study was to understand treatment outcomes informal carers perceive to be important to people with schizophrenia. METHOD: Qualitative interview study with 34 individuals and 8 couples who care for a person with schizophrenia/schizoaffective disorder. Interviews were transcribed verbatim and analysed by a thematic framework based approach. RESULTS: Carers described well-recognised outcomes of importance, alongside more novel outcomes relating to: Safety (of the patient/others); insight (e.g. into non-reality of psychotic phenomena); respite from fear, distress or pain; socially acceptable behaviour; getting out of the house; attainment of life milestones; changes in personality and/or temperament; reduction of vulnerability to stress; and several aspects of physical health. CONCLUSIONS: These findings have the potential to inform the development of patient- or carer- focused outcome measures that take into account the full range of domains that carers feel are important for patients. PMID- 28732483 TI - Effects of dual-task and walking speed on gait variability in people with chronic ankle instability: a cross-sectional study. AB - BACKGROUND: Recent evidence suggests that impaired central sensorimotor integration may contribute to deficits in movement control experienced by people with chronic ankle instability (CAI). This study compared the effects of dual task and walking speed on gait variability in individuals with and without CAI. METHODS: Sixteen subjects with CAI and 16 age- and gender-matched, able-bodied controls participated in this study. Stride time variability and stride length variability were measured on a treadmill under four different conditions: self paced walking, self-paced walking with dual-task, fast walking, and fast walking with dual-task. RESULTS: Under self-paced walking (without dual-task) there was no difference in stride time variability between CAI and control groups (P = 0.346). In the control group, compared to self-paced walking, stride time variability decreased in all conditions: self-paced walking with dual-task, fast speed, and fast speed with dual-task (P = 0.011, P = 0.016, P = 0.001, respectively). However, in the CAI group, compared to self-paced walking, decreased stride time variability was demonstrated only in the fast speed with dual-task condition (P = 1.000, P = 0.471, P = 0.008; respectively). Stride length variability did not change under any condition in either group. CONCLUSIONS: Subjects with CAI and healthy controls reduced their stride time variability in response to challenging walking conditions; however, the pattern of change was different. A higher level of gait disturbance was required to cause a change in walking in the CAI group compared to healthy individuals, which may indicate lower adaptability of the sensorimotor system. Clinicians may use this information and employ activities to enhance sensorimotor control during gait, when designing intervention programs for people with CAI. The study was registered with the Clinical Trials network (registration NCT02745834, registration date 15/3/2016). PMID- 28732484 TI - Characteristic differences in the mini-mental state examination used in Asian countries. AB - BACKGROUND: The mini-mental state examination (MMSE) was adapted by individual countries according to their languages and cultures, though it has not been systematically compared. The objective of this study was to compare the linguistic and cultural variations of the MMSE used in various Asian countries. With this, we can analyze the strengths and weaknesses of the MMSE and consider using a common version in future international clinical studies in Asia. METHODS: We collected the MMSEs used in 11 Asian nations. After translating those into English, we compared them to understand the differences in the questionnaires with regard to cultural aspects. RESULTS: Many items may be applicable or comparable with a little modification, for Asian countries. However, attention and calculation and repetition may be incomparable. There were some differences in the contents and the ways to administer. CONCLUSIONS: The lack of consideration of the cultural differences and their influences on the interpretation of the same cognitive test makes cross-cultural studies difficult. Some items of MMSE tasks need readjusting for, if any, multi-national studies. This study might serve as a first step in the development of a standardized cross cultural cognitive instrument, especially in Asia. PMID- 28732485 TI - Validity and reliability of the tuberculosis-related stigma scale version for Brazilian Portuguese. AB - BACKGROUND: Stigma associated with tuberculosis (TB) has been an object of interest in several regions of the world. The behaviour presented by patients as a result of social discrimination has contributed to delays in diagnosis and the abandonment of treatment, leading to an increase in the cases of TB and drug resistance. The identification of populations affected by stigma and its measurement can be assessed with the use of valid and reliable instruments developed or adapted to the target culture. This aim of this study was to analyse the initial psychometric properties of the Tuberculosis-Related Stigma scale in Brazil, for TB patients. METHODS: The Tuberculosis-Related Stigma scale is a specific scale for measuring stigma associated with TB, originally validated in Thailand. It presents two dimensions to be assessed, namely Community perspectives toward tuberculosis and Patient perspectives toward tuberculosis. The first has 11 items regarding the behaviour of the community in relation to TB, and the second is made up of 12 items related to feelings such as fear, guilt and sorrow in coping with the disease. A pilot test was conducted with 83 TB patients, in order to obtain the initial psychometric properties of the scale in the Brazilian Portuguese version, enabling simulation of the field study. RESULTS: As regards its psychometric properties, the scale presented acceptable internal consistency for its dimensions, with values >=0.70, the absence of floor and ceiling effects, which is favourable for the property of scale responsiveness, satisfactory converging validity for both dimensions, with values over 0.30 for initial studies, and diverging validity, with adjustment values different from 100%. CONCLUSION: The results found show that the Tuberculosis Related Stigma scale can be a valid and reliable instrument for the Brazilian context. PMID- 28732486 TI - The development of a collective quality system: challenges and lessons learned; a qualitative study. AB - BACKGROUND: The ongoing professionalization of medical education means that quality systems (QSs) aimed at improving medical education also continuously have to improve. The aim of this paper is to describe the development of a collective QS for eight Dutch General Practitioner (GP) specialty training institutes to provide insights into the considerations that are involved in developing a QS in medical education. METHODS: Experts in the field of GP education and quality assurance developed the QS. They studied the literature, prior QSs and involved stakeholders. The team interviewed the directors, and all meetings and steps in the development process were transcribed. All interviews and relevant documentation were analyzed. Results were checked by the developers. RESULTS: Stakeholders agreed on the goals, the relevance of the resulting domains, and the methods to assess. However, one major theme emerged. To enable benchmarking, the team developed detailed quantifiable indicators. Especially the development of these indicators gave discussion. CONCLUSIONS: Involving stakeholders was crucial as they directed the development of the QS. The framework of the World Federation for Medical Education (WFME) provided guidance in covering all the relevant processes. The major challenge consisted of formulating indicators. Our experience indicates that the process of quantifying indicators is not straightforward. The detailed level of the indicators chosen is perhaps not always suitable for QSs in the field of medical education. PMID- 28732488 TI - Expression of the scaffold connector enhancer of kinase suppressor of Ras 1 (CNKSR1) is correlated with clinical outcome in pancreatic cancer. AB - BACKGROUND: Despite the near universal occurrence of activating codon 12 KRAS somatic variants in pancreatic cancer, there is considerable heterogeneity in the molecular make-up, MAPK/ERK pathway activation states, and clinical outcome in this disease. We analyzed the expression levels of CNKSR1, a scaffold that influences MAPK/ERK pathway activity, in clinical pancreas cancer specimens and their impact on survival of patients with pancreatic cancer. METHODS: Immunohistochemical staining for CNKSR1 expression was performed on 120 specimens from three independent pancreatic cancer tissue registries, phospho-ERK levels were measured in 86 samples. Expression was divided into CNKSR1 low and CNKSR1 high and correlated with clinicopathological variables including overall survival using multivariate Cox proportional hazard ratio models. RESULTS: CNKSR1 expression was increased in tumors compared to matched normal uninvolved resection specimens (p = 0.004). 28.3% (34/120) of patient specimens stained as CNKSR1 low compared to 71.7% (86/120) of specimens which stained as CNKSR1 high. High CNKSR1 expression was more prevalent in low grade tumors (p = 0.04). In multivariate analysis, low CNKSR1 expression status was independently correlated with decreased overall survival (HR = 2.146; 95% CI 1.34 to 3.43). When stratifying primary, non-metastatic tumor biopsies by CNKSR1 expression, resection was associated with improved survival in patients with high CNKSR1 expression (p < 0.0001) but not low CNKSR1 expression (p = 0.3666). Pancreatic tumors with nuclear in addition to cytoplasmic CNKSR1 staining (32/107) showed increased nuclear phospho-ERK expression compared to tumor with cytoplasmic CNKSR1 staining only (p = 0.017). CONCLUSION: CNKSR1 expression is increased in pancreatic tissue specimens and was found to be an independent prognostic marker of overall survival. CNKSR1 may help to identify patient subgroups with unfavorable tumor biology in order to improve risk stratification and treatment selection. Cellular distribution of CNKSR1 was correlated with nuclear pERK expression. PMID- 28732487 TI - Alcohol use disorders and associated chronic disease - a national retrospective cohort study from France. AB - BACKGROUND: Evidence on diseases caused by or associated with alcohol use disorders (AUDs) has been based on two meta-analyses including rather dated studies. The objective of this contribution was to estimate the risks of all cause mortality and alcohol-attributable disease categories depending on a diagnosis of AUDs in a national sample for France. METHODS: In a national retrospective cohort study on all inpatient acute and rehabilitation care patients in Metropolitan France 2008-2012 (N = 26,356,361), AUDs and other disease categories were identified from all discharge diagnoses according to standard definitions, and we relied on in-hospital death for mortality (57.4% of all deaths). RESULTS: 704,803 (2.7%) patients identified with AUDs had a threefold higher risk of death (HR = 2.98; 95% CI: 2.96-3.00) and died on average 12.2 years younger (men: 10.4, 95% CI: 10.3-10.5; women: 13.7, 95% CI: 13.6 13.9). AUDs were associated with significantly higher risks of hospital admission for all alcohol-attributable disease categories: digestive diseases, cancers (exception: breast cancer), cardiovascular diseases, dementia, infectious diseases, and injuries. Elevated risks were highest for liver diseases that were associated with about two-third of deaths in patients with AUDs (men: 64.3%; women: 71.1%). CONCLUSIONS: AUDs were associated with marked premature mortality and higher risks of alcohol-attributable disease categories. Our results support the urgent need of measures to reduce the burden of AUDs. PMID- 28732489 TI - The impact of retirement on age related cognitive decline - a systematic review. AB - BACKGROUND: Knowledge on factors affecting the rate of cognitive decline and how to maintain cognitive functioning in old age becomes increasingly relevant. The purpose of the current study was to systematically review the evidence for the impact of retirement on cognitive functioning and on age related cognitive decline. METHOD: We conducted a systematic literature review, following the principles of the PRISMA statement, of longitudinal studies on the association between retirement and cognition. RESULTS: Only seven studies fulfilled the inclusion criteria. We found weak evidence that retirement accelerates the rate of cognitive decline in crystallised abilities, but only for individuals retiring from jobs high in complexity with people. The evidence of the impact of retirement on the rate of decline in fluid cognitive abilities is conflicting. CONCLUSION: The review revealed a major knowledge gap in regards to the impact of retirement on cognitive decline. More knowledge on the association between retirement and age related cognitive decline as well as knowledge on the mechanisms behind these associations is needed. PMID- 28732490 TI - Positive ageing perceptions among migrant Turkish and native Dutch older people: a matter of culture or resources? AB - BACKGROUND: This study examined ethnic differences in ageing perceptions of migrant Turkish and native Dutch elders residing in Rotterdam, and explored whether such differences could be attributed to culture or resources (personal, physical, economic and/or social). METHODS: This study was based on combined data from two research projects focusing on the health and well-being of community dwelling elderly people in Rotterdam. The first dataset contained data from 994 native Dutch elders aged 70-99 years. The Rotterdam municipal register was used to randomly sample respondents, stratified by age group (70-74, 75-79, 80-84, and >=85 years) and neighbourhood. Of the 2593 eligible respondents, 1075 returned filled-in questionnaires (41% response rate). Of these 1075 respondents a total of 994 were natives which is the sample we selected for the current study. The second dataset contained data from 680 Turkish migrants aged 65-90 years. All Turkish people aged >=65 years were identified using the Rotterdam municipal register and invited to participate. In total, 680 Turkish respondents returned filled-in questionnaires (32% response rate; out of 2350). Ageing perceptions were measured using the 21-item Ageing Perceptions Questionnaire-Short (APQ-S). Respondents were additionally asked about their current general health, income, education, marital status, age and gender. RESULTS: The results of this study clearly reveal the importance of culture for all ageing perceptions among Turkish and Dutch elders. We found that age, health, and education were also important factors. For Turkish elders, health and education were the most important resources; for Dutch elders, age and health were most important in relation to ageing perceptions. Ageing perceptions were generally more negative among Turkish than among Dutch elders. Turkish elders reported more negative awareness of ageing, felt less in control of their ageing processes, and had more negative emotional reactions to ageing. They also believed more firmly that their ageing processes would have both negative and positive effects on their lives. Results revealed poorer health, lower income and educational levels among Turkish than among Dutch elders. In addition, many more Dutch than Turkish elders were single/widowed/divorced. CONCLUSION: Physical and personal resources, in addition to culture, are most important for positive ageing perceptions among native Dutch and migrant Turkish elders residing in Rotterdam, the Netherlands. These resources are health and education for Turkish elders, and health and age for Dutch elders. Overall, ethnicity remained a significant predictor of ageing perceptions when other resources were taken into account. PMID- 28732491 TI - Job retention vocational rehabilitation for employed people with inflammatory arthritis (WORK-IA): a feasibility randomized controlled trial. AB - BACKGROUND: Inflammatory arthritis leads to work disability, absenteeism and presenteeism (i.e. at-work productivity loss) at high cost to individuals, employers and society. A trial of job retention vocational rehabilitation (VR) in the United States identified this helped people keep working. The effectiveness of this VR in countries with different socioeconomic policies and conditions, and its impact on absenteeism, presenteeism and health, are unknown. This feasibility study tested the acceptability of this VR, modified for the United Kingdom, compared to written advice about managing work problems. To help plan a randomized controlled trial, we tested screening, recruitment, intervention delivery, response rates, applicability of the control intervention and identified the relevant primary outcome. METHODS: A feasibility randomized controlled trial with rheumatoid, psoriatic or inflammatory arthritis patients randomized to receive either job retention VR or written information only (the WORK-IA trial). Following three days VR training, rheumatology occupational therapists provided individualised VR on a one to one basis. VR included work assessment, activity diaries and action planning, and (as applicable) arthritis self-management in the workplace, ergonomics, fatigue and stress management, orthoses, employment rights and support services, assistive technology, work modifications, psychological and disclosure support, workplace visits and employer liaison. RESULTS: Fifty five (10%) people were recruited from 539 screened. Follow-up response rates were acceptable at 80%. VR was delivered with fidelity. VR was more acceptable than written advice only (7.8 versus 6.7). VR took on average 4 h at a cost of L135 per person. Outcome assessment indicated VR was better than written advice in reducing presenteeism (Work Limitations Questionnaire (WLQ) change score mean: VR = -12.4 (SD 13.2); control = -2.5 (SD 15.9), absenteeism, perceived risk of job loss and improving pain and health status, indicating proof of concept. The preferred primary outcome measure was the WLQ, a presenteeism measure. CONCLUSIONS: This brief job retention VR is a credible and acceptable intervention for people with inflammatory arthritis with concerns about continuing to work due to arthritis. TRIAL REGISTRATION: ISRCTN 76777720 . Registered 21.9.12. PMID- 28732492 TI - Staphylococcus aureus Prostatic abscess: a clinical case report and a review of the literature. AB - BACKGROUND: Prostatic abscess is a rare complication of acute bacterial prostatitis and is most commonly caused byEnterobacteriaceae. We report on a case of prostatic abscess caused by Staphylococcus aureus and conduct a review of the literature. CASE PRESENTATIVE: We present a case of S. aureus prostatic abscess that was successfully treated with acombination of antibiotic and surgical therapy. The isolate was non-multidrug-resistant, methicillin resistantStaphylococcus aureus and was genotyped as clonal complex 5, an emerging regional clone that is trimethoprim resistant and Panton-Valentine leukocidin positive. This current case report is the first to describe the use of clindamycin step-down therapy. A literature review identified a further 39 cases of S. aureus prostatic abscesses, of which 26 were methicillin resistant. CONCLUSION: S. aureus is an uncommon cause of prostatic abscess. Optimal management includes both antibiotictherapy and surgical drainage. Our use of clindamycin as step-down therapy was guided by its excellent prostatic penetration. PMID- 28732493 TI - Evaluation of left atrial volume and function using single-beat real-time three dimensional echocardiography in atrial fibrillation patients. AB - BACKGROUND: This study was aimed to evaluate the feasibility and accuracy of real time three-dimensional echocardiography (RT-3DE) measurement of left atrial (LA) volume and function in comparison with two-dimensional echocardiography (2DE) measurements in atrial fibrillation (AF) patients. METHODS: A total of 50 pairs of AF patients and healthy controls were enrolled in this study. Indexed LA end diastole volume (ILAEDV) and indexed LA end-systolic volume (ILAESV), as well as LA function indices such as segmental LA ejection fraction (LAEF), were assessed using 2DE Simpson's method and the RT-3DE method. RESULTS: The images showed that regional LA volume-time curves and LAEF were disordered in AF patients. ILAEDV and ILAESV were markedly increased and global LAEF was significantly decreased in AF patients compared with those in healthy controls (P < 0.01). No significant differences were found in ILAEDV, ILAESV, and LAEF levels as determined by the RT 3DE method or 2DE Simpson's method. Bland-Altman analysis showed that the two methods agreed well for measuring ILAEDV, ILAESV, and segmental LAEF. CONCLUSION: The RT-3DE method may be a feasible and accurate method for evaluating LA volume and function of AF patients in clinical practice. PMID- 28732494 TI - The effects of therapeutic hip exercise with abdominal core activation on recruitment of the hip muscles. AB - BACKGROUND: Core stabilization has been utilized for rehabilitation and prevention of lower limb musculoskeletal injuries. Previous studies showed that activation of the abdominal core muscles enhanced the hip muscle activity in hip extension and abduction exercises. However, the lack of the direct measurement and quantification of the activation level of the abdominal core muscles during the execution of the hip exercises affect the level of evidence to substantiate the proposed application of core exercises to promote training and rehabilitation outcome of the hip region. The aim of the present study was to examine the effects of abdominal core activation, which is monitored directly by surface electromyography (EMG), on hip muscle activation while performing different hip exercises, and to explore whether participant characteristics such as gender, physical activity level and contractile properties of muscles, which is assessed by tensiomyography (TMG), have confounding effect to the activation of hip muscles in enhanced core condition. METHODS: Surface EMG of bilateral internal obliques (IO), upper gluteus maximus (UGMax), lower gluteus maximus (LGMax), gluteus medius (GMed) and biceps femoris (BF) of dominant leg was recorded in 20 young healthy subjects while performing 3 hip exercises: Clam, side-lying hip abduction (HABD), and prone hip extension (PHE) in 2 conditions: natural core activation (NC) and enhanced core activation (CO). EMG signals normalized to percentage of maximal voluntary isometric contraction (%MVIC) were compared between two core conditions with the threshold of the enhanced abdominal core condition defined as >20%MVIC of IO. RESULTS: Enhanced abdominal core activation has significantly promoted the activation level of GMed in all phases of clam exercise (P < 0.05), and UGMax in all phases of PHE exercise (P < 0.05), LGMax in eccentric phases of all 3 exercises (P < 0.05), and BF in all phases of all 3 exercises except the eccentric phase of PHE exercise (P < 0.05). The %MVIC of UGMax was significantly higher than that of LGMax in all phases of clam and HABD exercises under both CO and NC conditions (P < 0.001) while the %MVIC of LGMax was significantly higher than UGMax in concentric phase of PHE exercise under NC condition (P = 0.003). Gender, physical activity level and TMG parameters were not major covariates to activation of hip muscles under enhanced core condition. CONCLUSIONS: Abdominal core activation enhances the hip muscles recruitment in Clam, HABD and PHE exercises, and this enhancement is correlated with higher physical activity and stiffer hip muscle. Our results suggest the potential application of abdominal core activation for lower limb rehabilitation since the increased activation of target hip muscles may enhance the therapeutic effects of hip strengthening exercises. PMID- 28732495 TI - Carriage and serotype distribution of Streptococcus agalactiae in third trimester pregnancy in southern Ghana. AB - BACKGROUND: The aim of this study was to determine the prevalence of Streptococcus agalactiae (group B streptococci, GBS) among healthy, pregnant women attending antenatal care at different study sites in the Greater Accra Region, Ghana. METHODS: Between 2010 and June 2013, recto-vaginal swab samples were collected from pregnant women attending antenatal care from two study sites in southern Ghana. The samples were collected within 35 and 37 weeks of the gestation period. These were inoculated into Todd-Hewitt broth followed by sub culturing onto a sheep-blood agar plate. Identification was performed on a single subcultured colony. Gram staining was performed, and isolates were evaluated for beta-haemolytic reactions. Furthermore, the isolates were serotyped using the GBS latex serotyping kit. RESULTS: The carriage rates were found to be 25.5% (95% CI: 19.6-32.1) to 28.0% (95% CI: 21.9-34.8) for the two collection sites. The most common serotypes were serotypes VII and IX. The data showed that women below 20 years of age or above 30 years of age have a significantly (p = 0.037) higher risk of carrying GBS compared to women from the age group of 20 to 30 years. CONCLUSIONS: The findings of this study revealed that prevalence of GBS colonization in pregnant women in Greater Accra region is high and comparable to rates observed in South Africa and Western countries. The most prevalent serotypes were serotypes VII and IX, which have not been observed before in West Africa. PMID- 28732496 TI - Accuracy and determinants of perceived HIV risk among young women in South Africa. AB - BACKGROUND: HIV risk perceptions are a key determinant of HIV testing. The success of efforts to achieve an AIDS-free generation - including reaching the UNAIDS 90-90-90 target - thus depends critically on the content of these perceptions. We examined the accuracy of HIV-risk perceptions and their correlates among young black women in South Africa, a group with one of the highest HIV incidence rates worldwide. METHODS: We used individual-level longitudinal data from the Cape Area Panel Study (CAPS) from 2005 to 2009 on black African women (20-30 years old in 2009) to assess the association between perceived HIV-risk in 2005 and the probability of testing HIV-positive four years later. We then estimated multivariable logistic regressions using cross-sectional data from the 2009 CAPS wave to assess the relationship between risk perceptions and a wide range of demographic, sexual behaviour and psychosocial covariates of perceived HIV-risk. RESULTS: We found that the proportion testing HIV-positive in 2009 was almost identical across perceived risk categories in 2005 (no, small, moderate, great) (chi 2 = 1.43, p = 0.85). Consistent with epidemiologic risk factors, the likelihood of reporting moderate or great HIV-risk perceptions was associated with condom-use (aOR: 0.57; 95% CI: 0.36, 0.89; p < 0.01); having >=3 lifetime partners (aOR: 2.38, 95% CI: 1.53, 3.73; p < 0.01); knowledge of one's partner's HIV status (aOR: 0.67; 95% CI: 0.43, 1.07; p = 0.09); and being in an age-disparate partnerships (aOR: 1.73; 95% CI: 1.09, 2.76; p = 0.02). However, the likelihood of reporting moderate or great self-perceived risk did not vary with sexually transmitted disease history and respondent age, both strong predictors of HIV risk in the study setting. Risk perceptions were associated with stigmatising attitudes (aOR: 0.53; 95% CI: 0.26, 1.09; p = 0.09); prior HIV testing (aOR: 0.21; 95% CI: 0.13, 0.35; p < 0.01); and having heard that male circumcision is protective (aOR: 0.38; 95% CI: 0.22, 0.64; p < 0.01). CONCLUSIONS: Results indicate that HIV-risk perceptions are inaccurate. Our findings suggest that this inaccuracy stems from HIV-risk perceptions being driven by an incomplete understanding of epidemiological risk and being influenced by a range of psycho-social factors not directly related to sexual behaviour. Consequently, new interventions are needed to align perceived and actual HIV risk. PMID- 28732497 TI - Mental health differences between German gay and bisexual men and population based controls. AB - BACKGROUND: International studies have revealed that gay and bisexual men present more mental health problems than the general male population. Furthermore, there is evidence that minority stress predicts mental health problems in gay and bisexual men. The aim of the present study is to provide initial data on mental health differences in Germany and to analyze the effect of minority stress. METHODS: Mental health data on n = 1903 German gay and bisexual men and n = 958 men from a population-based sample were assessed using a shortened version of the SCL-90-S. The mental health of the two samples was compared. Furthermore, a linear regression was conducted for the gay and bisexual sample: mental health was used as the criterion and minority stressors as predictors. RESULTS: As compared to our population sample, gay and bisexual men demonstrated more mental health problems with a moderate effect size. In the regression, minority stress predicted mental health problems in the gay and bisexual sample. CONCLUSIONS: We observed pronounced mental health differences between gay and bisexual men versus the population sample. These differences could be at least partly due to the minority stress gay and bisexual men face. Research should focus on how to reduce and cope with minority stress. PMID- 28732498 TI - A qualitative study on the intersectional social determinants for indigenous people who become infected with HIV in their youth. AB - BACKGROUND: Indigenous young people are currently highly overrepresented in the HIV epidemic in Canada, especially in the Prairie Provinces, such as Manitoba. Understanding HIV-vulnerability in Indigenous peoples must begin with understanding that social determinants are intersectional and linked to the historical legacy of European colonization. In this paper findings that detail the influence of the intersectional social determinants on Indigenous people who become infected with HIV in their youth are presented. METHODS: The qualitative research design of phenomenology was used as it afforded the opportunity to understand Indigenous young people from their frames of reference and experiences of reality, resulting in a phenomenological understanding of their perspectives and experiences of the early years of living with HIV. A total of 21 Indigenous young people took part open-ended interviews. RESULTS: The stories that the Indigenous young people shared revealed their deeply interconnected social worlds, and how social determinants including abuse, trauma, being part of the child welfare system, and housing and food security were connected throughout various stages of their lives. Such stages included childhood, adolescence and young adulthood (the time of HIV infection), and later adulthood for older participants with the social determinants having multiple influences on their health trajectories. CONCLUSIONS: The findings highlight the need for policies and programs that are broadly focused, addressing multiple social determinants together. Overall, there needs to be more emphasis on the multiple social determinants in the life situations of all Indigenous youth. Reducing the health and social disparities in Indigenous youth is key to reducing the number of young Indigenous people diagnosed with HIV. The findings also shed light on the importance of listening to young Indigenous people who have experienced HIV diagnosis and life following diagnosis. PMID- 28732499 TI - Association between serum osteocalcin and glucose/lipid metabolism in Chinese Han and Uygur populations with type 2 diabetes mellitus in Xinjiang: two cross sectional studies. AB - BACKGROUND: Recent studies have shown osteocalcin (OC) plays an important role in regulating glucose and lipid metabolism. Thus, the aim of this study was to investigate the association of OC with glucose and lipid metabolism in patients with type 2 diabetes mellitus (T2DM) in the Chinese Han and Uygur population. METHODS: A total of 1397 T2DM patients (705 Han and 692 Uygur T2DM patients) were enrolled in the present study. Lipid profile, glucose metabolic indices and total OC (TOC) were measured. Homeostasis model assessment of beta-cells function (HOMA beta), insulin sensitivity (HOMA-IS) and insulin resistance (HOMA-IR) were also calculated in all participants. Pearson/Spearman correlation analysis and multivariate stepwise regression analysis were adopted to test the relationships between OC and those parameters. RESULTS: Uygur T2DM patients had significantly higher body mass index (BMI), hemoglobin A1C (HbA1C) and lower TOC compared with their Han counterparts (all P < 0.05). HbA1C was negatively associated with TOC in all Uygur and Han T2DM patients (Total: Uygur: t = -3.468, P = 0.001; Han: t = -4.169, P < 0.001). BMI was inversely associated with TOC in all Uygur T2DM patients (Males: t = -2.893, P = 0.014; Females: t = -2.250, P = 0.027, respectively). Multivariate stepwise regression analysis showed that TOC was positively correlated with HOMA-beta in the Uygur male group (beta = 2.101, P = 0.040) and negatively associated with BMI in all Uygur T2DM patients (Males: beta = -1.563, P = 0.011; Females: beta = -1.284, P = 0.016, respectively). No significant differences were observed between TOC and lipid profiles in all participants (all P > 0.05). CONCLUSION: There were differences in the associations between TOC and glucose metabolism in Han and Uygur T2DM patients, indicating genetic factors may play a role in modulating OC and glucose metabolism in different ethnic population. PMID- 28732500 TI - Linking clinical quality indicators to research evidence - a case study in asthma management for children. AB - BACKGROUND: Clinical quality indicators are used to monitor the performance of healthcare services and should wherever possible be based on research evidence. Little is known however about the extent to which indicators in common use are based on research. The objective of this study is to measure the extent to which clinical quality indicators used in asthma management in children with outcome measurements can be linked to results in randomised controlled clinical trial (RCT) reports. This work is part of a broader research program to trial methods that improve the efficiency and accuracy of indicator development. METHODS: National-level indicators for asthma management in children were extracted from the National Quality Measures Clearinghouse database and the National Institute for Health and Care Excellence quality standards by two independent appraisers. Outcome measures were extracted from all published English language RCT reports for asthma management in children below the age of 12 published between 2005 and 2014. The two sets were then linked by manually mapping both to a common set of Unified Medical Language System (UMLS) concepts. RESULTS: The analysis identified 39 indicators and 562 full text RCTs dealing with asthma management in children. About 95% (37/39) of the indicators could be linked to RCT outcome measures. CONCLUSIONS: It is possible to identify relevant RCT reports for the majority of indicators used to assess the quality of asthma management in childhood. The methods reported here could be automated to more generally support assessment of candidate indicators against the research evidence. PMID- 28732501 TI - Ambulatory monitoring demonstrates an acute association between cookstove-related carbon monoxide and blood pressure in a Ghanaian cohort. AB - BACKGROUND: Repeated exposure to household air pollution may intermittently raise blood pressure (BP) and affect cardiovascular outcomes. We investigated whether hourly carbon monoxide (CO) exposures were associated with acute increases in ambulatory blood pressure (ABP); and secondarily, if switching to an improved cookstove was associated with BP changes. We also evaluated the feasibility of using 24-h ambulatory blood pressure monitoring (ABPM) in a cohort of pregnant women in Ghana. METHODS: Participants were 44 women enrolled in the Ghana Randomized Air Pollution and Health Study (GRAPHS). For 27 of the women, BP was measured using 24-h ABPM; home blood pressure monitoring (HBPM) was used to measure BP in the remaining 17 women. Personal CO exposure monitoring was conducted alongside the BP monitoring. RESULTS: ABPM revealed that peak CO exposure (defined as >=4.1 ppm) in the 2 hours prior to BP measurement was associated with elevations in hourly systolic BP (4.3 mmHg [95% CI: 1.1, 7.4]) and diastolic BP (4.5 mmHg [95% CI: 1.9, 7.2]), as compared to BP following lower CO exposures. Women receiving improved cookstoves had lower post-intervention SBP (within-subject change in SBP of -2.1 mmHg [95% CI: -6.6, 2.4] as compared to control), though this result did not reach statistical significance. 98.1% of expected 24-h ABPM sessions were successfully completed, with 92.5% of them valid according to internationally defined criteria. CONCLUSIONS: We demonstrate an association between acute exposure to carbon monoxide and transient increases in BP in a West African setting. ABPM shows promise as an outcome measure for assessing cardiovascular health benefits of cookstove interventions. TRIAL REGISTRATION: The GRAPHS trial was registered with clinicaltrials.gov on 13 April 2011 with the identifier NCT01335490 . PMID- 28732502 TI - Chronic glucocorticoid exposure activates BK-NLRP1 signal involving in hippocampal neuron damage. AB - BACKGROUND: Neuroinflammation mediated by NLRP1 (nucleotide-binding oligomerization domain (NOD)-like receptor protein 1) inflammasome plays an important role in many neurological diseases such as Parkinson's disease (PD) and Alzheimer's disease (AD). Our previous studies showed that chronic glucocorticoid (GC) exposure increased brain inflammation via NLRP1 inflammasome and induce neurodegeneration. However, little is known about the mechanism of chronic GC exposure on NLRP1 inflammasome activation in hippocampal neurons. METHODS: Hippocampal neurons damage was assessed by LDH kit and Hoechst 33258 staining. The expression of microtubule-associated protein 2 (MAP2), inflammasome complex protein (NLRP1, ASC and caspase-1), inflammatory cytokines (IL-1beta), and large conductance Ca2+ and voltage-activated K+ channel (BK channels) protein was detected by Western blot. The inflammatory cytokines (IL-1beta and IL-18) were examined by ELISA kit. The mRNA levels of NLRP1, IL-1beta, and BK were detected by real-time PCR. BK channel currents were recorded by whole-cell patch-clamp technology. Measurement of [K+]i was performed by ion-selective electrode (ISE) technology. RESULTS: Chronic dexamethasone (DEX) treatment significantly increased LDH release and neuronal apoptosis and decreased expression of MAP2. The mechanistic studies revealed that chronic DEX exposure significantly increased the expression of NLRP1, ASC, caspase-1, IL-1beta, L-18, and BK protein and NLRP1, IL-1beta and BK mRNA levels in hippocampal neurons. Further studies showed that DEX exposure results in the increase of BK channel currents, with the subsequent K+ efflux and a low concentration of intracellular K+, which involved in activation of NLRP1 inflammasome. Moreover, these effects of chronic DEX exposure could be blocked by specific BK channel inhibitor iberiotoxin (IbTx). CONCLUSION: Our findings suggest that chronic GC exposure may increase neuroinflammation via activation of BK-NLRP1 signal pathway and promote hippocampal neurons damage, which may be involved in the development and progression of AD. PMID- 28732503 TI - Opium trade and the spread of HIV in the Golden Crescent. AB - The Golden Crescent region of South Asia-comprising Afghanistan, Iran, and Pakistan-is a principal global site for opium production and distribution. Over the past few decades, war, terrorism, and a shifting political landscape have facilitated an active heroin trade throughout the region. Protracted conflict has exacerbated already dire socio-economic conditions and political strife within the region and contributed to a consequent rise in opiate trafficking and addiction among the region's inhabitants. The worsening epidemic of injection drug use has paralleled the rising incidence of HIV and other blood-borne infections in the region and drawn attention to the broader implications of the growing opiate trade in the Golden Crescent. The first step in addressing drug use is to recognize that it is not a character flaw but a form of mental illness, hence warranting humane treatment of drug users. It is also recommended that the governments of the Golden Crescent countries encourage substitution of opium with licit crops and raise awareness among the general public about the perils of opium use. PMID- 28732505 TI - Body size in early life and risk of breast cancer. AB - BACKGROUND: Body size in early life is inversely associated with adult breast cancer (BC) risk, but it is unclear whether the associations differ by tumor characteristics. METHODS: In a pooled analysis of two Swedish population-based studies consisting of 6731 invasive BC cases and 28,705 age-matched cancer-free controls, we examined the associations between body size in early life and BC risk. Self-reported body sizes at ages 7 and 18 years were collected by a validated nine-level pictogram (aggregated into three categories: small, medium and large). Odds ratios (OR) and corresponding 95% confidence intervals (CI) were estimated from multivariable logistic regression models in case-control analyses, adjusting for study, age at diagnosis, age at menarche, number of children, hormone replacement therapy, and family history of BC. Body size change between ages 7 and 18 were also examined in relation to BC risk. Case-only analyses were performed to test whether the associations differed by tumor characteristics. RESULTS: Medium or large body size at age 7 and 18 was associated with a statistically significant decreased BC risk compared to small body size (pooled OR (95% CI): comparing large to small, 0.78 (0.70-0.86), Ptrend <0.001 and 0.72 (0.64-0.80), Ptrend <0.001, respectively). The majority of the women (~85%) did not change body size categories between age 7 and 18 . Women who remained medium or large between ages 7 and 18 had significantly decreased BC risk compared to those who remained small. A reduction in body size between ages 7 and 18 was also found to be inversely associated with BC risk (0.90 (0.81-1.00)). No significant association was found between body size at age 7 and tumor characteristics. Body size at age 18 was found to be inversely associated with tumor size (Ptrend = 0.006), but not estrogen receptor status and lymph node involvement. For all analyses, the overall inferences did not change appreciably after further adjustment for adult body mass index. CONCLUSIONS: Our data provide further support for a strong and independent inverse relationship between early life body size and BC risk. The association between body size at age 18 and tumor size could be mediated by mammographic density. PMID- 28732504 TI - Ischaemic stroke and the recanalization drug tissue plasminogen activator interfere with antibacterial phagocyte function. AB - BACKGROUND: Stroke induces immune alterations such as impaired oxidative burst and reduced release of neutrophil extracellular traps (NETs). We hypothesised that key enzymes of these defence mechanisms may be altered in ischaemic stroke. Therefore, we analysed the intra- and extracellular amounts of myeloperoxidase (MPO) and neutrophil elastase (NE) in patient sera and granulocytes and monocytes. Because the autonomous nervous system is thought to mediate stroke induced immune alterations, we also studied the influence of stress hormones and acetylcholine on MPO and NE. Rapid recanalization by recombinant tissue plasminogen activator (r-tPA) is the only available treatment for ischaemic stroke besides thrombectomy, and its influence on antibacterial defence mechanisms of granulocytes and monocytes were addressed here. METHODS: Ex vivo: Intracellular and serum MPO and NE were measured on days 0, 1, 3 and 5 post stroke by either flow cytometry or enzyme-linked immunosorbent assay (ELISA) and compared to controls. In vitro: Blood from healthy donors was incubated with catecholamines, dexamethasone and acetylcholine, and the percentage of NET producing cells and the area covered by NETs were quantified immunohistochemically. Intra- and extracellular MPO and NE were quantified by flow cytometry or ELISA. Blood samples from healthy donors were incubated with r tPA, and oxidative burst, phagocytosis, NETosis, cytokine release, MPO and NE were quantified by flow cytometry, ELISA and microscopy. RESULTS: MPO was reduced in granulocytes but increased in sera obtained from stroke patients compared to controls. NE was not altered intracellularly but was elevated in patient sera. The percentage of NET-producing neutrophils was decreased by stress hormones and increased by acetylcholine. Neither intracellular MPO nor NE was altered by hormone treatment; however, adrenaline and acetylcholine induced NE release. r tPA led to reduced phagocytosis and oxidative burst in granulocytes and monocytes in vitro. NETosis, MPO release and cytokines were not altered, whereas NE release was enhanced by r-tPA. CONCLUSIONS: Intracellular reduction of MPO might be responsible for reduced NETosis in stroke patients. The impact of enhanced MPO and NE serum levels in stroke patients should be addressed in future studies. r tPA impaired antibacterial defence function in vitro. Therefore, patients who undergo unsuccessful recanalization therapy might be at higher risk for infection, which should be analysed in future investigations. Immune alterations due to r-tPA effects in stroke patients should also be investigated. PMID- 28732507 TI - Long noncoding RNA expression profiles in sub-lethal heat-treated hepatoma carcinoma cells. AB - BACKGROUND: Sub-lethal heat treatment characterizes a transition zone of radiofrequency ablation (RFA) which explains hepatocellular carcinoma (HCC) residual cancer occurrence in this area after RFA treatment. The biochemistry of residual cancer cell recurrence is poorly understood, but long noncoding RNAs (lncRNAs) may have aberrant expression that is associated with diverse cancers. Thus, we measured lncRNA gene expression in sub-lethally heat-treated HCC cells using microarray. METHOD: Differentially expressed lncRNA and mRNA were measured with an Agilent Human lncRNA + mRNA Array V4.0 (4 * 180 K format) containing 41,000 lncRNAs and 34,000 mRNAs. Bioinformatics analysis was used to assess differentially expressed lncRNA and mRNA. Seven lncRNA and seven mRNA were validated by qRT-PCR analysis in HCC cells. RESULTS: Genome-wide lncRNA and mRNA expression data in sub-lethal heat-treated SMMC-7721 HCC cells 558 lncRNA and 250 mRNA were significantly up-regulated and 224 lncRNA and 1031 mRNA down-regulated compared to normal cultured SMMC-7721 cells. We demonstrated for the first time that ENST00000570843.1, ENST00000567668.1, ENST00000582249.1, ENST00000450304.1, TCONS_00015544, ENST00000602478.1, TCONS_00001266 and ARC, IL12RB1, HSPA6 were upregulated, whereas STAT3, PRPSAP1, MCU, URB2 were down-regulated in sub lethally heat-treated HCC cells. CONCLUSIONS: lncRNA expression data in sub lethally heat-treated HCC cells will provide important insights about lncRNAs' contribution to HCC recurrence after RFA treatment. PMID- 28732506 TI - New insights into Blimp-1 in T lymphocytes: a divergent regulator of cell destiny and effector function. AB - B lymphocyte-induced maturation protein-1 (Blimp-1) serves as a master regulator of the development and function of antibody-producing B cells. Given that its function in T lymphocytes has been identified within the past decade, we review recent findings with emphasis on its role in coordinated control of gene expression during the development, differentiation, and function of T cells. Expression of Blimp-1 is mainly confined to activated T cells and is essential for the production of interleukin (IL)-10 by a subset of forkhead box (Fox)p3+ regulatory T cells with an effector phenotype. Blimp-1 is also required to induce cell elimination in the thymus and critically modulates peripheral T cell activation and proliferation. In addition, Blimp-1 promotes T helper (Th) 2 lineage commitment and limits Th1, Th17 and follicular helper T cell differentiation. Furthermore, Blimp-1 coordinates with other transcription factors to regulate expression of IL-2, IL-21 and IL-10 in effector T lymphocytes. In CD8+ T cells, Blimp-1 expression is distinct in heterogeneous populations at the stages of clonal expansion, differentiation, contraction and memory formation when they encounter antigens. Moreover, Blimp-1 plays a fundamental role in coordinating cytokine receptor signaling networks and transcriptional programs to regulate diverse aspects of the formation and function of effector and memory CD8+ T cells and their exhaustion. Blimp-1 also functions as a gatekeeper of T cell activation and suppression to prevent or dampen autoimmune disease, antiviral responses and antitumor immunity. In this review, we discuss the emerging roles of Blimp-1 in the complex regulation of gene networks that regulate the destiny and effector function of T cells and provide a Blimp-1-dominated transcriptional framework for T lymphocyte homeostasis. PMID- 28732508 TI - Lysophosphatidic acid plasma concentrations in healthy subjects: circadian rhythm and associations with demographic, anthropometric and biochemical parameters. AB - BACKGROUND: Lysophosphatidic acid (LPA) is a bioactive lipid with a wide biological activity. Previous studies have shown its potential usefulness as a diagnostic marker for ovarian cancer. The aim of the study was to investigate which factors may influence plasma LPA concentrations in healthy subjects and to propose reference values. METHODS: The study group consisted of 100 healthy subjects. From all of them the blood samples were taken at 7 a.m. (fasting state). From 40 volunteers additional blood samples were taken at 2 p.m., at 8 p.m. and at 2 a.m. next morning. Concentrations of LPA were measured in plasma samples using enzyme-linked immunosorbent assay. RESULTS: Analysis of samples from 100 healthy volunteers showed significant influence of sex and age on plasma LPA. The reference range for the plasma LPA concentration corrected for age and sex, determined at 2.5-97.5 percentile interval is 0.14-1.64 MUM. LPA correlates positively with BMI, serum total cholesterol, triacylglycerols, uric acid and negatively with estimated glomerular filtration rate and serum albumin. Concentration of LPA at 2 a.m. was lower than at 2 p.m. There were not any significant differences between plasma LPA at 7 a.m. and any other time of the day. CONCLUSIONS: Plasma LPA is associated with demographic, anthropometric and biochemical parameters. It seems that LPA concentrations have no specific circadian rhythm and the time of donation and fasting state have marginal effect on plasma LPA. These findings may be helpful in future incorporation of LPA as a diagnostic marker. PMID- 28732509 TI - Response to comment on "Oestrogen-induced angiogenesis and implantation contribute to the development of parasitic myomas after laparoscopic morcellation". AB - According to the literature review, CO2 insufflation on parasitic myoma implantation is not well studied, and we concur that our study is related to "Morcellation-induced parasitic myomas." We did not compare CO2 insufflation to non-insufflation in our study. The reason is the efficacy of gasless laparoscopic myomectomy and morcellation is not well established and this modality is seldom performed. Moreover, the effects of pneumoperitoneum on mesothelial cells and the role of the entire peritoneal cavity as a cofactor in adhesion formation have become well established, the role of CO2 insufflation in the establishment of parasitic myomas has not yet been studied. As such, more in-depth and well designed studies for the role of CO2 insufflation are needed. PMID- 28732510 TI - Protective and therapeutic role of 2-carba-cyclic phosphatidic acid in demyelinating disease. AB - BACKGROUND: Multiple sclerosis is a neuroinflammatory demyelinating and neurodegenerative disease of the central nervous system characterized by recurrent and progressive demyelination/remyelination cycles, neuroinflammation, oligodendrocyte loss, demyelination, and axonal degeneration. Cyclic phosphatidic acid (cPA) is a natural phospholipid mediator with a unique cyclic phosphate ring structure at the sn-2 and sn-3 positions of the glycerol backbone. We reported earlier that cPA elicits a neurotrophin-like action and protects hippocampal neurons from ischemia-induced delayed neuronal death. We designed, chemically synthesized, and metabolically stabilized derivatives of cPA: 2-carba-cPA (2ccPA), a synthesized compound in which one of the phosphate oxygen molecules is replaced with a methylene group at the sn-2 position. In the present study, we investigated whether 2ccPA exerts protective effects in oligodendrocytes and suppresses pathology in the two most common mouse models of multiple sclerosis. METHODS: To evaluate whether 2ccPA has potential beneficial effects on the pathology of multiple sclerosis, we investigated the effects of 2ccPA on oligodendrocyte cell death in vitro and administrated 2ccPA to mouse models of experimental autoimmune encephalomyelitis (EAE) and cuprizone-induced demyelination. RESULTS: We demonstrated that 2ccPA suppressed the CoCl2-induced increase in the Bax/Bcl-2 protein expression ratio and phosphorylation levels of p38MAPK and JNK protein. 2ccPA treatment reduced cuprizone-induced demyelination, microglial activation, NLRP3 inflammasome, and motor dysfunction. Furthermore, 2ccPA treatment reduced autoreactive T cells and macrophages, spinal cord injury, and pathological scores in EAE, the autoimmune multiple sclerosis mouse model. CONCLUSIONS: We demonstrated that 2ccPA protected oligodendrocytes via suppression of the mitochondrial apoptosis pathway. Also, we found beneficial effects of 2ccPA in the multiperiod of cuprizone-induced demyelination and the pathology of EAE. These data indicate that 2ccPA may be a promising compound for the development of new drugs to treat demyelinating disease and ameliorate the symptoms of multiple sclerosis. PMID- 28732511 TI - Primary liver transplantation and liver retransplantation: comparison of health related quality of life and mental status - a cross-sectional study. AB - BACKGROUND: Liver Retransplantation (Re-LT) procedures are associated with an increased risk of morbidity and mortality. Up to date, there is no knowledge on the health-related quality of life and the mental status of these patients. METHODS: Health-Related Quality of Life (HRQoL) was assessed by using the Short Form 36 (SF-36) Health Survey and Mental Status was assessed by using the Hospital Anxiety and Depression Scale (HADS). The patients were examined in different assessments: During regular check-up examinations in the LT outpatient department in 2011 (Survey 1) and in a postal survey in 2013 (Survey 2). Their medical data was collected by using an established database. RESULTS: We received eligible surveys of 383 patients (55.6%) with a history of LT, of which 15 (3.9%) had undergone Re-LT (Re-LT group). These patients were compared to a group of 60 patients who had undergone only one LT. With regard to their HRQoL, the Re-LT group had significantly lower scores on the scales of physical function (PF, p = 0.026), their role-physical (RP, p = 0.008), their vitality (VIT, p = 0.040), and their role-emotional (RE, p = 0.005). The scores for anxiety and depression did not differ significantly between the groups. In a multiple regression analysis, chronic kidney disease was found to be an independent risk factor for decreased scores of PF (p = 0.023). CONCLUSIONS: Patients who have to undergo Re-LT procedures are faceing impairments in physical aspects of a HRQoL. Together with clinical results from other studies, the findings of the present examination underline the need for an optimized organ distribution strategy since not all patients listed for Re-LT appear to benefit from it. PMID- 28732512 TI - Prolonged acute care and post-acute care admission and recovery of physical function in survivors of acute respiratory failure: a secondary analysis of a randomized controlled trial. AB - BACKGROUND: The proportion of survivors of acute respiratory failure is growing; yet, many do not regain full function and require prolonged admission in an acute or post-acute care facility. Little is known about their trajectory of functional recovery. We sought to determine whether prolonged admission influenced the trajectory of physical function recovery and whether patient age modified the recuperation rate. METHODS: We performed a secondary analysis of a randomized clinical trial of intensive physical therapy for patients with acute respiratory failure requiring mechanical ventilation for >=4 days. The primary outcome was Continuous Scale Physical Functional Performance, short form (CS-PFP-10), score. Predictor variables included prolonged admission in an acute or post-acute care facility at 1 month, time, and patient age. To determine whether the association between admission and functional outcome varied over time, a multivariable mixed effects linear regression model was fit using an interaction between prolonged admission and time with a primary outcome of total CS-PFP-10 score. RESULTS: Of the 89 patients included, 56% (50 of 89) required prolonged admission. At 1 month, patients who remained admitted had CS-PFP-10 scores that were 20.1 (CI 10.4-29.8) points lower (p < 0.0001) than patients who were discharged to home. However, there was no difference in the rate at which physical function improved from 3 to 6 months for patients who required prolonged admission compared with those who returned home (p = 0.24 for interaction between prolonged admission and time). Adjusted for age, Acute Physiology and Chronic Health Evaluation II score, and sex, both groups had CS-PFP-10 scores that were 8.2 (CI 4.5-12.0) points higher at 6 months than at 3 months (p < 0.0001). For each additional year in patient age, CS-PFP-10 recovered 0.36 points slower (95% CI 0.12-0.61; p = 0.004). CONCLUSIONS: Patients who require prolonged admission after acute respiratory failure have significantly lower physical functional performance than patients who return home. However, the rates of physical functional recovery between the two groups do not differ. The majority of survivors do not recover sufficiently to achieve functional independence by 6 months. Older age negatively influences the trajectory of functional recovery. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01058421 . Registered on 26 January 2010. PMID- 28732513 TI - Competing for space in an already crowded market: a mixed methods study of why an online community of practice (CoP) for alcohol harm reduction failed to generate interest amongst the group of public health professionals at which it was aimed. AB - BACKGROUND: Improving mechanisms for knowledge translation (KT) and connecting decision-makers to each other and the information and evidence they consider relevant to their work remains a priority for public health. Virtual communities of practices (CoPs) potentially offer an affordable and flexible means of encouraging connection and sharing of evidence, information and learning among the public health community in ways that transgress traditional geographical, professional, institutional and time boundaries. The suitability of online CoPs in public health, however, has rarely been tested. This paper explores the reasons why particular online CoP for alcohol harm reduction hosted by the UK Health Forum failed to generate sufficient interest from the group of public health professionals at which it was aimed. METHODS: The study utilises online web-metrics demonstrating a lack of online activity on the CoP. One hundred and twenty seven responses to an online questionnaire were used to explore whether the lack of activity could be explained by the target audience's existing information and evidence practices and needs. Qualitative interviews with 10 members describe in more detail the factors that shape and inhibit use of the virtual CoP by those at which it was targeted. RESULTS: Quantitative and qualitative data confirm that the target audience had an interest in the kind of information and evidence the CoP was set up to share and generate discussion about, but also that participants considered themselves to already have relatively good access to the information and evidence they needed to inform their work. Qualitative data revealed that the main barriers to using the CoP were a proliferation of information sources meaning that participants preferred to utilise trusted sources that were already established within their daily routines and a lack of time to engage with new online tools that required any significant commitment. CONCLUSIONS: Specialist online CoPs are competing for space in an already crowded market. A target audience that regards itself as busy and over-supplied is unlikely to commit to a new service without the assurance that the service will provide unique and valuable well-summarised information, which would reduce the need to spend time accessing competing resources. PMID- 28732514 TI - In vitro assessment of the antimicrobial activity of silver and zinc oxide nanoparticles against fish pathogens. AB - BACKGROUND: Antibiotic resistance is a global issue that threatens public health. The excessive use of antibiotics contributes to this problem as the genes of antibiotic resistance can be transferred between the bacteria in humans, animals and aquatic organisms. Metallic nanoparticles could serve as future substitutes for some conventional antibiotics because of their antimicrobial activity. The aim of this study was to evaluate the antimicrobial effects of silver and zinc oxide nanoparticles against major fish pathogens and assess their safety in vitro. Silver nanoparticles were synthesized by chemical reduction and characterized with UV-Vis spectroscopy, transmission electron microscopy and zeta sizer. The concentrations of silver and zinc oxide nanoparticles were measured using inductively coupled plasma-mass spectrometry. Subsequently, silver and zinc oxide nanoparticles were tested for their antimicrobial activity against Aeromonas hydrophila, Aeromonas salmonicida subsp. salmonicida, Edwardsiella ictaluri, Edwardsiella tarda, Francisella noatunensis subsp. orientalis, Yersinia ruckeri and Aphanomyces invadans and the minimum inhibitory concentrations were determined. MTT assay was performed on eel kidney cell line (EK-1) to determine the cell viability after incubation with nanoparticles. The interaction between silver nanoparticles and A. salmonicida was investigated by transmission electron microscopy. RESULTS: The tested nanoparticles exhibited marked antimicrobial activity. Silver nanoparticles inhibited the growth of both A. salmonicida and A. invadans at a concentration of 17 ug/mL. Zinc oxide nanoparticles inhibited the growth of A. salmonicida, Y. ruckeri and A. invadans at concentrations of 15.75, 31.5 and 3.15 ug/mL respectively. Silver nanoparticles showed higher cell viability when compared to zinc oxide nanoparticles in the MTT assay. Transmission electron microscopy showed the attachment of silver nanoparticles to the bacterial membrane and disruption of its integrity. CONCLUSIONS: This is the first study on inhibitory effects of silver and zinc oxide nanoparticles towards A. salmonicida and A. invadans. Moreover, zinc oxide nanoparticles inhibited the growth of Y. ruckeri. In low concentrations, silver nanoparticles were less cytotoxic than zinc oxide nanoparticles and represent an alternative antimicrobial compound against A. hydrophila, A. salmonicida and A. invadans. PMID- 28732516 TI - Application of the new 8th TNM staging system for non-small cell lung cancer: treated with curative concurrent chemoradiotherapy. AB - BACKGROUND: The eighth tumor, node, metastasis (TNM) staging system (8-TNM) for non-small cell lung cancer (NSCLC) was newly released in 2015. This system had limitation because most patients included in the analysis were treated with surgery. Therefore, it might be difficult to reflect prognosis of patients treated with curative concurrent chemoradiotherapy (CCRT). Purpose of this study was to investigate clinical impact of the newly published 8-TNM compared to the current seventh TNM staging system (7-TNM) for locally advanced NSCLC patients treated with CCRT. METHODS: New 8-TNM was applied to 64 patients with locally advanced NSCLC who were treated with CCRT from 2010 to 2015. Changes in T category and stage group by 8-TNM were recorded and patterns of change were evaluated. Survival was analyzed according to T category, N category, and stage group in each staging system, respectively. RESULTS: Among the total of 64 patients, 38 (59.4%) patients showed change in T category while 22 (34.4%) patients showed change in stage group using 8-TNM compared to 7-TNM. Survival curves were significantly separated in the 8-TNM stage group (p = 0.001) than those in the 7-TNM (p > 0.05). Especially, survival of newly introduced stage IIIC by 8-TNM was significantly lower than that of others. On the other hand, there was no significant survival difference between T categories in each staging system. CONCLUSIONS: Subdivision of stage III into IIIA, IIIB, and IIIC by 8-TNM for patients treated with CCRT better reflected prognosis than 7-TNM. However, subdivision of T category according to tumor size in 8-TNM might be less significant. PMID- 28732517 TI - Erratum to: Predictors of chest wall toxicity after stereotactic ablative radiotherapy using real-time tumor tracking for lung tumors. PMID- 28732518 TI - Impact of the change of copay policy in Medicare Part D on zoster vaccine uptake among Medicare beneficiaries in a managed care organization. AB - BACKGROUND: Kaiser Permanente Southern California (KPSC) adopted the Medicare Part D Tier-6 with zero patient copay for zoster vaccination in 2012. We assessed the impact of the implementation on zoster vaccination rate (GSK study identifier: HO-13-14,182). METHODS: Zoster vaccination rate was examined among an open cohort of >=65-year-old Medicare Part D beneficiaries during 01/01/2008 06/30/2014, compared to >=65-year-old commercial health plan members and 60-64 year-old members. The demographics, vaccination records, and insurance and benefit type were confirmed through KPSC electronic medical record databases. Person-time based vaccination rate was calculated for each observation interval (calendar month or year). The changes in annual rates in one year pre- (2011) and post- (2012) Tier-6 implementation were compared in a difference-in-difference analysis. Linear spline Poisson regression models were fitted to compare the secular trend of monthly rates during pre and post Tier-6 implementation (01/2012). RESULTS: Zoster vaccination rate increased in Medicare Part D beneficiaries after the implementation of zero copay. The increase in annual vaccination rate from 2011 to 2012 was marginally higher in Medicare Part D beneficiaries but not statistically significant (difference in rate ratio [RR] = 0.04, p > 0.05) compared to commercial health plan members. Among non-Hispanic white members, the difference of RR was 0.09 (p = 0.020) between Medicare Part D beneficiaries and >=65-year-old commercial plan members, and it was 0.08 (p = 0.034) compared to 60-64-year-old commercial plan members. In secular trend analysis, we did not observe significant increase in overall and race stratified zoster vaccination rate attributable to the implementation of the Tier-6. CONCLUSIONS: The impact of Tier-6 on zoster vaccination was not substantial in elderly Medicare Part D beneficiaries in this population where a lower than average copay ($20 to $40) was applied prior to the Tier-6 implementation. Further research is necessary to explore the numerical relationship between vaccination and amount of copay. TRIAL REGISTRATION: GSK study identifier: HO-13 14,182. PMID- 28732515 TI - Sexually divergent induction of microglial-associated neuroinflammation with hippocampal aging. AB - BACKGROUND: The necessity of including both males and females in molecular neuroscience research is now well understood. However, there is relatively limited basic biological data on brain sex differences across the lifespan despite the differences in age-related neurological dysfunction and disease between males and females. METHODS: Whole genome gene expression of young (3 months), adult (12 months), and old (24 months) male and female C57BL6 mice hippocampus was analyzed. Subsequent bioinformatic analyses and confirmations of age-related changes and sex differences in hippocampal gene and protein expression were performed. RESULTS: Males and females demonstrate both common expression changes with aging and marked sex differences in the nature and magnitude of the aging responses. Age-related hippocampal induction of neuroinflammatory gene expression was sexually divergent and enriched for microglia-specific genes such as complement pathway components. Sexually divergent C1q protein expression was confirmed by immunoblotting and immunohistochemistry. Similar patterns of cortical sexually divergent gene expression were also evident. Additionally, inter-animal gene expression variability increased with aging in males, but not females. CONCLUSIONS: These findings demonstrate sexually divergent neuroinflammation with aging that may contribute to sex differences in age-related neurological diseases such as stroke and Alzheimer's, specifically in the complement system. The increased expression variability in males suggests a loss of fidelity in gene expression regulation with aging. These findings reveal a central role of sex in the transcriptomic response of the hippocampus to aging that warrants further, in depth, investigations. PMID- 28732519 TI - Effectiveness and cost-effectiveness of daily all-over-body application of emollient during the first year of life for preventing atopic eczema in high-risk children (The BEEP trial): protocol for a randomised controlled trial. AB - BACKGROUND: Atopic eczema (AE) is a common skin problem that impairs quality of life and is associated with the development of other atopic diseases including asthma, food allergy and allergic rhinitis. AE treatment is a significant cost burden for health care providers. The purpose of the trial is to investigate whether daily application of emollients for the first year of life can prevent AE developing in high-risk infants (first-degree relative with asthma, AE or allergic rhinitis). METHODS: This is a protocol for a pragmatic, two-arm, randomised controlled, multicentre trial. Up to 1400 term infants at high risk of developing AE will be recruited through the community, primary and secondary care in England. Participating families will be randomised in a 1:1 ratio to receive general infant skin-care advice, or general skin-care advice plus emollients with advice to apply daily to the infant for the first year of life. Families will not be blinded to treatment allocation. The primary outcome will be a blinded assessment of AE at 24 months of age using the UK Working Party Diagnostic Criteria for Atopic Eczema. Secondary outcomes are other definitions of AE, time to AE onset, severity of AE (EASI and POEM), presence of other allergic diseases including food allergy, asthma and hay fever, allergic sensitisation, quality of life, cost-effectiveness and safety of the emollients. Subgroup analyses are planned for the primary outcome according to filaggrin genotype and the number of first-degree relatives with AE and other atopic diseases. Families will be followed up by online and postal questionnaire at 3, 6, 12 and 18 months with a face-to-face visit at 24 months. Long-term follow-up until 60 months will be via annual questionnaires. DISCUSSION: This trial will demonstrate whether skin barrier enhancement through daily emollient for the first year of life can prevent AE from developing in high-risk infants. If effective, this simple and cheap intervention has the potential to result in significant cost savings for health care providers throughout the world by preventing AE and possibly other associated allergic diseases. TRIAL REGISTRATION: ISRCTN registry; ID: ISRCTN21528841 . Registered on 25 July 2014. PMID- 28732521 TI - Retroclavicular approach vs infraclavicular approach for plexic bloc anesthesia of the upper limb: study protocol randomized controlled trial. AB - BACKGROUND: The coracoid approach is recognized as the simplest approach to perform brachial plexus anaesthesia, but needle visualization needs to be improved. With a different needle entry point, the retroclavicular approach confers a perpendicular angle between the ultrasound and the needle, which theoretically enhances needle visualization. This trial compares these two techniques. The leading hypothesis is that the retroclavicular approach is comparable to the infraclavicular coracoid approach in general aspects, but needle visualization is better with this novel approach. METHODS: We designed a multicentre, randomized, non-inferiority trial. Patients eligible for the study are older than 18 years, able to consent, will undergo urgent or elective upper limb surgery distal to the elbow and are classified with American Society of Anaesthesiologists risk score (ASA) I-III. They will be excluded if they meet contraindicated criteria to regional anaesthesia, have affected anatomy of the clavicle or are pregnant. Randomization will be done by a computer-generated randomization schedule stratified for each site and in 1:1 ratio, and concealment will be maintained with opaque, sealed envelopes in a locked office. The primary outcome, the performance time, will be analyzed using non-inferiority analysis while secondary outcomes will be analyzed with superiority analysis. Needle visualization will be ranked on a Likert scale of 1-5 that is subjective and represents a pitfall. Two separate persons will rank needle visualization to compensate this pitfall. According to previous studies, 49 patients per group are required for statistical power of 0.90 and one-sided type I error of 0.05. DISCUSSION: The conduct of this study will bring clear answers to our questions and, if our hypothesis is confirmed, will confer an anatomic alternative to difficult coracoid infraclavicular brachial blocks or could even become a standard for brachial plexus anaesthesia. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02913625 . Registered on 12 September 2016. PMID- 28732520 TI - Characterization of background noise in capture-based targeted sequencing data. AB - BACKGROUND: Targeted deep sequencing is increasingly used to detect low-allelic fraction variants; it is therefore essential that errors that constitute baseline noise and impose a practical limit on detection are characterized. In the present study, we systematically evaluate the extent to which errors are incurred during specific steps of the capture-based targeted sequencing process. RESULTS: We removed most sequencing artifacts by filtering out low-quality bases and then analyze the remaining background noise. By recognizing that plasma DNA is naturally fragmented to be of a size comparable to that of mono-nucleosomal DNA, we were able to identify and characterize errors that are specifically associated with acoustic shearing. Two-thirds of C:G > A:T errors and one quarter of C:G > G:C errors were attributed to the oxidation of guanine during acoustic shearing, and this was further validated by comparative experiments conducted under different shearing conditions. The acoustic shearing step also causes A > G and A > T substitutions localized to the end bases of sheared DNA fragments, indicating a probable association of these errors with DNA breakage. Finally, the hybrid selection step contributes to one-third of the remaining C:G > A:T and one-fifth of the C > T errors. CONCLUSIONS: The results of this study provide a comprehensive summary of various errors incurred during targeted deep sequencing, and their underlying causes. This information will be invaluable to drive technical improvements in this sequencing method, and may increase the future usage of targeted deep sequencing methods for low-allelic fraction variant detection. PMID- 28732522 TI - The excretory-secretory products of Echinococcus granulosus protoscoleces directly regulate the differentiation of B10, B17 and Th17 cells. AB - BACKGROUND: Excretory-secretory products (ESPs) released by helminths are well known to regulate T cell responses in the host. However, their direct influence in the differentiation of naive T cells, and especially B cells, remains largely unknown. This study investigated the effects of Echinococcus granulosus protoscoleces ESPs (EgPSC-ESPs) on the differentiation of IL-10-producing B cells (B10), IL-17A-producing B cells (B17) and Th17 cells. METHODS: BALB/c mice injected with EgPSC were used to evaluate the in vivo profiles of B10, B17 and Th17 cells. In vitro purified CD19+ B and naive CD4+ T cells were cultured in the presence of native, heat-inactivated or periodate-treated EgPSC-ESPs, and the differentiation of these cell subsets were compared. RESULTS: In contrast to the control group, infected mice showed higher frequencies of B10, B17 and Th17 cells, and higher levels of IL-10 and IL-17A in the sera. Interestingly, B17 cells were first identified to express CD19+CD1dhigh. In vitro, B cells cultured with native ESPs exhibited a higher percentage of B10 cells but lower percentage of B17 and Th17 cells compared to the PBS group. Moreover, the relative expression of IL-10 and IL-17A mRNA were consistent with the altered frequencies. However, ESPs subjected to heat-inactivation or periodate treatment exhibited an inverse effect on the induction of these cell subsets. CONCLUSIONS: Our findings indicate that ESPs released by EgPSC can directly regulate the differentiation of B10, B17 and Th17 cells, which appear to be heat-labile and carbohydrate dependent. PMID- 28732524 TI - How to choose the best journal for your case report. AB - Since the establishment of the Journal of Medical Case Reports in 2006, the number of journals that publish case reports has increased rapidly, and most of these journals are open access. Open access publishing usually requires authors to pay publication fees while offering the articles online, free of charge, and free of most copyright and licensing restrictions. The movement for open access has gained support in the research community, with the publishers BioMed Central and PLOS ONE becoming leaders in scientific publishing in their number of articles and citations. As the number of open access publishers has exploded, so too has the number of publishers that act in bad faith to profit from the open access model. Simple guidelines have been developed and resources are available to help authors choose a suitable journal for publication of their case reports. PMID- 28732523 TI - Collaborative care for depression in general practice: study protocol for a randomised controlled trial. AB - BACKGROUND: Depression is a common illness with great human costs and a significant burden on the public economy. Previous studies have indicated that collaborative care (CC) has a positive effect on symptoms when provided to people with depression, but CC has not yet been applied in a Danish context. We therefore developed a model for CC (the Collabri model) to treat people with depression in general practice in Denmark. Since systematic identification of patients is an "active ingredient" in CC and some literature suggests case finding as the best alternative to standard detection, the two detection methods are examined as part of the study. The aim is to investigate if treatment according to the Collabri model has an effect on depression symptoms when provided to people with depression in general practice in Denmark, and to examine if case finding is a better method to detect depression in general practice than standard detection. METHODS/DESIGN: The trial is a cluster-randomised, clinical superiority trial investigating the effect of treatment according to the Collabri model for CC, compared to treatment as usual for 480 participants diagnosed with depression in general practice in the Capital Region of Denmark. The primary outcome is depression symptoms (Beck's Depression Inventory (BDI-II)) after 6 months. Secondary outcomes include depression symptoms (BDI-II) after 15 months, anxiety symptoms (Beck's Anxiety Inventory (BAI)), level of functioning (Global Assessment of Function (GAF)) and psychological stress (Symptom Checklist-90 Revised (SCL-90-R)). In addition, case finding (with the recommended screening tool Major Depression Inventory (MDI)) and standard detection of depression is examined in a cluster-randomized controlled design. Here, the primary outcome is the positive predictive value of referral diagnosis. DISCUSSION: If the Collabri model is shown to be superior to treatment as usual, the study will contribute with important knowledge on how to improve treatment of depression in general practice, with major benefit to patients and society. If case finding is shown to be superior to standard detection, it will be recommended as the detection method in future treatment according to the Collabri model. TRIAL REGISTRATION: ClinicalTrials.gov. NCT02678845 . Retrospectively registered on 7 February 2016. PMID- 28732525 TI - Effectiveness and cost-effectiveness of embedded simulation in occupational therapy clinical practice education: study protocol for a randomised controlled trial. AB - BACKGROUND: Clinical placements are a critical component of the training for health professionals such as occupational therapists. However, with growing student enrolments in professional education courses and workload pressures on practitioners, it is increasingly difficult to find sufficient, suitable placements that satisfy program accreditation requirements. The professional accrediting body for occupational therapy in Australia allows up to 200 of the mandatory 1000 clinical placement hours to be completed via simulation activities, but evidence of effectiveness and efficiency for student learning outcomes is lacking. Increasingly placement providers charge a fee to host students, leading educators to consider whether providing an internal program might be a feasible alternative for a portion of placement hours. Economic analysis of the incremental costs and benefits of providing a traditional versus simulated placement is required to inform decision-making. METHODS/DESIGN: This study is a pragmatic, non-inferiority, single-blind, multicentre, two-group randomised controlled trial (RCT) with an embedded economic analysis. The RCT will compare a block of 40 hours of simulated placement (intervention) with a 40 hour block of traditional placement (comparator), with a focus on student learning outcomes and delivery costs. Six universities will instigate the educational intervention within their respective occupational therapy courses, randomly assigning their cohort of students (1:1 allocation) to the simulated or traditional clinical placements. The primary outcome is achievement of professional behaviours (e.g. communication, clinical reasoning) as assessed by a post-placement written examination. Secondary outcomes include proportions passing the placement assessed using the Student Practice Evaluation Form Revised, changes in student confidence pre-/post-placement, student and educator evaluation of the placement experience and cost-effectiveness of simulated versus traditional clinical placements. Comprehensive cost data will be collected for both the simulated and traditional placement programs at each site for economic evaluation. DISCUSSION: Use of simulation in health-related fields like occupational therapy is common, but these activities usually relate to brief opportunities for isolated skill development. The simulated clinical placement evaluated in this trial is less common because it encapsulates a 5-day block of integrated activities, designed and delivered in a manner intended to emulate best-practice placement experiences. The planned study is rare due to inclusion of an economic analysis that aims to provide valuable information about the relationship between costs and outcomes across participating sites. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12616001339448 . Registered 26 September 2016. PMID- 28732526 TI - Ultrasonography and dual-energy computed tomography provide different quantification of urate burden in gout: results from a cross-sectional study. AB - BACKGROUND: Ultrasonography (US) and dual-energy computed tomography (DECT) can assess urate burden in gout. The objective of this study was to compare the quantification of urate deposition provided by US to the one provided by DECT. METHODS: Patients with a diagnosis of gout were prospectively recruited to undergo quantification of urate deposition using US and DECT. US examination for tophi and the double contour (DC) sign was performed on the knees and feet and corresponding DECT scans provided volumes of tophi and of overall urate deposition. The primary endpoint was the intra-class correlation coefficient (ICC) of the volume of the index tophus measured by US and DECT and its 95% confidence interval (CI 95%). RESULTS: Of the 64 patients included, 34 presented with at least one tophus on US. DECT inter-reader agreement for urate deposition was perfect with an ICC of 1 (1-1) and good for the measurement of the index tophus with an ICC of 0.69 (0.47-0.83). The ICC for the measurement of the index tophus between the two techniques was poor with a value of 0.45 (0.1-0.71). The average ratio between the index tophi volume as assessed by DECT and US was 0.65. The number of DC-positive joints did not correlate with DECT volume of overall deposits (Spearman correlation coefficient of 0.23). CONCLUSIONS: DECT measurements of tophi give smaller volumes to the same tophi measured with US, and US signs of urate deposition in joints do not correlate with overall DECT volumes of extra-articular deposition. PMID- 28732527 TI - Sero-prevalence and vaccination status of hepatitis A and hepatitis B among adults with cirrhosis in Sri Lanka: a hospital based cohort study. AB - BACKGROUND: As acute viral hepatitis can be fatal in patients with cirrhosis, vaccination against hepatitis A (HAV) and hepatitis B (HBV) is recommended for non-immune patients. With increasing affluence the incidence of hepatitis A in childhood has decreased leading to a significant proportion of non-immune adults. As part of their routine investigation, hepatitis A IgG antibodies (anti-HAV IgG), hepatitis B surface antigen (HBsAg) and anti-HCV antibodies was checked and immunization status was assessed among consenting newly diagnosed cirrhotic patients presenting to a tertiary referral center. FINDINGS: Out of 135 patients, 107 [79.3%; males 91; mean age (SD) at presentation: 55.5 (11.6) years] with complete data were included for analysis. Most patients had either cryptogenic cirrhosis (62.6%) or alcoholic cirrhosis (29.9%); 2 (1.9%) had HBV cirrhosis, none had hepatitis C (HCV) cirrhosis. None of the patients had received vaccination against hepatitis A, while 71 (67.6%) had been vaccinated against HBV. The majority [62 (58%)] were negative for anti-HAV IgG. CONCLUSION: Most cirrhotic patients in this cohort were not immune to hepatitis A. None had been vaccinated against HAV, while a third of patients had not been vaccinated against HBV. Cirrhotic patients should be routinely investigated for immunity against HAV and HBV, and vaccination offered to those found to be non-immune. PMID- 28732528 TI - Retraction Note to: The complete mitochondrial genomes of two freshwater snails provide new protein-coding gene rearrangement models and phylogenetic implications. PMID- 28732529 TI - Exiguobacterium sp. A1b/GX59 isolated from a patient with community-acquired pneumonia and bacteremia: genomic characterization and literature review. AB - BACKGROUND: Bacterial species belonging to the genus Exiguobacterium are facultative anaerobic, non-spore-forming, Gram-positive bacilli, and rarely associated with human infections. Herein, we reported the first case of community acquired pneumonia (CAP) and bacteremia due to Exiguobacterium spp. in China. CASE PRESENTATION: An adult male with severe CAP was hospitalized. The pathogen was isolated from his bloodstream and broncho-alveolar lavage fluid. The correct identification of the micro-organism was achieved using 16S rRNA sequencing, and its antibiotic susceptibility test was performed by microdilution method. The Whole Genome Sequencing (WGS) was used to characterize its genetic features and to elucidate its potential pathogenic mechanisms. Furthermore, its genome sequence was also compared with those of 3 publicly-available Exiguobacterium strains. A PubMed search was performed for further understanding the features of Exiguobacterium infections. Phylogenetic analysis of the 16S rRNA gene sequence showed that the strain GX59 was most closely related to Exiguobacterium AT1b (99.7%). The genome of GX59 was 2,727,929 bp in size, harbouring 2855 putative protein-coding genes, 5 rRNA operons, 37 tRNA genes and 1 tmRNA. The multiple genome comparison of 4 Exiguobacterium strains demonstrated that Exiguobacterium contained 37 genes of secretion systems, including sec, tat, FEA, Type IV Pili and competence-related DNA transformation transporter (Com). Virulence factors of the micro-organism included tlyC, NprR, MCP, Dam, which might play a critical role in causing lethal infection. CONCLUSIONS: The study highlighted the potential pathogenicity of the genus Exiguobacterium for its unique genes encoding various virulence factors and those associated with antibiotic resistance, therefore, its clinical significance should be valued. PMID- 28732530 TI - Minocycline modulates NFkappaB phosphorylation and enhances antimicrobial activity against Staphylococcus aureus in mesenchymal stromal/stem cells. AB - BACKGROUND: Mesenchymal stromal/stem cells (MSCs) have demonstrated pro-healing properties due to their anti-inflammatory, angiogenic, and even antibacterial properties. We have shown previously that minocycline enhances the wound healing phenotype of MSCs, and MSCs encapsulated in poly(ethylene glycol) and gelatin based hydrogels with minocycline have antibacterial properties against Staphylococcus aureus (SA). Here, we investigated the signaling pathway that minocycline modulates in MSCs which results in their enhanced wound healing phenotype and determined whether preconditioning MSCs with minocycline has an effect on antimicrobial activity. We further investigated the in-vivo antimicrobial efficacy of MSC and antibiotic-loaded hydrogels in inoculated full thickness cutaneous wounds. METHODS: Modulation of cell signaling pathways in MSCs with minocycline was analyzed via western blot, immunofluorescence, and ELISA. Antimicrobial efficacy of MSCs pretreated with minocycline was determined by direct and transwell coculture with SA. MSC viability after SA coculture was determined via a LIVE/DEAD(r) stain. Internalization of SA by MSCs pretreated with minocycline was determined via confocal imaging. All protein and cytokine analysis was done via ELISA. The in-vivo antimicrobial efficacy of MSC and antibiotic-loaded hydrogels was determined in Sprague-Dawley rats inoculated with SA. Two-way ANOVA for multiple comparisons was used with Bonferroni test assessment and an unpaired two-tailed Student's t test was used to determine p values for all assays with multiple or two conditions, respectively. RESULTS: Minocycline leads to the phosphorylation of transcriptional nuclear factor-kappaB (NFkappaB), but not c-Jun NH2-terminal kinase (JNK) or mitogen-activated protein kinase (ERK). Inhibition of NFkappaB activation prevented the minocycline-induced increase in VEGF secretion. Preconditioning of MSCs with minocycline led to a reduced production of the antimicrobial peptide LL-37, but enhanced antimicrobial activity against SA via an increased production of IL-6 and SA internalization. MSC and antibiotic-loaded hydrogels reduced SA bioburden in inoculated wounds over 3 days and accelerated reepithelialization. CONCLUSIONS: Minocycline modulates the NFkappaB pathway in MSCs that leads to an enhanced production of IL 6 and internalization of SA. This mechanism may have contributed to the in-vivo antibacterial efficacy of MSC and antibiotic-loaded hydrogels. PMID- 28732532 TI - GATE: an efficient procedure in study of pleiotropic genetic associations. AB - BACKGROUND: The association studies on human complex traits are admittedly propitious to identify deleterious genetic markers. Compared to single-trait analyses, multiple-trait analyses can arguably make better use of the information on both traits and markers, and thus improve statistical power of association tests prominently. Principal component analysis (PCA) is a well-known useful tool in multivariate analysis and can be applied to this task. Generally, PCA is first performed on all traits and then a certain number of top principal components (PCs) that explain most of the trait variations are selected to construct the test statistics. However, under some situations, only utilizing these top PCs would lead to a loss of important evidences from discarded PCs and thus makes the capability compromised. METHODS: To overcome this drawback while keeping the advantages of using the top PCs, we propose a group accumulated test evidence (GATE) procedure. By dividing the PCs which is sorted in the descending order according to the corresponding eigenvalues into a few groups, GATE integrates the information of traits at the group level. RESULTS: Simulation studies demonstrate the superiority of the proposed approach over several existing methods in terms of statistical power. Sometimes, the increase of power can reach 25%. These methods are further illustrated using the Heterogeneous Stock Mice data which is collected from a quantitative genome-wide association study. CONCLUSIONS: Overall, GATE provides a powerful test for pleiotropic genetic associations. PMID- 28732531 TI - Endometrial scratching in women with implantation failure after a first IVF/ICSI cycle; does it lead to a higher live birth rate? The SCRaTCH study: a randomized controlled trial (NTR 5342). AB - BACKGROUND: Success rates of assisted reproductive techniques (ART) are approximately 30%, with the most important limiting factor being embryo implantation. Mechanical endometrial injury, also called 'scratching', has been proposed to positively affect the chance of implantation after embryo transfer, but the currently available evidence is not yet conclusive. The primary aim of this study is to determine the effect of endometrial scratching prior to a second fresh in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) cycle on live birth rates in women with a failed first IVF/ICSI cycle. METHOD: Multicenter randomized controlled trial in Dutch academic and non-academic hospitals. A total of 900 women will be included of whom half will undergo an endometrial scratch in the luteal phase of the cycle prior to controlled ovarian hyperstimulation using an endometrial biopsy catheter. The primary endpoint is the live birth rate after the 2nd fresh IVF/ICSI cycle. Secondary endpoints are costs, cumulative live birth rate (after the full 2nd IVF/ICSI cycle and over 12 months of follow-up); clinical and ongoing pregnancy rate; multiple pregnancy rate; miscarriage rate and endometrial tissue parameters associated with implantation failure. DISCUSSION: Multiple studies have been performed to investigate the effect of endometrial scratching on live birth rates in women undergoing IVF/ICSI cycles. Due to heterogeneity in both the method and population being scratched, it remains unclear which group of women will benefit from the procedure. The SCRaTCH trial proposed here aims to investigate the effect of endometrial scratching prior to controlled ovarian hyperstimulation in a large group of women undergoing a second IVF/ICSI cycle. TRIAL REGISTRATION: NTR 5342 , registered July 31st, 2015. PROTOCOL VERSION: Version 4.10, January 4th, 2017. PMID- 28732533 TI - Spatial and temporal patterns of diarrhoea in Bhutan 2003-2013. AB - BACKGROUND: To describe spatiotemporal patterns of diarrhoea in Bhutan, and quantify the association between climatic factors and the distribution and dynamics of the disease. METHODS: Nationwide data on diarrhoea were obtained for 2003 to 2013 from the Health Information and Management System (HIMS), Ministry of Health, Bhutan. Climatic variables were obtained from the Department of Hydro Met Services, Ministry of Economic Affairs, Bhutan. Seasonal trend decomposition was used to examine secular trends and seasonal patterns of diarrhoea. A Bayesian conditional autoregressive (CAR) model was used to quantify the relationship between monthly diarrhoea, maximum temperature, rainfall, age and gender. RESULTS: The monthly average diarrhoea incidence was highly seasonal. Diarrhoea incidence increased by 0.6% (95% CrI: 0.5-0.6%) for every degree increase in maximum temperature; and 5% (95 Cr I: 4.9-5.1%) for a 1 mm increase in rainfall. Children aged <5 years were found to be 74.2% (95% CrI: 74.1-74.4) more likely to experience diarrhoea than children and adults aged >=5 years and females were 4.9% (95% CrI: 4.4-5.3%) less likely to suffer from diarrhoea as compared to males. Significant residual spatial clustering was found after accounting for climate and demographic variables. CONCLUSIONS: Diarrhoea incidence was highly seasonal, with positive associations with maximum temperature and rainfall and negative associations with age and being female. This calls for public health actions to reduce future risks of climate change with great consideration of local climatic conditions. In addition, protection of <5 years children should be prioritize through provision of rotavirus vaccination, safe and clean drinking water, and proper latrines. PMID- 28732534 TI - Information sought, information shared: exploring performance and image enhancing drug user-facilitated harm reduction information in online forums. AB - BACKGROUND: There is good evidence to suggest that performance and image enhancing drug (PIED) use is increasing in Australia and that there is an increase in those using PIEDs who have never used another illicit substance. Peers have always been an important source of information in this group, though the rise of the Internet, and the increased use of Internet forums amongst substance consumers to share harm reduction information, means that PIED users may have access to a large array of views and opinions. The aim of this study was to explore the type of information that PIED users seek and share on these forums. METHODS: An online search was conducted to identify online forums that discussed PIED use. Three discussion forums were included in this study: aussiegymjunkies.com, bodybuildingforums.com.au, and brotherhoodofpain.com. The primary source of data for this study was the 'threads' from the online forums. Threads were thematically analysed for overall content, leading to the identification of themes. RESULTS: One hundred thirty-four threads and 1716 individual posts from 450 unique avatars were included in this analysis. Two themes were identified: (1) personal experiences and advice and (2) referral to services and referral to the scientific literature. CONCLUSIONS: Internet forums are an accessible way for members of the PIED community to seek and share information to reduce the harms associated with PIED use. Forum members show concern for both their own and others' use and, where they lack information, will recommend seeking information from medical professionals. Anecdotal evidence is given high credence though the findings from the scientific literature are used to support opinions. The engagement of health professionals within forums could prove a useful strategy for engaging with this population to provide harm reduction interventions, particularly as forum members are clearly seeking further reliable information, and peers may act as a conduit between users and the health and medical profession. PMID- 28732535 TI - Case report: rare skeletal manifestations in a child with primary hyperparathyroidism. AB - BACKGROUND: Primary hyperparathyroidism (PHPT) is uncommon among children with an incidence of 1:300,000. This diagnosis is often missed in children in contrast to adults where it is detected at a pre symptomatic stage due to routine blood investigations. Etiology of PHPT can be due to adenoma, hyperplasia or rarely carcinoma. CASE PRESENTATION: A 12 year old Sri Lankan girl presented with progressive difficulty in walking since 1 year. On examination she had bilateral genu valgum. Skeletal survey revealed valgus deformity of knee joints, bilateral subluxation of upper femoral epiphysis(SUFE), epiphyseal displacement of bilateral humeri, rugger jersey spine and subperiosteal bone resorptions in lateral aspects of 2nd and 3rd middle phalanges. There were no radiological manifestations of rickets. Metabolic profile revealed hypercalcemia with hypophosphatemia. Intact parathyroid hormone levels were elevated at 790 pg/ml. Vitamin D levels were deficient. She had low bone mineral density with Z score of -3.4. Vitamin D supplementation resulted in worsening of hypercalcemia without reduction in PTH levels. Tc 99 Sestamibi uptake scan showed abnormal tracer retention in left inferior pole of thyroid. A large parathyroid gland was removed with histology favoring parathyroid adenoma. Post operatively she developed hypocalcemia. Bilateral osteotomy was done for SUFE and further surgeries for correction of limb deformities planned. CONCLUSION: PHPT in children is usually diagnosed late when irreversible organ damage has occurred. Children can present with non specific symptoms involving gastrointestinal, musculoskeletal, renal and neurological systems. PHPT can cause disarray in bone and epiphysis in children during pubertal growth spurt. Genu valgum and SUFE are rare skeletal manifestations in PHPT and only 10 cases of genu valgum and 9 cases of SUFE have been reported up to now. So far no cases have been reported on epiphyseal displacement of humeri. Awareness regarding the occurrence of these rare skeletal manifestations especially during puberty is important for early diagnosis to prevent irreversible outcomes. PMID- 28732537 TI - Negative Pressure Wound Therapy versus modified Barker Vacuum Pack as temporary abdominal closure technique for Open Abdomen management: a four-year experience. AB - BACKGROUND: We reviewed our experience with patients presenting with trauma and peritonitis who underwent an open abdomen (OA) procedure, and compared outcomes between Negative Pressure Wound Therapy (NPWT) and a modified Barker Vacuum Pack (mBVP) technique. METHODS: In this descriptive study, we retrospectively analyzed data regarding all patients who underwent OA for intra-abdominal sepsis or abdominal trauma at our Centre from January 2012 to December 2015. Demographic data, co-morbidities, indications to surgery, intra-operative details and Bjorck classification grade were considered. Outcomes included were: time to closure in days, fascial closure rates, ICU and hospital stay, in-hospital and overall mortality, and entero-atmospheric fistula rate. RESULTS: A total of 83 cases were considered. Mean closure time was 6 days versus 6.5 days (p = 0.71) in NPWT and mBVP groups, respectively; the fascial closure rate was 75.4% versus 93.8% (p = 0.10). At multivariate analysis, in-hospital and overall mortality were significantly higher within the mBVP, as compared to NPWT (OR 3.8, 95% CI 1.1 to 13.1, p = 0.02 - OR 4.2, 95% CI 1.2 to 14.1, p = 0.01). Entero-atmospheric fistula rate was 2.6% in the two groups. CONCLUSIONS: NPWT as a temporary abdominal closure technique, as compared to mBVP, appears to be associated with better outcomes in terms of mortality. PMID- 28732538 TI - Consistency, now what? PMID- 28732539 TI - Enzyme adsorption-induced activity changes: a quantitative study on TiO2 model agglomerates. AB - BACKGROUND: Activity retention upon enzyme adsorption on inorganic nanostructures depends on different system parameters such as structure and composition of the support, composition of the medium as well as enzyme loading. Qualitative and quantitative characterization work, which aims at an elucidation of the microscopic details governing enzymatic activity, requires well-defined model systems. RESULTS: Vapor phase-grown and thermally processed anatase TiO2 nanoparticle powders were transformed into aqueous particle dispersions and characterized by dynamic light scattering and laser Doppler electrophoresis. Addition of beta-galactosidase (beta-gal) to these dispersions leads to complete enzyme adsorption and the generation of beta-gal/TiO2 heteroaggregates. For low enzyme loadings (~4% of the theoretical monolayer coverage) we observed a dramatic activity loss in enzymatic activity by a factor of 60-100 in comparison to that of the free enzyme in solution. Parallel ATR-IR-spectroscopic characterization of beta-gal/TiO2 heteroaggregates reveals an adsorption-induced decrease of the beta-sheet content and the formation of random structures leading to the deterioration of the active site. CONCLUSIONS: The study underlines that robust qualitative and quantitative statements about enzyme adsorption and activity retention require the use of model systems such as anatase TiO2 nanoparticle agglomerates featuring well-defined structural and compositional properties. PMID- 28732541 TI - Endobronchial embolization for life-threatening hemoptysis with Endobronchial Watanabe Spigot. AB - BACKGROUND: Massive hemoptysis is a common encounter in respiratory medicine. Bronchoscopy plays an important role in localizing the origin of bleeding, as well as endoscopic treatment of centrally located lesions. Endobronchial embolization is a novel technique enabling the management of hemoptysis arising even from peripheral lesions, via occlusion of the culprit bronchus, thereby securing the airway. Endobronchial Watanabe Spigot had been advocate in the treatment of bronchopleural fistula and the use of this novel technique had since then been expanded into the management of massive hemoptysis. To the best of our knowledge, this is the first reported case in Malaysia. CASE PRESENTATION: 78 year-old lady who presented with life-threatening hemoptysis leading rapidly to cardiac arrest upon arrival. Spontaneous circulation was restored after resuscitation with an urgent thoracic computed tomography angiogram revealed bleeding likely from the posterior basal segment of left lower lobe, with bronchiectatic changes. Urgent flexible bronchoscopy revealed airway flooding, with bleeding originating from the lingular and posterior-basal segment of the left lower lobe. Airway toileting was performed and two 7 mm Endobronchial Watanabe Spigots were plugged into the culprit bronchi. Urgent bronchial artery embolization was then attempted, but was unsuccessful. She was managed conservatively, as surgical resection was deemed high risk. The spigots were removed 4 days later uneventfully. There was no recurrence of hemoptysis, and patient remained well during 1-month follow up. CONCLUSIONS: The utmost priority in managing life-threatening hemoptysis is to prevent airway flooding. Endobronchial embolization with Endobronchial Watanabe Spigot is useful as a temporary measure before definitive therapy, or can itself be the main therapeutic player in the hemoptysis armament for high-risk patients. PMID- 28732540 TI - Rubella sero-prevalence among children in Kilimanjaro region: a community based study prior to the introduction of rubella vaccine in Tanzania. AB - BACKGROUND: Childhood rubella infection is a mild, self-limiting illness. Rubella infection among pregnant women however, is a major public health concern. Depending on gestation age, it may result in fetal death, stillbirth or a new born with congenital rubella syndrome (CRS). Maternal antibodies protect young infants from rubella infection and lifelong immunity is acquired by vaccination or post-rubella infection. This study aims at characterizing rubella infection and its epidemiology in the Kilimanjaro region, prior to the introduction of the rubella vaccine in Tanzania. METHODS: This was a population based cross-sectional study, covering all the seven districts in Kilimanjaro region, North-eastern Tanzania. The study population included children of 0 to 36 months of age and their mothers/primary caretakers. A multistage sampling method was used to obtain a representative sample of the children. Interviews were conducted using a structured questionnaire. Dried blood spot (DBS) samples were taken from eligible children. Rubella specific IgG antibodies were detected from eluted serum by enzyme-linked immunosorbent assay (ELISA). Descriptive statistics were used to summarize the data, the difference between groups was tested by Fishers exact test or chi square test as appropriate. Univariate and multivariate analysis was used, with rubella sero-positive groups as dependent variables and the socio demographic, children, paediatric and parental factors as independent variables, the Odds ratio and their 95% confidence intervals were calculated to assess the strength of association between the dependent and independent variables. A p value less than 0.05 was considered significant. RESULTS: The overall rubella sero-prevalence was 1.8%. Rural residence was associated with greater risk for rubella infection. Other family characteristic did not predict rubella infection. CONCLUSIONS: This study highlights the low natural immunity to rubella among children prior to the introduction of rubella vaccine in Tanzania. Our research underscores the need for an effective rubella vaccination program to prevent CRS. More epidemiologic and immunologic studies are needed to guide the vaccination deployment and administration strategy in Tanzania. PMID- 28732542 TI - National disability-adjusted life years (DALYs) for 257 diseases and injuries in Ethiopia, 1990-2015: findings from the global burden of disease study 2015. AB - BACKGROUND: Disability-adjusted life years (DALYs) provide a summary measure of health and can be a critical input to guide health systems, investments, and priority-setting in Ethiopia. We aimed to determine the leading causes of premature mortality and disability using DALYs and describe the relative burden of disease and injuries in Ethiopia. METHODS: We used results from the Global Burden of Diseases, Injuries, and Risk Factors Study 2015 (GBD 2015) for non fatal disease burden, cause-specific mortality, and all-cause mortality to derive age-standardized DALYs by sex for Ethiopia for each year. We calculated DALYs by summing years of life lost due to premature mortality (YLLs) and years lived with disability (YLDs) for each age group and sex. Causes of death by age, sex, and year were measured mainly using Causes of Death Ensemble modeling. To estimate YLDs, a Bayesian meta-regression method was used. We reported DALY rates per 100,000 for communicable, maternal, neonatal, and nutritional (CMNN) disorders, non-communicable diseases, and injuries, with 95% uncertainty intervals (UI) for Ethiopia. RESULTS: Non-communicable diseases caused 23,118.1 (95% UI, 17,124.4 30,579.6), CMNN disorders resulted in 20,200.7 (95% UI, 16,532.2-24,917.9), and injuries caused 3781 (95% UI, 2642.9-5500.6) age-standardized DALYs per 100,000 in Ethiopia in 2015. Lower respiratory infections, diarrheal diseases, and tuberculosis were the top three leading causes of DALYs in 2015, accounting for 2998 (95% UI, 2173.7-4029), 2592.5 (95% UI, 1850.7-3495.1), and 2562.9 (95% UI, 1466.1-4220.7) DALYs per 100,000, respectively. Ischemic heart disease and cerebrovascular disease were the fourth and fifth leading causes of age standardized DALYs, with rates of 2535.7 (95% UI, 1603.7-3843.2) and 2159.9 (95% UI, 1369.7-3216.3) per 100,000, respectively. The following causes showed a reduction of 60% or more over the last 25 years: lower respiratory infections, diarrheal diseases, tuberculosis, neonatal encephalopathy, preterm birth complications, meningitis, malaria, protein-energy malnutrition, iron-deficiency anemia, measles, war and legal intervention, and maternal hemorrhage. CONCLUSIONS: Ethiopia has been successful in reducing age-standardized DALYs related to most communicable, maternal, neonatal, and nutritional deficiency diseases in the last 25 years, causing a major ranking shift to types of non communicable disease. Lower respiratory infections, diarrheal disease, and tuberculosis continue to be leading causes of premature death, despite major declines in burden. Non-communicable diseases also showed reductions as premature mortality declined; however, disability outcomes for these causes did not show declines. Recently developed non-communicable disease strategies may need to be amended to focus on cardiovascular diseases, cancer, diabetes, and major depressive disorders. Increasing trends of disabilities due to neonatal encephalopathy, preterm birth complications, and neonatal disorders should be emphasized in the national newborn survival strategy. Generating quality data should be a priority through the development of new initiatives such as vital events registration, surveillance programs, and surveys to address gaps in data. Measuring disease burden at subnational regional state levels and identifying variations with urban and rural population health should be conducted to support health policy in Ethiopia. PMID- 28732543 TI - The implementation of a quality system in the Dutch GP specialty training: barriers and facilitators; a qualitative study. AB - BACKGROUND: Quality assurance programs in medical education are introduced to gain insight into the quality of such programs and to trigger improvements. Although of utmost importance, research on the implementation of such programs is scarce. The Dutch General Practice (GP) specialty training institutes used an implementation strategy to implement a quality system (QS), and we aimed to study the success of this strategy and to learn about additional facilitators and barriers. METHODS: Seventeen structured interviews were conducted with the directors and quality coordinators (QCs) of the eight Dutch GP training institutes. A five-stage process model of implementation was used to structure these interviews and analyze the data. Two researchers analyzed the data with a framework approach. RESULTS: The strategy supported the institutes in implementing the QS. However, after the introduction of the QS, staff experienced the QS as demanding, although they noticed almost no concrete short-term results. Moreover, they experienced difficulties in integrating the QS into their local situation. Collectively working with the QS and following common deadlines did create a sense of commitment towards each other that appeared to be a true stimulus to the introduction of the QS. CONCLUSIONS: The implementation strategy focused mainly on the introduction of the QS in the GP specialty training, and it was, as such, rather successful. An important barrier concerned the acceptance of the QS and the integration of the QS into local structures, which suggests that there is a need for guidance on the translation of the QS to local contexts. All in all, we recommend more focus on the benefits of a QS. PMID- 28732544 TI - High-grade bursal-side partial rotator cuff tears: comparison of mid- and long term results following arthroscopic repair after conversion to a full-thickness tear. AB - BACKGROUND: Partial-thickness rotator cuff tears (PTRCTs) are one of the leading causes of shoulder dysfunction. Successful results have been reported with different treatment techniques, but the long-term consequences of these procedures are not yet clearly known. The purposes of this study were to evaluate and compare the mid- and long-term clinical outcomes of arthroscopically repaired bursal-side PTRCTs after conversion to full-thickness tears and identify the possible effects of age, gender, and hand dominance on clinical outcomes. METHODS: Twenty-nine patients who had undergone arthroscopic repair of a significant bursal-side PTRCT were functionally evaluated. The repair was made after conversion to a full-thickness tear. The average patient age was 55.2 years (range 35-69 years, SD +/-7.6 years). Clinical outcomes were evaluated at 2 and 5 years after surgery. Constant Shoulder Score (CSS) and Visual Analogue Scale for Pain (VAS pain) were used as outcome measures. RESULTS: The average CSS improved from 38.9 preoperatively to 89.2 and 87.8 at 2 and 5 years after surgery, respectively (p < 0.001). The average VAS pain score decreased from 7.90 preoperatively to 1.17 and 1.31 at 2 and 5 years after surgery, respectively (p < 0.001). A significant improvement was detected in patient functional outcomes and VAS pain scores at 2 and 5 years after surgery compared with the preoperative period. The patients who underwent surgery from their non-dominant extremity showed a significantly higher CSS increase relative to those who underwent surgery on the dominant extremity (p = 0.022). CONCLUSIONS: Arthroscopic repair of high-grade bursal-side PTRCTs after conversion to full-thickness tears is a reliable surgical technique with good functional outcomes and pain relief both at mid- and long-term follow-ups. Surgery on the non-dominant side may be related to better functional outcomes. PMID- 28732545 TI - Comment on "Oestrogen-induced angiogenesis and implantation contribute to the development of parasitic myomas after laparoscopic morcellation". AB - BACKGROUND: The cause of contamination and dissemination of leiomyoma tissue particles and cells in the peritoneal cavity during myomectomy is a challenging issue for both clinicians and researchers. Therefore, the article by Huang et al. recently published in your journal is the subject of this letter. MAIN BODY: We comment on the role of laparoscopic condition in xenograft implantation and also highlighted the shortcomings of this study. The surgical technique of intramural fibroid enucleation, cell spillage during morcellation and postsurgical hormonal impact on the development of parasitic myomas become evident, while the contribution of CO2 insufflation, the fibroid's nature, mutations and pseudocapsule impacts on angiogenesis are not clear. In addition, an exploration of the exact origin of implanted fragments harvested from the fibroid tissue and their nature might play a significant role in the implantation and the angiogenesis induction ability of xenografts. CONCLUSION: Taking into account the current literature in the scope of this study, we suggest that the factors involved in development of parasitic myomas can be classified as confirmed and doubtful contributions. PMID- 28732546 TI - The effectiveness of an educational intervention for sodium restriction in patients with hypertension: study protocol for a randomized controlled trial. AB - BACKGROUND: The effectiveness of nonpharmacological interventions in blood pressure reduction has been evidenced by several studies. Nevertheless, as adherence to a low-sodium diet is poor, interventions regarding habit changing should be of a motivational nature in order to develop the ability of overcoming obstacles regarding sodium-restriction behavior. The present study aims to describe the protocol and randomization of a clinical trial design in order to evaluate the effectiveness of an educational intervention based on Dietary Sodium Restriction Questionnaire (DSRQ) scores. The effectiveness measures are the DSRQ score variation and reduction in urinary sodium values from baseline to after 2 and 6 months. METHODS/DESIGN: This parallel, randomized clinical trial will include 120 participants, recruited and randomized as follows: 60 of them to be allocated to a sodium-restriction educational intervention group whose results are based on the DSRQ application; and the other 60 allocated to a control group with usual care. Educational orientation and usual care sessions will be conducted once a month for a period of 6 months. Both spot urine collection - estimating sodium intake - and the DSRQ will be applied at the baseline, in the eighth week and at the end of the follow-up. There will also be blood collection and 24-h ambulatory blood pressure monitoring (ABPM) at the beginning and end of the follow-up. Anthropometric measurements, blood pressure measurement and 24-h food recall will be collected during follow-up. DISCUSSION: The study "The effectiveness of an educational intervention to sodium restriction in patients with hypertension" is based on the results of the DSRQ application, whose objective is to evaluate aspects related to nonadherence to the recommendation of a low-sodium diet, identifying adherence barriers and facilitators, contributing to the planning of interventions for improving the adoption of a low-sodium diet and, consequently, hypertension control. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, Identifier: NCT02848690 . Registered retrospectively on 27 July 2016. PMID- 28732547 TI - Crescentic glomerular nephritis associated with rheumatoid arthritis: a case report. AB - BACKGROUND: Rheumatoid arthritis is a systemic disorder where clinically significant renal involvement is relatively common. However, crescentic glomerular nephritis is a rarely described entity among the rheumatoid nephropathies. We report a case of a patient with rheumatoid arthritis presenting with antineutrophil cytoplasmic antibody-negative crescentic glomerular nephritis. CASE PRESENTATION: A 54-year-old Sri Lankan woman who had recently been diagnosed with rheumatoid arthritis was being treated with methotrexate 10 mg weekly and infrequent nonsteroidal anti-inflammatory drugs. She presented to our hospital with worsening generalized body swelling and oliguria of 1 month's duration. Her physical examination revealed that she had bilateral pitting leg edema and periorbital edema. She was not pale or icteric. She had evidence of mild synovitis of the small joints of the hand bilaterally with no deformities. No evidence of systemic vasculitis was seen. Her blood pressure was 170/100 mmHg, and her jugular venous pressure was elevated to 7 cm with an undisplaced cardiac apex. Her urine full report revealed 2+ proteinuria with active sediment (dysmorphic red blood cells [17%] and granular casts). Her 24-hour urinary protein excretion was 2 g. Her serum creatinine level was 388 MUmol/L. Abdominal ultrasound revealed normal-sized kidneys with acute parenchymal changes and mild ascites. Her renal biopsy showed renal parenchyma containing 20 glomeruli showing diffuse proliferative glomerular nephritis, with 14 of 20 glomeruli showing cellular crescents, and the result of Congo red staining was negative. Her rheumatoid factor was positive with a high titer (120 IU/ml), but results for antinuclear antibody, double-stranded deoxyribonucleic acid, and antineutrophil cytoplasmic antibody (perinuclear and cytoplasmic) were negative. Antistreptolysin O titer <200 U/ml and cryoglobulins were not detected. The results of her hepatitis serology, retroviral screening, and malignancy screening were negative. Her erythrocyte sedimentation rate was 110 mm in the first hour, and her C-reactive protein level was 45 mg/dl. Her liver profile showed hypoalbuminemia of 28 g/dl. She was treated with immunomodulators and had a good recovery of her renal function. CONCLUSIONS: This case illustrates a rare presentation of antineutrophil cytoplasmic antibody-negative crescentic glomerular nephritis in a patient with rheumatoid arthritis, awareness of which would facilitate early appropriate investigations and treatment. PMID- 28732548 TI - Genome-wide mapping of transcriptional enhancer candidates using DNA and chromatin features in maize. AB - BACKGROUND: While most cells in multicellular organisms carry the same genetic information, in each cell type only a subset of genes is being transcribed. Such differentiation in gene expression depends, for a large part, on the activation and repression of regulatory sequences, including transcriptional enhancers. Transcriptional enhancers can be located tens of kilobases from their target genes, but display characteristic chromatin and DNA features, allowing their identification by genome-wide profiling. Here we show that integration of chromatin characteristics can be applied to predict distal enhancer candidates in Zea mays, thereby providing a basis for a better understanding of gene regulation in this important crop plant. RESULT: To predict transcriptional enhancers in the crop plant maize (Zea mays L. ssp. mays), we integrated available genome-wide DNA methylation data with newly generated maps for chromatin accessibility and histone 3 lysine 9 acetylation (H3K9ac) enrichment in young seedling and husk tissue. Approximately 1500 intergenic regions, displaying low DNA methylation, high chromatin accessibility and H3K9ac enrichment, were classified as enhancer candidates. Based on their chromatin profiles, candidate sequences can be classified into four subcategories. Tissue-specificity of enhancer candidates is defined based on the tissues in which they are identified and putative target genes are assigned based on tissue-specific expression patterns of flanking genes. CONCLUSIONS: Our method identifies three previously identified distal enhancers in maize, validating the new set of enhancer candidates and enlarging the toolbox for the functional characterization of gene regulation in the highly repetitive maize genome. PMID- 28732549 TI - Intraperitoneal lactate/pyruvate ratio and the level of glucose and glycerol concentration differ between patients surgically treated for upper and lower perforations of the gastrointestinal tract: a pilot study. AB - BACKGROUND: Secondary peritonitis is a condition associated with high morbidity and mortality. Continuous postoperative monitoring of patients to ensure timely intervention to treat complications without delay is important for survival and outcome. We aimed to (1) investigate potential differences in postoperative intraperitoneal biomarker levels between patients with upper and lower gastrointestinal tract lesion, and (2) compare postoperative biomarker levels between complicated and uncomplicated patients. METHODS: We included a total of 15 consecutive patients operated for upper (n = 7) and lower (n = 8) gastrointestinal tract perforation. We registered postoperative complications during a 30 days follow up-period. Complications were defined as intraabdominal complications, septic shock, and mortality. 5 patients were complicated. A microdialysis catheter was placed intraperitoneally in each patient. Samples were collected every 4th hour for up to 7 postoperative days. Samples were analysed for concentrations of glucose, lactate, pyruvate and glycerol. RESULTS: Microdialysis results showed that patients with upper gastrointestinal tract lesions had significantly higher levels of postoperative intraperitoneal glucose and glycerol concentrations, as well as lower lactate/pyruvate ratios and lactate/glucose ratios. In the group with perforation of the lower gastrointestinal tract, those patients with a complicated course showed lower levels of postoperative intraperitoneal glucose concentration and glycerol concentration and higher lactate/pyruvate ratios and lactate/glucose ratios than those patients with an uncomplicated course. CONCLUSION: Patients with upper and lower gastrointestinal tract lesions showed differences in postoperative biomarker levels. A difference was also seen between patients with complicated and uncomplicated postoperative courses. PMID- 28732551 TI - Novel Additions to the AJCC's New Staging Systems for Skin Cancer. AB - The eighth edition of the staging manual of the American Joint Committee on Cancer incorporates important changes in the classification of skin cancers. Coming 40 years after the first edition, the latest manual preserves its specific system for Merkel cell carcinoma and takes into account recent publications on the prognosis of squamous cell carcinoma by defining a completely new T category for this neoplasm. Staging for squamous cell carcinoma considers head and neck tumors (excluding the eyelid) and does not offer solutions for other sites except the vulva, penis, and perianal region. Regarding melanoma, use of the mitotic index has been eliminated and the prognosis of the primary tumor is based on Breslow thickness and ulceration. In addition, thickness is now recorded to an accuracy of 0.1mm, and the T0 concept has been introduced to define those metastatic melanomas in which the primary tumor has regressed completely. In this new edition, changes have also been made to the N category of all the skin cancer staging systems, and M1d has been added to the M category for melanoma to refer to metastatic involvement of the central nervous system, which, up to now, had been included in the M1c category. This new system will need to be validated with patient series to determine if it adequately satisfies the objective of tumor risk stratification. PMID- 28732552 TI - Current Interventions for Controlling Pathogenic Escherichia coli. AB - This review examined scientific reports and articles published from 2007 to 2016 regarding the major environmental sources of pathogenic Escherichia coli and the routes by which they enter the human gastrointestinal tract. The literature describes novel techniques used to combat pathogenic E. coli transmitted to humans from livestock and agricultural products, food-contact surfaces in processing environments, and food products themselves. Although prevention before contamination is always the best "intervention," many studies aim to identify novel chemical, physical, and biological techniques that inactivate or eliminate pathogenic E. coli cells from breeding livestock, growing crops, and manufactured food products. Such intervention strategies target each stage of the food chain from the perspective of "Farm to Table food safety" and aim to manage major reservoirs of pathogenic E. coli throughout the entire process. Issues related to, and recent trends in, food production must address not only the safety of the food itself but also the safety of those who consume it. Thus, research aims to discover new "natural" antimicrobial agents and to develop "multiple hurdle technology" or other novel technologies that preserve food quality. In addition, this review examines the practical application of recent technologies from the perspective of product quality and safety. It provides comprehensive insight into intervention measures used to ensure food safety, specifically those aimed at pathogenic E. coli. PMID- 28732550 TI - Epidemiology of taeniosis/cysticercosis in Europe, a systematic review: Western Europe. AB - BACKGROUND: Taenia solium and Taenia saginata are zoonotic parasites of public health importance. Data on their occurrence in humans and animals in western Europe are incomplete and fragmented. In this study, we aimed to update the current knowledge on the epidemiology of these parasites in this region. METHODS: We conducted a systematic review of scientific and grey literature published from 1990 to 2015 on the epidemiology of T. saginata and T. solium in humans and animals. Additionally, data about disease occurrence were actively sought by contacting local experts in the different countries. RESULTS: Taeniosis cases were found in twelve out of eighteen countries in western Europe. No cases were identified in Iceland, Ireland, Luxembourg, Norway, Sweden and Switzerland. For Denmark, Netherlands, Portugal, Slovenia, Spain and the UK, annual taeniosis cases were reported and the number of detected cases per year ranged between 1 and 114. Detected prevalences ranged from 0.05 to 0.27%, whereas estimated prevalences ranged from 0.02 to 0.67%. Most taeniosis cases were reported as Taenia spp. or T. saginata, although T. solium was reported in Denmark, France, Italy, Spain, Slovenia, Portugal and the UK. Human cysticercosis cases were reported in all western European countries except for Iceland, with the highest number originating from Portugal and Spain. Most human cysticercosis cases were suspected to have acquired the infection outside western Europe. Cases of T. solium in pigs were found in Austria and Portugal, but only the two cases from Portugal were confirmed with molecular methods. Germany, Spain and Slovenia reported porcine cysticercosis, but made no Taenia species distinction. Bovine cysticercosis was detected in all countries except for Iceland, with a prevalence based on meat inspection of 0.0002-7.82%. CONCLUSIONS: Detection and reporting of taeniosis in western Europe should be improved. The existence of T. solium tapeworm carriers, of suspected autochthonous cases of human cysticercosis and the lack of confirmation of porcine cysticercosis cases deserve further attention. Suspected cases of T. solium in pigs should be confirmed by molecular methods. Both taeniosis and human cysticercosis should be notifiable and surveillance in animals should be improved. PMID- 28732553 TI - Diversity, Application, and Synthetic Biology of Industrially Important Aspergillus Fungi. AB - The filamentous fungal genus Aspergillus consists of over 340 officially recognized species. A handful of these Aspergillus fungi are predominantly used for food fermentation and large-scale production of enzymes, organic acids, and bioactive compounds. These industrially important Aspergilli primarily belong to the two major Aspergillus sections, Nigri and Flavi. Aspergillus oryzae (section Flavi) is the most commonly used mold for the fermentation of soybeans, rice, grains, and potatoes. Aspergillus niger (section Nigri) is used in the industrial production of various enzymes and organic acids, including 99% (1.4 million tons per year) of citric acid produced worldwide. Better understanding of the genomes and the signaling mechanisms of key Aspergillus species can help identify novel approaches to enhance these commercially significant strains. This review summarizes the diversity, current applications, key products, and synthetic biology of Aspergillus fungi commonly used in industry. PMID- 28732554 TI - Microbial Ecology and Process Technology of Sourdough Fermentation. AB - From a microbiological perspective, sourdough is to be considered as a specific and stressful ecosystem, harboring yeasts and lactic acid bacteria (LAB), that is used for the production of baked goods. With respect to the metabolic impact of the sourdough microbiota, acidification (LAB), flavor formation (LAB and yeasts), and leavening (yeasts and heterofermentative LAB species) are most noticeable. Three distinct types of sourdough fermentation processes can be discerned based on the inocula applied, namely backslopped ones (type 1), those initiated with starter cultures (type 2), and those initiated with a starter culture followed by backslopping (type 3). A sourdough-characteristic LAB species is Lactobacillus sanfranciscensis. A sourdough-characteristic yeast species is Candida humilis. Although it has been suggested that the microbiota of a specific sourdough may be influenced by its geographical origin, region specificity often seems to be an artefact resulting from interpretation of the research data, as those are dependent on sampling, isolation, and identification procedures. It is however clear that sourdough-adapted microorganisms are able to withstand stress conditions encountered during their growth. Based on the technological setup, type 0 (predoughs), type I (artisan bakery firm sourdoughs), type II (industrial liquid sourdoughs), and type III sourdoughs (industrial dried sourdoughs) can be distinguished. The production of all sourdoughs, independent of their classification, depends on several intrinsic and extrinsic factors. Both the flour (type, quality status, etc.) and the process parameters (fermentation temperature, pH and pH evolution, dough yield, water activity, oxygen tension, backslopping procedure and fermentation duration, etc.) determine the dynamics and outcome of (backslopped) sourdough fermentation processes. PMID- 28732556 TI - Surfactant films in lyotropic lamellar (and related) phases: Fluctuations and interactions. AB - The analogy between soap films thinning under border capillary suction and lamellar stacks of surfactant bilayers dehydrated by osmotic stress is explored, in particular in the highly dehydrated limit where the soap film becomes a Newton black film. The nature of short-range repulsive interactions between surfactant covered interfaces and acting across water channels in both cases will be discussed. PMID- 28732555 TI - Hepatobiliary scintigraphy to evaluate liver function in associating liver partition and portal vein ligation for staged hepatectomy: Liver volume overestimates liver function. AB - BACKGROUND: Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) induces a rapid and extensive increase in liver volume. The functional quality of this hypertrophic response has been called into question because ALPPS is associated with a substantial incidence of liver failure and high perioperative mortality. This multicenter study aimed to evaluate functional liver regeneration in contrast to volumetric liver regeneration in ALPPS, using technetium-99m hepatobiliary scintigraphy and computed tomography volumetry, respectively. METHODS: Patients who underwent ALPPS and hepatobiliary scintigraphy in 6 centers were included. Hepatobiliary scintigraphy data were analyzed centrally at the Academic Medical Center in Amsterdam according to established protocols. Increase in liver function as measured by hepatobiliary scintigraphy after stage 1 of ALPPS was compared with the increase in liver volume. In addition, we analyzed the impact of liver function and volume on postoperative outcomes including liver failure, morbidity, and mortality. RESULTS: In 60 patients, future liver remnant volume increased by a median 78% (interquartile range 48-110) during a median 8 (interquartile range 6-14) days after stage 1, while function as measured by hepatobiliary scintigraphy increased by a median 29% (interquartile range 1-55) throughout 7 days (interquartile range 6-10) in the 27 patients with paired measurements. After stage 2 of ALPPS, liver failure occurred in 5/60 (8%) patients, severe complications in 24/60 (40%), and mortality occurred in 4/60 (7%). CONCLUSION: In ALPPS, volumetry overestimates liver function as measured by hepatobiliary scintigraphy and may be responsible for the high rate of liver failure. Quantitative liver function tests are highly recommended to avoid post hepatectomy liver failure. PMID- 28732557 TI - A Negative Slope Conductance of the Persistent Sodium Current Prolongs Subthreshold Depolarizations. AB - Neuronal subthreshold voltage-dependent currents determine membrane properties such as the input resistance (Rin) and the membrane time constant (taum) in the subthreshold range. In contrast with classical cable theory predictions, the persistent sodium current (INaP), a non-inactivating mode of the voltage dependent sodium current, paradoxically increases Rin and taum when activated. Furthermore, this current amplifies and prolongs synaptic currents in the subthreshold range. Here, using a computational neuronal model, we showed that the creation of a region of negative slope conductance by INaP activation is responsible for these effects and the ability of the negative slope conductance to amplify and prolong Rin and taum relies on the fast activation of INaP. Using dynamic clamp in hippocampal CA1 pyramidal neurons in brain slices, we showed that the effects of INaP on Rin and taum can be recovered by applying an artificial INaP after blocking endogenous INaP with tetrodotoxin. Furthermore, we showed that injection of a pure negative conductance is enough to reproduce the effects of INaP on Rin and taum and is also able to prolong artificial excitatory post synaptic currents. Since both the negative slope conductance and the almost instantaneous activation are critical for producing these effects, the INaP is an ideal current for boosting the amplitude and duration of excitatory post synaptic currents near the action potential threshold. PMID- 28732559 TI - SOCS-1 is involved in TNF-alpha-induced mitochondrial dysfunction and apoptosis in renal tubular epithelial cells. AB - Tumor necrosis factor-alpha (TNF-alpha) is suggested to induce mitochondrial dysfunction and apoptosis of renal tubular epithelial cells that possibly exacerbates renal function in chronic kidney disease (CKD). Here we investigated whether suppressor of cytokine signaling-1 (SOCS-1), an inhibitor of cytokine signaling, was involved in TNF-alpha-induced human renal tubular epithelial cells (HKCs) oxidative stress and apoptosis. TNF-alpha promoted the protein and mRNA expression of SOCS-1 in a time and dose dependent manner, along with increased cell apoptosis and activation of apoptosis signal regulating kinase-1(ASK1) in HKCs. Furthermore, overexpression of SOCS-1 in HKCs reduced TNF-alpha-mediated oxidative stress and apoptosis. Meanwhile, We also found that overexpression of SOCS-1 could regulate the activity of JAK/STAT signaling pathway. In addition, a specific JAK2 inhibitor, AG490, that both attenuated TNF-alpha-induced oxidative stress, also reduced apoptosis. Taken together, overexpression of SOCS-1 prevented TNF-alpha-mediated cell oxidative stress and apoptosis may be via suppression of JAK/STAT signaling pathway activation in HKCs. PMID- 28732558 TI - Resolvins as proresolving inflammatory mediators in cardiovascular disease. AB - Cardiovascular disease (CVD) represents a global burden with a prevalence that continues increasing progressively. CVD comprises a group of disorders of the heart and blood vessels including coronary heart disease, cerebrovascular disease and peripheral arterial disease. This group of disorders is associated with an inflammatory process which can participate in the pathophysiology of these diseases. Inflammation resolution is an active process involving the participation of pro-resolving mediators such as lipoxins, resolvins, protectins and maresins. Pro-resolving mediators are bioactive molecules generated from omega-3 polyunsaturated fatty acids (PUFAs); among these eicosapentaenoic acid (EPA; C20:5n3) and docosahexaenoic acid (DHA; C22:6n3) are the precursors of resolvins. Pro-resolving mediators orchestrate the correct resolution of inflammation and also stimulate tissue regeneration. Their deregulation can lead to chronic inflammation involving CVD. The discovery of these novel lipid mediators opens a new range of possibilities for the design of anti-inflammatory agents with therapeutic potential for a wide variety of diseases. The present work summarizes the available data about the general characteristics, structure and biosynthesis of resolvins and their relation as protective compounds in CVD. PMID- 28732560 TI - [Tubulocystic renal cell carcinoma with poorly differentiated foci]. AB - Tubulocystic renal cell carcinoma is a rare tumor with an indolent behavior in the majority of cases. In contrast, tubulocystic renal cell carcinoma with poorly differentiated foci has a bad prognosis with an aggressive and metastatic behavior. We present the case of a patient diagnosed with tubulocystic renal cell carcinoma with poorly differentiated foci. PMID- 28732561 TI - Open treatment of unilateral mandibular condyle fractures in adults: a systematic review. AB - Since the introduction of rigid internal fixation devices, more and more surgeons favour an open approach to treating condylar fractures of the mandible in adult patients. Different indications for open treatment have been published. Open treatment is associated with surgical complications because of the technique employed. The aim of this systematic review was to provide an overview of the studies published exclusively on open treatment, and to summarize the existing open treatment modalities and their clinical outcomes. A total of seventy studies were selected for detailed analysis. Most studies reported good results with regard to the outcome measures of open treatment. Surgical complications including hematoma, wound infection, weakness of the facial nerve, sialocele, salivary fistula, sensory disturbance of the great auricular nerve, unsatisfactory scarring, and fixation failure were reported in the studies. This review suggests that because of the high level of methodological variance in the relevant studies published to date, among other factors, there are currently no evidence-based conclusions or guidelines that can be formulated with regard to the most appropriate open treatment. Establishment of such standards could potentially improve treatment outcomes. PMID- 28732562 TI - Moral Distress in Rehabilitation. PMID- 28732563 TI - Risk factors and outcomes for the acquisition of carbapenem-resistant Gram negative bacillus bacteremia: A retrospective propensity-matched case control study. AB - BACKGROUND/PURPOSE: A substantial number of carbapenem-resistant Gram-negative bacilli (CR GNB) have been identified among the etiologic multidrug-resistant GNB in healthcare-associated infections. For achieving a better therapeutic outcome by minimizing inappropriate empirical antibiotic treatment before blood culture and susceptibility testing results are available, it is very important to identify patients who are at risk for the development of CR GNB bacteremia. METHODS: Retrospective analysis of propensity-score matched (PSM) adult patients with CR GNB bacteremia (PSM-group 1 [n = 95]) and those with non-CR GNB bacteremia (PSM-group 2 [n = 190]). RESULTS: PSM-group 1 was found to a significantly longer length of hospital stay (27 vs. 18 days; p < 0.001) after emerging GNB bacteremia and a higher 30-day all-cause mortality rate (27.4% vs. 5.8%; p < 0.001), when compared with PSM-2 group. Independent risk factors for the acquisition of CR GNB bacteremia were previous exposure to an antipseudomonal penicillin (odds ratio [OR] = 3.58; 95% confidence interval [CI] = 1.30-9.90), an antipseudomonal cephalosporin (OR = 3.49; 95% CI = 1.09-11.24), and a carbapenem (OR = 3.60; 95% CI = 1.37-9.47), and longer length of hospital stay before the development of GNB bacteremia (OR = 1.03; 95% CI = 1.01-1.05). CONCLUSION: Risk factors for acquisition of CR GNB bacteremia identified in this study each may serve as a reminder alerting clinicians to hospitalized patients at risk for CR GNB bacteremia requiring appropriate antibiotic coverage, and in these circumstances, combined antibiotics may be used until antimicrobial de escalation/adjustment is clearly indicated by the subsequently identified pathogenic GNB and its susceptibility profile. PMID- 28732564 TI - Desiccation and ethanol resistances of multidrug resistant Acinetobacter baumannii embedded in biofilm: The favorable antiseptic efficacy of combination chlorhexidine gluconate and ethanol. AB - BACKGROUND/PURPOSE: Globally, multidrug-resistant Acinetobacter baumannii (MDRAB) has emerged as an important pathogen in nosocomial outbreaks. This study aimed to investigate the correlation between the biofilm formation and survival of MDRABs, and to investigate the antiseptic efficacy of hand sanitizers for the MDRABs, embedded with biofilm (MDRAB-Bs). METHODS: The MDRABs were selected randomly after pulsed-field gel electrophoresis (PFGE), and their biofilm formation was analyzed. Desiccation and ethanol tolerances were assayed to test the bacterial survival. The antiseptic efficacy of combined chlorhexidine gluconate (CHG) and 70% ethanol agents against MDRAB-Bs were compared with the 70% ethanol cleanser. RESULTS: Eleven MDRABs, which varied in biofilm formation (MRDAB-B) and planktonic type (MDRAB-P), were tested. In desiccation survival, the mean survival time for the MDRAB-Bs was 49.0 days which was significantly higher than that of their planktonic type (17.3 days) (P < 0.005). The MDRAB-Ps could be eliminated after a 10 min contact with a 30% ethanol agent, however, it took 10 min of 70% ethanol to eliminate the MDRAB-Bs. On the other hand, a 2% CHG in 70% ethanol solution completely eliminated all MDRAB-Bs after 1 min contacted time. The 2% CHG in 70% ethanol agent provided a significantly superior efficacy than the 70% ethanol solution at eliminating the MDRAB-Bs (P < 0.005). CONCLUSION: MDRAB with biofilm-formation presented significantly higher desiccation and ethanol resistances than their planktonic type. Moreover, the 2% CHG in 70% ethanol agent provided a superior antiseptic efficacy for MDRAB-Bs than that of the 70% ethanol agent. PMID- 28732565 TI - Circulating irisin levels are lower in patients with either stable coronary artery disease (CAD) or myocardial infarction (MI) versus healthy controls, whereas follistatin and activin A levels are higher and can discriminate MI from CAD with similar to CK-MB accuracy. AB - BACKGROUND: Several myokines are produced by cardiac muscle. We investigated changes in myokine levels at the time of acute myocardial infarction (MI) and following reperfusion in relation to controls. METHODS: Patients with MI (MI Group, n=31) treated with percutaneous coronary intervention (PCI) were compared to patients with stable coronary artery disease (CAD) subjected to scheduled PCI (CAD Group, n=40) and controls with symptoms mimicking CAD without stenosis in angiography (Control Group, n=43). The number and degree of stenosis were recorded. Irisin, follistatin, follistatin-like 3, activin A and B, ALT, AST, CK and CK-MB were measured at baseline and 6 or 24h after the intervention. RESULTS: MI and CAD patients had lower irisin than controls (p<0.001). MI patients had higher follistatin, activin A, CK, CK-MB and AST than CAD patients and controls (all p<=0.001). None of the myokines changed following reperfusion. Circulating irisin was associated with the degree of stenosis in all patients (p=0.05). Irisin was not inferior to CK-MB in predicting MI while folistatin and activin A could discriminate MI from CAD patients with similar to CK-MB accuracy. None of these myokines was altered following PCI in contrast to CK-MB. CONCLUSIONS: Irisin levels are lower in MI and CAD implying that their production may depend on myocadial blood supply. Follistatin and activin A are higher in MI than in CAD suggesting increased release due to myocardial necrosis. They can predict MI with accuracy similar to CK-MB and their role in the diagnosis of MI remains to be confirmed by prospective large clinical studies. PMID- 28732566 TI - Association of circulating irisin levels with metabolic and metabolite profiles of Korean adolescents. AB - CONTEXT: Irisin, a novel exercise-induced myokine, has been suggested to regulate energy metabolism. OBJECTIVE: We studied the relationship between circulating irisin and metabolic and metabolite profiles of Korean adolescents, and investigated the effects of physical activity, obesity, and metabolic syndrome (MetS) on irisin levels. MATERIALS AND METHODS: Data were obtained from the Korean Children-Adolescents Study. Our cross-sectional study included 618 adolescents (370 normal-weight and 248 obese adolescents; 316 boys and 302 girls) aged 12-15years. Body composition was determined using an impedance body composition analyzer and general participant characteristics and lifestyle information were obtained from questionnaires. Serum irisin levels were measured using a commercial kit. RESULTS: Mean body mass index (BMI) was 19.4kg/m2 in normal-weight adolescents and 31.4kg/m2 in obese adolescents. Circulating irisin was positively correlated with adiposity indices, including BMI z-score, waist circumference, percent body fat, fat mass, fat-free mass, fat mass to fat-free mass ratio, and lipid and glucose metabolism markers, including total cholesterol, low-density lipoprotein cholesterol (LDL-C), triglycerides, glucose, insulin, and homeostasis model assessment-estimated insulin resistance (all p<=0.006). Of these, increased body fat mass [standardized (Std) beta, 0.23; p<0.0001], LDL-C (Std beta, 0.14; p=0.0005) and fasting glucose (Std beta, 0.08; p=0.0383) were the main independent factors associated with higher irisin levels. Moreover, elevated serum irisin was associated with the risk of obesity [odds ratio (OR], 2.2; confidence interval (CI), 1.19-3.87] and MetS (OR, 2.0; CI, 1.15 3.47). Furthermore, irisin and branched-chain amino acids were positively associated (p<4*10-4 for Bonferroni correction). Additionally, in the normal weight group, girls had higher irisin levels than boys (p=0.006) and adolescents who engaged in regular physical activity had higher levels of irisin than sedentary adolescents (p=0.0388). The relationship between physical activity and irisin levels was not observed in obese adolescents. CONCLUSIONS: Elevated serum irisin was independently associated with the risk of obesity and positively correlated with unhealthy metabolic parameters and metabolites. Moreover, irisin levels were higher in active versus sedentary adolescents in the normal-weight group, but not in the obese group. Our findings suggest that irisin plays an important role in metabolic disorders and may be affected by physiopathological status. PMID- 28732567 TI - Curcumin-3,4-Dichloro Phenyl Pyrazole (CDPP) overcomes curcumin's low bioavailability, inhibits adipogenesis and ameliorates dyslipidemia by activating reverse cholesterol transport. AB - BACKGROUND: Adipocyte dysfunction, obesity and associated metabolic disorders are of prime healthcare concern worldwide. Among available medications, natural products and inspired molecules hold 40% space in clinically prescribed medicines. In queue, this study overcomes the drawback of curcumin's low bioavailability with potent anti-adipogenic and anti-dyslipidemic activity. METHODS: To evaluate the role of CDPP on adipocyte differentiation, 3T3-L1 adipocytes were used as an in-vitro model. Flow cytometry was performed for cell cycle analysis. Syrian golden hamsters were used to study pharmacokinetic profile and dyslipidemic activity exhibited by CDPP. RESULT: CDPP was found to be a potent inhibitor of adipogenesis in-vitro. It blocked mitotic clonal expansion by causing cell cycle arrest. CDPP showed marked improvement in gastrointestinal stability and bioavailability in-vivo as compared to curcumin. Administration of CDPP (100mg/kg) significantly improved HFD induced dyslipidemic profile in hamsters and activated reverse cholesterol transport machinery. CONCLUSION: CDPP could be used as a potential drug candidate against adipogenesis and dyslipidemia with enhanced gastrointestinal stability and bioavailability. PMID- 28732568 TI - Effects of oral contraceptives on metabolic profile in women with polycystic ovary syndrome: A meta-analysis comparing products containing cyproterone acetate with third generation progestins. AB - BACKGROUND: Although oral contraceptives (OCs) are the most common treatment in women with polycystic ovary syndrome (PCOS), their effects and safety on the metabolic profiles of these patients are relatively unknown. In this meta analysis the effects of the different durations (from 3months to 1year) of OC treatment using cyproterone acetate (CA) or third generation progestins on metabolic profile of patients with PCOS were assessed. MATERIALS AND METHODS: PubMed, Scopus, Google Scholar and ScienceDirect databases (2001-2015) were searched to identify clinical trials investigating the effects of OC containing CA or third generation progestins on metabolic profiles of women with PCOS. Both fixed and random effect models were used. Subgroup analyses were performed based on the progestin compounds used and on duration of treatment. RESULTS: Oral contraceptive (OC) use was found to be associated with a worsening in lipid profiles but no changes were observed in other metabolic outcomes, including body mass index (BMI), fasting blood glucose (FBG), fasting insulin, homeostatic model for measuring insulin resistance (HOMA-IR) and in blood pressure (BP) values. All studied OCs showed similar effects on lipid profiles but with different timings, with products containing CA, requiring 6months to raise high density lipoprotein cholesterol (HDL-C) levels and 12months to increase triglycerides (TG). On the contrary, products containing drospirenone (DRSP) or desogestrel (DSG) increased HDL-C after only 3months but determined elevations of TG after 6months. All OCs induced an increase in low density lipoprotein-cholesterol (LDL-C) after 12months of use. CONCLUSIONS: The study shows that, in women with PCOS, OC use is associated with significant changes in lipid profiles, including elevation not only in HDL-C but also in TG and LDL-C. All OCs studied showed similar effects but with different timings, with products containing CA generally requiring more prolonged use to increase serum lipids. Instead, OC use does not affect body weight, BP or glucose levels, with only some minor increase of fasting insulin levels. PMID- 28732569 TI - High insulin-like growth factor-binding protein-1 (IGFBP-1) is associated with low relative muscle mass in older women. AB - OBJECTIVE: Skeletal muscles serve several important roles in maintaining good health. Insulin-like growth factor-1 (IGF-1) is a promoter of protein synthesis in skeletal muscle. Its binding protein, Insulin-like growth factor-binding protein-1 (IGFBP-1) can be one determinant of IGF-1 activity. In the present study we investigate the association between serum IGFBP-1 and muscle mass. DESIGN: Cross-sectional analysis of 4908 women, between 55 and 85years old, participating in the Swedish Mammography Cohort-Clinical. METHODS: We defined low relative muscle mass (LRMM) as an appendicular lean mass divided by height squared of less than 5.45 (kg/m2), assessed by dual energy x-ray absorptiometry. IGFBP-1 was measured by radioimmunoassay. Logistic regression was used to calculate odds-ratios of LRMM across quartiles of IGFBP-1. RESULTS: The odds of LRMM increased across quartiles of IGFBP-1. In the age-adjusted model the odds ratio (OR) of LRMM was 3.41 (95% CI: 2.55-4.56), comparing the highest to the lowest quartile. This estimate was attenuated in multivariate models (OR: 1.84, 95% CI: 1.34-2.53), mainly due to inclusion of fat mass index. CONCLUSION: Women with higher IGFBP-1 were more likely to have a low relative muscle mass. High IGFBP-1 may be a marker of a catabolic state. PMID- 28732571 TI - Examining the gut bacteriome, virome, and mycobiome in glucose metabolism disorders: Are we on the right track? AB - Human gut microbiome is defined as the gene complement of the gut microbial community, measured via laboratory metagenomic techniques. It includes bacteriome, virome and mycobiome, which represent, respectively, the assemblages of bacteria, viruses and fungi, living in the human gut. Gut microbiota function as a living "organ" that interacts with the gastro-intestinal environment, provides nutrients and vitamins to the organism and transduces hormonal messages, essentially influencing the main metabolic pathways, including drug metabolism. A clear association between gut, and glucose metabolism disorders has recently emerged. Medications acting on glucose absorption in the gut, or enhancing gut hormone activity are already extensively employed in the therapy of diabetes. Moreover, the gut is characterized by immune, and autonomous neuronal features, which play a critical role in maintaining glucose metabolism homeostasis. Gut microbes respond to neuroendocrine, and immune biochemical messages, affecting the health, and behavior of the host. There is vast heterogeneity in the studies included in this review, hence a meta-analysis, or a systematic review were not applicable. In this article, we attempt to reveal the interplay between human gut microbiota physiology, and hyperglycemic states, synthesizing, and interpreting findings from human studies. PMID- 28732570 TI - Incident type 2 diabetes is associated with HDL, but not with its anti-oxidant constituent - paraoxonase-1: The prospective cohort PREVEND study. AB - OBJECTIVE: High-density lipoprotein cholesterol (HDL-C) is an established risk marker for cardiovascular disease and consistently associated with type 2 diabetes risk. Serum paraoxonase-1 (PON-1) - an anti-oxidant constituent of HDL - is inversely associated with cardiovascular disease risk, but its relationship with incident type 2 diabetes is uncertain. We aimed to investigate the prospective association between PON-1 and type 2 diabetes risk. METHODS: PON-1 was measured as its arylesterase activity at baseline in the Prevention of Renal and Vascular End-stage Disease (PREVEND) prospective study of 5947 predominantly Caucasian participants aged 28-75years with no pre-existing diabetes, that recorded 500 type 2 diabetes cases during a median follow-up of 11.2years. RESULTS: Serum PON-1 was positively correlated with HDL-C (r=0.17; P<0.001). In analyses adjusted for conventional diabetes risk factors, the hazard ratio (95% CI) for type 2 diabetes per 1 standard deviation increase in PON-1 was 1.07 (0.98 to 1.18; P=0.13), which remained non-significant (1.02 (0.93 to 1.12) P=0.65) after additional adjustment for potential confounders. The association was unchanged on further adjustment for HDL-C (1.05 (0.96 to 1.15; P=0.29). However, in subsidiary analyses in the same set of participants, serum HDL-C concentration was inversely and independently associated with risk of type 2 diabetes. CONCLUSIONS: Incident type 2 diabetes is associated with HDL cholesterol but not with its anti-oxidant constituent - PON-1 - in a large cohort of apparently healthy men and women. The current data question the importance of PON-1 activity for the development of diabetes. PMID- 28732572 TI - Vitamin D supplementation and glycemic control in type 2 diabetes patients: A systematic review and meta-analysis. AB - INTRODUCTION: Low vitamin D status has been found to be associated with impaired glycemic control in patients who suffer from type 2 diabetes; however, whether vitamin D supplementation is associated with improved glycemic status remains controversial. The aim of this study was to summarize evidence from randomized controlled trials (RCTs) to assess the efficacy of vitamin D supplementation in reducing glycosylated haemoglobinA1c (HbA1c) and fasting blood glucose (FBG) levels. MATERIALS/METHODS: We searched PubMed, Web of Science and the Cochrane Library for reports published up to March 2017. We selected parallel RCTs investigating the effect of vitamin D or vitamin D analogues on HbA1c or FBG levels in type 2 diabetes patients. Cohen's d was calculated to represent the standardized mean difference (SMD) for each study, and the SMDs with 95%confidence intervals (CIs) were pooled using a random effects model. RESULTS: Twenty-four studies were included that evaluated HbA1c levels and 18 studies were included that evaluated FBG levels. Meta-analyses showed that vitamin D supplementation was associated with reduced HbA1c levels (standardized mean difference (SMD) -0.25 [-0.45 to -0.05]) but had no influence on FBG levels (SMD 0.14 [-0.31 to 0.03]). However, the subgroup analyses suggested that vitamin D supplementation was associated with reduced HbA1c levels (SMD -0.39 [-0.67 to 0.10]) and FBG (SMD -0.27 [-0.46 to -0.07]) among patients with 25-hydroxyvitamin D (25(OH) D) deficiency at baseline. Significantly reduced HbA1c levels were also observed in association with vitamin D supplementation in the subgroup including type 2 diabetes patients with a body mass index (BMI) <30kg m-2 (SMD -0.30 [-0.54 to -0.07]). CONCLUSIONS: Vitamin D supplementation could be effective at improving glycemic control in vitamin D deficient or non-obese type 2 diabetes patients. PMID- 28732573 TI - The association between immunoglobulin concentrations and prediabetes prevalence in a large Chinese cohort. AB - AIMS: Prediabetes has received public attention owing to the increasing prevalence worldwide. Mounting evidence has indicated that inflammation directly contributed to the etiology of glucose metabolism disorders. Although immunoglobulins play a crucial role in immune responses, little research has been done on the link between immunoglobulins and prediabetes in adults. Hence, the aim of the present study was to explore the associations between immunoglobulins levels and prevalence of prediabetes in a general adult population. METHODS: A cross-sectional study was conducted among 8856 adults (mean+/-standard deviation age: 48.4+/-10.7years) in Tianjin, China. The serum immunoglobulins concentrations were measured by the immunonephelometric technique. Prediabetes was diagnosed using the following parameters in accordance with the American Diabetes Association: fasting plasma glucose, postprandial glucose and glycosylated hemoglobin. The associations between concentrations of immunoglobulins and the prevalence of prediabetes were assessed using multiple logistic regression models. RESULTS: Overall, the prevalence of prediabetes was 37.4% (3311/8856). After controlling for confounders, compared with the lowest quintile, the odds ratios (95% confidence interval) of prediabetes for the highest quintile of immunoglobulins (immunoglobulin G, immunoglobulin E, immunoglobulin M and immunoglobulin A) were as follows: 1.06 (0.91-1.23), 1.31 (1.13-1.52), 0.86 (0.74-1.01), and 1.19 (1.03-1.38) (P for trend were 0.35, <0.0001, 0.04 and 0.02), respectively. CONCLUSIONS: Elevated immunoglobulin E and immunoglobulin A levels were independently and positively associated with prediabetes prevalence. There was also a trending association between immunoglobulin M concentrations and prediabetes prevalence. Further studies are necessary to clarify if there is a causal association of immunoglobulins in prediabetes or if they reflect early immunologic disturbances in these patients. PMID- 28732575 TI - Beraprost sodium, a prostacyclin analogue, reduces fructose-induced hepatocellular steatosis in mice and in vitro via the microRNA-200a and SIRT1 signaling pathway. AB - PURPOSE: To determine whether beraprost sodium, a prostacyclin analogue, could reduce hepatic lipid accumulation induced by fructose in mice and cultured human hepatocytes, and to investigate the expression of microRNAs and the sirtuin 1 (SIRT1) pathway. METHODS: Male C57BL/6JNju mice were divided into three groups and fed one of the following diets: a normal diet, a high fructose diet, or a high fructose diet with beraprost sodium treatment. In addition, human-derived HepG2 cells were cultured and treated with fructose (25mmol/L) with or without beraprost sodium (10MUmol/L) for 24h, and transfected with small interfering RNA (siRNA) against SIRT1, miR-200a mimic, or miR-200a inhibitor for 48h. The miRNA microarray analysis was performed on the HepG2 cells, and the expression profiles of miRNAs were analyzed using Gene Cluster 3.0 and verified using qPCR. RESULTS: Beraprost sodium treatment attenuated hepatic steatosis, induced the transcription of genes involved in lipid metabolism in C57BL/6 mice (P<0.05), and increased the expression of hepatic SIRT1 and peroxisome proliferator activated receptor alpha (PPARalpha) in the cells treated with fructose. These effects were blocked in HepG2 cells after transfection with siRNA against SIRT1. MiR-200a was highly expressed during fructose treatment and was down regulated by beraprost sodium (P<0.05). A luciferase assay showed that miR-200a regulated SIRT1 by binding to the 3' UTR. Overexpression of miR-200a inhibited expression of hepatic SIRT1. CONCLUSIONS: Our study demonstrated that SIRT1 pathway mediated the effects of beraprost sodium on attenuation of hepatic lipid disorders induced by fructose and revealed the primary role of miR-200a in the regulation of hepatic SIRT1 by beraprost sodium. Our findings suggested that SIRT1 might be a therapeutic target of fructose-related metabolism disorders. PMID- 28732574 TI - Albiflorin ameliorates obesity by inducing thermogenic genes via AMPK and PI3K/AKT in vivo and in vitro. AB - OBJECTIVE: Brown adipose tissue (BAT) activation has been identified as a possible target to treat obesity and to protect against metabolic diseases by increasing energy consumption. We explored whether albiflorin (AF), a natural compound, could contribute to lowering the high risk of obesity with BAT and primary brown preadipocytes in vivo and in vitro. MATERIALS/METHODS: Human adipose tissue-derived mesenchymal stem cells (hAMSCs) were cultured with adipogenic differentiation media with or without AF. Male C57BL/6J mice (n=5 per group) were fed a high-fat diet (HFD) for six weeks with or without AF. Brown preadipocytes from the interscapular BAT of mice were cultured with or without AF. RESULTS: In white adipogenic differentiation of hAMSCs, AF treatment significantly reduced the formation of lipid droplets and the expression of adipogenesis-related genes. In HFD-induced obese C57BL/6J mice, AF treatment significantly reduced body weight gain as well as the weights of the white adipose tissue, liver and spleen. Furthermore, AF induced the expression of genes involved in thermogenic function in BAT. In primary brown adipocytes, AF effectively stimulated the expressions of thermogenic genes and markedly up regulated the AMP-activated protein kinase (AMPK) signaling pathway. Pretreatment with phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 nullified the induction of the thermogenic genes by AF in primary brown adipocytes. Moreover, AF activated beige cell marker genes induced by the pharmacological activation of peroxisome proliferator-activated receptor gamma in hAMSCs. CONCLUSION: This study shows that AF prevents the development of obesity in hAMSCs and mice fed an HFD and that it is also capable of stimulating the differentiation of brown adipocytes through the modulation of thermogenic genes by AMPK and PI3K/AKT. PMID- 28732576 TI - FRAX Update. AB - The fracture risk assessment tool, FRAX, was released in 2008 and provides country-specific algorithms for estimating individualized 10-year probability of hip and major osteoporotic fracture (hip, clinical spine, distal forearm, and proximal humerus). Since its release, models are now available for 63 countries, covering 79% of the world population. The website receives approximately 3 million visits annually. Following independent validation, FRAX has been incorporated into more than 80 guidelines worldwide. However, the application of FRAX in guidelines has been heterogeneous with the adoption of several different approaches to setting intervention thresholds. The relationship between FRAX and efficacy of intervention has been explored and is expected to influence treatment guidelines in the future. A more unified approach to setting intervention thresholds with FRAX is a research priority. PMID- 28732577 TI - Cross Calibration of the GE Prodigy and iDXA for the Measurement of Total and Regional Body Composition in Adults. AB - Dual-energy X-ray absorptiometry (DXA) body composition measurements are widely performed in both clinical and research settings, and enable the rapid and noninvasive estimation of total and regional fat and lean mass tissues. DXA upgrading can occur during longitudinal monitoring or study; therefore, cross calibration of old and new absorptiometers is required. We compared soft tissue estimations from the GE Prodigy (GE Healthcare, Madison, WI) with the more recent iDXA (GE Healthcare) and developed translational equations to enable Prodigy values to be converted to iDXA values. Eighty-three males and females aged 20.1 63.3 yr and with a body mass index range of 17.0-34.4 kg/m2 were recruited for the study. Fifty-nine participants (41 females and 18 males) comprised the cross calibration group and 24 (14 females and 10 males) comprised the validation group. Total body Prodigy and iDXA scans were performed on each subject within 24 h. Predictive equations for total and regional soft tissue parameters were derived from linear regression of the data. Measures of lean and fat tissues were highly correlated (R2 = 0.95-0.99), but significant differences and variability between machines were identified. Bland-Altman analysis revealed significant biases for most measures, particularly for arm, android, and gynoid fat mass (12.3%-22.7%). The derived translational equations reduced biases and differences for most parameters, although limits of agreement exceeded iDXA least significant change. In conclusion, variability in soft tissue estimates between the Prodigy and iDXA were detected, supporting the need for translational equations in longitudinal monitoring. The derived equations are suitable for group analysis but not individual analysis. PMID- 28732578 TI - Osteoporosis-Assessing Fracture Risk. PMID- 28732579 TI - Survival rates and marginal bone loss of zirconia implants are promising, but more evidence on long-term outcomes is needed. PMID- 28732580 TI - Mechanical and antibiotic periodontal therapies may be no different in terms of tooth loss in patients with chronic periodontitis. PMID- 28732581 TI - Short implants may yield similar clinical outcomes as sinus grafting plus long implants at 3 years. PMID- 28732582 TI - Low-level laser therapy may reduce dentin hypersensitivity after scaling and root planing. PMID- 28732583 TI - Resilient liner-retained overdentures seem to have a lower rate of mechanical complications than clip-retained overdentures in patients with 2 implant supported bar-retained overdentures. PMID- 28732584 TI - Boric acid probably increases clinical attachment level and reduces probing depth and intrabony defect depth when used as an adjunct to scaling and root planing in patients with chronic periodontitis. PMID- 28732585 TI - Obtaining a high activity subtilisin preparation by controlled thermal stress in n-octane. AB - The use of enzymes in organic solvents has considerably widened their repertoire of applications. Such low water containing media also offer the possibility of carrying out enzymatic reactions at higher temperatures and enhancing reaction yields. The utility of such preparations is limited by the damage caused to the protein structure during freeze-drying. This work investigates the result of exposing the proteolytic enzyme subtilisin to high temperature in low water containing n-octane on its activity in aqueous and non-aqueous media. Exposing subtilisin at 90 degrees C for 5 h led to 18-fold improvement in its transesterification activity even at the normal assay temperature (37 degrees C) when compared with the untreated enzyme. The use of n-octane as the reaction medium was important as it helped to retain the three-dimensional architecture of the enzyme and should be considered while designing strategies for obtaining high activity preparations of other enzymes. Structural analysis using differential scanning fluorimetry showed that the enzyme lost its structure after heating in aqueous medium but retained it when heated in organic solvent. The simplicity and general applicability of the strategy should make it useful for obtaining highly active preparations of other enzymes as well. PMID- 28732586 TI - [Eosinophilic gastroenteropathy and digestive obstruction]. PMID- 28732587 TI - The skin as a window to the blood: Cutaneous manifestations of myeloid malignancies. AB - Cutaneous manifestations of myeloid malignancies are common and have a broad range of presentations. These skin findings are classified as specific, due to direct infiltration by malignant hematopoietic cells, or non-specific. Early recognition and diagnosis can have significant clinical implications, as skin manifestations may be the first indication of underlying hematologic malignancy, can reflect the immune status and stage of disease, and cutaneous reactions may occur from conventional and targeted agents used to treat myeloid disease. In addition, infections with cutaneous involvement are common in immunocompromised patients with myeloid disease. Given the varying presentations, dermatologic findings associated with myeloid malignancies can pose diagnostic challenges for hematologists and dermatologists. In this clinical review intended for the practicing hematologist/oncologist, we discuss the presentation, diagnosis, treatment, and prognostic value of the most common cutaneous manifestations associated with myeloid malignancies using illustrative macro- and microscopic figures and with a special emphasis on practical considerations. PMID- 28732588 TI - Editorial Comment. PMID- 28732589 TI - Accuracy of Diagnostic Imaging Modalities for Classifying Pediatric Eyes as Papilledema Versus Pseudopapilledema. AB - PURPOSE: To identify the most accurate diagnostic imaging modality for classifying pediatric eyes as papilledema (PE) or pseudopapilledema (PPE). DESIGN: Prospective observational study. SUBJECTS: Nineteen children between the ages of 5 and 18 years were recruited. Five children (10 eyes) with PE, 11 children (19 eyes) with PPE owing to suspected buried optic disc drusen (ODD), and 3 children (6 eyes) with PPE owing to superficial ODD were included. METHODS: All subjects underwent imaging with B-scan ultrasonography, fundus photography, autofluorescence, fluorescein angiography (FA), optical coherence tomography (OCT) of the retinal nerve fiber layer (RNFL), and volumetric OCT scans through the optic nerve head with standard spectral-domain (SD OCT) and enhanced depth imaging (EDI OCT) settings. Images were read by 3 masked neuro-ophthalmologists, and the final image interpretation was based on 2 of 3 reads. Image interpretations were compared with clinical diagnosis to calculate accuracy and misinterpretation rates of each imaging modality. MAIN OUTCOME MEASURES: Accuracy of each imaging technique for classifying eyes as PE or PPE, and misinterpretation rates of each imaging modality for PE and PPE. RESULTS: Fluorescein angiography had the highest accuracy (97%, 34 of 35 eyes, 95% confidence interval 92%-100%) for classifying an eye as PE or PPE. FA of eyes with PE showed leakage of the optic nerve, whereas eyes with suspected buried ODD demonstrated no hyperfluorescence, and eyes with superficial ODD showed nodular staining. Other modalities had substantial likelihood (30%-70%) of misinterpretation of PE as PPE. CONCLUSIONS: The best imaging technique for correctly classifying pediatric eyes as PPE or PE is FA. Other imaging modalities, if used in isolation, are more likely to lead to misinterpretation of PE as PPE, which could potentially result in failure to identify a life threatening disorder causing elevated intracranial pressure and papilledema. PMID- 28732590 TI - Cost-Utility of Evaluation for Posterior Vitreous Detachment and Prophylaxis of Retinal Detachment. AB - PURPOSE: To evaluate the costs and cost-utility of examination for posterior vitreous detachment (PVD) and treatment of associated pathology, and of managing various other peripheral retinal disorders to prevent retinal detachment (RD). DESIGN: A decision analysis model of cost-utility. PARTICIPANTS: There were no participants. METHODS: Published retrospective data on the natural course of PVD, retinal tears, and lattice degeneration were used to quantitate the visual benefits of examination and treatment. Center for Medicare and Medicaid Services data were used to calculate associated modeled costs in a hospital/facility-based and nonfacility/ambulatory surgical center (ASC)-based setting. Published standards of utility for a given level of visual acuity were used to derive costs and quality-adjusted life years (QALYs). MAIN OUTCOME MEASURES: Cost of evaluation and treatment, utility of defined health states, QALY, and cost per QALY. RESULTS: The modeled cost of evaluation of a patient with PVD and treatment of associated pathology in the facility/hospital (nonfacility/ASC)-based setting was $65 to $190 ($25-$71) depending on whether a single or 2-examination protocol was used. The cost per QALY saved was $255 to $638/QALY ($100-$239/QALY). Treatment of a symptomatic horseshoe tear resulted in a net cost savings of $1749 ($1314) and improved utility, whereas treatment of an asymptomatic horseshoe tear resulted in $2981/QALY ($1436/QALY). Treatment of asymptomatic lattice degeneration in an eye in which the fellow eye had a history of RD resulted in $4414/QALY ($2187/QALY). CONCLUSIONS: Evaluation and management of incident acute PVD (and symptomatic horseshoe tears) offer a low cost and a favorable cost utility (low $/QALY) as a result of the minimization of the cost and morbidity associated with the development of RD, thus justifying current practice standards. PMID- 28732592 TI - Correlation between early revascularization and major cardiac events demonstrated by ischemic myocardium in Japanese patients with stable coronary artery disease. AB - BACKGROUND: There is no report on correlation between early revascularization and the occurrence of major cardiac events (MCEs) except severe heart failure in Japanese patients with stable coronary artery disease (CAD). This study aimed to determine whether early revascularization affected the incidence of MCEs in Japanese patients with stable CAD. METHODS: We retrospectively investigated 3581 stable CAD patients who underwent rest 201Tl and stress 99mTc-tetrofosmin myocardial perfusion single-photon emission computed tomography (SPECT) and provided three-year-prognostic data. The endpoint was the onset of MCEs consisting of cardiac death, non-fatal myocardial infarction, and unstable angina pectoris. On the basis of estimated propensity scores, patients who underwent revascularization within the first 60 days after the SPECT and those who did not were matched in a 1:1 ratio (n=450 per group). We compared MCE rates in relation to the amount of ischemic myocardium detected with the SPECT between the two groups. RESULTS: The overall incidence of MCEs was not significantly different between the early-revascularization and no-early-revascularization groups (6.7% vs. 8.7%, p=0.2598). Nevertheless, the incidence of MCEs in the patients with <=5% ischemia was significantly higher in the early-revascularization group than in the no-early-revascularization group (5.8% vs. 0.8%, p=0.0226). In contrast, the incidence of MCEs in the patients with >10% ischemia was significantly lower in the early-revascularization group than in the no-early-revascularization group (7.0% vs. 16.8%, p=0.0036). The incidence of MCEs in the patients with 6-10% ischemia, however, was not significantly different between the early revascularization and no-early-revascularization groups (6.9% vs. 4.1%, p=0.3235). CONCLUSIONS: Early revascularization possibly leads to the occurrence of MCEs related to the treatment procedure but may be a therapeutic strategy leading to improvement in prognosis in patients with moderate to severe ischemia. PMID- 28732593 TI - Multisegment injections improve peptide identification rates in capillary zone electrophoresis-based bottom-up proteomics. AB - While capillary zone electrophoresis (CZE) provides dramatically improved numbers of peptide identifications compared with reversed-phase chromatography for bottom up proteomics of mass limited samples, CZE inevitably produces lower numbers of peptide identifications than RPLC for larger samples. One reason for this poorer performance is the dead time between injection of samples and subsequent appearance of the fastest moving component. This dead time is typically 25% of the separation window in CZE, but is only 5% of the separation window in gradient elution RPLC. This dead time can be eliminated in CZE by use of a multisegment injection mode where a series of samples is analyzed by injecting each sample while the preceding sample is still being separated. In this paper, we demonstrate that capillary zone electrophoresis employing sequential injections can produce a doubling in peptide identification rate with no degradation in separation efficiency. PMID- 28732594 TI - Thermodynamic models to elucidate the enantioseparation of drugs with two stereogenic centers by micellar electrokinetic chromatography. AB - An equilibrium model depicting the simultaneous protonation of chiral drugs and partitioning of protonated ions and neutral molecules into chiral micelles in micellar electrokinetic chromatography (MEKC) has been introduced. It was used for the prediction and elucidation of complex changes in migration order patterns with experimental conditions in the enantioseparation of drugs with two stereogenic centers. Palonosetron hydrochloride (PALO), a weakly basic drug with two stereogenic centers, was selected as a model drug. Its four stereoisomers were separated by MEKC using sodium cholate (SC) as chiral selector and surfactant. Based on the equilibrium model, equations were derived for a calculation of the effective mobility and migration time of each stereoisomer at a certain pH. The migration times of four stereoisomers at different pHs were calculated and then the migration order patterns were constructed with derived equations. The results were in accord with the experiment. And the contribution of each mechanism to the separation and its influence on the migration order pattern was analyzed separately by introducing virtual isomers, i.e., hypothetical stereoisomers with only one parameter changed relative to a real PALO stereoisomer. A thermodynamic model for a judgment of the correlation of interactions between two stereogenic centers of stereoisomers and chiral selector was also proposed. According to this model, the interactions of two stereogenic centers of PALO stereoisomers in both neutral molecules and protonated ions with chiral selector are not independent, so the chiral recognition in each pair of enantiomers as well as the recognition for diastereomers is not simply the algebraic sum of the contributions of two stereogenic centers due to their correlation. PMID- 28732595 TI - Probabilistic modeling of anatomical variability using a low dimensional parameterization of diffeomorphisms. AB - We present an efficient probabilistic model of anatomical variability in a linear space of initial velocities of diffeomorphic transformations and demonstrate its benefits in clinical studies of brain anatomy. To overcome the computational challenges of the high dimensional deformation-based descriptors, we develop a latent variable model for principal geodesic analysis (PGA) based on a low dimensional shape descriptor that effectively captures the intrinsic variability in a population. We define a novel shape prior that explicitly represents principal modes as a multivariate complex Gaussian distribution on the initial velocities in a bandlimited space. We demonstrate the performance of our model on a set of 3D brain MRI scans from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Our model yields a more compact representation of group variation at substantially lower computational cost than the state-of-the-art method such as tangent space PCA (TPCA) and probabilistic principal geodesic analysis (PPGA) that operate in the high dimensional image space. PMID- 28732596 TI - Structural and Functional Insights into Human Re-initiation Complexes. AB - After having translated short upstream open reading frames, ribosomes can re initiate translation on the same mRNA. This process, referred to as re initiation, controls the translation of a large fraction of mammalian cellular mRNAs, many of which are important in cancer. Key ribosomal binding proteins involved in re-initiation are the eukaryotic translation initiation factor 2D (eIF2D) or the homologous complex of MCT-1/DENR. We determined the structures of these factors bound to the human 40S ribosomal subunit in complex with initiator tRNA positioned on an mRNA start codon in the P-site using a combination of cryoelectron microscopy and X-ray crystallography. The structures, supported by biochemical experiments, reveal how eIF2D emulates the function of several canonical translation initiation factors by using three independent, flexibly connected RNA binding domains to simultaneously monitor codon-anticodon interactions in the ribosomal P-site and position the initiator tRNA. PMID- 28732591 TI - Diabetic retinopathy: Breaking the barrier. AB - Diabetic retinopathy (DR) remains a major complication of diabetes and a leading cause of blindness among adults worldwide. DR is a progressive disease affecting both type I and type II diabetic patients at any stage of the disease, and targets the retinal microvasculature. DR results from multiple biochemical, molecular and pathophysiological changes to the retinal vasculature, which affect both microcirculatory functions and ultimately photoreceptor function. Several neural, endothelial, and support cell (e.g., pericyte) mechanisms are altered in a pathological fashion in the hyperglycemic environment during diabetes that can disturb important cell surface components in the vasculature producing the features of progressive DR pathophysiology. These include loss of the glycocalyx, blood-retinal barrier dysfunction, increased expression of inflammatory cell markers and adhesion of blood leukocytes and platelets. Included in this review is a discussion of modifications that occur at or near the surface of the retinal vascular endothelial cells, and the consequences of these alterations on the integrity of the retina. PMID- 28732597 TI - Pattern of gene expression in different stages of schizophrenia: Down-regulation of NPTX2 gene revealed by a meta-analysis of microarray datasets. AB - Schizophrenia (SCZ) is a severe psychiatric disorder with a genetic susceptibility. Alterations in neurochemical signaling, as well as changes in brain structure and function, manifest during the course of SCZ and are likely causative of the symptoms shown by affected individuals. However, little is known about the timing of these changes, particularly in the pre-morbid and prodromal phases of SCZ. Here, we performed a gene-based and pathway-based meta-analysis of 5 microarray datasets from human induced pluripotent stem cells (hiPSCs)-derived neurons and post-mortem brain tissue from SCZ and healthy controls (HC), with the underlying assumption they might represent the neurobiological make-up of SCZ in the pre-morbid and chronic stages of illness, respectively. Thus, we identified 1 microarray expression profiling dataset of hiPSCs-derived neurons (GSE25673) and performed a systematic search of microarray expression profiling datasets from SCZ post-mortem brain publicly available on the Gene Expression Omnibus (GEO) repository. We selected 4 different SCZ post-mortem brain microarray expression profiling datasets (GSE17612, GSE21935, GSE12649, and GSE21338) according to specific inclusion and exclusion criteria. We downloaded raw data and performed quality controls, differential expression analysis, and gene-based, as well as pathway-based meta-analysis. Neuronal pentraxin 2 (NPTX2) gene was consistently down-regulated across all datasets, with highly significant association in the meta-analysis (FDR<1.0E-04). These results highlight the heuristic value of microarray meta-analysis and suggest a role of NPTX2 as a disease biomarker, provided that it achieves biological validation in future studies examining whether this down-regulation has predictive value with respect to the developmental trajectory of SCZ. PMID- 28732599 TI - Evolutionary Dynamics of Unreduced Gametes. AB - Unreduced gametes, which have the somatic (2n) chromosome number, are an important precursor to polyploid formation and apomixis. The product of irregularities in meiosis, 2n gametes are expected to be rare and deleterious in most natural populations, contrary to their wide taxonomic distribution and the prevalence of polyploidy. To better understand this discrepancy, we review contemporary evidence related to four aspects of 2n gamete dynamics in natural populations: (i) estimates of their frequency; (ii) their environmental and genetic determinants; (iii) adaptive and nonadaptive processes regulating their evolution; and (iv) factors regulating their union and production of polyploids in diploid populations. Aided by high-throughput methods of detection, these foci will advance our understanding of variation in 2n gametes within and among species, and their role in polyploid evolution. PMID- 28732598 TI - High-Throughput Imaging for the Discovery of Cellular Mechanisms of Disease. AB - High-throughput imaging (HTI) is a powerful tool in the discovery of cellular disease mechanisms. While traditional approaches to identify disease pathways often rely on knowledge of the causative genetic defect, HTI-based screens offer an unbiased discovery approach based on any morphological or functional defects of disease cells or tissues. In this review, we provide an overview of the use of HTI for the study of human disease mechanisms. We discuss key technical aspects of HTI and highlight representative examples of its practical applications for the discovery of molecular mechanisms of disease, focusing on infectious diseases and host-pathogen interactions, cancer, and rare genetic diseases. We also present some of the current challenges and possible solutions offered by novel cell culture systems and genome engineering approaches. PMID- 28732601 TI - Expanding refractive surgery. PMID- 28732602 TI - Pursuing perfection in intraocular lens calculations: I. Logical approach for classifying IOL calculation formulas. PMID- 28732600 TI - Hierarchy and Plasticity in the Intestinal Stem Cell Compartment. AB - Somatic stem cells maintain tissue homeostasis by organizing themselves in such a way that they can maintain proliferative output while simultaneously protecting themselves from DNA damage that may lead to oncogenic transformation. There is considerable debate about how such stem cell compartments are organized. Burgeoning evidence from the small intestine and colon provides support for a two stem cell model involving an actively proliferating but injury-sensitive stem cell and a rare, injury-resistant pool of quiescent stem cells. Parallel with this evidence, recent studies have revealed considerable plasticity within the intestinal stem cell (ISC) compartment. We discuss the evidence for plasticity and hierarchy within the ISC compartment and how these properties govern tissue regeneration and contribute to oncogenic transformation leading to colorectal cancers. PMID- 28732603 TI - Pars plana posterior capsulectomy with a 27-gauge microincision vitrectomy system for dense posterior capsule opacification. AB - We describe a surgical technique of pars plana posterior capsulectomy using a transconjunctival sutureless 2-port 27-gauge microincision vitrectomy system to deal with dense posterior capsule opacification (PCO). The technique was used successfully in 5 eyes of 5 patients with dense PCO that had been unsuccessfully treated by neodymium:YAG laser photodisruption. PMID- 28732604 TI - Artificial iris implantation in various iris defects and lens conditions. AB - We describe 6 surgical techniques used to implant a silicone iris prosthesis: sector-shaped iris segments that require suturing, injector-assisted sulcus fixation, injector-assisted capsular bag fixation with an intraocular lens (IOL) and capsular tension ring, folded iris tissue implanted with a forceps and sutured to the sclera with a scleral-fixated IOL, "sandwich" or "backpack" implantation with an IOL, and open-sky implantation with a perforating keratoplasty. The results of the techniques performed in 51 patients are discussed. Sector-shaped iris segments required longer surgery because of the complexity of intracameral sutures and carried risks for knots to loosen and sutures to cut through residual iris tissue. The combined implantation of an iris and IOL proved complex and lengthy but solved lens and iris abnormalities in 1 procedure and provided long-lasting stable conditions. The procedures that implanted a complete iris in pseudophakic eyes were shorter and required smaller incisions, a sutureless approach, and injector-assisted implantation. PMID- 28732605 TI - Prediction of postoperative intraocular lens tilt using swept-source optical coherence tomography. AB - PURPOSE: To compare crystalline lens tilt in eyes before and intraocular lens (IOL) tilt in eyes after cataract surgery using swept-source optical coherence tomography (SS-OCT) (IOLMaster 700). SETTING: Hanusch Hospital, Vienna, Austria. DESIGN: Prospective case series. METHODS: Patients' eyes were scanned 1 week before and 2 months after cataract surgery with IOL implantation using an SS-OCT device. This device performs B-scans along 6 meridians (0, 30, 60, 90, 120, and 150 degrees) to determine lens and IOL tilt. RESULTS: Sixty-two eyes (62 patients) were included in the analysis. The mean magnitude and direction of tilt showed mirror symmetry between both eyes along the vertical axis and a primarily nasal outward tilt for right eyes and left eyes. The mean tilt was 4.3 degrees at 15.8 degrees preoperatively and 6.2 degrees at 16.8 degrees postoperatively. The mean direction of crystalline lens tilt preoperatively and IOL tilt postoperatively showed a strong correlation (R = 0.71), whereas the mean magnitude of tilt showed a weaker correlation (R = 0.37). The direction and magnitude of tilt of the crystalline lens and IOL eyes were normally distributed around similar values before and after surgery. CONCLUSIONS: The correlations between crystalline lens tilt and IOL tilt using whole-eye scanning indicate that preoperative tilt determination using SS-OCT could help predict postoperative IOL tilt, assist in IOL (toric) power calculations, and potentially improve visual outcomes. PMID- 28732606 TI - Visual performance after bilateral implantation of 2 new presbyopia-correcting intraocular lenses: Trifocal versus extended range of vision. AB - PURPOSE: To compare the visual outcomes and quality of vision of 2 new diffractive multifocal intraocular lenses (IOLs) with those of a monofocal IOL. SETTING: Fatebenefratelli e Oftalmico Hospital, Milan, Italy. DESIGN: Prospective case series. METHODS: Patients had bilateral cataract surgery with implantation of a trifocal IOL (Panoptix), an extended-range-of-vision IOL (Symfony), or a monofocal IOL (SN60WF). Postoperative examinations included assessing distance, intermediate, and near visual acuity; binocular defocus; intraocular and total aberrations; point-spread function (PSF); modulation transfer function (MTF); retinal straylight; and quality-of-vision (QoV) and spectacle-dependence questionnaires. RESULTS: Seventy-six patients (152 eyes) were assessed for study eligibility. Twenty patients (40 eyes) in each arm of the study (60 patients, 120 eyes) completed the outcome assessment. At the 4-month follow-up, the trifocal group had significantly better near visual acuity than the extended-range-of vision group (P = .005). The defocus curve showed the trifocal IOL had better intermediate/near performance than the extended-range-of-vision IOL and both multifocal IOLs performed better than the monofocal IOL. Intragroup comparison of the total higher-order aberrations, PSF, MTF, and retinal straylight were not statistically different. The QoV questionnaire results showed no differences in dysphotopsia between the multifocal IOL groups; however, the results were significantly higher than in the monofocal IOL group. CONCLUSIONS: Both multifocal IOLs seemed to be good options for patients with intermediate-vision requirements, whereas the trifocal IOL might be better for patients with near vision requirements. The significant perception of visual side effects indicates that patients still must be counseled about these effects before a multifocal IOL is implanted. PMID- 28732607 TI - Refractive outcomes and complications after combined copolymer phakic intraocular lens explantation and phacoemulsification with intraocular lens implantation. AB - PURPOSE: To assess safety, efficacy, and predictability of combined Implantable Collamer Lens phakic intraocular lens (pIOL) explantation and phacoemulsification and to report the rate of complications. A secondary aim was to examine whether intraocular lens (IOL) power calculation was affected by the pIOL in situ. SETTING: Jules-Gonin Eye Hospital, Lausanne, Switzerland. DESIGN: Retrospective case series. METHODS: The records of patients having pIOL implantation with subsequent phacoemulsification were reviewed. Data analysis was performed between July 1, 2015, and December 31, 2015. The mean corrected distance visual acuity (CDVA), safety, stability of refraction, predictability of IOL power calculation, and postoperative complications were recorded. RESULTS: The study comprised 38 eyes (29 patients). Of the eyes, 32 (82%) were within +/-1.00 diopter (D) of the target refraction and 21 (57.9%) were within +/-0.50 D. The mean CDVA after IOL implantation was significantly better than before pIOL implantation (P < .001) and similar to after pIOL implantation (P = .87). The safety of this multistepped procedure was good; on average, 1.6 Snellen lines of CDVA were gained over before pIOL implantation. Branch retinal vein occlusion occurred in 1 eye; no other sight-threatening complications were observed. Posterior capsule opacification developed in 15 eyes (39.5%) and was treated successfully with neodymium:YAG capsulotomy. CONCLUSIONS: The highest mean CDVA was recorded at the final visit. Good safety, stability, and predictability were also observed. Postoperative complications were few and in all but 1 case, not sight threatening. Overall, results indicate the combination of procedures does not negatively affect the final visual outcome. PMID- 28732608 TI - Population-based analysis of intraocular lens exchange and repositioning. AB - PURPOSE: To determine the incidence and trends in intraocular lens (IOL) repositioning, exchange, and explantation. SETTING: Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, Ontario, Canada. DESIGN: Population-based retrospective data analysis. METHODS: Service claims from 2000 to 2013 were analyzed for the total yearly number of IOL repositionings, exchanges, and explantations in Ontario, Canada, including the number of surgeons performing them by subspecialty. The 5-year incidence proportion of secondary IOL surgery for patients who had cataract surgery in 2000 and 2009 was calculated and then stratified by sex, age, and year of second surgery. RESULTS: Of the 1252 secondary procedures performed in 2013 (75.6% increase from 2000), 43.2% were repositionings without suturing, 31.6% were exchanges without suturing, 10.5% were sutured repositionings, 7.0% were sutured exchanges, and 7.7% were explantations. The incidence proportion of risk for secondary IOL surgery was 0.93% from 2000 to 2004, which decreased to 0.78% from 2009 to 2013 (16.4% decrease; odds ratio, 0.83; 95% confidence interval [CI], 0.72-0.94; P < .001). Patients who had these procedures were 1.56 times more likely to be men (95% CI, 1.39-1.76; P < .001) and 1.52 times more likely to be younger than 65 years (95% CI, 1.33-1.73; P < .001). From 2000 to 2013, sutured repositionings and explantations increased by 568% and 531%, respectively, whereas exchanges without suturing decreased by 22.6%. In 2013, 11.6% of surgeons performed 52.0% of all secondary IOL surgeries. CONCLUSIONS: Although the absolute number of secondary IOL procedures increased from 2000 to 2013, the 5-year risk for surgery decreased. A large proportion of the surgeries was performed by a small number of surgeons, which suggests subspecialization. PMID- 28732609 TI - Refractive outcomes after multifocal intraocular lens exchange. AB - PURPOSE: To evaluate the refractive outcomes after multifocal intraocular lens (IOL) exchange. SETTING: Cullen Eye Institute, Baylor College of Medicine, Houston, Texas, USA. DESIGN: Retrospective case series. METHODS: Patients had multifocal IOL explantation followed by IOL implantation. Outcome measures included type of IOL, surgical indication, corrected distance visual acuity (CDVA), and refractive prediction error. RESULTS: The study comprised 29 patients (35 eyes). The types of IOLs implanted after multifocal IOL explantation included in-the-bag IOLs (74%), iris-sutured IOLs (6%), sulcus-fixated IOLs with optic capture (9%), sulcus-fixated IOLs without optic capture (9%), and anterior chamber IOLs (3%). The surgical indication for exchange included blurred vision (60%), photic phenomena (57%), photophobia (9%), loss of contrast sensitivity (3%), and multiple complaints (29%). The CDVA was 20/40 or better in 94% of eyes before the exchange and 100% of eyes after the exchange (P = .12). The mean refractive prediction error significantly decreased from 0.22 +/- 0.81 diopter (D) before the exchange to -0.09 +/- 0.53 D after the exchange (P < .05). The median absolute refractive prediction error significantly decreased from 0.43 D before the exchange to 0.23 D after the exchange (P < .05). CONCLUSIONS: Multifocal IOL exchange can be performed safely with good visual outcomes using different types of IOLs. A lower refractive prediction error and a higher likelihood of 20/40 or better vision can be achieved with the implantation of the second IOL compared with the original multifocal IOL, regardless of the final IOL position. PMID- 28732610 TI - Intraocular pressure change after phacoemulsification in angle-closure eyes without medical therapy. AB - PURPOSE: To evaluate the intraocular pressure (IOP) change and associated factors 6 months after phacoemulsification in eyes with primary angle-closure suspect (PACS) and eyes with primary angle closure (PAC) that had no medical therapy. SETTING: Singapore National Eye Center, Singapore, Singapore. DESIGN: Retrospective case series. METHODS: Patients with PACS or PAC (with corrected distance visual acuity <20/40) who had uneventful phacoemulsification were recruited. Patients were excluded if they were on IOP-lowering medications within 6 months preoperatively and postoperatively. Preoperative gonioscopy, A-scan biometry, anterior segment optical coherence tomography, and automated refraction were reviewed. Factors related to the percentage of and absolute IOP change were assessed using multiple linear regression analyses after adjusting for age, sex, and diagnosis. RESULTS: The study evaluated 85 patients (85 eyes; 52 PACS, 33 PAC) after 7 eyes (1 PACS, 6 PAC) were excluded because of poor quality imaging. Overall, IOP decreased by 19.9% from the preoperative mean of 16.1 mm Hg +/- 3.1 (SD) to 12.9 +/- 2.7 mm Hg. The IOP change between the PACS group (-3.3 +/- 2.8 mm Hg; -20.6%) and the PAC group (-3.2 +/- 4.7 mm Hg; -19.6%) was similar (P > .05). In multiple linear regression analyses, a higher preoperative IOP (beta = 0.68, P < .001) and fewer clock hours of peripheral anterior synechiae (PAS) (beta = -0.30, P = .03) predicted a greater absolute change in and percentage of reduction in IOP, respectively. CONCLUSIONS: The mean IOP reduction 6 months after phacoemulsification was 20%. Less IOP reduction was observed in the presence of lower preoperative IOP and more extensive PAS. PMID- 28732611 TI - Comparison of posterior capsule opacification development with 2 single-piece intraocular lens types. AB - PURPOSE: To evaluate the differences in the incidence of posterior capsule opacification (PCO) and visual and optical performance between 2 hydrophobic acrylic single-piece sharp-edged intraocular lenses (IOLs) over 3 years. SETTING: Department of Ophthalmology, Medical University of Vienna, Vienna, Austria. DESIGN: Prospective randomized case series. METHODS: Patients with bilateral cataract were prospectively randomized to receive an Eyecee One IOL (IOL A) or an Acrysof SN60WF IOL (IOL B) and were followed for 36 months. The corrected distance visual acuity (CDVA) and IOL decentration and tilt were measured. The PCO was quantified by analysis of standardized retroillumination images. RESULTS: The study comprised 160 eyes of 80 patients. The PCO incidence was low for both IOLs at all follow-up visits. Three years postoperatively, the median objective PCO score was 1.4 (range 0 to 5.6) for IOL A and 1.5 (range 0 to 5.0) for IOL B (P = .67). The neodymium:YAG (Nd:YAG) capsulotomy rate 3 years after surgery was 16.4% and 6.0% (P = .06), respectively. Visual acuity and contrast sensitivity outcomes were also comparable at all follow-up visits. CONCLUSIONS: Both IOLs showed good capsular bag performance and low PCO rates 3 years after surgery. Both IOLs also showed comparable results for visual acuity, contrast sensitivity, decentration and tilt, PCO score, slitlamp examination, and Nd:YAG capsulotomy rates. PMID- 28732612 TI - Image-guided system versus manual marking for toric intraocular lens alignment in cataract surgery. AB - PURPOSE: To compare the accuracy of toric intraocular lens (IOL) alignment using the Verion Image-Guided System versus a conventional manual ink-marking procedure. SETTING: University Eye Clinic Maastricht, Maastricht, the Netherlands. DESIGN: Prospective randomized clinical trial. METHODS: Eyes with regular corneal astigmatism of at least 1.25 diopters (D) that required cataract surgery and toric IOL implantation (Acrysof SN6AT3-T9) were randomly assigned to the image-guided group or the manual-marking group. The primary outcome was the alignment of the toric IOL based on preoperative images and images taken immediately after surgery. Secondary outcome measures were residual astigmatism, uncorrected distance visual acuity (UDVA), and complications. RESULTS: The study enrolled 36 eyes (24 patients). The mean toric IOL misalignment was significantly less in the image-guided group than in the manual group 1 hour (1.3 degrees +/- 1.6 [SD] versus 2.8 +/- 1.8 degrees; P = .02) and 3 months (1.7 +/- 1.5 degrees versus 3.1 +/- 2.1 degrees; P < .05) postoperatively. The mean residual refractive cylinder was -0.36 +/- 0.32 D and -0.47 +/- 0.28 D in the image-guided group and manual group, respectively (P > .05). The mean UDVA was 0.03 +/- 0.10 logarithm of minimum angle of resolution (logMAR) and 0.04 +/- 0.09 logMAR, respectively (both P > .05). No intraoperative complications occurred during any surgery. CONCLUSION: The IOL misalignment was significantly less with digital marking than with manual marking; this did not result in a better UDVA or lower residual refractive astigmatism. PMID- 28732613 TI - Photorefractive intrastromal corneal crosslinking for the treatment of myopic refractive errors: Six-month interim findings. AB - PURPOSE: To evaluate the safety and efficacy of photorefractive intrastromal corneal crosslinking (CXL) in low myopia. SETTING: Ruhr University Eye Hospital, Bochum, Germany. DESIGN: Prospective case series. METHODS: Healthy eyes with myopia or myopic astigmatism had photorefractive intrastromal CXL using the Mosaic system to apply ultraviolet-A (UVA) 365 nm (30 mW/cm2) irradiance (total calculated UVA dose of 10 J/cm2 or 15 J/cm2) with riboflavin 0.1% solution. Efficacy was determined by the change in the manifest refraction spherical equivalent (MRSE), uncorrected distance visual acuity (UDVA), and corneal curvature. Safety was determined by the corrected distance visual acuity (CDVA), slitlamp biomicroscopy, endothelial cell count, and adverse events. RESULTS: Twenty-six eyes of 14 patients with a mean age of 30.8 years +/- 9.3 (SD) were included. There were statistically significant improvements in UDVA 1, 3, and 6 months postoperatively (all P < .001). A significant improvement in CDVA was observed (P = .02). Improvements in the mean manifest sphere and MRSE versus baseline were noted at all visits (P < .001), with a mean change of 0.99 +/- 0.47 diopter (D) and 0.97 +/- 0.48 D, respectively, by 6 months postoperatively. Significant reductions in corneal curvature versus baseline occurred at all follow-up visits (all P < .05). At 1 month, there were no significant changes in the endothelial cell density (P = .282) or number of cells (P = .069). No safety issues or complications were reported. CONCLUSION: The findings show that patterned CXL using a custom CXL system is safe and effective for reducing myopic refractive error. PMID- 28732615 TI - New parameters for evaluating corneal biomechanics and intraocular pressure after small-incision lenticule extraction by Scheimpflug-based dynamic tonometry. AB - PURPOSE: To evaluate parameters and dynamic corneal densitometry with a new dynamic Scheimpflug analyzer (Corvis ST) in eyes having small-incision lenticule extraction (SMILE). SETTING: Qvision, Vithas Virgen del Mar Hospital, Almeria, Spain. DESIGN: Retrospective case series. METHODS: The study comprised eyes from the same institution having small-incision lenticule extraction surgery. Preoperative and 1-month postoperative measurements were taken. RESULTS: Forty three eyes were evaluated. The mean difference in intraocular pressure (IOP) and biomechanically corrected IOP before and after surgery was 2.24 mm Hg +/- 1.26 mm (SD) (P = .001) and 0.57 +/- 1.77 mm Hg (P = .04), respectively. All dynamic Scheimpflug analyzer parameters changed significantly after surgery (P < .05). The variation in each parameter was correlated with the removed corneal thickness (P < .05), except the stiffness parameter at the first applanation (P = .15). None of the 4 dynamic corneal densitometry parameters changed significantly as a result of surgery (P >= .29). A new sign, described as an inclined brightness fringe moving through the corneal periphery, appeared preoperatively in eyes with higher dynamic corneal densitometry. This sign was more prevalent postoperatively (48.8% versus 72.1%) (P = .04). CONCLUSIONS: The biomechanically corrected IOP measured after surgery with the dynamic Scheimpflug analyzer showed better agreement with the preoperative values than IOP. The stiffness parameter was not dependent on the amount of removed corneal thickness. A new sign correlated with dynamic corneal densitometry was found and might be related to changes in corneal hydration and biomechanics. PMID- 28732614 TI - Incidence and management of intraoperative complications during small-incision lenticule extraction in 3004 cases. AB - PURPOSE: To assess the intraoperative complications during small-incision lenticule extraction (SMILE) for myopia and myopic astigmatism correction and evaluate visual outcomes 6 months postoperatively. SETTING: Tianjin Eye Hospital, Tianjin, China. DESIGN: Retrospective case series. METHODS: Patients who had small-incision lenticule extraction surgery were examined 1 day, 7 days, 1 month, 3 months, and 6 months postoperatively. Demographic characteristics, visual outcomes, and intraoperative complications were recorded. Moreover, the incidence and management of the complications and the potential factors were analyzed. RESULTS: Of the 3004 eyes (1511 patients), 134 (4.46%) had intraoperative complications, including suction loss (28 cases [0.93%]), incisional bleeding (28 cases [0.93%]), opaque bubble layer (22 cases [0.73%]), subconjunctival hemorrhage (20 cases [0.67%]), black areas (10 cases [0.33%]), unintended posterior plane dissection (10 cases [0.33%]), tearing of the lenticule (8 cases [0.27%]), abrasion at the incision (5 cases [0.17%]), and inaccurate laser pulse placement due to eye movement (3 cases [0.10%]). The complications were resolved instantaneously using appropriate management procedures; all cases had good visual outcomes. Six months postoperatively, 99.80% of cases had an uncorrected distance visual acuity better than 20/25 and the mean corrected distance visual acuity was -0.06 logarithm of the minimum angle of resolution +/- 0.07 (SD). CONCLUSIONS: Although small-incision lenticule extraction shows promising outcomes for correction of myopia and myopic astigmatism, intraoperative complications still inevitably occur. However, satisfactory visual outcomes may be achieved using appropriate management techniques. PMID- 28732616 TI - Stromal remodeling and lenticule thickness accuracy in small-incision lenticule extraction: One-year results. AB - PURPOSE: To prospectively characterize the stromal thickness changes during the first year after myopic small-incision lenticule extraction using spectral-domain optical coherence tomography (SD-OCT). SETTING: Department of Ophthalmology, Kepler University Hospital, Linz, Austria. DESIGN: Prospective case series. METHODS: This study evaluated eyes that had small-incision lenticule extraction to treat myopia or myopic astigmatism. A high-resolution SD-OCT system (RS 3000 Advance) in conjunction with a custom image-segmentation algorithm was applied to directly measure stromal thickness within the central 5.0 mm corneal zone. Measurements were obtained preoperatively and postoperatively at 1 day, 1 week, 6 weeks, 3 months, 6 months, and 1 year. RESULTS: The study enrolled 42 eyes of 21 patients. The mean surgical refractive correction was -4.94 diopters +/- 1.75 (SD). Postoperatively, the stromal thickness showed a significant decrease during the first 6 weeks, which amounted to a mean of 10.4 +/- 6.3 MUm at the apex (P < .001). Subsequently, the central stroma thickened by a mean of 8.8 +/- 5.9 MUm up until the 1-year follow-up (P < .001). One year postoperatively, the mean observed central stromal thickness reduction was 18.7 +/- 5.7 MUm smaller than the planned lenticule thickness. This difference was smallest 6 weeks postoperatively (mean 9.8 +/- 7.8 MUm). CONCLUSIONS: Significant anatomic changes in the corneal stroma were detected during the first year after small-incision lenticule extraction. The achieved lenticule thickness was systematically lower than planned, and the mismatch was more pronounced with higher lenticule thickness. Refractive outcomes did not appear to be influenced by lenticule thickness accuracy. PMID- 28732617 TI - Vector analysis of astigmatic changes after small-incision lenticule extraction and wavefront-guided laser in situ keratomileusis. AB - PURPOSE: To evaluate and compare the efficacy of the astigmatic correction after wavefront-guided laser in situ keratomileusis (LASIK) and small-incision lenticule extraction (SMILE) and in myopic eyes. DESIGN: Prospective case series. SETTING: Horus Vision Correction Center and Ellite Vision Correction Center, Alexandria, Egypt. METHODS: Myopic eyes with astigmatism up to 4.00 diopters (D) had wavefront-guided LASIK or small-incision lenticule extraction. Visual and refractive changes were evaluated during a 6-month follow-up. The astigmatic changes were evaluated using the Alpins method. RESULT: The study evaluated 107 eyes (55 patients), 52 eyes having wavefront-guided LASIK and 55 eyes, small incision lenticule extraction. No statistically significant differences were found in the 6-month postoperative sphere between the 2 groups (P = .652). The postoperative manifest cylinder and spherical equivalent were significantly lower in the wavefront-guided LASIK group (P < .001). The 6-month postoperative cylinder was 0.50 D or less in all eyes in the wavefront-guided LASIK groups and in 79.8% in the small-incision lenticule extraction group (P < .001). Vector analysis showed a significantly higher difference vector (P < .001) and angle of error (P = .021) and a significantly lower correction index (P = .001) in the small-incision lenticule extraction group. The mean magnitude of error was -0.07 +/- 0.20 (SD) and -0.20 +/- 0.35 in the wavefront-guided LASIK group and small incision lenticule extraction group, respectively (P = .012). CONCLUSION: Wavefront-guided LASIK and small-incision lenticule extraction were safe and effective for the correction of myopic astigmatism, although there was a trend toward undercorrection with small-incision lenticule extraction. PMID- 28732618 TI - Predictors of myopic photorefractive keratectomy retreatment. AB - PURPOSE: To determine the factors associated with retreatment after photorefractive keratectomy (PRK) in myopic eyes. SETTING: Care-Vision Laser Centers, Tel-Aviv, Israel. DESIGN: Retrospective cohort study. METHODS: A large database on myopic PRK with mitomycin-C (MMC) performed from 2005 to 2012 was studied. Patients were divided into 2 groups according to whether they had retreatment. Multiple preoperative and intraoperative parameters were analyzed for association with retreatment. RESULTS: A total of 9699 eyes of 9699 consecutive patients were studied. The mean age was 25.9 years +/- 7.3 (SD); 54.1% were men. The mean preoperative subjective spherical equivalent and astigmatism were -4.30 +/- 2.18 diopters (D) (range -0.5 to -13.0 D) and 0.77 +/- 0.83 D (range 0 to 6.0 D), respectively. Two hundred twenty-three eyes (2.30%) were retreated. The 2-year retreatment rate decreased from 42 (6.17%) for primary PRK treatments done in 2005 to 2 (0.10%) for primary PRK done in 2012 (R2 = 0.79, P < .001). Multiple binary logistic regression analysis showed that transepithelial PRK, astigmatism equal to or higher than 3.5 D, and surgeon factor significantly increased the odds of retreatment. Additional parameters significant on univariate analysis alone included age older than 40 years, low preoperative sphere, maximum ablation depth less than 45 MUm, preoperative corrected distance visual acuity better than 20/20, MMC application longer than 40 seconds, and optical ablation zone smaller than 7.0 mm. CONCLUSION: The retreatment incidence of PRK has continued to decrease. High astigmatism and transepithelial PRK were associated with increased myopic PRK retreatment rates. PMID- 28732619 TI - Endophthalmitis prophylaxis by intracameral antibiotics: In vitro model comparing vancomycin, cefuroxime, and moxifloxacin. AB - PURPOSE: To compare the efficacy of intracameral vancomycin, cefuroxime, and moxifloxacin on postoperative bacterial endophthalmitis rates. SETTING: Norwalk Hospital, Norwalk, Connecticut, USA. DESIGN: Experimental study. METHODS: Bacteria and intraocular lenses (IOLs) were incubated with vancomycin, cefuroxime, moxifloxacin, or combinations. Antibiotic concentrations were high, corresponding to clinical maximum intracameral doses (1.0 mg vancomycin or cefuroxime, 0.5 mg moxifloxacin), or low (one third of clinical maximum dose). The following bacteria were isolated from patients with endophthalmitis: 18 strains including 6 staphylococci, 6 streptococci, 3 pseudomonad, and 3 propionibacteria. Samples were diluted by half every 2 hours to model the half life of intracameral antibiotics. At 24 hours, samples were vortexed to shake bacterial biofilms loose from the IOLs. The bacterial broth was plated and colonies were counted 24 hours later. RESULTS: Efficacy against staphylococci was concentration dependent; all antibiotics were effective at high concentrations, while low concentrations were in general ineffective. Streptococci and propionibacteria were nearly eliminated by all antibiotics at low concentrations. Pseudomonads were most effectively treated by high-dose moxifloxacin and its combinations. CONCLUSIONS: Broadest coverage against common pathogens should be obtained by high-dose moxifloxacin (0.5 mg intracameral). Submaximum dosing, which could occur if aqueous is released to lower intraocular pressure after injection, compromises the efficacy against staphylococci and pseudomonads. All antibiotics, even at low doses, were effective against streptococci and propionibacteria, suggesting that many of the worst endophthalmitis outcomes could be prevented by intracameral use of any of the 3 antibiotics used in this study. PMID- 28732620 TI - Results and methodology of cost-utility evaluation of cataract surgery in developed countries: Quality-adjusted life years and cataract. AB - This review surveyed the results and methods of cost-utility analyses of cataract surgery. Thirteen studies were included. Based on decision-theoretic time trade off, utilities ranged from 0.148 to 0.8 and quality-adjusted life years (QALY) ranged from 1.424 to 2.43. Based on psychometric instruments such as Euroqol 5 dimensions, utilities ranged from 0.017 to 0.056 and QALY ranged from 0.141 to 0.547. Reported costs per QALY were between $1307 and $14 302. Although the review found consistent favorable cost QALY ratios for cataract surgery according to the British National Institute for Care and Health Excellence threshold, the findings raise doubts about the general applicability of existing studies as a tool for allocation decision. The observed large heterogeneity of the approaches and outcomes for all parameters reflected the complexity of the various evaluation methods and medical care processes and, in some cases, inadequate data. PMID- 28732621 TI - Generic trypan blue as possible cause of a cluster of toxic anterior segment syndrome cases after uneventful cataract surgery. AB - Five of 16 patients having uneventful cataract surgery over 2 consecutive days presented on the first postoperative day with painless, unexpected blurry vision; marked limbus-to-limbus corneal edema; and severe anterior chamber inflammation with hypopyon and fibrin formation. Review of the records showed the 5 patients had received an intracameral injection of generic trypan blue solution 0.06% to facilitate the capsulorhexis. Patients who had not received the trypan blue injection had an uneventful first-day check and subsequent course. Management comprised intense topical steroids and close follow-up, which led to gradual improvement in all cases. The batch of trypan blue vials was withdrawn, and there were no additional cases of toxic anterior segment syndrome (TASS). This TASS cluster highlights a rarely reported cause of the syndrome, underscoring the need for thorough documentation of solutions and/or medications used intraoperatively and surgeon awareness of possible adverse events. PMID- 28732622 TI - Effect of altering lens constants. PMID- 28732623 TI - June consultation #2. PMID- 28732624 TI - Stromal scar in a laser in situ keratomileusis flap after photorefractive keratectomy enhancement: June consultation #1. PMID- 28732625 TI - June consultation #3. PMID- 28732626 TI - June consultation #4. PMID- 28732627 TI - June consultation #5. PMID- 28732628 TI - June consultation #6. PMID- 28732629 TI - June consultation #7. PMID- 28732630 TI - Editor's Comment. PMID- 28732631 TI - Topical moxifloxacin-induced Stevens-Johnson syndrome. PMID- 28732632 TI - Standard preoperative topical antibiotics do not additionally benefit in postcataract endophthalmitis prophylaxis. PMID- 28732633 TI - Reply. PMID- 28732634 TI - Reply. PMID- 28732635 TI - On the proinflammatory effect of femtosecond-laser assisted cataract surgery in diabetic retinopathy and its possible consequences on postoperative visual outcomes. PMID- 28732636 TI - Reply. PMID- 28732637 TI - Back calculation of prediction error compared with controlled trial prediction error of Goggin nomogram for toric intraocular lens cylinders. PMID- 28732638 TI - Reply. PMID- 28732640 TI - Erratum. PMID- 28732639 TI - Erratum. PMID- 28732642 TI - Performance of the phonatory deviation diagram in the evaluation of rough and breathy synthesized voices. AB - INTRODUCTION: Voice disorders alter the sound signal in several ways, combining several types of vocal emission disturbances and noise. The phonatory deviation diagram is a two-dimensional chart that allows the evaluation of the vocal signal based on the combination of periodicity (jitter, shimmer, and correlation coefficient) and noise (Glottal to Noise Excitation) measurements. The use of synthesized signals, where one has a greater control and knowledge of the production conditions, may allow a better understanding of the physiological and acoustic mechanisms underlying the vocal emission and its main perceptual auditory correlates regarding the intensity of the deviation and types of vocal quality. OBJECTIVE: To analyze the performance of the phonatory deviation diagram in the discrimination of the presence and degree of roughness and breathiness in synthesized voices. METHODS: 871 synthesized vocal signals were used corresponding to the vowel /E/. The perceptual-auditory analysis of the degree of roughness and breathiness of the synthesized signals was performed using visual analogue scale. Subsequently, the signals were categorized regarding the presence/absence of these parameters based on the visual analogue scale cutoff values. Acoustic analysis was performed by assessing the distribution of vocal signals according to the phonatory deviation diagram area, quadrant, shape, and density. The equality of proportions and the chi-square tests were performed to compare the variables. RESULTS: Rough and breathy vocal signals were located predominantly outside the normal range and in the lower right quadrant of the phonatory deviation diagram. Voices with higher degrees of roughness and breathiness were located outside the area of normality in the lower right quadrant and had concentrated density. CONCLUSION: The normality area and the phonatory deviation diagram quadrant can discriminate healthy voices from rough and breathy ones. Voices with higher degrees of roughness and breathiness are proportionally located outside the area of normality, in the lower right quadrant and with concentrated density. PMID- 28732641 TI - The cardiomyopathy-associated K15N mutation in tropomyosin alters actin filament pointed end dynamics. AB - Correct assembly of thin filaments composed of actin and actin-binding proteins is of crucial importance for properly functioning muscle cells. Tropomyosin (Tpm) mediates the binding of tropomodulin (Tmod) and leiomodin (Lmod) at the slow growing, or pointed, ends of the thin filaments. Together these proteins regulate thin filament lengths and actin dynamics in cardiac muscle. The K15N mutation in the TPM1 gene is associated with familial dilated cardiomyopathy (DCM) but the effect of this mutation on Tpm's function is unknown. In this study, we introduced the K15N mutation in striated muscle alpha-Tpm (Tpm1.1) and investigated its interaction with actin, Tmod and Lmod. The mutation caused a ~3 fold decrease in the affinity of Tpm1.1 for actin. The binding of Lmod and Tmod to Tpm1.1-covered actin filaments also decreased in the presence of the K15N mutation. Furthermore, the K15N mutation in Tpm1.1 disrupted the inhibition of actin polymerization and affected the competition between Tmod1 and Lmod2 for binding at the pointed ends. Our data demonstrate that the K15N mutation alters pointed end dynamics by affecting molecular interactions between Tpm1.1, Lmod2 and Tmod1. PMID- 28732643 TI - Development and Internal Validation of a Prediction Model to Estimate the Probability of Needing Aggressive Immunosuppressive Therapy With Cytostatics in de Novo Lupus Nephritis Patients. AB - OBJECTIVE: To develop a multivariable clinical prediction model for the requirement of aggressive immunosuppression with cytostatics, based on simple clinical record data and lab tests. The model is defined in accordance with the result of the kidney biopsies. METHODS: Retrospective study conducted with data from patients 16 years and older, with SLE and nephritis with less than 6 months of evolution. An initial bivariate analysis was conducted to select the variables to be included in a multiple logistic regression model. Goodness of fit was evaluated using a Hosmer-Lemeshow test (H-L) and the discrimination capacity of the model by means of the area under the ROC (AUC) curve. RESULTS: Data from 242 patients was gathered; of these, 18.2% (n=44) did not need an addition of cytostatics according to the findings of their kidney biopsies. The variables included in the final model were 24-h proteinuria, diastolic blood pressure, creatinine, C3 complement and the interaction of hematuria with leukocyturia in urinary sediment. The model showed excellent discrimination (AUC=0.929; 95% CI=0.894-0.963) and adequate calibration (H-L, P=.959). CONCLUSION: In recent onset LN patients, the decision to use or not to use intensive immunosuppressive therapy could be performed based on our prediction model as an alternative to kidney biopsies. PMID- 28732644 TI - Prevalence of primary immunodeficiencies in France is underestimated. PMID- 28732645 TI - Sleep deprivation predisposes allergic mice to neutrophilic lung inflammation. AB - BACKGROUND: Although different studies associated sleep deprivation (SD) with systemic inflammatory changes, the effect of sleep duration on the pathology of allergic chronic diseases is poorly understood. OBJECTIVE: We sought to evaluate the influence of SD on allergen-induced pulmonary inflammation. METHODS: Ovalbumin (OVA)-sensitized C57BL/6 mice were exposed to a first set of intranasal OVA challenge under SD or healthy sleep (HS) conditions, followed by a second OVA challenge, 1 week apart. Some groups were subjected to corticosteroid treatment with dexamethasone. RESULTS: OVA-sensitized mice with SD had more severe airway inflammation than the allergic group with HS. Analysis of lung parenchyma revealed that the inflammation in allergic mice with SD was marked by an influx of neutrophils (mainly) and eosinophils and secretion of IL-6, TNF-alpha, and IL 17 in contrast to the eosinophilic inflammation and IL-4 production observed in allergic mice with HS. The same cytokine profile was observed in ex vivo culture of cervical lymph node cells and splenocytes, indicating that in allergic mice SD favors immune responses toward a proinflammatory TH17 profile. This idea is supported by the fact that disruption of IL-17 signaling (IL-17 receptor A-/-) prevented airway neutrophilia in allergic mice with SD. Furthermore, allergic mice with SD became refractory to corticosteroid treatment in contrast to the allergic group with HS. CONCLUSION: Collectively, our data show that sleep quality participates in the progression of allergen-induced eosinophilic lung inflammation to corticosteroid-refractory neutrophilic manifestation. PMID- 28732646 TI - Phosphatase wild-type p53-induced phosphatase 1 controls the development of TH9 cells and allergic airway inflammation. AB - BACKGROUND: Allergic asthma is one of the most common diseases worldwide, resulting in a burden of diseases. No available therapeutic regimens can cure asthma thus far. OBJECTIVE: We sought to identify new molecular targets for TH9 cell-mediated allergic airway inflammation. METHODS: Wild-type p53-induced phosphatase 1 (Wip1) gene knockout mice, Wip1 inhibitor-treated mice, and ovalbumin-induced allergic airway inflammation mouse models were used to characterize the roles of Wip1 in allergic airway inflammation. The induction of TH cell subsets in vitro, real-time PCR, immunoblots, luciferase assays, and chromatin immunoprecipitation assays were used to determine the regulatory pathways of Wip1 in TH9 differentiation. RESULTS: Here we demonstrate that Wip1 deficient mice are less prone to allergic airway inflammation, as indicated by the decreased pathologic alterations in lungs. Short-term treatment with a Wip1 specific inhibitor significantly ameliorates allergic inflammation progression. Intriguingly, Wip1 selectively impaired TH9 but not TH1, TH2, and TH17 cell differentiation. Biochemical assays show that Wip1 deficiency increases c-Jun/c Fos activity in a c-Jun N-terminal kinase-dependent manner and that c-Jun/c-Fos directly binds to Il9 promoter and inhibits Il9 transcription. CONCLUSION: Wip1 controls TH9 cell development through regulating c-Jun/c-Fos activity on the Il9 promoter and is important for the pathogenesis of allergic airway inflammation. These findings shed light on the previously unrecognized roles of Wip1 in TH9 cell differentiation. The inhibitory effects of a Wip1 inhibitor on the pathogenesis of allergic airway inflammation can have important implications for clinical application of Wip1 inhibitors in allergy therapies. PMID- 28732647 TI - Mean difference effect size: Complementary contributions. PMID- 28732649 TI - Tuning up adjuvant endocrine therapy: the TEAM trial. PMID- 28732648 TI - A systematic review of women's satisfaction and regret following risk-reducing mastectomy. AB - OBJECTIVE: A systematic review of quantitative and qualitative studies, to describe patient satisfaction and regret associated with risk-reducing mastectomies (RRM), and the patient-reported factors associated with these among women at high risk of developing breast cancer. METHODS: Studies were identified using Medline, CINAHL, Embase and PsycInfo databases (1995-2016). Data were extracted and crosschecked for accuracy. Article quality was assessed using standardised criteria. RESULTS: Of the 1657 unique articles identified, 30 studies met the inclusion criteria (n=23 quantitative studies, n=3 qualitative studies, n=4 mixed-method studies). Studies included were cross-sectional (n=23) or retrospective (n=7). General satisfaction with RRM, decision satisfaction and aesthetic satisfaction were generally high, although some women expressed regret around their decision and dissatisfaction with their appearance. Factors associated with both patient satisfaction and regret included: post-operative complications, body image changes, psychological distress and perceived inadequacy of information. CONCLUSION: While satisfaction with RRM was generally high, some women had regrets and expressed dissatisfaction. Future research is needed to further explore RRM, and to investigate current satisfaction trends given the ongoing improvements to surgical and clinical practice. PRACTICE IMPLICATIONS: Offering pre-operative preparation, decisional support and continuous psychological input may help to facilitate satisfaction with this complex procedure. PMID- 28732650 TI - Adjuvant tamoxifen and exemestane in women with postmenopausal early breast cancer (TEAM): 10-year follow-up of a multicentre, open-label, randomised, phase 3 trial. AB - BACKGROUND: After 5 years of median follow-up, the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial reported no difference in disease-free survival between exemestane monotherapy and a sequential scheme of tamoxifen followed by exemestane in postmenopausal patients with early-stage, hormone receptor-positive breast cancer. As recurrence risk in hormone receptor-positive breast cancer remains linear beyond 5 years after diagnosis, we analysed long-term follow-up outcomes of this trial. METHODS: The TEAM trial, a multicentre, open-label, randomised, controlled, phase 3 trial, included postmenopausal patients with early-stage hormone receptor-positive breast cancer from nine countries. Patients were randomly allocated (1:1) by a computer-generated random permuted block method (block sizes 4-8) to either 5 years of oral exemestane monotherapy (25 mg once a day) or a sequential scheme of oral tamoxifen (20 mg once a day) followed by exemestane for a total duration of 5 years. After the publication of the IES trial, the protocol was amended (Dec 13, 2004). Patients assigned to tamoxifen were switched after 2.5-3.0 years to exemestane therapy for a total duration of 5.0 years of treatment. Randomisation was done centrally in each country. Long term follow-up data for disease recurrence and survival was collected in six participating countries and analysed by intention to treat. The primary endpoint was disease-free survival at 10 years of follow-up. The trial is registered with ClinicalTrials.gov, numbers NCT00279448 and NCT00032136; with Netherlands Trial Register, number NTR 267; and the Ethics Commission Trial, number 27/2001. FINDINGS: 6120 patients of the original 9776 patients in the TEAM trial were included in the current intention-to-treat analysis. Median follow-up was 9.8 years (IQR 8.0-10.3). During follow-up, 921 (30%) of 3075 patients in the exemestane group and 929 (31%) of 3045 patients in the sequential group had a disease-free survival event. Disease-free survival at 10 years was 67% (95% CI 65 69) for the exemestane group and 67% (65-69) for the sequential group (hazard ratio 0.96, 0.88-1.05; p=0.39). INTERPRETATION: The long-term findings of the TEAM trial confirm that both exemestane alone and sequential treatment with tamoxifen followed by exemestane are reasonable options as adjuvant endocrine therapy in postmenopausal patients with hormone receptor-positive early breast cancer. These results suggest that the opportunity to individualise adjuvant endocrine strategy accordingly, based on patient preferences, comorbidities, and tolerability might be possible. FUNDING: Pfizer, Dutch Cancer Foundation. PMID- 28732651 TI - Maternal Caffeine Consumption during Pregnancy and Behavioral Disorders in 11 Year-Old Offspring: A Danish National Birth Cohort Study. AB - OBJECTIVE: To examine the association between maternal caffeine consumption from coffee and tea during pregnancy and offspring behavioral disorders. STUDY DESIGN: We studied 47 491 children enrolled in the Danish National Birth Cohort between 1996 and 2002. Data on maternal coffee and tea consumption was collected at 15 and 30 weeks of gestation. When the child was 11 years old, the Strength and Difficulties Questionnaire was filled in by children, parents, and teachers. We estimated risk ratios (RRs) for offspring behavioral disorders. RESULTS: At 15 weeks of gestation 3% and 4% of the pregnant women consumed >=8 cups/d of coffee or tea, respectively. Maternal coffee consumption >=8 cups/d at 15 weeks of gestation was associated with increased risk of hyperactivity-inattention disorder (RR 1.47; 95% CI 1.18-1.83), conduct-oppositional disorders (RR 1.22; 95% CI 1.01-1.48), and any psychiatric disorder (RR 1.23; 95% CI 1.08-1.40). Maternal tea consumption >=8 cups/d at 15 weeks of gestation was associated with increased risk of anxiety-depressive disorders (RR 1.28; 95% CI 1.09-1.52) and any psychiatric disorder (RR 1.24; 95% CI 1.11-1.40). An increased risk of hyperactivity-inattention disorder was observed with increasing daily caffeine consumption at 15 weeks of gestation. CONCLUSION: High maternal caffeine consumption from coffee and tea at 15 weeks of gestation was associated with behavioral disorders in 11-year-old offspring. We hypothesize that caffeine exposure may affect the fetal brain and program for behavioral disorders later in life. The fetal brain seems to be more sensitive to caffeine exposure at 15 weeks of pregnancy compared with 30 weeks of gestation. PMID- 28732652 TI - Correlation of tenascin-C concentrations in serum with outcome of traumatic brain injury in humans. AB - BACKGROUND: Tenascin-C, a matricellular protein, is involved in brain injury. However, change of tenascin-C concentrations in peripheral blood remains unknown after traumatic brain injury (TBI). METHODS: Serum tenascin-C concentrations were measured in 100 healthy controls, 108 severe TBI patients, 79 moderate TBI patients and 32 mild TBI patients. RESULTS: Serum tenascin-C concentrations of patients were significantly higher than those of controls. Tenascin-C concentrations negatively correlated with Glasgow Coma Scale (GCS) scores in all patients (r=-0.658, P<0.001). In severe TBI patients, tenascin-C in serum significantly discriminated patients at risk of 6-month mortality (area under curve, 0.821; 95% confidence interval, 0.735-0.888) and poor outcome (Glasgow Outcome Scale score of 1-3) (area under curve, 0.833; 95% confidence interval, 0.749-0.898) and emerged as an independent predictor for 6-month mortality (odds ratio, 1.114; 95% confidence interval, 1.008-1.233; P=0.005), overall survival (hazard ratio, 1.085; 95% confidence interval, 1.010-1.166; P=0.003) and unfavorable outcome (odds ratio, 1.049; 95% confidence interval, 1.014-1.076; P=0.001). By receiver-operating characteristic analysis, serum tenascin-C concentrations had similar prognostic value compared with GCS scores. CONCLUSIONS: Enhanced serum tenascin-C concentrations are closely related to trauma severity and clinical outcomes, substantializing tenascin-C as a potential prognostic biomarker after TBI. PMID- 28732653 TI - Sestrins increase in patients with coronary artery disease and associate with the severity of coronary stenosis. AB - BACKGROUND: Sestrins (Sesns) family, which including three members Sesn1, Sesn2 and Sesn3, is known as stress-inducible proteins and participate in multiple diseases via regulating oxidative stress, inflammatory response and cell apoptosis. The present study aimed to investigate the plasma levels and the clinical significance of Sesns in patients with coronary artery disease (CAD). METHODS: In the case-control study, 119 CAD patients, including stable angina pectoris (SAP, n=44), unstable angina pectoris (UAP, n=41) and acute myocardial infarction (AMI, n=29) were included. Patients with chest pain syndrome but excluded CAD (n=35) were enrolled as control. Plasma levels of Sesn1, Sesn2, Sesn3, superoxide dismutase (SOD) and malondialdehyde (MDA) in all patients were measured and analyzed. RESULTS: Compared with control group, plasma levels of Sesn1, Sesn2 and Sesn3 were significantly increased in patients with SAP, UAP and AMI. In addition, a significant lower SOD levels and higher MDA levels were observed in CAD patients, Sesn1/2/3 levels were negatively correlated with SOD levels and positively correlated with MDA levels. Gensini Score were positively correlated with Sesn1/2/3 levels and MDA levels, whereas negatively correlated with SOD levels. Furthermore, as the main risk factors for CAD, the elderly and obesity increased plasma Sesn2 levels, diabetes increased both plasma Sesn2 and Sesn3 levels. CONCLUSIONS: Our study was the first to report that the plasma Sesns levels were increased in CAD patients and positively related to the severity of coronary heart disease. Although the exact mechanisms of Sesns in CAD are still unknown, alleviated oxidative stress may be the possible reasons. PMID- 28732654 TI - Effects of incretin-based therapies on neurocognitive function in humans: A systematic review of the literature. AB - We performed a PRISMA systematic review of incretin-based therapies and effects on neurocognitive function in humans. There was observational evidence to support dipeptidyl peptidase-IV inhibitors in improving cognition, whilst glucagon-like peptide-1 had positive effects on cerebral glucose metabolism. Powered clinical trials are now needed in patients with- and without diabetes. PMID- 28732655 TI - Assessing variability in compliance with recommendations given by the International Diabetes Federation (IDF) for patients with type 2 diabetes in primary care using electronic records. The APNA study. AB - OBJECTIVE: Assess compliance with the IDF recommendations for patients with Diabetes Type2 (DM2), and its variability, by groups of doctors and nurses who provide primary care services in Navarre (Spain). MATERIALS AND METHODOLOGIES: A cross-sectional study of a population of 462,568 inhabitants, aged >=18 years in 2013, attended by 381 units of doctor/nurse (quota). Clinical data were collected retrospectively through electronic records. Using cluster analysis, we identified two groups of units according to the score for each indicator. We calculated the Odds Ratio, adjusted for age sex, BMI, socioeconomic status and smoking, for complying with each recommendation whether a patient was treated by one of the quota from the highest score to the lowest. 30,312 patients with DM2 were identified: prevalence: 6.39%; coefficient of variation between UDN: 22.8%; biggest cluster 7.7% and smallest 5.3%; OR=1.54 (1.50-1.58). The HbA1c control at <=8% was 82.8% (82.2-83.3) and >9% was 7.6% (7.3-8.0), with OR 1.79 (1.69-1.89) and 2.62 (2.36-2.91) respectively. Control of BP and LDL-C show significant differences between the clusters. CONCLUSIONS: An important variability was identified according to the doctor treating patients. The average HbA1c control is acceptable being limited in BP and LDL-C. PMID- 28732656 TI - Searching for Win-Win Archetypes in the Food-Biodiversity Challenge: A Response to Fischer et al. PMID- 28732657 TI - We Need Qualitative Progress to Address the Food-Biodiversity Nexus: A Reply to Seppelt et al. PMID- 28732658 TI - Tumor cell uptake and selectivity of gadolinium(III)-phosphonium complexes: The role of delocalisation at the phosphonium centre. AB - The synthesis of a series of bifunctional Gd(III) complexes 1-3 covalently bound to arylphosphonium cations possessing a varying degree of delocalisation at the phosphonium centre is presented. The influence of the degree of delocalisation was investigated with regards to in vitro cytotoxicity, cellular uptake of Gd, tumor-cell selectivity and intracellular localisation of Gd within human glioblastoma (T98G) and human glial (SVG p12) cells. Cellular uptake and selectivity studies for the Gd(III) complexes indicate that a reduced delocalisation at the phosphonium centre can lead to an enhanced Gd uptake into SVG p12 cells which results in a decrease in the overall tumor cell selectivity. Synchrotron X-ray fluorescence (microbeam XRF) imaging has demonstrated for the first time that uniform uptake of Gd(III) complex 2 within a population of T98G cells increased as a function of increasing Gd incubation times. The Gd maps show dispersed spots of high intensity which are consistent with mitochondrial uptake. PMID- 28732659 TI - Eye tracking measures of uncertainty during perceptual decision making. AB - Perceptual decision making involves gathering and interpreting sensory information to effectively categorize the world and inform behavior. For instance, a radiologist distinguishing the presence versus absence of a tumor, or a luggage screener categorizing objects as threatening or non-threatening. In many cases, sensory information is not sufficient to reliably disambiguate the nature of a stimulus, and resulting decisions are done under conditions of uncertainty. The present study asked whether several oculomotor metrics might prove sensitive to transient states of uncertainty during perceptual decision making. Participants viewed images with varying visual clarity and were asked to categorize them as faces or houses, and rate the certainty of their decisions, while we used eye tracking to monitor fixations, saccades, blinks, and pupil diameter. Results demonstrated that decision certainty influenced several oculomotor variables, including fixation frequency and duration, the frequency, peak velocity, and amplitude of saccades, and phasic pupil diameter. Whereas most measures tended to change linearly along with decision certainty, pupil diameter revealed more nuanced and dynamic information about the time course of perceptual decision making. Together, results demonstrate robust alterations in eye movement behavior as a function of decision certainty and attention demands, and suggest that monitoring oculomotor variables during applied task performance may prove valuable for identifying and remediating transient states of uncertainty. PMID- 28732660 TI - Forging paths to improve diabetes care in low-income settings. PMID- 28732661 TI - Hyperglycaemia in pregnancy: time to ask the hard questions? PMID- 28732662 TI - Microvascular outcomes in type 2 diabetes. PMID- 28732663 TI - Oldest case of gigantism? Assessment of the alleged remains of Sa-Nakht, king of ancient Egypt. PMID- 28732664 TI - Microvascular outcomes in type 2 diabetes - Authors' reply. PMID- 28732665 TI - Correction to Lancet Diabetes Endocrinol 2017; 5: 597-609. PMID- 28732666 TI - Correction to Lancet Diabetes Endocrinol 2017; 5: 569-71. PMID- 28732667 TI - Contribution of BDNF/TrkB signalling in the rACC to the development of pain related aversion via activation of ERK in rats with spared nerve injury. AB - The rostral anterior cingulate cortex (rACC) is a key structure in mediating the negative affective component of chronic pain. Brain-derived neurotrophic factor (BDNF) is known to play a critical role in activity-dependent synaptic plasticity, learning and memory. It has been shown that BDNF signalling in the rACC might be involved in spontaneous pain-related aversion, but its underlying mechanism is still largely unknown. To address this question, we measured the mRNA and protein levels of BDNF in the rACC after nerve injury and found that BDNF expression was markedly higher in nerve-injured rats than in controls. Moreover, we found that conditioned place avoidance (CPA), a behavioural phenotype reflecting pain-related aversion, was acquired in rats with partial sciatic nerve transection. However, a local injection of a BDNF-tropomyosin receptor kinase B (TrkB) antagonist into the rACC completely suppressed this process. Importantly, we found that administration of exogenous BDNF into the rACC of intact rats was sufficient to produce CPA, while selectively blocking phosphorylated extracellular signal regulated kinase (p-ERK) with a mitogen activated protein kinase (MAPK) inhibitor U0126 completely abolished the acquisition of BDNF-induced CPA. In conclusion, we demonstrate, for the first time, that ERK is an important downstream effector of the BDNF/TrkB-mediated signalling pathway in the rACC that contributes to the development of neuropathic pain-related aversion. PMID- 28732668 TI - Spermatogenesis in a neotropical marsupial species, Philander frenatus (Olfers, 1818). AB - Despite the singular morphology of the male genital system and the different reproductive strategies of marsupials, little emphasis has been given to the testis morphology and spermatogenic kinetics in this mammalian order. The present study aimed to investigate the testis function and the duration of spermatogenesis in the southeastern four-eyed opossum, Philander frenatus. Testes of six adult males were routinely processed for histological and stereological analyses. In order to determine the duration of spermatogenesis, intratesticular injections of tritiated thymidine were performed 1h, 13days and 21days before the sacrifice. Based on the development of the acrosomic system, ten stages of the seminiferous epithelium cycle were characterized. The mean body and testis weights for the P. frenatus were respectively 326+/-20g and 0.4+/-0.05g, providing a gonadosomatic index of 0.3+/-0.02%. The most advanced germ cell types labeled at 1h, 13days and 21days after thymidine injections were, respectively, preleptotene spermatocytes at stage IV, pachytene spermatocytes at stage IV and diplotene spermatocytes at stage IX. Based on the stages frequencies and the most advanced labeled germ cells, each spermatogenic cycle and the entire spermatogenic process lasted respectively 13.5+/-0.5 and 60.9+/-2.4days. When compared to the vast majority of eutherian mammals already investigated, these data indicate that the Philander frenatus presents a relatively long duration of spermatogenesis. PMID- 28732669 TI - Clinical use of fetal measurements to determine the whelping day in German shepherd breed bitches. AB - The aim of this work was to use a linear regression model previously developed in a pilot study to calculate days before parturition (DbP) using inner chorionic cavity (ICC), biparietal diameter (BPD), crown-rump length (CRL), body diameter (BD) and deep portion of telencephalic vesicle (DPTV) in German shepherd dogs (GSD) with known ovulation day and then to test that model in bitches with unknown ovulation day. In our current study, a model for GSD bitches published in a previous report, proved satisfactory for ICC [DbP=44.76-(4.34*ICC)] and BPD [DbP=38.65-(12.86*BPD)]. We therefore used their model, but developed a new one for CRL, BD and DPTV. For ICC and BPD, we tested accuracy for more than 35days before parturition (ICC) and more than 15days before parturition (BPD). Measurements were taken on at least two fetuses during each ultrasound recording (US) of 22 GSD bitches with known (n=16) and unknown (n=6) ovulation days. The accuracy of the above model was 77-100% for ICC and 83-96% for BPD with a precision of +/-1 and +/-2days, respectively. Accuracy increased significantly when US was performed more than 35days before parturition for ICC and more than 15days before parturition for BPD. BD and CRL were the most accurate parameters (R2=0.95 and 0.85). In bitches with unknown ovulation day, BD accuracy was 71.4 100% with a precision of +/-1day and +/-2days, respectively. CRL and DPTV were less accurate (+/-1day, 60%; +/-2days, 80% accuracy). PMID- 28732670 TI - Long non-coding RNA NEAT1 overexpression is associated with unfavorable prognosis in patients with hepatocellular carcinoma after hepatectomy: A Chinese population based study. AB - AIM: To identify the association between the expression of lncRNA NEAT1 and clinicopathological characteristics of patients with HCC, and to explore the prognostic significance of lncRNA NEAT1 in predicting prognosis of HCC. METHODS: We retrospectively reviewed 86 patients with HCC (35 female, 51 male) managed in our institution between 2009 and 2014. The expression level of lncRNA NEAT1 was detected by real-time PCR. Prognostic factors were evaluated using Kaplan-Meier curves and Cox proportional hazards models. RESULTS: For the entire cohort of 86 patients, we showed that the expression level of NEAT1 was significantly higher in HCC tissues compared with non-tumorous tissues and NEAT1 was increased obviously in the HCC cell lines including SMMC-7721, Huh-7 and Hep3B (P < 0.001). MTT assay showed that si-NEAT1 remarkably inhibited the cell proliferation in three HCC cell lines. Moreover, over-expression of lncRNA NEAT1 was closely related to liver cirrhosis (P = 0.026), microvascular invasion (MVI) (P = 0.023), and TNM stage (P = 0.017). After adjusting for competing risk factors, we identified that expression level of lncRNA NEAT1 was an independently risk factor associated with the prognosis of patients with HCC (P = 0.031). CONCLUSIONS: In this study, we found NEAT1 expressed significantly higher in HCC tissues compared with non-tumorous tissues. Overexpression of lncRNA NEAT1 was an independently risk factor associated with the prognosis of patients with HCC. PMID- 28732671 TI - Psoas hitch ureteral reimplantation after surgery for locally advanced and locally recurrent colorectal cancer: Complications and oncological outcome. AB - INTRODUCTION: The most important prognostic factor for oncological outcome of rectal cancer is radical surgical resection. In patients with locally advanced T4 rectal cancer (LARC) or locally recurrent rectal cancer (LRRC) (partial) resection of the urinary tract is frequently required to achieve radical resection. The psoas bladder hitch (PBH) technique is the first choice for reconstruction of the ureter after partial resection and this bladder-preserving technique should not influence the oncological outcome. METHODS: Demographic and clinical data were collected prospectively for all patients operated on for LARC or LRRC between 1996 and 2014 who also underwent a psoas hitch ureter reconstruction. Urological complications and oncological outcome were assessed. RESULTS: The sample comprised 70 patients, 30 with LARC and 40 with LRRC. The mean age was 62 years (range: 39-86). Postoperative complications occurred in 38.6% of patients, the most frequent were urinary leakage (22.9%), ureteral stricture with hydronephrosis (8.6%) and urosepsis (4.3%). Surgical re intervention was required in 4 cases (5.7%), resulting in permanent loss of bladder function and construction of a ureter-ileo-cutaneostomy in 3 cases (4.3%). Oncological outcome was not influenced by postoperative complications. CONCLUSION: The rate of complications associated with the PBH procedure was higher in our sample than in previous samples with benign conditions, but most complications were temporary and did not require surgical intervention. We conclude that the bladder-sparing PBH technique of ureter reconstruction is feasible in locally advanced and recurrent rectal cancer with invasion of the urinary tract after pelvic radiotherapy. PMID- 28732672 TI - [Microbial inoculants: Pieces of a puzzle that still needs to be assembled]. PMID- 28732673 TI - Expanding the horizons for structural analysis of fully protonated protein assemblies by NMR spectroscopy at MAS frequencies above 100 kHz. AB - The recent breakthroughs in NMR probe technologies resulted in the development of MAS NMR probes with rotation frequencies exceeding 100 kHz. Herein, we explore dramatic increases in sensitivity and resolution observed at MAS frequencies of 110-111 kHz in a novel 0.7 mm HCND probe that enable structural analysis of fully protonated biological systems. Proton- detected 2D and 3D correlation spectroscopy under such conditions requires only 0.1-0.5 mg of sample and a fraction of time compared to conventional 13C-detected experiments. We discuss the performance of several proton- and heteronuclear- (13C-,15N-) based correlation experiments in terms of sensitivity and resolution, using a model microcrystalline fMLF tripeptide. We demonstrate the applications of ultrafast MAS to a large, fully protonated protein assembly of the 231-residue HIV-1 CA capsid protein. Resonance assignments of protons and heteronuclei, as well as 1H 15N dipolar and 1HN CSA tensors are readily obtained from the high sensitivity and resolution proton-detected 3D experiments. The approach demonstrated here is expected to enable the determination of atomic-resolution structures of large protein assemblies, inaccessible by current methodologies. PMID- 28732675 TI - Substrate stiffness regulates arterial-venous differentiation of endothelial progenitor cells via the Ras/Mek pathway. AB - Cells sense and respond to the biophysical properties of their surrounding environment by interacting with the extracellular matrix (ECM). Therefore, the optimization of these cell-matrix interactions is critical in tissue engineering. The vascular system is adapted to specific functions in diverse tissues and organs. Appropriate arterial-venous differentiation is vital for the establishment of functional vasculature in angiogenesis. Here, we have developed a polydimethylsiloxane (PDMS)-based substrate capable of simulating the physiologically relevant stiffness of both venous (7kPa) and arterial (128kPa) tissues. This substrate was utilized to investigate the effects of changes in substrate stiffness on the differentiation of endothelial progenitor cells (EPCs). As EPCs derived from mouse bone marrow were cultured on substrates of increasing stiffness, the mRNA and protein levels of the specific arterial endothelial cell marker ephrinB2 were found to increase, while the expression of the venous marker EphB4 decreased. Further experiments were performed to identify the mechanotransduction pathway involved in this process. The results indicated that substrate stiffness regulates the arterial and venous differentiation of EPCs via the Ras/Mek pathway. This work shows that modification of substrate stiffness may represent a method for regulating arterial-venous differentiation for the fulfilment of diverse functions of the vasculature. PMID- 28732674 TI - 3D-MB-MUSE: A robust 3D multi-slab, multi-band and multi-shot reconstruction approach for ultrahigh resolution diffusion MRI. AB - Recent advances in achieving ultrahigh spatial resolution (e.g. sub-millimeter) diffusion MRI (dMRI) data have proven highly beneficial in characterizing tissue microstructures in organs such as the brain. However, the routine acquisition of in-vivo dMRI data at such high spatial resolutions has been largely prohibited by factors that include prolonged acquisition times, motion induced artifacts, and low SNR. To overcome these limitations, we present here a framework for acquiring and reconstructing 3D multi-slab, multi-band and interleaved multi-shot EPI data, termed 3D-MB-MUSE. Through multi-band excitations, the simultaneous acquisition of multiple 3D slabs enables whole brain dMRI volumes to be acquired in-vivo on a 3 T clinical MRI scanner at high spatial resolution within a reasonably short amount of time. Representing a true 3D model, 3D-MB-MUSE reconstructs an entire 3D multi-band, multi-shot dMRI slab at once while simultaneously accounting for coil sensitivity variations across the slab as well as motion induced artifacts commonly associated with both 3D and multi-shot diffusion imaging. Such a reconstruction fully preserves the SNR advantages of both 3D and multi-shot acquisitions in high resolution dMRI images by removing both motion and aliasing artifacts across multiple dimensions. By enabling ultrahigh resolution dMRI for routine use, the 3D-MB-MUSE framework presented here may prove highly valuable in both clinical and research applications. PMID- 28732676 TI - Expansion of lymph node metastasis in mixed-type submucosal invasive gastric cancer. AB - BACKGROUND/OBJECTIVE: Mixed-type early gastric cancer (differentiated and undifferentiated components) incurs a higher risk of lymph node metastasis than pure-type early gastric cancer (only differentiated or only undifferentiated components). Therefore, we investigated the expansion of lymph node metastasis in mixed-type submucosal invasive gastric cancer in order to establish the most appropriate treatment for mixed-type cancer. METHODS: We retrospectively analyzed 279 consecutive patients with submucosal invasive gastric cancer who underwent curative gastrectomy for gastric cancer between 1996 and 2015. We classified the patients into the mixed-type and pure-type groups according to histologic examination and evaluated the expansion of lymph node metastasis. RESULTS: The rate of lymph node metastasis was 23.7% (66/279) in the total patients, 36.4% (36/99) in the mixed-type group, and 16.6% (30/180) in the pure-type group. The significant independent risk factors for lymph node metastasis were tumor size >=2.0 cm (P = 0.014), mixed-type gastric cancer (P < 0.001), and lymphatic invasion (P < 0.001). Lymphatic invasion and lymph node metastasis had a strong relationship in mixed-type group. The rates of no. 7 lymph node metastasis in the total patients and mixed-type group were 2.9% (8/279) and 5.1% (5/99), respectively; the rates of no. 8a lymph node metastasis were 1.4% (4/279) and 4.0% (4/99), respectively. CONCLUSION: Mixed histological type is an independent risk factor for lymph node metastasis. Lymph node metastasis in mixed-type gastric cancer involves expansion to the no. 7 and no. 8a lymph nodes. Therefore, lymphadenectomy for mixed-type submucosal invasive gastric cancer requires D1+ or D2 dissection. PMID- 28732677 TI - Assessment of bone repair in critical-size defect in the calvarium of rats after the implantation of tricalcium phosphate beta (beta-TCP). AB - OBJECTIVES: Evaluating the osteoconductive property of tricalcium phosphate beta (beta-TCP) in comparison to that of inorganic bovine bone for repair in a critical-size defect in the rat calvarium. MATERIALS AND METHODS: Critical-size defects of 7mm were made with a trephine in the calvaria of 48 Wistar rats. The animals were divided into four groups, and the defects in each group were filled with tricalcium phosphate beta (beta-TCP), inorganic bovine bone (Bio-Oss), autogenous bone, or left empty. The animals were euthanized at two different time points (30 and 60days post-operation). All defects were recovered with a absorbable membrane of bovine cortical bone. Histological, histometric, and immunohistochemical (osteocalcin) assessments were carried out at 30 and 60days post-operation. RESULTS: At 30days post-operation, all groups showed areas of bone formation, predominantly when autogenous grafts were used. However, there were no statistically significant differences between the treatment groups (p>0.05). After 60days, there were similarities in the bone formation patterns between the beta-TCP (26.32+/-) and Bio-Oss (17.35+/-) groups (p=0.549). In terms of the immunohistochemical assessment of osteocalcin, the clot group showed light to moderate staining at 30 and 60days. The autogenous group showed moderate staining at 30days and moderate to intense staining after 60days. The Bio-Oss group showed light to moderate staining after 30days and intense staining at 60days. The beta-TCP group showed moderate staining at 30 and 60days post operation. CONCLUSION: beta-TCP is a good osteoconductive material with similar effects to those of inorganic bovine bone graft and is suitable for utilization in the repair of bone defects. PMID- 28732678 TI - Ultrasound-guided fine-needle capillary cytology of parotid gland masses coupled with a rapid-on-site evaluation improves results. AB - OBJECTIVE OF THE STUDY: To test whether a direct-on-site microscopic examination of fresh, unstained puncture slides by the radiologist decreases the rate of false-negative cases on ultrasound-guided fine-needle cytology of parotid gland masses. PATIENTS: Thirty parotid gland masses from 28 patients were punctured under ultrasound guidance. The same group was used as its control group. METHODS: After one or two passes, the material was spread on slides and air-dried (control group, without microscopic examination). For the study group, it was thus analyzed unstained under the microscope. A sample was considered adequate if at least six clusters of parotid cells were found per slide on at least two slides. For the study group, new punctures were obtained and slides prepared until this condition was fulfilled. RESULTS: Of the 30 evaluated masses, 100% benefited from a cytological diagnosis after microscopy. Twenty-four were adequate in the control group, while 30 were adequate in the study group. The maximum number of punctures to obtain an adequate sample was six. On-site direct microscopy significantly increased the number of adequate specimens by 20% (P=0.03, CI [1.63 20%]). CONCLUSION: Direct and systematic examination of slides by a radiologist avoided the risk of false-negative results caused by having insufficient sample material. PMID- 28732679 TI - Serum 25-hydroxyvitamin D concentrations are associated with nuclear factor kappa B activity but not with inflammatory markers in healthy normoglycemic adults. AB - Vitamin D has been reported to have anti-inflammatory properties in in vitro and animal studies, which are thought to occur via inhibition of the nuclear factor kappa-B (NFkappaB) pathway. However, the association between vitamin D and in vivo NFkappaB activity in humans has not previously been reported. The aim of the present study was to examine the associations between circulating 25 hydroxyvitamin D (25(OH)D) concentrations and NFkappaB activity in peripheral blood mononuclear cells (PBMCs) as well as plasma inflammatory markers in healthy individuals. We hypothesized that 25(OH)D concentrations would be negatively associated with NFkappaB activity and pro-inflammatory markers downstream of NFkappaB, and positively associated with anti-inflammatory markers. We measured circulating 25(OH)D (chemiluminescent immunoassay); anthropometry: body mass index (BMI), waist-to-hip ratio (WHR), and % body fat (dual X-ray absorptiometry); plasma pro- and anti-inflammatory markers: high sensitivity C reactive protein (hsCRP), tumor necrosis factor (TNF), monocyte chemoattractant protein-1 (MCP-1), interleukin-6 (IL-6), and IL-10 (ELISA); and NFkappaB activity in PBMCs (DNA-binding assay). Forty-nine participants were included in the study (21M/28F; age=31.6+/-10.2years (mean+/-SD); BMI=28.4+/-4.6kg/m2; % body fat=30.2+/-9.3%). Mean 25(OH)D concentration was 48.2+/-24.5 nmol/l. There were no differences in 25(OH)D concentrations between genders and no association between 25(OH)D concentrations and age, BMI, or % body fat (all p>0.1). Serum 25(OH)D concentrations were positively associated with NFkappaB activity in PBMCs (r=0.48, p=0.0008) but not with any of the pro- or anti-inflammatory markers measured (all p>0.1). After adjusting for age, sex, and % body fat, 25(OH)D concentrations remained positively associated with NFkappaB activity in PBMCs (beta=0.55, p<0.0001). Although in-vitro studies suggest that vitamin D inhibits NFkappaB activity, our novel cross-sectional data from a cohort of healthy individuals suggest that vitamin D may regulate rather than inhibit the NFkappaB pathway. Large-scale intervention and mechanistic studies are needed to further investigate the effects of vitamin D on NFkappaB activity in vivo in humans. PMID- 28732680 TI - Stereoselective synthesis of 25S,26-dihydroxyvitamin D3. AB - A convergent approach to 25S,26-dihydroxyvitamin D3 (1) has been developed in our laboratories. The A-ring and the CD-fragment are constructed from ergocalciferol and Inhoffen-Lythgoe diol, respectively. The triene system is assembled by a Wittig-Horner coupling. With this convergent synthesis, a novel hydroxylated vitamin D metabolite in our laboratory is available for biological testing. PMID- 28732682 TI - Characterization and purification of proteins suitable for the production of antibodies against 'Ca. Liberibacter asiaticus'. AB - The citrus disease huanglongbing (HLB), which is caused by 'Candidatus Liberibacter asiaticus' (CaLas), is one of the most devastating pathogens of citrus, and with no effective method of control, poses a serious threat to citrus production throughout the world. In a previous study we described the production of single chain antibodies against several CaLas proteins that provide the basis for efficient and accurate detection of CaLas in citrus tissues. The isolation of a sufficient amount of purified antigen is a key step in the production of functional antibodies. The current report details purification procedures for six protein antigens used to select recombinant and produce polyclonal antibodies. These proteins include a flagellar biosynthesis protein (FlhA), a dinucleoside polyphosphate hydrolase (InvA), a portion of the major outer membrane protein (OmpA), a component of type IV pilus (CapB), the polysialic acid capsule expression protein (KpsA) and the outer membrane efflux protein (TolC). Results of purification under completely native or denatured conditions were not satisfactory. Therefore different hybrid purification conditions were optimized for each of the different proteins. The results of bioinformatic analysis also indicated that the six proteins contained a great diversity of potential antigenic epitopes, which varied in number, and that the antigenic clusters were not uniformly distributed throughout the proteins. The purified proteins are useful for the development of highly specific antibodies capable of differentiating specific strains of Liberibacter. PMID- 28732683 TI - A country fool's progress. PMID- 28732684 TI - The impact of current infection levels on the cost-benefit of vaccination. AB - When considering a new vaccine programme or modifying an existing one, economic cost-benefit analysis, underpinned by predictive epidemiological modelling, is a key component. This analysis is intimately linked to the willingness to pay for additional QALYs (quality-adjusted life-years) gained; currently in England and Wales a health programme is economically viable if the cost per QALY gained is less than L 20,000, and models are often used to assess if a vaccine programme is likely to fall below this threshold cost. Before a programme begins, infection levels are generally high and therefore vaccination may be expected to have substantial effects and therefore will often be economically viable. However, once a programme is established, and infection rates are lower, it might be expected that a re-evaluation of the programme (using current incidence information) will show it to be less cost-effective. This is the scenario we examine here with analytical tools and simple ODE models. Surprisingly we show that in most cases the benefits from maintaining an existing vaccination programme are at least equal to those of starting the programme initially, and in the majority of scenarios the differences between the two are minimal. In practical terms, this is an extremely helpful finding, allowing us to assert that the action of immunising individuals does not de-value the vaccination programme. PMID- 28732685 TI - The three paradigm shifts of the 1980s and the AAS. PMID- 28732681 TI - Diurnal rhythms of vitamin D binding protein and total and free vitamin D metabolites. AB - Vitamin D binding protein (DBP) concentration is known to influence the availability and bioactivity of vitamin D metabolites but its diurnal rhythm (DR), its inter-relationships with the DRs of vitamin D metabolites and its influence on free vitamin D metabolite concentrations are not well described. The DRs of plasma total 25(OH)D, total 1,25(OH)2D, DBP, albumin and calculated free 25(OH)D and free 1,25(OH)2D were measured in men and women aged 60-75 years and resident in the UK (n 30), Gambia (n 31) and China (n 30) with differences in lifestyle, dietary intake and vitamin D status. Blood samples were collected every 4h for 24h and DRs statistically analysed with Fourier regression. Gambians had significantly higher plasma concentrations of vitamin D metabolites and lower albumin concentration compared to the British and Chinese. Significant DRs were observed for all analytes and calculated free vitamin D metabolites (P<0.01). The pattern of DRs was similar between countries. The magnitude of the DRs of free 1,25(OH)2D was attenuated compared to that of total 1,25(OH)2D whereas it was not different between total and free 25(OH)D. Relationships between the DRs were generally weak. There was no phase shift between 1,25(OH)2D and DBP with the strongest cross correlation at 0h time lag (r=0.15, P=<0.001). In comparison, 25(OH)D correlated less well with DBP (1h time lag, r=0.07, P=0.12). These data demonstrate a relationship between the DRs of 1,25(OH)2D and DBP, possibly to maintain free 1,25(OH)2D concentrations. In contrast, the DRs of total and free 25(OH)D appeared to be less influenced by DBP, suggesting that DBP has comparatively less effect on 25(OH)D concentration and 25(OH)D availability. This work highlights the importance of standardisation in timing of sample collection particularly for the assessment of plasma protein concentrations. PMID- 28732687 TI - Selective Therapeutic Intervention: A Challenge against Off-Target Effects. AB - Despite the massive global spend on biology-driven drug discovery, tackling the issue of side effects and adverse events resulting from drug promiscuity represents a persistent challenge. Although delivering authentic medical innovations today is more complex than ever, minimization of off-target effects should be a priority. PMID- 28732686 TI - Health Conditions: Effect on Function, Health-Related Quality of Life, and Life Satisfaction After Traumatic Spinal Cord Injury. A Prospective Observational Registry Cohort Study. AB - OBJECTIVE: To analyze relations among injury, demographic, and environmental factors on function, health-related quality of life (HRQoL), and life satisfaction in individuals with traumatic spinal cord injury (SCI). DESIGN: Prospective observational registry cohort study. SETTING: Specialized acute and rehabilitation SCI centers. PARTICIPANTS: Participants (N=340) from the Rick Hansen Spinal Cord Injury Registry (RHSCIR) who were prospectively recruited from 2004 to 2014 were included. The model cohort participants were 79.1% men, with a mean age of 41.6+/-17.3 years. Of the participants, 34.7% were motor/sensory complete (ASIA Impairment Scale [AIS] grade A). INTERVENTIONS: None. MAIN OUTCOME MEASURES: Path analysis was used to determine relations among SCI severity (AIS grade and anatomic level [cervical/thoracolumbar]), age at injury, education, number of health conditions, functional independence (FIM motor score), HRQoL (Medical Outcomes Study 36-Item Short-Form Health Survey [Version 2] Physical Component Score [PCS] and Mental Component Score [MCS]), and life satisfaction (Life Satisfaction-11 [LiSat-11]). Model fit was assessed using recommended published indices. RESULTS: Goodness of fit of the model was supported by all indices, indicating the model results closely matched the RHSCIR data. Higher age, higher severity injuries, cervical injuries, and more health conditions negatively affected FIM motor score, whereas employment had a positive effect. Higher age, less education, more severe injuries (AIS grades A-C), and more health conditions negatively correlated with PCS (worse physical health). More health conditions were negatively correlated with a lower MCS (worse mental health), however were positively associated with reduced function. Being married and having higher function positively affected Lisat-11, but more health conditions had a negative effect. CONCLUSIONS: Complex interactions and enduring effects of health conditions after SCI have a negative effect on function, HRQoL, and life satisfaction. Modeling relations among these types of concepts will inform clinicians how to positively effect outcomes after SCI (eg, development of screening tools and protocols for managing individuals with traumatic SCI who have multiple health conditions). PMID- 28732688 TI - Molecular Pathophysiology of Gout. AB - Three contradictory clinical presentations of gout have puzzled clinicians and basic scientists for some time: first, the crescendo of sterile inflammation in acute gouty arthritis; second, its spontaneous resolution, despite monosodium urate (MSU) crystal persistence in the synovium; and third, immune anergy to MSU crystal masses observed in tophaceous or visceral gout. Here, we provide an update on the molecular pathophysiology of these gout manifestations, namely, how MSU crystals can trigger the auto-amplification loop of necroinflammation underlying the crescendo of acute gouty arthritis. We also discuss new findings, such as how aggregating neutrophil extracellular traps (NETs) might drive the resolution of arthritis and how these structures, together with granuloma formation, might support immune anergy, but yet promote tissue damage and remodeling during tophaceous gout. PMID- 28732689 TI - Defining coronary artery calcium concordance and repeatability - Implications for development and change: The Dallas Heart Study. AB - BACKGROUND: Development and change of coronary artery calcium (CAC) are associated with coronary heart disease. Interpretation of serial CAC measurements will require better understanding of changes in CAC beyond the variability in the test itself. METHODS: Dallas Heart Study participants (2888) with duplicate CAC scans obtained minutes apart were analyzed to determine interscan concordance and 95% confidence bounds (ie: repeatability limits) for each discrete CAC value. These data derived cutoffs were then used to define change above measurement variation and determine the frequency of CAC development and change among 1779 subjects with follow up CAC scans performed 6.9 years later. RESULTS: Binary concordance (0 vs. >0) was 91%. The value of CAC denoting true development of CAC by exceeding the 95% confidence bounds for a single score of 0 was 2.7 Agatston units (AU). Among those with scores >0, the 95% confidence bounds for CAC change were determined by the following formulas: for CAC<=100AU: 5.6?CAC + 0.3*CAC - 3.1; for CAC>100AU: 12.4?CAC - 67.7. Using these parameters, CAC development occurred in 15.0% and CAC change occurred in 48.9%. Although 225 individuals (24.9%) had a decrease in CAC over follow up, only 1 (0.1%) crossed the lower confidence bound. Compared with prior reported definition of CAC development (ie: >0), the novel threshold of 2.7AU resulted in better measures of model performance. In contrast, for CAC change, no consistent differences in performance metrics were observed compared with previously reported definitions. CONCLUSION: There is significant interscan variability in CAC measurement, including around scores of 0. Incorporating repeatability estimates may help discern true differences from those due to measurement variability, an approach that may enhance determination of CAC development and change. PMID- 28732691 TI - Letter to Editor: Functional study is not the only criterion to predict the pathogenicity of a novel mutation for cardiomyopathy. PMID- 28732690 TI - Cromolyn chitosan nanoparticles as a novel protective approach for colorectal cancer. AB - Colorectal cancer is the third most common cancer in the world. Cromolyn is a mast cell stabilizer and was proposed as an anticancer agent; however its high polarity limits its bioavailability by rapid washing from the body. We formulated 10 cromolyn chitosan nanoparticles (CCSNPs)1 following ionic gelation technique to improve its bioavailability and investigated the protective anticancer effect of the optimum formula against colorectal cancer in dimethylhydrazine-induced model in rats. Rats were divided into seven groups, group-1: normal control, group-2: cromolyn control, group-3: CCSNPs control, groups-4 to 7 received dimethylhydrazine for 16 weeks to induce colorectal cancer. Groups-5 to 7 received cromolyn solution, non-medicated chitosan nanoparticles and CCSNPs, respectively as protective treatments. Optimum CCSNPs (size 112.4 nm, charge +39.9 mV, enclosed 93.6% cromolyn and showed a sustained drug release pattern over 48 h) significantly reduced tumor-signaling molecules and the number of aberrant crypt foci compared to dimethylhydrazine. Histopathological examination of colon samples revealed that CCSNPs exerted an augmented protective anticancer effect by ameliorating tumor pathology compared to cromolyn solution. In conclusion, CCSNPs ameliorated tumor pathology and malignant oncogenic signaling molecules in colorectal cancer tissue. Thus, CCSNPs may provide a novel protective approach in colorectal cancer treatment. Moreover, encapsulating cromolyn in chitosan nanoparticles augmented the protective anticancer effect of the drug. PMID- 28732692 TI - Analytical and clinical performance of the Hologic Aptima HCV Quant Dx Assay for the quantification of HCV RNA in plasma samples. AB - BACKGROUND: Chronic hepatitis C virus (HCV) infection can be effectively treated with directly acting antiviral (DAA) therapy. Measurement of HCV RNA is used to evaluate patient compliance and virological response during and after treatment. OBJECTIVES: To compare the analytical performance of the Aptima HCV Quant Dx Assay (Aptima) and the COBAS Ampliprep/COBAS TaqMan HCV Test v2.0 (CAPCTMv2) for the quantification of HCV RNA in plasma samples, and compare the clinical utility of the two tests in patients undergoing treatment with DAA therapy. STUDY DESIGN: Analytical performance was evaluated on two sets of plasma samples: 125 genotyped samples and 172 samples referred for quantification of HCV RNA. Furthermore, performance was evaluated using dilutions series of four samples containing HCV genotype 1a, 2b, 3a, and 4a, respectively. Clinical utility was evaluated on 118 plasma samples obtained from 13 patients undergoing treatment with DAAs. RESULTS: Deming regression of results from 187 plasma samples with HCV RNA >2 Log IU/mL indicated that the Aptima assay quantified higher than the CAPCTMv2 test for HCV RNA >4.9 Log IU/mL. The linearity of the Aptima assay was excellent across dilution series of four HCV genotypes (slope of the regression line: 1.00-1.02). The Aptima assay detected significantly more replicates below targeted 2 Log IU/mL than the CAPCTMv2 test, and yielded clearly interpretable results when used to analyze samples from patients treated with DAAs. CONCLUSIONS: The analytical performance of the Aptima assay makes it well suited for monitoring patients with chronic HCV infection undergoing antiviral treatment. PMID- 28732693 TI - Sinonasal tumour presenting as status epilepticus in a child. PMID- 28732694 TI - Development and evaluation of latex agglutination tests for the detection of human antibodies to the lipopolysaccharides of verocytotoxin-producing Escherichia coli (VTEC) serogroups O157 and non-O157. AB - Latex agglutination tests (LAT) were developed and evaluated for the rapid detection of LPS antibodies against E. coli serogroup O157, O26, O104, O111 and O145. The latex tests have been proved to be sensitive, fast, easy-to-perform and cost-efficient tools for the screening serodiagnosis of VTEC infections causing haemolytic-uraemic syndrome. PMID- 28732695 TI - Optimization of genotypic and biochemical methods to profile P. acnes isolates from a patient population. AB - Propionibacterium acnes is a key factor in the pathogenesis of acne vulgaris, although currently it is also being associated with medical-device infections. The aim of this work was to validate a safe and quick identification and typing of 24 clinical isolates of Propionibacterium acnes, applying a range of biochemical as well as genetic methods, and investigating the pathogenic potential to associate the different types with human health. RAPD-PCRs revealed the existence of two discernible clusters in correspondence with the phylogroups I and II, according to the PAtig gene polymorphism, leading them to be assigned as P. acnes subsp. acnes subsp. nov. Biotyping according to the pattern of sugar fermentation evidenced that all the isolates from acne and the majority from opportunistic infections fit the biotype I-B3. Consistent with the multiplex touchdown analysis, nearly all the isolates included in this biotype belonged to the subgroups IA1 (the exception being four strains classified as IB). The remaining ones were assigned to phylogroup II, considered to be part of the normal cutaneous microbiota. The susceptibility to three antibiotics was also investigated to explore the relations with the virulence, although no clear trend was identified. PMID- 28732696 TI - Application of a competitive real time PCR for detection of Marteilia refringens genotype "O" and "M" in two geographical locations: The Ebro Delta, Spain and the Rhine-Meuse Delta, the Netherlands. AB - Species belonging to the genus Marteilia are protozoan parasites of bivalves. The species Marteilia refringens, jeopardizing the health of European bivalves, is included on the list of OIE notifiable pathogens. Two genotypes of Marteilia refringens are distinguished: type "O" affecting mainly oysters, and type "M" affecting mainly mussels. Historically, detection of Marteilia species is primarily carried out by histology. In recent years molecular assays are more frequently used for the detection of mollusc pathogens, also in routine monitoring. In the present work, a competitive real-time PCR assay was developed for rapid and sensitive detection of M. refringens and discrimination between "M" and "O" genotypes of M. refringens. The real-time PCR assay was shown to be analytically sensitive and specific and has a high repeatability and efficiency. Subsequent application of the assay on collected bivalves from two geographical locations, the Ebro Delta in Mediterranean Spain and the Rhine-Meuse Delta in the Netherlands resulted in detection of M. refringens type M in Mytilus galloprovincialis and M. refringens type O in Ostrea edulis from Spain. In two O. edulis specimen both M. refringens type O and type M were detected. In the Netherlands M. refringens was not observed in any of the tested Mytilus edulis and O. edulis. The results obtained by real time PCR were in correspondence with the results obtained by histopathology and a substantial agreement with the results obtained by conventional PCR. In conclusion, the developed real time PCR assay facilitates rapid detection and subtyping of M. refringens and could be applied for further studies on epidemiology of the parasite, geographical distribution and host specificity. PMID- 28732697 TI - Cytological study of DNA content and nuclear morphometric analysis for aid in the diagnosis of high-grade dysplasia within oral leukoplakia. AB - OBJECTIVE: To quantitatively examine the DNA content and nuclear morphometric status of oral leukoplakia (OL) and investigate its association with the degree of dysplasia in a cytologic study. STUDY DESIGN: Oral cytobrush biopsy was carried out to obtain exfoliative epithelial cells from lesions before scalpel biopsy at the same location in a blinded series of 70 patients with OL. Analysis of nuclear morphometry and DNA content status using image cytometry was performed with oral smears stained with the Feulgen-thionin method. RESULTS: Nuclear morphometric analysis revealed significant differences in DNA content amount, DNA index, nuclear area, nuclear radius, nuclear intensity, sphericity, entropy, and fractal dimension (all P < .01) between low-grade and high-grade dysplasia. DNA content analysis identified 34 patients with OL (48.6%) with DNA content abnormality. Nonhomogeneous lesion (P = .018) and high-grade dysplasia (P = .008) were significantly associated with abnormal DNA content. Importantly, the positive correlation between the degree of oral dysplasia and DNA content status was significant (P = .004, correlation coefficient = 0.342). CONCLUSION: Cytology analysis of DNA content and nuclear morphometric status using image cytometry may support their use as a screening and monitoring tool for OL progression. PMID- 28732698 TI - Rhabdomyosarcoma of the head and neck: impact of demographic and clinicopathologic factors on survival. AB - OBJECTIVE: To determine the survival factors for patients diagnosed with rhabdomyosarcoma of the head and neck. STUDY DESIGN: Data on patients diagnosed with rhabdomyosarcoma of the head and neck between 1973 and 2012 were extracted from the Surveillance, Epidemiology, and End Results database. Kaplan-Meier and Cox proportional hazard regression models were used to determine the demographic characteristics, prognostic factors, and treatment modalities that determine overall survival (OS) and disease-specific survival (DSS). RESULTS: Data on 503 patients diagnosed with rhabdomyosarcoma of the head and neck were analyzed; 51.3% were male and 48.7% were female, with a median OS of 4.9 years. Kaplan Meier analysis determined 5-year survival rates of 30% for OS and 50% for DSS. Multivariate analysis found that age at diagnosis, tumor extent of disease, surgical resection, and radiation therapy were independent predictors of OS and DSS. CONCLUSIONS: To our knowledge, this is the largest year-span study to date to determine the factors of survival for rhabdomyosarcoma of the head and neck. Older age at diagnosis, histologic subtype of alveolar rhabdomyosarcoma, and further extent of disease were associated with decreased survival. Surgical resection improves survival in patients with localized or regional disease, and radiation therapy confers survival benefits in patients with distant extent. PMID- 28732699 TI - Triggers of oral lichen planus flares and the potential role of trigger avoidance in disease management. AB - OBJECTIVE: Many patients with oral lichen planus (OLP) report triggers of flares, some of which overlap with triggers of other oral diseases, including oral allergy syndrome and oral contact dermatitis. The purpose of this study was to evaluate the prevalence of commonly reported triggers of OLP flares, their overlap with triggers of other oral diseases, and the potential role of trigger avoidance as a management strategy. STUDY DESIGN: Questionnaire-based survey of 51 patients with biopsy-proven lichen planus with oral involvement seen in an academic dermatology specialty clinic and/or oral pathology clinic between June 2014 and June 2015. RESULTS: Of the participants, 94% identified at least one trigger of their OLP flares. Approximately half of the participants (51%) reported at least one trigger that overlapped with known triggers of oral allergy syndrome, and 63% identified at least one trigger that overlapped with known triggers of oral contact dermatitis. Emotional stress was the most commonly reported trigger (77%). Regarding avoidance, 79% of the study participants reported avoiding their known triggers in daily life. Of those who actively avoided triggers, 89% reported an improvement in symptoms and 70% reported a decrease in the frequency of flares. CONCLUSIONS: Trigger identification and avoidance can play a potentially effective role in the management of OLP. PMID- 28732700 TI - Evaluation of trabecular structure changes in osteoarthritis of the temporomandibular joint with cone beam computed tomography imaging. AB - OBJECTIVES: To explore the possibility of using 2-dimensional image assessments in combination with cone beam computed tomography (CBCT) in patients with temporomandibular joint osteoarthritis (TMJOA) to enhance the clinical significance and applicability of the CBCT findings on TMJOA changes. STUDY DESIGN: Fifty-two patients with unilateral TMJOA and 40 healthy adults who had undergone CBCT in preparation for orthodontic treatment were selected for this study. Temporomandibular joint images were acquired with CBCT. All images were classified into 4 phases (slight erosion, widespread erosion, appearance of bone maintenance, and partial loss of condylar head with a remodeled cortical surface) and 4 levels of severity (absent, slight, moderate, and extensive). Quantitative microstructural analysis, including bone value fraction (BV/TV), trabecular number (Tb.N), trabecular thickness, and trabecular separation (Tb.Sp) of each image, was performed by using a customized software. RESULTS: In patients with unilateral TMJOA, the affected side had significantly higher BV/TV and Tb.N and significantly lower Tb.Sp compared with the unaffected side. Compared with healthy individuals, the affected joints in patients with TMJOA had significantly higher BV/TV and trabecular thickness and significantly lower Tb.N and Tb.Sp. No significant difference was found among different phase groups or different severity levels. CONCLUSIONS: CBCT combined with a software investigation protocol for microstructure measurement can be used to provide reliable trabecular parameters in assessing TMJOA. PMID- 28732701 TI - Persistent Hypokalemia With Renal Losses in a 31-Year-Old Pregnant Woman. PMID- 28732702 TI - Coffee Bean Sign With a Twist. PMID- 28732703 TI - Case of a Young Man With Abdominal Pain and Jaundice. PMID- 28732704 TI - Acute Abdominal Pain and Hematochezia in a Long-Distance Runner. PMID- 28732705 TI - An Unusual Colon Cystic Tumor. PMID- 28732706 TI - Stack of Coins Sign in a Patient With Recurrent Abdominal Pain. PMID- 28732707 TI - A Case of Mistaken Identity. PMID- 28732708 TI - Peeling the left ventricle as treatment for endocardial fibroelastosis: An exceptional surgical procedure in adults. PMID- 28732709 TI - Effects of antithrombotic therapy on bleeding after endoscopic submucosal dissection. AB - BACKGROUND AND AIMS: Bleeding is the most common adverse event after endoscopic submucosal dissection (ESD). Although several studies have reported on the use of antithrombotic agents and post-ESD bleeding, many issues remain controversial. We conducted a meta-analysis and systematic review to evaluate the effects of antithrombotic therapy on post-ESD bleeding. METHODS: The published literature was searched on online databases, and all studies were included up to January 2017. Standard forms were used to extract data by 2 independent reviewers. The Newcastle-Ottawa Scale score was used to assess the quality of studies. The pooled odds ratio (OR) was computed for the effect of antithrombotic agents. Publication bias was assessed by funnel plots. Heterogeneity was assessed by the Cochran Q test and I2 statistic. RESULTS: Sixteen retrospective articles were included. Regardless of discontinuation (OR, 1.66; 95% confidence interval [CI], 1.15-2.39; P = .007) or continuation (OR, 8.39; 95% CI, 4.64-15.17; P < .00001), antithrombotic therapy was significantly associated with post-ESD bleeding, particularly for delayed bleeding (OR, 2.66; 95% CI, 1.42-4.98; P = .002). The bleeding rate was higher in the discontinued multiple antithrombotics group (OR, 5.17; 95% CI, 3.13-8.54; P < .00001) than in the discontinued a single antithrombotic group (OR, 2.23; 95% CI, 1.29-3.85; P = .004) and single antiplatelet group (OR, 2.08; 95% CI, 0.93-4.63; P = .07). In the subgroup analysis, resuming antithrombotics within 1 week (OR, 2.46; 95% CI, 1.54-3.93; P = .0002) and using heparin replacement (OR, 4.20; 95% CI, 1.94-9.09; P= .0003) significantly increased post-ESD bleeding risk. Continued use of low-dose aspirin (OR, 1.22; 95% CI, 0.17-8.61; P = .84) did not significantly increase the bleeding risk. CONCLUSIONS: Antithrombotic therapy is a risk factor for post-ESD bleeding, especially for delayed bleeding. Using multiple antithrombotic drugs, resuming antithrombotics within 1 week, and heparin replacement were significantly associated with post-ESD bleeding; but continuous low-dose aspirin was not. However, much larger prospective studies are required. PMID- 28732710 TI - Cytokine profiling in the prefrontal cortex of Parkinson's Disease and Multiple System Atrophy patients. AB - Parkinson's Disease (PD) and Multiple System Atrophy (MSA) are neurodegenerative diseases characterized neuropathologically by alpha-synuclein accumulation in brain cells. This accumulation is hypothesized to contribute to constitutive neuroinflammation, and to participate in the neurodegeneration. Cytokines, which are the main inflammatory signalling molecules, have been identified in blood and cerebrospinal fluid of PD patients, but studies investigating the human brain levels are scarce. It is documented that neurotrophins, necessary for survival of brain cells and known to interact with cytokines, are altered in the basal ganglia of PD patients. In regards to MSA, no major study has investigated brain cytokine or neurotrophin protein expression. Here, we measured protein levels of 18 cytokines (IL-2, 4-8, 10, 12, 13, 17, G-CSF, GM-CSF, IFN-gamma, MCP-1, MIP 1alpha and 1beta, TNF-alpha) and 5 neurotrophins (BDNF, GDNF, bFGF, PDGF-BB, VEGF) in the dorsomedial prefrontal cortex in brains of MSA and PD patients and control subjects. We found altered expression of IL-2, IL-13, and G-CSF, but no differences in neurotrophin levels. Further, in MSA patients we identified increased mRNA levels of GSK3beta that is involved in neuroinflammatory pathways. Lastly, we identified increased expression of the neurodegenerative marker S100B, but not CRP, in PD and MSA patients, indicating local rather than systemic inflammation. Supporting this, in both diseases we observed increased MHC class II+ and CD45+ positive cells, and low numbers of infiltrating CD3+ cells. In conclusion, we identified neuroinflammatory responses in PD and MSA which seems more widespread in the brain than neurotrophic changes. PMID- 28732711 TI - Study of Rheology and Polymer Adsorption Onto Drug Nanoparticles in Pharmaceutical Suspensions Produced by Nanomilling. AB - Nanosuspensions provide a drug delivery approach to cope with erratic absorption of poorly water-soluble compounds. Despite extensive research over the last years, there are still open pharmaceutical challenges so it is often unclear how quality attributes such as viscosity and physical stability are generated, which requires a more thorough study of the colloidal structures and interactions in nanosuspensions. In this study, diffusing wave spectroscopy and microfluidics based rheology were used for the first time to assess pharmaceutical nanosuspensions that were obtained by wet milling. Further sample characterization following centrifugation was based on optical rotatory dispersion and conductivity experiments. Ketoconazole was selected as model drug in the presence of sodium dodecyl sulfate and hydroxypropyl cellulose as anionic and steric stabilizer, respectively. The results unexpectedly showed that the investigated nanosuspensions did not behave as Einstein-like suspensions because a viscosity decrease was evidenced for increased drug load. This effect was attributed to the polymer that formed a dominating network in the bulk solution from where adsorption occurred onto particle surfaces. This depletion of bulk polymer caused the observed rheological finding. Further colloidal research should be invested into different pharmaceutical nanosuspensions to gain a more complete structural understanding and to harness their full technological potential. PMID- 28732712 TI - Structure-Performance Relationships of Temperature-Responsive PLGA-PEG-PLGA Gels for Sustained Release of Bone Morphogenetic Protein-2. AB - PLGA (poly(lactic-co-glycolic) acid)-PEG (polyethylene glycol)-PLGA synthesis conditions have an impact on the physicochemical features of the copolymer and its usefulness as biomaterial. This study reports on an analysis of the composition and structural properties of PLGA-PEG-PLGA copolymers applying a variety of analytical techniques. Viscoelastic properties and particularly the temperature-responsive behavior of PLGA-PEG-PLGA showed a marked dependence on copolymer structural features. Physicochemical and biological properties, such as bioadhesion, biocompatibility and cell viability, of the raw copolymers and their gels were also evaluated. The most promising copolymer was chosen to formulate the osteoinductive protein bone morphogenetic protein-2 (125I-BMP-2), and the ability of its gels to sustain the release both in vitro and in vivo was monitored in situ using a gamma counter. In vitro diffusion studies were carried out using a bioinspired set-up that included a biorelevant receptor medium. In vivo release tests after implantation in a critical-size calvarial defect model showed an important burst, but then the release fitted well to the square-root kinetics. Importantly, the release rate constants recorded in vitro and in vivo matched each other suggesting close in vitro-in vivo correlation. Overall, the information gathered opens new perspectives in the biomedical application of these temperature-sensitive materials. PMID- 28732713 TI - Portal hypertension secondary to multiple hepatic hemangiomatosis. PMID- 28732714 TI - A Longitudinal Analysis of Stepfamily Relationship Quality and Adolescent Physical Health. AB - PURPOSE: Approximately one third of youth are estimated to live with a biological parent and stepparent before reaching adulthood. Additional research is warranted whereby stepfamily processes are identified that drive variation in youth adjustment, particularly physical health. We examined stepfather-child, mother child, and stepcouple relationship quality as predictors of levels and changes in adolescent physical health over time. METHODS: We used a nationally representative sample of 1,233 adolescents living in biological mother-stepfather families from waves I (1994-1995) and II (1996) of the National Longitudinal Study of Adolescent to Adult Health. We incorporated measures of stepfather child, mother-child, and stepcouple relationship quality, as well as adolescent reports of 10 physical health symptoms at waves I and II. Structural equation modeling was used to examine associations between wave I stepfamily relationships and adolescent physical symptoms at waves I and II. We used a zero-inflated negative binomial model to establish the validity of wave II adolescent physical symptoms as a predictor of an index of diagnosed chronic illnesses by wave IV (ages 26-32 years). RESULTS: Stepfather-child and mother-child relationship quality were negatively correlated with concurrent levels of adolescent physical symptoms. Stepfather-child relationship quality was negatively associated with change in adolescent physical symptoms over time. Adolescents with higher levels of physical symptoms at wave II were more likely to report chronic illnesses by adulthood. CONCLUSIONS: Stepfather-child relationship quality is a robust predictor of adolescent physical health throughout adolescence and is linked to chronic illness diagnoses in young adulthood. Future research should explore further the mechanisms that underlie this association. PMID- 28732716 TI - Clinical and Psychosocial Factors Associated With Suicidal Ideation in Adolescents With Type 1 Diabetes. AB - PURPOSE: This study delineates clinical and psychosocial characteristics of adolescents with type 1 diabetes and suicidal ideation (SI) and reports clinical and psychosocial outcomes after mental health intervention (safety assessment and brief in-clinic intervention). METHODS: Adolescents aged 13-17 years with type 1 diabetes completed the Children's Depression Inventory (CDI) from January 2011 to 2012. Youth with significant depressive symptoms and/or SI endorsement underwent mental health intervention. Two control subjects were matched to each adolescent endorsing SI and compared using t-tests to assess clinical and psychosocial variables. Trajectory of depressive symptoms and outcomes for case subjects were observed through January 2013. RESULTS: Twenty-seven percent (127/473) exhibited moderate to high risk for depression based on CDI scores and 38 (8%) endorsed SI. Adolescents who endorsed SI were more likely to have higher CDI scores and public insurance when compared with youth who denied SI. There was no difference in glycemic control, measured by hemoglobin A1c, between case and control groups. During the year after intervention, 28 participants who initially endorsed SI underwent repeat assessment; mean CDI scores declined by 10.57 (standard deviation: 6.92) points and 78% no longer endorsed SI. CONCLUSIONS: Given the potential lethality of insulin when taken in intentional overdose, the need for consistent identification of suicidality is an important feature of depression screening. Study findings indicate statistically significant differences in depressive symptoms and insurance status, when comparing adolescents who endorsed SI to those who denied. Improvement in depressive symptoms and SI endorsement occurred after integrating brief mental health intervention into diabetes visits. PMID- 28732715 TI - The Modifying Effects of Race/Ethnicity and Socioeconomic Status on the Change in Physical Activity From Elementary to Middle School. AB - PURPOSE: Youth physical activity (PA) levels differ by race/ethnicity and socioeconomic status (SES). It is well established that various multilevel factors may influence changes in PA. The present study examined whether the association between the change in individual, interpersonal, and environmental factors and the change in PA is modified by race/ethnicity or SES. METHODS: This study followed 643 youths and their parents from suburban and rural South Carolina participating in the Transitions and Activity Changes in Kids (TRACK) Study in 2008-2009 and 2010-2011. We assessed total PA in youth using accelerometry and categorized youth and parent survey data into blocks based on the socioecological model. Multivariate regression growth curve models evaluated whether the association between change in independent variables and change in PA was modified by race/ethnicity or SES. RESULTS: PA declined from fifth to seventh grade among all racial/ethnic and SES groups. Associations between the range of variables and change in PA were modified by race/ethnicity but not SES. Blacks did not share any common predictors of change in PA with whites or Hispanics. However, child-reported number of active friends was associated with total PA, and enjoyment of PA was associated with change in PA among both whites and Hispanics. Significant interactions by time varied by racial/ethnic group. CONCLUSIONS: The factors that influence changes in youth PA vary by race/ethnicity but not SES. These findings reinforce the complex nature of addressing PA behavior in diverse samples and further support the need for culturally appropriate interventions to promote PA in youth. PMID- 28732717 TI - Counseling About Skin Cancer Prevention Among Adolescents: What Do Parents Receive From Health Care Providers? AB - PURPOSE: Adolescence is a high-risk period for ultraviolet radiation exposure, a primary cause of skin cancer later in life. We sought to characterize receipt of health care provider-delivered counseling about skin cancer prevention (SCP) among parents of adolescents. METHODS: In 2016, we conducted an online survey with a national sample of parents of adolescents aged 11-17 years (n = 1,253). Multivariable logistic regression assessed correlates of receiving counseling from a health care provider about any of the six skin cancer prevention (SCP) topics. RESULTS: Only half (49%) of parents recalled discussing any SCP topic with their child's provider; the prevalence was highest for sunscreen (39%) and lowest for indoor tanning (3%). Parents had greater odds of receiving counseling if they had a child with more sun-reactive skin (odds ratio [OR] = 1.53); a family history of skin cancer (OR = 1.38); or a higher quality relationship with the provider (OR = 1.47; all p < .05). CONCLUSIONS: Greater attention to SCP counseling is needed, especially for exposures such as indoor tanning that remain prevalent among adolescents but are rarely addressed in clinical encounters. PMID- 28732718 TI - Longitudinal Latent Cognitive Profiles and Psychosocial Well-being in Early Adolescence. AB - PURPOSE: Engaging in exploratory risky behaviors and experiencing poor mental health during early adolescence are important markers for poor health during adulthood. Prior research suggests protective effects from cognition, but less is known about the associations between early childhood cognition and early adolescent psychosocial well-being, as identified by self-esteem, mental health, and exploratory risky behaviors. This article investigates the extent that early adolescent psychosocial well-being at the age of 11 years is associated with patterns of cognitive skills measured across the first decade of a child's life. METHODS: We used data collected from the four follow-up sweeps of the UK Millennium Cohort Study and utilized latent profile analysis to identify three discernible cognitive profiles (n = 16,899). RESULTS: We find cohort members in low-achieving profiles to be more likely to engage in exploratory risky behaviors drinking, smoking, and antisocial conduct-and to have poor self-esteem and more problem behaviors, compared with their peers in high-achieving profiles. Socioeconomic and family psychosocial markers considerably attenuated these disadvantages. CONCLUSIONS: Understanding which adolescents have adverse psychosocial well-being has implications for the prevention of chronic diseases and for clinical care and policy. PMID- 28732719 TI - Early Sexual Onset and Alcohol Use and Misuse From Adolescence Into Young Adulthood. AB - PURPOSE: Little is known about the longitudinal association between early first heterosexual intercourse (e.g., intercourse before the age of 15 years) and alcohol use during adolescence and young adulthood. This study sought to determine whether early first heterosexual intercourse is associated with (1) frequency of alcohol use at age 16 years, (2) changes in alcohol use from ages 16 to 22 years, and (3) alcohol misuse at age 22 years, while controlling for alcohol use, antisocial behavior, pubertal timing, and parental monitoring in early adolescence. METHODS: A sample of 289 participants (63% female) was surveyed annually from ages 12 to 22 years. RESULTS: Latent growth curve modeling indicated that youth who experienced an early first heterosexual intercourse report a higher frequency of alcohol use at age 16 years compared with those who have experienced their first heterosexual intercourse at an "on-time" age. However, timing of first heterosexual intercourse was not related to growth in frequency of alcohol use over time. Hierarchical multiple regression analysis showed that experiencing an early first heterosexual intercourse predicted problematic alcohol use at age 22 years (beta = .153, p = .027). These results were found while controlling for confounding individual- and family factor-level variables. CONCLUSIONS: The effect of early first heterosexual intercourse on adolescent alcohol use appears to be long lasting and is associated with a more problematic use of this substance in young adulthood. Further research should be conducted to uncover the developmental processes involved. PMID- 28732720 TI - Impact on mid-term kidney graft outcomes of pretransplant anti-HLA antibodies detected by solid-phase assays: Do donor-specific antibodies tell the whole story? AB - The detrimental impact of preformed anti-HLA donor-specific antibodies (DSA) is well defined, contrarily to non-donor-specific antibodies (NDSA). We sought to evaluate their clinical impact in a cohort of 724 kidney graft recipients in whom anti-HLA antibodies were thoroughly screened and identified in pre-transplant sera by solid-phase assays. NDSA or DSA were detected in 100 (13.8%) and 47 (6.5%) recipients respectively, while 577 (79.7%) were non-allosensitized (NaS). Incidence of antibody-mediated rejection at 1-year was 0.7%, 4.0% and 25.5% in NaS, NDSA and DSA patients, respectively (NaS vs. NDSA P=0.004; NaS vs. DSA P<0.001; NDSA vs. DSA P<0.001). Graft survival was lowest in DSA (78.7%), followed by NDSA (88.0%) and NaS (93.8%) recipients (NaS vs. NDSA P=0.015; NaS vs. DSA P<0.001; NDSA vs. DSA P=0.378). Multivariable competing risk analysis confirmed both NDSA (sHR=2.19; P=0.025) and DSA (sHR=2.87; P=0.012) as significant predictors of graft failure. The negative effect of NDSA and DSA on graft survival was significant in patients receiving no induction (P=0.019) or an anti-IL-2 receptor antibody (P<0.001), but not in those receiving anti-thymocyte globulin (P=0.852). The recognition of the immunological risk associated with preformed DSA but also NDSA have important implications in patients' risk stratification, and may impact clinical decisions at transplant. PMID- 28732722 TI - [Prevalence in the performance of mammographies in Spain: Analysis by Communities 2006-2014 and influencing factors]. AB - OBJECTIVE: To determine the frequency of the performance of mammography with preventive purpose of the screening of breast cancer in Spanish women, the evolution between the years 2006-2014, the sociodemographic profile of the women who undergo the mammography and to analyze the factors that influence in their adhesion. DESIGN: Transversal study. SITES: Spain. PARTICIPANTS: A total of 53.628 women over 15 years old that are surveyed in the National Health Survey in Spain 2006 and 2011/12 and the European Health Survey in Spain 2009 and 2014. MEASUREMENTS: The following variables were used: mammography, frequency of mammography performance and the reason for the realization, as well as sociodemographic variables. Social class was obtained from the last occupation of the main family supporter. A logistic regression analysis was performed with sociodemographic variables. RESULTS: The prevalence of mammography has been increasing from 2006 to 2014, and also for the reason that the participants had received a letter, they were telephoned or offered in their Health Center to undergo this test. There are significant differences in the performance of mammography in the different autonomous communities. CONCLUSIONS: Performing mammography has increased significantly from 2006 to 2014, although there are still differences between autonomous communities, with Ceuta and Melilla being the least percentage of performed mammography. The factors that are related to greater performed mammography are: higher educational level, higher social class, married civil status, Spanish nationality and age. PMID- 28732721 TI - Assessing a single targeted next generation sequencing for human leukocyte antigen typing protocol for interoperability, as performed by users with variable experience. AB - BACKGROUND: A simplified protocol for HLA-typing -by NGS, developed for use with the Illumina MiSeq, was performed by technologists with varying NGS experience to assess accuracy and reproducibility. METHODS: Technologists from six laboratories typed the same 16 samples at HLA-A, B, C, DRB1, and DQB1. The protocol includes long range PCR, library preparation, and paired-end 250bp sequencing. Two indexing strategies were employed: locus-specific indexing whereby each locus was tagged uniquely and sample-specific indexing whereby all 5 loci for a sample were pooled prior to library preparation. Sequence analysis was performed with two software packages, Target HLA (Omixon) and NGSengine (GenDx). RESULTS: The average number of sequence reads per library was 387,813; however, analysis was limited to 40,000 reads for locus-indexed libraries and 200,000 reads for sample indexed libraries resulting in an average depth of coverage of 1444 reads per locus. Sufficient reads for genotype analysis were obtained for 98.4% of libraries. Genotype accuracy was >97% in pooled amplicons and >99% in individual amplicons by both software analysis. Inter-laboratory reproducibility was 99.7% and only cause of discordance was cross-contamination of a single amplicon. CONCLUSIONS: This NGS HLA-typing protocol is simple, reproducible, scalable, highly accurate and amenable to clinical testing. PMID- 28732723 TI - Lipolytic bacteria use as bio-decontaminating natural in the water purification stations. AB - Different samples were collected from polluted waters by fat materials in the Mascara region for the isolation of bacterial strains capable of degrading fat materials and used in the production of lipase by the fermentation method. A total of two strains (Pseudemonas sp. et Streptococcus sp.) were isolated at 37 degrees C from the sample water rich slaughterhouses fat materials. Production of extracellular bacterial lipase was studied as a function of several inductors of lipid nature by the fermentation method. The enzyme activity reached a maximum value, in the presence of olive oil as inducer. The enzyme was purified by precipitation with ammonium sulfate in a yield of 63.73% and 50% in Streptocoques sp. and Pseudemonas sp. respectively. The lipase produced by these two bacteria is resistant to 50 degrees C and is strongly inhibited in the presence of 1mmol Zn+2 and Mg +2. PMID- 28732724 TI - Recombinant Bacillus amyloliquefaciens xylanase A expressed in Pichia pastoris and generation of xylooligosaccharides from xylans and wheat bran. AB - In this study, BaxA (GenBank: KM624029), which encodes the Bacillus amyloliquefaciens xylanase A (BaxA), was highly expressed in Pichia pastoris GS115 under the control of the AOX1 promoter. The recombinant xylanase, namely rePBaxA, was purified to homogeneity by using Ni-affinity resin and its molecular weight was 35.0kDa. The optimum temperature and pH of rePBaxA were 50 degrees C and 5.0, respectively. The kinetic parameters Michaelis-Menten constant (Km) and maximum reaction rate (Vmax) of rePBaxA were 5.41mg/mL and 22.42MUmol/min/mL, respectively. High-performance liquid chromatography results showed that after 6h of hydrolysis, rePBaxA released xylose-xylohexaose (X1-X6) mixture from beechwood and birchwood xylan, with xylobiose (X2) and xylotriose (X3) as the major products, respectively. The hydrolyates from oat spelt, wheat bran insoluble xylan and pretreated wheat bran by rePBaxA included X2-X6, with X6 having the highest concentration. The mode of action analysis revealed that rePBaxA was an endo-acting xylanase with transglycosylation activity. X2 might be the minimum oligomer hydrolyzed by rePBaxA. The pretreated wheat bran and wheat bran insoluble xylan could be directly hydrolyzed by rePBaxA. This study provided a basis for using agricultural waste by-products as substrates for manufacting value-added probiotics, namely, xylooligosaccharides. PMID- 28732725 TI - Isolation of polysaccharides from Malva aegyptiaca and evaluation of their antioxidant and antibacterial properties. AB - This study investigated the antioxidant and antibacterial properties of crude water-soluble polysaccharides extracted from the mallow (Malva aegyptiaca) by precipitation with cetylpyridinium chloride (P1) or ethanol (P2). The Polysaccharides fractions were characterized by FTIR spectroscopy, a monosaccharide composition, and antioxidant and antibacterial activities. P1 showed the highest total sugars (81.2%) and sulfated groups (2.9%) contents but with the lowest total proteins content (8.7%). The infrared spectroscopic spectra exhibited the typical bands and peak characteristic of polysaccharides. Monosaccharides analysis revealed the dominance of galactose (40.3-43.7%) and glucuronic acid (25.9-30.9%). Interestingly, P1 displayed an important antioxidant activity as evaluated by the (Fe2+) chelating activity (IC50=1.15mg/ml), (Fe3+) reducing power (EC50=1.22mg/ml), beta-carotene bleaching inhibition capacity (IC50=1.56mg/ml) and DPPH-radical scavenging activity (IC50=1.94mg/ml). Furthermore, P1 at 10mg/ml was highly active than P2 against several bacterial strains and especially the Gram-positive bacteria, where the inhibition rate ranged between 84.2 and 90.3%. Obtained results suggest that M. aegyptiaca polysaccharides precipitated by cetylpyridinium chloride could be used as a naural antioxidant and antibacterial agent. PMID- 28732726 TI - The immunoregulatory activities of astragalus polysaccharide liposome on macrophages and dendritic cells. AB - The objective of this study is to investigate the immunomodulatory activities of astragalus polysaccharide liposome (APSL) on murine peritoneal macrophages and bone marrow derived dendritic cells (DCs). The results showed that APSL not only significantly improved the phagocytosis of macrophages, the contents of IL-6 and IL-12, and the secretion of nitric oxide (NO) and inducible nitric oxide synthase (iNOS) in macrophages, but also promoted the proliferation of DCs precursor cells, enhanced the abilities of DCs on stimulating T-cell proliferation and presenting antigen, upregulated IFN-gamma and IL-2 production of DCs, and improved the expression of CD80 and CD86 in DCs compared with astragalus polysaccharide (APS). These findings indicated that the immune-modulating activities of APS were remarkably enhanced after encapsulated with liposome, and liposome possessed the potential to act as effective drug delivery system. Moreover, it also provided the theoretical basis for further researching the mechanism of APSL on improving the immune response. PMID- 28732727 TI - Multi-analyte validation in heterogeneous solution by ELISA. AB - Enzyme Linked Immunosorbent Assay (ELISA) is a standard assay that has been used widely to validate the presence of analyte in the solution. With the advancement of ELISA, different strategies have shown and became a suitable immunoassay for a wide range of analytes. Herein, we attempted to provide additional evidence with ELISA, to show its suitability for multi-analyte detection. To demonstrate, three clinically relevant targets have been chosen, which include 16kDa protein from Mycobacterium tuberculosis, human blood clotting Factor IXa and a tumour marker Squamous Cell Carcinoma antigen. Indeed, we adapted the routine steps from the conventional ELISA to validate the occurrence of analytes both in homogeneous and heterogeneous solutions. With the homogeneous and heterogeneous solutions, we could attain the sensitivity of 2, 8 and 1nM for the targets 16kDa protein, FIXa and SSC antigen, respectively. Further, the specific multi-analyte validations were evidenced with the similar sensitivities in the presence of human serum. ELISA assay in this study has proven its applicability for the genuine multiple target validation in the heterogeneous solution, can be followed for other target validations. PMID- 28732728 TI - Characterization and utilization of hydroxypropylated rice starches for improving textural and storage properties of rice puddings. AB - This work investigated the effect of hydroxypropylation on the physicochemical characteristics of Basmati and Irri rice starches with milk and water. The effect of hydroxypropylated starches on the storage, texture stability and sensory characteristics of rice pudding was studied. Pudding was prepared by replacing 3%, 5% and 10% of Irri rice flour with native and hydroxypropylated starches isolated from two predominant rice varieties of Pakistan; Irri and Basmati. Syneresis was not observed in pudding made with hydroxypropylated starches and native basmati starch. On the contrary, pudding prepared with Irri rice flour and Irri starches showed poor keeping quality. Sensory analysis showed that modification of rice starches did not significantly alter the color, flavor, taste and overall acceptability of pudding. The results suggested that rice pudding, a very popular dessert of South Asia could be prepared with improved storage characteristics using hydroxypropylated starches without altering the taste and acceptability of the product. PMID- 28732729 TI - Crystal structures of an atypical aldehyde dehydrogenase having bidirectional oxidizing and reducing activities. AB - Aldehyde dehydrogenases (ALDHs) are NAD(P)+-dependent oxidoreductases that catalyze the oxidation of a variety of aldehydes to their acid forms. In this study, we determined the crystal structures of ALDH from Bacillus cereus (BcALDH), alone, and in complex with NAD+ and NADP+. This enzyme can oxidize all trans-retinal to all-trans-retinoic acid using either NAD+ or NADP+ with equal efficiency, and atypically, as a minor activity, can reduce all-trans-retinal to all-trans-retinol using NADPH. BcALDH accommodated the additional 2'-phosphate of NADP+ by expanding the cofactor-binding pocket and upshifting the AMP moiety in NADP+. The nicotinamide moiety in NAD+ and NADP+ had direct interactions with the conserved catalytic residues (Cys300 and Glu266) and caused concerted conformational changes. We superimposed the structure of retinoic acid bound to human ALDH1A3 onto the BcALDH structure and speculated a model of the substrate all-trans-retinal bound to BcALDH. We also proposed a plausible mechanism for the minor reducing activity of BcALDH. These BcALDH structures will be useful in understanding cofactor specificity and the catalytic mechanism of an atypical bacterial BcALDH and should help the development of a new biocatalyst to produce retinoic acid and related high-end products. PMID- 28732730 TI - Thermo-responsive hydroxybutyl chitosan hydrogel as artery intervention embolic agent for hemorrhage control. AB - This work targeted to investigate the potential of thermo-responsive hydroxybutyl chitosan (HBC) hydrogel using as an embolic material for occlusion of selective blood vessels. HBC hydrogel was prepared via an etherification reaction between chitosan (CS) and 1, 2-butene oxide. The hydroxybutyl groups were introduced into CS backbone, which endowed HBC hydrogel with properties of porous structure, favorable hydrophilia and rapid sol-gel interconvertibility. The gelation temperatures and gelation time respectively decreased from 30.7 degrees C to 11.5 degrees C and 79.60+/-3.19s to 7.70+/-1.42s at 37 degrees C, with HBC solutions viscoelasticity increased from 3.0% to 7.0%. HBC hydrogel exhibited noncytotoxic to mouse embryo fibroblasts (MEFs) and excellent hemocompatibility with red blood cells (RBCs). After injection HBC solution into rat renal arteries, HBC solution transformed into hydrogel and attached onto blood vessel inner wall tightly, giving immediate blood vessels embolization. Meanwhile, RBCs could aggregate around HBC hydrogel to form moderate coagulation, which was beneficial to avoid hydrogel migration with blood flow. Above results suggested that HBC hydrogel could be applied as a promising embolic agent for hemorrage in the interventional vascular embolization field. PMID- 28732731 TI - Atomization of denatured whey proteins as a novel and simple way to improve oral drug delivery system properties. AB - In the sphere of drug delivery, denatured whey protein (DWP) has in recent times gained press. However, to date, no scalable and affordable dosage form has been developed. The objective of our study was to evaluate the potential use of spray dried DWP as a ready to use excipient for oral drug delivery. Therefore, solid state, FTIR spectra and wettability were studied. Dissolution, mucoadhesion and the effect on paracellular permeability were also evaluated. The spray-dried DWP particles were spherical with 4MUm mean diameter. Further, relative to native WP, the spray-dried DWP particles bore reduced wettability, and their structure was characterized by the exposure of a high amount of free thiol and by the formation of intermolecular beta-sheets. The DWP powders were mucoadhesive, enzymatic inhibitors, biocompatible and they induced the opening of tight junctions. Our study shows great potential for the use of spray-drying as a technique to modify the dissolution rate of drugs and enhance the oral bioavailability of molecules. That is, the use of spray drying as a single step ready to use DWP excipient. PMID- 28732732 TI - Porous chitosan beads of superior mechanical properties for the covalent immobilization of enzymes. AB - Porous chitosan beads of superior mechanical properties were produced via a two stepped treatment process. First, the chitosan ionotropic gelation solution was supplemented with Na2CO3, which acted as a porogen. Afterwards, the beads were chemically cross-linked with glutaraldehyde. This treatment also caused the produced porous chitosan beads to acquire higher observed activities of immobilized beta-d-galactosidase (beta-gal). The observed activities of the beta gal immobilized onto the 0.2M and the 0.35M Na2CO3 treated beads were 1.63 and 1.91 fold respectively, higher than the activity offered by the control beads. Nevertheless, both the control beads and the 0.2M Na2CO3 beads caused the optimum pH range of beta-gal to shift from 4.6-5.1 to ~2.7-5. The enzyme's optimum temperature shifted from 55 to 60 degrees C after its immobilization onto the control chitosan beads whereas the beta-gal immobilized onto the 0.2M Na2CO3 chitosan beads exhibited a temperature optimum of 55-60 degrees C. The reusability study revealed the superiority of the 0.2M Na2CO3 treated beads which retained 59.1% of their initial activity during the 13th enzymatic cycle. On the other hand, the control chitosan beads were fragmented and lost their activity after only four enzymatic cycles. PMID- 28732733 TI - Antibacterial activities and preservative effect of chitosan oligosaccharide Maillard reaction products on Penaeus vannamei. AB - The purpose of this study was to understand the influence of Maillard reaction (MR) on bioactivity of chitosan oligosaccharide (COS). The antibacterial activity against Pseudomonas aeruginosa and Vibrio parahaemolyticus and preservative effect of two kinds of COS MR products (MRPs) on Penaeus vannamei were evaluated. The structures of CG (MRPs of COS and glucose) and CM (MRPs of COS and maltose) were characterized by FT-IR and their molecular weights were measured by gel permeation chromatography (GPC). The results showed that CG has enhanced antibacterial activity and preservative effect compared to COS by evaluating total volatile base-nitrogen (TVB-N), trimethylamine (TMA), pH, total bacterial count (TBC) and sensory evaluation. Meanwhile, CM showed decreased antibacterial activity and preservative effect compared to COS by evaluating TMA, pH and TBC. The results indicated that antibacterial activity and preservative effect of COS increased or decreased after MR. In other words, the type of reducing sugar involved in MR had a great impact on the functional properties of COS-saccharide MRPs and their application to be used as a food preservative. PMID- 28732734 TI - UV protection and antibacterial properties of seaweed capped ZnO nanoparticles coated cotton fabrics. AB - Seaweed capped zinc oxide nanoparticles (SW-ZnO NPs) were prepared by simple chemical precipitation method of zinc nitrate in the presence of seaweed. The synthesized SW-ZnO NPs were characterised by FT-IR, UV-vis spectroscopy, XRD and BET analysis. These metal oxides were coated on cotton fabric using pad dry cure technique. The SW-ZnO NPs coated cotton fabrics, the surface morphology and chemical composition was analysed by HR-SEM with EDAX. The antibacterial activity of uncoated cotton, seaweed extract and SW-ZnO NPs coated cotton fabrics were investigated against Gram positive (S. aureus and S. pyogenes) and Gram negative (E. coli and K. aerogens). It showed that SW-ZnO NPs coated cotton fabric has higher antibacterial activity than other test samples against both bacteria's. Finally, a UV-protection property of the coated cotton fabric was also tested. PMID- 28732736 TI - Corrigendum to "Reproductive steroid receptors and actions in the locus coeruleus of male macaques: Part of an aggression circuit?" [Prog. Neuro-Psychopharmacol. Biol. Psychiatry 71 (2016) 210-222]. PMID- 28732735 TI - Acidic polysaccharide complexes from purslane, silver linden and lavender stimulate Peyer's patch immune cells through innate and adaptive mechanisms. AB - Three polysaccharide complexes (PSCs) were isolated from the aerial parts of common purslane (Portulaca oleracea L.), and the flowers of common lavender (Lavandula angustifolia Mill.) and silver linden (Tilia tomentosa Moench) by boiling water extraction and ethanol precipitation. The chemical composition and immunomodulating effects of isolated PSCs were characterized. The chemical characterization revealed that the three samples contain mainly pectic polysaccharides. They exhibited ex vivo intestinal immunomodulating activity through the murine Peyer's patch-mediated bone marrow cell proliferation test at 100MUg/ml concentration. At the same time, they stimulated ex vivo human blood T cell populations (CD4+/CD25+ and CD8+/CD25+), phagocytic leukocytes (CD14+ and CD64+ cells) and induced IL-6 production from human white blood cells and Peyer's patch cells. The herbal PSCs stimulated ex vivo ROS production from whole blood phagocytes and showed unspecific in vitro anti-proliferative activity against normal and A549, HeLa and LS180 tumor cells. This is the first report on immunomodulating studies of linden flower pectins and chemical and biological activity characterization of lavender polysaccharides. Our study demonstrates that similarly to purslane, lavender and silver linden herbal materials contain immunomodulating polysaccharides that could be useful for support of compromised immune system. PMID- 28732737 TI - MicroRNA-181a and its target Smad 7 as potential biomarkers for tracking child acute lymphoblastic leukemia. AB - Acute lymphoblastic leukemia (ALL) is the most common pediatric hematologic tumor. MiR-181a was expected to have a role in the development of hematological malignancies; it might act as tumor suppressor or oncogene. Smad7 was selected as miR-181a target pair. It is a negative regulator for the TGF-beta1 signaling pathway. In this study, relative expression levels of miR-181a by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), both Smad 7 and TGF beta1 proteins levels by enzyme linked immunosorbent assay (ELISA) were all measured in serum of 60 child, 30 with ALL and 30 age and sex matched healthy child as control group. MiR-181a expression showed highly significant decrease; plus a significant increase and decrease of Smad7 and TGF-beta1 protein levels respectively, in serum samples of ALL as compared to control group. MiR-181a expression achieved a highly significant positive and a significant negative correlation with TGF-beta1 and Smad7 respectively. Furthermore, the levels of Smad7 and TGF-beta1 were negatively correlated with each other (p<0.05). Although, positivity rate of both Smad7 and TGF-beta1 in ALL group increased with presence of hepatosplenomegaly, still there was no statistical significance. In conclusion, miR-181a could act as a tumor suppressor in pediatric ALL with over expression of its target pair, Smad7. Smad7 regulates TGF-beta1 signaling via a negative feedback loop and mediates the interaction between TGF-beta1 and other signaling pathways; suggesting that Smad7 over expression may have therapeutic potential in ALL. PMID- 28732738 TI - Association of microRNA-125a and microRNA-499a polymorphisms in chronic periodontitis in a sample south Indian population: A hospital-based genetic association study. AB - Periodontitis is a chronic inflammatory disease, caused by interaction between periodontopathic bacteria and the host immune response. MicroRNAs are small, single-stranded molecules, which play a key role in the regulation of diverse biological processes. Dysregulation of microRNAs function can lead to several diseases such as autoimmune and chronic inflammatory diseases. The objective of the study was to determine the association between selected single nucleotide polymorphisms in miR-125a, miR-499 and LIN28 homology A with chronic periodontitis susceptibility in a sample population from south India. Genotyping of the single nucleotide polymorphisms in miR-125a (rs41275794, rs12976445, rs10404453 and rs12975333), miR-499 (rs3746444) and LIN28 homolog A (rs3811463) was performed in DNA from288 controls (individuals with healthy gingiva) and 262 cases (chronic periodontitis patients) by direct dye-terminator sequencing. Disease association analysis revealed a significant association of the variant alleles of the miR-499a polymorphism (rs3746444) in chronic periodontitis [OR=2.07; 95%CI (1.35-3.17)]. The risk associated C-allele frequency was found to be higher in chronic periodontitis subjects as compared to that of healthy individuals. Similar results were also observed in the dominant model [OR=2.42; 95% CI (1.67-3.51)]. The recessive model for miR-125a polymorphism (rs12976445) was also found to be statistically significant with OR=1.54 and 95% CI (1.03 2.30). The haplotype "GCGGCA" was found to be higher in chronic periodontitis subjects than in healthy individuals. Pairwise linkage disequilibrium analysis exhibited that the polymorphisms, rs41275794 and rs12976445 in miR-125a, were in strong linkage equilibrium (D'=0.97). Epistatic interaction by multifactorial dimensionality reduction analysis revealed that the genotypes of the polymorphisms of miR-125a (rs41275794, rs12976445, rs10404453), miR-499a (rs3746444) and LIN28 (rs3811463) were interacting significantly [OR=2.54 (1.65 3.92)], thereby contributing to the risk of chronic periodontitis. PMID- 28732739 TI - Environmental scan of infection prevention and control practices for containment of hospital-acquired infectious disease outbreaks in acute care hospital settings across Canada. AB - BACKGROUND: Ward closure is a method of controlling hospital-acquired infectious diseases outbreaks and is often coupled with other practices. However, the value and efficacy of ward closures remains uncertain. PURPOSE: To understand the current practices and perceptions with respect to ward closure for hospital acquired infectious disease outbreaks in acute care hospital settings across Canada. METHODS: A Web-based environmental scan survey was developed by a team of infection prevention and control (IPC) experts and distributed to 235 IPC professionals at acute care sites across Canada. Data were analyzed using a mixed methods approach of descriptive statistics and thematic analysis. RESULTS: A total of 110 completed responses showed that 70% of sites reported at least 1 outbreak during 2013, 44% of these sites reported the use of ward closure. Ward closure was considered an "appropriate," "sometimes appropriate," or "not appropriate" strategy to control outbreaks by 50%, 45%, and 5% of participants, respectively. System capacity issues and overall risk assessment were main factors influencing the decision to close hospital wards following an outbreak. DISCUSSION: Results suggest the use of ward closure for containment of hospital acquired infectious disease outbreaks in Canadian acute care health settings is mixed, with outbreak control methods varying. The successful implementation of ward closure was dependent on overall support for the IPC team within hospital administration. PMID- 28732740 TI - Exposure Survey of Trends in Occupational Practice (EXPO-S.T.O.P.) 2015: A national survey of sharps injuries and mucocutaneous blood exposures among health care workers in US hospitals. AB - BACKGROUND: National blood exposure (BE) surveys are valuable to health care facilities striving to reduce percutaneous sharps injuries (SIs) or mucocutaneous (MC) exposures among their health care workers (HCWs). In the Exposure Survey of Trends in Occupational Practice (EXPO-S.T.O.P.) 2015 we surveyed hospital BE incidence among members of the Association of Occupational Health Professionals in Healthcare. METHODS: A 23-item electronic survey requested 2015 data on total SI and MC; SI in nurses, doctors, and surgery; staffed beds; teaching status; full time equivalent staff (FTE), nurse FTE, average daily census (ADC), and adjusted patient days (APD). RESULTS: One hundred eighty-one hospitals in 34 states reported 9,343 BE (71% SI and 29% MC exposures). SI rates were 25.2/100 ADC (17.5 in nonteaching hospitals and 30.4 in teaching hospitals), 2.1/100 FTE (significantly less than that in 2001), 3.2/100 nurse FTE, 0.36/1,000 APD, and 38% occurred during surgery. MC exposure incidence rates were 10.5/100 ADC (8.6 in nonteaching hospitals and 11.7 in teaching hospitals), 0.86/100 FTE, and 0.14/1000 APD. CONCLUSIONS: BE incidence rates have fallen slowly but significantly since 2001, but the reduction is far less than hoped. Occupied beds (ie, ADC) has become a less-useful denominator. We estimate more than 300,000 HCWs sustain SIs annually in hospital and nonhospital settings. Greater resources are needed for more frequent and correct use of safety devices, training to competency, and root-cause investigation of all SIs. PMID- 28732741 TI - Long-acting water-stable organosilane agent and its sustained effect on reducing microbial load in an intensive care unit. AB - BACKGROUND: Contaminated hospital surfaces contribute significantly to the transmission of health care-associated infections. Although disinfectants reduce bioburden by up to 99%, bacterial growth can rebound within hours to precleaning levels. We tested the effectiveness of an innovative, long-acting water-stable organosilane (WSO) to achieve sustained decreases in bioburden on hard surfaces. METHODS: A 5-month prospective, randomized, double-blind controlled study was performed. Eighteen intensive care unit rooms were randomly divided into placebo or treatment groups. Hard surfaces in all rooms were cleaned using the same protocol, except the placebo surfaces were cleaned with an inert saline solution and the treatment surfaces were treated with the WSO. Binomial regression with repeated measures were used to assess mean reductions in total bioburden as measured by colony forming units. RESULTS: The placebo resulted in average reductions in total colony forming units of 35% to 40% (relative risk reduction [RRR], 0.65; P < .01) and the WSO group averaged reductions of colony forming units by 66% to 99% (RRR, 0.55; P < .001). Total Staphylococcus aureus increased among the placebo rooms 30% (RRR, 0.69; P < .001), whereas in treatment rooms there was a reduction of 50%-60% (RRR, 0.57; P < .01). Although both sets of rooms saw reductions in bioburden or colony forming units, application of the WSO resulted in larger reductions. There was also greater variability in reductions in the placebo arm. CONCLUSION: This is the first randomized, double-blind controlled study of an innovative WSO on high-touch hard surfaces at risk for high bioburdens. Sustained reductions of bioburden with the monthly application of this unique WSO may be associated with significant reductions in the risk of health care-associated infections. PMID- 28732742 TI - What do visitors know and how do they feel about contact precautions? AB - Patients with Clostridium difficile infection (CDI) are placed in contact precautions. We surveyed 31 visitors of CDI patients to understand their compliance, knowledge, and perceptions of contact precautions. Although most visitors knew where to find the required personal protective equipment, only 42% were fully compliant with gown and gloves. Family members accounted for 90% of visitors, and roughly half of the reasons given for not gowning were related to a lack of perceived risk for family members. Nursing staff are fundamental sources of personal protective equipment (PPE) information for visitors; however, we found variation in staff communication regarding need for visitor PPE use. PMID- 28732743 TI - Antimicrobial stewardship in the treatment of skin and soft tissue infections. AB - BACKGROUND: Research on treating skin and soft tissue infections (SSTI) has shown improved patient outcomes with effective pharmaceutic prescribing. Antimicrobial stewardship programs can reduce consequences of broad-spectrum antimicrobial administration in SSTI treatment. METHODS: Prospective and historic control data were collected during two 7-month periods. Intervention consisted of implementing a new SSTI evidence-based treatment algorithm and provider education, including calls and medical record notes targeted at physicians. RESULTS: Of 412 patients, 76 and 86 were found eligible from the historic and intervention groups, respectively. The intervention group had a higher prevalence of appropriate antibiotic usage (33% vs 19%, respectively; P = .04). There was a lower median number of days from intravenous antibiotic therapy to oral conversion (3 vs 5; P < .0001) and a lower median number of days of antipseudomonal antibiotic use (3 vs 5; P = .03) in the intervention group, respectively. The intervention group also had fewer documented SSTI treatment complications (1% vs 8%, respectively; P = .04). The positive outcomes outlined demonstrate potential impacts made from the use of multidisciplinary antibiotic stewardship initiatives. CONCLUSIONS: Appropriate use of antimicrobial agents under the direction of an antimicrobial stewardship program can lead to improved outcomes for patients being treated for SSTIs. PMID- 28732744 TI - A proposal for appropriate countermeasures to infectious diseases in schools. PMID- 28732745 TI - Letter to the editor on "Antimicrobial copper alloys decreased bacteria on stethoscope surfaces". PMID- 28732746 TI - Methodology minute: Indirect standardization. PMID- 28732747 TI - Shorter overall operative time when barbed suture is used in primary laparoscopic gastric bypass: A cohort study of 25,006 cases. AB - BACKGROUND: Closing the remaining opening in a linear stapled anastomosis, for example in laparoscopic Roux-en-Y gastric bypass (LRYGB), can be challenging. OBJECTIVES: To evaluate if the novel unidirectional barbed suture (BS) is of value in LRYGB compared with polyfilament (PS) suture. We have compared operative time, early complications, and length of stay, as well as anastomotic strictures and small bowel obstruction during the first year. SETTING: Retrospective study from the Scandinavian Obesity Surgery Registry (SOReg). METHODS: A nationwide cohort of 25,006 primary LRYGB (2211 BS and 22,795 PS) from SOReg were studied. No preoperative differences in age or gender were noted; however, BS patients had lower Body Mass Index (BMI) (41.3 versus 42.3 kg/m2, P<.001) and less diabetes (13.7% versus 15.4%, P = .03). RESULTS: Total operative time was 11 minutes (16%) shorter using BS compared with PS (58 versus 69 minutes, P<.001), although the mesenteric openings were more frequently closed among BS patients (94% versus 71%, P<.001). No differences were seen in early complications; anastomotic leaks or intra-abdominal abscesses were noted in 1.8% and 1.4%, respectively, P = .17. The incidence of anastomotic strictures was similar (.13% versus .17%, P = .73) as was the incidence of surgery for small bowel obstruction (1.8% versus 1.6%, P = .69). CONCLUSIONS: The use of barbed suture for closing the remaining opening in the gastrojejunostomy shortened the operative time without increasing the risk of complications. BS is still uncommon in LRYGB, but its implementation could have significant impact on operative time. PMID- 28732748 TI - Controlling the pro-inflammatory function of 6-sulfo LacNAc (slan) dendritic cells with dimethylfumarate. AB - BACKROUND: The fumaric acid ester (FAE) dimethylfumarate (DMF) is a small molecule immunomodulator successfully used for the treatment of psoriasis and multiple sclerosis (MS). DMF is thought to inhibit pathogenic immune responses with Th17/Th1T cells, and IL-23/IL-12 producing dendritic cells (DCs). 6-sulfo LacNAc expressing dendritic cells (slanDCs) are a human pro-inflammatory cell type found frequently among the infiltrating leukocytes in skin lesions of psoriasis and brain lesions of MS. OBJECTIVE: To explore the influence of DMF on functional properties and cell signaling pathways of slanDCs. METHODS: In the context of slanDCs we studied the role of DMF in modulating cell migration, phenotypic maturation, cytokine production, cell signaling and T cell stimulation. RESULTS: Initially, we observed the reduction of slanDCs numbers in psoriasis skin lesions of FAE treated patients. Studying whether DMF controls the migratory capacity of slanDCs to chemotactic factors expressed in psoriasis we observed an inhibition of the CX3CL1 and C5a depedent cell migration. DMF also attenuated the rapid spontaneous phenotypic maturation of slanDCs, as judged by a reduced CD80, CD86, CD83 and HLA-DR expression. In addition, we observed a DMF dependent decrease of IL-23, IL-12, TNF-alpha and IL-10 secretion, and noticed a reduced capacity to stimulate Th17/Th1 responses. DMF targeted in slanDCs different intracellular cell signaling pathways including NFkappaB, STAT1 and HO 1. CONCLUSIONS: With this study we identify a frequent pro-inflammatory cell type found in psoriasis and MS as a relevant target for the therapeutic immunomodulatory effects of DMF. PMID- 28732749 TI - Body representation disorders predict left right orientation impairments after stroke: A voxel-based lesion symptom mapping study. AB - INTRODUCTION: Deficits in the ability to distinguish between the left and right side of the body can severely impair daily life functioning. The current study examined the relation between left right orientation (LRO) impairments and somatosensory related deficits, ranging from primary somatosensory impairments to body representation impairments, in patients who suffered a recent stroke. We also examined which areas in the brain are associated with LRO impairments using a Voxel-based Lesion Symptom Mapping (VLSM) analysis. METHOD: We tested 47 first ever stroke patients and 48 age-matched healthy controls. LRO was assessed with the Bergen Right Left Discrimination Test (BRLD). Impairments on primary somatosensory function (touch perception, proprioception), higher order somatosensory function (finger gnosis, subjective sense of body ownership) and other cognitive functions (language, attention & working memory, visuospatial neglect) were entered as predictors in a logistic regression analyses. Outcome measures consisted of the BRLD-total performance which was further subdivided in performance for 1) first person perspective stimuli, 2) third person perspective stimuli, 3) alternating between first- and third person perspective. RESULTS: Impairments on BRLD-total performance was predicted by impairments in finger gnosis and visuospatial neglect. For items placed in third person perspective, performance was predicted by body representation impairments; finger agnosia and the subjective sense of body ownership. VLSM analysis showed a significant association between LRO impairments and damage to the right insula. DISCUSSION: The current study suggests that the somatosensory system is important for LRO. Furthermore, the results indicate that an affected body representation may hinder adopting a third person perspective that may subsequently also lead to LRO impairments. The right insular cortex appeared crucially involved in these processes. PMID- 28732750 TI - Personality predicts the vibrancy of colour imagery: The case of synaesthesia. AB - In this study we show that personality traits predict the physical qualities of mentally generated colours, using the case of synaesthesia. Developmental grapheme-colour synaesthetes have the automatic lifelong association of colours paired to letters or digits. Although these colours are internal mental constructs, they can be measured along physical dimensions such as saturation and luminance. The personality of synaesthetes can also be quantified using self report questionnaires relating, for example, to the five major traits of Conscientiousness, Extraversion, Agreeableness, Neuroticism, and Openness to Experience. In this paper, we bring together both types of quality by examining whether the personality of individual synaesthetes predicts their synaesthetic colours. Twenty grapheme-colour synaesthetes were tested with the Big Five Inventory (BFI) personality questionnaire. Their synaesthesia was also tested in terms of consistency and average colour saturation and luminance. Two major results were found: although personality did not influence the overall robustness (i.e., consistency) of synaesthesia, it predicted the nature of synaesthetes' colours: the trait of Openness was positively correlated with the saturation of synaesthetic colours. Our study provides evidence that personality and internal perception are intertwined, and suggests future avenues of research for investigating the associations between the two. PMID- 28732752 TI - Effects of Voice Therapy: A Comparison Between Individual and Group Therapy. AB - OBJECTIVE: The primary aim of this clinical evaluation project is to study the effect of voice therapy given in the speech-language pathology clinic, as individual and group therapy, as well as finding out some of the reasons for not attending the recommended therapy. METHOD: All patients visiting the speech language department during the study period were asked to participate in a clinical evaluation project. The project included filling out the questionnaire Swedish Voice Handicap Index (VHI-11) twice: at their first visit at the clinic, and approximately 1 year later. Depending on the degree of voice problems, the patients were offered either individual or group therapy. RESULT: The study included 187 patients at their first visit to the clinic and 109 patients at follow-up. All participants completed self-evaluation of voice function with the VHI-11 and separate questions regarding overall voice problems, hoarseness, and vocal fatigue. For the patients who responded to the follow-up survey, statistically significant improvements of self-perceived voice function were demonstrated in individual and group therapy. The improvement between the first visit and the follow-up was found to be of moderate to large effect size, with statistically significant improvements for both patients who attended individual therapy and those who attended group therapy. The most common reason for not attending the recommended voice therapy was lack of time. CONCLUSION: Individual and group therapy is effective, resulting in improved VHI-11 scores. The magnitude of improvement is similar when comparing individual and group therapy. Patients with higher scores of the VHI-11 were generally recommended individual voice therapy. PMID- 28732751 TI - Voice Improvement in Patients with Functional Dysphonia Treated with the Proprioceptive-Elastic (PROEL) Method. AB - The objective of the study was to analyze the outcome of the proprioceptive elastic (PROEL) voice therapy method in patients with functional dysphonia (FD). Fifty-two patients with FD were involved in the study; they were composed of three subgroups of patients with (1) FD without glottal insufficiency (n = 28), (2) FD and glottal insufficiency (n = 9), and (3) FD, glottal insufficiency, and vocal nodules (n = 15). A multidimensional assessment protocol including videolaryngostroboscopy; maximum phonation time; perceptual evaluation of dysphonia with the Grade, Instability, Roughness, Breathiness, Asthenia, and Strain (GIRBAS) scale; and 10-item version of the Voice Handicap Index was conducted before and after 15 sessions of voice therapy. All voice therapy sessions were conducted by the same speech-language pathologist. The comparison between voice assessment before and after voice therapy with the PROEL method in patients with FD, in all the three subgroups, revealed a statistically significant improvement in periodicity and the mucosal wave in the laryngostroboscopy, maximum phonation time, GIRBAS scale scores, and VHI-10. Voice of patients with FD improved after treatment with the PROEL method. Further studies are needed to analyze the efficacy of the PROEL method with randomized double-blind clinical trials using different methods for voice therapy. At present, the PROEL method represents an alternative tool for the speech pathologist to improve voice in patients with FD. PMID- 28732753 TI - Gene expression changes in honey bees induced by sublethal imidacloprid exposure during the larval stage. AB - Honey bee larvae exposed to sublethal doses of imidacloprid show behavioural abnormalities as adult insects. Previous studies have demonstrated that this phenomenon originates from abnormal neural development in response to imidacloprid exposure. Here, we further investigated the global gene expression changes in the heads of newly emerged adults and observed that 578 genes showed more than 2-fold changes in gene expression after imidacloprid exposure. This information might aid in understanding the effects of pesticides on the health of pollinators. For example, the genes encoding major royal jelly proteins (MRJPs), a group of multifunctional proteins with significant roles in the sustainable development of bee colonies, were strongly downregulated. These downregulation patterns were further confirmed through analyses using quantitative reverse transcription-polymerase chain reaction on the heads of 6-day-old nurse bees. To our knowledge, this study is the first to demonstrate that sublethal doses of imidacloprid affect mrjp expression and likely weaken bee colonies. PMID- 28732754 TI - What is the Quality of Online Resources About Pain Control After Total Knee Arthroplasty? AB - BACKGROUND: With the growing opioid crisis in the United States, there has been a push to reduce the utilization of opioids in favor of multimodal analgesia options. The purpose of this study was to evaluate the quality of online resources that patients may use to learn about pain control after total knee arthroplasty (TKA). METHODS: We identified websites using a combination of search terms about TKA and pain control. A novel grading rubric was created with 25 maximum points, consisting of items that were deemed important for patients to know about the subject. Three authors then independently graded websites and the results averaged. Flesch-Kinkaid reading level was also evaluated. RESULTS: After identifying 166 unique websites, 32 met final inclusion criteria. The overall scores were low-4.7 of 25 total points (18.8%), written at an average 10th grade level. Subgroup scores were 50% for route of administration, 40% for types of analgesia, 23% for opioid-specific items, and 30% for general guidance. Only about half discussed the risks of opioid dependency. The top 3 website total scores ranged from 10.7-12.5 of 25 points. CONCLUSION: There is a paucity of online information for TKA patients to read about pain control. Most websites provide limited educational content, particularly about opioids. Higher quality information is needed to help patients make decisions with their physicians and to help combat the opioid epidemic. Given the lack of quality information available, there is an opportunity for subspecialty organizations to take a leadership role in such efforts. PMID- 28732755 TI - Two Cases of Acute Kidney Injury Due to Multiple Wasp Stings. AB - Acute kidney injury (AKI) is an unusual complication of wasp stings. Treatment of established AKI is largely supportive but the preventive strategies are not well documented. This is a report of 2 human cases that developed AKI after multiple wasp stings (Vespa magnifica). Each patient reached the hospital early in their clinical course and was treated with intravenous hydration and urine alkalization. In both the cases the severity of AKI, morbidity, and duration of hospitalization were reduced. The requirement of dialysis therapy was avoided. We propose early treatment with intravenous hydration, diuretic administration, and urine alkalization in such cases to prevent systemic and renal complications. PMID- 28732756 TI - Health of High Altitude Pilgrims: A Neglected Topic. PMID- 28732757 TI - Multimodal exercise training in multiple sclerosis: A randomized controlled trial in persons with substantial mobility disability. AB - BACKGROUND: Mobility disability is a common, debilitating feature of multiple sclerosis (MS). Exercise training has been identified as an approach to improve MS-related mobility disability. However, exercise randomized controlled trials (RCTs) on mobility in MS have generally not selectively targeted those with the onset of irreversible mobility disability. OBJECTIVES: The current multi-site RCT compared the efficacy of 6-months of supervised, multimodal exercise training with an active control condition for improving mobility, gait, physical fitness, and cognitive outcomes in persons with substantial MS-related mobility disability. METHODS: 83 participants with substantial MS-related mobility disability underwent initial mobility, gait, fitness, and cognitive processing speed assessments and were randomly assigned to 6-months of supervised multimodal (progressive aerobic, resistance, and balance) exercise training (intervention condition) or stretching-and-toning activities (control condition). Participants completed the same outcome assessments halfway through and immediately following the 6-month study period. RESULTS: There were statistically significant improvements in six-minute walk performance (F(2158)=3.12, p=0.05, etap2=0.04), peak power output (F(2150)=8.16, p<0.01, etap2=0.10), and Paced Auditory Serial Addition Test performance (F(2162)=4.67, p=0.01, etap2=0.05), but not gait outcomes, for those who underwent the intervention compared with those who underwent the control condition. CONCLUSIONS: This RCT provides novel, preliminary evidence that multimodal exercise training may improve endurance walking performance and cognitive processing speed, perhaps based on improvements in cardiorespiratory capacity, in persons with MS with substantial mobility disability. This is critical for informing the development of multi-site exercise rehabilitation programs in larger samples of persons with MS-related mobility disability. PMID- 28732758 TI - Effects of narrator empathy in a computer delivered brief intervention for alcohol use. AB - Computer-delivered, brief interventions (CDBIs) have been an increasingly popular way to treat alcohol use disorders; however, very few studies have examined which characteristics of CDBIs maximize intervention effectiveness. The literature has consistently demonstrated that therapist empathy is associated with reduced substance use in in-person therapy; however, it is unclear whether this principle applies to CDBIs. Therefore, the study aimed to examine whether the presence of an empathic narrator increased intentions to reduce heavy drinking in a CDBI. Results suggest that the presence of empathy increases motivation to reduce drinking, and makes participants feel more supported and less criticized. PMID- 28732759 TI - Hemispheric asymmetries in the processing of body sides: A study with ambiguous human silhouettes. AB - When required to indicate the perceived orientation of pictures of human silhouettes with ambiguous front/back orientation and handedness, both right- and left-handed participants perceive the figures more frequently as right-handed than as left-handed, which seems to indicate an attentional bias towards the right arm of human bodies. Given that past research exploiting the divided visual field paradigm indicated a processing advantage for contralateral body parts in both hemispheres, we tested whether human silhouettes with ambiguous handedness presented in the right visual field would be interpreted more frequently as right handed compared with those presented in the left visual field. We confirmed the expected lateralised embodiment of ambiguous human bodies, in line with previous studies showing that right and left limbs are processed faster and/or more accurately when presented in the right and left hemifield, respectively. PMID- 28732760 TI - Rutin alleviates chronic unpredictable stress-induced behavioral alterations and hippocampal damage in mice. AB - Chronic stress results in neurological complications like depression, cognitive dysfunction, and anxiety disorders. In our previous study, we observed that Urtica dioica leaf extract attenuated chronic stress-induced complications. Further, we observed that Urtica dioica contained a great amount of the flavonoid rutin in it. Hence, we aimed to evaluate the effect of rutin on 21days chronic unpredictable stress (CUS) mouse model. CUS led to a decline in locomotion & muscle coordination abilities, cognitive deficits, anxiety, and depression. These neurobehavioral outcomes were associated with neurodegeneration in the CA3 region of the hippocampus as found by H&E staining. Rutin efficiently rescued the CUS induced behavioral deficits by reducing depression, anxiety, improving cognition, and locomotor & muscle coordination skills. Further, rutin treatment protected the CUS-induced hippocampal neuronal loss. This study establishes the neuroprotective effect of rutin in chronic stress. PMID- 28732761 TI - The use of intermuscular coherence analysis as a novel approach to detect age related changes on postural muscle synergy. AB - The overall goal of this study was to investigate potential adaptations brought about by the natural processes of aging on the coordination of postural muscles. Considering the progressive and non-homogeneous deterioration of sensorimotor and neuromuscular systems as the individual grows older, it was hypothesized that aging is associated with a reorganization of synergistic mechanisms controlling postural muscles. Therefore, the presence, distribution, and strength of correlated neural inputs to three posterior postural muscles were measured by intermuscular coherence estimations at a low frequency band (0-55Hz). Nine healthy young adults and thirteen healthy older adults performed ten trials of a perturbed task: bipedal stance while holding a five kg load for fifteen seconds. Estimates of intermuscular coherence for each pair of electromyographic signals (soleus and biceps femoris, soleus and erector spinae, and biceps femoris and erector spinae) were computed. Results revealed significantly stronger levels of synchronization of posterior muscles within 0-10Hz in seniors compared to young adults. In addition, seniors presented similar spectra of intermuscular coherence within 0-55Hz for all three muscle pairs analyzed. These findings provide valuable information regarding compensatory mechanisms adopted by older adults to control balance. The age-related reorganization of neural drive controlling posterior postural muscles revealing a stronger synchronization within 0-10Hz might be related to the faster body sway and muscle co-activation patterns usually observed in this population. Finally, this study supports the use of Intermuscular Coherence Analysis as a sensitive method to detect age-related changes in multi-muscle control. PMID- 28732762 TI - Effect of Class II HDAC inhibition on glutamate transporter expression and survival in SOD1-ALS mice. AB - Transcriptional deregulation emerges as a key pathogenetic mechanism in ALS pathogenesis, and non-class-specific histone deacetylase (HDACs) inhibitors proved of therapeutic efficacy in preclinical models of ALS. When tested in patients, however, these drugs failed, probably because of a lack of selectivity toward pathogenetic HDACs. Here, we studied the effects of MC1568, an inhibitor of Class-II HDACs which have been reported to contribute to ALS pathogenesis. We focused on transcriptional regulation of glutamate transporter EAAT2, whose reduced expression may contribute to motor neuron degeneration in ALS. We report that MC1568 highly increased EAAT2 transcripts in primary cultures of mouse glia, but these increases did not correlate with increased glutamate uptake capacity. Accordingly, we found that MC1568 augmented protein expression of EAAT2 together with its sumoylation, a post-translational modification typically altering protein function and localization. When tested in SOD1G93A mice, however, MC1568 fully restored the reduced spinal cord expression of EAAT2 and glutamate uptake up to control levels. A prolonged treatment with MC1568 (from onset to end stage) was unable to prolong survival of mice. Data reveal a key role of Class-II HDACs in expression and function of glutamate transporter, further corroborating preclinical and clinical evidence that the sole restoration of glutamate uptake is not of therapeutic relevance to ALS therapy. PMID- 28732763 TI - Post-exercise cortical depression following repetitive passive finger movement. AB - This study aimed to clarify the influence of range of repetitive passive finger movement on corticospinal excitability. Thirteen healthy subjects participated in this study. Passive index finger adduction-abduction movements were performed from 15 degrees abduction to 15 degrees adduction, 15 degrees abduction to 0 degrees , 0 degrees to 15 degrees adduction, and 15 degrees adduction to 30 degrees adduction, each at 15 degrees /s for 10min on separate days. Motor evoked potentials (MEPs) elicited by transcranial magnetic stimulation and M- and F-waves were measured before and after each repetitive passive index finger movement protocol to evaluate changes in corticospinal excitability. MEP amplitude significantly decreased after all passive movements, while F-wave amplitude, F-wave persistence, and M-wave amplitude remained stable. These results suggest that cortical excitability decreases after repetitive passive movement. However, the range of repetitive passive movement does not markedly influence the magnitude of cortical depression. PMID- 28732764 TI - Vasculitic peripheral neuropathy induced by ischemia-reperfusion in the rat femoral artery involves activation of proinflammatory signaling pathway in the sciatic nerve. AB - Ischemia-reperfusion (IR) in the rat femoral artery has been proposed as an experimental model of vasculitic peripheral neuropathy (VPN) which presents neuropathic pain and peripheral nerve injury patterns observed clinically. This study investigates the involvement of the proinflammatory signaling pathway underlying the peripheral mechanisms of VPN. Male Sprague-Dawley rats were allocated to receive either a sham operation or IR. IR was induced by occluding the right femoral artery for 4h followed by reperfusion periods from 0 to 72h. The behavioral parameters were assessed at baseline as well as at days 1, 2 and 3 after reperfusion. The time-course analyses of proinflammatory mediators in the sciatic nerves were also performed on rats of the sham group or IR groups with reperfusion periods of 0, 2, 4, 24 and 72h, respectively. The behavioral data confirmed that this VPN model induced hindpaw mechano-allodynia and heat hyperalgesia as well as impaired hindpaw grip strength. The molecular data revealed that IR in the femoral artery activated the expression of nuclear factor kappaB (NF-kappaB) in the sciatic nerve indicating a neuroinflammatory response. Moreover, IR in the femoral artery increased the expression of proinflammatory cytokines TNF-alpha and IL-1beta in the sciatic nerve. This study elucidated the novel time-course expression profiles of NF-kappaB and proinflammatory cytokines in VPN induced by IR which may be involved in the development of neuropathic pain. Since NF-kappaB is a key element during neuroinflammation, strategies targeting the NF-kappaB signaling pathway may provide therapeutic potential against VPN induced by IR. PMID- 28732765 TI - Identification and expression analysis of fetuin B (FETUB) in turbot (Scophthalmus maximus L.) mucosal barriers following bacterial challenge. AB - Fetuin B (FETUB), a recently described cysteine proteinase inhibitor, has numerous conserved N-glycosylation sites, species-specific O-glycosylation sites, and two cystatin (CY) domains. FETUB is likely to play regulatory roles in acute inflammation, female infertility, fish organogenesis and tumor suppression. In the present study, transcript of turbot FETUB gene was captured, its protein structure and expression patterns in different tissues with emphasis on mucosal barriers following different bacterial infection were characterized. Turbot FETUB gene showed the closest relationship with Takifugu rubripes in phylogenetic analysis. In addition, FETUB was ubiquitously expressed in all examined tissues with the highest expression level in skin. Finally, FETUB gene showed different expression patterns following both bacterial challenge. The rapidly and significantly differential expression patterns of FETUB in mucosal surfaces against bacterial infections might indicate its key roles to prevent pathogen attachment and entry in turbot mucosal immunity. Functional studies should be carried out to further characterize the FETUB and avail utilization of its function to increase the disease resistance of turbot in maintaining the integrity of the mucosal barriers against infections and to facilitate selection of the fine family/varieties of disease resistance in turbot. PMID- 28732766 TI - Molecular, structural, and functional comparison of N lobe and C lobe of the transferrin from rock bream, Oplegnathus fasciatus, with respect to its immune response. AB - The iron-withholding strategy of innate immunity is an effective antimicrobial defense mechanism that combats microbial infection by depriving microorganisms of Fe3+, which is important for their growth and propagation. Transferrins (Tfs) are a group of iron-binding proteins that exert their antimicrobial function through Fe3+ sequestration. The current study describes both structural and functional characteristics of a transferrin ortholog from rock bream Oplegnathus fasciatus (RbTf). The RbTf cDNA possesses an open reading frame (ORF) of 2079 bp encoding 693 amino acids. It has a molecular mass of approximately 74 kDa and an isoelectric point of 5.4. In silico analysis revealed that RbTf has two conserved domains: N-terminal domain and C-terminal domain. Pairwise homology analysis and phylogenetic analysis revealed that RbTf shared the highest identity (82.6%) with Dicentrarchus labrax Tf. According to the genomic analysis, RbTf possesses 17 exons and 16 introns, similar to the other orthologs. Here, we cloned the N terminal and C terminal domains of RbTf to evaluate their distinct functional features. Results obtained through the CAS (chrome azurol S) assay confirmed the iron-binding ability of the RbTf, and it was further determined that the iron binding ability of rRbTfN was higher than that of rRbTfC. The antimicrobial functions of the rRbTfN and the rRbTfC were confirmed via the iron-dependent bacterial growth inhibition assay. Tissue distribution profiling revealed a ubiquitous expression with intense expression in the liver. Temporal assessment revealed that RbTf increased after stimulation of LPS, Edwardsiella tarda, and Streptococcus iniae post injection (p.i.). These findings demonstrated that RbTf is an important antimicrobial protein that can combat bacterial pathogens. PMID- 28732767 TI - Protective effects of CpG-ODN 2007 administration against Edwardsiella tarda infection in olive flounder (Paralichthys olivaceus). AB - In this study, we investigated the immunostimulatory and protective effects of CpG motif oligonucleotides (CpG-ODNs) against Edwardsiella tarda infection in olive flounder (Paralichthys olivaceus). Groups of fish injected with CpG-ODNs (1585, 1668, and 2007) or PBS (control) showed varying mortality rates in response to challenge with E. tarda. The survival rates of fish treated with CpG ODN 1668 and 2007, which belonged to the same class type B, were 45% and 60%, respectively, with CpG-ODN 2007 showing the highest survival rate. Further analysis showed that the respiratory burst and bactericidal activities induced by CpG-ODN 2007 were higher than those in the control group (induced by non-CpG ODNs) or in the group of fish induced by CpG-ODN 1585, which belonged to class type A. Additionally, the respiratory burst activity induced by CpG-ODN 2007 was higher than that induced by CpG-ODN 1668, despite similar bactericidal activity titers. In vivo experiments showed that CpG-ODN 2007 stimulation resulted in higher survival rates than CpG-ODN 1668 stimulation, possibly owing to differences in respiratory burst activity. In summary, we demonstrated that differences in CpG-motif or class type altered respiratory burst and bactericidal activities, resulting in differences in survival rates against E. tarda challenge in the olive flounder. Therefore, it is necessary to use CpG-ODNs optimized against E. tarda infection in olive flounder, because different CpG motifs belonging to the same class type have different effects. PMID- 28732768 TI - Molecular characterization and expression analysis of four fish-specific CC chemokine receptors CCR4La, CCR4Lc1, CCR4Lc2 and CCR11 in rainbow trout (Oncorhynchus mykiss). AB - The chemokine and chemokine receptor networks regulate leukocyte trafficking, inflammation, immune cell differentiation, cancer and other biological processes. Comparative immunological studies have revealed that both chemokines and their receptors have expanded greatly in a species/lineage specific way. Of the 10 human CC chemokine receptors (CCR1-10) that bind CC chemokines, orthologues only to CCR6, 7, 9 and 10 are present in teleost fish. In this study, four fish specific CCRs, termed as CCR4La, CCR4Lc1, CCR4Lc2 and CCR11, with a close link to human CCR1-5 and 8, in terms of amino acid homology and syntenic conservation, have been identified and characterized in rainbow trout (Oncorhynchus mykiss). These CCRs were found to possess the conserved features of the G protein-linked receptor family, including an extracellular N-terminal, seven TM domains, three extracellular loops and three intracellular loops, and a cytoplasmic carboxyl tail with multiple potential serine/threonine phosphorylation sites. Four cysteine residues known to be involved in forming two disulfide bonds are present in the extracellular domains and a DRY motif is present in the second intracellular loop. Signaling mediated by these receptors might be regulated by N glycosylation, tyrosine sulfation, S-palmitoylation, a PDZ ligand motif and di leucine motifs. Studies of intron/exon structure revealed distinct fish-specific CCR gene organization in different fish species/lineages that might contribute to the diversification of the chemokine ligand-receptor networks in different fish lineages. Fish-specific trout CCRs are highly expressed in immune tissues/organs, such as thymus, spleen, head kidney and gills. Their expression can be induced by the pro-inflammatory cytokines, IL-1beta, IL-6 and IFNgamma, by the pathogen associated molecular patterns, PolyIC and peptidoglycan, and by bacterial infection. These data suggest that fish-specific CCRs are likely to have an important role in immune regulation in fish. PMID- 28732769 TI - Transcriptome analysis of yellow catfish (Pelteobagrus fulvidraco) liver challenged with polyriboinosinic polyribocytidylic acid (poly I:C). AB - Yellow catfish (Pelteobagrus fulvidraco) is one of the most important economic freshwater species in China. However, infection by bacterial pathogenic diseases has caused high mortality and great economic loss in aquaculture. It is necessary for disease control to know more about the P. fulvidraco immune system and its related genes in response to bacterial or viral infections. In this study, the transcriptomic profiles of liver from P. fulvidraco stimulated by polyriboinosinic polyribocytidylic acid (poly I:C) was analyzed using high throughput sequencing method. After assembly and annotation, total 67,447 unigenes were acquired, with an average length of 1091 bp. Under the infection of poly I:C, 522 differentially expressed genes (DEGs) were identified, including 307 up-regulated genes and 215 down-regulated genes. To further investigate the immune-related DEGs, Gene ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment were performed. The result of GO enrichment indicated gene response to external stimulus, regulation of response to stimulus, cellular response to stimulus, immune response and immune system progress. Significant KEGG enrichment analysis identified major immune related pathways. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis revealed that 13 immune response genes were identified to be up-regulated after 12 h of poly I:C stimulation compared to controls. Taken together, the results of our study are beneficial for better understanding of the immune system and defense mechanisms of yellow catfish in response to poly I:C infection. PMID- 28732771 TI - Application of the gene editing tool, CRISPR-Cas9, for treating neurodegenerative diseases. AB - Increased accumulation of transcribed protein from the damaged DNA and reduced DNA repair capability contributes to numerous neurological diseases for which effective treatments are lacking. Gene editing techniques provide new hope for replacing defective genes and DNA associated with neurological diseases. With advancements in using such editing tools as zinc finger nucleases (ZFNs), meganucleases, and transcription activator-like effector nucleases (TALENs), etc., scientists are able to design DNA-binding proteins, which can make precise double-strand breaks (DSBs) at the target DNA. Recent developments with the CRISPR-Cas9 gene-editing technology has proven to be more precise and efficient when compared to most other gene-editing techniques. Two methods, non-homologous end joining (NHEJ) and homology-direct repair (HDR), are used in CRISPR-Cas9 system to efficiently excise the defective genes and incorporate exogenous DNA at the target site. In this review article, we provide an overview of the CRISPR Cas9 methodology, including its molecular mechanism, with a focus on how in this gene-editing tool can be used to counteract certain genetic defects associated with neurological diseases. Detailed understanding of this new tool could help researchers design specific gene editing strategies to repair genetic disorders in selective neurological diseases. PMID- 28732770 TI - Pharmacologic modeling of primary mitochondrial respiratory chain dysfunction in zebrafish. AB - Mitochondrial respiratory chain (RC) disease is a heterogeneous and highly morbid group of energy deficiency disorders for which no proven effective therapies exist. Robust vertebrate animal models of primary RC dysfunction are needed to explore the effects of variation in RC disease subtypes, tissue-specific manifestations, and major pathogenic factors contributing to each disorder, as well as their pre-clinical response to therapeutic candidates. We have developed a series of zebrafish (Danio rerio) models that inhibit, to variable degrees, distinct aspects of RC function, and enable quantification of animal development, survival, behaviors, and organ-level treatment effects as well as effects on mitochondrial biochemistry and physiology. Here, we characterize four pharmacologic inhibitor models of mitochondrial RC dysfunction in early larval zebrafish, including rotenone (complex I inhibitor), azide (complex IV inhibitor), oligomycin (complex V inhibitor), and chloramphenicol (mitochondrial translation inhibitor that leads to multiple RC complex dysfunction). A range of concentrations and exposure times of each RC inhibitor were systematically evaluated on early larval development, animal survival, integrated behaviors (touch and startle responses), organ physiology (brain death, neurologic tone, heart rate), and fluorescence-based analyses of mitochondrial physiology in zebrafish skeletal muscle. Pharmacologic RC inhibitor effects were validated by spectrophotometric analysis of Complex I, II and IV enzyme activities, or relative quantitation of ATP levels in larvae. Outcomes were prioritized that utilize in vivo animal imaging and quantitative behavioral assessments, as may optimally inform the translational potential of pre-clinical drug screens for future clinical study in human mitochondrial disease subjects. The RC complex inhibitors each delayed early embryo development, with short-term exposures of these three agents or chloramphenicol from 5 to 7 days post fertilization also causing reduced larval survival and organ-specific defects ranging from brain death, behavioral and neurologic alterations, reduced mitochondrial membrane potential in skeletal muscle (rotenone), and/or cardiac edema with visible blood pooling (oligomycin). Remarkably, we demonstrate that treating animals with probucol, a nutrient-sensing signaling network modulating drug that has been shown to yield therapeutic effects in a range of other RC disease cellular and animal models, both prevented acute rotenone-induced brain death in zebrafish larvae, and significantly rescued early embryo developmental delay from either rotenone or oligomycin exposure. Overall, these zebrafish pharmacologic RC function inhibition models offer a unique opportunity to gain novel insights into diverse developmental, survival, organ-level, and behavioral defects of varying severity, as well as their individual response to candidate therapies, in a highly tractable and cost-effective vertebrate animal model system. PMID- 28732772 TI - A brain-specific isoform of apoptosis-inducing factor 2 attenuates ischemia induced oxidative stress in HT22 cells. AB - Apoptosis-inducing factor (AIF) is a family of conserved mitochondrial flavoproteins that have both vital and lethal functions in cells. The function and regulation of AIF-1, the original described and most abundant isoform, has been extensively studied, whereas three other AIF isoforms have not been further characterized. Here, we investigated the role of AIF-2, a brain-specific isoform of AIF, in an in vitro ischemia model in neuronal HT22 cells. We showed that AIF 2 was constitutively expressed in HT22 cells, and the oxygen and glucose deprivation (OGD) did not alter AIF-2 expression. Downregulation of AIF-2 with specific siRNA aggravated OGD-induced lactate dehydrogenase (LDH) release, apoptosis and loss of cell viability, whereas overexpression of AIF-2 through lentivirus transfection exerted the opposite effects. In OGD-treated cells, AIF-2 overexpression promoted the endogenous antioxidant enzyme activities, preserved mitochondrial membrane potential (MMP), inhibited cytochrome c release, and thereby prevented reactive oxygen species (ROS) generation and lipid peroxidation. In addition, AIF-2 significantly prevented the OGD-induced AIF-1 translocation from cytoplasm to the nuclei. In view of these considerations, AIF 2 might represent an ideal strategy to avoid AIF-1 associated neurotoxicity, and could be tested against brain ischemia in animal models. PMID- 28732774 TI - Vaginal dysbiosis and pre-exposure prophylaxis efficacy. PMID- 28732775 TI - Statistical analysis of the inter-individual variations of the bone shape, volume fraction and fabric and their correlations in the proximal femur. AB - Including structural information of trabecular bone improves the prediction of bone strength and fracture risk. However, this information is available in clinical CT scans, only for peripheral bones. We hypothesized that a correlation exists between the shape of the bone, its volume fraction (BV/TV) and fabric, which could be characterized using statistical modeling. High-resolution peripheral computed tomography (HR-pQCT) images of 73 proximal femurs were used to build a combined statistical model of shape, BV/TV and fabric. The model was based on correspondence established by image registration and by morphing of a finite element mesh describing the spatial distribution of the bone properties. Results showed no correlation between the distribution of bone shape, BV/TV and fabric. Only the first mode of variation associated with density and orientation showed a strong relationship (R2>0.8). In addition, the model showed that the anisotropic information of the proximal femur does not vary significantly in a population of healthy, osteoporotic and osteopenic samples. In our dataset, the average anisotropy of the population was able to provide a close approximation of the patient-specific anisotropy. These results were confirmed by homogenized finite element (hFE) analyses, which showed that the biomechanical behavior of the proximal femur was not significantly different when the average anisotropic information of the population was used instead of patient-specific fabric extracted from HR-pQCT. Based on these findings, it can be assumed that the fabric information of the proximal femur follows a similar structure in an elderly population of healthy, osteopenic and osteoporotic proximal femurs. PMID- 28732776 TI - Rad GTPase is essential for the regulation of bone density and bone marrow adipose tissue in mice. AB - The small GTP-binding protein Rad (RRAD, Ras associated with diabetes) is the founding member of the RGK (Rad, Rem, Rem2, and Gem/Kir) family that regulates cardiac voltage-gated Ca2+ channel function. However, its cellular and physiological functions outside of the heart remain to be elucidated. Here we report that Rad GTPase function is required for normal bone homeostasis in mice, as Rad deletion results in significantly lower bone mass and higher bone marrow adipose tissue (BMAT) levels. Dynamic histomorphometry in vivo and primary calvarial osteoblast assays in vitro demonstrate that bone formation and osteoblast mineralization rates are depressed, while in vitro osteoclast differentiation is increased, in the absence of Rad. Microarray analysis revealed that canonical osteogenic gene expression (Runx2, osterix, etc.) is not altered in Rad-/- calvarial osteoblasts; instead robust up-regulation of matrix Gla protein (MGP, +11-fold), an inhibitor of extracellular matrix mineralization and a protein secreted during adipocyte differentiation, was observed. Strikingly, Rad deficiency also resulted in significantly higher marrow adipose tissue levels in vivo and promoted spontaneous in vitro adipogenesis of primary calvarial osteoblasts. Adipogenic differentiation of wildtype calvarial osteoblasts resulted in the loss of endogenous Rad protein, further supporting a role for Rad in the control of BMAT levels. These findings reveal a novel in vivo function for Rad and establish a role for Rad signaling in the complex physiological control of skeletal homeostasis and bone marrow adiposity. PMID- 28732773 TI - Efficacy of oral pre-exposure prophylaxis (PrEP) for HIV among women with abnormal vaginal microbiota: a post-hoc analysis of the randomised, placebo controlled Partners PrEP Study. AB - BACKGROUND: Daily oral tenofovir-based pre-exposure prophylaxis (PrEP) is high efficacious for HIV prevention among women with high adherence. However, the effect of abnormal vaginal microbiota on PrEP efficacy is of concern. We investigated whether bacterial vaginosis modified the efficacy of oral PrEP. METHODS: We used prospectively collected data from women in the Partners PrEP Study, a placebo-controlled trial of daily oral PrEP (either tenofovir monotherapy or a combination of tenofovir and emtricitabine) in HIV serodiscordant couples aged 18 years or older in Kenya and Uganda that showed high efficacy in women. We used Cox proportional hazards regression to assess PrEP efficacy among subgroups of women defined by bacterial vaginosis status based on yearly microscopy and Nugent scoring (0-3 indicated healthy microbiota, 4-6 intermediate, and 7-10 bacterial vaginosis). In separate efficacy analyses, we also investigated individual components of the score (ie, detection of Gardnerella vaginalis or Bacteroides spp and non-detection of Lactobacillus spp) as markers of abnormal microbiota. FINDINGS: Of 1470 women (median age 33 years), 357 (24%) had bacterial vaginosis at enrolment. 45 women seroconverted to HIV. The HIV prevention efficacy of PrEP did not differ significantly among women with healthy microbiota (incidence 0.6 per 100 person years in PrEP group and 2.5 per 100 person-years in the placebo group; efficacy 76.55% [95% CI 43.09 to 90.37]), intermediate microbiota (HIV incidence 1.8 per 100 person-years in the PrEP group and 3.5 per 100 person-years in the placebo group; efficacy 62.72% [95% CI -66.59 to 91.66]), or bacterial vaginosis (HIV incidence 0.9 per 100 person-years in the PrEP group and 3.5 per 100 person-years in the placebo group; efficacy 72.50% [95% CI 5.98 to 91.95]; pinteraction=0.871). PrEP efficacy was not significantly different between women with detected G vaginalis or Bacteroides spp morphotypes and those without these morphotypes (efficacy 68.62% vs 76.72%; pinteraction=0.652); or between those with Lactobacillus spp morphotypes and those without (70.48% vs 74.08%; pinteraction=0.86). INTERPRETATION: Among African women with a high prevalence of bacterial vaginosis and high adherence to PrEP, the efficacy of daily oral PrEP for HIV prevention did not differ significantly among women with abnormal versus healthy vaginal microbiota as defined by Nugent score. These data are reassuring that oral PrEP delivery to women can continue without the need for concurrent testing for bacterial vaginosis or vaginal dysbiosis. FUNDING: Bill & Melinda Gates Foundation, Eunice Kennedy Shriver National Institute of Child Health and Human Development, and National Institute of Allergy and Infectious Diseases. PMID- 28732777 TI - How useful is 3D printing in maxillofacial surgery? AB - INTRODUCTION: 3D printing seems to have more and more applications in maxillofacial surgery (MFS), particularly since the release on the market of general use 3D printers several years ago. The aim of our study was to answer 4 questions: 1. Who uses 3D printing in MFS and is it routine or not? 2. What are the main clinical indications for 3D printing in MFS and what are the kinds of objects that are used? 3. Are these objects printed by an official medical device (MD) manufacturer or made directly within the department or the lab? 4. What are the advantages and drawbacks? METHODOLOGY: Two bibliographic researches were conducted on January the 1st, 2017 in PubMed, without time limitation, using "maxillofacial surgery" AND "3D printing" for the first and for the second "maxillofacial surgery" AND "computer-aided design" AND "computer-aided manufacturing" as keywords. Articles in English or French dealing with human clinical use of 3D printing were selected. Publication date, nationality of the authors, number of patients treated, clinical indication(s), type of printed object(s), type of printing (lab/hospital-made or professional/industry) and advantages/drawbacks were recorded. RESULTS: Two hundred and ninety-seven articles from 35 countries met the criteria. The most represented country was the People's Republic of China (16% of the articles). A total of 2889 patients (10 per article on average) benefited from 3D printed objects. The most frequent clinical indications were dental implant surgery and mandibular reconstruction. The most frequently printed objects were surgical guides and anatomic models. Forty-five percent of the prints were professional. The main advantages were improvement in precision and reduction of surgical time. The main disadvantages were the cost of the objects and the manufacturing period when printed by the industry. DISCUSSION: The arrival on the market of low-cost printers has increased the use of 3D printing in MFS. Anatomic models are not considered to be MDs and do not have to follow any regulation. Nowadays, they are easily printed with low-cost printers. They allow for better preoperative planning and training for the procedures and for pre-shaping of plates. Occlusal splints and surgical guides are intended for the smooth transfer of planning to the operating room. They are considered to be MDs and even if they are easy to print, they have to follow the regulations applying to MDs. Patient specific implants (custom-made plates and skeletal reconstruction modules) are much more demanding objects and their manufacturing remains nowadays in the hands of the industry. The main limitation of in-hospital 3D printing is the restrictive regulations applying to MDs. The main limitations of professional 3D printing are the cost and the lead time. 3D printed objects are nowadays easily available in MFS. However, they will never replace a surgeon's skill and should only be considered as useful tools. PMID- 28732778 TI - Functional analysis of the MAPK pathways in fungi. AB - The Mitogen-Activated Protein Kinase (MAPK) signaling pathways constitute one of the most important and evolutionarily conserved mechanisms for the perception of extracellular information in all the eukaryotic organisms. The MAPK pathways are involved in the transfer to the cell of the information perceived from extracellular stimuli, with the final outcome of activation of different transcription factors that regulate gene expression in response to them. In all species of fungi, the MAPK pathways have important roles in their physiology and development; e.g. cell cycle control, mating, morphogenesis, response to different stresses, resistance to UV radiation and to temperature changes, cell wall assembly and integrity, degradation of cellular organelles, virulence, cell cell signaling, fungus-plant interaction, and response to damage-associated molecular patterns (DAMPs). Considering the importance of the phylogenetically conserved MAPK pathways in fungi, an updated review of the knowledge on them is discussed in this article. This information reveals their importance, their distribution in fungal species evolutionarily distant and with different lifestyles, their organization and function, and the interactions occurring between different MAPK pathways, and with other signaling pathways, for the regulation of the most complex cellular processes. PMID- 28732780 TI - Corrigendum to "Anonymity and Electronics: Adapting Preparation for Radiology Resident Examination": [Acad Radiol 2017; 24:657-663]. PMID- 28732779 TI - Characterization and phylogenetic analysis of a Cunninghamella bertholletiae isolate from a bottlenose dolphin (Tursiops truncatus). AB - BACKGROUND: Cunninghamella is a genus of the order Mucorales which includes saprophytic species, rarely causing mycoses. The most frequently reported in human mycoses is the thermophilic species Cunninghamella bertholletiae. However, this species does not appear to cause mucormycosis in animals, so there is scarce information about C. bertholletiae isolates from animals. AIMS: In this paper we describe the phenotypic and genotypic characterization, and the phylogenetic analysis, of an isolate of C. bertholletiae involved in a central nervous system mucormycosis in a dolphin. METHODS: The isolate studied in this publication was characterized using the current morphological and physiological identification system for Cunninghamella species. DNA sequencing and analysis of the D1/D2 regions of the 26S rRNA gene and the ITS-5.8S rRNA gene sequences were also performed. RESULTS: Colonies were fast-growing, white at first, although they became tannish-gray, covering the whole plate after 7 days of incubation at 30 and 40 degrees C. Limited growth was observed after 7 days at 45 degrees C. The micromorphology showed characteristic erect sporangiophores. The identification of the isolate was confirmed by DNA sequencing of the D1/D2 regions of the 26S and the ITS-5.8S (ITS) rRNA gene sequencing. CONCLUSIONS: In the phylogenetic study, the isolate clustered in the same clade as C. bertholletiae neotype strain although some differences were observed in the ITS sequences. In the cetacean cases, the possible sources of infection are unclear. The reasons why this pathogen has been found only in cetaceans and not in other domestic or wild animals are at the moment unknown and need further study. PMID- 28732781 TI - Immunoglobulin and B-cell disturbances in patients with chronic idiopathic neutropenia. AB - Chronic idiopathic neutropenia (CIN) is a granulocytic disorder associated with presence of activated, myelosuppressive T-lymphocytes. In the present study we have evaluated constituents of humoral immunity in CIN patients (n=48) compared to healthy controls (n=52). CIN patients displayed lower serum IgG levels due to a reduction in IgG1, IgG3, IgG4 but not IgG2, lower IgA and increased IgM levels compared to controls. The proportion of CD19+ cells did not differ between patients and controls; however the proportion of the naive IgD+/CD27- B-cells was increased and the proportion of class-switched memory IgD-/CD27+ B-cells was decreased in the patients. The percentage of CD40+ B-cells did not differ between patients and controls and no aberrations in the CD40-meadiated signal transduction pathway or in CD40-gene polymorphisms were identified. These data provide further evidence that immune disturbances are associated with the pathophysiology of CIN and point out for the first time the implication of the B cell system. PMID- 28732782 TI - Antimicrobial activity of disinfectants commonly used in the food industry in Mexico. AB - OBJECTIVES: Disinfectants are widely used in food processing environments for microorganism control; their activity can vary according the microorganism and their used in the appropriated concentrations is vital. Hence, the aim of this study was determined the effectiveness and minimum inhibitory concentration (MIC) of 15 disinfectants commonly used in the food industry in Mexico. METHODS: The antimicrobial activity and the MIC were determined according to AOAC and CLSI, respectively, with approved strains. RESULTS: Most disinfectants reduced 99.999% of microorganisms in suspension after 30s of contact, so reduction rate corresponded at least 5 Log10. Only for Pseudomonas aeruginosa ATCC 15442, did all disinfectants have 99.999% effectiveness. For the MIC, only the third generation quaternary ammonium compounds (QACs) in acid medium did not have values within the range in which is used in the food industry for Staphylococcus aureus ATCC 25923. In addition, for all disinfectants the MIC at 5min was two to four times greater than the concentration with the same effect at 10min; moreover, in most cases there was no difference in the MIC at 10 and 15min (p>0.05). CONCLUSIONS: At recommended concentrations, disinfectants had bactericidal activity for at least three of the six microorganisms evaluated. However, the MIC was affected by the exposure time: it was bigger at 5min than at 10min; moreover, in the majority of the cases, it was equal at 10 and 15min; with the results we could have a better understanding of disinfectants use in food processing environments. PMID- 28732783 TI - Future trends in the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infection: An in-depth review of newer antibiotics active against an enduring pathogen. AB - Methicillin-resistant Staphylococcus aureus (MRSA) continues to be a major public health problem. Vancomycin and teicoplanin have been in clinical use for several decades but their drawbacks are well described. In the last 10 years, several antibiotics have been made available for clinical use. Daptomycin and linezolid have been extensively used during this period. Other agents such as ceftaroline, ceftobiprole, dalbavancin, oritavancin, tedizolid and telavancin have been approved by regulatory agencies since 2009. Many others, such as the newer tetracyclines, fluoroquinolones, oxazolidinones and pleuromutilins, are in various stages of development. In addition, an ongoing multicentre trial is investigating the role of combination of vancomycin or daptomycin with beta lactam antibiotics. This review discusses the role of the newer antibiotics, reflecting the views of the 6th MRSA Consensus Conference meeting of the International Society of Chemotherapy MRSA Working Group that took place in 2016. PMID- 28732784 TI - Secondary antibiotic resistance of Helicobacter pylori isolates in Israeli children and adults. AB - BACKGROUND: Failure of standard therapy for Helicobacter pylori infections results primarily from increasing antibiotic resistance. Patients in Israel are referred for H. pylori culture after failure of at least two therapeutic regimens. OBJECTIVES: To estimate the prevalence of secondary antimicrobial resistance of H. pylori in Israel. METHODS: We retrospectively collected results of H. pylori cultures performed by gastric biopsies at Rambam Health Care Campus, Haifa, Israel, between the years 2012-2015. Antimicrobial susceptibility to five drugs was tested by gradient-diffusion. RESULTS: 107 patients, 46 adults and 61 children, were referred for performance of H. pylori cultures. Cultures were positive in 64 samples (63.7%). In adults, 23 (50%) patients had positive H. pylori cultures; 8.69% showed resistance to amoxicillin (AM), 39.1% to clarithromycin (CH), 61.9% to metronidazole (MZ), 8.69% to tetracycline (TC), and 21.7% to levofloxacin (LEV). In children, 41 (67%) patients had positive H. pylori cultures; 5.1% showed resistance to AM, 42.5% to CH, 46.66% to MZ, 2.5% to TC and 0% to LEV. In children, 94.9% of H. pylori strains were susceptible to both AM and LEV. In adults, 82.6% of the strains were susceptible to both AM and TC. 28.6% of adults and 24.1% children were resistant to both MZ and CH. CONCLUSIONS: The sensitivity of H. pylori culture was low. Resistance of H. pylori to MZ and CH was very high after failure of two therapeutic regimens in both adults and children. No LEV resistance was detected in children. AM resistance was higher in adults than in children. PMID- 28732785 TI - Previous antibiotic-related adverse drug reactions do not reduce expectations for antibiotic treatment of upper respiratory tract infections. AB - BACKGROUND: Patients' expectations may influence prescribers' decisions about antibiotic prescribing for upper respiratory tract infection (URTI). We examined whether a history of an antibiotic related adverse drug reaction (aADR) influenced a person's perception about the safety of antibiotics or their expectation of receiving an antibiotic prescription for an URTI. METHODS: We developed a questionnaire and surveyed 103 hospital inpatients, 38 of whom (37%) reported past experience of aADR. RESULTS: Of the 88 participants who reported recent antibiotic use, participants with a history of aADR reported increased perception of harm from their last antibiotic treatment (P<0.05). Overall, 41/103 (40%) participants expected their doctors to prescribe antibiotics to treat an URTI. Participants' perceptions of antibiotic safety or expectation of antibiotic treatment for an URTI did not differ between those who had personal experience of an aADR compared with those with no history of aADR. CONCLUSIONS: The almost universal belief that antibiotics are safe, beneficial medications, even among people with prior aADR, helps to explain the strong patient expectations for antibiotic treatment in a range of conditions. Educational campaigns about the prescription of antibiotics for viral URTI should include information that the risk of harm far outweighs any potential benefits. PMID- 28732786 TI - Antibiotic resistance of bacteria isolated from heavy metal-polluted soils with different land uses. AB - OBJECTIVES: The main objective of this study was to determine the relationship between the antibiotic and heavy metal tolerance of culturable bacteria isolated from mining waste, pasture, and agricultural soils containing different levels of heavy metals. MATERIALS AND METHODS: The populations of total culturable bacteria, and heavy metal- and antibiotic-tolerant bacteria in the soils were enumerated on nutrient agar, nutrient agar amended with metals, and Mueller Hinton agar amended with antibiotics, respectively. The multiple antibiotic resistance index, and patterns of antibiotic resistance and heavy metal antibiotic co-resistance were determined for 237 isolates. RESULTS: Among all the samples, those of the tailings of mines with higher levels of heavy metals had the lowest number of bacteria, but a relatively higher abundance of heavy metal- and antibiotic-resistant bacteria. A high degree of resistance was observed for ampicillin and amoxicillin in the isolates from all soils. The agricultural soil isolates had a high prevalence of resistance towards vancomycin, tetracycline, and streptomycin. Among all the tested antibiotics, gentamicin was the most potent. The most frequent pattern of multiple antibiotic resistance in the isolates from agricultural soils was amoxicillin, ampicillin, streptomycin, vancomycin, tetracycline, and doxycycline. The percentage of isolates with multiple antibiotic resistance was considerably higher in the agricultural soils than in the mining waste soils. A high rate of co-resistance towards Hg and antibiotics was observed among the gram-negative isolates, and towards Zn, Ni, Hg, and the beta-lactam antibiotics among the gram-positive isolates. CONCLUSIONS: The higher percentage of isolates with multiple antibiotic resistance in the agricultural soils that in the mining waste soils may be related to (1) the level of soil heavy metals, (2) the population and diversity of soil bacteria, (3) the application of manures, and (4) other factors affecting gene transfer between bacteria. PMID- 28732787 TI - Molecular characterization and antimicrobial resistance profile of atypical Citrobacter gillenii and Citrobacter sp. isolated from diseased rainbow trout (Oncorhynchus mykiss). AB - AIM: Over the last decade, Citrobacter species have been responsible for infections in fish and many species and also new Citrobacter species have been identified. In this study, molecular identifications and the phenotypic and genotypic antimicrobial-resistance characteristics of atypical and typical Citrobacter species were determined. MATERIALS AND METHODS: Seven Citrobacter isolates were investigated from rainbow trout of different lengths with signs of disease. Biochemical characteristics were determined using conventional tests and rapid test kits; moreover, molecular identifications were conducted with 16S rRNA and the gyrB housekeeping gene region. The sequencing results obtained from the gyrB gene region were deposited in the GenBank database and compared with isolates from different countries that were registered in the database. Resistances to florfenicol, sulfonamides, and tetracycline antimicrobials were determined using the broth micro dilution method, and molecular resistance genes against these antimicrobials were identified. All detected resistance genes were confirmed by sequence analyses. RESULTS: It was determined that three of the Citrobacter species with biochemical characteristics were atypical and showed oxidase-positive reactions. All the Citrobacter species were identified as Citrobacter sp. using the 16S rRNA gene; three isolates were identified as Citrobacter gillenii and four as Citrobacter sp. based on gyrB gene sequence analysis. Some isolates were found in the same group as other countries' isolates in the GenBank database, while isolates with high identities were found in different genogroups. All isolates were found to be phenotypically resistant to sulfamethoxazole and susceptible to tetracycline; these isolates' resistance genes included sulI, tetA, tetB, and tetD. PMID- 28732788 TI - Occurrence and clonal diversity of multidrug-resistant Klebsiella pneumoniae recovered from inanimate surfaces in Algerian hospital environment: First report of armA, qnrB and aac(6')-Ib-cr genes. AB - PURPOSE: The aim of this study is to characterize the molecular support of antibiotic resistance in MDR Klebsiella pneumoniae recovered from inanimate surfaces between March 2012 to February 2014 in three teaching hospitals (Setif, Bejaia and Constantine) in Algeria. RESULTS: Forty-four K. pneumoniae producing ESBL were detected and blaCTX-M-15 and blaCTX-M-3 were detected respectively in 41 and 3 isolates. These K. pneumoniae isolates producing ESBL were also resistant to gentamicin (87%), tobramicin (87%), ciprofloxacin (66%) and ofloxacin (62%). Aminoglycosides resistance genes detected were 16S rRNA methylase (armA), aminoglycoside acetyl-transferase (aac(6')-Ib), aminoglycoside nucleotidyl-transferase (aadA2) and aminoglycoside, phosphoryl-transferase (ant3"Ih-aac(6')-IId). Plasmid-mediated quinolone resistance (PMQR) genes detected were aac(6')-Ib-cr (34 isolates) and qnrB genes in (34 isolates). Multilocus sequence typing (MLST) resulted in 12 different sequence types (STs) regrouped into 5 clonal complexes (CC147, CC17, CC37, CC2 and CC23), one clonal group (CG485) and 4 singletons (ST1426, ST405, ST1308, ST873). CONCLUSION: Here, we report the detection of the ESBLs encoding gene linked with plasmid-mediated quinolone resistance (PMQR) and aminoglycosides resistance recovered from inanimate surfaces in hospital environment. PMID- 28732789 TI - Effect of ceftiofur and enrofloxacin on E. coli sub-population in pig gastrointestinal tract. AB - BACKGROUND: Antibiotic resistant sub-population of the gut microbiome in both human and animals may be enriched during antimicrobial treatment. METHODS: This study investigated how the size and antibiotic susceptibility profiles of antibiotic resistant sub-population organisms in the animal gastrointestinal tract changed upon exposure to different levels of ceftiofur and enrofloxacin by plating fecal samples collected from piglets before and after antibiotic treatment onto MacConkey agar containing 0.5MUg/ml cefotaxime and determination of the resistance rate. Genetic characteristics and relatedness of strains collected before and after treatment was tested to determine if resistant Escherichia coli strains that emerged after treatment was due to dissemination of resistance-encoding mobile elements or clonal expansion of specific strains. RESULTS: Antibiotic resistant organisms constituted a varied but significant proportion of the gut flora regardless of the degree of previous exposure to antibiotics; the proportion of sub-population resistant organisms in the gut flora decreased but remained detectable even 10 days after antibiotic selection pressure had been relieved, and increased again upon renewed exposure to antibiotic regardless of the approach of administration. The increased prevalence of cefotaxime resistant strains in the animal GI tract upon treatment with sub therapeutic and therapeutic concentrations of ceftiofur/enrofloxacin was respectively attributed to transmission of blaCTX-M-borne plasmids and clonal expansion of pre-existing resistant strains. CONCLUSION: The gut flora of animals comprises a high baseline level of resistance, among which resistant organisms cannot be eradicated but instead being further enriched in successive episodes of antibiotic treatment. PMID- 28732790 TI - Performance of the beta LACTATM test for rapid detection of expanded-spectrum cephalosporin-non-susceptible Enterobacteriaceae. AB - OBJECTIVES: The aim of this study was to examine the performance of the chromogenic beta LACTATM test for the rapid detection of expanded-spectrum cephalosporin (ESC) non-susceptibility among Enterobacteriaceae in a region endemic for potent beta-lactamases. METHODS: The beta LACTATM test was applied prospectively on 235 consecutive Enterobacteriaceae clinical isolates and 163 previously characterised ESC-non-susceptible Enterobacteriaceae producing a range of beta-lactamases. RESULTS: The beta LACTATM test exhibited excellent sensitivity (96.1%) and specificity (98.5%) for the detection of ESC non susceptibility in the 235 clinical isolates, which harboured mainly extended spectrum beta-lactamase (ESBL) and KPC- and NDM-type enzymes. Among the 163 challenged archived isolates, some false-negative or uninterpretable results were detected, mostly among ESC-non-susceptible isolates with AmpC/VIM/OXA-48-like enzymes. CONCLUSION: beta LACTATM may be effectively applied in regions where ESC non-susceptibility among Enterobacteriaceae is mainly due to ESBL, KPC or NDM beta-lactamases. PMID- 28732791 TI - Detection of a mecC-positive Staphylococcus saprophyticus from bovine mastitis in Argentina. AB - INTRODUCTION: Bovine mastitis causes important economic losses in the dairy industry. Coagulase-negative staphylococci (CNS) are a group of bacteria commonly isolated from bovine mastitis and can display resistance to a wide range of antimicrobial agents. OBJECTIVES: The objective of this study was to determine staphylococcal resistance towards beta-lactam, macrolide and lincosamide antimicrobials in quarters previously treated with third-generation cephalosporin and after lincosamide intramammary therapy. METHODS: Sick quarters of eighteen cows from Villaguay, Entre Rios (Argentina) with clinical mastitis were studied. All staphylococcal isolates were tested by disk diffusion for their antimicrobial susceptibilities. Cefoxitin resistance was investigated by PCR and sequencing for both the mecA and mecC genes. RESULTS: Resistances to penicillin, oxacillin and cefoxitin were observed, whereas no resistance to macrolide and lincosamide was detected. A cefoxitin-resistant Staphylococcus saprophyticus was found to be mecA negative but mecC-positive. CONCLUSIONS: This study reports for the first time the mecC gene from a CNS in bovine mastitis in South America. Because CNS may act as reservoirs of antimicrobial resistance genes, they can be seen as a potential public health threat with respect to antimicrobial resistance and the development of multiple resistance. Also, the emergence of methicillin-resistant phenotypes will limit therapeutic options. PMID- 28732792 TI - Drug resistance in B and non-B subtypes amongst subjects recently diagnosed as primary/recent or chronic HIV-infected over the period 2013-2016: Impact on susceptibility to first-line strategies including integrase strand-transfer inhibitors. AB - OBJECTIVES: To characterize the prevalence of transmitted drug resistance mutations (TDRMs) by plasma analysis of 750 patients at the time of HIV diagnosis from January 1, 2013 to November 16, 2016 in the Veneto region (Italy), where all drugs included in the recommended first line therapies were prescribed, included integrase strand transfer inhibitors (InNSTI). METHODS: TDRMs were defined according to the Stanford HIV database algorithm. RESULTS: Subtype B was the most prevalent HIV clade (67.3%). A total of 92 patients (12.3%) were expected to be resistant to one drug at least, most with a single class mutation (60/68-88.2% in subtype B infected subjectsand 23/24-95.8% in non-B subjects) and affecting mainly NNRTIs. No significant differences were observed between the prevalence rates of TDRMs involving one or more drugs, except for the presence of E138A quite only in patients with B subtype and other NNRTI in subjects with non-B infection. The diagnosis of primary/recent infection was made in 73 patients (9.7%): they had almost only TDRMs involving a single class. Resistance to InSTI was studied in 484 subjects (53 with primary-recent infection), one patient had 143C in 2016, a total of thirteen 157Q mutations were detected (only one in primary/recent infection). CONCLUSIONS: Only one major InSTI-TDRM was identified but monitoring of TDRMs should continue in the light of continuing presence of NNRTI-related mutation amongst newly diagnosed subjects, sometime impacting also to modern NNRTI drugs recommended in first-line therapy. PMID- 28732793 TI - Characterization of clarithromycin-resistant Helicobacter pylori strains in Iran: A systematic review and meta-analysis. AB - BACKGROUND: The high prevalence of clarithromycin-resistant strains of Helicobacter pylori is a main challenge for the successful treatment of gastrointestinal infections. Point mutations in the 23S rRNA gene are one of the main mechanisms leading to the resistance to clarithromycin in Iran. The purpose of the present review was to evaluate the prevalence of clarithromycin-resistant H. pylori strains in Iran and to identify the major molecular mechanisms of resistance in the resistant isolates. METHODS: Using related keywords and computer search in English and Persian databases (up to November 21, 2016), available data about prevalence of clarithromycin-resistant H. pylori strains and molecular mechanisms of resistance in Iran were retrieved. Relevant articles were selected using pre-defined inclusion and exclusion criteria. RESULTS: The results of the meta-analysis showed that the overall prevalence of clarithromycin resistant H. pylori strains in Iran is 14.7%. The highest and the lowest resistance to clarithromycin were reported from Kashan (33.7%) and Rasht (5.5%), respectively. The most prevalent point mutations in Iran were A2143G (59.1%), A2142G (17.8%), A2142C (8.8%), and A2144G (6.2%), respectively. CONCLUSION: The prevalence of clarithromycin-resistant H. pylori strains was in an acceptable level in our region. Therefore, clarithromycin can be used for the eradication of H. pylori infection in Iran. However, it seems that investigation about the role of other mechanisms involved in the induction of resistance to clarithromycin is needed. PMID- 28732794 TI - Glutamine protects intestinal calcium absorption against oxidative stress and apoptosis. AB - The aim of this study was to investigate whether glutamine (GLN) could block the inhibition of the intestinal Ca2+ absorption caused by menadione (MEN), and elucidate the underlying mechanisms. To do this, one-month old chicks were divided in four groups: 1) controls, 2) MEN treated, 3) GLN treated and 4) GLN treated before or after MEN treatment. Intestinal Ca2+ absorption as well as protein expression of molecules involved in the transcellular Ca2+ pathway were determined. Glutathione (GSH) and superoxide anion and activity of enzymes of the antioxidant system were evaluated. Apoptosis was measured by the TUNEL technique, the expression of FAS and FASL and the caspase-3 activity. A previous dose of 0.5gGLN/kg of b.w. was necessary to show its protector effect and a dose of 1g/kg of b.w. could restore the intestinal Ca2+ absorption after MEN treatment. GLN alone did not modify the protein expression of calbindin D28k and plasma membrane Ca2+-ATPase, but blocked the inhibitory effect of the quinone. GLN avoided changes in the intestinal redox state provoked by MEN such as a decrease in the GSH content, and increases in the superoxide anion and in the SOD and CAT activities. GLN abrogated apoptotic effects caused by MEN in intestinal mucosa, as indicated by the reduction of TUNEL (+) cells and the FAS/FASL/caspase-3 pathway. In conclusion, GLN could be an oral nutritional supplement to normalize the redox state and the proliferation/cell death ratio in the small intestine improving the intestinal Ca2+ absorption altered by oxidative stress. PMID- 28732795 TI - Incidence of cancer in outpatients with chronic obstructive pulmonary disease. AB - INTRODUCTION: The relationship between chronic obstructive pulmonary disease (COPD) and the overall incidence of cancer is poorly understood. The aim of this study was to analyse the incidence of cancer (pulmonary or extrapulmonary) in patients with COPD during follow-up in a specialised outpatient unit, as well as to assess its relationship with the degree of airflow obstruction. METHODOLOGY: A prospective observational study was conducted with a cohort of 308 patients with COPD in pulmonology outpatient follow-up consultations from January 2012 to December 2015. The diagnosed malignancies during this period were divided into pulmonary and extrapulmonary. RESULTS: The overall incidence rate of cancer, lung cancer and extrapulmonary cancer were 10.3, 3.4 and 7.3 cases per 1,000 patients with COPD per year, respectively. The most common cancers were lung cancer (31%), genitourinary tract cancer (29%) and gastrointestinal cancer (21%). Mild-moderate stages (gradeI-II of the 2009 GOLD classification) and the increase in the pack year index (PYI) were related to an increase in the onset of malignancies, with an odds ratio (OR) of 2.16 (95% confidence interval [95% CI]: 1.087-4.309; P=.026) and 1.01 (95% CI: 1.002-1.031; P=.023), respectively. CONCLUSION: The incidence of extrapulmonary cancer in patients with COPD was twice that of lung cancer; stagesI-II of the 2009 GOLD classification and the PYI were significantly related to the onset of malignancies. PMID- 28732796 TI - Transition from paediatric care to adult care for patients with mucopolysaccharidosis. AB - Mucopolysaccharidosis are multisystem diseases that require large multidisciplinary teams for their care. Specific recommendations are therefore needed for the transition from childhood to adulthood in this patient group. To overcome the barriers that might arise during the transition, the authors consider it essential to implement a flexible plan with a coordinator for the entire process, systematising the information through a standardised paediatric discharge report and educating the patient and their family about the disease, showing the characteristics of the healthcare system in this new stage. The final objective is that, once the transition to adulthood has been completed, the patient's autonomy and potential development are maximised and that the patient receives appropriate healthcare during this transition. PMID- 28732798 TI - The effect of antipsychotic medications on acoustic startle latency in schizophrenia. AB - Prepulse inhibition of the acoustic startle reflex (PPI) is extensively studied as a biomarker of schizophrenia (SCZ); however, antipsychotic medication can confound the measure. Latency, the time between the startling stimulus and the reflexive eye blink, provides an index of neural processing speed and is 90% heritable. SCZ subjects have slower latency than controls (CON). This study examined the effects of antipsychotic medication on startle latency. 108 CON and 132 SCZ subjects in three medication subgroups (94 on second-generation antipsychotics (SGA), 25 on first-generation antipsychotics (FGA), 13 unmedicated (NoMed)) were tested on a standard acoustic startle paradigm designed to measure startle magnitude, PPI, and latency. Latency was slower in SCZ compared to CON subjects (p=0.005). Latency did not differ between the three SCZ medication groups. When CON were added to that model, both the NoMed subjects (p=0.04) and the SGA subjects (p=0.003) were slower than CON subjects. For PPI, CON did not differ from SCZ analyzed as a single group. When SCZ subjects were divided into medication groups, PPI was lower in NoMed subjects than the CON group (p=0.03), the SGA group (p=0.02) and the FGA group (p=0.05). SCZ subjects on any medication did not differ from CON. Thus, latency was partially normalized by antipsychotic medication, but this did not obscure the slower latency in SCZ compared to CON. Therefore latency is both trait and state related, whereas medication normalized PPI and obscured any difference between SCZ and CON. PMID- 28732797 TI - Functional convergence of Akt protein with VEGFR-1 in human endothelial progenitor cells exposed to sera from patient with type 2 diabetes mellitus. AB - Diabetes mellitus type 2 predisposes patients to various microvascular complications. In the current experiment, the potent role of diabetes mellitus was investigated on the content of VEGFR-1, -2, Tie-1 and -2, and Akt in human endothelial progenitor cells. The gene expression profile of mTOR and Hedgehog signaling pathways were measured by PCR array. The possible crosstalk between RTKs, mTOR and Hedgehog signaling was also studied by bioinformatic analysis. Endothelial progenitor cells were incubated with serum from normal and diabetic for 7days. Compared to non-treated cells, diabetic serum-induced cell apoptosis (~2-fold) and prohibited cell migration toward bFGF (p<0.001). ELISA analysis showed that diabetes exposed cells had increased abundance of Tie-1, -2 and VEGFR 2 and reduced amount of VEGFR-1 (p<0.0001) in diabetic cells. Western blotting showed a marked reduction in the protein level of Akt after cells exposure to serum from diabetic subjects (p<0.0001). PCR array revealed a significant stimulation of both mTOR and Hedgehog signaling pathways in diabetic cells (p<0.05). According to data from bioinformatic datasets, we showed VEGFR-1, -2 and Tie-2, but not Tie-1, are master regulators of angiogenesis. There is a crosstalk between RTKs and mTOR signaling by involving P62, GABARAPL1, and HTT genes. It seems that physical interaction and co-expression of Akt decreased the level of VEGFR-1 in diabetic cells. Regarding data from the present experiment, diabetic serum contributed to uncontrolled induction of both mTOR and Hedgehog signaling in endothelial progenitor cells. Diabetes mellitus induces mTOR pathway by involving receptor tyrosine kinases while Hedgehog stimulation is independent of these receptors. PMID- 28732799 TI - Monocausal attribution and its relationship with reasoning biases in schizophrenia. AB - BACKGROUND: Aberrant attributional styles are counted to a set of circumscribed cognitive biases that are implicated in the pathogenesis of (paranoid) psychosis. However, evidence for a specific profile (e.g., an exaggerated self-serving bias, other-blaming bias) has become equivocal over the years. More recently, one-sided (monocausal) attributions have been reported in patients with psychosis. METHODS: We compared a large sample of patients with diagnosed schizophrenia (n=145) to nonclinical controls (n=30) on a revised version of the Internal, Personal and Situational Attributions Questionnaire (IPSAQ-R). In this task, participants have to assign probability estimates to each of three potential causes (i.e., myself, others, circumstances) for a specific (negative or positive) event. RESULTS: Participants with schizophrenia displayed an abolished self-serving bias and showed a significant preference for one-sided/monocausal attributions, which was neither correlated with jumping to conclusions nor overconfidence in errors. School education correlated with less monocausal attributions. We did not find any congruence between attributional styles with core delusional ideas. CONCLUSIONS: Our study corroborates earlier investigations showing that monocausal attributions may play a role in the pathogenesis of psychosis; this bias unlikely represents an epiphenomenon of established biases. Unexpectedly, attributional styles (e.g., external-blaming) did not shape delusional contents. The true prevalence of monocausal attributions in psychosis is perhaps underestimated in the study, as groups were equated on school education, which was correlated with monocausal attributions. PMID- 28732800 TI - Histological case-control study of peeling-induced skin changes by different peeling agents in surgically subcutaneous undermined skin flaps in facelift patients. AB - A histological evaluation of peeling-induced skin changes in subcutaneous undermined preauricular facial skin flaps of nine patients was performed. There were three treatment groups: Trichloroacetic acid (TCA) 25%, TCA 40% and phenol/croton oil; one group served as control. Two independent evaluators determined the epidermal and dermal thickness and the depth of necrosis (micrometre). The percentual tissue damage due to the peeling was calculated, and a one-sample t-test for statistical significance was performed. On the basis of the histomorphological changes, peeling depth was classified as superficial, superficial-partial, deep-partial and full thickness chemical burn. The histological results revealed a progression of wound depth for different peeling agents without full thickness necrosis. TCA peels of up to 40% can be safely applied on subcutaneous undermined facial skin flaps without impairing the vascular patency, producing a predictable chemical burn, whereas deep peels such as phenol/croton oil peels should not be applied on subcutaneous undermined skin so as to not produce skin slough or necrosis by impairing vascular patency. PMID- 28732801 TI - Bicarbonate in cystic fibrosis. AB - BACKGROUND: Cystic fibrosis (CF, mucoviscidosis) is caused by mutations in the gene encoding CF transmembrane conductance regulator (CFTR), which is a chloride and bicarbonate channel necessary for fluid secretion and extracellular alkalization. For a long time, research concentrated on abnormal Cl- and Na+ transport, but neglected bicarbonate as a crucial factor in CF. METHODS: The present short review reports early findings as well as recent insights into the role of CFTR for bicarbonate transport and its defects in CF. RESULTS: The available data indicate impaired bicarbonate transport not only in pancreas, intestine, airways, and reproductive organs, but also in salivary glands, sweat duct and renal tubular epithelial cells. Defective bicarbonate transport is closely related to the impaired mucus properties and mucus blocking in secretory organs of CF patients, causing the life threatening lung disease. CONCLUSIONS: Apart from the devastating lung disease, abrogated bicarbonate transport also leads to many other organ dysfunctions, which are outlined in the present review. PMID- 28732802 TI - Carica papaya ameliorates allergic asthma via down regulation of IL-4, IL-5, eotaxin, TNF-alpha, NF-KB, and iNOS levels. AB - BACKGROUND: Natural products have a prime importance as an essential source for new drug discovery. Carica papaya leaves (CPL) have been used to treat inflammation in traditional system of medicine. AIM/HYPOTHESIS: Current study evaluates the anti-inflammatory and immunomodulatory effects of CPL extract using mouse model of ovalbumin- (OVA) induced allergic asthma. METHODS: All the mice were intraperitoneally sensitized and subsequently given intranasal challenge with OVA except the control group. Group-III and -IV were treated for seven consecutive days with CPL extract and methylprednisolone (MP), respectively. At the end of study, histopathological examination of the lungs was performed and inflammatory cell counts were done in blood as well as bronchoalveolar lavage fluid (BALF). The mRNA expression levels of IL-4, IL-5, eotaxin, TNF-alpha, NF KB, and iNOS were measured using reverse transcription polymerase chain reaction (RT-PCR). RESULTS: Results showed significant attenuation of lung infiltration of inflammatory cells, alveolar thickening, and goblet cell hyperplasia after treatment with CPL extract. We also found significant suppression of total and differential leukocyte counts in both blood and BALF samples of CPL extract treated group. CPL extract also alleviated the expression levels of IL-4, IL-5, eotaxin, TNF-alpha, NF-KB, and iNOS. Similarly, treatment with MP, used as a reference drug, also significantly ameliorated all the pro-inflammatory markers. CONCLUSION: Current study shows that CPL extract possesses anti-inflammatory effect in mouse model of allergic airway inflammation by down-regulating IL-4, IL 5, eotaxin, TNF-alpha, NF-KB, and iNOS expression levels. PMID- 28732803 TI - (-)-7(S)-hydroxymatairesinol protects against tumor necrosis factor-alpha mediated inflammation response in endothelial cells by blocking the MAPK/NF kappaB and activating Nrf2/HO-1. AB - BACKGROUND: Endothelial inflammation is an increasingly prevalent condition in the pathogenesis of many cardiovascular diseases. (-)-7(S)-hydroxymatairesinol (7 HMR), a naturally occurring plant lignan, possesses both antioxidant and anti cancer properties and therefore would be a good strategy to suppress tumor necrosis factor-alpha (TNF-alpha)-mediated inflammation in vascular endothelial cells (VECs). PURPOSE: The objective of this study is to evaluate for its anti inflammatory effect on TNF-alpha-stimulated VECs and underling mechanisms. STUDY DESIGN/METHODS: The effect of the 7-HMR on suppression of TNF-alpha-induced inflammation mediators in VECs were determined by qRT-PCR and Western blot. MAPKs and phosphorylation of Akt, HO-1 and NF-kappaB p65 were examined using Western blot. Nuclear localisation of NF-kappaB was also examined using Western blot and immunofluorescence. RESULTS: Here we found that 7-HMR could suppress TNF-alpha induced inflammatory mediators, such as vascularcelladhesion molecule-1, interleukin-6 and inducible nitric oxide synthase expression both in mRNA and protein levels, and concentration-dependently attenuated reactive oxidase species generation. We further identified that 7-HMR remarkably induced superoxide dismutase and heme oxygenase-1 expression associated with degradation of Kelch like ECH-associated protein 1 (keap1) and up-regulated nuclear factor erythroid 2 related factor 2 (Nrf2). In addition, 7-HMR time- and concentration-dependently attenuated TNF-alpha-induced phosphorylation of extracellular signal-regulated kinase 1/2 (ERK) and Akt, but not p38, or c-Jun N-terminal kinase 1/2. Moreover, 7-HMR significantly suppressed TNF-alpha-mediated nuclear factor-kappaB (NF kappaB) activation by inhibiting phosphorylation and nuclear translocation of NF kappaB p65. CONCLUSION: Our results demonstrated that 7-HMR inhibited TNF-alpha stimulated endothelial inflammation, at least in part, through inhibition of NF kappaB activation and upregulation of Nrf2-antioxidant response element signaling pathway, suggesting 7-HMR might be used as a promising vascular protective drug. PMID- 28732804 TI - Interactions of a prenylated flavonoid from Dalea elegans with fluconazole against azole- resistant Candida albicans. AB - BACKGROUND: The prenylated flavonoid 2', 4'-dihydroxy-5'-(1'", 1'"-dimethylallyl) 8-prenylpinocembrin (8PP, formerly 6PP) shows antifungal activity, inhibits rhodamine 6G efflux and reverses fluconazole (FCZ) resistance in azole-resistant Candida albicans overexpressing cdr1, cdr2 and mdr1 transporters. PURPOSE AND DESIGN: In this paper, we tried to characterize 8PP in vitro interactions on the cell growth and lethality of C. albicans. We also initiated preliminary in vivo toxicological studies on mice. METHODS: The effects of 8PP and FCZ on cell growth and viability of C. albicans were evaluated by CLSI guidelines. The checkerboard assay was used to search for interactions on cell growth. The time-kill assay was used to study fungicidal effects. Acute toxicity was evaluated at a single dose schedules. RESULTS: From the checkerboard design, and using a starting inoculum of 103CFU/ml, the fractional inhibitory concentration (FIC) of FCZ and 8PP could be determined as 0.11 and 0.50, respectively, with a FIC index value (FICI) of 0.61. This FICI and the isobologram showing a concave shape suggests an additive interaction between them. At a higher starting inoculum (105CFU/ml), C. albicans growth and viability were decreased by FCZ, 8PP and their combination in a concentration-dependent way. For FCZ, minimum fungicidal concentration (MFC) and FC50 (the concentration that kills 50% of the fungal cells) were 4-fold reduced (280-70uM) in combination with 125uM 8PP. A decrease of 3 log units in viable counts with respect to control was reached (3.65 +/- 1.05 0/00, p< 0.0001). Thus, both fungistatic compounds when combined achieved an almost complete fungicidal effect at lower concentrations respecting of each of them alone. In preliminary toxicological assessment, lethal dose 50% (LD50) for 8PP by the i.p. route was 357 and 245mg/kg, for female and male adult albino mice, respectively. FCZ LD50 was 785 and 650mg/kg for female and male animals, respectively CONCLUSIONS: In vitro results suggest additive interactions between 8PP and FCZ with respect to C. albicans cell growth. Besides killing per se, 8PP helps FCZ to achieve an almost complete fungicidal effect, which would be crucial to eradicate fungal infections. PMID- 28732805 TI - Capillarisin attenuates exercise-induced muscle damage through MAPK and NF-kappaB signaling. AB - BACKGROUND: Intense exercise has the potential to increase oxidative stress and cause muscle damage. Mitogen-activated protein kinases (MAPKs) and nuclear factor kappaB (NF-kappaB) are two major regulators of gene transcription in response to oxidative stress in the skeletal muscle. Pure capillarisin (CAP) isolated from Artemisia capillaris Thunberg is known to have antioxidant and anti-inflammatory effects. HYPOTHESIS/PURPOSE: We hypothesized CAP to exert antioxidant activity against exercise-induced oxidative stress and suppress acute inflammatory response. We aimed to investigate skeletal muscle recovery after intense exercise with or without CAP administration. STUDY DESIGN: Eccentric exercise was conducted to induce muscle damage (C57BL6 mice, 13m/min for 60min downhill running). Mice were divided into four groups (n=6): the rested control, exercised, and exercised with CAP treatments (20mg/kg and 80mg/kg, ip injection 24h prior to exercise) groups. METHOD: After the intense exercise, mice were sacrificed immediately, and after 24h the gastrocnemius muscles and blood plasma were collected for further study. The DCFH-DA and TBARS assays were conducted for anti-oxidative capacity. Muscle damage markers, creatinine phosphate kinase (CPK) and lactate dehydrogenase (LDH) were investigated at plasma level. Muscle data were examined with H&E staining and microscopy. MAPK and NF-kappaB pathway, chemokine and cytokine productions were confirmed by western blotting and RT-PCR. RESULTS: From DCFH-DA and TBARS assays, exercise increased the level of ROS production, but these changes were suppressed by CAP treatment. Exercise induced muscle damage by raising the levels of soluble muscle enzymes, such as CPK and LDH. However, this result was improved in CAP-treated groups at plasma level. Exercise activated MAPK (ERK 1/2 and JNK but not p38) and NF-kappaB (nuclear p50 and p65, and cytosolic p-IkappaBalpha) subunits at protein level but CAP attenuated these increase in a dose dependent manner. At the mRNA level, the chemokines CINC-1 and MCP-1, and cytokine IL-6 in gastrocnemius muscle were increased by exercise, whereas CAP suppressed these increase. CONCLUSION: Overall, our results indicate that CAP, as a single compound, can attenuate muscle damage by exerting antioxidant and anti-inflammatory effects. Thus, CAP is a potential candidate for the muscle protective agent in the future. PMID- 28732806 TI - Artemisia annua dried leaf tablets treated malaria resistant to ACT and i.v. artesunate: Case reports. AB - BACKGROUND: Dried leaf Artemisia annua (DLA) has shown efficacy against Plasmodium sp. in rodent studies and in small clinical trials. Rodent malaria also showed resiliency against the evolution of artemisinin drug resistance. PURPOSE: This is a case report of a last resort treatment of patients with severe malaria who were responding neither to artemisinin combination therapy (ACT) nor i.v. artesunate. STUDY DESIGN: Of many patients treated with ACTs and i.v. artesunate during the 6 mon study period, 18 did not respond and were subsequently treated with DLA Artemisia annua. METHODS: Patients were given a dose of 0.5g DLA per os, twice daily for 5d. Total adult delivered dose of artemisinin was 55mg. Dose was reduced for body weight under 30kg. Clinical symptoms, e.g. fever, coma etc., and parasite levels in thick blood smears were tracked. Patients were declared cured and released from hospital when parasites were microscopically undetectable and clinical symptoms fully subsided. RESULTS: All patients were previously treated with Coartem(r) provided through Sante Rurale (SANRU) and following the regimen prescribed by WHO. Of 18 ACT-resistant severe malaria cases compassionately treated with DLA, all fully recovered. Of the 18, this report details two pediatric cases. CONCLUSIONS: Successful treatment of all 18 ACT-resistant cases suggests that DLA should be rapidly incorporated into the antimalarial regimen for Africa and possibly wherever else ACT resistance has emerged. PMID- 28732807 TI - Pharmacology and toxicology of alpha- and beta-Asarone: A review of preclinical evidence. AB - BACKGROUND: Asarone is one of the most researched phytochemicals and is mainly present in the Acorus species and Guatteria gaumeri Greenman. In preclinical studies, both alpha- and beta-asarone have been reported to have numerous pharmacological activities and at the same time, many studies have also revealed the toxicity of alpha- and beta-asarone. PURPOSE: The purpose of this comprehensive review is to compile and analyze the information related to the pharmacokinetic, pharmacological, and toxicological studies reported on alpha- and beta-asarone using preclinical in vitro and in vivo models. Besides, the molecular targets and mechanism(s) involved in the biological activities of alpha and beta-asarone were discussed. METHODS: Databases including PubMed, ScienceDirect and Google scholar were searched and the literature from the year 1960 to January 2017 was retrieved using keywords such as alpha-asarone, beta asarone, pharmacokinetics, toxicology, pharmacological activities (e.g. depression, anxiety). RESULTS: Based on the data obtained from the literature search, the pharmacokinetic studies of alpha- and beta-asarone revealed that their oral bioavailability in rodents is poor with a short plasma half-life. Moreover, the metabolism of alpha- and beta-asarone occurs mainly through cytochrome-P450 pathways. Besides, both alpha- and/or beta-asarone possess a wide range of pharmacological activities such as antidepressant, antianxiety, anti Alzheimer's, anti-Parkinson's, antiepileptic, anticancer, antihyperlipidemic, antithrombotic, anticholestatic and radioprotective activities through its interaction with multiple molecular targets. Importantly, the toxicological studies revealed that both alpha- and beta-asarone can cause hepatomas and might possess mutagenicity, genotoxicity, and teratogenicity. CONCLUSIONS: Taken together, further preclinical studies are required to confirm the pharmacological properties of alpha-asarone against depression, anxiety, Parkinson's disease, psychosis, drug dependence, pain, inflammation, cholestasis and thrombosis. Besides, the anticancer effect of beta-asarone should be further studied in different types of cancers using in vivo models. Moreover, further dose-dependent in vivo studies are required to confirm the toxicity of alpha- and beta-asarone. Overall, this extensive review provides a detailed information on the preclinical pharmacological and toxicological activities of alpha-and beta-asarone and this could be very useful for researchers who wish to conduct further preclinical studies using alpha- and beta-asarone. PMID- 28732808 TI - Safety evaluation of Astragalus extract mixture HT042 and its constituent herbs in Sprague-Dawley rats. AB - BACKGROUND: Astragalus extract mixture HT042 is a combination of three standardized extracts from Astragalus membranaceus root, Eleutherococcus senticosus stem, and Phlomis umbrosa root, which has proven to stimulate children's height growth. PURPOSE: The aim of this study was to demonstrate the safety of HT042 and its three constituent herbs when administered orally. METHODS: Acute and sub-chronic oral toxicity studies were conducted using male and female Sprague-Dawley rats. In the acute toxicity study, HT042 and each of the herbs was administered at single doses of up to 5000 mg/kg. In the 13-week sub-chronic toxicity study, HT042 was administered at repeated doses of up to 4000 mg/kg/day. RESULTS: In the acute toxicity study of HT042 and each of the herbs, no deaths occurred and there was no indication of toxicity, on the basis of clinical signs, body weight, and necropsy findings. In the sub-chronic toxicity study of HT042, there were no deaths and no changes in clinical signs or the findings of ophthalmic examinations. Although there were some treatment related changes in other findings, these alterations were not considered toxicologically significant because they remained within normal ranges or recovered during the recovery period. CONCLUSION: The oral approximate lethal doses of HT042 and each of the herbs were > 5000 mg/kg, and the no-observed adverse-effect level of HT042 was 4000 mg/kg/day in male and female rats. PMID- 28732809 TI - Oleacein may inhibit destabilization of carotid plaques from hypertensive patients. Impact on high mobility group protein-1. AB - BACKGROUND: In patients with hypertension the haemorrhage into carotid atherosclerotic plaque increases risk of plaque destabilization and rupture. Our previous study showed that oleacein, a secoiridoid present in extra virgin olive oil, enhanced uptake of haemoglobin-haptoglobin complex and change macrophage phenotype from pro-inflammatory M1 to anti-inflammatory M2. PURPOSE: The aim this study was to investigate a potential role of oleacein in attenuation of carotid plaque destabilisation ex vivo. METHODS: Samples of atherosclerotic plaque were harvested from 20 patients with hypertension /11 women and 9 men/, who underwent carotid endarterectomy after transient ischemic attacks. Matching pieces of each plaque were incubated with increased concentration of pure oleacein /range 0-20 uM/ for 24 h. HMGB1, MMP-9, MMP-9/NGAL, TF and IL-10, as well as HO-1 secretion from plaque was measured by enzyme-linked immunosorbent assay /ELISA/. Statistical significance was set at P < 0.05 and P < 0.001. RESULTS: Oleacein at the concentrations of 10 and 20 uM significantly (P < 0.001) decreased secretion of HMGB1 (up 90%), MMP-9 (up to 80%), MMP-9/NGAL complex (up to 80%) and TF (more than 90%) from the treated plaque, as compared to control. At the same time IL-10 and HO-1 release increased by more than 80% (P < 0.001). CONCLUSION: Our results indicate that oleacein possess ability to attenuate the destabilization of carotid plaque and could be potentially useful in the reduction of ischemic stroke risk. PMID- 28732810 TI - The interaction of auraptene and other oxyprenylated phenylpropanoids with glucose transporter type 4. AB - BACKGROUND: Glucose transporter 4 (GLUT4) is firmly established to play a pivotal role in glucose metabolism and in particular in modulating the insulin-stimulated glucose transport in several tissues, such as skeletal muscle and adipose tissue. Stimulation of GLUT4 by insulin results in its translocation to the plasma membrane, activation of several kinases, and finally in a large glucose influx into cells. PURPOSE: In this study we investigated the modulating properties of four biologically active oxyprenylated ferulic acid and umbelliferone derivatives and of their unprenylated parent compounds on GLUT-4 mediated glucose uptake and translocation. METHODS: Oxyprenylated phenylpropanoids have been synthesized in high yields and purity by already reported methodologies. All the synthesized chemicals were tested for their capacity to modulate GLUT4 mediated glucose uptake and GLUT4 translocation in L6 rat skeletal myoblasts in the concentration range 0.1 - 10 uM. Insulin (0.1 uM) was used as positive control. Western blot analysis was employed to assess if GLUT4 translocation occurred prior to increase of glucose uptake. Statistical analyses were carried out by the Dunnett multiple comparison test. RESULTS: 4'-Geranyloxyferulic acid (GOFA), 7 isopentenyloxycoumarin, and auraptene (7-geranyloxycoumarin) increased glucose uptake in a concentration-dependent manner, and significant increases were observed at 0.1 uM for GOFA, and 10 uM for 7-isopentenyloxycoumarin, and auraptene. These products also were able to significantly promote the translocation of GLUT4 to the plasma membrane of L6 myotubes. After treatment with compounds for 15 min, the incorporated amounts of GOFA, 7 isopentenyloxucoumarin, and auraptene were 0.15, 0.32, and 1.77 nmols/60-mm culture dish, respectively. A sample of raw Italian propolis, found to be rich in GOFA and auraptene, was also seen to mimic insulin-effect in the concentration range 0.01 - 1.0 mg/ml. CONCLUSIONS: Among the compounds assayed, auraptene showed to possess potentialities to be a potent activator of both translocation of GLUT4 and glucose influx into skeletal muscle cells with the highest bioavailability among effective compounds. Its capacity to modulate sugar metabolism, coupled to its presence in edible Citrus fruits, can be regarded as an additional reason to account for the already known stimulating properties of some vegetable (e.g. bitter orange). PMID- 28732811 TI - Kaurenoic acid activates TGF-beta signaling. AB - BACKGROUND: Kaurenoic acid (ent-kaur-16-en-19-oic acid: KA) is a key constituent found in the roots of Aralia continentalis Kitagawa (Araliaceae) that has been used for treating rheumatism in traditional Asian medicine. HYPOTHESIS: Although KA was reported to suppress inflammation by activating Nrf2, the anti inflammatory function of KA is less characterized. Given the complex nature of the inflammatory response and the critical role of TGF-beta in resolving inflammation, we hypothesized that KA suppresses inflammatory response by activating TGF-beta signaling. METHODS: Murine macrophage RAW 264.7, human lung epithelial cell MRC-5, and a TGFbetaRII defective cell HCT116 were treated with various amounts of KA. KA was also administered to mouse lung via intratracheal (i.t.) route. Phosphorylated Smad2 and Smad3 were analyzed by western blot. TGFbeta-dependent gene expression was determined by immunoblotting of alpha-SMA and luciferase assay. RESULTS: KA induced the phosphorylation of Smad2 and Smad3, key activator molecules in TGF-beta signaling. EW7197, an inhibitor for activin receptor-like kinase 5/TGF-beta receptor I (TGFbetaR1) suppressed KA-mediated phosphorylation of Smad2. Similarly, KA failed to phosphorylate Smad2 in HCT116, suggesting that KA acts through the prototypic TGFbetaR. KA treatment increased the transcriptional activity driven by a Smad-binding element in a luciferase reporter assay and induced the alpha-smooth muscle actin (alpha-SMA). Similarly, i.t. KA induced the phosphorylation of Smad2 and increased the expression ofalpha SMA in mouse lungs. CONCLUSION: KA activated TGF-beta signaling, suggesting that TGFbeta signaling is associated with KA suppressing inflammation. PMID- 28732812 TI - Extracts and compounds active on TRP ion channels from Waldheimia glabra, a ritual medicinal plant from Himalaya. AB - BACKGROUND: Waldheimia glabra (Decne.) Regel is a wild plant from the Himalayan Mountains, commonly known as Smooth Ground Daisy. This plant is traditionally used by local populations in religious rituals (incense) or in traditional herbal medicine to treat skin diseases, headache, joint pain and fever. In literature few data are available on the investigation of this aromatic plant. PURPOSE: The present work aims at deepening knowledge about the chemical composition of W. glabra extracts and incense, as well as its activity on TRP ion channels. METHODS: Extracts and incense of W. glabra were analyzed by using HS-SPME GC/MS, GC/MS and NMR analysis. Tests on the activity of W. glabra extracts and isolated compounds (+)-ludartin 1 and B-ring-homo-tonghaosu 2 on TRP channels were also performed. RESULTS: Some extracts and pure compounds from W. glabra showed an interesting activity in terms of efficacy and potency on rat TRPA1, an ion channel involved in several sensory mechanisms, including pungency, environmental irritation and pain perception. Activity is discussed and compared with that of other known TRPA1 natural agonists with different chemical structures. All compounds showed only a negligible inhibition activity on rat TRPM8 ion channel. CONCLUSIONS: Our findings demonstrate that W. glabra is involved in the receptor activation mechanism and therefore represents a new natural product potentially useful in pharmaceutical and agrifood research. PMID- 28732813 TI - A randomized, double-blind, placebo- controlled study on the anti-haemostatic effects of Curcuma longa, Angelica sinensis and Panax ginseng. AB - PURPOSE: Herbs with "blood-activating" properties by traditional medicine theory often raise concerns for their possible anti-platelet or anticoagulation effects based on reports from in vitro studies. Such herbs have been implicated for bleeding manifestations based on only anecdotal reports. In particular, the combination of such herbs with anti-platelet agents is often empirically advised against despite lack of good clinical evidence. Here we studied 3 commonly used herbal preparations Curcuma longa, Angelica sinensis and Panax ginseng on their respective anti-platelet and anticoagulation effect, alone and in combination with aspirin. STUDY DESIGN: This is a randomized, double-blind, placebo controlled trial involving 25 healthy volunteers for each herbal preparation. METHODS: Each subject underwent 3 phases comprising of herbal product alone, aspirin alone and aspirin with herbal product, where each phase lasted for 3 weeks with 2 weeks of washout between phases. PT/APTT, platelet function by light transmission aggregometry and thrombin generation assay by calibrated automated thrombogram were measured at baseline and after each phase. Information on adverse reaction including bleeding manifestations was collected after each phase. RESULTS: On the whole there was no clinically relevant impact on platelet and coagulation function. With the exception of 5 of 24 subjects in the Curcuma longa group, 2 of 24 subjects in the Angelica sinensis group and 1 of 23 subjects in the Panax ginseng group who had an inhibition in arachidonic-acid induced platelet aggregation, there was no effect of these 3 herbals products on platelet aggregation by other agonists. Combination of these herbal products with aspirin respectively did not further aggravate platelet inhibition caused by aspirin. None of the herbs impaired PT/APTT or thrombin generation. There was no significant bleeding manifestation. CONCLUSIONS: This study on healthy volunteers provides good evidence on the lack of bleeding risks of Curcuma longa, Angelica sinensis and Panax ginseng either used alone or in combination with aspirin. PMID- 28732814 TI - Bioresorbable scaffolds: in search of event-free dissolution. PMID- 28732815 TI - 2-year outcomes with the Absorb bioresorbable scaffold for treatment of coronary artery disease: a systematic review and meta-analysis of seven randomised trials with an individual patient data substudy. AB - BACKGROUND: Bioresorbable vascular scaffolds (BVS) offer the potential to improve long-term outcomes of percutaneous coronary intervention after their complete bioresorption. Randomised trials have shown non-inferiority between BVS and metallic drug-eluting stents at 1 year in composite safety and effectiveness outcomes, although some increases in rates of target vessel-related myocardial infarction and device thrombosis were identified. Outcomes of BVS following the first year after implantation are unknown. We sought to ascertain whether BVS are as safe and effective as drug-eluting stents within 2 years after implantation and between 1 and 2 years. METHODS: We did a systematic review and meta-analysis of randomised trials in which patients were randomly assigned to everolimus eluting Absorb BVS or metallic everolimus-eluting stents (EES) and followed up for at least 2 years. We searched MEDLINE, the Cochrane database, TCTMD, ClinicalTrials.gov, Clinical Trial Results, CardioSource, and abstracts and presentations from major cardiovascular meetings up to April 1, 2017, to identify relevant studies. The primary efficacy outcome measure was the device-oriented composite endpoint (cardiac mortality, target vessel-related myocardial infarction, or ischaemia-driven target lesion revascularisation) and the primary safety outcome measure was definite or probable device thrombosis. Individual patient data from the four ABSORB trials were used for landmark and subgroup analysis and multivariable modelling. FINDINGS: We identified seven randomised trials in which 5583 patients were randomly assigned to Absorb BVS (n=3261) or metallic EES (n=2322) and followed up for 2 years. BVS had higher 2-year relative risks of the device-oriented composite endpoint than did EES (9.4% [304 of 3217] vs 7.4% [169 of 2299]; relative risk [RR] 1.29 [95% CI 1.08-1.56], p=0.0059). These differences were driven by increased rates of target vessel-related myocardial infarction (5.8% [187 of 3218] vs 3.2% [74 of 2299]; RR 1.68 [95% CI 1.29-2.19], p=0.0003) and ischaemia-driven target lesion revascularisation (5.3% [169 of 3217] vs 3.9% [90 of 2300]; 1.40 [1.09-1.80], p=0.0090) with BVS, with non-significant differences in cardiac mortality. The cumulative 2-year incidence of device thrombosis was higher with BVS than with EES (2.3% [73 of 3187] vs 0.7% [16 of 2281]; RR 3.35 [95% CI 1.96-5.72], p<0.0001). Landmark analysis between 1 and 2 years also showed higher rates of the device-oriented composite endpoint (3.3% [69 of 2100] vs 1.9% [23 of 1193]; RR 1.64 [95% CI 1.03-2.61], p=0.0376) and device thrombosis (0.5% [11 of 2085] vs none [0 of 1183], p<0.0001) in BVS treated patients than in EES-treated patients. INTERPRETATION: BVS was associated with increased rates of composite device-oriented adverse events and device thrombosis cumulatively at 2 years and between 1 and 2 years of follow-up compared with EES. FUNDING: Abbott Vascular. PMID- 28732816 TI - Ending our shame: call for a fundamental reconsideration of Australian refugee policy. PMID- 28732817 TI - Severity and features of frailty in systemic sclerosis-associated interstitial lung disease. AB - BACKGROUND: Systemic sclerosis-associated interstitial lung disease (SSc-ILD) is characterized by multiple symptoms and comorbidities. The cumulative impact of these deficits can be summarized using the concept of frailty; however, frailty has not been characterized in patients with SSc-ILD. METHODS: Patients with SSc ILD and non-CTD fibrotic ILD were recruited from specialized clinics. Frailty was assessed using a 42-item patient-reported Frailty Index, calculated as the proportion of reported deficits divided by the total number of surveyed items. Frailty was defined as a Frailty Index >0.21. Unadjusted and multivariate analyses were used to identify correlates of frailty. RESULTS: The study cohort included 86 patients with SSc-ILD and 167 patients with non-CTD fibrotic ILD. The mean age in SSc-ILD was 60.5 years, 80% were women, and on average patients had mild to moderate restrictive lung function impairment (mean FVC 78%-predicted, DLCO 51%-predicted). The mean Frailty Index was 0.23 +/- 0.15, with 55% of the SSc-ILD population meeting criteria for frailty. Dyspnea had the strongest association with the Frailty Index (r = 0.62, p < 0.001) and was the only variable independently associated with frailty on multivariate analysis. Frailty severity was similar in SSc-ILD and non-CTD fibrotic ILD, including with adjustment for differences in baseline cohort characteristics. CONCLUSION: Frailty is highly prevalent in patients with SSc-ILD, indicating that chronological age significantly underestimates biological age in this population. Dyspnea is the variable with the strongest association with frailty in SSc-ILD; however, future studies are needed to identify additional modifiable determinants of frailty and the ability of frailty to predict outcomes in SSc-ILD. PMID- 28732818 TI - Adherence to COPD treatment: Myth and reality. AB - COPD is a chronic disease in which effective management requires long-term adherence to pharmacotherapies but the level of adhesion to the prescribed medications is very low and this has a negative influence on outcomes. There are several approaches to detect non-adherence, such as pharmacy refill methods, electronic monitoring, and self-report measures, but they are all burdened with important limitations. Medication adherence in COPD is multifactorial and is affected by patients (health beliefs, cognitive abilities, self-efficacy, comorbidities, psychological profile, conscientiousness), physicians (method of administration, dosing regimen, polypharmacy, side effects), and society (patient prescriber relationship, social support, access to medication, device training, follow-up). Patient-health care professional communication, especially that between patient and physician or pharmacist, is central to optimizing patient adherence. However, the most realistic approach is to keep in mind that non adherence is always possible, indeed, probable. PMID- 28732820 TI - The impact of cognitive impairment on self-management in chronic obstructive pulmonary disease: A systematic review. AB - OBJECTIVE: To determine the characteristics of persons with cognitive impairment being able to self-manage in chronic obstructive pulmonary disease (COPD). METHODS: In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidance this systematic review examined all studies in English from 1st January 2000 to 20 February 2016, describing the relationship between cognition and COPD self-management domains in older community dwelling persons with dementia or cognitive impairment. RESULTS: Of 4474 studies identified, thirteen studies were eligible for inclusion. No studies differentiated populations into recognized dementia subtypes. Study aims were variable; most (n = 7) examined inhaler competency alone. Studies identified a link between worsening cognition and the need for assistance in activities of daily living. Only one study evaluated the impact of cognition on overall self management and found no association between cognitive impairment and self-rated self-management. Mild degrees of cognitive impairment were associated with reduced symptom recall. Cognitive impairment in COPD was associated with high degrees of inhaler incompetency. Basic cognitive screening tests were able to predict inhaler incompetence with reduced overall cognitive function, dyspraxia, and/or executive function identified as predictors of incompetency. CONCLUSIONS: Multiple measures of disability consistently demonstrated that cognitive impairment in COPD significantly increased the need for assistance in many aspects of daily living, treatment adherence, and effective self-management. Given the nature of neuropsychological deficits seen in COPD, dedicated screening tools are required. Future research should investigate the impact of cognitive dysfunction in COPD and identify how to support those that lack capacity to self manage. PMID- 28732819 TI - Individual dose adjustment of riociguat in patients with pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. AB - Riociguat is a soluble guanylate cyclase stimulator that has been approved for the treatment of pulmonary arterial hypertension and inoperable chronic thromboembolic pulmonary hypertension or persistent/recurrent pulmonary hypertension following pulmonary endarterectomy. Riociguat is administered using an 8-week individual dose-adjustment scheme whereby a patient initially receives riociguat 1.0 mg three times daily (tid), and the dose is then increased every 2 weeks in the absence of hypotension, indicated by systolic blood pressure measurements and symptoms, up to a maximum dose of 2.5 mg tid. The established riociguat dose-adjustment scheme allows the dose of riociguat to be individually optimized in terms of tolerability and efficacy. The majority of patients in the phase III clinical trials and their long-term extension phases achieved the maximum riociguat dose, whereas some patients remained on lower doses. There is evidence that these patients may experience benefits at riociguat doses lower than 2.5 mg tid, with improvement in exercise capacity being observed after only 2-4 weeks of treatment in the phase III studies and in the exploratory 1.5 mg maximum patient group of PATENT-1. This review aims to provide an overview of the rationale behind the riociguat dose-adjustment scheme and examine its application to both clinical trials and real-life clinical practice. PMID- 28732821 TI - Optimizing inhalation technique using web-based videos in obstructive lung diseases. AB - BACKGROUND: Inhaled agents are widely used in the treatment of chronic airway diseases. Correct technique is required to ensure appropriate drug deposition, but poor technique is common. This study investigated whether inhalation technique could be improved by patient training using short videos from the German Airway League. METHODS: Outpatients from a university hospital respiratory clinic who had incorrect inhalation technique were asked to demonstrate this again immediately after viewing the training videos, and after 4-8 weeks' follow up. Inhalation technique was rated by a study nurse using specific checklists. RESULTS: One hundred and twelve patients with obstructive lung disease treated with inhaled bronchodilators or corticosteroids were included. More than half (51.8%) had at least one mistake in inhalation technique at baseline. Of these, most (88%) understood the training videos, 76% demonstrated correct device use immediately after training, and 72% were still able to demonstrate correct inhalation technique at follow-up (p = 0.0008 for trend). In addition, the number of mistakes decreased significantly after video training (by 1.82 [95% confidence interval 1.39-2.25]; p < 0.0001 vs. baseline). CONCLUSIONS: German Airway League inhalation technique training videos were easy to understand and effectively improved inhalation technique in patients with airway diseases. PMID- 28732822 TI - Atypical coverage in community-acquired pneumonia after outpatient beta-lactam monotherapy. AB - INTRODUCTION: In adults hospitalized with community-acquired pneumonia (CAP) after >48 h of outpatient beta-lactam monotherapy, coverage of atypical pathogens is recommended based on expert opinion. METHODS: In a post-hoc analysis of a large study of CAP treatment we included patients who received beta-lactam monotherapy for >48 h before hospitalization. Length of hospital stay (LOS), 30 day mortality, and number of treatment escalations were compared for those that continued beta-lactam monotherapy and those that received atypical coverage at admission. RESULTS: Of 179 patients (median age 66 years (IQR 50-78), 100 (56%) male), 131 (73%) received additional atypical coverage at admission. These patients were younger, had less comorbidities, and longer symptom duration, compared to those that continued beta-lactam monotherapy. In crude analysis, median (IQR) LOS was 6 (4-8) and 6 (4-9) days, mortality was 2% and 4%, and treatment escalations occurred in 8 (17%) and 11 (8%) patients without and with atypical coverage, respectively. Adjusted effect ratios for absence of atypical coverage on LOS, mortality, and treatment escalation were 0.77 (95% CI 0.61 0.97), 0.37 (0.04-3.67), and 2.75 (0.94-8.09), respectively. CONCLUSION: In adults hospitalized with CAP after >48 h of outpatient beta-lactam monotherapy, not starting antibiotics with atypical coverage was associated with a trend towards more treatment escalations, without evidence of increased LOS or mortality. PMID- 28732823 TI - Correlation of pulmonary function and usual interstitial pneumonia computed tomography patterns in idiopathic pulmonary fibrosis. AB - BACKGROUND: Little is known about presenting 'inconsistent' or 'possible' usual interstitial pneumonia (UIP) computed tomography (CT) patterns advancing to 'consistent' UIP as disease progresses in idiopathic pulmonary fibrosis (IPF). We hypothesized that if 'consistent' UIP represented more advanced disease, such a pattern on presentation should also correlate with more severe pulmonary function test (PFT) abnormalities. MATERIAL AND METHODS: Consecutive IPF patients (2005 2013) diagnosed by international criteria with baseline PFT and CT were included. Presenting CTs were assessed by three expert radiologists for consensus UIP pattern ('consistent', 'possible', and 'inconsistent'). Approximation of individual and combined interstitial abnormalities was also performed with correlation of interstitial abnormalities and UIP CT pattern made with PFT findings and survival. RESULTS: Three-hundred and fifty patients (70% male) were included with a mean age of 68.3 years. Mean percent predicted forced vital capacity (FVC%) and diffusion capacity (DLCO%) was 64% and 45.5% respectively. Older age and male gender correlated more with 'consistent' UIP CT pattern. FVC% was not associated with any UIP pattern but did correlate with total volume of radiologist assessed interstitial abnormalities. DLCO% was lower in those with 'consistent' UIP pattern. A 'consistent' UIP CT pattern was also not independently predictive of survival after correction for age, gender, FVC%, and DLCO%. CONCLUSION: PFT findings appear to correlate with extent of radiologic disease but not specific morphologic patterns. Whether such UIP patterns represent different stages of disease severity or radiologic progression is not supported by coinciding pulmonary function decline. PMID- 28732824 TI - A clinicopathological study of surgically resected lung cancer in patients with usual interstitial pneumonia. AB - BACKGROUND: The clinicopathological characteristics of lung cancer with concomitant usual interstitial pneumonia (UIP) are insufficiently understood. This study aimed to elucidate a characteristic pathological feature of lung cancer that develops in patients with UIP, with a focus on the location of its onset. METHODS: We reviewed surgically obtained specimens, including 547 tumors from 526 patients who underwent lobectomy for lung cancer. Surveyed patients were classified into three groups: patients with UIP (UIP group), patients with lung pathology other than UIP (non-UIP group), and patients without any associated lung pathology (normal group). The histology as well as the lobe and location of the onset of lung cancer were compared among these groups. The peripheral location was subdivided into subpleural, inner and tumor involved centrally secondary to extension. RESULTS: The UIP group comprised 82 patients (male, 71 [87%]; mean age, 71 years; smoking rate, 94%), the non-UIP group comprised 334 patients (male, 267 [80%]; mean age, 69 years; smoking rate, 81%), and the normal group comprised 110 patients (male, 33 [30%]; mean age, 63; smoking rate, 29%). No statistical differences were noted in sex, mean age, or smoking index between the UIP and non-UIP groups. Compared with the non-UIP group, the frequency of squamous cell carcinoma (63% vs. 32%), lower lobe origin (76% vs. 32%), and subpleural location (24% vs. 5%) were significantly higher in the UIP group. CONCLUSIONS: Lung cancers in patients with UIP show a predilection for the subpleural region, where UIP is also thought to originate. PMID- 28732826 TI - Corrigendum to "A multicenter, randomized, double-blind dose-ranging study of glycopyrrolate/formoterol fumarate fixed-dose combination metered dose inhaler compared to the monocomponents and open-label tiotropium dry powder inhaler in patients with moderate-to-severe COPD" [Respir. Med. 120 November 2016 16-24]. PMID- 28732825 TI - Heterogeneity of lung disease associated with NK2 homeobox 1 mutations. AB - We retrospectively studied the clinical presentation, treatment modalities and outcome in 16 patients with heterozygous NKX2-1 mutation associated with chronic lung disease. Twelve different NKX2-1 mutations, including 4 novel mutations, were identified in the 16 patients. Nine patients presented with brain-lung thyroid syndrome, 3 had neurological and lung symptoms and 4 had only pulmonary symptoms. Ten patients had neonatal respiratory distress, and 6 of them developed infiltrative lung disease (ILD). The other patients were diagnosed with ILD in childhood (n = 3) or in adulthood (n = 3). The median age at diagnosis was 36 months (IQ 3.5-95). Patient testing included HRCT (n = 13), BALF analysis (n = 6), lung biopsies (n = 3) and lung function tests (n = 6). Six patients required supplemental oxygen support with a median duration of 18 months (IQ 2.5-29). All symptomatic ILD patients (n = 12) benefited from a treatment consisting of steroids, azithromycin (n = 9), and/or hydroxychloroquine (n = 4). The median follow-up was 36 months (IQ 24-71.5). One patient died of respiratory failure at 18 months and another is waiting for lung transplantation. In summary, the initial diagnosis was based on clinical presentation and radiological features, but the presentation was heterogeneous. Definitive diagnosis required genetic analysis, which should be performed, even in absence of neurological or thyroid symptoms. PMID- 28732827 TI - The variability of respiratory symptoms and associated factors in COPD. AB - Few studies have investigated the variability of COPD-related symptoms or factors related to symptom variability. This observational, prospective, multicentre study was conducted to describe the number and intensity of morning and night time respiratory symptoms and their variability over one week using the Night time and Early Morning Symptoms of COPD Instruments (NiSCI and EMSCI) to evaluate stable COPD patients. Logistic regression analyses were performed to investigate factors associated with symptom variability. A total of 2669 patients were evaluated (mean age, 67.7 years; 80.9% men; mean FEV1 50.6%). Of these, 48% reported night-time symptoms and 71% reported morning symptoms. Of the 2293 patients who completed the NiSCI and EMSCI, 90% showed variability in either symptom number (89.6%) or symptom intensity (15.8%). More severe dyspnoea, more exacerbations during the previous year and the exacerbator or mixed COPD-asthma phenotypes were associated with variability in symptom number or intensity. Anxiety was significantly associated with variability in symptom number and intensity. Most COPD patients showed symptom variability over a weeklong period, especially in terms of symptom number. Several COPD-related factors, mainly factors related to more severe disease and more frequent exacerbations, were associated with increased symptom variability. PMID- 28732828 TI - Diagnostic implications of positive avian serology in suspected hypersensitivity pneumonitis. AB - BACKGROUND: The diagnostic evaluation of patients with interstitial lung disease (ILD) often involves serologic assessment for identifiable causes such as hypersensitivity pneumonitis (HP). While not on its own defining of HP, precipitin serologies are often obtained to support clinical suspicion if other findings are inconclusive. We studied the clinical relevance of positive avian serology in patients undergoing ILD evaluation. MATERIAL AND METHODS: We identified individuals with positive avian serology (>53.3 mg/L) and undifferentiated ILD seen at our institution over a three-year period. Clinical, laboratory, pathologic, and radiologic findings were evaluated for consensus HP diagnosis by two expert pulmonologists, blinded to presenting serology levels. RESULTS: Ninety-one ILD subjects with positive avian serology were identified; mean age was 62.7 +/- 15.3 years with a slight male predominance (56%). Forty nine (54%) received a consensus HP diagnosis. Those with HP had higher mean avian serology titer (95.0 +/- 38.7 mg/L vs. 68.3 +/- 16.7, (P < 0.0001). Never-smokers also had higher titers compared to prior or active smokers (P = 0.0008). Positive avian protein exposure (P < 0.0001, OR 21.3 (6.4-87)), DLCO% (P = 0.04, unit OR 0.96 (0.92-0.99)), and increasing serology titer (P < 0.015, unit OR 1.03 [1.01 1.06]) were independent predictors of HP diagnosis. CONCLUSION: Among patients with positive avian serology, those with higher titers were more likely to have HP diagnosis. Nonsmokers also manifested higher titers compared to those with smoking history. These results may guide the usage and interpretation of avian serology screening in the initial assessment of suspected HP. PMID- 28732829 TI - Budesonide + formoterol delivered via Spiromax(r) for the management of asthma and COPD: The potential impact on unscheduled healthcare costs of improving inhalation technique compared with Turbuhaler(r). AB - BACKGROUND: Fixed-dose combinations of inhaled corticosteroids and long-acting beta2 agonists are commonly used for the treatment of asthma and COPD. However, the most frequently prescribed dry powder inhaler delivering this medicine - Symbicort(r) (budesonide and formoterol, BF) Turbuhaler(r) - is associated with poor inhalation technique, which can lead to poor disease control and high disease management costs. A recent study showed that patients make fewer inhaler errors when using the novel DuoResp(r) (BF) Spiromax(r) inhaler, compared with BF Turbuhaler(r). Therefore switching patients from BF Turbuhaler(r) to BF Spiromax(r) could improve inhalation technique, and potentially lead to better disease control and healthcare cost savings. METHODS: A model was developed to estimate the budget impact of reducing poor inhalation technique by switching asthma and COPD patients from BF Turbuhaler(r) to BF Spiromax(r) over three years in Germany, Italy, Sweden and the UK. The model estimated changes to the number, and associated cost, of unscheduled healthcare events. The model considered two scenarios: in Scenario 1, all patients were immediately switched from BF Turbuhaler(r) to BF Spiromax(r); in Scenario 2, 4%, 8% and 12% of patients were switched in years 1, 2 and 3 of the model, respectively. RESULTS: In Scenario 1, per patient cost savings amounted to ?60.10, ?49.67, ?94.14 and ?38.20 in Germany, Italy, Sweden and the UK, respectively. Total cost savings in each country were ?100.86 million, ?19.42 million, ?36.65 million and ?15.44 million over three years, respectively, with an estimated 597,754, 151,480, 228,986 and 122,368 healthcare events avoided. In Scenario 2, cost savings totalled ?8.07 million, ?1.55 million, ?2.93 million and ?1.23 million over three years, respectively, with 47,850, 12,118, 18,319, and 9789 healthcare events avoided. Savings per patient were ?4.81, ?3.97, ?7.53 and ?3.06. CONCLUSIONS: We demonstrated that reductions in poor inhalation technique by switching patients from BF Turbuhaler(r) to BF Spiromax(r) are likely to improve patients' disease control and generate considerable cost savings through healthcare events avoided. PMID- 28732830 TI - Impact of LABA/LAMA combination on exercise endurance and lung hyperinflation in COPD: A pair-wise and network meta-analysis. AB - BACKGROUND: The ability to exercise is an important clinical outcome in COPD, and the improvement in exercise capacity is recognized to be an important goal in the management of COPD. Therefore, since the current interest in the use of bronchodilators in COPD is gradually shifting towards the dual bronchodilation, we carried out a meta-analysis to evaluate the impact of LABA/LAMA combination on exercise capacity and lung hyperinflation in COPD. METHODS: RCTs were identified after a search in different databases of published and unpublished trials. The aim of this study was to assess the influence of LABA/LAMA combinations on endurance time (ET) and inspiratory capacity (IC), vs. monocomponents. RESULTS: Eight RCTs including 1632 COPD patients were meta-analysed. LABA/LAMA combinations were significantly (P < 0.05) more effective than the LABA or LAMA alone in terms of the improvement in ET (+43 s and +22 s, respectively) and IC (+107 ml and +87 ml, respectively). LABA/LAMA combinations showed the highest probability of being the best therapy with regard of both ET and IC (100% and 100%, respectively), followed by LAMA (66% and 64%, respectively) and LABA (32% and 36%, respectively), as indicated by the analysis of surface under the cumulative ranking curve (SUCRA). No publication bias was detected in this meta analysis. CONCLUSIONS: This meta-analysis clearly demonstrates that if the goal of the therapy is to enhance exercise capacity in patients with COPD, LABA/LAMA combinations consistently meet the putative clinically meaningful differences for both ET and IC and, in this respect, are superior to their monocomponents. PMID- 28732831 TI - Initiating or changing to a fixed-dose combination of Fluticasone propionate/Formoterol over Fluticasone propionate/Salmeterol: A real-life effectiveness and cost impact evaluation. AB - OBJECTIVE: Asthma has a substantial impact on quality of life and health care resources. The identification of a more cost-effective, yet equally efficacious, treatment could positively influence the economic burden of this disease. Fluticasone propionate/Formoterol (FP/FOR) may be as effective as Fluticasone Salmeterol (FP/SAL). We evaluated non-inferiority of asthma control in terms of the proportion of patients free from exacerbations, and conducted a cost impact analysis. METHODS: This historical, matched cohort database study evaluated two treatment groups in the Optimum Patient Care Research Database in the UK: 1) an FP/FOR cohort of patients initiating treatment with FP/FOR or changing from FP/SAL to FP/FOR and; 2) an FP/SAL cohort comprising patients initiating, or remaining on FP/SAL pMDI combination therapy. The main outcome evaluated non inferiority of effectiveness (defined as prevention of severe exacerbations, lower limit of the 95% confidence interval (CI) of the mean difference between groups in patient proportions with no exacerbations is -3.5% or higher) in patients treated with FP/FOR versus FP/SAL. RESULTS: After matching 1:3, we studied a total of 2472 patients: 618 in the FP/FOR cohort (174 patients initiated on FP/FOR and 444 patients changed to FP/FOR) and 1854 in the FP/SAL cohort (522 patients initiated FP/SAL and 1332 continued FP/SAL). The percentage of patients prescribed FP/FOR met non-inferiority as the adjusted mean difference in proportion of no severe exacerbations (95%CI) was 0.008 (-0.032, 0.047) between the two cohorts. No other significant differences were observed except acute respiratory event rates, which were lower for patients prescribed FP/FOR (rate ratio [RR] 0.82, 95% CI 0.71, 0.94). CONCLUSIONS: Changing to, or initiating FP/FOR combination therapy, is associated with a non-inferior proportion of patients who are severe exacerbation-free at a lower average annual cost compared with continuing or initiating treatment with FP/SAL. PMID- 28732832 TI - Current approaches to the management of idiopathic pulmonary fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal lung disease associated with dyspnoea, cough and impaired quality of life. Currently, the aims of patient care are to improve outcomes for patients by slowing the progression of the disease, extending life, and improving quality of life. A prompt, accurate diagnosis is important to enable patients to receive treatment early in the course of the disease and to be considered for lung transplantation. Two anti-fibrotic drugs, nintedanib and pirfenidone, have been shown to reduce decline in lung function in patients with IPF. In addition to pharmacological therapy, optimal management of IPF includes treatment of comorbidities, symptom relief, pulmonary rehabilitation, and palliative care. Patient education is important to enable patients to make decisions about their care and to help them manage their disease and the side-effects of anti-fibrotic drugs. Research continues into new treatments and combinations of treatments that may improve outcomes for patients with this devastating disease. PMID- 28732833 TI - The multiple dimensions of Platypnea-Orthodeoxia syndrome: A review. AB - Platypnea-Orthodeoxia syndrome (POS) is a rare clinical entity characterized by dyspnea and arterial desaturation while in the upright position. The various pathophysiologic mechanisms leading to POS has puzzled clinicians for years. The hypoxia in POS has been attributed to the mixing of the deoxygenated venous blood with the oxygenated arterial blood via a shunt. The primary mechanisms of POS in these patients can be broadly classified based on intracardiac abnormalities, extracardiac abnormalities and miscellaneous etiologies. A Patent Foramen Ovale (PFO) was the most common reported site of an intracardiac shunt. In addition to PFO, intracardiac shunt leading to POS has been reported from either an Atrial Septal Defect (ASD) or an Atrial Septal Aneurysm (ASA). Most patients with an intracardiac shunt also demonstrated a secondary anatomic or a functional defect. Extracardiac causes of POS included intra-pulmonary arteriovenous malformations and lung parenchymal diseases. A systematic evaluation is necessary to identify the underlying cause and institute an appropriate intervention. We conducted a review of literature and reviewed 239 cases of POS. In this article, we review the etiology and pathophysiology of POS and also summarize the diagnostic algorithms and treatment modalities available for early diagnosis and prompt treatment of patients presenting with symptoms of platypnea and/or orthodeoxia. PMID- 28732834 TI - Patient-perceived acceptability and behaviour change benefits of inhaler reminders and adherence feedback: A qualitative study. AB - INTRODUCTION: Little is known about patients' perceptions of electronic inhaler reminders, which have emerged in recent years as adherence promotion aids. This study explored asthma patients' attitudes toward the acceptability and utility of inhaler reminders. METHODS: Participants from a 6-month cluster randomized controlled trial who received reminders for missed doses via SmartTrack adherence monitors (Adherium Ltd) were interviewed to explore their perceptions; interviews were audio-recorded, transcribed and analysed thematically. RESULTS: 18 participants (50% male, mean age 39 years [range 17-68]) were interviewed. Three themes were identified. Acceptability and Feasibility: Interviewees found the monitor easy to use. For some, concerns about the monitor itself affected adherence, e.g. leaving it at home to avoid breakage. Positive features included that reminders played only for missed doses, and the choice of reminder tunes. Utility and Behavioural Impact: Interviewees described reminders as an effective "training" tool for adherence, encouraging habit-formation, behaviour change and attitude change. Reminders were considered less acceptable or useful by participants who preferred taking medication only when symptomatic or who doubted the necessity or safety of their medication. Sustainability: Some interviewees reported sustained behaviour change, supported by reminders, through the establishment of routine or via experiential learning that good adherence improved their asthma. Other interviewees wanted ongoing support (i.e. reminders or substitute adherence cues) after study end. CONCLUSION: Patients with asthma found 6-months' use of reminders and adherence feedback acceptable and useful for improving their adherence attitudes, adherence behaviours and confidence in asthma self-management. Some patients may benefit from ongoing adherence support. PMID- 28732835 TI - Idiopathic pulmonary fibrosis: Clinical behavior and aging associated comorbidities. AB - Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible and usually lethal lung disease of unknown etiology. Once considered as a relatively homogeneous, slowly progressive disease, is now recognized that the clinical behavior shows substantial heterogeneity, including an accelerated variant, and the presence of acute exacerbations. In addition, since IPF largely affects individuals over 60 years of age, the patients are at increased risk of several comorbidities that in turn have a remarkable clinical impact on the disease and increases mortality rate. Among others, combined pulmonary fibrosis and emphysema, secondary pulmonary arterial hypertension, lung cancer, and cardiovascular diseases are frequently associated with IPF and impact survival. For these reasons clinical phenotypes and comorbidities should be timely identified and managed. The aim of this review is to describe the common pulmonary and extra-pulmonary comorbidities in IPF, as well as the putative mechanisms involved. PMID- 28732837 TI - Immune diffuse alveolar hemorrhage: Clinical presentation and outcome. AB - BACKGROUND: Diffuse alveolar haemorrhage (DAH) is a manifestation of several immune and nonimmune diseases. OBJECTIVE: The objective of this study was to characterize the clinical characteristics and short-term outcomes of patients with immune-mediated DAH requiring hospital admission. METHODS: A retrospective study from December 2010 to December 2015, was conducted by analyzing the clinical records of 39 patients with DAH with a proven immunological origin. The diagnosis of individual collagen vascular diseases (CVD) was made according to the criteria of the corresponding societies. RESULTS: Thirty-nine patients were included (median age 44.8 years, range 16-76). The main causes of DAH were ANCA related vasculitis (74.3%) mainly granulomatosis with polyangiitis (n = 14) and microscopic polyangiitis (n = 13). Thirty patients (76.9%) had hemoptysis. An alveolar airspace filling pattern was found in most of patients (59%). All the patients had a drop in hemoglobin level that ranged from 1.0 to 3.0 g/dL. BAL fluid was macroscopically bloody in 43.6% of patients (n = 17) and showed siderophagic alveolitis on BAL cytology in 100%. All patients received high doses of corticosteroids. Other additional treatments were antibiotics (53,8%, n = 21), intravenous cyclophosphamide (87.2%, n = 34), plasma exchange (35.9%, n = 14); intravenous immunoglobulin (12.8%, n = 5) and rituximab in 5 patients (12.8%). Mortality rate was higher amongst patients who required dialysis (50.0 vs 15.4%, p = 0.045), with SaO2 <90% at admission (50.0 vs 5.3%, p = 0.003) or those who required mechanical ventilation (76.9 vs 6.8%, p = < 0.001). CONCLUSION: DAH may present without hemoptysis and requires an early bronchoscopy to confirm the diagnosis and exclude infection. Other characteristics could be included in the abstract which are relevant to the paper. (relation between mortality, dialysis, ventilation, etc.). PMID- 28732836 TI - Adherence and healthcare utilization among older adults with COPD and depression. AB - BACKGROUND AND OBJECTIVE: Adherence to chronic obstructive pulmonary disease (COPD) maintenance medications and antidepressants may reduce healthcare utilization among multimorbid individuals with COPD and depression. We quantified the independent effects of adherence to antidepressants and COPD maintenance medications on healthcare utilization among individuals co-diagnosed with COPD and depression. PROCEDURES: We conducted a retrospective cohort study using a 2006-2012 5% random sample of Medicare beneficiaries co-diagnosed with COPD and depression who had two or more prescription fills of both COPD maintenance medications and antidepressants. We measured adherence to medications using the proportion of days covered per 30-day period. The primary outcomes were all-cause emergency department (ED) visits and hospitalizations. Beneficiaries were followed over a minimum 12-month follow-up period. RESULTS: Of the 16,075 beneficiaries meeting inclusion criteria, 21% achieved adherence >=80% to COPD maintenance medications and 55% achieved adherence >=80% to antidepressants. Compared to no use and controlling for antidepressant adherence and potential confounders, higher (>=80%) levels of adherence to COPD maintenance medications were associated with decreased risk of ED visits (hazard ratio (HR) 0.79; 95% CI 0.74, 0.83) and hospitalizations (HR 0.82; 95% CI 0.78, 0.87). Similarly, higher levels (>=80%) of adherence to antidepressants resulted in decreased risk of ED visits (HR 0.74; 95% CI 0.70, 0.78) and hospitalizations (HR 0.77; 95% CI 0.73, 0.81) compared to no use. CONCLUSIONS: Clinicians can assist in the improved management of their multimorbid patients' health by treating depression among patients with COPD and monitoring and encouraging adherence to the regimens they prescribe. PMID- 28732838 TI - Causes of misdiagnosis of chronic obstructive pulmonary disease: A systematic scoping review. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) has serious implications at both the individual and the societal level. It is crucial that COPD is diagnosed correctly to ensure provision of the right treatment. However, the current diagnostic procedures may lead to misdiagnosis. AIM: The aim of this scoping review was to disseminate knowledge about potential causes of misdiagnosis of COPD. METHODS: A systematic, comprehensive search was performed in PubMed, Embase and Cinahl. RESULTS: A thorough review produced a sample of 73 articles. The synthesis revealed five potential causes of misdiagnosis of COPD, including: the threshold for defining COPD (n = 36), errors made in primary care (n = 15), errors linked to the spirometry test (n = 13), differential diagnoses (n = 10), and patient-related factors (n = 8). CONCLUSIONS: The causes of misdiagnosis of COPD are attributable mainly to spirometry and to the healthcare professional performing the diagnostic assessment. With a view to limiting misdiagnosis of COPD, future research should help clarify strategies for alternative objective tests for determining if a patient has COPD and explore how to better support primary care in the diagnosing of COPD. PMID- 28732839 TI - Exacerbations and duration of smoking abstinence are associated with the annual loss of FEV1 in individuals with PiZZ alpha-1-antitrypsin deficiency. AB - BACKGROUND: Alpha-1-antitrypsin deficiency (AATD) is a genetic disorder that is associated with a higher risk of chronic obstructive pulmonary disease (COPD) and emphysema. The annual declines in lung function (FEV1) and transfer factor of the lung for carbon monoxide (TLCO) predict all-cause mortality. MATERIAL AND METHODS: We investigated the longitudinal follow-up data over 11 years (mean follow-up period of 4.89 years) from the German AATD registry and analyzed the relationship between annual loss of FEV1 and TLCO and sex, age, body mass index (BMI), nicotine consumption, occupational dust exposure, St. George's Respiratory Questionnaire (SGRQ) score, baseline FEV1 or TLCO, alpha-1-antitrypsin (AAT) serum level, exacerbation frequency and the duration of smoking abstinence by multiple linear generalized estimating equations models (GEE-models). RESULTS: We evaluated the data of 100 individuals with post-bronchodilator FEV1 measurements and from 116 individuals with TLCO measurements. The mean overall decline was 54.06 +/- 164.62 ml/year in FEV1 and -0.17 +/- 0.70 mmol/min/kPa/year in TLCO. Accelerated deterioration of FEV1 was associated with occupational dust exposure (p = 0.026), shorter duration of smoking abstinence (p = 0.008), higher baseline FEV1 (p = 0.003), higher annual exacerbation frequency (p = 0.003) and higher frequency of glucocorticoids intake (p = 0.004). Furthermore, patients with an elevated decline in TLCO showed significant impaired health-related quality of life at baseline (p = 0.039) and lower AAT serum levels (p < 0.001) in multivariate analysis. CONCLUSIONS: Annual decline in FEV1 is related to the exacerbation rate, occupational dust exposure and the duration of smoking abstinence. PMID- 28732840 TI - Characteristics of asthmatics with detectable IL-32gamma in induced sputum. AB - BACKGROUND: Interleukin-32(IL-32)gamma is a pro-inflammatory cytokine involved in the development and severity of chronic inflammatory diseases, but its role in asthma is unclear. OBJECTIVE: This study was conducted to evaluate the relationship of IL-32gamma levels in sputum with the severity of asthma. METHODS: IL-32gamma levels in the supernatant of induced sputum obtained from 89 patients with stable asthma were measured using a sandwich enzyme-linked immunosorbent assay (ELISA). The relationships between sputum IL-32gamma levels and baseline forced expiratory volume in 1 s (FEV1% pred.), inflammatory cell profiles in sputum, and annual frequency of asthma exacerbation were determined. RESULTS: IL 32gamma was detected in the sputum of 25 of 89 (28.1%) asthma patients, and the levels of sputum were negatively correlated with FEV1% pred. (rho = -0.312, p = 0.003). The annual exacerbation rate was significantly higher in this group than in the IL-32-negative group (n = 64) (p = 0.03). Sputum IL-32gamma levels correlated well with the annual exacerbation rate (rho = 0.261, p = 0.014), but there were no differences in the inflammatory cell profiles in the induced sputum of IL-32-positive and IL-32-negative patients. CONCLUSION: The level of IL 32gamma in induced sputum may be associated with asthma severity and related with higher risk of asthma exacerbation. PMID- 28732841 TI - Cobalt related interstitial lung disease. AB - Cobalt exposure in the hard metal and bonded diamond tool industry is a well established cause of ILD. The primary theories regarding the underlying mechanism of cobalt related ILD include an immunologic mechanism and an oxidant injury mechanism. Cobalt related ILD may present in subacute and chronic forms and often has associated upper respiratory symptoms. The evaluation begins with a thorough occupational history and includes PFTs, HRCT, and bronchoalveolar lavage. HRCT findings are nonspecific and may resemble NSIP, UIP, sarcoidosis, or HP. The finding of cannibalistic multinucleated giant cells is diagnostic provided there is a history of exposure and appropriate changes on imaging; however, when these cells are not found on lavage, lung biopsy is required for diagnosis. Giant cell interstitial pneumonia is the classic pathologic pattern, but cobalt related ILD may also present with pathologic findings of UIP, DIP, or HP. When cobalt related ILD is suspected, removal from exposure is the most important step in treatment. Case reports suggest that treatment with steroids results in symptomatic, physiologic, and radiographic improvement. PMID- 28732842 TI - Misuse and/or treatment delivery failure of inhalers among patients with asthma or COPD: A review and recommendations for the conduct of future research. AB - BACKGROUND: Asthma and chronic obstructive pulmonary disease (COPD) are widespread chronic conditions with medication frequently delivered by inhalers. These can be challenging to use correctly, but the scale of misuse and the specific aspects of failure are unclear. METHODS: We used systematic review methods to search 9 databases in May 2015 to identify and review studies that assessed adults (18 years or older) with asthma or COPD using inhalers of various types including pressurised metered dose inhalers (pMDIs), dry powder inhalers and the Respimat inhaler. Studies must have reported the scale of inhaler misuse, variation by type of inhaler or which steps patients had difficulty completing accurately. RESULTS: The types of inhalers, inhaler interventions and definitions of failure and misuse varied widely in the 38 studies identified. It was not possible to draw conclusions on the differential failure rates between different types of inhalers or any patient characteristics. Of the studies reporting failure or misuse rates, the majority ranged between 0 and 20%. Studies were inconsistent regarding the number of inhaler steps collected, reported and labelled as critical. CONCLUSIONS: There is evidence for all identified inhalers that some people may be using them incorrectly, but it is unclear which inhalers have higher rates of misuse or which steps within the inhaler technique are most difficult for patients. The optimal techniques for using inhalers are not standardised. Researchers undertaking future inhaler studies are respectfully directed to our recommendations for future research. PMID- 28732843 TI - Preliminary results with non-centrifuged autologous fat graft and percutaneous aponeurotomy for treating Dupuytren's disease. AB - The aim of this study was to describe our experience with treating Dupuytren's disease using needle aponeurotomy and non-centrifuged autologous fat grafting. The study included 17 patients (18 hands). Patients were treated with needle aponeurotomy and non-centrifuged autologous fat graft under general anesthesia. The fat grafts were injected into the surgical area so as to stay in contact with the operated site. An extension splint was used for 1 week postoperatively and the patients received hand therapy for 3 weeks. Before the treatment, the contracture in the proximal interphalangeal and metacarpophalangeal joints was a mean of 45.06 +/- 13.44 degrees and 36.56 +/- 13.09 degrees, respectively. It was 1.61 +/- 1.65 and -0.56 +/- 3.78 degrees at 3 months, respectively. The difference between these measurements was statistically significant. The mean follow-up period was 12 months. The results were satisfactory and no complications were observed during the follow-up period. Based on the results of the study, percutaneous aponeurotomy with non-centrifuged autologous fat grafting was found to have significantly beneficial effects in the treatment of Dupuytren's disease. PMID- 28732844 TI - Efficacy and safety of collagenase treatment for Dupuytren's disease: 2-year follow-up results. AB - Dupuytren's contracture is a common hand problem that affects the palmar fascia. Several treatment options exist, but none are curative and recurrence is common. Bacterial collagenase has recently been proven beneficial for treating Dupuytren's disease, cleaving the collagen fibers at different sites, with weakening and eventually rupture of the fibrous cords after manipulation. An independent prospective follow-up study was organized on 87 patients, treated with one or more collagenase injections. Inclusion criteria were a contracture of at least 20 degrees at the metacarpophalangeal (MCP) or the proximal interphalangeal (PIP) joint. The most diseased joint was taken into consideration for follow-up evaluation. The resulting extension deficit was measured at 1 month, 1 year and 2 years and was graded as "clinical success", "clinical improvement" or "clinical failure". The mean contracture improved from 45 degrees (39 degrees for MCP and 54 degrees for PIP joints) before treatment to 5 degrees (2 degrees for MCP and 9 degrees for PIP joints) 4 weeks after treatment. No serious complications occurred. After 2 years, 68 joints were evaluated; 61.5% of the MCP joints and 34.5% of the PIP joints had a contracture of <=20 degrees . When compared with the 4-week evaluation, 28.2% of MCP joints and 62.1% of PIP joints had a recurrence (20 degrees or greater worsening) or had received additional treatment. Collagenase injection is a safe and effective treatment option for Dupuytren disease, but recurrence is common especially for the PIP joint. PMID- 28732845 TI - Posterior interosseous nerve to the superficial branch of the ulnar nerve transfer at the distal third of the forearm through a single anterior approach: Anatomical feasibility study. AB - The purpose of this study was to determine in a cadaver model, whether transfer of the posterior interosseous nerve (PIN) to the superficial branch of the ulnar nerve (SBUN) by a single approach was feasible. The experiment was carried out on five fresh cadavers. The ulnar nerve was split into its motor branches and the SBUN. The PIN was collected behind the interosseous membrane and sutured to the SBUN on its anterior surface. All sutures were tensionless and technically possible with the PIN's diameter being at least 50% of the SBUN's diameter in all cases. Our results demonstrate that PIN to SBUN transfer through a single anterior approach is feasible in a cadaver model. PMID- 28732846 TI - Physicochemical study of mixed systems composed by bovine caseinate and the galactomannan from Gleditsia amorphoides. AB - Model systems formed by sodium caseinate (NaCAS) and espina corona gum (ECG) were studied. There was no evidence of attractive interactions between NaCAS and ECG macromolecules. Aqueous mixtures of NaCAS and ECG phase-separate segregatively over a wide range of concentrations. According to the images obtained by confocal laser scanning microscopy, NaCAS particles form larger protein aggregates when ECG is present in the system. An increase in the hydrodynamic diameter of NaCAS particles, as a result of ECG addition, was also observed by light scattering in diluted systems. A depletion-flocculation phenomenon, in which ECG is excluded from NaCAS surface, is proposed to occur in the concentrated mixed systems, resulting in NaCAS aggregation. ECG raises the viscosity of NaCAS dispersions without affecting the Newtonian flow behaviour of NaCAS. These results contribute to improve the knowledge of a barely-studied hydrocolloid which may be useful in the development of innovative food systems. PMID- 28732847 TI - Quaternized carboxymethyl chitosan/organic montmorillonite nanocomposite as a novel cosmetic ingredient against skin aging. AB - It is of technical and economic importance to develop an effective cosmetic ingredient against skin aging through low-cost and facile production. This study developed a polymer/layered silicate nanocomposite as cosmetic ingredient against skin aging. Firstly, quaternized carboxymethyl chitosan (QCMC)/organic montmorillonite (OMMT) nanocomposite (QCOM) was fabricated via solution-induced intercalation. QCOM with different mass ratios of QCMC to OMMT were studied by various characterizations as well as moisture-adsorption and retention activities and UV-protection capacity. QCOM was then added into a cosmetic formulation to prepare a cosmetic cream. And the evaluation of its efficacy about skin care was conducted. The results showed that the optimal QCOM had better moisture adsorption and retention behaviors than hyaluronic acid, and QCOM solution displayed good UV-protection ability. Furthermore, the QCOM-containing cosmetic cream meets the hygienic standard for cosmetics; it has negligible dermal irritation and a prominent moisture-retention efficacy on human stratum corneum. PMID- 28732848 TI - Optimization of pectin extraction from pistachio green hull as a new source. AB - In this paper, the influence of pH (0.5-2.5), temperature (50-90 degrees C), extraction time (30-150min) and liquid/solid ratio (10-50v/w) on the acidic extraction yield and degree of esterification (DE) of pistachio green hull pectin were studied by using central composite design. The results indicated that the yield and DE of pectin ranged from 7.31 to 19.02% and 26.00 to 53.01%, respectively. The optimization of pectin extraction condition showed that the optimal condition was pH of 0.5, temperature of 90 degrees C, time of 30min and liquid/solid ratio of 50 v/w. In this condition, the experimental yield (22.1+/ 0.5%) was fine accord among predicted yield (23.42%). Also, under the optimal extraction condition, the galacturonic acid content of pectin was about 65%. The FTIR spectrum showed that the pectin extracted under optimal condition is rich from polygalacturonic acid. PMID- 28732849 TI - Preparation and in vitro evaluation of FGF-2 incorporated carboxymethyl chitosan nanoparticles. AB - Fibroblast growth factor 2 (FGF-2) is a multi-functional protein involving in wound healing. However, FGF-2 is easily degradable in vivo, which limited its use for wound treatment. In this study, we investigated a drug-delivery model for FGF 2 via incorporation with biodegradable carboxylmethyl chitosan (CMCS). CMCS nanoparticles (NPs) could be synthesized by ionic gelation using CaCl2 as a crosslinking reagent with the CMCS:CaCl2 ratio of 1:0.8. Synthesized CMCS NPs had a diameter of 32.68+/-6.83nm, and were non-toxic at concentrations up to 2.5mg/ml. Incorporated CMCS:FGF-2 NPs had a diameter of 34.83+/-5.89nm and incorporation efficiency was 95%. CMCS:FGF-2 NPs released 36.36% and 58.47% of FGF-2 after 48h incubation in two different pH of 7.4 and 5.8, respectively. The incorporation and release processes did not have a significant effect on FGF-2 activity. Simultaneously, CMCS:FGF-2 NPs could protect FGF-2 from the degradation of trypsin in vitro. Our results laid the groundwork for the manufacturing of protein incorporated CMCS NPs for bio-applications. PMID- 28732850 TI - Promising bio-composites of polypyrrole and chitosan: Surface protective and in vitro biocompatibility performance on 316L SS implants. AB - Advanced biomedical materials can potentially be developed from combinations of natural biodegradable polymers and synthetic polymers. We synthesized bioactive composites based on polypyrrole/chitosan through in-situ electrochemical polymerization in oxalic acid medium. Surface characterization results revealed the influence of chitosan inclusion on polypyrrole (PPy) surface morphology. Contact angle results confirmed the enhancement in surface hydrophilicity due to the addition of chitosan into the PPy matrix. Electrochemical corrosion studies revealed that the composite coatings showed enhanced protective performance compared to pure PPy. Further, we investigated the effect of the composite coatings on the growth of MG-63 human osteoblast cells to assess their biocompatibility. Monte Carlo simulations were engaged to assess the interactions between the metal surface and composite coatings. The composite containing equal parts PPy and chitosan was found to be biocompatible; together with the corrosion protection results, the findings indicated that this bioactive coating material has potential for use in 316L SS implants. PMID- 28732851 TI - Nanoparticle assisted solvent selective transdermal combination therapy of curcumin and 5-flurouracil for efficient cancer treatment. AB - Skin cancer is one among the many prominent diseases of the modern world and millions of people are suffering due to the lack of proper medication. Even though transdermal drug delivery systems (TDDS) provide an efficient route of drug administration, the advantages of combination chemotherapy have rarely been extended into TDDS. In the present work, a polymer capable of simultaneously encapsulating two anti-cancer drugs: 5-flurouracil (5-FU) and curcumin (CUR), and releasing them with varying kinetics as a function of the leaching solvent was developed. The prepared TDDS had two copolymers: alginate coated aminated nanodextran (ALG@AND) and chitosan coated folate decorated aminated beta-CD nano particles (CS@FA-g-AbetaCD). After inducing surface charges, both copolymers were coupled together by electrostatic forces. All the synthetic procedures for the preparation of TDDS were monitored using FTIR, DLS, Zeta Potential, SEM and TEM. The final TDDS was then evaluated for its solvent selectivity. Sustained release of 5-FU and CUR was observed with ethanol (EtOH) and 1-butanol (BuOH) respectively. However, these solvents could also release a small amount of the second drug which led to combinatorial therapy. The in vitro solvent selective drug permeation profiles were evaluated using Franz diffusion cell on rat skin. In order to evaluate the economic feasibility of the prepared TDDS, in vivo skin adhesion tests, skin irritation analysis, water vapour permeability and average visible transmittance were performed. Results proved that solvents could not only elute the drugs in a sustained manner, but could also act as penetration enhancers. Biological and histological studies carried out on skin and cancer cell lines suggested the potential usefulness of the prepared material in combinatorial chemotherapy. PMID- 28732853 TI - Quantitative analysis of acid-catalyzed levulinic acid product mixture from cellulose by mixed-mode liquid chromatography. AB - A mixed-mode weak anion-exchange/reversed-phase liquid chromatography (LC) column was successfully applied for the analysis of levulinic acid (4-oxopentanoic acid, LA) product mixture derived from cellulose. Due to the existence of ionic and neutral byproducts, the analysis of the product mixture usually requires ion chromatography, LC and gas chromatography simultaneously. The new method enables accomplishment of the analysis in one LC run within 6min. LC mobile phase of 10mM phosphate buffer containing 5% acetonitrile with pH=5.5 was used. The linear regression coefficients for the UV signal of standard compounds with the corresponding mass concentrations were greater than 0.999. The method recoveries were between 98.57-103.48%. The limits of quantification were 5, 10,1000, 1500 and 3000ng/mL for 5-hydroxymethylfurfural, furfural, acetic acid, formic acid and LA respectively. The mixed-mode column exhibits comprehensive separation mechanism of both reversed-phase and ion-exchange interactions. The mobile phase with different pH, organic modifier solvent and buffer concentration provided flexible LC method for the sample with different complexity. PMID- 28732852 TI - Investigating the H2O/O2 selective permeability from a view of multi-scale structure of starch/SiO2 nanocomposites. AB - In order to control H2O/O2 selective permeability of starch based nanocompsites for food packaging, the addition of SiO2 nanoparticles was proven to be an effective method. The results suggested that the SiO2/hydroxypropyl starch (HPS) ratio was a feasible approach to regulate the film multi-scale structure. The H2O/O2 selective permeability was influenced by comprehensive factors including film short-range molecular conformation, crystalline structure and aggregated structure. The increase of micro-ordered region size was likely to favor the improvement of water vapor barrier property and the rise of compactness in this region seems to contribute to the oxygen prevention. Notably, the effect of film multi-scale structure on H2O/O2 selective permeability could be a supplement to conventional "tortuous path" theory for the explanation of barrier property improvement. This study could significantly guide to the rational design of H2O/O2 selective biodegradable food packaging in order to meet the requirement for different food systems. PMID- 28732854 TI - Self-assembled hyaluronic acid nanoparticles for controlled release of agrochemicals and diosgenin. AB - Commercial sodium hyaluronate (HA) and synthetic hydrazide-modified HA were functionalized with diosgenin and two agrochemicals (brassinosteroids DI31 and S7) with degree of substitution ranging from 5.6 to 13.1%. The HA-steroid conjugates were studied with FTIR, 1H NMR and differential scanning calorimetry. Dynamic light scattering revealed self-assembly of the HA-steroid conjugates into stable negatively charged nanoparticles of around 159nm-441nm in water, which after drying appeared as 140nm-370nm spherically shaped nanoparticles according to transmission electron microscopy. These nanoparticles exhibited almost constant release rates of steroids for the first 8h, demonstrating sustained steroids delivery for 72h in acidic medium. The nanoparticles formed from HA steroid conjugates were not cytotoxic to human microvascular endothelial cells (HMVEC), while the HA- brassinosteroid nanoparticles showed in vitro agrochemical activity that was superior to the activity observed for the parent brassinosteroids DI31 and S7 at 10-5 to 10-7mgmL-1. PMID- 28732855 TI - Effects of thermosensitive chitosan-gelatin based hydrogel containing glutathione on Cisd2-deficient chondrocytes under oxidative stress. AB - Aging is considered as a primary risk factor in the development of osteoarthritis (OA) which associated with mitochondrial dysfunction and oxidative stress. CDGSH iron sulfur domain 2 (Cisd2) deficiency causes mitochondrial dysfunction and drive premature aging. In the present study, thermosensitive chitosan-gelatin based hydrogel containing glutathione was developed as injectable drug delivery system for administration by minimal invasive surgery for the treatment of OA. Cisd2 deficiency (Cisd2-/-) mouse induced pluripotent stem cells-derived chondrocytes were established and characterized. The results suggested that 100MUM of glutathione may be an optimal concentration to treat Cisd2-/- chondrocytes without cytotoxicity. The developed hydrogel showed sustained release profile of the glutathione and could decrease the reactive oxygen species level. Post-treatment of glutathione-loaded hydrogel could rescue Cisd2-/- chondrocytes from oxidative damage via increasing catalase activity, down regulation of inflammation, and decreasing apoptosis. These results suggest that thermosensitive glutathione-loaded hydrogel may be a potential antioxidant therapeutic strategy for treating Cisd2-/- chondrocytes in the near future. PMID- 28732856 TI - Thermoplastic starch-nanohybrid films with polyhedral oligomeric silsesquioxane. AB - Thermoplastic starch forms packaging films that have low gas permeability, but they are more permeable to water vapour and they are attacked by water. Our approach was to create surface and internal localised hydrophobicity using added reactive nano-materials to form nano-silica hybrids with emphasis on enhancing surface water resistance. Functionalization was via epoxy-POS, that were further linked to hydrophobic erucamide or an amphiphilic poly(oxyethylene-co oxypropylene) mono-amine. High amylose thermoplastic starch was combined with mono-functionalised hepta-isobutyl polyhedral oligomeric silsesquioxane (POS). POS modified thermoplastic starch increased water resistance of TPS film. Wettability kinetics was a function of two distinct mechanisms each with independent linear behaviour. Surface water resistance increased and is proposed to be due to preferential location of the POS derivatives at the surface with associated increase of hydrophobicity due a surface change. PMID- 28732857 TI - Highly efficient and facile fabrication of monodispersed Au nanoparticles using pullulan and their application as anticancer drug carriers. AB - This work presented a simple, rapid, green and efficient approach to the synthesis of gold nanoparticles using pullulan as a reducing/stabilizing/capping agent for drug delivery systems to increase the safety and efficacy of these systems. Monodispersed AuNPs@pullulan with prolonged stability were fully characterized by UV-VIS, FTIR, TEM, EDX, TGA and zeta potential analyses. A mechanism of AuNPs formation was proposed in which pullulan created reducing species for the reduction of Au3+ to AuNPs (Au0) that resulted in the formation of spherical AuNPs@pullulan with an average size of approximately 11+/-5nm, while the hydroxyl groups of pullulan were oxidized to carboxylate compounds. Novel cassiarin A chloride derivatives (3d and 3i) as candidate anticancer drugs were successfully loaded onto AuNPs@pullulan through electrostatic interactions. AuNPs@pullulan-3d (IC50=6.0+/-0.1MUM) and AuNPs@pullulan-3i (5.2+/-0.1MUM) exhibited a 10.2-fold and 7.1-fold higher cytotoxicity against KATO-III cells than free compounds 3d (60.9+/-0.6MUM), 3i (37.1+/-0.2MUM) and cisplatin (64.5+/ 0.9MUM), respectively. AuNPs@pullulan exhibited high cellular uptake, biocompatibility and non-cytotoxicity to normal cells. Therefore, AuNPs@pullulan 3d or AuNPs@pullulan-3i have the potential to be developed for treatment of gastric cancer. PMID- 28732858 TI - Optimization of microwave-assisted extraction of Sargassum thunbergii polysaccharides and its antioxidant and hypoglycemic activities. AB - In the present work, optimization of microwave-assisted extraction of polysaccharides from Sargassum thunbergii was investigated. The physicochemical properties, structural characteristics, and in vitro antioxidant and hypoglycemic activities were determined. The optimal extraction conditions with a yield of 2.84+/-0.09% for extraction of polysaccharides (STP-1) were extraction time 23min, microwave power 547W, extraction temperature 80 degrees C, and the ratio of raw material to water 1:27g/mL. STP-1 contained 32.7% of total carbohydrate, 1.86% of protein, and 15.2% of sulfates. STP-1 had a major molecular weight of 190.4kDa, and comprised of arabinose, galactose, glucose, xylose, mannose, galacturonic acid, and glucuronic acid with molar percentages of 1.94, 30.7, 4.54, 23.2, 17.6, 8.11, and 13.9%, respectively. In addition, STP-1 showed strong antioxidant and alpha-glucosidase inhibitory activities, and could improve the glucose uptake in insulin-resistant HepG2 cells, suggesting that STP-1 can be exploited as a promising natural antioxidant and hypoglycemic agent. PMID- 28732859 TI - Surface behavior and bulk properties of aqueous chitosan and type-B gelatin solutions for effective emulsion formulation. AB - The behavior of aqueous chitosan (CH), type-B gelatin (GB) and CH-GB coacervate was studied on oil-in-water emulsion formulation at various pH and concentration ratio. The coacervate was formed by phase separation at ratios CH:GB, 1:10 to 1:1 with total biopolymer concentrations of 0.55%-1.0% (w/v) at pH 4.0-5.5. Soluble complexes were formed below pH 5.0 and coacervate formation was confirmed at pH 5.0 and above by zeta potential and UV-spectroscopy measurements. The coacervate formation was found maximum at the CH-GB ratios of 1:10 and 1:5 at pH 5.5. Formulated emulsions (>10MUm droplets) using 1% (w/v) chitosan and GB were found stable (+52.5mv and creaming index 86%) and unstable respectively. Emulsion stabilized by mixed CH:GB 1:5 (3%w/v) had no creaming effect. The instability was attributed to the lower surface activity (K=5.0Lg-1) of pure GB compared to CH (K=14.3Lg-1). The formulation and methods can successfully tune the stability of the emulsions. PMID- 28732860 TI - Structure features and in vitro hypoglycemic activities of polysaccharides from different species of Maidong. AB - Structures and in vitro hypoglycemic activities of polysaccharides from different species of Maidong were studied. The primary structures of polysaccharides were elucidated on the basis of GC, GC-MS, infrared, NMR and periodate oxidation-Smith degradation. Liriope spicata polysaccharide (LSP), Ophiopogon japonicus polysaccharide (OJP) and Liriope muscari polysaccharide (LMP) were composed of beta-fructose and alpha-glucose. The average molecular weights of LSP, OJP and LMP were 4742, 4925 and 4138Da with polydispersity indexes of 1.1, 1.2 and 1.1, respectively. The backbones of polysaccharides were formed by Fruf-(2->, ->2) Fruf-(6->, ->6)-Glcp-(1-> and ->1, 2)-Fruf-(6-> with a molar ratio of 5.0:18.2:1.0:5.3 (LSP), 6.8:15.8:1.0:5.8 (OJP), 8.3:12.3:1.0:3.9 (LMP), respectively. The RT-PCR and western blot analysis indicated that LSP, LMP and OJP increased the expression of PI3K, AKT, InsR, PPARgamma and decreased the expression of PTP1B in mRNA level and protein level in IR HepG2 cells. Furthermore, glucose consumption was increased after treated with polysaccharides. These results revealed that LSP, OJP and LMP had potential anti diabetic effects. PMID- 28732861 TI - Fabrication and characterization of hollow starch nanoparticles by gelation process for drug delivery application. AB - Hollow nanoparticles (HNPs) have been widely regarded as controlled drug carriers owing to their advantages, such as high drug-loading efficiency and superior control over drug delivery and release. In this study, a facile and efficient strategy has been exploited for preparation of hollow starch nanoparticles (HSNPs) via a sacrificial hard-template process using gelled starch as the shell. These nanocapsules have been characterized through various techniques, including transmission electron microscopy, differential scanning calorimetry, X-ray diffraction, and Fourier transform infrared spectroscopy. The HSNPs have diameters ranging from 30nm to 300nm, with shell thickness of 5-10nm. X-ray diffraction analysis has revealed that HSNPs exhibit B+V type diffraction peaks with a relative crystallinity of 34.2%. Doxorubicin hydrochloride (DOX.HCl) was readily encased in the nanocarriers with a high loading efficiency (97.56%) and a high loading content (37.12%). In addition, no cytotoxicity for normal liver cells was found in HSNPs. However, DOX.HCl-loaded HSNPs exhibited clear cytotoxicity for liver hepatocellular cells. Thus, the hollow starch nanoparticles form a highly promising platform for cancer therapy. PMID- 28732862 TI - Carbohydrate functionalized hybrid latex particles. AB - In this review we highlight the progress in the synthesis of carbohydrate functionalized hybrid latex particles, focusing on different synthetic approaches which use carbohydrates as a surfactant/stabilizer, initiator, grafting site and/or as a macromonomer. These nanocomposites are receiving increasing attention in academia as well as in industry, due to increasingly stringent societal demands for biobased, biodegradable, and biocompatible materials. Furthermore, we will report on the use of nanostructured carbohydrate materials, such as cellulose nanocrystals, starch nanocrystals, and starch nanoparticles. These novel materials represent an interesting emerging field, and examples of latex nanocomposites have only recently been reported. It is the authors' opinion that using carbohydrate materials for the synthesis and production of latex polymers will become of increasing importance as we move towards a more sustainable future. PMID- 28732863 TI - A novel, cost-effective and eco-friendly method for preparation of textile fibers from cellulosic pulps. AB - Although cellulosic fibers are increasingly used in textile products, current methods for production of cellulose-based textiles suffer certain economic and/or environmental drawbacks. We have developed a new, cost-effective and environmentally-friendly (CS2-free) process that overcomes some of the shortcomings of existing technologies. The process is based on a modified method for periodate oxidation of cellulose that is then cross-linked with chitosan and extruded to obtain cellulosic fibers in the form of textile fibers. The produced fibers have low content of aldehyde groups (~2mmol/g cellulose) and water retention values of 1.5-2.0g/g fibers. The new process makes use of both hardwood and softwood pulps, and offers significant yield advantages over the use of dissolving pulp as a raw material. The mechanical, water absorbency and morphological properties of the new textile fibers and their potential applications are discussed. The potential techno-economic and environmental benefits of the process are summarized. PMID- 28732864 TI - Blood coagulation evaluation of N-alkylated chitosan. AB - N-Alkylated chitosan (NACS) may improve the haemostatic efficiency of chitosan (CS). To study its coagulation capability and function, a series of NACS with various carbon chain lengths and substitution degrees (SD) of alkyl groups were synthesized and characterized by FTIR, NMR, and elemental analysis. Haemolysis and toxicity assays revealed that NACS showed good biocompatibility. In vitro blood clotting tests indicated that NACS had better haemostatic activity than CS, of which N-octadecyl CS with 3.85% SD showed the best results. Blood plasma coagulation tests showed that NACS was not favourable for activating coagulation factors. Platelet adhesion, intracellular Ca2+, and CD62p measurements demonstrated that the coagulation properties of NACS were not related to platelet activation. Erythrocyte adhesion examination indicated that blood coagulation of NACS may be attributable to its effects on erythrocytes. This study suggests that NACS is an ideal candidate for clotting. PMID- 28732865 TI - Effect of molecular weight of chitosan on the shelf life and other quality parameters of three different cultivars of Actinidia kolomikta (kiwifruit). AB - The kiwi fruit, Actinidia kolomikta, has valuable properties such as high antioxidant activity, high vitamin C, polyphenols, chlorophylls and organic acids content, but the species are hardly commercialized due to their short shelf life (less than two days). In this study three different cultivars of A. kolomikta (Anyksta, Sentiabrskaya and VIR2) were coated with low, medium and high molecular weight chitosan bio-polymer with the aim to extend the shelf life. The changes in fruit firmness, mass, phenolic compound content, vitamin C content and subjective criteria (withering level, decoloration level and aesthetic appearance) were monitored. It was observed that high molecular weight chitosan had higher positive effect on the shelf life of Sentiabrskaya and Anyksta cultivars than VIR2. Low molecular weight chitosan was found effective on VIR2. PMID- 28732866 TI - Probing cleavage promiscuity of heparinase III towards chemoenzymatically synthetic heparan sulfate oligosaccharides. AB - An insightful investigation into specificity of bacterial heparinase III has been intriguingly difficult due to heterogeneity of polymeric substrates. Herein, we chemoenzymatically synthesized a tailored library of HS oligosaccharides as substrates. A ~15-fold reactivity difference to heparinase III was found between trisaccharides bearing different primary cleavage sites. Variable glucosamine modification decreased reactivity of trisaccharides by >20-fold compared with their counterpart primary substrates, while iduronate-containing secondary linkage showed slightly less sensitivity. The 2-sulfated iduronate residue extremely reduced reactivity to its adjacent primary site at reducing end of oligosaccharides, but showed marginal influence on the non-reducing site. Moreover, oligosaccharide susceptibility to digestion was size-dependent and had an obvious preference for the internal linkages over those near to non reducing/reducing ends. Surface plasmon resonance revealed cleavage promiscuity attributed to different affinities or incorrect binding of substrates to the enzyme. The attractive information on heparinase III will be valuable in characterizing heparin and HS. PMID- 28732867 TI - Nano iron oxide impregnated in chitosan bead as a highly efficient sorbent for Cr(VI) removal from water. AB - Using Fe(III) salts and chitosan, nano iron oxide impregnated in chitosan bead (NIOC) was successfully synthesized for aqueous Cr(VI) detoxification via sol-gel technique without any additional crosslinking agent. NIOC characterization demonstrated that the iron in NIOC mainly existed as nano akaganeite (beta-FeOOH) and complex with chitosan. Intraparticle diffusion was the major rate-limiting step. The maximal adsorption capacity was 69.8mg/g (pH 5.0, 20 degrees C). Normal concentration of coexisting anions (SO42-, CO32-, SiO32-) showed insignificant competition, whereas PO43- suppressed the Cr(VI) sorption. Cr(VI)-loaded NIOC could be effectively regenerated by alkaline solutions. Column adsorption runs using granular NIOC could effectively treat about 1600 bed volumes of Cr(VI) solution (from 3.7mg Cr/L in influent to <0.5mg Cr/L in effluent). The Cr(VI) removal mechanisms involved the direct sorption of Cr(VI) (electrostatic attraction and ligand exchange), reduction of Cr(VI) into Cr(III) and re-sorption of Cr(III) via chelation on NIOC surface. PMID- 28732868 TI - Adsorption and desorption of cationic malachite green dye on cellulose nanofibril aerogels. AB - Ultra-light aerogels have been assembled from cellulose nanofibrils into hierarchically macroporous (several hundred MUm) honeycomb cellular structure surrounded with mesoporous (8-60nm) thin walls. The high specific surface (193m2/g) and surface carboxyl content (1.29mmol/g) of these aerogels were demonstrated to be highly capable of removing cationic malachite green (MG) dye from aqueous media. The rapid MG adsorption was driven by electrostatic interactions and followed a pseudo-second-order adsorption kinetic and monolayer Langmuir adsorption isotherm. At a low 1:5mg/mL aerogel/MG ratio, both initial MG adsorption rate (2.3-59.8mgg-1min-1) and equilibrium adsorption capacity (53.0 203.7mgg-1) increased with increasing initial MG concentrations from 10 to 200mg/L, reaching a maximum adsorption of 212.7mgg-1. The excellent dye removal efficiency was demonstrated by complete MG removal through four repetitive adsorptions at a low 1:5mg/mL aerogel/MG ratio and 10mg/L dye concentration as well as 92% MG adsorption in a single batch at one order of magnitude higher10:5mg/mL aerogel/MG ratio and 100mg/L dye concentration. The adsorbed MG in aerogels could be desorbed in aqueous media by increasing ionic strength, demonstrating facile recovery of both dye and aerogel as well as the robust capability of this aerogel for repetitive applications. PMID- 28732869 TI - In-situ formation of supramolecular aggregates between chitin nanofibers and silver nanoparticles. AB - Chitin and chitin derivatives have gained significant research interest over the years due to a number of beneficial properties that can be exploited in various application fields. Particularly, interactions between their nanostructures and other nanomaterials are of great interest. In situ photo-reduction of AgCl in chitin nanofiber aqueous dispersions resulted in significant loss of colloidal stability of both chitin nanofibers (CNF) and silver nanoparticles. UV-vis spectroscopy was used to characterize the extinction profiles of in-situ prepared CNF and several silver nanoparticle mixtures over the reaction steps. High resolution TEM characterization of the resulting structures indicated the presence of the aggregated form of nanofiber and nanoparticles. Energy filtered TEM analysis confirmed the existence of both CNF and silver nano particles in the aggregate, with silver in its chemically reduced state (Ag(0)). FT-IR, and 13C solid state NMR revealed the presence of strong interactions between Ag and CNF through hydroxyl and carbonyl moieties of the CNF structure. It was concluded that these interactions led to the formation of a supramolecular aggregate in the in-situ mixture as a result of wrapping of CNF around photo-reduced silver nanoparticles which resulted in the colloidal instability. PMID- 28732870 TI - Synthesis of novel biodegradable antibacterial grafted xanthan gum. AB - Xanthan gum (XG) is natural polysaccharides used in food industries as stabilizers and thickener agents. The problem is that some food products are found to be contaminated by pathogenic bacteria such as Escherichia coli (E. coli) and Staphyloccus aureus (S. aureus) that reduce their shelf life. This research aims to synthesize biodegradable antibacterial XG-grafted-poly(N-vinyl imidazole) PVI and the effect of reaction parameters were studied on grafting yield (G), grafting efficiency (GE), total conversion (TC) and homopolymer (H) %. XG-g-PVI was characterized via various analysis tools. Thermal analysis showed that grafted XG was more thermally stable than unmodified XG and their stability increased with increasing PVI%. XG-g-PVI was acting as antibacterial agent against (E. coli and S. aureus) bacteria that cause food borne diseases. Their activity increases with increasing grafting yield%. Surface morphology showed change from irregular lobules shape in XG to smooth surface in its graft with PVI. PMID- 28732871 TI - Cellulose-polyhydroxylated fatty acid ester-based bioplastics with tuning properties: Acylation via a mixed anhydride system. AB - The synthesis of microcrystalline cellulose (MCC) and 9,10,16-hydroxyhexadecanoic (aleuritic) acid ester-based bioplastics was investigated through acylation in a mixed anhydride (trifluoroacetic acid (TFA)/trifluoroacetic acid anhydride (TFAA)), chloroform co-solvent system. The effects of chemical interactions and the molar ratio of aleuritic acid to the anhydroglucose unit (AGU) of cellulose were investigated. The degree of substitution (DS) of new polymers were characterized by two-dimensional solution-state NMR and ranged from 0.51 to 2.60. The chemical analysis by attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR) confirmed the presence of aleuritate groups in the structure induces the formation of new H-bond networks. The tensile analysis and the contact angle measurement confirmed the ductile behavior and the hydrophobicity of the prepared bioplastics. By increasing the aleuritate amounts, the glass transition temperature decreased and the solubility of bioplastic films in most common solvents was improved. Furthermore, this new polymer exhibits similar properties compared to commercial cellulose derivatives. PMID- 28732872 TI - Chitin based heteroatom-doped porous carbon as electrode materials for supercapacitors. AB - Chitin biomass has received much attention as an amino-functional polysaccharide precursor for synthesis of carbon materials. Rich nitrogen and oxygen dual-doped porous carbon derived from cicada slough (CS), a renewable biomass mainly composed of chitin, was synthesized and employed as electrode materials for electrochemical capacitors, for the first time ever. The cicada slough-derived carbon (CSC) was prepared by a facile process via pre-carbonization in air, followed by KOH activation. The weight ratio of KOH and char plays an important role in fabricating the microporous structure and tuning the surface chemistry of CSC. The obtained CSC had a large specific surface area (1243-2217m2g-1), fairly high oxygen content (28.95-33.78 at%) and moderate nitrogen content (1.47-4.35 at%). The electrochemical performance of the CS char and CSC as electrodes for capacitors was evaluated in a three-electrode cell configuration with 6M KOH as the electrolyte. Electrochemical studies showed that the as-prepared CSC activated at the KOH-to-char weight ratio of 2 exhibited the highest specific capacitance (266.5Fg-1 at a current density of 0.5Ag-1) and excellent rate capability (196.2Fg-1 remained at 20Ag-1) and cycle durability. In addition, the CSC-2-based symmetrical device possessed the desirable energy density and power density of about 15.97Whkg-1 and 5000Wkg-1 at 5Ag-1, respectively. PMID- 28732873 TI - Macromolecular properties and hypolipidemic effects of four sulfated polysaccharides from sea cucumbers. AB - The present study investigates the relationship between the high-order structure and hypolipidemic activity of four well-defined sulfated fucans from sea cucumber. The chain conformation, determined by a combination of AFM and SEC MALLS-RI, indicate that fucosylated chondroitin sulfate (fCS) from Pearsonothuria graeffei (fCS-Pg) and Isostichopus badionotus (fCS-Ib), and fucoidan from P.graeffei (fuc-Pg) were assigned as a random coil conformation with polysaccharide chain outstretched, while I. badionotus (fuc-Ib) was assigned as a spherical conformation and exhibited high viscosity. Fuc-Pg and fuc-Ib with higher molecular weights had a greater impact in inhibiting pancreatic lipase activity in vitro. However, fCS-Pg, fCS-Ib and fuc-Pg with random linear conformation exhibited excellent hypolipidemic activity in Sprague-Dawley rats (SD rats) fed on high-fat diet (HFD), whereas fuc-Ib showed only a modest effect. Our results indicate that structural characteristics, including side branch and sulfation pattern can affect the chain conformation of polysaccharides, which determine their physicochemical properties and hypolipidemic activity. PMID- 28732874 TI - Preparation and prediction of physical properties of cellulose acetate and polyamide polymer blend. AB - In this paper the physical properties of the polymer blend of lab synthesized Polyamide (PA) and commercial Cellulose Acetate (CA) was focused. The molecular interactions of CA/PA were investigated thoroughly by means of solubility, viscosity, specific gravity and diffusivity study with different concentrations of the CA/PA combinations and the blend of CA/PA was characterized by optical microscope and differential scanning calorimetry (DSC). Dimethyl formamide (DMF) was selected as solvent for the CA/PA polymer blend at 28 degrees C. The diffusivity result for the polymer blend of CA/PA was suggested slight decrease in diffusivity coefficient with 1:1 blend ratio of CA/PA polymer. PMID- 28732875 TI - Specific ion effects in polysaccharide dispersions. AB - The specific effects induced by some strong electrolytes or neutral co-solutes on aqueous mixtures of guar gum (GG), sodium alginate (SA) and sodium hyaluronate (SH) were studied through rheology and DSC experiments. The results are discussed in terms of changes in the polymer conformation, structure of the network and hydration properties. This study is also aimed at controlling the viscosity of the aqueous mixtures for application in green formulations to be used as fracturing fluids for shale gas extraction plants. PMID- 28732876 TI - Extraction, isolation and characterization of nanocrystalline cellulose from industrial kelp (Laminaria japonica) waste. AB - Kelp (Laminaria japonica) is an economically important type of algae cultured in East Asia. Kelp waste is a by-product from the extraction of commercial alginate from kelp. This work reports the isolation of nanocrystalline cellulose (NCC) from the cellulose extracted from the kelp waste. X-ray diffraction (XRD) and Fourier transform infrared spectroscopy (FTIR) show that the crystallinity index of the isolated kelp NCC was 69.4%, which was slightly higher than that of kelp cellulose as well as maintained the cellulose I crystalline form and typical cellulose chemical structure. In thermogravimetric analysis (TGA), kelp NCC showed decreased thermostability and a higher residual mass. Transmission electronic microscopy (TEM) confirmed the ordinary rod-like shape of the produced NCC with various dimensions. The kelp NCC aqueous dispersions displayed the expected characteristic optical and gel effects. Studies on the variables and the orthogonal experiment of NCC preparation contributed a maximum yield of 52.3%. The exploration on the preparation of kelp NCC in this study lays foundations for future applications. PMID- 28732877 TI - Enhanced antitumor activity of gemcitabine by polysaccharide-induced NK cell activation and immune cytotoxicity reduction in vitro/vivo. AB - The polysaccharide SEP has been reported to activate NK and T cells via TLR2/4. Here, the combination of gemcitabine (GEM) and SEP against HepG-2 was investigated. SEP apparently enhanced antitumor activity of gemcitabine against liver cancer through stimulating NKG2D and DAP10/Akt pathway to activate NK cells. The NKG2D upregulation could improve the sensitivity of NK-92 cells targeting to its ligand MICA expressed on HepG-2 cells. Meanwhile, GEM up regulated MICA expression and attenuated soluble MICA secretion through inhibiting ADAM10 expression, which in turn enhanced the cytotoxicity of NK-92 cells against cancer cells. SEP remarkably enhanced GEM antitumor activity with an inhibitory rate of 79.1% in an H22-bearing mouse model. Moreover, SEP reversed atrophy and apoptosis caused by GEM in both spleen and bone marrow through suppressing ROS secretion in vivo. The data indicated that the combination of SEP and GEM is a potential chemo-immunotherapy strategy for liver cancer treatment clinically. PMID- 28732878 TI - Cyclodextrin-based nanosponges: A critical review. AB - Cyclodextrin-based nanosponges (CD-NS) are innovative cross-linked cyclodextrin polymers nanostructured within three-dimensional network. CD-NS are highly porous nanoparticles characterized by crystalline or amorphous structure, spherical shape and swelling properties. Different cross-linkers provide variety of nanosponges. The polarity, dimension of the polymer mesh and release of entrapped molecule can be easily tuned by varying the type of cross-linker and degree of cross-linking. The site-specific targeting can be achieved by conjugating various ligands on the surface of nanosponge. They offer unique advantage of controlled release and are biologically safe and biodegradable material. Cyclodextrin-based nanosponges can form complexes with different types of lipophilic or hydrophilic molecules. The nanosponges could be used to improve the aqueous solubility of poorly water-soluble molecules, protect degradable substances and as innovative carrier in pharmaceuticals, cosmetics, protein/peptide delivery, diagnostics, enzyme-catalysed reactions, environmental control and agrochemistry. PMID- 28732879 TI - Efficent removal of nickel(II) salts from aqueous solution using carboxymethylchitosan-coated silica particles as adsorbent. AB - Three types of organo-mineral composites have been probed as adsorbents for the removal of Ni(II) ions from aqueous solution. Native Aerosil 200 silica particles have been encapsulated with carboxymethylchitosan (CM-CS) providing SiO2+CM-CS, surface-silanized silica particles SiO2NH2+CM-CS were obtained by treatment with APTES and subsequent encapsulation by CM-CS. Alternatively, surface-carboxylated Aerosil 200 was coated by CM-CS affording SiO2CO2H+CM-CS. The materials have been characterized by various techniques. The effects of counter ions (Cl-, Br-, CH3COO-, NO3- and SO42-), pH and initial Ni(II) concentration on the adsorption capacities have been systematically investigated. The maximum adsorption capacity qm of CM-CS-coated silica was determined using the Langmuir adsorption isotherm. For SiO2CO2H+CM-CS, SiO2+CM-CS and SiO2NH2+CM-CS, they decrease at pH 7 in the order 256mg/g>140mg/g>105mg/g. The adsorption kinetic fits well with a pseudo second order model. These carbohydrate-derived biosorbents are excellent adsorbents with capacities superior to most other adsorbents reported in the literature. PMID- 28732880 TI - Vacuum-assisted bilayer PEDOT:PSS/cellulose nanofiber composite film for self standing, flexible, conductive electrodes. AB - Sustainable cellulose nanofiber (CNF)-based composites as functional conductive materials have garnered considerable attention recently for their use in soft electronic devices. In this work, self-standing, highly flexible, and conductive PEDOT:PSS-CNF composite films were developed using a simple vacuum-assisted filtration method. Two different composite films were successfully fabricated and then tested: 1) a single-layer composite composed of a mixture of PEDOT:PSS and CNF phases and 2) a bilayer composite composed of an upper PEDOT:PSS membrane layer and a CNF matrix sub-layer. The latter composite was constructed by electrostatic/hydrogen bonding interactions between PEDOT:PSS and CNFs coupled with sequential vacuum-assisted filtration. Our results demonstrated that the resultant bilayer composite film exhibited a competitive electrical conductivity (ca. 22.6Scm-1) compared to those of previously reported cellulose-based composites. Furthermore, decreases in the electrical properties were not observed in the composite films when they were bent up to 100 times at an angle of 180 degrees and bent multiple times at an angle of 90 degrees , clearly demonstrating their excellent mechanical flexibility. This study provides a straightforward method of fabricating highly flexible, lightweight, and conductive films, which have the potential to be used in high-performance soft electronic systems. PMID- 28732881 TI - Layer-by-layer assembled hydrophobic coatings for cellulose nanofibril films and textiles, made of polylysine and natural wax particles. AB - Herein we present a simple method to render cellulosic materials highly hydrophobic while retaining their breathability and moisture buffering properties, thus allowing for their use as functional textiles. The surfaces are coated via layer-by-layer deposition of two natural components, cationic poly-l lysine and anionic carnauba wax particles. The combination of multiscale roughness, open film structure, and low surface energy of wax colloids, resulted in long-lasting superhydrophobicity on cotton surface already after two bilayers. Atomic force microscopy, interference microscopy, scanning electron microscopy and X-ray photoelectron spectroscopy were used to decouple structural effects from changes in surface energy. Furthermore, the effect of thermal annealing on the coating was evaluated. The potential of this simple and green approach to enhance the use of natural cellulosic materials is discussed. PMID- 28732882 TI - Engineering of anp efficient mutant of Neisseria polysaccharea amylosucrase for the synthesis of controlled size maltooligosaccharides. AB - Amylosucrase from Neisseria polysaccharea naturally catalyzes the synthesis of alpha-1,4 glucans from sucrose. The product profile is quite polydisperse, ranging from soluble chains called maltooligosaccharides to high-molecular weight insoluble amylose. This enzyme was recently subjected to engineering of its active site to enable recognition of non-natural acceptor substrates. Libraries of variants were constructed and screened on sucrose, allowing the identification of a mutant that showed a 6-fold enhanced activity toward sucrose compared to the wild-type enzyme. Furthermore, its product profile was unprecedented, as only soluble maltooligosaccharides of controlled size chains (2150 degrees , rolling contact angle: 7 degrees ) in several kinds of solutions. Furthermore, the sponges exhibited high separation efficiency and good mass absorption capacity for a wide variety of oils and organic solvents (37-51 times of their own weight). Benefitting from the robust superhydrophobicity and good self-cleaning property of the sponges, the absorption capacity could be well maintained upon repeated use, demonstrating the superior recyclability. These advantages made the sponges ideal absorbents for oil spillage cleanup. PMID- 28732885 TI - Fouling resistant PVDF/Carboxymethyl chitosan composite nanofiltration membranes for humic acid removal. AB - In this work, carboxymethyl chitosan without a crosslinking agent was blended with polyvinylidene fluoride using non solvent induced phase inversion process. Carboxymethyl chitosan was synthesized using monochloroacetic acid and isopropanol and its structural elucidation was done. Synthesized carboxymethyl chitosan was incorporated with PVDF and investigated for its casting dope viscosity, x-ray photoelectron spectroscopy, thermal gravimetric analysis, mechanical properties, contact angle, scanning electron microscopy, atomic force microscopy and filtration studies. The designed precipitation kinetics was reflected on these composite membranes by having reduced pore sizes and increased thickness. MWCO was in the range between 600 and 2000 for the composite membranes. Low surface roughness and contact angle favoured the antifouling nature. Irreversible fouling minified as the carboxymethyl chitosan composition increased on the membrane and exhibited excellent mechanical and thermal stability and flux recovery ratio. The membranes were durable after two repeating cycles. PMID- 28732886 TI - Chitosan-hyaluronic acid composite sponge scaffold enriched with Andrographolide loaded lipid nanoparticles for enhanced wound healing. AB - In this work chitosan-hyaluronic acid composite sponge scaffold enriched with Andrographolide (AND) lipid nanocarriers was developed. Nanocarriers were prepared using solvent diffusion method by applying 23 factorial design. NLC4 had the highest desirability value (0.882) and therefore, it was chosen as an optimal nanocarrier. Itexhibited spherical shape with 253nm, 83.04% entrapment efficiency and a prolonged release of AND up to 48-h. Consecutively, NLC4 was incorporated in a chitosan-hyaluronic acid gel and lyophilized for 24h to obtain chitosan hyaluronic acid/NLC4 nanocomposite sponge to enhance AND delivery to wound sites. The morphology of sponge was characterized by scanning electron microscopy. Nanocomposites showed a porosity of 56.22% with enhanced swelling. The in vivo evaluation in rats reveals that the chitosan-hyaluronic acid/NLC4 sponge enhances the wound healing with no scar and improved tissue quality. These results strongly support the possibility of using this novel chitosan-hyaluronic acid/NLC4 sponge for wound care application. PMID- 28732887 TI - Thickening and water-absorbing agent made from euglenoid polysaccharide. AB - Paramylon, a storage polysaccharide of Euglena gracilis, is a linear beta-1,3 glucan with a weight-average molecular weight of ~2.0*105. Sequential long-chain acylation and succinylation of paramylon yielded amphiphilic paramylon acylate succinates. Owing to their amphiphilicity, these paramylon derivatives showed higher viscosity than paramylon succinate when dispersed in an aqueous solution. Examination of the viscosity of aqueous solutions containing paramylon acylate succinates differing in chain length and degree of substitution of long-chain acyl groups (DSlca) revealed that the longer the acyl chain and the higher the DSlca, the higher the viscosity of the aqueous solution. Solution casting yielded transparent and mechanically tough films from paramylon acylate succinates. These films had high water absorbability, up to ~1000 times their weight. PMID- 28732888 TI - Separation of polysaccharides from Spirulina platensis by HSCCC with ethanol ammonium sulfate ATPS and their antioxidant activities. AB - Three separation methods for water-soluble polysaccharides from Spirulina platensis (PSP) were compared, including sevage deproteinization and column chromatography, ethanol-ammonium sulfate aqueous two-phase system (ATPS) and column chromatography, and one-step high speed counter-current chromatography (HSCCC) with ethanol-ammonium sulfate ATPS. ATPS was confirmed as an efficient alternative method of protein removal for PSP purification. For the HSCCC with ethanol-ammonium sulfate ATPS, the stationary retention reached to 50.8% at the optimized rotation speed and flow rate. Moreover, the yield of PSP purified by one-step HSCCC rose nearly five times to 12.45mg/g(dry algae powder), it was higher than PSP yield by two-step column chromatography separation methods. PSP purified by HSCCC has the same purity as PSP obtained by traditional methods, which was proved by a single symmetrical peak of purified PSP with molecular weight of 12.33kDa through gel chromatography. Purified PSP was an alpha-acidic polysaccharide, composed of major glucose, slight rhamnose and mannose, which were detected within GC and FT-IR spectra. The antioxidation activity experiment showed that HSCCC-purified PSP had strong scavenging effects on hydroxyl free radical and DPPH free radical. PMID- 28732889 TI - A comparative study on chitosan/gelatin composite films with conjugated or incorporated gallic acid. AB - Gallic acid-grafted-chitosan (GA-g-CS) was synthesized in the presence of 1-ethyl 3-(3'-dimethylaminopropyl) carbodiimide and hydroxybenzotriazole under room temperature. To develop a kind of newly functional film, CS, gelatin, glycerol and Tween 20 were utilized to prepare CS-based composite films with incorporated GA (GA-CS) or conjugated GA (GA-g-CS), and the films were characterized in aspects of physical and functional properties, as well as microstructures. With the increasing of GA concentration, there was a reduction in transmittance, elongation at break and water vapor permeability (WVP) for GA-CS film. For GA-CS films, the higher tensile strength and lower WVP could be obtained when GA was evenly distributed across the films. Different from the GA-CS films, water solubility, swelling ratio, water vapor permeability and scavenging activities on 2,2-Diphenyl-1-picrylhydrazyl/2,2'-azino-bis-(3-ethylbenzothiazoline-6-sulphonic acid) radicals were enhanced for GA-g-CS films, which could be ascribed to the rough surface morphology. The GA-g-CS films exhibited enhanced water vapor permeability when the substitution degree of GA increased. Also, the antimicrobial activities of GA-g-CS films were superior to those of GA-CS films. Our present work developed a way to prepare GA-g-CS films that owned many desirable properties and could be explored as promising biomaterials in food packaging. PMID- 28732890 TI - Effects of supercritical carbon dioxide sterilization on polysaccharidic membranes for surgical applications. AB - Sterilization methods such as gamma-irradiation, steam sterilization and ethylene oxide gas treatment can have negative effects on molecular structure and properties of polysaccharide-based biomaterials. In this perspective, the use of supercritical carbon dioxide (scCO2) has been proposed as an alternative method for biomaterial sterilization. In this work, chemical, mechanical and biological properties of polysaccharidic membranes for surgical applications were investigated after sterilization by scCO2. Four sets of sterilizing conditions were considered and SEC analyses were performed in order to identify the one with lower impact on the polysaccharidic matrix of membranes (alginate). Mechanical tests showed that the resistance of membranes was slightly affected after sterilization. Biological analyses proved the biocompatibility of the sterilized membranes both in vitro and in a preliminary in vivo test. Overall, this study points out that this sterilization technique can be successfully employed to achieve an effective and safe sterilization of polysaccharidic membranes for surgical use. PMID- 28732891 TI - Direct production of cellulose nanocrystals from old newspapers and recycled newsprint. AB - Cellulose nanocrystals (CNC) are high added value products which can be used in many applications. In this research, CNC were directly produced from two recycled papers: old newspapers (ONP) and 100% recycled newsprint (NP). CNC were also obtained from NP by previously isolating the cellulose particles by alkali and bleaching treatments. CNC yield and quality was assessed through lignin and ash determination, X-ray diffraction analysis, atomic force microscopy and thermogravimetric analysis. Not only crystallinities resulted similar (92-95%), but also aspect ratios (L/d) (each in the range of 50-120). However, different CNC purities and hydrolysis and process yields were obtained. Thus, CNC purity decreased from 93 to 77%, hydrolysis yield was reduced from 64 to 58% but process yield strongly improved from 35 to 60% when no pretreatment was used. Therefore, this study proves the viability of the direct production of CNC from recycled papers. PMID- 28732892 TI - Biodegradable blend membranes of poly (butylene succinate)/cellulose acetate/dextran: Preparation, characterization and performance. AB - The aim of this study is to prepare biodegradable blend membranes of poly (butylene succinate) (PBS)/cellulose acetate (CA)/dextran (DEX). The effect of DEX concentration as an additive on morphology, porosity, hydrophilicity, mechanical strength, biodegradability, antifouling properties, and performance of dairy wastewater treatment of the membranes was investigated. Results demonstrated that larger pores were formed in the membrane structure and the porosity of the membranes was remarkably increased by adding DEX concentration. Moreover, contact angle was reduced up to 16% with the increase in the DEX concentration from 0 to 2wt.%. The presence of a larger amount of DEX increased the membrane degradation. Furthermore, the results of filtration tests showed that the amounts of pure water flux and permeate flux of wastewater was improved by 154% and 1543%, respectively, by increasing the additive concentration to 2wt.%. The PBS/CA/DEX membranes displayed a superior antifouling performance compared to the PBS/CA membrane. PMID- 28732893 TI - Polyethylene cellulose nanofibrils nanocomposites. AB - This paper investigates the use of an aqueous dispersion of polyethylene copolymer with a relatively high content of acrylic acid as a compatibilizer and as an alternative medium to obtain polyethylene CNF nanocomposites. The CNF content was varied from 1 to 90wt% and the appearance, optical, thermal, mechanical and rheological properties, as well the morphology of the films were evaluated. The PE/CNF films are transparent up to 20wt% of NFC indicating a good dispersion of CNF, but a poor distribution, with PE-rich and CNF-rich regions observed by SEM. Improved mechanical properties were achieved, with a 100% and 15,900% increase in the Young's modulus with 1wt% and 90wt% NFC, respectively. The rheological behavior indicated good melt processability. According to these results, aqueous polyolefin dispersions seem to be a promising, easy and relatively fast route for obtaining cellulose/polyolefins nanocomposites with low to high contents of cellulose nanofibrils. PMID- 28732895 TI - Wood-mimetic skins prepared using horseradish peroxidase catalysis to induce surface wrinkling of chitosan film upon drying. AB - We previously developed bio-based wrinkled surfaces induced by wood-mimetic skins upon drying in which microscopic wrinkles were fabricated on a chitosan (CS) film by immersing it in a phenolic acid solution, followed by horseradish peroxidase (HRP)-catalyzed surface reaction and drying. However, the detailed structure of the resulting wood-mimetic skins, including crosslinking mode and thickness, has not been clarified due to the difficulty of the analysis. Here, we prepare wrinkled films using ferulic acid (FE), vanillic acid (VA), and homovanillic acid (HO) and characterize their structures to clarify the unknown characteristics of wood-mimetic skin. Chemical and structural analyses of wood-mimetic skins prepared using VA and HO indicate that the crosslinking structure in the skin is composed of ionic bonds between CS and an oligophenolic residue generated by the HRP-catalyzed reaction on the CS surface. Moreover, the quantity of these ionic bonds is related to the skin hardness and wrinkle size. Finally, SEM and TOF-SIMS analyses indicate that the skin thickness is on the submicron order (<200nm). PMID- 28732894 TI - Structural properties and foaming of plant cell wall polysaccharide dispersions. AB - Water suspensions of cellulose nanofibres with xylan, xyloglucan and pectin were studied for foaming and structural properties as a new means for food structuring. The dispersions were analysed with rheological measurements, microscopy and optical coherence tomography. A combination of xylan with TEMPO oxidized nanocellulose produced a mixture with well-dispersed air bubbles, while the addition of pectin improved the elastic modulus, hardness and toughness of the structures. A similar structure was observed with native nanocellulose, but the elastic modulus was not as high. Shear flow caused cellulose nanofibres to form plate-like flocs in the suspension that accumulated near bubble interfaces. This tendency could be affected by adding laccase to the dispersion, but the effect was opposite for native and TEMPO-oxidized nanocellulose. Nanocellulose type also influenced the interactions between nanofibers and other polysaccharides. For example, xyloglucan interacted strongly with TEMPO-oxidized nanocellulose (high storage modulus) but not with native nanocellulose. PMID- 28732896 TI - A hydrogel actuator with flexible folding deformation and shape programming via using sodium carboxymethyl cellulose and acrylic acid. AB - Hydrogel actuator is an intelligent material, which can work as artificial muscle. However, most present hydrogel actuators, due to the inferior mechanical property and uncontrolled folding property, have always resulted in slipping off or the failure of grasping an object with specific shape and required weight. In order to solve this problem, here a tough hydrogel actuator with programmable folding deformation has been prepared by combining the "selective implanting method" and "ionic coordination". The shape and folding angle (from 0 to 180 o) of hydrogel actuator can be precisely controlled by altering the location and size of the implanting parts that seems like the joints of finger. The ionic coordination is not only the force to trigger the folding of hydrogel, but also utilized to reinforce the mechanical property. We believed the superior mechanical and shape-programmable property can endow the hydrogel actuator with great application prospect in soft machine. PMID- 28732897 TI - Preparation and characterization of novel chitosan and beta-cyclodextrin polymer sponges for wound dressing applications. AB - Chitosan (CS) presents antibacterial, mucoadhesive and hemostatic properties and is an ideal candidate for wound dressing applications. This work reports the development of sponge-like materials obtained from physical hydrogels after the interaction between CS and a beta-cyclodextrin polymer (PCD) in acidic conditions to provoke immediate gelation. Characterization consisted of zeta potential (ZP) measurements, rheology analysis, Fourier transform infrared (FTIR), Raman spectroscopy, wide angle X-ray scattering (WAXS) and scanning electron microscopy (SEM). Swelling behavior, cytotoxicity, drug sorption and drug delivery properties of sponges were assessed. ZP indicated that CS and PCD presented opposite charges needed for physical crosslinking. Rheology, swelling, and cytotoxicity of sponges depended on their CS:PCD weight ratios. Increasing PCD in the mixture delayed the gel time, reduced the swelling and increased the cytotoxicity. FTIR and Raman confirmed the physical crosslinking between CS and PCD through ionic interactions, and WAXS showed the amorphous state of the sponges. Finally, the efficiency of chlorhexidine loaded sponge against S. aureus bacteria was proved for up to 30days in agar diffusion tests. PMID- 28732898 TI - Facile approach to the fabrication of 3D cellulose nanofibrils (CNFs) reinforced poly(vinyl alcohol) hydrogel with ideal biocompatibility. AB - In this study, the reinforcing effects of cellulose nanofibrils (CNFs) on poly (vinyl alcohol) (PVA) matrix were explored. And ethylene glycol was used to enhance the water content and phosphate buffer saline (PBS) absorbency. The morphological aspects of the hydrogel were studied by transmission electron microscope (TEM) and scanning electron microscopy (SEM). The presence of interactions, changes in crystallinity as well as thermal behaviour were investigated by Fourier transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD) and thermogravimetry respectively. With the increase of CNFs concentration, the composite greatly improved its mechanical strength while maintaining remarkable ductility through tensile test results. The positive results of cell toxicity test suggested our porous hydrogel could provide ideal cell growth environment. This work revealed that CNFs hydrolysed by bacterial cellulose could perform as a perfect reinforcing agents which is of great interest in the fields of biotechnology and biomedicine with the potential values in cell culture, co-cultivation, as well as biomedical scaffold materials. PMID- 28732900 TI - Characterization of layered silicate-reinforced blends of thermoplastic starch (TPS) and poly(butylene adipate-co-terephthalate). AB - A two-step melt blending procedure was used to produce binary systems composed of thermoplastic starch (TPS) and poly(butylene adipate-co-terephthalate) (PBAT). To improve the properties of the blends, two different layered silicates, viz. bentonite (BT) and organically modified montmorillonite (oMMT) were incorporated. First, TPS and its layered silicate nanocomposites were prepared via extrusion compounding during which starch was plasticized with glycerol and water. In the second step, PBAT was added to TPS/layered silicate to produce blends in a batch type mixer. Mechanical and thermal properties were determined. The blends showed acceptable ductility over 50wt.% PBAT content, although at the cost of strength and stiffness. By contrast to oMMT the BT became intercalated in TPS and TPS/PBAT blends. The reinforcing effect of BT and oMMT was most prominent for the glassy states of both TPS and TPS/PBAT blends. Thermal, and thermooxidative properties were not significantly affected by the presence of layered silicates. PMID- 28732899 TI - In situ reduction of silver nanoparticles by chitosan-l-glutamic acid/hyaluronic acid: Enhancing antimicrobial and wound-healing activity. AB - Spongy composites with silver nanoparticles (AgNPs) were synthesized by freeze drying a mixture of silver nitrate (AgNO3) and chitosan-l-glutamic acid (CG) derivative loaded with hyaluronic acid (HA) solution. CG/AgNP spongy composites had an interconnected porous structure and rough surfaces. When AgNPs (5-20nm) were immobilized on these spongy composites, AgNP aggregation was dependent on AgNO3 concentration. The spongy composites exhibited good mechanical properties, swelling, and water retention capacity. In vitro antibacterial activity showed that the CG/AgNP spongy composites effectively inhibited bacterial (Escherichia coli and Staphylococcus aureus) growth and penetration. Spongy composites containing low concentrations of AgNP were non-toxic to L929 cells, while CG/HA/AgNP spongy composites promoted wound healing, as determined by in vivo tests, wound contraction ratio, average healing time, and histological examination. These results indicate that the spongy composites can serve as effective antibacterial wound dressings. PMID- 28732901 TI - Multiple polysaccharide-drug complex-loaded liposomes: A unique strategy in drug loading and cancer targeting. AB - In the present study, a unique strategy was developed to develop nanocarriers containing multiple therapeutics with controlled release characteristics. In this study, we demonstrated the synthesis of dextran sulfate-doxorubicin (DS-DOX) and alginate-cisplatin (AL-CIS) polymer-drug complexes to produce a transferrin ligand-conjugated liposome. The targeted nanoparticles (TL-DDAC) were nano-sized and spherical. The targeted liposome exhibited a specific receptor-mediated endocytic uptake in cancer cells. The enhanced cellular uptake of TL-DDAC resulted in a significantly better anticancer effect in resistant and sensitive breast cancer cells compared to that of the free drugs. Specifically, DOX and CIS at a molar ratio of 1:1 exhibited better therapeutic performance compared to that of other combinations. The combination of an anthracycline-based topoisomerase II inhibitor (DOX) and a platinum compound (CIS) resulted in significantly higher cell apoptosis (early and late) in both types of cancer cells. In conclusion, treatment with DS-DOX and AL-CIS based combination liposomes modified with transferrin (TL-DDAC) was an effective cancer treatment strategy. Further investigation in clinically relevant animal models is warranted to prove the therapeutic efficacy of this unique strategy. PMID- 28732902 TI - Review on production, downstream processing and characterization of microbial pullulan. AB - Pullulan, one of the commercially important microbial exopolysaccharides, is produced by the yeast like fungus Aureobasidium pullulans. It is non-mutagenic, non-toxic, non-hygroscopic, tasteless, odorless, water soluble and edible polymer. Owing to its excellent film forming properties, and typical rheological properties, it is extensively used in diverse industrial applications that include food, agriculture, textiles, cosmetics and pharmaceuticals. In the recent past, there has been growing interest to produce pullulan from low cost substrates in order to bring down cost of pullulan. The cost, productivity and properties of pullulan are highly influenced by the selection of raw material (upstream processing), type of fermentation & fermentation conditions (bioprocessing) and product recovery steps (downstream processing). In addition, both upstream and bioprocessing also affect the rheological, thermal and physical properties of the product. The present review discusses the literature on upstream processing, bioprocessing, product recovery and applications of pullulan. PMID- 28732903 TI - High-efficient production of fructo-oligosaccharides from inulin by a two-stage bioprocess using an engineered Yarrowia lipolytica strain. AB - A convenient and efficient two-stage bioprocess was established for fructo oligosaccharides (FOSs) production, during which the endo-inulinase was first produced and subsequently the inulin supplemented was directly hydrolyzed by the produced endo-inulinase, in the meantime the generated non-prebiotic saccharides was assimilated by the yeast cells. This process was implemented by an engineered Yarrowia lipolytica strain Enop56, in which an optimized endo-inulinase gene from Aspergillus niger was overexpressed. When the strain Enop56 was fermented with an inulin concentration of 600g/L in a 10-L bioreactor, the inulinase activity, FOSs titer, yield and productivity reached to 551.6U/mL, 546.6g/L, 0.91gFOS/gInulin, and 15.18g/L/h, respectively. Besides, the hydrolysis products were mainly FOSs with polymerization degrees of 3-5 and the total amount of non-prebiotic mono- and disaccharides was only 4.97% in the final fermentation broth. This study demonstrated that the two-stage bioprocess using the strain Enop56 was a promising strategy to produce FOSs on an industrial scale. PMID- 28732904 TI - Preparation and characterization of mucosal adhesive and two-step drug releasing cetirizine-chitosan nanoparticle. AB - To develop a functional nanosized mucosal drug delivery system, a series of amphiphilic cetirizine-chitosan polymer (CTZ-CSs) were constructed. CTZ-CSs could self-assemble into nanoparticles (NPs) which gradually evolved from irregular aggregates to spherical particles with an increasing substitution degree (DS) in CTZ group. The average particle size of CTZ-CSs-NPs with nano ZS90 Zetasizer varied from 153.92nm to 184.48nm and their zeta potential varied between +19.14mV and +22.93mV. Biocompatibility assay exhibited CTZ-CS-NPs had few adverse effects within a certain concentration range. Cetirizine dihydrochloride(CedH):CTZ-CS-NPs displayed burst and sustained drug release profiles in the presence of lysozyme. CedH showed a burst release during the first 6h, after which the release rate slowed down significantly. The release of CedH totally sustained for 72h. Ex vivo mucosal adhesion indicated CedH:CTZ-CS-NPs were able to prolong the residence time in the entire small intestine mucosa. PMID- 28732905 TI - Preparation of fungus-derived chitin nanocrystals and their dispersion stability evaluation in aqueous media. AB - The chitin nanocrystal is a promising nano-reinforcing agent, but the parasitic pathogens carried on crabs and shrimp shells as main sources limit its application in some fields. In this study, the ChNs which avoided possible safety risks were extracted from mushrooms via protein/mineral-purification and subsequent HCl-hydrolysis. Such fungus-derived ChNs presented an alpha-chitin crystalline structure with a length of 143+/-24nm and a diameter of 10+/-2nm. Since the dispersion stability of ChNs suspension determines their further applications, this present study emphasized the dispersity of ChNs in aqueous media evaluated by the viscosity under steady-shear flow and UV-vis absorption, whose results indicated that ChNs in dispersion would aggregate when the concentration of homogeneous dispersion reached 0.5-0.6wt%. To explore the effect of electrostatic repulsion on interactions between nanoparticles, the maximum energy barriers for parallel and crossed orientations of ChNs in suspension were analyzed using a traditional DLVO theory with additions of NaCl solutions. PMID- 28732906 TI - Developing of a magnetite film of carboxymethyl cellulose grafted carboxymethyl polyvinyl alcohol (CMC-g-CMPVA) for copper removal. AB - Crosslinked carboxymethyl cellulose grafted carboxymethyl polyvinyl alcohol (CMC g-CMPVA) was loaded with modified magnetite iron oxide (Fe3O4) nanoparticles to synthesise a new and easily separable adsorbent for the removal of copper (II) ions from water. The novel adsorbents were characterised by the presence of the functional group, surface morphology, crystallinity and magnetic property. The equilibrium time from the adsorption studies was found to be less than 240min for both film and bead forms while the rate of Cu2+ removal decreased as the initial Cu2+ concentration increased. In addition, CMC-g-CMPVA film loaded with Fe3O4/SiO2 nanoparticles was the best adsorbent with maximum adsorption capacity of 35.34mg/g and exhibited a reusable potential. The properties exhibited by the new heterogeneous material is a promising adsorbent for the removal and recovery of copper (II) from wastewater. PMID- 28732907 TI - Preparation of sodium cellulose sulfate oligomers by free-radical depolymerization. AB - Sodium cellulose sulfates with various degree of substitution (DS) and degree of polymerization (DP) were synthesized by homogeneous sulfation of cellulose with different DP by using SO3/pyridine (Py) complex in N,N-dimethylacetamide/lithium chloride (DMA/LiCl). Sodium cellulose sulfate (SCS) samples obtained were free radically depolymerized with hydrogen peroxide and copper (II) acetate at a controlled pH value of 7.5-8.0 and without control of the pH value (pH 2.5-4.0). The depolymerization process was studied with respect to changes in molecular mass, total DS, and substituent distribution of SCS. Elemental analysis, 13C NMR- and IR spectroscopic methods indicated that primary structures of SCS were retained with insignificant decreases in total sulfate content in the depolymerization. The depolymerization of SCS was randomly and obeyed pseudo first order kinetics under the conditions applied. SCS oligomers with low DP and very narrow molecular weight distribution were prepared by the depolymerization at pH 2.5-4.0. PMID- 28732908 TI - Manufacture and characterization of chitosan/PLGA nanoparticles nanocomposite buccal films. AB - Oral bioavailability of C-glycosyl flavonoid enriched fraction of Cecropia glaziovii (EFF-Cg) is limited due to its chemical complexity. The purpose of this study is the prospective evaluation of chitosan buccal films impregnated with EFF Cg-loaded nanospheres as a drug delivery system for labial herpes treatment or for buccal administration. EFF-Cg-loaded PLGA nanospheres were prepared by double emulsion solvent evaporation technique. Nanoparticles were embedded into buccoadhesive chitosan films in different concentrations in order to obtain nanocomposite films. Films were characterized in term of morphology, mechanical properties and water absorption test. Furthermore a cytotoxicity assay was analyzed to evaluate the biocompatibility of systems. The results obtained from these analyses revealed that nanocomposite films present transparent appearance in all composition and Scanning Electron Microscopy (SEM) images show a continuous and compact section structure. Compared to the control film, mechanical responses of nanocomposites presented lower tensile strength values and no significant effect on the elongation at break. Dynamic Mechanical Analysis (DMA) tests indicated that increasing of NP concentration caused decreased stiffness and an increased of glass transition temperature values. Direct cytotoxicity test shows that nanoparticles and chitosan films not induce cytotoxic effect. Given the promising results, the study concludes that the developed buccal film impregnated with EFF-Cg-loaded nanospheres could be a promising approach for effective delivery of EFF-Cg. PMID- 28732909 TI - Optimization, synthesis, and characterization of coaxial electrospun sodium carboxymethyl cellulose-graft-methyl acrylate/poly(ethylene oxide) nanofibers for potential drug-delivery applications. AB - In this study, nanofiber drug carriers were fabricated via coaxial electrospinning, using a new, degradable core-shell nanofiber drug carrier fabricated via coaxial electrospinning. Fabrication of the shell was carried out by graft polymerization of sodium carboxymethyl cellulose (NaCMC) with methyl acrylate (TCMC) and poly(ethylene oxide) (PEO). Tetracycline hydrochloride (TCH) was used as a drug model incorporated within the nanofibers as the core, and their performance as a drug carrier scaffold was evaluated. The loading of TCH within PEO nanofibers and the loading of TCH within the TCMC nanofibers were characterized via different techniques. The structure morphology of the obtained nanofibers was viewed under scanning electron microscope (SEM). The changes in the polymer structure before and after grafting and confirmation of incorporation of the drug in the fibers were characterized by Fourier transform infrared spectroscopy (FT-IR). Response surface methodology (RSM) was applied to predict the optimum conditions for fabrication of the nanofibers. The cell viability of the optimized samples was assessed with 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay. The TCH loaded into the optimized core shell sample of TCMC 3% (w/v)/PEO 1% (w/v) had a smooth and beadless morphology with a diameter of 86.12nm, slow and sustained drug release, and excellent bactericidal activity against a wide range of bacteria. This shows promise for use as an antibacterial material in such applications as tissue engineering and pharmaceutical science. PMID- 28732910 TI - Structural characterization and antioxidant property of released exopolysaccharides from Lactobacillus delbrueckii ssp. bulgaricus SRFM-1. AB - Three released exopolysaccharide fractions (r-EPS1, r-EPS2 and r-EPS3) were isolated from the fermented milk of Lactobacillus delbrueckii ssp. bulgaricus SRFM-1 and purified by anion exchange chromatography, and characterizations of the structures were conducted. The r-EPS1 and r-EPS2 were homogenous with the average molecular weights of 3.97*105Da and 3.86*105Da, respectively. Three r-EPS fractions were composed of galactose and glucose with a molar ratio of 1.23: 1.00, 1.33: 1.00 and 1.00: 1.34, respectively. Structural characterization indicated that the r-EPS1 contained a backbone of ->6-beta-d-Galp-(1->4)-beta-d Glcp-(1->4)-alpha-d-Galp-(1->4)-beta-d-Galp-(1->6)-beta-d-Galp-(1->4)-beta-d-Glcp (1->4)-alpha-d-Galp-(1->4)-beta-d-Galp-(1->4)-alpha-d-Glcp-(1->, and had three branching points which existed in terminal with D-Glcp residues with alpha/beta-d (1->6) linkages. The r-EPS2 was composed of ->6-beta-d-Galp-(1->4)-beta-d-Glcp-(1 >6)-alpha-d-Galp-(1-> as the backbone chain with a branching point which also existed in terminal D-Glcp residue with beta-(1->6) linkage. In addition, three r EPS fractions exhibited strong scavenging activities on superoxide radical, hydroxyl radical, DPPH radical and chelating activity on ferrous ion, and their antioxidant activities decreased in the order of r-EPS1>r-EPS2>r-EPS3. PMID- 28732911 TI - Toxicity of native and oxovanadium (IV/V) galactomannan complexes on HepG2 cells is related to impairment of mitochondrial functions. AB - Polysaccharides and vanadium compounds have been studied due to their antitumor potential. In this study, the cytotoxic effects of galactomannan preparations on HepG2 cells were investigated. Native galactomannan from S. amazonicum (SAGM) and its modified form (MSAGM) were complexed with oxovanadium resulting in SAGM:VO and MSAGM:VO, respectively. The complexation was confirmed by NMR, FTIR, and AAS. SAGM and MSAGM:VO (250MUg/mL) after 72h decreased viability by 51% and 58%, respectively, while the inhibition of the HepG2 cell proliferation was of ~27% and ~46%, respectively. SAGM and MSAGM:VO (250MUg/mL) significantly inhibited all states of respiration (basal: 85% and 63%; uncoupled: 90% and 70%; and leak: 30% and 58%) after 72h. ROS levels increased by ~149% after the treatment with MSAGM:VO (250MUg/mL) for 72h, while DeltaPsim decreased by ~50%. Our results indicate that galactomannan preparations from S. amazonicum, especially SAGM and the MSAGM:VO complex, could be considered as potential antitumor drugs for further investigations, once they have the ability to make HepG2 cells susceptible to death by affecting vital cellular processes such as respiration and ROS generation. PMID- 28732912 TI - Structural and mechanical characterization of bacterial cellulose-polyethylene glycol diacrylate composite gels. AB - This study explores the structural and mechanical properties of bacterial cellulose-polyethylene glycol diacrylate (BC-PEGDA) composite gels. The molecular dynamics results obtained by solid-state 13C nuclear magnetic resonance analyses suggested that BC and PEGDA molecules were incompatible as composite gels, though BC fibers and PEGDA interact with each other. The mechanical strength of the gels depended on the amount of PEGDA, becoming softer and more stretchable when a tensile force was applied, but for a large amount of PEGDA, they became brittle. The BC-3% and 5% PEGDA gels had similar viscoelastic behaviors as a BC gel, and these composite gels could stick to human skin. Since BC-PEGDA composite gels are composed of BC and PEGDA-both of which are biocompatible, it is thought that these composite gels also have excellent biocompatibility. Taken together, we concluded that the BC-3% and 5% PEGDA gels have great potential for use in medical and cosmetic fields. PMID- 28732913 TI - Anti-bacterial chitosan/zinc phthalocyanine fibers supported metallic and bimetallic nanoparticles for the removal of organic pollutants. AB - In this report, we prepared chitosan (CS) membrane, CS/zinc phthalocyanine (ZnPc CS) composite fibers and pellets as support for the synthesis of zero valent metal nanoparticles. The composite fibers and pellets of ZnPc-CS were prepared by simply dispersing 5wt% of ZnPc in CS solution. ZnPc-CS composite were applied as economical host material for the development of metallic and bimetallic zero valent nanoparticles. The composites of ZnPc-CS were put in 0.1M metals salt solutions (mono- and bi-metallic) for the adsorption of metal ions. The metal ions adsorbed ZnPc-CS fibers were treated with 0.1M sodium borohydride (NaBH4) aqueous solution for conversion of metal ions into nanoparticles. Thus, through water based in-situ preparation process, metals nanoparticles loaded on ZnPc-CS composite fibers and pellets were achieved. The presence of respective metals nanoparticles on the composite fibers was confirmed using FE-SEM, XRD and FTIR. Moreover, we determined that these composites exhibit excellent catalytic efficiency and recyclability in the reduction reactions of 4-nitrophenol (4-NP), methyl orange (MO) and cango red (CR). In addition, these composites displayed high antibacterial activity as tested against pathogenic bacteria Escherichia coli. PMID- 28732914 TI - Spermine modified starch-based carrier for gene delivery: Structure-transfection activity relationships. AB - This study aims at developing starch based gene carriers with low cytotoxicity and high transfection efficiency. Starch molecules with molecular weight of about 50kDa were cationically modified by spermine to obtain spermine modified starch (SMS) based gene carriers. Plasmid pAcGFP1-C1 (pDNA) was chosen as the model gene material and formed self-assembly nanocomplexes with SMS. The cytotoxicity and transfection efficiency of SMS/pDNA complexes were tested in HepG2 cell lines. Results showed that SMS/pDNA complexes formed by SMS-DS3 with the highest primary amine content (1.17MUmolmg-1) and pDNA at the weight ratio of 25 displayed the highest transfection efficiency (~40%) with low cytotoxicity. Dynamic Light Scattering (DLS) and Small Angel X-ray Scattering (SAXS) investigation under simulated acidified endosomal environments (pH 5.0-7.4) revealed that SMS DS3/pDNA complexes (~180nm) with moderately compact structures within acidic environments (i.e. no significant particle size changes, slightly shrunken shapes) showed superior transfection efficiency. PMID- 28732915 TI - Effect of silver contents in cellulose nanocrystal/silver nanohybrids on PHBV crystallization and property improvements. AB - Ternary nanocomposites including cellulose nanocrystals/silver nanohybrids (CNC Ag) and biodegradable poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) were prepared by using solution casting. The effect of different AgNPs contents in the nanohybrids on crystallization ability and properties of PHBV was comprehensively investigated. Compared to binary PHBV/CNC nanocomposite, the ternary nanocomposites with high AgNPs contents showed larger improvements in the thermal stability, mechanical, barrier, overall migration and antibacterial properties. The property transitions at various AgNPs contents were due to transition of the nanohybrids induced PHBV crystallization ability (from single CNC nucleation to synergistic nucleation of CNC and AgNPs), and increased crystallinity without compromising the amounts of hydrogen bonds. Especially, the PHBV/CNC-Ag-1.7 showed the good barrier property and lower migration levels in food simulants, high antibacterial ratio of 99.9% and biocompatibility to human MG-63 cells, suggesting its potential application in food packaging related materials. PMID- 28732916 TI - Preparation and characterization of hybrid double network chitosan/poly(acrylic amide-acrylic acid) high toughness hydrogel through Al3+ crosslinking. AB - Development of bio-based hydrogels with good mechanical properties is of great importance for their excellent biocompatibility and biodegradability. In this paper, chitosan (CS) based double network (DN) hydrogel was prepared by dissolving CS in AlCl3.6H2O aqueous solution instead of acetic acid solution. After dissolving acrylic amide (AM), acrylic acid (AA), N, N' methylenebisacrylamide and 2-hydroxy-4'-(2-hydoxyethoxy)-2-methylpropiophenone were added into the CS/Al3+ solution and the CS/PAMAA-Al3+ DN hydrogel was prepared by UV polymerization. The hybrid physical and chemical crosslinked network hydrogels were prepared. The tensile and compression properties of CS/PAMAA-Al3+ DN hydrogel were studied. The results showed that the CS/PAMAA-Al3+ DN hydrogels have high toughness, stretch-ability, and excellent shape recovery properties. The CS/PAMAA-Al3+ DN hydrogel could show the tensile strength of 0.54MPa and elongation at break of 2203.7%. These properties arise from the dynamic ionic interaction between Al3+ and CS/PAMAA macromolecular chains. PMID- 28732918 TI - Hydrophobic structural modification of chitosan and its impact on nanoparticle synthesis - A physicochemical study. AB - Chitin is a naturally occurring fully N-acylated biopolymer which cannot be converted into nanomaterial easily due to its inherent rigidity and chemical inertness. These properties limit the utility of chitin in nanomaterial-based applications. Therefore, our aim in the present work was, to prepare chitin like fully N-acylated derivatives with a hydrophobic moiety and study the impact on nanoparticles synthesis. We report such a fully substituted derivative, N (Thiophene-2-acetyl)chitosan, its characterization and physicochemical studies of the nanoparticles synthesized. The study confirms that the hydrophobic structural modification of chitosan improves the processability of the material and defines the nanoparticles synthesis. This kind of organic nanoparticles, stable under wide pH range due to amine group protection of chitosan, can be used as nano- reinforcement material to enhance the properties of various composites. PMID- 28732917 TI - Ultrasound assisted pectic polysaccharide extraction and its characterization from waste heads of Helianthus annus. AB - The main aim of this current work is to extract pectin from waste heads of Helianthus annus by ultrasound and optimize the process variables (ultrasound power (USP), pH, time of sonication (TS) and ratio of solid to liquid (RSL) on maximal recovery of pectin using central composite statistical experimental design. In addition to that, extracted pectin at optimal condition was characterized and compared with commercial pectin. The optimal extraction process condition was USP of 375w, pH of 3.2, TS of 32min and RSL of 1:15g/ml. Mean experimental pectin yield of 8.89+/-0.024% was well accord with predicted pectin yield (8.91%). Analysis of chemical composition and Fourier transform infrared spectroscopy of extracted pectin did not show any significant difference with commercial pectin. XRD analysis illustrated a similar crystalline profile in both extracted and commercial pectin. Morphological analysis was performed on fresh and extracted samples using scanning electron microscopy. PMID- 28732919 TI - Injectable thermosensitive hydrogel containing hyaluronic acid and chitosan as a barrier for prevention of postoperative peritoneal adhesion. AB - Peritoneal adhesion is one of the common complications after abdominal surgery. Injectable thermosensitive hydrogel could serve as an ideal barrier to prevent this postoperative tissue adhesion. In this study, poly(N-isopropylacrylamide) (PNIPAm) was grafted to chitosan (CS) and the polymer was further conjugated with hyaluronic acid (HA) to form thermosensitive HA-CS-PNIPAm hydrogel. Aqueous solutions of PNIPAm and HA-CS-PNIPAm at 10%(w/v) are both free-flowing and injectable at room temperature and exhibit sol-gel phase transition around 31 degrees C; however, HA-CS-PNIPAm shows less volume shrinkage after gelation and higher complex modulus than PNIPAm. Cell culture studies indicate both injectable hydrogel show barrier effects to reduce fibroblasts penetration while induce little cytotoxicity in vitro. From a sidewall defect-bowel abrasion model in rats, significant reduction of postoperative peritoneal adhesion was found for peritoneal defects treated with HA-CS-PNIPAm compared with those treated with PNIPAm and untreated controls from gross and histological evaluation. Furthermore, HA-CS-PNIPAm did not interfere with normal peritoneal tissue healing and did not elicit acute toxicity from blood analysis and tissue biopsy examination. By taking advantage of the easy handling and placement properties of HA-CS-PNIPAm during application, this copolymer hydrogel would be a potentially ideal injectable anti-adhesion barrier after abdominal surgeries. PMID- 28732920 TI - A rhamnan-type sulfated polysaccharide with novel structure from Monostroma angicava Kjellm (Chlorophyta) and its bioactivity. AB - A homogeneous polysaccharide was obtained from Monostroma angicava Kjellm by water extraction, preparative anion-exchange and size-exclusion chromatography. Results of chemical and spectroscopic analyses showed that the polysaccharide was a glucuronic acid-containing rhamnan-type sulfated polysaccharide. The backbone mainly consisted of ->3)-alpha-l-Rhap-(1-> and ->2)-alpha-l-Rhap-(1-> residues, partially sulfated at C-2 of ->3)-alpha-l-Rhap-(1-> and C-3/C-4 of ->2)-alpha-l Rhap-(1->. The branching contained unsulfated or monosulfated 3-linked, 2-linked, 4-linked alpha-l-rhamnose and terminal beta-d-glucuronic acid residues. The polysaccharide had strong antidiabetic activity assessed by glucose consumption, total cholesterol and triglyceride levels using human hepatocellular carcinoma (HepG2) and insulin-resistant HepG2 cells. The polysaccharide exhibited high anticoagulant property by activated partial thromboplastin time and thrombin time assays, and possessed high fibrin(ogen)olytic activity evaluated by plasminogen activator inhibitior-1, fibrin(ogen) degradation products and D-dimer levels using rats plasma. The investigation demonstrated that the polysaccharide from Monostroma angicava Kjellm was a novel sulfated rhamnan and could be a potential antidiabetic and anticoagulant polysaccharide. PMID- 28732921 TI - Glass transition of anhydrous starch by fast scanning calorimetry. AB - By means of fast scanning calorimetry, the glass transition of anhydrous amorphous starch has been measured. With a scanning rate of 2000Ks-1, thermal degradation of starch prior to the glass transition has been inhibited. To certify the glass transition measurement, structural relaxation of the glassy state has been investigated through physical aging as well as the concept of limiting fictive temperature. In both cases, characteristic enthalpy recovery peaks related to the structural relaxation of the glass have been observed. Thermal lag corrections based on the comparison of glass transition temperatures measured by means of differential and fast scanning calorimetry have been proposed. The complementary investigations give an anhydrous amorphous starch glass transition temperature of 312+/-7 degrees C. This estimation correlates with previous extrapolation performed on hydrated starches. PMID- 28732922 TI - The quality of functional whole-meal durum wheat spaghetti as affected by inulin polymerization degree. AB - The use of inulin in pasta improves the nutritional value decreasing the glycemic index in the blood after pasta ingestion but it compromises the sensory characteristics in terms of elasticity, firmness, bulkiness and adhesiveness. Thus, in this work, the impact of substituting whole-meal durum wheat flour with inulin on cooking quality, sensory and textural properties, digested starch and chemical composition of spaghetti was investigated. Two types of inulin at two different concentrations (2% and 4%) were adopted: inulin extracted from cardoon roots (CRI) (high polymerization degree) and commercial inulin (CHI) (low polymerization degree) produced from chicory. From the chemical point of view, the sample with 4% CRI showed the greatest total dietary fibres content and the lowest available carbohydrates content. A global acceptable quality was also recorded in all the other technological and sensory properties of enriched pasta with both types and both concentrations of inulin. The most feature of the work is that when CRI was added to the dough, better results were recorded, thus suggesting that for pasta enrichment, the selection of inulin with proper polymerization degree is a strategic factor for final product acceptance. PMID- 28732923 TI - Effect of TEMPO-oxidization and rapid cooling on thermo-structural properties of nanocellulose. AB - Recently, surface functionality and thermal property of the green nanomaterials have received wide attention in numerous applications. In this study, microcrystalline cellulose (MCC) was used to prepare the nanocrystalline celluloses (NCCs) using acid hydrolysis method. The NCCs was treated with TEMPO [(2,2,6,6-tetramethylpiperidin-1-yl)oxy radical]-oxidation to prepare TEMPO oxidized NCCs. Cellulose nanofibrils (CNFs) also prepared from MCC using TEMPO oxidation. The effects of rapid cooling and chemical treatments on the thermo structural property studies of the prepared nanocelluloses were investigated through FTIR, thermogravimetric analysis-derivative thermogravimetric (TGA-DTG), and XRD. A posteriori knowledge of the FTIR and TGA-DTG analysis revealed that the rapid cooling treatment enhanced the hydrogen bond energy and thermal stability of the TEMPO-oxidized NCC compared to other nanocelluloses. XRD analysis exhibits the effect of rapid cooling on pseudo 2I helical conformation. This was the first investigation performed on the effect of rapid cooling on structural properties of the nanocellulose. PMID- 28732924 TI - Ultrasonic irradiation enhanced the ability of Fluorescein-DA-Fe(III) on sonodynamic and sonocatalytic damages of DNA molecules. AB - The interaction of DNA with Bis [N,N-bis (carboxymethyl) aminomethyl] fluorescein Ferrous(III) (Fluorescein-DA-Fe(III)) with dual functional (sonodynamic and sonocatalytic) activity was studied by UV-vis spectroscopy, fluorescence spectroscopy, FT-IR spectroscopy, circular dichroism (CD) spectroscopy and viscosity measurements. And then, the damage of DNA caused by Fluorescein-DA Fe(III) under ultrasonic irradiation (US) was researched by agarose gel electrophoresis and cytotoxicity assay. Meanwhile, some influenced factors such as ultrasonic irradiation time and Fluorescein-DA-Fe(III) concentration on the damage degree of DNA molecules were also examined. As a control, for Bis [N,N-bis (carboxymethyl) aminomethyl] fluorescein (Fluorescein-DA), the same experiments were carried out. The results showed that both Fluorescein-DA-Fe(III) and Fluorescein-DA can interact with DNA molecules. Under ultrasonic irradiation, Fluorescein-DA shows sonodynamic activity, which can damage DNA molecules. While, in the presence of Fe(III) ion, the Fluorescein-DA-Fe(III) displays not only sonodynamic activity but also sonocatalytic activity under ultrasonic irradiation, which injures DNA more serious than Fluorescein-DA. The researches confirmed the dual function (sonodynamic activity and sonocatalytic activity) of Fluorescein-DA-Fe(III) and expanded the usage of Fluorescein-DA-Fe(III) as a sonosensitizer in sonodynamic therapy (SDT). PMID- 28732925 TI - Analysis of Staphylococcus aureus cell viability, sublethal injury and death induced by synergistic combination of ultrasound and mild heat. AB - This study was designed to investigate the combined effects of ultrasound and mild heat on the viability of S. aureus in association with the cell membrane integrity and intracellular enzyme activity. Cells were treated by ultrasound under 55 degrees C for 3, 5, 7, 10, and 15min. The dynamic changes of S. aureus cell viability, sublethal injury and death were evaluated using flow cytometric assay. Microscopies were applied to identify the morphological appearance, ultrastructure and topography of S. aureus. The results showed the membrane damage was synchronous with esterase inhibition during the exposure to sonication, leading to the immediate lethal effect. On the other hand, bacteria under the mild heat at 55 degrees C were inactivated via a sublethal injury process. The different lethal modes were observed between sonication and mild heat treatments, which could synergistically inactivate S. aureus. The antibacterial value of thermo-sonication was greater than the sum of the individual treatments. The thermo-sonication combination synergistically reduced the number of sublethal cells and also resulted in severe cell damage. PMID- 28732926 TI - Intensified oxalic acid crystallization using ultrasonic reactors: Understanding effect of operating parameters and type of ultrasonic reactor. AB - The present work reports the comparison of the effectiveness of ultrasonic bath and horn for intensifying the cooling crystallization of oxalic acid for the first time. The effect of various parameters such as temperature, crystallization time, irradiation time, ultrasonic frequency and ultrasonic power on the crystal characteristics has been investigated. The average particle size of oxalic acid crystals reduced with an increase in irradiation time and ultrasonic power dissipation. Comparison of crystal characteristics obtained in ultrasonic bath with that obtained in the ultrasonic horn under optimized parameters revealed that the average size in the case of ultrasonic horn and bath were only marginally different. The studies related to the effect of different cooling modes using ultrasonic horn revealed that a narrow size distribution and lower average size of 357.2um was obtained for the cooling using ice cold water as compared to air cooling where observed mean size was 439.7um. A narrow particle size distribution was also obtained in the scale-up studies using ultrasound horn with mean size of 96.70um, which was significantly lower than 161.1um obtained under conventional approach. Overall significant process intensification benefits have been established for the ultrasound assisted approach for cooling crystallization of oxalic acid. PMID- 28732928 TI - Sonocatalytic degradation of an anthraquinone dye using TiO2-biochar nanocomposite. AB - TiO2-biochar (TiO2-BC) nanocomposite was synthesized by sol-gel method. The characteristics of the prepared nanocomposite were examined using X-ray fluorescence, scanning electron microscopy, energy-dispersive X-ray spectroscopy, Fourier transform infrared spectroscopy and N2 adsorption-desorption analysis. The performance of synthesized TiO2-BC nanocomposite as efficient sonocatalyst was studied for the degradation of Reactive Blue 69 (RB69). Sonocatalytic degradation of RB69 in the presence of TiO2-BC nanocomposite could be explained by the mechanisms of hot spots and sonoluminescence. The optimized values for main operational parameters were determined as pH of 7, TiO2-BC dosage of 1.5g/L, RB69 initial concentration of 20mg/L and ultrasonic power of 300W. Furthermore, the effect of OH, h+ and O2- scavengers on the RB69 degradation efficiency was studied. Gas chromatography-mass spectroscopy analysis was used to identify intermediate compounds formed during the RB69 degradation. The results of repeated applications of TiO2-BC in the sonocatalytic process verified its stability in long-term usage. PMID- 28732927 TI - Ultrasound-promoted dispersive micro solid-phase extraction of trace anti hypertensive drugs from biological matrices using a sonochemically synthesized conductive polymer nanocomposite. AB - In this work, a rapid and efficient procedure named ultrasound meliorated dispersive micro solid-phase extraction followed by high performance liquid chromatography-ultra violet detection (US-D-MUSPE-HPLC-UV) was developed for the pre-concentration of the main trace anti-hypertensive drugs in complex matrices. The basis of this procedure was a polypyrrole-sodium dodecylbenzenesulfonate/zinc oxide (PPy-DBSNa/ZnO) nanocomposite. It was readily synthesized by the impressive way of in situ sonochemical oxidative polymerization in the presence of some additives such as FeCl3 and DBSNa, ultimately leading to the effective coating of PPy on the ZnO nanoparticle cores. Characterization of the proposed nanosorbent was performed by different techniques such as FESEM, XRD,EDX, and TGA, confirming the high quality and proper physico-chemical properties of the proposed sorbent. In order to better investigate the input variables, the central composite design (CCD) combined with the desirability function (DF) was utilized. The enriched optimum conditions consisted of the initial pH value of 11.8, 15mg of the PPy DBSNa/ZnO nanocomposite, a sonication time of 4.6min, and 100MUL of methanol, resulting in maximum responses at a relatively low extraction time with a logical DF. Under the optimum conditions, good linearity (5-5000, 2.5-3500, and 2.5 3000ngmL-1 for metoprolol, propranolol, and carvedilol, respectively, with the correlation of determinations (R2s) higher than 0.99), low limits of detection (LODs) (0.8-1.5ngmL-1), proper repeatabilities (relative standard deviation values (RSDs) below 6.3%, n=3), reasonable enrichment factors (EFs) (60-72), and good extraction recoveries (ERs) (higher than %75) were obtainable. These appropriate validations corroborated a good effectiveness of ultrasonic waves in the achievement of a supreme solid phase as well as a facile and efficient microextraction of the low therapeutic concentrations in human plasma and urine samples. PMID- 28732929 TI - Synthesis and characterization of a new nano lead(II) 0-D coordination supramolecular compound: A precursor to produce pure phase nano-sized lead(II) oxide. AB - Nano-structure of a new 0D Pb(II) coordination supramolecular compound, [Pb4(8 Quin)6](ClO4)2(1), L=8-HQuin=8-hydroxyquinolin ligand has been synthesized by use of a sonochemical process and characterized by scanning electron microscopy (SEM), X-ray powder diffraction (XRPD), Fourier transform infrared spectroscopy (FTIR) and elemental analyses. The structure of compound 1 was determined by single-crystal X-ray diffraction. The single crystal X-ray data of compound 1 implies that the Pb+2 ions are five coordinated. Each lead atom is coordinated to nitrogen and oxygen atoms of 8-hydroxyquinolin ligand. Topological analysis shows that the compound 1 is 1,2,3,4,4M12-1net. Nanoparticles of lead(II) oxide have been prepared by calcination of lead(II) coordination polymer at 500 degrees C that were characterized by scanning electron microscopy (SEM), X-ray powder diffraction (XRPD) and IR spectroscopy. PMID- 28732930 TI - Transglutaminase-set colloidal properties of wheat gluten with ultrasound pretreatments. AB - The low solubility of wheat gluten limits its accessibility. This work aimed to study the impact of ultrasonic pretreatments on the gelation of wheat gluten. The pretreatments included ultrasound combined with alkali, urea, Na2SO3, with or without the addition of transglutaminase (TGase). The gel strength of wheat gluten was 287g/cm2 after treatment with Na2SO3/ultrasound/TGase. The free sulfhydryl and disulfide bond content was significantly affected by ultrasound treatment. After treatments including TGase crosslinking, the molecular weight of wheat gluten complexes became larger. The network formed by the wheat gluten was transformed into a dense and homogenous structure after the pretreatment with Na2SO3/ultrasound/TGase. The content of random coil of wheat gluten increased. The gelation of wheat gluten could also be significantly enhanced by Na2SO3/ultrasound treatment followed by TGase treatment. Using physical and chemical pretreatments to allow TGase to enhance the gelation of wheat gluten may increase its uses as a food additive. PMID- 28732931 TI - Ultrasound-assisted synthesis of pH-responsive nanovector based on PEG/chitosan coated magnetite nanoparticles for 5-FU delivery. AB - pH-responsive magnetic carriers at the nanoscale are one of the most important agents for the targeted treatment of cancer. In this study, Fe3O4 nanoparticles were prepared by co-precipitation method and functionalized with three types of PEG using ultrasound waves. PEGlated particles were modified with chitosan shell through ultrasound-assisted double emulsion method. The prepared material which was used as a pH responsive carrier for pinpointed 5-FU delivery. The chemico physical properties of prepared nanoparticles have been investigated. Results demonstrated that pure Fe3O4 had a mean diameter of 20nm with the regular spherical shape which was increased after modification step depending on the type of PEG. 5-FU loading properties and releasing behaviors studies in different pHs which showed that 5-FU can be efficiently loaded in the Fe3O4@Cs-PEG. Also, in the case of release, the amount of 5-FU released at pH=5.8 is noticeably higher compared to the released amount at pH=7.4 in all three samples at any distinct time. For instance at pH=7.4, 27% of the 5-FU was released from the Fe3O4@Cs-PEG2 during 48h; as the pH decreases to 5.8, the cumulative amount of 5-FU released enhanced to 52%. The in vitro MTT assay results demonstrated that the cell viability decreases in all synthesized nanoparticles as the pH medium of MCF-7 culture became to 5.8. For example, cell viability of Fe3O4@Cs-sPEG decreased from 44+/-2% to 36+/-1.9% at a concentration of 5 (MUg/ml) as the pH varied from 7.4 to 5.8. PMID- 28732932 TI - Ultrasound assisted synthesis of performic acid in a continuous flow microstructured reactor. AB - The present work establishes in depth study of ultrasound assisted preparation of performic acid (PFA) in a continuous flow microstructured reactor. The influence of various parameters viz. formic acid: hydrogen peroxide molar ratio, flow rate, temperature and catalyst loading on the PFA formation were studied in a continuous flow microstructured reactor. In a continuous microstructured reactor in the presence of ultrasonic irradiation, the formation of PFA was found to be dependent on the molar ratio of formic acid: hydrogen peroxide, flow rate of reactants, temperature and catalyst loading (Amberlite IR-120H). The optimized parameter values are 1:1M ratio, 50mL/h, 40 degrees C and 471mg/cm3 respectively. Further, the performance of Amberlite IR-120H catalyst was evaluated for three successive cycles in continuous microstructured reactor. The performance of catalyst was found to be decreased with the usage of the catalyst and is attributed to neutralization of the sulfonic acid groups, catalyst shrinkage, or loss in pore sites. The experimental results revealed that, for an ultrasound assisted synthesis of PFA in continuous microstructured reactor the observed reaction time was even less than 10min. The observed intensification in the PFA synthesis process can be attributed to the intense collapse of the cavities formed at low temperature during ultrasonic irradiations, which further improved the heat and mass transfer rates with the formation of H2O2 during the reaction. The combined use of ultrasound and a continuous flow microstructured reactor has proved beneficial process of performic acid synthesis. PMID- 28732933 TI - Ultrasonic assisted synthesis of nanocomposite materials based on resole resin and surface modified nano CeO2: Chemical and morphological aspects. AB - In this study, phenol-formaldehyde (PF)/CeO2 nanocomposites (NC)s were prepared by in-situ polymerization of phenol and formaldehyde in alkali solution in the presence of surface modified CeO2 nanoparticles (NP)s by sonochemical assisted synthesis. The morphology and structure of PF/CeO2 NCs were characterized by using fourier transform infrared spectroscopy (FT-IR), field emission scanning electron microscopy (FE-SEM), atomic force microscopy (AFM), X-ray diffraction (XRD), and thermal analyses methods. It was found that due to the good dispersion of surface modified NPs in polymer matrix and the strong interfacial interaction between the CeO2 NPs and PF matrix, the thermal stability and thermo-mechanical properties of the PF/CeO2 NCs were greatly enhanced. FE-SEM and AFM analyses showed the uniform distribution of CeO2 NPs in PF matrix. The XRD patterns of NCs show the presence of crystalline CeO2 NPs in amorphous matrix. The thermal analysis results reveal that, with increases in the content of CeO2 NPs in PF matrix, the thermally stability factors of samples were drastically enhanced. PMID- 28732934 TI - Enhanced crack suppression ability of hybrid glass fiber reinforced laminated composites fabricated using GNP/epoxy system by optimized UDM parameters. AB - In this work, GFRPs with layer-up [+22/-22/90n]s were prepared and hybridized with 0.5wt% of GNPs to introduce in-situ crack suppression ability. Optimization of the processing parameters of ultrasonic dual mode mixing (UDM) process was adopted to disperse GNPs uniformly in the epoxy system and place them evenly at the interfacial zones of GFRPs. Test results show that 102% and 153% enhancement in tensile strength and Young's modulus has been achieved by the proposed method. Low stirring speed and low pulse-off time show significant effect on properties of the GFRPs. The fragmentation behaviour was investigated under optical microscope for GNP infused hybrid GFRPs and compared to that of the control. Failure investigation examined under FESEM showed reduced delamination for hybrid GFRPs having randomly oriented GNPs in their interfacial zone. This work exposes the effective espousal of the process to prepare GNP infused hybrid GFRPs having crack suppression ability at the interfaces. PMID- 28732935 TI - Preparation of nanostructured and nanosheets of MoS2 oxide using oxidation method. AB - Molybdenum disulfide (MoS2), a two-dimensional transition metal has a 2D layered structure and has recently attracted attention due to its novel catalytic properties. In this study, MoS2 has been successfully intercalated using chemical and physical intercalation techniques, while enhancing its surface properties. The final intercalated MoS2 is of many interests because of its low-dimensional and potential properties in in-situ catalysis. In this research, we report different methods to intercalate the layers of MoS2 successfully using acid treatment, ultrasonication, oxidation and thermal shocking. The other goal of this study is to form SO bonds mainly because of expected enhanced in-situ catalytic operations. The intercalated MoS2 is further characterized using analyses such as Fourier Transform Infrared Spectroscopy (FTIR), Raman, Contact Angle, X-ray diffraction (XRD), Field Emission Scanning Electron Microscope (FESEM), Energy Dispersive X-Ray Microanalysis (EDAX), Transmission electron microscopy (TEM), and BET. PMID- 28732936 TI - Oxygen and Indocyanine Green loaded microparticles for dual-mode imaging and sonodynamic treatment of cancer cells. AB - Oxygen and Indocyanine Green (ICG) loaded microparticles (OI-MPs) were fabricated by a gas-driven coaxial flow focusing (CFF) process for dual-mode imaging and sonodynamic therapy (SDT). The produced OI-MPs agent showed stable optical properties, superior imaging depth in near infrared (NIR) fluorescence imaging, and enhanced acoustic contrast after ultrasound mediation. We hypothesized that encapsulating ICG and oxygen in microparticles would enhance reactive oxygen species (ROS) production in SDT. This hypothesis was validated in a cell-free environment. We further hypothesized that ultrasound mediated fragmentation of the OI-MPs would induce cytotoxicity and apoptosis of cancer cells. This hypothesis was validated in SKOV3 ovarian cancer cells. Our research demonstrated that OI-MPs can be potentially used as a dual-mode theranostic agent for image guided SDT with enhanced efficacy. Further study is needed to delineate the mechanism of ROS-induced cell apoptosis and optimize the OI-MPs formulation for the maximal anti-cancer potency. PMID- 28732937 TI - Dispersion enhancing effect of sonochemically functionalized graphene oxide for catalysing antioxidant efficacy of curcumin. AB - The non-hazardous sonochemical approach has been developed for the functionalization of graphene oxide (GrO) with 5-Aminoindazole (5-AIND). The formation of f-(5-AIND) GrO is confirmed with 13C solid state NMR, HRXPS, XRD, Raman, TGA, DSC, FTIR etc. The >80% cell viabilities on MCF-7 and Vero cell lines have confirmed the high cytocompatibility of f-(5-AIND) GrO. Additionally, the morphological impact on Vero cell line has evidently confirmed the biocompatibility of f-(5-AIND) GrO. As compared to GrO, the f-(5-AIND) GrO has demonstrated an enhanced antioxidant efficacy of 69.4-72%, evaluated with 2, 2 diphenyl-1-picrylhydrazyl (DPPH) free radical assay. With a similar objective (0.01-0.05)mL peanut oil based curcumin micro and nanoemulsions have been prepared using ethanol and glycerol as co-solvent and co-surfactant respectively. The prepared emulsions are subsequently characterised with respect to morphological and physicochemical parameters via density, surface tension, viscosity, friccohesity measurement and DLS analysis. Henceforth, with an expectation to achieve higher dispersion, an ethanolic dispersion of f-(5-AIND) GrO has been mixed with curcumin carrying emulsions in 1:1. Notably, the radical scavenging activities (RSA) of the combined formulations are significantly enhanced to an extent of 26.6%. PMID- 28732938 TI - Commenting the "Sonochemical synthesis of two new zinc(II) 1,10-phenanthroline coordination supramolecular compounds: New precursors to produce nano-sized zinc(II) oxide". PMID- 28732939 TI - Electromechanical, acoustical and thermodynamical characterization of a low frequency sonotrode-type transducer in a small sonoreactor at different excitation levels and loading conditions. AB - The paper reports and compares the results of the electromechanical, acoustical and thermodynamical characterization of a low-frequency sonotrode-type ultrasonic device inside a small sonoreactor, immersed in three different loading media, namely, water, juice and milk, excited at different excitation levels, both below and above the cavitation threshold. The electroacoustic efficiency factor determined at system resonance through electromechanical characterization in degassed water as the reference medium is 88.7% for the device in question. This efficiency can be reduced up to three times due to the existence of a complex sound field in the reactor in linear driving conditions below the cavitation threshold. The behaviour of the system is more stable at higher excitation levels than in linear operating conditions. During acoustical characterization, acoustic pressure is spatially averaged, both below and above the cavitation threshold. The standing wave patterns inside the sonoreactor have a stronger influence on the variation of the spatially distributed RMS pressure in linear operating conditions. For these conditions, the variation of +/-1.7dB was obtained, compared to +/-1.4dB obtained in highly nonlinear regime. The acoustic power in the sonoreactor was estimated from the magnitude of the averaged RMS pressure, and from the reverberation time of the sonoreactor as the representation of the losses. The electroacoustic efficiency factors obtained through acoustical and electromechanical characterization are in a very good agreement at low excitation levels. The irradiated acoustic power estimated in nonlinear conditions differs from the dissipated acoustic power determined with the calorimetric method by several orders of magnitude. The number of negative pressure peaks that represent transient cavitation decreases over time during longer treatments of a medium with high-power ultrasound. The number of negative peaks decreases faster when the medium and the vessel are allowed to heat up. PMID- 28732940 TI - Sonochemical synthesis, formation mechanism, and solar cell application of tellurium nanoparticles. AB - Tellurium inherently tends to form 1-D structures and while the 0-D Te nanostructures have better properties and applications in solar cell. In the present study, 0-D Te nanostructures including rice-like and spherical nanoparticles with the particle size of 15-40nm were successfully synthesized via a facile sonochemical method. In the absence of ultrasonic irradiation nanorods were produced while performing the reaction under ultrasonic waves (at 200W for 30min) led to the formation of nanoparticles. Finally, the efficiency of various as-synthesized Te nanostructures in quantum dot-sensitized solar cells (QDSSCs) were evaluated. Using rice-like nanoparticles led to increase in JSC, VOC, FF and eta parameters from 1.22, 0.54, 0.49 and 0.32% to 1.57, 0.64, 0.63 and 0.63%, respectively, compared with nanorods. PMID- 28732941 TI - Comments on the use of loop reactors in sonochemical processes. AB - For sonochemical processing on an industrial scale the traditional choice is either a batch or flow system. The former is straightforward in concept but it requires large scale powerful ultrasonic transducers capable of delivering high intensity ultrasound to large volumes of liquid. Unfortunately at the moment the cost and problems involved in building very large sonication devices for batch processes cannot justify the replacement of existing industrial processes. For this reason most sonochemists prefer some form of flow system where small quantities of reagents can be treated as they are pumped from a large vat of reagents through a smaller sonochemical reactor where high intensity ultrasound can be applied. In this short paper we draw attention to a problem which seems common in a number of papers dealing with such flow systems - a confusion between the terms continuous reactor and loop reactor. Further we emphasise the importance of calculating the actual amount of ultrasonic processing experienced by the reaction mixture within the sonication zone of a loop reactor during its operation. The parameters required for such a calculation are: ultrasonic processor volume (Rv in L), pump flow rate (Fr in L/min), stock solution volume in the reservoir (Sv in L) and the overall system operating time (So in min). PMID- 28732942 TI - Decomposition of PPCPs by ultrasound-assisted advanced Fenton reaction: A case study with salicylic acid. AB - The study is about the degradation of a widely used pharmaceutical and personal care product-salicylic acid by sonocatalysis, and the experimental design of the reaction system. The first part of the study consists of sonication (572kHz) in the presence of zero-valent iron (ZVI) with or without H2O2 to select and optimize the operational parameters as frequency, time, initial solute concentration, dose of reagents and pH. The second part consists of the use of response surface methodology and multiple regression to develop an experimental design modeland to assess the individual and interactive effects of pH, power (Po), ZVI dose and H2O2. The results showed that the optimal conditions predicted by the model without defining any restrictions are: pH=2.0, Po=120W, ZVI=24mgL-1, which provide total salicyclic acid and 48% TOC decay. However, the prediction implies intensive consumption of energy and reagents, and must therefore be modified by restricting the value of TOC decay to a lower value and that of pH to a higher one. Cross-validation tests showed that the prediction accuracy of the model was considerably high with 5.0-9.4% deviation from the experimental data. PMID- 28732943 TI - Encompassment of Benzyl Isothiocyanate in cyclodextrin using ultrasonication methodology to enhance its stability for biological applications. AB - The use of methodical and innovative sonication method has been explored for the fabrication of inclusion complex of Benzyl Isothiocyanate, a potential anticancer and -antimicrobial agent. The advancement involved investigation of inclusion behaviour, characterisation and an in-depth study of thermal and UV stability of Benzyl Isothiocyanate with cyclodextrins; beta-CD and hp-beta-CD. The sonication driven encompassment in cyclodextrins helped to overcome the hindrance of low solubility and high volatility. Investigations of physical and thermodynamic parameters using UV-visible spectroscopy, FTIR, XRD, TGA etc confirmed stability of inclusion complexes. Both beta-CD and hp-beta-CD based inclusion complexes retained the antimicrobial property of the free Benzyl Isothiocyanate, indicating their potential utility as antimicrobial agents. Haematological safety and cellular uptake data gives direction to in-depth analysis for its exploitation of anti-tumour activity. PMID- 28732944 TI - Ultrasound degradation of xanthan polymer in aqueous solution: Its scission mechanism and the effect of NaCl incorporation. AB - Degradation of xanthan polymer in aqueous solution by ultrasonic irradiation was investigated. The effects of selected variables i.e. sonication intensity, irradiation time, concentration of xanthan gum and molar concentration of NaCl in solution were studied. Combined approach of full factorial design and conventional one-factor-at-a-time was applied to obtain optimum degradation at sonication power intensity of 11.5Wcm-2, irradiation time 120min and 0.1gL-1 xanthan in a salt-free solution. Molecular weight reduction of xanthan gum under sonication was described by an exponential decay function with higher rate constant for polymer degradation in the salt free solution. The limiting molecular weight where fragments no longer undergo scission was determined from the function. The incorporation of NaCl in xanthan solution resulted in a lower limiting molecular weight. The ultrasound-mediated degradation of aqueous xanthan polymer chain agreed with a random scission model. Side chain of xanthan polymer is proposed to be the primary site of scission action. PMID- 28732945 TI - Heat transfer enhancement using 2MHz ultrasound. AB - The present work focuses on possible heat transfer enhancement from a heating plate towards tap water in forced convection by means of 2MHz ultrasound. The thermal approach allows to observe the increase of local convective heat transfer coefficients in the presence of ultrasound and to deduce a correlation between ultrasound power and Nusselt number. Heat transfer coefficient under ultrasound remains constant while heat transfer coefficient under silent conditions increases with Reynolds number from 900 up to 5000. Therefore, heat transfer enhancement factor ranges from 25% up to 90% for the same energy conditions (supplied ultrasonic power=110W and supplied thermal power=450W). In the same time cavitational activity due to 2MHz ultrasound emission was characterized from mechanical and chemical viewpoints without significant results. At least, Particle Image Velocimetry (PIV) measurements have been performed in order to investigate hydrodynamic modifications due to the presence of 2MHz ultrasound. It was therefore possible to propose a better understanding of heat transfer enhancement mechanism with high frequency ultrasound. PMID- 28732946 TI - Effects of ultrasonic treatment on the maturation of Zhenjiang vinegar. AB - High-quality vinegars are traditionally produced by aging them in barrels or bottles. However, these processes are very time-consuming. To accelerate of Zhenjiang vinegar maturation, the ultrasound was used to treat the steeped vinegar. Results showed that, the optimum ultrasonic power, time and ethanol addition for aging vinegar were determined to be 50W/100mL, 75min and 0.75% (V/V), respectively. Under the optimum experimental conditions, the total amino acid of fresh vinegar decreased from 1082.259mg/100mL to 871.045mg/100mL. Several volatile components increased significantly, such as the total esters, aldehydes and heterocyclic. Total non-volatile organic acids increased from 202.59mg/10mL to 233.87mg/10mL. The changes of above-mentioned components develop towards the direction of mature vinegar. Coupling the HS-SPME/GC-MS analysis data with Principal Components Analysis, ultrasonic treatment vinegar was determined to be equivalent to 2-3years of natural aged Zhenjiang vinegar. This study has showed that ultrasound is promising not only in shortening the aging time and lowering costs for the vinegar-making industry, but also in producing fine vinegar. PMID- 28732947 TI - Transesterification of soybean oil by using the synergistic microwave-ultrasonic irradiation. AB - Microwave and ultrasound have been demonstrated to be outstanding process intensification techniques for transesterification of oil. According to their mechanisms, simultaneous effects can surely bring about better enhancement than sole microwave or ultrasound. Therefore, this study aimed to investigate the important factors and their suitable levels in the KOH-catalyzed transesterification of soybean oil with methanol by using synergistic assistance of microwave-ultrasound (CAMU). The feasibility of application of CAMU in transesterification of oil was demonstrated. When the dosage of methanol, soybean oil and KOH were 15.4g, 34.7g (with methanol-to-oil molar ratio of 12:1) and 1g, respectively, and the microwave power, ultrasonic power, ultrasonic mode, reaction temperature and reaction time were 700W, 800W, 1:0, 65 degrees C and 6min, respectively, the transesterification reached 98.0% of yield, being the highest yield among all the results obtained; while by using 600W of microwave plus stirring instead of CAMU, only 57.4% of yield could be obtained. Compared with other reaction techniques, the transesterification by applying novel CAMU was found to have remarkable advantages. Furthermore, by monitoring the variation of real-time temperature and microwave power during transesterification reactions with different microwave operation time and by taking comparison of the corresponding yield, it was demonstrated that the main reason for the acceleration of microwave-assisted transesterification was the polarization and further activation of reactants caused by microwave irradiation, but not the factor of fast heating. PMID- 28732948 TI - Real-time monitoring of controllable cavitation erosion in a vessel phantom with passive acoustic mapping. AB - Cavitation erosion in blood vessel plays an important role in ultrasound thrombolysis, drug delivery, and other clinical applications. The controllable superficial vessel erosion based on ultrasonic standing wave (USW) has been used to effectively prevent vessel ruptures and haemorrhages, and optical method is used to observe the experiments. But optical method can only work in transparent media. Compared with standard B-mode imaging, passive acoustic mapping (PAM) can monitor erosion in real time and has better sensitivity of cavitation detection. However, the conventionally used PAM has limitations in imaging resolution and artifacts. In this study, a unique PAM method that combined the robust Capon beamformer (RCB) with the sign coherence factor (SCF) was proposed to monitor the superficial vessel erosion in real time. The performance of the proposed method was validated by simulations. In vitro experiments showed that the lateral (axial) resolution of the proposed PAM was 2.31+/-0.51 (3.19+/-0.38) times higher than time exposure acoustics (TEA)-based PAM and 1.73+/-0.38 (1.76+/-0.48) times higher than RCB-based PAM, and the cavitation-to-artifact ratio (CAR) of the proposed PAM could be improved by 22.5+/-3.2dB and 7.1+/-1.2dB compared with TEA and RCB-based PAM. These results showed that the proposed PAM can precisely monitor the superficial vessel erosion and the erosion shift after USW modulation. This work may have the potential of developing a useful tool for precise spatial control and real-time monitoring of the superficial vessel erosion. PMID- 28732949 TI - Dependence of cavitation, chemical effect, and mechanical effect thresholds on ultrasonic frequency. AB - Cavitation, chemical effect, and mechanical effect thresholds were investigated in wide frequency ranges from 22 to 4880kHz. Each threshold was measured in terms of sound pressure at fundamental frequency. Broadband noise emitted from acoustic cavitation bubbles was detected by a hydrophone to determine the cavitation threshold. Potassium iodide oxidation caused by acoustic cavitation was used to quantify the chemical effect threshold. The ultrasonic erosion of aluminum foil was conducted to estimate the mechanical effect threshold. The cavitation, chemical effect, and mechanical effect thresholds increased with increasing frequency. The chemical effect threshold was close to the cavitation threshold for all frequencies. At low frequency below 98kHz, the mechanical effect threshold was nearly equal to the cavitation threshold. However, the mechanical effect threshold was greatly higher than the cavitation threshold at high frequency. In addition, the thresholds of the second harmonic and the first ultraharmonic signals were measured to detect bubble occurrence. The threshold of the second harmonic approximated to the cavitation threshold below 1000kHz. On the other hand, the threshold of the first ultraharmonic was higher than the cavitation threshold below 98kHz and near to the cavitation threshold at high frequency. PMID- 28732950 TI - Ultrasonic assisted synthesis of two urea functionalized metal organic frameworks for phenol sensing: A comparative study. AB - Two pillared metal-organic frameworks containing urea functional groups were synthesized by a sonochemical method and characterized by scanning electron microscopy, X-ray powder diffraction, IR spectroscopy and elemental analysis. The time of sonication and concentration of starting materials have been optimized to synthesize nanoparticles of TMU-31 and TMU-32. These two frameworks are interesting candidates for a comparative fluorescence study. Thus, their potential abilities for phenol sensing were investigated. This investigation revealed the prominent roles of hydrogen bond donating urea groups inside the pore cavity in the ability of these structures in phenol sensing. PMID- 28732951 TI - Application of ultrasonically modified cloud point extraction method for simultaneous enrichment of cadmium and lead in sera of different types of gallstone patients. AB - A novel and greener ultrasonically assisted/modified cloud point extraction procedure for the simultaneous preconcentration of lead and cadmium in serum samples of different types of gallstone patients was developed. The chelates of the under study metals, formerly formed with 8-hydroxyquinoline, were extracted in the micelles of a nonionic surfactant prior to analysis by flame atomic absorption spectrometer (FAAS). After the arrival of the cloud point, the critical micellar mass produced was homogenously dispersed in the aqueous phase with the help of ultrasound energy. The reliability of the developed procedure was tested by relative standard deviation (% RSD), which was found to be <5%. The performance of the proposed procedure was checked by applying to certified reference material and spiking standard in real samples. All the experimental parameters were optimized. The developed procedure of Um-CPE was applied successfully for the analysis of the target heavy metals in serum samples of different types of gallstone patients and referents. The higher levels of the understudy metals were observed in the patients as compared to the referents but the levels of the both metal were found to be considerably higher in patients with pigmented gallstones. PMID- 28732952 TI - Ultrasound-promoted direct functionalization of multi-walled carbon nanotubes in water via Diels-Alder "click chemistry". AB - A facile and environmentally friendly strategy for grafting polymers onto the surface of multi-walled carbon nanotubes (CNTs) was demonstrated by Diels-Alder "click chemistry". Firstly, the copolymers of poly(styrene-alt-maleic anhydride) (PSM) were prepared by the reversible addition-fragmentation chain transfer (RAFT) polymerization and subsequently functionalized with furfuryl amine to introduce anchoring groups. The copolymers were then grafted on CNTs via the Diels-Alder reaction in water through a conventional heating-stirring route and ultrasound-assisted method. The obtained nanocomposite materials were characterized by thermogravimetric analysis, Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy, Raman spectroscopy and transmission electron microscopy. The results indicated that the reaction rate under ultrasound irradiation was accelerated about 12 times than the one under the conventional heating-stirring condition without losing the grafting efficiency. The direct functionalization of CNTs formed a stably dispersed solution in water, promising a green and effective method for industrial process. PMID- 28732953 TI - Sonochemical surface functionalization of exfoliated LDH: Effect on textural properties, CO2 adsorption, cyclic regeneration capacities and subsequent gas uptake for simultaneous methanol synthesis. AB - To improve CO2 adsorption, amine modified Layered double hydroxide (LDH) were prepared via a two stage process, SDS/APTS intercalation was supported by ultrasonic irradiation and then followed by MEA extraction. The prepared samples were characterised using Scanning electron microscope-Energy dispersive X-ray spectroscopy (SEM-EDX), X-ray Photoelectron Spectroscopy (XPS), X-ray diffraction (XRD), Temperature Programmed Desorption (TPD), Brunauer-Emmett-Teller (BET), and Thermogravimetric analysis (TGA), respectively. The characterisation results were compared with those obtained using the conventional preparation method with consideration to the effect of sonochemical functionalization on textural properties, adsorption capacity, regeneration and lifetime of the LDH adsorbent. It is found that LDHs prepared by sonochemical modification had improved pore structure and CO2 adsorption capacity, depending on sonic intensity. This is attributed to the enhanced deprotonation of activated amino functional groups via the sonochemical process. Subsequently, this improved the amine loading and effective amine efficiency by 60% of the conventional. In addition, the sonochemical process improved the thermal stability of the adsorbent and also, reduced the irreversible CO2 uptake, CUirrev, from 0.18mmol/g to 0.03mmol/g. Subsequently, improving the lifetime and ease of regenerating the adsorbent respectively. This is authenticated by subjecting the prepared adsorbents to series of thermal swing adsorption (TSA) cycles until its adsorption capacity goes below 60% of the original CO2 uptake. While the conventional adsorbent underwent a 10 TSA cycles before breaking down, the sonochemically functionalized LDH went further than 30 TSA cycles. PMID- 28732954 TI - Ultrasonic-assisted dyeing of Nylon-6 nanofibers. AB - We first time report ultrasonic dyeing of the Nylon 6 nanofibers with two disperse dyes CI Disperse blue 56 and CI Disperse Red 167:1 by utilising ultrasonic energy during dyeing process. The Nylon 6 nanofibers were fabricated via electrospinning and dyed via batchwise method with and without sonication. Results revealed that ultrasonic dyeing produce higher color yield (K/S values) and substantially reduces dyeing time from 60min for conventional dyeing to 30min can be attributed to breakage of dye aggregate, transient cavitation near nanofiber surface and mass transfer within/between nanofibers. Color fastness results exhibited good to very good dye fixation. SEM images exhibit insignificant effect of sonication on morphology of the nanofibers. Our research results demonstrate ultrasonic dyeing as a better dyeing technique for Nylon 6 nanofibers with higher color yield and substantially reduced dyeing time. PMID- 28732955 TI - Kinetic modeling of sonocatalytic performance of Gd-doped CdSe nanoparticles for degradation of Acid Blue 5. AB - CdSe and Gd-doped CdSe nanoparticles were synthesized using a simple hydrothermal method, and their catalytic activity was examined toward degradation of Acid Blue 5 (AB5) in the sonocatalytic process. The structure and morphology of as-prepared nanomaterials were characterized using scanning electron microscopy (SEM), X-ray diffraction (XRD), transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS), Branauer, Emmett and Teller (BET) and Fourier infrared spectroscopy (FT-IR) techniques. Among the synthesized samples, 4% Gd-doped CdSe nanoparticles demonstrated the highest catalytic activity with band gap energy of 1.61eV. The effect of dopant content, initial dye concentration, catalyst dosage, ultrasonic power and inorganic radical scavengers on the degradation efficacy of AB5 was evaluated. The produced intermediates of AB5 degradation during sonocatalytic process were verified using gas chromatography-mass spectroscopy (GC-MS) technique. A novel intrinsic kinetic model for prediction of AB5 degradation efficiency was proposed. A good agreement was obtained between developed model and experimental data (R2>0.94). PMID- 28732956 TI - Sonocatalytic removal of ibuprofen and sulfamethoxazole in the presence of different fly ash sources. AB - We examined the feasibility of using two types of fly ash (an industrial waste from thermal power plants) as a low-cost catalyst to enhance the ultrasonic (US) degradation of ibuprofen (IBP) and sulfamethoxazole (SMX). Two fly ashes, Belews Creek fly ash (BFA), from a power station in North Carolina, and Wateree Station fly ash (WFA), from a power station in South Carolina, were used. The results showed that >99% removal of IBP and SMX was achieved within 30 and 60min of sonication, respectively, at 580kHz and pH 3.5. Furthermore, the removal of IBP and SMX achieved, in terms of frequency, was in the order 580kHz>1000kHz>28kHz, and in terms of pH, was in the order of pH 3.5>pH 7>pH 9.5. WFA showed significant enhancement in the removal of IBP and SMX, which reached >99% removal within 20 and 50min, respectively, at 580kHz and pH 3.5. This was presumably because WFA contains more silicon dioxide than BFA, which can enhance the formation of OH radicals during sonication. Additionally, WFA has finer particles than BFA, which can increase the adsorption capacity in removing IBP and SMX. The sonocatalytic degradation of IBP and SMX fitted pseudo first-order rate kinetics and the synergistic indices of all the reactions were determined to compare the efficiency of the fly ashes. Overall, the findings have showed that WFA combined with US has potential for treating organic pollutants, such as IBP and SMX, in water and wastewater. PMID- 28732957 TI - Sonochemical synthesis of silver nanoparticles anchored reduced graphene oxide nanosheets for selective and sensitive detection of glutathione. AB - Developed here an eco-friendly, one-pot approach toward rapid synthesis of silver nanoparticles anchored reduced graphene oxide (AgNPs(TMSPED)-rGO) nanosheets via sonochemical irradiation method, using an aqueous solution mixture of GO and AgNO3 in the presence of N-[3(trimethoxysilyl)propyl] ethylenediamine (TMSPED) without any reducing agent. As synthesized decorated nanosheets was thoroughly characterized by transmission electron microscopy (TEM), atomic force microscopy (AFM), Fourier transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD) spectroscopy, Raman spectroscopy and X-ray photoelectron spectroscopy (XPS). Pristine AgNPs(TMSPED), pristine rGO(TMSPED) and as prepared AgNPs(TMSPED)-rGO materials were employed to modify the glassy carbon (GC) electrode and demonstrated its excellent electrocatalytic activities towards glutathione (GSH). Voltammetry and amperometry measurements were utilized to assess the electrochemical properties towards the glutathione detection. When the Ag nanoparticles were anchored onto the rGO surface, the observed results illustrated that the electrocatalytic properties of rGO might be enhanced. The resulting sensor exhibits excellent repeatability and long-term stability. Furthermore, AgNPs(TMSPED)-rGO/GC electrode able to be employed for the selective determination of GSH in amperometric analysis in the presence of ascorbic acid (AA), dopamine (DA), uric acid (UA) and glucose. Finally, this modified electrode was effectively applied to determine glutathione in real samples with good recoveries. PMID- 28732958 TI - Comparison between dispersive solid-phase and dispersive liquid-liquid microextraction combined with spectrophotometric determination of malachite green in water samples based on ultrasound-assisted and preconcentration under multi variable experimental design optimization. AB - The ultrasound-assisted dispersive solid-phase microextraction (USA-DSPME) and the ultrasound-assisted dispersive liquid-liquid microextraction (USA-DLLME) developed for as an ultra preconcentration and/or technique for the determination of malachite green (MG) in water samples. Central composite design based on analysis of variance and desirability function guide finding best operational conditions and represent dependency of response to variables viz. volume of extraction, eluent and disperser solvent, pH, adsorbent mass and ultrasonication time has significant influence on methods efficiency. Optimum conditions was set for USA-DSPME as: 1mg CNTs/Zn:ZnO@Ni2P-NCs; 4min sonication time and 130MUL eluent at pH 6.0. Meanwhile optimum point for USA-DLLME conditions were fixed at pH 6.0; 4min sonication time and 130, 650MUL and 10mL of extraction solvent (CHCl3), disperser solvent (ethanol) and sample volume, respectively. Under the above specified best operational conditions, the enrichment factors for the USA DSPME and USA-DLLME were 88.89 and 147.30, respectively. The methods has linear response in the range of 20.0 to 4000.0ngmL-1 with the correlation coefficients (r) between 0.9980 to 0.9995, while its reasonable detection limits viz. 1.386 to 2.348ngmL-1 and good relative standard deviations varied from 1.1% to 2.8% (n=10) candidate this method for successful monitoring of analyte from various media. The relative recoveries of the MG dye from water samples at spiking level of 500ngmL-1 were in the range between 94.50% and 98.86%. The proposed methods has been successfully applied to the analysis of the MG dye in water samples, and a satisfactory result was obtained. PMID- 28732959 TI - Ultrasonic-assisted continuous methanolysis of Jatropha curcas oil in the appearance of biodiesel used as an intermediate solvent. AB - A environmental friendly system for fast transesterification of Jatropha curcas oil was developed for the production of biodiesel using an ultrasonic-assisted continuous tank reactor in the presence of fatty acid methyl ester (FAMEs) used as a green (intermediate) solvent with potassium hydroxide used as a catalyst. This research provide a new biodiesel production process, the optimal condition for the reaction were established: reaction temperature 25 degrees C oil to methanol molar ratio was 1:5, catalyst concentration 0.75wt% of oil, solvent concentration 7.5%, flow rate 241.68+/-0.80ml/min, ultrasonic amplitude 60% and ultrasonic cycles 0.7s, transesterification was completed within 1.09min (residence time). The purity and conversion of biodiesel was 98.75+/-0.50% analyzed by the reverse phase HPLC method. PMID- 28732961 TI - Effects of high power ultrasonic vibration on temperature distribution of workpiece in dry creep feed up grinding. AB - Temperature history and distribution of steel workpiece (X20Cr13) was measured by a high tech infrared camera under ultrasonic assisted dry creep feed up grinding. For this purpose, a special experimental setup was designed and fabricated to vibrate only workpiece along two directions by a high power ultrasonic transducer. In this study, ultrasonic effects with respect to grinding parameters including depth of cut (ae), feed speed (vw), and cutting speed (vs) has been investigated. The results indicate that the ultrasonic vibration has considerable effect on reduction of temperature, depth of thermal damage of workpiece and width of temperature contours. Maximum temperature reduction of 25.91% was reported at condition of vs=15m/s, vw=500mm/min, ae=0.4mm in the presence of ultrasonic vibration. PMID- 28732960 TI - Relationships between spray parameters, microstructures and ultrasonic cavitation erosion behavior of HVOF sprayed Fe-based amorphous/nanocrystalline coatings. AB - Fe-based amorphous/nanocrystalline coatings were prepared on the AISI 321 steel substrate by the high-velocity oxygen-fuel (HVOF) thermal spraying technology. The effect of selected parameters (oxygen flow, kerosene flow and spray distance) on the cavitation erosion resistance (denoted as Rc) of the coating were investigated by using the Taguchi method. Statistical tools such as design of experiments (DOE), signal-to-noise (S/N) ratio and analysis of variance (ANOVA) were used to meet the expected objective. It was concluded that the kerosene flow had greater influence on the Rc of the coating and followed by the spray distance and the oxygen flow, respectively. The optimum spray parameters (OSP) were 963L/min for the oxygen flow, 28L/h for the kerosene flow, and 330mm for the spray distance. The Rc of the coating increased with the increase of hardness or the decrease of porosity, and the hardness had a greater influence on Rc than the porosity. The Fe-based coating deposited under the OSP exhibited the best cavitation erosion resistance in distilled water. The cracks initiated at the edge of the pores and the interfaces between the un-melted or half-melted particles, and finally leaded to the delamination of the coating. PMID- 28732962 TI - Grain fragmentation in ultrasonic-assisted TIG weld of pure aluminum. AB - Under the action of acoustic waves during an ultrasonic-assisted tungsten inert gas (TIG) welding process, a grain of a TIG weld of aluminum alloy is refined by nucleation and grain fragmentation. Herein, effects of ultrasound on grain fragmentation in the TIG weld of aluminum alloy are investigated via systematic welding experiments of pure aluminum. First, experiments involving continuous and fixed-position welding are performed, which demonstrate that ultrasound can break the grain of the TIG weld of pure aluminum. The microstructural characteristics of an ultrasonic-assisted TIG weld fabricated by fixed-position welding are analyzed. The microstructure is found to transform from plane crystal, columnar crystal, and uniform equiaxed crystal into plane crystal, deformed columnar crystal, and nonuniform equiaxed crystal after application of ultrasound. Second, factors influencing ultrasonic grain fragmentation are investigated. The ultrasonic amplitude and welding current are found to have a considerable effect on grain fragmentation. The degree of fragmentation first increases and then decreases with an increase in ultrasonic amplitude, and it increases with an increase in welding current. Measurement results of the vibration of the weld pool show that the degree of grain fragmentation is related to the intensity of acoustic nonlinearity in the weld pool. The greater the intensity of acoustic nonlinearity, the greater is the degree of grain fragmentation. Finally, the mechanism of ultrasonic grain fragmentation in the TIG weld of pure aluminum is discussed. A finite element simulation is used to simulate the acoustic pressure and flow in the weld pool. The acoustic pressure in the weld pool exceeds the cavitation threshold, and cavitation bubbles are generated. The flow velocity in the weld pool does not change noticeably after application of ultrasound. It is concluded that the high-pressure conditions induced during the occurrence of cavitation, lead to grain fragmentation in a pure aluminum TIG weld during an ultrasonic-assisted TIG welding process. PMID- 28732963 TI - Ultrasonic-assisted synthesis of ZnTe nanostructures and their structural, electrochemical and photoelectrical properties. AB - Colloidal zinc telluride (ZnTe) nanostructures were successfully processed through a simple and facile ultrasonic (sonochemical) treatment for photoelectronic applications. The particle-like morphological features, phase and nature of valence state of various metal ions existing in ZnTe were examined using electron and X-ray photoelectron spectroscopic tools. Raman spectroscopic measurements revealed the dominance of exciton-phonon coupling and occurrence of TeO2 traces in ZnTe through the corresponding vibrations. Optical bandgap of the ZnTe suspension was estimated to be around 2.15eV, authenticating the direct allowed transitions. The p-type electrical conductivity and charge carrier density of ZnTe were additionally estimated from the Bode, Nyquist and Mott Schottky type impedance plots. The photoelectrical properties of ZnTe were investigated by fabricating p-ZnTe/n-Si heterostructures and studying their corresponding current-voltage characteristics under dark and white light illumination. The diodes revealed excellent rectifying behaviour with significant increase in reverse current under illumination. The stability of the devices were also affirmed through the time-dependent photoresponse characteristics, which actually suggested the improved and effective separation of photo generated electron hole pairs across the integrated heterojunctions. The obtained results also augment the potential of sonochemically processed ZnTe for application in photo detection and sensor related functions. PMID- 28732964 TI - Ultrasonic effect on RuO2 nanostructures prepared by direct calcination of two new Ru(II)-organic supramolecular polymers. AB - Two novel Ru(II) complexes [(eta6-p-cymene)RuCl(L1)]PF6 (R1) and [(eta6 C6H6)RuCl(L1)]PF6 (R3) with ligand (E)-4-(methylthio)-N-((quinolin-2 yl)methylene)benzenamine (L1), were synthesized and investigated using elemental analysis, IR, 1H NMR, 13C NMR spectroscopy and X-ray crystallography. Complexes R1 and R3 have coordination environments with formulated (eta6-p-cymene)Ru(N2Cl) and (eta6-C6H6)Ru(N2Cl) respectively. The thermal stabilities of compounds R1 and R3 were studied by thermal gravimetric (TG) and differential scanning calorimetry (DSC). The binding of the complexes R1 and R3 to calf thymus DNA (CT DNA) was investigated by using electronic absorption spectra, fluorescence and redox behavior studies. Such experimental data showed that there are interactions between complexes and CT-DNA and the nature of this binding is electrostatic interaction type. Calcination of ultrasonic treated R1 and R3 results in the formation of nanoparticles of RuO2. The nanoparticles were characterized by IR spectroscopy and X-ray diffraction (XRD). Also size and morphology of nanoparticles were investigated by scanning electron microscopy (SEM). PMID- 28732965 TI - Facile and cost-effective preparation of PVA/modified calcium carbonate nanocomposites via ultrasonic irradiation: Application in adsorption of heavy metal and oxygen permeation property. AB - This work is focused on the fabrication and determination of physicochemical behaviors of new poly(vinyl alcohol) (PVA) nanocomposites (NCs) containing various contents of calcium carbonate (CC) nanoparticles modified with gamma aminopropyl triethoxy silane (ATS) (henceforth designated as CC-ATS) which could be a crucial treatment for their application as gas barrier to O2 gas and uptake of metal ions in waste waters. Samples were produced through the solution casting method under ultrasound irradiation. Thermal and mechanical performances were also evaluated for all ultrasonically synthesized nanocomposites and the results indicated that thermal and mechanical stability are dramatically enhanced by addition of a small amount of modified CC-ATS within PVA up to 5wt% and higher amounts has low effect on the composite properties. The result of oxygen gas permeability of PVA showed a 25.44% reduction by adding of 5wt% of CC-ATS into polymer matrix. Experimental adsorption isotherm data indicated that PVA NC has more efficiency for Cu(II) adsorption relative to pure PVA and well simulated by Langmuir model with maximum adsorption capacity of 45.45mgg-1. Moreover, study of sorption kinetic indicated that the solute adsorption on PVA/CC-ATS NC 5wt% was well modeled using the pseudo-second-order. PMID- 28732966 TI - Effect of ultrasonic waves on the water turbidity during the oxidation of phenol. Formation of (hydro)peroxo complexes. AB - Analysis of the kinetics of aqueous phenol oxidation by a sono-Fenton process reveals that the via involving ortho-substituted intermediates prevails: catechol (25.0%), hydroquinone (7.7%) and resorcinol (0.6%). During the oxidation, water rapidly acquires color that reaches its maximum intensity at the maximum concentration of p-benzoquinone. Turbidity formation occurs at a slower rate. Oxidant dosage determines the nature of the intermediates, being trihydroxylated benzenes (pyrogallol, hydroxyhydroquinone) and muconic acid the main precursors causing turbidity. It is found that the concentration of iron species and ultrasonic waves affects the intensity of the turbidity. The pathway of (hydro)peroxo-iron(II) complexes formation is proposed. Operating with 20.0 27.8mgFe2+/kW rates leads to formation of (hydro)peroxo-iron(II) complexes, which induce high turbidity levels. These species would dissociate into ZZ-muconic acid and ferrous ions. Applying relationships around 13.9mgFe2+/kW, the formation of (hydro)peroxo-iron(III) complexes would occur, which could react with carboxylic acids (2,5-dioxo-3-hexenedioic acid). That reaction induces turbidity slower. This is due to the organic substrate reacting with two molecules of the (hydro)peroxo complex. Therefore, it is necessary to accelerate the iron regeneration, intensifying the ultrasonic irradiation. Afterwards, this complex would dissociate into maleic acid and ferric ions. PMID- 28732967 TI - Ultrasound assisted phytosynthesis of iron oxide nanoparticle. AB - The present work deals with the ultrasound assisted green synthesis of iron oxide nano particle using Coriandrum sativum leaf extract as a reducing agent. The synthesized iron oxide nanoparticle was confirmed by UV spectra. The characterization was done to know more about morphology and size of the particle by SEM analysis which shows spherical particles with size ranging from 20 to 90nm. The antimicrobial activity of the leaf extract and the synthesized nanoparticles was studied against the pathogens Micrococcus luteus, Staphylococcus aureus and Aspergillus niger. The ultrasound assisted iron oxide nanoparticle shows higher scavenging activity and antimicrobial activity compared with iron oxide nanoparticle synthesized by magnetic stirrer and Coriandrum sativum leaf extract. PMID- 28732968 TI - Simple sonochemical synthesis of Ho2O3-SiO2 nanocomposites as an effective photocatalyst for degradation and removal of organic contaminant. AB - In this work, highly photocatalytically active Ho2O3-SiO2 nanocomposites have been designed and applied for decomposition of methylene blue pollutant. Ho2O3 SiO2 nanocomposites have been produced by new, quick and facile sonochemical process with the aid of tetramethylethylenediamine as a novel basic agent for the first time. The effect of the kind of basic agent, ultrasonic time and dosage of Ho source on the grain size, photocatalytic behavior and shape of the Ho2O3-SiO2 nanocomposites have been evaluated for optimization the production condition. FESEM, EDX, FT-IR, DRS, XRD and TEM have been applied to characterize the as produced Ho2O3-SiO2 nanocomposites. Use of the as-produced Ho2O3-SiO2 nanocomposites as photocatalyst via destruction of methylene blue pollutant under UV illumination has been compared. It was observed that SiO2 has notable impact on catalytic activity of holmium oxide photocatalyst for destruction. Introducing of SiO2 to holmium oxide can enhance destruction efficiency of holmium oxide to methylene blue pollutant under ultraviolet light. PMID- 28732969 TI - Suspension characteristics of water droplet in oil under ultrasonic standing waves. AB - The suspension characteristics of water droplet in oil were investigated under ultrasonic standing waves with high-speed photography in this paper. Firstly, the suspension position of droplet was predicted by theoretical derivation. The motion trajectory of droplet was captured and a kinetic analysis was applied to characterize the suspension position of droplet. The effects of droplet size, acoustic pressure, frequency, as well as density ratio of water and oil on the suspension position of droplet were analyzed in details. It was proved that the droplet size had little effect on the suspension position at different frequencies. The suspension zone approached minimum at 39.4kHz, and the suspension position of droplet was insensitive to acoustic pressure amplitude and density ratio at this frequency. These would be advantageous to maintain the stability of droplet banding and shorten the width of banding. In addition, it was proved that the suspension position of droplet is approximately linear with the density ratio at different frequencies. PMID- 28732970 TI - Ultrasonic assisted synthesis of palladium-nickel/iron oxide core-shell nanoalloys as effective catalyst for Suzuki-Miyaura and p-nitrophenol reduction reactions. AB - In this study, ultrasonic assisted synthesis of Pd-Ni/Fe3O4 core-shell nanoalloys is reported. Unique reaction condition was prepared by ultrasonic irradiation, releasing the stored energy in the collapsed bubbles and heats the bubble contents that leads to Pd(II) and Ni(II) reduction. Co-precipitation method was applied for the synthesis of Fe3O4 nanoparticles (NPs). Immobilized solution was produced by sonicating the aqueous mixture of Fe3O4 and mercaptosuccinic acid to obtain Pd-Ni alloys on Fe3O4 magnetic NP cores. The catalytic activity of the synthesized Pd-Ni/Fe3O4 core-shells was investigated in the Suzuki-Miyaura CC coupling reaction and 4-nitrophenol reduction, which exhibited a high catalytic activity in both reactions. These magnetic NPs can be separated from the reaction mixture by external magnetic field. This strategy is simple, economical and promising for industrial applications. PMID- 28732971 TI - Application of airborne ultrasound in the convective drying of fruits and vegetables: A review. AB - The application of airborne ultrasound is a promising technology in the drying of foods, particularly to fruits and vegetables. In this paper, designs of dryers using ultrasound to combine the convective drying process are described. The main factors affecting the drying kinetics with the ultrasound application are discussed. The results show that the ultrasound application accelerated the drying kinetics. Ultrasound application during the convective drying of fruits and vegetables shorten the drying time. Ultrasound application can produce an increase of the effective moisture diffusivity and the mass transfer coefficient. The influence of ultrasound on physical and chemical parameters evaluating the product quality is reviewed. Ultrasound application can decrease the total color change, reveal a low water activity and reduce the loss of some nutrient elements. Meanwhile, ultrasound application can also better preserve the microstructure of fruits and vegetables in comparison to convective drying. PMID- 28732972 TI - State of the art and recent advances in the ultrasound-assisted synthesis, exfoliation and functionalization of graphene derivatives. AB - Sonochemistry, an almost a century old technique was predominantly employed in the cleaning and extraction processes but this tool has now slowly gained tremendous attention in the synthesis of nanoparticles (NPs) where particles of sub-micron have been produced with great stability. Following this, ultrasonication techniques have been largely employed in graphene synthesis and its dispersion in various solvents which would conventionally take days and offers poor yield. Ultrasonic irradiation allows the production of thin-layered graphene oxide (GO) and reduced graphene oxide (RGO) of up to 1nm thickness and can be produced in single layers. With ultrasonic treatment, reactions were made easy whereby graphite can be directly exfoliated to graphene layers. Oxidation to GO can also be carried out within minutes and reduction to RGO is possible without the use of any reducing agents. In addition, various geometry of graphene can be produced such as scrolled graphene, sponge or foam graphene, smooth as well as those with rough edges, each serving its own unique purpose in various applications such as supercapacitor, catalysis, biomedical, etc. In ultrasonic assisted reaction, deposition of metal NPs on graphene was more homogeneous with custom-made patterns such as core-shell formation, discs, clusters and specific deposition at the edges of graphene sheets. Graphene derivatives with the aid of ultrasonication are the perfect catalyst for various organic reactions as well as an excellent adsorbent. Reactions which used to take hours and days were significantly reduced to minutes with exceedingly high yields. In a more recent approach, sonophotocatalysis was employed for the combined effect of sonication and photocatalysis of metal deposited graphene. The system was highly efficient in organic dye adsorption. This review provides detailed fundamental concepts of ultrasonochemistry for the synthesis of graphene, its dispersion, exfoliation as well as its functionalization, with great emphasis only based on recent publications. Necessary parameters of sonication such as frequency, power input, sonication time, type of sonication as well as temperature and dual-frequency sonication are discussed in great length to provide an overview of the resultant graphene products. PMID- 28732973 TI - Enhanced photodegradation of dye in waste water using iron vanadate nanocomposite; ultrasound-assisted preparation and characterization. AB - The paper proposes a new approach to Schiff-base ligand assisted sonochemical synthesis of iron vanadate. In this disquisition, we tried to comparing various factors and reaction condition on morphology, size and uniformity of as-obtained samples. Some parameters including Schiff-base capping agent (Bis(acetylacetone) ethylenediamine=H2acacen), electrolyte (NH4F), solvent and reaction time were investigated to reach optimum condition. XRD, FT-IR, EDS, SEM and TEM were used in order to determine purity and structural morphology of as-synthesized products. Also, we explore the possibility of coupling vanadium pantaoxide into iron vanadate that improves optical properties and photocatalytic activity. With this in mind, FeVO4/V2O5 nanocomposite was prepared via in-situ ultrasound assisted procedure by using NH4F in one step. Influence of different parameters such as type of dye (Rhodamine B=Rh B, Phenol red=Ph R and Methyl violet=MV) and light source (Ultraviolet and visible) on photocatalytic ability of samples were studied. PMID- 28732974 TI - The effect of ultrasonic irradiation on the structure, morphology and photocatalytic performance of ZnO nanoparticles by sol-gel method. AB - In this research, the effect of ultrasonic irradiation power (0, 75, 150 and 200W) and time (0, 5, 15 and 20min) on the structure, morphology and photocatalytic activity of zinc oxide nanoparticles synthesized by sol-gel method was investigated. Crystallographic structures and the morphologies of the resultant powders were determined by X-ray diffraction (XRD) and transmission electron microscopy (TEM). The XRD patterns showed that ZnO samples were crystallized in their pure phase. The purity of samples was increased by increasing the ultrasonic irradiation power and time. Not only did ultrasonic irradiation unify both the structure and the morphology, but also it reduced the size and prohibited particles from aggregation. The optical behavior of the samples was studied by UV-vis spectroscopy. Photocatalytic activity of particles was measured by degradation of methyl orange under radiation of ultraviolet light. Ultrasound nanoparticles represented higher degradation compared to non ultrasound ones. PMID- 28732975 TI - High intensity ultrasound treatment of protein isolate extracted from dephenolized sunflower meal: Effect on physicochemical and functional properties. AB - The influence of high intensity ultrasound (HIUS) on physicochemical and functional properties of sunflower protein isolates was investigated. Protein solutions (10% w/v) were treated with ultrasound probe (20kHz) and ultrasound bath (40kHz) for 5, 10, 20 and 30min. Thermal stability of protein isolates was reduced as indicated by differential scanning calorimetry. Minimum thermal stability was observed at 20min of sonication and increased further with increase in treatment time indicating aggregation at prolonged sonication. SDS-PAGE profile of proteins showed a significant reduction in molecular weight. Further, surface hydrophobicity and sulfhydryl content increased after HIUS treatment indicating partial unfolding of proteins and reduction in the intermolecular interactions. The particle size analysis showed that HIUS treatment reduced the particle size. Less turbid solution were observed largely due to reduction in particle size. HIUS decreased the available lysine content in protein isolates. Solubility, emulsifying capacity, emulsion stability, foaming capacity, foam stability and oil binding capacity were improved significantly, while as, water binding capacity was decreased. The effect of HIUS on physicochemical and functional properties of sunflower protein isolates was more pronounced in probe sonication rather than bath sonication. Protein isolates with improved functional properties can be obtained using high intensity ultrasound technology. PMID- 28732976 TI - Preparation of waterborne dispersions of epoxy resin by ultrasonic-assisted supercritical CO2 nanoemulsification technique. AB - Waterborne nanoemulsion of diglycidyl ether of bisphenol A type epoxy resin (DGEBA) with droplet size of around 124nm was prepared by using an ultrasonic assisted supercritical carbon dioxide (scCO2) technique in an autoclave reactor at a low temperature (32 degrees C). A view cell positioned in-line with the ultrasonic probe allowed observation of the emulsification process. From the image analysis and droplet size measurement, the influence mechanisms of the ultrasonic power, the degree of mixing of scCO2 with DGEBA, the adding amount of emulsifier, and the system pressure on emulsification process and emulsion droplet size were investigated. In the emulsification process, scCO2 penetrated into the mixture and absorbed on the DGEBA molecular. The interactions between CO2 and the functional groups of DGEBA reduced the chain-chain interactions of polymer segments and therefore efficiently reduced the viscosity of DGEBA at a low temperature. Meantime, the cavitation and acoustic streaming of ultrasound provided a shear force for the nanoemulsification and a disturbance force for the homogeneity of the emulsion. Therefore, the combination of scCO2 and ultrasonication made it possible to prepare a long-term stable nanoemulsion under a low temperature. This ultrasonic-assisted scCO2 emulsification method provides an efficient and solvent-free process for the preparation of waterborne nanoemulsions of, for example, some heat-sensitive and water-insoluble active substances at low temperature. PMID- 28732977 TI - Large-scale synthesis of copper sulfide by using elemental sources via simple chemical route. AB - Copper sulfide is a low-cost and non-toxic material which is very attractive and promising for various applications. There is a need of a large-scale production of this material by simple methods. Here, a simple and ambient method is proposed for a large-scale preparation of copper sulfide. The synthesis is carried out at room temperature by using ultrasonication method where the elemental precursors, copper and sulfur are directly used. The present method gives gram scale synthesis with high yield in a short period of time. The materials are characterized by different techniques, their electrical conductivity and Seebeck coefficient are also measured and analyzed. The present method is one of the simple ways of producing copper sulfide just at room temperature. PMID- 28732978 TI - Ultrasonic-assisted environmentally-friendly synergetic synthesis of nitroaromatic compounds in core/shell nanoreactor: A green protocol. AB - An efficient sonochemical protocol for the nitration of aromatic compounds was described in the presence of a catalytic amount of sulfuric acid-functionalized silica-based core/shell magnetic nanocomposite at room temperature in an eco friendly and recyclable media, deep eutectic solvent (DES), based on choline chloride and urea. The particle size, morphology and elemental analysis of the core/shell nanocatalyst were carried out by TEM, SEM, EDX and XRD analyses. The nanocatalyst and DES were easily recovered from the reaction mixture quantitatively and reused several times. PMID- 28732979 TI - Sonocatalytic degradation of Reactive Yellow 39 using synthesized ZrO2 nanoparticles on biochar. AB - ZrO2-biochar (ZrO2-BC) nanocomposite was prepared by a modified sonochemical/sol gel method. The physicochemical properties of the prepared nanocomposite were evaluated using scanning electron microscopy, energy-dispersive X-ray spectroscopy, X-ray fluorescence, Fourier transform infrared spectroscopy and Brunauer-Emmett-Teller model. The sonocatalytic performance of ZrO2-BC was investigated in sonochemical degradation of Reactive Yellow 39 (RY39). The high observed sonocatalytic activity of the ZrO2-BC sample could be interpreted by the mechanisms of sonoluminescence and hot spots. Parameters including ZrO2-BC dosage, solution pH, initial RY39 concentration and ultrasonic power were selected as the main operational parameters and their influence on RY39 degradation efficiency was examined. A 96.8% degradation efficiency was achieved with a ZrO2-BC dosage of 1.5g/L, pH of 6, initial RY39 concentration of 20mg/L and ultrasonic power of 300W. In the presence of OH radical scavengers, RY39 degradation was significantly inhibited, providing evidence for the key role of hydroxyl radicals in the process. The sonodegradation intermediates were identified using gas chromatography-mass spectroscopy and the possible decomposition route was proposed. PMID- 28732980 TI - Synthesis of amine-modified zeolitic imidazolate framework-8, ultrasound-assisted dye removal and modeling. AB - The present research is focused on the ultrasound assisted adsorption of Acid blue 92 (AB92) and Direct red 80 (DR80) as anionic dyes in single and binary systems onto zeolitic imidazolate framework (ZIF-8) functionalized with 3 Aminopropyltrimethoxysilane (APTES). Different techniques such as Fourier transform infrared (FTIR), scanning electron microscope (SEM), field emission scanning electron microscopy (FE-SEM), X-ray diffraction (XRD), Brunauer-Emmett Teller (BET) and thermogravimetric analyses (TGA) were used to characterize the prepared adsorbent. The individual effects and possible interactions between the various parameters including adsorbent dosage, sonication time, initial dye concentrations and pH on dyes removal efficiency were investigated by response surface methodology (RSM). The optimized experimental conditions were fixed at adsorbent dosage 0.005g for AB92 and 0.01g for DR80, pH 2.1, sonication time 15min, and initial dyes concentration 15mgL-1 to get maximum removal percentage (>95.0%). A reliable and intelligent model based on least-squares support vector machine (LS-SVM) was developed to predict dye removal efficiency. The root mean square error (RMSE) of 0.604, 0.734 and 1.549 with high determination coefficient (R2) of 0.999, 0.996 and 0.997 for AB92, DR80 and binary system, respectively, were able to predict and model the adsorption process. The presented model illustrates better performance in predicting dye removal efficiency compared to the kinetic models. The results showed that the adsorption process had better conformation with pseudo-second order model. The adsorption equilibrium data was investigated by Langmuir, Freundlich, Tempkin and Dubinin-Radushkevich isotherm models and the data were well fitted by Langmuir model with maximum adsorption capacity of 633.4 and 500.2mgg-1 for AB92 and DR80 dyes, respectively. APTES@ZIF 8 was regenerated and found to be reusable after four successive cycles without considerable loss in adsorption capacity. PMID- 28732981 TI - Sonochemical effect on two new Ruthenium(II) complexes with ligand (E)-N-((6 bromopyridin-2-yl)methylene)-4-(methylthio)aniline precursors for synthesis of RuO2 nanoparticles. AB - Two novel Ru(II) complexes [(eta6-p-cymene)RuCl(L2)]PF6 (R2) and [(eta6 C6H6)RuCl(L2)]PF6 (R4), with ligand (E)-N-((6-bromopyridin-2-yl)methylene)-4 (methylthio)aniline (L2), were synthesized and characterized by elemental analysis, 1H NMR, 13C NMR and IR spectroscopy. Based on X-ray crystallography studies, complexes R2 and R4 have coordination environments with formulated (eta6 p-cymene)Ru(N2Cl) and (eta6-C6H6)Ru(N2Cl), respectively. The thermal stabilities of compounds R2 and R4 were studied by thermal gravimetric (TG) and differential scanning calorimetry (DSC). Thermal decomposition of these complexes was at 280 degrees C and 260 degrees C under air atmosphere respectively. The interaction of these complexes with calf thymus DNA (CT-DNA) was explored through electronic absorption spectra, fluorescence and redox behavior studies. The results showed that the complexes bind to CT-DNA with electrostatic interactions. Nanoparticles of RuO2 were prepared by calcination of R2 and R4. Also the role of the ultrasound waves on the characteristics of the RuO2 nanoparticles was studied. The nanoparticles were characterized by IR spectroscopy and X-ray diffraction (XRD). Also size and morphology of nanoparticles were studied by scanning electron microscopy (SEM). PMID- 28732983 TI - Effect of ultrasound and green solvents addition on the oil extraction efficiency from rapeseed flakes. AB - The current procedure of rapeseed oil extraction is based on a first extraction step by pressing followed by a second extraction step with hexane. This solvent being toxic for the users, the consumers and the environment, its use could be forbidden within the coming years. Stimulated by a stringent regulation, the research activity for the replacement of toxic solvents shows a significant development. The aim of this study was to select alternative solvent to hexane such as ethanol or isopropanol, and, to adjust the oil extraction process by developing an ultrasound assisted method. The objective was to reach a comparable efficiency but also to enhance the oil quality. When applied to isopropanol, the ultrasound assisted extraction method has shown promising results, and comparable to those obtained with hexane (oil yield of 80% for hexane and 79% for isopropanol at optimum extraction conditions (20min of ultrasound pretreatment followed by 2h of additional solid/liquid extraction)). Conversely, in studied conditions, ethanol did not seem to be an appropriate alternative solvent to hexane as the extraction yields obtained by using this solvent were quite low. PMID- 28732982 TI - Sonochemical green reduction to prepare Ag nanoparticles decorated graphene sheets for catalytic performance and antibacterial application. AB - The emerging popularity and wide acceptance of green chemistry and environmentally benign/ecofriendly approaches have comprehensively considered for catalyst synthesis methods. Natural resource derived carbogenic quantum dots has been used in assistance with ultrasonic shock wave to graphene oxide (GO) aqueous dispersion in order to prepare reduced graphene oxide decorated with silver nanoparticles following the 'top-down' method. The total reduction process is done without using any toxic external reducing agents and any surfactants or stabilizers, thus it can be accepted as green method. Sonochemical destratification of the GO layers provides green attributes due to scalable, non hazardous and relatively fast reduction to enhance surface area of the GO. Arresting the silver nanoparticles onto basal planes of graphene oxide can act as an efficient solid state support catalyst for fast reduction of toxic nitro aryls. Besides this work also reports bactericidal feature exhibited by the catalyst. Thus a dual functioning nanomaterial has been successfully developed which can be a suitable alternative for reductive forthcoming specialty/multifunctional membrane and other high-end medicinal or industrial applications. PMID- 28732984 TI - Ultrasonic-assisted biosurface modification of multi-walled carbon nanotubes with Thiamine and its influence on the properties of PVC/Tm-MWCNTs nanocomposite films. AB - The present paper represents a simple and efficient technique via ultrasonic irradiation, which utilized for chemical treatment of carboxylated multi-walled carbon nanotubes (MWCNTs-COOH) with Thiamine (Tm). Poly(vinyl chloride) (PVC) based nanocomposites (NC)s were prepared by the incorporation of various amounts of modified MWCNTs (4, 8, and 12wt%) within the PVC matrix by blending solution and ultrasonic distribution methods. The morphological, chemical structure and thermal stability of the PVC/Tm-MWCNT NCs were identified via Fourier transform infrared spectroscopy, Raman spectroscopy, X-ray diffraction, transmission electron microscopy, field emission scanning electron microscopy, and thermogravimetric analysis. The obtained results of thermal behavior indicated the high thermal stability of PVC/Tm-MWCNT NCs in comparison with the pure PVC via presenting diverse quantities of Tm-MWCNTs. In addition, the mechanical behavior of the PVC/Tm-MWCNT NCs films was examined and the results exhibited that mechanical properties of fabricated NCs were improved. PMID- 28732985 TI - Numerical models for the study of the nonlinear frequency mixing in two and three dimensional resonant cavities filled with a bubbly liquid. AB - The objective of this work is to develop versatile numerical models to study the nonlinear distortion of ultrasounds and the generation of low-ultrasonic frequency signals by nonlinear frequency mixing in two and three-dimensional resonators filled with bubbly liquids. The interaction of the acoustic field and the bubble vibrations is modeled through a coupled differential system formed by the multi-dimensional wave equation and a Rayleigh-Plesset equation. The numerical models we develop are based on multi-dimensional finite-volume techniques and a time discretization carried out by finite differences. Numerical experiments are performed for complex modes in many different cavities considering different kinds of boundary conditions and taking advantage of the dispersive character of the bubbly fluid to match specific resonances of the cavities. Results show the distribution of fundamental and harmonics for single frequency excitation and difference-frequency component for two-frequency excitation that are promoted by the strong nonlinearity of the bubbly medium. The numerous simulations analyzed suggest that the new numerical models developed and proposed in this paper are useful to understand the behavior of ultrasounds in bubbly liquids for sonochemical processes and applications of nonlinear frequency mixing. PMID- 28732986 TI - Continuous-flow ultrasound assisted oxidative desulfurization (UAOD) process: An efficient diesel treatment by injection of the aqueous phase. AB - A new continuous-flow ultrasound assisted oxidative desulfurization (UAOD) process was developed in order to decrease energy and aqueous phase consumption. In this process the aqueous phase is injected below the horn tip leading to enhanced mixing of the phases. Diesel fuel as the oil phase with sulfur content of 1550ppmw and an appropriate mixture of hydrogen peroxide and formic acid as the aqueous phase were used. At the first step, the optimized condition for the sulfur removal has been obtained in the batch mode operation. Hence, the effect of more important oxidation parameters; oxidant-to-sulfur molar ratio, acid-to sulfur molar ratio and sonication time were investigated. Then the optimized conditions were obtained using Response Surface Methodology (RSM) technique. Afterwards, some experiments corresponding to the best batch condition and also with objective of minimizing the residence time and aqueous phase to fuel volume ratio have been conducted in a newly designed double-compartment reactor with injection of the aqueous phase to evaluate the process in a continuous flow operation. In addition, the effect of nozzle diameter has been examined. Significant improvement on the sulfur removal was observed specially in lower sonication time in the case of dispersion method in comparison with the conventional contact between two phases. Ultimately, the flow pattern induced by ultrasonic device, and also injection of the aqueous phase were analyzed quantitatively and qualitatively by capturing the sequential images. PMID- 28732987 TI - Fish oil based vitamin D nanoencapsulation by ultrasonication and bioaccessibility analysis in simulated gastro-intestinal tract. AB - Recently, nanoemulsions have been employed for different applications including food and drug industries for efficient nutrient delivery system. In this study, vitamin D (a lipophilic molecule) was encapsulated in fish oil for higher oral bioavailability. The oil-in-water nanoemulsion was formulated by ultrasonication technique with a droplet size range of 300-450nm and a shelf life of more than 90days. The influence of oil, water and surfactant concentration was investigated by phase diagram. The formulated nanoemulsion had encapsulation efficiency in the range of 95.7-98.2%. Further, nanoemulsion passed through simulated gastro intestinal tract revealed an increased bioavailability than non-encapsulated vitamin. Thus, the formulation can be used as a drug delivery vehicle for various lipophilic compounds. Till date, no one have fabricated an efficient nano-vehicle for the delivery of vitamin D as well as analyzed the efficient delivery system in simulated GI-tract, this is first of its kind study in this regard. This can be scaled up further after analyzing the safety aspects. PMID- 28732988 TI - Sonochemical synthesis of two nanostructured silver(I) coordination polymers based on semi-rigid bis(benzimidazole) ligands. AB - Nanoparticles of two silver(I) coordination polymers (CPs), [Ag2(L1)2(DCTP)]n (1) and [Ag2(L2)(DCTP)]n (2) (L1=1,3-bis(5,6-dimethylbenzimidazol-1-ylmethyl)benzene, L2=1,4-bis(benzimidazol-1-yl)-2-butene, H2DCTP=2,5-dichloroterephthalic acid), were synthesized by the sonochemical approach and hydrothermal method. Both CPs were characterized by elemental analysis, IR spectra, single-crystal X-ray diffraction, scanning electron microscopy (SEM), and thermogravimetric analyses (TGA). CP 1 exhibits a 2D 4-connected sql net with the point symbol {44.62}. While CP 2 displays a 2D 3,4-connected 3,4L13 net with the point symbol {4.62}2{42.62.82}. The structural diversity indicates that semi-rigid bis(benzimidazole) co-ligands play important roles in tuning the structures of the mixed Ag(I) CPs. The ultrasound irradiation time, temperature, and power showed significant effects on the morphology and growth process of the nanoparticles of two silver(I) CPs. The luminescence and photocatalytic properties of the nanoparticles of CPs 1-2 on the degradation of methyl blue (MB) were also investigated in detail. PMID- 28732989 TI - Intensification of biodiesel production from soybean oil and waste cooking oil in the presence of heterogeneous catalyst using high speed homogenizer. AB - In the present work, high speed homogenizer has been used for the intensification of biodiesel synthesis from soybean oil and waste cooking oil (WCO) used as a sustainable feedstock. High acid value waste cooking oil (27mg of KOH/g of oil) was first esterified with methanol using sulphuric acid as catalyst in two stages to bring the acid value to desired value of 1.5mg of KOH/g of oil. Transesterification of soybean oil (directly due to lower acid value) and esterified waste cooking oil was performed in the presence of heterogeneous catalyst (CaO) for the production of biodiesel. Various experiments were performed for understanding the effect of operating parameters viz. molar ratio, catalyst loading, reaction temperature and speed of rotation of the homogenizer. For soybean oil, the maximum biodiesel yield as 84% was obtained with catalyst loading of 3wt% and molar ratio of oil to methanol of 1:10 at 50 degrees C with 12,000rpm as the speed of rotation in 30min. Similarly biodiesel yield of 88% was obtained from waste cooking oil under identical operating conditions except for the catalyst loading which was 1wt%. Significant increase in the rate of biodiesel production with yields from soybean oil as 84% (in 30min) and from WCO as 88% (30min) was established due to the use of high speed homogenizer as compared to the conventional stirring method (requiring 2-3h for obtaining similar biodiesel yield). The observed intensification was attributed to the turbulence caused at microscale and generation of fine emulsions due to the cavitational effects. Overall it can be concluded from this study that high speed homogenizer can be used as an alternate cavitating device to efficiently produce biodiesel in the presence of heterogeneous catalysts. PMID- 28732990 TI - Combination of sonodynamic with temozolomide inhibits C6 glioma migration and promotes mitochondrial pathway apoptosis via suppressing NHE-1 expression. AB - Temozolomide (TMZ) was used for clinical postoperative or non-surgical chemotherapy patients. However, its effect remains unsatisfactory and gradually discovered that the presence of chemoresistance. To explore more effective therapy using TMZ, we investigate the effects of combination of application of TMZ together with Sonodynamic therapy (SDT), which is based on the ultrasonic activation of a sonosensitizer, with low toxicity, noninvasive, deeper penetrability and a promising approach for treating malignant glioma by inducing apoptosis on glioma cells in vitro. Sodium-hydrogen exchanger isoform 1 (NHE1), which enable glioblastoma cells to escape TMZ-mediated toxicity via increased H+ extrusion and affect the apoptosis effect on C6 glioma cells in vitro. The C6 cells survival rate and time point of TMZ resistance were tested by the Cell Counting Kit-8 (CCK8) viability assay. Western blot analysis results showed that the expression of NHE1 and matrix metalloproteinase-2 (MMP-2) protein obviously decreased by TMZ+SDT. Meanwhile, combined treatments enhanced the expression of mitochondrial pathway apoptosis proteins, as well as suppressed MMP-2 to weaken the migration ability in TMZ-resistant C6 cell line. These results provided the first evidence that the sensitivity of TMZ chemotherapy in resistant malignant glioma may be improved by SDT. PMID- 28732991 TI - In situ observation of ultrasonic cavitation-induced fragmentation of the primary crystals formed in Al alloys. AB - The cavitation-induced fragmentation of primary crystals formed in Al alloys were investigated for the first time by high-speed imaging using a novel experimental approach. Three representative primary crystal types, Al3Ti, Si and Al3V with different morphologies and mechanical properties were first extracted by deep etching of the corresponding Al alloys and then subjected to ultrasonic cavitation processing in distilled water. The dynamic interaction between the cavitation bubbles and primary crystals was imaged in situ and in real time. Based on the recorded image sequences, the fragmentation mechanisms of primary crystals were studied. It was found that there are three major mechanisms by which the primary crystals were fragmented by cavitation bubbles. The first one was a slow process via fatigue-type failure. A cyclic pressure exerted by stationary pulsating bubbles caused the propagation of a crack pre-existing in the primary crystal to a critical length which led to fragmentation. The second mechanism was a sudden process due to the collapse of bubbles in a passing cavitation cloud. The pressure produced upon the collapse of the cloud promoted rapid monotonic crack growth and fast fracture in the primary crystals. The third observed mechanism was normal bending fracture as a result of the high pressure arising from the collapse of a bubble cloud and the crack formation at the branch connection points of dendritic primary crystals. The fragmentation of dendrite branches due to the interaction between two freely moving dendritic primary crystals was also observed. A simplified fracture analysis of the observed phenomena was performed. The specific fragmentation mechanism for the primary crystals depended on their morphology and mechanical properties. PMID- 28732992 TI - The effects of altering reaction conditions in green sonochemical synthesis of a thallium(I) coordination polymer and in achieving to different morphologies of thallium(III) oxide nanostructures via solid-state process. AB - In order to studies the effects of solvent and concentration of initial reagents on formation of [Tl(MU4-AB)]n (1), [HAB=4-aminobenzoic acid] coordination polymer, some experiments were designed and four samples of 1 were synthesized by sonochemical process. High concentration of initial reagents resulted in formation of compound 1 microrods. With low concentration of initial reagents, various morphologies of 1 were obtained. These four samples had been used as new precursors for preparation of thallium(III) oxide nanostructures via solid-state thermal decomposition process. One- and two-dimensional nanostructures of thallium(III) oxide can be prepared from 1. These micro and nanostructures were characterized by IR spectroscopy, X-ray powder diffraction (XRD) and Scanning Electron Microscopy (SEM). PMID- 28732994 TI - Sonocatalytic degradation of methylene blue by a novel graphene quantum dots anchored CdSe nanocatalyst. AB - Cadmium selenide/graphene quantum dots (CdSe/GQDs) nanocatalyst with small band gap energy and a large specific surface area was produced via a facile three-step sonochemical-hydrothermal process. The features of the as-prepared CdSe, GQDs and CdSe/GQDs samples were characterized by photoluminescence spectroscopy (PL), scanning electron microscopy (SEM), energy dispersive X-ray (EDX), X-ray diffraction (XRD), Fourier transformed infrared (FT-IR), diffuse-reflectance spectrophotometer (DRS), and Brunauer-Emmett-Teller (BET) analysis. The sonocatalytic activity of the synthesized CdSe/GQDs was effectively accelerated compared with that of pure CdSe nanoparticles in degradation of methylene blue (MB). The influence of the CdSe/GQDs dosage (0.25-1.25g/L), initial MB concentration (20-30mg/L), initial solution pH (3-12), and ultrasonic output power (200-600W/L) were examined on the sonocatalytic treatment of MB aqueous solutions. The degradation efficiency (DE%) of 99% attained at 1g/L of CdSe/GQDs, 20mg/L of MB, pH of 9, and an output power of 200W/L at 90min of ultrasonic irradiation. Furthermore, DE% increased with addition of K2S2O8 and H2O2 as the enhancers via producing more free radicals. However, addition of sulfate, carbonate, and chloride as radical sweeper decreased DE%. Furthermore, well reusability of the CdSe/GQDs sonocatalyst was demonstrated for 5 successive runs and some of the sonocatalytic generated intermediates were indicated by GC-MS analysis. PMID- 28732993 TI - Synthesis of a new Hg(II) coordination polymer: Ultrasonic-assisted synthesis and mechanical preparation of nanostructure. AB - A new mercury(II) coordination polymer, [Hg(4-bpmo)I2]n (1), (4-bpmo=N,N' bis(pyridin-4-ylmethyl)oxalamide), was synthesized, by branched tube method, and structurally characterized by single-crystal X-ray diffraction. Compound 1 is a polymer with a distorted tetrahedral HgN2I2 coordination environment. The thermal stability of 1 was studied by thermal gravimetric (TG) and differential thermal (DTA) analyses. Also 1 was prepared by a sonochemical process at ambient temperature. Reaction time and concentration of initial reagents effects on the size and morphology were studied. Nanoparticles of 1, was synthesized easily by a mechanical method (neat grinding). The resulting structures were characterized by scanning electron microscopy (SEM), IR spectroscopy and X-ray powder diffraction (XRD). PMID- 28732995 TI - Ultrasonic-assisted fabrication and characterization of PVC-SiO2 nanocomposites having bovine serum albumin as a bio coupling agent. AB - In this work, SiO2 nanoparticles (NPs) were modified with bovine serum albumin (BSA) under ultrasound irradiations as a green and fast route to achieve their good dispersion. Subsequently, different weight percentages of the modified NPs (3, 6, and 9wt%) were incorporated in poly(vinyl chloride) (PVC) as the matrix. Thermogravimetric analysis of the SiO2-BSA NPs indicated that 12wt% of the modifier was loaded on the surface of SiO2 NPs. Encapsulation of the SiO2-BSA resulted in a meaningful improvement in the optical, mechanical and thermal characteristics of the prepared PVC nanocomposites (NCs). X-ray diffraction (XRD) patterns for the PVC/SiO2-BSA NCs showed a crystalline behavior for the NC with 6wt% of the SiO2-BSA originated from the phosphate buffer on the NPs. Water contact angle of the PVC/SiO2-BSA NCs showed that the hydrophilicity enhanced with increasing of the NPs contents. PMID- 28732996 TI - Nanostructured beta-type titanium alloy fabricated by ultrasonic nanocrystal surface modification. AB - The surface of beta-type Ti-Nb-Ta-Zr (TNTZ) alloy, which is a promising material for biomedical applications, was treated with the ultrasonic nanocrystal surface modification (UNSM) technique to enhance its hardness. As a result, a gradient nanostructured (GNS) layer was generated in the surface; the microstructure of the top surface layer consisted of nanoscale lamellae with a width of about 60 200nm. In addition, there were lamellar grains consisting of nanostructured subgrains having unclear and wavy boundaries. The treated surface exhibited a hardness value of ~385HV compared to 190HV for the untreated alloy. It was further determined that highly dense deformation twins were generated at a depth of ~40-150um below the UNSM-treated surface. These deformation twins led to a significant work hardening effect which aided in enhancing the mechanical properties. It was also found that UNSM treatment resulted in the formation of micropatterns on the surface, which would be beneficial for high bioactivity and bone regeneration performance of TNTZ implants. PMID- 28732997 TI - Sonochemical effect of flat sweep frequency and pulsed ultrasound (FSFP) treatment on stability of phenolic acids in a model system. AB - To obtain greater knowledge on the stability of phenolic acids for the application of FSFP ultrasound technique in the extraction, the sonochemical effects of ultrasonic factors were investigated. The kinetic model and mechanism of degradation reaction were developed and identified by FT-IR and HPLC-ESIMS. The results showed that caffeic and sinapic acids were degraded under FSFP ultrasound treatment. The ultrasonic temperature, frequency, sweep range, sweep cycle, and pulse ratio were proved to be important factors in affecting the degradation rates of caffeic and sinapic acids. Relatively high temperature, frequency away from the resonance frequency, narrow sweep range, moderate sweep cycle, and relatively low or high pulse ratio were recommended to maintain high stability of caffeic and sinapic acids. The degradation kinetics of these two phenolic acids under FSFP ultrasound treatment were conformed to zeroth-order reaction at 10-50 degrees C. Moreover, FSFP ultrasound had a stronger sonochemical effect on sinapic acid than caffeic acid. The FT-IR and HPLC-ESIMS proved that decomposition and polymerization reactions occurred when caffeic and sinapic acids were subjected to FSFP ultrasound. Degradation products, such as the corresponding decarboxylation products and their dimers, were tentatively identified. PMID- 28732998 TI - Effects of dissolution conditions on the properties of PVDF ultrafiltration membranes. AB - Poly (vinylidene fluoride) (PVDF) is an important membrane forming material for water treatment. Earlier works have shown that major morphological changes can be achieved when PVDF is dissolved under different conditions with practical applications in membrane distillation and protein attachment. However, no previous report has discussed the effects of dissolution conditions on the performance of PVDF under ultrafiltration, which is one of the most important applications of the polymer. In this work, four different PVDF ultrafiltration membranes were produced from dopes dissolved either by stirring at 24 degrees C, 90 degrees C, 120 degrees C or by sonication. It is shown that dope sonication results in membrane with enhanced thermal and mechanical stability, improved permeate flux during oil emulsion filtration and high flux recovery of ~63% after cleaning. As a comparison, flux recovery of only ~26% was obtained for the membrane produced from dope dissolved at 24 degrees C. The outstanding performance of the dope-sonicated membrane was linked to its slightly lower porosity, narrow distribution of small pores and relatively smooth skin layer. Performance parameters for all membranes showed good correlation to porosity suggesting a tool for membrane design achievable by simple variation in the mode of polymer dissolution. The polymer dissolution effect was related to the degree of unfolding of the polymer molecular chains and their entanglements. PMID- 28732999 TI - Ultrasonic depolymerization of Li2O-Na2O-SiO2 type silicate melt. AB - Under the application of ultrasound, the organic polymers can be degraded for the reason of breakage of C-C or C-N bond induced by the cavitation effect, similar to organic polymers, the silicate melts are also one typical polymer connected with Si-O bonds. To verify the prediction of the depolymerization of silicate melt, the ultrasound was applied to one kind of silicate melt for the first time via a special designed experimental system. Results showed that, under the applying of the ultrasound, the Si-O (bridged O) bonds in the structure units of the silicate melt can be broken, which decreases the polymerization degree and the viscosity. Under the higher power of applied ultrasound, the polymerization degree and viscosity of the silicate melt further decrease. Unlike some organic polymers, once stopping applying ultrasound, the broken lower polymerized units reconnect to form higher polymerized units gradually, the degree of the polymerization and the viscosity reverse to its nature state of the silicate melts. According to these results, the potential applications in the steel continuous casting process and electrolytic aluminum process are predicted. PMID- 28733000 TI - Surface modification of TiO2 particles with the sono-assisted exfoliation method. AB - This study reported a novel approach to optimize the photocatalytic property of anatase TiO2 particles by delaminating their outer surface into highly reactive nanosheets via the sono-assisted exfoliation method. To modify the surface, TiO2 particles were dispersed in aqueous solution of 10M sodium hydroxide (NaOH) and tetrabutylammonium hydroxide (TBAOH), followed by irradiation with high intensity ultrasonic wave (20kHz, 150W/cm2) for 60min. The intercalation and exfoliation processes were accelerated with the driving force of the extreme acoustic cavitation leading to the delamination of TiO2 nanosheets with highly reactive exposed {001} facets from the mother TiO2 crystals. The presence of TBAOH increased yield of nanosheets formation and stabilized the nanosheet structure. The unique morphology of the surface modified TiO2 particles provided benefits in increasing the specific surface area and lowering the optical band gap energy (Eg) and electron-hole recombination rate resulting in an enhancement of methylene blue dye degradation efficiency. The surface modification of TiO2 particles by the sono-assisted exfoliation method can optimize the photocatalytic activity by yielding synergetic effects of the high surface reactive sites of the nanosheets and the high degree of crystallinity of the bulk structure. PMID- 28733001 TI - Degradation of endocrine disruptor bisphenol A by ultrasound-assisted electrochemical oxidation in water. AB - Micropollutants are becoming an increasing problem for the environment and wastewater treatment. One example is Bisphenol A (BPA), an endocrinic disruptor, which is widely used in plastic production. Due to its endocrine disrupting effects on aquatic (micro-)organisms and its ubiquity, in surface- and wastewater alike, adequate treatment techniques are necessary. In this study, the degradation of BPA by a sonoelectrochemical hybrid system was investigated, using a low frequency (24kHz) ultrasound horn and two boron doped diamond electrodes. It was found that by the combination of the individual processes, i.e. ultrasound and electrochemical oxidation, more than 90% of BPA could be removed within 30min at an initial concentration of 1mgL-1. Moreover, synergistic effects were discovered and a considerable improvement compared to the individual processes could be achieved by using a potential of 5V, whereas synergistic effects were absent at a potential of 10V. This study provides investigation of ultrasound amplitude, potential and electrode positioning on BPA degradation. The reaction was found to follow pseudo first order kinetics with a rate constant of 0.089min 1. Samples were analysed by high pressure liquid chromatography (HPLC) using a diode array detector. Moreover, the presence and distribution of hydroxyl radicals within the reactor was visualized by using sonochemiluminescence. PMID- 28733002 TI - Aggregation kinetics of single walled carbon nanotubes influenced by the frequency of ultrasound irradiation in the aquatic environment. AB - The colloidal stability of single-walled carbon nanotubes (SWNTs) sonicated at three different ultrasonication (US) frequencies (28, 580, and 1000kHz) were investigated under environmentally relevant conditions. In particular, correlations between surface chemistry, electrokinetic potential, interaction energy, and the aggregation kinetics of the aqueous SWNTs were studied. We observed that H2O2 production is negatively correlated with the yield of hydroxylation and carboxylation of SWNTs, which was dependent on the generation of ultrasonic energy by cavity collapse during US process. The SWNTs sonicated at relatively high US frequencies (580 and 1000kHz) aggregated rapidly in synthetic surface water, whereas alkalinity affected the stability of SWNTs insignificantly. This was because the SWNTs became less negatively charged under such conditions and were captured in deep primary energy wells, according to the Derjaguin-Landau-Verwey-Overbeek theory. Critical coagulation concentration values for the ultrasonicated SWNTs were determined to be 102mM NaCl for 28kHz, 22mM NaCl for 580kHz, and 43mM NaCl for 1000kHz. Suwannee River humic acid decreased the aggregation rate of SWNTs due to the steric hindrance, because of adsorbed macromolecules. Our findings show that the aggregate stability of SWNTs is controlled largely by a complex interplay between the evolution of surface functional groups on the SWNTs during US and solution chemistry. PMID- 28733003 TI - Interactions at the planar Ag3Sn/liquid Sn interface under ultrasonic irradiation. AB - The interactions at the interface between planar Ag3Sn and liquid Sn under ultrasonic irradiation were investigated. An intensive thermal grooving process occurred at Ag3Sn grain boundaries due to ultrasonic effects. Without ultrasonic application, planar shape of Ag3Sn layer gradually evolved into scalloped morphology after the solid-state Sn melting, due to a preferential dissolution of the intermetallic compounds from the regions at grain boundaries, which left behind the grooves embedding in the Ag3Sn layer. Under the effect of ultrasonic, stable grooves could be rapidly generated within an extremely short time (<10s) that was far less than the traditional soldering process (>10min). In addition, the deepened grooves leaded to the formation of necks at the roots of Ag3Sn grains, and further resulted in the strong detachment of intermetallic grains from the substrate. The intensive thermal grooving could promote the growth of Ag3Sn grains in the vertical direction but restrain their coarsening in the horizontal direction, consequently, an elongated morphology was presented. All these phenomena could be attributed to the acoustic cavitation and streaming effects of ultrasonic vibration. PMID- 28733004 TI - Study on thermal, mechanical and adsorption properties of amine-functionalized MCM-41/PMMA and MCM-41/PS nanocomposites prepared by ultrasonic irradiation. AB - In this study, two common industrial polymers, poly(methyl methacrylate) (PMMA) and polystyrene (PS), were incorporated into amine-functionalized MCM-41 mesoporous silica as reinforcement agents via an ultrasonic assisted method as a facile, fast, eco-friendly, and versatile synthetic tool. Amino functionalization of MCM-41 were performed by 3-aminopropyl triethoxysilane as a coupling agent and it is denoted as APTS-MCM-41. The obtained nanocomposites (NCs), APTS-MCM-41/PMMA and APTS-MCM-41/PS, were characterized by Fourier transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD), scanning and transmission electron microscopies (SEM and TEM), and thermogravimetric analysis (TGA). Their mechanical properties were also probed via stress-strain curves and improved tensile properties were observed in the NCs relative to the neat polymers. Additionally, APTS-MCM-41/PMMA exhibited better mechanical properties than APTS-MCM-41/PS. Sorption studies were carried out on the two NCs and the effect of different process parameters, namely, pH, contact time, and initial Cd(II) concentration investigated in batch mode. Pseudo-second order and intraparticle diffusion models explain the Cd(II) kinetics more effectively for APTS-MCM-41/PMMA and APTS-MCM-41/PS, respectively. The adsorption isotherm data fitted well to Langmuir isotherm for both NCs and the maximum monolayer adsorption capacities were found to be 24.75mg/g and 10.42mg/g for APTS-MCM-41/PMMA and APTS-MCM-41/PS, respectively. The results demonstrate that the NCs show potential for use in adsorption of heavy metal ion such as Cd(II) from aqueous media. PMID- 28733005 TI - Ultrasonic cavitation erosion of 316L steel weld joint in liquid Pb-Bi eutectic alloy at 550 degrees C. AB - Liquid lead-bismuth eutectic alloy (LBE) is applied in the Accelerator Driven transmutation System (ADS) as the high-power spallation neutron targets and coolant. A 19.2kHz ultrasonic device was deployed in liquid LBE at 550 degrees C to induce short and long period cavitation erosion damage on the surface of weld joint, SEM and Atomic force microscopy (AFM) were used to map out the surface properties, and Energy Dispersive Spectrometer (EDS) was applied to the qualitative and quantitative analysis of elements in the micro region of the surface. The erosion mechanism for how the cavitation erosion evolved by studying the element changes, their morphology evolution, the surface hardness and the roughness evolution, was proposed. The results showed that the pits, caters and cracks appeared gradually on the erode surface after a period of cavitation. The surface roughness increased along with exposure time. Work hardening by the bubbles impact in the incubation stage strengthened the cavitation resistance efficiently. The dissolution and oxidation corrosion and cavitation erosion that simultaneously happened in liquid LBE accelerated corrosion-erosion process, and these two processes combined to cause more serious damage on the material surface. Contrast to the performance of weld metal, base metal exhibited a much better cavitation resistance. PMID- 28733006 TI - Physical and chemical mechanism underlying ultrasonically enhanced hydrochloric acid leaching of non-oxidative roasting of bastnaesite. AB - In this study, we investigated an alternative to the conventional hydrochloric acid leaching of roasted bastnaesite. The studies suggested that the rare earth oxyfluorides in non-oxidatively roasted bastnaesite can be selectively leached only at elevated temperatures Further, the Ce(IV) in oxidatively roasted bastnaesite does not leach readily at low temperatures, and it is difficult to induce it to form a complex with F- ions in order to increase the leaching efficiency. Moreover, it is inevitably reduced to Ce(III) at elevated temperatures. Thus, the ultrasonically-assisted hydrochloric acid leaching of non oxidatively roasted bastnaesite was studied in detail, including, the effects of several process factors and the, physical and chemical mechanisms underlying the leaching process. The results show that the leaching rate for the ultrasonically assisted process at 55 degrees C (65% rare earth oxides) is almost the same as that for the conventional leaching process at 85 degrees C. Based on the obtained results, it is concluded that ultrasonic cavitation plays a key role in the proposed process, resulting not only in a high shear stress, which damages the solid surface, but also in the formation of hydroxyl radicals (OH) and hydrogen peroxide (H2O2). Standard electrode potential analysis and experimental results indicate that Ce(III) isoxidized by the hydroxyl radicals to Ce(IV), which can be leached with F- ions in the form of a complex, and that the Ce(IV) can subsequently be reduced to Ce(III) by the H2O2. This prevents the Cl- ions in the solution from being oxidized to form chlorine. These results imply that the ultrasonically-assisted process can be used for the leaching of non-oxidatively roasted bastnaesite at low temperatures in the absence of a reductant. PMID- 28733007 TI - Ultrasound-assisted synthesis of poly(MMA-co-BA)/ZnO nanocomposites with enhanced physical properties. AB - The present study reports synthesis and characterization of poly(MMA-co-BA)/ZnO nanocomposites using ultrasound-assisted in-situ emulsion polymerization. Methyl methacrylate (MMA) was copolymerized with butyl acrylate (BA), for enhanced ductility of copolymer matrix, in presence of nanoscale ZnO particles. Ultrasound generated strong micro-turbulence in reaction mixture, which resulted in higher encapsulation and uniform dispersion of ZnO (in native form - without surface modification) in polymer matrix, as compared to mechanical stirring. The nanocomposites were characterized for physical properties and structural morphology using standard techniques such as XRD, FTIR, particle size analysis, UV-Visible spectroscopy, electrical conductivity, TGA, DSC, FE-SEM and TEM. Copolymerization of MMA and BA (in presence of ZnO) followed second order kinetics. Thermal stability (T10%=324.9 degrees C) and glass transition temperature (Tg=67.8 degrees C) of poly(MMA-co-BA)/ZnO nanocomposites showed significant enhancement (35.1 degrees C for 1wt% ZnO and 15.7 degrees C for 4wt% ZnO, respectively), as compared to pristine poly(MMA-co-BA). poly(MMA-co-BA)/ZnO (5wt%) nanocomposites possessed the highest electrical conductivity of 0.192MUS/cm and peak UV absorptivity of 0.55 at 372nm. Solution rheological study of nanocomposites revealed enhancement in viscosity with increasing ZnO loading. Maximum viscosity of 0.01Pa-s was obtained for 5wt% ZnO loading. PMID- 28733008 TI - Highly transparent cerium doped gadolinium gallium aluminum garnet ceramic prepared with precursors fabricated by ultrasonic enhanced chemical co precipitation. AB - Cerium doped gadolinium gallium aluminum garnet (GGAG:Ce) ceramic precursors have been synthesized with an ultrasonic chemical co-precipitation method (UCC) and for comparison with a traditional chemical co-precipitation method (TCC). The effect of ultra-sonication on the morphology of powders and the transmittance of GGAG:Ce ceramics are studied. The results indicate that the UCC method can effectively improve the homogenization and sinterability of GGAG:Ce powders, which contribute to obtain high transparent GGAG ceramic with the highest transmittance of 81%. PMID- 28733009 TI - Design of a new technique based on combination of ultrasound waves via magnetite solid phase and cloud point microextraction for determination of Cr(III) ions. AB - In this work, we focused on development of a new techniques by coupling of ultrasound irradiation, cloud point method and magnetite solid phase microextraction for the extraction and preconcentration of Cr(III) ions from aqueous solutions. In order to reduce cost and improve practicability of proposed process a new efficient and regenerable magnetite sorbent (functionalized chitosan grafted-amino graphene oxide (GO) decorated by zinc ferrite nanoparticles (CS-GO-Zn: Fe2O4)) was synthesized through hydrothermal method and then characterized by FT-IR, FE-SEM, EDS and XRD analysis. Effect of initial sample volume and type, volume and concentration of eluent on the ER%Cr(III) were investigated and optimized using one at a time method. Correlation between the main and interaction effects of other operational parameters such as Cr(III) ion concentration, CS-GO-Zn: Fe2O4 mass, sonication time, pH and solution temperature on the ER%Cr(III) were investigated and optimized by central composite design coupled with desirability function approach. The results revealed that there were significant effects for most investigated terms on the ER%Cr(III) and maximum ER% of 88.09% was obtained in desirability value of 1.0. This maximum efficiency was obtained at 0.035ug/mL Cr(III) ion concentration, 40.16 degrees C temperature, 0.016g of CS-GO-Zn: Fe2O4, pH 6.36 and 9.20min sonication time. In addition, under the optimal conditions the linear range, limit of detection, enrichment factor and relative standard deviation were found to be 0.02-4.4ug/mL, 0.002ug/mL, 23.23 and 1.68% respectively. Finally, the method was successfully applied to the separation and preconcentration of Cr(III) ion from tap, river and mineral waters. PMID- 28733011 TI - Rapid preparation of high electrochemical performance LiFePO4/C composite cathode material with an ultrasonic-intensified micro-impinging jetting reactor. AB - A joint chemical reactor system referred to as an ultrasonic-intensified micro impinging jetting reactor (UIJR), which possesses the feature of fast micro mixing, was proposed and has been employed for rapid preparation of FePO4 particles that are amalgamated by nanoscale primary crystals. As one of the important precursors for the fabrication of lithium iron phosphate cathode, the properties of FePO4 nano particles significantly affect the performance of the lithium iron phosphate cathode. Thus, the effects of joint use of impinging stream and ultrasonic irradiation on the formation of mesoporous structure of FePO4 nano precursor particles and the electrochemical properties of amalgamated LiFePO4/C have been investigated. Additionally, the effects of the reactant concentration (C=0.5, 1.0 and 1.5molL-1), and volumetric flow rate (V=17.15, 51.44, and 85.74mLmin-1) on synthesis of FePO4.2H2O nucleus have been studied when the impinging jetting reactor (IJR) and UIJR are to operate in nonsubmerged mode. It was affirmed from the experiments that the FePO4 nano precursor particles prepared using UIJR have well-formed mesoporous structures with the primary crystal size of 44.6nm, an average pore size of 15.2nm, and a specific surface area of 134.54m2g-1 when the reactant concentration and volumetric flow rate are 1.0molL-1 and 85.74mLmin-1 respectively. The amalgamated LiFePO4/C composites can deliver good electrochemical performance with discharge capacities of 156.7mAhg-1 at 0.1C, and exhibit 138.0mAhg-1 after 100 cycles at 0.5C, which is 95.3% of the initial discharge capacity. PMID- 28733010 TI - Effects of high intensity ultrasound on acid-induced gelation properties of whey protein gel. AB - Pre-heated whey protein isolate (WPI) solution (10% w/v, 85 degrees C for 30min) was prepared and subjected to high-intensity ultrasound (HUS, 20kHz) at different durations (5-40min) before acidification to determine the effects of HUS on glucono-delta-lactone (GDL)-induced gelation properties of whey protein gel. Results showed that HUS reduced the particle size and increased surface free sulfhydryl groups of pre-heated whey protein solution. Free sulfhydryl (-SH) content of the acid-induced WPI gels (GIWG) and protein solubility in presence of 8M urea were significantly reduced (P<0.05) by HUS (20 or 40min), indicating that HUS facilitated formation of more disulfide bonds during/after the gelation process. HUS significantly increased (P<0.05) the water holding capacity (WHC), gel strength, gel firmness (G') as well as the frequency dependence of GIWG. The WHC, gel strength and gel firmness were positively correlated with surface free SH content of pre-heated WPI and negatively correlated with particle size of pre heated WPI and free -SH content of GIWG. The results indicated that high intensity ultrasound could be used for modifying whey protein to improve its gelling properties. PMID- 28733012 TI - Ultrasound-promoted copper-catalyzed synthesis of bis-arylselanyl chrysin derivatives with boosted antioxidant and anticancer activities. AB - Herein we report the use of ultrasonic irradiation (US) in the synthesis of six new semi-synthetic selenium-containing chrysin derivatives by a simple and effective methodology utilizing CuI as catalyst, in good to excellent yields (60 89%). It was observed that US accelerates the reaction compared to conventional heating with excellent selectivity for diselenylated products. Compounds were tested for their antioxidant and anticancer activities in vitro and it was observed that the presence of selenium in the A-ring of chrysin enhanced both antioxidant and anticancer properties. Semi-synthetic 6,8-bis(o-tolylselanyl) chrysin 3b has the best radical scavenging activity of DPPH (Imax: 39.79uM) and ABTS+ (IC50: 6.5uM) radicals. Similarly, in the Reactive Species (RS) assay, 3b showed high antioxidant activity in mice cortex (IC50: 5.67uM), whereas 6,8-bis(p anisoylselanyl)-chrysin 3c was the more active in the hippocampus (IC50: 5.63uM). The Se-chrysins were effective in prevention of lipid peroxidation, highlighting 6,8-bis(p-fluorophenylselanyl)-chrysin 3d in cortex (IC50: 0.54uM) and 3b in hippocampus (IC50: 0.27uM). In addition, 3d was effective in inhibiting human lung adenocarcinoma (A549) cells growth, with a IC50 of 19.9uM after 72h of treatment, while 6,8-bis(p-anisoylselanyl)-chrysin 3c presented the higher antiproliferative activity after 48h of treatment (IC50 of 41.4uM). PMID- 28733013 TI - Photoluminescence, electrochemical behavior and photocatalytic activities of cobalt(II) coordination polymer nanostructures synthesized by sonochemical process. AB - Nanostructures of a new Co(II) coordination polymer (CP), [Co(Hbibp)(nbta)]n (1), (bibp=4,4'-bis(1-imidazolyl)biphenyl, H3nbta=5-nitro-1,2,3-benzenetricarboxylic acid) was synthesized by a sonochemical method. The nano-sized CP 1 was characterized by elemental analysis, IR spectroscopy, X-ray powder diffraction and scanning electron microscopy (SEM). Structural analysis show that CP 1 exhibits a 1D chain structure with a 3-connected SP 1-periodic net (4,4)(0,2) topology, which can be further extended into a 2D supramolecular layer by the NH?O hydrogen bond interactions. The thermal stability for CP 1 as bulk and nanoparticles were investigated. The photoluminescence properties and electrochemical behavior for nano-sized CP 1 have also been explored. Moreover, nano-sized CP 1 shows high photocatalytic activities for the degradation of MB under UV irradiation and the photodegradation process is mainly caused by OH radicals. Effects of the sonication time and ultrasonic power on the morphology and size of nanoparticles were studied. PMID- 28733014 TI - Removal of Congo red dye from aqueous solution with nickel-based metal-organic framework/graphene oxide composites prepared by ultrasonic wave-assisted ball milling. AB - Metal-organic frameworks (MOFs) were successfully synthesized by ultrasonic wave assisted ball milling. In the absence of organic solvent, the coupling effect of ultrasonic wave and mechanical force played an significant role in the synthesis of MOFs. Adsorption of Congo red (CR) was studied in view of adsorption kinetic, isotherm and thermodynamics. The adsorbent was carried out using X-ray diffraction (XRD), thermogravimetric analysis (TGA), N2 adsorption-desorption isotherms, Raman spectroscopy and scanning electron microscope (SEM) methods. It was found that pseudo-second-order kinetic model and Freundlich adsorption isotherm matched well for the adsorption of CR onto nickel-based metal-organic framework/graphene oxide composites (Ni-MOF/GO). The results of the adsorption thermodynamics indicated that the adsorption process was a spontaneous and endothermic process. The adsorption capacity of graphene oxide/metal-organic frameworks (GO/MOFs) for CR reached 2489mg/g, much higher than previous reports. It was demonstrated that an increase in the number of active metal sites can dramatically improve the adsorption capacity of dye. A suitable dry temperature is beneficial for the improvement of adsorption capacity for dye. In this paper, the adsorption results indicated that ultrasonic wave-assisted ball milling has a good prospect for synthesis of MOFs with excellent adsorption performance. PMID- 28733015 TI - Ultrasonic-assisted synthesis of polyvinyl alcohol/phytic acid polymer film and its thermal stability, mechanical properties and surface resistivity. AB - In this paper, polyvinyl alcohol/phytic acid polymer (PVA/PA polymer) was synthesized through esterification reaction of PVA and PA in the case of acidity and ultrasound irradiation and characterized, and PVA/PA polymer film was prepared by PVA/PA polymer and characterized, and the influence of dosage of PA on the thermal stability, mechanical properties and surface resistivity of PVA/PA polymer film were researched, and the influence of sonication time on the mechanical properties of PVA/PA polymer film was investigated. Based on those, it was concluded that the hydroxyl group on the chain of PVA and the phosphonic group on PA were connected together in the form of phosphonate bond, and the hydroxyl group on the chain of PVA were connected together in the form of ether bond after the intermolecular dehydration; in the meantime, it was also confirmed that PVA/PA polymer film prepared from 1.20mL of PA not only had the high thermal stability and favorable ductility but also the low surface resistivity in comparison with PVA/PA polymer film with 0.00mL of PA, and the ductility of PVA/PA polymer film was very sensitive to the sonication time. PMID- 28733016 TI - Interaction between cavitation microbubble and cell: A simulation of sonoporation using boundary element method (BEM). AB - Sonoporation has been widely accepted as a significant tool for gene delivery as well as some bio-effects like hemolysis, bringing in high demands of looking into its underlying mechanism. A two-dimensional (2D) boundary element method (BEM) model was developed to investigate microbubble-cell interaction, especially the morphological and mechanical characteristics around the close-to-bubble point (CP) on cell membrane. Based on time evolution analysis of sonoporation, detailed information was extracted from the model for analysis, including volume expansion ratio of the bubble, areal expansion ratio of the cell, jet velocity and CP displacement. Parametric studies were carried out, revealing the influence of different ultrasound parameters (i.e., driving frequency and acoustic pressure) and geometrical configurations (i.e., bubble-cell distance and initial bubble radius). This model could become a powerful tool not only for understanding bubble-cell interactions, but also for optimizing the strategy of sonoporation, such that it could be safer and of higher efficiency for biological and medical studies especially in clinics. PMID- 28733017 TI - Combined sonochemical and short-wavelength UV degradation of hydrophobic perfluorinated compounds. AB - Perfluorochemicals (PFCs), which are common in the aquatic environment, are toxic substances that have high chemical and heat resistance because of their strong C F bonds. We investigated the effect of ultrasonication and short-wavelength UV irradiation on the degradation of perfluorooctane, perfluoropropionic acid, and perfluorooctanoic acid, which are examples of hydrophobic, hydrophilic, and intermediate PFCs, respectively. The results confirmed that ultrasonication was more effective for decomposing hydrophobic PFCs and UV irradiation was more effective for decomposing hydrophilic PFCs. Therefore, defluorination of the degradation intermediates was improved by a combination of ultrasonication and UV irradiation. Our results can be applied to the decomposition treatment of PFCs that have various levels of water solubility in the aquatic environment. PMID- 28733018 TI - Sono-assisted preparation of bio-nanocomposite for removal of Pb2+ ions: Study of morphology, thermal and wettability properties. AB - Multi-walled carbon nanotubes (MWCNT) loaded poly(ethylene terephthalate) (PET) composites, with different CNT contents, were fabricated through an ultrasound assisted method as a fast and green way. Then, the obtained composites were fully characterized via FT-IR, UV-Vis, XRD, TGA, FE-SEM and TEM, etc. For this purpose, PET bottle was recycled and applied as matrix of nanocomposites (NC)s. Then, we dispersed the covalent functionalization of MWCNTs with a protein dispersant and obtained a powder of protein-functionalized CNTs. Bio-functionalized MWCNTs showed higher Pb2+ removal efficiency compared to MWCNT-COOH as ascertained via batch equilibrium adsorption experiments. Also, the results indicated the novel NCs presents a high affinity for Pb2+ heavy metal owing to the presence of several good sites. The contact angle results indicated that the addition of MWCNT-BSA increased significantly the contact angle compared to the pure PET. It was concluded that inflame retarding feature of NC was higher than pure polymer. PMID- 28733019 TI - Sonochemical synthesis of hydrogenated amorphous silicon nanoparticles from liquid trisilane at ambient temperature and pressure. AB - Silicon nanoparticles (Si-NPs) are increasing in relevance in diverse fields of scientific and nanotechnological inquiry, where currently some of the most important areas of research involve energy storage and biomedical applications. The present article is concerned with a curious and scalable method for the preparation of discrete, unoxidized, hydrogenated, and amorphous Si-NPs of tunable size in the range of 1.5-50nm. Using ultrasound generated with a conventional ultrasonic horn, the "fusion" of Si-NPs is demonstrated at ambient temperature and pressure by sonicating solutions containing readily available, semiconductor-grade purity trisilane (Si3H8). The only requirement for the synthesis is that it be carried out in an inert atmosphere such as that of a N2 filled glove box. Various spectroscopic techniques and electron microscopy images are used to show that the size of the Si-NPs can be controlled by varying the amplitude of the ultrasonic waves or the concentration of trisilane in the solution. Moreover, sustained ultrasonic irradiation is found to yield highly porous Si-NP agglomerates that may find use in applications requiring non crystalline nanoscopic high specific surface area morphologies. PMID- 28733020 TI - Sonolysis and sono-Fenton oxidation for removal of ibuprofen in (waste)water. AB - Two sonochemical processes were compared for the removal of ibuprofen in different water matrixes (distilled water and effluent from wastewater treatment plant). The effect of various operating parameters, such as pH (2.6-8.0), ultrasound power density (25-100W/L), sonication frequency (12-862kHz), addition of radical promoters (H2O2 and Fenton's reagent) or scavengers (n-butanol and acetic acid), was evaluated. Sono-degradation of ibuprofen followed a first-order kinetic trend, whose rate constant increased with ultrasound density and frequency. For this hydrophobic and low volatile molecule, a free-radical mechanism at the bubble interface was established. Coupling ultrasound with Fenton reaction showed a positive synergy, especially in terms of mineralization yield, while adding H2O2 alone had no significant beneficial effect. Dedicated experiments proved this synergy to be due to the enhanced regeneration of ferrous ions by ultrasound. Efficacy of the sonolysis process was hampered in wastewater matrix, mainly as the consequence of higher pH increasing the molecule solubility. However, after convenient acidification, sono-Fenton oxidation results remained almost unchanged, indicating no significant radical scavenging effects from the effluent compounds. PMID- 28733021 TI - Sonochemical synthesis and structural characterization of a new nanostructured Co(II) supramolecular coordination polymer with Lewis base sites as a new catalyst for Knoevenagel condensation. AB - A new Co(II) mixed-ligand coordination supramolecular polymer with composition [Co2(ppda)(4-bpdh)2(NO3)2]n (1) (where, ppda=p-phenylenediacrylic acid, 4 bpdh=2,5-bis(4-pyridyl)-3,4-diaza-2,4-hexadiene) was synthesized using solvothermal, mechanochemical and sonochemical methods. Compound 1 and the new nanostructure have been characterized by single-crystal X-ray, infrared spectroscopy (IR), powder X-ray diffraction (PXRD) analysis and scanning electron microscopy (SEM). The thermal stability of compound 1 was also studied by thermal gravimetric analysis (TGA). The surface area of these compounds was determined by BET. The single-crystal X-ray data shows a new interesting two-dimensional coordination polymer (CP). In addition, the effect of various sonication concentrations of initial reagents, power of ultrasound irradiation and also the time on the size and morphology of nano-structured coordination polymer 1 were evaluated. Moreover, it has been demonstrated that the nanostructure of the CP1 can be used as a catalyst in Knoevenagel condensation reaction. PMID- 28733022 TI - Preparation and sonophotocatalytic performance of hierarchical Bi2WO6 structures and effects of various factors on the rate of Rhodamine B degradation. AB - Hierarchical Bi2WO6 structures with high surface area were prepared in the presence of polyvinylpyrrolidone by using an optimized hydrothermal method. The samples prepared were characterized by X-ray diffraction, field-emission scanning electron microscopy and N2 adsorption-desorption technique. The results of these characterizations showed the formation of the hierarchical Bi2WO6 structures with high surface area (51m2/g). The degradation of Rhodamine B (RhB) with or without visible light was investigated under various experimental conditions to evaluate the sonophotocatalytic activity of the hierarchical Bi2WO6 structures. The result showed that the degradation efficiency was found to be in the following order: sonocatalysis 0.05). CONCLUSIONS: Our study indicated miR-150, miR-146a and miR-424 may be potential biomarkers of T1DM with applications in the clinical setting as well as provided new insights into the molecular mechanisms involved in this disorder. PMID- 28733036 TI - [An unexpected window into neuropsychiatric symptoms]. PMID- 28733035 TI - MiR-18a-5p inhibits endothelial-mesenchymal transition and cardiac fibrosis through the Notch2 pathway. AB - Hyperglycemia plays a crucial role in the pathogenesis of diabetic complications; however, the mechanisms underlying diabetic cardiac fibrosis remain unclear. Endothelial cells are known to contribute to cardiac fibrosis through endothelial mesenchymal transition (EndMT) under high glucose stimulation. Here we investigated the expression of miR-18a-5p and examined its functional role in human aortic valvular endothelial cells (HAVECs). Using HAVECs, we revealed that miR-18a-5p regulated high glucose-induced EndMT. Moreover, high glucose levels induced Notch2 expression, which promoted EndMT, resulting in the downregulation of vascular endothelial cadherin and CD31 and upregulation of fibroblast-specific protein-1, alpha-smooth muscle actin, fibronectin, and vimentin. Furthermore, Notch2 was identified as a target of miR-18a-5p. Our data showed that the overexpression of miR-18a-5p could downregulate Notch2 expression and subsequently suppress EndMT. In conclusion, our findings demonstrated that miR 18a-5p/Notch2 signaling pathway participates in the regulation of high glucose induced EndMT, and may act as a novel promising target for myocardial fibrosis in diabetic cardiomyopathy. PMID- 28733037 TI - Efficient probabilistic finite element analysis of a lumbar motion segment. AB - Finite element models of the lumbar spine are useful in assessing biomechanics and performance of implants. Models are often developed using the anatomy of an individual subject. Average mechanical property values for the annulus and other soft tissue structures are typically utilized from the literature, as data for the same subject are not available. However, these properties can have significant variability. While probabilistic methods enable the impact of soft tissue property variability on spine mechanics to be assessed, they often require lengthy computation times. Accordingly, the objective of this study was to develop efficient methods to perform Monte Carlo simulations of a finite element model of the L4 L5 functional spinal unit considering variability in the properties of the soft tissue structures. Distributions for the soft tissue properties included the stiffness of spinal ligaments and parameters of a Holzapfel-Gasser-Ogden constitutive material model of the disc. Variance reduction sampling methods, including the Sobol and Descriptive sampling techniques, were assessed for efficiency and accuracy in comparison to traditional random Monte Carlo sampling. Comparisons were based on output torque rotation curves at the 10th and 90th percentile for flexion, extension, axial rotation, and lateral bending. The Descriptive sampling technique best matched the random sampling technique, at the extremes of rotation, with a 3.6% mean difference. This was achieved with a 10* reduction in the number of iterations and computation time. Improvements in efficiency and maintained accuracy enable intersubject variability to be considered in a variety of biomechanical evaluations, including design-phase screening of orthopedic implants. PMID- 28733038 TI - Ferulic acid reverses depression-like behavior and oxidative stress induced by chronic corticosterone treatment in mice. AB - Corticosterone (CORT) treatment has been evidenced to develop a depression-like state in animals, that mimic hypothalamic-pituitary-adrenal (HPA)-axis dysregulation implicated in the development of depression. The present study aimed to examine the ferulic acid (FA), a natural phenolic compound, antidepressant and antioxidant activities on the CORT chronic model. Mice orally treated with 20mg/kg of CORT for 21days were connsidered control group, while mice treated with FA (1mg/kg) or fluoxetine (10mg/kg) for the last week of CORT treatment, as drug groups. Three weeks of CORT treatment resulted in depressive like behavior, as indicated by the increase on the immobility time in the tail suspension test, grooming in the splash test and an increase in the oxidative stress markers in the brain. It was observed that FA ameliorated the behavioral and oxidative stress alterations induced by CORT, which may plausibly suggest a mode of action for the FA antidepressant effect. The involvement of FA repairing the stress caused by HPA-axis dysfunction evidenced that this phenolic acid could be further investigated as a novel potential agent to improve the management of depression. PMID- 28733039 TI - Can the leaf-bag technique detect benthic macrofauna responses to sediment contamination by metals and metalloids in estuaries? AB - The Estarreja Channel, Ria de Aveiro, Portugal, received industrial effluents for over 70years. Despite the discharges stopped a decade ago, a recent study showed negative ecological effects still associated with the metal and metalloid contaminated sediments. In contaminated versus reference channels, this study compared the benthic macrofauna collected with corer and mesh-bags for community structure and synthesis descriptors, namely taxa richness (S), Shannon-Wiener diversity (H'), taxonomic (AMBI and M-AMBI) and non-taxonomic (ISS) biotic indices and functional indicators (decomposition rates). The corer infauna dominated community and the associated S, H', M-AMBI and ISS indices detected significant differences between contaminated and reference channels, otherwise undistinguished by the decomposition rates and the mesh-bags epifauna dominated community and associated indices. This suggests that sediment contamination in the deeper layers is not being transferred to the surface layers, explaining the non-affectation of the benthic macrofauna communities sampled in the leaf-bags. PMID- 28733040 TI - Variations in the concentrations of heavy metals through enforcement of a rest year system and dredged sediment capping at the Yellow Sea-Byung dumping site, Korea. AB - In 2014, the concentrations of 13 heavy metals in surface sediments from 14 sampling stations were analyzed and compared to samples from previous years to evaluate the remediation effectiveness of the "rest-year" (RY) system and capping with dredged material at the Yellow Sea-Byung dumping site offshore Korea. Since the 2006 introduction of the RY system, annual variations in metal concentrations at stations within the RY zone have gradually decreased over time. Heavy metal concentrations at most stations were lower than sediment quality guidelines, indicating the success of the RY system. Additionally, the effects of capping the contaminated sediment with dredged materials were investigated. The results indicate that dredged materials successfully capped the contaminated sediment within the dredged material dumping area, as the concentrations of Cr and total organic carbon were significantly reduced. We conclude that dredged materials may be used as capping materials for the remediation of contaminated sediments. PMID- 28733041 TI - Ocean acidification narrows the acute thermal and salinity tolerance of the Sydney rock oyster Saccostrea glomerata. AB - Coastal and estuarine environments are characterised by acute changes in temperature and salinity. Organisms living within these environments are adapted to withstand such changes, yet near-future ocean acidification (OA) may challenge their physiological capacity to respond. We tested the impact of CO2-induced OA on the acute thermal and salinity tolerance, energy metabolism and acid-base regulation capacity of the oyster Saccostrea glomerata. Adult S. glomerata were acclimated to three CO2 levels (ambient 380MUatm, moderate 856MUatm, high 1500MUatm) for 5weeks (24 degrees C, salinity 34.6) before being exposed to a series of acute temperature (15-33 degrees C) and salinity (34.2-20) treatments. Oysters acclimated to elevated CO2 showed a significant metabolic depression and extracellular acidosis with acute exposure to elevated temperature and reduced salinity, especially at the highest CO2 of 1500MUatm. Our results suggest that the acute thermal and salinity tolerance of S. glomerata and thus its distribution will reduce as OA continues to worsen. PMID- 28733042 TI - Complications and unplanned outcomes following operative treatment of tibial plateau fractures. AB - INTRODUCTION: The operative management of tibial plateau fractures is challenging and post-operative complications do occur. The purpose of this study was three fold. 1). To report complications and unplanned outcomes in patients who had sustained tibial plateau fractures and were operatively managed 2). To report predictors of these post-operative events 3). To report if differences in clinical outcomes exist in patients who sustained a post-operative event. METHODS: Over 11 years, all tibial plateau fractures were prospectively followed. Clinical outcomes were assessed using the validated Short Musculoskeletal Functional Assessment (SMFA) score. Demographics, initial injury characteristics, surgical details and post-operative events were prospectively recorded. Student's t-tests were used for continuous variables and chi-squared analysis was used for categorical variables. Binary logistic regression and multivariate linear regression were conducted for independent predictors of post-operative events and complications and functional outcomes, respectively. RESULTS: 275 patients with 279 tibial plateau fractures were included in our analysis. Ten patients (3.6%) sustained a deep infection. Six patients (2.2%) developed a superficial infection. One patient (0.4%) presented with early implant failure. Two patients (0.7%) developed a fracture nonunion. Eight patients (2.9%) developed a venous thromboembolism. Seventeen patients (6.2%) went on to re-operation for symptomatic implant removal. Nine patients (3.3%) underwent a lysis of adhesions procedure. Univariate analysis demonstrated bicondylar tibial plateau fractures (P<0.001), Moore fracture-dislocations (P=0.005), open fractures (P=0.022), and compartment syndrome (P=0.001) to be associated with post-operative complications and unplanned outcomes. Long-term functional outcomes were worse among patients who developed a post-operative complication or unplanned outcome (P=0.031). CONCLUSION: Orthopaedic trauma surgeons should be aware of complications and unplanned outcomes following operatively managed tibial plateau fractures, along with having the knowledge of factors that are associated with development of post operative events. PMID- 28733043 TI - Perioperative hypotension and discharge outcomes in non-critically injured trauma patients, a single centre retrospective cohort study. AB - BACKGROUND: There is a lack of information on the effect of age on perioperative care and outcomes after minor trauma in the elderly. We examined the association between perioperative hypotension and discharge outcome among non-critically injured adult patients. METHODS: We conducted a retrospective study of non critically ill patients (ISS <9 or discharged within less than 24h) who received anaesthesia care for surgery and Recovery Room care at a level-1 trauma centre between 5/1/2012 and 11/30/2013. Perioperative hypotension was defined as systolic blood pressure (SBP) <90mmHg (traditional measure) for all patients, and SBP <110mmHg (strict measure) for patients >=65years. Poor outcome was defined as death or discharge to skilled nursing facility/hospice. RESULTS: 1744 patients with mean ISS 4.4 across age groups were included; 169 (10%) were >=65years. Among patients>=65years, intraoperative hypotension occurred in >75% (131/169, traditional measure) and in >95% (162/169, strict measure); recovery room hypotension occurred in 2% (4/169) and 29% (49/169), respectively. Mean age adjusted anaesthetic agent concentration (MAC) was similar across age groups. Opioid use decreased from 9.3 (SD 5.7) mg/h morphine equivalents in patients <55years to 6.2 (SD 4.0) mg/h in patients over 85 years. Adjusted for gender, ASA score, anaesthesia duration, morphine equivalent/hr, fluid balance, MAC and surgery type, and using traditional definition, older patients were more likely than patients <55 to experience perioperative hypotension: aRR 1.21, 95% CI 1.11 1.30 for 55-64 and aRR 1.19, 95% CI 1.07-1.32 for ages 65-74. Perioperative hypotension was associated with poor discharge outcome (aRR 1.55; 95% CI 1.04 2.31 and aRR 1.87; 95% CI 1.17-2.98, respectively). CONCLUSION: Despite age related reduction in doses of volatile anaesthetic and opioids administered during anaesthesia care, and regardless of hypotension definition used, non critically injured patients undergoing surgery experience a large perioperative hypotension burden. This burden is higher for patients 55-74 years and older and is a risk factor for poor discharge outcomes, independent of age and ASA status. PMID- 28733044 TI - Management of displaced inferior patellar pole fractures with modified tension band technique combined with cable cerclage using Cable Grip System. AB - INTRODUCTION: We present a modified tension band technique combined with cable cerclage using Cable Grip System for the treatment of displaced inferior patellar pole fractures and report the knee functional outcome. PATIENTS AND METHODS: The patients who had had operative treatment of a displaced inferior patellar pole fracture (AO/OTA 34-A1) between December 2013 and December 2015 were studied retrospectively. Eleven consecutive patients had had open reduction and internal fixation with the modified technique using Cable Grip System, of whom, five males and six females with an average age of 60.9 years (range, 29-81 years). All fractures occurred from direct fall onto the knee. The average time from injury to surgery was 6.1days (range, 2-12days). The range of motion (ROM) was measured in degrees by goniometry at postoperative intervals of 1, 2, 4, 12, and 48 weeks; Knee function was evaluated using the Rasmussen scores at final follow-up. RESULTS: No patients had nonunion, loss of reduction, migration of wire, irritation from the implant and fixation breakage during the follow-up period. Recovery of ROM was achieved at 12 weeks, with the average ROM at 1 week was 72 degrees (range, 65 degrees -78 degrees ), 86.4 degrees (range, 78 degrees -92 degrees ) at 2 weeks, 115.5 degrees (range, 103 degrees -122 degrees ) at 4 weeks, 129.6 degrees (range, 122 degrees -133 degrees ) at 12 weeks, 134.5 degrees (range, 129 degrees -139 degrees ) at 48 weeks after the operation. Concerning the knee function outcome assessment, all patients showed excellent results at final follow-up. The average Rasmussen scores was 27.9 out of 30 (range, 27-29). CONCLUSIONS: The modified tension band technique combined with cable cerclage using Cable Grip System for displaced inferior patellar pole fractures can provide stable fixation with excellent results in knee function, allows for immediate mobilization and early weight-bearing, which is a simple and valuable technique in routine clinical practice. PMID- 28733046 TI - Isolated orbital metastasis as an initial presentation of a breast cancer. PMID- 28733045 TI - Induction of Live Cell Phagocytosis by a Specific Combination of Inflammatory Stimuli. AB - Conditions of severe hyper-inflammation can lead to uncontrolled activation of macrophages, and the ensuing phagocytosis of live cells. However, relationships between inflammatory stimuli and uncontrolled phagocytosis of live cells by macrophages are poorly understood. To identify mediators of this process, we established phagocytosis assays of live cells by stimulating macrophages with CpG DNA, interferon-gamma, and anti-interleukin-10 receptor antibody. In this model, various cell surface receptors were upregulated on macrophages, and phagocytosis of live cells was induced in a Rac1-dependent manner. Subsequent inhibition of the ICAM-1, VCAM-1, and both of these receptors abolished in vitro and in vivo phagocytosis of live T cells, myeloid cells, and B cells, respectively. Specifically, the reduction in lymphocyte numbers due to in vivo activation of macrophages was ameliorated in Icam-1-deficient mice. In addition, overexpression of ICAM-1 or VCAM-1 in non-phagocytic NIH3T3 cells led to active phagocytosis of live cells. These data indicate molecular mechanisms underlying live cell phagocytosis induced by hyper-inflammation, and this experimental model will be useful to clarify the pathophysiological mechanisms of hemophagocytosis and to indicate therapeutic targets. PMID- 28733048 TI - Bioremediation advances. PMID- 28733047 TI - Idiopathic granulomatous mastitis. A rare benign entitiy that can simulate breast cancer. PMID- 28733049 TI - The time course of attention modulation elicited by spatial uncertainty. AB - Uncertainty regarding the target location is an influential factor for spatial attention. Modulation in spatial uncertainty can lead to adjustments in attention scope and variations in attention effects. Hence, investigating spatial uncertainty modulation is important for understanding the underlying mechanism of spatial attention. However, the temporal dynamics of this modulation remains unclear. To evaluate the time course of spatial uncertainty modulation, we adopted a Posner-like attention orienting paradigm with central or peripheral cues. Different numbers of cues were used to indicate the potential locations of the target and thereby manipulate the spatial uncertainty level. The time interval between the onsets of the cue and the target (stimulus onset asynchrony, SOA) varied from 50 to 2000ms. We found that under central cueing, the effect of spatial uncertainty modulation could be detected from 200 to 2000ms after the presence of the cues. Under peripheral cueing, the effect of spatial uncertainty modulation was observed from 50 to 2000ms after cueing. Our results demonstrate that spatial uncertainty modulation produces robust and sustained effects on target detection speed. The time course of this modulation is influenced by the cueing method, which suggests that discrepant processing procedures are involved under different cueing conditions. PMID- 28733050 TI - The optical imaging of idiopathic paracentral acute middle maculopathy in a Chinese young man and review of the literature. AB - We report a case of idiopathic paracentral acute middle maculopathy with typical optical imaging and clinical features. A 26-year-old Chinese policeman presented with a 20-day history of paracentral scotoma in the left eye after early wake-up and long-time working in front of computer the day before. He experienced sudden onset strong flash in his left eye. Paracentral scotoma appeared in his left eye after 6hours of rest. The general history was negative. His best corrected visual acuity was 20/20 OU. Anterior segment, dilated fundus examination, papillary evaluation and intraocular pressure were normal. Fuorescein angiography and blue light fundus autofluorescence showed no significant abnormality. In multicolor photography, the lesion was visible on the monochromic infrared/blue reflectance images and not clear in green reflectance. The 10 degree visual field examination revealed superior paracentral relative scotoma. Multifocal electroretinogram revealed reduced response in central area in the left eye. Spectral-domain optical coherence tomography showed that hyperreflective plaque was present at the IPL/INL/OPL level with hyperreflective point at the GCL. The plaque became thinner 3 months later and diminished 6 months later with obviously atrophied INL. In the 3 months follow-up, transverse scan revealed that there was a well demarcated hypo-refractive lesion in IPL and hyper-refractive lesion in INL. OCTA revealed the deceased flow signal intensity of focal deep capillaries. En face OCT imaging of the left eye revealed a relative well-defined, hypo-refractive lesion and non-flow area localized at the level of the deep capillary plexus. PMID- 28733051 TI - Compliance in weight control reduces atrial fibrillation worsening: A retrospective cohort study. AB - BACKGROUND AND AIM: Obesity plays a dominant role in the etiology of atrial fibrillation (AF), and the maintenance of a normal body mass index (BMI) seems to prevent and even reduce the incidence of the arrhythmia's recurrence. We selected 270 patients (pts) to assess whether this therapeutic effect was statistically significant even in Mediterranean patients. METHOD AND RESULTS: In this retrospective cohort study, we analyzed every symptomatic AF relapse during a total follow-up of 657 patient-years. Clinical data, BMI variations, and pts' history were available in our clinical database. We divided the pts in four groups (Gs), according to their BMI variation during the follow-up: G1, normal weight pts, maintaining their weight; G2, overweight pts, losing weight; G3, overweight pts, maintaining their weight; G4, pts gaining weight. Their follow-up (in months) was normalized according to their AF relapses, thus obtaining a mean AF-free period for each patient. Among the overweight groups, G2 showed the best AF-free period (9.7 months). However, G3 and G4 showed a reduced AF-free interval (4.6 and 1.7 months, respectively). G1, predictably, had the longest AF-free period (10 months). CONCLUSION: The results of the present study confirm that simple non-invasive intervention aimed to normalize BMI and to control risk factors through appropriate lifestyle can be highly effective in reducing the AF burden, by acting on comorbidities and proarrhythmic mechanisms. Therefore, serious attempt should be made to correct risk factors before an ablation therapy is proposed. PMID- 28733052 TI - Evolution of radiation techniques in the treatment of breast cancer (BC) patients: From 3D conformal radiotherapy (3D CRT) to intensity-modulated RT (IMRT) using Helical Tomotherapy (HT). PMID- 28733054 TI - Clinical and diagnosis characteristics of breast cancers in women with a history of radiotherapy in the first 30years of life: A French multicentre cohort study. AB - PURPOSE: Irradiation (>3Gy) to the breast or axillae before 30years of age increases the risk of secondary breast cancer (SBC). The purpose of this article is to describe the clinical characteristics of SBC and the way of diagnosis in young women (before the age of national screening) in France who had received previous radiotherapy for a childhood or a young adulthood cancer. PATIENTS AND METHODS: This retrospective, multicentre study reviewed the medical records of women with SBC before the age of the national screening who had received irradiation (>=3Gy) on part or all of the breast before 30years of age, for any type of tumour except BC. RESULTS: A total of 121 SBC were detected in 104 women with previous radiotherapy. Twenty percent of SBC were detected during regular breast screening and 16% of the women had a regular radiological follow-up. CONCLUSION: Our results points out that the main proportion of childhood cancer survivors did not benefit from the recommended breast cancer screening. This result is comparable to other previously published studies in other countries. A national screening programme is necessary and should take into account the patient's age, family history, personal medical history and previous radiotherapy to reduce the number of SBC diagnosed at an advanced stage. PMID- 28733053 TI - Dose-volume correlates of mandibular osteoradionecrosis in Oropharynx cancer patients receiving intensity-modulated radiotherapy: Results from a case-matched comparison. AB - PURPOSE: To determine dosimetric parameters associated with osteoradionecrosis (ORN) in oropharyngeal cancer (OPC) patients in the IMRT era. MATERIAL AND METHODS: Subsequent to institutional review board approval, we identified ORN in OPC patients treated with IMRT from 2002 to 2013. 1:2 case-control matching was implemented. Mandibular dose-volume histograms (DVH) were extracted. Dosimetric parameters were compared using non-parametric stats. Recursive partitioning analysis (RPA) was done to identify DVH correlates of ORN. RESULTS: 68 ORN cases and 131 controls were matched. Median follow-up was 41months and median time to development of ORN was 16months. Mandibular mean dose was significantly higher in the ORN cohort (48.1 vs 43.6Gy, p<0.0001). However, the maximum dose was not statistically different. DVH bins from V35 to V73 were all significantly higher in the ORN cohort compared with controls (p<0.0006). Two DVH parameters were identified in RPA analysis, V43 and V58. The majority (81%) of ORN cases were observed with both V44>=42% and V58>=25%. CONCLUSIONS: Our data demonstrate that a wide range of DVH parameters in the intermediate and high beam path were all significantly higher in ORN patients. Mandibular V44<42% and V58<25% represent reasonable DVH constraints for IMRT plan acceptability, when tumor coverage is not compromised. PMID- 28733055 TI - Avoiding antiperspirants during breast radiation therapy: Myth or sound advice? AB - Breast cancer patients are typically advised to avoid antiperspirants for fear of increasing radiation dermatitis in the axilla. We hypothesized that antiperspirants would have minimal effect on skin dose. We found no difference in surface dose+/-antiperspirants using 6MV photons at gantry angles of 0 degrees /30 degrees /60 degrees /90 degrees regardless of aluminum concentration. PMID- 28733056 TI - Uninsured Maternity Patients in Calgary: Local Trends and Survey of Health Care Workers. AB - OBJECTIVE: Uninsured maternity patients comprise a small but complex group of patients and include marginalized Canadians, undocumented immigrants, visitors, and non-Canadians seeking health care and/or citizenship for their newborn. This is the first Canadian study to quantify these patients and to review health care providers' perspectives and practices of care. METHODS: Data for all deliveries in Calgary, Alberta over a 4-year period (2013-2016) were analyzed. All Calgary anaesthesiologists, family physicians, midwives, neonatologists, obstetricians, and pediatricians were surveyed about their care of these patients, ethical perspectives, and knowledge of liability protection when providing such care. RESULTS: This study found a trend of uninsured deliveries in Calgary (from 0.5% in 2013 to 0.8% in 2016; P < 0.0001) that is accounted for by non-Canadian patients. Midwives and physicians agree on provision of emergency care but not preventive care. Across medical specialties, fewer caregivers felt obliged to care for non-Canadian patients seeking citizenship for their newborn. Among physicians, 61% were aware of the Canadian Medical Protective Association's guidelines on liability coverage for non-Canadian patients, and only 28% consistently protected themselves legally. There is large variation regarding whether physicians bill for services when the patient is uninsured. CONCLUSION: In Calgary, the study observed an increase in numbers of uninsured maternity patients. Differing ethical perspectives on the care of these patients may lead to conflict within health care teams because of differences on ethical perspectives of care among team members. Health care providers require education to understand the implications and challenges of obstetrical care of non Canadians. PMID- 28733057 TI - Clinical Validation of Non-Invasive Cardiac Output Monitoring in Healthy Pregnant Women. AB - OBJECTIVE: Non-invasive hemodynamic monitoring has the potential to be a valuable clinical tool for the screening and management of hypertensive disorders of pregnancy. The objective of this study was to validate the clinical utility of the non-invasive cardiac output monitoring (NICOM) system in pregnant women. METHODS: Twenty healthy pregnant women with a singleton pregnancy at 22 to 26 weeks' gestation were enrolled in this study. Measures of heart rate, stroke volume, and cardiac output were obtained through NICOM and compared with Doppler echocardiography. RESULTS: NICOM significantly overestimated measures of both stroke volume and cardiac output compared with Doppler echocardiography (95 +/- 4 vs. 73 +/- 4 mL, P < 0.0001; and 7.4 +/- 0.2 vs. 5.6 +/- 0.2 L/min, P < 0.0001; respectively). CONCLUSIONS: There is no gold standard for the measurement of cardiac output in the setting of pregnancy. However, once normal values have been established, NICOM has the potential to be a useful clinical tool for monitoring maternal hemodynamics in pregnant women. Further investigation regarding the validity of NICOM is required in larger populations of healthy and hypertensive pregnant women to determine whether this device is appropriate for maternal hemodynamic assessment during pregnancy. PMID- 28733058 TI - Unusual Perils of Pelvic Organ Prolapse. AB - BACKGROUND: Prolapse can be treated with expectant management, pessary, or surgery. Although we consider the first two options benign, rare but serious complications can arise. CASE 1: A 64-year-old presented with recurrent grade 4 prolapse. After 6 months of expectant management, she developed a fistula from an ulcerated area of the prolapse into the peritoneal cavity. CASE 2: An 81-year-old who diligently cared for her ring pessary for 18 years presented with a vesicovaginal fistula. CASE 3: An 80-year-old with a longstanding pessary who stopped using vaginal estrogen for 2 years before developing a vesicovaginal fistula. CONCLUSION: Management of prolapse expectantly and with pessaries are effective treatments, especially to avoid surgery, but can present with their own unusual and infrequent complications, such as fistula formation. PMID- 28733060 TI - Developing a Canadian Curriculum for Simulation-Based Education in Obstetrics and Gynaecology: A Delphi Study. AB - OBJECTIVE: As obstetrics and gynaecology (Ob/Gyn) residency training programs move towards a competence-based approach to training and assessment, the development of a national standardized simulation curriculum is essential. The primary goal of this study was to define the fundamental content for the Canadian Obstetrics and Gynecology Simulation curriculum. METHODS: A modified Delphi technique was used to achieve consensus in three rounds by surveying residency program directors or their local simulation educator delegates in 16 accredited Canadian Ob/Gyn residency programs. A consensus rate of 80% was agreed upon. Survey results were collected over 11 months in 2016. RESULTS: Response rates for the Delphi were 50% for the first round, 81% for the second round, and 94% for the third round. The first survey resulted in 84 suggested topics. These were organized into four categories: obstetrics high acuity low frequency events, obstetrics common events, gynaecology high acuity low frequency events, and gynaecology common events. Using the modified Delphi method, consensus was reached on 6 scenarios. CONCLUSION: This study identified the content for a national simulation-based curriculum for Ob/Gyn residency training programs and is the first step in the development of this curriculum. PMID- 28733059 TI - Evaluation of Recall and Reminder Letters on Retention Rates in an Organized Cervical Screening Program. AB - OBJECTIVE: It is key for women to return to screening at regular intervals to ensure the effectiveness of early detection and protective effects of the Pap test. A correspondence program was initiated in Ontario in 2013 to implement a recall and reminder letter sent to women 2.9 years from their prior normal Pap test. This study sought to evaluate the impact of the recall letter and reminder on retention rates for cervical screening. METHODS: A cohort study with a historical control was carried out with an exposed group, defined as women receiving a letter for recall in the week of November 21-27, 2013, and a non exposed, control arm of women who did not receive the letter but who would have been eligible for correspondence in the same time period in 2012. RESULTS: The study population comprised 5182 women in the exposed group and 4223 women in the non-exposed group. Women receiving the letter were more likely to return to screening, with an aOR of 1.82 (95% CI 1.66-1.99). Other significant factors included being registered with a Patient Enrolment Model family physician and having a series of prior Pap tests in the past screening history. CONCLUSION: A correspondence program benefits the retention of women in organized cervical screening programs. PMID- 28733061 TI - Mitochondrial Replacement Therapy: The Road to the Clinic in Canada. PMID- 28733062 TI - Remote Recurrence of Benign Multicystic Peritoneal Mesothelioma. AB - BACKGROUND: Benign peritoneal cystic mesothelioma (BPCM) is a rare disease entity that arises from mesothelioma cells. We describe a rare case of BPCM recurrence 36 years after its initial presentation. CASE: A 62-year-old woman was referred to an outpatient gynaecologic oncology clinic with an incidental finding of multiple pelvic cysts. She had a preceding history of known BPCM treated with extensive debulking surgery. She presented after 36 years of clinical remission. A repeat laparotomy for a debulking surgical procedure confirmed a recurrence of BPCM. CONCLUSION: Our current case represents a woman with a remote recurrence of BPCM after initial optimal debulking surgery. Her clinical presentation of recurrence after 36 years illustrates the need for long-term follow-up and clinical suspicion in symptomatic patients with previously diagnosed BPCM. PMID- 28733063 TI - Do Early Fetal Measurements and Nuchal Translucency Correlate With Term Birth Weight? AB - OBJECTIVE: Traditionally, physiological variation in fetal weight is believed to emerge during the latter half of pregnancy. Although recent evidence suggests that crown-rump length (CRL) and nuchal translucency (NT) measured at 11-14 weeks correlate with abnormal fetal growth, findings have been limited by dating accuracy in spontaneous gestations. Therefore, we sought to determine whether CRL or NT measurements correlated with term birth weight (BW) or BW ratio in a cohort of IVF pregnancies, in which the date of conception is precisely known. METHODS: This retrospective cohort study included 227 term, singleton IVF pregnancies. Subjects were included if they had an early first-trimester ultrasound examination and subsequent nuchal translucency (NT) screening. The difference between the measured and the expected CRL and the biparietal diameter (BPD) and NT measurement were calculated and correlated with the actual term BW or BW ratio. The BW ratio was calculated using the actual BW and the expected BW for GA. RESULTS: The difference between measured and expected mid-first-trimester CRL, and the BPD at NT assessment, correlated with BW ratio at delivery (rSpearman = 0.15, P = 0.023 and rSpearman = 0.27, P < 0.001, respectively). Absolute NT measurements and NT percentiles (adjusted for CRL) correlated with BW ratio at delivery (rSpearman = 0.18, r = 0.14, and P = 0.005 and 0.038, respectively). CONCLUSION: In this well-dated IVF population, we report a significant correlation between BW ratio and first-trimester CRL, BPD, and NT measurements. These findings support the hypothesis that physiological variation in BW can be reflected by variation in first-trimester fetal measurements. PMID- 28733064 TI - Pregnancy-Related Pain. PMID- 28733065 TI - Severe Maternal Morbidity Associated With Maternal Birthplace: A Population-Based Register Study. AB - OBJECTIVE: This study sought to quantify the risk of severe maternal morbidity (SMM) according to maternal country of birth in Canada. METHODS: The study analyzed 1 252 543 in-hospital deliveries of Ontario residents discharged between April 1, 2002, and March 31, 2012. The main outcome measure was a composite indicator of SMM used for surveillance. The top 10 most common component conditions were also evaluated. Maternal country of birth and other immigration characteristics were obtained through linkage with official immigration records. We used modified Poisson regression with generalized estimating equations to assess associations according to maternal country of birth. RESULTS: Overall, immigrant women (N = 335 544) did not differ from Canadian-born women (n = 916 999) in SMM rates (12.1 vs. 12.0 cases per 1000 deliveries, respectively). However, SMM varied substantially according to maternal region of birth, from 9.2 cases per 1000 deliveries among immigrants from Western countries to 23.0 cases per 1000 deliveries among immigrants from Sub-Saharan Africa. Even larger variations were found when immigrants were categorized by their specific countries of birth. The top 10 contributing conditions to SMM among Canadian-born women were also the main contributors among immigrant subgroups. The notable exception was HIV infection, the top contributor among immigrants from Sub Saharan Africa, whose rate of HIV infection was 43 times that of Canadian-born women (95% CI 34.39-55.23). After excluding HIV cases, disparities in SMM were largely reduced among Sub-Saharan African women but did not disappear. CONCLUSION: There is large heterogeneity in SMM and its component conditions among Canadian immigrants depending on country of origin. PMID- 28733066 TI - Effective use of levosimendan in anthracycline-induced cardiomyopathy: A case report. AB - BACKGROUND: Anthracycline-induced cardiomyopathy is a serious side effect that ranges from mild left ventricular systolic impairment to congestive heart failure and cardiogenic shock. Currently, there is no evidence indicating the effective use of levosimendan in these cases. OBJECTIVE: We aim to present a case of life threatening doxorubicin-induced cardiomyopathy that was successfully managed with levosimendan. CASE: A 48-year-old female with formerly normal heart function, who had been treated with doxorubicin-based regimens for dedifferentiated chondrosarcoma, presented with cardiomyopathy with low left ventricular ejection fraction eight months after the last infusion. As treatment with ramipril, carvedilol, and furosemide followed by dopamine and noradrenaline was not sufficient, levosimendan was administered. Left ventricular ejection fraction increased from 15% to 45% and her clinical condition improved. DISCUSSION: Although anthracycline-induced cardiomyopathy may have a poor prognosis, levosimendan was shown to be effective in this patient. Therefore, levosimendan may represent a possible therapeutic option in such cases. PMID- 28733067 TI - Hospital quality variation matters - A time-trend and cross-section analysis of outcomes in German hospitals from 2006 to 2014. AB - Awareness of care variation and associated differences in outcome quality is important for patients to recognize and leverage the benefits of hospital choice and for policy makers, providers, and suppliers to adapt initiatives to improve hospital quality of care. We examine panel data on outcome quality in German hospitals between 2006 and 2014 for cholecystectomy, pacemaker implantation, hip replacement, percutaneous coronary intervention (PCI), stroke, and acute myocardial infarction (AMI). We use risk-adjusted and unadjusted outcomes based on 16 indicators. Median outcome and outcome variation trends are examined via box plots, simple linear regressions and quintile differences. Outcome trends differ across treatment areas and indicators. We found positive quality trends for hip replacement surgery, stroke and AMI 30-day mortality, and negative quality trends for 90-day stroke and AMI readmissions and PCI inpatient mortality. Variation of risk-adjusted outcomes ranges by a factor of 3-12 between the 2nd and 5th quintile of hospitals, both at the national and regional level. Our results show that simply measuring and reporting hospital outcomes without clear incentives or regulation - "carrots and sticks" - to improve performance and to centralize care in high performing hospitals has not led to broad quality improvements. More substantial efforts must be undertaken to narrow the outcome spread between high- and low-quality hospitals. PMID- 28733068 TI - Effects of EU harmonization policies on national public supervision of clinical trials: A dynamic cycle of institutional change and institutional work. AB - BACKGROUND: The EU Clinical Trials Directive (EUCTD) and the EU Clinical Trials Regulation aim to harmonize good clinical practice (GCP) of clinical trials across Member States. Using the Netherlands as a case study, this paper analyzes how endeavours to implement the EUCTD set in motion a dynamic process of institutional change and institutional work. This process lead to substantial differences between policy and actual practice; therefore, it is important to learn more about the implementation of harmonization policies. METHODS: Relevant documents, such as legal texts and previous research, were analyzed. Interviews were conducted with stakeholders in clinical trials and inspectors from (inter)national supervisory bodies (n=33), and Dutch Health Care Inspectorate inspections were observed (n=4). RESULTS: Dutch legislators' efforts to implement the EUCTD created a new level of governance in an already multilevel legislative framework. Institutional layering caused a complex and fragmented organizational structure in public supervision, leading to difficulties in achieving GCP. This instigated institutional work by actors, which set in motion further incremental institutional change, principally drift and conversion. CONCLUSIONS: Harmonization processes can create dynamic cycles between institutional change and institutional work, leading to significant divergence from the intended effects of legislation. If legislation intended to strengthen harmonization is not carefully implemented, it can become counterproductive to its aims. PMID- 28733069 TI - Pulmonary hypertension and clinical correlates in hypertrophic cardiomyopathy. AB - BACKGROUND: Pulmonary hypertension (PH) in patients with hypertrophic cardiomyopathy (HCM) has been investigated in a small number of studies. Purpose of this study was to assess the prevalence and its association with outcome in a population of consecutive HCM outpatients. METHODS: We retrospectively analyzed data of 361 consecutive HCM outpatients in whom echocardiographic measurements of pulmonary artery systolic pressure (PASP) were available at initial and most recent evaluation. Four different clinical groups were specifically investigated: patients without left ventricular outflow tract obstruction (group A, 165), with obstruction (group B, 126), patients diagnosed at the age>=65 (group C, 50) and patients with end stage (ES) HCM (group D, 20). RESULTS: PH was identified in 41 (11.4%) of the 361 patients at initial evaluation while it has been recognized in 25 (7,8% [1.1%/year]) during a median follow-up of 3.4years. Analysis of subgroups showed that prevalence of PH increased from patient group A to D (8%, group A, 19%, group B, 28% group C, 70%, group D, respectively, p<0,01). During follow-up, patients with PH showed a significant higher HCM-related mortality (p=0.01) and morbidity (p<0.001) as compared with those without PH, but in multivariable analysis, PH resulted an independent risk factor only for HCM related morbidity (HR=2.50, 95% CI 1.08-5.79, p=0.03). CONCLUSION: PH affects a significant proportion of patients with HCM. Its prevalence varies according to different clinical profiles. It is associated with an unfavorable clinical outcome and is an independent predictor of morbidity. PMID- 28733070 TI - Spatial relationship of sites for atrial fibrillation drivers and atrial tachycardia in patients with both arrhythmias. AB - INTRODUCTION: Atrial fibrillation (AF) often converts to and from atrial tachycardia (AT), but it is undefined if these rhythms are mechanistically related in such patients. We tested the hypothesis that critical sites for AT may be related to regional AF sources in patients with both rhythms, by mapping their locations and response to ablation on transitions to and from AF. METHODS: From 219 patients undergoing spatial mapping of AF prior to ablation at 3 centers, we enrolled 26 patients in whom AF converted to AT by ablation (n=19) or spontaneously (n=7; left atrial size 42+/-6cm, 38% persistent AF). Both atria were mapped in both rhythms by 64-electrode baskets, traditional activation maps and entrainment. RESULTS: Each patient had a single mapped AT (17 reentrant, 9 focal) and 3.7+/-1.7 AF sources. The mapped AT spatially overlapped one AF source in 88% (23/26) of patients, in left (15/23) or right (8/23) atria. AF transitioned to AT by 3 mechanisms: (a) ablation anchoring AF rotor to AT (n=13); (b) residual, unablated AF source producing AT (n=6); (c) spontaneous slowing of AF rotor leaving reentrant AT at this site without any ablation (n=7). Electrogram analysis revealed a lower peak-to-peak voltage at overlapping sites (0.36+/-0.2mV vs 0.49+/-0.2mV p=0.03). CONCLUSIONS: Mechanisms responsible for AT and AF may arise in overlapping atrial regions. This mechanistic inter relationship may reflect structural and/or functional properties in either atrium. Future work should delineate how acceleration of an organized AT may produce AF, and whether such regions can be targeted a priori to prevent AT recurrence post AF ablation. PMID- 28733071 TI - Long-term stroke and bleeding risk in patients with atrial fibrillation treated with oral anticoagulants in contemporary practice: Providing evidence for shared decision-making. AB - BACKGROUND: Oral anticoagulation is recommended as a lifelong therapy for most patients with atrial fibrillation (AF). However, data on long-term outcomes in clinical practice on these drugs are scarce, particularly for the recently approved agents. We aimed to describe differences in characteristics between patients in everyday practice and those enrolled in the pivotal trials, and to report long-term outcomes on oral anticoagulation in practice. METHODS: We performed a retrospective cohort analysis using a large U.S. administrative database to identify patients with AF initiating oral anticoagulation and examine incident stroke (effectiveness endpoint, including ischemic stroke and systemic embolism) and major bleeding (safety endpoint). RESULTS: We identified 107,373 patients with AF initiating anticoagulants 7/1/2006-6/30/2016. These patients were more likely to be elderly, female, or to have advanced kidney disease in comparison to those enrolled in the trials. The event rates for major bleeding (3.1%, 2.8%, 4.0% and 4.9%/year for in apixaban-, dabigatran-, rivaroxaban- and warfarin-treated patients, respectively) were higher than those observed in trials. The event rates for stroke 0.9%, 1.0%, 0.9% and 1.4%/year the four drug cohorts), were similar to the trials. The three-year risk of stroke was 2.3%, 2.1%, 2.3% and 3.5%, and the three year risk of major bleeding was 5.4%, 7.0%, 8.2%, and 11.7% in the four drug cohorts. CONCLUSIONS: Clinical trials represent a narrow spectrum of the general AF population. The trials may underestimate the bleeding risk observed in practice. This study provides important data to help clinicians communicate expected outcomes to patient during shared decision making. PMID- 28733072 TI - Early myocardial edema after acute myocardial infarction is stable and not bimodal in humans - Evidence from a large CMR multicenter study. AB - BACKGROUND: Experimental data reported a temporal pattern of myocardial edema following acute myocardial infarction (AMI). Therefore, the aim of this study was to assess the time course of myocardial edema in a large population of patients with ST-segment elevation myocardial infarction (STEMI). METHODS: Myocardium at risk (MAR), infarct size (IS) and myocardial salvage index (MSI) were compared according to the time between infarction and cardiovascular magnetic resonance (CMR) imaging in a large multicenter STEMI cohort (n=795). CMR scans performed >8days (>192h) after AMI were excluded (n=23). Scans performed within 8days were reported at time-points 12-24h, 24-36h, 36-48h, and days 3 to 8 (192h). RESULTS: MAR/MSI and IS could be assessed in 693 and 755 patients, respectively. The extent of MAR over the first week after ischemia/reperfusion showed a slight rise and fall (p=0.029 in one-way analysis of variance). However, analysis of IS demonstrated a similar trend over time (p=0.026). Post-hoc testing did not reveal significant differences between particular time periods for both MAR and IS. A stable edematous reaction was also observed between 12-24h, 24-36h, 36-48h and up to 8days after infarction in a more detailed analysis. MSI did not show statistically significant variations (p=0.147). Multivariate regression analysis did not identify the time of CMR acquisition as a predictor of MAR (p=0.709), IS (p=0.810) or MSI (p=0.916). CONCLUSION: These data do not confirm a temporal pattern of myocardial edema over the first week after AMI in humans. PMID- 28733073 TI - Biomarkers of vascular inflammation. Cell stress offers new clues. PMID- 28733074 TI - Non-invasive assessment of microvascular dysfunction in patients with microvascular angina. AB - BACKGROUND: We aimed to evaluate the microvascular function in patients with microvascular angina (MVA) by assessing 1) the endothelial glycocalyx barrier properties using sublingual microscopy, and 2) the myocardial perfusion reserve using cardiovascular magnetic resonance (CMR) imaging. METHODS: Sublingual microscopy was performed in 13 MVA patients (angina pectoris, ST-depression on treadmill testing, normal coronary angiogram) and compared with 2 control groups of 13 volunteers and 14 patients with known obstructive coronary artery disease (CAD). To test the glycocalyx-mediated microvascular responsiveness, the erythrocyte perfused boundary region (PBR) was assessed at baseline and after nitroglycerin challenge. RESULTS: The baseline PBR of MVA patients was similar to controls with CAD (p=0.72), and larger than in volunteers (p=0.02). Only the volunteers demonstrated a significant increase in PBR after nitroglycerin (p=0.03). In the 13 MVA patients, adenosine stress CMR perfusion imaging was performed. Although a significant increase in myocardial perfusion was observed in both the subendocardium and subepicardium during stress, the subendocardial perfusion reserve was significantly lower (p=0.02). The PBR responsiveness of the sublingual microvasculature showed a strong correlation with the transmural myocardial perfusion reserve (r=0.86, p<0.001). CONCLUSIONS: Patients with MVA can be characterized by microvascular glycocalyx dysfunction using sublingual microscopy. The strong correlation between sublingual PBR responsiveness and myocardial perfusion reserve suggests that the glycocalyx may play an important role in the regulation of microvascular volume for myocardial perfusion and supports the concept of impaired glycocalyx barrier properties in MVA. PMID- 28733075 TI - The establishing of a new thoracic surgery department in Greece in the era of financial crisis. PMID- 28733076 TI - [Giant congenital cholesteatoma in an octogenarian patient]. PMID- 28733077 TI - [Factors associated with in-hospital complications in the elderly subjected to hip fracture surgery]. PMID- 28733078 TI - Respiratory Protection against Pandemic and Epidemic Diseases. AB - Respiratory protection against airborne pathogens is crucial for pandemic/epidemic preparedness in the context of personal protection, healthcare systems, and governance. We expect that the development of technologies that overcome the existing challenges in current respiratory protective devices will lead to a timely and effective response to the next outbreak. PMID- 28733079 TI - Is an Admission for Decompensated Heart Failure Inevitable? AB - Given the high prevalence of heart failure (HF) and the profound impact on morbid, mortality, and health care costs, strategies to improve outcomes and reduce cost have become progressively more attractive. Reducing HF hospitalizations as a study outcome has gained traction in recent years. The basic hypothesis of these investigations is that HF hospitalizations are preventable and harmful. This article examines advancements in pharmacotherapy, medical devices, and health care delivery techniques targeting reductions in HF hospitalizations and evaluates the role and implications of hospitalization in the natural history of HF. PMID- 28733080 TI - Cyclic Fatigue Resistance of Reciproc Blue and Reciproc Files in an S-shaped Canal. AB - INTRODUCTION: This study evaluated the cyclic fatigue resistance (CFR) of Reciproc (R25 and R40; VDW, Munich, Germany) and Reciproc Blue (R25 and R40, VDW) instruments used in an artificial S-shaped canal. METHODS: A total of 80 files were tested in an S-shaped canal (n = 20 for each file, Reciproc R25 and R40 and Reciproc Blue R25 and R40). This study compared Reciproc R25 with Reciproc Blue R25 files and Reciproc R40 with Reciproc Blue R40 files. All files were rotated in an S-shaped artificial canal until fracture. CFR was determined by recording the time to fracture in the artificial canal. The length of each fractured fragment was measured in millimeters. An independent sample t test was used to analyze the data. RESULTS: Between the R25 files, Reciproc Blue instruments showed significantly greater CFR than the Reciproc files in the apical and coronal curves (P < .05). Between the R40 files, Reciproc Blue instruments exhibited greater CFR in the apical and coronal curves (P < .05). There was no difference in the fractured fragment lengths of the Reciproc Blue files compared with the Reciproc files (P > .05). CONCLUSIONS: The Reciproc Blue R25 and R40 files showed greater CFR than the Reciproc R25 and R40 files in an S-shaped canal. PMID- 28733083 TI - Design, synthesis and in vitro anticancer activity of novel quinoline and oxadiazole derivatives of ursolic acid. AB - A series of new quinoline derivatives of ursolic acid were designed and synthesized in an attempt to develop potential anticancer agents. The structures of these compounds were identified by 1H NMR, 13C NMR, IR and ESI-MS spectra analysis. The target compounds were evaluated for their in vitro cytotoxicity against three human cancer cell lines (MDA-MB-231, Hela and SMMC-7721). From the results, compounds 3a-d displayed significant antitumor activity against three cancer cell lines. Especially, compound 3b was found to be the most potent derivative with IC50 values of 0.61+/-0.07, 0.36+/-0.05, 12.49+/-0.08MUM against MDA-MB-231, HeLa and SMMC-7721 cells, respectively, stronger than positive control etoposide. Furthermore, the Annexin V-FITC/PI dual staining assay revealed that compound 3b could significantly induce the apoptosis of MDA-MB-231 cells in a dose-dependent manner. The cell cycle analysis also indicated that compound 3b could cause cell cycle arrest of MDA-MB-231 cells at G0/G1 phase. PMID- 28733082 TI - Effects of novel triple-stage antimalarial ionic liquids on lipid membrane models. AB - Primaquine-based ionic liquids, obtained by acid-base reaction between parent primaquine and cinnamic acids, were recently found as triple-stage antimalarial hits. These ionic compounds displayed significant activity against both liver- and blood-stage Plasmodium parasites, as well as against stage V P. falciparum parasites. Remarkably, blood-stage activity of the ionic liquids against both chloroquine-sensitive (3D7) and resistant (Dd2) P. falciparum strains was clearly superior to those of the respective covalent (amide) analogues and of parent primaquine. Having hypothesized that such behaviour might be ascribed to an enhanced ability of the ionic compounds to permeate into Plasmodium-infected erythrocytes, we have carried out a differential scanning calorimetry-based study of the interactions between the ionic liquids and membrane models. Results provide evidence, at the molecular level, that the primaquine-derived ionic liquids may contribute to an increased permeation of the parent drug into malaria infected erythrocytes, which has relevant implications towards novel antimalarial approaches based on ionic liquids. PMID- 28733081 TI - Synapsin-antibodies in psychiatric and neurological disorders: Prevalence and clinical findings. AB - OBJECTIVE: To study the prevalence of autoantibodies to synapsin in patients with psychiatric and neurological disorders and to describe clinical findings in synapsin antibody positive patients. METHODS: Sera of 375 patients with different psychiatric and neurological disorders and sera of 97 healthy controls were screened (dilution 1:320) for anti-synapsin IgG using HEK293 cells transfected with rat synapsin Ia. Positive sera were further analyzed by immunoblots with brain tissue from wild type and synapsin knock out mice and with HEK293 cells transfected with human synapsin Ia and Ib. Binding of synapsin IgG positive sera to primary neurons was studied using murine hippocampal neurons. RESULTS: IgG in serum from 23 (6.1%) of 375 patients, but from none of the 97 healthy controls (p=0.007), bound to rat synapsin Ia transfected cells with a median (range) titer of 1:1000 (1:320-1:100,000). Twelve of the 23 positive sera reacted with a protein of the molecular size of synapsin I in immunoblots of wild type but not of synapsin knock out mouse brain tissue. Out of 19/23 positive sera available for testing, 13 bound to human synapsin Ia and 16 to human synapsin Ib transfected cells. Synapsin IgG positive sera stained fixed and permeabilized murine hippocampal neurons. Synapsin IgG positive patients had various psychiatric and neurological disorders. Tumors were documented in 2 patients (melanoma, small cell lung carcinoma); concomitant anti-neuronal or other autoantibodies were present in 8 patients. CONCLUSIONS: Autoantibodies to human synapsin Ia and Ib are detectable in a proportion of sera from patients with different psychiatric and neurological disorders, warranting further investigation into the potential pathophysiological relevance of these antibodies. PMID- 28733084 TI - Reciprocal regulation of beta2-adrenoceptor-activated cAMP response-element binding protein signalling by arrestin2 and arrestin3. AB - Activation of Gs coupled receptors (e.g. beta2-adrenoreceptor (beta2AR)) expressed within the uterine muscle layer (myometrium), promotes intracellular cAMP generation, inducing muscle relaxation through short-term inhibition of contractile proteins, and longer-term modulation of cellular phenotype to promote quiescence. In the myometrium cAMP-driven modulation of cell phenotype is facilitated by CREB activity, however despite the importance of CREB signalling in the promotion of myometrial quiescence during pregnancy, little is currently known regarding the molecular mechanisms involved. Thus, we have characterised beta-adrenoceptor-stimulated CREB signalling in the immortalised ULTR human myometrial cell line. The non-selective beta-adrenoceptor agonist isoprenaline induced time- and concentration-dependent CREB phosphorylation, which was abolished by the beta2AR selective antagonist ICI118,551. beta2AR-stimulated CREB phosphorylation was mediated through a short-term PKA-dependent phase, and longer term Src/p38 MAPK-dependent/PKA-independent phase. Since in model cells, arrestin2 can facilitate beta2AR-mediated Src/p38 recruitment, we examined whether CREB signalling was activated through a similar process in myometrial cells. Depletion of arrestin2 attenuated p38 phosphorylation, whilst arrestin3 depletion enhanced and prolonged isoprenaline-stimulated p38 signals, which was reversed following inhibition of Src. Knockdown of arrestin2 led to enhanced short-term (up to 10min), and attenuated longer-term (>10min) isoprenaline stimulated CREB phosphorylation. Contrastingly, removal of arrestin3 enhanced and prolonged isoprenaline-stimulated CREB phosphorylation, whilst depletion of both arrestins abolished CREB signals at time points >5min. In summary, we have delineated the molecular mechanisms coupling beta2AR activity to CREB signalling in ULTR myometrial cells, revealing a biphasic activation process encompassing short-term PKA-dependent, and prolonged Src/arrestin2/p38-dependent components. Indeed, our data highlight a novel arrestin-mediated modulation of CREB signalling, suggesting a reciprocal relationship between arrestin2 and arrestin3, wherein recruitment of arrestin3 restricts the ability of beta2AR to activate prolonged CREB phosphorylation by precluding recruitment of an arrestin2/Src/p38 complex. PMID- 28733085 TI - Functional consequences of chemically-induced beta-arrestin binding to chemokine receptors CXCR4 and CCR5 in the absence of ligand stimulation. AB - Chemokine receptor signaling is a tightly regulated process which was for a long time exclusively attributed to heterotrimeric G proteins. beta-Arrestins constitute a separable signaling arm from classical heterotrimeric G proteins, in addition to their well-established roles in receptor desensitization and endocytosis. In order to clearly dissect beta-arrestin- from G protein-dependent effects we forced the recruitment of beta-arrestin to CXCR4 and CCR5 independently of agonist-promoted receptor activation through chemically-induced dimerization. Targeting beta-arrestins to receptors at the plasma membrane prior to chemokine stimulation attenuated G protein-mediated calcium release. Association of beta-arrestins to the receptors was sufficient to induce their internalization in the absence of ligand and this effect could be further enhanced by translocation of a constitutively active beta-arrestin 1 variant. CXCR4 and CCR5 were targeted to different intracellular compartments upon chemical-induced dimerization with beta-arrestins and reproduced the intracellular distribution of receptors after activation with their respective ligands. Our data further provide evidence for direct beta-arrestin-mediated signaling via MAP kinases ERK 1/2. These results provide clear evidence that CXCR4- or CCR5-beta-arrestin complexes induce receptor endocytosis and signaling in the absence of G protein coupling and ligand-induced conformational changes of the receptor. PMID- 28733086 TI - Reply to: "Talking about mediation in health and physical activity sciences". PMID- 28733087 TI - Unobtrusive assessment of neonatal sleep state based on heart rate variability retrieved from electrocardiography used for regular patient monitoring. AB - As an approach of unobtrusive assessment of neonatal sleep state we aimed at an automated sleep state coding based only on heart rate variability obtained from electrocardiography used for regular patient monitoring. We analyzed active and quiet sleep states of preterm infants between 30 and 37weeks postmenstrual age. To determine the sleep states we used a nonlinear kernel support vector machine for sleep state separation based on known heart rate variability features. We used unweighted and weighted misclassification penalties for the imbalanced distribution between sleep states. The validation was performed with leave-one out-cross-validation based on the annotations of three independent observers. We analyzed the classifier performance with receiver operating curves leading to a maximum mean value for the area under the curve of 0.87. Using this sleep state separation methods, we show that automated active and quiet sleep state separation based on heart rate variability in preterm infants is feasible. PMID- 28733088 TI - Treating Advanced Prostate Cancer-the Human Factor. PMID- 28733089 TI - A computational protocol for the discovery of lead molecules targeting DNA unique to pathogens. AB - With the rapid emergence of drug resistant pathogens, it has become imperative to develop alternative medications as well as find new drug targets to overcome this crisis. Hence, this has become prime focus of several academic laboratories and pharmaceutical companies. Here, we report a computational protocol for identifying unique DNA sequence(s) in the pathogen which is absent in human and related non-pathogenic strains of the microbe. In order to use the unique sequence as drug target, the protocol, in the second step, uses virtual screening against a million compound library to identify candidate small molecules which can bind to these unique DNA targets in the pathogen only. Theoretically the molecules identified after screening should not bind to human DNA. This methodology is demonstrated on Mycobacterium tuberculosis H37Rv, wherein a new octamer sequence present only in H37Rv has been identified and a few candidate small molecules as potential drug have been proposed. Being fast and cost effective, this protocol could be of importance in generating new potential drug candidates against infectious organisms for further experimental studies. This methodology is freely available at http://www.scfbio-iitd.res.in/PSDDF/. PMID- 28733090 TI - Intravital multiphoton microscopy as a tool for studying renal physiology and pathophysiology. AB - The kidney is a complex and dynamic organ with over 40 cell types, and tremendous structural and functional diversity. Intravital multi-photon microscopy, development of fluorescent probes and innovative software, have rapidly advanced the study of intracellular and intercellular processes within the kidney. Researchers can quantify the distribution, behavior, and dynamic interactions of up to four labeled chemical probes and proteins simultaneously and repeatedly in four dimensions (time), with subcellular resolution in near real time. Thus, multi-photon microscopy has greatly extended our ability to investigate cell biology intravitally, at cellular and subcellular resolutions. Therefore, the purpose of the chapter is to demonstrate how the use in intravital multi-photon microscopy has advanced the understanding of both the physiology and pathophysiology of the kidney. PMID- 28733091 TI - Histological analysis of the association of low level laser therapy and platelet rich plasma in regeneration of muscle injury in rats. AB - OBJECTIVE: Muscle injuries are common, and their treatment requires costs and time off. Platelet rich plasma and low level laser therapy have been shown to be affordable and easy to use. The aim of this study was to evaluate the associated effects of low level laser therapy and platelet rich plasma on the treatment of the soleus muscle injured by strain in rats. METHODS: Thirty-five rats were randomly allocated into five groups: Control (C), Injury Control (IC), injury PRP (IP), injury LLLT (ILT) and injury LLLT and PRP (ILTP). The strain injury was induced in the soleus muscle and the IP group received application of platelet rich plasma immediately after the lesion, while the ILT group received low level laser therapy. After seven days, all animals were euthanized and the soleus muscle removed for further histological analysis. RESULTS: The association of both treatments (ILTP) resulted in better histological aspects than the low level laser therapy and platelet rich plasma alone, when compared with the injury group (IC). The collagen analysis exhibited a significant increase in the ILT group (2.99 SD=1.13) compared to the C (1.88 SD=0.41, p=0.012) and IP (2.04 SD=0.44, p=0.018). CONCLUSION: The association of low level laser therapy with platelet rich plasma produced better results on muscle injury compared to the isolated use of these therapies. Furthermore, none of the treatments could modulate the collagen deposition in relation to injury group. PMID- 28733092 TI - Exercise training to reduce sympathetic nerve activity in heart failure patients. A systematic review and meta-analysis. AB - OBJECTIVE: To determine the effects of exercise training on sympathetic nerve activity in heart failure patients. METHODS: A systematic review was performed. An electronic search of MEDLINE, ProQuest, SciELO, SPORTDiscus, Rehabilitation and Sport Medicine Source, Cumulative Index to Nursing and Allied Health Literature, Tripdatabase, Science Direct and PEDrO was performed from their inception to February 2017. Clinical trials and quasi-experimental studies were considered for primary article selection. The studies should include patients diagnosed with chronic heart failure that performed exercise training for at least 4 weeks. Sympathetic nerve activity should be measured by microneurography before and after the intervention. The Cochrane Collaboration's Risk of Bias Tool was used to evaluate risk of bias, and the quality of evidence was rated following the GRADE approach. Standardized mean differences (SMD) were calculated for control and experimental groups. Meta-analysis was performed using the random effects model. RESULTS: Five trials were included. Overall, the trials had moderate risk of bias. The experimental group indicated a significant decrease in the number of bursts per minute (SMD -2.48; 95% CI -3.55 to -1.41) when compared to the control group. Meanwhile, a significant decrease was also observed in the prevalence of bursts per 100 beats in the experimental group when compared to the control group (SMD -2.66; 95% CI -3.64 to -1.69). CONCLUSION: Exercise training could be effective in reducing sympathetic nerve activity in patients with heart failure. The quality of evidence across the studies was moderate. Future studies are necessary to confirm these results. PMID- 28733093 TI - Hydrotherapy improves pain and function in older women with knee osteoarthritis: a randomized controlled trial. AB - BACKGROUND: Currently, there is poor evidence of the effect of hydrotherapy alone on patients with hip or knee osteoarthritis. OBJECTIVES: The study aimed to assess the impact of hydrotherapy on pain, function, and muscle function in older women with knee osteoarthritis. METHODS: A randomized controlled trial was conducted to evaluate the efficacy of hydrotherapy in women with knee osteoarthritis. Seventy-three women aged 65 and older were randomized to hydrotherapy (n=36) or a control group (n=37). The hydrotherapy group received the intervention program in a heated pool (twice per week for six weeks) and an educational protocol while the control group received an educational protocol only. Primary outcomes (before and post-treatment) were pain intensity (0-100) and function (0-100), assessed with the WOMAC questionnaire. Secondary outcomes (before and post-treatment) were knee extensor and knee flexor muscle performance (strength, power, and endurance), assessed by an isokinetic dynamometer. The magnitude of change between the groups for the outcomes was calculated using linear regression models adjusted by baseline outcome values. RESULTS: The hydrotherapy group had better outcomes for pain (adjusted mean difference=11 points, 95% CI: 3-18) and function (adjusted mean difference=12 points, 95% CI: 5 18). Patients receiving hydrotherapy had better performance for knee flexor and extensor strength, knee flexor power, and knee extensor endurance. CONCLUSION: Older women with knee osteoarthritis are likely to have benefits from a course of hydrotherapy exercises. Registry of clinical trials (Trial number RBR-8F57KR) - http://www.ensaiosclinicos.gov.br/rg/RBR-8f57kr/. PMID- 28733094 TI - Isolated non-cardiogenic pulmonary edema - A rare complication of MDMA toxicity. AB - This is a case of a 19-year-old male who presented to the medical tent at an outdoor electronic dance music festival (EDMF) due to an altered mental state in the setting of acute 3,4-methylenedioxymethamphetamine (MDMA) intoxication. He was noted to be in severe respiratory distress, required endotracheal intubation in the field and subsequently developed Acute Respiratory Distress Syndrome (ARDS) without other acute organ dysfunction. He was hospitalized for 5days requiring endotracheal intubation and mechanical ventilation. By presenting this case, we will explore and discuss the cardiopulmonary effects of MDMA intoxication that can lead to a rare, deleterious complication of MDMA intoxication other than previously reported adverse outcomes. PMID- 28733095 TI - Computed tomography only useful for selected patients presenting with primary eye complaints in the emergency department. PMID- 28733096 TI - Brachial vein transposition is a promising ultimate upper limb autologous arteriovenous angioaccess despite its many pitfalls. AB - OBJECTIVE: The objective of this study was to retrospectively evaluate the possibility of using the brachial veins despite their deep location, small caliber, and thin wall. METHODS: There were 64 patients without superficial veins who were eligible for two-stage brachial vein transposition (BrVT); 54 patients were on hemodialysis, 9 patients had sickle cell disease, and 1 patient had long term parenteral nutrition. Preoperative imaging was performed with color duplex ultrasound as well as venography for suspected central vein stenosis. A surgical microscope was used to create an end-to-side anastomosis between the brachial vein (medial, if possible) and artery. No minimum vein diameter was required. Postoperative color duplex ultrasound imaging was scheduled at 1 month. Second stage superficialization was performed 2 to 3 months later with tunnelization and a new arteriovenous anastomosis. RESULTS: For the 64 patients, cumulative primary patency rates (+/- standard deviation [SD]) at 1 year, 2 years, 3 years, and 4 years were 50% (+/-7%), 42% (+/-7%), 37% (+/-8%), and 27% (+/-11%), respectively. Primary assisted patency rates (+/-SD) at 1 year, 2 years, 3 years, and 4 years were 60% (+/-6%), 51% (+/-7%), 45% (+/-7%), and 37% (+/-9%), respectively. Secondary patency rates (+/-SD) at 1 year, 2 years, 3 years, and 4 years were 60% (+/-6%), 53% (+/-7%), 53% (+/-7%), and 45% (+/-8%), respectively. Early complications included thrombosis, nonmaturation, and upper arm edema. At the second stage (n = 50), four patients presented with unexplained major fibrosis extending cephalad from the first surgical site and preventing any dissection of the vein. Four patients had more usual complications (one nonmaturation, two occlusions of the brachial vein at the previous arteriovenous graft-vein anastomosis), and two were lost to follow-up. Vein transposition in a subcutaneous tunnel was technically unfeasible in eight patients. Of the 64 patients, 40 (62%) had a functional BrVT that was cannulated for effective dialysis after a median interval of 72 days (15-420 days) from the first stage. Mean cumulative secondary patency rates (from first cannulation) at 1 year, 2 years, and 3 years were 91% +/- 5%, 72% +/- 8%, and 62% +/- 10%, respectively. Overall, 13 patients were lost to follow-up. Secondary complications were low flow and central vein occlusion. Long-term complications were related to stenosis and thrombosis, aneurysms, and puncture site necrosis. Median follow-up from the first stage was 1.62 years (0.02-11.3 years). CONCLUSIONS: Despite many pitfalls for the surgeon, BrVT offers promising long-term patency. PMID- 28733097 TI - Injectable naltrexone, oral naltrexone, and buprenorphine utilization and discontinuation among individuals treated for opioid use disorder in a United States commercially insured population. AB - We investigated prescribing patterns for four opioid use disorder (OUD) medications: 1) injectable naltrexone, 2) oral naltrexone, 3) sublingual or oralmucosal buprenorphine/naloxone, and 4) sublingual buprenorphine as well as transdermal buprenorphine (which is approved for treating pain, but not OUD) in a nationally representative claims-based database (Truven Health MarketScan(r)) of commercially insured individuals in the United States. We calculated the prevalence of OUD in the database for each year from 2010 to 2014 and the proportion of diagnosed patient months on OUD medication. We compared characteristics of individuals diagnosed with OUD who did and did not receive these medications with bivariate descriptive statistics. Finally, we fit a Cox proportional hazards model of time to discontinuation of therapy as a function of therapy type, controlling for relevant confounders. From 2010 to 2014, the proportion of commercially insured individuals diagnosed with OUD grew by fourfold (0.12% to 0.48%), but the proportion of diagnosed patient-months on medication decreased from 25% in 2010 (0.05% injectable naltrexone, 0.4% oral naltrexone, 23.1% sublingual or oralmucosal buprenorphine/naloxone, 1.5% sublingual buprenorphine, and 0% transdermal buprenorphine) to 16% in 2014 (0.2% injectable naltrexone, 0.4% oral naltrexone, 13.8% sublingual or oralmucosal buprenorphine/naloxone, 1.4% sublingual buprenorphine, and 0.3% transdermal buprenorphine). Individuals who received medication therapy were more likely to be male, younger, and have an additional substance use disorder compared with those diagnosed with OUD who did not receive medication therapy. Those prescribed injectable naltrexone were more often male, younger, and diagnosed with additional substance use disorders compared with those prescribed other medications for opioid use disorder (MOUDs). At 30 days after initiation, 52% for individuals treated with injectable naltrexone, 70% for individuals treated with oral naltrexone, 31% for individuals treated with sublingual or oralmucosal buprenorphine/naloxone, 58% for individuals treated with sublingual buprenorphine, and 51% for individuals treated with transdermal buprenorphine discontinued treatment. In the Cox proportional hazard model, use of injectable naltrexone, oral naltrexone, sublingual buprenorphine, and transdermal buprenorphine were all associated with significantly greater hazard of discontinuing therapy beginning >30days after MOUD initiation (HR=2.17, 2.54, 1.15, and 2.21, respectively, 95% CIs 2.04-2.30, 2.45-2.64, 1.10-1.19, and 2.11 2.33), compared with the use of sublingual or oralmucosal buprenorphine/naloxone. This analysis demonstrates that the use of evidence-based medication therapies has not kept pace with increases in OUD diagnoses in commercially insured populations in the United States. Among those who have been treated, discontinuation rates >30days after initiation are high. The proportion treated with injectable naltrexone, oral naltrexone, and transdermal buprenorphine grew over time but remains small, and the discontinuation rates are higher among those treated with these medications compared with those treated with sublingual or oralmucosal buprenorphine/naloxone. In the face of the opioid overdose and addiction crisis, new efforts are needed at the provider, health system, and policy levels so that MOUD availability and uptake keep pace with new OUD diagnoses and OUD treatment discontinuation is minimized. PMID- 28733098 TI - Obesity and Failure of Nonsurgical Management of Pediatric Both-Bone Forearm Fractures. AB - PURPOSE: In pediatric extremity fractures treated nonsurgically, maintaining reduction can be difficult in obese children owing to the larger soft tissue envelope. The purpose of this study was to investigate the relationship between obesity and failure of nonsurgical management of pediatric both-bone forearm fractures. METHODS: We conducted a retrospective review of 129 skeletally immature patients older than 2 years who received nonsurgical treatment for closed radius and ulna shaft fractures at a level I pediatric trauma center between 2011 and 2014. The patients were divided into 2 groups: (1) normal-weight children and (2) overweight and obese children. The primary outcome measure was failure of nonsurgical management, defined as the indication for repeat closed reduction under anesthesia or surgical intervention owing to unacceptable angulation after initial closed treatment. RESULTS: Of the 129 patients included in the study, 34 patients (26%) were female and 95 patients (74%) were male. Seventy-six patients (59%) were normal weight, 27 patients (22%) were obese, and 26 patients (20%) were overweight. Eighteen percent (14 of 76) of normal-weight children failed nonsurgical management compared with 34% (18 of 53) of overweight and obese children. Twenty-nine percent (4 of 14) of normal-weight children who failed nonsurgical management required surgery compared with 56% (10 of 18) of overweight and obese children. CONCLUSIONS: Overweight and obese children have a significantly higher rate of failure of nonsurgical management of both-bone forearm fractures compared with normal-weight children. These patients may benefit from closer clinical follow-up and a lower threshold for surgical intervention. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognosis II. PMID- 28733099 TI - Design of Anatomical Population-Based and Patient-Specific Radial Head Implants. AB - PURPOSE: The objective of this study was to characterize the morphology of the radial head and design population-based anatomical and patient-specific radial head implants. METHODS: Computed tomography (CT) images of 50 normal cadaveric upper extremities (34 male, 16 female) were obtained using a 64-slice CT scanner. Surface models were ellipse-fitted and characterized. Using an intersurface distance mapping approach, the surface geometry of the population-based anatomical design (PB-An), 3 distinct patient-specific designs, and an existing axisymmetrical implant (Com-Axi) were compared with the native radial head and the overall surface mismatch was measured. RESULTS: Morphological analysis indicated that the diameters of the outer and rim ellipses were correlated. The mean mismatch for the existing commercially available axisymmetrical implants was 0.5 +/- 0.1 mm.The PB-An implants showed significantly reduced surface mismatch (0.4 +/- 0.2 mm). The PS-An implant using 82 parameters in its design (0.1 +/- 0.0 mm), had the lowest mean surface mismatch of any of the implants investigated. CONCLUSIONS: The mean surface mismatch of radial head implants may be reduced using reverse engineering techniques to determine the required parameters for both population-based and patient-specific implant designs. Whether there is a significant clinical advantage of a more anatomically shaped radial head implant requires additional study. More anatomical implant shapes rely on a surgical technique to accurately position these implants during surgery. It is unclear if this can be achieved clinically using conventional techniques or whether computer-assisted surgery will be required to realize the potential advantages of a more anatomical implant. CLINICAL RELEVANCE: This study characterized the morphology of the radial head with implications for population based anatomical implants and patient-specific implants. The overall design of each implant was quantitatively compared with the native radial head. This study has implications for the design of patient-specific/anatomical implants and compares their use with commercially available generic implants. PMID- 28733100 TI - Long-Term Outcomes After Distal Scaphoid Fractures: A 10-Year Follow-Up. AB - PURPOSE: The aim of this study was to evaluate the functional, clinical, and radiological outcome 10 years after distal scaphoid fractures. METHODS: From a prospective epidemiological study on posttraumatic radial-sided wrist pain, we evaluated 41 cases of distal scaphoid fractures. All cases had been treated nonsurgically in a thumb spica cast. Patients were examined using radiographs, magnetic resonance imaging and computed tomography at the time of injury and with computed tomography after a median of 10 years (range, 8-11 years). Fractures were classified according to a modified Prosser classification system. The primary outcome was assessment of self-reported function using Disabilities of the Arm, Shoulder, and Hand (DASH) and Patient-Reported Wrist Evaluation (PRWE). Secondary outcomes were clinical status (range of motion and grip and pinch strength) and to evaluate fracture healing and arthritis in the scaphotrapezium trapezoid (STT) joint. RESULTS: Functional impairment and pain scores at follow up were low: median DASH score 2, median PRWE 0, and median visual analog scale (VAS) pain score 0. We found no impairment in range of motion or strength. We found 26 type I fractures, 12 type IIA, 1 type IIC, and 2 type IV. There was 1 asymptomatic nonunion in a type I fracture. Computed tomography revealed arthritis in the STT joint in 7 out of 41 wrists, none of which caused clinical symptoms. CONCLUSIONS: From an 8- to 11-year perspective, patients with distal scaphoid fractures report normal self-assessed hand function as well as good wrist motion and strength. The risk for development of posttraumatic STT arthritis was low. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic II. PMID- 28733101 TI - Patterns of physician prescribing for opioid maintenance treatment in Ontario, Canada in 2014. AB - BACKGROUND: Despite concerns surrounding high patient volumes in methadone clinics, little is known about the practice patterns of opioid maintenance therapy (OMT) providers in Ontario. We examined the distribution of these services and how physician characteristics differ based on prescribing volume. METHODS: We conducted a cross-sectional study among prescribers of methadone or buprenorphine to Ontario public drug beneficiaries in 2014 by stratifying physicians into low- (lower 50%), moderate- (51-89%) and high-volume (top 10%) prescribers. We summarized the distribution of OMT prescription days dispensed and urine drug screens (UDS) ordered using Lorenz curves and examined physician characteristics using descriptive statistics. RESULTS: We identified 893 OMT prescribers in 2014. Physicians were mostly male (67.5%; N=603), and middle-aged (median was 50). High-volume methadone providers (N=57) prescribed approximately 56% (N=4,115,322) of the total days of methadone (Gini coefficient=0.76, 95% CI 0.74-0.79) while high-volume buprenorphine providers (N=64) prescribed 61% (N=589,463) of the total days of buprenorphine (Gini coefficient=0.78, 95% CI 0.75-0.80). On average, each high-volume methadone prescriber treated 435 OMT patients and billed 43 UDS per patient, while each high-volume buprenorphine prescriber treated 64 OMT patients and billed 22 UDS per patient. Daily OMT patient volume was on average 74 for high-volume methadone prescribers and 6 for high-volume buprenorphine prescribers. CONCLUSIONS: OMT services are highly concentrated among a small portion of OMT providers who carry high daily patient volumes. Future research should examine the quality of primary care received by their patients to better elucidate the possible consequences of this highly unequal distribution of services. PMID- 28733102 TI - Transcriptome landscape of human primary monocytes at different sequencing depth. AB - Differential gene and transcript expression pattern of human primary monocytes from healthy young subjects were profiled under different sequencing depths (50M, 100M, and 200M reads). The raw data consisted of 1.3 billion reads generated from RNA sequencing (RNA-Seq) experiments. A total of 17,657 genes and 75,392 transcripts were obtained at sequencing depth of 200M. Total splice junction reads showed an even more significant increase. Comparative analysis of the expression patterns of immune-related genes revealed a total of 217 differentially expressed (DE) protein-coding genes and 50 DE novel transcripts, in which 40 DE protein-coding genes were related to the immune system. At higher sequencing depth, more genes, known and novel transcripts were identified and larger proportion of reads were allowed to map across splice junctions. The results also showed that increase in sequencing depth has no effect on the sequence alignment. PMID- 28733103 TI - Broadband diffuse optical characterization of elastin for biomedical applications. AB - Elastin is a key structural protein of dynamic connective tissues widely found in the extracellular matrix of skin, arteries, lungs and ligaments. It is responsible for a range of diseases related to aging of biological tissues. The optical characterization of elastin can open new opportunities for its investigation in biomedical studies. In this work, we present the absorption spectra of elastin using a broadband (550-1350nm) diffuse optical spectrometer. Distortions caused by fluorescence and finite bandwidth of the laser source on estimated absorption were effectively accounted for in measurements and data analysis and compensated. A comprehensive summary and comparison between collagen and elastin is presented, highlighting distinct features for its accurate quantification in biological applications. PMID- 28733104 TI - Comparative shoot proteome analysis of two potato (Solanum tuberosum L.) genotypes contrasting in nitrogen deficiency responses in vitro. AB - : Aiming at a better understanding of the physiological and biochemical background of nitrogen use efficiency, alterations in the shoot proteome under N deficiency were investigated in two contrasting potato genotypes grown in vitro with 60 and 7.5mM N, respectively. A gel based proteomic approach was applied to identify candidate proteins associated with genotype specific responses to N deficiency. 21% of the detected proteins differed in abundance between the two genotypes. Between control and N-deficiency conditions 19.5% were differentially accumulated in the sensitive and 15% in the tolerant genotype. 93% of the highly N-deficiency responsive proteins were identified by MALDI TOF/TOF mass spectrometry. The major part was associated with photosynthesis, carbohydrate metabolism, stress response and regulation. Differential accumulation of enzymes involved in the Calvin cycle and glycolysis suggest activation of alternative carbohydrate pathways. In the tolerant genotype, increased abundance under N deficiency was also found for enzymes involved in chlorophyll synthesis and stability of enzymes, which increase photosynthetic carbon fixation efficiency. Out of a total of 106 differentially abundant proteins, only eight were detected in both genotypes. Our findings suggest that mutually responsive proteins reflect universal stress responses while adaptation to N-deficiency in metabolic pathways is more genotype specific. SIGNIFICANCE: Nitrogen losses from arable farm land considerably contribute to environmental pollution. In potato, this is a special problem due cultivation on light soils, irrigation and the shallow root system. Therefore, breeding of cultivars with improved nitrogen use efficiency and stable yields under reduced N fertilization is an important issue. Knowledge of genotype dependent adaptation to N-deficiency at the proteome level can help to understand regulation of N efficiency and development of N-efficient cultivars. PMID- 28733105 TI - Adverse reactions of alpha2-adrenoceptor agonists in cats reported in 2003-2013 in Finland. AB - OBJECTIVE: To describe suspected adverse drug reactions in cats associated with use of alpha2-adrenoceptor agonists. STUDY DESIGN: Retrospective study. ANIMALS: A total of 90 cats. METHODS: Data were collected from reports on adverse reactions to veterinary medicines sent to the Finnish Medicines Agency during 2003-2013. All reports of suspected adverse reactions associated with use of alpha2-adrenoceptor agonists in cats were included. Probable pulmonary oedema was diagnosed based on post mortem or radiological examination, or presence of frothy or excess fluid from the nostrils or trachea. If only dyspnoea and crackles on auscultation were reported, possible pulmonary oedema was presumed. RESULTS: Pulmonary oedema was suspected in 61 cases. Of these cats, 37 were categorised as probable and 24 as possible pulmonary oedema. The first clinical signs had been noted between 1 minute and 2 days (median, 15 minutes) after alpha2-adrenoceptor agonist administration. Many cats probably had no intravenous overhydration when the first clinical signs were detected, as either they presumably had no intravenous cannula or the signs appeared before, during or immediately after cannulation. Of the 61 cats, 43 survived, 14 died and for four the outcome was not clearly stated. CONCLUSIONS AND CLINICAL RELEVANCE: Pulmonary oedema is a perilous condition that may appear within minutes of an intramuscular administration of sedative or anaesthetic agent in cats. The symptoms were not caused by intravenous overhydration, at least in cats having no venous cannula when the first clinical signs were detected. PMID- 28733106 TI - Haemodynamic changes occurring in a loggerhead sea turtle (Caretta caretta) during mechanical ventilation under general anaesthesia. PMID- 28733107 TI - Mortality trends for tuberculosis in European Union countries, 2000-2010. AB - BACKGROUND: The objective of this study was to update and analyze tuberculosis (TB) mortality data in the European Union between 2000 and 2010 separately for men and women and try to detect if there have been any changes in trends in each country and the association with the economic situation and inequalities. METHODS: Data were extracted for tuberculosis deaths in 2000-2010 for 29 European Union countries and for Switzerland, via the World Health Organization (WHO) European detailed mortality database (DMDB), using the Mortality tabulation list 1 (MTL1) codes for men and women separately for one age group (20-85+). We estimated age-standardised mortality rates, and analyzed data using the Joinpoint Regression Program for men and women separately in the European Union overall and by individual country for each year. RESULTS: Between 2000 and 2010, there were 68,771 recorded tuberculosis deaths in the European Union and the mortality rates were higher for men than women in the entire study zone. Overall, TB mortality rates declined linearly for both genders, but more in women than in men (from 5.43/100,000 in 2000 to 2.59/100,000 in 2010 in men and from 1.37/100,000 in 2000 to 0.51/100,000 in 2010 in women). There was decline in both genders for the entire study period, with a significant Estimated Annual Percentage Change (EAPC) of -8.1 for women and -7 for men when alpha<0.05 and with a 95% confidence interval (CI). A higher tuberculosis mortality was associated with lower economic resources and greater inequalities. CONCLUSIONS: TB mortality rates in the European Union decreased overall in 2000-2010 for both genders. Men have higher TB mortality rates than women in all countries. Our findings were consistent with the downward TB mortality trend in many other countries worldwide. PMID- 28733108 TI - First-line management of distal humerus fracture by total elbow arthroplasty in geriatric traumatology: Results in a 21-patient series at a minimum 2years' follow-up. AB - INTRODUCTION: Total elbow arthroplasty (TEA) is one option in distal humerus fracture in elderly osteoporotic patients. HYPOTHESIS: The study hypothesis was that, in patients aged 70years or more, TEA provides functional results and ranges of motion compatible with everyday activity, with a complications rate equal to or lower than with internal fixation, and no loss of autonomy or cognitive impairment. MATERIAL AND METHODS: In this retrospective study, 21 patients receiving TEA for distal humerus fracture were included. Mean follow-up was 3.2years, with functional (Quick DASH and MEPS), cognitive (MMSE), autonomy related (ADL) and radiological assessment (Morrey). RESULTS: Mean MEPS was 84 and QuickDASH 32.4. Mean extension deficit was 22 degrees , and mean flexion 125 degrees . There was no loss of autonomy or cognitive impairment. The complications rate was 9.5%. There were no revision surgeries. DISCUSSION: TEA proved reliable in comminuted distal humerus fracture in elderly patients. Functional results were comparable to those in the literature, and the complications rate was lower. Long-term implant survival needs confirmation to validate this option as a treatment of choice in these indications in geriatric traumatology. TYPE OF STUDY: Retrospective non-comparative, single-center. LEVEL OF EVIDENCE: 4. PMID- 28733109 TI - Reconstructing the chronically disrupted knee extensor mechanism after total knee arthroplasty: Hourglass variant of the original partial allograft technique. AB - Allograft reconstruction is a valuable treatment option for patients with chronic extensor mechanism disruption after total knee arthroplasty. Here, an hourglass variant of the original partial allograft technique is described. An hourglass shaped patellar bone block is press-fit into the native patella. The graft is fixed to both the patella and the tibia then sutured with the knee fully extended. Outcomes of this technique were assessed in 5 patients after at least 24months' follow-up. The mean knee and function Knee Society Score values were 77.8 and 64.0, respectively. Extension lag was less than 10 in all 5 patients. This hourglass variant of the partial allograft technique is a useful treatment option that can be used even after patellar resurfacing. PMID- 28733110 TI - A role of alpha-tocopherol and phylloquinone in the modulation of uterine contractility and reproductive function in mouse models. AB - BACKGROUND AND AIM: Alpha-tocopherol has been implicated in reproduction processes, and deficiency of phylloquinone has been associated with serious complications in pregnancy. This study was therefore aimed at investigating the effects of phylloquinone and alpha-tocopherol on uterine contractility and female reproductive function using mouse models. MATERIALS AND METHODS: Both in vivo and ex vivo animal models were employed and designed to assess changes on uterine contractility and reproductive functions in the non-pregnant uterus. The effect of alpha-tocopherol and phylloquinone on spontaneous uterine contractions, oxytocin-induced uterine contractions (11.82nM) and high KCl-induced tonic uterine contractions (80mM) were assessed. The effect of subcutaneous administration of alpha-tocopherol (10mg/kg) on reproductive hormone levels and reproductive tissues were also determined. RESULTS: Alpha-tocopherol increased the force of contractions while phylloquinone decreased the force of uterine contractions. Plasma levels of luteinizing hormone (P<0.01), estrogen (P<0.01) and progesterone (P<0.001) were elevated in the presence of alpha-tocopherol after 6 days subcutaneous administration. CONCLUSIONS: Alpha-tocopherol and phylloquinone have been shown to directly modulate uterine contractility and reproductive function and may contribute to the management and treatment of reproductive disorders. PMID- 28733111 TI - Anaerobic co-digestion of sugarcane press mud with vinasse on methane yield. AB - The conversion efficiency of high solids waste digestion as sugarcane press mud (P) may be limited due to hydrolysis step. The option of co-digestion with vinasse, main liquid waste generated from ethanol production, was investigated under batch regime at mesophilic conditions (37.5+/-1 degrees C) and the best mixture was evaluated under semicontinuous regime in stirred-tank reactors. The maximum values for methane yield in batch tests were for V75/P25 and V50/P50 mixtures (on basis of the chemical oxygen demand (COD) percentage added in the mixture), with an average value of 246NmL CH4g-1 CODfed, which was 13% higher than that of press mud alone. A highest methane production rate of 69.6NmL CH4g-1 CODfed-1d-1 was obtained for the mixtureV75/P25. During the experiment carried out in CSTR reactors, the organic loading rate (OLR) was increased from 0.5 up to 2.2gVSL-1d-1. Methane yields of 365L CH4 kg-1VS and biogas productivities of 1.6LL-1 were obtained in co-digestion, which was 64% higher in comparison to mono digestion. The performance of the process in mono-digestion was less stable than in co-digestion, with a significant fall of methane yield to 1.8kgVSm-3d-1, and a partial inhibition of the methanogenic archaeas when the OLR was increased up to 2.2kgVSm-3d-1. The co-digestion of vinasse with press mud is a good option for the treatment of streams at the alcohol-sugar industry. PMID- 28733112 TI - Distinctions in gene-specific changes in DNA methylation in response to folic acid supplementation between women with normal weight and obesity. AB - BACKGROUND/OBJECTIVES: Obesity and maternal folate deficiency are associated with increased risk for neural tube defects (NTDs). Limited knowledge exists on the impact of folate status or obesity on DNA methylation of genes related to NTD risk and folate metabolism. SUBJECTS/METHODS: Women (18-35y) with normal weight (NW; BMI 18.5-24.9kg/m2; n=12) and obesity (OB; BMI >30kg/m2; n=6) were provided FA (800MUg/d) for 8-weeks. Serum folate concentration and changes in DNA methylation across 2098 CpG sites in 91 genes related to NTD risk and folate metabolism were examined. RESULTS: Serum folate concentration increased in both groups following FA supplementation, but OB maintained a relative lower concentration (NW; 38.36+/-2.50-71.41+/-3.02nmol/L and OB; 27.12+/-3.09-56.85+/ 3.90nmol/L). Methylation of 56 and 99 CpG sites changed in response to supplementation in NW and OB, respectively, and majority of these sites decreased in methylation in both groups. Only 4 CpG sites responded to supplementation in both groups. Gene ontology analysis revealed a response to supplementation in 61 biological processes (BPs) from the selected genes. Five of the 61 BPs were identified only in NW, including neural tube closure, while 13 of the 61 BPs were enriched only in OB, including folate metabolism, vitamin B12 metabolism and methylation related processes. CONCLUSIONS: Changes in DNA methylation in genes related to NTD risk and folate metabolism in response to FA supplementation were different in NW and OB. Increased NTD risk and abnormal folate metabolism in obesity may be due to a distinctive epigenetic response to folate status in these genes. PMID- 28733113 TI - A heterologous prime-boost Ebola virus vaccine regimen induces durable neutralizing antibody response and prevents Ebola virus-like particle entry in mice. AB - Ebola virus (EBOV) is one of the most virulent pathogens known to humans. Neutralizing antibodies play a major role in the protection against EBOV infections. Thus, an EBOV vaccine capable of inducing a long-lasting neutralizing antibody response is highly desirable. We report here that a heterologous prime boost vaccine regimen can elicit durable EBOV-neutralizing antibody response in mice. A chimpanzee serotype 7 adenovirus expressing EBOV GP (denoted AdC7-GP) was generated and used for priming. A truncated version of EBOV GP1 protein (denoted GP1t) was produced at high levels in Drosophila S2 cells and used for boosting. Mouse immunization studies showed that the AdC7-GP prime/GP1t boost vaccine regimen was more potent in eliciting neutralizing antibodies than either the AdC7 GP or GP1t alone. Neutralizing antibodies induced by the heterologous prime-boost regimen sustained at high titers for at least 18 weeks after immunization. Significantly, in vivo challenge studies revealed that the entry of reporter EBOV like particles was efficiently blocked in mice receiving the heterologous prime boost regimen even at 18 weeks after the final dose of immunization. These results suggest that this novel AdC7-GP prime/GP1t boost regimen represents an EBOV vaccine approach capable of establishing long-term protection, and therefore warrants further development. PMID- 28733114 TI - Targeting heat shock factor 1 as an antiviral strategy against dengue virus replication in vitro and in vivo. AB - Fever onset is correlated with viremia in dengue virus (DENV) patients. Heat shock factor 1 (HSF1), a heat stress response host transcription factor, plays a crucial role in regulating multiple cellular functions, as well as the onset of infectious diseases. This study evaluated the role of HSF1 in DENV replication as a means of regulating DENV infection in vitro and in vivo. DENV infection activated HSF1 in both Ca2+ and protein kinase A-dependent manners. Inhibiting HSF1 effectively reduced DENV replication, not only in THP-1 cells but also in primary human monocytes. Activated HSF1 contributed to DENV replication by upregulating autophagy-related protein (Atg) 7, as autophagy is crucial for virus replication. Heat stress also activated HSF1, which in turn facilitated DENV replication. Activated HSF1, the increased Atg7, and autophagic induction were founded in the DENV-infected brains and pharmacologically inhibiting HSF1 reduced autophagy, viral protein expression, neuropathy, and mortality. These results provide new insight into HSF1 as a novel host factor for DENV infection through its role in facilitating autophagy-regulated viral replication in the brains. PMID- 28733115 TI - Dose distribution characteristic study of the Rotating Gamma Knife (RGK) by using the geometry analytic method. AB - The purpose of this study was to realize the processing of dose distribution of RGK at the treatment isocenter at any gantry rotational angle by using an analytic geometry method to avoid inadequate arc therapy angles when implementing the treatment plan. Gaf chromic film was used for dose evaluation. A calibration curve was first obtained using linear accelerator irradiation. The 50% dose relative to the central axis at fixed gantry angles at the x-, y- and z-axes was obtained using Gaf chromic film and was compared to the analytic geometry method. The full width half maximum (FWHM) on the x-, y- and z-axes was predicted for the RGK dose distribution characteristic analysis. The FWHM on the x-, y-, and z-axes varies with different gantry and rotational plate angles. The most dramatic intersection variation appeared at a static gantry angle of 25 degrees . The ratio of the FWHM of the y- and z-axes to that of the x-axis was up to 9 and 10. The geometric analytic method can be used for an accurate analysis of dose distribution in RGK replacing the actual film exposure experiment. It is essential to select the best arc irradiation angle to prescribe the dose to avoid excess irradiation of normal tissue. The geometric method used in this study can also be applied for rotational arc therapy dose analysis such as tomotherapy, linear-based stereotactic radiotherapy, or volume matrices arc therapy. PMID- 28733117 TI - Comparison of intercomparison results of gamma ray spectrometry of spiked and real samples. AB - The quality and comparability of results of different comparison schemes depend strongly on how the samples were prepared and how the reference values were determined. To test the influence of different approaches to preparing comparison samples and determination of reference values on the final evaluation of participants' results, analyses of S-shapes for Cs-134 and Cs-137 in different comparison schemes in time period 1986-2016 were performed. This study pointed out significant improvement in the quality of performance of comparison tests of selected providers. PMID- 28733118 TI - The benefits of being a video gamer in laparoscopic surgery. AB - INTRODUCTION: Video games are mainly considered to be of entertainment value in our society. Laparoscopic surgery and video games are activities similarly requiring eye-hand and visual-spatial skills. Previous studies have not conclusively shown a positive correlation between video game experience and improved ability to accomplish visual-spatial tasks in laparoscopic surgery. This study was an attempt to investigate this relationship. AIM: The aim of the study was to investigate whether previous video gaming experience affects the baseline performance on a laparoscopic simulator trainer. MATERIALS AND METHODS: Newly qualified medical officers with minimal experience in laparoscopic surgery were invited to participate in the study and assigned to the following groups: gamers (n = 20) and non-gamers (n = 20). Analysis included participants' demographic data and baseline video gaming experience. Laparoscopic skills were assessed using a laparoscopic simulator trainer. RESULTS: There were no significant demographic differences between the two groups. Each participant performed three laparoscopic tasks and mean scores between the two groups were compared. The gamer group had statistically significant better results in maintaining the laparoscopic camera horizon +/- 15 degrees (p value = 0.009), in the complex ball manipulation accuracy rates (p value = 0.024) and completed the complex laparoscopic simulator task in a significantly shorter time period (p value = 0.001). Although prior video gaming experience correlated with better results, there were no significant differences for camera accuracy rates (p value = 0.074) and in a two-handed laparoscopic exercise task accuracy rates (p value = 0.092). CONCLUSION: The results show that previous video-gaming experience improved the baseline performance in laparoscopic simulator skills. PMID- 28733116 TI - A Bright Future for Serial Femtosecond Crystallography with XFELs. AB - X-ray free electron lasers (XFELs) have the potential to revolutionize macromolecular structural biology due to the unique combination of spatial coherence, extreme peak brilliance, and short duration of X-ray pulses. A recently emerged serial femtosecond (fs) crystallography (SFX) approach using XFEL radiation overcomes some of the biggest hurdles of traditional crystallography related to radiation damage through the diffraction-before destruction principle. Intense fs XFEL pulses enable high-resolution room temperature structure determination of difficult-to-crystallize biological macromolecules, while simultaneously opening a new era of time-resolved structural studies. Here, we review the latest developments in instrumentation, sample delivery, data analysis, crystallization methods, and applications of SFX to important biological questions, and conclude with brief insights into the bright future of structural biology using XFELs. PMID- 28733119 TI - Artificial Intelligence in Medicine AIME 2015. PMID- 28733120 TI - Employing decomposable partially observable Markov decision processes to control gene regulatory networks. AB - OBJECTIVE: Formulate the induction and control of gene regulatory networks (GRNs) from gene expression data using Partially Observable Markov Decision Processes (POMDPs). METHODS AND MATERIAL: Different approaches exist to model GRNs; they are mostly simulated as mathematical models that represent relationships between genes. Actually, it has been realized that biological functions at the cellular level are controlled by genes; thus, by controlling the behavior of genes, it is possible to regulate these biological functions. The GRN control problem has been studied mostly with the aid of probabilistic Boolean networks, and corresponding control policies have been devised. Though turns into a more challenging problem, we argue that partial observability would be a more natural and realistic method for handling the control of GRNs. Partial observability is a fundamental aspect of the problem; it is mostly ignored and substituted by assumption that states of GRN are known precisely, prescribed as full observability. We propose a method for the construction of POMDP model of GRN from only raw gene expression data which is original and novel. Then, we introduce a novel approach to decompose/factor the POMDP model into sub-POMDP's in order to solve it efficiently with the help of divide-and-conquer strategy. RESULTS: In order to demonstrate the effectiveness of the proposed solution we experimented with two synthetic network and one real network data from the literature. We also conducted two sets of separate experiments used to explore the impact of network connectivity and data order to our approach CONCLUSIONS: The reported test results using both synthetic and real GRNs are promising in demonstrating the applicability, effectiveness and efficiency of the proposed approach. This is due to the fact that partial observability fits well to the problem of noisy acquisition of gene expression data as there are technological limitations to measure precisely exact expression levels of genes. PMID- 28733121 TI - Paradoxical Embolism in a Girl with Atrial Septal Defect After Paroxysmal Supraventricular Tachycardia Ablation. AB - Paradoxical embolism is a kind of important pathogenesis of cardiocerebrovascular diseases. In our case, radiofrequency current catheter ablation was accomplished successfully in a 15-year-old girl who had been experiencing supraventricular tachycardia for 6 months. She presented with abrupt onset of left hemiplegia and loss of consciousness on the first postoperative day. An urgent cerebral computed tomography showed a hyperdense right middle cerebral artery. Transthoracic echocardiogram examination revealed an atrial septal defect (ASD), with the diameter measuring 39 mm. The case highly suggests that the issue of ASD should be resolved by either closed or prompt anticoagulant therapy, especially for patients who are planned to receive catheter manipulation. PMID- 28733122 TI - The Effect of Eosinopenia on Mortality in Patients with Intracerebral Hemorrhage. AB - INTRODUCTION: Inflammation may determine the prognosis of intracerebral hemorrhage (ICH), which has high mortality and morbidity rates. Recent studies have increasingly demonstrated eosinopenia as a prognostic factor, particularly in bacteremia, chronic obstructive pulmonary disease, and myocardial and cerebral infarction. Nonetheless, its significance regarding the determination of prognosis in patients with ICH has not yet been clarified. MATERIALS AND METHODS: Our study included 296 patients who presented to our clinic within 24 hours of the onset of symptoms and who were diagnosed with ICH between January 2008 and June 2016, along with 180 age- and sex-matched controls. During their hospitalization, 120 of these 296 patients died. Patients and controls were compared in terms of neutrophil count/percentage and eosinophil count/percentage; these were also compared between nonsurviving and surviving patients. The significance of eosinopenia in predicting mortality was also evaluated. RESULTS: Patients had a significantly higher neutrophil count/percentage and a significantly lower eosinophil count/percentage than controls; these results were similar between nonsurviving and surviving patients (P < .001). Consequently, the patient group was divided into 4 subgroups depending on the presence of eosinopenia and/or neutrophilia. The mortality rate was highest (62%) in the group that had both eosinopenia and neutrophilia. Univariate and multivariate logistic regression analyses indicated that neutrophilia and eosinopenia were independent predictors of mortality in ICH (P = .002; P = .004) DISCUSSION: These results indicate that eosinopenia can occur in patients with ICH and that although the mechanism is unclear, eosinopenia is closely associated with mortality in these patients, particularly when accompanied by neutrophilia. PMID- 28733123 TI - Augmentative and Alternative Communication Effects on Quality of Life in Patients with Locked-in Syndrome and Their Caregivers. AB - BACKGROUND: The aim of this study was to evaluate the impact of the augmentative and alternative communication system on anxiety and depression performances and the quality of life (QoL) of patients who have the locked-in syndrome (LIS) and that of their caregivers. METHOD: We enrolled 15 patients and their principal caregivers. The assessment consisted of the administration of the employed Short Form-36 Questionnaire for the assessment of QoL, the Hamilton Anxiety Rating Scale (HAM-A) for anxiety, and the Beck Depression Inventory for depression. RESULTS: We compared the clinical test at baseline (T0) and after 3 months (T1) for each group (patients and caregivers). In the patients group, we observed a significant difference in all clinical test scores. In the caregivers group, we observed a significant difference for HAM-A (P = .003), vitality (P < .001), social activity (P < .001), social role functioning (P < .001), and emotional role functioning (P < .001) and no significant differences for other clinical scores. CONCLUSION: The possibility of being able to communicate allows patients with the LIS to recuperate a affective contact with their caregivers, improving global family atmosphere. PMID- 28733124 TI - Left Upper Lung Lobectomy Is an Embolic Risk Factor for Cerebral Infarction. AB - Cerebral embolism is typically caused by a cardiogenic thrombus. The patent foramen ovale is a well-known cause of paradoxical embolism. However, some idiopathic cases of stroke have been reported. Such strokes are designated as embolic stroke of undetermined sources. Among them, lung lobectomy may be a new embolic risk factor for cerebral embolism. The risk of thrombus formation is high at the pulmonary vein stump after lung lobectomy, especially in the left upper lobe. Interestingly, the risk remains several years after surgery. This condition is mostly overlooked, and reported cases of this condition are rare. Methods of early detection, prevention, and treatment have not been established. Here we report the case of a 66-year-old man who suffered a cerebral infarction 2 days after left upper lobectomy. Three-dimensional computed tomography scan clearly revealed the structural feature of the pulmonary vein stump. The stump of patients with cerebral infarction after lung lobectomy should be checked. PMID- 28733125 TI - Modulation of inflammatory and immune responses by vitamin D. AB - Vitamin D (VitD) is a prohormone most noted for the regulation of calcium and phosphate levels in circulation, and thus of bone metabolism. Inflammatory and immune cells not only convert inactive VitD metabolites into calcitriol, the active form of VitD, but also express the nuclear receptor of VitD that modulates differentiation, activation and proliferation of these cells. In vitro, calcitriol upregulates different anti-inflammatory pathways and downregulates molecules that activate immune and inflammatory cells. Administration of VitD has beneficial effects in a number of experimental models of autoimmune disease. Epidemiologic studies have indicated that VitD insufficiency is frequently associated with immune disorders and infectious diseases, exacerbated by increasing evidence of suboptimal VitD status in populations worldwide. To date, however, most interventional studies in human inflammatory and immune diseases with VitD supplementation have proven to be inconclusive. One of the reasons could be that the main VitD metabolite measured in these studies was the 25 hydroxyVitD (25OHD) rather than its active form calcitriol. Although our knowledge of calcitriol as modulator of immune and inflammatory reactions has dramatically increased in the past decades, further in vivo and clinical studies are needed to confirm the potential benefits of VitD in the control of immune and inflammatory conditions. PMID- 28733126 TI - In vitro stepwise selection of reduced susceptibility to lipoglycopeptides in enterococci. AB - The propensity of oritavancin to select for stably elevated oritavancin minimum inhibitory concentrations (MICs) was studied by serial passaging of strains in broth containing oritavancin for 20days. Seven clinical strains of Enterococcus faecalis and E. faecium were studied; they included vancomycin-susceptible and both VanA and VanB vancomycin-resistant isolates. Stepwise oritavancin selection yielded stably elevated oritavancin MICs in six of the seven strains, with MIC increases ranging from 4-32-fold. By comparison, stepwise selection with comparator agents dalbavancin (4- to >128-fold MIC increases), telavancin (4-8 fold MIC increases) and daptomycin (4-32-fold MIC increases) also yielded selectants with elevated MICs of the respective agents. Oritavancin selectants retained parental MICs of vancomycin, daptomycin, linezolid and rifampicin. Some, but not all of the oritavancin selectants also showed MIC increases to the lipoglycopeptides telavancin, dalbavancin and teicoplanin, suggesting that within the lipoglycopeptide class, different mechanisms of action may be elucidated. PMID- 28733127 TI - 2017 Residency Match Update and the New Interventional Radiology Residency. PMID- 28733130 TI - A Pilot Randomized Controlled Trial on the Effects of a Progressive Exercise Program on the Range of Motion and Upper Extremity Grip Strength in Young Adults With Breast Cancer. AB - BACKGROUND: The diagnosis of breast cancer in young women (aged 18-45 years) has been increasing. Women are commonly left coping with treatment-related disabilities of the upper limb that can persist for > 2 years postoperatively. PATIENTS AND METHODS: A total of 59 young breast cancer patients (29 in the intervention group and 30 in the control group) participated in a pilot prospective randomized controlled trial to determine whether a 12-week postradiation exercise program would improve long-term arm mobility, pain, and handgrip strength. During an 18-month period, range of motion, handgrip strength, and pain with shoulder movements were evaluated at 6 points. RESULTS: Although the differences were not statistically significant, external rotation and horizontal abduction of the shoulder improved in the intervention group immediately after the exercise intervention (3 months) and showed a trend toward less pain on movement. However, at 18 months after radiation the control and intervention groups both retained a residual loss of range and persistent pain with movement. Radiation to the axilla and/or chest wall yielded long-term (18 months) limitations in flexion and horizontal abduction compared with hypofractionation, which resulted in greater flexion and external rotation at 18 months. The median grip strength of the study participants corresponded to the 10th percentile of healthy aged-matched white women. CONCLUSION: The exercise intervention timed shortly after radiation improved short-term shoulder mobility and pain; however, these gains were not sustained at 18 months after radiation. PMID- 28733128 TI - Dance for Health: An Intergenerational Program to Increase Access to Physical Activity. AB - PURPOSE: The purpose of this study was to evaluate Dance for Health, an intergenerational program to increase access to physical activity in an underserved, high risk urban community. DESIGN AND METHODS: Dance for Health was developed using community-based participatory research methods and evaluated using an observational study design. The program entailed two hour line dancing sessions delivered by trained dance instructors in the neighborhood recreation center. The weekly sessions were delivered for one month in the spring and one month in the fall from 2012-2016. Nurse practitioner students mentored local high school students to assess outcomes: achievement of target heart rate, Borg Rating of Perceived Exertion, number of pedometer steps during dance session, Physical Activity Enjoyment Scale, and adiposity. Analytic methods included descriptive statistics and mixed effects models. RESULTS: From 2012-2016, 521 participants ranging from 2-79 years attended Dance for Health. Approximately 50% of children and 80% of adults achieved target heart rate. Achievement of target heart rate was not related to perceived exertion, though it was related to pedometer steps in adults. All participants rated the program highly for enjoyment. There was no change in adiposity. CONCLUSIONS: Dance for Health demonstrated high levels of community engagement and enjoyment. It led to adequate levels of exertion, particularly for adults. Our evaluation can inform program refinement and future intergenerational physical activity programs. PRACTICE IMPLICATIONS: Dance is an enjoyable, culturally appropriate, low cost method for increasing access to physical activity for children and families. PMID- 28733131 TI - Preclinical studies for a phase 1 clinical trial of autologous hematopoietic stem cell gene therapy for sickle cell disease. AB - BACKGROUND AIMS: Gene therapy by autologous hematopoietic stem cell transplantation (HSCT) represents a new approach to treat sickle cell disease (SCD). Optimization of the manufacture, characterization and testing of the transduced hematopoietic stem cell final cell product (FCP), as well as an in depth in vivo toxicology study, are critical for advancing this approach to clinical trials. METHODS: Data are shown to evaluate and establish the feasibility of isolating, transducing with the Lenti/betaAS3-FB vector and cryopreserving CD34+ cells from human bone marrow (BM) at clinical scale. In vitro and in vivo characterization of the FCP was performed, showing that all the release criteria were successfully met. In vivo toxicology studies were conducted to evaluate potential toxicity of the Lenti/betaAS3-FB LV in the context of a murine BM transplant. RESULTS: Primary and secondary transplantation did not reveal any toxicity from the lentiviral vector. Additionally, vector integration site analysis of murine and human BM cells did not show any clonal skewing caused by insertion of the Lenti/betaAS3-FB vector in cells from primary and secondary transplanted mice. CONCLUSIONS: We present here a complete protocol, thoroughly optimized to manufacture, characterize and establish safety of a FCP for gene therapy of SCD. PMID- 28733129 TI - Endocannabinoids exert CB1 receptor-mediated neuroprotective effects in models of neuronal damage induced by HIV-1 Tat protein. AB - In the era of combined antiretroviral therapy (cART), human immunodeficiency virus type 1 (HIV-1) is considered a chronic disease that specifically targets the brain and causes HIV-1-associated neurocognitive disorders (HAND). Endocannabinoids (eCBs) elicit neuroprotective and anti-inflammatory actions in several central nervous system (CNS) disease models, but their effects in HAND remain unknown. HIV-1 does not infect neurons, but produces viral toxins, such as transactivator of transcription (Tat), that disrupt neuronal calcium equilibrium and give rise to synaptodendritic injuries and cell death, the former being highly correlated with HAND. Consequently, we tested whether the eCBs N arachidonoylethanolamine (anandamide/AEA) and 2-arachidonoyl-glycerol (2-AG) offer neuroprotective actions in a neuronal culture model. Specifically, we examined the neuroprotective actions of these eCBs on Tat excitotoxicity in primary cultures of prefrontal cortex neurons (PFC), and whether cannabinoid receptors mediate this neuroprotection. Tat-induced excitotoxicity was reflected by increased intracellular calcium levels, synaptodendritic damage, neuronal excitability, and neuronal death. Further, upregulation of cannabinoid 1 receptor (CB1R) protein levels was noted in the presence of HIV-1 Tat. The direct application of AEA and 2-AG reduced excitotoxic levels of intracellular calcium and promoted neuronal survival following Tat exposure, which was prevented by the CB1R antagonist rimonabant, but not by the CB2R antagonist AM630. Overall, our findings indicate that eCBs protect PFC neurons from Tat excitotoxicity in vitro via a CB1R-related mechanism. Thus, the eCB system possesses promising targets for treatment of neurodegenerative disorders associated with HIV-1 infection. PMID- 28733132 TI - Plastic and micro-evolutionary responses of a nematode to the host immune environment. AB - Parasitic organisms have to cope with the defences deployed by their hosts and this can be achieved adopting immune evasion strategies or optimal life history traits according to the prevailing pattern of immune-mediated mortality. Parasites often encounter variable immune environments both within and between hosts, promoting the evolution of plastic strategies instead of fixed responses. Here, we explored the plasticity and micro-evolutionary responses of immunomodulatory mechanisms and life history traits to the immune environment provided by the host, using the parasitic nematode Heligmosomoides polygyrus. To test if the parasite responds plastically to the immune environment, we stimulated the systemic inflammatory response of mice and we assessed i) the expression of two genes with candidate immunomodulatory functions (Hp-Tgh2 and Hp CPI); ii) changes in the number of eggs shed in the faeces. To test if the immune environment induces a micro-evolutionary response in the parasite, we maintained the nematode in mice whose inflammatory response was up- or down-regulated during four generations. We found that H. polygyrus plastically responded to a sudden rise of pro-inflammatory cytokines, up-regulating the expression of two candidate genes involved in the process of immune modulation, and enhancing egg output. At the micro-evolutionary level, parasites maintained in hosts experiencing different levels of inflammation did not have differential expression of Hp-Tgh2 and Hp-CPI genes when infecting unmanipulated, control, mice. However, parasites maintained in mice with an up-regulated inflammation shed more eggs compared to the control line. Overall, our study shows that H. polygyrus can plastically adjust the expression of immunomodulatory genes and life history traits, and responds to selection exerted by the host immune system. PMID- 28733133 TI - Navigating the Gut Buffet: Control of Polysaccharide Utilization in Bacteroides spp. AB - Bacteroides spp. are members of the human gut microbiota that confer myriad benefits on their hosts. Among them is the provision of energy from otherwise indigestible polysaccharides comprising part of the host diet, lining the intestinal mucosal layer, and decorating the surface of other microbes. Bacteroides spp. devote ~20% of their genomes to the transport and breakdown of a wide variety of polysaccharides, and to the regulation of these processes. Bacteroides spp. rely on different families of transcriptional regulators to ensure that carbohydrate utilization genes are expressed under specific conditions. The regulators and mechanisms controlling carbohydrate utilization are often unique to these gut-dwelling bacteria, and do not conform to those of model organisms. PMID- 28733134 TI - Mobility of the First Ray in Patients With or Without Hallux Valgus Deformity: Systematic Review and Meta-Analysis. AB - The hypermobility theory of the first ray is the reason for the popularization of procedures such as the modified Lapidus procedure involving arthrodesis of the first tarsal-metatarsal joint for correction of hallux valgus deformity. Although many studies have involved motion of the first ray in hallux valgus patients, the presence and clinical significance of hypermobility in the first ray remains controversial. We performed a systematic review and meta-analysis to evaluate the difference in the first ray range of motion between patients with or without hallux valgus deformity. The databases used for the present review included Ovid EMBASE, Ovid MEDLINE, CINAHL, and the Cochrane Database. We searched for comparative studies that had evaluated the motion of the first ray in patients with or without hallux valgus. After screening for inclusion and exclusion criteria, we identified 3 studies that were relevant to our study question. All 3 studies showed more first ray motion in the hallux valgus group. Our quantitative synthesis showed a mean difference in the range of motion of the first ray of 3.62 mm (95% confidence interval 2.26 to 4.98) between those with and without hallux valgus deformity. Thus, we found statistically significantly increased first ray motion in patients with hallux valgus deformity compared with those without hallux valgus deformity. However, the clinical significance of this small amount of increased sagittal plane motion as a response to or a cause of hallux valgus remains unanswered. PMID- 28733135 TI - Centrally Mediated Cardiovascular Actions of the Angiotensin II Type 2 Receptor. AB - Sustained increases in the activity of the sympathetic neural pathways that exit the brain and which increase blood pressure (BP) are a major underlying factor in resistant hypertension. Recently available information on the occurrence of angiotensin II type 2 receptors (AT2Rs) within or adjacent to brain cardiovascular control centers is consistent with findings that stimulation of these receptors lowers BP, particularly during hypertension of neurogenic origin. Until recently brain AT2R had not been considered by many to play a role in the central control of BP. Demonstration of these powerful antihypertensive effects of brain AT2R opens the door to reconsideration of their role in BP regulation, and their consideration as a novel therapeutic avenue for resistant hypertension. PMID- 28733136 TI - Unexpected Bone Formation Produced by RANKL Blockade. AB - Denosumab (Dmab) is a humanized monoclonal antibody that blocks RANKL (receptor activator for nuclear factor kappaB ligand), thereby exerting a potent bone antiresorptive action. Dmab treatment leads to a dramatic and sustained increase in bone mass through mechanisms that are currently under debate. It is also a matter of controversy whether this potent action of Dmab could lead to intrabone dystrophic mineralization. Recent research has uncovered a possible anabolic role of Dmab involving RANKL-dependent reverse signaling in osteoblasts, and that bone marrow adipocytes can modulate osteoclastogenesis through the production of RANKL. We comment here on potential pathways which might account for the anabolic action of Dmab. The impact of this proposed mechanism needs to be addressed in further research. PMID- 28733137 TI - Can metabolic tumor parameters on primary staging 18F-FDG PET/CT aid in risk stratification of primary central nervous system lymphomas for patient management as a prognostic model? AB - OBJECTIVE: Primary central nervous system (CNS) lymphoma is an aggressive and fatal extranodal non-Hodgkin lymphoma jailed in CNS at initial diagnosis. Its prognosis is poor and the disease has a fatal outcome when compared with systemic non-Hodgkin lymphoma. A few baseline risk stratification scoring systems have been suggested to estimate the prognosis mainly based on serum lactate dehydrogenase level,age, Karnofsky performance score, involvement of deep brain structures and cerebrospinal fluid protein concentration. 18F-FDG PET/CT has a high prognostic value with respect to overall survival and disease-free survival in many cancers and lymphomas. We aimed to investigate metabolic tumor indexes on primary staging 18F-FDG PET/CT as prognostic markers in primary CNS lymphoma. MATERIAL AND METHODS: Fourteen patients with primary CNS diffuse large B-cell lymphoma (stage i) were enrolled in this retrospective cohort study. Primary staging 18F-FDG PET/CT was performed and quantitative parameters like maximum standardized uptake value, average standardized uptake value, metabolic tumor volume and total lesion glycolysis (TLG) were calculated for all patients before the treatment. Cox regression models were performed to determine their relation with survival time. RESULTS: In the evaluation of all potential risk factors impacting recurrence/metastases (age, sex, serum lactate dehydrogenase, involvement of deep brain structures, maximum standardized uptake value, average standardized uptake value, metabolic tumor volume, and TLG) with univariate analysis, TLG remained statistically significant (P=.02). CONCLUSION: Metabolic tumor parameters are useful in prognosis estimation of primary CNS lymphomas, especially TLG, which is the most important one and may play a role in patient management. PMID- 28733138 TI - A unusual pediatric case of focal nodular hyperplasia studied with 99mTc mebrofenin. PMID- 28733139 TI - CT-guided direct percutaneous treatment of a ruptured pulmonary artery pseudoaneurysm using N-butyl cyanoacrylate. PMID- 28733140 TI - ? PMID- 28733143 TI - Mechanisms of NLRP1-Mediated Autoinflammatory Disease in Humans and Mice. AB - NLRP1 was the first NOD-like receptor described to form an inflammasome, recruiting ASC to activate caspase-1, which processes interleukin-1beta and interleukin-18 to their active form. A wealth of new genetic information has now redefined our understanding of this innate immune sensor. Specifically, rare loss of-function variants in the N-terminal pyrin domain indicate that this part of NLRP1 is autoinhibitory and normally acts to prevent a familial autoinflammatory skin disease associated with cancer. In the absence of a ligand to trigger human NLRP1, these mutations have now confirmed the requirement of NLRP1 autolytic cleavage within the FIIND domain, which had previously been implicated in NLRP1 activation. Autolytic cleavage generates a C-terminal fragment of NLRP1 containing the CARD domain which then forms an ASC-dependent inflammasome. The CARD domain as an inflammasome linker is consistent with the observation that under some conditions, particularly for mouse NLRP1, caspase-1 can be engaged directly, and although it is no longer processed, it is still capable of producing mature IL-1beta. Additional rare variants in a linker region between the LRR and FIIND domains of NLRP1 also cause autoinflammatory disease in both humans and mice. This new genetic information is likely to provide for more mechanistic insight in the years to come, contributing to our understanding of how NLRP1 functions as an innate immune sensor of infection and predisposes to autoimmune or autoinflammatory diseases. PMID- 28733141 TI - Gastrin-releasing peptide and its receptor increase arthritis fibroblast-like synoviocytes invasiveness through activating the PI3K/AKT pathway. AB - Rheumatoid arthritis (RA) is an autoimmune disease that leads to joint destruction. The fibroblast-like synoviocytes (FLS) has a central role on the disease pathophysiology. The present study aimed to examine the role of gastrin releasing peptide (GRP) and its receptor (GRPR) on invasive behavior of mice fibroblast-like synoviocytes (FLS), as well as to evaluate GRP-induced signaling on PI3K/AKT pathway. The expression of GRPR in FLS was investigated by immunocytochemistry, western blot (WB) and qRT-PCR. The proliferation and invasion were assessed by SRB and matrigel-transwell assay after treatment with GRP and/or RC-3095 (GRPR antagonist), and/or Ly294002 (inhibitor of PI3K/AKT pathway). Finally, AKT phosphorylation was assessed by WB. GRPR protein was detected in FLS and the exposure to GRP increased FLS invasion by nearly two fold, compared with untreated cells (p<0.05), while RC-3095 reversed that effect (p<0.001). GRP also increased phosphorylated AKT expression in FLS. When Ly294002 was added with GRP, it prevented the GRP-induced increased cell invasiveness (p<0.001). These data suggest that GRPR expression in FLS and that exogenous GRP are able to activate FLS invasion. This effect occurs at least in part through the AKT activation. Therefore, understanding of the GRP/GRPR pathway could be relevant in the development of FLS-targeted therapy for RA. PMID- 28733142 TI - Deprescribing for frail older people - Learning from the case of Mrs. Hansen. AB - Drug treatment is often an essential part in treatment and prevention of diseases in older people, but there is much concern about inappropriate medication use. This paper aims to describe the complexity of medication safety issues and clinical judgments when optimizing prescribing in older individuals. It uses the case of Mrs. Hansen, an aged nursing home resident, to illustrate the facilitators and barriers of this process. With decreasing life expectancy, medication use should shift from cure to care, focusing on symptomatic treatment to increase the patient's well-being. In Mrs. Hansen's case, the number of (potentially) dangerous medications were reduced, and non-pharmacological alternatives were considered. There were some medicines added, as underprescribing can also be a problem in older people. Deprescribing long standing treatment can be interpreted by the patient and family as "giving up hope". More clinical evidence and practical communication tools are needed to guide deprescribing decisions, taking medical and patient-centered priorities into account. Studies evaluating such interventions should select outcome measures that are particularly relevant for frail old individuals. PMID- 28733144 TI - The Spliceosome: A Protein-Directed Metalloribozyme. AB - Pre-mRNA splicing is executed by the ribonucleoprotein machinery spliceosome. Nearly 40 years after the discovery of pre-mRNA splicing, the atomic structure of the spliceosome has finally come to light. Four distinct conformational states of the yeast spliceosome have been captured at atomic or near-atomic resolutions. Two catalytic metal ions at the active site are specifically coordinated by the U6 small nuclear RNA (snRNA) and catalyze both the branching reaction and the exon ligation. Of the three snRNAs in the fully assembled spliceosome, U5 and U6, along with 30 contiguous nucleotides of U2 at its 5'-end, remain structurally rigid throughout the splicing reaction. The rigidity of these RNA elements is safeguarded by Prp8 and 16 core protein components, which maintain the same overall conformation in all structurally characterized spliceosomes during the splicing reaction. Only the sequences downstream of nucleotide 30 of U2 snRNA are mobile; their movement, directed by the protein components, delivers the intron branch site into the close proximity of the 5'-splice site for the branching reaction. A set of additional structural rearrangement is required for exon ligation, and the lariat junction is moved out of the active site for recruitment of the 3'-splice site and 3'-exon. The spliceosome is proven to be a protein directed metalloribozyme. PMID- 28733145 TI - Adipocytes promote nicotine-induced injury of endothelial cells via the NF-kappaB pathway. AB - Cigarette smoking is one of the most important risk factors of atherosclerosis, which can induce endothelial injury. Meanwhile, adipocytes are the main cell type of perivascular adipose tissue (PVAT), the largest endocrine and paracrine organ and direct anatomical connection to adventitia, which may play a key role in the injury of endothelial cells. We used nicotine to induce dysfunctional HUVECs and adipocytes. In addition, we used a novel model to co-culture HUVECs and adipocytes in vitro by the transwell co-culture system to determine the effect of adipocytes on endothelial injury. Cell apoptosis was detected by Annexin V-FITC. Genes and proteins involved in the nuclear factor kappa B (NF-kappaB) signaling pathway were detected by qRT-PCR and western blot analysis, respectively. We also investigated the nuclear translocation of NF-kappaB p65 using immunofluorescence staining. Our results showed that nicotine dose-dependently induces the apoptosis of HUVECs and adipocytes and is associated with increased IKKbeta and NF-kappaB p65 expression and with IkBalpha degradation. Meanwhile through the co-culture system, adipocytes promoted the expression of IKKbeta and NF-kappaB p65, as well as the translocation of NF-kappaB p65, and they accelerated the degradation of IkBalpha, resulting in increased apoptosis of HUVECs compared with that of the single cultured system. In conclusion, adipocytes could promote endothelial injury via the NF-kappaB pathway. Moreover, the NF-kappaB pathway plays pivotal roles in nicotine-induced vascular injury. PMID- 28733147 TI - Everolimus to treat aggressive retinal astrocytic hamartoma in tuberous sclerosis complex. AB - Retinal astrocytic hamartomas (RAH) are the most frequent ocular manifestation of tuberous sclerosis complex and are usually indolent, requiring only observation. We report an aggressive RAH subtype in a child unresponsive to anti-VEGF and laser therapy. Treatment with systemic everolimus was well-tolerated and significantly reduced ocular (and nonocular) tumor size and fluid exudation. PMID- 28733146 TI - Resveratrol efficiently improves pulmonary function via stabilizing mast cells in a rat intestinal injury model. AB - BACKGROUND: Intestinal ischemia/reperfusion (IIR) leads to acute lung injury (ALI) distally by aggravating pulmonary oxidative stress. Resveratrol is effective in attenuating ALI through its antioxidant capacity. This study aimed to determine the effects of resveratrol on IIR-induced ALI and to explore the role of mast cells (MCs) activation in a rat model of IIR. METHODS: Adult Sprague Dawley rats were subjected to IIR by occluding the superior mesenteric artery for 60min followed by 4-hour reperfusion. Resveratrol was intraperitoneally injected at a dose of 15mg/kg for 5days before IIR. MCs stabilizer/inhibitor cromolyn sodium and degranulator compound 48/80 were used to explore the interaction between resveratrol and MCs. Lung tissues were collected for pathological detection and MCs staining. Pulmonary protein expression of surfactant protein-C (SP-C), tryptase, p47phox and gp91phox (two NADPH oxidase subunits), ICAM 1(intercellular adhesion molecule-1) and P-selectin were detected. The levels of oxidative stress markers (SOD, MDA, H2O2 and MPO) and beta-hexosaminidase were also measured. RESULTS: At the end of IIR, lung injury was significantly increased and was associated with decreased expression of SP-C and increased lung oxidative stress. Increased inflammation as well as activation of MCs was also observed in the lungs after IIR. All these changes were prevented or reversed by resveratrol pretreatment or MCs inhibition with cromolyn sodium. However, these protective effects of resveratrol or cromolyn sodium were reduced by MCs degranulator compound 48/80. CONCLUSIONS: These findings reveal that resveratrol attenuates IIR-induced ALI by reducing NADPH oxidase protein expression and inflammation through stabilizing MCs. PMID- 28733149 TI - A comprehensive pain assessment tool (COMPAT) for chronic pancreatitis: Development, face validation and pilot evaluation. AB - BACKGROUND/OBJECTIVES: Chronic pancreatitis (CP) pain is challenging to treat. Treatment selection is hampered by there being no validated pain assessment tool that accounts for the complexity of CP pain and its underlying mechanisms. This study aims to develop a comprehensive pain assessment tool (COMPAT) specific for CP, evaluate its face validity with experts and patients and test it with a pilot cohort of patients. METHODS: COMPAT was developed from existing pain assessment tools and a literature review. Face validity was conducted by pancreatologists and CP patients using an item-content validity index for importance, relevance and clarity. Subsequent revisions were made to COMPAT. A pilot cohort of CP patients tested COMPAT. RESULTS: COMPAT was developed and covered all important aspects of CP pain. Experts and CP patients reported that 70% of questions were important and relevant to CP pain. Most experts were willing to use COMPAT in clinic, ward/hospital and research settings. The most common location of pain was the epigastrium and food was the most important trigger. Pain Pattern C (constant background pain with pain attacks), had significantly higher frequency of pain attacks, higher opioid use, and affective descriptors of pain than Pattern A (pain attacks with no background pain). CONCLUSIONS: COMPAT has high face validity and met with high acceptance. CP patients successfully self-reported their pain with COMPAT. The results reveal many differences in the CP pain within the pilot cohort, which may reflect different mechanisms of pain. A larger prospective cohort study is planned to further validate COMPAT. PMID- 28733148 TI - Prevalence and predictors of pain and opioid analgesic use following total pancreatectomy with islet autotransplantation for pancreatitis. AB - BACKGROUND & OBJECTIVES: Total pancreatectomy with islet autotransplantation (TPIAT) is employed for the management of refractory pain in chronic pancreatitis (CP) with the prospect of partial beta cell preservation. The primary aim of this study is to evaluate the prevalence and predictors of abdominal pain and opioid use following TPIAT. METHODS: A single center cohort study of all adult patients who underwent TPIAT from 2011 to 2015 for CP. Postoperative pain outcomes included: opioid use, ongoing abdominal pain and new characteristic abdominal pain. Multiple logistic regression analysis was used to evaluate known and potential predictors of postoperative pain outcomes. RESULTS: During the study period, 46 patients underwent TPIAT. Following surgery, 89% of patients had resolution of their pre-operative abdominal pain; however, 83% of patients developed a new characteristic abdominal pain. Opioid independence was achieved in 46% of patients. Acute recurrent pancreatitis (ARP) (OR: 11.66; 95%CI: 1.47 92.39; p = 0.02) but not pain duration >3 years or >= 5 ERCPs was independently associated with resolution of pre-operative abdominal pain on multiple logistic regression. None of these factors were associated with cessation of opioid use. CONCLUSION: While the majority of patients have resolution of their initial abdominal pain following TPIAT, many will also develop a new characteristic abdominal pain and only half of all patients achieve opioid independence. ARP is the only independent factor associated with positive postoperative pain outcomes and should be considered a standard criterion for patient selection. PMID- 28733150 TI - Seven new lignan glycosides from the branches of Alangium kurzii Craib var. laxifolium. AB - Seven new lignan glycosides (1-3, 8-10, and 14) and 17 known compounds were isolated from the branches of Alangium kurzii Craib var. laxifolium. Their structures were established by spectroscopic analysis and circular dichroism (CD) and X-ray analysis. The isolated compounds were evaluated for their antibacterial activities against Staphylococcus aureus CI1011, Streptococcus suis CI1608, Salmonella gallinarum CI0912, Enterococcus faecalis CI1304, Aeromonas hydrophila CI1008, Escherichia coli CI151012, Vibrio parahaemolyticus CI150506, Klebsiella pneumoniae CI131216, Pseudomonas aeruginosa CI1011, Staphylococcus epidermidis CI1110, and Streptococcus agalactiae CI1302. Their minimum inhibitory concentrations (MICs) were determined by serial dilution in 96-well culture plates. PMID- 28733151 TI - Chewing gum decreases energy intake at lunch following a controlled breakfast. AB - The impact of chewing gum on fasting appetite or meal intake has not been studied. We tested the hypothesis that chewing gum would decrease lunch intake after a controlled breakfast, and reduce hunger in fasting and fed states. Seventeen males and sixteen females (21.4 +/- 6.3y, BMI 23.8 +/- 2.7 kg/m2) participated in a randomized crossover study in which subjects chewed sugar-free gum a total of 1 h on the test day (GC), and did not chew gum on a control day (NG). The 1 h of gum chewing included 20 min while fasting, and two 20-min sessions between breakfast and lunch. Subjects rated their appetite and mood on visual analog scales. After completing the fasting measures, subjects consumed a breakfast shake containing 30% of their measured resting energy expenditure. Three hours later they consumed an ad libitum lunch with water. Fasting ratings of hunger were lower in GC than NG (t = 2.66, p = 0.01). Subjects consumed significantly less pasta (41 g, 68 kcals, t = 2.32, p = 0.03) during GC than NG. In conclusion, gum chewing decreased fasting hunger ratings and lunch energy consumed. Chewing gum may be a useful tool impacting energy balance in this population. Longer studies, especially in other populations, will be required. PMID- 28733152 TI - Midwifery student reactions to workplace violence. AB - PROBLEM: Workplace violence, incidents against people in their workplaces, is a growing problem in Australia causing untold personal suffering as well as costing Australian businesses in productivity. Midwives have been highlighted as a group particularly at risk, yet in Australia there is little research into workplace violence against midwives and even less into midwifery students. AIM: This study aimed to explore Australian midwifery students' responses to workplace violence as well as to gauge the impact of workplace violence on them. METHODS: Cross sectional survey design was employed. Second and third year students were invited to participate at the end of a scheduled lecture. Fifty-two female midwifery students who had completed their work placement completed a survey indicating their immediate responses to workplace violence as well as the Impact of Event Scale. Data were analysed using descriptive statistics. FINDINGS: Most students notified a co-worker immediately after a workplace violence incident, yet few completed an incident form or received official debriefing. DISCUSSION: There is a need for the reporting of workplace violence against midwifery students to be made easier to access thereby ensuring they can receive the assistance they require. Midwifery students need to understand the processes and supports in place for managing instances of workplace violence. CONCLUSION: Clinical placements can impact on midwifery students' future careers. Universities need to prepare students for the possibility of workplace violence and arm them with appropriate strategies for safely dealing with it. PMID- 28733153 TI - Unsettling moods in rural midwifery practice. AB - BACKGROUND: Rural midwifery and maternity care is vulnerable due to geographical isolation, staffing recruitment and retention. Highlighting the concerns within rural midwifery is important for safe sustainable service delivery. METHOD: Hermeneutic phenomenological study undertaken in New Zealand (NZ). 13 participants were recruited in rural regions through snowball technique and interviewed. Transcribed interview data was interpretively analysed. Findings are discussed through the use of philosophical notions and related published literature. FINDINGS: Unsettling mood of anxiety was revealed in two themes (a) 'Moments of rural practice' as panicky moments; an emergency moment; the unexpected moment and (b) 'Feelings of being judged' as fearing criticism; fear of the unexpected happening to 'me' fear of losing my reputation; fear of feeling blamed; fear of being identified. CONCLUSIONS: Although the reality of rural maternity can be more challenging due to geographic location than urban areas this need not be a reason to further isolate these communities through negative judgement and decontextualized policy. Fear of what was happening now and something possibly happening in the future were part of the midwives' reality. The joy and delight of working rurally can become overshadowed by a tide of unsettling and disempowering fears. IMPLICATIONS: Positive images of rural midwifery need dissemination. It is essential that rural midwives and their communities are heard at all levels if their vulnerability is to be lessened and sustainable safe rural communities strengthened. PMID- 28733154 TI - Community pharmacists' knowledge of Alzheimer disease care in high- and low income Chicago. AB - OBJECTIVES: This pilot study examined community pharmacists' knowledge to provide care and services for persons with Alzheimer disease (AD) and area income-based disparities in knowledge and availability of cognitive enhancers. METHODS: A cross-sectional telephone survey of pharmacies (n = 137) in high- and low-income areas in Chicago was conducted on pharmacists' degree, experience, and continuing education, as well as knowledge of AD disease and treatment expectations, adverse effects (AEs) of donepezil, and self-care recommendations for insomnia. Pharmacies were selected from highest- and lowest-income zip code areas, defined using household area median incomes from the 2008-2012 American Community Survey 5-Year Estimates. In-stock availability of select cognitive enhancers was obtained. Chi-square, Fisher exact test, and simple and multiple logistic regression analyses were performed with the use of Stata 10.1. RESULTS: Odds were 70% lower that pharmacists in low-income areas would say there was nothing to reverse the course of AD (odds ratio [OR] 0.30, 95% confidence interval [CI] 0.13 0.70) and 7 times greater that they would recommend a medication to reverse the course of AD (OR 7.04, 95% CI 2.19-22.62) compared with pharmacists in high income areas. Odds were more than 50% lower that pharmacists in low-income areas would name at least 1 adverse effect for donepezil (OR 0.42, 95% CI 0.19-0.92) compared with peers in high-income areas. Pharmacies in low-income areas had lower odds of having 4 of the 5 surveyed formulations of cognitive enhancers in stock. CONCLUSION: It is concerning that 20%-30% of pharmacists recommended a medication to "reverse" the course of AD, about one-half of pharmacists could not mention a single adverse effect of donepezil, and more than one-fourth of pharmacists made an inappropriate self-care sleep aid recommendation for a person with AD who was using rivastigmine patch. Although overall results regarding pharmacists' knowledge were poor, performance was significantly poorer in low income areas. As our AD population increases, we need to strengthen pharmacists' knowledge on and competencies important for pharmacy-related AD care. PMID- 28733155 TI - Implementation of a health information exchange into community pharmacy workflow. AB - OBJECTIVES: To explore the feasibility and report preliminary outcomes of the integration of a health information exchange (HIE) into community pharmacy workflow clinical service delivery. SETTING: Independent pharmacy in eastern Tennessee. PRACTICE DESCRIPTION: The pharmacy offers medication reconciliation services via HIE access, as well as other clinical pharmacy services. The average number of prescriptions filled weekly is 1900, and staffing included 3.5 full time-equivalent (FTE) pharmacists, and 7 FTE technicians. PRACTICE INNOVATION: HIE integration within the workflow of the pharmacy was used to enhance existing patient care services, such as medication distribution, drug use review, medication therapy management, and immunizations, as well as to implement a novel transitional care service. EVALUATION: A mixed-methods design was used to explore HIE workflow. Data collection included a pharmacist and pharmacy technician perceptions survey, mapping steps involved in HIE use in workflow via a think aloud protocol, and quantitatively reporting the number and type of discordant medications found on medication reconciliation. RESULTS: In total, 25 patients qualified for the medication reconciliation intervention and data collection. All 25 patients (100%) had at least 1 discordant medication. HIE access was used for 60% of patients. Community pharmacists were confident in their abilities to perform medication reconciliation and were able to perform the medication reconciliation with the use of the HIE within their workflow, albeit with some reported barriers. The average time spent per patient for HIE-facilitated transitional care was 21 minutes. CONCLUSION: Integration and utilization of an HIE within the workflow for the purposes of patient care service delivery in the community pharmacy is feasible, but not without limitations. Such HIE utilization and extended access to the patient's clinical picture may represent a scalable method to enhance currently delivered pharmacist services. PMID- 28733156 TI - A structured patient identification model for medication therapy management services in a community pharmacy. AB - OBJECTIVES: To describe the development and implementation of a structured patient identification model for medication therapy management (MTM) services within traditional dispensing activities of a community pharmacy to facilitate pharmacist-provided completion of MTM services. DESIGN: A daily clinical opportunity report was developed as a structured model to identify MTM opportunities daily for all MTM-eligible patients expecting to pick up a prescription. Pharmacy staff was trained and the standardized model was implemented at study sites. SETTING AND PARTICIPANTS: One hundred nineteen grocery store-based community pharmacies throughout Ohio, West Virginia, and Michigan. OUTCOME MEASURES: A structured patient identification model in a community pharmacy consists of reviewing a clinical opportunity report, identifying interventions for MTM-eligible patients, and possibly collaborating with an interdisciplinary team. This model allows pharmacists to increase MTM cases performed by providing a structured process for identifying MTM-eligible patients and completing MTM services. RESULTS: The development and implementation of a structured patient identification model in the community pharmacy was completed and consists of pharmacists reviewing a clinical opportunity report to identify MTM opportunities and perform clinical interventions for patients. In a 3-month pre- and post-implementation comparison, there was a 49% increase in the number of MTM services provided by pharmacists (P < 0.001). CONCLUSION: A structured patient identification model in the community pharmacy was associated with an increase in the amount of MTM services provided by pharmacists. This method could be a useful tool at a variety of community pharmacies to solve challenges associated with MTM completion. PMID- 28733157 TI - Electrotaxis leads the way. PMID- 28733158 TI - Clinical and urodynamic outcomes in children with anorectal malformation subtype of recto-bladder neck fistula. AB - INTRODUCTION: Patients with anorectal malformations (ARMs) have a high incidence of genitourinary anomalies. Those with a recto-bladder neck fistula may represent a high-risk group, but their long-term urologic outcomes are poorly described. OBJECTIVE: To evaluate the clinical and urodynamic outcomes in a large cohort of patients with an ARM subtype of recto-bladder neck fistula. MATERIALS AND METHODS: A retrospective cohort study was performed of patients who had been treated for a recto-bladder neck fistula at the present institution since 2007. The primary outcomes were the ability to achieve urinary continence after 4 years of age, and development of a mildly decreased glomerular filtration rate (GFR) or worse (<89 ml/min/1.73 m2). Continence was defined as the ability to store urine for 3-4 h during the day and 8 h overnight without leakage. RESULTS: Demographic and clinical data are provided in the Summary Table. The most recent urodynamic findings included the presence of detrusor overactivity in 30 (75%) patients, median leak point pressure of 56.0 cmH2O (range, 14-140), median functional cystometric capacity at 40 cmH2O of 125.5% age-expected capacity (range, 36 473%), and median maximum cystometric capacity of 131.0% age-expected capacity (range, 44-473%). A mildly decreased GFR or worse developed in 13 (24%) patients. Of the 52 (78%) patients who were followed by pediatric urology at the present institution with a median follow-up of 30.9 months (range, 0.0-86.8), 35 (67%) were at least 4 years of age and could be assessed for continence. Continence was achieved in five (14%) patients voiding spontaneously and 15 (43%) performing CIC. Recurrent urinary tract infections (UTI) (OR 0.70, P = 0.006) were an independent predictor of incontinence, while urethral anomalies (OR 1.40, P = 0.03) were an independent predictor of chronic kidney disease (CKD) on multiple logistic regression analysis. DISCUSSION: The findings favorably compared with other studies, but were more robust due to the size of the cohort and breadth of urologic evaluation. Limitations included the retrospective design at a single institution. Incomplete clinical data and misclassification of continence may have lead to bias. CONCLUSIONS: This large cohort of patients with an ARM subtype of recto-bladder neck fistula had a high incidence of genitourinary anomalies. They were rarely able to achieve continence with spontaneous voiding alone and were at risk of developing CKD, both of which were likely multifocal in origin. Long-term urologic follow-up is warranted for patients with a recto-bladder neck fistula. PMID- 28733159 TI - The impact of a bladder training video versus standard urotherapy on quality of life of children with bladder and bowel dysfunction: A randomized controlled trial. AB - INTRODUCTION: Bladder and bowel dysfunction (BBD) can negatively impact the quality of life (QoL) of children. Urotherapy is an accepted treatment option for BBD; however, literature that examines the impact of management options on QoL in this population is scarce. OBJECTIVE: To determine whether a bladder training video (BTV) is non-inferior to standard urotherapy (SU) in improving QoL in children with BBD. METHODS: Children aged 5-10 years and who scored >=11 on the Vancouver Non-Neurogenic Lower Urinary Tract Dysfunction/Dysfunctional Elimination Syndrome Questionnaire (NLUTD/DES) were recruited from a pediatric tertiary care center. Children were excluded with known vesicoureteral reflux; spinal dysraphism; learning disabilities; recent urotherapy; and primary nocturnal enuresis. Quality of life was evaluated using the Pediatric Incontinence Quality-of-Life questionnaire (PinQ). Questionnaires were administered at the baseline and 3-month follow-up clinic visits. Following centralized electronic blocked randomization schemes to guarantee allocation concealment, patients were assigned to receive SU or BTV during their regular clinic visits. An intention-to-treat protocol was followed. Between-group baseline and follow-up QoL scores were compared using paired and unpaired t tests, and linear regression analysis. RESULTS: Of the 539 BBD patients who were screened, 173 (32%) were eligible, and 150 (87%) were randomized. Of these, 143 (96%) completed the study, five (3%) were lost to follow-up, and two (1%) withdrew. In total, 140/143 (97%) completed the QoL questionnaire at baseline and follow-up. Mean follow-up time was 3.5 +/- 1.1 months for BTV patients and 3.7 +/ 1.6 months for SU. At baseline, BTV and SU patients had a mean QoL score of 26.6 +/- 13 and 23.8 +/- 12, respectively (P = 0.17). Between-group mean change in PinQ scores from baseline was not statistically significant (BTV: 6.25 +/- 12.5 vs SU: 3.75 +/- 12.2; P = 0.23; Summary Fig.). Significant predictors of positive change in QoL were: higher symptomatology score, with a correlation coefficient of 0.5 (95% CI: 0.2-0.9; P = 0.003), and worse baseline QoL score, with a correlation coefficient of 0.5 (95% CI: 0.4-0.7; P < 0.001). Overall, most patients had improved symptomatology and QoL scores. CONCLUSION: Significant and similar QoL changes from baseline to follow-up were observed in both the BTV and SU groups, suggesting that BTV was non-inferior to SU in improving QoL in children with BBD. Quality of life assessment should be considered when evaluating interventions for BBD, as it appears to be an important clinical outcome with which to determine urotherapy success. PMID- 28733160 TI - Triamcinolone injection for treatment of Mitrofanoff stomal stenosis: Optimizing results and reducing cost of care. AB - INTRODUCTION: Stomal stenosis is the most common complication after the creation of a continent catheterizable channel (CCC), but is challenging to treat. OBJECTIVE: To describe early experience with triamcinolone injection for the treatment of stomal stenosis. MATERIALS AND METHODS: A retrospective review was performed of patients who had undergone a triamcinolone injection (40 mg/ml) for the treatment of stomal stenosis at the present institution. The primary outcome of success was defined as a patient-reported or caregiver-reported return to ease with catheterization, and avoidance of stomal revision or indwelling catheter. The cost of care with various techniques for the treatment of stomal stenosis was also assessed by representing the cost as a percentage of charges for a re operative Monti ileovesicostomy. RESULTS: A total of 22 injections were performed in 18 CCCs of 17 patients. Demographic and clinical data are provided in the Summary Table. Thirteen CCCs (72%) were successfully treated with a single injection. Three patients (10%) required a total of five repeat injections at a median of 5.1 months between injections (IQR, 4.6-12.4). One patient required a stomal revision at 34.9 months after the initial injection, while one patient also required a Chait cecostomy catheter. The median length of time for ease with catheterization was 11.6 months (IQR, 3.5-18.0) after the initial injection, and 10.4 months (IQR, 4.5-16.0) after any injection. No adverse effects or complications occurred from the injection. There were no variables associated with failure after the initial or any injection on univariate analysis. Represented as a percentage of charges for a reoperative Monti ileovesicostomy, the cost of care was 11.3% for a stomal revision, 5.8% for triamcinolone injection in the operating room, and 0.3% as an office-based procedure. DISCUSSION: The success rate for triamcinolone injection favorably compared with other options for the treatment of stomal stenosis. It surpassed the reported success rate of stomal dilation and approached that of stomal revision. Other studies have similarly observed a minimal risk of adverse effects and complications from both topical and intralesional corticosteroids. The limitations of the present study included its retrospective design at a single institution. A larger cohort of patients with a longer follow-up is necessary to determine its long-term durability. CONCLUSIONS: Triamcinolone injection was an effective and well-tolerated option for the treatment of stomal stenosis in any cutaneous stoma, thereby avoiding the need for a more invasive and costly stomal revision. PMID- 28733162 TI - Patterning the eye: A role for the cell cycle? AB - Although highly regulated cell cycle behavior accompanies specification of cell types in the Drosophila retina, no evidence has previously existed that cell cycle phase influences cell fate choice. Meserve and Duronio have now used genetic techniques to trace the fate of a sub-population of cells that accumulate in G2-phase of the cell cycle, discovering that they contribute to a particular fate, the precursor of the sensory inter-ommatidial bristles. Meserve and Duronio further show that G2 cells have an advantage acquiring inter-ommatidial bristle fate. This is the first evidence for a functional contribution of cell cycle phase to cell fate determination in the Drosophila eye and indicates that the fate of one population of retinal cells is established much earlier than previously recognized, during the larval stages when cell-cell interactions influence cell cycle phase. Inter-ommatidial bristle fate had been thought to arise much later, in the pupal stage, and models for how these neuronal eye structures arise will now have to be revised. PMID- 28733161 TI - Functional determination of the differentiation potential of ventral mesencephalic neural precursor cells during dopaminergic neurogenesis. AB - The ventral mesencephalic neural precursor cells (vmNPCs) that give rise to dopaminergic (DA) neurons have been identified by the expression of distinct genes (e.g., Lmx1a, Foxa2, Msx1/2). However, the commitment of these NPCs to the mesencephalic DA neuronal fate has not been functionally determined. Evaluation of the plasticity of vmNPCs suggests that their commitment occurs after E10.5. Here we show that E9.5 vmNPCs implanted in an ectopic area of E10.5 mesencephalic explants, retained their specification marker Lmx1a and efficiently differentiated into neurons but did not express the gene encoding tyrosine hydroxylase (Th), the limiting enzyme for dopamine synthesis. A proportion of E10.5-E11.5 implanted vmNPCs behaved as committed, deriving into Th+ neurons in ectopic sites. Interestingly, implanted cells from E12.5 embryos were unable to give rise to a significant number of Th+ neurons. Concomitantly, differentiation assays in culture and in mesencephalic explants treated with Fgf2+LIF detected vmNPCs with astrogenic potential since E11.5. Despite this, a full suspension of E12.5 vmNPCs give rise to DA neurons in a similar proportion as those of E10.5 when they were transplanted into adult brain, but astrocytes were only detected with the former population. These data suggest that the subventricular postmitotic progenitors present in E12.5 ventral mesencephalon are unable to implant in embryonic explants and are the source of DA neurons in the transplanted adult brain. Based on our findings we propose that during DA differentiation committed vmNPCs emerge at E10.5 and they exhaust their neurogenic capacity with the rise of NPCs with astrogenic potential. PMID- 28733163 TI - RNAi-mediated knockdown of SPOOK reduces ecdysteroid titers and causes precocious metamorphosis in the desert locust Schistocerca gregaria. AB - The Halloween gene SPOOK (SPO) is involved in the production of the active metabolite of ecdysteroid, 20-hydroxyecdysone (20E), in insects. A previous study showed that RNAi-mediated knockdown of SPO in Schistocerca gregaria last instar nymphs markedly reduced the hemolymph 20E titer, but did not affect metamorphosis. In the present study, the effects of SPO interference on development were re-examined in this locust. Injections of SPO double-stranded RNA (dsSPO) into nymphs at mid and late instars significantly delayed nymphal development and interfered with molting. The 20E levels of dsSPO-treated nymphs were generally low, with a delayed, small peak, suggesting that disturbance of the 20E levels caused the above developmental abnormalities. A small proportion of the dsSPO-injected nymphs metamorphosed precociously, producing adults and adultoids. Precocious adults were characterized by small body size, short wings with abbreviated venation, and normal reproductive activity. Fourth instar nymphs that precociously metamorphosed at the following instar exhibited temporal expression patterns of ecdysone-induced protein 93F and the juvenile hormone (JH) early-inducible gene Kruppel homolog 1 similar to those observed at the last instar in normal nymphs. Adultoids displayed mating behavior and adultoid females developed eggs, but never laid eggs. JH injection around the expected time of the 20E peak in the dsSPO-injected nymphs completely inhibited the appearance of adultoids, suggesting that appearance of adultoids might be due to a reduced titer of JH rather than of 20E. These results suggest that SPO plays an important role in controlling morphogenesis, metamorphosis, and reproduction in S. gregaria. PMID- 28733164 TI - The role of oxysterol-binding protein and its related proteins in cancer. AB - Oxysterol-binding protein (OSBP) and its related proteins (ORPs) constitute a large, evolutionarily conserved family of lipid-binding proteins that are associated with a wide range of cellular activities. The core function of OSBP/ORPs appears to be moving lipids between cellular membranes in a non vesicular manner. Recent studies have unveiled a novel, counter-transport mechanism of cellular lipid transfer mediated by OSBP/ORPs at the membrane contact sites that involves phosphatidylinositol 4-phosphate. Importantly, the OSBP/ORPs family has also been implicated in cell signalling pathways and cancer development. Here, we summarize recent progress in understanding the role of OSBP/ORPs in cancer development, and discuss how the lipid transfer function of OSBP/ORPs may underpin their role in tumorigenesis. PMID- 28733165 TI - ROS-related redox regulation and signaling in plants. AB - As sessile oxygenic organisms with a plastic developmental programme, plants are uniquely positioned to exploit reactive oxygen species (ROS) as powerful signals. Plants harbor numerous ROS-generating pathways, and these oxidants and related redox-active compounds have become tightly embedded into plant function and development during the course of evolution. One dominant view of ROS-removing systems sees them as beneficial antioxidants battling to keep damaging ROS below dangerous levels. However, it is now established that ROS are a necessary part of subcellular and intercellular communication in plants and that some of their signaling functions require ROS-metabolizing systems. For these reasons, it is suggested that "ROS processing systems" would be a more accurate term than "antioxidative systems" to describe cellular components that are most likely to interact with ROS and, in doing so, transmit oxidative signals. Within this framework, our update provides an overview of the complexity and compartmentation of ROS production and removal. We place particular emphasis on the importance of ROS-interacting systems such as the complex cellular thiol network in the redox regulation of phytohormone signaling pathways that are crucial for plant development and defense against external threats. PMID- 28733166 TI - Right Paracardiac Cystic Lymphatic Malformation. PMID- 28733167 TI - SAPIEN 3 Embolization Due to a Leak in the Y Connector. PMID- 28733168 TI - Chimeras intended for human gamete production: an ethical alternative? AB - Human eggs for basic, fertility and stem-cell research are in short supply. Many experiments that require their use cannot be carried out at present, and, therefore, the benefits that could emerge from these are either delayed or never materialise. This state of affairs is problematic for scientists and patients worldwide, and it is a matter that needs our attention. Recent advances in chimera research have opened the possibility of creating human/non-human animal chimeras intended for human gamete production (chimeras-IHGP). In this paper, I examine four arguments against the creation of such chimeras and prove that all of them are found wanting. I conclude by showing that there is a strong moral reason for scientists to pursue this research avenue. PMID- 28733169 TI - Implications of the 2014 Androgen Excess and Polycystic Ovary Syndrome Society guidelines on polycystic ovarian morphology for polycystic ovary syndrome diagnosis. AB - The Androgen Excess and Polycystic Ovary Syndrome Society (AEPCOS) has recommended an updated threshold for polycystic ovarian morphology (PCOM) of 25 follicles or more, 10 ml or more of ovarian volume, or both. We describe the effect of these guidelines on reproductive and metabolic characteristics in 404 women. These women were separated into four groups: group A: hyperandrogenism and oligo-amenorrhoea (n = 157); group B: hyperandrogenism or oligo-amenorrhoea and PCOM meeting AEPCOS 2014 criteria (n = 125); group C: hyperandrogenism or oligo amenorrhoea and PCOM meeting Rotterdam 2003 but not AEPCOS 2014 criteria (n = 72); and group D: non-PCOS not meeting either criteria (n = 50). Groups B, C and D did not differ across any metabolic markers. The AEPCOS 2014 guidelines may have limited utility in distinguishing metabolic risk factors and result in the exclusion of a large group of oligo-anovulatory women. PMID- 28733170 TI - Human-animal chimeras: circumventing rather than discussing ethical concerns comes at a price. PMID- 28733171 TI - Are Residents Prepared for Surgical Cases? Implications in Patient Safety and Education. AB - OBJECTIVE: In surgical education, the areas of focus and evaluation are skewed toward technical skill and operative knowledge; less emphasized is familiarity with the patient's medical history. The purposes of this study were to characterize how surgical trainees prepare for cases and to determine the comprehensiveness of their preparation. DESIGN: A 27-question survey was created through a web-based software program and distributed to all resident physicians and fellows in the Departments of Surgery, Neurosurgery, and Otolaryngology at our institution. Survey responses were collected anonymously and analyzed. Institutional review board exemption was obtained. SETTING: This study was performed at Washington University in St. Louis, Missouri, at an institutional hospital setting. PARTICIPANTS: The survey was distributed to current surgical trainees at Washington University in St. Louis in the Departments of Surgery, Neurosurgery, and Otolaryngology. Further, 130 of 169 surgical residents and fellows completed the survey. RESULTS: Most respondents (96%) taught themselves case preparation. Only 57% of respondents reviewed the patients medical record before every surgery. Although most respondents (83%) felt they were prepared or very prepared from a patient-specific standpoint, only 24% felt that their handoff of a patient to on-call colleagues was comprehensive enough to include all pertinent aspects of a patient's history and expected perioperative course. From a technical perspective, most residents (63%) felt they were prepared or very prepared, and this level of comfort increased with postgraduate year; 76% of respondents would not feel comfortable telling their attending they were not adequately prepared. CONCLUSIONS: Although most trainees feel prepared or very prepared for cases from a patient-specific regard, only half review the patient's medical record before every surgery. Furthermore, almost all trainees have taught themselves how to prepare for surgery. This represents a critical gap in residency education and an opportunity to improve patient safety and quality of care. PMID- 28733172 TI - SGLT2 inhibitors and amputations in the US FDA Adverse Event Reporting System. PMID- 28733173 TI - Clinical and biochemical characteristics of individuals with low cholesterol syndromes: A comparison between familial hypobetalipoproteinemia and familial combined hypolipidemia. AB - BACKGROUND: The most frequent monogenic causes of low plasma cholesterol are familial hypobetalipoproteinemia (FHBL1) because of truncating mutations in apolipoprotein B coding gene (APOB) and familial combined hypolipidemia (FHBL2) due to loss-of-function mutations in ANGPTL3 gene. OBJECTIVE: A direct comparison of lipid phenotypes of these 2 conditions has never been carried out. In addition, although an increased prevalence of liver steatosis in FHBL1 has been consistently reported, the hepatic consequences of FHBL2 are not well established. METHODS: We investigated 350 subjects, 67 heterozygous carriers of APOB mutations, 63 carriers of the p.S17* mutation in ANGPTL3 (57 heterozygotes and 6 homozygotes), and 220 noncarrier normolipemic controls. Prevalence and degree of hepatic steatosis were assessed by ultrasonography. RESULTS: A steady decrease of low-density lipoprotein cholesterol levels were observed from heterozygous to homozygous FHBL2 and to FHBL1 individuals, with the lowest levels in heterozygous FHBL1 carrying truncating mutations in exons 1 to 25 of APOB (P for trend <.001). Plasma triglycerides levels were similar in heterozygous FHBL1 and homozygous FHBL2 individuals, but higher in heterozygous FHBL2. The lowest high-density lipoprotein cholesterol levels were detected in homozygous FHBL2 (P for trend <.001). Compared with controls, prevalence and severity of hepatic steatosis were increased in heterozygous FHBL1 (P < .001), but unchanged in FHBL2 individuals. CONCLUSION: Truncating APOB mutations showed the more striking low density lipoprotein cholesterol lowering effect compared with p.S17* mutation in ANGPTL3. Reduced high-density lipoprotein cholesterol levels were the unique lipid characteristic associated with FHBL2. Mutations impairing liver synthesis or secretion of apolipoprotein B are crucial to increase the risk of liver steatosis. PMID- 28733175 TI - Probing the neural circuits of sex and aggression with precision genetics: Commentary on "Estrogen receptor alpha is required in GABAergic but not glutamatergic, neurons to masculinize behavior" by Wu and Tollkuhn. PMID- 28733174 TI - Lipoprotein insulin resistance score and risk of incident diabetes during extended follow-up of 20 years: The Women's Health Study. AB - BACKGROUND: Type II diabetes (T2D) is preceded by prolonged insulin resistance and relative insulin deficiency incompletely captured by glucose metabolism parameters, high-density lipoprotein (HDL) cholesterol and triglycerides. OBJECTIVE: Whether lipoprotein insulin resistance (LPIR) score, a metabolomic marker, is associated with incident diabetes and improves risk reclassification over traditional markers on extended follow-up. METHODS: Among 25,925 nondiabetic women aged 45 years or older, LPIR was measured by nuclear magnetic resonance spectroscopy as a weighted score of very low density lipoprotein, low-density lipoprotein, and HDL particle sizes, and their subsets concentrations. We run adjusted cox regression models for LPIR with incident T2D (20.4 years median follow-up). RESULTS: Adjusting for demographics, body mass index, life style factors, blood pressure, and T2D family history, the LPIR hazard ratio for T2D (hazard ratio [HR] per standard deviation, 95% confidence interval) was 1.95 (1.85, 2.06). Further adjusting for HbA1c, C-reactive protein, triglycerides, HDL and low-density lipoprotein cholesterol, LPIR HR was attenuated to 1.41 (1.31, 1.53) and had the strongest association with T2D after HbA1C in mutually adjusted models. The association persisted even in those with optimal clinical profiles, adjusted HR per standard deviation 1.91 (1.17, 3.13). In participants deemed at intermediate T2D risk by the Framingham Offspring T2D score, LPIR led to a net reclassification of 0.145 (0.117, 0.175). CONCLUSION: In middle-aged or older healthy women followed prospectively for over 20 years, LPIR was robustly associated with incident T2D, including among those with an optimal clinical metabolic profile. LPIR improved T2D risk classification and may guide early and targeted prevention strategies. PMID- 28733176 TI - A case of surgical delayed sovranastomotic perforation successfully treated with an over-the-scope clip (with video). PMID- 28733177 TI - Transjugular local thrombolysis with/without TIPS in patients with acute non cirrhotic, non-malignant portal vein thrombosis. AB - BACKGROUND & AIMS: Therapeutic anticoagulation is the standard treatment in patients with acute non-cirrhotic portal vein thrombosis (PVT). In critically ill patients, anticoagulation only may not suffice to achive rapid and stable recanalization. This study evaluates efficacy and safety of transjugular interventional therapy in acute non-cirrhotic PVT. METHODS: This retrospective study includes 17 consecutive patients with acute noncirrhotic, non-malignant PVT. Main indication for interventional therapy was imminent intestinal infarction (n=10). Treatment consisted of a combination of transjugular thrombectomy, local fibrinolysis and - depending on thrombus resolution - transjugular intrahepatic portosystemic shunt. RESULTS: Recanalization was successful in 94.1%. One- and two-year secondary PV patency rates were 88.2%. Major complications (n=3) resolved spontaneously in all but one patient (heparin induced thrombocytopenia type 2 with intestinal infarction). Symptoms improved in all patients. However, segmental bowel resection had to be performed in two (11.8%). During a median follow-up of 28.6 months, no patient experienced portal hypertensive complications. Presence of JAK2 V617F mutation predicted both short term and long-term technical success. CONCLUSIONS: Transjugular recanalization is safe and effective in patients with acute non-cirrhotic, non-malignant PVT. It should be considered especially in patients with imminent bowel infarction and low likelihood of recanalization following therapeutic anticoagulation. Patients with JAK2 mutation ought to be followed meticulously. PMID- 28733178 TI - Clinical usefulness of serum antibodies as biomarkers of gastrointestinal and liver diseases. AB - The progressively growing knowledge of the pathophysiology of a number of immune mediated gastrointestinal and liver disorders, including autoimmune atrophic gastritis, coeliac disease, autoimmune enteropathy, inflammatory bowel disease, autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cholangitis and autoimmune pancreatitis, together with the improvement of their detection methods have increased the diagnostic power of serum antibodies. In some cases - coeliac disease and autoimmune atrophic gastritis - they have radically changed gastroenterologists' diagnostic ability, while in others - autoimmune hepatitis, inflammatory bowel disease and autoimmune pancreatitis - their diagnostic performance is still inadequate. Of note, serum antibody misuse in clinical practice has raised a number of controversies, which may generate confusion in the diagnostic management of the aforementioned disorders. In this review, we critically re-evaluate the usefulness of serum antibodies as biomarkers of immune mediated gastrointestinal and liver disorders, and discuss their pitfalls and merits. PMID- 28733180 TI - Association Between Malnutrition and Oral Health in Dutch Nursing Home Residents: Results of the LPZ Study. AB - INTRODUCTION: According to the World Health Organization (WHO) and FDI World Dental Federation (FDI), malnutrition and bad oral health are of great concern to global health, especially among the older population. This study aimed to assess the associations between oral health problems ([artificial] teeth problems, chewing problems, and xerostomia) and malnutrition in residents of somatic and psychogeriatric wards in Dutch nursing homes. METHODS: Data of the cross sectional National Prevalence Measurement of Quality of Care study (Landelijke Prevalentiemeting Zorgproblemen study) in the Netherlands were used to evaluate nutritional status and oral health of 3220 residents, aged 65 or older and living in somatic or psychogeriatric wards in Dutch nursing homes. Cox regression was performed to calculate prevalence ratios (PR) of malnutrition among these residents. RESULTS: Of the total study population, 11.7% were malnourished, 28.6% suffered from xerostomia, 25.6% suffered from chewing problems, and 10.1% experienced problems eating due to (artificial) teeth problems. Within somatic wards, 9.0% were malnourished, whereas 13.2% of residents in psychogeriatric wards were malnourished. Increased risk for malnutrition was found among psychogeriatric residents who had problems with eating due to (artificial) teeth problems (PR 1.6, 95% CI 1.1-2.3). CONCLUSION: Poor oral health, mostly problems with eating due to (artificial) teeth problems, was associated with an almost twofold risk for malnutrition in older residents in Dutch nursing homes and even more so in psychogeriatric residents than in somatic residents. PMID- 28733179 TI - Nurse in patients' health status assessment: Data from a pilot study assessing agreement among nurse and gastroenterologist in computing IBD-clinical scores. AB - INTRODUCTION: Crohn's Disease (CD) and Ulcerative Colitis (UC) are chronic, systemic Inflammatory Bowel Diseases (IBDs) that need a multidisciplinary approach involving not only different medical specialists but also qualified nurses. AIM: We evaluated the concordance between IBD-nurse and physician in computing Clinical Activity Scores in IBD-patients treated with biologics. METHODS: We enrolled all consecutive IBD-patients treated with biologics in two referral centers for IBD-care. For each patient, a gastroenterologist and a nurse blindly filled-out a form to assess the Harvey-Bradshaw Index (HBI) in CD or the partial MAYO score in UC. All data were recorded to assess the beyond chance agreement (concordance) using the k statistic. RESULTS: 87 patients were enrolled. The agreement in all patients by k value was substantial (66%), ranging from moderate to substantial (95% CI from 51% to 80%). The main reason of disagreement was about the scoring of remission versus mild activity, and that of mild versus moderate activity, both in CD and UC. For the HBI, the best agreement was for well-being on the previous day (k 62%) and the least one for abdominal mass (k 35%). CONCLUSIONS: Our study shows an acceptable strength of agreement among nurse and gastroenterologist in evaluating the disease activity of IBD patients through the calculation of clinical scores. PMID- 28733181 TI - Caring for a Person With Dementia on the Margins of Long-Term Care: A Perspective on Burden From 8 European Countries. AB - OBJECTIVES: To explore associations between carer burden and characteristics of (1) the informal carer, (2) the person with dementia, and (3) the care support network in 8 European countries. DESIGN: Cross-sectional study. SETTING: People with dementia judged at risk of admission to long-term care (LTC) facilities in 8 European countries (Estonia, Finland, France, Germany, Netherlands, Spain, Sweden, United Kingdom). PARTICIPANTS: A total of 1223 people with dementia supported by community services at home or receiving day care or respite care and their informal carers. MEASUREMENTS: Variables regarding the informal carer included familial relationship and living situation. Variables relating to the person with dementia included cognitive functioning (S-MMSE), neuropsychiatric symptoms (NPI-Q), depressive symptoms (Cornell depression scale), comorbidity (Charlson Comorbidity Index), and physical functioning (Katz Activity of Daily Living [ADL] Index). The care support network was measured using hours of caregiving (ADLs, instrumental ADLs [IADLs], supervision), additional informal care support, and service receipt (home care, day care). Experience of carer burden was recorded using the Zarit Burden Interview. Logistic regression analysis was used to determine factors associated with high carer burden. RESULTS: Carer burden was highest in Estonia (mean 39.7/88) and lowest in the Netherlands (mean 26.5/88). High burden was significantly associated with characteristics of the informal carer (family relationship, specifically wives or daughters), of the person with dementia (physical dependency in ADLs; neuropsychiatric symptoms, in particular nighttime behaviors and irritability), the care support network (hours of caregiving supervision; receipt of other informal care support) and country of residence. CONCLUSION: A range of factors are associated with burden in informal carers of people with dementia judged to be on the margins of LTC. Support for informal carers needs to take account of gender differences. The dual challenges of distressed behaviors and difficulties in ADLs by the person with dementia may be addressed by specific nonpharmacological interventions focusing on both elements. The potential protective effect of additional informal support to carers highlights the importance of peer support or better targeted home support services. The implementation of appropriate and tailored interventions to reduce burden by supporting informal carers may enable people with dementia to remain at home for longer. PMID- 28733183 TI - Tears of Sorrow: Forgotten or Abandoned. PMID- 28733182 TI - The Association of Depressive Symptoms With Rates of Acute Exacerbations in Patients With COPD: Results From a 3-year Longitudinal Follow-up of the ECLIPSE Cohort. AB - BACKGROUND: Depression increases disability and health care utilization in older patients with chronic obstructive pulmonary disease (COPD). OBJECTIVES: To determine contribution of depressive symptoms to the incidence of moderate-severe and severe acute exacerbations of COPD (AECOPD) over 3 years. DESIGN: We analyzed data collected from a prospective cohort of patients with COPD (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints; ECLIPSE). SETTING: Multicentered outpatient. PARTICIPANTS: A total of 2059 patients with COPD with complete data (63.7% men, mean age 63.4 + 7.1 years). MEASUREMENTS: Depression was assessed using the Center for Epidemiologic Studies Depression Scale (CES-D). Moderate-severe AECOPDs were collected; a subset of very severe AECOPD was defined as requiring hospital admission. RESULTS: A total of 540 (26%) patients with COPD reported high depressive symptoms (CES-D >=16). High depressive symptoms at baseline related to an increased risk of moderate-severe and severe AECOPD during the follow-up (odds ratio [OR] 1.18; 95% confidence interval [CI] 1.07-1.30; for moderate-severe and OR 1.36; 95% CI 1.09-1.69 for severe events risk of hospitalizations) independent of key covariates of an AECOPD history before recruitment in the study, history of gastroesophageal reflux, baseline severity of airflow limitation, and white blood cell count that were also associated with an increased risk of moderate to severe exacerbations (all P < .001). CONCLUSION: Presence of high depressive symptoms at baseline were associated with subsequent moderate-severe exacerbations and hospital admissions in patients with COPD over 3 years, independent of a history of exacerbations and other demographic and clinical factors. Targeted personalized medicine that focuses both on AECOPD risk and depression may be a step forward to improving prognosis of patients with COPD. PMID- 28733184 TI - Medication Use and Its Potential Impact on the Oral Health Status of Nursing Home Residents in Flanders (Belgium). AB - BACKGROUND: Polypharmacy is considered the most important etiologic factor of hyposalivation, which in turn can initiate oral health problems. OBJECTIVES: To describe the medication use of nursing home residents, to identify the medications related to hyposalivation and to find possible associations between the different classes of medication, the number of medications, and the oral health status of the residents. DESIGN: A cross-sectional study. PARTICIPANTS: The study population consisted of the residents of a nonrandom sample of 23 nursing homes from 2 Belgian provinces, belonging to the oral health care network Gerodent. All residents of the sample visited the Gerodent mobile dental clinic between October 2010 and April 2012. MEASUREMENTS: For each resident, oral health data, demographic data, and an overview of the total medication intake were collected. RESULTS: The study sample consisted of 1226 nursing home residents with a mean age of 83.9 years [standard deviation (SD) 8.5]. The mean number of medications per person was 9.0 (SD 3.6, range 0-23, median 9.0). Of all prescribed medication, 49.6% had a potential hyposalivatory effect with a mean number per person of 4.5 (SD 2.2, range 0-15, median 4.0). In the bivariate analyses, associations were found between medication use and oral health of residents with natural teeth: the higher the number of medications (with risk of dry mouth) and the overall risk of medication-related dry mouth, the lower the number of natural teeth (P = .022, P = .005, and P = .017, respectively). In contrast, the total treatment need tended to decrease with rising medication intake, resulting in a clear increase of the treatment index with rising medication intake (P = .003, P < .001 and P = .002). The logistic regression model analysis confirmed that the proportion of carious teeth diminished and the treatment index increased in case of rising medication intake, especially when considering the number of medications with a risk of dry mouth and the overall risk of medication-related dry mouth. A possible explanation for this trend might be the finding that in the group with a high medication use, the teeth most sensitive to caries and plaque retention could already have been extracted at the moment of screening for the study, because of a lifelong history of caries pathology. CONCLUSIONS: This study shows a high level of medication use, including the substantial intake of medication with a possible hyposalivatory effect. Moreover, clear associations were found between the medication intake and the oral status of the residents. PMID- 28733185 TI - FDG-PET parameters as predictors of pathologic response and nodal clearance in patients with stage III non-small cell lung cancer receiving neoadjuvant chemoradiation and surgery. AB - OBJECTIVE: Pathologic complete response (pCR) following neoadjuvant chemoradiation (CRT) is associated with improved outcomes in stage III non-small cell lung cancer. Conflicting results exist regarding the value of 18F fluorodeoxyglucose positron emission tomography (FDG-PET) in predicting pCR. This study evaluated the association between post-CRT FDG-PET and pCR using novel FDG PET parameters. METHODS AND MATERIALS: This retrospective study included patients treated with CRT and resection. All underwent pre- and post-CRT FDG-PET imaging. Maximum standard uptake value (SUVmax), standard uptake ratio (SUR), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were measured. RESULTS: In total, 44 patients were included for review. The majority had cT2 disease (59.0%). Median radiation dose was 60 Gy (45-70.2 Gy). Rate of pCR and near-pCR within the primary lesion was 29.5% and 45.5%, respectively. Average reduction in SUVmax was 9.2, whereas SUR normalized to mediastinum and liver showed mean reductions of 4.7 and 3.5, respectively. No association was found between pCR and either MTV or TLG. Reduction in SUVmax and SUR were significantly associated with increased rate of pCR (P <= .02). A threshold of >75% decrease in SUR-liver showed significant association with near-pCR (diagnostic odds ratio [DOR]: 8.3; P = .007). No correlation was found between nodal FDG-PET parameters and nodal pCR. CONCLUSIONS: Our results indicate SUV and SUR have utility in predicting pCR after neoadjuvant CRT. SUR parameters trended toward higher DORs, suggesting improved predictive utility compared with SUVmax. Notably, no association was found with nodal pCR. Furthermore, MTV and TLG changes were not predictive, potentially resulting from inflammation after full-dose radiation, but this warrants further investigation. PMID- 28733186 TI - EASIX in patients with acute graft-versus-host disease: a retrospective cohort analysis. AB - BACKGROUND: Endothelial dysfunction links thrombotic microangiopathy to steroid refractory graft-versus-host disease (GVHD) after allogeneic stem-cell transplantation. We aimed to assess if the simple formula-lactate dehydrogenase (U/L) * creatinine (mg/dL)/thrombocytes (109 cells per L)-termed the Endothelial Activation and Stress Index (EASIX), might be valuable for the prediction of death in patients with acute GVHD after allogeneic stem-cell transplantation. METHODS: For this retrospective analysis, we analysed a training cohort (in Germany) and three validation cohorts (in Germany and the USA) of patients with acute GVHD who had received consecutive allogeneic stem-cell transplantation. The primary endpoint was prediction of overall survival when measured at acute GVHD onset (EASIX-GVHD). We validated the prognostic strength of EASIX-GVHD for overall survival and non-relapse mortality in the three independent cohorts by calculating the prediction error (integrated Brier score), and concordance index. FINDINGS: In the total cohort of patients with acute GVHD (n=311), EASIX-GVHD predicted overall survival in univariable and multivariable models (univariate analysis, hazard ratio [HR] for a one-fold increase 1.16, 95% CI 1.12-1.20, p=0.0004). However, in the subpopulation of patients with myeloablative conditioning (n=72), EASIX-GVHD did not predict overall survival, which is probably attributable to thrombocytopenia at GVHD onset (73 * 109 cells per L [IQR 29.75-180.00] for myeloablative conditioning vs 160 * 109 cells per L [90.0 250.5] for reduced-intensity conditioning; p<0.0001). In patients who received reduced-intensity conditioning (n=239), EASIX-GVHD was a strong predictor of overall survival (HR for a two-fold change of 1.23, 95% CI 1.13-1.34; p<0.0001) and non-relapse mortality (cause-specific HR for a two-fold change of 1.24, 1.12 1.38; p<0.0001). Model validation for prediction of overall survival and non relapse mortality by EASIX-GVHD was successful in two independent cohorts of adult patients with reduced-intensity conditioning (n=141, n=173) and in a cohort with mainly paediatric patients (n=89). INTERPRETATION: In patients with reduced intensity conditioning, EASIX-GVHD is a powerful predictor of survival after GVHD. EASIX-GVHD could be the future basis for development of risk-adapted GVHD treatment strategies. FUNDING: There was no external funding source for this study. PMID- 28733187 TI - A confidence building exercise in data and identifiability: Modeling cancer chemotherapy as a case study. AB - Mathematical modeling has a long history in the field of cancer therapeutics, and there is increasing recognition that it can help uncover the mechanisms that underlie tumor response to treatment. However, making quantitative predictions with such models often requires parameter estimation from data, raising questions of parameter identifiability and estimability. Even in the case of structural (theoretical) identifiability, imperfect data and the resulting practical unidentifiability of model parameters can make it difficult to infer the desired information, and in some cases, to yield biologically correct inferences and predictions. Here, we examine parameter identifiability and estimability using a case study of two compartmental, ordinary differential equation models of cancer treatment with drugs that are cell cycle-specific (taxol) as well as non-specific (oxaliplatin). We proceed through model building, structural identifiability analysis, parameter estimation, practical identifiability analysis and its biological implications, as well as alternative data collection protocols and experimental designs that render the model identifiable. We use the differential algebra/input-output relationship approach for structural identifiability, and primarily the profile likelihood approach for practical identifiability. Despite the models being structurally identifiable, we show that without consideration of practical identifiability, incorrect cell cycle distributions can be inferred, that would result in suboptimal therapeutic choices. We illustrate the usefulness of estimating practically identifiable combinations (in addition to the more typically considered structurally identifiable combinations) in generating biologically meaningful insights. We also use simulated data to evaluate how the practical identifiability of the model would change under alternative experimental designs. These results highlight the importance of understanding the underlying mechanisms rather than purely using parsimony or information criteria/goodness-of-fit to decide model selection questions. The overall roadmap for identifiability testing laid out here can be used to help provide mechanistic insight into complex biological phenomena, reduce experimental costs, and optimize model-driven experimentation. PMID- 28733188 TI - Assay Stability, the missing component of the Error Budget. AB - Gaining a better understanding of Quality Control (QC) processes is a key requirement to improving performance and reducing patient risk. Detecting analytical error is dependent on a QC strategy that reliably detects a critical shift in a result away from the true value. Recently the concept of Six Sigma has been used by diagnostic laboratories to assess the performance of assays and to assist in the selection of QC rules. The sigma metric is one measure of an assay's ability to perform within specification. However an additional dimension to managing an assay is its stability in bias over time. The concept of long term stability is the same as measured QC drift (SEdrift) which is the effect of numerous calibrations, changes in reagent lots and other conditions i.e. a long term effect. This implies that the standard error budget is wrong because it is modelled on short term QC and misses this SEdrift stability component. We show that SEdrift provides a measure of Assay Stability that should be included in Quality Planning and that by including an allowance for this drift, determining target imprecision appropriate for matched QC algorithms that provide high error detection is as simple as dividing the Allowable Performance Specification by 4, 5 or 6. PMID- 28733189 TI - Systematic review of serum steroid reference intervals developed using mass spectrometry. AB - The aim of this study was to perform a systematic review of the published literature to determine the available serum/plasma steroid reference intervals generated by mass spectrometry (MS) methods across all age groups in healthy subjects and to suggest recommendations to achieve common MS based reference intervals for serum steroids. MEDLINE, EMBASE and PubMed databases were used to conduct a comprehensive search for English language, MS-based reference interval studies for serum/plasma steroids. Selection of steroids to include was based on those listed in the Royal College of Pathologists of Australasia Quality Assurance Programs, Chemical Pathology, Endocrine Program. This methodology has been registered onto the PROSPERO International prospective register of systematic reviews (ID number: CRD42015029637). After accounting for duplicates, a total of 60 manuscripts were identified through the search strategy. Following critical evaluation, a total of 16 studies were selected. Of the 16 studies, 12 reported reference intervals for testosterone, 11 for 17 hydroxy-progesterone, nine for androstenedione, six for cortisol, three for progesterone, two for dihydrotestosterone and only one for aldosterone and dehydroepiandrosterone sulphate. No studies established MS-based reference intervals for oestradiol. As far as we are aware, this report provides the first comparison of the peer reviewed literature for serum/plasma steroid reference intervals generated by MS based methods. The reference intervals based on these published studies can be used to inform the process to develop common reference intervals, and agreed reporting units for mass spectrometry based steroid methods. PMID- 28733190 TI - Reference interval estimation: Methodological comparison using extensive simulations and empirical data. AB - OBJECTIVE: To statistically compare and evaluate commonly used methods of estimating reference intervals and to determine which method is best based on characteristics of the distribution of various data sets. DESIGN AND METHODS: Three approaches for estimating reference intervals, i.e. parametric, non parametric, and robust, were compared with simulated Gaussian and non-Gaussian data. The hierarchy of the performances of each method was examined based on bias and measures of precision. The findings of the simulation study were illustrated through real data sets. RESULTS: In all Gaussian scenarios, the parametric approach provided the least biased and most precise estimates. In non-Gaussian scenarios, no single method provided the least biased and most precise estimates for both limits of a reference interval across all sample sizes, although the non parametric approach performed the best for most scenarios. The hierarchy of the performances of the three methods was only impacted by sample size and skewness. Differences between reference interval estimates established by the three methods were inflated by variability. CONCLUSIONS: Whenever possible, laboratories should attempt to transform data to a Gaussian distribution and use the parametric approach to obtain the most optimal reference intervals. When this is not possible, laboratories should consider sample size and skewness as factors in their choice of reference interval estimation method. The consequences of false positives or false negatives may also serve as factors in this decision. PMID- 28733191 TI - Ethnomedicobotanical study of indigenous knowledge on medicinal plants used for the treatment of reproductive problems in Nalbari district, Assam, India. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Reproductive problems are becoming the most predominant health care problems in many countries. World Health Organization (WHO), in 2012, also exemplified maternal illnesses, for instance, birth asphyxia and post birth difficulties are rising at an alarming rate. In addition, not all abnormalities of the human reproductive system have the same origin; the effects of reproductive problems would likely been affected by both male and female. For easy accessibility and affordability, medicinal plants are playing crucial role in primary healthcare services in India and their use is moreover, an integral part of the cultural heritage. However, our growing understanding of the human reproductive problems are segregated and scanty for herbal medications. AIM OF THE STUDY: To document the local name of the medicinal plants used by both male and female from indigenous knowledge for the treatment of reproductive ailments and to explore their biological and pharmacological confirmation and to address the class of secondary metabolites present therein. MATERIALS AND METHODS: The results stem in September 2015-April 2016 from an array of informations that were collected by direct interviews of the traditional medicinal practitioners in three villages, viz. Jaha, Niz-Bahjani and Madhupur of the southern Nalbari district, Assam. Both semi-structured and open-ended interview schedule was carried out with purposively selected individuals and focus group discussion (FGD) in the three selected sites for this study. Systematic analysis of fidelity level percentage (FL %), preference ranking percentage (PR %) and formulation scoring (FS) were calculated. Electronic databases such as Google, Google Scholar, and ScienceDirect were also been used to search existing pharmacological citations. Finally, qualitative chemical profiling were executed for the plants whose PR % scores >= 65. RESULTS: A total of 71 plant species belonging to 48 families and 64 genera are reported to be used for the treatment of several reproductive problems such as, infertility in male, impotence, erectile dysfunctioning, retrograde ejaculation and sexual potency in men and in women, aphrodisiac, metrorrhagia, infertility, dysmenorrhea and/or post birth difficulties under mono (57), di (17) and poly (8) herbal formulations. Herbs (40.85%) were reported as the most common lifeform, whereas leaves (22.54%) and the roots (22.54%) were the commonly used plant parts against different ailments. Extracts of Abroma augusta L. (stem) (FL: 66.67%, PR: IM-77.33%, L-65.33, FS: 2), Morinda angustifolia Roxb. (bark) (FL: 64.29%, PR: L-68%, FS: 1), Hodgsonia heteroclita Roxb. (fruit) (FL: 63.64%, PR: IF-65.33, FS: 0.25) and Hibiscus mutabilis L. (stem) (FL: 40%, PR: IM-68%, IIM: 65.33%, IML-68%, FS: 2) were than selected for further phytochemical analysis. CONCLUSIONS: Of the 71 plants used for reproductive management system, the highest number of plants were used for the treatment of irregular menstruation (22) followed by infertility (in both men and women) (19), vaginal disorder and leucorrhoea (9) and sexual potency (8). The qualitative chemical profiling have demonstrated the presence of alkaloids, carbohydrates, phenolic compounds, flavonoids and phytosterols, in maximum concentrations. Additionally, these data may be the most important resource for the new discovery of many bioactive principles. PMID- 28733192 TI - Pharmacological evaluation of phytochemicals from South Indian Black Turmeric (Curcuma caesia Roxb.) to target cancer apoptosis. AB - Curcuma caesia Roxb. (Black turmeric), a perennial herb of the family Zingiberaceae is indigenous to India. C. caesia is used as a spice, food preservative and coloring agent commonly in the Indian subcontinent. Functional parametric pharmacological evaluations like drug ability and toxicity profile of this endangered species is poorly documented. In our present study, among all the extracts of dried C. caesia rhizome viz- hexane, ethyl acetate, methanol and water tested for free radical scavenging capacity by total antioxidant activity (TAO) method, Hexane Rhizome Extract (HRE) was found to possess remarkable activity (1200mg ascorbic acid equivalent/100g). In MTT assay across three cancer cell lines and a control cell line, HRE exhibited a dose-dependent inhibition only in cancer cells, with notable activity in HepG2 cell lines (IC50: 0976ug/mL). Further, western blotting and flow cytometry experiments proved that HRE induces cell arrest at G2/M phase along with cellular apoptosis as suggestive by multiple-point mitochondrial mediated intrinsic pathway of Programmed Cell Death (PCD). Gas Chromatography-Mass Spectrophotometry (GC-MS) analysis of HRE suggested twenty compounds that when docked in silico with Tubulin (1SA0) and Epidermal Growth Factor Receptor/ EGFR (1XKK) showed very intimate binding with the original ligands. Our results provided significant evidence of the toxicity mechanisms of HRE that may be beneficial for more rational applications of drug discovery for slowing down cancer progression. PMID- 28733193 TI - Traditional neurotherapeutics approach intended for direct nose to brain delivery. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Nasal delivery systems have a significant role in Persian traditional medicine. Most of them were utilized for central nervous system (CNS)-related disorders. In modern medicine, nasal drug delivery systems for brain delivery are highly regarded. AIM OF THE STUDY: Despite recent advances in drug delivery to the (CNS), delivery of therapeutics to the brain remains a major challenge because of the blood brain barrier (BBB). There are several mechanisms which regulate the drug transfer across the BBB. Local administration methods of therapeutic agents are often associated with adverse events, while the intranasal pathway has been suggested as a non-invasive alternative route to deliver drugs to the brain. This route can bypass the BBB and deliver drug molecules directly to the CNS. There are different nasal formulations have been addressed in Persian traditional pharmacopeias. The present review attempt to explore the famous and practical Qarabadin to find ancient nasal dosage forms. MATERIALS AND METHODS: With an explore on traditional herbs in google scholar, scopus and science direct, we have found some original and review articles which have demonstrated our findings on the use of traditional herbs for CNS disorders. Four encyclopedia of multi-component formulations, including Qarabadin Salehi (1766), Qarabadin kabir (1781),Qarabadin Ghaderi (18th century), and Qarabadin Azam (1853), were searched for nasal formulations having CNS-related indications. Formulations were categorized based on dosage forms, and also, diseases which they were suggested for. While the names of illnesses were in ancient terminology of Traditional Medicine, they were translated to modern medical terminology by comparing their definitions, signs, and symptoms from two medical systems. Typical samples of each dosage form have been mentioned with details like amount of ingredients, scientific names of plants, and considerations pertaining to preparation or usage. RESULTS: Among all traditional nasal formulations, seven types were found that is used for sicknesses relating to CNS including Saoot, Nafookh, Atoos, Nashoogh, Shamoom, Lakhlakheh, and Bakhoor. CONCLUSIONS: The findings of this study reveal the physicochemical characteristics of each formulation, route of administration, and type of disease which they are suitable and also present some famous formulations. PMID- 28733194 TI - Breast Cancer Molecular Stratification: From Intrinsic Subtypes to Integrative Clusters. AB - Breast carcinomas can be stratified into different entities based on clinical behavior, histologic features, and/or by biological properties. A classification of breast cancer should be based on underlying biology, which we know must be determined by the somatic genomic landscape of mutations. Moreover, because the latest generations of anticancer agents are founded on biological mechanisms, a detailed molecular stratification is a requirement for appropriate clinical management. Such stratification, based on genomic drivers, will be important for selecting patients for clinical trials. It will also facilitate the discovery of novel drivers, the study of tumor evolution, and the identification of mechanisms of treatment resistance. Assays for risk stratification have focused mainly on response prediction to existing treatment regimens. Molecular stratification based on gene expression profiling revealed that breast cancers could be classified in so-called intrinsic subtypes (luminal A and B, HER2-enriched, basal like, and normal-like), which mostly corresponded to hormone receptor and HER2 status, and further stratified luminal tumors based on proliferation. The realization that a significant proportion of the gene expression landscape is determined by the somatic copy number alterations that drive expression in cis led to the newer classification of breast cancers into integrative clusters. This stratification of breast cancers into integrative clusters reveals prototypical patterns of single-nucleotide variants and is associated with distinct clinical courses and response to therapy. PMID- 28733195 TI - The Evolving Role of Companion Diagnostics for Breast Cancer in an Era of Next Generation Omics. AB - A companion diagnostic is a test for a specific biomarker-approved by the United States Food and Drug Administration-qualifying a patient to receive a specific, associated therapy. As interest has grown in precision medicine over the past decade, the principle of companion diagnostics has gained increasing purchase among laboratory professionals, clinicians, regulators, and even patients. The evolution of the biomarkers used to stratify and treat breast cancer illustrates the history of companion diagnostics and provides a lens through which to examine potential challenges. As new targeted therapies and corresponding biomarkers accumulate, algorithms for diagnosis and treatment necessarily become lengthier and more complex. To accommodate future needs of breast cancer patients, the companion diagnostic model will continue to adapt and evolve. PMID- 28733196 TI - Proteasome Subunit Beta Type 1 P11A Polymorphism Is a New Prognostic Marker in Multiple Myeloma. AB - BACKGROUND: Proteasome subunit beta type 1 (PSMB1) rs12717 polymorphism, a single nucleotide polymorphism with unknown functional effect, was recently reported to influence response to bortezomib-based therapy in follicular lymphoma. PATIENTS AND METHODS: We retrospectively analyzed the prognostic impact of this polymorphism in 211 consecutively diagnosed multiple myeloma cases, and performed in vitro experiments to look into its functional consequences. RESULTS: On univariate analysis, patients carrying the variant G allele showed significantly shorter progression-free survival (PFS) with a pattern suggestive of a gene-dose effect (PFS 26.4, 22.3, and 16.4 months in C/C, C/G, and G/G patients, respectively, P = .002). On multivariate analysis, carrying the G/G genotype was a significant independent risk factor for relapse (hazard ratio [HR] 2.29, P < .001) with a similar trend in C/G carriers (HR 1.33, P = .097) when compared with the major allele carrier C/C cohort. Our subsequent in vitro analyses demonstrated significantly reduced protease activity in proteasomes of individuals with G/G genotype compared with that of C/C carriers, despite that PSMB1 expression and proteasome assembly remained unaltered. Bortezomib exhibited a lower inhibitory capacity on the caspase- and trypsin-like activity of proteasomes from G/G individuals. CONCLUSION: Our results show that carriership of PSMB1 rs12717 minor allele is predictive for suboptimal response with bortezomib treatment, which could be explained by less active proteasomes that are less sensitive to bortezomib, and myeloma cells consequently relying on other escape mechanisms to cope with the abundance of misfolded proteins. PMID- 28733197 TI - Extrafollicular PD1 and Intrafollicular CD3 Expression Are Associated With Survival in Follicular Lymphoma. AB - INTRODUCTION: Both microenvironment and tumor biomarkers impact outcome in follicular lymphoma (FL). We aimed to study the effect of Ki-67, CD3, CD68, and PD1 expression on outcome of FL. MATERIALS AND METHODS: Forty-eight patients were included. Stained slides were visually assessed and marker expression was correlated with outcome. Both intra- and extrafollicular expression of Ki-67, CD68, and PD1 were evaluated. CD3 was evaluated only in the intrafollicular area. The median values of expression served as a cutoff point for low- and high expression groups. RESULTS: High extrafollicular PD1 expression predicted superior FFTF (freedom from treatment failure) compared with low expression (5 year 52% vs. 44%, P = .04). Five-year FFTF markedly increased from 37% to 67% (P = .057) in patients with low intrafollicular CD3 expression. CONCLUSION: Our study supports the hypothesis that survival in FL depends on the immunologic cross talk between malignant cells and microenvironment; however, the specific types of cells that influence the clinical behavior of FL are still unknown. PMID- 28733198 TI - The role of intrinsic disorder and dynamics in the assembly and function of the type II secretion system. AB - Many Gram-negative commensal and pathogenic bacteria use a type II secretion system (T2SS) to transport proteins out of the cell. These exported proteins or substrates play a major role in toxin delivery, maintaining biofilms, replication in the host and subversion of host immune responses to infection. We review the current structural and functional work on this system and argue that intrinsically disordered regions and protein dynamics are central for assembly, exo-protein recognition, and secretion competence of the T2SS. The central role of intrinsic disorder-order transitions in these processes may be a particular feature of type II secretion. PMID- 28733199 TI - Robust, highly customizable, and economical multi-channel electrode for chronic multi-unit recording in behaving animals. AB - Multi-unit recording has been one of the most widely used techniques to investigate the correlation between multiple neuronal activities and behavior. However, a common problem of currently used multi-channel electrodes is their physical weakness. In this study, we developed a novel multi-channel electrode with sufficient physical strength to penetrate a thickened dura mater. This electrode consists of low-cost materials and is easily fabricated, and it enables recording without removing dura mater, thereby reducing the risk of inflammation, infection, or brain herniation. The low-cost multi-channel electrode developed in this study would be a useful tool for chronic recording in behaving animals. PMID- 28733200 TI - Hypothermic Cooling Measured by Thermal Magnetic Resonance Imaging; Feasibility and Implications for Virtual Imaging in the Urogenital Pelvis. AB - OBJECTIVE: To study the combination of thermal magnetic resonance imaging (MRI) and novel hypothermic cooling, via an endorectal cooling balloon (ECB), to assess the effective dispersion and temperature drop in pelvic tissue to potentially reduce inflammatory cascade in surgical applications. METHODS: Three male subjects, before undergoing robot-assisted radical prostatectomy, were cooled via an ECB, rendered MRI compatible for patient safety before ECB hypothermia. MRI studies were performed using a 3T scanner and included T2-weighted anatomic scan for the pelvic structures, followed by a temperature mapping scan. The sequence was performed repeatedly during the cooling experiment, whereas the phase data were collected using an integrated MR-high-intensity focused ultrasound workstation in real time. Pelvic cooling was instituted with a cooling console located outside the MRI magnet room. RESULTS: The feasibility of pelvic cooling measured a temperature drop of the ECB of 20-25 degrees in real time was achieved after an initial time delay of 10-15 seconds for the ECB to cool. The thermal MRI anatomic images of the prostate and neurovascular bundle demonstrate cooling at this interface to be 10-15 degrees, and also that cooling extends into the prostate itself ~5 degrees, and disperses into the pelvic region as well. CONCLUSION: An MRI-compatible ECB coupled with thermal MRI is a feasible method to assess effective hypothermic diffusion and saturation to pelvic structures. By inference, hypothermia-induced rectal cooling could potentially reduce inflammation, scarring, and fistula in radical prostatectomy, as well as other urologic tissue procedures of high-intensity focused ultrasound, external beam radiation therapy, radioactive seed implants, transurethral microwave therapy, and transurethral resection of the prostate. PMID- 28733201 TI - Prone Percutaneous Nephrolithotomy: Does Bolster Orientation Matter? AB - OBJECTIVE: To assess whether horizontal vs vertical bolster orientation affects kidney position during prone percutaneous nephrolithotomy as this could impact the need for supracostal access and therefore the likelihood of pleural injury. MATERIALS AND METHODS: In a prospective trial, 10 subjects with 20 renal units underwent magnetic resonance imaging in prone position with standard cylindrical bolsters oriented vertically and then horizontally. Vertical bolsters were placed along the lateral aspect of the chest. Horizontal bolsters were placed at the xiphoid and symphysis pubis. The position of the kidney relative to the pleura was assessed by measuring distances from the kidney upper pole to diaphragm, to the top of the first lumbar vertebra, and inferior-most rib. Nephrostomy tract length and tract proximity to adjacent organs were also measured. RESULTS: Right and left kidney-to-diaphragm distance significantly increased with horizontal vs vertical bolsters by 3.44 cm and 1.86 cm, respectively (P = .02, P = .01). Right kidney-to-rib distance significantly increased by 2.4 cm (P = .025); left kidney to-rib distance increased by 0.5 cm (P = .123). Right kidney-to-vertebral distance significantly increased by 2.16 cm (P = .007); left kidney-to-vertebral distance increased by 0.9 cm (P = .059). There was no significant difference in maximum access angle, overall tract length, or colon position between horizontal and vertical bolsters. CONCLUSION: Orienting bolsters horizontally results in caudal kidney displacement without affecting access angle, overall tract length, or colon position. In comparison with vertical orientation, this may improve safety of percutaneous nephrolithotomy by decreasing the need for supracostal access and increasing the safety of supracostal access when required. PMID- 28733202 TI - Vgamma4 gammadelta T Cells Provide an Early Source of IL-17A and Accelerate Skin Graft Rejection. AB - Activated gammadelta T cells have been shown to accelerate allograft rejection. However, the precise role of skin-resident gammadelta T cells and their subsets Vgamma5 (epidermis), Vgamma1, and Vgamma4 (dermis)-in skin graft rejection have not been identified. Here, using a male to female skin transplantation model, we demonstrated that Vgamma4 T cells, rather than Vgamma1 or Vgamma5 T cells, accelerated skin graft rejection and that IL-17A was essential for Vgamma4 T-cell mediated skin graft rejection. Moreover, we found that Vgamma4 T cells were required for early IL-17A production in the transplanted area, both in skin grafts and in the host epidermis around grafts. Additionally, the chemokine (C-C motif) ligand 20-chemokine receptor 6 pathway was essential for recruitment of Vgamma4 T cells to the transplantation area, whereas both IL-1beta and IL-23 induced IL-17A production from infiltrating cells. Lastly, Vgamma4 T-cell-derived IL-17A promoted the accumulation of mature dendritic cells in draining lymph nodes to subsequently regulate alphabeta T-cell function after skin graft transplantation. Taken together, our data reveal that Vgamma4 T cells accelerate skin graft rejection by providing an early source of IL-17A. PMID- 28733203 TI - In silico pharmacogenetic approach: The natalizumab case study. AB - Natalizumab is a humanized monoclonal antibody to alpha4beta1 integrin and is approved for the treatment of Multiple Sclerosis. In patients there is a great variation in drug response and there is much evidence that genetic contributors play an important role in defining an individual's susceptibility. Natalizumab binds to alpha4-residues Gln-152, Lys-201, Lys256, and these seem to be essential for its activity. Studies on a range of species in disease model have showed a loss of reactivity when any one of those three residues were different to human. Based on these animal studies, we thought that the single nucleotide polymorphism in the ITGA4 human gene causing a lysine to arginine transversion at amino acid position 256 require further investigations in the context of individual drug susceptibility. So, the aim of our study was to investigate the association between this genetic polymorphism and the resistance to natalizumab. We had applied molecular dynamics simulation to study the possible conformational changes induced by Lys256Arg transversion on the overall structure of integrin and we have analyzed the binding affinities of natalizumab in the non-mutated and mutated structures through HINT score. We found that this SNP does not affect the VLA4-natalizumab interaction. Instead, the binding affinities are slightly higher in the mutated complex than in the wild-type. We reported one of the first work in which MD simulation was applied in the pharmacogenetic context, and this approach is rapid and cost effective, since a population survey is carried out only after the positive prediction of simulation. PMID- 28733204 TI - The polymorphism XRCC1 Arg194Trp and 8-hydroxydeoxyguanosine increased susceptibility to arsenic-related renal cell carcinoma. AB - This study was designed to explore the relationship between X-ray repair cross complementing group 1 (XRCC1) gene polymorphisms and renal cell carcinoma (RCC) and to investigate whether individuals with an XRCC1 risk genotype, a high level of 8-OHdG or a high urinary total arsenic concentration have a modified odds ratio (OR) of RCC. We recruited 180 RCC patients and 360 age- and sex-matched controls from a hospital-based pool. Image-guided biopsy or surgical resection of renal tumors was performed on RCC patients for pathological verification. Genomic DNA was used to examine the genotype of XRCC1(Arg399Gln), XRCC1(Arg194Trp), XRCC3(Thr241Met) and XPD(Lys751Gln) by PCR-RFLP. Liquid chromatography with tandem mass spectrometry was used to determine urinary 8-OHdG levels. A HPLC-HG AAS was used to determine the concentrations of urinary arsenic species. Participants with the genotype XRCC1(Arg194Trp) Arg/Trp+Trp/Trp had a significantly higher OR of RCC than those with the Arg/Arg genotype; the OR and 95% confidence interval was 0.66 (0.45-0.97) after multivariate adjustment. The OR of RCC for the combined effect of high urinary 8-OHdG levels and high urinary total arsenic concentration in individuals with a XRCC1(Arg194Trp) Arg/Trp+Trp/Trp genotype was higher than in patients with an Arg/Arg genotype, which was evident in a dose response manner. In conclusion, this is the first study to show that the XRCC1 Arg194 allele is a predicting factor for RCC. The more risk factors (high urinary 8-OHdG levels, high urinary total arsenic concentrations, and XRCC1 Arg194 allele) that were present, the higher the OR of RCC. PMID- 28733205 TI - (+)-Dehydrofukinone modulates membrane potential and delays seizure onset by GABAa receptor-mediated mechanism in mice. AB - (+)-Dehydrofukinone (DHF), isolated from Nectandra grandiflora (Lauraceae) essential oil, induces sedation and anesthesia by modulation of GABAa receptors. However, no study has addressed whether DHF modulates other cellular events involved in the control of cellular excitability, such as seizure behavior. Therefore, the aim of the present study was to investigate the effect of DHF on cellular excitability and seizure behavior in mice. For this purpose, we used isolated nerve terminals (synaptosomes) to examine the effect of DHF on the plasma membrane potential, the involvement of GABAa receptors and the downstream activation of Ca2+ mobilization. Finally, we performed an in vivo assay in order to verify whether DHF could impact on seizures induced by pentylenetetrazole (PTZ) in mice. The results showed that DHF induced a GABA-dependent sustained hyperpolarization, sensitive to flumazenil and absent in low-[Cl-] medium. Additionally, (1-100MUM) DHF decreased KCl-evoked calcium mobilization over time in a concentration-dependent manner and this effect was prevented by flumazenil. DHF increased the latency to myoclonic jerks (10mg/kg), delayed the onset of generalized tonic-clonic seizures (10, 30 and 100mg/kg), and these effects were also blocked by the pretreatment with flumazenil. Our data indicate that DHF has anticonvulsant properties and the molecular target underlying this effect is likely to be the facilitation of GABAergic neuronal inhibition. The present study highlights the therapeutic potential of the natural compound DHF as a suppressor of neuronal excitability. PMID- 28733206 TI - Omics-based identification of the combined effects of idiosyncratic drugs and inflammatory cytokines on the development of drug-induced liver injury. AB - The mechanisms of idiosyncratic drug-induced hepatotoxicity remain largely unclear. It has demonstrated that the drug idiosyncrasy is potentiated in the context of inflammation and intracellular ceramides may play a role in this process. To study the mechanisms, HepG2 cells were co-treated with high and low doses of three idiosyncratic (I) and three non-idiosyncratic (N) compounds, with (I+ and N+) or without (I- and N-) a cytokine mix. Microarray, lipidomics and flow cytometry were performed to investigate the genome-wide expression patterns, the intracellular ceramide levels and the induction of apoptosis. We found that all I+ treatments significantly influenced the immune response- and response to stimulus-associated gene ontology (GO) terms, but the induction of apoptotic pathways, which was confirmed by flow cytometry, only appeared to be induced after the high-dose treatment. The ceramide signaling-, ER stress-, NF-kB activation- and mitochondrial activity-related pathways were biologically involved in apoptosis induced by the high-dose I+. Additionally, genes participating in ceramide metabolism were significantly altered resulting in a measurable increase in ceramide levels. The increases in ceramide concentrations may induce ER stress and activate the JNK pathway by affecting the expression of the related genes, and eventually trigger the mitochondria-independent apoptosis in hepatocytes. Overall, our study provides a potential mechanism to explain the role of inflammation in idiosyncratic drug reactions. PMID- 28733207 TI - UPLC-Q-TOF/MS-based urine and plasma metabonomics study on the ameliorative effects of aspirin eugenol ester in hyperlipidemia rats. AB - The main objective of this study was to investigate the ameliorative effects of aspirin eugenol ester (AEE) in hyperlipidemic rat. After five-week oral administration of AEE in high fat diet (HFD)-induced hyperlipidemic rats, the impact of AEE on plasma and urine metabonomics was investigated to explore the underlying mechanism by UPLC-Q-TOF/MS analysis. Blood lipid levels and histopathological changes of liver, stomach and duodenum were also evaluated after AEE treatment. Without obvious gastrointestinal (GI) side effects, AEE significantly relieved fatty degeneration of liver and reduced triglyceride (TG), low density lipoprotein (LDL) and total cholesterol (TCH) (P<0.01). Clear separations of metabolic profiles were observed among control, model and AEE groups by using principal component analysis (PCA) and orthogonal partial least squares-discriminate analysis (OPLS-DA). 16 endogenous metabolites in plasma and 18 endogenous metabolites in urine involved in glycerophospholipid metabolism, fatty acid metabolism, fatty acid beta-oxidation, amino acid metabolism, TCA cycle, sphingolipid metabolism, gut microflora and pyrimidine metabolism were considered as potential biomarkers of hyperlipidemia and be regulated by AEE administration. It might be concluded that AEE was a promising drug candidate for hyperlipidemia treatment. These findings could contribute to the understanding of action mechanisms of AEE and provide evidence for further studies. PMID- 28733208 TI - Influence of cued-fear conditioning and its impairment on NREM sleep. AB - Many studies suggest that fear conditioning influences sleep. It is, however, not known if the changes in sleep architecture after fear conditioning are essentially associated with the consolidation of fearful memory or with fear itself. Here, we have observed that within sleep, NREM sleep consistently remained augmented after the consolidation of cued fear-conditioned memory. But a similar change did not occur after impairing memory consolidation by blocking new protein synthesis and glutamate transmission between glial-neuronal loop in the lateral amygdala (LA). Anisomycin (a protein synthesis inhibitor) and DL-alpha amino-adipic acid (DL- alpha -AA) (a glial glutamine synthetase enzyme inhibitor) were microinjected into the LA soon after cued fear-conditioning to induce memory impairment. On the post-conditioning day, animals in both the groups exhibited significantly less freezing. In memory-consolidated groups (vehicle groups), NREM sleep significantly increased during 2nd to 5th hours after training compared to their baseline days. However, in memory impaired groups (anisomycin and DL- alpha -AA microinjected groups), similar changes were not observed. Our results thus suggest that changes in sleep architecture after cued fear-conditioning are indeed a consolidation dependent event. PMID- 28733209 TI - Intervention strength does not differentially affect memory reconsolidation of strong memories. AB - Recently, it has become clear that retrieval (i.e., reactivation) of consolidated memories may return these memories into a labile state before they are restored into long-term memory ('reconsolidation'). Using behavioral manipulations, reactivated memories can be disrupted via the mechanism of novel learning. In the present study, we investigated whether changing a strong memory during reconsolidation depends on the strength of novel learning. To test this, participants (N=144) in six groups acquired a relatively strong memory on Day 1 by viewing and recalling a series of pictures three times. On Day 8, these pictures were reactivated in three groups, and they were not reactivated in the other three groups. Then, participants viewed and recalled new pictures once (weak new learning) or three times (strong new learning), or they did not learn any new pictures. On Day 9, participants performed a recognition test in which their memory for Day 1 pictures was assessed. Two main results are noted. First, the groups that reactivated pictures from Day 1 and received weak or strong new learning did not differ in memory performance. Second, these two groups consistently performed similar to groups that controlled for new learning without reactivation. Because these results contradict what was expected based on the reconsolidation hypothesis, we discuss possible explanations and implications. PMID- 28733210 TI - Threat effects on human oculo-motor function. AB - Neuro-anatomical evidence supports the potential for threat-related factors, such as fear, anxiety and vigilance, to influence brainstem motor nuclei controlling eye movements, as well as the vestibular nuclei. However, little is known about how threat influences human ocular responses, such as eye saccades (ES), smooth pursuit eye tracking (SP), and optokinetic nystagmus (OKN), and whether these responses can be facilitated above normal baseline levels with a natural source of threat. This study was designed to examine the effects of height-induced postural threat on the gain of ES, SP and OKN responses in humans. Twenty participants stood at two different surface heights while performing ES (ranging from 8 degrees to 45 degrees from center), SP (15, 20, 30 degrees /s) and OKN (15, 30, 60 degrees /s) responses in the horizontal plane. Height did not significantly increase the slope of the relationship between ES peak velocity and initial amplitude, or the gain of ES amplitude. In contrast height significantly increased SP and OKN gain. Significant correlations were found between changes in physiological arousal and OKN gain. Observations of changes with height in OKN and SP support neuro-anatomical evidence of threat-related mechanisms influencing both oculo-motor nuclei and vestibular reflex pathways. Although further study is warranted, the findings suggest that potential influences of fear, anxiety and arousal/alertness should be accounted for, or controlled, during clinical vestibular and oculo-motor testing. PMID- 28733212 TI - The peroxyl radical-induced oxidation of Escherichia coli FtsZ and its single tryptophan mutant (Y222W) modifies specific side-chains, generates protein cross links and affects biological function. AB - FtsZ (filamenting temperature-sensitive mutant Z) is a key protein in bacteria cell division. The wild-type Escherichia coli FtsZ sequence (FtsZwt) contains three tyrosine (Tyr, Y) and sixteen methionine (Met, M) residues. The Tyr at position 222 is a key residue for FtsZ polymerization. Mutation of this residue to tryptophan (Trp, W; mutant Y222W) inhibits GTPase activity resulting in an extended time in the polymerized state compared to FtsZwt. Protein oxidation has been highlighted as a determinant process for bacteria resistance and consequently oxidation of FtsZwt and the Y222W mutant, by peroxyl radicals (ROO*) generated from AAPH (2,2'-azobis(2-methylpropionamidine) dihydrochloride) was studied. The non-oxidized proteins showed differences in their polymerization behavior, with this favored by the presence of Trp at position 222. AAPH treatment of the proteins inhibited polymerization. Protein integrity studies using SDS-PAGE revealed the presence of both monomers and oligomers (dimers, trimers and high mass material) on oxidation. Western blotting indicated the presence of significant levels of protein carbonyls. Amino acid analysis showed that Tyr, Trp (in the Y222W mutant), and Met were consumed by ROO*. Quantification of the number of moles of amino acid consumed per mole of ROO* shows that most of the initial oxidant can be accounted for at low radical fluxes, with Met being a major target. Western blotting provided evidence for di tyrosine cross-links in the dimeric and trimeric proteins, confirming that oxidation of Tyr residues, at positions 339 and/or 371, are critical to ROO* mediated crosslinking of both the FtsZwt and Y222W mutant protein. These findings are in agreement with di-tyrosine, N-formyl kynurenine, and kynurenine quantification assessed by UPLC, and with LC-MS data obtained for AAPH-treated protein samples. PMID- 28733211 TI - Synaptically Localized Transcriptional Regulators in Memory Formation. AB - At the neuronal cell level, long-term memory formation emerges from interactions between initial activity-dependent molecular changes at the synapse and subsequent regulation of gene transcription in the nucleus. This in turn leads to strengthening of the connections back at the synapse that received the initial signal. However, the mechanisms through which this synapse-to-nucleus molecular exchange occurs remain poorly understood. Here we discuss recent studies that delineate nucleocytoplasmic transport of a special class of synaptically localized transcriptional regulators that upon receiving initial external signal by the synapse move to the nucleus to modulate gene transcription. PMID- 28733213 TI - Risk factors for infection and/or colonisation with extended-spectrum beta lactamase-producing bacteria in the neonatal intensive care unit: a meta analysis. AB - Extended-spectrum beta-lactamase (ESBL)-producing bacteria are an important cause of healthcare-associated infections in the neonatal intensive care unit (NICU). The aim of this meta-analysis was to identify risk factors associated with infection and/or colonisation with ESBL-producing bacteria in the NICU. Electronic databases were searched for relevant studies published from 1 January 2000 to 1 July 2016. The literature was screened and data were extracted according to the inclusion and exclusion criteria. The Z-test was used to calculate the pooled odds ratio (OR) of the risk factors. ORs and their 95% confidence intervals were used to determine the significance of the risk. A total of 14 studies, including 746 cases and 1257 controls, were identified. Thirteen risk factors were determined to be related to infection and/or colonisation with ESBL-producing bacteria in the NICU: birthweight [standardised mean difference (SMD) = 1.17]; gestational age (SMD = 1.36); Caesarean delivery (OR = 1.76); parenteral nutrition (OR = 7.51); length of stay in the NICU (SMD = 0.72); mechanical ventilation (OR = 4.8); central venous catheter use (OR = 2.85); continuous positive airway pressure (OR = 5.0); endotracheal intubation (OR = 2.82); malformations (OR = 2.89); previous antibiotic use (OR = 6.72); ampicillin/gentamicin (OR = 2.31); and cephalosporins (OR = 6.0). This study identified risk factors for infection and/or colonisation with ESBL-producing bacteria in the NICU, which may provide a theoretical basis for preventive measures and targeted interventions. PMID- 28733214 TI - Strategies to improve the efficiency of celiac disease diagnosis in the laboratory. AB - The demand for testing to detect celiac disease (CD) autoantibodies has increased, together with the cost per case diagnosed, resulting in the adoption of measures to restrict laboratory testing. We designed this study to determine whether opportunistic screening to detect CD-associated autoantibodies had advantages compared to efforts to restrict testing, and to identify the most cost effective diagnostic strategy. We compared a group of 1678 patients in which autoantibody testing was restricted to cases in which the test referral was considered appropriate (G1) to a group of 2140 patients in which test referrals were not reviewed or restricted (G2). Two algorithms A (quantifying IgA and Tissue transglutaminase IgA [TG-IgA] in all patients), and B (quantifying only TG IgA in all patients) were used in each group, and the cost-effectiveness of each strategy was calculated. TG-IgA autoantibodies were positive in 62 G1 patients and 69 G2 patients. Among those positive for tissue transglutaminase IgA and endomysial IgA autoantibodies, the proportion of patients with de novo autoantibodies was lower (p=0.028) in G1 (11/62) than in G2 (24/69). Algorithm B required fewer determinations than algorithm A in both G1 (2310 vs 3493; p<0.001) and G2 (2196 vs 4435; p<0.001). With algorithm B the proportion of patients in whom IgA was tested was lower (p<0.001) in G2 (29/2140) than in G1 (617/1678). The lowest cost per case diagnosed (4.63 euros/patient) was found with algorithm B in G2. We conclude that opportunistic screening has advantages compared to efforts in the laboratory to restrict CD diagnostic testing. The most cost effective strategy was based on the use of an appropriate algorithm. PMID- 28733215 TI - Development of NanoLuc bridging immunoassay for detection of anti-drug antibodies. AB - Anti-drug antibodies (ADAs) are generated in-vivo as an immune response to therapeutic antibody drugs and can significantly affect the efficacy and safety of the drugs. Hence, detection of ADAs is recommended by regulatory agencies during drug development process. A widely accepted method for measuring ADAs is "bridging" immunoassay and is frequently performed using enzyme-linked immunosorbent assay (ELISA) or electrochemiluminescence (ECL) platform developed by Meso Scale Discovery (MSD). ELISA is preferable due to widely available reagents and instruments and broad familiarity with the technology; however, MSD platform has gained wide acceptability due to a simpler workflow, higher sensitivity, and a broad dynamic range but requires proprietary reagents and instruments. We describe the development of a new bridging immunoassay where a small (19kDa) but ultra-bright NanoLuc luciferase enzyme is used as an antibody label and signal is luminescence. The method combines the convenience of ELISA format with assay performance similar to that of the MSD platform. Advantages of the NanoLuc bridging immunoassay are highlighted by using Trastuzumab and Cetuximab as model drugs and developing assays for detection of anti-Trastuzumab antibodies (ATA) and anti-Cetuximab antibodies (ACA). During development of the assay several aspects of the method were optimized including: (a) two different approaches for labeling drugs with NanoLuc; (b) sensitivity and dynamic range; and (c) compatibility with the acid dissociation step for improved drug tolerance. Assays showed high sensitivity of at least 1.0ng/mL, dynamic range of greater than four log orders, and drug tolerance of >500. PMID- 28733216 TI - SLDAssay: A software package and web tool for analyzing limiting dilution assays. AB - Serial limiting dilution (SLD) assays are used in many areas of infectious disease related research. This paper presents SLDAssay, a free and publicly available R software package and web tool for analyzing data from SLD assays. SLDAssay computes the maximum likelihood estimate (MLE) for the concentration of target cells, with corresponding exact and asymptotic confidence intervals. Exact and asymptotic goodness of fit p-values, and a bias-corrected (BC) MLE are also provided. No other publicly available software currently implements the BC MLE or the exact methods. For validation of SLDAssay, results from Myers et al. (1994) are replicated. Simulations demonstrate the BC MLE is less biased than the MLE. Additionally, simulations demonstrate that exact methods tend to give better confidence interval coverage and goodness-of-fit tests with lower type I error than the asymptotic methods. Additional advantages of using exact methods are also discussed. PMID- 28733217 TI - Protective effect of forsythiaside A on OVA-induced asthma in mice. AB - Forsythiaside A (FSA), an active constituent isolated from the Chinese medicinal herb Forsythia suspensa, has been known to have anti-inflammatory effect. However, the effect of FSA on allergic airway inflammation remains unclear. The aim of this study was to investigate the effect of FSA on OVA-induced asthma in mice. Mice model of asthma was induced by OVA. OVA-induced airway hyperresponsiveness (AHR) and inflammatory cells in BALF were detected. The production of IgE, IL-4, IL-5, IFN-gamma, and IL-13 were detected by ELISA. The effects of FSA on Nrf2 and NF-kappaB signaling pathways were detected by western blot analysis. The results showed that treatment of FSA significantly attenuated OVA-induced lung histopathological changes. FSA inhibited OVA-induced AHR and inflammatory cells in BALF. OVA-induced IgE, IL-4, IL-5, and IL-13 production were also inhibited by FSA. Western blot analysis showed that treatment of FSA inhibited OVA-induced NF-kappaB activation. Treatment of FSA dose-dependently up regulated the expression of Nrf2 and HO-1. In addition, we found that FSA up regulated the expression of Nrf2 and HO-1 both in A549 cells and MS-H cells. Taken together, FSA suppressed inflammatory responses in OVA-induced asthma through activating Nrf2/HO-1 signaling pathway. FSA may be a promising potential preventive agent for asthma treatment. PMID- 28733218 TI - Esculentoside A inhibits LPS-induced BV2 microglia activation through activating PPAR-gamma. AB - Neuroinflammation has been recognized as a factor in the pathogenesis of neurodegenerative diseases. Esculentoside A (EsA), a saponin isolated from Phytolacca esculenta, has been reported to have anti-inflammatory activity. However, little research has been reported on the anti-neuroinflammatory effects of EsA. EsA concentration-dependently suppressed LPS-induced TNF-alpha, IL-1beta, and PGE2 production. LPS-induced NF-kappaB activation was inhibited by treatment of EsA. Furthermore, EsA concentration-dependently up-regulated the expression of PPAR-gamma. In addition, GW9662, a specific PPAR-gamma inhibitor, reversed the anti-inflammatory effects of EsA. In conclusion, these results indicate that EsA exerts anti-inflammatory effects by activating PPAR-gamma. PMID- 28733219 TI - Hepatocellular carcinoma recurrence after direct antiviral agent treatment: A European multicentre study. PMID- 28733221 TI - Incidence, predictors and outcomes of acute-on-chronic liver failure in outpatients with cirrhosis. AB - BACKGROUND & AIMS: Acute-on-chronic liver failure (ACLF) is the most life threatening complication of cirrhosis. Prevalence and outcomes of ACLF have recently been described in hospitalized patients with cirrhosis. However, no data is currently available on the prevalence and the risk factors of ACLF in outpatients with cirrhosis. The aim of this study was to evaluate incidence, predictors and outcomes of ACLF in a large cohort of outpatients with cirrhosis. METHODS: A total of 466 patients with cirrhosis consecutively evaluated in the outpatient clinic of a tertiary hospital were included and followed up until death and/or liver transplantation for a mean of 45+/-44months. Data on development of hepatic and extrahepatic organ failures were collected during this period. ACLF was defined and graded according to the EASL-CLIF Consortium definition. RESULTS: During the follow-up, 118 patients (25%) developed ACLF: 57 grade-1, 33 grade-2 and 28 grade-3. The probability of developing ACLF was 14%, 29%, and 41% at 1year, 5years, and 10years, respectively. In the multivariate analysis, baseline mean arterial pressure (hazard ratio [HR] 0.96; p=0.012), ascites (HR 2.53; p=0.019), model of end-stage liver disease score (HR 1.26; p<0.001) and baseline hemoglobin (HR 0.07; p=0.012) were found to be independent predictors of the development of ACLF at one year. As expected, ACLF was associated with a poor prognosis, with a 3-month probability of transplant-free survival of 56%. CONCLUSIONS: Outpatients with cirrhosis have a high risk of developing ACLF. The degree of liver failure and circulatory dysfunction are associated with the development of ACLF, as well as low values of hemoglobin. These simple variables may help to identify patients at a high risk of developing ACLF and to plan a program of close surveillance and prevention in these patients. LAY SUMMARY: There is a need to identify predictors of acute-on-chronic liver failure (ACLF) in patients with cirrhosis in order to identify patients at high risk of developing ACLF and to plan strategies of prevention. In this study, we identified four simple predictors of ACLF: model of end-stage liver disease (MELD) score, ascites, mean arterial pressure and hemoglobin. These variables may help to identify patients with cirrhosis, at a high risk of developing ACLF, that are candidates for new strategies of surveillance and prevention. Anemia is a potential new target for treating these patients. PMID- 28733220 TI - Pan-mTOR inhibitor MLN0128 is effective against intrahepatic cholangiocarcinoma in mice. AB - BACKGROUND & AIMS: Intrahepatic cholangiocarcinoma (ICC) is a lethal malignancy without effective treatment options. MLN0128, a second generation pan-mTOR inhibitor, shows efficacy for multiple tumor types. We evaluated the therapeutic potential of MLN0128 vs. gemcitabine/oxaliplatin in a novel ICC mouse model. METHODS: We established a novel ICC mouse model via hydrodynamic transfection of activated forms of AKT (myr-AKT) and Yap (YapS127A) protooncogenes (that will be referred to as AKT/YapS127A). Genetic approaches were applied to study the requirement of mTORC1 and mTORC2 in mediating AKT/YapS127A driven tumorigenesis. Gemcitabine/oxaliplatin and MLN0128 were administered in AKT/YapS127A tumor bearing mice to study their anti-tumor efficacy in vivo. Multiple human ICC cell lines were used for in vitro experiments. Hematoxylin and eosin staining, immunohistochemistry and immunoblotting were applied for the characterization and mechanistic study. RESULTS: Co-expression of myr-AKT and YapS127A promoted ICC development in mice. Both mTORC1 and mTORC2 complexes were required for AKT/YapS127A ICC development. Gemcitabine/oxaliplatin had limited efficacy in treating late stage AKT/YapS127A ICC. In contrast, partial tumor regression was achieved when MLN0128 was applied in the late stage of AKT/YapS127A cholangiocarcinogenesis. Furthermore, when MLN0128 was administered in the early stage of AKT/YapS127A carcinogenesis, it led to disease stabilization. Mechanistically, MLN0128 efficiently inhibited AKT/mTOR signaling both in vivo and in vitro, inducing strong ICC cell apoptosis and only marginally affecting proliferation. CONCLUSIONS: This study suggests that mTOR kinase inhibitors may be beneficial for the treatment of ICC, even in tumors that are resistant to standard of care chemotherapeutics, such as gemcitabine/oxaliplatin-based regimens, especially in the subset of tumors exhibiting activated AKT/mTOR cascade. Lay summary: We established a novel mouse model of intrahepatic cholangiocarcinoma (ICC). Using this new preclinical model, we evaluated the therapeutic potential of mTOR inhibitor MLN0128 vs. gemcitabine/oxaliplatin (the standard chemotherapy for ICC treatment). Our study shows the anti-neoplastic potential of MLN0128, suggesting that it may be superior to gemcitabine/oxaliplatin-based chemotherapy for the treatment of ICC, especially in the tumors exhibiting activated AKT/mTOR cascade. PMID- 28733222 TI - Molecular classification of hepatocellular adenoma in clinical practice. AB - Hepatocellular adenomas (HCA) are rare benign liver tumors occurring in young women taking contraception. They are associated with rare complications such as bleeding or malignant transformation into hepatocellular carcinoma. A molecular classification has divided HCA in several subgroups linked with risk factors, clinical behaviour, histological features and imaging: HNF1A inactivated HCA, Inflammatory HCA, CTNNB1 mutated HCA in exon 3, CTNNB1 mutated in exon 7 and 8 HCA, sonic hedgehog HCA and unclassified HCA. CTNNB1 mutated HCA in exon 3 and sonic hedgehog HCA have been linked with a high risk of malignant transformation and bleeding respectively. Herein, we review how molecular classification has modified our understanding of the pathophysiology and risk factors of HCA development, analysing its impact on clinical care in the field of diagnosis and therapeutic stratification. PMID- 28733223 TI - Sequencing of FIC1, BSEP and MDR3 in a large cohort of patients with cholestasis revealed a high number of different genetic variants. AB - BACKGROUND & AIMS: The bile salt export pump (BSEP, ABCB11), multidrug resistance protein 3 (MDR3, ABCB4) and the ATPase familial intrahepatic cholestasis 1 (FIC1, ATP8B1) mediate bile formation. This study aimed to determine the contribution of mutations and common variants in the FIC1, BSEP and MDR3 genes to cholestatic disorders of differing disease onset and severity. METHODS: Coding exons with flanking intron regions of ATP8B1, ABCB11, and ABCB4 were sequenced in cholestatic patients with assumed genetic cause. The effects of new variants were evaluated by bioinformatic tools and 3D protein modeling. RESULTS: In 427 patients with suspected inherited cholestasis, 149 patients carried at least one disease-causing mutation in FIC1, BSEP or MDR3, respectively. Overall, 154 different mutations were identified, of which 25 were novel. All 13 novel missense mutations were disease-causing according to bioinformatics analyses and homology modeling. Eighty-two percent of patients with at least one disease causing mutation in either of the three genes were children. One or more common polymorphism(s) were found in FIC1 in 35.3%, BSEP in 64.3% and MDR3 in 72.6% of patients without disease-causing mutations in the respective gene. Minor allele frequencies of common polymorphisms in BSEP and MDR3 varied in our cohort compared to the general population, as described by gnomAD. However, differences in ethnic background may contribute to this effect. CONCLUSIONS: In a large cohort of patients, 154 different variants were detected in FIC1, BSEP, and MDR3, 25 of which were novel. In our cohort, frequencies for risk alleles of BSEP (p.V444A) and MDR3 (p.I237I) polymorphisms were significantly overrepresented in patients without disease-causing mutation in the respective gene, indicating that these common variants can contribute to a cholestatic phenotype. LAY SUMMARY: FIC1, BSEP, and MDR3 represent hepatobiliary transport proteins essential for bile formation. Genetic variants in these transporters underlie a broad spectrum of cholestatic liver diseases. To confirm a genetic contribution to the patients' phenotypes, gene sequencing of these three major cholestasis-related genes was performed in 427 patients and revealed 154 different variants of which 25 have not been previously reported in a database. In patients without a disease-causing mutation, common genetic variants were detected in a high number of cases, indicating that these common variants may contribute to cholestasis development. PMID- 28733224 TI - CELF1 preferentially binds to exon-intron boundary and regulates alternative splicing in HeLa cells. AB - The current RIP-seq approach has been developed for the identification of genome wide interaction between RNA binding protein (RBP) and the bound RNA transcripts, but still rarely for identifying its binding sites. In this study, we performed RIP-seq experiments in HeLa cells using a monoclonal antibody against CELF1. Mapping of the RIP-seq reads showed a biased distribution at the 3'UTR and intronic regions. A total of 15,285 and 1384 CELF1-specific sense and antisense peaks were identified using the ABLIRC software tool. Our bioinformatics analyses revealed that 5' and 3' splice site motifs and GU-rich motifs were highly enriched in the CELF1-bound peaks. Furthermore, transcriptome analyses revealed that alternative splicing was globally regulated by CELF1 in HeLa cells. For example, the inclusion of exon 16 of LMO7 gene, a marker gene of breast cancer, is positively regulated by CELF1. Taken together, we have shown that RIP-seq data can be used to decipher RBP binding sites and reveal an unexpected landscape of the genome-wide CELF1-RNA interactions in HeLa cells. In addition, we found that CELF1 globally regulates the alternative splicing by binding the exon-intron boundary in HeLa cells, which will deepen our understanding of the regulatory roles of CELF1 in the pre-mRNA splicing process. PMID- 28733225 TI - Microneurosurgical Clip Ligation of Acutely Ruptured Cerebral Aneurysm Immediately Preceded by Intentional Subtotal Endovascular Coil Embolization Under a Single Anesthesia: Observations Using a Deliberate Combined Sequential Treatment Strategy in 13 Cases. AB - BACKGROUND: Endovascular coil embolization and craniotomy with clip ligation are the 2 most commonly used treatments for ruptured cerebral aneurysm. Although coiling maintains the advantages of brevity and complete avoidance of brain retraction and manipulation, clipping offers the benefits of decompression of the injured brain and lower rates of aneurysm recurrence. A combined, immediately sequential treatment strategy for acutely ruptured cerebral aneurysm that simultaneously maximizes the advantages of both techniques, while minimizing their respective disadvantages, may be a useful paradigm. OBJECTIVE: To demonstrate the complementarity of clipping and coiling in acutely ruptured cerebral aneurysm. METHODS: Patients with ruptured anterior circulation cerebral aneurysm standing to benefit from brain decompression were treated by a combination of coiling and microneurosurgery in rapid succession, under the same general anesthetic. Surgery consisted of clipping of the aneurysm via either craniotomy or craniectomy with expansion duraplasty in all cases, and ventriculostomy in selected cases. RESULTS: Coil embolization of the ruptured aneurysm was carried out rapidly and improved the efficiency of subsequent clipping by allowing early unequivocal identification of the aneurysm dome and decreased brain retraction, reducing risk of intraoperative rupture and obviating temporary occlusion. All aneurysms were shown eliminated by postoperative cerebral angiography. CONCLUSIONS: A deliberate combined treatment strategy that uses clipping immediately preceded by subtotal coiling under a single anesthetic may be ideal for selected ruptured cerebral aneurysms, takes advantage of the unique strengths of both techniques, makes both techniques easier, and maximizes opportunity for brain protection against delayed complications in the prolonged aftermath of aneurysmal subarachnoid hemorrhage. PMID- 28733226 TI - Allatoregulatory-like systems and changes in cytosolic Ca2+ modulate feeding behavior in Hydra. AB - Allatotropin (AT) and allatostatin-C (AST-C) are neuropeptides originally characterized by their ability to modulate the secretion of juvenile hormones in insects. Beyond the allatoregulatory function, these neuropeptides are pleiotropic acting as myoregulators not only in insects, but also in other groups of invertebrates. We have previously proposed the existence of AT and AST-C like systems in Hydra sp., a member of the phylum Cnidaria, which is a basal group of Metazoa, sharing a common ancestor with Bilateria. In the present study we analyze the regulatory effects of both peptides on the activity of the hypostome during feeding in Hydra sp. Furthermore, the importance of changes in the cytosolic Ca2+ levels involved in the response of the hypostome were analyzed. Physiological assays showed that while the presence of food or treatment with AT stimulates the extrusion of the hypostome, AST-C has an inhibitory effect on the behavior induced by both, food and AT. These facts suggest that both systems participate in the regulatory mechanisms associated with feeding and, as in insects, AST-C and AT may exert opposite effects. The use of thapsigargin (TG) and nifedipine, two compounds that modify the levels of cytosolic Ca2+, showed that changes in the levels of this ion are involved in the regulation of the activity of the hypostome. Indeed, these results suggest that the two basic mechanisms operating to increase the cytosolic levels of Ca2+ (i.e. the influx from the extracellular space and the release from endoplasmic reticulum) are relevant for the extrusion of the hypostome. Like in insects, the treatment with TG counteracted the effect of AST-C, suggesting that this peptide acts by reducing cytosolic Ca2+ levels. Furthermore, nifedipine prevented the myostimulatory effect of AT, showing that the effect of this peptide depends on the influx of Ca2+ throughout voltage-gated calcium channels. Altogether, these results suggest that the Allatotropin/Orexin and Allatostatin/Somatostatin regulatory systems could represent an ancestral mechanisms regulating hypostome activity and feeding behavior in Cnidaria. PMID- 28733227 TI - Captivity influences immune responses, stress endocrinology, and organ size in house sparrows (Passer domesticus). AB - Studies using wild animals in laboratory-based research require bringing wild captured organisms into a novel setting, which can have long-lasting impacts on physiology and behavior. In several species, captivity stimulates stress hormone production and can alter immune function. Despite this, there is little consensus on how captivity influences stress hormone regulation, or if captivity-induced changes in stress hormone production and regulation mediate changes in immune function. In this study, we investigate the influence of captivity on the physiology of a wild bird commonly-used in laboratory-based research, the house sparrow (Passer domesticus). We tested how captivity influences stress endocrinology, immune responses, and organ mass, and also investigated if the production or regulation of corticosterone, the main stress hormone in birds, correlated with changes in immunity. We found that baseline corticosterone concentrations and maximum capacity of the adrenals to secrete corticosterone increase following captivity and remain elevated after 9weeks of captivity. A measure of innate immune function, the bactericidal ability of plasma, also increased with time spent in captivity. Wound healing was also influenced by time spent in captivity, with birds taking almost 2days longer to heal if they were wounded after 3weeks in captivity when compared with birds that were wounded immediately upon capture. Additionally, captivity caused notable reductions in spleen and liver mass. Together, these results imply that captivity can have long lasting effects on house sparrow corticosterone release and immune function, and suggest that even after 9weeks house sparrows do not acclimate physiologically to life in captivity. PMID- 28733228 TI - Progressive erosion of the Relaxin1 gene in bovids. AB - The relaxin/insulin-like (RLN/INSL) gene family is a group of genes that encode peptide hormones involved in a variety of physiological functions related to reproduction. Previous studies have shown that relaxin plays a key role in widening of the pubic bone during labor and in gamete maturation. Because of these functions, studying the evolution of RLN1, the gene encoding for relaxin, is relevant in livestock species, most of which belong in the group Laurasiatheria, which includes cow, pig, horse, goat, and sheep in addition to bats, cetaceans and carnivores. Experimental evidence suggests that cows do not synthesize relaxin, but respond to it, and sheep apparently have a truncated RLN1 gene. Thus, we made use of genome sequence data to characterize the genomic locus of the RLN1 gene in Laurasiatherian mammals to better understand how cows lost the ability to synthesize this peptide. We found that all ruminants in our study (cow, giraffe, goat, sheep and Tibetan antelope) lack a functional RLN1 gene, and document the progressive loss of RLN1 in the lineage leading to cows. Our analyses indicate that 1 - all ruminants have lost all key regulatory elements upstream of the first exon, 2 - giraffe, goat, sheep and Tibetan antelope have multiple inactivating mutations in the RLN1 pseudogene, and 3 - the cow genome has lost all traces of RLN1. The 5' regulatory sequence plays a key role in activating expression, and the loss of this sequence would impair synthesis of mRNA. Our results suggest that changes in regulatory sequence preceded mutations in coding sequence and highlight the importance of these regions in maintaining proper gene function. In addition, we found that all bovids examined posses copies of the relaxin receptors, which explains why they are able to respond to relaxin despite their inability to produce it. PMID- 28733229 TI - Estrogen signaling through both membrane and nuclear receptors in the liver of fathead minnow. AB - Estradiol is a potent sex steroid hormone that controls reproduction and other cellular pathways in fish. It is known to regulate important proteins such as vitellogenin, the egg yolk precursor protein, and zona radiata proteins that form the eggshell for fish eggs. These proteins are made in the liver and transported out into the blood from where they are taken up into the ovary during oogenesis. Estradiol can exert its influence directly through soluble nuclear receptors (there are three in fish) or indirectly through membrane receptors and a phosphorylation cascade. Often there is coordination through both genomic and non genomic pathways. We have used a toxicogenomics approach to determine the contribution of genomic and non-genomic regulation in the liver of fathead minnows exposed to 5ng ethinylestradiol per liter or to a mixture of 5ng ethinylestradiol and 100ng ZM189,154 (ZM) per liter. ZM has previously been shown to be a "perfect" antagonist for the fish nuclear estrogen receptors but has displayed agonistic activities for membrane receptors. We find that both nuclear and membrane receptors contribute to the biosynthesis of vitellogenin 1 and estrogen receptor one (Esr1), among others. In addition, lipid metabolism pathways appear to require both activities. PMID- 28733230 TI - Clostridium perfringens and C. difficile in parvovirus-positive dogs. AB - The aim of this study was to investigate Clostridium difficile and Clostridium perfringens in 82 diarrheic dogs positive for canine parvovirus type 2 (CPV). Enterotoxigenic C. perfringens type A was isolated from three (3.6%) dogs. One (1.2%) strain was also positive for NetE- and NetF-encoding genes, which are commonly associated with diarrhea in dogs. Toxigenic C. difficile was isolated from one animal (1.2%), which was also positive for A/B toxins. The present study identified C. difficile and C. perfringens infection in CPV-positive dogs. Further studies are necessary to clarify if clostridial infections may predispose or potentiate CPV-infection in dogs or vice versa. PMID- 28733231 TI - Tussilagonone-induced Nrf2 pathway activation protects HepG2 cells from oxidative injury. AB - Tussilagonone is a compound derived from the medicinal plant Tussilago farfara L., which is used as a traditional medicine for respiratory diseases, including asthma and pneumonia. Recent reports suggest that tussilagonone exhibits anti inflammatory effects; however, the scope of protective functions has not been elucidated yet. In this study, we demonstrate that tussilagonone enhances cellular detoxification by increasing quinone reductase activity in Hepa1c1c7 cells. In addition, tussilagonone decreased tert-butyl hydroperoxide(t-BHP) induced ROS production and cell death, suggesting that it also acts as a potent antioxidant. To verify the molecular mechanism underlying tussilagonone activity, we examined the expression of nuclear factor erythroid 2-related factor 2(Nrf2)-a transcription factor that regulates antioxidant protein expression-in HepG2 cells. Significantly, these results showed that tussilagonone induces Nrf2 activation and nuclear accumulation, resulting in the upregulation of the detoxifying enzymes NAD(P)H quinone dehydrogenase 1(NQO1) and heme oxygenase-1(HO 1) that protect cells from oxidative stress. Further molecular analyses revealed that tussilagonone-induced Nrf2 activation was mediated by ERK1/2 in HepG2 cells. Collectively, these data indicate that tussilagonone attenuates t-BHP-induced ROS and activates quinone reductase activity via Nrf2 pathway activation and target gene expression, and thereby acts as an antioxidant that protects HepG2 cells from oxidative stress and associated damage. PMID- 28733232 TI - RIFM FRAGRANCE INGREDIENT SAFETY ASSESSMENT, 2,2,4-trimethyl-4-phenyl-butane nitrile CAS Registry Number 75490-39-0. PMID- 28733233 TI - Estimation of dietary intake and target hazard quotients for metals by consumption of wines from the Canary Islands. AB - This paper describes the impact of mineral content on wines and assesses the potential health risk from consuming these wines from Canary Islands. The metal content (B, Ca, Co, Cr, Cu, Fe, K, Li, Mg, Mn, Mo, Na, Ni, Pb, Zn) of red wines belonging to different regions in the Canary Islands was determined by ICP-OES. The studied wine regions were Valle de la Orotava, Tacoronte-Acentejo, Ycoden Daute-Isora, Abona and Valle de Guimar in Tenerife Island and only one in La Gomera and La Palma Islands. According to the content found, elements could be classified in two categories: the main group including Ca, K, Mg, Na, and the ''minor'' set consisting of B, Co, Cr, Cu, Fe, Li, Mn, Mo, Ni, Pb and Zn. Once calculated the metal intake through red wines consumption, we can conclude that Canarian drinkers are not exposed to unsafe levels of the metals studied, actually, the safety intake limits (daily) ranges between 0.9% in Zn and 2% in Cu, for normal drinkers. And also it has been demonstrated the good quality of Canarian red wines and there is no reason for health concern through the THQ calculation being the highest values determined in La Gomera wines. PMID- 28733234 TI - Curcumin, a component of turmeric, efficiently prevents diclofenac sodium-induced gastroenteropathic damage in rats: A step towards translational medicine. AB - There is a need to find/discover novel leads to treat complex and/or multi factorial disease(s). Curcumin (CUR) is one of the promising lead molecules which need its further evaluation against NSAID-induced gastroenteropathy. Hence, the aim of the present study was to explore the pharmaco-mechanistic efficacy of CUR against NSAID-induced gastroenteropathy. Rats were treated twice daily with CUR (25, 50 and 100 mg kg-1 peroral) or vehicle for 10 days. In some experiments, diclofenac sodium (DIC; 9 mg kg-1) was administered orally twice daily for the final 5 days of CUR/vehicle administration. After the last dose on 9th day, rats were fasted. 12 h after the last dose on 10th day, rats were euthanized and their GI tracts were assessed for haemorrhagic lesions, lipid peroxidation, intestinal permeability and GI luminal pH alterations along with haemato-biochemical estimations. The macroscopic, biochemical, haematological and histological evidences suggested that co-administration of CUR resulted in dose dependent attenuation of the NSAID-induced gastroenteropathic damage and the mechanisms may be related to its ability to prevent the NSAID-induced alterations in the GI luminal pH, lipid peroxidation/oxidative stress, GI blood loss and intestinal permeability alteration. Based on these pharmaco-mechanistic results we propose it as a promising lead to treat NSAID-gastroenteropahty. PMID- 28733235 TI - Determination of fumonisin B1 levels in body fluids and hair from piglets fed fumonisin B1-contaminated diets. AB - The levels of fumonisin B1 (FB1) residues in plasma, urine, feces and hair from 24 piglets fed FB1-contaminated diets containing 3.1, 6.1 or 9.0 MUg FB1.g-1 for 28 days were determined using liquid chromatography coupled to mass spectrometry (LC-MS/MS). The levels of FB1 in plasma, urine, feces and pooled hair (n = 3) samples varied from 0.15 to 1.08 MUg.L-1, 16.09-75.01 MUg.L-1, 1.87-13.89 MUg.g-1 and 2.08-8.09 ng.g-1, respectively. Significant correlations (r = 0.808-0.885; P < 0.001; N = 18) were found between FB1 intake and plasma FB1 on days 7, 14, 21 and 28. However, urinary FB1 correlated with FB1 intake only on days 7 and 14 (r = 0.561-572; P = 0.02; N = 18). A significant correlation (r = 0.509; P = 0.02; N = 24) was also found for the first time between FB1 in hair samples and FB1 intake. Plasma and urinary FB1 are good biomarkers of early exposure of pigs to low dietary FB1 levels, although plasma is recommended to assess prolonged exposure (>14 days). The possibility to evaluate hair as a biomarker of fumonisin exposure was established, although further studies are needed to provide physiologically based toxicokinetics of residual FB1 in the pig hair. PMID- 28733236 TI - Novel tryptophan metabolic pathways in auxin biosynthesis in silkworm. AB - In the course of our study of the biosynthetic pathway of auxin, a class of phytohormones, in insects, we proposed the biosynthetic pathway tryptophan (Trp) >indole-3-acetaldoxime (IAOx)->indole-3-acetadehyde (IAAld)->indole-3-acetic acid (IAA). In this study, we identified two branches in the metabolic pathways in the silkworm, possibly affecting the efficiency of IAA production: Trp->indole-3 pyruvic acid->indole-3-lactic acid and IAAld->indole-3-ethanol. We also determined the apparent conversion activities (2.05*10-7UmL-1 for Trp->IAA, 1.30*10-5UmL-1 for IAOx->IAA, and 3.91*10-1UmL-1 for IAAld->IAA), which explain why IAOx and IAAld are barely detectable as either endogenous compounds or metabolites of their precursors. The failure to detect IAAld, even in the presence of an inhibitor of the conversion IAAld->IAA, is explained by a switch in the conversion from IAAld->IAA to IAAld->IEtOH. PMID- 28733237 TI - A critical test of Drosophila anaesthetics: Isoflurane and sevoflurane are benign alternatives to cold and CO2. AB - Anaesthesia is often a necessary step when studying insects like the model organism Drosophila melanogaster. Most studies of Drosophila and other insects that require anaesthesia use either cold exposure or carbon dioxide exposure to induce a narcotic state. These anaesthetic methods are known to disrupt physiology and behavior with increasing exposure, and thus ample recovery time is required prior to experimentation. Here, we examine whether two halogenated ethers commonly used in vertebrate anaesthesia, isoflurane and sevoflurane, may serve as alternative means of insect anaesthesia. Using D. melanogaster, we generated dose-response curves to identify exposure times for each anaesthetic (cold, CO2, isoflurane and sevoflurane) that allow for five-minutes of experimental manipulation of the animals after the anaesthetic was removed (i.e. 5min recovery doses). We then compared the effects of this practical dose on high temperature, low temperature, starvation, and desiccation tolerance, as well as locomotor activity and fecundity of female flies following recovery from anaesthesia. Cold, CO2 and isoflurane each had significant or near significant effects on the traits measured, but the specific effects of each anaesthetic differed, and effects on stress tolerance generally did not persist if the flies were given 48h to recover from anaesthesia. Sevoflurane had no measureable effect on any of the traits examined. Care must be taken when choosing an anaesthetic in Drosophila research, as the impacts of specific anaesthetics on stress tolerance, behavior and reproduction can widely differ. Sevoflurane may be a practical alternative to cold and CO2 anaesthesia in insects - particularly if flies are to be used for experiments shortly after anesthesia. PMID- 28733238 TI - Circadian regulation of caterpillar feeding and growth. AB - Circadian clocks orchestrate many physiological processes in adult organisms. For example, rhythmic feeding behavior is regulated by the central clock in the nervous system in coordination with metabolic rhythms, which in turn depend mostly on peripheral clocks localized in many tissues. Disruption of the circadian clock leads to metabolic dysregulation both in mammals and in the model insect Drosophila melanogaster. Circadian coordination of feeding and metabolism has been studied mainly in adult insects and not in larval stages, which are dramatically different from adults in species with complete full metamorphosis. The goal of this study was to determine whether feeding and metabolism in lepidopteran larvae are subject to circadian regulation. We show that cotton leafworm caterpillars, Spodoptera littoralis, display rhythmic feeding behavior and that circadian clock genes are expressed in two peripheral tissues, the midgut and fat body. Even though both tissues display rhythmic circadian clock gene expression, the main component of the clock, per, is arrhythmic in the gut and rhythmic in the fat body. In both tissues, the presence of rhythmic physiological processes was observed, which suggested that metabolism is already driven by the circadian clock in the insect's juvenile stages. PMID- 28733239 TI - Protein-carbohydrate regulation in Helicoverpa amigera and H. punctigera and how diet protein-carbohydrate content affects insect susceptibility to Bt toxins. AB - Many animals, including insects, demonstrate a remarkable ability to regulate their intake of key macronutrients (e.g., soluble protein and digestible carbohydrates), which allows them to optimize fitness and performance. Additionally, regulating the intake of these two macronutrients enhances an animal's ability to defend itself against pathogens, mitigate the effects of secondary plant metabolites, and decrease susceptibility to toxins. In this study, we first compared how Bt-resistant and -susceptible lines of Helicoverpa armigera and Helicoverpa punctigera regulate their intake of protein (p) and digestible carbohydrates (c). We found that there was no difference in the self selected protein-carbohydrate intake target between resistant and susceptible genotypes of either species. We then explored the extent to which food protein carbohydrate content altered the susceptibility of these species to three Bt toxins: Cry1Ac, Cry2Ab, and Vip3Aa. We found that H. armigera on diets that had protein-carbohydrate profiles that matched their self-selected protein carbohydrate intake target were significantly less susceptible to Cry1Ac. In contrast, diet protein-carbohydrate content did not affect H. punctigera susceptibility to Cry1Ac. For both H. armigera and H. punctigera, susceptibility to Cry2Ab and Vip3Aa toxins did not change as a function of diet protein carbohydrate profile. These results, when combined with earlier work on H. zea, suggest food protein-carbohydrate content can modify susceptibility to some Bt toxins, but not others. An increased understanding of how the nutritional environment can modify susceptibility to different Bt toxins could help improve pest management and resistance management practices. PMID- 28733241 TI - Live imaging using a FRET glucose sensor reveals glucose delivery to all cell types in the Drosophila brain. AB - All complex nervous systems are metabolically separated from circulation by a blood-brain barrier (BBB) that prevents uncontrolled leakage of solutes into the brain. Thus, all metabolites needed to sustain energy homeostasis must be transported across this BBB. In invertebrates, such as Drosophila, the major carbohydrate in circulation is the disaccharide trehalose and specific trehalose transporters are expressed by the glial BBB. Here we analyzed whether glucose is able to contribute to energy homeostasis in Drosophila. To study glucose influx into the brain we utilized a genetically encoded, FRET-based glucose sensor expressed in a cell type specific manner. When confronted with glucose all brain cells take up glucose within two minutes. In order to characterize the glucose transporter involved, we studied Drosophila Glut1, the homologue of which is primarily expressed by the BBB-forming endothelial cells and astrocytes in the mammalian nervous system. In Drosophila, however, Glut1 is expressed in neurons and is not found at the BBB. Thus, Glut1 cannot contribute to initial glucose uptake from the hemolymph. To test whether gap junctional coupling between the BBB forming cells and other neural cells contributes to glucose distribution we assayed these junctions using RNAi experiments and only found a minor contribution of gap junctions to glucose metabolism. Our results provide the entry point to further dissect the mechanisms underlying glucose distribution and offer new opportunities to understand brain metabolism. PMID- 28733240 TI - Metabolomics reveal physiological changes in mayfly larvae (Neocloeon triangulifer) at ecological upper thermal limits. AB - Aquatic insects play critical roles in freshwater ecosystems and temperature is a fundamental driver of species performance and distributions. However, the physiological mechanisms that determine the thermal performance of species remain unclear. Here we used a metabolomics approach to gain insights into physiological changes associated with a short-term, sublethal thermal challenge in the mayfly Neocloeon triangulifer (Ephemeroptera: Baetidae). Larvae were subjected to a thermal ramp (from 22 to 30 degrees C at a rate of 1 degrees C/h) and metabolomics analysis (both Nuclear Magnetic Resonance (NMR) Spectroscopy and Gas Chromatography coupled Time-of-Flight Mass Spectrometry (GC-TOF-MS)) indicated that processes related to energetics (sugar metabolism) and membrane stabilization primarily differentiated heat treated larvae from controls. Limited evidence of anaerobic metabolism was observed in the heat treated larvae at 30 degrees C, a temperature that is chronically lethal to larvae. PMID- 28733242 TI - Dual centrifugation - A new technique for nanomilling of poorly soluble drugs and formulation screening by an DoE-approach. AB - The development of nanosuspensions of poorly soluble APIs takes a lot of time and high amount of active material is needed. In this publication the use of dual centrifugation (DC) for an effective and rapid API-nanomilling is described for the first time. DC differs from normal centrifugation by an additional rotation of the samples during centrifugation, resulting in a very fast and powerful movement of the samples inside the vials, which - in combination with milling beads - result in effective milling. DC-nanomilling was compared to conventional wet ball milling and results in same or even smaller particle sizes. Also drug concentrations up to 40% can be processed. The process is fast (typical 90min) and the temperature can be controlled. DC-nanomilling appears to be very gentle, experiments showed no change of the crystal structure during milling. Since batch sizes are very small (100-1000mg) and since 40 sample vials can be processed in parallel, DC is ideal for the screening of suitable polymer/surfactant combinations. Fenofibrate was used to investigate DC-nanomilling for formulation screening by applying a DoE-approach. The presented data also show that the results of DC-nanomilling experiments are highly comparable to the results obtained by common agitator mills. PMID- 28733243 TI - Application of machine learning in prediction of hydrotrope-enhanced solubilisation of indomethacin. AB - Systematic in-vitro studies have been conducted to determine the ability of a range of 10 potential hydrotropes to improve the apparent aqueous solubility of the poorly water soluble drug, indomethacin. Solubilisation of the drug in the presence of the hydrotropes was determined experimentally using high-performance liquid chromatography (HPLC) with ultraviolet (UV) detection. These experimental data, together with various known and computed physicochemical properties of the hydrotropes were thereafter used in silico to train an artificial neural network (ANN) to allow for predictions of indomethacin solubilisation. The trained ANN was found to give highly accurate predictions of indomethacin solubilisation in the presence of hydrotropes and was thus shown to provide a valuable means by which hydrotrope efficacy could be screened computationally. Interrogation of the network connection weights afforded a quantitative assessment of the relative importance of the various hydrotrope physicochemical properties in determining the extent of the enhancement in indomethacin solubilisation. It is concluded that in-silico screening of drug/hydrotrope systems using artificial neural networks offers significant potential to reduce the need for extensive laboratory testing of these systems, and could thus provide an economy in terms of reduced costs and time in drug formulation development. PMID- 28733244 TI - Response surface optimization, Ex vivo and In vivo investigation of nasal spanlastics for bioavailability enhancement and brain targeting of risperidone. AB - Transnasal brain drug targeting could ensure better drug delivery to the brain through the olfactory pathway. Risperidone bioavailability is 66% in extensive metabolizers and 82% in slow metabolizers. The aim of this study is to investigate the ability of the nanovesicular spanlastics to effectively deliver risperidone through the nasal route to the brain and increase its bioavailability. Spanlastics formulae, composed of span and polyvinyl alcohol, were designed based on central composite statistical design. The planned formulae were prepared using ethanol injection method. The prepared formulae were characterized by testing their particle size, polydispersity index, zeta potential and encapsulation efficiency. The optimized formula having the lowest particle size, polydispersity index, the highest zeta potential and encapsulation efficiency was subjected to further investigations including characterization of its rheological properties, elasticity, transmission electron microscopy, in vitro diffusion, ex vivo permeation, histopathology and in vivo biodistribution. The optimized formula was composed of 5mg/mL span and 30mg/mL polyvinyl alcohol. It showed significantly higher transnasal permeation and better distribution to the brain, when compared to the used control regarding the brain targeting efficiency and the drug transport percentage (2.16 and 1.43 folds increase, respectively). The study introduced a successful and promising formula to directly and effectively carry the drug from nose to brain. PMID- 28733245 TI - Engineered nanoparticles for the detection, treatment and prevention of atherosclerosis: how close are we? AB - Atherosclerosis is one of the leading causes of morbidity and mortality worldwide. Nanotechnology has provided the possibility of designing nanoparticles that can translocate through tissues and home in to atherosclerotic plaques to achieve desired diagnostic, therapeutic, theranostic or 'theralivery' outcomes. Although nanomedicine approaches have demonstrated exciting possibilities, clinical reality is still distant and challenges are aplenty, such as specificity of targeting and nanotoxicity. Nevertheless, developments in formulations, delivery strategies and experimental models over the coming years will generate new knowledge to define the true potential of this field. This review discusses the most recent developments, current challenges and future possibilities. PMID- 28733246 TI - Defective recognition and naming of famous people from voice in patients with unilateral temporal lobe tumours. AB - Twenty-nine patients who underwent surgery for a temporal glioma, either in the left (16 patients) or right (13 patients) hemisphere, were administered standardized tests of unknown voice discrimination (UVD) and of famous voice recognition (VO-REC), which included tasks of familiarity evaluation, semantic identification and naming of famous voices. The UVD consisted of twenty stimuli, in which two audio files were consecutively presented; the subject was requested to judge whether the voices belonged to the same or different persons. In the VO REC, patients were requested to recognize the voices of 40 very well known people; these voices were intermingled with the voices of 20 unknown people for a familiarity check, followed by identification and naming of persons recognized as familiar. We aimed at verifying the effect of laterality and intra-temporal site of lesion on familiarity assessment, false alarms, identification and naming of familiar people. As for the effect of lesion side, our results showed that patients with right temporal gliomas were significantly more impaired in voices discrimination and produced more false alarms than patients with a left glioma, who, in turn, were significantly more impaired in name retrieval than patients with a right temporal glioma. The high number of false alarms in patients with a right temporal glioma suggests that familiarity judgment was impaired. Regarding the neuroanatomical correlates of these different patterns of impairment, MRI data suggested that: (a) UVD disorders are due to lesions involving the whole right anterior temporal lobe and extending to lateral portions of the temporal and frontal lobes; (b) familiarity judgments (testified by an increased number of false alarms) are impaired in lesions restricted to the right anterior temporal lobe; (c) name retrieval deficits are found only in patients with left temporal lesions. UVD disorders were interpreted, at least in part, as due to an impairment of executive functions, resulting from a disconnection of the right temporal lobe from the frontal lobe control. A partly unexpected finding was that some patients with a right temporal tumour had a normal performance in famous voice recognition and identification, in spite of having severe voice discrimination disturbances. These unexpected results, in agreement with previous observation made in the visual (face) modality, are inconsistent with strictly hierarchical models of voice processing. PMID- 28733247 TI - Effective connectivity during successful and unsuccessful recollection in young and old adults. AB - Aging effects on regional brain activation have been studied extensively to explain the gradual recollection failure that occurs with advancing age. However, little is known about the consequence of aging on the interaction among brain regions that support recollection. The purpose of this study was to examine effective connectivity at encoding and retrieval during successful and unsuccessful recollection in young and old adults. In particular, we analyzed a recollection network that is characterized by its susceptibility to aging effects by middle age or later, which is comprised of the occipital cortex, hippocampus and orbitofrontal cortex. Participants' brains were scanned using functional magnetic resonance imaging while they performed a spatial source memory task. Dynamic causal modeling and Bayesian model selection revealed that subsequent recollection during encoding and recollection during retrieval modulated the influence of the orbitofrontal cortex on the hippocampus in both age groups; this particular connectivity was not modulated by unsuccessful encoding in either group. Successful encoding and retrieval of item-source associations modulated all connections within the network in old adults. The findings revealed that the orbitofrontal cortex influences processes in the hippocampus to ensure successful recollection, and aging alters the recollection network by engaging non specialized connections. PMID- 28733248 TI - Pupil dilations induced by barely conscious reward goal-priming. AB - The topic of unconscious influences on behavior has long been explored as a way of understanding human performance and the neurobiological correlates of intention, motivation and action. Previous research using transcranial magnetic stimulation has demonstrated that barely visible priming of an action concept, when combined with reward in the form of a consciously perceived positive stimulus, can alter the state of the motor system and enhance the maximal voluntary force level. One possible explanation is that positive stimulus-induced reward signals are processed by the dopaminergic system in the basal ganglia, motivating individuals to increase the effort they invest in particular behaviors, or to recruit the resources necessary for maintaining those behaviors. If so, given that the dopaminergic system has functionally and anatomically close connections with the noradrenergic system, we hypothesize that the state of the noradrenergic system may be enhanced by the same process. In accord with this hypothesis, we observed that barely visible goal priming with reward caused pupil dilation, suggesting that activity in the noradrenergic system increased. Importantly, this enhancement was accompanied by an unconscious increase in handgrip force. This is the first objective evidence that the pupil-linked neuromodulatory system is related to implicit learning of the link between physical exertion and reward, probably in the noradrenergic system, resulting in more forceful voluntary motor action in the absence of conscious awareness. PMID- 28733249 TI - DNA based random key generation and management for OTP encryption. AB - One-time pad (OTP) is a principle of key generation applied to the stream ciphering method which offers total privacy. The OTP encryption scheme has proved to be unbreakable in theory, but difficult to realize in practical applications. Because OTP encryption specially requires the absolute randomness of the key, its development has suffered from dense constraints. DNA cryptography is a new and promising technology in the field of information security. DNA chromosomes storing capabilities can be used as one-time pad structures with pseudo-random number generation and indexing in order to encrypt the plaintext messages. In this paper, we present a feasible solution to the OTP symmetric key generation and transmission problem with DNA at the molecular level. Through recombinant DNA technology, by using only sender-receiver known restriction enzymes to combine the secure key represented by DNA sequence and the T vector, we generate the DNA bio-hiding secure key and then place the recombinant plasmid in implanted bacteria for secure key transmission. The designed bio experiments and simulation results show that the security of the transmission of the key is further improved and the environmental requirements of key transmission are reduced. Analysis has demonstrated that the proposed DNA-based random key generation and management solutions are marked by high security and usability. PMID- 28733250 TI - Sphingosine kinase 1 protects renal tubular epithelial cells from renal fibrosis via induction of autophagy. AB - Autophagy is an important homoeostatic mechanism for the lysosomal degradation of protein aggregates and damaged cytoplasmic components. Recent studies suggest that autophagy which is induced by TGF-beta1 suppresses kidney fibrosis in renal tubular epithelial cells (RTECs) of obstructed kidneys. Sphingosine kinase 1(SK1), converting sphingosine into endogenous sphingosine-1-phosphate (S1P), was shown to modulate autophagy and involved in the processes of fibrotic diseases. Since SK1 activity is also up-regulated by TGF-beta1, we explored its effect on the induction of autophagy and development of renal fibrosis in this study. In vitro, SK1 expression and activity were markedly increased by TGF-beta1 stimulation in a time and concentration dependent manner, and concomitant changes in autophagic response were observed in HK-2 cells. Further, knockdown of SK-1 led to a decrease of autophagy whereas overexpression of SK1 caused a greater induction of autophagy. In addition, overexpression of SK1 resulted in decreased of mature TGF-beta levels through autophagic degradation. In vivo, SK1 enzymatic activity and autophagic response were both up-regulated in a mouse model of kidney fibrosis induced by unilateral ureteral obstruction (UUO); meanwhile, increased of mature TGF-beta1 and deposition of extracellular matrix (ECM) were observed in tubulointerstitial areas compared with sham-operated mice. However, aggravation of renal fibrosis was detected when SK1 inhibitor PF-543 was applied to suppress SK1 enzymatic activity in UUO mice. At the same time, autophagy was also inhibited by PF-543. Thus, our findings suggest that SK1 activation is renoprotective via induction of autophagy in the fibrotic process. PMID- 28733251 TI - RNA binding protein RALY promotes Protein Arginine Methyltransferase 1 alternatively spliced isoform v2 relative expression and metastatic potential in breast cancer cells. AB - Aberrant expression of Protein Arginine Methyltransferases (PRMTs) has been observed in several cancer types, including breast cancer. We previously reported that the PRMT1v2 isoform, which is generated through inclusion of alternative exon 2, is overexpressed in breast cancer cells and promotes their invasiveness. However, the precise mechanism by which expression of this isoform is controlled and how it is dysregulated in breast cancer remains unknown. Using a custom RNA interference-based screen, we identified several RNA binding proteins (RBP) which, when knocked down, altered the relative abundance of the alternatively spliced PRMT1v2 isoform. Amongst the top hits were SNW Domain containing 1 (SNW1) and RBP-associated with lethal yellow mutation (RALY), which both associated with the PRMT1 pre-mRNA and upon depletion caused an increase or decrease in the relative abundance of PRMT1v2 isoform mRNA and protein. Most importantly, a significant decrease in invasion was observed upon RALY knockdown in aggressive breast cancer cells, consistent with targeting PRMT1v2 directly, and this effect was rescued by the exogenous re-expression of PRMT1v2. We show that SNW1 expression is decreased, while RALY expression is increased in breast cancer cells and tumours, which correlates with decreased patient survival. This work revealed crucial insight into the mechanisms regulating the expression of the PRMT1 alternatively spliced isoform v2 and its dysregulation in breast cancer. It also provides proof-of-concept support for the development of therapeutic strategies where regulators of PRMT1 exon 2 alternative splicing are targeted as an approach to selectively reduce PRMT1v2 levels and metastasis in breast cancer. PMID- 28733252 TI - State of the Science of Spirituality and Palliative Care Research Part I: Definitions, Measurement, and Outcomes. AB - The State of the Science in Spirituality and Palliative Care was convened to address the current landscape of research at the intersection of spirituality and palliative care and to identify critical next steps to advance this field of inquiry. Part I of the SOS-SPC two-part series focuses on questions of 1) What is spirituality? 2) What methodological and measurement issues are most salient for research in palliative care? And 3) What is the evidence relating spirituality and health outcomes? After describing current evidence we make recommendations for future research in each of the three areas of focus. Results show wide variance in the ways spirituality is operationalized and the need for definition and conceptual clarity in research in spirituality. Furthermore, the field would benefit from hypothesis-driven outcomes research based on a priori specification of the spiritual dimensions under investigation and their longitudinal relationship with key palliative outcomes, the use of validated measures of predictors and outcomes, and rigorous assessment of potential confounding variables. Finally, results highlight the need for research in more diverse populations. PMID- 28733253 TI - State of the Science of Spirituality and Palliative Care Research: Research Landscape and Future Directions. PMID- 28733254 TI - Pre-travel advice at a crossroad: Medical preparedness of travellers to South and Southeast-Asia - The Hamburg Airport Survey. AB - BACKGROUND: Specific travel-related recommendations exist for the prevention or self-treatment of infectious diseases contracted by travellers to the tropics. In the current study, we assessed the medical preparedness per these recommendations, focusing on whether travellers carried antidiarrheal and antimalarial medication with them stratified by type of pre-travel advice. METHODS: We surveyed travellers departing from Hamburg International Airport to South or Southeast Asia, using a questionnaire on demographic, medical and travel characteristics. RESULTS: 975 travellers were analysed - the majority (817, 83%) being tourists. A large proportion packed any antidiarrheal medication (612, 63%) - most frequently loperamide (440, 72%). Only 176 of 928 (19%) travellers to destinations with low-to medium risk for malaria packed a recommended antimalarial medication. The majority (162, 17%) of them carried antimalarials as stand-by emergency treatment (SBET). 468 (48%) travellers had a pre-travel medical consultation. This lead to higher odds of carrying SBET- with the highest odds associated with a consultation at a travel medicine specialist (OR 7.83 compared to no consultation). CONCLUSIONS: Attending a travel medicine specialist was associated with better adherence to current recommendations concerning the carriage of stand-by emergency treatment of malaria. However, the proportion of travellers seeking pre-travel health advice was overall low in our population. Promoting pre-travel consultations may, therefore, lead to higher adherence to the current recommendations in travel medicine. PMID- 28733255 TI - Nanofiber-structured hydrogel yarns with pH-response capacity and cardiomyocyte drivability for bio-microactuator application. AB - : Polymeric hydrogels have great potential in soft biological micro-actuator applications. However, inappropriate micro-architecture, non-anisotropy, weak biomechanics, and inferior response behaviors limit their development. In this study, we designed and manufactured novel polyacrylonitrile (PAN)-based hydrogel yarns composed with uniaxially aligned nanofibers. The nanofibrous hydrogel yarns possessed anisotropic architecture and robust mechanical properties with flexibility, and could be assembled into defined scaffold structures by subsequent processes. The as-prepared hydrogel yarns showed excellent pH response behaviors, with around 100% maximum length and 900% maximum diameter changes, and the pH response was completed within several seconds. Moreover, the hydrogel yarns displayed unique cell-responsive abilities to promote the cell adhesion, proliferation, and smooth muscle differentiation of human adipose derived mesenchymal stem cells (HADMSC). Chicken cardiomyocytes were further seeded onto our nanofibrous hydrogel yarns to engineer living cell-based microactuators. Our results demonstrated that the uniaxially aligned nanofibrous networks within the hydrogel yarns were the key characteristics leading to the anisotropic organization of cardiac cells, and improved sarcomere organization, mimicking the cardiomyocyte bundles in the native myocardium. The construct is capable of sustaining spontaneous cardiomyocyte pumping behaviors for 7days. Our PAN-based nanofibrous hydrogel yarns are attractive for creating linear microactuators with pH-response capacity and biological microactuators with cardiomyocyte drivability. STATEMENT OF SIGNIFICANCE: A mechanically robust polyacrylonitrile based nanofibrous hydrogel yarn is fabricated by using a modified electrospinning setup in combination with chemical modification processes. The as-prepared hydrogel yarn possesses a uniaxially aligned nanofiber microarchitecture and supports a rapid, pH-dependent expansion/contraction response within a few seconds. Embryonic cardiomyocytes-seeded hydrogel yarn improves the sarcomere organization and mimics the cardiomyocyte bundles in the native myocardium, which sustains spontaneous cardiomyocyte pumping behaviors. The nanofibrous hydrogel yarn has several advantages over traditional bulk hydrogel scaffolds in terms of robust biomechanics, anisotropic aligned architecture, and superior pH response behaviors. Our nanofibrous hydrogel yarn holds the potential to be developed into novel linear and biological microactuators for various biomedical applications. PMID- 28733256 TI - Prefrontal neuromodulation reverses spatial associations of non-numerical sequences, but not numbers. AB - Numerical and non-numerical sequence items interact with spatial responding, pointing towards mental representations that are grounded in space and referred to as SNARC effects (spatial-numerical association of response codes). An ongoing controversy pertains to the universal origin of different SNARC effects and whether their underpinning is a spatial arrangement of cardinal magnitude (mental number line) or a sequential arrangement of ordinal elements in working memory. Recent results from prefrontal neuromodulation with transcranial direct current stimulation (tDCS) were supportive of the unified working memory account. The current tDCS experiment was designed to empirically test the generalizability of the prefrontal modulation effects previously found for numbers in a non-numerical sequence (weekdays) and to examine predictions from the universal account. Participants performed a series of classification tasks with numerical and non numerical sequences (1-5, Monday-Friday) before and concurrent to a prefrontal stimulation with either anodal (N=24) or cathodal polarity (N=24). Results show a dissociation of SNARC effects for numbers and weekdays by anodal tDCS: Spatial associations of weekdays were reversed by stimulation, when order was relevant for the task, but SNARC effects with number symbols were emphasized in the regular left-to-right direction, corroborating previous results. A control experiment showed that the polarity-dependent neuromodulation effects were absent in order-irrelevant font color classification, supporting the tDCS principle of activity-dependence. We discuss differences in linguistic markedness between temporal and magnitude-related classifications in an integrative account explaining the full pattern. We suggest that stimulation-enhanced psycholinguistic processing can evoke space-number associations whose direction is opposite to cultural visuospatial experience. PMID- 28733257 TI - Analysis of Fine-Needle Biopsy vs Fine-Needle Aspiration in Diagnosis of Pancreatic and Abdominal Masses: A Prospective, Multicenter, Randomized Controlled Trial. AB - BACKGROUND & AIMS: Endoscopic ultrasound (EUS)-guided fine needles with side fenestrations are used to collect aspirates for cytology analysis and biopsy samples for histologic analysis. We conducted a large, multicenter study to compare the accuracy of diagnosis via specimens collected with fine-needle biopsy (FNB) versus fine-needle aspiration (FNA) for patients with pancreatic and nonpancreatic masses. METHODS: We performed a prospective single-blind study at 5 tertiary care centers in China. The study comprised 408 patients undergoing EUS for a solid mass (>1 cm) in the pancreas, abdomen, mediastinum, or pelvic cavity, from December 2014 through January 2016. Patients were randomly assigned to groups (1:1) for assessment by FNA (n = 190) or FNB (n = 187). After lesions were identified by EUS, samples were collected in a total of 4 passes by each needle. All procedures were performed by experienced endosonographers; cytologists and pathologists were blinded to the sample collection method. Patients were followed for at least 48 weeks, and final diagnoses were obtained after surgery, imaging analysis, or resolution of lesion. The primary aim was to compare diagnostic yields of EUS-FNA with EUS-FNB for all solid masses, then separately as pancreatic and nonpancreatic masses. The secondary endpoint was the quality of histologic specimen. RESULTS: Findings from FNB analysis were accurate for 91.44% of all cases, compared with 80.00% for all FNA cases, based on final patient diagnoses (P = .0015). In patients with pancreatic masses (n = 249), findings from histologic analysis of FNBs were accurate for 92.68% of the cases, compared with 81.75% for FNAs (P = .0099). In cytology analysis of pancreatic masses, samples collected by FNB accurately identified 88.62% of all pancreatic lesions, whereas samples collected by FNA accurately identified 79.37% (P = .00468). Analyses of samples of nonpancreatic masses collected by FNA versus FNB produced similar diagnostic yields. CONCLUSIONS: In a prospective study of patients with pancreatic masses, we found EUS-guided FNB samples to produce more accurate diagnoses than samples collected by EUS-guided FNA samples. No difference in diagnostic yield was seen between EUS-FNA and EUS-FNB for nonpancreatic masses. Clinical Trials.gov no: NCT02327065. PMID- 28733258 TI - Immunoprophylaxis Failure of Infants Born to Hepatitis B Carrier Mothers Following Routine Vaccination. PMID- 28733259 TI - Addressing Physician Burnout Among Practicing Physicians. PMID- 28733260 TI - Significant Hepatic Fibrosis Among Treatment-Naive Chronic Hepatitis B Virus With Increased Hepatitis B Virus DNA and Normal Alanine Aminotransferase. PMID- 28733261 TI - Sessile Serrated Adenoma of the Appendix in an Asymptomatic Patient. PMID- 28733262 TI - Cost-effectiveness of High-performance Biomarker Tests vs Fecal Immunochemical Test for Noninvasive Colorectal Cancer Screening. AB - BACKGROUND & AIMS: Biomarker assays could increase the accuracy of noninvasive detection of colorectal cancer (CRC); fecal immunochemical tests (FITs) are estimated to miss 27%-47% of CRCs and 70%-80% of advanced adenomas per round of screening. We investigated the conditions under which biomarker screens would be cost-effective compared with FIT screens of average-risk individuals. METHODS: We used the MISCAN-Colon microsimulation model to estimate the effects of various CRC screening test characteristics on life-years gained (LYG) and; age-specific all-cause mortality was based on the 2010 Dutch life tables. Simulated CRC incidence rate and CRC stage distribution were calibrated to observed data in The Netherlands from 1999 through 2003 (before opportunities for screening). Survival rates after diagnosis of CRC at an age younger than 75 years were based on CRC relative survival data from 1985 through 2004; survival for individuals diagnosed at an age of 75 years or older was adjusted to fit the observed age-increasing mortality/incidence ratio. We modeled FIT along with hypothetical biomarker tests with different test performance levels. For each biomarker test we calculated the maximum unit cost for the test to be cost-effective compared with FIT, assuming a willingness-to-pay threshold of ?50,000 ($56,000) per LYG. RESULTS: Biennial FIT screening of subjects 55-75 years old provided 84.9 LYG at a cost of ?122,000 ($137,000) per 1000 participants. Considering a unit cost of ?7 ($8) for FIT (including kit and analysis only, excluding organizational costs), a biomarker test that detects CRC with higher levels of specificity and sensitivity (100%) and advanced adenomas at a proportionally higher level of sensitivity (53%) should never exceed a cost of ?51 ($57). The threshold cost could increase to more than ?200 ($224) for high-performing biomarker tests in cases of limited colonoscopy capacity or higher uptake of this test. CONCLUSIONS: By using the MISCAN-Colon microsimulation model to estimate effects of CRC screening tests, we found that for a biomarker test with increased overall performance to be cost effective, it should not exceed 7-fold the unit cost of FIT. This maximum would increase substantially if colonoscopy becomes more expensive or scarce, or if the new test has higher screening uptake. These values could be used to estimate the added value of new biomarkers compared with current FIT screening. PMID- 28733263 TI - Consolidation Therapy for Newly Diagnosed Pediatric Patients with High-Risk Neuroblastoma Using Busulfan/Melphalan, Autologous Hematopoietic Cell Transplantation, Anti-GD2 Antibody, Granulocyte-Macrophage Colony-Stimulating Factor, Interleukin-2, and Haploidentical Natural Killer Cells. AB - The treatment of pediatric high-risk neuroblastoma is intensive and multimodal. Despite the introduction of immunotherapy for minimal residual disease, survival rates remain suboptimal and new therapies are needed. As part of a phase 2 trial, we are using a consolidation therapy regimen that combines a busulfan/melphalan conditioning schema, autologous hematopoietic cell transplantation (AHCT), and experimental immunotherapy with hu14.18K322A (a humanized anti-GD2 monoclonal antibody), granulocyte-macrophage colony-stimulating factor (GM-CSF), and IL-2, with or without the adoptive transfer of haploidentical natural killer cells (NKs). Here we report on 30 patients who have undergone AHCT with this experimental immunotherapy regimen, 21 of whom received haploidentical NKs. The median time to neutrophil engraftment was 13 days (range, 10 to 28 days) and to platelet engraftment of at least 20 * 103/mm3 was 36.5 days (range, 0 to 102 days); no clinical difference was seen in those who did or did not receive NKs. Eight patients developed veno-occlusive disease, with 3 having multiorgan dysfunction. Toxicities were similar for patients who did or did not receive NKs. We conclude that this consolidation regimen is feasible and has an acceptable acute toxicity profile. PMID- 28733264 TI - The Impact of Toxicities on First-Year Outcomes after Ex Vivo CD34+-Selected Allogeneic Hematopoietic Cell Transplantation in Adults with Hematologic Malignancies. AB - Factors that impact first-year morbidity and mortality in adults undergoing myeloablative allogeneic hematopoietic cell transplantation with ex vivo CD34+ selection have not been previously reported. We assessed all toxicities >= grade 3 from the start of conditioning to date of death, relapse, or last contact in 200 patients during the first year after transplantation, identifying 1885 individual toxicities among 17 organ-based toxicity groups. The most prevalent toxicities in the first year were of infectious, metabolic, hematologic, oral/gastrointestinal, hepatic, cardiac, and pulmonary etiologies. Renal complications were minimal. Grades II to IV and III and IV acute GVHD at day 100 were 11.5% and 3%, respectively. In separate multivariate models, cardiovascular, hematologic, hepatic, neurologic, pulmonary, and renal toxicities negatively impacted nonrelapse mortality (NRM) and overall survival during the first year. A higher-than-targeted busulfan level, patient cytomegalovirus seropositivity, and an Hematopoietic Cell Transplantation-Specific Comorbidity Index of >=3 were associated with increased risk of NRM and all-cause death. Ex vivo CD34+ selection had a favorable 1-year OS of 75% and NRM of 17% and a low incidence of sinusoidal obstruction syndrome. These data establish a benchmark to focus efforts in reducing toxicity burden while improving patient outcomes. PMID- 28733265 TI - Outcomes of Hematopoietic Stem Cell Transplantation at a Limited-Resource Center in Mexico Are Comparable to Those in Developed Countries. AB - The first hematopoietic stem cell transplantation (HSCT) in Mexico was performed at our institution in 1980. Eighteen years later, our HSCT program was restructured to reduce transplantation-related mortality (TRM) and improve overall survival (OS). The aim of this study was to describe outcomes of HSCT at our institution despite limited resources. Consecutive patients undergoing HSCT, from November 1998 to February 2017, were retrospectively analyzed at the National Institute of Medical Sciences and Nutrition Salvador Zubiran in Mexico City. Three hundred nine HSCT (59% autologous) were performed in 275 patients. From 114 patients (41%) undergoing an allogeneic HSCT, acute and chronic graft versus-host disease developed in 21% and 33%, respectively. From the entire cohort, 98 patients relapsed after HSCT and at the last follow-up, 183 (67%) patients were alive. The 100-day TRM rates were 1.9% and 6.1% for autologous and allogeneic HSCT, respectively. Ten-year relapse/progression-free survival were 54% and 65%, for autologous and allogeneic HSCT, respectively. Ten-year OS rates in autologous and allogeneic HSCT were 61% and 57%, respectively. We highlight that HSCT is feasible in developing countries, despite financial and infrastructure limitations, and conclude that our results are comparable to international literature and probably better in terms of TRM and cost effectiveness. PMID- 28733266 TI - Long-Term Results of High-Dose Therapy and Autologous Stem Cell Transplantation for Mantle Cell Lymphoma: Effectiveness of Maintenance Rituximab. AB - High-dose therapy followed by autologous stem cell transplantation (ASCT) can improve outcomes for mantle cell lymphoma (MCL) but is associated with a high incidence of relapse. A retrospective study of 191 MCL patients who underwent ASCT at City of Hope was performed to examine prognostic factors for outcomes after ASCT. For all patients the 5-year overall survival (OS) was 71% (95% confidence interval [CI], 63% to 77%) and progression-free survival (PFS) was 53% (95% CI, 45% to 60%). The 5-year cumulative incidence of relapse was 41% (95% CI, 34% to 48%) with a continuous pattern of relapse events occurring at a median of 2.1 years (range, .2 to 13.4) after ASCT. In multivariate analysis, post transplant maintenance rituximab was the factor most significantly associated with both OS (relative risk [RR], .17; 95% CI, .07 to .38) and PFS (RR, .25; 95% CI, .14 to .44). For the subset of patients who had positron emission tomography (PET) data available and were in a PET-negative first complete remission at ASCT (n = 105), maintenance rituximab was significantly associated with superior OS (RR, .17; 95% CI, .05 to .59) and PFS (RR, .20; 95% CI, .09 to .43). These results support a benefit with maintenance rituximab for all MCL patients treated with ASCT. PMID- 28733267 TI - ANGPTL4 promotes bile acid absorption during taurocholic acid supplementation via a mechanism dependent on the gut microbiota. AB - Angiopoietin-like 4 (ANGPTL4) raises plasma triglyceride levels by inhibiting lipoprotein lipase. A set of compounds that are able to reduce plasma triglyceride levels are bile acids (BA). Because BA have been shown to decrease ANGPTL4 secretion by intestinal cells, we hypothesized that BA lower plasma triglycerides (partly) via ANGPTL4. To test that hypothesis, wild-type and Angptl4-/- mice were fed chow supplemented with taurocholic acid (TCA) for seven days. TCA supplementation effectively lowered plasma triglycerides in wild-type and Angptl4-/- mice, indicating that ANGPTL4 is not required for plasma triglyceride-lowering by BA. Intriguingly, however, plasma and hepatic BA concentrations were significantly lower in TCA-supplemented Angptl4-/- mice than in TCA-supplemented wild-type mice. These changes in the Angptl4-/- mice were accompanied by lower BA levels in ileal scrapings and decreased expression of FXR target genes in the ileum, including the BA transporter Slc10a2. By contrast, faecal excretion of specifically primary BA was higher in the Angptl4-/- mice, suggesting that loss of ANGPTL4 impairs intestinal BA absorption. Since the gut microbiota converts primary BA into secondary BA, elevated excretion of primary BA in Angptl4-/- mice may reflect differences in gut microbial composition and/or functionality. Indeed, colonic microbial composition was markedly different between Angptl4-/- and wild-type mice. Suppression of the gut bacteria using antibiotics abolished differences in plasma, hepatic, and faecal BA levels between TCA-supplemented Angptl4-/- and wild-type mice. In conclusion, 1) ANGPTL4 is not involved in the triglyceride-lowering effect of BA; 2) ANGPTL4 promotes BA absorption during TCA supplementation via a mechanism dependent on the gut microbiota. PMID- 28733268 TI - Carriers of an apolipoprotein E epsilon 4 allele are more vulnerable to a dietary deficiency in omega-3 fatty acids and cognitive decline. AB - Carriers of an epsilon 4 allele (E4) of apolipoprotein E (APOE) develop Alzheimer's disease (AD) earlier than carriers of other APOE alleles. The metabolism of plasma docosahexaenoic acid (DHA, 22:6n-3), an omega-3 fatty acid (n-3 FA), taken up by the brain and concentrated in neurons, is disrupted in E4 carriers, resulting in lower levels of brain DHA. Behavioural and cognitive impairments have been observed in animals with lower brain DHA levels, with emphasis on loss of spatial memory and increased anxiety. E4 mice provided a diet deficient in n-3 FA had a greater depletion of n-3 FA levels in organs and tissues than mice carrying other APOE alleles. However, providing n-3 FA can restore levels of brain DHA in E4 animals and in other models of n-3 FA deficiency. In E4 carriers, supplementation with DHA as early as possible might help to prevent the onset of AD and could halt the progression of, and reverse some of the neurological and behavioural consequences of their higher vulnerability to n-3 FA deficiency. PMID- 28733269 TI - The Current Role of Whole Brain Radiation Therapy in Non-Small Cell Lung Cancer Patients. AB - The incidence of brain metastases has increased in patients with NSCLC as a result of better systemic disease control and advances in imaging modalities. Whole brain radiotherapy (WBRT) has been the mainstay treatment of multiple symptomatic brain metastases for years. A number of recent publications have questioned its place in the absence of a survival and quality of life benefit and the possible risk for long-term neurotoxicity. Omission or deferral of WBRT and strategies consisting of stereotactic radiosurgery or delivery of systemic therapies alone are being proposed more and more. However, critical analysis of the literature shows that WBRT still has relevant indications in well-selected patients. Within this review, we discuss the place of WBRT in the modern management of patients with NSCLC. PMID- 28733271 TI - Telerehabilitation: Review of the State-of-the-Art and Areas of Application. AB - BACKGROUND: Telemedicine applications have been increasing due to the development of new computer science technologies and of more advanced telemedical devices. Various types of telerehabilitation treatments and their relative intensities and duration have been reported. OBJECTIVE: The objective of this review is to provide a detailed overview of the rehabilitation techniques for remote sites (telerehabilitation) and their fields of application, with analysis of the benefits and the drawbacks related to use. We discuss future applications of telerehabilitation techniques with an emphasis on the development of high-tech devices, and on which new tools and applications can be used in the future. METHODS: We retrieved relevant information and data on telerehabilitation from books, articles and online materials using the Medical Subject Headings (MeSH) "telerehabilitation," "telemedicine," and "rehabilitation," as well as "disabling pathologies." RESULTS: Telerehabilitation can be considered as a branch of telemedicine. Although this field is considerably new, its use has rapidly grown in developed countries. In general, telerehabilitation reduces the costs of both health care providers and patients compared with traditional inpatient or person to-person rehabilitation. Furthermore, patients who live in remote places, where traditional rehabilitation services may not be easily accessible, can benefit from this technology. However, certain disadvantages of telerehabilitation, including skepticism on the part of patients due to remote interaction with their physicians or rehabilitators, should not be underestimated. CONCLUSIONS: This review evaluated different application fields of telerehabilitation, highlighting its benefits and drawbacks. This study may be a starting point for improving approaches and devices for telerehabilitation. In this context, patients' feedback may be important to adapt rehabilitation techniques and approaches to their needs, which would subsequently help to improve the quality of rehabilitation in the future. The need for proper training and education of people involved in this new and emerging form of intervention for more effective treatment can't be overstated. PMID- 28733270 TI - Evaluating a Web-Based Coaching Program Using Electronic Health Records for Patients With Chronic Obstructive Pulmonary Disease in China: Randomized Controlled Trial. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is now the fourth leading cause of death in the world, and it continues to increase in developing countries. The World Health Organization expects COPD to be the third most common cause of death in the world by 2020. Effective and continuous postdischarge care can help patients to maintain good health. The use of electronic health records (EHRs) as an element of community health care is new technology in China. OBJECTIVE: The aim of this study was to develop and evaluate a Web-based coaching program using EHRs for physical function and health-related quality of life for patients with COPD in China. METHODS: A randomized controlled trial was conducted from 2008 to 2015 at two hospitals. The control group received routine care and the intervention group received routine care with the addition of the Web-based coaching program using EHRs. These were used to manage patients' demographic and clinical variables, publish relevant information, and have communication between patients and health care providers. Participants were not blinded to group assignment. The effects of the intervention were evaluated by lung function, including percent of forced expiratory volume in 1 second (FEV1%), percent of forced vital capacity (FVC%), peak expiratory flow (PEF), maximum midexpiratory flow; St George's Respiratory Questionnaire (SGRQ); Modified Medical Research Council Dyspnea Scale (MMRC); and 6-Minute Walk Test (6MWT). Data were collected before the program, and at 1, 3, 6, and 12 months after the program. RESULTS: Of the 130 participants, 120 (92.3%) completed the 12-month follow-up program. There were statistically significant differences in lung function (FEV1%: F1,4=5.47, P=.002; FVC%: F1,4=3.06, P=.02; PEF: F1,4=12.49, P<.001), the total score of SGRQ (F1,4=23.30, P<.001), symptoms of SGRQ (F1,4=12.38, P<.001), the activity of SGRQ (F1,4=8.35, P<.001), the impact of SGRQ (F1,4=12.26, P<.001), MMRC (F1,4=47.94, P<.001), and 6MWT (F1,4=35.54, P<.001) between the two groups with the variation of time tendency. CONCLUSIONS: The Web-based coaching program using EHRs in China appears to be useful for patients with COPD when they are discharged from hospital into the community. It promotes the sharing of patients' medical information by hospital and community nurses, and achieves dynamic management and follow-up analysis for patients' disease. In addition, this program can postpone the decreasing rate of lung function, improve quality of life, decrease dyspnea, and increase physical capacity. PMID- 28733273 TI - WhatsApp Messenger as an Adjunctive Tool for Telemedicine: An Overview. AB - BACKGROUND: The advent of telemedicine has allowed physicians to deliver medical treatment to patients from a distance. Mobile apps such as WhatsApp Messenger, an instant messaging service, came as a novel concept in all fields of social life, including medicine. The use of instant messaging services has been shown to improve communication within medical teams by providing means for quick teleconsultation, information sharing, and starting treatment as soon as possible. OBJECTIVE: The aim of this study was to perform a comprehensive systematic review of present literature on the use of the WhatsApp Messenger app as an adjunctive health care tool for medical doctors. METHODS: Searches were performed in PubMed, EMBASE, and the Cochrane Library using the term "whatsapp*" in articles published before January 2016. A bibliography of all relevant original articles that used the WhatsApp Messenger app was created. The level of evidence of each study was determined according to the Oxford Levels of Evidence ranking system produced by the Oxford Centre for Evidence-Based Medicine. The impact and the indications of WhatsApp Messenger are discussed in order to understand the extent to which this app currently functions as an adjunctive tool for telemedicine. RESULTS: The database search identified a total of 30 studies in which the term "whatsapp*" was used. Each article's list of references was evaluated item-by-item. After literature reviews, letters to the editor, and low quality studies were excluded, a total of 10 studies were found to be eligible for inclusion. Of these studies, 9 had been published in the English language and 1 had been published in Spanish. Five were published by medical doctors. CONCLUSIONS: The pooled data presents compelling evidence that the WhatsApp Messenger app is a promising system, whether used as a communication tool between health care professionals, as a means of communication between health care professionals and the general public, or as a learning tool for providing health care information to professionals or to the general population. However, high quality and properly evaluated research is needed, as are improvements in descriptions of the methodology and the study processes. These improvements will allow WhatsApp Messenger to be categorically defined as an effective telemedicine tool in many different fields of health care. PMID- 28733272 TI - Adherence to Web-Based Self-Assessments in Long-Term Direct-to-Patient Research: Two-Year Study of Multiple Sclerosis Patients. AB - BACKGROUND: Direct-to-patient research via Web-based questionnaires is increasingly being used. Missed data or delayed reporting of data may negatively affect the quality of study results. It is insufficiently known to what degree patients adhere to agreed self-assessment schedule over the long term and whether questionnaires are filled out in a timely manner. OBJECTIVE: The objective of this study was to investigate patients' adherence to a self-assessment schedule with low-frequency long questionnaires versus that with a high-frequency short questionnaire. METHODS: In this study, the 36-item MS Impact Profile (MSIP) questionnaire measured (perceived) disabilities and the 54-item MS Quality of Life-54 (MSQoL-54) questionnaire measured health-related quality of life at 6 month intervals. Additionally, the 2-item Medication and Adherence (MA) questionnaire documented medication and adherence to disease-modifying medication every month. An experienced MS nurse assessed the Expanded Disability Status Scale (EDSS) score via phone. For both the self-assessment schedules, we calculated the percentage of patients who had completed all the questionnaires in the first 2 years (completion adherence), the percentage of patients who completed all the questionnaires within set time frames (interval adherence), the relationship between adherence and the EDSS score, and the timing of EDSS assessment. RESULTS: Of the 331 patients who enrolled themselves, 301 patients completed at least one questionnaire. At month six (M6), M12, M18, and M24, the MSIP was completed by 83.4% (251/301), 71.8% (216/301), 68.1% (205/301), and 58.5% (176/301) of the patients, respectively; the MSQoL-54 by 82.1% (247/301), 71.8% (216/301), 66.8% (201/301), and 57.1% (172/301), respectively; and the MA questionnaire by 80.1% (241/301), 70.4% (212/301), 62.1% (187/301), and 53.5% (161/301), respectively. For the MSIP, 56.8% (171/301) of the patients were 2 year completion adherent; 55.5% (167/301) and 53.5% (161/301) of the patients were completion adherent for the MSQoL-54 and MA questionnaires, respectively. Whereas 85.5% (142/166) of the patients were interval adherent for the MSIP and MSQoL-54, 25.5% (41/161) were interval adherent for the MA questionnaire, with 73.9% (119/161) exceeding the maximum MA monthly interassessment interval. Completion adherence for the monthly short MA questionnaire was higher in patients with moderately high disability (EDSS 5.0-5.5) than for those with no or minimal disability (EDSS 0-2.5) (OR 5.47, 95% CI 1.08-27.69; P=.040). Completion adherence was also higher in patients with EDSS assessment within 6 months after baseline than in those with later assessment (OR 1.810, 95% CI 0.999-3.280; P=.050). CONCLUSIONS: The 2-year completion adherence to Web-based self assessments did not differ between the low-frequency long questionnaires and a high-frequency short questionnaire, but the interval adherence was substantially higher for the low-frequency long questionnaires. Personal contact with a member of the research team regarding a clinically relevant professional-reported outcome early in the study might positively affect the long-term completion adherence in direct-to-patient studies. PMID- 28733274 TI - Designing toughness and strength for soft materials. PMID- 28733275 TI - Which way to low-density liquid water? PMID- 28733276 TI - Whether the hearing brain hears it or the deaf brain sees it, it's just the same. PMID- 28733277 TI - A civilised society should enable people to end their life. PMID- 28733278 TI - Microbiomarkers in inflammatory bowel diseases: caveats come with caviar. PMID- 28733279 TI - Cholangiocytes and the environment in primary sclerosing cholangitis: where is the link? PMID- 28733280 TI - Construction and Optimization of a Heterologous Pathway for Protocatechuate Catabolism in Escherichia coli Enables Bioconversion of Model Aromatic Compounds. AB - The production of biofuels from lignocellulose yields a substantial lignin by product stream that currently has few applications. Biological conversion of lignin-derived compounds into chemicals and fuels has the potential to improve the economics of lignocellulose-derived biofuels, but few microbes are able both to catabolize lignin-derived aromatic compounds and to generate valuable products. While Escherichia coli has been engineered to produce a variety of fuels and chemicals, it is incapable of catabolizing most aromatic compounds. Therefore, we engineered E. coli to catabolize protocatechuate, a common intermediate in lignin degradation, as the sole source of carbon and energy via heterologous expression of a nine-gene pathway from Pseudomonas putida KT2440. We next used experimental evolution to select for mutations that increased growth with protocatechuate more than 2-fold. Increasing the strength of a single ribosome binding site in the heterologous pathway was sufficient to recapitulate the increased growth. After optimization of the core pathway, we extended the pathway to enable catabolism of a second model compound, 4-hydroxybenzoate. These engineered strains will be useful platforms to discover, characterize, and optimize pathways for conversions of lignin-derived aromatics.IMPORTANCE Lignin is a challenging substrate for microbial catabolism due to its polymeric and heterogeneous chemical structure. Therefore, engineering microbes for improved catabolism of lignin-derived aromatic compounds will require the assembly of an entire network of catabolic reactions, including pathways from genetically intractable strains. Constructing defined pathways for aromatic compound degradation in a model host would allow rapid identification, characterization, and optimization of novel pathways. We constructed and optimized one such pathway in E. coli to enable catabolism of a model aromatic compound, protocatechuate, and then extended the pathway to a related compound, 4-hydroxybenzoate. This optimized strain can now be used as the basis for the characterization of novel pathways. PMID- 28733281 TI - Structural and Mechanistic Insights into the Improvement of the Halotolerance of a Marine Microbial Esterase by Increasing Intra- and Interdomain Hydrophobic Interactions. AB - Halotolerant enzymes are beneficial for industrial processes requiring high salt concentrations and low water activity. Most halophilic proteins are evolved to have reduced hydrophobic interactions on the surface and in the hydrophobic cores for their haloadaptation. However, in this study, we improved the halotolerance of a thermolabile esterase, E40, by increasing intraprotein hydrophobic interactions. E40 was quite unstable in buffers containing more than 0.3 M NaCl, and its kcat and substrate affinity were both significantly reduced in 0.5 M NaCl. By introducing hydrophobic residues in loop 1 of the CAP domain and/or alpha7 of the catalytic domain in E40, we obtained several mutants with improved halotolerance, and the M3 S202W I203F mutant was the most halotolerant. ("M3" represents a mutation in loop 1 of the CAP domain in which residues R22-K23-T24 of E40 are replaced by residues Y22-K23-H24-L25-S26 of Est2.) Then we solved the crystal structures of the S202W I203F and M3 S202W I203F mutants to reveal the structural basis for their improved halotolerance. Structural analysis revealed that the introduction of hydrophobic residues W202 and F203 in alpha7 significantly improved E40 halotolerance by strengthening intradomain hydrophobic interactions of F203 with W202 and other residues in the catalytic domain. By further introducing hydrophobic residues in loop 1, the M3 S202W I203F mutant became more rigid and halotolerant due to the formation of additional interdomain hydrophobic interactions between the introduced Y22 in loop 1 and W204 in alpha7. These results indicate that increasing intraprotein hydrophobic interactions is also a way to improve the halotolerance of enzymes with industrial potential under high-salt conditions.IMPORTANCE Esterases and lipases for industrial application are often subjected to harsh conditions such as high salt concentrations, low water activity, and the presence of organic solvents. However, reports on halotolerant esterases and lipases are limited, and the underlying mechanism for their halotolerance is still unclear due to the lack of structures. In this study, we focused on the improvement of the halotolerance of a salt-sensitive esterase, E40, and the underlying mechanism. The halotolerance of E40 was significantly improved by introducing hydrophobic residues. Comparative structural analysis of E40 and its halotolerant mutants revealed that increased intraprotein hydrophobic interactions make these mutants more rigid and more stable than the wild type against high concentrations of salts. This study shows a new way to improve enzyme halotolerance, which is helpful for protein engineering of salt-sensitive enzymes. PMID- 28733283 TI - Osmotic Compounds Enhance Antibiotic Efficacy against Acinetobacter baumannii Biofilm Communities. AB - Biofilm-associated infections are a clinical challenge, in part because a hydrated matrix protects the bacterial community from antibiotics. Herein, we evaluated how different osmotic compounds (maltodextrin, sucrose, and polyethylene glycol [PEG]) enhance antibiotic efficacy against Acinetobacter baumannii biofilm communities. Established (24-h) test tube biofilms (strain ATCC 17978) were treated with osmotic compounds in the presence or absence of 10* the MIC of different antibiotics (50 MUg/ml tobramycin, 20 MUg/ml ciprofloxacin, 300 MUg/ml chloramphenicol, 30 MUg/ml nalidixic acid, or 100 MUg/ml erythromycin). Combining antibiotics with hypertonic concentrations of the osmotic compounds for 24 h reduced the number of biofilm bacteria by 5 to 7 log (P < 0.05). Increasing concentrations of osmotic compounds improved the effect, but there was a trade off with increasing solution viscosity, whereby low-molecular-mass compounds (sucrose, 400-Da PEG) worked better than higher-mass compounds (maltodextrin, 3,350-Da PEG). Ten other A. baumannii strains were similarly treated with 400-Da PEG and tobramycin, resulting in a mean 2.7-log reduction in recoverable bacteria compared with tobramycin treatment alone. Multivariate regression models with data from different osmotic compounds and nine antibiotics demonstrated that the benefit from combining hypertonic treatments with antibiotics is a function of antibiotic mass and lipophilicity (r2 > 0.82; P < 0.002), and the relationship was generalizable for biofilms formed by A. baumannii and Escherichia coli K-12. Augmenting topical antibiotic therapies with a low-mass hypertonic treatment may enhance the efficacy of antibiotics against wound biofilms, particularly when using low-mass hydrophilic antibiotics.IMPORTANCE Biofilms form a barrier that protects bacteria from environmental insults, including exposure to antibiotics. We demonstrated that multiple osmotic compounds can enhance antibiotic efficacy against Acinetobacter baumannii biofilm communities, but viscosity is a limiting factor, and the most effective compounds have lower molecular mass. The synergism between osmotic compounds and antibiotics is also dependent on the hydrophobicity and mass of the antibiotics. The statistical models presented herein provide a basis for predicting the optimal combination of osmotic compounds and antibiotics against surface biofilms communities. PMID- 28733282 TI - Differentiating Botulinum Neurotoxin-Producing Clostridia with a Simple, Multiplex PCR Assay. AB - Diverse members of the genus Clostridium produce botulinum neurotoxins (BoNTs), which cause a flaccid paralysis known as botulism. While multiple species of clostridia produce BoNTs, the majority of human botulism cases have been attributed to Clostridium botulinum groups I and II. Recent comparative genomic studies have demonstrated the genomic diversity within these BoNT-producing species. This report introduces a multiplex PCR assay for differentiating members of C. botulinum group I, C. sporogenes, and two major subgroups within C. botulinum group II. Coding region sequences unique to each of the four species/subgroups were identified by in silico analyses of thousands of genome assemblies, and PCR primers were designed to amplify each marker. The resulting multiplex PCR assay correctly assigned 41 tested isolates to the appropriate species or subgroup. A separate PCR assay to determine the presence of the ntnh gene (a gene associated with the botulinum neurotoxin gene cluster) was developed and validated. The ntnh gene PCR assay provides information about the presence or absence of the botulinum neurotoxin gene cluster and the type of gene cluster present (ha positive [ha+] or orfX+). The increased availability of whole-genome sequence data and comparative genomic tools enabled the design of these assays, which provide valuable information for characterizing BoNT-producing clostridia. The PCR assays are rapid, inexpensive tests that can be applied to a variety of sample types to assign isolates to species/subgroups and to detect clostridia with botulinum neurotoxin gene (bont) clusters.IMPORTANCE Diverse clostridia produce the botulinum neurotoxin, one of the most potent known neurotoxins. In this study, a multiplex PCR assay was developed to differentiate clostridia that are most commonly isolated in connection with human botulism cases: C. botulinum group I, C. sporogenes, and two major subgroups within C. botulinum group II. Since BoNT-producing and nontoxigenic isolates can be found in each species, a PCR assay to determine the presence of the ntnh gene, which is a universally present component of bont gene clusters, and to provide information about the type (ha+ or orfX+) of bont gene cluster present in a sample was also developed. The PCR assays provide simple, rapid, and inexpensive tools for screening uncharacterized isolates from clinical or environmental samples. The information provided by these assays can inform epidemiological studies, aid with identifying mixtures of isolates and unknown isolates in culture collections, and confirm the presence of bacteria of interest. PMID- 28733284 TI - Specific Signatures of the Gut Microbiota and Increased Levels of Butyrate in Children Treated with Fermented Cow's Milk Containing Heat-Killed Lactobacillus paracasei CBA L74. AB - We recently demonstrated that cow's milk fermented with the probiotic Lactobacillus paracasei CBA L74 (FM-CBAL74) reduces the incidence of respiratory and gastrointestinal tract infections in young children attending school. This effect apparently derives from a complex regulation of non-immune and immune protective mechanisms. We investigated whether FM-CBAL74 could regulate gut microbiota composition and butyrate production. We randomly selected 20 healthy children (12 to 48 months) from the previous randomized controlled trial, before (t0) and after 3 months (t3) of dietary treatment with FM-CBAL74 (FM) or placebo (PL). Fecal microbiota was profiled using 16S rRNA gene amplicon sequencing, and the fecal butyrate concentration was also measured. Microbial alpha and beta diversities were not significantly different between groups prior to treatment. FM-CBAL74 but not PL treatment increased the relative abundance of Lactobacillus Individual Blautia, Roseburia, and Faecalibacterium oligotypes were associated with FM-CBAL74 treatment and demonstrated correlative associations with immune biomarkers. Accordingly, PICRUSt analysis predicted an increase in the proportion of genes involved in butyrate production pathways, consistent with an increase in fecal butyrate observed only in the FM group. Dietary supplementation with FM CBAL74 induces specific signatures in gut microbiota composition and stimulates butyrate production. These effects are associated with changes in innate and acquired immunity.IMPORTANCE The use of a fermented milk product containing the heat-killed probiotic strain Lactobacillus paracasei CBAL74 induces changes in the gut microbiota, promoting the development of butyrate producers. These changes in the gut microbiota composition correlate with increased levels of innate and acquired immunity biomarkers. PMID- 28733285 TI - Transcriptional Modulation of Transport- and Metabolism-Associated Gene Clusters Leading to Utilization of Benzoate in Preference to Glucose in Pseudomonas putida CSV86. AB - The effective elimination of xenobiotic pollutants from the environment can be achieved by efficient degradation by microorganisms even in the presence of sugars or organic acids. Soil isolate Pseudomonas putida CSV86 displays a unique ability to utilize aromatic compounds prior to glucose. The draft genome and transcription analyses revealed that glucose uptake and benzoate transport and metabolism genes are clustered at the glc and ben loci, respectively, as two distinct operons. When grown on glucose plus benzoate, CSV86 displayed significantly higher expression of the ben locus in the first log phase and of the glc locus in the second log phase. Kinetics of substrate uptake and metabolism matched the transcription profiles. The inability of succinate to suppress benzoate transport and metabolism resulted in coutilization of succinate and benzoate. When challenged with succinate or benzoate, glucose-grown cells showed rapid reduction in glc locus transcription, glucose transport, and metabolic activity, with succinate being more effective at the functional level. Benzoate and succinate failed to interact with or inhibit the activities of glucose transport components or metabolic enzymes. The data suggest that succinate and benzoate suppress glucose transport and metabolism at the transcription level, enabling P. putida CSV86 to preferentially metabolize benzoate. This strain thus has the potential to be an ideal host to engineer diverse metabolic pathways for efficient bioremediation.IMPORTANCEPseudomonas strains play an important role in carbon cycling in the environment and display a hierarchy in carbon utilization: organic acids first, followed by glucose, and aromatic substrates last. This limits their exploitation for bioremediation. This study demonstrates the substrate-dependent modulation of ben and glc operons in Pseudomonas putida CSV86, wherein benzoate suppresses glucose transport and metabolism at the transcription level, leading to preferential utilization of benzoate over glucose. Interestingly, succinate and benzoate are cometabolized. These properties are unique to this strain compared to other pseudomonads and open up avenues to unravel novel regulatory processes. Strain CSV86 can serve as an ideal host to engineer and facilitate efficient removal of recalcitrant pollutants even in the presence of simpler carbon sources. PMID- 28733286 TI - Regulator LdhR and d-Lactate Dehydrogenase LdhA of Burkholderia multivorans Play Roles in Carbon Overflow and in Planktonic Cellular Aggregate Formation. AB - LysR-type transcriptional regulators (LTTRs) are the most commonly found regulators in Burkholderia cepacia complex, comprising opportunistic pathogens causing chronic respiratory infections in cystic fibrosis (CF) patients. Despite LTTRs being global regulators of pathogenicity in several types of bacteria, few have been characterized in Burkholderia Here, we show that gene ldhR of B. multivorans encoding an LTTR is cotranscribed with ldhA encoding a d-lactate dehydrogenase and evaluate their implication in virulence traits such as exopolysaccharide (EPS) synthesis and biofilm formation. A comparison of the wild type (WT) and its isogenic DeltaldhR mutant grown in medium with 2% d-glucose revealed a negative impact on EPS biosynthesis and on cell viability in the presence of LdhR. The loss of viability in WT cells was caused by intracellular acidification as a consequence of the cumulative secretion of organic acids, including d-lactate, which was absent from the DeltaldhR mutant supernatant. Furthermore, LdhR is implicated in the formation of planktonic cellular aggregates. WT cell aggregates reached 1,000 MUm in size after 24 h in liquid cultures, in contrast to DeltaldhR mutant aggregates that never grew more than 60 MUm. The overexpression of d-lactate dehydrogenase LdhA in the DeltaldhR mutant partially restored the formed aggregate size, suggesting a role for fermentation inside aggregates. Similar results were obtained for surface-attached biofilms, with WT cells producing more biofilm. A systematic evaluation of planktonic aggregates in Burkholderia CF clinical isolates showed aggregates in 40 of 74. As CF patients' lung environments are microaerophilic and bacteria are found as free aggregates/biofilms, LdhR and LdhA might have central roles in adapting to this environment.IMPORTANCE Cystic fibrosis patients often suffer from chronic respiratory infections caused by several types of microorganisms. Among them are the Burkholderia cepacia complex bacteria, which cause progressive deterioration of lung function that, in some patients, might develop into fatal necrotizing pneumoniae with bacteremia, known as "cepacia syndrome." Burkholderia pathogenesis is multifactorial as they express several virulence factors, form biofilms, and are highly resistant to antimicrobial compounds, making their eradication from the CF patients' airways very difficult. As Burkholderia is commonly found in CF lungs in the form of cell aggregates and biofilms, the need to investigate the mechanisms of cellular aggregation is obvious. In this study, we demonstrate the importance of a d-lactate dehydrogenase and a regulator in regulating carbon overflow, cellular aggregates, and surface-attached biofilm formation. This not only enhances our understanding of Burkholderia pathogenesis but can also lead to the development of drugs against these proteins to circumvent biofilm formation. PMID- 28733287 TI - Identification of the hcb gene operon involved in catalyzing aerobic hexachlorobenzene dechlorination in Nocardioides sp. strain PD653. AB - Nocardioides sp. strain PD653 was the first aerobic bacterium capable of mineralizing hexachlorobenzene (HCB) that was identified. In this study, strain PD653-B2, which was unexpectedly isolated from a subculture of strain PD653, was found to lack the ability to transform HCB or pentachloronitrobenzene into pentachlorophenol. Comparative genome analysis of the two strains revealed that genetic rearrangement had occurred in strain PD653-B2, with a genomic region present in strain PD653 being deleted. In silico analysis allowed three open reading frames within this region to be identified as candidate genes involved in HCB dechlorination. Assays using recombinant Escherichia coli cells revealed that an operon is responsible for both oxidative HCB dechlorination and pentachloronitrobenzene denitration. The metabolite pentachlorophenol was detected in the cultures produced in the E. coli assays. Significantly less HCB degrading activity occurred in assays under oxygen-limited conditions ([O2] < 0.5 mg L-1) than in aerobic assays, suggesting that monooxygenase is involved in the reaction. In this operon, hcbA1 was found to encode a monooxygenase involved in HCB dechlorination. this monooxygenase may form a complex with the flavin reductase encoded by hcbA3, increasing the HCB-degrading activity of PD653.Importance: The organochlorine fungicide HCB is widely distributed in the environment. Bioremediation can effectively remove HCB from contaminated sites, but HCB-degrading microorganisms have been isolated in few studies, and the genes involved in HCB degradation have not been identified. In this study, possible genes involved in the initial step of the mineralization of HCB by Nocardioides sp. strain PD653 were identified. The results improve our understanding of the protein families involved in the dechlorination of HCB to give pentachlorophenol. PMID- 28733288 TI - Bacillomycin D Produced by Bacillus amyloliquefaciens Is Involved in the Antagonistic Interaction with the Plant-Pathogenic Fungus Fusarium graminearum. AB - Fusarium graminearum (teleomorph: Ascomycota, Hypocreales, Gibberella, Gibberella zeae) is a destructive fungal pathogen that threatens the production and quality of wheat and barley worldwide. Controlling this toxin-producing pathogen is a significant challenge. In the present study, the commercially available strain Bacillus amyloliquefaciens (Bacteria, Firmicutes, Bacillales, Bacillus) FZB42 showed strong activity against F. graminearum The lipopeptide bacillomycin D, produced by FZB42, was shown to contribute to the antifungal activity. Purified bacillomycin D showed strong activity against F. graminearum, and its 50% effective concentration was determined to be approximately 30 MUg/ml. Analyses using scanning and transmission electron microscopy revealed that bacillomycin D caused morphological changes in the plasma membranes and cell walls of F. graminearum hyphae and conidia. Fluorescence microscopy combined with different dyes showed that bacillomycin D induced the accumulation of reactive oxygen species and caused cell death in F. graminearum hyphae and conidia. F. graminearum secondary metabolism also responded to bacillomycin D challenge, by increasing the production of deoxynivalenol. Biological control experiments demonstrated that bacillomycin D exerted good control of F. graminearum on corn silks, wheat seedlings, and wheat heads. In response to bacillomycin D, F. graminearum genes involved in scavenging reactive oxygen species were downregulated, whereas genes involved in the synthesis of deoxynivalenol were upregulated. Phosphorylation of MGV1 and HOG1, the mitogen-activated protein kinases of F. graminearum, was increased in response to bacillomycin D. Taken together, these findings reveal the mechanism of the antifungal action of bacillomycin D.IMPORTANCE Biological control of plant disease caused by Fusarium graminearum is desirable. Bacillus amyloliquefaciens FZB42 is a representative of the biocontrol bacterial strains. In this work, the lipopeptide bacillomycin D, produced by FZB42, showed strong fungicidal activity against F. graminearum Bacillomycin D caused morphological changes in the plasma membrane and cell wall of F. graminearum, induced accumulation of reactive oxygen species, and ultimately caused cell death in F. graminearum Interestingly, when F. graminearum was challenged with bacillomycin D, the deoxynivalenol production, gene expression, mitogen-activated protein kinase phosphorylation, and pathogenicity of F. graminearum were significantly altered. These findings clarified the mechanisms of the activity of bacillomycin D against F. graminearum and highlighted the potential of B. amyloliquefaciens FZB42 as a biocontrol agent against F. graminearum. PMID- 28733289 TI - An Enterotoxin-Like Binary Protein from Pseudomonas protegens with Potent Nematicidal Activity. AB - Soil microbes are a major food source for free-living soil nematodes. It is known that certain soil bacteria have evolved systems to combat predation. We identified the nematode-antagonistic Pseudomonas protegens strain 15G2 from screening of microbes. Through protein purification we identified a binary protein, designated Pp-ANP, which is responsible for the nematicidal activity. This binary protein inhibits Caenorhabditis elegans growth and development by arresting larvae at the L1 stage and killing older-staged worms. The two subunits, Pp-ANP1a and Pp-ANP2a, are active when reconstituted from separate expression in Escherichia coli The binary toxin also shows strong nematicidal activity against three other free-living nematodes (Pristionchus pacificus, Panagrellus redivivus, and Acrobeloides sp.), but we did not find any activity against insects and fungi under test conditions, indicating specificity for nematodes. Pp-ANP1a has no significant identity to any known proteins, while Pp ANP2a shows ~30% identity to E. coli heat-labile enterotoxin (LT) subunit A and cholera toxin (CT) subunit A. Protein modeling indicates that Pp-ANP2a is structurally similar to CT/LT and likely acts as an ADP-ribosyltransferase. Despite the similarity, Pp-ANP shows several characteristics distinct from CT/LT toxins. Our results indicate that Pp-ANP is a new enterotoxin-like binary toxin with potent and specific activity to nematodes. The potency and specificity of Pp ANP suggest applications in controlling parasitic nematodes and open an avenue for further research on its mechanism of action and role in bacterium-nematode interaction.IMPORTANCE This study reports the discovery of a new enterotoxin-like binary protein, Pp-ANP, from a Pseudomonas protegens strain. Pp-ANP shows strong nematicidal activity against Caenorhabditis elegans larvae and older-staged worms. It also shows strong activity on other free-living nematodes (Pristionchus pacificus, Panagrellus redivivus, and Acrobeloides sp.). The two subunits, Pp ANP1a and Pp-ANP2a, can be expressed separately and reconstituted to form the active complex. Pp-ANP shows some distinct characteristics compared with other toxins, including Escherichia coli enterotoxin and cholera toxin. The present study indicates that Pp-ANP is a novel binary toxin and that it has potential applications in controlling parasitic nematodes and in studying toxin-host interaction. PMID- 28733291 TI - Revalidation plan could reduce burden on doctors, says BMA. PMID- 28733290 TI - Feral Swine in the United States Have Been Exposed to both Avian and Swine Influenza A Viruses. AB - Influenza A viruses (IAVs) in swine can cause sporadic infections and pandemic outbreaks among humans, but how avian IAV emerges in swine is still unclear. Unlike domestic swine, feral swine are free ranging and have many opportunities for IAV exposure through contacts with various habitats and animals, including migratory waterfowl, a natural reservoir for IAVs. During the period from 2010 to 2013, 8,239 serum samples were collected from feral swine across 35 U.S. states and tested against 45 contemporary antigenic variants of avian, swine, and human IAVs; of these, 406 (4.9%) samples were IAV antibody positive. Among 294 serum samples selected for antigenic characterization, 271 cross-reacted with >=1 tested virus, whereas the other 23 did not cross-react with any tested virus. Of the 271 IAV-positive samples, 236 cross-reacted with swine IAVs, 1 with avian IAVs, and 16 with avian and swine IAVs, indicating that feral swine had been exposed to both swine and avian IAVs but predominantly to swine IAVs. Our findings suggest that feral swine could potentially be infected with both avian and swine IAVs, generating novel IAVs by hosting and reassorting IAVs from wild birds and domestic swine and facilitating adaptation of avian IAVs to other hosts, including humans, before their spillover. Continued surveillance to monitor the distribution and antigenic diversities of IAVs in feral swine is necessary to increase our understanding of the natural history of IAVs.IMPORTANCE There are more than 5 million feral swine distributed across at least 35 states in the United States. In contrast to domestic swine, feral swine are free ranging and have unique opportunities for contact with wildlife, livestock, and their habitats. Our serological results indicate that feral swine in the United States have been exposed to influenza A viruses (IAVs) consistent with those found in both domestic swine and wild birds, with the predominant infections consisting of swine-adapted IAVs. Our findings suggest that feral swine have been infected with IAVs at low levels and could serve as hosts for the generation of novel IAVs at the interface of feral swine, wild birds, domestic swine, and humans. PMID- 28733292 TI - Natural history of autoimmune primary ovarian insufficiency in patients with Addison's disease: from normal ovarian function to overt ovarian dysfunction. AB - CONTEXT: Women with autoimmune Addison's disease with normal ovulatory cycles but positive for steroid cell antibodies (StCA) have been considered at risk of premature ovarian insufficiency (POI). DESIGN: Thirty-three women younger than 40 years, with subclinical-clinical autoimmune Addison's disease but with normally ovulatory menses, were followed up for 10 years to evaluate the long-term time related variations of StCA, ovarian function and follicular reserve. All patients and 27 control women were investigated at the start and every year for the presence and titre of StCA (by indirect immunofluorescence), serum concentrations of anti-Mullerian hormone (AMH) and ovarian function at four consecutive menses every year. RESULTS: At the start of the study StCA were present in 16 women (group 1), at low/middle titres (<=1:32) in seven of them (43.8%, group 1A), at high titres (>1:32) in the remaining nine patients (group 1B, 56.2%), while they were absent from 17 patients (group 2). During the follow-up period, all women in group 1A remained StCA-positive at low/middle titres with normal ovulatory menses and normal gonadotrophin and AMH levels, while all patients in group 1B showed a further increase of StCA titres (1:128-1:256) and progressed through three stages of ovarian function. None of the patients in group 2 and controls showed the appearance of StCA or ovarian dysfunction during the follow-up. CONCLUSIONS: The presence of StCA at high titres can be considered a good predictive marker of subsequent development of autoimmune POI. To single out the stages of autoimmune POI may allow a timely therapeutic choice in the subclinical and early clinical stages. PMID- 28733293 TI - Androgen-responsive non-coding small RNAs extend the potential of HCG stimulation to act as a bioassay of androgen sufficiency. AB - BACKGROUND: It is unclear whether a short-term change in circulating androgens is associated with changes in the transcriptome of the peripheral blood mononuclear cells (PBMC). AIMS AND METHODS: To explore the effect of hCG stimulation on the PBMC transcriptome, 12 boys with a median age (range) of 0.7 years (0.3, 11.2) who received intramuscular hCG 1500u on 3 consecutive days as part of their investigations underwent transcriptomic array analysis on RNA extracted from peripheral blood mononuclear cells before and after hCG stimulation. RESULTS: Median pre- and post-hCG testosterone for the overall group was 0.7 nmol/L (<0.5, 6) and 7.9 nmol/L (<0.5, 31.5), respectively. Of the 12 boys, 3 (25%) did not respond to hCG stimulation with a pre and post median serum testosterone of <0.5 nmol/L and <0.5 nmol/L, respectively. When corrected for gene expression changes in the non-responders to exclude hCG effects, all 9 of the hCG responders consistently demonstrated a 20% or greater increase in the expression of piR 37153 and piR-39248, non-coding PIWI-interacting RNAs (piRNAs). In addition, of the 9 responders, 8, 6 and 4 demonstrated a 30, 40 and 50% rise, respectively, in a total of 2 further piRNAs. In addition, 3 of the responders showed a 50% or greater rise in the expression of another small RNA, SNORD5. On comparing fold change in serum testosterone with fold-change in the above transcripts, a positive correlation was detected for SNORD5 (P = 0.01). CONCLUSIONS: The identification of a dynamic and androgen-responsive PBMC transcriptome extends the potential value of the hCG test for the assessment of androgen sufficiency. PMID- 28733294 TI - Determining the worldwide epidemiology of surgical site infections after gastrointestinal resection surgery: protocol for a multicentre, international, prospective cohort study (GlobalSurg 2). AB - INTRODUCTION: Surgical site infection (SSI) is the most common complication following major gastrointestinal surgery, affecting between 25% and 40% of patients. The rate of SSI doubles from low-income to high-income settings, persisting after risk adjustment. The relative impact of antibiotic-resistant organisms and the effectiveness of antibiotic prophylaxis globally are unknown. This study aims to determine SSI rates following gastrointestinal surgery across worldwide hospital settings. METHODS AND ANALYSIS: This multicentre, international, prospective cohort study will be undertaken by any hospital providing emergency or elective gastroenterological surgical services. Centres will collect observational data on consecutive patients undergoing emergency or elective gastrointestinal resection, cholecystectomy or appendicectomy during a 6 month period. The primary outcome is the incidence of SSI with secondary outcomes describing the organisms causing SSIs, including their antibiotic susceptibility, and the microbiological tests used to identify them. ETHICS AND DISSEMINATION: This project will not affect clinical practice and has been classified as clinical audit following research ethics review. The protocol will be disseminated through the international GlobalSurg network. TRIAL REGISTRATION NUMBER: NCT02662231. PMID- 28733295 TI - The impact of healthcare professionals' personality and religious beliefs on the decisions to forego life sustaining treatments: an observational, multicentre, cross-sectional study in Greek intensive care units. AB - OBJECTIVES: To assess the opinion of intensive care unit (ICU) personnel and the impact of their personality and religious beliefs on decisions to forego life sustaining treatments (DFLSTs). SETTING: Cross-sectional, observational, national study in 18 multidisciplinary Greek ICUs, with >6 beds, between June and December 2015. PARTICIPANTS: 149 doctors and 320 nurses who voluntarily and anonymously answered the End-of-Life (EoL) attitudes, Personality (EPQ) and Religion (SpREUK) questionnaires. Multivariate analysis was used to detect the impact of personality and religious beliefs on the DFLSTs. RESULTS: The participation rate was 65.7%. Significant differences in DFLSTs between doctors and nurses were identified. 71.4% of doctors and 59.8% of nurses stated that the family was not properly informed about DFLST and the main reason was the family's inability to understand medical details. 51% of doctors expressed fear of litigation and 47% of them declared that this concern influenced the information given to family and nursing staff. 7.5% of the nurses considered DFLSTs dangerous, criminal or illegal. Multivariate logistic regression identified that to be a nurse and to have a high neuroticism score were independent predictors for preferring the term 'passive euthanasia' over 'futile care' (OR 4.41, 95% CI 2.21 to 8.82, p<0.001, and OR 1.59, 95% CI 1.03 to 2.72, p<0.05, respectively). Furthermore, to be a nurse and to have a high-trust religious profile were related to unwillingness to withdraw mechanical ventilation. Fear of litigation and non-disclosure of the information to the family in case of DFLST were associated with a psychoticism personality trait (OR 2.45, 95% CI 1.25 to 4.80, p<0.05). CONCLUSION: We demonstrate that fear of litigation is a major barrier to properly informing a patient's relatives and nursing staff. Furthermore, aspects of personality and religious beliefs influence the attitudes of ICU personnel when making decisions to forego life-sustaining treatments. PMID- 28733296 TI - A unified multi-level model approach to assessing patient responsiveness including; return to normal, minimally important differences and minimal clinically important improvement for patient reported outcome measures. AB - OBJECTIVE: This article reviews and compares four commonly used approaches to assess patient responsiveness with a treatment or therapy (return to normal (RTN), minimal important difference (MID), minimal clinically important improvement (MCII), OMERACT-OARSI [Outcome Measures in Rheumatology-Osteoarthris Reseach Society International] (OO)) and demonstrates how each of the methods can be formulated in a multilevel modelling (MLM) framework. DESIGN: Cohort study. SETTING: A cohort of patients undergoing total hip and knee replacement were recruited from a single UK National Health Service hospital. POPULATION: 400 patients from the Arthroplasty Pain Experience cohort study undergoing total hip (n=210) and knee (n=190) replacement who completed the Intermittent and Constant Osteoarthritis Pain questionnaire prior to surgery and then at 3, 6 and 12 months after surgery. PRIMARY OUTCOMES: The primary outcome was defined as a response to treatment following total hip or knee replacement. We compared baseline scores, change scores and proportion of individuals defined as 'responders' using traditional and MLM approaches with patient responsiveness. RESULTS: Using existing approaches, baseline and change scores are underestimated, and the variance of baseline and change scores overestimated in comparison with MLM approaches. MLM increases the proportion of individuals defined as responding in RTN, MID and OO criteria compared with existing approaches. Using MLM with the MCII criteria reduces the number of individuals identified as responders. CONCLUSION: MLM improves the estimation of the SD of baseline and change scores by explicitly incorporating measurement error into the model and avoiding regression to the mean when making individual predictions. Using refined definitions of responsiveness may lead to a reduction in misclassification when attempting to predict who does and does not respond to an intervention and clarifies the similarities between existing methods. PMID- 28733297 TI - Behind the smile: qualitative study of caregivers' anguish and management responses while caring for someone living with heart failure. AB - BACKGROUND: Caregivers support self-management in heart failure but often experience stress, anxiety and ill health as a result of providing care. AIMS: 1. To identify the factors that contribute to the experience of anguish.2. To understand how caregivers learn to live with what is frequently a challenging and demanding role. METHODS: Individual interviews with caregivers who had been caring for someone with heart failure for a minimum of 6 months. We used thematic analysis to inductively analyse transcripts. RESULTS: Twenty-two caregivers, from three centres in the United Kingdom, took part in individual interviews. The caregivers were aged between 39 and 84 years, and six were men. Twenty were in spousal or partner relationships. We found that caregivers often hide the extent of their emotional stress or anguish. We identified four main themes with explanatory subthemes-emotional impact (fear for the future and sense of hopelessness), role definition (changing sense of who I am, reduced resilience, learning care skills, role conflict and changing role), exclusion (exclusion by the cared-for person and by health professionals and feeling alone) and ignoring one's own health-that were associated with anguish. From these findings, we produced a caregiver needs assessment model in the context of caring for a person with heart failure. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Caregivers have many unmet and hidden needs. Primary care health professionals are well placed to meet the needs of caregivers. The model may be used by health and social care professionals to identify needs and to provide caregivers with targeted practical and emotional support; and for researchers developing interventions to enhance self-management in heart failure. PMID- 28733298 TI - Are there patient-related factors that influence sickness certification in patients with severe subjective health complaints? A cross-sectional exploratory study from different European countries. AB - OBJECTIVES: To develop hypotheses about whether there are patient-related factors that influence physicians' decision-making that can explain why some patients with severe subjective health complaints (SHCs) are more likely to be granted sick leave than others. DESIGN: Exploratory cross-sectional. SETTING: Assessments of patient-related factors after watching nine authentic video recordings of patients with severe SHC from a Norwegian general practice. Our previous study showed that three of these nine patients were less likely than the remaining six patients to be granted sick leave by physicians from five European countries. PARTICIPANTS: In total, 10 assessors from Norway, the Netherlands and France. OUTCOMES: The direction in which the assessments may contribute towards the decision to grant a sickness certificate (increasing or decreasing the likelihood of granting sick leave). RESULTS: Physicians consider a wide variety of patient related factors when assessing sickness certification. The overall assessment of these factors may provide an indication of whether a patient is more likely or less likely to be granted sick leave. Additionally, some single questions (notable functional limitations in the consultation, visible suffering, a clear purpose for sick leave and psychiatric comorbidity) may indicate differences between the two patient groups. CONCLUSIONS: Next to the overall assessment, no notable effect of the complaints on functioning and suffering, a lack of a clear purpose for sick leave and the absence of psychiatric comorbidity may be factors that could help guide the decision to grant sick leave. These hypotheses should be tested and validated in representative samples of professionals involved in sickness certification. This may help to understand the tacit knowledge we believe physicians have when assessing work capacity of patients with severe SHC. PMID- 28733299 TI - Robot-assisted surgery in a broader healthcare perspective: a difference-in difference-based cost analysis of a national prostatectomy cohort. AB - OBJECTIVE: To estimate costs attributable to robot-assisted laparoscopic prostatectomy (RALP) as compared with open prostatectomy (OP) and laparoscopic prostatectomies (LP) in a National Health Service perspective. PATIENTS AND METHODS: Register-based cohort study of 4309 consecutive patients who underwent prostatectomy from 2006 to 2013 (2241 RALP, 1818 OP and 250 LP). Patients were followed from 12 months before to 12 months after prostatectomy with respect to service use in primary care (general practitioners, therapists, specialists etc) and hospitals (inpatient and outpatient activity related to prostatectomy and comorbidity). Tariffs of the activity-based remuneration system for primary care and the Diagnosis-Related Grouping case-mix system for hospital-based care were used to value service use. Costs attributable to RALP were estimated using a difference-in-difference analytical approach and adjusted for patient-level and hospital-level risk selection using multilevel regression. RESULTS: No significant effect of RALP on resource-use was observed except for a marginally lower use of primary care and fewer bed days as compared with OP (not LP). The overall cost consequence of RALP was estimated at an additional ?2459 (95% CI 1377 to 3540, p=0.003) as compared with OP and an additional ?3860 (95% CI 559 to 7160, p=0.031) as compared with LP, mainly due to higher cost intensity during the index admissions. CONCLUSIONS: In this study from the Danish context, the use of RALP generates a factor 1.3 additional cost when compared with OP and a factor 1.6 additional cost when compared with LP, on average, based on 12 months follow up. The policy interpretation is that the use of robots for prostatectomy should be driven by clinical superiority and that formal effectiveness analysis is required to determine whether the current and eventual new purchasing of robot capacity is best used for prostatectomy. PMID- 28733300 TI - Exploring the relationship between frequent internet use and health and social care resource use in a community-based cohort of older adults: an observational study in primary care. AB - OBJECTIVES: Given many countries' ageing populations, policymakers must consider how to mitigate or reduce health problems associated with old age, within budgetary constraints. Evidence of use of digital technology in delaying the onset of illness and reducing healthcare service use is mixed, with no clear consensus as yet. Our aim was to investigate the relationship between frequent internet use and patterns of health or social care resource use in primary care attendees who took part in a study seeking to improve the health of older adults. METHODS: Participants recruited from primary care, aged >65 and living in semirural or urban areas in the south of England, were followed up at 3 and 6 months after completing a comprehensive questionnaire with personalised feedback on their health and well-being. We performed logistic regression analyses to investigate relationships between frequent internet use and patterns of service use, controlling for confounding factors, and clustering by general practitioner practice. Four categories of service use data were gathered: use of primary National Health Service (NHS) care; secondary NHS care; other community health and social care services; and assistance with washing, shopping and meals. RESULTS: Our results show, in this relatively healthy population, a positive relationship (OR 1.72, 95% CI 1.33 to 2.23) between frequent internet use and use of any other community-based health services (physiotherapist, osteopath/chiropractor, dentist, optician/optometrist, counselling service, smoking cessation service, chiropodist/podiatrist, emergency services, other non specific health services) and no relationship with the other types of care. No causal relationship can be postulated due to the study's design. CONCLUSIONS: No observed relationship between frequent internet use and primary or secondary care use was found, suggesting that older adults without internet access are not disadvantaged regarding healthcare use. Further research should explore how older people use the internet to access healthcare and the impact on health. PMID- 28733301 TI - A 3D navigation template for guiding a unilateral lumbar pedicle screw with contralateral translaminar facet screw fixation: a study protocol for multicentre randomised controlled trials. AB - INTRODUCTION: The incidence of lumbar disc degeneration disease has increased in recent years. Lumbar interbody fusion using two unilateral pedicle screws and a translaminar facet screw fixation has advantages of minimal invasiveness and lower costs compared with the traditional methods. Moreover, a method guided by a three-dimensional (3D) navigation template may help us improve the surgical accuracy and the success rate. This is the first randomised study using a 3D navigation template to guide a unilateral lumbar pedicle screw with contralateral translaminar facet screw fixation. METHODS AND ANALYSIS: Patients who meet the criteria of the surgery will be randomly divided into experimental groups and control groups by a computer-generated randomisation schedule. We will preoperatively design an individual 3D navigation template using CATIA software and MeditoolCreate. The following primary outcomes will be collected: screw angles compared with the optimal screw trajectories in 3D digital images, length of the wound incision, operative time, intraoperative blood loss and complications. The following secondary outcomes will be collected: visual analogue scale (VAS) for back pain, VAS for leg pain and the Oswestry Disability Index. These parameters will be evaluated on day 1 and then 3, 6, 12 and 24 months postoperatively. ETHICS AND DISSEMINATION: The study has been reviewed and approved by the institutional ethics review board of the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University. The results will be presented at scientific communities and peer-reviewed journals. TRIAL REGISTRATION NUMBER: ChiCTR-IDR-17010466. PMID- 28733302 TI - Influences on university students' intention to receive recommended vaccines: a cross-sectional survey. AB - OBJECTIVES: To explore predictors of university students' intention to receive a recommended vaccine and the main sources of vaccine-related information accessed by university students. SETTING: Participants were recruited from University College London (UK) in summer 2015. PARTICIPANTS: 177 university students participated. The majority of participants were female (58%), White (68%) and had no religion (58%). Participants were aged 18 to 42 (mean age=23.6). PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcome measures included vaccine attitude, perceived subjective norm, perceived behavioural control, perceived self efficacy, past receipt of recommended childhood vaccines, perceived adverse reaction to past vaccination and needle fear. As a secondary outcome sources of vaccine-related information were assessed. RESULTS: Students classified as high intenders were more likely to have received all recommended childhood vaccines (OR 3.57; 95% CI 1.21 to 10.59; p=0.022), be less afraid of needles (OR 2.44; 95% CI 1.12 to 5.36; p=0.026) and to have lived in the UK until at least the age of 4 compared with those not living in the UK until at least the age of 4 (OR 0.39; 95% CI 0.18 to 0.83; p=0.015) and those who lived both in the UK and elsewhere (OR 0.42; 95% CI 0.04 to 4.06; p=0.424). The multivariable model explained 25.5% of variance in intention to receive a recommended vaccine. The internet was the most commonly reported source of vaccination information. CONCLUSIONS: Findings provide an indication of the factors that may need to be addressed by interventions aiming to increase uptake of recommended vaccines in a university population. Future research is recommended using a prospective cohort design. PMID- 28733304 TI - How do trends in mortality inequalities by deprivation and education in Scotland and England & Wales compare? A repeat cross-sectional study. AB - OBJECTIVE: To compare the trends in mortality inequalities by educational attainment with trends using area deprivation. SETTING: Scotland and England & Wales (E&W). PARTICIPANTS: All people resident in Scotland and E&W between 1981 and 2011 aged 35-79 years. PRIMARY OUTCOME MEASURES: Absolute inequalities (measured using the Slope Index of Inequality (SII)) and relative inequalities (measured using the Relative Index of Inequality (RII)) in all-cause mortality. RESULTS: Relative inequalities in mortality by area deprivation have consistently increased for men and women in Scotland and E&W between 1981-1983 and 2010-2012. Absolute inequalities increased for men and women in Scotland, and for women in E&W, between 1981-1983 and 2000-2002 before subsequently falling. For men in E&W, absolute inequalities were more stable until 2000-2002 before a subsequent decline. Both absolute and relative inequalities were consistently higher in men and in Scotland. These trends contrast markedly with the reported declines in mortality inequalities by educational attainment and apparent improvement of Scotland's inequalities with those in E&W. CONCLUSIONS: Trends in health inequalities differ when assessed using different measures of socioeconomic status, reflecting either genuinely variable trends in relation to different aspects of social stratification or varying error or bias. There are particular issues with the educational attainment data in Great Britain prior to 2001 that make these education-based estimates less certain. PMID- 28733305 TI - In This Issue of Diabetes. PMID- 28733303 TI - Oral glucocorticoid use and osteonecrosis in children and adults with chronic inflammatory diseases: a population-based cohort study. AB - OBJECTIVES: We studied oral glucocorticoids and osteonecrosis, a rare but serious bone disease, in individuals with various chronic inflammatory diseases. We hypothesised that we would find stronger associations in adults versus children and in people with autoimmune diseases. DESIGN: Retrospective cohort study. SETTING: Population-representative data (1994-2013) from general practices in the UK. PARTICIPANTS: Children and adults diagnosed with asthma; inflammatory bowel disease; juvenile, psoriatic or rheumatoid arthritis; psoriasis; or systemic lupus. EXPOSURES: Oral glucocorticoid patterns. PRIMARY AND SECONDARY OUTCOME MEASURES: Diagnosed osteonecrosis (primary) and osteonecrosis plus clinical features (eg, symptoms, pain medication, surgical repair) (secondary). Discrete time failure models estimated the adjusted hazard ratio (aHR) of incident osteonecrosis following oral glucocorticoid exposure. Hypothesis testing was one sided (with corresponding 90% CI) since glucocorticoids were unlikely protective. RESULTS: After adjusting for demographic, disease-related and health utilisation factors, glucocorticoid exposure was associated with osteonecrosis in adults (ages 18-49, aHR 2.1 (90% CI 1.5 to 2.9); ages >=50, aHR 1.3 (90% CI 1.01 to 1.7)). However, low-dose glucocorticoids, corresponding to average doses <7.5 mg prednisolone daily and maximum doses <30 mg daily, were not associated with osteonecrosis in adults. Furthermore, even at high glucocorticoid doses, there was no evidence of increased osteonecrosis among glucocorticoid-exposed children (p=0.04 for interaction by age) (any glucocorticoid exposure, ages 2-9: aHR 1.1 (90% CI 0.7 to 1.7); ages 10-17: aHR 0.6 (90% CI 0.3 to 1.6)). Arthritis, inflammatory bowel disease and lupus were independently associated with osteonecrosis, but there was a similar dose relationship between glucocorticoids and osteonecrosis among adults with low-risk and high-risk diseases. CONCLUSIONS: Glucocorticoid use was clearly associated with osteonecrosis in a dose-related fashion in adults, especially young adults, but this risk was not detectable in children. The absolute risk of glucocorticoid-associated osteonecrosis in the general paediatric population and in adults taking low glucocorticoid doses is at most extremely small. PMID- 28733306 TI - Species-Dependent Mechanisms Regulating Glucose-Dependent GLP-1 Secretion? PMID- 28733307 TI - Bait and Trap: Enriching Autoreactive T Cells With beta-Cell Antigen-Loading Biomaterial Scaffolds for Early Detection of Type 1 Diabetes. PMID- 28733308 TI - Some Doubts About the Mantra on the Deleterious Cardiovascular Effects of Sulfonylureas. PMID- 28733310 TI - Comment on Muka et al. Associations of Steroid Sex Hormones and Sex Hormone Binding Globulin With the Risk of Type 2 Diabetes in Women: A Population-Based Cohort Study and Meta-analysis. Diabetes 2017;66:577-586. PMID- 28733311 TI - Regional septal hinge-point injury contributes to adverse biventricular interactions in pulmonary hypertension. AB - Death and morbidity in pulmonary arterial hypertension (PAH) are often due to right ventricular (RV) failure and associated left ventricular (LV) dysfunction. We investigated regional myocardial remodeling and function as the basis for adverse ventricular-ventricular interactions in experimental chronic RV pressure overload. Two distinct animal models were studied: A rabbit model of increased RV pressure-load through progressive pulmonary artery banding A rat model of monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH). Regional myocardial function was assessed by speckle-tracking strain echocardiography and ventricular pressures measured by catheterization before termination. Regional RV and LV myocardium was analyzed for collagen content, apoptosis and pro-fibrotic signaling gene and protein expression. Although the RV developed more fibrosis than the LV; in both models the LV was substantially affected. In both ventricles, particularly the LV, fibrosis developed predominantly at the septal hinge-point regions in association with decreased regional and global circumferential strain, reduced global RV and LV function and up-regulation of regional transforming growth factor-beta1 (TGFbeta1) and apoptosis signaling. A group of PAH rats who received the TGFbeta blocker SB431542 showed improved RV function and reduced regional hinge-point myocardial fibrosis. RV pressure loading and PAH lead to biventricular TGFbeta1 signaling, fibrosis and apoptosis, predominantly at the septal hinge-point regions, in association with regional myocardial dysfunction. This suggests that altered geometry and wall stress lead to adverse RV-LV interactions through the septal hinge-points to induce LV fibrosis and dysfunction. PMID- 28733313 TI - Granzyme A Deficiency Breaks Immune Tolerance and Promotes Autoimmune Diabetes Through a Type I Interferon-Dependent Pathway. AB - Granzyme A is a protease implicated in the degradation of intracellular DNA. Nucleotide complexes are known triggers of systemic autoimmunity, but a role in organ-specific autoimmune disease has not been demonstrated. To investigate whether such a mechanism could be an endogenous trigger for autoimmunity, we examined the impact of granzyme A deficiency in the NOD mouse model of autoimmune diabetes. Granzyme A deficiency resulted in an increased incidence in diabetes associated with accumulation of ssDNA in immune cells and induction of an interferon response in pancreatic islets. Central tolerance to proinsulin in transgenic NOD mice was broken on a granzyme A-deficient background. We have identified a novel endogenous trigger for autoimmune diabetes and an in vivo role for granzyme A in maintaining immune tolerance. PMID- 28733314 TI - Effects of an Airway Clearance Device on Inflammation, Bacteriology, and Mucus Transport in Bronchiectasis. AB - BACKGROUND: Bronchiectasis is characterized by abnormal and permanent dilation of the bronchi, caused by the perpetuation of inflammation and impairment of mucociliary clearance. Physiotherapy techniques can help to decrease the retention of respiratory secretions. The flutter valve combines high-frequency oscillation and positive expiratory pressure to facilitate the removal of secretions. We evaluated the effects of the flutter valve on sputum inflammation, microbiology, and transport of respiratory secretions in patients with bronchiectasis. METHODS: Seventeen participants underwent sessions with flutter or control (flutter-sham), for 30 min/d, in a randomized crossover study, with 4 weeks with one of the therapies, a 2-week wash-out period, and then another 4 weeks with the other modality. Secretion samples were collected every week throughout the protocol and were assessed for the mucociliary transport, displacement in a simulated cough machine, contact angle, and cell cytology with percentage of neutrophil count, eosinophils, and macrophages, and the microbiology was assessed by the number of colony-forming units. RESULTS: Treatment with flutter resulted in greater displacement in a simulated cough machine and smaller contact angle, comparing the results between the first week (9.94 +/- 3.12 cm and 26.5 +/- 3.21 degrees , respectively) and fourth week of treatment (13.96 +/- 5.76 cm and 22.76 +/- 3.64 degrees , respectively) and was associated with a decrease in the total number of inflammatory cells. CONCLUSIONS: The use of a flutter valve for 30 min/d for at least 4 weeks is enough to change physical properties and improve mucus transport by coughing and can contribute to the reduction of the total number of inflammatory cells of the respiratory secretions of subjects with bronchiectasis. (ClinicalTrials.gov registration NCT01209546.). PMID- 28733315 TI - Evaluation of the Safety and Effectiveness of the Rapid Flow Expulsion Maneuver to Clear Subglottic Secretions In Vitro and In Vivo. PMID- 28733312 TI - Baseline aortic pulse wave velocity is associated with central and peripheral pressor responses during the cold pressor test in healthy subjects. AB - Cold environmental temperatures increase sympathetic nerve activity and blood pressure, and increase the risk of acute cardiovascular events in aged individuals. The acute risk of cardiovascular events increases with aortic pulse wave velocity as well as elevated central and peripheral pulse pressures. The aim of this study was to examine the independent influence of aortic pulse wave velocity upon central and peripheral pressor responses to sympathetic activation via the cold pressor test (CPT). Twenty-two healthy subjects (age: 18-73 years) completed a CPT with the left hand immersed in 2-4 degrees C water for 3 min. During the CPT, central (from: 36 +/- 7 to: 51 +/- 12 mmHg) and peripheral pulse pressure increased (from: 54 +/- 7 to: 66 +/- 11; both P < 0.05). In all subjects the increase in central pulse pressure during the CPT was independently associated with baseline aortic pulse wave velocity (r2 = 0.221, P = 0.027) but not age (P > 0.05). In a subset of subjects with higher arterial stiffness, the increase in peripheral pulse pressure during the CPT was independently associated with baseline aortic pulse wave velocity (r2 = 0.415, P = 0.032) but not age (P > 0.05). These data indicate that central and peripheral pulse pressure responses during sympathetic activation are positively and independently associated with aortic pulse wave velocity through a wide age range. Decreasing aortic pulse wave velocity in aged individuals with elevated arterial stiffness may help reduce the incidence of acute cardiovascular events upon exposure to cold environmental temperatures. PMID- 28733316 TI - Inhaled Prostacyclin as Salvage Therapy for ARDS: Can We Find the Right Patient? PMID- 28733317 TI - High-Flow Nasal Cannula in the Pediatric ICU: Popular or Efficient? PMID- 28733318 TI - Enteral Nutrition During Noninvasive Ventilation: We Should Go Deeper in the Investigation. PMID- 28733319 TI - Enteral Nutrition During Noninvasive Ventilation: We Should Go Deeper in the Investigation-Reply. PMID- 28733320 TI - Noninvasive Respiratory Care Received by Individuals With Duchenne Muscular Dystrophy Since 1979. PMID- 28733321 TI - Noninvasive Respiratory Care Received by Individuals With Duchenne Muscular Dystrophy Since 1979-Reply. PMID- 28733323 TI - Five-year follow-up of brentuximab vedotin combined with ABVD or AVD for advanced stage classical Hodgkin lymphoma. PMID- 28733324 TI - NADPH oxidase-2 derived superoxide drives mitochondrial transfer from bone marrow stromal cells to leukemic blasts. AB - Improvements in the understanding of the metabolic cross-talk between cancer and its microenvironment are expected to lead to novel therapeutic approaches. Acute myeloid leukemia (AML) cells have increased mitochondria compared with nonmalignant CD34+ hematopoietic progenitor cells. Furthermore, contrary to the Warburg hypothesis, AML relies on oxidative phosphorylation to generate adenosine triphosphate. Here we report that in human AML, NOX2 generates superoxide, which stimulates bone marrow stromal cells (BMSC) to AML blast transfer of mitochondria through AML-derived tunneling nanotubes. Moreover, inhibition of NOX2 was able to prevent mitochondrial transfer, increase AML apoptosis, and improve NSG AML mouse survival. Although mitochondrial transfer from BMSC to nonmalignant CD34+ cells occurs in response to oxidative stress, NOX2 inhibition had no detectable effect on nonmalignant CD34+ cell survival. Taken together, we identify tumor-specific dependence on NOX2-driven mitochondrial transfer as a novel therapeutic strategy in AML. PMID- 28733326 TI - Ann Miller: Shaping cells and scientists. AB - Miller studies how the cytoskeleton controls cellular shape change. PMID- 28733325 TI - Protease cleavage site fingerprinting by label-free in-gel degradomics reveals pH dependent specificity switch of legumain. AB - Determination of protease specificity is of crucial importance for understanding protease function. We have developed the first gel-based label-free proteomic approach (DIPPS-direct in-gel profiling of protease specificity) that enables quick and reliable determination of protease cleavage specificities under large variety of experimental conditions. The methodology is based on in-gel digestion of the gel-separated proteome with the studied protease, enrichment of cleaved peptides by gel extraction, and subsequent mass spectrometry analysis combined with a length-limited unspecific database search. We applied the methodology to profile ten proteases ranging from highly specific (trypsin, endoproteinase GluC, caspase-7, and legumain) to broadly specific (matrix-metalloproteinase-3, thermolysin, and cathepsins K, L, S, and V). Using DIPPS, we were able to perform specificity profiling of thermolysin at its optimal temperature of 75 degrees C, which confirmed the applicability of the method to extreme experimental conditions. Moreover, DIPPS enabled the first global specificity profiling of legumain at pH as low as 4.0, which revealed a pH-dependent change in the specificity of this protease, further supporting its broad applicability. PMID- 28733328 TI - Thermal imprinting modifies bone homeostasis in cold-challenged sea bream (Sparus aurata). AB - Fish are ectotherms and temperature plays a determinant role in their physiology, biology and ecology, and is a driver of seasonal responses. The present study assessed how thermal imprinting during embryonic and larval stages modified the response of adult fish to low water temperature. We targeted the gilthead sea bream, which develops a condition known as winter syndrome when it is exposed to low water temperatures. Eggs and larvae of sea bream were exposed to four different thermal regimes and then the response of the resulting adults to a low temperature challenge was assessed. Sea bream exposed to a high-low thermal regime as eggs and larvae (HLT; 22 degrees C until hatch and then 18 degrees C until larvae-juvenile transition) had increased plasma cortisol and lower sodium and potassium in response to a cold challenge compared with the other thermal history groups. Plasma glucose and osmolality were increased in cold-challenged HLT fish relative to the unchallenged HLT fish. Cold challenge modified bone homeostasis/responsiveness in the low-high thermal regime group (LHT) relative to other groups, and ocn, ogn1/2, igf1, gr and tralpha/beta transcripts were all downregulated. In the low temperature group (LT) and HLT group challenged with a low temperature, alkaline phosphatase (ALP) and tartrate-resistant acid phosphatase (TRAP) activities were decreased relative to unchallenged groups, and bone calcium content also decreased in the LT group. Overall, the results indicate that thermal imprinting during early development of sea bream causes a change in the physiological response of adults to a cold challenge. PMID- 28733327 TI - CENP-A and topoisomerase-II antagonistically affect chromosome length. AB - The size of mitotic chromosomes is coordinated with cell size in a manner dependent on nuclear trafficking. In this study, we conducted an RNA interference screen of the Caenorhabditis elegans nucleome in a strain carrying an exceptionally long chromosome and identified the centromere-specific histone H3 variant CENP-A and the DNA decatenizing enzyme topoisomerase-II (topo-II) as candidate modulators of chromosome size. In the holocentric organism C. elegans, CENP-A is positioned periodically along the entire length of chromosomes, and in mitosis, these genomic regions come together linearly to form the base of kinetochores. We show that CENP-A protein levels decreased through development coinciding with chromosome-size scaling. Partial loss of CENP-A protein resulted in shorter mitotic chromosomes, consistent with a role in setting chromosome length. Conversely, topo-II levels were unchanged through early development, and partial topo-II depletion led to longer chromosomes. Topo-II localized to the perimeter of mitotic chromosomes, excluded from the centromere regions, and depletion of topo-II did not change CENP-A levels. We propose that self-assembly of centromeric chromatin into an extended linear array promotes elongation of the chromosome, whereas topo-II promotes chromosome-length shortening. PMID- 28733329 TI - The antifungal activity of the peptide, periplanetasin-2, derived from American cockroach Periplaneta americana. AB - The cockroach, which is a household insect, is an established model organism in research. Periplanetasin-2, derived from the American cockroach Periplaneta americana, exerted potent antifungal effect against pathogenic fungi without causing hemolysis. Periplanetasin-2 induced oxidative stress by generation of reactive oxygen species (ROS) and lipid peroxidation. Periplanetasin-2 also caused apoptosis by exposure of phosphatidylserine and fragmentation of DNA, exerted in a concentration-dependent manner. Hence, we investigated the mitochondrial apoptotic mechanism of periplanetasin-2 in Candida albicans After treatment with periplanetasin-2, we observed mitochondrial depolarization and calcium accumulation. Moreover, we observed a decrease in cytosolic glutathione, and an increase in mitochondrial glutathione, indicating that periplanetasin-2 induced oxidative stress and high ROS production in the mitochondria. Because of this mitochondrial dysfunction, cytochrome c was released from the mitochondria into the cytosol, and caspase was activated in a time-dependent manner. In summary, the antifungal peptide periplanetasin-2 activates apoptotic signals in the mitochondria by induction of oxidative stress. PMID- 28733331 TI - N-Glycosylation is required for FDNC5 stabilization and irisin secretion. AB - Irisin, a myokine derived from the extracellular domain of FNDC5, has been shown to mediate thermogenesis of white adipose tissue. Biochemical data have shown that N-glycosylation of FNDC5 is unlikely to affect ligand or receptor activation of irisin. The N-glycosylation of FNDC5 remains poorly understood. In the present study, we analysed N-glycosylation sites of FNDC5 and found that two potential N glycosylation sites (Asn36 and Asn81) could indeed be occupied by N-glycan. Furthermore we showed that the lack of N-glycosylation decreases the secretion of irisin, which is relevant to the instability of FNDC5 and the deficiency of cleavage of the signal peptide. We also found that the expression level of N glycosylated FNDC5 was elevated after myoblast differentiation. These findings show that the secretion of irisin is modulated by N-glycosylation, which in turn enhances our understanding of the secretion of glycosylated irisin. PMID- 28733330 TI - The helicase, DDX3X, interacts with poly(A)-binding protein 1 (PABP1) and caprin 1 at the leading edge of migrating fibroblasts and is required for efficient cell spreading. AB - DDX3X, a helicase, can interact directly with mRNA and translation initiation factors, regulating the selective translation of mRNAs that contain a structured 5' untranslated region. This activity modulates the expression of mRNAs controlling cell cycle progression and mRNAs regulating actin dynamics, contributing to cell adhesion and motility. Previously, we have shown that ribosomes and translation initiation factors localise to the leading edge of migrating fibroblasts in loci enriched with actively translating ribosomes, thereby promoting steady-state levels of ArpC2 and Rac1 proteins at the leading edge of cells during spreading. As DDX3X can regulate Rac1 levels, cell motility and metastasis, we have examined DDX3X protein interactions and localisation using many complementary approaches. We now show that DDX3X can physically interact and co-localise with poly(A)-binding protein 1 and caprin-1 at the leading edge of spreading cells. Furthermore, as depletion of DDX3X leads to decreased cell motility, this provides a functional link between DDX3X, caprin-1 and initiation factors at the leading edge of migrating cells to promote cell migration and spreading. PMID- 28733332 TI - Demonstration of the Maintaining of the Validated State of a System Used to Generate Water for Injection by Thermocompression Distillation. AB - Water for injection is used in multiple applications in the biopharmaceutical industry. Regarding this, several methods have been use to generate water with this high quality. Within them, the thermocompression distillation method has been widely employed. However, reports on the maintenance of the qualification and validation status of thermocompression systems used for water for injection generation are non-existent in the scientific literature. Therefore, this paper sought to give results of continuous process verification of a system used for water for injection generation over 2 years analyzing the level of conductivity, nitrate, total organic carbon, endotoxins, and microbiology in 1284 water samples. The main findings were that conductivity and nitrate values were always below the specification limit defined according to the United States Pharmacopeia and European Pharmacopoeia, respectively. The highest total organic carbon value measured was 156 ppb. Regarding the microbiology results, the maximum endotoxin content detected was 0.063 EU/mL and 2 cfu/100 mL. In conclusion, this study demonstrated that the analyzed water for injection system operated under a validated status for 2 years, and it was supported by an appropriate monitoring program according to current process validation guidelines.LAY ABSTRACT: There are multiple methods used to produce water for injection in the biopharmaceutical industry. The thermocompression distillation method has been one of the most used methods for the production of this high-quality water. Nevertheless, to verify maintenance of the validated state of these systems it is necessary to carry out continued process verification of different parameters such as conductivity, total organic carbon, limulus amebocyte lysate, and microbiology according to the mandatory requirements of the United States Pharmacopeia and the European Pharmacopoeia. Therefore, this article presents an example of the application of thermocompression technology to generate water for injection and evidence of continuous monitoring to allow demonstration of the efficiency and reliability of these systems used in the biotechnological industry. PMID- 28733333 TI - Method Development for Container Closure Integrity Evaluation via Headspace Gas Ingress by Using Frequency Modulation Spectroscopy. AB - USP <1207.1> Section 3.5 states that "A deterministic leak test method having the ability to detect leaks at the product's maximum allowable leakage limit is preferred when establishing the inherent integrity of a container-closure system." Ideally, container closure integrity of parenteral packaging would be evaluated by measuring a physical property that is sensitive to the presence of any package defect that breaches package integrity by increasing its leakage above its maximum allowable leakage limit. The primary goals of the work presented herein were to demonstrate the viability of the nondestructive, deterministic method known as laser-based gas headspace analysis for evaluating container closure integrity and to provide a physical model for predicting leak rates for a variety of container volumes, headspace conditions, and defect sizes. The results demonstrate that laser-based headspace analysis provides sensitive, accurate, and reproducible measurements of the gas ingress into glass vial stopper package assemblies that are under either diffusive or effusive leak conditions. Two different types of positive controls were examined. First, laser drilled micro-holes in thin metal disks that were crimped on top of 15R glass vials served as positive controls with a well-characterized defect geometry. For these, a strong correlation was observed between the measured ingress parameter and the size of the defect for both diffusive and effusive conditions. Second, laser-drilled holes in the wall of glass vials served as controls that more closely simulate real-world defects. Due to their complex defect geometries, their diffusive and effusive ingress parameters did not necessarily correlate; this is an important observation that has significant implications for standardizing the characterization of container defects. Regardless, laser-based headspace analysis could readily differentiate positive and negative controls for all leak conditions, and the results provide a guide for method development of container closure integrity tests.LAY ABSTRACT: The new USP 39 <1207>, "Package Integrity Evaluation-Sterile Products", states in section 3.4.1: "tracer gas tests performed using ... laser-based gas headspace analysis [have] been shown to be sensitive enough to quantitatively analyze leakage through the smallest leak paths found to pose the smallest chance of liquid leakage or microbial ingress in rigid packaging." In addition, USP <1207> also states that "for such methods, the limit of detection can be mathematically predicted on the basis of gas flow kinetics." Using the above statements as a foundation, this paper presents a theoretical basis for predicting the gas ingress through well-defined defects in product vials sealed under a variety of headspace conditions. These calculated predictions were experimentally validated by comparing them to measurements of changes in the headspace oxygen content or total pressure for several different positive controls using laser-based headspace analysis. The results demonstrated that laser-based headspace analysis can, by readily differentiating between negative controls and positive controls with a range of defect sizes on the micron scale, be used to assess container closure integrity. The work also demontrated that caution must be used when attempting to correlate a leak rate to an idealized defect-size parameter. PMID- 28733334 TI - Application of Recombinant Factor C Reagent for the Detection of Bacterial Endotoxins in Pharmaceutical Products. AB - Recombinant Factor C (rFC) is non-animal-derived reagent used to detect bacterial endotoxins in pharmaceutical products. Despite the fact that the reagent was first commercially available nearly 15 years ago, the broad use of rFC in pharmaceutical industry has long been lagging, presumably due to historical single-source supplier concerns and the lack of inclusion in worldwide pharmacopeias. Commercial rFC reagents are now available from multiple manufacturers, thus single sourcing is no longer an issue. We report here the successful validation of several pharmaceutical products by an end-point florescence-based endotoxin method using the rFC reagent. The method is equivalent or superior to the compendia bacterial endotoxins test method. Based on the comparability data and extenuating circumstances, the incorporation of the end point fluorescence technique and rFC reagent in global compendia bacterial endotoxins test chapters is desired and warranted.LAY ABSTRACT: Public health has been protected for over 30 years with the use of a purified blood product of the horseshoe crab, limulus amebocyte lysate. More recently, this blood product can be produced in biotech manufacturing processes, which reduces potential impacts to the horseshoe crab and related species dependent upon the crab, for example, migrating shorebirds. The pharmaceutical industry has been slow to adopt the use of this reagent, Recombinant Factor C (rFC), for various reasons. We evaluated the use of rFC across many pharmaceutical products, and in other feasibility demonstration experiments, and found rFC to be a suitable alternative to the animal-derived limulus amebocyte lysate. Incorporation of rFC and its analytical method into national testing standards would provide an equivalent or better test while continuing to maintain patient safety for those who depend on medicines and while securing pharmaceutical supply chains. In addition, widespread use of this method would benefit existing animal conservation efforts. PMID- 28733335 TI - Motor speech signature of behavioral variant frontotemporal dementia: Refining the phenotype. AB - OBJECTIVE: To provide a comprehensive description of motor speech function in behavioral variant frontotemporal dementia (bvFTD). METHODS: Forty-eight individuals (24 bvFTD and 24 age- and sex-matched healthy controls) provided speech samples. These varied in complexity and thus cognitive demand. Their language was assessed using the Progressive Aphasia Language Scale and verbal fluency tasks. Speech was analyzed perceptually to describe the nature of deficits and acoustically to quantify differences between patients with bvFTD and healthy controls. Cortical thickness and subcortical volume derived from MRI scans were correlated with speech outcomes in patients with bvFTD. RESULTS: Speech of affected individuals was significantly different from that of healthy controls. The speech signature of patients with bvFTD is characterized by a reduced rate (75%) and accuracy (65%) on alternating syllable production tasks, and prosodic deficits including reduced speech rate (45%), prolonged intervals (54%), and use of short phrases (41%). Groups differed on acoustic measures derived from the reading, unprepared monologue, and diadochokinetic tasks but not the days of the week or sustained vowel tasks. Variability of silence length was associated with cortical thickness of the inferior frontal gyrus and insula and speech rate with the precentral gyrus. CONCLUSIONS: One in 8 patients presented with moderate speech timing deficits with a further two-thirds rated as mild or subclinical. Subtle but measurable deficits in prosody are common in bvFTD and should be considered during disease management. Language function correlated with speech timing measures derived from the unprepared monologue only. PMID- 28733336 TI - DNA methylation predicts stroke outcome better: The epigenetic clock is ticking. PMID- 28733337 TI - Inpatient quality metrics in neurology: A grand challenge. PMID- 28733339 TI - Quality improvement in neurology: Inpatient and emergency care quality measure set: Executive summary. PMID- 28733338 TI - Early and lethal neurodegeneration with myasthenic and myopathic features: A new ALG14-CDG. AB - OBJECTIVE: To describe the presentation and identify the cause of a new clinical phenotype, characterized by early severe neurodegeneration with myopathic and myasthenic features. METHODS: This case study of 5 patients from 3 families includes clinical phenotype, serial MRI, electrophysiologic testing, muscle biopsy, and full autopsy. Genetic workup included whole exome sequencing and segregation analysis of the likely causal mutation. RESULTS: All 5 patients showed severe muscular hypotonia, progressive cerebral atrophy, and therapy refractory epilepsy. Three patients had congenital contractures. All patients died during their first year of life. In 2 of our patients, electrophysiologic testing showed abnormal decrement, but treatment with pyridostigmine led only to temporary improvement. Causative mutations in ALG14 were identified in all patients. The mutation c.220 G>A (p.Asp74Asn) was homozygous in 2 patients and heterozygous in the other 3 patients. Additional heterozygous mutations were c.422T>G (p.Val141Gly) and c.326G>A (p.Arg109Gln). In all cases, parents were found to be heterozygous carriers. None of the identified variants has been described previously. CONCLUSIONS: We report a genetic syndrome combining myasthenic features and severe neurodegeneration with therapy-refractory epilepsy. The underlying cause is a glycosylation defect due to mutations in ALG14. These cases broaden the phenotypic spectrum associated with ALG14 congenital disorders of glycosylation as previously only isolated myasthenia has been described. PMID- 28733340 TI - Biological age is better than chronological as predictor of 3-month outcome in ischemic stroke. AB - OBJECTIVE: To analyze the effect of age-related DNA methylation changes in multiple cytosine-phosphate-guanine (CpG) sites (biological age [b-age]) on patient outcomes at 3 months after an ischemic stroke. METHODS: We included 511 patients with first-ever acute ischemic stroke assessed at Hospital del Mar (Barcelona, Spain) as the discovery cohort. Demographic and clinical data, including chronological age (c-age), vascular risk factors, initial stroke severity, recanalization treatment, and previous and 3-month modified Rankin Scale (p-mRS and 3-mRS, respectively) were registered. B-age was estimated with an algorithm, based on DNA methylation in 71 CpGs. Bivariate analysis determined variables associated with 3-mRS for inclusion in ordinal multivariate analysis. RESULTS: After ordinal regressions for 3-month ischemic stroke outcome (3-mRS), b age was associated with outcome (odds ratio 1.04 [95% confidence interval 1.01 1.07]), nullifying c-age. Stepwise regression kept b-age, basal NIH Stroke Scale, sex, p-mRS, and recanalization treatment as better explanatory variables, instead of c-age. These results were successfully replicated in an independent cohort. CONCLUSIONS: B-age, estimated by DNA methylation, is an independent predictor of ischemic stroke outcome regardless of chronological years. PMID- 28733342 TI - Early genetic testing for neonatal epilepsy: When, why, and how? PMID- 28733341 TI - Activity limitations and subjective well-being after stroke. AB - OBJECTIVE: As limitations in activities of daily living are major components of many stroke outcome scales, we examined how well activity limitations predicted subjective well-being among stroke survivors in a nationally representative survey. METHODS: Individuals with a self-reported history of stroke were identified from the National Health and Aging Trends Study. Subjective well-being (primary outcome) was assessed with a validated 7-item measure (higher = greater well-being) assessing emotions (cheerful, bored, full of life, and upset) and self-realization (purpose in life, self-acceptance, and environmental mastery). Activity limitations were defined by the receipt of help in any of 11 activities of daily living/instrumental activities of daily living. Multivariable linear regression assessed predictors of well-being including medical, physical, cognitive, psychological, and environmental factors. RESULTS: A total of 738 stroke survivors age 65 or older were included (57% female, 9% African American, 6% Hispanic). Activity limitations were modestly associated with well-being after adjusting for demographic characteristics and availability of assistance (estimate -0.49, 95% confidence interval -0.61 to -0.37). However, in the fully adjusted model (R2 = 0.28), neither activity limitations nor physical capacity was associated with subjective well-being. Predictors of lower well-being in the final model included depressive symptoms, chewing/swallowing problems, pain that limited activity, and restricted participation in valued life activities. Income and executive function were modestly associated with improved well-being, while comorbidities and communication technology access were not associated. CONCLUSIONS: Activity limitations were not associated with stroke survivors' subjective well-being after adjustment for other factors. While some predictors of well-being after stroke were identified, the determinants of well-being remained largely unexplained. PMID- 28733343 TI - Profile of neonatal epilepsies: Characteristics of a prospective US cohort. AB - OBJECTIVE: Although individual neonatal epilepsy syndromes are rare, as a group they represent a sizable subgroup of neonatal seizure etiologies. We evaluated the profile of neonatal epilepsies in a prospective cohort of newborns with seizures. METHODS: Consecutive newborns with seizures were enrolled in the Neonatal Seizure Registry (an association of 7 US children's hospitals). Treatment and diagnostic testing were at the clinicians' discretion. Neonates with seizures related to epileptic encephalopathies (without structural brain abnormalities), brain malformations, or benign familial epilepsies were included in this analysis. RESULTS: Among 611 consecutive newborns with seizures, 79 (13%) had epilepsy (35 epileptic encephalopathy, 32 congenital brain malformations, 11 benign familial neonatal epilepsy [BFNE], 1 benign neonatal seizures). Twenty nine (83%) with epileptic encephalopathy had genetic testing and 24/29 (83%) had a genetic etiology. Pathogenic or likely pathogenic KCNQ2 variants (n = 10) were the most commonly identified etiology of epileptic encephalopathy. Among 23 neonates with brain malformations who had genetic testing, 7 had putative genetic etiologies. Six infants with BFNE had genetic testing; 3 had pathogenic KCNQ2 variants and 1 had a pathogenic KCNQ3 variant. Comorbid illnesses that predisposed to acute symptomatic seizures occurred in 3/35 neonates with epileptic encephalopathy vs 10/32 with brain malformations (p = 0.03). Death or discharge to hospice were more common among newborns with brain malformations (11/32) than those with epileptic encephalopathy (3/35, p = 0.01). CONCLUSIONS: Neonatal epilepsy is often due to identifiable genetic causes. Genetic testing is now warranted for newborns with epilepsy in order to guide management and inform discussions of prognosis. PMID- 28733344 TI - Effects of exercise on fitness and health of adults with spinal cord injury: A systematic review. AB - OBJECTIVE: To synthesize and appraise research testing the effects of exercise interventions on fitness, cardiometabolic health, and bone health among adults with spinal cord injury (SCI). METHODS: Electronic databases were searched (1980 2016). Included studies employed exercise interventions for a period >=2 weeks, involved adults with acute or chronic SCI, and measured fitness (cardiorespiratory fitness, power output, or muscle strength), cardiometabolic health (body composition or cardiovascular risk factors), or bone health outcomes. Evidence was synthesized and appraised using Grading of Recommendations Assessment, Development, and Evaluation (GRADE). RESULTS: A total of 211 studies met the inclusion criteria (22 acute, 189 chronic). For chronic SCI, GRADE confidence ratings were moderate to high for evidence showing exercise can improve all of the reviewed outcomes except bone health. For acute SCI, GRADE ratings were very low for all outcomes. For chronic SCI, there was low to moderate confidence in the evidence showing that 2-3 sessions/week of upper body aerobic exercise at a moderate to vigorous intensity for 20-40 minutes, plus upper body strength exercise (3 sets of 10 repetitions at 50%-80% 1-repetition maximum for all large muscle groups), can improve cardiorespiratory fitness, power output, and muscle strength. For chronic SCI, there was low to moderate confidence in the evidence showing that 3-5 sessions per week of upper body aerobic exercise at a moderate to vigorous intensity for 20-44 minutes can improve cardiorespiratory fitness, muscle strength, body composition, and cardiovascular risk. CONCLUSIONS: Exercise improves fitness and cardiometabolic health of adults with chronic SCI. The evidence on effective exercise types, frequencies, intensities, and durations should be used to formulate exercise guidelines for adults with SCI. PMID- 28733345 TI - Genes of cellular components of morphogenesis in porcine oocytes before and after IVM. AB - Proper oocyte maturation in mammals produces an oocyte capable of monospermic fertilization and embryo preimplantation. The cumulus-oocyte complexes (COCs), surrounding an oocyte, play a significant role in oocyte maturation. During this process, when the COCs undergo cumulus expansion wherein tightly compact cumulus cells (CCs) form a dispersed structure, permanent biochemical and molecular modifications occur in the maturing oocytes, indicating that the gene expression between immature and mature oocytes differs significantly. This study focuses on the genes responsible for the cellular components of morphogenesis within the developing oocyte. Brilliant cresyl blue (BCB) was used to determine the developmental capability of porcine oocytes. The immature oocytes (GV stage) were compared with matured oocytes (MII stage), using microarray and qRT-PCR analysis to track changes in the genetic expression profile of transcriptome genes. The data showed substantial upregulation of genes influencing oocyte's morphology, cellular migration and adhesion, intracellular communication, as well as plasticity of nervous system. Conversely, downregulation involved genes related to microtubule reorganization, regulation of adhesion, proliferation, migration and cell differentiation processes in oocytes. This suggests that most genes recruited in morphogenesis in porcine oocyte in vitro, may have cellular maturational capability, since they have a higher level of expression before the oocyte's matured form. It shows the process of oocyte maturation and developmental capacity is orchestrated by significant cellular modifications during morphogenesis. PMID- 28733346 TI - Regulation and action of early growth response 1 in bovine granulosa cells. AB - Fibroblast growth factors (FGF) modify cell proliferation and differentiation through receptor tyrosine kinases, which stimulate the expression of transcription factors including members of the early growth response (EGR) family. In ovarian granulosa cells, most FGFs activate typical response genes, although the role of EGR proteins has not been described. In the present study, we determined the regulation of EGR mRNA by FGFs and explored the role of EGR1 in the regulation of FGF-response genes. Addition of FGF1, FGF2, FGF4 or FGF8b increased EGR1 and EGR3 mRNA levels, whereas FGF18 increased only EGR1 mRNA abundance. No mRNA encoding EGR2 or EGR4 was detected. Overexpression of EGR1 increased EGR3 mRNA levels as well as the FGF-response genes SPRY2, NR4A1 and FOSL1 and also increased the phosphorylation of MAPK3/1. Knockdown of EGR3 did not alter the ability of FGF8b to stimulate SPRY2 mRNA levels. These data demonstrate the regulation of EGR1 and EGR3 mRNA abundance by FGFs in granulosa cells and suggest that EGR1 is likely an upstream component of FGF signaling in granulosa cells. PMID- 28733347 TI - Ultrastructural characteristics and immune profile of equine MSCs from fetal adnexa. AB - Both in human and equine species, mesenchymal stem cells (MSCs) from amniotic membrane (AM) and Wharton's jelly (WJ), may be particularly useful for immediate use or in later stages of life, after cryopreservation in cell bank. The aim of this study was to compare equine AM- and WJ-MSCs in vitro features that may be relevant for their clinical employment. MSCs were more easily isolated from WJ, even if MSCs derived from AM exhibited more rapid proliferation (P < 0.05). Osteogenic and chondrogenic differentiation were more prominent in MSCs derived from WJ. This is also suggested by the lower adhesion of AM cells, demonstrated by the greater volume of spheroids after hanging drop culture (P < 0.05). Data obtained by PCR confirmed the immunosuppressive function of AM and WJ-MSCs and the presence of active genes specific for anti-inflammatory and angiogenic factors (IL-6, IL 8, IL-beta1). For the first time, by means of transmission electron microscopy (TEM), we ascertained that equine WJ-MSCs constitutively contain a very impressive number of large vesicular structures, scattered throughout the cytoplasm. Moreover, an abundant extracellular fibrillar matrix was located in the intercellular spaces among WJ-MSCs. Data recorded in this study reveal that MSCs from different fetal tissues have different characteristics that may drive their therapeutic use. These finding could be noteworthy for horses as well as for other mammalian species, including humans. PMID- 28733348 TI - Molecular forms of ruminant BMP15 and GDF9 and putative interactions with receptors. AB - Bone morphogenetic factor 15 (BMP15) and growth differentiation factor 9 (GDF9) are oocyte-secreted factors with demonstrable effects on ovarian follicular development and ovulation rate. However, the molecular forms of BMP15 and GDF9 produced by oocytes remain unclear. The aims herein, using Western blotting (WB) procedures with specific monoclonal antibodies (mabs), were to identify the molecular forms of BMP15 and GDF9 synthesised and secreted by isolated ovine (o) and bovine (b) oocytes in vitro The mabs were known to recognise the biological forms of BMP15 or GDF9 since they had previously been shown to inhibit their bioactivities in vitro and in vivo Using recombinant variants of oBMP15 and oGDF9, including a cysteine mutant form of oBMP15 (S356C) and a human (h) BMP15:GDF9 heterodimer (cumulin), it was established that the mabs were able to identify monomeric, dimeric, promature and higher-molecular-weight forms of BMP15 and GDF9 and cumulin (GDF9 mab only). After using non-reducing, reducing and reducing + cross-linking conditions, the major oocyte-secreted forms of o and b BMP15 and GDF9 were the cleaved and uncleaved monomeric forms of the promature proteins. There was no evidence for dimeric or heterodimeric forms of either mature BMP15 or GDF9. From in silico modelling studies using transforming growth factor beta (TGFB), activin or BMP crystal templates, and both present and previously published data, a model is proposed to illustrate how the monomeric forms of BMP15 and GDF9 may interact with their type II and type I cell-surface receptors to initiate the synergistic actions of these growth factors. PMID- 28733350 TI - Adiponectin limits differentiation and trophoblast invasion in human endometrial cells. AB - Successful human embryo implantation requires a proper differentiation of endometrial stromal cells (ESCs) into decidual cells, during a process called decidualization. ESCs express specific molecules, such as prolactin, insulin-like growth factor-binding protein-1 (IGFBP-1) and connexin-43. Decidual cells are also involved in the control of trophoblast invasion, by secreting various factors, such as matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). Adiponectin is an adipokine with insulin-sensitizing, anti-inflammatory and anti-proliferative effects. At the embryo-maternal interface, adiponectin promotes differentiation and invasion of human trophoblastic cells. We hypothesize that the effects of adiponectin on endometrium could counteract its pro-invasive effects previously described in the human trophoblast. In this context, we have firstly demonstrated that adiponectin downregulates IGFBP-1 and connexin-43 mRNA expressions, as well as prolactin secretion in ESCs, suggesting an anti-differentiative effect of adiponectin. Secondly, we found that invasive capacities of trophoblastic cell line HTR 8/SVneo are reduced in the presence of conditioned media from ESC cultured in the presence of adiponectin. Adiponectin's anti-invasive action is associated with a decreased activity of MMP-2 and MMP-9, and an increased TIMP-3 mRNA expression in ESCs. Finally, adiponectin receptors (ADIPOR1 and ADIPOR2) knockdown abolishes the anti-differentiative and anti-invasive effects of adiponectin in human ESCs. Altogether, our results suggest that adiponectin reduces the decidualization process and inversely induces the production of endometrial factors that limit trophoblast invasion. Thus, through a dual control in trophoblast and endometrial cells, adiponectin appears as a pivotal actor of the embryo implantation process. PMID- 28733352 TI - The Possibilities to Improve Kidney Health with Proteomics. PMID- 28733351 TI - Multicellular Transcriptional Analysis of Mammalian Heart Regeneration. AB - BACKGROUND: The inability of the adult mammalian heart to regenerate following injury represents a major barrier in cardiovascular medicine. In contrast, the neonatal mammalian heart retains a transient capacity for regeneration, which is lost shortly after birth. Defining the molecular mechanisms that govern regenerative capacity in the neonatal period remains a central goal in cardiac biology. Here, we assemble a transcriptomic framework of multiple cardiac cell populations during postnatal development and following injury, which enables comparative analyses of the regenerative (neonatal) versus nonregenerative (adult) state for the first time. METHODS: Cardiomyocytes, fibroblasts, leukocytes, and endothelial cells from infarcted and noninfarcted neonatal (P1) and adult (P56) mouse hearts were isolated by enzymatic dissociation and fluorescence-activated cell sorting at day 3 following surgery. RNA sequencing was performed on these cell populations to generate the transcriptome of the major cardiac cell populations during cardiac development, repair, and regeneration. To complement our transcriptomic data, we also surveyed the epigenetic landscape of cardiomyocytes during postnatal maturation by performing deep sequencing of accessible chromatin regions by using the Assay for Transposase-Accessible Chromatin from purified mouse cardiomyocyte nuclei (P1, P14, and P56). RESULTS: Profiling of cardiomyocyte and nonmyocyte transcriptional programs uncovered several injury-responsive genes across regenerative and nonregenerative time points. However, the majority of transcriptional changes in all cardiac cell types resulted from developmental maturation from neonatal stages to adulthood rather than activation of a distinct regeneration-specific gene program. Furthermore, adult leukocytes and fibroblasts were characterized by the expression of a proliferative gene expression network following infarction, which mirrored the neonatal state. In contrast, cardiomyocytes failed to reactivate the neonatal proliferative network following infarction, which was associated with loss of chromatin accessibility around cell cycle genes during postnatal maturation. CONCLUSIONS: This work provides a comprehensive framework and transcriptional resource of multiple cardiac cell populations during cardiac development, repair, and regeneration. Our findings define a regulatory program underpinning the neonatal regenerative state and identify alterations in the chromatin landscape that could limit reinduction of the regenerative program in adult cardiomyocytes. PMID- 28733354 TI - Selective Silencing of Hippocampal Parvalbumin Interneurons Induces Development of Recurrent Spontaneous Limbic Seizures in Mice. AB - Temporal lobe epilepsy (TLE) is the most frequent form of focal epilepsies and is generally associated with malfunctioning of the hippocampal formation. Recently, a preferential loss of parvalbumin (PV) neurons has been observed in the subiculum of TLE patients and in animal models of TLE. To demonstrate a possible causative role of defunct PV neurons in the generation of TLE, we permanently inhibited GABA release selectively from PV neurons of the ventral subiculum by injecting a viral vector expressing tetanus toxin light chain in male mice. Subsequently, mice were subjected to telemetric EEG recording and video monitoring. Eighty-eight percent of the mice presented clusters of spike-wave discharges (C-SWDs; 40.0 +/- 9.07/month), and 64% showed spontaneous recurrent seizures (SRSs; 5.3 +/- 0.83/month). Mice injected with a control vector presented with neither C-SWDs nor SRSs. No neurodegeneration was observed due to vector injection or SRS. Interestingly, mice that presented with only C-SWDs but no SRSs, developed SRSs upon injection of a subconvulsive dose of pentylenetetrazole after 6 weeks. The initial frequency of SRSs declined by ~30% after 5 weeks. In contrast to permanent silencing of PV neurons, transient inhibition of GABA release from PV neurons through the designer receptor hM4Di selectively expressed in PV-containing neurons transiently reduced the seizure threshold of the mice but induced neither acute nor recurrent seizures. Our data demonstrate a critical role for perisomatic inhibition mediated by PV-containing interneurons, suggesting that their sustained silencing could be causally involved in the development of TLE.SIGNIFICANCE STATEMENT Development of temporal lobe epilepsy (TLE) generally takes years after an initial insult during which maladaptation of hippocampal circuitries takes place. In human TLE and in animal models of TLE, parvalbumin neurons are selectively lost in the subiculum, the major output area of the hippocampus. The present experiments demonstrate that specific and sustained inhibition of GABA release from parvalbumin-expressing interneurons (mostly basket cells) in sector CA1/subiculum is sufficient to induce hyperexcitability and spontaneous recurrent seizures in mice. As in patients with nonlesional TLE, these mice developed epilepsy without signs of neurodegeneration. The experiments highlight the importance of the potent inhibitory action mediated by parvalbumin cells in the hippocampus and identify a potential mechanism in the development of TLE. PMID- 28733355 TI - ERK/MAPK Signaling Is Required for Pathway-Specific Striatal Motor Functions. AB - The ERK/MAPK intracellular signaling pathway is hypothesized to be a key regulator of striatal activity via modulation of synaptic plasticity and gene transcription. However, prior investigations into striatal ERK/MAPK functions have yielded conflicting results. Further, these studies have not delineated the cell-type-specific roles of ERK/MAPK signaling due to the reliance on globally administered pharmacological ERK/MAPK inhibitors and the use of genetic models that only partially reduce total ERK/MAPK activity. Here, we generated mouse models in which ERK/MAPK signaling was completely abolished in each of the two distinct classes of medium spiny neurons (MSNs). ERK/MAPK deletion in D1R-MSNs (direct pathway) resulted in decreased locomotor behavior, reduced weight gain, and early postnatal lethality. In contrast, loss of ERK/MAPK signaling in D2R MSNs (indirect pathway) resulted in a profound hyperlocomotor phenotype. ERK/MAPK deficient D2R-MSNs exhibited a significant reduction in dendritic spine density, markedly suppressed electrical excitability, and suppression of activity associated gene expression even after pharmacological stimulation. Our results demonstrate the importance of ERK/MAPK signaling in governing the motor functions of the striatal direct and indirect pathways. Our data further show a critical role for ERK in maintaining the excitability and plasticity of D2R MSNs.SIGNIFICANCE STATEMENT Alterations in ERK/MAPK activity are associated with drug abuse, as well as neuropsychiatric and movement disorders. However, genetic evidence defining the functions of ERK/MAPK signaling in striatum-related neurophysiology and behavior is lacking. We show that loss of ERK/MAPK signaling leads to pathway-specific alterations in motor function, reduced neuronal excitability, and the inability of medium spiny neurons to regulate activity induced gene expression. Our results underscore the potential importance of the ERK/MAPK pathway in human movement disorders. PMID- 28733356 TI - Steady-State Free Ca2+ in Astrocytes Is Decreased by Experience and Impacts Arteriole Tone. AB - Astrocytes can control basal synaptic strength and arteriole tone via their resting Ca2+ activity. However, whether resting astrocyte Ca2+ can adjust to a new steady-state level, with an impact on surrounding brain cells, remains unknown. Using two-photon Ca2+ imaging in male rat acute brain slices of the somatosensory neocortex, we found that theta burst neural activity produced an unexpected long-lasting reduction in astrocyte free Ca2+ in the soma and endfeet. The drop in intracellular Ca2+ was attenuated by antagonists targeting multiple ionotropic and metabotropic glutamate receptors, and intracellular cascades involved Ca2+ stores and nitric oxide. The reduction in astrocyte endfoot Ca2+ was coincident with an increase in arteriole tone, and both the Ca2+ drop and the tone change were prevented by an NMDA receptor antagonist. Astrocyte patch-clamp experiments verified that the glutamate receptors in question were located on astrocytes and that Ca2+ changes within astrocytes were responsible for the long lasting change in arteriole diameter caused by theta burst neural activity. In astrocytes from animals that lived in an enriched environment, we measured a relatively lower resting Ca2+ level that occluded any further drop in Ca2+ in response to theta burst activity. These data suggest that electrically evoked patterns of neural activity or natural experience can adjust steady-state resting astrocyte Ca2+ and that the effect has an impact on basal arteriole diameter.SIGNIFICANCE STATEMENT The field of astrocyte-neuron and astrocyte arteriole interactions is currently in a state of refinement. Experimental evidence ex vivo suggests that direct manipulation of astrocyte-free Ca2+ regulates synaptic signaling and local blood flow control; however, in vivo experiments fail to link synaptically evoked astrocyte Ca2+ transients and immediate changes to various astrocyte-mediated processes. To clarify this discrepancy, we examined a different aspect of astrocyte Ca2+: the resting, steady-state free Ca2+ of astrocytes, its modulation, and its potential role in the tonic regulation of surrounding brain cells. We found that ex vivo or in vivo neural activity induced a long-lasting reduction in resting free astrocyte Ca2+ and that this phenomenon changed arteriole tone. PMID- 28733358 TI - Pattern Analyses Reveal Separate Experience-Based Fear Memories in the Human Right Amygdala. AB - Learning fear via the experience of contingencies between a conditioned stimulus (CS) and an aversive unconditioned stimulus (US) is often assumed to be fundamentally different from learning fear via instructions. An open question is whether fear-related brain areas respond differently to experienced CS-US contingencies than to merely instructed CS-US contingencies. Here, we contrasted two experimental conditions where subjects were instructed to expect the same CS US contingencies while only one condition was characterized by prior experience with the CS-US contingency. Using multivoxel pattern analysis of fMRI data, we found CS-related neural activation patterns in the right amygdala (but not in other fear-related regions) that dissociated between whether a CS-US contingency had been instructed and experienced versus merely instructed. A second experiment further corroborated this finding by showing a category-independent neural response to instructed and experienced, but not merely instructed, CS presentations in the human right amygdala. Together, these findings are in line with previous studies showing that verbal fear instructions have a strong impact on both brain and behavior. However, even in the face of fear instructions, the human right amygdala still shows a separable neural pattern response to experience-based fear contingencies.SIGNIFICANCE STATEMENT In our study, we addressed a fundamental problem of the science of human fear learning and memory, namely whether fear learning via experience in humans relies on a neural pathway that can be separated from fear learning via verbal information. Using two new procedures and recent advances in the analysis of brain imaging data, we localized purely experience-based fear processing and memory in the right amygdala, thereby making a direct link between human and animal research. PMID- 28733357 TI - A Role for the Left Angular Gyrus in Episodic Simulation and Memory. AB - Functional magnetic resonance imaging (fMRI) studies indicate that episodic simulation (i.e., imagining specific future experiences) and episodic memory (i.e., remembering specific past experiences) are associated with enhanced activity in a common set of neural regions referred to as the core network. This network comprises the hippocampus, medial prefrontal cortex, and left angular gyrus, among other regions. Because fMRI data are correlational, it is unknown whether activity increases in core network regions are critical for episodic simulation and episodic memory. In the current study, we used MRI-guided transcranial magnetic stimulation (TMS) to assess whether temporary disruption of the left angular gyrus would impair both episodic simulation and memory (16 participants, 10 females). Relative to TMS to a control site (vertex), disruption of the left angular gyrus significantly reduced the number of internal (i.e., episodic) details produced during the simulation and memory tasks, with a concomitant increase in external detail production (i.e., semantic, repetitive, or off-topic information), reflected by a significant detail by TMS site interaction. Difficulty in the simulation and memory tasks also increased after TMS to the left angular gyrus relative to the vertex. In contrast, performance in a nonepisodic control task did not differ statistically as a function of TMS site (i.e., number of free associates produced or difficulty in performing the free associate task). Together, these results are the first to demonstrate that the left angular gyrus is critical for both episodic simulation and episodic memory.SIGNIFICANCE STATEMENT Humans have the ability to imagine future episodes (i.e., episodic simulation) and remember episodes from the past (i.e., episodic memory). A wealth of neuroimaging studies have revealed that these abilities are associated with enhanced activity in a core network of neural regions, including the hippocampus, medial prefrontal cortex, and left angular gyrus. However, neuroimaging data are correlational and do not tell us whether core regions support critical processes for simulation and memory. In the current study, we used transcranial magnetic stimulation and demonstrated that temporary disruption of the left angular gyrus leads to impairments in simulation and memory. The present study provides the first causal evidence to indicate that this region is critical for these fundamental abilities. PMID- 28733360 TI - Thirsting to understand the temporal dynamics of physical activity and alcohol use. PMID- 28733361 TI - Is unintentional doping real, or just an excuse? PMID- 28733362 TI - Loss of Cln5 causes altered neurogenesis in a mouse model of a childhood neurodegenerative disorder. AB - Neural stem/progenitor cells (NPCs) generate new neurons in the brain throughout an individual's lifetime in an intricate process called neurogenesis. Neurogenic alterations are a common feature of several adult-onset neurodegenerative diseases. The neuronal ceroid lipofuscinoses (NCLs) are the most common group of inherited neurodegenerative diseases that mainly affect children. Pathological features of the NCLs include accumulation of lysosomal storage material, neuroinflammation and neuronal degeneration, yet the exact cause of this group of diseases remains poorly understood. The function of the CLN5 protein, causative of the CLN5 disease form of NCL, is unknown. In the present study, we sought to examine neurogenesis in the neurodegenerative disorder caused by loss of Cln5 Our findings demonstrate a newly identified crucial role for CLN5 in neurogenesis. We report for the first time that neurogenesis is increased in Cln5-deficient mice, which model the childhood neurodegenerative disorder caused by loss of Cln5 Our results demonstrate that, in Cln5 deficiency, proliferation of NPCs is increased, NPC migration is reduced and NPC differentiation towards the neuronal lineage is increased concomitantly with functional alterations in the NPCs. Moreover, the observed impairment in neurogenesis is correlated with increased expression of the pro-inflammatory cytokine IL-1beta. A full understanding of the pathological mechanisms that lead to disease and the function of the NCL proteins are critical for designing effective therapeutic approaches for this devastating neurodegenerative disorder. PMID- 28733364 TI - Magnetic Resonance Imaging of Myocardial Strain After Acute ST-Segment-Elevation Myocardial Infarction: A Systematic Review. AB - The purpose of this systematic review is to provide a clinically relevant, disease-based perspective on myocardial strain imaging in patients with acute myocardial infarction or stable ischemic heart disease. Cardiac magnetic resonance imaging uniquely integrates myocardial function with pathology. Therefore, this review focuses on strain imaging with cardiac magnetic resonance. We have specifically considered the relationships between left ventricular (LV) strain, infarct pathologies, and their associations with prognosis. A comprehensive literature review was conducted in accordance with the PRISMA guidelines. Publications were identified that (1) described the relationship between strain and infarct pathologies, (2) assessed the relationship between strain and subsequent LV outcomes, and (3) assessed the relationship between strain and health outcomes. In patients with acute myocardial infarction, circumferential strain predicts the recovery of LV systolic function in the longer term. The prognostic value of longitudinal strain is less certain. Strain differentiates between infarcted versus noninfarcted myocardium, even in patients with stable ischemic heart disease with preserved LV ejection fraction. Strain recovery is impaired in infarcted segments with intramyocardial hemorrhage or microvascular obstruction. There are practical limitations to measuring strain with cardiac magnetic resonance in the acute setting, and knowledge gaps, including the lack of data showing incremental value in clinical practice. Critically, studies of cardiac magnetic resonance strain imaging in patients with ischemic heart disease have been limited by sample size and design. Strain imaging has potential as a tool to assess for early or subclinical changes in LV function, and strain is now being included as a surrogate measure of outcome in therapeutic trials. PMID- 28733363 TI - Lipidomic profiling of patient-specific iPSC-derived hepatocyte-like cells. AB - Hepatocyte-like cells (HLCs) differentiated from human induced pluripotent stem cells (iPSCs) offer an alternative model to primary human hepatocytes to study lipid aberrations. However, the detailed lipid profile of HLCs is yet unknown. In the current study, functional HLCs were differentiated from iPSCs generated from dermal fibroblasts of three individuals by a three-step protocol through the definitive endoderm (DE) stage. In parallel, detailed lipidomic analyses as well as gene expression profiling of a set of lipid-metabolism-related genes were performed during the entire differentiation process from iPSCs to HLCs. Additionally, fatty acid (FA) composition of the cell culture media at different stages was determined. Our results show that major alterations in the molecular species of lipids occurring during DE and early hepatic differentiation stages mainly mirror the quality and quantity of the FAs supplied in culture medium at each stage. Polyunsaturated phospholipids and sphingolipids with a very long FA were produced in the cells at a later stage of differentiation. This work uncovers the previously unknown lipid composition of iPSC-HLCs and its alterations during the differentiation in conjunction with the expression of key lipid-associated genes. Together with biochemical, functional and gene expression measurements, the lipidomic analyses allowed us to improve our understanding of the concerted influence of the exogenous metabolite supply and cellular biosynthesis essential for iPSC-HLC differentiation and function. Importantly, the study describes in detail a cell model that can be applied in exploring, for example, the lipid metabolism involved in the development of fatty liver disease or atherosclerosis. PMID- 28733365 TI - Contrasting Determinants of Mutation Rates in Germline and Soma. AB - Recent studies of somatic and germline mutations have led to the identification of a number of factors that influence point mutation rates, including CpG methylation, expression levels, replication timing, and GC content. Intriguingly, some of the effects appear to differ between soma and germline: in particular, whereas mutation rates have been reported to decrease with expression levels in tumors, no clear effect has been detected in the germline. Distinct approaches were taken to analyze the data, however, so it is hard to know whether these apparent differences are real. To enable a cleaner comparison, we considered a statistical model in which the mutation rate of a coding region is predicted by GC content, expression levels, replication timing, and two histone repressive marks. We applied this model to both a set of germline mutations identified in exomes and to exonic somatic mutations in four types of tumors. Most determinants of mutations are shared: notably, we detected an effect of expression levels on both germline and somatic mutation rates. Moreover, in all tissues considered, higher expression levels are associated with greater strand asymmetry of mutations. However, mutation rates increase with expression levels in testis (and, more tentatively, in ovary), whereas they decrease with expression levels in somatic tissues. This contrast points to differences in damage or repair rates during transcription in soma and germline. PMID- 28733367 TI - Gynaecologist at UK's largest Polish speaking clinic is struck off. PMID- 28733366 TI - The available evidence on demineralised bone matrix in trauma and orthopaedic surgery: A systematic review. AB - OBJECTIVES: The aim of this systematic literature review was to assess the clinical level of evidence of commercially available demineralised bone matrix (DBM) products for their use in trauma and orthopaedic related surgery. METHODS: A total of 17 DBM products were used as search terms in two available databases: Embase and PubMed according to the Preferred Reporting Items for Systematic Reviews and Meta Analyses statement. All articles that reported the clinical use of a DBM-product in trauma and orthopaedic related surgery were included. RESULTS: The literature search resulted in 823 manuscripts of which 64 manuscripts met the final inclusion criteria. The included manuscripts consisted of four randomised controlled trials (level I), eight cohort studies (level III) and 49 case-series (level IV). No clinical studies were found for ten DBM products, and most DBM products were only used in combination with other grafting materials. DBM products were most extensively investigated in spinal surgery, showing limited level I evidence that supports the use Grafton DBM (Osteotech, Eatontown, New Jersey) as a bone graft extender in posterolateral lumbar fusion surgery. DBM products are not thoroughly investigated in trauma surgery, showing mainly level IV evidence that supports the use of Allomatrix (Wright Medical, London, United Kingdom), DBX (DePuy Synthes, Zuchwil, Switzerland), Grafton DBM, or OrthoBlast (Citagenix Laval, Canada) as bone graft extenders. CONCLUSIONS: The clinical level of evidence that supports the use of DBM in trauma and orthopaedic surgery is limited and consists mainly of poor quality and retrospective case series. More prospective, randomised controlled trials are needed to understand the clinical effect and impact of DBM in trauma and orthopaedic surgery.Cite this article: J. van der Stok, K. A. Hartholt, D. A. L. Schoenmakers, J. J. C. Arts. The available evidence on demineralised bone matrix in trauma and orthopaedic surgery: A systemati c review. Bone Joint Res 2017;6:423-432. DOI: 10.1302/2046 3758.67.BJR-2017-0027.R1. PMID- 28733368 TI - Moving Beyond the Assumed: Improving Fistula Success Rates. PMID- 28733369 TI - Measurement with a wink. PMID- 28733370 TI - Reliable adherence to a COPD care bundle mitigates system-level failures and reduces COPD readmissions: a system redesign using improvement science. AB - BACKGROUND: Readmissions of chronic obstructive pulmonary disease (COPD) have devastating effects on patient quality-of-life, disease progression and healthcare cost. Effective interventions to reduce COPD readmissions are needed. OBJECTIVES: Reduce 30-day all-cause readmissions by (1) creating a COPD care bundle that addresses care delivery failures, (2) using improvement science to achieve 90% bundle adherence. SETTING: An 800-bed academic hospital in Ohio, USA. The COPD 30-day all-cause readmission rate was 22.7% from August 2013 to September 2015. METHOD: We performed a cross-sectional study of COPD 30-day readmissions from October 2014 to March 2015 to identify care delivery failures. We interviewed readmitted patients with COPD to identify their needs after discharge. A multidisciplinary team created a care bundle designed to mitigate system failures. Using a quasi-experimental study and 'Model for Improvement', we redesigned care delivery to improve bundle adherence. We used statistical process control charts to analyse bundle adherence and all-cause 30-day readmissions. RESULTS: Cross-sectional review of the index (first-time) admissions revealed COPD was the most common readmission diagnosis and identified 42 system-level failures. The most prevalent failures were deficient inhaler regimen at discharge, late or non-existent follow-up appointments, and suboptimal discharge instructions. Patient interviews revealed confusing discharge instructions, especially regarding inhaler use. The COPD care-bundle components were: (1) appropriate inhaler regimen, (2) 30-day inhaler supply, (3) inhaler education on the device available postdischarge, (4) follow-up within 15 days (5) standardised patient-centred discharge instructions. The adherence to completing bundle components reached 90% in 5.5 months and was sustained. The COPD 30-day readmission rate decreased from 22.7% to 14.7%. Patients receiving all bundle components had a readmission rate of 10.9%. As a balancing measure for the targeted reduction in readmission rate, we assessed length of stay, which did not change (4.8 days before vs 4.6 days after; p=0.45). CONCLUSION: System-level failures and unmet patient needs are modifiable risks for readmissions. Development and reliable implementation of a COPD care bundle that mitigates these failures reduced COPD readmissions. PMID- 28733372 TI - In This Issue of Diabetes Care. PMID- 28733373 TI - Diabetes Care: Change Is Constant, Part 2. PMID- 28733371 TI - An Mtr4/ZFC3H1 complex facilitates turnover of unstable nuclear RNAs to prevent their cytoplasmic transport and global translational repression. AB - Many long noncoding RNAs (lncRNAs) are unstable and rapidly degraded in the nucleus by the nuclear exosome. An exosome adaptor complex called NEXT (nuclear exosome targeting) functions to facilitate turnover of some of these lncRNAs. Here we show that knockdown of one NEXT subunit, Mtr4, but neither of the other two subunits, resulted in accumulation of two types of lncRNAs: prematurely terminated RNAs (ptRNAs) and upstream antisense RNAs (uaRNAs). This suggested a NEXT-independent Mtr4 function, and, consistent with this, we isolated a distinct complex containing Mtr4 and the zinc finger protein ZFC3H1. Strikingly, knockdown of either protein not only increased pt/uaRNA levels but also led to their accumulation in the cytoplasm. Furthermore, all pt/uaRNAs examined associated with active ribosomes, but, paradoxically, this correlated with a global reduction in heavy polysomes and overall repression of translation. Our findings highlight a critical role for Mtr4/ZFC3H1 in nuclear surveillance of naturally unstable lncRNAs to prevent their accumulation, transport to the cytoplasm, and resultant disruption of protein synthesis. PMID- 28733374 TI - The Fallacy of Average: How Using HbA1c Alone to Assess Glycemic Control Can Be Misleading. AB - HbA1c is a valuable metric for comparing treatment groups in a randomized trial, for assessing glycemic trends in a population over time, or for cross-sectional comparisons of glycemic control in different populations. However, what is not widely appreciated is that HbA1c may not be a good indicator of an individual patient's glycemic control because of the wide range of mean glucose concentrations and glucose profiles that can be associated with a given HbA1c level. To illustrate this point, we plotted mean glucose measured with continuous glucose monitoring (CGM) versus central laboratory-measured HbA1c in 387 participants in three randomized trials, showing that not infrequently HbA1c may underestimate or overestimate mean glucose, sometimes substantially. Thus, if HbA1c is to be used to assess glycemic control, it is imperative to know the patient's actual mean glucose to understand how well HbA1c is an indicator of the patient's glycemic control. With knowledge of the mean glucose, an estimated HbA1c (eA1C) can be calculated with the formula provided in this article to compare with the measured HbA1c. Estimating glycemic control from HbA1c alone is in essence applying a population average to an individual, which can be misleading. Thus, a patient's CGM glucose profile has considerable value for optimizing his or her diabetes management. In this era of personalized, precision medicine, there are few better examples with respect to the fallacy of applying a population average to a specific patient rather than using specific information about the patient to determine the optimal approach to treatment. PMID- 28733375 TI - Addressing Reverse Causation Bias in the Obesity Paradox Is Not "One Size Fits All". PMID- 28733376 TI - Detection of Osteomyelitis in the Diabetic Foot by Imaging Techniques: A Systematic Review and Meta-analysis Comparing MRI, White Blood Cell Scintigraphy, and FDG-PET. AB - OBJECTIVE: Diagnosing bone infection in the diabetic foot is challenging and often requires several diagnostic procedures, including advanced imaging. We compared the diagnostic performances of MRI, radiolabeled white blood cell (WBC) scintigraphy (either with 99mTc-hexamethylpropyleneamineoxime [HMPAO] or 111In oxine), and [18F]fluorodeoxyglucose positron emission tomography (18F-FDG PET)/computed tomography. RESEARCH DESIGN AND METHODS: We searched Medline and Embase as of August 2016 for studies of diagnostic tests on patients known or suspected to have diabetes and a foot infection. We performed a systematic review using criteria recommended by the Cochrane Review of a database that included prospective and retrospective diagnostic studies performed on patients with diabetes in whom there was a clinical suspicion of osteomyelitis of the foot. The preferred reference standard was bone biopsy and subsequent pathological (or microbiological) examination. RESULTS: Our review found 6,649 articles; 3,894 in Medline and 2,755 in Embase. A total of 27 full articles and 2 posters was selected for inclusion in the analysis. The performance characteristics for the 18F-FDG-PET were: sensitivity, 89%; specificity, 92%; diagnostic odds ratio (DOR), 95; positive likelihood ratio (LR), 11; and negative LR, 0.11. For WBC scan with 111In-oxine, the values were: sensitivity, 92%; specificity, 75%; DOR, 34; positive LR, 3.6; and negative LR, 0.1. For WBC scan with 99mTc-HMPAO, the values were: sensitivity, 91%; specificity, 92%; DOR, 118; positive LR, 12; and negative LR, 0.1. Finally, for MRI, the values were: sensitivity, 93%; specificity, 75%; DOR, 37; positive LR, 3.66, and negative LR, 0.10. CONCLUSIONS: The various modalities have similar sensitivity, but 18F-FDG-PET and 99mTc-HMPAO labeled WBC scintigraphy offer the highest specificity. Larger prospective studies with a direct comparison among the different imaging techniques are required. PMID- 28733378 TI - Is It Time to Change the Type 2 Diabetes Treatment Paradigm? No! Metformin Should Remain the Foundation Therapy for Type 2 Diabetes. AB - Most treatment guidelines, including those from the American Diabetes Association/European Association for the Study of Diabetes and the International Diabetes Federation, suggest metformin be used as the first-line therapy after diet and exercise. This recommendation is based on the considerable body of evidence that has accumulated over the last 30 years, but it is also supported on clinical grounds based on metformin's affordability and tolerability. As such, metformin is the most commonly used oral antihyperglycemic agent in the U.S. However, based on the release of newer agents over the recent past, some have suggested that the modern approach to disease management should be based upon identification of its etiology and correcting the underlying biological disturbances. That is, we should use interventions that normalize or at least ameliorate the recognized derangements in physiology that drive the clinical manifestation of disease, in this circumstance, hyperglycemia. Thus, it is argued that therapeutic interventions that target glycemia but do not correct the underlying pathogenic disturbances are unlikely to result in a sustained benefit on the disease process. In our field, there is an evolving debate regarding the suggested first step in diabetes management and a call for a new paradigm. Given the current controversy, we provide a Point-Counterpoint debate on this issue. In the point narrative that precedes the counterpoint narrative below, Drs. Abdul Ghani and DeFronzo provide their argument that a treatment approach for type 2 diabetes based upon correcting the underlying pathophysiological abnormalities responsible for the development of hyperglycemia provides the best therapeutic strategy. Such an approach requires a change in the recommendation for first-line therapy from metformin to a GLP-1 receptor agonist. In the counterpoint narrative below, Dr. Inzucchi argues that based on the medical community's extensive experience and the drug's demonstrated efficacy, safety, low cost, and cardiovascular benefits, metformin should remain the "foundation therapy" for all patients with type 2 diabetes, barring contraindications.-William T. CefaluChief Scientific, Medical & Mission Officer, American Diabetes Association. PMID- 28733377 TI - Is It Time to Change the Type 2 Diabetes Treatment Paradigm? Yes! GLP-1 RAs Should Replace Metformin in the Type 2 Diabetes Algorithm. AB - Most treatment guidelines, including those from the American Diabetes Association/European Association for the Study of Diabetes and the International Diabetes Federation, suggest metformin be used as the first-line therapy after diet and exercise. This recommendation is based on the considerable body of evidence that has accumulated over the last 30 years, but it is also supported on clinical grounds based on metformin's affordability and tolerability. As such, metformin is the most commonly used oral antihyperglycemic agent in the U.S. However, based on the release of newer agents over the recent past, some have suggested that the modern approach to disease management should be based upon identification of its etiology and correcting the underlying biological disturbances. That is, we should use interventions that normalize or at least ameliorate the recognized derangements in physiology that drive the clinical manifestation of disease, in this circumstance, hyperglycemia. Thus, it is argued that therapeutic interventions that target glycemia but do not correct the underlying pathogenic disturbances are unlikely to result in a sustained benefit on the disease process. In our field, there is an evolving debate regarding the suggested first step in diabetes management and a call for a new paradigm. Given the current controversy, we provide a Point-Counterpoint debate on this issue. In the point narrative below that precedes the counterpoint narrative, Drs. Abdul Ghani and DeFronzo provide their argument that a treatment approach for type 2 diabetes based upon correcting the underlying pathophysiological abnormalities responsible for the development of hyperglycemia provides the best therapeutic strategy. Such an approach requires a change in the recommendation for first-line therapy from metformin to a GLP-1 receptor agonist. In the counterpoint narrative that follows Drs. Abdul-Ghani and DeFronzo's contribution, Dr. Inzucchi argues that, based on the medical community's extensive experience and the drug's demonstrated efficacy, safety, low cost, and cardiovascular benefits, metformin should remain the "foundation therapy" for all patients with type 2 diabetes, barring contraindications.-William T. CefaluChief Scientific, Medical & Mission Officer, American Diabetes Association. PMID- 28733380 TI - Comment on Niewczas et al. Circulating Modified Metabolites and a Risk of ESRD in Patients With Type 1 Diabetes and Chronic Kidney Disease. Diabetes Care 2017;40:383-390. PMID- 28733381 TI - Response to Comment on Niewczas et al. Circulating Modified Metabolites and a Risk of ESRD in Patients With Type 1 Diabetes and Chronic Kidney Disease. Diabetes Care 2017;40:383-390. PMID- 28733383 TI - Response to Comment on Harlan. Islet Transplantation for Hypoglycemia Unawareness/Severe Hypoglycemia: Caveat Emptor. Diabetes Care 2016;39:1072-1074. PMID- 28733382 TI - Comment on Harlan. Islet Transplantation for Hypoglycemia Unawareness/Severe Hypoglycemia: Caveat Emptor. Diabetes Care 2016;39:1072-1074. PMID- 28733384 TI - Comment on Nachum et al. Glyburide Versus Metformin and Their Combination for the Treatment of Gestational Diabetes Mellitus: A Randomized Controlled Study. Diabetes Care 2017;40:332-337. PMID- 28733385 TI - Response to Comment on Nachum et al. Glyburide Versus Metformin and Their Combination for the Treatment of Gestational Diabetes Mellitus: A Randomized Controlled Study. Diabetes Care 2017;40:332-337. PMID- 28733386 TI - miR-99 regulates normal and malignant hematopoietic stem cell self-renewal. AB - The microRNA-99 (miR-99) family comprises a group of broadly conserved microRNAs that are highly expressed in hematopoietic stem cells (HSCs) and acute myeloid leukemia stem cells (LSCs) compared with their differentiated progeny. Herein, we show that miR-99 regulates self-renewal in both HSCs and LSCs. miR-99 maintains HSC long-term reconstitution activity by inhibiting differentiation and cell cycle entry. Moreover, miR-99 inhibition induced LSC differentiation and depletion in an MLL-AF9-driven mouse model of AML, leading to reduction in leukemia-initiating activity and improved survival in secondary transplants. Confirming miR-99's role in established AML, miR-99 inhibition induced primary AML patient blasts to undergo differentiation. A forward genetic shRNA library screen revealed Hoxa1 as a critical mediator of miR-99 function in HSC maintenance, and this observation was independently confirmed in both HSCs and LSCs. Together, these studies demonstrate the importance of noncoding RNAs in the regulation of HSC and LSC function and identify miR-99 as a critical regulator of stem cell self-renewal. PMID- 28733387 TI - Linking Auxin with Photosynthetic Rate via Leaf Venation. AB - Land plants lose vast quantities of water to the atmosphere during photosynthetic gas exchange. In angiosperms, a complex network of veins irrigates the leaf, and it is widely held that the density and placement of these veins determines maximum leaf hydraulic capacity and thus maximum photosynthetic rate. This theory is largely based on interspecific comparisons and has never been tested using vein mutants to examine the specific impact of leaf vein morphology on plant water relations. Here we characterize mutants at the Crispoid (Crd) locus in pea (Pisum sativum), which have altered auxin homeostasis and activity in developing leaves, as well as reduced leaf vein density and aberrant placement of free ending veinlets. This altered vein phenotype in crd mutant plants results in a significant reduction in leaf hydraulic conductance and leaf gas exchange. We find Crispoid to be a member of the YUCCA family of auxin biosynthetic genes. Our results link auxin biosynthesis with maximum photosynthetic rate through leaf venation and substantiate the theory that an increase in the density of leaf veins coupled with their efficient placement can drive increases in leaf photosynthetic capacity. PMID- 28733388 TI - Improving Plant Nitrogen Use Efficiency through Alteration of Amino Acid Transport Processes. AB - Improving the efficiency of nitrogen (N) uptake and utilization in plants could potentially increase crop yields while reducing N fertilization and, subsequently, environmental pollution. Within most plants, N is transported primarily as amino acids. In this study, pea (Pisum sativum) plants overexpressing AMINO ACID PERMEASE1 (AAP1) were used to determine if and how genetic manipulation of amino acid transport from source to sink affects plant N use efficiency. The modified plants were grown under low, moderate, or high N fertilization regimes. The results showed that, independent of the N nutrition, the engineered plants allocate more N via the vasculature to the shoot and seeds and produce more biomass and higher seed yields than wild-type plants. Dependent on the amount of N supplied, the AAP1-overexpressing plants displayed improved N uptake or utilization efficiency, or a combination of the two. They also showed significantly increased N use efficiency in N-deficient as well as in N-rich soils and, impressively, required half the amount of N to produce as many fruits and seeds as control plants. Together, these data support that engineering N allocation from source to sink presents an effective strategy to produce crop plants with improved productivity as well as N use efficiency in a range of N environments. PMID- 28733389 TI - Cytokinin Biosynthesis Promotes Cortical Cell Responses during Nodule Development. AB - Legume mutants have shown the requirement for receptor-mediated cytokinin signaling in symbiotic nodule organogenesis. While the receptors are central regulators, cytokinin also is accumulated during early phases of symbiotic interaction, but the pathways involved have not yet been fully resolved. To identify the source, timing, and effect of this accumulation, we followed transcript levels of the cytokinin biosynthetic pathway genes in a sliding developmental zone of Lotus japonicus roots. LjIpt2 and LjLog4 were identified as the major contributors to the first cytokinin burst. The genetic dependence and Nod factor responsiveness of these genes confirm that cytokinin biosynthesis is a key target of the common symbiosis pathway. The accumulation of LjIpt2 and LjLog4 transcripts occurs independent of the LjLhk1 receptor during nodulation. Together with the rapid repression of both genes by cytokinin, this indicates that LjIpt2 and LjLog4 contribute to, rather than respond to, the initial cytokinin buildup. Analysis of the cytokinin response using the synthetic cytokinin sensor, TCSn, showed that this response occurs in cortical cells before spreading to the epidermis in L. japonicus While mutant analysis identified redundancy in several biosynthesis families, we found that mutation of LjIpt4 limits nodule numbers. Overexpression of LjIpt3 or LjLog4 alone was insufficient to produce the robust formation of spontaneous nodules. In contrast, overexpressing a complete cytokinin biosynthesis pathway leads to large, often fused spontaneous nodules. These results show the importance of cytokinin biosynthesis in initiating and balancing the requirement for cortical cell activation without uncontrolled cell proliferation. PMID- 28733392 TI - Editorial changes. AB - Here at Development we are very sad to be saying goodbye to two of our editors: Ottoline Leyser and Geraldine Seydoux. Both Ottoline and Geraldine have been valued members of the editorial team since 2011, and we are hugely grateful for the time and effort they have put in to handling research papers, helping to shape the journal's future plans and, in Ottoline's case, coordinating our 2016 Special Issue on Plant Development. They will both be greatly missed, but will maintain connections with and continue to provide input on the journal as members of our Editorial Advisory Board. PMID- 28733390 TI - Triphosphate Tunnel Metalloenzyme Function in Senescence Highlights a Biological Diversification of This Protein Superfamily. AB - The triphosphate tunnel metalloenzyme (TTM) superfamily comprises a group of enzymes that hydrolyze organophosphate substrates. They exist in all domains of life, yet the biological role of most family members is unclear. Arabidopsis (Arabidopsis thaliana) encodes three TTM genes. We have previously reported that AtTTM2 displays pyrophosphatase activity and is involved in pathogen resistance. Here, we report the biochemical activity and biological function of AtTTM1 and diversification of the biological roles between AtTTM1 and 2 Biochemical analyses revealed that AtTTM1 displays pyrophosphatase activity similar to AtTTM2, making them the only TTMs characterized so far to act on a diphosphate substrate. However, knockout mutant analysis showed that AtTTM1 is not involved in pathogen resistance but rather in leaf senescence. AtTTM1 is transcriptionally up regulated during leaf senescence, and knockout mutants of AtTTM1 exhibit delayed dark-induced and natural senescence. The double mutant of AtTTM1 and AtTTM2 did not show synergistic effects, further indicating the diversification of their biological function. However, promoter swap analyses revealed that they functionally can complement each other, and confocal microscopy revealed that both proteins are tail-anchored proteins that localize to the mitochondrial outer membrane. Additionally, transient overexpression of either gene in Nicotiana benthamiana induced senescence-like cell death upon dark treatment. Taken together, we show that two TTMs display the same biochemical properties but distinct biological functions that are governed by their transcriptional regulation. Moreover, this work reveals a possible connection of immunity-related programmed cell death and senescence through novel mitochondrial tail-anchored proteins. PMID- 28733391 TI - Phospholipid:Diacylglycerol Acyltransferase-Mediated Triacylglyerol Synthesis Augments Basal Thermotolerance. AB - High temperatures rapidly induce a genetically programmed heat-shock response (HSR) that is essential to establish short-term acquired thermotolerance. In addition, an immediate HSR-independent metabolic response is triggered, resulting in an accumulation of unsaturated triacylglycerols (TAGs) in the cytosol. The metabolic processes involved in heat-induced TAG formation in plants and their physiological significance remain to be clarified. Lipidomic analyses of Arabidopsis (Arabidopsis thaliana) seedlings indicated that during heat stress, polyunsaturated fatty acids from thylakoid galactolipids are incorporated into cytosolic TAGs. In addition, rapid conversion of plastidic monogalactosyl diacylglycerols (MGDGs) into oligogalactolipids, acylated MGDGs, and diacylglycerols (DAGs), the direct precursor of TAGs, was observed. For TAG synthesis, DAG requires a fatty acid from the acyl-CoA pool or phosphatidylcholine. Since seedlings deficient in PHOSPHOLIPID:DIACYLGLYCEROL ACYLTRANSFERASE1 (PDAT1) were unable to accumulate TAGs after heat stress, phosphatidylcholine appears to be the major fatty acid donor. Results suggest that rapid plastid lipid metabolism drives TAG accumulation during heat stress. PDAT1-mediated TAG accumulation was found to increase heat resistance, since nonacclimated pdat1 mutant seedlings were more sensitive to severe heat stress, as indicated by a more dramatic decline of the maximum efficiency of PSII and lower seedling survival compared to wild-type seedlings. In contrast, nonacclimated trigalactosyldiacylglycerol1 (tgd1) mutants overaccumulating TAGs and oligogalactolipids were more resistant to heat stress. Hence, thylakoid lipid metabolism and TAG formation increases thermotolerance in addition to the genetically encoded HSR. PMID- 28733393 TI - Microscopic Observation of Living Cells Stained with Fluorescent Probes. AB - Fluorescence imaging of living cells provides a unique opportunity to follow dynamic behavior of specific molecules under physiological conditions. In the fission yeast Schizosaccharomyces pombe, expression of a target protein genetically fused with a fluorescent protein such as the jellyfish green fluorescent protein (GFP) is widely used. In addition, fluorescent chemical reagents are also used to stain specific molecules (e.g., Hoechst 33324 to stain DNA). Specimens of S. pombe cells for live cell imaging are prepared by either of two methods: sandwiching the cells between glass coverslips and by mounting the cells on a glass-bottom culture dish. For time-lapse observation, it is necessary to immobilize fission yeast cells on the glass surface of the glass-bottom dish because they are nonadherent and tend to move easily as a result of stage movement, convection flow of culture medium, and the contact and pushing of neighboring cells during cell growth. Either concanavalin A or soybean lectin, which bind to S. pombe cell walls, can be used for immobilization. Considerations for sample preparations and observation conditions are described. PMID- 28733394 TI - Genetic Interaction Mapping in Schizosaccharomyces pombe Using the Pombe Epistasis Mapper (PEM) System and a ROTOR HDA Colony Replicating Robot in a 1536 Array Format. AB - This protocol describes an optimized high-throughput procedure for generating double deletion mutants in Schizosaccharomyces pombe using the colony replicating robot ROTOR HDA and the PEM (pombe epistasis mapper) system. The method is based on generating high-density colony arrays (1536 colonies per agar plate) and passaging them through a series of antidiploid and mating-type selection (ADS MTS) and double-mutant selection (DMS) steps. Detailed program parameters for each individual replication step are provided. Using this procedure, batches of 25 or more screens can be routinely performed. PMID- 28733395 TI - Induction of Hyphal Growth in Schizosaccharomyces japonicus. AB - Schizosaccharomyces japonicus is a dimorphic yeast. Depending on the nutrient conditions, the transition between growth as yeast cells and growth as hyphal cells can be reversibly induced. In addition to nutrient stress, induced DNA lesions, such as those produced by camptothecin, also induce hyphal growth regardless of the nutrient status. This protocol describes both methods of induction. PMID- 28733396 TI - Two-Dimensional Gel Electrophoresis of DNA Replication Intermediates in Schizosaccharomyces pombe. AB - Two-dimensional gel electrophoresis allows direct detection of DNA replication and recombination intermediates in preparations of total genomic DNA. This technique is widely used to identify replication origins in the yeast genome and is based on the different mobility in agarose gels of linear and branched DNA molecules depending on their mass and structure. During the first dimension, low voltage and a low-percentage agarose gel favors separation of the molecules by their mass and minimizes the effect of their structure. In contrast, during the second dimension, a higher voltage, a higher percentage agarose gel, and the presence of ethidium bromide significantly delays the migration of branched structures relative to linear molecules of the same mass. This technique is appropriate for the detection of replication initiation and, therefore, an active origin of replication, within regions of approximately 2.5-5.5 kb. Consequently, it is not well suited for genome-wide replication analyses. PMID- 28733397 TI - Transformation of Schizosaccharomyces pombe in a 96-Well Format. AB - This protocol describes chemical transformation of Schizosaccharomyces pombe with linear DNA in a 96-well format. This procedure has been successfully used for large-scale strain construction in fission yeast. PMID- 28733398 TI - Live Imaging of Chromosome Segregation during Meiosis in the Fission Yeast Schizosaccharomyces pombe. AB - This protocol describes the live observation of chromosome segregation during fission yeast meiosis. To visualize one chromosome of interest, the lac operator (lacO array) is integrated at its centromere-proximal locus, and the lac repressor (lacI)-GFP fusion protein is expressed in a haploid strain. This haploid strain, in which mCherry-tagged tubulin is also expressed exogenously to monitor meiotic progression, is crossed with a nonlabeled haploid strain to induce meiosis. GFP and mCherry signals in resulting zygotes are observed by a fluorescent microscopy during the progression of meiosis. PMID- 28733399 TI - Synchronous Induction of Meiosis in the Fission Yeast Schizosaccharomyces pombe. AB - In fission yeast Schizosaccharomyces pombe, initiation of meiosis is repressed by Pat1 kinase. This protocol describes how ectopic inactivation of the temperature sensitive Pat1-114 kinase in G1-arrested h- /h- diploid cells carrying mat1-Pc induces a highly synchronized commitment to and execution of meiosis. Haploid or diploid pat1-114 mutants without mat1-Pc can also be used for convenience, although less synchrony may be attained compared with induction using true diploids. An essentially identical protocol can be used for induction via inhibition of genetically sensitized Pat1 kinase by ATP analogs. PMID- 28733400 TI - Visualization of a Specific Genome Locus by the lacO/LacI-GFP System. AB - Observing the dynamics of a specific chromosome locus in living cells can provide important information as to the molecular mechanisms underlying events such as chromosome segregation, homologous chromosome pairing, chromosome arrangement, and gene expression. The lacO/LacI-GFP system provides a simple and useful method in which a chromosome locus is visualized by inserting lacO repeat arrays and then expressing an LacI-GFP fusion that specifically binds to the lacO sequence. This system has been adapted for use in Schizosaccharomyces pombe by expressing the LacI-GFP under a promoter of the dis1+ gene. Furthermore, a two-step integration method has been developed that ensures high-efficiency integration of lacO arrays to a desired target position. PMID- 28733401 TI - Mating, Spore Dissection, and Selection of Diploid Cells in Schizosaccharomyces japonicus. AB - Haploid yeast cells mate to form heterozygotes and subsequently undergo meiosis to form spores. This process can be used to produce gene combinations and variants that are useful for genetic analysis. For example, these spores can be used to generate double mutants or to measure genetic distances in a mutational analysis. Here, we describe mating and spore dissection procedures for Schizosaccharomyces japonicus cells. Although the overall procedures resemble those used in Schizosaccharomyces pombe, some differences exist, including the use of EMM2 medium without nitrogen (EMM-N) for mating and the shorter incubation time of 16-20 h for S. japonicus cells. Furthermore, the S. japonicus zygotes produce eight spores and thus require an "octad" analysis. PMID- 28733402 TI - Analysis of DNA Metabolism in Fission Yeast. AB - The fission yeast Schizosaccharomyces pombe is an excellent model organism to study DNA metabolism, in which the DNA replication and repair mechanisms are evolutionarily conserved. In this introduction we describe a range of methods commonly used to study aspects of DNA metabolism in fission yeast, focusing on approaches used for the analysis of genome stability, DNA replication, and DNA repair. We describe the use of a minichromosome, Ch16, for monitoring different aspects of genome stability. We introduce two-dimensional gel electrophoresis and immunofluorescent visualization of combed DNA molecules for the analysis of DNA replication. Further, we introduce a pulsed field gel electrophoresis (PFGE) assay to physically monitor chromosome integrity, which can be used in conjunction with a DNA double-strand break (DSB) repair assay to genetically quantitate different DSB repair and misrepair outcomes, including gross chromosomal rearrangements, in fission yeast. PMID- 28733404 TI - High-Throughput Quantitative Genetic Interaction Mapping in the Fission Yeast Schizosaccharomyces pombe. AB - Epistasis mapping, in which the phenotype that emerges from combining pairs of mutations is measured quantitatively, is a powerful tool for unbiased study of gene function. When performed at a large scale, this approach has been used to assign function to previously uncharacterized genes, define functional modules and pathways, and study their cross talk. These experiments rely heavily on methods for rapid sampling of binary combinations of mutant alleles by systematic generation of a series of double mutants. Epistasis mapping technologies now exist in various model systems. Here we provide an overview of different epistasis mapping technologies, including the pombe epistasis mapper (PEM) system designed for the collection of quantitative genetic interaction data in fission yeast Schizosaccharomyces pombe Comprising a series of high-throughput selection steps for generation and characterization of double mutants, the PEM system has provided insight into a wide range of biological processes as well as facilitated evolutionary analysis of genetic interactomes across different species. PMID- 28733403 TI - Transformation of Schizosaccharomyces japonicus. AB - This protocol describes the use of electroporation to transform Schizosaccharomyces japonicus with plasmids or linear DNA. Plasmids are helpful for the complementation testing of mutations and for the expression of specific genes. Linear DNA fragments integrated into chromosomal DNA by homologous recombination are useful for gene deletion or to fuse a gene with a tag sequence (e.g., encoding a fluorescent protein). To introduce DNA into S. japonicus, electroporation methods are recommended because S. japonicus is sensitive to lithium acetate (LiOAc). PMID- 28733405 TI - Analysis of DNA Replication in Fission Yeast by Combing. AB - DNA replication studies based on population experiments give an average estimate of replication kinetics from many cells. This average replication profile masks the stochastic nature of origin firing in eukaryotes, which is revealed by using single-molecule techniques, such as DNA combing. The analysis of replication kinetics by DNA combing involves isolating DNA from cells that have been pulse labeled with thymidine analogs and stretching it on a silanized coverslip. The analog-labeled patches on the stretched DNA fibers can then be detected using fluorescent antibodies against the analog. Each fiber represents a part of the genome from a single cell; therefore, it is possible to study the variation in behavior of individual origins from one cell to another. Furthermore, each DNA fiber is uniformly stretched, making it possible to measure distances accurately at kilobase resolution. It is also possible to stretch a high density of fibers on coverslips enabling quantitative data collection. PMID- 28733407 TI - Fission Yeast Cell Wall Analysis. AB - The Schizosaccharomyces pombe cell wall is a rigid exoskeletal structure mainly composed of interlinked glucose polysaccharides and galactomannoproteins. It is essential for survival of the fission yeast, as it prevents cells from bursting from internal turgor pressure and protects them from mechanical injuries. Additionally, the cell wall determines the cell shape and, therefore, a better knowledge of cell wall structure and composition could provide valuable data in S. pombe morphogenetic studies. Here, we provide information about this structure and the current reliable methods for rapid analysis of the cell wall polymers by specific enzymatic and chemical degradations of purified cell walls. PMID- 28733406 TI - Genetic Interaction Score (S-Score) Calculation, Clustering, and Visualization of Genetic Interaction Profiles for Yeast. AB - This protocol describes computational analysis of genetic interaction screens, ranging from data capture (plate imaging) to downstream analyses. Plate imaging approaches using both digital camera and office flatbed scanners are included, along with a protocol for the extraction of colony size measurements from the resulting images. A commonly used genetic interaction scoring method, calculation of the S-score, is discussed. These methods require minimal computer skills, but some familiarity with MATLAB and Linux/Unix is a plus. Finally, an outline for using clustering and visualization software for analysis of resulting data sets is provided. PMID- 28733408 TI - DNA Double-Strand Break Repair Assay. AB - DNA double-strand breaks (DSBs), arising during normal DNA metabolism or following exposure to mutagenic agents such as ionizing radiation can lead to chromosomal rearrangements and genome instability, and are potentially lethal if unrepaired. Therefore, understanding the mechanisms of DSB repair and misrepair, and identifying the factors involved in these processes is of biological as well as medical interest. Here we describe a DSB assay in Schizosaccharomyces pombe that can be used to identify and quantify different repair, misrepair, and failed repair events resulting from a site-specific DSB within the context of a nonessential minichromosome, Ch16 This assay can be used to determine the contribution of most genes or genetic backgrounds to DSB repair and genome stability, and can also provide mechanistic insights into their function. PMID- 28733409 TI - Using Pulsed-Field Gel Electrophoresis to Analyze Schizosaccharomyces pombe Chromosomes and Chromosomal Elements. AB - Pulsed field gel electrophoresis (PFGE) uses alternatively oriented pulsed electrical fields to separate large DNA molecules. Here, we describe PFGE protocols and conditions for separating and visualizing chromosomes between 0.5 and 6 Mb (optimal for analyzing the endogenous fission yeast chromosomes of 5.7, 4.6, and 3.5 Mb), and for shorter chromosomal elements of between 50 and 600 kb, such as the 530 kb Ch16 minichromosome. In addition to determining chromosome size, this technique has a wide range of applications, including determining whether DNA replication or repair is complete, defining the molecular karyotype of cells, analyzing chromosomal rearrangements, assigning genes or constructs to particular chromosomes, and isolating DNA from specific chromosomes. PMID- 28733410 TI - Radioactive Labeling and Fractionation of Fission Yeast Walls. AB - Fungal cells contain an essential structure external to the cell, made of polysaccharides and proteins, termed the cell wall. Polysaccharides represent ~96% of the cell wall on a dry-weight basis. They are complex insoluble polymers connected to each other by covalent linkages and hydrogen bonds with specific localizations in the cell wall and septum. Fission yeast contains three beta glucans (a major branched beta(1,3)-glucan, a minor linear beta(1,3)-glucan, and a minor branched beta(1,6)-glucan), two alpha-glucans (a major alpha(1,3)-glucan and a minor alpha(1,4)-glucan), and a minor amount of galactomannan-linked glycoproteins. We provide here a simple protocol to label uniformly the cell wall using d-[U-14C]-glucose as a carbon source and to fractionate the cell wall into the three or four main cell wall components: galactomannoproteins, alpha-glucan, and beta-glucan, which can be subdivided into beta(1,3)-glucan and beta(1,6) glucan. This simple protocol uses enzymatic and chemical fractionations of the different cell wall components that permit the quantification of each polysaccharide in the cell wall and in the cell. This protocol is very useful for the analysis of the many morphological alterations caused by a variety of cellular processes that ultimately affect the cell wall and thus cell morphogenesis. PMID- 28733411 TI - DNA Preparation from Schizosaccharomyces pombe. AB - This protocol includes two methods for genomic DNA preparation from Schizosaccharomyces pombe The first is a quick method for preparation of DNA suitable for polymerase chain reaction (PCR) genotyping. The second, longer method yields high-quality DNA that can be used for amplification of targeting cassettes. PMID- 28733412 TI - Schizosaccharomyces japonicus: A Distinct Dimorphic Yeast among the Fission Yeasts. AB - Genomic sequencing data and morphological properties demonstrate evolutionary relationships among groups of the fission yeast, Schizosaccharomyces Phylogenetically, S. japonicus is the furthest removed from other species of fission yeast. The basic characteristics of cell proliferation are shared among all fission yeast, including the process of binary fission during vegetative growth, conjugation and karyogamy with horsetail movement, mating-type switching, and sporulation. However, S. japonicus also exhibits characteristics that are unique to filamentous fungi. S. japonicus is a nonpathogenic yeast that exhibits dimorphism. Depending on the environmental conditions, S. japonicus transforms from yeast cells into filamentous cells (hyphae), and blue light triggers synchronous septation of hyphal cells. A rough version of the whole-genome sequence is now available, facilitating genetic manipulation of S. japonicus. Furthermore, the extensive genetic knowledge available for S. pombe is aiding the development of genetic tools for analyzing S. japonicus. S. japonicus will help shed light on the evolutionary relationships among the fission yeast. PMID- 28733413 TI - Live Cell Imaging of the Schizosaccharomyces pombe Sexual Life Cycle. AB - The fission yeast Schizosaccharomyces pombe is an invaluable model system for studying the principles that drive sexual differentiation and the meiotic cell division cycle. We describe a simple protocol for microscopic observation of the entire sexual life cycle that can be adapted to focus on specific stages of sexual differentiation. After growth to exponential phase in a nitrogen-rich medium, cell cultures are switched to a nitrogen-deprived medium until the population is enriched for the specific stage of the sexual lifecycle to be studied. Cells are then mounted in easily constructed customized agarose pad chambers for imaging. PMID- 28733414 TI - Live Cell Imaging in Fission Yeast. AB - Live cell imaging complements the array of biochemical and molecular genetic approaches to provide a comprehensive insight into functional dependencies and molecular interactions in fission yeast. Fluorescent proteins and vital dyes reveal dynamic changes in the spatial distribution of organelles and the proteome and how each alters in response to changes in environmental and genetic composition. This introduction discusses key issues and basic image analysis for live cell imaging of fission yeast. PMID- 28733415 TI - Introduction to Fission Yeast as a Model System. AB - Here, we briefly outline the history of fission yeast, its life cycle, and aspects of its biology that make it a useful model organism for studying problems of eukaryotic molecular and cell biology. PMID- 28733416 TI - Genetic Interaction Screens in Schizosaccharomyces pombe Using the Pombe Epistasis Mapper (PEM) System and a Manual Colony Replicator. AB - In laboratories in which a colony-replicating robot is not available, manual replication provides a good, low-cost alternative for genetic interaction screening using the Pombe Epistasis Mapper (PEM) system. The protocol presented here describes the minimum number of steps required to identify genetic interactions. First, a query deletion is introduced to a library of deletion mutants by mating. Through a series of subsequent selection steps, single and double mutants are isolated and analyzed. PMID- 28733417 TI - Analysis of Schizosaccharomyces pombe Meiosis. AB - Meiosis is a specialized cell cycle that generates haploid gametes from diploid cells. The fission yeast Schizosaccharomyces pombe is one of the best model organisms for studying the regulatory mechanisms of meiosis. S. pombe cells, which normally grow in the haploid state, diploidize by conjugation and initiate meiosis when starved for nutrients, especially nitrogen. Following two rounds of chromosome segregation, spore formation takes place. The switch from mitosis to meiosis is controlled by a kinase, Pat1, and an RNA-binding protein, Mei2. Mei2 is also a key factor for meiosis-specific gene expression. Studies on S. pombe have offered insights into cell cycle regulation and chromosome segregation during meiosis. Here we outline the current understanding of the molecular mechanisms regulating the initiation and progression of meiosis, and introduce methods for the study of meiosis in fission yeast. PMID- 28733418 TI - A Simple Method to Induce Meiosis and Sporulation Semisynchronously in the Fission Yeast Schizosaccharomyces pombe. AB - Schizosaccharomyces pombe cells initiate a sexual differentiation program, which comprises meiosis and spore formation, on nitrogen starvation. This protocol describes a simple procedure to induce meiosis and sporulation semisynchronously in heterozygous diploid S. pombe cells. The procedure is appropriate for a variety of applications, including fluorescence-activated cell sorting (FACS) and northern and western blotting. Zygotic meiosis can also be induced by the same procedure, although less synchronously. PMID- 28733419 TI - MYC2 Orchestrates a Hierarchical Transcriptional Cascade That Regulates Jasmonate Mediated Plant Immunity in Tomato. AB - The hormone jasmonate (JA), which functions in plant immunity, regulates resistance to pathogen infection and insect attack through triggering genome-wide transcriptional reprogramming in plants. We show that the basic helix-loop-helix transcription factor (TF) MYC2 in tomato (Solanum lycopersicum) acts downstream of the JA receptor to orchestrate JA-mediated activation of both the wounding and pathogen responses. Using chromatin immunoprecipitation sequencing (ChIP-seq) coupled with RNA sequencing (RNA-seq) assays, we identified 655 MYC2-targeted JA responsive genes. These genes are highly enriched in Gene Ontology categories related to TFs and the early response to JA, indicating that MYC2 functions at a high hierarchical level to regulate JA-mediated gene transcription. We also identified a group of MYC2-targeted TFs (MTFs) that may directly regulate the JA induced transcription of late defense genes. Our findings suggest that MYC2 and its downstream MTFs form a hierarchical transcriptional cascade during JA mediated plant immunity that initiates and amplifies transcriptional output. As proof of concept, we showed that during plant resistance to the necrotrophic pathogen Botrytis cinerea, MYC2 and the MTF JA2-Like form a transcription module that preferentially regulates wounding-responsive genes, whereas MYC2 and the MTF ETHYLENE RESPONSE FACTOR.C3 form a transcription module that preferentially regulates pathogen-responsive genes. PMID- 28733420 TI - SG2-Type R2R3-MYB Transcription Factor MYB15 Controls Defense-Induced Lignification and Basal Immunity in Arabidopsis. AB - Lignification of cell wall appositions is a conserved basal defense mechanism in the plant innate immune response. However, the genetic pathway controlling defense-induced lignification remains unknown. Here, we demonstrate the Arabidopsis thaliana SG2-type R2R3-MYB transcription factor MYB15 as a regulator of defense-induced lignification and basal immunity. Loss of MYB15 reduces the content but not the composition of defense-induced lignin, whereas constitutive expression of MYB15 increases lignin content independently of immune activation. Comparative transcriptional and metabolomics analyses implicate MYB15 as necessary for the defense-induced synthesis of guaiacyl lignin and the basal synthesis of the coumarin metabolite scopoletin. MYB15 directly binds to the secondary wall MYB-responsive element consensus sequence, which encompasses the AC elements, to drive lignification. The myb15 and lignin biosynthetic mutants show increased susceptibility to the bacterial pathogen Pseudomonas syringae, consistent with defense-induced lignin having a major role in basal immunity. A scopoletin biosynthetic mutant also shows increased susceptibility independently of immune activation, consistent with a role in preformed defense. Our results support a role for phenylalanine-derived small molecules in preformed and inducible Arabidopsis defense, a role previously dominated by tryptophan-derived small molecules. Understanding the regulatory network linking lignin biosynthesis to plant growth and defense will help lignin engineering efforts to improve the production of biofuels and aromatic industrial products as well as increase disease resistance in energy and agricultural crops. PMID- 28733421 TI - Differentially Regulated Orthologs in Sorghum and the Subgenomes of Maize. AB - Identifying interspecies changes in gene regulation, one of the two primary sources of phenotypic variation, is challenging on a genome-wide scale. The use of paired time-course data on cold-responsive gene expression in maize (Zea mays) and sorghum (Sorghum bicolor) allowed us to identify differentially regulated orthologs. While the majority of cold-responsive transcriptional regulation of conserved gene pairs is species specific, the initial transcriptional responses to cold appear to be more conserved than later responses. In maize, the promoters of genes with conserved transcriptional responses to cold tend to contain more micrococcal nuclease hypersensitive sites in their promoters, a proxy for open chromatin. Genes with conserved patterns of transcriptional regulation between the two species show lower ratios of nonsynonymous to synonymous substitutions. Genes involved in lipid metabolism, known to be involved in cold acclimation, tended to show consistent regulation in both species. Genes with species-specific cold responses did not cluster in particular pathways nor were they enriched in particular functional categories. We propose that cold-responsive transcriptional regulation in individual species may not be a reliable marker for function, while a core set of genes involved in perceiving and responding to cold stress are subject to functionally constrained cold-responsive regulation across the grass tribe Andropogoneae. PMID- 28733422 TI - Differences in DNA Binding Specificity of Floral Homeotic Protein Complexes Predict Organ-Specific Target Genes. AB - Floral organ identities in plants are specified by the combinatorial action of homeotic master regulatory transcription factors. However, how these factors achieve their regulatory specificities is still largely unclear. Genome-wide in vivo DNA binding data show that homeotic MADS domain proteins recognize partly distinct genomic regions, suggesting that DNA binding specificity contributes to functional differences of homeotic protein complexes. We used in vitro systematic evolution of ligands by exponential enrichment followed by high-throughput DNA sequencing (SELEX-seq) on several floral MADS domain protein homo- and heterodimers to measure their DNA binding specificities. We show that specification of reproductive organs is associated with distinct binding preferences of a complex formed by SEPALLATA3 and AGAMOUS. Binding specificity is further modulated by different binding site spacing preferences. Combination of SELEX-seq and genome-wide DNA binding data allows differentiation between targets in specification of reproductive versus perianth organs in the flower. We validate the importance of DNA binding specificity for organ-specific gene regulation by modulating promoter activity through targeted mutagenesis. Our study shows that intrafamily protein interactions affect DNA binding specificity of floral MADS domain proteins. Differential DNA binding of MADS domain protein complexes plays a role in the specificity of target gene regulation. PMID- 28733428 TI - TCR Repertoire Intratumor Heterogeneity in Localized Lung Adenocarcinomas: An Association with Predicted Neoantigen Heterogeneity and Postsurgical Recurrence. AB - Genomic intratumor heterogeneity (ITH) may be associated with postsurgical relapse of localized lung adenocarcinomas. Recently, mutations, through generation of neoantigens, were shown to alter tumor immunogenicity through T cell responses. Here, we performed sequencing of the T-cell receptor (TCR) in 45 tumor regions from 11 localized lung adenocarcinomas and observed substantial intratumor differences in T-cell density and clonality with the majority of T cell clones restricted to individual tumor regions. TCR ITH positively correlated with predicted neoantigen ITH, suggesting that spatial differences in the T-cell repertoire may be driven by distinct neoantigens in different tumor regions. Finally, a higher degree of TCR ITH was associated with an increased risk of postsurgical relapse and shorter disease-free survival, suggesting a potential clinical significance of T-cell repertoire heterogeneity.Significance: The present study provides insights into the ITH of the T-cell repertoire in localized lung adenocarcinomas and its potential biological and clinical impact. The results suggest that T-cell repertoire ITH may be tightly associated to genomic ITH and disease relapse. Cancer Discov; 7(10); 1088-97. (c)2017 AACR.This article is highlighted in the In This Issue feature, p. 1047. PMID- 28733429 TI - Proteogenomic Analysis and Discovery of Immune Antigens in Mycobacterium vaccae. AB - Tuberculosis (TB) is one of the leading causes of death worldwide, especially in developing countries. Neonatal BCG vaccination occurs in various regions, but the level of protection varies in different populations. Recently, Mycobacterium vaccae is found to be an immunomodulating therapeutic agent that could confer a significant level of protection against TB. It is the only vaccine in a phase III trial from WHO to assess its efficacy and safety in preventing TB disease in people with latent TB infection. However, the mechanism of immunotherapy of M. vaccae remains poorly understood. In this study, the full genome of M. vaccae was obtained by next-generation sequencing technology, and a proteogenomic approach was successfully applied to further perform genome annotation using high resolution and high accuracy MS data. A total of 3,387 proteins (22,508 unique peptides) were identified, and 581 proteins annotated as hypothetical proteins in the genome database were confirmed. Furthermore, 38 novel protein products not annotated at the genome level were detected and validated. Additionally, the translational start sites of 445 proteins were confirmed, and 98 proteins were validated through extension of their translational start sites based on N terminus-derived peptides. The physicochemical characteristics of the identified proteins were determined. Thirty-five immunogenic proteins of M. vaccae were identified by immunoproteomic analysis, and 20 of them were selected to be expressed and validated by Western blot for immunoreactivity to serum from patients infected with M. tuberculosis The results revealed that eight of them showed strong specific reactive signals on the immunoblots. Furthermore, cellular immune response was further examined and one protein displayed a higher cellular immune level in pulmonary TB patients. Twelve identified immunogenic proteins have orthologous in H37Rv and BCG. This is the first study to obtain the full genome and annotation of M. vaccae using a proteogenomic approach, and some immunogenic proteins that were validated by immunoproteomic analysis could contribute to the understanding of the mechanism of M. vaccae immunotherapy. PMID- 28733430 TI - Atherogenic Lipoprotein Determinants of Cardiovascular Disease and Residual Risk Among Individuals With Low Low-Density Lipoprotein Cholesterol. AB - BACKGROUND: Levels of LDL (low-density lipoprotein) cholesterol in the population are declining, and increasing attention is being focused on residual lipid related pathways of atherosclerotic cardiovascular disease risk beyond LDL cholesterol. Among individuals with low (<130 mg/dL) LDL cholesterol, we undertook detailed profiling of circulating atherogenic lipoproteins in relation to incident cardiovascular disease in 2 populations. METHODS AND RESULTS: We performed proton nuclear magnetic resonance spectroscopy to quantify concentrations of LDL and VLDL (very low-density lipoprotein) particle subclasses in 11 984 JUPITER trial participants (NCT00239681). Adjusted Cox models examined cardiovascular disease risk associated with lipoprotein measures according to treatment allocation. Risk (adjusted hazard ratio [95%CI] per SD increment) among placebo-allocated participants was associated with total LDL particles (1.19 [1.02, 1.38]) and total VLDL particles (1.21 [1.04, 1.41]), as well as apolipoprotein B, non-high-density lipoprotein cholesterol, and triglycerides, but not LDL-c. Rosuvastatin reduced LDL measures but had variable effects on triglyceride and VLDL measures. On-statin levels of the smallest VLDL particle subclass were associated with a 68% per-SD (adjusted hazard ratio 1.68 [1.28, 2.22]) increase in residual risk-this risk was related to VLDL cholesterol and not triglyceride or larger VLDL particles. There was evidence that residual risk prediction during statin therapy could be significantly improved through the inclusion of key VLDL measures (Harrell C-index 0.780 versus 0.712; P<0.0001). In an independent, prospective cohort of 4721 individuals referred for cardiac catheterization (CATHGEN), similar patterns of lipoprotein-related risk were observed. CONCLUSIONS: Atherogenic lipoprotein particle concentrations were associated with cardiovascular disease risk when LDL cholesterol was low. VLDL lipoproteins, particularly the smallest remnant subclass, may represent unused targets for risk prediction and potential therapeutic intervention for reducing residual risk. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00239681. PMID- 28733431 TI - Addition of 24-Hour Heart Rate Variability Parameters to the Cardiovascular Health Study Stroke Risk Score and Prediction of Incident Stroke: The Cardiovascular Health Study. AB - BACKGROUND: Heart rate variability (HRV) characterizes cardiac autonomic functioning. The association of HRV with stroke is uncertain. We examined whether 24-hour HRV added predictive value to the Cardiovascular Health Study clinical stroke risk score (CHS-SCORE), previously developed at the baseline examination. METHODS AND RESULTS: N=884 stroke-free CHS participants (age 75.3+/-4.6), with 24 hour Holters adequate for HRV analysis at the 1994-1995 examination, had 68 strokes over <=8 year follow-up (median 7.3 [interquartile range 7.1-7.6] years). The value of adding HRV to the CHS-SCORE was assessed with stepwise Cox regression analysis. The CHS-SCORE predicted incident stroke (HR=1.06 per unit increment, P=0.005). Two HRV parameters, decreased coefficient of variance of NN intervals (CV%, P=0.031) and decreased power law slope (SLOPE, P=0.033) also entered the model, but these did not significantly improve the c-statistic (P=0.47). In a secondary analysis, dichotomization of CV% (LOWCV% <=12.8%) was found to maximally stratify higher-risk participants after adjustment for CHS SCORE. Similarly, dichotomizing SLOPE (LOWSLOPE <-1.4) maximally stratified higher-risk participants. When these HRV categories were combined (eg, HIGHCV% with HIGHSLOPE), the c-statistic for the model with the CHS-SCORE and combined HRV categories was 0.68, significantly higher than 0.61 for the CHS-SCORE alone (P=0.02). CONCLUSIONS: In this sample of older adults, 2 HRV parameters, CV% and power law slope, emerged as significantly associated with incident stroke when added to a validated clinical risk score. After each parameter was dichotomized based on its optimal cut point in this sample, their composite significantly improved prediction of incident stroke during <=8-year follow-up. These findings will require validation in separate, larger cohorts. PMID- 28733432 TI - Should Bilateral Internal Thoracic Artery Grafting Be Used in Patients After Recent Myocardial Infarction? AB - BACKGROUND: Bilateral internal thoracic artery grafting (BITA) is associated with improved survival. However, surgeons do not commonly use BITA in patients after myocardial infarction (MI) because survival is good with single internal thoracic artery grafting (SITA). We aimed to compare the outcomes of BITA with those of SITA and other approaches in patients with multivessel disease after recent MI. METHODS AND RESULTS: In total, 938 patients with recent MI (<3 months) who underwent BITA between 1996 and 2011 were compared with 682 who underwent SITA. SITA patients were older and more likely to have comorbidities (diabetes mellitus, chronic obstructive pulmonary disease, chronic renal failure, peripheral vascular disease), to be female, and to have had a previous MI. Acute MI and 3-vessel disease were more prevalent in the BITA group. Operative mortality of BITA patients was lower (3.0% versus 5.8%, P=0.01), and sternal infections and strokes were similar. Median follow-up was 15.21 years (range: 0 21.25 years). Survival of BITA patients was better (70.3% versus 52.5%, P<0.001). Propensity score matching was used to account for differences in preoperative characteristics between groups. Overall, 551 matched pairs had similar preoperative characteristics. BITA was a predictor of better survival in the matched groups (hazard ratio: 0.679; P=0.002; Cox model). Adjusted survival of emergency BITA and SITA patients was similar (hazard ratio: 0.883; P=0.447); however, in the nonemergency group, BITA was a predictor of better survival (hazard ratio: 0.790; P=0.009; Cox model). CONCLUSIONS: This study suggests that survival is better with BITA compared with SITA in nonemergency cases after recent MI, with proper patient selection. PMID- 28733433 TI - Intensive Exercise Training Improves Cardiac Electrical Stability in Myocardial Infarcted Rats. AB - BACKGROUND: Moderate exercise training has been shown to decrease sudden cardiac death post myocardial infarction. However, the effects of intensive exercise are still controversial. METHODS AND RESULTS: Fourteen myocardial-infarcted rats were divided into sedentary (n=8) and intensive training groups (n=6) and 18 sham control rats to sedentary (n=10) and intensive training groups (n=8). Heart rate variability was obtained at weeks 1 and 8. The inducibility of ventricular tachycardia/fibrillation was assessed in a Langendorff system. Fast Fourier transforms were applied on the recorded ventricular tachycardia/fibrillations. Training reduces low to high frequency ratio of heart rate variability at week 8 compared with that at week 1 (P<0.05). In isolated hearts, the probability for ventricular tachycardia/fibrillation was decreased from 4.5+/-0.8% in sedentary controls to 1.56+/-0.2% in intensive training controls (P<0.05) and from 13.5+/ 2.1% in the sedentary group to 5.4+/-1.2% in the intensive training group (P<0.01). Moreover, the pacing current required for ventricular fibrillation induction in the trained groups was increased following exercise (P<0.05). Fast Fourier transform analysis of ECG findings revealed an exercise-induced ventricular fibrillation transition from a narrow, single-peak spectrum at 17 Hz in sedentary controls to a broader range of peaks ranging from 13 to 22 Hz in the intensive training controls. CONCLUSIONS: Intensive exercise in infarcted rats leads to reduced ventricular fibrillation propensity and is associated with normalization of refractoriness and intrinsic spatiotemporal electrical variations. PMID- 28733434 TI - Added Value of Patient-Reported Outcome Measures in Stroke Clinical Practice. AB - BACKGROUND: There is uncertainty regarding the clinical utility of the data obtained from patient-reported outcome measures (PROMs) for patient care. We evaluated the incremental information obtained by PROMs compared to the clinician reported modified Rankin Scale (mRS). METHODS AND RESULTS: This was an observational study of 3283 ischemic stroke patients seen in a cerebrovascular clinic from September 14, 2012 to June 16, 2015 who completed the routinely collected PROMs: Stroke Impact Scale-16 (SIS-16), EQ-5D, Patient Health Questionnaire-9, PROMIS Physical Function, and PROMIS fatigue. The amount of variation in the PROMs explained by mRS was determined using r2 after adjustment for age and level of stroke impairment. The proportion with meaningful change was calculated for patients with >=2 visits. Concordance with change in the other scales and the ability to discriminate changes in health state as measured by c statistic was evaluated for mRS versus SIS-16. Correlation between PROMs and mRS was highest for SIS-16 (r=-0.64, P<0.01). The r2 ranged from 0.11 (PROMIS fatigue) to 0.56 (SIS-16). Change in scores occurred in 51% with mRS and 35% with SIS-16. There was lower agreement and less ability to discriminate change in mRS than in SIS-16 with change in the other measures. CONCLUSIONS: PROMs provide additional valuable information compared to the mRS alone in stroke patients seen in the ambulatory setting. SIS-16 may have a better ability to identify change than mRS in health status of relevance to the patient. PROMs may be a useful addition to mRS in the assessment of health status in clinical practice. PMID- 28733435 TI - Different Implications of Heart Failure, Ischemic Stroke, and Mortality Between Nonvalvular Atrial Fibrillation and Atrial Flutter-a View From a National Cohort Study. AB - BACKGROUND: Atrial flutter (AFL) has been identified to be equivalent to atrial fibrillation (AF) in terms of preventing ischemic stroke, although differences exist in atrial rate, substrate, and electrophysiological mechanisms. This study aimed to investigate differences in clinical outcomes between nonvalvular AF and AFL. METHODS AND RESULTS: AF and AFL patients without any prescribed anticoagulation were enrolled from a 13-year national cohort database. Under series exclusion criteria, ischemic stroke, heart failure hospitalization, and all-cause mortality were compared between the groups in real-world conditions and after propensity score matching. We identified 175 420 patients in the AF cohort and 6239 patients in the AFL cohort, and the prevalence of most comorbidities and frequency of medications were significantly higher in the AF group than the AFL group. In the real-world setting the AF patients had higher incidence rates of ischemic stroke, heart failure hospitalization, and all-cause mortality than the AFL patients (all P<0.001). After propensity score matching, the incidence rate of ischemic stroke in the AF cohort was 1.63-fold higher than in the AFL cohort (P<0.001), the incidence rate of heart failure hospitalization in the AF cohort was 1.70-fold higher than in the AFL cohort (P<0.001), and the incidence rate of all-cause mortality in the AF cohort was 1.08-fold higher than in the AFL cohort (P=0.002). CONCLUSIONS: There were differences between AF and AFL in comorbidities and prognosis with regard to ischemic stroke, heart failure hospitalization, and all-cause mortality. PMID- 28733437 TI - More than 2000 more emergency medicine consultants needed in England, says royal college. PMID- 28733436 TI - Survival, by Birth Weight and Gestational Age, in Individuals With Congenital Heart Disease: A Population-Based Study. AB - BACKGROUND: Congenital heart disease (CHD) survival estimates are important to understand prognosis and evaluate health and social care needs. Few studies have reported CHD survival estimates according to maternal and fetal characteristics. This study aimed to identify predictors of CHD survival and report conditional survival estimates. METHODS AND RESULTS: Cases of CHD (n=5070) born during 1985 2003 and notified to the Northern Congenital Abnormality Survey (NorCAS) were matched to national mortality information in 2008. Royston-Parmar regression was performed to identify predictors of survival. Five-year survival estimates conditional on gestational age at delivery, birth weight, and year of birth were produced for isolated CHD (ie, CHD without extracardiac anomalies). Year of birth, gestational age, birth weight, and extracardiac anomalies were independently associated with mortality (all P<=0.001). Five-year survival for children born at term (37-41 weeks) in 2003 with average birth weight (within 1 SD of the mean) was 96.3% (95% CI, 95.6-97.0). Survival was most optimistic for high-birth-weight children (>1 SD from the mean) born post-term (>=42 weeks; 97.9%; 95% CI, 96.8-99.1%) and least optimistic for very preterm (<32 weeks) low birth-weight (<1 SD from mean) children (78.8%; 95% CI, 72.8-99.1). CONCLUSIONS: Five-year CHD survival is highly influenced by gestational age and birth weight. For prenatal counseling, conditional survival estimates provide best- and worst case scenarios, depending on final gestational age and birth weight. For postnatal diagnoses, they can provide parents with more-accurate predictions based on their baby's birth weight and gestational age. PMID- 28733438 TI - Dairy consumption, systolic blood pressure, and risk of hypertension. PMID- 28733440 TI - Dose Transition Pathways: The Missing Link Between Complex Dose-Finding Designs and Simple Decision-Making. AB - The ever-increasing pace of development of novel therapies mandates efficient methodologies for assessment of their tolerability and activity. Evidence increasingly support the merits of model-based dose-finding designs in identifying the recommended phase II dose compared with conventional rule-based designs such as the 3 + 3 but despite this, their use remains limited. Here, we propose a useful tool, dose transition pathways (DTP), which helps overcome several commonly faced practical and methodologic challenges in the implementation of model-based designs. DTP projects in advance the doses recommended by a model-based design for subsequent patients (stay, escalate, de escalate, or stop early), using all the accumulated information. After specifying a model with favorable statistical properties, we utilize the DTP to fine-tune the model to tailor it to the trial's specific requirements that reflect important clinical judgments. In particular, it can help to determine how stringent the stopping rules should be if the investigated therapy is too toxic. Its use to design and implement a modified continual reassessment method is illustrated in an acute myeloid leukemia trial. DTP removes the fears of model based designs as unknown, complex systems and can serve as a handbook, guiding decision-making for each dose update. In the illustrated trial, the seamless, clear transition for each dose recommendation aided the investigators' understanding of the design and facilitated decision-making to enable finer calibration of a tailored model. We advocate the use of the DTP as an integral procedure in the co-development and successful implementation of practical model based designs by statisticians and investigators. Clin Cancer Res; 23(24); 7440 7. (c)2017 AACR. PMID- 28733439 TI - Implementation of a Model-Based Design in a Phase Ib Study of Combined Targeted Agents. AB - In recent years, investigators have recognized the rigidity of single-agent, safety-only, traditional designs, rendering them ineffective for conducting contemporary early-phase clinical trials, such as those involving combinations and/or biological agents. Novel approaches are required to address these research questions, such as those posed in trials involving targeted therapies. We describe the implementation of a model-based design for identifying an optimal treatment combination, defined by low toxicity and high efficacy, in an early phase trial evaluating a combination of two oral targeted inhibitors in relapsed/refractory mantle cell lymphoma. Operating characteristics demonstrate the ability of the method to effectively recommend optimal combinations in a high percentage of trials with reasonable sample sizes. The proposed design is a practical, early-phase, adaptive method for use with combined targeted therapies. This design can be applied more broadly to early-phase combination studies, as it was used in an ongoing study of a melanoma helper peptide vaccine plus novel adjuvant combinations. Clin Cancer Res; 23(23); 7158-64. (c)2017 AACR. PMID- 28733441 TI - Molecular Screening for Cancer Treatment Optimization (MOSCATO-01) in Pediatric Patients: A Single-Institutional Prospective Molecular Stratification Trial. AB - Purpose: This single-institutional feasibility study prospectively characterized genomic alterations in recurrent or refractory solid tumors of pediatric patients to select a targeted therapy.Experimental Design: Following treatment failure, patients with signed consent and ages above 6 months, underwent tumor biopsy or surgical resection of primary or metastatic tumor site. These newly acquired samples were analyzed by comparative genomic hybridization array, next-generation sequencing for 75 target genes, whole-exome and RNA sequencing. Biological significance of the alterations and suggestion of most relevant targeted therapies available were discussed in a multidisciplinary tumor board.Results: From December 2012 to January 2016, 75 patients were included, 73 patients underwent 79 interventions, 56 of which were research biopsies with a low complication rate. All patients were pretreated, 37.0% had a brain tumor, and 63.0% had an extra-cranial solid tumor. Median tumor cell content was 70% (range, 0%-100%). Successful molecular analysis in 69 patients detected in 60.9% of patients an actionable alteration in various oncogenic pathways (42.4% with copy number change, 33.3% with mutation, 2.1% with fusion), and change in diagnosis in three patients. Fourteen patients received 17 targeted therapies; two had received a matched treatment before inclusion.Conclusions: Research biopsies are feasible in advanced pediatric malignancies that exhibit a considerable amount of potentially actionable alterations. Genetic events affecting different cancer hallmarks and limited access to targeted agents within pediatric clinical trials remain the main obstacles that are addressed in our two subsequent precision medicine studies MAPPYACTS and AcSe-ESMART. Clin Cancer Res; 23(20); 6101-12. (c)2017 AACR. PMID- 28733444 TI - NHS to stop funding homeopathy and some drugs in targeted savings drive. PMID- 28733442 TI - 89Zr-Lumretuzumab PET Imaging before and during HER3 Antibody Lumretuzumab Treatment in Patients with Solid Tumors. AB - Purpose: We evaluated biodistribution and tumor targeting of 89Zr-lumretuzumab before and during treatment with lumretuzumab, a human epidermal growth factor receptor 3 (HER3)-targeting monoclonal antibody.Experimental Design: Twenty patients with histologically confirmed HER3-expressing tumors received 89Zr lumretuzumab and underwent positron emission tomography (PET). In part A, 89Zr lumretuzumab was given with additional, escalating doses of unlabeled lumretuzumab, and scans were performed 2, 4, and 7 days after injection to determine optimal imaging conditions. In part B, patients were scanned following tracer injection before (baseline) and after a pharmacodynamic (PD)-active lumretuzumab dose for saturation analysis. HER3 expression was determined immunohistochemically in skin biopsies. Tracer uptake was calculated as standardized uptake value (SUV).Results: Optimal PET conditions were found to be 4 and 7 days after administration of 89Zr-lumretuzumab with 100-mg unlabeled lumretuzumab. At baseline using 100-mg unlabeled lumretuzumab, the tumor SUVmax was 3.4 (+/-1.9) at 4 days after injection. SUVmean values for normal blood, liver, lung, and brain tissues were 4.9, 6.4, 0.9 and 0.2, respectively. Saturation analysis (n = 7) showed that 4 days after lumretuzumab administration, tumor uptake decreased by 11.9% (+/-8.2), 10.0% (+/-16.5), and 24.6% (+/-20.9) at PD-active doses of 400, 800, and 1,600 mg, respectively, when compared with baseline. Membranous HER3 was completely downregulated in paired skin biopsies already at and above 400-mg lumretuzumab.Conclusions: PET imaging showed biodistribution and tumor-specific 89Zr-lumretuzumab uptake. Although, PD-active lumretuzumab doses decreased 89Zr-lumretuzumab uptake, there was no clear evidence of tumor saturation by PET imaging as the tumor SUV did not plateau with increasing doses. Clin Cancer Res; 23(20); 6128-37. (c)2017 AACR. PMID- 28733443 TI - Direct Metabolic Interrogation of Dihydrotestosterone Biosynthesis from Adrenal Precursors in Primary Prostatectomy Tissues. AB - Purpose: A major mechanism of castration-resistant prostate cancer (CRPC) involves intratumoral biosynthesis of dihydrotestosterone (DHT) from adrenal precursors. We have previously shown that adrenal-derived androstenedione (AD) is the preferred substrate over testosterone (T) for 5alpha-reductase expressed in metastatic CRPC, bypassing T as an obligate precursor to DHT. However, the metabolic pathway of adrenal-derived DHT biosynthesis has not been rigorously investigated in the setting of primary disease in the prostate.Experimental Design: Seventeen patients with clinically localized prostate cancer were consented for fresh tissues after radical prostatectomy. Prostate tissues were cultured ex vivo in media spiked with an equimolar mixture of AD and T, and stable isotopic tracing was employed to simultaneously follow the enzymatic conversion of both precursor steroids into nascent metabolites, detected by liquid chromatography-tandem mass spectrometry. CRPC cell line models and xenograft tissues were similarly assayed for comparative analysis. A tritium labeled steroid radiotracing approach was used to validate our findings.Results: Prostatectomy tissues readily 5alpha-reduced both T and AD. Furthermore, 5alpha reduction of AD was the major directionality of metabolic flux to DHT. However, AD and T were comparably metabolized by 5alpha-reductase in primary prostate tissues, contrasting the preference exhibited by CRPC in which AD was favored over T. 5alpha-reductase inhibitors effectively blocked the conversion of AD to DHT.Conclusions: Both AD and T are substrates of 5alpha-reductase in prostatectomy tissues, resulting in two distinctly nonredundant metabolic pathways to DHT. Furthermore, the transition to CRPC may coincide with a metabolic switch toward AD as the favored substrate. Clin Cancer Res; 23(20); 6351-62. (c)2017 AACR. PMID- 28733445 TI - Enhanced NO-dependent pulmonary vasodilation limits increased vasoconstrictor sensitivity in neonatal chronic hypoxia. AB - Augmented vasoconstrictor reactivity is thought to play an important role in the development of chronic hypoxia (CH)-induced neonatal pulmonary hypertension. However, whether this response to CH results from pulmonary endothelial dysfunction and reduced nitric oxide (NO)-mediated vasodilation is not well understood. We hypothesized that neonatal CH enhances basal tone and pulmonary vasoconstrictor sensitivity by limiting NO-dependent pulmonary vasodilation. To test this hypothesis, we assessed the effects of the NO synthase (NOS) inhibitor Nomega-nitro-l-arginine (l-NNA) on baseline pulmonary vascular resistance (PVR) and vasoconstrictor sensitivity to the thromboxane mimetic U-46619 in saline perfused lungs (in situ) from 2-wk-old control and CH (12-day exposure, 0.5 atm) Sprague-Dawley rats. Basal tone was defined as that reversed by exogenous NO (spermine NONOate). CH neonates displayed elevated right ventricular systolic pressure (in vivo) and right ventricular hypertrophy, indicative of pulmonary hypertension. Perfused lungs from CH rats demonstrated greater baseline PVR, basal tone, and U-46619-mediated vasoconstriction compared with control rats in the absence of l-NNA. l-NNA markedly increased baseline PVR and reactivity to U 46619 in lungs from CH neonates, further augmenting vasoconstrictor sensitivity compared with control lungs. Exposure to CH also enhanced NO-dependent vasodilation to arginine vasopressin, pulmonary expression of NOS III [endothelial NOS (eNOS)], and eNOS phosphorylation at activation residue Ser1177 However, CH did not alter lung nitrotyrosine levels, a posttranslational modification reflecting [Formula: see text] scavenging of NO. We conclude that, in contrast to our hypothesis, enhanced basal tone and agonist-induced vasoconstriction after neonatal CH is limited by increased NO-dependent pulmonary vasodilation resulting from greater eNOS expression and phosphorylation at activation residue Ser1177NEW & NOTEWORTHY This research is the first to demonstrate enhanced nitric oxide-dependent vasodilation that limits increased vasoconstrictor reactivity in neonatal pulmonary hypertension. These results suggest that augmented vasoconstriction in this setting reflects changes in smooth muscle reactivity rather than a reduction in nitric oxide-dependent pulmonary vasodilation. PMID- 28733448 TI - Pathophysiology of cardiorenal syndrome in patients with heart failure: potential therapeutic targets. AB - Despite the development of pharmacological inventions and new nonpharmacological techniques to prevent and treat heart failure (HF), the mortality rate in patients with symptomatic HF remains high. To conquer these difficulties, the pathophysiology of HF should be considered within a wide range of views. Given the diverse mechanisms of HF pathophysiology, renal and cardiac functions have close and complementary interconnections. Recent studies have suggested that communication between the kidney and heart through bidirectional pathways causes significant pathological changes. This review summarizes the pathophysiology of cardiorenal syndrome (CRS) from three different viewpoints, namely, underlying chronic kidney disease, worsening renal function during hospitalization due to HF, and resistance to diuretics. We also summarize the presently available data on the pathophysiology of CRS, identify the challenges associated with some clinical approaches, and explore the potential therapeutic target for CRS. PMID- 28733447 TI - Mineralocorticoid receptor antagonists attenuate exaggerated exercise pressor reflex responses in hypertensive rats. AB - Exaggerated heart rate (HR) and blood pressure responses to exercise in hypertension are mediated, in part, by overactivity of the exercise pressor reflex (EPR). The mechanisms underlying this EPR dysfunction have not been fully elucidated. Previous studies have shown that stimulation of mineralocorticoid receptors (MRs) with exogenous administration of aldosterone in normal, healthy rats reproduces the EPR overactivity characteristic of hypertensive animals. Conversely, the purpose of this study was to examine whether antagonizing MR with spironolactone (SPIR) or eplerenone (EPL) in decerebrated hypertensive rats ameliorates abnormal EPR function. Changes in mean arterial pressure (MAP) and HR induced by EPR or muscle mechanoreflex (a component of EPR) activation were assessed in normotensive Wistar-Kyoto rats and spontaneously hypertensive rats (SHRs) fed normal chow (NC) or a customized diet containing either SPIR or EPL for 3 wk. SHRs treated with SPIR or EPL had significantly attenuated MAP responses to EPR (NC: 45 +/- 7 mmHg, SPIR: 26 +/- 4 mmHg, and EPL: 24 +/- 5 mmHg, P = 0.02) and mechanoreflex (NC: 34 +/- 9 mmHg, SPIR: 17 +/- 3 mmHg, and EPL: 15 +/- 3 mmHg, P = 0.03) activation. SHRs treated with SPIR or EPL also showed significantly attenuated HR responses to EPR (NC: 17 +/- 3 beats/min, SPIR: 9 +/- 1 beats/min, and EPL: 9 +/- 2 beats/min, P = 0.01) and mechanoreflex (NC: 15 +/- 3 beats/min, SPIR: 6 +/- 1 beats/min, and EPL: 7 +/- 1 beats/min, P = 0.01) activation. Wistar-Kyoto rats treated with SPIR did not demonstrate significant differences in MAP or HR responses to EPR or mechanoreflex activation. The data suggest that antagonizing MRs may be an effective strategy for the treatment of EPR overactivity in hypertension.NEW & NOTEWORTHY Exaggerated cardiovascular responses to exercise in hypertensive patients are linked with overactive exercise pressor reflexes (EPRs). Administration of low-dose mineralocorticoid receptor antagonists (spironolactone or eplerenone) effectively ameliorates abnormal EPR function in hypertension. Effective treatment of EPR overactivity may reduce the cardiovascular risks associated with physical activity in hypertension. PMID- 28733446 TI - How does pressure overload cause cardiac hypertrophy and dysfunction? High ouabain affinity cardiac Na+ pumps are crucial. AB - Left ventricular hypertrophy is frequently observed in hypertensive patients and is believed to be due to the pressure overload and cardiomyocyte stretch. Three recent reports on mice with genetically engineered Na+ pumps, however, have demonstrated that cardiac ouabain-sensitive alpha2-Na+ pumps play a key role in the pathogenesis of transaortic constriction-induced hypertrophy. Hypertrophy was delayed/attenuated in mice with mutant, ouabain-resistant alpha2-Na+ pumps and in mice with cardiac-selective knockout or transgenic overexpression of alpha2-Na+ pumps. The latter, seemingly paradoxical, findings can be explained by comparing the numbers of available (ouabain-free) high-affinity (alpha2) ouabain-binding sites in wild-type, knockout, and transgenic hearts. Conversely, hypertrophy was accelerated in alpha2-ouabain-resistant (R) mice in which the normally ouabain resistant alpha1-Na+ pumps were mutated to an ouabain-sensitive (S) form (alpha1S/Salpha2R/R or "SWAP" vs. wild-type or alpha1R/R alpha2S/S mice). Furthermore, transaortic constriction-induced hypertrophy in SWAP mice was prevented/reversed by immunoneutralizing circulating endogenous ouabain (EO). These findings show that EO and its receptor, ouabain-sensitive alpha2, are critical factors in pressure overload-induced cardiac hypertrophy. This complements reports linking elevated plasma EO to hypertension, cardiac hypertrophy, and failure in humans and elucidates the underappreciated role of the EO-Na+ pump pathway in cardiovascular disease. PMID- 28733449 TI - Mitochondrial function in engineered cardiac tissues is regulated by extracellular matrix elasticity and tissue alignment. AB - Mitochondria in cardiac myocytes are critical for generating ATP to meet the high metabolic demands associated with sarcomere shortening. Distinct remodeling of mitochondrial structure and function occur in cardiac myocytes in both developmental and pathological settings. However, the factors that underlie these changes are poorly understood. Because remodeling of tissue architecture and extracellular matrix (ECM) elasticity are also hallmarks of ventricular development and disease, we hypothesize that these environmental factors regulate mitochondrial function in cardiac myocytes. To test this, we developed a new procedure to transfer tunable polydimethylsiloxane disks microcontact-printed with fibronectin into cell culture microplates. We cultured Sprague-Dawley neonatal rat ventricular myocytes within the wells, which consistently formed tissues following the printed fibronectin, and measured oxygen consumption rate using a Seahorse extracellular flux analyzer. Our data indicate that parameters associated with baseline metabolism are predominantly regulated by ECM elasticity, whereas the ability of tissues to adapt to metabolic stress is regulated by both ECM elasticity and tissue alignment. Furthermore, bioenergetic health index, which reflects both the positive and negative aspects of oxygen consumption, was highest in aligned tissues on the most rigid substrate, suggesting that overall mitochondrial function is regulated by both ECM elasticity and tissue alignment. Our results demonstrate that mitochondrial function is regulated by both ECM elasticity and myofibril architecture in cardiac myocytes. This provides novel insight into how extracellular cues impact mitochondrial function in the context of cardiac development and disease.NEW & NOTEWORTHY A new methodology has been developed to measure O2 consumption rates in engineered cardiac tissues with independent control over tissue alignment and matrix elasticity. This led to the findings that matrix elasticity regulates basal mitochondrial function, whereas both matrix elasticity and tissue alignment regulate mitochondrial stress responses. PMID- 28733450 TI - Muscle sympathetic nerve activity and volume-regulating factors in healthy pregnant and nonpregnant women. AB - Healthy, normotensive human pregnancies are associated with striking increases in both plasma volume and vascular sympathetic nerve activity (SNA). In nonpregnant humans, volume-regulatory factors including plasma osmolality, vasopressin, and the renin-angiotensin-aldosterone system have important modulatory effects on control of sympathetic outflow. We hypothesized that pregnancy would be associated with changes in the relationships between SNA (measured as muscle SNA) and volume-regulating factors, including plasma osmolality, plasma renin activity, and arginine vasopressin (AVP). We studied 46 healthy, normotensive young women (23 pregnant and 23 nonpregnant). We measured SNA, arterial pressure, plasma osmolality, plasma renin activity, AVP, and other volume-regulatory factors in resting, semirecumbent posture. Pregnant women had significantly higher resting SNA (38 +/- 12 vs. 23 +/- 6 bursts/min in nonpregnant women), lower osmolality, and higher plasma renin activity and aldosterone (all P < 0.05). Group mean values for AVP were not different between groups [4.64 +/- 2.57 (nonpregnant) vs. 5.17 +/- 2.03 (pregnant), P > 0.05]. However, regression analysis detected a significant relationship between individual values for SNA and AVP in pregnant (r = 0.71, P < 0.05) but not nonpregnant women (r = 0.04). No relationships were found for other variables. These data suggest that the link between AVP release and resting SNA becomes stronger in pregnancy, which may contribute importantly to blood pressure regulation in healthy women during pregnancy.NEW & NOTEWORTHY Sympathetic nerve activity and blood volume are both elevated during pregnancy, but blood pressure is usually normal. Here, we identified a relationship between vasopressin and sympathetic nerve activity in pregnant but not nonpregnant women. This may provide mechanistic insights into blood pressure regulation in normal pregnancy and in pregnancy-related hypertension. PMID- 28733451 TI - Prolonged sitting leg vasculopathy: contributing factors and clinical implications. AB - Atherosclerotic peripheral artery disease primarily manifests in the medium- to large-sized conduit arteries of the lower extremities. However, the factors underlying this increased vulnerability of leg macrovasculature to disease are largely unidentified. On the basis of recent studies, we propose that excessive time spent in the sitting position and the ensuing reduction in leg blood flow induced shear stress cause endothelial cell dysfunction, a key predisposing factor to peripheral artery disease. In particular, this review summarizes the findings from laboratory-based sitting studies revealing acute leg vascular dysfunction with prolonged sitting in young healthy subjects, discusses the primary physiological mechanisms and the potential long-term implications of such leg vasculopathy with repeated exposure to prolonged sitting, as well as identifies strategies that may be effective at evading it. PMID- 28733454 TI - "Independent" reanalysis of landmark starch solutions trial was published by original authors. PMID- 28733453 TI - A Novel Functional Splice Variant of AKT3 Defined by Analysis of Alternative Splice Expression in HPV-Positive Oropharyngeal Cancers. AB - The incidence of HPV-related oropharyngeal squamous cell carcinoma (OPSCC) has increased more than 200% in the past 20 years. Recent genetic sequencing efforts have elucidated relevant genes in head and neck cancer, but HPV-related tumors have consistently shown few DNA mutations. In this study, we sought to analyze alternative splicing events (ASE) that could alter gene function independent of mutations. To identify ASE unique to HPV-related tumors, RNA sequencing was performed on 46 HPV-positive OPSCC and 25 normal tissue samples. A novel algorithm using outlier statistics on RNA-sequencing junction expression identified 109 splicing events, which were confirmed in a validation set from The Cancer Genome Atlas. Because the most common type of splicing event identified was an alternative start site (39%), MBD-seq genome-wide CpG methylation data were analyzed for methylation alterations at promoter regions. ASE in six genes showed significant negative correlation between promoter methylation and expression of an alternative transcriptional start site, including AKT3 The novel AKT3 transcriptional variant and methylation changes were confirmed using qRT-PCR and qMSP methods. In vitro silencing of the novel AKT3 variant resulted in significant growth inhibition of multiple head and neck cell lines, an effect not observed with wild-type AKT3 knockdown. Analysis of ASE in HPV-related OPSCC identified multiple alterations likely involved in carcinogenesis, including a novel, functionally active transcriptional variant of AKT3 Our data indicate that ASEs represent a significant mechanism of oncogenesis with untapped potential for understanding complex genetic changes that result in the development of cancer. Cancer Res; 77(19); 5248-58. (c)2017 AACR. PMID- 28733452 TI - Chronic hypertension increases aortic endothelial hydraulic conductivity by upregulating endothelial aquaporin-1 expression. AB - Numerous studies have examined the role of aquaporins in osmotic water transport in various systems, but virtually none have focused on the role of aquaporin in hydrostatically driven water transport involving mammalian cells save for our laboratory's recent study of aortic endothelial cells. Here, we investigated aquaporin-1 expression and function in the aortic endothelium in two high-renin rat models of hypertension, the spontaneously hypertensive genetically altered Wistar-Kyoto rat variant and Sprague-Dawley rats made hypertensive by two-kidney, one-clip Goldblatt surgery. We measured aquaporin-1 expression in aortic endothelial cells from whole rat aortas by quantitative immunohistochemistry and function by measuring the pressure-driven hydraulic conductivities of excised rat aortas with both intact and denuded endothelia on the same vessel. We used them to calculate the effective intimal hydraulic conductivity, which is a combination of endothelial and subendothelial components. We observed well-correlated enhancements in aquaporin-1 expression and function in both hypertensive rat models as well as in aortas from normotensive rats whose expression was upregulated by 2 h of forskolin treatment. Upregulated aquaporin-1 expression and function may be a response to hypertension that critically determines conduit artery vessel wall viability and long-term susceptibility to atherosclerosis.NEW & NOTEWORTHY The aortic endothelia of two high-renin hypertensive rat models express greater than two times the aquaporin-1 and, at low pressures, have greater than two times the endothelial hydraulic conductivity of normotensive rats. Data are consistent with theory predicting that higher endothelial aquaporin-1 expression raises the critical pressure for subendothelial intima compression and for artery wall hydraulic conductivity to drop. PMID- 28733455 TI - The E3 ubiquitin ligase NEDD4 induces endocytosis and lysosomal sorting of connexin 43 to promote loss of gap junctions. AB - Intercellular communication via gap junctions has an important role in controlling cell growth and in maintaining tissue homeostasis. Connexin 43 (Cx43; also known as GJA1) is the most abundantly expressed gap junction channel protein in humans and acts as a tumor suppressor in multiple tissue types. Cx43 is often dysregulated at the post-translational level during cancer development, resulting in loss of gap junctions. However, the molecular basis underlying the aberrant regulation of Cx43 in cancer cells has remained elusive. Here, we demonstrate that the oncogenic E3 ubiquitin ligase NEDD4 regulates the Cx43 protein level in HeLa cells, both under basal conditions and in response to protein kinase C activation. Furthermore, overexpression of NEDD4, but not a catalytically inactive form of NEDD4, was found to result in nearly complete loss of gap junctions and increased lysosomal degradation of Cx43 in both HeLa and C33A cervical carcinoma cells. Collectively, the data provide new insights into the molecular basis underlying the regulation of gap junction size and represent the first evidence that an oncogenic E3 ubiquitin ligase promotes loss of gap junctions and Cx43 degradation in human carcinoma cells. PMID- 28733456 TI - Nestin contributes to skeletal muscle homeostasis and regeneration. AB - Nestin, a member of the cytoskeletal family of intermediate filaments, regulates the onset of myogenic differentiation through bidirectional signaling with the kinase Cdk5. Here, we show that these effects are also reflected at the organism level, as there is a loss of skeletal muscle mass in nestin-/- (NesKO) mice, reflected as reduced lean (muscle) mass in the mice. Further examination of muscles in male mice revealed that these effects stemmed from nestin-deficient muscles being more prone to spontaneous regeneration. When the regeneration capacity of the compromised NesKO muscle was tested by muscle injury experiments, a significant healing delay was observed. NesKO satellite cells showed delayed proliferation kinetics in conjunction with an elevation in p35 (encoded by Cdk5r1) levels and Cdk5 activity. These results reveal that nestin deficiency generates a spontaneous regenerative phenotype in skeletal muscle that relates to a disturbed proliferation cycle that is associated with uncontrolled Cdk5 activity. PMID- 28733459 TI - Advice given by NHS Direct in Wales: do deprived patients get more urgent decisions? Study of routine data. AB - BACKGROUND: In the UK, National Health Service Direct Wales (NHSDW) uses computerised decision support software to advise patients on appropriate care. However, the effect of deprivation on the advice given is not known. We aimed to estimate the effect of deprivation on advice given by nurses in NHSDW adjusting for confounding variables. METHODS: We included 400 000 calls to NHSDW between January 2002 and June 2004. We used logistic regression to model the effect of deprivation on advice given by nurses in response to calls seeking advice or information. We analysed two outcomes: receiving advice to phone 999 emergency care rather than to seek other care and receiving advice to seek care face to face rather than self-care. RESULTS: After adjustment for covariates, an increase in deprivation from one-fifth of the distribution to the next fifth increased by 13% the probability that those calling for advice rather than information received advice to phone 999 (OR 1.127; 95% CI from 1.113 to 1.143). Deprivation increased the corresponding probability of being advised to seek care face to face rather than self-care by 5% (OR 1.049; 95% CI from 1.041 to 1.058) within advice calls and by 3% (OR 1.034; 95% CI from 1.022 to 1.047) within information calls. CONCLUSIONS: Deprivation increased the chance of receiving more urgent advice, particularly advice to call 999. While our dataset may underestimate the 'need' of deprived patients, it yields no evidence of major inequity in advice given to these patients. PMID- 28733457 TI - Role of bone morphogenetic proteins in sprouting angiogenesis: differential BMP receptor-dependent signaling pathways balance stalk vs. tip cell competence. AB - Before the onset of sprouting angiogenesis, the endothelium is prepatterned for the positioning of tip and stalk cells. Both cell identities are not static, as endothelial cells (ECs) constantly compete for the tip cell position in a dynamic fashion. Here, we show that both bone morphogenetic protein 2 (BMP2) and BMP6 are proangiogenic in vitro and ex vivo and that the BMP type I receptors, activin receptor-like kinase 3 (ALK3) and ALK2, play crucial and distinct roles in this process. BMP2 activates the expression of tip cell-associated genes, such as delta-like ligand 4 (DLL4) and kinase insert domain receptor (KDR), and p38-heat shock protein 27 (HSP27)-dependent cell migration, thereby generating tip cell competence. Whereas BMP6 also triggers collective cell migration via the p38 HSP27 signaling axis, BMP6 induces in addition SMAD1/5 signaling, thereby promoting the expression of stalk cell-associated genes, such as hairy and enhancer of split 1 (HES1) and fms-like tyrosine kinase 1 (FLT1). Specifically, ALK3 is required for sprouting from HUVEC spheroids, whereas ALK2 represses sprout formation. We demonstrate that expression levels and respective complex formation of BMP type I receptors in ECs determine stalk vs. tip cell identity, thus contributing to endothelial plasticity during sprouting angiogenesis. As antiangiogenic monotherapies that target the VEGF or ALK1 pathways have not fulfilled efficacy objectives in clinical trials, the selective targeting of the ALK2/3 pathways may be an attractive new approach.-Benn, A., Hiepen, C., Osterland, M., Schutte, C., Zwijsen, A., Knaus, P. Role of bone morphogenetic proteins in sprouting angiogenesis: differential BMP receptor-dependent signaling pathways balance stalk vs. tip cell competence. PMID- 28733458 TI - Mapping of Wnt-Frizzled interactions by multiplex CRISPR targeting of receptor gene families. AB - Signaling pathway modules are often encoded by several closely related paralogous genes that can have redundant roles and are therefore difficult to analyze by loss-of-function analysis. A typical example is the Wnt signaling pathway, which in mammals is mediated by 19 Wnt ligands that can bind to 10 Frizzled (FZD) receptors. Although significant progress in understanding Wnt-FZD receptor interactions has been made in recent years, tools to generate systematic interaction maps have been largely lacking. Here we generated cell lines with multiplex mutant alleles of FZD1, FZD2, and FZD7 and demonstrate that these cells are unresponsive to canonical Wnt ligands. Subsequently, we performed genetic rescue experiments with combinations of FZDs and canonical Wnts to create a functional ligand-receptor interaction map. These experiments showed that whereas several Wnt ligands, such as Wnt3a, induce signaling through a broad spectrum of FZD receptors, others, such as Wnt8a, act through a restricted set of FZD genes. Together, our results map functional interactions of FZDs and 10 Wnt ligands and demonstrate how multiplex targeting by clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 can be used to systematically elucidate the functions of multigene families.-Voloshanenko, O., Gmach, P., Winter, J., Kranz, D., Boutros, M. Mapping of Wnt-Frizzled interactions by multiplex CRISPR targeting of receptor gene families. PMID- 28733460 TI - Number of new HIV infections is rising in Russia. PMID- 28733461 TI - Should heart failure be regarded as a terminal illness requiring palliative care? A study of heart failure patients', carers' and clinicians' understanding of heart failure prognosis and its management. AB - OBJECTIVES: Communication and planning for heart failure (HF) care near the end of life is known to be complex. Little is known about how the patient experience of palliative assessment and communication needs change over time, and how this might inform management. Our aim was to explore experiences of giving or receiving a prognosis and advanced palliative care planning (ACP) for those with HF. METHODS: We carried out a longitudinal grounded theory study, employing in depth interviews with 14 clinicians (primary and secondary care) and observations of clinic and home appointments, followed by a series of interviews with 13 patients with HF and 9 carers. RESULTS: Overall, the majority of participants rejected notions of HF as a terminal illness in favour of a focus on day-to-day management and maintenance, despite obvious deterioration in disease stage and needs over time. Clinicians revealed frustration about the uncertain nature of HF prognosis, leading to difficulties in planning. Others highlighted the need to deliver problem-based, individualised care but felt constrained sometimes by the lack of multidisciplinary ACP. Patients reported an absence of prognostic discussions with clinicians. CONCLUSIONS: This is the first study exploring the experiences of prognostic communication at all stages of HF. Findings raise questions regarding the pragmatic utility of the concept of HF as a terminal illness and have implications for future HF care pathway development. Findings support the incorporation of a problem-based approach to management, which recognises the importance of everyday functioning for patients and carers as well as the opportunity for ACP. PMID- 28733463 TI - TLR4 and C5aR crosstalk in dendritic cells induces a core regulatory network of RSK2, PI3Kbeta, SGK1, and FOXO transcription factors. AB - Crosstalk between complement component 5a receptors (C5aRs) and TLRs in dendritic cells (DCs) occurs upon pathogen invasion; however, studies on C5aR and TLR crosstalk mainly focused on the modulating effect of C5a on TLR-induced cytokine production. To elucidate the breadth of C5aR and TLR4 crosstalk, the effect of simultaneous treatment with C5a and LPS was investigated in human monocyte derived DCs (moDCs) 2 h after stimulation using whole transcriptome sequencing analysis. Although the effect of C5a on hallmark genes defining TLR4-induced DC maturation was limited at this time point, RNA sequencing analysis revealed a great variety of novel C5a targets, of which many interfere with TLR4-mediated immune activation. Analysis of functional relationships among these genes uncovered induction of a central immune regulatory network upon C5aR and TLR4 crosstalk, involving the transcription factors forkhead box (FOX)O1 and FOXO3 and the signaling molecules serum- and glucocorticoid-inducible kinase (SGK1), ribosomal S6 kinase 2 (RSK2), and PI3Kbeta. C5aR and TLR crosstalk, furthermore, yielded down-regulation of mainly proinflammatory network branches, including IL 12B, IL-2Ralpha (IL-2RA), and jagged 1 (JAG1) and cooperative induction of predominantly anti-inflammatory network branches, including sphingosine kinase 1 (SPHK1), beta2 adrenergic receptor (ADRB2), gastric inhibitory polypeptide receptor (GIPR), and four-and-a-half Lin11, Isl-1, and Mec-3 domains protein 2 (FHL2). Together, these data point toward induction of generalized immune regulation of DC function. Motif enrichment analysis indicate a prominent role for basic leucine zipper (bZIP) and IFN regulatory factor 4 (IRF4) transcription factors upon C5aR and TLR4 crosstalk. Additionally, differences were observed in the modulating capacity of C5a on DCs in the absence or presence of a pathogen (TLR stimulus). Our findings shed new light on the depth and complexity of C5aR and TLR4 crosstalk and provide new foci of research for future studies. PMID- 28733462 TI - Human T cell immunosenescence and inflammation in aging. AB - The aging process is driven by a finite number of inter-related mechanisms that ultimately lead to the emergence of characteristic phenotypes, including increased susceptibility to multiple chronic diseases, disability, and death. New assays and analytical tools have become available that start to unravel some of these mechanisms. A prevailing view is that aging leads to an imbalance between stressors and stress-buffering mechanisms that causes loss of compensatory reserve and accumulation of unrepaired damage. Central to this paradigm are changes in the immune system and the chronic low-grade proinflammatory state that affect many older individuals, even when they are apparently healthy and free of risk factors. Independent of chronological age, high circulating levels of proinflammatory markers are associated with a high risk of multiple adverse health outcomes in older persons. In this review, we discuss current theories about causes and consequences of the proinflammatory state of aging, with a focus on changes in T cell function. We examine the role of NF-kappaB activation and its dysregulation and how NF-kappaB activity differs among subgroups of T cells. We explore emerging hypotheses about immunosenescence and changes in T cell behavior with age, including consideration of the T cell antigen receptor and regulatory T cells (Tregs). We conclude by illustrating how research using advanced technology is uncovering clues at the core of inflammation and aging. Some of the preliminary work in this field is already improving our understanding of the complex mechanisms by which immunosenescence of T cells is intertwined during human aging. PMID- 28733464 TI - Lineage tracing of epithelial cells in developing teeth reveals two strategies for building signaling centers. AB - An important event in organogenesis is the formation of signaling centers, which are clusters of growth factor-secreting cells. In the case of tooth development, sequentially formed signaling centers known as the initiation knot (IK) and the enamel knot (EK) regulate morphogenesis. However, despite the importance of signaling centers, their origin, as well as the fate of the cells composing them, remain open questions. Here, using lineage tracing of distinct epithelial populations, we found that the EK of the mouse incisor is derived de novo from a group of SRY-box 2 (Sox2)-expressing cells in the posterior half of the tooth germ. Specifically, EK progenitors are located in the posterior ventral basal layer, as demonstrated by DiI labeling of cells. Lineage tracing the formed EK with ShhCreER , which encodes an inducible Cre recombinase under the control of the Sonic hedgehog promoter, at subsequent developmental stages showed that, once formed, some EK cells in the incisor give rise to differentiated cells, whereas in the molar, EK cells give rise to the buccal secondary EK. This work thus establishes the developmental origin as well as the fate of the EK and reveals two strategies for the emergence of serially formed signaling centers: one through de novo establishment and the other by incorporation of progeny from previously formed signaling centers. PMID- 28733465 TI - The retinol-binding protein receptor STRA6 regulates diurnal insulin responses. AB - It has long been appreciated that insulin action is closely tied to circadian rhythms. However, the mechanisms that dictate diurnal insulin sensitivity in metabolic tissues are not well understood. Retinol-binding protein 4 (RBP4) has been implicated as a driver of insulin resistance in rodents and humans, and it has become an attractive drug target in type II diabetes. RBP4 is synthesized primarily in the liver where it binds retinol and transports it to tissues throughout the body. The retinol-RBP4 complex (holo-RBP) can be recognized by a cell-surface receptor known as stimulated by retinoic acid 6 (STRA6), which transports retinol into cells. Coupled to retinol transport, holo-RBP can activate STRA6-driven Janus kinase (JAK) signaling and downstream induction of signal transducer and activator of transcription (STAT) target genes. STRA6 signaling in white adipose tissue has been shown to inhibit insulin receptor responses. Here, we examined diurnal rhythmicity of the RBP4/STRA6 signaling axis and investigated whether STRA6 is necessary for diurnal variations in insulin sensitivity. We show that adipose tissue STRA6 undergoes circadian patterning driven in part by the nuclear transcription factor REV-ERBalpha. Furthermore, STRA6 is necessary for diurnal rhythmicity of insulin action and JAK/STAT signaling in adipose tissue. These findings establish that holo-RBP and its receptor STRA6 are potent regulators of diurnal insulin responses and suggest that the holo-RBP/STRA6 signaling axis may represent a novel therapeutic target in type II diabetes. PMID- 28733466 TI - The reliability of the American Community Survey for injury surveillance. AB - BACKGROUND: To evaluate the reliability and predictability of 49 socioeconomic indicators constructed from the annual and multiyear American Community Survey (ACS) data cycles for monitoring injury inequalities across the USA. METHODS: Cross-sectional analysis of the 2006-2013 annual and multiyear county-level ACS data cycles. Indicator reliability was assessed using the margin of error and coefficient of variation (CV). Overlapping multiyear data cycles were assessed for statistical dependence in the estimates. Negative binomial regression models were constructed from a selection of the most reliable indicators over time and across all data cycles using all-cause unintentional and homicide-related mortality records from the National Center for Health Statistics (NCHS). RESULTS: Fewer than half of all indicators for each data cycle generated 'high reliability' CV estimates for at least 95% of all census counties. Indicator reliability did not linearly improve with increasing sample size afforded from the multiyear surveys. On average, changes in socioeconomic conditions for the same geographic areas were statistically significantly different (p<0.05) in 14% (rage 0-99%) to 16% (rage 0-93%) of all overlapping multiyear data cycles. ACS indicators that were among the most reliable across data cycles corroborated variable relationships derived using estimates from the 2000 decennial census and corresponding NCHS records for that year. CONCLUSIONS: Few of the socioeconomic indicators previously used to measure injury disparities are consistently reliable across all ACS data cycles. Researchers should be judicious when selecting consecutive multiyear data cycles to approximate changes in annual socioeconomic conditions. Among the indicators that are reliable, it is advisable to use estimates from the annual ACS data cycle as a crude barometer of injury inequalities and the multiyear files to confirm and add precedence to national trends every three and five years. PMID- 28733468 TI - Management impact: effects on quality of life and prognosis in MEN1. AB - Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant endocrine tumor syndrome, caused by inactivating mutations of the MEN1 tumor suppressor gene at 11q13 locus, which predisposes to develop tumors in target neuroendocrine tissues. As the positional cloning and identification of the causative gene in 1997, genetic diagnosis, by the sequencing-based research of gene mutations, has become an important tool in the early and differential diagnosis of the disease. Application of the genetic test, in MEN1 index cases and in first-degree relatives of mutated patients, has been constantly increasing during the last two decades, also thanks to the establishment of multidisciplinary referral centers and specific genetic counseling, and thanks to the wide availability of high throughput instruments for gene sequencing and gene mutation identification. The MEN1 genetic test helps the specific diagnosis of probands, and allows the early identification of asymptomatic carriers, strongly contributing, together with progressions in tumor diagnostic techniques and in pharmacological and surgical therapeutic approaches, to the reduction of morbidity and mortality associated with the syndrome. International clinical guidelines for MEN1 have been drafted by panels of specialists in the field, with the main goal to improve the management of the disease and grant patients a better quality of life. Here, we review main recommendations and suggestions derived by the last published general guidelines in 2012, and by most recent published studies about MEN1 syndrome diagnosis, clinical management, therapeutic approaches and patients' quality of life. PMID- 28733467 TI - Acromegaly at diagnosis in 3173 patients from the Liege Acromegaly Survey (LAS) Database. AB - Acromegaly is a rare disorder caused by chronic growth hormone (GH) hypersecretion. While diagnostic and therapeutic methods have advanced, little information exists on trends in acromegaly characteristics over time. The Liege Acromegaly Survey (LAS) Database, a relational database, is designed to assess the profile of acromegaly patients at diagnosis and during long-term follow-up at multiple treatment centers. The following results were obtained at diagnosis. The study population consisted of 3173 acromegaly patients from ten countries; 54.5% were female. Males were significantly younger at diagnosis than females (43.5 vs 46.4 years; P < 0.001). The median delay from first symptoms to diagnosis was 2 years longer in females (P = 0.015). Ages at diagnosis and first symptoms increased significantly over time (P < 0.001). Tumors were larger in males than females (P < 0.001); tumor size and invasion were inversely related to patient age (P < 0.001). Random GH at diagnosis correlated with nadir GH levels during OGTT (P < 0.001). GH was inversely related to age in both sexes (P < 0.001). Diabetes mellitus was present in 27.5%, hypertension in 28.8%, sleep apnea syndrome in 25.5% and cardiac hypertrophy in 15.5%. Serious cardiovascular outcomes like stroke, heart failure and myocardial infarction were present in <5% at diagnosis. Erythrocyte levels were increased and correlated with IGF-1 values. Thyroid nodules were frequent (34.0%); 820 patients had colonoscopy at diagnosis and 13% had polyps. Osteoporosis was present at diagnosis in 12.3% and 0.6-4.4% had experienced a fracture. In conclusion, this study of >3100 patients is the largest international acromegaly database and shows clinically relevant trends in the characteristics of acromegaly at diagnosis. PMID- 28733470 TI - Dendritic cell-targeted lentiviral vector immunization uses pseudotransduction and DNA-mediated STING and cGAS activation. AB - Dendritic cell (DC) activation and antigen presentation are critical for efficient priming of T cell responses. Here, we study how lentiviral vectors (LVs) deliver antigen and activate DCs to generate T cell immunization in vivo. We report that antigenic proteins delivered in vector particles via pseudotransduction were sufficient to stimulate an antigen-specific immune response. The delivery of the viral genome encoding the antigen increased the magnitude of this response in vivo but was irrelevant in vitro. Activation of DCs by LVs was independent of MyD88, TRIF, and MAVS, ruling out an involvement of Toll-like receptor or RIG-I-like receptor signaling. Cellular DNA packaged in LV preparations induced DC activation by the host STING (stimulator of interferon genes) and cGAS (cyclic guanosine monophosphate-adenosine monophosphate synthase) pathway. Envelope-mediated viral fusion also activated DCs in a phosphoinositide 3-kinase-dependent but STING-independent process. Pseudotransduction, transduction, viral fusion, and delivery of cellular DNA collaborate to make the DC-targeted LV preparation an effective immunogen. PMID- 28733471 TI - Helicobacter species are potent drivers of colonic T cell responses in homeostasis and inflammation. AB - Specific gut commensal bacteria improve host health by eliciting mutualistic regulatory T (Treg) cell responses. However, the bacteria that induce effector T (Teff) cells during inflammation are unclear. We addressed this by analyzing bacterial-reactive T cell receptor (TCR) transgenic cells and TCR repertoires in a murine colitis model. Unexpectedly, we found that mucosal-associated Helicobacter species triggered both Treg cell responses during homeostasis and Teff cell responses during colitis, as suggested by an increased overlap between the Teff/Treg TCR repertoires with colitis. Four of six Treg TCRs tested recognized mucosal-associated Helicobacter species in vitro and in vivo. By contrast, the marked expansion of luminal Bacteroides species seen during colitis did not trigger a commensurate Teff cell response. Unlike other Treg cell inducing bacteria, Helicobacter species are known pathobionts and cause disease in immunodeficient mice. Thus, our study suggests a model in which mucosal bacteria elicit context-dependent Treg or Teff cell responses to facilitate intestinal tolerance or inflammation. PMID- 28733469 TI - Bone morphogenetic proteins, breast cancer, and bone metastases: striking the right balance. AB - Bone morphogenetic proteins (BMPs) belong to the TGF-beta super family, and are essential for the regulation of foetal development, tissue differentiation and homeostasis and a multitude of cellular functions. Naturally, this has led to the exploration of aberrance in this highly regulated system as a key factor in tumourigenesis. Originally identified for their role in osteogenesis and bone turnover, attention has been turned to the potential role of BMPs in tumour metastases to, and progression within, the bone niche. This is particularly pertinent to breast cancer, which commonly metastasises to bone, and in which studies have revealed aberrations of both BMP expression and signalling, which correlate clinically with breast cancer progression. Ultimately a BMP profile could provide new prognostic disease markers. As the evidence suggests a role for BMPs in regulating breast tumour cellular function, in particular interactions with tumour stroma and the bone metastatic microenvironment, there may be novel therapeutic potential in targeting BMP signalling in breast cancer. This review provides an update on the current knowledge of BMP abnormalities and their implication in the development and progression of breast cancer, particularly in the disease-specific bone metastasis. PMID- 28733472 TI - Effects of RNA interference-mediated gene silencing of VEGF on the ultrafiltration failure in a rat model of peritoneal dialysis. AB - We investigated the effects of RNAi-mediated gene silencing of vascular endothelial growth factor (VEGF) on ultrafiltration failure (UFF) in rats with peritoneal dialysis (PD). Sprague-Dawley (SD) male rats were classified into normal, sham operation, and uremic model groups. Uremic rats were subcategorized into uremia, PD2, VEGF shRNA-2, vector-2, PD2 + Endostar, PD4, VEGF shRNA-4, Vector-4, and PD4 + Endostar groups. Peritoneal Equilibration Test (PET) was conducted to assess ultrafiltration volume (UFV) and mass transfer of glucose (MTG). mRNA and protein expressions of VEGF were detected using quantitative real time PCR (qRT-PCR) and Western blotting. Immunohistochemistry was performed to detect microvessel density (MVD). Compared with the normal group, decreased UFV and increased MTG were observed in rest of the groups. Compared with the uremia group, UFV decreased, while MTG, expression of VEGFs, and number of new blood capillaries increased in the PD2, Vector-2, PD4, and Vector-4 groups. The PD4 and Vector-4 groups exhibited lower UFV and higher MTG than the PD2 group. In the VEGF shRNA-2, PD2 + Endostar, VEGF shRNA-4, and in PD4 + Endostar group increased UFV, reduced MTG and expression of VEGF, and decreased number of new blood capillaries were detected. Compared with the PD4 group, in the VEGF shRNA-4 and PD4 + Endostar groups, UFV increased, MTG and expression of VEGF decreased, and number of new blood capillaries reduced. VEGF expression was negatively correlated with UFV, but positively correlated with MTG. The results obtained in the study revealed that down-regulation of VEGF by RNAi could be a novel target approach for the treatment of UFF. PMID- 28733475 TI - GPER modulates tone and coronary vascular reactivity in male and female rats. AB - Compared with age-matched men, premenopausal women are largely protected from coronary artery disease, a difference that is lost after menopause. The effects of oestrogens are mediated by the activation of nuclear receptors (ERalpha and ERbeta) and by the G protein-coupled oestrogen receptor (GPER). This study aims to evaluate the potential role of GPER in coronary circulation in female and male rats. The baseline coronary perfusion pressure (CPP) and the concentration response curve with a GPER agonist (G-1) were evaluated in isolated hearts before and after the blockade of GPER. GPER, superoxide dismutase (SOD-2), catalase and gp91phox protein expression were assessed by Western blotting. Superoxide production was evaluated 'in situ' via dihydroethidium fluorescence (DHE). GPER blockade significantly increased the CPP in both groups, demonstrating the modulation of coronary tone by GPER. G-1 causes relaxation of the coronary bed in a concentration-dependent manner and was significantly higher in female rats. No differences were detected in GPER, SOD-2 and catalase protein expression. However, gp91phox expression and DHE fluorescence were higher in male rats, indicating elevated superoxide production. Therefore, GPER plays an important role in modulating coronary tone and reactivity in female and male rats. The observed differences in vascular reactivity may be related to the higher superoxide production in male rats. These findings help to elucidate the role of GPER-modulating coronary circulation, providing new information to develop a potential therapeutic target for the treatment of coronary heart disease. PMID- 28733474 TI - Persons with chronic widespread pain experience excess mortality: longitudinal results from UK Biobank and meta-analysis. AB - OBJECTIVE: It is uncertain whether persons with chronic widespread pain (CWP) experience premature mortality. Using the largest study conducted, we determine whether such a relationship exists, estimate its magnitude and establish what factors mediate any relationship. METHODS: UK Biobank, a cohort study of 0.5 million people aged 40-69 years, recruited throughout Great Britain in 2006-2010. Participants reporting 'pain all over the body' for >3 months were compared with persons without chronic pain. Information on death (with cause) was available until mid-2015. We incorporated these results in a meta-analysis with other published reports to calculate a pooled estimate of excess risk. RESULTS: 7130 participants reported CWP and they experienced excess mortality (mortality risk ratio 2.43, 95%CI 2.17 to 2.72). Specific causes of death in excess were cancer (1.73adjusted age and sex, 95% CI 1.46 to 2.05), cardiovascular (3.24adjusted age and sex, 95% CI 2.55 to 4.11), respiratory (5.66adjusted age and sex, 95% CI 4.00 to 8.03) and other disease-related causes (4.04adjusted age and sex, 95% CI 3.05 to 5.34). Excess risk was substantially reduced after adjustment for low levels of physical activity, high body mass index, poor quality diet and smoking. In meta-analysis, all studies showed significant excess all-cause (combined estimate 1.59 (95% CI 1.05 to 2.42)), cardiovascular and cancer mortality. CONCLUSIONS: Evidence is now clear that persons with CWP experience excess mortality. UK Biobank results considerably reduce uncertainty around the magnitude of excess risk and are consistent with the excess being explained by adverse lifestyle factors, which could be targeted in the management of such patients. PMID- 28733473 TI - Do depression and anxiety reduce the likelihood of remission in rheumatoid arthritis and psoriatic arthritis? Data from the prospective multicentre NOR DMARD study. AB - OBJECTIVE: To investigate the predictive value of baseline depression/anxiety on the likelihood of achieving joint remission in rheumatoid arthritis (RA) and psoriatic arthritis (PsA) as well as the associations between baseline depression/anxiety and the components of the remission criteria at follow-up. METHODS: We included 1326 patients with RA and 728 patients with PsA from the prospective observational NOR-DMARD study starting first-time tumour necrosis factor inhibitors or methotrexate. The predictive value of depression/anxiety on remission was explored in prespecified logistic regression models and the associations between baseline depression/anxiety and the components of the remission criteria in prespecified multiple linear regression models. RESULTS: Baseline depression/anxiety according to EuroQoL-5D-3L, Short Form-36 (SF-36) Mental Health subscale <=56 and SF-36 Mental Component Summary <=38 negatively predicted 28-joint Disease Activity Score <2.6, Simplified Disease Activity Index <=3.3, Clinical Disease Activity Index <=2.8, ACR/EULAR Boolean and Disease Activity Index for Psoriatic Arthritis <=4 remission after 3 and 6 months treatment in RA (p<=0.008) and partly in PsA (p from 0.001 to 0.73). Baseline depression/anxiety was associated with increased patient's and evaluator's global assessment, tender joint count and joint pain in RA at follow-up, but not with swollen joint count and acute phase reactants. CONCLUSION: Depression and anxiety may reduce likelihood of joint remission based on composite scores in RA and PsA and should be taken into account in individual patients when making a shared decision on a treatment target. PMID- 28733476 TI - miR-30e targets GLIPR-2 to modulate diabetic nephropathy: in vitro and in vivo experiments. AB - The objectives of this study are to investigate the effect of miR-30e targeting GLIPR-2 on the pathological mechanism of DN. The renal tissues of db/db and db/m mice at different age of weeks were stained with PAS. qRT-PCR was applied to detect the expression of miR-30e and GLIPR-2, not only in the renal tissues of mice but also in the renal tubular epithelial cells (RTECs). By luciferase reporter gene assays, we found the 3'-UTR of the GLIPR-2 mRNA as a direct target of miR-30e. The RTECs cultured in high glucose were divided into blank control, NC, miR-30e mimics, miR-30e inhibitors, miR-30e inhibitor + si-GLIPR-2 and si GLIPR-2 groups. MTT and flow cytometry were utilized to measure the proliferation and apoptosis of RTECs, while qRT-PCR and Western blot to detect the expression of GLIPR-2- and EMT-related factors. The following results were obtained: In the renal tissues of over 8-week-old db/db mice and the RTECs cultured for 6 h in high glucose, miR-30e was downexpressed while GLIPR-2 was upregulated in a time dependent manner. Besides, overexpression of miR-30e and si-GLIPR-2 can not only greatly improve the proliferation of RTECs cultured in high glucose, but also downregulate the apoptosis rate of RTECs and the expressions of GLIPR-2, vimentin, alpha-SMA, Col-I and FN and upregulate E-cadherin. Moreover, si-GLIPR-2 can reverse the proliferation reduction, GLIPR-2 and EMT occurrence caused by the downexpression of miR-30e in RTECs. In conclusion, miR-30e is downregulated in DN, and the overexpression of miR-30e can inhibit GLIPR-2, promote the proliferation of RTECs and inhibit EMT, ultimately avoid leading to renal fibrosis in DN. PMID- 28733478 TI - Growth and morbidity of extremely preterm infants after early full enteral nutrition. AB - OBJECTIVES: To evaluate feasibility and consequences of accelerated feeding advancement on short-term outcomes in extremely low gestational age neonates (ELGANs) who stayed in our institution for >28 days. METHODS: Retrospective single-centre cohort analysis covering the years 2011-2013. Data are presented as median (IQR). RESULTS: Infants '(n=77) birth weight was 745 (640 to 960) g and gestational age at birth 26.7 (25.1 to 27.4) weeks. Full enteral feeds were attained by postnatal day 7 (5 to 11). Weight gain from birth to discharge was 14.3 (13.3 to 16.1) g/kg/day, change in SD score for weight -0.03 (-0.55 to 0.46) and 0.09 (-0.78 and 0.82) for head circumference. Rates of necrotising enterocolitis and spontaneous intestinal perforation in all ELGANs admitted during the study period were 3.1% and 9.4%, respectively. CONCLUSIONS: This cohort of ELGANs showed good weight gain and head growth after early full enteral nutrition. The impact of this feeding practice on neonatal morbidity and long term outcome remains to be tested in adequately powered randomised trials. PMID- 28733479 TI - Use and Timing of Tracheostomy After Severe Stroke. PMID- 28733480 TI - Response by Brinjikji et al to Letter Regarding Article, "Neurons Over Nephrons: Systematic Review and Meta-Analysis of Contrast-Induced Nephropathy in Patients With Acute Stroke". PMID- 28733481 TI - Focal Cerebral Arteriopathy: Do Steroids Improve Outcome? AB - BACKGROUND AND PURPOSE: Focal cerebral arteriopathy accounts for up to 35% of arterial ischemic stroke (AIS) in children and is the most important predictor of stroke recurrence. The study objective was to compare outcomes for children with focal cerebral arteriopathy treated with combined corticosteroid antithrombotic treatment (CAT) to those receiving antithrombotic treatment (AT) alone. METHODS: This multicenter retrospective Swiss/Australian cohort study analyzed consecutive children, aged 1 month to 18 years, presenting with first AIS because of a focal cerebral arteriopathy from 2000 to 2014. Children with CAT were compared with those treated with AT. Primary outcome was the presence of neurological deficits at 6 months post-AIS as measured by the Pediatric Stroke Outcome Measure. Secondary outcomes included resolution of stenosis and stroke recurrence. Analysis of covariance was used to adjust for potential confounders (baseline pediatric National Institute of Health Stroke Scale and concomitant acyclovir use). RESULTS: A total of 73 children (51% males) were identified, 21 (29%) of whom received CAT. Mean (SD) age at stroke for the entire group was 7.9 years (4.7). Median (interquartile range) pediatric National Institute of Health Stroke Scale was 3 (2.0-8.0) in the CAT group and 5 (3.0-9.0) in the AT group (P=0.098). Median (interquartile range) Pediatric Stroke Outcome Measure 6 months post-AIS was 0.5 (0-1.5) in the CAT group compared with 1.0 (0.5-2.0) in the AT group (P=0.035), the finding was sustained after adjusting for potential confounders. Complete resolution of stenosis at last MRI was noted in 17 (81%) in the CAT group compared with 24 (59%) in the AT group (P=0.197). Stroke recurrence occurred in 1 patient in each group. CONCLUSIONS: Corticosteroid treatment may provide additional benefit over AT for improved neurological outcome in childhood AIS because of focal cerebral arteriopathy. Larger prospective studies are warranted to further investigate these differences and understand mechanisms by which steroids modify outcome. PMID- 28733482 TI - Letter by O'Sullivan Regarding Article, "Neurons Over Nephrons: Systematic Review and Meta-Analysis of Contrast-Induced Nephropathy in Patients With Acute Stroke". PMID- 28733483 TI - Two pore channel 2 (TPC2) inhibits autophagosomal-lysosomal fusion by alkalinizing lysosomal pH. PMID- 28733484 TI - Cutting Edge: CD3 ITAM Diversity Is Required for Optimal TCR Signaling and Thymocyte Development. AB - For the alphabeta or gammadeltaTCR chains to integrate extracellular stimuli into the appropriate intracellular cellular response, they must use the 10 ITAMs found within the CD3 subunits (CD3gammaepsilon, CD3deltaepsilon, and zetazeta) of the TCR signaling complex. However, it remains unclear whether each specific ITAM sequence of the individual subunit (gammaepsilondeltazeta) is required for thymocyte development or whether any particular CD3 ITAM motif is sufficient. In this article, we show that mice utilizing a single ITAM sequence (gamma, epsilon, delta, zetaa, zetab, or zetac) at each of the 10 ITAM locations exhibit a substantial reduction in thymic cellularity and limited CD4-CD8- (double negative) to CD4+CD8+ (double-positive) maturation because of low TCR expression and signaling. Together, the data suggest that ITAM sequence diversity is required for optimal TCR signal transduction and subsequent T cell maturation. PMID- 28733485 TI - IL-17 Promotes Differentiation of Splenic LSK- Lymphoid Progenitors into B Cells following Plasmodium yoelii Infection. AB - Lineage-Sca-1+c-Kit- (LSK-) cells are a lymphoid progenitor population that expands in the spleen and preferentially differentiates into mature B cells in response to Plasmodium yoelii infection in mice. Furthermore, LSK- derived B cells can subsequently contribute to the ongoing immune response through the generation of parasite-specific Ab-secreting cells, as well as germinal center and memory B cells. However, the factors that promote their differentiation into B cells in the spleen postinfection are not defined. In this article, we show that LSK- cells produce the cytokine IL-17 in response to Plasmodium infection. Using Il-17ra-/- mice, IL-17R signaling in cells other than LSK- cells was found to support their differentiation into B cells. Moreover, primary splenic stromal cells grown in the presence of IL-17 enhanced the production of CXCL12, a chemokine associated with B cell development in the bone marrow, by a population of IL-17RA-expressing podoplanin+CD31- stromal cells, a profile associated with fibroblastic reticular cells. Subsequent blockade of CXCL12 in vitro reduced differentiation of LSK- cells into B cells, supporting a direct role for this chemokine in this process. Immunofluorescence indicated that podoplanin+ stromal cells in the red pulp were the primary producers of CXCL12 after P. yoelii infection. Furthermore, podoplanin staining on stromal cells was more diffuse, and CXCL12 staining was dramatically reduced in Il-17ra-/- mice postinfection. Together, these results identify a distinct pathway that supports lymphoid development in the spleen during acute Plasmodium infection. PMID- 28733488 TI - Identification of optimal strategies for state transition of complex biological networks. AB - Complex biological networks typically contain numerous parameters, and determining feasible strategies for state transition by parameter perturbation is not a trivial task. In the present study, based on dynamical and structural analyses of the biological network, we optimized strategies for controlling variables in a two-node gene regulatory network and a T-cell large granular lymphocyte signaling network associated with blood cancer by using an efficient dynamic optimization method. Optimization revealed the critical value for each decision variable to steer the system from an undesired state into a desired attractor. In addition, the minimum time for the state transition was determined by defining and solving a time-optimal control problem. Moreover, time-dependent variable profiles for state transitions were achieved rather than constant values commonly adopted in previous studies. Furthermore, the optimization method allows multiple controls to be simultaneously adjusted to drive the system out of an undesired attractor. Optimization improved the results of the parameter perturbation method, thus providing a valuable guidance for experimental design. PMID- 28733489 TI - Interaction of misfolded proteins and mitochondria in neurodegenerative disorders. AB - The number of the people affected by neurodegenerative disorders is growing dramatically due to the ageing of population. The major neurodegenerative diseases share some common pathological features including the involvement of mitochondria in the mechanism of pathology and misfolding and the accumulation of abnormally aggregated proteins. Neurotoxicity of aggregated beta-amyloid, tau, alpha-synuclein and huntingtin is linked to the effects of these proteins on mitochondria. All these misfolded aggregates affect mitochondrial energy metabolism by inhibiting diverse mitochondrial complexes and limit ATP availability in neurones. beta-Amyloid, tau, alpha-synuclein and huntingtin are shown to be involved in increased production of reactive oxygen species, which can be generated in mitochondria or can target this organelle. Most of these aggregated proteins are capable of deregulating mitochondrial calcium handling that, in combination with oxidative stress, lead to opening of the mitochondrial permeability transition pore. Despite some of the common features, aggregated beta-amyloid, tau, alpha-synuclein and huntingtin have diverse targets in mitochondria that can partially explain neurotoxic effect of these proteins in different brain regions. PMID- 28733486 TI - alpha-Toxin Regulates Local Granulocyte Expansion from Hematopoietic Stem and Progenitor Cells in Staphylococcus aureus-Infected Wounds. AB - The immune response to Staphylococcus aureus infection in skin involves the recruitment of polymorphonuclear neutrophils (PMNs) from the bone marrow via the circulation and local granulopoiesis from hematopoietic stem and progenitor cells (HSPCs) that also traffic to infected skin wounds. We focus on regulation of PMN number and function and the role of pore-forming alpha-toxin (AT), a virulence factor that causes host cell lysis and elicits inflammasome-mediated IL-1beta secretion in wounds. Infection with wild-type S. aureus enriched in AT reduced PMN recruitment and resulted in sustained bacterial burden and delayed wound healing. In contrast, PMN recruitment to wounds infected with an isogenic AT deficient S. aureus strain was unimpeded, exhibiting efficient bacterial clearance and hastened wound resolution. HSPCs recruited to infected wounds were unaffected by AT production and were activated to expand PMN numbers in proportion to S. aureus abundance in a manner regulated by TLR2 and IL-1R signaling. Immunodeficient MyD88-knockout mice infected with S. aureus experienced lethal sepsis that was reversed by PMN expansion mediated by injection of wild-type HSPCs directly into wounds. We conclude that AT-induced IL 1beta promotes local granulopoiesis and effective resolution of S. aureus infected wounds, revealing a potential antibiotic-free strategy for tuning the innate immune response to treat methicillin-resistant S. aureus infection in immunodeficient patients. PMID- 28733491 TI - Call for government action as illegal puppy sales fuel canine welfare crisis. PMID- 28733492 TI - Two universities join up to announce plans for new West Midlands vet school. PMID- 28733497 TI - When is it safe to report abuse? PMID- 28733487 TI - The STAT4/MLL1 Epigenetic Axis Regulates the Antimicrobial Functions of Murine Macrophages. AB - Macrophages are critical immune cells for the clearance of microbial pathogens and cellular debris from peripheral tissues. Macrophage inflammatory responses are governed by gene expression patterns, and these patterns are often subject to epigenetic control. Chromatin modifications, such as histone methylation, regulate gene accessibility in macrophages, and macrophage polarization is governed in part by the expression and function of chromatin-modifying enzymes. The histone methyltransferase mixed-lineage leukemia 1 (MLL1) preferentially modifies lysine residue 4 on the unstructured protein tail of histone H3. MLL1 expression and function have been shown to be governed by signal transduction pathways that are activated by inflammatory stimuli, such as NF-kappaB. Therefore, we sought to investigate the role of MLL1 in mediating macrophage inflammatory responses. Bone marrow-derived macrophages from mice with a targeted MLL1 gene knockout (Lys2-Cre+/- MLL1fx/fx) exhibited decreased proinflammatory gene expression with concurrent decreases in activating histone methylation. However, MLL1-deficient macrophages also exhibited increased phagocytic and bacterial killing activity in vitro. RNA profiling of MLL1-knockout macrophages identified numerous genes involved with inflammatory responses whose expression was altered in response to TLR ligands or proinflammatory cytokines, including STAT4. STAT4-dependent cytokines, such as type I IFNs were able to drive MLL1 expression in macrophages, and MLL1-knockout macrophages exhibited decreased activating histone methylation in the STAT4 promoter. These results implicate an important role for MLL1-dependent epigenetic regulation of macrophage antimicrobial functions. PMID- 28733498 TI - Dealing with abuse cases: what can vets do? PMID- 28733499 TI - Easing the emergency burden: ethical dilemmas faced by the out-of-hours vet. PMID- 28733501 TI - Helping vets assess quality of life. PMID- 28733500 TI - Clinical Decision Making. PMID- 28733502 TI - Past cases of Alabama rot? PMID- 28733503 TI - Reviewing the Vet Futures Action Plan. PMID- 28733504 TI - Consulting on halal meat labelling. PMID- 28733505 TI - Official controls in slaughterhouses. PMID- 28733507 TI - Birth cohort study of pet dogs underway and recruiting. PMID- 28733506 TI - Looking to India's workforce following Brexit. PMID- 28733508 TI - Diagnosis of botulism in waterfowl. PMID- 28733509 TI - ? PMID- 28733510 TI - ? PMID- 28733516 TI - My week: Jenny Jaffe. AB - Jenny Jaffe is a veterinarian who works on disease risk analysis and health surveillance at the Zoological Society of London. Here, she describes a recent week. PMID- 28733517 TI - Mental health awareness. AB - Independent, family-owned veterinary group White Cross Vets has been focusing on wellbeing. One of its clinic directors, Rob Reid, joined a group from the practice for some training in mental health awareness. PMID- 28733561 TI - Workplace violence toward mental healthcare workers: A call for action. PMID- 28733562 TI - Incidence of cutaneous adverse drug reactions among medical inpatients of Sultanah Aminah Hospital Johor Bahru. AB - INTRODUCTION: Cutaneous adverse drug reactions (cADRs) are common. There are only few studies on the incidence of cADRs in Malaysia. OBJECTIVE: To determine the incidence, clinical features and risk factors of cADRs among hospitalized patients. METHODS: A prospective study was conducted among medical inpatients from July to December 2014. RESULTS: A total of 43 cADRs were seen among 11 017 inpatients, yielding an incidence rate of 0.4%. cADR accounted for hospitalization in 26 patients. Previous history of cADR was present in 14 patients, with 50% exposed to the same drug taken previously. Potentially lifethreatening severe cutaneous adverse reactions (SCAR), namely drug reaction with eosinophilia and systemic symptoms (DRESS: 14 cases) and Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN: 6 cases) comprise almost 50% of cADRs. The commonest culprit drug group was antibiotics (37.2%), followed by anticonvulsants (18.6%). Cotrimoxazole, phenytoin and rifampicin were the main causative drugs for DRESS. Anticonvulsants were most frequently implicated in SJS/TEN (66.7%). Most cases had "probable" causality relationship with suspected drug (69.8%). The majority of cases were of moderate severity (65.1%), while 18.6% had severe reaction with 1 death recorded. Most cases were not preventable (76.7%). Older age (> 60 years) and mucosal involvement were significantly associated with a more severe reaction. CONCLUSION: The incidence of cADRs was 0.4%, with most cases classified as moderate severity and not preventable. The commonest reaction pattern was DRESS, while the main culprit drug group was antibiotics. Older age and mucosal membrane involvement predicts a severe drug reaction. PMID- 28733563 TI - Prevalence, factors influencing and knowledge about adherence to lipid-lowering therapy among hyperlipidemia patients. AB - BACKGROUND: Hyperlipidaemia is a significant risk factor for cardiovascular disease. However, adherence to lipidlowering therapy is often unsatisfactory due to a combination of patient factors, therapy, socio-economic and health system related factors. AIMS: to identify the prevalence of adherence to lipidlowering therapy, the factors contributing to non-adherence and knowledge regarding hyperlipidaemia and its' treatment among Malaysian patients with hyperlipidemia. METHODS: A quantitative study using a cross-sectional survey was carried out in an urban primary care clinic in August 2015. Patients on lipid-lowering therapy for >= 1 year aged >= 18 years were selected using simple random sampling. consenting patients answered a selfadministered questionnaire (in Malay/English) which included socio-demographic profile, hyperlipidaemia profile, adherence to lipid-lowering therapy (using the Morisky Medication Adherence scale-8; score >= 6 taken as adherent), reasons leading to non-adherence, knowledge regarding hyperlipidaemia and its' treatment, and use of non-allopathic medicine. RESULTS: the response rate was 90.7%. the prevalence of adherence to lipid-lowering therapy was 82.4%. "the most common reasons for non-adherence was being worried about side effect of lipid-lowering agent (71.4%), followed by the need to take too many drugs in a day (61.4%) and negative influences by friends, relative and mass media (60%)". Factors associated with non-adherence include male gender, on longer duration of therapy, less frequency of follow-up, less number of follow-up clinics, taking medication at night/random timing and having lower knowledge scores. CONCLUSION: Overall the prevalence of adherence was high in patients with hyperlipidaemia. Interventions to boost adherence should target those who were identified as nonadherent. PMID- 28733564 TI - The clinical features and treatment outcome of chronic hepatitis C with pegylated interferon and ribavirin in routine care. AB - AIM: To describe the clinical characteristic of hepatitis C (HCV) patients and the results of pegylated interferon and ribavirin (PegIFN/RBV) therapy in a routine clinical practice. METHODS: A retrospective review of consecutive HCV patients treated with PegIFN/RBV in 2004 to 2012. RESULTS: A total of 273 patients received treatment. The mean age was 44.16 +/- 10.5 years and 76% were male. The top 2 self-reported risks were blood or blood product transfusion before 1994 and injection drug use, found in 57.1% of patients. The predominant HCV genotype (GT) was 3 at 60.6%, second was GT1 at 36.1% and other GTs were uncommon at about 1% or less. About half of our patients have high baseline viral load (>800,000 iu/ml), 18.3% had liver cirrhosis and 22.3% had HIV co-infection. Co-morbid illness was found in 42.9%, hypertension and type 2 diabetes were the two most common. The overall sustained virological response (SVR) by intention-to treat analysis were 54.9% (n=150/273), 41.2% (40/97) for GT1, 100% (5/5) for GT2 and 62% (101/163) for GT3. Subgroup analysis for HCV monoinfected, treatment naive showed SVR of 49.2% (31/63) for GT1, 100% (5/5) for GT2 and 67% (69/103) for GT3. In HCV mono-infected and treatment experienced (n=29), the SVR was 28.6% (4/14) for GT1, 21.4% (69/103) for GT3. In the HIV/HCV co-infected, treatment naive (n=56), the SVR was 28.6% (4/14) for GT1 and 64.3% (27/42) for GT3. Treatment naive GT3 mono-infected patients had a statistically significant higher SVR compared to treatment experienced patients (P=0.001). In GT3 patients who achieved rapid virological response, the SVR was significantly higher at 85.2% (P< 0.001). The SVR for cirrhotics were low especially for GT1 at 21% (4/19) and 31% (4/13) based on all patients and treatment naive HCV monoinfected respectively. In GT3 cirrhotics the corresponding SVR were 57.1% (16/28) and 60.9% (14/23). Premature discontinuation rate was 21.2% with the majority due to intolerable adverse events at 12.1%. CONCLUSIONS: In our routine clinical practice, the HCV patients we treated were young, predominantly of GT3 and many had difficult-to-treat clinical characteristics. The SVR of our patients were below those reported in Asian clinical trials but in keeping with some "real world" data. PMID- 28733565 TI - Customary Marriages in Rural Pakistan. AB - BACKGROUND: Although the incidents of customary marriages are frequently reported in Pakistani press, yet no large scale community-based study has ever been conducted to gauge the magnitude of such marriages. The present study is the first-ever community based study on this topic. METHODS: 4,385 ever-married women, aged 18-83 years, from six rural districts, were interviewed to enquire about the types of their marriages. The data was collected through interviews conducted by trained female interviewers and analysed through SPSS-20. RESULTS: Twelve percent marriages were the result of Vanni, Swara, Sang Chatti, Badal , Bazo i.e. to settle blood feuds; 58.7% were Watta-Satta / Pait Likhai i.e. exchange marriages and pledging a fetus; in 7.9% case bride was bought; 1.0% marriages were Badle-Sullah i.e to settle dispute other than murder and 0.1% women were married to Quran. The traditional marriages, where wishes of both families and consent of the couple to be married are also considered, constituted 20.3%. The prevalence of Vanni, Swara / Sang Chatti / Badal / Bazo was the highest in Balochistan (22-24%) followed by Sindh (5-17%) and the least in Punjab (0-4%). The other practices in Balochistan were selling the bride (10-17%), Badle Sulah (3%) and marriage to Quran (1%). Watta Satta was most prevalent in Sindh (66-78%), where 3-13% brides were bought. In Punjab also Watta-Satta was common (44-47%), where 0.5-4% brides were bought and 0.3-3% marriages were Budle-Sullah. CONCLUSIONS: Since laws against these harmful customs exist but are not applied forcefully, there is a great need to create massive awareness against such customs. PMID- 28733566 TI - Newly diagnosed end stage kidney disease in a single centre in Sabah. AB - AIM: To study the epidemiology, clinical characteristics, vascular access, and the short term survival of ESRD patients initiated on dialysis from Hospital Queen Elizabeth (HQE). BACKGROUND: The number of patients with ESRD is increasing in Sabah, Malaysia. Most patients present late and some live in remote areas with difficult access to healthcare services. Many therefore present with potentially fatal complications. METHODS: All the newly confirmed ESRD patients who were initiated on renal replacement therapy (RRT) from 1 January to 31 December 2014 were included. The basic epidemiological and clinical data were collected. They were divided into three groups: Group 1 - those known to the medical service and had been prepared properly for the initiation of RRT; Group 2 - those known to the medical service, but were not prepared for the RRT; Group 3 - those with undiagnosed CKD. Outcome is mainly survival at 3rd, 6th, 9th and 12th month. RESULTS: There were 249 ESRD patients. 153 (61.4%) were male. The average age was 53.3 (range 12 - 83). The main cause of ESRD was diabetic nephropathy (128 patients, 51.4%). Most patients were started on RRT with a catheter (74.3%), 47 patients (18.9%) with a fistula, and 17 patients (6.8%) with a Tenckhoff catheter. 185 (74.3%) patients were not prepared properly (Group 2 - 66.3%, and Group 3 - 8.0%). The survival for 249 patients were 86.3% at 6 months, 77.9% at 12 months. Group 2 has the worst survival (81.9% at 6 months, 71.1% at 12 months). CONCLUSIONS: Our data showed that most patients (74.3%) were started on dialysis in an unplanned manner with poor survival. A comprehensive and well supported predialysis programme is needed. PMID- 28733567 TI - Prevalence and factors associated with erectile dysfunction in male patients with human immunodeficiency virus in a teaching hospital in West Malaysia. AB - INTRODUCTION: Erectile dysfunction (ED) has been associated with the treatment of human immunodeficiency virus (HIV) and chronic diseases. Sexual dysfunction data of male patients infected with HIV are still scarce in Malaysia, and ED appears to be under-reported. Therefore, this study aims to determine the prevalence and predictors of ED among male HIV patients at the University Malaya Medical Centre. METHODS: A cross sectional study was conducted among male HIV patients on antiretroviral therapy (ART) attending the outpatient clinic of a teaching hospital in Malaysia. A systematic random sampling method was employed in the selection of respondents. Participants were interviewed using a structured questionnaire with a 15-item international index of erectile function (IIEF-15). An appropriate statistical analysis was used to determine the associate and potential risk factors. RESULTS: A total of 220 males participated in this study with a mean age of 37.9+/-9.9; prevalence of ED among HIV patients was 82.3 % (n=180). The severity of ED was further categorized into: severe (24.1%), moderate (19.1%), mild to moderate (20.9%), and mild (18.3%). In a multivariate logistic regression analysis, patients with a lower educational background were more likely to be associated with ED (odds ratio [OR] 2.62, 95% confidence interval [CI] 1.02-6.72; pvalue 0.046). CONCLUSION: This study reports that ED was prevalent among adult HIV males who are on an ART regimen. Those with a lower educational background are more likely to have ED. Hence, in managing patients with HIV, physicians should seek to identify those patients at risk of developing ED for further intervention. PMID- 28733568 TI - Mycology of Onychomycosis: A 5-year retrospective review (2011 - 2015) in Hospital Kuala Lumpur. AB - Onychomycosis is a common nail disease with numerous etiological pathogens. In order to determine and trend the local mycological pattern of culture-positive diseased nail samples sent from the Department of Dermatology, Hospital Kuala Lumpur, a five-year retrospective audit was carried out, which revealed that non dermatophyte molds were the predominant fungi isolated, followed by yeasts and dermatophytes. This is similar to two previous studies in Malaysia, but varies greatly from other studies around the world which showed a dermatophyte predominant prevalence. This could be due to the nature of the environment our patients encountered. PMID- 28733569 TI - A case of missed blunt traumatic aortic injury (BTAI). AB - We are reporting a case of missed blunt traumatic aortic injury (BTAI). A 28 year male presented with chest pain following a motor vehicle accident. He was discharged following normal clinical signs and chest radiograph. The following day he complained of lower limb weakness. Traumatic aortic dissection was revealed via computer tomography (CT) of the thorax. BTAI cannot be ruled out with normal clinical signs and chest radiograph alone. CT thorax is mandatory to rule out BTAI in high impact chest injury. PMID- 28733570 TI - Frank's sign - A dermatological link to coronary artery disease? AB - Frank's sign, also known as diagonal earlobe crease (DELC), was observed to be an aural sign of coronary artery disease (CAD). Since then, there has been much interest in examining this unique and controversial association. This report describes a patient who has bilateral complete and deep diagonal ear lobe creases, presented with angina and diagnosed to have coronary artery disease on angiography. The characteristics of the sign and its association with atherosclerotic disease were discussed. PMID- 28733571 TI - A rare case of methicillin resistant Staphylococcus aureus (MRSA) cerebral abscess secondary to conjunctivitis. AB - This case report discusses the rare association of cerebral abscess related to conjunctivitis in an otherwise healthy child. A 6 year old boy presented with conjunctivitis was treated with topical antibiotics and resolved after a week. Conjunctival swab cultures grew MRSA. A month later he developed status epileptics and CT scans revealed a large cerebral abscess. He was treated with intravenous antibiotics which covered for MRSA, along with an incision and drainage for the cerebral abscess. Pus cultures grew MRSA. The patient recovered well with no disturbance in visual acuity or visual field. On post-operative follow ups, he had no other neurological deficit apart from a slight limp. PMID- 28733572 TI - Lower eyelid reconstruction following a traumatic full thickness loss. AB - Eyelid reconstruction is complex and challenging since it is not only for structural and functional restoration, but also for an acceptable aesthetic result. In full thickness eyelid injuries, it will involve both anterior and posterior lamella. Therefore, when reconstructing the defect, it requires at least two layers; one will be a flap with blood supply, and the other can be a free graft. In this case, a rotational advancement cheek flap and composite graft were used to reconstruct the lower eyelid. PMID- 28733573 TI - Inadvertent Introduction of Tissue Coring Into Joints During Arthrocentesis: An Experimental Study. AB - BACKGROUND The aim of this study was to investigate whether needles introduce skin plugs into joints during arthrocentesis. MATERIAL AND METHODS In the first part of this study, the arthrocentesis site was scrubbed with a fluorescein sodium swab, and 90 needles were inserted through the joint tissue and collected for examination under a fluorescence microscope. In the second part of this study, the joints were injected using 720 needles of different gauges. Two different randomly assigned needle insertion techniques were used: needle insertion straight through the joint capsule (subgroup 1) or insertion of the needle into the subcutaneous tissue followed by flushing of the needle with 0.5 mL of 0.9% normal saline prior to advancing the needle through the joint capsule (subgroup 2). RESULTS Of the 90 needle tips examined in the first part of this study, 21 had high-grade fluorescein contamination. In the second part of this study, the incidence of tissue, epidermis, and dermis contamination in subgroup 1 was 57.2%, 43.1%, and 25.0%, respectively. There was no significant difference in the incidence among different gauge needles, except for a difference in epidermis contamination between the 21-gauge and 23-gauge needles. Compared to subgroup 1, subgroup 2 had a significantly lower OR for tissue contamination. CONCLUSIONS It is common to introduce tissue coring with epidermis and dermis into the joint during arthrocentesis, which poses a potential risk for septic arthritis. However, tissue contamination of the joint may be reduced by flushing saline through the needle into the subcutaneous tissues prior to entering the joint capsule. PMID- 28733574 TI - Metabolomic characteristics of cholesterol-induced non-obese nonalcoholic fatty liver disease in mice. AB - Nonalcoholic fatty liver disease (NAFLD) in non-obese patients remains a clinical condition with unclear etiology and pathogenesis. Using a metabolomics approach in a mouse model that recapitulates almost all the characteristic features of non obese NAFLD, we aimed to advance mechanistic understanding of this disorder. Mice fed high fat, high cholesterol, cholate (HFHCC) diet for three weeks consistently developed hepatic pathology similar to NAFLD and nonalcoholic steatohepatitis (NASH) without changes to body weight or fat pad weights. Gas- and liquid chromatography/mass spectrometry-based profiling of lipidomic and primary metabolism changes in the liver and plasma revealed that systemic mechanisms leading to steatosis and hepatitis in this non-obese NAFLD model were driven by a combination of effects directed by elevated free cholesterol, cholesterol esters and cholic acid, and associated changes to metabolism of sphingomyelins and phosphatidylcholines. These results demonstrate that mechanisms underlying cholesterol-induced non-obese NAFLD are distinct from NAFLD occurring as a consequence of metabolic syndrome. In addition, this investigation provides one of the first metabolite reference profiles for interpreting effects of dietary and hepatic cholesterol in human non-obese NAFLD/NASH patients. PMID- 28733575 TI - Densimetry for the Quantification of Sorption Phenomena on Nonporous Media Near the Dew Point of Fluid Mixtures. AB - Phase equilibria of fluid mixtures are important in numerous industrial applications and are, thus, a major focus of thermophysical property research. Improved data, particularly along the dew line, are needed to improve model predictions. Here we present experimental results utilizing highly accurate densimetry to quantify the effects of sorption and capillary condensation, which exert a distorting influence on measured properties near the dew line. We investigate the (pressure, density, temperature, composition) behaviour of binary (CH4 + C3H8) and (Ar + CO2) mixtures over the temperature range from (248.15 to 273.15) K starting at low pressures and increasing in pressure towards the dew point along isotherms. Three distinct regions are observed: (1) minor sorption effects in micropores at low pressures; (2) capillary condensation followed by wetting in macro-scale surface scratches beginning approximately 2% below the dew point pressure; (3) bulk condensation. We hypothesize that the true dew point lies within the second region. PMID- 28733576 TI - MAIT cells accumulate in placental intervillous space and display a highly cytotoxic phenotype upon bacterial stimulation. AB - During pregnancy, the maternal immune system must tolerate the developing foetus, and yet retain a potent antimicrobial response to prevent infections. Mucosal associated invariant T (MAIT) cells recognize microbial-derived vitamin B metabolites presented on the MR1 molecule, but their presence and function at the foetal-maternal interface is not known. We here isolated mononuclear cells from paired samples of peripheral blood (PB), intervillous blood (IVB), and decidua parietalis (DP) following uncomplicated term pregnancies. Interestingly, MAIT cells were highly enriched in IVB compared to PB and DP. The activation status of IVB MAIT cells was similar to that of PB MAIT cells, except for a lower expression of PD-1. Both IVB MAIT cells and conventional T cells were more dominated by an effector memory phenotype compared to PB MAIT cells and T cells. IVB MAIT cells also responded more vigorously with expression of IFN-gamma, granzyme B, and perforin in response to Escherichia coli stimulation compared to PB. MR1 was not expressed in syncytiotrophoblasts, but in placental villous and decidual macrophages. These data indicate that maternal MAIT cells accumulate in the intervillous space of the placenta and that they are highly armed to quickly respond if bacteria are encountered at the foetal-maternal interface. PMID- 28733578 TI - Protecting quantum Fisher information of N-qubit GHZ state by weak measurement with flips against dissipation. AB - In this paper we propose a scheme by using weak-measurement-based pre- and post flips (WMPPF) to protect the average quantum Fisher information (QFI) in the independent amplitude-damping channel (ADC) for N-qubit GHZ state and generalized N-qubit GHZ states. We also discuss the weak measurement and quantum measurement reversal (WMQMR) with the same ADC. Based on the analytical and numerical results we obtain the main result: the WMPPF can reduce the effect of dissipation on the average QFI of the phase or the frequency for GHZ state and some generalized GHZ states, and the WMQMR can reduce the effect of dissipation on the average fidelity for GHZ state and generalized GHZ states in ADC. Comparing QFI with fidelity for WMPPF or for WMQMR, a scheme protecting the average fidelity does not necessarily protect the average QFI, even with the same parameters, and vice versa. We also focus on the average QFI versus N in the phase estimation and the frequency estimation of WMPPF, both of which show the advantages over the do nothing (DN) case. From the investigation of the QFI of weight factor, we find that increasing qubit number can protect it both for WMPPF and for DN. PMID- 28733577 TI - Skin renewal activity of non-thermal plasma through the activation of beta catenin in keratinocytes. AB - For recent years, devices that generate non-thermal plasma (NTP) have been introduced into the field of dermatology. Since NTP has demonstrated strong anti pathogenic activity with safety of use, NTP was first applied to sterilize the skin surface to aid in the healing of various kinds of skin diseases. However, the effect of NTP on skin regeneration has not yet been fully explored. In this study, the effect of NTP on the growth of keratinocytes was tested using the HaCaT human keratinocyte cell line and HRM2 hairless mice. Treatment with NTP allowed confluent keratinocytes to escape from G1 cell cycle arrest and increased the proportion of cells in S and G2 phases. In particular, NTP treatment immediately dispersed E-cadherin-mediated cell-to-cell interactions, resulting in the translocation of beta-catenin to the nucleus and leading to the enhanced transcription of target genes including c-MYC and cyclin D1. Moreover, repeated treatment of the mice with NTP also stimulated epidermal expansion by activating beta-catenin in the epidermal cells. The symptoms of cellular DNA damage were not detected after NTP treatment. Taken together, these results demonstrate that NTP may be employed as a new type of skin regenerating device. PMID- 28733579 TI - The permeability of fractured rocks in pressurised volcanic and geothermal systems. AB - The connectivity of rocks' porous structure and the presence of fractures influence the transfer of fluids in the Earth's crust. Here, we employed laboratory experiments to measure the influence of macro-fractures and effective pressure on the permeability of volcanic rocks with a wide range of initial porosities (1-41 vol. %) comprised of both vesicles and micro-cracks. We used a hand-held permeameter and hydrostatic cell to measure the permeability of intact rock cores at effective pressures up to 30 MPa; we then induced a macro-fracture to each sample using Brazilian tensile tests and measured the permeability of these macro-fractured rocks again. We show that intact rock permeability increases non-linearly with increasing porosity and decreases with increasing effective pressure due to compactional closure of micro-fractures. Imparting a macro-fracture both increases the permeability of rocks and their sensitivity to effective pressure. The magnitude of permeability increase induced by the macro fracture is more significant for dense rocks. We finally provide a general equation to estimate the permeability of intact and fractured rocks, forming a basis to constrain fluid flow in volcanic and geothermal systems. PMID- 28733580 TI - Implementing a universal gate set on a logical qubit encoded in an oscillator. AB - A logical qubit is a two-dimensional subspace of a higher dimensional system, chosen such that it is possible to detect and correct the occurrence of certain errors. Manipulation of the encoded information generally requires arbitrary and precise control over the entire system. Whether based on multiple physical qubits or larger dimensional modes such as oscillators, the individual elements in realistic devices will always have residual interactions, which must be accounted for when designing logical operations. Here we demonstrate a holistic control strategy which exploits accurate knowledge of the Hamiltonian to manipulate a coupled oscillator-transmon system. We use this approach to realize high-fidelity (98.5%, inferred), decoherence-limited operations on a logical qubit encoded in a superconducting cavity resonator using four-component cat states. Our results show the power of applying numerical techniques to control linear oscillators and pave the way for utilizing their large Hilbert space as a resource in quantum information processing.A logical qubit is a two-dimensional subspace of a higher dimensional system, whose manipulation requires precise control over the whole system. Here the authors demonstrate a control strategy which exploits precise knowledge of the Hamiltonian to manipulate a coupled oscillator-transmon system. PMID- 28733581 TI - Structural determinants at the M2 muscarinic receptor modulate the RGS4-GIRK response to pilocarpine by impairment of the receptor voltage sensitivity. AB - Membrane potential controls the response of the M2 muscarinic receptor to its ligands. Membrane hyperpolarization increases response to the full agonist acetylcholine (ACh) while decreasing response to the partial agonist pilocarpine. We previously have demonstrated that the regulator of G-protein signaling (RGS) 4 protein discriminates between the voltage-dependent responses of ACh and pilocarpine; however, the underlying mechanism remains unclear. Here we show that RGS4 is involved in the voltage-dependent behavior of the M2 muscarinic receptor mediated signaling in response to pilocarpine. Additionally we revealed structural determinants on the M2 muscarinic receptor underlying the voltage dependent response. By electrophysiological recording in Xenopus oocytes expressing M2 muscarinic receptor and G-protein-gated inwardly rectifying K+ channels, we quantified voltage-dependent desensitization of pilocarpine-induced current in the presence or absence of RGS4. Hyperpolarization-induced desensitization of the current required for RGS4, also depended on pilocarpine concentration. Mutations of charged residues in the aspartic acid-arginine tyrosine motif of the M2 muscarinic receptor, but not intracellular loop 3, significantly impaired the voltage-dependence of RGS4 function. Thus, our results demonstrated that voltage-dependence of RGS4 modulation is derived from the M2 muscarinic receptor. These results provide novel insights into how membrane potential impacts G-protein signaling by modulating GPCR communication with downstream effectors. PMID- 28733582 TI - Discontinuous boundaries of slow slip events beneath the Bungo Channel, southwest Japan. AB - The down-dip limit of the seismogenic zone and up-dip and down-dip limits of the deep low-frequency tremors in southwest Japan are clearly imaged by the hypocentre distribution. Previous studies using smooth constraints in inversion analyses estimated that long-term slow slip events (L-SSEs) beneath the Bungo Channel are distributed smoothly from the down-dip part of the seismogenic zone to the up-dip part of the tremors. Here, we use fused regularisation, a type of sparse modelling suitable for detecting discontinuous changes in the model parameters to estimate the slip distribution of L-SSEs. The largest slip abruptly becomes zero at the down-dip limit of the seismogenic zone, is immediately reduced to half at the up-dip limit of the tremors, and becomes zero near its down-dip limit. Such correspondences imply that some thresholds exist in the generation processes for both tremors and SSEs. Hence, geodetic data inversion with sparse modelling can detect such high resolution in the slip distribution. PMID- 28733583 TI - Activation of LXRalpha improves cardiac remodeling induced by pulmonary artery hypertension in rats. AB - Inflammatory factors regulated by NF-kappaB play a significant role in PAH and myocardial hypertrophy. LXR activation may inhibit myocardial hypertrophy via suppressing inflammatory pathways; it is unknown whether LXR is also involved in PAH-induced myocardial hypertrophy or remodeling. To further explore the protective effect of LXR in PAH-induced cardiac hypertrophy and remodeling, a PAH model was developed, and T0901317, an agonist of LXR, was used to examine the effect of LXR activation. PAH rats demonstrated obvious cardiac hypertrophy and remodeling in the right ventricle, but significant improvement of cardiac hypertrophy and remodeling was observed in PAH rats treated with T0901317. Through RT-PCR, Western blot and ELISA examination, NF-kappaB, IL-6, TNF-alpha, and iNOS were found to be significantly reduced in PAH rats treated with T0901317 compared to PAH rats treated with DMSO. Apoptosis was also significantly reduced in PAH rats treated with T0901317. Thus, LXR activation may inhibit PAH-induced cardiac hypertrophy and remodeling by inhibiting NF-kappaB-mediated inflammatory pathways. PMID- 28733585 TI - Robust hierarchical 3D carbon foam electrode for efficient water electrolysis. AB - Herein we report a 3D heterostructure comprising a hierarchical macroporous carbon foam that incorporates mesoporous carbon nanotubes decorated with cobalt oxide nanoparticles as an unique and highly efficient electrode material for the oxygen evolution reaction (OER) in electrocatalytic water splitting. The best performing electrode material showed high stability after 10 h, at constant potential of 1.7 V vs. RHE (reversible hydrogen electrode) in a 0.1 M KOH solution and high electrocatalytic activity in OER with low overpotential (0.38 V vs RHE at 10 mA cm-2). The excellent electrocatalytic performance of the electrode is rationalized by the overall 3D macroporous structure and with the firmly integrated CNTs directly grown on the foam, resulting in a large specific surface area, good electrical conductivity, as well as an efficient electrolyte transport into the whole electrode matrix concurrent with an ability to quickly dispose oxygen bubbles into the electrolyte. The eminent properties of the three dimensional structured carbon matrix, which can be synthesized through a simple, scalable and cost effective pyrolysis process show that it has potential to be implemented in large-scale water electrolysis systems. PMID- 28733586 TI - Study of microstructure and fracture properties of blunt notched and sharp cracked high density polyethylene specimens. AB - This paper examines the effect of a broad range of crosshead speed (0.05 to 100 mm/min) and a small range of temperature (25 degrees C and 45 degrees C) on the failure behaviour of high density polyethylene (HDPE) specimens containing a) standard size blunt notch and b) standard size blunt notch plus small sharp crack - all tested in air. It was observed that the yield stress properties showed linear increase with the natural logarithm of strain rate. The stress intensity factors under blunt notch and sharp crack conditions also increased linearly with natural logarithm of the crosshead speed. The results indicate that in the practical temperature range of 25 degrees C and 45 degrees C under normal atmosphere and increasing strain rates, HDPE specimens with both blunt notches and sharp cracks possess superior fracture properties. SEM microstructure studies of fracture surfaces showed craze initiation mechanisms at lower strain rate, whilst at higher strain rates there is evidence of dimple patterns absorbing the strain energy and creating plastic deformation. The stress intensity factor and the yield strength were higher at 25 degrees C compared to those at 45 degrees C. PMID- 28733584 TI - Therapeutic effects of sphingosine kinase inhibitor N,N-dimethylsphingosine (DMS) in experimental chronic Chagas disease cardiomyopathy. AB - Chagas disease cardiomyopathy is a parasite-driven inflammatory disease to which there are no effective treatments. Here we evaluated the therapeutic potential of N,N-dimethylsphingosine(DMS), which blocks the production of sphingosine-1 phosphate(S1P), a mediator of cellular events during inflammatory responses, in a model of chronic Chagas disease cardiomyopathy. DMS-treated, Trypanosoma cruzi infected mice had a marked reduction of cardiac inflammation, fibrosis and galectin-3 expression when compared to controls. Serum concentrations of galectin 3, IFNgamma and TNFalpha, as well as cardiac gene expression of inflammatory mediators were reduced after DMS treatment. The gene expression of M1 marker, iNOS, was decreased, while the M2 marker, arginase1, was increased. DMS-treated mice showed an improvement in exercise capacity. Moreover, DMS caused a reduction in parasite load in vivo. DMS inhibited the activation of lymphocytes, and reduced cytokines and NO production in activated macrophage cultures in vitro, while increasing IL-1beta production. Analysis by qRT-PCR array showed that DMS treatment modulated inflammasome activation induced by T. cruzi on macrophages. Altogether, our results demonstrate that DMS, through anti-parasitic and immunomodulatory actions, can be beneficial in the treatment of chronic phase of T. cruzi infection and suggest that S1P-activated processes as possible therapeutic targets for the treatment of Chagas disease cardiomyopathy. PMID- 28733587 TI - Identification and analysis of mtDNA genomes attributed to Finns reveal long stagnant demographic trends obscured in the total diversity. AB - In Europe, modern mitochondrial diversity is relatively homogeneous and suggests an ubiquitous rapid population growth since the Neolithic revolution. Similar patterns also have been observed in mitochondrial control region data in Finland, which contrasts with the distinctive autosomal and Y-chromosomal diversity among Finns. A different picture emerges from the 843 whole mitochondrial genomes from modern Finns analyzed here. Up to one third of the subhaplogroups can be considered as Finn-characteristic, i.e. rather common in Finland but virtually absent or rare elsewhere in Europe. Bayesian phylogenetic analyses suggest that most of these attributed Finnish lineages date back to around 3,000-5,000 years, coinciding with the arrival of Corded Ware culture and agriculture into Finland. Bayesian estimation of past effective population sizes reveals two differing demographic histories: 1) the 'local' Finnish mtDNA haplotypes yielding small and dwindling size estimates for most of the past; and 2) the 'immigrant' haplotypes showing growth typical of most European populations. The results based on the local diversity are more in line with that known about Finns from other studies, e.g., Y-chromosome analyses and archaeology findings. The mitochondrial gene pool thus may contain signals of local population history that cannot be readily deduced from the total diversity. PMID- 28733588 TI - Neurogenesis from Sox2 expressing cells in the adult cerebellar cortex. AB - We identified a rare undifferentiated cell population that is intermingled with the Bergmann glia of the adult murine cerebellar cortex, expresses the stem cell markers Sox2 and Nestin, and lacks markers of glial or neuronal differentiation. Interestingly, such Sox2+ S100- cells of the adult cerebellum expanded after adequate physiological stimuli in mice (exercise), and Sox2+ precursors acquired positivity for the neuronal marker NeuN over time and integrated into cellular networks. In human patients, SOX2+ S100- cells similarly increased in number after relevant pathological insults (infarcts), suggesting a similar expansion of cells that lack terminal glial differentiation. PMID- 28733589 TI - Physiological dynamics of stress contagion. AB - Can viewing others experiencing stress create a "contagious" physiological stress response in the observer? To investigate second-hand stress, we first created a stimulus set of videos, which featured participants speaking under either minimal stress, high stress, or while recovering from stress. We then recruited a second set of participants to watch these videos. All participants (speakers and observers) were monitored via electrocardiogram. Cardiac activity of the observers while watching the videos was then analyzed and compared to that of the speakers. Furthermore, we assessed dispositional levels of empathy in observers to determine how empathy might be related to the degree of stress contagion. Results revealed that depending on the video being viewed, observers experienced differential changes in cardiac activity that were based on the speaker's stress level. Additionally, this is the first demonstration that individuals high in dispositional empathy experience these physiological changes more quickly. PMID- 28733590 TI - Hypersaline sapropels act as hotspots for microbial dark matter. AB - Present-day terrestrial analogue sites are crucial ground truth proxies for studying life in geochemical conditions close to those assumed to be present on early Earth or inferred to exist on other celestial bodies (e.g. Mars, Europa). Although hypersaline sapropels are border-of-life habitats with moderate occurrence, their microbiological and physicochemical characterization lags behind. Here, we study the diversity of life under low water activity by describing the prokaryotic communities from two disparate hypersaline sapropels (Transylvanian Basin, Romania) in relation to geochemical milieu and pore water chemistry, while inferring their role in carbon cycling by matching taxa to known taxon-specific biogeochemical functions. The polyphasic approach combined deep coverage SSU rRNA gene amplicon sequencing and bioinformatics with RT-qPCR and physicochemical investigations. We found that sapropels developed an analogous elemental milieu and harbored prokaryotes affiliated with fifty-nine phyla, among which the most abundant were Proteobacteria, Bacteroidetes and Chloroflexi. Containing thirty-two candidate divisions and possibly undocumented prokaryotic lineages, the hypersaline sapropels were found to accommodate one of the most diverse and novel ecosystems reported to date and may contribute to completing the phylogenetic branching of the tree of life. PMID- 28733591 TI - Predictive and tempo-flexible synchronization to a visual metronome in monkeys. AB - Predictive and tempo-flexible synchronization to an auditory beat is a fundamental component of human music. To date, only certain vocal learning species show this behaviour spontaneously. Prior research training macaques (vocal non-learners) to tap to an auditory or visual metronome found their movements to be largely reactive, not predictive. Does this reflect the lack of capacity for predictive synchronization in monkeys, or lack of motivation to exhibit this behaviour? To discriminate these possibilities, we trained monkeys to make synchronized eye movements to a visual metronome. We found that monkeys could generate predictive saccades synchronized to periodic visual stimuli when an immediate reward was given for every predictive movement. This behaviour generalized to novel tempi, and the monkeys could maintain the tempo internally. Furthermore, monkeys could flexibly switch from predictive to reactive saccades when a reward was given for each reactive response. In contrast, when humans were asked to make a sequence of reactive saccades to a visual metronome, they often unintentionally generated predictive movements. These results suggest that even vocal non-learners may have the capacity for predictive and tempo-flexible synchronization to a beat, but that only certain vocal learning species are intrinsically motivated to do it. PMID- 28733592 TI - Machine Learning Model Analysis of Breeding Habitats for the Black-necked Crane in Central Asian Uplands under Anthropogenic Pressures. AB - The black-necked crane (Grus nigricollis) is the only alpine crane species and is endemic to the Tibetan Plateau. The breeding habitats of this species are poorly understood, which greatly hampers practical research and conservation work. Using machine learning methods and the best-available data from our 7,000-kilometer mega-transect survey and open access data, we built the first species distribution model (SDM) to analyze the black-necked crane's breeding habitats. Our model showed that current conservation gaps account for 26.7% of its predicted breeding habitats. Specifically, the northern parts of the Hengduan Mountains and the southeastern Tibet Valley, the northern side of the middle Kunlun Mountains, parts of the Pamir Plateau, the northern Pakistan Highlands and the western Hindu Kush should be considered as its main potential breeding areas. Additionally, our model suggested that the crane prefers to breed in alpine meadows at an elevation over 2,800 m, a maximum temperature of the warmest month below 20.5 degrees C, and a temperature seasonality above 7,800 units. The identified conservation gaps and potential breeding areas can aid in clearly prioritizing future conservation and research, but more attention and study should be directed to the unassessed Western Development of China to secure this endangered crane lineage and other wildlife on the Tibetan Plateau. PMID- 28733593 TI - Fasciclin-like arabinogalactan proteins, PtFLAs, play important roles in GA mediated tension wood formation in Populus. AB - In Populus, the transcripts of fasciclin-like arabinogalactan proteins (FLAs) are accumulated in tension wood (TW) xylem, however their biological functions in TW formation are largely unknown. In this work, we demonstrated that PtFLA6, one of poplar TW-associated PtFLAs, was abundantly expressed in TW, and mainly localized in differentiating G-fibers. The bended stems of PtFLA6 antisense transgenic poplar showed decreased transcripts of PtFLAs, including PtFLA6, and reduced PtFLA6 like proteins, leading to inhibited TW differentiation and formation. We also showed that gibberellin A3 (GA3) was enriched in the xylem of TW side, accompanied with a lowered level of PtRGA1, a poplar DELLA protein. When GA3 biosynthesis was restrained in the bended poplar stems by a GA biosynthesis inhibitor (daminozide), TW formation was obviously repressed, as a result of restricted PtRGA1 degradation, and reduced PtFLA6 like proteins and PtFLA expression. Further studies indicated that PtFLAs were negatively regulated by PtRGA1. This study suggests that PtFLAs play important roles in the poplar TW formation, possibly regulated by GA signaling. PMID- 28733595 TI - How cholesteryl ester transfer protein can also be a potential triglyceride transporter. AB - CETP transfers cholesteryl esters (CEs) and triglycerides (TGs) between different lipoproteins and came in limelight as a drug-target against CVD. In the search for detailed mechanism of lipid transfer through CETP, enormous effort is devoted employing crystallographic, cryo-EM, and Molecular Dynamics (MD) studies. However, these studies primarily focused on CE-bound CETP structure and CE transfer mechanism. With the reported correlation that CETP looses significant CE transfer activity upon inhibiting TG transfer, it is of tremendous importance to understand the structure and dynamics of TG-bound CETP. Our results from large scale all-atom and coarse-grained MD simulations show that CETP can accommodate two TG molecules in parallel N-N orientation with TG oleate chains majorly attaining the tuning-fork conformation. In TG-bound form, CETP not only maintained its secondary structures but also exhibited similar bending-twisting motions as reported for CE-CETP crystal structure. Obtained structural information are further validated by correlating to available functional data of 2-8 fold slower transfer rate of TG through CETP, where we show that TGs make 20% additional contacts with CETP compared to CEs. Identified CETP residues facilitating TG binding also match very well with reported mutagenesis data. The study could accelerate the drug-designing processes to combat CETP functionality and CVD. PMID- 28733594 TI - CD56 Is a Pathogen Recognition Receptor on Human Natural Killer Cells. AB - Aspergillus (A.) fumigatus is an opportunistic fungal mold inducing invasive aspergillosis (IA) in immunocompromised patients. Although antifungal activity of human natural killer (NK) cells was shown in previous studies, the underlying cellular mechanisms and pathogen recognition receptors (PRRs) are still unknown. Using flow cytometry we were able to show that the fluorescence positivity of the surface receptor CD56 significantly decreased upon fungal contact. To visualize the interaction site of NK cells and A. fumigatus we used SEM, CLSM and dSTORM techniques, which clearly demonstrated that NK cells directly interact with A. fumigatus via CD56 and that CD56 is re-organized and accumulated at this interaction site time-dependently. The inhibition of the cytoskeleton showed that the receptor re-organization was an active process dependent on actin re arrangements. Furthermore, we could show that CD56 plays a role in the fungus mediated NK cell activation, since blocking of CD56 surface receptor reduced fungal mediated NK cell activation and reduced cytokine secretion. These results confirmed the direct interaction of NK cells and A. fumigatus, leading to the conclusion that CD56 is a pathogen recognition receptor. These findings give new insights into the functional role of CD56 in the pathogen recognition during the innate immune response. PMID- 28733596 TI - Lateral-drag propulsion forces induced by anisotropy. AB - We predict the existence of lateral drag forces near the flat surface of an absorbing slab made of an anisotropic material. The forces originate from the fluctuations of the electromagnetic field, when the anisotropy axis of the material forms a certain angle with the surface. In this situation, the spatial spectra of the fluctuating electromagnetic fields becomes asymmetric, different for positive and negative transverse wave vectors components. Differently from the case of van der Waals interactions in which the forward-backward symmetry is broken due to the particle movement, in our case the lateral motion results merely from the anisotropy of the slab. This new effect, of particular significance in hyperbolic materials, could be used for the manipulation of nanoparticles. PMID- 28733597 TI - Design of new Mott multiferroics via complete charge transfer: promising candidates for bulk photovoltaics. AB - Optimal materials to induce bulk photovoltaic effects should lack inversion symmetry and have an optical gap matching the energies of visible radiation. Ferroelectric perovskite oxides such as BaTiO3 and PbTiO3 exhibit substantial polarization and stability, but have the disadvantage of excessively large band gaps. We use both density functional theory and dynamical mean field theory calculations to design a new class of Mott multiferroics-double perovskite oxides A 2VFeO6 (A = Ba, Pb, etc). While neither perovskite AVO3 nor AFeO3 is ferroelectric, in the double perovskite A 2VFeO6 a 'complete' charge transfer from V to Fe leads to a non-bulk-like charge configuration-an empty V-d shell and a half-filled Fe-d shell, giving rise to a polarization comparable to that of ferroelectric ATiO3. Different from nonmagnetic ATiO3, the new double perovskite oxides have an antiferromagnetic ground state and around room temperatures, are paramagnetic Mott insulators. Most importantly, the V d 0 state significantly reduces the band gap of A 2VFeO6, making it smaller than that of ATiO3 and BiFeO3 and rendering the new multiferroics a promising candidate to induce bulk photovoltaic effects. PMID- 28733598 TI - Role of HDAC9-FoxO1 Axis in the Transcriptional Program Associated with Hepatic Gluconeogenesis. AB - Histone deacetylase 9 (HDAC9) regulates hepatic gluconeogenesis by deacetylating Forkhead box O 1 (FoxO1). HDAC9 upregulation is involved in hepatitis C virus (HCV)-associated exaggerated gluconeogenesis. Herein, we found in addition to FoxO1, HDAC9 also regulates other gluconeogenic transcription factors, including peroxisomeproliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha), cyclic AMP-responsive element-binding protein (CREB), and glucocorticoid receptor (GR). Unlike FoxO1, which is regulated by post-translational modification responses to HDAC9, HDAC9 regulates PGC-1alpha, CREB and GR by altering gene expression. Similar to PGC-1alpha, CREB and GR were found to be novel regulatory targets of FoxO1 by examination of the FoxO1 binding site in their promoter. PGC 1alpha, CREB and GR were upregulated in response to HDAC9 via FoxO1 deacetylation. These findings indicate that HDAC9-FoxO1 signalling contributes to gluconeogenesis by modulating the expression of gluconeogenic transcription factors. In particular, metabolic profiling demonstrated a clear shift towards gluconeogenesis metabolism, and HDAC9-FoxO1 signalling can be strongly induced to upregulate gluconeogenic transcription factors following HCV infection. The positive correlation between HDAC9 and gluconeogenic transcription factor expression levels in the livers of both HCV-infected patients and normal individuals further emphasizes the clinical relevance of these results. Thus, HDAC9-FoxO1 signalling axis is involved in regulating gluconeogenic transcription factors, gluconeogenesis, and HCV-induced type 2 diabetes. PMID- 28733599 TI - Nanoscale Investigation of Generation 1 PAMAM Dendrimers Interaction with a Protein Nanopore. AB - Herein, we describe at uni-molecular level the interactions between poly(amidoamine) (PAMAM) dendrimers of generation 1 and the alpha-hemolysin protein nanopore, at acidic and neutral pH, and ionic strengths of 0.5 M and 1 M KCl, via single-molecule electrical recordings. The results indicate that kinetics of dendrimer-alpha-hemolysin reversible interactions is faster at neutral as compared to acidic pH, and we propose as a putative explanation the fine interplay among conformational and rigidity changes on the dendrimer structure, and the ionization state of the dendrimer and the alpha-hemolysin. From the analysis of the dendrimer's residence time inside the nanopore, we posit that the pH- and salt-dependent, long-range electrostatic interactions experienced by the dendrimer inside the ion-selective alpha-hemolysin, induce a non-Stokesian diffusive behavior of the analyte inside the nanopore. We also show that the ability of dendrimer molecules to adapt their structure to nanoscopic spaces, and control the flow of matter through the alpha-hemolysin nanopore, depends non-trivially on the pH- and salt-induced conformational changes of the dendrimer. PMID- 28733600 TI - beta-Ginkgotides: Hyperdisulfide-constrained peptides from Ginkgo biloba. AB - Hyperdisulfide-constrained peptides are distinguished by their high stability and diverse functions. Thus far, these peptides have been reported from animals only but their occurrence in plants are rare. Here, we report the discovery, synthesis and characterization of a hyperdisulfide-constrained peptides family of approximately 2 kDa, beta-ginkgotides (beta-gB1 and beta-gB2) from Ginkgo biloba. Proteomic analysis showed beta-ginkgotides contain 18-20 amino acids, of which 16 residues form a conserved six-cysteine core with a highly clustered cysteine spacing of C-CC-C-CC, an arrangement that has not been reported in cysteine-rich peptides. Disulfide mapping revealed a novel disulfide connectivity of CysI-IV, CysII-VI and CysIII-V. Oxidative folding of synthetic beta-gB1 to the native form was obtained in 70% yield. The synthetic beta-gB1 displays a compact structure with no regular secondary structural elements, as determined by NMR spectroscopy. Transcriptomic analysis showed precursor betagb1 has a four-domain architecture and revealed an additional 76 beta-ginkgotide-like peptides in 59 different gymnosperms, but none in angiosperms. Phylogenetic clustering analysis demonstrated beta-ginkgotides belong to a new cysteine-rich peptide family. beta Ginkgotide is resistant to thermal, chemical and proteolytic degradation. Together, beta-ginkgotides represent the first-in-class hyperdisulfide constrained peptide family from plants with a novel scaffold that could be useful for engineering metabolically stable peptidyl therapeutics. PMID- 28733601 TI - Anti-tubercular Activity of Pyrazinamide is Independent of trans-Translation and RpsA. AB - Pyrazinamide (PZA) is a first line anti-tubercular drug for which the mechanism of action remains unresolved. Recently, it was proposed that the active form of PZA, pyrazinoic acid (POA), disrupts the ribosome rescue process of trans translation in Mycobacterium tuberculosis. This model suggested that POA binds within the carboxy-terminal domain of ribosomal protein S1 (RpsA) and inhibits trans-translation leading to accumulation of stalled ribosomes. Here, we demonstrate that M. tuberculosis RpsA interacts with single stranded RNA, but not with POA. Further, we show that an rpsA polymorphism previously identified in a PZA resistant strain does not confer PZA resistance when reconstructed in a laboratory strain. Finally, by utilizing an in vitro trans-translation assay with purified M. tuberculosis ribosomes we find that an interfering oligonucleotide can inhibit trans-translation, yet POA does not inhibit trans-translation. Based on these findings, we conclude that the action of PZA is entirely independent of RpsA and trans-translation in M. tuberculosis. PMID- 28733603 TI - Sediment transport drives tidewater glacier periodicity. AB - Most of Earth's glaciers are retreating, but some tidewater glaciers are advancing despite increasing temperatures and contrary to their neighbors. This can be explained by the coupling of ice and sediment dynamics: a shoal forms at the glacier terminus, reducing ice discharge and causing advance towards an unstable configuration followed by abrupt retreat, in a process known as the tidewater glacier cycle. Here we use a numerical model calibrated with observations to show that interactions between ice flow, glacial erosion, and sediment transport drive these cycles, which occur independent of climate variations. Water availability controls cycle period and amplitude, and enhanced melt from future warming could trigger advance even in glaciers that are steady or retreating, complicating interpretations of glacier response to climate change. The resulting shifts in sediment and meltwater delivery from changes in glacier configuration may impact interpretations of marine sediments, fjord geochemistry, and marine ecosystems.The reason some of the Earth's tidewater glaciers are advancing despite increasing temperatures is not entirely clear. Here, using a numerical model that simulates both ice and sediment dynamics, the authors show that internal dynamics drive glacier variability independent of climate. PMID- 28733602 TI - Distinct selective forces and Neanderthal introgression shaped genetic diversity at genes involved in neurodevelopmental disorders. AB - In addition to high intelligence, humans evolved specialized social-cognitive skills, which are specifically affected in children with autism spectrum disorder (ASD). Genes affected in ASD represent suitable candidates to study the evolution of human social cognition. We performed an evolutionary analysis on 68 genes associated to neurodevelopmental disorders; our data indicate that genetic diversity was shaped by distinct selective forces, including natural selection and introgression from archaic hominins. We discuss the possibility that segregation distortion during spermatogenesis accounts for a subset of ASD mutations. Finally, we detected modern-human-specific alleles in DYRK1A and TCF4. These variants are located within regions that display chromatin features typical of transcriptional enhancers in several brain areas, strongly suggesting a regulatory role. These SNPs thus represent candidates for association with neurodevelopmental disorders, and await experimental validation in future studies. PMID- 28733604 TI - The N-terminal dimerization is required for TDP-43 splicing activity. AB - TDP-43 is a nuclear factor that functions in promoting pre-mRNA splicing. Deletion of the N-terminal domain (NTD) and nuclear localization signal (NLS) (i.e., TDP-35) results in mislocalization to cytoplasm and formation of inclusions. However, how the NTD functions in TDP-43 activity and proteinopathy remains largely unknown. Here, we studied the structure and function of the NTD in inclusion formation and pre-mRNA splicing of TDP-43 by using biochemical and biophysical approaches. We found that TDP-43 NTD forms a homodimer in solution in a concentration-dependent manner, and formation of intermolecular disulfide results in further tetramerization. Based on the NMR structure of TDP-43 NTD, the dimerization interface centered on Leu71 and Val72 around the beta7-strand was defined by mutagenesis and size-exclusion chromatography. Cell experiments revealed that the N-terminal dimerization plays roles in protecting TDP-43 against formation of cytoplasmic inclusions and enhancing pre-mRNA splicing activity of TDP-43 in nucleus. This study may provide mechanistic insights into the physiological function of TDP-43 and its related proteinopathies. PMID- 28733605 TI - GeneXpert MTB/RIF assay in the diagnosis of urinary tuberculosis from urine specimens. AB - Conventional bacteriological methods are not generally helpful in diagnosing urinary tuberculosis (UTB). GeneXpert is endorsed for the detection of pulmonary tuberculosis, whereas the data on its utility for urine specimens is limited. In this study, we aimed to evaluate its performance on urine specimens in a country with high TB incidence. A total of 163 suspected UTB patients were consecutively enrolled in the analysis, including 37 (22.7%) culture-positive and 44 (27.0%) clinically diagnosed UTB cases. Compared with conventional culture, the sensitivity of GeneXpert (94.6%) was significantly higher than that of smear microscopy (40.5%, P < 0.001). When setting clinical diagnosis as gold standard, 51 out of 81 clinically diagnosed UTB cases were detected by GeneXpert, demonstrating a sensitivity of 63.0%, which was significantly higher than that of smear microscopy (18.5%, P < 0.001) and culture (45.7%, P = 0.027), respectively. In addition, the proportion of UTB cases in the migrant population was significantly higher than that in the resident population (P = 0.019). To conclude, our data demonstrate that GeneXpert outperforms AFB smear and culture for the detection of MTB in urine samples, which provides an alternative for the diagnosis of UTB. The migrant population and previously diagnosed TB cases are high risk factors for developing UTB cases. PMID- 28733606 TI - Critical behavior of the van der Waals bonded high T C ferromagnet Fe3GeTe2. AB - Fe3GeTe2 is a promising candidate for van der Waals bonded ferromagnet because of its high Curie temperature and the prediction that its ferromagnetism can maintain upon exfoliating down to single layer. Here, we have reported the critical behavior to understand its ferromagnetic exchange. Based on various techniques including modified Arrott plot, Kouvel-Fisher plot, and critical isotherm analysis, a set of reliable critical exponents (beta = 0.327 +/- 0.003, gamma = 1.079 +/- 0.005, and delta = 4.261 +/- 0.009) has been obtained. The critical behavior suggests a three-dimensional long-range magnetic coupling with the exchange distance decaying as J(r) ~ r -4.6 in Fe3GeTe2. The possible origin of three-dimensional magnetic characteristics in van der Waals bonded magnets is discussed. PMID- 28733607 TI - Two-Year Follow-Up of Vascular Events in Peripheral Arterial Disease Treated With Antiplatelet Agents: A Prospective Observational Multicenter Cohort Study (SEASON). AB - The present analysis was intended to evaluate the real-world management of peripheral arterial disease (PAD) in Asia, and to explore cardiovascular events in patients with PAD undergoing antiplatelet therapy over 2 years of follow-up. The Surveillance of cardiovascular Events in Antiplatelet-treated arteriosclerosis Obliterans patients in JapaN (SEASON) registry is a prospective observational multicenter study of cardiovascular events in antiplatelet-treated patients with PAD in Japan. The SEASON registry included 11,375 patients who were scheduled to receive treatment for PAD. Two analysis populations were defined: a real-world population (RWP; n = 10,322) and a definite PAD population (DPP; n = 3992) who had ankle-brachial pressure index (ABPI) <0.9 and intermittent claudication, or a history of lower limb revascularization. The primary outcome measure was the rate of the composite of cerebrovascular, cardiovascular, and peripheral vascular events. The composite event rates (95% confidence interval) were 3.28 (3.00-3.57) and 5.71 (5.13-6.34) events per 100 patient-years in the RWP and DPP groups, respectively. Fontaine IV classification and ABPI <0.4 at baseline were both identified as strong risk factors for vascular events. These findings contribute to understanding the situation for real-world patients with PAD receiving antiplatelet therapy. PMID- 28733608 TI - Revealing higher than expected meiofaunal diversity in Antarctic sediments: a metabarcoding approach. AB - An increasing number of studies are showing that Antarctic mega- and macrofauna are highly diverse, however, little is known about meiofaunal biodiversity in sediment communities, which are a vital part of a healthy and functional ecosystem. This is the first study to analyse community DNA (targeting meiofauna) using metabarcoding to investigate biodiversity levels in sediment communities of the Antarctic Peninsula. The results show that almost all of the meiofaunal biodiversity in the benthic habitat has yet to be characterised, levels of biodiversity were higher than expected and similar to temperate regions, albeit with the existence of potentially new and locally adapted species never described before at the molecular level. The Rothera meiofaunal sample sites showed four dominant eukaryotic groups, the nematodes, arthropods, platyhelminthes, and the annelids; some of which could comprise species complexes. Comparisons with deep sea data from the same region suggest little exchange of Operational Taxonomic Units (OTUs) between depths with the nematodes prevalent at all depths, but sharing the shallow water benthos with the copepods. This study provides a preliminary analysis of benthic Antarctic Peninsula meiofauna using high throughput sequencing which substantiates how little is known on the biodiversity of one of the most diverse, yet underexplored communities of the Antarctic: the benthos. PMID- 28733609 TI - Suppression of HBV replication by the expression of nickase- and nuclease dead Cas9. AB - Complete removal of hepatitis B virus (HBV) DNA from nuclei is difficult by the current therapies. Recent reports have shown that a novel genome-editing tool using Cas9 with a single-guide RNA (sgRNA) system can cleave the HBV genome in vitro and in vivo. However, induction of a double-strand break (DSB) on the targeted genome by Cas9 risks undesirable off-target cleavage on the host genome. Nickase-Cas9 cleaves a single strand of DNA, and thereby two sgRNAs are required for inducing DSBs. To avoid Cas9-induced off-target mutagenesis, we examined the effects of the expressions of nickase-Cas9 and nuclease dead Cas9 (d-Cas9) with sgRNAs on HBV replication. The expression of nickase-Cas9 with a pair of sgRNAs cleaved the target HBV genome and suppressed the viral-protein expression and HBV replication in vitro. Moreover, nickase-Cas9 with the sgRNA pair cleaved the targeted HBV genome in mouse liver. Interestingly, d-Cas9 expression with the sgRNAs also suppressed HBV replication in vitro without cleaving the HBV genome. These results suggest the possible use of nickase-Cas9 and d-Cas9 with a pair of sgRNAs for eliminating HBV DNA from the livers of chronic hepatitis B patients with low risk of undesirable off-target mutation on the host genome. PMID- 28733610 TI - Environmental impact of omnivorous, ovo-lacto-vegetarian, and vegan diet. AB - Food and beverage consumption has a great impact on the environment, although there is a lack of information concerning the whole diet. The environmental impact of 153 Italian adults (51 omnivores, 51 ovo-lacto-vegetarians, 51 vegans) and the inter-individual variability within dietary groups were assessed in a real-life context. Food intake was monitored with a 7-d dietary record to calculate nutritional values and environmental impacts (carbon, water, and ecological footprints). The Italian Mediterranean Index was used to evaluate the nutritional quality of each diet. The omnivorous choice generated worse carbon, water and ecological footprints than other diets. No differences were found for the environmental impacts of ovo-lacto-vegetarians and vegans, which also had diets more adherent to the Mediterranean pattern. A high inter-individual variability was observed through principal component analysis, showing that some vegetarians and vegans have higher environmental impacts than those of some omnivores. Thus, regardless of the environmental benefits of plant-based diets, there is a need for thinking in terms of individual dietary habits. To our knowledge, this is the first time environmental impacts of three dietary regimens are evaluated using individual recorded dietary intakes rather than hypothetical diet or diets averaged over a population. PMID- 28733612 TI - Photoluminescence associated with the site occupations of Ho3+ ions in BaTiO3. AB - A nominal (Ba1-x Ho x )Ti1-x/4O3 (x = 0.01) (BHTH) ceramic with a single-phase tetragonal structure was prepared at 1400 degrees C using the solid-state reaction method. The analysis on the defect chemistry revealed that the real formula of BHTH is (Ba1-x Ho3x/4)(Ti1-x/4Ho x/4)O3 with Ba vacancies via electron paramagnetic resonance (EPR). Photoluminescence (PL) was investigated on the basis of excitation with different wavelength lasers. The results indicated that under 488-nm excitation, PL and Raman scattering can occur simultaneously as two distinct optical processes for BHTH ceramic powders, and the strongest PL band at 564 nm was discovered and verified to originate from the 5G6/5F1 -> 5I7 transition of Ho3+ ions on the Ti sites in the BaTiO3 lattice. Upon 532- and 638 nm excitations, three PL bands of 5F4/5S2 -> 5I8, 5F5 -> 5I8, and 5F4/5S2 -> 5I7 transitions are attributed to the contributions from Ho3+ ions on the Ba sites. The common Raman spectrum of BaTiO3 can be observed without PL disturbance using 785-nm excitation wavelength. The PL effect may provide a probe for the site occupations of Ho3+ ions in widely-used BaTiO3 dielectric ceramics co-doped with Ho3+ and other dopants. PMID- 28733611 TI - Integrin alpha6beta4 Upregulates Amphiregulin and Epiregulin through Base Excision Repair-Mediated DNA Demethylation and Promotes Genome-wide DNA Hypomethylation. AB - Aberrant DNA methylation patterns are a common theme across all cancer types. Specific DNA demethylation of regulatory sequences can result in upregulation of genes that are critical for tumor development and progression. Integrin alpha6beta4 is highly expressed in pancreatic carcinoma and contributes to cancer progression, in part, through the specific DNA demethylation and upregulation of epidermal growth factor receptor (EGFR) ligands amphiregulin (AREG) and epiregulin (EREG). Whole genome bisulfite sequencing (WGBS) revealed that integrin alpha6beta4 signaling promotes an overall hypomethylated state and site specific DNA demethylation of enhancer elements within the proximal promoters of AREG and EREG. Additionally, we find that the base excision repair (BER) pathway is required to maintain expression of AREG and EREG, as blocking DNA repair molecules, TET1 GADD45A, TDG, or PARP-1 decreased gene expression. Likewise, we provide the novel finding that integrin alpha6beta4 confers an enhanced ability on cells to repair DNA lesions and survive insult. Therefore, while many known signaling functions mediated by integrin alpha6beta4 that promote invasive properties have been established, this study demonstrates that integrin alpha6beta4 can dramatically impact the epigenome of cancer cells, direct global DNA methylation levels toward a hypomethylated state, and impact DNA repair and subsequent cell survival. PMID- 28733613 TI - RNAi screening identifies Trypanosoma brucei stress response protein kinases required for survival in the mouse. AB - Protein kinases (PKs) are a class of druggable targets in Trypanosoma brucei, the causative agent of Human African Trypanosomiasis (sleeping sickness), yet little is known about which PKs are essential for survival in mammals. A recent kinome wide RNAi screen with 176 individual bloodstream form Trypanosoma brucei lines identified PKs required for proliferation in culture. In order to assess which PKs are also potential virulence factors essential in vivo, lines were pooled, inoculated into mice, and screened for loss of fitness after 48 h RNAi. The presence of trypanosomes in the bloodstream was assessed using RNAi target sequencing (RITseq) and compared to growth in culture. We identified 49 PKs with a significant loss of fitness in vivo in two independent experiments, and a strong correlation between in vitro and in vivo loss of fitness for the majority. Nine PKs had a more pronounced growth defect in vivo, than in vitro. Amongst these PKs were several with putative functions related to stress responses mediated through the PI3K/TOR or MAPK signaling cascades, which act to protect the parasite from complement-mediated and osmotic lysis. Identification of these virulence-associated PKs provides new insights into T. brucei-host interaction and reveals novel potential protein kinase drug targets. PMID- 28733614 TI - Raman evidence for pressure-induced formation of diamondene. AB - Despite the advanced stage of diamond thin-film technology, with applications ranging from superconductivity to biosensing, the realization of a stable and atomically thick two-dimensional diamond material, named here as diamondene, is still forthcoming. Adding to the outstanding properties of its bulk and thin-film counterparts, diamondene is predicted to be a ferromagnetic semiconductor with spin polarized bands. Here, we provide spectroscopic evidence for the formation of diamondene by performing Raman spectroscopy of double-layer graphene under high pressure. The results are explained in terms of a breakdown in the Kohn anomaly associated with the finite size of the remaining graphene sites surrounded by the diamondene matrix. Ab initio calculations and molecular dynamics simulations are employed to clarify the mechanism of diamondene formation, which requires two or more layers of graphene subjected to high pressures in the presence of specific chemical groups such as hydroxyl groups or hydrogens.The synthesis of two-dimensional diamond is the ultimate goal of diamond thin-film technology. Here, the authors perform Raman spectroscopy of bilayer graphene under pressure, and obtain spectroscopic evidence of formation of diamondene, an atomically thin form of diamond. PMID- 28733616 TI - Capturing 3D Water Flow in Rooted Soil by Ultra-fast Neutron Tomography. AB - Water infiltration in soil is not only affected by the inherent heterogeneities of soil, but even more by the interaction with plant roots and their water uptake. Neutron tomography is a unique non-invasive 3D tool to visualize plant root systems together with the soil water distribution in situ. So far, acquisition times in the range of hours have been the major limitation for imaging 3D water dynamics. Implementing an alternative acquisition procedure we boosted the speed of acquisition capturing an entire tomogram within 10 s. This allows, for the first time, tracking of a water front ascending in a rooted soil column upon infiltration of deuterated water time-resolved in 3D. Image quality and resolution could be sustained to a level allowing for capturing the root system in high detail. Good signal-to-noise ratio and contrast were the key to visualize dynamic changes in water content and to localize the root uptake. We demonstrated the ability of ultra-fast tomography to quantitatively image quick changes of water content in the rhizosphere and outlined the value of such imaging data for 3D water uptake modelling. The presented method paves the way for time-resolved studies of various 3D flow and transport phenomena in porous systems. PMID- 28733615 TI - Impact of Natural Blind Spot Location on Perimetry. AB - We study the spatial distribution of natural blind spot location (NBSL) and its impact on perimetry. Pattern deviation (PD) values of 11,449 reliable visual fields (VFs) that are defined as clinically unaffected based on summary indices were extracted from 11,449 glaucoma patients. We modeled NBSL distribution using a two-dimensional non-linear regression approach and correlated NBSL with spherical equivalent (SE). Additionally, we compared PD values of groups with longer and shorter distances than median, and larger and smaller angles than median between NBSL and fixation. Mean and standard deviation of horizontal and vertical NBSL were 14.33 degrees +/- 1.37 degrees and -2.06 degrees +/- 1.27 degrees , respectively. SE decreased with increasing NBSL (correlation: r = 0.14, p < 0.001). For NBSL distances longer than median distance (14.32 degrees ), average PD values decreased in the upper central (average difference for significant points (ADSP): -0.18 dB) and increased in the lower nasal VF region (ADSP: 0.14 dB). For angles in the direction of upper hemifield relative to the median angle (-8.13 degrees ), PD values decreased in lower nasal (ADSP: -0.11 dB) and increased in upper temporal VF areas (ADSP: 0.19 dB). In conclusion, we demonstrate that NBSL has a systematic effect on the spatial distribution of VF sensitivity. PMID- 28733617 TI - Partitioning Evapotranspiration into Green and Blue Water Sources in the Conterminous United States. AB - In this study, we combined two 1 km actual evapotranspiration datasets (ET), one obtained from a root zone water balance model and another from an energy balance model, to partition annual ET into green (rainfall-based) and blue (surface water/groundwater) sources. Time series maps of green water ET (GWET) and blue water ET (BWET) are produced for the conterminous United States (CONUS) over 2001 2015. Our results indicate that average green and blue water for all land cover types in CONUS accounts for nearly 70% and 30% of the total ET, respectively. The ET in the eastern US arises mostly from GWET, and in the western US, it is mostly BWET. Analysis of the BWET in the 16 irrigated areas in CONUS revealed interesting results. While the magnitude of the BWET gradually showed a decline from west to east, the increase in coefficient of variation from west to east confirmed greater use of supplemental irrigation in the central and eastern US. We also established relationships between different hydro-climatology zones and their blue water requirements. This study provides insights on the relative contributions and the spatiotemporal dynamics of GWET and BWET, which could lead to improved water resources management. PMID- 28733618 TI - Cellular interfaces with hydrogen-bonded organic semiconductor hierarchical nanocrystals. AB - Successful formation of electronic interfaces between living cells and semiconductors hinges on being able to obtain an extremely close and high surface area contact, which preserves both cell viability and semiconductor performance. To accomplish this, we introduce organic semiconductor assemblies consisting of a hierarchical arrangement of nanocrystals. These are synthesised via a colloidal chemical route that transforms the nontoxic commercial pigment quinacridone into various biomimetic three-dimensional arrangements of nanocrystals. Through a tuning of parameters such as precursor concentration, ligands and additives, we obtain complex size and shape control at room temperature. We elaborate hedgehog shaped crystals comprising nanoscale needles or daggers that form intimate interfaces with the cell membrane, minimising the cleft with single cells without apparent detriment to viability. Excitation of such interfaces with light leads to effective cellular photostimulation. We find reversible light-induced conductance changes in ion-selective or temperature-gated channels.Nanomaterials that form a bioelectronic interface with cells are fascinating tools for controlling cellular behavior. Here, the authors photostimulate single cells with spiky assemblies of semiconducting quinacridone nanocrystals, whose nanoscale needles maximize electronic contact with the cells. PMID- 28733620 TI - Adaptive evolution of a hyperthermophilic archaeon pinpoints a formate transporter as a critical factor for the growth enhancement on formate. AB - Previously, we reported that the hyperthermophilic archaeon Thermococcus onnurineus NA1 could grow on formate and produce H2. Formate conversion to hydrogen was mediated by a formate-hydrogen lyase complex and was indeed a part of chemiosmotic coupling to ATP generation. In this study, we employed an adaptation approach to enhance the cell growth on formate and investigated molecular changes. As serial transfer continued on formate-containing medium at the serum vial, cell growth, H2 production and formate consumption increased remarkably. The 156 times transferred-strain, WTF-156T, was demonstrated to enhance H2 production using formate in a bioreactor. The whole-genome sequencing of the WTF-156T strain revealed eleven mutations. While no mutation was found among the genes encoding formate hydrogen lyase, a point mutation (G154A) was identified in a formate transporter (TON_1573). The TON_1573 (A52T) mutation, when introduced into the parent strain, conferred increase in formate consumption and H2 production. Another adaptive passage, carried out by culturing repeatedly in a bioreactor, resulted in a strain, which has a mutation in TON_1573 (C155A) causing amino acid change, A52E. These results implicate that substitution of A52 residue of a formate transporter might be a critical factor to ensure the increase in formate uptake and cell growth. PMID- 28733619 TI - Maternal dendrimer-based therapy for inflammation-induced preterm birth and perinatal brain injury. AB - Preterm birth is a major risk factor for adverse neurological outcomes in ex preterm children, including motor, cognitive, and behavioral disabilities. N acetyl-L-cysteine therapy has been used in clinical studies; however, it requires doses that cause significant side effects. In this study, we explore the effect of low dose N-acetyl-L-cysteine therapy, delivered using a targeted, systemic, maternal, dendrimer nanoparticle (DNAC), in a mouse model of intrauterine inflammation. Our results demonstrated that intraperitoneal maternal DNAC administration significantly reduced the preterm birth rate and altered placental immune profile with decreased CD8+ T-cell infiltration. Furthermore, we demonstrated that DNAC improved neurobehavioral outcomes and reduced fetal neuroinflammation and long-term microglial activation in offspring. Our study is the first to provide evidence for the role of CD8+ T-cell in the maternal-fetal interface during inflammation and further support the efficacy of DNAC in preventing preterm birth and prematurity-related outcomes. PMID- 28733621 TI - Semi-quantitative analysis of multiple chemical mixtures in solution at trace level by surface-enhanced Raman Scattering. AB - Surface-enhanced Raman scattering (SERS) technology combines with chemometric method of principal component analysis (PCA) was used to calculate the composition of chemical mixtures in solution. We reported here that there exists composition discrepancy between molecules in solution and molecules adsorbed on Ag@Al2O3 nanorods substrates due to difference in adsorption kinetics of each component. We proposed here a way to calculate the adsorption kinetics factor for each component using a standard sample as the reference, with which one could correct the predictions given by PCA. We demonstrate the validity of this approach in estimating the compositions of mixtures with two, three and four components of 1, 4-Benzenedithiol, 2-Naphthalenethiol, 4-Mercaptobenzoic acid, and 4-Mercaptopyridine molecules, with acceptable errors. Furthermore, a general formula applied to more complex mixtures was proposed to calculate compositions in solution. PMID- 28733622 TI - Tumor-targeted delivery of siRNA using fatty acyl-CGKRK peptide conjugates. AB - Tumor-targeted carriers provide efficient delivery of chemotherapeutic agents to tumor tissue. CGKRK is one of the well-known tumor targeting peptides with significant specificity for angiogenic blood vessels and tumor cells. Here, we designed fatty acyl conjugated CGKRK peptides, based on the hypothesis that hydrophobically-modified CGKRK peptide could enhance cellular permeation and delivery of siRNA targeted to tumor cells for effective silencing of selected proteins. We synthesized six fatty acyl-peptide conjugates, using a diverse chain of saturated and unsaturated fatty acids to study the efficiency of this approach. At peptide:siRNA weight/weight ratio of 10:1 (N/P ~ 13.6), almost all the peptides showed complete binding with siRNA, and at a w/w ratio of 20:1 (N/P ~ 27.3), complete protection of siRNA from early enzymatic degradation was observed. Conjugated peptides and peptide/siRNA complexes did not show significant cytotoxicity in selected cell lines. The oleic acid-conjugated peptide showed the highest efficiency in siRNA uptake and silencing of kinesin spindle protein at peptide:siRNA w/w ratio of 80:1 (N/P ~ 109). The siRNA internalization into non-tumorigenic kidney cells was negligible with all fatty acyl-peptide conjugates. These results indicate that conjugation of fatty acids to CGKRK could create an efficient delivery system for siRNA silencing specifically in tumor cells. PMID- 28733623 TI - Crystal structure of a low molecular weight activator Blm-pep with yeast 20S proteasome - insights into the enzyme activation mechanism. AB - Proteasomes are responsible for protein turnover in eukaryotic cells, degrading short-lived species but also removing improperly folded or oxidatively damaged ones. Dysfunction of a proteasome results in gradual accumulation of misfolded/damaged proteins, leading to their aggregation. It has been postulated that proteasome activators may facilitate removal of such aggregation-prone proteins and thus prevent development of neurodegenerative disorders. However, the discovery of pharmacologically relevant compounds is hindered by insufficient structural understanding of the activation process. In this study we provide a model peptidic activator of human proteasome and analyze the structure-activity relationship within this novel scaffold. The binding mode of the activator at the relevant pocket within the proteasome has been determined by X-ray crystallography. This crystal structure provides an important basis for rational design of pharmacological compounds. Moreover, by providing a novel insight into the proteasome gating mechanism, our results allow the commonly accepted model of proteasome regulation to be revisited. PMID- 28733624 TI - Scenarios of polaron-involved molecular adsorption on reduced TiO2(110) surfaces. AB - The polaron introduced by the oxygen vacancy (Vo) dominates many surface adsorption processes and chemical reactions on reduced oxide surfaces. Based on IR spectra and DFT calculations of NO and CO adsorption, we gave two scenarios of polaron-involved molecular adsorption on reduced TiO2(110) surfaces. For NO adsorption, the subsurface polaron electron transfers to a Ti:3d-NO:2p hybrid orbital mainly on NO, leading to the large redshifts of vibration frequencies of NO. For CO adsorption, the polaron only transfers to a Ti:3d state of the surface Ti5c cation underneath CO, and thus only a weak shift of vibration frequency of CO was observed. These scenarios are determined by the energy-level matching between the polaron state and the LUMO of adsorbed molecules, which plays a crucial role in polaron-adsorbate interaction and related catalytic reactions on reduced oxide surfaces. PMID- 28733625 TI - Electronic Structure of Polyethylene: Role of Chemical, Morphological and Interfacial Complexity. AB - The electronic structure of an insulator encodes essential signatures of its short-term electrical performance and long-term reliability. A critical long standing challenge though is that key features of the electronic structure of an insulator (and its evolution) under realistic conditions have not been entirely accessible, either via experimental or computational approaches, due to the inherent complexities involved. In this comprehensive study, we reveal the role of chemical and morphological imperfections that inevitably exist within the technologically important prototypical and pervasive insulator, polyethylene (PE), and at electrode/PE interfaces. Large-scale density functional theory computations and long-time molecular dynamics simulations were employed to accurately recover, explain and unravel a wide variety of experimental data obtained during the electrical degradation of PE. This scheme has allowed us to directly and realistically address the role of chemical, morphological and interfacial complexity in determining electronic structure. These efforts take us a step closer to understanding and potentially controlling dielectric degradation and breakdown. PMID- 28733626 TI - Activation of Dinitrogen as A Dipolarophile in 1,3-Dipolar Cycloadditions: A Theoretical Study Using Nitrile Imines as "Octet" 1,3-Dipoles. AB - Theoretical calculations at the G4MP2 level of theory demonstrate that it is possible to activate dinitrogen to make it react in dipolar cycloadditions using neutral beryllium derivatives and other neutral metallic compounds. For the particular case of beryllium, the barrier decreases more than 40 kJ.mol-1 with respect to the non-catalysed reaction. The activation achieved is lower than using diazonium salts (models of protonated N2), but still in a range that can be experimentally attainable. PMID- 28733627 TI - Decreasing prevalence of dementia in 85-year olds examined 22 years apart: the influence of education and stroke. AB - Individuals aged 80 years and older constitute the fastest growing segment of the population worldwide, leading to an expected increase in dementia cases. Education level and treatment of vascular risk factors has increased during the last decades. We examined whether this has influenced the prevalence of dementia according to DSM-III-R using population-based samples of 85-year-olds (N = 1065) examined with identical methods 1986-87 and 2008-10. The prevalence of dementia was 29.8% in 1986-87 and 21.7% in 2008-10 (OR 0.66; 95%-CI: 0.50-0.86). The decline was mainly observed for vascular dementia. The proportion with more than basic education (25.2% and 57.7%), and the prevalence of stroke (20% and 30%) increased, but the odds ratio for dementia with stroke decreased from 4.3 to 1.8 (interaction stroke*birth cohort; p = 0.008). In a logistic regression, education (OR 0.70; 95%-CI 0.51-0.96), stroke (OR 3.78; 95%-CI 2.28-6.29), interaction stroke*birth cohort (OR 0.50; 95%-CI 0.26-0.97), but not birth cohort (OR 0.98; 95%-CI 0.68-1.41), were related to prevalence of dementia. Thus, the decline in dementia prevalence was mainly explained by higher education and lower odds for dementia with stroke in later born birth cohorts. The findings may be related to an increased cognitive reserve and better treatment of stroke in later-born cohorts. PMID- 28733628 TI - Solute carriers affect Anopheles stephensi survival and Plasmodium berghei infection in the salivary glands. AB - Malaria is caused by mosquito-borne Plasmodium spp. parasites that must infect and survive within mosquito salivary glands (SGs) prior to host transmission. Recent advances in transcriptomics and the complete genome sequencing of mosquito vectors have increased our knowledge of the SG genes and proteins involved in pathogen infection and transmission. Membrane solute carriers are key proteins involved in drug transport and are useful in the development of new interventions for transmission blocking. Herein, we applied transcriptomics analysis to compare SGs mRNA levels in Anopheles stephensi fed on non-infected and P. berghei infected mice. The A. stephensi solute carriers prestinA and NDAE1 were up regulated in response to infection. These molecules are predicted to interact with each other, and are reportedly involved in the maintenance of cell homeostasis. To further evaluate their functions in mosquito survival and parasite infection, these genes were knocked down by RNA interference. Knockdown of prestinA and NDAE1 resulted in reduction of the number of sporozoites in mosquito SGs. Moreover, NDAE1 knockdown strongly impacted mosquito survival, resulting in the death of half of the treated mosquitoes. Overall, our findings indicate the importance of prestinA and NDAE1 in interactions between mosquito SGs and Plasmodium, and suggest the need for further research. PMID- 28733629 TI - Improving nitrogen source utilization from defatted soybean meal for nisin production by enhancing proteolytic function of Lactococcus lactis F44. AB - Nisin, one kind of natural antimicrobial peptide, is produced by certain Lactococcus lactis strains, which generally require expensive high-quality nitrogen sources due to limited ability of amino acids biosynthesis. Here we use defatted soybean meal (DSM) as sole nitrogen source to support L. lactis growth and nisin production. DSM medium composition and fermentation conditions were optimized using the methods of Plackett-Burman design and central composite design. The highest nisin production of 3879.58 IU/ml was obtained in DSM medium, which was 21.3% higher than that of commercial medium. To further increase the utilization ability of nitrogen sources, we enhanced the proteolytic function in L. lactis through rationally expressing the related enzymes, which were selected according to the compositions of amino acids and molecular weight of peptides in DSM medium. Significantly, an artificial proteolytic system consisting of a heterologous protease (NprB), an oligopeptides transporter subunit (OppA) and two peptidases (PepF and PepM) was introduced into L.lactis. The constructed strain BAFM was capable of achieving efficient biomass accumulation and nisin yield with 30% decreased amount of DSM hydrolysates, which further reduced the cost of nisin production. The strategy described here offers opportunities for low-cost L. lactis fermentation and large-scale nisin production in industry. PMID- 28733630 TI - Plasma dipeptidyl-peptidase-4 activity is associated with left ventricular systolic function in patients with ST-segment elevation myocardial infarction. AB - Plasma dipeptidyl-peptidase-4 activity (DPP4a) is inversely associated with left ventricular function in patients with heart failure (HF) or diabetes. However, the association between DPP4a and left ventricular function in ST-segment elevation myocardial infarction (STEMI) patients has not been reported. We studied this association in 584 consecutive STEMI patients at a tertiary referral center from July 2014 to October 2015. DPP4a and plasma N-terminal prohormone of B-type natriuretic peptide (NT-proBNP) levels were quantified by enzymatic assays. The median serum NT-proBNP levels were highest in patients of the lowest tertile (T1) of DPP4a compared with that of the highest tertile (T3) (p = 0.028). The STEMI patients in T1 exhibited lower left ventricular systolic function (T1 vs. T3: left ventricular ejection fraction (LVEF): 50.13 +/- 9.12 vs. 52.85 +/- 6.82%, p = 0.001). Multivariate logistic-regression analyses (adjusted for confounding variables) showed that a 1 U/L increase in DPP4a was associated with a decreased incidence of left ventricular systolic dysfunction (LVSD) (adjusted odds ratio: 0.90; 95% CI: 0.87-0.94; p < 0.01). In conclusion, low DPP4a is independently associated with LVSD in STEMI patients, which suggests that DPP4 may be involved in the mechanisms of LVSD in STEMI patients. PMID- 28733631 TI - VGLL4 Selectively Represses YAP-Dependent Gene Induction and Tumorigenic Phenotypes in Breast Cancer. AB - Members of the mammalian Vestigial-like (VGLL) family of transcriptional cofactors activate genes in response to a wide variety of environmental cues. Recently, VGLL proteins have been proposed to regulate key signaling networks involved in cancer development and progression. However, the biological and clinical significance of VGLL dysregulation in human breast cancer pathogenesis remains unknown. Here, we report that diminished VGLL4 expression, but not VGLL1 3, correlated with both shorter relapse-free survival and shorter disease specific survival of cancer patients with different molecular subtypes of breast cancer. Additionally, we further demonstrate that overexpression of VGLL4 reduces breast cancer cell proliferation, migration, intravasation/extravasation potential, favors cell death, and suppresses tumor growth in vivo. Mechanistically, VGLL4 negatively regulates the TEAD1-YAP1 transcriptional complex and exerts its growth inhibitory control through its evolutionary conserved TDU2 domain at its C-terminus. The results suggest that VGLL4 is a candidate tumor suppressor gene which acts by selectively antagonizing YAP dependent tumor growth. VGLL4 may be a promising therapeutic target in breast cancer. PMID- 28733632 TI - 3D anatomical and perfusion MRI for longitudinal evaluation of biomaterials for bone regeneration of femoral bone defect in rats. AB - Magnetic Resonance Imaging (MRI) appears as a good surrogate to Computed Tomography (CT) scan as it does not involve radiation. In this context, a 3D anatomical and perfusion MR imaging protocol was developed to follow the evolution of bone regeneration and the neo-vascularization in femoral bone defects in rats. For this, three different biomaterials based on Pullulan-Dextran and containing either Fucoidan or HydroxyApatite or both were implanted. In vivo MRI, ex vivo micro-CT and histology were performed 1, 3 and 5 weeks after implantation. The high spatially resolved (156 * 182 * 195 um) anatomical images showed a high contrast from the defects filled with biomaterials that decreased over time due to bone formation. The 3D Dynamic Contrast Enhanced (DCE) imaging with high temporal resolution (1 image/19 s) enabled to detect a modification in the Area-Under-The-Gadolinium-Curve over the weeks post implantation. The high sensitivity of MRI enabled to distinguish which biomaterial was the least efficient for bone regeneration, which was confirmed by micro-CT images and by a lower vessel density observed by histology. In conclusion, the methodology developed here highlights the efficiency of longitudinal MRI for tissue engineering as a routine small animal exam. PMID- 28733633 TI - High-fidelity de novo synthesis of pathways using microchip-synthesized oligonucleotides and general molecular biology equipment. AB - Engineering and evaluation of synthetic routes for generating valuable compounds require accurate and cost-effective de novo synthesis of genetic pathways. Here, we present an economical and streamlined de novo DNA synthesis approach for engineering a synthetic pathway with microchip-synthesized oligonucleotides (oligo). The process integrates entire oligo pool amplification, error-removal, and assembly of long DNA molecules. We utilized this method to construct a functional lycopene biosynthetic pathway (11.9 kb encoding 10 genes) in Escherichia coli using a highly error-prone microchip-synthesized oligo pool (479 oligos) without pre-purification, and the error-frequency was reduced from 14.25/kb to 0.53/kb. This low-equipment-dependent and cost-effective method can be widely applied for rapid synthesis of biosynthetic pathways in general molecular biology laboratories. PMID- 28733634 TI - Unconventional band inversion and intrinsic quantum spin Hall effect in functionalized group-V binary films. AB - Adequately understanding band inversion mechanism, one of the significant representations of topological phase, has substantial implications for design and regulation of topological insulators (TIs). Here, by identifying an unconventional band inversion, we propose an intrinsic quantum spin Hall (QSH) effect in iodinated group-V binary (ABI2) monolayers with a bulk gap as large as 0.409 eV, guaranteeing its viable application at room temperature. The nontrivial topological characters, which can be established by explicit demonstration of Z2 invariant and gapless helical edge states, are derived from the band inversion of antibonding states of p x,y orbitals at the K point. Furthermore, the topological properties are tunable under strain engineering and external electric field, which supplies a route to manipulate the spin/charge conductance of edge states. These findings not only provide a new platform to better understand the underlying origin of QSH effect in functionalized group-V films, but also are highly desirable to design large-gap QSH insulators for practical applications in spintronics. PMID- 28733635 TI - Sample-based approach can outperform the classical dynamical analysis - experimental confirmation of the basin stability method. AB - In this paper we show the first broad experimental confirmation of the basin stability approach. The basin stability is one of the sample-based approach methods for analysis of the complex, multidimensional dynamical systems. We show that investigated method is a reliable tool for the analysis of dynamical systems and we prove that it has a significant advantages which make it appropriate for many applications in which classical analysis methods are difficult to apply. We study theoretically and experimentally the dynamics of a forced double pendulum. We examine the ranges of stability for nine different solutions of the system in a two parameter space, namely the amplitude and the frequency of excitation. We apply the path-following and the extended basin stability methods (Brzeski et al., Meccanica 51(11), 2016) and we verify obtained theoretical results in experimental investigations. Comparison of the presented results show that the sample-based approach offers comparable precision to the classical method of analysis. However, it is much simpler to apply and can be used despite the type of dynamical system and its dimensions. Moreover, the sample-based approach has some unique advantages and can be applied without the precise knowledge of parameter values. PMID- 28733636 TI - PI3K p85alpha Subunit-deficient Macrophages Protect Mice from Acute Colitis due to the Enhancement of IL-10 Production. AB - We investigated the role of the PI3K p85alpha subunit in the development of acute colitis with a focus on intestinal macrophages. Experimental acute colitis was induced using 3% dextran sulfate sodium (DSS) in drinking water for 7 days. The severity of DSS-induced acute colitis was significantly attenuated in p85alpha hetero-deficient (p85alpha+/-) mice compared with WT mice. The expression of proinflammatory mediators in intestinal macrophages isolated from the inflamed colonic mucosa was significantly suppressed in p85alpha+/- colitis mice compared with WT colitis mice. Interestingly, we found that bone marrow-derived macrophages (BMDMs) from p85alpha+/- mice produced a significantly higher amount of IL-10 than BMDMs from WT mice. The adoptive transfer of p85alpha+/- BMDMs, but not WT BMDMs, significantly improved the severity in WT colitis mice, and this effect was reversed by anti-IL-10 antibody. Furthermore, the expression of IL-10 in the intestinal macrophages of p85alpha+/- normal colonic mucosa was significantly higher than that in the intestinal macrophages of WT normal colonic mucosa. The present results demonstrate that p85alpha+/- mice exhibit a reduced susceptibility to DSS-induced acute colitis. Our study suggests that a deficiency of PI3K p85alpha enhances the production of IL-10 in intestinal macrophages, thereby suppressing the development of DSS-induced acute colitis. PMID- 28733637 TI - C26-Ceramide as highly sensitive biomarker for the diagnosis of Farber Disease. AB - Farber disease (FD) is a rare autosomal recessive disease caused by mutations in the acid ceramidase gene (ASAH1). Low ceramidase activity results in the accumulation of fatty substances, mainly ceramides. Hallmark symptoms at clinical level are periarticular nodules, lipogranulomas, swollen and painful joints and a hoarse voice. FD phenotypes are heterogeneous varying from mild to very severe cases, with the patients not surviving past their first year of life. The diagnostic aspects of FD are poorly developed due to the rarity of the disease. In the present study, the screening for ceramides and related molecules was performed in Farber affected patients (n = 10), carriers (n = 11) and control individuals (n = 192). This study has the highest number of enrolled Farber patients and carriers reported to present. Liquid chromatography multiple reaction mass spectrometry (LC/MRM-MS) studies revealed that the ceramide C26:0 and especially its isoform 1 is a highly sensitive and specific biomarker for FD (p < 0.0001). The new biomarker can be determined directly in the dried blood spot extracts with low sample consumption. This allows for easy sample preparation, high reproducibility and use in high throughput screenings. PMID- 28733638 TI - Quantum Thermalization and the Expansion of Atomic Clouds. AB - The ultimate consequence of quantum many-body physics is that even the air we breathe is governed by strictly unitary time evolution. The reason that we perceive it nonetheless as a completely classical high temperature gas is due to the incapacity of our measurement machines to keep track of the dense many-body entanglement of the gas molecules. The question thus arises whether there are instances where the quantum time evolution of a macroscopic system is qualitatively different from the equivalent classical system? Here we study this question through the expansion of noninteracting atomic clouds. While in many cases the full quantum dynamics is indeed indistinguishable from classical ballistic motion, we do find a notable exception. The subtle quantum correlations in a Bose gas approaching the condensation temperature appear to affect the expansion of the cloud, as if the system has turned into a diffusive collision full classical system. PMID- 28733639 TI - Particle Adsorption on Hydrogel Surfaces in Aqueous Media due to van der Waals Attraction. AB - Particle adhesion onto hydrogels has recently attracted considerable attention because of the potential biomedical applications of the resultant materials. A variety of interactions have been taken advantage of for adsorption, including electrostatic forces, hydrophobic interactions and hydrogen bonding. In this study, we report significant adsorption of submicron-sized silica particles onto hydrogel surfaces in water, purely by van der Waals (vdW) attraction. The vdW forces enabled strong adhesions between dielectric materials in air. However, because the Hamaker constant decreases in water typically by a factor of approximately 1/100, it is not clear whether vdW attraction is the major driving force in aqueous settings. We investigated the adsorption of silica particles (diameter = 25-600 nm) on poly(acrylamide) and poly(dimethylacrylamide) gels using optical microscopy, under conditions where chemical and electrostatic adsorption is negligible. The quantity of adsorbed particles decreased on decreasing the Hamaker constant by varying the refractive indices of the particles and medium (ethyleneglycol/water), indicating that the adsorption is because of the vdW forces. The adsorption isotherm was discussed based on the adhesive contact model in consideration of the deformation of the gel surface. The present findings will advance the elucidation and development of adsorption in various types of soft materials. PMID- 28733640 TI - Interleukin 37 promotes angiogenesis through TGF-beta signaling. AB - IL-37 is a novel pro-angiogenic cytokine that potently promotes endothelial cell activation and pathological angiogenesis in our previous study, but the mechanisms behind the pro-angiogenic effect of IL-37 are less well understood. Extending our observations, we found that TGF-beta interacts with IL-37, and potently enhances the binding affinity of IL-37 to the ALK1 receptor complex, thus allowing IL-37 to signal through ALK1 to activate pro-angiogenic responses. We further show that TGF-beta and ALK1 are required in IL-37 induced pro angiogenic response in ECs and in the mouse model of Matrigel plug and oxygen induced retinopathy. The result suggests that IL-37 induces pro-angiogenic responses through TGF-beta, which may act as the bridging molecule that mediates IL-37 binding to the TGF-beta receptor complex. PMID- 28733641 TI - Influence of C-terminal truncation of murine Serum amyloid A on fibril structure. AB - Amyloid A (AA) amyloidosis is a systemic protein misfolding disease affecting humans and other vertebrates. While the protein precursor in humans and mice is the acute-phase reactant serum amyloid A (SAA) 1.1, the deposited fibrils consist mainly of C-terminally truncated SAA fragments, termed AA proteins. For yet unknown reasons, phenotypic variations in the AA amyloid distribution pattern are clearly associated with specific AA proteins. Here we describe a bacterial expression system and chromatographic strategies to obtain significant amounts of C-terminally truncated fragments of murine SAA1.1 that correspond in truncation position to relevant pathological AA proteins found in humans. This enables us to investigate systematically structural features of derived fibrils. All fragments form fibrils under nearly physiological conditions that show similar morphological appearance and amyloid-like properties as evident from amyloid specific dye binding, transmission electron microscopy and infrared spectroscopy. However, infrared spectroscopy suggests variations in the structural organization of the amyloid fibrils that might be derived from a modulating role of the C terminus for the fibril structure. These results provide insights, which can help to get a better understanding of the molecular mechanisms underlying the different clinical phenotypes of AA amyloidosis. PMID- 28733643 TI - Recent Wetting and Glacier Expansion in the Northwest Himalaya and Karakoram. AB - Hydroclimatic variability driven by global warming in the climatically vulnerable cold semi-arid to arid northwest (NW) Himalaya is poorly constrained due to paucity of continuous weather records and annually resolved proxies. Applying a network of annually resolved tree-ring-width chronologies from semi-arid region of Kishtwar, Jammu and Kashmir, India, we reconstructed April-May standardized precipitation index extending back to A.D. 1439 (576 years). The reconstructed series is featured by the most conspicuous long-term droughts during the 15th to early 17th centuries followed by a general wetting, with 1984-2014 being the wettest interval in the past 576 years. The data, consistent with other independently developed tree-ring-based hydrological records from cold semi-arid to arid NW Himalaya and Karakoram, point to an increased regional wetting in the recent decades. Such an increased wetting might have led to the anomalous behaviour of glaciers in the NW Himalaya and Karakoram in contrast to the general receding trends in the central and eastern Himalaya. PMID- 28733642 TI - Gap junction-mediated regulation of endothelial cellular stiffness. AB - Endothelial monolayers have shown the ability to signal each other through gap junctions. Gap junction-mediated cell-cell interactions have been implicated in the modulation of endothelial cell functions during vascular inflammation. Inflammatory mediators alter the mechanical properties of endothelial cells, although the exact role of gap junctions in this process remains unclear. Here, we sought to study the role of gap junctions in the regulation of endothelial stiffness, an important physical feature that is associated with many vascular pathologies. The endothelial cellular stiffness of living endothelial cells was determined by using atomic force microscopy. We found that tumor necrosis factor alpha transiently increased endothelial cellular stiffness, which is regulated by cytoskeletal rearrangement and cell-cell interactions. We explored the role of gap junctions in endothelial cellular stiffening by utilizing gap junction blockers, carbenoxolone, inhibitory anti-connexin 32 antibody or anti-connexin 43 antibody. Blockade of gap junctions induced the cellular stiffening associated with focal adhesion formation and cytoskeletal rearrangement, and prolonged tumor necrosis factor-alpha-induced endothelial cellular stiffening. These results suggest that gap junction-mediated cell-cell interactions play an important role in the regulation of endothelial cellular stiffness. PMID- 28733644 TI - Differentiating malignant from benign thyroid nodules with indeterminate cytology by 99mTc-MIBI scan: a new quantitative method for improving diagnostic accuracy. AB - Quantitative 99mTc-MIBI thyroid scintigraphy is a useful tool in differentiating malignant from benign thyroid nodules with indeterminate cytology. The aim of our report is to compare the diagnostic performance of different quantitative methods. We prospectively evaluated 20 patients affected by a thyroid nodule with a cytological diagnosis of class III or IV according to the Bethesda system. Planar images of the thyroid were acquired 10 and 60 minutes after 99mTc-MIBI administration and two different quantitative methods applied (i.e. wash-out index, WOind; retention index, R.I.). All patients underwent lobectomy or thyroidectomy and final histological findings were matched with MIBI results obtained with both quantitative methods. Four out of 20 patients had a final histological result of differentiated thyroid cancer, while benign findings were found in the remaining cases. Overall sensitivity, specificity, accuracy, PPV and NPV were 100% in all for the WOind and 100%, 57.1%, 62.5%, 25% for the R.I., respectively. In conclusion 99mTc-semiquantitative MIBI thyroid scintigraphy with WOind calculation is highly accurate in differential diagnosis of nodules with indeterminate cytology reading. PMID- 28733645 TI - HDAC3 is a molecular brake of the metabolic switch supporting white adipose tissue browning. AB - White adipose tissue (WAT) can undergo a phenotypic switch, known as browning, in response to environmental stimuli such as cold. Post-translational modifications of histones have been shown to regulate cellular energy metabolism, but their role in white adipose tissue physiology remains incompletely understood. Here we show that histone deacetylase 3 (HDAC3) regulates WAT metabolism and function. Selective ablation of Hdac3 in fat switches the metabolic signature of WAT by activating a futile cycle of de novo fatty acid synthesis and beta-oxidation that potentiates WAT oxidative capacity and ultimately supports browning. Specific ablation of Hdac3 in adipose tissue increases acetylation of enhancers in Pparg and Ucp1 genes, and of putative regulatory regions of the Ppara gene. Our results unveil HDAC3 as a regulator of WAT physiology, which acts as a molecular brake that inhibits fatty acid metabolism and WAT browning.Histone deacetylases, such as HDAC3, have been shown to alter cellular metabolism in various tissues. Here the authors show that HDAC3 regulates WAT metabolism by activating a futile cycle of fatty acid synthesis and oxidation, which supports WAT browning. PMID- 28733646 TI - Prognostic role of Glasgow prognostic score in patients with colorectal cancer: evidence from population studies. AB - Glasgow prognostic score (GPS) has been reported to be an indicator of prognosis for various cancers. However, the relationship between GPS and colorectal cancers (CRC) remains unclear. A comprehensive search of Pubmed, Embase, Cochrane library, Web of Science, ChinaInfo and Chinese National Knowledge Infrastructure was performed to identify eligible studies, from which the risk of overall survival (OS) and cancer-specific survival (CSS) were extracted. A random-effect model was adopted to combine hazard ratio (HR) and 95% confidence interval (CI). 25 articles with a total of 5660 participants were included. The pooled results indicated that elevated GPS was associated with poor OS (HR = 2.83, 95%CI: 2.00 4.00, P < 0.01) and CSS (HR = 1.94, 95%CI: 1.51-2.49, P < 0.01). This correlation was confirmed both in primary operable and advanced inoperable patients. Increased GPS was also closely related to advanced tumour-node-metastasis (TNM) stage (odds ratio [OR] = 1.44, 95% CI: 1.010-2.065, P < 0.05) and elevated level of serum carcinoembryonic antigen (OR = 2.252, 95% CI: 1.508-3.362, P < 0.01). Subgroup analysis revealed a significant association between high GPS and poor survival outcome according to the factors of sample size, study of region and cut off value of GPS level. These findings suggest that GPS may serve as a reliable predictive index for patients with CRC. PMID- 28733647 TI - Boiling and quenching heat transfer advancement by nanoscale surface modification. AB - All power production, refrigeration, and advanced electronic systems depend on efficient heat transfer mechanisms for achieving high power density and best system efficiency. Breakthrough advancement in boiling and quenching phase-change heat transfer processes by nanoscale surface texturing can lead to higher energy transfer efficiencies, substantial energy savings, and global reduction in greenhouse gas emissions. This paper reports breakthrough advancements on both fronts of boiling and quenching. The critical heat flux (CHF) in boiling and the Leidenfrost point temperature (LPT) in quenching are the bottlenecks to the heat transfer advancements. As compared to a conventional aluminum surface, the current research reports a substantial enhancement of the CHF by 112% and an increase of the LPT by 40 K using an aluminum surface with anodized aluminum oxide (AAO) nanoporous texture finish. These heat transfer enhancements imply that the power density would increase by more than 100% and the quenching efficiency would be raised by 33%. A theory that links the nucleation potential of the surface to heat transfer rates has been developed and it successfully explains the current finding by revealing that the heat transfer modification and enhancement are mainly attributed to the superhydrophilic surface property and excessive nanoscale nucleation sites created by the nanoporous surface. PMID- 28733649 TI - An In Vitro Model for the Ocular Surface and Tear Film System. AB - Dry eye is a complicated ocular surface disease whose exact pathogenesis is not yet fully understood. For the therapeutic evaluation and pathogenesis study of dry eye, we established an in vitro three-dimensional (3D) coculture model for the ocular surface. It is composed of rabbit conjunctival epithelium and lacrimal gland cell spheroids, and recapitulates the aqueous and mucin layers of the tear film. We first investigated the culture conditions for both cell types to optimize their secretory functions, by employing goblet cell enrichment, air lifting culture, and 3D spheroid formation techniques. The coculture of the two cell components leads to elevated secretion and higher expression of tear secretory markers. We also compared several coculture systems, and found that direct cell contact between the two cell types significantly increased tear secretion. Inflammation was induced to mimic dry eye disease in the coculture model system. Our results showed that the coculture system provides a more physiologically relevant therapeutic response compared to monocultures. Our work provides a complex 3D model as a recapitulation of the ocular surface and tear film system, which can be further developed as a model for dry eye disease and therapeutic evaluation. PMID- 28733648 TI - Modulation of polypeptide conformation through donor-acceptor transformation of side-chain hydrogen bonding ligands. AB - Synthetic polypeptides have received increasing attention due to their ability to form higher ordered structures similar to proteins. The control over their secondary structures, which enables dynamic conformational changes, is primarily accomplished by tuning the side-chain hydrophobic or ionic interactions. Herein we report a strategy to modulate the conformation of polypeptides utilizing donor acceptor interactions emanating from side-chain H-bonding ligands. Specifically, 1,2,3-triazole groups, when incorporated onto polypeptide side-chains, serve as both H-bond donors and acceptors at neutral pH and disrupt the alpha-helical conformation. When protonated, the resulting 1,2,3-triazolium ions lose the ability to act as H-bond acceptors, and the polypeptides regain their alpha helical structure. The conformational change of triazole polypeptides in response to the donor-acceptor pattern was conclusively demonstrated using both experimental-based and simulation-based methods. We further showed the utility of this transition by designing smart, cell-penetrating polymers that undergo acid activated endosomal escape in living cells.Hydrogen bonding plays a major role in determining the tridimensional structure of biopolymers. Here, the authors show that control over a polypeptide conformation can be achieved by altering the donor-acceptor properties of side-chain triazole units via protonation deprotonation. PMID- 28733650 TI - Emergence of polysaccharide membrane walls through macro-space partitioning via interfacial instability. AB - Living organisms in drying environments build anisotropic structures and exhibit directionality through self-organization of biopolymers. However, the process of macro-scale assembly is still unknown. Here, we introduce a dissipative structure through a non-equilibrium process between hydration and deposition in the drying of a polysaccharide liquid crystalline solution. By controlling the geometries of the evaporation front in a limited space, multiple nuclei emerge to grow vertical membrane walls with macroscopic orientation. Notably, the membranes are formed through rational orientation of rod-like microassemblies along the dynamic three phase contact line. Additionally, in the non-equilibrium state, a dissipative structure is ultimately immobilized as a macroscopically partitioned space by multiple vertical membranes. We foresee that such oriented membranes will be applicable to soft biomaterials with direction controllability, and the macroscopic space partitionings will aid in the understanding of the space recognition ability of natural products under drying environments. PMID- 28733651 TI - Synthesis of renewable high-density fuel with isophorone. AB - 1,1,3-Trimethyl-5-(2,4,4-trimethylcyclohexyl)cyclohexane, a renewable high density fuel, was first produced in a high overall carbon yield (~70%) with isophorone which can be derived from hemicellulose. The synthetic route used this work contains three steps. In the first step, 3,3,5-trimethylcyclohexanone was synthesized by the selective hydrogenation of isophorone. Among the investigated catalysts, the Pd/C exhibited the highest activity and selectivity. Over this catalyst, a high carbon yield (99.0%) of 3,3,5-trimethylcyclohexanone was achieved under mild conditions (298 K, 2 MPa H2, 1 h). In the second step, 3,5,5 trimethyl-2-(3,3,5-trimethylcyclohexylidene)cyclohexanone was produced in a high carbon yield (76.4%) by the NaOH catalyzed self-aldol condensation of 3,3,5 trimethylcyclohexanone which was carried out in a round bottom flask attached to the Dean-Stark apparatus. In the third step, the 3,5,5-trimethyl-2-(3,3,5 trimethylcyclohexylidene)cyclohexanone was hydrodeoxygenated under solvent-free conditions. High carbon yield (93.4%) of 1,1,3-trimethyl-5-(2,4,4 trimethylcyclohexyl)cyclohexane was obtained over the Ni/SiO2 catalyst. The 1,1,3 trimethyl-5-(2,4,4-trimethylcyclohexyl)cyclohexane as obtained has a density of 0.858 g mL-1 and a freezing point of 222.2 K. As a potential application, it can be blended into conventional fuels (such as RP-1, RG-1, etc.) for rocket propulsion. PMID- 28733652 TI - Deficient glutamate biosynthesis triggers a concerted upregulation of ribosomal protein genes in Arabidopsis. AB - Biomass production requires the coordination between growth and metabolism. In a large-scale screen for mutants affected in leaf morphology, we isolated the orbiculata1 (orb1) mutants, which exhibit a pale green phenotype and reduced growth. The combination of map-based cloning and next-generation sequencing allowed us to establish that ORB1 encodes the GLUTAMATE SYNTHASE 1 (GLU1) enzyme, also known as FERREDOXIN-DEPENDENT GLUTAMINE OXOGLUTARATE AMINOTRANSFERASE 1 (Fd GOGAT1). We performed an RNA-seq analysis to identify global gene expression changes in the orb1-3 mutant. We found altered expression levels of genes encoding enzymes involved in nitrogen assimilation and amino acid biosynthesis, such as glutamine synthetases, asparagine synthetases and glutamate dehydrogenases, showing that the expression of these genes depends on the levels of glutamine and/or glutamate. In addition, we observed a concerted upregulation of genes encoding subunits of the cytosolic ribosome. A gene ontology (GO) analysis of the differentially expressed genes between Ler and orb1-3 showed that the most enriched GO terms were 'translation', 'cytosolic ribosome' and 'structural constituent of ribosome'. The upregulation of ribosome-related functions might reflect an attempt to keep protein synthesis at optimal levels even when the pool of glutamate is reduced. PMID- 28733653 TI - Synthesis and thermochromic property studies on W doped VO2 films fabricated by sol-gel method. AB - Tungsten-doped VO2 thin films have been synthesized by a modified sol-gel process and followed by a post annealing. Vanadium pentoxide and tungstic acid as raw materials with the addition of hydrogen peroxide, concentrated hydrochloric acid (catalyst) and oxalic acid used as reducing agent were reacted in isobutanol. Finally, the uniform sol of vanadyl oxalate in isobutanol solvent was obtained as precursor. Detailed study suggested that W doped in VO2 introduces additional electron carriers and induces the formation of V3+. Post annealing under vacuum promotes the releasing of chemical stress and generates oxygen vacancies in the samples. Temperature dependent transmittance study revealed that the releasing of chemical stress and deliberately introducing oxygen vacancies in W-doped VO2 films have positive effects on enhancing its switching ability in the infrared transmittance as the metal-insulator transition (MIT) occurs. The largest switching of transmittance was obtained about 48% in the infrared range at 43 degrees C in 1.5%W doped VO2 films, which is significantly larger than the reported ones. The findings in this work open a new way to synthesize the novel and thermochromic W doped VO2 films with facility and low cost. Therefore, it has extensive application to construct smart windows and electronic devices. PMID- 28733654 TI - Direct observation of topological surface-state arcs in photonic metamaterials. AB - The discovery of topological phases has introduced new perspectives and platforms for various interesting physics originally investigated in quantum contexts and then, on an equal footing, in classic wave systems. As a characteristic feature, nontrivial Fermi arcs, connecting between topologically distinct Fermi surfaces, play vital roles in the classification of Dirac and Weyl semimetals, and have been observed in quantum materials very recently. However, in classical systems, no direct experimental observation of Fermi arcs in momentum space has been reported so far. Here, using near-field scanning measurements, we show the observation of photonic topological surface-state arcs connecting topologically distinct bulk states in a chiral hyperbolic metamaterial. To verify the topological nature of this system, we further observe backscattering-immune propagation of a nontrivial surface wave across a three-dimension physical step. Our results demonstrate a metamaterial approach towards topological photonics and offer a deeper understanding of topological phases in three-dimensional classical systems.Topological effects known from condensed matter physics have recently also been explored in photonic systems. Here, the authors directly observe topological surface-state arcs in momentum space by near-field scanning the surface of a chiral hyperbolic metamaterial. PMID- 28733655 TI - Lectin-mediated reversible immobilization of human cells into a glycosylated macroporous protein hydrogel as a cell culture matrix. AB - 3D cell culture is a helpful approach to study cell-cell interaction in a native like environment, but is often limited due the challenge of retrieving cells from the material. In this study, we present the use of recombinant lectin B, a sugar binding protein with four binding cavities, to enable reversible cell integration into a macroporous protein hydrogel matrix. By functionalizing hydrogel precursors with saccharose, lectin B can both bind to sugar moieties on the cellular surface as well as to the modified hydrogel network. Confocal microscopy and flow cytometry analysis revealed cells to be integrated into the network and to adhere and proliferate. Furthermore, the specificity and reversibility was investigated by using a recombinantly produced yellow fluorescent - lectin B fusion protein and a variety of sugars with diverging affinities for lectin B at different concentrations and elution times. Cells could be eluted within minutes by addition of L-fucose to the cell-loaded hydrogels to make cells available for further analysis. PMID- 28733656 TI - Efficacy of Cyclophosphamide treatment for immunoglobulin G4-related disease with addition of glucocorticoids. AB - Aim to evaluate the efficacy and safety of glucocorticoid monotherapy vs combination therapy of cyclophosphamide (CYC) for IgG4 related disease (IgG4-RD). 102 newly diagnosed IgG4-RD patients were enrolled and assigned to 2 groups: Group I was prednisone monotherapy (0.5-1.0 mg/kg.d, tapered gradually) and Group II was glucocorticoid and CYC (50-100 mg per day). Patients were assessed at different periods. Primary end point was relapse rate; secondary end points included response, remission rate and adverse effects. 52 patients were in Group I and 50 in Group II. At 1 month, both groups achieved obvious improvement. Accumulated relapse rate during 1 year was 38.5% in Group 1, including 12 cases with clinical relapse and 8 patients manifesting only serological relapse; whereas there was 12.0% of relapse in Group 2, only 1 with clinical relapse and other 5 patients got serological relapse. The mean flare time in Group II was significantly longer than that in Group I. All relapsing patients in Group I were sensitive to immunosuppressants. Most patients involving more than 6 organs in Group I relapsed during 1 year. IgG4 levels of relapse cases were significantly higher than non-relapsing patients at baseline. Bile duct, lacrimal glands and lymph nodes were commonly relapsed organs in Group I. PMID- 28733657 TI - A gene network regulated by FGF signalling during ear development. AB - During development cell commitment is regulated by inductive signals that are tightly controlled in time and space. In response, cells activate specific programmes, but the transcriptional circuits that maintain cell identity in a changing signalling environment are often poorly understood. Specification of inner ear progenitors is initiated by FGF signalling. Here, we establish the genetic hierarchy downstream of FGF by systematic analysis of many ear factors combined with a network inference approach. We show that FGF rapidly activates a small circuit of transcription factors forming positive feedback loops to stabilise otic progenitor identity. Our predictive network suggests that subsequently, transcriptional repressors ensure the transition of progenitors to mature otic cells, while simultaneously repressing alternative fates. Thus, we reveal the regulatory logic that initiates ear formation and highlight the hierarchical organisation of the otic gene network. PMID- 28733658 TI - Structural and Functional Analysis of Latex Clearing Protein (Lcp) Provides Insight into the Enzymatic Cleavage of Rubber. AB - Latex clearing proteins (Lcps) are rubber oxygenases that catalyse the extracellular cleavage of poly (cis-1,4-isoprene) by Gram-positive rubber degrading bacteria. Lcp of Streptomyces sp. K30 (LcpK30) is a b-type cytochrome and acts as an endo-type dioxygenase producing C20 and higher oligo-isoprenoids that differ in the number of isoprene units but have the same terminal functions, CHO-CH2- and -CH2-COCH3. Our analysis of the LcpK30 structure revealed a 3/3 globin fold with additional domains at the N- and C-termini and similarities to globin-coupled sensor proteins. The haem group of LcpK30 is ligated to the polypeptide by a proximal histidine (His198) and by a lysine residue (Lys167) as the distal axial ligand. The comparison of LcpK30 structures in a closed and in an open state as well as spectroscopic and biochemical analysis of wild type and LcpK30 muteins provided insights into the action of the enzyme during catalysis. PMID- 28733659 TI - Thickness dependence of anomalous Nernst coefficient and longitudinal spin Seebeck effect in ferromagnetic NixFe100-x films. AB - Spin Seebeck effect (SSE) measured for metallic ferromagnetic thin films in commonly used longitudinal configuration contains the contribution from anomalous Nernst effect (ANE). The ANE is considered to arise from the bulk of the ferromagnet (FM) and the proximity-induced FM boundary layer. We fabricate a FM alloy with zero Nernst coefficient to mitigate the ANE contamination of SSE and insert a thin layer of Cu to separate the heavy metal (HM) from the FM to avoid the proximity contribution. These modifications to the experiment should permit complete isolation of SSE from ANE in the longitudinal configuration. However, further thickness dependence studies and careful analysis of the results revealed, ANE contribution of the isolated FM alloy is twofold, surface and bulk. Both surface and bulk contributions, whose magnitudes are comparable to that of the SSE, can be modified by the neighboring layer. Hence surface contribution to the ANE in FM metals is an important effect that needs to be considered. PMID- 28733660 TI - Probing low-energy hyperbolic polaritons in van der Waals crystals with an electron microscope. AB - Van der Waals materials exhibit intriguing structural, electronic, and photonic properties. Electron energy loss spectroscopy within scanning transmission electron microscopy allows for nanoscale mapping of such properties. However, its detection is typically limited to energy losses in the eV range-too large for probing low-energy excitations such as phonons or mid-infrared plasmons. Here, we adapt a conventional instrument to probe energy loss down to 100 meV, and map phononic states in hexagonal boron nitride, a representative van der Waals material. The boron nitride spectra depend on the flake thickness and on the distance of the electron beam to the flake edges. To explain these observations, we developed a classical response theory that describes the interaction of fast electrons with (anisotropic) van der Waals slabs, revealing that the electron energy loss is dominated by excitation of hyperbolic phonon polaritons, and not of bulk phonons as often reported. Thus, our work is of fundamental importance for interpreting future low-energy loss spectra of van der Waals materials.Here the authors adapt a STEM-EELS system to probe energy loss down to 100 meV, and apply it to map phononic states in hexagonal boron nitride, revealing that the electron loss is dominated by hyperbolic phonon polaritons. PMID- 28733661 TI - Helical Phase Structure of Radiation from an Electron in Circular Motion. AB - We theoretically show that a single free electron in circular motion radiates an electromagnetic wave possessing helical phase structure, which is closely related to orbital angular momentum carried by it. We experimentally demonstrate it by interference and double-slit diffraction experiments on radiation from relativistic electrons in spiral motion. Our results indicate that photons carrying orbital angular momentum should be created naturally by cyclotron/synchrotron radiations or Compton scatterings in various situations in cosmic space. We propose promising laboratory vortex photon sources in various wavelengths ranging from radio wave to gamma-rays. PMID- 28733662 TI - Probing the Gas-Phase Dynamics of Graphene Chemical Vapour Deposition using in situ UV Absorption Spectroscopy. AB - The processes governing multilayer nucleation in the chemical vapour deposition (CVD) of graphene are important for obtaining high-quality monolayer sheets, but remain poorly understood. Here we show that higher-order carbon species in the gas-phase play a major role in multilayer nucleation, through the use of in-situ ultraviolet (UV) absorption spectroscopy. These species are the volatilized products of reactions between hydrogen and carbon contaminants that have backstreamed into the reaction chamber from downstream system components. Consequently, we observe a dramatic suppression of multilayer nucleation when backstreaming is suppressed. These results point to an important and previously undescribed mechanism for multilayer nucleation, wherein higher-order gas-phase carbon species play an integral role. Our work highlights the importance of gas phase dynamics in understanding the overall mechanism of graphene growth. PMID- 28733663 TI - Electronic structure of SrSn2As2 near the topological critical point. AB - Topological materials with exotic quantum properties are promising candidates for quantum spin electronics. Different classes of topological materials, including Weyl semimetal, topological superconductor, topological insulator and Axion insulator, etc., can be connected to each other via quantum phase transition. For example, it is believed that a trivial band insulator can be twisted into topological phase by increasing spin-orbital coupling or changing the parameters of crystal lattice. With the results of LDA calculation and measurement by angle resolved photoemission spectroscopy (ARPES), we demonstrate in this work that the electronic structure of SrSn2As2 single crystal has the texture of band inversion near the critical point. The results indicate the possibility of realizing topological quantum phase transition in SrSn2As2 single crystal and obtaining different exotic quantum states. PMID- 28733664 TI - Charge Injection, Carriers Recombination and HOMO Energy Level Relationship in Perovskite Solar Cells. AB - We present a comparative study between a series of well-known semiconductor polymers, used in efficient organic solar cells as hole transport materials (HTM), and the state-of-the art material used as hole transport material in perovskite solar cells: the spiro-OMeTAD. The observed differences in solar cell efficiencies are studied in depth using advanced photoinduced spectroscopic techniques under working illumination conditions. We have observed that there is no correlation between the highest occupied molecular orbital (HOMO) energy levels of the organic semiconductors and the measured open-circuit voltage (VOC). For instance, spiro-OMeTAD and P3HT have a comparable HOMO level of ~5.2 eV vs vacuum even though a difference in VOC of around 200 mV is recorded. This difference is in good agreement with the shift observed for the charge vs voltage measurements. Moreover, hole transfer from the perovskite to the HTM, estimated qualitatively from fluorescence quenching and emission lifetime, seems less efficient for the polymeric HTMs. Finally, the recombination currents from all devices were estimated by using the measured charge (calculated using photoinduced differential charging) and the carriers' lifetime and their value resulted in accordance with the registered short-circuit currents (JSC) at 1 sun. PMID- 28733665 TI - Human intrahepatic CD69 + CD8+ T cells have a tissue resident memory T cell phenotype with reduced cytolytic capacity. AB - Tissue resident memory T cells (TRM) have been identified in various tissues, however human liver TRM to date remain unidentified. TRM can be recognized by CD69 and/or CD103 expression and may play a role in the pathology of chronic hepatitis B (CHB) and hepatitis C virus infection (CHC). Liver and paired blood mononuclear cells from 17 patients (including 4 CHB and 6 CHC patients) were isolated and CD8+ T cells were comprehensively analysed by flowcytometry, immunohistochemistry and qPCR. The majority of intrahepatic CD8+ T cells expressed CD69, a marker used to identify TRM, of which a subset co-expressed CD103. CD69 + CD8+ T cells expressed low levels of S1PR1 and KLF2 and a large proportion (>90%) was CXCR6+, resembling liver TRM in mice and liver resident NK cells in human. Cytotoxic proteins were only expressed in a small fraction of liver CD69 + CD8+ T cells in patients without viral hepatitis, however, in livers from CHB patients more CD69 + CD8+ T cells were granzyme B+. In CHC patients, less intrahepatic CD69 + CD8+ T cells were Hobit+ as compared to CHB and control patients. Intrahepatic CD69 + CD8+ T cells likely TRM which have a reduced cytolytic potential. In patients with chronic viral hepatitis TRM have a distinct phenotype. PMID- 28733666 TI - Improved Liver R2* Mapping by Averaging Decay Curves. AB - Liver R2* mapping is often degraded by the low signal-to-noise ratio (SNR) especially in the presence of severe iron. This study aims to improve liver R2* mapping at low SNRs by averaging decay curves before the process of curve fitting. Independently filtering echo images by nonlocal means (NLM) demonstrated improved quality of R2* mapping, but may introduce new errors due to the nonlinear nature of the NLM filter, during which the averaging weights may vary with different image contents at multiple echo times. In addition, the image denoising effect of the NLM may decline when no sufficient similar patches are available. To overcome these drawbacks, we proposed to filter decay curves instead of images. In this novel scheme, decay curves were averaged in a local window, each with a weight assigned according to the curve-similarity measured by the distance between one of the neighboring curves and the targeted one. The proposed method was tested on simulated, phantom and patient data. The results demonstrate that the proposed method can provide more accurate R2* mapping compared with the NLM algorithm, and hence has the potential to improve diagnosis and therapy in patients with liver iron. PMID- 28733667 TI - RTN1 and RTN3 protein are differentially associated with senile plaques in Alzheimer's brains. AB - Reticulon proteins (RTNs), consisting of RTN1 to RTN4, were previously shown to interact with BACE1 by negatively modulating its secretase activity. In RTN3-null mice, RTN1 expression was slightly elevated. To understand the in vivo role of RTN1, we generated RTN1-null mice and compared the effects of RTN1 and RTN3 on BACE1 modulation. We show that RTN1 is mostly expressed by neurons and not by glial cells under normal conditions, similar to the expression of RTN3. However, RTN1 is more localized in dendrites and is an excellent marker for dendrites of Purkinje cells, while RTN3 expression is less evident in dendrites. This differential localization also correlates with their associations with amyloid plaques in Alzheimer's brains: RTN3, but not RTN1, is abundantly enriched in dystrophic neurites. RTN3 deficiency causes elevation of BACE1 protein levels, while RTN1 deficiency shows no obvious effects on BACE1 activity due to compensation by RTN3, as RTN1 deficiency causes elevation of RTN3 expression. Hence, expression of RTN1 and RTN3 is tightly regulated in mouse brains. Together, our data show that RTN1 and RTN3 have differential effects on the formation of senile plaques in Alzheimer's brains and that RTN3 has a more prominent role in Alzheimer's pathogenesis. PMID- 28733668 TI - Two visual working memory representations simultaneously control attention. AB - It has been proposed that only one visual working memory (VWM) representation can be activated to influence perception directly, whereas other VWM representations are accessory items which have little influence on visual selection. The sole active VWM representation might reflect a fundamental bottleneck in the information processing of human beings. However, the present study showed that each of two VWM representations can capture attention and interfere with concurrent visual search. In addition, each of two VWM representations can interfere with concurrent visual search as much as can a single cued VWM representation. Moreover, when two memory-matching distractors appear in visual search, two VWM representations produce a larger memory-driven capture effect than a single memory-matching distractor. Thus, two VWM representations can simultaneously control attention. PMID- 28733669 TI - High-Resolution Imaging of a Single Gliding Protofilament of Tubulins by HS-AFM. AB - In vitro gliding assay of microtubules (MTs) on kinesins has provided us with valuable biophysical and chemo-mechanical insights of this biomolecular motor system. Visualization of MTs in an in vitro gliding assay has been mainly dependent on optical microscopes, limited resolution of which often render them insufficient sources of desired information. In this work, using high speed atomic force microscopy (HS-AFM), which allows imaging with higher resolution, we monitored MTs and protofilaments (PFs) of tubulins while gliding on kinesins. Moreover, under the HS-AFM, we also observed splitting of gliding MTs into single PFs at their leading ends. The split single PFs interacted with kinesins and exhibited translational motion, but with a slower velocity than the MTs. Our investigation at the molecular level, using the HS-AFM, would provide new insights to the mechanics of MTs in dynamic systems and their interaction with motor proteins. PMID- 28733670 TI - BRD3 and BRD4 BET Bromodomain Proteins Differentially Regulate Skeletal Myogenesis. AB - Myogenic differentiation proceeds through a highly coordinated cascade of gene activation that necessitates epigenomic changes in chromatin structure. Using a screen of small molecule epigenetic probes we identified three compounds which inhibited myogenic differentiation in C2C12 myoblasts; (+)-JQ1, PFI-1, and Bromosporine. These molecules target Bromodomain and Extra Terminal domain (BET) proteins, which are epigenetic readers of acetylated histone lysine tail residues. BETi-mediated anti-myogenic effects were also observed in a model of MYOD1-mediated myogenic conversion of human fibroblasts, and in primary mouse and human myoblasts. All three BET proteins BRD2, BRD3 and BRD4 exhibited distinct and dynamic patterns of protein expression over the course of differentiation without concomitant changes in mRNA levels, suggesting that BET proteins are regulated at the post-transcriptional level. Specific BET protein knockdown by RNA interference revealed that BRD4 was required for myogenic differentiation, whereas BRD3 down-regulation resulted in enhanced myogenic differentiation. ChIP experiments revealed a preferential binding of BRD4 to the Myog promoter during C2C12 myoblast differentiation, co-incident with increased levels of H3K27 acetylation. These results have identified an essential role for BET proteins in the regulation of skeletal myogenesis, and assign distinct functions to BRD3 and BRD4. PMID- 28733671 TI - Short-chain fatty acids and inulin, but not guar gum, prevent diet-induced obesity and insulin resistance through differential mechanisms in mice. AB - The role of dietary fibre and short-chain fatty acids (SCFA) in obesity development is controversially discussed. Here, we investigated how various types of dietary fibre and different SCFA ratios affect metabolic syndrome-related disorders. Male mice (B6) were fed high-fat diets supplemented with dietary fibres (either cellulose, inulin or guar gum) or different Ac:Pr ratios (high acetate (HAc) or propionate (HPr)) for 30 weeks. Body-fat gain and insulin resistance were greatly reduced by inulin, but not by guar gum, and completely prevented by SCFA supplementation. Only inulin and HAc increased body temperature, possibly by the induction of beige/browning markers in WAT. In addition, inulin and SCFA lowered hepatic triglycerides and improved insulin sensitivity. Both, inulin and HAc reduced hepatic fatty acid uptake, while only inulin enhanced mitochondrial capacity and only HAc suppressed lipogenesis in liver. Interestingly, HPr was accompanied by the induction of Nrg4 in BAT. Fermentable fibre supplementation increased the abundance of bifidobacteria; B. animalis was particularly stimulated by inulin and B. pseudolongum by guar gum. We conclude that in contrast to guar gum, inulin and SCFA prevent the onset of diet-induced weight gain and hepatic steatosis by different mechanisms on liver and adipose tissue metabolism. PMID- 28733672 TI - Trainee Surgeons Affect Operative Time but not Outcome in Minimally Invasive Total Hip Arthroplasty. AB - Training of young surgeons in total hip arthroplasty (THA) is crucial, but might affect operative time and outcome especially in minimally invasive (MIS) THA. We asked whether the learning curve of orthopaedic residents trained on MIS THA has an impact on (1) operative time (2) complication rates and (3) early postoperative outcome. In a retrospective analysis of over 1000 MIS THAs from our institutional joint registry, operative time, complication rates, patient reported outcome measures (Western Ontario and McMaster Universities Arthritis Index [WOMAC] and Euro-Qol 5D-5L [EQ-5D]) within the first year and responder rates for positive outcome as defined by the Outcome Measures in Rheumatology and Osteoarthritis Research Society International consensus responder (OMERACT-OARSI) criteria were compared between trainee and senior surgeons. Mean operative time was nine minutes longer for trainees compared to senior surgeons (78.1 +/- 25.4 min versus 69.3 +/- 23.8 min, p < 0.001). Dislocation (p = 0.21), intraoperative fracture (p = 0.84) and infection rates (p = 0.58) were comparably low in both groups. Both trainee and senior THAs showed excellent improvement of EQ-5D (0.34 +/- 0.26 versus 0.32 +/- 0.23, p = 0.40) and WOMAC (45.9 +/- 22.1 versus 44.9 +/- 20.0, p = 0.51) within the first year after surgery without clinical relevant differences. Similarly, responder rates for positive outcome were comparable between trainees with 92.9% and senior surgeons with 95.2% (p = 0.17). MIS THA seems to be a safe procedure during the learning curve of young orthopaedic specialists, but requires higher operative time. PMID- 28733673 TI - Emergence of hysteresis loop in social contagions on complex networks. AB - Understanding the spreading mechanisms of social contagions in complex network systems has attracted much attention in the physics community. Here we propose a generalized threshold model to describe social contagions. Using extensive numerical simulations and theoretical analyses, we find that a hysteresis loop emerges in the system. Specifically, the steady state of the system is sensitive to the initial conditions of the dynamics of the system. In the steady state, the adoption size increases discontinuously with the transmission probability of information about social contagions, and trial size exhibits a non-monotonic pattern, i.e., it first increases discontinuously then decreases continuously. Finally we study social contagions on heterogeneous networks and find that network topology does not qualitatively affect our results. PMID- 28733675 TI - Computation of Equilibrium Bilayer Monodisperse Foam Structures Using the Surface Evolver. AB - The Surface Evolver is used to minimize the surface energy of two ordered structures for bilayer monodisperse wet foams with arbitrary liquid fraction. Previous researchers have found a reversible structural transition in bilayer monodisperse foams by changing the foam liquid fraction in a physical experiment. We simulated this phenomenon by analyzing the interfacial energy of two bilayer foam systems with varying liquid fractions. The calculations reported here show that the Toth structure is energy minimizing when the liquid fraction is below a critical value, around 2.26%, above which point the honeycomb structure becomes preferable, although the Toth structure remains metastable. PMID- 28733674 TI - Role of SCCmec type in resistance to the synergistic activity of oxacillin and cefoxitin in MRSA. AB - beta-lactam antibiotics target penicillin-binding proteins (PBPs) preventing peptidoglycan synthesis and this inhibition is circumvented in methicillin resistant Staphylococcus aureus (MRSA) strains through the expression of an additional PBP, named PBP2A. This enzyme is encoded by the mecA gene located within the Staphylococcal Chromosome Cassette mec (SCCmec) mobile genetic element, of which there are 12 types described to date. Previous investigations aimed at analysing the synergistic activity of two beta-lactams, oxacillin and cefoxitin, found that SCCmec type IV community-acquired MRSA strains exhibited increased susceptibility to oxacillin in the presence of cefoxitin, while hospital-acquired MRSA strains were unaffected. However, it is not clear if these differences in beta-lactam resistance are indeed a consequence of the presence of the different SCCmec types. To address this question, we have exchanged the SCCmec type I in COL (HA-MRSA) for the SCCmec type IV from MW2 (CA-MRSA). This exchange did not decrease the resistance of COL against oxacillin and cefoxitin, as observed in MW2, indicating that genetic features residing outside of the SCCmec element are likely to be responsible for the discrepancy in oxacillin and cefoxitin synergy against these MRSA strains. PMID- 28733676 TI - After infection with Leishmania infantum, Golden Hamsters (Mesocricetus auratus) become more attractive to female sand flies (Lutzomyia longipalpis). AB - In Brazil, human and canine visceral leishmaniasis is caused by infection with Leishmania infantum, a Protist parasite transmitted by blood-feeding female Lutzomyia longipalpis sand flies. The objective of this study was to determine if the odour of hamsters, infected with Le. infantum, was more attractive than the odour of the same hamsters, before they were infected. The attractiveness of odour collected from individual hamsters (n = 13), before they were infected, was compared in a longitudinal study, with the attractiveness of the odour of the same hamster in a Y-tube olfactometer bioassay, at a late stage of infection. The odour of six of the golden hamsters was significantly more attractive to 50% of the female sand flies at the end of infection compared to before infection and the odour of four of the golden hamsters was significantly more attractive to 75% of the female sand flies at the end of infection. These results strongly indicate that hamsters infected with Le. infantum become significantly more attractive to a greater proportion of female sand flies as the infection progresses. PMID- 28733677 TI - Inductively powered wireless pacing via a miniature pacemaker and remote stimulation control system. AB - Pacemakers have existed for decades as a means to restore cardiac electrical rhythms. However, lead-related complications have remained a clinical challenge. While market-released leadless devices have addressed some of the issues, their pacer-integrated batteries cause new health risks and functional limitations. Inductive power transfer enables wireless powering of bioelectronic devices; however, Specific Absorption Rate and size limitations reduce power efficiency for biomedical applications. We designed a remote-controlled system in which power requirements were significantly reduced via intermittent power transfer to control stimulation intervals. In parallel, the cardiac component was miniaturized to facilitate intravascular deployment into the anterior cardiac vein. Given size constraints, efficiency was optimal via a circular receiver coil wrapped into a half-cylinder with a meandering tail. The pacemaker was epicardially tested in a euthanized pig at 60 beats per minute, 2 V amplitude, and 1 ms pulse width, restoring mean arterial pressure from 0 to 37 mmHg. Power consumption was 1 mW at a range of > 3 cm with no misalignment and at 2 cm with 45 degrees displacement misalignment, 45 degrees x-axis angular misalignment, or 45 degrees y-axis angular misalignment. Thus, we demonstrated a remote controlled miniaturized pacing system with low power consumption, thereby providing a basis for the next generation of wireless implantable devices. PMID- 28733678 TI - Physiological and transcriptome analysis of He-Ne laser pretreated wheat seedlings in response to drought stress. AB - Drought stress is a serious problem worldwide that reduces crop productivity. The laser has been shown to play a positive physiological role in enhancing plant seedlings tolerance to various abiotic stresses. However, little information is available about the molecular mechanism of He-Ne laser irradiation induced physiological changes for wheat adapting to drought conditions. Here, we performed a large-scale transcriptome sequencing to determine the molecular roles of He-Ne laser pretreated wheat seedlings under drought stress. There were 98.822 transcripts identified, and, among them, 820 transcripts were found to be differentially expressed in He-Ne laser pretreated wheat seedlings under drought stress compared with drought stress alone. Furthermore, most representative transcripts related to photosynthesis, nutrient uptake and transport, homeostasis control of reactive oxygen species and transcriptional regulation were expressed predominantly in He-Ne laser pretreated wheat seedlings. Thus, the up-regulated physiological processes of photosynthesis, antioxidation and osmotic accumulation because of the modified expressions of the related genes could contribute to the enhanced drought tolerance induced by He-Ne laser pretreatment. These findings will expand our understanding of the complex molecular events associated with drought tolerance conferred by laser irradiation in wheat and provide abundant genetic resources for future studies on plant adaptability to environmental stresses. PMID- 28733679 TI - Increased overall cortical connectivity with syndrome specific local decreases suggested by atypical sleep-EEG synchronization in Williams syndrome. AB - Williams syndrome (7q11.23 microdeletion) is characterized by specific alterations in neurocognitive architecture and functioning, as well as disordered sleep. Here we analyze the region, sleep state and frequency-specific EEG synchronization of whole night sleep recordings of 21 Williams syndrome and 21 typically developing age- and gender-matched subjects by calculating weighted phase lag indexes. We found broadband increases in inter- and intrahemispheric neural connectivity for both NREM and REM sleep EEG of Williams syndrome subjects. These effects consisted of increased theta, high sigma, and beta/low gamma synchronization, whereas alpha synchronization was characterized by a peculiar Williams syndrome-specific decrease during NREM states (intra- and interhemispheric centro-temporal) and REM phases of sleep (occipital intra-area synchronization). We also found a decrease in short range, occipital connectivity of NREM sleep EEG theta activity. The striking increased overall synchronization of sleep EEG in Williams syndrome subjects is consistent with the recently reported increase in synaptic and dendritic density in stem-cell based Williams syndrome models, whereas decreased alpha and occipital connectivity might reflect and underpin the altered microarchitecture of primary visual cortex and disordered visuospatial functioning of Williams syndrome subjects. PMID- 28733680 TI - CID fragmentation, H/D exchange and supermetallization of Barnase-Barstar complex. AB - The barnase-barstar complex is one of the most stable protein-protein complexes and has a very wide range of possible applications. Here we report the use of top down mass spectrometry for the investigation of the structure of this complex, its ionization via ESI, isolation and fragmentation. It was found that the asymmetry of the resulting charge state distributions of the protein monomer product ions increased as the charge state of the precursor ions increased. For the investigation of the 3D structure of the complex, the gas phase H/D exchange reaction was used. In addition, supermetallized ions of the complex with Zn were produced and investigated. It was observed that an increase in the number of metals bound to the complex results in a change in complex stability and the charge distribution between protein fragment. Analysis of the fragmentation pattern of the supermetallized complex [bn-b* + 5Zn]10+ indicated that this ion is present in different conformations with different charges and Zn distributions. Since Zn cannot migrate, such structures must be formed during ionization. PMID- 28733681 TI - Gestational age-specific sex difference in mortality and morbidities of preterm infants: A nationwide study. AB - This study aims to determine whether male sex has adverse effect on mortality and morbidities in very low birth weight infants (VLBWI) <30 weeks of gestation and to ascertain this sex effect, stratified by gestational age, adjusting for perinatal risk factors. This is a population-based study from Korean Neonatal Network for VLBWI born at 23+0 and 29+6 weeks of gestation between January 2013 and December 2014. The primary outcome was gestation-specific sex difference in the occurrence of mortality, combined morbidities, and individual morbidity. A total of 2228 VLBWI were enrolled (males, 51.7%). Mortality was not different between sexes. The risk of bronchopulmonary dysplasia and combined morbidities was significantly higher in males <=25 weeks of gestation (odds ratio [OR] 2.08, 95% confidence interval [CI] 1.35-3.20 and OR 2.00, CI 1.19-3.39, respectively). Males had a significantly higher incidence of periventricular leukomalacia at 23 and 29 weeks of gestation. The risk of severe retinopathy of prematurity was higher in females >25 weeks of gestation. Although both sexes have similar risk for mortality, male sex remains an independent risk for major morbidities, especially at <=25 weeks of gestation. The risk of each outcome for males has a specific pattern with increasing gestational age. PMID- 28733682 TI - Modulation of water diffusion by activation-induced neural cell swelling in Aplysia Californica. AB - Diffusion functional magnetic resonance imaging (DfMRI) has been proposed as a method for functional neuroimaging studies, as an alternative to blood oxygenation level dependent (BOLD)-fMRI. DfMRI is thought to more directly reflect neural activation, but its exact mechanism remains unclear. It has been hypothesized that the water apparent diffusion coefficient (ADC) decrease observed upon neural activation results from swelling of neurons or neuron parts. To elucidate the origin of the DfMRI response at cellular level we performed diffusion MR microscopy at 17.2 T in Aplysia californica buccal ganglia and compared the water ADCs at cellular and ganglia levels before and after neuronal activation induced by perfusion with a solution containing dopamine. Neural cell swelling, evidenced from optical microscopy imaging, resulted in an intracellular ADC increase and an ADC decrease at ganglia level. Furthermore, the intracellular ADC increase was found to have a significant positive correlation with the increase in cell size. Our results strongly support the hypothesis that the ADC decrease observed with DfMRI upon neuronal activation at tissue level reflects activation-induced neural cell swelling. PMID- 28733683 TI - Radiation loss of planar surface plasmon polaritons transmission lines at microwave frequencies. AB - Radiation loss of a typical spoof surface plasmon polaritons (SSPPs) transmission line (TL) is investigated in this paper. A 325 mm-long SSPPs TL is designed and fabricated. Simulated results show that radiation loss contributes more to transmission loss than dielectric loss and conductor loss from 2 GHz to 10 GHz. Radiation loss of the SSPPs TL could be divided into two parts, one is caused by the input mode converter, and the other is caused by the corrugated metallic strip. This paper explains mechanisms of radiation loss from different parts, designs a loaded SSPPs TL with a series of resistors to absorb electromagnetic energy on corrugated metallic strip, and then discriminates radiation loss from the input mode converter, proposes the concept of average radiation length (ARL) to evaluate radiation loss from SSPPs of finite length, and concludes that radiation loss is mainly caused by corrugated structure of finite length at low frequency band and by the input mode converter at high frequency band. To suppress radiation loss, a mixed slow wave TL based on the combination of coplanar waveguides (CPWs) and SSPPs is presented. The designed structure, sample fabrication and experimental verification are discussed. PMID- 28733684 TI - Distinct contributions by frontal and parietal cortices support working memory. AB - Although subregions of frontal and parietal cortex both contribute and coordinate to support working memory (WM) functions, their distinct contributions remain elusive. Here, we demonstrate that perturbations to topographically organized human frontal and parietal cortex during WM maintenance cause distinct but systematic distortions in WM. The nature of these distortions supports theories positing that parietal cortex mainly codes for retrospective sensory information, while frontal cortex codes for prospective action. PMID- 28733686 TI - Comparison of the Proportion and Healthcare Utilisation of Adult Patients with Uncontrolled Severe Asthma versus Non-Severe Asthma Seen in a Southeast Asian Hospital-Based Respiratory Specialist Clinic. AB - INTRODUCTION: Understanding the burden of uncontrolled severe asthma is essential for disease-targeted healthcare planning. There is a scarcity of data regarding the proportion, healthcare utilisation and costs of patients with uncontrolled severe asthma in Asia. This study aimed to plug the knowledge gap in this area. MATERIALS AND METHODS: Consecutive patients with asthma managed in our respiratory specialist clinic were evaluated prospectively. Healthcare utilisation comprising unscheduled asthma-related primary care visits, emergency department (ED) visits and hospital admissions were obtained from the national health records system. We defined uncontrolled severe asthma as poor symptom control (Asthma Control Test score <20); 2 or more asthma exacerbations requiring >=3 days of systemic corticosteroids in the previous year; 1 or more serious asthma exacerbation requiring hospitalisation in the previous year; or airflow limitation with pre-bronchodilator forced expiratory volume in 1 second (FEV1) <80% predicted despite high dose inhaled corticosteroids and another controller medication. RESULTS: Of the 423 study participants, 49 (11.6%) had uncontrolled severe asthma. Compared to non-severe asthma, patients with uncontrolled severe asthma were older and more likely to be female and obese. They had a median of 2 (interquartile range: 0 to 3) exacerbations a year, with 51% having >=2 exacerbations in the past 12 months. They were responsible for 43.9% of the hospital admissions experienced by the whole study cohort. Mean annual direct asthma costs per patient was S$2952 +/- S$4225 in uncontrolled severe asthma vs S$841 +/- S$815 in non-severe asthma. CONCLUSION: Approximately 12% of patients with asthma managed in a hospital-based respiratory specialist clinic in Singapore have uncontrolled severe asthma. They account for a disproportionate amount of healthcare utilisation and costs. Healthcare strategies targeting these patients are urgently needed. PMID- 28733685 TI - Trypanosoma brucei growth control by TNF in mammalian host is independent of the soluble form of the cytokine. AB - Infection of C57Bl/6 mice by pleomorphic African trypanosomes Trypanosoma brucei and T. congolense is characterized by parasitemia waves coupled with the production of systemic levels of TNF. This cytokine is known to control T. brucei growth, but also to contribute to tissue damage, shortening the survival time of infected mice. Using a dominant-negative version of TNF to discriminate between the effects of the membrane-form versus the soluble form of TNF, we show that the second form is involved in neither parasite control nor induction of liver injury. Therefore, soluble TNF is likely not a major contributor to disease outcome. We propose that membrane-bound TNF is responsible for both T. brucei control and host pathology. PMID- 28733687 TI - An Ecologic Study of Trends in the Prevalence of Myopia in Chinese Adults in Singapore Born from the 1920s to 1980s. AB - INTRODUCTION: This study aimed to investigate secular trends in the prevalence of myopia over 6 decades (from the 1920s to 1980s) in Chinese adults in Singapore. MATERIALS AND METHODS: Parental myopia prevalence was estimated using a parent completed questionnaire in paediatric cohorts that included: 1) The Singapore Cohort Of Risk factors for Myopia (SCORM), 2) The Strabismus, Amblyopia and Refractive Error in Singaporean Children (STARS), and 3) The Growing Up in Singapore Towards healthy Outcomes (GUSTO). Published estimates for myopia prevalence from 5 adult studies in Singapore were reviewed. Secular trends in the prevalence of myopia were correlated with changes in the education system. RESULTS: The prevalence of parental myopia in SCORM (n = 2943), STARS (n = 4938), and GUSTO (n = 1072) was 47.8%, 53.4%, and 73.4%, respectively; corresponding calendar years these parents might have started schooling were 1966, 1973, and 1983 (born in 1960, 1967, and 1977), respectively. Mean age of parents was 41.3, 40.1, and 33.4 years, respectively. Prevalence of myopia in adult studies in persons who started elementary school in 1928, 1934, 1938, 1939, 1942, 1948, 1952, 1958, 1962, 1972, 1982, and 1995 were 36.4%, 39.7%, 30.0%, 31.5%, 33.0%, 26.4%, 32.5%, 48.7%, 39.4%, 52.0%, 82.2%, and 85.9%, respectively. CONCLUSION: During the past few decades, the prevalence of myopia increased rapidly, especially in persons who started elementary school after the 1980s (born after 1970). The education system was expanded after Singapore's independence in 1965, and the new education system was introduced in 1978. These changes, together with increasing intensive schooling, may have contributed to the increase in myopia prevalence. PMID- 28733689 TI - Return to Work is an Important Therapeutic Goal. PMID- 28733688 TI - Predicting Pneumonia in Acute Ischaemic Stroke: Comparison of Five Prediction Scoring Models. AB - INTRODUCTION: Although pneumonia is a major complication after acute ischaemic stroke (AIS), pneumonia prediction scores have not been extensively validated. This study aimed to compare the discrimination performance of 5 pneumonia prediction scores in AIS patients. MATERIALS AND METHODS: We retrospectively reviewed all consecutive adult AIS patients whom presented to our emergency department within 4.5 hours of symptom-onset between January 2012 and February 2015. Diagnosis had to be made by a neurologist and infarcts confirmed by neuroimaging. We excluded patients with pneumonia on presentation. Pneumonia predictors were based on the 5 prediction scoring models: Kwon's score, Chumbler's score, Acute Ischaemic Stroke-Associated Pneumonia Score (AIS-APS), A2DS2 score and ISAN score. The definition of stroke-associated pneumonia was based on the criteria by the Pneumonia in Stroke Consensus Group. Analysis using area under receiver operating characteristics curve (AUROC) was performed. RESULTS: Forty (5.5%) out of 731 patients analysed had stroke-associated pneumonia (SAP). A2DS2 score had the highest discrimination capacity (AUROC 0.88; 95% CI, 0.84 to 0.92), followed by AIS-APS (AUROC 0.87; 95% CI, 0.83 to 0.91), Kwon's score (AUROC 0.86; 95% CI, 0.82 to 0.92), Prestroke Independence, Sex, Age and National Institutes of Health Stroke Scale (ISAN) score (AUROC 0.85; 95% CI, 0.80 to 0.90) and Chumbler's score (AUROC 0.79; 95% CI, 0.74 to 0.84). However, there was no statistical difference of discrimination capacity among A2DS2 score, AIS-APS and Kwon's score. CONCLUSION: A2DS2 , AIS-APS and Kwon's scores performed comparably in discriminating SAP in AIS patients. PMID- 28733690 TI - Do Obstetric Patients Opt to Undergo General Anaesthesia to Avoid Being Conscious Despite Safer Alternatives? AB - There are various modes of anaesthesia available in the community today. This gives anaesthesiologists the freedom to select those that are safe, efficacious and most suitable for patients. However, patients may not always agree with their anaesthesiologist on the preferred mode of anaesthesia because they may have a different set of priorities, with many of them electing to have the lack of intraoperative awareness as the primary objective. Hence, disagreements between anaesthesiologists and patients may arise and could potentially disrupt doctor patient relationship. This paper attempts to explore the possible reasons for obstetric patients championing for certain modes of anaesthesia and to provide an insight into the need for adequate patient education. PMID- 28733691 TI - Pancreatic Panniculitis Sans Pancreatitis in a Patient with Diabetic Ketoacidosis. PMID- 28733692 TI - The Early Effect of Laporascopic Sleeve Gastrectomy on Taste Change in a Multiethnic Asian Cohort. PMID- 28733693 TI - Asia's First Minimal-Access Left Ventricular Assist Device Implantation. PMID- 28733694 TI - Inaugural Chee Kuan Tsee Lecture: Mental Health Care for the 21st Century. PMID- 28733695 TI - Professor Vettiveloo Kandasamy Pillay (1929 - 2016). PMID- 28733696 TI - Vaccination against influenza at a European pediatric cancer center: immunization rates and attitudes among staff, patients, and their families. AB - BACKGROUND: Influenza is an important cause of infectious morbidity in pediatric cancer patients. We conducted a single-center survey to explore adherence and attitudes towards the recommended annual influenza vaccination. METHODS: Self administered, standardized questionnaires were distributed to 143 staff members and 264 families. Items analyzed included demographic data, knowledge about influenza, history of prior influenza infections and vaccinations, routes of information and education, and attitudes towards the recommended influenza. Variables associated with vaccination were explored by univariate and multivariate analyses. RESULTS: One hundred six staff members with patient contact and 139 primary caretakers completed the questionnaire. Fifty-nine percent of staff members and 60% of the caretakers provided correct answers to all four knowledge questions; 32 and 54% reported a history of prior influenza, and 61 and 47% had received at least one influenza vaccination in the past. Vaccination rates for the previous season were 47, 34, 30, 25, and 29% in staff members, primary caretakers, their partners, diseased children, and their siblings, respectively. Main motivations (>75% in >= 1 cohort) for vaccination were prevention of influenza disease and concerns to transmit it to others (77 100%) and reasons for not being immunized concerns of adverse effects and use of alternative protection (33-83%). Variables significantly associated with vaccination by multivariate analysis included receipt of influenza vaccinations in the past (OR 2.2-20.5), recommendations by health care providers (OR 4.8 45.5), a lower level of education (caretakers; OR 2.2), and younger age (children; OR 0.9). CONCLUSIONS: The results of this survey indicate insufficient vaccination rates and provide potential approaches for improved vaccination strategies in the setting of pediatric cancer care. PMID- 28733697 TI - Perspectives of newly diagnosed advanced cancer patients receiving dignity therapy during cancer treatment. AB - PURPOSE: Dignity therapy is a psychosocial intervention that has been used primarily at the end of life to improve quality of life and other patient outcomes, but many individuals are unable to complete it due to health decline and death. The purpose of this study was to identify what individuals with advanced pancreatic or lung cancer with limited life expectancy, undergoing active cancer treatment describe during the dignity therapy intervention as important to them when not immediately facing end of life. METHODS: Twenty patients undergoing chemotherapy for advanced cancer participated in a dignity therapy intervention study. Initial interviews were analyzed using descriptive content analysis. RESULTS: Family provided the overall context and background for emerging themes of defining events, accomplishments, and God's plan, which led to lessons learned, and resulted in messages of hope. Interviews were often autobiographical in nature and contained much reminiscence, consistent with dignity therapy's intent. Few participants spoke about their cancer diagnoses during the interview. CONCLUSIONS: This study adds unique insight into the use of dignity therapy for those still receiving active cancer treatment, different from work by others in which it was offered only at end of life. As part of supportive care, clinicians need to validate the importance of family to those with advanced cancer and to provide opportunities for patients to share what they have learned throughout life and to impart messages of hope to those closest to them. PMID- 28733698 TI - Expert agreed standards for the selection and development of cancer support group leaders: an online reactive Delphi study. AB - PURPOSE: The aim of this study was to develop pragmatic, consensus-based minimum standards for the role of a cancer support group leader. Secondly, to produce a structured interview designed to assess the knowledge, skills and attributes of the individuals who seek to undertake the role. METHODS: An expert panel of 73 academics, health professionals, cancer agency workers and cancer support group leaders were invited to participate in a reactive online Delphi study involving three online questionnaire rounds. Participants determined and ranked requisite knowledge, skills and attributes (KSA) for cancer support group leaders, differentiated ideal from required KSA to establish minimum standards, and agreed on a method of rating KSA to determine suitability and readiness. RESULTS: Forty five experts (62%) participated in round 1, 36 (49%) in round 2 and 23 (31%) in round 3. In round 1, experts confirmed 59 KSA identified via a systemic review and identified a further 55 KSA. In round 2, using agreement >=75%, 52 KSA emerged as minimum standards for support group leaders. In round 3, consensus was reached on almost every aspect of the content and structure of a structured interview. Panel member comments guided refinement of wording, re-ordering of questions and improvement of probing questions. CONCLUSIONS: Alongside a novel structured interview, the first consensus-based minimum standards have been developed for cancer support group leaders, incorporating expert consensus and pragmatic considerations. Pilot and field testing will be used to appraise aspects of clinical utility and establish a rational scoring model for the structured interview. PMID- 28733699 TI - A prospective study of docetaxel-associated pain syndrome. AB - PURPOSE: To investigate the natural history of taxane-associated acute pain syndrome (TAPS) in a docetaxel patient cohort and to examine the long-term manifestation of TAPS. PATIENTS AND METHODS: For three consecutive treatment cycles, taxane-naive breast cancer patients completed diaries on days 1-7, 14, and 21 and telephone questionnaires 1, 3, 6, 9, and 12 months following treatment. Questionnaires to assess pain and interference were adapted from the Brief Pain Inventory. To examine the experience of arthralgia and myalgia as one syndrome, information on patient experiences with arthralgia or myalgia was elicited separately in order to determine how closely experiences of each toxicity correlated with each other. A >=2 point increase from baseline was defined as an arthralgia or myalgia "pain flare," and only those with "flare" were included in calculations of incidence. RESULTS: A total of 278 patients were accrued. Thirty-eight patients were omitted due to missing information, and 24 patients were omitted due to metastatic disease, for a total of 216 patients overall and 188 in the docetaxel cohort. A total of 74.5% of docetaxel patients experienced joint pain flare, and 78.2% experienced muscle pain flare at some point in the overall course of three treatment cycles. Joint and muscle pain peaked on days 4-5 for each cycle, and median pain severity for both joint and muscle pain was 4/10 during the 21-day period. Median onset of joint pain flare was 3 days for cycle 1 and 4 days for cycles 2 and 3, with an average median duration of 4 days. Median onset of muscle pain flare was 4 days for all three cycles, with a median duration of 4 days for cycles 1 and 2, and 5 days for cycle 3. Both joint and muscle pain persisted 1 year after treatment in approximately half of responding patients. CONCLUSION: This study documents the significant incidence of TAPS in patients treated with docetaxel chemotherapy and shows a long-term persistence of the syndrome. PMID- 28733700 TI - Feasibility of olanzapine, multi acting receptor targeted antipsychotic agent, for the prevention of emesis caused by continuous cisplatin- or ifosfamide-based chemotherapy. AB - Background To determine the feasibility and efficacy of olanzapine, which is approved by the Pharmaceuticals and Medical Devices Agency as multi acting receptor targeted antipsychotic agent of the thienobenzodiazepine class, for prevention of chemotherapy-induced nausea and vomiting (CINV) in patients undergoing continuous five-day chemotherapy. Patients and methods This study was a prospective dose escalation study at a single center (UMIN ID: UMIN000015386). Patients received a combination of adriamycin and ifosfamide (AI) or a combination of bleomycin, etoposide, and cisplatin (BEP). On days 1-5, all patients received intravenous granisetron (1 mg) and intravenous dexamethasone sodium phosphate (24 mg). Olanzapine was administrated on day-1 to day5 at bedtime. The dose of olanzapine followed a dose-escalation scheme, with monitoring of safety and tolerability at each dose. A 3 + 3 cohort design was used, with three to six patients per cohort. Results Nine patients were enrolled (three for each cohort). No patients experienced dose-limiting toxicity (DLT). The most frequent adverse events were dry mouth and constipation. In each cohort, the maximum severity of nausea was Grade 2, and no patients experienced a vomiting episode. Conclusion A 2.5 mg/day dosage of olanzapine is sufficient to prevent from CINV in Japanese patients receiving continuous five-day chemotherapy. A dose of 10 mg/day, which is recommended by international CINV guidelines, is also tolerated. If CINV is not controlled by an initial dose of 2.5 mg/day of olanzapine, dosage escalation is encouraged. Future studies should compare olanzapine with aprepitant. PMID- 28733701 TI - Copper (II) complexes of bidentate ligands exhibit potent anti-cancer activity regardless of platinum sensitivity status. AB - Insensitivity to platinum, either through inherent or acquired resistance, is a major clinical problem in the treatment of many solid tumors. Here, we explored the therapeutic potential of diethyldithiocarbamate (DDC), pyrithione (Pyr), plumbagin (Plum), 8-hydroxyquinoline (8-HQ), clioquinol (CQ) copper complexes in a panel of cancer cell lines that differ in their sensitivity to platins (cisplatin/carboplatin) using a high-content imaging system. Our data suggest that the copper complexes were effective against both platinum sensitive (IC50 ~ 1 MUM platinum) and insensitive (IC50 > 5 MUM platinum) cell lines. Furthermore, copper complexes of DDC, Pyr and 8-HQ had greater therapeutic activity compared to the copper-free ligands in all cell lines; whereas the copper-dependent activities of Plum and CQ were cell-line specific. Four of the copper complexes (Cu(DDC)2, Cu(Pyr)2, Cu(Plum)2 and Cu(8-HQ)2) showed IC50 values less than that of cisplatin in all tested cell lines. The complex copper DDC (Cu(DDC)2) was selected for in vivo evaluation due to its low nano-molar range activity in vitro and the availability of an injectable liposomal formulation. Liposomal (Cu(DDC)2) was tested in a fast-growing platinum-resistant A2780-CP ovarian xenograft model and was found to achieve a statistically significant reduction (50%; p < 0.05) in tumour size. This work supports the potential use of copper-based therapeutics to treat cancers that are insensitive to platinum drugs. PMID- 28733702 TI - Anti-invasive effects of CXCR4 and FAK inhibitors in non-small cell lung carcinomas with mutually inactivated p53 and PTEN tumor suppressors. AB - Non-small cell lung carcinoma (NSCLC) is the most common type of lung cancer. At the time of diagnosis, a large percentage of NSCLC patients have already developed metastasis, responsible for extremely high mortality rates. CXCR4 receptor and focal adhesion kinase (FAK) are known to regulate such invasive cancer behavior. Their expression is downregulated by p53 and PTEN tumor suppressors which are commonly co-inactivated in NSCLC patients and contribute to metastasis. Therefore, targeting CXCR4 or FAK seems to be a promising strategy in suppressing metastatic spread of p53/PTEN deficient NSCLCs. In this study, we first examined the invasive characteristics of NSCLC cells with suppressed p53 and PTEN activity using wound healing, gelatin degradation and invasion assays. Further, changes in the expression of CXCR4 and FAK were evaluated by RT-qPCR and Western Blot analysis. Finally, we tested the ability of CXCR4 and FAK inhibitors (WZ811 and PF-573228, respectively) to suppress the migratory and invasive potential of p53/PTEN deficient NSCLC cells, in vitro and in vivo using metastatic models of human NSCLC. Our results showed that cells with mutually inactive p53 and PTEN have significantly increased invasive potential associated with hyperactivation of CXCR4 and FAK signaling pathways. Treatments with WZ811 and PF-573228 inhibitors significantly reduced migratory and invasive capacity in vitro and showed a trend of improved survival in vivo. Accordingly, we demonstrated that p53/PTEN deficient NSCLCs have extremely invasive phenotype and provided a rationale for the use of CXCR4 or FAK inhibitors for the suppression of NSCLC dissemination. PMID- 28733703 TI - Induction of accelerated senescence by the microtubule-stabilizing agent peloruside A. AB - Chemotherapeutic agents can induce accelerated senescence in tumor cells, an irreversible state of cell cycle arrest. Paclitaxel, a microtubule-stabilizing agent used to treat solid tumors of the breast, ovary, and lung and discodermolide, another stabilizing agent from a marine sponge, induce senescence in cultured cancer cells. The aim of this study was to determine if the microtubule-stabilizing agent peloruside A, a polyketide natural product from a marine sponge, can induce accelerated senescence in a breast cancer cell line MCF7. Doxorubicin, a DNA-damaging agent, paclitaxel, and discodermolide were used as positive controls. Senescence-associated-beta-galactosidase activity was increased by peloruside A, similar to paclitaxel, discodermolde, and doxorubicin, with a potency heirarchy of doxorubicin > paclitaxel > discodermolide > peloruside, based on IC25 concentrations that inhibit proliferation. Clonogenic survival was significantly decreased by peloruside A, similar to doxorubicin and the two other microtubule-stabilizing agents. The tumor suppressor protein p53 increased after treatment, whereas pRb decreased in response to all four compounds. It was concluded that in addition to apoptosis, peloruside A causes accelerated senescence in a subpopulation of MCF7 cells that contributes to its potential anticancer activity in a breast cancer cell line. PMID- 28733705 TI - [Unclear right atrial tumor in a 40-year-old patient with Marfan syndrome]. PMID- 28733704 TI - [Adverse effects of immunotherapy : Clinical aspects, radiological and nuclear medicine results]. AB - BACKGROUND: The increasing use of immunotherapy in oncology increases the need for radiologic evaluation of frequent and severe immune-related adverse events. OBJECTIVE: Determination of the incidence and manifestation of radiologic and nuclear medicine findings of immune-related adverse events. MATERIAL AND METHODS: Literature review of clinical and imaging findings of immune-related adverse events induced by the immune checkpoint inhibitors ipilimumab, nivolumab and pembrolizumab. Findings are illustrated with pictorial examples and contrasted to other relevant differential diagnoses. RESULTS: The most frequent imaging manifestations are colitis, hepatitis, pancreatitis, hypophysitis, pneumonitis, arthritis and sarcoid-like lymphadenopathy. Severe to life-threatening complications may result from colitis, pneumonitis and hypophysitis. A clear differentiation from other autoimmune diseases and discrimination of immune related and infectious pulmonary findings can be very difficult and need close multidisciplinary collaboration. CONCLUSION: Knowledge of clinical and imaging findings of adverse events induced by immunotherapy is essential for timely and adequate therapeutic decisions. In addition to staging and follow-up imaging, identification and monitoring of immune-related adverse events adds to the radiologic responsibility in oncologic care. PMID- 28733706 TI - Phage Display Selection, In Vitro Characterization, and Correlative PET Imaging of a Novel HER3 Peptide. AB - PURPOSE: HER3 (ERBB3) is a receptor tyrosine kinase that is implicated in treatment resistance across multiple cancers, including those of the breast, lung, and prostate. Overexpression of HER3 following targeted therapy can occur rapidly and heterogeneously both within a single lesion and across sites of metastasis, making protein quantification by biopsy highly challenging. A global, non-invasive methodology such as positron emission tomography (PET) imaging can permit serial quantification of HER3, providing a useful approach to monitor HER3 expression across the entire tumor burden both prior to and following treatment. PET imaging of HER3 expression may permit a more personalized approach to targeted therapy by allowing for detection of HER3-mediated resistance, in addition to informing clinical trial patient selection for novel therapies targeting HER3. PROCEDURES: Phage display selection targeting the HER3 extracellular domain was performed in order to develop a peptide with optimal blood clearance and highly accurate HER3 quantification. RESULTS: The selection converged to a consensus peptide sequence that was subsequently found to bind HER3 with an affinity of 270 +/- 151 nM. The peptide, termed HER3P1, was bound with high selectivity to HER3 over other similar receptor tyrosine kinases such as EGFR and HER2. Furthermore, HER3P1 was able to distinguish between high and low HER3-expressing cells in vitro. The peptide was radiolabeled with Ga-68 and demonstrated to specifically bind HER3 by in vivo PET imaging. Uptake of [68Ga]HER3P1 was highly specific for HER3-positive tumors, with tumor-to background ratios ranging from 1.59-3.32, compared to those of HER3-negative tumors, ranging from 0.84-0.93. The uptake of [68Ga]HER3P1 also demonstrated high (P < 0.001) correlation with protein expression as quantified by Western blot and confirmed by biodistribution. CONCLUSIONS: HER3P1 accurately quantifies expression of HER3 by PET imaging and has potential utility as a clinical imaging agent. PMID- 28733708 TI - Methane Ebullition in Temperate Hydropower Reservoirs and Implications for US Policy on Greenhouse Gas Emissions. AB - The United States is home to 2198 dams actively used for hydropower production. With the December 2015 consensus adoption of the United Nations Framework Convention on Climate Change Paris Agreement, it is important to accurately quantify anthropogenic greenhouse gas emissions. Methane ebullition, or methane bubbles originating from river or lake sediments, has been shown to account for nearly all methane emissions from tropical hydropower reservoirs to the atmosphere. However, distinct ebullitive methane fluxes have been studied in comparatively few temperate hydropower reservoirs globally. This study measures ebullitive and diffusive methane fluxes from two eastern Washington reservoirs, and synthesizes existing studies of methane ebullition in temperate, boreal, and tropical hydropower reservoirs. Ebullition comprises nearly all methane emissions (>97%) from this study's two eastern Washington hydropower reservoirs to the atmosphere. Summer methane ebullition from these reservoirs was higher than ebullition in six southeastern U.S. hydropower reservoirs, however it was similar to temperate reservoirs in other parts of the world. Our literature synthesis suggests that methane ebullition from temperate hydropower reservoirs can be seasonally elevated compared to tropical climates, however annual emissions are likely to be higher within tropical climates, emphasizing the possible range of methane ebullition fluxes and the need for the further study of temperate reservoirs. Possible future changes to the Intergovernmental Panel on Climate Change and UNFCCC guidelines for national greenhouse gas inventories highlights the need for accurate assessment of reservoir emissions. PMID- 28733707 TI - Angiotensin II Type 1 Receptor Blockers Inhibit KAT II Activity in the Brain-Its Possible Clinical Applications. AB - Angiotensin II receptor blockers (ARBs) are one of the most frequently recommended antihypertensive drugs. Apart from their activity towards the circulatory system, ARBs also penetrate the blood-brain barrier and display neuroprotective effects. Kynurenic acid (KYNA) is an endogenous metabolite of tryptophan produced by kynurenine aminotransferase II (KAT II) in the brain. Antagonism towards all ionotropic glutamate (GLU) receptors is the main mechanism of KYNA action. An elevated brain level of KYNA is linked with memory impairment and psychotic symptoms. The aim of this study was to examine the influence of three ARBs: irbesartan, losartan, and telmisartan on KYNA production and KAT II activity in rat brain. The effect of ARBs on KYNA production was analyzed in rat brain cortical slices and on isolated KAT II enzyme. Irbesartan, losartan, and telmisartan decreased KYNA production and KAT II activity in a dose-dependent manner in rat brain cortex in vitro. Molecular docking suggested that the examined ARBs could bind to an active site of KAT II. In conclusion, ARBs decrease KYNA production in rat brain by direct inhibition of KAT II enzymatic activity. This novel mechanism of ARBs action may be advantageous in the treatment of cognitive impairment or the management of schizophrenia. PMID- 28733709 TI - IL-4 blockade alters the tumor microenvironment and augments the response to cancer immunotherapy in a mouse model. AB - Recent findings show that immune cells constitute a large fraction of the tumor microenvironment and that they modulate tumor progression. Clinical data indicate that chronic inflammation is present at tumor sites and that IL-4, in particular, is upregulated. Thus, we tested whether IL-4 neutralization would affect tumor immunity. Current results demonstrate that the administration of a neutralizing antibody against IL-4 enhances anti-tumor immunity and delays tumor progression. IL-4 blockade also alters inflammation in the tumor microenvironment, reducing the generation of both immunosuppressive M2 macrophages and myeloid-derived suppressor cells, and enhancing tumor-specific cytotoxic T lymphocytes. In addition, IL-4 blockade improves the response to anti-OX40 Ab or CpG oligodeoxynucleotide immunotherapies. These findings suggest that IL-4 affects anti-tumor immunity and constitutes an attractive therapeutic target to reduce immune suppression in the tumor microenvironment, thus enhancing the efficacy of cancer therapy. PMID- 28733710 TI - A Matched Case-Control Study on Early and Late Results of Carotid Endarterectomy Performed in Young Patients. AB - OBJECTIVE: The aim of the study was to describe the perioperative and long-term results of carotid endarterectomy (CEA) in patients aged 60 or less and compare them to patients of more advanced age in a retrospective single-centre case control study. METHODS: From January 1996 to December 2014, 5893 consecutive CEAs were performed in our institution. Data concerning these interventions were prospectively inserted in a dedicated database. A retrospective analysis of that database was performed and 457 interventions performed in patients aged 60 or less were found (group 1). The control group was represented by 457 interventions selected from the remaining 5436 by a one-to-one coarsened exact matching on the basis of all the baseline demographic and clinical covariates significantly different in the two groups (group 2). The two groups were compared in terms of intraoperative technical features and perioperative (<30 days) results of interventions (transient ischaemic attack-TIA, stroke and death rates) with chi 2 test. Follow-up data were analysed by life-table analysis (Kaplan-Meier test) in terms of survival, stroke-free and neurological symptom-free survival, freedom from severe restenosis and occlusion and freedom from reintervention, and the results in the two groups were compared by means of log rank test. RESULTS: There were no differences between the two groups in terms of clinical presentation and of degree of carotid stenosis on operated side. Anaesthesiological and surgical details were also similar between the two groups. Thirty-day stroke and death rate was 0.6% in both groups (p = 0.9). Follow-up was available for 877 patients (96% of the study group) with a mean duration of 50 months. Estimated 10-year survival rates were 85% in group 1 (SE 0.03) and 76% in group 2 (SE 0.04, p = 0.003, log rank 8.9). At the same time interval, stroke-free survival was also significantly better in group 1 (85%, SE 0.035) than in group 2 (72.5%, SE 0.03; p = 0.002, log rank 10.1). The corresponding figures in terms of any neurological symptom-free survival were 82.8% in group 1 (SE 0.04) and 70.3% in group 2 (SE 0.04, p = 0.002, log rank 9.7). Estimated freedom from severe restenosis and occlusion was 76.5% in group 1 (SE 0.04) and 88.5% in group 2 (SE 0.035, p = 0.001, log rank 11.9). Disease recurrence was symptomatic in six cases, three in each group. Estimated freedom from reintervention rates at 10 years was 87% in group 1 (SE 0.035) and 91.5% in group 2 (SE 0.03; p = 0.2, log rank 1.1). CONCLUSIONS: CEA in patents aged 60 or less is safe and provides significantly better long-term results than those obtained in patients over 60 in terms of survival and stroke-free survival. Younger patients appear to have higher rates of recurrent carotid stenosis compared to the older cohort; however, these rarely require a secondary intervention. PMID- 28733711 TI - A brief history of neurological botulinum toxin therapy in Germany. AB - Botulinum toxin (BT) has long been infamous in food safety and biological warfare. In the early 1970s, Alan B Scott of San Francisco invented its therapeutic use originally in extraocular eye muscles to treat strabismus using a therapeutic BT type A preparation provided by Edward J Schantz and Eric A Johnson. Subsequently a large number of medical indications based on motor and glandular hyperactivity and-most recently-chronic migraine are now treated by BT therapy. BT's highly specific and elaborate mechanism of action represents a completely novel therapeutic principle which will have consequences far beyond existing indications. BT therapy entered neurology through Stanley Fahn in New York from where C David Marsden brought it to London. From here neurological BT therapy came to Germany through Reiner Benecke and Dirk Dressler. Ophthalmological BT therapy was brought directly to Germany by Peter Roggenkamper, a fellow of Scott. By the early 1990s, several users in Germany had learned about BT therapy and made the country one of the most productive countries in clinical BT science-backed up by a long tradition of solid basic BT research. For several years now, however, BT therapy in Germany has been stagnating due to a lack of reimbursement for the medical treatment and due to off-label use challenges. PMID- 28733712 TI - Fertility and ploidy of gametes of allodiploid and allotriploid loaches produced by diploid Misgurnus anguillicaudatus females and Paramisgurnus dabryanus males. AB - Artificial and natural hybridization of dojo loach Misgurnus anguillicaudatus (2N = 50, DD for short) and large-scale loach Paramisgurnus dabryanus (2N = 48, PP for short) are well-grown. However, these hybrid loaches have not yet been examined for fertility and ploidy of gametes. Here, histological observations, artificial propagation, observations of embryonic development, larval morphology, and ploidy analyses were conducted to determine the fertility and ploidy of gametes of allodiploid (DP for short) and allotriploid (DDP for short) loaches, produced by DD females * PP males and induced from fertilized eggs of DD females * PP males by cold shock to prevent the second polar body release, respectively. The ovaries of DP and DDP included smaller number of eggs when compared with those of the control DD, while full-grown oocytes were observed. Testes of these two loaches were delayed-developed without spermatids or mature spermatozoa. Results obtained here showed that DP and DDP were fertility-weakened female and sterile male. Moreover, DP females and DDP females could, respectively, produce few viable haploid eggs and few viable haploid and diploid eggs. This study will provide valuable information for fish hybrid researches. PMID- 28733713 TI - Diel cyclic hypoxia alters plasma lipid dynamics and impairs reproduction in goldfish (Carassius auratus). AB - Diel cyclic hypoxia occurs with varying frequency and duration in freshwater habitats, yet little is known about its effects on reproduction of freshwater fishes. The present study shows that long-term exposure of goldfish (Carassius auratus) to cyclic hypoxia (0.8 +/- 0.2 mg/l dissolved oxygen) for 9 h or more, per day, altered plasma lipid and sex steroid profiles, which in turn directly or indirectly suppressed ovarian growth and viable spermatozoa production. Hypoxia decreased total cholesterol and high density lipoprotein (HDL p < 0.05) and elevated triglycerides (TG; p < 0.05) in both sexes. Plasma steroid concentrations particularly of 17alpha-hydroxyprogesterone (17-HP), estradiol (E2), testosterone (T) in females, and T and 11-ketotestosterone (11-KT) in males were attenuated under diel hypoxic conditions. Intriguingly, both diel and continuous hypoxia elevated plasma E2 and vitellogenin levels in males. However, neither lipid nor steroid profiles recorded any variation in a dose-dependent manner in response to diel hypoxia. The reduced GSI, decreased number of tertiary oocytes, and motile spermatozoa in hypoxic fish clearly indicate suppression of gametogenesis. Thereby, prolonged diel cyclic hypoxia may affect valuable fishery resources and fish population structure by impairing reproductive performances and inducing estrogenic effects in males. PMID- 28733715 TI - Clinical performance of an updated trabecular bone score (TBS) algorithm in men and women: the Manitoba BMD cohort. AB - : This is the first study to directly compare the original and recently updated versions of the trabecular bone score (TBS) algorithm. We confirmed improved performance of the new algorithm, especially among men. INTRODUCTION: Lumbar spine trabecular bone score (TBS) predicts major osteoporotic fractures (MOFs) and hip fractures (HFs) independent of bone density. The original TBS algorithm (version 1; [TBS-v1]) was optimized for women of average body size. Limitations were identified when used in men or extremes of body mass index (BMI). The current study evaluates an updated TBS algorithm (version 2; [TBS-v2]) modified to address these issues. METHODS: From a registry with all DXA results for Manitoba, Canada, we identified 47,736 women and 4348 men age >= 40 with baseline spine DXA (GE Prodigy, 1999-2011). Spine TBS was measured using both TBS-v1 and TBS-v2 algorithms. Risk stratification for incident fractures identified from population-based data was assessed from area under the receiver operating characteristic curve (AUROC). RESULTS: With the TBS-v1 algorithm, average TBS for men was significantly lower than for women (p < 0.001) and showed significant inverse correlations with BMI (Pearson r-0.40 in men, -0.18 in women [both p < 0.001]). With the TBS-v2 algorithm, average values for men were slightly greater than for women (p < 0.001) and there were no significant correlations with BMI (Pearson r 0.01 in men, -0.01 in women [both p > 0.1]). During mean follow-up of 5 years in men, there were 214 incident MOFs and 47 HFs; during 6 years mean follow-up in women, there were 2895 incident MOFs and 694 HFs. Improvements in fracture prediction were seen with TBS-v2 in both men (change in AUROC for MOFs +0.021 [p = 0.17], HFs +0.046 [p = 0.04]) and women (change in AUROC for MOFs +0.012 [p < 0.001], HFs +0.020 [p < 0.001]). CONCLUSION: The updated TBS algorithm is less affected by BMI, gives higher mean results for men than women consistent with their lower fracture risk, and improves fracture prediction in both men and women. PMID- 28733714 TI - A Developmental Perspective in Mental Health Services Use Among Adults with Mental Disorders. AB - This study examined factors associated with mental health services (MHS) use by individuals with mental disorders within a developmental perspective of adulthood. Bivariate and multivariate analyses were conducted separately for each developmental stage on independent variables using the Andersen's behavioral health service model. For 18-29-year-old emerging adults (n = 141), autonomy, daily life/relations, Internet searching, alcohol dependence, cognitive impulsiveness, number of stressful events, and self-harm were associated with MHS use. For 30-49-year olds (n = 292), being female, country of origin, being on welfare, social integration, Internet searching, and number of stressful events were associated with MHS use. For 50-64-year-old middle-aged adults (n = 126), current occupation was associated with MHS use. Developing online resources for emerging adults may increase MHS use. For 30-49-year olds, outreach should target male, immigrants, and individuals less socially integrated and on welfare. For middle-aged adults, workplace programs that reduce stigma and offer psychological help could increase MHS use. PMID- 28733717 TI - Mortality rate in Polish intensive care units is lower than predicted according to the APACHE II scoring system. PMID- 28733716 TI - Osteosarcopenia: where bone, muscle, and fat collide. AB - As the world's population ages, the prevalence of chronic diseases increases. Sarcopenia and osteoporosis are two conditions that are associated with aging, with similar risk factors that include genetics, endocrine function, and mechanical factors. Additionally, bone and muscle closely interact with each other not only anatomically, but also chemically and metabolically. Fat infiltration, a phenomenon observed in age-related bone and muscle loss, is highly prevalent and more severe in sarcopenic and osteoporotic subjects. Clinically, when individuals suffer a combination of both disorders, negative outcomes such as falls, fractures, loss of function, frailty, and mortality increase, thus generating significant personal and socio-economic costs. Therefore, it is suggested that when bone mineral density loss is synchronic with decreased muscle mass, strength, and function, it should be interpreted as a single diagnosis of osteosarcopenia, which may be preventable and treatable. Simple interventions such as resistance training, adequate protein and calcium dietary intake, associated with maintenance of appropriate levels of vitamin D, have a dual positive effect on bone and muscle, reducing falls, fractures, and, consequently, disability. It is essential that fracture prevention approaches including postfracture management-involve assessment and treatment of both osteoporosis and sarcopenia. This is of particular importance as in older persons the combination of osteopenia/osteoporosis and sarcopenia has been proposed as a subset of frailer individuals at higher risk of institutionalization, falls, and fractures. This review summarizes osteosarcopenia epidemiology, pathophysiology, diagnosis, outcomes, and management strategies. PMID- 28733719 TI - Rare complication of femoral venous catheter malposition: abdominal compartment syndrome. PMID- 28733718 TI - Antimicrobial resistance in the next 30 years, humankind, bugs and drugs: a visionary approach. AB - PURPOSE: To describe the current standards of care and major recent advances with regard to antimicrobial resistance (AMR) and to give a prospective overview for the next 30 years in this field. METHODS: Review of medical literature and expert opinion were used in the development of this review. RESULTS: There is undoubtedly a large clinical and public health burden associated with AMR in ICU, but it is challenging to quantify the associated excess morbidity and mortality. In the last decade, antibiotic stewardship and infection prevention and control have been unable to prevent the rapid spread of resistant Gram-negative bacteria (GNB), in particular carbapenem-resistant Pseudomonas aeruginosa (and other non fermenting GNB), extended-spectrum beta-lactamase (ESBL)-producing and carbapenem resistant Enterobacteriaceae (CRE). The situation appears more optimistic currently for Gram-positive, where Staphylococcus aureus, and particularly methicillin-resistant S. aureus (MRSA), remains a cardinal cause of healthcare associated infections worldwide. Recent advancements in laboratory techniques allow for a rapid identification of the infecting pathogen and antibiotic susceptibility testing. Their impact can be particularly relevant in settings with prevalence of MDR, since they may guide fine-tuning of empirically selected regimen, facilitate de-escalation of unnecessary antimicrobials, and support infection control decisions. Currently, antibiotics are the primary anti infective solution for patients with known or suspected MDR bacteria in intensive care. Numerous incentives have been provided to encourage researchers to work on alternative strategies to reverse this trend and to provide a means to treat these pathogens. Although some promising antibiotics currently in phase 2 and 3 of development will soon be licensed and utilized in ICU, the continuous development of an alternative generation of compounds is extremely important. There are currently several promising avenues available to fight antibiotic resistance, such as faecal microbiota, and phage therapy. PMID- 28733720 TI - Low energy chronic traumatic spondylolisthesis of the axis. AB - OBJECTIVE: The aim of this study is to present a unique case of a patient who presented to our Emergency Department with evidence of a chronic traumatic spondylolisthesis of the axis with severe displacement treated with anterior cervical discectomy and fusion (ACDF) of C2-C3 as well as and posterior cervical fusion (PCF) of C1-C3. METHODS: One patient with an untreated traumatic spondylolisthesis of the axis with Levine type II injury pattern and 1.2 cm of anterior subluxation underwent ACDF C2-C3 and PCF C1-C3. RESULTS: The patient recovered well, radiographs demonstrated reduction of the anterior subluxation, and the patient reported a neck disability index (NDI) score of 20 at 6-month follow-up with full neurologic function intact. The patient was then lost to follow-up. CONCLUSION: In this report, we present an alcoholic patient with a history of many falls who presented with a Levine type II traumatic spondylolisthesis of the axis with signs of chronicity seen on magnetic resonance imaging (MRI). We were able to partially reduce the anterior displacement with traction, but needed both anterior and posterior cervical approaches to achieve adequate reduction and stabilization of the injury. PMID- 28733721 TI - Factors associated with postoperative C5 palsy after expansive open-door laminoplasty: retrospective cohort study using multivariable analysis. AB - PURPOSE: The aim of the present study was to investigate the factors associated with C5 palsy by focusing on radiological parameters using multivariable analysis. METHODS: The authors retrospectively assessed 190 patients with cervical spondylotic myelopathy treated by open-door laminoplasty. Four radiographic parameters-the number of expanded lamina, C3-C7 angle, lamina open angle and space anterior to the spinal cord-were evaluated to clarify the factors associated with C5 palsy. RESULTS: Of the 190 patients, 11 developed C5 palsy, giving an overall incidence of 5.8%. Although the number of expanded lamina, lamina open angle and space anterior to the spinal cord were significantly larger in C5 palsy group than those in non-palsy group, a multiple logistic regression analysis revealed that only the space anterior to the spinal cord (odds ratio 2.60) was a significant independent factor associated with C5 palsy. A multiple linear regression analysis indicated that the lamina open angle was associated with the space anterior to the spinal cord and the analysis identified the following equation: space anterior to the spinal cord (mm) = 1.54 + 0.09 * lamina open angle (degree). A cut-off value of 53.5 degrees for the lamina open angle predicted the development of C5 palsy with a sensitivity of 72.7% and a specificity of 83.2%. CONCLUSIONS: The larger postoperative space anterior to the spinal cord, which was associated with the lamina open angle, was positively correlated with the higher incidence of C5 palsy. PMID- 28733722 TI - Non-specific chronic low back pain: differences in spinal kinematics in subgroups during functional tasks. AB - PURPOSE: A multidimensional classification approach suggests that motor control impairment subgroups exist in non-specific chronic low back pain (NSCLBP). Differences in sitting lumbar posture have been identified between two such subgroups [flexion pattern (FP) and active extension pattern (AEP)] and healthy individuals; however, functional spinal movement has not been explored. This study will evaluate whether NSCLBP subgroups exhibit regional spinal kinematic differences, compared to healthy individuals, during functional tasks. METHODS: Observational, cross-sectional study design. Spinal kinematics of 50 NSCLBP subjects (27 FP, 23 AEP) and 28 healthy individuals were investigated using 3D motion analysis (ViconTM) during functional tasks [reaching upwards, step down, step up, lifting, and replacing a box, stand-to-sit, sit-to-stand, bending to retrieve (and returning from retrieving) a pen from the floor]. Mean sagittal angle for the total thoracic, total lumbar, upper thoracic, lower thoracic, upper lumbar, and lower lumbar regions between groups was compared. RESULTS: Significant differences were observed in lower thoracic and upper lumbar regions between NSCLBP subgroups during most tasks. Significant differences were observed between the FP and healthy group in the lower thoracic region during stand-to-sit to-stand tasks and bending (and returning from) to retrieve a pen from the floor. All significant results demonstrated the FP group to operate in comparatively greater flexion. CONCLUSIONS: The thoraco-lumbar spine discriminated between FP and AEP, and FP and healthy groups during functional tasks. FP individuals demonstrated more kyphotic thoraco-lumbar postures, which may be pain provocative. No significant differences were observed between AEP and healthy groups, suggesting that alternative mechanisms may occur in AEP. PMID- 28733723 TI - An individualized radiation dose escalation trial in non-small cell lung cancer based on FDG-PET imaging. AB - AIM: The aim of the study was to assess the feasibility of an individualized 18F fluorodeoxyglucose positron emission tomography (FDG-PET)-guided dose escalation boost in non-small cell lung cancer (NSCLC) patients and to assess its impact on local tumor control and toxicity. PATIENTS AND METHODS: A total of 13 patients with stage II-III NSCLC were enrolled to receive a dose of 62.5 Gy in 25 fractions to the CT-based planning target volume (PTV; primary turmor and affected lymph nodes). The fraction dose was increased within the individual PET based PTV (PTVPET) using intensity modulated radiotherapy (IMRT) with a simultaneous integrated boost (SIB) until the predefined organ-at-risk (OAR) threshold was reached. Tumor response was assessed during follow-up by means of repeat FDG-PET/computed tomography. Acute and late toxicity were recorded and classified according to the CTCAE criteria (Version 4.0). Local progression-free survival was determined using the Kaplan-Meier method. RESULTS: The average dose to PTVPET reached 89.17 Gy for peripheral and 75 Gy for central tumors. After a median follow-up period of 29 months, seven patients were still alive, while six had died (four due to distant progression, two due to grade 5 toxicity). Local progression was seen in two patients in association with further recurrences. One and 2-year local progression free survival rates were 76.9% and 52.8%, respectively. Three cases of acute grade 3 esophagitis were seen. Two patients with central tumors developed late toxicity and died due to severe hemoptysis. CONCLUSION: These results suggest that a non-uniform and individualized dose escalation based on FDG-PET in IMRT delivery is feasible. The doses reached were higher in patients with peripheral compared to central tumors. This strategy enables good local control to be achieved at acceptable toxicity rates. However, dose escalation in centrally located tumors with direct invasion of mediastinal organs must be performed with great caution in order to avoid severe late toxicity. PMID- 28733724 TI - Motion monitoring during a course of lung radiotherapy with anchored electromagnetic transponders : Quantification of inter- and intrafraction motion and variability of relative transponder positions. AB - PURPOSE: Anchored electromagnetic transponders for tumor motion monitoring during lung radiotherapy were clinically evaluated. First, intrafractional motion patterns were analyzed as well as their interfractional variations. Second, intra and interfractional changes of the geometric transponder positions were investigated. MATERIALS AND METHODS: Intrafractional motion data from 7 patients with an upper or middle lobe tumor and three implanted transponders each was used to calculate breathing amplitudes, overall motion amount and motion midlines in three mutual perpendicular directions and three-dimensionally (3D) for 162 fractions. For 6 patients intra- and interfractional variations in transponder distances and in the size of the triangle defined by the transponder locations over the treatment course were determined. RESULTS: Mean 3D values of all fractions were up to 4.0, 4.6 and 3.4 mm per patient for amplitude, overall motion amount and midline deviation, respectively. Intrafractional transponder distances varied with standard deviations up to 3.2 mm, while a maximal triangle shrinkage of 36.5% over 39 days was observed. CONCLUSIONS: Electromagnetic real time motion monitoring was feasible for all patients. Detected respiratory motion was on average modest in this small cohort without lower lobe tumors, but changes in motion midline were of the same size as the amplitudes and greater midline motion can be observed in some fractions. Intra- and interfractional variations of the geometric transponder positions can be large, so for reliable motion management correlation between transponder and tumor motion needs to be evaluated per patient. PMID- 28733725 TI - Carotid artery intimal medial thickness and carotid artery plaques in hypertensive patients with non-arteritic anterior ischaemic optic neuropathy. AB - PURPOSE: To assess the correlation of carotid artery intimal medial thickness (C IMT) and carotid artery plaque score (CPS) of the common carotid artery with non arteritic anterior ischemic optic neuropathy (NAION) in hypertensive patients. METHODS: This case-control study recruited 192 subjects. Forty-eight patients had NAION with systemic hypertension, 46 had hypertension without visual complaints, and 98 were normal controls. C-IMT and common carotid arterial plaque were measured by high-resolution vascular ultrasonography. RESULTS: High-density lipoprotein (HDL) in patients with NAION (1.24 +/- 0.31) was significantly lower than that of the Hypertensive group (1.39 +/- 0.30, P = 0.034). The C-IMT in the affected side of patients with NAION (1.00 +/- 0.23) was significantly increased compared to the unaffected side (0.83 +/- 0.19, P < 0.001), the Hypertensive group (0.83 +/- 0.17, P < 0.001), and the Normal group (0.69 +/- 0.16, P < 0.001). The presence of carotid artery plaque was more frequent in the patients with NAION, compared to either the Hypertensive group (P = 0.001) or the Normal group (P < 0.001). By multiple regression analysis, lower high-density lipoprotein (HDL) (P = 0.009), thicker C-IMT (P = 0.002), CPS Grade = 1 (P = 0.028), and Grade = 2 (P = 0.005) were associated with increased NAION risk, when the NAION group compared with the Hypertensive group (OR > 1.0). Systolic blood pressure (P = 0.001), thicker C-IMT (P < 0.001), CPS Grade = 1 (P = 0.006), Grade = 2 (P = 0.002), and Grade = 3 (P = 0.015) were associated with increased NAION risk, when the NAION group compared with the Normal group (OR > 1.0). CONCLUSIONS: C-IMT and CPS were associated with NAION in hypertensive patients, suggesting that NAION might be associated with carotid artery atherosclerosis. This association may be due to similar pathological changes of the inner vascular walls in the carotid artery and the arteries supplying the optic nerve head. PMID- 28733726 TI - Enhancing capacity among faith-based organizations to implement evidence-based cancer control programs: a community-engaged approach. AB - Evidence-based interventions (EBIs) to promote cancer control among Latinos have proliferated in recent years, though adoption and implementation of these interventions by faith-based organizations (FBOs) is limited. Capacity building may be one strategy to promote implementation. In this qualitative study, 18 community key informants were interviewed to (a) understand existing capacity for health programming among Catholic parishes, (b) characterize parishes' resource gaps and capacity-building needs implementing cancer control EBIs, and (c) elucidate strategies for delivering capacity-building assistance to parishes to facilitate implementation of EBIs. Semi-structured qualitative interviews were conducted. Key informants concurred about the capacity of Catholic parishes to deliver health programs, and described attributes of parishes that make them strong partners in health promotion initiatives, including a mission to address physical and mental health, outreach to marginalized groups, altruism among members, and existing engagement in health programming. However, resource gaps and capacity building needs were also identified. Specific recommendations participants made about how existing resources might be leveraged to address challenges include to: establish parish wellness committees; provide "hands-on" learning opportunities for parishioners to gain program planning skills; offer continuous, tailored, on-site technical assistance; facilitate relationships between parishes and community resources; and provide financial support for parishes. Leveraging parishes' existing resources and addressing their implementation needs may improve adoption of cancer control EBIs. PMID- 28733727 TI - Low-density lipoproteins investigated under high hydrostatic pressure by elastic incoherent neutron scattering. AB - Human low-density lipoprotein (LDL) is a highly complex nano-particle built up of various lipid classes and a single large protein moiety (apoB-100) owning essential physiological functions in the human body. Besides its vital role as a supplier of cholesterol and fat for peripheral tissues and cells, it is also a known key player in the formation of atherosclerosis. Due to these important roles in physiology and pathology the elucidation of structural and dynamical details is of great interest. In the current study we drew a broader picture of LDL dynamics using elastic incoherent neutron scattering (EINS) as a function of specified temperature and pressure points. We not only investigated a normolipidemic LDL sample, but also a triglyceride-rich and an oxidized one to mimic pathologic conditions as found under hyperlipidemic conditions or in atherosclerotic plaques, respectively. We could show that pressure has a significant effect on atomic motions in modified forms of LDL, whereas the normolipidemic sample seems to cope much better with high-pressure conditions irrespective of temperature. These findings might be explained by the altered lipid composition, which is either caused through elevated triglyceride content or modifications through lipid peroxidation. PMID- 28733728 TI - Totally extraperitoneal approach for ventral hernia. AB - BACKGROUND: In open surgery, extraperitoneal sublay mesh implantation is generally preferred to intraperitoneal placement, following the same principles as in "giant prosthetic reinforcement of the visceral sac" described for inguinal hernia repair [1, 2]. Miserez and Penninckx in 2002 described an endoscopic totally preperitoneal ventral hernia repair in a small cohort of 15 cases [3]. Unfortunately, this technique has not spread, probably because of the technical difficulties that require, but not for effectiveness. METHODS: This video demonstrates the detailed operative technique and feasibility for performing extraperitoneal mesogastric hernia repair endoscopically. After insufflation of CO2 in Retzius space, 3 trocars were introduced on semilunar line once identified the correct retromuscular plane. Blunt dissection was done up to midline. Above arcuate line, linea alba was incised in order to open the contralateral posterior rectus sheath and dissection proceeded laterally until the contralateral semilunar line. Hernia sac was reduced and the defect of posterior rectus sheath and peritoneum was closed with continuous suture. A composite mesh was placed without fixation. RESULTS: Operative time was 150 min without blood loss. Interruption of pain medication was in the first post operative day and discharge in second post operative day. One week after surgery, an ultrasound assessment was done to evaluate presence of seroma. CONCLUSIONS: Although this approach will not become the gold standard, certainly it presents some innovative elements such as non-exposure of the mesh with the abdominal viscera and the improvement of the comfort avoiding fixing system such as tacks. Comparison between the current endoscopic techniques is required. Totally extraperitoneal (TEP) approach for ventral hernia is safe and feasible. PMID- 28733729 TI - Laparoscopic left hepatectomy for mucinous cystic neoplasm of the liver. AB - BACKGROUND: Among liver cystic lesions, mucinous cystic neoplasm of the liver (MCN-L) constitutes a challenging issue in terms of management: preoperative diagnosis is often unachievable and this may mislead to inappropriate treatment [1-3]. We present the case of an otherwise healthy 29-year-old female who underwent laparotomic cyst unroofing in segment 4 and cholecystectomy in another institution. Post-operative course was complicated by biliary leakage that was endoscopically treated. Short term follow-up showed early recurrence with a volumetric enlargement of the cyst occupying most of the left hepatic lobe and new satellite cyst in Sg5. The doubt of MCN-L arose, and the patient was scheduled for laparoscopic removal at our Centre, despite the previous laparotomic procedure. METHODS: An optic port was placed into right upper abdominal quadrant and 3 further ports were placed. A long and difficult adhesiolysis was performed and Pringle's manoeuver was settled. Intraoperative US confirmed the anatomic limits of the cysts in Sg5 and in the left hepatic lobe. The cyst on Sg5 was resected first and frozen section was suspicious for MCN-L. In order to prevent recurrence, left laparoscopic hepatectomy was performed. The specimen was extracted through the previous midline laparotomy. RESULTS: Post operative course was uneventful and the patient was discharged on POD 5. Pathology and immunochemistry confirmed the diagnosis of MCN-L. CONCLUSION: Hepatic cystic lesions may be insidious and preoperative biopsy is not always possible due to lack of solid tissue. In unclear settings, an intraoperative frozen section is mandatory to guide intraoperative decisions. In the suspicion of malignancy, resection with oncologic criteria must be chosen as the most appropriate treatment, as well as the retrieving of MCN-L requires hepatic resection to avoid early recurrence [4, 5]. Despite of previous laparotomy, we consider a laparoscopic approach could be attempted in selected cases, in institution with particular expertise in laparoscopic liver surgery. PMID- 28733730 TI - Comparison of pure laparoscopic versus open left hemihepatectomy by multivariate analysis: a retrospective cohort study. AB - INTRODUCTION: To compare the outcomes of pure laparoscopic left hemihepatectomy (LLH) versus open left hemihepatectomy (OLH) for benign and malignant conditions using multivariate analysis. MATERIALS AND METHODS: All consecutive cases of LLH and OLH between October 2007 and December 2013 in a tertiary referral hospital were enrolled in this retrospective cohort study. All surgical procedures were performed by one surgeon. The LLH and OLH groups were compared in terms of patient demographics, preoperative data, clinical perioperative outcomes, and tumor characteristics in patients with malignancy. Multivariate analysis of the prognostic factors associated with severe complications was then performed. RESULTS: The LLH group (n = 62) had a significantly shorter postoperative hospital stay than the OLH group (n = 118) (9.53 +/- 3.30 vs 14.88 +/- 11.36 days, p < 0.001). Multivariate analysis revealed that the OLH group had >4 times the risk of the LLH group in terms of developing severe complications (Clavien Dindo grade >=III) (odds ratio 4.294, 95% confidence intervals 1.165-15.832, p = 0.029). DISCUSSION: LLH was a safe and feasible procedure for selected patients. LLH required shorter hospital stay and resulted in less operative blood loss. Multivariate analysis revealed that LLH was associated with a lower risk of severe complications compared to OLH. The authors suggest that LLH could be a reasonable treatment option for selected patients. PMID- 28733731 TI - Novel laparoscopic training system with continuously perfused ex-vivo porcine liver for hepatobiliary surgery. AB - OBJECTIVE: To introduce a novel laparoscopic training system with a continuously perfused ex-vivo porcine liver for hepatobiliary surgery. BACKGROUND: Existing models for laparoscopic training, such as box trainers and virtual reality simulators, often fail to provide holistic training and real haptic feedback. We have formulated a new training system that addresses these problems. METHODS: Real-Liver Laptrainer consists of a porcine liver, customized mannequin, ex-vivo machine perfusion system, and monitoring software. We made a detailed comparison of Real-Liver Laptrainer with the LapSim virtual reality simulator and the FLS Trainer Box systems. Five laparoscopic surgeons assessed the new system on multiple features. We assessed the performances of 43 trainees who used the new system to perform laparoscopic cholecystectomy (LC) three times. RESULTS: Real Liver Laptrainer offered more functions and better tactile feedback than the FLS or LapSim system. All five surgeons graded the quality of the new system as realistic. The utility of the system for training was scored as 3.6 +/- 1.1 on a scale of 1-5. Between the first and third attempts, the number of successfully performed LCs increased (9 vs 14 vs 23; P = .011), while the numbers of liver damage incidents (25 vs. 21 vs. 18, P = .303) and gallbladder perforations decreased (17 vs. 12 vs. 9, P = .163). The mean LC operation time significantly decreased (63 vs. 50 vs. 44, P < .0001). CONCLUSION: Real-Liver Laptrainer is a feasible, stable, and practical training model that has potential for improving the laparoscopic skills of surgeons. PMID- 28733732 TI - Predictive risk factors associated with cholangitis following ERCP. AB - BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) with stent placement is used for the management of many pancreaticobiliary disorders. It is generally safe with a few short-term complications. The risk factors for the development of post-ERCP cholangitis due to stent occlusion have not been previously described. This study identified such risk factors among patients undergoing ERCP and stent placement for pancreatic or biliary obstruction. METHODS: 3648 ERCPs performed at the University of Louisville from 2008 to 2016 were reviewed. Data including patient demographics, diagnostic, laboratory, and ERCP related data were included. Patients were classified as having post-ERCP cholangitis if they developed jaundice, fever, right upper quadrant abdominal pain, and confirmatory findings of stent occlusion and/or purulent drainage at the time of repeat ERCP. These patients were compared to those who did not develop post-ERCP cholangitis using univariate and multivariate analyses. RESULTS: A total of 431 patients met inclusion criteria. Of these, 57 (13.2%) developed post-ERCP cholangitis. The average age of patients was 57 years with 57% women and 43% men. On univariate analysis, patients developing post-ERCP cholangitis were more likely to be of increased age, have higher white blood cell count (WBC), total bilirubin (TBili), AST, ALT, and alkaline phosphatase (AlkPhos), and a decreased serum albumin level. Risk factors for post-ERCP cholangitis due to stent occlusion identified on multivariate analysis include: a diagnosis of cancer, the placement of multiple biliary stents at index ERCP, and low serum albumin level. CONCLUSIONS: The development of post-ERCP cholangitis due to stent occlusion is strongly associated with the presence of malignancy, the placement of multiple biliary stents, and low serum albumin. A decreased threshold to monitor for stent occlusion, including routine liver function tests and prophylactic stent removal or exchange, should be employed in patients with these characteristics. PMID- 28733733 TI - Outcome of dilatation and predictors of failed dilatation in patients with acid induced corrosive esophageal strictures. AB - Outcome of endoscopic dilatation in acid-induced corrosive esophageal stricture is less known. This study aims to determine the outcome of dilatation and predictors of failed dilatation in patients with acid-induced corrosive esophageal stricture. Patients diagnosed of corrosive esophageal strictures were included. Endoscopic dilatation with graded Savary-Gilliard dilator was performed as the first line treatment. Outcome of dilatation was considered favorable when patients were able to swallow solid without intervention at least six months after successful dilatation. Failure of dilatation was defined as one of the following; complete luminal stenosis, inability to perform safe dilatation, perforation, and inability to maintain adequate luminal patency. Surgery or repeated dilatation was indicated in failed dilatations. There were 55 patients with corrosive esophageal strictures. Of 55 patients, 41 (75%) had failed dilatation (38 having esophageal replacement procedure, two continue repeated dilatation and one unfit for surgery). Of 323 sessions of dilatations, eight out of 55 patients (14.5%) had perforations. There was no dilatation-related mortality. Patients with concomitant pharyngeal stricture (p = 0.0001), long (>= 10 cm) stricture length (p < 0.0001), number of dilatation >6 sessions per year (p = 0.01) and refractory stricture (inability to pass a larger than 11 mm dilator within three sessions) (p = 0.01) were more likely to have failed dilatation. Thirty-two of 38 patients with surgery had good swallow outcome with one operative mortality (2.6%). At the median follow-up of 61 months, overall favorable outcome was 84% after surgery and 25% for dilatation (p < 0.0001). Majority of patients with acid-induced corrosive esophageal stricture were refractory to dilatation. Esophageal dilatations were ultimately failed in three fourth of the patients. Concomitant cricopharyngeal stricture, long stricture length, requiring frequent dilatation, and refractory to >11 mm dilatation were factors associated with failed dilatation. PMID- 28733734 TI - Combined in vivo and ex vivo analysis of mesh mechanics in a porcine hernia model. AB - BACKGROUND: Hernia meshes exhibit variability in mechanical properties, and their mechanical match to tissue has not been comprehensively studied. We used an innovative imaging model of in vivo strain tracking and ex vivo mechanical analysis to assess effects of mesh properties on repaired abdominal walls in a porcine model. We hypothesized that meshes with dissimilar mechanical properties compared to native tissue would alter abdominal wall mechanics more than better matched meshes. METHODS: Seven mini-pigs underwent ventral hernia creation and subsequent open repair with one of two heavyweight polypropylene meshes. Following mesh implantation with attached radio-opaque beads, fluoroscopic images were taken at insufflation pressures from 5 to 30 mmHg on postoperative days 0, 7, and 28. At 28 days, animals were euthanized and ex vivo mechanical testing performed on full-thickness samples across repaired abdominal walls. Testing was conducted on 13 mini-pig controls, and on meshes separately. Stiffness and anisotropy (the ratio of stiffness in the transverse versus craniocaudal directions) were assessed. RESULTS: 3D reconstructions of repaired abdominal walls showed stretch patterns. As pressure increased, both meshes expanded, with no differences between groups. Over time, meshes contracted 17.65% (Mesh A) and 0.12% (Mesh B; p = 0.06). Mesh mechanics showed that Mesh A deviated from anisotropic native tissue more than Mesh B. Compared to native tissue, Mesh A was stiffer both transversely and craniocaudally. Explanted repaired abdominal walls of both treatment groups were stiffer than native tissue. Repaired tissue became less anisotropic over time, as mesh properties prevailed over native abdominal wall properties. CONCLUSIONS: This technique assessed 3D stretch at the mesh level in vivo in a porcine model. While the abdominal wall expanded, mesh-ingrown areas contracted, potentially indicating stresses at mesh edges. Ex vivo mechanics demonstrate that repaired tissue adopts mesh properties, suggesting that a better-matched mesh could reduce changes to abdominal wall mechanics. PMID- 28733735 TI - Laparoscopic repair of giant paraesophageal hernia: are there factors associated with anatomic recurrence? AB - BACKGROUND: Repair of giant paraesophageal hernia (PEH) is associated with a favorably high rate of symptom improvement; however, rates of recurrence by objective measures remain high. Herein we analyze our experience with laparoscopic giant PEH repair to determine what factors if any can predict anatomic recurrence. METHODS: We prospectively collected data on PEH characteristics, variations in operative techniques, and surgeon factors for 595 patients undergoing laparoscopic PEH repair from 2008 to 2015. Upper GI study was performed at 6 months postoperatively and selectively thereafter-any supra diaphragmatic stomach was considered hiatal hernia recurrence. Exclusion criteria included revisional operation (22.4%), size <5 cm (17.6%), inadequate follow-up (17.8%), and confounding concurrent operations (6.9%). Inclusion criteria were met by 202 patients (31% male, median age 71 years, and median BMI 28.7). RESULTS: At a median follow-up of 6 months (IQR 6-12), overall anatomic recurrence rate was 34.2%. Symptom recurrence rate was 9.9% and revisional operation was required in ten patients (4.9%). Neither patient demographics nor PEH characteristics (size, presence of Cameron erosions, esophagitis, or Barrett's) correlated with anatomic recurrence. Technical factors at operation (mobilized intra-abdominal length of esophagus, Collis gastroplasty, number of anterior/posterior stitches, use of crural buttress, use of pledgeted or mattress sutures, or gastrostomy) were also not correlated with recurrence. Regarding surgeon factors, annual volume of fewer than ten cases per year was associated with increased risk of anatomic failure (54 vs 33%, P = 0.02). Multivariate analysis identified surgeon experience (<10 cases per year) as an independent factor associated with early hiatal hernia recurrence (OR 3.7, 95% CI 1.34-10.9). CONCLUSIONS: Laparoscopic repair of giant PEH is associated with high anatomic recurrence rate but excellent symptom control. PEH characteristics and technical operative variables do not appear to significantly affect rates of recurrence. In contrast, surgeon volume does appear to contribute significantly to durability of repair. PMID- 28733736 TI - Effects of steroid use for stenosis prevention after wide endoscopic submucosal dissection for gastric neoplasm. AB - BACKGROUND: Stenosis is a troublesome complication after wide endoscopic submucosal dissection (ESD). As steroids are known to prevent post-ESD esophageal stenosis, this study aimed to clarify the gastric effects. METHODS: This was a retrospective single-institution study. Between September 2002 and June 2015, 132 patients with a post-ESD mucosal defect exceeding three-fourths of the circumference were identified. Among them, 107 patients who did not undergo additional surgery for non-curative resection were reviewed. Steroid treatment (local injection and/or systemic) for stenosis prevention was administered to 28 patients within 10 days after ESD (steroid group). The incidence of stenosis and course of therapeutic endoscopic balloon dilation (EBD) were analyzed between the steroid and non-steroid group. RESULTS: Stenosis occurred in 31% (33/107) of patients. Full circumferential defect and defect extending to the pyloric ring were significantly related with stenosis. The proportion of patients with a full circumferential defect was relatively higher in the steroid group (14%) compared to the non-steroid group (5%) (p = 0.111). There was no significant relationship between the incidence of stenosis and the use of steroids (steroid group 39%, non steroid group 28%, p = 0.260). However, the interval from ESD to stenosis was significantly delayed among steroid-treated patients with a near-circumferential to three-fourth mucosal defect (p = 0.001) and among patients with ESD in the lower stomach (p = 0.002). The number of therapeutic EBDs and treatment duration did not differ significantly between the groups. Steroid treatment did not increase the incidence of ESD- and EBD-related complications. CONCLUSION: Despite the retardation of the occurrence of stenosis in some subgroups, early steroid treatment did not a show a significant effect on stenosis prevention after wide gastric ESD. Further evaluation is needed to determine the dose and timing of steroid treatment for stenosis after wide gastric ESD. PMID- 28733737 TI - Surveillance strategy according to age after endoscopic resection of early gastric cancer. AB - BACKGROUND: Whether surveillance strategy after curative endoscopic submucosal dissection (ESD) for early gastric cancer (EGC) differs in young patients is unclear. This study aimed to evaluate the risk of metachronous and extragastric recurrence in young patients with EGC after curative ESD. METHODS: We retrospectively enrolled 1237 consecutive patients who underwent curative ESD for EGC from 2005 to 2014 at a single tertiary hospital. The patients were divided into group 1 (<50 years of age, n = 86), group 2 (age 50-74, n = 985), or group 3 (>=75 years of age, n = 166). The clinical characteristics and outcomes were compared among the three age groups. RESULTS: Group 1 had more frequent Helicobacter pylori infection (P < 0.001), less frequent intestinal metaplasia (P = 0.021), and more frequent undifferentiated tumors (P = 0.039). Although the 5 year risk of developing metachronous recurrence appeared to be lower in group 1 (2.7%) than in groups 2 (8.6%) or 3 (8.7%), the risk became quite similar at the 7-year follow-up (6.4, 12.7, and 8.7% for groups 1, 2, and 3, respectively; P = 0.409 by log-rank test). Extragastric recurrences developed in only 2 cases in group 2 (0.2%). CONCLUSIONS: Surveillance for metachronous and extragastric recurrence after curative ESD in patients <50 years of age should not be different from that in patients >=50 years of age. Endoscopic surveillance for metachronous recurrence should be continued for longer than 5 years, even in young patients. PMID- 28733738 TI - Robot-assisted total mesorectal excision for rectal cancer: case-matched comparison of short-term surgical and functional outcomes between the da Vinci Xi and Si. AB - BACKGROUND: Robotic rectal resection with da Vinci Si has some technical limitations, which could be overcome by the new da Vinci Xi. We compare short term surgical and functional outcomes following robotic rectal resection with total mesorectal excision for cancer, with the da Vinci Xi (Xi-RobTME group) and the da Vinci Si (Si-RobTME group). METHODS: The first consecutive 30 Xi-RobTME were compared with a Si-RobTME control group of 30 patients, selected using a one to-one case-matched methodology from our prospectively collected Institutional database, comprising all cases performed between April 2010 and September 2016 by a single surgeon. Perioperative outcomes were compared. The impact of minimally invasive TME on autonomic function and quality of life was analyzed with specific questionnaires. RESULTS: The docking and overall operative time were shorter in the Xi-RobTME group (p < 0.001 and p < 0.05 respectively). The mean differences of overall operative time and docking time were -33.8 min (95% CI -5.1 to -64.5) and -6 min (95% CI -4.1 to -7.9), respectively. A fully-robotic approach with complete splenic flexure mobilization was used in 30/30 (100%) of the Xi-RobTME cases and in 7/30 (23%) of the Si-RobTME group (p < 0.001). The hybrid approach in males and patients with BMI > 25 kg/m2 was necessary in ten patients (45 vs. 0%, p < 0.001) and in six patients (37 vs. 0%, p < 0.05), in the Si-RobTME and Xi RobTME groups, respectively. There were no differences in conversion rate, mean hospital stay, pathological data, and in functional outcomes between the two groups before and at 1 year after surgery. CONCLUSION: The technical advantages offered by the da Vinci Xi seem to be mainly associated with a shorter docking and operative time and with superior ability to perform a fully-robotic approach. Clinical and functional outcomes seem not to be improved, with the introduction of the new Xi platform. PMID- 28733739 TI - Variation and treatment of vessels in laparoscopic right hemicolectomy. AB - BACKGROUND: With the introduction of complete mesocolic excision (CME) and the application of laparoscopic technique, surgery for colon cancer has become more standardized and the curative effect has improved [1]. The key points in laparoscopic right hemicolectomy are high ligation of main vessels and root dissection of lymph nodes. The wide range of variations in vascular architecture and intraoperative bleeding are common causes of prolonged surgical time, wound hemorrhage, and even transfer to the opening operation. METHODS: The superior mesenteric vein (SMV) is the most important anatomical landmark in CME for the right colon, and guides all the steps of lymph node dissection. The SMV appears as a pale blue bulge on laparoscopy, which enables accurate positioning. The ileocolic vessel pedicle is relatively constant and facilitates accurate positioning. The intersection of the ileocolic vessel pedicle and the SMV is the optimal starting point in laparoscopic right hemicolectomy using a medial-to lateral approach. A sheath with an avascular plane can be reached after opening the SMV vascular sheath, which results in less bleeding and enables vascular root and thorough lymph node dissection. The first step is to manage the ileocolic vessels. The ileocolic artery (ICA) is located anterior to the ileocolic vein (ICV) for about one-third of the incidence. The ileocolic vessels are relatively long and are easy to work with. In the vast majority of cases, the ICV drains into the SMV, and into the gastrocolic trunk (GCT) in about 2.5% of cases. The reported incidence of a right colic artery (RCA) is controversial; the RCA is absent in about 50% of cases and often crosses the SMV. The right colic vein (RCV) usually drains into the GCT, but sometimes drains directly into the SMV. The middle colic vessels have great variability and a close anatomical relationship with the pancreas, duodenum, and GCT. Moreover, the transverse colon and mesentery are long, and root positioning and processing of the middle colic vein (MCV) are relatively difficult. With the SMV and pancreas as anatomic landmarks, it is more feasible to locate the blood vessels in the neck of the pancreas. The middle colic artery (MCA) originates from the superior mesenteric artery (SMA), and the distance from the inferior border of the pancreas differs slightly in the literature, but is at the most 5 cm. Identification of the MCA trunk and branches, as well as the common origin of the MCA and RCA, is of great importance for the maintaining the blood supply during surgery for primary colon cancer. The MCV mainly drains into the SMV and GCT; however, if branching variation drains into the jejunal vein, inferior mesenteric vein, or splenic vein, the effect is serious when a vessel is torn. Isolation of the GCT is the step at which bleeding will likely occur in standard right resection and is a difficult stage of the surgery. The GCT has five origins including the right gastroepiploic vein (RGV), right colic vein (RCV), accessory right colic vein (ARCV), pancreaticduodenal vein (PDV), and MCV, which can have 2, 3, or 4 branches; therefore, familiarity with variants may be helpful to avoid bleeding. Approximately 5-10% of colon cancers at the hepatic flexure have No. 6 group lymph node metastasis, and laparoscopic radical extended right hemicolectomy requires thorough dissection of No. 6 group lymph nodes and the omental arcade 10 cm from the pylorus. The inferior arteriovenous vessels are a common source of bleeding, and the RGV can serve as a clue to finding the artery. CONCLUSIONS: The core area of laparoscopic radical extended right hemicolectomy includes the pancreatic neck, duodenum, and right gastroepiploic vessels. The difficulty lies with the standard treatment of the GCT. A medial-to-lateral approach is more in line with the principle of no-touch in tumor surgery and is applied from lower to upper, inside to outside, and left to right, for both the vessels and plane of dissection. Familiarity with vascular variation and the management of vessels in key areas are essential for successful surgery. PMID- 28733740 TI - Laparoscopic splenopexy for wandering spleen, a video demonstration of technique by encircling the spleen with polyglactin 910 woven mesh. AB - BACKGROUND: Wandering spleen is a rare clinical entity caused by absence of the spleen's peritoneal attachments, allowing the spleen to move freely within the peritoneal cavity [1]. This disease is most commonly seen in children and young women [1, 2]. Affected individuals are predisposed to complications including splenic torsion, splenic infarction, and pancreatic necrosis [3, 4]. Patients may present with constipation, an abdominal mass, swelling, or acute abdominal pain if splenic torsion has occurred [4]. Wandering spleen is difficult to diagnose without imaging, as symptoms are non-specific or may be absent. Imaging studies to confirm the diagnosis may include computed tomography (CT) scan or duplex ultrasonography [5]. Definitive management of a wandering spleen is primarily surgical [2]. Splenectomy is the preferred treatment in patients who present with an acute splenic infarction [2, 6]. Splenopexy, however, is first line treatment for patients with a non-infarcted wandering spleen [2, 7, 8]. CASE PRESENTATION: In this video, we present a case of an 11 year old male with a symptomatic wandering spleen who was treated at our institution with laparoscopic splenopexy. The patient had a history of arthrogryposis multiplex congenita and presented with recurrent, episodic abdominal pain, nausea, and vomiting. The diagnosis was confirmed by CT scan which demonstrated the spleen in the right lower quadrant. We performed laparoscopic splenopexy by encircling the spleen with polyglactin 910 woven mesh and attaching the mesh to the left lateral abdominal wall with absorbable tacks. DISCUSSION: Our surgical technique for splenopexy was successful and the patient returned home on postoperative day four. No significant complications occurred. This video demonstrates this technique and highlights the key steps. Splenopexy by encircling the spleen with polyglactin 910 mesh is feasible, preserves splenic function, and can be performed with standard laparoscopic equipment. Tacks or transfascial sutures are a potential option for securing mesh. PMID- 28733741 TI - Tips and tricks of splenic vessel preservation during laparoscopic distal pancreatectomy. AB - BACKGROUND: While a laparoscopic approach can minimize postoperative morbidity in splenic vessel preserving (SVP) distal pancreatectomy (DP), this procedure can be technically challenging. A systematic approach to SVP minimizes the chances of vascular injury and maximizes the chances of successful splenic preservation. This video demonstrates a laparoscopic DP with SVP, highlighting technical tips and tricks that optimize the chances for SVP. PATIENT: The patient is a 14-year old male with an incidentally discovered pancreatic tail mass. CT imaging demonstrates a 4.5 cm well-circumscribed tumor with the typical solid and cystic components of a solid pseudopapillary tumor (SPPT). Since SPPT is a rare pancreatic tumor associated with excellent prognosis following surgery, upfront minimally invasive DP with SPV was considered the optimal approach in this young patient. Following successful surgery, the postoperative course was uneventful. Pathology confirmed the diagnosis of a pT3N0. SPPT with negative margins. TECHNIQUE: Here we demonstrate a systematic approach to maximize the changes of SVP in DP. This approach, as demonstrated in the video, includes optimal patient and port positioning, dissection to optimize exposure of the distal splenic vessels, techniques to minimize vascular trauma especially splenic venous trauma, as well as supplemental measures to ensure postoperative patency of splenic vessels following completion of the case. CONCLUSIONS: This systematic approach may maximize the changes of successful SVP, while avoiding postoperative complications such as splenic infarct, left-sided portal hypertension or overwhelming post-splenectomy sepsis. PMID- 28733742 TI - Self-expandable metal stents for the extraction of common bile duct stones in patients receiving dual antiplatelet agents: a pilot study. AB - BACKGROUND: Endoscopic sphincterotomy or endoscopic papillary balloon dilatation during endoscopic retrograde cholangiopancreatography (ERCP) are associated with a high risk of bleeding in patients receiving dual antiplatelet agents (APAs). However, the discontinuation of antiplatelet agents increases the risk of thromboembolic events in these patients. To date, the placement of self expandable metal stents (SEMSs) in patients receiving dual APAs has not been well investigated. The aim of this study was to evaluate the feasibility and safety of SEMS placement for the removal of common bile duct (CBD) stones in patients in whom APAs were not discontinued. METHODS: Ten consecutive patients who were suspected of having CBD stones and who were receiving dual APAs were prospectively enrolled and underwent temporary SEMS placement, followed by stone extraction and SEMS removal. The patients continued taking dual APAs at the time of undergoing the procedure. RESULTS: SEMS placement was successful in all ten patients. Complete duct clearance with the SEMSs was achieved in a single session in all patients with CBD stones (9/9, 100%). One patient had cholangitis, but ERCP did not reveal biliary stones. There were no cases of bleeding during or after the procedure, even though all patients continued to take dual APAs. There were no new thromboembolic events. CONCLUSIONS: SEMSs can be used for the extraction of CBD stones in patients on dual APAs, and does not lead to hemorrhagic or thromboembolic events. PMID- 28733743 TI - Therapeutic peroral direct cholangioscopy using a single balloon enteroscope in patients with Roux-en-Y anastomosis (with videos). AB - BACKGROUND: Peroral cholangioscopic lithotripsy is a useful procedure in patients with a normal gastrointestinal anatomy who have difficult-to-treat stones. We evaluated the usefulness of peroral direct cholangioscopy (PDCS) using single balloon enteroscope (SBE) in patients with difficult-to-treat stones who had undergone Roux-en-Y reconstruction. METHODS: Among 118 patients (169 sessions) who underwent SBE-assisted endoscopic retrograde cholangiopancreatography to treat biliary stones after Roux-en-Y reconstruction, patients in whom it was difficult to remove biliary stones via a transpapillary or transanastomotic approach and difficult to switch to ultra-slim endoscope, were retrospectively enrolled. The biliary insertion success rate, procedure success rate, procedure time, and procedural complications were assessed. The SBE was inserted into the bile-duct, first using a free-hand technique, second using a guide wire, and third using the large balloon anchoring and deflation (LBAD) technique. RESULTS: A total of 11 patients (14 sessions) were enrolled in this study. The biliary insertion success rate was 100%. Bile-duct insertion was performed using a free hand technique in 4 sessions, a guide wire in 3 sessions (rendezvous technique, 2 sessions), and the LBAD technique in 7 sessions. The procedure success rate was 86% in first session, and 100% in second session. The median procedure time was 81 min (range 49-137). The median procedure time in the bile-duct was 21.5 min (range 6-60). Mild pancreatitis occurred as a complication in one patient. The median follow-up was 528 days (range 282-764). No patient had stone recurrence. CONCLUSIONS: PDCS using SBE is a useful procedure in patients with Roux-en-Y reconstruction. The LBAD technique is an useful technique of inserting SBE into the bile-duct. PMID- 28733744 TI - Comparison of one stage laparoscopic cholecystectomy combined with intra operative endoscopic sphincterotomy versus two-stage pre-operative endoscopic sphincterotomy followed by laparoscopic cholecystectomy for the management of pre operatively diagnosed patients with common bile duct stones: a meta-analysis. AB - BACKGROUND: Laparoscopic cholecystectomy (LC) for symptomatic gallstone disease is one of the most common surgical procedures. Concomitant common bile duct (CBD) stones are detected with an incidence of 4-20% and the ideal management is still controversial. The frequent practice is to perform endoscopic sphincterotomy pre operatively (POES) followed by LC, to allow subsequent laparoscopic or open exploration if POES fails. However, POES has shown different drawbacks such as need for two hospital admissions, need of two anesthesia inductions, higher rate of pancreatitis, and longer hospital stay. Hence, an intra-operative endoscopic sphincerotomy (IOES) has been proposed. OBJECTIVE: To compare the 1 stage laparoscopic cholecystectomy (LC) combined with IOES versus 2-stage POES followed by LC for the management of pre-operatively known cholecystocholedocholithiasis. SEARCH STRATEGY: The search terms bile duct stones/calculi, ERCP, endoscopic sphincterotomy, laparoendoscopic rendezvous (LERV), and laparoscopic ductal clearance/choledochotomy/exploration were used. A comprehensive hand-based search of reference lists of published articles and review articles was performed to ensure inclusion of all possible studies and exclude duplicates. SELECTION CRITERIA: RCTs comparing 1 stage LC combined with IOES versus 2-stage POES followed by LC for the management of pre-operatively known cholecystocholedocholithiasis in adults. DATA COLLECTION & ANALYSIS: Three reviewers assessed trial quality and extracted the data. Data were entered in revman version 5.3. The trials were grouped according to the outcome measure assessed such as success rate of CBD stone clearance, incidence of pancreatitis, overall morbidity, and length of hospital stay. MAIN RESULTS: A total of 629 patients in 5 RCTs met the inclusion criteria. The success rate of CBD clearance (IOES = 93%, POES = 92%) was the same in both groups (OR 1.34; 95% CI 0.45-0.97; p = 0.60). Findings showed that IOES was associated with less pancreatitis (0.6%) than POES (4.4%) (OR 0.19; 95% CI 0.06-0.67; p = 0.01; I 2 = 43%). The incidence of overall morbidity was lower in the IOES group (6%) than the POES group (11%) (OR 0.54; 95% CI 0.31-0.96; p = 0.03; I 2 = 20%). The mean days of hospital stay for IOES group (M = 3.52, SD = 1.434, N = 5) was significantly less than the POES group (M = 6.10, SD = 2.074, N = 5), t(8) = 2.29, p <= 0.051. CONCLUSION: IOES is at par with two-stage POES in terms of CBD clearance, with less incidence of post operative pancreatitis, overall morbidity, and less hospital stay. PMID- 28733745 TI - Perioperative and oncological outcomes of laparoscopic anatomical hepatectomy for hepatocellular carcinoma introduced gradually in a single center. AB - BACKGROUND: Anatomical hepatectomy is an ideal curative treatment for hepatocellular carcinoma (HCC). We have standardized our laparoscopic anatomical hepatectomy (LAH) procedure, gradually extending its indications. In the present study, we describe our experience and the perioperative and oncological outcomes of LAH for HCC compared to those of open anatomical hepatectomy (OAH) during the gradual introduction of LAH. METHODS: Seventy patients with primary HCC underwent anatomical hepatectomy in our institution from November 2008 to April 2014. As we gained experience with LAH, our indications for choosing LAH over OAH gradually expanded. Ultimately, 40 and 30 patients underwent LAH and OAH, respectively. Perioperative and oncological outcomes were compared between the two groups. RESULTS: There were no significant differences in age, sex, background of liver disease, liver function, tumor size, tumor number, or type of liver resection between the two groups. Major complications and mortality rates were similar between the LAH and OAH groups (12.5% vs. 20%; p = 0.582, and 0% vs. 3.3%; p = 0.429, respectively). The median follow-up time after surgery was 40.5 months in the LAH group and 32.9 months in the OAH group (p = 0.835). The 1-, 3-, and 5 year overall survival rates were 89.9, 84.7, and 70.9%, in the LAH group, and 89.8, 68.0, and 63.1% in the OAH group, respectively (p = 0.255). The 1-, 3-, and 5-year disease-free survival rates were 79.5, 58.0, and 42.5%, in the LAH group, and 72.4, 56.1, and 50.4% in the OAH group, respectively (p = 0.980). CONCLUSIONS: Through gradual introduction of LAH, we obtained comparable results to those achieved with OAH. LAH can be a feasible surgical treatment for primary HCC, with good oncological outcomes. PMID- 28733746 TI - Comparative analysis of perioperative outcomes of robotic versus open transversus abdominis release. AB - BACKGROUND: Transversus abdominis release (TAR) has evolved as an effective approach to complex abdominal wall reconstructions. Although the role of robotics in hernia surgery is rapidly expanding, the benefits of a robotic approach for abdominal wall reconstruction have not been established well. We aimed to compare the impact of the application of robotics to the TAR procedure on the perioperative outcomes when compared to the open TAR repairs. METHODS: Case matched comparison of patients undergoing robotic TAR (R-TAR) at two specialized hernia centers to a matched historic cohort of open TAR (O-TAR) patients was performed. Outcome measures included patient demographics, operative details, postoperative complications, and length of hospitalization. RESULTS: 38 consecutive patients undergoing R-TAR were compared to 76 matched O-TAR. Patient demographics were similar between the groups, but ASA III status was more prevalent in the O-TAR group. The average operative time was significantly longer in the R-TAR group (299 +/- 95 vs.. 211 +/- 63 min, p < 0.001) and blood loss was significantly lower for the R-TAR group (49 +/- 60 vs. 139 +/- 149 mL, p < 0.001). Wound morbidity was minimal in the R-TAR, but the rate of surgical site events and surgical site infection was not different between groups. Systemic complications were significantly less frequent in the R-TAR group (0 vs. 17.1%, p = 0.026). The length of hospitalization was significantly reduced in the R-TAR group (1.3 +/- 1.3 vs. 6.0 +/- 3.4 days, p < 0.001). CONCLUSIONS: In our early experience, robotic TAR was associated with longer operative times. However, we found that the use of robotics was associated with decreased intraoperative blood loss, fewer systemic complications, shorter hospitalizations, and eliminated readmissions. While long-term outcomes and patient selection criteria for robotic TAR repair are under investigations, we advocate selective use of robotics for TAR reconstructions in patients undergoing AWR. PMID- 28733747 TI - Model to identify early-stage gastric cancers with deep invasion of submucosa based on endoscopy and endoscopic ultrasonography findings. AB - BACKGROUND: Conventional endoscopy and endoscopic ultrasonography (EUS) are used to estimate the invasion depth of early-stage gastric cancers (EGCs), but estimates made by either technique are often inaccurate. We developed a model to determine the invasion depth of EGCs using conventional endoscopy and EUS findings, with pathology results as the reference. METHODS: We performed a retrospective study of 195 patients (205 lesions) diagnosed with gastric cancers who underwent endoscopy and EUS followed by resection. Based on pathology analyses, lesions (n = 205) were assigned to categories of: mucosa invasion or minute invasion into the submucosal layer less than 500 MUm from the muscularis mucosae (M-SM1) or penetration of 500 MUm or more (>=SM2). The lesions were randomly assigned to derivation (138 lesions) and validation sets (67 lesions). A depth predictive model was proposed in the derivation set using multivariate logistic regression analyses. The discriminative power of this model was assessed in both sets. RESULTS: Remarkable redness (OR 5.42; 95% CI 1.32-22.29), abrupt cutting of converging folds (OR 8.58; 95% CI 1.65-44.72), lesions location in the upper third of the stomach (OR 10.26; 95% CI 2.19-48.09), and deep invasion based on EUS findings (OR 16.53; 95% CI 4.48-61.15) significantly associated with >=SM2 invasion. A model that incorporated these 4 variables discriminated between M-SM1 and >=SM2 lesions with the area under the ROC curve of 0.865 in the derivation set and 0.797 in the validation set. In the derivation set, a cut-off score of 8 identified lesions as >=SM2 with 54% sensitivity and 97% specificity. The model correctly predicted the invasion depth 89.86% of lesions; it overestimated the depth of 2.17% of lesions. CONCLUSIONS: We developed a model to identify EGCs with invasion depth >=SM2 based on endoscopy and EUS findings. This model might reduce overestimation of gastric tumor depth and prevent unnecessary gastrectomy. PMID- 28733748 TI - Preoperative Botulinum toxin A enabling defect closure and laparoscopic repair of complex ventral hernia. AB - INTRODUCTION: Operative management of complex ventral hernia still remains a significant challenge for surgeons. Closure of large defects in the unprepared abdomen has serious pathophysiological consequences due to chronic contraction and retraction of the lateral abdominal wall muscles. We report outcomes of 56 consecutive patients who had preoperative Botulinum toxin A (BTA) abdominal wall relaxation facilitating closure and repair. METHODS: This was a prospective observational study of 56 patients who underwent ultrasound-guided BTA into the lateral abdominal oblique muscles prior to elective ventral hernia repair between November 2012 and January 2017. Serial non-contrast abdominal CT imaging was performed to evaluate changes in lateral oblique muscle length and thickness. All hernias were repaired laparoscopically, or laparoscopic-open-laparoscopic (LOL) using intraperitoneal onlay mesh. RESULTS: 56 patients received BTA injections at predetermined sites to the lateral oblique muscles, which were well tolerated. Mean patient age was 59.7 years, and mean BMI was 30.9 kg/m2 (range 21.8-54.0). Maximum defect size was 24 * 27 cm. A subset of 18 patients underwent preoperative pneumoperitoneum as an adjunct procedure. A comparison of pre-BTA to post-BTA imaging demonstrated an increase in mean lateral abdominal wall length from 16.1 cm to 20.1 cm per side, a mean gain of 4.0 cm/side (range 1.0-11.7 cm/side) (p < 0.0001). This corresponds to an unstretched mean length gain of 8.0 cm of the lateral abdominal wall. Laparoscopic/LOL primary closure was achieved in all cases, with no clinical evidence of raised intra-abdominal pressures. One patient presented with a new fascial defect 26 months post-operative. CONCLUSION: Preoperative BTA to the lateral abdominal wall muscles is a safe and effective technique for the preparation of patients prior to operative management of complex ventral hernias. BTA temporary flaccid paralysis relaxes, elongates and thins the chronically contracted abdominal musculature. This in turn reduces lateral traction forces facilitating laparoscopic repair and fascial closure of large defects under minimal tension. PMID- 28733749 TI - Usefulness of the S-O clip for gastric endoscopic submucosal dissection (with video). AB - BACKGROUND: Endoscopic submucosal dissection (ESD) is technically one of the most complicated endoscopic procedures. Traction methods have been reported to be effective for ESD. A recent study revealed that the S-O clip allowed faster and safer colonic ESD. We assessed the efficacy and safety of gastric ESD with the S O clip for gastric epithelial neoplasm. METHODS: We performed a retrospective cohort study of patients treated for gastric ESD using the S-O clip between September and November 2016 (SO group, n = 48). The subjects were matched with patients treated with conventional gastric ESD from September 2015 to August 2016 (control group, n = 258) at Sendai Kousei Hospital, a tertiary endoscopic center. The primary outcome was procedure time. Multivariate logistic regression and propensity score matching analyses were performed to reduce the effects of selection bias for potential confounding factors differences like age, sex, lesion location, lesion position, presence of ulcer scarring, resected specimen size, and operator experiences. RESULTS: Forty-eight pairs were created after propensity score matching. The mean procedure time (including the S-O clip attachment time) was significantly shorter in the SO group (47.2 +/- 24.6 vs. 69.2 +/- 67.1 min, p = 0.035). The mean clip attachment time was 4.4 (range 2-15) min. There were no significant differences in other treatment outcomes (en-bloc resection rate: 100 vs. 100%, p = 1.000; perforation rate: 0 vs. 2.1%, p = 0.315; delayed bleeding rate: 2.1 vs. 4.3%, p = 0.558). CONCLUSIONS: The S-O clip improved the speed of gastric ESD by approximately 25%, without increasing adverse events. PMID- 28733750 TI - Magnetic surgery: first U.S. experience with a novel device. AB - INTRODUCTION: Magnet-assisted surgery is a new platform within minimally invasive surgery. The LevitaTM Magnetic Surgical System, the first magnetic surgical system to receive Food and Drug Administration (FDA) approval, includes a deployable, magnetic grasper and an external magnet that is used to manipulate the grasper within the peritoneal cavity. This system is currently approved for patients undergoing laparoscopic cholecystectomy with a body mass index (BMI) between 21 and 34 kg/m2. Herein, we detail the first United States experience with the LevitaTM Magnetic Surgical System during laparoscopic cholecystectomy. METHODS: The LevitaTM Magnetic Surgical System was used on consecutive patients undergoing laparoscopic cholecystectomy at our institution from June 2016 through November 2016. Only patients undergoing elective surgery and those with a body mass index (BMI) between 21 and 34 kg/m2 were included. Baseline patient characteristics, operative time, and perioperative details were collected. RESULTS: A total of ten patients underwent laparoscopic cholecystectomy with the LevitaTM Magnetic Surgical System during the defined study period. The mean age at the time of surgery was 49.0 years and the average BMI of the cohort was 27.6 kg/m2. The average operative time was 64.4 min. There were no perioperative complications. Seven (70.0%) patients were discharged to home on the day of surgery, while the remaining three (30.0%) patients were discharged to home on postoperative day number one. Surgeons reported that the magnetic grasper was easy to use and provided adequate tissue retraction and exposure. CONCLUSIONS: The LevitaTM Magnetic Surgical System is safe and feasible to use in patients undergoing laparoscopic cholecystectomy. Routine use of this system may facilitate a reduction in the total number of laparoscopic trocars used, leading to less tissue trauma and improved cosmesis. Additional studies are needed to determine the applicability and utility of this system for other general surgery cases. PMID- 28733751 TI - Evaluation of the safety and efficacy of metoprolol infusion for children and adolescents with hypertensive crises: a retrospective case series. AB - BACKGROUND: Acute severe hypertension occurs infrequently in pediatric patients and, consequently, data on the efficacy and safety of most antihypertensive agents, as well as the adverse events associated with these agents, are very limited in this population. In this case series, we evaluated the use of metoprolol infusion in children with hypertensive emergencies. METHODS: The study population comprised children younger than 18 years who had been admitted to the pediatric intensive care unit at King Abdullah University Hospital with blood pressure above the 99th percentile for age, height, and sex and who were symptomatic at the time of presentation. Metoprolol was given as an infusion at a dose of 1-5 mcg/kg/min. The rate of decrease in blood pressure, side effects from the medication, and outcome were assessed. RESULTS: Thirteen patients ranging in age from 2 months to 16 years were included in this study. The initial mean blood pressure was 23-75 mmHg above the 99th percentile for age, height, and sex. Metoprolol was initiated at a dose of 0.5 mcg/kg/min and titrated according to the target blood pressure to a maximum of 5 mcg/kg/min. Mean blood pressure fell by an average of 12.3, 20.4, and 27.1% at 1, 8, and 24 h, respectively, which is consistent with findings on the use of other intravenous medications reported in published studies. The heart rate did not decrease below the normal range for age. There were no significant side effects of the metoprolol infusion. All patients were discharged home with no neurological sequelae secondary to their hypertension. CONCLUSION: An infusion of metoprolol for a hypertensive emergency is a safe and effective treatment for pediatric patients. PMID- 28733752 TI - Generic immunosuppressants. AB - Immunosuppressive drugs for solid organ transplantation are critical dose drugs with a narrow therapeutic index. Many of the most commonly used innovator drugs are off patent and have been replicated by generic counterparts, often at substantial cost-savings to the patient. However, serious adverse events caused by the transition from innovator to generic medications, specifically in pediatric solid organ transplant recipients, have questioned these autosubstitutions. The purpose of this review is to summarize the criteria set forth by the regulatory bodies, and to examine how major immunosuppressive drugs conform to these recommendations. Regulatory bodies have established inconsistent criteria to demonstrate bioequivalence between innovator and generic medications, causing approved generic variations to have varying levels of equivalence with the innovator drugs. In order to minimize the risk for under-immunosuppression, the following recommendations have been concluded. Brand prescribing of cyclosporine and tacrolimus are recommended due to evidence of adverse events after conversion to generic formulations and differences in dissolution parameters. Mycophenolate mofetil (MMF) shows better bioequivalence between innovator and generic formulations, however caution should be advised when switching between formulations. The institution of 'innovator only' policies may be appropriate at this time in order to minimize the risk of under immunosuppressing patients until the evidence of more stringent bioequivalence has been established. PMID- 28733753 TI - Modeling of semi-competing risks by means of first passage times of a stochastic process. AB - In semi-competing risks one considers a terminal event, such as death of a person, and a non-terminal event, such as disease recurrence. We present a model where the time to the terminal event is the first passage time to a fixed level c in a stochastic process, while the time to the non-terminal event is represented by the first passage time of the same process to a stochastic threshold S, assumed to be independent of the stochastic process. In order to be explicit, we let the stochastic process be a gamma process, but other processes with independent increments may alternatively be used. For semi-competing risks this appears to be a new modeling approach, being an alternative to traditional approaches based on illness-death models and copula models. In this paper we consider a fully parametric approach. The likelihood function is derived and statistical inference in the model is illustrated on both simulated and real data. PMID- 28733754 TI - The influence of imagery capacity in motor performance improvement. AB - Motor imagery (MI) training improves motor performance, but the inter-individual variability of this improvement remains still unexplored. In this study, we tested the influence of imagery ability on the performance improvement following MI training. Twenty participants were randomly distributed into the MI or control group. They actually performed, at pre- and post-test sessions, a revisited version of the Nine Hole Peg Test, a speed-accuracy trade-off task, commonly used in clinics. Between the tests, the MI group mentally trained on the task (5 blocks of 10 trials), while the control group watched a non-emotional documentary. Before and during MI training, we tested the imagery ability of the MI group, by the revised version of Movement Imagery Questionnaire and by the estimation of vividness for the movement task at each block (subjective evaluation-SE). In the post-test, the MI group significantly decreased the movement duration by -12.1 +/- 5.7% (P < 0.001), whereas the control group did not (-2.68 +/- 5%, P = 0.68). For the MI group, the percentage of improvement was correlated neither to the MIQ-R nor to the SE reported after block 1. However, we observed an evolution of the SE during training, with a positive correlation between performance improvement and SE at block 4 (R = 0.61, P = 0.03) and at block 5 (R = 0.68, P = 0.04). The current study shows that motor performance may be positively influenced, whilst not predicted, by the capacity to form vivid movement images throughout the mental training. These findings are of interest for clinical interventions using MI as a complementary rehabilitation tool. PMID- 28733755 TI - Automatic regional analysis of myocardial native T1 values: left ventricle segmentation and AHA parcellations. AB - Native T1 value is emerging as a reliable indicator of abnormal heart conditions related to myocardial fibrosis. Investigators have extensively used the standardized myocardial segmentation of the American Heart Association (AHA) to measure regional T1 values of the left ventricular (LV) walls. In this paper, we present a fully automatic system to analyze modified Look-Locker inversion recovery images and to report regional T1 values of AHA segments. Ten healthy individuals participated in the T1 mapping study with a 3.0 T scanner after providing informed consent. First, we obtained masks of an LV blood-pool region and LV walls by using an image synthesis method and a layer-growing method. Subsequently, the LV walls were divided into AHA segments by identifying the boundaries of the septal regions and by using a radial projection method. The layer-growing method significantly enhanced the accuracy of the derived myocardium mask. We compared the T1 values that were obtained using manual region of interest selections and those obtained using the automatic system. The average T1 difference of the calculated segments was 4.6 +/- 1.5%. This study demonstrated a practical and robust method of obtaining native T1 values of AHA segments in LV walls. PMID- 28733756 TI - Glial and neuronal antibodies in patients with idiopathic intracranial hypertension. AB - Headache and visual disturbances are the main presenting symptoms of idiopathic intracranial hypertension (IIH) characterized by increased intracranial pressure (ICP) with an unknown cause. We aimed to investigate the antibodies against optic neuritis-associated glial antigens, aquaporin-4 (AQP4) and myelin oligodendrocyte glycoprotein (MOG) and uncharacterized neuronal membrane antigens in IIH patients. Consecutive patients diagnosed according to Friedman revised diagnostic criteria and control subjects were included after their consent. All serum samples were analyzed for antibodies against AQP4 and MOG using cell-based immunofluorescent assays and for uncharacterized neuronal membrane antigens by indirect immunocytochemistry utilizing live neurons. Sera of 34 patients with IIH and 40 control subjects were investigated but none of the patients showed AQP4 and MOG antibodies. However, serum IgG of five IIH patients showed reactivity against membrane antigens of rat hippocampal and cortical neurons. Interestingly, three out of these five patients had nonspecific white matter lesions on MRI, whereas only four of all other patients had these lesions (p = 0.048). AQP4 and MOG antibodies do not seem to have a role in the pathophysiology of IIH. However, association of immunocytochemistry findings with the presence of white matter lesions may suggest that immunological factors contribute to the pathogenesis of IIH in at least some of the patients. PMID- 28733757 TI - The clinico-radiological spectrum of Dyke-Davidoff-Masson syndrome in adults. AB - Dyke-Davidoff-Masson syndrome (DDMS) is characterized by cerebral hemiatrophy, seizure, contralateral hemiplegia/hemiparesis, and mental retardation. In this study, clinical and radiological investigations of seven patients who were diagnosed with DDMS as adult age were evaluated and discussed. Seven patients (four male, three female) were included. The mean age +/- SD of the patients was 46 +/- 21 years. Clinical presentation of six patients was epileptic seizure. One patient was presented with head trauma due to a fall. Two patients had complex partial seizures, three patients had generalized tonic-clonic seizures (GTC), and one had GTC and myoclonic seizure. Mental retardation was in five patients. A congenital cause was detected in one patient in the etiologic investigation and acquired causes in two patients. In four patients, the etiology was not identified. We observed left-hemisphere involvement in four patients and right hemisphere involvement in three patients. Brain imaging was performed by CT only in four patients and by MRI only in three patients. All patients were diagnosed with DDMS at adulthood. Atrophy in basal ganglia was detected in five patients, and atrophy in brain stem in four patients. Calvarial thickening was observed in four patients. Three patients had hyperpneumatization in mastoid cells. Sinus hyperpneumatization, including the paranasal and frontal sinuses, was seen in six patients. DDMS can also be diagnosed in adulthood symptomatically (mild-severe) or asymptomatically in adulthood. As a result, DDMS is a syndrome with wide clinical and radiological spectra that can be variably symptomatic at different stages of life. PMID- 28733758 TI - Mechanistic Insights of Empagliflozin-Mediated Cardiac Benefits: Nearing the Starting Line : Editorial to: "Empagliflozin Improves Left Ventricular Diastolic Dysfunction in a Genetic Model of Type 2 Diabetes" by N. Hammoudi et al. PMID- 28733759 TI - Management of Gait Changes and Fall Risk in MCI and Dementia. AB - OPINION STATEMENT: Gait disorders and falls are very prevalent in aging, especially in older adults with cognitive impairment: older adults with dementia are 2-3 times more likely to fall than their non-demented counterparts. The management of gait disorders and falls in older adults with mild cognitive impairment (MCI) or dementia begins by their identification with the use of specific screening tools, such as measuring gait speed, use of dual-task gait tests, or diagnosing motoric cognitive risk syndrome, a newly described pre dementia syndrome. This clinical approach is useful to reveal subtle gait changes that may lead to an increased risk of falls in older adults. Various non pharmacological interventions have been tested in older adults with MCI or dementia to reduce risk of falls. Physical activity interventions are feasible in older adults with cognitive impairments, and may improve gait, and thereby decrease risk of falls. Besides non-pharmacological interventions, identification and removal of potentially inappropriate medications (i.e., psychotropic drugs) is part of a comprehensive falls management strategy in older patients. The use of anti-dementia drugs, such as cholinesterase inhibitors or memantine, may help to improve gait in demented older adults. Adopting a multidisciplinary care strategy that integrates general practitioners, geriatricians, neurologists, cardiologists, physical therapists, and occupational therapists to identify older adults at increased risk of falling or with subtle gait changes, prior to applying individualized non-pharmacological and/or pharmacological interventions, is essential to reduce the burden of gait disorders and falls in older adults with cognitive impairment. PMID- 28733760 TI - Intrauterine therapy of cytomegalovirus infection with valganciclovir: review of the literature. AB - Congenital cytomegalovirus (CMV) infection is the leading cause for sensorineural hearing loss and mental retardation in children without genetic diseases worldwide. There is little evidence guiding therapeutic strategies during pregnancy when intrauterine fetal CMV infection is confirmed. We provide a systematic review of the use of ganciclovir (GCV) or VGCV during pregnancy discussing safety of its use for mother and fetus and describe two cases of intrauterine therapy of fetal CMV infection with valganciclovir (VGCV). A PubMed database search was done up to November 16, 2016 without any restrictions of publication date or journal, using the following keywords: "valganciclovir" or "ganciclovir" and "pregnan*". Furthermore, citations were searched and expert references were obtained. Reported cases were considered if therapy was in humans and initiation of treatment of the CMV infection was during pregnancy. In total, seven case reports were retrieved which described GCV or VGCV use during pregnancy for fetal or maternal CMV infection. In the four cases of treatment for maternal CMV infection, no negative effects on the fetus were reported. Three cases of GCV administration to pregnant woman with the intention of fetal treatment after proven fetal infection were found. We additionally present two cases of VGCV treatment in pregnancy from our center of tertiary care. VGCV seems to be a safe treatment for congenital CMV infection for the mother and the fetus. Therapeutic concentrations can be achieved in the fetus by oral intake of the mother and CMV replication can be suppressed. Larger studies are needed to evaluate this therapeutic intervention and the long-term effects. PMID- 28733761 TI - Spontaneous photosensitization by Heterophyllaea pustulata Hook. f. (Rubiaceae), in sheep from Northwestern Argentina. AB - Heterophyllaea pustulata Hook. f. (Rubiaceae) is a phototoxic plant. It grows in the Andean area of northwest of Argentina, and it causes significant economic losses in the livestock. This plant induces dermal lesions by photosensitization probably due to its content of photosensitizing anthraquinones. This paper describes an outbreak of poisoning in Corriedale sheepfold, which had an incidence of 49%. Ear skin biopsies and blood samples were collected of six affected animals. Liver enzymes remained within the reference limits. Histopathologically, a deep necrotizing dermatitis was identified in all samples. H. pustulata was identified in the areas of grazing. Anthraquinone concentration in leaves was 0.84% p/p, expressed as rubiadin. All findings allow us to conclude that the diagnosis is a primary photosensitization. Huge regional economic losses could be attributed to H. pustulata poisoning, although its toxicity has been little studied. PMID- 28733762 TI - Reconsidering betaine as a natural anti-heat stress agent in poultry industry: a review. AB - Betaine is found ubiquitously in plants, animals, microorganisms, and rich dietary sources including seafood, spinach, and wheat bran. The chief physiological role of betaine is to function as a methyl donor and an osmolyte. Betaine also acts as an osmolyte, to maintain the avian's cellular water and ion balance to improve the avian's capacity against heat stress via preventing dehydration and osmotic inactivation. It helps in maintaining the protective osmolytic activity, especially in heat-stressed birds. Betaine may promote various intestinal microbes against osmotic variations and thus improve microbial fermentation activity. Previous studies showed that dietary supplementation of betaine in poultry diets could positively affect nutrients' digestibility, reduce abdominal fat weight, and increase breast meat yield. In addition, betaine has been reported to protect internal organs and boost their performance. Its inclusion in poultry diet is sparing essential amino acids like choline and methionine. In addition, it may play an important role in lean meat production by positively affecting the lipid metabolism with increased fatty acids catabolism and thus reducing carcass fat deposition. The aim of this review article was to broaden the knowledge regarding betaine and its importance in the poultry industry to cope with the heat stress problem. Moreover, it should be added to the diet as a natural anti-stressor through different routes (water/feed) to overcome the heat stress problem. However, further studies need to be conducted at the genetic and molecular basis to elucidate the mechanism behind the betaine as a natural anti-heat agent to decrease the heat stress problem in the poultry industry. PMID- 28733763 TI - Predictive value of 18F-FDG PET/CT in adults with T-cell lymphoblastic lymphoma: post hoc analysis of results from the GRAALL-LYSA LLO3 trial. AB - PURPOSE: We examined whether FDG PET can be used to predict outcome in patients with lymphoblastic lymphoma (LL). METHODS: This was a retrospective post hoc analysis of data from the GRAAL-LYSA LL03 trial, in which the treatment of LL using an adapted paediatric-like acute lymphoblastic leukaemia protocol was evaluated. PET data acquired at baseline and after induction were analysed. Maximum standardized uptake values (SUVmax), total metabolic tumour volume and total lesion glycolysis were measured at baseline. The relative changes in SUVmax from baseline (DeltaSUVmax) and the Deauville score were determined after induction. RESULTS: The population analysed comprised 36 patients with T-type LL. SUVmax using a cut-off value of <=8.76 vs. >8.76 was predictive of 3-year event free survival (31.6% vs. 80.4%; p = 0.013) and overall survival (35.0% vs. 83.7%; p = 0.028). DeltaSUVmax using a cut-off value of <=80% vs. >80% tended also to be predictive of 3-year event-free survival (40.0% vs. 76.0%; p = 0.054) and overall survival (49.2% vs. 85.6%; p = 0.085). Total metabolic tumour volume, baseline total lesion glycolysis and response according to the Deauville score were not predictive of outcome. CONCLUSIONS: A low initial SUVmax was predictive of worse outcomes in our series of patients with T-type LL. Although relatively few patients were included, the study also suggested that DeltaSUVmax may be useful for predicting therapeutic efficacy. PMID- 28733765 TI - Close-up of a leadless pacemaker 3 days after implantation. PMID- 28733764 TI - Cardiac sympathetic neuronal damage precedes myocardial fibrosis in patients with Anderson-Fabry disease. AB - PURPOSE: Cardiac sympathetic denervation may be detectable in patients with Anderson-Fabry disease (AFD), suggesting its usefulness for early detection of the disease. However, the relationship between sympathetic neuronal damage measured by 123I-metaiodobenzylguanidine (MIBG) imaging with myocardial fibrosis on cardiac magnetic resonance (CMR) is still unclear. METHODS: Cardiac sympathetic innervation was assessed by 123I-MIBG single-photon emission computed tomography (SPECT) in 25 patients with genetically proved AFD. Within one month from MIBG imaging, all patients underwent contrast-enhanced CMR. MIBG defect size and fibrosis size on CMR were measured for the left ventricle (LV) and expressed as %LV. RESULTS: Patients were divided into three groups according to MIBG and CMR findings: (1) matched normal, without MIBG defects and without fibrosis on CMR (n = 10); (2) unmatched, with MIBG defect but without fibrosis (n = 5); and (3) matched abnormal, with MIBG defect and fibrosis (n = 10). The three groups did not differ with respect to age, gender, alpha-galactosidase, proteinuria, glomerular filtration rate, and troponin I, while New York Heart Association class (p = 0.008), LV hypertrophy (p = 0.05), and enzyme replacement therapy (p = 0.02) were different among groups. Although in patients with matched abnormal findings, there was a significant correlation between MIBG defect size and area of fibrosis at CMR (r2 = 0.98, p < 0.001), MIBG defect size was larger than fibrosis size (26 +/- 23 vs. 18 +/- 13%LV, p = 0.02). CONCLUSION: Sympathetic neuronal damage is frequent in AFD patients, and it may precede myocardial damage, such as fibrosis. Thus, 123I-MIBG imaging can be considered a challenging technique for early detection of cardiac involvement in AFD. PMID- 28733766 TI - Magnetic resonance imaging in patients with cardiac implantable electronic devices: a single-center prospective study. AB - PURPOSE: Cardiac implantable electronic devices (CIEDs) have traditionally been a contraindication for magnetic resonance imaging (MRI). Recent studies suggest that MRI can be conducted safely in select patients with pacemakers (PPMs) and implantable cardioverter defibrillators (ICDs). We sought to determine the safety of MRI in patients with CIEDs, using a protocol for patient selection and device programming. METHODS: This is a prospective, single-center study. Patients with a PPM or ICD and a clinical indication for MRI were considered. Exclusion criteria included newly implanted devices (<4 weeks), PPMs manufactured before 1996 and ICDs before 2000, epicardial and abandoned leads, and pacemaker-dependent ICD patients. Pacemaker-dependent PPM patients were programmed to asynchronous pacing. Tachycardia detection/therapies were disabled for ICDs. Devices were interrogated pre- and post-scan, and at follow-up 1-6 weeks later. Defibrillation threshold (DFT) was not tested post-scan. Patients were followed to monitor device therapies. RESULTS: Two hundred twenty-seven patients underwent 293 scans. Devices included 170 (70.6%) PPMs and 71 (29.5%) ICDs. Thirteen (4.4%) scans were aborted mainly due to subjective complaints or artifact on scout cardiac imaging. Post-scan and follow-up interrogation demonstrated no changes in device parameters requiring reprogramming or revision. Over long-term follow-up (median, 354 days [IQR 65-629]), nine ICD patients had appropriate shocks (median, 3 [IQR 1-8]). One had four inappropriate shocks for atrial fibrillation. All tachyarrhythmias meeting criteria for defibrillation were successfully terminated. CONCLUSIONS: MRI can be conducted safely in patients with CIEDs when done in a protocoled manner with appropriate supervision. DFT testing after MRI may not be necessary. PMID- 28733768 TI - Estimates of health utility scores in chronic kidney disease. AB - INTRODUCTION: Coverage decisions in publicly funded healthcare systems require a formal, systematic and transparent assessment process for policies related to distribution of resources. The process is complex and employs multiple types of information, such as clinical effectiveness, costs and health utility scores which are used to produce quality-adjusted life years. The purpose of this study was to create health utility scores for CKD patients within the Canadian population. METHODS: This is a cross-sectional study of CKD patients. We administered the Short-Form 36 Quality of Life Questions to all participants and employed the Short-Form 6 Dimension index to create health utility scores which were created using a set of parametric preference weights, nonparametric preference weights and ordinal health state valuation techniques obtained from a sample of the general population. RESULTS: Utility values in the dialysis group were lower than in the non-dialysis group. There was a significant relationship between age and health utility scores: As age increases, health utility scores decrease. Diabetes was associated with lower health utility scores in dialysis patients, whereas other covariates did not reach levels of statistical significance in our stepwise regression models. The parametric Bayesian model and standard gamble approach yielded the same results, while the correlation between the nonparametric and parametric methods was above 0.9. CONCLUSION: Health utility scores were low relative to the general population norm in our study cohort. Longitudinal assessment of CKD patients to capture possible fluctuations in health utility scores may add useful information. PMID- 28733767 TI - Relationship between plasma pentraxin 3 level and risk of chronic kidney disease in the Korean elderly: the Dong-gu study. AB - : Purpose This study investigated the cross-sectional association between chronic kidney disease (CKD) and plasma pentraxin 3 (PTX3) levels in a Korean population, in a community-based cohort study. METHODS: A total of 1816 (891 men, 925 women) subjects were randomly selected from the cohort of participants for the final analyses. Plasma PTX3 concentration was determined using enzyme-linked immunosorbent assays. The participants were divided into four quartiles according to the PTX3 levels. Multivariate logistic regression was performed to evaluate the association between plasma PTX3 level and CKD. Covariates inserted into the multivariate model included smoking status, systolic blood pressure, body mass index, waist circumference, high-density lipoprotein, low-density lipoprotein uric acid, white blood cell count, and carotid intima-media thickness. RESULTS: Compared to the lowest PTX3 group (Q1), a significantly higher risk of CKD was found in the highest group (Q4), with an odds ratio of 1.58 and 95% confidence interval of 1.18-2.11 (P for trend <0.001). CONCLUSIONS: This study showed that higher plasma PTX3 levels are significantly associated with CKD risk. The biological mechanism remains unclear; therefore, further molecular investigation of association between CKD and PTX3 is needed. PMID- 28733769 TI - Communication for coordination: gesture kinematics and conventionality affect synchronization success in piano duos. AB - Ensemble musicians often exchange visual cues in the form of body gestures (e.g., rhythmic head nods) to help coordinate piece entrances. These cues must communicate beats clearly, especially if the piece requires interperformer synchronization of the first chord. This study aimed to (1) replicate prior findings suggesting that points of peak acceleration in head gestures communicate beat position and (2) identify the kinematic features of head gestures that encourage successful synchronization. It was expected that increased precision of the alignment between leaders' head gestures and first note onsets, increased gesture smoothness, magnitude, and prototypicality, and increased leader ensemble/conducting experience would improve gesture synchronizability. Audio/MIDI and motion capture recordings were made of piano duos performing short musical passages under assigned leader/follower conditions. The leader of each trial listened to a particular tempo over headphones, then cued their partner in at the given tempo, without speaking. A subset of motion capture recordings were then presented as point-light videos with corresponding audio to a sample of musicians who tapped in synchrony with the beat. Musicians were found to align their first taps with the period of deceleration following acceleration peaks in leaders' head gestures, suggesting that acceleration patterns communicate beat position. Musicians' synchronization with leaders' first onsets improved as cueing gesture smoothness and magnitude increased and prototypicality decreased. Synchronization was also more successful with more experienced leaders' gestures. These results might be applied to interactive systems using gesture recognition or reproduction for music-making tasks (e.g., intelligent accompaniment systems). PMID- 28733771 TI - A National Study of Veterans Treatment Court Participants: Who Benefits and Who Recidivates. AB - Although there are now over 400 veterans treatment courts (VTCs) in the country, there have been few studies on participant outcomes in functional domains. Using national data on 7931 veterans in the Veterans Affairs (VA) Veterans Justice Outreach program across 115 VA sites who entered a VTC from 2011 to 2015, we examined the housing, employment, income, and criminal justice outcomes of VTC participants; and identified veteran characteristics predictive of outcomes. VTC participants spent an average of nearly a year in the program and 14% experienced a new incarceration. From program admission to exit, 10% more participants were in their own housing, 12% more were receiving VA benefits, but only 1% more were employed. Controlling for background characteristics, a history of incarceration predicted poor criminal justice, housing, and employment outcomes. Participants with property offenses or probation/parole violations and those with substance use disorders were more likely to experience a new incarceration. Participants with more mental health problems were more likely to be receiving VA benefits and less likely to be employed at program exit. Together, these findings highlight the importance of proper substance abuse treatment as well as employment services for VTC participants so that they can benefit from the diversion process. PMID- 28733770 TI - Distinct and flexible rates of online control. AB - Elliott et al. (Hum Mov Sci 10:393-418, 1991) proposed a pseudocontinuous model of online control whereby overlapping corrections lead to the appearance of smooth kinematic profiles in the presence of online feedback. More recently, it was also proposed that online control is not a singular process [see Elliott et al. (Psychol Bull 136(6):1023-1044, 2010)]. However, support for contemporary models of online control were based on methodologies that were not designed to be sensitive to different online control sub-processes. The current study sought to evaluate the possibility of multiple distinct (i.e., visual and non-visual) mechanisms contributing to the control of reaching movements completed in either a full-vision, a no-vision, or a no-vision memory-guided condition. Frequency domain analysis was applied to the acceleration traces of reaching movements. In an attempt to elicit a modulation in the online control mechanisms, these movements were completed at two levels of spatio-temporal constraint, namely with 10 and 30 cm target distances. One finding was that performance in the full vision relative to both no-vision conditions could be distinguished via two distinct frequency peaks. Increases in the peak magnitude at the lower frequencies were associated with visuomotor mechanisms and increases in the peak magnitude at the higher frequencies were associated with non-visual mechanisms. In addition, performance to the 30-cm target led to a lower peak at a lower frequency relative to the 10 cm target, indicating that the iterative rates of visuomotor control mechanisms are flexible and sensitive to the spatio-temporal constraints of the associated movement. PMID- 28733772 TI - State Minority Health Officers' Perceptions of their Successes and Barriers to Reducing Racial and Ethnic Health Disparities. AB - BACKGROUND: Minimal research has been conducted to examine the impact and reach of state offices of minority health (SOMH) and their role in reducing racial and ethnic health disparities within their states. Accordingly, the purpose of this study was to describe the shared experiences of SOMH officers to provide context for why these individuals believe that state organizational efforts have not yielded much success in reducing racial and ethnic health disparity gaps. METHODS: Using a telephone interview guide, the investigators conducted telephone interviews with SOMH officers. Data were analyzed thematically based on emergent patterns in participant responses. A total of 47 of 50 state officers (94%) completed the interview. RESULTS: Though many officers were encouraged by increased awareness regarding health disparities, nearly every officer listed inadequate resources as the most impactful barrier impeding the success of their offices' missions. CONCLUSION: SOMH continue to be severely underfunded and are concerned about their potential for success, leaving them with minimal ability to engage in activities beyond educational awareness campaigns. For SOMH officers to be successful in eliminating disparities, legislators must provide them with adequate funding so they can engage in wider-reaching interventions targeting the social determinants of health. PMID- 28733773 TI - The Influence of Black Identity on Wellbeing and Health Behaviors. AB - BACKGROUND: The aim of this study was to investigate the influence of Black identity on wellbeing and health behaviors. METHODS: Data from the third year (wave) of a longitudinal cohort study (N = 1316) from a large, majority Black, Protestant church of 16,000 members located in Houston, Texas, were used to conduct secondary data analyses. Univariate analyses were used to obtain participants' sociodemographic and health characteristics. ANCOVA and linear regression analyses and Bonferroni adjustments were used to examine the influence of the centrality, public and private regard aspects of Black identity as measured by the Multidimensional Inventory of Black Identity subscales on wellbeing (CES-D scores and self-reported general health) and health behaviors (diet and physical activity levels). RESULTS: Associations were noted between fruit consumption and centrality (F (95,1216) = 2.27) p = .046); soda consumption and private regard (F (5,1214) = 3.04; p = .010); public regard (F (2,1186) = 4.70; p = .009) and physical activity levels; self-reported general health status and private (F (4,1219) = 4.78; p = .001) and public regard (F (4,1211) = 8.53; p < .001). Psychological wellbeing was negatively associated with regard (private (B = -0.030; p < .001) and public regard (B = -0.060; p < .001)). CONCLUSION: Findings suggest that racial identity remain an important factor to consider in addressing health disparities. Racial identity influences mental health, general health, diet and the physical activity levels. Utilizing identity congruent health promotion interventions may positively impact mental, exercise levels, self-reported general health and diet. PMID- 28733774 TI - A study of anatomy of distal femur pertaining to total knee replacement: an analysis, conclusions and recommendations. AB - BACKGROUND: Multiple landmarks including the transepicondylar axis (TEA), posterior condylar axis (PCA) and anterior trochlear line (TL) have been used to set up the femoral component rotation, but each is faced with its own practical obstacle that limits its usage. Also a common practice is to set the femoral component rotation at 3 degrees external rotation to PCA and valgus resection angle at 5 degrees -7 degrees to anatomical axis of femur. For the reason that the anatomy of each knee is different, it may not be justified to practice such a set protocol in all cases. The aim of the study was to compare the anatomical landmarks used to set up the femoral component rotation and to study the variability in the different anatomical relationships relevant to total knee replacement. MATERIALS AND METHODS: The study had 52 patients (94 knees) with grade IV osteoarthritis. Full-length lower limb scanogram and 1 mm cross sectional cuts of distal femur were taken. aTEA, sTEA, PCL, TL, CTA, PCA, TLA and valgus angles were taken for all knees. RESULTS: aTEA is identifiable in all cases but sTEA in only 59 knees (62.77%). Correspondingly, CTA is calculable in all knees and PCA in 62.77% cases. Mean CTA and mean PCA were 5.4 degrees +/- 1.88 degrees SD and 0.71 degrees +/- 1.95 degrees SD, respectively. Mean angle between aTEA and sTEA was 4.88. TL is a line difficult to draw because of high incidence of anterior osteophytes, making CTA a more reliable parameter than TLA. Mean TLA was 10.31 degrees +/- 3.52 degrees SD. Mean valgus resection angle was 4.86 degrees +/- 2.53 degrees SD. Gender- or side-based differences in any of these values were not statistically different. CONCLUSIONS: Using aTEA or sTEA can make a big difference in femoral component rotation; therefore, whether aTEA or sTEA should be used needs to be further investigated. CTA, PCA and valgus resection angle need to be individually calculated for each knee. Use of TLA is not recommended. PMID- 28733776 TI - Erratum to: What Type of Food Can Older Adults Masticate?: Evaluation of Mastication Performance Using Color-Changeable Chewing Gum. PMID- 28733775 TI - How Swallow Pressures and Dysphagia Affect Malnutrition and Mealtime Outcomes in Long-Term Care. AB - Malnutrition is a major cause of hospitalization for residents of long-term care facilities (LTC). Dysphagia is thought to contribute to malnutrition. Tongue weakness is suggested to predict poor food intake, longer meals, and dysphagia. We explored the relationships between tongue strength, dysphagia, malnutrition and mealtime outcomes in LTC residents. Data were collected from 639 LTC residents (199 male), aged 62-102 (mean 87). Maximum isometric tongue pressures (MIPs) and saliva swallow pressures (MSPs) were measured using the Iowa Oral Performance Instrument. Participants also completed the Screening Tool for Acute Neuro Dysphagia. Nutrition status was assessed using the Patient-Generated Subjective Global Assessment. A series of repeated meal observations provided measures of meal duration and calories consumed. Mean MIPs were 33 kPa (95% CI 29 37) and MSPs were 26 kPa (95% CI 23-29). The odds of showing signs of dysphagia were 3.7 times greater in those with MSPs less than 26 kPa (p < 0.05). The odds of being malnourished were almost double in those showing signs of dysphagia. Co occurrence of dysphagia and malnutrition was seen in 29%. Residents with low MSPs also had significantly longer mealtime durations (MTD) (p < 0.05). Moreover, those with both low swallowing pressures and suspected dysphagia consumed fewer calories/minute (p < 0.05) and had significantly longer MTDs (p < 0.05). This study confirms associations between tongue weakness, signs of dysphagia, mealtime outcomes and malnutrition among LTC residents. These findings suggest that saliva swallow pressure measures may be helpful for early identification of dysphagia and nutritional risk in this population. PMID- 28733777 TI - Erratum to: Exercise induced laryngeal obstruction: a review of diagnosis and management. PMID- 28733778 TI - Letter to the Editor regarding "Revision adenoidectomy in children: a population based cohort study in Taiwan". PMID- 28733779 TI - Clinical efficacy of main radiological diagnostic methods for odontogenic maxillary sinusitis. AB - The objective of the study was to compare the ability of dental, ENT and radiology specialists to identify the dental cause of maxillary sinusitis with conventional computed tomography, dental and panoramic radiographs. Out of 34 dental records from subjects treated at ENT and Oral and Maxillofacial Surgery Department, LUHS Kaunas Clinics, 22 females and 12 males with the diagnosis of odontogenic maxillary sinusitis, periapical (DPA), panoramic (DPR) and computed tomography (CT) images of posterior maxilla were selected for further studies. In total, 39 sinuses with an odontogenic and 37 sinuses with only rhinogenic cause (control group) were included in the study. Sinuses with mucosal thickening less than 3 mm were excluded from the research. Each image was evaluated by 5 endodontologists, 5 oral surgeons, 6 general dentists, 6 otorhinolaryngologists and an experienced oral radiologist. DPR and DPA views were not evaluated by ENT specialists. The dental cause of maxillary sinusitis was marked according to the given scale. Intraclass correlation coefficient and ROC curve statistical analysis were performed. The best accuracy was observed when CT views were evaluated by experienced oral radiologist and oral surgeons: the AUC was 0.958 and 0.859, respectively. DPR views showed the best accuracy when evaluated by oral surgeons (0.763) and DPA-by endodontologists (0.736). The highest inter rater agreement was observed between experienced oral radiologist and oral surgeons/otorhinolaryngologists (0.87/0.78) evaluating CT. Sensitivity and specificity of CT were 89.7 and 94.6%, DPR-68.2 and 77.3%, DPA-77.9 and 67%. Identification of dental cause of maxillary sinusitis sometimes is a challenge, which depends on radiological method and, more importantly, on evaluator's experience. PMID- 28733780 TI - Robotic left lateral sectionectomy as stepwise approach for cirrhotic liver. AB - Laparoscopy is considered the gold standard approach to perform left lateral sectionectomy (LLS). Furthermore, laparoscopy for cirrhotic patients can reduce intraoperative bleeding and postoperative morbidity when compared to open surgery. Although robotic surgery is feasible for both minor and major liver resections, it remains a work in progress and only few series reported this approach for cirrhotic patients. We reported two cases of 62-year-old men, both with hepatitis C virus and alcoholic cirrhosis, but with compensated liver functions (MELD 9-10 and Child-Pugh A5-A6). The patients were diagnosed with a single lesion in the left lobe. Robotic LLS was performed using intraoperative ultrasound to confirm findings of pre-operative image, and linear staplers were used to control left lobe inflow and outflow. The specimens were removed through Pfannenstiel incision in both patients. Both procedures followed the same standardization. The total operative time was 250 and 151 min with estimated blood loss of 100 and 70 ml, respectively, for cases 1 and 2. The procedures were made without Pringle maneuver and postoperative course was uneventful with hospital discharge at third and fourth postoperative day, respectively. The pathology examination confirmed a 2.5- and 4.5-cm hepatocellular carcinoma, respectively; both presented negative margins and cirrhosis. Robotic LLS seems to be as feasible as conventional laparoscopic approach as a stepwise procedure in a robotic learning curve for liver resection. Its benefits can also be offered to selected cirrhotic patients. PMID- 28733781 TI - BITC and S-Carvone Restrain High-Fat Diet-Induced Obesity and Ameliorate Hepatic Steatosis and Insulin Resistance. AB - PURPOSE: To investigate the preventative activity of benzyl isothiocyante and S carvone against high-fat diet-induced obesity and metabolic complications. METHODS: Ten-week-old C57BL/6 male mice were fed a high-fat diet and injected intraperitoneally twice per week with benzyl isothiocyante, S-carvone, or vehicle for 8 weeks. The body weight, food intake, and body composition were monitored, and glucose tolerance and insulin tolerance tests were performed at the end of the experiment. Serum and tissue samples were studied using serum biochemistry, histological, and gene expression analysis to define the effects of benzyl isothiocyante and S-carvone treatments on lipid and glucose metabolism and inflammatory responses. RESULTS: Benzyl isothiocyante and S-carvone blocked high fat diet-induced weight gain, fat accumulation in the liver, and insulin resistance. The beneficial effects were found to be associated with an improvement of expression of macrophage marker genes in white adipose tissue, including F4/80, Cd11b, Cd11c, Cd206, and Tnf-alpha, and reduced expression of genes (Ppargamma2, Scd1, Cd36) responsible for lipid synthesis and transport in the liver. CONCLUSION: Benzyl isothiocyante and S-carvone block high-fat diet induced obesity and metabolism disorders and can be considered for management of the obesity epidemic that affects approximately 36% of adults and 17% of children in the USA. PMID- 28733783 TI - Perianth organs in Nymphaeaceae: comparative study on epidermal and structural characters. AB - The perianth organs of six species of Nymphaeaceae, representing Euryale, Nymphaea and Victoria, were studied on the basis of macroscopical, micromorphological, and anatomical characters. The aims were to determine whether perianth is differentiated among tepal whorls considering the presence of sepaloid and petaloid characters, and to evaluate the occurrence of both features in individual tepals. Selected perianth series were examined macroscopically, with light microscopy, and scanning electron microscopy. Osmophores were detected using neutral red and Sudan. In all tepals examined, stomata and hydropotes were present on the abaxial and adaxial surfaces. These are anomocytic or stephanocytic; hydropotes of irregular type are also present. The outer series of tepals display morpho-anatomical characters in most part related with photosynthetic and protective functions. Osmophore activity is very scarce and petaloid epidermal morphology is present only in N. lotus, thus allowing interpretation of this whorl as primarily sepaloid. The second series exhibits both petal-like and sepal-like characters; in N. amazonum and N. gardneriana sepaloid and petaloid group of cells are present on the abaxial surface of individual tepals. Therefore, this whorl is transitional between the outer and the innermost ones. Both the morpho-anatomy and presence of osmophore activity indicate that the innermost series is entirely petaloid. Inner tepals of E. ferox, N. alba, and V. cruziana share the presence of epidermal cells with predominantly smooth cuticle, whereas those of N. amazonum, N. gardneriana, and N. lotus share a cuticular ornamentation consisting of numerous papillae on each cell. Morphological characters of the perianth epidermis are in some respects congruent with the molecular phylogeny of Nymphaeaceae. Our results support the co-expression of sepaloidy and petaloidy within individual tepals and the mosaic model of perianth evolution proposed for the angiosperms. PMID- 28733782 TI - Catheter Ablation of Atrial Fibrillation: An Overview for Clinicians. AB - Catheter ablation (CA) of atrial fibrillation (AF) is currently one of the most commonly performed electrophysiology procedures. Ablation of paroxysmal AF is based on the elimination of triggers by pulmonary vein isolation (PVI), while different strategies for additional AF substrate modification on top of PVI have been proposed for ablation of persistent AF. Nowadays, various technologies for AF ablation are available. The radiofrequency point-by-point ablation navigated by electro-anatomical mapping system and cryo-balloon technology are comparable in terms of the efficacy and safety of the PVI procedure. Long-term success of AF ablation including multiple procedures varies from 50 to 80%. Arrhythmia recurrences commonly occur, mostly due to PV reconnection. The recurrences are particularly common in patients with non-paroxysmal AF, dilated left atrium and the "early recurrence" of AF within the first 2-3 post-procedural months. In addition, this complex procedure can be accompanied by serious complications, such as cardiac tamponade, stroke, atrio-esophageal fistula and PV stenosis. Therefore, CA represents a second-line treatment option after a trial of antiarrhythmic drug(s). Good candidates for the procedure are relatively younger patients with symptomatic and frequent episodes of AF, with no significant structural heart disease and no significant left atrial enlargement. Randomized trials demonstrated the superiority of ablation compared to antiarrhythmic drugs in terms of improving the quality of life and symptoms in AF patients. However, nonrandomized studies reported additional clinical benefits from ablation over drug therapy in selected AF patients, such as the reduction of the mortality and stroke rates and the recovery of tachyarrhythmia-induced cardiomyopathy. Future research should enable the creation of more durable ablative lesions and the selection of the optimal lesion set in each patient according to the degree of atrial remodeling. This could provide better long-term CA success and expand indications for the procedure, especially among the patients with non-paroxysmal AF. PMID- 28733784 TI - Environmental impact of coal mining and coal seam gas production on surface water quality in the Sydney basin, Australia. AB - The extraction of coal and coal seam gas (CSG) will generate produced water that, if not adequately treated, will pollute surface and groundwater systems. In Australia, the discharge of produced water from coal mining and related activities is regulated by the state environment agency through a pollution licence. This licence sets the discharge limits for a range of analytes to protect the environment into which the produced water is discharged. This study reports on the impact of produced water from coal mine activities located within or discharging into high conservation environments, such as National Parks, in the outer region of Sydney, Australia. The water samples upstream and downstream from the discharge points from six mines were taken, and 110 parameters were tested. The results were assessed against a water quality index (WQI) which accounts for pH, turbidity, dissolved oxygen, biochemical oxygen demand, total dissolved solids, total phosphorus, nitrate nitrogen and E .coli. The water quality assessment based on the trace metal contents against various national maximum admissible concentration (MAC) and their corresponding environmental impacts was also included in the study which also established a base value of water quality for further study. The study revealed that impacted water downstream of the mine discharge points contained higher metal content than the upstream reference locations. In many cases, the downstream water was above the Australia and New Zealand Environment Conservation Council and international water quality guidelines for freshwater stream. The major outliers to the guidelines were aluminium (Al), iron (Fe), manganese (Mn), nickel (Ni) and zinc (Zn). The WQI of surface water at and downstream of the discharge point was lower when compared to upstream or reference conditions in the majority of cases. Toxicology indices of metals present in industrial discharges were used as an additional tool to assess water quality, and the newly proposed environmental water quality index (EWQI) lead to better trend in the impact of coal and coal seam gas mining activities on surface water quality when compared to the upstream reference water samples. Metal content limits were based on the impact points assigned by the Agency for Toxic Substances and Disease Registry, USA. For environmental and health impact assessment, the approach used in this study can be applied as a model to provide a basis to assess the anthropogenic contribution from the industrial and mining activities on the environment. PMID- 28733785 TI - Fertiliser management effects on dissolved inorganic nitrogen in runoff from Australian sugarcane farms. AB - Dissolved inorganic nitrogen (DIN) movement from Australian sugarcane farms is believed to be a major cause of crown-of-thorns starfish outbreaks which have reduced the Great Barrier Reef coral cover by ~21% (1985-2012). We develop a daily model of DIN concentration in runoff based on >200 field monitored runoff events. Runoff DIN concentrations were related to nitrogen fertiliser application rates and decreased after application with time and cumulative rainfall. Runoff after liquid fertiliser applications had higher initial DIN concentrations, though these concentrations diminished more rapidly in comparison to granular fertiliser applications. The model was validated using an independent field dataset and provided reasonable estimates of runoff DIN concentrations based on a number of modelling efficiency score results. The runoff DIN concentration model was combined with a water balance cropping model to investigate temporal aspects of sugarcane fertiliser management. Nitrogen fertiliser application in December (start of wet season) had the highest risk of DIN movement, and this was further exacerbated in years with a climate forecast for 'wet' seasonal conditions. The potential utility of a climate forecasting system to predict forthcoming wet months and hence DIN loss risk is demonstrated. Earlier fertiliser application or reducing fertiliser application rates in seasons with a wet climate forecast may markedly reduce runoff DIN loads; however, it is recommended that these findings be tested at a broader scale. PMID- 28733786 TI - Developing an environmental water quality monitoring program for Haraz River in Northern Iran. AB - Water quality management plans are an indispensable strategy for conservation and utilization of water resources in a sustainable manner. One common industrial use of water is aquaculture. The present study is an attempt to use statistical analyses in order to prepare an environmental water quality monitoring program for Haraz River, in Northern Iran. For this purpose, the analysis of a total number of 18 physicochemical parameters was performed at 15 stations during a 1 year sampling period. According to the results of the multivariate statistical methods, the optimal monitoring would be possible by only 3 stations and 12 parameters, including NH3, EC, BOD, TSS, DO, PO4, NO3, TDS, temperature, turbidity, coliform, and discharge. In other words, newly designed network, with a total number of 36 measurements (3 stations * 12 parameters = 36 parameters), could achieve exactly the same performance as the former network, designed based on 234 measurements (13 stations * 18 parameters = 234 parameters). Based on the results of cluster, principal component, and factor analyses, the stations were divided into three groups of high pollution (HP), medium pollution (MP), and low pollution (LP). By clustering the stations, it would be possible to track the water quality of Haraz River, only by one station at each cluster, which facilitates rapid assessment of the water quality in the river basin. Emphasizing on three main axes of monitoring program, including measurement parameters, sampling frequency, and spatial pattern of sampling points, the water quality monitoring program was optimized for the river basin based on natural conditions of the study area, monitoring objectives, and required financial resources (a total annual cost of about US $2625, excluding the overhead costs). PMID- 28733787 TI - Gatekeepers' perceptions of the quality and availability of services for breast and cervical cancer patients in the English-speaking Windward Islands: an exploratory investigation. AB - PURPOSE: Although extensive screening services for breast and cervical cancers are available in the Caribbean, these cancers continue to be the leading causes of cancer death among women in this region. The purpose of this study was to determine the quality and availability of breast and cervical cancer treatment care and support services from the perspective of the gatekeepers who provide care for the patients in the Windward Islands of Dominica, Grenada, St Lucia, and St. Vincent. METHODS: A qualitative research design using semi-structured, in depth interviews was used to gather data from gatekeepers who provided oncology prevention and care services to patients for at least one year. Data were collected on availability and quality of cancer care and treatment services and coded using the themes obtained via thematic analysis of the data. RESULTS: Twenty-three current providers participated in the study (Dominica, 5; Grenada, 7; St. Lucia, 5; St. Vincent and the Grenadines, 6). The participants' years of work experience ranged from 2 to 45 years. The codes encompassed a range of social ecological factors that influence breast and cervical cancer screening and treatment in the Windward Islands. The emergent themes were availability of resources, cost of care, and social support. CONCLUSION: The findings of this study emphasize the varying social determinants of health that affect breast and cervical cancer prevention and treatment. It also highlights the disparities in availability of treatment within the wider Caribbean. It is necessary to broaden the perspective on health from a purely biomedical paradigm to a social perspective. PMID- 28733788 TI - Isolated Metachronous Splenic Metastasis from Colon Cancer: Possible Explanations for This Rare Entity. PMID- 28733789 TI - Is That Possible to Stop or Cease the NASH to Turn into HCC? PMID- 28733790 TI - Is a "dragging sensation" a symptom of female pelvic organ prolapse? AB - INTRODUCTION AND HYPOTHESIS: Pelvic organ prolapse (POP) commonly presents with a "vaginal lump or bulge" and/or a "dragging sensation." The first symptom correlates strongly with clinical and imaging data. However, a "dragging sensation" may be less specific. Hence, we investigated the predictive value of both symptoms for POP. METHODS: This was a retrospective study involving archived data sets of women seen between November 2013 and May 2014. All underwent a clinical interview, POPQ examination, and 4D translabial ultrasound (TLUS). The main outcome measure was organ descent on clinical examination and TLUS. Offline analysis for organ descent was undertaken blinded against all other data. RESULTS: A total of 224 women were assessed. Mean age was 57 (23-84) years. Median parity was 3 (0-7). Ninety-three percent (n=208) were vaginally parous. Fifty-eight percent (n=129) complained of symptoms of prolapse: 49% (n=110) of a vaginal lump, 27% (n=61) of a dragging sensation. Clinically, mean point B anterior (Ba) was -0.86 (-3 to +7.5) cm, mean cervical station (C) was -4.1 (-9 to +8) cm, mean point B posterior (Bp) was -1.1 (-3 to +5) cm. On imaging, mean bladder, uterine, and rectal descent were -8.3 (-68.0 to 34) mm, +18.6 (-56.4 to 46.3) mm, and -5.3 (-39.8 to 36) mm respectively. On univariate analysis, both symptoms were strongly associated with objective prolapse clinically and on TLUS, with "vaginal lump" consistently the stronger predictor. CONCLUSIONS: The symptom of a "vaginal lump or bulge" was consistently a stronger predictor of objective POP than "dragging sensation." This finding was insensitive to adjustments for potential confounders. However, a "dragging sensation" is clearly a symptom of prolapse. PMID- 28733792 TI - Re: Did King Herod suffer from a rheumatic disease? doi: 10.1007/s10067-017-3583 z. PMID- 28733791 TI - Current clinical evidence of tocilizumab for the treatment of ANCA-associated vasculitis: a prospective case series for microscopic polyangiitis in a combination with corticosteroids and literature review. AB - The purpose of this study is to report the efficacy and safety of a combination of tocilizumab (TCZ) and high-dose corticosteroid (CS) in two patients with microscopic polyangiitis (MPA) and review the published current clinical evidence on TCZ in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV), except for large vessel vasculitis (LVV) and polymyalgia rheumatica (PMR). Two MPA patients were treated with TCZ at 8 mg/kg every month for 1 year and CS (prednisolone 1 mg/kg/day for 2 weeks, followed by tapering) in a prospective single-arm, single-center, cohort, open-label pilot study (UMIN clinical trials: 000012072). We performed a systematic literature search (PubMed and ICHUSHI [Japan Medical Abstracts Society] until June 30, 2017) to identify published reports on patients with all vasculitis other than LVV/PMR, who were treated with TCZ. We successfully treated the first patient. However, the other patient had serious infection probably associated with the combination of TCZ and high-dose CS. The literature review identified 22 reports with a total of 34 patients who received TCZ for AAV, rheumatoid vasculitis, and other types of vasculitis, in addition to our patients. In 15 of 17 patients (88.2%) with primary and secondary AAV, especially MPA, TCZ induced clinical remission, although TCZ use for rheumatoid vasculitis and vasculitis with mucocutaneous lesions is controversial. This study suggested that TCZ therapy is a potential treatment strategy for patients with AAV. However, TCZ combined with high-dose of CS might not be an appropriate treatment. Future studies are needed to confirm our findings. PMID- 28733793 TI - Re: Re: Did King Herod suffer from a rheumatic disease? doi: 10.1007/s10067-017 3583-z. PMID- 28733794 TI - Fatigue associated with newly approved vascular endothelial growth factor receptor tyrosine kinase inhibitors in cancer patients: an up-to-date meta analysis. AB - The fatigue associated with five newly approved vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) (regorafenib, vandetanib, cabozantinib, lenvatinib, axitinib) is poorly understood. We conducted this systematic review to fully investigate the fatigue associated with these VEGFR TKIs in cancer patients. Relevant studies of randomized controlled trials in cancer patients treated with the five VEGFR-TKIs were retrieved and a systematic evaluation was conducted. EMBASE, MEDLINE, and PubMed were searched for articles published until March 2017. Thirteen randomized controlled trials and 4395 patients were included. The current analysis suggested that the use of five newly approved VEGFR-TKIs increased the risk of all-grade fatigue (1.43; 95% CI 1.23 1.66; p < 0.00001) and high-grade (>=grade 3) fatigue (1.97; 95% CI1.44-2.70; p < 0.0001). On subgroup analysis, the risk ratio (RR) of all-grade fatigue varied significantly within drug type, but high-grade fatigue did not. The RR of all grade and high-grade fatigue did not vary significantly according to cancer type, treatment line, and treatment duration. The risk of high-grade fatigue may vary with treatment duration, whereas all-grade fatigue may not. The available data suggest that the use of the five newly approved VEGFR-TKIs is associated with a significantly increased risk of fatigue in cancer patients. Physicians should be aware of this adverse effect and should monitor cancer patients receiving these drugs. PMID- 28733795 TI - Early response of C-reactive protein as a predictor of survival in patients with metastatic renal cell carcinoma treated with tyrosine kinase inhibitors. AB - BACKGROUND: Pretreatment C-reactive protein (CRP) has been shown to be an independent prognostic factor for metastatic renal cell carcinoma (mRCC) treated with tyrosine kinase inhibitors (TKIs). We further evaluated the early response of CRP after the initiation of TKIs. METHODS: A total of 103 patients (80 men and 23 women) were treated with TKIs for mRCC from 2008-2013. Patients were divided into three groups according to their early CRP kinetics-patients whose baseline CRP levels were <10 mg/L (non-elevated), patients whose baseline CRP levels were >=10 mg/L and had decreased by >20% at 4 weeks after the initiation of TKIs (early CRP responder), and the remaining patients (non-early CRP responder). The endpoints were progression-free survival (PFS) and overall survival (OS). RESULTS: The median follow-up period was 21 (interquartile range 10-34) months. The numbers of patients classified as non-elevated, early CRP responder, and non early CRP responder were 62, 19, and 22, respectively. The 1-year PFS rates of patients in the non-elevated, early CRP responder, and non-early CRP responder groups were 50, 23, and 9.7%, respectively (p < 0.001). The 1-year OS rates of patients in these three groups were 79, 62, and 36%, respectively (p < 0.001). In multivariate analysis, the early CRP kinetics assessment was a significant independent factor for PFS and OS. CONCLUSIONS: Early CRP response at 4 weeks is predictive of survival for patients with mRCC treated with TKI. PMID- 28733796 TI - Beyond integrating social sciences: Reflecting on the place of life sciences in empirical bioethics methodologies. AB - Empirical bioethics is commonly understood as integrating empirical research with normative-ethical research in order to address an ethical issue. Methodological analyses in empirical bioethics mainly focus on the integration of socio empirical sciences (e.g. sociology or psychology) and normative ethics. But while there are numerous multidisciplinary research projects combining life sciences and normative ethics, there is few explicit methodological reflection on how to integrate both fields, or about the goals and rationales of such interdisciplinary cooperation. In this paper we will review some drivers for the tendency of empirical bioethics methodologies to focus on the collaboration of normative ethics with particularly social sciences. Subsequently, we argue that the ends of empirical bioethics, not the empirical methods, are decisive for the question of which empirical disciplines can contribute to empirical bioethics in a meaningful way. Using already existing types of research integration as a springboard, five possible types of research which encompass life sciences and normative analysis will illustrate how such cooperation can be conceptualized from a methodological perspective within empirical bioethics. We will conclude with a reflection on the limitations and challenges of empirical bioethics research that integrates life sciences. PMID- 28733797 TI - Population genetic analysis of a 21-plex DIP panel in seven Chinese ethnic populations. AB - A 21-plex DIP (deletion and insertion polymorphism) panel has a good performance in analyzing biogeographic ancestry in three main global population groups (European, African, and Asian). This panel was used to investigate 450 unrelated individuals in seven Chinese ethnic groups (Han, Dong, Miao, Zhuang, Uyghur, Tibetan, and Mongolian). Allele frequencies were calculated. Mho (mean value of observed heterozygosity) ranged from 0.3019 to 0.4367, MHe (mean value of expected heterozygosity) ranged from 0.31175 to 0.38341, CMP (combined matching probability) ranged from 3.5834E-07 to 2.5985E-06, CDP (combined power of discrimination) ranged from 0.99999740150 to 0.99999964166, and CPE (combined power of paternity exclusion) ranged from 0.85884504 to 0.97949131. The results suggested the potential of the panel for individual identification and paternity testing in Chinese populations. Pairwise genetic differences Fst values (-0.00091 to 0.05873) and the analysis by STRUCTURE indicated that Chinese populations have good internal consistency. PMID- 28733798 TI - Silence Surrounding Hepatitis C Status in Risk Relationships Among Rural People Who Use Drugs. AB - Hepatitis C virus (HCV) has reached epidemic proportions in rural Central Appalachia in recent years. We sought to identify demographic, behavioral, and interpersonal characteristics associated with HCV serostatus disclosure among high risk people who use drugs (PWUD) in Appalachian Kentucky. HCV antibody positive participants (n = 243), drawn from the fifth follow-up assessment of a longitudinal study of rural PWUD, completed interviewer-administered questionnaires eliciting demographic and interpersonal characteristics, risk behaviors, and information about HCV disclosure. We assessed correlates of HCV disclosure using gender-stratified multivariate logistic regression. Participants reported having disclosed their HCV-positive status to a current sex partner (44.0%), family member (35.8%), close friend (9.5%), or past sex partner (6.6%). Of those reporting current (n = 72) or past (n = 215) injection drug use (IDU), only 2.8% disclosed to current and 0.9% disclosed to past IDU partners, respectively. Female participants were more likely than male participants to disclose to current sex partners and family member(s). In multivariate analyses, adjusting for time since testing HCV positive, older age and lifetime history of drug treatment were associated with decreased odds of HCV disclosure among females, while only lifetime history of drug treatment was associated with decreased odds of HCV disclosure among males. In summary, the almost complete absence of disclosure to current or former injection drug use partners was concerning. However, most participants (69.1%) reported disclosing their HCV status to at least one of their social referents, suggesting that family members, partners, and friends of people living with HCV could play a critical role in encouraging uptake of treatment. Although further research is warranted, it is clear that interventions are needed to encourage HCV disclosure among those most at risk of transmitting HCV. PMID- 28733799 TI - A Toddler Parenting Intervention in Primary Care for Caregivers With Depression Symptoms. AB - Caregiver depression impacts parenting behaviors and has deleterious effects on child behavior. Evidence-based interventions to address parenting have not been adapted for use with depressed caregivers in pediatric primary care settings. Our study examined the feasibility and explored outcomes of an evidence-based parenting program implemented in primary care and adapted for caregivers with depressive symptoms caring for toddlers. We conducted a randomized controlled trial with a wait-list control. Participants were caregivers who screened positive for depressive symptoms in pediatric settings with a toddler. Our study was implemented from July 2011 to June 2012. We adapted the Incredible Years Parents, Babies and Toddlers program with the addition of depression psychoeducation (12 weekly sessions), and assessed caregivers at baseline and immediately post-intervention. We assessed participation rates, depressive symptoms, parenting discipline practices, social support, and parenting stress. Our results revealed that 32 caregivers participating in the intervention group had significantly greater improvement in self-reported parenting discipline practices compared to the 29 wait-list control group caregivers. We found no differences between groups in depressive symptoms, social support, or parenting stress. Our study demonstrated that the average attendance was poor (mean attendance = 3.7 sessions). We adapted an evidence-based parenting intervention for caregivers with depressive symptoms and toddlers in primary care; however, participation was challenging. Alternative intervention strategies are needed to reach and retain low-income caregivers with depression symptoms as they face multiple barriers to participation in groups within center-based services. Trial Registration Clinical Trials.gov identifier NCT01464619. PMID- 28733801 TI - Effect of follicular flushing on reproductive outcomes in patients with poor ovarian response undergoing assisted reproductive technology. AB - PURPOSE: The purpose of this study is to investigate the impact of follicular flushing on the number of oocytes retrieved, oocyte maturity, fertilization rate, embryo development, and pregnancy rate of poor ovarian responders (POR). METHODS: Retrospective study of 524 cycles of 384 patients with POR submitted to assisted reproductive technology (ART) and who had follicular flushing during oocyte retrieval was used in the study. We included patients with <5 oocytes at oocyte retrieval (POR group) and matching the Bologna criteria. RESULTS: POR patients had a mean age of 38.2 +/- 4.2 years. A total of 1355 follicles (mean = 3.5 +/- 1.6) were aspirated and 1040 oocytes recovered, with 709 (68.2%) obtained by direct aspiration and 331 (31.8%) by follicular flushing. We found a difference between the total number of oocytes and the number of aspirated oocytes. Overall pregnancy rate was 22%. Association was observed between pregnancy rate and the number of oocytes retrieved, the number of MII oocytes, and the number of embryos transferred. The patients matching the Bologna criteria had a mean age of 38.9 +/ 3.9 years. A total of 309 follicles were aspirated (mean = 3.1 +/- 1.5) and 242 oocytes recovered, with 156 (64.5%) obtained by direct aspiration and 86 (35.5%) by follicular flushing. There was a significant difference between the total number of oocytes and the number of aspirated oocytes. Overall pregnancy rate was 12.1%. There was no association between the pregnancy rate and the number of oocytes retrieved, the number of MII, and the number of embryos. CONCLUSIONS: Follicular flushing might be a suitable alternative to increase the number of oocytes and pregnancy rates in patients with POR. PMID- 28733800 TI - Steroid-Mediated Decrease in Blood Mesenchymal Stem Cells in Liver Transplant could Impact Long-Term Recovery. AB - Orthotopic liver transplant (OLT) remains the standard of care for end stage liver disease. To circumvent allo-rejection, OLT subjects receive gluococorticoids (GC). We investigated the effects of GC on endogenous mesenchymal stem (stromal) cells (MSCs) in OLT. This question is relevant because MSCs have regenerative potential and immune suppressor function. Phenotypic analyses of blood samples from 12 OLT recipients, at pre-anhepatic, anhepatic and post-transplant (2 h, Days 1 and 5) indicated a significant decrease in MSCs after GC injection. The MSCs showed better recovery in the blood from subjects who started with relatively low MSCs as compared to those with high levels at the prehepatic phase. This drop in MSCs appeared to be linked to GC since similar change was not observed in liver resection subjects. In order to understand the effects of GC on decrease MSC migration, in vitro studies were performed in transwell cultures. Untreated MSCs could not migrate towards the GC-exposed liver tissue, despite CXCR4 expression and the production of inflammatory cytokines from the liver cells. GC-treated MSCs were inefficient with respect to migration towards CXCL12, and this correlated with retracted cytoskeleton and motility. These dysfunctions were partly explained by decreases in the CXCL12/receptor axis. GC-associated decrease in MSCs in OLT recipients recovered post-transplant, despite poor migratory ability towards GC-exposed liver. In total, the study indicated that GC usage in transplant needs to be examined to determine if this could be reduced or avoided with adjuvant cell therapy. PMID- 28733802 TI - Assisted reproductive technology treatments and quality of life: a longitudinal study among subfertile women and men. AB - PURPOSE: Quality of life (QoL) may represent a comprehensive indicator for the assessment of the psychological impact of complex clinical conditions, such as infertility. Infertile women have a worse QoL compared to both infertile men and non-infertile controls. However, the initial phases of infertility treatments have been frequently investigated using cross-sectional study designs. This prospective longitudinal study aimed at assessing the health-related QoL change across different phases of assisted reproductive technology (ART) treatments in subfertile women and men. METHODS: Eighty-five subfertile women and men undergoing ART cycles were assessed at the beginning of the ovarian stimulation, during oocyte retrieval before discharging, and around 14 days after the embryo transfer. QoL was assessed through the Short Form 36. RESULTS: Irrespective of the cause of infertility, work status, and age, QoL levels decreased from the first to the third assessment, and women scored significantly lower than men to each QoL indicator. Additionally, a higher number of previous ART failures had a negative impact on QoL, irrespective of gender and the phase of treatment. ART outcome marginally affected women's QoL across time. CONCLUSION: Infertile women have a worse QoL throughout all phases of ARTs compared to men, and this difference increases in infertile patients with more than one previous ART failure. PMID- 28733804 TI - Surgical Masculinization of the Breast: Clinical Classification and Surgical Procedures. AB - Level of Evidence V This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266. PMID- 28733803 TI - Vocoder Simulations Explain Complex Pitch Perception Limitations Experienced by Cochlear Implant Users. AB - Pitch plays a crucial role in speech and music, but is highly degraded for people with cochlear implants, leading to severe communication challenges in noisy environments. Pitch is determined primarily by the first few spectrally resolved harmonics of a tone. In implants, access to this pitch is limited by poor spectral resolution, due to the limited number of channels and interactions between adjacent channels. Here we used noise-vocoder simulations to explore how many channels, and how little channel interaction, are required to elicit pitch. Results suggest that two to four times the number of channels are needed, along with interactions reduced by an order of magnitude, than available in current devices. These new constraints not only provide insights into the basic mechanisms of pitch coding in normal hearing but also suggest that spectrally based complex pitch is unlikely to be generated in implant users without significant changes in the method or site of stimulation. PMID- 28733805 TI - OnabotulinumtoxinA (Botox) in the Treatment of Crow's Feet Lines in Japanese Subjects. AB - BACKGROUND: This study evaluated the safety and efficacy of onabotulinumtoxinA in Japanese subjects with crow's feet lines (CFL). METHODS: This phase 3, multicenter, double-blind, randomized study included 2 treatment periods: 6-month placebo-controlled period followed by a 7-month open-label period. In period 1, subjects with moderate to severe CFL received onabotulinumtoxinA 24 U (n = 104) or 12 U (n = 99), or placebo (n = 97). In period 2, placebo subjects switched to onabotulinumtoxinA 24 U or 12 U (double-blind dose). Up to 5 total treatments were permitted for subjects meeting re-treatment criteria. The primary efficacy measure was the proportion of investigator-assessed responders (achieving CFL severity of none or mild at maximum smile using the Facial Wrinkle Scale with Asian Photonumeric Guide [FWS-A] at day 30 of treatment 1). Additional endpoints included other responders (achieving at least 1-grade improvement at maximum smile and at rest using the FWS-A at day 30), responders at other time points, duration of effect, subject-reported outcomes, and safety. RESULTS: All efficacy endpoints were met. At day 30, the proportion of subjects achieving none or mild severity at maximum smile was significantly greater (P < 0.001) in the onabotulinumtoxinA 24 and 12 U groups (68.3 and 56.6%, respectively) compared with the placebo group (8.2%). Efficacy results were consistent over repeated treatments, and subjects' self-assessed outcomes were similar to investigator assessed results. CONCLUSIONS: Treatment with onabotulinumtoxinA 24 and 12 U improved the appearance of CFL in Japanese subjects and was well tolerated, with no new safety findings. LEVEL OF EVIDENCE I: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 28733806 TI - Revisional Surgery Following Laparoscopic Gastric Plication. PMID- 28733807 TI - More than a Case Report? Should Wernicke Encephalopathy After Sleeve Gastrectomy be a Concern? PMID- 28733808 TI - The Effect of Ventilation Strategy on Arterial and Cerebral Oxygenation During Laparoscopic Bariatric Surgery. PMID- 28733809 TI - Gastric Remnant Dilatation: a Rare Technical Complication Following Laparoscopic One Anastomosis (Mini) Gastric Bypass. PMID- 28733810 TI - Precision of guided scanning procedures for full-arch digital impressions in vivo. AB - PURPOSE: System-specific scanning strategies have been shown to influence the accuracy of full-arch digital impressions. Special guided scanning procedures have been implemented for specific intraoral scanning systems with special regard to the digital orthodontic workflow. The aim of this study was to evaluate the precision of guided scanning procedures compared to conventional impression techniques in vivo. METHOD: Two intraoral scanning systems with implemented full arch guided scanning procedures (Cerec Omnicam Ortho; Ormco Lythos) were included along with one conventional impression technique with irreversible hydrocolloid material (alginate). Full-arch impressions were taken three times each from 5 participants (n = 15). Impressions were then compared within the test groups using a point-to-surface distance method after best-fit model matching (OraCheck). Precision was calculated using the (90-10%)/2 quantile and statistical analysis with one-way repeated measures ANOVA and post hoc Bonferroni test was performed. RESULTS: The conventional impression technique with alginate showed the lowest precision for full-arch impressions with 162.2 +/- 71.3 um. Both guided scanning procedures performed statistically significantly better than the conventional impression technique (p < 0.05). Mean values for group Cerec Omnicam Ortho were 74.5 +/- 39.2 um and for group Ormco Lythos 91.4 +/- 48.8 um. CONCLUSIONS: The in vivo precision of guided scanning procedures exceeds conventional impression techniques with the irreversible hydrocolloid material alginate. Guided scanning procedures may be highly promising for clinical applications, especially for digital orthodontic workflows. PMID- 28733811 TI - Pharmacological evidence that 5-HT2C receptor blockade selectively improves decision making when rewards are paired with audiovisual cues in a rat gambling task. AB - RATIONALE: Adding reward-concurrent cues to a rat gambling task (rGT) increases risky choice. This cued version of the task may reflect an "addiction-like" cognitive process, more similar to human gambling than the uncued task. Serotonergic drugs that target 5-HT2 receptors alter mechanisms linked to impulse control. However, relatively little is known regarding the impact of such agents on either risky decision making, or the ability of conditioned stimuli to bias the choice process, despite potential relevance to addiction development and treatment. OBJECTIVES: The aim of this study was to determine the effects of SB 242,084 and M100907, selective antagonists at the 5-HT2C and 5-HT2A receptors respectively, as well as the selective 5-HT2C receptor agonist Ro-60-0175, on performance of both cued and uncued versions of the rGT. RESULTS: SB 242,084 significantly and dose-dependently increased choice of the most optimal option in the cued rGT only, despite concurrently increasing impulsive responses made prematurely on both the cued and uncued rGT. M100907 and Ro-60-0175 did not alter risky decision making, but nevertheless produced the expected decrease in premature responses on both task variants. CONCLUSIONS: These findings demonstrate that the 5-HT2 receptor-mediated regulation of risky decision making and motor impulsivity can be pharmacologically dissociated and further show that the presence of highly salient reward-paired cues critically alters the neurochemical regulation of the choice process. Importantly, these results suggest that 5-HT2C receptor antagonists may be of use in disrupting maladaptive patterns of decision making. PMID- 28733812 TI - Melatonin increases reactive aggression in humans. AB - OBJECTIVE: Melatonin, a hormone released preferentially by the pineal gland during the night, affects circadian rhythms and aging processes. As animal studies have shown that melatonin increases resident-intruder aggression, this study aimed to investigate the impact of melatonin treatment on human aggression. METHODS: In a double-blind, randomized, placebo-controlled between-participant design, 63 healthy male volunteers completed the Taylor Aggression Paradigm (TAP) after oral administration of melatonin or placebo. RESULTS: We found that when given the opportunity to administer high or low punishments to an opponent, participants who ingested melatonin selected the high punishment more often than those who ingested placebo. The increased reactive aggression under melatonin administration remained after controlling for inhibitory ability, trait aggression, trait impulsiveness, circadian preference, perceptual sensibility to noise, and changes in subjective sleepiness and emotional states. CONCLUSION: This study provides novel and direct evidence for the involvement of melatonin in human social processes. PMID- 28733813 TI - Individual and combined effects of cannabis and tobacco on drug reward processing in non-dependent users. AB - RATIONALE: Cannabis and tobacco are often smoked simultaneously in joints, and this practice may increase the risks of developing tobacco and/or cannabis use disorders. Currently, there is no human experimental research on how these drugs interact on addiction-related measures. OBJECTIVES: This study aimed to investigate how cannabis and tobacco, each alone and combined together in joints, affected individuals' demand for cannabis puffs and cigarettes, explicit liking of drug and non-drug-related stimuli and craving. METHOD: A double-blind, 2 (active cannabis, placebo cannabis) * 2 (active tobacco, placebo tobacco) crossover design was used with 24 non-dependent cannabis and tobacco smokers. They completed a pleasantness rating task (PRT), a marijuana purchase task (MPT) and a cigarette purchase task (CPT) alongside measures of craving pre- and post drug administration. RESULTS: Relative to placebo cannabis, active cannabis reduced liking of cannabis-associated stimuli and increased response time to all stimuli except cigarette-related stimuli. Relative to placebo cannabis, active cannabis decreased demand for cannabis puffs (trends for breakpoint and elasticity) and cigarettes (breakpoint, P max, O max) on several characteristics of the purchase tasks. We found no evidence that active tobacco, both alone or combined with cannabis, had an effect on liking, demand or craving. CONCLUSIONS: Acutely, cannabis reduced liking of cannabis-related stimuli and demand for cannabis itself. Acute cannabis also reduced demand for cigarettes on the CPT. Acute tobacco administration did not affect demand or pleasantness ratings for cigarettes themselves or cannabis. In non-dependent cannabis and tobacco co users, tobacco did not influence the rewarding effects of cannabis. PMID- 28733815 TI - Structure of isolated Z-disks from honeybee flight muscle. AB - The Z-disk is a complex structure comprising some 40 proteins that are involved in the transmission of force developed during muscle contraction and in important signalling pathways that govern muscle homeostasis. In the Z-disk the ends of antiparallel thin filaments from adjacent sarcomeres are crosslinked by alpha actinin. The structure of the Z-disk lattice varies greatly throughout the animal kingdom. In vertebrates the thin filaments form a tetragonal lattice, whereas invertebrate flight muscle has a hexagonal lattice. The width of the Z-disk varies considerably and correlates with the number of alpha-actinin bridges. A detailed description at a high resolution of the Z-disk lattice is needed in order to better understand muscle function and disease. The molecular architecture of the Z-disk lattice in honeybee (Apis mellifera) is known from plastic embedded thin sections to a resolution of 7 nm, which is not sufficient to dock component protein crystal structures. It has been shown that sectioning is a damaging process that leads to the loss of finer details present in biological specimens. However, the Apis Z-disk is a thin structure (120 nm) suitable for cryo EM. We have isolated intact honeybee Z-disks from indirect flight muscle, thus obviating the need of plastic sectioning. We have employed cryo electron tomography and image processing to investigate the arrangement of proteins within the hexagonal lattice of the Apis Z-disk. The resolution obtained, ~6 nm, was probably limited by damage caused by the harshness of the conditions used to extract the myofibrils and isolate the Z-disks. PMID- 28733814 TI - Neuroprotective effect of ipriflavone against scopolamine-induced memory impairment in rats. AB - BACKGROUND: Alzheimer's disease is an age-related neurodegenerative disorder characterized clinically by a progressive loss of memory and cognitive functions resulting in severe dementia. Ipriflavone (IPRI) is a non-hormonal, semi synthetic isoflavone, clinically used in some countries for the treatment and prevention of postmenopausal osteoporosis. Moreover, ipriflavone is a non peptidomimetic small molecule AChE inhibitor with an improved bioavailability after systemic administration, due to its efficient blood-brain barrier permeability in comparison with peptidomimetic inhibitors. OBJECTIVE: The present study aimed to evaluate the possible enhancing effects of IPRI on memory impairments caused by scopolamine administration. METHODS: Male rats were administered IPRI (50 mg/kg, oral) 2 h before scopolamine injection (2 mg/kg, intraperitoneally injected) daily for 4 weeks. Effects of IPRI on acetylcholinesterase activity, amyloid-beta precursor processing, and neuroplasticity in the rats' hippocampus were investigated. RESULTS: Daily administration of IPRI reverted memory impairment caused by scopolamine as measured by the reduction of the escape latency. IPRI significantly alleviated the oxidative stress and restored the mRNA expression of both cAMP-response element-binding protein and brain-derived neurotrophic factor in the hippocampus. Furthermore, it significantly increased the expression of ADAM10 and ADAM17 (two putative alpha-secretase enzymes) and phosphorylated extracellular signal regulated kinase 1/2 (pERK1/2) that associated with decreased expression of beta secretase (BACE) in the hippocampus. Finally, both the amyloid-beta (Abeta) and Tau pathologies were reduced. CONCLUSIONS: IPRI showed promising neuroprotective effects against scopolamine-induced memory dysfunction in rats. These findings contributed to the stimulation of alpha-secretase enzymes, the activation of MAPK/ERK1/2, and the alleviation of oxidative stress. PMID- 28733816 TI - Relative weighting of acoustic information during mating decisions in grasshoppers indicates signatures of sexual selection. AB - The decision with whom to mate is crucial in determining an individual's fitness and is often based on the evaluation of visual or acoustic displays produced during courtship. Accordingly, the algorithms for evaluating such courtship signals are shaped by sexual selection and should reflect the expected benefits and costs of mating: signals bearing heterospecific features should be rapidly rejected, since mating would produce no fertile offspring, while signals resembling conspecific ones should be weighted proportional to mate quality. We test these hypotheses in females of the grasshopper Chorthippus biguttulus who assess males by their song, which is produced as a sequence of subunits with species and individual specific signatures. We present mixed sequences of subunits with conflicting cues and use a computational model of decision-making to infer how sensory information is weighted and integrated over the song. Consistent with our hypothesis, females do weight sensory cues according to the expected fitness benefits/costs: heterospecific subunits are weighted particularly negatively and lead to a rejection of the male early in the song. Conspecific subunits are weighted moderately, permitting a more complete evaluation of the full song. However, there exists an overall negative bias against mating, possible causes of which are discussed. PMID- 28733817 TI - Enriching an intraspecific genetic map and identifying QTL for fiber quality and yield component traits across multiple environments in Upland cotton (Gossypium hirsutum L.). AB - Cotton is a significant commercial crop that plays an indispensable role in many domains. Constructing high-density genetic maps and identifying stable quantitative trait locus (QTL) controlling agronomic traits are necessary prerequisites for marker-assisted selection (MAS). A total of 14,899 SSR primer pairs designed from the genome sequence of G. raimondii were screened for polymorphic markers between mapping parents CCRI 35 and Yumian 1, and 712 SSR markers showing polymorphism were used to genotype 180 lines from a (CCRI 35 * Yumian 1) recombinant inbred line (RIL) population. Genetic linkage analysis was conducted on 726 loci obtained from the 712 polymorphic SSR markers, along with 1379 SSR loci obtained in our previous study, and a high-density genetic map with 2051 loci was constructed, which spanned 3508.29 cM with an average distance of 1.71 cM between adjacent markers. Marker orders on the linkage map are highly consistent with the corresponding physical orders on a G. hirsutum genome sequence. Based on fiber quality and yield component trait data collected from six environments, 113 QTLs were identified through two analytical methods. Among these 113 QTLs, 50 were considered stable (detected in multiple environments or for which phenotypic variance explained by additive effect was greater than environment effect), and 18 of these 50 were identified with stability by both methods. These 18 QTLs, including eleven for fiber quality and seven for yield component traits, could be priorities for MAS. PMID- 28733819 TI - Estimating environmental value losses from earth materials excavation and infilling for large-scale airport construction: a case of Dalian Offshore Airport, Dalian, China. AB - Large-scale airport construction removes large quantities of earth materials, resulting in serious environmental pollution and ecosystem damage. However, studies of environmental concerns caused by the materials used in airport construction are still preliminary, and those case studies on the impacts of large-scale offshore airport development are very limited. China's Dalian Offshore Airport is considered here to study the environmental value loss from 240 million m3 of materials excavations and 21 km2 of artificial island infillings. The findings show that the calculated annual environmental value loss for the development of the Dalian Offshore Airport is approximately US$7.75 million, including US$1.81 million and US$1.47 million of direct economic loss of timber resources and marine biology resources, respectively, and US$1.53 million and US$2.79 million value losses of forest and marine ecosystem services damaged caused by materials excavation and infilling, respectively. The conclusions of this study provide an important foundation to quantitatively analyse the environmental impact of the Dalian Offshore Airport's development and can be used as a reference for similar engineering and environment impact assessment programs. PMID- 28733818 TI - Occurrence and distribution of six selected endocrine disrupting compounds in surface- and groundwaters of the Romagna area (North Italy). AB - Endocrine disrupting compounds (EDCs) are a wide group of contaminants of emerging concern known to be harmful for organisms. The aim of the study was to assess the occurrence and distribution of six EDCs (estrone-E1, beta-estradiol E2, 17alpha-ethinylestradiol-EE2, bisphenol A-BPA, perfluooctanoic acid-PFOA, perfluorooctane sulfonate-PFOS) in the Apenninic rivers and groundwaters of the Romagna area (North of Italy). Groundwaters were unaffected by EDC contamination, while all classes of compounds were detected at concentrations above the method quantification limit (MQL) in the majority of the river bodies. In detail, PFOA and PFOS concentrations varied between autumn > spring > winter, which was positively correlated with the change of the average ambient temperature, while it was the contrary in particulate phase. In autumn, the gas phase and the total air concentration of SCCPs in 2016 were 2.57 times more than that in 2010, while the congener group patterns of SCCPs were similar. Spearman's rank correlation analysis between the concentrations of SCCPs with meteorological parameters was conducted. The gas-particle distribution was examined through the relationship of the logarithm of the gas-particle partition coefficient with that of the subcooled vapor pressure and the octanol-air partitioning coefficient of SCCPs. Results indicated that the absorption mechanisms contributed more to the partitioning process. The exposure risk of SCCPs was evaluated, which illustrated that the estimated exposure of SCCPs via the outdoor environment in Dalian did not exceed the health concern threshold of the European risk assessment. PMID- 28733823 TI - Bioaccumulation kinetics of arsenite and arsenate in Dunaliella salina under different phosphate regimes. AB - Dunaliella salina is a potential candidate for the phycoremediation of saline water contaminated with arsenic (As) due to its strong tolerance of salt and this toxic metalloid. However, the efficiency of As removal by this microalga varies under different phosphate regimes and the underlying mechanisms remain unresolved. Therefore, more detailed studies are needed to optimize As remediation using D. salina. Here, we investigated the dynamic processes of arsenite (As(III)) and arsenate (As(V)) uptake, transformation, and excretion by D. salina under phosphate-deficient (-P) and phosphate-enriched (+P) conditions through short-term and long-term uptake experiments. In the short-term uptake experiment, the absorption of As(III) or As(V) by D. salina was significantly suppressed by an increased phosphate supply. The V max values for As(III) and As(V) decreased by 2- and 2.5-fold, respectively, under +P conditions, although the Michaelis constants (K m ) were similar irrespective of the phosphate supply. Long-term uptake experiments also revealed enhanced As(III)/As(V) absorption and efflux rates and As(V) reduction by D. salina under -P conditions. This study quantified the kinetic processes of As metabolism in D. salina. More importantly, the results imply that the optimal As remediation by this microalga may be achieved by regulating the phosphate level in the culture. PMID- 28733824 TI - Diagnosis of rare diseases under focus: impacts for Canadian patients. AB - This paper presents an in-depth qualitative analysis of the impact of diagnosis on the lives of rare disease (RD) patients. While diagnosis may be described as a watershed step for RD patients, no extensive account of non-medical outcomes following a RD diagnosis exists within the literature. This study aims to fill this knowledge gap through an analysis of the impact of diagnosis on the lives of RD patients according to their personal experiences. Qualitative research was conducted in three provinces across Canada, with a total of 23 participants, both adult and parents of children with RD, diagnosed and not yet diagnosed. A thematic approach guided the analysis of the transcripts. The results reveal that the impacts of a RD diagnosis for both adults and paediatric patients are multifold, ranging from social to personal and medical impacts (including cases where etiological treatments for the diseases are non-existent). Furthermore, the results shed light on distinct factors that affect the scope of impacts of a diagnosis. PMID- 28733825 TI - Face Validity Ratings of Sexual Orientation Scales by Sexual Minority Adults: Effects of Sexual Orientation and Gender Identity. AB - The present research explored sexual minority individuals' ratings of two traditional (Kinsey and Klein Sexual Orientation Grid [KSOG]) and two novel (Sexual-Romantic and Gender Inclusive) sexual orientation scales with regard to how well they capture their sexuality. Participants included 363 sexual minority individuals who identified as lesbian, gay, bisexual, pansexual, or queer, and included individuals who identified as transgender (n = 85) and cisgender (n = 278). The findings indicated clear patterns of responses across both sexual orientation and gender identity, where participants differed in the degree to which they felt the scales captured their sexuality. A main effect of sexual orientation was found for all four scales, where participants endorsing monosexual (lesbian/gay) identities rated the scales more positively than did participants endorsing plurisexual (bisexual and pansexual/queer) identities. Bisexual individuals had a unique pattern of ratings, which sometimes aligned with those of lesbian/gay participants and sometimes aligned with pansexual/queer participants. A main effect of gender identity was found for the Kinsey, KSOG, and Sexual-Romantic (but not Gender Inclusive) scales, where cisgender individuals rated the scales more positively than did transgender individuals. There were no significant interaction effects between sexual orientation and gender identity for any of the four scales. The present findings can be used to understand sexual minority individuals' assessment of the face validity of four sexual orientation measures. Discussion focused on the implications for using traditional measures of sexual orientation in research as well as for the development of new measures that better capture the range of sexual minority experience. PMID- 28733826 TI - Validation of the HIV Risk Assessment of Sexual Partnerships (H-RASP): Comparison to a 2-Month Prospective Diary Study. AB - The HIV Risk Assessment of Sexual Partnerships (H-RASP) was developed in order to create a retrospective measure of sexual risk-taking that can account for the differing contexts of sexual partnership(s) within a specified period of time. In order to validate the H-RASP relative to other methods of measuring sexual risk taking, measurements from the H-RASP were compared to data from a prospective diary study of 95 young men who have sex with men over the same two-month period. We found that the H-RASP was not significantly different at measuring participants' total number of sexual partners and total number of anal sex partners in comparison with the diaries. The two measures were significantly different in measurement of total number of condomless anal sex (CAS) partners and number of CAS acts within partnerships, such that participants on average estimated more CAS partners and acts in the H-RASP. The two measures shared 40.8% of variance on measurement of CAS partners and 44.6% of variance on CAS acts within partnerships. These results suggest that even though the H-RASP is not a perfect replication of prospective diary data, it captures a moderate proportion of the same variance, and, in the case of CAS acts within partnerships, a proportion of the variance that likely would not be measured by retrospective measures that do not ask about behaviors specific to partnerships. PMID- 28733828 TI - Thermosensitive In Situ Gel Based on Solid Dispersion for Rectal Delivery of Ibuprofen. AB - The objective of this study was to develop a thermosensitive in situ gel based on solid dispersions (SDs) for rectal delivery of ibuprofen (IBU). Thermosensitive (poloxamer 407) and mucoadhesive (hydroxypropylmethyl cellulose E5 and sodium alginate) polymers were used to prepare the in situ gel and the sol-gel transition temperature (T sol-gel) and gel strength were optimized. The in vitro release performance and in vivo pharmacokinetic properties of the in situ gel after their rectal administration to rabbits were investigated. Compared with the solid suppository, the cumulative release of the IBU SDs loaded in situ gel was significantly increased. The in vivo pharmacokinetics indicated that in situ gel had a higher peak plasma concentration (C max) and area under the curve (AUC(0 infinity)) in plasma than the solid suppositories. Histopathology results showed that the IBU in situ gel given at a dose of 15 mg/kg did not produce any irritation. In conclusion, this study suggested that the in situ gel could be an effective rectal formulation for IBU. PMID- 28733829 TI - A teenager presenting with a forearm mass. Reversed palmaris longus. PMID- 28733827 TI - Adding Adjuvant Systemic Treatment after Neoadjuvant Therapy in Breast Cancer: Review of the Data. AB - PURPOSE OF REVIEW: Residual disease after neoadjuvant chemotherapy is a poor prognostic factor; however, proven strategies to reduce recurrence risk and improve overall survival in this patient population are limited. Previous studies of residual disease have illustrated the importance of tumor intrinsic subtypes in treatment response and mechanisms of resistance. This review summarizes the rationale for various therapeutic approaches as well as completed and ongoing clinical trials for this high-risk group of patients. RECENT FINDINGS: Regimens utilizing additional chemotherapy and targeted therapies (such as PARP inhibitors or bisphosphonates) have met with limited efficacy. Notably, a recently published randomized study of capecitabine in patients with residual disease demonstrated an improvement in disease-free survival and overall survival. While the results for capecitabine are promising, particularly for patients with triple-negative disease, the generalizability of these findings is an open question. Meanwhile, ongoing trials with novel agents that target specific tumor subtypes and the biology of residual disease may improve outcomes for other patient populations. PMID- 28733831 TI - Nocturnal Blood Pressure Dipping is Abolished in Old-Elderly Hospitalized Patients. AB - INTRODUCTION: During sleep there is reduction of blood pressure (BP) caused by a decrease of the sympathetic nervous tone. This nocturnal "dipping" phenomenon, assessable with ambulatory blood pressure monitoring (ABPM), is blunted with increasing age. AIM: To assess the effect of hospitalization on night-time BP fall in old-elderly patients. METHODS: We analysed 78 ABPM of old-elderly hospitalized patients (mean age 91 +/- 0.5 years) and those of 18 outpatients as control group. The nocturnal BP fall was assessed calculating: the dipping value (DV) i.e. the difference between mean diurnal systolic BP (mDSBP) and mean nocturnal systolic BP (mNSBP) and the "dipping pattern" i.e. mNSBP/mDSBPx100. RESULTS: Hospitalized patients showed a lower rate of normal dipping patterns (9 vs. 39%), an higher rate of reverse dippers (59 vs. 28%; p < 0.05) and a lower DV (-0.9 +/- 1 vs. 9 +/- 4 mmHg; p < 0.05) than patients of control group. At multivariate regression analysis including age, gender and hospitalization, DV was significantly correlated only with the hospitalization (beta -0.3, t -2.9; p < 0.05). CONCLUSIONS: In old-elderly hospitalized patients nocturnal BP fall is abolished. This enhancement of the age related reduction of nocturnal BP dipping may be due to the stress associated with hospital environment. PMID- 28733832 TI - Seasonal reorganization of hypothalamic neurogenic niche in adult sheep. AB - Neurogenesis is the process by which new neurons are generated. This process, well established during development, persists in adulthood owing to the presence of neural stem cells (NSCs) localized in specific brain areas called neurogenic niches. Adult neurogenesis has recently been shown to occur in the hypothalamus, a structure involved in the neuroendocrine regulation of reproduction and metabolism, among others. In the adult sheep-a long-lived mammalian model-we have previously reported the existence of such a neurogenic niche located in the hypothalamic arcuate nucleus and the median eminence. In addition, in this seasonal species, the proliferation as well as neuroblasts production varies depending on the time of the year. In the present study, we provide a better characterization of the hypothalamic neurogenic niche by identifying the main components (NSCs, migrating cells, glial cells and blood vessels) using immunohistochemistry for validated markers. Then, we demonstrate the strong sensitivity of these various neurogenic niche components to the season, particularly in the arcuate nucleus. Further, using an electron microscopic approach, we reveal the cellular and cytoarchitectural reorganization of the arcuate nucleus niche following exposure to contrasting seasons. This study provides evidence that the arcuate nucleus and the median eminence contain two independent niches that react differently to the season. In addition, our results support the view that the cytoarchitectural organization of the sheep arcuate nucleus share comparable features with the structure of the subventricular zone in humans and non-human primates. PMID- 28733833 TI - Neuroanatomy of pain-deficiency and cross-modal activation in calcium channel subunit (CACN) alpha2delta3 knockout mice. AB - The phenotype of calcium channel subunit (CACN) alpha2delta3 knockout (KO) mice includes sensory cross-activation and deficient pain perception. Sensory cross activation defines the activation of a sensory cortical region by input from another modality due to reorganization in the brain such as after sensory loss. To obtain mechanistic insight into both phenomena, we employed a comprehensive battery of neuroanatomical techniques. While CACNalpha2delta3 was ubiquitously expressed in wild-type mice, it was absent in alpha2delta3 KO animals. Immunostaining of alpha1A, alpha1B, and alpha1E revealed upregulation of N-type and R-type, but not P/Q-type Cav2 channels in cortical neurons of CACNalpha2delta3 KO mice. Compared to wild-type mice, axonal processes in somatosensory cortex were enhanced, and dendritic processes reduced, in CACNalpha2delta3 KO mice. Immunohistochemical and MRI analyses, investigating morphology, thalamocortical and intra-/intercortical trajectories, revealed a disparity between projection and commissural fibers with reduction of the number of spatial specificity of thalamocortical projections. L1cam staining revealed wide-ranging projections of thalamocortical fibers reaching both somatosensory/motor and visual cortical areas. Activation (c-fos+) of excitatory and inhibitory neurons suggested that deficient pain perception in alpha2delta3 KO mice is unlikely to result from cortical disinhibition. Collectively, our data demonstrate that knock out of CACN alpha2delta3 results in some structural abnormalities whose functional implications converge to dedifferentiation of sensory activation. PMID- 28733834 TI - Long-term intensive gymnastic training induced changes in intra- and inter network functional connectivity: an independent component analysis. AB - Long-term intensive gymnastic training can induce brain structural and functional reorganization. Previous studies have identified structural and functional network differences between world class gymnasts (WCGs) and non-athletes at the whole-brain level. However, it is still unclear how interactions within and between functional networks are affected by long-term intensive gymnastic training. We examined both intra- and inter-network functional connectivity of gymnasts relative to non-athletes using resting-state fMRI (R-fMRI). R-fMRI data were acquired from 13 WCGs and 14 non-athlete controls. Group-independent component analysis (ICA) was adopted to decompose the R-fMRI data into spatial independent components and associated time courses. An automatic component identification method was used to identify components of interest associated with resting-state networks (RSNs). We identified nine RSNs, the basal ganglia network (BG), sensorimotor network (SMN), cerebellum (CB), anterior and posterior default mode networks (aDMN/pDMN), left and right fronto-parietal networks (lFPN/rFPN), primary visual network (PVN), and extrastriate visual network (EVN). Statistical analyses revealed that the intra-network functional connectivity was significantly decreased within the BG, aDMN, lFPN, and rFPN, but increased within the EVN in the WCGs compared to the controls. In addition, the WCGs showed uniformly decreased inter-network functional connectivity between SMN and BG, CB, and PVN, BG and PVN, and pDMN and rFPN compared to the controls. We interpret this generally weaker intra- and inter-network functional connectivity in WCGs during the resting state as a result of greater efficiency in the WCGs' brain associated with long-term motor skill training. PMID- 28733835 TI - Competition and coexistence in a small carnivore guild. AB - The potential for strong competition among small sympatric carnivores results in a need for coexistence strategies whereby competitors partition along spatial, temporal and dietary axes as a means to reduce ecological overlaps. We determined spatial and temporal partitioning patterns of a guild of small African carnivores: the African wildcat Felis silvestris lybica, grey mongoose Galerella pulverulenta, small-spotted genet Genetta genetta, striped polecat Ictonyx striatus, and the yellow mongoose Cynictis penicillata. We quantified the degree of spatial and temporal co-occurrence of the small carnivores using camera trap data over a year-long period. Carnivores separated into two temporal groups: nocturnal species (wildcat, polecat and genet) and diurnal species (mongooses). In addition, carnivores within the same temporal group had strong patterns of reduced spatial co-occurrence. The smaller bodied carnivores showed lower co occurrence with the larger bodied African wildcat than expected by chance, supporting the idea of dominant competitor avoidance. Thus, small carnivores likely minimise competitive interactions through spatio-temporal habitat partitioning. PMID- 28733836 TI - On separating the magnocellular from the parvocellular: Responses to two statements by Goodhew et al. AB - Goodhew et al. (Attention Perception & Psychophysics, 79, 1147-1164, 2017) claim we (Skottun & Skoyles) hold: (1) that it is not possible to separate contributions from the magno- and parvocellular systems to psychophysical tasks, and (2) that there are no differences between magno- and parvocellular cells. Neither of these claims is correct. PMID- 28733837 TI - Orientation categories used in guidance of attention in visual search can differ in strength. AB - We investigated orientation categories in the guidance of attention in visual search. In the first two experiments, participants had a limited amount of time to find a target line among distractors lines. We systematically varied the orientation of the target and the angular difference between the target and distractors. We find vertical, horizontal, and 45 degrees targets require the least target/distractor angular difference to be found reliably and that the rate at which increases in target/distractor difference decrease search difficulty to be independent of target identity. Unexpectedly, even when the angular difference between the target and distractors was large, search performance was never optimal when the target orientation was 45 degrees . A third experiment investigates this unexpected finding by correlating target/distractor difference and error rate with performance on tasks that measure a specific perceptual or cognitive ability. We find that the elevated error rate is correlated with performance on stimulus recognition and identification tasks, while the amount of target/distractor difference needed to detect the target reliably is correlated with performance on a stimulus reproduction task. We conclude that the target/distractor difference reveals the number of orientation categories in visual search, and, accordingly, that there are four such categories: two strong ones centred on 0 degrees and 90 degrees and two weak ones centred on 45 degrees and 135 degrees . PMID- 28733838 TI - Don't let it distract you: how information about the availability of reward affects attentional selection. AB - Previous research has shown that attentional selection is affected by reward contingencies: previously selected and rewarded stimuli continue to capture attention even if the reward contingencies are no longer in place. In the current study, we investigated whether attentional selection also is affected by stimuli that merely signal the magnitude of reward available on a given trial but, crucially, have never had instrumental value. In a series of experiments, we show that a stimulus signaling high reward availability captures attention even when that stimulus is and was never physically salient or part of the task set, and selecting it is harmful for obtaining reward. Our results suggest that irrelevant reward-signaling stimuli capture attention, because participants have learned about the relationship between the stimulus and reward. Importantly, we only observed learning after initial attentional prioritization of the reward signaling stimulus. We conclude that nonsalient, task-irrelevant but reward signaling stimuli can affect attentional selection above and beyond top-down or bottom-up attentional control, however, only after such stimuli were initially prioritized for selection. PMID- 28733839 TI - Limits in feature-based attention to multiple colors. AB - Attention to a feature enhances the sensory representation of that feature. Although much has been learned about the properties of attentional modulation when attending to a single feature, the effectiveness of attending to multiple features is not well understood. We investigated this question in a series of experiments using a color-detection task while varying the number of attended colors in a cueing paradigm. Observers were shown either a single cue, two cues, or no cue (baseline) before detecting a coherent color target. We measured detection threshold by varying the coherence level of the target. Compared to the baseline condition, we found consistent facilitation of detection performance in the one-cue and two-cue conditions, but performance in the two-cue condition was lower than that in the one-cue condition. In the final experiment, we presented a 50% valid cue to emulate the situation in which observers were only able to attend a single color in the two-cue condition, and found equivalent detection thresholds with the standard two-cue condition. These results indicate a limit in attending to two colors and further imply that observers could effectively attend a single color at a time. Such a limit is likely due to an inability to maintain multiple active attentional templates for colors. PMID- 28733840 TI - Identification of a rare COCH mutation by whole-exome sequencing : Implications for personalized therapeutic rehabilitation in an Austrian family with non syndromic autosomal dominant late-onset hearing loss. AB - BACKGROUND: Non-syndromic autosomal dominant hearing impairment is characteristically postlingual in onset. Genetic diagnostics are essential for genetic counselling, disease prognosis and understanding of the molecular mechanisms of disease. To date, 36 causative genes have been identified, many in only individual families. Gene selection for genetic screening by traditional methods and genetic diagnosis in autosomal dominant patients has therefore been fraught with difficulty. Whole-exome sequencing provides a powerful tool to analyze all protein-coding genomic regions in parallel, thus allowing the comprehensive screening of all known genes and associated alterations. METHODS: In this study, a previously undiagnosed late-onset progressive autosomal dominant hearing loss in an Austrian family was investigated by means of whole-exome sequencing. Results were confirmed by Sanger sequencing. RESULTS: A previously described c.151C>T missense (p.Pro51Ser) mutation in the LCCL (limulus factor C, cochlin, late gestation lung protein Lgl1) domain of the cochlin gene (COCH) was identified as causative and segregated with disease in five members of the family. Molecular diagnostics led to the decision to perform cochlear implantation in an index patient who subsequently showed excellent postoperative auditory performance. The c.151C>T mutation was not found in 18 screened Austrian families with autosomal dominant hearing loss but was represented alongside other known pathogenic mutant COCH alleles in the Genome Aggregation Database (gnomAD) in European populations. A combined allele frequency of 0.000128 implies an orphan disease frequency for COCH-induced hearing loss of 1:3900 in Europe. CONCLUSIONS: Exome sequencing successfully resolved the genetic diagnosis in a family suffering from autosomal dominant hearing impairment and allowed prediction of purported auditory outcome after cochlear implantation in an index patient. Personalized treatment approaches based on the molecular mechanisms of disease may become increasingly important in the future. PMID- 28733841 TI - Analgosedation of adult patients with elevated intracranial pressure : Survey of current clinical practice in Austria. AB - BACKGROUND: Analgesia and sedation are key items in intensive care. Recently published S3 guidelines specifically address treatment of patients with elevated intracranial pressure. METHODS: The Austrian Society of Anesthesiology, Resuscitation and Intensive Care Medicine carried out an online survey of neurointensive care units in Austria in order to evaluate the current state of practice in the areas of analgosedation and delirium management in this high-risk patient group. RESULTS: The response rate was 88%. Induction of anesthesia in patients with elevated intracranial pressure is carried out with propofol/fentanyl/rocuronium in >80% of the intensive care units (ICU), 60% use midazolam, 33.3% use esketamine, 13.3% use barbiturates and 6.7% use etomidate. For maintenance of analgosedation up to 72 h, propofol is used by 80% of the ICUs, followed by remifentanil (46.7%), sufentanil (40%) and fentanyl (6.7%). For long-term sedation, 86.7% of ICUs use midazolam, 73.3% sufentanil and 73.3% esketamine. For sedation periods longer than 7 days, 21.4% of ICUs use propofol. Reasons for discontinuing propofol are signs of rhabdomyolysis (92.9%), green urine, elevated liver enzymes (71.4% each) and elevated triglycerides (57.1%). Muscle relaxants are only used during invasive procedures. Inducing a barbiturate coma is rated as a last resort by 53.3% of respondents. The monitoring methods used are bispectral index (BISTM, 61.5% of ICUs), somatosensory-evoked potentials (SSEP, 53.8%), processed electroencephalography (EEG, 38.5%), intraparenchymal partial pressure of oxygen (pO2, 38.5%) and microdialysis (23.1%). Sedation and analgesia are scored using the Richmond agitation and sedation score (RASS, 86.7%), sedation agitation scale (SAS, 6.7%) or numeric rating scale (NRS, 50%) and behavioral pain scale (BPS, 42.9%), visual analogue scale (VAS), critical care pain observation tool (CCPOT, each 14.3%) and verbal rating scale (VRS, 7.1%). Delirium monitoring is done using the confusion assessment method for intensive care units (CAM-ICU, 46.2%) and intensive care delirium screening checklist (ICDSC, 7.7%). Of the ICUs 46.2% do not carry out delirium monitoring. CONCLUSION: We found good general compliance with the recommendations of the current S3 guidelines. Room for improvement exists in monitoring and the use of scores to detect delirium. PMID- 28733842 TI - Human Dirofilaria repens infections diagnosed in Slovakia in the last 10 years (2007-2017). AB - Human dirofilariosis is currently considered to be an emerging zoonosis of Central Europe with climate change and globalization playing a key role in its spreading. Additionally, the occurrence of Dirofilaria spp. is strongly subject to a certain number of microfilaremic dogs and the presence of the mosquito vectors. Both conditions are fulfilled in Slovakia. The first human case of autochthonous dirofilariosis in Slovakia was diagnosed in 2007, 2 years after the infection had been observed in the Slovak dog population. Since then, a total of 12 human cases caused by Dirofilaria repens have been registered at the Institute of Parasitology, Slovak Academy of Sciences, 7 subcutaneous, 4 ocular and 1 pulmonary; however, it is likely that some cases remain undiagnosed, seeing that this infection is still missed by physicians. Of the patients 9 were male and 3 were female and their age varied between 15 and 72 years (mean 49 years). The majority of those affected came from the southern regions of the country, bordering Austria and Hungary, which are considered to be endemic areas for canine dirofilariosis. In this paper all published and unpublished cases are reviewed, with a special emphasis on the rare pulmonary form of D. repens infection. PMID- 28733844 TI - Polyamine-binding protein PotD2 is required for stress tolerance and virulence in Actinobacillus pleuropneumoniae. AB - Actinobacillus pleuropneumoniae is the cause of porcine contagious pleuropneumonia, which is one of the most important respiratory diseases in swine and causes huge economic losses in the swine industry. PotD, a polyamine-binding protein, has been well characterised in many pathogens of humans and animals. In this study, a DeltapotD2 mutant of A. pleuropneumoniae strain MS71 (serovar 1) was constructed successfully by homologous recombination. Growth curves of different strains showed that the growth of the DeltapotD2 mutant was affected greatly in the logarithmic phase compared with that of parental strain. In vitro stress assays revealed that the viability of DeltapotD2 mutant strain was significantly impaired under multiple environmental stresses, including high temperature, oxidation and hyperosmosis. Additionally, the DeltapotD2 mutant caused significantly decreased mortality in a mouse model. Taken together, the findings in this study suggest an important role of PotD2 in the growth, stress tolerance and virulence of A. pleuropneumoniae. PMID- 28733845 TI - Genome-wide identification, in silico characterization and expression analysis of ZIP-like genes from Trichomonas vaginalis in response to Zinc and Iron. AB - Trace elements such as Zinc and Iron are essential components of metalloproteins and serve as cofactors or structural elements for enzymes involved in several important biological processes in almost all organisms. Because either excess or insufficient levels of Zn and Fe can be harmful for the cells, the homeostatic levels of these trace minerals must be tightly regulated. The Zinc regulated transporter, Iron regulated transporter-like Proteins (ZIP) comprise a diverse family, with several paralogues in diverse organisms and are considered essential for the Zn and Fe uptake and homeostasis. Zn and Fe has been shown to regulate expression of proteins involved in metabolism and pathogenicity mechanisms in the protozoan pathogen Trichomonas vaginalis, in contrast high concentrations of these elements were also found to be toxic for T. vaginalis trophozoites. Nevertheless, Zn and Fe uptake and homeostasis mechanisms is not yet clear in this parasite. We performed a genome-wide analysis and localized the 8 members of the ZIP gene family in T. vaginalis (TvZIP1-8). The bioinformatic programs predicted that the TvZIP proteins are highly conserved and show similar properties to the reported in other ZIP orthologues. The expression patterns of TvZIP1, 3, 5 and 7 were diminished in presence of Zinc, while the rest of the TvZIP genes showed an unchanged profile in this condition. In addition, TvZIP2 and TvZIP4 showed a differential expression pattern in trophozoites growth under different Iron conditions. These results suggest that TvZIP genes encode membrane transporters that may be responsible for the Zn and Fe acquisition in T. vaginalis. PMID- 28733846 TI - Implementation of a standardized protocol to manage elderly patients with low energy pelvic fractures: can service improvement be expected? AB - PURPOSE: The incidence of low energy pelvic fractures (FPFs) in the elderly is increasing. Comorbidities, decreased bone-quality, problematic fracture fixation and poor compliance represent some of their specific difficulties. In the absence of uniform management, a standard operating procedure (SOP) was introduced to our unit, aiming to improve the quality of services provided to these patients. METHODS: A cohort study was contacted to test the impact of (1) using a specific clinical algorithm and (2) using different antiosteoporotic drugs. Multivariate regression analysis was used to determine prognostic factors. Study endpoints were the time-to-healing, length-of-stay, return to pre-injury mobility, union status, mortality and complications. RESULTS: A total of 132 elderly patients (>=65 years) admitted during the period 2012-2014 with FPFs were enrolled. High energy fractures, acetabular fractures, associated trauma affecting mobility, pathological pelvic lesions and operated FPFs were used as exclusion criteria. The majority of included patients were females (108/132; 81.8%), and the mean age was 85.8 years (range 67-108). Use of antiosteoporotics was associated with a shorter time of healing (p = 0.036). Patients treated according to the algorithm showed a significant protection against malunion (p < 0.001). Also, adherence to the algorithm allowed more patients to return to their pre-injury mobility status (p = 0.039). CONCLUSIONS: The use of antiosteoporotic medication in elderly patients with fragility pelvic fractures was associated with faster healing, whilst the adherence to a structured clinical pathway led to less malunions and non-unions and return to pre-injury mobility state. PMID- 28733847 TI - Posterior only approach for fifth lumbar corpectomy: indications and technical notes. AB - PURPOSE: To evaluate the efficacy and safety of a posterior-only approach for L5 corpectomy, with lumbopelvic fixation for treatment of secondaries, infections, or burst fractures. METHODS: Between 2010 and 2013, 17 patients with L5 pathology had corpectomy through a posterior-only approach, with reconstruction of the anterior column using titanium cages filled with bone graft. The indication for surgery was presence of secondaries in nine patients, spondylitis and spondylodiscitis in five patients and burst fractures due to high energy trauma in three patients. All patients underwent detailed neurological examination as well as plain radiography, computed tomography, and magnetic resonance imaging studies. RESULTS: This study included 17 patients (8 males and 9 females) with a mean age of 48.3 years. The mean operative time was 186.1 minutes with mean blood loss of 744 ml. No intra-operative or immediate post-operative complications were encountered. Three patients died during follow-up due to advanced malignancy. The remaining 14 patients were followed-up for a mean of 24.9 months. One patient had cut through of L3 screws two years after surgery requiring metal removal. One patient had asymptomatic broken screw, with no need for further intervention. CONCLUSIONS: L5 corpectomy is a challenging procedure indicated for treatment of various cases of metastasis, infections, or comminuted fractures. The posterior approach is safe, efficient, and allows both rigid posterior stabilization and anterior reconstruction after L5 corpectomy without the need for an anterior approach and its possible related morbidity. PMID- 28733848 TI - Femoro-acetabular impingement: anatomic study of reliability and accuracy of alpha angle and offset ratio on fifty consecutive peri-operatively resected femoral heads. AB - PURPOSE: The purpose of this study was to determine whether X-ray attributes of the femoro-acetabular impingement (FAI) - alpha angle (AA) and offset ratio (OR) reflect real measurements on resected femoral heads. METHODS: FAI AA and OR were assessed on 50 consecutively-resected femoral heads. The parameters were measured on heads cut through the maximum range of the deformity and compared to the same parameters on standardized X-ray projections (anterior-posterior [AP] and axial views). RESULTS: Mean AA was 76.47 degrees on dissected heads vs. 75.81 degrees on axial X-ray (p = 0.688). Mean OR was 0.132 on dissected heads vs. 0.220 on axial X-ray (p < 0.001). Mean AA on ideal AP X-ray was 79.46 degrees vs. 81.51 degrees on AP standing plain X-ray view (p = 0.431). AA measurements on plain X ray AP and axial view of halved femoral heads correlated highly. CONCLUSIONS: AA on axial X-ray view reflected the real AA in our series, but the risk of cartilage damage cannot be predicted. PMID- 28733849 TI - Novel Pacing Strategies for Heart Failure Management. AB - OPINION STATEMENT: Cardiac resynchronization therapy has emerged as the gold standard for heart failure patients with left ventricular systolic dysfunction and electrical dyssynchrony from an intrinsic intraventricular conduction delay or right ventricular pacing. However, the limits imposed by the coronary sinus venous anatomy restrict the applicability of the technology for many potential recipients. Furthermore, conventional resynchronization, by virtue of utilizing a single site of epicardial origin for left ventricular activation, is non physiological. Several technologies on the horizon, including multisite pacing, left ventricular endocardial, and leadless devices, and direct His-bundle pacing are aimed at improving the response rate of cardiac resynchronization and extending candidacy to patients ineligible for conventional therapy. In this review, we discuss the limitations of the present technology and the role for these new therapies. PMID- 28733850 TI - Comparison of Autism Screening in Younger and Older Toddlers. AB - This study examined the effect of age at completion of an autism screening test on item failure rates contrasting older (>20 months) with younger (<20 months) toddlers in a community primary care sample of 73,564 children. Items related to social development were categorized into one of three age sets per criteria from Inada et al. (Research in Autism Spectrum Disorders 4(4):605-611, 2010). Younger toddlers produced higher rates of item failure than older toddlers and items in both of the later acquired item sets had higher probability rates for failure than the earliest acquired item set (prior to 8 months). Use of the same items and the same scoring throughout the target age range for autism screening may not be the best strategy for identifying the youngest toddlers at risk for autism. PMID- 28733851 TI - Autism and Equine-Assisted Interventions: A Systematic Mapping Review. AB - This systematic mapping review mapped current knowledge of equine-assisted interventions for people with autism to help guide future practice and research. Thirty-three studies including children and adolescents with autism, 3 of which confirmed diagnoses, were reviewed. Five types of equine-assisted activities were identified across 25 studies, with reported improvements in behavior, social interaction, and communication. Four types of equine-assisted therapies were identified across 8 studies, with reported improvements in motor control and self care. Different approaches to therapeutic riding and hippotherapy, the most studied interventions, were evident. While this literature reflected early scientific development, it offered broad proof of concept that equine-assisted interventions can benefit children and adolescents with autism. Promising outcomes support continued investigation focused on standardization, appropriateness, and efficacy. PMID- 28733852 TI - Wax Crystal-Sparse Leaf 4, encoding a beta-ketoacyl-coenzyme A synthase 6, is involved in rice cuticular wax accumulation. AB - KEY MESSAGE: WSL4 encodes a KCS6 protein which is required for cuticular wax accumulation in rice. Very long chain fatty acids (VLCFAs) are essential precursors for cuticular wax biosynthesis. VLCFA biosynthesis occurs in the endoplasmic reticulum and requires the fatty acid elongase (FAE) complex. The beta-ketoacyl-coenzyme A synthase (KCS) catalyzes the first step of FAE-mediated VLCFA elongation. Here we characterized the Wax Crystal-Sparse Leaf 4 (WSL4) gene involved in leaf cuticular wax accumulation in rice. The wsl4 mutant displayed a pleiotropic phenotype including dwarfism, less tiller numbers and reduced surface wax load. Map-based cloning and nucleotide sequencing results revealed that wsl4 carried a single nucleotide substitution in the second exon of a putative KCS6 gene, encoding one subunit of the FAE complex for VLCFAs. Genetic complementation confirmed that the mutation in WSL4 was responsible for the phenotype of wsl4. WSL4 was constitutively expressed in various rice tissues and localized in the endoplasmic reticulum. Both WSL4-RNAi transgenic lines and WSL4 knocked-out mutants exhibited wax-deficient phenotypes similar to the wsl4 mutant. These data indicate that WSL4 is required for cuticular wax accumulation in rice. PMID- 28733853 TI - Cerebral magnetic resonance findings during enzyme replacement therapy in mucopolysaccharidosis. AB - BACKGROUND: Although enzyme replacement therapy (ERT) is an effective treatment for mucopolysaccharidosis (MPS) types I, II, IVA and VI, its effectiveness in children with central nervous system (CNS) disorders is said to be poor because the blood-brain barrier cannot be penetrated by ERT drugs. OBJECTIVE: To assess CNS involvement in mucopolysaccharidosis at the start of enzyme replacement therapy and to investigate the time course of ERT in the central nervous system. MATERIALS AND METHODS: We performed brain MRI in 17 children and young adults who underwent ERT. The clinical severity was classified as attenuated or severe by a specialist pediatrician, based on the clinical symptoms and genotypes. At the start of ERT, we scored nine parameters using two- or three-point scales based on the severity of the disease revealed on MRI scans. After the start of ERT, we compared the initial and follow-up MRI scans, and classified the findings as no change, improved or worse. We then compared the results with the changes in clinical findings. RESULTS: At the start of ERT, comparison of the clinical symptoms and image scores revealed differences between severe and attenuated mucopolysaccharidosis. The scores in patients with severe MPS ranged from 9 to 16 (mean 12.2); for patients with attenuated MPS, they ranged from 2 to 11 (mean 6.4). Images of the four patients with severe MPS showed ventricular dilation and brain atrophy. Such findings were made in only 2 of 13 patients with attenuated MPS. The results after the start of ERT showed that 11/17 (65%) patients manifested improvement or no change. All five patients with MPS I experienced improvement in some regions. There were no new lesions. One patient with MPS II experienced worsening of his CNS symptoms, and his MRI findings revealed more severe ventricular dilation, brain atrophy and white matter lesions. CONCLUSION: Ventricular dilation and brain atrophy on imaging studies might represent useful markers in predicting the severity of mucopolysaccharidosis and worsening of CNS symptoms. Enzyme replacement therapy improves CNS images in MPS I and has an inhibitory effect on the occurrence of new lesions in MPS II. PMID- 28733854 TI - Process Evaluation of a Clinical Trial to Test School Support as HIV Prevention Among Orphaned Adolescents in Western Kenya. AB - Orphaned adolescents are a large and vulnerable population in sub-Saharan Africa, at higher risk for HIV than non-orphans. Yet prevention of new infection is critical for adolescents since they are less likely than adults to enter and remain in treatment and are the only age group with rising AIDS death rates. We report process evaluation for a randomized controlled trial (RCT) testing support to stay in school (tuition, uniform, nurse visits) as an HIV prevention strategy for orphaned Kenyan adolescents. The RCT found no intervention effect on HIV/HSV 2 biomarker outcomes. With process evaluation, we examined the extent to which intervention elements were implemented as intended among the intervention group (N = 412) over the 3-year study period (2012-2014), the implementation effects on school enrollment (0-9 terms), and whether more time in school impacted HIV/HSV 2. All analyses examined differences as a whole, and by gender. Findings indicate that school fees and uniforms were fully implemented in 94 and 96% of cases, respectively. On average, participants received 79% of the required nurse visits. Although better implementation of nurse visits predicted more terms in school, a number of terms did not predict the likelihood of HIV/HSV-2 infection. Attending boarding school also increased number of school terms, but reduced the odds of infection for boys only. Four previous RCTs have been conducted in sub-Saharan Africa, and only one found limited evidence of school impact on adolescent HIV/HSV-2 infection. Our findings add further indication that the association between school support and HIV/HSV-2 prevention appears to be weak or under specified. PMID- 28733856 TI - Existence (or, Our Patient with Superpowers). PMID- 28733855 TI - Transportability of an Evidence-Based Early Childhood Intervention in a Low Income African Country: Results of a Cluster Randomized Controlled Study. AB - Children in Sub-Saharan Africa (SSA) are burdened by significant unmet mental health needs. Despite the successes of numerous school-based interventions for promoting child mental health, most evidence-based interventions (EBIs) are not available in SSA. This study investigated the implementation quality and effectiveness of one component of an EBI from a developed country (USA) in a SSA country (Uganda). The EBI component, Professional Development, was provided by trained Ugandan mental health professionals to Ugandan primary school teachers. It included large-group experiential training and small-group coaching to introduce and support a range of evidence-based practices (EBPs) to create nurturing and predictable classroom experiences. The study was guided by the Consolidated Framework for Implementation Research, the Teacher Training Implementation Model, and the RE-AIM evaluation framework. Effectiveness outcomes were studied using a cluster randomized design, in which 10 schools were randomized to intervention and wait-list control conditions. A total of 79 early childhood teachers participated. Teacher knowledge and the use of EBPs were assessed at baseline and immediately post-intervention (4-5 months later). A sample of 154 parents was randomly selected to report on child behavior at baseline and post-intervention. Linear mixed effect modeling was applied to examine effectiveness outcomes. Findings support the feasibility of training Ugandan mental health professionals to provide Professional Development for Ugandan teachers. Professional Development was delivered with high levels of fidelity and resulted in improved teacher EBP knowledge and the use of EBPs in the classroom, and child social competence. PMID- 28733857 TI - What Is It About This Substance? PMID- 28733858 TI - Snapshots from the Cutting Edge: Innovations in Child and Adolescent Psychiatry Training to Address Workforce Shortages. PMID- 28733859 TI - The past and future in understanding the health risks of and responses to climate variability and change. AB - Climate change and health was established as a formal field of endeavor in the early 1990s, with the number of publications increasing since the mid-2000s. The key findings in assessment reports from the Intergovernmental Panel on Climate Change in 1995, 2001, 2007, and 2014 indicate the progress in understanding the magnitude and pattern of the health risks of a changing climate. The assessments maintained a similar structure, focusing on assessing the state of knowledge of individual climate-sensitive health outcomes, with confidence in the key findings tending to increase over time with greater understanding. The knowledge base is smaller than for other key sectors (e.g., agriculture) because of limited research investment in climate change and health. Vulnerability, adaptation, and capacity assessments can inform prioritization of the significant research gaps in understanding and managing the health risks of a changing climate; filling these research gaps would provide policy- and decision-makers with insights to increase short- and longer-term resilience in health and other sectors. Research needs include to understand how climate and development pathways could interact to alter health risks over time, better understand upstream drivers of climate sensitive health outcomes, project aggregate health impacts to understand the breadth and depth of challenges that may need to be managed at geographic scales of interest, and project the time of emergence of changes in the geographic range and intensity of transmission of infectious diseases and other climate conditions. Engagement with other sectors is needed to ensure that their mitigation and adaptation activities also promote and protect health and take the health sector's needs into account. Making progress in these areas is critical for protecting the health of future populations. PMID- 28733860 TI - Climate threats on growth of rear-edge European beech peripheral populations in Spain. AB - European beech (Fagus sylvatica L.) forests in the Iberian Peninsula are a clear example of a temperate forest tree species at the rear edge of its large distribution area in Europe. The expected drier and warmer climate may alter tree growth and species distribution. Consequently, the peripheral populations will most likely be the most threatened ones. Four peripheral beech forests in the Iberian Peninsula were studied in order to assess the climate factors influencing tree growth for the last six decades. The analyses included an individual tree approach in order to detect not only the changes in the sensitivity to climate but also the potential size-mediated sensitivity to climate. Our results revealed a dominant influence of previous and current year summer on tree growth during the last six decades, although the analysis in two equally long periods unveiled changes and shifts in tree sensitivity to climate. The individual tree approach showed that those changes in tree response to climate are not size dependent in most of the cases. We observed a reduced negative effect of warmer winter temperatures at some sites and a generalized increased influence of previous year climatic conditions on current year tree growth. These results highlight the crucial role played by carryover effects and stored carbohydrates for future tree growth and species persistence. PMID- 28733861 TI - An infant with acute gastroenteritis caused by a secondary infection with a Rotarix-derived strain. AB - : Rotavirus vaccines have been successful in controlling severe diarrhea and have decreased deaths of young children globally. Rotarix and RotaTeq are the two currently available live-attenuated rotavirus vaccines. The vaccine virus can grow in a recipient's gut and spread from the vaccinee to naive individuals. The potential for the emergence of revertant viruses is a concern with live attenuated vaccines. We identified a previously healthy infant with severe acute gastroenteritis that was positive for rotavirus in a non-endemic season. A whole genome sequencing revealed that all of the viral genome segments were highly similar to those of the Rotarix virus, with the exception of five amino acid mutations in viral genes that could be associated with virulence. The younger sibling of this patient was administered Rotarix before the onset of disease in this patient, although no gastrointestinal symptoms were reported. Epidemiological data, circumstantial evidence, and the genome analysis suggest that the vaccine virus was transmitted from the vaccinee to the patient. CONCLUSION: This is a severe acute gastroenteritis case most probably attributed to the secondary infection of Rotarix-related virus without underlying diseases. The importance of molecular surveillance of rotavirus infections is discussed. What is Known: * The live-attenuated rotavirus vaccines, Rotarix and RotaTeq, have been successful in controlling severe diarrhea and have decreased deaths of young children globally. * Attenuated vaccine virus can grow in a recipient's gut and spread to naive individuals and may revert to cause secondary symptomatic infections. What is New: * This is the first report describing a Rotarix associated secondary infection resulting in severe acute gastroenteritis in an infant without underlying diseases. * Amino acid mutations that might contribute to viral pathogenesis were identified by whole genome sequencing. PMID- 28733862 TI - Recommendations for Systematic Statistical Computation of Immunogenicity Cut Points. AB - Today, the assessment of immunogenicity is integral in nonclinical and clinical testing of new biotherapeutics and biosimilars. A key component in the risk-based evaluation of immunogenicity involves the detection and characterization of anti drug antibodies (ADA). Over the past couple of decades, much progress has been made in standardizing the generalized approach for ADA testing with a three tiered testing paradigm involving screening, confirmation, and quasi-quantitative titer assessment representing the typical harmonized scheme. Depending on a biotherapeutic's structural attributes, more characterization and testing may be appropriate. Unlike bioanalytical assays used to support the evaluation of pharmacokinetics or toxicokinetics, an important component in immunogenicity testing is the calculation of cut points for the identification (screening), confirmation (specificity), and titer assessment responses in animals and humans. Several key publications have laid an excellent foundation for statistical design and data analysis to determine immunogenicity cut points. Yet, the process for statistical determination of cut points remains a topic of active discussion by investigators who conduct immunogenicity assessments to support biotherapeutic drug development. In recent years, we have refined our statistical approach to address the challenges that have arisen due to the evolution in biotherapeutics and the analytical technologies used for quasi-quantitative detection. Based on this collective experience, we offer a simplified statistical analysis process and flow-scheme for cut point evaluations that should work in a large majority of projects to provide reliable estimates for the screening, confirmatory, and titering cut points. PMID- 28733864 TI - Can single-cell RNA sequencing crack the mystery of cells? PMID- 28733863 TI - Population-level coordination of pigment response in individual cyanobacterial cells under altered nitrogen levels. AB - Cyanobacterial phycobilisome (PBS) pigment-protein complexes harvest light and transfer the energy to reaction centers. Previous ensemble studies have shown that cyanobacteria respond to changes in nutrient availability by modifying the structure of PBS complexes, but this process has not been visualized for individual pigments at the single-cell level due to spectral overlap. We characterized the response of four key photosynthetic pigments to nitrogen depletion and repletion at the subcellular level in individual, live Synechocystis sp. PCC 6803 cells using hyperspectral confocal fluorescence microscopy and multivariate image analysis. Our results revealed that PBS degradation and re-synthesis comprise a rapid response to nitrogen fluctuations, with coordinated populations of cells undergoing pigment modifications. Chlorophyll fluorescence originating from photosystem I and II decreased during nitrogen starvation, but no alteration in subcellular chlorophyll localization was found. We observed differential rod and core pigment responses to nitrogen deprivation, suggesting that PBS complexes undergo a stepwise degradation process. PMID- 28733865 TI - Checkpoint kinase 2 is dispensable for regulation of the p53 response but is required for G2/M arrest and cell survival in cells with p53 defects under heat stress. AB - Hyperthermia induced by heat stress (HS) is known to inhibit proliferation and induce cell death in cancer. We previously demonstrated that checkpoint kinase 1 (Chk1) contributes to G2/M arrest and cell survival under HS; however, the role of Chk2, a functional analog of Chk1, in regulation of the cell cycle and cell death under HS is still unknown. Here, we addressed the role of Chk2 using Molt-4 cells with p53-targeted shRNA (Molt-4/shp53) and parental control cells (Molt 4/V). Chk2 inhibition suppressed C-terminal acetylation of p53 and delayed the induction of p53-target genes in Molt-4/V cells under HS; however, Chk2 inhibition failed to inhibit apoptosis induced by HS, indicating that Chk2 was dispensable for p53-dependent apoptosis under HS. In contrast, Chk2 inhibition abrogated G2/M arrest and promoted cell death induced by HS in HeLa cells and Molt-4/shp53 cells. Thus, we demonstrated for the first time that Chk2 was required for cell cycle arrest and cell survival, particularly in cells with p53 defects under HS. These findings indicated that Chk2 may be a selective target for p53-mutated or -deficient cancer treated with hyperthermia. PMID- 28733866 TI - Inhibitory effect and mechanism of mesenchymal stem cells on melanoma cells. AB - PURPOSE: To explore the inhibitory effect and mechanism of MSCs on melanoma proliferation. METHODS: The inhibitory effect of MSCs on melanoma A375 cells was detected by co-culture and conditioned medium (CM) experiments using MTT method. The cell cycle was analyzed by flow cytometry. Then, Western Blot experiment detected the expression of proteins related to NF-kappaB signaling in A375 cells. The expression of IL-1Ra in MSCs was proved by RT-PCR. The over-expression and silencing vector pcDNA3.1-EGFP-IL-1Ra and pGPH1-IL-1R were constructed and transfected into MSCs cells. After that, the changes of inhibitory effect and cell cycle from MSCs-S and MSCs-O CM on A375 cells were explored. The expression of proteins related to NF-kappaB signaling in A375 cells after MSCs-S or MSCs-O CM treatment was detected by Western Blot. MSCs, MSCs-S, or MSCs-O and A375 cells were co-injected into nude mice under the arms, the growth of tumor was observed, the frozen sections were made, and H&E staining of tumor tissue was performed. RESULTS: The proliferation of A375 cells was inhibited and the cell cycle of A375 was arrested by MSCs. The expressions of cytokines related to NF-kappaB signaling were down-regulated. Over-expression and silence of Interleukin 1 receptor antagonist (IL-1Ra), specifically blocking activation of NF-kappaB signaling, indicated that inhibitory effect from MSCs was enhanced or weakened respectively, which suggested that IL-1Ra was involved in the inhibitory effect. In vivo, tumor initiation and growth were significantly inhibited when A375 cells were co injected with MSCs into nude mice, which were related to the expression level of IL-1Ra. CONCLUSION: MSCs could inhibit the proliferation and tumor initiation of melanoma A375 cells through NF-kappaB signaling. MSCs could secret IL-1Ra and inhibit expressions of NF-kappaB signaling-related factors of tumor cells, and cause cell cycle arrest in G1 phase. PMID- 28733868 TI - Impact of Age on the Risk of Advanced Colorectal Neoplasia in a Young Population: An Analysis Using the Predicted Probability Model. AB - BACKGROUND: The incidence of colorectal cancer is decreasing in adults aged >=50 years and increasing in those aged <50 years. AIMS: We aimed to establish risk stratification model for advanced colorectal neoplasia (ACRN) in persons aged <50 years. METHODS: We reviewed the records of participants who had undergone a colonoscopy as part of a health examination at two large medical examination centers in Korea. By using logistic regression analysis, we developed predicted probability models for ACRN in a population aged 30-49 years. RESULTS: Of 96,235 participants, 57,635 and 38,600 were included in the derivation and validation cohorts, respectively. The predicted probability model considered age, sex, body mass index, family history of colorectal cancer, and smoking habits, as follows: Y ACRN = -8.755 + 0.080.X age - 0.055.X male + 0.041.X BMI + 0.200.X family_history_of_CRC + 0.218.X former_smoker + 0.644.X current_smoker. The optimal cutoff value for the predicted probability of ACRN by Youden index was 1.14%. The area under the receiver-operating characteristic curve (AUROC) values of our model for ACRN were higher than those of the previously established Asia Pacific Colorectal Screening (APCS), Korean Colorectal Screening (KCS), and Kaminski's scoring models [AUROC (95% confidence interval): model in the current study, 0.673 (0.648-0.697); vs. APCS, 0.588 (0.564-0.611), P < 0.001; vs. KCS, 0.602 (0.576-0.627), P < 0.001; and vs. Kaminski's model, 0.586 (0.560-0.612), P < 0.001]. CONCLUSION: In a young population, a predicted probability model can assess the risk of ACRN more accurately than existing models, including the APCS, KCS, and Kaminski's scoring models. PMID- 28733867 TI - Gaseous Mediators in Gastrointestinal Mucosal Defense and Injury. AB - Of the numerous gaseous substances that can act as signaling molecules, the best characterized are nitric oxide, carbon monoxide and hydrogen sulfide. Contributions of each of these low molecular weight substances, alone or in combination, to maintenance of gastrointestinal mucosal integrity have been established. There is considerable overlap in the actions of these gases in modulating mucosal defense and responses to injury, and in some instances they act in a cooperative manner. Each also play important roles in regulating inflammatory and repair processes throughout the gastrointestinal tract. In recent years, significant progress has been made in the development of novel anti inflammatory and cytoprotective drugs that exploit the beneficial activities of one or more of these gaseous mediators. PMID- 28733869 TI - BMI Is a Risk Factor for Colorectal Cancer Mortality. AB - BACKGROUND: The relationship between dietary and lifestyle risk factors and long term mortality from colorectal cancer is poorly understood. Several factors, such as obesity, intakes of red meat, and use of aspirin, have been reported to be associated with risk of colorectal cancer mortality, though these findings have not been replicated in all studies to date. METHODS: In the Minnesota Colon Cancer Control Study, 46,551 participants 50-80 years old were randomly assigned to usual care (control) or annual or biennial screening by fecal occult blood testing. Colon cancer mortality was assessed after 30 years of follow-up. Dietary intake and lifestyle risk factors were assessed by questionnaire at baseline. RESULTS: Age [hazard ratio (HR) 1.09; 95% CI 1.07, -1.11], male sex (HR 1.25; 95% CI 1.01, 1.57), and higher body mass index (BMI) (HR 1.03; 95% CI 1.00-1.05) increased the risk of CRC mortality, while undergoing screening for CRC was associated with a reduced risk of colorectal cancer mortality (HR 0.76; 95% CI 0.61-0.94 and 0.67; 95% CI 0.53-0.83 for biennial and annual screening, respectively). Intakes of grains, meats, proteins, coffee, alcohol, aspirin, fiber, fruits, and vegetables were not associated with colorectal cancer mortality. CONCLUSIONS: Our study confirms the relationship between BMI and long term colorectal cancer mortality. Modulation of BMI may reduce risk of CRC mortality. PMID- 28733873 TI - ["Panel physician 2020"]. PMID- 28733870 TI - Rethinking childhood ependymoma: a retrospective, multi-center analysis reveals poor long-term overall survival. AB - Ependymoma is the third most common brain tumor in children, but there is a paucity of large studies with more than 10 years of follow-up examining the long term survival and recurrence patterns of this disease. We conducted a retrospective chart review of 103 pediatric patients with WHO Grades II/III intracranial ependymoma, who were treated at Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Chicago's Ann & Robert H. Lurie Children's Hospital between 1985 and 2008, and an additional 360 ependymoma patients identified from the Surveillance Epidemiology and End Results (SEER) database. For the institutional cohort, we evaluated clinical and histopathological prognostic factors of overall survival (OS) and progression-free survival (PFS) using the log-rank test, and univariate and multivariate Cox proportional-hazards models. Overall survival rates were compared to those of the SEER cohort. Median follow-up time was 11 years. Ten-year OS and PFS were 50 +/- 5% and 29 +/- 5%, respectively. Findings were validated in the independent SEER cohort, with 10 year OS rates of 52 +/- 3%. GTR and grade II pathology were associated with significantly improved OS. However, GTR was not curative for all children. Ten year OS for patients treated with a GTR was 61 +/- 7% and PFS was 36 +/- 6%. Pathological examination confirmed most recurrent tumors to be ependymoma, and 74% occurred at the primary tumor site. Current treatment paradigms are not sufficient to provide long-term cure for children with ependymoma. Our findings highlight the urgent need to develop novel treatment approaches for this devastating disease. PMID- 28733871 TI - A MDR transporter contributes to the different extracellular production of sesquiterpene pyridine alkaloids between adventitious root and hairy root liquid cultures of Tripterygium wilfordii Hook.f. AB - KEY MESSAGE: TwMDR1 transports sesquiterpene pyridine alkaloids, wilforine and wilforgine, into the hairy roots of T. wilfordii Hook.f. resulting in low secretion ratio of alkaloids. Hairy roots (HRs) exhibit high growth rate and biochemical and genetic stability. However, varying secondary metabolites in HR liquid cultures mainly remain in root tissues, and this condition may affect cell growth and cause inconvenience in downstream extraction. Studies pay less attention to adventitious root (AR) liquid cultures though release ratio of some metabolites in AR liquid cultures is significantly higher than that of HR. In Tripterygium wilfordii Hook.f., release ratio of wilforine in AR liquid cultures reached 92.75 and 13.32% in HR on day 15 of culture. To explore potential roles of transporters in this phenomenon, we cloned and functionally identified a multidrug resistance (MDR) transporter, TwMDR1, which shows high expression levels in HRs and is correlated to transmembrane transportation of alkaloids. Nicotiana tabacum cells with overexpressed TwMDR1 efficiently transported wilforine and wilforgine in an inward direction. To further prove the feasibility of genetically engineered TwMDR1 and improve alkaloid production, we performed a transient RNAi experiment on TwMDR1 in T. wilfordii Hook.f. suspension cells. Results indicated that release ratios of wilforine and wilforgine increased by 1.94- and 1.64-folds compared with that of the control group, respectively. This study provides bases for future studies that aim at increasing secretion ratios of alkaloids in root liquid cultures in vitro. PMID- 28733872 TI - Metabolic profiles of flooding-tolerant mechanism in early-stage soybean responding to initial stress. AB - KEY MESSAGE: Metabolomic analysis of flooding-tolerant mutant and abscisic acid treated soybeans suggests that accumulated fructose might play a role in initial flooding tolerance through regulation of hexokinase and phosphofructokinase. Soybean is sensitive to flooding stress, which markedly reduces plant growth. To explore the mechanism underlying initial-flooding tolerance in soybean, mass spectrometry-based metabolomic analysis was performed using flooding-tolerant mutant and abscisic-acid treated soybeans. Among the commonly-identified metabolites in both flooding-tolerant materials, metabolites involved in carbohydrate and organic acid displayed same profile at initial-flooding stress. Sugar metabolism was highlighted in both flooding-tolerant materials with the decreased and increased accumulation of sucrose and fructose, respectively, compared to flooded soybeans. Gene expression of hexokinase 1 was upregulated in flooded soybean; however, it was downregulated in both flooding-tolerant materials. Metabolites involved in carbohydrate/organic acid and proteins related to glycolysis/tricarboxylic acid cycle were integrated. Increased protein abundance of phosphofructokinase was identified in both flooding-tolerant materials, which was in agreement with its enzyme activity. Furthermore, sugar metabolism was pointed out as the tolerant-responsive process at initial-flooding stress with the integration of metabolomics, proteomics, and transcriptomics. Moreover, application of fructose declined the increased fresh weight of plant induced by flooding stress. These results suggest that fructose might be the critical metabolite through regulation of hexokinase and phosphofructokinase to confer initial-flooding stress in soybean. PMID- 28733874 TI - [Androgen deprivation plus abiraterone/prednisone in metastatic hormone-sensitive prostate cancer : Joint statement by the Study Group on Oncology (AKO) and the Working Group on Urological Oncology (AUO)]. PMID- 28733875 TI - [Management for unilateral ureteric-pelvic junction obstruction in children less than two years of age]. PMID- 28733876 TI - Human papillomavirus type 8 E7 protein binds nuclear myosin 1c and downregulates the expression of pre-rRNA. AB - Our aim was to search for new cellular binding partners for the E6 and E7 oncogenes of beta human papillomaviruses (HPV), whose direct role in skin carcinogenesis has not been thoroughly investigated. By employing glutathione S transferase pulldown and coimmunoprecipitation, we identified nuclear myosin 1c as a binding partner of HPV 8 E7 protein. As nuclear myosin 1c is an essential component of the RNA polymerase I transcription complex, we studied the effects of HPV 8 E7 protein expression on ribosomal RNA (rRNA) expression. Here we show that the activity of RNA polymerase I is decreased and that pre-rRNA expression is consequently reduced due to HPV 8 E7 expression. However, the expression levels of mature cytoplasmic 18S and 28S rRNA are retained. We propose that by relieving their resources from the energy-consuming process of rRNA transcription, HPV 8 E7 expressing cells might support more efficient virus replication in the differentiating epithelium. PMID- 28733877 TI - Expanding the Spectrum of Colonic Manifestations in Tuberous Sclerosis: L-Cell Neuroendocrine Tumor Arising in the Background of Rectal PEComa. AB - Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous condition that predisposes to numerous proliferative lesions, including perivascular epithelioid cell tumors (PEComas), such as lymphangioleiomyomatosis (LAM) and angiomyolipomas, and rare neuroendocrine neoplasms. We describe herein a TSC2-harboring tuberous sclerosis patient manifesting with a synchronous well differentiated L-cell rectal neuroendocrine tumor and leiomyomatosis-like LAM of the rectum. The background large bowel wall was thickened by confluent nodular areas comprising vessels and spindle-to-epithelioid cells, which are immunoreactive for myoid (smooth muscle actin, muscle specific actin, and desmin) and melanocytic markers (HMB45, Melan-A, microphthalmia transcription factor, and CD117). With the exception of TSC-related pancreatic neuroendocrine tumors, the association between tuberous sclerosis and neuroendocrine neoplasms remains largely unknown in the gastrointestinal tract. Neuroendocrine tumorigenesis in tuberous sclerosis is often linked to inactivating mutations of TSC2 leading to aberrant activation of mammalian target of rapamycin (mTOR) pathway. In this report, we document, for the first time, two foci of L-cell rectal neuroendocrine tumor arising in the setting of tuberous sclerosis, thus broadening the spectrum of TSC-associated endocrine disorders. Moreover, to our knowledge, this is only the second documented case of gastrointestinal leiomyomatosis-like LAM in a patient with tuberous sclerosis. The current case provides further evidence that, similar to pancreatic neuroendocrine tumors, neuroendocrine tumors of the luminal gastrointestinal tract may also be a feature of tuberous sclerosis and can be seen in association with PEComas. PMID- 28733878 TI - Role of TGF-beta in Self-Peptide Regulation of Autoimmunity. AB - Transforming growth factor (TGF)-beta has been implicated in regulation of the immune system, including autoimmunity. We have found that TGF-beta is readily produced by T cells following immunization with self-peptide epitopes that downregulate autoimmune responses in type 1 diabetes (T1D) prone nonobese diabetic (NOD) mice. These include multiple peptide epitopes derived from the islet beta-cell antigens GAD65 (GAD65 p202-221, GAD65 p217-236), GAD67 (GAD67 p210-229, GAD67 p225-244), IGRP (IGRP p123-145, IGRP p195-214) and insulin B chain (Ins. B:9-23) that protected NOD mice from T1D. Immunization of NOD mice with the self-MHC class II I-Ag7 beta-chain-derived peptide, I-Abetag7 p54-76 also induced large amounts of TGF-beta and also protected these mice from diabetes development. These results indicate that peptides derived from disease related self-antigens and MHC class II molecules primarily induce TGF-beta producing regulatory Th3 and Tr1-like cells. TGF-beta produced by these cells could enhance the differentiation of induced regulatory iTreg and iTreg17 cells to prevent induction and progression of autoimmune diseases. We therefore suggest that peripheral immune tolerance could be induced and maintained by immunization with self-peptides that induce TGF-beta producing T cells. PMID- 28733879 TI - Anticancer activity of salicin and fenofibrate. AB - Cancer refers to a disorder of cell proliferation that leads to tumor production. Cancer is usually treated by surgery, chemotherapeutic drugs, and radiation. Despite the presence of many anticancer drugs, cancer is still an uncontrolled disease and is a major cause of death worldwide. In addition, most anticancer drugs have severe side effects that can limit their use in some patients. This study aims to investigate the possible anticancer activity of two clinically used drugs: a natural antioxidant agent (salicin) and an antihyperlipidemic agent (fenofibrate) against two breast cancer models (in vivo EAC and in vitro MCF7) and the pancreatic cancer cell line (Panc-1).Our results have shown that both salicin and fenofibrate exerted an in vivo anticancer activity as evidenced by the decrease in tumor weight, tumor volume, CEA level, and reduced tumor cholesterol content through an antioxidant (reduced MDA level and increased GSH and catalase content) and an antiinflammatory activity (reduced TNF-? level). In addition, both salicin and fenofibrate were shown to be cytotoxic to MCF-7 and Panc-1 cell lines through activation of the caspase 3/7 apoptotic pathway.In conclusion, salicin and fenofibrate are promising anticancer drugs that are already used clinically with acceptable safety profile which can be incorporated into clinical trials to determine their possible application in cancer treatment. PMID- 28733881 TI - A DFT study of hydrogen and methane activation by B(C6F5)3/P(t-Bu)3 and Al(C6F5)3/P(t-Bu)3 frustrated Lewis pairs. AB - This contribution presents a computational study aimed at understanding factors affecting barriers associated with the activation of the H-H bond in molecular hydrogen and the H-CH3 bond in methane mediated by intermolecular Frustrated Lewis Pairs (FLPs). The classical phosphine P(t-Bu)3 Lewis base in conjunction with two Lewis acids, B(C6F5)3 and Al(C6F5)3, were used as representative models of intermolecular FLPs. DFT calculations were performed using the dispersion corrected omegaB97x-D functional, including toluene as a solvent through the PCM SMD implicit solvent scheme. The results show that, in all cases, the activation barrier is larger for methane than for hydrogen. We conclude that the observed increase in the barrier for methane activation is due primarily to a larger distortion in methane compared to hydrogen to reach the transition state. Second, a large distortion of the Lewis acid to attain a better interaction with the sigma-bond in methane was observed. Finally, we found that, for both hydrogen and methane activation, a considerable reduction in the free energy activation barrier is observed when the Lewis acid Al(C6F5)3 is used. From the results extracted in this study, we propose the use of alanes acids as good candidates for methane activation. PMID- 28733880 TI - Effect of asiatic acid on the Ang II-AT1R-NADPH oxidase-NF-kappaB pathway in renovascular hypertensive rats. AB - Asiatic acid, a triterpenoid compound derived from Centella asiatica, has been demonstrated to have antioxidant and anti-inflammatory effects. The present study evaluated the effects of asiatic acid on hemodynamic alterations, renin angiotensin system (RAS), oxidative stress, and inflammation in 2K-1C hypertensive rats. Renovascular hypertension was induced in male Sprague-Dawley rats and treated with vehicle, asiatic acid (30 mg/kg/day), or captopril (5 mg/kg/day) for 4 weeks. We observed that 2K-1C hypertensive rats exhibited hemodynamic alterations such as high blood pressure, heart rate, hindlimb vascular resistance, and low hindlimb blood flow. Signs of RAS activation, such as increased plasma angiotensin II and serum angiotensin-converting enzyme activity, enhanced AT1R protein expression, and suppressed AT2R expression was observed in 2K-1C hypertensive rats. Overproduction of vascular superoxide, high levels of plasma MDA, low levels of plasma nitric oxide metabolites (NOx), and upregulation of gp91phox protein expression were observed in hypertensive rats. Furthermore, inflammation was observed in hypertensive rats, as evidenced by increased plasma TNF-alpha, NF-kappaB, and phospho-NF-kappaB protein expression. Asiatic acid or captopril alleviated hemodynamic alterations, RAS activation, oxidative stress, and inflammation in 2K-1C hypertensive rats. These findings indicate that asiatic acid is an antihypertensive agent that ameliorates hemodynamic alterations in 2K-1C hypertensive rats. This effect may involve one or both of the following mechanisms: the direct effect of asiatic acid on RAS activation, oxidative stress and inflammation, and/or asiatic acid acting as an ACE inhibitor agent to inhibit the Ang II-AT1R-NADPH oxidase-NF-kappaB pathway. PMID- 28733883 TI - Coming soon: an expansion of the Journal's critical care offerings. PMID- 28733882 TI - Prediction of the lowest charge-transfer excited-state energy at the donor acceptor interface in a condensed phase using ground-state DFT calculations with generalized Kohn-Sham functionals. AB - Knowledge of the charge (electron) transfer process at the donor-acceptor interface is required to understand the working mechanisms of different organic photovoltaic materials. Investigating the lowest charge-transfer state in organic donor-acceptor solar cells is important as it allows the destruction/formation of excitons and polarons to be studied, and is directly related to the open circuit voltage. By performing low-cost and feasible calculations of ground-state electronic structures using the Mulliken rule as well as the optimally tuned range-separated hybrid (OTRSH) density functional and a regular long-range corrected functional, the lowest charge-transfer (CT) state energies of a series of dimers containing functionalized anthracene (the donor) and tetracyanoethylene (the acceptor) were obtained. The jumping distances of excited electrons during CT were calculated. The polarizable continuum model was applied to account for the effects of the solvent methylene chloride (CH2Cl2) on the lowest CT state energies obtained from gas-phase calculations. The calculated lowest CT state energies of the dimers were close to the corresponding experimental results, with a root mean square deviation (RMSD) of 0.22 eV. PMID- 28733884 TI - Paediatric hepatocellular carcinoma in tight junction protein 2 (TJP2) deficiency. PMID- 28733885 TI - A simple and rapid in vitro test for large-scale screening of fungal endophytes from drought-adapted Australian wild plants for conferring water deprivation tolerance and growth promotion in Nicotiana benthamiana seedlings. AB - Some fungal endophytes confer novel phenotypes and enhance existing ones in plants, including tolerance to water deprivation stress. A range of fungal endophytes was isolated from wild Nicotiana plants growing in arid parts of northern Australia. These were screened for ability to enhance water deprivation stress tolerance by inoculating seedlings of the model plant N. benthamiana in two in vitro tests. Sixty-eight endophyte isolates were co-cultivated with N. benthamiana seedlings on either damp filter paper or on agar medium before being subjected to water deprivation. Seventeen isolates were selected for further testing under water deprivation conditions in a sand-based test in a glasshouse. Only two fungal isolates, Cladosporium cladosporioides (E-162) and an unknown fungus (E-284), significantly enhanced seedling tolerance to moisture deprivation consistently in both in vitro and sand-based tests. Although a strongly significant correlation was observed between any two screening methods, the result of filter paper test was more strongly reflected (r = 0.757, p < 0.001) in results of the glasshouse test, indicating its relative suitability over the agar based test. In another experiment, the same 17 isolates carried forward to the sand-based test used in the glasshouse screening test were inoculated to N. benthamiana plants in pots in a nutrient-limiting environment to test their influence on growth promotion. Isolates related to C. cladosporioides, Fusarium equiseti, and Thozetella sp. promoted seedling growth by increasing shoot length and biomass. The fungal isolate E-162 (C. cladosporioides) significantly enhanced moisture deprivation tolerance as well as promoted seedling growth. PMID- 28733886 TI - Cognitive Reappraisal and Depression in Children with a Parent History of Depression. AB - Although decades of research have documented that children whose parents have a history of Major Depressive Disorder (MDD) are at a higher risk of developing depression themselves, not all of these children go on to develop depression themselves, thus highlighting the need to understand potential moderators of risk. The current study examined whether child emotion regulation, specifically, the use of cognitive reappraisal and suppression, moderated the link between parent and child depression. We recruited 458 parents and their children between the ages of 7-11 from the community. The majority of children were Caucasian (74.2%) and approximately half were girls (46.1%). Among children with a parent history of MDD, those who reported using cognitive reappraisal more frequently were less likely to have a history of depressive diagnoses themselves and had higher current levels of positive affect. Although children's use of suppression was not associated with their levels of depressive symptoms among children with a parent history of MDD, higher levels of suppression were related to higher levels of depressive symptoms among children with no parent history of MDD. These findings suggest that, among children with a history of parent depression, children's use of cognitive reappraisal may influence their own risk for developing depression and highlights the potential utility of early interventions that focus on improving the use of emotion regulation strategies like cognitive reappraisal among children of depressed parents. PMID- 28733887 TI - Erratum to: Modelling foetal exposure to maternal smoking using hepatoblasts from pluripotent stem cells. PMID- 28733888 TI - In response to the comments on our recently published paper entitled "on the mechanisms of melatonin in protection of aluminum phosphide cardiotoxicity". PMID- 28733889 TI - Comment on Asghari et al. 2017: On the mechanisms of melatonin in protection of aluminum phosphide cardiotoxicity. Arch Toxicol [Epub ahead of print]. doi:10.1007/s00204-017-1998-6. PMID- 28733890 TI - Down-regulation of miRNA-451a and miRNA-486-5p involved in benzene-induced inhibition on erythroid cell differentiation in vitro and in vivo. AB - Exposure to high-dose benzene leads to the inhibition of erythroid differentiation. However, whether lower doses of benzene exposure resemble high dose effects in erythroid differentiation, as well as the underlying mechanisms, remains largely unknown. To identify the microRNAs (miRNAs) specifically responsible for benzene exposure and their regulatory role in erythroid differentiation, we performed miRNA microarray in CD34+ hematopoietic progenitor cells isolated from human umbilical cord blood after treatment with hydroquinone (HQ), a metabolite of benzene at concentrations of 0, 1.0, 2.5, and 5.0 MUM. As a result, HQ treatment inhibited erythroid differentiation in a dose-response manner. miRNA microarray analysis revealed that miRNA-451a, miRNA-486-5p and miRNA-126-3p expression were significantly lower in HQ-treated CD34+ hematopoietic progenitor cells. In vitro studies showed that miRNA-451a and miRNA 486-5p were up-regulated during erythroid differentiation both in CD34+ hematopoietic progenitor cells and K562 cells. The increase in the percentage of benzidine-positive cells and the expression of gamma-globin in K562 cells transfected with either miRNA-451a or miRNA-486-5p mimic indicated that both miRNAs played a role in the promotion of erythroid cell differentiation. Overexpression of either miRNA-451a or miRNA-486-5p attenuated the inhibitory effects on erythroid differentiation in HQ-treated K562 cells. In vivo study showed a decreasing count of peripheral red blood cell (RBC) in C57BL/6J male mice treated with aerosol benzene at concentrations of 0, 1, 5, 25 ppm (time weight average, TWA). In addition, the expression of miRNA-451a or miRNA-486-5p was negatively correlated with the concentration of benzene inhalation on erythroid toxicity of C57BL/6J mice. Particularly, the decline in miRNA-451a and miRNA-486-5p expression appeared in male chronic benzene poisoning patients, and was correlated with a constant decrease in their RBC counts over the first 3 months after being diagnosed. These findings indicate that the suppression of miRNA-451a or miRNA-486-5p might be associated with the benzene-induced perturbation of erythroid cell differentiation. PMID- 28733891 TI - Consequences of bisphenol a perinatal exposure on immune responses and gut barrier function in mice. AB - The potent immunomodulatory effect of the endocrine disruptor bisphenol A during development and consequences during life span are of increasing concern. Particular interests have been raised from animal studies regarding the risk of developing food intolerance and infection. We aimed to identify immune disorders in mice triggered by perinatal exposure to bisphenol A. Gravid mice were orally exposed to bisphenol (50 MUg/kg body weight/day) from day 15 of pregnancy until weaning. Gut barrier function, local and systemic immunity were assessed in adult female offspring. Mice perinatally exposed to bisphenol showed a decrease in ileal lysozyme expression and a fall of fecal antimicrobial activity. In offspring mice exposed to bisphenol, an increase in colonic permeability was observed associated with an increase in interferon-gamma level and a drop of colonic IgA+ cells and fecal IgA production. Interestingly, altered frequency of innate lymphoid cells type 3 occurred in the small intestine, with an increase in IgG response against commensal bacteria in sera. These effects were related to a defect in dendritic cell maturation in the lamina propria and spleen. Activated and regulatory T cells were decreased in the lamina propria. Furthermore, perinatal exposure to bisphenol promoted a sharp increase in interferon-gamma and interleukin-17 production in the intestine and elicited a T helper 17 profile in the spleen. To conclude, perinatal exposure to bisphenol weakens protective and regulatory immune functions in the intestine and at systemic level in adult offspring. The increased susceptibility to inflammatory response is an interesting lead supporting bisphenol-mediated adverse consequences on food reactions and infections. PMID- 28733892 TI - Comparison of RECIST to immune-related response criteria in patients with non small cell lung cancer treated with immune-checkpoint inhibitors. AB - PURPOSE: Given that immune-related response in non-small cell lung cancer (NSCLC) has not been well evaluated, we assessed tumor response using the response evaluation criteria in solid tumors, version 1.1 (RECIST v1.1) and immune-related response criteria (irRC) to identify atypical responses in patients with advanced NSCLC treated with immunotherapeutic agents. METHODS: Patients received immune checkpoint inhibitors (pembrolizumab, atezolizumab, nivolumab, and durvalumab plus tremelimumab) to treat metastatic or recurrent NSCLC after failed platinum based chemotherapy. Tumor response was assessed according to both RECIST v1.1 and irRC. RESULTS: Responses by 41 patients were analyzed. The overall response rate (ORR) was 29.2% (95% CI 17.6-44.5) assessed by RECIST v1.1 and 34.1% (95% CI 21.6 49.4) by irRC, showing similar results from the two methods (p = 0.923). Two patients (4.9%) were defined as having progressive disease as assessed by RECIST but not by irRC. The patients eventually experienced tumor regression, suggesting delayed pseudoprogression. For all patients, the median PFS was 5.1 months (95% CI 3.4-6.7) and OS was 18.3 months (95% CI 6.7-29.8). In multivariate analysis, ex- or current smokers (HR 0.34, p = 0.14) and EGFR mutation negativity (HR 0.16, p = 0.05) were associated with significantly longer PFS. CONCLUSION: Our study found that pseudoprogression was not frequently observed in NSCLC. Conventional RECIST v1.1 might underestimate the benefit of immune-checkpoint inhibitors. Given the small number of patients studied, further study is warranted on whether treatment with immune-checkpoint inhibitors beyond RECIST progression benefits patients with advanced NSCLC. PMID- 28733893 TI - Effects of new-generation TMEM16A inhibitors on calcium-activated chloride currents in rabbit urethral interstitial cells of Cajal. AB - Interstitial cells of Cajal (ICC) isolated from the rabbit urethra exhibit Ca2+ activated Cl- currents (I ClCa) that are important for the development of urethral tone. Here, we examined if TMEM16A (ANO1) contributed to this activity by examining the effect of "new-generation" TMEM16A inhibitors, CACCinh-A01 and T16Ainh-A01, on I ClCa recorded from freshly isolated rabbit urethral ICC (RUICC) and on contractions of intact strips of rabbit urethra smooth muscle. Real-time quantitative PCR experiments demonstrated that TMEM16A was highly expressed in rabbit urethra smooth muscle, in comparison to TMEM16B and TMEM16F. Single-cell RT-PCR experiments revealed that only TMEM16A was expressed in freshly isolated RUICC. Depolarization-evoked I ClCa in isolated RUICC, recorded using voltage clamp, were inhibited by CACCinh-A01 and T16Ainh-A01 with IC50 values of 1.2 and 3.4 MUM, respectively. Similarly, spontaneous transient inward currents (STICs) recorded from RUICC voltage clamped at -60 mV and spontaneous transient depolarizations (STDs), recorded in current clamp, were also inhibited by CACCinh A01 and T16Ainh-A01. In contrast, spontaneous Ca2+ waves in isolated RUICC were only partially reduced by CACCinh-A01 and T16Ainh-A01. Finally, neurogenic contractions of strips of rabbit urethra smooth muscle (RUSM), evoked by electric field stimulation (EFS), were also significantly reduced by CACCinh-A01 and T16Ainh-A01. These data are consistent with the idea that TMEM16A is involved with CACCs in RUICC and in contraction of rabbit urethral smooth muscle. PMID- 28733894 TI - Risk and maintenance factors for young women's DSM-5 eating disorders. AB - Recent research with young women attending colleges, who are at the average age of eating disorder (ED) onset, established that the ED symptoms are not only prevalent but also relatively stable over the college period. Nonetheless, our knowledge regarding the course and modifiable factors associated with both the onset and maintenance of diagnosable (DSM-5) EDs in this population is limited. The objective of this report was to address these key research gaps. Data were examined from 2713 women who completed assessments of potential vulnerability factors and EDs in the autumn semester of the first (baseline) and fourth (follow up) college years. A total of 13.1% of the sample met DSM-5 criteria for an ED diagnosis at baseline. At 4-year follow-up, 7.6% of the sample met DSM-5 criteria for an ED, with 67.5% of these cases representing women who had maintained an ED diagnosis from baseline, and 32.5% representing new onset EDs. Elevated appearance-ideal internalization, body dissatisfaction, self-objectification, dieting, and negative affectivity at baseline as well as changes in these factors between assessments all predicted onset and maintenance of DSM-5 EDs at 4-year follow-up. Self-objectification (thinking about and monitoring the body's appearance from an external observer's perspective) was the largest contributor to both ED onset and maintenance. In addition to enhancing our knowledge about the course of young women's (DSM-5) EDs during college, this work highlights potentially similar psychological foci for prevention and treatment efforts. Implications for improving existing preventive and treatment approaches are outlined. PMID- 28733895 TI - Clinical impact of pre-transplant gut microbial diversity on outcomes of allogeneic hematopoietic stem cell transplantation. AB - Post-transplant microbial diversity in the gastrointestinal tract is closely associated with clinical outcomes following allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, little is known about the impact of the fecal microbiota before allo-HSCT. We analyzed fecal samples approximately 2 weeks before conditioning among 107 allo-HSCT recipients between 2013 and 2015. Microbial analysis was performed using 16S rRNA gene sequencing. Operational taxonomic unit-based microbial diversity was estimated by calculating the Shannon index. Patients were classified into three groups based on the diversity index: low (<2), intermediate (2, 3), and high (>3) diversity (18 (16.8%), 48 (44.9%), and 41 (38.3%) patients, respectively). There were no significant differences in the 20-month overall survival, cumulative incidence of relapse, and non-relapse mortality among three groups. The cumulative incidence of grade II to IV acute graft-versus-host disease (aGVHD) was similar among the three groups (low 55.6%; intermediate 35.4%; high 48.8%, p = 0.339, at day 100). Furthermore, we found no differences in the cumulative incidence of grade II to IV acute gastrointestinal GVHD among the three groups (low 38.9%; intermediate 21.3%; high 24.4%, p = 0.778, at day 100). Regarding the composition of microbiota before allo-HSCT, aGVHD patients showed a significantly higher abundance of phylum Firmicutes (p < 0.01) and a lower tendency for Bacteroidetes (p = 0.106) than non-aGVHD patients. Maintenance of Bacteroidetes throughout allo-HSCT may be a strategy to prevent aGVHD. PMID- 28733896 TI - Precancerous ACF induction affects their regional distribution forsaking oxidative stress implication in 1,2-dimethylhydrazine-induced colon carcinogenesis model. AB - Colon cancer is thought to develop in a stepwise fashion. In this study, the relationship between aberrant crypt foci (ACF) regional distribution and oxidative stress evolution was studied in a murine model of initial colon carcinogenesis induced by dimethylhydrazine (DMH). Mice were given 2 weekly subcutaneous injections of DMH (20 mg/kg) and killed at the 10th, 12th or 14th week. ACF was scored for number, distribution and crypt multiplicity after methylene-blue coloration and histologically analyzed afterwards. Oxidative stress evaluation was assessed through myeloperoxidase activity (MPO), nitric oxide (NO), L-ornithine and malondialdehyde (MDA) levels as well as antioxidant CAT, SOD and GSH. DMH treatment showed a shift from small to large ACF but also from distal to proximal colon between week 10 and 14 (p < 0.05). This was further illustrated histologically with crypt disruption and mucin depletion. Oxidative stress imbalance was observed in all DMH-treated groups. All markers (MPO, MDA and NO) peaked at week 12 (p < 0.01) and decreased at week 14 (p < 0.05) while L ornithine decreased through all protocol (p < 0.01). Antioxidants decreased in all points (p < 0.05) but only GSH increased at week 14 (p < 0.05). This work provided insight to response-patterns of oxidative stress between distal and proximal colon, showing for the first time a decreasing implication during the development process and suggesting other inflammatory, immunologic or microbiota implication as factors to be considered during chemotherapy approaches. PMID- 28733897 TI - Alleviation of Neuropathology by Inhibition of Monoacylglycerol Lipase in APP Transgenic Mice Lacking CB2 Receptors. AB - Inhibition of monoacylglycerol lipase (MAGL), the primary enzyme that hydrolyzes the endocannabinoid 2-arachidonoylglycerol (2-AG) in the brain, produces profound anti-inflammatory and neuroprotective effects and improves synaptic and cognitive functions in animal models of Alzheimer's disease (AD). However, the molecular mechanisms underlying the beneficial effects produced by inhibition of 2-AG metabolism are still not clear. The cannabinoid receptor type 2 (CB2R) has been thought to be a therapeutic target for AD. Here, we provide evidence, however, that CB2R does not play a role in ameliorating AD neuropathology produced by inactivation of MAGL in 5XFAD APP transgenic mice, an animal model of AD. We observed that expression of APP and beta-secretase as well as production of total Abeta and Abeta42 were significantly reduced in APP transgenic mice lacking CB2R (TG-CB2-KO) treated with JZL184, a selective and potent inhibitor for MAGL. Inactivation of MAGL also alleviated neuroinflammation and neurodegeneration in TG-CB2-KO mice. Importantly, TG-CB2-KO mice treated with JZL184 still exhibited improvements in spatial learning and memory. In addition, MAGL inhibition prevented deterioration in expression of important synaptic proteins in TG-CB2-KO mice. Our results suggest that CB2R is not required in ameliorating neuropathology and preventing cognitive decline by inhibition of 2-AG metabolism in AD model animals. PMID- 28733898 TI - D-Cycloserine Ameliorates Autism-Like Deficits by Removing GluA2-Containing AMPA Receptors in a Valproic Acid-Induced Rat Model. AB - Valproic acid (VPA)-exposed rat offspring have demonstrated autism spectrum disorder (ASD) phenotypes and impaired N-methyl-D-aspartate receptor (NMDAR) dependent long-term depression (LTD) in the lateral nucleus of the amygdala. NMDAR partial agonist D-cycloserine (DCS) has been reported to act as a cognitive enhancer by increasing the NMDAR response to improve autistic-like phenotypes in animals. However, the mechanism of DCS in alleviating the ASD is still unknown. Using combined behavioral, electrophysiological, and molecular approaches, we found that DCS administration rescued social interaction deficits and anxiety/repetitive-like behaviors observed in VPA-exposed offspring. In the amygdala synapses, DCS treatment reversed the decreased paired pulse ratio (PPR) and the impaired NMDAR-dependent LTD, increased the frequency and amplitude of miniature excitatory post-synaptic currents (mEPSCs), and resulted in a higher dendritic spine density at the amygdala synapses in the VPA-exposed offspring. Moreover, we found that DCS facilitated the removal of GluA2-containing alpha amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (GluA2/AMPARs) by inducing NMDAR-dependent LTD in the VPA-exposed offspring. We further established that the effects of DCS treatment, including increased GluA2/AMPAR removal and rescues of impaired social behavior, were blocked by Tat-GluA23Y, a GluA2-derived peptide that disrupted regulation of AMPAR endocytosis. These results provided the first evidence that rescue of the ASD-like phenotype by DCS is mediated by the mechanism of GluA2/AMPAR removal in VPA-exposed rat offspring. PMID- 28733899 TI - 6-OHDA Induces Oxidation of F-box Protein Fbw7beta by Chaperone-Mediated Autophagy in Parkinson's Model. AB - Parkinson's disease (PD) is the most common movement disorder disease, and its pathological feature is the degenerative loss of dopaminergic neurons in the substantia nigra compacta (SNc). In this study, we investigated whether distinct stress conditions target F-box protein Fbw7beta via converging mechanisms. Our results showed that the 6-hyroxydopamine (6-OHDA), which causes PD in animals' models, led to decreased stability of Fbw7beta in DA neuronal SN4741 cells. Further experiments suggested that oxidized Fbw7beta bound to heat-shock cognate protein 70 kDa, the key regulator for chaperone-mediated autophagy (CMA), at a higher affinity. Oxidative stress also increased the level of lysosomal associated membrane protein 2A (LAMP2A), the rate-limiting receptor for CMA substrate flux, and stimulated CMA activity. These changes resulted in accelerated degradation of Fbw7beta. 6-OHDA induced Fbw7beta oxidation and increased LAMP2A in the SNc region of the mouse models. Consistently, the levels of oxidized Fbw7beta were higher in postmortem PD brains compared with the controls. These findings for the first time revealed the specific mechanism of ubiquitin ligases, oxidative stress, and CMA-mediated protein degradation, to provide a new theoretical basis for further clarifying the mechanism of PD. PMID- 28733902 TI - Clustering and Candidate Motif Detection in Exosomal miRNAs by Application of Machine Learning Algorithms. AB - BACKGROUND: The clustering pattern and motifs give immense information about any biological data. An application of machine learning algorithms for clustering and candidate motif detection in miRNAs derived from exosomes is depicted in this paper. Recent progress in the field of exosome research and more particularly regarding exosomal miRNAs has led much bioinformatic-based research to come into existence. The information on clustering pattern and candidate motifs in miRNAs of exosomal origin would help in analyzing existing, as well as newly discovered miRNAs within exosomes. Along with obtaining clustering pattern and candidate motifs in exosomal miRNAs, this work also elaborates the usefulness of the machine learning algorithms that can be efficiently used and executed on various programming languages/platforms. RESULT: Data were clustered and sequence candidate motifs were detected successfully. The results were compared and validated with some available web tools such as 'BLASTN' and 'MEME suite'. CONCLUSION: The machine learning algorithms for aforementioned objectives were applied successfully. This work elaborated utility of machine learning algorithms and language platforms to achieve the tasks of clustering and candidate motif detection in exosomal miRNAs. With the information on mentioned objectives, deeper insight would be gained for analyses of newly discovered miRNAs in exosomes which are considered to be circulating biomarkers. In addition, the execution of machine learning algorithms on various language platforms gives more flexibility to users to try multiple iterations according to their requirements. This approach can be applied to other biological data-mining tasks as well. PMID- 28733903 TI - The effect of aspartate supplementation on the microbial composition and innate immunity on mice. AB - The study was conducted to investigate the changes of intestinal microbiota composition and innate immunity with different dietary dosages of aspartate (Asp) supplementation. Thirty-six female ICR mice were divided randomly to four groups and thereafter fed the basal diets (controls) or those supplemented with additional 0.5, 1.0 and 2.0% aspartate. After 2 week feeding, microbial composition in ileum and feces, gene expression of pro-inflammatory cytokine, and innate immune factors in ileum were determined. The ratio of Firmicutes: Bacteroidetes in ileum and feces decreased in 0.5 and 1.0% Asp-supplemented groups, whereas this ratio increased in feces in 2.0% Asp-supplemented group. Meanwhile, the gene expression of IL-17 and IFN-gamma in ileum decreased in 1.0% Asp-supplemented group; the gene expression in ileum of Muc2 decreased in 0.5 and 1.0% Asp-supplemented groups. Dietary supplementation with 2.0% Asp enhanced the expression of pIgR and Crp1 as compared to the other three groups. The results indicated that dietary 1.0% Asp supplementation lowers the ratio of Firmicutes:Bacteroidetes, which affects the innate immunity by decreasing the gene expression of IL-17, IFN-gamma, and Muc2 in ileum. PMID- 28733901 TI - Current knowledge on exosome biogenesis and release. AB - Exosomes are nanosized membrane vesicles released by fusion of an organelle of the endocytic pathway, the multivesicular body, with the plasma membrane. This process was discovered more than 30 years ago, and during these years, exosomes have gone from being considered as cellular waste disposal to mediate a novel mechanism of cell-to-cell communication. The exponential interest in exosomes experienced during recent years is due to their important roles in health and disease and to their potential clinical application in therapy and diagnosis. However, important aspects of the biology of exosomes remain unknown. To explore the use of exosomes in the clinic, it is essential that the basic molecular mechanisms behind the transport and function of these vesicles are better understood. We have here summarized what is presently known about how exosomes are formed and released by cells. Moreover, other cellular processes related to exosome biogenesis and release, such as autophagy and lysosomal exocytosis are presented. Finally, methodological aspects related to exosome release studies are discussed. PMID- 28733900 TI - The Putative Role of Environmental Mercury in the Pathogenesis and Pathophysiology of Autism Spectrum Disorders and Subtypes. AB - Exposure to organic forms of mercury has the theoretical capacity to generate a range of immune abnormalities coupled with chronic nitro-oxidative stress seen in children with autism spectrum disorder (ASD). The paper discusses possible mechanisms explaining the neurotoxic effects of mercury and possible associations between mercury exposure and ASD subtypes. Environmental mercury is neurotoxic at doses well below the current reference levels considered to be safe, with evidence of neurotoxicity in children exposed to environmental sources including fish consumption and ethylmercury-containing vaccines. Possible neurotoxic mechanisms of mercury include direct effects on sulfhydryl groups, pericytes and cerebral endothelial cells, accumulation within astrocytes, microglial activation, induction of chronic oxidative stress, activation of immune inflammatory pathways and impairment of mitochondrial functioning. (Epi-)genetic factors which may increase susceptibility to the toxic effects of mercury in ASD include the following: a greater propensity of males to the long-term neurotoxic effects of postnatal exposure and genetic polymorphisms in glutathione transferases and other glutathione-related genes and in selenoproteins. Furthermore, immune and inflammatory responses to immunisations with mercury containing adjuvants are strongly influenced by polymorphisms in the human leukocyte antigen (HLA) region and by genes encoding effector proteins such as cytokines and pattern recognition receptors. Some epidemiological studies investigating a possible relationship between high environmental exposure to methylmercury and impaired neurodevelopment have reported a positive dose dependent effect. Retrospective studies, on the other hand, reported no relationship between a range of ethylmercury-containing vaccines and chronic neuropathology or ASD. On the basis of these results, we would argue that more clinically relevant research is required to examine whether environmental mercury is associated with ASD or subtypes. Specific recommendations for future research are discussed. PMID- 28733904 TI - Polyamines: therapeutic perspectives in oxidative stress and inflammatory diseases. AB - Polyamines are naturally occurring aliphatic compounds, particularly essential elements for biological functions. These compounds play a central role in regulating molecular pathways which are responsible for cellular proliferation, growth, and differentiation. Importantly, excessive polyamine catabolism can lead to a prominent source of oxidative stress which increases inflammatory response and thought to be involved in several diseases including stroke, renal failure, neurological disease, liver disease, and even cancer. Moreover, polyamine supplementation increases life span in model organisms and may encounter oxidative stress via exerting its potential anti-oxidant and anti-inflammatory properties. The revealed literature indicates that an emerging role of polyamine biosynthetic pathway could be a novel target for drug development against inflammatory diseases. In this review, we expand the knowledge on the metabolism of polyamines, and its anti-oxidant and anti-inflammatory activities which might have future implications against inflammatory diseases in humans and animals. PMID- 28733905 TI - GLP-1/glucagon receptor co-agonism for treatment of obesity. AB - Over a relatively short period, obesity and type 2 diabetes have come to represent a large medical and economic burden to global societies. The epidemic rise in the prevalence of obesity has metabolic consequences and is paralleled by an increased occurrence of other diseases, such as diabetes, cancer and cardiovascular complications. Together, obesity and type 2 diabetes constitute one of the more preventable causes of premature death and the identification of novel, safe and effective anti-obesity drugs is of utmost importance. Pharmacological attempts to treat obesity have had limited success, with notable adverse effects, rendering bariatric surgery as the only current therapy for substantially improving body weight. Novel unimolecular, multifunctional peptides have emerged as one of the most promising medicinal approaches to enhance metabolic efficacy and restore normal body weight. In this review, we will mainly focus on the discovery and translational relevance of dual agonists that pharmacologically function at the receptors for glucagon and glucagon-like peptide-1. Such peptides have advanced to clinical evaluation and inspired the pursuit of multiple related approaches to achieving polypharmacy within single molecules. PMID- 28733907 TI - Multiple intracranial aneurysms: a direct hemodynamic comparison between ruptured and unruptured vessel malformations. AB - PURPOSE: Despite numerous studies addressing the rupture risk of intracranial aneurysms that have been published, the assessment thereof still remains challenging. Image-based simulations enable a precise prediction of patient specific blood flow information. However, those approaches normally consider only small segments of the complete cerebral vasculature. METHODS: To test the validity of the consideration of single aneurysms in one computational setup, domains of the complete anterior and posterior circulations with multiple intracranial aneurysms (MIA) were simulated. Six patients with MIA were investigated, while 3D surfaces of eleven unruptured and six ruptured aneurysms were segmented. The segmentations were used for the determination of morphological parameters and also for image-based blood flow simulations used to characterize the hemodynamic properties of each aneurysm. RESULTS: In the geometric comparison, neck aspect ratios of unruptured and ruptured aneurysms did not differ significantly. In contrast, size ratios, aspect ratios, surface areas, volumes, and non-sphericity indices were significantly higher in the ruptured cases. The analysis of hemodynamic parameters demonstrated that in each patient, the ruptured aneurysm exhibited the lowest averaged wall shear stresses and highest oscillatory shears. Unstable flow was also detected in ruptured aneurysms based on increased oscillatory velocity. CONCLUSION: In this small study involving patients with MIA, different morphologies and flow patterns were observed between ruptured and unruptured aneurysms. The analysis of the hemodynamics in such patients revealed a good agreement with studies that only considered single malformations. Additionally, complex flow patterns are detected in ruptured cases, which require deeper investigation. PMID- 28733906 TI - The advanced-DiaRem score improves prediction of diabetes remission 1 year post Roux-en-Y gastric bypass. AB - AIMS/HYPOTHESIS: Not all people with type 2 diabetes who undergo bariatric surgery achieve diabetes remission. Thus it is critical to develop methods for predicting outcomes that are applicable for clinical practice. The DiaRem score is relevant for predicting diabetes remission post-Roux-en-Y gastric bypass (RYGB), but it is not accurate for all individuals across the entire spectrum of scores. We aimed to develop an improved scoring system for predicting diabetes remission following RYGB (the Advanced-DiaRem [Ad-DiaRem]). METHODS: We used a retrospective French cohort (n = 1866) that included 352 individuals with type 2 diabetes followed for 1 year post-RYGB. We developed the Ad-DiaRem in a test cohort (n = 213) and examined its accuracy in independent cohorts from France (n = 134) and Israel (n = 99). RESULTS: Adding two clinical variables (diabetes duration and number of glucose-lowering agents) to the original DiaRem and modifying the penalties for each category led to improved predictive performance for Ad-DiaRem. Ad-DiaRem displayed improved area under the receiver operating characteristic curve and predictive accuracy compared with DiaRem (0.911 vs 0.856 and 0.841 vs 0.789, respectively; p = 0.03); thus correcting classification for 8% of those initially misclassified with DiaRem. With Ad-DiaRem, there were also fewer misclassifications of individuals with mid-range scores. This improved predictive performance was confirmed in independent cohorts. CONCLUSIONS/INTERPRETATION: We propose the Ad-DiaRem, which includes two additional clinical variables, as an optimised tool with improved accuracy to predict diabetes remission 1 year post-RYGB. This tool might be helpful for personalised management of individuals with diabetes when considering bariatric surgery in routine care, ultimately contributing to precision medicine. PMID- 28733908 TI - Assessment of Cultivable Oral Bacterial Flora from Important Venomous Snakes of India and Their Antibiotic Susceptibilities. AB - Snakebite is a common, frequently devastating, occupational, socio-economic hazard, and it has a great impact on the rural population of India. Snakebite is a major cause of the human morbidity and mortality since ancient times, as it not only affects the victim by systemic envenomation but also by wound infections originating from deadly pathogenic microorganisms from the oral cavity of the offending snake. The pathogens from the oral cavity of the snake tend to initiate an infection, resulting in gas gangrene, soft tissue necrosis, and permanent physical disabilities. In light of this, the present study is designed to evaluate the oral microbiota of venomous snakes commonly found in India and assessment of their antibiotic susceptibilities. Oral cavity swabs of twenty snakes representing the Indian cobra, Russell's viper, Saw-scaled viper, and Common krait were selected for the study. These materials were enriched using microbiological media to facilitate the growth of bacteria and their subsequent isolation to assess the antibiotic susceptibilities. A total 205 strains were isolated from the oropharyngeal cavity of snakes, which represent the common pathogens, especially Morganella morganii, Escherichia coli, Aeromonas hydrophila, Pseudomonas aeruginosa, coagulase-negative Staphylococcus aureus, Bacillus species, Micrococcus species, and some anaerobes including Clostridium perfringens. The study can conclude that the oral cavity of the snakes has a diversity of Gram-positive and Gram-negative bacteria are susceptible to several antibiotics. The Gram-negative microorganisms showed 100% susceptibility to imipenem and levofloxacin, whereas Gram-positive microorganisms to azithromycin and amoxicillin/clavulanic acid. PMID- 28733910 TI - A review study to evaluate holmium:YAG laser lithotripsy with flexible ureteroscopy in patients on ongoing oral anticoagulant therapy. AB - The objective of this study was to evaluate the safety and efficacy of flexible ureteroscopy (FURS) and holmium:YAG laser lithotripsy for the treatment of upper urinary tract stones in patients on active oral anticoagulants. The records of 1081 patients who underwent flexible ureteroscopic holmium:YAG (Ho:YAG) laser lithotripsy for upper ureteral and renal calculi from 1999 to 2015 were retrospectively reviewed. A total of 84 patients on continuous oral anticoagulation or antiplatelet therapy (warfarin, aspirin, or clopidogrel) were identified. Of these patients, 40 were on warfarin, 25 on aspirin, 11 on clopidogrel, and 8 on both aspirin and clopidogrel. The drugs were not discontinued. The baseline characteristics, indications for anticoagulation therapy, perioperative data, stone-free rate, and complications were documented. Evaluation of outcomes was assessed at 1-, 3-, and 6-month follow-up postoperatively. Mean stone size was 19.7 +/- 9.4 (range 8 to 31 mm). Twenty patients had upper ureteral and 64 patients had intrarenal calculi. Two patients had bilateral renal calculi. Mean operation time was 78.2 +/- 23.8 min (range 17 to 144 min). Two procedures (2.3%) in warfarin group were terminated due to persistent bleeding causing visual impairment. No transfusions were required. The mean serum hemoglobin levels did not change significantly (12.9 +/- 3.7 to 12.2 +/- 3.3 g/dL). No thromboembolic or cardiac adverse events were observed perioperatively. The double-j (DJ) ureteral catheterization time was 29.6 +/- 9.3 days (range 14 to 68 days) and the hospital stay was 1.6 +/- 0.6 days (range 1 to 4). The stone-free rate was 95.2% (80 patients) at 6 months. Flexible ureteroscopic Ho:YAG laser lithotripsy in patients requiring long-term anticoagulation therapy seems to be a safe and effective procedure and should be considered as a first-line treatment option in such patients for the surgical management of upper urinary tract stones. PMID- 28733909 TI - Genetics, Molecular, and Proteomics Advances in Filamentous Fungi. AB - Filamentous fungi play a dynamic role in health and the environment. In addition, their unique and complex hyphal structures are involved in their morphogenesis, integrity, synthesis, and degradation, according to environmental and physiological conditions and resource availability. However, in biotechnology, it has a great value in the production of enzymes, pharmaceuticals, and food ingredients. The beginning of nomenclature of overall fungi started in early 1990 after which the categorization, interior and exterior mechanism, function, molecular and genetics study took pace. This mini-review has emphasized some of the important aspects of filamentous fungi, their pattern of life cycle, history, and development of different strategic methods applied to exploit this unique organism. New trends and concepts that have been applied to overcome obstacle because of their basic structure related to genomics and systems biology has been presented. Furthermore, the future aspects and challenges that need to be deciphered to get a bigger and better picture of filamentous fungi have been discussed. PMID- 28733911 TI - Effects of cognitive behavioural therapy for depression in heart failure patients: a systematic review and meta-analysis. AB - This systematic review and meta-analysis aimed to evaluate the effects of cognitive behavioural therapy (CBT) on depression, quality of life, hospitalisations and mortality in heart failure patients. The search strategy was developed for Ovid MEDLINE and modified accordingly to search the following bibliographic databases: PubMed, EMBASE, PsycINFO, CENTRAL and CINAHL. Databases were searched from inception to 6 March 2016 for randomised controlled trials (RCTs) or observational studies that used CBT in heart failure patients with depression or depressive symptoms. Six studies were identified: 5 RCTs and 1 observational study, comprising 320 participants with predominantly NYHA classes II-III, who were mostly male, with mean age ranging from 55 to 66 years. Compared to usual care, CBT was associated with a greater improvement in depression scores both initially after CBT sessions (standardised mean difference -0.34, 95% CI 0.60 to -0.08, p = 0.01) and at 3 months follow-up (standardised mean difference 0.32, 95% CI -0.59 to -0.04, p = 0.03). Greater improvement in quality of life scores was evident for the CBT group initially after CBT sessions, but with no difference at 3 months. Hospital admissions and mortality were similar, regardless of treatment group. CBT may be more effective than usual care at improving depression scores and quality of life for heart failure patients initially following CBT and for depression at 3 months. Larger and more robust RCTs are needed to evaluate the long-term clinical effects of CBT in heart failure patients. PMID- 28733912 TI - Failing better: a new paradigm of care. PMID- 28733913 TI - Social identity continuity and mental health among Syrian refugees in Turkey. AB - PURPOSE: Building upon social psychological work on social identity and mental health, this study among Syrian refugees in Turkey examined the importance of multiple group memberships and identity continuity for mental health and well being. METHOD: A survey study was conducted among the very difficult to reach population of Syrian refugees (N = 361). With path analysis in AMOS the associations were examined between multiple group memberships, social identity continuity and mental health and psychological well-being. RESULTS: Indicate that belonging to multiple groups before migration was related to a higher likelihood of having preserved group memberships after migration (i.e., sense of social identity continuity), which, in turn, predicted greater life satisfaction and lower levels of depression. Multiple group membership, however, was also directly related to higher depression. CONCLUSIONS: Findings are discussed in relation to the importance of multiple group membership and feelings of identity continuity for refugees. PMID- 28733916 TI - Hysterectomy technique and risk of pelvic organ prolapse repair: a Danish nationwide cohort study. AB - PURPOSE: The purpose was to investigate, in a large cohort, how hysterectomy technique influences the incidence of subsequent pelvic organ prolapse (POP) repair among women hysterectomized for benign conditions. METHODS: From the Danish National Patient Registry, we collected data on all hysterectomies on benign indications, and all POP operations performed in Denmark from January 1, 1977 to June 10, 2016. We excluded patients with prior POP repair. We analyzed the incidence of POP surgery by cumulative incidence curves and hazard ratio (HR) for women with and without POP diagnoses or concomitant POP repair at hysterectomy. RESULTS: In all, 178,282 women underwent hysterectomy in the study period and were included in the cohort. When examining the crude HR for the risk of POP repair after hysterectomy, vaginal hysterectomy (VH) had a threefold rise in HR compared to total abdominal hysterectomy (TAH). When restricting the analyses to women without POP at time of hysterectomy, the HR for VH decreased to 1.25. The same tendency was noticed when stratifying by compartment. In the subgroup of women without POP at hysterectomy, we found that supravaginal abdominal hysterectomy had a small increase in risk compared to TAH. Laparoscopic hysterectomy had the same risk of POP as TAH. CONCLUSIONS: Overall, we found only small differences in risk of POP repair between the different hysterectomy techniques after restricting the analyses to women without POP at hysterectomy. PMID- 28733915 TI - Characteristics of undiagnosed children with parent-reported ADHD behaviour. AB - There is an ongoing public debate on the diagnosis of attention deficit hyperactivity disorder (ADHD) in which critics have claimed that the disorder is over-diagnosed, while the potential under-diagnosis of children with ADHD has received little attention. In this study we estimate the number of children with parent-reported ADHD behaviour at age 7 and absence of recorded ADHD diagnosis through adolescence, and investigate whether socio-demographic characteristics of this group differed from the children diagnosed with ADHD during follow-up. Our study was based on data from the Danish National Birth Cohort, where parents of 51,527 children completed questionnaires, including the Strength and Difficulties Questionnaire (SDQ). ADHD diagnosis was identified through Danish registers and parent-reported ADHD behaviour by the specific SDQ subscale. Socio-demographic predictors of positive parent-reported SDQ ADHD behaviour and absence of recorded ADHD diagnosis in their children were examined using logistic regression analyses. Children with parent-reported ADHD behaviour and no diagnosis (1.3%) were more likely to be girls (OR 1.83; 95% CI 1.45; 2.29), more likely to have mothers with a low socioeconomic status (OR high vs. low 1.49; 95% CI 1.10; 2.02), and to live in certain regions of the country (OR: Capital vs. Southern: 2.04; 95% CI 1.51; 2.73) than children with an ADHD diagnosis. The children showed markedly impairments on all the SDQ subscales. The results demonstrate a considerable number of children with ADHD symptoms who potentially go undetected and underline the influence of socio-demographic factors in the pathway to a diagnosis of ADHD. PMID- 28733914 TI - Molecular and functional analysis of monoclonal antibodies in support of biologics development. AB - Monoclonal antibody (mAb)-based therapeutics are playing an increasingly important role in the treatment or prevention of many important diseases such as cancers, autoimmune disorders, and infectious diseases. Multi-domain mAbs are far more complex than small molecule drugs with intrinsic heterogeneities. The critical quality attributes of a given mAb, including structure, post translational modifications, and functions at biomolecular and cellular levels, need to be defined and profiled in details during the developmental phases of a biologics. These critical quality attributes, outlined in this review, serve an important database for defining the drug properties during commercial production phase as well as post licensure life cycle management. Specially, the molecular characterization, functional assessment, and effector function analysis of mAbs, are reviewed with respect to the critical parameters and the methods used for obtaining them. The three groups of analytical methods are three essential and integral facets making up the whole analytical package for a mAb-based drug. Such a package is critically important for the licensure and the post-licensure life cycle management of a therapeutic or prophylactic biologics. In addition, the basic principles on the evaluation of biosimilar mAbs were discussed briefly based on the recommendations by the World Health Organization. PMID- 28733917 TI - Evaluation of a modified "Triple-P" procedure in women with morbidly adherent placenta after previous caesarean section. AB - AIM: To describe a modified "Triple-P" procedure and evaluate its outcome in women with morbidly adherent placenta (MAP) after previous caesarean section (CS). METHODS: A retrospective cohort study of 96 women with MAP after CS was recruited with 45 women receiving the modified "Triple-P" procedure as study group and the other 51 cases receiving the conventional managements as the control. The maternal outcomes were compared. RESULTS: The modified "Triple-P" procedure was described in step by step. Women in study group demonstrated reduction of blood loss, transfusion blood volume and operation time, as well as less hospital days and lower hospitalization cost (P < 0.05). In addition, there was no difference in uterine healing rate, hysterectomy rate, and ICU transferring rate (P > 0.05). CONCLUSION: Our modified "Triple-P" procedure for MAP after previous CS maintained the advantages of Chandraharan's "Triple-P" procedure in preservation of uterus for further fertility, less intraoperative blood loss, shorter hospital stays, and lower hospitalization cost but also advanced in feasibility and convenience during introducing into routine clinical practice. PMID- 28733919 TI - Substance Use, Violence, and Antiretroviral Adherence: A Latent Class Analysis of Women Living with HIV in Canada. AB - We used latent class analysis to identify substance use patterns for 1363 women living with HIV in Canada and assessed associations with socio-economic marginalization, violence, and sub-optimal adherence to combination antiretroviral therapy (cART). A six-class model was identified consisting of: abstainers (26.3%), Tobacco Users (8.81%), Alcohol Users (31.9%), 'Socially Acceptable' Poly-substance Users (13.9%), Illicit Poly-substance Users (9.81%) and Illicit Poly-substance Users of All Types (9.27%). Multinomial logistic regression showed that women experiencing recent violence had significantly higher odds of membership in all substance use latent classes, relative to Abstainers, while those reporting sub-optimal cART adherence had higher odds of being members of the poly-substance use classes only. Factors significantly associated with Illicit Poly-substance Users of All Types were sexual minority status, lower income, and lower resiliency. Findings underline a need for increased social and structural supports for women who use substances to support them in leading safe and healthy lives with HIV. PMID- 28733918 TI - Feasibility of optimized ultralow-dose pulsed fluoroscopy for upper gastrointestinal tract examinations: a phantom study with clinical correlation. AB - PURPOSE: To establish an optimized ultralow-dose digital pulsed fluoroscopy (FP) protocol for upper gastrointestinal tract examinations and to investigate the radiation dose and image quality. MATERIALS AND METHODS: An Alderson-Rando Phantom with 60 thermoluminescent dosimeters was used for dose measurements to systematically evaluate the dose-area product (DAP) and organ doses of the optimized FP protocol with the following acquisition parameters: 86.7 kV; 77 mA; 0.9 mm3, automatic image noise and contrast adaption. Subjective image quality, depiction of contrast agent and image noise (5-point Likert scale; 5 = excellent) were assessed in 41 patients, who underwent contrast-enhanced FP with the aforementioned optimized protocol by two radiologists in consensus. A conventional digital radiograph (DR) acquisition protocol served as the reference standard for radiation dose and image quality analyses. RESULTS: Phantom measurements revealed a general dose reduction of approximately 96% per image for the FP protocol as compared to the DR standard. DAP could be reduced by 97%. Significant dose reductions were also found for organ doses, both in the direct and scattered radiation beam with negligible orbital (FP 5.6 * 10-3 vs. DR 0.11; p = 0.02) and gonadal dose exposure (female FP 2.4 * 10-3 vs. DR 0.05; male FP 8 * 10-4 vs. DR 0.03; p <= 0.0004). FP provided diagnostic image quality in all patients, although reading scores were significantly lower for all evaluated parameters as compared to the DR standard (p < 0.05). CONCLUSION: Ultralow-dose FP is feasible for clinical routine allowing a significant reduction of direct and scattered dose exposure while providing sufficient diagnostic image quality for reliable diagnosis. PMID- 28733920 TI - Complementary and Alternative Medicine Among Persons living with HIV in the Era of Combined Antiretroviral Treatment. AB - Complementary and alternative medicine (CAM), often pursued independent of prescribing clinicians, may interact with traditional treatments, yet CAM use has not been well characterized among people living with HIV (PLWH) in the combined antiretroviral therapy (ART) era. We analyzed data from the Veterans Aging Cohort Study (October 2012-April 2015) to characterize CAM use in PLWH on ART. CAM users were more likely to have lived longer with HIV, report more bothersome symptoms, be prescribed more benzodiazepines and opioids, and consume less nicotine and alcohol. Given its high prevalence, clinicians should routinely assess for CAM use and its impact among PLWH. PMID- 28733921 TI - Social Support Networks and HIV/STI Risk Behaviors Among Latino Immigrants in a New Receiving Environment. AB - The objectives of this study were to: (1) describe the quantity and quality of social support networks of Latino immigrants living in a new receiving environment, and (2) determine the role such networks play in their HIV/STI risk behaviors, including substance use. Double incentivized convenience sampling was used to collect egocentric social support network data on 144 Latino immigrants. Latent class analysis was used for data reduction and to identify items best suited to measure quality and quantity of social support. Moderate and high quantity and quality of social support were protective of HIV/STI sexual risk behavior compared to low quantity and quality of support, after adjustment for gender, years in New Orleans and residing with family. Neither measure of social support was associated with binge drinking. The findings suggest that increased quantity and quality of social support decrease HIV/STI sexual risk behaviors but do not influence binge drinking. Interventions that improve the quantity and quality of social support are needed for Latino immigrants. PMID- 28733922 TI - Effect of collagen fibre orientation on intervertebral disc torsion mechanics. AB - The intervertebral disc is a complex fibro-cartilaginous material, consisting of a pressurized nucleus pulposus surrounded by the annulus fibrosus, which has an angle-ply structure. Disc injury and degeneration are noted by significant changes in tissue structure and function, which significantly alters stress distribution and disc joint stiffness. Differences in fibre orientation are thought to contribute to changes in disc torsion mechanics. Therefore, the objective of this study was to evaluate the effect of collagen fibre orientation on internal disc mechanics under compression combined with axial rotation. We developed and validated a finite element model (FEM) to delineate changes in disc mechanics due to fibre orientation from differences in material properties. FEM simulations were performed with fibres oriented at [Formula: see text] throughout the disc (uniform by region and fibre layer). The initial model was validated by published experimental results for two load conditions, including [Formula: see text] axial compression and [Formula: see text] axial rotation. Once validated, fibre orientation was rotated by [Formula: see text] or [Formula: see text] towards the horizontal plane, resulting in a decrease in disc joint torsional stiffness. Furthermore, we observed that axial rotation caused a sinusoidal change in disc height and radial bulge, which may be beneficial for nutrient transport. In conclusion, including anatomically relevant fibre angles in disc joint FEMs is important for understanding stress distribution throughout the disc and will be important for understanding potential causes for disc injury. Future models will include regional differences in fibre orientation to better represent the fibre architecture of the native disc. PMID- 28733924 TI - Cellular mechanosensitivity to substrate stiffness decreases with increasing dissimilarity to cell stiffness. AB - Computational modelling has received increasing attention to investigate multi scale coupled problems in micro-heterogeneous biological structures such as cells. In the current study, we investigated for a single cell the effects of (1) different cell-substrate attachment (2) and different substrate modulus [Formula: see text] on intracellular deformations. A fibroblast was geometrically reconstructed from confocal micrographs. Finite element models of the cell on a planar substrate were developed. Intracellular deformations due to substrate stretch of [Formula: see text], were assessed for: (1) cell-substrate attachment implemented as full basal contact (FC) and 124 focal adhesions (FA), respectively, and [Formula: see text]140 KPa and (2) [Formula: see text], 140, 1000, and 10,000 KPa, respectively, and FA attachment. The largest strains in cytosol, nucleus and cell membrane were higher for FC (1.35[Formula: see text], 0.235[Formula: see text] and 0.6[Formula: see text]) than for FA attachment (0.0952[Formula: see text], 0.0472[Formula: see text] and 0.05[Formula: see text]). For increasing [Formula: see text], the largest maximum principal strain was 4.4[Formula: see text], 5[Formula: see text], 5.3[Formula: see text] and 5.3[Formula: see text] in the membrane, 9.5[Formula: see text], 1.1[Formula: see text], 1.2[Formula: see text] and 1.2[Formula: see text] in the cytosol, and 4.5[Formula: see text], 5.3[Formula: see text], 5.7[Formula: see text] and 5.7[Formula: see text] in the nucleus. The results show (1) the importance of representing FA in cell models and (2) higher cellular mechanical sensitivity for substrate stiffness changes in the range of cell stiffness. The latter indicates that matching substrate stiffness to cell stiffness, and moderate variation of the former is very effective for controlled variation of cell deformation. The developed methodology is useful for parametric studies on cellular mechanics to obtain quantitative data of subcellular strains and stresses that cannot easily be measured experimentally. PMID- 28733923 TI - Cardiovascular mechanics in the early stages of pulmonary hypertension: a computational study. AB - We formulate and study a new mathematical model of pulmonary hypertension. Based on principles of fluid and elastic dynamics, we introduce a model that quantifies the stiffening of pulmonary vasculature (arteries and arterioles) to reproduce the hemodynamics of the pulmonary system, including physiologically consistent dependence between compliance and resistance. This pulmonary model is embedded in a closed-loop network of the major vessels in the body, approximated as one dimensional elastic tubes, and zero-dimensional models for the heart and other organs. Increasingly severe pulmonary hypertension is modeled in the context of two extreme scenarios: (1) no cardiac compensation and (2) compensation to achieve constant cardiac output. Simulations from the computational model are used to estimate cardiac workload, as well as pressure and flow traces at several locations. We also quantify the sensitivity of several diagnostic indicators to the progression of pulmonary arterial stiffening. Simulation results indicate that pulmonary pulse pressure, pulmonary vascular compliance, pulmonary RC time, luminal distensibility of the pulmonary artery, and pulmonary vascular impedance are much better suited to detect the early stages of pulmonary hypertension than mean pulmonary arterial pressure and pulmonary vascular resistance, which are conventionally employed as diagnostic indicators for this disease. PMID- 28733925 TI - Polypropelene-mesh properties and type of anchoring do not influence strength of parietal ingrowth. AB - PURPOSE: In laparoscopic ventral hernia repair, parietal ingrowth of the mesh is of crucial importance. Until significant ingrowth occurs integrity of the repair depends solely on mesh overlap and anchoring device. Relatively few studies have addressed the effect of mesh properties and anchoring device on long-term parietal ingrowth. METHODS: In 20 sheep, using laparoscopy, we inserted two different polypropylene-based meshes, PhysiomeshTM and VentralightTM ST, anchored with ProtackTM, SecureStrapTM, or GlubranTM. After 6 and 12 months, 10 sheep at each time point were euthanized, and we harvested the meshes with corresponding fascia. Mesh with fascia was attached on an AlwetronTM materials testing machine and pulled apart obtaining the peel-off energy (kilojoule (kJ)). RESULTS: The strength of parietal ingrowth at 6 months was 5.99 +/- 0.54 kJ (mean +/- SEM), 4.94 +/- 0.54 kJ and 7.35 +/- 0.55 kJ when anchored with ProtackTM, GlubranTM, or SecureStrapTM, respectively. At 6 months, the strength of parietal ingrowth of SecureStrapTM was significantly higher than GlubranTM (p = 0.04). No significant difference was seen between any other combinations. Parietal ingrowth at 12 months was 7.05 +/- 0.56 kJ, 7.55 +/- 0.54 kJ, and 5.73 +/- 0.54 kJ when anchored with ProtackTM, GlubranTM, and SecureStrapTM, respectively. No significant difference in strength of parietal ingrowth was seen between the three types of anchoring, (p = 1.00, p = 1.00, and p = 0.29). CONCLUSIONS: At 12 months, the strength of parietal ingrowth was the same for all comparisons. The two polypropylene meshes showed equal strength of parietal ingrowth independent of mesh properties and anchoring devices used. PMID- 28733926 TI - Perioperative management of endocrine insufficiency after total pancreatectomy for neoplasia. AB - PURPOSE: Indications for total pancreatectomy (TP) have increased, including for diffuse main duct intrapapillary mucinous neoplasms of the pancreas and malignancy; therefore, the need persists for surgeons to develop appropriate endocrine post-operative management strategies. The brittle diabetes after TP differs from type 1/2 diabetes in that patients have absolute deficiency of insulin and functional glucagon. This makes glucose management challenging, complicates recovery, and predisposes to hospital readmissions. This article aims to define the disease, describe the cause for its occurrence, review the anatomy of the endocrine pancreas, and explain how this condition differs from diabetes mellitus in the setting of post-operative management. The morbidity and mortality of post-TP endocrine insufficiency and practical treatment strategies are systematically reviewed from the literature. Finally, an evidence-based treatment algorithm is created for the practicing pancreatic surgeon and their care team of endocrinologists to aid in managing these complex patients. METHODS: A PubMed, Science Citation Index/Social sciences Citation Index, and Cochrane Evidence Based Medicine database search was undertaken along with extensive backward search of the references of published articles to identify studies evaluating endocrine morbidity and treatment after TP and to establish an evidence-based treatment strategy. RESULTS: Indications for TP and the etiology of pancreatogenic diabetes are reviewed. After TP, ~80% patients develop hypoglycemic episodes and 40% experience severe hypoglycemia, resulting in 0-8% mortality and 25-45% morbidity. Referral to a nutritionist and endocrinologist for patient education before surgery followed by surgical reevaluation to determine if the patient has the appropriate understanding, support, and resources preoperatively has significantly reduced morbidity and mortality. The use of modern recombinant long-acting insulin analogues, continuous subcutaneous insulin infusion, and glucagon rescue therapy has greatly improved management in the modern era and constitute the current standard of care. A simple immediate post-operative algorithm was constructed. CONCLUSION: Successful perioperative surgical management of total pancreatectomy and resulting pancreatogenic diabetes is critical to achieve acceptable post-operative outcomes, and we review the pertinent literature and provide a simple, evidence-based algorithm for immediate post-resection glycemic control. PMID- 28733929 TI - Outcomes of Ahmed glaucoma valve implantation for steroid-induced elevated intraocular pressure in patients with retinitis pigmentosa. AB - PURPOSE: To evaluate the outcomes of Ahmed glaucoma valve (AGV) in the management of elevated intraocular pressure (IOP) secondary to steroid use for macular edema in patients with retinitis pigmentosa (RP). METHODS: A total of nine eyes of five patients were evaluated retrospectively. Complete success was defined as IOP <= 21 mmHg without glaucoma medications, while qualified success was defined as IOP <= 21 mmHg with glaucoma medications. RESULTS: Mean age at surgery was 25.0 +/- 8.3 years, and mean follow-up time was 38.4 +/- 13.2 months. Mean IOP was 41.0 +/ 8.3 mmHg preoperatively, 9.4 +/- 3.5 mmHg at first week (p = 0.008), 13.1 +/- 3.6 mmHg at first month (p = 0.008), 14.8 +/- 4.1 mmHg at 6th month (p = 0.008), 11.7 +/- 2.6 mmHg at 12th month (p = 0.008), 12.4 +/- 2.9 mmHg at 24th month (p = 0.008), 12.6 +/- 3.6 mmHg at 36th month (p = 0.043) and 12.8 +/- 4.2 mmHg at 48th month (p = 0.068) postoperatively. The mean number of topical anti-glaucomatous medications decreased from 2.8 +/- 0.4 preoperatively to 0.4 +/- 0.9 postoperatively (p = 0.007). Complete success was obtained in 7 (77%) eyes, and qualified success in 2 (23%) eyes. No failure was detected. CONCLUSIONS: AGV implantation can be considered as an alternative and safe option in the management of resistant, elevated IOP secondary to steroid treatment for macular edema in patients with RP. PMID- 28733928 TI - Structural neurodegeneration correlates with early diabetic retinopathy. AB - PURPOSE: To examine differences in structural and functional neurodegenerative measurements between patients with no and early diabetic retinopathy (DR). METHODS: In this cross-sectional study, we examined 103 patients with type 2 diabetes mellitus. In 7-field fundus photographs acquired with Topcon TRC-NW6S, a single, certified grader determined the presence of DR according to the Early Treatment Diabetic Retinopathy Study (ETDRS) scale. Retinal neurodegeneration was evaluated by Topcon 3D OCT-2000 spectral domain optical coherence tomography (OCT) and by a RETI-scan multifocal electroretinography (mf-ERG) system in rings 1-6. RESULTS: Median age and duration of diabetes were 63.6 and 10 years, respectively, and 46% were men. Median HbA1c was 50 mmol/mol (6.7%), and ETDRS levels were 10 (41.7%, n = 43), 20 (35.0%, n = 36), and 35 (23.3%, n = 24). The duration of diabetes increased with higher levels of DR (p = 0.04), but patients with different level of DR did not differ according to age, sex, blood pressure, HbA1c, and mf-ERG or OCT parameters. In a multiple logistic regression model, macular ganglion cell layer thickness was associated with the presence of DR (OR 1.73 per 5 MUm increase, 95% CI 1.06-2.85, p = 0.03). Conversely, retinal nerve fibre layer thickness at optic disc was inversely related to DR (OR 0.69 per 5 MUm increase, 95% CI 0.51-0.95, p = 0.02). There were no associations between DR and mf-ERG outcomes. CONCLUSION: In patients with type 2 diabetes, structural neurogenic characteristics were associated with DR. If confirmed by larger prospective studies, these results may indicate that a complex neurovascular interaction is an early event in the pathogenesis of DR. PMID- 28733927 TI - Nut intake and 5-year changes in body weight and obesity risk in adults: results from the EPIC-PANACEA study. AB - PURPOSE: There is inconsistent evidence regarding the relationship between higher intake of nuts, being an energy-dense food, and weight gain. We investigated the relationship between nut intake and changes in weight over 5 years. METHODS: This study includes 373,293 men and women, 25-70 years old, recruited between 1992 and 2000 from 10 European countries in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Habitual intake of nuts including peanuts, together defined as nut intake, was estimated from country-specific validated dietary questionnaires. Body weight was measured at recruitment and self-reported 5 years later. The association between nut intake and body weight change was estimated using multilevel mixed linear regression models with center/country as random effect and nut intake and relevant confounders as fixed effects. The relative risk (RR) of becoming overweight or obese after 5 years was investigated using multivariate Poisson regressions stratified according to baseline body mass index (BMI). RESULTS: On average, study participants gained 2.1 kg (SD 5.0 kg) over 5 years. Compared to non-consumers, subjects in the highest quartile of nut intake had less weight gain over 5 years (-0.07 kg; 95% CI -0.12 to -0.02) (P trend = 0.025) and had 5% lower risk of becoming overweight (RR 0.95; 95% CI 0.92 0.98) or obese (RR 0.95; 95% CI 0.90-0.99) (both P trend <0.008). CONCLUSIONS: Higher intake of nuts is associated with reduced weight gain and a lower risk of becoming overweight or obese. PMID- 28733931 TI - Do 6 months of whole-body vibration training improve lean mass and bone mass acquisition of adolescent swimmers? AB - : Swimming has little effect on bone mass. Therefore, adolescent swimmers should complement their water training with a short and intense weight-bearing training, aiming to increase their bone acquisition. Forty swimmers performed a six-month whole-body vibration (WBV) training. WBV had no effect on adolescent swimmers' bone mass or lean mass. PURPOSE: The aims of the present study were to evaluate the effects of a whole-body vibration (WBV) intervention on bone mineral density (BMD), bone mineral content (BMC) and lean mass (LM) in adolescent swimmers. METHODS: Forty male and female adolescent swimmers (VIB; mean age 14.2 +/- 1.9 years) completed the WBV protocol that consisted of 15 min of training 3 days per week during a 6-month period (ranging from 3.6 to 11.6 g), while 23 swimmers (SWI; mean age 15.0 +/- 2.2 years) continued with their regular swimming training alone. VIB were divided into tertiles according to training compliance in order to evaluate if any dose-effect relation existed. BMD, BMC and LM were measured longitudinally by dual energy X-ray at the whole body, lumbar-spine and hip. RESULTS: No group by time interactions and no differences in change percentage were found for BMD, BMC or LM in any of the measured variables. The mean change percentage of the subtotal body (whole body minus the head) for VIB and SWI, respectively, was 2.3 vs. 2.4% for BMD, 5.7 vs 5.7% for BMC and 7.3 vs. 8.0% for lean mass. Moreover, no indication for dose-response was observed. CONCLUSIONS: The proposed WBV protocol had no effect on BMD, BMC and LM in adolescent swimmers. Other types of training should be used in this population to improve both bone and lean mass. PMID- 28733930 TI - Best practices for the use and evaluation of animal serum as a component of cell culture medium. AB - Animal serum is a common additive for cell culture medium and is often required at 5 to 10% (v/v) for the attachment and growth of primary and continuous anchorage-dependent (monolayer) cultures. The use of animal serum in cell culture medium confers several advantages and also some risks. This article discusses the use of animal serum as a component of cell culture medium. The best practices associated with the sourcing, storage, thawing, testing, and mitigation of risk associated with the use of animal sera are among the topics described in this article. PMID- 28733932 TI - A new algorithm for ECG interference removal from single channel EMG recording. AB - This paper presents a new method to remove electrocardiogram (ECG) interference from electromyogram (EMG). This interference occurs during the EMG acquisition from trunk muscles. The proposed algorithm employs progressive image denoising (PID) algorithm and ensembles empirical mode decomposition (EEMD) to remove this type of interference. PID is a very recent method that is being used for denoising digital images mixed with white Gaussian noise. It detects white Gaussian noise by deterministic annealing. To the best of our knowledge, PID has never been used before, in the case of EMG and ECG separation or in other 1D signal denoising applications. We have used it according to this fact that amplitude of the EMG signal can be modeled as white Gaussian noise using a filter with time-variant properties. The proposed algorithm has been compared to the other well-known methods such as HPF, EEMD-ICA, Wavelet-ICA and PID. The results show that the proposed algorithm outperforms the others, on the basis of three evaluation criteria used in this paper: Normalized mean square error, Signal to noise ratio and Pearson correlation. PMID- 28733935 TI - G3 GEP NENs category: are basic and clinical investigations well integrated? AB - Gastroenteropancreatic neuroendocrine neoplasms grade 3, all of them with >20% Ki 67, can be heterogeneous on the basis of their morphological features, comprising well and poorly differentiated neoplasms; the former are named tumors and the latter carcinomas. Several papers about gastroenteropancreatic neuroendocrine neoplasms grade 3 heterogeneity have been reporting over the last years by clinicians and pathologists, indicating that the differential diagnosis between named tumors grade 3 and named carcinomas grade 3 may be relevant in defining a different approach in terms of characterization of disease, staging, and treatment. To well define the sub-type of gastroenteropancreatic neuroendocrine neoplasms grade 3 pathologist's expertise in recognizing tumor morphology, immunohistochemical, and molecular techniques were reported remarkable. Although current evidence about grade 3 gastroenteropancreatic neuroendocrine neoplasms heterogeneity is still far from producing validated specific therapies for specific subcategories, the hypotheses generated from the several retrospective analyses published so far on this topic represent solid bases for designing prospective therapeutic clinical trials in homogenous clinical settings. PMID- 28733933 TI - Immunohistochemical analysis of H3K27me3 demonstrates global reduction in group-A childhood posterior fossa ependymoma and is a powerful predictor of outcome. AB - Posterior fossa ependymomas (EPN_PF) in children comprise two morphologically identical, but biologically distinct tumor entities. Group-A (EPN_PFA) tumors have a poor prognosis and require intensive therapy. In contrast, group-B tumors (EPN_PFB) exhibit excellent prognosis and the current consensus opinion recommends future clinical trials to test the possibility of treatment de escalation in these patients. Therefore, distinguishing these two tumor subtypes is critical. EPN_PFA and EPN_PFB can be distinguished based on DNA methylation signatures, but these assays are not routinely available. We have previously shown that a subset of poorly prognostic childhood EPN_PF exhibits global reduction in H3K27me3. Therefore, we set out to determine whether a simple immunohistochemical assay for H3K27me3 could be used to segregate EPN_PFA from EPN_PFB tumors. We assembled a cohort of 230 childhood ependymomas and H3K27me3 immunohistochemistry was assessed as positive or negative in a blinded manner. H3K27me3 staining results were compared with DNA methylation-based subgroup information available in 112 samples [EPN_PFA (n = 72) and EPN_PFB tumors (n = 40)]. H3K27me3 staining was globally reduced in EPN_PFA tumors and immunohistochemistry showed 99% sensitivity and 100% specificity in segregating EPN_PFA from EPN_PFB tumors. Moreover, H3K27me3 immunostaining was sufficient to delineate patients with worse prognosis in two independent, non-overlapping cohorts (n = 133 and n = 97). In conclusion, immunohistochemical evaluation of H3K27me3 global reduction is an economic, easily available and readily adaptable method for defining high-risk EPN_PFA from low-risk posterior fossa EPN_PFB tumors to inform prognosis and to enable the design of future clinical trials. PMID- 28733936 TI - An Examination of the Association of Multiple Acculturation Measures with Asthma Status Among Elementary School Students in El Paso, Texas. AB - Some researchers posit that the lower prevalence of asthma among those of Mexican descent may result from an under-diagnosis and recommend a critical appraisal of factors related to race/ethnicity, like acculturation, and its influence on asthma status. Survey data were analyzed using multinomial logistic regression to examine the association of child's asthma status (no wheezing/no asthma symptoms, possible undiagnosed and diagnosed asthma) with measures of acculturation among Hispanic students (n = 1095). In this population, the prevalence of diagnosed asthma (15%) was higher than both national (7.6%) and state (6.8%) averages for Hispanic children in 2012. While bivariate analyses showed significant associations for asthma status and measures of acculturation, multivariate analyses did not. There is an underestimated burden of illness among Hispanic children in El Paso County. More research on the suitability of acculturation constructs is needed to delineate what they actually measure and how acculturation influences asthma status. PMID- 28733934 TI - Draft Genome Sequence of the Deep-Sea Bacterium Moritella sp. JT01 and Identification of Biotechnologically Relevant Genes. AB - Deep-sea bacteria can produce various biotechnologically relevant enzymes due to their adaptations to high pressures and low temperatures. To identify such enzymes, we have sequenced the genome of the polycaprolactone-degrading bacterium Moritella sp. JT01, isolated from sediment samples from Japan Trench (6957 m depth), using a Illumina HiSeq2000 sequencer (12.1 million paired-end reads) and CLC Genomics Workbench (version 6.5.1) for the assembly, resulting in a 4.83-Mb genome (42 scaffolds). The genome was annotated using Rapid Annotation using Subsystem Technology (RAST), Protein Homology/analogY Recognition Engine V 2.0 (PHYRE2), and BLAST2Go, revealing 4439 protein coding sequences and 101 RNAs. Gene products with industrial relevance, such as lipases (three) and esterases (four), were identified and are related to bacterium's ability to degrade polycaprolactone. The annotation revealed proteins related to deep-sea survival, such as cold-shock proteins (six) and desaturases (three). The presence of secondary metabolite biosynthetic gene clusters suggests that this bacterium could produce nonribosomal peptides, polyunsaturated fatty acids, and bacteriocins. To demonstrate the potential of this genome, a lipase was cloned an introduced into Escherichia coli. The lipase was purified and characterized, showing activity over a wide temperature range (over 50% at 20-60 degrees C) and pH range (over 80% at pH 6.3 to 9). This enzyme has tolerance to the surfactant action of sodium dodecyl sulfate and shows 30% increased activity when subjected to a working pressure of 200 MPa. The genomic characterization of Moritella sp. JT01 reveals traits associated with survival in the deep-sea and their potential uses in biotechnology, as exemplified by the characterized lipase. PMID- 28733937 TI - Sequential Extraction as Novel Approach to Compare 12 Medicinal Plants From Kenya Regarding Their Potential to Release Chromium, Manganese, Copper, and Zinc. AB - This study is focusing on a novel approach to screen a large number of medicinal plants from Kenya regarding their contents and availability of selected metals potentially relevant for treatment of diabetes patients. For this purpose, total levels of zinc, chromium, manganese, and copper were determined by flame atomic absorption spectrometry and inductively coupled plasma mass spectrometry as well as BCR sequential extraction to fractionate the elemental species in anti diabetic medicinal plants collected from five natural locations in two sub counties in Nyamira County, Kenya. Solanum mauense had the highest zinc level of 123.0 +/- 3.1 mg/kg while Warburgia ugandensis had the lowest level of 13.9 +/- 0.4 mg/kg. The highest level of copper was in Bidens pilosa (29.0 +/- 0.6 mg/kg) while the lowest was in Aloe vera (3.0 +/- 0.1 mg/kg). Croton macrostachyus had the highest manganese level of 1630 +/- 40 mg/kg while Clerodendrum myricoides had the lowest (80.2 +/- 1.2 mg/kg). The highest level of chromium was in Solanum mauense (3.20 +/- 0.06 mg/kg) while the lowest (0.04 +/- 0.01 mg/kg) were in Clerodendrum myricoides and Warburgia ugandesis among the medicinal plants from Nyamira and Borabu, respectively. The levels of the elements were statistically different from that of other elements while the level of a given element was not statistically different in the medicinal plants from the different sub counties. Sequential extraction was performed to determine the solubility and thus estimate the bioavailability of the four investigated essential and potentially therapeutically relevant metals. The results showed that the easily bioavailable fraction (EBF) of chromium, manganese, zinc, and copper ranged from 6.7 to 13.8%, 4.1 to 10%, 2.4 to 10.2%, and 3.2 to 12.0% while the potentially bioavailable fraction (PBF) ranged from 50.1 to 67.6%, 32.2 to 48.7%, 23.0 to 41.1%, and 34.6 to 53.1%, respectively. Bidens pilosa, Croton macrostachyus, Ultrica dioica, and Solanum mauense medicinal plants used to treat diabetes by 80 % of the herbalists in Nyamira County were found to be rich in chromium, manganese, copper, and zinc. The EBF of zinc, manganese, and chromium constitutes adequate amounts recommended for daily intake not exceeding the ADI and delivered a low percentage of RDA when estimating daily intake during therapy from typically applied doses. The plants did not show any significant differences at p < 0.05 in terms of concentrations of the elements between the two study areas though the levels of the different elements were statistically significant. Another major observation was that high total levels of the metals in a given plant did not necessarily translate to high bioavailable levels, and hence the need to determine bioavailable form as it is the one accessible to the patient. PMID- 28733938 TI - Molecular cloning, heterologous expression, and functional characterization of a cellulolytic enzyme (Cel PRII) from buffalo rumen metagenome. AB - A cellulase encoding gene, Cel PRII, was identified from Mehsani buffalo rumen metagenome, and cloned and expressed in Escherichia coli BL21(DE3)pLysS. The 1170 bp full length gene encodes a 389 residue polypeptide (Cel PRII) containing a catalytic domain belonging to glycosyl hydrolase (GH) 5 family. The fusion protein consisting of the Cel PRII, thioredoxin tag and 6x Histidine tag with predicted molecular weight of 63 kDa when recovered from inclusion bodies under denaturing conditions, exhibited cellulolytic activity against carboxymethyl cellulose (CMC). Recombinant Cel PRII was stable in the pH range 4.0-10.0 with pH optima 6.0. The optimal reaction temperature of Cel PRII was 30 degrees C with more than 50% of its activity retained at the temperatures ranging from 0 to 50 degrees C. Cel PRII exhibited enhanced enzymatic activity in the presence of Mn2+ ions and was inhibited in the presence of chelating agent EDTA. The K m and V max values for CMC were found to be 166 mg/mL and 1292 IU/mg, respectively. Cel PRII identified in the present study may act as an excellent candidate for industrial applications, and may aid in lignocellulosic biomass conversion because of its potential cellulolytic activity, thermostability, and excellent pH stability. PMID- 28733939 TI - Comparison of endotracheal tube cuff pressure values before and after training seminar. AB - It is recommended that endotracheal cuff (ETTc) pressure be between 20 and 30 cm H2O. In this present study, we intend to observe average cuff pressure values in our clinic and the change in these values after the training seminar. The cuff pressure values of 200 patients intubated following general anesthesia induction in the operating theatre were measured following intubation. One hundred patients whose values were measured before the training seminar held for all physician assistants, and 100 patients whose values were measured after the training seminar were regarded as Group 1 and Group 2, respectively. Cuff pressures of both groups were recorded, and the difference between them was shown. Moreover, cuff pressure values were explored according to the working period of the physician assistants. There was no significant difference between the groups in terms of age, gender and tube diameters. Statistically significant difference was found between cuff pressure values before and after the training (p < 0.001). Average pressure measure for Group I was 54 cm H2O, while average pressure in Group II declined to 33 cm H2O. It was observed that as the working period and experience of physician assistants increased, cuff pressure values decreased, however no statistically significant different was found (p < 0.375). We believe that clinical experience does not have significant effects on cuff pressure and that training seminars held at intervals would prevent high cuff pressure values and potential complications. PMID- 28733940 TI - Pituitary tuberculoma: a rare cause of sellar mass. AB - INTRODUCTION: Pituitary tuberculosis is an uncommon cause of sellar mass [1]; the estimated prevalence worldwide is not known, and there have been no reports of the condition occurring in Ireland. Tuberculosis of the pituitary gland may present as a sellar mass or with symptoms of hypopituitarism. CASE PRESENTATION: A 41-year-old woman, with a short prodromal history without endocrine symptoms, was found to have pituitary tuberculosis after the demonstration of a sellar mass on MRI, and lumbar puncture findings consistent with lymphocytic meningitis. CONCLUSION: To our knowledge, this is the first published case of pituitary tuberculoma in Ireland. PMID- 28733942 TI - Perceived stress in patients with migraine: a case-control study. AB - BACKGROUND: Perceived stress is the most common trigger for migraine. The objective of this study was to examine the clinical significance of perceived stress in migraine patients. METHODS: This is a case-control study. Consecutive migraine patients who visited a tertiary care hospital were enrolled for this study. They completed self-reported questionnaires including Perceived Stress Scale (PSS), 12-item Allodynia Symptom Checklist (ASC-12), Migraine Disability Assessment Scale (MIDAS), Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder-7 (GAD-7), Epworth Sleepiness Scale (ESS), Insomnia Severity Index (ISI), and Migraine-Specific Quality of Life Questionnaire (MSQ). Degree of perceived stress in migraine patients was measured and compared to that in healthy controls. Predictors for perceived stress and their impact on quality of life (QOL) of migraine patients were also determined. RESULTS: A total of 227 migraine patients were eligible for this study, including 103 (45.4%) who had chronic migraine (CM). Mean PSS score was significantly (p < 0.05) higher in CM patients than that in controls after adjusting for education, depression, and anxiety. Although several factors were associated with PSS score, major predictors for PSS were GAD-7 score (beta = 0.358, p < 0.001), PHQ-9 score (beta = 0.304, p < 0.001), ISI score (beta = 0.154, p = 0.005), and CM (beta = -0.104, p = 0.027). There was an inverse relationship between PSS scores and three dimensional scores of MSQ (p < 0.001). CONCLUSIONS: Chronic migraine is a critical factor for perceived stress. Perceived stress affects QOL of migraine patients. PMID- 28733941 TI - Assessment of gray and white matter structural alterations in migraineurs without aura. AB - BACKGROUND: Migraine constitute a disorder characterized by recurrent headaches, and have a high prevalence, a high socio-economic burden and severe effects on quality of life. Our previous fMRI study demonstrated that some brain regions are functional alterations in migraineurs. As the function of the human brain is related to its structure, we further investigated white and gray matter structural alterations in migraineurs. METHODS: In current study, we used surface based morphometry, voxel-based morphometry and diffusion tensor imaging analyses to detect structural alterations of the white matter and gray matter in 32 migraineurs without aura compared with 32 age- and gender-matched healthy controls. RESULTS: We found that migraineurs without aura exhibited significantly increased gray matter volume in the bilateral cerebellar culmen, increased cortical thickness in the lateral occipital-temporal cortex, decreased cortical thickness in the right insula, increased gyrification index in left postcentral gyrus, superior parietal lobule and right lateral occipital cortex, and decreased gyrification index in the left rostral middle frontal gyrus compared with controls. No significant change in white matter microstructure was found in DTI analyses. CONCLUSION: The significantly altered gray matter brain regions were known to be associated with sensory discrimination of pain, multi-sensory integration and nociceptive information processing and were consistent with our previous fMRI study, and may be involved in the pathological mechanism of migraine without aura. PMID- 28733943 TI - OnabotulinumtoxinA injections in chronic migraine, targeted to sites of pericranial myofascial pain: an observational, open label, real-life cohort study. AB - BACKGROUND: OnabotulinumtoxinA has proven its efficacy in reducing the number of headache days in chronic migraine (CM) patients. The usual paradigm includes 31 pericranial injection sites with low dose (5 U) per site. The aim of this study is to present the results obtained using a simpler injection protocol of onabotulinumtoxinA, with injection sites targeted to pericranial myofascial sites of pain. METHODS: Observational, open label, real-life, cohort study. We enrolled 63 consecutive patients fulfilling the diagnostic criteria of CM, and refractory to conventional treatments. The patients were injected using a "follow-the-pain" pattern into the corrugator and/or temporalis and/or trapezius muscles. The doses per muscle were fixed. According to the number of muscles injected, the total dose could vary from 70 to 150 U per session. Patients were considered responders if they had a >= 50% decrease in number of headache days in at least two consecutive injection cycles. RESULTS: Forty one patients (65.1% in intention to treat analysis) responded to treatment. In 70.7% of responders, the effect size was even higher, with a reduction >=70% in the number of headache days. The associated cervical pain and muscle tenderness, present in 33 patients, was reduced by >=50% in 31 patients (94%). Triptan consumption dramatically decreased (81%) in responders. The trapezius was the most frequently injected muscle. We observed no serious adverse event. The mean patient satisfaction rate was 8.5/10. CONCLUSIONS: This study provides additional robust evidence supporting the efficacy of onabotulinumtoxinA injections in CM. Furthermore, the paradigm we used, with reduced number of injection sites targeted to pericranial myofascial sites of pain, may provide evidence in favor of the implication of myofascial trigger points in migraine chronicization. TRIAL REGISTRATION: ClinicalTrials.gov Protocol Record I17022 ClinicalTrials.gov Identifier: NCT03175263 . Date of registration: June 7, 2017. Retrospectively registered. PMID- 28733945 TI - Abdominal involvement in minimal change nephrotic syndrome. PMID- 28733946 TI - Caretaker Awareness of Health Care Provided Developmental Screening: Increases from 2007 to 2012. AB - Objectives Developmental screening is considered critical to identifying children with developmental delays and disabilities so that they may receive early intervention. To date, only a handful of studies report data on the percentage of health care professionals (HCP) who provide developmental screening. These reports are limited by low participation rates and reporters being pediatricians who may be biased towards reporting higher rates of developmental screening. The purpose of this study is to verify reported increases by reporting on changes in caretakers' awareness of HCP provided developmental screening from 2007/2008 to 2011/2012. Methods Authors report data on caretaker reported receipt of HCP provided developmental screening from the National Survey of Children's Health (NSCH, 2007/2008) and NSCH (2011/2012), as well as changes from the 2007/2008 to 2011/2012. Changes for the 50 states plus Washington D.C. are visualized using 'micromapST' and states are organized in ascending order according to changes in caretaker awareness of developmental screening. Results Nationally, the proportion of caretakers aware that their HCP provided developmental screening increased from 23.0% in 2007/2008 (range 12.6-46%) to 33.3% in 2011/2012 (range 19.4-61.6%) and states level changes ranged from -2 to +35%, with a median change of +10%. Conclusions for Practice Data reported here indicate that a greater number of caretakers are aware that their HCP is providing developmental screening. This reinforces the existing reports indicating increases in HCP reported developmental screening. Despite growth, there is still a need to increase developmental screening efforts in many states. PMID- 28733944 TI - The Gastric and Intestinal Microbiome: Role of Proton Pump Inhibitors. AB - PURPOSE OF REVIEW: The discovery of Helicobacter pylori and other organisms colonizing the stomach and the intestines has shed some light on the importance of microbiome in maintaining overall health and developing pathological conditions when alterations in biodiversity are present. The gastric acidity plays a crucial role in filtering out bacteria and preventing development of enteric infections. In this article, we discuss the physiology of gastric acid secretion and bacterial contribution to the composition of gastric and intestinal barriers and review the current literature on the role of proton pump inhibitors (PPIs) in the microbial biodiversity of the gastrointestinal tract. RECENT FINDINGS: Culture-independent techniques, such as 16S rRNA sequencing, have revolutionized our understanding of the microbial biodiversity in the gastrointestinal tract. Luminal and mucosa-associated microbial populations are not identical. Streptococcus is overrepresented in the biopsies of patients with antral gastritis and may also be responsible for the development of peptic ulcer disease. The use of PPIs favors relative streptococcal abundance irrespective of H. pylori status and may explain the persistence of dyspeptic symptoms in patients on PPI therapy. Increased risk of enteric infections has also been seen in patients taking PPIs. The overuse of PPIs leads to significant shift of the gastrointestinal microbiome towards a less healthy state. With the advent of PPIs, many studies have demonstrated the significant changes in the microbial composition of both gastric and intestinal microbiota. Although they are considered relatively safe over-the-counter medications, PPIs in many cases are over- and even inappropriately used. Future studies assessing the safety of PPIs and their role in the development of microbiome changes should be encouraged. PMID- 28733947 TI - Improvement of Rosacea During Acyclovir Treatment: A Case Report. PMID- 28733948 TI - Evaluation of Distress and Religious Coping Among Cancer Patients in Turkey. AB - The purpose of this study was to determine distress levels and religious coping styles of cancer patients and the relationship between religious coping styles and distress. This study was conducted as descriptive design. It was determined that 60.7% of the patients experienced distress related to the disease. The field of problem from which the patients mostly experienced distress was physical problems. It was observed that positive coping scores of the patients were higher. There was a negative correlation between their mean scores for positive religious styles and distress total scores. PMID- 28733949 TI - Security Techniques for the Electronic Health Records. AB - The privacy of patients and the security of their information is the most imperative barrier to entry when considering the adoption of electronic health records in the healthcare industry. Considering current legal regulations, this review seeks to analyze and discuss prominent security techniques for healthcare organizations seeking to adopt a secure electronic health records system. Additionally, the researchers sought to establish a foundation for further research for security in the healthcare industry. The researchers utilized the Texas State University Library to gain access to three online databases: PubMed (MEDLINE), CINAHL, and ProQuest Nursing and Allied Health Source. These sources were used to conduct searches on literature concerning security of electronic health records containing several inclusion and exclusion criteria. Researchers collected and analyzed 25 journals and reviews discussing security of electronic health records, 20 of which mentioned specific security methods and techniques. The most frequently mentioned security measures and techniques are categorized into three themes: administrative, physical, and technical safeguards. The sensitive nature of the information contained within electronic health records has prompted the need for advanced security techniques that are able to put these worries at ease. It is imperative for security techniques to cover the vast threats that are present across the three pillars of healthcare. PMID- 28733950 TI - Tendon end separation with loading in an Achilles tendon repair model: comparison of non-absorbable vs. absorbable sutures. AB - BACKGROUND: Rupture of the Achilles tendon often leads to long-term morbidity, particularly calf weakness associated with tendon elongation. Operative repair of Achilles tendon ruptures leads to reduced tendon elongation. Tendon lengthening is a key problem in the restoration of function following Achilles tendon rupture. A study was performed to determine differences in initial separation, strength and failure characteristics of differing sutures and numbers of core strands in a percutaneous Achilles tendon repair model in response to initial loading. METHODS: Nineteen bovine Achilles tendons were repaired using a percutaneous/minimally invasive technique with a combination of a modified Bunnell suture proximally and a Kessler suture distally, using non-absorbable 4 strand 6-strand repairs and absorbable 8-strand sutures. Specimens were then cyclically loaded using phases of 10 cycles of 100 N, 100 cycles of 100 N, 100 cycles of 190 N consistent with early range of motion training and weight bearing, before being loaded to failure. RESULTS: Pre-conditioning of 10 cycles of 100 N resulted in separations of 4 mm for 6-strand, 5.9 mm for 4-strand, but 11.5 mm in 8-strand repairs, this comprised 48.5, 68.6 and 72.7% of the separation that occurred after 100 cycles of 100 N. The tendon separation after the third phase of 100 cycles of 190 N was 17.4 mm for 4-strand repairs, 16.6 mm for 6-strand repairs and 26.6 mm for 8-strand repairs. There were significant differences between the groups (p < 0.0001). Four and six strand non-absorbable repairs had significantly less separation than 8-strand absorbable repairs (p = 0.017 and p = 0.04 respectively). The mean (SEM) ultimate tensile strengths were 4-strand 464.8 N (27.4), 6-strand 543.5 N (49.6) and 8-strand 422.1 N (80.5). Regression analysis reveals no significant difference between the overall strength of the 3 repair models (p = 0.32) (4 vs. 6: p = 0.30, 4 vs. 8: p = 0.87; 6 vs. 8: p = 0.39). The most common mode of failure was pull out of the Kessler suture from the distal stump in 41.7% of specimens. CONCLUSION: The use of a non absorbable suture resulted in less end-to-end separation when compared to absorbable sutures when an Achilles tendon repair model was subject to cyclical loading. Ultimate failure occurred more commonly at the distal Kessler suture end although this occurred with separations in excess of clinical failure. The effect of early movement and loading on the Achilles tendon is not fully understood and requires more research. PMID- 28733951 TI - CORR Insights(r): Is Dual Semitendinosus Allograft Stronger Than Turndown for Achilles Tendon Reconstruction? An In Vitro Analysis. PMID- 28733952 TI - Editor's Spotlight/Take 5: Do Surgeon Expectations Predict Clinically Important Improvements in WOMAC Scores After THA and TKA? PMID- 28733953 TI - Response to Loucks et al.'s Comment on "Clinical Evaluation of Bone Strength and Fracture Risk". PMID- 28733954 TI - Assessment of simplified ratio-based approaches for quantification of PET [11C]PBR28 data. AB - PURPOSE: Kinetic modelling with metabolite-corrected arterial plasma is considered the gold standard for quantification of [11C]PBR28 binding to the translocator protein (TSPO), since there is no brain region devoid of TSPO that can serve as reference. The high variability in binding observed using this method has motivated the use of simplified ratio-based approaches such as standardised uptake value ratios (SUVRs) and distribution volume (VT) ratios (DVRs); however, the reliability of these measures and their relationship to VT have not been sufficiently evaluated. METHODS: Data from a previously published [11C]PBR28 test-retest study in 12 healthy subjects were reanalysed. VT was estimated using a two-tissue compartment model. SUVR and DVR values for the frontal cortex were calculated using the whole brain and cerebellum as denominators. Test-retest reliability was assessed for all measures. Interregional correlations were performed for SUV and VT, and principal component analysis (PCA) was applied. Lastly, correlations between ratio-based outcomes and VT were assessed. RESULTS: Reliability was high for VT, moderate to high for SUV and SUVR, and poor for DVR. Very high interregional correlations were observed for both VT and SUV (all R 2 > 85%). The PCA showed that almost all variance (>98%) was explained by a single component. Ratio-based methods correlated poorly with VT (all R 2 < 34%, divided by genotype). CONCLUSIONS: The reliability was good for SUVR, but poor for DVR. Both outcomes showed little to no association with VT, questioning their validity. The high interregional correlations for VT and SUV suggest that after dividing by a denominator region, most of the biologically relevant signal is lost. These observations imply that results from TSPO PET studies using SUVR or DVR estimates should be interpreted with caution. PMID- 28733955 TI - Detection of Plasma Biomarkers Using Immunomagnetic Reduction: A Promising Method for the Early Diagnosis of Alzheimer's Disease. AB - Alzheimer's disease (AD) is the most common form of dementia. The development of assay technologies able to diagnose early-stage AD is important. Blood tests to detect biomarkers, such as amyloid and total Tau protein, are among the most promising diagnostic methods due to their low cost, low risk, and ease of operation. However, such biomarkers in blood occur at extremely low levels and are difficult to detect precisely. In the early 2000s, a highly sensitive assay technology, immunomagnetic reduction (IMR), was developed. IMR involves the use of antibody-functionalized magnetic nanoparticles dispersed in aqueous solution. The concentrations of detected molecules are converted to reductions in the ac magnetic susceptibility of this reagent due to the association between the magnetic nanoparticles and molecules. To achieve ultra-high sensitivity, a high Tc superconducting-quantum-interference-device (SQUID) ac magnetosusceptometer was designed and applied to detect the tiny reduction in the ac magnetic susceptibility of the reagent. Currently, a 36-channeled high-Tc SQUID-based ac magnetosusceptometer is available. Using the reagent and this analyzer, extremely low concentrations of amyloid and total Tau protein in human plasma could be detected. Further, the feasibility of identifying subjects in early-stage AD via assaying plasma amyloid and total Tau protein is demonstrated. The results show a diagnostic accuracy for prodromal AD higher than 80% and reveal the possibility of screening for early-stage AD using SQUID-based IMR. PMID- 28733956 TI - Amyloid Beta and Tau as Alzheimer's Disease Blood Biomarkers: Promise From New Technologies. AB - The utility of the levels of amyloid beta (Abeta) peptide and tau in blood for diagnosis, drug development, and assessment of clinical trials for Alzheimer's disease (AD) has not been established. The lack of availability of ultra sensitive assays is one critical issue that has impeded progress. The levels of Abeta species and tau in plasma and serum are much lower than levels in cerebrospinal fluid. Furthermore, plasma or serum contain high levels of assay interfering factors, resulting in difficulties in the commonly used singulex or multiplex ELISA platforms. In this review, we focus on two modern immune-complex based technologies that show promise to advance this field. These innovative technologies are immunomagnetic reduction technology and single molecule array technology. We describe the technologies and discuss the published studies using these technologies. Currently, the potential of utilizing these technologies to advance Abeta and tau as blood-based biomarkers for AD requires further validation using already collected large sets of samples, as well as new cohorts and population-based longitudinal studies. PMID- 28733957 TI - A Review of Biomarkers for Alzheimer's Disease in Down Syndrome. AB - Down syndrome (Trisomy 21; DS) is a unique disease known to be associated with early-onset Alzheimer's disease (AD). The initial presentation of AD in DS is usually difficult to recognize, owing to the underlying intellectual disabilities. Using biomarkers as a prediction tool for detecting AD in at-risk people with DS may benefit patient care. The objective of this review is to discuss the utility of biomarkers in DS on the basis of the pathophysiology of the disease and to provide an update on recent studies in this field. Only through the comprehensive assessment of clinical symptoms, imaging studies, and biomarker analyses can people with DS who are at risk for AD be diagnosed early. Studies for biomarkers of AD in DS have focused on the common pathophysiology of AD in people with DS and in the general population. The most extensively studied biomarkers are amyloid and tau. Owing to the nature of amyloid precursor protein overproduction in DS, the baseline beta-amyloid (Abeta) plasma levels are higher than those in controls. Hence, the changes in Abeta are considered to be a predictive marker for AD in DS. In addition, other markers related to telomere length, neuroinflammation, and methylation have been investigated for their correlation with AD progression. Future studies including different ethnic groups may be helpful to collect sufficient data to monitor drug safety and efficacy, stratify patients at risk for AD, and quantify the benefit of treatment. PMID- 28733958 TI - The Study of Postmortem Human Synaptosomes for Understanding Alzheimer's Disease and Other Neurological Disorders: A Review. AB - Synaptic dysfunction is thought to play important roles in the pathophysiology of many neurological diseases, including Alzheimer's disease, Parkinson's disease, and schizophrenia. Over the past few decades, there have been systematic efforts to collect postmortem brain tissues via autopsies, leading to the establishment of dozens of human brain banks around the world. From cryopreserved human brain tissues, it is possible to isolate detached-and-resealed synaptic terminals termed synaptosomes, which remain metabolically and enzymatically active. Synaptosomes have become important model systems for studying human synaptic functions, being much more accessible than ex vivo brain slices or primary neuronal cultures. Here we review recent advances in the establishment of human brain banks, the isolation of synaptosomes, their biological activities, and various analytical techniques for investigating their biochemical and ultrastructural properties. There are unique insights to be gained by directly examining human synaptosomes, which cannot be substituted by animal models. We will also discuss how human synaptosome research has contributed to better understanding of neurological disorders, especially Alzheimer's disease. PMID- 28733959 TI - Increasing Precision of Clinical Diagnosis of Alzheimer's Disease Using a Combined Algorithm Incorporating Clinical and Novel Biomarker Data. AB - Establishing the in vivo diagnosis of Alzheimer's disease (AD) or other dementias relies on clinical criteria; however, the accuracy of these criteria can be limited. The diagnostic accuracy is 77% for a clinical diagnosis of AD, even among experts. We performed a review through PubMed of articles related to specific diagnostic modalities, including APOE genotyping, cerebrospinal fluid (CSF) testing, fludeoxyglucose F 18 positron emission tomography (PET), amyloid PET, tau PET, computed tomography (CT), single-photon emission CT, magnetic resonance imaging (MRI), and B12 and thyroid-stimulating hormone screening, to determine the specificity and sensitivity of each test used in the clinical diagnosis of AD. We added a novel immunomagnetic reduction assay that provides ultrasensitivity for analyzing the levels of plasma tau and beta amyloid 42 (Abeta42). The sensitivity and specificity of the current diagnostic approach (structural CT or MRI with screening labs) remain low for clinical detection of AD and are primarily used to exclude other conditions. Because of limited diagnostic capabilities, physicians do not feel comfortable or skilled in rendering a clinical diagnosis of AD. Compounding this problem is the fact that inexpensive, minimally invasive diagnostic tests do not yet exist. Biomarkers (obtained through CSF testing or PET imaging), which are not routinely incorporated in clinical practice, correlate well with pathologic changes. While PET is particularly costly and difficult to assess, CSF measures of tau and beta amyloid are not costly, and these tests may be worthwhile when the tiered approach proposed here warrants further testing. There is a need for developing bloodborne biomarkers that can aid in the clinical diagnosis of AD. Here we present a streamlined questionnaire-enriched, biomarker-enriched approach that is more cost-effective than the current diagnosis of exclusion and is designed to increase clinical confidence for a diagnosis of dementia due to AD. PMID- 28733960 TI - A Review of Fluid Biomarkers for Alzheimer's Disease: Moving from CSF to Blood. AB - A set of core cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease (AD) includes total tau (T-tau), phosphorylated tau (P-tau) and beta-amyloid 42 (Abeta42). These biomarkers reflect some of the key aspects of AD pathophysiology, including neuronal degeneration, tau phosphorylation with tangle formation, and Abeta aggregation with deposition of the peptide into plaques. The core AD CSF biomarkers have been validated clinically in numerous studies, and found to have a very high diagnostic performance to identify AD, both in the dementia and in the mild cognitive impairment stages of the disease. CSF Abeta42 has also been found to show very high concordance with amyloid PET to identify brain amyloid deposition. The synaptic protein neurogranin is a novel candidate CSF biomarker for AD and prodromal AD. High CSF neurogranin predicts future cognitive decline and seems to be more specific for AD than, for example, T-tau. Importantly, technical developments have given ultrasensitive measurement techniques that allow measurement of brain-specific proteins such as tau and neurofilament light (NFL) in blood samples. Both plasma tau and NFL are increased in AD, and a recent study showed that plasma NFL has a diagnostic performance comparable to the core AD CSF biomarkers, and predicted future cognitive decline. Future large longitudinal clinical studies are warranted to determine the potential for plasma tau and NFL to serve as first-in-line screening tools for neurodegeneration in primary care. PMID- 28733962 TI - Editorial Introduction to the Special Issue from the International Symposium on Biomarkers for Alzheimer's Disease and Related Disorders. PMID- 28733961 TI - A Review of Biomarkers for Neurodegenerative Disease: Will They Swing Us Across the Valley? AB - Measures of the severity of cognitive impairment or parkinsonism are the usual endpoints in clinical trials for Alzheimer's disease (AD) and Parkinson's disease (PD), but are critically hampered by their lack of disease sensitivity and specificity. Due to the high failure rate of clinical trials, the rate of regulatory approval for efficacious new drugs has stagnated in the past few decades, with the gap between basic science discovery and clinical application metaphorically termed the "Valley of Death". While the causes for this are probably multiple and complex, the usage of biomarkers as surrogate endpoints, particularly when they are molecularly-specific for the disease, has achieved some success in cancer trials, and it is likely that neurodegenerative disease trials would benefit from the same approach. As dementia and parkinsonism are not disease-specific clinical syndromes, both AD and PD trials have been flawed by reliance on clinical diagnosis and clinical endpoints. Clinical improvement has been a requirement for regulatory approval, but molecularly-specific biomarkers should improve both diagnostic accuracy and tracking of disease progression, allowing quicker screening of drug candidates. However, even when a molecularly specific biomarker is found, such as amyloid imaging for AD, it may not reflect the entire extant molecular disease repertoire and may not serve equally well in the different roles of preclinical detection, diagnostic confirmation and surrogate endpoint, necessitating the usage of two, three or more biomarkers, deployed in series or in parallel. PMID- 28733963 TI - Peroxisome proliferator-activated receptor gamma expression in peripheral blood mononuclear cells and angiopoietin-like protein 4 levels in obese children and adolescents. AB - PURPOSE: The peroxisome proliferator-activated receptor gamma (PPARgamma) is highly expressed in adipose tissue and functions as transcriptional regulator of metabolism and adipocyte differentiation. Angiopoietin-like protein 4 (ANGPTL4), a central player in various aspects of energy homoeostasis, is induced by PPARgamma. The aim of this study was to evaluate ANGPTL4 plasma levels and PPARgamma gene expression in peripheral blood mononuclear cells (PBMCs) of children and adolescents with obesity and their association with metabolic parameters. METHODS: Seventy children and adolescents (35 obese and 35 age- and gender-matched control subjects), were selected. PBMCs were separated and their total RNA was extracted. After cDNA synthesis, PPARG gene expression was analyzed by real-time PCR. Relative differences in gene expression were calculated by DeltaCt method using beta-actin as a normalizer. Serum ANGPTL4 and insulin were measured using ELISA, and insulin resistance (IR) was calculated by the homeostatic model assessment of insulin resistance (HOMA-IR). Fasting plasma glucose (FPG), triglyceride, total cholesterol, LDL-C and HDL-C were also measured. RESULTS: The expression of the PPARG gene as well as the plasma ANGPTL4 levels were significantly diminished in obese subjects as compared to control ones. However, they were not significantly different in obese children with IR compared to obese children without IR or in those with or without metabolic syndrome. A significant positive correlation was found between PPARgamma and ANGPTL4 (r = 0.364, p = 0.002). PPARgamma expression levels were also significantly correlated with FPG (r = -0.35, p = 0.003). CONCLUSION: PPARgamma is decreased in childhood obesity and may be responsible for diminished ANGPTL4 levels. PMID- 28733964 TI - The Global Burden of Occupational Disease. AB - PURPOSE OF REVIEW: Burden of occupational disease estimation contributes to understanding of both magnitude and relative importance of different occupational hazards and provides essential information for targeting risk reduction. This review summarises recent key findings and discusses their impact on occupational regulation and practice. RECENT FINDINGS: New methods have been developed to estimate burden of occupational disease that take account of the latency of many chronic diseases and allow for exposure trends and workforce turnover. Results from these studies have shown in several countries and globally that, in spite of improvements in workplace technology, practices and exposures over the last decades, occupational hazards remain an important cause of ill health and mortality worldwide. Major data gaps have been identified particularly regarding exposure information. Reliable data on employment and disease are also lacking especially in developing countries. Burden of occupational disease estimates form an important part of decision-making processes. PMID- 28733965 TI - Molecular Communication over Gas Stream Channels using Portable Mass Spectrometry. AB - The synthetic generation/coding and transmission of olfactory information over a gas stream or an odor network is a new and unexplored field. Application areas vary from the entertainment or advertisement industry to security and telemedicine. However, current technological limitations frustrate the accurate reproduction of decoded and transmitted olfactory data. This study describes the development, testing, and characterization of a novel odor emitter (OE) that is used to investigate the generation-encoding of gaseous standards with odorous characteristics with a regulatable way, for scent transmission purposes. The calibration and the responses of a developed OE were examined using a portable quadrupole mass spectrometer (MS). Experiments were undertaken for a range of volatile organic compounds (VOCs) at different temperatures and flow rates. Individual compounds and mixtures were tested to investigate periodic and dynamic transmission characteristics within two different size tubular containers for distances up to 3 m. Olfactory information transmission is demonstrated using MS as the main molecular sensor for odor detection and monitoring and for the first time spatial encryption of olfactory information is shown. Graphical Abstract ?. PMID- 28733966 TI - Quantitative Collision Cross-Sections from FTICR Linewidth Measurements: Improvements in Theory and Experiment. AB - Two corrections to the equation used in the cross-sectional areas by Fourier transform ion cyclotron resonance ("CRAFTI") technique are identified. In CRAFTI, ion collision cross-sections are obtained from the pressure-dependent ion linewidths in Fourier transform mass spectra. The effects of these corrections on the accuracy of the cross-sections obtained using the CRAFTI technique are evaluated experimentally using the 20 biogenic amino acids and several crown ether complexes with protonated alkyl monoamines. Good absolute agreement is obtained between the CRAFTI cross-sections and the corresponding cross-sections obtained using both static drift ion mobility spectrometry and computational simulations. These results indicate that the CRAFTI cross-sections obtained using the updated equation presented here are quantitatively descriptive of the size and shape of the gas-phase ions. Cross-sections that differ by less than 3% are measured for the isobaric isomers n-butylamine and tert-butylamine complexed with the crown ethers. This level of precision is similar to what has been achieved previously using traveling wave ion mobility devices. These results indicate that CRAFTI can be used to probe subtle structural differences between ions with approximately the same precision as that achieved in traveling wave ion mobility devices. Graphical Abstract ?. PMID- 28733967 TI - Mass Defect from Nuclear Physics to Mass Spectral Analysis. AB - Mass defect is associated with the binding energy of the nucleus. It is a fundamental property of the nucleus and the principle behind nuclear energy. Mass defect has also entered into the mass spectrometry terminology with the availability of high resolution mass spectrometry and has found application in mass spectral analysis. In this application, isobaric masses are differentiated and identified by their mass defect. What is the relationship between nuclear mass defect and mass defect used in mass spectral analysis, and are they the same? Graphical Abstract ?. PMID- 28733968 TI - On the Nature of Mass Spectrometer Analyzer Contamination. AB - Sample throughput in electrospray ionization mass spectrometry (ESI-MS) is limited by the need for frequent ion path cleaning to remove accumulated debris that can lead to charging and general performance degradation. Contamination of ion optics within the vacuum system is particularly problematic as routine cleaning requires additional time for cycling the vacuum pumps. Differential mobility spectrometry (DMS) can select targeted ion species for transmission, thereby reducing the total number of charged particles entering the vacuum system. In this work, we characterize the nature of instrument contamination, describe efforts to improve mass spectrometer robustness by applying DMS prefiltering to reduce contamination of the vacuum ion optics, and demonstrate the capability of DMS to extend the interval between mass spectrometer cleaning. In addition, we introduce a new approach to effectively detect large charged particles formed during the electrospray ionization (ESI) process. Graphical Abstract ?. PMID- 28733969 TI - Tailoring Ion Charge State Distribution in Tetramethyltin Clusters under Influence of Moderate Intensity Picosecond Laser Pulse: Role of Laser Wavelength and Rate of Energy Deposition. AB - Systematic manipulation of ionic-outcome in laser-cluster interaction process has been realized for studies carried out on tetramethyltin (TMT) clusters under picosecond laser conditions, determined by choice of laser wavelength and intensity. As a function of laser intensity, TMT clusters exhibit gradual enhancement in overall ionization of its cluster constituents, up to a saturation level of ionization, which was distinct for different wavelengths (266, 355, and 532 nm). Simultaneously, systematic appearance of higher multiply charged atomic ions and shift in relative abundance of multiply charged atomic ions towards higher charge state was observed, using time-of-flight mass spectrometer. At saturation level, multiply charged atomic ions up to (C2+, Sn2+) at 266 nm, (C4+, Sn4+) at 355 nm, and (C4+, Sn6+) at 532 nm were detected. In addition, at 355 nm intra-cluster ion chemistry within the ionized cluster leads to generation of molecular hydrogen ion (H2+) and triatomic molecular hydrogen ion (H3+). Generation of multiply charged atomic ions is ascribed to efficient coupling of laser pulse with the cluster media, facilitated by inner-ionized electrons produced within the cluster, at the leading edge of laser pulse. Role of inner ionized electrons is authenticated by measuring kinetic energy distribution of electrons liberated upon disintegration of excessively ionized cluster, under the influence of picosecond laser pulse. Graphical Abstract ?. PMID- 28733970 TI - New Genes Causing Hereditary Parkinson's Disease or Parkinsonism. AB - PURPOSE OF REVIEW: This article reviews was to review genes where putative or confirmed pathogenic mutations causing Parkinson's disease or Parkinsonism have been identified since 2012, and summarizes the clinical and pathological picture of the associated disease subtypes. RECENT FINDINGS: Newly reported genes for dominant Parkinson's disease are DNAJC13, CHCHD2, and TMEM230. However, the evidence for a disease-causing role is not conclusive, and further genetic and functional studies are warranted. RIC3 mutations have been reported from one family but not yet encountered in other patients. New genes for autosomal recessive disease include SYNJ1, DNAJC6, VPS13C, and PTRHD1. Deletions of a region on chromosome 22 (22q11.2del) are also associated with early-onset PD, but the mode of inheritance and the underlying causative gene remain unclear. PODXL mutations were reported in autosomal recessive PD, but their roles remain to be confirmed. Mutations in RAB39B cause an X-linked Parkinsonian disorder. Mutations in the new dominant PD genes have generally been found in medium- to late-onset Parkinson's disease. Many mutations in the new recessive and X-chromosomal genes cause severe atypical juvenile Parkinsonism, but less devastating mutations in these genes may cause PD. PMID- 28733971 TI - The Fetal Safety of Enoxaparin Use During Pregnancy: A Population-Based Retrospective Cohort Study. AB - INTRODUCTION: Enoxaparin is widely used during pregnancy as pregnancy is a hypercoagulable state; however, its fetal safety has scarcely been investigated. OBJECTIVE: Our study aimed to examine fetal safety following enoxaparin exposure during pregnancy. METHODS: A population-based, retrospective cohort study was performed by linking computerized databases, including the drug dispensing registries of Clalit Health Services in Israel and maternal and infant hospital records, between 1998 and 2009. Multivariate logistic regression models were used to examine associations between first- and third-trimester exposure to enoxaparin, major malformations, and other adverse birth outcomes, adjusted for confounders. RESULTS: From a total of 109,473 singleton pregnancies, 418 and 572 were exposed to enoxaparin during the first and third trimesters, respectively. Exposure to enoxaparin during the first trimester of pregnancy was not associated with an increased risk of major congenital malformations [adjusted odds ratio (aOR) 1.1, 95% confidence interval (CI) 0.8-1.6], while exposure during the third trimester was not associated with an increased risk of low birth weight (aOR 1.1, 95% CI 0.8-1.4), low Apgar score (aOR 0.9, 95% CI 0.4-1.8), or risk of perinatal mortality (aOR 0.6, 95% CI 0.1-2.9). CONCLUSION: Exposure to enoxaparin during pregnancy was not associated with an increased risk of major malformations in general or according to organ systems. Nonetheless, risk for specific malformations cannot be ruled out. PMID- 28733973 TI - ISMRM Young Investigator Award Winners. PMID- 28733972 TI - Expression and function of the metabotropic purinergic P2Y receptor family in experimental seizure models and patients with drug-refractory epilepsy. AB - OBJECTIVE: ATP is released into the extracellular space during pathologic processes including increased neuronal firing. Once released, ATP acts on P2 receptors including ionotropic P2X and metabotropic P2Y receptors, resulting in changes to glial function and neuronal network excitability. Evidence suggests an involvement of P2Y receptors in the pathogenesis of epilepsy, but there has been no systematic effort to characterize the expression and function of the P2Y receptor family during seizures and in experimental and human epilepsy. METHODS: Status epilepticus was induced using either intra-amygdala kainic acid or pilocarpine to characterize the acute- and long-term changes in hippocampal P2Y expression. P2Y expression was also investigated in brain tissue from patients with temporal lobe epilepsy. Finally, we analyzed the effects of two specific P2Y agonists, ADP and UTP, on seizure severity and seizure-induced cell death. RESULTS: Both intra-amygdala kainic acid and pilocarpine-induced status epilepticus increased the transcription of the uracil-sensitive P2Y receptors P2ry2 , P2ry4 , and P2ry6 and decreased the transcription of the adenine sensitive P2Y receptors P2ry1 , P2ry12 , P2ry13 . Protein levels of P2Y1 , P2Y2 , P2Y4 , and P2Y6 were increased after status epilepticus, whereas P2Y12 expression was decreased. In the chronic phase, P2ry1 , P2ry2 , and P2ry6 transcription and P2Y1 , P2Y2 , and P2Y12 protein levels were increased with no changes for the other P2Y receptors. In hippocampal samples from patients with temporal lobe epilepsy, P2Y1 and P2Y2 protein expression was increased, whereas P2Y13 levels were lower. Demonstrating a functional contribution of P2Y receptors to seizures, central injection of ADP exacerbated seizure severity, whereas treatment with UTP decreased seizure severity during status epilepticus in mice. SIGNIFICANCE: The present study is the first to establish the specific hippocampal expression profile and function of the P2Y receptor family after experimental status epilepticus and in human temporal lobe epilepsy and offers potential new targets for seizure control and disease modification. PMID- 28733974 TI - Impact of diabetes mellitus on procedural and one year clinical outcomes following treatment of severely calcified coronary lesions with the orbital atherectomy system: A subanalysis of the ORBIT II study. AB - OBJECTIVES: The goal of the study was to investigate the safety and efficacy of the coronary orbital atherectomy system to treat severe coronary artery calcification (CAC) prior to stent placement in diabetic and non-diabetic patients. BACKGROUND: The ORBIT II study reported the safety and efficacy of orbital atherectomy treatment in 443 patients with severe CAC. Percutaneous coronary intervention in diabetic patients is associated with an increased risk of major adverse cardiac events (MACE) compared with non-diabetics. The outcomes of diabetic patients who undergo orbital atherectomy are unknown. METHODS: Patients were sub-grouped as either diabetic (160/443, 36.1%) or non-diabetic (283/443, 63.9%). The MACE rate, defined as cardiac death, myocardial infarction (MI; CK-MB > 3X ULN), and target vessel revascularization, was examined at 30 days and 1 year after treatment. RESULTS: Procedural success was similar in the diabetic and non-diabetic groups (89.3 vs. 88.6%, P = 0.88). There was no significant difference in the 30-day and 1-year MACE rates between the diabetic and non-diabetic groups (30 day: 8.8 vs. 11.3%; P = 0.40; 1 year: 17.1 vs. 16.7%, P = 0.97). The individual components of cardiac death (3.9 vs. 2.9%, P = 0.58), MI (9.4 vs. 11.3%, P = 0.52), and target vessel revascularization (5.9 vs. 5.8%, P = 0.99) were also similar in both groups at 1 year. CONCLUSIONS: The rates of adverse clinical events in diabetic patients who underwent orbital atherectomy were low and similar to non-diabetic patients. This study suggests orbital atherectomy is a reasonable treatment strategy for diabetic patients with severe CAC. PMID- 28733976 TI - NUDT15 polymorphism and severe azathioprine-induced myelosuppression in a Chinese man with pemphigus vulgaris. PMID- 28733975 TI - Deep convolutional neural network and 3D deformable approach for tissue segmentation in musculoskeletal magnetic resonance imaging. AB - PURPOSE: To describe and evaluate a new fully automated musculoskeletal tissue segmentation method using deep convolutional neural network (CNN) and three dimensional (3D) simplex deformable modeling to improve the accuracy and efficiency of cartilage and bone segmentation within the knee joint. METHODS: A fully automated segmentation pipeline was built by combining a semantic segmentation CNN and 3D simplex deformable modeling. A CNN technique called SegNet was applied as the core of the segmentation method to perform high resolution pixel-wise multi-class tissue classification. The 3D simplex deformable modeling refined the output from SegNet to preserve the overall shape and maintain a desirable smooth surface for musculoskeletal structure. The fully automated segmentation method was tested using a publicly available knee image data set to compare with currently used state-of-the-art segmentation methods. The fully automated method was also evaluated on two different data sets, which include morphological and quantitative MR images with different tissue contrasts. RESULTS: The proposed fully automated segmentation method provided good segmentation performance with segmentation accuracy superior to most of state-of the-art methods in the publicly available knee image data set. The method also demonstrated versatile segmentation performance on both morphological and quantitative musculoskeletal MR images with different tissue contrasts and spatial resolutions. CONCLUSION: The study demonstrates that the combined CNN and 3D deformable modeling approach is useful for performing rapid and accurate cartilage and bone segmentation within the knee joint. The CNN has promising potential applications in musculoskeletal imaging. Magn Reson Med 79:2379-2391, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28733977 TI - Molecular classification of tumour cells in a patient with intravascular large B cell lymphoma. AB - BACKGROUND: Intravascular large B-cell lymphoma (IVLBCL) is a rare type of extranodal LBCL. It is characterized by the proliferation of tumour cells exclusively intraluminally in small blood vessels of different organs. The clinical manifestation depends on the type of organ affected; additionally, a haemophagocytic syndrome can be observed in some patients. OBJECTIVES: The aim was to further understand the nosology of this lymphoma as, due to its rarity and in spite of detailed immunohistochemical investigations, its exact nosology is only incompletely understood. METHODS: We used microarray-based analysis of gene expression of tumour cells isolated from a patient with primary manifestation of the lymphoma in the skin and compared it with various other diffuse LBCLs (DLBCLs) as well as a previously published DLBCL classifier. RESULTS: In unsupervised analyses, the tumour cells clustered together with non-germinal centre B-cell (non-GCB) DLBCL samples but were clearly distinct from GCB-DLBCL. Analogous to non-GCB DLBCL, molecular cell-of-origin classification revealed similarity to bone-marrow derived plasma cells. CONCLUSIONS: The IVLBCL of this patient showed molecular similarity to non-GCB DLBCL. Due to the prognostic and increasingly also therapeutic relevance of molecular subtyping in DLBCL, this method, in addition to immunohistochemistry, should also be considered for the diagnosis of IVLBCL in the future. PMID- 28733978 TI - Severe subcutaneous hematoma in a patient with psoriatic arthritis: Changes of platelet count in psoriatic patients with biologic agents. AB - The effectiveness of biologics has changed therapeutic strategies for psoriasis dramatically, but biologics are known to have various adverse effects. We report a 63-year-old woman with psoriatic arthritis who suddenly developed a subcutaneous hematoma after being successfully treated with adalimumab. As she had also suffered from alcoholic cirrhosis, we speculated that she had developed thrombocytopenia severe enough to cause a subcutaneous hematoma. Furthermore, we investigated the changes of platelet counts in 65 psoriatic patients treated with biologics at a single institute from 2010 to 2016. Platelet counts were found to have decreased by 17.4 +/- 2.8% during adalimumab therapy (n = 16), 18.5 +/- 3.8% during infliximab therapy (n = 17), 14.8 +/- 2.1% during ustekinumab therapy (n = 20) and 18.5 +/- 5.1% during secukinumab therapy (n = 12). Platelet counts decrease after the administration of biologics in accordance with disease activity, and there is the potential risk of subcutaneous hematoma and other adverse effects. When administrating biologics to psoriatic patients, especially to those with chronic liver disease, dermatologists should carefully monitor for thrombocytopenia. PMID- 28733980 TI - Importance of the skeletal muscle carnitine stores in fuel selection. PMID- 28733979 TI - Novel clinical and molecular findings in Spanish patients with naevoid basal cell carcinoma syndrome. AB - BACKGROUND: Naevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder characterized by developmental alterations and multiple basal cell carcinomas. Mutations in PTCH1, which encodes a membrane receptor for Sonic Hedgehog, are associated with the development of the disease. Most of them produce a truncated protein, which is unable to suppress Smoothened protein and continuously activates the downstream pathway. OBJECTIVES: We aimed to characterize 22 unrelated Spanish patients with NBCCS, the largest cohort with Gorlin syndrome reported to date in Spain. METHODS: Genomic analysis of PTCH1 was performed in patients with NBCCS and controls, and mutations were analysed using bioinformatics tools. RESULTS: We report for the first time two young patients, one each with uterus didelphys and ganglioneuroma, within the context of NBCCS. One patient showing a severe phenotype of the disease had developed basal cell carcinomas since childhood. Sanger sequencing of PTCH1 in this cohort identified 17 novel truncating mutations (11 frameshift, five nonsense and one mutation affecting an exon-intron splice site) and two novel missense mutations that were predicted to be pathogenic. The patients showed great clinical variability and inconsistent genotype-phenotype correlation, as seen in relatives carrying similar mutations. CONCLUSIONS: This study contributes to increase the pool of clinical manifestations of NBCCS, as well as increasing the number of pathogenic mutations identified in PTCH1 predisposing to the condition. The inconsistencies found between phenotype and genotype suggest the involvement of other modifying factors, genetic, epigenetic or environmental. PMID- 28733981 TI - Novel heterozygous mutation of protoporphyrinogen oxidase gene in a Chinese patient with variegate porphyria. PMID- 28733982 TI - Postoperative complications in individuals aged 70 and over undergoing elective surgery for colorectal cancer. AB - AIM: This study aims to describe the nature, incidence, severity and outcomes of in-hospital postoperative complications (POCs) in older patients undergoing elective surgery for colorectal cancer. METHOD: Patients >= 70 years old were identified from a prospectively collected database (2009-2015) focusing on the implementation of geriatric screening and assessment in patients with cancer. Medical and surgical POCs were retrieved retrospectively from the medical records, and the severity of the POCs was graded by the Clavien-Dindo (CD) grading system. The following outcomes were analysed comparing patients with and without CD >= 2 and CD >= 3 POCs: length of stay (LOS), transfer to the intensive care unit, 30-day readmission rates, 30-day and 1-year mortality. RESULTS: In the 190 patients included, medical POCs (40.5%) were more frequent than surgical POCs (17.9%), and 37.9% experienced CD >= 2 POCs. The most common medical POCs were infections (26.8%), transient confusion or altered mental function (12.1%), cardiac arrhythmia (4.7%), and ileus/gastroparesis/prolonged recovery of transit (4.7%). The most common surgical POCs were surgical site infections (12.1%), wound dehiscence/bleeding (4.7%), anastomotic leak (3.7%) and surgical site bleeding (3.7%). The reoperation rate was 7.9%. CD >= 2 POCs led to 11 intensive care unit admissions and increased median postoperative LOS by 114% (P < 0.0001 for both), but did not significantly alter 30-day readmission and 30-day and 1 year mortality rates. CD >= 3 POCs increased LOS by 162% (P < 0.0001) and showed an increased 1-year mortality (P = 0.07). CONCLUSION: This study shows that in hospital medical and surgical complications after surgery for colorectal cancer in patients >= 70 years old are frequent and that complications lead to less favourable outcomes. PMID- 28733984 TI - Implant treatment in pharmacologically immunosuppressed liver transplant patients: A prospective-controlled study. AB - OBJECTIVES: The main objective of this prospective study was to evaluate the long term outcome of implant therapy in liver transplant patients (LTP). The secondary goal was to assess several implant- and patient-dependent variables, such as peri implantitis (PI), peri-implant mucositis (PIM), bone loss (BL), and immediate postoperative complications. MATERIAL AND METHODS: Two groups, including 16 pharmacologically immunosuppressed LTP and 16 matched controls, received 52 and 54 implants, respectively, between 1999 and 2008. After evaluating the postoperative healing, a mean follow-up of more than 8 years was carried out, and radiographic, clinical, and periodontal parameters were recorded to evaluate implant survival and implant- and patient-dependent outcomes. RESULTS: The early postsurgical complications were similar in both groups. Implant survival rate was 100% in the LTP group and 98.15% in the CG. PIM was diagnosed in 35.42% of the implants and 64.29% of the patients of LTP group (LTPG) and in 43.40% of the implants and 56.25% of the patients in the CG. PI was detected in 4.17% of the implants and 7.10% of the patients in the LTPG and in 9.43% of the implants and 18.80% of the patients in the CG. CONCLUSION: Pharmacologically immunosuppression in liver transplant patients was not a risk factor for implant failure, nor for the incidence of peri-implant diseases. Liver transplant is not a contraindication for dental implant treatment, although these patients should be carefully monitored during follow-up care. PMID- 28733983 TI - Population pharmacokinetics and exposure-response of trastuzumab emtansine in advanced breast cancer previously treated with >=2 HER2-targeted regimens. AB - AIMS: We conducted population pharmacokinetic (PopPK) and exposure-response analyses for trastuzumab emtansine (T-DM1), to assess the need for T-DM1 dose optimization in patients with low exposure by using TH3RESA [A Study of Trastuzumab Emtansine in Comparison With Treatment of Physician's Choice in Patients With human epidermal growth factor receptor 2 (HER2)-positive Breast Cancer Who Have Received at Least Two Prior Regimens of HER2-directed Therapy] study data (NCT01419197). The randomized phase III TH3RESA study investigated T DM1 vs. treatment of physician's choice (TPC) in patients with heavily pretreated HER2-positive advanced breast cancer. METHODS: We compared a historical T-DM1 PopPK model with T-DM1 pharmacokinetics in TH3RESA and performed exposure response analyses using model-predicted cycle 1 maximum concentration (Cmax ), cycle 1 minimum concentration (Cmin ) and area under the concentration-time curve at steady state (AUCss ). Kaplan-Meier analyses [overall survival (OS), progression-free survival (PFS)] and logistic regression [overall response rate (ORR), safety] were stratified by T-DM1 exposure metrics. Survival hazard ratios (HRs) in the lowest exposure quartile (Q1) of cycle 1 Cmin were compared with matched TPC-treated patients. RESULTS: T-DM1 concentrations in TH3RESA were described well by the historical PopPK model. Patients with higher cycle 1 Cmin and AUCss exhibited numerically longer median OS and PFS and higher ORR than patients with lower exposure. Exposure-response relationships were less evident for cycle 1 Cmax . No relationship between exposure and safety was identified. HRs for the comparison of T-DM1-treated patients in the Q1 subgroup with matched TPC-treated patients were 0.96 [95% confidence interval (CI) 0.63, 1.47] for OS and 0.92 (95% CI 0.64, 1.32) for PFS. CONCLUSIONS: Exposure-response relationships for efficacy were inconsistent across exposure metrics. HRs for survival in patients in the lowest T-DM1 exposure quartile vs. matched TPC treated patients suggest that, compared with TCP, the approved T-DM1 dose is unlikely to be detrimental to patients with low exposure. PMID- 28733986 TI - Erratum. PMID- 28733985 TI - LALF32-51 -E7, a HPV-16 therapeutic vaccine candidate, forms protein body-like structures when expressed in Nicotiana benthamiana leaves. AB - High-risk human papillomaviruses (HPVs) cause cervical cancer, and while there are good prophylactic vaccines on the market, these are ineffective against established infections, creating a clear need for therapeutic vaccines. The HPV E7 protein is one of the essential oncoproteins for the onset and maintenance of malignancy and is therefore an ideal therapeutic vaccine target. We fused the HPV 16 E7 protein to the Limulus polyphemus antilipopolysaccharide factor (LALF32-51 ), a small hydrophobic peptide that can penetrate cell membranes and that has immunomodulatory properties. LALF32-51 -E7 was transiently expressed in Nicotiana benthamiana, and we previously determined that it accumulated better when targeted to chloroplasts compared to being localized in the cytoplasm. Subsequently, we aimed to prove whether LALF32-51 -E7 was indeed associated with the chloroplasts by determining its subcellular localization. The LALF32-51 -E7 gene was fused to one encoding enhanced GFP to generate a LG fusion protein, and localization was determined by confocal laser scanning microscopy and transmission electron microscopy (TEM). The fluorescence observed from chloroplast-targeted LG was distinctively different from that of the cytoplasmic LG. Small spherical structures resembling protein bodies (PBs) were seen that clearly localized with the chloroplasts. Larger but less abundant PB-like structures were also seen for the cytoplasmic LG. PB-like structure formation was confirmed for both LG and LALF32-51 -E7 by TEM. LALF32-51 -E7 was indeed targeted to the chloroplasts by the chloroplast transit peptide used in this study, and it formed aggregated PB-like structures. This study could open a new avenue for the use of LALF32-51 as a PB-inducing peptide. PMID- 28733988 TI - Non-Planar [n]Cyclo-1,8-carbazolylenes (n=3,4,6) and [3]Cyclo-1,8-carbazolylenyl B, P, PO, SiPh Complexes. AB - A new family of non-planar heterocyclic molecules consisting of carbazoles was created. A bowl-shaped cyclodimer, a flake-shaped cyclotrimer, a double-decker ring-shaped cyclotetramer and a cyclohexamer were synthesized by Ni0 -mediated one-shot cyclo-oligomerization of 1,8-dibromocarbazole, and were named [n]cyclo 1,8-carbazolylenes (n=3,4,6). [3]Cyclo-1,8-carbazolylene was found to act as a trivalent tridentate ligand for heteroatoms (B, P, Si), giving flake-shaped complexes. The boron derivative acted as a Lewis acid, and the tetra-coordinated complexes showed an unprecedented red-shift of absorption and emission spectra by the coordination. The synthetic method, the distorted C2 or C1 symmetric shape, the trivalent tridentate coordination ability and the kinds of introduced heteroatoms of [3]cyclo-1,8-carbazolylenes, the electronic structure, the photophysical property, and the Lewis acidity were distinct from those of related subporphyrins/subphthalocyanines. PMID- 28733989 TI - Detecting ancient codispersals and host shifts by double dating of host and parasite phylogenies: Application in proctophyllodid feather mites associated with passerine birds. AB - Inferring cophylogeographic events requires matching the timing of these events on both host and symbiont (e.g., parasites) phylogenies because divergences of hosts and their symbionts may not temporally coincide, and host switches may occur. We investigate a large radiation of birds (Passeriformes) and their permanent symbionts, the proctophyllodid feather mites (117 species from 116 bird species; six genes, 11,468 nt aligned) using two time-calibration strategies for mites: fossils only and host phylogeography only. Out of 10 putative cophylogeographic events 4 agree in timing for both symbiont and host events being synchronous co-origins or codispersals; three were based on host shifts, but agree in timing being very close to the origin of modern hosts; two disagree; and one large basal mite split was seemingly independent from host phylogeography. Among these events was an ancient (21-25.3 Mya), synchronous codispersal from the Old World leading to the origin and diversifications of New World emberizoid passerids and their mites, the thraupis + quadratus species groups of Proctophyllodes. Our framework offers a more robust detection of host and symbiont cophylogeographic events (as compared to host-symbiont reconciliation analysis and using host phylogeography for time-calibration) and provides independent data for testing alternative hypotheses on timing of host diversification and dispersal. PMID- 28733990 TI - Dimethyl fumarate modulates neutrophil extracellular trap formation in a glutathione- and superoxide-dependent manner. AB - BACKGROUND: Neutrophil (polymorphonuclear) granulocytes (PMN) have been shown to contribute to the pathogenesis of psoriasis by releasing interleukin-17 and LL37 DNA complexes via neutrophil extracellular traps (NETs), webs of chromatin strands decorated with antimicrobial peptides, in psoriatic skin. Fumaderm(r) , a fumaric acid ester (FAE) formulation consisting of different FAE salts, has been successfully used to treat psoriasis for decades. Most recently, FAE treatment was reported to inhibit NET formation in murine epidermolysis bullosa acquisita. OBJECTIVES: To elucidate the effect of FAE treatment on human psoriasis and healthy donor NET formation. RESULTS: Among the compounds present in the FAE formulation, dimethyl fumarate (DMF) pretreatment of human psoriasis and healthy donor PMN resulted in a consistent inhibitory effect on NET formation in response to phorbol 12-myristate 13-acetate but not to platelet activating factor and ionomycin. This effect was l-glutathione (GSH) dependent and involved a decrease in reactive oxygen species (ROS) production, a key event in NET formation. In contrast, G-protein-coupled signalling and protein synthesis were not involved. Monomethyl fumarate (MMF) was found to slightly reduce ROS production without affecting NET formation. CONCLUSIONS: We report DMF as a potent, stimulus specific, GSH- and ROS-dependent modulator of NET formation. Our results support the notion that modulation of NET formation contributes to the beneficial effects of FAEs in a variety of inflammatory conditions. PMID- 28733992 TI - Case of mycotic cyst caused by Scedosporium apiospermum developed liver dysfunction following administration of voriconazole. PMID- 28733991 TI - pH-sensitive amide proton transfer effect dominates the magnetization transfer asymmetry contrast during acute ischemia-quantification of multipool contribution to in vivo CEST MRI. AB - PURPOSE: To determine the origins of in vivo magnetization transfer asymmetry contrast during acute ischemic stroke, particularly in the diffusion lesion, perfusion lesion, and their mismatch using a middle cerebral artery occlusion rat model of acute stroke. METHODS: Adult male Wistar rats underwent multiparametric MRI of diffusion, perfusion, T1 , and amide proton transfer (APT) imaging at 4.7 T following a middle cerebral artery occlusion procedure. A multipool Lorentzian model, including the nuclear Overhauser effect, magnetization transfer, direct water saturation, amine and amide chemical exchange saturation transfer effects, was applied for Z-spectrum fitting to determine the sources of in vivo magnetization transfer asymmetry following acute stroke. RESULTS: We showed that changes in amine chemical exchange saturation transfer (2 ppm) and APT (3.5 ppm) effects, particularly the APT MRI effect, dominate the commonly used magnetization transfer asymmetry analysis and hence confer pH sensitivity to APT imaging of acute stroke. Also, the nuclear Overhauser effect and magnetization transfer show small changes that counteracted each other, contributing less than 0.3% to magnetization transfer asymmetry at 3.5 ppm. Moreover, we showed that diffusion lesion had worsened acidosis from perfusion/diffusion lesion mismatch (P < 0.05). CONCLUSIONS: The study complements recent in vivo quantitative chemical exchange saturation transfer work to shed light on the sensitivity and specificity of endogenous APT MRI to tissue acidosis. Magn Reson Med 79:1602 1608, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28733993 TI - Editorial Comment to Silodosin versus naftopidil in the treatment of premature ejaculation: A prospective multicenter trial. PMID- 28733994 TI - Seasonal recruitment and survival strategies of Palisada cervicornis comb. nov. (Ceramiales, Rhodophyta) in coral reefs. AB - As marine tropical ecosystems deteriorate and lose biodiversity, their communities are shifting to being dominated by a few species, altering ecosystem's functioning and services. Macroalgae are becoming dominant on coral reefs, and are frequently observed outcompeting corals. Turf algal assemblages are the base of energy flow in these systems and one of the most abundant types of macroalgae on coral reefs, but little is known about their biology and diversity. Through molecular and morphological analyses, we identified the turf forming species Laurencia cervicornis, and by studying seasonal recruitment and the impact of herbivorous fishes on its abundance, we describe its survival strategy. The molecular analyses used a total of 45 rbcL gene sequences including eight current genera within the Laurencia complex and two new sequences of L. cervicornis and strongly support the new combination of Palisada cervicornis comb. nov. In addition, a detailed morphological characterization including the description of reproductive structures is provided. Palisada cervicornis was seen recruiting in all seasons but was typically in low abundance. Specimens grown on tiles in fish exclosure cages were devoured in less than 4 h when offered to fishes. Even though many species of the Laurencia complex have chemicals that deter herbivory, species within the genus Palisada lack feeding deterrents and thus are highly palatable. We suggest that P. cervicornis is a palatable species that seems to survive in the community by obtaining a size-refuge from herbivory within turf communities. PMID- 28733995 TI - Incidence, predictors, and clinical outcomes of early stent thrombosis in acute myocardial infarction patients treated with primary percutaneous coronary angioplasty (insights from the University of Ottawa Heart Institute STEMI registry). AB - BACKGROUND: Early stent thrombosis (ST) remains an important complication of primary percutaneous intervention (PCI). To date, our information on angiographic and clinical predictors of early ST in ST-segment elevation myocardial infarction (STEMI) patients treated with primary PCI is limited. METHODS: We tried to evaluate the incidence, predictors, and outcomes of early ST in real-world patients treated with primary PCI. We identified all the patients presenting with STEMI between June 2004 and January 2011 who underwent primary PCI as the primary mode of revascularization. Diagnosis of ST was made as per the standard definition proposed by the Academic Research Consortium. RESULTS: The incidence of early ST was 1% among 2,303 patients treated with primary PCI. Definite and probable early ST occurred in 22 and 2 patients, respectively. Patients with early ST had higher in-hospital (P = 0.03) and 30-day mortality (P = 0.048). The rate of cardiogenic shock (P = 0.0006) and cerebrovascular accident (P = 0.0004) was also greater in the early ST group. Smaller stent diameter and lower use of intracoronary glycoprotein IIb/IIIa inhibitor were associated with higher rate of early ST. There was a trend of higher bivalirudin use in ST group, which did not reach significance (P = 0.07) On IVUS imaging, stent malapposition and uncovered plaque area were noted in 6 out of 11 cases. CONCLUSION: The incidence of early ST in primary PCI cohort is low. However, it is still associated with higher mortality and morbidity. Small stent diameter and disuse of intracoronary glycoprotein IIb/IIIa inhibitor may be associated with early ST. PMID- 28733996 TI - Long-term effectiveness of the preoperative smoking cessation programme at Western Health. AB - BACKGROUND: Smoking is associated with adverse effects in the perioperative period, including elevated risk of death. The perioperative period provides an opportunity to engage with patients who are smokers to encourage smoking cessation, often referred to as a 'teachable moment'. We developed a smoking intervention model for the pre-admission clinic (PAC) at Western Health, Victoria, Australia. This case series aimed to assess the impact of the smoking intervention model, which is standard of care, on the participant's smoking habits over four time points. METHODS: We enrolled 50 consecutive participants for elective surgery who were smokers and had attended PAC at Western Health, Footscray. All smokers were offered a standard intervention package to address their smoking. Participants underwent a brief interview to elicit their current smoking behaviour on their day of surgery, 3 and 12 months post-operatively. RESULTS: We found a reduction at each time point post-intervention in the average number of cigarettes smoked per day by all participants with a 43% reduction at 12 months compared with PAC. We found that the number of participants who had quit increased at each time point, with 29% abstinent at 12 months post operatively. At 12 months, we found 71% of participants had either quit or reduced the number of cigarettes smoked compared with the amount reported at PAC. CONCLUSION: This study adds to the evidence that a simple intervention preoperatively can contribute to long-term changes in smoking behaviour. PMID- 28733997 TI - Natural history of periodontitis: Disease progression and tooth loss over 40 years. AB - OBJECTIVES: To assess long-term attachment and periodontitis-related tooth loss (PTL) in untreated periodontal disease over 40 years. MATERIAL AND METHODS: Data originated from the natural history of periodontitis study in Sri Lankan tea labourers first examined in 1970. In 2010, 75 subjects (15.6%) of the original cohort were re-examined. RESULTS: PTL over 40 years varied between 0 and 28 teeth (mean 13.1). Four subjects presented with no PTL, while 12 were edentulous. Logistic regression revealed attachment loss as a statistically significant covariate for PTL (p < .004). Markov chain analysis showed that smoking and calculus were associated with disease initiation and that calculus, plaque, and gingivitis were associated with loss of attachment and progression to advanced disease. Mean attachment loss <1.81 mm at the age of 30 yielded highest sensitivity and specificity (0.71) to allocate subjects into a cohort with a dentition of at least 20 teeth at 60 years of age. CONCLUSIONS: These results highlight the importance of treating early periodontitis along with smoking cessation, in those under 30 years of age. They further show that calculus removal, plaque control, and the control of gingivitis are essential in preventing disease progression, further loss of attachment and ultimately tooth loss. PMID- 28733998 TI - Quiescent Oct4+ Neural Stem Cells (NSCs) Repopulate Ablated Glial Fibrillary Acidic Protein+ NSCs in the Adult Mouse Brain. AB - Adult primitive neural stem cells (pNSCs) are a rare population of glial fibrillary acidic protein (GFAP)- Oct4+ cells in the mouse forebrain subependymal zone bordering the lateral ventricles that give rise to clonal neurospheres in leukemia inhibitory factor in vitro. pNSC neurospheres can be passaged to self renew or give rise to GFAP+ NSCs that form neurospheres in epidermal growth factor and fibroblast growth factor 2, which we collectively refer to as definitive NSCs (dNSCs). Label retention experiments using doxycycline-inducible histone-2B (H2B)-green fluorescent protein (GFP) mice and several chase periods of up to 1 year quantified the adult pNSC cell cycle time as 3-5 months. We hypothesized that while pNSCs are not very proliferative at baseline, they may exist as a reserve pool of NSCs in case of injury. To test this function of pNSCs, we obtained conditional Oct4 knockout mice, Oct4fl/fl ;Sox1Cre (Oct4CKO ), which do not yield adult pNSC-derived neurospheres. When we ablated the progeny of pNSCs, namely all GFAP+ dNSCs, in these Oct4CKO mice, we found that dNSCs did not recover as they do in wild-type mice, suggesting that pNSCs are necessary for dNSC repopulation. Returning to the H2B-GFP mice, we observed that the cytosine beta-d-arabinofuranoside ablation of proliferating cells including dNSCs-induced quiescent pNSCs to proliferate and significantly dilute their H2B-GFP label. In conclusion, we demonstrate that pNSCs are the most quiescent stem cells in the adult brain reported to date and that their lineage position upstream of GFAP+ dNSCs allows them to repopulate a depleted neural lineage. Stem Cells 2017;35:2071-2082. PMID- 28733999 TI - Retinyl propionate and climbazole combination demonstrates clinical improvement to the appearance of hyperpigmentation and deep wrinkling with minimal irritation. AB - OBJECTIVE: To evaluate a combination of retinyl propionate and climbazole (RPC) compared to 0.1% retinol for its efficacy, tolerance and ageing appearance. METHOD: Forty-five healthy Caucasian females, ages 40-70, with moderately photodamaged facial skin, were recruited for a 16-week randomized, double-blind, IRB-approved facial study. The efficacy of RPC treatment was compared to 0.1% retinol, in the same product base formulation, with twice daily, split-face product application. Changes in overall photodamage, fine lines and wrinkles, pigmentation and irritation were visually evaluated and measured by instrumentation. Subjective appraisal of efficacy was self-assessed from images where subjects were blinded to treatment and time point. Irritancy potential was also evaluated in a 5-day randomized, double-blind, IRB-approved patch study. RESULTS: Treatment with RPC resulted in significant (P < 0.05) improvement in ageing attributes compared to 0.1% retinol treatment, with minimal irritation. More than 50% of subjects showed improvement to deep wrinkles in the crow's feet area after 5 weeks of product application, and continued improvement to deep wrinkles was observed throughout the course of the study. Similarly, improvement was observed for the appearance of lines and wrinkles in the nasolabial fold (NLF) and for mottled hyperpigmentation. The results from subjective self assessment confirmed in vivo clinical assessments. In a separate patch study, significantly less irritation was observed with the RPC product as compared to the 0.1% retinol control product. CONCLUSION: RPC delivered significant skin anti ageing benefits comparable or greater than 0.1% retinol, with minimal irritation. PMID- 28734000 TI - Incidence, prevalence, mortality and causes of death in systemic sclerosis in Korea: a nationwide population-based study. PMID- 28734001 TI - Control of Reversible Activation Dynamics of [Ru{eta6 :kappa1 -C6 H5 (C6 H4 )NH2 }(XY)]n+ and the Effect of Chelating-Ligand Variation. AB - The potential use of organoruthenium complexes as anticancer drugs is well known. Herein, a family of activatable tethered ruthenium(II) arene complexes of general formula [Ru{eta6 :kappa1 -C6 H5 (C6 H4 )NH2 }(XY)]n+ (closed tether ring) bearing different chelating XY ligands (XY=aliphatic diamine, phenylenediamine, oxalato, bis(phosphino)ethane) is reported. The activation of these complexes (closed- to open-tether conversion) occurs in methanol and DMSO at different rates and to different reaction extents at equilibrium. Most importantly, RuII -complex activation (cleavage of the Ru-Ntether bond) occurs in aqueous solution at high proton concentration (upon Ntether protonation). The activation dynamics can be modulated by rational variation of the XY chelating ligand. The electron-donating capability and steric hindrance of XY have a direct impact on the reactivity of the Ru-N bond, and XY=N,N'-dimethyl-, N,N'-diethyl-, and N,N,N',N' tetramethylethylenediamine afford complexes that are more prone to activation. Such activation in acidic media is fully reversible, and proton concentration also governs the deactivation rate, that is, tether-ring closure slows down with decreasing pH. Interaction of a closed-tether complex and its open-tether counterpart with 5'-guanosine monophosphate revealed selectivity of the active (open) complex towards interaction with nucleobases. This work presents ruthenium tether complexes as exceptional pH-dependent switches with potential applications in cancer research. PMID- 28734002 TI - Dermoscopy in facilitating the recognition of acrodermatitis continua of Hallopeau. PMID- 28734003 TI - Dysregulation of inflammatory gene expression in lesional and nonlesional skin of patients with pyoderma gangrenosum. PMID- 28734004 TI - Comparison of preferences of healthcare professionals and MS patients for attributes of disease-modifying drugs: A best-worst scaling. AB - BACKGROUND: The choice between disease-modifying drugs (DMDs) for the treatment of multiple sclerosis (MS) becomes more often a shared decision between the patient and the neurologist and MS nurse. This study aimed to assess which DMD attributes are most important for the healthcare professionals in selecting a DMD for a patient. Subsequently, within this perspective, the neurologists' and nurses' perspectives were compared. Lastly, the healthcare professionals' perspective was compared with the patients' perspective to detect any differences that may need attention in the communication about DMDs. DESIGN: A best-worst scaling (BWS) was conducted among 27 neurologists and 33 MS nurses treating patients with MS to determine the importance of 27 DMD attributes. These attributes were identified through three focus groups with MS patients in a previous study (N=19). Relative importance scores (RISs) were estimated for each attribute. Multivariable linear regression analyses were used to compare the different perspectives. RESULTS: According to the neurologists and nurses, safety of the DMD was the most important DMD attribute in the treatment decision, closely followed by effect on disability progression, quality of life and relapse rate. Patients with MS agreed with the importance of the last three attributes, but valued safety significantly lower (b=-2.59, P<.001). CONCLUSIONS: This study suggests that, overall, neurologists and nurses regard the same DMD attributes as important as MS patients with the notable exception of safety. This study provides valuable information for the development of interventions to support shared decision making and highlights which attributes of DMDs may need additional attention. PMID- 28734005 TI - Rapidly developed BRAF inhibitor-induced verrucous keratosis. PMID- 28734006 TI - Appearance of antidesmocollin 1 autoantibodies leading to a vegetative lesion in a patient with pemphigus vulgaris. PMID- 28734007 TI - Real-world complexity of atrial fibrillation treatment with oral anticoagulants: design and interpretation of pharmacoepidemiological studies. PMID- 28734008 TI - Editorial Statement. PMID- 28734010 TI - A pilot study of fatigue in patients with hidradenitis suppurativa. PMID- 28734009 TI - KIT mutations and CD117 overexpression are markers of better progression-free survival in vulvar melanomas. AB - BACKGROUND: Few studies have addressed prognostic markers and none has correlated molecular status and prognosis in vulvar melanomas. OBJECTIVES: To evaluate the clinicopathological features of 95 cases of vulvar melanoma. METHODS: p53, CD117, Ki-67, neurofibromin, brafv600e and nrasq61r immunostains, and molecular analyses by either targeted next-generation or direct sequencing, were performed on available archival materials. RESULTS: Molecular testing detected mutations in KIT (44%), BRAF (25%), NF1 (22%), TP53 (17%), NRAS (9%) and TERT promoter (9%). Co-mutation of KIT and NF1 and of KIT and NRAS were identified in two and one cases, respectively. KIT mutations were significantly associated with better progression-free survival in univariate analyses. In multivariate analyses CD117 expression was significantly associated with better progression-free survival. Tumour thickness was significantly associated with worse progression-free and overall survival, and perineural invasion significantly correlated with reduced melanoma-specific survival and reduced overall survival. Cases were from multiple centres and only a subset of samples was available for molecular testing. CONCLUSIONS: KIT mutations and CD117 overexpression are markers of better progression-free survival. In addition to its prognostic value, molecular testing may identify cases that might respond to targeted agents or immunotherapeutic approaches. PMID- 28734012 TI - Successful treatment by negative-pressure wound therapy for ulcer located on diffuse plexiform neurofibroma. PMID- 28734011 TI - Maternal SSRI discontinuation, use, psychiatric disorder and the risk of autism in children: a meta-analysis of cohort studies. AB - We undertook an exclusive meta-analysis of cohort studies investigating the possible link between prenatal selective serotonin reuptake inhibitor (SSRI) exposure and autism spectrum disorders (ASD) in children to further investigate our previous suggestion of confounding by indication. The point estimates regarding the following cohorts were extracted and pooled: (1) pregnant women who discontinued SSRI until 3 months before pregnancy; (2) pregnant women who were exposed to SSRI during pregnancy; and (3) pregnant women with maternal psychiatric disorder but no exposure to SSRI during pregnancy. Although the pooled point estimate of the first cohort showed a trend for increase, it did not reach significance. The pooled point estimates of the latter cohorts showed a significant association with ASD which strengthens our previous suggestion of confounding by indication. Future studies should be adequately designed to differentiate whether the previously suggested association is a result of maternal psychiatric disorder or SSRI exposure or both. PMID- 28734013 TI - Cervical cancer in Africa, Latin America and the Caribbean and Asia: Regional inequalities and changing trends. AB - The vast majority (86% or 453,000 cases) of the global burden of cervical cancer occurs in Africa, Latin America and the Caribbean and Asia, where one in nine new cancer cases are of the cervix. Although the disease has become rare in high resource settings (e.g., in North America, parts of Europe, Japan) that have historically invested in effective screening programs, the patterns and trends are variable elsewhere. While favourable incidence trends have been recorded in many populations in Asia and Latin America and the Caribbean in the past decades, rising rates have been observed in sub-Saharan African countries, where high quality incidence series are available. The challenge for countries heavily affected by the disease in these regions is to ensure resource-dependent programmes of screening and vaccination are implemented to transform the situation, so that accelerated declines in cervical cancer are not the preserve of high-income countries, but become the norm in all populations worldwide. PMID- 28734014 TI - Improving postmortem testing for perinatal death from the parents' perspective. PMID- 28734015 TI - Different miR-21-3p isoforms and their different features in colorectal cancer. AB - MiR-21, the only microRNA (miRNA) found to be overexpressed in any type of solid tumor, its guide stand, miR-21-5p, has been studied a lot in colorectal cancer (CRC); however, few researchers focused on its passenger strand, miR-21-3p. In our study, based on The Cancer Genome Atlas (TCGA) data, we found that there were more varieties and quantities of miR-21-3p isoforms in microsatellite instability (MSI)-type CRC. We further examined the role of miR-21-3p by in vitro and in vivo studies. MiR-21-3p may be an oncogene in CRC by promoting cellular mobility through epithelial-mesenchymal transition. However, different isoforms, especially miR-21-3p 0 | 2, may be a favorable prognostic marker for CRC survival, probably due to increased complementary effect of miR-21-5p and/or target genes. Further study investigating the underlying mechanism of miRNA isoforms is needed. PMID- 28734016 TI - FRET-based binding assay between a fluorescent cAMP analogue and a cyclic nucleotide-binding domain tagged with a CFP. AB - The cyclic nucleotide-binding domain (CNBD) functions as a regulatory domain of many proteins involved in cyclic nucleotide signalling. We developed a straightforward and reliable binding assay based on intermolecular fluorescence resonance energy transfer (FRET) between an adenosine-3', 5'-cyclic monophosphate analogue labelled with fluorescein and a recombinant CNBD of human EPAC1 tagged with a cyan fluorescence protein (CFP). The high FRET efficiency of this method (~ 80%) allowed us to perform several types of binding experiments with nanomolar range of sample using conventional equipment. In addition, the CFP tag on the CNBD enabled us to perform a specific binding experiment using an unpurified protein. Considering these advantages, this technique is useful to study poorly characterized CNBDs. PMID- 28734017 TI - Evaluation of the impact of strain correction on the orientation of cardiac diffusion tensors with in vivo and ex vivo porcine hearts. AB - PURPOSE: To evaluate the importance of strain-correcting stimulated echo acquisition mode echo-planar imaging cardiac diffusion tensor imaging. METHODS: Healthy pigs (n = 11) were successfully scanned with a 3D cine displacement encoded imaging with stimulated echoes and a monopolar-stimulated echo-planar imaging diffusion tensor imaging sequence at 3 T during diastasis, peak systole, and strain sweet spots in a midventricular short-axis slice. The same diffusion tensor imaging sequence was repeated ex vivo after arresting the hearts in either a relaxed (KCl-induced) or contracted (BaCl2 -induced) state. The displacement encoded imaging with stimulated echoes data were used to strain-correct the in vivo cardiac diffusion tensor imaging in diastole and systole. The orientation of the primary (helix angles) and secondary (E2A) diffusion eigenvectors was compared with and without strain correction and to the strain-free ex vivo data. RESULTS: Strain correction reduces systolic E2A significantly when compared without strain correction and ex vivo (median absolute E2A = 34.3 degrees versus E2A = 57.1 degrees (P = 0.01), E2A = 60.5 degrees (P = 0.006), respectively). The systolic distribution of E2A without strain correction is closer to the contracted ex vivo distribution than with strain correction, root mean square deviation of 0.027 versus 0.038. CONCLUSIONS: The current strain-correction model amplifies the contribution of microscopic strain to diffusion resulting in an overcorrection of E2A. Results show that a new model that considers cellular rearrangement is required. Magn Reson Med 79:2205-2215, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28734018 TI - Influence of cryoprecipitate, Factor XIII, and fibrinogen concentrate on hyperfibrinolysis. AB - BACKGROUND: Hyperfibrinolysis is a potentially life-threatening condition associated with poor clot integrity and excessive bleeding. Although antifibrinolytics are an effective treatment, more liberal use of these drugs may lead to a prothrombotic risk, and an earlier and potentially safer treatment option would be desirable. Hyperfibrinolysis has been shown to be attenuated by in vitro supplementation of purified human Factor (F)XIII concentrate. Cryoprecipitate represents an alternative source of FXIII and the only approved source of concentrated FXIII in some countries. The aim of this study was to investigate whether cryoprecipitate, FXIII, and fibrinogen concentrate mitigate hyperfibrinolysis. STUDY DESIGN AND METHODS: Ten citrate blood specimens from healthy subjects were spiked with tissue plasminogen activator (t-PA) and subsequently supplemented with cryoprecipitate, FXIII, fibrinogen concentrate, and E-aminocaproic acid (EACA). Thromboelastometry tests were performed at baseline, after t-PA, and after supplementation. Hyperfibrinolysis was assessed using the clot lysis index at 60 minutes (LI60; reciprocal of maximum lysis). RESULTS: The LI60 was significantly improved (fibrinolysis attenuated) after cryoprecipitate supplementation compared to t-PA alone and compared to FXIII and fibrinogen concentrate. Hyperfibrinolysis was only fully reversed using EACA. In addition, cryoprecipitate demonstrated the least variability in the attenuation of hyperfibrinolysis among 10 healthy subjects, compared to FXIII and fibrinogen concentrate. CONCLUSION: This is the first study to show that cryoprecipitate is able to significantly mitigate hyperfibrinolysis in an in vitro model. Further investigations are warranted to determine whether cryoprecipitate may have a previously unrecognized benefit and should be administered earlier in resuscitation protocols. PMID- 28734019 TI - Association between androgen deprivation therapy and anxiety among 78 000 patients with localized prostate cancer. AB - OBJECTIVES: To examine whether any androgen deprivation therapy use or longer duration is associated with an increased risk of anxiety in patients with prostate cancer. METHODS: We identified 78 552 men aged >=66 years with stage I III prostate cancer using the Surveillance, Epidemiology, and End Results Medicare linked database from 1992 to 2006, excluding patients with psychiatric diagnoses within the year prior or 6 months after prostate cancer diagnosis. Multivariable Cox regression was used to examine the association between pharmacological androgen deprivation therapy and diagnosis of anxiety. RESULTS: The 43.1% (33 882) of patients who received androgen deprivation therapy experienced a higher 3-year cumulative incidence of anxiety compared with men who did not (4.1% vs 3.5%, P < 0.001). Any androgen deprivation therapy use was associated with a nearly significant increased risk of anxiety (adjusted hazard ratio 1.08, 95% confidence interval 1.00-1.17, P = 0.054). There was a significant trend between a longer duration of therapy and increased risk of anxiety (P-trend = 0.012), with a 16% higher risk for >=12 months (adjusted hazard ratio 1.16, 95% confidence interval 1.04-1.29, P = 0.010). CONCLUSIONS: Androgen deprivation therapy was associated with an elevated risk of anxiety in this cohort of elderly men with localized prostate cancer, with the risk higher with a longer duration of treatment. Anxiety should be considered among the possible psychiatric effects of androgen deprivation therapy and discussed before initiating treatment, particularly if a long course is anticipated. PMID- 28734021 TI - Effect of fixed value positive end expiratory pressure valves on canine thoracic volume and atelectasis. AB - OBJECTIVES: The objective of this study was to investigate whether a fixed 10 cm H2 O positive end-expiratory pressure valve would increase the aeration of, and reduce atelectasis formation in, the lungs after induction of anaesthesia in dogs undergoing thoracic CT. MATERIALS AND METHODS: 28 dogs were paired based on breed, bodyweight and body condition score and then randomly allocated to either Group Z (0 cm H2 O) or Group P (10 cm H2 O positive end-expiratory pressure valve) immediately after the induction of anaesthesia. All patients received a standardised anaesthetic protocol, and their lungs were manually hyperventilated before image acquisition. Cardiorespiratory parameters were recorded every 5 minutes. Total lung volume, lung density and degree of atelectasis were determined for each dog from the acquired images. RESULTS: The 10 cm H2 O positive end-expiratory pressure valve significantly increased lung volume (mL/kg) (Group Z: 52 +/-14; Group P: 83 +/-17; P<0.001) whilst significantly reducing lung density (Hounsfield units) (Group Z: -775 +/-30; Group P: -856 +/ 22; P<0.001) and the amount of atelectasis (P=0.004). Dogs in Group P had significantly higher end-tidal carbon dioxide (P<0.05), but there was no difference between the groups for respiratory rate or any cardiovascular variable. CLINICAL SIGNIFICANCE: A fixed-value positive end-expiratory pressure valve provides a simple, cost-effective technique for improving expiratory thoracic CT studies by increasing lung volume and decreasing atelectasis formation. PMID- 28734020 TI - Molecular analysis of brazilian patients with combined pituitary hormone deficiency and orthotopic posterior pituitary lobe reveals eight different PROP1 alterations with three novel mutations. AB - BACKGROUND: Mutations in PROP1, HESX1 and LHX3 are associated with combined pituitary hormone deficiency (CPHD) and orthotopic posterior pituitary lobe (OPP). OBJECTIVE: To identify mutations in PROP1, HESX1 and LHX3 in a large cohort of patients with CPHD and OPP (35 Brazilian, two Argentinian). DESIGN AND METHODS: We studied 23 index patients with CPHD and OPP (six familial and 17 sporadic) as well as 14 relatives. PROP1 was sequenced by the Sanger method in all except one sporadic case studied using a candidate gene panel. Multiplex ligation-dependent probe amplification (MLPA) was applied to one familial case in whom PROP1 failed to amplify by PCR. In the 13 patients without PROP1 mutations, HESX1 and LHX3 were sequenced by the Sanger method. RESULTS: We identified PROP1 mutations in 10 index cases. Three mutations were novel: one affecting the initiation codon (c.1A>G) and two affecting splicing sites, c.109+1G>A and c.342+1G>C. The known mutations, c.150delA (p.Arg53Aspfs*112), c.218G>A (p.Arg73His), c.263T>C (p.Phe88Ser) and c.301_302delAG (p.Leu102Cysfs*8), were also detected. MLPA confirmed complete PROP1 deletion in one family. We did not identify HESX1 and LHX3 mutations by Sanger. CONCLUSION: PROP1 mutations are a prevalent cause of congenital CPHD with OPP, and therefore, PROP1 sequencing must be the first step of molecular investigation in patients with CPHD and OPP, especially in populations with a high frequency of PROP1 mutations. In the absence of mutations, massively parallel sequencing is a promising approach. The high prevalence and diversity of PROP1 mutations is associated with the ethnic background of this cohort. PMID- 28734022 TI - 3D Printed Vascularized Device for Subcutaneous Transplantation of Human Islets. AB - Transplantation of pancreatic islets or stem cell derived insulin secreting cells is an attractive treatment strategy for diabetes. However, islet transplantation is associated with several challenges including function-loss associated with dispersion and limited vascularization as well as the need for continuous immunosuppression. To overcome these limitations, here we present a novel 3D printed and functionalized encapsulation system for subcutaneous engraftment of islets or islet like cells. The devices were 3D printed with polylactic acid and the surfaces treated and patterned to increase the hydrophilicity, cell attachment, and proliferation. Surface treated encapsulation systems were implanted with growth factor enriched platelet gel, which helped to create a vascularized environment before loading human islets. The device protected the encapsulated islets from acute hypoxia and kept them functional. The adaptability of the encapsulation system was demonstrated by refilling some of the experimental groups transcutaneously with additional islets. PMID- 28734023 TI - How do we manage blood donors and recipients after a positive Zika screening result? AB - Zika virus (ZIKV) is a mosquito-borne flavivirus that is the focus of an ongoing pandemic. ZIKV is notable for its severe neurologic sequelae in babies born to infected mothers. High rates of subclinical infection, as evidenced by the finding of ZIKV RNA in asymptomatic donors, raise concerns of risk to the blood supply. To date, a total of four suspected cases of transfusion-transmitted ZIKV have been reported (all in Brazil), none of which were associated with clinical infection in the transfusion recipients. In 2016, the US Food and Drug Administration issued a guidance mandating national blood donor screening for ZIKV in the United States. Five days after implementation of donor screening at our facility, we encountered a ZIKV-positive donor. We provide a practical approach to donor, recipient, and blood product management in the setting of a positive donor ZIKV result. Such has been informed by the challenges we faced in the workup of a ZIKV-reactive donation and recipient lookback. PMID- 28734026 TI - Falling into a routine: from habits to situated practices. AB - In line with the concept of 'nudging' people to change their behaviour, there has been increased attention on habit as a focus for psychologically-based health interventions. It is hoped that behaviours initiated by interventions not only become so regular that they are normalised into people's everyday lives, but that through repetition they may eventually become fixed and habitual. In this paper we draw on people's accounts of participating in a trial designed to encourage greater physical activity, and attend to the ways they describe their engagement with interventions within wider narratives of their everyday lives. In contrast to the idea that habit refers to automatic behaviour cued by external stimuli and governed by unconscious cognitive processes, our study describes how people identify many diverse elements that are felt to have equal significance in achieving a routine. Paradoxically, the sense of stability derives not from exact repetition, but from the ability for an assemblage of elements to be configured slightly differently each time. We consequently argue that attending to the diverse range of contextual elements bracketed off from interventions designed to be tested in trials, and the idea that continuity might emerge from variation, demands a reconceptualisation of the concept of habit adopted within many areas of current health psychology. PMID- 28734024 TI - Effect of solvent and protein dynamics in ligand recognition and inhibition of aminoglycoside adenyltransferase 2"-Ia. AB - The aminoglycoside modifying enzyme (AME) ANT(2")-Ia is a significant target for next generation antibiotic development. Structural studies of a related aminoglycoside-modifying enzyme, ANT(3")(9), revealed this enzyme contains dynamic, disordered, and well-defined segments that modulate thermodynamically before and after antibiotic binding. Characterizing these structural dynamics is critical for in situ screening, design, and development of contemporary antibiotics that can be implemented in a clinical setting to treat potentially lethal, antibiotic resistant, human infections. Here, the first NMR structural ensembles of ANT(2")-Ia are presented, and suggest that ATP-aminoglycoside binding repositions the nucleotidyltransferase (NT) and C-terminal domains for catalysis to efficiently occur. Residues involved in ligand recognition were assessed by site-directed mutagenesis. In vitro activity assays indicate a critical role for I129 toward aminoglycoside modification in addition to known catalytic D44, D46, and D48 residues. These observations support previous claims that ANT aminoglycoside sub-class promiscuity is not solely due to binding cleft size, or inherent partial disorder, but can be controlled by ligand modulation on distinct dynamic and thermodynamic properties of ANTs under cellular conditions. Hydrophobic interactions in the substrate binding cleft, as well as solution dynamics in the C-terminal tail of ANT(2")-Ia, advocate toward design of kanamycin-derived cationic lipid aminoglycoside analogs, some of which have already shown antimicrobial activity in vivo against kanamycin and gentamicin resistant P. aeruginosa. This data will drive additional in silico, next generation antibiotic development for future human use to combat increasingly prevalent antimicrobial resistance. PMID- 28734025 TI - Dual-site right ventricular pacing in patients undergoing cardiac resynchronization therapy: Results of a multicenter propensity-matched analysis. AB - BACKGROUND: Dual-site right ventricular pacing (Dual RV) has been proposed as an alternative for patients with heart failure undergoing cardiac resynchronization therapy (CRT) with a failure to deliver a coronary sinus (CS) lead. Only short term hemodynamic and echocardiographic results of Dual RV are available. We aimed to assess the long-term results of Dual RV and its impact on survival. METHODS: Multicenter retrospective assessment of all CRT implants during a 12-year period. Patients with failed CS lead implantation, treated with Dual RV, were followed and assessed for the primary endpoint of all-cause mortality and/or heart transplant. A control group was obtained from contemporary patients using propensity matching for all available baseline variables. RESULTS: Ninety-three patients were implanted with Dual RV devices and compared with 93 matched controls. During a median of 1,273 days (interquartile range 557-2,218), intention-to-treat analysis showed that all-cause mortality and/or heart transplant was higher in the Dual RV group (adjusted hazard ratio [HR] = 1.66, 95% confidence interval [CI] 1.12-2.47, P = 0.012). As-treated analysis yielded similar results (HR = 1.97, 95% CI 1.31-2.96, P = 0.001). Cardiac device-related infections occurred seven times more frequently in the Dual RV site group (HR = 7.60, 95% CI 1.51-38.33, P = 0.014). Among Dual RV nonresponders, four had their apical leads switched off, five required an epicardial LV lead insertion, a transseptal LV lead was implanted in two, and in nine patients, after reviewing the CS venogram, a new CS lead insertion was successfully attempted. CONCLUSION: Dual RV pacing is associated with worse clinical outcomes and higher complication rates than conventional CRT. PMID- 28734028 TI - Editorial Comment to Chronic kidney disease as a risk factor for recurrence and progression in patients with primary non-muscle-invasive bladder cancer. PMID- 28734027 TI - Chronic kidney disease as a risk factor for recurrence and progression in patients with primary non-muscle-invasive bladder cancer. AB - OBJECTIVES: To investigate the relationship between chronic kidney disease and primary non-muscle-invasive bladder cancer. METHODS: Disease outcomes were analyzed in 418 patients treated with transurethral resection for primary non muscle-invasive bladder cancer, and were correlated to traditional risk factors as well as chronic kidney disease stage according to estimated glomerular filtration rate: >=60 (G1-2), 45-59 (G3a) or <45 (G3b-5). RESULTS: The median follow-up time was 40.0 months. There were 287 (68.7%), 98 (23.4%), and 33 (7.9%) patients with G1-2, G3a and G3b-5 chronic kidney disease, respectively. T1 tumor was present in 29.6% of G1-2, 43.9% of G3a and 51.4% of G3b-5 chronic kidney disease (P = 0.004). The proportion of histological grade 3 non-muscle-invasive bladder cancer was higher in G3a and G3b-5 than G1-2 (P < 0.001). Higher chronic kidney disease stage was associated with worse recurrence-free (P < 0.001) and progression-free survival (P = 0.017). In multivariable analysis, G3b-5 was found to be an independent predictor for recurrence (hazard ratio 1.87; P = 0.004) and progression (hazard ratio 2.96; P = 0.019). Chronic kidney disease stage was also strongly associated with the European Association of Urology bladder cancer risk groups (P < 0.001), and with shorter time to recurrence and progression in each group. CONCLUSIONS: Chronic kidney disease predicts the clinical outcome of primary non-muscle-invasive bladder cancer. Adding chronic kidney disease to the conventional risk factors might increase the accuracy of risk stratification. PMID- 28734029 TI - Successful treatment of metastatic clear cell carcinoma with nivolumab in a patient receiving dialysis treatment. AB - The efficacy and safety of nivolumab for patients receiving dialysis treatment has not been established yet. Herein, we describe a patient on dialysis successfully treated with nivolumab as seventh-line therapy for metastatic renal cell carcinoma. Before initiating nivolumab, he had respiratory discomfort induced by a lesion occluding the left intermediate bronchus that originated from the metastatic lymph node behind the tracheal bifurcation. Four weeks after nivolumab was initiated, his symptom remarkably improved, and the occlusion disappeared according to the bronchoscopy examination. The effectiveness and safety of nivolumab has continued for 6 months. There are few cases in which nivolumab has been given to patients on dialysis. In the present case, nivolumab was given to a patient on dialysis, and it resulted in a remarkable improvement without any adverse events. PMID- 28734030 TI - A computational method for selecting short peptide sequences for inorganic material binding. AB - Discovering or designing biofunctionalized materials with improved quality highly depends on the ability to manipulate and control the peptide-inorganic interaction. Various peptides can be used as assemblers, synthesizers, and linkers in the material syntheses. In another context, specific and selective material-binding peptides can be used as recognition blocks in mining applications. In this study, we propose a new in silico method to select short 4 mer peptides with high affinity and selectivity for a given target material. This method is illustrated with the calcite (104) surface as an example, which has been experimentally validated. A calcite binding peptide can play an important role in our understanding of biomineralization. A practical aspect of calcite is a need for it to be selectively depressed in mining sites. PMID- 28734031 TI - Downregulation of DEC1 contributes to the neurotoxicity induced by MPP+ by suppressing PI3K/Akt/GSK3beta pathway. AB - AIM: Differentiated embryonic chondrocyte gene 1 (DEC1) is involved in the neuronal differentiation and development. The aim of this study is to investigate the role of DEC1 in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPP+ )-induced PD model. METHODS: The location of DEC1 and tyrosine hydroxylase (TH)-positive neurons were detected by immunofluorescence. 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP)-induced mouse subacute model of PD was established to evaluate the change of DEC1 expression in midbrain. Then, SH-SY5Y cells were used to investigate the role of DEC1 in MPP+ -induced neurotoxicity. RESULTS: We showed that the co-expressed DEC1 and TH neurons took up more than 80% of the expressed TH neurons in the midbrain of mice. DEC1/TH double-positive neurons decreased by 40.6% in SNpc and 28.8% in VTA of MPTP-injured mice. Consistently, DEC1, TH and dopamine transporter (DAT) expression decreased in the midbrain of MPTP mice. In SY-SY5Y cells, MPP+ significantly suppressed DEC1 expression and increased the cleaved caspase 3/caspase 3 and Bax/Bcl-2. DEC1 overexpression relieved, whereas DEC1 knockdown aggravated MPP+ -induced cytotoxicity. Likewise, DEC1 overexpression and knockdown inversely regulated the expression of beta catenin and PI3Kp110alpha (PIK3CA), an essential role in Wnt/beta-catenin and PI3K/Akt signaling pathways. Interestingly, LY294002, an inhibitor of PI3K/Akt signaling, aggravated, whereas LiCl, an activator of Wnt/beta-catenin signaling, abolished the reduction in DEC1 by MPP+ . It is established that these two pathways are interconnected by the phosphorylation status of GSK3beta. DEC1 overexpression increased but MPP+ and DEC1 knockdown decreased GSK3beta phosphorylation. CONCLUSION: Downregulation of DEC1 contributes to MPP+ -induced neurotoxicity by suppressing PI3K/Akt/GSK3beta pathway. PMID- 28734032 TI - Characterization of the axon initial segment of mice substantia nigra dopaminergic neurons. AB - The axon initial segment (AIS) is the site of initiation of action potentials and influences action potential waveform, firing pattern, and rate. In view of the fundamental aspects of motor function and behavior that depend on the firing of substantia nigra pars compacta (SNc) dopaminergic neurons, we identified and characterized their AIS in the mouse. Immunostaining for tyrosine hydroxylase (TH), sodium channels (Nav ) and ankyrin-G (Ank-G) was used to visualize the AIS of dopaminergic neurons. Reconstructions of sampled AIS of dopaminergic neurons revealed variable lengths (12-60 MUm) and diameters (0.2-0.8 MUm), and an average of 50% reduction in diameter between their widest and thinnest parts. Ultrastructural analysis revealed submembranous localization of Ank-G at nodes of Ranvier and AIS. Serial ultrathin section analysis and 3D reconstructions revealed that Ank-G colocalized with TH only at the AIS. Few cases of synaptic innervation of the AIS of dopaminergic neurons were observed. mRNA in situ hybridization of brain-specific Nav subunits revealed the expression of Nav 1.2 by most SNc neurons and a small proportion expressing Nav 1.6. The presence of sodium channels, along with the submembranous location of Ank-G is consistent with the role of AIS in action potential generation. Differences in the size of the AIS likely underlie differences in firing pattern, while the tapering diameter of AIS may define a trigger zone for action potentials. Finally, the conspicuous expression of Nav 1.2 by the majority of dopaminergic neurons may explain their high threshold for firing and their low discharge rate. PMID- 28734033 TI - Genistein and enterolactone in relation to Ki-67 expression and HER2 status in postmenopausal breast cancer patients. AB - SCOPE: Phytoestrogens (PE) may improve breast cancer prognosis by modifying tumor prognostic markers, such as cell proliferation marker Ki-67 and human epidermal growth factor receptor 2 (HER2). Epidemiological evidence linking lignans and isoflavones to Ki-67 and HER2 is limited. We examined associations between the major metabolites of lignans and isoflavones - enterolactone (ENL) and genistein (GEN) - respectively, and Ki-67 expression and HER2 in tumor tissue of breast cancer patients. METHODS AND RESULTS: Data from 1060 invasive breast cancer patients from the population-based MARIE study were used. Multivariate-adjusted linear (Ki-67 log-transformed) and quantile regression, and logistic regression analyses (HER2, Ki-67 dichotomized) were performed to calculate beta estimates and ORs, respectively. Median post-diagnostic ENL and GEN concentrations were 19.5 and 4.8 nmol/L, respectively. Median Ki-67 was 12.0%, and 21.2% of the tumors were HER2+. After adjustment, there was an inverse association between GEN and Ki-67 at high expression levels (OR for Ki-67 >=20% versus <20% of 0.93 (95%CI [0.87;0.99]) per 10 nmol/L GEN increment). CONCLUSION: Our findings indicate an inverse association between GEN and Ki-67 at high levels of Ki-67 expression. Additional investigations are recommended to confirm our findings and to further elucidate mechanisms linking PE metabolites to breast cancer survival. PMID- 28734034 TI - Protein features as determinants of wild-type glycoside hydrolase thermostability. AB - Thermostable enzymes for conversion of lignocellulosic biomass into biofuels have significant advantages over enzymes with more moderate themostability due to the challenging application conditions. Experimental discovery of thermostable enzymes is highly cost intensive, and the development of in-silico methods guiding the discovery process would be of high value. To develop such an in silico method and provide the data foundation of it, we determined the melting temperatures of 602 fungal glycoside hydrolases from the families GH5, 6, 7, 10, 11, 43, and AA9 (formerly GH61). We, then used sequence and homology modeled structure information of these enzymes to develop the ThermoP melting temperature prediction method. Futhermore, in the context of thermostability, we determined the relative importance of 160 molecular features, such as amino acid frequencies and spatial interactions, and exemplified their biological significance. The presented prediction method is made publicly available at http://www.cbs.dtu.dk/services/ThermoP. PMID- 28734035 TI - Vector flow imaging techniques: An innovative ultrasonographic technique for the study of blood flow. AB - Doppler ultrasonography is routinely used to identify abnormal blood flow. Nevertheless, conventional Doppler can be used to determine only the axial component of blood flow velocity and is angle dependent. A new method of multidimensional angle-independent estimation of flow velocity, called Vector Flow Imaging (VFI), has been proposed. It quantitatively evaluates the true velocity vector's amplitude and direction at any location into a vessel and displays a more intuitive depiction of the flow movements. High frame rate VFI, based on plane wave imaging, allows a detailed dynamic visualization of complex flow by showing even transient events, otherwise undetectable. (c) 2017 Wiley Periodicals, Inc. J Clin Ultrasound 45:582-588, 2017. PMID- 28734036 TI - (-)-Epicatechin regulates blood lipids and attenuates hepatic steatosis in rats fed high-fat diet. AB - SCOPE: (-)-Epicatechin (EC) is a natural flavanol monomer found in cocoa, green tea, and a variety of other plant foods. In this study, effects of EC on blood lipids and hepatic steatosis, and the underlying mechanisms were investigated. METHODS AND RESULTS: A hyperlipidemic rat model was induced by high-fat, high cholesterol diet. EC was then administrated to the animals by gavage at doses of 10, 20, 40 mg/kg body weight (BW) for 12 weeks. Simvastatin was included as a positive control. The results showed that EC significantly reduced total cholesterol, LDL cholesterol and triglyceride, alleviated liver fat accumulation, while increased HDL cholesterol, in hyperlipidemic rats. EC also reduced lipid peroxidation, inhibited the pro-inflammatory cytokines, and lowered serum AST and ALT. The potential molecular mechanisms of EC underlying these effects were proposed to be associated to regulating Insig-1-SREBP-SCAP pathway, and other lipid metabolic related genes including LXR-alpha, FAS, and SIRT1. CONCLUSION: EC effectively improved blood lipid profile and protected liver from accumulating excessive fat in hyperlipidemic rats. The results shed a light on the potential role of EC as a promising natural product in preventing hyperlipidemia and nonalcoholic fatty liver disease. PMID- 28734037 TI - Setting up a pediatric robotic urology program: A USA institution experience. AB - Implementing a robotic urological surgery program requires institutional support, and necessitates a comprehensive, detail-oriented plan that accounts for training, oversight, cost and case volume. Given the prevalence of robotic surgery in adult urology, in many instances it might be feasible to implement a pediatric robotic urology program within the greater context of adult urology. This involves, from an institutional standpoint, proportional distribution of equipment cost and operating room time. However, the pediatric urology team primarily determines goals for volume expansion, operative case selection, resident training and surgical innovation within the specialty. In addition to the clinical model, a robust economic model that includes marketing must be present. This review specifically highlights these factors in relationship to establishing and maintaining a pediatric robotic urology program. In addition, we share our data involving robot use over the program's first nine years (December 2007-December 2016). PMID- 28734038 TI - Erratum. PMID- 28734039 TI - Optimal control for micro-algae on a raceway model. AB - We apply numerical optimal control methods to an existing algae growth model with the aim to determine the best performance of the model under known conditions using a variety of decision variables. We transform the system of differential algebraic equations in the existing model to a system of ordinary differential equations which introduces dynamics for average light intensity and chlorophyll. In addition, we allow for variable nitrogen concentration of the inflow as well as variable initial nitrogen concentration of the raceway. Our main focus is on optimizing of the production of lipids. We calculate both open and closed loop optimal controllers and test their robustness. Finally, we also consider raceway depth as a decision variable. (c) 2017 American Institute of Chemical Engineers Biotechnol. Prog., 34:107-119, 2018. PMID- 28734040 TI - MicroRNA-374a Promotes Hepatocellular Carcinoma Cell Proliferation by Targeting Mitogen-Inducible Gene 6 (MIG-6). AB - Hepatocellular carcinoma (HCC) is a disease with poor prognosis rates and ineffective therapeutic options. Previous studies have reported the involvement of mitogen-inducible gene 6 (MIG-6) as a negative regulator in tumor formation. MicroRNAs (miRNAs) play crucial roles in the development of different types of cancer. However, the underlying mechanisms of miRNAs in HCC are poorly understood. This study was aimed to investigate the role of miR-374a in HCC and its role in the regulation of expression of MIG-6. The results showed that MIG-6 overexpression significantly inhibited cell viability of HepG2 cells after 4 days posttransfection. Moreover, MIG-6 was a direct target of miR-374a, and the expression of MIG-6 was remarkably downregulated by the overexpression of miR 374a in HepG2 cells. Furthermore, we found that overexpression of miR-374a promoted cell viability; however, the protective effect was abolished by MIG-6 overexpression. In addition, overexpression of miR-374a activated the EGFR and AKT/ERK signaling pathways by regulation of MIG-6. Our findings suggest that miR 374a could promote cell viability by targeting MIG-6 and activating the EGFR and AKT/ERK signaling pathways. These data provide a promising therapeutic strategy for HCC treatment. PMID- 28734041 TI - miR-103 Functions as a Tumor Suppressor by Directly Targeting Programmed Cell Death 10 in NSCLC. AB - Non-small cell lung cancer (NSCLC) accounts for about 85% of all lung cancer cases. Absence of miR-103 has recently been identified to be associated with metastatic capacity of primary lung tumors. However, the exact role of miR-103 in NSCLC and the molecular mechanism are unclear. In the present study, we showed that miR-103 expression was reduced in NSCLC tissues and cells. miR-103 expression was negatively correlated with tumor size and stage. The overall survival was longer in patients with higher miR-103 level than in those with lower miR-103 expression. miR-103 inhibited cell proliferation in A549 cells, decreased tumor weight and volume, and prolonged survival of tumor-implanted nude mice. miR-103 increased apoptotic cell death in A549 cells. Furthermore, miR-103 decreased the invasion and migration abilities in A549 cells, as evidenced by Transwell and wound healing results. Downregulation of miR-103 significantly reduced the level of programmed cell death 10 (PDCD10). We found a significant decrease in the relative luciferase activity of the reporter gene in A549 cells cotransfected with the miR-103 mimic and pGL3-PDCD10 WT 3'-UTR, but not pGL3 PDCD10 mut 3'-UTR. We showed that overexpression of PDCD10 significantly inhibited miR-103-induced inhibition of cell proliferation, increased apoptosis, and decreased invasion and migration in A549 cells. Moreover, we found that PDCD10 expression was increased in NSCLC tissues and cells. PDCD10 expression was positively correlated with tumor size and stage. Overexpression of PDCD10 increased cell proliferation and inhibited apoptosis in A549 cells. The data demonstrated that dysregulation of the miR-103/PDCD10 signal may be a novel therapeutic target for the treatment of NSCLC. PMID- 28734042 TI - Multivariate Optimization of Conditions for Digestion of Wet Feeds for Dogs and Cats Using a Closed Digester Block and Multielement Determination by ICP-OES. AB - A full 24 factorial design was applied to find the best combination of diluted reagents (HNO3 and H2O2), time, and temperature for the digestion of samples of wet feed for dogs and cats using a closed digestion block. The residual carbon concentration (RCC) was used as the response in the factorial design. All variables and their interactions significantly influenced the digestion of the feed samples, as indicated by the RCC. The conditions established for the digestion of 0.05 g (dry mass) wet feed samples were the addition of 3.0 mol/L HNO3 and 5.0% m/m H2O2 in a final volume of 10 mL, followed by heating in a closed digestion block at a temperature of 170 degrees C for 120 min. Analyses were performed by inductively coupled plasma (ICP) optical emission spectrometry (OES). LOQs ranged from 0.2 MUg/g (Mg and Sr) to 51 MUg/g (P). Accuracy of the analytical method was confirmed through the analysis of the Standard Reference Materials Tomato Leaves (NIST 1573), Apple Leaves (NIST 1515), and Peach Leaves (NIST 1547). The agreement values achieved ranged from 80.2 +/- 0.3% for Ba to 113.8 +/- 7.1% for Zn (n = 3). Addition and recovery tests were carried out by adding the analytes to a feed sample at two concentration levels, and the recoveries were between 84 +/- 6 and 114 +/- 10% for macroelements (Ca, K, Mg, and P; n = 3) and between 88 +/- 3 and 113 +/- 7% for microelements and trace elements (B, Cu, Fe, Sr, and Zn; n = 3). The precision values achieved for the different elements, expressed as RSDs, were better than 7.3% (Zn; n = 3) except for Cu determination, that was 14.6% (n=3). The optimized analytical method was applied to 10 commercial samples of wet feed for cats and dogs, with the concentrations of Al, B, Ba, Ca, Cu, Fe, K, Mg, Mn, P, Sr, and Zn determined by ICP-OES. PMID- 28734043 TI - ENabling Reduction of Low-grade Inflammation in SEniors Pilot Study: Concept, Rationale, and Design. AB - OBJECTIVES: To test two interventions to reduce interleukin (IL)-6 levels, an indicator of low-grade chronic inflammation and an independent risk factor for impaired mobility and slow walking speed in older adults. DESIGN: The ENabling Reduction of low-Grade Inflammation in SEniors (ENRGISE) Pilot Study was a multicenter, double-blind, placebo-controlled randomized pilot trial of two interventions to reduce IL-6 levels. SETTING: Five university-based research centers. PARTICIPANTS: Target enrollment was 300 men and women aged 70 and older with an average plasma IL-6 level between 2.5 and 30 pg/mL measured twice at least 1 week apart. Participants had low to moderate physical function, defined as self-reported difficulty walking one-quarter of a mile or climbing a flight of stairs and usual walk speed of less than 1 m/s on a 4-m usual-pace walk. INTERVENTION: Participants were randomized to losartan, omega-3 fish oil (omega 3), combined losartan and omega-3, or placebo. Randomization was stratified depending on eligibility for each group. A titration schedule was implemented to reach a dose that was safe and effective for IL-6 reduction. Maximal doses were 100 mg/d for losartan and 2.8 g/d for omega-3. MEASUREMENTS: IL-6, walking speed over 400 m, physical function (Short Physical Performance Battery), other inflammatory markers, safety, tolerability, frailty domains, and maximal leg strength were measured. RESULTS: Results from the ENRGISE Pilot Study will provide recruitment yields, feasibility, medication tolerance and adherence, and preliminary data to help justify a sample size for a more definitive randomized trial. CONCLUSION: The ENRGISE Pilot Study will inform a larger subsequent trial that is expected to have important clinical and public health implications for the growing population of older adults with low-grade chronic inflammation and mobility limitations. PMID- 28734044 TI - Metabolomic analysis reveals the composition differences in 13 Chinese tea cultivars of different manufacturing suitabilities. AB - BACKGROUND: Green tea and black tea are manufactured using appropriate tea cultivars in China. However, the metabolite differences relating to the manufacturing suitability of tea cultivars are unclear. In the present study, we performed a non-targeted metabolomic analysis on 13 Chinese tea cultivars using ultra-high performance liquid chromatography coupled with quadrupole-time-of flight mass spectrometry to investigate comprehensively the metabolite differences between cultivars suitable for manufacturing green tea (GT cultivars) and cultivars suitable for manufacturing both green tea and black tea (G&BT cultivars). RESULTS: Multivariate statistical analysis and cluster analysis divided the 13 cultivars into two groups, namely GT cultivars and G&BT cultivars, which correlated with their manufacturing suitability. The GT cultivars contained higher levels of flavonoid glycosides, whereas the G&BT cultivars contained higher levels of catechins, dimeric catechins, phenolic acids and alkaloids. CONCLUSION: Metabolic pathway analysis revealed that the flavonoid pathway inclined toward the synthesis of flavonoid glycosides in GT cultivars, whereas it inclined toward the synthesis of catechins and phenolic acids in G&BT cultivars. The results of the present study will be helpful for discriminating the manufacturing suitability of tea cultivars and investigating their breeding. (c) 2017 Society of Chemical Industry. PMID- 28734045 TI - Effectiveness of Light Therapy in Cognitively Impaired Persons: A Metaanalysis of Randomized Controlled Trials. AB - OBJECTIVES: To explore the effects of light therapy on behavioral disturbances (BDs), sleep quality, and depression. DESIGN: Meta-analysis of randomized controlled trials. SETTING: PubMed, Cochrane Library, Medline, EMBASE, Web of Science, and clinicaltrials.gov of selected randomized controlled trials and previous systematic reviews were searched. PARTICIPANTS: Cognitively impaired persons. MEASUREMENTS: Information was extracted on study characteristics, quality assessment, and outcomes. Outcome measures included BDs, sleep quality, and depression. RESULTS: Nine randomized controlled trials were examined. The results showed that light therapy has a moderate effect on BD (g = -0.61) and depression (g = -0.58) and a small effect on total sleep time at night (g = 0.25). Subgroup analysis indicated that a light intensity of 2,500 lux or greater has a greater effect on depression than an intensity of less than 2,500 lux (P = .03), and the low risk of bias in blinding was superior to the RCTs deemed to be of high or unclear risk of bias in blinding in terms of BD (P = .02). CONCLUSION: Light therapy can relieve BD, improve sleep quality, and alleviate symptoms of depression for cognitively impaired persons. PMID- 28734046 TI - Effect of a Community-Based Service Learning Experience in Geriatrics on Internal Medicine Residents and Community Participants. AB - Community-based service learning (CBSL) provides an opportunity to teach internal medicine residents the social context of aging and clinical concepts. The objectives of the current study were to demonstrate the feasibility of a CBSL program targeting internal medicine residents and to assess its effect on medical residents and community participants. internal medicine residents participated in a CBSL experience for half a day during ambulatory blocks from 2011 to 2014. Residents attended a senior housing unit or center, delivered a presentation about a geriatric health topic, toured the facility, and received information about local older adult resources. Residents evaluated the experience. Postgraduate Year 3 internal medicine residents (n = 71) delivered 64 sessions. Residents felt that the experience increased their ability to communicate effectively with older adults (mean 3.91 +/- 0.73 on a Likert scale with 5 = strongly agree), increased their knowledge of resources (4.09 +/- 1.01), expanded their knowledge of a health topic pertinent to aging (3.48 +/- 1.09), and contributed to their capacity to evaluate and care for older adults (3.84 +/- 0.67). Free-text responses demonstrated that residents thought that this program would change their practice. Of 815 older adults surveyed from 36 discrete teaching sessions, 461 (56%) thought that the medical residents delivered health information clearly (4.55 +/- 0.88) and that the health topics were relevant (4.26 +/- 0.92). Free-text responses showed that the program helped them understand their health concerns. This CBSL program is a feasible and effective tool for teaching internal medicine residents and older adults. PMID- 28734047 TI - Preselection of recombinant gene integration sites enabling high transcription rates in CHO cells using alternate start codons and recombinase mediated cassette exchange. AB - Site-specific recombinase mediated cassette exchange (RMCE) enables the transfer of the gene of interest (GOI) into pre-selected genomic locations with defined expression properties. For the generation of recombinant production cell lines, this has the advantage that screening for high transcription rates at the genome integration site would be required only once, with the possibility to reuse the selected site for new products. Here, we describe a strategy that aims at the selection of transcriptionally active genome integration sites in Chinese Hamster Ovary (CHO) cells by using alternate start codons in the surface reporter protein CD4, in combination with FACS sorting for high expressers. The alternate start codon reduces the translation initiation efficiency and allows sorting for CHO cells with the highest transcription rates, while RMCE enables the subsequent exchange of the CD4 against the GOI. We have shown that sorted cell pools with the CD4 reporter gene containing the alternate start codon CTG lead to higher GFP signals and higher antibody titers upon RMCE as compared to cell pools containing the ATG start codon of the CD4 reporter. Despite the absence of any subcloning step, the final cell pool contained the CD4 gene in a single genome integration site. PMID- 28734048 TI - Non-anthocyanin polyphenolic transformation by native yeast and bacteria co inoculation strategy during vinification. AB - BACKGROUND: Co-inoculation has been adapted by many wine-producing countries because it enhances the success of malolactic fermentation and reduces the fermentation cost, as well as time. However, wine phenolics have been sparsely highlighted during co-inoculation, even though polyphenols are an important parameter affecting wine colour, astringency and aroma. In the present study, we investigated the impact of co-inoculation on non-anthocyanin polyphenol profile for two different grape varieties. RESULTS: Co-inoculation of native yeast strain (AAV2) along with Oenococcus oeni was adapted for Cabernet Sauvignon and Shiraz wine. It was observed that the co-inoculation had minimal yet significant impact on the phenolic composition of wines for both the grape varieties. Color loss, as well as fruity aroma development, was observed in co-inoculated wines. The wines were on a par with the commercial wine, as well as wines without malolactic fermentation, in terms of phenolic compounds and overall organoleptic acceptance. Principal component analysis and hierarchical cluster analysis further suggested that the varietal influence on phenolic composition was dominating compared to inoculation strategies. Among the varieties, the inoculation strategies have significantly influenced the Cabernet wines compared to Shiraz wines. CONCLUSION: The results of the present study demonstrate that the phenolic compounds are not drastically affected by metabolic activities of malolactic bacteria during co inoculation and, hence, are equally suitable for wine fermentation. (c) 2017 Society of Chemical Industry. PMID- 28734049 TI - Development of aptamers against unpurified proteins. AB - SELEX (Systematic Evolution of Ligands by EXponential enrichment) has been widely used for the generation of aptamers against target proteins. However, its requirement for pure target proteins remains a major problem in aptamer selection, as procedures for protein purification from crude bio-samples are not only complicated but also time and labor consuming. This is because native proteins can be found in a large number of diverse forms because of posttranslational modifications and their complicated molecular conformations. Moreover, several proteins are difficult to purify owing to their chemical fragility and/or rarity in native samples. An alternative route is the use of recombinant proteins for aptamer selection, because they are homogenous and easily purified. However, aptamers generated against recombinant proteins produced in prokaryotic cells may not interact with the same proteins expressed in eukaryotic cells because of posttranslational modifications. Moreover, to date recombinant proteins have been constructed for only a fraction of proteins expressed in the human body. Therefore, the demand for advanced SELEX methods not relying on complicated purification processes from native samples or recombinant proteins is growing. This review article describes several such techniques that allow researchers to directly develop an aptamer from various unpurified samples, such as whole cells, tissues, serum, and cell lysates. The key advantages of advanced SELEX are that it does not require a purification process from a crude bio-sample, maintains the functional states of target proteins, and facilitates the development of aptamers against unidentified and uncharacterized proteins in unpurified biological samples. PMID- 28734050 TI - Estimating synchronous demographic changes across populations using hABC and its application for a herpetological community from northeastern Brazil. AB - Many studies propose that Quaternary climatic cycles contracted and/or expanded the ranges of species and biomes. Strong expansion-contraction dynamics of biomes presume concerted demographic changes of associated fauna. The analysis of temporal concordance of demographic changes can be used to test the influence of Quaternary climate on diversification processes. Hierarchical approximate Bayesian computation (hABC) is a powerful and flexible approach that models genetic data from multiple species, and can be used to estimate the temporal concordance of demographic processes. Using available single-locus data, we can now perform large-scale analyses, both in terms of number of species and geographic scope. Here, we first compared the power of four alternative hABC models for a collection of single-locus data. We found that the model incorporating an a priori hypothesis about the timing of simultaneous demographic change had the best performance. Second, we applied the hABC models to a data set of seven squamate and four amphibian species occurring in the Seasonally Dry Tropical Forests (Caatinga) in northeastern Brazil, which, according to paleoclimatic evidence, experienced an increase in aridity during the Pleistocene. If this increase was important for the diversification of associated xeric-adapted species, simultaneous population expansions should be evident at the community level. We found a strong signal of synchronous population expansion in the Late Pleistocene, supporting the increase of the Caatinga during this time. This expansion likely enhanced the formation of communities adapted to high aridity and seasonality and caused regional extirpation of taxa adapted to wet forest. PMID- 28734052 TI - A deeply superficial brain stimulation. PMID- 28734051 TI - A user's guide for alpha-synuclein biomarker studies in biological fluids: Perianalytical considerations. AB - Parkinson's disease biomarkers are needed to increase diagnostic accuracy, to objectively monitor disease progression and to assess therapeutic efficacy as well as target engagement when evaluating novel drug and therapeutic strategies. This article summarizes perianalytical considerations for biomarker studies (based on immunoassays) in Parkinson's disease, with emphasis on quantifying total alpha-synuclein protein in biological fluids. Current knowledge and pitfalls are discussed, and selected perianalytical variables are presented systematically, including different temperature of sample collection and types of collection tubes, gradient sampling, the addition of detergent, aliquot volume, the freezing time, and the different thawing methods. We also discuss analytical confounders. We identify gaps in the knowledge and delineate specific areas that require further investigation, such as the need to identify posttranslational modifications of alpha-synuclein and antibody-independent reference methods for quantification, as well as the analysis of potential confounders, such as comorbidities, medication, and phenotypes of Parkinson's disease in larger cohorts. This review could be used as a guideline for future Parkinson's disease biomarker studies and will require regular updating as more information arises in this growing field, including new technical developments as they become available. In addition to reviewing best practices, we also identify the current technical limitations and gaps in the knowledge that should be addressed to enable accurate and quantitative assessment of alpha-synuclein levels in the clinical setting. (c) 2017 International Parkinson and Movement Disorder Society. PMID- 28734053 TI - Hearing Impairment and Incident Dementia: Findings from the English Longitudinal Study of Ageing. AB - OBJECTIVES: To determine whether hearing loss is associated with incident physician-diagnosed dementia in a representative sample. DESIGN: Retrospective cohort study. SETTING: English Longitudinal Study of Ageing. PARTICIPANTS: Adults aged 50 and older. MEASUREMENTS: Cross-sectional associations between self reported (n = 7,865) and objective hearing measures (n = 6,902) and dementia were examined using multinomial-logistic regression. The longitudinal association between self-reported hearing at Wave 2 (2004/05) and cumulative physician diagnosed dementia up to Wave 7 (2014/15) was modelled using Cox proportional hazards regression. RESULTS: After adjustment for potential confounders, in cross sectional analysis, participants who had self-reported or objective moderate and poor hearing were more likely to have a dementia diagnosis than those with normal hearing (self-reported: odds ratio OR = 1.6, 95% CI = 1.1-2.4 moderate hearing; OR = 2.6, 95% CI = 1.7-3.9 poor hearing, objective: OR = 1.6, 95% CI = 1.0-2.8 moderate hearing; OR = 4.4, 95% CI = 1.9-9.9 poor hearing). Longitudinally, the hazard of developing dementia was 1.4 (95% CI = 1.0-1.9) times as high in individuals who reported moderate hearing and 1.6 (95% CI = 1.1-2.0) times as high in those who reported poor hearing. CONCLUSION: Older adults with hearing loss are at greater risk of dementia than those with normal hearing. These findings are consistent with the rationale that correction of hearing loss could help delay the onset of dementia, or that hearing loss itself could serve as a risk indicator for cognitive decline. PMID- 28734054 TI - Population demography and heterozygosity-fitness correlations in natural guppy populations: An examination using sexually selected fitness traits. AB - Heterozygosity-fitness correlations (HFCs) have been examined in a wide diversity of contexts, and the results are often used to infer the role of inbreeding in natural populations. Although population demography, reflected in population level genetic parameters such as allelic diversity or identity disequilibrium, is expected to play a role in the emergence and detectability of HFCs, direct comparisons of variation in HFCs across many populations of the same species, with different genetic histories, are rare. Here, we examined the relationship between individual microsatellite heterozygosity and a range of sexually selected traits in 660 male guppies from 22 natural populations in Trinidad. Similar to previous studies, observed HFCs were weak overall. However, variation in HFCs among populations was high for some traits (although these variances were not statistically different from zero). Population-level genetic parameters, specifically genetic diversity levels (number of alleles, observed/expected heterozygosity) and measures of identity disequilibrium (g2 and heterozygosity heterozygosity correlations), were not associated with variation in population level HFCs. This latter result indicates that these metrics do not necessarily provide a reliable predictor of HFC effect sizes across populations. Importantly, diversity and identity disequilibrium statistics were not correlated, providing empirical evidence that these metrics capture different essential characteristics of populations. A complex genetic architecture likely underpins multiple fitness traits, including those associated with male fitness, which may have reduced our ability to detect HFCs in guppy populations. Further advances in this field would benefit from additional research to determine the demographic contexts in which HFCs are most likely to occur. PMID- 28734055 TI - Past, present, and future of Parkinson's disease. PMID- 28734056 TI - In vivo placental MRI shape and textural features predict fetal growth restriction and postnatal outcome. AB - PURPOSE: To investigate the ability of three-dimensional (3D) MRI placental shape and textural features to predict fetal growth restriction (FGR) and birth weight (BW) for both healthy and FGR fetuses. MATERIALS AND METHODS: We recruited two groups of pregnant volunteers between 18 and 39 weeks of gestation; 46 healthy subjects and 34 FGR. Both groups underwent fetal MR imaging on a 1.5 Tesla GE scanner using an eight-channel receiver coil. We acquired T2-weighted images on either the coronal or the axial plane to obtain MR volumes with a slice thickness of either 4 or 8 mm covering the full placenta. Placental shape features (volume, thickness, elongation) were combined with textural features; first order textural features (mean, variance, kurtosis, and skewness of placental gray levels), as well as, textural features computed on the gray level co-occurrence and run length matrices characterizing placental homogeneity, symmetry, and coarseness. The features were used in two machine learning frameworks to predict FGR and BW. RESULTS: The proposed machine-learning based method using shape and textural features identified FGR pregnancies with 86% accuracy, 77% precision and 86% recall. BW estimations were 0.3 +/- 13.4% (mean percentage error +/- standard error) for healthy fetuses and -2.6 +/- 15.9% for FGR. CONCLUSION: The proposed FGR identification and BW estimation methods using in utero placental shape and textural features computed on 3D MR images demonstrated high accuracy in our healthy and high-risk cohorts. Future studies to assess the evolution of each feature with regard to placental development are currently underway. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:449-458. PMID- 28734057 TI - Major life events and risk of alcohol use disorders: a prospective cohort study. AB - AIMS: To estimate associations of individual major life events as well as accumulated major life events in childhood, adult private life and adult work life with risk of alcohol use disorders (AUD). DESIGN: Prospective cohort study with baseline examination in 1991-93 and linkage to national registers to identify AUD at follow-up. SETTING: Copenhagen, Denmark. PARTICIPANTS: Individuals (aged 21-93 years) who participated in the Copenhagen City Heart Study in 1991-93 (n = 8758). MEASUREMENTS: The primary outcome was first registration with AUD during follow-up (n = 249). AUD was identified in the Danish National Patient Register, in the Danish Psychiatric Central Register and in an outpatient treatment register. Major life events were assessed by a questionnaire in the Copenhagen City Heart study. Data were analysed by Cox proportional hazards models adjusted for age, sex, educational level, household income, cohabitation status and psychiatric comorbidity. FINDINGS: Serious family conflicts in childhood [hazard ratio (HR) = 1.35; 95% confidence interval (CI) = 1.00, 1.83] and serious economic problems in adult life (HR = 2.22; 95% CI = 1.64, 3.01) were associated significantly with increased risk of AUD. Prospective analyses did not show consistent effects of accumulation of major life events in childhood or adult life, but an additional analysis based on all AUD registrations suggested an association between accumulated childhood events and risk of AUD. CONCLUSIONS: Serious economic problems in adult life are associated strongly with risk of alcohol use disorders, and there may be an influence of accumulated childhood events on risk of alcohol use disorders. PMID- 28734058 TI - Evaluation of 2-benzylidene-1-tetralone derivatives as antagonists of A1 and A2A adenosine receptors. AB - Antagonists of the adenosine receptors (A1 and A2A ) are thought to be beneficial in neurological disorders, such as Alzheimer's and Parkinson's disease. The aim of this study was to explore 2-benzylidene-1-tetralone derivatives as antagonists of A1 and/or A2A adenosine receptors. In general, the test compounds were found to be selective for the A1 adenosine receptor, with only three test compounds possessing affinity for both the A1 and A2A adenosine receptor. The 2-benzylidene 1-tetralones bearing a hydroxyl substituent at either position C5, C6 or C7 of ring A displayed favourable adenosine A1 receptor binding, while C5 hydroxy substitution led to favourable A2A adenosine receptor affinity. Interestingly, para-hydroxy substitution on ring B in combination with ring A bearing a hydroxy at position C6 or C7 provided the 2-benzylidene-1-tetralones with both A1 and A2A adenosine receptor affinity. Compounds 4 and 8 displayed the highest A1 and A2A adenosine receptor affinity with values below 7 MUm. Both these compounds behaved as A1 adenosine receptor antagonists in the performed GTP shift assays. In conclusion, the 2-benzylidene-1-tetralone derivatives can be considered as lead compounds to design a new class of dual acting adenosine A1 /A2A receptor antagonists that may have potential in treating both dementia and locomotor deficits in Parkinson's disease. PMID- 28734059 TI - Localized reductions in resting-state functional connectivity in children with prenatal alcohol exposure. AB - Fetal alcohol spectrum disorders (FASD) are characterized by impairment in cognitive function that may or may not be accompanied by craniofacial anomalies, microcephaly, and/or growth retardation. Resting-state functional MRI (rs-fMRI), which examines the low-frequency component of the blood oxygen level dependent (BOLD) signal in the absence of an explicit task, provides an efficient and powerful mechanism for studying functional brain networks even in low-functioning and young subjects. Studies using independent component analysis (ICA) have identified a set of resting-state networks (RSNs) that have been linked to distinct domains of cognitive and perceptual function, which are believed to reflect the intrinsic functional architecture of the brain. This study is the first to examine resting-state functional connectivity within these RSNs in FASD. Rs-fMRI scans were performed on 38 children with FASD (19 with either full fetal alcohol syndrome (FAS) or partial FAS (PFAS), 19 nonsyndromal heavily exposed (HE)), and 19 controls, mean age 11.3 +/- 0.9 years, from the Cape Town Longitudinal Cohort. Nine resting-state networks were generated by ICA. Voxelwise group comparison between a combined FAS/PFAS group and controls revealed localized dose-dependent functional connectivity reductions in five regions in separate networks: anterior default mode, salience, ventral and dorsal attention, and R executive control. The former three also showed lower connectivity in the HE group. Gray matter connectivity deficits in four of the five networks appear to be related to deficits in white matter tracts that provide intra-RSN connections. Hum Brain Mapp 38:5217-5233, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28734061 TI - Evaluation of a technique for color correction in restoring anterior teeth. AB - OBJECTIVE: This study aimed to evaluate the ability of the proposed technique in producing restorations that exhibit mimesis with tooth structure and to define a restorative clinical protocol. MATERIALS AND METHODS: For this study a typodont was used. The right upper central incisor with Class IV lesion was restored with the layering technique (reference tooth, RT). For the left upper central incisor with Class IV lesion, six teeth were restored monochromatically (test teeth, TT), using DA3.5 (n = 3) and DA4 (n = 3) composite resins-resulting in six unsatisfactory color restorations. TT were divided into six groups depending on the color of unsatisfactory restoration and preparation depth. First, a preparation was realized on the labial surface with 0.5 mm, 0.7 mm or 1.0 mm of depth. A second preparation was then performed to reproduce the dentinal mamelons. Next, adhesive procedures were performed and the teeth restored. Opaque halo, opalescent halo and vestibular enamel were then reproduced by the addition of different composite resins. The RT and TT were photographed side by side in typodont to obtain six photographic prints. The photographs of the groups were subjected to visual evaluation by 120 volunteers via a questionnaire. Data were analyzed by the prevalence of answers, and Chi-square test was used to investigate the association between variables at .05 significance. Furthermore, DeltaE of groups was evaluated in comparison RT. RESULTS: The results demonstrated that the moderate intensity restorations (DA3.5) with depths of 0.5 mm and 0.7 mm had the highest prevalence of acceptance. For severe intensity restorations (DA4), the preparation depth of 1.0 mm obtained better acceptance. CONCLUSIONS: The technique was able to modify the final color of Class IV restorations, producing satisfactory color restorations. CLINICAL SIGNIFICANCE: This technique can be used for color correction in cases of Class IV restorations, in situations where there is no time for immediate layered restoration, and as a restorative technique. PMID- 28734060 TI - Effects of eddy currents on selective spectral editing experiments at 3T. AB - PURPOSE: To investigate frequency-offset effects in edited magnetic resonance spectroscopy (MRS) experiments arising from B0 eddy currents. MATERIALS AND METHODS: Macromolecule-suppressed (MM-suppressed) gamma-aminobutyric acid (GABA) edited experiments were performed at 3T. Saturation-offset series of MEGA-PRESS experiments were performed in phantoms, in order to investigate different aspects of the relationship between the effective editing frequencies and eddy currents associated with gradient pulses in the sequence. Difference integrals were quantified for each series, and the offset dependence of the integrals was analyzed to quantify the difference in frequency (Deltaf) between the actual vs. nominal expected saturation frequency. RESULTS: Saturation-offset N-acetyl aspartate-phantom experiments show that Deltaf varied with voxel orientation, ranging from 10.4 Hz (unrotated) to 6.4 Hz (45 degrees rotation about the caudal cranial axis) and 0.4 Hz (45 degrees rotation about left-right axis), indicating that gradient-related B0 eddy currents vary with crusher-gradient orientation. Fixing the crusher-gradient coordinate-frame substantially reduced the orientation dependence of Deltaf (to ~2 Hz). Water-suppression crusher gradients also introduced a frequency offset, with Deltaf = 0.6 Hz ("excitation" water suppression), compared to 10.2 Hz (no water suppression). In vivo spectra showed a negative edited "GABA" signal, suggesting Deltaf on the order of 10 Hz; with fixed crusher-gradient coordinate-frame, the expected positive edited "GABA" signal was observed. CONCLUSION: Eddy currents associated with pulsed field gradients may have a considerable impact on highly frequency-selective spectral editing experiments, such as MM-suppressed GABA editing at 3T. Careful selection of crusher gradient orientation may ameliorate these effects. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;47:673-681. PMID- 28734062 TI - Coumarins and adenosine receptors: New perceptions in structure-affinity relationships. AB - Adenosine receptor (AR) subtypes are involved in several physiological and pharmacological processes. Ligands that are able to selectively modulate one receptor subtype can delay or slow down the progression of diverse diseases. In this context, our research group focused its investigation into the discovery and development of novel, potent and selective AR ligands based on coumarin scaffold. Therefore, a series of 3-phenylcarboxamidocoumarins were synthesized and their affinity for the human AR subtypes was screened by radioligand binding assays for A1 , A2A and A3 receptors and for A2B by adenylyl cyclase assay. Compound 26 was found to be the most remarkable, with a hA1 /hA3 and hA2A /hA3 selectivity of 42, for the A3 AR (Ki = 2.4 MUm). Receptor-driven molecular modelling studies have provided valuable information on the binding/selectivity data of compound 26 and for the following optimization process. Moreover, compound 26 presents drug-like properties according to the general guidelines linked to the concept. PMID- 28734063 TI - ATP and astrocytes play a prominent role in the control of the respiratory pattern generator in the lamprey. AB - KEY POINTS: The paratrigeminal respiratory group (pTRG) is responsible for the respiratory pattern generation in the lamprey. The role of ATP and astrocytes, known to control respiratory activity in mammals, was investigated in the lamprey respiratory network. ATP microinjected into the pTRG induces a biphasic response consisting of marked increases in respiratory frequency mediated by P2X receptors followed by a decrease in the respiratory motor output due to the ATP metabolite adenosine. We provide evidence that astrocytes are involved in the genesis of the normal respiratory pattern, ATP-induced responses and acidification-induced increases of the respiratory activity. The function of astrocytes in rhythmic networks appears to be phylogenetically conserved. ABSTRACT: The role of ATP and astrocytes in respiratory rhythm modulation has been recently investigated in neonatal rodents. However, no information on the role of ATP and astrocytes within the respiratory network of the lamprey is available, particularly within the paratrigeminal respiratory group (pTRG), the proposed respiratory central pattern generator. To address these issues, the present study was carried out on isolated brainstems of the adult lamprey. Bath application of ATP caused marked increases in respiratory frequency followed by decreases in the respiratory motor output, mediated by the ATP metabolite adenosine at the level of the pTRG. Bath applications and microinjections of agonists and antagonists of purinergic receptors showed that ATP increased respiratory activity through an action on pTRG P2X receptors. To disclose the respiratory role of astrocytes, we used bath application of the gliotoxin aminoadipic acid, which dramatically depressed the respiratory motor output that, however, promptly recovered following glutamine application. Furthermore, the excitatory responses to ATP-gamma-S (a non hydrolysable ATP analogue), but not to substance P, microinjected into the pTRG, were abolished. Finally, we also demonstrated that acidification-induced increases in respiratory activity were ATP-independent, but mediated by the astrocytes' glutamate-glutamine cycle. The results show for the first time that ATP and especially astrocytes strongly contribute to the modulation of the lamprey respiratory pattern. Their role in the modulation or maintenance of rhythmic neuronal activities appears to be phylogenetically conserved. PMID- 28734064 TI - Extensive seed and pollen dispersal and assortative mating in the rain forest tree Entandrophragma cylindricum (Meliaceae) inferred from indirect and direct analyses. AB - Pollen and seed dispersal are key processes affecting the demographic and evolutionary dynamics of plant species and are also important considerations for the sustainable management of timber trees. Through direct and indirect genetic analyses, we studied the mating system and the extent of pollen and seed dispersal in an economically important timber species, Entandrophragma cylindricum (Meliaceae). We genotyped adult trees, seeds and saplings from a 400 ha study plot in a natural forest from East Cameroon using eight nuclear microsatellite markers. The species is mainly outcrossed (t = 0.92), but seeds from the same fruit are often pollinated by the same father (correlated paternity, rp = 0.77). An average of 4.76 effective pollen donors (Nep ) per seed tree contributes to the pollination. Seed dispersal was as extensive as pollen dispersal, with a mean dispersal distance in the study plot approaching 600 m, and immigration rates from outside the plot to the central part of the plot reaching 40% for both pollen and seeds. Extensive pollen- and seed-mediated gene flow is further supported by the weak, fine-scale spatial genetic structure (Sp statistic = 0.0058), corresponding to historical gene dispersal distances (sigmag ) reaching approximately 1,500 m. Using an original approach, we showed that the relatedness between mating individuals (Fij = 0.06) was higher than expected by chance, given the extent of pollen dispersal distances (expected Fij = 0.02 according to simulations). This remarkable pattern of assortative mating could be a phenomenon of potentially consequential evolutionary and management significance that deserves to be studied in other plant populations. PMID- 28734065 TI - FDG PET, dopamine transporter SPECT, and olfaction: Combining biomarkers in REM sleep behavior disorder. AB - BACKGROUND: Idiopathic REM sleep behavior disorder is a prodromal stage of Parkinson's disease and dementia with Lewy bodies. Hyposmia, reduced dopamine transporter binding, and expression of the brain metabolic PD-related pattern were each associated with increased risk of conversion to PD. The objective of this study was to study the relationship between the PD-related pattern, dopamine transporter binding, and olfaction in idiopathic REM sleep behavior disorder. METHODS: In this cross-sectional study, 21 idiopathic REM sleep behavior disorder subjects underwent 18 F-fluorodeoxyglucose PET, dopamine transporter imaging, and olfactory testing. For reference, we included 18 F-fluorodeoxyglucose PET data of 19 controls, 20 PD patients, and 22 patients with dementia with Lewy bodies. PD related pattern expression z-scores were computed from all PET scans. RESULTS: PD related pattern expression was higher in idiopathic REM sleep behavior disorder subjects compared with controls (P = 0.048), but lower compared with PD (P = 0.001) and dementia with Lewy bodies (P < 0.0001). PD-related pattern expression was higher in idiopathic REM sleep behavior disorder subjects with hyposmia and in subjects with an abnormal dopamine transporter scan (P < 0.05, uncorrected). CONCLUSION: PD-related pattern expression, dopamine transporter binding, and olfaction may provide complementary information for predicting phenoconversion. (c) 2017 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society. PMID- 28734066 TI - A review on comparative mechanistic studies of antimicrobial peptides against archaea. AB - Archaea was until recently considered as a third domain of life in addition to bacteria and eukarya but recent studies support the existence of only two superphyla (bacteria and archaea). The fundamental differences between archaeal, bacterial, and eukaryal cells are probably the main reasons for the comparatively lower susceptibility of archaeal strains to current antimicrobial agents. The possible emerging pathogenicity of archaea and the role of archaeal methanogens in methane emissions, a potent greenhouse gas, has led many researchers to examine the sensitivity patterns of archaea and make attempts to find agents that have significant anti-archaeal activity. Even though antimicrobial peptides (AMPs) are well known with several published reviews concerning their mode of action against bacteria and eukarya, to our knowledge, to date no reviews are available that focus on the action of these peptides against archaea. Herein, we present a review on all the peptides that have been tested against archaea. In addition, in an attempt to shed more light on possible future work that needs to be performed we have included a brief overview of the chemical characteristics, spectrum of activity, and the known mechanism of action of each of these peptides against bacteria and/or fungi. We also discuss the nature of and key physiological differences between Archaea, Bacteria, and Eukarya that are relevant to the development of anti-archaeal peptides. Despite our relatively limited knowledge about archaea, available data suggest that AMPs have an even broader spectrum of activity than currently recognized. PMID- 28734067 TI - Range instability leads to cytonuclear discordance in a morphologically cryptic ground squirrel species complex. AB - The processes responsible for cytonuclear discordance frequently remain unclear. Here, we employed an exon capture data set and demographic methods to test hypotheses generated by species distribution models to examine how contrasting histories of range stability vs. fluctuation have caused cytonuclear concordance and discordance in ground squirrel lineages from the Otospermophilus beecheyi species complex. Previous studies in O. beecheyi revealed three morphologically cryptic and highly divergent mitochondrial DNA lineages (named the Northern, Central and Southern lineages based on geography) with only the Northern lineage exhibiting concordant divergence for nuclear genes. Here, we showed that these mtDNA lineages likely formed in allopatry during the Pleistocene, but responded differentially to climatic changes that occurred since the last interglacial (~120,000 years ago). We find that the Northern lineage maintained a stable range throughout this period, correlating with genetic distinctiveness among all genetic markers and low migration rates with the other lineages. In contrast, our results suggested that the Southern lineage expanded from Baja California Sur during the Late Pleistocene to overlap and potentially swamp a contracting Central lineage. High rates of intraspecific gene flow between Southern lineage individuals among expansion origin and expansion edge populations largely eroded Central ancestry from autosomal markers. However, male-biased dispersal in this system preserved signals of this past hybridization and introgression event in matrilineal-biased X-chromosome and mtDNA markers. Our results highlight the importance of range stability in maintaining the persistence of phylogeographic lineages, whereas unstable range dynamics can increase the tendency for lineages to merge upon secondary contact. PMID- 28734069 TI - Pathogen richness and abundance predict patterns of adaptive major histocompatibility complex variation in insular amphibians. AB - The identification of the factors responsible for genetic variation and differentiation at adaptive loci can provide important insights into the evolutionary process and is crucial for the effective management of threatened species. We studied the impact of environmental viral richness and abundance on functional diversity and differentiation of the MHC class Ia locus in populations of the black-spotted pond frog (Pelophylax nigromaculatus), an IUCN-listed species, on 24 land-bridge islands of the Zhoushan Archipelago and three nearby mainland sites. We found a high proportion of private MHC alleles in mainland and insular populations, corresponding to 32 distinct functional supertypes, and strong positive selection on MHC antigen-binding sites in all populations. Viral pathogen diversity and abundance were reduced at island sites relative to the mainland, and islands housed distinctive viral communities. Standardized MHC diversity at island sites exceeded that found at neutral microsatellites, and the representation of key functional supertypes was positively correlated with the abundance of specific viruses in the environment (Frog virus 3 and Ambystoma tigrinum virus). These results indicate that pathogen-driven diversifying selection can play an important role in maintaining functionally important MHC variation following island isolation, highlighting the importance of considering functionally important genetic variation and host-pathogen associations in conservation planning and management. PMID- 28734068 TI - Evolution of antero-posterior patterning of the limb: Insights from the chick. AB - The developing limbs of chicken embryos have served as pioneering models for understanding pattern formation for over a century. The ease with which chick wing and leg buds can be experimentally manipulated, while the embryo is still in the egg, has resulted in the discovery of important developmental organisers, and subsequently, the signals that they produce. Sonic hedgehog (Shh) is produced by mesenchyme cells of the polarizing region at the posterior margin of the limb bud and specifies positional values across the antero-posterior axis (the axis running from the thumb to the little finger). Detailed experimental embryology has revealed the fundamental parameters required to specify antero-posterior positional values in response to Shh signaling in chick wing and leg buds. In this review, the evolution of the avian wing and leg will be discussed in the broad context of tetrapod paleontology, and more specifically, ancestral theropod dinosaur paleontology. How the parameters that dictate antero-posterior patterning could have been modulated to produce the avian wing and leg digit patterns will be considered. Finally, broader speculations will be made regarding what the antero-posterior patterning of chick limbs can tell us about the evolution of other digit patterns, including those that were found in the limbs of the earliest tetrapods. PMID- 28734070 TI - Genome scans on experimentally evolved populations reveal candidate regions for adaptation to plant resistance in the potato cyst nematode Globodera pallida. AB - Improving resistance durability involves to be able to predict the adaptation speed of pathogen populations. Identifying the genetic bases of pathogen adaptation to plant resistances is a useful step to better understand and anticipate this phenomenon. Globodera pallida is a major pest of potato crop for which a resistance QTL, GpaVvrn , has been identified in Solanum vernei. However, its durability is threatened as G. pallida populations are able to adapt to the resistance in few generations. The aim of this study was to investigate the genomic regions involved in the resistance breakdown by coupling experimental evolution and high-density genome scan. We performed a whole-genome resequencing of pools of individuals (Pool-Seq) belonging to G. pallida lineages derived from two independent populations having experimentally evolved on susceptible and resistant potato cultivars. About 1.6 million SNPs were used to perform the genome scan using a recent model testing for adaptive differentiation and association to population-specific covariables. We identified 275 outliers and 31 of them, which also showed a significant reduction in diversity in adapted lineages, were investigated for their genic environment. Some candidate genomic regions contained genes putatively encoding effectors and were enriched in SPRYSECs, known in cyst nematodes to be involved in pathogenicity and in (a)virulence. Validated candidate SNPs will provide a useful molecular tool to follow frequencies of virulence alleles in natural G. pallida populations and define efficient strategies of use of potato resistances maximizing their durability. PMID- 28734071 TI - Cophylogenetic signal is detectable in pollination interactions across ecological scales. AB - That evolutionary history can influence the way that species interact is a basic tenet of evolutionary ecology. However, when the role of evolution in determining ecological interactions is investigated, focus typically centers on just one side of the interaction. A cophylogenetic signal, the congruence of evolutionary history across both sides of an ecological interaction, extends these previous explorations and provides a more complete picture of how evolutionary patterns influence the way species interact. To date, cophylogenetic signal has most typically been studied in interactions that occur between fine taxonomic clades that show high intimacy. In this study, we took an alternative approach and made an exhaustive assessment of cophylogeny in pollination interactions. To do so, we assessed the strength of cophylogenetic signal at four distinct scales of pollination interaction: (1) across plant-pollinator associations globally, (2) in local pollination communities, (3) within the modular structure of those communities, and (4) in individual modules. We did so using a globally distributed dataset comprised of 54 pollination networks, over 4000 species, and over 12,000 interactions. Within these data, we detected cophylogenetic signal at all four scales. Cophylogenetic signal was found at the level of plant-pollinator interactions on a global scale and in the majority of pollination communities. At the scale defined by the modular structure within those communities, however, we observed a much weaker cophylogenetic signal. Cophylogenetic signal was detectable in a significant proportion of individual modules and most typically when within-module phylogenetic diversity was low. In sum, the detection of cophylogenetic signal in pollination interactions across scales provides a new dimension to the story of how past evolution shapes extant pollinator-angiosperm interactions. PMID- 28734072 TI - Plant species richness and productivity determine the diversity of soil fungal guilds in temperate coniferous forest and bog habitats. AB - Fungi have important roles as decomposers, mycorrhizal root symbionts and pathogens in forest ecosystems, but there is limited information about their diversity and composition at the landscape scale. This work aimed to disentangle the factors underlying fungal richness and composition along the landscape-scale moisture, organic matter and productivity gradients. Using high-throughput sequencing, we identified soil fungi from 54 low-productivity Pinus sylvestris dominated plots across three study areas in Estonia and determined the main predictors of fungal richness based on edaphic, floristic and spatial variables. Fungal richness displayed unimodal relationship with organic matter and deduced soil moisture. Plant richness and productivity constituted the key predictors for taxonomic richness of functional guilds. Composition of fungi and the main ectomycorrhizal fungal lineages and hyphal exploration types was segregated by moisture availability and soil nitrogen. We conclude that plant productivity and diversity determine the richness and proportion of most functional groups of soil fungi in low-productive pine forests on a landscape scale. Adjacent stands of pine forest may differ greatly in the dominance of functional guilds that have marked effects on soil carbon and nitrogen cycling in these forest ecosystems. PMID- 28734074 TI - Association of clinical and serological parameters of systemic lupus erythematosus patients with Epstein-Barr virus antibody profile. AB - Epstein-Barr viral infection is one of the known environmental factors involved in development of Systemic Lupus Erythematous (SLE). Though not much is known about the exact role of Epstein-Barr virus (EBV) in SLE pathogenesis, the theory of switching of lytic and lysogenic cycles of EBV in memory B cells fits well with the periods of waning disease activity and intermittent flares in SLE patients. In this study, we investigate the association of EBV antibody profile with clinical and serological parameters in SLE. Eighty-seven clinically diagnosed SLE patients fulfilling the American College of Rheumatology (ACR) classification criteria and fifty healthy individuals were enrolled in this case control study. Anti-VCA IgM, anti-VCA IgG, and anti-EBNA IgG were detected by ELISA technique. Antibodies concentrations between two groups were compared using Mann-Whitney whereas the difference in categorical data was compared using Chi square considering statistical significance at P < 0.05. This study demonstrated a significant increase in EBV VCA-IgG, VCA-IgM, and EBNA-IgG antibodies levels of SLE patients when compared to healthy controls (P < 0.05). High seroprevalence was seen in both the study groups for EBV VCA-IgG and EBNA-IgG antibodies when compared to VCA-IgM antibodies. A significant increase was noted in the anti-VCA IgG levels with dsDNA autoantibody positivity (P < 0.05). Though there was no significant association between EBV antibody profile and clinical manifestations, 100% seropositivity for anti-VCA-IgG was seen in SLE patients with renal manifestations. Association of anti-VCA IgG levels with presence of anti-dsDNA antibodies suggests a possible role of EBV as an environmental trigger in pathogenesis of SLE. PMID- 28734073 TI - Differential calcium sensitivity in NaV 1.5 mixed syndrome mutants. AB - KEY POINTS: SCN5a mutations may express gain-of-function (Long QT Syndrome-3), loss-of-function (Brugada Syndrome 1) or both (mixed syndromes), depending on the mutation and environmental triggers. One such trigger may be an increase in cytosolic calcium, accompanying exercise. Many mixed syndromes mutants, including ?KPQ, E1784K, 1795insD and Q1909R, are found in calcium-sensitive regions. Elevated cytosolic calcium attenuates gain-of-function properties in ?KPQ, 1795insD and Q1909R, but not in E1784K. By contrast, elevated cytosolic calcium further exacerbates gain-of-function in E1784K by destabilizing slow inactivation. Action potential modelling, using a modified O'Hara Rudy model, suggests that elevated heart rate rescues action potential duration in ?KPQ, 1795insD and Q1909R, but not in E1784K. Action potential simulations suggest that E1784K carriers have an increased intracellular sodium-to-calcium ratio under bradycardia and tachycardia conditions. Elevated cytosolic calcium, which is common during high heart rates, ameliorates or exacerbates the mixed syndrome phenotype depending on the genetic signature. ABSTRACT: Inherited arrhythmias may arise from mutations in the gene for SCN5a, which encodes the cardiac voltage gated sodium channel, NaV 1.5. Mutants in NaV 1.5 result in Brugada Syndrome (BrS1), Long-QT Syndrome (LQT3) or mixed syndromes (an overlap of BrS1/LQT3). Exercise is a potential arrhythmogenic trigger in mixed syndromes. We aimed to determine the effects of elevated cytosolic calcium, which is common during exercise, in mixed syndrome NaV 1.5 mutants. We used whole-cell patch clamp to assess the biophysical properties of NaV 1.5 wild-type (WT), ?KPQ, E1784K, 1795insD and Q1909R mutants in human embryonic kidney 293 cells transiently transfected with the NaV 1.5 alpha subunit (WT or mutants), beta1 subunit and enhanced green fluorescent protein. Voltage-dependence and kinetics were measured at cytosolic calcium levels of approximately 0, 500 and 2500 nm. In silico, action potential (AP) model simulations were performed using a modified O'Hara Rudy model. Elevated cytosolic calcium attenuates the late sodium current in ?KPQ, 1795insD and Q1909R, but not in E1784K. Elevated cytosolic calcium restores steady-state slow inactivation (SSSI) to the WT-form in Q1909R, but depolarized SSSI in E1784K. Our AP simulations showed a frequency-dependent reduction of AP duration in ?KPQ, 1795insD and Q1909R carriers. In E1784K, AP duration is relatively prolonged at both low and high heart rates, resulting in a sodium overload. Cellular perturbations during exercise may affect BrS1/LQT3 patients differently depending on their individual genetic signature. Thus, exercise may be therapeutic or may be an arrhythmogenic trigger in some SCN5a patients. PMID- 28734075 TI - High occurrence of jellyfish predation by black-browed and Campbell albatross identified by DNA metabarcoding. AB - Gelatinous zooplankton are a large component of the animal biomass in all marine environments, but are considered to be uncommon in the diet of most marine top predators. However, the diets of key predator groups like seabirds have conventionally been assessed from stomach content analyses, which cannot detect most gelatinous prey. As marine top predators are used to identify changes in the overall species composition of marine ecosystems, such biases in dietary assessment may impact our detection of important ecosystem regime shifts. We investigated albatross diet using DNA metabarcoding of scats to assess the prevalence of gelatinous zooplankton consumption by two albatross species, one of which is used as an indicator species for ecosystem monitoring. Black-browed and Campbell albatross scats were collected from eight breeding colonies covering the circumpolar range of these birds over two consecutive breeding seasons. Fish was the main dietary item at most sites; however, cnidarian DNA, primarily from scyphozoan jellyfish, was present in 42% of samples overall and up to 80% of samples at some sites. Jellyfish was detected during all breeding stages and consumed by adults and chicks. Trawl fishery catches of jellyfish near the Falkland Islands indicate a similar frequency of jellyfish occurrence in albatross diets in years of high and low jellyfish availability, suggesting jellyfish consumption may be selective rather than opportunistic. Warmer oceans and overfishing of finfish are predicted to favour jellyfish population increases, and we demonstrate here that dietary DNA metabarcoding enables measurements of the contribution of gelatinous zooplankton to the diet of marine predators. PMID- 28734076 TI - Ensemble characterization of an intrinsically disordered FG-Nup peptide and its F>A mutant in DMSO-d6. AB - Intrinsically disordered proteins (IDP) lack a well-defined 3D-structure under physiological conditions, yet, the inherent disorder represented by an ensemble of conformation plays a critical role in many cellular and regulatory processes. Nucleoporins, or Nups, are the proteins found in the nuclear pore complex (NPC). The central pore of the NPC is occupied by Nups, which have phenylalanine-glycine domain repeats and are intrinsically disordered, and therefore are termed FG Nups. These FG-domain repeats exhibit differing cohesiveness character and differ from least (FG) to most (GLFG) cohesive. The designed FG-Nup is a 25 AA model peptide containing a noncohesive FG-motif flanked by two cohesive GLFG-motifs (WT peptide). Complete NMR-based ensemble characterization of this peptide along with a control peptide with an F>A substitution (MU peptide) are discussed. Ensemble characterization of the NMR-determined models suggests that both the peptides do not have consistent secondary structures and continue to be disordered. Nonetheless, the role of cohesive elements mediated by the GLFG motifs is evident in the WT ensemble of structures that are more compact than the MU peptide. The approach presented here allows an alternate way to investigate the specific roles of distinct amino acid motifs that translate into the long-range organization of the ensemble of structures and in general on the nature of IDPs. PMID- 28734077 TI - Integrative studies implicate matrix metalloproteinase-12 as a culprit gene for large-artery atherosclerotic stroke. AB - BACKGROUND: Ischaemic stroke and coronary heart disease are important contributors to the global disease burden and share atherosclerosis as the main underlying cause. Recent evidence from a genome-wide association study (GWAS) suggested that single nucleotide polymorphisms (SNP) near the MMP12 gene at chromosome 11q22.3 were associated with large-vessel ischaemic stroke. Here, we evaluated and extended these results by examining the relationship between MMP12 and atherosclerosis in clinical and experimental studies. METHODS AND RESULTS: Plasma concentrations of MMP12 were measured at baseline in 3394 subjects with high-risk for cardiovascular disease (CVD) using the Olink ProSeek CVD I array. The plasma MMP12 concentration showed association with incident cardiovascular and cerebrovascular events (130 and 67 events, respectively, over 36 months) and carotid intima-media thickness progression (P = 3.6 * 10-5 ). A GWAS of plasma MMP12 concentrations revealed that SNPs rs499459, rs613084 and rs1892971 at chr11q22.3 were independently associated with plasma MMP12 (P < 5 * 10-8 ). The lead SNPs showed associations with mRNA levels of MMP12 and adjacent MMPs in atherosclerotic plaques. MMP12 transcriptomic and proteomic levels were strongly significantly increased in carotid plaques compared with control arterial tissue and in plaques from symptomatic versus asymptomatic patients. By combining immunohistochemistry and proximity ligation assay, we demonstrated that MMP12 localizes to CD68 + macrophages and interacts with elastin in plaques. MMP12 silencing in human THP-1-derived macrophages resulted in reduced macrophage migration. CONCLUSIONS: Our study supports the notion that MMP12 is implicated in large-artery atherosclerotic stroke, functionally by enhancing elastin degradation and macrophage invasion in plaques. PMID- 28734078 TI - Associations between adolescent cannabis use and neuropsychological decline: a longitudinal co-twin control study. AB - AIMS: This study tested whether adolescents who used cannabis or met criteria for cannabis dependence showed neuropsychological impairment prior to cannabis initiation and neuropsychological decline from before to after cannabis initiation. DESIGN: A longitudinal co-twin control study. SETTING AND PARTICIPANTS: Participants were 1989 twins from the Environmental Risk (E-Risk) Longitudinal Twin Study, a nationally representative birth cohort of twins born in England and Wales from 1994 to 1995. MEASUREMENTS: Frequency of cannabis use and cannabis dependence were assessed at age 18. Intelligence quotient (IQ) was obtained at ages 5, 12 and 18. Executive functions were assessed at age 18. FINDINGS: Compared with adolescents who did not use cannabis, adolescents who used cannabis had lower IQ in childhood prior to cannabis initiation and lower IQ at age 18, but there was little evidence that cannabis use was associated with IQ decline from ages 12-18. For example, adolescents with cannabis dependence had age 12 and age 18 IQ scores that were 5.61 (t = -3.11, P = 0.002) and 7.34 IQ points (t = -5.27, P < 0.001) lower than adolescents without cannabis dependence, but adolescents with cannabis dependence did not show greater IQ decline from age 12-18 (t = -1.27, P = 0.20). Moreover, adolescents who used cannabis had poorer executive functions at age 18 than adolescents who did not use cannabis, but these associations were generally not apparent within twin pairs. For example, twins who used cannabis more frequently than their co-twin performed similarly to their co-twin on five of six executive function tests (Ps > 0.10). The one exception was that twins who used cannabis more frequently than their co-twin performed worse on one working memory test (Spatial Span reversed; beta = -0.07, P = 0.036). CONCLUSIONS: Short-term cannabis use in adolescence does not appear to cause IQ decline or impair executive functions, even when cannabis use reaches the level of dependence. Family background factors explain why adolescent cannabis users perform worse on IQ and executive function tests. PMID- 28734080 TI - Transumbilical laparoendoscopic single-site radical prostatectomy and cystectomy with the aid of a transurethral port: a feasibility study. AB - OBJECTIVE: To describe the surgical technique and report early outcomes of transurethral assisted laparoendoscopic single-site (LESS) radical prostatectomy (RP) and LESS radical cystectomy (RC) in a single institution. MATERIALS AND METHODS: Between December 2014 and March 2016, a total of 114 LESS RPs and RCs were performed, comprising 68 LESS RPs, 38 LESS RCs with cutaneous ureterostomy (CU) and eight LESS RCs with orthotopic ileal neobladder (OIN). Access was achieved via a single-port, with four channels placed through a transumblical incision. After the apex of prostate was separated from the urethra, a self developed port ('Zhu's port') was inserted through the urethra to facilitate resection of prostate and urethrovesical anastomosis. The peri-operative and postoperative data were collected and analysed retrospectively. Patients were followed up postoperatively for evidence of long-term side effects. RESULTS: All the procedures were completed successfully. No conversion to conventional laparoscopic surgery was necessary. For LESS RP, the average operating time was 152 min. Estimated blood loss was 117 mL. The mean hospital stay was 16.4 days after surgery. For LESS RC with CU and LESS RC with OIN, the mean operating times were 215 and 328 min, mean estimated blood loss was 175 and 252 mL, and mean hospital stay was 9.4 and 18.2 days, respectively. Six patients required blood transfusion (5.26%). Intra-operative complications occurred in two patients (1.75%), and postoperative complications in nine (7.89%). Fourteen out of 68 (20.6%) patients who underwent LESS RP had positive surgical margins. Follow-up ranged from 10 to 30.6 months. In the prostate cancer cases, good urinary control was observed in 35.3%, 97.1% and 100% of patients at 1, 6 and 12 months after the operation, respectively, while biochemical recurrence was observed in 11.8% patients. In the bladder cancer cases, two patients had local recurrence and two patients had distant metastasis. CONCLUSION: Our results showed that LESS RP and LESS RC are feasible and safe with the aid of a transurethral port. Operating through the transurethral port might overcome the challenges posed by the single port laparoscopic approach. PMID- 28734079 TI - Post-translational palmitoylation controls the voltage gating and lipid raft association of the CALHM1 channel. AB - KEY POINTS: Calcium homeostasis modulator 1 (CALHM1), a new voltage-gated ATP- and Ca2+ -permeable channel, plays important physiological roles in taste perception and memory formation. Regulatory mechanisms of CALHM1 remain unexplored, although the biophysical disparity between CALHM1 gating in vivo and in vitro suggests that there are undiscovered regulatory mechanisms. Here we report that CALHM1 gating and association with lipid microdomains are post translationally regulated through the process of protein S-palmitoylation, a reversible attachment of palmitate to cysteine residues. Our data also establish cysteine residues and enzymes responsible for CALHM1 palmitoylation. CALHM1 regulation by palmitoylation provides new mechanistic insights into fine-tuning of CALHM1 gating in vivo and suggests a potential layer of regulation in taste and memory. ABSTRACT: Emerging roles of CALHM1, a recently discovered voltage gated ion channel, include purinergic neurotransmission of tastes in taste buds and memory formation in the brain, highlighting its physiological importance. However, the regulatory mechanisms of the CALHM1 channel remain entirely unexplored, hindering full understanding of its contribution in vivo. The different gating properties of CALHM1 in vivo and in vitro suggest undiscovered regulatory mechanisms. Here, in searching for post-translational regulatory mechanisms, we discovered the regulation of CALHM1 gating and association with lipid microdomains via protein S-palmitoylation, the only reversible lipid modification of proteins on cysteine residues. CALHM1 is palmitoylated at two intracellular cysteines located in the juxtamembrane regions of the third and fourth transmembrane domains. Enzymes that catalyse CALHM1 palmitoylation were identified by screening 23 members of the DHHC protein acyltransferase family. Epitope tagging of endogenous CALHM1 proteins in mice revealed that CALHM1 is basally palmitoylated in taste buds in vivo. Functionally, palmitoylation downregulates CALHM1 without effects on its synthesis, degradation and cell surface expression. Mutation of the palmitoylation sites has a profound impact on CALHM1 gating, shifting the conductance-voltage relationship to more negative voltages and accelerating the activation kinetics. The same mutation also reduces CALHM1 association with detergent-resistant membranes. Our results comprehensively uncover a post-translational regulation of the voltage-dependent gating of CALHM1 by palmitoylation. PMID- 28734081 TI - Whitening-dependent changes of fluorescence of extracted human teeth. AB - OBJECTIVE: To evaluate in vitro the fluorescence properties of extracted human teeth whitened with 40% hydrogen peroxide. MATERIALS AND METHODS: A total of 28 extracted human teeth were pumiced for 1 minute using a low-speed dental handpiece and a disposable rubber cup. Pre-whitening fluorescence measurements (T0), maximum excitation (Exmax ), maximum emission (Emmax ), and maximum intensity (Imax 108 ), were performed using a spectrofluorometer. After T0 measurements, the teeth were whitened using the in-office method with 40% hydrogen peroxide, three times for 20 minutes. The fluorescence parameters were measured under the same conditions 7 and 14 days after bleaching (T1 and T2, respectively). RESULTS: Exmax exhibited a broader range 7 days after whitening and decreased after 14 days. The Emmax and Imax 108 displayed a narrower range after whitening. The mean Exmax differed significantly between the time points (F = 20.09. P < .001). The corresponding analysis for the mean Emmax differed significantly between the time points (F = 16.69, P < .001). The same was true for the mean Imax 108 (F = 9.69, P < .001). CONCLUSIONS: Within the limitations of this study, whitening provoked statistically significant changes in fluorescence of the intact teeth in vitro. CLINICAL SIGNIFICANCE: The appearance of human teeth and dental materials and their changes upon aging and exposure to different agents (staining, whitening) is a topic of great relevance to esthetic dentistry. While some appearance parameters, such as color, translucency, and gloss, have been thoroughly studied, fluorescence and its influence on overall tooth appearance is still not well understood, yet it has influenced the development of fluorescence emitting restorative materials. PMID- 28734082 TI - Differential protein expression in exosomal samples taken from trauma patients. PMID- 28734083 TI - Highly Selective and Efficient Ring Hydroxylation of Alkylbenzenes with Hydrogen Peroxide and an Osmium(VI) Nitrido Catalyst. AB - The OsVI nitrido complex, OsVI (N)(quin)2 (OTs) (1, quin=2-quinaldinate, OTs=tosylate), is a highly selective and efficient catalyst for the ring hydroxylation of alkylbenzenes with H2 O2 at room temperature. Oxidation of various alkylbenzenes occurs with ring/chain oxidation ratios ranging from 96.7/3.3 to 99.9/0.1, and total product yields from 93 % to 98 %. Moreover, turnover numbers up to 6360, 5670, and 3880 can be achieved for the oxidation of p-xylene, ethylbenzene, and mesitylene, respectively. Density functional theory calculations suggest that the active intermediate is an OsVIII nitrido oxo species. PMID- 28734084 TI - Thrombolysis for pulmonary embolism using the superficial veins of the upper extremity. AB - This report describes a novel approach of accessing the superficial veins of the upper extremity for the treatment of pulmonary emboli (PE) with an ultrasound enhanced thrombolytic infusion catheter. In a patient suffering from saddle PE and impending right heart failure, separate basilic and cephalic venous access sites in the right arm were utilized to insert EKOS EndoWave Infusion Catheter (EKOS Corporation, Bothell, WA) insertion in each pulmonary artery (PA). This technique could be advantageous, particularly for patients at high risk for access site complications and those unable to lie supine for prolonged duration of infusion therapy. PMID- 28734085 TI - Novel menadione hybrids: Synthesis, anticancer activity, and cell-based studies. AB - A series of novel menadione-based triazole hybrids were designed and synthesized by employing copper-catalyzed azide-alkyne cycloaddition (CuAAC). All the synthesized hybrids were characterized by their spectral data (1 H NMR, 13 C NMR, IR, and HRMS). The synthesized compounds were evaluated for their anticancer activity against five selected cancer cell lines including lung (A549), prostate (DU-145), cervical (Hela), breast (MCF-7), and mouse melanoma (B-16) using MTT assay. The screening results showed that majority of the synthesized compounds displayed significant anticancer activity. Among the tested compounds, the triazoles 5 and 6 exhibited potent activity against all cell lines. In particular, compound 6 showed higher potency than the standard tamoxifen and parent menadione against MCF-7 cell line. Flow cytometric analysis revealed that compound 6 arrested cell cycle at G0/G1 phase and induced apoptotic cell death which was further confirmed by Hoechst staining, measurement of mitochondrial membrane potential (DeltaPsim) and Annexin-V-FITC assay. Thus, compound 6 can be considered as lead molecule for further development as potent anticancer therapeutic agent. PMID- 28734086 TI - The role of serum hyaluronic acid determination in the diagnosis of liver fibrosis. AB - The common pathway leading to liver fibrosis and cirrhosis is growing deposition of extracellular matrix (ECM). It results from molecular and histological rearrangement of collagens, glycoproteins and hyaluronans. Hyaluronic acid is a chief component of the extracellular matrix of connective tissues and plays the main structural role in the formation of ECM. The most important organ involved in the synthesis of hyaluronic acid is the liver. In this paper the meaning of hyaluronic acid in the diagnostics of liver diseases is discussed. Here, we focus on the described changes of hyaluronic acid concentration in the pathological processes of the liver, including alcoholic and non-alcoholic liver diseases. The results of published clinical studies have shown its high diagnostic sensitivity, which probably enables its application in laboratory diagnosis. PMID- 28734087 TI - Density dependence governs when population responses to multiple stressors are magnified or mitigated. AB - Population endangerment typically arises from multiple, potentially interacting anthropogenic stressors. Extensive research has investigated the consequences of multiple stressors on organisms, frequently focusing on individual life stages. Less is known about population-level consequences of exposure to multiple stressors, especially when exposure varies through life. We provide the first theoretical basis for identifying species at risk of magnified effects from multiple stressors across life history. By applying a population modeling framework, we reveal conditions under which population responses from stressors applied to distinct life stages are either magnified (synergistic) or mitigated. We find that magnification or mitigation critically depends on the shape of density dependence, but not the life stage in which it occurs. Stressors are always magnified when density dependence is linear or concave, and magnified or mitigated when it is convex. Using Bayesian numerical methods, we estimated the shape of density dependence for eight species across diverse taxa, finding support for all three shapes. PMID- 28734089 TI - Dementia risk and prevention by targeting modifiable vascular risk factors. AB - The incidence of dementia is expected to double in the next 20 years and will contribute to heavy social and economic burden. Dementia is caused by neuronal loss that leads to brain atrophy years before symptoms manifest. Currently, no cure exists and extensive efforts are being made to mitigate cognitive impairment in late life in order to reduce the burden on patients, caregivers, and society. The most common type of dementia, Alzheimer's disease (AD), and vascular dementia (VaD) often co-exists in the brain and shares common, modifiable risk factors, which are targeted in numerous secondary prevention trials. There is a growing need for non-pharmacological interventions and infrastructural support from governments to encourage psychosocial and behavioral interventions. Secondary prevention trials need to be redesigned based on the risk profile of individual subjects, which require the use of validated and standardized clinical, biological, and neuroimaging biomarkers. Multi-domain approaches have been proposed in high-risk populations that target optimal treatment; clinical trials need to recruit individuals at the highest risk of dementia before symptoms develop, thereby identifying an enriched disease group to test preventative and disease modifying strategies. The underlying aim should be to reduce microscopic brain tissue loss by modifying vascular and lifestyle risk factors over a relatively short period of time, thus optimizing the opportunity for preventing dementia in the future. Collaboration between international research groups is of key importance to the optimal use and allocation of existing resources, and the development of new techniques in preventing dementia. This article is part of the Special Issue "Vascular Dementia". PMID- 28734088 TI - The stability of baseline-defined categories of alcohol consumption during the adult life-course: a 28-year prospective cohort study. AB - BACKGROUND AND AIMS: Studies that report the relationship between alcohol consumption and disease risk have predominantly operationalized drinking according to a single baseline measure. The resulting assumption of longitudinal stability may be simplistic and complicate interpretation of risk estimates. This study aims to describe changes to the volume of consumption during the adult life course according to baseline categories of drinking. DESIGN: A prospective observational study. SETTING: United Kingdom. PARTICIPANTS: A cohort of British civil servants totalling 6838 men and 3372 women aged 34-55 years at baseline, followed for a mean 19.1 (standard deviation = 9.5) years. MEASUREMENTS: The volume of weekly alcohol consumption was estimated from data concerning the frequency and number of drinks consumed. Baseline categories were defined: non current drinkers, infrequent drinkers, 0.1-50.0 g/week, 50.1-100.0 g/week, 100.1 150.0 g/week, 150.1-250.0 g/week and >250.0 g/week. For women, the highest category was defined as > 100.0 g/week. Baseline frequency was derived as 'daily or almost daily' and 'not daily or almost daily'. Trajectories were estimated within baseline categories using growth curve models. FINDINGS: Trajectories differed between men and women, but were relatively stable within light-to moderate categories of baseline consumption. Drinking was least stable within the highest categories of baseline consumption (men: > 250.0 g/week; women: > 100.0 g/week), declining by 47.0 [95% confidence interval (CI) = 40.7, 53.2] and 16.8 g/week (95% CI = 12.6, 21.0), respectively, per 10-year increase in age. These declines were not a consequence of sudden transitions to complete abstention. Rates of decline appear greatest in older age, with trajectories converging toward moderate volumes. CONCLUSION: Among UK civil servants, consumption within baseline drinking categories is generally stable during the life-course, except among heavier baseline drinkers, for whom intakes decline with increasing age. This shift does not appear to be driven by transitions to non-drinking. Cohorts of older people may be at particular risk of misclassifying former heavy drinkers as moderate consumers of alcohol. PMID- 28734090 TI - Sleep duration and progression to diabetes in people with prediabetes defined by HbA1c concentration. AB - AIMS: To evaluate the association between sleep duration and the risk of progression to diabetes among people with prediabetes, defined by HbA1c values. METHODS: We conducted a cohort study in 17 983 adults who underwent health check up examinations, including assessments of sleep duration and quality. Diabetes was defined as either HbA1c >=48 mmol/mol (6.5%), or the use of antidiabetic medication. Time-dependent proportional hazards models were used to evaluate the association between sleep duration and the risk of progression to diabetes. RESULTS: During 31,582 person-years of follow-up, 664 incident cases of diabetes were identified; the incidence rate was 21.0 per 1000 person-years. The multivariate adjusted hazard ratios for progression to diabetes in people with sleep durations of <=5, 6 and >=8 h compared with 7 h were 1.68 (95% CI 1.30 2.16), 1.44 (95% CI 1.17-1.76) and 1.23 (95% CI 0.85-1.78), respectively (P for quadratic trend <0.001). This association was partially mediated by biomarkers of adiposity, fatty liver and insulin resistance. CONCLUSION: In this large study in young and middle-aged adults with prediabetes, we found an association between short sleep duration and the risk of progression to diabetes. Our findings suggest that sufficient sleep duration is important for delaying or preventing the progression of prediabetes to diabetes. PMID- 28734092 TI - Disentangling the role of seed bank and dispersal in plant metapopulation dynamics using patch occupancy surveys. AB - In plants, the presence of a seed bank challenges the application of classical metapopulation models to aboveground presence surveys; ignoring seed bank leads to overestimated extinction and colonization rates. In this article, we explore the possibility to detect seed bank using hidden Markov models in the analysis of aboveground patch occupancy surveys of an annual plant with limited dispersal. Patch occupancy data were generated by simulation under two metapopulation sizes (N = 200 and N = 1,000 patches) and different metapopulation scenarios, each scenario being a combination of the presence/absence of a 1-yr seed bank and the presence/absence of limited dispersal in a circular 1-dimension configuration of patches. In addition, because local conditions often vary among patches in natural metapopulations, we simulated patch occupancy data with heterogeneous germination rate and patch disturbance. Seed bank is not observable from aboveground patch occupancy surveys, hence hidden Markov models were designed to account for uncertainty in patch occupancy. We explored their ability to retrieve the correct scenario. For 10 yr surveys and metapopulation sizes of N = 200 or 1,000 patches, the correct metapopulation scenario was detected at a rate close to 100%, whatever the underlying scenario considered. For smaller, more realistic, survey duration, the length for a reliable detection of the correct scenario depends on the metapopulation size: 3 yr for N = 1,000 and 6 yr for N = 200 are enough. Our method remained powerful to disentangle seed bank from dispersal in the presence of patch heterogeneity affecting either seed germination or patch extinction. Our work shows that seed bank and limited dispersal generate different signatures on aboveground patch occupancy surveys. Therefore, our method provides a powerful tool to infer metapopulation dynamics in a wide range of species with an undetectable life form. PMID- 28734091 TI - Prediction of alcohol use disorder using personality disorder traits: a twin study. AB - BACKGROUND AND AIMS: The DSM-IV personality disorders (PDs) are comorbid with alcohol use disorder (AUD) and with each other. It remains unclear which PD criteria are most likely to drive onset and recurrence of AUD and which are merely confounded with those criteria. We determine which individual PD criteria predict AUD and the degree of underlying genetic and/or environmental aetiology. DESIGN: A prospective observational twin study. SETTING: Norway 1999-2011. PARTICIPANTS: A total of 2528 and 2275 Norwegian adult twins in waves 1 and 2 variable-selection analyses, and 2785 in biometric analyses. MEASUREMENTS: DSM-IV PDs and their 80 criteria were assessed using a structured personal interview, and AUD using the World Health Organization's Composite International Diagnostic Interview. FINDINGS: In a variable-selection analysis, two PD criteria were associated with AUD even after taking all the other criteria into account: criterion 8 of antisocial PD (childhood conduct disorder) and criterion 4 of borderline PD (self-damaging impulsive behaviours). Adjusting for each other, their respective odds ratios were 3.4 [confidence interval (CI) = 2.1-5.4] and 5.0 (CI = 3.3-7.7). Endorsement strength of the criteria was associated with AUD in a dose-response manner and they explained 5.5% of variation in AUD risk-more than the full diagnoses of antisocial and borderline PDs together (0.5%). The association between borderline criterion 4 and AUD 10 years later derived mainly from their overlapping genetic factors, whereas the association between antisocial criterion 8 and AUD 10 years later was due to both genetic and non genetic factors. CONCLUSIONS: Conduct disorder and self-harming impulsivity are the foremost risk traits for alcohol use disorder among the 80 personality disorder criteria of DSM-IV, predicting alcohol use disorder more effectively than personality disorder diagnoses. The twin-study analysis suggested that conduct disorder represents a joint genetic and developmental risk for alcohol use disorder and that impulsivity is a genetic risk. PMID- 28734094 TI - Moving alcohol prevention research forward-Part I: introducing a complex systems paradigm. AB - BACKGROUND AND AIMS: The drinking environment is a complex system consisting of a number of heterogeneous, evolving and interacting components, which exhibit circular causality and emergent properties. These characteristics reduce the efficacy of commonly used research approaches, which typically do not account for the underlying dynamic complexity of alcohol consumption and the interdependent nature of diverse factors influencing misuse over time. We use alcohol misuse among college students in the United States as an example for framing our argument for a complex systems paradigm. METHODS: A complex systems paradigm, grounded in socio-ecological and complex systems theories and computational modeling and simulation, is introduced. Theoretical, conceptual, methodological and analytical underpinnings of this paradigm are described in the context of college drinking prevention research. RESULTS: The proposed complex systems paradigm can transcend limitations of traditional approaches, thereby fostering new directions in alcohol prevention research. By conceptualizing student alcohol misuse as a complex adaptive system, computational modeling and simulation methodologies and analytical techniques can be used. Moreover, use of participatory model-building approaches to generate simulation models can further increase stakeholder buy-in, understanding and policymaking. CONCLUSIONS: A complex systems paradigm for research into alcohol misuse can provide a holistic understanding of the underlying drinking environment and its long-term trajectory, which can elucidate high-leverage preventive interventions. PMID- 28734095 TI - Increased trend in the incidence of diabetes among youths in the USA during 2002 2012. AB - The current SEARCH Study concludes that the incidence of both type 1 and type 2 diabetes among youths in the United States increased significantly over the period 2002-2012, particularly in minority racial and ethnic groups. Environmental and behavioral factors play an important role in developing both types of diabetes. PMID- 28734093 TI - Scaling-up HCV prevention and treatment interventions in rural United States model projections for tackling an increasing epidemic. AB - BACKGROUND AND AIMS: Effective strategies are needed to address dramatic increases in hepatitis C virus (HCV) infection among people who inject drugs (PWID) in rural settings of the United States. We determined the required scale up of HCV treatment with or without scale-up of HCV prevention interventions to achieve a 90% reduction in HCV chronic prevalence or incidence by 2025 and 2030 in a rural US setting. DESIGN: An ordinary differential equation model of HCV transmission calibrated to HCV epidemiological data obtained primarily from an HIV outbreak investigation in Indiana. SETTING: Scott County, Indiana (population 24 181), USA, a rural setting with negligible baseline interventions, increasing HCV epidemic since 2010, and 55.3% chronic HCV prevalence among PWID in 2015. PARTICIPANTS: PWID. MEASUREMENTS: Required annual HCV treatments per 1000 PWID (and initial annual percentage of infections treated) to achieve a 90% reduction in HCV chronic prevalence or incidence by 2025/30, either with or without scaling up syringe service programmes (SSPs) and medication-assisted treatment (MAT) to 50% coverage. Sensitivity analyses considered whether this impact could be achieved without re-treatment of re-infections, and whether greater intervention scale-up was required due to the increasing epidemic in this setting. FINDINGS: To achieve a 90% reduction in incidence and prevalence by 2030, without MAT and SSP scale-up, 159 per 1000 PWID (initially 24.9% of infected PWID) need to be HCV treated annually. However, with MAT and SSP scaled-up, treatment rates are halved (89 per 1000 annually or 14.5%). To reach the same target by 2025 with MAT and SSP scaled-up, 121 per 1000 PWID (19.9%) need treatment annually. These treatment requirements are threefold higher than if the epidemic was stable, and the impact targets are unattainable without retreatment. CONCLUSIONS: Combined scale-up of hepatitis C virus treatment and prevention interventions is needed to decrease the increasing burden of hepatitis C virus incidence and prevalence in rural Indiana, USA, by 90% by 2025/30. PMID- 28734096 TI - Association of Toxoplasma gondii infection with schizophrenia and its relationship with suicide attempts in these patients. AB - OBJECTIVES: To investigate the association between schizophrenia and Toxoplasma gondii, and to assess the association of infection with suicide attempts and age of onset of schizophrenia in these patients. METHODS: Case-control study Fars Province, southern Iran. Cases were individuals with psychiatric diagnosis of schizophrenia as per Diagnostic and Statistical Manual of Mental Disorders (DSM IV) criteria. Controls were healthy blood donors, frequency-matched with patients according to age and sex. For the detection of IgG antibodies, enzyme-linked immunosorbent assay (ELISA) was used. Data about demographic information in all subjects and duration of illness and history of suicide attempts in patients with schizophrenia were collected using a brief questionnaire and hospital records. Chi-square test and multivariable logistic regression were used for statistical analyses. RESULTS: Among 99 cases, 42 individuals (42%) were positive for T. gondii antibody, vs. 41 (27%) among 152 controls (OR = 2, 95% CI: 1.2-3.4, P = 0.012). We compared the suicide attempts in patients with schizophrenia based on their T. gondii serologic status. There was a lower rate of suicide attempts in seropositive male patients than seronegative ones (OR = 0.3, 95% CI: 0.1-0.97, P = 0.04). Age of onset of schizophrenia did not differ between T. gondii-infected and non-infected patients. CONCLUSIONS: These findings may have implications for schizophrenia and suicide prevention programmes. However, clearly further studies are required to confirm them. PMID- 28734097 TI - First report of Ser653Asn mutation endowing high-level resistance to imazamox in downy brome (Bromus tectorum L.). AB - BACKGROUND: Bromus tectorum L. is one of the most troublesome grass weed species in cropland and non-cropland areas of the northwestern USA. In summer 2016, a B. tectroum accession (R) that survived imazamox at the field-use rate (44 g ha-1 ) in an imidazolinone-tolerant (IMI-tolerant or ClearfieldTM) winter wheat field was collected from a wheat field in Carter County, MT, USA. The aim of this study was to determine the resistance profile of the B. tectroum R accession to imazamox and other ALS inhibitors, and investigate the mechanism of resistance to imazamox. RESULTS: The R B. tectorum accession had a high-level resistance (110.1 fold) to imazamox (IMI) and low to moderate-levels cross-resistance to pyroxsulam (TP) (4.6-fold) and propoxycarbazone (SCT) (13.9-fold). The R accession was susceptible to sulfosulfuron (SU) and quizalofop and clethodim (ACCase inhibitors), paraquat (PS I inhibitor), glyphosate (EPSPS inhibitor) and glufosinate (GS inhibitor). Sequence analysis of the ALS gene revealed a single, target-site Ser653Asn mutation in R plants. Pretreatment of malathion followed by imazamox at 44 or 88 g ha-1 did not reverse the resistance phenotype. CONCLUSION: This is the first report of evolution of cross-resistance to ALS-inhibiting herbicides in B. tectorum. A single-point mutation, Ser653Asn, was identified, conferring the high-level resistance to imazamox. (c) 2017 Society of Chemical Industry. PMID- 28734098 TI - Proliferating trichilemmal cyst of the mamma. PMID- 28734099 TI - Measuring the social impact of dental research: An insight into the most influential articles on the Web. AB - OBJECTIVES: To identify the most discussed dental articles on the Web and to assess the association between the intensity of online attention, publication characteristics, and citations. MATERIALS AND METHODS: An Altmetric Explorer search was conducted for articles published in the 91 dental journals included in 2015 InCitesTM Journal Citation Report(r) and mentioned online at all times. The 100 articles with the highest online attention, as measured by the "Altmetric Attention Score" (AAS), were screened for journal title, quartile of impact factor distribution (Q1-Q4), publication date, origin and affiliation of first author, article topic, type, and access. Citation counts were harvested from Scopus. RESULTS: The top 100 articles presented a median AAS of 119 and were mostly discussed on news outlets, Twitter, and Mendeley. Forty-one articles were published in Q1 journals, 24 in Q2 journals, 32 in Q3 journals, and three in Q4 journals. AAS was significantly higher in articles of Q2 journals (median AAS = 398, range = 70-513) than in articles of Q1. A weak reverse correlation existed between AAS and time since publication (r = -.25, p < .05). No correlation was detected between AAS and other publication characteristics or number of citations. CONCLUSIONS: Increased social impact of dental articles is not significantly associated with high citation rates. PMID- 28734100 TI - Oxygenation of Simple Olefins through Selective Allylic C-C Bond Cleavage: A Direct Approach to Cinnamyl Aldehydes. AB - A novel metal-free allylic C-C sigma-bond cleavage of simple olefins to give valuable cinnamyl aldehydes is reported. 1,2-Aryl or alkyl migration through allylic C-C bond cleavage occurs in this transformation, which is assisted by an alkyl azide reagent. This method enables O-atom incorporation into simple unfunctionalized olefins to construct cinnamyl aldehydes. The reaction features simple hydrocarbon substrates, metal-free conditions, and high regio- and stereoselectivity. PMID- 28734101 TI - HLA-B*40:356, identified by next-generation sequence based typing in a Chinese tuberculosis patient. AB - HLA-B*40:356 differs from B*40:02:01 by only one nucleotide transition, C>A 1040 in exon 6. PMID- 28734102 TI - Are electromagnetic fields in incubators a risk factor for autism? PMID- 28734103 TI - Levels of wound calprotectin and other inflammatory biomarkers aid in deciding which patients with a diabetic foot ulcer need antibiotic therapy (INDUCE study). AB - AIMS: Deciding if a diabetic foot ulcer is infected in a community setting is challenging without validated point-of-care tests. Four inflammatory biomarkers were investigated to develop a composite algorithm for mildly infected diabetic foot ulcers: venous white cell count, C-reactive protein (CRP) and procalcitonin, and a novel wound exudate calprotectin assay. Calprotectin is a marker of neutrophilic inflammation. METHODS: In a prospective study, people with uninfected or mildly infected diabetic foot ulcers who had not received oral antibiotics in the preceding 2 weeks were recruited from community podiatry clinics for measurement of inflammatory biomarkers. Antibiotic prescribing decisions were based on clinicians' baseline assessments and participants were reviewed 1 week later; ulcer infection was defined by clinicians' overall impression from their two assessments. RESULTS: Some 363 potential participants were screened, of whom 67 were recruited, 29 with mildly infected diabetic foot ulcers and 38 with no infection. One participant withdrew early in each group. Ulcer area was 1.32 cm2 [interquartile range (IQR) 0.32-3.61 cm2 ] in infected ulcers and 0.22 cm2 (IQR 0.09-1.46 cm2 ) in uninfected ulcers. Baseline CRP for mild infection was 9.00 mg/ml and 6.00 mg/ml for uninfected ulcers; most procalcitonin levels were undetectable. Median calprotectin level in infected diabetic foot ulcers was 1437 ng/ml and 879 ng/ml in uninfected diabetic foot ulcers. Area under the receiver operating characteristic curve for a composite algorithm incorporating calprotectin, CRP, white cell count and ulcer area was 0.68 (95% confidence intervals 0.52-0.82), sensitivity 0.64, specificity 0.81. CONCLUSIONS: A composite algorithm including CRP, calprotectin, white cell count and ulcer area may help to distinguish uninfected from mildly infected diabetic foot ulcers. Venous procalcitonin is unhelpful for mild diabetic foot ulcer infection. PMID- 28734105 TI - Effects of Median Nerve Neural Mobilization in Treating Cervicobrachial Pain: A Randomized Waiting List-Controlled Clinical Trial. AB - BACKGROUND: There is a current lack of sufficiently high-quality randomized controlled clinical trials that measure the effectiveness of neural tissue mobilization techniques such as median nerve neural mobilization (MNNM) and their specific effects on cervicobrachial pain (CP). The aim of this study was to compare the effectiveness of MNNM in subjects with CP vs. a waiting list control group (WLCG). METHODS: A single-blinded, parallel, randomized controlled clinical trial was performed (NCT02596815). Subjects were recruited with a medical diagnosis of CP corroborated by magnetic resonance imaging. In total, 156 individuals were screened, 60 subjects were recruited, and 51 completed the trial. Pain intensity reported using the Numeric Rating Scale for Pain (NRSP; primary outcome), cervical range of motion (CROM), and functionality using the Quick Disabilities of the Arm, Shoulder and Hand (QuickDASH) scale were the outcome measurements. Assessments were conducted at baseline and 1 hour after treatment (intervention days 1, 15, and 30). Therefore, MNNM was implemented with 30 days of follow-up. RESULTS: The NRSP values of the MNNM group were significantly (P < 0.0001; 95% confidence interval [CI]) superior to those obtained in the WLCG. Subjects treated with MNNM reported an NRSP decrease of 3.08 points at discharge. CROM and QuickDASH outcome values were significantly (P ? 0.0001; 95% CI) improved only in the MNNM group. Hedges' g showed a very large effect of the MNNM intervention. CONCLUSION: MNNM may be superior to no treatment in reducing pain and increasing function in the affected upper limbs of subjects with CP. PMID- 28734104 TI - Predictors of early renal function decline in adults with Type 1 diabetes: the Coronary Artery Calcification in Type 1 Diabetes and the Pittsburgh Epidemiology of Diabetes Complications studies. AB - AIM: Diabetic kidney disease is one of the leading complications of Type 1 diabetes, but its prediction remains a challenge. We examined predictors of rapid decline in estimated GFR (eGFR) in two Type 1 diabetes cohorts: the Coronary Artery Calcification in Type 1 Diabetes (CACTI) and the Pittsburgh Epidemiology of Diabetes Complications (EDC). METHODS: A select subset of participants (CACTI: n = 210 and EDC: n = 98) diagnosed before 17 years of age with Type 1 diabetes duration >= 7 years, and follow-up data on eGFR by CKD-EPI creatinine for up to 8 years were included in the analyses. Early renal function decline was defined as annual decline in eGFR >= 3 ml/min/1.73 m2 , and normal age-related decline as eGFR <= 1 ml/min/1.73 m2 . Parallel logistic regression models were constructed in the two cohorts. RESULTS: Early renal function decline incidence was 36% in CACTI and 41% in EDC. In both cohorts, greater baseline eGFR (CACTI: OR 3.12, 95% CI 1.97-5.05; EDC: OR 1.92, 95% CI 1.17-3.15 per 10 ml/min/1.73 m2 ) and log albumin-to-creatinine (ACR) (CACTI: OR 3.24, 95% CI 1.80-5.83; EDC: OR 1.87, 95% CI 1.18-2.96 per 1 unit) predicted greater odds of early renal function decline in fully adjusted models. Conversely, ACE inhibition predicted lower odds of early renal function decline in women in CACTI, but similar relationships were not observed in women in EDC. CONCLUSIONS: A substantial proportion of people with Type 1 diabetes in the EDC and CACTI cohorts experienced early renal function decline over time. ACE inhibition appeared to be protective only in women in CACTI where the prevalence of its use was twofold higher compared with the EDC. PMID- 28734106 TI - Insecticide resistance in Trialeurodes vaporariorum populations and novel diagnostics for kdr mutations. AB - BACKGROUND: Neonicotinoids, pyrethroids and ketoenols are currently used for the control of Trialeurodes vaporariorum (Hemiptera: Aleyrodidae). In this study, insecticide resistance status and mechanisms were investigated using classical bioassays and molecular techniques. RESULTS: Dose-response bioassays were performed on 19 Greek populations, among the 35 different whitefly populations used for the whole analysis. Resistance factors scaled up to 207-, 4657- and 59 fold for imidacloprid, bifenthrin and spiromesifen, respectively. Molecular assays were used to investigate the frequency of known resistance mutations. A simple polymerase chain reaction-restriction fragment length polymorphism (PCR RFLP) assay was developed for detecting the pyrethroid-resistant alleles r1 (mutation L925I) and r2 (mutation T929I) of the para-type voltage-gated sodium channel gene (VGSC). Both alleles were present at high frequencies (on average 65% and 33%, respectively) in 14 populations from Greece. The M918 L pyrethroid resistance mutation was not detected in any of the Greek populations. Sequencing and a Taqman allelic discrimination were used to monitor the frequency of the mutation E645K of the acetyl-coenzyme A carboxylase gene (ACC) recently linked to spiromesifen resistance. This mutation was detected in 20 of the 24 populations examined in ~38% frequency among the 433 individuals tested. However, its association with the spiromesifen resistance phenotype was not confirmed in the Greek populations. Finally, two homologues of the CYP6CM1 Bemisia tabaci P450, the known neonicotinoid metabolizer, were found upregulated in two T. vaporariorum neonicotinoid-resistant populations; they were both functionally expressed in Escherichia coli, but the recombinant proteins encoded did not metabolize those neonicotinoid insecticides tested. CONCLUSION: The development of simple diagnostics and their use alongside classical and molecular techniques for the early detection of resistant populations are of great importance for pest management strategies. The practical implications of our results are discussed in light of whitefly control. (c) 2017 Society of Chemical Industry. PMID- 28734108 TI - Detection of a novel HLA-A*11 variant, A*11:263, in a Taiwanese individual. AB - One nucleotide substitution at residue 998 of HLA-A*11:01:01:01 results in a novel allele, HLA-A*11:263. PMID- 28734107 TI - Extended-release naltrexone for methamphetamine dependence among men who have sex with men: a randomized placebo-controlled trial. AB - BACKGROUND AND AIMS: Methamphetamine use is increasingly prevalent and associated with HIV transmission. Early-phase human studies suggested naltrexone reduced amphetamine use among dependent individuals. We tested if extended-release naltrexone (XRNTX) reduces methamphetamine use and associated sexual risk behaviors among high-risk methamphetamine-dependent men who have sex with men (MSM). DESIGN: Double-blind, placebo-controlled, randomized trial of XRTNX versus placebo over 12 weeks from 2012 to 2015. SETTING: San Francisco Department of Public Health, California, USA. PARTICIPANTS: One hundred community-recruited, sexually-active, actively-using methamphetamine-dependent MSM. Mean age was 43.2 years; 96% were male, 3% transfemale, and 1% transmale; 55.0% were white, 19.0% African American, and 18.0% Latino. INTERVENTIONS: XRNTX 380 mg (n = 50) or matched placebo (n = 50) administered by gluteal injection at 4-week intervals. MEASUREMENTS: Regression estimated average level and change in level of positive urines during the period 2-12 weeks (primary outcomes) and sexual risk behaviors (secondary outcome). FINDINGS: Ninety per cent of visits were completed. By intent-to-treat, participants assigned to XRNTX had similar differences during 2 12 weeks in methamphetamine-positive urines as participants assigned to placebo [incidence rate ratio (IRR) = 0.95, 95% confidence interval (CI) = 0.76-1.20; Bayes factor < 0.3]. Observed urine positivity declined from 78 to 70% in the XRNTX arm and 74 to 64% in the placebo arm. Adherence to injections was 96.7% in the XRNTX arm and 91.3% in the placebo arm. Sexual risk behaviors declined similarly among participants in both arms (all P > 0.05). There were no serious adverse events related to study drug and no differences in frequency of adverse events by treatment arm. CONCLUSIONS: Notwithstanding very high medication adherence for this study, extended-release naltrexone does not appear to reduce methamphetamine use or sexual risk behaviors among methamphetamine-dependent men who have sex with men compared with placebo. PMID- 28734109 TI - The cost of oropharyngeal cancer in England: A retrospective hospital data analysis. AB - OBJECTIVES: To estimate the total costs of treating head and neck cancers, specifically oropharyngeal, laryngeal and oral cavity cancer, in secondary care facilities in England during the period 2006/2007 to 2010/2011. DESIGN: Patient records were extracted from an English hospital database to estimate the number of patients treated for oropharyngeal, laryngeal and oral cavity cancer in England. Identified resource use was linked to published United Kingdom cost estimates to quantify the reimbursement of treatment through the Payment by Results system. SETTING: Retrospective hospital data analysis. PARTICIPANTS: From the hospital data, patient records of patients treated for oropharyngeal, laryngeal and oral cavity cancer were selected. MAIN OUTCOME MEASURES: Annual total costs of treatment, stratified by inpatient and outpatient setting and by male and female patients. RESULTS: From 2006/2007 to 2010/2011, total costs of treatment across the three head and neck cancer sites were estimated to be approximately L309 million, with 90% attributable to inpatient care (bundled costs). Oropharyngeal cancer accounted for 37% of total costs. Costs and patient numbers increased over time, largely due to a rise in oropharyngeal cancer, where total costs increased from L17.21 million to L30.32 million, with over 1400 (52%) more inpatients treated in 2010/11 compared to 2006/07. CONCLUSIONS: In 4 years, the number of patients with oropharyngeal cancer receiving some form of inpatient care increased by more than half, and associated costs increased by three quarters. This reinforces the case for prevention and early detection strategies to help contain this epidemiological and economic burden. PMID- 28734110 TI - When can refuges mediate the genetic effects of fire regimes? A simulation study of the effects of topography and weather on neutral and adaptive genetic diversity in fire-prone landscapes. AB - Understanding how landscape heterogeneity mediates the effects of fire on biodiversity is increasingly important under global changes in fire regimes. We used a simulation experiment to investigate how fire regimes interact with topography and weather to shape neutral and selection-driven genetic diversity under alternative dispersal scenarios, and to explore the conditions under which microrefuges can maintain genetic diversity of populations exposed to recurrent fire. Spatial heterogeneity in simulated fire frequency occurred in topographically complex landscapes, with fire refuges and fire-prone "hotspots" apparent. Interannual weather variability reduced the effect of topography on fire patterns, with refuges less apparent under high weather variability. Neutral genetic diversity was correlated with long-term fire frequency under spatially heterogeneous fire regimes, being higher in fire refuges than fire-prone areas, except under high dispersal or low fire severity (low mortality). This generated different spatial genetic structures in fire-prone and fire-refuge components of the landscape, despite similar dispersal. In contrast, genetic diversity was only associated with time since the most recent fire in flat landscapes without predictable refuges and hotspots. Genetic effects of selection driven by fire related conditions depended on selection pressure, migration distance and spatial heterogeneity in fire regimes. Allele frequencies at a locus conferring higher fitness under successional environmental conditions followed a pattern of "temporal adaptation" to contemporary conditions under strong selection pressure and high migration. However, selected allele frequencies were correlated with spatial variation in long-term mean fire frequency (relating to environmental predictability) under weak dispersal, low selection pressure and strong spatial heterogeneity in fire regimes. PMID- 28734112 TI - Fused multivariate empirical mode decomposition (MEMD) and inverse solution method for EEG source localization. AB - EEG source localization is determining possible cortical sources of brain activities with scalp EEG. Generally, every step of the data processing sequence affects the accuracy of EEG source localization. In this paper, we introduce a fused multivariate empirical mode decomposing (MEMD) and inverse solution algorithm with an embedded unsupervised eye blink remover in order to localize the epileptogenic zone accurately. For this purpose, we constructed realistic forward models using MRI and boundary element method (BEM) for each patient to obtain results that are more realistic. We also developed an unsupervised algorithm utilizing a wavelet method to remove eye blink artifacts. Additionally, we applied MEMD, which is one of the recent and suitable feature extraction methods for non-linear, non-stationary, and multivariate signals such as EEG, to extract the signal of interest. We examined the localization results using the two most reliable linear distributed inverse methods in the literature: weighted minimum norm estimation (wMN) and standardized low resolution tomography (sLORETA). Results affirm the success of the proposed algorithm with the highest agreement compared to MRI reference by a specialist. Fusion of MEMD and sLORETA results in approximately zero localization error in terms of spatial difference with the validated MRI reference. High accuracy results of proposed algorithm using non-invasive and low-resolution EEG provide the potential of using this work for pre-surgical evaluation towards epileptogenic zone localization in clinics. PMID- 28734111 TI - Adult interest in using a hypothetical modified risk tobacco product: findings from wave 1 of the Population Assessment of Tobacco and Health Study (2013-14). AB - BACKGROUND AND AIMS: The US Family Smoking Prevention and Tobacco Control Act provides a pathway for manufacturers to market a modified risk tobacco product (MRTP). This study examines socio-demographic and tobacco use correlates of interest in a hypothetical MRTP in a nationally representative sample of US adults. DESIGN: Cross sectional wave 1 data from the 2013-14 Population Assessment of Tobacco and Health (PATH) Study. SETTING: Household Audio-Computer Assisted Self-Interviews of US adults conducted in 2013-14. PARTICIPANTS: A total of 32 320 civilian, non-institutionalized adults in the United States. MEASUREMENTS: Interest in using a hypothetical MRTP ('If a tobacco product made a claim that it was less harmful to health than other tobacco products, how likely would you be to use that product?'), socio-demographics, tobacco use history and mental health and substance use problems. All estimates were weighted. FINDINGS: Overall, 16.7% [95% confidence interval (CI) = 16.28, 17.18] of US adults reported interest in a hypothetical MRTP. Tobacco use was associated significantly with interest in a hypothetical MRTP, with interest most common among current established smokers (54.4%; 95% CI = 53.31, 55.39) and least common among never tobacco users (3.0%; 95% CI = 2.49, 3.55). Interest in a hypothetical MRTP was associated with experimental e-cigarette use among current experimental, current established and former smokers. Among non-smokers, race, age, education and substance use were associated with interest in using a hypothetical MRTP. CONCLUSIONS: Among adults in the United States, interest in using a hypothetical modified risk tobacco product is low overall, and highest among current experimental and established smokers. A small percentage of non-smokers are interested in using a hypothetical hypothetical modified risk tobacco product. PMID- 28734113 TI - OpenICE medical device interoperability platform overview and requirement analysis. AB - We give an overview of OpenICE, an open source implementation of the ASTM standard F2761 for the Integrated Clinical Environment (ICE) that leverages medical device interoperability, together with an analysis of the clinical and non-functional requirements and community process that inspired its design. PMID- 28734114 TI - Effects of pomegranate peel extract on histopathology, testosterone levels and sperm of testicular torsion-detorsion induced in adult Wistar rats. AB - : Background In the present study, effects of pomegranate peel extract have been evaluated on decreasing the damage induced by testis torsion. Methods In this study, 30 adult Wistar rats were randomly divided into three groups of control, experimental (1) and experimental (2). CONTROL: no ischemia, received vehicle alone, exposed to sham operation. Experimental (1): Received the vehicle alone during ischemia followed by 60 days' reperfusion. Experimental (2): After performing ischemia reperfusion, 500 mg/kg of pomegranate peel extract has been used for 60 days. Blood samples and sperm samples were collected. Testes were harvested and stained with haematoxylin and eosin to study the structure of seminiferous tubules. Results The statistical comparison between sperm count and their viability and testosterone hormone amount showed a significant difference between control and experimental (1) groups and control and experimental (2) groups. The results showed an improvement of morphological condition of seminiferous tubules. Conclusions Pomegranate peel extract has revealed desirable changes on the effective parameters in infertility. PMID- 28734115 TI - Regularized estimation in sparse high-dimensional multivariate regression, with application to a DNA methylation study. AB - In this article, we consider variable selection for correlated high dimensional DNA methylation markers as multivariate outcomes. A novel weighted square-root LASSO procedure is proposed to estimate the regression coefficient matrix. A key feature of this method is tuning-insensitivity, which greatly simplifies the computation by obviating cross validation for penalty parameter selection. A precision matrix obtained via the constrained l1 minimization method is used to account for the within-subject correlation among multivariate outcomes. Oracle inequalities of the regularized estimators are derived. The performance of our proposed method is illustrated via extensive simulation studies. We apply our method to study the relation between smoking and high dimensional DNA methylation markers in the Normative Aging Study (NAS). PMID- 28734117 TI - Hybrid piezoresistive-optical tactile sensor for simultaneous measurement of tissue stiffness and detection of tissue discontinuity in robot-assisted minimally invasive surgery. AB - To compensate for the lack of touch during minimally invasive and robotic surgeries, tactile sensors are integrated with surgical instruments. Surgical tools with tactile sensors have been used mainly for distinguishing among different tissues and detecting malignant tissues or tumors. Studies have revealed that malignant tissue is most likely stiffer than normal. This would lead to the formation of a sharp discontinuity in tissue mechanical properties. A hybrid piezoresistive-optical-fiber sensor is proposed. This sensor is investigated for its capabilities in tissue distinction and detection of a sharp discontinuity. The dynamic interaction of the sensor and tissue is studied using finite element method. The tissue is modeled as a two-term Mooney-Rivlin hyperelastic material. For experimental verification, the sensor was microfabricated and tested under the same conditions as of the simulations. The simulation and experimental results are in a fair agreement. The sensor exhibits an acceptable linearity, repeatability, and sensitivity in characterizing the stiffness of different tissue phantoms. Also, it is capable of locating the position of a sharp discontinuity in the tissue. Due to the simplicity of its sensing principle, the proposed hybrid sensor could also be used for industrial applications. PMID- 28734116 TI - Preparing Platelet-Rich Plasma with Whole Blood Harvested Intraoperatively During Spinal Fusion. AB - BACKGROUND Platelet-rich plasma (PRP) has gained growing popularity in use in spinal fusion procedures in the last decade. Substantial intraoperative blood loss is frequently accompanied with spinal fusion, and it is unknown whether blood harvested intraoperatively qualifies for PRP preparation. MATERIAL AND METHODS Whole blood was harvested intraoperatively and venous blood was collected by venipuncture. Then, we investigated the platelet concentrations in whole blood and PRP, the concentration of growth factors in PRP, and the effects of PRP on the proliferation and viability of human bone marrow-derived mesenchymal stem cells (HBMSCs). RESULTS Our results revealed that intraoperatively harvested whole blood and whole blood collected by venipuncture were similar in platelet concentration. In addition, PRP formulations prepared from both kinds of whole blood were similar in concentration of platelet and growth factors. Additional analysis showed that the similar concentrations of growth factors resulted from the similar platelet concentrations of whole blood and PRP between the two groups. Moreover, these two kinds of PRP formulations had similar effects on promoting cell proliferation and enhancing cell viability. CONCLUSIONS Therefore, intraoperatively harvested whole blood may be a potential option for preparing PRP spinal fusion. PMID- 28734118 TI - The perniciousness of perfectionism: A meta-analytic review of the perfectionism suicide relationship. AB - OBJECTIVE: Over 50 years of research implicates perfectionism in suicide. Yet the role of perfectionism in suicide needs clarification due to notable between-study inconsistencies in findings, underpowered studies, and uncertainty about whether perfectionism confers risk for suicide. We addressed this by meta-analyzing perfectionism's relationship with suicide ideation and attempts. We also tested whether self-oriented, other-oriented, and socially prescribed perfectionism predicted increased suicide ideation, beyond baseline ideation. METHOD: Our literature search yielded 45 studies (N = 11,747) composed of undergraduates, medical students, community adults, and psychiatric patients. RESULTS: Meta analysis using random effects models revealed perfectionistic concerns (socially prescribed perfectionism, concern over mistakes, doubts about actions, discrepancy, perfectionistic attitudes), perfectionistic strivings (self-oriented perfectionism, personal standards), parental criticism, and parental expectations displayed small-to-moderate positive associations with suicide ideation. Socially prescribed perfectionism also predicted longitudinal increases in suicide ideation. Additionally, perfectionistic concerns, parental criticism, and parental expectations displayed small, positive associations with suicide attempts. CONCLUSIONS: Results lend credence to theoretical accounts suggesting self-generated and socially based pressures to be perfect are part of the premorbid personality of people prone to suicide ideation and attempts. Perfectionistic strivings' association with suicide ideation also draws into question the notion that such strivings are healthy, adaptive, or advisable. PMID- 28734119 TI - A systematic review of patient oncofertility support needs in reproductive cancer patients aged 14 to 45 years of age. AB - OBJECTIVE: Decline in fertility potential brought about by a cancer diagnosis or cancer treatment is one of the biggest impacts to cancer patients' long-term quality of life. As such, the current manuscript aimed to systematically review the literature on oncofertility support needs for cancer patients of a reproductive age (14-45 years of age). METHODS: A systematic review of the literature was conducted in May 2016 through the searching of electronic databases Medline, EMBASE, PSYCH Info, Web of Science and SCOPUS, alongside the screening of relevant reference lists. An initial search identified 351 potentially relevant studies. The papers were divided into 2 categories; papers on patient oncofertility support needs were reviewed for this systematic review, and papers on clinician provision of oncofertility support were reviewed for a separate systematic review. RESULTS: A total of 30 studies were included within the final review. Support needs were categorised as information, service, clinician-patient interactions, psychological, and family. A number of studies indicated that cancer patients place great important on their oncofertility care and have unmet support needs. Patients were satisfied and felt supported when additional care was taken to ensure fertility information and service needs were met. CONCLUSIONS: Patients desire for clinicians to support their concerns through the provision of adequate information, access to oncofertility services, taking time to discuss oncofertility treatment and concerns, specialised psychological support, and responsiveness to individual needs. PMID- 28734120 TI - Continuation of nonselective beta-blockers for patients with liver cirrhosis and hemodynamic nonresponse? PMID- 28734121 TI - The impact of chronic psychiatric disorders on cognitive decline. AB - OBJECTIVES: Based on seemingly contradictory results in the existing literature, the objective of our study was to investigate whether older individuals suffering from chronic psychiatric disorders show a more rapid decline in cognitive performances than their non-psychiatric counterparts, or if the pattern of decline through older age is similar in both groups. METHOD: A total of 820 older adults were selected from the Ageing Multidisciplinary Investigation (AMI) cohort study, which studies health-related issues of people over 65 years old living in rural areas. Among them, 30 suffer from chronic psychiatric disorders. Cognition was assessed with four neuropsychological tests: the Mini-Mental State Examination, the Digit Symbol Substitution Test, the Free and Cued Selective Reminding test and the Isaacs Set Test. Linear mixed models were used to compare the evolution of cognitive performances in the two groups between baseline and the four-year follow-up. RESULTS: Despite lower performances at baseline, the pattern of cognitive decline of the psychiatric group is similar to that of the control group. CONCLUSION: As suggested by this study conducted in rural communities, community-dwelling people suffering from chronic psychiatric disorders should not be considered at greater risk of age-related accelerated cognitive decline than the non-psychiatric older population. PMID- 28734122 TI - Portal venous stenosis following liver transplant: Role of transsplenic intervention. PMID- 28734123 TI - Transplant for the very sick: No limitations in donor quality? PMID- 28734124 TI - Steatotic donor livers: Where is the risk-benefit maximized? PMID- 28734125 TI - A systematic review and meta-analysis of cold in situ perfusion and preservation of the hepatic allograft: Working toward a unified approach. AB - The efficacy of cold in situ perfusion and static storage of the liver is a possible determinant of transplantation outcomes. The aim of this study was to determine whether there is evidence to substantiate a preference for a particular perfusion route (aortic or dual) or perfusion/preservation solution in donation after brain death (DBD) liver transplantation. The Embase, MEDLINE, and Cochrane databases were used (1980-2017). Random effects modeling was used to estimate effects on transplantation outcomes based on (1) aortic or dual in situ perfusion and (2) the use of University of Wisconsin (UW), histidine tryptophan ketoglutarate (HTK), Celsior, and/or Institut Georges Lopez-1 (IGL-1) solutions for perfusion/preservation. A total of 22 articles were included (2294 liver transplants). The quality of evidence ranged from very low to moderate Grading of Recommendations, Assessment, Development and Evaluations score. Meta-analyses were conducted for 14 eligible studies. Although there was no difference in the primary nonfunction (PNF) rate, a higher peak alanine aminotransferase (ALT) was recorded in dual compared with aortic-only UW-perfused livers (standardized mean difference, 0.24; 95% confidence interval, 0.01-0.47); a back-table portal venous flush was undertaken in the majority of aortic-only perfused livers. There were no relevant differences in peak enzymes, PNF, thrombotic graft loss, biliary complications, or 1-year graft survival in comparisons between dual-perfused livers using UW, HTK, Celsior, or IGL-1. In conclusion, there is no significant evidence that aortic-only perfusion of the DBD liver compromises transplantation outcomes, and it may be favored because of its simplicity. However, there is currently insufficient evidence to advocate for the use of any particular perfusion/preservation fluid over the others. Liver Transplantation 23 1615-1627 2017 AASLD. PMID- 28734126 TI - German EstSmoke: estimating adult smoking-related costs and consequences of smoking cessation for Germany. AB - AIMS: We compared predicted life-time health-care costs for current, never and ex smokers in Germany under the current set of tobacco control polices. We compared these economic consequences of the current situation with an alternative in which Germany were to implement more comprehensive tobacco control policies consistent with the World Health Organization (WHO) Framework Convention for Tobacco Control (FCTC) guidelines. DESIGN: German EstSmoke, an adapted version of the UK EstSmoke simulation model, applies the Markov modelling approach. Transition probabilities for (re-)currence of smoking-related diseases were calculated from large German disease-specific registries and the German Health Update (GEDA 2010). Estimations of both health-care costs and effect sizes of smoking cessation policies were taken from recent German studies and discounted at 3.5%/year. SETTING: Germany. PARTICIPANTS: German population of prevalent current, never and ex-smokers in 2009. MEASUREMENT: Life-time cost and outcomes in current, never and ex-smokers. FINDINGS: If tobacco control policies are not strengthened, the German smoking population will incur ?41.56 billion life-time excess costs compared with never smokers. Implementing tobacco control policies consistent with WHO FCTC guidelines would reduce the difference of life-time costs between current smokers and ex-smokers by at least ?1.7 billion. CONCLUSIONS: Modelling suggests that the life-time healthcare costs of people in Germany who smoke are substantially greater than those of people who have never smoked. However, more comprehensive tobacco control policies could reduce health-care expenditures for current smokers by at least 4%. PMID- 28734127 TI - Fecal microbiota transplantation for hepatic encephalopathy: Ready for prime time? PMID- 28734129 TI - Largest reported orbital solitary fibrous tumour. PMID- 28734128 TI - The experience of initiating injection drug use and its social context: a qualitative systematic review and thematic synthesis. AB - BACKGROUND AND AIM: Understanding the experience of initiating injection drug use and its social contexts is crucial to inform efforts to prevent transitions into this mode of drug consumption and support harm reduction. We reviewed and synthesized existing qualitative scientific literature systematically to identify the socio-structural contexts for, and experiences of, the initiation of injection drug use. METHODS: We searched six databases (Medline, Embase, PsychINFO, CINAHL, IBSS and SSCI) systematically, along with a manual search, including key journals and subject experts. Peer-reviewed studies were included if they qualitatively explored experiences of or socio-structural contexts for injection drug use initiation. A thematic synthesis approach was used to identify descriptive and analytical themes throughout studies. RESULTS: From 1731 initial results, 41 studies reporting data from 1996 participants were included. We developed eight descriptive themes and two analytical (higher-order) themes. The first analytical theme focused on injecting initiation resulting from a social process enabled and constrained by socio-structural factors: social networks and individual interactions, socialization into drug-using identities and choices enabled and constrained by social context all combine to produce processes of injection initiation. The second analytical theme addressed pathways that explore varying meanings attached to injection initiation and how they link to social context: seeking pleasure, responses to increasing tolerance to drugs, securing belonging and identity and coping with pain and trauma. CONCLUSIONS: Qualitative research shows that injection drug use initiation has varying and distinct meanings for individuals involved and is a dynamic process shaped by social and structural factors. Interventions should therefore respond to the socio structural influences on injecting drug use initiation by seeking to modify the contexts for initiation, rather than solely prioritizing the reduction of individual harms through behavior change. PMID- 28734130 TI - Right lobe living donors ages 55 years old and older in liver transplantation. AB - The evidence is insufficient for safe use of elderly donors in adult-to-adult living donor liver transplantation (LDLT). The aim of this study was to evaluate the outcomes of right lobe LDLT by donor age (>=55 versus < 55 years). All living donors who underwent right hepatectomy at the authors' institution between March 2008 and December 2015 were divided into 2 groups: group A with an age >= 55 years and group B with an age of <55 years. The selection criteria for elderly donor were preservation of middle hepatic vein, remnant liver volume >=30%, and no or mild fatty liver. The matching criteria of recipients for the elderly donor grafts were Model for End-Stage Liver Disease score of <25, graft-to-recipient weight ratio of >0.8%, and body mass index of <25 kg/m2 . Perioperative data, complications by the Clavien classification, and the outcomes with at least 12 months follow-up were compared. A total of 42 donors were enrolled in group A and 498 in group B. No significant differences in operative parameters were observed between the 2 groups. The peak postoperative aspartate aminotransferase, alanine aminotransferase, and total bilirubin levels made no difference between the 2 groups. The peak international normalized ratio level was significantly lower in group A than in group B (P = 0.001). All donors recovered completely with no significant differences in overall complications between the 2 groups. All recipients of grafts from donors in group A showed good initial function with no significant differences in 1-year graft and patient survival or biliary complications between 2 groups. These results provide clinical evidence for feasibility of right hepatectomy in living donors aged >= 55 years without compromising donor safety or recipient outcomes. Liver Transplantation 23 1305 1311 2017 AASLD. PMID- 28734131 TI - Changes in health-related quality of life in older candidates waiting for kidney transplantation. AB - AIM: There is limited available knowledge regarding health-related quality of life (HRQoL) in older patients with chronic kidney disease. We aimed to describe HRQoL in renal transplant candidates 65 years or older at transplant acceptance, and during the first year on the waiting list. METHODS: A nationwide prospective observational study in Norway was conducted. HRQoL was evaluated at baseline (wait listing) and after 6 and 12 months using the patient self-reported Kidney Disease and Quality of Life Short form version 1.3. Intra-individual scores at different times were evaluated. Generic HRQoL was compared with scores from an age-matched Norwegian population. RESULTS: From January 2013 to November 2016, 261 patients >=65 years accepted for deceased donor kidney transplantation were included. Mean age at inclusion was 71.1 years, 67% male and 69% were on dialysis. HRQoL sum scores significantly decreased during the first year on the waiting list. Physical, mental and kidney disease component summary score reduced from 39.6 to 38.1 (P = 0.045), 48.8 to 44.7 (P < 0.001) and 72.1 to 70.2 (P = 0.03), respectively. When evaluating each domain separately, only the decrease in social function was clinically significant. Age and being on dialysis were the most important predictors for low HRQoL. Compared to the age-matched general population, males had significant lower HRQoL scores. Females were comparable to the general female population at baseline except in general health and vitality. CONCLUSIONS: HRQoL in older patients waiting for kidney transplantation decreases during the first year on the waiting list, but only the change in social function is clinically significant. PMID- 28734132 TI - High-dimensional single cell mapping of cerium distribution in the lung immune microenvironment of an active smoker. AB - BACKGROUND: Mass cytometry leverages inductively coupled mass spectrometry to perform high dimensional single cell analyses using antibodies tagged with rare earth isotopes that are considered to be largely absent in biological samples. We have recently noted an unusual exception to this rule while analyzing tissue samples from patients undergoing surgical resection for early stage lung cancer, and here we present a detailed cytometric characterization of cerium in a clinical patient sample. METHODS: We performed a CyTOF analysis on cell suspensions derived from matched blood, tumor lesion, and non-involved lung tissue from an active smoker undergoing surgical resection for early stage lung adenocarcinoma. The samples were stained with a 31-parameter antibody panel to allow a detailed characterization of the cellular heterogeneity of the samples. The data were visualized using viSNE, major immune subsets were identified based on canonical marker expression patterns, and single cell cerium levels were evaluated across each of these defined subsets. RESULTS: High dimensional immune cell mapping revealed that high levels of cerium were specifically associated with a phenotypically distinct subset of lung macrophages that were most prevalent in noninvolved lung tissue, whereas tumor associated macrophages showed relatively lower levels of cerium. We hypothesize that these findings reflect alveolar macrophage phagocytosis of inhaled cerium derived from cigarette flint lighters. CONCLUSIONS: These results demonstrate the first high-dimensional single cell characterization of environmental metal exposure associated with smoking, and offer a demonstration of the unique potential for applying mass cytometry to the field of environmental toxicology. (c) 2017 International Clinical Cytometry Society. PMID- 28734133 TI - Physicians' self-reported practice behaviour regarding fertility-related discussions in paediatric oncology in Sweden. AB - OBJECTIVE: The aim of this study was to investigate practice behaviours of Swedish physicians with regard to discussing the impact of cancer treatment on fertility with paediatric oncology patients and their parents, and to identify factors associated with such discussions. METHODS: A cross-sectional survey study was conducted targeting all physicians in Sweden working in paediatric oncology care settings. Participants responded to a questionnaire measuring practice behaviour, attitudes, barriers, and confidence in knowledge. Multivariable logistic regression was used to determine factors associated with seldom discussing fertility. RESULTS: More than half of the physicians routinely talked with their patients/parents about the treatment's potential impact on fertility (male patients: 62%; female patients: 57%; P = 0.570). Factors associated with less frequently discussing fertility with patients/parents were working at a non university hospital (male patients: OR 11.49, CI 1.98-66.67; female patients: OR 33.18, CI 4.06-271.07), concerns that the topic would cause worry (male patients: OR 8.23, CI 1.48-45.89; female patients: OR 12.38, CI 1.90-80.70), and perceiving the parents as anxious (male patients: OR 7.18, CI 1.20-42.85; female patients: OR 11.65, CI 1.32-103.17). CONCLUSIONS: Based on our findings, we recommend structured training in how to communicate about fertility issues in stressful situations, which in turn might increase fertility-related discussions in paediatric oncology. PMID- 28734134 TI - The role of maternal elaborative structure and control in children's memory and suggestibility for a past event. AB - In this investigation, preschool-aged children experienced a staged event about which their mothers received misinformation suggesting that their children witnessed an activity that did not occur. Later, mothers were asked to talk about this event with their children. Consistent with previous research, mothers' provision of structure (defined as elaborative questions and statements) and degree of control (defined in terms of functional control of conversational turns) emerged as separate dimensions of maternal memory sharing style. When later interviewed by an unfamiliar examiner about the event, children whose mothers demonstrated both high structure and high control provided the highest levels of false reports of the activity suggested to mothers and generously embellished their accounts of this activity with nonoccurring details. In contrast, children with mothers who provided low structure, regardless of their degree of control, made few false reports and used sparse narrative detail. The implications of these findings for children's memory and suggestibility are discussed. PMID- 28734135 TI - Folding while bound to chaperones. AB - Chaperones are important in preventing protein aggregation and aiding protein folding. How chaperones aid protein folding remains a key question in understanding their mechanism. The possibility of proteins folding while bound to chaperones was reintroduced recently with the chaperone Spy, many years after the phenomenon was first reported with the chaperones GroEL and SecB. In this review, we discuss the salient features of folding while bound in the cases for which it has been observed and speculate about its biological importance and possible occurrence in other chaperones. PMID- 28734136 TI - The good and bad of targeting cancer-associated extracellular matrix. AB - The maintenance of tissue homeostasis requires extracellular matrix (ECM) remodeling. Immune cells actively participate in regenerating damaged tissues contributing to ECM deposition and shaping. Dysregulated ECM deposition characterizes fibrotic diseases and cancer stromatogenesis, where a chronic inflammatory state sustains the ECM increase. In cancer, the ECM fosters several steps of tumor progression, providing pro-survival and proliferative signals, promoting tumor cell dissemination via collagen fibers or acting as a barrier to impede drug diffusion. Interfering with processes leading to chronic ECM deposition, as occurring in cancer, might allow the simultaneous targeting of both primary tumors and metastatic lesions. However, a note of caution comes from data showing that defective ECM deposition is associated with an exacerbated inflammatory and autoimmune phenotype and to lymphomagenesis. Immune cells display ITIM-inhibitory receptors recognizing collagens as counter ligands, which negatively regulate the immune response. This is in line with the idea that ECM components can provide homeostatic signals to immune cells to regulate and prevent unwanted activation, a concept particularly relevant in cancer where these mechanisms could be in place to keep infiltrating immune cells in a suppressive pro-tumoral state. In this context, the pharmacological targeting of myeloid cells, for which both direct and indirect roles in ECM deposition have been shown, can be a relevant option to this purpose. PMID- 28734137 TI - Precision targeting by phosphoinositides: how PIs direct endomembrane trafficking in plants. AB - Each phosphoinositide (PI, also known as phosphatidylinositol phosphate, polyphosphoinositide, PtdInsP or PIP) species is partitioned in the endomembrane system and thereby contributes to the identity of membrane compartments. However, membranes are in constant flux within this system, which raises the questions of how the spatiotemporal pattern of phosphoinositides is established and maintained within the cell. Here, we review the general mechanisms by which phosphoinositides and membrane trafficking feedbacks on each other to regulate cellular patterning. We then use the specific examples of polarized trafficking, endosomal sorting and vacuolar biogenesis to illustrate these general concepts. PMID- 28734138 TI - Ghrelin plasma concentration does not covary with energy demand in adult laying hens. AB - The peptide hormone ghrelin is suggested to be involved in food intake regulation in young growing chicken. Whether ghrelin is involved in the regulation of energetic balance associated with laying performance in adult laying hens was studied by use of 4 chicken lines that differ in laying performance and phylogeny (4 lines; 16 hens per line). As housing conditions are also known to affect energy demand, half of the hens per line were housed in single cages and the other half of hens were maintained in a floor housing system. Plasma samples were collected at 17 to 19, 33 to 35, 49 to 51, and 72 wk of age and analyzed with a chicken ghrelin ELISA Kit. From caged hens, individual food consumption and laying performance additionally was recorded. Due to its function in growth and its relationship with ghrelin, also GH plasma concentrations were analyzed. Ghrelin concentrations did not differ between the 4 lines at any of the test periods (all P > 0.05). Ghrelin was negatively related to food consumption only in the growing period of the high-performing lines (both P < 0.0001). During this phase, floor-housed hens showed greater ghrelin concentrations compared with caged hens (P < 0.0001). Our results suggest that in adult layers ghrelin is not involved in regulating energy intake related to laying performance but rather seems to be related to body growth and housing condition before start of lay, the latter possibly due to differences in hens' behavioral activity. PMID- 28734139 TI - Iotanfluenza A(H3N2) genetic variants in vaccinated patients in northern Greece. AB - BACKGROUND: Influenza A(H3N2) viruses predominated during the influenza 2016/2017 season and showed extensive genetic diversification. A high vaccination failure rate was noticed during the 2016/17 season in Greece, especially among the elderly. OBJECTIVES: The scope of the study was to investigate the genetic characteristics of A(H3N2) circulating viruses and viruses detected in vaccinated patients. STUDY DESIGN: Virus samples originated from vaccinated and unvaccinated patients, obtained at the National Influenza Centre for northern Greece. Phylogenetic analysis and comparison of the haemagglutinin gene of the viruses to the vaccine virus A/Hong Kong/4801/2014 was performed. RESULTS: The majority of analysed viruses are clustering in the genetic clade 3C.2a, and in a newly emerged subclade, designated as 3C.2a1. The highest proportion of viruses detected in vaccinated patients fell into a distinct subcluster within the 3C.2a1 subclade, which is characterised by the amino acid substitutions N122D and T135K in haemagglutinin. CONCLUSIONS: Viruses that belong to the 3C.2a clade are generally considered to resemble antigenically to the northern hemisphere vaccine component A/Hong Kong/4801/2014 that was recommended by WHO to be included also into the 2017/18 vaccine. However, viruses belonging to a specific 3C.2a1 subcluster was extensively circulating in northern Greece and among vaccinated individuals. Both substitutions carried by this strain were located on antigenic sites and caused losses of N-linked glycosylation sites of the virus, which could potentially affect viral antigenicity. Further studies are needed to determine the antigenicity of this variant strain and its possible implication in vaccine effectiveness. PMID- 28734140 TI - Deregulation of levels of angiopoietin-1 and angiopoietin-2 is associated with severe courses of hantavirus infection. AB - BACKGROUND: Hantavirus disease is characterized by endothelial dysfunction. Angiopoietin-1 (Ang-1) and its antagonist angiopoietin-2 (Ang-2) play a key role in the control of capillary permeability. Ang-1 is responsible for maintenance of cell-to-cell contacts whereas Ang-2 destabilizes monolayers. An imbalance of Ang 1 and Ang-2 levels results in enhanced permeability and capillary leakage. OBJECTIVES: To analyze the involvement of angiopoietins in hantavirus-induced disruption of endothelia, we measured the levels of Ang-1 and Ang-2 in hantavirus infection. STUDY DESIGN: Levels of angiopoietins of 31 patients with acute Puumala virus (PUUV) infection and a patient infected with Dobrava-Belgrade virus genotype Sochi (DOBV-Sochi) were analyzed. An age-matched group of 16 healthy volunteers served as control. The ratios of Ang-2 to Ang-1 levels were calculated and correlated with laboratory parameters. RESULTS: Patients with PUUV and DOBV Sochi infection exhibited elevated ratios of Ang-2/Ang-1 compared to the control group. The imbalance of Ang-2 to Ang-1 levels was observed early after onset of symptoms and lasted for the acute phase of infection. The deregulation in DOBV Sochi infection was more prominent than in PUUV infection. Analysis of Ang-2/Ang 1 ratio and laboratory parameters in the PUUV cohort revealed a positive correlation with serum creatinine and a negative correlation with serum albumin and thrombocyte levels. CONCLUSIONS: We observed an imbalance between levels of Ang-1 and Ang-2 in patients infected with PUUV and DOBV-Sochi. Elevated Ang-2/Ang 1 ratios correlate with disease severity. The virus-induced deregulation of angiopoietin levels may enhance capillary permeability and contribute to the pathogenesis of hantavirus disease. PMID- 28734141 TI - New dinuclear palladium(II) complexes: Studies of the nucleophilic substitution reactions, DNA/BSA interactions and cytotoxic activity. AB - Six new dinuclear Pd(II) complexes, [{Pd(2,2'-bipy)Cl}2(MU-pz)](ClO4)2 (Pd1), [{Pd(dach)Cl}2(MU-pz)](ClO4)2 (Pd2), [{Pd(en)Cl}2(MU-pz)](ClO4)2 (Pd3), [{Pd(2,2' bipy)Cl}2(MU-4,4'-bipy)](ClO4)2 (Pd4), [{Pd(dach)Cl}2(MU-4,4'-bipy)](ClO4)2 (Pd5) and [{Pd(en)Cl}2(MU-4,4'-bipy)](ClO4)2 (Pd6) (where 2,2'-bipy=2,2'-bipyridyl, pz=pyrazine, dach=trans-(+/-)-1,2-diaminocyclohexane, en=ethylenediamine, 4,4' bipy=4,4'-bipyridyl) have been synthesized and characterized by elemental microanalysis, IR, 1H NMR and MALDI-TOF mass spectrometry. The pKa values of corresponding diaqua complexes were determined by spectrophotometric pH titration. Substitution reactions with thiourea (Tu), l-methionine (l-Met), l cysteine (l-Cys), l-histidine (l-His) and guanosine-5'-monophosphate (5'-GMP) were studied under the pseudo-first order conditions at pH7.2. Reactions of Pd1 with Tu, l-Met and l-Cys were followed by decomposition of complexes, while structures of dinuclear complexes were preserved during the substitution with nitrogen donors. Interactions with calf-thymus DNA (CT-DNA) were followed by absorption spectroscopy and fluorescence quenching measurements. All complexes can bind to CT-DNA exhibiting high intrinsic binding constants (Kb=104-105M-1). Competitive studies with ethidium bromide (EB) have shown that complexes can displace DNA-bound EB. High values of binding constants towards bovine serum albumin protein (BSA) indicate good binding affinity. Finally, all complexes showed moderate to high cytotoxic activity against HeLa (human cervical epithelial carcinoma cell lines) and MDA-MB-231 (human breast epithelial carcinoma cell lines) tumor cell lines inducing apoptotic type cell death, whereas normal fibroblasts were significantly less sensitive. The impact on cell cycle of these cells was distinctive, where Pd4, Pd5 and Pd6 showed the most prominent effect arresting MDA-MB-231 (human lung fibroblast cell lines) cell in G1/S phase of cell cycle. PMID- 28734142 TI - Differences between genders in colorectal morphology on CT colonography using a quantitative approach: a pilot study. AB - PURPOSE: To explore quantitative differences between genders in morphologic colonic metrics and determine metric reproducibility. METHODS: Quantitative colonic metrics from 20 male and 20 female CTC datasets were evaluated twice by two readers; all exams were performed after incomplete optical colonoscopy. Intra /inter-reader reliability was measured with intraclass correlation coefficient (ICC) and concordance correlation coefficient (CCC). RESULTS: Women had overall decreased colonic volume, increased tortuosity and compactness and lower sigmoid apex height on CTC compared to men (p<0.0001,all). Quantitative measurements in colonic metrics were highly reproducible (ICC=0.9989 and 0.9970; CCC=0.9945). CONCLUSION: Quantitative morphologic differences between genders can be reproducibility measured. PMID- 28734143 TI - Cortical thickness changes in adult moyamoya disease assessed by structural magnetic resonance imaging. AB - PURPOSE: To characterize the changes in cortical thickness of adult patients with moyamoya disease (MMD). METHODS: 60 patients with MMD and 60 age and sex-matched healthy volunteers were recruited. Structural images were acquired by MRI. Freesurfer was used to measure cortical thickness in patients and controls, and this was compared with MRA scores and cerebrovascular accident (CVA) scores. RESULTS: Compared with controls, the average cortical thickness of both cerebral hemispheres was lower in patients than in controls and symmetrical differences were seen in the regional cortex: bilateral precentral gyri were thinner, bilateral postcentral gyri and posterior cingulate gyri were thicker, and thinning and thickening were both found in the insula. CVA scores were negatively correlated with the average cortical thicknesses. CONCLUSIONS: Cortical thickness can be used as a biological indicator to assess the severity of MMD. PMID- 28734145 TI - Colorectal cancer risk associated with the CHEK2 1100delC variant. PMID- 28734144 TI - Expression of planar cell polarity genes during mouse tooth development. AB - OBJECTIVE: Planar cell polarity (PCP) refers to the cell polarity across the tissue plane and controls various cell behaviors and structures. Although the expression of several PCP signaling components has been detected in tooth germs, knowledge of the gene expression patterns of these PCP components during tooth development remains incomplete. The aim of this study is to characterize the temporal and spatial changes in PCP gene expression during tooth development. DESIGN: Expression of Celsr1 and 2, Fzd3 and 6, Vangl1 and 2, and Dvl1-3 genes was analyzed in mouse molar germs from the bud to the bell stage using in situ hybridization. RESULTS: At the bud stage, all target genes were expressed in all areas of the tooth bud. In the enamel organ at the cap stage, expression of Fzd3 was suppressed in the enamel knot, whereas Fzd6 was strongly expressed there. Expression of Vangl2 was strongly expressed in the inner dental epithelium from the cap stage onwards. In the inner dental epithelium, strong expression of Fzd3, Dvl2 and Vangl2 was noted at the early bell stage, and of Celsr1, Fzd3, Fzd6, Vangl2 and Dvl2 at the bell stage. Furthermore, differentiated odontoblasts strongly expressed Celsr1, Vangl2, and Dvl2. CONCLUSION: The gene expression patterns delineated in this study improve our understanding of the role(s) of PCP components during tooth development. PMID- 28734146 TI - Diagnostic value of whole body diffusion-weighted MRI compared to computed tomography for pre-operative assessment of patients suspected for ovarian cancer. AB - BACKGROUND: Despite excellent per-lesion performance for peritoneal staging, the additional clinical value of diffusion-weighted magnetic resonance imaging (DWI/MRI) compared to computed tomography (CT) remains to be established in ovarian cancer. Our purpose was to evaluate whole body (WB)-DWI/MRI for diagnosis, staging and operability assessment of patients suspected for ovarian cancer compared to CT. METHODS: One hundred and sixty-one patients suspected for ovarian carcinoma underwent 3 T WB-DWI/MRI and contrast-enhanced CT. WB-DWI/MRI and CT were compared for confirmation of the malignant nature and primary origin of the ovarian mass, Federation Internationale de Gynecologie et d'Obstetrique (FIGO) staging and prediction of incomplete resection using institutional operability criteria. Interobserver agreement between two readers was determined for WB-DWI/MRI and CT. RESULTS: WB-DWI/MRI showed a significantly higher accuracy than CT (93 versus 82%, p = 0.001) to confirm the malignant nature of the ovarian mass and correctly identified 26 of 32 (81%) cancers of non-ovarian origin compared to 10/32 (31%) for CT (p < 0.001). WB-DWI/MRI assigned more ovarian carcinoma patients to the correct FIGO stage (82/94, 87%) compared with CT (33/94, 35%). For prediction of incomplete resection, WB-DWI/MRI showed significantly higher sensitivity (94 versus 66%), specificity (97.7 versus 77.3%) and accuracy (95.7 versus 71.3%) compared to CT (p < 0.001). Interobserver agreement was almost perfect (kappa = 0.90) for WB-DWI/MRI and moderate (kappa = 0.52) for CT for prediction of incomplete resection. CONCLUSIONS: WB-DWI/MRI was superior to CT for primary tumour characterisation, staging and prediction of incomplete resection in patients suspected for ovarian cancer. PMID- 28734147 TI - Rapid response of metastatic cutaneous squamous cell carcinoma to pembrolizumab in a patient with xeroderma pigmentosum: Case report and review of the literature. PMID- 28734148 TI - Apathy in early and late-life depression. AB - BACKGROUND: Late-life depression is thought to differ in clinical presentation from early-life depression. Particularly, late-life depression is considered to be more characterized by apathy than is early-life depression. Lacking convincing evidence, this study examines the presence and associated socio demographic/clinical characteristics of apathy in older compared to younger depressed persons. METHODS: This cross-sectional study used data from two naturalistic cohort studies, i.e. the Netherlands Study of Depression in Older Persons (NESDO) and the Netherlands Study of Depression and Anxiety (NESDA). These studies included 605 persons (aged 18-93 years) with a major depressive disorder, divided into 217 early-life (< 60 years) and 388 late-life (>= 60 years) depressed persons. Apathy was considered present if a score of >=14 on the Apathy Scale. RESULTS: Apathy was strongly associated with age: it was more frequently present in persons with late-life depression (74.5%) than in those with early-life depression (53.5%). Independent of age, the following characteristics were associated with the presence of apathy: male gender, low education, use of benzodiazepines, chronic diseases, and more severe depression. Of all potential risk factors, only former and current smoking was associated with the presence of apathy in older depressed persons but not in younger depressed persons (p-value for age interaction = 0.01). LIMITATIONS: No causal relationships can be drawn due to the cross-sectional design of the study. CONCLUSIONS: In depressed individuals, clinically relevant apathy was more frequently present in older compared to younger persons. Both age groups showed largely the same associated risk factors. Apathy was independently associated with older age, male gender and more severe depression. PMID- 28734149 TI - Discharge management strategies and post-discharge care interventions for depression - Systematic review and meta-analysis. AB - BACKGROUND: Patients with depression require treatment continuity when discharged from inpatient care. Interventions aimed at optimizing transition into outpatient care may be effective in preventing symptom deterioration and readmission. We aimed to evaluate the effectiveness of care transition interventions for patients with depression after psychiatric hospitalization. METHODS: Systematic review and random-effects meta-analysis of controlled trials. Primary outcomes were readmissions and symptoms of depression. The control condition was treatment as usual. RESULTS: We included 16 publications reporting the results of 13 different studies. Studies were heterogeneous concerning patient selection and interventional approach. Effects on readmissions and depression symptoms were non significant in meta-analysis of 8 studies/710 patients and 7 studies/592 patients, respectively. Overall risk ratio for readmission during follow-up was 0.65 (95% CI [0.42;1.01], p=0.06), standardized mean difference for depression symptoms was -0.09 (95% CI [-0.37;0.19], p=0.53). Subgroup analyses indicated no preference for a specific interventional strategy. Data point to considerable risk for selection and publication bias. LIMITATIONS: Included studies are heterogeneous; subgroups are often small and may not attain the power to detect effects. Reasonable classification of interventions into groups of comparable approaches was a challenge and may be arbitrary in some cases. CONCLUSIONS: This systematic review and meta-analysis could not identify any convincingly effective interventional transition approach for patients with depression after psychiatric hospitalization. Current evidence regarding discharge management for depression is limited, heterogeneous and potentially prone to bias. Interventions might be more appropriate for patients with other diagnoses than depression. Further high quality randomized studies are required. PMID- 28734150 TI - Growing Platinum-Ruthenium-Tin ternary alloy nanoparticles on reduced graphene oxide for strong ligand effect toward enhanced ethanol oxidation reaction. AB - Uniform Pt1Ru0.5Sn0.5 ternary alloy nanoparticles are in situ deposited on reduced graphene oxide (Pt1Ru0.5Sn0.5-RGO) through its functional groups and defects as nucleation sites to greatly electrocatalyze ethanol oxidation reaction for much higher mass current densities, larger apparent specific current densities and better stability than commercial Pt-C catalyst (Pt-C(commer)). Mechanistic studies indicate that the excellent electrocatalytic activity and anti-poisoning are resulted from a strong ligand effect of the ternary alloy components, in which the charge transfer is boosted while decreasing the density of states close to the Fermi level of Pt to reduce bond energy between Pt and CO like adsorbates for greatly improved anti-poisoning ability. This work holds a great promise to fabricate a high performance anode catalyst with a low Pt loading for direct ethanol fuel cells. PMID- 28734151 TI - Magnetically recyclable reduced graphene oxide nanosheets/magnetite-palladium aerogel with superior catalytic activity and reusability. AB - A two-step method was employed to synthesize reduced graphene oxide nanosheets/magnetite-palladium (rGSs/Fe3O4-Pd) aerogel, with excellent catalytic activity and recyclability. Firstly, graphene oxide nanosheet (GS) hydrogels were formed by the self-assembly of GSs during the hydrothermal process. Meanwhile, hematite (alpha-Fe2O3) and Pd nanoparticles (NPs) were synthesized and anchored onto the surface of the hydrogel. During heat-treatment, GSs were reduced to rGSs, while nonmagnetic alpha-Fe2O3NPs were converted to magnetic Fe3O4 NPs. The as-obtained rGSs/Fe3O4-Pd aerogel displayed a three-dimensional interconnected hierarchical porous architecture, which was rich in mesopores and macropores. Such a structure was suitable for catalysis, since it not only improved the mass diffusion and transport, but also readily exposed the catalytic Pd NPs to the reactants. The typical reduction of 4-nitrophenol was chosen as a model reaction to evaluate the catalytic performance of the aerogel. As anticipated, both the reaction rate constant and turn over frequency of the aerogel were much higher than those of the commercial Pd/C catalyst. Moreover, due to incorporation of Fe3O4 NPs, the rGSs/Fe3O4-Pd aerogel could be magnetically separated from the reaction solution and reused, without obvious loss of catalytic activity. PMID- 28734152 TI - Trajectories of alcohol use in the UK military and associations with mental health. AB - INTRODUCTION: There are higher levels of alcohol misuse in the military compared to the general population. Yet there is a dearth of research in military populations on the longitudinal patterns of alcohol use. This study aims to identify group trajectories of alcohol consumption in the UK military and to identify associations with childhood adversity, deployment history and mental disorder. METHODS: Data on weekly alcohol consumption across an eight year period and three phases of a UK military cohort study (n=667) were examined using growth mixture modelling. RESULTS: Five alcohol trajectory classes were identified: mid average drinkers (55%), abstainers (4%), low level drinkers (19%), decreasing drinkers (3%) and heavy drinkers (19%). Alcohol consumption remained stable over the three periods in all classes, other than in the small decreasing trajectory class. Individuals in the heavy drinking class were more likely to have deployed to Iraq. Abstainers and heavy drinkers were more likely to report post-traumatic stress disorders at baseline compared to average drinkers. CONCLUSIONS: Heavy drinkers in the UK military did not change their drinking pattern over a period of eight years. This highlights the need to develop effective preventive programmes to lessen the physical and psychological consequences of long-term heavy alcohol use. Individuals with a mental health problem appeared more likely to either be drinking at a high level or to be abstaining from use. PMID- 28734153 TI - The impact of youth internalising and externalising symptom severity on the effectiveness of brief personality-targeted interventions for substance misuse: A cluster randomised trial. PMID- 28734154 TI - Reducing alcohol consumption to minimize weight gain and facilitate smoking cessation among military beneficiaries. AB - INTRODUCTION: Smoking cessation-related weight gain can have significant negative health and career consequences for military personnel. Alcohol reduction combined with smoking cessation may decrease weight gain and relapse. METHOD: A randomized clinical trial of military beneficiaries compared a standard smoking cessation (i.e., brief informational) intervention (N=159), with a brief motivational smoking cessation intervention that emphasized reduced drinking to lessen caloric intake and minimize weight gain (N=158). RESULTS: Participants who received the motivational intervention were significantly more likely to quit smoking at the 3 month follow-up (p=0.02), but the differences were not maintained at 6 (p=0.18) or 12months (p=0.16). Neither weight change nor alcohol reduction distinguished the 2 groups. Smoking cessation rates at 12months (motivational group=32.91%, informational group=25.79%) were comparable to previous studies, but successful cessation was not mediated by reduced drinking. CONCLUSIONS: Alcohol reduction combined with smoking cessation did not result in decreased weight gain or improved outcomes. PMID- 28734155 TI - Activation of mTOR is involved in anti-beta2GPI/beta2GPI-induced expression of tissue factor and IL-8 in monocytes. AB - Previous study has demonstrated that activation of the mammalian target of rapamycin (mTOR) pathway in endothelial cells (ECs) results in the formation of chronic vascular lesions associated with antiphospholipid syndrome (APS). In addition, it has been shown that stimulation of monocytes and ECs by antiphospholipid antibodies (aPL) leads to a prothrombotic and proinflammatory state and up-regulated expression of tissue factor (TF) and inflammatory cytokines. However, the role of mTOR in pathogenic mechanisms of APS remains largely unexplored. In the present study, we aimed to investigate whether mTOR was involved in anti-beta2GPI/beta2GPI complex-induced expression of TF and interleukin-8 (IL-8/CXCL8) in monocytes and explore the relationship among TLR4, mTOR, MAPKs and NF-kappaB in such a process. The results showed that treatment of anti-beta2GPI/beta2GPI or APS-IgG/beta2GPI complex could markedly induce mTOR activation as well as expression of TF and IL-8 in THP-1 cells or primary monocytes. The mTOR inhibitor rapamycin (100nM) could attenuate the elevated expression of TF and IL-8. In addition, rapamycin could also decrease the phosphorylation of p38, ERK1/2 and NF-kappaB p65 stimulated by anti beta2GPI/beta2GPI or APS-IgG/beta2GPI complex, but it had no effect on JNK. Moreover, the anti-beta2GPI/beta2GPI or APS-IgG/beta2GPI complex-induced phosphorylation of mTOR in THP-1 cells was down-regulated through inhibition of p38 (10MUM, SB203580) or ERK (5MUM, U0126) rather than inhibition of JNK (90nM, SP600125) or NF-kappaB (20MUM, PDTC). Finally, the mTOR activation could also be affected by exposure to TLR4 inhibitor TAK-242 (5MUM). Taken together, our results indicated that mTOR was involved in regulating anti-beta2GPI/beta2GPI induced expression of TF and IL-8 in monocytes. In addition, the inhibition of mTOR pathway might be beneficial for the prevention and treatment of aPL-mediated thrombosis and inflammation in APS patients. PMID- 28734156 TI - A novel hypoxia response element regulates oxygen-related repression of tissue factor pathway inhibitor in the breast cancer cell line MCF-7. AB - BACKGROUND: Hypoxia is one of the most pervasive physiological stresses in solid tumors. We have previously demonstrated that tissue factor (TF) pathway inhibitor (TFPI) expression was transcriptionally repressed by the activation of hypoxia inducible factor (HIF)-1alpha under hypoxic conditions. However, the role of HIF 2alpha, also known as endothelial PAS domain-containing protein 1 (EPAS1), on TFPI expression remains unclear. AIM: To explore the role of HIF-2alpha/EPAS1 in the regulation of TFPI expression under hypoxia in breast cancer cells. METHODS AND RESULTS: Quantitative RT-PCR showed that total TFPI mRNA and protein levels were decreased by the overexpression of HIF-2alpha/EPAS1 in MCF7 cells. Luciferase reporter assay and chromatin immunoprecipitation (ChIP) assay indicated a HIF-2alpha/EPAS1 responsive region located in the TFPI promoter region at -170 to +21 relative to the transcriptional start site. Subsequent mutagenesis demonstrated a functional hypoxia response element (HRE) 5'-AAACAGGA 3' for HIF-2alpha/EPAS1 within the TFPI promoter located at -45 to -38. In breast cancer patients, a positive correlation between HIF-2alpha/EPAS1 and total TFPI mRNA expression was observed by using gene expression analysis. CONCLUSIONS: This study provides evidence that HIF-2alpha/EPAS1 is involved in the regulation of TFPI gene expression in breast cancer cells, suggesting that the activation of coagulation and the increased risk of thrombosis observed in breast cancer patients may correlate with local hypoxic regulation of coagulation factors and their inhibitors. PMID- 28734157 TI - Management and 3-month outcomes of isolated superficial vein thrombosis of the lower limb: A real-world cohort study. PMID- 28734158 TI - Interaction between platelet-derived microRNAs and CYP2C19*2 genotype on clopidogrel antiplatelet responsiveness in patients with ACS. AB - BACKGROUND: Both platelet-derived microRNAs and the genotype of CYP2C19*2 were implicated for the variability of clopidogrel antiplatelet responsiveness. However, their interaction on the antiplatelet responsiveness of clopidogrel in patients with acute coronary syndrome (ACS) remains unknown. METHODS: Consecutive clopidogrel-treated patients with ACS were recruited, with their antiplatelet responsiveness evaluated by the relative platelet inhibition (RI), as measured by light transmittance aggregometry (LTA) at baseline and 5days' after the maintenance treatment of clopidogrel. Extreme cases were selected according to the octiles of RI value. Expression of the microRNAs targeting the mRNAs of P2RY12 was analyzed in the platelet of the extreme cases. Genotyping of CYP2C19*2 was performed for each extreme case. RESULTS: Among the included 272 ACS patients, 21 cases were screened as the extremely high-responders with RI>84%, and 18 as the extremely low-responders with RI<10%. Bioinformatics tools predicted the candidate microRNAs of miR-223, miR-221, and miR-21 could bind directly to the mRNA of P2RY12. Compared with the extremely low-responders, the expression of miR-223, miR-221, and miR-21 was significantly higher in the extremely high-responders (miR-223: 7.18+/-2.95 vs. 0.99+/-0.64, p=0.022; miR 221: 3.60+/-2.54 vs. 1.14+/-0.81, p=0.004; miR-21: 4.36+/-3.33 vs. 2.31+/-1.69, p=0.01). ROC curve showed ideal discriminatory power of the platelet-derived miRNAs for the prediction of clopidogrel antiplatelet responsiveness (c index=0.70 for miR-223; c-index=0.76 for miR-221; c-index=0.79 for miR-21). After stratified by the carrier status of CYP2C19*2, the association between platelet derived miRNAs and clopidogrel antiplatelet responsiveness could be found only in CYP2C19*2 carriers, but not in non-carriers. CONCLUSIONS: Platelet-derived miRNAs (miR-223, miR-221 and miR-21) are independently associated with clopidogrel antiplatelet responsiveness in ACS patients. However, the association could be influenced by the interaction with CYP2C19*2 genotype. PMID- 28734159 TI - Development of a LC-MS/MS method for the determination of CKD-712 in rat plasma: Application to a pharmacokinetic study in rats. AB - CKD-712 is a potential treatment for sepsis, as it exhibits protective effects against lipopolysaccharide-mediated platelet aggregation, inducible nitric oxide synthase expression, and cecum-ligation puncture-induced septic mortality in mice. In this study, we develop a rapid and sensitive LC-MS/MS method for determining CKD-712 in rat plasma. CKD-712 and papaverine hydrochloride (an internal standard) were analyzed using an LC-MS/MS system consisting of an Agilent HPLC system (HP-1100) equipped with an Atlantis HILIC Silica (2.1*50mm, 3MUm) column and a API 4000 (Applied Biosystems/MDS Sciex, USA) in a positive ESI mode. We utilized multiple reaction monitoring (MRM) at m/z transitions of 306.2 164.0 to analyze CKD-712, and 340.3-202.1 m/z for IS, with a mobile phase of acetonitrile (0.025% trifluoroacetic acid):20mM ammonium acetate (94:6, v/v) at a flow rate of 0.25mL/min. The lower limit of quantification (LLOQ) was 5ng/mL, with a linearity ranging from 5 to 1000ng/mL (r>0.999). Validation parameters including specificity, precision, accuracy, matrix effect, recovery, dilution effect and stability results were well within acceptance criteria, and applied successfully on a pharmacokinetic study in rats. PMID- 28734160 TI - Selective and accurate C5 acylcarnitine quantitation by UHPLC-MS/MS: Distinguishing true isovaleric acidemia from pivalate derived interference. AB - Tandem MS acylcarnitine "profiles" are extremely valuable. Although used appropriately in newborn screening programs to identify patients with possible diseases, their inadequate quantitative accuracy and lack of selectivity is problematic for confirmatory testing. In this report, we show the application of our validated, selective, accurate, precise, and robust UHPLC-MS/MS method for quantitation of acylcarnitines, specifically to C5 acylcarnitines: pivaloyl-, 2 methylbutyryl-, isovaleryl-, and valerylcarnitine. Standardized calibrants were used to generate 13-point, 200-fold concentration range calibration curves. Samples were isolated by solid-phase extraction and derivatized with pentafluorophenacyl trifluoromethanesulfonate. Acylcarnitine pentafluorophenacyl esters were eluted in 14min chromatograms. Data demonstrating quantitative stability and method robustness over a five year time period are shown and these results validate the method's accuracy and robustness. Urine from patients with isovaleric acidemia (with the disease marker isovalerylcarnitine) and with pivaloylcarnitine present are shown. These results demonstrate the method's ability to distinguish true isovaleric acidemia from pivalate derived interference. Our method for acylcarnitine quantitation is shown to be accurate, precise, and robust for selective quantitation of isovalerylcarnitine, and thus is recommended for confirmatory testing of suspected isovaleric acidemia patients. PMID- 28734161 TI - Evaluation of the effect of extraction solvent and organ selection on the chemical profile of Astragalus spinosus using HPTLC- multivariate image analysis. AB - The evaluation of extraction protocols for untargeted and targeted metabolomics was implemented for root and aerial organs of Astragalus spinosus in this work. The efficiency and complementarity of commonly used extraction solvents, namely petroleum ether, methylene chloride, ethyl acetate and n-butanol were considered for method evaluation using chemometric techniques in conjunction with new, simple, and fast high performance thin layer chromatography (HPTLC) method for fingerprint analysis by extracting information from a digitalized HPTLC plate using ImageJ software. A targeted approach was furtherly implemented by developing and validating an HPTLC method allowing the quantification of three saponin glycosides. The results of untargeted and targeted principle component analysis (PCA) and hierarchical cluster analysis (HCA) revealed that the apparent saponins profile seems to depend on a combined effect of matrix composition and the properties of the selected solvent for extraction, where both the biological matrix of the investigated plant organs, as well as the extraction solvent can influence the precision of metabolite abundances. Although, the aerial part is frequently discarded as waste, it is shown hereby that it has similar chemical profile compared to the medicinal part, roots, yet a different extraction solvents pattern is recognized between the two organs which can be attributed to the differences in the composition, permeability or accessibility of the sample matrix/organ tissues, rather than the chemical structures of the detected metabolites. PMID- 28734163 TI - World-wide seasonal variation of 7Be related to large-scale atmospheric circulation dynamics. PMID- 28734162 TI - Extraction and in vitro screening of potential acetylcholinesterase inhibitors from the leaves of Panax japonicus. AB - Ultrafiltration liquid chromatography-mass spectrometry (UFLC-MS) is an efficient method that can be applied to rapidly screen and identify ligands for acetylcholinesterase (AChE) from the leaves of Panax japonicus. Using this method, we identified 5 major compounds, chikusetsusaponins V, Ib, IV, IVa, and IVa ethyl ester, as potent AChE inhibitors, which were assessed for anti Alzheimer disease activity using the PC12 cell model. A continuous online method, which consisted of microwave-assisted extraction, a solvent concentration tank, and centrifugal partition chromatography (MAE-SCT-CPC), was newly developed for scaled up production of these compounds with high purity and efficiency. The bioactivities of the compounds separated were assessed by the PC12 cell model. This novel approach of using UFLC-MS coupled with MAE-SCT-CPC and a PC12 cell model could be applied to efficiently screen, extract, and separate AChE inhibitors from complex samples, and could serve as an important platform for the large-scale production of functional food and nutraceutical ingredients. PMID- 28734164 TI - Cognitive strategies in the mental rotation task revealed by EEG spectral power. AB - The classic mental rotation task (MRT; Shepard & Metzler, 1971) is commonly thought to measure mental rotation, a cognitive process involving covert simulation of motor rotation. Yet much research suggests that the MRT recruits both motor simulation and other analytic cognitive strategies that depend on visuospatial representation and visual working memory (WM). In the present study, we investigated cognitive strategies in the MRT using time-frequency analysis of EEG and independent component analysis. We scrutinized sensorimotor mu (u) power reduction, associated with motor simulation, parietal alpha (palpha) power reduction, associated with visuospatial representation, and frontal midline theta (fmtheta) power enhancement, associated with WM maintenance and manipulation. u power increased concomitant with increasing task difficulty, suggesting reduced use of motor simulation, while palpha decreased and fmtheta power increased, suggesting heightened use of visuospatial representation processing and WM, respectively. These findings suggest that MRT performance involves flexibly trading off between cognitive strategies, namely a motor simulation-based mental rotation strategy and WM-intensive analytic strategies based on task difficulty. Flexible cognitive strategy use may be a domain-general cognitive principle that underlies aptitude and spatial intelligence in a variety of cognitive domains. We close with discussion of the present study's implications as well as future directions. PMID- 28734165 TI - Rhodamine spirolactam sensors operated by sulfur-cooperated metal complexation. AB - New rhodamine Schiff base sensors were developed to improve selective sensing by introducing sulfide, ester, and dithiocarbonate groups, as well as using ketones coupled to rhodamine-hydrazine. Metal sensing proceeded through the 1:1 complexation of the metal ion for most sensors in the presence of Cu2+ and Hg2+. A sensor carrying a dithiocarbonate group responded selectively to Hg2+ showing a strong colorimetric change and intense fluorescence. The association constants of the sensors were determined from a linear plot performed at micro-molar concentrations to afford values in the range of 104. Sensing was interrupted at the initial time of Hg2+ exposure due to the isomerization of imine and preferential metal bonding of two dithiocarbonate groups regardless of the main structure of rhodamine. The sensors exhibited the reversible and reproducible performance for Hg2+ sensing. PMID- 28734166 TI - Naturally occurring immunomodulators with antitumor activity: An insight on their mechanisms of action. AB - Natural products with immunomodulatory activity are widely used in treatment of many diseases including autoimmune diseases, inflammatory disorders in addition to cancer. They gained a great interest in the last decades as therapeutic agents since they provide inexpensive and less toxic products than the synthetic chemotherapeutic agents. Immunomodulators are the agents that have the ability to boost or suppress the host defense response that can be used as a prophylaxis as well as in combination with other therapeutic modalities. The anticancer activity of these immunomodulators is due to their anti-inflammatory, antioxidant, and induction of apoptosis, anti-angiogenesis, and anti-metastasis effect. These natural immunomodulators such as genistein, curcumin, and resveratrol can be used as prophylaxis against the initiation of cancer besides the inhibition of tumor growth and proliferation. Whereas, immunostimulants can elicit and activate humoral and cell-mediated immune responses against the tumor that facilitate the recognition and destruction of the already existing tumor. This review represents the recent studies on various natural immunomodulators with antitumor effects. We have focused on the relationship between their anticancer activity and immunomodulatory mechanisms. The mechanisms of action of various immunomodulators such as polyphenolic compounds, flavonoids, organosulfur compounds, capsaicin, vinca alkaloids, bromelain, betulinic acid and zerumbone, the affected cancerous cell lines in addition to the targeted molecules and transcriptional pathways have been review and critically analyzed. PMID- 28734167 TI - Mindfulness practice moderates the relationship between craving and substance use in a clinical sample. AB - Relapse following treatment for substance use disorders is highly prevalent, and craving has been shown to be a primary predictor of relapse. Mindfulness-Based Relapse Prevention (MBRP) is a psychosocial aftercare program integrating mindfulness and cognitive-behavioral approaches, aimed at reducing the risk and severity of relapse. Results from a recent randomized clinical trial demonstrate enhanced remission resilience for MBRP participants versus both cognitive behavioral and treatment-as-usual controls. The current study investigated between-session formal and informal mindfulness practice, a hypothesized primary mechanism of action in this treatment, as an attenuating factor in the relationship between craving and substance use. Participants in this secondary analysis were 57 eligible adults who completed either inpatient treatment or intensive outpatient treatment for substance use disorders, were randomized in the parent study to receive MBRP, and completed relevant follow-up assessments. For formal mindfulness practice at post-intervention, both number of days per week and number of minutes per day significantly moderated the relationship between craving at post-intervention and number of substance use days at 6-month follow up. Informal practice did not significantly influence the craving-use relationship in this analysis. These results indicate that increasing formal mindfulness practice may reduce the link between craving and substance use for MBRP participants and enhance remission resiliency. PMID- 28734168 TI - Effect of neurodynamic mobilization on fluid dispersion in median nerve at the level of the carpal tunnel: A cadaveric study. AB - OBJECTIVES: To evaluate the effect of neurodynamics mobilization (NDM) on an artificially induced edema in the median nerve at the level of the carpal tunnel in unembalmed cadavers and to assess whether NDM tensioning techniques (TT) and NDM sliding techniques (SLT) induce similar effects on intraneural fluid dispersion. DESIGN: Fourteen upper extremities of seven unembalmed cadavers were used in this study. A biomimetic solution was injected directly under the epineurium of the median nerve at the level of the proximal transverse carpal ligament. The initial dye spread was allowed to stabilize and measured with a digital caliper. Tensioning and sliding techniques were applied following a randomized crossover design to each upper extremity and were performed for a total of 5 min each. Post-intervention dye spread measurements were taken after each technique. RESULTS: After the first mobilization, the mean longitudinal dye spread (7.5 +/- 6.6 mm) was significantly greater (p = 0.024) compared to the stabilized dye spread. There was a significant longitudinal diffusion effect with both, TT (p = 0.018) and SLT (p = 0.016), with no statistically significant difference between techniques (p = 0.976). The order in which techniques were administered did not influence the diffusion. CONCLUSION: Five minute of passive NDM in the form of tensioning or sliding technique induced significant fluid dispersion in the median nerve at the carpal tunnel of unembalmed human cadavers. This study provides support for clinical mechanism of NDM in reducing intraneural edema. PMID- 28734169 TI - Development and psychometric validation of the headache screening questionnaire - Dutch Version. AB - BACKGROUND: Headache is a common disorder which may lead to substantial socio economic loss. Treatment options include self-management strategies, medication and physiotherapy. Physiotherapists need to be able to screen for the presence of migraine and tension-type headache (TTH), so they can adjust their treatment strategies to the type of headache. A quick screening questionnaire to recognize migraine and TTH in the physiotherapy practice is needed. OBJECTIVE: The aim of this study was to create a headache screening questionnaire based on the ICHD-3 beta criteria for migraine and TTH, and to establish its content and criterion validity. DESIGN: A cross-sectional design was used during the validation phase of the study. METHODS: A screening questionnaire was developed for migraine and TTH. Content validity was checked by the research group and a headache research expert. For validation of this questionnaire, patients from the headache clinic of the Canisius Wilhelmina Hospital in Nijmegen were recruited. The outcome of the questionnaire was compared to the ICHD-3 beta diagnosis of the headache specialist. For criterion validity, sensitivity, specificity, likelihood ratios, and positive- and negative predictive values were calculated. RESULTS: A 10-item questionnaire has been developed: the Headache Screening Questionnaire. For validation of the Dutch version (HSQ-DV), 105 patients were included in the study. The sensitivity and specificity were 0.89 and 0.54 respectively for probable migraine, and for probable TTH 0.92 and 0.48 respectively. CONCLUSION: The HSQ-DV is a sensitive screening tool to detect patients with probable migraine and probable TTH. PMID- 28734170 TI - Web-based physical activity interventions: a systematic review and meta-analysis of randomized controlled trials. AB - OBJECTIVES: It was estimated that approximately 60% of the world's population is classified as inactive or insufficiently active. This meta-analysis investigated the effect of web-based interventions on different types of physical activity (PA) measurements in general population and potential moderating variables. STUDY DESIGN: PubMed, CINAHL, EBSCOhost, PsycINFO, Scopus, Ovid, and ScienceDirect literature searches were conducted to identify studies investigating the effect of web-based interventions on PA. METHODS: Randomized controlled trials on PA changes reported in moderate to vigorous intensity, walking, and step count in the intervention group in comparison with the control group were pooled with a fixed-effects model separately. RESULTS: A total of 22 studies comprising 16,476 and 14,475 subjects in intervention and control groups respectively were included. Web-based interventions had positive and significant effect on increasing PA. Of 14 trials reporting moderate to vigorous physical activity (MVPA), five showed a significant increase in the MVPA level after the intervention. There was significant heterogeneity between studies (P < 0.001 and I2 = 67.8%). Of six trials that reported the number of steps by using the pedometer, three showed a significant increase for the step counts in intervention groups (P < 0.001 and I2 = 93.3%), of 14 trials assessed PA level by reporting walking minutes per week, four studies showed a significant increase in walking minutes. There was significant heterogeneity between studies (P < 0.001, I2 = 68.1%). Overall, the effect of web-based interventions seemed to be influenced by the characteristics of mean age of participants, trial duration, and study quality (P < 0.05). CONCLUSION: The web-based PA interventions had a positive significant effect on increasing all the three types of PA among the general population. However, the effects appear to depend on the design of the study, age, and duration of studies. PMID- 28734171 TI - Muscle synergies reveal impaired trunk muscle coordination strategies in individuals with thoracic spinal cord injury. AB - Spinal cord injury (SCI) can result in paralysis of trunk muscles, which can affect sitting balance. The objective of this study was to analyze trunk muscle coordination of individuals with thoracic SCI and compare it to able-body individuals. A total of 27 individuals were recruited and subdivided into: (a) high thoracic SCI; (b) low thoracic SCI; and (c) able-body groups. Participants were seated and asked to lean their trunk in eight directions while trunk muscle activity was recorded. Muscle coordination was assessed using the non-negative matrix factorization (NMF) method to extract muscle modules, which are the synergistic trunk muscle activations, and their directional activation patterns. Our results showed that individuals with SCI used less muscle modules, more co contractions, and less directional tuning, compared to able-bodied people. These results suggest impaired and simplified muscle coordination due to the loss of supraspinal input after SCI. Observed variability in muscle coordination within SCI groups also suggests that other mechanisms such as spasticity and muscle stretch reflexes or individual factors such as experience and training contributed to the postural muscle synergies. Overall, muscle coordination deficits revealed impaired neuromuscular strategies which provide implications for rehabilitation of trunk muscles during sitting balance after SCI. PMID- 28734172 TI - Clear evidence for item limits in visual working memory. AB - There is a consensus that visual working memory (WM) resources are sharply limited, but debate persists regarding the simple question of whether there is a limit to the total number of items that can be stored concurrently. Zhang and Luck (2008) advanced this debate with an analytic procedure that provided strong evidence for random guessing responses, but their findings can also be described by models that deny guessing while asserting a high prevalence of low precision memories. Here, we used a whole report memory procedure in which subjects reported all items in each trial and indicated whether they were guessing with each response. Critically, this procedure allowed us to measure memory performance for all items in each trial. When subjects were asked to remember 6 items, the response error distributions for about 3 out of the 6 items were best fit by a parameter-free guessing model (i.e. a uniform distribution). In addition, subjects' self-reports of guessing precisely tracked the guessing rate estimated with a mixture model. Control experiments determined that guessing behavior was not due to output interference, and that there was still a high prevalence of guessing when subjects were instructed not to guess. Our novel approach yielded evidence that guesses, not low-precision representations, best explain limitations in working memory. These guesses also corroborate a capacity limited working memory system - we found evidence that subjects are able to report non-zero information for only 3-4 items. Thus, WM capacity is constrained by an item limit that precludes the storage of more than 3-4 individuated feature values. PMID- 28734173 TI - Reliability and validity of the Tilburg Frailty Indicator (TFI) among Chinese community-dwelling older people. AB - OBJECTIVE: To translate the Tilburg Frailty Indicator (TFI) into Chinese and assess its reliability and validity. METHODS: A sample of 917 community-dwelling older people, aged >=60 years, in a Chinese city was included between August 2015 and March 2016. Construct validity was assessed using alternative measures corresponding to the TFI items, including self-rated health status (SRH), unintentional weight loss, walking speed, timed-up-and-go tests (TUGT), making telephone calls, grip strength, exhaustion, Short Portable Mental Status Questionnaire (SPMSQ), Geriatric Depression scale (GDS-15), emotional role, Adaptability Partnership Growth Affection and Resolve scale (APGAR) and Social Support Rating Scale (SSRS). Fried's phenotype and frailty index were measured to evaluate criterion validity. Adverse health outcomes (ADL and IADL disability, healthcare utilization, GDS-15, SSRS) were used to assess predictive (concurrent) validity. RESULTS: The internal consistency reliability was good (Cronbach's alpha=0.71). The test-retest reliability was strong (r=0.88). Kappa coefficients showed agreements between the TFI items and corresponding alternative measures. Alternative measures correlated as expected with the three domains of TFI, with an exclusion that alternative psychological measures had similar correlations with psychological and physical domains of the TFI. The Chinese TFI had excellent criterion validity with the AUCs regarding physical phenotype and frailty index of 0.87 and 0.86, respectively. The predictive (concurrent) validities of the adverse health outcomes and healthcare utilization were acceptable (AUCs: 0.65 0.83). CONCLUSIONS: The Chinese TFI has good validity and reliability as an integral instrument to measure frailty of older people living in the community in China. PMID- 28734175 TI - CD8+ T cell programming by cytomegalovirus vectors: applications in prophylactic and therapeutic vaccination. AB - Vectors based on cytomegalovirus (CMV) represent a novel vaccine platform that maintains high frequencies of non-exhausted effector memory T cells in both CMV sero-positive and sero-negative individuals. In non-human primate models, CMV vectored vaccines provide unprecedented protection against simian immunodeficiency virus (SIV). Moreover, CMV vectors can be genetically altered to program highly diverse CD8+ T cell responses that differ in their epitope targeting including conventional, MHC-I restricted CD8+ T cells as well as unconventional CD8+ T cells restricted by MHC class II or non-polymorphic MHC-E. By modifying cytomegaloviral determinants that control unconventional T cell priming it is possible to uniquely tailor the CD8+ T cell response for each individual disease target in order to maximize prophylactic or therapeutic protection. PMID- 28734174 TI - Old and new adjuvants. AB - Adjuvants have been deliberately added to vaccines since the 1920's when alum was discovered to boost antibody responses, leading to better protection. The first adjuvants were discovered by accident and were used in the safer but less immunogenic subunit vaccines, supposedly by providing an antigen depot to extend antigen presentation. Since that time, much has been discovered about how these adjuvants impact cells at the tissue site to activate innate immune responses, mobilize dendritic cells and drive adaptive immunity. New approaches to vaccine construction for infectious diseases that have so far not been well addressed by conventional vaccines often attempt to induce antibodies, polyfunctional CD4+ T cells and CD8+ CTLs. The discovery of pattern recognition receptors and ligands that drive desired T cell responses has led to development of novel adjuvant strategies using immunomodulatory agents to direct appropriate immune responses. PMID- 28734176 TI - Cancer immunotherapy: moving forward with peptide T cell vaccines. AB - Recent advances in cancer immunology, such as the discovery of immune checkpoint inhibitors, have validated immune cells as potential key players for effective cancer treatment. The efficacy of these therapies seems to be codependent on a tumor-reactive T lymphocyte response. For many years, numerous attempts and strategies in developing vaccines to generate tumor-reactive T cells have yielded poor results in the clinic due to suboptimal immunogenicity and the inability to overcome an immunosuppressive tumor microenvironment. In this review, we summarize past and current advances in T cell vaccines and describe our experience in developing optimized methods for antigen/adjuvant selection and vaccine administration in order to induce powerful anti-tumor responses. PMID- 28734177 TI - Manual morphometry of hippocampus and amygdala in adults with attention-deficit hyperactivity disorder. AB - Previous studies have pointed to the involvement of limbic structures in the genesis of attention deficit hyperactivity disorder (ADHD). The present researchers manually segmented magnetic resonance images of 30 individuals with ADHD and 30 individually matched controls, focusing on amygdala and hippocampus volumes. Neither hippocampus nor amygdala volume differed significantly between individuals with and without ADHD. However, ADHD patients with higher hyperactivity scores had significantly smaller left amygdala volumes. This finding suggests that limbic alterations are significant in hyperactive symptoms in the pathophysiology of ADHD. PMID- 28734178 TI - Subcortical surface shape in youth at familial high risk for schizophrenia. AB - Abnormalities in the subcortical brain regions that support cognitive functions have been reported in schizophrenia. Relatives of those with schizophrenia often present with psychosis-like traits (schizotypy) and similar cognition as those with schizophrenia. To evaluate the relationships between subcortical structure, schizotypy, and cognitive function, we assessed shape and volume of the hippocampus, amygdala and thalamus in untreated youth at familial high risk for schizophrenia (HRSZ). The sample consisted of 66 HRSZ and 69 age-matched healthy controls (HC). Subjects' cognitive functions and schizotypy were assessed, and T1 weighted brain MRI were analyzed using the FSL software FIRST. The right hippocampus and right amygdala showed significantly increased concavity (inward displacement) in HRSZ compared to HC. While regional subcortical shape displacements were significantly correlated with sustained attention and executive function scores in HC, fewer correlations were seen in HRSZ. This suggests a possible alteration of the local structure-function relationship in subcortical brain regions of HRSZ for these cognitive domains, which could be related to anomalous plasticity. PMID- 28734179 TI - Computational analysis for the determination of deleterious nsSNPs in human MTHFD1 gene. AB - Single nucleotide polymorphisms (SNPs) are the most common genetic polymorphisms and play a major role in many inherited diseases. Methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) is one of the enzymes involved in folate metabolism. In the present study, the functional and structural consequences of nsSNPs of human MTHFD1 gene was analyzed using various computational tools like SIFT, PolyPhen2, PANTHER, PROVEAN, SNAP2, nsSNPAnalyzer, PhD-SNP, SNPs&GO, I-Mutant, MuPro, ConSurf, InterPro, NCBI Conserved Domain Search tool, ModPred, SPARKS-X, RAMPAGE, FT Site and PyMol. Out of 327 nsSNPs form human MTHFD1 gene, total 45 SNPs were predicted as functionally most significant SNPs, among which 17 were highly conserved and functional, 17 were highly conserved and structural residues. Among 45 most significant SNPs, 15 were predicted to be involved in post translational modifications. The p.Gly165Arg may interfere in homodimer interface formation. The p.Asn439Lys and p.Asp445Asn may interfere in binding interactions of MTHFD1 protein with cesium cation and potassium. The two SNPs (p.Asp562Gly and p.Gly637Cys) might interfere in interactions of MTHFD1 with ligand. PMID- 28734181 TI - Evaluating a nursing erasmus exchange experience: Reflections on the use and value of the Nominal Group Technique for evaluation. AB - This paper discusses the use of Nominal Group Technique (NGT) for European nursing exchange evaluation at one university. The NGT is a semi-quantitative evaluation method derived from the Delphi method popular in the 1970s and 1980s. The NGT was modified from the traditional version retaining the structured cycles and but adding a broader group discussion. The NGT had been used for 2 successive years but required analysis and evaluation itself for credibility and 'fit' for purpose which is presented here. It aimed to explore nursing students' exchange experiences and aid programme development futures exchanges and closure from exchange. Results varied for the cohorts and students as participants enthusiastically engaged generating ample data which they ranked and categorised collectively. Evaluation of the NGT itself was two fold: by the programme team who considered purpose, audience, inclusivity, context and expertise. Secondly, students were asked for their thoughts using a graffiti board. Students avidly engaged with NGT but importantly also reported an effect from the process itself as an opportunity to reflect and share their experiences. The programme team concluded the NGT offered a credible evaluation tool which made use of authentic student voice and offered interactive group processes. Pedagogially, it enabled active reflection thus aiding reorientation back to the United Kingdom and awareness of 'transformative' consequences of their exchange experiences. PMID- 28734180 TI - Bottom-up assembly of salivary gland microtissues for assessing myoepithelial cell function. AB - Myoepithelial cells are flat, stellate cells present in exocrine tissues including the salivary glands. While myoepithelial cells have been studied extensively in mammary and lacrimal gland tissues, less is known of the function of myoepithelial cells derived from human salivary glands. Several groups have isolated tumorigenic myoepithelial cells from cancer specimens, however, only one report has demonstrated isolation of normal human salivary myoepithelial cells needed for use in salivary gland tissue engineering applications. Establishing a functional organoid model consisting of myoepithelial and secretory acinar cells is therefore necessary for understanding the coordinated action of these two cell types in unidirectional fluid secretion. Here, we developed a bottom-up approach for generating salivary gland microtissues using primary human salivary myoepithelial cells (hSMECs) and stem/progenitor cells (hS/PCs) isolated from normal salivary gland tissues. Phenotypic characterization of isolated hSMECs confirmed that a myoepithelial cell phenotype consistent with that from other exocrine tissues was maintained over multiple passages of culture. Additionally, hSMECs secreted basement membrane proteins, expressed adrenergic and cholinergic neurotransmitter receptors, and released intracellular calcium [Ca2+i] in response to parasympathetic agonists. In a collagen I contractility assay, activation of contractile machinery was observed in isolated hSMECs treated with parasympathetic agonists. Recombination of hSMECs with assembled hS/PC spheroids in a microwell system was used to create microtissues resembling secretory complexes of the salivary gland. We conclude that the engineered salivary gland microtissue complexes provide a physiologically relevant model for both mechanistic studies and as a building block for the successful engineering of the salivary gland for restoration of salivary function in patients suffering from hyposalivation. PMID- 28734182 TI - Using medically-derived iodine-131 to track sewage effluent in the Laurentian Great Lakes. AB - Tracking sewage wastewater in a large lake is difficult. Concentrations of pharmaceuticals that can be used as indicator compounds are quickly diluted and not easy to measure. In this study, we examined the potential of using medically derived iodine-131 (131I, t1/2 = 8.02 d) as a tracer for Milwaukee sewage effluent in Lake Michigan. 131I activities in sewage effluent from two Milwaukee wastewater treatment plants (WWTPs) were measured in conjunction with 131I activities in water, sediment and biota in the Milwaukee Outer Harbor and Lake Michigan. 131I discharge rates from both WWTPS ranged from 34 +/- 15 to 1807 +/- 24 MBq d-1, with average and median 131I discharges of 278 and 129 MBq d-1. A budget of 131I in the Milwaukee Outer Harbor - based on measured sediment and water column inventories - showed that ~11% of the 131I discharged to the harbor was scavenged to bottom sediments, ~19% decayed in the harbor water column, and ~70% was flushed out of the harbor to Lake Michigan. From this budget, we derived a harbor flushing rate of 3.1 days. In Lake Michigan, 131I activity was found in Cladophora algae (undetected to 91 +/- 2 Bq kg-1) along ~40 km of shoreline. Benthic trawl samples showed 131I activity up to 8 km from shore. Calculated 131I length scales were 30 km alongshore and 3.4 km offshore and corresponded to sewage effluent dispersion rates of ~2.6 km d-1 and ~0.3 km d-1 in along- and offshore directions. Using 131I as a tracer of sewage effluent from other coastal municipalities to the Laurentian Great Lakes appears feasible, particularly for larger (>105) population centers. PMID- 28734183 TI - Influence of non-measurable disease on progression-free survival in patients with metastatic breast cancer. AB - BACKGROUND: The presence of non-measurable disease is common in metastatic breast cancer. It is unknown whether treatment effect on progression free survival (PFS) is consistent among patients with measurable and non-measurable disease. METHODS: A systematic literature search identified phase III randomized controlled trials (RCTs) in metastatic breast cancer that reported outcomes in patients with non measurable and measurable disease. Hazard ratios (HRs) and 95% confidence intervals were computed to compare the individual trial treatment effect on PFS in non-measurable versus measurable disease. Analyses were repeated for bone-only compared to non-bone-only disease and based on drug mechanism of action. RESULTS: Among 82 RCTs that enrolled patients with non-measurable disease, data were available from 16 trials comprising 8516 patients. Treatment effect on PFS was similar in patients with non-measurable and measurable disease (HR for intra study comparison=1.01, p=0.82). However, compared to non-bone-only disease, a significantly greater effect on PFS was seen in those with bone-only disease (HR 0.83, p=0.03). Compared to patients with measurable disease, there was a greater effect on PFS in those with non-measurable disease in RCTs of signal transduction inhibitors and endocrine therapy (HR 0.74, p=0.01) and a lesser effect on PFS in RCTs of antiangiogenic drugs (HR 1.34, p=0.02). Comparable effect on PFS was shown in RCTs evaluating endocrine therapy (HR 1.13, p=0.23) and chemotherapy (HR 0.73, p=0.22). CONCLUSIONS: There is variability in treatment effect on PFS in patients with measurable and non-measurable disease, especially those with bone only disease. Standardization of PFS determination in these patients is warranted. PMID- 28734185 TI - Primary small cell neuroendocrine carcinoma of the breast - A case report and review of the literature. AB - INTRODUCTION: Primary small cell neuroendocrine carcinoma of the breast (SCNCB) is a very uncommon type of breast cancer. Histology and morphology are virtually indistinguishable from small cell neuroendocrine carcinomas of the lung (SCNCL), mandating a search for a primary site elsewhere in the body. There is no standard approach to treatment as there are only a limited number of cases reported in the literature. This report summarizes a case of primary SCNCB and presents a review of the literature. PRESENTATION OF CASE: A 65-year-old female presented to her gynecologist with a right breast mass. After biopsy, she was diagnosed with a primary SCNCB with regional lymph node involvement. She was treated with chemotherapy and radiation therapy with a good clinical response. DISCUSSION: Due to the rare nature of this tumor, no standard treatment exits. Case reports have described breast conserving therapy combined with neoadjuvant or adjuvant chemotherapy as well as chemoradiation therapy alone for metastatic disease. Both chemotherapy regimens, those used to treat SCNCL and invasive breast cancer, have been described in these reports. CONCLUSION: Primary SCNCB is a very rare type of breast cancer with no standard treatment. Further research is needed to better understand the behavior of this rare tumor in order to develop a standard approach to treatment. PMID- 28734184 TI - An empirical review of potential mediators and mechanisms of prolonged exposure therapy. AB - Prolonged exposure (PE) is an empirically-supported treatment for posttraumatic stress disorder (PTSD), but the precise mechanism(s) by which PE promotes symptom change are not well established. Understanding how PE works is critical to improving clinical outcomes, advancing dissemination efforts, and enhancing transdiagnostic models of psychopathology. However, mechanisms research conducted in clinical treatment settings is complex, and findings may be difficult to interpret without appropriate context. This is the first review of potential mechanisms of PE to provide such context, by rigorously evaluating empirical findings in line with essential criteria for effective research on mechanisms (or mediators). We begin by describing six putative mechanisms identified by emotional processing theory and contemporary models of fear extinction, before thoroughly reviewing empirical findings from clinical research on PE and similar PTSD treatments. We provide a detailed description of each study and mechanism test, as well as ratings of strength of evidence and quality of evaluation based on a novel rating scheme. We highlight variables with strong evidence (belief change and between-session habituation), intermediate evidence (inhibitory learning and emotional engagement), and minimal support (narrative organization and within-session habituation). After discussing limitations of the extant literature and this review, we summarize specific challenges for research on PE mechanisms and highlight directions for future study based on clinical and research implications. PMID- 28734186 TI - Bilateral vocal cord palsy after total thyroidectomy-A new treatment-Case reports. AB - INTRODUCTION: Dyspnea due to bilateral vocal cord palsy after total thyroidectomy (BVCPATT) is a life-threatening complication; nevertheless, we try to avoid tracheotomy. METHODS: Using normalized glottal area (NGA), we retrospectively studied 14 patients with BVCPATT. Nine patients without dyspnea were treated conservatively, while five with dyspnea received immediate bilevel positive air way pressure (BiPAP) treatment. Both right and left recurrent nerves were grossly intact during surgery. RESULTS: The mean NGA during inspiration of five patients with dyspnea was less than that of nine patients without (6.21+/-1.57 (mean+/ standard deviation) vs. 20.5+/-9.5; p=0.001). The mean age of patients with dyspnea was more than that of patients without (61.6+/-15.6 vs. 38+/-10.2; p=0.007). Five patients with dyspnea that occurred at 0-8days post operation recovered within 3-17days after BiPAP. CONCLUSION: Dyspnea occurred in patients with BVCPATT who were relatively older. The mean NGA during inspiration in patients with dyspnea was less than that in patients without. BiPAP might be a new treatment for dyspnea. PMID- 28734187 TI - Proximal femoral nail antirotation versus hemiarthroplasty in the treatment of senile intertrochanteric fractures: Case report. AB - BACKGROUND: Primary hemiarthroplasty was recommended by some surgeons as the preferred choice in treating unstable senile intertrochanteric fractures with osteoporosis. However, many studies reported that proximal femoral nail antirotation (PFNA) currently was as an optimal implant for the treatment of different type of intertrochanteric fractures. Which method is better for treating senile intertrochanteric fractures remains controversial due to the insufficient clinical evidences. METHODS: We reviewed all consecutive senile intertrochanteric fractures treated with PFNA or cemented hemiarthroplasty at our institution between July 2010 and March 2015. The primary outcome measures were postoperative complications, reoperation rate and hip function. The secondary outcome measures were intraoperative blood loss, transfusion rate, surgical time, postoperative hemoglobin, hospital stay and 1- year mortality. RESULTS: Seventy one patients in PFNA group and 52 patients in hemiarthroplasty group were included for analysis. There were no significant differences between the two groups regarding to the orthopaedic complications, reoperation rate, surgical time and Harris Hip Score at 1year follow-up. Significant differences were found between PFNA and hemiarthroplasty group in comparison of intraoperative blood loss (P<0.001), transfusion rate, medical complications (P=0.037) and hospital stay (P=0.001). Patients treated with hemiarthroplasty had a trend of higher postoperative 1- year mortality compared to those underwent PFNA but this was statistically not significant (P=0.134). CONCLUSIONS: These findings indicate that PFNA has obvious advantages over hemiarthroplasty in the treatment of senile intertrochanteric fractures. Hemiarthroplasty in treating these fractures is associated with greater surgical trauma and higher incidence of postoperative medical complications. PMID- 28734188 TI - The effects of neurologic assessment E-learning in nurses. AB - BACKGROUND: A firm understanding of the preliminary assessment of a patient with neurological disorders is needed for ensuring optimal patient outcomes. OBJECTIVES: The purpose of this study is to evaluate the effects of using e learning on neurologic assessment knowledge, ability, and self-confidence among nurses. DESIGN: This study used a non-equivalent control group pretest-posttest design. SETTINGS: Nurses working in the neurology and neurosurgery wards, Republic of Korea PARTICIPANTS: A convenience sample of 50 nurses was assigned to either the experimental group (n=24) or the control group (n=26). METHODS: The experimental group participated in the self-directed e-learning program related to neurologic assessment, and control group underwent self-directed learning with handout. Knowledge, ability, and self-confidence were measured at pretest and posttest. RESULTS: There were no significant differences in knowledge (U=270, p=0.399) and self-confidence (U=241.5, p=0.171) between the two groups. Nurses in the experimental group showed higher neurologic assessment ability compared with those in the control group (U=199, p=0.028). CONCLUSIONS: Self-directed neurologic assessment e-learning induced improvement in the neurologic assessment ability among nurses. Self-directed e-learning can be applied for improving competencies in neurologic assessment. PMID- 28734189 TI - Two dimensional modeling of elastic wave propagation in solids containing cracks with rough surfaces and friction - Part I: Theoretical background. AB - Our study aims at the creation of a numerical toolbox that describes wave propagation in samples containing internal contacts (e.g. cracks, delaminations, debondings, imperfect intergranular joints) of known geometry with postulated contact interaction laws including friction. The code consists of two entities: the contact model and the solid mechanics module. Part I of the paper concerns the modeling of internal contacts (called cracks for brevity), while part II is related to the integration of the developed contact model into a solid mechanics module that allows the description of wave propagation processes. The contact model is used to produce normal and tangential load-displacement relationships, which in turn are used by the solid mechanics module as boundary conditions at the internal contacts. Due to friction, the tangential reaction curve is hysteretic and memory-dependent. In addition, it depends on the normal reaction curve. An essential feature of the proposed contact model is that it takes into account the roughness of the contact faces. On one hand, accounting for roughness makes the contact model more complicated since it gives rise to a partial slip regime when some parts on the contact area experience slip and some do not. On the other hand, as we will show, the concept of contact surfaces covered by asperities receding under load makes it possible to formulate a consistent contact model that provides nonlinear load-displacement relationships for any value of the drive displacements and their histories. This is a strong advantage, since this way, the displacement-driven model allows for a simple explicit procedure of data exchange with the solid mechanics module, while more traditional flat-surface contacts driven by loads generate a complex iterative procedure. More specifically, the proposed contact model is based on the previously developed method of memory diagrams that allows one to automatically obtain memory-dependent solutions to frictional contact problems in the particular case of partial slip. Here we extend the solution onto cases of total sliding and contact loss which is possible while using the displacement-driven formulation. The method requires the knowledge of the normal contact response obtained in our case as a result of statistical consideration of roughness of contact faces. PMID- 28734190 TI - Two dimensional modeling of elastic wave propagation in solids containing cracks with rough surfaces and friction - Part II: Numerical implementation. AB - Our study aims at the creation of a numerical toolbox that describes wave propagation in samples containing internal contacts (e.g. cracks, delaminations, debondings, imperfect intergranular joints) of known geometry with postulated contact interaction laws including friction. The code consists of two entities: the contact model and the solid mechanics module. Part I of the paper concerns an in-depth description of a constitutive model for realistic contacts or cracks that takes into account the roughness of the contact faces and the associated effects of friction and hysteresis. In the crack model, three different contact states can be recognized: contact loss, total sliding and partial slip. Normal (clapping) interactions between the crack faces are implemented using a quadratic stress-displacement relation, whereas tangential (friction) interactions were introduced using the Coulomb friction law for the total sliding case, and the Method of Memory Diagrams (MMD) in case of partial slip. In the present part of the paper, we integrate the developed crack model into finite element software in order to simulate elastic wave propagation in a solid material containing internal contacts or cracks. We therefore implemented the comprehensive crack model in MATLAB(r) and introduced it in the Structural Mechanics Module of COMSOL Multiphysics(r). The potential of the approach for ultrasound based inspection of solids with cracks showing acoustic nonlinearity is demonstrated by means of an example of shear wave propagation in an aluminum sample containing a single crack with rough surfaces and friction. PMID- 28734192 TI - Trajectories of risk behaviors across adolescence and young adulthood: The role of race and ethnicity. AB - INTRODUCTION: Despite important advances of longitudinal research in substance use behaviors, most studies stratify analyses by gender or race, which limits the ability to directly compare the likelihood of a particular developmental pathway across demographic groups. Thus, there is critical need for well-designed research to examine the associations of race/ethnicity with developmental trajectories of substance use behaviors across adolescence through adulthood. METHODS: Using an accelerated longitudinal design, we examined behaviors across ages 12-31 from Waves I-IV of the National Longitudinal Study of Adolescent to Adult Health. We performed growth mixture modeling, resulting in estimated trajectories over time. Next, we assessed the association between race/ethnicity and trajectory membership using multinomial logistic regression. RESULTS: Five trajectories resulted for marijuana use, four for cigarette smoking, three for smokeless tobacco use and number of days drunk, and two trajectories for heavy episodic drinking. Controlling for gender and family socioeconomic status, African Americans and Hispanics were less likely than non-Hispanic Whites to use cigarettes or smokeless tobacco early or to use alcohol heavily. CONCLUSIONS: Substance use behavior development follows different pathways for US adolescents and young adults, with some individuals experimenting earlier in adolescence and others beginning to use later in adolescence or in early adulthood. We extend developmental knowledge about these behaviors by demonstrating that the patterns of behavior vary by race/ethnicity; members of lower-risk trajectories (those involving later or no initiation of substance use) are more likely to be African American or Hispanic than to be non-Hispanic White. PMID- 28734191 TI - Evolutionary dynamics of recent peste des petits ruminants virus epidemic in China during 2013-2014. AB - Peste des petits ruminants virus (PPRV) causes a highly contagious disease, peste des petits ruminants (PPR), in sheep and goats which has been considered as a serious threat to the local economy in Africa and Asia. However, the in-depth evolutionary dynamics of PPRV during an epidemic is not well understood. We conducted phylogenetic analysis on genomic sequences of 25 PPRV strains from China 2013-2014 outbreaks. All these strains clustered into a novel clade in lineage 4. An evolutionary rate of 2.61 * 10-6 nucleotide substitutions per site per day was estimated, dating the most recent common ancestor of PPRV China 2013 2014 strains to early August 2013. Transmission network analysis revealed that all the virus sequences could be grouped into five clusters of infection, suggesting long-distance animal transmission play an important role in the spread of PPRV in China. These results expanded our knowledge for PPRV evolution to achieve effective control measures. PMID- 28734193 TI - Improved 225Ac daughter retention in InPO4 containing polymersomes. AB - Alpha-emitting radionuclides like actinium-225 (225Ac) are ideal candidates for the treatment of small metastasised tumours, where the long half-life of 225Ac enables it to also reach less accessible tumours. The main challenge lies in retaining the recoiled alpha-emitting daughter nuclides, which are decoupled from targeting agents upon emission of an alpha particle and can subsequently cause unwanted toxicity to healthy tissue. Polymersomes, vesicles composed of amphiphilic block copolymers, are capable of transporting (radio)pharmaceuticals to tumours, and are ideal candidates for the retention of these daughter nuclides. In this study, the Geant4 Monte Carlo simulation package was used to simulate ideal vesicle designs. Vesicles containing an InPO4 nanoparticle in the core were found to have the highest recoil retention, and were subsequently synthesized in the lab. The recoil retention of two of the daughter nuclides, namely francium-221 (221Fr) and bismuth-213 (213Bi) was determined at different vesicle sizes. Recoil retention was found to have improved significantly, from 37 +/- 4% and 22 +/- 1% to 57 +/- 5% and 40 +/- 2% for 221Fr and 213Bi respectively for 100nm polymersomes, as compared to earlier published results by Wang et al. where 225Ac was encapsulated using a hydrophilic chelate (Wang et al. 2014). To better understand the different parameters influencing daughter retention, simulation data was expanded to include vesicle polydispersity and nanoparticle position within the polymersome. The high retention of the recoiling daughters and the 225Ac itself makes this vesicle design very suitable for future in vivo verification. PMID- 28734194 TI - High yield one-pot production of [18F]FCH via a modified TRACERlab FxFN module. AB - INTRODUCTION: [18F]Fluoromethylcholine ([18F]FCH) is a potent tumors imaging agent. In order to fulfill the demand of pre-clinical and clinical studies, we have developed an automated high yield one-pot synthesis of this potent tumors imaging agent. METHODS: [18F]FCH was synthesized using a modified TRACERlab FxFN module. Briefly, dibromomethane (10% in CH3CN) was fluorinated with K[18F]/K 2.2.2 in a glassy carbon reaction vessel at 120 degrees C for about 5min to generate [18F]fluorobromomethane ([18F]FBM). The resulting [18F]FBM was then bubbling (He, 700mL/min) through four Sep-Pak(r) Silica Plus Long cartridges to react with dimethylaminoethanol (10% DMAE in 0.3mL DMSO) which was pre-loaded on Sep-Pak(r) C18 Plus Short cartridge. The [18F]FCH was purified by solid-phase extraction (SPE) using one Sep-Pak(r) C18 Plus Short and one Sep-Pak(r) CM Plus Short in series. The quality of [18F]FCH synthesized by this method was verified by HPLC and TLC as compared to authentic sample. RESULTS: Using this improved one pot method, the RCY of [18F]FCH was 18.8 +/- 2.1% (EOB, n = 27) in a synthesis time of 49 +/- 5min from EOB. The radiochemical purity of [18F]FCH was greater than 90% and the residual DMAE concentration in the final product was less than 10ppm. CONCLUSIONS: This optimized method could fulfill the demand of [18F]FCH for both pre-clinical and clinical studies, especially for nearby study sites without a cyclotron. PMID- 28734195 TI - Implementation of psychological clinical trials in epilepsy: Review and guide. AB - The International League Against Epilepsy (ILAE) Neuropsychiatry commission and United States Institute of Medicine report both identified cognitive and psychological comorbidities as a significant issue for individuals with epilepsy, with rates as high as 60%. However, there is a paucity of evidence-based treatments for many psychological conditions (e.g., learning disorders, cognitive disorders, behavioral disorders). Because of inherent challenges in the implementation of psychological therapy trials and specific considerations for the population with epilepsy, the focus of the current review was to provide guidance and recommendations to conduct psychological trials for individuals with epilepsy. Several key areas will be discussed, including selection of patients, trial design, psychological intervention considerations, outcomes and evaluation of results, publication of trial results, and special issues related to pediatric clinical trials. Rigorously designed psychological therapy trials will set the stage for evidence-based practice in the care of individuals with epilepsy, with the goal of improving seizures, side effects, and HRQOL. PMID- 28734196 TI - On status epilepticus and pins: A systematic content analysis. AB - Status epilepticus (SE) can be defined as abnormally prolonged, persistent, or recurrent clinical and/or electrographic epileptic activity and, as such, is a challenging medical emergency requiring an aggressive treatment aimed at promptly terminating the seizures. It imposes a relevant clinical burden, both in terms of comorbidity and mortality. In the era of the Web 2.0, most people search the Web to obtain SE-related information. The current investigation aimed at qualitatively characterizing the pins related to SE: Pinterest, "the world's catalog of ideas", is a visual social networking site that enables users to freely upload visual material, to bookmark, and to share it (repin). Using SE as a keyword, 192 pins were extracted and analyzed on the basis of their content. Fifty-five were found to meet the inclusion criteria. Fifty-six point four percent of the pins reported at least one cause of SE, the most quoted of which being remote brain injuries (47.3% of the pins); 54.5% and 45.5% of the included pins reported SE symptoms and diagnosis, respectively; 72.7% and 40.0% of pins focused on SE treatment and on prognosis, respectively; and 50.9%, 30.9%, and 40.0% of the pins were intended for physicians, medical/nursing students, and lay people, respectively. Only 12.7% of pins were patient-centered and devoted to fund-raising and advocacy. In the field of neurological diseases, Pinterest, despite being a "pinstructive" tool, is too much overlooked and underused for advocacy purposes. Healthcare workers and stakeholders should be aware of the opportunities offered by Pinterest and exploit this visual social networking site for raising awareness of the life-threatening condition of SE, promoting fund raising campaigns. PMID- 28734197 TI - Life impact of caregiving for severe childhood epilepsy: Results of expert panels and caregiver focus groups. AB - Severe epilepsy in children and young adults can significantly affect the lives of their caregivers. However, the lack of a reliable and valid measure of caregiver impact has limited our understanding of the scope and correlates of this impact, as well as our ability to measure the effects of treatments that could lessen it. The purpose of this study was to facilitate focus groups and interviews with an international group of clinician experts and caregivers to identify the most important domains that should be assessed in a measure of caregiver impact. Ten specific subdomains emerged from the panel discussions, which could be classified into the four overarching categories of physical health, mental health, social function, and financial resources. The caregivers highlighted the impact on the subdomains of sleep and fatigue as most critical. A review of existing caregiver impact measures confirmed that there is no measure currently available that assesses all of these relevant domains, indicating the need for the development of such a measure. The current findings highlight the significant life effects of caring for a child with severe epilepsy and can be used to inform the development of such a tool. PMID- 28734198 TI - Length of stay for 25,791 California patients found incompetent to stand trial. AB - Referrals and admissions to state psychiatric hospitals of criminal defendants found Incompetent to Stand Trial (IST) are on the rise in the state of California and other parts of the country. Studies of treatment outcomes of this population have primarily focused on factors that determine competency and/or restorability. However, as IST patients place an increasing resource burden on state psychiatric hospital systems, other outcomes such as length of stay (LOS) are becoming increasingly important for practitioners and policy makers to understand. This study employs the largest sample of IST patients in the literature; it includes all IST patients admitted to California's state psychiatric hospitals between 2003 and 2016. This study analyzes demographics, clinical diagnoses, and hospital placement as predictors of LOS. Results suggest that demographics, with the exception of age, are poor predictors of LOS. However, diagnoses, especially of severe mental disorders (e.g., schizophrenia) were strongly related to LOS. Hospital placement was the strongest predictor of LOS. Explanations of these results and implications for forensic practitioners are discussed. PMID- 28734199 TI - Endosulfan poisoning: An overview. AB - Endosulfan, an organochlorine (OC) insecticide, is a widely used agricultural pesticide, despite its life threatening toxic effects. In this review, the pharmacokinetics of endosulfan, mechanism of endosulfan toxicity, clinical presentations and management, histopathological findings, and toxicological analysis are described, in addition to its environmental toxicity. The toxic effects of endosulfan can affect many organs and systems presenting in a wide array of signs and symptoms. Although termed a restricted OC-classed pesticide, it continues to be used, especially in the developing world, owing to its beneficial effects on agriculture. Several cases of endosulfan poisoning have been reported from different regions of the world. Whether accidental or intentional, endosulfan ingestion proves to be fatal unless immediate, aggressive treatment is initiated. Management is mainly supportive as no antidote exists for endosulfan poisoning as yet. The use of endosulfan needs to be strictly regulated and eventually banned worldwide altogether to lower the current morbidity and mortality resulting from this pesticide. Additionally, monitoring biological samples, using non-invasive techniques such as breast milk sampling, can provide an effective method of observing the elimination of this environmentally persistent organic pollutant from the general population. PMID- 28734200 TI - Rates of meaningful change in the mental health of children in long-term out-of home care: A seven- to nine-year prospective study. AB - Children residing in long-term out-of-home care have high rates of clinical-level mental health difficulties. However, the stability of these children's difficulties throughout their time in care is uncertain. This paper reports estimates of the seven- to nine-year stability of carer-reported scores on the Child Behavior Checklist (CBCL) and Assessment Checklists for Children (ACC) and Adolescents (ACA) for 85 children in long-term foster or kinship care. Prospective score changes on the CBCL total problems and ACC-ACA shared-item scales were assigned to one of four change groups: 'sustained mental health'; 'meaningful improvement'; 'no meaningful change'; and 'meaningful deterioration'. On each of the two measures, more than 60% of children manifested either sustained mental health or meaningful improvement in their mental health, while less than a quarter showed meaningful deterioration. Mean mental health scores for the aggregate sample did not change over the 7-9year period. Findings discount the presence of a uniform, population-wide effect-suggesting instead, that children's mental health follows several distinct trajectories. Rather than asking whether long-term care is generally therapeutic or harmful for the development of previously maltreated children, future investigations should focus on the questions "...what are the systemic and interpersonal characteristics of care that promote and sustain children's psychological development throughout childhood, and what characteristics are developmentally harmful?" and "...for which children is care therapeutic, and for which children is it not?" PMID- 28734201 TI - Modification of chemical properties, Cu fractionation and enzymatic activities in an acid vineyard soil amended with winery wastes: A field study. AB - The effects of adding two winery wastes, perlite waste (PW) and bentonite waste (BW), to an acid vineyard soil were assessed using some chemical and biological soil properties in a field study that lasted 18 months. The addition of PW (up to 81 Mg ha-1) had neither significant nor permanent effects on soil characteristics such as the pH, organic matter content or nutrient concentrations, the amounts of copper or zinc, or the electrical conductivity. Moreover, no persistent negative effects were found on the enzymatic activities after PW application. In contrast, soil that was amended with up to 71 Mg BW ha-1 showed increases in its soil pH values, exchangeable potassium and water soluble potassium and phosphorus contents. In addition, it caused significant increases in the electrical conductivity and water-soluble Cu. In addition, the phosphomonoesterase enzymatic activity decreased significantly (up to 28%) in response to the amendment with 71 Mg BW ha-1. These results showed that adding BW and PW to the soil may be a good agronomic practice for recycling these types of wastes. However, in the case of PW, its use as a soil amendment must be performed with caution to control its possible harmful effects. PMID- 28734202 TI - Creating institutional flexibility for adaptive water management: insights from two management agencies. AB - Adaptive management is an experimental approach used by water management agencies around the world to manage and restore aquatic ecosystems. The effectiveness of the approach can often be constrained by inflexible institutional arrangements. In this paper we compare two cases where agencies have implemented adaptive management to manage and restore aquatic ecosystems. Our aim was to understand practitioners' perceptions of how institutional flexibility can be created for adaptive management. We interviewed 14 adaptive management practitioners working in the Murray-Darling Basin, Australia and 14 practitioners in Southern Florida, United States of America. We found that in both cases, just enough flexibility was created to enable experimentation, but informal institutional arrangements tended to constrain adaptive management. We also found that adaptive management was effective when an agency adopted collaborative and distributed leadership, but these leadership styles were difficult to sustain, and not always appropriate when attempting to create institutional flexibility. Our results illustrate how agencies, stakeholders and researchers can develop a shared understanding of how to manage and restore aquatic ecosystems, which in turn, helps create institutional flexibility for an agency to manage adaptively. PMID- 28734203 TI - Exenatide mitigated diet-induced vascular aging and atherosclerotic plaque growth in ApoE-deficient mice under chronic stress. AB - BACKGROUND AND AIMS: Exposure to psychosocial stress is a risk factor for cardiovascular disorders. Because the glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) agonist prevents cardiovascular injury, we investigated the beneficial effects and mechanism of the GLP-1 analogue exenatide on stress-related vascular senescence and atherosclerosis in apolipoprotein E-deficient (ApoE-/-) mice fed a high-fat (HF) diet. METHODS: ApoE-/- mice fed the HF diet were assigned to non stressed and immobilized-stress groups for 12 weeks. Mice fed the HF diet were divided into 2 groups and administered vehicle or exenatide for 12 weeks under stress conditions. RESULTS: Chronic stress enhanced vascular endothelial senescence and atherosclerotic plaque growth. The stress increased the levels of plasma depeptidyl peptidase-4 activity and decreased the levels of plasma GLP-1 and both plasma and adipose adiponectin (APN). As compared with the mice subjected to stress alone, the exenatide-treated mice had decreased plaque microvessel density, macrophage accumulation, broken elastin, and enhanced plaque collagen volume, and lowered levels of peroxisome proliferator-activated receptor alpha, gp91phox osteopontin, C-X-C chemokine receptor-4, toll-like receptor-2 (TLR2), TLR4, and cathepsins K, L, and S mRNAs and/or proteins. Exenatide reduced aortic matrix metalloproteinase-9 (MMP-9) and MMP-2 gene expression and activities. Exenatide also stimulated APN expression of preadipocytes and inhibited ox-low density lipoprotein-induced foam cell formation of monocytes in stressed mice. CONCLUSIONS: These results indicate that the exenatide-mediated beneficial vascular actions are likely attributable, at least in part, to the enhancement of APN production and the attenuation of plaque oxidative stress, inflammation, and proteolysis in ApoE-/- mice under chronic stress. PMID- 28734204 TI - Molecular dynamics of conformation-specific dopamine transporter-inhibitor complexes. AB - The recreational psychostimulant cocaine inhibits dopamine reuptake from the synapse, resulting in excessive stimulation of postsynaptic dopamine receptors in brain areas associated with reward and addiction. Cocaine binds to and stabilizes the outward- (extracellular-) facing conformation of the dopamine transporter (DAT) protein, while the low abuse potential DAT inhibitor benztropine prefers the inward- (cytoplasmic-) facing conformation. A correlation has been previously postulated between psychostimulant abuse potential and preference for the outward facing DAT conformation. The 3beta-aryltropane cocaine analogs LX10 and LX11, however, differ only in stereochemistry and share a preference for the outward facing DAT, yet are reported to vary widely in abuse potential in an animal model. In search of the molecular basis for DAT conformation preference, complexes of cocaine, benztropine, LX10 or LX11 bound to each DAT conformation were subjected to 100ns of all-atom molecular dynamics simulation. Results were consistent with previous findings from cysteine accessibility assays used to assess an inhibitor's DAT conformation preference. The respective 2beta- and 2alpha-substituted phenyltropanes of LX10 and LX11 interacted with hydrophobic regions of the DAT S1 binding site that were inaccessible to cocaine. Solvent accessibility measurements also revealed subtle differences in inhibitor positioning within a given DAT conformation. This work serves to advance our understanding of the conformational selectivity of DAT inhibitors and suggests that MD may be useful in antipsychostimulant therapeutic design. PMID- 28734205 TI - Identification of Mycobacterium tuberculosis enoyl-acyl carrier protein reductase inhibitors: A combined in-silico and in-vitro analysis. AB - Mycobacterium tuberculosis (Mtb), had developed evolutionary changes in its genome to adapt for survival and thereby generated multi-drug resistant strains. However, novel drug targets that remained unchanged for their biochemical role has impressed the research community to target such proteins. The comprehensive analysis of multiple protein targets has influenced us to make a consensus structural rule exploited by pharmacophore and other allied techniques from a large repository of protein structures. In this pursuit, we made a retrospective analysis of pharmacophores mapped from the tuberculosis structural proteome and identified unique patterns that can be employed for the novel molecules design. The current work on NADH-dependent enoyl-acyl carrier protein reductase (InhA) has yielded top scored pharmacophore models which were searched over SPECS natural product database to prioritize the molecules that can be targeted against Mtb. With efforts on rigorous validation and expertise, we have identified such pharmacophoric patterns from natural compounds that can be used as initial hits. Subsequently, these hits were subjected to in-vitro antitubercular evaluation to ensure the inhibitory activity against the mycobacterium culture growth (MtbH37Rv). Furthermore, docking simulations were carried out to provide an insight on the possible modes of interaction between the experimentally explored compounds and InhA. PMID- 28734206 TI - Theoretical investigation of the conformational space of baicalin. AB - Flavonoids are a large group of polyphenolic compounds ubiquitously present in plants. They are important components of human diet. They are recognized as potential drug candidates to be used in the treatment and prevention of a lot of pathological disorders, due to their protective effects. Baicalin (7-glucuronic acid 5, 6-dihydroxyflavone) is one of the main single active constituents isolated from the dried roots of Scutellaria baicalensis Georgi. The great interest on this flavonoid is due to its various pharmacological properties, such as antioxidant, antimicrobial, anti-inflammatory, anticancer and so on, and its high accumulation in the roots of S. baicalensis. The aim of our work was to analyze the geometric and electronic properties of baicalin conformers (BCL), thus performing a complete search on the conformational space of this flavonoid in gas phase and in aqueous solution. The results indicate that the conformational space of baicalin is formed by eight conformers in gas phase and five conformers in aqueous solution optimized at B3LYP/6-311++G** theory level. BCLa2TT and BCLa1TT conformers have low stability in gas phase and very high stability in aqueous solution. This variation is related to a modification in the tau1 angle that represents the relative position of the glucuronide unit respect to the central rings of the flavan nucleus (A and C). This modification was successfully explained by examining the changes in the hydrogen bond (HB) interactions that occur in the region around the hydroxyl group located in position 6 of ring A. Besides, the molecular electrostatic potential (MEP) and frontier molecular orbital (FMO) analyses indicate that BCLa2TT and BCLa1TT conformers are the most favorable conformers for interacting with positively charged species (such as metal ions) in aqueous media (such as biological fluids). PMID- 28734207 TI - In silico designing of therapeutic protein enriched with branched-chain amino acids for the dietary treatment of chronic liver disease. AB - Leucine, isoleucine, and valine are three essential branched-chain amino acids (BCAA) account for 40-45% of total essential amino acids. BCAA stimulates protein synthesis primarily in skeletal muscles, and it can directly transport to circulatory blood stream bypassing the liver. Hence, a protein enriched with BCAA is an important therapeutic target for the dietary treatment of chronic liver disease. The present study is to design a synthetic protein enriched with BCAA and the challenge is to maximize the BCAA content, keeping the balanced ratio of leucine, isoleucine, valine - 2: 1: 1.2 as specified by WHO/UNU/FAO. Here, we turned the general concept of homology modeling and tried to find a suitable scaffold (alpha-helix) to host an excess amount of BCAA for increased stability and digestibility. A total of 50 protein models were constructed by using SWISS MODEL, Modeller 9.17, ProtParam tool, and allergen online tools. Out of 50 different protein models, protein model-50 was found to be best, which had a well defined 3D structure, good in silico digestibility, balanced ratio of BCAA and showed 65.57% structure identity to the template apo-bovine alpha-lactalbumin (1F6R). Templates search was performed against PDB using PSI-BLAST, SWISS-MODEL, PROFUNC, I-TASSER, and ConSurf. The secondary structure was predicted by PSSPred, PSIPRED, I-TASSER, PORTER, and SPIDER2. The modeled structure of protein Model-50 was validated by PROCHECK, ERRAT, ProSA, and QMEAN. COACH and ProFUNC tools were performed to determine the functional effects of protein model-50. Overall, the BCAA was enriched from 22 to 56.4% with the balanced ratio of Leu: Ile: Val (2: 1: 1.2). The Ramachandran plot showed 97.7% of the amino acid residues in allowed regions with ERRAT score of 86.05. We have successfully modeled the complete three-dimensional structure of the target protein model-50 using highly reputed computational tools. PMID- 28734208 TI - Effect of mutation on Abeta1-42-Heme complex in aggregation mechanism: Alzheimer's disease. AB - Amyloid beta (Abeta) peptide aggregation is one of the root causes for Alzheimer's disease. Recently, experimental studies show that three active binding sites (His6, His13 and His14) of Abeta peptides were bound with heme to form Abeta-Heme complex, which leads to inhibit the aggregation process. We apply molecular dynamic simulation to investigate the aggregation pathways of Abeta Heme peptides. The above three binding sites were mutated by Glycine residue individually and generate three complex systems such as Abeta(His6Gly)-Heme, Abeta(His13Gly)-Heme and Abeta(His14Gly)-Heme. These complexes were simulated in explicit water using gromos53a6 force field for 200ns. We found that the His13Gly mutation increase the beta-sheet contents (75%) in Abeta peptide. On the other hand, heme binds with His13 residue of native peptide plays an important role to reduce the formation beta-sheet content (50%) in Abeta peptide. This finding is in agreement with experimental study, which showed that the effect of mutation on His6 is not directly involved in beta-sheet formation, but the effect of mutation in His13 and His14 has involved in beta-sheet formation [J. Neurochem. (2009), 110, 1784-1795]. So, our results may be useful to understand the pathway mechanism of aggregation of Abeta peptides. PMID- 28734209 TI - New insight into the environmental impact of two imidazolium ionic liquids. Effects on seed germination and soil microbial activity. AB - The next generation of ionic liquids must be synthetized taking into account structures that guarantee the suitable properties for a defined application as well as ecological data. Thus, searching of the right methodologies to know, quickly and efficiently, the ecological effects of these compounds is a preliminary task. The effects of two imidazolium based ionic liquids with different anions, 1-butyl-3-methylimidazolium tetrafluoroborate, [C4C1Im][BF4], and 1-propyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide, [C3C1Im][NTf2], on seedling emergence of six tree species and on the microbial behaviour of two soils were determined in this work. Results showed that the highest doses of both ionic liquids caused the total inhibition of germination for almost all the species studied and that the seeds are more sensitive to the presence of these compounds than soil microbial activity. Nevertheless, signals of stress and death are observed from the results of heat released by microorganisms after the addition of the highest doses of both ionic liquids. The novelty of this work resides in the enlargement of knowledge of toxicity of ILs on complex organisms such as arboreal species and microbial activity of soils studied for the first time through a microcalorimetric technique. PMID- 28734210 TI - Effects analysis of substituent characteristics and solvents on the photodegradation of polybrominated diphenyl ethers. AB - The ultraviolet spectra and electron transition information of 209 polybrominated diphenyl ethers (PBDEs) in gas were first calculated via time-dependent density functional theory using Gaussian 09 software. The main and second-order interactional effects of substituent characteristics on the photodegradation of PBDEs were then analysed using a full factorial experimental design. Solvent effects were considered to research the effect and promotion mechanism of solvent molecules on the photodegradation of PBDEs compared with that in gas. The results showed that the introduction of substituents at each position promoted excitation of PBDEs from their ground states to excited states to induce photodegradation. The different positions affected the photodegradation of PBDEs with magnitudes of para > meta > ortho. The congeners with a concentrated distribution of substituents can always be photodegraded more easily than those with separated substituents. From the viewpoint of light-induced reactions, the electron transfer reactions between molecules of PBDE* T1 and Solvent* T1 are the main driving force for the enhanced photodegradation of PBDEs in solvents compared with that in gas. PMID- 28734211 TI - Organotropism of methylmercury in fish of the southeastern of Brazil. AB - This is one of the first studies to evaluate the effect of biometric variables (total length and weight), diet, and abiotic matrices (sediment and water column) on the bioaccumulation of methylmercury in tissues (muscle, liver, and gills) of four fish (two carnivore-invertivores, Pimelodus fur and Pachyurus adspersus; one carnivore-piscivore, Oligosarcus hepsetus; and one omnivore, Pimelodella lateristriga) in the lower section of a river in southeastern Brazil. Samples of fish (n = 120), water (n = 5) and sediment (n = 5) were collected at five sites characterized by pollution with mercury due to the use of organomercury fungicides and stream bed gold mining, commonly carried out in that section of the river in the 1980s. The results show that biometric variables are strongly correlated with methylmercury levels in muscle (r = 0.61, p < 0.0005) of P. fur. As a rule, concentrations of total mercury and methylmercury did not vary considerably between the organs of the species of different food habits, because of the environmental conditions in the study area. Despite the low concentrations of mercury in sediments (<0.05 mg kg-1 wet. wt), this compartment is a representative source of this pollutant for the organisms investigated, due to the close contact these animals keep with it in view of the low water columns in that section of the river. PMID- 28734212 TI - Treatment of refractory contaminants by sludge-derived biochar/persulfate system via both adsorption and advanced oxidation process. AB - A novel strategy for the removal of refractory organic contaminants was realized through sludge-derived biochar (SDBC)/persulfate (PS) system via both adsorption and advanced oxidation process under ambient conditions. SDBC was prepared by one single step of slow pyrolysis of municipal sewage sludge, appeared a porous structure, and contained abundant oxygen-containing functional groups as well as amorphous Fe species. Large surface area and porous structure of SDBC benefitted the adsorption and enrichment of contaminants, while oxygen-containing functional groups and Fe species on the surface were considered as reactive components for the activation of PS. Under conditions of [PS]0 = 1.85 mM, [4-chlorophenol]0 = 0.039 mM, [SDBC]0 = 1 g L-1, pH0 = 6.30 and temperature = 25 degrees C, the removal of model compound of 4-chlorophenol achieved 92.3%, and this significant performance of SDBC/PS system was consistent in a broad pH window. Radical scavengers and electron paramagnetic resonance (EPR) studies suggested that SDBC successfully activated PS to produce various oxidative radicals. Meanwhile, recycle experiments and Fe3+ leaching tests further demonstrated the stability of SDBC during the activation of PS. Municipal landfill leachate effluent through a membrane bio-reactor was testified as the refractory real wastewater, in which both the removal of total organic carbon and ammonia was significant. Thus, SDBC showed certain advantages in PS activation such as feasible preparation method, remarkable efficiency and stability. These advantages proved SDBC/PS system as an effective strategy of controlling waste by waste, and implicated its potential application in full-scale for the treatment of refractory organic contaminants. PMID- 28734213 TI - Enhanced cadmium phytoremediation of Glycine max L. through bioaugmentation of cadmium-resistant bacteria assisted by biostimulation. AB - This study examined the potential of three strains of cadmium-resistant bacteria, including Micrococcus sp., Pseudomonas sp. and Arthrobacter sp., to promote root elongation of Glycine max L. seedlings, soil cadmium solubility and cadmium phytoremediation in G. max L. planted in soil highly polluted with cadmium with and without nutrient biostimulation. Micrococcus sp. promoted root length in G. max L. seedlings under toxic cadmium conditions. Soil inoculation with Arthrobacter sp. increased the bioavailable fraction of soil cadmium, particularly in soil amended with a C:N ratio of 20:1. Pot culture experiments observed that the highest plant growth was in Micrococcus sp.-inoculated plants with nutrient biostimulation. Cadmium accumulation in the roots, stems and leaves of G. max L. was significantly enhanced by Arthrobacter sp. with nutrient biostimulation. A combined use of G. max L. and Arthrobacter sp. with nutrient biostimulation accelerated cadmium phytoremediation. In addition, cadmium was retained in roots more than in stems and leaves and G. max L. had the lowest translocation factor at all growth stages, suggesting that G. max L. is a phytostabilizing plant. We concluded that biostimulation-assisted bioaugmentation is an important strategy for improving cadmium phytoremediation efficiency. PMID- 28734214 TI - Effects of damming on the distribution and methylation of mercury in Wujiang River, Southwest China. AB - Newly built reservoirs are regarded as sensitive ecosystem for mercury (Hg) methylation. A comprehensive study was conducted to understand the influence of damming on the distribution and methylation of Hg within a river-reservoir ecosystem in Wujiang River Basin (WRB), Southwest China. Hg species in inflow outflow rivers of six cascade reservoirs were analyzed each month during 2006. Mean concentrations of total Hg (THg) and methylmercury (MeHg) in river water in WRB were 3.41 +/- 1.98 ng L-1 and 0.15 +/- 0.06 ng L-1, respectively. THg and particulate Hg (PHg) concentrations in outflow rivers of reservoirs significantly decreased after dam construction, suggesting that a considerable amount of PHg was intercepted by way of sedimentation. However, the influence of damming on the distributions of dissolved Hg (DHg) and reactive Hg (RHg) in rivers was less pronounced. MeHg concentrations in outflow rivers of the older reservoirs significantly increased compared to inflow rivers with the maximum increasing factor of 92%, indicating the active net Hg methylation in the reservoirs. However, the difference between MeHg in inflow rivers and outflow rivers were less pronounced in the newly constructed reservoirs, indicating that these reservoirs were not active sites of Hg methylation. The construction of the cascade reservoirs resulted in the elevation of MeHg in several sections of the Wujiang River, which attributed to the net Hg methylation in reservoirs and discharge of MeHg from hypolimnion. MeHg-enriched water in outflow rivers from hypolimnetic water could be transported to downstream, posing potential threat to the aquatic food web and human health. PMID- 28734215 TI - DNA damage and cytotoxicity induced on common carp by pollutants in water from an urban reservoir. Madin reservoir, a case study. AB - Madin Reservoir provides a substantial amount of drinking water to two municipalities close to Mexico City metropolitan area. However, it receives untreated wastewater discharges from domestic sources in the towns of Nuevo Madin and others, as well as diverse pollutants which are hauled by the Rio Tlalnepantla from its upper reaches, so that the xenobiotics in the reservoir are highly diverse in terms of type and quantity. Previous studies showed that MR is contaminated with xenobiotics such as Al, Hg and Fe, as well as NSAIDs, at concentrations exceeding the limits established for aquatic life protection. These pollutants have been shown to induce oxidative stress on Cyprinus carpio and may therefore also damage the genetic material of exposed organisms, eliciting cytotoxicity as well. The present study aimed to determine the genotoxicity and cytotoxicity induced on blood, liver and gill of C. carpio by the pollutants present in MR water. Specimens were exposed to water from five sampling sites and the following biomarkers were evaluated: DNA damage by comet assay, frequency of micronuclei, apoptosis by TUNEL assay and caspase-3 activity. Significant increases relative to the control group (P < 0.05) were found with all biomarkers in all tissues evaluated, with the level of damage differing between sampling sites. In conclusion, pollutants present in MR water are genotoxic and cytotoxic to C. carpio, and this sentinel species, coupled with the biomarkers evaluated herein, is a reliable tool for assessing the health risk to wildlife posed by exposure to pollutants in freshwater bodies. PMID- 28734216 TI - Releasing of hexabromocyclododecanes from expanded polystyrenes in seawater field and laboratory experiments. AB - Expanded polystyrene (EPS) is a major component of marine debris globally. Recently, hazardous hexabromocyclododecanes (HBCDDs) were detected in EPS buoys used for aquaculture farming. Subsequently, enrichment of HBCDDs was found in nearby marine sediments and mussels growing on EPS buoys. It was suspected that EPS buoys and their debris might be sources of HBCDDs. To confirm this, the release of HBCDDs from EPS spherules detached from a buoy to seawater was investigated under field (open sea surface and closed outdoor chambers with sun exposure and in the dark) and laboratory (particle-size) conditions. In all exposure groups, initial rapid leaching of HBCDDs was followed by slow desorption over time. Abundant release of HBCDDs was observed from EPS spherules exposed to the open sea surface (natural) and on exposure to sunlight irradiation or in the dark in controlled saline water. Water leaching and UV-light/temperature along with possibly biodegradation were responsible for about 37% and 12% of HBCDDs flux, respectively. Crumbled EPS particles (<=1 mm) in samples deployed on the sea surface for 6 months showed a high degree of weathering. This implies that surface erosion and further fragmentation of EPS via environmental weathering could enhance the leaching of HBCDDs from the surface of EPS. Overall, in the marine environment, HBCDDs could be released to a great extent from EPS products and their debris due to the cumulative effects of the movement of large volumes of water (dilution), biodegradation, UV-light/temperature, wave action (shaking), salinity and further fragmentation of EPS spherules. PMID- 28734217 TI - Emotional arousal and recognition memory are differentially reflected in pupil diameter responses during emotional memory for negative events in younger and older adults. AB - A better memory for negative emotional events is often attributed to a conjoint impact of increased arousal and noradrenergic modulation (NA). A decline in NA during aging is well documented but its impact on memory function during aging is unclear. Using pupil diameter (PD) as a proxy for NA, we examined age differences in memory for negative events in younger (18-30 years) and older (62-83 years) adults based on a segregation of early arousal to negative events, and later retrieval-related PD responses. In keeping with the hypothesis of reduced age related NA influences, older adults showed attenuated induced PD responses to negative emotional events. The findings highlight a likely contribution of NA to negative emotional memory, mediated via arousal that may be compromised with aging. PMID- 28734218 TI - The evaluation of polycyclic aromatic hydrocarbons (PAHs) biodegradation kinetics in soil amended with organic fertilizers and bulking agents. AB - The aim of this study was to investigate the polycyclic aromatic hydrocarbons (PAHs) biodegradation kinetics in soils fertilized with organic amendments (sewage sludge, compost), bulking agents (mineral sorbent, silicon dioxide in form of nano powder), and novel compositions of those materials. The scope of conducted works includes a cyclic CO2 production measurements and the determinations of PAHs content in soil samples, before and after 3-months of incubation. Obtained results show that the use of both type of organic fertilizers have a positive effect on the PAHs removal from soil. However, the CO2 emission remains higher only in the first stage of the process. The best acquired means in terms of PAHs removal as well as most sustained CO2 production were noted in samples treated with the mixtures of organic fertilizers and bulking agents. In conclusion the addition of structural forming materials to the organic fertilizers was critical for the soil bioremediation efficiency. Therefore, the practical implementation of collected data could find a wide range of applications during the design of new, more effective solutions for the soil bioremediation purposes. PMID- 28734219 TI - Acute toxicity of cadmium in Anisops sardeus (Heteroptera:Notonectidae): Effects on adult and nymphal survival and swimming behavior. AB - Adult female and male, and final instar nymph of Anisops sardeus (Heteroptera: Notonectidae) were exposed to graded concentrations of cadmium in 96h static-with renewal acute toxicity tests, which were conducted in dry (March) and wet (May June) seasons. The 96h LC50 values for instar V nymph, adult female and male were found to be 0.9, 0.59 and 0.51mgL-1 Cd, respectively, in wet season, while these were 26.7 and 20.2mgL-1 Cd for adult female and male, respectively, in dry season. Adult males were most sensitive to Cd, followed by females in both seasons, while highest tolerance in wet season was observed in instar V nymph. There was a steep decline in LC50 values from 24 to 96h in wet season. Besides mortality at higher concentrations of Cd, sublethal effects in terms of reduced 'velocity magnitude' (swimming speed) and mostly increased 'rotation angle' (turning angle) could be discerned at concentrations as low as 0.03mgL-1. The swimming pattern of Cd-exposed nymph and adults were also affected. Based on the bioaccumulation factor (BAF) values, A. sardeus could be designated as a macroconcentrator of Cd (BAF > 2), with highest Cd accumulation in instar V nymph, followed by that in female, and with lowest Cd accumulation in male. PMID- 28734220 TI - Effect analysis of quantum chemical descriptors and substituent characteristics on Henry's law constants of polybrominated diphenyl ethers at different temperatures. AB - Twelve substituent descriptors, 17 quantum chemical descriptors and 1/T were selected to establish a quantitative structure-property relationship (QSPR) model of Henry's law constants for 7 polybrominated diphenyl ethers (PBDEs) at five different temperatures. Then, the lgH of 202 congeners at different temperatures were predicted. The variation rule and regulating mechanism of lgH was studied from the perspectives of both quantum chemical descriptors and substituent characteristics. The R2 for modeling and testing sets of the final QSPR model are 0.977 and 0.979, respectively, thus indicating good fitness and predictive ability for Henry' law constants of PBDEs at different temperatures. The favorable hydrogen binding sites are the 5,5',6,6'-positions for high substituent congeners and the O atom of the ether bond for low substituent congeners, which affects the interaction between PBDEs and water molecules. lgH is negatively and linearly correlated with 1/T, and the variation trends of lgH with temperature are primarily regulated by individual substituent characteristics, wherein: the more substituents involved, the smaller the lgH. The significant sequence for the main effect of substituent positions is para>meta>ortho, where the ortho positions are mainly involved in second-order interaction effect (64.01%). Having two substituents in the same ring also provides a significant effect, with 81.36% of second-order interaction effects, particularly where there is an adjacent distribution (55.02%). PMID- 28734221 TI - Treatment of highly toxic cardboard plant wastewater by a combination of electrocoagulation and electrooxidation processes. AB - The objective of this study was to investigate the removal efficiencies of the electrochemical treatment systems as an alternative for the treatment of cardboard plant wastewater (CPW). In accordance with this purpose, CPW was treated by electrocoagulation (EC) with Al electrodes and the effects of current density (CD), operating time (t), and initial pH (pHi) were investigated. The results showed that EC at optimum treatment conditions (CD: 7.5mA/cm2, pHi: 7.0 and t: 60min) have limited removal efficiencies for total organic carbon (TOC; 17.1%) and chemical oxygen demand (COD, 14.2%), on the contrary of turbidity (98.7%). Due to the low TOC and COD removal efficiencies, a secondary treatment was needed and the electrocoagulated effluent was subjected to electrooxidation (EO) by using a boron doped diamond (BDD) electrode for investigating the effect of CD, t, pHi and electrolyte concentration (Ce). Higher TOC (83.7%) and COD (82.9%) removal efficiencies were obtained by EO under the optimum treatment conditions (CD: 100mA/cm2, pHi: 7.2, Ce: 5.0g/L Na2SO4 and t: 180min). In addition, a toxicity test was carried out to the raw and treated wastewater under the optimum operating conditions. This study demonstrated that the combination of EC and EO have a satisfactory potential for real industrial wastewater with a high organic content, suspended solids and toxicity. PMID- 28734222 TI - Species sensitivity distribution for pentachlorophenol to aquatic organisms based on interval ecotoxicological data. AB - Species sensitivity distribution (SSD) model is often used to extrapolate the chemicals' effects from the ecotoxicological data on individual species to ecosystems, and is widely applied to derive water quality criteria or to assess ecological risk. Because of the influence of various factors, the ecotoxicological data of a specific chemicals to an individual usually exist in a range. The feasibility of interval ecotoxicological data directly applied to build SSD model has not been clearly stated. In the present study, by means of Bayesian statistics, the half maximal effective concentration (EC50) of pentachlorophenol (PCP) to 161 aquatic organisms, which were organized into 7 groups, i.e., single determined value, geometric mean estimation, median estimation, interval data, and combination of single determined data with other groups, were used to develop SSD models and to estimate the minimum sample sizes. The results showed that the interval data could be directly applied to build SSD model, and when combined with single point data could give the narrowest credible interval that indicates a stable and robust SSD model. Meanwhile, the results also implied that at least 6-14 ecotoxicological data were required to build a stable SSD model. It suggests that the utilization of interval data in building SSD model can effectively enhance the availability of ecotoxicological data, reduce the uncertainty brought by sample size or point estimation, and provide a reliable way to widen the application of SSD model. PMID- 28734223 TI - Differential effects of citric acid on cadmium uptake and accumulation between tall fescue and Kentucky bluegrass. AB - Organic acids play an important role in cadmium availability, uptake, translocation, and detoxification. A sand culture experiment was designed to investigate the effects of citric acid on Cd uptake, translocation, and accumulation in tall fescue and Kentucky bluegrass. The results showed that two grass species presented different Cd chemical forms, organic acid components and amount in roots. The dormant Cd accumulated in roots of tall fescue was the pectate- and protein- integrated form, which contributed by 84.85%. However, in Kentucky bluegrass, the pectate- and protein- integrated Cd was only contributed by 35.78%, and the higher proportion of Cd form was the water soluble Cd-organic acid complexes. In tall fescue, citric acid dramatically enhanced 2.8 fold of Cd uptake, 3 fold of root Cd accumulation, and 2.3 fold of shoot Cd accumulation. In Kentucky bluegrass, citric acid promoted Cd accumulation in roots, but significantly decreased Cd accumulation in shoots. These results suggested that the enhancements of citric acid on Cd uptake, translocation, and accumulation in tall fescue was associated with its promotion of organic acids and the water soluble Cd-organic acid complexes in roots. PMID- 28734224 TI - Structural characterization of glucosylated lactose derivatives synthesized by the Lactobacillus reuteri GtfA and Gtf180 glucansucrase enzymes. AB - Glucansucrase enzymes from lactic acid bacteria are receiving strong interest because of their wide range of gluco-oligosaccharide and polysaccharide products from sucrose, some of which have prebiotic potential. Glucansucrases GtfA and Gtf180 from Lactobacillus reuteri strains are known to convert sucrose into alpha glucans with different types of linkages, but also to use other molecules as acceptor substrates. Here we report that incubation of (N-terminally truncated versions of) these enzymes with lactose plus sucrose resulted in synthesis of at least 5 glucosylated lactose products of a degree of polymerization (DP) of 3-4. Only glucansucrase Gtf180-DeltaN also produced larger lactose-based oligosaccharides (up to DP9). Structural characterization of the glucosylated lactose products DP3-4 revealed glycosidic bonds other than (alpha1->4)/(alpha1 >6) typical for GtfA-DeltaN and (alpha1->3)/(alpha1->6) typical for Gtf180 DeltaN: Both GtfA-DeltaN and Gtf180-DeltaN now introduced a glucosyl residue (alpha1->3)- or (alpha1->4)-linked to the non-reducing galactose unit of lactose. Both enzymes also were able to introduce a glucosyl residue (alpha1->2)-linked to the reducing glucose unit of lactose. These lactose derived oligosaccharides potentially are interesting prebiotic compounds. PMID- 28734225 TI - Adverse effects of methylmercury (MeHg) on life parameters, antioxidant systems, and MAPK signaling pathways in the rotifer Brachionus koreanus and the copepod Paracyclopina nana. AB - To evaluate the adverse effects of MeHg on the rotifer Brachionus koreanus and the copepod Paracyclopina nana, we assessed the effects of MeHg toxicity on life parameters (e.g. growth retardation and fecundity), antioxidant systems, and mitogen-activated protein kinase (MAPK) signaling pathways at various concentrations (1ng/L, 10ng/L, 100ng/L, 500ng/L, and 1000ng/L). MeHg exposure resulted in the growth retardation with the increased ROS levels but decreased glutathione (GSH) levels in a dose-dependent manner in both B. koreanus and P. nana. Antioxidant enzymatic activities (e.g. glutathione S-transferase [GST], glutathione reductase [GR], and glutathione peroxidase [GPx]) in B. koreanus showed more positive responses compared the control but in P. nana, those antioxidant enzymatic activities showed subtle changes due to different no observed effect concentration (NOEC) values among the two species. Expression of antioxidant genes (e.g. superoxide dismutase [SOD], GSTs, glutathione peroxidase [GPx], and catalase [CAT]) also demonstrated similar effects as shown in antioxidant enzymatic activities. In B. koreanus, the level of p-ERK was decreased in the presence of 1000ng/L MeHg, while the levels of p-ERK and p-p38 in P. nana were reduced in the presence of 10ng/L MeHg. However, p-JNK levels were not altered by MeHg in B. koreanus and P. nana, compared to the corresponding controls. In summary, life parameters (e.g. reduced fecundity and survival rate) were closely associated with effects on the antioxidant system in response to MeHg. These observations provide a better understanding on the adverse effects of MeHg on in vivo life parameters and molecular defense mechanisms in B. koreanus and P. nana. PMID- 28734226 TI - Inhibition of pRB Pathway Differentially Modulates Apoptosis in Esophageal Cancer Cells. AB - Esophageal cancer is the sixth most common cause of cancer-related death worldwide. Current chemotherapy regimens include a combination of 5-fluorouracil (5-FU) and cisplatin, but more efficient therapy strategies are needed to increase 5-year survival. Alterations in the signaling pathway of the tumor suppressor gene Rb-1, which encodes a phosphoprotein (pRB) that negatively regulates the G1/S transition of the cell cycle, are present in 70% of all tumors, but its role in esophageal cancer is still unclear. Most of these are alterations leading to up-regulation of the activity of cyclin-dependent kinases (CDKs) to phosphorylate pRB, which suggests that keeping the wild type pRB phosphorylated might be advantageous. Besides proliferation, pRB also regulates apoptosis induced by tumor necrosis factor-alpha (TNF-alpha) and DNA-damage. We investigated the status of phosphorylation of pRB along esophageal tumorigenesis stages, as well as whether hyperphosphorylation of pRB could suppress apoptosis induced by cisplatin, 5-FU, or TNF-alpha in esophageal cancer cells. pRB phosphorylation increased progressively from normal esophageal tissue to metaplasia and adenocarcinoma, suggesting that pRB phosphorylation increases along esophageal tumor stages. When RB-1 was knocked down or CDK inhibitors reduced the levels of phosphorylated pRB, opposite apoptotic effects were observed, depending on the combination of drugs tested: whereas TNF-alpha- and cisplatin-induced apoptosis increased, 5-FU-induced apoptosis decreased. Taken together, these data suggest that pRB plays a role in esophageal adenocarcinoma and that, depending on the type of anti-cancer treatment, combining CDK inhibitors and chemotherapy has the potential to increase the sensitivity of esophageal cancer cells to cell death. PMID- 28734227 TI - Continuous Delivery of Neutralizing Antibodies Elevate CCL2 Levels in Mice Bearing MCF10CA1d Breast Tumor Xenografts. AB - Chemokines are small soluble molecules that play critical roles in wound healing, infection, and cancer progression. In particular, overexpression of the C-C motif chemokine ligand 2 (CCL2) in multiple cancer types correlates with poor patient prognosis. Animal studies have shown that CCL2 signals to macrophages and breast cancer cells to promote tumor growth, invasion, and metastasis, indicating that CCL2 is a promising therapeutic target. However, the effectiveness of human specific neutralizing antibodies has not been fully evaluated. Furthermore, controversies remain on the use of neutralizing antibodies to target CCL2 and could be due to mode of drug delivery. Here, we investigated the effects of continuous delivery of human CCL2-neutralizing antibodies on breast cancer progression. Nude mice bearing MCF10CA1d breast tumor xenografts were implanted with osmotic pumps containing control IgG or anti-CCL2 and analyzed for CCL2 levels and tumor progression over 4 weeks. Despite inhibiting CCL2-induced migration in vitro, CCL2-neutralizing antibodies did not significantly affect tumor growth, invasion, macrophage recruitment, or tumor angiogenesis. CCL2 antibodies did not affect murine CCL2 levels but significantly increased human CCL2 levels in circulating blood and tumor interstitial fluid. CCL2-neutralizing antibodies reduced CCL2 levels in cultured cells short term at high concentrations. Enzyme-linked immunosorbent assay analysis of CCL2 in cultured fibroblasts and breast cancer cells revealed that the neutralizing antibodies sequestered CCL2 in the media. CCL2 levels were restored once the antibodies were removed. These studies reveal limitations in CCL2-neutralizing antibodies as a therapeutic agent, with important implications for translating CCL2 targeting to the clinic. PMID- 28734228 TI - Effect of education on ability of AI professionals and herd-owner inseminators to detect cows not in oestrus and its relation with progesterone concentration on day of re-insemination. AB - The effect of training background of persons performing artificial insemination (AI) (herd-owner inseminators (OWNER), AI technicians (AI-T), and fertility consultants (FC)) on pregnancy rate and their ability to detect cows not in oestrus were studied. A total of 1584 re-AI occasions on 754 dairy farms were included. Milk samples for progesterone (P4) analysis in all cases were collected, as were data on the herd, previous breeding attempts, oestrous signs, uterine tone, slipperiness of cervix, and co-operation of the cow. Further breeding attempts and next calving or culling date were sought from registers. The cases were distributed into three categories based on P4 concentrations; <6 nmol/l (no luteal activity, could be in oestrus), 6-10 nmol/l (some luteal activity), and >10 nmol/l (high luteal activity, not in oestrus). Of cows offered for re-AI 7.7% had P4 concentration >10 nmol/l, with no difference between OWNER farms and farms using AI service. OWNERs chose for AI more cows having intermediate P4 than farms using AI service (9.8% vs. 5.9%, p < 0.05). AI-Ts recommended no AI significantly less often than FCs (1.6% vs. 4.9%, p < 0.01). Both groups were equally right: 71% and 68% of cows that were recommended to have no AI had high P4 concentration. Due to courageous and correct rejection of cows with high P4, FCs inseminated proportionally more cows in low P4 and less cows in intermediate P4 than OWNERs (p < 0.05). Of cows finally inseminated, 36.7% became pregnant, with no difference between OWNER farms and farms using AI service. Fertility consultants had higher pregnancy rates than AI-Ts (39.6% vs. 32.6%, p < 0.05). Toneless uterus and sticky cervix at AI significantly correlated with AI occurring at the wrong time (p < 0.001). Behaviour of the cow at AI did not predict P4 concentration. In conclusion, 7.7% of cows offered for re-AI had high P4 concentration. Training of AI personnel increased their ability to detect and reject these cows. PMID- 28734229 TI - Effects of dietary starch types on early postmortem muscle energy metabolism in finishing pigs. AB - This study aimed to investigate the effects of different dietary starch types on early postmortem muscle energy metabolism in finishing pigs. Ninety barrows (68.0+/-2.0kg) were randomly allotted to three experimental diets with five replicates of six pigs, containing pure waxy maize starch (WMS), nonwaxy maize starch (NMS), and pea starch (PS) (amylose/amylopectin were 0.07, 0.19 and 0.28 respectively). Compared with the WMS diet, pigs fed the PS diet exhibited greater creatine kinase activity, higher adenosine triphosphate and adenosine diphosphate contents, lower phosphocreatine (PCr), adenosine monophosphate and glycogen contents, and lower glycolytic potential (P<0.05). Moreover, the PS diet led to reduced percentage of bound hexokinase activity, decreased level of phosphorylated AKT (P<0.05) and increased level of hypoxia-inducible factor 1alpha (P<0.05). In conclusion, diet with high amylose content might promote PCr degradation and inhibit the rate of glycolysis, followed by attenuation of early postmortem glycolysis in finishing pigs. PMID- 28734230 TI - Simultaneous scanning tunneling microscopy and synchrotron X-ray measurements in a gas environment. AB - A combined X-ray and scanning tunneling microscopy (STM) instrument is presented that enables the local detection of X-ray absorption on surfaces in a gas environment. To suppress the collection of ion currents generated in the gas phase, coaxially shielded STM tips were used. The conductive outer shield of the coaxial tips can be biased to deflect ions away from the tip core. When tunneling, the X-ray-induced current is separated from the regular, 'topographic' tunneling current using a novel high-speed separation scheme. We demonstrate the capabilities of the instrument by measuring the local X-ray-induced current on Au(1 1 1) in 800 mbar Ar. PMID- 28734231 TI - Weight misperception and disordered weight control behaviors among U.S. high school students with overweight and obesity: Associations and trends, 1999-2013. AB - OBJECTIVE: To examine prevalence of weight misperception (incongruence between one's perceived weight status and one's actual weight status) and disordered weight control behaviors (DWCBs; unhealthy behaviors aiming to control or modify weight), associations between weight misperception and DWCBs, and temporal trends in prevalence and associations among adolescents with overweight and obesity from 1999 to 2013. METHODS: Self-reported data from eight biennial cycles (1999-2013) of the cross-sectional national Youth Risk Behavior Survey were used in analyses restricted to respondents with overweight/obesity. Data on weight status perception, use of fasting, purging, and diet pills to control weight, sex, race/ethnicity, and grade in school were used in multivariate logistic regression models. RESULTS: Among U.S. high school students with overweight and obesity, no linear temporal trends were detected for prevalence of weight misperception, fasting, or purging between 1999 and 2013, while a significant linear decrease was observed for prevalence of diet pill use between 1999 and 2013 (b=-0.81, p<0.01). Using data pooled across 1999-2013, weight misperception predicted lower use of all DWCBs examined in this study among females and lower use of fasting to control weight among males. No significant changes over time in associations of weight misperception with fasting or purging were observed, though the association between weight misperception and diet pill use weakened somewhat across 1999-2013. DISCUSSION: In the context of increasing prevalence of overweight and obesity, weight misperception appears to be a robust protective factor for DWCBs. PMID- 28734232 TI - The impact of a faculty training program on inclusive education and disability. AB - This paper describes the knowledge gained by 20 faculty members following their participation in a training program on inclusive education and disability. The study, which was conducted at an university in Spain, aimed to design, implement and evaluate a program for training faculty members to respond in an inclusive manner to the needs of students with disabilities. An initial, formative and summative qualitative evaluation was carried out and four instruments were used for collecting the data: group and individual interviews, written open-ended questionnaires and observations. The data were analyzed inductively, using a category and code system. The results reveal that, after the training program, faculty considered what they had learned to be useful for their professional practice and highlighted that they felt better-informed and better-trained in relation to disability and were more aware of the needs of students with disabilities. Finally, in the conclusions section, the paper discusses the results in relation to those reported by other studies, and offers some recommendations for universities planning to implement training policies designed to build more inclusive learning environments. PMID- 28734233 TI - Risk of hospitalization among survivors of childhood and adolescent acute lymphoblastic leukemia compared to siblings and a general population sample. AB - BACKGROUND: Acute Lymphoblastic Leukemia (ALL) has a high survival rate, but cancer-related late effects in the early post-treatment years need documentation. Hospitalizations are an indicator of the burden of late effects. We identify rates and risk factors for hospitalization from five to ten years after diagnosis for childhood and adolescent ALL survivors compared to siblings and a matched population sample. METHODS: 176 ALL survivors were diagnosed at <=22 years between 1998 and 2008 and treated at an Intermountain Healthcare facility. The Utah Population Database identified siblings, an age- and sex-matched sample of the Utah population, and statewide inpatient hospital discharges. Sex- and birth year-adjusted Poisson models with Generalized Estimating Equations and robust standard errors calculated rates and rate ratios. Cox proportional hazards models identified demographic and clinical risk factors for hospitalizations among survivors. RESULTS: Hospitalization rates for survivors (Rate:3.76, 95% CI=2.22 6.36) were higher than siblings (Rate:2.69, 95% CI=1.01-7.18) and the population sample (Rate:1.87, 95% CI=1.13-3.09). Compared to siblings and population comparisons, rate ratios (RR) were significantly higher for survivors diagnosed between age 6 and 22 years (RR:2.87, 95% CI=1.03-7.97 vs siblings; RR:2.66, 95% CI=1.17-6.04 vs population comparisons). Rate ratios for diagnosis between 2004 and 2008 were significantly higher compared to the population sample (RR:4.29, 95% CI=1.49, 12.32), but not siblings (RR:2.73, 95% CI=0.54, 13.68). Survivors originally diagnosed with high-risk ALL did not have a significantly higher risk than siblings or population comparators. However, high-risk ALL survivors (Hazard ratio [HR]:3.36, 95% CI=1.33-8.45) and survivors diagnosed from 2004 to 2008 (HR:9.48, 95% CI=1.93-46.59) had the highest risk compared to their survivor counterparts. CONCLUSIONS: Five to ten years after diagnosis is a sensitive time period for hospitalizations in the ALL population. Survivors of childhood ALL require better long-term surveillance. PMID- 28734234 TI - Association of primary central nervous system vasculitis with the presence of specific human leucocyte antigen gene variant. AB - OBJECTIVES: The etiology and genetic susceptibility of primary central nervous system vasculitis (PCNSV) are still unclear. PATIENTS AND METHODS: We analyzed the DNA of 25 Caucasian patients with PCNSV for human leucocyte antigen genes HLA A, HLA-B, HLA-DRB1, and HLA-DQB1, respectively. HLA-frequencies of the 25 patients with PCNSV were compared with HLA-frequencies of matched Caucasian controls. RESULTS: No statistically significant associations were found for HLA B, HLA-DR1 and HLA-DQB1 variant. In the PCNSV group, only the HLA-A*69 variant was found more often than expected statistically. CONCLUSION: The results of this study indicate a potential association of HLA marker with PCNSV in Caucasian patients. Further studies are needed to elucidate the role of genes within the human major histocompatibility complex in the pathogenesis of this angiopathy. PMID- 28734235 TI - Characterization of cognitive performance and evaluation of quality of life among patients with HTLV-1. AB - OBJECTIVE: To characterize cognitive alterations among patients with HTLV-1, ascertain what is associated with these alterations and evaluate these patients' quality of life. PATIENTS AND METHODS: This was a cross-sectional study. Patients infected by HTLV-1 who were seen at the Oswaldo Cruz University Hospital from March 2014 to June 2015 were included in the study. A semi-structured questionnaire and the Mini-Mental State Examination, Color Trails Test, Wechsler Adult Intelligence Scale (WAIS-III), Hospital Anxiety and Depression Scale and Medical Outcomes Study 36-Item Short-Form Health Survey (SF36) were used. "Low IQ" scores were defined for WAIS-III as under 80 points. Results Fifty-five patients were evaluated: 26% presented altered MMSE, 38%, altered Color Trails Test; 10.9% presented low total IQ; 12.7%, low executive IQ; and 10.9%, low verbal IQ. There was no association between low total IQ and any characteristics of the patient or of the HTLV infection. Paraparesis and anxiety disorders were significantly associated with worse quality of life. CONCLUSION: High frequency of cognitive impairment was found in patients with HTLV, thus suggesting that these alterations are an important clinical manifestation of this virus. PMID- 28734236 TI - Determinants of mental and physical health-related quality of life among patients hospitalized for suicidal behavior. AB - The current study was interested in exploring the clinical factors related to mental and physical health-related quality of life among patients hospitalized for suicidal behavior. A multicenter cross-sectional study was designed to compare data obtained form 246 patients hospitalized for suicide behavior. Results suggest that mental health-related quality of life was negatively associated with hopelessness while physical health-related quality of life was negatively associated with age, medical disease and the number of previous suicide attempts and positively associated with employment. Findings are discussed in the context of theoretical evidence and clinical implications. PMID- 28734237 TI - The spider and the snake - A psychometric study of two phobias and insights from the Hungarian validation. AB - Specific phobias-particularly zoophobias-are prevalent worldwide and can have fairly dramatic health consequences. Self-report measurements play a crucial role in phobia research studies; thus, it is important to have a reliable tool in different languages. The present investigation examined the psychometric properties of the Hungarian version of two commonly used measures of fear: the Spider Phobia Questionnaire (i.e. SPQ) and the Snake Questionnaire (i.e. SNAQ). The SPQ and SNAQ scores both demonstrated excellent reliability, including a test retest over a 4-week period. Supportive evidence for the validity of the SPQ and SNAQ scores was found using questions assessing fainting and avoidance history, regarding snakes and spiders, based on DSM-V criteria. Both questionnaires could discriminate between participants who reported such an event and those who did not. Further analyses also revealed a sex difference, with women scoring higher than men on both scales. Moreover, 9.5% and 4.24% of the respondents reached the cut-off point, set by previous studies, for spider and snake phobias, respectively. These findings suggest that the SPQ and SNAQ have excellent psychometric properties, making them suitable for use in further cross-cultural research and epidemiological studies. PMID- 28734238 TI - Decreased levels of G protein-coupled estrogen receptor in children with autism spectrum disorders. AB - Sex hormones, specially estrogen, and it is receptors plays a critical role in the pathogenesis of psychiatric disorders including autism spectrum disorders (ASD). The aim of this study was to investigate the relationship between ASD and G protein-coupled estrogen receptor (GPER), a recently discovered estrogen receptors, and also to study the relation of serum GPER levels with the severity of autistic symptoms. The present study included 45 children with drug naive ASD diagnosed by DSM-V criteria, aged between 3 and 12 years and 40 age- and gender matched healthy controls. The severity of ASD was evaluated with the Childhood Autism Rating Scale (CARS) total score. The GPER levels in the serum were measured using the quantitative sandwich enzyme immunoassay technique. The serum GPER level was significantly lower in the ASD patients than in the controls. There was a negative significant correlation between the GPER level and the CARS score. There were no significant correlations between GPER level with estradiol and age. In conclusion, this study demonstrated that the decreased serum GPER levels were associated with ASD and GPER may play an important role in the etiology of ASD. PMID- 28734239 TI - Stigma resistance and its association with internalised stigma and psychosocial outcomes among psychiatric outpatients. AB - Studies have suggested that stigma resistance plays an important role in the recovery from mental illness. However, there has been limited research in Asian countries that has examined the benefits of stigma resistance among the mentally ill in Asian populations. Hence, this study aimed to assess the prevalence of stigma resistance and establish the socio-demographic correlates of stigma resistance, as well as its association with internalised stigma and psychosocial outcomes among a multi-ethnic population of 280 outpatients with obsessive compulsive disorder (OCD), schizophrenia, depressive disorders and anxiety disorders in Singapore. Prevalence of stigma resistance measured using the Stigma Resistance subscale of the Internalised Stigma of Mental Illness Scale was 82.9%. ANOVA and logistic regressions were conducted and results revealed that: (i) Stigma resistance was positively associated with being separated/divorced/widowed but negatively associated with depression diagnosis; (ii) Psychosocial outcomes such as self-esteem and psychological health were positively associated with stigma resistance; and (iii) Internalised stigma was negatively associated with stigma resistance. Moving forward, treatments could emphasize on improving the self-esteem and psychological health of patients to increase their stigma resistance for counteracting effects of public and internalised stigma. PMID- 28734240 TI - Decreased levels of serum fibroblast growth factor-2 in children with autism spectrum disorder. AB - The neurodevelopment and functioning of the central nervous system, and especially the cerebral cortex, have basic importance to understand neuropsychiatric disorders like autism. Fibroblast growth factor-2 (FGF-2) plays a very important role in the development and functioning of the cortex. FGF-2 is related to developmental processes in the central nervous system such as neurogenesis, migration, differentiation and survival. This study researched the serum FGF-2 levels in children with autism spectrum disorder (ASD). With this aim, 60 ASD children and 40 healthy controls were compared. We applied a sociodemographic form and the Childhood Autism Rating Scale (CARS) to each subject with their family to assess the severity of autism. Additionally, all subjects had routine laboratory tests performed. Serum samples were studied with ELISA. The results found that serum FGF-2 levels were statistically significantly low in the patient group compared to the healthy control group (p value 0.003). Additionally there was a statistically significant negative correlation identified between serum FGF-2 levels and CARS score for all subjects (r = 0.300; p = 0.02). In conclusion, FGF-2 may contribute to the etiopathogenesis of ASD. PMID- 28734241 TI - Entrapment, perceived burdensomeness and thwarted belongingness as predictors of suicide ideation. AB - The Integrated Motivational-Volitional (IMV) Model of suicide posits that perceived burdensomeness and thwarted belongingness moderate the association between perceptions of entrapment and suicide ideation. However, the proposed moderation is yet to be tested. Possible moderator effects were investigated in an online sample (N = 480; 74% female; Mage = 28.5, SDage = 11.1). Entrapment and perceived burdensomeness predicted suicide ideation. However, neither perceived burdensomeness nor thwarted belongingness moderated the association between entrapment and suicide ideation. The present results do not support a key assumption of the IMV-Model. Nonetheless, they underscore the importance of perceived burdensomeness and entrapment in the prediction of suicide ideation. PMID- 28734242 TI - Environmental estrogen(s) induced swimming behavioural alterations in adult zebrafish (Danio rerio). AB - The present study is an attempt to investigate the effects of long-term (75days) exposure to environmental estrogens (EE) on the swimming behaviour of zebrafish (Danio rerio). Adult zebrafish were exposed semi-statically to media containing commonly detected estrogenic water contaminants (EE2, DES and BPA) at a concentration (5ng/L) much lower than environmentally recorded levels. Time spent in swimming, surface preference, patterns and path of swimming were recorded (6mins) for each fish using two video cameras on day 15, 30 60 and 75. Video clips were analysed using a software program. Results indicate that chronic exposure to EE leads to increased body weight and size of females, reduced (P<0.05) swimming time, delay in latency, increased (P<0.05) immobility, erratic movements and freezing episodes. We conclude that estrogenic contamination of natural aquatic systems induces alterations in locomotor behaviour and associated physiological disturbances in inhabitant fish fauna. PMID- 28734243 TI - Caveolin 1-related autophagy initiated by aldosterone-induced oxidation promotes liver sinusoidal endothelial cells defenestration. AB - Aldosterone, with pro-oxidation and pro-autophagy capabilities, plays a key role in liver fibrosis. However, the mechanisms underlying aldosterone-promoted liver sinusoidal endothelial cells (LSECs) defenestration remain unknown. Caveolin 1 (Cav1) displays close links with autophagy and fenestration. Hence, we aim to investigate the role of Cav1-related autophagy in LSECs defenestration. We found the increase of aldosterone/MR (mineralocorticoid receptor) level, oxidation, autophagy, and defenestration in LSECs in the human fibrotic liver, BDL or hyperaldosteronism models; while antagonizing aldosterone or inhibiting autophagy relieved LSECs defenestration in BDL-induced fibrosis or hyperaldosteronism models. In vitro, fenestrae of primary LSECs gradually shrank, along with the down-regulation of the NO-dependent pathway and the augment of the AMPK-dependent autophagy; these effects were aggravated by rapamycin (an autophagy activator) or aldosterone treatment. Additionally, aldosterone increased oxidation mediated by Cav1, reduced ATP generation, and subsequently induced the AMPK-dependent autophagy, leading to the down-regulation of the NO-dependent pathway and LSECs defenestration. These effects were reversed by MR antagonist spironolactone, antioxidants or autophagy inhibitors. Besides, aldosterone enhanced the co immunoprecipitation of Cav1 with p62 and ubiquitin, and induced Cav1 co immunofluorescence staining with LC3, ubiquitin, and F-actin in the perinuclear area of LSECs. Furthermore, aldosterone treatment increased the membrane protein level of Cav1, whereas decrease the cytoplasmic protein level of Cav1, indicating that aldosterone induced Cav1-related selective autophagy and F-actin remodeling to promote defenestration. Consequently, Cav1-related selective autophagy initiated by aldosterone-induced oxidation promotes LSECs defenestration via activating the AMPK-ULK1 pathway and inhibiting the NO-dependent pathway. PMID- 28734244 TI - Renal denervation attenuates hypertension and renal dysfunction in a model of cardiovascular and renal disease, which is associated with reduced NADPH and xanthine oxidase activity. AB - Oxidative stress is considered a central pathophysiological event in cardiovascular disease, including hypertension. Early age reduction in renal mass is associated with hypertension and oxidative stress in later life, which is aggravated by increased salt intake. The aim of the present study was to examine if renal sympathetic denervation can exert blood pressure lowering effects in uninephrectomized (UNX) rats (3-week old) fed with high salt (HS, 4%; w/w) diet for 4 weeks. Moreover, we investigated if renal denervation is associated with changes in NADPH and xanthine oxidase-derived reactive oxygen species. Rats with UNX + HS had reduced renal function, elevated systolic and diastolic arterial pressures, which was accompanied by increased heart weight, and cardiac superoxide production compared to sham operated Controls. UNX + HS was also associated with higher expression and activity of NADPH and xanthine oxidase in the kidney. Renal denervation in rats with UNX + HS attenuated the development of hypertension and cardiac hypertrophy, but also improved glomerular filtration rate and reduced proteinuria. Mechanistically, renal denervation was associated with lower expression and activity of both NADPH oxidase and xanthine oxidase in the kidney, but also reduced superoxide production in the heart. In conclusion, our study shows for the first time that renal denervation has anti-hypertensive, cardio- and reno-protective effects in the UNX + HS model, which can be associated with decreased NADPH oxidase- and xanthine oxidase-derived reactive oxygen species (i.e., superoxide and hydrogen peroxide) in the kidney. PMID- 28734245 TI - Azaphenothiazines - promising phenothiazine derivatives. An insight into nomenclature, synthesis, structure elucidation and biological properties. AB - For the last two decades, classical phenothiazines have attracted attention of researchers, as the hitherto investigations have revealed many significant biological activities within this class of compounds, other than originally discovered neuroleptic ones. Important, new pharmaceutical results on phenothiazines, as 10-substituted dibenzothiazines, were recently highlighted in several reviews. Azaphenothiazines are structurally modified phenothiazines by substitution of one or both benzene rings in the phenothiazine ring system with the azine rings, such as: pyridine, pyridazine, pyrimidine, pyrazine, 1,2,4 triazine, quinoline, quinoxaline, benzoxazine and benzothiazine. They form over 50 different heterocyclic systems, of tri-, tetra-, penta- and hexacyclic structures, and contain from one to even four azine nitrogen atoms. This review summarizes the methodical knowledge on azaphenothiazines, referring to their nomenclature, synthesis, structure analysis and above all significant varied biological activities, examined in vitro and in vivo. It describes, in addition, current trends in the synthesis of azaphenothiazines. The influence of the azaphenothiazine ring system, the nature of the substituents, predominantly at the thiazine nitrogen atom, as well as at the azine nitrogen atom and carbon atom, on the biological activities, were also discussed. PMID- 28734246 TI - Topological pattern for the search of new active drugs against methicillin resistant Staphylococcus aureus. AB - Molecular topology was used to develop a mathematical model capable of classifying compounds according to antimicrobial activity against methicillin resistant Staphylococcus aureus (MRSA). Topological indices were used as structural descriptors and their relation to antimicrobial activity was determined by using linear discriminant analysis. This topological model establishes new structure activity relationships which show that the presence of cyclopropyl, chlorine and ramification pairs at a distance of two bonds favor this activity, while the presence of tertiary amines decreases it. This model was applied to a combinatorial library of a thousand and one 6-fluoroquinolones, from which 117 theoretical active molecules were obtained. The compound 10 and five new quinolones were tested against MRSA. They all showed some activity against MRSA, although compounds 6, 8 and 9 showed anti-MRSA activity similar to ciprofloxacin. This model was also applied to 263 theoretical antibacterial agents described by us in a previous work, from which 34 were predicted as theoretically active. Anti-MRSA activity was found bibliographically in 9 of them (ensuring at least 26% of success), and from the rest, 3 compounds were randomly chosen and tested, finding mitomycin C to be more active than ciprofloxacin. The results demonstrate the utility of the molecular topology approaches for identifying new drugs active against MRSA. PMID- 28734247 TI - Seasonal variation in water uptake patterns of three plant species based on stable isotopes in the semi-arid Loess Plateau. AB - Water is a limiting factor and significant driving force for ecosystem processes in arid and semi-arid areas. Knowledge of plant water uptake pattern is indispensable for understanding soil-plant interactions and species coexistence. The 'Grain for Green' project that started in 1999 in the Loess Plateau of China has led to large scale vegetation change. However, little is known about the water uptake patterns of the main plant species that inhabit in this region. In this study, the seasonal variations in water uptake patterns of three representative plant species, Stipa bungeana, Artemisia gmelinii and Vitex negundo, that are widely distributed in the semi-arid area of the Loess Plateau, were identified by using dual stable isotopes of delta2H and delta18O in plant and soil water coupled with a Bayesian mixing model MixSIAR. The soil water at the 0-120cm depth contributed 79.54+/-6.05% and 79.94+/-8.81% of the total water uptake of S. bungeana and A. gmelinii, respectively, in the growing season. The 0 40cm soil contributed the most water in July (74.20+/-15.20%), and the largest proportion of water (33.10+/-15.20%) was derived from 120-300cm soils in August for A. gmelinii. However, V. negundo obtained water predominantly from surface soil horizons (0-40cm) and then switched to deep soil layers (120-300cm) as the season progressed. This suggested that V. negundo has a greater degree of ecological plasticity as it could explore water sources from deeper soils as the water stress increased. This capacity can mainly be attributed to its functionally dimorphic root system. V. negundo may have a competitive advantage when encountering short-term drought. The ecological plasticity of plant water use needs to be considered in plant species selection and ecological management and restoration of the arid and semi-arid ecosystems in the Loess Plateau. PMID- 28734248 TI - Effects of constructed wetland design on ibuprofen removal - A mesocosm scale study. AB - This study aimed to investigate the effects of constructed wetland design (unsaturated, saturated and aerated saturated) and plant species (Juncus, Typha, Berula, Phragmites and Iris) on the mass removal and removal kinetics of the pharmaceutical ibuprofen. Planted systems had higher ibuprofen removal rates (29% 99%) than in the unplanted ones (15%-85%) in all designs. The use of forced aeration improved ibuprofen removal only in the unplanted mesocosms. In general, ibuprofen removal followed an area-based first-order removal kinetics model with removal rate coefficients (kA) varying between 3 and 35cm/d. The ibuprofen removal was mainly attributed to microbial degradation by the fixed bed biofilm, but plant uptake and degradation within plant tissues also occurred. The ibuprofen removal was positively correlated with the oxygen concentration in the water and the removal of nutrients, indicating that degradation may be due to co metabolisation processes. PMID- 28734249 TI - Nitrogen losses and greenhouse gas emissions under different N and water management in a subtropical double-season rice cropping system. AB - Nitrogen non-point pollution and greenhouse gas (GHG) emission are major challenges in rice production. This study examined options for both economic and environmental sustainability through optimizing water and N management. Field experiments were conducted to examine the crop yields, N use efficiency (NUE), greenhouse gas emissions, N losses under different N and water management. There were four treatments: zero N input with farmer's water management (N0), farmer's N and water management (FP), optimized N management with farmer's water management (OPTN) and optimized N management with alternate wetting and drying irrigation (OPTN+AWD). Grain yields in OPTN and OPTN+AWD treatments increased by 13.0-17.3% compared with FP. Ammonia volatilization (AV) was the primary pathway for N loss for all treatments and accounted for over 50% of the total losses. N losses mainly occurred before mid-tillering. N losses through AV, leaching and surface runoff in OPTN were reduced by 18.9-51.6% compared with FP. OPTN+AWD further reduced N losses from surface runoff and leaching by 39.1% and 6.2% in early rice season, and by 46.7% and 23.5% in late rice season, respectively, compared with OPTN. The CH4 emissions in OPTN+AWD were 20.4-45.4% lower than in OPTN and FP. Total global warming potential of CH4 and N2O was the lowest in OPTN+AWD. On-farm comparison confirmed that N loss through runoff in OPTN+AWD was reduced by over 40% as compared with FP. OPTN and OPTN+AWD significantly increased grain yield by 6.7-13.9%. These results indicated that optimizing water and N management can be a simple and effective approach for enhancing yield with reduced environmental footprints. PMID- 28734250 TI - Assessment of direct exposure and leaching risk from PAHs in roadway and stormwater system residuals. AB - Wastes generated from municipal cleaning activities such as street sweeping, ditch cleaning, stormwater pond maintenance, and catch basin sediment removal require appropriate management. Beneficial use of these types of waste is a good alternative to landfilling; however, there are genuine concerns about possible soil and groundwater contamination by pollutants such as polycyclic aromatic hydrocarbons (PAHs). This study assessed the potential risks associated with beneficial use of roadway and stormwater system residuals collected from 14 cities across the state of Florida, USA. Total and leachable concentrations of 16 priority PAHs in the residual samples were measured and compared to appropriate risk-based regulatory threshold values. The bioaccessibility of the PAHs found in the waste streams was also determined using in vitro gastrointestinal leaching test. Of the PAHs studied, benzo [a] pyrene measured concentrations were above appropriate risk-based regulatory threshold values for soil and groundwater, while all other detected PAHs measured concentrations were below. Benzo [a] pyrene concentration (mg/kg) in street sweepings was 1.2 times higher than residential threshold values and 6 times lower than industrial threshold values. The in vitro study found PAH bioaccessibility to range from 1.7% to 49% in six roadway and stormwater system residual samples. PMID- 28734251 TI - Climatic controls of ecohydrological responses in the highlands of northern Ethiopia. AB - Climate variability and recurrent droughts have a strong negative impact on agricultural production and hydrology in the highlands northern Ethiopia. Since the 1980s, numerous mitigation and land rehabilitation measures have been implemented by local and national authorities to reduce these impacts, are often poorly effective. As underlying reason may be that controlling relationships between climate and ecohydrology at medium-sized catchments (10-10,000km2) of semi-arid highlands are not well known. We investigated trends and relationships in precipitation, temperature, streamflow, and net primary productivity (NPP). The results were mixed, with both significant increasing and decreasing trends for temperature and streamflow. Precipitation time series did not show a significant trend for the majority of stations, both over the years and over each season, except for a few stations. A time series indicated a significant abrupt increase of NPP in annual, seasonal and monthly timescale. Cross-correlation and regression analysis indicate precipitation and maximum temperature were the dominant climatic variables in the Geba catchment for streamflow and NPP. In view of these results, also land use and land cover change over the past three decades was analysed as a possible factor of importance, as human intervention, may affect streamflow and NPP. Factors that mainly correlate with streamflow and NPP are precipitation and maximum temperature. Important interventions that appear beneficial for these responses are construction of micro-dams, soil and water conservation and ecological restoration measures. The awareness that interactions can be quite different in semi-arid and semi-humid regions, as well as in upstream and downstream areas, should be reflected in management aimed at sustainable water and land resources use. PMID- 28734252 TI - River sequesters atmospheric carbon and limits the CO2 degassing in karst area, southwest China. AB - CO2 fluxes across water-air interfaces of river systems play important roles in regulating the regional and global carbon cycle. However, great uncertainty remains as to the contribution of these inland water bodies to the global carbon budget. Part of the uncertainty stems from limited understanding of the CO2 fluxes at diurnal and seasonal frequencies caused by aquatic metabolism. Here, we measured surface water characteristics (temperature, pH, and DO, DIC, Ca2+ concentrations) and CO2 fluxes across the air-water interface at two transects of Guijiang River, southwest China to assess the seasonal and diurnal dynamics of fluvial carbon cycling and its potential role in regional and global carbon budgets. The two transects had differing bedrock; DM transect is underlain by carbonate and detrital rock and PY is underlain by pure carbonate. Our results show that the river water both degasses CO2 to and absorbs CO2 from the atmosphere in both summer and winter, but the degassing and absorption varied between the two transects. Further, CO2 fluxes evolve through diurnal cycles. At DM, the river evaded CO2 from early morning through noon and absorbed CO2 from afternoon through early morning. At PY in summer, the CO2 evasion decreased during the daytime and increased at night while in winter at night, CO2 uptake increased in the morning and decreased in the afternoon but remained relatively stable at night. Although the river is a net source of carbon to the atmosphere (~15mMm-2day-1), the evasion rate is the smallest of all reported world's inland water bodies reflecting sequestration of atmospheric carbon through the carbonate dissolution and high primary productivity. These results emphasize the need of seasonal and diurnal monitoring of CO2 fluxes across water-air interface, particularly in highly productive rivers, to reduce uncertainty in current estimates of global riverine CO2 emission. PMID- 28734253 TI - Polybrominated diphenyl ether flame retardant concentrations in faeces from young children in Queensland, Australia and associations with environmental and behavioural factors. AB - The aim of our study was to investigate children's exposure to the flame retardants polybrominated diphenyl ethers (PBDEs) by analysing faecal content, a non-invasive matrix, as well as responses to an exposure-assessment questionnaire. A convenience sample of 61 parents with children (aged >3 months to <2 years) completed an online pre-tested questionnaire and provided faecal samples for analysis by high resolution gas chromatography/mass spectrometry. BDE 209 was the dominant congener in faecal samples adjusted to 8.3ng/g dry weight (dw), with >80% samples above the limit of detection (LOD). BDE-47 (0.23ng/g dw) and BDE-153 (0.03ng/g dw) were each detected above the LOD in approximately 60% of samples. Age was associated with BDE-47 (-7%/month) and BDE-153 (-12%/month) concentrations in faeces, but not BDE-209. Other variables associated with PBDE concentrations included features of the home (carpet, pets) and behaviour (hand to-mouth, removing shoes, using a car sunshade, frequency of walks outdoors). However, given the small sample size of this study additional research is required to confirm these findings. In this study we demonstrated that faeces may be a viable alternative to monitor human exposure to PBDEs, but further validation studies are required. PMID- 28734255 TI - Use of electronic cigarettes in public and private settings in Barcelona (Spain). AB - OBJECTIVES: To describe the prevalence of e-cigarette users who use them in selected indoor public and workplaces, and private venues in Barcelona (Spain) in 2015. METHODS: This is a cross-sectional study of a sample of e-cigarette users (>= 18 years) from Barcelona (n = 600). We calculated the proportion of e cigarette users who used the device in public and private settings (in the last 30 days). We fit multivariate logistic regression models adjusted for sex and age to calculate the odds ratios (OR) with their 95% confidence intervals (CI) of e cigarette use by socio-demographic factors, dual use and nicotine-containing e cigarettes. RESULTS: The highest proportion of e-cigarette users who used them in public places was found at restaurants or bars (69.4%) and nightclubs or pubs (55.4%). Also being current conventional tobacco smokers (dual users) was significantly associated with lower use of e-cigarettes in workplaces (OR = 0.61, 95%CI:0.41-0.91), restaurants (OR = 0.66, 95%CI:0.45-0.97) and nightclubs (OR = 0.56, 95%CI:0.37-0.86). Moreover, being a nicotine-containing e-cigarette user was associated with higher odds of using the device in workplaces (OR = 2.01, 95%CI:1.34-3.01), and lower odds of using it in nightclubs (OR = 0.56, 95%CI:0.39 0.82). 96.8% of the included e-cigarette users declared to use the device at home. Being a current tobacco smoker was associated with increased odds of using e-cigarettes at home (OR = 3.17, 95%CI:1.22-8.22). CONCLUSIONS: E-cigarette use in private settings and in public settings where their use is not regulated by law is high. Therefore, the public health administration in Spain should consider expanding the prohibition of e-cigarette use to indoor public places and should take into account the possibility of exposure to aerosol from e-cigarettes. PMID- 28734254 TI - Childhood polybrominated diphenyl ether (PBDE) exposure and neurobehavior in children at 8 years. AB - BACKGROUND: Prenatal polybrominated diphenyl ether (PBDE) exposure has been associated with decrements in IQ and increased attention deficit/hyperactivity disorder related behaviors in children; however, data are limited for the role of postnatal exposures. OBJECTIVES: We investigated the association between a series of childhood PBDE concentrations and Full-Scale Intelligence Quotient (FSIQ) and externalizing problems at 8 years. METHODS: We used data from 208 children in the Health Outcomes and Measures of the Environment (HOME) Study, a prospective pregnancy and birth cohort. Child serum PBDEs were measured at 1, 2, 3, 5, and 8 years; missing serum PBDE concentrations were estimated via multiple imputation. The Wechsler Intelligence Scales for Children-IV and the Behavior Assessment System for Children-2 was used to assess intelligence and externalizing behavior, respectively, in children at 8 years. We used multiple informant models to estimate associations between repeated lipid-adjusted PBDEs and child neurobehavior and to test for windows of susceptibility. RESULTS: Postnatal exposure to PBDE congeners (- 28, - 47, - 99, - 100, and - 153) at multiple ages was inversely associated with FSIQ at 8 years. For instance, a 10-fold increase in BDE-153 concentrations at 2, 3, 5, and 8 years were all related to lower FSIQ at age 8 (beta for 3 years: - 7.7-points, 95% CI - 12.5, - 2.9; beta for 8 years: - 5.6-points, 95% CI - 10.8, - 0.4). Multiple PBDE congeners at 8 years were associated with increased hyperactivity and aggressive behaviors at 8 years. CONCLUSIONS: Postnatal PBDE exposure was associated with decrements in FSIQ and increases in hyperactivity and aggressive behaviors. PMID- 28734256 TI - 3D porous polyurethanes featured by different mechanical properties: Characterization and interaction with skeletal muscle cells. AB - The fabrication of biomaterials for interaction with muscle cells has attracted significant interest in the last decades. However, 3D porous scaffolds featured by a relatively low stiffness (almost matching the natural muscle one) and highly stable in response to cyclic loadings are not available at present, in this context. This work describes 3D polyurethane-based porous scaffolds featured by different mechanical properties. Biomaterial stiffness was finely tuned by varying the cross-linking degree of the starting foam. Compression tests revealed, for the softest material formulation, stiffness values close to the ones possessed by natural skeletal muscles. The materials were also characterized in terms of local nanoindenting, rheometric properties and long-term stability through cyclic compressions, in a strain range reflecting the contraction extent of natural muscles. Preliminary in vitro tests revealed a preferential adhesion of C2C12 skeletal muscle cells over the softer, rougher and more porous structures. All the material formulations showed low cytotoxicity. PMID- 28734257 TI - Comparison of femoropopliteal artery stents under axial and radial compression, axial tension, bending, and torsion deformations. AB - High failure rates of Peripheral Arterial Disease (PAD) stenting appear to be associated with the inability of certain stent designs to accommodate severe biomechanical environment of the femoropopliteal artery (FPA) that bends, twists, and axially compresses during limb flexion. Twelve Nitinol stents (Absolute Pro, Supera, Lifestent, Innova, Zilver, Smart Control, Smart Flex, EverFlex, Viabahn, Tigris, Misago, and Complete SE) were quasi-statically tested under bench-top axial and radial compression, axial tension, bending, and torsional deformations. Stents were compared in terms of force-strain behavior, stiffness, and geometrical shape under each deformation mode. Tigris was the least stiff stent under axial compression (6.6N/m axial stiffness) and bending (0.1N/m) deformations, while Smart Control was the stiffest (575.3N/m and 105.4N/m, respectively). Under radial compression Complete SE was the stiffest (892.8N/m), while Smart Control had the lowest radial stiffness (211.0N/m). Viabahn and Supera had the lowest and highest torsional stiffness (2.2MUNm/ degrees and 959.2MUNm/ degrees ), respectively. None of the 12 PAD stents demonstrated superior characteristics under all deformation modes and many experienced global buckling and diameter pinching. Though it is yet to be determined which of these deformation modes might have greater clinical impact, results of the current analysis may help guide development of new stents with improved mechanical characteristics. PMID- 28734258 TI - Mechanical properties and biocompatibility of porous titanium scaffolds for bone tissue engineering. AB - Synthetic scaffolds are a highly promising new approach to replace both autografts and allografts to repair and remodel damaged bone tissue. Biocompatible porous titanium scaffold was manufactured through a powder metallurgy approach. Magnesium powder was used as space holder material which was compacted with titanium powder and removed during sintering. Evaluation of the porosity and mechanical properties showed a high level of compatibility with human cortical bone. Interconnectivity between pores is higher than 95% for porosity as low as 30%. The elastic moduli are 44.2GPa, 24.7GPa and 15.4GPa for 30%, 40% and 50% porosity samples which match well to that of natural bone (4 30GPa). The yield strengths for 30% and 40% porosity samples of 221.7MPa and 117MPa are superior to that of human cortical bone (130-180MPa). In-vitro cell culture tests on the scaffold samples using Human Mesenchymal Stem Cells (hMSCs) demonstrated their biocompatibility and indicated osseointegration potential. The scaffolds allowed cells to adhere and spread both on the surface and inside the pore structures. With increasing levels of porosity/interconnectivity, improved cell proliferation is obtained within the pores. It is concluded that samples with 30% porosity exhibit the best biocompatibility. The results suggest that porous titanium scaffolds generated using this manufacturing route have excellent potential for hard tissue engineering applications. PMID- 28734259 TI - Polishability and wear resistance of splint material for oral appliances produced with conventional, subtractive, and additive manufacturing. AB - Occlusal splints to treat bruxism are commonly made from polymethylmethacrylate (PMMA) in a manual workflow (powder-liquid technique). Today digitalization allows a machine-based manufacturing in subtractive (milling) and additive (printing) means using industrial-made PMMA or comparable resins. An in-vitro study should assess the surface finish and screen the wear resistance of conventional and industrial materials. Therefore, a total of 30 specimens made from conventionally PMMA (group C; powder-liquid, Palapress), polycarbonate ingots (group S; innoBlanc splint plus), and light-curing resin (group A; VarseoWax splint) were polished to examine the surface roughness (Ra) by profilometry and further analyzed by SEM. The specimens were loaded with a steatite ball moving 5000 times along 1cm with 5N of surface pressure under constant wetting (artificial saliva). The total height of profile (Pt) was calculated by further profilometry of the specimens. All specimen showed initially comparable Ra values ranging between 0.06 and 0.05um (SD = 0.01) after polishing. SEM investigations revealed no visual cues for scratches or irregularities in any group. After abrasion test, the comparison of the wear depths, revealed mean Pt values of 111.4um (SD = 18.5) in C, 85.7um (SD = 21.5) in S, and 99.1um (SD = 21.5) in A, whereas the mean of S was statistically different from C (p = 0.025). No signs of abrasion were found on the steatite balls. All materials showed comparable polished surfaces and a similar scale of wear. It remains questionable if the detected statistical differences are of clinical relevance, but indicates the need for tests of novel materials, especially in additive manufacturing. PMID- 28734260 TI - Time-averaged concentrations are effective for predicting chronic toxicity of varying copper pulse exposures for two freshwater green algae species. AB - Intermittent, fluctuating and pulsed contaminant discharges may result in organisms receiving highly variable contaminant exposures. This study investigated the effects of dissolved copper pulse concentration and exposure duration on the toxicity to two freshwater green algae species. The effects of single copper pulses of between 1 and 48 h duration and continuous exposures (72 h) on growth rate inhibition of Pseudokirchneriella subcapitata and Chlorella sp. were compared on a time-averaged concentration (TAC) basis. Relationships were then derived between the exposure concentration and duration required to elicit different levels of toxicity expressed as inhibition concentration (IC). Continuous exposure IC50's of 3.0 and 1.9 MUg/L were measured on a TAC basis for P. subcapitata and Chlorella sp., respectively. Algal growth rates generally recovered to control levels within 24-48 h of the copper pulse removal, with some treatments exhibiting significantly (p < 0.05) higher rates of cell division than controls in this recovery period. For both algae, when exposed to treatments with equivalent TACs, the continuous exposure elicited similar or slightly greater growth rate inhibition than the pulsed exposures. To elicit equivalent inhibition, the exposure concentration increased as the exposure duration decreased, and power models fitted this relationship reasonably well for both species. Water quality guideline values (WQGVs) are predominantly derived using data from continuous exposure toxicity bioassays, despite intermittent contaminant exposures often occurring in aquatic systems. The results indicate the WQGV for copper may be relaxed for pulsed exposures by a factor less than or equivalent to the TAC and still achieve a protection to these sensitive algae species. PMID- 28734261 TI - Abundant plankton-sized microplastic particles in shelf waters of the northern Gulf of Mexico. AB - Accumulation of marine debris is a global problem that affects the oceans on multiple scales. The majority of floating marine debris is composed of microplastics: plastic particles up to 5 mm in diameter. With similar sizes and appearances to natural food items, these small fragments pose potential risks to many marine organisms including zooplankton and zooplanktivores. Semi-enclosed seas are reported to have high concentrations of microplastics, however, the distribution and concentration of microplastics in one such system, the Gulf of Mexico, remains unknown. Our study documented and characterized microplastics in continental shelf waters off the Louisiana coast in the northern Gulf of Mexico, using bongo nets, neuston nets, and Niskin bottles. Additionally, we compared the size distributions of microplastics and zooplankton collected using the nets. Plastics were manually sorted from the samples, documented, and measured using digital microscopy. Confirmation of putative plastics was carried out by hydrofluoric acid digestion and a subsample was analyzed using FTIR microscopy. Estimated concentrations of microplastics collected on the inner continental shelf during this study are among the highest reported globally. Total microplastic concentrations ranged from 4.8 to 8.2 particles m-3 and 5.0-18.4 particles m-3 for the bongo and neuston samples, respectively. Niskin bottles collected smaller plastic particles than the nets and indicated total microplastic concentrations (primarily fibers) from 6.0E4 - 15.7E4 particles m-3. Microplastic concentrations were greater than the abundances of all but four of the five most abundant taxa from bongo nets and were not statistically different from the abundances of any of the most numerous taxa from neuston nets. Sizes of microplastics and zooplankton partially or completely overlapped, suggesting the potential for confusion with natural prey. PMID- 28734262 TI - Mercury risk in poultry in the Wanshan Mercury Mine, China. AB - In this study, total mercury (THg) and methylmercury (MeHg) concentrations in muscles (leg and breast), organs (intestine, heart, stomach, liver) and blood were investigated for backyard chickens, ducks and geese of the Wanshan Mercury Mine, China. THg in poultry meat products range from 7.9 to 3917.1 ng/g, most of which exceeded the Chinese national standard limit for THg in meat (50 ng/g). Elevated MeHg concentrations (0.4-62.8 ng/g) were also observed in meat products, suggesting that poultry meat can be an important human MeHg exposure source. Ducks and geese showed higher Hg levels than chickens. For all poultry species, the highest Hg concentrations were observed in liver (THg: 23.2-3917.1 ng/g; MeHg: 7.1-62.8 ng/g) and blood (THg: 12.3-338.0 ng/g; MeHg: 1.4-17.6 ng/g). We estimated the Hg burdens in chickens (THg: 15.3-238.1 MUg; MeHg: 2.2-15.6 MUg), ducks (THg: 15.3-238.1 MUg; MeHg: 3.5-14.7 MUg) and geese (THg: 83.8-93.4 MUg; MeHg: 15.4-29.7 MUg). To not exceed the daily intake limit for THg (34.2 MUg/day) and MeHg (6 MUg/day), we suggested that the maximum amount (g) for chicken leg, breast, heart, stomach, intestine, liver, and blood should be 1384, 1498, 2315, 1214, 1081, 257, and 717, respectively; the maximum amount (g) for duck leg, breast, heart, stomach, intestine, liver, and blood should be 750, 1041, 986, 858, 752, 134, and 573, respectively; and the maximum amount (g) for goose leg, breast, heart, stomach, intestine, liver, and blood should be 941, 1051, 1040, 1131, 964, 137, and 562, respectively. PMID- 28734263 TI - Study of the influencing factors of the blood levels of toxic elements in Africans from 16 countries. AB - Africa's economy is growing faster than any other continent and it has been estimated that the middle class in Africa now exceeds 350 million people. This has meant a parallel increase in the importation of consumer goods and in the implementation of communication and information technologies (ICT), but also in the generation of large quantities of e-waste. However, inadequate infrastructure development remains a major constraint to the continent's economic growth and these highly toxic residues are not always adequately managed. Few studies have been conducted to date assessing the possible association between socioeconomic development factors, including e-waste generation, and blood levels of inorganic elements in African population. To disclose the role of geographical, anthropogenic, and socioeconomic development determinants on the blood levels of Ag, Al, As, Be, Cd, Co, Cr, Hg, Ni, Pb, Sb, and V -all of them frequently found in e-waste-, an immigrant population-based study was made including a total of 245 subjects from 16 countries recently arrived to the Canary Islands (Spain). Women presented higher levels of blood elements than men, and Northern Africans (Moroccans) were the most contaminated. People from low-income countries exhibited significantly lower blood levels of inorganic elements than those from middle-income countries. We found a significant association between the use of motor vehicles and the implementation of information and communication technologies (ICT) and the level of contamination. Immigrants from the countries with a high volume of imports of second-hand electronic equipment, telephone and internet use had higher levels of inorganic elements. In general terms, the higher level of economic development the higher the blood levels of inorganic pollutants, suggesting that the economic development of Africa, in parallel to e waste generation and the existence of informal recycling sites, have directly affected the level of contamination of the population of the continent. PMID- 28734264 TI - A small-scale, portable method for extracting microplastics from marine sediments. AB - Microplastics (plastic particles, 0.1 MUm-5 mm in size) are widespread marine pollutants, accumulating in benthic sediments and shorelines the world over. To gain a clearer understanding of microplastic availability to marine life, and the risks they pose to the health of benthic communities, ecological processes and food security, it is important to obtain accurate measures of microplastic abundance in marine sediments. To date, methods for extracting microplastics from marine sediments have been disadvantaged by complexity, expense, low extraction efficiencies and incompatibility with very fine sediments. Here we present a new, portable method to separate microplastics from sediments of differing types, using the principle of density floatation. The Sediment-Microplastic Isolation (SMI) unit is a custom-built apparatus which consistently extracted microplastics from sediments in a single step, with a mean efficiency of 95.8% (+/-SE 1.6%; min 70%, max 100%). Zinc chloride, at a density of 1.5 g cm-3, was deemed an effective and relatively inexpensive floatation media, allowing fine sediment to settle whilst simultaneously enabling floatation of dense polymers. The method was validated by artificially spiking sediment with low and high density microplastics, and its environmental relevance was further tested by extracting plastics present in natural sediment samples from sites ranging in sediment type; fine silt/clay (mean size 10.25 +/- SD 3.02 MUm) to coarse sand (mean size 149.3 +/- SD 49.9 MUm). The method presented here is cheap, reproducible and is easily portable, lending itself for use in the laboratory and in the field, eg. on board research vessels. By employing this method, accurate estimates of microplastic type, distribution and abundance in natural sediments can be achieved, with the potential to further our understanding of the availability of microplastics to benthic organisms. PMID- 28734265 TI - Decreased lung function with mediation of blood parameters linked to e-waste lead and cadmium exposure in preschool children. AB - Blood lead (Pb) and cadmium (Cd) levels have been associated with lower lung function in adults and smokers, but whether this also holds for children from electronic waste (e-waste) recycling areas is still unknown. To investigate the contribution of blood heavy metals and lung function levels, and the relationship among living area, the blood parameter levels, and the lung function levels, a total of 206 preschool children from Guiyu (exposed area), and Haojiang and Xiashan (reference areas) were recruited and required to undergo blood tests and lung function tests during the study period. Preschool children living in e-waste exposed areas were found to have a 1.37 MUg/dL increase in blood Pb, 1.18 MUg/L increase in blood Cd, and a 41.00 * 109/L increase in platelet counts, while having a 2.82 g/L decrease in hemoglobin, 92 mL decrease in FVC and 86 mL decrease in FEV1. Each unit of hemoglobin (1 g/L) decline was associated with 5 mL decrease in FVC and 4 mL decrease in FEV1. We conclude that children living in e-waste exposed area have higher levels of blood Pb, Cd and platelets, and lower levels of hemoglobin and lung function. Hemoglobin can be a good predictor for lung function levels. PMID- 28734266 TI - Air quality and health effects of biogenic volatile organic compounds emissions from urban green spaces and the mitigation strategies. AB - Biogenic volatile organic compounds (BVOCs) emissions lead to fine particulate matter (PM2.5) and ground-level ozone pollution, and are harmful to human health, especially in urban areas. However, most BVOCs estimations ignored the emissions from urban green spaces, causing inaccuracies in the understanding of regional BVOCs emissions and their environmental and health effects. In this study, we used the latest local vegetation datasets from our field survey and applied an estimation model to analyze the spatial-temporal patterns, air quality impacts, health damage and mitigating strategies of BVOCs emissions in the Greater Beijing Area. Results showed that: (1) the urban core was the hotspot of regional BVOCs emissions for the highest region-based emission intensity (3.0 g C m-2 yr-1) among the 11 sub-regions; (2) urban green spaces played much more important roles (account for 62% of total health damage) than rural forests in threating human health; (3) BVOCs emissions from green spaces will more than triple by 2050 due to urban area expansion, tree growth and environmental changes; and (4) adopting proactive management (e.g. adjusting tree species composition) can reduce 61% of the BVOCs emissions and 50% of the health damage related to BVOCs emissions by 2050. PMID- 28734267 TI - Status epilepticus-related etiology, incidence and mortality: A meta-analysis. AB - Status epilepticus (SE) is a severe medical condition. To determine its epidemiology and outcome of SE, we performed a meta-analysis to investigate the etiology, incidence and mortality of SE. We searched PubMed and Embase between Jan 1, 2000, and Oct 31, 2016, with no regional restrictions, for observational studies of the etiology, incidence and mortality of SE. Forty-three studies were included in the meta-analysis. The pooled crude annual incidence rate, the pooled case fatality rate and the pooled crude annual mortality rate of SE were 12.6/100,000 (95% CI: 10.0-15.3), 14.9% (95% CI: 11.7-118.7) and 0.98/100,000 (95% CI: 0.74-1.22), respectively. Elderly subjects with SE had a higher case fatality rate (28.4% (95% CI: 17.7-42.3)) and crude annual incidence rate (27.1% (95% CI: 15.8-38.2)). The most important etiology-specific attributable fraction of patients with SE was acute symptomatic etiology (OR 0.411, 95% CI: 0.315 0.507). Age and economic income contributed to differences in SE incidence and short-term case fatality rate. PMID- 28734268 TI - DNA barcoding allows identification of European Fanniidae (Diptera) of forensic interest. AB - In forensic entomology practice, species identification is a prerequisite for any further analysis of collected material. Although morphology-based taxonomy may be hindered by a range of factors, these are not obstacles for a molecular identification approach, so-called DNA barcoding. The Fanniidae are a dipteran family that is attracted to and breeds in decomposing animal carrion and dead human bodies. However, morphological identification of fanniids, both at adult and immature stages, is considered to be difficult, particularly for non-experts. We investigated the usefulness of molecular taxonomy methods as an alternative/supplement for morphology-based identification in European Fanniidae of forensic interest. The material used in this study was collected from various regions in Asia, Europe and North America. We sequenced a barcode region of the mitochondrial cytochrome c oxidase subunit I (COI) in 27 species. For 13 species, including some taxa breeding in dead bodies, this study describes COI sequences for the first time. Our analysis revealed that both mini-barcode and full-length COI barcode sequences give very high specimen identification success. Despite the large number of COI barcode sequences referring to Fanniidae in the BOLD and GenBank databases, previous identification of forensically relevant Fanniidae was hindered by uneven taxonomic sampling. The majority of available sequences refer to species that are not of medico-legal interest, and many species of forensic interest are unrepresented or represented only by a single sequence. Because of erroneous data that are present in depository databases, DNA barcoding must be used with caution and cannot be considered to be the sole alternative to other identification methods. Wolbachia infections in the examined material did not disrupt specimen identification. The obtained results will facilitate precise identification of European Fanniidae of forensic interest, badly preserved material with degraded DNA, as well as matching of unidentified females and immature stages to already described specimens. PMID- 28734269 TI - Crime scene reconstruction-Sex prediction from blood stained foot sole impressions. AB - It is often difficult to predict the sex of an individual based on bloody incomplete footprints. However, such prints/impressions are particularly common in a crime scene. Again variability in the texture, color of the target surface has an impact on the bloodstained impression formed. The study of bare foot, footprint, footwear (i.e. shoe, canvas etc.) within the legal context is referred to as forensic podiatry. Based on the fact that it is possible to predict the sex of an individual from footprint impressions, an automated model has been proposed in this paper for analyzing the sex of an individual from his/her broken/incomplete footprint impressions based on morphological features alone. Five male and female volunteers aged between 20 to 65 years participated in dataset development. Keeping the blood volume constant and having stepped on differently shaped porcine blood pools, the individuals were asked to walk on herbarium sheets. The footprints were recorded and documented in accordance with the guidelines in place for physical evidence documentation within the forensic domain. The morphological features that were extracted from each of the footprint impressions are footprint length, footprint breadth, angle of walking, approximated heel radius etc. Using exhaustive cross validation technique, the dataset was divided into training and test set. Non-redundant, relevant features that are particularly effective at sex prediction were marked out using the relief algorithm in coherence with the correlation metric. Supervised learning techniques were used on the dataset to predict the sex of the owner of an unknown footprint. The study concentrates on morphological features in order to deal with bloodstain footprint transfer stains formed on any non-porous/non-absorbent surfaces such as cemented floor, glass, mosaic floor space, colored and designed tiled floor spaces. Features such as the angle of walking and foot breadth were found to be particularly influential in sex prediction from incomplete bloodstained foot sole impressions. In comparison to a system for sex prediction from complete footprint impressions (82.2%), the automated system developed on incomplete foot impressions recorded an accuracy level of 83.47%. PMID- 28734270 TI - A case study of an unknown mass grave - Hostages killed 70 years ago by a Nazi firing squad identified thanks to genetics. AB - Almost 6 million people died in Poland during the Nazi occupation and about 570 thousand during the Soviet occupation. But the end of the war was not the end of the trauma. Historians estimate that at least 30 thousand people were killed during the Stalinist regime in Poland. In 2012 the Institute of National Remembrance started to search for hidden burials of victims of communism. Many exhumations were carried out under the project. One of them took place in Bialystok, eastern Poland. According to information gathered by local historians, a detention centre in the heart of city was the place of secret burials of victims of the communist regime. During the exhumation work a burial pit with the remains of 24 victims was found. It's characteristics supported the hypothesis that these people were shot on the spot, in a mass execution during the Nazi occupation. Historians knew of only one such execution, but its victims - according to the available records - were supposed to have been exhumed at the end of the war. Exhumation works and the discovery of the discussed mass grave put in question the events of 1944, which would have been impossible without the field work. The first identifications confirmed the doubts of historians, since both the results of genetic profiling and the conducted anthropological analysis revealed that at the end of the war a mistake was made, and bodies other than those suspected had been exhumed. Having established this fact, the mass grave created at that time should be investigated to reveal the identity of the remains uncovered then. PMID- 28734271 TI - Development and validation of sensitive LC-MS/MS method for the quantification of SUVN-502 and its metabolite and its application for first in human pharmacokinetic study. AB - A sensitive and rapid LC-MS/MS method was developed and validated for the quantification of SUVN-502 and M1 of SUVN-502, a 5-HT6 receptor antagonist for the treatment of dementia associated with Alzheimer's disease. Following solid phase extraction, SUVN-502 and M1 of SUVN-502 and IS were eluted with 10mM ammonium acetate (pH 4.0) and acetonitrile using a rapid gradient program on reverse phase column. Multiple reaction monitoring mode was used to monitor the respective transitions of m/z 478.2->377.7 for SUVN-502 and m/z 464.1->377.7 for M1 of SUVN-502. The assay exhibited a linear dynamic range of 10-10000pg/mL for SUVN-502 and 20-20000pg/mL for M1 of SUVN-502 in human plasma. Acceptable precision and accuracy were obtained for concentrations over the standard curve range. The within batch accuracy and precision were within acceptable limits. All the other validation parameters were within the acceptable limits. The validated method was applied to analyze human plasma samples obtained from a human pharmacokinetic study consisting single and multiple ascending doses. PMID- 28734272 TI - Glycosylation patterns of selected proteins in individual serum and cerebrospinal fluid samples. AB - A method we previously developed has been applied to the determination of the glycosylation pattern of specific proteins in biological samples. Six proteins (alpha-1-antitrypsin, transferrin, haptoglobin, C1 inhibitor, alpha-1 acid glycoprotein, and immunoglobulin G) were studied in serum samples from five individuals and cerebrospinal fluid (CSF) samples from three individuals, to investigate the expected normal distribution of glycosylation patterns and to assess whether this methodology can be used to discriminate between samples from different individuals. For serum samples, the differences were shown to be small, while much larger differences were found for the CSF samples, with a greater number of glycoforms present. This can be linked to the occurrence of differential glycosylation in proteins expressed in the brain compared with proteins expressed elsewhere in the body. The developed method could distinguish differences in the glycosylation pattern of specific proteins in the individual samples, which was not reflected in the glycan content of total CSF. This is the first time that the glycoforms of several of these proteins have been investigated in CSF. PMID- 28734273 TI - Association between Thrombophilic Genes Polymorphisms and Recurrent Pregnancy Loss Susceptibility in the Iranian Population: a Systematic Review and Meta Analysis AB - Background: Studies have indicated that thrombophilic genes polymorphisms are associated with recurrent pregnancy loss (RPL) in the Iranian population. However, the results from these studies remained inconsistent and inconclusive. The aim of this systematic review and meta-analysis was to evaluate the precise association between thrombophilic genes polymorphisms (MTHFR C677T, MTHFR A1298C, Prothrombin G20210A, FVL G1691A, and PAI-1 4G/5G) and RPL risk in the Iranian population. Method: Electronic databases of PubMed, Web of Science, Google Scholar, and ISC were searched for eligible articles published up to April 1, 2017. The association between genetic polymorphisms and RPL risk was measured by ORs with 95% CI. Results: A total of 37 case-control studies in 18 relevant publications were selected in the final meta-analysis, including 1,199 RPL cases and 1,079 controls for MTHFR C677T, 1,194 RPL cases and 1079 controls for MTHFR A1298C, 630 RPL cases and 594 controls for Prothrombin G20210A, 830 RPL cases and 794 controls for FVL G1691A, and 955 RPL cases and 499 controls for PAI-1 4G/5G. When all the eligible studies were pooled into the meta-analysis of MTHFR C677T and A1298C polymorphisms, a significant increased risk of RPL was observed in all genetic models in the population. In addition, Prothrombin G20210A (in allelic and dominant models), FVL G1691A (in allelic and dominant model), and PAI-1 4G/5G (in allelic, homozygote, dominant and recessive genetic models) polymorphisms were associated with RPL risk in the Iranian population. Conclusion: The findings suggest that the thrombophilic genes polymorphisms are associated with an increased RPL risk in the Iranian population. PMID- 28734274 TI - Genetic Analysis of Iranian Patients with Familial Hypercholesterolemia AB - Background: Familial hypercholesterolemia (FH) is a frequent autosomal dominant disorder of lipoprotein metabolism. This disorder is generally caused by mutations in low-density lipoprotein receptor (LDLR), apolipoprotein B 100 (APOB), and proprotein convertase subtilisin/kexin type 9 (PCSK9) genes. In the present study, we aimed at identifying the common LDLR and APOB gene mutations in an Iranian population. Methods: Eighty unrelated Iranian patients with FH entered the study, based on Simon Broome diagnostic criteria. All samples were screened for two common APOB gene mutations, including R3500Q and R3500W, by the means of ARMS-PCR and PCR- RFLP assays, respectively. In addition, exons 3, 4, 9, and 10 of LDLR gene were sequenced in all patients. Results: A novel mutation in exon 3 (C95W) and a previously described mutation in exon 4 (D139H) of LDLR gene were found. Three previously reported polymorphisms in LDLR gene as well as three novel polymorphisms were detected in the patients. However, in the studied population, no common mutations were observed in APOB gene. Conclusion: The results of our study imply that the genetic basis of FH in Iranian patients is different from other populations. PMID- 28734276 TI - Embedding for bulk systems using localized atomic orbitals. AB - We extend projection-based embedding techniques to bulk systems to treat point defects in semiconductors and insulators. To avoid non-additive kinetic energy contributions, we construct the density partition using orthogonal subsets of orbitals. We have implemented our approach in the popular Vienna ab initio simulation package software package. We demonstrate its power for defect structures in silicon and polaron formation in titania, two challenging cases for conventional Kohn-Sham density functional theory. PMID- 28734275 TI - Low Level of Autophagy-Related Gene 10 (ATG10) Expression in the 6 Hydroxydopamine Rat Model of Parkinson's Disease AB - Background: Autophagy is a mechanism disassembling the damaged organelles from the cell. This study attempted to examine the expression of several autophagy related genes in Parkinson's disease (PD) rat model. Methods: The male Wistar rats were divided into three groups as control, sham, and lesion. In the latter group, the PD rat model was induced by the injection of 6-hydroxydopamine in the striatum. The behavioral test was conducted one (baseline) and four weeks after the surgery through apomorphine hydrochloride. Then the RT-PCR technique was employed to evaluate the expressions of p62/SQSTM, autophagy-related genes (ATG)5, ATG12, ATG16L1, ATG10, as well as GAPDH and LC3. Results: By injecting apomorphine, the striatal lesion group showed a significant contralateral rotation at fourth week as compared to the baseline. The examination of p62, ATG5, ATG12, ATG16L1, and LC3 expressions using RT-PCR revealed that p62, ATG5, ATG12, LC3, and ATG16L1 were expressed in the substantia nigra of PD rat model, while ATG10 was not expressed. Conclusion: ATG10 expression is necessary for the initiation of autophagy. Thus, these results show that autophagy deregulation occurs in the initiation stages of the process in the rat model of PD. PMID- 28734277 TI - Note: Density functional theory for uniformly charged hard-sphere ions. AB - The density function theory has been proposed for studying the structural properties of electrolytes containing uniformly charged hard-spherical ions. The calculated result shows good agreement with the corresponding Monte Carlo simulation data of Bohinc et al. [J. Chem. Phys. 145, 234901 (2016)]. The results confirm that the attraction between like-charged planar surfaces is the results of the intra-ionic correlation and depends strongly on the charge distribution of hard-sphere ions. PMID- 28734278 TI - The constant force continuous molecular dynamics for potentials with multiple discontinuities. AB - In this work, we present an extension of the constant force approach [P. Orea and G. Odriozola, J. Chem. Phys. 138, 214105 (2013)] to the case of potentials with multiple discontinuities. To illustrate the method, we selected the square well potential of range lambda=1.5 that exhibits two discontinuities. Square well single phase properties, vapor-liquid phase diagram, and surface tension were calculated and compared with available simulation data. Besides, we analyzed the internal energies of a square well plus a square shoulder potential having three discontinuities. For both potentials, a good agreement has been found when compared with results of other simulation techniques (discontinuous molecular dynamics and Monte Carlo methods). This extension can be easily implemented to more general and efficient continuous molecular dynamics packages (HOOMD, GROMACS, NAMD, etc.). PMID- 28734279 TI - A discrete Fourier-encoded, diagonal-free experiment to simplify homonuclear 2D NMR correlations. AB - Nuclear magnetic resonance (NMR) spectroscopy has long served as an irreplaceable, versatile tool in physics, chemistry, biology, and materials sciences, owing to its ability to study molecular structure and dynamics in detail. In particular, the connectivity of chemical sites within molecules, and thereby molecular structure, becomes visible by multi-dimensional NMR. Homonuclear correlation experiments are a powerful tool for identifying coupled spins. Generally, diagonal peaks in these correlation spectra display the strongest intensities and do not offer any new information beyond the standard one-dimensional spectrum, whereas weaker, symmetrically placed cross peaks contain most of the coupling information. The cross peaks near the diagonal are often affected by the tails of strong diagonal peaks or even obscured entirely by the diagonal. In this paper, we demonstrate a homonuclear encoding approach based on imparting a discrete phase modulation of the targeted cross peaks and combine it with a site-selective sculpting scheme, capable of simplifying the patterns arising in these 2D correlation spectra. The theoretical principles of the new methods are laid out, and experimental observations are rationalized on the basis of theoretical analyses. The ensuing techniques provide a new way to retrieve 2D coupling information within homonuclear spin systems, with enhanced sensitivity, speed, and clarity. PMID- 28734280 TI - Selected configuration interaction method using sampled first-order corrections to wave functions. AB - A new selected configuration interaction (CI) method was proposed for the potential energy surfaces of quasi-degenerate and excited states. Slater determinants are generated by sampling the first-order corrections to the target state wave functions using the quantum Monte Carlo method in determinant space. As in the Monte Carlo (MC) CI method, the wave function is improved at each iteration by generating new determinants and applying a pruning step. Compared to the random generation in the MCCI calculations, the number of iterations before convergence is significantly reduced. Regarding the potential energy curves of the ground and excited states of C2, the non-parallelity errors were sufficiently small, thus indicating the method's applicability to the calculations of potential energy surfaces. PMID- 28734281 TI - Hybrid stochastic-deterministic calculation of the second-order perturbative contribution of multireference perturbation theory. AB - A hybrid stochastic-deterministic approach for computing the second-order perturbative contribution E(2) within multireference perturbation theory (MRPT) is presented. The idea at the heart of our hybrid scheme-based on a reformulation of E(2) as a sum of elementary contributions associated with each determinant of the MR wave function-is to split E(2) into a stochastic and a deterministic part. During the simulation, the stochastic part is gradually reduced by dynamically increasing the deterministic part until one reaches the desired accuracy. In sharp contrast with a purely stochastic Monte Carlo scheme where the error decreases indefinitely as t-1/2 (where t is the computational time), the statistical error in our hybrid algorithm displays a polynomial decay ~t-n with n = 3-4 in the examples considered here. If desired, the calculation can be carried on until the stochastic part entirely vanishes. In that case, the exact result is obtained with no error bar and no noticeable computational overhead compared to the fully deterministic calculation. The method is illustrated on the F2 and Cr2 molecules. Even for the largest case corresponding to the Cr2 molecule treated with the cc-pVQZ basis set, very accurate results are obtained for E(2) for an active space of (28e, 176o) and a MR wave function including up to 2*107 determinants. PMID- 28734282 TI - Cluster expansion of the solvation free energy difference: Systematic improvements in the solvation of single ions. AB - The cluster expansion method has been used in the imperfect gas theory for several decades. This paper proposes a cluster expansion of the solvation free energy difference. This difference, which results from a change in the solute solvent potential energy, can be written as the logarithm of a finite series. Similar to the Mayer function, the terms in the series are related to configurational integrals, which makes the integrand relevant only for configurations of the solvent molecules close to the solute. In addition, the terms involve interaction of solute with one, two, and so on solvent molecules. The approach could be used for hybrid quantum mechanical and molecular mechanics methods or mixed cluster-continuum approximation. A simple form of the theory was applied for prediction of pKa in methanol; the results indicated that three explicit methanol molecules and the dielectric continuum lead to a root of mean squared error (RMSE) of only 1.3 pKa units, whereas the pure continuum solvation model based on density method leads to a RMSE of 6.6 pKa units. PMID- 28734283 TI - A unified thermostat scheme for efficient configurational sampling for classical/quantum canonical ensembles via molecular dynamics. AB - We show a unified second-order scheme for constructing simple, robust, and accurate algorithms for typical thermostats for configurational sampling for the canonical ensemble. When Langevin dynamics is used, the scheme leads to the BAOAB algorithm that has been recently investigated. We show that the scheme is also useful for other types of thermostats, such as the Andersen thermostat and Nose Hoover chain, regardless of whether the thermostat is deterministic or stochastic. In addition to analytical analysis, two 1-dimensional models and three typical real molecular systems that range from the gas phase, clusters, to the condensed phase are used in numerical examples for demonstration. Accuracy may be increased by an order of magnitude for estimating coordinate-dependent properties in molecular dynamics (when the same time interval is used), irrespective of which type of thermostat is applied. The scheme is especially useful for path integral molecular dynamics because it consistently improves the efficiency for evaluating all thermodynamic properties for any type of thermostat. PMID- 28734284 TI - Cage model of polar fluids: Finite cage inertia generalization. AB - The itinerant oscillator model describing rotation of a dipole about a fixed axis inside a cage formed by its surrounding polar molecules is revisited in the context of modeling the dielectric relaxation of a polar fluid via the Langevin equation. The dynamical properties of the model are studied by averaging the Langevin equations describing the complex orientational dynamics of two bodies (molecule-cage) over their realizations in phase space so that the problem reduces to solving a system of three index linear differential-recurrence relations for the statistical moments. These are then solved in the frequency domain using matrix continued fractions. The linear dielectric response is then evaluated for extensive ranges of damping, dipole moment ratio, and cage-dipole inertia ratio and along with the usual inertia corrected microwave Debye absorption gives rise to significant far-infrared absorption with a comb-like structure of harmonic peaks. The model may be also regarded as an extension of Budo's [J. Chem. Phys. 17, 686 (1949)] treatment of molecules containing rotating polar groups to include inertial effects. PMID- 28734285 TI - Extension of the D3 dispersion coefficient model. AB - A new model, termed D4, for the efficient computation of molecular dipole-dipole dispersion coefficients is presented. As in the related, well established D3 scheme, these are obtained as a sum of atom-in-molecule dispersion coefficients over atom pairs. Both models make use of dynamic polarizabilities obtained from first-principles time-dependent density functional theory calculations for atoms in different chemical environments employing fractional atomic coordination numbers for interpolation. Different from the D3 model, the coefficients are obtained on-the-fly by numerical Casimir-Polder integration of the dynamic, atomic polarizabilities alpha(iomega). Most importantly, electronic density information is now incorporated via atomic partial charges computed at a semi empirical quantum mechanical tight-binding level, which is used to scale the polarizabilities. Extended statistical measures show that errors for dispersion coefficients with the proposed D4 method are significantly lower than with D3 and other, computationally more involved schemes. Alongside, accurate isotropic charge and hybridization dependent, atom-in-molecule static polarizabilities are obtained with an unprecedented efficiency. Damping function parameters are provided for three standard density functionals, i.e., TPSS, PBE0, and B3LYP, allowing evaluation of the new DFT-D4 model for common non-covalent interaction energy benchmark sets. PMID- 28734286 TI - Communication: Light driven remote control of microgels' size in the presence of photosensitive surfactant: Complete phase diagram. AB - Here we report on a light triggered remote control of microgel size in the presence of photosensitive surfactant. The hydrophobic tail of the cationic surfactant contains azobenzene group that undergoes a reversible photo isomerization reaction from a trans- to a cis-state accompanied by a change in the hydrophobicity of the surfactant. We have investigated light assisted behaviour and the complex formation of the microgels with azobenzene containing surfactant over the broad concentrational range starting far below and exceeding several times of the critical micelle concentration (CMC). At small surfactant concentration in solution (far below CMC), the surfactant in the trans-state accommodates within the microgel causing its compaction, while the cis-isomer desorbs out of microgel resulting in its swelling. The process of the microgel size change can be described as swelling on UV irradiation (trans-cis isomerization) and shrinking on irradiation with blue light (cis-trans isomerization). However, at the surfactant concentrations larger than CMC, the opposite behaviour is observed: the microgel swells on blue irradiation and shrinks during exposure to UV light. We explain this behaviour theoretically taking into account isomer dependent micellization of surfactant within the microgels. PMID- 28734287 TI - On the thermophysical and transport properties of 3He and 4He: A bubble interaction potential versus state of the art. AB - Three keynote thermophysical and transport properties of 3He and 4He, namely, the second virial coefficient, the shear viscosity, and the thermal conductivity, are reported for the "extended Dirac bubble potential" (EDbp), a novel model for He He [M. Chrysos, J. Chem. Phys. 146, 024106 (2017)]. Comparisons with the experiment as well as with potentials with a proven track record and with the oversimplified Dbp are being made in the range 0.1-500 K to analyze the performance of the EDbp, which is shown here to emerge as a promising analytic model for He-He. A flowchart of how to treat the "buffer" in scattering cross section measurements is designed and conducted, offering a route to EDbp optimization. An impressive consistency with state-of-the-art calculations (which is just striking for such a simple analytic model) is found, essentially thanks to the performance of the phase-shift expression cotdeltal = lambdakr0xilyl(kr0) yl(krc)lambdakr0xiljl(kr0)-jl(krc), xil=jl(kr0)yl(krc)-jl(krc)yl(kr0). A Multimedia view of deltal(k,rc) versus k and rc is part of the material presented in this article. Data for the "best" rc(k) is given as a supplementary material. PMID- 28734288 TI - Common behaviors associated with the glass transitions of water-like models. AB - We perform molecular dynamics simulations to ascertain effects of the molecular polarity on structural and dynamical properties of water-like systems, in particular, on their glassy slowdown. To systematically vary the molecular dipole moments, we scale the partial charges of the established SPC/E and TIP4P/2005 models. In broad ranges of the molecular polarity, the studied SPC/E and TIP4P/2005 descendants show a density anomaly, which can be attributed to the removal of water molecules interstitial between the first and the second neighbor shells upon cooling. While all considered modified water models behave as typical glass formers, the structural relaxation time tau heavily depends on the molecular dipole moment. This large dynamical diversity is exploited to systematically ascertain characteristic properties of glass-forming liquids. For all studied water-like systems, we observe a close relation between the activation energy Einfinity describing the Arrhenius behavior of the regular liquid and the glass transition temperature Tg characterizing the supercooled liquid, explicitly, Einfinity/Tg~10. Moreover, decomposing the activation energy of the structural relaxation according to E(T)=Einfinity+Ec(T), we show that the glassy slowdown of all modified water molecules can fully be traced back to an exponential temperature dependence of the contribution Ec(T) related to cooperative dynamics. Extrapolation of this behavior suggests a common value at the glass transition temperature, Ec(Tg)/Tg~25. Finally, we discuss links between the structural relaxation and the vibrational displacement, as proposed in various theoretical approaches to the glass transition. PMID- 28734289 TI - Perspective: Photocatalytic reduction of CO2 to solar fuels over semiconductors. AB - Increasing emissions of carbon dioxide and the depletion of finite fossil fuels have led to many concerns about global warming and energy crises. Consequently, a sustainable and alternative method, photocatalytic CO2 reduction to chemical fuels has received considerable attention. This perspective highlights recent knowledge and the main challenges in CO2 photoreduction primarily from the theoretical field. The fundamental understanding of CO2 adsorption and reaction mechanism at an atomic level is fully addressed, and the relevant effects dominating the process of CO2 photoreduction are also elucidated. Moreover, recent development of photocatalysts including structural modification is presented, which greatly affects the efficiency and selectivity of CO2 conversion. Finally, the possibilities and challenges in this field are discussed. PMID- 28734290 TI - Effect of interlamellar interactions on shear induced multilamellar vesicle formation. AB - Shear-induced multilamellar vesicle (MLV) formation has been studied by coupling the small-angle neutron scattering (SANS) technique with neutron spin echo (NSE) spectroscopy. A 10% mass fraction of the nonionic surfactant pentaethylene glycol dodecyl ether (C12E5) in water was selected as a model system for studying weak inter-lamellar interactions. These interactions are controlled either by adding an anionic surfactant, sodium dodecyl sulfate, or an antagonistic salt, rubidium tetraphenylborate. Increasing the charge density in the bilayer induces an enhanced ordering of the lamellar structure. The charge density dependence of the membrane bending modulus was determined by NSE and showed an increasing trend with charge. This behavior is well explained by a classical theoretical model. By considering the Caille parameters calculated from the SANS data, the layer compressibility modulus B- is estimated and the nature of the dominant inter lamellar interaction is determined. Shear flow induces MLV formation around a shear rate of 10 s-1, when a small amount of charge is included in the membrane. The flow-induced layer undulations are in-phase between neighboring layers when the inter-lamellar interaction is sufficiently strong. Under these conditions, MLV formation can occur without significantly changing the inter-lamellar spacing. On the other hand, in the case of weak inter-lamellar interactions, the flow-induced undulations are not in-phase, and greater steric repulsion leads to an increase in the inter-lamellar spacing with shear rate. In this case, MLV formation occurs as the amplitude of the undulations gets larger and the steric interaction leads to in-phase undulations between neighboring membranes. PMID- 28734291 TI - Relaxation dynamics and transformation kinetics of deeply supercooled water: Temperature, pressure, doping, and proton/deuteron isotope effects. AB - Above its glass transition, the equilibrated high-density amorphous ice (HDA) transforms to the low-density pendant (LDA). The temperature dependence of the transformation is monitored at ambient pressure using dielectric spectroscopy and at elevated pressures using dilatometry. It is found that near the glass transition temperature of deuterated samples, the transformation kinetics is 300 times slower than the structural relaxation, while for protonated samples, the time scale separation is at least 30 000 and insensitive to doping. The kinetics of the HDA to LDA transformation lacks a proton/deuteron isotope effect, revealing that this process is dominated by the restructuring of the oxygen network. The x-ray diffraction experiments performed on samples at intermediate transition stages reflect a linear combination of the LDA and HDA patterns implying a macroscopic phase separation, instead of a local intermixing of the two amorphous states. PMID- 28734292 TI - Single-file mobility of water-like fluid in a generalized Frenkel-Kontorova model. AB - In this work, we used a generalized Frenkel-Kontorova model to study the mobility of water molecules inside carbon nanotubes with small radius at low temperatures. Our simulations show that the mobility of confined water decreases monotonically increasing the amplitude of the substrate potential at fixed commensurations. On the other hand, the mobility of the water molecules shows a non-monotonic behavior when varying the commensuration. This result indicates that the mobility of the confined fluid presents different behavior regimes depending on the amplitude of the water-nanotube interaction. In order to qualitatively understand these results, we study analytically the driven Frenkel-Kontorova model at finite temperatures. This analysis allows us to obtain the curves of the mobility versus commensurations, at fixed substrate potentials. Such curves show the existence of three regimes of mobility behavior as a function of the commensuration ratio. Additionally, our study indicates a nontrivial and strong dependence of the mobility with a quantity that can be interpreted as an effective amplitude of the substrate potential, depending on the bare amplitude of the substrate potential, the commensuration ratio, and temperature. PMID- 28734293 TI - The stretching force on a tethered polymer in pressure-driven flow. AB - We use mesoscopic lattice-Boltzmann/molecular dynamics simulations to study the stretching behavior of a single tethered polymer in micro- and nanochannels. In particular, we are interested in the connection between fluid flow properties and the force on the polymer chain. An analytical expression for the stretching force is proposed, which linearly depends on the number of monomers and the boundary shear rate. In agreement with theory, the numerical findings reveal that the influence of hydrodynamic interactions can be ignored, which is also supported by results of additional Langevin dynamics simulations. Our simulation data coincide with the analytical expression for the fractional extension of the chain and further indicate that even weak Poiseuille flow profiles induce a strong alignment of the chain along the channel walls. The numerical results are in good agreement with experimental data obtained by microfluidic stretching of tethered lambda-DNA. PMID- 28734294 TI - The standard mean-field treatment of inter-particle attraction in classical DFT is better than one might expect. AB - In classical density functional theory (DFT), the part of the Helmholtz free energy functional arising from attractive inter-particle interactions is often treated in a mean-field or van der Waals approximation. On the face of it, this is a somewhat crude treatment as the resulting functional generates the simple random phase approximation (RPA) for the bulk fluid pair direct correlation function. We explain why using standard mean-field DFT to describe inhomogeneous fluid structure and thermodynamics is more accurate than one might expect based on this observation. By considering the pair correlation function g(x) and structure factor S(k) of a one-dimensional model fluid, for which exact results are available, we show that the mean-field DFT, employed within the test-particle procedure, yields results much superior to those from the RPA closure of the bulk Ornstein-Zernike equation. We argue that one should not judge the quality of a DFT based solely on the approximation it generates for the bulk pair direct correlation function. PMID- 28734295 TI - Estimating the intrinsic limit of the Feller-Peterson-Dixon composite approach when applied to adiabatic ionization potentials in atoms and small molecules. AB - Benchmark adiabatic ionization potentials were obtained with the Feller-Peterson Dixon (FPD) theoretical method for a collection of 48 atoms and small molecules. In previous studies, the FPD method demonstrated an ability to predict atomization energies (heats of formation) and electron affinities well within a 95% confidence level of +/-1 kcal/mol. Large 1-particle expansions involving correlation consistent basis sets (up to aug-cc-pV8Z in many cases and aug-cc pV9Z for some atoms) were chosen for the valence CCSD(T) starting point calculations. Despite their cost, these large basis sets were chosen in order to help minimize the residual basis set truncation error and reduce dependence on approximate basis set limit extrapolation formulas. The complementary n-particle expansion included higher order CCSDT, CCSDTQ, or CCSDTQ5 (coupled cluster theory with iterative triple, quadruple, and quintuple excitations) corrections. For all of the chemical systems examined here, it was also possible to either perform explicit full configuration interaction (CI) calculations or to otherwise estimate the full CI limit. Additionally, corrections associated with core/valence correlation, scalar relativity, anharmonic zero point vibrational energies, non-adiabatic effects, and other minor factors were considered. The root mean square deviation with respect to experiment for the ionization potentials was 0.21 kcal/mol (0.009 eV). The corresponding level of agreement for molecular enthalpies of formation was 0.37 kcal/mol and for electron affinities 0.20 kcal/mol. Similar good agreement with experiment was found in the case of molecular structures and harmonic frequencies. Overall, the combination of energetic, structural, and vibrational data (655 comparisons) reflects the consistent ability of the FPD method to achieve close agreement with experiment for small molecules using the level of theory applied in this study. PMID- 28734296 TI - Spherical harmonics analysis of surface density fluctuations of spherical ionic SDS and nonionic C12E8 micelles: A molecular dynamics study. AB - The surface structure and its fluctuation of spherical micelles were investigated using a series of density correlation functions newly defined by spherical harmonics and Legendre polynomials based on the molecular dynamics calculations. To investigate the influence of head-group charges on the micelle surface structure, ionic sodium dodecyl sulfate and nonionic octaethyleneglycol monododecylether (C12E8) micelles were investigated as model systems. Large-scale density fluctuations were observed for both micelles in the calculated surface static structure factor. The area compressibility of the micelle surface evaluated by the surface static structure factor was tens-of-times larger than a typical value of a lipid membrane surface. The structural relaxation time, which was evaluated from the surface intermediate scattering function, indicates that the relaxation mechanism of the long-range surface structure can be well described by the hydrostatic approximation. The density fluctuation on the two dimensional micelle surface has similar characteristics to that of three dimensional fluids near the critical point. PMID- 28734297 TI - Nonequilibrium phase coexistence and criticality near the second explosion limit of hydrogen combustion. AB - While hydrogen is a promising source of clean energy, the safety and optimization of hydrogen technologies rely on controlling ignition through explosion limits: pressure-temperature boundaries separating explosive behavior from comparatively slow burning. Here, we show that the emergent nonequilibrium chemistry of combustible mixtures can exhibit the quantitative features of a phase transition. With stochastic simulations of the chemical kinetics for a model mechanism of hydrogen combustion, we show that the boundaries marking explosive domains of kinetic behavior are nonequilibrium critical points. Near the pressure of the second explosion limit, these critical points terminate the transient coexistence of dynamical phases-one that autoignites and another that progresses slowly. Below the critical point temperature, the chemistry of these phases is indistinguishable. In the large system limit, the pseudo-critical temperature converges to the temperature of the second explosion limit derived from mass action kinetics. PMID- 28734298 TI - Excited state absorption spectra of dissolved and aggregated distyrylbenzene: A TD-DFT state and vibronic analysis. AB - A time-dependent density functional theory study is performed to reveal the excited state absorption (ESA) features of distyrylbenzene (DSB), a prototype pi conjugated organic oligomer. Starting with a didactic insight to ESA based on simple molecular orbital and configuration considerations, the performance of various density functional theory functionals is tested to reveal the full vibronic ESA features of DSB at short and long probe delay times. PMID- 28734299 TI - State-of-the-art ab initio potential energy curve for the xenon atom pair and related spectroscopic and thermophysical properties. AB - A new ab initio interatomic potential energy curve for two ground-state xenon atoms is presented. It is based on supermolecular calculations at the coupled cluster level with single, double, and perturbative triple excitations [CCSD(T)] employing basis sets up to sextuple-zeta quality, which were developed as part of this work. In addition, corrections were determined for higher coupled-cluster levels up to CCSDTQ as well as for scalar and spin-orbit relativistic effects at the CCSD(T) level. A physically motivated analytical function was fitted to the calculated interaction energies and used to compute the vibrational spectrum of the dimer, the second virial coefficient, and the dilute gas transport properties. The agreement with the best available experimental data for the investigated properties is excellent; the new potential function is superior not only to previous ab initio potentials but also to the most popular empirical ones. PMID- 28734300 TI - Potential energy surfaces of quintet and singlet O4. AB - We present global ground-state potential energy surfaces for the quintet and singlet spin states of the O4 system that are suitable for treating high-energy vibrational-rotational energy transfer and collision-induced dissociation in electronically adiabatic, spin-conserving O2-O2 collisions. The surfaces are based on MS-CASPT2/maug-cc-pVTZ electronic structure calculations with scaled external correlation. The active space has 16 electrons in 12 orbitals. The calculations cover nine kinds of geometrical arrangements corresponding to dissociative diatom-diatom collisions of O2, geometries corresponding to O3-O, geometries identified by running trajectories, and geometries along linear synchronous transit paths. The global ground-state potential energy surfaces were obtained by a many-body approach with an accurate O-O pairwise interaction and a fit of the many-body interaction to 12 684 electronic structure data points for the singlet and 10 543 electronic structure data points for the quintet. The many body fit is based on permutationally invariant polynomials in terms of bond-order functions of the six interatomic distances; the bond-order functions are mixed exponential-Gaussian functions. PMID- 28734301 TI - Communication: Influence of external static and alternating electric fields on water from long-time non-equilibrium ab initio molecular dynamics. AB - The response of water to externally applied electric fields is of central relevance in the modern world, where many extraneous electric fields are ubiquitous. Historically, the application of external fields in non-equilibrium molecular dynamics has been restricted, by and large, to relatively inexpensive, more or less sophisticated, empirical models. Here, we report long-time non equilibrium ab initio molecular dynamics in both static and oscillating (time dependent) external electric fields, therefore opening up a new vista in rigorous studies of electric-field effects on dynamical systems with the full arsenal of electronic-structure methods. In so doing, we apply this to liquid water with state-of-the-art non-local treatment of dispersion, and we compute a range of field effects on structural and dynamical properties, such as diffusivities and hydrogen-bond kinetics. PMID- 28734302 TI - Analytical derivatives of the individual state energies in ensemble density functional theory method. I. General formalism. AB - The state-averaged (SA) spin restricted ensemble referenced Kohn-Sham (REKS) method and its state interaction (SI) extension, SI-SA-REKS, enable one to describe correctly the shape of the ground and excited potential energy surfaces of molecules undergoing bond breaking/bond formation reactions including features such as conical intersections crucial for theoretical modeling of non-adiabatic reactions. Until recently, application of the SA-REKS and SI-SA-REKS methods to modeling the dynamics of such reactions was obstructed due to the lack of the analytical energy derivatives. In this work, the analytical derivatives of the individual SA-REKS and SI-SA-REKS energies are derived. The final analytic gradient expressions are formulated entirely in terms of traces of matrix products and are presented in the form convenient for implementation in the traditional quantum chemical codes employing basis set expansions of the molecular orbitals. The implementation and benchmarking of the derived formalism will be described in a subsequent article of this series. PMID- 28734303 TI - Behavior of a supercooled chalcogenide liquid in the non-Newtonian regime under steady vs. oscillatory shear. AB - The steady and oscillatory shear rate dependence of viscosity of a supercooled chalcogenide liquid of composition As10Se90 is measured at Newtonian viscosities ranging between 103 and 107 Pa s using capillary and parallel plate rheometry. The liquid displays strong violation of the Cox-Merz rule in the non-Newtonian regime where the viscosity under steady shear is nearly an order of magnitude lower than that under oscillatory shear. This behavior is argued to be related to the emergence of unusually large (6-8 nm) cooperatively rearranging regions with long relaxation times in the liquid that result from significant structural rearrangements under steady shear. PMID- 28734304 TI - Temperature dependence of the translocation time of polymer through repulsive nanopores. AB - The forced translocation of a polymer chain through repulsive nanopores was studied by using Langevin dynamics simulations. The polymer is in the compact globule state at low temperature and in the random coil state at high temperature. Simulation results show that the mean translocation time is highly dependent on the temperature T and the minimal is located near the coil-globule transition temperature. Moreover, the scaling behaviors ~ Nalpha and ~ F-delta are studied, with N the polymer length and F the driving force inside the nanopore. Universal values alpha = 1.4 and delta = 0.85 are observed for the polymer in the random coil state. While for the polymer in the compact globule state, alpha decreases from alpha = 2 at weak driving to 1.2 at strong driving for short N and delta increases with decreasing T in the low F region, but we find universal exponents alpha = 1.6 for long N and delta = 0.85 in the large F region. Results show that polymer's conformation plays a much more important role than the diffusion coefficient in controlling the translocation time of the polymer chain. PMID- 28734305 TI - Exploring the free energy gain of phase separation via Markov state modeling. AB - The gain of free energy upon unmixing is determined via application of Markov state modeling (MSM), using an Ising model with a fixed number of up- and down spins. MSM yields reasonable estimates of the free energies. However, a closer look reveals significant differences that point to residual non-Markovian effects. These non-Markovian effects are rather unexpected since the typical criteria to study the quality of Markovianity indicate complete Markovian behavior. We identify the sparse connectivity between different Markov states as a likely reason for the observed bias. By studying a simple five state model system, we can analytically elucidate different sources of the bias and thus explain the different deviations that were observed for the Ising model. Based on this insight, we can modify the determination of the count matrix in the MSM approach. In this way, the estimation of the free energy is significantly improved. PMID- 28734306 TI - Theoretical study of resonance formation in microhydrated molecules. II. Thymine (H2O)n, n = 1,2,3,5. AB - We have investigated the effect of microsolvation on the low-lying pure shape pi* resonances of thymine. Static-exchange R-matrix calculations for elastic electron scattering from microhydated thymine, i.e., Thy-(H2O)n with n = 1,2,3,5 are discussed. We look at the additive effect of water molecules hydrogen-bonding to thymine. The results for Thy-(H2O)5 show that both pi* resonances appear at lower energy in the cluster than in isolated thymine, but that the energy shift is different for each resonance. We discuss how our results could help explain the quenching of hydrogen loss in dissociative electron attachment of microhydrated thymine recently recorded experimentally. PMID- 28734307 TI - A confinement induced spectroscopic study of noble gas atoms using equation of motion architecture: Encapsulation within fullerene's voids. AB - A relativistic study of spectroscopic properties of the endohedral fullerenes Ng@C60q (where Ng = He, Ne and q=0,+/-1,+/-2 are the charges) associated with the C60 molecule has been done using the equation of motion coupled cluster (EOM-CC) methodology. Specific properties estimated are the transition energies, dipole oscillator strengths, and transition probabilities for the low-lying excitations 1s2(1S0) -> 1snp (1P1) (n = 2, 3, 4) for He@C60q and 1s22s22p6 (1S0) -> 1s22s22p5ns/nd (1P1) (n = 3, 4) for Ne@C60q, which have been compared with those for the isolated atom to depict the confinement effect of the host molecule on the encapsulated atom. This is accomplished by introducing an effective potential to the atomic Hamiltonian induced by the fullerene moiety and its charge. The EOM CC results have been compared with those estimated with the random phase approximation (and configuration interaction singles) to understand the effect of electron correlation under such confinement. The systematic and interesting behavior of the properties is highlighted indicating the effect of fullerene cage potential on the redistribution of electron density of the guest atom. PMID- 28734309 TI - Universal two-dimensional characteristics in perovskite-type oxyhydrides ATiO2H (A = Li, Na, K, Rb, Cs). AB - A series of unsynthesized perovskite-type oxyhydrides ATiO2H (A = Li, Na, K, Rb, Cs) are investigated by the density functional calculations. These oxyhydrides are stable in the sense of the formation energies for some possible synthesis reactions. They are crystallized into quite similar crystal structures with the long c-axis, and the corner-sharing TiO4H2 octahedra of the ideal perovskite-type structure are deformed into the 5-fold coordinated titanium atoms with the OH plane and the apical oxygen atoms. All of these oxyhydrides exhibit two dimensional electronic states at the valence band maximum characterized by the in plane oxygen 2p and the hydrogen 1s orbitals. While the c-axis becomes short as the ionic radius of the A atom becomes small and the two-dimensional characteristics are weakened, the electronic state at the valence band maximum is still characterized as the O-H in-plane state. Additionally, the Born effective charge tensors, spontaneous electric polarizations, dielectric tensors, and piezoelectric tensors are evaluated. It is found that the spontaneous electric polarizations of these oxyhydrides are much larger than that of tetragonal BaTiO3. PMID- 28734308 TI - Molecular simulation of caloric properties of fluids modelled by force fields with intramolecular contributions: Application to heat capacities. AB - The calculation of caloric properties such as heat capacity, Joule-Thomson coefficients, and the speed of sound by classical force-field-based molecular simulation methodology has received scant attention in the literature, particularly for systems composed of complex molecules whose force fields (FFs) are characterized by a combination of intramolecular and intermolecular terms. The calculation of a thermodynamic property for a system whose molecules are described by such a FF involves the calculation of the residual property prior to its addition to the corresponding ideal-gas property, the latter of which is separately calculated, either using thermochemical compilations or nowadays accurate quantum mechanical calculations. Although the simulation of a volumetric residual property proceeds by simply replacing the intermolecular FF in the rigid molecule case by the total (intramolecular plus intermolecular) FF, this is not the case for a caloric property. We describe the correct methodology required to perform such calculations and illustrate it in this paper for the case of the internal energy and the enthalpy and their corresponding molar heat capacities. We provide numerical results for cP, one of the most important caloric properties. We also consider approximations to the correct calculation procedure previously used in the literature and illustrate their consequences for the examples of the relatively simple molecule 2-propanol, CH3CH(OH)CH3, and for the more complex molecule monoethanolamine, HO(CH2)2NH2, an important fluid used in carbon capture. PMID- 28734310 TI - Stability limits for the supercooled liquid and superheated crystal of Lennard Jones particles. AB - We have studied the limits of stability in the first order liquid-solid phase transition in a Lennard-Jones system by means of the short-time relaxation method and using the bond-orientational order parameter Q6. These limits are compared with the melting line. We have paid special attention to the supercooled liquid, comparing our results with the point where the free energy cost of forming a nucleating droplet goes to zero. We also indirectly estimate the dimension associated to the critical nucleus at the spinodal, expected to be fractal according to mean field theories of nucleation. PMID- 28734311 TI - A Monte-Carlo simulation of ionic conductivity and viscosity of highly concentrated electrolytes based on a pseudo-lattice model. AB - Simulating three transport phenomena-ionic conductivity, viscosity, and self diffusion coefficient-in a common Monte-Carlo framework, we discuss their relationship to the intermolecular interactions of electrolyte solutions at high concentrations (C/mol l-1 ~ 1). The simulation is predicated on a pseudolattice model of the solution. The ions and solvents (collectively termed "molecules") are considered dimensionless points occupying the lattice sites. The molecular transport is realized by a repetition of swapping two adjacent molecules by the stochastic Gibbs sampling process based on simple intermolecular interactions. The framework has been validated by the fact that the simulated ionic conductivity and dynamic viscosity of 1:1- and 2:1-salts qualitatively well represent the experimental data. The magnitude of the Coulombic interaction itself is not reflected in the ionic conductivity, but the extent to which the Coulombic interaction is shielded by the dielectric constant has a significant influence. On the other hand, the dielectric constant barely influences the viscosity, while the magnitude of the Coulombic interaction is directly reflected in the viscosity. PMID- 28734312 TI - Diffusion quantum Monte Carlo calculations of SrFeO3 and LaFeO3. AB - The equations of state, formation energy, and migration energy barrier of the oxygen vacancy in SrFeO3 and LaFeO3 were calculated with the diffusion quantum Monte Carlo (DMC) method. Calculations were also performed with various Density Functional Theory (DFT) approximations for comparison. DMC reproduces the measured cohesive energies of these materials with errors below 0.23(5) eV and the structural properties within 1% of the experimental values. The DMC formation energies of the oxygen vacancy in SrFeO3 and LaFeO3 under oxygen-rich conditions are 1.3(1) and 6.24(7) eV, respectively. Similar calculations with semi-local DFT approximations for LaFeO3 yielded vacancy formation energies 1.5 eV lower. Comparison of charge density evaluated with DMC and DFT approximations shows that DFT tends to overdelocalize the electrons in defected SrFeO3 and LaFeO3. Calculations with DMC and local density approximation yield similar vacancy migration energy barriers, indicating that steric/electrostatic effects mainly determine migration barriers in these materials. PMID- 28734313 TI - Singlet fission in chiral carbon nanotubes: Density functional theory based computation. AB - Singlet fission (SF) process, where a singlet exciton decays into a pair of spin one exciton states which are in the total spin singlet state, is one of the possible channels for multiple exciton generation (MEG). In chiral single-wall carbon nanotubes (SWCNTs), efficient SF is present within the solar spectrum energy range which is shown by the many-body perturbation theory calculations based on the density functional theory simulations. We calculate SF exciton-to biexciton decay rates R1->2 and biexciton-to-exciton rates R2->1 in the (6,2), (6,5), (10,5) SWCNTs, and in the (6,2) SWCNT functionalized with Cl atoms. Within the solar energy range, we predict R1->2~1014-1015 s-1, while biexciton-to exciton recombination is weak with R2->1/R1->2<=10-2. SF MEG strength in pristine SWCNTs varies strongly with the excitation energy, which is due to highly non uniform density of states at low energy. However, our results for the (6,2) SWCNT with chlorine atoms adsorbed to the surface suggest that MEG in the chiral SWCNTs can be enhanced by altering the low-energy electronic states via surface functionalization. PMID- 28734314 TI - Theoretical study of resonance formation in microhydrated molecules. I. Pyridine (H2O)n, n = 1,2,3,5. AB - We present R-matrix calculations for electron scattering from microhydrated pyridine. We studied the pyridine-H2O cluster at static-exchange (SE), SE + polarization, and close-coupling levels, and pyridine-(H2O)n n = 2, 3, and 5 at SE level only in order to investigate the effect of hydrogen bonding on the resonances of pyridine. We analyse the results in terms of direct and indirect effects. We observe that the total (direct plus indirect) effect of microhydration leads to the stabilization of all resonances studied, both shape and core-excited. The size of the shift is different for different resonances and seems to be linked to the dipole moment of the cluster. PMID- 28734315 TI - Specialist practitioners. PMID- 28734316 TI - MY APPROACH to choosing ventricular pacing sites in patients with severe heart failure. PMID- 28734317 TI - The 4D Nucleome. PMID- 28734318 TI - [Public health and political will: Convergence and divergence]. PMID- 28734319 TI - Attention-Deficit/Hyperactivity Disorder and Disordered Eating. PMID- 28734320 TI - The Role of Parents and Families in Preventing Young Adult Alcohol Use. PMID- 28734321 TI - The Time Is Here: A Comprehensive Curriculum for Adolescent Health Teaching and Learning From the Society for Adolescent Health and Medicine. PMID- 28734322 TI - Association Between Childhood to Adolescent Attention Deficit/Hyperactivity Disorder Symptom Trajectories and Late Adolescent Disordered Eating. AB - PURPOSE: Disordered eating is more prevalent among adolescents with attention deficit/hyperactivity disorder. Both inattention and hyperactivity/impulsivity symptoms show strong associations with disordered eating, but few investigations of these associations have been longitudinal. Thus, we examined the effect of childhood to adolescent inattention and hyperactivity/impulsivity symptom trajectories on late adolescent disordered eating. METHODS: We used growth mixture modeling to identify distinct inattention and hyperactivity/impulsivity symptom trajectories (called "classes") across three time points (ages 8-9, 13 14, and 16-17 years) in the Swedish Twin study of CHild and Adolescent Development. The resulting classes were used to predict Eating Disorder Inventory 2 Bulimia, Drive for Thinness, and Body Dissatisfaction subscales at age 16-17 years, with adjustment for sex and body mass index at age 16-17 years. RESULTS: The combined inattention and hyperactivity/impulsivity symptom trajectory classes included: a "low symptom" class characterized by low inattention and hyperactivity/impulsivity throughout childhood/adolescence; a "predominantly inattention" class characterized by elevated inattention, but not hyperactivity/impulsivity, throughout childhood/adolescence; a "predominantly hyp/imp" class characterized by elevated hyperactivity/impulsivity, but not inattention, throughout childhood/adolescence; and a "both inattention and hyp/imp" class characterized by elevated inattention and hyperactivity/impulsivity throughout childhood/adolescence. After adjusting for sex and body mass index or sex and anxiety/depression symptoms, the "both inattention and hyp/imp" (vs. "low symptom") class predicted significantly higher Eating Disorder Inventory-2 subscale scores during late adolescence. CONCLUSIONS: Increased vigilance for disordered eating among children who have both inattention and hyperactivity/impulsivity symptoms throughout childhood and adolescence could aid in early identification of eating disorders. PMID- 28734325 TI - The Obesity Phenotypes in Adolescents: Some Lessons From the HELENA Study. PMID- 28734324 TI - Adolescence and Later Life Disease Burden: Quantifying the Contribution of Adolescent Tobacco Initiation From Longitudinal Cohorts. AB - PURPOSE: Adolescence is a time of initiation of behaviors leading to noncommunicable diseases (NCDs). We use tobacco to illustrate a novel method for assessing the contribution of adolescence to later burden. METHODS: Data on initiation of regular smoking during adolescence (10-19 years) and current adult smoking were obtained from the 1958 British Birth Cohort, the U.S. National Longitudinal Study of Adolescent Health (Add Health), the Pelotas 1982 Birth Cohort, and the Victorian Adolescent Health Cohort Study. We estimated an "adolescent attributable fraction" (AAF) by calculating the proportion of persisting adult daily smoking initiated < age 20 years. We used findings to estimate AAFs for >155 countries using contemporary surveillance data. RESULTS: In the 1958 British Birth Cohort, 81.6% of daily smokers at age 50 years initiated < age 20 years, with a risk ratio of 6.1 for adult smoking related to adolescent initiation. The adjusted AAF was 69.1. Proportions of smokers initiating <20 years, risk ratio, and AAFs were 83.3%, 7.0%, and 70.4% for Add Health; 75.5%, 3.7%, and 50.2% in Victorian Adolescent Health Cohort Study; and 70.9%, 5.8%, and 56.9% in Pelotas males and 89.9%, 6.4%, and 75.9% in females. Initiation <16 years resulted in the highest AAFs. Estimated AAFs globally ranged from 35% in China to 76% in Argentina. CONCLUSIONS: The contribution of adolescent smoking initiation to adult smoking burden is high, suggesting a need to formulate and implement effective actions to reduce smoking initiation in adolescents. Similar trends in other NCD risks suggest that adolescents will be central to future efforts to control NCDs. PMID- 28734323 TI - Parental Influences on Heavy Episodic Drinking Development in the Transition to Early Adulthood. AB - PURPOSE: The purpose of this study was to examine how parental relationship quality (communication frequency, time spent together, and closeness) during early adulthood is related to heavy episodic drinking (HED) during this developmental period and whether effects vary according to age, youth sex, or parent sex. METHODS: National data from the Panel Study of Income Dynamics Transition to Adulthood Study were analyzed. Youth participated in up to four interviews (2005, 2007, 2009, and 2011; n = 1,320-1,489) between ages 18-25 years. At each wave, respondents reported past-year HED and their communication frequency, time spent, and closeness with each parent (items combined into an index). We tested differences in parental effects by age, parent sex, and youth sex using multigroup latent curve models. RESULTS: Paternal relationship quality was negatively associated with HED for both males and females at each age; associations did not vary by respondent age or sex (odds ratio [OR] = .73, 95% confidence interval [CI]: .63-.85). Maternal relationship quality was significantly negatively associated with HED at ages 18-19 years among both sexes equally (OR = .50, 95% CI: .41-.61). Although protective associations continued until the age of 25 years for males, they weakened and became nonsignificant at ages 20-25 years for females (OR = .87, 95% CI: .72-1.04). Findings were robust to inclusion of multiple covariates associated with both parenting and alcohol use. CONCLUSIONS: Having close, communicative parental relationships seems protective against HED in early adulthood, although for females maternal effects appear limited to late adolescence. Programs to improve relationship quality between young adults and their parents may help curb problematic drinking during this vulnerable period. PMID- 28734326 TI - Response to "the Obesity Phenotypes in Adolescents: Some Lessons From the HELENA Study" by Dr. Rey-Lopez and Dr. de Rezende. PMID- 28734327 TI - Treatment of Acute Conjunctivitis in the United States and Evidence of Antibiotic Overuse: Isolated Issue or a Systematic Problem? PMID- 28734328 TI - A Metallic Intraocular Foreign Body in a Young Man. PMID- 28734329 TI - Leptochoroid in a Case of Alagille Syndrome (Arteriohepatic Dysplasia). PMID- 28734330 TI - Acute-on-Chronic: Retinal Artery Occlusion Following Retinal Vein Occlusion. PMID- 28734331 TI - Optic Nerve Head Drusen as a Rare Manifestation of Cowden Syndrome: Multimodal Imaging. PMID- 28734332 TI - Retinal Loop Vessel Captured with Optical Coherence Tomography-Angiography. PMID- 28734333 TI - Solitary Nonvascularized Corneal Epithelial Dysplasia. PMID- 28734334 TI - Optical Coherence Tomography Imaging of a Large Spherical Seed in Retinoblastoma. PMID- 28734335 TI - Tidal Wave Retinal Detachment. PMID- 28734336 TI - Exudative Vitreoretinopathy in Dyskeratosis Congenita. PMID- 28734337 TI - Multifocal Choroiditis with Peripheral Subretinal Fibrosis and Optic Nerve Involvement. PMID- 28734338 TI - Reply. PMID- 28734339 TI - Re: Jaffe et al.: Injectable fluocinolone acetonide long-acting implant for noninfectious intermediate uveitis, posterior uveitis, and panuveitis: 2-year results (Ophthalmology. 2016;123:1940-1948). PMID- 28734340 TI - Re: Maleki et al.: Selective laser trabeculoplasty in controlled uveitis with steroid-induced glaucoma (Ophthalmology. 2016;123:2630-2632). PMID- 28734341 TI - Reply. PMID- 28734342 TI - Re: Lee et al.: Evaluating access to eye care in the contiguous United States by calculated driving time in the United States Medicare population (Ophthalmology. 2016;123:2456-2461). PMID- 28734343 TI - Reply. PMID- 28734344 TI - Re: Masket et al.: Special report: The American Academy of Ophthalmology task force consensus statement on adverse events with intraocular lenses (Ophthalmology. 2017;124:142-144). PMID- 28734345 TI - Reply. PMID- 28734346 TI - HAP nanoparticle and substrate surface electrical potential towards bone cells adhesion: Recent results review. AB - Nanostructured hydroxyapatite (HAP) and its nanoparticles are widely used for implantation into the human organism. The biocompatibility of the implants depends very much on the interaction between the implant and the cells regenerating tissue to be connected to the implant. An implant surface electrical charged density plays an important role in these processes. Possible instruments managing the surface electrical potential of HAP are in the focus of this paper. Both theoretical and experimental results evidence that: - the surface electrical charge density of the nanoparticle depends on its size and shape; - the electrical charge density of HAP could be engineered by contact less technique because of deposition of the electrical charge from the external radiation source, surface couples reconstruction. PMID- 28734347 TI - Different approaches to study protein films at air/water interface. AB - In this review classical studies on insoluble liquid monolayers formed by proteins are examined and compared. It has been focused the attention on the information that it is possible to obtain from the pi-a isotherms recorded by compression of the monolayers. In recent decades new techniques have developed, mainly microscopy, that provide valuable information on the behavior and structure of fluid films. However, frequently the data are difficult to interpret and require a previous thermodynamic study of them on the basis of the surface tension (or surface pressure) as a function of the molecular area measurement. The main aim of this paper is to underline that surface balance type of Langmuir is a powerful technique since it enables to obtain information at molecular level from a macroscopic analysis. Notably, this information is revealed very interesting when it comes to studying protein films. From this point of view it has been reviewed the study methods and results for four proteins. PMID- 28734348 TI - Ion mobility spectrometry combined with ultra performance liquid chromatography/mass spectrometry for metabolic phenotyping of urine: Effects of column length, gradient duration and ion mobility spectrometry on metabolite detection. AB - The need for rapid and efficient high throughput metabolic phenotyping (metabotyping) in metabolomic/metabonomic studies often requires compromises to be made between analytical speed and metabolome coverage. Here the effect of column length (150, 75 and 30 mm) and gradient duration (15, 7.5 and 3 min respectively) on the number of features detected when untargeted metabolic profiling of human urine using reversed-phase gradient ultra performance chromatography with, and without, ion mobility spectrometry, has been examined. As would be expected, reducing column length from 150 to 30 mm, and gradient duration, from 15 to 3 min, resulted in a reduction in peak capacity from 311 to 63 and a similar reduction in the number of features detected from over ca. 16,000 to ca. 6500. Under the same chromatographic conditions employing UPLC/IMS/MS to provide an additional orthogonal separation resulted in an increase in the number of MS features detected to nearly 20,000 and ca. 7500 for the 150 mm and the 30 mm columns respectively. Based on this limited study the potential of LC/IMS/MS as a tool for improving throughput and increasing metabolome coverage clearly merits further in depth study. PMID- 28734350 TI - Dried urine spots - A novel sampling technique for comprehensive LC-MSn drug screening. AB - Dried matrix spot (DMS) technique as alternative sampling strategy, especially dried urine spots (DUS), might be an alternative for drug screening. So far only particular drugs or drug classes were covered in DMS screenings. Therefore, workup of DUS for a broad comprehensive library-based LC-MSn screening was developed. It consisted of enzymatic on-spot deconjugation followed by liquid extraction and LC-MSn analysis. This workup was compared to established urine precipitation (UP) and validated according to international guidelines for qualitative approaches, using exemplary compounds of several drug classes (antidepressants, benzodiazepines, cardiovascular drugs, neuroleptics, opioids, stimulants, etc.) with a broad range of (physico-)chemical properties and chromatographic behaviors. On-spot conjugate cleavage and liquid extraction was sufficient for most compounds and the validation results comparable to those obtained after simple UP. For demonstrating the applicability, 103 authentic urine samples, six rat urine samples after low dose substance administrations, and two proficiency tests for systematic toxicological urinalysis were worked up with the new DUS approach or by UP without or with conjugate cleavage. In the authentic urine samples, 112 different drugs out of 43 categories plus metabolites were identified via the used LC-MSn library. With the new DUS approach, 5% less positive hits could be found compared to the UP approach and 15% less than the latter after conjugate cleavage. The differences should be caused mainly by smaller urine volumes used for DUS. In the two proficiency tests, all 15 drugs could be detected. Unfortunately, all three approaches were not able to detect very low-dosed substances in rat urine samples. However, they could be detected using a more sensitive LC-high resolution-MS/MS approach showing that the DUS workup was also suitable for those. In conclusion, DUS might be an alternative sampling technique for comprehensive drug testing or adherence monitoring. PMID- 28734349 TI - Integrated preservation and sample clean up procedures for studying water ingestion by recreational swimmers via urinary biomarker determination. AB - The use of cyanuric acid as a biomarker for ingestion of swimming pool water may lead to quantitative knowledge of the volume of water ingested during swimming, contributing to a better understanding of disease resulting from ingestion of environmental contaminants. When swimming pool water containing chlorinated cyanurates is inadvertently ingested, cyanuric acid is excreted quantitatively within 24 h as a urinary biomarker of ingestion. Because the volume of water ingested can be quantitatively estimated by calculation from the concentration of cyanuric acid in 24 h urine samples, a procedure for preservation, cleanup, and analysis of cyanuric acid was developed to meet the logistical demands of large scale studies. From a practical stand point, urine collected from swimmers cannot be analyzed immediately, given requirements of sample collection, shipping, handling, etc. Thus, to maintain quality control to allow confidence in the results, it is necessary to preserve the samples in a manner that ensures as quantitative analysis as possible. The preservation and clean-up of cyanuric acid in urine is complicated because typical approaches often are incompatible with the keto-enol tautomerization of cyanuric acid, interfering with cyanuric acid sample preparation, chromatography, and detection. Therefore, this paper presents a novel integration of sample preservation, clean-up, chromatography, and detection to determine cyanuric acid in 24 h urine samples. Fortification of urine with cyanuric acid (0.3-3.0 mg/L) demonstrated accuracy (86-93% recovery) and high reproducibility (RSD < 7%). Holding time studies in unpreserved urine suggested sufficient cyanuric acid stability for sample collection procedures, while longer holding times suggested instability of the unpreserved urine. Preserved urine exhibited a loss of around 0.5% after 22 days at refrigerated storage conditions of 4 degrees C. PMID- 28734351 TI - Capillary electrophoresis-tandem mass spectrometry as a highly selective tool for the compositional and site-specific assessment of multiple peptide-deamidation. AB - Site-specific mapping of multiple deamidations in peptides is a challenging analytical task. In this work, capillary electrophoresis-tandem mass spectrometry (CE-MS/MS) is presented as a high-resolution tool for the detailed characterization of these subtle modifications in peptides. The 4.5-kDa peptide drug TRI-1144, which contains five closely-positioned potential deamidation sites, was selected as model compound. TRI-1144 was exposed to acidic conditions and/or elevated temperatures for 1-14 h. Stressed samples were analyzed using a background electrolyte (BGE) of 150 mM ammonium formate (pH 6.0) in combination with a capillary coated with a bilayer of Polybrene-dextran sulfate. Separation of deamidated and deacetylated TRI-1144 species, including several positional isomers, was greatly enhanced by adding up to 40 vol% of acetonitrile-isopropanol (87.5:12.5, v/v) to the BGE, allowing reliable determination of the number of deamidations/deacetylations per degradation product. Collision-induced dissociation MS/MS was conducted on the separated peptide components in order to reveal the exact position of deamidation on the peptide chain. Obtained fragment ions showed overlapping isotopic distributions in their MS/MS spectra resulting from the comigration of different isomeric deamidated species. Comparison of theoretical and measured isotope distributions for specific y ions of peptide fragments yielded the identity and relative abundance of isomeric deamidated products. The developed CE-MS/MS methodology was used for the highly selective evaluation of TRI-1144 stability under different stress conditions, providing detailed qualitative and semi-quantitative degradation maps of the peptide drug. PMID- 28734352 TI - Real-time observation of perturbation of a Drosophila embryo's early cleavage cycles with microfluidics. AB - It is of great importance to understand biochemical system's behavior toward environmental perturbation during the development of living organisms. Here a microfluidic platform for Drosophila embryo's online development and observation is presented. The system is capable of developing the embryo's anterior and posterior halves controlled at different temperature environments, and it can be easily coupled with a confocal microscope for real-time image acquisition. The microfluidic chip is consisted of a polymethylmethacrylate (PMMA) substrate with a thickness of 4.0 mm and a polydimethylsiloxane (PDMS) cover designed with a typical 'Y' channel with a depth of 400 MUm, width of 800 MUm. Temperature gradients were created across the anterior half and posterior half of the embryo by utilizing two streams of laminar flow with different temperatures. It was found that thermal gradient would result in asynchronous development of the two halves of the embryos, and the developing difference was related to the direction of thermal gradient. This may result from the presence of an unknown mechanism located in the anterior half of the embryo, which oversees nuclear division synchronicity. These observations would help better understand compensatory mechanisms of Drosophila embryo's development under environmental perturbations. PMID- 28734353 TI - Streptavidin-biotin-peroxidase nanocomplex-amplified microfluidics immunoassays for simultaneous detection of inflammatory biomarkers. AB - Simultaneous, sensitive and quantitative detection of biomarkers in infectious disease is crucial for guiding antimicrobial treatment and predicting prognosis. This work reported an ultrasensitive and quantitative microfluidic immunoassay combined with the streptavidin-biotin-peroxidase (SA-B-HRP) nanocomplex-signal amplification system (MIS) to detect two inflammatory biomarkers, procalcitonin (PCT, for discriminating bacterial infections from nonbacterial infections) and interleukin-6 (IL-6, for monitoring the kinetics of infectious disease) simultaneously. The amplification system was based on the one step self-assembly of SA and B-HRP to form the SA-B-HRP nanocomplex, which effectively amplified the chemiluminescent signals. The linear ranges for PCT and IL-6 detections by MIS were 250-1.28 * 105 pg mL-1 and 5-1280 pg mL-1, and the limit of detection (LOD) were 48.9 pg mL-1 and 1.0 pg mL-1, respectively, both of which were significantly improved compared with microfluidic immunoassays without amplification system (MI). More importantly, PCT and IL-6 in human serum could be simultaneously detected in the same run by MIS, which could greatly improve the detection efficiency and reduce the cost. Given the advantages of high sensitivity, multiplex and quantitative detection, MIS could be potentially applied for detection of biomarkers at low concentration in clinical diagnosis. PMID- 28734354 TI - Determination of aqueous antibiotic solutions using SERS nanogratings. AB - The emergence of antibiotics and their active metabolites in aquatic ecosystem has motivated the development of sensitive and reliable sensors to monitor traces of antibiotics and metabolites in drinking water sources (i.e. surface water). The surface enhanced Raman scattering (SERS) technique, which is widely recognized as a high sensitivity method for molecular vibrational detection, is potentially a powerful tool for trace environmental contamination analysis. The main goal of this work is to demonstrate pharmaceutical and metabolite multiplexing detection using the SERS approach. Periodic metallic nanostructures were fabricated using laser interference lithography (LIL) and used as SERS substrates (platform that supports the SERS effect). The LIL method allowed excellent substrate-to-substrate geometric parameters variations; for instance, the variations in periodicity were determined to be less than 1%. A common fluoroquinolone (FQ) parent-and-metabolite pair, enrofloxacin (ENRO) and ciprofloxacin (CIPRO), was targeted for multiplexing detection on the relative uniform substrates fabricated by LIL. The quantifications of the analytes mixtures were achieved by chemometric analysis (i.e. non-negative matrix factorization with alternating least square algorithm (NMF-ALS)). The limit of the quantification (LOQ) of the present method is in the ppm-level with less than 10% spatial variation in the SERS signal. PMID- 28734355 TI - Highly sensitive strategy for identification of trace chemicals in complex matrix: Application to analysis of monacolin analogues in monascus-fermented rice product. AB - Trace analysis of chemical analogues was always a hot topic and attracted the researchers' attentions. In this study, a database/multi-step filtering strategy was developed by using HPLC-Chip-MS system for comprehensive characterization of monacolin analogues in monascus-fermented rice product (MFRP). This strategy mainly included three steps, including chemical profile of MFRP by HPLC-Chip-MS, establishment of monacolin analogue database, multi-step filtering of monacolins based on modified mass defect filtering. All target compounds showed the symmetrical peak shapes and high MS response by using nanoflow HPLC-Chip-MS. According to the previous literature and experimental MS data, a database including 720 monacolin analogues was established. The original 522 ions in MFRP were automatically extracted by molecular feature extraction function. And then, through rectangular mass defect filtering and analogues distribution area filtering, 298 ions were further excluded. Finally, a total of 84 monacolins including 16 new compounds were unambiguously identified or tentatively characterized based on MS/MS information. In comparison with conventional mass defect filtering method, the proposed method was accurately able to exclude false positive results. The 438 false positive results were excluded in our study, while only 250 ones would be filtered out by using conventional method. This study provided a sensitive and powerful method for rapidly characterization of trace chemicals in complex matrix. PMID- 28734356 TI - Palladium-copper nanowires-based biosensor for the ultrasensitive detection of organophosphate pesticides. AB - A highly sensitive acetylcholinesterase (AChE) electrochemical biosensor for the quantitative determination of organophosphate pesticides (OPs) in vegetables and fruits based on palladium-copper nanowires (Pd-Cu NWs) was reported. AChE immobilized on the modified electrode could catalyze hydrolysis of acetylthiocholine chloride (ATCl), generating an irreversible oxidation peak. When exposed to the OPs, the activity of the AChE was inhibited and the current significantly decreased. The detection mechanism is based on the inhibition of AChE. The Pd-Cu NWs not only provide a large active surface area (0.268 +/- 0.01) cm2 for the immobilization of AChE, which was approximately 3.8 times higher than the bare glass carbon electrode, but also exhibit excellent electro-catalytic activity and remarkable electron mobility. The biosensor modified with Pd-Cu NWs displayed a good affinity to ATCl and catalyzed hydrolysis of ATCl, with a low Michaelis-Menten constant (KM) of 50.56 MUM. Under optimized conditions, the AChE Cs/Pd-Cu NWs/GCE biosensor detected malathion with wide linear ranges of 5-1000 ppt and 500-3000 ppb, and the low detection limit was 1.5 ppt (4.5 pM). In addition, the OPs biosensor has been applied to the analysis of malathion in commercial vegetable and fruit samples, with excellent recoveries in the range of 98.5%-113.5%. This work provides a simple, sensitive and effective platform for biosensors and exhibits future potential in practical application for the OPs assay. PMID- 28734357 TI - YSZ-based sensor using Cr-Fe-based spinel-oxide electrodes for selective detection of CO. AB - A selective carbon monoxide (CO) sensor was developed by the use of both of CuCrFeO4 and CoCrFeO4 as the sensing electrode (SE) for yttria-stabilized zirconia (YSZ)-based potentiometric sensor. The sensing-characteristic examinations of the YSZ-based sensors using each of spinel oxides as the single SE sensor showed that CuCrFeO4-SE had the ability to detect CO, hydrocarbons and NOx gases, while CoCrFeO4-SE was sensitive to hydrocarbons and NOx gases. Thus, when both SEs were paired as a combined-SEs sensor, the resulting sensor could generate a selective response to CO at 450 degrees C under humid conditions. The sensor was also capable of detecting CO in the concentration range of 20-700 ppm. Its sensing mechanism that was examined via polarization-curve measurements was confirmed to be based on mixed-potential model. The CO response generated by the combined-SEs sensor was unaffected by the change of water vapor concentration in the range of 1.3-11.5 vol% H2O. Additionally, the sensing performance was stable during 13 days tested. PMID- 28734358 TI - Fluorescent quenching immune chromatographic strips with quantum dots and upconversion nanoparticles as fluorescent donors for visual detection of sulfaquinoxaline in foods of animal origin. AB - In this study, two novel fluorescence quenching immune chromatographic strips (FQICS) were developed to detect sulfaquinoxaline (SQX) in foods of animal origin. These proposed FQICSs were based on fluorescence resonance energy transfer (FRET) from fluorescence donors (quantum dots or upconversion nanoparticles) to fluorescence acceptors (colloidal gold nanoparticles). Compared with traditional colloidal gold-based immune chromatographic strips (ICS), these FQICSs showed positive correlation between the fluorescent signals and the targets, and allowed user to get test results from weak fluorescent signals. The visual detection limits of these two FQICSs were both 1 ng mL-1 in standard solution and 8 MUg kg-1 in samples, while the visual detection limit of the colloidal gold-based ICS was 10 ng mL-1 in standard solution and 80 MUg kg-1 in samples. Besides, the results we obtained by the use of FQICS showed high agreement with those obtained by the use of commercial ELISA kits, indicating the good accuracy of these strips. As a conclusion, these proposed FQICS based on quantum dots and upconversion nanoparticles can be applied in sensitive, rapid and on-site detection of SQX in foods of animal origin. PMID- 28734359 TI - Fast multiplex analysis of antibodies in complex sample matrix using the microfluidic EvalutionTM platform. AB - Biosensor development requires comprehensive research for establishing the optimal bioassay conditions that determine the final kinetics, sensitivity and specificity. Different systems have been developed to study bioreceptor-target interactions but they often have drawbacks, such as long hands-on time, low throughput, high sample consumption and high cost. In this work, the potential of the novel microfluidic EvalutionTM platform has been evaluated for developing sandwich-based assays in a fast and high-throughput fashion. An immunoassay for the detection of influenza A nucleoprotein was used as a model system. Exploiting the platform's unique features, various typical bioassay parameters (e.g. aspecific binding between assay components, different reagent concentrations and incubation times) were tested for three capture antibodies in a simple and fast manner (2 runs of 80 min). The selected conditions, giving the highest signal-to noise ratio, were directly employed on the same platform to detect nucleoprotein in buffer and nasopharyngeal swabs. Two antibodies with a higher dissociation constant (Ab11 and Ab12) required longer incubation times (60 min) for sensitive detection (limit of detection (LOD) of 0.48 and 0.26 ng mL-1, respectively) compared to an antibody with lower dissociation constant (LOD of 0.04 ng mL-1 for Ab66 within 30 min). Moreover, one antibody (Ab12) showed limited capacity to capture nucleoprotein directly in sample matrix. The obtained results were in accordance with previous studies performed on an ELISA and SPR platform with the same antibodies. This positions the EvalutionTM platform as a reliable platform for fast and multiplex analysis of antibodies' performance both in buffer and complex sample matrices. PMID- 28734360 TI - Revealing the biography of a hidden medieval manuscript using synchrotron and conventional imaging techniques. AB - Reading the content of hidden texts from ancient manuscripts has become an increasingly important endeavor thanks to the variety of non-destructive analytical tools and image processing routines available for this task. In this study, portable macro X-Ray Fluorescence (MA-XRF-tube), Visible Hyperspectral Imaging (HSI) together with Synchrotron based macro X-Ray Fluorescence (MA-XRF SR) are combined with signal processing methods to reveal the biography of a degraded manuscript recycled as binding material for a 16th century printed edition of Hesiod's Works and Days. The analytical techniques allow visualizing the hidden text, revealing passages from the Institutes Justinian, a 6th century A.D codification of the Roman Law, with further marginal comments on medieval Canon Law. In addition, the identification of the materials (e.g. pigments, inks) part of the original manuscript together with their sequence of use are revealed: i) the preparation of the parchment using a Ca-based preparation layer, ii) drawing of ruled guide lines, using a Pb-based pen or ink, iii) writing of the main text using a rich Fe-gall ink with modulating color pigments (Hg-, Cu- and Pb- based) and iv) addition of two types of comments to the main text, one of the ink used for the comments being a Fe-gall ink rich in Cu. PMID- 28734361 TI - Preparation of intact mitochondria using free-flow isoelectric focusing with post pH gradient sample injection for morphological, functional and proteomics studies. AB - Mitochondria play essential roles in both energy metabolism and cell signaling, which are critical for cell survival. Although significant efforts have been invested in understanding mitochondrial biology, methods for intact mitochondria preparation are technically challenging and remain to be improved. New methods for heterogeneous mitochondria purification will therefore boost our understanding on their physiological and biophysical properties. Herein, we developed a novel recycling free-flow isoelectric focusing (RFFIEF) with post-pH gradient sample injection (post-PGSI) for preparative separation of mitochondria. Crude mitochondria of rabbit liver obtained from differential centrifugation were purified by the developed method according to their pI values as six fractions. Transmission electron microscope images revealed that intact mitochondria existed in two fractions of pH 6.24 and 6.61, degenerative mitochondria were in two fractions of pH 5.46 and 5.72, and inner membrane vesicles (IMVs) appeared in the fractions of pH 4.70 and 5.04. Membrane potential measurement proved a dramatic difference between intact mitochondria and IMVs, which reflected the bioactivity of obtained populations. Particularly, proteomics analyses revealed that more number of proteins were identified in the intact fractions than that of IMVs or crude mitochondria, which demonstrated that RFFIEF could be powerful tool for the preparation of intact organelle as well as their proteomic and in-depth biological analysis. PMID- 28734362 TI - Discrimination of bacteria by rapid sensing their metabolic volatiles using an aspiration-type ion mobility spectrometer (a-IMS) and gas chromatography-mass spectrometry GC-MS. AB - The objective of our study was to investigate whether one may quickly and reliably discriminate different microorganism strains by direct monitoring of the headspace atmosphere above their cultures. Headspace samples above a series of in vitro bacterial cultures were directly interrogated using an aspiration type ion mobility spectrometer (a-IMS), which produced distinct profiles ("fingerprints") of ion currents generated simultaneously by the detectors present inside the ion mobility cell. Data processing and analysis using principal component analysis showed net differences in the responses produced by volatiles emitted by various bacterial strains. Fingerprint assignments were conferred on the basis of product ion mobilities; ions of differing size and mass were deflected in a different degree upon their introduction of a transverse electric field, impacting finally on a series of capacitors (denominated as detectors, or channels) placed in a manner analogous to sensor arrays. Three microorganism strains were investigated Escherichia coli, Bacillus subtilis and Staphylococcus aureus; all strains possess a relatively low pathogenic character. Samples of air with a 5 cm3 volume from the headspace above the bacterial cultures in agar growth medium were collected using a gas-tight chromatographic syringe and injected inside the closed-loop pneumatic circuit of the breadboard a-IMS instrument model ChemPro 100i (Environics Oy, Finland), at a distance of about 1 cm from the ionization source. The resulting chemical fingerprints were produced within two seconds from the moment of injection. The sampling protocol involved to taking three replicate samples from each of 10 different cultures for a specific strain, during a total period of 72 h after the initial incubation - at 24, 48 and 72 h, respectively. Principal component analysis (PCA) was used to discriminate between the IMS fingerprints. PCA was found to successfully discriminate between bacteria at three levels in the experimental campaign: 1) between blank samples from growth medium and samples from bacterial cultures, 2) between samples from different bacterial strains, and 3) between time evolutions of headspace samples from the same bacterial strain over the 3-day sampling period. Consistent classification between growth medium samples and growth medium inoculated with bacteria was observed in both positive and negative detection/ionization modes. In parallel, headspace air samples of 1 dm3 were collected from each bacterial culture and loaded onto TenaxTM-Carbograph desorption tubes, using a custom built sampling unit based on a portable sampling pump. One sample was taken for each of 10 different cultures of a strain, at 24, 48 and 72 h after the initial incubation. These adsorption tubes were subsequently analyzed using thermal desorption - gas chromatography - mass spectrometry (TD-GC-MS). This second dataset was intended to produce a qualitative analysis of the volatiles present in the headspace above the bacterial cultures. PMID- 28734363 TI - Multi-energy calibration applied to atomic spectrometry. AB - Multi-energy calibration (MEC) is a novel strategy that explores the capacity of several analytes of generating analytical signals at many different wavelengths (transition energies). Contrasting with traditional methods, which employ a fixed transition energy and different analyte concentrations to build a calibration plot, MEC uses a fixed analyte concentration and multiple transition energies for calibration. Only two calibration solutions are required in combination with the MEC method. Solution 1 is composed of 50% v v-1 sample and 50% v v-1 of a standard solution containing the analytes. Solution 2 has 50% v v-1 sample and 50% v v-1 blank. Calibration is performed by running each solution separately and monitoring the instrument response at several wavelengths for each analyte. Analytical signals from solutions 1 and 2 are plotted on the x-axis and y-axis, respectively, and the analyte concentration in the sample is calculated from the slope of the resulting calibration curve. The method has been applied to three different atomic spectrometric techniques (ICP OES, MIP OES and HR-CS FAAS). Six analytes were determined in complex samples (e.g. green tea, cola soft drink, cough medicine, soy sauce, and red wine), and the results were comparable with, and in several cases more accurate than, values obtained using the traditional external calibration, internal standardization, and standard additions methods. MEC is a simple, fast and efficient matrix-matching calibration method. It may be applied to any technique capable of simultaneous or fast sequential monitoring of multiple analytical signals. PMID- 28734364 TI - Improved variable reduction in partial least squares modelling by Global-Minimum Error Uninformative-Variable Elimination. AB - The calibration performance of Partial Least Squares regression (PLS) can be improved by eliminating uninformative variables. For PLS, many variable elimination methods have been developed. One is the Uninformative-Variable Elimination for PLS (UVE-PLS). However, the number of variables retained by UVE PLS is usually still large. In UVE-PLS, variable elimination is repeated as long as the root mean squared error of cross validation (RMSECV) is decreasing. The set of variables in this first local minimum is retained. In this paper, a modification of UVE-PLS is proposed and investigated, in which UVE is repeated until no further reduction in variables is possible, followed by a search for the global RMSECV minimum. The method is called Global-Minimum Error Uninformative Variable Elimination for PLS, denoted as GME-UVE-PLS or simply GME-UVE. After each iteration, the predictive ability of the PLS model, built with the remaining variable set, is assessed by RMSECV. The variable set with the global RMSECV minimum is then finally selected. The goal is to obtain smaller sets of variables with similar or improved predictability than those from the classical UVE-PLS method. The performance of the GME-UVE-PLS method is investigated using four data sets, i.e. a simulated set, NIR and NMR spectra, and a theoretical molecular descriptors set, resulting in twelve profile-response (X-y) calibrations. The selective and predictive performances of the models resulting from GME-UVE-PLS are statistically compared to those from UVE-PLS and 1-step UVE, one-sided paired t-tests. The results demonstrate that variable reduction with the proposed GME UVE-PLS method, usually eliminates significantly more variables than the classical UVE-PLS, while the predictive abilities of the resulting models are better. With GME-UVE-PLS, a lower number of uninformative variables, without a chemical meaning for the response, may be retained than with UVE-PLS. The selectivity of the classical UVE method thus can be improved by the application of the proposed GME-UVE method resulting in more parsimonious models. PMID- 28734366 TI - A label-free genetic biosensor for diabetes based on AuNPs decorated ITO with electrochemiluminescent signaling. AB - The variation of I27L gene closely relates to increasing risk of type 2 diabetes, thus it is greatly significant to develop various methods for its identification or monitoring. We report here a novel label-free electrochemiluminescent (ECL) biosensor for simple and effective determination of I27L gene based on Au nanoparticles functionalized ITO electrode. The ECL technique is employed to monitor the hybridization of DNA strands by measuring the changes of its intensity. Here, the ECL signal was quenched by blocked access of probe (luminol anion) owing to the electrostatic repulsion of negatively charged sensor surface and the space resistance. The quantification of target strand can be directly realized by calibrating the quenched ECL signal toward its logarithm concentration in good linearity within the range from 1.0 * 10-11 to 1.0 * 10-7 M and a detection limit of 8.1 * 10-12 M. In addition, the biosensor exhibited good stability, excellent reproducibility and outstanding selectivity against one-base mismatched strand. What's more, the simple, low-cost, sensitive device could be easily miniaturized, makes it as an attractive candidate for integrating into portable platforms for point-of-care molecular diagnostics. PMID- 28734365 TI - Automatic feed phase identification in multivariate bioprocess profiles by sequential binary classification. AB - In this paper, we propose a new strategy for retrospective identification of feed phases from online sensor-data enriched feed profiles of an Escherichia Coli (E. coli) fed-batch fermentation process. In contrast to conventional (static), data driven multi-class machine learning (ML), we exploit process knowledge in order to constrain our classification system yielding more parsimonious models compared to static ML approaches. In particular, we enforce unidirectionality on a set of binary, multivariate classifiers trained to discriminate between adjacent feed phases by linking the classifiers through a one-way switch. The switch is activated when the actual classifier output changes. As a consequence, the next binary classifier in the classifier chain is used for the discrimination between the next feed phase pair etc. We allow activation of the switch only after a predefined number of consecutive predictions of a transition event in order to prevent premature activation of the switch and undertake a sensitivity analysis regarding the optimal choice of the (time) lag parameter. From a complexity/parsimony perspective the benefit of our approach is three-fold: i) The multi-class learning task is broken down into binary subproblems which usually have simpler decision surfaces and tend to be less susceptible to the class-imbalance problem. ii) We exploit the fact that the process follows a rigid feed cycle structure (i.e. batch-feed-batch-feed) which allows us to focus on the subproblems involving phase transitions as they occur during the process while discarding off-transition classifiers and iii) only one binary classifier is active at the time which keeps effective model complexity low. We further use a combination of logistic regression and Lasso (i.e. regularized logistic regression, RLR) as a wrapper to extract the most relevant features for individual subproblems from the whole set of high-dimensional sensor data. We train different soft computing classifiers, including decision trees (DT), k nearest neighbors (k-NN), support vector machines (SVM) and an own developed fuzzy classifier and compare our method with conventional multi-class ML. Our results show a remarkable out-performance of the here proposed method over static ML approaches in terms of accuracy and robustness. We achieved close to error free feed phase classification while reducing the misclassification rates in 17 out of 20 investigated test cases in the range between 39% and 98.2% depending on feature set and classifier architecture. Models trained on features based on selection by RLR significantly outperformed those trained on features suggested by experts and their predictive performance was considerably less affected by the choice of the lag parameter. PMID- 28734367 TI - A solid-contact potassium-selective electrode with MoO2 microspheres as ion-to electron transducer. AB - A solid-contact ion-selective electrode (SC-ISE) for potassium with MoO2 microspheres as ion-to-electron transducer is described. MoO2 microsphers can be synthesized via the reduction of MoO3 nanobelts in an isopropanol solvent with a mild process, and the obtained MoO2 microspheres have been characterized by X-ray diffraction and field-emission scanning electron microscopy. With the application of MoO2 microspheres, the newly fabricated SC-ISE for K+ exhibits a stable and rapid potential response. A near Nernstian slope of 55 mV/decade to potassium activities in the range of 10-5 - 10-3 M is found and the detection limit is 10 5.5 M. Impedance spectra and chronopotentiometry results show that a smaller resistance together with a larger double layer capacitance is guaranteed due to the introduction of the intermediate layer of MoO2 microspheres. Additionally, light, O2 and CO2 do not induce significant influences to the present SC-ISE, and a reduced water layer between the ion selective membrane and the underlying conductor is formed. Thus, it is clear that MoO2 microspheres, as metallic analogues, can be used as a good candidate for the new type of transducing layer in SC-ISEs. PMID- 28734368 TI - Exploring pralidoxime chloride as a universal electrochemical probe for organophosphorus pesticides detection. AB - An electrochemical method based on non-enzymatic inhibition for the determination of organophosphorus pesticide (OPPs) using pralidoxime chloride (PAM-Cl) as a universal electrochemical probe was reported. Cyclic voltammetry was performed to characterize the redox properties of pralidoxime and OPPs. Differential pulse voltammetry (DPV) was carried out to analyze the influence of anion (chloride and iodide ions), to optimize the pH of testing condition, and to explore the relationship between pralidoxime and OPPs. The results showed that iodide ion generated an anodic peak close to the peak of pralidoxime, which would interfere in the detection of OPPs. Phosphate buffer solution (pH 7.0) was chosen because of its high peak current and low peak potential when testing PAM-Cl by DPV. Chlorpyrifos, fenthion, and methyl parathion were examples of three existing OPPs detection methods. The peak current of PAM-Cl decreased along with the increase of concentration of OPPs in the solution. The limit of detection was 0.018 MUM, 0.100 MUM, and 0.215 MUM, respectively. It was the first time for PAM-Cl to be used as a universal electrochemical probe to develop a simple, cheap and stable method for OPPs detection. PMID- 28734369 TI - Systematic comparison of exosomal proteomes from human saliva and serum for the detection of lung cancer. AB - Circulating tumor exosomes harbor plenty of cancer biological information, which have emerged as promising targets for cancer early detection and diagnosis. Human serum and saliva are unique diagnostic body fluids, which contain numerous circulating exosomes. It is necessary to establish standardized isolation method and compare their proteome profiling for translational medicine. High abundant proteins in these body fluids were removed before exosomes isolation and obtained exosomes were further confirmed by morphology analysis and surface biomarker test. Label free quantification was applied to systematically compare the protein profiling in saliva and serum exosomes. 319 and 994 exosomal proteins were identified from saliva and serum by LC-MS/MS, respectively. To explore their utility for cancer proteomics, we systematically compared the proteome of saliva and serum exosomes from healthy subjects and lung cancer patients. In particular, 11 potential candidates were coincidently discovered in both body fluids of lung cancer patients. Our finding enforced the hypothesis that cancer related proteins were presented in saliva and serum exosomes, which promoted the unique features of exosomes in our body fluids. A circulating exosomes based body fluid test could be easily established for monitoring cancer once these candidates were validated. PMID- 28734370 TI - Class-modelling in food analytical chemistry: Development, sampling, optimisation and validation issues - A tutorial. AB - Qualitative data modelling is a fundamental branch of pattern recognition, with many applications in analytical chemistry, and embraces two main families: discriminant and class-modelling methods. The first strategy is appropriate when at least two classes are meaningfully defined in the problem under study, while the second strategy is the right choice when the focus is on a single class. For this reason, class-modelling methods are also referred to as one-class classifiers. Although, in the food analytical field, most of the issues would be properly addressed by class-modelling strategies, the use of such techniques is rather limited and, in many cases, discriminant methods are forcedly used for one class problems, introducing a bias in the outcomes. Key aspects related to the development, optimisation and validation of suitable class models for the characterisation of food products are critically analysed and discussed. PMID- 28734371 TI - Electrospun nanofibrous mercury filter: Efficient concentration and determination of trace mercury in water with high sensitivity and tunable dynamic range. AB - Herein, we reported a simple and highly sensitive method for the concentration and determination of trace mercury in water samples based on a novel electropsun nanofibrous mercury filter (ENMF). The method consisted of two simple steps: first, the concentration of mercury on a piece of thiol-containing ENMF; and second, the determination of mercury captured on the ENMF using a direct mercury analyzer (DMA). By changing the volume of water sample, the dynamic range of the method could extend from 0.0025 to 6.0 ng/mL with the lowest limit of detection (LOD) of 2.5 pg/mL (2.5 ppt, 12.5 pM). The proposed method exhibited good precision with the relative standard deviations (RSDs, n = 11) of 9.4%, 5.5%, and 3.7% at the concentrations of 0.01, 0.1 and 1.0 ng/mL, respectively, as well as satisfying accuracy for the analysis of certified reference materials (GSB 07 3173-2014 202033 and GBW 08603). The proposed method showed good agreement with the Chinese AFS standard method (GB/T 5750.6) in the measurement of three different real water samples, with the relative errors of -6.2-2.6% and standard addition recoveries of 90.6-108.2%. This strategy provided a simple and efficient approach to the highly sensitive determination of trace mercury in water, and extended the application of electrospun nanofibrous membranes for environmental pollutant analysis. PMID- 28734372 TI - Role of Niacin in Cardiovascular Prevention: The Debate Continues. PMID- 28734373 TI - Concerning Niacin in Current Clinical Practice. PMID- 28734374 TI - The Reply. PMID- 28734375 TI - Excess Ticagrelor Mortality: Reporting Bias or a Canary in the Coal Mine? PMID- 28734376 TI - The Reply. PMID- 28734377 TI - Unreliable Observations from a Confounded Analysis of a Skewed Database. PMID- 28734378 TI - The Reply. PMID- 28734379 TI - Screening Those with the Lowest Cardiovascular Mortality? PMID- 28734380 TI - The Reply. PMID- 28734381 TI - Renal Function and Direct Oral Anticoagulant Dose Reduction. PMID- 28734382 TI - The Reply. PMID- 28734384 TI - The Reply. PMID- 28734383 TI - Effects of Treatment with Azoles Are Overstated. PMID- 28734385 TI - Beall's List Removed: What Stands Between Us and Open Access Predators? PMID- 28734386 TI - Increasing Anticoagulation Use Among Inpatients Receiving Inferior Vena Cava Filters. PMID- 28734387 TI - International Conference on Current Trends in Biotechnology & post ICCB-2016 conference on Strategies for Environmental Protection and Management (ICSEPM 2016). PMID- 28734388 TI - Axonal transport dysfunction in neurodegenerative diseases: the "holy grail" for developing disease modifying therapies? PMID- 28734389 TI - Inflammatory variant of cerebral amyloid angiopathy. PMID- 28734390 TI - Letter from the Editor: Lung Cancer Screening Facts. PMID- 28734391 TI - Letter From the Guest Editor: Lung Cancer Screening in the year 2017. PMID- 28734392 TI - Brief History of Lung Cancer Screening Including the National Lung Screening Trial. PMID- 28734393 TI - Elements of a Lung Cancer Screening Program. PMID- 28734394 TI - Low-Dose Computed Tomography for Lung Cancer Screening: The Protocol and The Dose. PMID- 28734395 TI - Lung Computed Tomography Screening Reporting and Data System Version 1.0. PMID- 28734396 TI - Spectrum of Subsolid Pulmonary Nodules and Overdiagnosis. PMID- 28734397 TI - Incidental Findings in Lung Cancer Screening: Which Ones are Relevant? PMID- 28734398 TI - Managing Patients With Screen-Detected Nodules: The Nodule Clinic. PMID- 28734399 TI - Role of Fluorodeoxyglucose Positron Emission Tomography-Computed Tomography in the Evaluation of Suspicious Pulmonary Nodules. PMID- 28734400 TI - Sampling of Suspicious Solitary Pulmonary Nodules: Percutaneous Needle Biopsy and Preoperative Localization. PMID- 28734401 TI - Sampling of Suspicious Solitary Pulmonary Nodules: Electromagnetic Navigational Bronchoscopy and Video-Assisted Thoracoscopic Surgery. PMID- 28734402 TI - The Role of Liquid Biopsies in Lung Cancer Screening. PMID- 28734403 TI - Introduction to the special issue on bullying. PMID- 28734404 TI - Defending the Truth in a Post-Truth Era. PMID- 28734405 TI - Aortic Coarctation Repair: How I Teach It. PMID- 28734406 TI - Invited Commentary. PMID- 28734407 TI - Invited Commentary. PMID- 28734408 TI - Invited Commentary. PMID- 28734409 TI - Invited Commentary. PMID- 28734410 TI - Clinical Trials in Thoracic Surgery: A Report From Ginsberg Day 2017 and Early Risers at STS 2017. AB - No unified source lists clinical trials relevant to general thoracic surgery. This description summarizes the current offerings across the National Cancer Institute Cooperative Group-sponsored clinical trials, and includes trials involving surgery for lung cancer and esophageal cancer, and in some instances, perioperative management of patients undergoing thoracic surgery. PMID- 28734411 TI - Reply. PMID- 28734412 TI - About Commissural Prolapse and Mitral Valve Repair. PMID- 28734413 TI - Endoballoon Use With Robotics. PMID- 28734414 TI - Reply. PMID- 28734415 TI - How to Prevent Pacemaker Implantation After Sutureless Aortic Valve Replacement: Tips and Tricks. PMID- 28734416 TI - It Might be Misleading to Validate EuroSCORE II Performances on Samples Operated Before Its Creation. PMID- 28734417 TI - Reply. PMID- 28734418 TI - Reply. PMID- 28734419 TI - Nonresectional Technique for Large Posterior Leaflet Prolapse Causing Mitral Regurgitation. PMID- 28734420 TI - Prolonged Air Leak After Lung Resection and Emphysema. PMID- 28734421 TI - Reply. PMID- 28734422 TI - Venoarterial Extracorporeal Membrane Oxygenation: Lower Speed, and You May Be Faster. PMID- 28734423 TI - Reply. PMID- 28734424 TI - Reply. PMID- 28734426 TI - Corrigendum. PMID- 28734425 TI - Give to Caesar What Belongs to Caesar. PMID- 28734427 TI - Libman-Sacks Endocarditis Due to Systemic Lupus Erythematosus Activation After Mitral Valve Plasty. AB - Libman-Sacks endocarditis is a cardiac manifestation of systemic lupus erythematosus (SLE) and antiphospholipid syndrome. We report a case of mitral valve destruction due to Libman-Sacks endocarditis, which was caused by activation of SLE, despite prompt initiation of systemic steroid therapy. The prevention of SLE activation is critically important in valve surgery for patients with SLE. To the best of our knowledge, this is the first case of repaired mitral valve destruction due to activation of SLE, which was caused by valve surgery itself. PMID- 28734428 TI - Rupture of Anterolateral Papillary Muscle Resulting From Small Artery Occlusion. AB - A 69-year-old man was admitted to our hospital for dyspnea and fever. Echocardiography showed a mobile mass on the anterolateral papillary muscle and severe mitral regurgitation. Coronary artery angiography showed no stenotic lesion. Infective endocarditis or cardiac tumor was suspected, and a mitral valve operation was performed. Intraoperative observation revealed a partially ruptured anterolateral papillary muscle and no evidence of infection or tumor. Pathologic examination of the resected papillary muscle showed atherosclerotic changes in small arteries and infarcted areas in different postinfarct time phases along the ruptured edge. It could be speculated that microvascular stenosis caused the repeated localized subendocardial infarction over time. PMID- 28734429 TI - Ascending Aorta Stenting After Off-Pump Aortic Wrapping in Stanford A Retrograde Aortic Dissection. AB - We report 4 cases of off-pump ascending aorta wrapping combined with ascending aorta stenting in retrograde Stanford A acute aortic dissection (SAAD). Since 2008, 18 patients have undergone wrapping of the ascending aorta at our institution. Four patients had a persistent circulating false lumen in the ascending aorta after wrapping, with a threat to the aortic root. We chose an endovascular approach with ascending aorta stenting. Follow-up computed tomography showed a reapplication of the intimal flap in the reinforced aorta. Ascending aorta stenting after aortic wrapping for retrograde SAAD is a safe and efficient technique to prevent proximal progression of the dissection. PMID- 28734430 TI - Transcatheter Aortic Valve Implantation Under Direct Visualization in Homograft Valve Endocarditis. AB - Prosthetic valve endocarditis is a very grave and often terminal disease. Surgical valve replacement remains the cornerstone treatment for this disease. However, it is often contraindicated. Herein, we describe the implantation under direct visualization of a self-expandable transcatheter heart valve in a prohibitive surgical risk patient with homograft aortic valve endocarditis. PMID- 28734431 TI - Thoracic Endovascular Aortic Repair Including Total Debranching on Femoral Artery for Arch Rupture. AB - A 94-year-old woman with rupture of a thoracic aortic aneurysm (rTAA) was referred to us. She previously underwent thoracic endovascular aortic repair and was considered to be at high risk for a conventional open operation. Therefore an endovascular procedure was planned. The proximal landing zone needed to be placed at the ascending aorta to seal a type 1a endoleak. A hybrid operation consisting of supraaortic total debranching on the common femoral artery and endovascular repair was performed. All debranched bypasses were patent and the aneurysm was excluded. The patient regained sufficient ambulatory strength and showed no symptoms of syncope. PMID- 28734432 TI - Outbreak of Middle East Respiratory Syndrome-Coronavirus Causes High Fatality After Cardiac Operations. AB - Middle East respiratory syndrome-coronavirus (MERS-CoV) resembles a severe form of community-acquired pneumonia initially reported in Saudi Arabia in 2012. The MERS-CoV epidemic poses a big challenge because of its high mortality. In January 2015, a patient who was potentially incubating MERS-CoV arrived from the emergency department of another hospital and was admitted with acute coronary syndrome. This resulted in an outbreak in the cardiac surgery ward that caused the deaths of 5 of 6 patients who had undergone cardiac operations. PMID- 28734433 TI - Hybrid Approach for the Treatment of Superior Vena Cava Syndrome Induced by Pacemaker. AB - Pacemaker-induced superior vena cava syndrome (SVCS) is a rare but incapacitating adverse event that can occur years after implantation. Inasmuch as it is a rare disease, there is no consensus about its treatment. The most widely used option is balloon angioplasty and venous stent implantation, with preservation of the lead or previous extraction and subsequent reimplantation after the procedure, which is associated with new episodes of thrombosis. The epicardial implantation reduces the risk of thrombosis. We report a case of pacemaker-induced SVCS for which we used a hybrid approach for epicardial lead implantation and electrode extraction, balloon angioplasty, and stent implantation. PMID- 28734434 TI - The First Operation for Apical Hypertrophic Cardiomyopathy-Dr Dwight McGoon, 1972. AB - The first operation for apical hypertrophic cardiomyopathy (ApHCM) was performed on September 7, 1972 by Dr Dwight McGoon at Mayo Clinic on a 16-year-old boy who was thought to have a cardiac neoplasm. PMID- 28734435 TI - Laparoscopic Approach for Treatment of Symptomatic Intra-Pericardial Cyst. AB - Symptomatic pericardial cysts requiring operative management are rare entities. We present a patient with a symptomatic intra-pericardial cystic lesion with intermittent syncope who underwent treatment using a laparoscopic approach, thus minimizing pain and allowing quick recovery. PMID- 28734436 TI - Repair of Circumflex Aortic Arch in an Adult. AB - We describe the diagnoses and repair of a symptomatic circumflex aortic arch in an adult. PMID- 28734437 TI - Two Pumps for Single Ventricle: Mechanical Support for Establishment of Biventricular Circulation. AB - A 31-year-old patient with a univentricular heart and double-inlet left ventricle, moderate pulmonary stenosis, and severe mitral valve regurgitation experienced irreversible heart failure after mitral valve replacement. "Biventricular" mechanical circulatory support was initiated. The systemic circulation was supported using the HeartWare ventricular assist device (HVAD) (HeartWare, Framingham, MA) pump in the usual manner. The second pump was inserted into the right atrium and connected to the pulmonary artery after closure of the pulmonary valve and atrial separation. This solution allowed optimal circulatory support, reduction of pulmonary resistance, and normal peripheral oxygen saturation. Thus the patient was listed for heart transplantation. PMID- 28734438 TI - Extracardiac Fontan Operation Through a Right Thoracotomy. AB - An extracardiac Fontan operation through a right thoracotomy incision is an alternative approach in children who have an ascending aorta that is in close proximity to the sternum, as in aortic atresia or transposed great vessels, and in those who have had prior mediastinitis. PMID- 28734439 TI - Coronary Sinus Orifice Atresia After the Fontan Completion: Unique Repair Technique. AB - We report a successful unroofing of the coronary sinus via a unique technique. Our patient was diagnosed with single ventricle morphology. Pulmonary artery banding and bidirectional cavopulmonary shunt were performed at 1 and 6 months old, respectively. Ordinary univentricular repair strategy was performed; extracardiac total cavopulmonary connection was achieved at 18 months old. Catheterization performed 1 year after the Fontan procedure revealed the coronary sinus orifice atresia, diffuse coronary artery stenosis, and sinusoid formation of the coronary system. We present a new technique using a small bronchial fiberscope to identify a coronary sinus buried in the atrial wall. PMID- 28734440 TI - Use of Mechanical Circulatory Support in Isolated Right Heart Failure: A Bridge to Transplantation. AB - Acute myocarditis may lead to left ventricular dysfunction and subsequent need for cardiac transplantation. We describe a 15-month-old child who presented with right heart failure of unclear cause. Echocardiography showed normal left ventricular function; however, right ventricular function was markedly reduced. The patient required extracorporeal membrane oxygenation followed by placement of a right-sided Berlin EXCOR ventricular assist device. There was little recovery, and the child underwent cardiac transplantation. Subsequent pathologic examination revealed lymphocytic myocarditis. We believe this is the first use of an isolated right ventricular assist device as a bridge to heart transplantation. PMID- 28734441 TI - A Novel and Successful Repair of a Left Atriogastric Fistula After Esophagectomy. AB - Atriogastric fistulas remain a rare adverse event in patients who undergo esophagectomy with gastric pullthrough. The presentation of an atriogastric fistula ranges from self-limited gastrointestinal bleeding to life-threatening hemorrhage, end-organ dysfunction from septic emboli, or both. These fistulas are associated with significant mortality. Previous reports describe successful repairs of gastrocardiac fistulas with the use of cardiopulmonary bypass. This report describes a patient with a significant burden of cerebral embolic disease, which therefore required a unique approach to fistula repair. PMID- 28734442 TI - Nonintubated Spontaneous Respiration Anesthesia for Tracheal Glomus Tumor. AB - Previous tracheal surgeries were performed under tracheal and cross-field intubation. However, the intubation would lead to bleeding if the tumors were large or hemorrhagic. Moreover, the tracheal intubation might interfere the surgical vision and anastomosis during the reconstruction process. Therefore, we performed a tracheal tumor resection and reconstruction via nonintubated spontaneous anesthesia. We describe the feasibility and safety of tracheal surgeries via such anesthesia. PMID- 28734443 TI - Lung Abscess as Delayed Manifestation of Pulmonary Arterial Narrowing After Sleeve Resection. AB - A patient who had undergone right upper bilobectomy because of a carcinoid experienced lung abscesses 17 months after operation. After recurrences, despite different antibiotic agents, dual-energy computed tomography showed subtotal stenosis of the right lower lobe pulmonary artery with marked pulmonary perfusion reduction. Rare causes of lung-abscesses should be considered. PMID- 28734444 TI - Systemic Artery to Pulmonary Vein Fistula After Right Upper Lobectomy Demonstrated by 4-Dimensional Flow Magnetic Resonance Imaging. AB - Postoperative systemic artery to pulmonary vein fistula is very rare. In this report, we describe an exceptional condition of both intrapulmonary arteriovenous fistula and systemic artery to pulmonary vein fistula, involving all right hemithoracic systemic arteries, inducing left-to-left shunt. This condition was responsible for heart failure, 24 years after a right upper lobectomy for inflammatory tumor. Investigations included computed tomographic angiography, arteriography, and four-dimensional flow magnetic resonance imaging. Differential diagnosis and management are discussed. PMID- 28734445 TI - Primary Solitary Fibrous Tumor of the Forearm With Frequent Late-Onset Recurrence in the Pleura. AB - Solitary fibrous tumor (SFT) is a relatively rare form of mesenchymal tumor that generally has a benign clinical course. However, SFTs have malignant potential. We report the case of a 36-year-old man with local relapse and frequent late onset pleural metastasis of primary SFT of the forearm. Pleural metastasis was first seen 11 years after the initial operation. During a 17-year period, he underwent 5 surgical resections. He has been free of disease for 61 months since the most recent operation. PMID- 28734446 TI - Successful Lung Transplantation Using a Deceased Donor Mechanically Ventilated for Ten Months. AB - A successful outcome after lung transplant was achieved using lungs donated from a teenage boy who underwent prolonged mechanical ventilation. The donor experienced hypoxic brain damage and was declared brain dead 324 days after tracheal intubation. At the time of referral, the donor's lungs revealed diffuse radiologic infiltration and atelectasis but excellent function, with a PaO2/FiO2 ratio of 450. The lungs were transplanted to a 10-year-old girl with bronchiolitis obliterans. She developed grade 2 primary graft dysfunction, but recovered quickly. She is doing well and has not experienced any other critical adverse events 12 months after lung transplantation. PMID- 28734447 TI - Plication of the Diaphragm in Postpneumectomy Right-to-Left Shunting. AB - A rare adverse event of a right-sided pneumectomy with an elevated hemidiaphragm is right-to-left shunting through a patent foramen ovale. In this case report we describe our experience with plication of the right hemidiaphragm with instantaneous hemodynamic results and pain relief, followed by secondary closure of the foramen ovale. PMID- 28734448 TI - Alternative Strategy for Biventricular Assist Device in an Infant With Hypertrophic Cardiomyopathy. AB - We report an infant with hypertrophic cardiomyopathy who underwent biventricular assist device placement with two 15-mL Berlin Heart EXCOR pediatric ventricular assist devices using an alternative atrial cannulation strategy. The systemic circulation was supported by left atrium (LA) to aorta cannulation. The LA was accessed through the right atrium by extending a 6-mm EXCOR cannula with a Gore Tex graft connected to an atrial septal defect. The pulmonary circulation was supported with cannulation of the right atrium to pulmonary artery. This alternative cannulation strategy facilitated effective biventricular support and may be applicable to other patients with hypertrophic or restrictive physiology. PMID- 28734449 TI - Double Aortic Arch Complicated by Acute Type A Dissection in an Aged Patient. PMID- 28734450 TI - Massive Pulmonary Embolization From Intravenous Leiomyosarcoma With Intracardial Extension. PMID- 28734451 TI - Computed Tomography Better Than Magnetic Resonance Imaging for Resternotomy Risk Assessment. PMID- 28734452 TI - An Unusual Double Connection in Mixed Type of Total Anomalous Pulmonary Venous Connection. PMID- 28734453 TI - "Double-Stick" Transsubclavian Transcatheter Aortic Valve Replacement With Use of a Balloon Expandable Valve: A Less Invasive Option for Alternative Access. AB - Access options for transcatheter aortic valve replacement (TAVR) currently include transfemoral, transaortic, transapical, transsubclavian, and other approaches. Transsubclavian access for balloon expandable valves is gaining popularity when transfemoral access is not suitable, given its peripheral access compared with central access. With the transsubclavian approach, second femoral or radial artery access is necessary for pigtail catheter placement. We describe a "double-stick" transsubclavian technique that eliminates secondary arterial access. With this technique, the transsubclavian approach can still be used in patients with advanced femoral disease, and it allows for rapid ambulation in most patients. PMID- 28734454 TI - Patient-Specific Ventricular Access Site Selection for the NeoChord Mitral Valve Repair Procedure. AB - Selecting the ventricular access site on the basis of mitral valve anatomy improves the outcomes for a subgroup of patients undergoing the transapical echocardiographically guided NeoChord (NeoChord, Inc, St. Louis Park, MN) repair procedure to correct mitral regurgitation and who have a leaflet-to-annulus index lower than the recommended efficacy threshold of 1.25. PMID- 28734455 TI - Translocation of Intramural Coronary Artery During Switch Procedure: A New Technique. AB - Intramural course of a coronary artery is a rare association in patients with transposition of great arteries. Various techniques have been described for translocation of these during the arterial switch procedure, with mixed results. This report focuses on a novel technique that is reproducible and provides an alternative in this difficult subset of patients. PMID- 28734456 TI - Clamshell Closure With Absorbable Sternal Pins in Lung Transplant Recipients. AB - Clamshell (bilateral anterolateral thoracotomy combined to transverse sternotomy) is an invasive surgical approach that is helpful in particular situations, especially bilateral lung transplantation. The closure technique remains challenging because clamshell incision can end with override, separation, or sternal pseudarthrosis complications. We describe the use of new absorbable sternal pins to stabilize the sternal closure and to help avoid additional sternal complications. PMID- 28734457 TI - Total lower lip and chin reconstruction with radial forearm free flap: A novel approach. AB - BACKGROUND: The management of large chin and lower lip defects is challenging due to this facial subunit's tremendous functional and aesthetic importance. Specific methods for total lower lip and mentum reconstruction are not well chronicled. Aesthetic and functional goals of this reconstruction include restoration of oral competence by maintaining lower lip height, vermilion reestablishment, color matched skin introduction to the chin, sensation restoration, and ideally restoration of dynamic activity to the lower lip. METHODS: Literature review performed. RESULTS: Presentation of novel, two-stage technique for lower lip and chin reconstruction with a submental flap and a radial forearm free flap, suspension of the lower lip and chin with a tensor fascia lata graft, and vermilion reconstruction with a buccal mucosal flap. CONCLUSIONS: This procedure meets all goals of total lower lip reconstruction with the exception of the introduction of dynamic tissue and represents a novel solution to a challenging reconstructive problem. PMID- 28734458 TI - Rett-like Severe Encephalopathy Caused by a De Novo GRIN2B Mutation Is Attenuated by D-serine Dietary Supplement. AB - BACKGROUND: N-Methyl-D-aspartate receptors (NMDARs) play pivotal roles in synaptic development, plasticity, neural survival, and cognition. Despite recent reports describing the genetic association between de novo mutations of NMDAR subunits and severe psychiatric diseases, little is known about their pathogenic mechanisms and potential therapeutic interventions. Here we report a case study of a 4-year-old Rett-like patient with severe encephalopathy carrying a missense de novo mutation in GRIN2B(p.P553T) coding for the GluN2B subunit of NMDAR. METHODS: We generated a dynamic molecular model of mutant GluN2B-containing NMDARs. We expressed the mutation in cell lines and primary cultures, and we evaluated the putative morphological, electrophysiological, and synaptic plasticity alterations. Finally, we evaluated D-serine administration as a therapeutic strategy and translated it to the clinical practice. RESULTS: Structural molecular modeling predicted a reduced pore size of mutant NMDARs. Electrophysiological recordings confirmed this prediction and also showed gating alterations, a reduced glutamate affinity associated with a strong decrease of NMDA-evoked currents. Moreover, GluN2B(P553T)-expressing neurons showed decreased spine density, concomitant with reduced NMDA-evoked currents and impaired NMDAR dependent insertion of GluA1 at stimulated synapses. Notably, the naturally occurring coagonist D-serine was able to attenuate hypofunction of GluN2B(p.P553T)-containing NMDARs. Hence, D-serine dietary supplementation was initiated. Importantly, the patient has shown remarkable motor, cognitive, and communication improvements after 17 months of D-serine dietary supplementation. CONCLUSIONS: Our data suggest that hypofunctional NMDARs containing GluN2B(p.P553T) can contribute to Rett-like encephalopathy and that their potentiation by D-serine treatment may underlie the associated clinical improvement. PMID- 28734459 TI - The Roles of Phasic and Tonic Dopamine in Tic Learning and Expression. AB - Tourette syndrome (TS) prominently involves dopaminergic disturbances, but the precise nature of those disturbances has remained elusive. A substantial body of empirical work and recent computational models have characterized the specific roles of phasic and tonic dopamine (DA) in action learning and selection, respectively. Using insights from this work and models, we suggest that TS involves increases in both phasic and tonic DA, which produce increased propensities for tic learning and expression, respectively. We review the evidence from reinforcement-learning and habit-learning studies in TS, which supports the idea that TS involves increased phasic DA responses; we also review the evidence that tics engage the habit-learning circuitry. On the basis of these findings, we suggest that tics are exaggerated, maladaptive, and persistent motor habits reinforced by aberrant, increased phasic DA responses. Increased tonic DA amplifies the tendency to execute learned tics and also provides a fertile ground of motor hyperactivity for tic learning. We review evidence suggesting that antipsychotics may counter both the increased propensity for tic expression, by increasing excitability in the indirect pathway, and the increased propensity for tic learning, by shifting plasticity in the indirect pathway toward long-term potentiation (and possibly also through more complex mechanisms). Finally, we review evidence suggesting that low doses of DA agonists that effectively treat TS decrease both phasic and tonic DA, thereby also reducing the propensity for both tic learning and tic expression, respectively. PMID- 28734460 TI - Affected Anatomical Rich Club and Structural-Functional Coupling in Young Offspring of Schizophrenia and Bipolar Disorder Patients. AB - BACKGROUND: Emerging evidence suggests disruptions in the wiring organization of the brain's network in schizophrenia (SZ) and bipolar disorder (BD). As the importance of genetic predisposition has been firmly established in these illnesses, children (offspring) of patients constitute an at-risk population. This study examines connectome organization in children at familial high risk for psychosis. METHODS: Diffusion-weighted magnetic resonance imaging scans were collected from 127 nonpsychotic offspring 8 to 18 years of age (average age = 13.5 years) of a parent diagnosed with SZ (SZ offspring; n = 28) or BD (BD offspring; N = 60) and community control subjects (n = 39). Resting-state functional magnetic resonance imaging scans were available for 82 subjects. Anatomical and functional brain networks were reconstructed and examined using graph theoretical analysis. RESULTS: SZ offspring were found to show connectivity deficits of the brain's central rich club (RC) system relative to both control subjects and BD offspring. The disruption in anatomical RC connectivity in SZ offspring was associated with increased modularity of the functional connectome. In addition, increased coupling between structural and functional connectivity of long-distance connections was observed in both SZ offspring and BD offspring. CONCLUSIONS: This study shows lower levels of anatomical RC connectivity in nonpsychotic young offspring of SZ patients. This finding suggests that the brain's anatomical RC system is affected in at-risk youths, reflecting a connectome signature of familial risk for psychotic illness. Moreover, finding no RC deficits in offspring of BD patients suggest a differential effect of genetic predisposition for SZ versus BD on the developmental formation of the connectome. PMID- 28734461 TI - Risk Factors for Mortality Among Individuals With Peripheral Arterial Disease. AB - Morbidity and mortality from peripheral arterial disease (PAD) continues to increase. Traditional cardiovascular risk factors are implicated in the development of PAD, yet the extent to which those risk factors correlate with mortality in such patients remains insufficiently assessed. Using data from the 1999 to 2004 National Health and Nutrition Examination Survey, Cox proportional hazards models were used to examine the association of cardiovascular risk factors and all-cause and cardiovascular mortality. A total of 647 individuals >=40 years old with PAD (i.e., ankle-brachial index [ABI] <= 0.9) were followed for a median of 7.8 years. There were 336 deaths, of which 98 were attributable to cardiovascular disease. Compared with never smokers, current (hazard ratio [HR] 2.45, 95% confidence interval [CI] 1.62 to 3.71) and former (HR 1.62, 95% CI 1.14 to 2.29) smokers with PAD had higher rates of death. Moderate or vigorous physical activity of >=10 minutes monthly was associated with lower death rates (HR 0.63, 95% CI 0.44 to 0.91). Also associated with increased rates of cardiovascular death were an ABI of <0.5 (HR 2.56, 95% CI 1.28 to 5.15, compared with those with an ABI of 0.7 to 0.9) and diabetes mellitus (HR 2.50, 95% CI 1.33 to 4.73). Neither C-reactive protein nor body mass index was associated with mortality. In conclusion, tobacco use increased the risk of all-cause and cardiovascular death, whereas physical activity was associated with a decreased mortality risk. A low ABI and diabetes were also predictive of cardiovascular death. PMID- 28734462 TI - Effect of Bariatric Surgery on Emergency Department Visits and Hospitalizations for Atrial Fibrillation. AB - Atrial fibrillation (AF) and obesity are major health problems in the United States. However, little is known about whether bariatric surgery affects AF related morbidities. This study investigated whether bariatric surgery is associated with short-term and long-term changes in the risk of emergency department (ED) visits or hospitalizations for AF. We performed a self-controlled case series study of obese adults with AF who underwent bariatric surgery by using population-based ED and inpatient databases in California, Florida, and Nebraska from 2005 to 2011. The primary outcome was ED visit or hospitalization for AF. We used conditional logistic regression to compare each patient's risk of the outcome event during sequential 12-month periods, using presurgery months 13 to 24 as a reference period. Our sample consisted of 523 obese adults with AF who underwent bariatric surgery. The median age was 57 years (interquartile range 48 to 64 years), 59% were female, and 84% were non-Hispanic white. During the reference period, 15.9% (95% confidence interval [CI] 12.7% to 19.0%) of patients had an ED visit or hospitalization for AF. The risk remained similar in the subsequent 12-month presurgery period (adjusted OR [aOR] 1.29 [95% CI, 0.94 to 1.76] p = 0.11). In contrast, the risk significantly increased within 12 months after bariatric surgery (aOR 1.53 [95% CI 1.13 to 2.07] p = 0.006). The risk remained elevated during 13-24 months after bariatric surgery (aOR 1.41 [95% CI, 1.03 to 1.91] p = 0.03). In conclusion, this population-based study demonstrated that bariatric surgery was associated with an increased risk of AF episodes requiring an ED visit or hospitalization for at least 2 years after surgery among obese patients with AF. PMID- 28734463 TI - Usefulness of Elevated Levels of Growth Differentiation Factor-15 to Classify Patients With Acute Coronary Syndrome Having Percutaneous Coronary Intervention Who Would Benefit from High-Dose Statin Therapy. AB - The aim of this study was to evaluate whether growth differentiation factor-15 (GDF-15) plasma concentration at the time of percutaneous coronary intervention (PCI) might help identify those patients with acute coronary syndrome (ACS), who benefit most from high-dose statin treatment. Two hundred eighty-four consecutive patients, who underwent percutaneous coronary intervention (PCI) for ACS, were included in a prospective registry. The combined end point at 3 months after PCI consisted of cardiovascular death, nonfatal myocardial infarction, and unstable angina. Patients were divided into those with elevated levels of GDF-15 and those with lower levels in relation to the median plasma concentration. Results were compared between patients receiving high-dose, highly efficient statins and patients receiving low-dose statins or no statins. The median GDF-15 plasma concentration was 3.31 ng/ml. One hundred six patients (74.6%) of the high GDF-15 group and 122 patients (85.9%) of the low GDF-15 group received high-dose statins. The combined end point was statistically lower in patients with high levels of GDF-15 treated with high-dose statins compared with patients treated with low-dose statins or without statin treatment (3.8% vs 22.2%, hazard ratio [HR] = 0.156; 95% confidence interval [CI], 0.047 to 0.519; p = 0.002). After propensity score adjustment, the results remained significant (adjusted HR for high-dose statins = 0.148; 95% CI, 0.045 to 0.494; p = 0.002). In contrast, in patients with lower levels of GDF-15, there was no significant reduction in combined end point rates associated with high-dose statin treatment (1.6% vs 5.0%, HR = 0.320; 95% CI 0.029 to 3.534; p = 0.353). In conclusion, increased GDF 15 plasma concentrations at the time of PCI and stent implantation might classify high-risk patients with ACS who benefit from high-dose, highly efficient statins. PMID- 28734464 TI - Double-Chambered Right Ventricle in a 49-Year-Old Man. AB - Most patients with double-chambered right ventricles are diagnosed in childhood, but some escape definitive diagnosis until adulthood, as was the case in the patient described here. PMID- 28734465 TI - Elderly Female With Elbow Pain. PMID- 28734466 TI - Does the Intranasal Route Pass the Sniff Test? PMID- 28734467 TI - The Best Day. PMID- 28734468 TI - My Story. PMID- 28734469 TI - Falling Back in Love With Emergency Medicine. PMID- 28734470 TI - Pulmonary Embolism Prevalence in Admitted Syncope Patients: 1 in 6 Really?: Answers to the March 2017 Journal Club Questions. PMID- 28734471 TI - Young Girl With Swollen Wrists and Ankles. PMID- 28734472 TI - Words Matter: Researchers Should Avoid Implying Causation in Studies of Association. PMID- 28734473 TI - In reply. PMID- 28734474 TI - Young Male With Severe Ankle Pain. PMID- 28734475 TI - Woman with right upper quadrant pain. PMID- 28734479 TI - The Internal Medicine of the 21st century: Organizational and operational standards. AB - The Spanish Society of Internal Medicine has developed a consensus document on the standards and recommendations that they consider essential to the organisation of internal medicine units for conducting their activities efficiently and with high quality. We defined 3 groups of key processes: the care of acutely ill adult patients, the comprehensive care of complex chronic patients and the examination of a patient with a difficult diagnosis and no organ-specific disease. As support processes, we identified the structure and operation of the Internal Medicine units. As strategic processes, we identified training and research. The main subprocesses are structured below, and we established the standards and recommendations for each of them. Lastly, we proposed resulting workloads. The prepared standards must be reviewed within a maximum of 4 years. PMID- 28734476 TI - Quantifying the Interaction between EGFR Dimers and Grb2 in Live Cells. AB - Adaptor proteins are a class of cytoplasmic proteins that bind to phosphorylated residues in receptor tyrosine kinases and trigger signaling cascades that control critically important cellular processes, such as cell survival, growth, differentiation, and motility. Here, we seek to characterize the interaction between epidermal growth factor receptor (EGFR) and the cytoplasmic adaptor protein growth factor receptor-bound protein 2 (Grb2) in a cellular context. To do so, we explore the utility of a highly biologically relevant model system, mammalian cells under reversible osmotic stress, and a recently introduced Forster resonance energy transfer microscopy method, fully quantified spectral imaging. We present a method that allows us to quantify the stoichiometry and the association constant of the EGFR-Grb2 binding interaction in the plasma membrane, in the presence and absence of activating ligand. The method that we introduce can have broad utility in membrane protein research, as it can be applied to different membrane protein-cytoplasmic protein pairs. PMID- 28734478 TI - pH-Dependent Membrane Interactions of the Histidine-Rich Cell-Penetrating Peptide LAH4-L1. AB - The histidine-rich designer peptide LAH4-L1 exhibits antimicrobial and potent cell-penetrating activities for a wide variety of cargo including nucleic acids, polypeptides, adeno-associated viruses, and nanodots. The non-covalent complexes formed between the peptide and cargo enter the cell via an endosomal pathway where the pH changes from neutral to acidic. Here, we investigated the membrane interactions of the peptide with phospholipid bilayers and its membrane topology using static solid-state NMR spectroscopy. Oriented 15N solid-state NMR indicates that in membranes composed of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) and 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-L-serine (POPS) 3:1 mol/mole and at neutral pH, the peptide adopts transmembrane topologies. Furthermore, 31P and 2H solid-state NMR spectra show that liquid crystalline 1,2-dimyristoyl-sn glycero-3-phosphocholine (DMPC) and POPC/POPS 3:1 liposomes retain a bilayer macroscopic phase even at the highest peptide concentrations investigated, with an oblate orientational distribution of the phospholipids at a peptide/lipid ratio of 1:5. At pH 5, as it occurs in the endosome, the alignment of LAH4-L1 at a peptide/lipid ratio of 1:25 is predominantly parallel to POPC/POPS 3:1 bilayers (prolate deformation) when at the same time it induces a considerable decrease of the deuterium order parameter of POPC/2H31-POPS 3:1. In addition, when studied in mechanically supported lipid membranes, a pronounced disordering of the phospholipid alignment is observed. In the presence of even higher peptide concentrations, lipid spectra are observed that suggest the formation of magnetically oriented or isotropic bicelles. This membrane-disruptive effect is enhanced for gel phase DMPC membranes. By protonation of the four histidines in acidic environments, the overall charge and hydrophobic moment of LAH4-L1 considerably change, and much of the peptide is released from the cargo. Thus, the amphipathic peptide sequences become available to disrupt the endosomal membrane and to assure highly efficient release from this organelle. PMID- 28734477 TI - Polarity-Sensitive Probes for Superresolution Stimulated Emission Depletion Microscopy. AB - The lateral organization of molecules in the cellular plasma membrane plays an important role in cellular signaling. A critical parameter for membrane molecular organization is how the membrane lipids are packed. Polarity-sensitive dyes are powerful tools to characterize such lipid membrane order, employing, for example, confocal and two-photon microscopy. The investigation of potential nanodomains, however, requires the use of superresolution microscopy. Here, we test the performance of the polarity-sensitive membrane dyes Di-4-ANEPPDHQ, Di-4 AN(F)EPPTEA, and NR12S in superresolution stimulated emission depletion microscopy. Measurements on cell-derived membrane vesicles, in the plasma membrane of live cells, and on single virus particles, show the high potential of these dyes for probing nanoscale membrane heterogeneity. PMID- 28734480 TI - An unusual cause of acute liver failure: Tumour infiltration by neuroendocrine carcinoma. PMID- 28734481 TI - Cytomegalovirus primoinfection in inflammatory bowel disease. PMID- 28734482 TI - Editorial Comment. PMID- 28734483 TI - Cross-training the Nurse Scientist in Data Science and Genomics. PMID- 28734484 TI - College nursing faculty job satisfaction and retention: A national perspective. AB - The need for registered nurses in the United States continues to grow. To meet this need for increased numbers of nurses, recruitment and retention of qualified nurse educators has become a priority. In addition, the factors associated with nursing faculties' intent to stay have emerged as important considerations for administrators. The concepts of job satisfaction and intent to stay become vital to recruiting and retaining nursing faculty. In the past decade few empirical studies have been conducted on a national scale to address job satisfaction and intent to stay in academia. The purpose of this retrospective study is to analyze variables of relationships with nurse faculty job satisfaction and intent to stay from data collected throughout the United States. The Collaborative on Academic Careers in Higher Education (COACHE) survey was employed for the purposes of this study. Over 1350 nurse educators were included in the survey. The findings support a variety of modifiable variables that are viewed as important by nursing faculty. The strongest relationship was found to be institutional leadership. The implications can inform academic administrators seeking to retain nursing faculty. PMID- 28734485 TI - The power of nursing: An innovative course in values clarification and self discovery. AB - Teaching for a practice is more than the dissemination of knowledge and information to the learner. Professional nursing education requires teachers to facilitate students' self-reflection and awareness and assimilation of core professional and personal values in order for the new nurse to anchor and internalize these values as part of a professional identity. To achieve this, nursing educators recognize the importance of learning opportunities centered in the affective domain and the importance of teaching for professional formation that supports nursing students' commitment to the values of their chosen community of practice. This paper describes the development, implementation and evaluation of a learning innovation for pre-RN students. The Power of Nursing: Embracing the Healer's Art, a five-session, 15-hour discovery model course that uses guided reflection and personal sharing is described, as are course outcomes for 68 students from four nursing schools in the U.S. Overall students' reports were strongly favorable and the learning experience was valued and identified as unique within the nursing curriculum. PMID- 28734486 TI - Nurse practitioner malpractice data: Informing nursing education. AB - BACKGROUND: Nurse practitioners (NPs) are often identified in medical malpractice claims. However, the use of malpractice data to inform the development of nursing curriculum is limited. The purpose of this study is to examine medical errors committed by NPs. METHODS: Using National Practitioner Data Bank public use data, years 1990 to 2014, NP malpractice claims were classified by event type, patient outcome, setting, and number of practitioners involved. RESULTS: The greatest proportion of malpractice claims involving nurse practitioners were diagnosis related (41.46%) and treatment related (30.79%). Severe patient outcomes most often occurred in the outpatient setting. Nurse practitioners were independently responsible for the event in the majority of the analyzed claims. CONCLUSION: Moving forward, nurse practitioner malpractice data should be continuously analyzed and used to inform the development of nurse practitioner education standards and graduate program curriculum to address areas of clinical weakness and improve quality of care and patient safety. PMID- 28734487 TI - Clinical nurse preceptors' perception of e-portfolio use for undergraduate students. AB - Nursing schools and hospitals form partnerships to foster nursing education. Clinical nurse preceptors (CNPs) have a profound influence on nursing students' Last Mile practicum. Assisting preceptors to prepare students as future staff nurses has become a critical issue. E-portfolios utilize digital access and hyperlinks to integrate student knowledge, skills, and achievements with teaching assessment, process and evaluation. Based on the school-hospital partnership, preceptors require a teaching application to facilitate student learning. This descriptive qualitative study explored preceptors' perceptions regarding the use of e-portfolios. Data were collected from November 2012 to March 2013. One-on-one in-depth interviews with preceptors from different hospitals in Taiwan were examined using content analysis. Four key themes were revealed: utilizing students' learning experiences to design the CNP's teaching plan; a group-based discussion platform as a communication channel is needed; posting teaching content to facilitate student learning process; and, motivation usage factors in ease of use, sustaining use and win (student) - win (preceptor) outcomes. The use of e-portfolios allows preceptors to prepare for the learning needs of students. By considering preceptors' preferences, the design of e-portfolios may become more user friendly and useful for preceptors to expedite their teaching process and enhance student learning experiences. PMID- 28734488 TI - Clinical fellowship for an innovative, integrated BSN-PhD program: An academic and practice partnership. AB - Opportunities for research-focused doctoral education must be available to nurses early in their careers in order to ensure the further development of nursing science. Early entry into the research doctorate through an integrated BSN-PhD program is one innovative approach. This approach highlights the value of integrating post-licensure clinical training into the doctoral curriculum. To better prepare innovative nurse scientists early in their careers we developed a clinical nurse fellowship within an integrated BSN-PhD program in partnership with an affiliated health system. The aims of this clinical fellowship are to integrate post-licensure clinical experience with academic preparation, cultivate scholarly reflection on the connections between research and practice, educate nurse researchers to work effectively in interdisciplinary teams, and develop nurses' contributions to health care innovation. Major considerations for the development of similar clinical training opportunities include clarifying and articulating the major aims of the fellowship, enlisting the support of executive clinical leadership, and placing fellows on nursing units with experienced and advanced nursing teams and management that supports the fellowship's aims. We emphasize the fully integrated and collaborative activities, decision-making, and commitment required of both academic and health system partners to successfully implement similar clinical training opportunities. PMID- 28734489 TI - The mediating effect of self-reflection and learning effectiveness on clinical nursing performance in nursing students: A follow-up study. AB - The effectiveness of simulation learning and the effects of anxiety in the simulated situation have been understudied. In addition, research on the association between learning effectiveness and students' clinical care performance in the hospital setting is very limited in Taiwan. The aim of this study is to examine the mediating effect of self-reflection and simulation learning effectiveness on the clinical nursing performance of nursing students. A Prospective, longitudinal, and correlational design was used. The study was conducted from December 2014 to July 2015. Participants were 293 nursing students in southern Taiwan. A structural model was specified and tested using partial least squares structural equation modeling to examine the relationships between the variables. The results revealed that the model was robust in terms of its measurement quality (reliability, validity, and goodness of fit), with the data's explaining 38.3% of variance in nursing competence. As self-reflection and learning effectiveness were added into the structural model, the effect of anxiety on nursing competence was still significant, but the regression coefficient (beta) estimate of -0.41 (p<0.05) changed to beta=-0.15 (p<0.050),indicating that self-reflection and learning effectiveness mediated the relationship between anxiety and nursing competence. Nursing competence was negatively affected by anxiety and positively affected by self-reflection (beta=0.49, p<0.05) and simulation learning effectiveness (beta=0.10, p<0.05). The teacher's encouraging learning can have a positive influence on students' self-reflection and learning effectiveness, which then decreases the effect of anxiety on nursing competence and further promotes students' clinical care ability. PMID- 28734490 TI - Preconception Peer Educators' exploratory outreach to the Bahamas: A foundation for an international service learning initiative. AB - A service learning outreach was undertaken to assess the feasibility of adapting the Preconception Peer Educator (PPE) program to Bahamian youth. By focusing on preconception health, the PPE program is a logical step toward ensuring age sensitive and developmentally appropriate education to improve potential birth outcomes and decrease infant mortality rates (IMR) associated with the complex societal problems on Grand Bahama. Concerned with the prevalence of adolescent pregnancy, lack of social support, depression, and failure to complete high school, a nurse midwife invited PPEs from a School of Nursing to meet with stakeholders to introduce the PPE program to Bahamian youth. Mentored by a faculty advisor, the PPEs assumed a leadership role and determined that the primary needs of Grand Bahamian adolescents were messages of self-empowerment and proactive life planning within a cultural context. Positive responses from stakeholders and the promise of a partnership between a School of Nursing and a Caribbean community encouraged the PPEs to adapt their PPE program to the cultural climate and needs of the island of Grand Bahama. The experience informed students' practice and leadership ability by enhancing cultural awareness and sensitivity, expanding world-views, and instilling an ethic of social responsibility. PMID- 28734491 TI - An accent modification program. PMID- 28734492 TI - Perceptions of simulation-assisted teaching among baccalaureate nursing students in Chinese context: Benefits, process and barriers. AB - AIM: To explore the subjective learning experiences of baccalaureate nursing students participating in simulation sessions in a Chinese nursing school. METHOD: This was a qualitative descriptive study. We used semi-structured interviews to explore students' perception about simulation-assisted learning. Each interview was audio-taped and transcribed verbatim. Thematic analysis was used to identify the major themes or categories from the transcript and the field notes. FINDINGS: Only 10 students were needed to achieve theoretical saturation, due to high group homogeneity. Three main themes which were found from the study included 1. Students' positive views of the new educational experience of simulation; 2. Factors currently making simulation less attractive to students; and 3. The teacher's role in insuring a positive learning experience. CONCLUSION: Simulation-assisted teaching has been a positive experience for majority nursing students. Further efforts are needed in developing quality simulation-based course curriculum as well as planning and structuring its teaching process. The pedagogy approach requires close collaboration between faculty and students. PMID- 28734493 TI - Is there a real consensus among anesthetists and surgeons about the neuromuscular block? Methodological considerations about the ACHILLES study. PMID- 28734494 TI - Bone transport versus acute shortening for the management of infected tibial non unions with bone defects. AB - INTRODUCTION: This study compared bone transport to acute shortening/lengthening in a series of infected tibial segmental defects from 3 to 10cm in length. METHODS: In a retrospective comparative study 42 patients treated for infected tibial non-union with segmental bone loss measuring between 3 and 10cm were included. Group A was treated with bone transport and Group B with acute shortening/lengthening. All patients were treated by Ilizarov methods for gradual correction as bi-focal or tri-focal treatment; the treating surgeon selected either transport or acute shortening based on clinical considerations. The principle outcome measure was the external fixation index (EFI); secondary outcome measures included functional and bone results, and complication rates. RESULTS: The mean size of the bone defect was 7cm in Group A, and 5.8cm in Group B. The mean time in external fixation in Group A was 12.5 months, and in Group B was 10.1 months. The external fixation index (EFI) measured 1.8 months/cm in Group A and 1.7 months/cm in Group B (P=0.09). Minor complications were 1.2 per patient in the transport group and 0.5 per patient in the acute shortening group (P=0.00002). Major complications were 1.0 per patient in the transport group versus 0.4 per patient in the acute shortening group (P=0.0003). Complications with permanent residual effects (sequelae) were 0.5 per patient in the transport group versus 0.3 per patient in the acute shortening group (P=0.28). CONCLUSIONS: While both techniques demonstrated excellent results, acute shortening/lengthening demonstrated a lower rate of complications and a slightly better radiographic outcome. Bone grafting of the docking site was often required with both procedures. LEVEL OF EVIDENCE: Level III; Retrospective comparative study. PMID- 28734495 TI - Clinical experiences in the use of a gentamicin-coated titanium nail in tibia fractures. AB - Despite the improvement of surgical techniques surgical site infections (SSIs) still remain clinically challenging in high risk patients undergoing osteosynthesis for tibia fractures. The use of an antibiotic coated implant might reduce the adhesion of bacteria on the implant surface and could therefore reduce the rate of implant-related infection or osteomyelitis. A gentamicin-coated tibia nail was evaluated in a prospective study. Four centers enrolled 100 patients (99 treated) with fresh open or closed tibia fractures, or for non-union revision surgery and followed them for 18 months. Data collected included infection events, radiographs, SF-12, EQ-5D, Iowa Ankle score, and the WOMAC questionnaire. Sixty-eight of the 99 treated patients suffered from a fresh fracture, while in 31 patients, the intramedullary nail was implanted for revision purposes, including non-unions due to infection. Fifteen (22%) of the fresh fractures were GA Type III. The follow-up rate was 87% and 82% at 12 months and 18 months, respectively. Deep surgical site infections occurred in 3 fresh fractures and two in revision surgeries. We did not observe any local or systemic toxic effects related to gentamicin during this study. The use of the antibiotic coated nail is an option in patients with a high infection risk, like open factures or infected non unions, in the prevention of the onset of an implant-related infection or osteomyelitis. PMID- 28734496 TI - Endometrial cancer surveillance adherence reduces utilization and subsequent costs. AB - OBJECTIVES: In June 2011, the SGO recommended that physical exam and symptoms be the primary surveillance methods in patients with endometrial cancer. We sought to evaluate adherence to these guidelines by comparing the use of CT scans, paps and serum CA125 ordered for endometrial cancer surveillance before and after publication of these guidelines. METHODS: A retrospective review was performed for all patients undergoing surveillance for endometrial cancer at a single institution between June 2009 and June 2013. We assessed the number of patients without symptoms or abnormal physical exam findings who underwent surveillance CT scans, paps and/or CA125 during the 2years pre- and 2years post-SGO guidelines. RESULTS: 92 patients (n=48 pre-6/2011, n=44 post-6/2011) were identified. Mean patient age was 58years. No significant difference in age, ethnicity, body mass index, or disease grade or stage was noted. There was a significant decline in surveillance CT scans (n=13, 27% vs. n=4, 9%, p=0.03), CA125 (n=14, 29% vs. 5, 11%, p=0.035) and paps (n=34, 71% vs. n=8 vs. 18%, p<0.001). There was no significant difference in disease status at the last follow-up. Institutional cost of surveillance also declined ($14,102.46 2years pre-guidelines, $3,054.99 2years post-guidelines). CONCLUSIONS: In a single urban academic public hospital, after only 2years, clinical adherence to the 2011 SGO endometrial cancer surveillance guidelines resulted in a significant decline in the use of CT scans, CA125 and paps. This reduction does not appear to affect patient outcomes and led to an appreciable decrease in surveillance costs. PMID- 28734497 TI - Functional not chronologic age: Frailty index predicts outcomes in advanced ovarian cancer. AB - OBJECTIVES: To assess the impact of frailty as measured by a frailty deficit index (FI) on outcomes in advanced epithelial ovarian cancer (EOC) after primary debulking surgery (PDS). METHODS: Women with Stage IIIC/IV EOC who underwent PDS between 1/1/2003-12/31/2011 were included. Medical records were reviewed for patient characteristics and outcomes. The FI includes 30 items scored at 0, 0.5 or 1 and is calculated by summing across all the item scores and dividing by the total. Frailty was defined as a FI >=0.15. Associations were assessed using logistic regression and Cox proportional hazards regression. RESULTS: Of the 535 studied, 78% had stage IIIC disease and mean (SD) age was 64.3 (11.3) years. Median FI was 0.08, and 131 patients (24.5%) were considered frail with FI >=0.15. Compared to non-frail patients, frail patients were more likely to have an Accordion grade 3+ complication (28.2 vs. 18.8%; odds ratio (OR): 1.70, 95% CI: 1.08-2.68) and more likely to die within 90days of surgery (16.0 vs. 5.2%; OR: 3.48, 95% CI: 1.83-6.61). After adjusting for known risk factors, these associations remained significant, adjusted OR (aOR): 1.62, 95% CI: 1.00-2.62; aOR: 2.60, 95% CI 1.32-5.10; and aOR: 0.57, 95% CI 0.34-0.97, respectively. Overall survival (OS) for the entire cohort was 39.6months (m). OS was shorter in the frail versus non-frail (median 26.5 vs 44.9m, p<0.001). Frailty was independently associated with death (adjusted hazard ratio: 1.52, 95% CI: 1.21 1.92) after adjusting for known risk factors. CONCLUSIONS: Frailty is a common finding in patients with EOC and is independently associated with worse surgical outcomes and poorer OS. Routine assessments of frailty can be incorporated into patient counseling and decision-making for the EOC patient beyond simple reliance on single factors such as age. PMID- 28734499 TI - Observer-based stabilization for switched positive system with mode-dependent average dwell time. AB - This paper concerns the exponential stabilization problem for a class of switched positive systems. The switching signal satisfies mode-dependent average dwell time (MDADT) and the state variables are partially unmeasurable. A further explanation of mode-dependent average dwell time is included. By employing a set of quasi-time variables, which is first proposed for switched systems with MDADT, new stability results are obtained for the switched nonlinear systems and the underlying linear systems. Observer-based stabilization controllers, both for single-input case and multi-input case, are designed such that the closed-loop system converges exponentially. The designed observers and controllers are both mode-dependent and quasi-time-dependent, which is proved to be less conservative than the ones only mode-dependent. A simplified design strategy is provided to reduce the computation burden. Illustrative examples are provided to demonstrate the effectiveness of the results. PMID- 28734498 TI - Surgical site infection reduction bundle in patients with gynecologic cancer undergoing colon surgery. AB - OBJECTIVE: Surgical site infections (SSIs) can lead to substantial morbidity, prolonged hospitalization, increased costs, and death in patients undergoing colorectal procedures. We sought to investigate the effect of using an SSI reduction bundle on the rate of SSIs in gynecologic cancer patients undergoing colon surgery. METHODS: We identified all gynecologic cancer patients who underwent colon resection at our institution from 2014 to 2016, during which time a service-wide SSI reduction bundle was introduced. The intervention included preoperative oral antibiotics with optional mechanical bowel preparation, skin preparation with antibacterial solution, and the use of a separate surgical closing tray. SSI rates were assessed within 30days post-surgery. RESULTS: Of 233 identified patients, 115 had undergone colon surgery prior to (PRE) and 118 after (POST) the implementation of the intervention. A low anterior resection was the most common colon surgery in both cohorts. The incidence of SSI within 30days of surgery was 43/115 (37%) in the PRE and 14/118 (12%) in the POST cohorts (p<=0.001). Wound dehiscence was noted in 30/115 (26%) and 2/118 (2%) patients, respectively (p<=0.001). In patients whose operation took longer than 360min, 30 day SSI rates were 37% (28/76) and 12% (8/67), respectively (p<=0.001). In patients with an estimated blood loss >500cm3, SSI rates were 44% (27/62) and 15% (10/67), respectively (p<=0.001). CONCLUSIONS: The implementation of an SSI reduction bundle was associated with a significant reduction in 30-day SSIs in these patients. The intervention remained effective in patients undergoing longer operations and in those with increased blood loss. PMID- 28734500 TI - A new online delay estimation-based robust adaptive stabilizer for multi-input neutral systems with unknown actuator nonlinearities. AB - This paper studies the problem of actuator-nonlinearities compensation in the multi-input uncertain neutral systems. The neutral systems with different unknown time-varying delays, unmodeled dynamics, nonlinear perturbations and disturbances are considered. A new methodology based on the online estimation of the delays to compensate for the effects generated by dead-zone and saturation, acting in series on a system's input are presented. The online estimations of the unknown delays are accomplished by adaptive laws that guarantee the exponential stabilities of the estimated delays. In the presence of state time delay, derivative state time delay, unmodeled dynamics, nonlinear perturbations, disturbances and both input dead-zone and saturation, the asymptotic stability of the closed-loop system is ensured and the state response converge to the origin. Finally, the practicability and the efficacy of the proposed approach is demonstrated via a numerical example. PMID- 28734501 TI - [Idiopathic normal pressure hydrocephalus: High incidence in people over 80 years of age]. AB - INTRODUCTION: Idiopathic normal pressure hydrocephalus is usually observed in adults over 60 years of age. The highest incidence of cases is between 70 and 80 years-old, and it could be under-diagnosed in over 80 year-olds. OBJECTIVE: A description is presented on the overall incidence and age group incidence, the delay in the diagnosis, and main outcomes. PATIENTS AND METHODS: A descriptive study was performed on patients with idiopathic normal pressure hydrocephalus, in the population of Osona County during the years 2010-2015. RESULTS: The annual incidence rate was 4.43 per 100,000 inhabitants. The incidence increased with age; from 8.09 per 100,000 in the 60 to 69 years age group, to 23.61 per 100,000 in the 70-79 years age group of, and to 37.02 per 100,000 in the 80-89 years age. The delay in the diagnosis was 15.01 +/- 10.35 months. All the patients improved after surgery, but only 73.3% of the patients maintained the improvement after one year. CONCLUSIONS: Idiopathic normal pressure hydrocephalus is an age related disease and probably underdiagnosed in the elderly. An early diagnosis and a clinical suspicion are essential in patients over 80 years old. PMID- 28734502 TI - [Validation of a prevention and detection procedure for physical and economic abuse of the elderly]. AB - INTRODUCTION: The study carried out for the "Physical and economic abuse sign detection procedure for the elderly in the Basque Country" Pilotage and Validation is described. There barely exist appropriate and validated tools to assist the issue, and the existing ones are hardly adequate for people with cognitive deterioration; therefore, the issue's both visibility in our society and professional intervention are strained. The proposed procedure is a composed by screening tool that determines a likelihood of abuse and an evaluation of signs for determining the abuse practice. It is intended to be used in the social area as well as the sanitary one by any professional. It is composed of two questionnaires: one of risk-factor valuation and a second one concerning indicators based on three severity levels. METHODOLOGY: Both quantitative and qualitative methodologies were used. The sample was made of 649 elders: 596 evaluated by the risk-factor questionnaire, 138 by the indicators questionnaire, and 85 evaluated by both; 94 professionals from several backgrounds (sanitary, social and economic) participated. Eight of the detected cases were checked by the team of experts that elaborated the procedure; the sessions were analysed after their transcription. CONCLUSIONS: The procedure has been validated as sensitive for its goal, being equally valid for the social and health areas. It can be used by any professional, although some differences have been detected. As regards the ability to differentiate items and the final evaluation of the severity of the situation, some changes and corrections have been proposed. PMID- 28734503 TI - [Lytic bone metastasis in prostate cancer: a case report]. PMID- 28734504 TI - [Relationship between family variables and conjugal adjustment]. AB - OBJECTIVE: To determine whether family variables, such as type of relationship, years of marriage, existence of offspring, number of members of family, stage of family life cycle, transition between stages, perceived social support, and/or stressful life events are related to conjugal adjustment. DESIGN: A cross sectional and correlational study using questionnaires. LOCATION: Primary care and hospital units of selected centres in the province of Seville, Spain. PARTICIPANTS: Consecutive stratified sampling by quotas of 369 heterosexual couples over 18years of age, who maintained a relationship, with or without children, living in Seville. MAIN MEASUREMENTS: A self-report questionnaire for the sociodemographic variables, and the abbreviated version of the Dyadic Adjustment Scale, Questionnaire MOS Perceived Social Support, and Social Readjustment Rating Scale, were used. Descriptive and inferential statistics were performed with correlation analysis and multivariate regression. RESULTS: Statistically significant associations were found between conjugal adjustment and marriage years (r=-10: P<.05), stage of family life cycle (F=2.65; P<.05), the transition between stages (RPB=.11; P<.05) and perceived social support (r=.44; P<.001). The regression model showed the predictive power of perceived social support and the family life cycle stage (mature-aged stage) on conjugal adjustment (R2=.21; F=9.9; df=356; P<.001). CONCLUSIONS: Couples may be assessed from Primary Care and be provide with resources and support. In addition, it can identify variables that may help improve the conjugal relationship. PMID- 28734505 TI - Landmarks and legacies in pediatric surgery. PMID- 28734506 TI - Phenotypic and genetic characteristics of fluoroquinolone- and methicillin resistant Staphylococcus aureus. AB - INTRODUCTION: Fluoroquinolone resistance in methicillin-resistant Staphylococcus aureus (MRSA) has increased in recent years. The objective of this study was to characterise two MRSA populations, one susceptible to fluoroquinolones and other resistant identifying the clonal types and the differential characteristics of both MRSA populations. METHODS: Molecular typing using PFGE, MLST, spa and SSCmec was performed on 192 MRSA strains isolated from 2009 to 2011, 49 only oxacillin resistant (OX-R) and 143 oxacillin and levofloxacin-resistant (OX-R-LEV-R). Mutations that conferred resistance to fluoroquinolones, hypermutable phenotypes and the presence of eight microbial surface components recognising adhesive matrix molecules (MSCRAMMs) were also studied. RESULTS: A statistically significant increase in the OX-R-LEV-R phenotype was observed (p<0.05). The most common clone of the OX-R isolates was sequence type (ST) 8 (32.6%), followed by ST72 (26.5%) and ST5 (26.5%). In the OX-R-LEV-R phenotype, the ST5 clone was the most common (65.7%), followed by ST72 (15.4%), and ST125 (12.6%). All isolates except the ST398 clone carried the SCCmecIVc. Clones ST5, ST72, ST125, and ST30 had hypermutable phenotypes. The ST72 clone and the ST30 clone in the OX-R phenotype harboured the highest number of MSCRAMMs. CONCLUSION: ST5 and ST72 clones were the most frequent clones identified in OX-R-LEV-R phenotype. Both clones showed a hypermutable phenotype that favours their selection as the fluoroquinolone resistant clones. The genetic relationships identified indicate that OX-R-LEV-R clones have evolved from OX-R MRSA clones. PMID- 28734507 TI - Child Health and Survival in a Changing World. AB - Ninety-nine percent of the 5.9 million annual child deaths occur in low and middle-income countries. Undernutrition underlies 45% of deaths. Determinants include access to care, maternal education, and absolute and relative poverty. Socio-political-economic factors and policies tremendously influence health and their determinants. Most deaths can be prevented with interventions that are currently available and recommended for widespread implementation. Millennium Development Goal 4 was not achieved. Sustainable Development Goal 3.2 presents an even more ambitious target and opportunity to save millions of lives; and requires attention to scaling up interventions, especially among the poorest and most vulnerable children. PMID- 28734508 TI - Assessing and Improving Childhood Nutrition and Growth Globally. AB - Improving maternal and child nutrition is central to global development goals and reducing the noncommunicable disease burden. Although the process of becoming malnourished starts in utero, the consequences of poor nutrition extend across the life cycle and into future generations. The global nutrition targets for 2025 include reducing infant and young child growth faltering, halting the increase of overweight children, improving breastfeeding practices, and reducing maternal anemia. In this review, we address nutritional assessment, discuss nonnutritive factors that affect growth, and endorse the evidence-based interventions that should be scaled up to improve maternal and child nutrition. PMID- 28734509 TI - Global Disability: Empowering Children of all Abilities. AB - Worldwide, children are often not meeting their developmental potential owing to malnutrition, infection, lack of stimulation, and toxic stress. Children with disabilities are more likely to experience poverty, neglect, and abuse, and are less likely to have adequate access to education and medical care. Early childhood developmental stimulation can improve language, learning, and future participation in communities. Therapeutic supports and endeavors to reduce stigma for people of all abilities strengthen communities and allow for human thriving. PMID- 28734510 TI - Neonatal and Perinatal Infections. AB - Lack of success in achieving considerable reductions in neonatal mortality is a contributory factor in failing to achieve Millennium Development Goal 4.2.6 million neonates still die each year, with preterm birth and infections the two leading causes. Maternal infections and environmental and infant factors influence acquisition of viral and bacterial infections in the perinatal and neonatal period. Scaling up evidence-based interventions addressing maternal risk factors and underlying causes could reduce neonatal infections by 84%. The emergence of new infections and increasing antimicrobial resistance present public health challenges that must be addressed to achieve substantial reductions in neonatal mortality. PMID- 28734511 TI - The Burden and Etiology of Diarrheal Illness in Developing Countries. AB - Reductions in mortality from diarrheal diseases among young children have occurred in recent decades; however, approximately 500,000 children continue to die each year. Moreover, similar reductions in disease incidence have not been seen, episodes that impact the growth and development of young children. Two recent studies, MAL-ED and GEMS, have more clearly defined the burden and cause of diarrhea among young children, identifying four leading pathogens: rotavirus, CryptosporidiumShigella, and heat stable toxin-producing enterotoxigenic Escherichia coli. Global introduction of rotavirus vaccine is poised to substantially reduce the incidence of rotavirus infection. Interventions are needed to reduce the burden that remains. PMID- 28734513 TI - Cryptosporidium and Giardia Infections in Children: A Review. AB - Diarrheal disease remains the second leading cause of mortality in children in developing countries. Cryptosporidium is a leading cause and its importance stands to increase as rotavirus vaccine becomes used around the world. Cryptosporidium is particularly problematic in children younger than 2 years old and in the immunocompromised. Giardia lamblia is a common intestinal protozoan that is associated with diarrhea and, perhaps, growth faltering in impoverished settings. This review establishes the current prevalence of these infections in global settings and reviews current diagnosis and management approaches. PMID- 28734512 TI - The Burden of Enteropathy and "Subclinical" Infections. AB - Environmental enteropathy is a chronic condition of the small intestine associated with increased intestinal permeability, mucosal inflammation, malabsorption, and systemic inflammation. It is commonly accompanied by enteric infections and is misleadingly considered a subclinical disease. Potential effects of enteric infections and enteropathy on vaccine responses, child growth, cognitive development, and even later life obesity, diabetes, and metabolic syndrome are increasingly being recognized. Herein, we review the evolving challenges to defining environmental enteropathy and enteric infections, current evidence for the magnitude and determinants of its burden, new assessment tools, and relevant interventions. PMID- 28734514 TI - Malaria in Children. AB - Malaria is a leading cause of morbidity and mortality in endemic areas, leading to an estimated 438,000 deaths in 2015. Malaria is also an important health threat to travelers to endemic countries and should be considered in evaluation of any traveler returning from a malaria-endemic area who develops fever. Considering the diagnosis of malaria in patients with potential exposure is critical. Prompt provision of effective treatment limits the complications of malaria and can be life-saving. Understanding Plasmodium species variation, epidemiology, and drug-resistance patterns in the geographic area where infection was acquired is important for determining treatment choices. PMID- 28734515 TI - The Global State of Helminth Control and Elimination in Children. AB - Helminth infections, including soil-transmitted helminths and schistosomiasis, remain one of the most common infections in the world with over 1 billion people infected. These infections cause significant morbidity, particularly in young children, that may last a lifetime, including growth and cognitive stunting. There is an urgent need for the control and elimination of helminth infections from areas of poverty to reduce morbidity in children. Mass drug administration programs were adopted by the World Health Assembly in 2001 and have evolved to provide coverage with multiple anthelmintic medications in a single rapid impact package and more extensive coverage within a community. PMID- 28734516 TI - Pediatric Human Immunodeficiency Virus Continuum of Care: A Concise Review of Evidence-Based Practice. AB - Children and adolescents living with human immunodeficiency virus (HIV) represent a population that requires a unique approach to HIV care. Prevention, testing, initiation of antiretroviral therapy (ART), and retention and engagement in care are critical steps. Each step requires providers to address age-specific barriers, so that successful and prolonged viral suppression can occur. Adherence to ART, disclosure of HIV-positive status, and stigma are examples of struggles faced by youth, their families, and health care providers. A multifaceted approach and thoughtful transitions of care are needed, but with sustained ART, youth living with HIV can survive and thrive with the expectation of a normal lifespan. PMID- 28734518 TI - Influenza: A Global Perspective. AB - Influenza is a common respiratory illness in children and accounts for substantial morbidity and mortality on an annual basis. Inactivated and live influenza vaccines are approved for children and are safe and efficacious. The absolute effectiveness of vaccines varies by year and is influenced by several factors. The reason for recent reduced performance of live-attenuated influenza vaccines is poorly understood, and active research is ongoing. Vaccination programs are less common in tropical and subtropical countries, where unique logistical and feasibility challenges exist. Antiviral medications for prevention and treatment of influenza in children are an important adjunct to vaccines. PMID- 28734519 TI - Zika Virus Infection. AB - In less than 2 years since entry into the Americas, we have witnessed the emergent spread of Zika virus into large subsets of immunologically naive human populations and then encountered the devastating effects of microcephaly and brain anomalies that can arise from in utero infection with the virus. Diagnostic evaluation and management of affected infants continues to evolve as our understanding of Zika virus rapidly advances. The development of a safe and effective vaccine holds the potential to attenuate the spread of infection and limit the impact of congenital infection. PMID- 28734517 TI - Tuberculosis in Children. AB - Mycobacterium tuberculosis is the leading cause of death worldwide from a single bacterial pathogen. The World Health Organization estimates that annually 1 million children have tuberculosis (TB) disease and many more harbor a latent form. Accurate estimates are hindered by under-recognition and challenges in diagnosis. To date, an accurate diagnostic test to confirm TB in children does not exist. Treatment is lengthy but outcomes are generally favorable with timely initiation. With the End TB Strategy, there is an urgent need for improved diagnostics and treatment to prevent the unnecessary morbidity and mortality from TB in children. PMID- 28734520 TI - Management of Refugees and International Adoptees. AB - Refugee children and international adoptees have special medical considerations that must be addressed. Providers must be aware of the immigration history, where, and under what circumstances the child lived and migrated to the United States. Federal guidelines exist regarding which infections should be screened for, and how and when and which vaccines should be administered. PMID- 28734521 TI - Global Infections and Child Health. PMID- 28734522 TI - Global Infections and Child Health. PMID- 28734523 TI - Laparoscopic Choledochoduodenostomy. AB - INTRODUCTION: Today's options for biliary bypass procedures, for difficult choledocholithiasis, range from open surgery to laparo-endoscopic hybrid procedures. The aim of this study was to analyze the outcomes of patients with difficult choledocholithiasis treated with laparoscopic choledochoduodenostomy. METHODS: We performed a prospective observational study from March 2011 to June 2016. We included patients with difficult common bile duct stones (recurrent or unresolved by ERCP) in which a biliary bypass procedure was required. We performed a laparoscopic bile duct exploration with choledochoduodenostomy and intraoperative cholangioscopy. RESULTS: A total of 19 patients were included. We found female predominance (78.9%), advanced mean age (72.4+/-12 years) and multiple comorbidities. Most patients with previous episodes of choledocholitiasis or cholangitis, mode 1 (min-max: 1-7). Mean common bile duct diameter 24.9+/-7mm. Mean operative time 218.5+/-74min, estimated blood loss 150 (30-600)mL, resume of oral intake 3.2+/-1 days, postoperative length of stay 4.9+/-2 days. We found a median of 18 (12-32) months of follow-up. All patients with normalization of liver enzymes during follow-up. One patient presented with sump syndrome and one patient died due to nosocomial pneumonia. CONCLUSIONS: Laparoscopic choledochoduodenostomy with intraoperative cholangioscopy seems to be safe and effective treatment for patients with difficult common bile duct stones no resolved by endoscopic procedures. This procedure is a good option for patients with advanced age and multiple comorbidities. We offer all the advantages of minimally invasive surgery to these patients. PMID- 28734524 TI - Endovascular repair of an arterial pseudoaneurysm due to ureteral-iliac fistula. PMID- 28734525 TI - Classification of cardiovascular tissues using LBP based descriptors and a cascade SVM. AB - BACKGROUND AND OBJECTIVE: Histological images have characteristics, such as texture, shape, colour and spatial structure, that permit the differentiation of each fundamental tissue and organ. Texture is one of the most discriminative features. The automatic classification of tissues and organs based on histology images is an open problem, due to the lack of automatic solutions when treating tissues without pathologies. METHOD: In this paper, we demonstrate that it is possible to automatically classify cardiovascular tissues using texture information and Support Vector Machines (SVM). Additionally, we realised that it is feasible to recognise several cardiovascular organs following the same process. The texture of histological images was described using Local Binary Patterns (LBP), LBP Rotation Invariant (LBPri), Haralick features and different concatenations between them, representing in this way its content. Using a SVM with linear kernel, we selected the more appropriate descriptor that, for this problem, was a concatenation of LBP and LBPri. Due to the small number of the images available, we could not follow an approach based on deep learning, but we selected the classifier who yielded the higher performance by comparing SVM with Random Forest and Linear Discriminant Analysis. Once SVM was selected as the classifier with a higher area under the curve that represents both higher recall and precision, we tuned it evaluating different kernels, finding that a linear SVM allowed us to accurately separate four classes of tissues: (i) cardiac muscle of the heart, (ii) smooth muscle of the muscular artery, (iii) loose connective tissue, and (iv) smooth muscle of the large vein and the elastic artery. The experimental validation was conducted using 3000 blocks of 100 * 100 sized pixels, with 600 blocks per class and the classification was assessed using a 10 fold cross-validation. RESULTS: using LBP as the descriptor, concatenated with LBPri and a SVM with linear kernel, the main four classes of tissues were recognised with an AUC higher than 0.98. A polynomial kernel was then used to separate the elastic artery and vein, yielding an AUC in both cases superior to 0.98. CONCLUSION: Following the proposed approach, it is possible to separate with very high precision (AUC greater than 0.98) the fundamental tissues of the cardiovascular system along with some organs, such as the heart, arteries and veins. PMID- 28734526 TI - Development and clinical application of a computer-aided real-time feedback system for detecting in-bed physical activities. AB - BACKGROUND AND OBJECTIVE: Being bedridden long-term can cause deterioration in patients' physiological function and performance, limiting daily activities and increasing the incidence of falls and other accidental injuries. Little research has been carried out in designing effective detecting systems to monitor the posture and status of bedridden patients and to provide accurate real-time feedback on posture. The purposes of this research were to develop a computer aided system for real-time detection of physical activities in bed and to validate the system's validity and test-retest reliability in determining eight postures: motion leftward/rightward, turning over leftward/rightward, getting up leftward/rightward, and getting off the bed leftward/rightward. METHODS: The in bed physical activity detecting system consists mainly of a clinical sickbed, signal amplifier, a data acquisition (DAQ) system, and operating software for computing and determining postural changes associated with four load cell sensing components. Thirty healthy subjects (15 males and 15 females, mean age = 27.8 +/- 5.3 years) participated in the study. All subjects were asked to execute eight in bed activities in a random order and to participate in an evaluation of the test retest reliability of the results 14 days later. Spearman's rank correlation coefficient was used to compare the system's determinations of postural states with researchers' recordings of postural changes. The test-retest reliability of the system's ability to determine postures was analyzed using the interclass correlation coefficient ICC(3,1). RESULTS: The system was found to exhibit high validity and accuracy (r = 0.928, p < 0.001; accuracy rate: 87.9%) in determining in-bed displacement, turning over, sitting up, and getting off the bed. The system was particularly accurate in detecting motion rightward (90%), turning over leftward (83%), sitting up leftward or rightward (87-93%), and getting off the bed (100%). The test-retest reliability ICC(3,1) value was 0.968 (p < 0.001). CONCLUSIONS: The system developed in this study exhibits satisfactory validity and reliability in detecting changes in-bed body postures and can be beneficial in assisting caregivers and clinical nursing staff in detecting the in-bed physical activities of bedridden patients and in developing fall prevention warning systems. PMID- 28734527 TI - A novel method to identify and grade DNA damage on comet images. AB - BACKGROUND AND OBJECTIVE: In recent years, development of software programs in medicine field has proceeded in a rapid manner. Comet assay is one of the research methods in medicine field that displays whether DNA has damage. In this study, it is aimed to share experience of dynamic time warping method and decision tree to decide whether DNA has damage and grade DNA damage by means of the software program. METHODS: The application analyzes manually extracted RGB single comet images whose centers are manually marked. The application performs pixel profile analysis at the directions of vertical and horizontal based on the center of comet. The bidirectional pixel profile results are used as inputs of dynamic time warping. Four novel and one conventional measurement parameters some of which are calculated by dynamic time warping are given to decision tree. RESULTS: The decision tree identifies whether DNA has damage and grades DNA damage categorizing four damage levels with accuracy of 99.03% using only two of five measurement parameters. CONCLUSIONS: This paper mainly focuses on features and usage of dynamic time warping and decision tree as a novel method to identify and grade DNA damage on comet images. PMID- 28734528 TI - Exploring risk patterns for incident ischemic stroke during more than a decade of follow-up: A survival tree analysis. AB - BACKGROUND AND PURPOSE: The burden of stroke is increasing in low to middle income countries. Identifying risk patterns for ischemic stroke (IS) can help develop individualized preventive measures for at risk populations. METHODS: The study population included 3088 Iranian subjects (1426 men) aged >=50 years, free of cardiovascular diseases at baseline. The risk factors for ischemic stroke were identified by multivariate Cox analysis. A survival tree model was used to explore interactions between risk factors. RESULTS: During 12years of follow-up, 106 cases of IS occurred. Age (hazard ratio (HR): 1.08), male gender (HR: 1.69), diastolic blood pressure (DBP) (HR: 1.04), fasting plasma glucose (HR: 1.10), waist circumference (WC) (HR: 1.03) and smoking (HR: 1.96), were associated with increased risk and estimated glomerular filtration rate (eGFR) (HR: 0.97) and wrist circumference (HR: 0.68) decreased the risk of IS (all P-values <0.05). The survival tree identified six risk patterns. The highest and lowest risks were related to subjects >=60.5years with DBP >=100mmHg and subjects <60.5years with DBP<97mmHg, respectively. In subjects >=60.5years with DBP <100mmHg, risk of ischemic stroke was determined by WC >=96.5cm or (eGFR) <60.87ml/min/1.73m2. CONCLUSION: By applying survival tree as a complementary method to the conventional Cox-analysis, for the first time, we identified risk patterns of ischemic stroke and explored the interactions between risk factors of the disease. DBP was the most important predictor of ischemic stroke in middle-aged and old subjects. In elderly subjects with DBP <100mmHg, abdominal obesity was associated with high risk; however, among non-obese subjects, kidney dysfunction increased the risk of ischemic stroke. Wrist circumference was reported as a novel predictor. PMID- 28734529 TI - Ultrasound-based differentiation of malignant and benign thyroid Nodules: An extreme learning machine approach. AB - BACKGROUND AND OBJECTIVES: It is important to be able to accurately distinguish between benign and malignant thyroid nodules in order to make appropriate clinical decisions. The purpose of this study was to improve the effectiveness and efficiency for discriminating the malignant from benign thyroid cancers based on the Ultrasonography (US) features. METHODS: There were 114 benign nodules in 106 patients (82 women and 24 men) and 89 malignant nodules in 81 patients (69 women and 12 men) included in this study. The potential of extreme learning machine (ELM) has been explored for the first time to discriminate malignant and benign thyroid nodules based on the sonographic features in ultrasound images. The influence of two key parameters (the number of hidden neurons and type of activation function) on the performance of ELM was investigated. The relationship between feature subsets obtained by the feature selection method and the classification performance of ELM was also examined. A real-life dataset was used to evaluate the effectiveness of the proposed method in terms of classification accuracy, sensitivity, specificity, and area under the ROC (receiver operating characteristic) curve (AUC). RESULTS: The results demonstrate that there are significant differences between the malignant and benign thyroid nodules (p value<0.01), the most discriminative features are echogenicity, calcification, margin, composition and shape. Compared with other methods, the proposed method not only has achieved very promising classification accuracy via 10-fold cross validation (CV) scheme, but also greatly reduced the computational cost compared to other counterparts. The proposed ELM-based approach achieves 87.72% ACC, 0.8672 AUC, 78.89% sensitivity, and 94.55% specificity. CONCLUSIONS: Based on the empirical analysis, the proposed ELM-based approach for thyroid cancer detection has promising potential in clinical use, and it can be of assistance as an optional tool for the clinicians. PMID- 28734530 TI - Joint optic disc and cup boundary extraction from monocular fundus images. AB - BACKGROUND AND OBJECTIVE: Accurate segmentation of optic disc and cup from monocular color fundus images plays a significant role in the screening and diagnosis of glaucoma. Though optic cup is characterized by the drop in depth from the disc boundary, most existing methods segment the two structures separately and rely only on color and vessel kink based cues due to the lack of explicit depth information in color fundus images. METHODS: We propose a novel boundary-based Conditional Random Field formulation that extracts both the optic disc and cup boundaries in a single optimization step. In addition to the color gradients, the proposed method explicitly models the depth which is estimated from the fundus image itself using a coupled, sparse dictionary trained on a set of image-depth map (derived from Optical Coherence Tomography) pairs. RESULTS: The estimated depth achieved a correlation coefficient of 0.80 with respect to the ground truth. The proposed segmentation method outperformed several state-of the-art methods on five public datasets. The average dice coefficient was in the range of 0.87-0.97 for disc segmentation across three datasets and 0.83 for cup segmentation on the DRISHTI-GS1 test set. The method achieved a good glaucoma classification performance with an average AUC of 0.85 for five fold cross validation on RIM-ONE v2. CONCLUSIONS: We propose a method to jointly segment the optic disc and cup boundaries by modeling the drop in depth between the two structures. Since our method requires a single fundus image per eye during testing it can be employed in the large-scale screening of glaucoma where expensive 3D imaging is unavailable. PMID- 28734531 TI - Event-Based control of depth of hypnosis in anesthesia. AB - BACKGROUND AND OBJECTIVE: In this paper, we propose the use of an event-based control strategy for the closed-loop control of the depth of hypnosis in anesthesia by using propofol administration and the bispectral index as a controlled variable. METHODS: A new event generator with high noise-filtering properties is employed in addition to a PIDPlus controller. The tuning of the parameters is performed off-line by using genetic algorithms by considering a given data set of patients. RESULTS: The effectiveness and robustness of the method is verified in simulation by implementing a Monte Carlo method to address the intra-patient and inter-patient variability. A comparison with a standard PID control structure shows that the event-based control system achieves a reduction of the total variation of the manipulated variable of 93% in the induction phase and of 95% in the maintenance phase. CONCLUSIONS: The use of event based automatic control in anesthesia yields a fast induction phase with bounded overshoot and an acceptable disturbance rejection. A comparison with a standard PID control structure shows that the technique effectively mimics the behavior of the anesthesiologist by providing a significant decrement of the total variation of the manipulated variable. PMID- 28734532 TI - The novel use of an Extreme learning machines for clinical decision support systems. PMID- 28734533 TI - Changes in pitching mechanics after ulnar collateral ligament reconstruction in major league baseball pitchers. AB - BACKGROUND: Medial ulnar collateral ligament (UCL) reconstruction is a common procedure performed on Major League Baseball pitchers. Variations in pitching mechanics before and after UCL reconstructive surgery are not well understood. METHODS: Publicly available pitch tracking data (PITCHf/x) were compared for all Major League Baseball pitchers who underwent UCL reconstruction between 2008 and 2013. Specific parameters analyzed were fastball percentage, release location, velocity, and movement of each pitch type. These data were compared before and after UCL reconstructive surgery and compared with a randomly selected control cohort. RESULTS: There were no statistically significant changes in pitch selection or pitch accuracy after UCL reconstruction, nor was there a decrease in pitch velocity. The average pitch release location for 4-seam and 2-seam fastballs, curveballs, and changeups is more medial after UCL reconstruction (P < .01). Four-seam fastballs and sliders showed decreased horizontal breaking movement after surgery (P < .05), whereas curveballs showed increased downward breaking movement after surgery (P < .05). CONCLUSIONS: Pitch selection, pitch velocity, and pitch accuracy do not significantly change after UCL reconstruction, nor do players who require UCL reconstruction have significantly different pitch selection, velocity, or accuracy than a randomly selected control cohort. Pitch release location is more medial after UCL reconstruction for all pitch types except sliders. Breaking movement of fastballs, sliders, and curveballs changes after UCL reconstruction. PMID- 28734534 TI - Elbow vascularized composite allotransplantation-surgical anatomy and technique. AB - BACKGROUND: Elbow reconstruction with vascularized composite allotransplantation (VCA) may hold promise in treating end-stage arthritis as no current treatment is both functional and durable. We describe the vascular and gross anatomy of the elbow in the context of VCA procurement and propose a step-by-step surgical technique for human elbow VCA. METHODS: We injected latex in the arterial tree of 16 fresh adult cadaveric upper extremities. We identified and measured arteries and nerves and their branch points relative to the medial epicondyle. Based on our determination of the dominant blood supply to osseous and capsular elbow structures, we derived a cadaveric model of elbow VCA by performing donor preparation on 2 fresh cadaveric upper extremities by elevating a lateral arm flap in conjunction with the vascularized elbow joint. We prepared and transplanted 2 size-matched recipient specimens to refine the surgical technique. RESULTS: The elbow arterial supply was composed of consistent branches contributing to medial, lateral, and posterior arcades. Preservation of the elbow arterial network requires sectioning of the brachial, radial, and ulnar arteries 12 cm proximal, 1 cm distal, and 6 cm distal to the ulnar artery takeoff, respectively. The supinator, anconeus, distal brachialis, proximal aspects of the flexor digitorum profundus, and flexor carpi ulnaris must be preserved to protect osseous perforators. Articular innervation was most commonly derived from ulnar and median nerve branches. We refined our proposed surgical technique after performing 2 cadaveric elbow VCAs. CONCLUSIONS: Elbow VCA may be technically feasible on the basis of its consistent vascular anatomy and our proposed surgical technique. PMID- 28734535 TI - Transcatheter arterial embolization of abnormal vessels as a treatment for lateral epicondylitis refractory to conservative treatment: a pilot study with a 2-year follow-up. AB - BACKGROUND: Abnormal vessels and accompanying nerves are possible sources of pain with lateral epicondylitis. The purpose of this study was to describe the safety and efficacy of transcatheter arterial embolization (TAE) for lateral epicondylitis resistant to conservative treatment. METHODS: This prospective study was conducted in 24 patients with lateral epicondylitis resistant to conservative treatments for more than 3 months, with a symptom duration longer than 6 months, and with moderate to severe pain who were treated with TAE between March 2013 and October 2014. Two patients were lost to follow-up, and the remaining 22 patients were followed up for 2 years after TAE. RESULTS: Abnormal vessels were identified in all of the patients. No major adverse events were observed. The Quick Disabilities of the Arm, Shoulder and Hand scores at baseline significantly decreased at 1, 3, 6, and 24 months after treatment (50.8 vs 23.4, 8.3, 5.3, and 2.7, respectively; all P < .001). There was a statistically significant (P < .001) change from baseline to the last observed value in all of the clinical parameters, including visual analog scale pain score, Patient-Rated Tennis Elbow Evaluation score, and pain-free grip strength. Magnetic resonance images obtained 2 years after TAE showed an improvement in tendinosis and tear scores compared with baseline, and no patients showed bone marrow necrosis, obvious cartilage loss, or muscle atrophy. CONCLUSION: TAE could be one possible treatment option for patients with lateral epicondylitis that fails to improve with conservative treatments. PMID- 28734536 TI - Evaluation of functional outcome after nonsurgical management of terrible triad injuries of the elbow. AB - BACKGROUND: Terrible triad (TT) is one of the severe injuries of the elbow that generally requires surgery. Nonsurgical treatment has recently been applied in selected cases of TT injury. Evaluation of the results of this treatment was the main aim of this study. METHODS: In a prospective cohort study, 10 patients with a mean follow-up of 30.6 months were evaluated. The inclusion criteria included a congruent joint after closed reduction, no indication for surgery of the coronoid and radial head fractures, no block in supination and pronation up to 60 degrees , no intra-articular fragments, and a free and stable joint with ulnohumeral extension up to a minimum of 45 degrees . Mayo Elbow Performance Index and Disabilities of the Arm, Shoulder, and Hand score were used for assessment of the functional outcome. A standard physical examination to record elbow range of motion was also performed. RESULTS: For the affected and the contralateral elbows, respectively, the mean extension of the elbow was 11 degrees +/- 7 degrees and 0.0 degrees +/- 2 degrees ; the mean flexion was 131 degrees +/- 9 degrees and 140 degrees +/- 10 degrees ; the mean supination was 58 degrees +/ 17 degrees and 85 +/- 7 degrees ; and the mean pronation was 53 degrees +/- 23 degrees and 85 degrees +/- 7 degrees . The mean Disabilities of the Arm, Shoulder, and Hand score was 4.76 +/- 5.17. The mean Mayo Elbow Performance Index was 95 +/- 8.16. CONCLUSION: Nonsurgical management of the TT injury can result in acceptable functional outcomes when a patient meets the criteria set for nonsurgical treatment. PMID- 28734537 TI - Total elbow arthroplasty for primary osteoarthritis. AB - BACKGROUND: Primary osteoarthritis of the elbow is a less common indication for total elbow arthroplasty (TEA). Higher complication rates in younger, active patients may offset short-term improvements in pain and function. The purpose of this study was to determine pain relief, functional outcomes, complications, and survival of TEA in this population. METHODS: Between 1984 and 2011, 20 consecutive TEAs were performed for primary elbow osteoarthritis. Two patients died before the 2-year follow-up. Mean age at surgery was 68 years (range, 51-85 years). Outcome measures included pain, motion, Mayo Elbow Performance Score, satisfaction, complications, and reoperations. Mean follow-up was 8.9 years (range, 2-20 years). RESULTS: Three elbows sustained mechanical failures. Complications included intraoperative fracture (n = 2), wound irrigation and debridement (n = 1), bony ankylosis (n = 1), humeral loosening (n = 1), humeral component fracture (n = 1), and mechanical failure of a radial head component (n = 1). Fifteen elbows without mechanical failure were examined clinically. Pain improved from 3.6 to 1.5 (P < .001). Range of motion remained clinically unchanged (P > .05), with preoperative flexion contractures not improving. Mayo Elbow Performance Scores were available for 13 elbows without mechanical failure, averaging 81.5 points (range, 60-100 points); these were graded as excellent (n = 5), good (n = 2), and fair (n = 6). Subjectively, all patients without mechanical failure were satisfied. CONCLUSION: TEA represents a reliable surgical option for pain relief in patients with primary osteoarthritis. However, restoration of extension is not always obtained, indicating that more aggressive soft tissue releases or bony resection should be considered. Complications occurred in a large number of elbows, but mechanical failure was low considering the nature of this population and the length of follow-up. PMID- 28734538 TI - Accuracy of infraspinatus isometric testing in predicting tear size and tendon reparability: comparison with imaging and arthroscopy. AB - BACKGROUND: The purpose of this study was to examine the accuracy of external rotation in neutral (0 degrees external position) and in shortened position (45 degrees external position) in relation to rotator cuff tear size, tendon reparability, and other clinical, surgical, and imaging findings. METHODS: This was a prospective blinded diagnostic study of consecutive surgical candidates for rotator cuff repair using magnetic resonance imaging and arthroscopic surgery as the "gold standards." The area under a receiver operating characteristic (AUROC) curve was calculated for each position. RESULTS: Eighty-five patients (35 female [41%] and 50 male [59%]; age, 65 years [standard deviation = 10]) were included. Sixty patients (71%) had a minor tear (4 small, 56 moderate), and 25 patients (29%) had a major tear (17 large and 8 massive). Seventy patients (82%) had a full repair, and 15 (18%) patients underwent a partial repair. There were 26 (31%) associated full-thickness tears of the infraspinatus. The isometric strength testing in both positions had good to excellent accuracy (range, 0.80 0.90) for detecting reparability, tear retraction, infraspinatus atrophic changes observed by the clinician, and infraspinatus fatty infiltration on magnetic resonance images. The shortened position had an overall higher accuracy than the neutral position and was more clinically useful for detecting an infraspinatus full-thickness tear (AUROC = 0.84 vs 0.78) and rotator cuff tear size (AUROC = 0.80 vs. 0.75). CONCLUSIONS: The isometric external rotation is an accurate test in diagnosing different aspects of rotator cuff disease and specifically of the infraspinatus muscle. The isometric strength at the shortened position was a better predictor of clinical, surgical, and imaging findings. PMID- 28734540 TI - Complete avulsion of the rotator cuff footprint in an irreducible traumatic posterior glenohumeral fracture-dislocation due to infraspinatus interposition. PMID- 28734539 TI - Evidence-based thresholds for the volume-value relationship in shoulder arthroplasty: outcomes and economies of scale. AB - BACKGROUND: Whereas several studies suggest that high-volume surgeons and hospitals deliver superior patient outcomes with greater cost efficiency, no evidence-based thresholds separating high-volume surgeons and hospitals from those that are low or medium volume exist in shoulder arthroplasty. The objective of this study was to establish meaningful thresholds that take outcomes and cost into consideration for surgeons and hospitals performing shoulder arthroplasty. METHODS: Using 9546 patients undergoing primary shoulder arthroplasty for osteoarthritis from an administrative database, we created and applied 4 models using stratum-specific likelihood ratio (SSLR) analysis of a receiver operating characteristic (ROC) curve. We generated 4 sets of thresholds predictive of adverse outcomes, namely, increased length of stay (LOS) and increased cost for both surgeon and hospital volume. RESULTS: SSLR analysis of the 4 ROC curves by surgeon volume produced 3 volume categories. LOS and cost by annual shoulder arthroplasty surgeon volume produced the same strata: 0-4 (low), 5-14 (medium), and 15 or more (high). LOS and cost by annual shoulder arthroplasty hospital volume produced the same strata: 0-3 (low), 4-14 (medium), and 15 or more (high). LOS and cost decreased significantly (P < .05) in progressively higher volume categories. CONCLUSIONS: Our study validates economies of scale in shoulder arthroplasty by demonstrating a direct relationship between volume and value through SSLR analysis of ROC curves for risk-based volume stratification using meaningful volume definitions for low-, medium-, and high-volume surgeons and hospitals. The described volume-value relationship offers patients, surgeons, hospitals, and other stakeholders meaningful thresholds for the optimal delivery of shoulder arthroplasty. PMID- 28734541 TI - Response to 'Mortality, length-of-stay, bloodstream and respiratory viral infections in a pediatric intensivecare unit: comment on data sparsity. PMID- 28734542 TI - Improved survival after retrieval of 12 or more regional lymph nodes in appendiceal cancer. AB - BACKGROUND: To evaluate the role of regional lymph node (RLN) retrieval on stage migration, overall (OS), and cancer-specific survival (CSS) in appendiceal cancer. METHODS: Between 2004 and 2012, 1046 patients with primary stage I-III carcinoma of the appendix were identified in the Surveillance, Epidemiology and End Results database. The impact of the number of RLN removed on OS and CSS was assessed using joinpoint regression, Cox regression, and propensity score methods. RESULTS: The rate of node-positive cancer increased with the number of retrieved RLN from 10.5% in patients with one RLN removed to 30.6% in patients with 10 RLNs removed. This leveling off at 10 RLN was confirmed by joinpoint regression analysis (p = 0.023). Despite the finding that retrieval of 10 RLN should be sufficient for appendiceal cancer, for the survival analysis the somewhat higher cutoff of 12 RLN was applied, since this cutoff is recommended by the guidelines for colorectal cancer. Retrieval of 12 or more RLN was beneficial compared to less than 12 RLN retrieved for OS (HR = 0.60, p < 0.001) and CSS (HR = 0.67, p = 0.020) in multivariable analysis, as well as in propensity score matched analysis (OS: HR = 0.58, p = 0.001, CSS: HR = 0.61, p = 0.005). CONCLUSION: The rate of node-positive cancer increased with the number of retrieved RLN up to about 10 RLN (95%CI: 3.6-16.3, p = 0.023). Over 10 retrieved RLN, the node-positive cancer rate no longer increased. This correlates with the recommended number of 12 RLN to be retrieved in colorectal cancer, but differs from the guideline for neuroendocrine tumors. PMID- 28734543 TI - Crouch severity is a poor predictor of elevated oxygen consumption in cerebral palsy. AB - Children with cerebral palsy (CP) expend more energy to walk compared to typically-developing peers. One of the most prevalent gait patterns among children with CP, crouch gait, is often singled out as especially exhausting. The dynamics of crouch gait increase external flexion moments and the demand on extensor muscles. This elevated demand is thought to dramatically increase energy expenditure. However, the impact of crouch severity on energy expenditure has not been investigated among children with CP. We evaluated oxygen consumption and gait kinematics for 573 children with bilateral CP. The average net nondimensional oxygen consumption during gait of the children with CP (0.18+/ 0.06) was 2.9 times that of speed-matched typically-developing peers. Crouch severity was only modestly related to oxygen consumption, with measures of knee flexion angle during gait explaining only 5-20% of the variability in oxygen consumption. While knee moment and muscle activity were moderately to strongly correlated with crouch severity (r2=0.13-0.73), these variables were only weakly correlated with oxygen consumption (r2=0.02-0.04). Thus, although the dynamics of crouch gait increased muscle demand, these effects did not directly result in elevated energy expenditure. In clinical gait analysis, assumptions about an individual's energy expenditure should not be based upon kinematics or kinetics alone. Identifying patient-specific factors that contribute to increased energy expenditure may provide new pathways to improve gait for children with CP. PMID- 28734544 TI - Lower limb joint work and joint work contribution during downhill and uphill walking at different inclinations. AB - Work performance and individual joint contribution to total work are important information for creating training protocols, but were not assessed so far for sloped walking. Therefore, the purpose of this study was to analyze lower limb joint work and joint contribution of the hip, knee and ankle to total lower limb work during sloped walking in a healthy population. Eighteen male participants (27.0+/-4.7yrs, 1.80+/-0.05m, 74.5+/-8.2kg) walked on an instrumented ramp at inclination angles of 0 degrees , +/-6 degrees , +/-12 degrees and +/-18 degrees at 1.1m/s. Kinematic and kinetic data were captured using a motion-capture system (Vicon) and two force plates (AMTI). Joint power curves, joint work (positive, negative, absolute) and each joint's contribution to total lower limb work were analyzed throughout the stance phase using an ANOVA with repeated measures. With increasing inclination positive joint work increased for the ankle and hip joint and in total during uphill walking. Negative joint work increased for each joint and in total work during downhill walking. Absolute work was increased during both uphill (all joints) and downhill (ankle & knee) walking. Knee joint contribution to total negative and absolute work increased during downhill walking while hip and ankle contributions decreased. This study identified, that, when switching from level to a 6 degrees and from 6 degrees to a 12 degrees inclination the gain of individual joint work is more pronounced compared to switching from 12 degrees to an 18 degrees inclination. The results might be used for training recommendations and specific training intervention with respect to sloped walking. PMID- 28734545 TI - Engineered Hydrogels in Cancer Therapy and Diagnosis. AB - Over the last decade, numerous investigations have attempted to clarify the intricacies of tumor development to propose effective approaches for cancer treatment. Thanks to the unique properties of hydrogels, researchers have made significant progress in tumor model reconstruction, tumor diagnosis, and associated therapies. Notably, hydrogel-based systems can be adjusted to respond to cancer-specific hallmarks and/or external stimuli. These well-known drug reservoirs can be used as smart carriers for multiple cargos, including both naked and nanoparticle-encapsulated chemotherapeutics, genes, and radioisotopes. Recent works have attempted to specialize hydrogels for cancer research; we comprehensively review this topic for the first time, synthesizing past results and defining paths for future work. PMID- 28734546 TI - Whole breast radiotherapy in the lateral isocentric lateral decubitus position: Long-term efficacy and toxicity results. AB - PURPOSE: To evaluate previously published whole breast radiotherapy (WBRT) using ILD (isocentring lateral decubitus) technique in terms of toxicity and efficacy. MATERIALS AND METHODS: From 2006 to 2010, 832 female patients with early-stage breast cancer (BC) treated by conservative surgery underwent 3D-conformal WBRT ILD at Institut Curie. The acute toxicity of treatment was evaluated weekly and the late toxicity (6months and later after the treatment) was evaluated every 6months till the 5th year after the end of the radiotherapy using NCI CTC v3.0 scale. Dosimetric study was performed to analyse the mean cardiac dose and the mean homolateral and contralateral lung doses. RESULTS: The median follow up was 6.4years. The median age was 61.5years (range, 29-90), and median body mass index (BMI) was 26.3. Fifty one percent of the patients presented left sided BC and 49% right sided. Different type of fractions were used: 46.5% of pts.: 50 (breast)+16Gy (boost) in 33fractions (fr), in 17.9%-50Gy/25fr, in 26.1%-40/15fr or 41.6Gy/13fr and in 9.5%: 30Gy/5fr. Acute dermatitis was present in 93% with a median of apparition of 4weeks, and only 2,8% grade 3. In multivariate analysis, the cup size had significant influence (p=0.0004) and the fractionation had a significative influence (p=0.0001). In the all patients' population, 94.1% of cases had no skin toxicity at 1year. No cardiac or pulmonary toxicity was reported. The median overall survival had not been reached at the end of follow up. We observed 36 (3.6%) recurrences, as following: 30 local (breast) recurrences, 4 lymph node (LN), and 2pts experiencing both. CONCLUSION: Whole breast radiotherapy in the lateral decubitus position provides excellent results in terms of local control and survival. ILD is well tolerated with very good acute toxicity profile. No cardiac or pulmonary toxicity were observed in this study. Longer follow-up is needed to confirm these results. PMID- 28734547 TI - Management of Hemostatic Disorders in Patients With Advanced Liver Disease Admitted to an Intensive Care Unit. AB - Patients with liver diseases frequently acquire complex changes in their hemostatic system. Traditionally, bleeding complications in patients with liver disease were ascribed to these hemostatic changes, and liver diseases were considered as an acquired bleeding disorder. Nowadays, it is increasingly acknowledged that patients with liver diseases are in "hemostatic rebalance" due to a commensurate decline in pro- and anticoagulant drivers. Indeed, both thrombosis and bleeding may complicate liver disease. Such complications may be particularly worrisome in critically ill patients with liver disease. This review will outline knowns and unknowns in prediction, prevention, and treatment of bleeding and thrombosis in patients with liver disease admitted to an intensive care unit. PMID- 28734548 TI - Ubiquitin-like modifications in the DNA damage response. AB - Genomic DNA is damaged at an extremely high frequency by both endogenous and environmental factors. An improper response to DNA damage can lead to genome instability, accelerate the aging process and ultimately cause various human diseases, including cancers and neurodegenerative disorders. The mechanisms that underlie the cellular DNA damage response (DDR) are complex and are regulated at many levels, including at the level of post-translational modification (PTM). Since the discovery of ubiquitin in 1975 and ubiquitylation as a form of PTM in the early 1980s, a number of ubiquitin-like modifiers (UBLs) have been identified, including small ubiquitin-like modifiers (SUMOs), neural precursor cell expressed, developmentally down-regulated 8 (NEDD8), interferon-stimulated gene 15 (ISG15), human leukocyte antigen (HLA)-F adjacent transcript 10 (FAT10), ubiquitin-fold modifier 1 (UFRM1), URM1 ubiquitin-related modifier-1 (URM1), autophagy-related protein 12 (ATG12), autophagy-related protein 8 (ATG8), fan ubiquitin-like protein 1 (FUB1) and histone mono-ubiquitylation 1 (HUB1). All of these modifiers have known roles in the cellular response to various forms of stress, and delineating their underlying molecular mechanisms and functions is fundamental in enhancing our understanding of human disease and longevity. To date, however, the molecular mechanisms and functions of these UBLs in the DDR remain largely unknown. This review summarizes the current status of PTMs by UBLs in the DDR and their implication in cancer diagnosis, therapy and drug discovery. PMID- 28734550 TI - Verb naming fluency in hypokinetic and hyperkinetic movement disorders. AB - Cortical motor regions are considered to play a role in action related language. These regions are affected differently in different types of movement disorders. Parkinson's disease, a hypokinetic movement disorder, has been shown to cause action language disruptions alongside movement deficits. Action language, however, has not been investigated in primary cervical dystonia, a hyperkinetic movement disorder. The aim of this study is to investigate whether action language is affected differently in hypokinetic and hyperkinetic movement disorders which have different effects on movements. Thirty patients with Parkinson's disease, thirty primary cervical dystonia patients and thirty healthy controls were included in the study. Participants performed phonemic, semantic and action fluency tasks. Verbs produced during action fluency were grouped as action and non-action verbs and group differences were investigated. Our results showed that all participants performed similarly in all of the fluency tasks. Mean action content of the verbs produced in action fluency did not differ between groups. During action fluency, however, whereas healthy controls produced more action verbs than non-action verbs, both patient groups did not have this difference between verb groups. Primary cervical dystonia patients produced less action verbs compared to healthy controls. The lack of action language deficits in Parkinson's disease and only an action verb deficit in primary cervical dystonia without any other action language deficits reject strong embodiment. PMID- 28734549 TI - Habitual versus goal-driven attention. AB - Recent research has expanded the list of factors that control spatial attention. Beside current goals and perceptual salience, statistical learning, reward, motivation and emotion also affect attention. But do these various factors influence spatial attention in the same manner, as suggested by the integrated framework of attention, or do they target different aspects of spatial attention? Here I present evidence that the control of attention may be implemented in two ways. Whereas current goals typically modulate where in space attention is prioritized, search habits affect how one moves attention in space. Using the location probability learning paradigm, I show that a search habit forms when people frequently find a visual search target in one region of space. Attentional cuing by probability learning differs from that by current goals. Probability cuing is implicit and persists long after the probability cue is no longer valid. Whereas explicit goal-driven attention codes space in an environment-centered reference frame, probability cuing is viewer-centered and is insensitive to secondary working memory load and aging. I propose a multi-level framework that separates the source of attentional control from its implementation. Similar to the integrated framework, the multi-level framework considers current goals, perceptual salience, and selection history as major sources of attentional control. However, these factors are implemented in two ways, controlling where spatial attention is allocated and how one shifts attention in space. PMID- 28734551 TI - The preanalytical phase should be carefully assessed during the comparisons of point-of-care versus central laboratory measurements. PMID- 28734552 TI - Prevalence and predictive value of pre-therapeutic sarcopenia in cancer patients: A systematic review. AB - BACKGROUND & AIMS: To assess the prevalence of sarcopenia before cancer treatment and its predictive value during the treatment. METHODS: We searched MEDLINE via PubMed for articles published from 2008 to 2016 that reported prospective observational or interventional studies of the prevalence of pre-therapeutic sarcopenia and its consequences in adults with cancer who were 18 years or older. Two independent reviewers selected articles based on titles and/or abstracts before a complete review. Sarcopenia had to be measured before cancer treatment. Methods recommended by consensuses (CT scan, MRI, dual X-ray absorptiometry or bio-impedancemetry) to assess sarcopenia were considered. Characteristics of the studies included the prevalence of pre-therapeutic sarcopenia and the prognostic value for outcomes during the cancer treatment. RESULTS: We selected 35 articles involving 6894 participants (in/out patients, clinical trials). The mean age ranged from 53 to 69.6 years. Pre-therapeutic sarcopenia was found in 38.6% of patients [95% CI 37.4-39.8]. Oesophageal and small-cell lung cancers showed the highest prevalence of pre-therapeutic sarcopenia. Pre-therapeutic sarcopenia was significantly and independently associated with post-operative complications, chemotherapy-induced toxicity and poor survival in cancer patients. CONCLUSIONS: Pre-therapeutic sarcopenia is highly prevalent in cancer patients and has severe consequences for outcomes of cancer patients. PMID- 28734554 TI - Serial electrophysiological studies using transcranial magnetic stimulation and blink reflex demonstrating demyelinating origin of isolated facial diplegia subtype of Guillain-Barre syndrome. PMID- 28734553 TI - Dietary Inflammatory Index and liver status in subjects with different adiposity levels within the PREDIMED trial. AB - BACKGROUND & AIMS: To assess the possible association between a validated Dietary Inflammatory Index (DII) and specific dietary components with suitable non invasive markers of liver status in overweight and obese subjects within the PREDIMED study. METHODS: A cross-sectional study encompassing 794 randomized overweight and obese participants (mean +/- SD age: 67.0 +/- 5.0 y, 55% females) from the PREDIMED (PREvencion con DIeta MEDiterranea) trial was conducted. DII is a validated tool evaluating the effect of diet on six inflammatory biomarkers (IL 1b, IL-4, IL-6, IL-10, TNF-alpha and C-reactive protein). Furthermore, a validated 137-item food-frequency-questionnaire was used to obtain the information about the food intake. In addition, anthropometric measurements and several non-invasive markers of liver status were assessed and the Fatty Liver Index (FLI) score was calculated. RESULTS: A higher DII and lower adherence to Mediterranean diet (MeDiet) were associated with a higher degree of liver damage (FLI > 60) in obese as compared to overweight participants. Furthermore, the DII score was positively associated with relevant non-invasive liver markers (ALT, AST, GGT and FLI) and directly affected FLI values. Interestingly, a positive correlation was observed between liver damage (>50th percentile FLI) and nutrients and foods linked to a pro-inflammatory dietary pattern. CONCLUSIONS: This study reinforced the concept that obesity is associated with liver damage and revealed that the consumption of a pro-inflammatory dietary pattern might contribute to obesity and fatty liver disease features. These data suggest that a well-designed precision diet including putative anti-inflammatory components could specifically prevent and ameliorate non-alcoholic fatty liver manifestations in addition to obesity. PMID- 28734555 TI - Decisional and Dispositional Capacity Determinations: Neuropsychiatric Illness and an Integrated Clinical Paradigm. AB - BACKGROUND: Assessment of decisional capacity requires thorough clinical review of a patient's current psychiatric symptoms and cognitive processes. The assessment to determine the patient's capacity for self-management postdischarge is a different clinical concept from decisional capacity. OBJECTIVES: Standardized guidelines for capacity determinations (both for informed consent and for disposition) would be helpful to clinicians, patients, and their caregivers. METHOD: The authors reviewed the recent clinical literature on neuropsychiatric illnesses associated with impaired decisional capacity, as well as for the term "dispositional capacity." RESULTS: Neurocognitive disorders and neurologic disorders are commonly associated with impaired decisional capacity; other psychiatric illnesses are less commonly associated. There were no articles identified that used the term "dispositional capacity" to describe a subtype of decisional capacity determination. No definition or guidelines for determination of dispositional capacity were found. CONCLUSIONS: Routine evaluation for neurocognitive disorders including standardized cognitive assessment should be included in decisional capacity determinations. There is a need for a new subtype of decisional capacity determination, for which we propose the term "dispositional capacity." This concept is introduced and defined. For dispositional capacity determinations, supplementation of the usual decisional capacity evaluation with in vivo demonstration of self-management skills is recommended. Decisional and dispositional capacity determination is conceptualized with a biopsychosociocultural approach and guidelines for standardized assessment are presented. PMID- 28734556 TI - A Model of Collaborative Spiritual and Psychiatric Care of Oncology Patients. AB - BACKGROUND: Many oncology patients see both chaplains and consultation-liaison (C L) psychiatrists during medical hospitalizations. Studies show that spirituality and mental health influence one another, and that patients often prefer that physicians understand their spirituality. Though models of inpatient chaplaincy psychiatry collaboration likely exist, none are apparent in the literature. In this study, we present one model of chaplaincy-psychiatry collaboration, hypothesizing that both specialties would find the intervention helpful. METHODS: From April through December 2015, the C-L psychiatry service at Brigham & Women's Hospital piloted 13 sessions of interdisciplinary rounds, where chaplains and C-L psychiatrists discussed common oncology patients. Participants completed questionnaires including quantitative and qualitative prompts before the intervention, after each session, and at the study's conclusion. RESULTS: Eighteen individuals completed baseline questionnaires. Between baseline and final surveys, the proportion of participants describing themselves as "very satisfied" with the 2 services' integration rose from 0-36%. The proportion of participants feeling "not comfortable" addressing issues in the other discipline declined from 17-0%. The most frequently chosen options on how discussions had been helpful were that they had enhanced understanding of both patient needs (83.3%) and the other discipline (78.6%). Qualitative data yielded similar themes. At conclusion, all respondents expressed preference that interdisciplinary rounds continue. CONCLUSION: This study describes a model of enhancing collaboration between chaplains and C-L psychiatrists, an intervention not previously studied to our knowledge. A pilot intervention of the model was perceived by both specialties to enhance both patient care and understanding of the other discipline. PMID- 28734557 TI - "Conversational Advice": A mixed-methods analysis of medical residents' experiences co-managing primary care patients with behavioral health providers. AB - OBJECTIVE: When integrated behavioral health clinicians (IBHCs) and residents co manage patients, residents may learn new approaches. We aimed to understand the effect of co-management on residents' behavioral health (BH) management learning. METHODS: Residents completed a web-based survey enquiring: whether co-management included a shared visit and/or face-to-face meeting with an IBHC, whether residents received feedback from the IBHC, and what they learned. Qualitative responses were coded thematically using a constant comparative method. RESULTS: Among 117 respondents (overall response rate 72%, 117/163), from five residencies recruited from 40 residencies with BH integration, residents were significantly more likely to receive feedback if they had a shared visit with the patient and an IBHC (yes 69% vs. no 33%; adjusted OR 3.0, 95% CI 1.2-7.6). Residents reported three major learning themes: interpersonal communication skills awareness, BH skills awareness, and newly adopted attitudes toward BH. Residents who received feedback were more likely to report themes of interpersonal communication skills awareness (yes 26.6% vs. no 9.4%). CONCLUSION: BH integration promotes increased feedback for residents practicing face-to-face co-management with IBHCs, and a positive influence regarding residents' attitudes and perceived skills. PRACTICAL IMPLICATIONS: Residency programs can meaningfully improve residents' learning by promoting face-to-face co-management with IBHCs. PMID- 28734558 TI - Patient evaluation of breast cancer follow-up: A Danish survey. AB - OBJECTIVE: The purpose of this study was to determine how age influences the degree to which patients with breast cancer feel comfortable with standard follow up and to assess their satisfaction with the contact to health professionals. METHODS: Data was from a Danish population-based questionnaire survey from 2012 including adult cancer patients. 1120 patients with breast cancer returned the questionnaire (response rate: 73%). Age groups were decided before conducting analyses. RESULTS: Overall, patients with breast cancer evaluated the follow-up programme positively. However, in five of six items of interest, patients aged 40 49 and 50-59 years differed statistically significantly from patients >=70 years, by being less comfortable with the follow-up, less satisfied with the health care professionals' ability to listen, and less satisfied with the health care professionals' answers. Satisfaction with the length of consultations, and the number of involved health care professionals were also lower in these age groups compared to patients >=70 years. CONCLUSION: Overall, satisfaction with follow-up was high, but considerable age-related variations were found. PRACTICE IMPLICATIONS: The findings suggest a potential for improving the services provided for patients aged 40-59 years with breast cancer. PMID- 28734559 TI - A systematic review and meta-analysis of written self-administered psychosocial interventions among adults with a physical illness. AB - OBJECTIVE: The cost of implementing professionally-led psychosocial interventions has limited their integration into routine care. To enhance the translation of effective psychosocial interventions in routine care, a self-administered format is sometimes used. The meta-analysis examined the efficacy of written self administered, psychosocial interventions to improve outcomes among individuals with a physical illness. METHODS: Studies comparing a written self-administered intervention to a control group were identified through electronic databases searching. Pooled effect sizes were calculated across follow-up time points using random-effects models. Studies were also categorised according to three levels of guidance (self-administered, minimal contact, or guided) to examine the effect of this variable on outcomes. RESULTS: Forty manuscripts were retained for the descriptive review and 28 for the meta-analysis. Findings were significant for anxiety, depression, distress, and self-efficacy. Results were not significant for quality of life and related domains as well as coping. Purely self administered interventions were efficacious for depression, distress, and self efficacy; only guided interventions had an impact on anxiety. CONCLUSIONS: Findings showed that written self-administered interventions show promise across a number of outcomes. PRACTICE IMPLICATIONS: Self-administered interventions are a potentially efficacious and cost-effective approach to address some of the most common needs of patients with a physical illness. PMID- 28734561 TI - Avoiding adult in-hospital cardiac arrest: A retrospective cohort study to determine preventability. AB - INTRODUCTION: This study had three main aims. Develop a methodology for reviewing in-hospital cardiac arrests (IHCA). Assess appropriateness and potential preventability of IHCAs. Identify areas for improvement within the rapid response system (RRS). DESIGN: A retrospective cohort study of IHCA identified from an existing organisational electronic database of medical emergency (MET) and Code Blue team activation. Potential preventability of IHCA and Code Blue team activation were established by an expert panel based on a standardised case review process with descriptive and content analyses for each IHCA event. SETTING: A university affiliated tertiary referral hospital with an established two-tier RRS in Melbourne, Australia. PARTICIPANTS: Same day and multi-day stay patients identified from an existing database as having an IHCA defined as attempted resuscitation with chest compressions, defibrillation, or both from January 2014 to December 2015. MAIN OUTCOME MEASURES: Outcome measures were: number of Code Blue activations; potential preventability of Code Blue activations and potential preventability of the IHCA event. RESULTS: A total of 120 IHCA events equating to 0.58 per 1000 total admissions occurred. 11 (9%) of IHCA were determined to be potentially preventable due to a failure to escalate, medication errors and inappropriate management. 39 (33%) of 120 Code Blue team activations were determined to be potentially preventable. These were typically due to lack of identification and documentation for end of life (EOL) care in 16 (62%) cases and inappropriate resuscitation when limitations of care were already in place in 10 (38%) cases. CONCLUSIONS: The study centre has a comparably low rate of preventable IHCA which could be reduced further through improvements in documentation and handover process. A focus on improved communication, recognition and earlier instigation of appropriate EOL care will reduce this rate further. PMID- 28734560 TI - Deciding on breast cancer risk reduction: The role of counseling in individual decision-making - A qualitative study. AB - OBJECTIVES: The presentation of risks and benefits in clinical practice is common particularly in situations in which treatment recommendations involve trade-offs. The treatment of breast cancer risk with selective estrogen receptor modulators (SERMs) is such a decision. We investigated the influence of health care provider (HCP) counseling on women's decision-making. METHODS: Thirty breast cancer risk counseling sessions were recorded from April 2012-August 2013 at a comprehensive cancer center and at a safety-net, community hospital in the US. Participating women and HCPs were interviewed. A cross-case synthesis was used for analysis. RESULTS: Of 30 participants 21 received a SERM-recommendation, 11 decided to take SERMs. Counseling impacted decision-making, but did not determine it. Three categories emerged: 1.) ability to change the decision anytime, 2.) perceptions on medications, and 3.) proximity of cancer. CONCLUSION: Decision-making under conditions of a risk diagnosis such as increased breast cancer risk is a continuous process in which risk information is transformed into practical and experiential considerations. PRACTICE IMPLICATIONS: Individuals' health care decision-making is only marginally dependent on the interactions in the clinic. Accepting patients' experiences and beliefs in their own right and letting them guide the discussion may be important for a satisfying decision-making process. PMID- 28734562 TI - Long-term sustainability of a multi-step intervention to reduce unnecessary diagnostic testing. PMID- 28734563 TI - Malignancy risks after herpes zoster: Hospital-based matched cohort study. PMID- 28734564 TI - Risk of bone fractures among users of oral anticoagulants: An administrative database cohort study. PMID- 28734565 TI - Topical brinzolamide in congenital nystagmus: A retrospective study. AB - OBJECTIVE: To evaluate the effect of treatment with topical brinzolamide on visual acuity and nystagmus intensity in patients with congenital nystagmus. MATERIAL AND METHODS: A retrospective study was designed in which the clinical records of 14 patients with congenital nystagmus were reviewed. All patients underwent a complete ophthalmological examination and a Perea video-oculography (VOG) before, and three days after, initiation of treatment with topical brinzolamide (Azopt). Five expert researchers evaluated the intensity of nystagmus by video before and after treatment. Finally, the subjective improvement of the patients was recorded. RESULTS: Statistically significant differences were found in pre- and post-treatment binocular near visual acuity. A slight increase in the frequency of nystagmus was found, which was statistically significant with the horizontal gaze to the left and with the gaze downwards (P=.04, P=.03, respectively). The kappa index concordance between the researchers evaluating the intensity of nystagmus was 0.014. Only two of the patients noticed improvement in visual acuity, and one patient noticed improvement in the aesthetic aspect. CONCLUSIONS: In spite of an improvement in nystagmus, it was slight, not cosmetically appreciable by patients in most cases, and was not related to a significant improvement in visual acuity or in patient quality of life. Further studies are needed to evaluate the effects of topical brinzolamide, and to establish potential therapeutic indications in nystagmus. PMID- 28734566 TI - Long-term outcome of eosinophilic fasciitis: A cross-sectional evaluation of 35 patients. AB - BACKGROUND: Eosinophilic fasciitis (EF) is a connective tissue disease with an unknown long-term course. OBJECTIVE: To evaluate presence and determinants of residual disease damage in patients with EF after long-term follow-up. METHODS: Patients with biopsy-proven EF were included for this cross-sectional study. Outcome measures included the Physician's Global Assessment of Disease Activity, Physician's Global Assessment of Damage (PhysGA-D), skin pliability scores, passive range of motion, and health-related quality of Life (HRQoL) questionnaires. RESULTS: In total, 35 patients (24 of whom were female [68.6%]) with a median age of 60 years participated. All patients had detectable residual damage. Impairment of HRQoL, assessed by the Dermatology Quality of Life Index and the 36-Item Short-Form Survey, correlated to the extent of residual damage. The PhysGA-D score at participation correlated to signs of severe disease at presentation, such as increased C-reactive protein level (Spearman's rho [rs ] = 0.486, P = .006), involvement of the neck (rs = 0.528, P = .001) and trunk (rs = 0.483, P = .003), prolonged time to disease remission (rs = 0.575, P = .003), and presence of concomitant morphea (rs = 0.349, P = .040). Lastly, maximum methotrexate dose correlated negatively to PhysGA-D score at study participation (rs = -0.393, P = .022). LIMITATIONS: Sample size. CONCLUSION: All patients with EF had detectable residual damage. Impairment of HRQoL correlated to the extent of residual damage. Advanced age and signs of severe disease at presentation were associated with the severity of residual damage. PMID- 28734567 TI - Effect of calcium phosphate nanocomposite on in vitro remineralization of human dentin lesions. AB - OBJECTIVE: Secondary caries is a primary reason for dental restoration failures. The objective of this study was to investigate the remineralization of human dentin lesions in vitro via restorations using nanocomposites containing nanoparticles of amorphous calcium phosphate (NACP) or NACP and tetracalcium phosphate (TTCP) for the first time. METHODS: NACP was synthesized by a spray drying technique and incorporated into a resin consisting of ethoxylated bisphenol A dimethacrylate (EBPADMA) and pyromellitic glycerol dimethacrylate (PMGDM). After restoring the dentin lesions with nanocomposites as well as a non releasing commercial composite control, the specimens were treated with cyclic demineralization (pH 4, 1h per day) and remineralization (pH 7, 23h per day) for 4 or 8 weeks. Calcium (Ca) and phosphate (P) ion releases from composites were measured. Dentin lesion remineralization was measured at 4 and 8 weeks by transverse microradiography (TMR). RESULTS: Lowering the pH increased ion release of NACP and NACP-TTCP composites. At 56 days, the released Ca concentration in mmol/L (mean+/-SD; n=3) was (13.39+/-0.72) at pH 4, much higher than (1.19+/ 0.06) at pH 7 (p<0.05). At 56 days, P ion concentration was (5.59+/-0.28) at pH 4, much higher than (0.26+/-0.01) at pH 7 (p<0.05). Quantitative microradiography showed typical subsurface dentin lesions prior to the cyclic demineralization/remineralization treatment, and dentin remineralization via NACP and NACP-TTCP composites after 4 and 8 weeks of treatment. At 8 weeks, NACP nanocomposite achieved dentin lesion remineralization (mean+/-SD; n=15) of (48.2+/-11.0)%, much higher than (5.0+/-7.2)% for dentin in commercial composite group after the same cyclic demineralization/remineralization regimen (p<0.05). SIGNIFICANCE: Novel NACP-based nanocomposites were demonstrated to achieve dentin lesion remineralization for the first time. These results, coupled with acid neutralization and good mechanical properties shown previously, indicate that the NACP-based nanocomposites are promising for restorations to inhibit caries and protect tooth structures. PMID- 28734568 TI - Antibacterial properties of nano-silver coated PEEK prepared through magnetron sputtering. AB - OBJECTVE: We aimed to investigate the cytotoxicity and antibacterial properties of nano-silver-coated polyetheretherketone (PEEK) produced through magnetron sputtering and provide a theoretical basis for its use in clinical applications. METHODS: The surfaces of PEEKs were coated with nano-silver at varying thicknesses (3, 6, 9, and 12nm) through magnetron sputtering technology. The resulting coated PEEK samples were classified into the following groups according to the thickness of the nano-silver coating: PEEK-3 (3nm), PEEK-6 (6nm), PEEK-9 (9nm), PEEK-12 (12nm), and PEEK control group. The surface microstructure and composition of each sample were observed by scanning electron microscopy (SEM), atomic force microscopy (AFM), and energy dispersive spectrum (EDS) analysis. The water contact angle of each sample was then measured by contact angle meters. A cell counting kit (CCK-8) was used to analyze the cytotoxicity of the mouse fibroblast cells (L929) in the coated groups (n=5) and group test samples (n=6), negative control (polyethylene, PE) (n=6), and positive control group (phenol) (n=6). The antibacterial properties of the samples were tested by co-culturing Streptococcus mutans and Straphylococcus aureus. The bacteria that adhered to the surface of samples were observed by SEM. The antibacterial adhesion ability of each sample was then evaluated. RESULTS: SEM and AFM analysis results showed that the surfaces of control group samples were smooth but compact. Homogeneous silver nano-particles (AgNPs) and nano-silver coating were uniformly distributed on the surface of the coated group samples. Compared with the control samples, the nano silver coated samples had a significant increase in surface roughness (P<0.05) as the thickness of their nano-silver coating increased. EDS analysis showed that not only C and O but also Ag were present on the surface of the coated samples. Moreover, the water contact angle of modified samples significantly increased after nano-silver coating modification (P<0.01). CCK-8 cytotoxicity test results showed that coated samples did not exhibit cytotoxicity. The antibacterial experimental results showed that the nano-silver coating can significantly improve the antibacterial activity and bacterial adhesion ability of the PEEK samples. SIGNIFICANCE: The compact and homogeneous nano-silver coating was successfully prepared on the surface of PEEK through magnetron sputtering. The nano-silver coated PEEKs demonstrated enhanced antibacterial activities and bacterial adhesion abilities and had no cytotoxic effects. PMID- 28734569 TI - Factor associated variations in the home range of a resident Adriatic common bottlenose dolphin population. AB - This study investigates the influence of the most dominant factors (association patterns, gender, natal philopatry and anthropogenic pressure) on the home range size of the 44 most resident common bottlenose dolphins (Tursiops truncatus) inhabiting the waters of the Cres-Losinj archipelago (north Adriatic Sea, Croatia), a recently declared NATURA 2000 SCI. Results show that variations in home range patterns (MCP, 95% KDE and 50% KDE home range size) among the individual resident dolphins are primarily related to differences in gender and reflect the way in which different genders respond to external stressors. In addition, results confirm the seasonal influence of nautical tourism on both female and male dolphins through changes in their home range sizes. The overall results improve current knowledge of the main anthropogenic threats that should be taken into consideration when developing conservation measures to be applied to this Cres and Losinj SCI. PMID- 28734570 TI - Spatial and temporal variations of heavy metals in marine sediments from Liaodong Bay, Bohai Sea in China. AB - An integrated analysis has been carried out using surface sediment monitoring data in order to characterize the spatial distributions and temporal trends of heavy metals within ten years from 2004 to 2013 in the entire Liaodong Bay. Hg, Cd and As were predominant contaminants with their median concentrations of 0.04 0.15, 0.01-0.65, and 1.80-30.3mg/kg respectively. Both areas and levels of Cu and Pb contamination were low. Cd contents exhibited an obvious decreasing trend and As presented a similar law during these 10years. Further, emissions from different sources were analyzed to identify the possible reasons contributing to the metal pollution. Dramatic descending of waste water might be the top reason for Cd and As variations. Local flue gases and smoke emissions might not be the main sources contributing to Hg pollution, whereas atmospheric deposition at a larger scale was supposed to be the leading factor. PMID- 28734571 TI - Multimodal ultrasound computer-assisted tomography: An approach to the recognition of breast lesions. AB - The research here presented aims at developing a new, promising method for the imaging diagnostics of breast lesions - ultrasound tomography (UST). A currently implemented device enables the reconstruction three complementary images for each coronal breast section. Based on in vivo breast examination, the authors developed an approach to breast diagnostics which employs ultrasound transmission and reflection tomography imaging. The obtained transmission images of ultrasound speed distribution show good correlation of glandular tissue areas with their visualization on MRI images. The results also allow a prediction that the implemented UST device offering fusion of reconstructed images may contribute to achieving a new standard for breast cancer diagnostics through non-invasive, fast and cheap screening tests. PMID- 28734572 TI - Experience of the Implementation of Rapid On-Site Evaluation in Ultrasound-Guided Fine-Needle Aspiration Biopsy of Thyroid Nodules. AB - OBJECTIVE: To evaluate the effect of the implementation of the rapid on-site evaluation (ROSE) technique in ultrasound-guided fine-needle aspiration biopsy of thyroid nodules. MATERIALS AND METHODS: We conducted an observational and retrospective study approved by the Institutional Ethics Committee as an investigation without risk. Between January 2012 and December 2015, 892 ultrasound-guided fine-needle aspiration biopsy procedures were performed under ultrasound guidance. In our study, we included 522 procedures from 473 patients that were taken as part of an investigation of the thyroid nodule (average age: 56 +/- 14; 84% were women). We compared the percentage of unsatisfactory samples in the procedures performed with and without the use of the ROSE technique, the cytology adequacy agreement with the cytopathology, and we also assessed the relationship with the number of years of experience of the radiologist. RESULTS: The ROSE technique led to a decrease of 30.5% of unsatisfactory samples. By 2014, more than half of the procedures were performed with the ROSE technique, and the percentage of unsatisfactory samples decreased progressively each year. The technical implementation of ROSE improved the results of all radiologists; however, those radiologists with the least number of years of experience showed the greatest benefits from the implementation of the ROSE technique. The concordance between the ROSE technique and the cytopathology report was good (Cohen kappa = 0.75). CONCLUSION: In our experience, the implementation of the ROSE technique has helped to reduce the percentage of unsatisfactory samples, which improves the quality and safety of patient care. PMID- 28734573 TI - Corrigendum to "Small, unrepaired ventricular septal defects reveal poor exercise capacity compared with healthy peers: A prospective, cohort study" [Int. J. Cardiol. 227 (2017) 631-634]. PMID- 28734574 TI - Early reduction of matrix metalloproteinase-8 serum levels is associated with leptin drop and predicts diabetes remission after bariatric surgery. AB - BACKGROUND: We aimed at investigating whether the acute abrogation of leptin after bariatric surgery is able to reduce neutrophil activation and potentially affect type 2 diabetes mellitus (T2DM) remission. METHODS: Metabolic and inflammatory parameters (i.e. leptin, IL-6 and neutrophil products) were compared at baseline (before bariatric surgery), one month, one and three years after surgery in morbid obese (MOB) T2DM patients (n=12) and non-MOB controls (n=32). In vitro, the effects of leptin on Il-6-induced human neutrophil degranulation and integrin upregulation were assessed. RESULTS: At baseline, MOB T2DM patients had a similar demographic, lipid and glycemic profiles than non-MOB T2DM controls, but higher levels of inflammatory mediators, such as CRP, fibrinogen, neutrophil-to-lymphocyte ratio (NLR), matrix metalloproteinase (MMP)-8 and leptin. One month after surgery, CRP, fibrinogen and MMP-8 were reduced only in MOB T2DM patients, while serum leptin was reduced in both groups. In the overall cohort, leptin and MMP-8 drops from baseline to one month post-surgery were positively correlated (Deltaleptin vs. DeltaMMP8: r=0.391, p=0.025). Moreover, DeltaMMP8 inversely correlated with fasting glucose levels at one-year follow-up and with glycated hemoglobin at both one- and three-year. At the cut-off point identified by ROC curve analysis (>0ng/mL), DeltaMMP8 predicted complete T2DM remission at 3-year follow-up. In vitro, leptin increased IL-6-induced MMP-8 release and abrogated CD18 up-regulation. CONCLUSION: Bariatric surgery is associated to an acute abrogation of leptin that could affect MMP-8 levels, particularly in MOB T2DM patients. This beneficial event is associated with T2DM remission at 3-year follow-up. PMID- 28734575 TI - Outcomes associated to serum phosphate levels in patients with suspected acute coronary syndrome. AB - BACKGROUND: We investigated the association between phosphate and the risk of adverse clinical outcomes in patients with manifest cardiovascular disease (CVD). METHODS: Observational study of patients hospitalized during 2006-2011 in Stockholm, Sweden, because of suspected acute coronary syndrome (ACS). The exposure was serum phosphate during the hospitalization. We modeled the association between phosphate and in-hospital death or in-hospital events (composite of myocardial infarction, cardiogenic shock, resuscitated cardiac arrest, atrial fibrillation, or atrioventricular block) as well as the one-year post-discharge risk of death or cardiovascular event (composite of myocardial re infarction, heart failure and stroke). Confounders included demographics, comorbidities, kidney function, diagnoses, in-hospital procedures and therapies. RESULTS: Included were 2547 patients (68% men, mean age 67+/-14years) with median phosphate of 1.10 (range 0.14-4.20) mmol/L. During hospitalization, 198 patients died and 328 suffered an adverse event. Within one year post-discharge, further 381 deaths and 632 CVD events occurred. The associations of phosphate with mortality and CVD were J-shaped, with highest risk magnitudes at higher phosphate levels. For instance, compared to patients in the 50th percentile of phosphate distribution, those above the 75th percentile (1.3mmol/L, normal range) had significantly higher odds for in-hospital death [odds ratio 1.36, 95% confidence interval (CI) (1.08-1.71)] and of CVD post-discharge [sub-hazard ratios 1.17 (1.03-1.33)]. CONCLUSIONS: In patients with suspected ACS, both higher and lower phosphate levels associated with increased risk of adverse outcomes during the index hospitalization and within one year post-discharge. The risk association was present already within normal-range serum phosphate values. PMID- 28734576 TI - Predictive validity analysis of six reference equations for the 6-minute walk test in healthy Brazilian men: a cross-sectional study. AB - BACKGROUND: The six-minute walk test (6MWT) is an important tool for evaluating functional capacity and exercise tolerance. The reference equations for the 6MWT in healthy subjects were established on the basis of American and European populations, but reference equations have been proposed with different variables for the Brazilian population. OBJECTIVE: To analyze the predictive validity of six reference equations for the six-minute walking distance (6MWD) in healthy adult men. METHODS: We evaluated 103 individuals in relation to level of physical activity (IPAQ), respiratory symptoms (MRC), handgrip strength, and 6MWD test. The data were submitted to a normality test, then the Bland-Altman agreement test was used to compare individual 6MWD values with that expected for each equation. RESULTS: The subjects were active, with a mean age of 34.12 (SD=8.88) years and no respiratory symptoms. The mean of the 6MWD was 663.43 (SD=93.01)m. The 6MWD's predicted values came closest to the walked distance covered by Britto et al.'s equation (using BMI) of 647.62 (SD=38.62)m. CONCLUSIONS: The equation proposed by Britto et al. using body mass index (BMI) was the closest to the 6MWD for the individuals studied and could be widely used as a reference tool during the 6MWT in healthy Brazilian men. PMID- 28734577 TI - Characterization of a PVL-negative community-acquired methicillin-resistant Staphylococcus aureus strain of sequence type 88 in China. AB - Sequence type 88 community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) strain SR434, isolated from an outpatient with skin and soft tissue infection, was subjected to whole genome sequencing, antimicrobial susceptibility testing, mouse skin infection model and hemolysis analysis to identify its virulence and resistance determinants. MRSA strain SR434 is resistant to clindamycin, erythromycin and fosfomycin. Four plasmids with resistance genes were identified in this strain, including a 20,658bp blaZ-carrying plasmid, a 2473bp ermC-carrying plasmid, a 2622bp fosB7-carrying plasmid (86% identity with plasmid in a ST2590 MRSA strain) and a 4817bp lnuA-carrying plasmid (99% identity with pLNU4 from bovine coagulase-nagetive Staphylococci). This strain contains staphylococcal cassette chromosome mec type IV and does not contain arginine catabolic mobile element or Panton-Valentine-Leukocidin. SR434 harbors genomic islands nuSaalpha, nuSabeta, nuSagamma and PhiSa3 and pathogenicity islands nuSa2 that carries genes encoding toxic shock syndrome toxin 1, superantigen enterotoxin C and superantigen enterotoxin L. Mouse skin infection model results show that SR434 had similar virulence potential causing invasive skin infection as a PVL-negative epidemic Korea clone HL1 (ST72). CA-MRSA strain of ST88 lineage might be a great concern for its high virulence. PVL has limited contribution to virulence phenotype among this lineage. PMID- 28734579 TI - [A left peri-renal infiltration]. PMID- 28734580 TI - [Cutaneous lesions in a 69-year-old woman]. PMID- 28734578 TI - Phosphatidylserine Is the Signal for TAM Receptors and Their Ligands. AB - Nature repeatedly repurposes, in that molecules that serve as metabolites, energy depots, or polymer subunits are at the same time used to deliver signals within and between cells. The preeminent example of this repurposing is ATP, which functions as a building block for nucleic acids, an energy source for enzymatic reactions, a phosphate donor to regulate intracellular signaling, and a neurotransmitter to control the activity of neurons. A series of recent studies now consolidates the view that phosphatidylserine (PtdSer), a common phospholipid constituent of membrane bilayers, is similarly repurposed for use as a signal between cells and that the ligands and receptors of the Tyro3/Axl/Mer (TAM) family of receptor tyrosine kinases (RTKs) are prominent transducers of this signal. PMID- 28734581 TI - Discovery of (R)-5-(benzo[d][1,3]dioxol-5-yl)-7-((1-(vinylsulfonyl)pyrrolidin-2 yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (B6) as a potent Bmx inhibitor for the treatment of NSCLC. AB - Described as a Btk inhibitor, ibrutinib also potently inhibits Bmx and EGFR, two good targets for lung cancer. Owing to its high CLogP (4.07) and low aqueous solubility (<0.01mg/ml), resulting in unfavorable bioavailability, ibrutinib requires high dosages to achieve good clinical response in the treatment of non small cell lung cancer (NSCLC). In our effort to improve the CLogP of ibrutinib by structural optimization led to the discovery of a potent anti-cancer agent B6, with beneficial physicochemical parameters (CLogP=2.56, solubility in water~0.1mg/ml) meeting the principles of oral drugs. B6 exhibited anti proliferation activities against EGFR-expressing cells, especially the mutant ones, such as H1975 (L858R/T790M, IC50=0.92+/-0.19MUM) and HCC827 (Del119 IC50=0.014+/-0.01MUM). Moreover, B6 significantly slowed down H1975 tumor growth with anti-tumor rate of 73.9% (p<0.01). Enzyme potencies assay demonstrated B6 moderately selectively inhibited Bmx (IC50=35.7+/-0.1nM) over other kinases. So, as a potent Bmx inhibitor, B6 has the potential to be an efficacious treatment for NSCLC with acquired drug resistance. PMID- 28734582 TI - The hydrolytic susceptibility of prochelator BSIH in aqueous solutions. AB - The prochelator BSIH ((E)-N'-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 yl)benzylidene)isonicotinohydrazide) contains a boronate group that prevents metal coordination until reaction with peroxide releases the iron chelator SIH ((E)-N'-(2-hydroxybenzylidene)isonicotinohydrazide). BSIH exists in aqueous buffer and cell culture media in equilibrium with its hydrolysis products isoniazid and (2-formylphenyl)boronic acid (FBA). The relative concentrations of these species limit the yield of intact SIH available for targeted iron chelation. While the hydrolysis fragments are nontoxic to retinal pigment epithelial cells, these results suggest that modifications to BSIH that improve its hydrolytic stability yet maintain its low inherent cytotoxicity are desirable for creating more efficient prochelators for protection against cellular oxidative damage. PMID- 28734583 TI - Kidney transplantation from HLA-incompatible live donors: Efficiency and outcome of 32 patients after desensitisation. AB - : Desensitisation is a procedure undergone by the recipient of a kidney transplant from a donor who is cross-match positive. The aim of this study was to present the outcomes from our hospital of kidney transplant recipients from HLA incompatible live donors after desensitisation. We studied 32 patients aged 46+/ 14 years with a mean fluorescence intensity (MFI) versus class I HLA of 7979+/ 4089 and 6825+/-4182 MFI versus class II and relative intensity scale (RIS) of 8.9+/-7.6. The complement-dependent cytotoxicity (CDC) cross-matching test was positive in 18 patients, flow cytometry was positive in 7 patients and donor specific antibodies (DEA) were detected in 7. The protocol used was rituximab, plasmapheresis/immunoadsorption, immunoglobulins, tacrolimus, mycophenolic acid derivatives and prednisone. After 8+/-3 sessions of plasmapheresis/immunoadsorption, 23 patients were trasplanted (71.9%) and desensitisation was ineffective in 9. There were baseline differences in MFI class I (P<.001), RIS (P=.008), and CDC cross-matching, DSA and flow cytometry (P=.05). MFI class I and RIS were predictors of inefficiency in ROC curves. After follow-up of 43+/-30 months, 13 patients (56%) presented postoperative bleeding, 3 (13%) delayed graft function, 4 (17.4%) acute rejection, 6 (26%) CMV viraemia and 1 (4%) BK viraemia. Five-year patient survival was 90%, with 86% allograft survival. Five-year creatinine was 1.5+/-0.4 and proteinuria was 0.5+/-0.7. CONCLUSIONS: Kidney transplantation from HLA-incompatible live donors after desensitisation was possible in 71.9% of patients. MFI class I and RIS predict the inefficiency of desensitisation. Five-year allograft survival (86%) was acceptable with a low incidence of acute rejection (17.4%), although with a greater trend towards postoperative bleeding. PMID- 28734585 TI - Increased time for homeostasis in hemodialysis. Factor XI deficiency (hemophilia C): Report of a case. PMID- 28734586 TI - The citizen participation and practice of health and medical policy making. PMID- 28734584 TI - Prospective evaluation of the development of contrast-induced nephropathy in patients with acute coronary syndrome undergoing rotational coronary angiography vs. conventional coronary angiography: CINERAMA study. AB - INTRODUCTION AND OBJECTIVES: Rotational coronary angiography (RCA) requires less contrast to be administered and can prevent the onset of contrast-induced nephropathy (CIN) during invasive coronary procedures. The aim of the study is to evaluate the impact of RCA on CIN (increase in serum creatinine >=0.5mg/dl or >=25%) after an acute coronary syndrome. METHODS: From April to September 2016, patients suffering acute coronary syndromes who underwent diagnostic coronary angiography, with the possibility of ad hoc coronary angioplasty, were prospectively enrolled. At the operator's discretion, patients underwent RCA or conventional coronary angiography (CCA). CIN (primary endpoint), as well as analytical, angiographic and clinical endpoints, were compared between groups. RESULTS: Of the 235 patients enrolled, 116 patients received RCA and 119 patients received CCA. The RCA group was composed of older patients (64.0+/-11.8 years vs. 59.7+/-12.1 years; p=0.006), a higher proportion of women (44.8 vs. 17.6%; p<0.001), patients with a lower estimated glomerular filtration rate (76+/-25 vs. 86+/-27ml/min/1.73 m2; p=0.001), and patients who underwent fewer coronary angioplasties (p<0.001) compared with the CCA group. Furthermore, the RCA group, received less contrast (113+/-92 vs. 169+/-103ml; p<0.001), including in diagnostic procedures (54+/-24 vs. 85+/-56ml; p<0.001) and diagnostic-therapeutic procedures (174+/-64 vs. 205+/-98ml; p=0.049) compared with the CCA group. The RCA group presented less CIN (4.3 vs. 22.7%; p<0.001) compared to the CCA group, and this finding was maintained in the regression analysis (Adjusted relative risk: 0.868; 95% CI: 0.794-0.949; p=0.002). There were no differences in clinical endpoints between the groups. CONCLUSIONS: RCA was associated with lower administration of contrast during invasive coronary procedures in acute coronary syndrome patients, resulting in lower incidence of CIN, in comparison with CCA. PMID- 28734587 TI - Computed tomography predict regression of coronary artery aneurysm in patients with Kawasaki disease. AB - BACKGROUND/PURPOSE: The study evaluated possible factors influencing the regression of coronary artery aneurysm (CAA) in patients with Kawasaki disease (KD) through electrocardiographically gated cardiac computed tomography (CT). METHODS: 18 patients with KD exhibited CAAs in at least 2 CT examinations conducted from December 2004 to September 2015, and 37 aneurysms were observed. Every aneurysm was corrected through the descending aorta at the origin level of the left main coronary artery under a normal distribution and measured under a fixed window level. These aneurysms were divided into 2 groups according to regression. Clinical symptoms, laboratory data, and imaging characteristics of both groups were analyzed. RESULTS: All the aneurysms of 4 patients decreased in size, and totally, 14 aneurysms (37%) regressed. CAA regression tends to occur early after disease onset. No significant differences were observed in sex, aneurysm location, and the distance to the orifice between the 2 groups. The aneurysms with no calcification (p = 0.012), smaller diameter (p = 0.004), younger disease onset age (p = 0.048), and ectatic shape (p < 0.001) were more likely to regress according to univariate analysis. Receiver operating characteristic analysis revealed that the possible cut-off point of the maximal diameter to yield the highest sensitivity (91.3%) and specificity (92.9%) to predict CAA regression was 5.6 mm. CONCLUSION: Calcified CAAs in patients with KD was less likely to regress. The aneurysm size and shape as well as disease onset age were possible factors influencing regression. PMID- 28734588 TI - High-throughput sequencing analysis of bacterial community spatiotemporal distribution in response to clogging in vertical flow constructed wetlands. AB - The aim of this study was to characterize bacterial communities in vertical flow constructed wetlands (VFCWs) using Illumina high-throughput sequencing. The bacterial communities developed lower richness and diversity in response to clogging. Bacterial diversity did not overtly decrease with depth. A variety of bacterial phyla were found in VFCWs' bacterial communities, including Bacteroidetes, Actinobacteria and Acidobacteria, among which Proteobacteria was dominant. At the genus level, a spatiotemporal variation was illustrated in the diversity and structure of bacterial communities. Clustering analysis of bacterial composition in the operational taxonomic units (OTUs) at the phylum and genus levels had a consistent trend, namely, that bacterial communities were more similar at similar column depths. PMID- 28734589 TI - Phosphorus and Cu2+ removal by periphytic biofilm stimulated by upconversion phosphors doped with Pr3+-Li. AB - Upconversion phosphors (UCPs) can convert visible light into luminescence, such as UV, which can regulate the growth of microbes. Based on these fundamentals, the community composition of periphytic biofilms stimulated by UCPs doped with Pr3+-Li+ was proposed to augment the removal of phosphorus (P) and copper (Cu). Results showed that the biofilms with community composition optimized by UCPs doped with Pr3+-Li+ had high P and Cu2+ removal rates. This was partly due to overall bacterial and algal abundance and biomass increases. The synergistic actions of algal, bacterial biomass and carbon metabolic capacity in the Pr-Li stimulated biofilms facilitated the removal of P and Cu2+. The results show that the stimulation of periphytic biofilms by lanthanide-doped UCPs is a promising approach for augmenting P and Cu2+ removal. PMID- 28734590 TI - Evaluation of electricity generation from lignin residue and biogas in cellulosic ethanol production. AB - This study takes the first insight on the rigorous evaluation of electricity generation based on the experimentally measured higher heating value (HHV) of lignin residue, as well as the chemical oxygen demand (COD) and biological oxygen demand (BOD5) of wastewater. For producing one metric ton of ethanol fuel from five typical lignocellulose substrates, including corn stover, wheat straw, rice straw, sugarcane bagasse and poplar sawdust, 1.26-1.85tons of dry lignin residue is generated from biorefining process and 0.19-0.27tons of biogas is generated from anaerobic digestion of wastewater, equivalent to 4335-5981kWh and 1946 2795kWh of electricity by combustion of the generated lignin residue and biogas, respectively. The electricity generation not only sufficiently meets the electricity needs of process requirement, but also generates more than half of electricity surplus selling to the grid. PMID- 28734591 TI - Increased inflammatory effect of electronegative LDL and decreased protection by HDL in type 2 diabetic patients. AB - BACKGROUND AND AIMS: Type 2 diabetic patients have an increased proportion of electronegative low-density lipoprotein (LDL(-)), an inflammatory LDL subfraction present in blood, and dysfunctional high-density lipoprotein (HDL). We aimed at examining the inflammatory effect of LDL(-) on monocytes and the counteracting effect of HDL in the context of type 2 diabetes. METHODS: This was a cross sectional study in which the population comprised 3 groups (n = 12 in each group): type 2 diabetic patients with good glycaemic control (GC-T2DM patients), type 2 diabetic patients with poor glycaemic control (PC-T2DM), and a control group. Total LDL, HDL, and monocytes were isolated from plasma of these subjects. LDL(-) was isolated from total LDL by anion-exchange chromatography. LDL(-) from the three groups of subjects was added to monocytes in the presence or absence of HDL, and cytokines released by monocytes were quantified by ELISA. RESULTS: LDL( ) proportion and plasma inflammatory markers were increased in PC-T2DM patients. LDL(-) from PC-T2DM patients induced the highest IL1beta, IL6, and IL10 release in monocytes compared to LDL(-) from GC-T2DM and healthy subjects, and presented the highest content of non-esterified fatty acids (NEFA). In turn, HDL from PC T2DM patients showed the lowest ability to inhibit LDL(-)-induced cytokine release in parallel to an impaired ability to decrease NEFA content in LDL(-). CONCLUSIONS: Our findings show an imbalance in the pro- and anti-inflammatory effects of lipoproteins from T2DM patients, particularly in PC-T2DM. PMID- 28734592 TI - Publishing with Objective Charisma: Breaking Science's Paradox. AB - Good writing takes time, but in a research environment where speed is master, is it a superfluous pursuit? Scientists spend most of their working life writing, yet our writing style obstructs its key purpose: communication. We advocate more accessible prose that boosts the influence of our publications. For those who change, the proof of their success will be science that is read, understood, and remembered. PMID- 28734593 TI - Unifying Research on Social-Ecological Resilience and Collapse. AB - Ecosystems influence human societies, leading people to manage ecosystems for human benefit. Poor environmental management can lead to reduced ecological resilience and social-ecological collapse. We review research on resilience and collapse across different systems and propose a unifying social-ecological framework based on (i) a clear definition of system identity; (ii) the use of quantitative thresholds to define collapse; (iii) relating collapse processes to system structure; and (iv) explicit comparison of alternative hypotheses and models of collapse. Analysis of 17 representative cases identified 14 mechanisms, in five classes, that explain social-ecological collapse. System structure influences the kind of collapse a system may experience. Mechanistic theories of collapse that unite structure and process can make fundamental contributions to solving global environmental problems. PMID- 28734594 TI - Editorial Commentary: Closure of the patent foramen ovale viewed from a different angle. PMID- 28734595 TI - Arrhythmias after left ventricular assist device implantation: Incidence and management. AB - The use of mechanical circulatory support has become an increasingly common practice in patients with heart failure, whether used as bridge to transplantation or as destination therapy. The last couple of decades has seen a drastic change in the functioning of the left ventricular assist devices (LVAD), changing from the first generation devices running on pulsatile flow to the current continuous flow devices. Atrial and ventricular arrhythmias are common among heart failure patients, and though the systematic circulation is well supported in patients on mechanical circulatory support, these arrhythmias can still be the cause of detrimental symptoms and lead to potentially fatal outcomes. Several studies have shown that mortality rates in LVAD recipients secondary to lethal arrhythmias are uncommon, and newer generation continuous flow devices particularly seem to support hemodynamic support well. While it is common practice to implant ICDs in patients with LVADs and a history of ventricular arrhythmias, the efficacy behind this practice at preventing sudden death in this population is unknown. In this review, we highlight what is already known about the complications, management and treatment of atrial and ventricular arrhythmias in patients with LVAD devices. PMID- 28734596 TI - Developments in urologic oncology "OncoForum": The best of 2016. AB - OBJECTIVE: To put forth new findings of urologic oncology with impact on clinical practice presented during 2016 in the main annual meetings. ACQUISITION OF EVIDENCE: This document reviews abstracts on prostate, kidney and bladder cancer presented at the congresses of 2016 (EAU, AUA, ASCO, ESMO and ASTRO) and publications with the highest impact in this period valued with the highest scores by the OncoForum committee. SYNTHESIS OF EVIDENCE: In High-Risk Renal-Cell carcinoma after nephrectomy, disease-free survival was significantly greater for sunitinib than placebo group, with adverse events more frequents. In locally advanced and metastatic urotherial carcinoma patients, aletozumab achieved overall response rate in all subgroups of patients, included poor prognostic. In localized prostate cancer, the difference of prostate-cancer-specific mortality among active monitoring, radical prostatectomy and external-beam radiotherapy was not significant (P=0,48). In TERRAIN study, with castration-resistant prostate cancer patients, adverse events was reported in 31% and 23% of patients treated with enzalutamide and bicalutamide, respectively. Moreover, enzalutamide significantly improved median progression-free survival (15.7 months) compared bicalutamide (5.8 months) (P<.0001). In SRTIVE study, Enzalutamide reduced the risk of progression or death by 76% compared with bicalutamide (P<.001). CONCLUSIONS: In high-risk renal-cell carcinoma after nephrectomy, sunitinb has been considered as treatment choice. In localized prostate cancer, prostate cancer-specific mortality was low irrespective of the treatment assigned (active monitoring, radical prostatectomy and external-beam radiotherapy). In metastatic castration-resistant prostate cancer new results of treatment with enzalutamide and abiraterone has been published, wich have been shown beneficial effects in metastatic and no metastatic patients. PMID- 28734598 TI - Segregation and mortality over time and space. AB - Few studies have been able to measure the evolution of segregation on health disparities or assess whether those disparities existed in rural communities prior to the Great Migration of African Americans to urban centers. We use a newly developed measure of historical racial residential segregation based on individual-level data. The measure exploits complete census manuscript files to identify the races of next-door neighbors. This measure is the first and only measure of historical segregation for rural communities, allowing us to greatly extend the empirical analysis of the effects of racial segregation on health over space and time. Using this comprehensive measure of racial residential segregation, we estimate the historical relationship between racial segregation and mortality. We find that conditional on racial composition, racially segregated environments had higher mortality rates and it was not always the case that the outcomes for blacks were worse than those of whites. These effects of segregation on health differed between urban and rural locations. We conclude by noting how comprehensive measures of segregation can extend the analysis of structural factors in racial health disparities to rural residents and to the historical evolution of health disparities. PMID- 28734599 TI - Short communication: Survival of Vaccinia virus in inoculated cheeses during 60 day ripening. AB - Bovine vaccinia is a neglected zoonosis caused by Vaccinia virus (VACV) and has a major economic and public health effect in Brazil. Previous studies showed infectious VACV particles in milk from either experimentally or naturally infected cows and in fresh cheeses prepared with experimentally contaminated milk. Ripening is a process that leads to major changes in the physical and chemical characteristics of cheese, reducing contamination by spoilage, pathogenic microorganisms, or both. However, it is not known if VACV infectious particles persist after the ripening process. To investigate this issue, viral infectivity at different ripening times was studied in cheeses manufactured with milk experimentally contaminated with VACV strain Guarani P2 (GP2). Cheeses were analyzed at 1, 7, 14, 21, 45, and 60 d of ripening at 25 degrees C. Viral DNA was quantified by real-time PCR, and VACV isolation and titration were performed in Vero cells. The whole experiment was repeated 4 times. Analysis of the mean viral DNA quantification and infectivity indicated a reduction of approximately 2 logs along the ripening process; however, infectious viral particles (1.7 * 102 pfu/mL) could still be recovered at d 60 of ripening. These findings indicate that the ripening process reduces VACV infectivity, but it was not able to inactivate completely the viral particles after 60 d. PMID- 28734600 TI - Tracking Amazonian cheese microbial diversity: Development of an original, sustainable, and robust starter by freeze drying/spray drying. AB - Marajo cheese made with raw buffalo milk in the Amazon region of Brazil can be considered a good source of wild lactic acid bacteria strains with unexplored and promising characteristics. The aim of this study was to develop a potential probiotic starter culture for industrial applications using freeze drying and spray drying. A decrease in the survival rates of freeze-dried samples compared with spray-dried samples was noted. The spray-dried cultures remained approximately 109 cfu.g-1, whereas the freeze-dried samples showed 107 cfu.g-1 after 60 d of storage at 4 degrees C. All of the spray-dried samples showed a greater ability to decrease the pH in 10% skim milk over 24 h compared with the freeze-dried samples. The spray-dried samples showed a greater resistance to acidic conditions and to the presence of bile salts. In addition, under heat stress conditions, reduction was under 2 log cycles in all samples. Although the survival rate was similar among the evaluated samples after drying, the technological performance for skim milk showed some differences. This study may direct further investigations into how to preserve lactic acid bacteria probiotics to produce spray-dried starters that have a high number of viable cells that can then be used for industrial applications in a cost-effective way. PMID- 28734601 TI - Influence of Saccharomyces cerevisiae fermentation products, SmartCare in milk replacer and Original XPC in calf starter, on the performance and health of preweaned Holstein calves challenged with Salmonella enterica serotype Typhimurium. AB - This study was designed to investigate the effects of supplementing SmartCare (SC; Diamond V, Cedar Rapids, IA) in milk replacer and Original XPC (XPC; Diamond V) in calf starter on performance and health of preweaned calves following an oral challenge with Salmonella enterica. The study was performed in two 35-d periods with 30 Holstein bull calves (2 +/- 1 d of age) per period. In each period, calves were blocked by location in the barn and randomly assigned to treatments that included control, base milk replacer and calf starter with no added Saccharomyces cerevisiae fermentation products; SC, milk replacer with 1 g of SC/calf per day and base calf starter; and SC+XPC, milk replacer with 1 g of SC/calf per day and calf starter with 0.5% XPC on a dry matter basis. Calves were fed 350 g of milk replacer solids at 14% dry matter twice daily at 0700 and 1700 h. Calf starter and water were offered ad libitum and intakes were recorded daily. Calves were challenged with 108 cfu of sulfamethazine-resistant Salmonella enterica serotype Typhimurium orally on d 14 of the study. Fecal Salmonella shedding was determined on d 14 to 21 (daily), 24, 28, and 35 using selective media. Blood samples were collected on d 0, 7, 14, 16, 18, 21, 24, 28, and 35 and analyzed for hematology; plasma were analyzed for haptoglobin concentrations. All data were reported as CON, SC, and SC+XPC, respectively. Calf starter intake was increased from d 22 to 35 among SC+XPC calves and from d 29 to 35 among SC calves. The SC+XPC calves had a lower neutrophil-to-lymphocyte ratio (0.81, 0.83, and 0.69 +/- 0.051) throughout the study. The SC+XPC calves also had lower hematocrits (35.1, 35.3, and 33.4 +/- 0.54%) and hemoglobin concentrations (10.8, 10.6, and 10.1 +/- 0.16 mg/dL) throughout the study. We found a tendency for calves fed SC and SC+XPC to have more solid fecal scores during the week after the challenge. We observed no treatment or treatment * time differences on plasma haptoglobin concentrations (63, 48, and 60 +/- 0.5 MUg/mL). No treatment differences were observed in the fecal shedding of the Salmonella; however, we noted a tendency for a treatment difference in the percentage of calves positive for Salmonella present in the ileal tissue at d 21 after the challenge (25, 50, and 60%). Supplementing preweaned Holstein calves with both SC in milk replacer and XPC in calf starter improved starter intake and improved fecal consistency immediately after a mild Salmonella enterica challenge, but more data are needed to further understand how these yeast fermentation products influence the immune responses to Salmonella enterica. PMID- 28734602 TI - Fatty acids, vitamins and cholesterol content, and sensory properties of cheese made with milk from sheep fed rapeseed oilcake. AB - The aim of the present study was to evaluate the influence of rapeseed oilcake used for feeding sheep on the content of fatty acids (FA), tocopherols, retinoids, and cholesterol of milk and cheese, and on the sensory properties of cheese. Indoor animal feeding (in winter) is the highest cost of production for cheesemakers, and the inclusion of locally produced rapeseed oilcake in the concentrate feed formulation can reduce the cost of cheese production, as long as the quality of the cheese is not altered. The experiment was carried out in March (mid lactation) with 72 Latxa sheep from an experimental farm located in the Basque Country (northern Spain). Two homogeneous groups of animals (n = 36) were set to receive each a different diet based on commercial or rapeseed concentrate, respectively, and forage (Festuca hay). Animal production parameters were individually recorded for each feeding group, whereas bulk milk from each group was used for cheesemaking trials. The rapeseed concentrate had higher amounts of unsaturated FA (mainly C18:1 cis isomers, C18:2 cis-9,cis-12 and C18:3 cis-9,cis 12,cis-15) and tocopherols than the commercial concentrate. The inclusion of rapeseed oilcake in the diet of dairy sheep did not compromise animal production parameters or milk gross composition. Bulk milk and cheese from sheep fed rapeseed concentrate showed higher content of unsaturated FA and tocopherols than those from sheep fed commercial concentrate. No differences were observed in the content of retinoid in milk and cheese between feeding groups, whereas the cholesterol content was slightly lower in cheese made with milk from sheep fed rapeseed concentrate. Thus, milk and cheese from sheep fed rapeseed concentrate had a healthier lipid profile. In addition, the inclusion of rapeseed oilcake in the diet of sheep did not change the typical sensory attributes of Protected Denomination of Origin Idiazabal cheese. Therefore, rapeseed concentrate could be a good local resource for feeding sheep to improve the nutritional quality of dairy products and to provide higher returns to farms. PMID- 28734603 TI - Determination of volatile organic compounds in pen inks by a dynamic headspace needle trap device combined with gas chromatography-mass spectrometry. AB - Some harmful volatile organic compounds (VOCs), such as methylbenzene, ethylbenzene, xylene, chlorobenzene and bromobenzene, are the commonly found chemicals in pen inks. In this work, a dynamic headspace needle-trap device (D-HS NTD) with a ZIF-8-derived nanoporous carbon (ZIF-8-NPC) as the adsorbent was developed for the extraction of some VOCs in different pen inks prior to GC-MS detection. The main important influencing experimental parameters including the flow rate of the purge gas N2, extraction temperature, extraction time, desorption temperature and desorption time for the extraction were optimized to obtain a high extraction efficiency. Under the optimized conditions, a good linearity was obtained in the concentration range of 0.1-400MUgkg-1 with the correlation coefficients (r) ranging from 0.9911 to 0.9990 for the eleven VOCs. The LODs at a signal-to-noise ratio of 3 (S/N=3) were measured to be 10-20ngkg-1 for the VOCs. The developed method was applied to determine the VOCs from 20 pen inks. The recoveries of the VOCs for the method at the spiking levels of 0.5 and 20.0MUgkg-1 fell in the range from 80.0% to 108%. PMID- 28734604 TI - A hybrid material as a sorbent phase for the disposable pipette extraction technique enhances efficiency in the determination of phenolic endocrine disrupting compounds. AB - In this study, the hybrid material 3-n-propyl(3-methylpyridinium) silsesquioxane chloride (Si3Py+Cl-) was synthesized and investigated as a novel sorbent phase for the disposable pipette extraction (DPX) technique coupled to high-performance liquid chromatography-florescence detection. This sorbent phase was characterized by scanning electron microscopy (SEM) and Fourier transform infrared spectroscopy (FTIR). Aqueous samples containing the phenolic endocrine-disrupting compounds bisphenol A (BPA), 17alpha-ethynylestradiol (EE2), 4-tert-octylphenol (4-t-OP), 4 octylphenol (4-OP) and 4-nonylphenol (4-NP) were subjected to DPX procedures and a series of optimizations was performed to determine the ideal extraction conditions using this approach. The proposed sorbent phase exhibited higher extraction efficiency than DPX-RP (reversed phase tips containing styrene divinylbenzene), commonly used for the determination of the phenolic endocrine- disrupting-compounds under study. Satisfactory analytical performance was achieved with linear ranges from 2 to 100MUgL-1 for 4-t-OP and 1-100MUgL-1 for the other analytes. Limits of detection of 0.60MUgL-1 for 4-t-OP and 0.30MUgL-1 for other analytes, RSDs ranging from 1 to 20% and relative recoveries of 83-116% were obtained. Based on these satisfactory results, this sorbent phase represents a valuable alternative for the extraction of compounds with polar moieties in their structure. PMID- 28734605 TI - Surface-bonded amide-functionalized imidazolium ionic liquid as stationary phase for hydrophilic interaction liquid chromatography. AB - The amide group modified silica materials are popular stationary phases for hydrophilic interaction liquid chromatography (HILIC). Meanwhile, surface confined imidazolium ionic liquids (ILs) have been proved to be useful HILIC stationary phases and possess many unique properties. In this study, the synthesis of an amide-functionalized imidazolium IL was conducted which was then bonded onto silica surface to obtain a novel imidazolium-embedded amide stationary phase for HILIC. The combination of the amide group and imidazolium IL moiety might bring some advantages in selectivity or retention and therefore extended its applications. After characterizing the prepared IL and the resulting modified silica materials, the chromatographic performance and separation selectivity of the packed column were evaluated and compared with a commercial amide column. Then, the retention behavior was investigated through observing the retention factors at different chromatographic conditions using a wide range of compounds. Exceptionally, the prepared amide IL column exhibited superior separation performance towards complex samples such as flavonoids mixture, soybean flavonoids and human urine. All the results indicated that the novel amide IL column possessed an anion-exchange/HILIC mixed-mode retention mechanism and could be useful in the sample analysis as a promising candidate for HILIC stationary phase. PMID- 28734606 TI - Thiol-yne click synthesis of boronic acid functionalized silica nanoparticle graphene oxide composites for highly selective enrichment of glycoproteins. AB - In this work, a facile novel strategy is developed for the preparation of 4 mercapto-phenylboronic acid functionalized silica nanoparticle-graphene oxide composite (GO@MPBA) via thiol-yne click reaction. The morphology, structure and composition of the resulting GO@MPBA was characterized by transmission electron microscopy, X-ray powder diffraction, Fourier transform infrared spectroscopy, Fourier transform Raman spectroscopy, Thermogravimetric analysis and X-ray photoelectron spectrometry. GO@MPBA exhibited the high binding capacity towards glycoproteins such as ovalbumin (1288.8mgg-1), immunoglobulin G (1144.1mgg-1), transferrin (592.1mgg-1) and horseradish peroxidase (392.4mgg-1), in contrast, the binding capacity of each non-glycoproteins (cytochrome c, deoxyribonuclease A, pepsin, trypsin, lysozyme and bovine serum albumin) is less than 50mgg-1. Furthermore, the GO@MPBA still remained a good binding capacity after the five times of adsorption-desorption cycles. The selective enrichment of glycoproteins from real egg white samples by GO@MPBA was demonstrated by sodium dodecyl sulfate polyacrylamide gel electrophoresis analysis. This work could present a facile novel approach of surface modification to design environmentally friendly and more efficient adsorbents for the isolation and enrichment of glycoprotein from complex biological samples. PMID- 28734607 TI - Impact of instrument and column parameters on high-throughput liquid chromatography performance. AB - The speed and separation performance of high-throughput liquid chromatography (HT LC) was investigated. We evaluated the contributions of various experimental parameters to the total analysis cycle time, including column length (column void time), gradient delay, flow rate, auto-sampler (A/S) speed, and software related delays. The best case injection-to-injection cycle time of 22s was achieved using 12s gradient time and 2.1*20mm columns packed with 1.7MUm C18 particles. The total 22s analytical duty cycle consisted of 2.5s column void time, 1.8s gradient delay, 12s gradient time, and approximately 5.7s for software setup delay time that served as column re-equilibration time. The achieved peak capacity for an alkylphenone sample was approximately 35, giving a peak production rate of 95 peaks per minute. We estimated the impact of LC system dispersion on peak capacity and peak production rate (peak capacity per unit of time). For HT LC scenarios (5-50mm columns and 4.8-120s long gradients) we observed that even a minor amount of system dispersion (2MUL2) reduces the achievable peak capacity and peak productivity rate significantly. HT LC-MS analysis using 2.1*5mm guard column with duty cycle of 22s was successfully demonstrated. PMID- 28734608 TI - Sequence-specific DNA solid-phase extraction in an on-chip monolith: Towards detection of antibiotic resistance genes. AB - Antibiotic resistance of bacteria is a growing problem and presents a challenge for prompt treatment in patients with sepsis. Currently used methods rely on culturing or amplification; however, these steps are either time consuming or suffer from interference issues. A microfluidic device was made from black polypropylene, with a monolithic column modified with a capture oligonucleotide for sequence selective solid-phase extraction of a complementary target from a lysate sample. Porous properties of the monolith allow flow and hybridization of a target complementary to the probe immobilized on the column surface. Good flow through properties enable extraction of a 100MUL sample and elution of target DNA in 12min total time. Using a fluorescently labeled target oligonucleotide related to Verona Integron-Mediated Metallo-beta-lactamase it was possible to extract and detect a 1pM sample with 83% recovery. Temperature-mediated elution by heating above the duplex melting point provides a clean extract without any agents that interfere with base pairing, allowing various labeling methods or further downstream processing of the eluent. Further integration of this extraction module with a system for isolation and lysis of bacteria from blood, as well as combining with single-molecule detection should allow rapid determination of antibiotic resistance. PMID- 28734609 TI - Reinforcements in avian wing bones: Experiments, analysis, and modeling. AB - Almost all species of modern birds are capable of flight; the mechanical competency of their wings and the rigidity of their skeletal system evolved to enable this outstanding feat. One of the most interesting examples of structural adaptation in birds is the internal structure of their wing bones. In flying birds, bones need to be sufficiently strong and stiff to withstand forces during takeoff, flight, and landing, with a minimum of weight. The cross-sectional morphology and presence of reinforcing structures (struts and ridges) found within bird wing bones vary from species to species, depending on how the wings are utilized. It is shown that both morphology and internal features increases the resistance to flexure and torsion with a minimum weight penalty. Prototypes of reinforcing struts fabricated by 3D printing were tested in diametral compression and torsion to validate the concept. In compression, the ovalization decreased through the insertion of struts, while they had no effect on torsional resistance. An elastic model of a circular ring reinforced by horizontal and vertical struts is developed to explain the compressive stiffening response of the ring caused by differently oriented struts. PMID- 28734610 TI - Towards integral utilization of grape pomace from winemaking process: A review. AB - Grape is the main fruit crop in several countries. Although many grape-based food products can be found in the market, studies have shown that around 75% of the world grape production is destined for the wine industry. Grape pomace is an abundant by-product from the wine industry, which consists of the remaining skin, seeds and stalks and represents around 25% of total grape weight used in the winemaking process. In countries such as Italy, France and Spain, where wine production is more relevant, the annual grape pomace generation can reach nearly 1200 tonnes per year. In order to reach a sustainable winemaking process there is a need of a waste reduction policy. Several studies explore this subject using grape pomace as a source of healthy and technological compounds that could be applied in animal feed, pharmaceutical, cosmetic or food industry to improve stability and nutritional characteristics, and in cosmetic industry, where grape seeds oil is widely used. This review aims to approach the recent winemaking scenario and the benefits achieved when a waste management policy is implemented, as well as to compare available extractive technologies and a wide alternative of uses for grape pomace. PMID- 28734611 TI - Survivorship of a Porous Tantalum Monoblock Acetabular Component in Primary Hip Arthroplasty With a Mean Follow-Up of 18 Years. AB - BACKGROUND: The use of porous tantalum for the acetabular component in primary total hip arthroplasty (THA) has demonstrated excellent short-term and midterm results. However, long-term data are scarce. The purpose of this prospective study is to report the long-term clinical and radiologic outcome following use of an uncemented porous tantalum acetabular component in primary THA with a minimum follow-up of 17.5 years, in a previously studied cohort of patients. METHODS: We prospectively followed 128 consecutive primary THAs in 140 patients, between November 1997 and June 1999. A press-fit porous tantalum monoblock acetabular component was used in all cases. All patients were followed clinically and radiographically for a mean of 18.1 years (range, 17.5-19 years). RESULTS: Mean age of patients at the time of operation was 60.4 years. Harris hip score, Oxford hip score, and range of motion were dramatically improved in all cases (P < .001). At last follow-up, all cups were radiographically stable with no evidence of migration, gross polyethylene wear, progressive radiolucencies, osteolytic lesions, or acetabular fractures. The survivorship with reoperation for any reason as end point was 92.8% and the survivorship for aseptic loosening as an end point was 100%. CONCLUSION: The porous tantalum monoblock cup in primary THA demonstrated excellent clinical and radiographic outcomes with no failures because of aseptic loosening at a mean follow-up of 18.1 years. PMID- 28734612 TI - Primary Total Knee Arthroplasty: How Does Residual Patellar Thickness Affect Patient-Oriented Outcomes? AB - BACKGROUND: Maintenance of the native patellar thickness has been deemed important for proper clinical outcomes after total knee arthroplasty (TKA). Our objective was to study the effects of the change in patellar thickness on patient perceived outcomes (PPOs) after TKA. We hypothesized that reestablishing native patellar thickness after TKA results in better PPOs. METHODS: 819 consecutive patients undergoing primary TKA were studied. Patients were classified according to their postoperative patellar thickness into: (1) less than native patella thickness; (2) equal to native patella thickness; and (3) greater than native patella thickness. Difference in postoperative range of motion (ROM), PPOs and clinical scores, and delta-Delta-change were assessed. MANCOVA was used to assess for differences. RESULTS: No significant differences found based on postoperative patellar thickness (mean follow-up: 4.9 +/- 2.1 years) for each ROM assessments. Those who reported more stiffness (Western Ontario and McMaster Universities Arthritis Index stiffness; P = .011) and lower knee active flexion (P = .046) preoperatively had "greater than native patella thickness" after surgery. Postoperatively, the "equal to native patella thickness" group reported significantly better quality of life (quality of well-being scale 7 total; P = .008) as well as better physical score (Short Form-36 role physical score; P = .03). The amount of improvement (delta-Delta-change), when restoring patellar thickness equal to the native demonstrated greatest improvements in quality of life (quality of well-being scale 7 total; P = .016) physical measures (Short Form-36 role physical [P = .025], and Western Ontario and McMaster Universities Arthritis Index stiffness scores [P = .006]). CONCLUSION: When compared with the native patellar thickness, a final postoperative difference (delta thickness) that ranges from -1.06 to 2.58 mm provides satisfactory results and does not seem to affect ROM after surgery. PMID- 28734613 TI - Obesity Does Not Affect Outcomes in Hybrid Versus Cemented Total Knee Arthroplasty in Asians. AB - BACKGROUND: This study aims to evaluate patient reported and functional outcomes following hybrid versus cemented total knee arthroplasty (TKA) in patients, stratified by body mass index (BMI). METHODS: Registry data of patients undergoing primary TKA between January 2004 and January 2013 were collected. Baseline interviews were conducted preoperatively to assess sociodemographic characteristics, BMI, and knee arthritis severity, using the Knee Society Score which consists of the Knee Society Knee Score and the Knee Society Function Score (KSFS) and Oxford Knee Score (OKS). These scores were collected prospectively, preoperatively, and postoperatively up to 2 years. Two-year outcomes and 5-year revision rates were then compared between (1) hybrid and cemented TKA groups and (2) BMI subclasses within the hybrid and cemented TKA groups. RESULTS: Patients who underwent cemented TKA had marginally better flexion range, KSFS, and OKS at 2 years postoperatively. In the overweight category, flexion range, KSFS, and OKS were marginally lower for hybrid TKAs. There were no differences in outcomes between the 2 groups in Class I and II obesity. Within the cemented TKA group, there were no differences in the outcomes between BMI subclasses. There were significant differences in the KSFS (0.023) and OKS (0.030) between the BMI subclasses within the hybrid TKA group, with patients in Class II obesity faring the worst. There was no statistically significant difference in the revision rates. CONCLUSION: We conclude that obesity does not affect outcomes in hybrid versus cemented TKA. PMID- 28734614 TI - Correlation of the Caprini Score and Venous Thromboembolism Incidence Following Primary Total Joint Arthroplasty-Results of a Single-Institution Protocol. AB - BACKGROUND: Venous thromboembolism (VTE), including pulmonary embolism (PE) and deep vein thrombosis, is a serious complication after total joint arthroplasty (TJA). Risk assessment models are increasingly used to provide patient-specific risk stratification. A recently implemented protocol mandates calculation of a Caprini Score for all surgical patients at our institution. We investigated the accuracy of the Caprini Score in predicting VTE events following TJA. METHODS: A retrospective review of patients undergoing primary total hip (THA) and total knee arthroplasty (TKA) over a 1-year time period was performed. The 90-day postoperative incidence of emergency department evaluations, hospital readmissions, medical complications, need for revision surgery, and symptomatic VTE was recorded. "Preoperative" Caprini Scores routinely recorded per protocol and calculated during review ("Calculated") were compared and assessed for relationship with VTE events. A "VTEstimator" Score was calculated for each patient. RESULTS: Three hundred seventy-six arthroplasties (151 TKA and 225 THA) meeting inclusion criteria were identified. Ten patients (2.5%) had symptomatic VTE postoperatively, with 3 pulmonary embolism (0.8%) and 7 deep vein thrombosis (1.8%). Eight VTE (5.3%) occurred following TKA and 2 (0.9%) occurred following THA. For each surgical characteristic evaluated, no significant difference was observed between mean Preoperative or Calculated Caprini Scores for patients with and without VTE (P > .05). Additionally, the distribution of VTEstimator Scores for patients with and without VTE was not significantly different (P = .93). CONCLUSION: The Caprini risk assessment model does not appear to provide clinically useful risk stratification for TJA patients. Alternative risk stratification protocols may provide assistance in balancing safety and efficacy of thromboprophylaxis. PMID- 28734615 TI - Highly Cross-Linked Polyethylene Reduces Osteolysis Incidence and Wear-Related Reoperation Rate in Cementless Total Hip Arthroplasty Compared With Conventional Polyethylene at a Mean 12-Year Follow-Up. AB - BACKGROUND: A number of studies on total hip arthroplasty have compared highly cross-linked polyethylene (HXLPE) with conventional polyethylene (CPE) liners beyond 10 years. However, the impact of HXLPE on the wear-related reoperation rate is unclear. The purpose of this study was to evaluate the clinical advantage of using a single manufacturer's HXLPE in terms of reducing the reoperation rate. METHODS: The study was a follow-up retrospective cohort study over a mean of 12 years that examined patients aged 45-70 years with cementless total hip arthroplasty using a 26-mm-diameter cobalt-chromium head. Sixty-seven patients (79 hips; HXLPE group = 41 hips, CPE group = 38 hips) were evaluated for a minimum 10-year follow-up. Kaplan-Meier survival analysis was performed, with wear-related reoperations and radiographic osteolysis serving as the end points. The polyethylene wear rate was also assessed. RESULTS: The mean 12-year follow-up rates of survivorship that were evaluated using wear-related reoperations as the end point were 100% and 91.4% in the HXLPE and CPE groups, respectively (P = .007), and the mean 12-year follow-up rates of survivorship with osteolysis as the end point were 100% and 36.2%, respectively (P < .001). Compared with the CPE group, the HXLPE group presented a significantly reduced wear rate (HXLPE group, 0.035 mm/y; CPE group, 0.118 mm/y). CONCLUSION: A unique strength of this study is that we assessed a single manufacturer's HXLPE while keeping most other implant parameters uniform. This study reveals the clinical advantage of using a single manufacturer's HXLPE in terms of a reduced wear-related reoperation rate at a mean 12-year follow-up. PMID- 28734617 TI - Epidemiology, Evolution, and Pathogenesis of H7N9 Influenza Viruses in Five Epidemic Waves since 2013 in China. AB - H7N9 influenza viruses were first isolated in 2013 and continue to cause human infections. H7N9 infections represent an ongoing public health threat that has resulted in 1344 cases with 511 deaths as of April 9, 2017. This highlights the continued threat posed by the current poultry trade and live poultry market system in China. Until now, there have been five H7N9 influenza epidemic waves in China; however, the steep increase in the number of humans infected with H7N9 viruses observed in the fifth wave, beginning in October 2016, the spread into western provinces, and the emergence of highly pathogenic (HP) H7N9 influenza outbreaks in chickens and infection in humans have caused domestic and international concern. In this review, we summarize and compare the different waves of H7N9 regarding their epidemiology, pathogenesis, evolution, and characteristic features, and speculate on factors behind the recent increase in the number of human cases and sudden outbreaks in chickens. The continuous evolution of the virus poses a long-term threat to public health and the poultry industry, and thus it is imperative to strengthen prevention and control strategies. PMID- 28734618 TI - Association of Asthma Illness Representations and Reported Controller Medication Adherence Among School-Aged Children and Their Parents. AB - This study examined the relationship between asthma illness representations and reported controller medication adherence of school-aged children (6-11 years) with persistent asthma and their parents. Thirty-four parent-child dyads independently reported on asthma controller medication adherence and asthma illness representations. Hierarchical regression analyses were used to test parent and child illness representation domain variables as predictors of reported medication adherence. Parent beliefs about medication necessity versus concerns was a significant predictor of parent-reported adherence (beta = .55, p < .01), and child treatment control was also a significant predictor of parent reported adherence (beta = -.50, p < .01). Child beliefs about medication necessity versus concerns was a significant predictor of child-reported adherence (beta = .50, p < .01), and no parent variables reached significance. Although there are similarities between parent and child asthma illness representations, findings indicate that school-aged children develop illness representations somewhat independently from their parents and, therefore, are critical participants in both asthma care and research. PMID- 28734619 TI - Fibromyalgia: Prevalence, epidemiologic profiles and economic costs. AB - Fibromyalgia is an idiopathic chronic condition that causes widespread musculoskeletal pain, hyperalgesia and allodynia. This review aims to approach the general epidemiology of fibromyalgia according to the most recent published studies, identifying the general worldwide prevalence of the disease, its basic epidemiological profiles and its economic costs, with specific interest in the Spanish and Comunidad Valenciana cases. Fibromyalgia affects, on average, 2.10% of the world's population; 2.31% of the European population; 2.40% of the Spanish population; and 3.69% of the population in the Comunidad Valenciana. It supposes a painful loss of the quality of life of the people who suffer it and the economic costs are enormous: in Spain is has been estimated at more than 12,993 million euros annually. PMID- 28734616 TI - Do Shoot the Messenger: PASTA Kinases as Virulence Determinants and Antibiotic Targets. AB - All domains of life utilize protein phosphorylation as a mechanism of signal transduction. In bacteria, protein phosphorylation was classically thought to be mediated exclusively by histidine kinases as part of two-component signaling systems. However, it is now well appreciated that eukaryotic-like serine/threonine kinases (eSTKs) control essential processes in bacteria. A subset of eSTKs are single-pass transmembrane proteins that have extracellular penicillin-binding-protein and serine/threonine kinase-associated (PASTA) domains which bind muropeptides. In a variety of important pathogens, PASTA kinases have been implicated in regulating biofilms, antibiotic resistance, and ultimately virulence. Although there are limited examples of direct regulation of virulence factors, PASTA kinases are critical for virulence due to their roles in regulating bacterial physiology in the context of stress. This review focuses on the role of PASTA kinases in virulence for a variety of important Gram-positive pathogens and concludes with a discussion of current efforts to develop kinase inhibitors as novel antimicrobials. PMID- 28734620 TI - Treatment of dogs with compensated myxomatous mitral valve disease with spironolactone-a pilot study. AB - OBJECTIVES: Spironolactone improves outcome in dogs with advanced myxomatous mitral valve disease (MMVD). Its efficacy in preclinical MMVD is unknown. The hypothesis was the administration of spironolactone to dogs with compensated MMVD demonstrating risk factors for poorer prognosis will decrease the rate of disease progression. The aim was to provide pilot data to evaluate preliminary effects and sample size calculation for a definitive clinical trial. ANIMALS: Twenty-five client-owned dogs with MMVD with at least one of the following; left atrial to aortic ratio (LA:Ao) >= 1.5, normalized left ventricular internal diameter in diastole >= 1.6), N-terminal pro-B-type natriuretic peptide (NT-proBNP) > 550 pmol/L, cardiac troponin I > 0.025 ng/mL. METHODS: Prospective, single-center, equally randomized, placebo-controlled, double-blinded, parallel grouped pilot study. No dogs were receiving medications for cardiac disease before the enrollment. RESULTS: Twelve dogs received placebo; 13 received spironolactone. One dog in the spironolactone group died suddenly, 1 developed congestive heart failure, and 2 received suboptimal spironolactone doses. At enrollment, NT-proBNP was significantly higher in the spironolactone group (p=0.005). Left atrial to aortic ratio (p=0.002) and left ventricular internal diameter in diastole (p=0.005) increased over time in the placebo group, but not the spironolactone group; the change did not differ significantly between groups. The change in biomarker concentrations did not differ significantly between groups; there was a tendency toward an increase in NT-proBNP over time in the placebo group. Enrollment of 76 dogs would be necessary to demonstrate a difference in the change in LA:Ao over 6 months between the groups. CONCLUSIONS: Preliminary results support undertaking a larger clinical trial of treatment of dogs with preclinical MMVD with spironolactone. PMID- 28734621 TI - Use of n-butyl cyanoacrylate to reduce left to right shunting of an abdominal arteriovenous malformation in a dog. AB - A 9-month old castrated male Labradoodle presented to the cardiology service at Purdue University for evaluation of a low-grade murmur. Physical examination, thoracic radiography, and echocardiography were strongly supportive of an extracardiac left-to-right shunt. Subsequent evaluation with nuclear scintigraphy and computed tomography angiography revealed a large, complex arteriovenous malformation within the cranial abdomen. Staged interventional attenuation of the shunt was performed using n-butyl cyanoacrylate that resulted in a reduction in echocardiographic and nuclear scintigraphy derived shunt estimation. PMID- 28734622 TI - Mild to moderate clozapine-induced gastrointestinal hypomotility should not require cessation of clozapine. PMID- 28734624 TI - Discussion. PMID- 28734623 TI - Eight-year follow-up of the Clopidogrel After Surgery for Coronary Artery Disease (CASCADE) trial. AB - OBJECTIVE: In this 8 years' follow-up study, we evaluated the long-term outcomes of the addition of clopidogrel to aspirin during the first year after coronary artery bypass grafting, versus aspirin plus placebo, with respect to survival, major adverse cardiac, or major cerebrovascular events, including revascularization, functional status, graft patency, and native coronary artery disease progression. METHODS: In the initial Clopidogrel After Surgery for Coronary Artery Disease trial, 113 patients were randomized to receive either daily clopidogrel (n = 56) or placebo (n = 57), in addition to aspirin, in a double-blind fashion for 1 year after coronary artery bypass grafting. All patients were re-evaluated to collect long-term clinical data. Surviving patients with a glomerular filtration rate > 30 mL/min were asked to undergo a coronary computed tomography angiogram to evaluate the late saphenous vein graft patency and native coronary artery disease progression. RESULTS: At a median follow-up of 7.6 years, survival rate was 85.5% +/- 3.8% (P = .23 between the 2 groups). A trend toward enhanced freedom from all-cause death or major adverse cardiac or cerebrovascular events, including revascularization, was observed in the aspirin clopidogrel group (P = .11). No difference in functional status or freedom from angina was observed between the 2 groups (P > .57). The long-term patency of saphenous vein graft was 89.11% in the aspirin-clopidogrel group versus 91.23% in the aspirin-placebo group (P = .79). A lower incidence of moderate to severe native disease progression was observed in the aspirin-clopidogrel group versus the aspirin-placebo group (7 out of 122 vs 13 out of 78 coronary segments that showed progression, respectively [odds ratio, 0.3 +/- 0.2; 95% confidence interval, 0.1-0.8; P = .02]). CONCLUSIONS: At 8 years' follow-up, the addition of clopidogrel to aspirin during the first year after coronary artery bypass grafting exhibited a lower incidence of moderate to severe progression of native coronary artery disease and a trend toward higher freedom from major adverse cardiac or cerebrovascular events, including revascularization, or death in the aspirin-clopidogrel group. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov. Unique identifier: NCT00228423. PMID- 28734625 TI - Preoperative determination of artificial chordae length with 320-slice computed tomographic images. PMID- 28734626 TI - Staged treatment of mega aortic syndrome using the frozen elephant trunk and hybrid thoracoabdominal repair. AB - OBJECTIVE: We report our experience with a staged hybrid approach for the treatment of extended aortic disease, also known as "mega aortic syndrome." METHODS: A total of 15 patients (10 male, 5 female) underwent staged repair of the thoracoabdominal aorta, consisting of 3 separate stages (repair of ascending aorta and aortic arch using the frozen elephant trunk technique and hybrid thoracoabdominal repair with debranching of the renovisceral branches and stent graft implantation). RESULTS: The procedure was completed in 14 patients. After the first stage (repair of ascending aorta and aortic arch), no mortality or spinal cord ischemia occurred. One patient required temporary dialysis. After the thoracoabdominal repair, permanent paraplegia developed in 1 patient. One patient died intraoperatively after aneurysm rupture. The in-hospital mortality for the complete repair reached 6.7%. None of the surviving patients required permanent dialysis. Interval aortic events consisted of 1 contained rupture. CONCLUSIONS: The concept of a staged hybrid repair of the mega aortic syndrome is technically feasible. The frozen elephant trunk technique represents an attractive treatment option, offering an adequate landing zone for later thoracoabdominal repair in patients with extended aortic disease. For completion of the repair, a staged hybrid approach with renovisceral debranching and aneurysm exclusion using off the-shelf stent grafts shows promising results with low surgical morbidity and mortality. PMID- 28734627 TI - The impact of frailty on functional survival in patients 1 year after cardiac surgery. AB - OBJECTIVE: This study determined whether frailty provides incremental value to the European System for Cardiac Operative Risk Evaluation II in identifying patients at risk of poor 1-year functional survival. METHODS: This prospective study in patients undergoing cardiac surgery defined frailty using 3 common definitions: (1) the Modified Fried Criteria; (2) the Short Physical Performance Battery; and (3) the Clinical Frailty Scale. The primary outcome was functional survival, defined as being alive at 1 year postsurgery with a health-related quality of life score greater than 60 on the EuroQol-Visual Analogue Scale. RESULTS: Of the 188 participants, 49.5%, 52.6%, and 31.9% were deemed frail according to the Modified Fried Criteria, Short Physical Performance Battery, and Clinical Frailty Scale, respectively. The median age of our cohort was 71.0 years (29.3% female). The probability of functional survival at 1 year for the entire cohort was 73.9%. After adjusting for the European System for Cardiac Operative Risk Evaluation II, patients deemed frail under the Modified Fried Criteria, Short Physical Performance Battery, and Clinical Frailty Scale had an increased odds ratio for poor functional survival of 3.44, 3.47, and 2.08, respectively. When compared with the European System for Cardiac Operative Risk Evaluation II alone, the Modified Fried Criteria, Short Physical Performance Battery, and Clinical Frailty Scale showed an absolute improvement in the discrimination slope of 6.7%, 6.5%, and 2.4% with a category-free classification improvement of 59.6%, 59.2%, and 35.1%, respectively. CONCLUSIONS: Preoperative frailty was associated with a 2- to 3.5-fold higher risk of poor functional survival 1 year after cardiac surgery. The addition of frailty to the European System for Cardiac Operative Risk Evaluation II provides incremental value in identifying patients at risk of poor functional survival 1 year postsurgery, regardless of frailty definition. PMID- 28734629 TI - Shewanella putrefaciens necrotizing fasciitis of the lower limb. PMID- 28734628 TI - Adrenergic receptor genotypes influence postoperative outcomes in infants in the Single-Ventricle Reconstruction Trial. AB - OBJECTIVES: Adrenergic receptor (ADR) genotypes have been associated with adverse outcomes in heart failure. Our objective was to evaluate the association of ADR genotypes with post-Norwood outcomes in infants with hypoplastic left heart syndrome (HLHS). METHODS: Infants with HLHS participating in the Pediatric Heart Network Single-Ventricle Reconstruction Trial underwent genotyping for 4 single nucleotide polymorphisms in 3 ADR genes: ADRB1_231A/G, ADRB1_1165G/C, ADRB2_5318C/G, and ADRA2A_2790C/T. The association of genotype with freedom from serious adverse events (SAEs) (death, transplant, extracorporeal membrane oxygenation, cardiopulmonary resuscitation, acute shunt failure, unplanned reoperations, or necrotizing enterocolitis) during 14 months' follow-up was assessed with Cox regression and the association with post-Norwood complications was assessed with Poisson regression. Models were adjusted for clinical and surgical factors. RESULTS: The study included 351 eligible patients (62% male; 83% white). The mean age at Norwood procedure was 5.6 +/- 3.6 days. A total of 152 patients had SAEs during 14-month follow-up including 84 deaths and 10 transplants. ADRA2A_2790CC genotype had lower SAE-free survival compared with CT/TT genotypes during follow-up (Log rank test, P = .02), and this association was independent of clinical and surgical risk factors (adjusted Cox regression, hazard ratio 1.54 [95% confidence interval 1.04, 2.30] P = .033). Post-Norwood complication rate did not differ by genotype. CONCLUSIONS: Infants with HLHS harboring ADR genotypes that are associated with greater catecholamine release or sensitivity had lower event-free survival after staged palliation. Excess catecholamine activation may adversely affect cardiovascular adaptation after the Norwood procedure. Future studies should explore whether targeting adrenergic activation in those harboring risk genotypes can improve outcomes. (ClinicalTrials.gov number NCT00115934). PMID- 28734630 TI - Management of an Acinetobacter baumannii outbreak in an intensive care unit. AB - INTRODUCTION: Acinetobacter baumannii is a ubiquitous pathogen resistant to desiccation and responsible for healthcare-associated infections (HAI), especially in intensive care units (ICU) where it is responsible for 5-10% of HAIs. An A. baumannii outbreak occurred in the ICU of the University Hospital of Angers, France. OBJECTIVES: To describe the A. baumannii outbreak and to evaluate the control measures taken. The secondary objective was to evaluate the impact of the electronic alert system on the incidence of multidrug resistance to antibiotics. METHODS: We performed a descriptive study of A. baumannii carriers during the outbreak. Case contacts and carriers were described using the epidemic curve and a case synopsis table. RESULTS: From August 2011 to September 2013, 49 patients presenting with an extended-spectrum beta-lactamase-producing A. baumannii infection were identified: thirty-four were colonized and 15 were infected. No death was due to the outbreak. Measures taken were: geographical and technical isolation of patients, dedicated team implementation, contact precaution implementation including hand hygiene measures, appropriate use of gloves, and reinforcement of bio-cleaning procedures. CONCLUSION: Some patients were re-admitted to hospital while still being carriers; this could explain epidemic peaks. The immersion mission of the hygiene nurse contributed to answering healthcare workers' queries and led to a better cooperation between the ICU and the hygiene team. PMID- 28734631 TI - Sexting and the Definition Issue. AB - Sexting among youths has become a necessary topic of interest in research because of the negative consequences that this activity could create, especially when content is shared with others. Indeed, this loss of control could lead to humiliation, (cyber)bullying, or harassment. The development of new technologies, press coverage, and increase of prevalence rates could also explain the growth of interest in sexting. However, its definition is still a gray area. This review examines the different definitions of sexting used in the literature and its correlates. Several elements of the definition of sexting were assessed: actions (sending, receiving, and forwarding); media types (text, images, and videos); sexual characteristics; and transmission modes. Nine databases were searched for studies on sexting among youths up to 18 years of age. Eighteen studies published between 2012 and 2015 were included. Prevalence rates of sexting ranged between .9% and 60% partly depending on the definition. Most studies assessed sending, but when sending and receiving were measured, prevalence rates were higher for receiving. Some articles found associations with age, gender, race, sexual behavior, romantic relationships, risky behaviors, online activity, psychological difficulties, and social pressure. Finding a consensus regarding the definition is essential to assess accurately the activity and adapt prevention. Adolescents' interpretations of the activity are important as sexting could be used as a sexual behavior between two consenting persons. Prevention strategies should focus on sexting that goes wrong when it is forwarded to a third party and when it occurs in a context of pressure or harassment. PMID- 28734633 TI - Clinically meaningful benefit: Half of the value equation. PMID- 28734632 TI - Expectancy and Achievement Gaps in Educational Attainment and Subsequent Adverse Health Effects Among Adolescents With and Without Chronic Medical Conditions. AB - PURPOSE: While education-based disparities in health are common, the extent to which chronic conditions contribute to education gaps and to consequent health disparities is not fully understood. As such, we sought to investigate educational aspirations, expectations, and attainment among youth with and without chronic conditions and to determine if these relationships mediated subsequent disparities in health and well-being. METHODS: Longitudinal data on 3,518 youths are from the 1997-2013 Panel Study of Income Dynamics, a population based survey. Multivariate regression was used to assess disparities in educational aspirations, expectations, and attainment by chronic conditions and the subsequent effects on health and well-being, adjusting for important potential confounders. RESULTS: Youth with chronic medical conditions (YCMCs) did not report significantly lower educational aspirations than their healthy peers; however, YCMC reported lower expectations for their educational attainment and fewer YCMC had earned their desired degree by the end of follow-up (e.g., >=bachelor's degree: 19.9% for YCMC vs. 26.0% for peers, p < .05). YCMC reported significantly worse general health, lower life satisfaction, and lower psychological well-being in young adulthood than did their healthy peers. These disparities persisted after adjustment for confounders; the association between chronic disease and health was partially, but significantly, mediated by actual educational attainment. CONCLUSIONS: Findings suggest an important risk mechanism through which YCMC may acquire socioeconomic disadvantage as they develop and progress through educational settings. Disproportionate lags in education, from expectation to attainment, may in turn increase YCMC's susceptibility to poor health and well-being in the future. PMID- 28734634 TI - Immediate implant placement: the fate of the buccal crest. A retrospective cone beam computed tomography study. AB - This retrospective study aimed to analyse the fate of the buccal crest after immediate implant placement (IIP) through the use of cone beam computed tomography (CBCT). In 16 consecutive patients, an implant was placed in a more palatal position after extraction, thereby creating a gap of at least 2mm between the implant and the buccal crest. Subsequently, this gap was filled with a bone substitute. Preoperatively, immediate postoperatively, and late postoperatively, a CBCT was made to measure the thickness of the buccal crest. After application of the bone substitute, the buccal crest increased in thickness from 0.9mm to 2.4mm (mean). At a mean of 103 weeks after IIP, late postoperative CBCT scans showed that the thickness of the buccal crest was compacted to 1.8mm. In the same period, the height of the buccal crest increased by 1.6mm (mean) to, on average, 1.2mm above the implant shoulder. The aesthetic outcome was analysed using the White and Pink Esthetic Score (WES and PES). Both scored high: 8.4 and 11.8, respectively. Within the limitations of this study, the results of this IIP protocol are promising. Long-term prospective research on this topic on a large number of patients is necessary. PMID- 28734636 TI - [Clinical and genetic aspects of albinism]. AB - Albinism is a genetic disease affecting 1/17,000 person worldwide. It constitutes the second cause of congenital loss of visual acuity after optic atrophy. Albinism is heterogeneous both at the clinical and genetic levels. It is characterized by ocular development anomalies and by a variable degree of hypopigmentation. Clinically, three forms of the disease are described: oculocutaneous, ocular and syndromic (Hermansky-Pudlak syndrome, Chediak-Higashi syndrome). Nineteen genes involved in the different types of albinism have been described so far. The broad phenotypic variability between the different forms but also within a particular form renders the establishment of phenotype-genotype correlations impossible. A genetic test exploring all 19 genes is necessary to establish the diagnosis and to distinguish between syndromic and non-syndromic forms. We present the creation of an albinism-dedicated Day Hospital at the University Hospital of Bordeaux. PMID- 28734637 TI - [Asthma and heroin use]. AB - INTRODUCTION: Heroin use can be responsible for many respiratory complications including asthma. OBJECTIVES: Systematic literature review of data on asthma in heroin users. DOCUMENTARY SOURCES: Medline(r), on the period 1980-2017 with the following keywords: keywords: "asthma" or "bronchospasm" and "heroin" or "opiate" or "opiates", limits "title/abstract"; the selected languages were English or French. Among 97 articles, 67 abstracts have given use to a dual reading to select 23 studies. RESULTS: The seven case reports included 21 patients (mean age: 28 years [19-46 years]; sex-ratio: 2.5 [males: 71.5%]). Heroin was inhaled (71.4%), sniffed (19%) or injected by intravenous route (9.5%). Associated addictive substances were tobacco (81%), cannabis (38%), alcohol (4.7%) and cocaine (4.7%). Outcome was fatal in 3 subjects (14.3%). Other studies included one cross-sectional study, 3 case-control studies and 12 longitudinal studies (11 retrospective studies and one prospective study). The proportion of heroin users was higher in asthmatic subjects and the prevalence of asthma and bronchial hyperreactivity was higher in heroin users. Heroin use can be responsible for asthma onset, with a temporal relationship between the onset of heroin use and asthma onset in 28 to 31% of subjects. A positive association between inhaled heroin use and acute asthma exacerbation was observed. Asthma treatment observance was lower in heroin users. In case of asthma exacerbation, heroin users were more likely to seek care in the emergency department, to be admitted in intensive care units and to require intubation and invasive ventilation. Asthma deaths related to heroin use mainly occurred following an intravenous injection (especially in the case of overdose), but also following heroin use by nasal (sniff) or pulmonary route. CONCLUSION: Heroin use may be responsible for asthma onset, acute asthma exacerbations (which may require intubation and invasive ventilation) or deaths related to asthma. Heroin use must be sought in case of asthma exacerbation in young persons and practitioners must help heroin users to stop their consumption. PMID- 28734635 TI - Programmed Cell Death and Inflammation: Winter Is Coming. AB - The life of an organism requires the assistance of an unlikely process: programmed cell death. Both development and the maintenance of homeostasis result in the production of superfluous cells that must eventually be disposed of. Furthermore, programmed cell death can also represent a defense mechanism; for example, by depriving pathogens of a replication niche. The responsibility of handling these dead cells falls on phagocytes of the immune system, which surveil their surroundings for dying or dead cells and efficiently clear them in a quiescent manner. This process, termed efferocytosis, depends on cooperation between the phagocyte and the dying cell. In this review we explore different types of programmed cell death and their impact on innate immune responses. PMID- 28734638 TI - [Annular sarcoidosis]. PMID- 28734640 TI - Does telomerase activity have an effect on infertility in patients with endometriosis? Methodological issues. PMID- 28734641 TI - [Towards the end of the French contradiction regarding embryo diagnosis]. PMID- 28734639 TI - FFA4/GPR120: Pharmacology and Therapeutic Opportunities. AB - Free Fatty Acid receptor 4 (FFA4), also known as GPR120, is a G-protein-coupled receptor (GPCR) responsive to long-chain fatty acids that is attracting considerable attention as a potential novel therapeutic target for the treatment of type 2 diabetes mellitus (T2DM). Although no clinical studies have yet been initiated to assess efficacy in this indication, a significant number of primary publications and patents have highlighted the ability of agonists with potency at FFA4 to improve glucose disposition and enhance insulin sensitivity in animal models. However, the distribution pattern of the receptor suggests that targeting FFA4 may also be useful in other conditions, ranging from cancer to lung function. Here, we discuss and contextualise the basis for these ideas and the results to support these conclusions. PMID- 28734642 TI - Extreme hypofractionation for high-risk prostate cancer: Dosimetric correlations with rectal bleeding. AB - PURPOSE: We explored the association of dosimetric parameters with late rectal bleeding among high-risk prostate cancer patients treated with hypofractionated simultaneous in-field boost (H-SIB) to prostate with nodal treatment. METHODS AND MATERIALS: Rectal toxicity results and dose-volume histogram (DVH) information from patients treated on FASTR and SATURN were combined. Patients in both trials received long-term androgen deprivation and H-SIB with prescription dose 40 Gy to the prostate and proximal seminal vesicles and 25 Gy to the lymph nodes delivered over 5 weekly fractions using image guidance with cone beam computed tomography. Mean rectal DVH values at 5-Gy intervals and mean DVH curves were compared between patients with rectal bleeding (B) versus no bleeding (NB). RESULTS: There were 12 B and 33 NB patients in the pooled group. Rectal bleeding was more frequent and of higher grade among FASTR patients (8/15, 5 grade 2 or higher) than among SATURN patients (4/30, all grade 1). For any bleeding (grade >=1), individual dose-volume points in the 20 to 40 Gy range were significantly different (2-sided P < .05) between the B and NB groups, with the 40 Gy point being the most significant (B: V40 = 1.53%, standard deviation (SD), 1.32; NB: V40 = 0.69%, SD, 1.46; P = .006). For grade >=2 bleeding, the V20 Gy was most significant (B: 68.4%, SD, 4.76; NB: 40.45%, SD, 13.9; P < .001). CONCLUSIONS: The higher relative dose volumes to the rectum (V20-V40) were most strongly associated with clinically significant bleeding in this analysis and are consistent with findings of series that used H-SIB to treat prostate only. Differences in the prostate target volumes and planning margins likely account for the differences in the rates and grades of rectal bleeding observed between trials. PMID- 28734643 TI - Where evidence meets experience. PMID- 28734644 TI - Postmastectomy radiation therapy technique and cardiopulmonary sparing: A dosimetric comparative analysis between photons and protons with free breathing versus deep inspiration breath hold. AB - PURPOSE: Dosimetric studies have suggested greater cardiopulmonary sparing with protons over photons for left-sided postmastectomy radiation therapy (PMRT). Modern techniques such as deep inspiration breath hold (DIBH) can help spare the heart. This analysis compares photon and proton delivery with and without DIBH. METHODS AND MATERIALS: Ten women with left breast cancer referred for PMRT on a prospective clinical trial with unfavorable cardiac anatomy underwent free breathing (FB) and DIBH computed tomography simulation. A partially wide tangent photon (PWTF) during DIBH, passively scattered proton during FB, pencil-beam scanning (PBS) proton during FB, and PBS proton during DIBH plan was completed for each patient. Plans were designed to achieve 95% prescription dose coverage to 95% of chest wall and regional lymphatics while maximally sparing heart and lungs. RESULTS: All techniques resulted in similar target coverage, although protons improved homogeneity indices and cardiopulmonary sparing (omnibus P < .0001 for each metric). Heart/lung metrics for PWTF with DIBH, scattered protons with FB, PBS protons with FB, and PBS protons with DIBH, respectively, were as follows: mean heart dose (2.09, 0.39, 0.98, 0.71 Gy relative biological effectiveness [RBE]), mean left ventricle dose (3.72, 0.08, 0.19, 0.21 GyRBE), V20 left ventricle (2.73, 0.03, 0, 0%), maximum left anterior descending artery dose (46.14, 8.28, 4.58, 4.63 GyRBE), mean lung dose (13.30, 5.74, 7.63, 7.49 GyRBE), and V20 lung (26.04, 12.04, 15.18, 14.43 %). Pairwise testing confirmed an improvement in each metric with all proton plans compared with PWTF with DIBH; there were no differences in homogeneity indices or cardiopulmonary sparing between passively scattered and PBS protons, regardless of addition of DIBH. CONCLUSIONS: For left-sided PMRT, passively scattered or PBS protons with or without DIBH improves homogeneity and cardiopulmonary sparing without compromise in target coverage compared with PWTF photons with DIBH. Furthermore, the addition of DIBH to proton therapy did not provide a significant dosimetric benefit. PMID- 28734645 TI - Computational study of the competitive binding of valproic acid glucuronide and carbapenem antibiotics to acylpeptide hydrolase. AB - The efficacy of the antiepileptic drug VPA is decreased by co-administered carbapenems (CBPMs). The mechanism of CBPM selective inhibition of acylpeptide hydrolase (APEH) hydrolysis of VPA-glucuronide (VPA-G) to VPA is unclear due to the lack of APEH structural information. Here we performed homology modeling of the three-dimensional structure of APEH and subsequent docking simulations with a modeled structure to understand this mechanism. Docking simulations indicated that four groups of binding structures were involved in the binding of VPA-G, panipenem, and meropenem to APEH, but only one or two binding structures were involved in the binding of meropenem with an open beta-lactam ring structure and other antibiotics involving ampicillin. One of the four VPA-G binding structures was close enough to the APEH catalytic triad to facilitate VPA-G hydrolysis. This binding structure was also the most stable binding structure for panipenem, suggesting potential inhibition of VPA-G hydrolysis by panipenem. Fragment molecular orbital calculations of interaction energies of amino acid residues of APEH with VPA-G, panipenem, and meropenem indicated that the binding structure for panipenem closest to the catalytic triad is stabilized upon APEH interaction. These data suggest that APEH binding characteristics with CBPMs may help explain the selective inhibition of APEH by CBPMs. PMID- 28734647 TI - Rare Root Canal Configuration of Mandibular Second Premolar Using Cone-beam Computed Tomographic Scanning. AB - The aim of this case report was to demonstrate how the use of cone-beam computed tomographic (CBCT) imagery is beneficial when treating a tooth with an unusual anatomic variation. A 43-year-old female patient presented to our private practice after a referral from her general dentist. Endodontic therapy was previously initiated and unable to be completed because of suspicious anatomic anatomy. CBCT imagery confirmed the presence of a C-shaped root configuration and 3 canals within the tooth. Root canal treatment was completed successfully without complications. The use of CBCT imaging was valuable in determining the root morphology and rare canal anatomy to enhance treatment and success. PMID- 28734646 TI - Quantitative prediction of therapeutic antibody pharmacokinetics after intravenous and subcutaneous injection in human. AB - Prediction of the plasma/serum mAb concentration-time profile in human is important to determine the required dose regime. This study proposes an approach for predicting the plasma/serum mAb concentration-time profile after intravenous and subcutaneous injection in human based on comprehensive analysis of reported pharmacokinetic data. Optimal scaling exponents from cynomolgus monkey to human for CL, Q, Vc, and Vp were estimated as 0.8, 0.75, 1.0, and 0.95, respectively. The estimated exponents were used to predict plasma/serum mAb concentration-time profile in human from pharmacokinetic data in cynomolgus monkey, and the results had reasonable accuracy with symmetric variability of prediction. Then, data reported for pharmacokinetics in human were used to estimate optimal ka and F after subcutaneous injection. The geometric mean of ka was suitable to predict Tmax, and F which was estimated from CL was suitable to predict Cmax. Our approach is useful for predicting the plasma/serum mAb concentration-time profile after intravenous and subcutaneous injection in human. Moreover, the study also investigated the possibility of predicting pharmacokinetic parameters of mAbs with increased FcRn binding mutations in human and found that our approach of prediction based on reported pharmacokinetic data may also be applicable to mAbs with these mutations. PMID- 28734648 TI - Minimally Invasive Treatment of Class 4 Invasive Cervical Resorption with Internal Approach: A Case Series. AB - Invasive cervical resorption (ICR) is a type of external resorption that can involve the coronal, middle, and apical parts of the root in its advanced stages. The diagnosis and treatment of ICR depend on the extent of the resorption into the dentin. The treatment of advanced ICR is challenging, and these teeth have poor prognoses. This article describes 4 cases of class 4 ICR diagnosed by using cone-beam computed tomography and treated with a minimally invasive internal approach with sodium hypochlorite irrigation and calcium hydroxide dressing. All cases were followed for at least 3 years. PMID- 28734649 TI - Maxillary and Mandibular Non-Hodgkin Lymphoma with Concurrent Periapical Endodontic Disease: Diagnosis and Management. AB - Extranodal non-Hodgkin lymphoma (NHL) in the oral region can present similarly to diseases of odontogenic origin. The objective of this report was to describe a rare case of maxillary and mandibular NHL that presented similarly to and concurrently with lesions of odontogenic origin.A unique case of extranodal NHL, which presented at the apices of maxillary and mandibular teeth in conjunction with lesions of odontogenic origin in a 68-year-old white man, is described. The patient sought care because of a lesion in the right maxillary paranasal region that caused him paresthesia. Radiographically, periapical radiolucencies were present along teeth #5-8, #23 and 24, and #30 and 31. Biopsies of the right maxillary and anterior mandibular lesions were completed and led to a diagnosis of NHL at the apices of teeth #5-8 extending to the hard palate and granulation tissue at the apices of teeth #23 and 24. Two years later, the patient returned because of pressure and sensitivity associated with teeth #30 and 31. Vestibular swelling was noted clinically, and a multilocular periapical radiolucency was present radiographically. Via endodontic therapy and a positron emission tomographic scan, the lesion associated with teeth #30 and 31 was determined to be of both odontogenic and nonodontogenic origin because it possessed both a sinus tract associated with tooth #30 and NHL. Lesions of odontogenic and nonodontogenic origin possess diagnostic and treatment challenges because they may present similarly and/or concurrently. Thoughtful and conservative management of odontogenic lesions with associated NHL is imperative. Interprofessional collaboration and communication among providers must be thorough and clear to properly coordinate care and prevent delays in diagnosis and treatment when these entities occur together. PMID- 28734650 TI - Treatment of Cracked Teeth. AB - Although many options are proposed for the treatment of cracked posterior teeth, most treatment decisions are not evidence based. Thus, considerable individual variation can occur regarding treatment recommendations for the same scenario. To our knowledge, there are no studies in the literature assessing practitioners' attitudes toward the treatment of cracked teeth. This research recorded variations between general practitioners and specialist groups regarding the treatment approaches of cracked teeth. In a cross-sectional structured questionnaire survey, 32 prosthodontists, 34 endodontists, and 29 general practitioners working in public and private dental health services in Kuwait were assessed regarding their treatment approach to 5 different clinical cracked tooth scenarios. Chosen treatment options varied greatly. Within each scenario, there was a wide range in treatment preferences across all groups and within each group, especially with respect to asymptomatic cracked teeth. Overall, treatment approaches did not relate to specialty training. Statistically significant differences were noticed between endodontists and general practitioners, in case of crowning teeth, in scenario 3 (P = .032), and in extracting teeth for scenario 5 (P = .048). This study highlights that, despite suggested guidelines, there are large differences in the approach to treatment planning for cracked teeth by practitioners and specialists, both as a whole and within each group. Further multicountry studies involving larger dental populations are needed to determine factors that influence practitioners' treatment choices and/or whether better or more widely accepted guidelines need to be established. More prospective well controlled clinical case-based research with long-term follow-ups is required. PMID- 28734651 TI - Chromographic Analysis and Cytotoxic Effects of Chlorhexidine and Sodium Hypochlorite Reaction Mixtures. AB - INTRODUCTION: The literature reveals controversies regarding the formation of para-chloroaniline (PCA) when chlorhexidine (CHX) is mixed with sodium hypochlorite (NaOCl). This study aimed to investigate the stability of PCA in the presence of NaOCl and to examine the in vitro cytotoxic effects of CHX/NaOCl reaction mixtures. METHODS: Different volumes of NaOCl were added to CHX (mix 1) or PCA (mix 2). Upon centrifugation, the supernatant and precipitate fractions collected from samples were analyzed using high-performance liquid chromatography. The cytotoxic effects of both fractions were examined on human periodontal ligament and 3T3 fibroblast cell lines. RESULTS: High-performance liquid chromatographic analysis showed no PCA signal when NaOCl was mixed with CHX (mix 1). In mix 2, the intensity of PCA was decreased when NaOCl was added to PCA, and chromatographic signals, similar to that of CHX/NaOCl, were also observed. The mortality of precipitates exerted on both cell lines was lower compared with that of supernatants. CONCLUSIONS: The discrepancy in the data from the literature could be caused by the instability of the PCA in the presence of NaOCl. The CHX/NaOCl reaction mixture exhibits a wide range of cytotoxic effects. PMID- 28734652 TI - Worldwide Prevalence of Mandibular Second Molar C-Shaped Morphologies Evaluated by Cone-Beam Computed Tomography. AB - INTRODUCTION: The aim of this study was to evaluate and compare the C-shaped mandibular second molar prevalence in different regions around the world with the aid of cone-beam computed tomography technology. METHODS: Nine field observers from 9 different geographic regions were calibrated. A total of 400 samples were collected in each region. The prevalence of C-shaped anatomy was calculated. The number of roots and the configuration of the C-shaped canals at 3 different axial levels were also evaluated. The z-test was used to analyze the difference between the means of each independent group. Intrarater reliability was also tested. RESULTS: A total of 3600 teeth from 2735 patients were included in this research; 499 teeth presented C-shaped root canal configuration, representing a global prevalence of 13.9%. China had a prevalence of 44.0%, which was significantly higher than any other region. The C-shape prevalence in women was 16.5%, which was significantly higher than the 10.4% prevalence found in men. No difference between sides (37 or 47) was evident in the global sample. CONCLUSIONS: Cone-beam computed tomography is a valuable tool to evaluate the C-shaped root canal configuration in vivo. In the present study, China presented the highest prevalence of C-shaped mandibular second molars when compared with other regions. Women exhibited a higher prevalence than men. PMID- 28734653 TI - Amyloid beta concentrations and stable isotope labeling kinetics of human plasma specific to central nervous system amyloidosis. AB - INTRODUCTION: Cerebrospinal fluid analysis and other measurements of amyloidosis, such as amyloid-binding positron emission tomography studies, are limited by cost and availability. There is a need for a more practical amyloid beta (Abeta) biomarker for central nervous system amyloid deposition. METHODS: We adapted our previously reported stable isotope labeling kinetics protocol to analyze the turnover kinetics and concentrations of Abeta38, Abeta40, and Abeta42 in human plasma. RESULTS: Abeta isoforms have a half-life of approximately 3 hours in plasma. Abeta38 demonstrated faster turnover kinetics compared with Abeta40 and Abeta42. Faster fractional turnover of Abeta42 relative to Abeta40 and lower Abeta42 and Abeta42/Abeta40 concentrations in amyloid-positive participants were observed. DISCUSSION: Blood plasma Abeta42 shows similar amyloid-associated alterations as we have previously reported in cerebrospinal fluid, suggesting a blood-brain transportation mechanism of Abeta. The stability and sensitivity of plasma Abeta measurements suggest this may be a useful screening test for central nervous system amyloidosis. PMID- 28734654 TI - Schlafen 14 (SLFN14) is a novel antiviral factor involved in the control of viral replication. AB - Schlafen (SLFN) proteins have been suggested to play important functions in cell proliferation and immune cell development. In this study, we determined the antiviral activities of putative RNA-helicase domain-containing SLFN14. Murine SLFN14 expression was specifically induced by TLR3-mediated pathways and type I interferon (IFN) in RAW264.7 mouse macrophages. To examine the role of SLFN during viral infection, cells were infected with either wild-type PR8 or delNS1/PR8 virus. SLFN14 expression was specifically induced following influenza virus infection. Overexpression of SLFN14 in A549 cells reduced viral replication, whereas knockdown of SLFN14 in RAW264.7 cells enhanced viral titers. Furthermore, SLFN14 promoted the delay in viral NP translocation from cytoplasm to nucleus and enhanced RIG-I-mediated IFN-beta signaling. In addition, SLFN14 overexpression promoted antiviral activity against varicella zoster virus (VZV), a DNA virus. In conclusion, our data suggest that SLFN14 is a novel antiviral factor for both DNA and RNA viruses. PMID- 28734656 TI - Patterns of Emergency Department Care for Newly Diagnosed Immune Thrombocytopenia in United States Children's Hospitals. AB - We used the Pediatric Health Information Systems database to ascertain treatment patterns of immune thrombocytopenia across the US. Despite the recently published guidelines by the American Society of Hematology, most patients are still being hospitalized for immune thrombocytopenia, even in the absence of documented bleeding symptoms. PMID- 28734655 TI - Cognitive Function in Children with Lupus Nephritis: A Cross-Sectional Comparison with Children with Other Glomerular Chronic Kidney Diseases. AB - OBJECTIVE: To identify factors contributing to cognitive impairment in children with lupus nephritis. STUDY DESIGN: A cross-sectional analysis of a large multicenter national cohort of children with chronic kidney disease (CKD) using standardized measures to determine baseline neuropsychiatric function and health related quality of life (HRQoL) in children with lupus nephritis (n = 34), and to compare baseline function with that in children with other forms of glomerular CKD (gCKD; n = 171). We used inverse probability weighting via a logistic model for propensity score analysis to achieve balance between children with lupus nephritis and those with other glomerular causes of CKD, adjusting for known confounders. We used linear regression models to compare neurocognitive outcomes between exposure groups, adjusting for current prednisone use and testing for an interaction between current prednisone use and lupus nephritis, and to test for an association between cognitive function and HRQoL. RESULTS: Current prednisone use was independently associated with worse attention (P < .01) and better adaptive skills (P = .04), and there was a significant interaction between current prednisone use and lupus nephritis for internalizing problems, with worse parent-reported internalizing problems in children with lupus nephritis on prednisone (P = .047). Better parent-reported HRQoL was associated with better visual memory (P = .01), and better child-reported HRQoL was associated with better attention (P < .01) and inhibitory control (P < .01). Both parent and child HRQoL were associated with better measures of executive function (P = .02 and < .001, respectively). CONCLUSION: Children with lupus nephritis have comparable or better cognitive function than their peers with other gCKDs, which is reassuring given the multiorgan and lifelong complications associated with lupus. PMID- 28734657 TI - Exercise Performance and 22q11.2 Deletion Status Affect Quality of Life in Tetralogy of Fallot. AB - OBJECTIVE: To identify mediators of health status and quality of life (QOL) in children and adolescents aged 8-18 years old following surgical repair for tetralogy of Fallot (TOF), including resource use, exercise performance, and 22q11.2 deletion status. STUDY DESIGN: We performed a corollary study to a cross sectional analysis of subjects following repair for TOF that completed cardiac magnetic resonance imaging, cardiopulmonary exercise tests, and instruments assessing health status and QOL. General linear models were used to test for mediation. RESULTS: A total of 29 of 151 (19%) patients carried a 22q11.2 deletion. Parents of children with a deletion compared with those without a deletion reported worse physical and psychosocial functioning on the Child Health Questionnaire. The patients with a 22q11.2 deletion and their parents reported lower total and Disease Impact scores compared with the group without a deletion on the Pediatric Cardiac Quality of Life Inventory. Medical care use negatively correlated with measures of health status/QOL. Greater maximum work correlated with better patient health status and QOL, regardless of deletion status. Exercise performance mediated the association between deletion status and parent reported outcomes (unstandardized effects ranging from 2.4 to 4.2) and patient reported Disease Impact (0.99; 95% CI 0.02-2.70). CONCLUSION: Children and adolescents following repair for TOF seem to suffer significant challenges to their health status and QOL, which is amplified markedly in the context of the 22q11.2 deletion syndrome, and related to exercise performance. PMID- 28734658 TI - Kidney transplantation: A new era of laparoscopic living donor nephrectomy in Indonesia. AB - BACKGROUND: Since its introduction in 1995, laparoscopic living donor nephrectomy (LLDN) has been a standard procedure in many transplantation centers worldwide. In 2011, LLDN was performed for the first time in Indonesia and became a standard procedure at our institution. The aim of this study is to evaluate the first 250 cases of LLDN at our institution. METHODS: Retrospective analyses were conducted of the first 250 cases of LLDN. All operations were performed between November 2011 and July 2015 at Cipto Mangunkusumo Hospital, Jakarta. We grouped each 100 consecutive cases and the last 50 cases (three groups) to evaluate operation related parameters, and complications. RESULTS: Significant decreases in the first warm ischemic time, blood loss, length of stay, and number of complications were observed among the three groups. There was only one conversion to open case during LLDN surgery and no mortality case observed. CONCLUSION: Laparoscopic living donor nephrectomies had been performed successfully with improvement of surgical parameter in due time. Thus, laparoscopic approach has entered a new era for kidney procurement in Indonesia. PMID- 28734659 TI - Comparative effectiveness study between negative pressure wound therapy and conventional wound dressing on perforator flap at the Chinese tertiary referral teaching hospital. AB - BACKGROUND: Perforator flap techniques with conventional wound dressing have being extensively used in the management of soft-tissue defects. However; the flap's survival rate is not always guaranteed and the wound healing time always long. The aim of this study was to investigate the clinical effectiveness use of a freshly transplanted perforator flap in conjunction with Vacuum-assisted closure (VAC) for better clinical outcomes. METHODS: A prospective, randomized, effectiveness study comparing the clinical outcomes of VAC versus traditional wrap and bandages for the treatment of open wounds that required hospital admission and operative debridement using perforator flaps, was carried out from March 1, 2014 to March 31, 2016 at Wuhan University Zhongnan Hospital. Fifty-one eligible patients were randomized into two groups; study group (perforator flaps covered by VAC) and control group (perforator flaps covered by traditional wrap and bandages). The measured clinical endpoints included the time of the first post-operative dressing change, pain visual analogical scale, perforator flap infection rate, 95% perforator flap healing time and percentage of survived perforator flap. RESULTS: There was no statistically significant difference in the demographic profiles in the two cohorts. There were statistically significant differences in the clinical endpoints in the two groups (p < 0.001; p < 0.05, Table 2). CONCLUSIONS: In summary, VAC combining with perforator flap technique, can diminish accumulated exudation of the transferring flap, protect against postoperative infection, prolong the interval between perforator flap relocation and first postoperative dressing change, decrease pain during removal of dressing, increase perforator flap survival rate, and shorten wound healing time, with a good aesthetic outcome, a good mobility and a satisfactory therapeutic result. PMID- 28734660 TI - Efficacy and Tolerability of Combination Therapy Versus Monotherapy with Candesartan and/or Amlodipine for Dose Finding in Essential Hypertension: A Phase II Multicenter, Randomized, Double-blind Clinical Trial. AB - PURPOSE: Intensive blood pressure (BP) lowering is important for the treatment of hypertension; however, it has been a challenge to achieve target BP in many patients. The purpose of this study was to explore the optimal dosage of a fixed dose combination of candesartan cilexetil (CAN) and amlodipine besylate (AML), by examining the tolerability and efficacy of CAN/AML combination therapy compared with those of monotherapy with either drug in patients with essential hypertension. METHODS: This Phase II multicenter, randomized, double-blind clinical trial enrolled patients aged 19 years or older with essential hypertension, defined as a mean sitting diastolic BP (msDBP) between 95 and 115 mm Hg, and a mean sitting systolic BP (msSBP) of <200 mm Hg after a 2-week placebo run-in period. A total of 635 patients were screened, of whom 439 were randomized to receive treatment; 425 patients were included in the full analysis set (combination therapy, 212; monotherapy, 213). Participants were randomly assigned to receive 1 of 8 treatments: CAN (8 or 16 mg), AML (5 or 10 mg), CAN/AML (8 mg/5 mg, 8 mg/10 mg, 16 mg/5 mg, or 16 mg/10 mg), once daily for 8 weeks. FINDINGS: After 8 weeks of treatment, changes in msDBP were significantly greater in the groups receiving CAN/AML combination therapies compared with monotherapies at matched doses, with the exception of CAN 8 mg/AML 10 mg versus AML 10 mg. The response to treatment and the achievement of target BP (both msSBP and msDBP) at week 8 were significantly greater overall in the groups that received combination therapy versus monotherapy. All medications were relatively well tolerated in each group. IMPLICATIONS: Eight-week administration of CAN/AML (8 mg/5 mg, 16 mg/5 mg, and 16 mg/10 mg) resulted in a significantly greater BP reduction than that with CAN or AML monotherapy, and was determined to be well tolerated. ClinicalTrials.gov identifier: NCT02944734. PMID- 28734661 TI - Systematic Literature Review and Meta-analysis of Tumor Necrosis Factor-Alpha Experienced Rheumatoid Arthritis. AB - PURPOSE: The goal of this study was to compile all available evidence regarding the efficacy of tumor necrosis factor-alpha (TNF) inhibitors, non-TNF biologics, and tofacitinib for TNF-experienced patients who have rheumatoid arthritis (RA). METHODS: A systematic literature review of MEDLINE, EMBASE, and rheumatology conference abstracts was performed to identify observational studies and randomized controlled trials (RCTs) reporting American College of Rheumatology response rates (ACR 20/50/70) for adult patients with RA who switched from at least 1 TNF to another TNF or a non-TNF therapy. A direct random effects meta analysis was performed to evaluate ACR 20/50/70 response rates for TNF and non TNF therapies. Separate analyses were conducted among 3-, 6-, and 12-month observational studies and for 6-month RCTs. FINDINGS: A total of 18 observational studies and 6 RCTs were selected. Among 3-month observational studies, the percentages of ACR20/50/70 responders switching to another TNF were similar to those switching to a non-TNF biologic (ACR20, 54.5% vs 58.6%; ACR50, 33.3% vs 33.3%; and ACR70, 13.0% vs 14.6%, respectively). Among 6-month observational studies, the percentages of TNF ACR20/50/70 responders were higher than those of non-TNF responders (ACR20, 67.7% vs 50.4%; ACR50, 50.4% vs 26.6%; and ACR70, 24.9% vs 11.6%). Among 6-month RCTs, the percentages of non-TNF biologic ACR20/50/70 responders were similar to those in the 6-month non-TNF observational studies (ACR20, 50.7% vs 50.4%; ACR50, 27.5% vs 26.6%; and ACR70, 11.9% vs 11.6%). For 12-month observational studies, TNF biologic ACR20/50/70 percentages were higher than those of non-TNF therapies (ACR20, 72.2% vs 57.0%; ACR50, 42.1% vs 28.9%; and ACR70, 22.9% vs 10.0%). IMPLICATIONS: For TNF-experienced patients with RA, subsequent TNF therapy and non-TNF biologic therapy have comparable efficacy. PMID- 28734662 TI - Transient Global Cerebral Ischemia Induces RNF213, a Moyamoya Disease Susceptibility Gene, in Vulnerable Neurons of the Rat Hippocampus CA1 Subregion and Ischemic Cortex. AB - The RING finger protein 213 (RNF213) is an important susceptibility gene for moyamoya disease (MMD) and is also implicated in other types of intracranial major artery stenosis/occlusion (ICAS); however, the role of RNF213 in the development of ICAS including MMD is unclear. The constitutive expression of the RNF213 gene is relatively weak in brain tissue, while information regarding the expression patterns of the RNF213 gene under cerebral ischemia, which is one of characteristic pathologies associated with ICAS, is currently limited. Our objective was to address this critical issue, and we investigated Rnf213 mRNA expression in rat brains after 5 minutes of transient global cerebral ischemia (tGCI) by occluding the common carotid arteries coupled with severe hypotension. Rnf213 gene expression patterns were investigated with in situ RNA hybridization and a real-time polymerase chain reaction (PCR) from 1 to 72 hours after tGCI. In situ RNA hybridization revealed a significant increase in Rnf213 mRNA levels in the hippocampus CA1 sub-region 48 hours after tGCI. The significant induction of the Rnf213 gene was also evident in the ischemic cortex. Double staining of Rnf213 mRNA with NeuN immunohistochemistry revealed Rnf213 hybridization signal expression exclusively in neurons. The real-time PCR analysis confirmed the induction of the Rnf213 gene after tGCI. The up-regulation of the Rnf213 gene in vulnerable neurons in the hippocampus CA1 after tGCI suggests its involvement in forebrain ischemia, which is an underlying pathology of MMD. Further investigations are needed to elucidate its exact role in the pathophysiology of ICAS including MMD. PMID- 28734663 TI - mtDNA sequence diversity of Hazara ethnic group from Pakistan. AB - The present study was undertaken to investigate mitochondrial DNA (mtDNA) control region sequences of Hazaras from Pakistan, so as to generate mtDNA reference database for forensic casework in Pakistan and to analyze phylogenetic relationship of this particular ethnic group with geographically proximal populations. Complete mtDNA control region (nt 16024-576) sequences were generated through Sanger Sequencing for 319 Hazara individuals from Quetta, Baluchistan. The population sample set showed a total of 189 distinct haplotypes, belonging mainly to West Eurasian (51.72%), East & Southeast Asian (29.78%) and South Asian (18.50%) haplogroups. Compared with other populations from Pakistan, the Hazara population had a relatively high haplotype diversity (0.9945) and a lower random match probability (0.0085). The dataset has been incorporated into EMPOP database under accession number EMP00680. The data herein comprises the largest, and likely most thoroughly examined, control region mtDNA dataset from Hazaras of Pakistan. PMID- 28734664 TI - pH responsive biodegradable nanogels for sustained release of bleomycin. AB - : Site specific drug delivery with desired therapeutic effect still remains challenging task due to suboptimal release, tissue toxicity, low selectivity and meager therapeutic efficacy in skin cancers. The aim of the current study was to fabricate pH responsive, self-assembled, chemically cross-linked biodegradable chitosan nanogel loaded with bleomycin to target the dermal area of the skin. The nanogel synthesized by ion gelation technique and was characterized for drug loading, swelling and thermal stability followed by in vitro analysis. HaCaT (Human Keratinocyte cell) and HDF (Human dermal fibroblast) cell line were used for the biocompatibility and cytocompatibility evaluation prior to the hemolysis assay and coagulation assessment. The nanogel had a size range of 150nm as determined by TEM and DLS. The nanogel possessed optimum thermal stability as analyzed by thermogravimetry (TG) and differential thermal analysis (DTA). Biodegradation was confirmed by lysozyme enzyme degradation assays. The drug entrapment efficacy was about 55% in the swollen state. The In vitro drug release profile revealed sustained release pattern. The hemolysis of 2.39% and prothrombin time (PT) and activated partial thromboplastin time (APTT) of 12.9 and 31s revealed the biocompatibility of nanogels. The cell uptake and localization profile was validated by fluorescence and confocal microscopy using HDF and HaCaT cell lines. Finally, the MTT assay demonstrated the cytocompatibility of nanogels. In conclusion, the present findings suggest that biodegradable chitosan nanogels with stimuli responsive nature can release the anticancer drug cargo in a sustained and controlled manner and offer promising potentials for treating skin cancers. STATEMENT OF SIGNIFICANCE: Drug delivery to the targeted site is a major challenge in clinical medicine. The newly constructed pH responsive biodegradable nanogel consisting of bleomycin revealed pH triggered drug release in a sustained manner to the dermal area offering novel approach against skin cancer. The nanogel system is biodegradable in nature possessing high drug entrapment efficiency and offers patient compliance with biocompatible and cytocompatible characteristics. This nanogel system can thus be highly useful for delivery of anticancer drugs to the skin in a controlled and sustained manner. PMID- 28734665 TI - Potential peptidic proteasome inhibitors by incorporation of an electrophilic trap based on amino acid derived alpha-substituted sulfonyl fluorides. AB - Peptido sulfonyl fluoride derivatives were designed and synthesized containing a substituent on the alpha position (alphaPSFs) with respect to the sulfonyl fluoride electrophilic trap. The chemical reactivity of these alpha-substituted amino sulfonyl fluorides was studied and compared with the previously described beta-substituted amino sulfonyl fluorides in order to get a deeper insight into the importance of the immediate structural environment of the sulfonyl fluoride moiety. Unfortunately, the poor solubility of the resulting alphaPSFs precluded a proper evaluation of their biological activity. PMID- 28734667 TI - Characterization of cartilage defects detected by MRI in Kellgren-Lawrence grade 0 or 1 knees. AB - INTRODUCTION: Osteoarthritis of the knee is generally evaluated by plain X-rays, which are incapable of detecting small cartilage damage. There are some patients who have small cartilage defects on MRI with no abnormal findings on plain X rays. In this study, the prevalence and regional characteristics of cartilage defects detected by MRI were studied in cases with normal X-ray findings (Kellgren-Lawrence grade 0 and 1). Relationships between the cartilage defects and OA risk factors such as obesity and leg alignment were also investigated. METHODS: A total of 51 knees of Kellgren-Lawrence grade 0 or 1 without knee joint pain were included. Fat-suppressed spoiled-gradient recalled (SPGR) sagittal images were scanned by 3 T MRI, and the presence of cartilage damage was confirmed. Cartilage damage was visualized three-dimensionally, and its location and morphology were analyzed. On a full length standing radiograph of the lower extremities, leg alignment and other parameters were measured, and their associations with cartilage damage were analyzed. RESULTS: Cartilage defects were detected in 26% of women aged >50 years. Cartilage damage was located on the medial femoral condyle near the intercondylar notch, and was mostly elliptically shaped in the anteroposterior direction. Subjects with damaged cartilage were not obese and did not have abnormal leg alignment. CONCLUSION: It should be borne in mind that some elderly women may have damaged cartilage on the intercondylar notch side of the medial joint, even though plain X-rays appear normal, and this cannot be predicted by obesity or leg alignment. PMID- 28734666 TI - Development of novel LP1-based analogues with enhanced delta opioid receptor profile. AB - Pain relief achieved by co-administration of drugs acting at different targets is more effective than that obtained with conventional MOR selective agonists usually associated to relevant side effects. It has been demonstrated that simultaneously targeting different opioid receptors is a more effective therapeutic strategy. Giving the promising role for DOR in pain management, novel LP1-based analogues with different N-substituents were designed and synthesized with the aim to improve DOR profile. For this purpose, we maintained the phenyl ring in the N-substituent of 6,7-benzomorphan scaffold linked to an ethyl spacer bearing a hydroxyl/methyl or methoxyl group at carbon 2 or including it in a 1,4 benzodioxane ring. LP1 analogues were tested by competition binding assays. Compounds 6 (KiMOR=2.47nM, KiDOR=9.6nM), 7 (KiMOR=0.5nM and KiDOR=0.8nM) and 9 (KiMOR=1.08nM, KiDOR=6.6nM) retained MOR affinity but displayed an improved DOR binding capacity as compared to LP1 (KiMOR=0.83nM, KiDOR=29.1nM). Moreover, GPI and MVD functional assays indicated that compounds 6 (IC50=49.2 and IC50=10.8nM), 7 (IC50=9.9 and IC50=11.8nM) and 9 (IC50=21.5 and IC50=4.4nM) showed a MOR/DOR agonist profile, unlike LP1 that was a MOR agonist/DOR antagonist (IC50=1.9 and IC50=1240nM). Measurements of their antinociceptive effect was evaluated by mice radiant tail flick test displaying for compounds 6, 7 and 9 ED50 values of 1.3, 1.0 and 0.9mg/kg, i.p., respectively. Moreover, the antinociceptive effect of compound 9 was longer lasting with respect to LP1. In conclusion the N substituent nature of compounds 6, 7 and 9 shifts the DOR profile of LP1 from antagonism to agonism. PMID- 28734668 TI - Corrigendum to "Multifactorial sleep disturbance in Parkinson's disease" [Sleep Med 35 (2017) 41-48]. PMID- 28734669 TI - Demodex mites in lymph nodes. PMID- 28734671 TI - Health inequality across prefectures in Japan. PMID- 28734670 TI - Population health and regional variations of disease burden in Japan, 1990-2015: a systematic subnational analysis for the Global Burden of Disease Study 2015. AB - BACKGROUND: Japan has entered the era of super-ageing and advanced health transition, which is increasingly putting pressure on the sustainability of its health system. The level and pace of this health transition might vary across regions within Japan and concern is growing about increasing regional variations in disease burden. The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 (GBD 2015) provides a comprehensive, comparable framework. We used data from GBD 2015 with the aim to quantify the burden of disease and injuries, and to attribute risk factors in Japan at a subnational, prefecture-level. METHODS: We used data from GBD 2015 for 315 causes and 79 risk factors of death, disease, and injury incidence and prevalence to measure the burden of diseases and injuries in Japan and in the 47 Japanese prefectures from 1990 to 2015. We extracted data from GBD 2015 to assess mortality, causes of death, years of life lost (YLLs), years lived with disability (YLDs), disability-adjusted life-years (DALYs), life expectancy, and healthy life expectancy (HALE) in Japan and its 47 prefectures. We split extracted data by prefecture and applied GBD methods to generate estimates of burden, and attributable burden due to known risk factors. We examined the prefecture-level relationships of common health system inputs (eg, health expenditure and workforces) to the GBD outputs in 2015 to address underlying determinants of regional health variations. FINDINGS: Life expectancy at birth in Japan increased by 4.2 years from 79.0 years (95% uncertainty interval [UI] 79.0 to 79.0) to 83.2 years (83.1 to 83.2) between 1990 and 2015. However, the gaps between prefectures with the lowest and highest life expectancies and HALE have widened, from 2.5 to 3.1 years and from 2.3 to 2.7 years, respectively, from 1990 to 2015. Although overall age-standardised death rates decreased by 29.0% (28.7 to 29.3) from 1990 to 2015, the rates of mortality decline in this period substantially varied across the prefectures, ranging from 32.4% (-34.8 to -30.0) to -22.0% (-20.4 to -20.1). During the same time period, the rate of age-standardised DALYs was reduced overall by 19.8% (17.9 to 22.0). The reduction in rates of age-standardised YLDs was very small by 3.5% (2.6 to 4.3). The pace of reduction in mortality and DALYs in many leading causes has largely levelled off since 2005. Known risk factors accounted for 34.5% (32.4 to 36.9) of DALYs; the two leading behavioural risk factors were unhealthy diets and tobacco smoking in 2015. The common health system inputs were not associated with age-standardised death and DALY rates in 2015. INTERPRETATION: Japan has been successful overall in reducing mortality and disability from most major diseases. However, progress has slowed down and health variations between prefectures is growing. In view of the limited association between the prefecture-level health system inputs and health outcomes, the potential sources of regional variations, including subnational health system performance, urgently need assessment. FUNDING: Bill & Melinda Gates Foundation, Japan Ministry of Education, Science, Sports and Culture, Japan Ministry of Health, Labour and Welfare, AXA CR Fixed Income Fund and AXA Research Fund. PMID- 28734672 TI - Diabetes of 5 years duration does not lead to photoreceptor degeneration in the canine non-tapetal inferior-nasal retina. PMID- 28734673 TI - Somatostatin protects human retinal pericytes from inflammation mediated by microglia. AB - Diabetic retinopathy (DR) is usually considered a microvascular disease. However, involvement of the neuroretina in the early stages of DR has recently gained major credit. Inflammatory processes, leading to glial activation and neuronal apoptosis, develop early in the retina of diabetic subjects. Pericytes constitute a link between the vascular and the neural retina, play a central role in blood retinal barrier maintenance, and may influence neuroinflammation. Somatostatin (SST) is a potent neuroprotective factor, which is down-regulated during early DR. In this paper, we have investigated the effects of the inflammatory signals triggered by the activation of microglia on inflammation and apoptosis/survival pathways in pericytes. Microglia cells (Bv-2) were stimulated with lipopolysaccharide (LPS) and/or SST. Human retinal pericytes (HRP) were exposed to conditioned media (CM) collected from Bv-2 cells in physiological conditions and in the settings described above. A panel of inflammation, apoptosis and survival mediators was analyzed. HRP treated with LPS-CM showed a significant increase of pro-inflammatory (iNos and TNFalpha) and pro-apoptotic mediators (FasL, active caspase-8, tBid and Bax), and a concomitant decrease in pro survival factors (BclxL and pAkt). SST added to LPS was able to counteract these effects in all conditions. In conclusion, SST is able to modulate apoptosis/survival pathways in HRP during microglia-mediated inflammation. These results demonstrate a crosstalk between microglia and retinal pericytes, evidencing a possible defensive role of microglia in the early phases of DR. PMID- 28734674 TI - Retinal exposure to high glucose condition modifies the GABAergic system: Regulation by nitric oxide. AB - Diabetic retinopathy is a severe retinal complication that diabetic patients are susceptible to present. Although this disease is currently characterized as a microvascular disease, there is growing evidence that neural changes occur and maybe precede vascular impairments. Using chicken retina, an avascular tissue with no direct contact with blood vessels and neural retina, this study aimed to evaluate the influence of acute exposure to high glucose concentration in the retinal GABAergic system, and the role of nitric oxide (NO) in this modulation. Therefore, in ex vivo experiments, retinas were incubated in control (10 mM glucose) or high glucose condition (35 mM) for 30 min. By using DAF-FM to evaluate NO production, it was possible to show that high glucose (HG) significantly increased NO levels in the outer nuclear layer, inner nuclear layer (outer and inner portion), and inner plexiform layer. It was also observed that HG increased GABA immunoreactivity (IR) in amacrine and horizontal cells. HG did not change glutamic acid decarboxylase-IR, whereas it decreased GABA Transporter (GAT) 1-IR and increased GAT-3-IR. The co-treatment with 7-NI, an inhibitor of neuronal nitric oxide synthase (nNOS), blocked all changes stimulated by HG exposure. The concomitant exposure with SNAP-5114, a GAT-2/3 inhibitor, blocked the increase in GABA-IR caused by HG incubation. Therefore, our data suggest that hyperglycemia induces GABA accumulation in the cytosol by modulating GABA transporters. This response is dependent on NO production and signaling. PMID- 28734675 TI - Safety and effectiveness of tocilizumab in treating patients with rheumatoid arthritis - A three-year study in Taiwan. AB - OBJECTIVE: To evaluate the long-term safety and effectiveness of tocilizumab (TCZ) for the treatment of rheumatoid arthritis (RA) in a real-world clinical setting in Taiwan. METHOD: All refractory RA patients who initiated intravenous TCZ between August 2012 and March 2015 were enrolled. Data on patient characteristics, drug safety and effectiveness were collected. RESULTS: A total of 114 RA patients were recruited. Despite the majority of them (93%) had previous biologic failure, 43.75% of the patients were able to reach ACR50 after one year. Serious adverse events commonly found were bacterial pneumonia (4.24/100 patient-years) followed by cellulitis (2.12/100 patient-years). Twenty three patients had old or latent TB infections, 11 patients had chronic hepatitis B. During the 3 years follow-up, none of them had reactivation of TB, or hepatitis B with concomitant use of isoniazid prophylaxis or pre-emptive antiviral treatment. CONCLUSION: In this 3-year real-world study on RA patients of Taiwan, we found a good long-term effectiveness and similar safety profiles for the TCZ treatment. With prophylactic strategy for latent TB and pre-emptive antiviral treatment for HBV carriers, the risk of reactivation of latent TB and HBV may be reassured. PMID- 28734676 TI - Analyses of clinical and laboratory characteristics of dengue adults at their hospital presentations based on the World Health Organization clinical-phase framework: Emphasizing risk of severe dengue in the elderly. AB - BACKGROUND/PURPOSE: Dengue clinically dynamically changes over time; the World Health Organization (WHO) dengue classification framework proposed 3 dengue clinical phases-febrile (days 1-3), critical (days 4-6) and recovery (days >=7) phases. This study aimed to better understand clinical and laboratory characteristics in adults (>=18 years) suffering dengue in different clinical phases at their hospital presentations. METHODS: A retrospective analysis of adults suffering dengue between 2008 and 2014. RESULTS: Of the 669 included dengue adults, 146 (21.8%) were elderly (>=65 years), and 27 (4%) suffered severe dengue. When compared with those in febrile phase, significantly higher incidence of ascites, mucosal bleeding, and/or gastrointestinal bleeding; lower white blood cell (WBC) and platelet counts; higher hematocrit, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) values were found in critical phase. When compared with their younger counterparts, elderly at febrile phase had significantly lower frequencies of bone pain, myalgia, headache and rash; higher frequencies of vomiting, pleural effusion and mucosal bleeding; higher WBC count, AST and ALT levels, and lower platelet count; in critical phase, elderly had significantly higher frequencies of pleural effusion, mucosal bleeding and gum bleeding. Four (0.6%) patients experienced severe dengue in recovery phase. Significantly higher proportions of elderly developed severe dengue in both febrile and critical phases as compared with younger adults. CONCLUSIONS: Elderly had lower frequency of classical dengue symptoms, yet were at higher risk of development of severe dengue during their early dengue course. A small number of patients developed severe dengue at the WHO-proposed recovery phase. PMID- 28734677 TI - [Histoseminar on inflammatory bowel diseases (IBD): Case no 04]. PMID- 28734678 TI - Improvement of adipose tissue-derived cells by low-energy extracorporeal shock wave therapy. AB - BACKGROUND: Cell-based therapies with autologous adipose tissue-derived cells have shown great potential in several clinical studies in the last decades. The majority of these studies have been using the stromal vascular fraction (SVF), a heterogeneous mixture of fibroblasts, lymphocytes, monocytes/macrophages, endothelial cells, endothelial progenitor cells, pericytes and adipose-derived stromal/stem cells (ASC) among others. Although possible clinical applications of autologous adipose tissue-derived cells are manifold, they are limited by insufficient uniformity in cell identity and regenerative potency. METHODS: In our experimental set-up, low-energy extracorporeal shock wave therapy (ESWT) was performed on freshly obtained human adipose tissue and isolated adipose tissue SVF cells aiming to equalize and enhance stem cell properties and functionality. RESULTS: After ESWT on adipose tissue we could achieve higher cellular adenosine triphosphate (ATP) levels compared with ESWT on the isolated SVF as well as the control. ESWT on adipose tissue resulted in a significantly higher expression of single mesenchymal and vascular marker compared with untreated control. Analysis of SVF protein secretome revealed a significant enhancement in insulin-like growth factor (IGF)-1 and placental growth factor (PLGF) after ESWT on adipose tissue. DISCUSSION: Summarizing we could show that ESWT on adipose tissue enhanced the cellular ATP content and modified the expression of single mesenchymal and vascular marker, and thus potentially provides a more regenerative cell population. Because the effectiveness of autologous cell therapy is dependent on the therapeutic potency of the patient's cells, this technology might raise the number of patients eligible for autologous cell transplantation. PMID- 28734679 TI - Assessment of biodistribution using mesenchymal stromal cells: Algorithm for study design and challenges in detection methodologies. AB - BACKGROUND AIMS: Biodistribution of candidate cell-based therapeutics is a critical safety concern that must be addressed in the preclinical development program. We aimed to design a decision tree based on a series of studies included in actual dossiers approved by competent regulatory authorities, noting that the design, execution and interpretation of pharmacokinetics studies using this type of therapy is not straightforward and presents a challenge for both developers and regulators. METHODS: Eight studies were evaluated for the definition of a decision tree, in which mesenchymal stromal cells (MSCs) were administered to mouse, rat and sheep models using diverse routes (local or systemic), cell labeling (chemical or genetic) and detection methodologies (polymerase chain reaction [PCR], immunohistochemistry [IHC], fluorescence bioimaging, and magnetic resonance imaging [MRI]). Moreover, labeling and detection methodologies were compared in terms of cost, throughput, speed, sensitivity and specificity. RESULTS: A decision tree was defined based on the model chosen: (i) small immunodeficient animals receiving heterologous MSC products for assessing biodistribution and other safety aspects and (ii) large animals receiving homologous labeled products; this contributed to gathering data not only on biodistribution but also on pharmacodynamics. PCR emerged as the most convenient technique despite the loss of spatial information on cell distribution that can be further assessed by IHC. DISCUSSION: This work contributes to the standardization in the design of biodistribution studies by improving methods for accurate assessment of safety. The evaluation of different animal models and screening of target organs through a combination of techniques is a cost effective and timely strategy. PMID- 28734681 TI - Transient anger attacks associated with bifrontal transcranial direct current stimulation. PMID- 28734680 TI - Response to letter to the editor: Safety of transcranial direct current stimulation: Evidence based update 2016. PMID- 28734682 TI - How have systematic priority setting approaches influenced policy making? A synthesis of the current literature. AB - BACKGROUND: There is a growing body of literature on systematic approaches to healthcare priority setting from various countries and different levels of decision making. This paper synthesizes the current literature in order to assess the extent to which program budgeting and marginal analysis (PBMA), burden of disease & cost-effectiveness analysis (BOD/CEA), multi-criteria decision analysis (MCDA), and accountability for reasonableness (A4R), are reported to have been institutionalized and influenced policy making and practice. METHODS: We searched for English language publications on health care priority setting approaches (2000-2017). Our sources of literature included PubMed and Ovid databases (including Embase, Global Health, Medline, PsycINFO, EconLit). FINDINGS: Of the four approaches PBMA and A4R were commonly applied in high income countries while BOD/CEA was exclusively applied in low income countries. PBMA and BOD/CEA were most commonly reported to have influenced policy making. The explanations for limited adoption of an approach were related to its complexity, poor policy maker understanding and resource requirements. CONCLUSIONS: While systematic approaches have the potential to improve healthcare priority setting; most have not been adopted in routine policy making. The identified barriers call for sustained knowledge exchange between researchers and policy-makers and development of practical guidelines to ensure that these frameworks are more accessible, applicable and sustainable in informing policy making. PMID- 28734683 TI - Health-seeking behavior and medical facility choice in Samsun, Turkey. AB - OBJECTIVE: Examining the factors that play a role in determining patient preferences for different healthcare institutions. METHOD: This descriptive study was conducted in five family health centers (FHC) and in six hospitals in Samsun Province in Turkey. The data were collected from 1700 volunteer patients by using a structured questionnaire, while they were waiting for consultation. RESULT: The average number of out-patient visits was 9.5+/-6.4 per person in 2012. Individuals aged less than 18 and more than 65 years old had higher preferences for FHCs, while those aged 19-64 years preferred primarily private hospitals. The order of preferences for FHC, public and private hospitals did not vary with the educational level. An increase in educational level was associated with a decrease in the preference for FHCs and in increase in the preference for private hospitals. The first three reasons given for preferring a hospital were 'the presence of a specialist', 'availability of good equipment and technology', and 'trust on the diagnosis and treatment', while 'proximity', 'receiving adequate information', and 'being treated well' were the reasons given by participants who preferred a FHC. CONCLUSION: Providing medical equipment and staff support for improving diagnostic capacity of FHCs can accommodate patient expectations and shift the demand from hospitals to FHCs. PMID- 28734684 TI - Factors Influencing List Prices for Radiologists' Services. AB - PURPOSE: To identify factors associated with list price variation for radiologists' services. METHODS: The 2014 Medicare Physician and Other Supplier Public Use File was used to identify submitted charges ("list prices") and payments for radiologists' services (ie, not hospital service charges). Charge-to payment ratios were computed for individual radiologists as a measure of excess charges. Numerous radiologist-level factors identifiable using publicly available data sets were explored. RESULTS: Among 26,715 radiologists nationally, the mean charge-to-payment ratio was 4.2 +/- 2.0. A greater charge-to-payment ratio was most strongly predicted for those serving higher-complexity patients (ratio ranging from 3.8 +/- 1.8 to 4.1 +/- 1.6 for radiologists in the first through third quartiles in terms of patient complexity, compared with a ratio of 4.8 +/- 2.8 for radiologists in the highest quartile in terms of patient complexity). A higher charge-to-payment ratio was also observed among those with, rather than without, a teaching institutional affiliation (4.7 +/- 2.8 versus 4.0 +/- 1.8, respectively) and among subspecialists rather than generalists (4.4 +/- 2.5 versus 3.9 +/- 1.5, respectively). Among subspecialties, charge-to-payment ratios ranged from 3.3 +/- 1.3 (breast imaging) to 5.7 +/- 4.1 (interventional radiology). Charge-to-payment ratios showed weak inverse correlations with total service volume (r = -0.13) and total payments (r = -0.11). CONCLUSION: Distinct from hospital prices and historically considered arbitrary, higher charges for radiologists' services demonstrate consistent patterns of variation and are most strongly seen for those serving higher complexity patients. As price transparency initiatives expand, radiologists should be aware of how and why their list prices compare with local and national benchmarks. PMID- 28734685 TI - R-SCAN: Cardiac CT Angiography for Acute Chest Pain. PMID- 28734686 TI - Tales from the Table. PMID- 28734687 TI - Three-dimensional interlead distance predicts response and outcomes after cardiac resynchronization therapy. AB - BACKGROUND: Approximately one-third of patients do not respond favourably to cardiac resynchronization therapy (CRT). A longer distance between ventricular leads may improve response. AIM: To study the impact of the true three dimensional interlead distance (ILD) on outcomes. METHODS: Consecutive patients undergoing CRT device implantation were included prospectively. Interlead separation was measured from postprocedural anterior-posterior and lateral chest X-rays. The three-dimensional ILD was calculated using the Pythagorean theorem. Response to CRT was defined using a composite clinical score at 6 months. RESULTS: Forty-two patients were included (mean age 70+/-9 years; QRS duration 154+/-31ms; left ventricular ejection fraction 26+/-7%; 50% ischaemic). At 6 months, 71% of patients were considered to be responders. Responders had a significantly longer ILD (108+/-17 vs. 87+/-21mm; P=0.002). When the ILD was corrected for cardiac size, the optimal cut-off value was >= 0.53 for predicting response (sensitivity 83%, specificity 75%, area under the curve 0.84; P=0.0002). Similar results were obtained in a historical retrospective cohort. The use of proximal electrodes on the left ventricular lead was associated with a longer ILD in 95% of patients, compared with more distal pacing configurations. In the total cohort of 74 patients (median follow-up, 420 days), those with an indexed ILD >= 0.53 had a 70% reduction in risk of hospitalization for heart failure (P=0.004). CONCLUSION: Longer three-dimensional ILD corrected for cardiac size measured on chest radiographs can accurately predict response to CRT and outcomes. This simple variable may be used to identify optimal lead placement and pacing configuration during CRT implantation. PMID- 28734688 TI - PTGS2 down-regulation in cumulus cells of infertile women with endometriosis. AB - A deleterious effect of endometriosis on oocyte quality has been proposed. Evidence suggests that cumulus cells could be used as indirect biomarkers of oocyte quality. The PTGS2 gene, which encodes cyclooxygenase 2 (COX-2), is deregulated in endometriotic lesions and plays a crucial role in the acquisition of oocyte competence. To date, research evaluating PTGS2 expression in cumulus cells of infertile patients with endometriosis has not been conducted. The aim this study was to compare the expression levels of PTGS2 in cumulus cells of infertile women, with and without endometriosis, undergoing ovarian stimulation for intracytoplasmic sperm injection (ICSI). Therefore, a case-control study compared PTGS2 gene expression in the cumulus cells of 38 infertile patients with endometriosis and 40 without, using real-time polymerase chain reaction. For the first time, decreased expression of PTGS2 was found in cumulus cells of infertile women with endometriosis compared with controls (7.2 +/- 10.5 versus 12.4 +/- 15.7), which might be related to reduced levels of COX-2 in the cumulus cells of women with the disease. Consequently, we hypothesize that lower transcript levels of PTGS2 in cumulus cells may be involved in the impairment of oocyte quality, suggesting a possible mechanism involved in disease-related infertility. PMID- 28734689 TI - Influence of maternity leave on exclusive breastfeeding. AB - OBJECTIVES: To describe the profile of women with children aged under 4 months living in the Brazilian state capitals and in the Federal District according to their working status and to analyze the influence of maternity leave on exclusive breastfeeding (EBF) among working women. METHODS: This was a cross-sectional study with data extracted from the II National Maternal Breastfeeding Prevalence Survey carried out in 2008. Initially, a descriptive analysis of the profile of 12,794 women was performed, according to their working status and maternity leave and the frequency of maternity leave in the Brazilian regions and capitals. The study used a multiple model to identify the influence of maternity leave on EBF interruption, including 3766 women who declared they were working and were on maternity leave at the time of the interview. The outcome assessed in the study was the interruption of the EBF, classified by the WHO. RESULTS: Regarding the working status of the mothers, 63.4% did not work outside of their homes and among those who worked, 69.8% were on maternity leave. The largest prevalence among workers was of women older than 35 years of age, with more than 12 years of schooling, primiparous and from the Southeast and South regions. The lack of maternity leave increased by 23% the chance of EBF interruption. CONCLUSION: Maternity leave contributed to increase the prevalence of EBF in the Brazilian states capitals, supporting the importance of increasing the maternity leave period from four to six months. PMID- 28734690 TI - Salivary C-reactive protein, mean platelet volume and neutrophil lymphocyte ratio as diagnostic markers for neonatal sepsis. AB - OBJECTIVE: To assess the applicability of salivary C-reactive protein, mean platelet volume, neutrophil-lymphocyte ratio, and platelet lymphocyte ratio in the diagnosis of neonatal sepsis. METHODS: Prospective case-control study of 70 full-term neonates, 35 with sepsis (20 with proven sepsis and 15 with clinical sepsis) and 35 healthy controls. Serum and salivary C-reactive protein concentrations were measured by enzyme-linked immunosorbent assay while mean platelet volume, neutrophil-lymphocyte ratio, and platelet lymphocyte ratio were measured by automated blood cell counter. RESULTS: This study showed statistically significant difference of mean salivary C-reactive protein between septic neonates and controls (12.0+/-4.6ng/L vs. 2.8+/-1.2ng/L) respectively. At a cut-off point of 3.48ng/L, salivary C-reactive protein showed 94.3% sensitivity and 80% specificity. Salivary C-reactive protein also showed good predictive accuracy for predicting elevated serum C-reactive protein values in septic neonates. Mean platelet volume and neutrophil-lymphocyte ratio showed significant difference between septic neonates and controls (10.2+/-1.2fL vs.8.0+/-0.5fL; 2.9+/-1.7 vs. 1.6+/-0.4, respectively). At a cut-off point of 10.2fL, mean platelet volume presented 80% sensitivity and specificity. At a cut-off point of 2.7, neutrophil-lymphocyte ratio presented 80% sensitivity and 57.1% specificity. CONCLUSION: This study provides support for further studies on the usefulness of salivary C-reactive protein, mean platelet volume, and neutrophil-lymphocyte ratio as diagnostic markers for neonatal sepsis. PMID- 28734691 TI - Cerebellar fits in the 2000s. AB - Acute compression on the brainstem or acute increase in intracranial pressure may induce non-epileptic events varying from tonic seizures to axial rigidity with motor automatism, sometimes clearly characterized by decerebrate or decorticate paroxysmal posturing. The EEG correlate is characterized by diffuse asynchronous slow waves of variable amplitude. The mechanism behind such events, known as "cerebellar seizures or fits", is linked to cerebellar herniation and brainstem compression and is not of cortical origin. Misrecognition of such entity may entail an incongruous therapeutic intervention in a life-threatening situation. We describe two emblematic paediatric cases of cerebellar fits caused by diffuse oedema and brainstem compression: a 10-year-old girl with acute disseminated encephalomyelitis (ADEM) and a 2-year-old girl with severe respiratory distress symptomatic of Fallot tetralogy. We also describe the EEG correlate recorded during the events. PMID- 28734692 TI - Respiratory arrest at the onset of idiopathic childhood occipital epilepsy of Gastaut. AB - Occipital lobe epilepsy of childhood includes two entities: Panayiotopoulos syndrome in pre-school children, and idiopathic childhood occipital epilepsy of Gastaut (ICOEG) in school-age children. The typical initial manifestation of the former is vomiting, and that of the latter is visual hallucinations. Ictal cardiopulmonary arrest at initial presentation has been reported for Panayiotopoulos syndrome, but not for ICOEG. We document a 7-year-old previously healthy girl who experienced an acute elemental visual hallucination of seeing insects, followed by a new-onset generalized seizure. Upon arrival at the local hospital, she was unconscious and soon thereafter, developed respiratory arrest. She was resuscitated and initiated on mechanical ventilation. An electroencephalogram taken three days after seizure cessation showed frequent occipital spikes, consistent with the diagnosis of ICOEG. The sequence of acute elementary visual hallucination followed by a motor seizure, and then witnessed respiratory arrest illustrated occurrence of life-threatening autonomic involvement at initial onset in ICOEG. We speculate that the epileptic propagation from the occipital lobes eventually compromised the respiratory center in the brainstem. The possibility of occipital lobe epilepsy should be considered in school-age children presenting with acute visual hallucination followed by respiratory arrest. Such a presentation should prompt an urgent electroencephalogram and initiation of antiepileptic treatment if indicated. PMID- 28734693 TI - A systematic review and meta-analysis comparing the prognosis of multicentric occurrence and vs. intrahepatic metastasis in patients with recurrent hepatocellular carcinoma after hepatectomy. AB - BACKGROUND: The aim of this meta-analysis was to evaluate the prognosis of patients with different types of hepatocellular cancer (HCC) recurrence following hepatectomy. Specifically, it evaluated overall survival and disease-free survival in HCC patients with multicentric occurrence (MO) or intrahepatic metastasis (IM). METHODS: Medline, Cochrane, EMBASE, and Google Scholar were searched until August 22, 2016 using the following search terms: hepatocellular carcinoma, multicentric occurrence, intrahepatic metastasis, early recurrence, and late recurrence. Prospective, retrospective, and case control studies were included. RESULTS: The pooled results showed that patients in the MO group had lower risk of death than the IM group (pooled HR = 0.495, 95% CI = 0.378 to 0.648, P < 0.001). The MO group also had significantly longer disease-free survival than the IM group (pooled HR = 0.774, 95% CI = 0.663 to 0.903, P = 0.001). Sensitivity analysis indicated that no one study dominated the findings and that the data are robust. Overall the included studies were of good quality. CONCLUSION: This study found that MO patients have greater survival following surgery than IM patients, indicating the prognosis of MO patients is significantly better than that for IM patients. PMID- 28734694 TI - Regenerative biosensor for use with biotinylated bait molecules. AB - Label-free biosensors are ideally suited for the quantitative analysis of specific interactions among biomolecules or of biomolecules with drugs, as well as for quantitation of diagnostic markers in biofluids. In contrast to the label dependent methods, a new assay for a particular prey molecule can be set up within few minutes by immobilizing the corresponding bait molecule on the sensor surface, using one of the common immobilization procedures. Unfortunately, the extensive application of label-free biosensors is still hampered by the fact that the immobilization of the bait molecule is usually irreversible; for that reason, a new chip (which is expensive) is required for every successful or futile attempt. Here, we present a general method for the switchable immobilization of biotinylated bait molecules on a new desthiobiotin surface, using wild-type streptavidin as a robust bridge between the chip and the biotinylated bait. The immobilization of the bait is very stable, so that many cycles of prey injection and subsequent prey removal can be carried out. For the latter, common reagents like HCl, Na2CO3, glycine buffer, or SDS are employed. When desired, however, streptavidin plus the biotinylated bait can be completely removed by 3min injections of biotin, guanidinium thiocyanate, pepsin, and SDS, which makes it possible to immobilize new biotinylated bait. The number of in situ regeneration cycles is unlimited during the lifetime of the chip (2-3 weeks). One chip can easily be shared by many users with unrelated tasks (as is typical in academics), or used for the fully automated screening of many different interactions (for example in pharmaceutical research). In comparison to other regenerative chips, the new chip surface has much wider applicability and all of its structural and functional parameters have been disclosed. PMID- 28734695 TI - Response of the bacterial community in an on-farm biopurification system, to which diverse pesticides are introduced over an agricultural season. AB - A biopurification system (BPS) is used on-farm to clean pesticide-contaminated wastewater. Due to high pesticide loads, a BPS represents a hot spot for the proliferation and selection as well as the genetic adaptation of discrete pesticide degrading microorganisms. However, while considerable knowledge exists on the biodegradation of specific pesticides in BPSs, the bacterial community composition of these systems has hardly been explored. In this work, the Shannon diversity, the richness and the composition of the bacterial community within an operational BPS receiving wastewater contaminated with various pesticides was, for the first time, elucidated over the course of an agricultural season, using DGGE profiling and pyrosequencing of 16S rRNA gene fragments amplified from total community DNA. During the agricultural season, an increase in the concentration of pesticides in the BPS was observed along with the detection of significant community changes including a decrease in microbial diversity. Additionally, a significant increase in the relative abundance of Proteobacteria, mainly the Gammaproteobacteria, was found, and OTUs (operational taxonomic units) affiliated to Pseudomonas responded positively during the course of the season. Furthermore, a banding-pattern analysis of 16S rRNA gene-based DGGE fingerprinting, targeting the Alpha- and Betaproteobacteria as well as the Actinobacteria, indicated that the Betaproteobacteria might play an important role. Interestingly, a decrease of Firmicutes and Bacteroidetes was observed, indicating their selective disadvantage in a BPS, to which pesticides have been introduced. PMID- 28734696 TI - 18F-Fluoromisonidazole positron emission tomography (FMISO-PET) may reflect hypoxia and cell proliferation activity in oral squamous cell carcinoma. AB - OBJECTIVE: Hypoxia is a common feature and prognostic factor in cancer. 18F fluoromisonidazole (FMISO) positron emission tomography (PET) can detect tumor hypoxia noninvasively. The aim of this study was to assess the correlations between FMISO-PET and 18 F-fluorodexyglucose (FDG)-PET parameters with cell proliferation and hypoxia in patients with oral squamous cell carcinoma (OSCC). STUDY DESIGN: Twenty-three preoperative patients with OSCC were included. The tumor/muscle ratio (TMR) of FMISO-PET, the maximum standardized uptake values (SUVmax) of FDG-PET, metabolic tumor volume, and total lesion glycolysis were measured. Ki-67 and hypoxia-inducible factor-1alpha (HIF-1alpha) expression was immunohistochemically evaluated. RESULTS: FMISO TMR (P = .003) and FDG SUVmax (P = .04) were significantly higher in patients with high expression of Ki-67 compared with those with low expression of Ki-67. FMISO TMR (P = .006) and FDG SUVmax (P = .01) were also significantly higher in patients with HIF-1alpha expression than in those without HIF-1alpha expression. Metabolic tumor volume was not significantly related to either Ki-67 or HIF-1alpha expression. Multivariate analysis showed that FMISO TMR was independently predictive of Ki-67 (P = .002; odds ratio 31.1) and HIF-1alpha (P = .049; odds ratio 10.5) expression. CONCLUSIONS: FMISO-PET showed significant relationships with Ki-67 and HIF-1alpha expression, which are key features of cell proliferation and hypoxia in OSCC. PMID- 28734698 TI - Toddlers show sensorimotor activity during auditory verb processing. AB - Language that describes actions, for instance verbs, can help to predict future actions of conspecifics in social interactions. Language and action are therefore interrelated. This interrelation has been described on a behavioral level for adults and toddlers. Furthermore, in adults, the sensorimotor system is involved in this interrelation. However, little is known about the early interrelation on the neural level at the onset of verb acquisition. In the present study, we examined the role of the sensorimotor system during the processing of acoustically presented verbs that describe dynamic actions and visually presented actions in toddlers, who are in the earliest stage of expressive language development. The activity of the sensorimotor system, in particular the suppression of the mu rhythm, was measured by means of electroencephalography (EEG). Results showed a significant suppression of the mu rhythm during both the processing of action verbs and observed actions, but not during the processing of pseudoverbs. This suggests that the sensorimotor system is already involved in the processing of action and language early in life. PMID- 28734697 TI - Prognostic significance of hMSH2, hMSH3, and hMSH6 expression in ameloblastoma. AB - OBJECTIVE: The aim of this study was to investigate hMutS proteins in developing human tooth, ameloblastomas, and ameloblastic carcinoma and to determine whether the expression of these proteins has any prognostic potential. STUDY DESIGN: Ten cases of developing human tooth, 39 ameloblastomas, and 2 ameloblastic carcinomas were used to determine the distribution of the proteins during the process of carcinogenesis. Simultaneously, another sample of 73 ameloblastomas was arranged in tissue microarray, and their clinical, microscopic, and radiographic features; treatment outcome; presence of BRAF-V600E mutation; and follow-up data were assessed to determine the prognostic relevance of the expression of hMutS (hMSH2, hMSH3, hMSH6) and Ki-67. hMSH2 and hMSH6 were significantly downexpressed in ameloblastomas (P = .0059) compared with developing human tooth (P < .0001). RESULTS: hMSH2, hMSH3 expression were significantly associated with BRAF-V600E mutation (P < .05). Simultaneous overexpression of hMutS was associated with recurrence (P = .035); however, these did not predict the disease-free survival of patients (P > .05). CONCLUSIONS: hMutS proteins are downregulated in ameloblastoma; moreover, simultaneous overexpression of these proteins in ameloblastoma was associated with recurrence but did not predict disease-free survival. PMID- 28734700 TI - Predicting muscle forces during the propulsion phase of single leg triple hop test. AB - Functional biomechanical tests allow the assessment of musculoskeletal system impairments in a simple way. Muscle force synergies associated with movement can provide additional information for diagnosis. However, such forces cannot be directly measured noninvasively. This study aims to estimate muscle activations and forces exerted during the preparation phase of the single leg triple hop test. Two different approaches were tested: static optimization (SO) and computed muscle control (CMC). As an indirect validation, model-estimated muscle activations were compared with surface electromyography (EMG) of selected hip and thigh muscles. Ten physically healthy active women performed a series of jumps, and ground reaction forces, kinematics and EMG data were recorded. An existing OpenSim model with 92 musculotendon actuators was used to estimate muscle forces. Reflective markers data were processed using the OpenSim Inverse Kinematics tool. Residual Reduction Algorithm (RRA) was applied recursively before running the SO and CMC. For both, the same adjusted kinematics were used as inputs. Both approaches presented similar residuals amplitudes. SO showed a closer agreement between the estimated activations and the EMGs of some muscles. Due to inherent EMG methodological limitations, the superiority of SO in relation to CMC can be only hypothesized. It should be confirmed by conducting further studies comparing joint contact forces. The workflow presented in this study can be used to estimate muscle forces during the preparation phase of the single leg triple hop test and allows investigating muscle activation and coordination. PMID- 28734699 TI - An update on the genetics of dementia with Lewy bodies. AB - The genetic architecture of dementia with Lewy bodies (DLB) is increasingly taking shape. Initially, genetic research focused mainly on linkage and candidate gene studies in small series of DLB patients. More recently, association and exome sequencing studies in larger groups have been conducted, and have shown that several variants in GBA and the APOE epsilon4 allele are important genetic risk factors for DLB. However, genetic research in DLB is still in its infancy. So far, many genetic studies have been biased and performed in clinically and pathologically heterogeneous populations. Therefore, it is likely that multiple DLB-specific genetic determinants still have to be identified. To further our understanding of the role of genetics in DLB, future genetic studies should be unbiased and performed in large series of DLB patients, ideally with both a clinical diagnosis and pathological confirmation. The combination of genomic techniques with other research modalities, such as proteomic research, is a promising approach to identify novel genetic determinants. More knowledge about the genetics of DLB will increase our understanding of the pathophysiology of the disease and its relation with Parkinson's Disease and Alzheimer's Disease, and may eventually lead to the development of disease modifying treatments. PMID- 28734701 TI - Highly chemoselective and efficient production of 2,6-difluorobenzamide using Rhodococcus ruber CGMCC3090 resting cells. AB - Chemoselective biocatalytic hydrolysis of nitriles is a valuable alternative to chemical hydrolysis that operates under harsh conditions. 2,6-Difluorobenzamide (DFBAM) is an essential intermediate derived from synthesis of benzoyl urea insecticide from 2,6-difluorobenzonitrile (DFBN). High yield of DFBAM was achieved, and the method using resting cells of Rhodococcus ruber CGMCC3090 exhibited excellent product specificity. The reaction parameters for DFBAM biosynthesis were also investigated. The resting cells effectively converted DFBN at high concentrations of up to 3.5 mol L-1 without forming acids or other by products. Therefore, biological production of DFBAM features high yield, chemoselectivity, low cost, and environment friendliness and is more suitable to the industry than chemical synthesis techniques. PMID- 28734702 TI - Impact of hypotension after return of spontaneous circulation on survival in patients of out-of-hospital cardiac arrest. AB - OBJECTIVE: To investigate the relationship between hypotension in the first 3h after return of spontaneous circulation (ROSC) in patients with out-of-hospital cardiac arrest. METHOD: This retrospective cohort study occurred at two regional hospitals and included adult OHCA patients who experienced ROSC from July 1, 2014 to December 31, 2015. Hemodynamic and inotrope administration data were retrieved for 3h after ROSC. We calculated the hypotensive exposure index (HEI) as the surrogate marker of the exposure of hypotension. The area under the ROC curve and multivariate logistic regression models were performed to analyze the effect of HEI on survival. Mean arterial pressure (MAP) was explored in the surviving and non-surviving patient groups using repeated measures MANCOVA, adjusted for the use of inotropes and down time. RESULTS: A total of 289 patients were included in the study, and 29 survived. The median 1-hour HEI and 3-hour HEI were significantly lower in the survival group (p<0.001). The area under the ROC curve for 3-hour HEI was 0.861. The repeated measures MANCOVA indicated that an interaction existed between post-ROSC time and downtime [F(5,197)=2.31, p=0.046]. No significant change in the MAP was observed in the 3h after ROSC, except in the group with a prolonged down time. According to the tests examining the effects of the use of inotropes on the survival outcomes of the different subjects, the MAP was significantly higher in the surviving group [F(1,201)=4.11; p=0.044; etap2=0.020]. CONCLUSION: Among the patients who experienced ROSC after OHCA, post-ROSC hypotension was an independent predictor of survival. PMID- 28734703 TI - The differential diagnosis of wide QRS complex tachycardia. AB - Wide complex tachycardia is defined as a cardiac rhythm with a rate greater than 100 beats/min (bpm) and a QRS complex duration greater than 0.10 to 0.12seconds (s) in the adult patient; wide complex tachycardia (WCT) in children is defined according to age-related metrics. The differential diagnosis of the WCT includes ventricular tachycardia and supraventricular tachycardia with aberrant intraventricular conduction, including both relatively benign and life threatening dysrhythmias. This review focuses on the differential diagnosis of WCT with a discussion of strategies useful in making the appropriate diagnosis, when possible. PMID- 28734704 TI - Massive pneumomediastinum following orbital fracture. AB - Pneumomediastinum is a rare complication of facial fractures, always persuading the physicians to search for other and potentially more serious injuries such as esophageal or tracheal rupture. A 75-year old man presented to the Emergency Department (ED) reporting an accidental fall while walking on the road. He did not report loss of consciousness (LOS), was not taking anticoagulant drugs, did not report chest, abdomen or limb trauma. On physical examination he only showed swelling of nose and right orbit. The patient underwent a Computed Tomography (CT) scan of head and facial bones, showing a complex fracture involving right nasal bone, ethmoid, right orbital lateral wall, and right maxillary sinus lateral wall. No intracranial lesions were found. Due to the finding of subcutaneous emphysema in the right cheek, the scan was extended to the whole neck and chest. The exam showed a massive pneumomediastinum, extending till the diaphragmatic hiatus. The patient thus underwent bronchoscopy and esophagogastroscopy, but no further lesions could be found. Antibiotics therapy was then administered, and was discharged in good conditions after a five-days observation. In our patient, air had probably escaped into the pharyngo-maxillary space from the right maxillary sinus and tracked into both the retropharyngeal space and, for contiguity, into the pre-tracheal space. As our case report shows, if the airway is secure, the pneumomediastinum does not necessarily require treatment other than clinical observation and management of the fracture. If no other injuries are present, resolution of the pneumomediastinum may be expected without further medical interventions. PMID- 28734705 TI - A Proficiency Based Stepwise Endovascular Curricular Training (PROSPECT) Program Enhances Operative Performance in Real Life: A Randomised Controlled Trial. AB - OBJECTIVES: Healthcare evolution requires optimisation of surgical training to provide safe patient care. Operating room performance after completion of proficiency based training in vascular surgery has not been investigated. DESIGN: A randomised controlled trial evaluated the impact of a Proficiency based Stepwise Endovascular Curricular Training program (PROSPECT) on the acquisition of endovascular skills and the transferability of these skills to real life interventions. MATERIALS: All subjects performed two endovascular interventions treating patients with symptomatic iliac and/or superficial femoral artery stenosis under supervision. Primary outcomes were technical performances (Global Rating Scale [GRS]; Examiner Checklist), operative metrics, and patient outcomes, adjusted for case difficulty and trainee experience. Secondary outcomes included knowledge and technical performance after 6 weeks and 3 months. METHODS: Thirty two general surgical trainees were randomised into three groups. Besides traditional training, the first group (n = 11) received e-learning and simulation training (PROSPECT), the second group (n = 10) only had access to e-learning, while controls (n = 11) did not receive supplementary training. RESULTS: Twenty nine trainees (3 dropouts) performed 58 procedures. Trainees who completed PROSPECT showed superior technical performance (GRS 39.36 +/- 2.05; Checklist 63.51 +/- 3.18) in real life with significantly fewer supervisor takeovers compared with trainees receiving e-learning alone (GRS 28.42 +/- 2.15; p = .001; Checklist 53.63 +/- 3.34; p = .027) or traditional education (GRS 23.09 +/- 2.18; p = .001; Checklist 38.72 +/- 3.38; p = .001). Supervisors felt more confident in allowing PROSPECT trained physicians to perform basic (p = .006) and complex (p = .003) procedures. No differences were detected in procedural parameters (such as fluoroscopy time, DAP, procedure time, etc.) or complications. Proficiency levels were maintained up to 3 months. CONCLUSIONS: A structured, stepwise, proficiency based endovascular curriculum including e-learning and simulation based training should be integrated early into training programs to enhance trainee performance. PMID- 28734707 TI - Anything New for Nocturia? PMID- 28734706 TI - Emerging Minimally Invasive Treatment Options for Male Lower Urinary Tract Symptoms. AB - CONTEXT: Lower urinary tract symptoms (LUTS) are one of the most common and troublesome nonmalignant conditions affecting quality of life in aging men. A spectrum of established medical and surgical options is available to provide relief of bothersome LUTS. Both the adverse events of medication and the morbidity with surgical treatment modalities have to be counterbalanced against efficacy. Novel minimally invasive treatment options aim to be effective, ideally to be performed in an ambulatory setting under local anaesthesia and to offer a more favourable safety profile than existing reference techniques. OBJECTIVE: A comprehensive, narrative review of novel minimally invasive treatment modalities for the management of male LUTS due to benign prostatic enlargement is presented. EVIDENCE ACQUISITION: Medline, PubMed, Cochrane database, and Embase were screened for randomised controlled trials (RCTs), clinical trials, and reviews on novel minimally invasive treatment options for male LUTS due to benign prostatic enlargement. EVIDENCE SYNTHESIS: With regard to newly devised intraprostatic injectables (botulinum neurotoxin A, NX1207, PRX302), PRX302 is currently the only substance that was superior to placebo in a phase 3 RCT providing proof of efficacy and safety. The prostatic urethral lift technique has been evaluated in several phase 3 trials showing rapid and durable relief of LUTS without compromising sexual function in carefully selected patients without a prominent median lobe. The first clinical experience of the temporary implantable nitinol device demonstrated that implantation of this novel device is a safe procedure, easy, and fast to perform. Further studies are required to evaluate efficacy, durability, and to define appropriate patient selection. New ablative approaches like the image guided robotic waterjet ablation (AquaBeam) or procedures based on convective water vapour energy (Rezum) are in the early stages of development. Prostatic artery embolization performed by interventional radiologists at specialised centres shows a high technical success rate in the treatment of bothersome LUTS. However, a substantial clinical failure rate and a particular spectrum of complications not commonly seen after urologic interventions do occur and need to be critically evaluated. CONCLUSIONS: Initial promising clinical results on novel minimally invasive treatment options indicate efficacy comparable to standard techniques, often associated with a more favourable safety profile, in particular with preservation of sexual function. Many of these techniques are in their infancy and based on experience of new developments in the past. Further RCTs are required to evaluate efficacy, safety, and durability of novel techniques with long-term follow-up and careful evaluation of the selection criteria, which have been applied in clinical trials. The prostatic urethral lift is the only procedure with Level 1 evidence data and that can therefore be recommended for treatment of male LUTS in clinical practice for selected patients. PATIENT SUMMARY: Minimally invasive treatment options have been developed to provide relief of lower urinary tract symptoms comparable to standard surgical techniques with a more favourable safety profile. However, long term clinical evaluation is still needed for most of these innovations before they can be recommended to be an effective replacement for standard surgical treatment. PMID- 28734708 TI - Fractures and Repeated Falls. PMID- 28734709 TI - Worldwide Fracture Prediction. AB - The substantial increase in the burden of non-communicable diseases in general and osteoporosis in particular, necessitates the establishment of efficient and targeted diagnosis and treatment strategies. This chapter reviews and compares different tools for osteoporosis screening and diagnosis; it also provides an overview of different treatment guidelines adopted by countries worldwide. While access to dual-energy X-ray absorptiometry to measure bone mineral density (BMD) is limited in most areas in the world, the introduction of risk calculators that combine risk factors, with or without BMD, have resulted in a paradigm shift in osteoporosis screening and management. To-date, forty eight risk assessment tools that allow risk stratification of patients are available, however only few are externally validated and tested in a population-based setting. These include Osteoporosis Self-Assessment Tool; Osteoporosis Risk Assessment Instrument; Simple Calculated Osteoporosis Risk Estimation; Canadian Association of Radiologists and Osteoporosis Canada calculator; Fracture Risk Assessment Calculator (FRAX); Garvan; and QFracture. These tools vary in the number of risk factors incorporated. We present a detailed analysis of the development, characteristics, validation, performance, advantages and limitations of these tools. The World Health Organization proposes a dual-energy X-ray absorptiometry BMD T-score <= -2.5 as an operational diagnostic threshold for osteoporosis, and many countries have also adopted this cut-off as an intervention threshold in their treatment guidelines. With the introduction of the new fracture assessment calculators, many countries chose to include fracture risk as one of the major criteria to initiate osteoporosis treatment. Of the 52 national guidelines identified in 36 countries, 30 included FRAX derived risk in their intervention threshold and 22 were non-FRAX based. No universal tool or guideline approach will address the needs of all countries worldwide. Osteoporosis screening and management guidelines are best tailored according to the needs and resources of individual counties. While few countries have succeeded in generating valuable epidemiological data on osteoporotic fractures, to validate their risk calculators and base their guidelines, many have yet to find the resources to assess variations and secular trends in fractures, the performance of various calculators, and ultimately adopt the most convenient care pathway algorithms. PMID- 28734710 TI - Use of Trabecular Bone Score (TBS) as a Complementary Approach to Dual-energy X ray Absorptiometry (DXA) for Fracture Risk Assessment in Clinical Practice. AB - Osteoporosis is a common bone disease characterized by low bone mass and altered bone microarchitecture, resulting in decreased bone strength with an increased risk of fractures. In clinical practice, physicians can assess the risk of fracture for a patient based on several risk factors. Some such as age, weight, and history of fractures after 50 years of age, parental fracture, smoking status, and alcohol intake are incorporated into FRAX, an assessment tool that estimates the 10-year probability of hip fracture and major osteoporotic fractures based on the individual's risk factors profile. The diagnosis of osteoporosis is currently based on bone mineral density (BMD) assessed by dual energy X-ray absorptiometry scans. Among other widely recognized limitations of BMD is that BMD considers only the density of the bone and fails in measuring bone microarchitecture, for which novel techniques, such as trabecular bone score (TBS), have been developed. TBS is a texture parameter related to bone microarchitecture that may provide skeletal information that is not captured from the standard BMD measurement. Several studies have examined the value of TBS on predicting osteoporotic fractures. Our study aimed to summarize a review of the current scientific literature with focus on fracture risk assessment and to present both its findings and its conclusions regarding how and when TBS should be used. The existing literature indicates that low lumbar spine TBS is associated with a history of fracture and the incidence of new fracture. The effect is largely independent of BMD and of sufficient magnitude to enhance risk stratification with BMD. The TBS effect is also independent of FRAX, with likely greatest utility for those individuals whose BMD levels lie close to an intervention threshold. The clinical and scientific evidence supporting the use of TBS, with the ability of this technology to be seamlessly integrated into a daily workflow, makes TBS an attractive and useful clinical tool for physicians to improve patient management in osteoporosis. Further research is ongoing and necessary to further clarify the role of TBS in additional specific disorders. PMID- 28734711 TI - [Bifidobacterium scardovii isolated from 2 consecutive urine samples]. AB - Bifidobacterium scardovii species consists of facultative anaerobic gram-positive rods whose growth is stimulated by CO2 and anaerobiosis. Exceptionally it has been associated with infections in humans. An elderly male patient with a urinary tract infection due to B. scardovii and Enterococcus faecalis is presented here; both microorganisms were isolated from two consecutive urine samples. The bacillus did not grow on standard media, but on chocolate agar incubated in CO2 and on supplemented Brucella agar in an anaerobic atmosphere, incubated for 72h at 35 degrees C. Gram staining with abundant irregular gram-positive rods with Y shaped ends and some gram-positive cocci alerted to its presence. The importance of the Gram stain test in urine samples with pyuria and the growth on enriched media for long periods is highlighted here. In this case, if we had not had the Gram stain test results, and had considered only the E. faecalis growth, we would have lost the major etiologic agent. PMID- 28734712 TI - [Candidemia in Pediatrics: Species distribution and antifungal susceptibility]. AB - Serious infections caused by Candida yeasts are frequent in the hospital population. Due to differences in species distribution and antifungal susceptibility testing depending on the geographic area and the type of patient, it is important to study the epidemiology of each institution. For this purpose, we conducted a retrospective, descriptive study on the occurrence of candidemia in the Children's Hospital "Superiora Sor Maria Ludovica" of the city of La Plata. In a 6-year period (2010-2015), 177 candidemia episodes were recorded. The predominant species were Candida albicans (45%) and Candida parapsilosis (28%). The hospital wards with the highest number of candidemia episodes were the pediatric, neonatal and cardiovascular intensive care units (58%). No resistance to amphotericin B was observed throughout the period whereas resistance to azoles was limited to 4 strains of less frequent species. PMID- 28734713 TI - Epidemiological and molecular characteristics of Chlamydia psittaci from 8 human cases of psittacosis and 4 related birds in Argentina. AB - In Argentina, the epidemiological and molecular characteristics of Chlamydia psittaci infections are still not sufficiently known. A total of 846 respiratory and 10 ocular samples from patients with suspected human psittacosis were tested for C. psittaci from January 2010 to March 2015. Four samples of birds related to these patients were also studied. Forty-eight samples were positive for C. psittaci by a nested PCR. The molecular characterization of twelve C. psittaci PCR-positive samples received in the National Reference Laboratory INEI-ANLIS "Dr. Carlos G. Malbran", Buenos Aires, Argentina was performed. Eight positive samples from humans and four from birds were genotyped by ompA gene sequencing. C. psittaci genotype A was found in all human samples and in the related birds. This report contributes to our increasing knowledge of the epidemiological and molecular characteristics of C. psittaci to conduct effective surveillance of its zoonotic infections. PMID- 28734714 TI - Arthroscopic treatment of posterior shoulder instability in patients with and without glenoid dysplasia: a comparative outcomes analysis. AB - BACKGROUND: The purpose of this study was to evaluate the influence of glenoid dysplasia on outcomes after isolated arthroscopic posterior labral repair in a young military population. METHODS: Thirty-seven male patients who underwent arthroscopic posterior labral repair for symptomatic posterior shoulder instability were evaluated at a mean duration of 3.1 years. A comparative analysis was performed for those with glenoid dysplasia and without dysplasia. Additional factors analyzed included military occupational specialty (MOS), preoperative mental health clinical encounters and mental health medication use, and radiographic characteristics (version, posterior humeral head subluxation, and posterior capsular area) on a preoperative standard shoulder magnetic resonance arthrogram. The groups were analyzed with regard to shoulder outcome scores (subjective shoulder value [SSV], American Shoulder and Elbow Surgeons [ASES] rating scale, Western Ontario Shoulder Instability Index [WOSI]), need for revision surgery, and medical separation from the military. RESULTS: Of 37 patients, 3 (8.1%) underwent revision surgery and 6 (16%) underwent medical separation. Overall outcome assessment demonstrated a mean SSV of 67.9 (range, 25 100) +/- 22.1, mean ASES of 65.6 (range, 15-100) +/- 22, and mean WOSI of 822.6 (range, 5-1854) +/- 538. There were no significant differences in clinical outcome scores between the glenoid dysplasia and no dysplasia groups (SSV, P = .55; ASES, P = .57; WOSI, P = .56). MOS (P = .02) and a history of mental health encounters (P = .04) were significantly associated with diminished outcomes. CONCLUSIONS: The presence or absence of glenoid dysplasia did not influence the outcome after arthroscopic posterior labral repair in a young military population. However, a history of mental health clinical encounters and an infantry MOS were significantly associated with poorer clinical outcomes. PMID- 28734715 TI - Elbow flexion and forearm supination strength in a healthy population. AB - BACKGROUND AND HYPOTHESIS: Despite the lack of representative data of a healthy population, many clinical trials concerning the measurement of postoperative elbow flexion or forearm supination strength use the contralateral side as a control. We hypothesized that there are no differences in elbow flexion and supination strength between the dominant and nondominant sides in healthy volunteers. METHODS: The study was performed on a cross-sectional cohort of healthy subjects without any prior injuries or surgical interventions of the upper extremities. Isometric elbow flexion strength and supination strength were measured on both the dominant and nondominant sides. The results were analyzed for the entire group and subanalyzed for female vs. male, for different age groups, and according to handedness and regular practice of overhead sports. RESULTS: A total of 150 subjects (75 female and 75 male subjects; mean age, 44 +/ 15 years [range, 18-72 years]) were included in this study. Within the entire collective, no significant differences concerning the elbow flexion strength between the dominant and nondominant sides could be detected, whereas the supination strength was 7% higher on the dominant side (P = .010). Women, right hand-dominant subjects, and subjects who do not regularly practice overhead sports have a significant 8% higher supination strength on the dominant side compared with the nondominant side (P < .05). Left-hand-dominant subjects have an 8% higher elbow flexion strength on the nondominant right side (P < .05). CONCLUSION: Elbow flexion strength and forearm supination strength differ between the dominant and nondominant sides. The contralateral upper extremity cannot be used as a matched control without some adjustments. PMID- 28734716 TI - Short-term clinical outcome of an anatomic short-stem humeral component in total shoulder arthroplasty. AB - BACKGROUND: Short-stem press-fit humeral components have recently been developed in an effort to preserve bone in total shoulder arthroplasty (TSA), but few studies have reported outcomes of these devices. The purpose of this study was to evaluate the short-term clinical outcomes of an anatomic short-stem humeral component in TSA. We hypothesized that the implant would lead to significant functional improvement with low rates of radiographic loosening. METHODS: A multicenter retrospective review was performed of TSAs using an anatomic short stem humeral component (Apex; Arthrex, Inc., Naples, FL, USA). The minimum follow up was 2 years. Functional outcome was evaluated according to the American Shoulder and Elbow Surgeons score, Visual Analog Scale for pain, Single Assessment Numeric Evaluation, Simple Shoulder Test, and range of motion. A radiographic analysis was performed to evaluate component loosening. RESULTS: Sixty-four patients with a mean age of 64.1 years were available for follow-up at a mean of 25 months postoperatively. There were significant improvements in the Visual Analog Scale (6 to 2; P < .001), Simple Shoulder Test (4 to 10; P < .001), Single Assessment Numeric Evaluation (32 to 84; P < .001), and American Shoulder and Elbow Surgeons (37 to 80; P < .001) scores. Forward flexion improved from 116 degrees to 148 degrees (P < .001), external rotation improved from 30 degrees to 57 degrees (P < .001), and internal rotation improved from an average spinal level of S1 to L2 (P < .001). On radiographic examination, 9% of stems were deemed at risk for loosening, but there was no gross loosening in any patient. CONCLUSIONS: TSA with an anatomic press-fit short-stem humeral component is associated with significant improvements in clinical outcomes, without evidence of component loosening at short-term follow-up. PMID- 28734717 TI - Preoperative doxycycline does not decolonize Propionibacterium acnes from the skin of the shoulder: a randomized controlled trial. AB - BACKGROUND: Propionibacterium acnes is frequently cultured in patients undergoing both primary and revision shoulder surgery. The purpose of this study was to evaluate the efficacy and safety of preoperative oral administration of doxycycline in decreasing the colonization of skin around the shoulder by P. acnes. METHODS: This was a single-institution, prospective, randomized controlled trial of male patients undergoing shoulder arthroscopy. Patients were randomized to receive oral doxycycline (100 mg twice a day) for 7 days or to the standard of care (no drug). Before skin incision, 2 separate 3-mm punch biopsy specimens were obtained from the sites of the anterior and posterior arthroscopic portals and were sent for culture in anaerobic and aerobic medium held for 13 days. RESULTS: There were 22 of 37 (59.5%) patients in the no-drug group and 16 of 37 (43.2%) patients in the doxycycline group who had at least 1 dermal culture positive for P. acnes (P = .245). In the no-drug group, 10 patients (45.5%) had 1 positive culture and 12 (54.5%) had 2 positive cultures (34 total positive cultures [45.9%]). In the doxycycline group, 6 (37.5%) patients had 1 positive culture and 10 (62.5%) had 2 positive cultures (26 total positive cultures [35.1%]; P = .774). DISCUSSION: Administration of oral doxycycline for 7 days before surgery did not reduce colonization of P. acnes significantly. Given the potential risk for emergence of bacterial resistance and the adverse effects associated with administration of antibiotics, we do not recommend routine use of oral doxycycline for preoperative decolonization of the shoulder. PMID- 28734718 TI - Shoulder activity level and progression of degenerative cuff disease. AB - BACKGROUND: This study prospectively examined the relationship of direct and indirect measures of shoulder activity with the risks of tear progression and pain development in subjects with an asymptomatic degenerative rotator cuff tear. METHODS: A cohort of asymptomatic degenerative rotator cuff tears was prospectively monitored annually, documenting tear size progression with ultrasound imaging and potential shoulder pain development. Shoulder activity level, self-reported occupational and physical demand level, and hand dominance were compared with risks of tear enlargement and future pain development. RESULTS: The study monitored 346 individuals with a mean age of 62.1 years for a median duration of 4.1 years (interquartile range [IQR], 2.4-7.9 years). Tear enlargement was seen in 177 shoulders (51.2%), and pain developed in 161 shoulders (46.5%) over time. Tear presence in the dominant shoulder was associated with a greater risk of tear enlargement (hazard ratio, 1.40; P = .03) and pain development (hazard ratio, 1.63; P = .002). Shoulder activity level (P = .37) and occupational demand level (P = .62) were not predictive of tear enlargement. Occupational demand categories of manual labor (P = .047) and "in between" (P = .045) had greater risks of pain development than sedentary demands. The median shoulder activity score for shoulders that became painful was lower than for shoulders that remained asymptomatic (10.0 [IQR, 7.0-13.0] vs. 11.0 [IQR, 8.0-14.0], P = .02). CONCLUSIONS: Tear enlargement and pain development in asymptomatic tears are more common with involvement of the dominant shoulder. Shoulder activity level is not related to tear progression risks. Pain development is associated with a lower shoulder activity level even though patients with higher occupational demands are more likely to develop pain. PMID- 28734719 TI - Coronoid reconstruction using osteochondral grafts: a biomechanical study. AB - HYPOTHESIS: The purposes of this study were to test the hypothesis that coronoid deficiency in the setting of posteromedial rotatory instability (PMRI) must be reconstructed to restore articular contact pressures to normal and to compare 3 different osteochondral grafts for this purpose. METHODS: After creation of a anteromedial fracture, six cadaveric elbows were tested under gravity varus stress using a custom-made machine designed to simulate muscle loads and to passively flex the elbow. Mean articular surface contact pressure data were collected and processed using TekScan sensors and software. After testing of the intact specimen (intact condition), a PMRI injury was created (PMRI condition). Testing was repeated after reconstruction of the lateral collateral ligament (LCL) (LCL-only condition), followed by reconstruction of the coronoid with 3 different osteochondral graft techniques (reconstructed conditions). RESULTS: Contact pressure was consistently significantly higher in the PMRI elbow compared with the intact, LCL-only, and reconstructed conditions (P < .006). The LCL-only elbow contact pressure was significantly higher than that of the intact and reconstructed conditions from 5 degrees to 55 degrees of flexion (P = .018). The contact pressure of the intact elbow was never significantly different from that of the reconstructed elbow, except at 5 degrees of flexion (P <= .008). No significant difference was detected between each of the reconstructed techniques (P >= .15). However, the annular surface of the radial head was the only graft that yielded contact pressures not significantly different from normal at any flexion angle. CONCLUSION: Isolated reconstruction of the LCL did not restore native articular surface contact pressure, and reconstruction of the coronoid using osteochondral graft was necessary. There was no difference in contact pressures among the 3 coronoid reconstruction techniques. PMID- 28734720 TI - Rectal nonsteroidal anti-inflammatory drugs administration is effective for the prevention of post-ERCP pancreatitis: An updated meta-analysis of randomized controlled trials. AB - BACKGROUND: Acute pancreatitis is one of the most common complications of endoscopic retrograde cholangiopancreatography (ERCP). Whether the prophylactic administration of rectal non-steroidal anti-inflammatory drugs (NSAIDs) peri-ERCP is effective in preventing post-ERCP pancreatitis (PEP) remains controversial. The aim of this study was to assess the effect of rectal NSAIDs on PEP. METHODS: A systematic search of literature databases (Cochrane Library, PubMed, EMBASE, and Web of Science) was performed to identify eligible randomized controlled trials (RCTs). The Jadad score for assessing risk of bias was used to evaluate the quality of included studies. The primary endpoint of the study was efficacy for PEP prevention. Sub-analyses were performed to determine the risk reduction for different NSAID types, for general vs. high-risk patients, by timing of administration and for moderate to severe PEP. RESULTS: Twelve RCTs, including a total of 3989 patients, were identified and included in the analysis. The risk of PEP was lower in the NSAIDs group than in the placebo group (RR 0.52; 95% CI 0.43 0.64; P < 0.01). The risk of moderate to severe PEP was also lower in the NSAIDs group. (RR 0.44; 95% CI 0.28-0.69; P < 0.01). There was no difference in efficacy between rectal indomethacin and diclofenac, nor between pre-ERCP and post-ERCP administration timing of rectal NSAIDs. CONCLUSIONS: A single rectal dose of NSAIDs is effective in preventing PEP both in high-risk and in unselected patients, regardless of timing of administration (pre- or post-ERCP) and NSAID type (indomethacin or diclofenac). PMID- 28734721 TI - Factors influencing survival of patients with pancreatic adenocarcinoma and synchronous liver metastases receiving palliative care. AB - BACKGROUND AND AIMS: Patients with pancreatic ductal adenocarcinoma and synchronous liver metastases (PACLM) have an extremely limited life expectancy. We performed a single-center analysis to explore the clinical results and prognostic factors of patients with PACLM receiving palliative care. METHODS: We retrospectively reviewed 189 patients undergoing palliative care at Tianjin Medical University Cancer Hospital over a 15-year period. Clinical characteristics, survival condition, and factors associated with survival were analyzed. Treatment methods included palliative bypass surgery, percutaneous transhepatic cholangiodrainage, drug analgesia, symptomatic treatment, and other nutritional or supportive measures. RESULTS: The overall survival (OS) was 3.6 months for all patients. Multivariate analysis for clinical features showed that Karnofsky performance score (KPS), ascites, cigarette smoking, primary tumor size, and lactate dehydrogenase (LDH) were prognostic variables with statistical significance (P < 0.05). The patients were classified into three groups of patients according to how many of these 5 risk factors were present: 0-1, 2, or 3 5 risk factors. The median OS of the 3 groups of patients were 5.0, 3.3, and 2.5 months, respectively, with a notable statistical significance (P < 0.0001). CONCLUSIONS: KPS<80, ascites, cigarette smoking, primary tumor size>=5 cm, and LDH>=250U/L are effective predictive factors of poor prognosis for patients with PACLM. The stratification of treatment outcome groups based on these factors facilitates evaluation of individual prognosis and can guide clinical decisions. PMID- 28734722 TI - Guidelines for the understanding and management of pain in chronic pancreatitis. AB - Abdominal pain is the foremost complication of chronic pancreatitis (CP). Pain can be related to recurrent or chronic inflammation, local complications or neurogenic mechanisms with corresponding changes in the nervous systems. Both pain intensity and the frequency of pain attacks have been shown to reduce quality of life in patients with CP. Assessment of pain follows the guidelines for other types of chronic pain, where the multidimensional nature of symptom presentation is taken into consideration. Quantitative sensory testing may be used to characterize pain, but is currently used in a research setting in advanced laboratories. For pain relief, current guidelines recommend a simple stepwise escalation of analgesic drugs with increasing potency until pain relief is obtained. Abstinence from alcohol and smoking should be strongly advised. Pancreatic enzyme therapy and antioxidants may be helpful as initial treatment. Endoscopic treatment can be used in patients with evidence of ductal obstruction and may be combined with extracorporeal shock wave lithothripsy. The best candidates are those with distal obstruction of the main pancreatic duct and in early stage of disease. Behavioral interventions should be part of the multidisciplinary approach to chronic pain management particularly when psychological impact is experienced. Surgery should be considered early and after a maximum of five endoscopic interventions. The type of surgery depends on morphological changes of the pancreas. Long-term effects are variable, but high success rates have been reported in open studies and when compared with endoscopic treatment. Finally, neurolytical interventions and neuromodulation can be considered in difficult patients. PMID- 28734723 TI - Response to letter of K. Singh, 'Role of silver nitrate in the efficacy of hydrogen peroxide aerial decontamination systems' regarding S. Ali et al. 'Efficacy of two hydrogen peroxide vapour aerial decontamination systems for enhanced disinfection of meticillin-resistant Staphylococcus aureus, Klebsiella pneumoniae and Clostridium difficile in single isolation rooms'. PMID- 28734724 TI - Vitek(r)2 cannot identify vancomycin-intermediate isolates: missing the opportunity for Staphylococcus aureus therapy. PMID- 28734725 TI - Estrogen receptor alpha is required in GABAergic, but not glutamatergic, neurons to masculinize behavior. AB - Masculinization of the altricial rodent brain is driven by estrogen signaling during a perinatal critical period. Genetic deletion of estrogen receptor alpha (Esr1/ERalpha) results in altered hypothalamic-pituitary-gonadal (HPG) axis signaling and a dramatic reduction of male sexual and territorial behaviors. However, the role of ERalpha in masculinizing distinct classes of neurons remains unexplored. We deleted ERalpha in excitatory or inhibitory neurons using either a Vglut2 or Vgat driver and assessed male behaviors. We find that Vglut2 Cre;Esr1lox/lox mutant males lack ERalpha in the ventrolateral region of the ventromedial hypothalamus (VMHvl) and posterior ventral portion of the medial amygdala (MePV). These mutants recapitulate the increased serum testosterone levels seen with constitutive ERalpha deletion, but have none of the behavioral deficits. In contrast, Vgat-Cre;Esr1lox/lox males with substantial ERalpha deletion in inhibitory neurons, including those of the principal nucleus of the bed nucleus of the stria terminalis (BNSTpr), posterior dorsal MeA (MePD), and medial preoptic area (MPOA) have normal testosterone levels, but display alterations in mating and territorial behaviors. These mutants also show dysmasculinized expression of androgen receptor (AR) and estrogen receptor beta (Esr2). Our results demonstrate that ERalpha masculinizes GABAergic neurons that gate the display of male-typical behaviors. PMID- 28734727 TI - Treatment of pharyngotympanic tube dysfunction. AB - Eustachian tube dysfuntion intends to describe a variety of signs, symptoms, and physical findings that result from the impairment of ET function. A large variety of methods have been employed to assess ET function in the literature. Due to the lack of high level evidence, it is difficult to draw conclusions on the effectiveness of medical and surgical treatments. There are various medical and surgical interventions available for chronic obstructive ET dysfunction including balloon Eustachian tuboplasty (BET) and laser or microdebrider tuboplasty. Consensus on diagnostic criteria for ETD is required to define inclusion criteria of future trials. There is however emerging work with reassuring, but preliminary, results that suggest evidence for safety in the surgical management of ETD. Like many newly introduced techniques the current data remains limited to non-controlled case-series, with heterogeneous data collection methods and lacking substantial long-term outcomes. Nevertheless, short-term data provide favorable results. Current treatment options comprising BET and patulous ET surgery may be offered as a treatment possibility to selected patients. PMID- 28734728 TI - A new PPARgamma/DNA origami biochromatography and offline high performance liquid chromatography-mass spectrometry method for screening PPARgamma receptor antagonists from ginsenosides. AB - To rapidly identify novel PPARgamma ligands, a robust binding assay amenable to high-efficiency screening toward PPARgamma would be desirable. In this study, a new PPARgamma assembled on DNA origami (PPARgamma/DNA origami) biochromatography drug screening model was constructed and evaluated. The method was used to screen active ingredients acted on PPARgamma from the total ginsenosides. The total ginsenosides were handled on this biochromatography column by HPLC. The collected retention fraction from the biochromatography column was analyzed by HPLC and HPLC/MS. The results showed that ginsenoside Re from the total ginsenosides was the targeted component which could act on PPARgamma receptor in similar manner of rosiglitazone as a control drug. This method will be a useful method for drug screening with natural medicinal herbs as a leading compound resource, compared with previous drug screening, this method without the need for complex and time consuming separation steps previously. PMID- 28734729 TI - MiR-143 regulates the proliferation and migration of osteosarcoma cells through targeting MAPK7. AB - Accumulating documents have been suggested that microRNA-143 (miR-143) function as a tumor suppressor, involved in many biological processes including tumor initiation and progression. However, the biological function and molecular mechanism of miR-143 in Osteosarcoma (OS) still remains to be further investigated. Despite many efforts have been made, the prognosis of OS is still unsatisfied. Thus, exploring the underlying mechanism of OS and finding new treatment targets is essential for improving the survival rate of OS patients. In our study, we determined the level of miR-143 in clinical OS tissues and cells, and explored its function and underlying mechanisms in the tumorigenesis of OS. Our findings revealed that miR-143 expression was significantly downregulated in OS tissues and cell lines. Gain-of-function assays indicated that forced expression of miR-143 in OS cells inhibited cell proliferation and migration/invasion. Bioinformatics and luciferase reporter assays confirmed that MAPK7 was targets gene of miR-143. The results of the present study indicated that miR-143 could be a potential target for treating OS. PMID- 28734731 TI - Postnatal corticosteroids to prevent or treat bronchopulmonary dysplasia - Who might benefit? AB - Newborn infants born very preterm are at high risk of developing bronchopulmonary dysplasia, which is associated with not only mortality but also adverse long-term neurological and respiratory outcomes in survivors. Postnatal corticosteroids might reduce the risk of developing bronchopulmonary dysplasia, or reduce its severity. However, it is important to minimize exposure to the potentially harmful effects of corticosteroids, particularly on the developing brain. Systemic corticosteroids started after the first week of life have shown the most benefit in infants at highest risk of developing bronchopulmonary dysplasia, whereas inhaled corticosteroids have little effect in children with established lung disease. Systemic corticosteroids in the first week of life are not recommended, but inhaled corticosteroids, or corticosteroids instilled into the trachea using surfactant as a vehicle to distribute the corticosteroids through the lungs, offer promise with respect to prevention of bronchopulmonary dysplasia. PMID- 28734730 TI - Multifaceted C-X-C Chemokine Receptor 4 (CXCR4) Inhibition Interferes with Anti Vascular Endothelial Growth Factor Therapy-Induced Glioma Dissemination. AB - Resistance to antiangiogenic therapy in glioblastoma (GBM) patients may involve hypoxia-induced expression of C-X-C motif chemokine receptor 4 (CXCR4) on invading tumor cells, macrophage/microglial cells (MGCs), and glioma stem cells (GSCs). We determined whether antagonizing CXCR4 with POL5551 disrupts anti vascular endothelial growth factor (VEGF) therapy-induced glioma growth and dissemination. Mice bearing orthotopic CT-2A or GL261 gliomas received POL5551 and/or anti-VEGF antibody B20-4.1.1. Brain tissue was analyzed for tumor volume, invasiveness, hypoxia, vascular density, proliferation, apoptosis, GSCs, and MGCs. Glioma cells were evaluated for CXCR4 expression and polymorphism and POL5551's effects on CXCR4 ligand binding, cell viability, and migration. No CXCR4 mutations were identified. POL5551 inhibited CXCR4 binding to its ligand, stromal cell-derived factor-1alpha, and reduced hypoxia- and stromal cell-derived factor-1alpha-mediated migration dose-dependently but minimally affected cell viability. In vivo, B20-4.1.1 increased hypoxic foci and invasiveness, as seen in GBM patients receiving anti-VEGF therapy. Combination of POL5551 and B20-4.1.1 reduced both glioma invasiveness by 16% to 39% and vascular density compared to B20-4.1.1 alone in both glioma models. Reduced populations of GSCs and MGCs were also seen in CT-2A tumors. POL5551 concentrations, evaluated by mass spectrometry, were higher in tumors than in neighboring brain tissues, likely accounting for the results. Inhibition of CXCR4-regulated tumoral, stem cell, and immune mechanisms by adjunctive CXCR4 antagonists may help overcome antiangiogenic therapy resistance, benefiting GBM patients. PMID- 28734732 TI - Perinatal and neonatal use of sedation and analgesia. AB - Optimal obstetric and neonatal care requires the provision of adequate analgesia for painful procedures. However, anesthetic and analgesic agents have the potential to adversely impact the developing fetal/neonatal brain. In this setting, clinicians must assess the risks and benefits of pharmacologic anesthesia and analgesia for specific indications in this population. General anesthesia is required for non-obstetric surgery and cesarean section in the absence of neuraxial anesthesia for the health of the mother and fetus. Although experimental data raise concerns, human data are reassuring and future research may focus on neuroprotective adjuncts in the setting of repeated or prolonged anesthetic exposures. Opioid analgesia is standard of care for preterm infants undergoing major procedures including invasive surgery and endotracheal intubation. The use of opioids for agitation resulting from mechanical ventilation is controversial, but prevalent. Randomized and retrospective studies detect short-term toxicity with inconclusive long-term impact, suggesting the need to explore alternative therapies. PMID- 28734733 TI - Diatom Frustule Morphogenesis and Function: a Multidisciplinary Survey. AB - Diatoms represent the major component of phytoplankton and are responsible for about 20-25% of global primary production. Hundreds of millions of years of evolution led to tens of thousands of species differing in dimensions and morphologies. In particular, diatom porous silica cell walls, the frustules, are characterized by an extraordinary, species-specific diversity. It is of great interest, among the marine biologists and geneticists community, to shed light on the origin and evolutionary advantage of this variability of dimensions, geometries and pore distributions. In the present article the main reported data related to frustule morphogenesis and functionalities with contributions from fundamental biology, genetics, mathematics, geometry and physics are reviewed. PMID- 28734734 TI - Nuclear Pore Complexes: A Scaffold Regulating Developmental Transcription? AB - Nuclear pore complexes (NPCs) have a conserved, but poorly understood, role in transcriptional regulation. Recently, in Developmental Cell, Raices et al. argued that tissue-specific nuclear pore proteins (Nups) act as scaffolds that recruit the transcription factor Mef2C to the NPC, promoting transcription of NPC associated genes during muscle development. PMID- 28734736 TI - Analysis of medication adherence-related notes from a service-oriented community pharmacy. AB - BACKGROUND: Medication nonadherence is a significant public health problem. Community pharmacists are positioned to intervene, however, the process is not well understood. OBJECTIVE: To classify and quantify the reasons for nonadherence documented by community pharmacists. METHODS: A retrospective content analysis of pharmacist notes related to nonadherence at a service oriented community pharmacy in the Midwest United States. Notes from the site's dispensing custom documentation software were obtained from September 1, 2014 through February 28, 2015 that were labeled "compliance", either prompted by proportion of days covered calculations or entered as a drug therapy problem. A code list was iterated for the notes based on the literature and by reading the notes and generating descriptive codes. A reliability analysis was calculated for two coders. Notes were coded, check-coded, and discrepancies were resolved using a consensus process. Frequencies were calculated for each code and representative text was selected. RESULTS: Pharmacists documented 3491 notes as part of their continuous medication monitoring process. Nineteen codes were developed. The reliability for the coders had a Cohen's Kappa of 0.749. The majority of notes (61.4%) documented the pharmacist evaluated the refill and had no concerns or would continue to follow. Also documented were specific reasons for out of range PDCs not indicative of a nonadherence problem. Only 2.2% of notes specifically documented a nonadherence problem, such as forgetfulness or cost. CONCLUSION: While pharmacists encountered many false positive nonadherence alerts, following up with patients led to hundreds of discussions and clarifications about how patients use their medications at home. These results suggest a small minority of late refills are judged by pharmacists as indicative of an adherence problem, contrary to the prevailing literature. Pharmacists may benefit from modifying their approach to nonadherence interviewing and documentation as they seek to address nonadherence in practice. SYNOPSIS: This study descriptively coded community pharmacist notes related to medication nonadherence. Most notes were prompted by automatic calculations by the documentation software of the proportion of days covered. This prompted regular conversations about non adherence issues and clarifications on how medications are being used at home. Documentation suggested most adherence problems were technical in nature rather than stemming from patient factors like medication beliefs. Pharmacists could be more intentional and descriptive when documenting nonadherence issues so that more targeted follow up can be made, including a greater investigation of medication beliefs. PMID- 28734737 TI - Ginsenoside F2 induces the release of mediators associated with Anaphylactoid reactions. AB - Recently, the allergenicity of ginsenosides, as main active components in ginseng, has attracted much attention. Ginsenoside Rb1 and Rd. have been reported to induce anaphylactoid reaction. In this study, the allergenicity of a series of 20(S)-protopanaxadiol (PPD) type ginsenosides, including Rb1, Rd., F2, Compound K and 20(S)-PPD, was evaluated in rat basophilic leukemia 2H3 (RBL2H3) cells. As a result, 20(S)-PPD had no effect on the mast cell degranulation, but other components showed anaphylactoid potential to different extent. The allergenicity was stronger and stronger according to the order "Rb1, Rd., F2, Compound K". Then, F2 was further verified in RBL-2H3 cells, mouse peritoneal mast cells (MPMCs), Laboratory of Allergic Disease 2 (LAD2) human mast cells in vitro and mice in vivo. Results showed that F2 could induce a significant increase of histamine release and translocation of phosphatidylserine in RBL-2H3 cells. F2 also increased beta-hexosaminidase release and the intracellular Ca2+ concentration of MPMCs and LAD2 cells. In addition, histamine level in serum of mice was elevated dose-dependently. Our study revealed the potential structure allergenicity relationship of 20(S)-PPD type ginsenosides and first verified the allergenicity of ginsenoside F2. This study could guide the establishment of quality standards for safe application of ginsenoside-containing preparations. PMID- 28734735 TI - Metabolic Interactions in the Tumor Microenvironment. AB - Tumors are dynamic pseudoorgans that contain numerous cell types interacting to create a unique physiology. Within this network, the malignant cells encounter many challenges and rewire their metabolic properties accordingly. Such changes can be experienced and executed autonomously or through interaction with other cells in the tumor. The focus of this review is on the remodeling of the tumor microenvironment that leads to pathophysiologic interactions that are influenced and shaped by metabolism. They include symbiotic nutrient sharing, nutrient competition, and the role of metabolites as signaling molecules. Examples of such processes abound in normal organismal physiology, and such heterocellular metabolic interactions are repurposed to support tumor metabolism and growth. The importance and ubiquity of these processes are just beginning to be realized, and insights into their role in tumor development and progression are being used to design new drug targets and cancer therapies. PMID- 28734738 TI - Evaluation of the biotechnological potential of bacterioplankton from Niteroi coast, RJ. AB - Production of antibiotics and enzymes by microorganisms is well recognized for its economic benefits. Searching potentially exploitable microorganisms, strains of heterotrophic bacteria were isolated from marine and estuarine waters in Niteroi-RJ, Brazil, and tested for the production of enzymes and antimicrobial substances. From the 76 isolated colonies, 09.21% showed antimicrobial potential, 63.16% showed enzymatic activity for at least one of the substrates tested and 91% showed multidrug resistance. Strains that presented the better results were identified by sequencing. The species identified are widely distributed in many different types of environments, having been isolated previously from marine environment. Our results suggest that marine and estuarine waters can be a source for bioprospecting bacteria with potential biotechnological uses. PMID- 28734739 TI - Serum levels of squamous cell carcinoma antigens 1 and 2 reflect disease severity and clinical type of atopic dermatitis in adult patients. AB - BACKGROUND: Recent studies have indicated that serum levels of squamous cell carcinoma antigen (SCCA) 1 and 2 induced by type 2 cytokines such as IL-4 and IL 13, are increased in patients with atopic dermatitis (AD). However, no clinical studies have analyzed serum levels of SCCA2 in larger series of AD patients or their association with various clinical characteristics. This study was performed to clarify whether serum levels of SCCA2 are associated with disease severity and clinical phenotypes of adult AD patients. METHODS: An enzyme-linked immunosorbent assay was performed to examine serum SCCA2 levels in 240 adult patients with AD and 25 healthy controls in this study. Serum SCCA2 levels were analyzed with clinical characteristics and laboratory parameters including thymus and activation-regulated chemokine (TARC), lactate dehydrogenase (LDH), blood eosinophils, total IgE, and specific IgE (Japanese cedar pollen, Dermatophagoides farina, Candida, malassezia, Staphylococcal enterotoxin B). Expression of SCCA2 in AD eruption was examined by immunohistochemistry. The effect of treatment on serum SCCA2 was also assessed. RESULTS: Serum SCCA2 level showed a positive correlation with disease severity, levels of TARC, LDH, eosinophil counts, and IgE levels. Robust expression of SCCA2 was detected in the supra basal keratinocytes in the epidermis of AD patients. Serial measurements of serum SCCA2 revealed decreased levels of SCCA2 after treatment for AD. CONCLUSIONS: Serum SCCA2 levels reflected disease severity and clinical type of AD. Serum SCCA2 may thus be a relevant biomarker for AD. PMID- 28734740 TI - Immediate-type allergic reactions to local anesthetics. PMID- 28734741 TI - Beneficial effects of TQRF and TQ nano- and conventional emulsions on memory deficit, lipid peroxidation, total antioxidant status, antioxidants genes expression and soluble Abeta levels in high fat-cholesterol diet-induced rats. AB - The study determined the effect of thymoquinone rich fraction (TQRF) and thymoquinone (TQ) in the forms of nano- and conventional emulsions on learning and memory, lipid peroxidation, total antioxidant status, antioxidants genes expression and soluble beta-amyloid (Abeta) levels in rats fed with a high fat cholesterol diet (HFCD). The TQRF was extracted from Nigella sativa seeds using a supercritical fluid extraction system and prepared into nanoemulsion, which later named as TQRF nanoemulsion (TQRFNE). Meanwhile, TQ was acquired commercially and prepared into thymoquinone nanoemulsion (TQNE). The TQRF and TQ conventional emulsions (CE), named as TQRFCE and TQCE, respectively were studied for comparison. Statin (simvastatin) and non-statin (probucol) cholesterol-lowering agents, and a mild-to-severe Alzheimer's disease drug (donepezil) were served as control drugs. The Sprague Dawley rats were fed with HFCD for 6 months, and treated with the intervention groups via oral gavage daily for the last 3 months. As a result, HFCD-fed rats exhibited hypercholesterolaemia, accompanied by memory deficit, increment of lipid peroxidation and soluble Abeta levels, decrement of total antioxidant status and down-regulation of antioxidants genes expression levels. TQRFNE demonstrated comparable effects to the other intervention groups and control drugs in serum biomarkers as well as in the learning and memory test. Somehow, TQRFNE was more prominent than those intervention groups and control drugs in brain biomarkers concomitant to gene and protein expression levels. Supplementation of TQRFNE into an HFCD thus could ameliorate memory deficit, lipid peroxidation and soluble Abeta levels as well as improving the total antioxidant status and antioxidants genes expression levels. PMID- 28734742 TI - Efficacy of a nonadjuvanted recombinant FeLV vaccine and two inactivated FeLV vaccines when subject to consistent virulent FeLV challenge conditions. AB - The purpose of this study was to compare the efficacy of three FeLV vaccines, under identical conditions in a laboratory challenge model that closely mimics natural infection. Four groups of cats (n = 20 per group) were administered two doses of vaccine, 21 days apart, starting at 9-10 weeks of age (Purevax(r) FeLV, Versifel(r) FeLV, Nobivac(r) feline 2-FeLV, and a placebo). Cats were challenged 3 weeks later with a virulent, heterologous FeLV isolate. FeLV antigenemia was determined at weekly intervals from 3 to 15 weeks postchallenge. Circulating proviral DNA was determined on terminal PBMC samples. Following challenge, persistent antigenemia developed in 15 (75%) placebo-vaccinated cats, 3 (15%) cats in the Versifel FeLV vaccinated group, and 1 cat (5%) each in the Purevax FeLV and the Nobivac FeLV vaccinated groups. The prevented fractions for three vaccine groups were 93%, 93%, and 80% respectively. The adjusted p-values for all vaccine group comparisons fail to approach statistical significance. There was excellent agreement between proviral FeLV DNA in circulating PBMCs and persistent antigenemia. It is shown that when cats are managed under the same conditions during a virulent challenge, via the normal route of infection, the tested vaccines all show a comparable degree of protection. PMID- 28734743 TI - Adjuvantation of inactivated Foot and Mouth Disease Virus vaccine with IL-15 expressing plasmid improves the immune response in Guinea Pigs. AB - Foot and mouth disease is a highly contagious disease affecting cloven footed animals. Vaccination using inactivated virus is followed to control the disease. As the immune response conferred by the inactivated vaccine is short lived, there is a need for an alternate vaccine with increased duration of immunity. Inclusion of adjuvant which enhances B and T cell responses is one of the strategies to increase the duration of immune responses of the vaccine. Interleukin 15 is one such a cytokine which improves the cell mediated immune response and also involved in the maintenance of memory T and B cells. In the present communication, we evaluated the role of bovine IL-15 as an adjuvant to inactivated FMD vaccine in guinea pig model. Animals injected with FMD inactivated vaccine and IL-15 plasmid showed improved levels of neutralizing antibodies which were maintained up to 6 months (as the level of neutralizing antibodies is more >1.5 which is considered to give protection). Increased Th1 and Th2 responses (by measuring the level of IL-4 and IFN- gamma responses) were seen in IL-15 adjuvanted guinea pigs compared to animals injected with inactivated vaccine alone. PMID- 28734744 TI - Post-war prevention: Emerging frameworks to prevent drug use after the War on Drugs. AB - The prevention of drug use is one of the primary goals of the War on Drugs. However, despite investment in high-profile interventions such as social marketing campaigns and enforcement-based deterrence, these efforts have generally failed. With the emergence of novel policy frameworks to control and regulate drug use, a window of opportunity exists to test approaches to drug prevention that take into account existing evidence and the rights of individuals who use drugs. Specifically, there is a growing consensus that entry into drug use is a socially-defined event that individuals experience within particular socio-structural contexts. This understanding, coupled with a distinction between the value of preventing problematic drug use rather than all drug use, provides a useful framework within which to develop effective and rights-based approaches to drug prevention. PMID- 28734746 TI - Spina Bifida Management. AB - Myelomeningocele, commonly known as spina bifida, is a birth defect in which the spinal cord does not develop properly due to incomplete closure of the neural tube at 28 days of gestation. With advances in treatment modalities, technologies, and medical knowledge, people with spina bifida in the United States are living well into adulthood. Myelomeningocele management includes life long comprehensive neurologic, urologic, musculoskeletal, skin, and habilitation management. We describe approaches to the same, with an emphasis on the signs and symptoms of medical urgencies and emergencies of which every pediatrician must be aware. PMID- 28734745 TI - Why are some people who have received overdose education and naloxone reticent to call Emergency Medical Services in the event of overdose? AB - BACKGROUND: Overdose Education and Naloxone Distribution (OEND) training for persons who inject drugs (PWID) underlines the importance of summoning emergency medical services (EMS). To encourage PWID to do so, Colorado enacted a Good Samaritan law providing limited immunity from prosecution for possession of a controlled substance and/or drug paraphernalia to the overdose victim and the witnesses who in good faith provide emergency assistance. This paper examines the law's influence by describing OEND trained PWIDs' experience reversing overdoses and their decision about calling for EMS support. METHODS: Findings from two complementary studies, a qualitative study based on semi-structured interviews with OEND trained PWID who had reversed one or more overdoses, and an on-going fieldwork-based project examining PWIDs' self-identified health concerns were triangulated to describe and explain participants' decision to call for EMS. RESULTS: In most overdose reversals described, no EMS call was made. Participants reported several reasons for not doing so. Most frequent was the fear that despite the Good Samaritan law, a police response would result in arrest of the victim and/or witness for outstanding warrants, or sentence violations. Fears were based on individual and collective experience, and reinforced by the city of Denver's aggressive approach to managing homelessness through increased enforcement of misdemeanors and the imposition of more recent ordinances, including a camping ban, to control space. The city's homeless crisis was reflected as well in the concern expressed by housed PWID that an EMS intervention would jeopardize their public housing. CONCLUSION: Results suggest that the immunity provided by the Good Samaritan law does not address PWIDs' fear that their current legal status as well as the victim's will result in arrest and incarceration. As currently conceived, the Good Samaritan law does not provide immunity for PWIDs' already enmeshed in the criminal justice system, or PWID fearful of losing their housing. PMID- 28734747 TI - Retroperitoneal fibrosis associated with immunoglobulin g4-related disease in the differential diagnosis in retroperitoneal tumors. Case report. AB - The patient was a 55-year-old woman with a 4-month history of pain in left flank that irradiated to the lumbar region. Computed tomography revealed a cystic tumor in the retroperitoneal region that compresses the ureter and left renal pelvis in contact with pancreatic body and tail. Surgery was performed and the definitive pathological report diagnosed nodular retroperitoneal fibrosis associated with IgG4; Ki67-positive in germinal centers (5%) and IgG4-positive (40 plasma cells in 3 fields of 40x) by immunohistochemistry. Retroperitoneal fibrosis is a rare disease, that develops gradually and has an excellent response to steroid management. Surgical treatment is reserved for cases that compromise adjacent structures. Thus, identifying it when studying a retroperitoneal tumor leads to better prognosis and survival. PMID- 28734748 TI - Effects of arginine-based immunonutrition on inpatient total costs and hospitalization outcomes for patients undergoing colorectal surgery. AB - OBJECTIVE: The aim of this study was to assess the effects of an arginine-based immunonutrition intervention for patients undergoing elective colorectal surgery on postsurgical utilization and cost outcomes. METHODS: This analysis was based on data from two Washington State databases: Surgical Care and Outcomes Assessment Program (SCOAP) linked to the Comprehensive Hospital Abstract Reporting System (CHARS). The sample (N=722) comprises adult patients who underwent elective colorectal surgery with anastomosis in a Washington State hospital that participated in the Strong for Surgery (S4S) initiative between January 1, 2012, and December 31, 2013. A generalized linear model was used to predict the outcomes, adjusting for demographic characteristics and patient health conditions within a multivariate regression framework. RESULTS: Findings from this study demonstrated significantly fewer readmissions and hospital days for the intervention group during the 180 d after index hospitalization. Clinical benefits included decreased risk for infections and venous thromboembolism. There was a similar pattern toward lower total costs in the immunonutrition patient group; however, these were not statistically different compared with the control group at any time point. Savings in the immunonutrition group were substantial mean total costs per patient were less by ~$2500 at index hospitalization, $3500 less through 30 d of follow-up, and $5300 less over 180 d compared with the control group. CONCLUSION: These findings suggest that arginine-based immunonutrition should be thoroughly evaluated for incorporation into clinical practice for patients undergoing elective surgery. Moreover, there is a need to assess the effects of the intervention in other hospitals both within and outside Washington. PMID- 28734749 TI - Understanding the main route of drug entry in adult Fasciola hepatica: Further insights into closantel pharmacological activity. AB - Closantel (CLS) is highly effective against adult liver flukes after its oral or subcutaneous (sc) administration in ruminants. Trans-tegumental diffusion and oral ingestion are the two potential routes available for the entry of drugs into Fasciola hepatica. The work reported here contributes to improve the understanding of CLS pharmacology. The main goals of were: I) to determine the pattern of in vivo CLS accumulation into adult F. hepatica and relevant tissues in CLS-treated sheep; II) to investigate the influence of the physicochemical composition of the incubation medium on the CLS diffusion process into adult F. hepatica; III) to assess the ovicidal activity of CLS against F. hepatica eggs; and IV) to investigate the in vivo effect of CLS treatment on glutathione S transferases activity in adult liver flukes exposed to CLS. Fourteen healthy sheep were each orally infected with 75 F. hepatica metacercariae. Sixteen (16) weeks after infection, animals were treated with CLS by oral (n = 6, 10 mg/kg) or sub-cutaneous (sc) (n = 6, 5 mg/kg) route. At 12, 24 and 36 h post-treatment, animals were sacrificed (n = 2) and samples of blood, bile and adult F. hepatica were collected. In addition, flukes recovered from non-treated sheep (n = 2) were ex vivo incubated (60 min) in the presence of CLS in either RPMI or bile as incubation medium. CLS concentration was measured by HPLC. The ovicidal activity of CLS was investigated using eggs obtained from the bile of untreated sheep. Finally, glutathione S-transferase activity in F. hepatica recovered from untreated and CLS-treated sheep was assessed. In the in vivo studies, the highest CLS concentrations were measured in plasma and adult liver flukes. A positive correlation was observed between CLS concentration in plasma and in F. hepatica. Results obtained in the current work indicate that the in vivo accumulation of CLS into adult liver flukes occurs mainly by the oral route. After ex vivo incubation, the uptake of CLS by the parasite was markedly diminished in the presence of bile compared with that observed in the presence of RPMI as incubation medium. CLS lacks ovicidal activity at therapeutically relevant concentrations. Lastly, CLS significantly increased glutathione S-transferase activity in flukes recovered at 12 h (oral treatment) and 24 h (sc treatment), compared to the control liver flukes. PMID- 28734750 TI - Deconstructing stigma in psychogenic nonepileptic seizures: An exploratory study. AB - Psychogenic nonepileptic seizures (PNES) are classified as a mental disorder, the manifestations of which superficially resemble epileptic seizures. There is a notable lack of in-depth qualitative or quantitative studies investigating the stigma attached to PNES. The current study is an exploratory analysis into the nature of perceived stigma in those with PNES when compared with individuals with epilepsy. Individuals with epilepsy (n=78) and PNES (n=47) were recruited from a United Kingdom hospital or membership-led organizations for individuals living with seizures. Participants were asked to complete a series of questionnaires investigating health-related quality-of-life components (NEWQOL-6D), anxiety (GAD 7), depression (NDDI-E), seizure frequency and severity (LSSS-3), and illness perception (B-IPQ). Perceived stigma was measured using one question taken from the NEWQOL-6D. Individuals with PNES reported a greater level of perceived stigma than those with epilepsy (p=0.04). Our results indicate that the risk of experiencing perceived stigma in PNES was 42% higher than the risk in epilepsy. In epilepsy, but not PNES, perceived stigma was significantly associated with seizure frequency, anxiety, depression, and many of the sequelae of the condition. In both conditions, self-control was associated with stigma (rho>=0.34, p<=0.01). This study was exploratory, and so definitive conclusions cannot be made; however, our findings suggest that the majority (87.2%) of individuals with PNES reported experiencing some degree of perceived stigma, the risk of which is greater than that in epilepsy. Further research is needed into the prevalence, nature, and consequences of stigma in PNES. PMID- 28734751 TI - How many people work in your operating room? An assessment of factors associated with instrument recounts within plastic surgery. AB - BACKGROUND: Intraoperative instrument recounts are performed to avoid retained foreign surgical items. These additional counts, however, beget risks of their own, including prolonged operative times, exposure to radiation, and increased cost. Our study aimed to identify factors that increase the likelihood of instrument recounts during plastic surgery procedures, and use our findings to guide potential solutions for preventing unnecessary recounts across all surgical fields. STUDY DESIGN: This is a retrospective review of all plastic surgical cases in the main operating setting at New York University Langone Medical Center (NYULMC) between March 2014 and February 2015. RESULTS: Of 1285 plastic surgery cases, 35 (2.7%) reported a missing instrument necessitating a recount. Of all subspecialties within plastic surgery, only microsurgery conferred an increased risk of a recount event. We identified multiple factors that increased the odds of a recount event, including increased operative time, number of surgical sites, and intraoperative instrument handoffs. CONCLUSION: Instrument recounts, although designed to prevent inadvertently retained surgical items, present inherent risks of their own. In a large retrospective review of plastic surgery cases at our medical center, we identified many factors that increased the likelihood of an instrument recount. On the basis of our findings and prior literature, we recommend limiting the number of staff handling instrument, the number of handoffs, and a heightened awareness by surgeons and perioperative staff of specific procedures and factors that increase the risk of a miscount event. PMID- 28734752 TI - Long-term effect of oncoplastic breast-conserving surgery using latissimus dorsi miniflaps on mammographic surveillance and the detection of local recurrence. AB - INTRODUCTION: Latissimus dorsi miniflap is a breast-conserving volume replacement technique for the reconstruction of large breast defects. While mammographic features of miniflap reconstruction have been described, little is known about the incidence, mode of presentation and size of local recurrence after this procedure. This study aimed to investigate the impact of latissimus dorsi miniflap reconstruction on the frequency, presentation and detection of local recurrence. METHODS: Clinical, radiological and pathological data were reviewed in 261 patients. Complete records were available for 11 patients developing local recurrence, including mode, time of presentation and size of the recurrent tumours. All mammograms before and after local recurrence were assessed in relation to a range of specific characteristics including parenchymal density, flap visibility, architectural distortion, mass, calcifications, fat necrosis, skin thickening and breast oedema. RESULTS: Twenty-one patients developed local recurrence at 10.4 years following reconstruction (mean age 49 years, resection weight 182 g and tumour size 33 mm). Following radiotherapy, 0.5% of patients developed local recurrence each year, which increased five-fold when radiotherapy was omitted (HR 4.99). Local recurrences were diagnosed in five patients by mammography alone, in three by mammography and palpable lump, and in three by palpable lump alone. They were detected when small (15 mm) and were associated with new mammographic abnormalities in 10 patients. CONCLUSIONS: Long follow-up demonstrates that latissimus dorsi miniflap reconstruction allows oncologically safe breast conservation when combined with postoperative radiotherapy. Local recurrences are detected early, either by mammography, clinical examination or both, and detection is not compromised by the presence of a flap. PMID- 28734753 TI - Cranial bone structure in children with sagittal craniosynostosis: Relationship with surgical outcomes. AB - BACKGROUND: While spring-assisted cranioplasty has become a widespread technique to correct scaphocephaly in children with sagittal synostosis, predicting head shape changes induced by the gradual opening of the springs remains challenging. This study aimed to explore the role of cranial bone structure on surgical outcomes. METHODS: Patients with isolated sagittal synostosis undergoing spring assisted cranioplasty at GOSH (London, UK) were recruited (n = 18, age: 3-8 months). Surgical outcome was assessed by the change in cephalic index measured on 3D head scans acquired before spring insertion and after their removal using a 3D handheld scanner. Parietal bone samples routinely discarded during spring assisted cranioplasty were collected and scanned using micro-computed tomography. From visual assessment of such scans, bone structure was classified into one- or three-layered, the latter indicating the existence of a diploe cavity. Bone average thickness, volume fraction and surface density were computed and correlated with changes in cephalic index. RESULTS: Cephalic index increased for all patients (p < 0.001), but individual improvement varied. Although the patient age and treatment duration were not significantly correlated with changes in cephalic index, bone structural parameters were. The increase of cephalic index was smaller with increasing bone thickness (Pearson's r = -0.79, p < 0.001) and decreasing bone surface density (r = 0.77, p < 0.001), associated with the three layered bone structure. CONCLUSIONS: Variation in parietal bone micro-structure was associated with the magnitude of head shape changes induced by spring assisted cranioplasty. This suggests that bone structure analysis could be a valuable adjunct in designing surgical strategies that yield optimal patient specific outcomes. PMID- 28734754 TI - Cost analysis of microtia treatment in the Netherlands. AB - INTRODUCTION: Ear reconstruction for microtia is a challenging procedure. Although analyzing esthetic outcome is crucial, there is a paucity of information with regard to financial aspects of microtia reconstruction. This study was conducted to analyze the costs associated with ear reconstruction with costal cartilage in patients with microtia. METHODS: Ten consecutive children with autologous ear reconstruction of a unilateral microtia were included in this analysis. All patients had completed their treatment protocol for ear reconstruction. Direct costs (admission to hospital, diagnostics, and surgery) and indirect cost (travel expenses and absence from work) were obtained retrospectively. RESULTS: The overall mean cumulative cost per patient was ?14,753. Direct and indirect costs were ?13,907 and ?846, respectively. Hospital admission and surgery cover 55% and 32% of all the costs, respectively. DISCUSSION: This study analyzes the costs for autologous ear reconstruction. Hospital admission and surgery are the most important factors of the total costs. Total costs could be decreased by possibly decreasing admission days and surgical time. These data can be used for choosing and developing future treatment strategies. PMID- 28734755 TI - Prenatal ultrasound detection of micrognathia and its association with Robin sequence. PMID- 28734756 TI - 3D bioprinting for reconstructive surgery: Principles, applications and challenges. AB - Despite the increasing laboratory research in the growing field of 3D bioprinting, there are few reports of successful translation into surgical practice. This review outlines the principles of 3D bioprinting including software and hardware processes, biocompatible technological platforms and suitable bioinks. The advantages of 3D bioprinting over traditional tissue engineering techniques in assembling cells, biomaterials and biomolecules in a spatially controlled manner to reproduce native tissue macro-, micro- and nanoarchitectures are discussed, together with an overview of current progress in bioprinting tissue types relevant for plastic and reconstructive surgery. If successful, this platform technology has the potential to biomanufacture autologous tissue for reconstruction, obviating the need for donor sites or immunosuppression. The biological, technological and regulatory challenges are highlighted, with strategies to overcome these challenges by using an integrated approach from the fields of engineering, biomaterial science, cell biology and reconstructive microsurgery. PMID- 28734757 TI - Editorial overview: Systems biology for biotechnology. PMID- 28734758 TI - Atypical interference control in children with AD/HD with elevated theta/beta ratio. AB - The theta/beta ratio (TBR) is a major area of interest within electroencephalogram (EEG) research in AD/HD. While researchers suggest a prognostic role for TBR in AD/HD, its relationship to behavior remains uncertain. Recent evidence suggests that elevated TBR in AD/HD may be related to atypical inhibition, particularly at an attentional level. This study aimed to examine the performance on three inhibitory tasks of children with AD/HD. Fifty-eight children with AD/HD participated, divided into an elevated TBR (ET) group and a control group (CT). A behavioral disassociation was found - compared to CT, ET showed more difficulty in inhibiting surrounding stimuli but had less day-to-day inhibitory issues measured by BRIEF. There was no significant group difference on response inhibition. The results support the prognostic value of TBR in AD/HD. Elevated TBR may be an inhibitory biomarker; further studies are needed to explore the behavioral implications in patients without elevated TBR. PMID- 28734760 TI - PD-1 inhibition in metastatic dMMR/MSI-H colorectal cancer. PMID- 28734759 TI - Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. AB - BACKGROUND: Metastatic DNA mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) colorectal cancer has a poor prognosis after treatment with conventional chemotherapy and exhibits high levels of tumour neoantigens, tumour-infiltrating lymphocytes, and checkpoint regulators. All of these features are associated with the response to PD-1 blockade in other tumour types. Therefore, we aimed to study nivolumab, a PD-1 immune checkpoint inhibitor, in patients with dMMR/MSI-H metastatic colorectal cancer. METHODS: In this ongoing, multicentre, open-label, phase 2 trial, we enrolled adults (aged >=18 years) with histologically confirmed recurrent or metastatic colorectal cancer locally assessed as dMMR/MSI-H from 31 sites (academic centres and hospitals) in eight countries (Australia, Belgium, Canada, France, Ireland, Italy, Spain, and the USA). Eligible patients had progressed on or after, or been intolerant of, at least one previous line of treatment, including a fluoropyrimidine and oxaliplatin or irinotecan. Patients were given 3 mg/kg nivolumab every 2 weeks until disease progression, death, unacceptable toxic effects, or withdrawal from study. The primary endpoint was investigator-assessed objective response as per Response Evaluation Criteria in Solid Tumors (version 1.1). All patients who received at least one dose of study drug were included in all analyses. This trial is registered with ClinicalTrials.gov, number NCT02060188. FINDINGS: Of the 74 patients who were enrolled between March 12, 2014, and March 16, 2016, 40 (54%) had received three or more previous treatments. At a median follow-up of 12.0 months (IQR 8.6-18.0), 23 (31.1%, 95% CI 20.8-42.9) of 74 patients achieved an investigator-assessed objective response and 51 (69%, 57-79) patients had disease control for 12 weeks or longer. Median duration of response was not yet reached; all responders were alive, and eight had responses lasting 12 months or longer (Kaplan-Meier 12-month estimate 86%, 95% CI 62-95). The most common grade 3 or 4 drug-related adverse events were increased concentrations of lipase (six [8%]) and amylase (two [3%]). 23 (31%) patients died during the study; none of these deaths were deemed to be treatment related by the investigator. INTERPRETATION: Nivolumab provided durable responses and disease control in pre treated patients with dMMR/MSI-H metastatic colorectal cancer, and could be a new treatment option for these patients. FUNDING: Bristol-Myers Squibb. PMID- 28734761 TI - Patients with Duchenne muscular dystrophy are significantly shorter than those with Becker muscular dystrophy, with the higher incidence of short stature in Dp71 mutated subgroup. AB - Duchenne and Becker muscular dystrophy (DMD/BMD) are caused by mutations in the dystrophin gene and are characterized by severe and mild progressive muscle wasting, respectively. Short stature has been reported as a feature of DMD in the Western hemisphere, but not yet confirmed in Orientals. Height of young BMD has not been fully characterized. Here, height of ambulant and steroid naive Japanese 179 DMD and 42 BMD patients between 4 and 10 years of age was retrospectively examined using height standard deviation score (SDS). The mean height SDS of DMD was -1.08 SD that was significantly smaller than normal (p < 0.001), indicating short stature of Japanese DMD. Furthermore, the mean height SDS of BMD was -0.27 SD, suggesting shorter stature than normal. Remarkably, the mean height SDS of DMD was significantly smaller than that of BMD (p < 0.0001). In DMD higher incidence of short stature (height SDS < -2.5 SD) was observed in Dp71 subgroup having mutations in dystrophin exons 63-79 than others having mutations in exons 1-62 (27.8% vs. 7.5%, p = 0.017). These suggested that height is influenced by dystrophin in not only DMD but also BMD and that dystrophin Dp71 has a role in height regulation. PMID- 28734762 TI - Breast cancer mortality in European Union: An outlook of good news and bad news in a two-speed Europe! PMID- 28734763 TI - Uncleaved 2A-peptide of foot-and-mouth disease virus can display foreign epitope tag at the virion surface. AB - Foot-and-mouth disease virus (FMDV) capsid precursor protein P1-2A is cleaved by viral-encoded 3C protease (3Cpro) to generate VP0, VP3, VP1 and 2A proteins. It was reported earlier that substitution of a single amino acid residue within the 2A peptide sequence (L2P) blocked the 3Cpro mediated VP1/2A cleavage and produced 'self-tagged' FMDV particles containing uncleaved 2A-peptide. To determine whether the uncleaved 2A-peptide can function as a target structure to harbour and display exogenous epitope on FMDV particles, a full-length FMDV cDNA clone containing a HA-tag within the uncleaved 2A-peptide sequence was constructed. Subsequently, chimeric marker FMDV, displaying a HA-tag on the viral surface was rescued through reverse genetics approach. The 2A-HA epitope tag-inserted recombinant chimeric FMDV serotype O was genetically stable through up to ten serial passages in cell culture and exhibited growth properties similar to the parental virus. Furthermore the surface displayed HA-epitope tag was able to react with anti-HA antibodies as determined by various immuno-assays. The results from our study suggest that the uncleaved 2A-peptide of FMDV is suitable to present foreign antigenic epitopes on the surface of FMD virion. PMID- 28734764 TI - Comparative genomic analysis of Mycobacterium tuberculosis Beijing-like strains revealed specific genetic variations associated with virulence and drug resistance. AB - Isolates of the Mycobacterium tuberculosis lineage 2/East-Asian are considered one of the most successful strains due to their increased pathogenicity, hyper virulence associated with drug resistance, and high transmission. Recent studies in Colombia have shown that the Beijing-like genotype is associated with multidrug-resistance and high prevalence in the southwest of the country, but the genetic basis of its success in dissemination is unknown. In contribution to this matter, we obtained the whole sequences of six genomes of clinical isolates assigned to the Beijing-like genotype. The genomes were compared with the reference genome of M. tuberculosis H37Rv and 53 previously published M. tuberculosis genomes. We found that the six Beijing-like isolates belong to a modern Beijing sub-lineage and share specific genomic variants: i.e. deletion in the PPE8 gene, in Rv3806c (ubiA) responsible of high ethambutol resistance and in Rv3862c (whiB6) which is involved in granuloma formation and virulence, are some of them. Moreover, each isolated has exclusively single nucleotide polymorphisms (SNPs) in genes related with cell wall processes and cell metabolism. We identified polymorphisms in genes related to drug resistance that could explain the drug-resistant phenotypes found in the six isolates from Colombia. We hypothesize that changes due to these genetic variations contribute to the success of these strains. Finally, we analyzed the IS6110 insertion sequences finding very low variance between them, suggesting that SNPs is the major cause of variability found in Beijing-like strains circulating in Colombia. PMID- 28734766 TI - TRPV1 modulates morphine-induced conditioned place preference via p38 MAPK in the nucleus accumbens. AB - Emerging evidence suggests that the transient receptor potential vanilloid type 1 channel (TRPV1) is a novel target for the treatment of drug addiction, such as cocaine and morphine. Previously we reported that TRPV1 inhibition reduced morphine reward in the dorsal striatum (DSt) of mice and morphine self administration through a decrease in accumbal activity in rats. However, the role of TRPV1 on morphine-conditioned reward in addiction-related brain regions, such as the nucleus accumbens (NAc), has not been previously established. Here, we investigated the effects of TRPV1 on morphine conditioned place preference (CPP) and intracellular mechanisms of TRPV1 using Western blot analysis and immunohistochemistry (IHC) in morphine-administered mice. TRPV1 knockout mice did not exhibit morphine reward responses, and both i.p. and intra-NAc injections of SB366791, a selective TRPV1 antagonist, reduced morphine-induced CPP in wild-type mice. Furthermore, i.p. injection of SB203580, a selective p38 MAPK inhibitor, also dampened morphine-induced CPP. To determine the molecular mechanisms of the TRPV1/p38 MAPK pathway in morphine CPP, we investigated the expression of adenylyl cyclase type 1 (AC1) and phospho-p38 mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-kappaB) in the NAc. Either SB366791 or SB203580 decreased the protein expression levels of phospho-p38 MAPK, phosphor-NF kappaB, and AC1 in the NAc of morphine CPP mice. Taken together, our findings suggest that TRPV1 may modulate morphine-induced conditioned reward effects via the p38 MAPK signaling pathway in the NAc. Therefore, blockade of TRPV1 may provide a novel therapeutic approach for the prevention and treatment of opioid addiction. PMID- 28734765 TI - AMPAkines and morphine provide complementary analgesia. AB - Glutamate signaling in the central nervous system is known to play a key role in pain regulation. AMPAkines can enhance glutamate signaling through alpha-amino-3 hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. previous studies have shown that AMPAkines are effective analgesic agents, and their site of action is likely in the brain. It is not known, however, if AMPAkines can provide complementary analgesia in combination with opioids, the most commonly used analgesics. Here, we show that the co-administration of an AMPAkine with morphine can provide additional analgesia, both in naive rats and in rats that experience postoperative pain. Furthermore, we show that this AMPAkine can be administered directly into the prefrontal cortex to provide analgesia, and that prefrontal AMPAkine infusion, similar to systemic administration, can provide added pain relief to complement morphine analgesia. PMID- 28734767 TI - Type II olecranon fractures in patients over 65. Tension band or pre-formed plate? Analysis and results. AB - OBJECTIVE: The objective of this study was to compare the clinical outcomes of surgical treatment using tension band with needles and preformed plates in type ii olecranon fractures according to the Mayo classification in patients older than 65 years. MATERIAL AND METHOD: A descriptive, retrospective study of 49 patients with a mean age of 75.1 years who underwent surgery olecranon fracture using 2 different fixing systems. The Mayo classification was used to define them, excluding type i and iii, and the VAS to assess postoperative pain. Patients were assessed functionally by the questionnaire Quick DASH. All measurement was performed with goniometer and joint balance serial radiographs at one month, 3, 6 and 12 months. Minimum follow-up was one year. RESULTS: In 26 patients the tension band was used and the preformed plates in 23. There were no statistically significant differences in functional outcomes, joint balance or postoperative VAS between the 2 groups. There were a greater proportion of patients who had to be operated because of problems related to osteosynthesis material in those in which preformed plates were used. CONCLUSIONS: Treatment of olecranon fractures with tension band with needles and cerclage remains the surgery of choice in patients older than 65 years. PMID- 28734768 TI - Effect of the monotherapy of sitagliptin on glycemic control of patients with type 2 diabetes in different duration. PMID- 28734769 TI - Influence of epileptic activity during sleep on cognitive performance in benign childhood epilepsy with centrotemporal spikes. AB - BACKGROUND: Benign childhood epilepsy with centrotemporal spikes is benign childhood epilepsy, presenting between 4 and 10 years of age, characterized by typical clinical and EEG findings. Despite excellent prognosis, there are reports of mild cognitive, language, fine motor and behavioral difficulties. In its atypical form - electrical status epilepticus during slow wave sleep, continuous epileptiform activity during sleep lead to severe neurocognitive deterioration. Our objective was to investigate the influence of abundant sleep epileptiform activity, not fulfilling the criteria for electrical status epilepticus during Slow Wave Sleep, discovered randomly in children without overt intellectual impairment. METHODS: We retrospectively reviewed the charts and EEG's of 34 children with benign childhood epilepsy with centrotemporal spikes, who underwent neurocognitive evaluation. The neurocognitive battery included items in the following domains: attention span, memory, language, fine motor and behavior. Patients were divided into two groups according to the spike wave index on sleep EEG, with a cut-off point of 50%. The groups were compared regarding to neurocognitive performance. OUTCOMES: Children with epileptiform activity of more than 50%, were diagnosed at a significantly younger age (5.13 +/- 1.94 years vs. 7.17 +/- 2.45, p = 0.014 T test), had less controlled seizures and received more antiepileptic drugs. However, there was no difference in neurocognitive performance, except in fine motor tasks (Pegboard), where children with more abundant activity were scored lower (-0.79 +/- 0.96 vs. 0.20 +/- 1.05, p = 0.011, T test). CONCLUSION: Our study did not show negative cognitive effect of abundant epileptiform activity discovered randomly in children with benign childhood epilepsy with centrotemporal spikes, warranting aggressive treatment. PMID- 28734770 TI - When Did Old Age Stop Being Depressing? Depression Trajectories of Older Americans and Britons 2002-2012. AB - OBJECTIVE: This study aims to investigate the implications of the heterogeneous cohort composition on depression trajectories of older adults in the United States and England. METHODS: Using growth curve models to identify depressive symptom trajectories and data spanning six waves over 10 years (2002-2012) from the U.S. Health Retirement Study and the English Longitudinal Study of Ageing, community-dwelling Americans and Britons aged 50 years and older were studied. Depressive symptoms were measured using the eight-item Center for Epidemiologic Studies Depression Scale. RESULTS: The sample included 11,919 respondents (7,095 women [59.53%]) in the United States and 10,606 respondents (5,802 women [54.7%]) in England aged 50 and older. Older cohorts were shown to have higher depressive symptoms than younger cohorts in the United States and England. The trajectories of depression of older cohorts, particularly those of the prewar cohorts in both countries and the war cohort in England, followed a U-shape. Conversely, the trajectories of depression of the younger cohort, particularly those of the postwar cohorts in both countries and the war cohort in the United States, took an inverted U-shape. CONCLUSION: The trajectories of depression in later life between cohorts took different shapes. This finding may lead to the development of more cost-effective policies for treating depression in later life. PMID- 28734772 TI - Biology of aging: New models, new methods. PMID- 28734771 TI - New advances in autophagy in plants: Regulation, selectivity and function. AB - Autophagy is a major and conserved pathway for delivering unwanted proteins or damaged organelles to the vacuole for degradation and recycling. In plants, it functions as a housekeeping process to maintain cellular homeostasis under normal conditions and is induced by stress and senescence; it thus plays important roles in development, stress tolerance and metabolism. Autophagy can both execute bulk degradation and be highly selective in targeting cargos under specific environmental conditions or during certain developmental processes. Here, we review recent research on autophagy in plants, and discuss new insights into its core mechanism, regulation, selectivity and physiological roles. Potential future directions are also highlighted. PMID- 28734773 TI - EPICO 4.0. 'Total quality' in the management of invasive candidiasis in critically ill patients by analysing the integrated process. AB - BACKGROUND: A high quality integrated process in the clinical setting of non neutropenic critically ill patients at risk for invasive candidiasis is a necessary tool to improve the management of these patients. AIMS: To identify the key points on invasive candidiasis in order to develop a set of recommendations with a high level of consensus required for the creation of a total quality integrated process for the management of non-neutropenic critically ill patients at risk of invasive candidiasis. METHODS: After a thorough review of the literature of the previous five years, a Spanish prospective questionnaire, which measured consensus by the Delphi technique, was anonymously conducted by e-mail, including 31 national multidisciplinary experts with extensive experience in invasive fungal infections, from six national scientific societies. The experts included a specialist in intensive care medicine, anesthetists, microbiologists, pharmacologists, and specialists in infectious diseases that responded 27 questions prepared by the coordination group. The educational objectives considered six processes that included knowledge of the local epidemiology, the creation and development of multidisciplinary teams, the definitions of the process, protocols, and indicators (KPI), an educational phase, hospital implementation, and the measurement of outcomes. The level of agreement among experts in each category to be selected should exceed 70%. In a second phase, after drawing up the recommendations of the selected processes, a face to face meeting with more than 60 specialists was held. The specialists were asked to validate the pre-selected recommendations. MEASURES AND MAIN OUTCOMES: Firstly, 20 recommendations from all the sections were pre-selected: Knowledge of local epidemiology (3 recommendations), creation and development of multidisciplinary teams (3), definition of the process, protocols and indicators (1), educational phase (3), hospital implementation (3), and measurement of outcomes (7). After the second phase, 18 recommendations were validated, and it was concluded that the minimum team or core necessary for the development of an efficient program in the use of antifungal drugs in non-neutropenic critically ill patients must consist of a specialist in infectious diseases, a clinical pharmacist, a microbiologist, a specialist in intensive care medicine, a specialist in anesthesia and recovery, and an administrator or member of the medical management team, and, in order to be cost-effective, it should be implemented in hospitals with over 200 beds. In addition, it is recommended to apply a consensual check list for the evaluation of the diagnostic process and treatment of invasive candidiasis in patients that have started an antifungal treatment. The management of external knowledge and individual learning stand out as active educational strategies. The main strategies for measuring patient safety outcomes are the analysis of the results achieved, and learning activities; assess, review and refine the deployment of the processes; quality control; epidemiological surveillance and applied research; benchmarking; and basic research. The results of the integrated process should be annually disseminated outside the hospital. CONCLUSIONS: Optimizing the management of invasive candidiasis requires the application of the knowledge and skills detailed in our recommendations. These recommendations, based on the Delphi methodology, facilitate the creation of a total quality integrated process in critically-ill patients at risk for invasive candidiasis. PMID- 28734774 TI - [Does chewing gum improve postoperative results in patients undergoing radical cystectomy? A systematic review of literature and meta-analysis]. AB - INTRODUCTION: Postoperative ileus occurs in different degrees, in the majority of patients undergoing radical cystectomy, which may increase the length of hospital stay. The use of chewing gum has demonstrated its effectiveness in reducing time to-bowel function and the length of hospital stay in several surgical procedures. OBJECTIVE: To evaluate the benefit of post-operative chewing gum use in patients undergoing radical cystectomy through a systematic review of the literature and meta-analysis. MATERIAL AND METHODS: We performed a literature search of MedLine, Scopus, CochraneLibrary and ClinicalTrials.Gov in March 2017 according to the Cochrane Handbook and the Preferred Reporting Items for Systematic Reviews and Meta-Analyzes. The studies were evaluated according to the "Oxford Center for Evidence-Based Medicine" criteria. The outcome measures evaluated were time-to flatus, time-to-defecation, length of the hospital stay, and the rates of general and gastrointestinal postoperative complications. Continuous and dichotomous variables were compared respectively using weighted means differences and odds ratios with 95 % confidence intervals. The presence of publication bias was examined by funnel plots. RESULTS: Three studies (including 274 patients in total) met the inclusion criteria. The pooled results demonstrated a 11.82hour reduction in time-to-flatus (95 % CI : -15.43, -8.22h, P <0.00001), and 19.57hours in time-to-defecation (95 % CI : -29.33, -9.81h, P <0.0001), and a decreasing trend of 2.85 days in the length of the hospital stay (95 % CI : 6.13, -0.43, P=0.09), by the use of chewing gum. There was no significant difference between the "chewing gum" and "control" groups in terms of general and gastrointestinal complications (Peto Odds ratio 1.04 [0.60, 1.79], 95 % CI, P=0.89 and Peto Odds ratio 0.65 [0.26, 1.61], 95 % CI, P=0.35 respectively). CONCLUSION: Chewing gum may be recommended postoperatively in patients undergoing radical cystectomy to improve time-to-bowel function. PMID- 28734775 TI - Type II-III ERCP-related perforations treated with temporary Fully covered self expandable stents. PMID- 28734776 TI - A preoperative score to predict early death after pancreatic cancer resection. AB - BACKGROUND: This study aimed to develop and validate a preoperative prognostic model for death within one year post-surgery in patients with resectable pancreatic ductal adenocarcinoma (PDAC). METHODS: A derivation cohort study of 296 patients who underwent surgical resection of PDAC was prospectively enrolled in an observational study. Preoperative predictors of one year mortality were used to develop a risk score which was then validated in an external cohort of 182 patients with resectable PDAC. RESULTS: Seventy-eight out of 296 patients (26%) died within the first year. Preoperative independent predictors of one year mortality were: nutritional status (Geriatric Nutritional Risk Index, OR 2.23, 1.14-4.38; p=0.02), American Society of Anaesthesiologists' score (OR 2.56, 1.1 5.98; p=0.03), abdominal or back pain at presentation (OR 2.51, 1.05-5.9; p=0.038) and non metastatic liver disease as comorbidity (OR 4.5, 1.05-19.3; p=0.043). A score ranging from 0 to 7 points was developed. In the validation cohort, the model was able to predict early mortality (OR 7.1, 3.9-12.7; p<0.0001), with a predictive ability of 53.5% (Nagelkerke R2), an area under the receiver operating characteristic curve of 88.7% and an acceptable calibration (goodness-of-fit test, p=0.403). CONCLUSIONS: Our new simple risk score proved reliable in forecasting one year mortality in patients with resectable PDAC. PMID- 28734777 TI - Inhibitor mechanisms in the S1 binding site of the dopamine transporter defined by multi-site molecular tethering of photoactive cocaine analogs. AB - Dopamine transporter (DAT) blockers like cocaine and many other abused and therapeutic drugs bind and stabilize an inactive form of the transporter inhibiting reuptake of extracellular dopamine (DA). The resulting increases in DA lead to the ability of these drugs to induce psychomotor alterations and addiction, but paradoxical findings in animal models indicate that not all DAT antagonists induce cocaine-like behavioral outcomes. How this occurs is not known, but one possibility is that uptake inhibitors may bind at multiple locations or in different poses to stabilize distinct conformational transporter states associated with differential neurochemical endpoints. Understanding the molecular mechanisms governing the pharmacological inhibition of DAT is therefore key for understanding the requisite interactions for behavioral modulation and addiction. Previously, we leveraged complementary computational docking, mutagenesis, peptide mapping, and substituted cysteine accessibility strategies to identify the specific adduction site and binding pose for the crosslinkable, photoactive cocaine analog, RTI 82, which contains a photoactive azide attached at the 2beta position of the tropane pharmacophore. Here, we utilize similar methodology with a different cocaine analog N-[4-(4-azido-3-I-iodophenyl)-butyl] 2-carbomethoxy-3-(4-chlorophenyl)tropane, MFZ 2-24, where the photoactive azide is attached to the tropane nitrogen. In contrast to RTI 82, which crosslinked into residue Phe319 of transmembrane domain (TM) 6, our findings show that MFZ 2 24 adducts to Leu80 in TM1 with modeling and biochemical data indicating that MFZ 2-24, like RTI 82, occupies the central S1 binding pocket with the (+)-charged tropane ring nitrogen coordinating with the (-)-charged carboxyl side chain of Asp79. The superimposition of the tropane ring in the three-dimensional binding poses of these two distinct ligands provides strong experimental evidence for cocaine binding to DAT in the S1 site and the importance of the tropane moiety in competitive mechanisms of DA uptake inhibition. These findings set a structure function baseline for comparison of typical and atypical DAT inhibitors and how their interactions with DAT could lead to the loss of cocaine-like behaviors. PMID- 28734778 TI - Diagnostic value of 18F-FDG-PET/CT for the follow-up and restaging of soft tissue sarcomas in adults. AB - PURPOSE: The purpose of this study was to evaluate the clinical utility of 2 [18F] fluoro-2-deoxy-D-glucose (18FDG) positron emission tomography (PET)/computed tomography (CT) (18F-FDG-PET/CT) in the follow-up of adult patients with soft tissue sarcomas. MATERIALS AND METHODS: We prospectively evaluated 37 consecutive patients with known soft tissue sarcoma with 18F-FDG PET/CT examination for suspected recurrence of disease. They were 21 men and 16 women with a mean age of 49.6+/-10.6 (SD) years (range, 34-75years). The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy of 18F-FDG-PET/CT examination were calculated on a per patient basis. RESULTS: 18F-FDG-PET/CT showed an overall diagnostic accuracy of 91.8%, sensitivity of 90% and a specificity of 100%. The positive predictive value and negative predictive value were 100 and 70%, respectively. The 18F-FDG PET/CT interpretations were correct in 34/37 patients (91.8%). Incorrect interpretations occurred in three patients (8.1%). Reasons for false negative findings were low 18F-FDG uptake of local recurrence in one patient and low 18F FDG uptake of subcentimetric inguinal lymph node metastases. CONCLUSION: 18F-FDG PET/CT has a high diagnostic value in the follow-up of patients with soft tissue sarcoma. PMID- 28734780 TI - Imaging features of primary cardiac lymphoma. PMID- 28734779 TI - Metabolic bone disease in preterm infants: Relationship between radiologic grading in the wrist and serum biochemical markers. AB - PURPOSE: To assess the relationship between radiographic findings of metabolic bone disease (MBD) and serum biochemical markers in preterm infants. MATERIALS AND METHODS: A total of 159 preterm infants were included in this study. Two readers reviewed the wrist radiography for grading according to MBD severity. We recorded the levels of alkaline phosphatase (ALP) and phosphorous (P) immediately after birth, on the same day of the first wrist radiography (ALP-s, P-s), the highest/lowest ALP/P levels before the first wrist radiography (ALP-hb/P-lb) and during follow-up (ALP-h/P-l). For analysis, the patients were first subdivided into 4 groups according to MBD severity, and were then divided into 2 groups according to MBD presence or absence. RESULTS: Of the 159 patients, 94, 39, 19, and 7 infants were classified into grades 0,1, 2, and 3. Analysis according to severity showed that ALP-s, ALP-hb, and ALP-h differed between grades 0-1 and 2-3 (all P<0.001); P-lb differed between grades 0 and 2 (P=0.001); and P-l differed between grades 0 and 2 or 3 (P<0.001 or P=0.001). Moreover, ALP-s, ALP-hb, ALP-h, P-s, P-lb, and P-l differed according to the presence or absence of MBD (P<0.001). ALP-h showed the largest area under the curve value (0.752, 95% confidence interval=0.676-0.828, P<0.001). The optimal cut-off value of ALP-h was 473.5U/L. The sensitivity and specificity were 81.5% and 47.9%. ALP-h was measured at 6.9+/-5.3 weeks after birth. CONCLUSION: Taking the wrist radiography with reference to an ALP level measured at around 6.9 weeks after birth could be helpful for screening of MBD in preterm infants, unless a fracture is clinically suspected. PMID- 28734781 TI - Toward uniform standards for pharmacy technicians: Summary of the 2017 Pharmacy Technician Stakeholder Consensus Conference. PMID- 28734782 TI - The ADAPT online education program: A tool for practicing pharmacists delivering patient-centered care. AB - OBJECTIVES: The ADapting pharmacists' skills and Approaches to maximize Patient's drug Therapy effectiveness (ADAPT) e-learning program was developed by a consortium of Canadian pharmacy educators and researchers to prepare practicing pharmacists for patient-centered care. We selected this education program to provide training for pharmacists as the workforce transformation component of a Center for Medicare and Medicaid Innovation project. In this report we share our experiences with this educational program. SETTING: Online educational program. PRACTICE DESCRIPTION: ADAPT presents a standard approach to medication assessment, team collaboration, patient assessment, evidence-based decision making, and documentation. PRACTICE INNOVATIONS: ADAPT was used to prepare practicing pharmacists for new roles in direct patient care in patient-centered medical homes. EVALUATION: Participants were surveyed at the midpoint and end of the program to determine its impact on their confidence in providing patient centered care and to elicit feedback about their perceptions of the program. Participants completed written action plans for each module that included their reflections on the course material and the skills they desired to implement in practice. Descriptive statistics were used to analyze Likert-type questions, and a content analysis was performed to analyze responses to open-ended questions and action plan responses. RESULTS: Two pharmacist cohorts completed the 20-week program from October 2012 to March 2013 (n = 13) and from August 2013 to January 2014 (n = 10). Pharmacists' perceived that their confidence in providing patient centered care improved for all modules. Almost all pharmacists reported improved confidence in patient interviewing (89%), documentation (88%), and collaboration skills (83%). The content analysis identified the modules on interviewing and documentation as the most valuable and likely to result in changes to the pharmacists' practice. The opportunity to learn from colleagues was cited as a strength of the program. CONCLUSION: The ADAPT educational program provided pharmacists with the tools necessary to deliver patient-centered care in ambulatory care settings. PMID- 28734783 TI - Dementia prevalence and incidence in a federation of European Electronic Health Record databases: The European Medical Informatics Framework resource. AB - INTRODUCTION: The European Medical Information Framework consortium has assembled electronic health record (EHR) databases for dementia research. We calculated dementia prevalence and incidence in 25 million persons from 2004 to 2012. METHODS: Six EHR databases (three primary care and three secondary care) from five countries were interrogated. Dementia was ascertained by consensus harmonization of clinical/diagnostic codes. Annual period prevalences and incidences by age and gender were calculated and meta-analyzed. RESULTS: The six databases contained 138,625 dementia cases. Age-specific prevalences were around 30% of published estimates from community samples and incidences were around 50%. Pooled prevalences had increased from 2004 to 2012 in all age groups but pooled incidences only after age 75 years. Associations with age and gender were stable over time. DISCUSSION: The European Medical Information Framework initiative supports EHR data on unprecedented number of people with dementia. Age-specific prevalences and incidences mirror estimates from community samples in pattern at levels that are lower but increasing over time. PMID- 28734784 TI - Drug Delivery Innovations to Address Global Health Challenges for Pediatric and Geriatric Populations (Through Improvements in Patient Compliance). AB - Despite significant advances in pharmaceutical and biotechnological drug discovery, the global population is plagued with many challenging diseases. These are further compounded by anticipated explosion in an ageing population, which presents several problems such as polypharmacy, dysphagia, and neurologic conditions, resulting in noncompliance and disease complications. For antibiotics, poor compliance, can result in development of drug-resistant infections which can be fatal. Furthermore, children, especially, in developing countries die unnecessarily from easily treatable diseases (e.g., malaria), due to poor compliance arising from bitter taste and inability to swallow currently available medication. Although some of these challenges require the discovery of new drug compounds, a significant number can be resolved by employing pharmaceutics approaches to reduce the incidence of poor patient compliance. Such solutions are expected to make swallowing easier and reduce the need to swallow several solid medications, which is difficult for vulnerable pediatric and geriatric patients. This commentary will explore the current state of the art in the use of drug delivery innovations to overcome some of these challenges, taking cues from relevant regulatory agencies such as the Food and Drug Administration, the European Medicines Agency, World Health Organization, and the peer-reviewed scientific and clinical literature. PMID- 28734785 TI - Impact of Magnetic Stirring on Stainless Steel Integrity: Effect on Biopharmaceutical Processing. AB - Stainless steel containers are widely used in the pharmaceutical and biopharmaceutical industry for the storage of buffers, process intermediates, and purified drug substance. They are generally held to be corrosion resistant, biocompatible, and nonreactive, although it is well established that trace amounts of metal ions can leach from stainless steel equipment into biopharmaceutical products. We report here that the use of stainless steel containers in conjunction with magnetic stirring bars leads to significantly aggravated metal contamination, consisting of both metal particles and significantly elevated metal ions in solution, the degree of which is several orders of magnitude higher than described for static conditions. Metal particles are analyzed by scanning electron microscopy with electron-dispersive X-ray spectroscopy, and metal content in solution is quantitated at different time points by inductively coupled plasma-mass spectrometry. The concentration of iron, chromium, nickel, and manganese increases with increasing stirring time and speed. We describe the impact of buffer components on the extent of metal particles and ions in solution and illustrate the effect on model proteins. PMID- 28734786 TI - Clinical Usefulness of Tools to Support Decision-making for Palliative Treatment of Metastatic Colorectal Cancer: A Systematic Review. AB - BACKGROUND: Decision-making regarding palliative treatment for patients with metastatic colorectal cancer (mCRC) is complex and comprises numerous decisions. Decision-making should be guided by the premise of maintaining and/or improving patients' quality of life, by patient preference, and by the trade-off between treatment benefits and harm. Decision support systems (DSSs) for clinicians (eg, nomograms) can assist in this process. The present systematic review aimed to provide a comprehensive overview of the available DSSs for incurable mCRC and to assess their clinical usefulness. MATERIALS AND METHODS: A systematic literature search was performed in PubMed, Embase, and the Cochrane Library. We extracted information on the DSS characteristics and their discriminatory ability, calibration, and user-friendliness. RESULTS: From 5205 studies, we identified 14 DSSs for decisions regarding palliative resection of the primary tumor (n = 3), radiotherapy for metastases (n = 2), treatment type (invasive vs. symptomatic only; n = 7), and selection of chemotherapy (n = 2). The predictors varied greatly among the DSSs, and only 1 DSS incorporated a genetic marker (ie, UGT1A1). None of the DSSs included > 1 treatment option, nor did any DSS present estimates of treatment benefits and harms. Five tools had not been externally validated, two had only been validated in < 35 patients, and the rest had only been validated in populations similar to the population used for their development. Discriminatory accuracy was generally moderate to poor. Calibration measures were only reported for 2 tools. CONCLUSION: A limited number of DSSs are available to support palliative treatment decisions for patients with mCRC, and the evidence regarding their discriminatory ability and calibration is too limited to recommend their use. New DSSs comparing multiple treatment options and presenting both treatment benefits and harms are needed. PMID- 28734787 TI - Selenium deficiency-induced thioredoxin suppression and thioredoxin knock down disbalanced insulin responsiveness in chicken cardiomyocytes through PI3K/Akt pathway inhibition. AB - Thioredoxin (Txn) system is the most crucial antioxidant defense mechanism in cell consisting of Txn, thioredoxin reductase (TR) and Nicotinamide Adenine Dinucleotide Phosphate (NADPH). Perturbations in Txn system may compromise cell survival through oxidative stress induction. Metabolic activity of insulin plays important roles in fulfilling the stable and persistent demands of heart through glucose metabolism. However, the roles of Txn and Txn system in insulin modulated cardiac energy metabolism have been less reported. Therefore, to investigate the role of Txn in myocardial metabolism, we developed a Se-deficient chicken model (0.033mg/kg) for in-vivo and Txn knock down cardiomyocytes culture model (siRNA) for in-vitro studies. Quantitative real time PCR and western blotting was performed. Se deficiency suppressed Txn and TR in cardiac tissues. Significant increases in ROS (P<0.05) levels signify the onset of oxidative stress and in both models. Se deficiency-induced Txn suppression model and Txn knock down cardiomyocytes models significantly decreased (P<0.05), the mRNA and protein levels of insulin-like growth factors (IGF1, IGF2), IGF-binding proteins (IGFBP2, IGFBP4), insulin receptor (IR), insulin receptor substrates (IRS1, IRS2), and glucose transporters (GLUT1, GLUT3, GLUT8), however, IGFBP3 expression increased in Txn knock down cardiomyocytes. In addition, in contrast to their respective controls, Se deficiency-induced Txn depleted tissues and Txn deleted cardiomyocytes showed suppression in mRNA and protein levels of PI3K, AKT, P PI3K, and repression in FOX, P-FOX JNK genes. Combing the in vitro and in vivo experiments, we demonstrate that Txn gene suppression can cause dysfunction of insulin-modulated cardiac energy metabolism and increase insulin resistance through PI3K-Akt pathway inhibition. Herein, we conclude that inactivation of Txn system can alter cellular insulin response through IRS/PI3K/Akt pathway repression and JNK and FOX expression. These findings point out that Txn system can redox regulate the insulin dependent glucose metabolism in heart and is essential for cell vitality. Moreover, the increased expression of IGFBP3 indicates that it can be a potential negative modulator of metabolic activity of insulin in Txn deficient cells. PMID- 28734788 TI - Neuropathic pain in experimental autoimmune neuritis is associated with altered electrophysiological properties of nociceptive DRG neurons. AB - Guillain-Barre syndrome (GBS) is an acute, immune-mediated polyradiculoneuropathy characterized by rapidly progressive paresis and sensory disturbances. Moderate to severe and often intractable neuropathic pain is a common symptom of GBS, but its underlying mechanisms are unknown. Pathology of GBS is classically attributed to demyelination of large, myelinated peripheral fibers. However, there is increasing evidence that neuropathic pain in GBS is associated with impaired function of small, unmyelinated, nociceptive fibers. We therefore examined the functional properties of small DRG neurons, the somata of nociceptive fibers, in a rat model of GBS (experimental autoimmune neuritis=EAN). EAN rats developed behavioral signs of neuropathic pain. This was accompanied by a significant shortening of action potentials due to a more rapid repolarization and an increase in repetitive firing in a subgroup of capsaicin-responsive DRG neurons. Na+ current measurements revealed a significant increase of the fast TTX sensitive current and a reduction of the persistent TTX-sensitive current component. These changes of Na+ currents may account for the significant decrease in AP duration leading to an overall increase in excitability and are therefore possibly directly linked to pathological pain behavior. Thus, like in other animal models of neuropathic and inflammatory pain, Na+ channels seem to be crucially involved in the pathology of GBS and may constitute promising targets for pain modulating pharmaceuticals. PMID- 28734789 TI - Weathered MC252 crude oil-induced anemia and abnormal erythroid morphology in double-crested cormorants (Phalacrocorax auritus) with light microscopic and ultrastructural description of Heinz bodies. AB - Injury assessment of birds following the Deepwater Horizon (DWH) oil spill in 2010 was part of the Natural Resource Damage Assessment. One reported effect was hemolytic anemia with the presence of Heinz bodies (HB) in birds, however, the role of route and magnitude of exposure to oil is unknown. The purpose of the present study was to determine if double-crested cormorants (Phalacocorax auritis; DCCO) exposed orally and dermally to artificially weathered crude oil would develop hemolytic anemia including HB and reticulocytosis. In the oral experiment, sub-adult, mixed-sex DCCOs were fed control (n = 8) or oil-injected fish with a daily target dose of 5 (n = 9) or 10 (n = 9) ml oil/kg for 21 days. Then, subadult control (n = 12) and treated (n = 13) cormorant groups of similar sex-ratio were dermally treated with approximately 13ml of water or weathered MC252 crude oil, respectively, every 3 days for 6 dosages approximating 20% surface coverage. Collected whole blood samples were analyzed by light (new methylene blue) and transmission electron microscopy. Both oral and dermal treatment with weathered DWH MC252 crude oil induced regenerative, but inadequately compensated, anemia due to hemolysis and hematochezia as indicated by decreased packed cell volume, relative increase in reticulocytes with lack of difference in corrected reticulocyte count, and morphologic evidence of oxidant damage at the ultrastructural level. Hemoglobin precipitation, HB formation, degenerate organelles, and systemic oxidant damage were documented. Heinz bodies were typically <2um in length and smaller than in mammals. These oblong cytoplasmic inclusions were difficult to see upon routine blood smear evaluation and lacked the classic button appearance found in mammalian red blood cells. They could be found as light, homogeneous blue inclusions upon new methylene blue staining. Ultrastructurally, HB appeared as homogeneous, electron-dense structures within the cytosol and lacked membranous structure. Oxidant damage in avian red blood cells results in degenerate organelles and precipitated hemoglobin or HB with different morphology than that found in mammalian red blood cells. Ultrastructural evaluation is needed to definitively identify HB and damaged organelles to confirm oxidant damage. The best field technique based on the data in this study is assessment of PCV with storage of blood in glutaraldehyde for possible TEM analysis. PMID- 28734790 TI - Organ weights and histopathology of double-crested cormorants (Phalacrocorax auritus) dosed orally or dermally with artificially weathered Mississippi Canyon 252 crude oil. AB - A series of toxicity tests were conducted to assess the effects of low to moderate exposure to artificially weathered Deepwater Horizon Mississippi Canyon 252 crude oil on representative avian species as part of the Natural Resource Damage Assessment. The present report summarizes effects of oral exposure (n=26) of double-crested cormorants (DCCO; Phalacrocorax auritus) to 5 or 10ml oil kg-1 day-1 for up to 21 days or dermal application (n=25) of 13ml oil to breast and back feathers every three days totaling 6 applications in 21 days on organ weights and histopathology. Absolute and relative kidney and liver weights were increased in birds exposed to oil. Additionally, gross and/or histopathologic lesions occurred in the kidney, heart, pancreas and thyroid. Clinically significant renal lesions in the orally dosed birds included squamous metaplasia and increased epithelial hypertrophy of the collecting ducts and renal tubules and mineralization in comparison to controls. Gross cardiac lesions including thin walls and flaccid musculature were documented in both orally and dermally dosed birds and myocardial fibrosis was found in low numbers of dermally dosed birds only. Cytoplasmic vacuolation of the exocrine pancreas was noted in orally dosed birds only. Thyroid follicular hyperplasia was increased in dermally dosed birds only possibly due to increased metabolism required to compensate damaged feather integrity and thermoregulate. Gastrointestinal ulceration was found in orally dosed birds only. There were no significant hepatic histopathologic lesions induced by either exposure route. Therefore, hepatic histopathology is likely not a good representation of oil-induced damage. Taken together, the results suggest that oral or dermal exposure of DCCOs to artificially weathered MC252 crude oil induced organ damage that could potentially affect survivability. PMID- 28734791 TI - Association between nocturnal blood pressure variation and wake-up ischemic stroke. AB - Ischemic stroke during nocturnal sleep, known as wake-up stroke (WUS), has been reported to have more severe symptoms and worse outcomes than non-WUS. However, studies on risk factors for WUS are scarce and the association between nocturnal blood pressure (BP) and WUS is unclear. In this study, we used ambulatory blood pressure monitoring (ABPM) to examine the association between WUS and variation in nocturnal BP. A total of 369 patients with ischemic stroke within one week were consecutively enrolled. ABPM was applied 1-2weeks after the ictus because of possible reactive increments of BP; antihypertensive medications were delayed until ABPM. Patients were classified into two groups: WUS and non-WUS. Clinical characteristics, including ABPM parameters, were compared. Sixty-seven (18%) patients had WUS. In univariate analysis, patients with WUS had more severe stroke symptoms than patients with non-WUS. There were no differences in clinical characteristics. In addition, ABPM parameters, including nocturnal BP dipping and morning BP surge, were not associated with occurrence of WUS. Patients with WUS had more severe stroke symptoms and worse outcomes than those with non-WUS. Variation in nocturnal BP may not associated with the occurrence of WUS. PMID- 28734792 TI - Genetic factors of cervical spondylotic myelopathy-a systemic review. AB - BACKGROUND: Cervical spondylotic myelopathy (CSM) is a degenerative disorder of the neck. Recent studies have reported the roles of single nucleotide polymorphisms and abnormal gene expression in the etiology and development of CSM. However, a systemic review of these findings is currently unavailable. METHODS: A systemic review of genetic factors of CSM was conducted through searching PubMed and EMbase databases. A total of 9 studies were included in this study, which included 8 genes: brain derived neurotrophic factor (BDNF), osteopontin (OPN), bone morphogenic protein (BMP) 4, collagen IX, vitamin D receptor (VDR), apolipoprotein E (ApoE), hypoxia-inducible factor alpha (HIF 1alpha), and cyclooxygenase 2 (COX-2). RESULTS: The polymorphisms of 6 genes (OPN, BMP-4, collagen IX, VDR, HIF-1alpha) showed significant association with the susceptibility to or risk of CSM. The polymorphisms of 3 genes (BMP-4, ApoE4, HIF-1alpha) were significantly associated with the postoperative outcome. The polymorphism of BDNF, VDR, and expression of COX-2 were associated with the severity of disease. CONCLUSION: This review demonstrates that 8 genes were associated with CSM although there is no repeated study. This review also suggests that large scale and high quality studies are needed to provide more reliable evidence for future evaluation. PMID- 28734793 TI - Hardware failure in patients with metastatic cancer to the spine. AB - BACKGROUND: The spine is the most common site of skeletal metastases, affecting approximately 30% of individuals with cancer. The aim of surgical treatment for metastatic spine disease is generally palliative to address pain and/or neurologic compromise, significantly improving patients' quality of life. Patients with metastatic spine disease, however, represent a vulnerable cohort and may have comorbidities or previous treatments that impair the structural integrity of spinal hardware. As such, identifying factors that may contribute to hardware failure is an essential component in treating individuals with metastatic spine disease. OBJECTIVE: The aim of this study was to identify pre operative risk factors associated with hardware failure in patients undergoing surgical treatment for metastatic spine disease. METHODS: A retrospective cohort study was conducted to include patients surgically treated for metastatic spine tumors between 2003 and 2013, at a single institution. A univariate analysis was initially performed to identify associated factors. Any associated factor with a p-value <0.20 was included in the multivariate analysis. RESULTS: 3 patients (1.9%), of the 159 patients included in the study, had failure of the spine instrumentation. 1 patient had metastatic prostate cancer, and 2 had metastatic breast cancer. Patient demographics, co-morbidities, tumor location, and primary tumor etiology were not found to be statistically significant, with respect to hardware failure. Predictive factors included in the multivariate model were other bone metastasis, visceral metastasis, brain metastasis, Modified Rankin scale, previous systemic chemotherapy, previous radiation to the spine, and mean survival. Previous radiation to the spine was the only factor to be significantly associated (p=0.029), present in all three patients with hardware failure. Of note, there was a trend indicating that patients with longer life expectancies were more likely to experience hardware failure (mean survival of 16.7months in non-failure cohort vs. 33months in failure cohort), though this did not achieve statistical significance due to the limited sample size of patients with hardware failure. CONCLUSION: Hardware failure is a risk for all patients who undergo instrumentation following resection for metastatic spine tumors. This study identified that pre-operative radiation may increase the risk for hardware failure in this population. PMID- 28734794 TI - Botulinum toxin A is effective to treat tension-type headache caused by hemifacial spasm. AB - OBJECTIVE: We examined the relationship between hemifacial spasm (HFS; a form of cranio-cervical dystonia) and chronic primary headache, including tension-type headache (TTH). We also examined whether botulinum toxin A (BoNT/A) therapy for HFS ameliorates concomitant TTH. METHODS: Fifty-one HFS patients receiving BoNT/A therapy were recruited. Patients' characteristics (including age, gender, chronic headache history, exercise habits, stiff neck, cervical spondylolysis history), stress factors, worsening/new onset of headache associated with HFS, and dose of BoNT/A were examined. We diagnosed headache types according to The International Classification of Headache Disorders, 3rd edition, beta. Numerical Rating Scale (NRS) and Headache Impact Test-6 (HIT-6) scores for headache severity were compared between the 6-week baseline before BoNT/A therapy and 6-week follow-up after BoNT/A therapy. RESULTS: Of 51 patients with HFS, 17 (33.3%) reported worsening or new onset of headache (especially TTH) associated with HFS (Group S), and 34 were not aware of headache (Group-N). Twelve patients (70.6%) in group S reported improvement of headache after BoNT/A therapy. NRS (from 7 [5-9] to 0 [0-5], p<0.01) and HIT-6 (from 55 [54-64] to 44 [36-52], p<0.001) scores were significantly improved after BoNT/A therapy. Logistic regression analysis revealed significant interaction between TTH associated with HFS and the presence of stress factors (odds ratio 43.11: 2.95-629.39, p<0.001) and history of chronic headache (odds ratio 28.53: 2.96-275.10, p<0.001). CONCLUSIONS: Primary headache, especially TTH, is associated with HFS. BoNT/A therapy for HFS may also be indirectly effective for treatment of TTH. PMID- 28734795 TI - Monoclonal Antibodies in Multiple Myeloma: A New Wave of the Future. AB - In 2015, 2 monoclonal antibodies were approved for the treatment of relapsed or refractory multiple myeloma (RRMM), elotuzumab and daratumumab. Elotuzumab is a monoclonal IgG-kappa antibody directed against SLAMF7 (signaling lymphocytic activation molecule F7), a cell surface receptor involved in natural killer cell activation. Daratumumab is a monoclonal IgG-kappa antibody that binds to CD38, a transmembrane protein found on the surface of myeloma cells and responsible for cellular adhesion and ectoenzymatic activity. Both elotuzumab and daratumumab act through recruitment of the immune system to enhance cellular cytotoxicity directed against myeloma cells. Elotuzumab requires lenalidomide and dexamethasone combined to enhance progression-free survival in patients with RRMM, and daratumumab has both single-agent and combination activity with either lenalidomide or the proteasome inhibitor bortezomib in RRMM. The adverse effect profile of both agents mainly consists of allergic-type infusion reactions. Other considerations for monoclonal antibody use in the treatment of MM include the potential for interference in serum protein electrophoresis testing and cross reactivity of daratumumab with CD38 present on red blood cells. In the present report, we discussed the clinical development of daratumumab and elotuzumab and newer immunologic approaches to the treatment of MM. PMID- 28734796 TI - Clonal composition of human ovarian cancer based on copy number analysis reveals a reciprocal relation with oncogenic mutation status. AB - Intratumoral heterogeneity of cancer cells remains largely unexplored. Here we investigated the composition of ovarian cancer and its biological relevance. A whole-genome single nucleotide polymorphism array was applied to detect the clonal composition of 24 formalin-fixed, paraffin-embedded samples of human ovarian cancer. Genome-wide segmentation data consisting of the log2 ratio (log2R) and B allele frequency (BAF) were used to calculate an estimate of the clonal composition number (CC number) for each tumor. Somatic mutation profiles of cancer-related genes were also determined for the same 24 samples by next generation sequencing. The CC number was estimated successfully for 23 of the 24 cancer samples. The mean +/- SD value for the CC number was 1.7 +/- 1.1 (range of 0-4). A somatic mutation in at least one gene was identified in 22 of the 24 ovarian cancer samples, with the mutations including those in the oncogenes KRAS (29.2%), PIK3CA (12.5%), BRAF (8.3%), FGFR2 (4.2%), and JAK2 (4.2%) as well as those in the tumor suppressor genes TP53 (54.2%), FBXW7 (8.3%), PTEN (4.2%), and RB1 (4.2%). Tumors with one or more oncogenic mutations had a significantly lower CC number than did those without such a mutation (1.0 +/- 0.8 versus 2.3 +/- 0.9, P = 0.0027), suggesting that cancers with driver oncogene mutations are less heterogeneous than those with other mutations. Our results thus reveal a reciprocal relation between oncogenic mutation status and clonal composition in ovarian cancer using the established method for the estimation of the CC number. PMID- 28734797 TI - The effects of continuously acoustical stress on cortisol in milkfish (Chanos chanos). AB - Strong underwater acoustic noise has been known that may cause hearing loss and actual stress in teleost. However, the long-term physiological effects of relatively quiet but continuously noise on fish were less understood. In present study, milkfish, Chanos chanos, were exposed to the simulated-wind farm noise either quiet (109dB re 1MUPa/125.4Hz; approx. 10-100m distant from the wind farm) or noisy (138dB re 1MUPa/125.4Hz; nearby the wind farm) conditions for 24h, 3days and 1week. Comparing to the control group (80dB re 1MUPa/125.4Hz), the fish exposed to noisy conditions had higher plasma cortisol levels in the first 24h. However, the cortisol levels of 24h spot returned to the resting levels quickly. The fish exposed under noisy condition had significantly higher head kidney star (steroidogenic acute regulatory) and hsd11b2 (11-beta-hydroxysteroid dehydrogenase 2) mRNA levels at the following treatment time points. In addition, noise exposure did not change hypothalamus crh (Corticotropin-releasing hormone) mRNA levels in this experiment. The results implied that the weak but continuously noise was a potential stressor to fish, but the impacts may be various depending on the sound levels and exposure time. Furthermore, this study showed that the continuous noise may up-regulate the genes that are related to cortisol synthesis and possibly make the fish more sensitive to ambient stressors, which may influence the energy allocation appearance in long-term exposures. PMID- 28734798 TI - Barriers to conducting ambulatory and home blood pressure monitoring during hypertension screening in the United States. AB - In 2015, the US Preventive Services Task Force updated their hypertension recommendations to advise that adults with elevated office blood pressure (BP) undergo out-of-office BP measurement to exclude white coat hypertension before diagnosis. Our goal was to determine the most important barriers to primary care providers' ordering ambulatory and home BP monitoring in the United States. We enrolled 63 primary care providers into nominal group panels in which participants iteratively listed and ranked barriers to ambulatory and home BP monitoring. Top-ranked barriers to ambulatory BP monitoring were challenges in accessing testing, costs of testing, concerns about the willingness or ability of patients to successfully complete tests, and concerns about the accuracy and benefits of testing. Top-ranked barriers to home BP monitoring were concerns about compliance with the correct test protocol, accuracy of tests results, out of-pocket costs of home BP devices, and time needed to instruct patients on home BP monitoring protocol. Efforts to increase the use of ambulatory and home BP monitoring by primary care providers in the United States should prioritize increasing the financial and personnel resources available for testing and addressing provider concerns about patients' ability to conduct high-quality tests. PMID- 28734799 TI - EEG analysis of seizure patterns using visibility graphs for detection of generalized seizures. AB - BACKGROUND: The traditional EEG features in the time and frequency domain show limited seizure detection performance in the epileptic population with intellectual disability (ID). In addition, the influence of EEG seizure patterns on detection performance was less studied. NEW METHOD: A single-channel EEG signal can be mapped into visibility graphs (VGS), including basic visibility graph (VG), horizontal VG (HVG), and difference VG (DVG). These graphs were used to characterize different EEG seizure patterns. To demonstrate its effectiveness in identifying EEG seizure patterns and detecting generalized seizures, EEG recordings of 615h on one EEG channel from 29 epileptic patients with ID were analyzed. RESULTS: A novel feature set with discriminative power for seizure detection was obtained by using the VGS method. The degree distributions (DDs) of DVG can clearly distinguish EEG of each seizure pattern. The degree entropy and power-law degree power in DVG were proposed here for the first time, and they show significant difference between seizure and non-seizure EEG. The connecting structure measured by HVG can better distinguish seizure EEG from background than those by VG and DVG. COMPARISON WITH EXISTING METHOD: A traditional EEG feature set based on frequency analysis was used here as a benchmark feature set. With a support vector machine (SVM) classifier, the seizure detection performance of the benchmark feature set (sensitivity of 24%, FDt/h of 1.8s) can be improved by combining our proposed VGS features extracted from one EEG channel (sensitivity of 38%, FDt/h of 1.4s). CONCLUSIONS: The proposed VGS-based features can help improve seizure detection for ID patients. PMID- 28734800 TI - Advocating for well-defined and validated procedures: Comment on Griffanti et al., Neuroimage 154:188-205. AB - Griffanti et al. (2017) provide a rich set of expert-consensus guidelines for how to label components derived from ICA as either belonging to signal of interest or noise to be filtered from fMRI data. These general hypotheses concerning procedures for "hand" classification of components are a good starting point that with further detail would improve reproduction of experiments and facilitate comparisons of alternative hypotheses/procedures. Empirical validation could help to resolve questions by supporting or disconfirming the proposed guidelines. PMID- 28734801 TI - Sex-specific differences in the modulation of Growth Differentiation Factor 15 (GDF15) by hyperoxia in vivo and in vitro: Role of Hif-1alpha. AB - Male premature neonates are more susceptible than females to the development of bronchopulmonary dysplasia (BPD). The reasons underlying sexually dimorphic outcomes in premature neonates are not known. GDF15 (Growth and differentiation factor 15) is a secreted cytokine and plays a role in cell proliferation, apoptosis, and angiogenesis. In this study, we sought to elucidate the sex specific expression of Gdf15 in the lung in vivo in neonatal hyperoxic lung injury and its regulation by Hif-1alpha, and to delineate the differences in GDF15 expression in male and female human umbilical venous endothelial cells in an in vitro model of oxygen toxicity. Following hyperoxia exposure (95% FiO2, PND (postnatal day 1-5: saccular stage of lung development), neonatal male mice (C57BL/6) show increased GDF15 and decreased HIF-1alpha expression compared to female mice. For the in vitro experiments, male and female HUVECs were exposed to room air condition (21% O2, 5% CO2) or in hyperoxia condition (95% O2, 5% CO2) for up to 72h. Male HUVECs had greater expression of GDF15 mRNA and protein. To study the inter-relationship between GDF15 and HIF-1alpha, we measured the expression of GDF15 in H441 cells after HIF-1alpha knockdown using promoter dual luciferase reporter assay, which showed that HIF-1alpha and GDF15 expression are inversely related under normoxia and hyperoxia. The results indicate that sex differences exist in the expression and modulation of GDF15 by HIF-1alpha in neonatal hyperoxic injury both in vivo and in vitro. These differences could explain in part the mechanisms behind sex-specific differences in BPD. PMID- 28734802 TI - Co-transplantation of mesenchymal and neural stem cells and overexpressing stromal-derived factor-1 for treating spinal cord injury. AB - Genetic engineering of mesenchymal stem cells (MSCs) and neuronal stem cells (NSCs) has been used to treat spinal cord injuries (SCI). As a mechanism of therapy, MSCs secrete high amounts of trophic factors, while NSCs can differentiate into neuronal lineages and aid in tissue replacement. Additionally, the forced overexpression of secreted proteins can enhance the secretome of transplanted cells, which can increase therapeutic efficacy. This study utilized a combinational treatment consisting of MSCs, NSCs, and the forced overexpression of the chemokine stromal-derived factor-1 (SDF-1) from MSCs (SDF-1-MSCs) as treatment in a rat model of SCI. Transplants occurred at 9-days post-injury, and motor functions were evaluated for 7-weeks post-injury. White matter sparing and axon densities surrounding the lesions were quantified. Findings from this study demonstrate that co-transplanting SDF-1-MSCs with NSCs improved motor functions and enhanced axon densities surrounding the lesion. However, no improvements in white matter sparing were found and tumors were found in some of the animals that received co-transplantations with either SDF-1-MSCs and NSCs or unmodified-MSCs and NSCs, but not in any animal treated with a single cell type. This study offers evidence that providing SDF-1 to NSCs, through the forced expression from MSCs, can enhance the therapeutic potential of the graft, but developing a safe means of doing this requires further work. PMID- 28734803 TI - Distribution of KIR genes and KIR2DS4 gene variants in two Mexican Mestizo populations. AB - Killer immunoglobulin-like receptors (KIR) are transmembrane proteins that regulate NK and T cell subsets by recognizing HLA-I molecules as ligands. The KIR gene family consists of 16 genes, located at chromosome 19q13.4. KIR gene frequencies vary among populations. In Mexico, HLA and genetic ancestry studies show that Mestizo populations have different genetic backgrounds based on admixture with European, African, and Asian ancestry. This study aimed to evaluate the frequencies of KIR genes and genotypes in Guerrero and Jalisco, two Mexican Mestizo populations located in the south and the west of the country, respectively, and to compare these frequencies with those of other populations. KIR genotyping was performed by SSP-PCR. We observed that KIR gene frequencies were similar in both populations. There were 24 genotypes observed in Guerrero, 38 genotypes observed in Jalisco, 15 genotypes shared in both populations and 32 genotypes unique to one population or the other. In 10 individuals, nine novel genotypes were identified. KIR2DS4 gene variants showed significant differences: The KIR2DS4full gene was more common in Guerrero (p<0.0001), and the KIR2DS4del variant was more common in Jalisco (p<0.05). Differences in KIR2DS4 gene variants and genotypic profiles could be influenced by the genetic admixture in both regions. PMID- 28734804 TI - Tracheobronchomegaly in Intubated Ventilation of ARDS. PMID- 28734807 TI - [A survey on premedication prior to intubation in very preterm infants (28-32WG) with respiratory distress syndrome in French neonatal intensive care units]. AB - INTRODUCTION/OBJECTIVES: Tracheal intubation is a painful procedure for which the routine use of analgesia is recommended. However, the use of premedication for intubation is not yet generalized and there is great diversity in the drugs used. The main objective of this study was to describe the frequency of premedication use in preterm neonates aged between 28 and 32weeks of gestation, intubated for respiratory distress syndrome. Secondary objectives were to describe the existence of a written protocol, its influence on the frequency of premedication and the drugs used. MATERIALS AND METHODS: Declarative survey on Google.docs forms addressed to physicians and residents working in neonatal intensive care units in France. RESULTS: One hundred thirty respondents from 64 units completed this survey between 1 June and 31 July 2014. Fifty-seven percent of respondents declared always using a premedication, and 64 % of participants had a written protocol in their units. Persons working in a unit with a written protocol more frequently reported using premedication (P=0.04). The drugs used were various (mostly a hypnotic/morphine combination) and their dosages scattered. DISCUSSION: The results found by this survey confirm data from the literature and the situation seems to have stagnated over the last few years. A written protocol might encourage premedication use. CONCLUSION: Improvements in practices and increased knowledge are required to generalize the sedation/analgesia practices for tracheal intubation in neonatal intensive care units in France. PMID- 28734806 TI - SNORA21 - An Oncogenic Small Nucleolar RNA, with a Prognostic Biomarker Potential in Human Colorectal Cancer. AB - BACKGROUND: Emerging evidence indicates that small nucleolar RNAs (snoRNAs) play a central role in oncogenesis. Herein, we systematically evaluated expression profiles of snoRNAs in colorectal cancer (CRC) and investigated their clinical and functional role in this malignancy. METHODS: We compared expression levels of snoRNAs between cancer and normal tissues using publicly available datasets and identified the most differentially expressed and commonly upregulated snoRNAs in CRC. These results were examined in 489 colorectal tissues to assess their clinical significance, followed by a series of in vitro and in vivo experiments to evaluate the functional role of candidate snoRNAs. RESULTS: Using multiple RNA profiling datasets, we identified consistent overexpression of SNORA21 in CRC. In the clinical validation cohorts, the expression level of SNORA21 was upregulated in colorectal adenomas and cancers. Furthermore, elevated SNORA21 emerged as an independent factor for predicting poor survival. Both in vitro and in vivo experiments revealed that CRISPR/Cas9-mediated inhibition of SNORA21 expression resulted in decreased cell proliferation and invasion through modulation of multiple cancer related pathways. CONCLUSIONS: We systematically identified SNORA21 as a key oncogenic snoRNA in CRC, which plays an important role in cancer progression, and might serve as an important prognostic biomarker in CRC. PMID- 28734805 TI - C-Reactive Protein Mediating Immunopathological Lesions: A Potential Treatment Option for Severe Influenza A Diseases. AB - Severe influenza diseases with high mortality have been frequently reported, especially in those patients infected with avian influenza A (H5N1, H7N9 or H10N8) or during a pandemic. Respiratory distress, which is attributed to alveolar damage associated with immunopathological lesions, is the most common cause of death. There is a wealth of information on pathogenesis or treatment options. In this study, we showed that high levels of C-reactive protein (CRP) were induced and correlated with complement activation in patients infected with severe influenza A (H5N1, H7N9 or H10N8), and higher levels were induced in fatal patients than in survivors. CRP treatment enhanced the phagocytosis of monocytes THP-1 to H5N1 virus as well as the expression of proinflammatory cytokines or apoptosis-associated genes in THP-1 cells or pneumocytes A-549 respectively. CRP may link to proinflammatory mediators contributing to activation of complement and boosting inflammatory response in severe influenza infections. Compound 1,6 bis(phosphocholine)-hexane improved the severity and mortality of mice infected with lethal influenza virus significantly. These observations showed that CRP is involved in deterioration of severe influenza diseases, and indicated a substantial candidate molecule for immunotherapy of severe influenza diseases. PMID- 28734808 TI - [Congenital cytomegalovirus infection manifesting as neonatal respiratory distress in an HIV-exposed uninfected newborn]. AB - BACKGROUND: Cytomegalovirus (CMV) is one of the most common intrauterine infections, affecting approximately 1% of all live births. There are few reports on congenital CMV infections manifesting as isolated pneumonitis. CASE REPORT: We report a case of congenital CMV with neonatal respiratory distress affecting an HIV-exposed uninfected infant. This infant required noninvasive ventilation beginning within the first 15min of life. The initial chest X-ray showed diffuse bilateral ground-glass opacifications. Bacterial infection, meconium aspiration and hyaline membrane disease were excluded. Salivary quantitative CMV PCR was positive (2,342,261IU/mL) and serum viral load for CMV was low (476IU/mL). Bronchoalveolar lavage (BAL) performed on day 12 for quantitative CMV PCR was significantly positive (1,045,942IU/mL). Intravenous ganciclovir treatment was started on day 14 (7.5mg/kg/12h) for 2 weeks and oral valganciclovir (15mg/kg/12h) was given for 4 weeks afterwards. Ventilatory support was stopped on day 18. HIV serum viral load was negative on day 30. DISCUSSION: Congenital CMV infection can present as isolated pneumonitis with persistent neonatal respiratory symptoms, emphysematous lung disease, or persistent pulmonary hypertension. If this diagnosis is suspected, and even if CMV viremia remains low, BAL with quantitative CMV PCR must be performed to ascertain the diagnosis and indicate antiviral treatment. HIV-exposed uninfected infants have higher rates of congenital CMV infection when the mother's CD4 rate is<200/mm3. Most cases of CMV transmission in HIV-exposed uninfected infants have occurred by maternal endogenous reactivation or reinfection. PMID- 28734809 TI - [Severe poisoning by traditional medication in the newborn]. AB - The use of traditional products for therapeutic purposes in the newborn cause many cases of severe poisoning, especially in newborns. The aim of this study was to identify the main medicinal plants causing poisoning and emphasize the seriousness of poisonous plants. We report a series of eight newborns admitted for intake of poisonous medicinal plants admitted to the neonatal unit and neonatal intensive care unit at the Fez (Morocco) Hassan II University Hospital in 2014. The reasons for use were dominated by the infant's refusing to suckle. Clinical signs at admission were neurological signs and respiratory distress. The decision was spontaneously declared by the family for only two patients. A particular smell of the urine and unusual lesion associations were the main signs drawing the attention of physicians in other cases. The amounts and rates differed. Laboratory tests revealed renal failure in two cases. Transaminases (SGOT and SGPT) were greater than three times normal and the TP was below 50% in two newborns. Hemoglobin less than 9g/dL in three cases and thrombocytopenia less than 50,000/mm3 in two newborns. The main poisonous plants were identified as cade oil and henna. Medicinal plants were associated in all cases. Toxicological analysis was negative in three cases and was not done in the other five cases. The management was symptomatic and etiological. The outcome was favorable in six newborns. Death occurred in two neonates despite resuscitation. Medicinal plants must, like drugs, obey strict rules that only the standard herbal medicine specialist can answer. This necessarily involves the regulation of the profession in our country. PMID- 28734810 TI - Retinal Pigment Epithelium Humps in High Myopia. AB - PURPOSE: To report on the presence of retinal pigment epithelium (RPE) humps in high myopia, and to describe the distinctive features from pathologic RPE detachments and choroidal neovascularizations (CNVs). DESIGN: Retrospective cross sectional study. METHODS: Charts and imaging studies of highly myopic patients presenting between September 2015 and February 2017 at a university teaching hospital were consecutively reviewed. All patients underwent spectral-domain optical coherence tomography (OCT). RPE humps were defined as RPE elevations above its physiologic profile, without any evidence of pathologic sub-RPE material. Multimodal imaging was analyzed to assess abnormalities of the RPE and choroid. RESULTS: One hundred and ninety-five eyes of 101 highly myopic patients were included. RPE humps on structural OCT were identified in 99 out of 195 eyes (estimated prevalence of 50.8%; 43.8%-57.8, 95% confidence intervals). In all eyes, RPE humps corresponded to large choroidal vessels lifting the RPE. Patchy, diffuse, or CNV-related atrophy was more common in eyes with RPE humps (60.6% vs 34.4%; P < .05). The presence of a large choroidal vessel elevating the RPE and the absence of abnormal material between the RPE and the Bruch membrane were the features distinctive from pathologic RPE detachments and CNVs. DISCUSSION: RPE humps were frequently observed in highly myopic eyes and they resulted from the presence of an underlying large choroidal vessel. They are more likely to appear in highly myopic eyes with advanced choroidal atrophy. To prevent unnecessary treatments, they should be distinguished from pathologic RPE detachments and CNVs. PMID- 28734811 TI - Treatment-Naive Quiescent Choroidal Neovascularization in Geographic Atrophy Secondary to Nonexudative Age-Related Macular Degeneration. AB - PURPOSE: To describe the characteristics and natural history of quiescent choroidal neovascularization (CNV) in geographic atrophy (GA) secondary to nonexudative age-related macular degeneration (AMD) through multimodal imaging. DESIGN: Retrospective observational case series. METHODS: Patients diagnosed with quiescent CNV were analyzed in 2 high-volume referral centers. Imaging features obtained using fluorescein angiography (FA), indocyanine green angiography (ICGA), structural optical coherence tomography (OCT), and OCT angiography (OCT A) were noted at first presentation and during the study period. RESULTS: Nineteen eyes of 19 patients were included. Mean (+SD) follow-up was 45.7 +/- 14.7 months. Quiescent CNV appeared as an ill-defined hyperfluorescent lesion without leakage or pooling of dye in the late phase of FA. On ICGA, quiescent CNV appeared as a distinct area of hyperfluorescence (vascular network) in early to intermediate frames and as a hyperfluorescent plaque in the late frame (late plaque). OCT-A revealed a flow signal beneath the small irregular elevation of the retinal pigment epithelium at the site of the quiescent CNV visualized by structural OCT. During the study period, 5 of the 19 CNV patients developed exudation. The remainder showed specific alterations in both structural OCT and OCT-A imaging. At last follow-up, 92% of the quiescent CNV seemed to cover the area spared from atrophy. CONCLUSIONS: The characteristics of the quiescent CNVs were very similar to those already described for intermediate AMD, although they had several specific features in the context of GA. PMID- 28734812 TI - Quantitative Retinal Vascular Changes in Obstructive Sleep Apnea. AB - PURPOSE: To examine the relationship between both static and dynamic retinal vascular caliber and the severity of obstructive sleep apnea (OSA). DESIGN: Prospective cross-sectional study. METHODS: Adult patients undergoing diagnostic polysomnography studies at a private Australian university teaching hospital were recruited. OSA severity was defined by the apnea-hypopnea index (AHI): severe >30, moderate >15-30, mild 5-15, and controls <5. Of 115 patients recruited (73 male; mean age 58 +/- 13 years), there were 41 severe, 35 moderate, and 25 mild OSA patients and 14 controls. Static retinal vascular caliber was measured as the average diameter of retinal arterioles (CRAE) and venules (CRVE), and summarized as the arteriovenous ratio (AVR). Dynamic retinal vascular caliber was evaluated as the average pulsation amplitude of retinal arterioles (SRAP) and venules (SRVP). Comparisons across groups were performed using multivariate linear regression analysis. All results were adjusted for age, body mass index, and mean arterial pressure. RESULTS: Increasing AHI was significantly associated with decreasing AVR (P = .008) and CRAE (P = .016). A significant relationship was demonstrated between increasing AHI and attenuated retinal vascular pulsation amplitude (arterioles P = .028; venules P < .0001). CONCLUSIONS: Increasing OSA severity is independently associated with retinal arteriolar narrowing and attenuated vascular pulsation amplitude. The retinal vasculature is easily imaged, and may be a surrogate biomarker of cerebral and systemic vascular risk in patients with OSA requiring further comprehensive investigation. PMID- 28734813 TI - Incidence and Types of Pediatric Nystagmus. AB - PURPOSE: To report the incidence, prevalent subtypes, and clinical characteristics of pediatric nystagmus diagnosed over a 30-year period. DESIGN: Retrospective, population-based study. METHODS: Using the Rochester Epidemiology Project, we reviewed the medical records of all children (<19 years) diagnosed as residents in Olmsted County, Minnesota, with any form of nystagmus from January 1, 1976, through December 31, 2005. RESULTS: Seventy-one children were diagnosed during the 30-year period, yielding an annual incidence of 6.72 per 100,000 younger than 19 years (95% confidence interval [CI], 5.15-8.28) Infantile nystagmus, onset by 6 months, comprised 62 (87.3%) of the study patients, corresponding to a birth prevalence of 1 in 821. The median age at diagnosis for the cohort was 12.7 months (range, 0 days to 18.6 years) and 42 subjects (59.2%) were male. The main types of nystagmus, in declining order, were nystagmus associated with retinal/optic nerve disease in 23 (32.4%), idiopathic or congenital motor nystagmus in 22 (31.0%), manifest latent nystagmus or latent nystagmus in 17 (24.0%), and 2 (2.8%) each associated with Chiari malformation, medication use, tumor of the central nervous system, and no diagnosis. Developmental delay was diagnosed in 31 (43.6%), strabismus in 25 (35.2%), and amblyopia in 10 (14.1%). Eighty percent had 20/40 (or equivalent) or better vision at presentation in at least 1 eye. CONCLUSIONS: This study provides population-based data on incidence and clinical characteristics of childhood nystagmus in North America. Idiopathic and nystagmus associated with retinal/optic nerve disease were the most common presentations, with most patients having good vision. Developmental delay, strabismus, and amblyopia were common in this cohort. PMID- 28734814 TI - Conjunctival Autograft Versus Amniotic Membrane Transplantation for Treatment of Pterygium: Findings From a Cochrane Systematic Review. AB - PURPOSE: To summarize key findings from a systematic review of the effectiveness and risks of conjunctival autograft (CAG) compared with amniotic membrane transplant (AMT) for pterygium. DESIGN: Cochrane systematic review. METHODS: We included only randomized controlled trials (RCTs) in which CAG and AMT had been compared for primary or recurrent pterygia. The primary outcome was recurrence of pterygium >=1 mm onto the cornea by 3 and 6 months post surgery. We adhered to Cochrane methods for trial selection, data extraction, risk of bias evaluation, and data synthesis. RESULTS: Twenty RCTs with 1866 participants (1947 eyes) were included. Pterygium recurrence 6 months after surgery ranged from 3.3% to 16.7% in the CAG group and 6.4% to 42.3% in the AMT group based on data from 1021 eyes in 10 RCTs. Estimated risk ratios from meta-analysis indicated that CAG-treated eyes had a 47% lower risk of recurrence 6 months after surgery compared with the AMT group (RR, 0.53, 95% confidence interval [CI], 0.33-0.85). For 96 eyes with recurrent pterygium, the risk of recurrence 6 months after CAG was reduced by 55% compared with AMT (risk ratio [RR], 0.45, 95% CI, 0.21-0.99). Three-month recurrence rates were similar for CAG and AMT based on data from 538 eyes (6 RCTs). CONCLUSIONS: CAG was more effective than AMT to prevent pterygium recurrence by 6 months post surgery, especially in recurrent pterygia. CAG treated eyes had half the recurrence rates of AMT-treated eyes. Future RCTs should assess changes in patient-reported outcomes (symptoms, cosmesis) and visual acuity, and evaluate effects of surgical variations. PMID- 28734815 TI - Progressive Macula Vessel Density Loss in Primary Open-Angle Glaucoma: A Longitudinal Study. AB - PURPOSE: To characterize the rate of macula vessel density loss in primary open angle glaucoma (POAG), glaucoma-suspect, and healthy eyes. DESIGN: Longitudinal, observational cohort from the Diagnostic Innovations in Glaucoma Study. METHODS: One hundred eyes (32 POAG, 30 glaucoma-suspect, and 38 healthy) followed for at least 1 year with optical coherence tomography angiography (OCT-A) imaging on at least 2 visits were included. Vessel density was calculated in the macula superficial layer. The rate of change was compared across diagnostic groups using a multivariate linear mixed-effects model. RESULTS: Baseline macula vessel density was highest in healthy eyes, followed by glaucoma-suspect and POAG eyes (P < .01). The rate of vessel density loss was significantly different from zero in the POAG, but not in the glaucoma-suspect or healthy eyes. The mean rate of change in macula whole en face vessel density was significantly faster in glaucoma eyes (-2.23%/y) than in glaucoma-suspect (0.87%/y, P = .001) or healthy eyes (0.29%/y, P = .004). Conversely, the rate of change in ganglion cell complex (GCC) thickness was not significantly different from zero in any diagnostic group, and no significant differences in the rate of GCC change among diagnostic groups were found. CONCLUSIONS: With a mean follow-up of less than 14 months, eyes with POAG had significantly faster loss of macula vessel density than either glaucoma-suspect or healthy eyes. Serial OCT-A measurements also detected glaucomatous change in macula vessel density in eyes without evidence of change in GCC thickness. PMID- 28734816 TI - Glaucoma Screening in Nepal: Cup-to-Disc Estimate With Standard Mydriatic Fundus Camera Compared to Portable Nonmydriatic Camera. AB - PURPOSE: To compare cup-to-disc ratio (CDR) measurements from images taken with a portable, 45-degree nonmydriatic fundus camera to images from a traditional tabletop mydriatic fundus camera. DESIGN: Prospective, cross-sectional, comparative instrument validation study. METHODS: Setting: Clinic-based. STUDY POPULATION: A total of 422 eyes of 211 subjects were recruited from the Tilganga Institute of Ophthalmology (Kathmandu, Nepal). Two masked readers measured CDR and noted possible evidence of glaucoma (CDR >= 0.7 or the presence of a notch or disc hemorrhage) from fundus photographs taken with a nonmydriatic portable camera and a mydriatic standard camera. Each image was graded twice. MAIN OUTCOME MEASURES: Effect of camera modality on CDR measurement; inter- and intraobserver agreement for each camera for the diagnosis of glaucoma. RESULTS: A total of 196 eyes (46.5%) were diagnosed with glaucoma by chart review; 41.2%-59.0% of eyes were remotely diagnosed with glaucoma over grader, repeat measurement, and camera modality. There was no significant difference in CDR measurement between cameras after adjusting for grader and measurement order (estimate = 0.004, 95% confidence interval [CI], 0.003-0.011, P = .24). There was moderate interobserver reliability for the diagnosis of glaucoma (Pictor: kappa = 0.54, CI, 0.46-0.61; Topcon: kappa = 0.63, CI, 0.55-0.70) and moderate intraobserver agreement upon repeat grading (Pictor: kappa = 0.63 and 0.64, for graders 1 and 2, respectively; Topcon: kappa = 0.72 and 0.80, for graders 1 and 2, respectively). CONCLUSIONS: A portable, nonmydriatic, fundus camera can facilitate remote evaluation of disc images on par with standard mydriatic fundus photography. PMID- 28734817 TI - Detection of Functional Change in Preperimetric and Perimetric Glaucoma Using 10 2 Matrix Perimetry. AB - PURPOSE: To evaluate an effective functional strategy for detecting glaucomatous damage of the macula in preperimetric to perimetric glaucoma. DESIGN: Cross sectional study. METHODS: Preperimetric glaucoma patients (n = 102) and perimetric glaucoma patients (n = 88) with isolated paracentral scotoma or combined paracentral scotoma were enrolled in this study. Global and sectoral mean sensitivities (MS) were evaluated using 10-2 standard automated perimetry (SAP) with a stimulus of sizes III (0.43-degree diameter) and V (1.72 degrees), and 10-2 Matrix perimetry with a stimulus of 2 degrees. Ganglion cell-inner plexiform layer (GCIPL) was measured using spectral-domain optical coherence tomography. RESULTS: The percentage of significantly depressed visual field (VF) points <5% and <1% in the pattern deviation plot was higher with frequency doubling technology (FDT) 10-2 than with SAP 10-2 III in patients with preperimetric glaucoma (both P < .001). Using FDT 10-2 tests, the global structure-function correlation was superior to SAP 10-2 (III or V) in both preperimetric and perimetric glaucoma. Topographic structure-function relationships for each VF test were more favorable with the FDT 10-2 test. The preperimetric glaucoma patients showing VF abnormalities on FDT 10-2 or SAP 10-2 (III) showed thinner average, minimum, superior, inferior, and inferotemporal GCIPL thicknesses than in those without VF abnormalities (all P < .05). CONCLUSIONS: FDT 10-2 was found to detect functional damage of the macula early in preperimetric glaucoma, and to perform better than with SAP 10-2 (size III or V) from preperimetric to perimetric glaucoma in the structure-function relationship. FDT 10-2 can be considered a useful tool to detect glaucomatous damage of the macula early and appropriately. PMID- 28734818 TI - Preoperative Aqueous Cytokine Levels Are Associated With a Rapid Reduction in Endothelial Cells After Penetrating Keratoplasty. AB - PURPOSE: To evaluate the influence of preoperative inflammatory cytokine levels in the aqueous humor (AqH) on the endothelial cell density (ECD) after penetrating keratoplasty (PKP). DESIGN: Prospective, interventional, consecutive case series. METHODS: This study includes 70 consecutive patients (mean age 73.7 +/- 10.6 years) who underwent PKP (37 eyes) or cataract surgery (controls, 33 eyes). A total of 70 AqH samples were collected at the beginning of each surgery. The levels of cytokines (interleukin [IL]-1alpha, IL-1beta, IL-4, IL-6, IL-8, IL 10, IL-12p70, IL-13, IL-17A, interferon [IFN]-alpha, IFN-gamma, monocyte chemotactic protein [MCP]-1, E-selectin and P-selectin) in AqH were measured by multiplex bead immunoassay. The subjects who underwent PKP were classified into 2 groups: ECD >= 1200 cells/mm2 at 6 months (24 eyes), and ECD < 1200 cells/mm2 at 6 months (13 eyes). RESULTS: The ECD at 3 months significantly correlated with the preoperative levels of IL-10 (r = -0.428, P = .02) and IFN-gamma (r = -0.412, P = .029). The ECD at 6 months significantly correlated with the preoperative levels of IL-10 (r = -0.399, P = .024), MCP-1 (r = -0.444, P = .011), and IFN gamma (r = -0.474, P = .006). The preoperative levels of IL-6, IL-10, MCP-1, IFN gamma, and P-selectin in AqH were significantly higher in eyes with ECD < 1200 cells/mm2 compared with those with ECD >= 1200 cells/mm2 at 6 months (P < .05). CONCLUSIONS: Higher preoperative levels of IL-10, MCP-1, and IFN-gamma in the AqH were associated with low ECD after PKP. PMID- 28734819 TI - The Prevalence of Chronic Conditions and Poor Health Among People With and Without Vision Impairment, Aged >=65 Years, 2010-2014. AB - PURPOSE: To examine the prevalence of 13 chronic conditions and fair/poor health among people aged >=65 years in the United States with and without vision impairment. DESIGN: Cross-sectional study from the 2010-2014 National Health Interview Survey. METHODS: We examined hypertension, heart disease, high cholesterol, stroke, arthritis, asthma, chronic obstructive pulmonary disease, cancer, weak/failing kidneys, diabetes, hepatitis, depression, and hearing impairment. We used logistic regression to show the association between vision impairment and chronic conditions and the association between vision impairment and poor health for those with chronic conditions. RESULTS: People aged >=65 years with vision impairment reported greater prevalence of chronic conditions compared to people without vision impairment. After controlling for covariates (age, sex, education, race, smoking, physical activity, and obesity), people with vision impairment were more likely than those without to report chronic conditions (hypertension: OR [odds ratio] 1.43; heart disease: OR 1.68; high cholesterol: OR 1.26; stroke: OR 1.99; arthritis; OR 1.71; asthma: OR 1.56; chronic obstructive pulmonary disease: OR 1.65; cancer: OR 1.23; weak/failing kidneys: OR 2.29; diabetes: OR 1.56; hepatitis: OR 1.30; depression: OR 1.47; hearing impairment: OR 1.91) (all P < .05). Among older people with chronic conditions, those with vision impairment and chronic conditions compared to people without vision impairment and chronic conditions were 1.66-2.98 times more likely to have fair/poor health than those without vision impairment (all P < .05). CONCLUSION: Higher prevalence of chronic conditions is strongly associated with vision impairment among the older people and poor health is strongly associated with vision impairment and chronic conditions. PMID- 28734820 TI - Brain metastases in patients with EGFR-mutant non-small-cell lung cancer. PMID- 28734821 TI - Deep learning poised to revolutionise diagnostic imaging. PMID- 28734822 TI - Icotinib versus whole-brain irradiation in patients with EGFR-mutant non-small cell lung cancer and multiple brain metastases (BRAIN): a multicentre, phase 3, open-label, parallel, randomised controlled trial. AB - BACKGROUND: For patients with non-small-cell lung cancer (NSCLC) and multiple brain metastases, whole-brain irradiation (WBI) is a standard-of-care treatment, but its effects on neurocognition are complex and concerning. We compared the efficacy of an epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), icotinib, versus WBI with or without chemotherapy in a phase 3 trial of patients with EGFR-mutant NSCLC and multiple brain metastases. METHODS: We did a multicentre, open-label, parallel randomised controlled trial (BRAIN) at 17 hospitals in China. Eligible participants were patients with NSCLC with EGFR mutations, who were naive to treatment with EGFR-TKIs or radiotherapy, and had at least three metastatic brain lesions. We randomly assigned participants (1:1) to either icotinib 125 mg orally (three times per day) or WBI (30 Gy in ten fractions of 3 Gy) plus concurrent or sequential chemotherapy for 4-6 cycles, until unacceptable adverse events or intracranial disease progression occurred. The randomisation was done by the Chinese Thoracic Oncology Group with a web based allocation system applying the Pocock and Simon minimisation method; groups were stratified by EGFR gene mutation status, treatment line (first line or second line), brain metastases only versus both intracranial and extracranial metastases, and presence or absence of symptoms of intracranial hypertension. Clinicians and patients were not masked to treatment assignment, but individuals involved in the data analysis did not participate in the treatments and were thus masked to allocation. Patients receiving icotinib who had intracranial progression only were switched to WBI plus either icotinib or chemotherapy until further progression; those receiving icotinib who had extracranial progression only were switched to icotinib plus chemotherapy. Patients receiving WBI who progressed were switched to icotinib until further progression. Icotinib could be continued beyond progression if a clinical benefit was observed by the investigators (eg, an improvement in cognition or intracranial pressure). The primary endpoint was intracranial progression-free survival (PFS), defined as the time from randomisation to either intracranial disease progression or death from any cause. We assessed efficacy and safety in the intention-to-treat population (all participants who received at least one dose of study treatment), hypothesising that intracranial PFS would be 40% longer (hazard ratio [HR] 0.60) with icotinib compared with WBI. This trial is registered with ClinicalTrials.gov, number NCT01724801. FINDINGS: Between Dec 10, 2012, and June 30, 2015, we assigned 176 participants to treatment: 85 to icotinib and 91 to WBI. 18 withdrew from the WBI group before treatment, leaving 73 for assessment. Median follow-up was 16.5 months (IQR 11.5-21.5). Median intracranial PFS was 10.0 months (95% CI 5.6-14.4) with icotinib versus 4.8 months (2.4-7.2) with WBI (equating to a 44% risk reduction with icotinib for an event of intracranial disease progression or death; HR 0.56, 95% CI 0.36-0.90; p=0.014). Adverse events of grade 3 or worse were reported in seven (8%) of 85 patients in the icotinib group and 28 (38%) of 73 patients in the WBI group. Raised concentrations of alanine aminotransferase and rash were the most common adverse events of any grade in both groups, occurring in around 20-30% of each group. At the time of final analysis, 42 (49%) patients in the icotinib group and 37 (51%) in the WBI group had died. 78 of these patients died from disease progression, and one patient in the WBI group died from thrombogenesis related to chemotherapy. INTERPRETATION: In patients with EGFR-mutant NSCLC and multiple brain metastases, icotinib was associated with significantly longer intracranial PFS than WBI plus chemotherapy, indicating that icotinib might be a better first-line therapeutic option for this patient population. FUNDING: Guangdong Provincial Key Laboratory of Lung Cancer Translational Medicine, National Health and Family Planning Commission of China, Guangzhou Science and Technology Bureau, Betta Pharmaceuticals, and the Chinese Thoracic Oncology Group. PMID- 28734823 TI - Evaluation of early administration of simvastatin in the prevention and treatment of delirium in critically ill patients undergoing mechanical ventilation (MoDUS): a randomised, double-blind, placebo-controlled trial. AB - BACKGROUND: Delirium in critically ill patients is associated with poor clinical outcomes. Neuroinflammation might be an important mechanism in the pathogenesis of delirium, and since simvastatin has anti-inflammatory properties it might reduce delirium. We aimed to establish whether early treatment with simvastatin would decrease the time that survivors of critical illness spent in delirium or coma. METHODS: We undertook this randomised, double-blind, placebo-controlled trial in a general adult intensive care unit (ICU) in Watford General Hospital (Watford, UK). We enrolled critically ill patients (>=18 years) needing mechanical ventilation within 72 h of admission. We randomly assigned patients (1:1 ratio) to receive either simvastatin 80 mg or placebo daily for up to a maximum of 28 days, irrespective of coma or delirium status. We assessed delirium using the Confusion Assessment Method for the ICU (CAM-ICU). The primary outcome was number of days alive and was assessed as delirium-free and coma-free in the first 14 days after being randomly allocated to receive treatment or placebo. ICU clinical and research staff and patients were masked to treatment. We did intention-to-treat analyses with no extrapolation. This trial is registered with the International Standard Randomised Controlled Trial Registry, number ISRCTN89079989. FINDINGS: Between Feb 1, 2013, and July 29, 2016, 142 patients were randomly assigned to receive simvastatin (n=71) or placebo (n=71), and were included in the final analysis. The mean number of days alive without delirium and without coma at day 14 did not differ significantly between the two groups (5.7 days [SD 5.1] with simvastatin and 6.1 days [5.2] with placebo; mean difference 0.4 days, 95% CI -1.3 to 2.1; p=0.66). The most common adverse event was an elevated creatine kinase concentration to more than ten times the upper limit of normal (eight [11%] in the simvastatin group vs three [4%] in the placebo group p=0.208). No patient had a serious adverse event related to the study drug. INTERPRETATION: These results do not support the hypothesis that simvastatin modifies duration of delirium and coma in critically ill patients. FUNDING: National Institute for Health Research. PMID- 28734824 TI - Is there a vanishing pulmonary capillary syndrome? PMID- 28734825 TI - Trials of statins in delirium-stymied by complex methods? PMID- 28734826 TI - Biophysical Constraints Arising from Compositional Context in Synthetic Gene Networks. AB - Synthetic gene expression is highly sensitive to intragenic compositional context (promoter structure, spacing regions between promoter and coding sequences, and ribosome binding sites). However, much less is known about the effects of intergenic compositional context (spatial arrangement and orientation of entire genes on DNA) on expression levels in synthetic gene networks. We compare expression of induced genes arranged in convergent, divergent, or tandem orientations. Induction of convergent genes yielded up to 400% higher expression, greater ultrasensitivity, and dynamic range than divergent- or tandem-oriented genes. Orientation affects gene expression whether one or both genes are induced. We postulate that transcriptional interference in divergent and tandem genes, mediated by supercoiling, can explain differences in expression and validate this hypothesis through modeling and in vitro supercoiling relaxation experiments. Treatment with gyrase abrogated intergenic context effects, bringing expression levels within 30% of each other. We rebuilt the toggle switch with convergent genes, taking advantage of supercoiling effects to improve threshold detection and switch stability. PMID- 28734827 TI - Multi-omics Analyses of Starvation Responses Reveal a Central Role for Lipoprotein Metabolism in Acute Starvation Survival in C. elegans. AB - Starvation causes comprehensive metabolic changes, which are still not fully understood. Here, we used quantitative proteomics and RNA sequencing to examine the temporal starvation responses in wild-type Caenorhabditis elegans and animals lacking the transcription factor HLH-30. Our findings show that starvation alters the abundance of hundreds of proteins and mRNAs in a temporal manner, many of which are involved in central metabolic pathways, including lipoprotein metabolism. We demonstrate that premature death of hlh-30 animals under starvation can be prevented by knockdown of either vit-1 or vit-5, encoding two different lipoproteins. We further show that the size and number of intestinal lipid droplets under starvation are altered in hlh-30 animals, which can be rescued by knockdown of vit-1. Taken together, this indicates that survival of hlh-30 animals under starvation is closely linked to regulation of intestinal lipid stores. We provide the most detailed poly-omic analysis of starvation responses to date, which serves as a resource for further mechanistic studies of starvation. PMID- 28734828 TI - Bacterial endotoxin exposure invokes transcriptional changes in embryonic murine neural stem cells. PMID- 28734829 TI - Feasibility of prophylactic salpingectomy during vaginal hysterectomy. AB - BACKGROUND: The American Congress of Obstetricians and Gynecologists recommends that "the surgeon and patient discuss the potential benefits of the removal of the fallopian tubes during a hysterectomy in women at population risk of ovarian cancer who are not having an oophorectomy," resulting in an increasing rate of salpingectomy at the time of hysterectomy. Rates of salpingectomy are highest for laparoscopic and lowest for vaginal hysterectomy. OBJECTIVE: The primary objective of this study was to determine the feasibility of bilateral salpingectomy at the time of vaginal hysterectomy. Secondary objectives included identification of factors associated with unsuccessful salpingectomy and assessment of its impact on operating time, blood loss, surgical complications, and menopausal symptoms. STUDY DESIGN: This was a multicenter, prospective study of patients undergoing planned vaginal hysterectomy with bilateral salpingectomy. Baseline medical data along with operative findings, operative time, and blood loss for salpingectomy were recorded. Uterine weight and pathology reports for all fallopian tubes were reviewed. Patients completed the Menopause Rating Scale at baseline and at postoperative follow-up. Descriptive analyses were performed to characterize the sample and compare those with successful and unsuccessful completion of planned salpingectomy using Student t test, and chi2 test when appropriate. Questionnaire scores were compared using paired t tests. RESULTS: Among 77 patients offered enrollment, 74 consented (96%), and complete data were available regarding primary outcome for 69 (93%). Mean age was 51 years. Median body mass index was 29.1 kg/m2; median vaginal parity was 2, and 41% were postmenopausal. The indications for hysterectomy included prolapse (78%), heavy menstrual bleeding (20%), and fibroids (11%). When excluding conversions to alternate routes, vaginal salpingectomy was successfully performed in 52/64 (81%) women. Mean operating time for bilateral salpingectomy was 11 (+/-5.6) minutes, with additional estimated blood loss of 6 (+/-16.3) mL. There were 8 surgical complications: 3 hemorrhages >500 mL and 5 conversions to alternate routes of surgery, but none of these were due to the salpingectomy. Mean uterine weight was 102 g and there were no malignancies on fallopian tube pathology. Among the 17 patients in whom planned bilateral salpingectomy was not completed, unilateral salpingectomy was performed in 7 patients. Reasons for noncompletion included: tubes high in the pelvis (8), conversion to alternate route for pathology (4), bowel or sidewall adhesions (3), tubes absent (1), and ovarian adhesions (1). Prior adnexal surgery (odds ratio, 2.9; 95% confidence interval, 1.5-5.5; P = .006) and uterine fibroids (odds ratio, 5.8; 95% confidence interval, 1.5-22.5; P = .02) were the only significant factors associated with unsuccessful bilateral salpingectomy. Mean menopause scores improved after successful salpingectomy (12.7 vs 8.6; P < .001). CONCLUSION: Vaginal salpingectomy is feasible in the majority of women undergoing vaginal hysterectomy and increases operating time by 11 minutes and blood loss by 6 mL. Women with prior adnexal surgery or uterine fibroids should be counseled about the possibility that removal may not be feasible. PMID- 28734830 TI - Active Choice and Financial Incentives to Increase Rates of Screening Colonoscopy A Randomized Controlled Trial. AB - Behavioral economic approaches could increase uptake for colorectal cancer screening. We performed a randomized controlled trial of 2245 employees to determine whether an email containing a phone number for scheduling (control), an email with the active choice to opt in or opt out (active choice), or the active choice email plus a $100 incentive (financial incentive) increased colonoscopy completion within 3 months. Higher proportions of participants in the financial incentive group underwent screening (3.7%) than in the control (1.6%) or active choice groups (1.5%) (P = .01 and P < .01). We found no difference in uptake of screening between the active choice and control groups (P = .88). The $100 conditional incentive modestly but significantly increased colonoscopy use. ClinicalTrials.gov no: NCT02660671. PMID- 28734831 TI - Effects of All-Oral Anti-Viral Therapy on HVPG and Systemic Hemodynamics in Patients With Hepatitis C Virus-Associated Cirrhosis. AB - BACKGROUND & AIMS: Patients with hepatitis C virus-associated cirrhosis and clinical significant portal hypertension (CSPH, hepatic venous pressure gradient [HVPG] 10 mmHg or greater), despite achieving sustained virological response (SVR) to therapy, remain at risk of liver decompensation. We investigated hemodynamic changes following SVR in patients with CSPH and whether liver stiffness measurements (LSMs) can rule out the presence of CSPH. METHODS: We performed a multicenter prospective study of 226 patients with hepatitis C virus associated cirrhosis and CSPH who had SVR to interferon-free therapy at 6 Liver Units in Spain. The portal pressure gradient was determined based on HVPG at baseline and 24 weeks after therapy; patients also underwent right-heart catheterization and LSM at these time points. Primary outcomes were effects of SVR on the hepatic, pulmonary, and systemic hemodynamics; factors related to HVPG >=10% reduction and to CSPH persistence; and whether LSMs can rule out the presence of CSPH after SVR. RESULTS: Most patients (75%) had esophageal varices, 21% were Child-B, and 29% had at least 1 previous episode of liver decompensation. Overall, HVPG decreased from 15 (IQR: 12-18) before treatment to 13 (10-16) mmHg after SVR (reduction of 2.1 +/- 3.2 mmHg; P < .01). However, CSPH persisted in 78% of patients. HVPG decreased by 10% or more from baseline in 140 patients (62%). Baseline level of albumin below 3.5 g/dL was the only negative factor associated with an HVPG reduction of 10% or more. LSM decreased from 27 (20-37) kPa before treatment to 18 (14-28) kPa after SVR (P < .05). One third of patients with a reduction in LSM to below 13.6 kPa after SVR still had CSPH. A higher baseline HVPG and a lower decrease in LSM after treatment were associated with persistence of CSPH after SVR. Systemic hemodynamics improved after SVR. Interestingly, pulmonary hypertension was present in 13 patients at baseline and 25 after SVR, although only 3 patients had increased pulmonary resistance. CONCLUSIONS: In a multicenter prospective study of patients with hepatitis C virus-associated cirrhosis, an SVR to all-oral therapy significantly reduced HVPG, compared with before treatment. Nevertheless, CSPH persists in most patients despite SVR, indicating persistent risk of decompensation. In this population, changes in LSM do not correlate with HVPG and cut-off values are not reliable in ruling out CSPH after SVR. PMID- 28734832 TI - Superficial Esophageal Mucosal Afferent Nerves May Contribute to Reflux Hypersensitivity in Nonerosive Reflux Disease. AB - BACKGROUND & AIMS: Little is known about the causes of heartburn in patients with gastro-esophageal reflux disease. Visible epithelial damage is seldom associated with symptom severity, evidenced by the significant symptom burden in patients with nonerosive reflux disease (NERD) compared with patients with erosive reflux disease (ERD) or Barrett's esophagus (BE). We studied the distribution of mucosal nerve fibers in patients with NERD, ERD, and BE, and compared the results with those of healthy subjects. METHODS: We performed a prospective study of 13 patients with NERD, 11 patients with ERD, and 16 patients with BE undergoing endoscopic evaluation in the United Kingdom or Greece. Biopsies were obtained from the proximal and distal esophageal mucosa of patients with NERD, from the distal esophageal mucosa of patients with ERD, and the distal-most squamous epithelium of patients with BE. These were examined for the presence and location of nerve fibers that reacted with a labeled antibody against calcitonin gene related peptide (CGRP), a marker of nociceptive sensory nerves. The results were compared with those from 10 healthy volunteers (controls). RESULTS: The distribution of CGRP-positive nerves did not differ significantly between the distal esophageal mucosa of controls (median, 25.5 cell layers to surface; interquartile range [IQR], 21.4-28.8) vs patients with ERD (median, 23 cell layers to surface; IQR, 16-27.5), or patients with BE (median, 21.5 cell layers to surface; IQR, 16.1-27.5). However, CGRP-positive nerves were significantly more superficial in mucosa from patients with NERD-both distal (median, 9.5 cell layers to surface; IQR, 1.5-13.3; P < .0001 vs ERD, BE, and controls) and proximal (median, 5.0 cell layers to surface; IQR, 2.5-9.3 vs median 10.4 cell layers to surface; IQR, 8.0-16.9; P = .0098 vs controls). CONCLUSIONS: Proximal and distal esophageal mucosa of patients with NERD have more superficial afferent nerves compared with controls or patients with ERD or BE. Acid hypersensitivity in patients with NERD might be partially explained by the increased proximity of their afferent nerves to the esophageal lumen, and therefore greater exposure to noxious substances in refluxate. PMID- 28734833 TI - Transforming Growth Factor-beta Promotes Liver Tumorigenesis in Mice via Up regulation of Snail. AB - BACKGROUND & AIMS: Transforming growth factor beta (TGF-beta) suppresses early stages of tumorigenesis, but also contributes to migration and metastasis of cancer cells. A large number of human tumors contain mutations that inactivate its receptors, or downstream proteins such as Smad transcription factors, indicating that the TGF-beta signaling pathway prevents tumor growth. We investigated the effects of TGF-beta inhibition on liver tumorigenesis in mice. METHODS: C57BL/6 mice received hydrodynamic tail-vein injections of transposons encoding HRASG12V and a short hairpin RNA (shRNA) to down-regulate p53, or those encoding HRASG12V and MYC, or those encoding HRASG12V and TAZS89A, to induce liver tumor formation; mice were also given injections of transposons encoding SMAD7 or shRNA against SMAD2, SMAD3, SMAD4, or SNAI1 (Snail), with or without ectopic expression of Snail. Survival times were compared, and livers were weighted and examined for tumors. Liver tumor tissues were analyzed by quantitative reverse-transcription PCR, RNA sequencing, immunoblots, and immunohistochemistry. We analyzed gene expression levels in human hepatocellular carcinoma samples deposited in The Cancer Genome Atlas. A cell proliferation assay was performed using human liver cancer cell lines (HepG2 and Huh7) stably expressing Snail or shRNA against Snail. RESULTS: TGF-beta inhibition via overexpression of SMAD7 (or knockdown of SMAD2, SMAD3, or SMAD4) consistently reduced formation and growth of liver tumors in mice that expressed activated RAS plus shRNA against p53, or in mice that expressed activated RAS and TAZ. TGF-beta signaling activated transcription of the Snail gene in liver tumors induced by HRASG12V and shRNA against p53, and by activated RAS and TAZ. Knockdown of Snail reduced liver tumor formation in both tumor models. Ectopic expression of Snail restored liver tumorigenesis suppressed by disruption of TGF-beta signaling. In human hepatocellular carcinoma, Snail expression correlated with TGF-beta activation. Ectopic expression of Snail increased cellular proliferation, whereas Snail knockdown led to reduced proliferation in human hepatocellular carcinoma cells. CONCLUSIONS: In analyses of transgenic mice, we found TGF-beta signaling to be required for formation of liver tumors upon expression of activated RAS and shRNA down-regulating p53, and upon expression of activated RAS and TAZ. Snail is the TGF-beta target that is required for hepatic tumorigenesis in these models. PMID- 28734834 TI - Dynein binds and stimulates axonal motility of the endosome adaptor and NEEP21 family member, calcyon. AB - The neuron-enriched, endosomal protein Calcyon (Caly) regulates endocytosis and vesicle sorting, and is important for synaptic plasticity and brain development. In the current investigation of Caly interacting proteins in brain, the microtubule retrograde motor subunit, cytoplasmic dynein 1 heavy chain (DYNC1H), and microtubule structural proteins, alpha and beta tubulin, were identified as Caly associated proteins by MALDI-ToF/ToF. Direct interaction of the Caly-C terminus with dynein and tubulin was further confirmed in in vitro studies. In Cos-7 cells, mCherry-Caly moved along the microtubule network in organelles largely labeled by the late endosome marker Rab7. Expression of the dynein inhibitor CC1, produced striking alterations in Caly distribution, consistent with retrograde motors playing a prominent role in Caly localization and movement. In axons of cultured adult rat sensory neurons, Caly-positive organelles co-localized with dynein intermediate chain (DYNC1I1-isoform IC-1B) and the dynein regulator, lissencephaly 1 (LIS1), both of which co-precipitated from brain with the Caly C-terminus. Manipulation of dynein function in axons altered the motile properties of Caly indicating that Caly vesicles utilize the retrograde motor. Altogether, the current evidence for association with dynein motors raises the possibility that the endocytic and cargo sorting functions of Caly in neurons could be regulated by interaction with the microtubule transport system. PMID- 28734835 TI - Migration ability and Toll-like receptor expression of human mesenchymal stem cells improves significantly after three-dimensional culture. AB - While the conventional two-dimensional (2D) culture protocol is well accepted for the culture of mesenchymal stem cells (MSCs), this method fails to recapitulate the in vivo native three-dimensional (3D) cellular microenvironment, and may result in phenotypic changes, and homing and migration capacity impairments. MSC preparation in 3D culture systems has been considered an attractive preparatory and delivery method recently. We seeded human umbilical cord-derived MSCs (hUCMSCs) in a 3D culture system with porcine acellular dermal matrix (PADM), and investigated the phenotypic changes, the expression changes of some important receptors, including Toll-like receptors (TLRs) and C-X-C chemokine receptor type 4 (CXCR4) when hUCMSCs were transferred from 2D to 3D systems, as well as the alterations in in vivo homing and migration potential. It was found that the percentage of CD105-positive cells decreased significantly, whereas that of CD34- and CD271-positive cells increased significantly in 3D culture, compared to that in 2D culture. The mRNA and protein expression levels of TLR2, TLR3, TLR4, TLR6, and CXCR4 in hUCMSCs were increased significantly upon culturing with PADM for 3 days, compared to the levels in 2D culture. The numbers of migratory 3D hUCMSCs in the heart, liver, spleen, and bone marrow were significantly greater than the numbers of 2D hUCMSCs, and the worst migration occurred in 3D + AMD3100 (CXCR4 antagonist) hUCMSCs. These results suggested that 3D culture of hUCMSCs with PADM could alter the phenotypic characteristics of hUCMSCs, increase their TLR and CXCR4 expression levels, and promote their migratory and homing capacity in which CXCR4 plays an important role. PMID- 28734836 TI - Criticality in the brain: A synthesis of neurobiology, models and cognition. AB - Cognitive function requires the coordination of neural activity across many scales, from neurons and circuits to large-scale networks. As such, it is unlikely that an explanatory framework focused upon any single scale will yield a comprehensive theory of brain activity and cognitive function. Modelling and analysis methods for neuroscience should aim to accommodate multiscale phenomena. Emerging research now suggests that multi-scale processes in the brain arise from so-called critical phenomena that occur very broadly in the natural world. Criticality arises in complex systems perched between order and disorder, and is marked by fluctuations that do not have any privileged spatial or temporal scale. We review the core nature of criticality, the evidence supporting its role in neural systems and its explanatory potential in brain health and disease. PMID- 28734837 TI - Neural reuse of action perception circuits for language, concepts and communication. AB - Neurocognitive and neurolinguistics theories make explicit statements relating specialized cognitive and linguistic processes to specific brain loci. These linking hypotheses are in need of neurobiological justification and explanation. Recent mathematical models of human language mechanisms constrained by fundamental neuroscience principles and established knowledge about comparative neuroanatomy offer explanations for where, when and how language is processed in the human brain. In these models, network structure and connectivity along with action- and perception-induced correlation of neuronal activity co-determine neurocognitive mechanisms. Language learning leads to the formation of action perception circuits (APCs) with specific distributions across cortical areas. Cognitive and linguistic processes such as speech production, comprehension, verbal working memory and prediction are modelled by activity dynamics in these APCs, and combinatorial and communicative-interactive knowledge is organized in the dynamics within, and connections between APCs. The network models and, in particular, the concept of distributionally-specific circuits, can account for some previously not well understood facts about the cortical 'hubs' for semantic processing and the motor system's role in language understanding and speech sound recognition. A review of experimental data evaluates predictions of the APC model and alternative theories, also providing detailed discussion of some seemingly contradictory findings. Throughout, recent disputes about the role of mirror neurons and grounded cognition in language and communication are assessed critically. PMID- 28734838 TI - Expression, purification and characterization of sll1981 protein from cyanobacterium Synechocystis sp. PCC6803. AB - The sll1981 protein from cyanobacterium Synechocystis sp. PCC6803 had been reported to exhibit acetolactate synthase (ALS) and L-myo-inositol-1-phosphate synthase (MIPS) activities previously. Based on amino acids sequences alignment, sll1981 protein was postulated to function as alpha-ketoglutarate decarboxylase (alpha-KGD), which played important role in completing cyanobacterial tricarboxylic acid (TCA) cycle. However the detailed enzymatic kinetics of sll1981 as ALS, MIPS and alpha-KGD were not determined yet. In this study, the recombinant sll1981 protein was purified from supernatant of E. coli cell and the substrate specificity of sll1981 towards pyruvate, d-glucose-6-phosphate and alpha-ketoglutarate was examined using homogenous recombinant sll1981. Steady state kinetics results showed that sll1981 was a dual functional enzyme, which displayed much higher activity as alpha-KGD than as ALS. At the same time the MIPS activity of sll1981 was not detectable, although it was reported to be as MIPS previously. These findings not only confirmed the previous statement of the function of sll1981 as ALS and disputed the claimed function of sll1981 as MIPS, but also affirmed the new function of sll1981 as alpha-KGD. Therefore sll1981 was probably a key enzyme in completing the TCA cycle of Synechocystis sp. PCC6803. PMID- 28734839 TI - Recombinant expression of Ixolaris, a Kunitz-type inhibitor from the tick salivary gland, for NMR studies. AB - Ixolaris is an anticoagulant protein identified in the tick saliva of Ixodes scapularis. Ixolaris contains 2 Kunitz like domains and binds to Factor Xa or Factor X as a scaffold for inhibition of the Tissue Factor (TF)/Factor VIIa (FVIIa). In contrast to tissue factor pathway inhibitor (TFPI), however, Ixolaris does not bind to the active site cleft of FXa. Instead, complex formation is mediated by the FXa heparin-binding exosite. Due to its potent and long-lasting antithrombotic activity, Ixolaris is a promising agent for anticoagulant therapy. Although numerous functional studies of Ixolaris exist, three-dimensional structure of Ixolaris has not been obtained at atomic resolution. Using the pET32 vector, we successfully expressed a TRX-His6-Ixolaris fusion protein. By combining Ni-NTA chromatography, enterokinase protease cleavage, and reverse phase HPLC (RP-HPLC), we purified isotopically labeled Ixolaris for NMR studies. 1D 1H and 2D 15N-1H NMR analysis yielded high quality 2D 15N-1H HSQC spectra revealing that the recombinant protein is folded. These studies represent the first steps in obtaining high-resolution structural information by NMR for Ixolaris enabling the investigation of the molecular basis for Ixolaris coagulation factors interactions. PMID- 28734840 TI - An improved purification method for the lysosomal storage disease protein beta glucuronidase produced in CHO cells. AB - Human beta-glucuronidase (GUS; EC 3.2.1.31) is a lysosomal enzyme that catalyzes the hydrolysis of beta-d-glucuronic acid residues from the non-reducing termini of glycosaminoglycans. Impairment in GUS function leads to the metabolic disorder mucopolysaccharidosis type VII, also known as Sly syndrome. We produced GUS from a CHO cell line grown in suspension in a 15 L perfused bioreactor and developed a three step purification procedure that yields ~99% pure enzyme with a recovery of more than 40%. The method can be completed in two days and has the potential to be integrated into a continuous manufacturing scheme. PMID- 28734841 TI - Potential involvement of mi-RNA 574-3p in progression of prostate cancer: A bioinformatic study. AB - Aberrant gene expression is a hallmark of prostate cancer (PCa), the second deadliest disease affecting males worldwide. Dysregulation of miRNA has been associated with the progression of PCa and in recent studies, miRNA 574-3p was found to be upregulated in cancerous prostate tissue. In this study, we characterize the effects of upregulated miRNA 574-3p on gene expression in the tumor microenvironment through different bioinformatic tools such as Diana-Tools, the KEGG Pathway Database, and the Reactome Database. We have identified nine regulatory genes that are targeted by miRNA 574-3p and downregulated in prostate cells. Pathway analysis of these genes shows that they are involved in the regulation of the Notch signaling pathway, Wnt signaling pathway, apoptosis, DNA damage response, G1 to S cell-cycle control, inflammatory response pathway, angiogenesis, translation factors, and the expression of oncogenes. Our results show the oncogenic potential of miRNA 574-3p in PCa progression and metastasis. Moreover, this study highlights the complex molecular mechanisms and pathways affected by the upregulation of miRNA 574-3p in prostate cells. In future studies, the presented data may aid in designing new therapies for PCa with improved efficacy. PMID- 28734842 TI - Hydration forces between aligned DNA helices undergoing B to A conformational change: In-situ X-ray fiber diffraction studies in a humidity and temperature controlled environment. AB - Hydration forces between DNA molecules in the A- and B-Form were studied using a newly developed technique enabling simultaneous in situ control of temperature and relative humidity. X-ray diffraction data were collected from oriented calf thymus DNA fibers in the relative humidity range of 98%-70%, during which DNA undergoes the B- to A-form transition. Coexistence of both forms was observed over a finite humidity range at the transition. The change in DNA separation in response to variation in humidity, i.e. change of chemical potential, led to the derivation of a force-distance curve with a characteristic exponential decay constant of~2A for both A- and B-DNA. While previous osmotic stress measurements had yielded similar force-decay constants, they were limited to B-DNA with a surface separation (wall-to-wall distance) typically>5A. The current investigation confirms that the hydration force remains dominant even in the dry A-DNA state and at surface separation down to~1.5A, within the first hydration shell. It is shown that the observed chemical potential difference between the A and B states could be attributed to the water layer inside the major and minor grooves of the A-DNA double helices, which can partially interpenetrate each other in the tightly packed A phase. The humidity-controlled X-ray diffraction method described here can be employed to perform direct force measurements on a broad range of biological structures such as membranes and filamentous protein networks. PMID- 28734843 TI - A high resolution melting (HRM) technology-based assay for cost-efficient clinical detection and genotyping of herpes simplex virus (HSV)-1 and HSV-2. AB - Genital herpes can be caused by two very similar viruses, herpes simplex virus (HSV)-1 or HSV-2. These two HSV types cannot be distinguished clinically, but genotyping is recommended in the first-episodes of genital herpes to guide counselling and management. Quantitative polymerase chain reaction (qPCR) is the preferred diagnostic method for HSV typing. However, commercial qPCR methods use expensive fluorescent labeled probes for detection. Furthermore, most low-cost methods are not able to differentiate between HSV-1 and -2. The aim of this study was to develop a high resolution melting (HRM) technology-based assay for sensitive HSV-1 and HSV-2 detection and genotyping. Using a panel of 46 clinical specimens, the performance of the HRM assay was compared to two commercial HSV tests: the HRM assay detected HSV in all 23 positive samples, with no false positive results (100% concordance with HSV I/II Real-TM assay). Additionally, the HRM assay correctly genotyped both HSV types in a subset of these clinical samples, as determined by the Realstar HSV PCR Kit. The HSV HRM assay provides a cost-effective alternative method to conventional more expensive assays and can be used in routine clinical specimens, in cases where it is particularly necessary to detect and distinguish HSV-1 from -2. PMID- 28734844 TI - Toll-like receptor 3 blockade in rhinovirus-induced experimental asthma exacerbations: A randomized controlled study. AB - BACKGROUND: Human rhinoviruses (HRVs) commonly precipitate asthma exacerbations. Toll-like receptor 3, an innate pattern recognition receptor, is triggered by HRV, driving inflammation that can worsen asthma. OBJECTIVE: We sought to evaluate an inhibitory mAb to Toll-like receptor 3, CNTO3157, on experimental HRV 16 inoculation in healthy subjects and asthmatic patients. METHODS: In this double-blind, multicenter, randomized, parallel-group study in North America and Europe, healthy subjects and patients with mild-to-moderate stable asthma received single or multiple doses of CNTO3157 or placebo, respectively, and were then inoculated with HRV-16 within 72 hours. All subjects were monitored for respiratory symptoms, lung function, and nasal viral load. The primary end point was maximal decrease in FEV1 during 10 days after inoculation. RESULTS: In asthmatic patients (n = 63) CNTO3157 provided no protection against FEV1 decrease (least squares mean: CNTO3157 [n = 30] = -7.08% [SE, 8.15%]; placebo [n = 25] = 5.98% [SE, 8.56%]) or symptoms after inoculation. In healthy subjects (n = 12) CNTO3157 versus placebo significantly attenuated upper (P = .03) and lower (P = .02) airway symptom scores, with area-under-the-curve increases of 9.1 (15.1) versus 34.9 (17.6) and 13.0 (18.4) versus 50.4 (25.9) for the CNTO3157 (n = 8) and placebo (n = 4) groups, respectively, after inoculation. All of the severe and 4 of the nonserious asthma exacerbations occurred while receiving CNTO3157. CONCLUSION: In summary, CNTO3157 was ineffective in attenuating the effect of HRV 16 challenge on lung function, asthma control, and symptoms in asthmatic patients but suppressed cold symptoms in healthy subjects. Other approaches, including blockade of multiple pathways or antiviral agents, need to be sought for this high unmet medical need. PMID- 28734845 TI - Leveraging Siglec-8 endocytic mechanisms to kill human eosinophils and malignant mast cells. AB - BACKGROUND: Sialic acid-binding immunoglobulin-like lectin (Siglec)-8 is a cell surface protein expressed selectively on human eosinophils, mast cells, and basophils, making it an ideal target for the treatment of diseases involving these cell types. However, the effective delivery of therapeutic agents to these cells requires an understanding of the dynamics of Siglec-8 surface expression. OBJECTIVES: We sought to determine whether Siglec-8 is endocytosed in human eosinophils and malignant mast cells, identify mechanisms underlying its endocytosis, and demonstrate whether a toxin can be targeted to Siglec-8-bearing cells to kill these cells. METHODS: Siglec-8 surface dynamics were examined by flow cytometry using peripheral blood eosinophils, mast cell lines, and Siglec-8 transduced cells in the presence of inhibitors targeting components of endocytic pathways. Siglec-8 intracellular trafficking was followed by confocal microscopy. The ribosome-inhibiting protein saporin was conjugated to a Siglec-8-specific antibody to examine the targeting of an agent to these cells through Siglec-8 endocytosis. RESULTS: Siglec-8 endocytosis required actin rearrangement, tyrosine kinase and protein kinase C activities, and both clathrin and lipid rafts. Internalized Siglec-8 localized to the lysosomal compartment. Maximal endocytosis in Siglec-8-transduced HEK293T cells required an intact immunoreceptor tyrosine based inhibitory motif. Siglec-8 was also shuttled to the surface via a distinct pathway. Sialidase treatment of eosinophils revealed that Siglec-8 is partially masked by sialylated cis ligands. Targeting saporin to Siglec-8 consistently caused extensive cell death in eosinophils and the human mast cell leukemia cell line HMC-1.2. CONCLUSIONS: Therapeutic payloads can be targeted selectively to eosinophils and malignant mast cells by exploiting this Siglec-8 endocytic pathway. PMID- 28734846 TI - Matrix Gla protein T-138C polymorphism is associated with carotid intima media thickness and predicts mortality in patients with diabetic nephropathy. AB - AIMS: We sought to determine the predictive value of Matrix Gla Protein MGP T 138C polymorphism in relation to all-cause mortality, cardiovascular mortality and cardiovascular events in patients with diabetic nephropathy (DN). METHODS: MGP T-138C polymorphism was assessed in 40 diabetic patients without nephropathy and 118 patients at different stages of DN, including patients on hemodialysis. Measurement of carotid intima-media thickness (cIMT) was performed using real time B-mode ultrasonography. Plasma levels of dephoshorylated uncarboxylated Matrix Gla Protein (dp-ucMGP) were determined in a subgroup of 67 patients by ELISA. Mortality and cardiovascular events were assessed during a 7year follow up. RESULTS: TT homozygotes for the MGP T-138C polymorphism had higher values of cIMT compared to combined TC and CC genotypes (P=0.006) whereas no association was observed between cIMT and dp-ucMGP levels. MGP T-138C polymorphism was a strong independent predictor of cIMT (P<0.0001), after adjustment for several well-known atherosclerosis risk factors. Patients with TT genotype presented a significantly higher all-cause and cardiovascular mortality risk compared to patients with TC and CC genotypes (P=0.01 and P=0.04 respectively), after adjustment for several traditional risk factors. CONCLUSIONS: MGP T-138C polymorphism is a strong and independent predictor of increased cIMT as well as all-cause and cardiovascular mortality in DN patients. PMID- 28734847 TI - Noise-Optimized Virtual Monoenergetic Dual-Energy CT Improves Diagnostic Accuracy for the Detection of Active Arterial Bleeding of the Abdomen. AB - PURPOSE: To evaluate diagnostic accuracy of a noise-optimized virtual monoenergetic imaging (VMI+) reconstruction technique for detection of active arterial abdominal bleeding on dual-energy (DE) CT angiography compared with standard image reconstruction. MATERIALS AND METHODS: DE CT angiography data sets of 71 patients (46 men; age 63.6 y +/- 13.3) with suspected arterial bleeding of the abdomen or pelvis were reconstructed with standard linearly blended (F_0.5), VMI+, and traditional virtual monoenergetic imaging (VMI) algorithms in 10-keV increments from 40 to 100 keV. Attenuation measurements were performed in the descending aorta, area of hemorrhage, and feeding artery to calculate contrast-to noise ratios (CNRs) in patients with active arterial bleeding. Based on quantitative image quality results, the best series for each reconstruction technique were chosen to analyze the diagnostic performance of 3 blinded radiologists. RESULTS: DE CT angiography showed acute arterial bleeding in 36 patients. Mean CNR was superior in 40-keV VMI+ compared with VMI series (all P < .001), which showed highest CNRs in 70-keV VMI and F_0.5 (21.6 +/- 7.9, 12.9 +/- 4.7, and 10.4 +/- 3.6) images. Area under the curve analysis for detection of arterial bleeding showed significantly superior (P < .001) results for 40-keV VMI+ (0.963) compared with 70-keV VMI (0.775) and F_0.5 (0.817) series. CONCLUSIONS: Diagnostic accuracy in patients with active arterial bleeding of the abdomen can be significantly improved using VMI+ reconstructions at 40 keV compared with standard linearly blended and traditional VMI series in DE CT angiography. PMID- 28734848 TI - Liver Resection versus Radiofrequency Ablation plus Transcatheter Arterial Chemoembolization in Cirrhotic Patients with Solitary Large Hepatocellular Carcinoma. AB - PURPOSE: To compare liver resection (LR) with single-step, balloon-occluded radiofrequency (RF) ablation plus drug-eluting embolics transarterial chemoembolization in cirrhotic patients with single hepatocellular carcinoma (HCC) >= 3 cm. MATERIALS AND METHODS: From 2010 to 2014, 25 patients with compensated cirrhosis and single HCC >= 3 cm (median size 4.5 cm; range, 3.0-6.8 cm) not suitable for LR or liver transplantation were treated with RF ablation plus transarterial chemoembolization in a prospective observational single-center pilot study; all patients had complete tumor necrosis after treatment. A retrospective control group included 29 patients (median HCC size 4.0 cm; range, 3.0-7.4 cm) who underwent LR. RF ablation plus transarterial chemoembolization group included more patients with severe portal hypertension (65.5% vs 35.0%, P = .017). Primary endpoints were overall survival (OS) and tumor recurrence (TR) rates. RESULTS: One death and 1 major complication (4%) were observed in LR group. No major complications were reported in RF ablation plus transarterial chemoembolization group (P = .463). OS rates at 1 and 3 years were 91.8% and 79.3% in LR group and 89.4% and 48.2% in RF ablation plus transarterial chemoembolization group (P = 0.117). TR rates at 1 and 3 years were 29.5% and 45.0% in LR group and 42.4% and 76.0% in RF ablation plus transarterial chemoembolization group (P = .034). Local tumor progression (LTP) rates at 3 years were significantly lower in LR group (21.8% vs 58.1%, P = .005). Similar results were found in patients with HCC <= 5 cm (TR rates 35.4% vs 75.1%, P = .016; LTP 16.0% vs 55.7%, P = .013). CONCLUSIONS: LR achieved lower TR and LTP rates than RF ablation plus transarterial chemoembolization, but 3-years OS rates were not statistically different between the 2 groups. RF ablation plus transarterial chemoembolization is an effective treatment option in patients with compensated cirrhosis and solitary HCC >= 3 cm unsuitable for LR. PMID- 28734849 TI - Preface: Towards a global understanding of development and evolution. PMID- 28734850 TI - Progression and reversibility of stretch induced atrial remodeling: Characterization and clinical implications. AB - Atrial fibrillation (AF) is the most common sustained arrhythmia and across the developed nations, it contributes to increasing hospitalizations and healthcare burden. Several comorbidities and risk factors including hypertension, heart failure, obstructive sleep apnoea and obesity are known to play an important role in the initiation and perpetuation of AF and atrial stretch or dilatation may play a central mechanistic role. The impact of atrial stretch in the development of AF can vary dependent on the underlying disease. This review focuses on understanding the substrate for AF in conditions of acute and chronic stretch and in the presence of common co-morbidities or risk factors through the review of findings in both animal and human studies. Additionally, the reversibility of atrial remodeling following stretch release will also be discussed. Identification of clinical conditions associated with increased atrial stretch as well as the treatment or prevention of these conditions may help to prevent AF progression and improve sinus rhythm maintenance. PMID- 28734851 TI - Regulatory accepted but out of domain: In vitro skin irritation tests for agrochemical formulations. AB - Several in vitro methods have gained regulatory acceptance for the prediction of skin irritation and corrosion. However, the test guidelines for the majority of in vitro methods do not state whether they are applicable to agrochemical formulations. Hence, we would like to share the results from our routine skin corrosion and irritation testing of agrochemical formulations in which both in vitro (according to OECD TG 431 and OECD TG 439) and in vivo (according to OECD TG 404) tests were conducted as regulatory requirements. The in vitro skin irritation test did not correlate well with the CLP classification by in vivo results (44% sensitivity, 60% specificity, and 54% accuracy, based on 65 data pairs). This indicates a lack of applicability of the current protocol of the in vitro skin irritation test for agrochemical formulations. The data set did not contain formulations which were skin corrosive in vivo and hence its applicability could not be assessed. The correlation of in vitro skin corrosion testing to formulations which were not corrosive in vivo was, however, high (95% specificity based on 81 data pairs). PMID- 28734852 TI - Azodicarbonamide (ADCA): A reconsideration of classification as a respiratory sensitiser. AB - Azodicarbonamide (ADCA) is widely used by industry in the manufacture of a variety of products. ADCA has been classified as a respiratory allergen, and the purpose of this article was to consider whether this classification is appropriate based upon the available data. Here both clinical experience and relevant experimental data have been reviewed. Although there have been reports of an association between workplace exposure to ADCA and symptoms of respiratory allergy and occupational asthma, the evidence is less than persuasive, with in many instances a lack of properly controlled and executed diagnostic procedures. In addition, ADCA fails to elicit positive responses in mouse and guinea pig predictive tests for skin sensitisation; a lack of activity that is regarded as being inconsistent with respect to respiratory sensitising potential. Collectively, the data reviewed here do not provide an adequate basis for the classification of ADCA as a respiratory allergen. PMID- 28734853 TI - The impact of MK-467 on sedation, heart rate and arterial blood pressure after intramuscular coadministration with dexmedetomidine in conscious cats. AB - OBJECTIVE: To study the effects of MK-467, a peripheral alpha2-adrenoceptor antagonist, on sedation, heart rate and blood pressure after intramuscular (IM) coadministration with 25 MUg kg-1 of dexmedetomidine in cats. STUDY DESIGN: Prospective, randomized, controlled, blinded, cross-over, experimental study. ANIMALS: A total of eight healthy, adult, neutered male cats. METHODS: Cats were administered five IM treatments at least 2 weeks apart, consisting of dexmedetomidine 25 MUg kg-1 (D25), MK-467 600 MUg kg-1 (M600) and D25 combined with 300, 600 and 1200 MUg kg-1 of MK-467 (D25M300, D25M600 and D25M1200, respectively). Heart rate and direct arterial blood pressure were recorded via telemetry and sedation assessed prior to treatments and at intervals for 8 hours thereafter. RESULTS: Heart rate decreased significantly after all treatments with dexmedetomidine and remained below baseline up to 240 (D25), 20 (D25M300) and 3 minutes (D25M600 and D25M1200). Mean arterial pressure (MAP) increased with D25, remained unchanged with M600 and decreased over time with all combination treatments. The highest and lowest MAP after each treatment were 168+/-17 and 100+/-14 (D25), 157+/-18 and 79+/-11 (D25M300), 153+/-11 and 74+/-10 (D25M600), 144+/-12 and 69+/-7 (D25M1200) and 136+/-9 and 104+/-13 mmHg (M600). All treatments with dexmedetomidine produced sedation although its duration was significantly reduced by the addition of MK-467. CONCLUSIONS AND CLINICAL RELEVANCE: Dexmedetomidine induced bradycardia and hypertension, which were attenuated by all three doses of MK-467. The duration of sedation was reduced by MK-467. MK-467 may improve the cardiovascular tolerance of IM dexmedetomidine in cats. PMID- 28734854 TI - Pulse pressure variation as a guide for volume expansion in dogs undergoing orthopedic surgery. AB - OBJECTIVE: To investigate whether pulse pressure variation (PPV) can predict fluid responsiveness in healthy dogs during clinical surgery. STUDY DESIGN: Prospective clinical study. ANIMALS: Thirty-three isoflurane-anesthetized dogs with arterial hypotension during orthopedic surgery. METHODS: Fluid challenge with lactated Ringer's solution (15 mL kg-1 in 15 minutes) was administered in mechanically ventilated dogs (tidal volume 10 mL kg-1) with hypotension [mean arterial pressure (MAP) < 65 mmHg]. The volume expansion was considered effective if cardiac output (CO; transesophageal Doppler) increased by >= 15%. Cardiopulmonary data were analyzed using two-way ANOVA, receiver operating characteristics (ROC) curves and Spearman coefficient; p < 0.05 was considered significant. RESULTS: Effective volume expansion, mean +/- standard deviation 42 +/- 4% increase in CO (p < 0.0001) was observed in 76% of the dogs, resulting in a decrease in PPV (p < 0.0001) and increase in MAP (p < 0.0001), central venous pressure (CVP; p = 0.02) and ejection fraction (p < 0.0001) compared with before the fluid challenge. None of these changes occurred when volume expansion resulted in a nonsignificant CO increase of 4 +/- 5%. No significant differences were observed in blood gas analysis between responsive and nonresponsive dogs. The increase in CO was correlated with the decrease in PPV (r = -0.65; p < 0.0001) but absolute values of CO and PPV were not correlated. The PPV performance (ROC curve area: 0.89 +/- 0.06, p = 0.0011) was better than that of CVP (ROC curve area: 0.54 +/- 0.12) and MAP (ROC curve area: 0.59 +/- 0.13) to predict fluid responsiveness. The best cut-off for PPV to distinguish responders and nonresponders was 15% (50% sensitivity and 96% specificity). CONCLUSIONS AND CLINICAL RELEVANCE: In mechanically ventilated, healthy, isoflurane-anesthetized dogs, PPV predicted fluid responsiveness to volume expansion, and MAP and CVP did not show such applicability. PMID- 28734855 TI - Effects of constant rate infusions of dexmedetomidine or MK-467 on the minimum alveolar concentration of sevoflurane in dogs. AB - OBJECTIVE: To determine the effects of low and high dose infusions of dexmedetomidine and a peripheral alpha2-adrenoceptor antagonist, MK-467, on sevoflurane minimum alveolar concentration (MAC) in dogs. STUDY DESIGN: Crossover experimental study. ANIMALS: Six healthy, adult Beagle dogs weighing 12.6+/-0.9 kg (mean+/-standard deviation). METHODS: Dogs were anesthetized with sevoflurane in oxygen. After a 60-minute instrumentation and equilibration period, the MAC of sevoflurane was determined in triplicate using the tail clamp technique. PaCO2 and temperature were maintained at 40+/-5 mmHg (5.3+/-0.7 kPa) and 38+/-0.5 oC, respectively. After baseline MAC determination, dogs were administered two incremental loading and infusion doses of either dexmedetomidine (1.5 MUg kg-1 then 1.5 MUg kg-1 hour-1 and 4.5 MUg kg-1 then 4.5 MUg kg-1 hour-1) or MK-467 (90 MUg kg-1 then 90 MUg kg-1 hour-1 and 180 MUg kg-1 then 180 MUg kg-1 hour-1); loading doses were administered over 10 minutes. MAC was redetermined in duplicate starting 30 minutes after the start of drug administration at each dose. End-tidal sevoflurane concentrations were corrected for calibration and adjusted to sea level. A repeated-measures analysis was performed and comparisons between doses were conducted using Tukey's method. Statistical significance was considered at p<0.05. RESULTS: Sevoflurane MAC decreased significantly from 1.86+/-0.3% to 1.04+/-0.1% and 0.57+/-0.1% with incremental doses of dexmedetomidine. Sevoflurane MAC significantly increased with high dose MK-467, from 1.93+/-0.3% to 2.29+/-0.5%. CONCLUSIONS AND CLINICAL RELEVANCE: Dexmedetomidine caused a dose-dependent decrease in sevoflurane MAC, whereas MK 467 caused an increase in MAC at the higher infusion dose. Further studies evaluating the combined effects of dexmedetomidine and MK-467 on MAC and cardiovascular function may elucidate potential benefits of the addition of a peripheral alpha2-adrenergic antagonist to inhalation anesthesia in dogs. PMID- 28734856 TI - Four cases of delayed onset systemic reaction to shellfish. PMID- 28734857 TI - Comorbidities in Difficult-to-Control Asthma. AB - BACKGROUND: Difficult-to-control asthma is associated with significant medical and financial burden. Comorbidities are known to contribute to uncontrolled asthma. Better insight into the prevalence, nature, and risk factors of comorbidities may optimize treatment strategies in patients with difficult-to control asthma and decrease disease burden. OBJECTIVES: The objectives of this study were to assess the prevalence, number, and type of comorbidities in difficult-to-control asthma compared with not-difficult-to-control asthma, and to investigate whether specific patient characteristics are associated with particular comorbidities. METHODS: A total of 5,002 adult patients with a prescription for high-dose (>1,000 MUg) fluticasone or oral corticosteroids, extracted from 65 Dutch pharmacy databases, were sent questionnaires about patient characteristics. Of the 2,312 patients who returned the questionnaires, 914 were diagnosed with difficult-to-control asthma. Diagnoses of comorbidities (gastroesophageal reflux, nasal polyps, cardiovascular disease, anxiety/depression, obesity, and diabetes) were based on treatment prescriptions or questionnaires. Associations were assessed using multivariable logistic regression analyses. RESULTS: A total of 92% of patients with difficult-to control asthma had >=1 comorbidity. Patients with difficult-to-control asthma had more comorbidities (mean +/- SD comorbidities 2.22 +/- 1.27 vs 1.69 +/- 1.32; P < .01), and a significantly higher prevalence of each comorbidity, compared with patients with not-difficult-to-control asthma, except for diabetes and nasal polyposis. Comorbidities were associated with specific patient characteristics, including older age, female gender, smoking history, and chronic prednisone use. CONCLUSIONS: Almost all patients with difficult-to-control asthma have comorbidities, in particular asthmatic women of older age, former smokers, and asthmatics who are prednisone dependent. Recognition of these typical characteristics can help physicians in the diagnostic workup, so that adequate preventive measures can be taken. PMID- 28734858 TI - Safety Review of 5-Grass Pollen Tablet from Pooled Data of Clinical Trials. AB - BACKGROUND: The 5-grass pollen sublingual tablet has been approved for the treatment of grass pollen-induced allergic rhinoconjunctivitis in subjects with or without intermittent asthma. OBJECTIVE: To provide a comprehensive analysis of the safety profile of the 5-grass tablet on the basis of pooled data from 8 clinical trials. METHODS: Subjects (5-65 years old) with medically confirmed grass pollen-induced allergic rhinoconjunctivitis were included in the double blind studies. Those with intermittent asthma not requiring treatment other than inhaled beta-2 agonists could participate. Randomized subjects received a 5-grass or placebo tablet daily 2 or 4 months preseasonally and coseasonally (5 single season studies, over 3 years in a long-term study) or outside the season (phase I studies). Adverse events were pooled and analyzed descriptively. RESULTS: Among 2,512 subjects enrolled, 1,514 received the 5-grass tablet. A total of 1,038 adults and 154 pediatric (5-17 years old) subjects were treated with the 300 Index of Reactivity dose (vs 840 and 158 placebo recipients, respectively); 17% had intermittent asthma, and 62% were polysensitized. Adverse reactions (ADRs) reported in more than 10% of actively treated subjects were mild or moderate application-site reactions, for example, oral pruritus 25% (placebo 4%) and throat irritation 21% (placebo 3%). These generally occurred during the first week of treatment and decreased over time. They led to discontinuation in less than 2.5% of subjects. None of the 3 serious ADRs were reports of anaphylaxis. No notable differences were detected in terms of incidence, nature, and severity of ADRs between adult and pediatric populations, nor between subjects with or without asthma. CONCLUSIONS: The pooled analysis in 1,514 subjects from 8 clinical studies demonstrates that the 5-grass pollen sublingual tablet has a similar good safety profile in adult and pediatric patients with or without mild, intermittent asthma. PMID- 28734859 TI - Provider Health and Wellness. AB - Provider health and wellness is a significant issue and can impact patient care, including patient satisfaction, quality of care, medical errors, malpractice risk, as well as provider and office staff turnover and early retirement. Health and wellness encompasses various areas including burnout, depression, divorce, and suicide and affects providers of all specialties and at all levels of training. Providers deal with many everyday stresses, including electronic health records, office politics, insurance and billing issues, dissatisfied patients, and their own personal and family issues. Approximately half of all physicians suffer from burnout, and the rate of burnout among physicians of all specialties is increasing. An important first step in dealing with burnout is recognition and then seeking assistance. Strategies to prevent and treat burnout include increasing provider resiliency as well as implementing practical changes in the everyday practice of medicine. There is currently very little data regarding health and wellness specifically in the field of allergy and immunology, and studies are necessary to determine the prevalence of burnout and related issues in this field. Many medical specialties as well as state and national medical associations have health and wellness committees and other resources, which are essential for providers. Health and wellness programs should be introduced early in a provider's training and continued throughout a provider's career. PMID- 28734860 TI - The Expanding Field of Biologics in the Management of Chronic Urticaria. AB - Chronic urticaria (CU) is the occurrence of urticaria with or without angioedema for at least 6 weeks. Management has traditionally involved antihistamines as first-line therapy with various alternative therapies for refractory cases. Largely based on the success of biologics for various diseases, this class of drugs has come to the forefront of medical research. The first and only Food and Drug Administration-approved biologic for the management of CU is omalizumab (humanized anti-IgE mAb). In the past decade, a substantial amount of research has been centered on the mechanism of action, efficacy, dosing, and safety of omalizumab. This review will focus on the data surrounding the management of CU with omalizumab, off-label use of other biologics for CU, and biologics currently under investigation for use in CU. We will also discuss management considerations and areas of interest for future research. PMID- 28734862 TI - Respiratory Infections and Antibiotic Usage in Common Variable Immunodeficiency. AB - BACKGROUND: Patients with common variable immunodeficiency (CVID) suffer frequent respiratory tract infections despite immunoglobulin replacement and are prescribed significant quantities of antibiotics. The clinical and microbiological nature of these exacerbations, the symptomatic triggers to take antibiotics, and the response to treatment have not been previously investigated. OBJECTIVES: To describe the nature, frequency, treatment, and clinical course of respiratory tract exacerbations in patients with CVID and to describe pathogens isolated during respiratory tract exacerbations. METHODS: We performed a prospective diary card exercise in 69 patients with CVID recruited from a primary immunodeficiency clinic in the United Kingdom, generating 6210 days of symptom data. We collected microbiology (sputum microscopy and culture, atypical bacterial PCR, and mycobacterial culture) and virology (nasopharyngeal swab multiplex PCR) samples from symptomatic patients with CVID. RESULTS: There were 170 symptomatic exacerbations and 76 exacerbations treated by antibiotics. The strongest symptomatic predictors for commencing antibiotics were cough, shortness of breath, and purulent sputum. There was a median delay of 5 days from the onset of symptoms to commencing antibiotics. Episodes characterized by purulent sputum responded more quickly to antibiotics, whereas sore throat and upper respiratory tract symptoms responded less quickly. A pathogenic virus was isolated in 56% of respiratory exacerbations and a potentially pathogenic bacteria in 33%. CONCLUSIONS: Patients with CVID delay and avoid treatment of symptomatic respiratory exacerbations, which could result in structural lung damage. However, viruses are commonly represented and illnesses dominated by upper respiratory tract symptoms respond poorly to antibiotics, suggesting that antibiotic usage could be better targeted. PMID- 28734861 TI - Low Food Allergy Prevalence Despite Delayed Introduction of Allergenic Foods-Data from the GUSTO Cohort. AB - BACKGROUND: There is mounting evidence that early introduction of allergenic food decreases the risk of food allergy development, especially in high-risk infants with eczema. However, there is a lack of data to suggest whether this association holds true in Asian populations. OBJECTIVE: To investigate the relationship between the timing of introduction of allergenic foods and food allergy outcomes in infants in the Growing Up in Singapore Towards healthy Outcomes (GUSTO) study. METHODS: The GUSTO cohort recruited 1152 mothers of Chinese, Malay, and Indian ethnicity who had singleton, naturally conceived pregnancies and followed their offspring prospectively. Information on demographic characteristics, child health, infant feeding practices, and a convincing history of IgE-mediated food allergy was obtained from interviewer-administered questionnaires at multiple time points. Corroborative skin prick tests to food allergens were performed at 18 and 36 months. RESULTS: Most of the infants were introduced to egg (49.6%), peanut (88.7%), and shellfish (90.2%) after age 10 months. Food allergy prevalence was, however, very low between age 12 and 48 months: egg, 0.35% to 1.8%; peanut allergy, 0.1% to 0.3%; and shellfish, 0.2% to 0.9%. There were no significant associations between the timing of introduction of allergenic foods and the development of food allergy, adjusted for confounders including breast feeding and eczema. CONCLUSIONS: Food allergy rates in Singapore are low despite delayed introduction of allergenic foods. Early introduction of allergenic foods may thus not be necessary in populations in which overall food allergy prevalence is low, and thus infant feeding recommendations should be carefully tailored to individual populations. PMID- 28734863 TI - Significant Linkage Evidence for Interstitial Cystitis/Painful Bladder Syndrome on Chromosome 3. AB - PURPOSE: Interstitial cystitis/painful bladder syndrome is a chronic pelvic pain condition of unknown etiology. We hypothesized that related interstitial cystitis/painful bladder syndrome cases were more likely to have a genetic etiology. The purpose of this study was to perform a genetic linkage analysis. MATERIALS AND METHODS: We identified interstitial cystitis/painful bladder syndrome cases using diagnostic codes linked to the Utah Population Database genealogy resource and to electronic medical records. For this analysis we used 13 high risk pedigrees, defined as having a statistical excess number of interstitial cystitis/painful bladder syndrome cases among descendants compared to matched hospital population rates. Case status was confirmed in medical records using natural language processing. DNA was obtained from stored, nonneoplastic, formalin fixed, paraffin embedded tissue blocks. Each pedigree had at least 2 cases with DNA available. Parametric linkage analysis was performed. RESULTS: Pedigrees ranged in size from 2 to 12 genotyped cases for a total of 48 cases. Significant genome wide linkage evidence was found under a dominant model on chromosome 3p13-p12.3 (maximum heterogeneity theta logarithm of odds 3.56). Two pedigrees showed at least nominal linkage evidence in this region (logarithm of odds greater than 0.59). The most informative pedigree included 12 interstitial cystitis/painful bladder syndrome cases (pedigree theta logarithm of odds 2.1). Other regions with suggestive linkage evidence included 1p21-q25, 3p21.1-p14.3, 4q12-q13, 9p24-p22 and 14q24-q31, all under a dominant model. CONCLUSIONS: While the etiology of interstitial cystitis/painful bladder syndrome is unknown, this study provides evidence that a genetic variant(s) on chromosome 3 and possibly on chromosomes 1, 4, 9 and 14 contribute to an interstitial cystitis/painful bladder syndrome predisposition. Sequence analysis of affected cases in identified pedigrees may provide insight into genes contributing to interstitial cystitis/painful bladder syndrome. PMID- 28734864 TI - Reasons for Seeking Clinical Care for Lower Urinary Tract Symptoms: A Mixed Methods Study. AB - PURPOSE: The primary objective of this study was to evaluate reasons for seeking care among men and women with lower urinary tract symptoms. MATERIALS AND METHODS: Participants were recruited from urology and urogynecology clinics, and the community. The sample was enriched with persons expected to have abnormal or diminished bladder sensations (eg participants with lower back surgery and participants 65 years old or older). Interviews were performed in person beginning with an open-ended assessment of urinary symptoms and associated bother followed by more directed questions, including reasons for seeking or not seeking treatment. We also examined the relationship between symptom frequency and bother using the LUTS (Lower Urinary Tract Symptoms) Tool. RESULTS: A total of 88 participants, including 38 men and 50 women, with a mean +/- SD age of 52.2 +/- 14.3 years provided information about urinary symptoms, including a range of quality of life consequences and coping behaviors. They sought treatment mostly because of new, continuing or bothersome symptoms. Factors associated with not seeking treatment included low symptom severity and concerns about the costs vs the benefits of treatment (eg side effects of medication). Symptom frequency and bother were associated with each other across symptoms assessed by the LUTS Tool. CONCLUSIONS: In this large qualitative study we obtained useful insights into the impact of lower urinary tract symptoms from the perspective of the person with the symptoms. Removing barriers and misconceptions about the treatment of lower urinary tract symptoms may increase the number of people who seek clinical care and improve the clinical course of men and women who experience lower urinary tract symptoms. PMID- 28734865 TI - Single factors alone can induce mesenchymal-like morphology, but not promote full EMT in breast cancer cell lines with different hormone statuses. AB - BACKGROUND: Epithelial to mesenchymal transition (EMT) is considered to be important for cancer invasion and metastasis. Tumour hypoxia, in addition to Transforming Growth Factor-beta (TGF-beta) and Notch, amongst others, have been suggested to be involved in EMT. We therefore investigated if hypoxia, TGF-beta1 and the Notch ligand Jagged-1 alone induced morphological changes with corresponding EMT signatures in different epithelial breast cancer cell lines in vitro. Furthermore, we also studied whether or not TGF-beta1, or Jagged-1 in combination with hypoxia added any effect on EMT. METHODS: The cells were exposed to normoxia or hypoxia alone or in combination with TGF-beta1 or Jagged-1. Morphological responses to treatment were investigated by light microscopy, and changes in markers for EMT and hypoxia were evaluated by western blot analysis and immunofluorescence studies. RESULTS: One of the four cell lines (MCF7) became elongated and highly multipolar, indicative of EMT, following hypoxia, TGF-beta1 and Jagged-1 treatment per se with the most distinct morphological shift seen with Jagged-1 treatment in combination with hypoxia. Also, when regarding hypoxia, MCF7 cells showed the greatest change in EMT-markers of the four cell lines tested, but these changes were not consistent with a typical EMT pattern. The morphology of BT474 cells was not altered following Jagged-1 treatment, however, Jagged-1 increased E-cadherin levels. Morphology was changed following TGF-beta1 treatment of BT474 cells, but it did not affect E-cadherin levels. Neither Jagged-1 nor TGF-beta1 altered the levels of Vimentin in the BT474 cell line. The E-cadherin responses to hypoxia varied with end-point in both MCF7 and BT474 cells, and in most cases were not consistent with EMT. CONCLUSION: Our results using four different breast cancer cell lines in vitro do not provide evidence that EMT is induced by hypoxia alone or in combination with TGF-beta1 or the Notch ligand Jagged-1. The inconsistency in morphological appearance and EMT markers, as well as the time dependent variation in E-cadherin responses could not support EMT. Importantly, there was not one single common response pattern to the stimuli used, suggesting that cell lines with different hormone statuses display individual traits that respond differently to the stimuli applied. Thus, based on the present results, common statements that single factors by themselves can induce EMT seem questionable. PMID- 28734866 TI - Label-free profiling of cell dynamics: A sequence of impedance-based assays to estimate tumor cell invasiveness in vitro. AB - Dynamic properties of cancer cells, most notably their ability to migrate, have been correlated successfully with their invasive nature in vivo. To establish a stronger experimental basis for such a correlation we subjected five different cancer cell lines of well-defined metastatic potential to a sequence of three independent assays reporting on three different aspects of cell dynamics, namely (1) the kinetics of cell spreading, (2) cell shape fluctuations, and (3) cell migration. The sequentially applied assays correspond to different measuring modes of the well-established ECIS technique that is based on non-invasive and label-free impedance readings of planar gold-film electrodes that serve as the growth substrate for the cells under study. Every individual assay returned a characteristic parameter describing the behavior of the cell lines in that particular assay quantitatively. The parameters of all three assays were ranked to establish individual profiles of cell dynamics for every cell line that correlate favorably with the cells' invasive properties. The sequence of impedance-based assays described here requires only small cell populations (< 10.000 cells), it is highly automated and easily adapted to 96-well formats. It provides an in-depth dynamic profile of adherent cells that might be useful in other areas besides cancer research as well. PMID- 28734868 TI - A single- and multiple-dose study to investigate the pharmacokinetics and pharmacodynamics of opicapone, a novel COMT inhibitor, in rat. AB - Opicapone is a novel catechol-O-methyltransferase (COMT) inhibitor that emerged to fulfil the need of a safer and more efficacious COMT inhibitor. The present study was carried out in order to assess and compare the pharmacokinetics and pharmacodynamics (COMT inhibition) of opicapone after single and multiple oral administrations (30 mg/kg) to Wistar rats. For this purpose, at predefined time points up to 72 h post-dosing, blood, liver and kidneys were collected and, then, the concentrations of opicapone and its active metabolite (BIA 9-1079) were determined in plasma and in liver and kidney tissues, as well as the erythrocyte, liver and kidney COMT activity. No systemic, renal or hepatic accumulation of opicapone was observed following repeated administration. Furthermore, the tissue systemic exposure relationships to opicapone suggested a low drug exposure in the liver and kidneys. After single-dosing, COMT inhibition profiles were reasonably comparable in all the studied matrices; although similar results were found after multiple-dosing, a higher degree of inhibition was observed, indicating a continuous peripheral COMT inhibition when opicapone is administered once-daily. Despite having a short elimination half-life (<=2.94 h), opicapone showed a strong and long-lasting COMT inhibition in both studies, since more than 50% of the COMT activity was still inhibited at 24 h post-dosing. PMID- 28734867 TI - P/Q-type voltage-gated calcium channels mediate the ethanol and CRF sensitivity of central amygdala GABAergic synapses. AB - The central amygdala (CeA) GABAergic system is hypothesized to drive the development of alcohol dependence, due to its pivotal roles in the reinforcing actions of alcohol and the expression of negative emotion, anxiety and stress. Recent work has also identified an important role for the CeA corticotropin releasing factor (CRF) system in the interaction between anxiety/stress and alcohol dependence. We have previously shown that acute alcohol and CRF each increase action potential-independent GABA release in the CeA via their actions at presynaptic CRF type 1 receptors (CRF1s); however, the shared mechanism employed by these two compounds requires further investigation. Here we report that acute alcohol interacts with the CRF/CRF1 system, such that CRF and alcohol act via presynaptic CRF1s and P/Q-type voltage-gated calcium channels to promote vesicular GABA release and that both compounds occlude the effects of each other at these synapses. Chronic alcohol exposure does not alter P/Q-type voltage-gated calcium channel membrane abundance or this CRF1/P/Q-type voltage-gated calcium channel mechanism of acute alcohol-induced GABA release, indicating that alcohol engages this molecular mechanism at CeA GABAergic synapses throughout the transition to dependence. Thus, P/Q-type voltage-gated calcium channels, like CRF1s, are key regulators of the effects of alcohol on GABAergic signaling in the CeA. PMID- 28734869 TI - P2X receptors up-regulate the cell-surface expression of the neuronal glycine transporter GlyT2. AB - Glycinergic inhibitory neurons of the spinal dorsal horn exert critical control over the conduction of nociceptive signals to higher brain areas. The neuronal glycine transporter 2 (GlyT2) is involved in the recycling of synaptic glycine from the inhibitory synaptic cleft and its activity modulates intra and extracellular glycine concentrations. In this report we show that the stimulation of P2X purinergic receptors with betagamma-methylene adenosine 5'-triphosphate induces the up-regulation of GlyT2 transport activity by increasing total and plasma membrane expression and reducing transporter ubiquitination. We identified the receptor subtypes involved by combining pharmacological approaches, siRNA mediated protein knockdown, and dorsal root ganglion cell enrichment in brainstem and spinal cord primary cultures. Up-regulation of GlyT2 required the combined stimulation of homomeric P2X3 and P2X2 receptors or heteromeric P2X2/3 receptors. We measured the spontaneous glycinergic currents, glycine release and GlyT2 uptake concurrently in response to P2X receptor agonists, and showed that the impact of P2X3 receptor activation on glycinergic neurotransmission involves the modulation of GlyT2 expression or activity. The recognized pro-nociceptive action of P2X3 receptors suggests that the fine-tuning of GlyT2 activity may have consequences in nociceptive signal conduction. PMID- 28734870 TI - Elucidation of the neural circuits activated by a GABAB receptor positive modulator: Relevance to anxiety. AB - Although there is much evidence for a role of GABAB receptors in the pathophysiology of anxiety, the underlying neuronal mechanisms are largely unclear. The GABAB receptor allosteric positive modulator, GS39783, exerts anxiolytic effects without interfering with GABAB-mediated modulation of body temperature, cognitive performance and locomotor activity thus offering advantages over GABAB receptor agonists. However, the precise neural circuits underlying the anxiolytic effects of GS39783 are unknown. The aim of the present study was to identify brain structures and associated neuronal circuits that are modulated by GS39783 under either basal or mild stress conditions. To this end, the expression pattern of c-Fos, a marker of neuronal activation, was examined in mice acutely treated with GS39783 under basal conditions or following a mild anxiogenic challenge induced by exposure to the Open Arm (OA) of an Elevated Plus Maze. OA exposure enhanced c-Fos expression in vehicle-treated animals in several brain regions, including the medial prefrontal cortex, lateral septum, amygdala, hippocampus, paraventricular nucleus of the hypothalamus and the periaqueductal gray (PAG). Under basal conditions, GS39783 increased c-Fos in a restricted panel of areas notably amygdala nuclei, cortical areas and PAG subregions, while it inhibited c-Fos expression in the dorsal raphe nucleus (DRN). Under stress conditions, GS39783 reversed OA-induced c-Fos expression in the granular cell layer of the dentate gyrus, no longer increased c-Fos expression in the amygdala nor reduced c-Fos expression in the DRN. These specific patterns of neural activation by GS39783 might explain the neurobiological correlates implicated in GABAB-mediated anti-anxiety effects. This article is part of the "Special Issue Dedicated to Norman G. Bowery". PMID- 28734872 TI - Modeling the cleavage of von Willebrand factor by ADAMTS13 protease in shear flow. AB - Von Willebrand factor (VWF) is a key protein in hemostasis as it mediates adhesion of blood platelets to a site of vascular injury. A proper distribution of VWF lengths is important for normal functioning of hemostatic processes, because a diminished number of long VWF chains may significantly limit blood clotting and lead to bleeding, while an abundant number of long VWFs may result in undesired thrombotic events. VWF size distribution is controlled by ADAMTS13 protease, which can cleave VWF chains beyond a critical shear rate when the chains are stretched enough such that cleavage sites become accessible. To better understand the cleavage process, we model VWF cleavage in shear flow using mesoscopic hydrodynamic simulations. Two cleavage models are proposed, a geometrical model based on the degree of local stretching of VWF, and a tension force model based on instantaneous tension force within VWF bonds. Both models capture the susceptibility of VWF to cleavage at high shear rates; however, the geometrical model appears to be much more robust than the force model. Our simulations show that VWF susceptibility to cleavage in shear flow becomes a universal function of shear rate, independent of VWF length for long enough chains. Furthermore, VWF is cleaved with a higher probability close to its ends in comparison to cleaving in the middle, which results into longer circulation lifetimes of VWF multimers. Simulations of dynamic cleavage of VWF show an exponential distribution of chain lengths, consistently with available in vitro experiments. The proposed cleavage models can be used in realistic simulations of hemostatic processes in blood flow. PMID- 28734871 TI - The role of temporal contrast and blue light in emmetropization. AB - A previous experiment showed that blue light (as a component of white light) protected against low temporal frequency dependent eye growth. This experiment investigated the role of temporal contrast. White leghorn chicks were exposed to white (with blue) or yellow (without blue) LED lighting modulated at either low (0.2Hz) or high (10Hz) temporal frequencies. Four cone contrast conditions were used: low (16%), medium (32%), medium-high (60%) and very-high (80%). Chicks were exposed to the lighting condition for 3days (mean 680lux). Exposure to high temporal frequencies, with very high temporal contrast, reduced eye growth, regardless of spectral content. However, at low temporal frequencies, eye growth was dependent on the illuminant. At lower temporal contrast levels, growth increased regardless of temporal or spectral characteristics. To conclude, very high temporal contrast, white light, provides a "stop" signal for eye growth that overrides temporal cues for growth that manifest in yellow light. PMID- 28734873 TI - A computational fluid-structure interaction analysis of coronary Y-grafts. AB - Coronary artery disease is one of the leading causes of death worldwide. The stenotic coronary vessels are generally treated with coronary artery bypass grafts (CABGs), which can be either arterial (internal mammary artery, radial artery) or venous (saphenous vein). However, the different mechanical properties of the graft can influence the outcome of the procedure in terms of risk of restenosis and subsequent graft failure. In this paper, we perform a computational fluid-structure interaction (FSI) analysis of patient-specific multiple CABGs (Y-grafts) with the aim of better understanding the influence of the choice of bypass (arterial vs venous) on the risk of graft failure. Our results show that the use of a venous bypass results in a more disturbed flow field at the anastomosis and in higher stresses in the vessel wall with respect to the arterial one. This could explain the better long-term patency of the arterial bypasses experienced in the clinical practice. PMID- 28734874 TI - Robotic assistants in personal care: A scoping review. AB - The aim of this study is to present an overview of the technological advances in the field of robotics developed for assistance with activities of daily living (ADL), and to present areas where further research is required. Four databases were searched for articles presenting either a novel design of one of these personal care robotic system or trial results relating to these systems. Articles presenting nine different robotic personal care systems were examined, six of which had been developed after 2005. These six also all have publications relating to their trials. In the majority of trials, patient independence was improved with operation of the robotic device for a specific subset of ADL. A map of the current state of the field of personal care robotics is presented in this study. Areas requiring further research include improving feedback and awareness, as well as refining control methods and pre-programmed behaviors. Developing an affordable, easy to use system would help fill the current gap in the commercial market. PMID- 28734875 TI - Investigation of the feasibility of non-invasive optical sensors for the quantitative assessment of dehydration. AB - This study explores the feasibility of prospectively assessing infant dehydration using four non-invasive, optical sensors based on the quantitative and objective measurement of various clinical markers of dehydration. The sensors were investigated to objectively and unobtrusively assess the hydration state of an infant based on the quantification of capillary refill time (CRT), skin recoil time (SRT), skin temperature profile (STP) and skin tissue hydration by means of infrared spectrometry (ISP). To evaluate the performance of the sensors a clinical study was conducted on a cohort of 10 infants (aged 6-36 months) with acute gastroenteritis. High sensitivity and specificity were exhibited by the sensors, in particular the STP and SRT sensors, when combined into a fusion regression model (sensitivity: 0.90, specificity: 0.78). The SRT and STP sensors and the fusion model all outperformed the commonly used "gold standard" clinical dehydration scales including the Gorelick scale (sensitivity: 0.56, specificity: 0.56), CDS scale (sensitivity: 1.0, specificity: 0.2) and WHO scale (sensitivity: 0.13, specificity: 0.79). These results suggest that objective and quantitative assessment of infant dehydration may be possible using the sensors investigated. However, further evaluation of the sensors on a larger sample population is needed before deploying them in a clinical setting. PMID- 28734876 TI - T Cell Depletion as an Alternative Approach for Patients 55 Years or Older Undergoing Allogeneic Stem Cell Transplantation as Curative Therapy for Hematologic Malignancies. AB - T cell-depleted (TCD) allogeneic hematopoietic stem cell transplantation (HSCT) is curative treatment for hematologic malignancies in adults, shown to reduce graft-versus-host disease (GVHD) without increased relapse. We retrospectively reviewed a single-center, 11-year experience of 214 patients aged >= 55 years to determine tolerability and efficacy in the older adult. Most patients (70%) had myeloid diseases, and most acute leukemias were in remission. Median age was 61 years, with related and unrelated donors >=8/10 HLA matched. Hematopoietic cell transplantation-specific comorbidity index scores were intermediate and high for 84%. Conditioning regimens were all myeloablative. Grafts were peripheral blood stem cells (97%) containing CD3 dose <=103-4/kg body weight, without pharmacologic GVHD prophylaxis. With median follow-up of 70 months among survivors, Kaplan-Meier estimates of overall and relapse-free survival were 44% and 41%, respectively (4 years). Cumulative incidence of nonrelapse mortality at day +100 was only 10%. Incidence of GVHD for acute (grades II to IV) was 9% at day +100 and for chronic was 7% at 2 and 4 years (8 extensive, 1 overlap). Median Karnofsky performance status for patients > 2 years post-transplant was 90%. As 1 of the largest reports for patients >=2 aged >=55 years receiving TCD HSCTs, it demonstrates curative therapy with minimal GVHD, similar to that observed in a younger population. PMID- 28734878 TI - Cardiac Resynchronization and Coronary Sinus Orifice Atresia. PMID- 28734877 TI - Enzymatic and free radical formation of cis- and trans- epoxyeicosatrienoic acids in vitro and in vivo. AB - Epoxyeicosatrienoic acids (EETs) are metabolites of arachidonic acid (AA) oxidation that have important cardioprotective and signaling properties. AA is an omega-6 polyunsaturated fatty acid (PUFA) that is prone to autoxidation. Although hydroperoxides and isoprostanes are major autoxidation products of AA, EETs are also formed from the largely overlooked peroxyl radical addition mechanism. While autoxidation yields both cis- and trans-EETs, cytochrome P450 (CYP) epoxygenases have been shown to exclusively catalyze the formation of all regioisomer cis EETs, on each of the double bonds. In plasma and red blood cell (RBC) membranes, cis- and trans-EETs have been observed, and both have multiple physiological functions. We developed a sensitive ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) assay that separates cis- and trans- isomers of EETs and applied it to determine the relative distribution of cis- vs. trans-EETs in reaction mixtures of AA subjected to free radical oxidation in benzene and liposomes in vitro. We also determined the in vivo distribution of EETs in several tissues, including human and mouse heart, and RBC membranes. We then measured EET levels in heart and RBC of young mice compared to old. Formation of EETs in free radical reactions of AA in benzene and in liposomes exhibited time- and AA concentration-dependent increase and trans-EET levels were higher than cis-EETs under both conditions. In contrast, cis-EET levels were overall higher in biological samples. In general, trans-EETs increased with mouse age more than cis-EETs. We propose a mechanism for the non-enzymatic formation of cis- and trans-EETs involving addition of the peroxyl radical to one of AA's double bonds followed by bond rotation and intramolecular homolytic substitution (SHi). Enzymatic formation of cis-EETs by cytochrome P450 most likely occurs via a one-step concerted mechanism that does not allow bond rotation. The ability to accurately measure circulating EETs resulting from autoxidation or enzymatic reactions in plasma and RBC membranes will allow for future studies investigating how these important signaling lipids correlate with heart disease outcomes. PMID- 28734879 TI - Ventricular Arrhythmias Ablation in Brugada Syndrome. Current and Future Directions. PMID- 28734880 TI - Dual Versus Single Antiplatelet Regimen With or Without Anticoagulation in Transcatheter Aortic Valve Replacement: Indirect Comparison and Meta-analysis. AB - INTRODUCTION AND OBJECTIVES: There is uncertainty on the correct management of antithrombotic therapies after transcatheter aortic valve replacement (TAVR), with dual antiplatelet therapy (DAPT) being currently recommended on an empirical basis. The aim of the present meta-analysis was to assess the safety and effectiveness of DAPT in patients undergoing TAVR. METHODS: Studies comparing different antithrombotic regimens after TAVR were included. The primary endpoint was 30-day overall mortality. RESULTS: We included 9 studies, 5 comparing DAPT with aspirin monotherapy and 4 comparing DAPT with monoantiplatelet therapy (MAPT) + oral anticoagulation. Among 7991 patients, 72% were on DAPT. The median follow-up was 3.5 months. Mortality was significantly lower in the DAPT group (12.2% vs 14.4%; OR, 0.81; 95%CI, 0.70-0.93; P = .003; Phet = .93), with similar benefits compared with aspirin monotherapy (OR, 0.80; 95%CI, 0.69-0.93; P = .004; Phet = .60), which were not statistically significant when compared with MAPT + oral anticoagulation (OR, 0.86; 95%CI, 0.55-1.35; P = .51; Phet = .97). A similar trend for DAPT was observed for stroke (OR, 0.83 95%CI, 0.63-1.10; P = .20; Phet = .67), with no increase in the rate of major bleedings (OR, 1.69; 95%CI, 0.86 3.31; P = .13; Phet< .0001). On indirect comparison analysis, no benefit in survival, stroke, or bleedings was identified for additional oral anticoagulation. CONCLUSIONS: The present meta-analysis supports the use of DAPT after TAVR, reducing mortality and offering slight benefits in stroke, with no increase in major bleedings compared with MAPT. The strategy of aspirin + oral anticoagulation did not provide significant benefits compared with MAPT or DAPT. PMID- 28734881 TI - State of the Science of Spirituality and Palliative Care Research Part II: Screening, Assessment, and Interventions. AB - The State of the Science in Spirituality and Palliative Care was convened to address the current landscape of research at the intersection of spirituality and palliative care and to identify critical next steps to advance this field of inquiry. Part II of the SOS-SPC report addresses the state of extant research and identifies critical research priorities pertaining to the following questions: 1) How do we assess spirituality? 2) How do we intervene on spirituality in palliative care? And 3) How do we train health professionals to address spirituality in palliative care? Findings from this report point to the need for screening and assessment tools that are rigorously developed, clinically relevant, and adapted to a diversity of clinical and cultural settings. Chaplaincy research is needed to form professional spiritual care provision in a variety of settings, and outcomes assessed to ascertain impact on key patient, family, and clinical staff outcomes. Intervention research requires rigorous conceptualization and assessments. Intervention development must be attentive to clinical feasibility, incorporate perspectives and needs of patients, families, and clinicians, and be targeted to diverse populations with spiritual needs. Finally, spiritual care competencies for various clinical care team members should be refined. Reflecting those competencies, training curricula and evaluation tools should be developed, and the impact of education on patient, family, and clinician outcomes should be systematically assessed. PMID- 28734883 TI - Spontaneous Coronary Artery Dissection: Failure of the Conservative Strategy Due to Predominance of the False Lumen. PMID- 28734884 TI - Vascular Injury Caused by Retrieval of Ruptured and Detached Balloon Valvuloplasty Catheter During Transcatheter Aortic Valve Replacement. PMID- 28734882 TI - Opioid Prescribing Among Cancer and Non-cancer Patients: Time Trend Analysis in the Elderly Using Administrative Data. AB - CONTEXT: In 2007, Cancer Care Ontario introduced a provincial symptom screening program, which included pain, for cancer patients. Over this same time, opioid prescribing has been increasingly scrutinized among non-cancer patients. The study purpose was to see if opioid prescribing changed among older adults after 2007 in the context of changing opioid regulations, and whether effects were different among patients with a cancer history. METHODS: Ontario residents aged >=65 years were identified from 2004 to 2013. Subjects were annually stratified into three groups: no cancer history, cancer diagnosis >5 years ago, and cancer diagnosis <=5 years ago. We evaluated time trends by year for: 1) opioid prescription rate, comparing trends before and after 2007 and 2) mean daily opioid dose. RESULTS: Between 2004 and 2013, opioid prescribing was relatively constant for cancer patients with no observed change in trends after 2007. For non-cancer patients, there was a 2% relative annual increase during this period. Significant changes were seen for opioid sub-classes (e.g., decreasing use of long-acting oxycodone). These were similar for those with or without a history of cancer. Among all groups, changes in the mean daily dose over time were similar in all drug classes. CONCLUSION: Overall prescribing rates for cancer patients aged >=65 years remain unchanged over time, in spite of the introduction of a provincial symptom screening program. Decreasing prescription rates in some drug sub-classes were observed. The potential impact of these changes on the quality of symptom control for cancer patients needs further investigation. PMID- 28734886 TI - Pre-Transcatheter Aortic Valve Replacement Right Bundle Branch Block: A Bundle of Trouble. PMID- 28734887 TI - Catastrophic Consequence of Gauze During Percutaneous Coronary Intervention. PMID- 28734885 TI - Clinical Impact of Baseline Right Bundle Branch Block in Patients Undergoing Transcatheter Aortic Valve Replacement. AB - OBJECTIVES: This study sought to assess the influence of baseline right bundle branch block (RBBB) on all-cause and cardiovascular mortality as well as sudden cardiac death (SCD) among patients undergoing transcatheter aortic valve replacement (TAVR). BACKGROUND: Few data exist regarding the late clinical impact of pre-existing RBBB in TAVR recipients. METHODS: A total of 3,527 patients (mean age 82 +/- 8 years, 50.1% men) were evaluated according to the presence of RBBB on baseline electrocardiography. Intraventricular conduction abnormalities were classified according to the American Heart Association, American College of Cardiology Foundation, and Heart Rhythm Society recommendations for standardization and interpretation of the electrocardiogram. TAVR complications and causes of death were defined according to Valve Academic Research Consortium 2 definitions. RESULTS: RBBB was present on baseline electrocardiography in 362 patients (10.3%) and associated with higher 30-day rates of permanent pacemaker implantation (PPI) (40.1% vs. 13.5%; p < 0.001) and death (10.2% vs. 6.9%; p = 0.024). At a mean follow-up of 20 +/- 18 months, pre-existing RBBB was independently associated with all-cause mortality (hazard ratio [HR]: 1.31; 95% confidence interval [CI]: 1.06 to 1.63; p = 0.014) and cardiovascular mortality (HR: 1.45; 95% CI: 1.11 to 1.89; p = 0.006) but not with SCD (HR: 0.71; 95% CI: 0.22 to 2.32; p = 0.57). Patients with pre-existing RBBB and without PPI at discharge from the index hospitalization had the highest 2-year risk for cardiovascular death (27.8%; 95% CI: 20.9% to 36.1%; log-rank p = 0.007). In a subanalysis of 1,245 patients without PPI at discharge from the index hospitalization and with complete follow-up regarding the need for PPI, pre existing RBBB was independently associated with the composite of SCD and PPI (HR: 2.68; 95% CI: 1.16 to 6.17; p = 0.023). CONCLUSIONS: Pre-existing RBBB was found in 10% of TAVR recipients and was associated with poorer clinical outcomes. Patients with baseline RBBB without permanent pacemakers at hospital discharge may be at especially high risk for high-degree atrioventricular block and/or SCD during follow-up. Future studies should evaluate strategies aimed at the early detection of patients at risk for late development of high-degree atrioventricular block. PMID- 28734888 TI - Severe Intramyocardial Hematoma as a Complication of Retrograde Approach in Chronic Total Occlusion. PMID- 28734889 TI - Subaortic Membrane and Hypertrophic Obstructive Cardiomyopathy in the Cardiac Catheterization Lab. PMID- 28734890 TI - Hybrid Imaging to Assess Prosthesis-Patient Mismatch After Transcatheter Aortic Valve Replacement: In Search of Validation. PMID- 28734892 TI - Correlation between RNA-Seq and microarrays results using TCGA data. AB - RNA sequencing (RNA-Seq) and microarray are two of the most commonly used high throughput technologies for transcriptome profiling; however, they both have their own inherent strengths and limitations. This research aims to analyze the correlation between microarrays and RNA-Seq detection of transcripts in the same tissue sample to explore the reproducibility between the techniques. Using data of RNA-Seq v2 and three different microarrays provided by The Cancer Genome Atlas, 11,120 genes of 111 lung squamous cell carcinoma samples were simultaneously detected by the four methods. Then we analyzed the Pearson correlation between microarrays and RNA-Seq. Finally, in the six comparison results, 9984 (89.8%) genes, irrespective of which two methods were used, simultaneously showed the existence of correlation, whereas only 83 (0.1%) genes proved to have no significant correlation in either comparison. In addition, the comparisons between 3266 (29.3%) genes showed high correlation (R>=0.8) in all six comparisons, only for 1643 (14.8%) genes correlation were not as high in either comparison. Meanwhile, transcripts with extreme high or low expression levels were more highly discrepant across the methods. In conclusion, we found that, for most transcripts, the results obtained by RNA-Seq and microarrays were highly reproducible. PMID- 28734891 TI - CT-Defined Prosthesis-Patient Mismatch Downgrades Frequency and Severity, and Demonstrates No Association With Adverse Outcomes After Transcatheter Aortic Valve Replacement. AB - OBJECTIVES: This study sought to determine if indexed effective orifice area (EOAi), using left ventricular outflow tract measured from computed tomography (EOAiCT), reclassified prosthesis-patient mismatch (PPM) compared with conventional echocardiogram-defined measurements (EOAiTTE). BACKGROUND: PPM does not predict mortality following transcatheter aortic valve replacement (TAVR). However, it is unknown if the EOAiCT of the left ventricular outflow tract improves risk stratification. METHODS: A total of 765 TAVR patients from the PARTNER II (Placement of Aortic Transcatheter Valves II) trial S3i cohort were evaluated. EOAi was calculated using the continuity equation, and the left ventricular outflow tract area was derived from baseline computed tomography. Traditional echocardiographic categories defined PPM: absent (>0.85 cm2/m2), moderate (>=0.65 and <=0.85 cm2/m2), or severe (<=0.65 cm2/m2). Correlation of EOAiCT and EOAiTTE to 1-year outcomes was performed. RESULTS: The incidence of PPM was 24% with EOACT compared with 45% with EOAiTTE. Only 6% of PPM was graded severe by EOAiCT compared with 9% by EOAiTTE. EOAiTTE, but not EOAiCT, defined PPM showed association with reduced left ventricular mass regression (p = 0.03 vs. p = 0.52). There was no association between PPM and death or rehospitalization at 1 year with either modality. EOACT was associated with minor stroke at 1 year (log-rank p = 0.04), and EOAiTTE with stroke/transient ischemic attack (log-rank p = 0.030). Furthermore, when subjects with mild or greater paravalvular regurgitation were excluded, the presence of PPM did not show association with any outcome. CONCLUSIONS: EOAiCT downgrades frequency and severity of PPM in patients after TAVR, and was not associated with mortality 1 year after TAVR. EOAiTTE, but not EOAiCT, was associated with less left ventricular mass regression. PMID- 28734893 TI - Genetic polymorphisms in CYP2A6 are associated with a risk of cigarette smoking and predispose to smoking at younger ages. AB - Nicotine is the main component of cigarettes that causes addiction, which is considered a complex disease, and genetic factors have been proposed to be involved in the development of addiction. The CYP2A6 gene encodes the main enzyme responsible for nicotine metabolism. Depending on the study population, different genetic variants of CYP2A6 associated with cigarette smoking have been described. Therefore, we evaluated the possible association between SNPs in CYP2A6 with cigarette smoking and nicotine addiction-related variables in Mexican mestizo smokers. We performed a genetic association study comparing light smokers (LS, n=349), heavy smokers (HS, n=351) and never-smokers (NS, n=394). SNPs rs1137115, rs4105144, rs1801272 and rs28399433 were genotyped in the CYP2A6 gene. We found that the A allele of rs1137115 (OR=1.41) in exon 1 of CYP2A6 and the T allele of rs4105144 (OR=1.32) in the 5' UTR of the gene are associated with the risk of cigarette smoking (p<0.05); rs1137115 affects the level of alternative splicing, resulting in a CYP2A6 isoform with low enzymatic activity, whereas rs4105144 is likely to be in a binding site for the transcription factor for glucocorticoids receptor (GR) and regulates the expression of CYP2A6. In addition, having a greater number of risk alleles (rs1137115 (A), rs4105144 (T) and rs28399433 (G)) is associated with a younger age at onset. The present study shows that in Mexican mestizos, the analyzed SNPs confer greater risk in terms of consumption and age of onset. PMID- 28734894 TI - GLCE rs3865014 (Val597Ile) polymorphism is associated with breast cancer susceptibility and triple-negative breast cancer in Siberian population. AB - d-Glucuronyl C5-epimerase (GLCE) is one of key enzymes in heparan sulfate biosynthesis and possesses tumour-suppressor function in breast carcinogenesis. Here, we investigated a potential involvement of GLCE polymorphism(s) in breast cancer development in Siberian women population. Comprehensive analysis of SNP databases revealed GLCE rs3865014 (Val597Ile) missense polymorphism as the main significantly present in human populations. According the TaqMan-based SNP assay, allele distributions for the rs3865014 (A>G) were similar in healthy Siberian women (n=136) and cancer patients (n=129) (A0,73:G0,27) and intermediate between the European and Asian populations, while genotype distributions were different, with the increase of AG rate in breast cancer patients (OR=1.76; 95% CI=1.04 1.90; P(Y)=0.035 chi2=4.44). Heterozygous AG genotype was associated with tumour size (OR=3.67, P(Y)=0.004), ER-negative tumours (OR=3.25, P(Y)=0.0028), triple negative tumours (OR=4.94, P(Y)=0.015) but not menopausal status, PR and HER-2 status, local or distant metastasis. Homozygous GLCE genotypes (AA/GG) were more common for ER+PR+ luminal A breast cancer (OR=0.25, P(Y)=0.031). Loss-of heterozigosity was identified in 5 of 51 breast tumours and the loss of G allele was associated with the decreased GLCE expression. Epidemiologic data for the GLCE SNP in different racial/ethnic groups demonstrated high AG genotype rates as a risk factor not for breast cancer incidence but for poor prognosis of the disease. The obtained data suggest an involvement of GLCE rs3865014 in breast cancer development. Heterozygous AG genotype might be a risk factor for breast cancer susceptibility in Siberian women and is associated with aggressive ER negative and triple-negative cancer subtypes. PMID- 28734895 TI - A sensitive and convenient method for clinical detection of non-syndromic hearing loss-associated common mutations. AB - BACKGROUND: The majority of non-syndromic hearing loss (NSHL) patients result from causative mutations in GJB2, SLC26A4 and mitochondrial 12S rRNA genes. Accurate detection of these genetic mutations is increasingly recognized for its clinical significance to reduce incidence and guide individual treatment of NSHL. Current methods for clinical practice are labor intensive, expensive or of low sensitivity. METHODS: Genomic DNA from 7 newborns not passing the hearing screening and 94 newborns passing the hearing screening were analyzed for the common mutations using high resolution melting analysis (HRMA) and Sanger sequencing. RESULTS: Our newly developed HRMA allowed the hot-spot mutations of GJB2 c.176_191del16 and c.235delC, SLC26A4 IVS7-2A>G and mitochondrial 12S rRNA 1494C>T and 1555A>G to be detected by melting profiles based on small amplicons. HRMA can distinguish different content mutant DNA from wildtype DNA, with a detection limit of 5%. Moreover, the results were highly concordant between HRMA and Sanger sequencing. CONCLUSIONS: These results indicate that HRMA could be used as a routine clinical method for prenatal diagnosis and newborn genetic screening due to its accuracy, sensitivity, and rapid, low-cost and less laborious workflows. PMID- 28734896 TI - Porcine CD14 gene silencing partially inhibited the bacterial immune response mediated by TLR4 signaling pathway. AB - Cluster of differentiation antigen 14 (CD14) is the membrane receptor protein in Toll-like Receptor 4 (TLR4) signaling pathway, which plays an important regulation role in not only innate immune response but also adaptive immune response. In this study, the pig kidney epithelial cell (PK15) line with CD14 gene silencing mediated by lentivirus was established and cells of CD14-RNAi and NC group were exposed to three kinds of Escherichia coli (E. coli F18ab, E. coli F18ac and E. coli K88ac) and LPS. Then qPCR and western blot were used to detect expression levels of TLR4 signaling pathway-related genes. Finally, ELISA was used to detect the level of proinflammatory cytokines in the cell culture supernatant. The results showed that the expression level of TLR4 signaling pathway-related genes in the entire signal pathway had obvious increases when cells were exposed to the stimulation induced by E. coli and LPS. In addition, the expression levels of CD14-RNAi group were overall significantly lower than NC group (P<0.05 or P<0.01), which was the same with the release levels of proinflammatory cytokines. This study revealed that pig CD14 gene silencing partially inhibited immune response to E. coli F18 invasion mediated by TLR4 signaling pathway. PMID- 28734897 TI - Exploiting Helminth-Host Interactomes through Big Data. AB - Helminths facilitate their parasitic existence through the production and secretion of different molecules, including proteins. Some helminth proteins can manipulate the host's immune system, a phenomenon that is now being exploited with a view to developing therapeutics for inflammatory diseases. In recent years, hundreds of helminth genomes have been sequenced, but as a community we are still taking baby steps when it comes to identifying proteins that govern host-helminth interactions. The information generated from genomic, immunomic, and proteomic studies, as well as from cutting-edge approaches such as proteogenomics, is leading to a substantial volume of big data that can be utilised to shed light on fundamental biology and provide solutions for the development of bioactive-molecule-based therapeutics. PMID- 28734898 TI - Anopheles Vectors in Mainland China While Approaching Malaria Elimination. AB - China is approaching malaria elimination; however, well-documented information on malaria vectors is still missing, which could hinder the development of appropriate surveillance strategies and WHO certification. This review summarizes the nationwide distribution of malaria vectors, their bionomic characteristics, control measures, and related studies. After several years of effort, the area of distribution of the principal malaria vectors was reduced, in particular for Anopheles lesteri (synonym: An. anthropophagus) and Anopheles dirus s.l., which nearly disappeared from their former endemic regions. Anopheles sinensis is becoming the predominant species in southwestern China. The bionomic characteristics of these species have changed, and resistance to insecticides was reported. There is a need to update surveillance tools and investigate the role of secondary vectors in malaria transmission. PMID- 28734900 TI - Molecular imaging in stem cell-based therapies of cardiac diseases. AB - In the past 15years, despite that regenerative medicine has shown great potential for cardiovascular diseases, the outcome and safety of stem cell transplantation has shown controversial results in the published literature. Medical imaging might be useful for monitoring and quantifying transplanted cells within the heart and to serially characterize the effects of stem cell therapy of the myocardium. From the multiple available noninvasive imaging techniques, magnetic resonance imaging and nuclear imaging by positron (PET) or single photon emission computer tomography (SPECT) are the most used clinical approaches to follow the fate of transplanted stem cells in vivo. In this article, we provide a review on the role of different noninvasive imaging modalities and discuss their advantages and disadvantages. We focus on the different in-vivo labeling and reporter gene imaging strategies for stem cell tracking as well as the concept and reliability to use imaging parameters as noninvasive surrogate endpoints for the evaluation of the post-therapeutic outcome. PMID- 28734901 TI - Gastroresistant oral peptide for fluorescence imaging of colonic inflammation. AB - The use of molecular markers for inflammation in the gastrointestinal tract could empower optical imaging modalities for early diagnosis and eventually personalized timely treatments. A major hurdle to the widespread use of functional fluorescence imaging is the absence of suitable contrast agents, in particular to be administered via the oral route due to the usual proteolytic susceptibility of the biomarkers. By designing a retro-inverso peptide, starting from a previously described sequence specific for N-cadherin, we achieved resistance to gastrointestinal degradation and even slightly improved specificity towards the target, both in ex vivo and in vivo experimental colitis. Simulations at fundamental molecular level suggested that the introduced retro-inverso modifications did not affect the folding of the peptide, leaving its ability to interact with the binding pocket of the monomeric N-cadherin unaltered, even when fluorescently labeled. Possible further derivatization of this sequence could be envisaged to further extend the potential of the designed retro-inverso peptide as diagnostic or theranostic agent for the oral route. PMID- 28734902 TI - NanoDDS 2016: The 14th International Nanomedicine and Drug Delivery Symposium. PMID- 28734903 TI - The olfactory bulbectomized rat model is not an appropriate model for studying depression based on morphological/stereological studies of the hippocampus. AB - Bilateral olfactory bulbectomy (OBX) has been used as an animal model for major depression that results in behavioral, neurochemical, and neuroendocrinological changes were reversed by chronic treatment with antidepressants, including fluoxetine. However, both etiological and construct validities are lacking in OBX for rats. In the present study, we investigated the morphological changes in the hippocampi of rats undergoing OBX that were treated with fluoxetine (10mg/kg, p.o. once daily for 4 and 12 weeks) using stereological techniques. Our results revealed that OBX caused a reduction in the volumes of the CA1/2, CA3, and dentate gyrus regions 4 weeks after OBX without fluoxetine treatment. With fluoxetine treatment, these reductions were achieved 12 weeks after OBX and the volumes were comparable to normal control rats. Nevertheless, fluoxetine treatment did not reverse neuron loss in all hippocampal regions 12 weeks after OBX. Therefore, we suggest that the OBX rat model should not be used to detect the antidepressant activity of various pharmacological agents such as fluoxetine. PMID- 28734899 TI - Strategies to develop endogenous stem cell-recruiting bioactive materials for tissue repair and regeneration. AB - A leading strategy in tissue engineering is the design of biomimetic scaffolds that stimulate the body's repair mechanisms through the recruitment of endogenous stem cells to sites of injury. Approaches that employ the use of chemoattractant gradients to guide tissue regeneration without external cell sources are favored over traditional cell-based therapies that have limited potential for clinical translation. Following this concept, bioactive scaffolds can be engineered to provide a temporally and spatially controlled release of biological cues, with the possibility to mimic the complex signaling patterns of endogenous tissue regeneration. Another effective way to regulate stem cell activity is to leverage the inherent chemotactic properties of extracellular matrix (ECM)-based materials to build versatile cell-instructive platforms. This review introduces the concept of endogenous stem cell recruitment, and provides a comprehensive overview of the strategies available to achieve effective cardiovascular and bone tissue regeneration. PMID- 28734904 TI - Identifying novel members of the Wntless interactome through genetic and candidate gene approaches. AB - Wnt signaling is an important pathway that regulates several aspects of embryogenesis, stem cell maintenance, and neural connectivity. We have recently determined that opioids decrease Wnt secretion, presumably by inhibiting the recycling of the Wnt trafficking protein Wntless (Wls). This effect appears to be mediated by protein-protein interaction between Wls and the mu-opioid receptor (MOR), the primary cellular target of opioid drugs. The goal of this study was to identify novel protein interactors of Wls that are expressed in the brain and may also play a role in reward or addiction. Using genetic and candidate gene approaches, we show that among a variety of protein, Wls interacts with the dopamine transporter (target of cocaine), cannabinoid receptors (target of THC), Adenosine A2A receptor (target of caffeine), and SGIP1 (endocytic regulator of cannabinoid receptors). Our study shows that aside from opioid receptors, Wntless interacts with additional proteins involved in reward and/or addiction. Future studies will determine whether Wntless and WNT signaling play a more universal role in these processes. PMID- 28734905 TI - [Recovery from episodes of Clostridium difficile infection following the implementation of a consensus document]. PMID- 28734906 TI - Results from 15years of quality surveillance for a National Indigenous Point-of Care Testing Program for diabetes. AB - INTRODUCTION: Diabetes is a major health problem for Australia's Aboriginal and Torres Strait Islander peoples. Point-of-care testing for haemoglobin A1c (HbA1c) has been the cornerstone of a long-standing program (QAAMS) to manage glycaemic control in Indigenous people with diabetes and recently, to diagnose diabetes. METHODS: The QAAMS quality management framework includes monthly testing of quality control (QC) and external quality assurance (EQA) samples. Key performance indicators of quality include imprecision (coefficient of variation [CV%]) and percentage acceptable results. This paper reports on the past 15years of quality testing in QAAMS and examines the performance of HbA1c POC testing at the 6.5% cut-off recommended for diagnosis. RESULTS: The total number of HbA1c EQA results submitted from 2002 to 2016 was 29,093. The median imprecision for EQA testing by QAAMS device operators averaged 2.81% (SD 0.50; range 2.2 to 3.9%) from 2002 to 2016 and 2.44% (SD 0.22; range 2.2 to 2.9%) from 2009 to 2016. No significant difference was observed between the median imprecision achieved in QAAMS and by Australasian laboratories from 2002 to 2016 (p=0.05; two-tailed paired t-test) and from 2009 to 2016 (p=0.17; two-tailed paired t-test). For QC testing from 2009 to 2016, imprecision averaged 2.5% and 3.0% for the two levels of QC tested. Percentage acceptable results averaged 90% for QA testing from 2002 to 2016 and 96% for QC testing from 2009 to 2016. The DCA Vantage was able to measure a patient and an EQA sample with an HbA1c value close to 6.5% both accurately and precisely. CONCLUSION: HbA1c POC testing in QAAMS has remained analytically sound, matched the quality achieved by Australasian laboratories and met profession-derived analytical goals for 15years. PMID- 28734907 TI - Predicting relapse in schizophrenia: Is BDNF a plausible biological marker? AB - Understanding the biological processes that underlie why patients relapse is an issue of fundamental importance to the detection and prevention of relapse in schizophrenia. Brain Derived Neurotrophic Factor (BDNF), a facilitator of brain plasticity, is reduced in patients with schizophrenia. In the present study, we examined whether decreases in plasma BDNF levels could be used as a biological predictor of relapse in schizophrenia. A total of 221 patients were prospectively evaluated for relapse over 30months in the Preventing Relapse in Schizophrenia: Oral Antipsychotics Compared to Injectables: eValuating Efficacy (PROACTIVE) study. Serial blood samples were collected at a maximum of 23 time points during the 30-month trial and BDNF levels were measured in plasma samples by ELISA. Receiver Operating Characteristic (ROC) curve analysis indicated that BDNF was not a significant predictor of relapse, hospitalization or exacerbation. Regardless of treatment group (oral second generation antipsychotic vs. long acting injectable risperidone microspheres), baseline BDNF value did not differ significantly between those who experienced any of the adverse outcomes and those who did not. While contrary to the study hypothesis, these robust results offer little support for the use of plasma BDNF alone as a biomarker to predict relapse in schizophrenia. PMID- 28734909 TI - Prognostic Value of Exercise-Stress Echocardiography in Asymptomatic Patients With Aortic Valve Stenosis. AB - OBJECTIVES: This study sought to evaluate the prognostic value of mean pressure gradient (MPG) increase and peak systolic pulmonary artery pressure (SPAP) measured during exercise stress echocardiography in asymptomatic patients with aortic stenosis (AS). BACKGROUND: Exercise testing is recommended in asymptomatic AS patients, but the additional value of exercise-stress echocardiography, especially the prognostic value of MPG increase and peak SPAP, is still debated. METHODS: We enrolled all consecutive patients with pure, isolated, asymptomatic AS and preserved ejection fraction >=50% and normal SPAP (<50 mm Hg) who underwent symptom-limited exercise echocardiography at our institution. Occurrence of AS-related events (symptoms or congestive heart failure) or occurrence of aortic valve replacement was recorded. RESULTS: We enrolled 148 patients (66 +/- 15 years of age; 74% males; MPG: 47 +/- 13 mm Hg; SPAP: 34 +/- 6 mm Hg). No complications were observed. Thirty-six patients (24%) had an abnormal exercise test result (occurrence of symptoms, fall in blood pressure, and/or ST segment depression) and were referred for surgery. Among the 112 patients with a normal exercise test result, 38 patients (34%) had abnormal exercise echocardiography scores (MPG increase >20 mm Hg and/or SPAP at peak exercise >60 mm Hg). These 112 patients were managed conservatively. During a mean follow-up of 14 +/- 8 months, an AS-related event occurred in 30 patients, and 25 patients underwent surgery. Neither MPG increase >20 mm Hg nor peak SPAP >60 mm Hg was predictive of occurrence of AS-related events or aortic valve replacement (all p > 0.20). In contrast, baseline AS severity was an important prognostic factor (all p < 0.01). CONCLUSIONS: In this observational study including 148 patients with asymptomatic AS, we confirmed and extended the importance of exercise testing for unveiling functional limitation. More importantly, neither the increase in MPG nor in SPAP at peak exercise was predictive of outcome. Our results do not support the use of these parameters in risk-stratification and clinical management of asymptomatic AS patients. PMID- 28734910 TI - 3-Dimensional Ultrasound in Carotid Stenosis Quantitation and Beyond. PMID- 28734908 TI - Why transition risk to psychosis is not declining at the OASIS ultra high risk service: The hidden role of stable pretest risk enrichment. AB - BACKGROUND: The reason for declining risk to psychosis across individuals assessed and meeting Ultra High Risk (UHR) criteria is still unclear. No studies have investigated the potential substantial role of the underlying risk enrichment across all the individuals undergoing an UHR assessment. METHODS: Cohort study including all non-psychotic subjects who were assessed on suspicion of psychosis risk by the OASIS UHR service in the period 2001 to 2015. Posttest (after UHR assessment) and pretest risk (before UHR assessment) of psychosis were stratified and compared across three time periods (2001-2005, 2006-2010, 2011 2015) with Cox analysis and modulating factors were investigated. RESULTS: The posttest risk of psychosis at the OASIS service has increased from the initial pilot years of the service (2001-2005) and then stabilised and not declined over the following decade (2006-2010 and 2011-2015). This was paralleled by a similar course of pretest risk for psychosis. Stability of pretest risk for psychosis over the past decade was associated with a lack of change in ethnicity and to counterweighting changes in the type of referral sources over different time periods. CONCLUSIONS: The time course of transition risk to psychosis in UHR services is strictly associated with the time course of pretest risk enrichment. If the latter remains stable over time, as for the OASIS service, no declining transition risk is observed over the most recent years. Pretest risk enrichment is determined by recruitment and sampling strategies. This study confirms the need to control these factors in the UHR field. PMID- 28734912 TI - Coronary Artery Calcification: A Janus-Faced Biomarker? PMID- 28734911 TI - Plaque Rupture in Coronary Atherosclerosis Is Associated With Increased Plaque Structural Stress. AB - OBJECTIVES: The aim of this study was to identify the determinants of plaque structural stress (PSS) and the relationship between PSS and plaques with rupture. BACKGROUND: Plaque rupture is the most common cause of myocardial infarction, occurring particularly in higher risk lesions such as fibroatheromas. However, prospective intravascular ultrasound-virtual histology studies indicate that <10% higher risk plaques cause clinical events over 3 years, indicating that other factors also determine plaque rupture. Plaque rupture occurs when PSS exceeds its mechanical strength; however, the determinants of PSS and its association with plaques with proven rupture are not known. METHODS: We analyzed plaque structure and composition in 4,053 virtual histology intravascular ultrasound frames from 32 fibroatheromas with rupture from the intravascular ultrasound-virtual histology in Vulnerable Atherosclerosis study and 32 fibroatheromas without rupture on optical coherence tomography from a stable angina cohort. Mechanical loading in the periluminal region was estimated by calculating maximum principal PSS by finite element analysis. RESULTS: PSS increased with increasing lumen area (r = 0.46; p = 0.001), lumen eccentricity (r = 0.32; p = 0.001), and necrotic core >=10% (r = 0.12; p = 0.001), but reduced when dense calcium was >=10% (r = -0.12; p = 0.001). Ruptured fibroatheromas showed higher PSS (133 kPa [quartiles 1 to 3: 90 to 191 kPa] vs. 104 kPa [quartiles 1 to 3: 75 to 142 kPa]; p = 0.002) and variation in PSS (55 kPa [quartiles 1 to 3: 37 to 75 kPa] vs. 43 kPa [quartiles 1 to 3: 34 to 59 kPa]; p = 0.002) than nonruptured fibroatheromas, with rupture primarily occurring either proximal or immediately adjacent to the minimal luminal area (87.5% vs. 12.5%; p = 0.001). PSS was higher in segments proximal to the rupture site (143 kPa [quartiles 1 to 3: 101 to 200 kPa] vs. 120 kPa [quartiles 1 to 3: 78 to 180 kPa]; p = 0.001) versus distal segments, associated with increased necrotic core (19.1% [quartiles 1 to 3: 11% to 29%] vs. 14.3% [quartiles 1 to 3: 8% to 23%]; p = 0.001) but reduced fibrous/fibrofatty tissue (63.6% [quartiles 1 to 3: 46% to 78%] vs. 72.7% [quartiles 1 to 3: 54% to 86%]; p = 0.001). PSS >135 kPa was a good predictor of rupture in higher risk regions. CONCLUSIONS: PSS is determined by plaque composition, plaque architecture, and lumen geometry. PSS and PSS variability are increased in plaques with rupture, particularly at proximal segments. Incorporating PSS into plaque assessment may improve identification of rupture-prone plaques. PMID- 28734913 TI - Uncovered Culprit Plaque Ruptures in Patients With ST-Segment Elevation Myocardial Infarction Assessed by Optical Coherence Tomography and Intravascular Ultrasound With iMap. AB - OBJECTIVES: This study assessed the incidence and course of healing of uncovered plaque ruptures (PR) following primary percutaneous coronary intervention. BACKGROUND: The infarct-related occlusion is frequently located at the lesion site with maximum thrombus burden, whereas the culprit PR may be situated more proximally or distally. METHODS: Uncovered PR in segments adjacent to the stent were identified by optical coherence tomography and intravascular ultrasound using iMap (Boston Scientific, Marlborough, Massachusetts) within 48 h and after 12 months. The percentages of necrotic core, fibrotic tissue, lipid tissue, and calcific tissue were determined. RESULTS: Eleven uncovered PR were found in 10 of 77 patients (13.0%). Eight of these ruptures (10.4%) were identified as culprit and were located proximal to the stent. Two patients were treated before follow up due to recurrent symptoms. After 12 months, 3 PR had healed incompletely without causing symptoms. The lumen area at the PR site was reduced (7.5 mm2 [interquartile range (IQR): 4.8 to 9.3 mm2] to 3.6 mm2 [IQR: 2.8 to 8.0 mm2]; p = 0.012). Proximal segments with uncovered PR had greater plaque volumes (62.1 mm3 [IQR: 50.2 to 83.6 mm3] vs. 38.7 mm3 [IQR: 29.6 to 47.6 mm3], respectively; p < 0.001), vessel volumes (110.7 mm3 [IQR: 92.3 to 128.1 mm3] vs. 76.0 mm3 [IQR: 63.8 to 100.3 mm3], respectively; p < 0.001), and greater percentages of necrotic core (34.0% [IQR: 29.0% to 44.5%] vs. 20.5% (IQR: 10.0% to 29.0%]; p < 0.001). Conversely, percentages of fibrotic tissue were lower (44.0% [IQR: 32.0% to 47.0%] vs. 56.0% [IQR: 46.0% to 66.0%]; p = 0.001), whereas no differences were found for lipid tissue and calcific tissue. CONCLUSIONS: Uncovered culprit ruptures detected by optical coherence tomography were common following primary percutaneous coronary intervention and were found to be associated with significant lumen reduction during the healing process. PMID- 28734914 TI - The Ongoing Quest to Predict Plaque Rupture. PMID- 28734915 TI - Asymptomatic Aortic Stenosis: From Flights of Stairs to Exercise Testing to Exercise Echocardiography? PMID- 28734916 TI - Juxta-Lesional Cavitary Formation in Coronary Intervention: Imaginary, Incidental, or Iatrogenic? PMID- 28734917 TI - LVH and CAD: New Steps Down an Old Path. PMID- 28734919 TI - Some Laws Were Not Made to Be Broken: When Frank-Starling Reserve Is Lost in Heart Failure. PMID- 28734918 TI - RV Myocardial Strain During Pre-Load Augmentation Is Associated With Exercise Capacity in Patients With Chronic HF. AB - OBJECTIVES: The aim of this study was to assess the relationship between right ventricular (RV) function during pre-load augmentation and exercise tolerance. BACKGROUND: Peak oxygen uptake (VO2) is a strong predictor of mortality in chronic heart failure. Cardiac function during pre-load augmentation is an important part of the phenomenon in the evaluation of exercise capacity. METHODS: We prospectively performed echocardiographic studies in 68 chronic heart failure patients with cardiopulmonary exercise testing (mean age 60 +/- 12 years; 69% male). After resting evaluations, echocardiographic parameters were repeated during leg positive pressure (LPP). Exercise capacity was assessed by peak VO2 in all patients (left ventricular ejection fraction: 43 +/- 15%). RESULTS: Patients with severely reduced exercise capacity (peak VO2 <14 ml/kg/min) had significantly lower stroke volume index, left ventricular global longitudinal strain and RV strain and higher filling pressure (E/e' and pulmonary arterial systolic pressure) than the remainder. Stroke volume index (beta = 0.49), global longitudinal strain (beta = -0.61), E/e' (beta = -0.32), pulmonary arterial systolic pressure (beta = -0.57), and RV strain (beta = -0.66) during LPP were independently correlated to peak VO2 (all p < 0.01). RV strain during LPP was the most powerful predictor in identifying patients with severely reduced exercise capacity (cut off value: -17%; sensitivity: 81%; specificity: 88%; areas under the curve: 0.88; p < 0.001) compared with other variables including resting parameters. CONCLUSIONS: RV strain during pre-load augmentation correlated independently to peak VO2 and was a powerful predictor in identifying patients with severely reduced exercise capacity. PMID- 28734920 TI - Artificial Intelligence-Based Assessment of Left Ventricular Filling Pressures From 2-Dimensional Cardiac Ultrasound Images. PMID- 28734921 TI - Imaging Ischemic and Reperfusion Injury in Acute Myocardial Infarction: Putting the Pieces Together With CMR. PMID- 28734922 TI - Warfarin Use Is Associated With Progressive Coronary Arterial Calcification: Insights From Serial Intravascular Ultrasound. AB - OBJECTIVES: This study compared serial changes in coronary percent atheroma volume (PAV) and calcium index (CaI) in patients with coronary artery disease who were treated with and without warfarin. BACKGROUND: Warfarin blocks the synthesis and activity of matrix Gla protein, a vitamin K-dependent inhibitor of arterial calcification. The longitudinal impact of warfarin on serial coronary artery calcification in vivo in humans is unknown. METHODS: In a post hoc patient-level analysis of 8 prospective randomized trials using serial coronary intravascular ultrasound examinations, this study compared changes in PAV and CaI in matched arterial segments in patients with coronary artery disease who were treated with (n = 171) and without (n = 4,129) warfarin during an 18- to 24-month period. RESULTS: Patients (mean age 57.9 +/- 9.2 years; male 73%; prior and concomitant 3 hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statin) use, 73% and 97%, respectively) demonstrated overall increases in PAV of 0.41 +/- 0.07% (p = 0.001 compared with baseline) and in CaI (median) of 0.04 (interquartile range [IQR]: 0.00 to 0.11; p < 0.001 compared with baseline). Following propensity weighted adjustment for clinical trial and a range of clinical, ultrasonic, and laboratory parameters, there was no significant difference in the annualized change in PAV in the presence and absence of warfarin treatment (0.33 +/- 0.05% vs. 0.25 +/- 0.05%; p = 0.17). A significantly greater annualized increase in CaI was observed in warfarin-treated compared with non-warfarin-treated patients (median 0.03; IQR: 0.0 to 0.08 vs. median 0.02; IQR: 0.0 to 0.06; p < 0.001). In a sensitivity analysis evaluating a 1:1 matched cohort (n = 164 per group), significantly greater annualized changes in CaI were also observed in warfarin treated compared with non-warfarin-treated patients. In a multivariate model, warfarin was independently associated with an increasing CaI (odds ratio: 1.16; 95% confidence interval: 1.05 to 1.28; p = 0.003). CONCLUSIONS: Warfarin therapy is associated with progressive coronary atheroma calcification independent of changes in atheroma volume. The impact of these changes on plaque stability and cardiovascular outcomes requires further investigation. PMID- 28734923 TI - Diagnostic Accuracy of Coronary CT Angiography for the Evaluation of Bioresorbable Vascular Scaffolds. AB - OBJECTIVES: The purpose of this study was to assess the diagnostic accuracy of coronary computed tomography angiography (CTA) for bioresorbable vascular scaffold (BVS) evaluation. BACKGROUND: Coronary CTA has emerged as a noninvasive method to evaluate patients with suspected or established coronary artery disease. The diagnostic accuracy of coronary CTA to evaluate angiographic outcomes after BVS implantation has not been well established. METHODS: In the ABSORB II (A Bioresorbable Everolimus-Eluting Scaffold Versus a Metallic Everolimus-Eluting Stent II) study, patients were randomized either to receive treatment with the BVS or everolimus-eluting metallic stent. At the 3-year follow up, 238 patients (258 lesions) treated with BVS underwent coronary angiography with intravascular ultrasound (IVUS) evaluation and coronary CTA. The diagnostic accuracy of coronary CTA was assessed by the area under the receiver-operating characteristic curve with coronary angiography and IVUS as references. RESULTS: The mean difference in coronary CTA-derived minimal luminal diameter was -0.14 mm (limits of agreement -0.88 to 0.60) with quantitative coronary angiography as reference, whereas the mean difference in minimal lumen area was 0.73 mm2 (limits of agreement -1.85 to 3.30) with IVUS as reference. The per-scaffold diagnostic accuracy of coronary CTA for detecting stenosis based on coronary angiography diameter stenosis of >=50% revealed an area under the receiver-operating characteristic curve of 0.88 (95% confidence interval [CI]: 0.82 to 0.92) with a sensitivity of 80% (95% CI: 28% to 99%) and a specificity of 100% (95% CI: 98% to 100%), whereas diagnostic accuracy based on IVUS minimal lumen area <=2.5 mm2 showed an area under the receiver-operating characteristic curve of 0.83 (95% CI: 0.77 to 0.88) with a sensitivity of 71% (95% CI: 44% to 90%) and a specificity of 82% (95% CI: 75% to 87%). The diagnostic accuracy of coronary CTA was similar to coronary angiography in its ability to identify patients with a significant lesion based on the IVUS criteria (p = 0.75). CONCLUSIONS: Coronary CTA has good diagnostic accuracy to detect in-scaffold luminal obstruction and to assess luminal dimensions after BVS implantation. Coronary angiography and coronary CTA yielded similar diagnostic accuracy to identify the presence and severity of obstructive disease. Coronary CTA might become the method of choice for the evaluation of patients treated with BVS. PMID- 28734924 TI - The Many Dimensions of Diastolic Function: A Curse or a Blessing? PMID- 28734925 TI - Coronary CT Angiography and Bioresorbable Vascular Scaffolds: Is There Clarity? PMID- 28734926 TI - Derivation and Evaluation of Age-Specific Multivariate Reference Regions to Aid in Identification of Abnormal Filling Patterns: The HUNT and VaMIS Studies. AB - OBJECTIVES: This study aimed to derive age-specific multivariate reference regions (MVRs) able to classify subjects into those having normal or abnormal filling patterns and to evaluate the prognostic impact of this classification. BACKGROUND: The integration of several parameters is necessary to diagnose disorders of left ventricular (LV) filling because no single measurement accurately describes the complexity of diastolic function. However, no generally accepted validated multiparametric algorithm currently exists. METHODS: A cohort of 1,240 apparently healthy subjects from HUNT (Nord-Trondelag Health Study) with measured early (E) and late (A) mitral inflow velocity and early mitral annular diastolic tissue velocity (e') were used to derive univariate 95% reference bands and age-specific MVRs. Subsequently, the prognostic impact of this MVR-based classification was evaluated by Cox regression in a community-based cohort (n = 726) and in a cohort of subjects with recent acute myocardial infarction (n = 551). Both evaluation cohorts were derived from VaMIS (the Vastmanland Myocardial Infarction Study). RESULTS: Univariate reference bands and MVRs are presented graphically and as regression equations. After adjustment for sex, age, hypertension, body mass index, diabetes, prior ischemic heart disease, LV mass, LV ejection fraction, and left atrial size, the hazard ratio associated with abnormal filling patterns in the community-based cohort was 3.5 (95% confidence interval: 1.7 to 7.0; p < 0.001) and that in the acute myocardial infarction cohort was 1.8 (95% confidence interval: 1.1 to 2.8; p = 0.011). CONCLUSIONS: This study derived age-specific MVRs for identification of abnormal LV filling patterns and showed, in a community-based cohort and in a cohort of patients with recent acute myocardial infarction, that these MVRs conveyed important prognostic information. An MVR-based classification of LV filling patterns could lead to more consistent diagnostic algorithms for identification of different filling disorders. PMID- 28734927 TI - 4-Dimensionally Guided 3-Dimensional Color-Doppler Ultrasonography Quantifies Carotid Artery Stenosis With High Reproducibility and Accuracy. AB - OBJECTIVES: The purpose was to analyze the agreement and binary accuracy of the degree of internal carotid artery stenosis (ICAS) as determined by 4 dimensionally (4D) real-time gray-scale guided 3-dimensional (3D) color-Doppler ultrasonography (3DC-US) (4D/3DC-US) compared with catheter angiography (CA) and duplex ultrasonography (DUS). This study hypothesized that 4D/3DC-US is noninferior to CA and DUS in grading ICAS in selected patients. BACKGROUND: Clinical stratification in patients with ICAS largely depends on a patient's symptomatic status and the degree of stenosis. METHODS: Screening with 4D/3DC-US was prospectively performed in 93 study patients (with 122 ICASs), thus yielding 80 patients for analysis (with 103 ICASs) after excluding patients with insufficient image quality, previous revascularization, and contraindications to CA. The ultrasound examination (10 MHz) consisted of consensus conform DUS examination and independent real-time 4D-guided gray-scale views for orientation followed by static 3DC-US NASCET (North American Symptomatic Carotid Endarterectomy Trial) percent stenosis quantification using off-line multiplanar rendering. Multiplanar selective CA of the same ICASs was quantified with dedicated software in a blinded fashion. RESULTS: Quantitative CA of 103 stenoses with a mean degree of 65 +/- 17% was compared with 4D/3DC-US, with a resulting concordance correlation coefficient of 0.89 and a standard deviation of differences (SDD) of 8.1% at a bias of +1.7%. Binary 50% and 70% stenosis detection with 4D/3DC-US revealed a sensitivity of 97% and 87%, respectively, and a specificity of 92% and 84%, respectively. Interobserver SDD for CA of 52 stenoses (7.2%) did not differ from SDD for 4D/3DC-US and CA (p = 0.274). Accuracy of 50% stenosis detection by 4D/3DC-US was tendentially higher compared with DUS (96% vs. 91%). CONCLUSIONS: The 4D/3DC-US method provides reliable and accurate stenosis quantification and binary classification with good diagnostic accuracy compared with CA and DUS. PMID- 28734928 TI - LV Mass Independently Predicts Mortality and Need for Future Revascularization in Patients Undergoing Diagnostic Coronary Angiography. AB - OBJECTIVES: The goal of this study was to assess associations between left ventricular (LV) mass, all-cause mortality, and need for revascularization in patients undergoing coronary angiography. BACKGROUND: LV hypertrophy is associated with adverse cardiovascular outcomes in healthy subjects. However, its influence in those with known or suspected coronary artery disease is poorly understood. METHODS: A total of 3,754 patients (mean age 59.3 +/- 13.1 years) undergoing invasive coronary angiography and cardiac magnetic resonance (CMR) (mean interval 1.0 +/- 1.5 months) were studied. LV mass and volumes were determined from cine images and indexed to body surface area. Analyses were adjusted for CMR variables, medical comorbidities, and severity of coronary artery disease (Duke Jeopardy Score) and were stratified to LV function. RESULTS: At a median of 44.9 months, 315 patients (8.4%) died and 168 patients (4.5%) underwent revascularization. Multivariable analysis showed that each 10 g/m2 increase in LV mass index was associated with a 6% greater risk of mortality (hazard ratio: 1.06; 95% confidence interval [CI]: 1.01 to 1.11; p = 0.02) and a 10% greater need for revascularization (hazard ratio: 1.10; 95% CI: 1.04 to 1.17; p < 0.01). According to pre-defined thresholds, moderate to severe hypertrophy was associated with a 1.7-fold risk of mortality (95% CI: 1.2 to 2.3) and 1.8 fold need for revascularization (95% CI: 1.18 to 2.67). These findings were predominantly observed in those with a left ventricular ejection fraction >35% with respective hazard ratios of 2.93 (95% CI: 1.92 to 4.47) and 2.20 (95% CI: 1.21 to 3.98). CONCLUSIONS: LV mass index is an independent predictor of all cause mortality and need for revascularization. This finding establishes relevance for LV mass measurements in clinical decision-making surrounding both the need and timing of revascularization in this population. PMID- 28734929 TI - Aripiprazole prevents renal ischemia/reperfusion injury in rats, probably through nitric oxide involvement. AB - Renal ischemia/reperfusion (I/R) injury is strongly related to morbidity and mortality. Oxidative stress, inflammation, and apoptosis play key roles in renal dysfunction following renal I/R. Aripiprazole is an atypical antipsychotic which used for the treatment of schizophrenia and bipolar disorder. Recent studies have reported aripiprazole as displaying certain anti-inflammatory effects. Regarding the underlying mechanisms of renal ischemia-reperfusion, therefore, nephroprotective effects might be predicted to be seen with aripiprazole. I/R injury was induced by bilateral clamping of the renal pedicles (45min) followed by reperfusion (24h). The mechanism of aripiprazole-mediated nephroprotection was explored by a combined use of aripiprazole and L-NAME (non-selective nitric oxide synthase inhibitor). Animals were given aripiprazole (2.5, 5, 10 and 20mg/kg) intraperitoneally, 30min before ischemia. L-NAME was administered before the aripiprazole injection. Serum creatinine and blood urea nitrogen were assessed after 24h of reperfusion. Serum levels of malondialdehyde (MDA), TNF-alpha and IL 1beta were measured for rats treated with aripiprazole. The extent of necrosis was measured by the stereology method. Ischemia/reperfusion caused significant renal dysfunction and marked renal injury. Aripiprazole reduced creatinine and blood urea nitrogen. Serum levels of MDA, IL-1beta and TNF-alpha were significantly lower in the aripiprazole group. Aripiprazole treatment also decreased the volume of kidney necrosis. The administration of L-NAME reversed the renoprotective effect of aripiprazole on BUN and creatinine, but enhanced the anti-necrotic effect of aripiprazole. The results show that a single dose of aripiprazole significantly improved renal function following ischemia/reperfusion injury - probably through the involvement of nitric oxide. PMID- 28734930 TI - Bidirectional allosteric interactions between cannabinoid receptor 1 (CB1) and dopamine receptor 2 long (D2L) heterotetramers. AB - Type 1 cannabinoid (CB1) and dopamine 2 long form (D2L) receptors can physically interact to form heteromers that display unique pharmacology in vitro compared to homomeric complexes. Co-expression of CB1 and D2L and co-application of CB1 and D2 agonists increases cAMP levels while administration of either agonist alone decreases cAMP levels. To understand the observed co-agonist response, our first goal of the current study was to define the stoichiometry of CB1/D2L/Galpha protein complexes. Using bioluminescence resonance energy transfer 2 (BRET2), we confirmed that, CB1 homodimers, D2L homodimers, and CB1/D2L heteromers are formed. By using sequential resonance energy transfer 2 (SRET2) combined with bimolecular fluorescence complementation (BiFC), we were able to demonstrate that CB1/D2L form heterotetramers consisting of CB1 and D2L homodimers. We demonstrated that CB1/D2L heterotetramers are coupled to at least two Galpha proteins. The second aim of the study was to investigate allosteric effects of a D2L agonist (quinpirole) on CB1 receptor function and to investigate the effects of a CB1 agonist [arachidonyl-2-chloroethylamide (ACEA)] on D2L receptor function within CB1/D2L heterotetramers. Treating cells co-expressing CB1 and D2L with both ACEA and quinpirole switched CB1 and D2L receptor coupling and signaling from Galphai to Galphas proteins, enhanced beta-arrestin1 recruitment and receptor co-internalization. The concept of bidirectional allosteric interaction within CB1/D2 heterotetramers has important implications for understanding the activity of receptor complexes in native tissues and under pathological conditions. PMID- 28734931 TI - Piperlongumine inhibits TGF-beta-induced epithelial-to-mesenchymal transition by modulating the expression of E-cadherin, Snail1, and Twist1. AB - Cancer is a life-threatening disease, and the occurrence of metastasis, which increases the lethality of primary tumors, is increasing. The epithelial-to mesenchymal transition (EMT) is a biological process by which epithelial cells lose cell-cell adhesion properties and acquire mesenchymal properties, including motility and invasiveness. EMT is considered an early stage of metastasis; therefore, inhibiting EMT may be an effective anticancer therapy. In the present study, the antimetastatic effect of piperlongumine (PL) was assessed in human cancer cells. PL is a single component isolated from long pepper (Piper longum) and it has been studied for its antibacterial, antiangiogenic, and antidiabetic activities. Migration assays (wound healing assay) and transwell invasion assays showed that PL inhibited the migration and invasion of cancer cells. Western blotting and immunofluorescence imaging showed that TGF-beta upregulated the transcription factors Snail1 and Twist1 and downregulated E-cadherin, a marker of epithelial cells, inducing EMT. PL might inhibit TGF-beta-induced EMT by downregulating Snail1 and Twist1 and upregulating E-cadherin in cancer cells. In summary, PL might inhibit TGF-beta-induced EMT, suggesting that it is a promising anticancer agent. PMID- 28734932 TI - A pyridone derivative activates SERCA2a by attenuating the inhibitory effect of phospholamban. AB - The cardiac sarco/endoplasmic reticulum Ca2+-dependent ATPase 2a (SERCA2a) plays a central role in Ca2+ handling within cardiomyocytes and is negatively regulated by phospholamban (PLN), a sarcoplasmic reticulum (SR) membrane protein. The activation of SERCA2a, which has been reported to improve cardiac dysfunction in heart failure, is a potential therapeutic approach for heart failure. Therefore, we developed a novel small molecule, compound A and characterized it both in vitro and in vivo. Compound A activated the Ca2+-dependent ATPase activity of cardiac SR vesicles but not that of skeletal muscle SR vesicles that lack PLN. The surface plasmon resonance assay revealed a direct interaction between compound A and PLN, suggesting that the binding of compound A to PLN attenuates its inhibition of SERCA2a, resulting in SERCA2a activation. This was substantiated by inhibition of the compound A-mediated increase in Ca2+ levels within the SR of HL-1 cells by thapsigargin, a SERCA inhibitor. Compound A also increased the Ca2+ transients and contraction and relaxation of isolated adult rat cardiomyocytes. In isolated perfused rat hearts, the compound A enhanced systolic and diastolic functions. Further, an infusion of compound A (30mg/kg, i.v. bolus followed by 2mg/kg/min, i.v. infusion) significantly enhanced the diastolic function in anesthetized normal rats. These results indicate that compound A is a novel SERCA2a activator, which attenuates PLN inhibition and enhances the systolic and diastolic functions of the heart in vitro and in vivo. Therefore, compound A might be a novel therapeutic lead for heart failure. PMID- 28734933 TI - Photosystem II-cyclic electron flow powers exceptional photoprotection and record growth in the microalga Chlorella ohadii. AB - The desert microalga Chlorella ohadii was reported to grow at extreme light intensities with minimal photoinhibition, tolerate frequent de/re-hydrations, yet minimally employs antenna-based non-photochemical quenching for photoprotection. Here we investigate the molecular mechanisms by measuring Photosystem II charge separation yield (chlorophyll variable fluorescence, Fv/Fm) and flash-induced O2 yield to measure the contributions from both linear (PSII-LEF) and cyclic (PSII CEF) electron flow within PSII. Cells grow increasingly faster at higher light intensities (MUE/m2/s) from low (20) to high (200) to extreme (2000) by escalating photoprotection via shifting from PSII-LEF to PSII-CEF. This shifts PSII charge separation from plastoquinone reduction (PSII-LEF) to plastoquinol oxidation (PSII-CEF), here postulated to enable proton gradient and ATP generation that powers photoprotection. Low light-grown cells have unusually small antennae (332 Chl/PSII), use mainly PSII-LEF (95%) and convert 40% of PSII charge separations into O2 (a high O2 quantum yield of 0.06mol/mol PSII/flash). High light-grown cells have smaller antenna and lower PSII-LEF (63%). Extreme light-grown cells have only 42 Chl/PSII (no LHCII antenna), minimal PSII-LEF (10%), and grow faster than any known phototroph (doubling time 1.3h). Adding a synthetic quinone in excess to supplement the PQ pool fully uncouples PSII-CEF from its natural regulation and produces maximum PSII-LEF. Upon dark adaptation PSII-LEF rapidly reverts to PSII-CEF, a transient protection mechanism to conserve water and minimize the cost of antenna biosynthesis. The capacity of the electron acceptor pool (plastoquinone pool), and the characteristic times for exchange of (PQH2)B with PQpool and reoxidation of (PQH2)pool were determined. PMID- 28734934 TI - Analysis of RNA-protein interactions in vertebrate embryos using UV crosslinking approaches. AB - A decade ago, we believed that at least 300 RNA binding proteins (RBPs) were encoded in our genomes based on annotations of known or predicted RNA binding domains. Deciphering the roles of those RBPs in regulated gene expression was a vast frontier awaiting exploration. Since then, the field has developed a number of key tools that navigate the landscape of cellular RNA. These rely principally on UV crosslinking to create covalent bonds between RBPs and target RNAs in vivo, revealing not only target identities but also local binding sites upon RNA-Seq. More recently, a reverse protocol - mRNA interactome capture - has enabled the identification of the proteins that interact with mRNA. Astonishingly, the number of RBPs has grown to more than 1000, and we must now understand what they do. Here, we discuss the application of these methods to model organisms, focusing on the zebrafish Danio rerio, which provide unique biological contexts for the analysis of RBPs and their functions. PMID- 28734935 TI - Outcome of lung transplantation in idiopathic pulmonary fibrosis with previous anti-fibrotic therapy. AB - BACKGROUND: Anti-fibrotic drugs may interfere with wound-healing after major surgery, theoretically preventing sufficient bronchial anastomosis formation after lung transplantation (LTx). The aim of this study was to assess the impact of previous treatment with pirfenidone and nintedanib on outcomes after LTx in patients with idiopathic pulmonary fibrosis (IPF). METHODS: All patients with IPF undergoing LTx at the University of Munich between January 2012 and November 2016 were retrospectively screened for previous use of anti-fibrotics. Post-transplant outcome and survival of patients with and without anti-fibrotic treatment were analyzed. RESULTS: A total of 62 patients with IPF were transplanted (lung allocation score [mean +/- SD] 53.1 +/- 16.1). Of these, 23 (37.1%) received pirfenidone and 7 (11.3%) received nintedanib before LTx; the remaining 32 (51.6%) did not receive any anti-fibrotic drug (control group). Patients receiving anti-fibrotics were significantly older (p = 0.004) and their carbon monoxide diffusion capacity was significantly higher (p = 0.008) than in controls. Previous anti-fibrotic treatment did not increase blood product utilization, wound-healing or anastomotic complications after LTx. Post transplant surgical revisions due to bleeding and/or impaired wound-healing were necessary in 18 (29.0%) patients (pirfenidone 30.4%, nintedanib 14.3%, control 31.3%; p = 0.66). Anastomosis insufficiency occurred in 2 (3.2%) patients, both in the control group. No patient died within the first 30 days post-LTx, and no significant differences regarding survival were seen during the follow-up (12 month survival: pirfenidone 77.0%, nintedanib 100%, control 90.6%; p = 0.29). CONCLUSION: Our data show that previous use of anti-fibrotic therapy does not increase surgical complications or post-operative mortality after LTx. PMID- 28734936 TI - Rehabilitation Interventions for Upper Limb Function in the First Four Weeks Following Stroke: A Systematic Review and Meta-Analysis of the Evidence. AB - OBJECTIVE: To investigate the therapeutic interventions reported in the research literature and synthesize their effectiveness in improving upper limb (UL) function in the first 4 weeks poststroke. DATA SOURCES: Electronic databases and trial registries were searched from inception until June 2016, in addition to searching systematic reviews by hand. STUDY SELECTION: Randomized controlled trials (RCTs), controlled trials, and interventional studies with pre/posttest design were included for adults within 4 weeks of any type of stroke with UL impairment. Participants all received an intervention of any physiotherapeutic or occupational therapeutic technique designed to address impairment or activity of the affected UL, which could be compared with usual care, sham, or another technique. DATA EXTRACTION: Two reviewers independently assessed eligibility of full texts, and methodological quality of included studies was assessed using the Cochrane Risk of Bias Tool. DATA SYNTHESIS: A total of 104 trials (83 RCTs, 21 nonrandomized studies) were included (N=5225 participants). Meta-analyses of RCTs only (20 comparisons) and narrative syntheses were completed. Key findings included significant positive effects for modified constraint-induced movement therapy (mCIMT) (standardized mean difference [SMD]=1.09; 95% confidence interval [CI], .21-1.97) and task-specific training (SMD=.37; 95% CI, .05-.68). Evidence was found to support supplementary use of biofeedback and electrical stimulation. Use of Bobath therapy was not supported. CONCLUSIONS: Use of mCIMT and task specific training was supported, as was supplementary use of biofeedback and electrical simulation, within the acute phase poststroke. Further high-quality studies into the initial 4 weeks poststroke are needed to determine therapies for targeted functional UL outcomes. PMID- 28734937 TI - Longitudinal Examination of Resilience After Traumatic Brain Injury: A Traumatic Brain Injury Model Systems Study. AB - OBJECTIVES: To evaluate (1) the trajectory of resilience during the first year after a moderate-severe traumatic brain injury (TBI); (2) factors associated with resilience at 3, 6, and 12 months postinjury; and (3) changing relationships over time between resilience and other factors. DESIGN: Longitudinal analysis of an observational cohort. SETTING: Five inpatient rehabilitation centers. PARTICIPANTS: Patients with TBI (N=195) enrolled in the resilience module of the TBI Model Systems study with data collected at 3-, 6-, and 12-month follow-up. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: Connor-Davidson Resilience Scale. RESULTS: Initially, resilience levels appeared to be stable during the first year postinjury. Individual growth curve models were used to examine resilience over time in relation to demographic, psychosocial, and injury characteristics. After adjusting for these characteristics, resilience actually declined over time. Higher levels of resilience were related to nonminority status, absence of preinjury substance abuse, lower anxiety and disability level, and greater life satisfaction. CONCLUSIONS: Resilience is a construct that is relevant to understanding brain injury outcomes and has potential value in planning clinical interventions. PMID- 28734938 TI - Hepatitis E virus infection and acute non-traumatic neurological injury: A prospective multicentre study. AB - BACKGROUND & AIMS: Hepatitis E virus (HEV) has been associated with a number of neurological syndromes, but causality has not yet been established. The aim of this study was to explore the relationship between HEV and neurological illness by prospective HEV testing of patients presenting with acute non-traumatic neurological injury. METHODS: Four hundred and sixty-four consecutive patients presenting to hospital with acute non-traumatic neurological illnesses were tested for HEV by serology and PCR from four centres in the UK, France and the Netherlands. RESULTS: Eleven of 464 patients (2.4%) had evidence of current/recent HEV infection. Seven had HEV RNA identified in serum and four were diagnosed serologically. Neurological cases in which HEV infection was found included neuralgic amyotrophy (n=3, all PCR positive); cerebral ischemia or infarction (n=4); seizure (n=2); encephalitis (n=1); and an acute combined facial and vestibular neuropathy (n=1). None of these cases were clinically jaundiced and median ALT at presentation was 24IU/L (range 8-145). Cases of HEV-associated neuralgic amyotrophy were found in each of the participating countries: all were middle-aged males with bilateral involvement of the brachial plexus. CONCLUSIONS: In this cohort of patients with non-traumatic neurological injury, 2.4% had evidence of HEV infection. Symptoms of hepatitis were mild or absent and no patients were jaundiced. The cases of HEV-associated neuralgic amyotrophy had similarities with other HEV-associated cases described in a large retrospective study. This observation supports a causal relationship between HEV and neuralgic amyotrophy. To further understand the relevance of HEV infection in patients with acute neurological illnesses, case-control studies are warranted. Lay summary: Hepatitis E virus (HEV), as its name suggests, is a hepatotropic virus, i.e. it causes damage to the liver (hepatitis). Our findings show that HEV can also be associated with a range of injury to the nervous system. PMID- 28734939 TI - Acetaminophen (APAP) hepatotoxicity-Isn't it time for APAP to go away? AB - Acetaminophen (APAP) is the most commonly used drug for the treatment of pain and fever around the world. At the same time, APAP can cause dose-related hepatocellular necrosis, responsible for nearly 500 deaths annually in the United States (US) alone, as well as 100,000 calls to US Poison Control Centers, 50,000 emergency room visits and 10,000 hospitalisations per year. As an over-the counter and prescription product (with opioids), APAP toxicity dwarfs all other prescription drugs as a cause of acute liver failure in the US and Europe, but it is not regulated in any significant way. In this review the ongoing controversy surrounding the proper role for this ubiquitous pain reliever: its history, pathogenesis, clinical challenges in recognition and management, and current regulatory status are highlighted. A new solution to a 50-year-old problem is proposed. PMID- 28734940 TI - Role of orbitofrontal sulcogyral pattern on lifetime cannabis use and depressive symptoms. AB - Orbitofrontal cortex (OFC) sulcogyral patterns are stable morphological variations established early in life. They consist of three distinct pattern types, with Type III in particular being associated with poor regulatory control (e.g., high sensation seeking and negative emotionality, low constraint), which may confer risk for earlier onset of cannabis (CB) use and greater use in later life. The OFC sulcogyral pattern may therefore be a stable trait marker in understanding individual differences in substance-use vulnerability and associated affective disturbances in users. In a large multisite cross-sectional study, we compared OFC pattern type distribution between 128 healthy controls (HC) and 146 CB users. Within users (n=140), we explored the association between OFC pattern type and CB use level, and subsequently if level of CB use informed by OFC pattern type may mediate disturbances in affective tone, as indexed by depressive symptoms. While OFC pattern distribution did not distinguish between HC and CB groups, it informed greater lifetime use within users. Specifically, CB users with pattern Type III in the right OFC tended to use more CB over their lifetime, than did CB users with pattern Type I or II. Greater lifetime CB use was subsequently associated with higher depressive symptoms, such that it mediated an indirect association between right OFC pattern Type III and higher depressive symptoms. The present study provides evidence for neurobiological differences, specifically sulcogyral pattern of the OFC, to modulate level of CB use, which may subsequently influence the expression of depressive symptoms. PMID- 28734941 TI - Sleep, chronic pain, and opioid risk for apnea. AB - Pain is an unwelcome sleep partner. Pain tends to erode sleep quality and alter the sleep restorative process in vulnerable patients. It can contribute to next day sleepiness and fatigue, affecting cognitive function. Chronic pain and the use of opioid medications can also complicate the management of sleep disorders such as insomnia (difficulty falling and/or staying asleep) and sleep-disordered breathing (sleep apnea). Sleep problems can be related to various types of pain, including sleep headache (hypnic headache, cluster headache, migraine) and morning headache (transient tension type secondary to sleep apnea or to sleep bruxism or tooth grinding) as well as periodic limb movements (leg and arm dysesthesia with pain). Pain and sleep management strategies should be personalized to reflect the patient's history and ongoing complaints. Understanding the pain-sleep interaction requires assessments of: i) sleep quality, ii) potential contributions to fatigue, mood, and/or wake time functioning; iii) potential concomitant sleep-disordered breathing (SDB); and more importantly; iv) opioid use, as central apnea may occur in at-risk patients. Treatments include sleep hygiene advice, cognitive behavioral therapy, physical therapy, breathing devices (continuous positive airway pressure - CPAP, or oral appliance) and medications (sleep facilitators, e.g., zolpidem; or antidepressants, e.g., trazodone, duloxetine, or neuroleptics, e.g., pregabalin). In the presence of opioid-exacerbated SDB, if the dose cannot be reduced and normal breathing restored, servo-ventilation is a promising avenue that nevertheless requires close medical supervision. PMID- 28734942 TI - Calcium/calmodulin-dependent protein kinase IV gene polymorphisms in Korean alcohol-dependent patients. AB - INTRODUCTION: A relationship between alcohol dependence (AD) and calcium/calmodulin-dependent protein kinase IV (CAMKIV) has been reported in a whole genome study of Korean AD patients. The purpose of the present study is to compare the frequency of CAMKIV genotypes and alleles between AD and control subjects in Korea. METHODS: The present study includes 281 AD patients and 139 control subjects. Seven single nucleotide polymorphism of CAMKIV gene known to show significant separation ratio in Asians were searched in SNP database and previous studies related to CAMKIV gene. Polymerase chain reaction and restriction fragment length polymorphism techniques were used to analyze genotype of CAMKIV gene SNPs. RESULTS: Major TT genotype and T allele frequencies of rs 25917 in AD patients were significantly higher than those of control subjects (genotype frequency, p=0.002; allele frequency, p=0.001). Major CC genotype and C allele frequencies of rs 117590959 in AD patients were also significantly higher than those of control subjects (genotype frequency, p<0.001; allele frequency, p=0.001). Major genotypes of rs25917 (p=0.002, odd ratio: 3.13, 95% CI: 1.54 6.38) and rs11790959 (p=0.002, odd ratio: 3.22, 95% CI: 1.52-6.81) showed significantly higher odds ratios associated with AD than minor genotypes in logistic regression. DISCUSSION: These results suggest that CAMKIV might be a candidate AD gene. Further research is needed to determine the precise relationship between CAMKIV and AD and the function of each SNP. PMID- 28734943 TI - Deficits in Col5a2 Expression Result in Novel Skin and Adipose Abnormalities and Predisposition to Aortic Aneurysms and Dissections. AB - Classic Ehlers-Danlos syndrome (cEDS) is characterized by fragile, hyperextensible skin and hypermobile joints. cEDS can be caused by heterozygosity for missense mutations in genes COL5A2 and COL5A1, which encode the alpha2(V) and alpha1(V) chains, respectively, of collagen V, and is most often caused by COL5A1 null alleles. However, COL5A2 null alleles have yet to be associated with cEDS or other human pathologies. We previously showed that mice homozygous null for the alpha2(V) gene Col5a2 are early embryonic lethal, whereas haploinsufficiency caused aberrancies of adult skin, but not a frank cEDS-like phenotype, as skin hyperextensibility at low strain and dermal cauliflower-contoured collagen fibril aggregates, two cEDS hallmarks, were absent. Herein, we show that ubiquitous postnatal Col5a2 knockdown results in pathognomonic dermal cauliflower-contoured collagen fibril aggregates, but absence of skin hyperextensibility, demonstrating these cEDS hallmarks to arise separately from loss of collagen V roles in control of collagen fibril growth and nucleation events, respectively. Col5a2 knockdown also led to loss of dermal white adipose tissue (WAT) and markedly decreased abdominal WAT that was characterized by miniadipocytes and increased collagen deposition, suggesting alpha2(V) to be important to WAT development/maintenance. More important, Col5a2 haploinsufficiency markedly increased the incidence and severity of abdominal aortic aneurysms, and caused aortic arch ruptures and dissections, indicating that alpha2(V) chain deficits may play roles in these pathologies in humans. PMID- 28734945 TI - The Epigenomic Revolution in Breast Cancer: From Single-Gene to Genome-Wide Next Generation Approaches. AB - From the first identification of aberrant DNA methylation in primary tumors in humans more than 3 decades ago, progress in cancer epigenetics research has been exponential. For many years, cancer epigenetics studies relied on the identification of DNA methylation and histone modifications at specific genes. Those studies laid the foundation for the field and revealed the epigenetic alterations as hallmarks of cancer, as well as the crucial role of epigenetic mechanisms in tumorigenesis. The introduction of next-generation sequencing and array-based technologies for analyzing epigenetic states has accelerated our understanding about cancer and have become potent tools in our fight against the disease. Findings emerging from epigenome-wide analyses have led to new discoveries with remarkable clinical applications. This review summarizes the gene-specific epigenetic alterations common in breast cancer and discusses the recent advances in breast cancer epigenomics, focusing on their contribution to diagnosis, prognosis, patient stratification, and treatment of the disease. PMID- 28734944 TI - Triple-Negative Breast Cancer: Next-Generation Sequencing for Target Identification. AB - Presently, the ability to study disease at the most fundamental molecular level has led to a reclassification of human cancers into numerous subtypes that vary in disease progression and response to therapy. Similar to most solid tumors, breast cancer is a heterogeneous disease with considerable variation in histologic and biological features. Triple-negative breast cancer (TNBC) is a subtype of breast cancer in which the estrogen receptor and progesterone receptor are not expressed, and human epidermal growth factor-receptor 2 is not amplified or overexpressed. Data derived from highly complex molecular technologies, such as microarrays and next-generation sequencing, have identified gene expression and somatic mutation profile subsets of TNBC that reflect biological behavior more accurately and may lead to further effective therapeutic targets, better prognosis, and improved outcomes. Herein, we review the genomic findings of TNBC and discuss current efforts in precision medicine as they relate to TNBC. PMID- 28734946 TI - Impaired Rhodopsin Generation in the Rat Model of Diabetic Retinopathy. AB - Diabetic retinopathy is a common complication of diabetes mellitus. Diabetic patients experience functional deficits in dark adaptation, contrast sensitivity, and color perception before microvascular pathologies become apparent. Herein, we evaluated early changes in neural retinal function and in retinoid metabolism in the eye in diabetes. Streptozotocin-induced diabetic rats showed decreased a- and b-wave amplitudes of scotopic and photopic electroretinography responses 4 months after diabetes induction compared to nondiabetic controls. Although Western blot analysis revealed no difference in opsin expression, rhodopsin content was decreased in diabetic retinas, as shown by a difference in absorbance. Consistently, levels of 11-cis-retinal, the chromophore for visual pigments, were significantly lower in diabetic retinas compared to those in controls, suggesting a retinoid deficiency. Among visual cycle proteins, interphotoreceptor retinoid binding protein and stimulated by retinoic acid 6 protein showed significantly lower levels in diabetic rats than those in nondiabetic controls. Similarly, serum levels of retinol-binding protein 4 and retinoids were significantly lower in diabetic rats. Overall, these results suggest that retinoid metabolism in the eye is impaired in type 1 diabetes, which leads to deficient generation of visual pigments and neural retinal dysfunction in early diabetes. PMID- 28734948 TI - The Effectiveness of a Simulation-Based Flipped Classroom in the Acquisition of Laparoscopic Suturing Skills in Medical Students-A Pilot Study. AB - OBJECTIVE: To evaluate the effectiveness of a simulation-based flipped classroom in gaining the laparoscopic skills in medical students. DESIGN: An intervention trial. SETTING: Taipei Medical University Hospital, an academic teaching hospital. PARTICIPANTS AND METHODS: Fifty-nine medical students participating in a 1-hour laparoscopic skill training session were randomly assigned to a conventional classroom (n = 29) or a flipped classroom approach (n = 30) based on their registered order. At the end of the session, instructors assessed participants' performance in laparoscopic suturing and intracorporeal knot-tying using the assessment checklist based on a modified Objective Structured Assessment of Technical Skills tool. RESULTS: Students in the flipped group completed more numbers of stitches (mean [M] = 0.47; standard deviation [SD] = 0.507) than those in the conventional group (M = 0.10; SD = 0.310) (mean difference: 0.37; 95% CI: 0.114-582; p = 0.002). Moreover, students in the flipped group also had higher stitch quality scores (M = 7.17; SD = 2.730) than those in the conventional group (M = 5.14; SD = 1.767) (mean difference = 2.03; 95% CI: 0.83-3.228; p = 0.001). Meanwhile, students in the flipped group had higher pass rates for the second throw (p < 0.001), third throw (p = 0.002), appropriate tissue reapproximation without loosening or strangulation (p < 0.001), needle cut from suture under direct visualization (p = 0.004), and needle safely removed under direct visualization (p = 0.018) than those in the conventional group. CONCLUSIONS: Comparing with traditional approach, a simulation-based flipped classroom approach may improve laparoscopic intracorporeal knot-tying skill acquisition in medical students. PMID- 28734947 TI - Platelet-Derived Growth Factor Receptor alpha Contributes to Human Hepatic Stellate Cell Proliferation and Migration. AB - Platelet-derived growth factor receptor alpha (PDGFRalpha), a tyrosine kinase receptor, is up-regulated in hepatic stellate cells (HSCs) during chronic liver injury. HSCs mediate hepatic fibrosis through their activation from a quiescent state partially in response to profibrotic growth factors. HSC activation entails enhanced expression of profibrotic genes, increase in proliferation, and increase in motility, which facilitates migration within the hepatic lobule. We show colocalization of PDGFRalpha in murine carbon tetrachloride, bile duct ligation, and 0.1% 3,5-diethoxycarbonyl-1,4-dihydrocollidine models of chronic liver injury, and investigate the role of PDGFRalpha on proliferation, profibrotic gene expression, and migration in primary human HSCs (HHSteCs) using the PDGFRalpha specific inhibitory monoclonal antibody olaratumab. Although lacking any effects on HHSteC transdifferentiation assessed by gene expression of ACTA2, TGFB1, COL1A1, SYP1, and FN1, olaratumab specifically reduced HHSteC proliferation (AlamarBlue assay) and cell migration (transwell migration assays). Using phospho specific antibodies, we show that olaratumab attenuates PDGFRalpha activation in response to PDGF-BB, and reduced phosphorylation of extracellular signal regulated kinase 1 and 2, Elk-1, p38, Akt, focal adhesion kinase, mechanistic target of rapamycin, C10 regulator of kinase II, and C10 regulator of kinase like, suggesting that PDGFRalpha contributes to mitogenesis and actin reorganization through diverse downstream effectors. Our findings support a distinct contribution of PDGFRalpha signaling to HSC proliferation and migration and provide evidence that inhibition of PDGFRalpha signaling could alter the pathogenesis of hepatic fibrosis. PMID- 28734949 TI - The Program Evaluation Committee in Action: Lessons Learned From a General Surgery Residency's Experience. AB - OBJECTIVE: To evaluate the success of the annual program evaluation process and describe the experience of a Program Evaluation Committee for a General Surgery residency program. DESIGN: We conducted a retrospective review of the Program Evaluation Committee's meeting minutes, data inputs, and outcomes from 2014 to 2016. We identified top priorities by year, characterized supporting data, summarized the improvement plans and outcome measures, and evaluated whether the outcomes were achieved at 1 year. SETTING: Virginia Mason Medical Center General Surgery Residency Program. PARTICIPANTS: Program Evaluation Committee members including the Program Director, 2 Associate Program Directors, 2 Senior Faculty Members, and 1 Resident. RESULTS: All outcome measures were achieved or still in progress at 1 year. This included purchasing a GI mentor to improve endoscopic simulation training, establishing an outpatient surgery rotation to increase the volume of cases, and implementing a didactic course on adult learning principles for faculty development to improve intraoperative teaching. Primary reasons for slow progress were lack of follow-through by delegates or communication breakdown. CONCLUSIONS: The annual program evaluation process has been successful in identifying top priorities, developing action plans, and achieving outcome measures using our systematic evaluation process. PMID- 28734950 TI - Management of undescended testes: European Association of Urology/European Society for Paediatric Urology guidelines. PMID- 28734951 TI - Emergency Department Management of Diabetic Ketoacidosis and Hyperosmolar Hyperglycemic State in Adults: National Survey of Attitudes and Practice. AB - OBJECTIVES: In 2013, the Canadian Diabetes Association, now Diabetes Canada, published national clinical practice guidelines for the effective management of diabetic ketoacidosis and hyperosmolar hyperglycemic states in adults. We sought to determine emergency physician compliance rates and attitudes toward these guidelines and to identify potential barriers to their use in Canadian emergency departments. METHODS: An online survey consisting of questions related to the awareness and use of the Canadian Diabetes Association 2013 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada was distributed to 500 randomly selected members of the Canadian Association of Emergency Physicians. Also included in the survey were 3 clinical vignettes to assess adherence rates to the guidelines. RESULTS: The survey response rate was 62.2% (311 of 500). The majority of physicians reported the guidelines to be useful (83.6%); 54.6% of respondents were familiar with the guidelines, and 54.7% claimed to use them in clinical practice. The most frequently reported barrier to guideline implementation was a lack of education (56.0%). The clinical vignettes demonstrated respondent variability in fluid administration and sodium bicarbonate administration, as well as some variability in insulin and potassium administration. CONCLUSIONS: Although Canadian emergency physicians were generally supportive of the guidelines, many were unaware that these guidelines existed, and barriers to their implementation were reported. These results suggest the need to improve knowledge translation strategies across Canadian emergency departments to standardize management of diabetic ketoacidosis and hyperosmolar hyperglycemic states and support the highest quality of patient care, as well as to ensure that future guidelines include management strategies applicable to the emergency department setting. PMID- 28734952 TI - Potential Predictive Role of Lipid Peroxidation Markers for Type 2 Diabetes in the Adult Tunisian Population. AB - OBJECTIVES: We evaluated the potential clinical relevance of malondialdehyde (MDA) and autoantibodies to copper oxidized low-density lipoprotein (CuOx-LDL) in type 2 diabetes occurrence. METHODS: This cross-sectional study enrolled 69 normoglycemic subjects, 18 prediabetic patients and 108 type 2 diabetes patients. MDA concentration was assessed spectrophotometrically. Plasma IgG, IgA and IgM levels to CuOx-LDL were determined by ELISA. RESULTS: Plasma MDA levels were considerably higher in obese, prediabetic and type 2 diabetes subjects compared to controls. In multiple linear regression analysis, both MDA and IgA to CuOx-LDL were significantly associated with glucose metabolism markers (p<0.05). Multiple logistic regression analyses showed that high plasma MDA and IgA to CuOx-LDL were independent risk factors for type 2 diabetes (OR 1.196, 95% CI: 1.058 to 1.353; p=0.004; OR 1.626, 95% CI: 1.066 to 2.481; p=0.024; respectively). Importantly, elevated IgA to CuOx-LDL predicted incident diabetes in patients with prediabetes (OR 2.321, 95% CI:1.063 to 5.066; p=0.035). From stratified analyses by body mass index (BMI), both MDA and IgA to CuOx-LDL remained independent predictors of type 2 diabetes occurrence in non-obese subjects (p<0.05). More interesting, elevated IgA to CuOx-LDL levels could be predictors of type 2 diabetes in obese prediabetic subjects (p=0.044). Conversely, neither IgG nor IgM to CuOx-LDL was associated with glucose metabolism markers, obesity or type 2 diabetes. CONCLUSIONS: Plasma MDA and IgA to CuOx-LDL were significantly associated with blood markers of glucose metabolism. High levels of MDA and IgA to CuOx-LDL could independently predict type 2 diabetes development in normoglycemia and prediabetic subjects. PMID- 28734953 TI - Estimating relative mitochondrial DNA copy number using high throughput sequencing data. AB - We hypothesize that the relative mitochondria copy number (MTCN) can be estimated by comparing the abundance of mitochondrial DNA to nuclear DNA reads using high throughput sequencing data. To test this hypothesis, we examined relative MTCN across 13 breast cancer cell lines using the RT-PCR based NovaQUANT Human Mitochondrial to Nuclear DNA Ratio Kit as the gold standard. Six distinct computational approaches were used to estimate the relative MTCN in order to compare to the RT-PCR measurements. The results demonstrate that relative MTCN correlates well with the RT-PCR measurements using exome sequencing data, but not RNA-seq data. Through analysis of copy number variants (CNVs) in The Cancer Genome Atlas, we show that the two nuclear genes used in the NovaQUANT assay to represent the nuclear genome often experience CNVs in tumor cells, questioning the accuracy of this gold-standard method when it is applied to tumor cells. PMID- 28734954 TI - Sparse MRI reconstruction using multi-contrast image guided graph representation. AB - Accelerating the imaging speed without sacrificing image structures plays an important role in magnetic resonance imaging. Under-sampling the k-space data and reconstructing the image with sparsity constraint is one efficient way to reduce the data acquisition time. However, achieving high acceleration factor is challenging since image structures may be lost or blurred when the acquired information is not sufficient. Therefore, incorporating extra knowledge to improve image reconstruction is expected for highly accelerated imaging. Fortunately, multi-contrast images in the same region of interest are usually acquired in magnetic resonance imaging protocols. In this work, we propose a new approach to reconstruct magnetic resonance images by learning the prior knowledge from these multi-contrast images with graph-based wavelet representations. We further formulate the reconstruction as a bi-level optimization problem to allow misalignment between these images. Experiments on realistic imaging datasets demonstrate that the proposed approach improves the image reconstruction significantly and is practical for real world application since patients are unnecessarily to stay still during successive reference image scans. PMID- 28734955 TI - Predicting the nodal status in gastric cancers: The role of apparent diffusion coefficient histogram characteristic analysis. AB - PURPOSE: To explore the application of histogram analysis in preoperative T and N staging of gastric cancers, with a focus on characteristic parameters of apparent diffusion coefficient (ADC) maps. MATERIALS AND METHODS: Eighty-seven patients with gastric cancers underwent diffusion weighted magnetic resonance imaging (b=0, 1000s/mm2), which generated ADC maps. Whole-volume histogram analysis was performed on ADC maps and 7 characteristic parameters were obtained. All those patients underwent surgery and postoperative pathologic T and N stages were determined. RESULTS: Four parameters, including skew, kurtosis, s-sDav and sample number, showed significant differences among gastric cancers at different T and N stages. Most parameters correlated with T and N stages significantly and worked in differentiating gastric cancers at different T or N stages. Especially skew yielded a sensitivity of 0.758, a specificity of 0.810, and an area under the curve (AUC) of 0.802 for differentiating gastric cancers with and without lymph node metastasis (P<0.001). All the parameters, except AUClow, showed good or excellent inter-observer agreement with intra-class correlation coefficients ranging from 0.710 to 0.991. CONCLUSION: Characteristic parameters derived from whole-volume ADC histogram analysis could help assessing preoperative T and N stages of gastric cancers. PMID- 28734956 TI - Fast carotid artery MR angiography with compressed sensing based three dimensional time-of-flight sequence. AB - OBJECTIVE: In this study, we sought to investigate the feasibility of fast carotid artery MR angiography (MRA) by combining three-dimensional time-of-flight (3D TOF) with compressed sensing method (CS-3D TOF). MATERIALS AND METHODS: A pseudo-sequential phase encoding order was developed for CS-3D TOF to generate hyper-intense vessel and suppress background tissues in under-sampled 3D k-space. Seven healthy volunteers and one patient with carotid artery stenosis were recruited for this study. Five sequential CS-3D TOF scans were implemented at 1, 2, 3, 4 and 5-fold acceleration factors for carotid artery MRA. Blood signal-to tissue ratio (BTR) values for fully-sampled and under-sampled acquisitions were calculated and compared in seven subjects. Blood area (BA) was measured and compared between fully sampled acquisition and each under-sampled one. RESULTS: There were no significant differences between the fully-sampled dataset and each under-sampled in BTR comparisons (P>0.05 for all comparisons). The carotid vessel BAs measured from the images of CS-3D TOF sequences with 2, 3, 4 and 5-fold acceleration scans were all highly correlated with that of the fully-sampled acquisition. The contrast between blood vessels and background tissues of the images at 2 to 5-fold acceleration is comparable to that of fully sampled images. The images at 2* to 5* exhibit the comparable lumen definition to the corresponding images at 1*. CONCLUSION: By combining the pseudo-sequential phase encoding order, CS reconstruction, and 3D TOF sequence, this technique provides excellent visualizations for carotid vessel and calcifications in a short scan time. It has the potential to be integrated into current multiple blood contrast imaging protocol. PMID- 28734957 TI - Effect of schwertmannite and jarosite on the formation of hypoxic blackwater during inundation of grass material. AB - This study focused on understanding the effect of schwertmannite and jarosite, commonly found in floodplains containing acid sulfate soil materials, on the characteristics of the hypoxic blackwaters that can form when floodplain vegetation experiences prolonged inundation. The formation of these 'blackwaters' was simulated in the laboratory by inundating flood-intolerant pasture grass leaf material in both the presence of schwertmannite/jarosite (schwertmannite and jarosite treatments) minerals and their absence (control treatment) at 27.5 degrees C for 32 days. The presence of either schwertmannite or jarosite was able to decrease the concentrations of DOC, nutrients (e.g. NH3 and PO43-) and the biological oxygen demand (BOD) in the incubating water compared to the control treatment. Being fresh and labile, the pasture grass material liberated DOC immediately following inundation with a concomitant decrease in dissolved O2 thereby resulting in anoxic and reducing conditions in the incubating water. With the onset of anoxic and reducing conditions, the biogeochemical cycling of DOC in schwertmannite and jarosite treatments might have proceeded via microbially mediated iron(III) and sulfate reduction and electron shuttling processes. Under anoxic, slightly acidic conditions, microbially mediated iron(III) reduction and subsequent dissolution of schwertmannite and jarosite were triggered by liberating Fe2+, SO42- and alkalinity to the incubating water. The resultant increase in pH led to SO42- reduction in schwertmannite, and the Fe2+ catalysed transformation of both schwertmannite and jarosite to goethite. Schwertmannite almost completely transformed to goethite within two weeks of incubation. Iron(III) in goethite (formed from schwertmannie transformation) was also reduced and likely proceeded via direct microbial reduction or via electron shuttling using the humic acids in the incubating water derived from pasture grass. These findings are highly useful in managing the coastal low lying acid sulfate soils landscapes which are subject to frequent flooding during wet seasons. PMID- 28734958 TI - The relative importance of water temperature and residence time in predicting cyanobacteria abundance in regulated rivers. AB - Despite a growing awareness of the problems associated with cyanobacterial blooms in rivers, and particularly in regulated rivers, the drivers of bloom formation and abundance in rivers are not well understood. We developed a Bayesian hierarchical model to assess the relative importance of predictors of summer cyanobacteria abundance, and to test whether the relative importance of each predictor varies by site, using monitoring data from 16 sites in the four major rivers of South Korea. The results suggested that temperature and residence time, but not nutrient levels, are important predictors of summer cyanobacteria abundance in rivers. Although the two predictors were of similar significance across the sites, the residence time was marginally better in accounting for the variation in cyanobacteria abundance. The model with spatial hierarchy demonstrated that temperature played a consistently significant role at all sites, and showed no effect from site-specific factors. In contrast, the importance of residence time varied significantly from site to site. This variation was shown to depend on the trophic state, indicated by the chlorophyll a and total phosphorus levels. Our results also suggested that the magnitude of weir inflow is a key factor determining the cyanobacteria abundance under baseline conditions. PMID- 28734959 TI - Removal of both N-nitrosodimethylamine and trihalomethanes precursors in a single treatment using ion exchange resins. AB - Drinking water utilities are relying more than ever on water sources impacted by wastewater effluents. Disinfection/oxidation of these waters during water treatment may lead to the formation of several disinfection by-products, including the probable human carcinogen N-nitrosodimethylamine (NDMA) and the regulated trihalomethanes (THMs). In this study, the potential of ion exchange resins to control both NDMA and THMs precursors in a single treatment is presented. Two ion exchange resins were examined, a cation exchange resin (Plus) to target NDMA precursors and an anion exchange resin (MIEX) for THMs precursors control. We applied the resins, individually and combined, in the treatment of surface and wastewater effluent samples. The treatment with both resins removed simultaneously NDMA (43-85%) and THMs (39-65%) precursors. However, no removal of NDMA precursors was observed in the surface water with low initial NDMA FP (14 ng/L). The removals of NDMA FP and THMs FP with Plus and MIEX resins applied alone were (49-90%) and (41-69%), respectively. These results suggest no interaction between the resins, and thus the feasibility of effectively controlling NDMA and THMs precursors concomitantly. Additionally, the effects of the wastewater impact and the natural attenuation of precursors were studied. The results showed that neither the wastewater content nor the attenuation of the precursor affected the removals of NDMA and THMs precursors. Finally, experiments using a wastewater effluent sample showed that an increase in the calcium concentration resulted in a reduction in the removal of NDMA precursors of about 50%. PMID- 28734960 TI - Pharmacokinetic interactions of curcuminoids with conventional drugs: A review. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Herb-drug interactions are of great concern in health practices. Curcumin is a natural polyphenol extracted from turmeric, a spice widely used all over the world. Curcumin is clinically used due to its acceptable safety profile and therapeutic efficacy. AIM OF THE STUDY: Current paper aims to highlight the effect of curcumin on concomitantly used drugs. METHODS: Electronic databases including PubMed, Scopus and Science Direct were searched with the keywords "curcumin" in the title/abstract and "drug interaction," "drug metabolism," "cytochrome," "P-glycoprotein" and "P450" in the whole text. RESULTS: Curcumin can induce pharmacokinetic alterations such as changes in Cmax and AUC when concomitantly used with pharmacological agents like cardiovascular drugs, antidepressants, anticoagulants, antibiotics, chemotherapeutic agents, and antihistamines. The underlying mechanisms of these interactions include inhibition of cytochrome (CYP) isoenzymes and P glycoprotein. There is only one clinical trial which proved a significant alteration of conventional drugs in concomitant use with curcumin indicating the need for further human studies. CONCLUSIONS: Although in vitro and in vivo studies do not provide enough evidence to judge the clinical drug interactions of curcumin, physicians must remain cautious and avoid drug combinations which may lead to curcumin-drug interactions. PMID- 28734961 TI - Radix Puerariae modulates glutamatergic synaptic architecture and potentiates functional synaptic plasticity in primary hippocampal neurons. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Neurologic disorders are frequently characterized by synaptic pathology, including abnormal density and morphology of dendritic spines, synapse loss, and aberrant synaptic signaling and plasticity. Therefore, to promote and/or protect synapses by the use of natural molecules capable of modulating neurodevelopmental events, such as, spinogenesis and synaptic plasticity, could offer a preventive and curative strategy for nervous disorders associated with synaptic pathology. Radix Puerariae, the root of Pueraria monatana var. lobata (Willd.) Sanjappa&Pradeep, is a Chinese ethnomedicine, traditionally used for the treatment of memory-related nervous disorders including Alzheimer's disease. In the previous study, we showed that the ethanolic extracts of Radix Puerariae (RPE) and its prime constituent, puerarin induced neuritogenesis and synapse formation in cultured hippocampal neurons, and thus could improve memory functions. AIMS OF THE STUDY: In the present study, we specifically investigated the abilities of RPE and puerarin to improve memory related brain disorders through modulating synaptic maturation and functional potentiation. MATERIALS AND METHODS: Rat embryonic (E19) brain neurons were cultured in the absence or presence of RPE or puerarin. At predetermined times, cells were live-stained with DiO or fixed and immunostained to visualize neuronal morphologies, or lysed for protein harvesting. Morphometric analyses of dendritic spines and synaptogenesis were performed using Image J software. Functional pre- and postsynaptic plasticity was measured by FM1-43 staining and whole-cell patch clamping, respectively. RPE or puerarin-mediated changes in actin-related protein 2 were assessed by Western blotting. Neuronal survivals were measured using propidium iodide exclusion assay. RESULTS: RPE and puerarin both: (1) promoted a significant increase in the numbers, and maturation, of dendritic spines; (2) modulated the formation of glutamatergic synapses; (3) potentiated synaptic transmission by increasing the sizes of reserve vesicle pools at presynaptic terminals; (4) enhanced NMDA receptor-mediated postsynaptic currents, and (5) increased cell viability against naturally occurring cell death. Moreover, upregulation of actin-related protein 2 (ARP2) in RPE and puerarin treated brain neurons suggest that RPE and puerarin induced synaptic plasticity might be associated, at least in part, with ARP2-mediated actin-dependent regulation of spinogenesis. CONCLUSIONS: Our findings indicate that RPE and puerarin might play a substantial role in the morphological and functional maturation of brain neurons and suggest that RPE and puerarin are potentially valuable preventative therapeutics for memory-related nervous disorders. PMID- 28734962 TI - Analyzing the hepatoprotective effect of the Swertia cincta Burkillextract against ANIT-induced cholestasis in rats by modulating the expression of transporters and metabolic enzymes. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Swertia cincta Burkill was traditionally used for treating jaundice and various types of chronic and acute hepatitis in Yunnan and Tibet in China for hundreds of years. This study aims to investigate the protective effect of S. cincta Burkill (ESC) extract on alpha naphthylisothiocyanate (ANIT)-induced hepatotoxicity and cholestasis in rats. MATERIALS AND METHODS: Crude extracts were prepared using 90% ethanol and by vacuum drying. We utilized an ultra-high-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight tandem mass spectrometry (UHPLC/Q-TOF-MS) system to conduct a phytochemical analysis of the active components of ESC. Liver function was evaluated by measuring the serum levels of enzymes and components and by analyzing the liver histology. We also measured the expression of bile metabolism-related transporters and metabolic enzymes at both protein and mRNA levels to elucidate the underlying mechanisms. RESULTS: ESC analysis using an UHPLC/Q-TOF-MS revealed eight compounds. Oral administration of ESC to ANIT-treated rats can significantly reduce the increases in serum levels of ALT, AST, ALP, TBIL, and TBA. It can also improve liver pathology and bile flow. Western blot and qRT-PCR analyses showed that ESC upregulated the protein and mRNA expression of Fxr, Ntcp, Bsep, Cyp7a1, Mrp2, and Mdr2. CONCLUSION: ESC could alleviate liver injury by reducing enzyme activities of serums, improving liver pathology and bile flow. The protective mechanism was associated with regulation of the expression of hepatic transporters and metabolic enzymes. PMID- 28734963 TI - Variability in elective day-surgery rates between Belgian hospitals - Analyses of administrative data explained by surgical experts. AB - BACKGROUND: In the last decades, day surgery has steadily and significantly grown in many countries, yet the increase has been uneven. There are large variations in day-surgery activity between countries, but also within countries between hospitals and surgeons. This paper explores the variability in day-care activity for elective surgical procedures between Belgian hospitals. MATERIALS AND METHODS: The administrative hospital data of all patients formally admitted in a Belgian hospital for inpatient or day-care surgery between 2011 and 2013 were analysed and summarized in graphs. During 11 expert meetings with ad-hoc surgical expert groups the variability in day-surgery share between hospitals was discussed in depth. RESULTS: The variability in day-care share between Belgian hospitals is considerable. For 37 out of 486 elective surgical procedures, the variability ranged between 0 and 100%. High national day-care rates do not preclude room for improvement for certain hospitals as for the majority of these procedures there are "low performers". According to the consulted clinical experts, the high variability in day-care share may for the greater part be explained by medical team related factors, customs and traditions, the lack of clinical guidelines, financial factors, organisational factors and patient related factors. CONCLUSION: If a further expansion of day surgery is envisaged in Belgium the factors that contribute to the current variability in day-surgery rates between hospitals should be addressed. In addition, a feedback system in which hospitals and health care providers have the figures on their percentage of procedures carried out in day surgery compared to other hospitals and care providers (benchmarking) and the monitoring of a number of quality indicators (e.g. unplanned readmission, unplanned inpatient stay, emergency department visit) should be installed. PMID- 28734964 TI - Removing user fees for health services: A multi-epistemological perspective on access inequities in Senegal. AB - Plan Sesame (PS) is a user fee exemption policy launched in 2006 to provide free access to health services to Senegalese citizens aged 60 and over. Analysis of a large household survey evaluating PS echoes findings of other studies showing that user fee removal can be highly inequitable. 34 semi-structured interviews and 19 focus group discussions with people aged 60 and over were conducted in four regions in Senegal (Dakar, Diourbel, Matam and Tambacounda) over a period of six months during 2012. They were analysed to identify underlying causes of exclusion from/inclusion in PS and triangulated with the household survey. The results point to three steps at which exclusion occurs: (i) not being informed about PS; (ii) not perceiving a need to use health services under PS; and (iii) inability to access health services under PS, despite having the information and perceived need. We identify lay explanations for exclusion at these different steps. Some lay explanations point to social exclusion, defined as unequal power relations. For example, poor access to PS was seen to be caused by corruption, patronage, poverty, lack of social support, internalised discrimination and adverse incorporation. Other lay explanations do not point to social exclusion, for example: poor implementation; inadequate funding; high population demand; incompetent bureaucracy; and PS as a favour or moral obligation to friends or family. Within a critical realist paradigm, we interpret these lay explanations as empirical evidence for the presence of the following hidden underlying causal mechanisms: lacking capabilities; mobilisation of institutional bias; and social closure. However, social constructionist perspectives lead us to critique this paradigm by drawing attention to contested health, wellbeing and corruption discourses. These differences in interpretation lead to subsequent differential policy recommendations. This demonstrates the need for the adoption of a "multi epistemological" perspective in studies of health inequity and social exclusion. PMID- 28734965 TI - Enhanced immunostimulatory activity of in silico discovered agonists of Toll-like receptor 2 (TLR2). AB - BACKGROUND: Emergent therapies in anticancer vaccination use Toll-like receptors (TLRs) agonists as dendritic cell (DC) vaccine adjuvants. DCs from the patient are isolated, stimulated with TLR agonists and tumor antigens ex vivo and then infused back into the patient. Although some TLR ligands have been tested in clinical trials, novel TLR agonists with improved immunomodulatory properties are essential to optimize treatment success. We report on the discovery of small molecule TLR2 agonists, with favorable properties as synthetic adjuvants. METHODS: We performed a shape- and featured-based similarity virtual screening against a commercially available compound library. The selected virtual hits were experimentally tested in TLR2-reporter cells and their activity in phagocytes and DCs was characterized. A binding model of the compounds to TLR2 (docking studies) was proposed. RESULTS: Through a virtual screening approach against a library of three million compounds four virtual hits (AG1, AG2, AG3, AG4) were found to synergistically augment the NF-kB activation induced by the lipopeptide ligand Pam3CSK4 in luciferase reporter assays using HEK293-TLR2 cells. Biacore experiments indicated that AG1-AG4 are ago-allosteric modulators of TLR2 and AG2 bound TLR2 with high affinity (KD 0.8MUM). The compounds induced TNF-alpha production in human peripheral blood mononuclear cells (PBMCs) and they activated DCs as indicated by IL-12 production and upregulation of CD83/CD86. CONCLUSIONS: Following a combined in silico/in vitro approach we have discovered TLR2-agonists (AG1-AG4) that activate human and mouse immune cells. GENERAL SIGNIFICANCE: We introduce four novel TLR2 ago-allosteric modulators that stimulate myeloid cell activity and constitute promising candidates as synthetic adjuvants. PMID- 28734966 TI - Development of new ganglioside probes and unraveling of raft domain structure by single-molecule imaging. AB - Gangliosides are involved in a variety of biological roles and are a component of lipid rafts found in cell plasma membranes (PMs). Gangliosides are especially abundant in neuronal PMs and are essential to their physiological functions. However, the dynamic behaviors of gangliosides have not been investigated in living cells due to a lack of fluorescent probes that behave like their parental molecules. We have recently developed, using an entirely chemical method, four new ganglioside probes (GM1, GM2, GM3, and GD1b) that act similarly to their parental molecules in terms of raft partitioning and binding affinity. Using single fluorescent-molecule imaging, we have found that ganglioside probes dynamically enter and leave rafts featuring CD59, a GPI-anchored protein. This occurs both before and after stimulation. The residency time of our ganglioside probes in rafts with CD59 oligomers was 48ms, after stimulation. The residency times in CD59 homodimer and monomer rafts were 40ms and 12ms, respectively. In this review, we introduce an entirely chemical-based ganglioside analog synthesis method and describe its application in single-molecule imaging and for the study of the dynamic behavior of gangliosides in cell PMs. Finally, we discuss how raft domains are formed, both before and after receptor engagement. This article is part of a Special Issue entitled Neuro-glycoscience, edited by Kenji Kadomatsu and Hiroshi Kitagawa. PMID- 28734967 TI - Assessment of complex water pollution with heavy metals and Pyrethroid pesticides on transcript levels of metallothionein and immune related genes. AB - Alteration of immunological function of an aquatic organism can be used as an indicator for evaluating the direct effect of exposure to pollutants. The aim of this work is to assess the impact of complex water pollution with special reference to Pyrethroid pesticides and heavy metals on mRNA transcript levels of Metallothionine and some immune related genes of Nile tilapia (Oreochromas Niloticus). Residues of six heavy metals and six Pyrethroid were assessed in water as well as fish tissues at three different sites of Lake Burullus, located at Northern Egypt. Variations of water physicochemical properties associated with different levels of heavy metals at the three different sections were recorded. Tissue residues of Fe, Mn and Zn, Cu, Ni exceed water levels in contrast to elevated water level of Pb. All assessed Pyrethroids are detected in fish tissue samples with higher concentration (3-42 folds) than that found in water samples especially Cypermethrin. Significant down-regulation of expression levels of metallothionein (MT) at the three sections of the lake was observed. The expression of immune related genes (IgM) and inflammatory cytokines (TNF, IL.8 and IL.1) were affected. IgM and TNF were significantly down-regulated at eastern and western section of the lake; meanwhile the expression of IL8 is down regulated at the three sections of the lack. IL1 was significantly up-regulated at eastern and middle sections. We conclude that, variable gene expression of MT and immune-related genes at the three sections of the lack impose different response to complex water pollution in relation to variable aquatic environment. PMID- 28734968 TI - Identification of an MITF gene and its polymorphisms associated with the Vibrio resistance trait in the clam Meretrix petechialis. AB - Microphthalmia-associated transcription factor (MITF) regulates the transcription of its target genes by binding to their promoters. In this study, an MITF gene, MpMITF was identified in the clam Meretrix petechialis. The full-length cDNA of MpMITF is 3564 bp with an ORF of 1365 bp. The deduced amino acid sequence consists of a conserved functional structure of bHLH-LZ, which could bind with E box. The mRNA and protein expression levels of MpMITF were significantly up regulated 6 h post-Vibrio injection. The mRNA expression of MpMITF increased on day 2 and peaked on day 10 post-Vibrio immersion. Furthermore, MpMITF expression was significantly up-regulated in most resistant families of clams (P < 0.05) but did not change significantly in most susceptive families of clams after the Vibrio immersion challenge. These results suggest that, in clams, MpMITF participates in the immune response against a Vibrio infection. Genotyping in two clam groups with different resistant levels to Vibrio parahaemolyticus (i.e., 11 R and 11-S), thirteen SNPs and five haplotypes were detected in the DNA sequence of MpMITF, of which five SNPs and two haplotypes were associated with Vibrio resistance. Four SNPs (SNP2, 5, 6 and 13) and one haplotype (Hap1) were further confirmed to be associated with Vibrio resistance in M. petechialis by association analysis in different clam families. This study deepens the understanding of MITF in marine bivalves and provides potential candidate markers for resistance selection in the clam M. petechialis. PMID- 28734969 TI - Integrated analysis of mRNA-seq in the haemocytes of Eriocheir sinensis in response to Spiroplasma eriocheiris infection. AB - The Chinese mitten crab Eriocheir sinensis is an important economic crustacean that has been exposed to various diseases. Spiroplasma eriocheiris, isolated from tremor-diseased E. sinensis, was first identified as a lethal pathogen of freshwater crustaceans. To understand the pathogenesis of S. eriocheiris to E. sinensis, the transcriptomic profiles of haemocytes in the experimental and control groups at 1 d and 7 d post-injection were obtained using Illumina HiSeq 2500. These results showed that 40,358,724, 44,462,112, 45,516,576 and 37,713,728 paired-end clean reads were obtained from the cDNA libraries of DZ1 (the control group at 1 d), DZ7 (the control group at 7 d), SY1 (the experimental group at 1 d) and SY7 (the experimental group at 7 d), respectively. In total, 106,641 unique transcript fragments (unigenes) were assembled, with an average length of 710 bp. On the first day of stimulation, 33,084 up-regulated transcripts and 19,208 down-regulated transcripts were found in the experimental group compared with those in the control group. On the seventh day of stimulation, 40,198 up regulated transcripts and 12,032 down-regulated transcripts were found in the experimental group compared with those in the control group. Some canonical immune-related pathways were identified via KEGG pathway analysis, including complement and coagulation cascades, the VEGF signalling pathway, the Wnt signalling pathway, natural killer cell-mediated cytotoxicity, the MAPK signalling pathway, neuroactive ligand-receptor interactions, and the Lysosome pathway. We found important immune-related genes (GNPTAB, MASP2, F7, F5, NFATC, TRAF6, MAP3K5, and TRa) in the KEGG pathway, and those genes were confirmed by qRT-PCR analysis. In addition, the significantly enriched neuroactive ligand receptor interaction pathway was associated with intense paroxysmal tremors of infected crabs. Our results provide valuable information for the further analysis of the mechanisms of E. sinensis defence against S. eriocheiris invasion. PMID- 28734970 TI - Genetic variation in low-dose effects of neonatal DES exposure in female rats. AB - To confirm genetic variation in low-dose effects of diethylstilbestrol (DES), two inbred strains of rats, which have been selectively bred for high- and low avoidance learning (HAA and LAA, respectively), were used in this study. LAA rats characteristically show later sexual maturation, earlier reproductive senescence, and lower body weight as compared to HAA rats. Female neonates of each strain were daily administered DES by oral gavage at doses of 0 (vehicle only), 0.05 and 0.5MUg/kg for the first 5days after birth. As a result, early onset of abnormal estrous cycles was observed during the same period in HAA and LAA rats treated with 0.5MUg/kg. However, accelerated puberty and excessive body weight gains were observed only in LAA rats treated with 0.05 and 0.5MUg/kg. These results suggest that the effects of neonatal DES exposure vary with the genetic background of the female rats used. PMID- 28734971 TI - Robotic Assistance Confers Ambidexterity to Laparoscopic Surgeons. AB - STUDY OBJECTIVE: To examine whether a robotic surgical platform can complement the fine motor skills of the nondominant hand, compensating for the innate difference in dexterity between surgeon's hands, thereby conferring virtual ambidexterity. DESIGN: Crossover intervention study (Canadian Task Force classification II-1). SETTING: Centers for medical simulation in 2 tertiary care hospitals of Harvard Medical School. PARTICIPANTS: Three groups of subjects were included: (1) surgical novices (medical graduates with no robotic/laparoscopic experience); (2) surgeons in training (postgraduate year 3-4 residents and fellows with intermediate robotic and laparoscopic experience); and (3) advanced surgeons (attending surgeons with extensive robotic and laparoscopic experience). INTERVENTIONS: Each study group completed 3 dry laboratory exercises based on exercises included in the Fundamentals of Laparoscopic Surgery (FLS) curriculum. Each exercise was completed 4 times: using the dominant and nondominant hands, on a standard laparoscopic FLS box trainer, and in a robotic dry laboratory setup. Participants were randomized to the handedness and setting order in which they tackled the tasks. MEASUREMENTS AND MAIN RESULTS: Performance was primarily measured as time to completion, with adjustments based on errors. Means of performance for the dominant versus nondominant hand for each task were calculated and compared using repeated-measures analysis of variance. A total of 36 subjects were enrolled (12 per group). In the laparoscopic setting, the mean overall time to completion of all 3 tasks with the dominant hand differed significantly from that with the nondominant hand (439.4 seconds vs 568.4 seconds; p = .0008). The between-hand performance difference was nullified with the robotic system (374.4 seconds vs 399.7 seconds; p = .48). The evaluation of performance for each individual task also revealed a statistically significant disparate performance between hands for all 3 tasks when the laparoscopic approach was used (p = .003, .02, and .01, respectively); however, no between hand difference was observed when the tasks were performed robotically. On analysis across the 3 surgeon experience groups, the performance advantage of robotic technology remained significant for the surgical novice and intermediate level experience groups. CONCLUSION: Robot-assisted laparoscopy may eliminate the operative handedness observed in conventional laparoscopy, allowing for virtual ambidexterity. This ergonomic advantage is particularly evident in surgical trainees. Virtual ambidexterity may represent an additional aspect of surgical robotics that facilitates mastery of minimally invasive skills. PMID- 28734972 TI - Non-tubal Ectopic Pregnancies: Overview and Treatment via Local Injection. AB - Ectopic pregnancies account for 1.5% to 2% of all pregnancy in the United States. Of these, approximately 10% implant in nontubal locations, including the abdominal cavity, cervix, ovary, interstitial portion of the fallopian tube, broad ligament, the uterine cornua, or within a cesarean section scar. Because these pregnancies tend to present later than typical tubal pregnancies, they have been associated with greater maternal morbidity and mortality. Advances in ultrasound technology have allowed for earlier diagnosis of nontubal ectopic pregnancies, which in turn has led to the development of novel minimally invasive techniques to manage them. One of these methods involves the local injection of 1 of several agents directly into the ectopic pregnancy. In this article we provide a guide to this technique of local injection, including an overview of the potential agents that can be used, and review the diagnostic and specific ultrasound criteria, other possible treatment options, and overall outcomes for nontubal ectopic pregnancies. PMID- 28734973 TI - Minimally Invasive Approaches to Myoma Management. AB - Patients affected by the presence of leiomyomas may incur a substantial physical, emotional, social, and financial toll as well as losses in their quality of life. Although many myomas are not amenable to medical therapy or hysteroscopic resection, many others are amenable to minimally invasive surgical approaches. In patients who prefer to retain their fertility, laparoscopic myomectomy should be considered the intervention of choice. In this review, we expand on the surgical techniques of both conventional laparoscopic and robotic-assisted myomectomies. We discuss port placement, enucleation of myomas, tissue extraction, minimization of blood loss, adhesion prevention, and the technique for closure of uterine incisions. Finally, we discuss the available data supporting the use of these 2 approaches as the preferred, safe, and effective fertility-sparing surgical option. We also briefly discuss the emerging technologies of uterine artery embolization, ultrasound surgery, and radiofrequency ablation. PMID- 28734974 TI - Effects of Pneumoperitoneum and the Steep Trendelenburg Position on Heart Rate Variability and Cerebral Oxygenation during Robotic Sacrocolpopexy. AB - STUDY OBJECTIVE: The aim of this study was to investigate how steep Trendelenburg positioning with pneumoperitoneum modifies brain oxygenation and autonomic nervous system modulation of heart rate variability during robotic sacrocolpopexy. DESIGN: Prospective study (Canadian Task Force classification III). SETTING: Rambam Health Care Campus. PATIENTS: Eighteen women who underwent robotic sacrocolpopexy for treatment of uterovaginal or vaginal apical prolapse. INTERVENTIONS: Robotic sacrocolpopexy. MEASUREMENTS AND MAIN RESULTS: A 5-minute computerized electrocardiogram, cerebral O2 saturation (cSO2), systemic O2 saturation, heart rate (HR), diastolic blood pressure (BP), systolic BP, and end tidal CO2 tension were recorded immediately after anesthesia induction (baseline phase) and after alterations in positioning and in intra-abdominal pressure. HR variability was assessed in time and frequency domains. Cerebral oxygenation was measured by the technology of near-infrared spectrometry. cSO2 at baseline was 73% +/- 9%, with minor and insignificant elevation during the operation. Mean HR decreased significantly when the steep Trendelenburg position was implemented (66 +/- 10 vs 55 +/- 9 bpm, p < .05) and returned gradually to baseline with advancement of the operation and the decrease in intra-abdominal pressure. Concomitant with this decrease, the power of both arms of the autonomic nervous system increased significantly (2.8 +/- .8 vs 3.3 +/- .9 ms2/Hz and 2.5 +/- 1.2 vs 3.2 +/- .9 ms2/Hz, respectively, p < .05). All these effects occurred without any significant shifts in systolic or diastolic BP or in systemic or cerebral oxygenation. CONCLUSION: This study supports the safety of robotic sacrocolpopexy performed with steep Trendelenburg positioning with pneumoperitoneum. Only minor alterations were observed in cerebral oxygenation and autonomic perturbations, which did not cause clinically significant alterations in HR rate and HR variability. PMID- 28734975 TI - How consumers are affected by product descriptions in online shopping: Event related potentials evidence of the attribute framing effect. AB - Due to the limitations of the human ability to process information, e-consumers' decisions are likely to be influenced by various cognitive biases, such as the attribute framing effect. This effect has been well studied by numerous scholars; however, the associated underlying neural mechanisms with a critical temporal resolution have not been revealed. Thus, this study applies the measurement of event-related potentials (ERPs) to directly examine the role of attribute framing in information processing and decision-making in online shopping. The behavioral results showed that participants demonstrated a higher purchase intention with a shorter reaction time under a positive framing condition compared to participants under a negative framing condition. Compared with positive framing messages, the results of ERPs indicated that negative framing messages attracted more attention resources at the early stage of rapid automatic processing (larger P2 amplitude) and resulted in greater cognitive conflict and decision difficulty (larger P2-N2 complex). Moreover, compared with negative messages, positive framing messages allowed consumers to perceive a better future performance of products and classify these products as a categorization of higher evaluation (larger LPP amplitude) at the late cognitive processing stage of evaluation. Based on these results, we provide evidence for a better understanding of how different attribute framing messages are processed and ultimately lead to the framing effect. PMID- 28734976 TI - Structural basis of the substrate specificity and instability in solution of a glycosidase from Lactobacillus plantarum. AB - Statistics from structural genomics initiatives reveal that around 50-55% of the expressed, non-membrane proteins cannot be purified and therefore structurally characterized due to solubility problems, which emphasized protein solubility as one of the most serious concerns in structural biology projects. Lactobacillus plantarum CECT 748T produces an aggregation-prone glycosidase (LpBgl) that we crystallized previously. However, this result could not be reproduced due to protein instability and therefore further high-resolution structural analyses of LpBgl were impeded. The obtained crystals of LpBgl diffracted up to 2.48A resolution and permitted to solve the structure of the enzyme. Analysis of the active site revealed a pocket for phosphate-binding with an uncommon architecture, where a phosphate molecule is tightly bound suggesting the recognition of 6-phosphoryl sugars. In agreement with this observation, we showed that LpBgl exhibited 6-phospho-beta-glucosidase activity. Combination of structural and mass spectrometry results revealed the formation of dimethyl arsenic adducts on the solvent exposed cysteine residues Cys211 and Cys292. Remarkably, the double mutant Cys211Ser/Cys292Ser resulted stable in solution at high concentrations indicating that the marginal solubility of LpBgl can be ascribed specifically to these two cysteine residues. The 2.30A crystal structure of this double mutant showed no disorder around the newly incorporated serine residues and also loop rearrangements within the phosphate-binding site. Notably, LpBgl could be prepared at high yield by proteolytic digestion of the fusion protein LSLt-LpBgl, which raises important questions about potential hysteretic processes upon its initial production as an enzyme fused to a solubility enhancer. PMID- 28734977 TI - Modulation of the interaction between human P450 3A4 and B. megaterium reductase via engineered loops. AB - Chimerogenesis involving cytochromes P450 is a successful approach to generate catalytically self-sufficient enzymes. However, the connection between the different functional modules should allow a certain degree of flexibility in order to obtain functional and catalytically efficient proteins. We previously applied the molecular Lego approach to develop a chimeric P450 3A4 enzyme linked to the reductase domain of P450 BM3 (BMR). Three constructs were designed with the connecting loop containing no glycine, 3 glycine or 5 glycine residues and showed a different catalytic activity and coupling efficiency. Here we investigate how the linker affects the ability of P450 3A4 to bind substrates and inhibitors. We measure the electron transfer rates and the catalytic properties of the enzyme also in the presence of ketoconazole as inhibitor. The data show that the construct 3A4-5GLY-BMR with the longest loop better retains the binding ability and cooperativity for testosterone, compared to P450 3A4. In both 3A4 3GLY-BMR and 3A4-5GLY-BMR, the substrate induces an increase in the first electron transfer rate and a shorter lag phase related to a domain rearrangements, when compared to the construct without Gly. These data are consistent with docking results and secondary structure predictions showing a propensity to form helical structures in the loop of the 3A4-BMR and 3A4-3GLY BMR. All three chimeras retain the ability to bind the inhibitor ketoconazole and show an IC50 comparable with those reported for the wild type protein. This article is part of a Special Issue entitled: Cytochrome P450 biodiversity and biotechnology, edited by Erika Plettner, Gianfranco Gilardi, Luet Wong, Vlada Urlacher, Jared Goldstone. PMID- 28734978 TI - Insights into the functional properties of the marneral oxidase CYP71A16 from Arabidopsis thaliana. AB - The Arabidopsis thaliana gene encoding CYP71A16 is part of the gene cluster for the biosynthesis and modification of the triterpenoid marneral. Previous investigations of A. thaliana have revealed that CYP71A16 catalyzes marneral oxidation, while it also can accept marnerol as substrate. The aim of the present study was to investigate functional properties of CYP71A16 in vitro. For this purpose, heterologous expression of a N-terminally modified version of CYP71A16 was established in Escherichia coli, which yielded up to 50mgL-1 recombinant enzyme. The enzyme was purified and activity was reconstituted in vitro with different redox partners. A heterologous bacterial redox partner system consisting of the flavodoxin YkuN from Bacillus subtilis and the flavodoxin reductase Fpr from E. coli clearly outperformed the cytochrome P450 reductase ATR2 from A. thaliana in supporting the CYP71A16-mediated hydroxylation of marnerol. Substrate binding experiments with CYP71A16 revealed a dissociation constant KD of 225MUM for marnerol. CYP71A16 catalyzed the hydroxylation of marnerol to 23-hydroxymarnerol with a KM of 142MUM and a kcat of 3.9min-1. Furthermore, GC/MS analysis revealed an as of yet unidentified overoxidation product of this in vitro reaction. This article is part of a Special Issue entitled: Cytochrome P450 biodiversity and biotechnology, edited by Erika Plettner, Gianfranco Gilardi, Luet Wong, Vlada Urlacher, Jared Goldstone. PMID- 28734979 TI - Rumination interacts with life stress to predict depressive symptoms: An ecological momentary assessment study. AB - Rumination is a well-established vulnerability factor for depression that may exert deleterious effects both independently and in interaction with stress. The current study examined momentary ruminative self-focus (MRS) and stress-reactive rumination (SRR) as predictors of depressive symptoms utilizing a smartphone ecological momentary assessment (EMA) design. 121 undergraduates responded to four text message alerts per day for one week in which they indicated the occurrence of life stress, rumination, and depressed mood. SRR, but not MRS, independently predicted increases in depressive symptoms. MRS interacted with depressive symptoms to predict increases in symptoms at the subsequent timepoint, supporting the deleterious effects of depressive rumination on future mood state. Interactions emerged between stress and both MRS and SRR, such that experiencing higher levels of stressors and rumination at an observation predicted greater increases in depressive symptoms. To our knowledge, this study is the first to demonstrate that state rumination moderates the effect of stress in predicting depressive symptoms using EMA methodology. Results suggest that rumination levels in response to stress vary within individuals and can have an important effect on depressed mood. Findings may have important clinical implications, as lessening individuals' tendency to engage in rumination following stress may help to alleviate depressive symptoms. PMID- 28734981 TI - Apigenin attenuates patulin-induced apoptosis in HEK293 cells by modulating ROS mediated mitochondrial dysfunction and caspase signal pathway. AB - Mycotoxins like patulin (PAT) are among the most significant food contaminant with regard to public health. This study aimed to evaluate the protective effect of apigenin (API), one of the most bioactive flavonoids in plant-derived food, on PAT-induced apoptosis in HEK293 cells. Cells were treated under basic conditions, 8 MUM PAT without or with API (2.5, 5 and 10 MUM) concomitantly for 10 h. API exerted renoprotective effect by inhibiting intracellular reactive oxygen species (ROS) accumulation, modulating oxidative phosphorylation especially elevating the expression of ATP synthase, re-establishing mitochondrial membrane potential (MMP) and maintaining higher intracellular ATP level, accompanied by p53, Bax downregulation and Bcl-2 upregulation. Thereby, cytochrome c release from mitochondria to cytoplasm was reduced, causing inhibition of initiator caspases-9 and executioner caspases (3, 6 and 7) expression and enzyme activities. Results revealed dietary apigenin attenuates patulin-induced apoptosis in HEK293 cells by modulating ROS-mediated mitochondrial dysfunction and caspase signal pathway. PMID- 28734982 TI - Isolation and characterization of renin-like aspartic-proteases from Echis ocellatus venom. AB - Three aspartic proteases (SVAPs) have been isolated from venom of the saw-scaled viper, Echis ocellatus. In confirmation of prior transcriptomic predictions, all three forms match to sequences of either of the two SVAP transcripts (EOC00051 and EOC00123), have a molecular weight of 42 kDa and possess a single N-glycan. The SVAPs act in a renin-like manner, specifically cleaving human and porcine angiotensinogen into angiotensin-1 and possess no general protease activity. Their activity is completely inhibited by the aspartyl protease inhibitor Pepstatin A. PMID- 28734980 TI - Histone demethylase PHF8 regulates hypoxia signaling through HIF1alpha and H3K4me3. AB - Hypoxia through transcription factor HIF1alpha plays a critical role in cancer development. In prostate cancer, HIF1alpha interplays with androgen receptor (AR) to contribute to the progression of this disease to its lethal form-castration resistant prostate cancer (CRPC). Hypoxia upregulates several epigenetic factors including histone demethylase KDM3A which is a critical co-factor of HIF1alpha. However, how histone demethylases regulate hypoxia signaling is not fully understood. Here, we report that histone demethylase PHF8 plays an essential role in hypoxia signaling. Knockdown or knockout of PHF8 by RNAi or CRISPR-Cas9 system reduced the activation of HIF1alpha and the induction of HIF1alpha target genes including KDM3A. Mechanistically, PHF8 regulates hypoxia inducible genes mainly through sustaining the level of trimethylated histone 3 lysine 4 (H3K4me3), an active mark in transcriptional regulation. The positive role of PHF8 in hypoxia signaling extended to hypoxia-induced neuroendocrine differentiation (NED), wherein PHF8 cooperates with KDM3A to regulate the expression of NED genes. Moreover, we discovered that the role of PHF8 in hypoxia signaling is associated with the presence of full-length AR in CRPC cells. Collectively, our study identified PHF8 as a novel epigenetic factor in hypoxia signaling, and the underlying regulatory mechanisms likely apply to general cancer development involving HIF1alpha. Therefore, targeting PHF8 can potentially be a novel therapeutic strategy in cancer therapy. PMID- 28734983 TI - Dietary administration of tetrodotoxin and its putative biosynthetic intermediates to the captive-reared non-toxic Japanese fire-bellied newt, Cynops pyrrhogaster. AB - The origin of tetrodotoxin (TTX) in amphibians has long been disputed. In this study, TTX and its putative biosynthetic intermediates or shunt compounds (4,9 anhydro-10-hemiketal-5-deoxyTTX and Cep-242) were dietary administered to the captive-reared, non-toxic Japanese fire-bellied newt, Cynops pyrrhogaster. After 4 weeks, the ingested compounds were detected mainly in the newt body using liquid chromatography-mass spectrometry (LC-MS), while these compounds were not converted into other TTX analogues in newts. PMID- 28734984 TI - Germline versus somatic mutations in genetic atrial fibrillation. PMID- 28734985 TI - Safety of catheter ablation of atrial fibrillation using fiber optic-based contact force sensing. AB - BACKGROUND: While the body of evidence showing the benefit of contact force (CF) sensing catheters in improving atrial fibrillation ablation success rate is growing, real-world safety data of this technology are limited. OBJECTIVE: The aim of this study was to report the complication rate in patients undergoing ablation using a specific CF-sensing catheter (TactiCath Quartz CF ablation catheter, Abbott, St. Paul, MN) in a large worldwide database. METHODS: User reported adverse event data from January 1, 2014 to December 31, 2015 were reviewed for the ablation catheter. These adverse events included cardiac perforation, cerebrovascular accident, atrioesophageal (AE) fistula, steam pop, and death. Rates of these adverse events, including geographic and temporal relationships, were calculated. RESULTS: Adverse events were reported in 178 of 41,709 patients (adverse event rate 0.427%). Adverse events included 117 cardiac perforations (0.281%), 5 cerebrovascular accidents (0.012%), 10 AE fistulas (0.024%), 53 audible steam pops (0.127%), and 13 deaths (0.031%). The total event rate in European countries was 0.53% vs 0.38% in the United States (P = .0082). The AE fistula event rate peaked in late 2014 and early 2015 at 0.06% and decreased over time to a steady-state 0.01%, corresponding to the initial US release, subsequent increased use, and training on the manufacturer recommended settings. CONCLUSION: Complication rates while using the TactiCath CF ablation catheter appear to decrease with training and experience. The major complication rate associated with this technology is low in the context of similar reports of conventional radiofrequency catheters. PMID- 28734987 TI - Bioavailable and free 25-hydroxyvitamin D and vitamin D binding protein in polycystic ovary syndrome: Relationships with obesity and insulin resistance. AB - Polycystic ovary syndrome (PCOS) is a common condition characterised by both reproductive and metabolic features (obesity, insulin resistance, diabetes risk). Some evidence suggests that women with PCOS have lower vitamin D levels compared to healthy controls. Vitamin D binding protein (DBP) is the main carrier of vitamin D in circulation and plays an important role in regulating vitamin D concentration and bioavailability for target tissues. To our knowledge, no previous studies have examined DBP, bioavailable and free 25-hydroxyvitamin D (25(OH)D) in women with PCOS. The primary aim of this study was to compare DBP, bioavailable and free 25(OH)D concentrations in women with PCOS and controls. The secondary aim was to investigate relationships between DBP, bioavailable and free 25(OH)D and metabolic features (anthropometric measures, insulin resistance, and lipid profile). In a cross sectional study using bio-banked samples, we measured 25(OH)D, DBP and albumin. Bioavailable and free 25(OH)D were calculated using previously validated formula. BMI, body composition (dual X-ray absorptiometry, DXA), insulin resistance (homeostatic model assessment of insulin resistance (HOMA-IR)) and glucose infusion rate (GIR) from hyperinsulinaemic euglycaemic clamp and serum lipids (ELISA) were also measured in a physically and biochemically well-characterised cohort of women with and without PCOS. We studied 90 women with PCOS and 59 controls aged 18-48 years. DBP concentrations were lower in PCOS compared to controls (median [IQR]: 443.40 [314.4] vs 482.4 [156.8] MUg/ml, p=0.02). No significant differences were found in bioavailable or free 25(OH)D concentrations between groups. DBP was not associated with BMI, percent body fat or markers of insulin resistance (all p>0.2). High-density lipoprotein (HDL) was the main determinant of DBP in the overall cohort (beta= 0.12, p=0.02), after adjusting for covariates including PCOS/control status, age, BMI, total 25(OH)D and HOMA-IR. In PCOS, total and free 25(OH)D were related to markers of insulin resistance and lipids. Only the associations between free 25(OH)D and triglycerides (p=0.02), and HDL (p=0.03) remained significant after adjusting for age and BMI. In conclusion, women with PCOS had lower DBP, but similar bioavailable or free 25(OH)D concentrations compared to controls, independent of BMI and age. DBP was not associated with insulin resistance or BMI in PCOS. Further studies are needed to investigate the pathophysiology and clinical implications of reduced DBP in PCOS. PMID- 28734986 TI - Exogenous hedgehog antagonist delays but does not prevent fracture healing in young mice. AB - Fracture healing recapitulates many aspects of developmental osteogenesis. The hedgehog (Hh) signaling pathway, essential to skeletal development, is upregulated during fracture healing, although its importance is unclear. Our goal was to assess the functional importance of Hh signaling in endochondral fracture healing. We created closed, transverse diaphyseal femur fractures in mice, stabilized with an intramedullary pin, and administered a systemic Hh inhibitor or vehicle. Because Hh pathway activation is mediated by the receptor Smoothened (Smo), we used the Smo antagonist GDC-0449 (GDC, 50mg/kg, twice daily) to target the pathway. First, in vehicle-treated 10-wk. female C57BL/6 mice we confirmed that Hh signaling was increased in fracture callus compared to intact bone, with >5-fold upregulation of target genes Ptch1 and Gli1. Additionally, using 10-wk. male and female Gli1 reporter mice, we saw a strong activation of the reporter in the osseous regions of the fracture callus 7-10days after fracture. GDC treatment significantly blunted these responses, indicating effective inhibition of fracture-induced Hh signaling in bone. Moreover, microCT analysis revealed that GDC treatment significantly reduced cancellous and cortical bone volume at non fracture sites (tibial metaphysis and diaphysis), suggesting that the drug inhibited normal bone formation. GDC treatment had a modest effect on fracture healing, with evidence of delayed callus mineralization radiographically (significantly lower Goldberg score at day 14) and by microCT (reduced callus vBMD at 14days), and a delay in the recovery of torsional rotation to normal (elevated rotation-at-peak torque at 21days). On the other hand, GDC treatment did not inhibit qPCR or morphological measures of chondrogenesis or angiogenesis, and did not impair the recovery of failure torque (at day 14 or 21), a measure of biomechanical competence. In summary, GDC treatment inhibited Hh signaling, which delayed but did not prevent fracture healing in young mice. We conclude that Hh signaling is strongly induced after fracture and may play a role in early callus mineralization, although it does not appear to be required for eventual healing. PMID- 28734988 TI - Can adverse effects of excessive vitamin D supplementation occur without developing hypervitaminosis D? AB - Vitamin D is a fat-soluble hormone that has endocrine, paracrine and autocrine functions. Consumption of vitamin D-supplemented food & drugs have increased significantly in the last couple of decades due to campaign and awareness programs. Despite such wide use of artificial vitamin D supplements, serum level of 25 hydroxyvitamin D does not always reflect the amount of uptake. In contrast to the safe sunlight exposure, prolonged and disproportionate consumption of vitamin D supplements may lead to vitamin D intoxication, even without developing hypervitaminosis D. One of the reasons why vitamin D supplementation is believed to be safe is, it rarely raises serum vitamin D levels to the toxic range even after repeated intravenous ingestion of extremely high doses of synthetic vitamin D analogs. However, prolonged consumption of vitamin D supplementation may induce hypercalcemia, hypercalciuria and hyperphosphatemia, which are considered to be the initial signs of vitamin D intoxication. It is likely that calcium and phosphorus dysregulation, induced by exogenous vitamin D supplementation, may lead to tissue and organ damages, even without developing hypervitaminosis D. It is needed to be emphasized that, because of tight homeostatic control of calcium and phosphorus, when hypercalcemia and/or hyperphosphatemia is apparent following vitamin D supplementation, the process of tissue and/or organ damage might already have been started. PMID- 28734989 TI - Hydroxyvitamin D assays: An historical perspective from DEQAS. AB - Recent years have seen a substantial increase in demand for 25-hydroxyvitamin D (25-OHD) assays. DEQAS (the Vitamin D External Quality Assessment Scheme) has been monitoring the performance of these assays since 1989. The first DEQAS distribution was in June 1989 and results were submitted by 13 laboratories in the UK, two of which used HPLC/UV; the rest used ligand binding assays with a tritium tracer. Inter-laboratory CVs (ALTM) ranged from 29.3% (42.7nmol/L) to 53.7% (20.0nmol/L). Currently the scheme has participants in 56 countries using 30 methods or variants of methods. In January 2017, 918 participants returned results and inter-laboratory CVs (ALTM) ranged from 10.3% (73.1nmol/L) to 15.3% (29.4nmol/L). Over the last 27 years, there have been a number of significant milestones in assay development. The first major advance was the development of an iodinated 25-OHD tracer by Hollis and Napoli in 1992, subsequently used in an RIA kit marketed by DiaSorin. This and other commercial radioimmunoassays that followed brought 25-OHD assays within reach of many more non-specialist routine laboratories. With the introduction of fully automated non-isotopic assays without solvent extraction, measurement of 25-OHD became available to any clinical chemistry laboratory with an appropriate analytical platform. However, as the limitations of these non-extraction assays became apparent more laboratories started using LC-MS/MS methodology. Meanwhile the variable accuracy of 25-OHD methods has been addressed by the Vitamin D Standardization Program (VDSP) which encourages manufacturers to produce methods traceable to the reference measurement procedures (RMPs) of NIST, University of Ghent and the Centers for Disease Control and Prevention (CDC). DEQAS changed to an accuracy based scheme in 2013 and now assesses assay accuracy against the NIST RMP. This review will use DEQAS results and statistics to chart the historical development in 25-OHD assay technology and highlight some of the problems encountered in obtaining reliable results for this most challenging of analytes. PMID- 28734990 TI - Cardiac ischemia after epinephrine injection during EMR for a large rectal polyp. PMID- 28734991 TI - Endoscopic full-thickness resection using suture loop needle T-tag tissue anchors in the porcine stomach (with video). AB - BACKGROUND AND AIMS: Endoscopic full-thickness resection (EFTR) is still challenging, and a reliable technique is desirable. The aim of this study was to evaluate the feasibility of controlled EFTR using a pseudopolyp made from suture loop needle T-tag (SLNT) tissue anchors in ex vivo porcine stomachs. METHODS: Five pig stomachs were used. Two concentric circumferential border mucosal incisions were made to facilitate isolating a target lesion for full-thickness excision and pseudopolyp formation. SLNT tissue anchors were placed with a fishing line around the edges of the larger outer incision by endoscopic suturing. A suture pulley was created in the center of the targeted area and brought outside for traction. A large inverted pseudopolyp of the targeted lesion was made, visualizing apposing serosa with traction on the suture pulley while simultaneously cinching the encircling fishing line. EFTR was then performed on the isolated targeted tissue with the use of a needle-knife. RESULTS: Pseudopolyps were successful in all attempts. In the first attempt the encircling fishing line was cut, releasing the pseudopolyp during EFTR, with obvious leak. The remaining 4 EFTRs were performed with intact serosal apposing pseudopolyps and no air leaks. The median number of SLNT tissue anchors placed for a pseudopolyp was 5 (interquartile range, 4-5). The median size of full-thickness lesions was 37 mm (interquartile range, 29-49) and the median maximum pressure for the leak testing 9 mm Hg (interquartile range, 4-14) in the successful 4 attempts. CONCLUSION: This proof of principle study suggests that EFTR with SLNT fashioned pseudopolyps is feasible. PMID- 28734992 TI - Endoscopic muscle biopsy sampling of the duodenum and rectum: a pilot survival study in a porcine model to detect myenteric neurons. AB - BACKGROUND AND AIMS: Small bowel and colorectal muscle biopsy sampling requires a surgical approach. Advancing our understanding of the pathophysiology of motility disorders, such as functional bowel disorders, intestinal pseudo-obstruction, and slow-transit constipation, is hindered by our inability to noninvasively obtain muscularis propria (MP) for evaluation of multiple cell types, including myenteric neurons. The aims of this study were to determine (1) technical feasibility, reproducibility, and safety of performing duodenal endoscopic muscle biopsy sampling (dEMB) and rectal endoscopic muscle biopsy sampling (rEMB) using a clip-assist technique and (2) the presence of myenteric neurons in tissue samples. METHODS: Five 40-kg pigs were studied. Each animal underwent a dEMB and rEMB procedure. dEMB was performed using a single resection clip-assist technique. An over-the-scope clip was advanced to the duodenum. Tissue was suctioned into the cap and the clip deployed. The pseudopolyp of the duodenal wall created was then resected using snare electrocautery. rEMB was performed using a double resection clip-assist technique. EMR was initially performed to uncover the underlying MP using a band ligation technique. An over-the-scope clip was then advanced to the exposed MP. The MP was retracted and suctioned into the cap and the clip deployed. The pseudopolyp of the MP was resected using snare electrocautery. An antibody to protein gene product 9.5 was used to determine the presence of myenteric neurons in the samples. Animals were kept alive for 2 weeks, at which time an upper endoscopy and necropsy were performed. RESULTS: dEMB and rEMB were successfully performed in all animals with no procedural adverse events using this "no hole" (close then cut) approach. Mean procedure times for dEMB and rEMB were 23.7 +/- 2.5 minutes and 13.25 +/- 2.8 minutes, respectively. Mean length of resected full-thickness duodenal wall was 13.25 +/- 4.3 mm and rectal MP was 12.5 +/- 1.7 mm. Hematoxylin and eosin stain and antibody to protein gene product 9.5 confirmed the presence of MP with inner circular, outer longitudinal, and intermuscular layers, including myenteric neurons, in all samples. Clinical course was uneventful in all animals. Repeat upper endoscopy at 2 weeks showed well-healed dEMB sites. Necropsy in all animals showed no perforation, fluid collection, or abscess at the dEMB and rEMB sites. CONCLUSIONS: Based on this preclinical study, dEMB and rEMB appear to be technically feasible, reproducible, and safe. Sufficient MP tissue was obtained to identify myenteric neurons. These promising results are a step toward successful and safe implementation of these techniques into clinical practice for tissue diagnosis of muscle-based pathologies. PMID- 28734993 TI - Esthetically Favorable Surgical Alternative for the Removal of Sinonasal Malignant Tumors-The Modified Facial Degloving Technique. AB - PURPOSE: The widely used external approach (Weber-Fergusson incision) for the removal of maxillary ethmoid tumors leaves stigmatizing scars and deformities on the patient's face. As an alternative technique, the scarless facial degloving approach was first described in the 1970s; since then, several modifications have been developed. PATIENTS AND METHODS: The authors have been using a modified facial degloving technique for 7 years to remove maxillary ethmoid tumors. This article is a retrospective methodologic review. The inclusion criteria for this retrospective study were patients who underwent the modified facial degloving technique for management of malignant maxillary ethmoid tumors. The exclusion criteria were patients who did not undergo a surgical procedure (who received primary chemoradiation therapy) and patients who underwent an endoscopic surgical procedure for an early-stage localized tumor. The authors describe their method, which provides for a wide surgical approach using an osteoplastic flap for the entire nasal and paranasal region, with good cosmetic results. They present the adaptability of their method for 3 malignant maxillary ethmoid tumors in different locations. RESULTS: From 2012 through 2016, 23 consecutive patients underwent surgery with the modified facial degloving approach at the Department of Otorhinolaryngology, Head and Neck Surgery at the University of Szeged (Szeged, Hungary). The authors evaluated their results with acoustic rhinometry and photographic documentation of postoperative facial expressions. Neither narrowing of the nasal cavity on the operated side (loss of nasal breathing function) nor facial movement dysfunction was visible in these patients. CONCLUSION: Although several modifications of the original facial degloving approach have been published, in the present technique, the novel osteoplastic flap and the intact soft tissue of the nasal and midfacial region result in shorter hospitalization time and fewer complications. No functional or esthetic distortion was visible. No severe complications were observed; the patients' only complaint was the dryness of the nasal mucosa and temporary crusting of the nose. The present modified facial degloving technique offers proper and safe surgical resection for tumors of the maxillary ethmoid region. It can be routinely combined with endoscopic techniques and, if necessary, can be converted to an open approach. PMID- 28734994 TI - Distraction Osteogenesis Normalizes Mandibular Body-Symphysis Morphology in Infants With Robin Sequence. AB - PURPOSE: To evaluate changes in mandibular morphology in infants with Robin sequence (RS) after mandibular distraction osteogenesis (MDO) and compare the post-distraction morphology with that in infants without RS and infants with RS who had not undergone MDO. MATERIALS AND METHODS: Infants with RS treated with MDO were retrospectively evaluated over a 12-year period. All patients had pre distraction and end-consolidation maxillofacial computed tomograms. Morphologic features of the mandible were divided into ramus and condyle, body and symphysis, and composite measurements. Post-distraction RS mandibular morphology was compared with pre-distraction morphology, as well as to age-matched infants without RS and age-matched infants with RS who had not undergone MDO. Comparisons were done using nonparametric paired-samples analyses. RESULTS: During the study period, 17 patients with RS treated with MDO met the inclusion criteria for the study. The mean ages at distraction and end-consolidation were 1.95 +/- 3.24 and 8.46 +/- 5.99 months, respectively. The post-MDO mandible was significantly different from the pre-MDO mandible with regard to the ramps-condyle unit and body-symphysis measurements, including development of a more parabolic mandibular arch form (P <= .001). Compared with age-matched non-RS infant mandibles, the post-distraction RS mandibles had similar morphologies. Compared with age-matched non-MDO RS mandibles, the post-distraction mandibles had significantly different morphologies anterior to the gonial angle, including a more parabolic arch form (P <= .006). CONCLUSIONS: MDO normalized mandibular morphology in infants with RS, with the greatest effect on measurements anterior to the gonial angle. PMID- 28734995 TI - Senior Oral and Maxillofacial Surgery Resident Confidence in Performing Invasive Temporomandibular Joint Procedures. AB - PURPOSE: The purpose of this study was to evaluate the level of confidence that senior-level oral and maxillofacial surgery (OMS) residents have in the management of temporomandibular joint (TMJ) disorders, determine their exposure to various invasive TMJ procedures during training, and assess their confidence in performing those procedures on completion of residency. MATERIALS AND METHODS: A questionnaire was designed, and a link to a University of Illinois at Chicago Qualtrics Survey platform (Qualtrics, Provo, UT) was e-mailed to all program directors at Commission on Dental Accreditation-accredited OMS training programs in the United States. The program directors were asked to forward the 20-multiple choice question anonymous survey to their senior-level residents for completion. The survey included the program's demographic characteristics, resident's confidence in assessing and managing patients with temporomandibular disorders (TMDs), resident's experience performing various invasive TMJ procedures, and whether the resident believed he or she had received sufficient education and clinical experience in the management of TMJ disorders. The data were collected and summarized by use of a standard spreadsheet analysis, as well as appropriate descriptive and analytical statistical tests. RESULTS: The response rate was 28.0%. Of the 56 respondents, 52 (92.9%) reported having received instruction in nonsurgical management of TMDs. All respondents confirmed that invasive TMJ procedures were performed in their program. The most commonly performed procedure was TMJ arthrocentesis (mean rating, 3.11), followed by open TMJ surgery (mean rating, 2.82). The least-performed invasive surgical procedure was autogenous total TMJ replacement surgery (mean rating, 1.39). Eighty percent of residents reported being comfortable managing the TMD patient. The only procedure with which the respondents were highly confident was TMJ arthrocentesis (mean rating, 3.89). CONCLUSIONS: This study suggests that confidence levels in the management of the TMD patient are related directly to the invasive TMJ procedure experience obtained during residency. This finding may have implications on the practice patterns of OMS surgeons as it relates to access to care for the TMD patient. PMID- 28734996 TI - The design of novel visible light driven Ag/CdO as smart nanocomposite for photodegradation of different dye contaminants. AB - In this paper, we report a novel visible light driven Ag/CdO photocatalyst, fabricated for the first time via one pot hydrothermal method and further applied for the photodegradation of two important exemplar water contaminants, Malachite green and Acid Orange 7. The microstructure, composition and optical properties of Ag/CdO nanocomposites were thoroughly investigated by various techniques. Scanning electron microscopy clearly shows that Ag NPs were strongly embedded between the CdO nanoparticles. Among the series of synthesized Ag/CdO nanocomposites, (5%) Ag/CdO nanocomposite possesses enhanced photocatalytic activity. This result was attributed to the synergistic effect between Ag and CdO, and mainly Ag NPs can act as an electron trap site, which could reduce the recombination of the electron-hole and induce the visible light absorption. The active species trapping experiments implicate OH and O2- radicals as the respective primary and secondary reactive species responsible for oxidative photodegradation of organic pollutants. On the basis of the results, a possible photocatalytic mechanism has also been proposed. PMID- 28734997 TI - Influence of preparation, fitting, and cementation on the vitro performance and fracture resistance of CAD/CAM crowns. AB - OBJECTIVES: To investigate debonding and stability of CAD/CAM composite crowns as a function of (a) preparation design, (b) fitting parameters of the milling process, and (c) type of cementation. METHODS: Extracted human molars were prepared providing either retentive design (R) or no retention (NR). After digitalization, full-contour crowns were milled using either optimal (OF) or reduced (RF) fitting parameters. A total of 112 crowns were milled from the composite materials Lava Ultimate (L) and Grandio Blocs (G) and a ceramic reference. The crowns were either cemented with self-adhesive cement (SE) or were adhesively bonded (A). After water storage, thermal cycling and mechanical loading was performed. Restorations which failed during storage or TCML were analyzed using scanning electron microscopy and surviving restorations were loaded to fracture. RESULTS: L crowns survived only with R/OF/A conditions. No debondings were observed for G crowns with OF/A conditions as well as R/OF/SE conditions. Surviving L crowns showed mean fracture values of 1227N (NR/RF/A) and 1534N (R/OF/A), and for surviving G crowns mean fracture values of 2021N (R/OF), 1872N (R/RF), 2242N (NR/OF), and 2070N (NR/RF) were identified. CONCLUSIONS: Retentive preparation design and/or optimal fitting reduced the number of debondings. For composite restorations, adhesive cementation should be preferred. CLINICAL SIGNIFICANCE: Preparation design, fitting parameters as well as the type of cementation impact the performance of composite crowns. Retentive preparation design and/or good fitting are mandatory to avoid debonding of composite restorations; adhesive cementation should be preferred in any case. PMID- 28734998 TI - Oxidative stress with tau hyperphosphorylation in memory impaired 1,2 diacetylbenzene-treated mice. AB - Long-term exposure to organic solvent may be related to the incidence of neuronal diseases, such as, Alzheimer's disease, depression, multiple sclerosis, dementia, Parkinson's disease. Previously, the authors reported 1,2-diacetylbenzene (DAB; a neurotoxic metabolite of 1,2-diethylbenzene) causes central and peripheral neuropathies that lead to motor neuronal deficits. Furthermore, it is known DAB increases oxidative stress and protein adduct levels and impairs hippocampal neurogenesis in mice. The authors examined the relevance of oxidative stress and tau hyperphosphorylation in the hippocampus. Five-week-old male C57BL/6 mice were treated with 1 or 5mg/kg/day DAB for 2weeks. Neither overall body weight increases nor behavioral differences were observed after treatment, but kidney and liver weights decreased. Increased ROS production, activated glycogen synthase kinase-3beta (GSK-3beta) and tau hyperphosphorylation were observed in hippocampal homogenates. To assess memory impairment, the Morris Water Maze was used. Animals in the DAB-treated groups took longer to reach the platform. Movement patterns of DAB treated mice were more complicated and their swimming speeds were lower than those of controls. When SHSY5Y neuroblastoma cells were pretreated with NAC (an antioxidant) or a GSK-3beta inhibitor, the expression of active GSK-3beta and tau hyperphosphorylation were reduced. These results suggest ROS produced by DAB causes tau hyperphosphorylation via GSK-3beta phosphorylation and it might be related to impaired memory deficit. PMID- 28734999 TI - The reversion of anti-cancer drug antagonism of tamoxifen and docetaxel by the hyaluronic acid-decorated polymeric nanoparticles. AB - Docetaxel (DTX) and tamoxifen (TMX) are first-line drugs used to treat breast cancer. However when used in combination, they produce antagonism because of their differential metabolic pathways. In order to prevent this antagonism, an amphiphilic copolymer, cholesterol modified hyaruronic acid (HA-CHOL), was synthesized for investigating the co-delivery of TMX and DTX. In vitro drug release experiment of the Co-encapsulated (encapsulated DTX+TMX) nanoparticles (Co-NPs) revealed that NPs with unique release mechanism can markedly reduce the release of these drugs in the circulatory system. However, when reaching in cell, TMX can release rapidly to prevent DTX from coming into contact with metabolizing enzymes. In vitro cytotoxicity experiment revealed that the Co-NPs exhibited a significant synergistic effect for inhibiting the proliferation of the cancer cell lines A549, MCF7 and S180. NPs carrying Coumarin-6(Cou6) exhibited increased cellular uptake compared with Cou6 solution at similar drug concentrations. As an in vivo treatment of xenograft tumors involving 180 cells, the Co-NPs displayed a clear tumor-inhibiting effect. This led us to conclude that the reversion of drug antagonism by NPs was attributed to the increased stability of the nanoparticles in the blood circulation, the efficient cellular uptake, the hierarchical drug metabolism in the tumor and the good and orderly delivery of the drugs to the tumor tissue. PMID- 28735000 TI - Application of pharmacometrics and quantitative systems pharmacology to cancer therapy: The example of luminal a breast cancer. AB - Breast cancer (BC) is the most common cancer in women, and the second most frequent cause of cancer-related deaths in women worldwide. It is a heterogeneous disease composed of multiple subtypes with distinct morphologies and clinical implications. Quantitative systems pharmacology (QSP) is an emerging discipline bridging systems biology with pharmacokinetics (PK) and pharmacodynamics (PD) leveraging the systematic understanding of drugs' efficacy and toxicity. Despite numerous challenges in applying computational methodologies for QSP and mechanism based PK/PD models to biological, physiological, and pharmacological data, bridging these disciplines has the potential to enhance our understanding of complex disease systems such as BC. In QSP/PK/PD models, various sources of data are combined including large, multi-scale experimental data such as -omics (i.e. genomics, transcriptomics, proteomics, and metabolomics), biomarkers (circulating and bound), PK, and PD endpoints. This offers a means for a translational application from pre-clinical mathematical models to patients, bridging the bench to bedside paradigm. Not only can these models be applied to inform and advance BC drug development, but they also could aid in optimizing combination therapies and rational dosing regimens for BC patients. Here, we review the current literature pertaining to the application of QSP and pharmacometrics-based pharmacotherapy in BC including bottom-up and top-down modeling approaches. Bottom-up modeling approaches employ mechanistic signal transduction pathways to predict the behavior of a biological system. The ones that are addressed in this review include signal transduction and homeostatic feedback modeling approaches. Alternatively, top-down modeling techniques are bioinformatics reconstruction techniques that infer static connections between molecules that make up a biological network and include (1) Bayesian networks, (2) co-expression networks, and (3) module-based approaches. This review also addresses novel techniques which utilize the principles of systems biology, synthetic lethality and tumor priming, both of which are discussed in relationship to novel drug targets and existing BC therapies. By utilizing QSP approaches, clinicians may develop a platform for improved dose individualization for subpopulation of BC patients, strengthen rationale in treatment designs, and explore mechanism elucidation for improving future treatments in BC medicine. PMID- 28735001 TI - Characterization of full-length tubuliform spidroin gene from Araneus ventricosus. AB - Orb-web spiders produce at least seven different protein-based silk that exhibit different mechanical properties. Egg case silk is spun by tubuliform glands and used to form the outer shell of egg case. To date, only two complete cDNA sequences have been reported for tubuliform spidroin (TuSp, also known as CySp for cylindrical spidroin). Here, we report the complete genomic DNA sequence for a tubuliform spidroin (TuSp1) gene from orb-web weaving spider species Araneus ventricosus, which was obtained by using a long distance PCR approach. The primary component of Araneus ventricosus TuSp1 gene contains a single large exon (5763bp) and encodes 1921 amino acid residues dominated by 9 tandem repeats flanked by conserved non-repetitive N- and C-terminal domains. These repeats (each 176-155 amino acids long) found in Araneus ventricosus TuSp1 are highly conserved (>96% identical at amino acid level). PMID- 28735002 TI - Immobilization of beta-galactosidase on surface modified cobalt/multiwalled carbon nanotube nanocomposite improves enzyme stability and resistance to inhibitor. AB - The present study aimed to work out a high yield procedure for immobilization of Aspergillus oryzae beta-galactosidase on polyaniline cobalt multiwalled carbon nanotubes nanocomposite (PANI/Co/MWCNTNC) by physical adsorption and covalent attachment via glutaraldehyde. The binding was confirmed by scanning and transmission electron microscopy along with Fourier transform-infrared spectroscopy. The immobilization yields obtained for adsorbed and cross-linked enzymes were 93% and 97%, respectively. The covalently immobilized enzyme was remarkably more stable at extremes of pH and temperature compared to native and adsorbed enzymes. The Ki values were found to increase ten-folds for covalently immobilized beta-galactosidase indicating that this immobilized enzyme was markedly more resistant to galactose inhibition. The covalently attached enzyme retained 92% activity after its 10th successive reuse compared to the adsorbed beta-galactosidase which exhibited 74% of its initial activity. Furthermore, no significant change was noticed in the band intensity of pBR322 plasmid when exposed to free and bound nanocomposite. The covalently bound enzyme exhibited superiority in terms of stability and reusability when compared to the adsorbed and native beta-galactosidase. The results, presented here demonstrate an efficient method of immobilization of beta-galactosidase on PANI/Co/MWCNTNC in order to construct a convenient and novel biosensor for the detection of lactose concentration. PMID- 28735003 TI - Feeding strategies for tuning poly (3-hydroxybutyrate-co-4-hydroxybutyrate) monomeric composition and productivity using Burkholderia sacchari. AB - Poly(3-hydroxybutyrate-co-4-hydroxybutyrate) (P(3HB-4HB)) co-polymers were produced at bench-scale in fed-batch cultivations by Burkholderia sacchari from glucose (main carbon-source) and gamma-butyrolactone (GBL) as co-substrate. As P(3HB-4HB) properties highly depend on the 4-hydroxybutyrate (4HB) molar fraction, it is advantageous to have a thorough knowledge of the process in order to promote the production of the targeted final product. In this work, polymers with a 4HB molar percentage ranging from 1.5 to 8.4% (mol/mol) were obtained as consequence of a fine tuning of the fed-batch operation conditions, namely regarding the co-substrate feeding rate and its addition time, as GBL is toxic to B. sacchari cells. The best results regarding both the 4HB incorporation (molar%) and the co-polymer productivity (7.1% and 1.1g/(L.h) respectively) were reached when a pulse of GBL (<10g/L) was added early in the accumulation phase followed by a constant GBL addition at a rate similar to that of consumption so that a steady co-substrate concentration in the medium was maintained. PMID- 28735004 TI - tRNA conjugation with folic acid-chitosan conjugates. AB - The conjugation of tRNA with folic acid-chitosan conjugates was studied, using multiple spectroscopic methods and transmission electron microscopy (TEM). Thermodynamic analysis DeltaH -14 to -10 (KJMol-1) and DeltaS 14 to -1 (JMol-1, K 1) showed tRNA-folic acid-chitosan bindings occur via H-bonding, hydrophobic and van der Waals contacts. The loading efficacy and the stability of tRNA conjugates were enhanced as folic acid-chitosan size increased. TEM analysis showed major tRNA morphological changes, upon folic acid-chitosan conjugation. No alteration of tRNA conformation was observed on conjugate formation. Folic acid-chitosan conjugates can deliver tRNA in vitro. PMID- 28735005 TI - Immobilization of antimicrobial peptides onto cellulose nanopaper. AB - In this work we report the production of cellulose nanopapers modified with alkyl ketene dimer (AKD) in order to allow the immobilization of antimicrobial peptides (AMPs) to produce surfaces with antimicrobial properties. Cellulose nanofibers (CNF) were prepared from softwood bleached pulp via high pressure homogenization after chemical pretreatment of fibers via TEMPO oxidation. Nanopapers were then prepared after a casting technique and functionalized with alkyl ketene dimer before AMPs were immobilized. The immobilization process was performed by submerging the samples into AMP aqueous solutions and then dried at room temperature. Antimicrobial activity was tested against B. subtilis. Results indicated that AMPs were bound onto the nanopaper surface and released when the nanopaper was put in contact with the culture medium, which effectively demonstrates the viability of the immobilization process. PMID- 28735006 TI - Chitosan as a bioactive polymer: Processing, properties and applications. AB - Chitin is one of the most abundant natural polysaccharides in the world and it is mainly used for the production of chitosan by a deacetylation process. Chitosan is a bioactive polymer with a wide variety of applications due to its functional properties such as antibacterial activity, non-toxicity, ease of modification, and biodegradability. This review summarizes the most common chitosan processing methods and highlights some applications of chitosan in various industrial and biomedical fields. Finally, environmental concerns of chitosan-based films, considering the stages from raw materials extraction up to the end of life after disposal, are also discussed with the aim of finding more eco-friendly alternatives. PMID- 28735007 TI - Lignocellulosic micro/nanofibers from wood sawdust applied to recycled fibers for the production of paper bags. AB - In the present work, lignocellulosic micro/nanofibers (LCMNF) were produced from pine sawdust. For that, pine sawdust was submitted to alkali treatment and subsequent bleaching stages, tailoring its chemical composition with the purpose of obtaining effective LCMNF. The obtained LCMNF were characterized and incorporated to recycled cardboard boxes with the purpose of producing recycled paper. The obtained results showed that it was possible to obtain LCMNF with the same reinforcing potential than those cellulose nanofibers (CNF) prepared by oxidative or other chemical methods In fact, the obtained papers increased the breaking length of recycled cardboard from 3338m to 5347m, being a value significantly higher than the requirements to produce paper bags. Overall, the studied strategies could allow a significant reduction of paper basis weight, with the consequent material saving and, thus, contribution to the environment. PMID- 28735008 TI - Trehalose induced structural modulation of Bovine Serum Albumin at ambient temperature. AB - Trehalose is a well-known protein stabilizing osmolyte. The present study has been designed to understand the interaction of trehalose with BSA at ambient temperature. Steady state fluorescence and life-time analysis along with CD, DLS and ITC have been employed to show that trehalose causes surface-associated structural perturbation of BSA to promote its compaction. Trehalose at 0.1M concentration resulted in increased solvent exposure of one of the two tryptophans of BSA with a 5nm redshift in emission and enhanced susceptibility to acrylamide quenching with an increase in KSV from 2.61M-1to 5.16M-1. 0.5M trehalose resulted in reduced accessibility of tryptophan and destabilization of ANS binding (Forster radius increased from 24A to 27.36A for tryptophan-ANS FRET) indicating shielding of BSA in trehalose matrix. Simultaneously, there was compaction of BSA as shown by increased alpha-helicity from 45.85% to 48.81%, decreased thioflavin-T binding and reduction in hydrodynamic radius from 9.69nm to 6.59nm. Trehalose induced solution viscosity resulted in significant decrease in binding affinity of BSA towards curcumin and resveratrol. The results are in unison with the preferential exclusion and vitrification models to explain protein stabilization by trehalose and also points at the structure-function trade-off of proteins in presence of trehalose. PMID- 28735009 TI - Serotonergic network in the subesophageal zone modulates the motor pattern for food intake in Drosophila. AB - The functional organization of central motor circuits underlying feeding behaviors is not well understood. We have combined electrophysiological and genetic approaches to investigate the regulatory networks upstream of the motor program underlying food intake in the Drosophila larval central nervous system. We discovered that the serotonergic network of the CNS is able to set the motor rhythm frequency of pharyngeal pumping. Pharmacological experiments verified that modulation of the feeding motor pattern is based on the release of serotonin. Classical lesion and laser based cell ablation indicated that the serotonergic neurons in the subesophageal zone represent a redundant network for motor control of larval food intake. PMID- 28735010 TI - Maternal age affects offspring nutrient dynamics. AB - The internal physiological state of a mother can have major effects on her fitness and that of her offspring. We show that maternal effects in the parasitic wasp Eupelmus vuilleti become apparent when old mothers provision their eggs with less protein, sugar and lipid. Feeding from a host after hatching allows the offspring of old mothers to overcome initial shortages in sugars and lipids, but adult offspring of old mothers still emerged with lower protein and glycogen quantities. Reduced egg provisioning by old mothers had adverse consequences for the nutrient composition of adult female offspring, despite larval feeding from a high-quality host. Lower resource availability in adult offspring of old mothers can affect behavioural decisions, life histories and performance. Maternal effects on egg nutrient provisioning may thus affect nutrient availability and fitness of future generations in oviparous animals. PMID- 28735011 TI - Assessment and elimination of the effects of head movement on MEG resting-state measures of oscillatory brain activity. AB - Magnetoencephalography (MEG) is increasingly being used to study brain function because of its excellent temporal resolution and its direct association with brain activity at the neuronal level. One possible cause of error in the analysis of MEG data comes from the fact that participants, even MEG-experienced ones, move their head in the MEG system. Head movement can cause source localization errors during the analysis of MEG data, which can result in the appearance of source variability that does not reflect brain activity. The MEG community places great importance in eliminating this source of possible errors as is evident, for example, by recent efforts to develop head casts that limit head movement in the MEG system. In this work we use software tools to identify, assess and eliminate from the analysis of MEG data any possible correlations between head movement in the MEG system and widely-used measures of brain activity derived from MEG resting-state recordings. The measures of brain activity we study are a) the Hilbert-transform derived amplitude envelope of the beamformer time series and b) functional networks; both measures derived by MEG resting-state recordings. Ten minute MEG resting-state recordings were performed on healthy participants, with head position continuously recorded. The sources of the measured magnetic signals were localized via beamformer spatial filtering. Temporal independent component analysis was subsequently used to derive resting-state networks. Significant correlations were observed between the beamformer envelope time series and head movement. The correlations were substantially reduced, and in some cases eliminated, after a participant-specific temporal high-pass filter was applied to those time series. Regressing the head movement metrics out of the beamformer envelope time series had an even stronger effect in reducing these correlations. Correlation trends were also observed between head movement and the activation time series of the default-mode and frontal networks. Regressing the head movement metrics out of the beamformer envelope time series completely eliminated these correlations. Additionally, applying the head movement correction resulted in changes in the network spatial maps for the visual and sensorimotor networks. Our results a) show that the results of MEG resting-state studies that use the above-mentioned analysis methods are confounded by head movement effects, b) suggest that regressing the head movement metrics out of the beamformer envelope time series is a necessary step to be added to these analyses, in order to eliminate the effect that head movement has on the amplitude envelope of beamformer time series and the network time series and c) highlight changes in the connectivity spatial maps when head movement correction is applied. PMID- 28735013 TI - Simultaneous intrinsic signal imaging of auditory and visual cortex reveals profound effects of acute hearing loss on visual processing. AB - It has been suggested that primary sensory cortices do not work in isolation but receive subthreshold inputs originating from other senses. However, repercussions of an acute loss of one sense on multimodal sensory processing remain elusive. Here we investigated the early effects of acute hearing loss on visual processing in adult mice. For this, we developed a method to simultaneously map the primary auditory (A1) and visual cortex (V1) using periodic intrinsic optical imaging. We found that reducing sound evoked A1 responsiveness due to the induction of conductive hearing loss (CHL) led to a concomitant increase of visually driven V1 activity. Accordingly, using the neuronal activity marker c-fos we found the number of stained pyramidal cells to be increased in V1 layer 2/3 after CHL. In contrast, numbers of c-fos positive parvalbumin (PV) and somatostatin (SOM) expressing inhibitory neurons were reduced after CHL. Finally, we adapted the periodic intrinsic imaging method to determine V1 contrast and spatial frequency tuning. Using this method we could show that visual acuity and contrast sensitivity were improved after CHL. In addition, retrograde tracing experiments revealed direct anatomical projections from A1 to V1 which could potentially serve as a substrate for the observed effects. In summary, our results suggest that CHL rapidly disrupts the functional interplay between A1 and V1 leading to altered visually evoked V1 responses. PMID- 28735012 TI - FGWAS: Functional genome wide association analysis. AB - Functional phenotypes (e.g., subcortical surface representation), which commonly arise in imaging genetic studies, have been used to detect putative genes for complexly inherited neuropsychiatric and neurodegenerative disorders. However, existing statistical methods largely ignore the functional features (e.g., functional smoothness and correlation). The aim of this paper is to develop a functional genome-wide association analysis (FGWAS) framework to efficiently carry out whole-genome analyses of functional phenotypes. FGWAS consists of three components: a multivariate varying coefficient model, a global sure independence screening procedure, and a test procedure. Compared with the standard multivariate regression model, the multivariate varying coefficient model explicitly models the functional features of functional phenotypes through the integration of smooth coefficient functions and functional principal component analysis. Statistically, compared with existing methods for genome-wide association studies (GWAS), FGWAS can substantially boost the detection power for discovering important genetic variants influencing brain structure and function. Simulation studies show that FGWAS outperforms existing GWAS methods for searching sparse signals in an extremely large search space, while controlling for the family-wise error rate. We have successfully applied FGWAS to large-scale analysis of data from the Alzheimer's Disease Neuroimaging Initiative for 708 subjects, 30,000 vertices on the left and right hippocampal surfaces, and 501,584 SNPs. PMID- 28735014 TI - Initial Clinical Experience With Testosterone Undecanoate Therapy (AVEED) in Men With Testosterone Deficiency in the United States. AB - OBJECTIVE: To report our initial experiences with testosterone undecanoate (TU 750) mg (AVEED) in men with testosterone deficiency. METHODS: All patients receiving TU 750 mg at our center between July 1, 2014, and August 1, 2016, were identified. Clinical response was assessed through structured interviews and laboratory evaluations. Adverse events were documented, including increase in prostate specific antigen (PSA), increase in hematocrit (Hct), and the development of postinjection cough. RESULTS: More than 2 injections were received by 147 men, with mean age 63.2 years. Mean baseline total testosterone (T) and free T were 305 ng/dL and 0.69 ng/dL, respectively. Nadir mean results during treatment were higher for total and free T, at 413.2 ng/dL and 0.81 ng/dL, respectively (P < .001 for each). Symptomatic improvement was reported by 97 of 147 patients (66.0%). Thirty patients (20.4%) discontinued therapy. Return of symptoms before the next injection was noted by 34%, managed by reduced interval between injections and/or supplemental injections of T cypionate. Three patients (2%) experienced transient cough immediately after TU injection, none requiring intervention. Mean Hct rose from 45.6% to 47.2%. Mean PSA rose from 1.7 ng/mL to 2.0 ng/mL. There were no strokes, myocardial infarctions, or deaths, and no new cases of prostate cancer. CONCLUSION: This initial clinical experience with TU 750 mg provides evidence for good patient satisfaction and persistence with treatment, together with a favorable safety profile. Optimal dosing may be less than 10 weeks for some individuals. PMID- 28735015 TI - Preliminary Experience of Nontransecting Urethroplasty for Pelvic Fracture related Urethral Injury. AB - OBJECTIVE: To evaluate the urinary outcomes and preservation of erectile function in patients with pelvic fracture-related urethral injury (PFUI) after nontransecting spongiosum anastomotic urethroplasty (NTSAU). MATERIALS AND METHODS: Fifty-nine male patients with PFUI following traumatic pelvic fracture underwent NTSAU. Inclusion criteria were age 18-60 years, posterior urethral stenosis <2.5 cm without previous urethroplasty, and intact erectile function. Exclusion criteria were history of open urethroplasty, long-segment posterior urethral stenosis (>2.5 cm), preoperative impotency, or age over 60 years. Pre- and postoperative outcome analyses were performed with a paired t test and chi square test. RESULTS: Between January 2011 and August 2015, 59 patients with a mean age of 38.5 years (range, 21-59 years) and a mean stricture length of 2.0 cm (range, 1-2.5 cm) underwent simple NTSAU (group 1, n = 41) or NTSAU with inferior pubectomy (group 2, n = 18). Patients were followed for a mean 25 months (range, 12-60 months). The primary success rate was 96.6% (57 of 59), and stricture recurrence occurred in 2 (3.4%) patients. The secondary outcomes revealed no significant changes in number of events, tip rigidity, or duration of best episode between pre- and postoperative nocturnal penile tumescence test (on RigiScan) in group 1, but a slight decrease in group 2 (P <.05). The limitation was the small sample size and heterogeneous population. CONCLUSION: NTSAU is a safe, feasible, minimally invasive procedure for PFUI, optimizing erectile preservation. PMID- 28735016 TI - Timing of Prostate-specific Antigen Nadir After Radical Prostatectomy and Risk of Biochemical Recurrence. AB - OBJECTIVE: To evaluate the association between the prostate-specific antigen (PSA) nadir level and the time to nadir (TTN) with biochemical recurrence (BCR) risk after radical prostatectomy (RP) in the Shared Equal-Access Research Cancer Hospital (SEARCH) database. MATERIALS AND METHODS: This is a retrospective analysis of 1939 men from the SEARCH database treated with RP between 1998 and 2015 with available ultrasensitive PSA nadir within 1-6 months after RP. Uni- and multivariable analyses of PSA nadir and TTN with time from nadir to BCR were performed with Cox models (adjusted for demographics, tumor features, and preoperative PSA). RESULTS: Among men with an undetectable PSA nadir, the TTN was unrelated to BCR (1.0-2.9 vs 3-6 months: hazard ratio [HR] 0.86, P = .46). Regardless of TTN, men with detectable nadir had an increased risk of BCR (TTN of 3-6 months: HR 1.81, P = .024; TTN of 1.0-2.99 months: HR 3.75, P <.001 vs undetectable nadir and TTN of 3-6 months). Among men with a detectable PSA at 1-3 months, 53% had a lower PSA level during follow-up 3-6 months after RP, which was undetectable in 32% and lower but still detectable in 21%. CONCLUSION: In the post-RP setting, men with both a detectable nadir and a shorter TTN had an increased risk of BCR. Intriguingly, about half of the men with a detectable PSA in the first 3 months after RP had a lower PSA level during follow-up between 3 and 6 months after RP. If confirmed in future studies, this has important implications for patients considering adjuvant therapy based on postoperative PSA values in the first 3 months after RP. PMID- 28735017 TI - En Bloc Thulium Laser Enucleation of the Prostate: Surgical Technique and Advantages Compared With the Classical Technique. AB - OBJECTIVE: To report a new technique for thulium laser enucleation of the prostate, which we called "en bloc" ThuLEP. METHODS: A full anatomic description of the technique is provided. We assessed operative variables of a 50-patient series, treated with the new "en bloc" ThuLEP, and compared them with another series of 50 patients (who had the same preoperative parameters) operated with the classical "3-lobe" technique, to assess the feasibility of the new one. All procedures were carried out by the same surgeon. RESULTS: In our experience, "en bloc" ThuLEP permits an easier enucleation of the adenoma, reduces operating time, and reduces the amount of energy delivered per adenoma gram compared with the classical technique. Further studies are needed to validate this technical evolution of prostatic enucleation and verify the reduction of postoperative irritative symptoms. CONCLUSION: "En bloc" ThuLEP may represent a valid alternative for prostatic adenoma enucleation, mostly in medium-sized prostates. PMID- 28735018 TI - Safety and Feasibility of Direct Magnetic Resonance Imaging-guided Transperineal Prostate Biopsy Using a Novel Magnetic Resonance Imaging-safe Robotic Device. AB - OBJECTIVE: To evaluate safety and feasibility in a first-in-human trial of a direct magnetic resonance imaging (MRI)-guided prostate biopsy using a novel robotic device. METHODS: MrBot is an MRI-safe robotic device constructed entirely with nonconductive, nonmetallic, and nonmagnetic materials and developed by our group. A safety and feasibility clinical trial was designed to assess the safety and feasibility of a direct MRI-guided biopsy with MrBot and to determine its targeting accuracy. Men with elevated prostate-specific antigen levels, prior negative prostate biopsies, and cancer-suspicious regions (CSRs) on MRI were enrolled in the study. Biopsies targeting CSRs, in addition to sextant locations, were performed. RESULTS: Five men underwent biopsy with MrBot. Two men required Foley catheter insertion after the procedure, with no other complications or adverse events. Even though this was not a study designed to detect prostate cancer, biopsies confirmed the presence of a clinically significant cancer in 2 patients. On a total of 30 biopsy sites, the robot achieved an MRI-based targeting accuracy of 2.55 mm and a precision of 1.59 mm normal to the needle, with no trajectory corrections and no unsuccessful attempts to target a site. CONCLUSION: Robot-assisted MRI-guided prostate biopsy appears safe and feasible. This study confirms that a clinically significant prostate cancer (>=5-mm radius, 0.5 cm3) depicted in MRI may be accurately targeted. Direct confirmation of needle placement in the CSR may present an advantage over fusion-based technology and gives more confidence in a negative biopsy result. Additional study is warranted to evaluate the efficacy of this approach. PMID- 28735019 TI - One-year Surgical Outcomes of Complete or Incomplete Enucleation of Prostate by Monopolar Electrocoagulation, Photoselective Vapoenucleation of 120-W GreenLight Laser, and Holmium Laser. AB - OBJECTIVE: To evaluate surgical outcomes of patients who underwent complete or incomplete enucleation technique during a short-term postoperative period. MATERIALS AND METHODS: Patients having intractable lower urinary tract symptoms/benign prostatic hyperplasia and prostates >30 g with obstructed pattern in the urodynamic examinations were included. They underwent transurethral resection of prostate (TUR-P), 120 W GreenLight laser high power system photoselective vapoenucleation of prostate (HPS-PVEP), or holmium laser enucleation of prostate (HoLEP). Patients with the size of remnant prostates minus surgical defects <25 g were grouped into the completely enucleated group (group C), and others were grouped into the partially enucleated group (group P). RESULTS: Mean prostate-specific antigen value was 3.5 +/- 4.5 ng/mL, and mean prostate volume was 58.4 +/- 31.0 mL. Complete enucleation rates in TUR-P, HPS PVEP, and HoLEP groups were 39% (37 out of 95), 54.6% (83 out of 152), and 54.4% (31 out of 57), respectively. Complete enucleation rate of the TUR-P was significantly lower than those of the other 2 groups. Compared with group C, group P had lower maximal flow rate, higher bladder outlet obstruction index, and higher overactive bladder symptom scores. Multivariate logistic regression analyses showed that smaller prostate, presence of intravesical prostatic protrusion, HoLEP operation, and surgeons' experience were significant predictors for achieving complete enucleation of prostate. Voiding subscores of group C were significantly higher than those of group P at postoperative 12 months. CONCLUSION: The performance of HoLEP was superior to other surgical techniques. However, HPS-PVEP with vapoenucleation showed the comparable enucleation rate with that of HoLEP. Complete enucleation was effective in maintaining outcomes of prostate resection, especially voiding subscores. PMID- 28735020 TI - Pilot Study of Prostate Cancer Angiogenesis Imaging Using a Photoacoustic Imaging System. AB - OBJECTIVES: To investigate a link between the appearance of photoacoustic imaging (PAI) and microvasculature in prostate cancer and to assess the feasibility of PAI for angiogenesis imaging in prostate cancer. METHODS: We have developed a PAI system equipped with a transrectal ultrasound (TRUS)-type probe. Three patients who underwent PAI just before prostate biopsy and subsequently underwent radical prostatectomy were included. The PAI appearance was retrospectively reviewed, and in each patient, 4 representative areas were selected: 1 with high PAI signal intensity, 1 with low PAI signal intensity, 1 peripheral to the index tumor, and 1 inside the index tumor. The correlation of PAI intensity with 3 microvascular parameters-microvascular density, total vascular area (TVA), and total vascular length (TVL)-assessed by CD34-immunostaining in resected specimens was analyzed. RESULTS: In all 3 patients the PAI intensity, TVA, and TVL in areas with high intensity PAI signals were significantly higher than those in areas with low intensity PAI signals, suggesting that PAI appearance describes the distribution of microvasculature in prostatic tissue correctly. All index tumors showed a ring like PAI appearance consisting of a peripheral area of high signal intensity completely or partially surrounding an area with low signal intensity. The PAI intensity, TVA, and TVL in the periphery of the index tumors were significantly higher than those inside of the index tumors. CONCLUSION: The intensity of PAI signals might reflect the microvascularity in normal prostatic tissues and index tumors. PAI could be a novel modality for imaging prostate cancer angiogenesis. PMID- 28735021 TI - WISP1/CCN4 aggravates cartilage degeneration in experimental osteoarthritis. AB - OBJECTIVE: Increased Wisp1 expression was previously reported in experimental and human osteoarthritis (OA). Moreover, adenoviral overexpression of Wisp1 in naive mouse knee joints resulted in early OA-like cartilage lesions. Here, we determined how the matricellular protein WISP1 is involved in the pathology that occurs in the complex osteoarthritic environment with aging and experimental OA in wild type (WT) and Wisp1-/- mice. METHODS: WT and Wisp1-/- mice were aged or experimental OA was induced with intraarticular collagenase injection, destabilization of the medial meniscus (DMM) or anterior cruciate ligament transection (ACLT). Joint pathology was assessed using histology and microCT. Protease expression was evaluated with qRT-PCR and activity was determined by immunohistochemical staining of the aggrecan neoepitope NITEGE. Protease expression in human end-stage OA synovial tissue was determined with qRT-PCR after stimulation with WISP1. RESULTS: With aging, spontaneous cartilage degeneration in Wisp1-/- was not decreased compared to their WT controls. However, we observed significantly decreased cartilage degeneration in Wisp1-/- mice after induction of three independent experimental OA models. While the degree of osteophyte formation was comparable between WT and Wisp1-/- mice, increased cortical thickness and reduced trabecular spacing was observed in Wisp1 /- mice. In addition, we observed decreased MMP3/9 and ADAMTS4/5 expression in Wisp1-/- mice, which was accompanied by decreased levels of NITEGE. In line with this, stimulation of human OA synovium with WISP1 increased the expression of various proteases. CONCLUSIONS: WISP1 plays an aggravating role in the development of post-traumatic experimental OA. PMID- 28735022 TI - Emerging Players in the Nitrate Signaling Pathway. PMID- 28735023 TI - Arabidopsis WRKY45 Interacts with the DELLA Protein RGL1 to Positively Regulate Age-Triggered Leaf Senescence. AB - Leaf senescence can be triggered and promoted by various environmental stressors, developmental cues, and endogenous hormone signals. Several lines of evidence have suggested the involvement of WRKY transcription factors in regulating leaf senescence, but the underlying mechanisms and signaling pathways involved remain elusive. In this study, we identified Arabidopsis thaliana WRKY DNA-binding protein 45 (WRKY45) as a positive regulator of age-triggered leaf senescence. Loss of WRKY45 function resulted in increased leaf longevity in age-triggered senescence, whereas overexpression of WRKY45 significantly accelerated age triggered leaf senescence. Consistently, expression of SENESCENCE-ASSOCIATED GENEs (SAGs) was significantly reduced in wrky45 mutants but markedly enhanced in transgenic plants overexpressing WRKY45. Chromatin immunoprecipitation assays revealed that WRKY45 directly binds the promoters of several SAGs such as SAG12, SAG13, SAG113, and SEN4. Both in vivo and in vitro biochemical analyses demonstrated that WRKY45 interacts with the DELLA protein RGA-LIKE1 (RGL1), a repressor of the gibberellin (GA) signaling pathway. We found that RGL1 repressed the transcription activation function of WRKY45, thereby attenuating the expression of its regulon. Consistent with this finding, overexpression of RGL1 resulted in significantly increased leaf longevity in age-triggered senescence. Taken together, our results provide compelling evidence that WRKY45 functions as a critical component of the GA-mediated signaling pathway to positively regulate age-triggered leaf senescence. PMID- 28735024 TI - N-Linked Glycosylation of the p24 Family Protein p24delta5 Modulates Retrograde Golgi-to-ER Transport of K/HDEL Ligands in Arabidopsis. AB - The K/HDEL receptor ERD2 mediates the transport of soluble endoplasmic reticulum (ER)-resident proteins containing a C-terminal K/HDEL signal from the Golgi apparatus back to the ER via COPI (COat Protein I)-coated vesicles. Sorting of ERD2 within COPI vesicles is facilitated by p24 proteins. In Arabidopsis, p24delta5 has been shown to interact directly with ERD2 via its luminal GOLD (GOLgi Dynamics) domain and with COPI proteins via its cytoplasmic C-terminal tail at the acidic pH of the Golgi apparatus. Several members of the p24 family in mammals and yeast have been shown to be glycosylated, but whether Arabidopsis p24 proteins are glycosylated and the role of the sugar moiety in p24 function remain unclear. Here, we show that Arabidopsis p24delta5 protein is N glycosylated in its GOLD domain. Furthermore, we demonstrate that this post translational modification is important for its coupled transport with p24beta2 at the ER-Golgi interface, for its interaction with the K/HDEL receptor ERD2, and for retrograde transport of ERD2 and K/HDEL ligands from the Golgi apparatus back to the ER. PMID- 28735025 TI - A Toolbox for the Analysis of Peptide Signal Biogenesis. PMID- 28735026 TI - Regulated viral BDNF delivery in combination with Schwann cells promotes axonal regeneration through capillary alginate hydrogels after spinal cord injury. AB - : Grafting of cell-seeded alginate capillary hydrogels into a spinal cord lesion site provides an axonal bridge while physically directing regenerating axonal growth in a linear pattern. However, without an additional growth stimulus, bridging axons fail to extend into the distal host spinal cord. Here we examined whether a combinatory strategy would support regeneration of descending axons across a cervical (C5) lateral hemisection lesion in the rat spinal cord. Following spinal cord transections, Schwann cell (SC)-seeded alginate hydrogels were grafted to the lesion site and AAV5 expressing brain-derived neurotrophic factor (BDNF) under control of a tetracycline-regulated promoter was injected caudally. In addition, we examined whether SC injection into the caudal spinal parenchyma would further enhance regeneration of descending axons to re-enter the host spinal cord. Our data show that both serotonergic and descending axons traced by biotinylated dextran amine (BDA) extend throughout the scaffolds. The number of regenerating axons is significantly increased when caudal BDNF expression is activated and transient BDNF delivery is able to sustain axons after gene expression is switched off. Descending axons are confined to the caudal graft/host interface even with continuous BDNF expression for 8weeks. Only with a caudal injection of SCs, a pathway facilitating axonal regeneration through the host/graft interface is generated allowing axons to successfully re enter the caudal spinal cord. STATEMENT OF SIGNIFICANCE: Recovery from spinal cord injury is poor due to the limited regeneration observed in the adult mammalian central nervous system. Biomaterials, cell transplantation and growth factors that can guide axons across a lesion site, provide a cellular substrate, stimulate axon growth and have shown some promise in increasing the growth distance of regenerating axons. In the present study, we combined an alginate biomaterial with linear channels with transplantation of Schwann cells within and beyond the lesion site and injection of a regulatable vector for the transient expression of brain-derived neurotrophic factor (BDNF). Our data show that only with the full combination axons extend across the lesion site and that expression of BDNF beyond 4weeks does not further increase the number of regenerating axons. PMID- 28735028 TI - Protein-only, antimicrobial peptide-containing recombinant nanoparticles with inherent built-in antibacterial activity. AB - : The emergence of bacterial antibiotic resistances is a serious concern in human and animal health. In this context, naturally occurring cationic antimicrobial peptides (AMPs) might play a main role in a next generation of drugs against bacterial infections. Taking an innovative approach to design self-organizing functional proteins, we have generated here protein-only nanoparticles with intrinsic AMP microbicide activity. Using a recombinant version of the GWH1 antimicrobial peptide as building block, these materials show a wide antibacterial activity spectrum in absence of detectable toxicity on mammalian cells. The GWH1-based nanoparticles combine clinically appealing properties of nanoscale materials with full biocompatibility, structural and functional plasticity and biological efficacy exhibited by proteins. Because of the largely implemented biological fabrication of recombinant protein drugs, the protein based platform presented here represents a novel and scalable strategy in antimicrobial drug design, that by solving some of the limitations of AMPs offers a promising alternative to conventional antibiotics. STATEMENT OF SIGNIFICANCE: The low molecular weight antimicrobial peptide GWH1 has been engineered to oligomerize as self-assembling protein-only nanoparticles of around 50nm. In this form, the peptide exhibits potent and broad antibacterial activities against both Gram-positive and Gram-negative bacteria, without any harmful effect over mammalian cells. As a solid proof-of-concept, this finding strongly supports the design and biofabrication of nanoscale antimicrobial materials with in-built functionalities. The protein-based homogeneous composition offer advantages over alternative materials explored as antimicrobial agents, regarding biocompatibility, biodegradability and environmental suitability. Beyond the described prototype, this transversal engineering concept has wide applicability in the design of novel nanomedicines for advanced treatments of bacterial infections. PMID- 28735027 TI - Translation of an injectable triple-interpenetrating-network hydrogel for intervertebral disc regeneration in a goat model. AB - : Degeneration of the intervertebral discs is a progressive cascade of cellular, compositional and structural changes that is frequently associated with low back pain. As the first signs of disc degeneration typically arise in the disc's central nucleus pulposus (NP), augmentation of the NP via hydrogel injection represents a promising strategy to treat early to mid-stage degeneration. The purpose of this study was to establish the translational feasibility of a triple interpenetrating network hydrogel composed of dextran, chitosan, and teleostean (DCT) for augmentation of the degenerative NP in a preclinical goat model. Ex vivo injection of the DCT hydrogel into degenerated goat lumbar motion segments restored range of motion and neutral zone modulus towards physiologic values. To facilitate non-invasive assessment of hydrogel delivery and distribution, zirconia nanoparticles were added to make the hydrogel radiopaque. Importantly, the addition of zirconia did not negatively impact viability or matrix producing capacity of goat mesenchymal stem cells or NP cells seeded within the hydrogel in vitro. In vivo studies demonstrated that the radiopaque DCT hydrogel was successfully delivered to degenerated goat lumbar intervertebral discs, where it was distributed throughout both the NP and annulus fibrosus, and that the hydrogel remained contained within the disc space for two weeks without evidence of extrusion. These results demonstrate the translational potential of this hydrogel for functional regeneration of degenerate intervertebral discs. STATEMENT OF SIGNIFICANCE: The results of this work demonstrate that a radiopaque hydrogel is capable of normalizing the mechanical function of the degenerative disc, is supportive of disc cell and mesenchymal stem cell viability and matrix production, and can be maintained in the disc space without extrusion following intradiscal delivery in a preclinical large animal model. These results support evaluation of this hydrogel as a minimally invasive disc therapeutic in long-term preclinical studies as a precursor to future clinical application in patients with disc degeneration and low back pain. PMID- 28735029 TI - Peptide modification of polyimide-insulated microwires: Towards improved biocompatibility through reduced glial scarring. AB - : The goal of this study is to improve the integration of implanted microdevices with tissue in the central nervous system (CNS). The long-term utility of neuroprosthetic devices implanted in the CNS is affected by the formation of a scar by resident glial cells (astrocytes and microglia), limiting the viability and functional stability of the devices. Reduction in the proliferation of glial cells is expected to enhance the biocompatibility of devices. We demonstrate the modification of polyimide-insulated microelectrodes with a bioactive peptide KHIFSDDSSE. Microelectrode wires were functionalized with (3-aminopropyl) triethoxy silane (APTES); the peptide was then covalently bonded to the APTES. The soluble peptide was tested in 2D mixed cultures of astrocytes and microglia, and reduced the proliferation of both cell types. The interactions of glial cells with the peptide-modified wires was then examined in 3D cell-laden hydrogels by immunofluorescence microscopy. As expected for uncoated wires, the microglia were first attracted to the wire (7days) followed by astrocyte recruitment and hypertrophy (14days). For the peptide-treated wires, astrocytes coated the wires directly (24h), and formed a thin, stable coating without evidence of hypertrophy, and the attraction of microglia to the wire was significantly reduced. The results suggest a mechanism to improve tissue integration by promoting uniform coating of astrocytes on a foreign body while lessening the reactive response of microglia. We conclude that the bioactive peptide KHIFSDDSSE may be effective in improving the biocompatibility of neural interfaces by both reducing acute glial reactivity and generating stable integration with tissue. STATEMENT OF SIGNIFICANCE: The peptide KHIFSDDSSE has previously been shown in vitro to both reduce the proliferation of astrocytes, and to increase the adhesion of astrocyte to glass substrates. Here, we demonstrate a method to apply uniform coatings of peptides to microwires, which could readily be generalized to other peptides and surfaces. We then show that when peptide-modified wires are inserted into 3D cell-laden hydrogels, the normal cellular reaction (microglial activation followed by astrocyte recruitment and hypertrophy) does not occur, rather astrocytes are attracted directly to the surface of the wire, forming a relatively thin and uniform coating. This suggests a method to improve tissue integration of implanted devices to reduce glial scarring and ultimately reduce failure of neural interfaces. PMID- 28735030 TI - Effect of bosentan therapy in persistent pulmonary hypertension of the newborn. AB - BACKGROUND: Persistent pulmonary hypertension of the newborn (PPHN) contributes to neonatal hypoxemia and is associated with a high mortality. Some PPHN patients are unresponsive to inhaled nitric oxide (iNO). Bosentan, an oral endothelin-1 receptor antagonist, reduces pulmonary vascular resistance and hence may play a role in the treatment of PPHN. METHODS: A retrospective medical records review was performed in newborns who received oral bosentan as an adjunctive therapy for treatment of PPHN between January 2013 and February 2016 at the neonatal intensive care unit of Songklanagarind Hospital. The main outcomes were the effect of bosentan on oxygenation and hemodynamic status after commencement of treatment and the safety of bosentan. RESULTS: Forty neonates at a median (IQR) gestation of 38 (36.8-40) weeks and an initial median (IQR) oxygen index (OI) of 29.2 (13.4-40.1) received bosentan therapy. Oral bosentan was commenced at a median (IQR) age of 27 (14.5-40.2) hours and the mean (SD) duration of treatment was 6.2 (3.1) days. The OI, alveolar-arterial oxygen difference (AaDO2) and oxygen saturation (SpO2) improved significantly at 2 h after treatment (p = 0.002, p = 0.01 and p < 0.001, respectively). In 21 (52.5%) neonates who received iNO and bosentan, the median OI (IQR) was 34.2 (29.0-42.6) with a significant decrease of OI at 6 h (p = 0.005) after treatment. In 19 (47.5%) neonates who received bosentan alone, the median OI (IQR) was 13.0 (9.8-30.9) with a significant decrease of OI in 2 h (p = 0.01) after treatment. The blood pressures before and after bosentan treatment were not statistically significantly different. The mortality rate was 12.5% (5/40). CONCLUSION: Oral bosentan may be a safe and effective treatment to improve oxygenation in neonates with PPHN. Bosentan can be used as an adjuvant therapy with iNO and can be an alternative therapy option in mild-to-moderate PPHN. PMID- 28735031 TI - Taking the alternative route: Women's experience of intranasal fentanyl, subcutaneous fentanyl or intramuscular pethidine for labour analgesia. AB - OBJECTIVE: To compare women's experience of receiving either intranasal fentanyl, subcutaneous fentanyl or intramuscular pethidine for labour analgesia. DESIGN: A content analysis was undertaken as part of the third phase of a larger randomised controlled trial, using the per-protocol dataset to examine women's experiences of treatment received. Healthy women birthing at term, who received intranasal fentanyl (n=41), subcutaneous fentanyl (n=37) and/or intramuscular pethidine (n=38) for labour analgesia, were contacted at 6 weeks postpartum to complete a phone questionnaire. SETTING: A tertiary and regional maternity unit in South Australia. FINDINGS: Over 80% of women who received intranasal or subcutaneous fentanyl reported that they would use the treatment again compared to 44.8% of women who had received pethidine (self-administered intranasal fentanyl provided more expressive responses emphasising the route provided a strong sense of control and enablement. KEY CONCLUSIONS: Route of administration influenced the women's experience, more women who self-administered intranasal fentanyl reported positive emotional responses, with women reporting increased autonomy and satisfaction. Whereas, women who relied on the midwife to administer subcutaneous fentanyl or intramuscular pethidine, were more often focused on the physical effect of the drug. Pethidine was the least preferred option due to adverse effects. IMPLICATIONS FOR PRACTICE: For women requesting parenteral analgesia, fentanyl administered by less invasive routes offers women additional options that may better meet their emotional, cognitive and physical needs than the current practice of administering intramuscular pethidine. PMID- 28735032 TI - A prospective study of breastfeeding intentions of healthy weight and overweight women as predictors of breastfeeding outcomes. AB - OBJECTIVE: Women with a higher BMI are at increased risk of breastfeeding for a shorter duration, however it is unclear if weight status itself or other factors such as feeding intentions are responsible for early breastfeeding cessation. The aim of this study was determine the influence of maternal pre-pregnancy weight status on infant feeding intentions during pregnancy using a validated scale and assess whether high intentions to exclusively breastfeed measured during pregnancy predicted feeding mode at discharge and at 4 months postpartum in both healthy weight (Hwt) (BMI< 25kg/m2) and overweight (Owt)(BMI > 25kg/m2) women. DESIGN: This prospective, observational study commenced when participants were <20 weeks gestation, continuing until four months post partum. Self-administered questionnaires assessed pre-pregnancy weight, infant feeding intentions at 36 weeks gestation, and breastfeeding practices at hospital discharge and 4 months postpartum. Hospital records provided details of delivery mode, gestation and breastfeeding during hospital stay. Binary logistic regression analyses were used to compare weight groups on the breastfeeding beliefs and practices adjusting for selected covariates PARTICIPANTS AND SETTING: A consecutive sample of pregnant women (n = 715) were recruited from an Australian metropolitan hospital between August 2010 and January 2011. All women <20 weeks gestation were eligible unless they had pre-existing Type 1 or 2 diabetes or insufficient English language skills to complete questionnaires. MEASUREMENTS AND FINDINGS: Of 715 women recruited, 402 had complete data at 4 months post-partum. There were no differences in high breastfeeding intentions (66% vs 53%, p = 0.10) or initiation (96% vs. 98%, p = 0.33) between Hwt and Owt women. Owt women were less likely to be exclusively breastfeeding at hospital discharge AOR [95%CI] 0.57 [0.33,0.98] and 4 months post-partum 0.62 [0.40,0.97]. High intention to breastfeed was positively associated with exclusively/fully breastfeeding at hospital discharge in Hwt 3.24 [1.52,6.89] but not Owt women 1.73 [0.75,4.00] and 4 months post partum in both weight groups (Hwt 4.1 [2.4-7.2], Owt 6.5 [2.9-14.3]). KEY CONCLUSIONS: Healthy and overweight women appear to have similar antenatal intentions for infant feeding but overweight mothers are less likely to be exclusive breastfeeding at hospital discharge. High antenatal intentions for breastfeeding are related to exclusively/fully breastfeeding at 4 months post partum in both healthy and overweight women. IMPLICATIONS FOR PRACTICE: Investigation of early hospital practices that support and hinder the establishment of successful breastfeeding in overweight mothers may help to identify effective strategies to protect breastfeeding relationships between mother-infant dyads, particularly those who have experienced a caesarean delivery. PMID- 28735033 TI - NF-kappaB-vimentin is involved in steroidogenesis stimulated by mono-butyl phthalate in primary cultured ovarian granulosa cells. AB - Di-n-butyl phthalate (DBP) and its active metabolite, monobutyl phthalate (MBP) are the most common endocrine disrupting chemicals. Many studies indicated the effects of MBP on male steroidogenesis, however, little attention have been paid on the effects of low levels of MBP on female steroidogenesis. This study was aimed to assess steroidogenesis stimulated by low-dose MBP on primary cultured ovarian granulosa cells (mGCs). Ovarian granulosa cells were isolated from ICR female mice. Hormone levels in medium were detected by ELISA, mRNA and protein expressions of vimentin, NF-kappaB p65 and phosphorylation of NF-kappaB p65 (p p65) were assayed by qRT-PCR, western blot and immunohistochemistry, respectively. Besides, confocal immunofluorescence and electrophoretic mobility shift assay (EMSA) were used for detecting vimentin expression and activity of NF kappaB p65 binding to the promoter of vimentin, respectively. Progesterone levels, mRNA and protein levels of vimentin and p-p65 in cells were increased significantly in mGCs treated by MBP at 10-10M. Additionally, MBP-induced steroidogenesis was blocked when vimentin protein was knocked down or activity of NF-kappaB was inhibited. EMSA assay showed that binding activity of NF-kappaB to the promoter regions of vimentin was boosted after MBP exposure. Accordingly, the results suggested that MBP could up-regulated steroidogenesis through NF-kappaB vimentin signal in mGCs. PMID- 28735034 TI - Language: A fresh concept to integrate syntactic and semantic information in life sciences. AB - Several fields in biology tend to view the concept of information from one or the other of two extreme positions. Exclusionists base their stance of total rejection on gene-centrism and gene-determinism, typified by the recently established endo-Darwinist school of life sciences. At the other end of the spectrum, there is total acceptance, as in the newly developed information centred paradigms that populate biosemiotics. We propose in this paper to split the informational concepts into two irreducible (but linked) poles: the syntactic (concerned with the quantification of the information structure or complexity in a system), and the semantic (concerned with the organization rules and causality weights of interactions in a system). We claim that the past and present uses of the concept could then be classified as various degrees of oscillation between the two poles. The concept of language presents itself as a good tool with which to bridge the syntactic and the semantic poles, combining as it does the form related and the meaning-related aspects of information, while methodologically supporting formal grammatical models in life sciences. We aim to show, at the same time, that neither of these poles alone can suffice to efficiently and holistically describe, model, and predict natural phenomena. PMID- 28735035 TI - The lamin code. AB - Unicellular eukaryotes and metazoa present a nuclear envelope (NE) and metazoa express in it one or more lamins that give rise to the nuclear lamina. The expression of different types of lamins is related to the complexity of the organism and the expression of type-A lamins is related to the initial steps of tissue-specific cell differentiation. Several posttranslational modifications characterize the expression of lamin A in the course of cell differentiation, and the alteration of this expression pattern leads to impressive phenotypic diseases that are collectively referred to as laminopathies. This indicates a link between differential lamin A expression and tissue-specific cell commitment, and makes it conceivable that the lamin posttranslational modifications constitute a lamin code, utilized by metazoan cells to induce tissue-specific cell differentiation. Although the rules of this code are not yet deciphered, at the moment, the presence of adaptors, represented by NE transmembrane proteins (NETs), and of effectors, constituted by epigenetic repressors that modulate chromatin arrangement and gene expression, strongly supports the possibility that the rules of lamin modification represent one of the organic codes that characterize cell evolution. PMID- 28735036 TI - Proactive tobacco treatment for individuals with and without a mental health diagnosis: Secondary analysis of a pragmatic randomized controlled trial. AB - INTRODUCTION: Individuals with (vs. without) mental illness use tobacco at higher rates and have more difficulty quitting. Treatment models for smokers with mental illness are needed. METHODS: This secondary analysis of the Victory Over Tobacco study [a pragmatic randomized clinical trial (N=5123) conducted in 2009-2011 of Proactive Care (proactive outreach plus connection to smoking cessation services) vs. Usual Care] tests the effectiveness of treatment assignment in participants with and without a mental health diagnosis on population-level, 6month prolonged abstinence at one year follow-up. RESULTS: Analyses conducted in 2015-6 found that there was no interaction between treatment group and mental health group on abstinence (F(1,3300=1.12, p=0.29)). Analyses stratified by mental health group showed that those without mental illness, assigned to Proactive Care, had a significantly higher population-level abstinence rate than those assigned to Usual Care (OR=1.40, 95% CI=1.17-1.67); in those with mental illness, assignment to Proactive Care produced a non-significant increase in abstinence compared to Usual Care (OR=1.18, 95% CI=0.98-1.41). Those with mental illness reported more medical visits, cessation advice and treatment (p<0.001), similar levels of abstinence motivation (p>0.05), but lower abstinence self-efficacy (p<0.001). CONCLUSIONS: Those with a mental health diagnosis benefitted less from proactive outreach regarding tobacco use. VA primary care patients with mental illness may not need additional outreach because they are connected to cessation resources during medical appointments. This group may also require more intensive cessation interventions targeting self-efficacy to improve cessation rates. Clinicaltrials.gov registration # NCT00608426. PMID- 28735037 TI - Injection drug use and overdose among young adults who use prescription opioids non-medically. AB - INTRODUCTION: Non-medical prescription opioid (NMPO) use is a critical public health problem in the United States, with 2.1 million new initiates annually. Young adult NMPO users are at high risk for initiating injection drug use. We assessed correlates of injection drug use among young adult NMPO users in Rhode Island, a state heavily impacted by opioid overdose. METHODS: We used data from the Rhode Island Young Adult Prescription Drug Study (RAPiDS), which recruited 199 residents aged 18-29 who reported past-30-day NMPO use (65.3% male). We compared individuals who reported ever having injected with individuals who reported never injecting, using logistic regression to identify independent correlates of injection. RESULTS: Among eligible participants, the mean age was 24.6years and 61.3% were white. Over one-quarter (n=59, 29.6%) of the sample had ever injected drugs. The majority (n=46, 78.0%) of participants who had ever injected drugs reported injecting heroin as her/his first drug; the majority also reported previously snorting her/his first drug that was injected (n=46, 78.0%). In multivariable analyses, white race, older age, lifetime homelessness, and ever having overdosed or seen someone overdose were independently associated with an increased likelihood of ever injecting drugs. CONCLUSIONS: These findings demonstrate a high prevalence of lifetime injection drug use among young adults who use prescription opioids non-medically. Given the observed associations between injection drug use and witnessing as well as experiencing overdose, interventions are urgently needed to improve overdose education and naloxone distribution to young adult NMPO users who inject drugs. PMID- 28735038 TI - Perceived academic benefit is associated with nonmedical prescription stimulant use among college students. AB - INTRODUCTION: College students are at higher than average risk for nonmedical use of prescription stimulants (NPS). A commonly identified motive among students who engage in NPS is to improve grades. Several research studies have observed that NPS most likely does not confer an academic advantage, and is associated with excessive drinking and other drug use. This study documents the proportion of the general college student population who believe that NPS will lead to improvements in academic performance. METHODS: This study gathered online survey data from a large, demographically diverse sample of college students to document the prevalence of perceived academic benefit of NPS for improving grades and to examine the association between such belief and NPS. RESULTS: Overall, 28.6% agreed or strongly agreed that NPS could help students earn higher grades, and an additional 38.0% were unsure. Students with a higher level of perceived academic benefit of NPS and more frequent patterns of drinking and marijuana use were more likely to engage in NPS, even after adjustment for a wide range of covariates. CONCLUSIONS: The results underscore the need for interventions that simultaneously correct misperceptions related to academic benefit and target alcohol and marijuana use to reduce NPS. PMID- 28735039 TI - Frequency and correlates of sleep disturbance in methadone and buprenorphine maintained patients. AB - BACKGROUND: Opioid use disorder (OUD) is a significant public health problem, and opioid maintenance treatment (OMT) on methadone or buprenorphine is a common approach. This study characterized sleep impairment in patients maintained on methadone or buprenorphine, and evaluated its association with psychiatric and medical comorbidities. METHODS: Participants (N=185) maintained on methadone (N=125) or buprenorphine (N=60) for OUD completed the Medical Outcomes Study Sleep Scale (MOS) to provide a point-prevalence assessment of sleep impairment. Measures of lifetime problems and current functioning were also examined and compared as both a function of OMT and level of sleep impairment. RESULTS: Participants reported high levels of sleep impairment on the MOS, including not getting the amount of sleep they needed (42.9%), not sleeping enough to feel rested (39.6%) and trouble falling asleep (23.3%) or falling back asleep after waking (25.8%). Few differences were observed between OMT groups, and psychiatric dysfunction emerged as the most robust predictor of sleep impairment ratings. Patients with sleep impairment, independent of OMT medications, also reported current opioid withdrawal, psychiatric impairment, negative affect, and pain. CONCLUSIONS: Results demonstrate substantial and clinically-significant impairments in sleep that are associated with a variety of current problems that could impact OMT outcomes and decrease quality of life. Outcomes support the development of methods to improve sleep in OMT patients, and to examine the degree to which sleep improvements may be associated with improvements in mood and other health-related measures. PMID- 28735040 TI - Co-encapsulation of paclitaxel and C6 ceramide in tributyrin-containing nanocarriers improve co-localization in the skin and potentiate cytotoxic effects in 2D and 3D models. AB - Considering that tumor development is generally multifactorial, therapy with a combination of agents capable of potentiating cytotoxic effects is promising. In this study, we co-encapsulated C6 ceramide (0.35%) and paclitaxel (0.50%) in micro and nanoemulsions containing tributyrin (a butyric acid pro-drug included for potentiation of cytotoxicity), and compared their ability to co-localize the drugs in viable skin layers. The nanoemulsion delivered 2- and 2.4-fold more paclitaxel into viable skin layers of porcine skin in vitro at 4 and 8h post application than the microemulsion, and 1.9-fold more C6 ceramide at 8h. The drugs were co-localized mainly in the epidermis, suggesting the nanoemulsion ability for a targeted delivery. Based on this result, the nanoemulsion was selected for evaluation of the nanocarrier-mediated cytotoxicity against cells in culture (2D model) and histological changes in a 3D melanoma model. Encapsulation of the drugs individually decreased the concentration necessary to reduce melanoma cells viability to 50% (EC50) by approximately 4- (paclitaxel) and 13 fold (ceramide), demonstrating an improved nanoemulsion-mediated drug delivery. Co-encapsulation of paclitaxel and ceramide further decreased EC50 by 2.5-4.5 fold, and calculation of the combination index indicated a synergistic effect. Nanoemulsion topical administration on 3D bioengineered melanoma models for 48h promoted marked epidermis destruction, with only few cells remaining in this layer. This result demonstrates the efficacy of the nanoemulsion, but also suggests non-selective cytotoxic effects, which highlights the importance of localizing the drugs within cutaneous layers where the lesions develop to avoid adverse effects. PMID- 28735041 TI - Self-assembled polypeptide nanoparticles for intracellular irinotecan delivery. AB - In this research poly(l-lysine)-b-poly(l-leucine) (PLys-b-PLeu) polymersomes were developed. It was shown that the size of nanoparticles depended on pH of self assembly process and varied from 180 to 650nm. The biodegradation of PLys-b-PLeu nanoparticles was evaluated using in vitro polypeptide hydrolysis in two model enzymatic systems, as well as in human blood plasma. The experiments on the visualization of cellular uptake of rhodamine 6g-loaded and fluorescein-labeled nanoparticles were carried out and the possibility of their penetration into the cells was approved. The cytotoxicity of polymersomes obtained was tested using three cell lines, namely, HEK, NIH-3T3 and A549. It was shown that tested nanoparticles did not demonstrate any cytotoxicity in the concentrations up to 2mg/mL. The encapsulation of specific to colorectal cancer anti-tumor drug irinotecan into developed nanocontainers was performed by means of pH gradient method. The dispersion of drug-loaded polymersomes in PBS was stable at 4 degrees C for a long time (at least 1month) without considerable drug leakage. The kinetics of drug release was thoroughly studied using two model enzymatic systems, human blood serum and PBS solution. The approximation of irinotecan release profiles with different mathematical drug release models was carried out and allowed identification of the release mechanism, as well as the morphological peculiarities of developed particles. The dependence of encapsulation efficiency, as well as maximal loading capacity, on initial drug concentration was studied. The maximal drug loading was found as 320+/-55MUg/mg of polymersomes. In vitro anti-tumoral activity of irinotecan-loaded polymersomes on a colon cancer cell line (Caco-2) was measured and compared to that for free drug. PMID- 28735042 TI - Improved selectivity and cytotoxic effects of irinotecan via liposomal delivery: A comparative study on Hs68 and HeLa cells. AB - Irinotecan (CPT-11) is an effective chemotherapeutic agent widely used to treat different cancers. Otherwise, the liposomal delivery of anti-tumor agents has been shown to be a promising strategy. The aim of this study has been to analyze the effect of liposomal CPT-11 (CPT-11lip) on two human cell lines (Hs68 and HeLa) to establish the suitability of this CPT-11 nanocarrier. We have demonstrated the highest uptake of CPT-11lip in comparison with that of CPT 11sol, in lactate buffer, and that CPT-11lip was internalized in the cells through an endocytic process whereas CPT-11sol does so by passive diffusion. CPT 11lip was not cytotoxic to normal fibroblast Hs68 cells, but induced a massive apoptosis accompanied by cell senescence in HeLa cells. CPT-11lip treatment modified the morphology of HeLa cells, induced different cell cycle alterations and accumulated into lysosomes in both cell lines. In particular, CPT-11lip treatment showed that surviving HeLa cells remained in a state of senescence whereas only a temporal growth arrest was induced in Hs68 cells. Results of RT PCR indicated that the different responses in Hs68 (survival) and HeLa cells (apoptotic death), seemed to be induced by a p53- and p53- independent mechanism, respectively. An analysis of DNA damage also determined that released CPT-11 from liposomes was able to reach the nucleus and exert a genotoxic effect in both cell lines, which was repaired in Hs68 but not in HeLa cells. All results indicate that phospholipid-cholesterol liposomes possess optimum properties for CPT-11 delivery, being biocompatible and selectively cytotoxic against HeLa tumorigenic cells. PMID- 28735043 TI - A high-sensitivity electrochemical aptasensor of carcinoembryonic antigen based on graphene quantum dots-ionic liquid-nafion nanomatrix and DNAzyme-assisted signal amplification strategy. AB - In this work, we have developed an electrochemical aptasensor for high sensitivity determination of carcinoembryonic antigen (CEA) based on lead ion (Pb2+)-dependent DNAzyme-assisted signal amplification and graphene quantum dot ionic liquid-nafion (GQDs-IL-NF) composite film. We designed hairpin DNA containing CEA-specific aptamers and DNAzyme chains. In the presence of CEA, hairpin DNA recognized the target and performed a DNAzyme-assisted signal amplification reaction to yield a large number of single-stranded DNA. The GQDs IL-NF composite film was immobilized on the glassy carbon electrode for the interaction with single-stranded DNA through noncovalent pi-pi stacking interaction. Therefore, the methylene blue-labeled substrate DNA (MB-substrate) was fixed on the electrode and exhibited an initial electrochemical signal. Under optimal conditions, the response current change was proportional to the concentration of CEA, demonstrating a wide linear range from 0.5fgmL-1 to 0.5ngmL 1, with a low detection limit of 0.34fgmL-1. Furthermore, the proposed aptasensor was successfully applied in determining CEA in serum samples, showing its superior prospects in clinical diagnosis. PMID- 28735044 TI - Sensing platform for neuron specific enolase based on molecularly imprinted polymerized ionic liquids in between gold nanoarrays. AB - A molecularly imprinted electrochemical sensor for neuron specific enolase (NSE) was developed by electrochemical polymerizing ionic liquid, which was functionalized with pyrrole moiety, in between gold nanoarrays. A well-defined 3D structured gold nanoarray was fabricated on a glassy carbon electrode (GCE) surface by using template-assisted electrochemical deposition technique. 1-(3 mercaptopropyl)-3-vinyl-imidazolium tetrafluoroborate was self-assembled onto the surface of gold nanoarrays to produce active sites for anchoring the molecularly imprinted film. Subsequently, an electrochemical polymerization procedure was carried out in an aqueous solution containing 1,3-di(3-N-pyrrolpropyl)imidazolium bromine ionic liquid and neuron specific enolase (NSE). After removing NSE templates, a molecularly imprinted sensor was successfully fabricated. The sensor showed high selectivity and sensitivity towards NSE, produced a linear response in the concentration range from 0.01 to 1.0ngmL-1 and had a detection limit of 2.6pgmL-1 with an incubation time of 15min. The developed sensor was demonstrated successful in determining NSE in clinical serum samples. PMID- 28735045 TI - Multiplexed capillary microfluidic immunoassay with smartphone data acquisition for parallel mycotoxin detection. AB - The field of microfluidics holds great promise for the development of simple and portable lab-on-a-chip systems. The use of capillarity as a means of fluidic manipulation in lab-on-a-chip systems can potentially reduce the complexity of the instrumentation and allow the development of user-friendly devices for point of-need analyses. In this work, a PDMS microchannel-based, colorimetric, autonomous capillary chip provides a multiplexed and semi-quantitative immunodetection assay. Results are acquired using a standard smartphone camera and analyzed with a simple gray scale quantification procedure. The performance of this device was tested for the simultaneous detection of the mycotoxins ochratoxin A (OTA), aflatoxin B1 (AFB1) and deoxynivalenol (DON) which are strictly regulated food contaminants with severe detrimental effects on human and animal health. The multiplexed assay was performed approximately within 10min and the achieved sensitivities of<40, 0.1-0.2 and<10ng/mL for OTA, AFB1 and DON, respectively, fall within the majority of currently enforced regulatory and/or recommended limits. Furthermore, to assess the potential of the device to analyze real samples, the immunoassay was successfully validated for these 3 mycotoxins in a corn-based feed sample after a simple sample preparation procedure. PMID- 28735046 TI - Ceftolozane-tazobactam activity against drug-resistant Enterobacteriaceae and Pseudomonas aeruginosa causing healthcare-associated infections in Australia and New Zealand: Report from an Antimicrobial Surveillance Program (2013-2015). AB - OBJECTIVES: To evaluate the in vitro activity of ceftolozane-tazobactam and comparator agents tested against isolates of Enterobacteriaceae and Pseudomonas aeruginosa from patients in Australia and New Zealand with healthcare-associated infection. METHODS: A total of 1459 gram-negative organisms (440 P. aeruginosa and 1019 Enterobacteriaceae) were consecutively collected from 11 medical centers located in Australia and New Zealand. The organisms were tested for susceptibility by broth microdilution methods as described by the CLSI M07-A10 document and the results interpreted according to EUCAST and CLSI breakpoint criteria. RESULTS: Ceftolozane-tazobactam (MIC50/90, 0.25/0.5MUg/mL; 97.7/95.9% susceptible [CLSI/EUCAST]), meropenem (MIC50/90, <=0.06/<=0.06MUg/mL; 99.8/99.9% susceptible [CLSI/EUCAST]) and amikacin (MIC50/90, 2/4MUg/mL; 99.8/99.6% susceptible [CLSI/EUCAST]) were the most active compounds tested against Enterobacteriaceae. Enterobacteriaceae isolates displayed susceptibility rates to other beta-lactam agents ranging from 95.3/94.4% for cefepime, 94.1/91.4% for piperacillin-tazobactam, and 93.3/91.5% for ceftazidime using CLSI/EUCAST breakpoints. Among the Enterobacteriaceae isolates tested, 0.1% were CRE and 6.6% exhibited an ESBL non-CRE phenotype. Whereas ceftolozane-tazobactam showed good activity against ESBL non-CRE phenotype strains of Enterobacteriaceae (MIC50/90, 0.5/2MUg/mL), it lacked useful activity (MIC, >32MUg/mL) against the single isolate with a CRE resistant phenotype. Ceftolozane-tazobactam was the most potent (MIC50/90, 0.5/2MUg/mL) beta-lactam agent tested against P. aeruginosa isolates, inhibiting 95.7% at an MIC of <=4MUg/mL. CONCLUSIONS: Ceftolozane tazobactam was the most active beta-lactam agent tested against P. aeruginosa and demonstrated higher in vitro activity than currently available cephalosporins and piperacillin-tazobactam when tested against Enterobacteriaceae. PMID- 28735047 TI - Sesamol exhibits potent antimycobacterial activity: Underlying mechanisms and impact on virulence traits. AB - OBJECTIVES: Novel strategies to overcome multidrug resistance (MDR) in Tuberculosis (TB) still remain a concern. Usage of natural compounds nowadays to surmount the increasing burden of MDR-TB has shown promising results. The aim of this study was to evaluate the antimycobacterial potential of sesamol (Ses) a natural phenolic compound against Mycobacterium smegmatis, a surrogate for MTB and its underlying mechanism of action along with its effect on mycobacterial virulence traits. METHODS: Cell surface phenotypes were estimated microscopically and spectrophotometrically respectively. Membrane parameters were assessed using propidium iodide (PI) uptake, passive diffusion of drug with substrate EtBr and phenotypic susceptibility assay. Changes in lipid profiles were estimated by lipase assay. Oxidative and genotoxic damage were studied using fluorescent probes DCFDA and DAPI. Biofilm formation was studied using crystal violet and calcoflour white staining probes along with biomass measurement. Cell adherence was estimated using buccal epithelial cells. RESULTS: We observed that antimycobacterial activity of Ses was 6mM and it enhances the efficiency of known anti-TB drugs. Ses affects cell surface phenotypes as displayed by altered colony morphology, impaired sliding motility and enhanced cell sedimentation rate. Membrane perturbation was revealed by hypersensitivity against SDS, reduced PI uptake, enhanced passive diffusion and lipase activity. In addition, Ses leads to oxidative and DNA damage along with abrogated iron homeostasis. Furthermore, we uncover phenotypes related to virulence like inhibited biofilm formation and cell adherence to buccal epithelial cells. CONCLUSION: This study for the first time establishes the anti-mycobacterial potential of Ses that may be further exploited for improving the therapeutic strategies and warrants further attention. PMID- 28735048 TI - Emergence of different Acinetobacter baumannii clones in a Croatian hospital and correlation with antibiotic susceptibility. AB - OBJECTIVES: During routine diagnostic laboratory work, the clinical microbiologist observed an increase of Acinetobacter baumannii isolates with three different carbapenem susceptibility patterns: susceptible, intermediate and resistant. Isolates belonging to the same carbapenem susceptibility phenotype exhibited identical susceptibility/resistance patterns to non-beta-lactam antibiotics. This prompted us to analyse the mechanisms of carbapenem-resistance and the molecular epidemiology of the isolates. A total of 59 A. baumannii isolates were analysed and grouped according to their susceptibility to imipenem: group 1 were susceptible (N=24), group 2 were intermediate (N=8) and group 3 were resistant (N=27) to imipenem. MATERIAL AND METHODS: PCR and sequencing was used to detect resistance genes. Genotyping of the isolates was performed by PFGE and MLST. RESULTS: Out of 27 resistant isolates, 20 harboured blaOXA-40-like and 7 blaOXA-23-like genes. ISAba1 was found upstream of blaOXA-51 and blaOXA-23 genes. PFGE genotyping demonstrated the existence of three major A. baumannii clones in GH Pula and determination of sequence groups showed that the isolates belonged to international clones commonly associated with multidrug-resistance. MLST (performed on six isolates) showed diverse population structure of isolates belonging to the same cluster, including ST 195, ST 231, ST 775 and ST 1095. CONCLUSIONS: A previous study conducted in 2009-2010 showed that reduced susceptibility to carbapenems in GH Pula was only associated with upregulation of the intrinsic OXA-51 beta-lactamase. In this study a shift to isolates with acquired oxacillinases, belonging to two major clones was reported. PMID- 28735049 TI - In vitro activity of daptomycin combinations with rifampicin, gentamicin, fosfomycin and fusidic acid against MRSA strains. AB - OBJECTIVES: Although new antimicrobial agents designed to treat infections with limited therapeutic options have been introduced in the past few years, resistant Gram positive cocci have continued to emerge and spread. Daptomycin is a cyclic lipopeptide antibiotic that has rapid bactericidal activity against broad spectrum of Gram positive bacteria, including methicillin resistant Staphylococcus aureus (MRSA). Antibiotics are sometimes used in combination in an attempt to prevent or delay the in vivo emergence of drug-resistant subpopulations of pathogenic organisms. The aim of the study was to evaluate in vitro activity of daptomycin combinations with rifampicin, gentamicin, fosfomycin, and fusidic acid against MRSA strains. METHODS: In total, 25 strains were tested. The minimum inhibitory concentrations of all antibiotics were determined using a microbroth dilution assay. The in vitro activities of antibiotics in combination were assessed using the microbroth checkerboard technique. With this method, the fractional inhibitory concentration index was interpreted as follows: synergism <=0.5; additive/indifference >0.5-<=4; antagonism >4. RESULTS: According to the MIC values, all strains (100%) were susceptible to daptomycin, 16% (4/25) to rifampicin, 20% (5/25) to gentamicin, 44% (11/25) to fosfomycin, and 72% (18/25) to fusidic acid. Synergistic interaction of daptomycin in combinations with rifampicin, gentamicin, fosfomycin, and fusidic acid were found as 12%, 68%, 100% and 16%, respectively. No antagonism was observed. CONCLUSION: The combination of daptomycin with fosfomycin may be a promising alternative therapy of MRSA infections. PMID- 28735050 TI - Antimicrobial resistance profiles and genotypes of extended-spectrum beta lactamase- and AmpC beta-lactamase-producing Klebsiella pneumoniae isolated from dogs in Beijing, China. AB - OBJECTIVES: Klebsiella pneumoniae, which exists in the intestinal and respiratory tracts of humans and animals, is an important conditional pathogen in many animals. The aim of the current study was to investigate the antimicrobial resistance profiles and genotypes of extended-spectrum beta-lactamase (ESBL)- and AmpC beta-lactamase-producing K. pneumoniae isolated from dogs. METHODS: A total of 285 isolates, collected from faecal and urine samples of diseased dogs in a Veterinary Teaching Hospital in Beijing, were characterised by antimicrobial susceptibility testing and screened for ESBL and AmpC beta-lactamase phenotypes. The relevant genes were identified by polymerase chain reaction and sequencing. RESULTS: All K. pneumoniae isolates were susceptible to meropenem, while the rates of resistance to the remaining 27 tested antimicrobials ranged from 24% to 97%. A total of 53% and 18% of K. pneumoniae isolates were positive for ESBL and AmpC beta-lactamase production, respectively. ESBL/AmpC-producing strains were significantly resistant to more antimicrobial agents compared non-ESBL/AmpC producing strains (P<0.05). CTX-M groups 1 and 9, and DHA-1 were the predominant genotypes of the ESBL/AmpC-producing K. pneumoniae isolates. CONCLUSIONS: In conclusion, the high percentage of drug resistance among K. pneumoniae isolates suggests that routine detection of ESBL production by reliable laboratory methods is required in small animal clinical practice. PMID- 28735051 TI - Telavancin activity in vitro tested against a worldwide collection of Gram positive clinical isolates (2014). AB - OBJECTIVES: Telavancin activity was measured against Gram-positive pathogens collected worldwide during 2014 using the revised broth microdilution testing method. The results were compared with previous reports. METHODS: A total of 10552 isolates from 86 sites located in 32 countries were included as part of the Telavancin International Surveillance Program for the Americas, Europe and Asia Pacific. RESULTS: Telavancin had MIC50 and MIC90 values of 0.03MUg/mL and 0.06MUg/mL, respectively, against Staphylococcus aureus, regardless of methicillin susceptibility, and inhibited all S. aureus isolates at the CLSI breakpoint (<=0.12MUg/mL). Telavancin was eight-fold more active than daptomycin (MIC50/90, 0.25/0.5MUg/mL) and 16-32-fold more active than vancomycin (MIC50/90, 1/1MUg/mL) and linezolid (MIC50/90, 1/1MUg/mL) against methicillin-resistant S. aureus (MRSA). Telavancin was also active against coagulase-negative staphylococci isolates (MIC50/90, 0.06/0.06MUg/mL). Vancomycin-susceptible Enterococcus faecalis isolates (n=718) were all inhibited by telavancin (MIC50/90, 0.12/0.12MUg/mL) at <=0.25MUg/mL (CLSI breakpoint), except for a single isolate (MIC, 0.5MUg/mL). All Enterococcus faecium and E. faecalis isolates with telavancin MICs of >=0.5MUg/mL and >=1MUg/mL, respectively, had a VanA phenotype. Based on the MIC90 values, telavancin was at least eight-fold more potent than comparators against vancomycin-susceptible enterococci. With the exception of Streptococcus agalactiae (MIC50, 0.03MUg/mL), all tested species of streptococci exhibited telavancin MIC50 values of <=0.015MUg/mL. CONCLUSIONS: These in vitro results from 2014 highlight the potent in vitro activity of telavancin and demonstrate that its activity was virtually unchanged compared with the corresponding 2013 telavancin surveillance results. PMID- 28735052 TI - Spa typing and identification of pvl genes of meticillin-resistant Staphylococcus aureus isolated from a Libyan hospital in Tripoli. AB - OBJECTIVES: The purpose of the study was to investigate the molecular characteristics of meticillin-resistant Staphylococcus aureus (MRSA) isolated from clinical sources in Tripoli, Libya. METHODS: A total of 95 MRSA strains collected at the Tripoli medical Centre were investigated by spa typing and identification of the Panton-Valentine Leukocidin (pvl) genes. RESULTS: A total of 26 spa types were characterized and distributed among nine clonal complexes; CC5 (n=32), CC80 (n=18), CC8 (n=17) and CC22 (n=12) were the most prevalent clonal complexes. In total, 34% of the isolates were positive for PVL. CONCLUSIONS: This study demonstrated the presence of CA-MRSA and pvl positive strains in hospital settings and underlines the importance of using molecular typing to investigate the epidemiology of MRSA. Preventative measures and surveillance systems are needed to control and minimize the spread of MRSA in the Libyan health care system. PMID- 28735053 TI - Activity of dalbavancin tested against Gram-positive clinical isolates causing skin and skin-structure infections in paediatric patients from US hospitals (2014 2015). AB - OBJECTIVES: This study provides an in vitro analysis of dalbavancin activity against isolates causing skin and skin-structure infections (SSSIs) in children. METHODS: A total of 770 Staphylococcus aureus, 167 beta-haemolytic streptococci (BHS), 42 coagulase-negative staphylococci (CoNS), 25 Enterococcus faecalis and 13 viridans group streptococci (VGS) were collected from children (<18years old) in the USA (2014-2015). RESULTS: Dalbavancin had MIC50/90 values of 0.03/0.06MUg/mL against S. aureus and CoNS, including methicillin-resistant (MRSA) and -susceptible (MSSA) isolates. Dalbavancin MICs were 8-32-fold lower than those of daptomycin (MIC50/90, 0.25/0.5MUg/mL), vancomycin (MIC50/90, 0.5/1MUg/mL) and linezolid (MIC50/90, 1/1MUg/mL) against MRSA. These agents showed 100.0% susceptibility against MRSA, and clindamycin also had a high (92.7%) susceptibility rate. Dalbavancin (MIC50/90, 0.03/0.06MUg/mL) and daptomycin (MIC50/90, 0.25/0.5MUg/mL) were the most active agents against CoNS. When tested against E. faecalis, dalbavancin was up to 32-fold more active than ampicillin (MIC50/90, <=0.5/1MUg/mL), daptomycin (MIC50/90, 1/1MUg/mL), linezolid (MIC50/90, 1/2MUg/mL) and vancomycin (MIC50/90, 1/2MUg/mL). Dalbavancin (MIC50/90, 0.008/0.03MUg/mL), ceftriaxone (MIC50/90, <=0.06/<=0.06MUg/mL) and penicillin (MIC50/90, <=0.06/<=0.06MUg/mL) were the most active against BHS. VGS isolates were susceptible to dalbavancin (MIC100, 0.03MUg/mL), with MICs 32-64 fold lower than daptomycin (MIC50/90, 0.5/0.5MUg/mL), linezolid (MIC50/90, 0.5/1MUg/mL) and vancomycin (MIC50/90, 0.5/0.5MUg/mL). CONCLUSIONS: Approved agents available for the treatment of SSSI in children are limited. Dalbavancin demonstrated potent in vitro activity against isolates causing SSSI in children. Developing dalbavancin for SSSI treatment in children is warranted, provided safety and tolerability are satisfactory. PMID- 28735054 TI - Linezolid activity against clinical Gram-positive cocci with advanced antimicrobial drug resistance in Iran. AB - OBJECTIVES: The aim of the study was to investigate the linezolid activity against clinical Gram-positive cocci with advanced antimicrobial drug resistance. METHODS: A collection of methicillin resistant Staphylococcus aureus (MRSA), vancomycin resistant enterococci (VRE), penicillin non-susceptible Streptococcus pneumoniae (PNSP), and group B streptococci (GBS) were isolated from various clinical samples. Antimicrobial susceptibility tests were done using standard methods Subsequently, we investigated linezolid antibacterial activities, the first approved oxazolidinone against isolates by the standard broth microdilution method. RESULTS: According to our results, MRSA and PNSP isolates were multidrug resistant, and almost half of the VRE isolates were high level gentamicin resistant (HLGR). Furthermore, resistance to linezolid was not seen among the isolates. The MIC90 values for MRSA, VRE, PNSP and GBS isolates were 4MUg/ml, 2MUg/ml, 1MUg/ml, and 0.5MUg/ml, respectively. Only 6.25% of vancomycin resistant enterococci showed intermediate susceptibility to this antibiotic. CONCLUSIONS: These findings indicate that linezolid has an excellent activity against clinical drug resistant Gram-positive isolates in Iran. Constant monitoring and surveillance of linezolid MIC distribution allows the researchers to assess and detect gradual upward MIC drifts. PMID- 28735055 TI - Analysis of virulence genes and accessory gene regulator (agr) types among methicillin-resistant Staphylococcus aureus strains in Iran. AB - OBJECTIVES: Methicillin-resistant Staphylococcus aureus (MRSA) strains are a major cause of hospital-acquired infections and are considered a serious public health concern. MRSA isolates have abundant virulence factors that are the basis for their pathogenicity. The accessory gene regulator (agr) locus co-ordinates the expression of these genes. The aim of this study was to determine the presence and frequency of various virulence genes encoding enterotoxins and adhesins as well as to identify agr specificity groups in MRSA isolates. METHODS: This descriptive study included a total of 296 MRSA strains isolated from clinical samples collected in Tehran Heart Center (Tehran, Iran) between October 2004 and March 2013. Following DNA extraction, PCR-based assays were used to evaluate the presence of various virulence genes. IBM SPSS Statistics for Windows v.21.0 was used for statistical analysis. RESULTS: The results indicated that the most frequent toxin genes were see (120/296; 40.5%), followed by sea (79/296; 26.7%); the other genes were encoded less frequently. The presence of seb and seh was not found in any of the isolates. Furthermore, the most frequent adhesin genes were clfA, spa, cna, map/eap and bbp, found in 281 (94.9%), 275 (92.9%), 267 (90.2%), 265 (89.5%) and 264 (89.2%) isolates, respectively. The majority of isolates belonged to agr group I (53.0%), followed by agr group III (1.4%). None of the isolates belonged to agr group II. CONCLUSIONS: The relatively high frequency of various virulence genes suggests the emergence and pathogenic potential of MRSA isolates containing these genes in the study area. PMID- 28735056 TI - Distribution of macrolide resistance mechanisms in Bulgarian clinical isolates of Streptococcus pyogenes during the years of 2013-2016. AB - : Streptococcus pyogenes, or group A streptococcus (GAS), is the main etiological agent of bacterial tonsillopharyngitis and a common cause of a wide variety of other mild to severe infections. OBJECTIVES: Objectives of the present study was to determine and evaluate the distribution of genetic mechanisms associated with certain phenotypes of macrolide resistance in Bulgarian GAS isolated during the years of 2013-2016. METHODS: All GAS strains were screened for the macrolide resistance genes erm(A), erm(B) and mef(A), using multiplex polymerase chain reaction (PCR). The minimal inhibitory concentrations (MICs) of erythromycin, azithromycin, clarithromycin, clindamycin were determined by E-tests. RESULTS: Almost 23% of GAS isolates obtained in 2013-2014 and near 40% of them in 2015 2016 contained various elements of resistance. The predominant gene was mef(A), which encodes an efflux pump (M-phenotype), identified in 57.84% of the macrolide resistant strains. The next frequently prevalent mechanism was a combination of mef(A) and erm(B) in 22.55%, which determined high-level inducible or constitutive resistance to macrolides, lincosamides and streptogramins (iMLSB or cMLSB). The highest MIC value (>256mg/L) was detected in association with erm(B) (p<0.05). The MIC range was observed to be much higher in the isolates with combinations of resistance genes vs. those with mef genes alone (p<0.05). CONCLUSION: The data about the distribution and prevalence of macrolide resistance mechanisms obtained in this study can help in the treatment of persistent and recurrent GAS infections and in the correct choice of empiric therapy. PMID- 28735057 TI - Brazil's resolutions to regulate the sale of antibiotics: Impact on consumption and Escherichia coli resistance rates. AB - OBJECTIVE: The aim of this study was to determine the impact of two resolutions to restrict antibiotic use (RDCs no. 44/2010 and 20/2011) in the Campinas metropolitan area (Sao Paulo, Brazil) on antibiotic consumption, resistance rates, and trends in Escherichia coli-causing community-acquired urinary tract infection (UTI). METHODS: The annual retail sale information of antibiotics from drugstores in the Campinas metropolitan area between 2008 and 2012 were obtained through the Intercontinental Medical Statistics Health of Brazil. The daily defined dose (DDD)/1000 inhabitants/day was calculated from these data to measure consumption. To examine resistance rates, we performed an observational retrospective study in a Campinas teaching hospital, where urinary cultures from outpatients with a clinical suspicion of UTI between October 2009 and September 2015 were analyzed. RESULTS: We observed an increase in rates of antibiotic sales from 2008 to 2011 (cephalosporin: 216.8%, quinolones: 170.9%, aminopenicillins: 140.9%), followed by a decrease in sales in 2012 (cephalosporin: 19.4%, quinolones: 12.7%, aminopenicillins: 11.1%). Sale of nitrofurans, however, did not significantly change during this period. In the retrospective analysis, we observed a significant increasing trend of E. coli resistance for all antibiotic classes, except nitrofurans and folate pathway inhibitors. CONCLUSIONS: We found changes in antibiotic consumption, with an initial increase, followed by a decrease in sales after implementation of the resolutions. However, bacterial resistance does not appear to be affected by the RDCs. PMID- 28735058 TI - Prevalence of PMQR genes in E. coli and Klebsiella spp. isolated from North-West of Morocco. AB - OBJECTIVES: Plasmid mediated quinolone resistance (PMQR) genes are increasingly detected worldwide. However, in Morocco a few studies have been carried out. The aim of this study was to investigate the prevalence of these determinants among Escherichia coli and Klebsiella spp. isolated from North-West of Morocco. METHODS: The prevalence of PMQR genes was investigated among 398 E. coli and 118 Klebsiella spp. clinical isolates collected between 2012 and 2015 from North-West of Morocco. Antimicrobial susceptibility was determined by disc diffusion assay and minimal inhibitory concentrations (MIC) of quinolone were determined by micro dilution. The screening of qnrA, qnrB, qnrC qnrS, Aac(6')-Ib and qepA genes were done by PCR, DNA sequencing and RFLP analyses. RESULTS: Among 398 E. coli and 118 Klebsiella spp. analyzed, 51% of E. coli and 61% of Klebsiella spp. were multidrug resistant (MDR). For the E. coli group, qnrB, qnrS, and aac(6')-Ib-cr genes were detected in 05.02%, 01.50%, and 13.81%, respectively. These determinants were more prevalent in Klebsiella spp. group, hence they represented 11.86%, 05.93% and 18.64% respectively. QnrA, qnrC and qepA were absent in this study. For aac(6')Ib determinant, 84.41% were belong to the Aac(6') Ib-cr variant while for qnrB and qnrS the most determined variants were qnrB1, B6, B16, B42, B66 and qnrS1, S4, S7. Different plasmid sizes were detected in PMQR strains. CONCLUSION: This is the first study conducted in North-West of Morocco and shows important dissemination of MDR and PMQR among Enterobacteriaceae. PMID- 28735059 TI - Too young to be vaccinated: hospitalizations caused by varicella among children in the first year of life. AB - AIM: The aim of this study was to analyse the causes of hospitalization in the course of varicella in children during the first year of life. METHODS: An analysis was performed of the medical documentation of 359 children hospitalized for varicella on the infectious diseases ward at the Children's Hospital in Poznan (Poland) between January 2007 and August 2015. RESULTS: Of the 359 children in the study group, 96 were younger than 1 year old. The most common cause of hospitalization was respiratory infections, found in 31 (32%) children. A severe course of varicella was observed in 38 (14%) children, and 21 (22%) developed skin infections, while 11 (11%) exhibited more than one complication. Treatment with acyclovir was implemented in 90 cases and parenteral antibiotic therapy was applied in 49 children. Contact with siblings suffering from varicella was confirmed in 46 children; for 16, the source of the infection was the mother. CONCLUSIONS: The main source of varicella virus among hospitalized children in the first year of life is home contact. An infant may become infected from its mother suffering from zoster. Children who are exclusively breastfed and are born of mothers who have previously had varicella may develop varicella with a severe course during the first year of life. PMID- 28735060 TI - Individual roles of brain and serum alcohol dehydrogenase isoforms in regulation of alcohol consumption in SPF Wistar rats. AB - Alcohol dehydrogenases (ADH) are key enzymes of ethanol metabolism that mediate its oxidation to acetaldehyde. ADHs are also able to oxidize some types of neurotransmitters such as dopamine, serotonin and norepinephrine. Increased level of ADHs activity, induced by chronic alcohol consumption, is presumably associated with disturbed neurotransmitters metabolism that leads to stable alcohol craving. As earlier reported, intraperitoneal administration of 4 methilpirasole (non-specific inhibitor of ADHs) has shown to provide a short-term anti-alcoholic effect, but individual roles of ADH isoforms in this process were still unclear. The aim of this work was to study the roles of brain and serum ADH isoforms in alcohol consumption and neurotransmitter metabolism in the rats. In the study we used specific-pathogen-free (SPF) Wistar rats chronically alcoholized with 15% ethanol. 4-methilpirasole intranasal administration in small doses led to local inhibition of ADH III activity in the brain estimated by spectrophotometric assay. It correlated with dose-dependent reduction of dopamine concentration and increased level of its metabolic products in the brain but did not influence alcohol consumption. These data allowed us to propose an important role of brain ADHs (predominantly ADH III) in metabolism of dopamine in chronically alcoholized rats but not in regulation of alcohol consumption. To evaluate the role of serum ADH isoforms we immunized the rats with recombinant horse ADH that led to production of high levels of cross-reactive anti-ADH antibodies verified by ELISA assay. Immunization led to 30% decrease in alcohol consumption and recovery of general behavioral parameters such as motor activity, anxiety and depression level. At the same time active immunization did not cause any impairments in animal blood composition. We can conclude that immunization against ADHs appeared to be a safe way to decrease alcohol consumption that could be possibly associated with neurotransmitters metabolism correction. PMID- 28735061 TI - Up-regulation of GluR1 in paraventricular nucleus and greater expressions of synapse related proteins in the hypothalamus of chronic unpredictable stress induced depressive rats. AB - Converging evidence indicates that abnormal glutamatergic and synaptic systems may be associated with the pathophysiology of depression. Over-activation of corticotropin-releasing hormone (CRH) neurons in the hypothalamic paraventricular nucleus (PVN) plays a key role in the hypothalamic-pituitary-adrenal (HPA) axis hyperactivity and is a prominent feature in depression. In this study, we examined the effect of chronic unpredictable stress (CUS) in rats on the expression of AMPA subunit GluR1 protein in the hypothalamic PVN as well as on the expression of GluR1 and several synapse-related proteins in the hypothalamus. We found that CUS in rats induced CRH over-expression accompanied by significant GluR1 up-regulation in the hypothalamic PVN and GluR1 co-localized with CRH in the PVN area. The expression of GluR1 and three synapse-related proteins (PSD95, SYP and MAP2) in the hypothalamus were also increased at both mRNA and protein levels in CUS rats. Correlation analysis showed that the levels of the above proteins are directly correlated with depression-like behaviors of rats in sucrose preference test, open field test and forced swim test. These findings suggest that the augmented glutamatergic and synaptic signaling might be a potential mechanism underlying CRH over-activation in the hypothalamic PVN and contribute to CUS-induced depression-like behaviors in rats. PMID- 28735062 TI - Silibinin ameliorates anxiety/depression-like behaviors in amyloid beta-treated rats by upregulating BDNF/TrkB pathway and attenuating autophagy in hippocampus. AB - Depression is one of the most frequent psychiatric disorders of Alzheimer's disease (AD). Depression and anxiety are associated with increased risk of developing AD. Silibinin, a flavonoid derived from milk thistle (Silybum marianum), has been used as a hepato-protectant in the clinical treatment of liver diseases. In this study, the effect of silibinin on Abeta-induced anxiety/depression-like behaviors in rats was investigated. Silibinin significantly attenuated anxiety/depression-like behaviors caused by Abeta1-42 treatment as shown in tail suspension test (TST), elevated plus maze (EPM) and forced swimming tests (FST). Moreover, silibinin was able to attenuate the neuronal damage in the hippocampus of Abeta1-42-injected rats. Silibinin treatment up-regulated the function through BDNF/TrkB pathway and attenuated autophagy in the hippocampus. Our study provides a new insight into the protective effects of silibinin in the treatment of anxiety/depression. PMID- 28735063 TI - Serum uric acid as a simple risk factor in patients with rheumatic heart disease undergoing valve replacement surgery. AB - BACKGROUND: We evaluated the relationship between admission serum uric acid (SUA) and in-hospital and one-year mortality after valve replacement surgery (VRS) for patients with rheumatic heart disease (RHD). METHODS: One-thousand five-hundred thirty-six consecutive patients with RHD undergoing VRS were divided into 4 groups based on the quartiles of SUA on admission. The association between SUA and adverse outcomes was analyzed. RESULTS: The in-hospital mortality (2.1% vs 2.6% vs 5.3% vs 7.7%, p<0.001) and postoperative acute kidney injury (AKI) (52.0% vs 52.6% vs 61.6% vs 63.3%, p=0.001) increased from the lowest to the highest SUA quartiles. SUA levels were negatively correlated with eGFR value (r=-0.426, p<0.001) and positively correlated with C-reactive protein value (r=0.103, p<0.001). ROC analysis showed that SUA had good predictive value for in-hospital death (AUC=0.665, p<0.001) and was similar to Euro score (Z=0.966, p=0.334). Multiple logistic regression analysis showed that SUA was independently associated with in-hospital (OR=1.21, 95% CI: 1.06, 1.37, p=0.004) and one-year mortality (HR=1.17, 95% CI: 1.05, 1.29, p=0.003). Kaplan-Meier analysis demonstrated that the cumulative rate of one-year mortality after surgery was higher in patients with SUA>7.3mg/dl (Log-rank=21.1, p<0.001). CONCLUSIONS: Admission SUA could be used as a preoperative risk assessment factor in RHD patients who underwent VRS. PMID- 28735064 TI - Associations of fibroblast growth factor 21 with cardiovascular risk and beta cell function in patients who had no history of diabetes. AB - BACKGROUND: We investigated the associations of fibroblast growth factor 21 (FGF 21) with cardiovascular risk and beta-cell function in patients who had no history of diabetes. METHODS: We enrolled 269 outpatients who had been referred for an oral glucose tolerance test (OGTT). Plasma glucose, insulin, and FGF-21 were measured before and at 2h after the OGTT. beta-cell function was assessed using the insulinogenic index, corrected for insulin resistance. Patients' 10 year coronary heart disease (CHD) risk was assessed using the Chinese Multi provincial Cohort Study functions. RESULTS: Overall, there was a 10% decrease in FGF-21 after OGTT (p<0.001). The decrease of FGF-21 after OGTT in patients with normal glucose tolerance, prediabetes, and diabetes was 8%, 10%, and 21%, respectively (all p<0.05). Patients with a history of admission for coronary angiography had a higher 10-year CHD risk and fasting FGF-21 (both p<0.001). In multivariate regression analysis, fasting FGF-21 was positively associated with 10-year CHD risk, while FGF-21 relative change 2h after OGTT was positively associated with beta-cell function. CONCLUSIONS: In patients who had no history of diabetes, fasting FGF-21 was positively associated with 10-year CHD risk, while FGF-21 relative change 2h after OGTT was positively associated with beta cell function. PMID- 28735065 TI - Time required for resetting postural effects on serum constituents in healthy individuals. AB - OBJECTIVE: We investigated postural effects on concentrations of commonly measured serum analytes and sought for optimal duration of sitting before venipuncture in an outpatient setting. METHODS: Seven healthy volunteers changed posture serially at 30-minute (min) intervals from lying, sitting, slowly walking, sitting, and to lying again. At the end of the first lying posture, wing needle was inserted into cubital vein and 3mL of blood was drawn every 5min. All the serum was stored at -80 degrees C until the time of collective measurements for 16 major chemistry analytes two weeks later. RESULTS: Concentrations of macromolecular analytes (albumin, total cholesterol, alkaline phosphatase, etc.) in supine position were increased (on average 5-7%) after 30min of sitting and further increased (10-14%) during 30min of walking. After slow walking, time required for return of values to the levels of sitting posture took approximately 20min. Concentrations of small molecules (sodium, urea, etc.) did not show any variation by the postural changes. Potassium and inorganic phosphate showed walking-related increase in concentrations. Creatinine was lowered in sitting posture, which implicates postural changes in renal flow. CONCLUSION: It is generally recommended to sit for 20min or more before venipuncture, although the effect of prior physical movement remains a little longer for potassium and inorganic phosphate. PMID- 28735066 TI - Exclusive breastfeeding at three months and infant sleep-wake behaviors at two weeks, three and six months. AB - This study assessed infant sleep-wake behavior at two weeks, three and six months as function of feeding method at three months (exclusively breastfed, partially breastfed, and exclusively formula fed infants). Mothers of 163 first-born, full term, normal birth weight, healthy infants completed socio-demographic, depression, anxiety, and infant sleep-wake behavior measures. No effects were found for sleep arrangements, depression or anxiety, on feeding methods and sleep wake behavior at three months. At two weeks exclusively breastfed infants at three months spent more hours sleeping and less hours awake during the 24-h period than partially breastfed infants. At three months, exclusively breastfed infants had a shorter of the longest sleep period at night than exclusively formula fed infants. At six months, exclusively breastfed infants at three months spent more hours awake at night than partially breastfed infants, awake more at night than exclusively formula fed infants, and had a shorter sleep period at night than partially breastfed and exclusively formula fed infants. This study showed differences in sleep-wake behaviors at two weeks, three and six months, when exclusively breastfed infants are compared with partially breastfed and exclusively formula fed infants at three months, while no effects were found for sleep arrangements, depression or anxiety. PMID- 28735068 TI - Primary metastatic breast cancer in the era of targeted therapy - Prognostic impact and the role of breast tumour surgery. AB - BACKGROUND: Except for meeting the individual palliative need, the benefit of breast surgery in primary metastatic breast cancer (PMBC), also known as de novo metastatic breast cancer, on long-term outcomes remains controversial. Twenty four hundred and one patients with metastatic breast cancer, enrolled between 2000 and 2011 in two prospective non-interventional studies on targeted therapy, were screened with respect to this question. METHODS: One study investigated trastuzumab therapy for human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer in addition to mainly first-line chemotherapy. The other observed bevacizumab added to chemotherapy as first-line treatment for mostly HER2-negative disease. RESULTS: Five-hundred and seventy (24%) patients presented with PMBC, and valid information on resection of the primary tumour was available for 568 women. Out of these, 426 (75%) underwent local resection. The latter group was characterised by less overall metastatic burden and a lower proportion of T4 tumours. No major differences were observed with respect to age, hormone receptor and HER2 status, visceral disease and performance status. Numerically, the surgery group showed a slightly favourable progression-free survival (PFS, medians: 13.6 versus 11.8 months; P = 0.18) and overall survival (OS, 34.1 versus 31.7; P = 0.23). However, in multivariable analysis, including all other univariably significant parameters, no trend for better outcome after surgery remained detectable, neither for PFS (hazard ratio 0.99; P = 0.92) nor for OS (0.95; P = 0.71). CONCLUSIONS: Our findings suggest no major survival benefit for local resection in the overall PMBC population treated with modern targeted therapies. However, further analyses are warranted to define specific risk groups, which may benefit from surgical removal of the primary. PMID- 28735067 TI - Treatment sequence with either irinotecan/cetuximab followed by FOLFOX-4 or the reverse strategy in metastatic colorectal cancer patients progressing after first line FOLFIRI/bevacizumab: An Italian Group for the Study of Gastrointestinal Cancer phase III, randomised trial comparing two sequences of therapy in colorectal metastatic patients. AB - INTRODUCTION: The optimal treatment strategy for RAS wild type (WT) mCRC is controversial. Our phase III study investigated the effect of introducing earlier (second-line) or later (third-line) cetuximab in patients progressed after FOLFIRI/bevacizumab first-line. PATIENTS AND METHODS: mCRC patients progressing after FOLFIRI/bevacizumab first-line were randomised to receive second-line irinotecan/cetuximab followed by third-line FOLFOX-4 (arm A) or the reverse sequence (arm B). Primary end-point was progression-free survival (PFS). RESULTS: About 54 and 56 patients were randomised in arm A and in arm B, respectively. After a median follow-up of 37.5 months, 100 PFS events were recorded. Median PFS was 9.9 months in arm A and 11.3 months in arm B (Hazard ratio [HR] 1.04, 95% confidence interval [CI]: 0.69-1.56, p = 0.854), while median overall survival was 12.3 months in arm A and 18.6 months in arm B (HR 0.84, 95% CI: 0.55-1.28; p = 0.411). No overall difference in side-effects were observed between the two treatment arms. CONCLUSIONS: This trial did not meet the primary end-point (PFS). Like other preclinical and clinical evidences, our study seems to suggest a reduced activity of cetuximab after a first-line bevacizumab-based therapy. PMID- 28735069 TI - Surgical versus non-surgical approach in primary desmoid-type fibromatosis patients: A nationwide prospective cohort from the French Sarcoma Group. AB - PURPOSE: The outcome of desmoid-type fibromatosis (DTF) is unpredictable. Currently, a wait-and-see approach tends to replace large en bloc resection as the first therapeutic approach. Nevertheless, there are no validated factors to guide the treatment choice. METHOD: We conducted a prospective study of 771 confirmed cases of DTF. We analysed event-free survival (EFS) based on the occurrence of relapse after surgery, progressive disease during the wait-and-see approach, or change in therapeutic strategy. Identification of prognostic factors was performed using classical methods (log-rank test and Cox model). RESULTS: Overall, the 2-year EFS was 56%; this value did not differ between patients undergoing an operation and those managed by the wait-and-see approach (53% versus 58%, p = 0.415). In univariate analysis, two prognostic factors significantly influenced the outcome: the nature of diagnostic sampling (p = 0.466) and primary location (p = 0.0001). The 2-year EFS was only 32% after open biopsy. The 2-year EFS was 66% for favourable locations (abdominal wall, intra abdominal, breast, digestive viscera and lower limb) and 41% for unfavourable locations. Among patients with favourable locations, the 2-year EFS was similar in patients treated by both surgery (70%) and the wait-and-see approach (63%; p = 0.413). Among patients with unfavourable locations, the 2-year EFS was significantly enhanced in patients initially managed with the wait-and-see approach (52%) compared with those who underwent initial surgery (25%; p = 0.001). CONCLUSION: The location of DTF is a major prognostic factor for EFS. If these findings are confirmed by independent analysis, personalised management of DTF must consider this easily obtained parameter. PMID- 28735071 TI - Fulminant response to combined checkpoint inhibition with ipilimumab plus nivolumab after failure of nivolumab monotherapy in metastatic melanoma. PMID- 28735070 TI - Suppression of the ATP-binding cassette transporter ABCC4 impairs neuroblastoma tumour growth and sensitises to irinotecan in vivo. AB - The ATP-binding cassette transporter ABCC4 (multidrug resistance protein 4, MRP4) mRNA level is a strong predictor of poor clinical outcome in neuroblastoma which may relate to its export of endogenous signalling molecules and chemotherapeutic agents. We sought to determine whether ABCC4 contributes to development, growth and drug response in neuroblastoma in vivo. In neuroblastoma patients, high ABCC4 protein levels were associated with reduced overall survival. Inducible knockdown of ABCC4 strongly inhibited the growth of human neuroblastoma cells in vitro and impaired the growth of neuroblastoma xenografts. Loss of Abcc4 in the Th-MYCN transgenic neuroblastoma mouse model did not impact tumour formation; however, Abcc4-null neuroblastomas were strongly sensitised to the ABCC4 substrate drug irinotecan. Our findings demonstrate a role for ABCC4 in neuroblastoma cell proliferation and chemoresistance and provide rationale for a strategy where inhibition of ABCC4 should both attenuate the growth of neuroblastoma and sensitise tumours to ABCC4 chemotherapeutic substrates. PMID- 28735072 TI - Long-term outcomes of adults with first-relapsed/refractory systemic anaplastic large-cell lymphoma in the pre-brentuximab vedotin era: A LYSA/SFGM-TC study. AB - BACKGROUND: Long-term outcomes of adults with first-relapsed/refractory (R/R) systemic anaplastic large-cell lymphoma (ALCL) are not definitively established and should be evaluated. PATIENTS AND METHODS: We previously published the long term outcomes of adults with ALCL initially treated with polychemotherapy in LYmphoma Study Association (LYSA) prospective clinical trials conducted during the pre-brentuximab vedotin era. Herein, we report the long-term outcomes of those patients after the first-relapsed/refractory (R/R) events. RESULTS: Among the 138 (64 (anaplastic lymphoma kinase (ALK(+)) and 74 ALK(-) ALCL) adults initially treated in clinical trials, 40 (14 ALK(+) and 26 ALK(-)) first-R/R ALCL patients and their long-term outcomes were analysed. Median follow-up from the first-R/R events was 12.5 years. For ALK(+) and ALK(-) patients, respectively, median [range] findings were as follows: age at first-R/R event: 35 [19-76] and 61 [34-81] years; time between inclusion in first-line clinical trials and first R/R events was 6 [1.5-34] and 11.1 [1-67] months (P = 0.36); with median (95% confidence interval) progression-free survival after the first-R/R events: 3.8 (0.7-14.8) and 5.3 (2.4-8.4) months (P = 0.39); and overall survival: 13.6 (0.7 89) and 8.1 (3.3-25) months (P = 0.96). ALCL was the main cause of death. CONCLUSION: Most adults with first-R/R ALCL have poor outcomes, with no significant differences between patients with ALK(+) or ALK(-) disease. These results could be used as reference for the evaluation of new drugs to treat R/R ALCL. PMID- 28735073 TI - From minutes to days-The ability of sows (Sus scrofa) to estimate time intervals. AB - Time estimation helps allocating time to different tasks and to plan behavioural sequences. It may also be relevant to animal welfare if it enables animals assessing the duration of a negative situation. Here, we investigated the ability of dry sows to estimate short and long time periods. We used a variant of the peak-interval procedure and the choice between 2 resources of different quality and replenishment rates to assess time periods in the order of minutes and days, respectively. In the minute-experiment, the sows were trained to expect an interruption while feeding at the end of an interval. Heart rate and heart rate variability slightly and continuously increased and decreased, respectively, towards the end of that interval. In the day-experiment, lasting about 60days, the sows were increasingly more likely to open the door to a high food reward on the correct day when this food reward was presented every fifth day. We conclude that the sows learnt to estimate time intervals of 5days after lengthy training but did not accurately learn intervals in the range of minutes. Therefore, they might re-visit replenishing resources after several days, but may not base short term decisions solely on the passing of time. PMID- 28735074 TI - Increased ventilation in female erythropoietin-deficient mouse line is not progesterone and estrous stage-dependent. AB - Previous studies suggest that chronic erythropoietin (Epo) deficiency in male mice does not alter normoxic/hypoxic ventilation. As effects of Epo are sex specific and as progesterone could be a respiratory stimulant, we evaluated the impact of Epo deficiency and its possible interaction with progesterone in ventilatory control in female mice during estrous cycle phases. Compared to wild type (WT) animals, Epo-TAgh female mice exhibited higher ventilation in hypoxia. However, when data were separated into luteal and follicular phases of the estrous cycle, basal ventilation and hypoxic ventilation were not different in both mice strains. As progesterone is known to be a potent respiratory stimulant, additional experiments were performed to elucidate its role. Interestingly, after mifepristone treatment, HVR was not modified in WT and Epo-TAgh mice, showing that the ventilatory stimulation observed in females was not directly mediated by progesterone. We conclude that Epo-TAgh female mice show no estrous stage dependent increase of ventilatory control and progesterone independent response to hypoxia. PMID- 28735075 TI - An entropic model of Gaia. AB - We modify the Tangled Nature Model of Christensen et. al. (2002) so that the agents affect the carrying capacity. This leads to a model of species-environment co-evolution where the system tends to have a larger carrying capacity with life than without. We discuss the model as an example of an entropic hierarchy and some implications for Gaia theory. PMID- 28735076 TI - Quantifying the influence of oscillatory flow disturbances on blood flow. AB - Pulsatile blood flow is renowned for inducing localised flow disturbances that are characterised by significant oscillations. These flow disturbances are recognised to have a physiologic significance within the cardiovascular system, particularly with respect to their proatherogenic expression on endothelial cells. Flow disturbances also impart significant influence on the mechanics of cardiovascular flow and are formally shown in the present study to be coupled to the period-average behaviour of a pulsatile flow field, causing it to be misrepresented by its steady-equivalent; which is often used in models of atherogenesis and hence limits their reliability. It is demonstrated that a measure of the localised influence of flow disturbances on the period-average flow can be realised by the relative significance of their kinetic energy, which is quantified by the introduced Oscillatory Kinetic Energy Index (OKEI). A specific measure of direction-reversing oscillations is also developed with the introduction of the Oscillatory Flow Index (OFI), which is an extension of the wall-bound Oscillatory Shear Index (OSI) onto flow and wall spaces. A case study of a human carotid artery is made; wherein pulsatile flow is studied relative to its steady-equivalent state. The introduced indices are demonstrated to collectively identify oscillatory flow disturbances within the flow; quantifying their spatial distribution and influence on the flow field. PMID- 28735077 TI - Opioid medication misuse among unhealthy drinkers. AB - BACKGROUND: Combining opioid medications and alcohol has serious implications for patient health, including overdose. Information regarding those who use/misuse opioid medications and engage in unhealthy alcohol use is limited to pharmacological and epidemiological descriptions. This study presents opioid medication misuse and behavioral, mental, and physical health characteristics of persons filling opioid medications that are engaged in unhealthy alcohol use. METHODS: We conducted a cross-sectional survey at 5 community pharmacies in Southwestern, Pennsylvania among patients filling opioid medications. Respondents completed validated opioid medication misuse, alcohol use, illicit drug use, depression, posttraumatic stress disorder (PTSD), and physical health functioning assessments. We present univariate and multivariate statistics describing opioid medication misuse and health risks among those positive for unhealthy alcohol use. RESULTS: A total of 344 patients completed the survey (75.8% response). A total of 15.9% of respondents screened positive for opioid medication misuse, of whom 20.3% reported unhealthy alcohol use. Taking opioid medications too often was reported among a larger proportion of the sample with unhealthy alcohol use (34.3%) compared to those without (22.1%, p=0.04). Further, among respondents with unhealthy alcohol use, illicit drug use (Adjusted odds ratio [AOR]=12.14, 95% Confidence Interval [CI]=1.64-89.72) and PTSD (AOR=9.77, 95% CI=1.70-56.11) were associated with increased odds for opioid medication misuse. CONCLUSION: Results suggest respondents with unhealthy alcohol use had distinct health profiles, which may place them at risk for opioid misuse and adverse events, such as overdose. Continued research must work to further understand these relationships and identify intervention and treatment strategies. PMID- 28735078 TI - Revisiting the role of the insula and smoking cue-reactivity in relapse: A replication and extension of neuroimaging findings. AB - INTRODUCTION: The ability to direct smoking cessation treatment based on neuroscientific findings holds incredible promise. However, there is a strong need for consistency across studies to confirm neurobiological targets. While our prior work implicated enhanced insula reactivity to smoking cues in tobacco smoking relapse vulnerability, this finding has not been confirmed. METHOD: Using functional magnetic resonance imaging (fMRI), we evaluated the pre-cessation brain reactivity to smoking vs. neutral cues in nicotine dependent smokers who were and were not able to maintain subsequent abstinence. RESULTS: Of the 23 (7 women) individuals assessed, 13 relapsed and there were no demographic differences between those who did and did not relapse. However, smokers who relapsed showed enhanced reactivity to smoking cues in the right insula and dorsal striatum, showing significant overlap between our current and prior work despite methodological differences, including the fact that our previous work only included women. CONCLUSION: The current work supports our prior results and builds on the concept that the insula and dorsal striatum work in concert to maintain nicotine dependence. Specifically, dorsal striatal-mediated habitual responding may be triggered both by the external drug-associated cues, and the insula-mediated internal states that provide additional context motivating drug use. This replicated finding also mirrors preclinical work that finds the same individualized distinction, as only some rodents attribute incentive salience to drug cues and are more likely to reinstate drug seeking after extinction. To effectively treat addiction, these individual characteristics and their underlying neurobiological foundations must be considered. PMID- 28735079 TI - Synthesis and characterization of nanoparticles conjugated tannase and using it for enhancement of antibacterial activity of tannase produced by Serratia marcescens. AB - Fourteen isolates of Serratia marcescens were collected from patients suffering from septicemia. All theseisolates revealed different levels in tannase production. Tannase was partially purified from Serratia marcescens b9 by precipitation method at 70% saturation of ammonium sulfate. Au, Pt, SnO2 and SiO2 nanoparticles were prepared by laser ablation and examined by transmission electron microscopy (TEM), X-ray diffraction pattern and UV-Visible absorption spectroscopy. Conjugation of SiO2 nanoparticles to tannase by feeding and pulses methods were prepared and characterized by TEM, X-ray diffraction pattern and UV Visible spectrum. SiO2 nanoparticles conjugated partially purified tannase by feeding showed the higher effectiveness and higher significant level against all tested UTI causing in comparison with ciprofloxacin antibiotic, SiO2 nanoparticles alone, partially purified tannase alone and partially purified tannase by pulses. So that we can conclude that feeding method was the best method for enhancement partially purified tannase activity to maximum level thus SiO2 nanoparticles conjugated partially purified tannase may be a useful antibacterial agent for the treatment of urinary tract infection. PMID- 28735080 TI - Recombinant truncated E protein as a new vaccine candidate against nontypeable H. influenzae: Its expression and immunogenic evaluation. AB - Protein E (PE) is a conserved entity observed in both nontypeable Haemophilus influenzae (NTHi) and encapsulated H. influenzae. This is a small surface lipoprotein, consisting of only 160 amino acids, involved in the adhesion of H. influenzae to various types of epithelial cells. A 384-bp-long fragment from NTHi PE was cloned into the prokaryotic expression vector pBAD-gIIIA. The recombinant protein was expressed with arabinose and then purified by affinity purification on an Ni-NTA agarose matrix. BALB/c mice were immunized by subcutaneous injection with purified recombinant truncated PE mixed with an alum adjuvant. Serum antibody response and the functional activity of antibodies were evaluated by enzyme-linked immunosorbent assay (ELISA) and serum bactericidal assay (SBA), respectively. Colony PCR, double digestion, and sequencing were used to verify successful cloning of truncated PE. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and western blot analyses indicated the presence of a ~15-kDa recombinant protein. Serum IgG, IgG1, and IgG2a levels were significantly higher in the group immunized by recombinant truncated PE mixed with an alum adjuvant, compared to the non-vaccinated control group. Development of a strong bactericidal effect against NTHi was observed in the serum samples from immunized animals. Our findings suggest that recombinant truncated PE is a potential vaccine candidate for NTHi. PMID- 28735081 TI - Anti-inflammatory activity of cecropin-A2 from Musca domestica. AB - This study aimed to investigate the anti-inflammatory activity of Musca domestica cecropin-A2 (Mdc-A2) toward Staphylococcus aureus (S. aureus) to learn more about their immunological functions. RAW264.7 cells were transfected with recombinant lentiviruses introduce pLEX-Mdc-A2into the RAW264.7 cell line (RAW-Mdc-A2). The RAW264.7 cell line with empty pLEX (RAW-pLEX) was produced in the same manner as a negative control. Real-time quantitative reverse transcription PCR (RT-PCR) was performed to analyze the mRNA expression of TNF-a, IL-1beta, NFkappaB-1 and NFkappaB-2 in S. aureus-stimulated RAW-Mdc-A2 cells and RAW-pLEX cells in untreated cells and cells treated for 3 h, 6 h, 12 h and 24 h. RT-PCR was performed to analyze the mRNA expression of TNF-a, NFkappaB-1 and NFkappaB-2 stimulated by Lipoteichoic acid (LTA). Production of TNF-a was detected by enzyme linked immunosorbent assay (ELISA). Colony counts were used to calculate the number of CFU per mL of cell culture supernatants. The results showed that compared to RAW-pLEX cells, stable transfection of Mdc-A2 in RAW264.7 cells stimulated by S. aureus significantly down-regulated the mRNA expression of TNF-a transcript variant 1 (TNF-a-tv-1) at 6 h and 12 h and the mRNA expression of TNF a transcript variant 2 (TNF-a-tv-2) at 3 h, 6 h and 12 h. Compared to RAW-pLEX cells, stable transfection of Mdc-A2 in RAW264.7 cells stimulated by S. aureus significantly down-regulated the mRNA expression of IL-1beta-T at 3 h, 6 h and 12 h as well as the mRNA expression of IL-1beta at 3 h and 6 h. The expression and production of TNF-a and bacterial burden of cell culture supernatants were significantly down-regulated in RAW-Mdc-A2 cells stimulated by S. aureus, and the expression and production of TNF-a were significantly down-regulated in RAW-Mdc A2 cells stimulated by LTA. Compared to RAW-pLEX cells, stable transfection of Mdc-A2 in RAW264.7 cells stimulated by S. aureus significantly down-regulated the mRNA expression of NFkappaB-1 at 3 h, 6 h and 12 h as well as the mRNA expression of NFkappaB-2 at 6 h. Additionally, stable transfection of Mdc-A2 in RAW264.7 cells stimulated by LTA significantly down-regulated the mRNA expression of NFkappaB-1. In conclusion, Mdc-A2 possesses potent anti-inflammatory activity and potent antimicrobial activity. Additionally, Mdc-A2 may interact with LTA and execute strong anti-inflammatory activity by blocking the activation of NF-kappaB signaling pathways. PMID- 28735083 TI - WITHDRAWN: Incidence of methicillin resistant Staphylococcus aureus (MRSA) in microbial community of cancer patients and evaluation of their resistant pattern. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our business/policies/article-withdrawal. PMID- 28735082 TI - Aeromonas caviae alters the cytosolic and mitochondrial creatine kinase activities in experimentally infected silver catfish: Impairment on renal bioenergetics. AB - Cytosolic and mitochondrial creatine kinases (CK), through the creatine kinase phosphocreatine (CK/PCr) system, provide a temporal and spatial energy buffer to maintain cellular energy homeostasis. However, the effects of bacterial infections on the kidney remain poorly understood and are limited only to histopathological analyses. Thus, the aim of this study was to investigate the involvement of cytosolic and mitochondrial CK activities in renal energetic homeostasis in silver catfish experimentally infected with Aeromonas caviae. Cytosolic CK activity decreased in infected animals, while mitochondrial CK activity increased compared to uninfected animals. Moreover, the activity of the sodium-potassium pump (Na+, K+-ATPase) decreased in infected animals compared to uninfected animals. Based on this evidence, it can be concluded that the inhibition of cytosolic CK activity by A. caviae causes an impairment on renal energy homeostasis through the depletion of adenosine triphosphate (ATP) levels. This contributes to the inhibition of Na+, K+-ATPase activity, although the mitochondrial CK activity acted in an attempt to restore the cytosolic ATP levels through a feedback mechanism. In summary, A. caviae infection causes a severe energetic imbalance in infected silver catfish, which may contribute to disease pathogenesis. PMID- 28735084 TI - A category-specific top-down attentional set can affect the neural responses outside the current focus of attention. AB - A top-down set can guide attention to enhance the processing of task-relevant objects. Many studies have found that the top-down set can be tuned to a category level. However, it is unclear whether the category-specific top-down set involving a central search task can exist outside the current area of attentional focus. To directly probe the neural responses inside and outside the current focus of attention, we recorded continuous EEG to measure the contralateral ERP components for central targets and the steady-state visual evoked potential (SSVEP) oscillations associated with a flickering checkerboard placed on the visual periphery. The relationship of color categories between targets and non targets was manipulated to investigate the effect of category-specific top-down set. Results showed that when the color categories of targets and non-targets in the central search arrays were the same, larger SSVEP oscillations were evoked by target color peripheral checkerboards relative to the non-target color ones outside the current attentional focus. However, when the color categories of targets and non-targets were different, the peripheral checkerboards in two different colors of the same category evoked similar SSVEP oscillations, indicating the effects of category-specific top-down set. These results firstly demonstrate that the category-specific top-down set can affect the neural responses of peripheral distractors. The results could support the idea of a global selection account and challenge the attentional window account in selective attention. PMID- 28735085 TI - Minocycline attenuates streptomycin-induced cochlear hair cell death by inhibiting protein nitration and poly (ADP-ribose) polymerase activation. AB - This study aimed to elucidate the protective effect of minocycline against streptomycin-induced damage of cochlear hair cells and its mechanism. Cochlear membranes were isolated from newborn Wistar rats and randomly divided into control, 500MUmol/L streptomycin, 100MUmol/L minocycline, and streptomycin and minocycline treatment groups. Hair cell survival was analyzed by detecting the expression of 3-nitrotyrosine (3-NT) in cochlear hair cells by immunofluorescence and an enzyme-linked immunosorbent assay. Expression of 3-NT and inducible nitric oxide synthase (iNOS), and poly (ADP-Ribose) polymerase (PARP) and caspase-3 activation were evaluated by western blotting. The results demonstrated hair cell loss at 24h after streptomycin treatment. No change was found in supporting cells of the cochleae. Minocycline pretreatment improved hair cell survival and significantly reduced the expression of iNOS and 3-NT in cochlear tissues compared with the streptomycin treatment group. PARP and caspase-3 activation was increased in the streptomycin treatment group compared with the control group, and pretreatment with minocycline decreased cleaved PARP and activated caspase-3 expression. Minocycline protected cochlear hair cells from injury caused by streptomycin in vitro. The mechanism underlying the protective effect may be associated with the inhibition of excessive formation of nitric oxide, reduction of the nitration stress reaction, and inhibition of PARP and caspase-3 activation in cochlear hair cells. Combined minocycline therapy can be applied to patients requiring streptomycin treatment. PMID- 28735086 TI - A series of population models for Hyphantria cunea with delay and seasonality. AB - In this paper, we establish and study a basic stage-structured model for the population of Hyphantria cunea, a delay differential equation model and a model incorporating the resource and seasonality. By introducing the population reproduction number R0, we show that R0 acts as a threshold parameter for the existence and stability of equilibria. The trivial equilibria of the above models are all globally asymptotically stable when R0<1; the basic model and the delay differential model have a unique positive equilibrium respectively, and they are both locally asymptotically stable when R0>1; the model with periodic season is uniformly persistent and admits a positive periodic solution if R0>1. Numerical simulations are carried out to illustrate the theoretical results. In addition, we consider the effect of temperature and season on the population of Hyphantria cunea. PMID- 28735087 TI - Fisher-KPP with time dependent diffusion is able to model cell-sheet activated and inhibited wound closure. AB - The popular 2D Fisher-KPP equation with constant parameters fails to predict activated or inhibited cell-sheet wound closure. Here, we consider the case where the collective diffusion coefficient is time dependent, with a 3-parameter sigmoid profile. The sigmoid is taken S-shaped for the activated assays, and Z shaped for the inhibited ones. For two activated and two inhibited assays, our model is able to predict with a very good accuracy features of the wound closure like as the time evolution of the wound area and migration rate. The calibrated parameters are consistent with respect to different subsets of the experimental datasets used for the calibration. However, the assumption of sigmoid time profile for the proliferation rate yields calibrated parameters critically dependent on the dataset used for calibration. PMID- 28735088 TI - Excessive application of pig manure increases the risk of P loss in calcic cinnamon soil in China. AB - Soil phosphorus (P) is a critical factor affecting crop yields and water environmental quality. To investigate the degree of loss risk and forms of soil P in calcic cinnamon soil, the P fraction activities in soils were analysed using chemical methods, combined with an in situ field experiment. Seven treatments were set in this study, including control (unfertilized), no P fertilizer (No-P), mineral P fertilizer (Min-P), low (L-Man) and high (H-Man) quantities of pig manure, Min-P+L-Man, and Min-P+H-Man. The results showed that manure fertilizer could not only significantly increase maize yield but could also enhance the accumulation of soil P in organic and inorganic forms. After 23years of repeated fertilization, the soil Olsen-P contents respectively showed 64.7-, 43.7- and 31.9-fold increases in the Min-P+H-Man, Min-P+L-Man and H-Man treatments, while the soil Olsen-P in Min-P treatment only increased 23.7-fold. The soil Olsen-P thresholds ranged from 22.59 to 32.48mgkg-1 in calcic cinnamon soil to maintain a higher maize yield as well as a lower risk of P loss. Therefore, long-term excessive manure application could obviously raise the content of soil Olsen-P and increase the risk of P loss in calcic cinnamon soil. PMID- 28735089 TI - Biodeterioration of marble in an underwater environment. AB - This study examines the deterioration of geomaterials used throughout history that today may be found lying on the ocean floor. Submerged archaeological sites including cargoes from shipwrecks or ancient city ruins have been a topic of interest from a perspective of in situ musealization, as a way of making underwater cultural heritage accessible to the public. In an experimental study conducted at an underwater archaeological site in the Bay of Cadiz (SW Spain), we subjected two types of marble (Carrara and Macael) to three conditions to which submerged archaeological objects are often exposed: full exposure to the water column, natural processes of burial and unearthing, or permanent burial. After an 18-month study period, the factor found to mostly affect these materials was their biological colonization. This factor was assessed by estimating total surface biocover and the rate of surface biocolonization, and also through the identification of skeletons and associated alteration forms by light microscopy, and scanning electron microscopy (SEM). Biofouling and bioerosion were the main causes of biodeterioration and dependent on the position of the marble specimens in the seawater. The response of both materials was similar, though dolomite crystals in the Carrara marble acted as a protective barrier against actively penetrating microorganisms. These investigations have allowed the study of tracers left by epilithic encrusting organisms and endolithic bioeroders on marbles intentionally exposed to seawater, providing new insights to the understanding of the biodeterioration processes occurring in cultural heritage stones, with significant implications when they are part of underwater archaeological remains. PMID- 28735090 TI - Impacts of the 2003 and 2015 summer heatwaves on permafrost-affected rock-walls in the Mont Blanc massif. AB - Rockfall is one of the main geomorphological processes that affects the evolution and stability of rock-walls. At high elevations, rockfall is largely climate driven, very probably because of the warming of rock-wall permafrost. So with the ongoing global warming that drives the degradation of permafrost, the related hazards for people and infrastructure could continue to increase. The heatwave of summer 2015, which affected Western Europe from the end of June to August, had a serious impact on the stability of high-altitude rock-walls, including those in the Mont Blanc massif. A network of observers allowed us to survey the frequency and intensity of rock-wall morphodynamics in 2015, and to verify its relationship with permafrost. These observations were compared with those of the 2003 summer heatwave, identified and quantified by remote sensing. A comparison between the two years shows a fairly similar rockfall pattern in respect of total volumes and high frequencies (about 160 rockfalls >100m3) but the total volume for 2003 is higher than the 2015 one (about 300,000m3 and 170,000m3 respectively). In both cases, rockfalls were numerous but with a low magnitude and occurred in permafrost-affected areas. This suggests a sudden and remarkable deepening of the active layer during these two summers, rather than a longer-term warming of the permafrost body. PMID- 28735091 TI - Effect of extracellular polymeric substance components on the sorption behavior of 2,2',4,4'-tetrabromodiphenyl ether to soils: Kinetics and isotherms. AB - Microbial extracellular polymeric substances (EPS) and persistent organic pollutants (POPs) commonly exist in the soil environment. Currently, there is a knowledge gap regarding the effect of EPS on the fate of POPs in soil. In the present study, 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) was used as a model compound to investigate the effects of bovine serum albumin (BSA) and sodium alginate (SA) - mimicking the main components of EPS - on sorption of POPs to soils, through batch experiments. Irrespective of the concentration of BSA: the addition of BSA did enhance the sorption capacity of BDE-47 to soils, due to generation of more sorption sites. For SA, it increased the sorption capacity of BDE-47 at low BDE-47 concentrations, while the presence of SA negatively affected sorption of BDE-47 at high BDE-47 concentrations. The partition effect dominates the sorption of BDE-47 to soils, but after adding either BSA or SA, the sorption of BDE-47 to soils is dominated by surface sorption. Film diffusion and intra particle diffusion were also involved in the sorption process with and without BSA or SA, with the latter being the rate-limiting step. The heterogeneous surface and nonlinear sorption behavior of BDE-47 to soils increased in the presence of either BSA or SA. The FTIR spectra indicated that the aromatic CC, H bonds and OH groups may be involved in the sorption process. Therefore, BSA enhanced the retention of BDE-47 to soil, while SA's influence on BDE-47 sorption to soil depended on the concentration of BDE-47. PMID- 28735092 TI - Rodenticide incidents of exposure and adverse effects on non-raptor birds. AB - Interest in the adverse effects of rodenticides on birds has focused primarily on raptors. However, non-raptor birds are also poisoned (rodenticide exposure resulting in adverse effects including mortality) by rodenticides through consumption of the rodenticide bait and contaminated prey. A literature search for rodenticide incidents (evidence of exposure to a rodenticide, adverse effects, or exposure to placebo baits) involving non-raptor birds returned 641 records spanning the years 1931 to 2016. The incidents included 17 orders, 58 families, and 190 non-raptor bird species. Nineteen anticoagulant and non anticoagulant rodenticide active ingredients were associated with the incidents. The number of incidents and species detected were compared by surveillance method. An incident was considered to have been reported through passive surveillance if it was voluntarily reported to the authorities whereas the report of an incident found through field work that was conducted with the objective of documenting adverse effects on birds was determined to be from active surveillance. More incidents were reported from passive surveillance than with active surveillance but a significantly greater number of species were detected in proportion to the number of incidents found through active surveillance than with passive surveillance (z=7.61, p<0.01). Results suggest that reliance on only one surveillance method can underestimate the number of incidents that have occurred and the number of species that are affected. Although rodenticides are used worldwide, incident records were found from only 15 countries. Therefore, awareness of the breadth of species diversity of non-raptor bird poisonings from rodenticides may increase incident reportings and can strengthen the predictions of harm characterized by risk assessments. PMID- 28735093 TI - Stable isotope labeling by fatty acids in cell culture (SILFAC) coupled with isotope pattern dependent mass spectrometry for global screening of lipid hydroperoxide-mediated protein modifications. AB - : Lipid hydroperoxide-mediated modifications of proteins are receiving increasing attention because of their possible involvement in various degenerative diseases. These biological effects are attributed to the ability of lipid peroxidation derived aldehydes to react with the nucleophilic sites of proteins. Here we describe a methodology involving metabolic labeling coupled with mass spectrometry-based proteomic analysis that enables global screening of lipid hydroperoxide-mediated protein modifications in a cell system. The lipidome of MCF-7 cells was labeled by incubating the cells with 1.4MUM [13C18]-linoleic acid (LA) until the LA to [13C18]-LA ratio became 1:1. This approach was termed SILFAC (stable isotope labeling by fatty acids in cell culture). Analysis of the cellular phospholipids indicated that [13C18]-LA was incorporated quantitatively. The labeled cells were subjected to oxidative stress using a calcium ionophore and l-ascorbic acid, which promote the generation of reactive aldehydes from cellular LA and [13C18]-LA. After protein extraction and digestion with trypsin, isotope pattern dependent MS was used to analyze peptides modified by 1:1 ratios of the 12C and 13C aldehyde isomers. Using the current methodology, we identified the major lipid hydroperoxide-mediated modifications to proteins in MCF-7 cells without the need for chemical labeling or further affinity purification. SIGNIFICANCE: Lipid peroxidation-derived aldehydes (LPDAs) such as 4-oxo-2(E) nonenal and 4-hydroxy-2(E)-nonenal can readily react with proteins and peptides to produce a variety of covalent modifications and cross-linkages, resulting in protein dysfunction and altered gene regulation. Various analytical approaches have therefore been developed to detect and characterize protein modifications mediated by LPDAs. However, most of the methods are not specific for LPDA modifications or designed for proteins modified by a target aldehyde. Here we describe the coupling of stable isotope labeling by fatty acids in cell culture (SILFAC) with an isotope pattern dependent MS-based proteomic strategy to provide a global screening tool for the identification of lipid hydroperoxide-mediated protein modifications. PMID- 28735094 TI - Dedicated tool to assess the impact of a rhetorical task on human body temperature. AB - INTRODUCTION: Functional infrared thermal imaging is a method widely used in medicine, including analysis of the mechanisms related to the effect of emotions on physiological processes. The article shows how the body temperature may change during stress associated with performing a rhetorical task and proposes new parameters useful for dynamic thermal imaging measurements MATERIALS AND METHODS: 29 healthy male subjects were examined. They were given a rhetorical task that induced stress. Analysis and processing of collected body temperature data in a spatial resolution of 256*512pixels and a temperature resolution of 0.1 degrees C enabled to show the dynamics of temperature changes. This analysis was preceded by dedicated image analysis and processing methods RESULTS: The presented dedicated algorithm for image analysis and processing allows for fully automated, reproducible and quantitative assessment of temperature changes and time constants in a sequence of thermal images of the patient. When performing the rhetorical task, the temperature rose by 0.47+/-0.19 degrees C in 72.41% of the subjects, including 20.69% in whom the temperature decreased by 0.49+/-0.14 degrees C after 237+/-141s. For 20.69% of the subjects only a drop in temperature was registered. For the remaining 6.89% of the cases, no temperature changes were registered CONCLUSIONS: The performance of the rhetorical task by the subjects causes body temperature changes. The ambiguous temperature response to the given stress factor indicates the complex mechanisms responsible for regulating stressful situations. Stress associated with the examination itself induces body temperature changes. These changes should always be taken into account in the analysis of infrared data. PMID- 28735095 TI - Regulation of lipid droplet-associated proteins by peroxisome proliferator activated receptors. AB - Excess fatty acids are stored in cells as triglycerides in specialized organelles called lipid droplets (LD). LD can be found in nearly all cell types and may expand during certain (patho)physiological conditions. The synthesis and breakdown of triglycerides and their deposition in LD is governed by a diverse set of enzymes and LD-associated proteins. These proteins serve structural roles in and around LD and regulate the activity of key lipogenic and lipolytic enzymes. The LD-associated proteins are subject to multiple regulatory mechanisms at the protein and gene expression level. A group of transcription factors that govern the expression of many LD-associated proteins are the Peroxisome Proliferator-Activated Receptors (PPARs). PPARs are lipid-activated transcription factors that play a key role in the regulation of lipid metabolism in liver (PPARalpha), adipose tissue (PPARgamma), and skeletal muscle (PPARdelta). This review provides an overview of the regulation of LD-associated proteins by PPARalpha, PPARdelta, and PPARgamma in adipose tissue, liver, macrophages, and skeletal muscle. It is concluded that many LD-associated proteins, including members of the PLIN family, CIDEC, CIDEA, HILPDA, FITM1, FITM2, and G0S2 are under direct transcriptional control of PPARs. Upregulation of LD-associated proteins by PPARs provides a mechanism to link uptake of lipids to regulation of lipid storage capacity. This article is part of a Special Issue entitled: Recent Advances in Lipid Droplet Biology edited by Rosalind Coleman and Matthijs Hesselink. PMID- 28735097 TI - Protecting the heart through MK2 modulation, toward a role in diabetic cardiomyopathy and lipid metabolism. AB - Various signaling pathways have been identified in the heart as important players during development, physiological adaptation or pathological processes. This includes the MAPK families, particularly p38MAPK, which is involved in several key cellular processes, including differentiation, proliferation, apoptosis, inflammation, metabolism and survival. Disrupted p38MAPK signaling has been associated with several diseases, including cardiovascular diseases (CVD) as well as diabetes and its related complications. Despite efforts to translate this knowledge into therapeutic avenues, p38 inhibitors have failed in clinical trials due to adverse effects. Inhibition of MK2, a downstream target of p38, appears to be a promising alternative strategy. Targeting MK2 activity may avoid the adverse effects linked to p38 inhibition, while maintaining its beneficial effects. MK2 was first considered as a therapeutic target in inflammatory diseases such as rheumatoid polyarthritis. A growing body of evidence now supports a key role of MK2 signaling in the pathogenesis of CVD, particularly ischemia/reperfusion injury, hypertrophy, and hypertension and that its inhibition or inactivation is associated with improved heart and vascular functions. More recently, MK2 was shown to be a potential player in diabetes and related complications, particularly in liver and heart, and perturbations in calcium handling and lipid metabolism. In this review, we will discuss recent advances in our knowledge of the role of MK2 in p38MAPK-mediated signaling and the benefits of its loss of function in CVD and diabetes, with an emphasis on the roles of MK2 in calcium handling and lipid metabolism. This article is part of a Special issue entitled Cardiac adaptations to obesity, diabetes and insulin resistance, edited by Professors Jan F.C. Glatz, Jason R.B. Dyck and Christine Des Rosiers. PMID- 28735098 TI - Cholangiocytes: Cell transplantation. AB - BACKGROUND: Due to significant limitations to the access to orthotropic liver transplantation, cell therapies for liver diseases have gained large interest worldwide. SCOPE OF REVIEW: To revise current literature dealing with cell therapy for liver diseases. We discussed the advantages and pitfalls of the different cell sources tested so far in clinical trials and the rationale underlying the potential benefits of transplantation of human biliary tree stem cells (hBTSCs). MAJOR CONCLUSIONS: Transplantation of adult hepatocytes showed transient benefits but requires immune-suppression that is a major pitfall in patients with advanced liver diseases. Mesenchymal stem cells and hematopoietic stem cells transplanted into patients with liver diseases are not able to replace resident hepatocytes but rather they target autoimmune or inflammatory processes into the liver. Stem cells isolated from fetal or adult liver have been recently proposed as alternative cell sources for advanced liver cirrhosis and metabolic liver disease. We demonstrated the presence of multipotent cells expressing a variety of endodermal stem cell markers in (peri)-biliary glands of bile ducts in fetal or adult human tissues, and in crypts of gallbladder epithelium. In the first cirrhotic patients treated in our center with biliary tree stem cell therapy, we registered no adverse event but significant benefits. GENERAL SIGNIFICANCE: The biliary tree stem cell could represent the ideal cell source for the cell therapy of liver diseases. This article is part of a Special Issue entitled: Cholangiocytes in Health and Diseaseedited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen. PMID- 28735099 TI - Subcellular expression of aquaporin-4 in substantia nigra of normal and MPTP treated mice. AB - Aquaporin-4 (AQP4) is the predominant water channel in mammalian CNS where it is localized at the perivascular astrocytic foot processes abutting brain microvessels. Several lines of evidence suggest that AQP4 is involved in important homeostatic functions and that mislocalization of the perivascular pool of AQP4 is implicated in several different brain disorders. A recent study suggests that the differential susceptibility of midbrain dopaminergic neurons to the parkinsonogenic toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) depends on the expression of AQP4. Further, MRI studies of patients with Parkinson's disease (PD) point to an excessive water accumulation in the substantia nigra (SN). This prompted us to investigate the cellular and subcellular distribution of AQP4 in mouse SN using immunofluorescence and quantitative immunogold cytochemistry. Compared with neocortex, SN exhibits a higher concentration of AQP4. Specifically, judged by electron microscopic immunogold analysis, the perivascular density of AQP4 in SN exceeds by 70% the perivascular density of AQP4 in the neocortex. An even larger difference in AQP4 labeling was found for astrocytic processes in the neuropil. Treatment with MPTP further increased (by >30%) the perivascular AQP4 density in SN, but also increased AQP4 labeling in the neocortex. Our data indicate that the perivascular AQP4 pool in SN is high in normal animals and even higher after treatment with MPTP. This would leave the SN more prone to water accumulation and supports the idea that AQP4 could be involved in the pathogenesis of PD. PMID- 28735096 TI - Lipid droplet functions beyond energy storage. AB - Lipid droplets are cytoplasmic organelles that store neutral lipids and are critically important for energy metabolism. Their function in energy storage is firmly established and increasingly well characterized. However, emerging evidence indicates that lipid droplets also play important and diverse roles in the cellular handling of lipids and proteins that may not be directly related to energy homeostasis. Lipid handling roles of droplets include the storage of hydrophobic vitamin and signaling precursors, and the management of endoplasmic reticulum and oxidative stress. Roles of lipid droplets in protein handling encompass functions in the maturation, storage, and turnover of cellular and viral polypeptides. Other potential roles of lipid droplets may be connected with their intracellular motility and, in some cases, their nuclear localization. This diversity highlights that lipid droplets are very adaptable organelles, performing different functions in different biological contexts. This article is part of a Special Issue entitled: Recent Advances in Lipid Droplet Biology edited by Rosalind Coleman and Matthijs Hesselink. PMID- 28735101 TI - Electrophysiological Correlates of Speaker Segregation and Foreground-Background Selection in Ambiguous Listening Situations. AB - In everyday listening environments, a main task for our auditory system is to follow one out of multiple speakers talking simultaneously. The present study was designed to find electrophysiological indicators of two central processes involved - segregating the speech mixture into distinct speech sequences corresponding to the two speakers, and then attending to one of the speech sequences. We generated multistable speech stimuli that were set up to create ambiguity as to whether only one or two speakers are talking. Thereby we were able to investigate three perceptual alternatives (no segregation, segregated - speaker A in the foreground, segregated - speaker B in the foreground) without any confounding stimulus changes. Participants listened to a continuously repeating sequence of syllables, which were uttered alternately by two human speakers, and indicated whether they perceived the sequence as an inseparable mixture or as originating from two separate speakers. In the latter case, they distinguished which speaker was in their attentional foreground. Our data show a long-lasting event-related potential (ERP) modulation starting at 130ms after stimulus onset, which can be explained by the perceptual organization of the two speech sequences into attended foreground and ignored background streams. Our paradigm extends previous work with pure-tone sequences toward speech stimuli and adds the possibility to obtain neural correlates of the difficulty to segregate a speech mixture into distinct streams. PMID- 28735102 TI - Intra-operatively measured spastic semimembranosus forces of children with cerebral palsy. AB - The knee kept forcibly in a flexed position is typical in cerebral palsy. Using a benchmark, we investigate intra-operatively if peak spastic hamstring force is measured in flexed knee positions. This tests the assumed shift of optimal length due to adaptation of spastic muscle and a decreasing force trend towards extension. Previously we measured spastic gracilis (GRA) and semitendinosus (ST) forces. Presently, we studied spastic semimembranosus (SM) and tested the following hypotheses: spastic SM forces are (1) high in flexed and (2) low in extended positions. We compared the data to those of GRA and ST to test (3) if percentages of peak force produced in flexed positions are different. During muscle lengthening surgery of 8 CP patients (9years, 4months; GMFCS levels=II-IV; limbs tested=13) isometric SM forces were measured from flexion (120 degrees ) to full extension (0 degrees ). Spastic SM forces were low in flexed knee positions (only 4.2% (3.4%) and 10.7% (9.7%) of peak force at KA=120 degrees and KA=90 degrees respectively, indicating less force production compared to the GRA or ST) and high in extended knee positions (even 100% of peak force at KA=0 degrees ). This indicates an absence of strong evidence for a shift of optimal muscle length of SM towards flexion. PMID- 28735100 TI - Attention modulates specific motor cortical circuits recruited by transcranial magnetic stimulation. AB - Skilled performance and acquisition is dependent upon afferent input to motor cortex. The present study used short-latency afferent inhibition (SAI) to probe how manipulation of sensory afference by attention affects different circuits projecting to pyramidal tract neurons in motor cortex. SAI was assessed in the first dorsal interosseous muscle while participants performed a low or high attention-demanding visual detection task. SAI was evoked by preceding a suprathreshold transcranial magnetic stimulus with electrical stimulation of the median nerve at the wrist. To isolate different afferent intracortical circuits in motor cortex SAI was evoked using either posterior-anterior (PA) or anterior posterior (PA) monophasic current. In an independent sample, somatosensory processing during the same attention-demanding visual detection tasks was assessed using somatosensory-evoked potentials (SEP) elicited by median nerve stimulation. SAI elicited by AP TMS was reduced under high compared to low visual attention demands. SAI elicited by PA TMS was not affected by visual attention demands. SEPs revealed that the high visual attention load reduced the fronto central P20-N30 but not the contralateral parietal N20-P25 SEP component. P20-N30 reduction confirmed that the visual attention task altered sensory afference. The current results offer further support that PA and AP TMS recruit different neuronal circuits. AP circuits may be one substrate by which cognitive strategies shape sensorimotor processing during skilled movement by altering sensory processing in premotor areas. PMID- 28735103 TI - Voluntary activation of the trapezius muscle in cases with neck/shoulder pain compared to healthy controls. AB - Subjects reporting neck/shoulder pain have been shown to generate less force during maximal voluntary isometric contractions (MVC) of the shoulder muscles compared to healthy controls. This has been suggested to be caused by a pain related decrease in voluntary activation (VA) rather than lack of muscle mass. The aim of the present study was to investigate VA of the trapezius muscle during MVCs in subjects with and without neck/shoulder pain by use of the twitch interpolation technique. Ten cases suffering from pain and ten age and gender matched, healthy controls were included in the study. Upper trapezius muscle thickness was measured using ultrasonography and pain intensity was measured on a 100mm visual analog scale (VAS). VA was calculated from five maximal muscle activation attempts. Superimposed stimuli were delivered to the accessory nerve at peak force and during a 2% MVC following the maximal contraction. Presented as mean+/-SD for cases and controls, respectively: VAS; 16.0+/-14.4mm and 2.1+/ 4.1mm (P=0.004), MVC; 545+/-161N and 664+/-195N (P=0.016), upper trapezius muscle thickness; 10.9+/-1.9mm and 10.4+/-1.5mm (P=0.20), VA; 93.6+/-14.2% and 96.3+/ 6.0% (P=0.29). In spite of significantly eight-fold higher pain intensity and ~20% lower MVC for cases compared to controls, no difference was found in VA. Possible explanations for the reduction in MVC could be differences in co activation of antagonists and synergists as well as muscle quality. PMID- 28735104 TI - Effect of limb dominance and sex on neuromuscular activation patterns in athletes under 12 performing unanticipated side-cuts. AB - Non-contact ACL injuries are one of the most common injuries to the knee joint among adolescent/collegiate athletes, with sex and limb dominance being identified as risk factors. In children under 12years of age (U12), these injuries occur less often and there is no sex-bias present. This study set out to explore if sex and/or limb dominance differences exist in neuromuscular activations in U12 athletes. Thirty-four U12 males and females had six bilateral muscles analyzed during unanticipated side-cuts. Principal component analysis was performed, capturing differences in overall magnitudes and timing of peak magnitudes. Two-way mixed-model ANOVAs determined significant limb effects with both sexes displaying (i) greater magnitudes in the lateral gastrocnemius and both hamstrings in the dominant limb and (ii) earlier timing of peak magnitudes in both gastrocnemii, both hamstrings and vastus medialis in the non-dominant limb, while no sex differences were identified. This study demonstrated that limb dominance, not sex, affects neuromuscular activation strategies in U12 athletes during unanticipated side-cuts. When developing injury prevention programs for younger athletes, an increased focus on balancing neuromuscular activations in both limbs could be beneficial in reducing the likelihood of ACL injuries in these athletes as they mature through puberty. PMID- 28735105 TI - Inherent inferior quality of follicular fluid in repeat breeder heifers as evidenced by low rates of in vitro production of bovine embryos. AB - The aims of the present study were to determine the effect of follicular fluid obtained from the ovulatory follicle of repeat breeder heifers on in vitro oocyte maturation (Experiment 1), fertilization (Experiment 2) and production of bovine embryos (Experiment 3). Holstein virgin heifers (VH, n = 5) with normal fertility or repeat breeder syndrome (RBH, n = 5) were used in the present study. Follicular fluid of VH and RBH was aspirated from ovulatory follicles and used as maturation medium. Bovine oocytes were aspirated from follicles of slaughterhouse ovaries and randomly allocated in three groups; in Group 1, oocytes cultured in TCM-199 supplemented with 10% heat-treated fetal calf serum and hormones (5 IU/mL hCG plus 0.1 IU/mL rFSH); in Group 2, oocytes cultured in TCM-199 supplemented with 10% filtered follicular fluid of VH without hormones; in Group 3, oocytes cultured in TCM-199 supplemented with 10% filtered follicular fluid of RBH without hormones. The mean (+/-SEM) percentage of matured oocytes was different between VH and RBH groups (72.2 +/- 4.0 vs 56.4 +/- 4.6%; P < 0.05, respectively). Further, the mean (+/-SEM) percentage of normal oocyte fertilization was higher in the VH than the RBH group (49.3 +/- 2.1 vs 32.0 +/- 4.2; P < 0.05, respectively). The mean percentage of embryos developed to the blastocyst stage was higher in the VH than the RBH group (12.0 +/- 1.3 vs 7.0 +/- 1.6; respectively; P < 0.05). In conclusion, our findings support our hypothesis that the ovulatory follicle microenvironment of Holstein repeat breeder heifers places their oocytes at a developmental disadvantage compared with Holstein fertile virgin heifers and that this suggest the existence of an inherent inferior quality of the ovulatory follicle microenvironment in repeat breeding Holstein heifers. PMID- 28735106 TI - Color-Doppler signals of blood flow in the corpus luteum and vascular perfusion index for ovarian and uterine arteries during expansion of the allantochorion in Bos taurus heifers. AB - Hemodynamics of the CL and each main uterine artery during expansion of the allantochorion from the ipsilateral side (CL side) to the contralateral side were studied in heifers (n = 8 nonbred, 9 pregnant). Progesterone concentration, vascular perfusion index for each uterine artery (by spectral ultrasonography), extent of blood flow in the CL (percentage of CL tissue with color-Doppler signals of blood flow), and intrauterine location of the expanding allantochorion (by gray-scale ultrasonic imaging) were determined daily from Days 14-60 (Day 0 = ovulation). In the pregnant group, but not in the nonbred group, the percentage of CL tissue with blood-flow signals increased (P < 0.003) from Days 16 (66.7 +/- 4.2%) to 23 (79.4 +/- 2.5) and then more slowly increased (P < 0.02) from Days 24 (76.7 +/- 2.9%) to 50 (85.0 +/- 2.0%). The volume of CL increased (P < 0.0001) progressively from Days 26 (6.1 +/- 0.4 cm3) to 60 (7.3 +/- 0.7 cm3). The vascular perfusion index in the ipsilateral uterine artery did not change in the nonbred group and progressively increased in the pregnant group beginning on Day 17 in approximate temporal association with the increase in luteal blood-flow signals. Functional increases in the CL during early pregnancy were attributed to the greater uterine arterial blood flow on the ipsilateral or CL side and the reported prominent anastomosis from a branch of the uterine artery to the ovarian artery that supplies the CL ovary. After an initial significant decrease in vascular perfusion index in each uterine artery in the pregnant group, the index began to increase on Day 17 in the ipsilateral artery and on Day 18 in the contralateral artery. The perfusion continued in the ipsilateral artery but discontinued in the contralateral artery on Day 21. Perfusion and diameter of the uterine artery were greater for the ipsilateral side until the vesicle entered the contralateral horn on Day 33 and increased for the contralateral horn between vesicle entry and filling of the horn on Day 44. During Days 35-60, the perfusion index (P < 0.04) and artery diameter (P < 0.001) were lower in the contralateral than in the ipsilateral artery. Results supported the hypotheses that (1) CL function increases during early pregnancy in temporal association with an increase in blood flow in the ipsilateral uterine artery and (2) blood flow in each of the ipsilateral and contralateral uterine arteries increases as the allantochorion expands in each uterine horn. PMID- 28735108 TI - Structural Biology outside the box-inside the cell. AB - Recent developments in cellular cryo-electron tomography, in-cell single-molecule Forster resonance energy transfer-spectroscopy, nuclear magnetic resonance spectroscopy and electron paramagnetic resonance-spectroscopy delivered unprecedented insights into the inner workings of cells. Here, we review complementary aspects of these methods and provide an outlook toward joint applications in the future. PMID- 28735107 TI - Integrative modelling of cellular assemblies. AB - A wide variety of experimental techniques can be used for understanding the precise molecular mechanisms underlying the activities of cellular assemblies. The inherent limitations of a single experimental technique often requires integration of data from complementary approaches to gain sufficient insights into the assembly structure and function. Here, we review popular computational approaches for integrative modelling of cellular assemblies, including protein complexes and genomic assemblies. We provide recent examples of integrative models generated for such assemblies by different experimental techniques, especially including data from 3D electron microscopy (3D-EM) and chromosome conformation capture experiments, respectively. We highlight general concepts in integrative modelling and discuss the need for careful formulation and merging of different types of information. PMID- 28735109 TI - Design and rationale for a real-world observational cohort of patients with nonalcoholic fatty liver disease: The TARGET-NASH study. AB - Nonalcoholic fatty liver disease (NAFLD) is highly prevalent and can lead to cirrhosis, hepatocellular carcinoma, and end-stage liver disease. NAFLD comprises the spectrum from simple steatosis (nonalcoholic fatty liver, NAFL), to steatosis with inflammation (nonalcoholic steatohepatitis, NASH). Current primary therapy recommended for NAFLD is weight loss induced by lifestyle modification. The difficulty in achieving this has led to robust pharmacological therapy development. While new drugs may show efficacy in selected phase II/III clinical trial populations, their real-world effectiveness is unknown. TARGET-NASH is a 5 year, longitudinal, observational study of patients with NAFLD designed to evaluate the effectiveness of clinical practice interventions and provide practical information unobtainable in registration trials. A biological specimen repository is included in TARGET-NASH for translational studies of genomics and biomarkers of disease activity. Patients are enrolling at adult and pediatric sites representing multiple specialties. All patients being managed for NAFLD are eligible, whereas those in other NASH registries or clinical trials will be excluded. Enrolled patients range in age from 6 and up and will have 3years of clinical data reviewed. Patient comorbidities, concomitant medications, disease progression and off-label interventions will be assessed, and adverse outcomes, monitored. Confirming the use, safety and effectiveness of NAFLD interventions in children and adults and establishing pragmatic methods of assessing disease progression under real-world conditions are key study outcomes. Ultimately, TARGET-NASH will establish a large, diverse registry of NAFLD patients at academic and community practices to be leveraged to improve health and reduce development of cirrhosis and hepatocellular carcinoma. PMID- 28735110 TI - Blinded sample size recalculation in clinical trials incorporating historical data. AB - Recruiting sufficient patients within an acceptable time horizon is an issue for most clinical trials and is especially challenging in the field of rare diseases. It is therefore an attractive option to include historical data from previous (pilot) trials in the current study thus reducing the recruitment burden. In clinical trials with binary endpoint, the required sample size does not only depend on the type I error rate, the power, and the treatment group difference but additionally on the overall event rate. However, there is usually some uncertainty in the planning phase about the value of this nuisance parameter. We present methods for blinded sample size recalculation in the setting of two-arm superiority trials with historical control data where the overall rate is estimated mid-course and the sample size is recalculated accordingly. The operating characteristics of the method are investigated in terms of actual type I error rate, power, and expected sample size. Application is illustrated with a clinical trial example in patients with systemic sclerosis, a rare connective tissue disorder. PMID- 28735111 TI - Screening disrupted molecular functions and pathways associated with clear cell renal cell carcinoma using Gibbs sampling. AB - OBJECTIVE: To explore the disturbed molecular functions and pathways in clear cell renal cell carcinoma (ccRCC) using Gibbs sampling. METHODS: Gene expression data of ccRCC samples and adjacent non-tumor renal tissues were recruited from public available database. Then, molecular functions of expression changed genes in ccRCC were classed to Gene Ontology (GO) project, and these molecular functions were converted into Markov chains. Markov chain Monte Carlo (MCMC) algorithm was implemented to perform posterior inference and identify probability distributions of molecular functions in Gibbs sampling. Differentially expressed molecular functions were selected under posterior value more than 0.95, and genes with the appeared times in differentially expressed molecular functions >=5 were defined as pivotal genes. Functional analysis was employed to explore the pathways of pivotal genes and their strongly co-regulated genes. RESULTS: In this work, we obtained 396 molecular functions, and 13 of them were differentially expressed. Oxidoreductase activity showed the highest posterior value. Gene composition analysis identified 79 pivotal genes, and survival analysis indicated that these pivotal genes could be used as a strong independent predictor of poor prognosis in patients with ccRCC. Pathway analysis identified one pivotal pathway - oxidative phosphorylation. CONCLUSIONS: We identified the differentially expressed molecular functions and pivotal pathway in ccRCC using Gibbs sampling. The results could be considered as potential signatures for early detection and therapy of ccRCC. PMID- 28735112 TI - Evaluation of the accuracy of mono-energetic electron and beta-emitting isotope dose-point kernels using particle and heavy ion transport code system: PHITS. AB - We assessed the accuracy of mono-energetic electron and beta-emitting isotope dose-point kernels (DPKs) calculated using the particle and heavy ion transport code system (PHITS) for patient-specific dosimetry in targeted radionuclide treatment (TRT) and compared our data with published data. All mono-energetic and beta-emitting isotope DPKs calculated using PHITS, both in water and compact bone, were in good agreement with those in literature using other MC codes. PHITS provided reliable mono-energetic electron and beta-emitting isotope scaled DPKs for patient-specific dosimetry. PMID- 28735113 TI - Characterisation of the secondary neutron field generated by a compact PET cyclotron with MCNP6 and experimental measurements. AB - The production of the most common used PET radioisotope Fluorine-18 with commercial cyclotrons is obtained from the 18O(p,n)18F nuclear reaction when 18O enriched water is bombarded with a proton beam. We present the characterization of the secondary neutron field spectra produced by this reaction in different locations around the cyclotron, through a comparison between MCNP6 Monte Carlo simulation results and experimental data obtained with Neutron Activation Analysis (NAA) of thin target foils of different materials. PMID- 28735114 TI - Determination of impurities in graphite using synchrotron radiation based X-ray fluorescence spectrometry. AB - Determination of impurities namely Ca, Mn, Fe, Ni, Zn, Sr and Pb in graphite by energy dispersive X-ray fluorescence spectrometry is described using microfocused synchrotron radiation. The internal standard and standard addition methodologies were adopted for quantification and the results were compared with tube-based X ray fluorescence spectrometry. Analysis of the results by the F and t-tests revealed their statistical equivalence. Synchrotron measurements improved the detection limits by an order of magnitude compared to the tube based technique. Cr and Zr, which were below the quantification limit in tube based technique, were also quantified by synchrotron based technique. PMID- 28735115 TI - The C-terminal region of the Turnip mosaic virus P3 protein is essential for viral infection via targeting P3 to the viral replication complex. AB - Like other positive-strand RNA viruses, plant potyviruses assemble viral replication complexes (VRCs) on modified cellular membranes. Potyviruses encode two membrane proteins, 6K2 and P3. The former is known to play pivotal roles in the formation of membrane-associated VRCs. However, P3 remains to be one of the least characterized potyviral proteins. The P3 cistron codes for P3 as well as P3N-PIPO which results from RNA polymerase slippage. In this study, we show that the P3N-PIPO of Turnip mosaic virus (TuMV) is required for viral cell-to-cell movement but not for viral replication. We demonstrate that the C-terminal region of P3 (P3C) is indispensable for P3 to form cytoplasmic punctate inclusions and target VRCs. We reveal that TuMV mutants that lack P3C are replication-defective. Taken together, these data suggest that the P3 cistron has two distinct functions: P3N-PIPO as a dedicated movement protein and P3 as an essential component of the VRC. PMID- 28735116 TI - Surgical technique of percutaneous iliosacral screw fixation in S3 level in unstable pelvic fracture with closed degloving injury and morrell lavallee lesion: Two case reports. AB - INTRODUCTION: Percutaneous screw fixation is considered the best option in unstable pelvic fracture with severe soft tissue injury. However, fixation technique at the level of S3 has not been well established. This paper showed the feasible surgical technique of S3 screw insertion in unstable pelvic fracture with severe soft tissue injury. METHODS: We reported 2 cases of unstable pelvic injury of an 11 years old boy with Marvin-Tile (MT) C1 pelvic fracture with sacroiliac (SI) joint disruption, skin avulsion and Morel-Lavallee lesion. Second case was 30 years old male with open pelvic fracture MTB2 and vertical sacral fracture Denis zone I with Morel-Lavallee lesion, intraperitoneal bladder rupture, infected laparotomy wound dehiscence. We performed percutaneous screws insertion on both pubic rami and IS screw on S1 and S3 to both cases. Functional outcome was evaluated using Majeed and Hannover pelvic score. RESULTS: All patients survived and had good reduction with no residual displacement on SI joint. The former case at 21-month follow up presented with excellent outcome (100/100) by Majeed score and very good outcome (4/4) by Hannover score; while the latter case, at 18-month, present with good outcome (85/100) Majeed score and fair outcome (2/4) Hannover score. CONCLUSIONS: Percutaneous screw fixation at the level of S3 is feasible and can be inserted in S3 level by sacroiliac type and sacral type with minimal soft tissue intervention and good functional outcome. PMID- 28735117 TI - Pubic osteomyelitis after surgery for perforated colonic diverticulitis with fecal peritonitis: A case report. AB - INTRODUCTION: Pubic osteomyelitis is a rare type of suppurative osteomyelitis. Early diagnosis of pubic osteomyelitis is difficult, and prolonged inflammation results in progressive bone degradation, severe pelvic pain and a wide-based gait. PRESENTATION OF CASE: We report the case of an 82-year-old woman who was admitted to a previous hospital with severe abdominal pain caused by a perforated colonic diverticulum with fecal peritonitis. She underwent an emergency operation and a postoperative wound infection occurred. Despite treatment of the infection, purulent exudate was discharged for three months and she gradually showed a gait disturbance. CT and MRI revealed that pubic symphysis showed osteolysis and there was severe inflammation around the wound. After administration of appropriate antibiotics, an operation, which included the removal of a fistula, debridement of sequestra and lavage of the abscess cavity, was performed. The inflammation improved promptly after the operation, and the patient was discharged on postoperative day 27 without any complications. DISCUSSION: Pubic osteomyelitis does not show the findings of typical acute suppurative osteomyelitis and hematological findings are nonspecific. It is important for early diagnosis to consider the risk factors of pubic osteomyelitis during examination. CONCLUSION: We would emphasize that a definitive diagnosis by CT and MRI and appropriate antimicrobial therapy combined with surgical treatment are important for pubic osteomyelitis. PMID- 28735118 TI - Giant Meckel's diverticulum compressing root of mesentery - A rare cause of ileal gangrene - Case report and review of literature. AB - INTRODUCTION: Meckel's diverticulum (MD) commonly presents as gastrointestinal bleeding in the pediatric population and intestinal obstruction in adults. There is no consensus for surgical excision of an incidentally diagnosed MD. We present a hitherto unreported vascular cause of intestinal gangrene due to MD. CASE PRESENTATION: A 16year old boy was referred as an acute abdomen for tertiary hospital management. Clinical examination and CT suggested small bowel obstruction and emergency laparotomy was performed. A giant MD compressing the root of mesentery, causing critical occlusion of the ileal vessels and extensive ileal gangrene was found. The gangrenous bowel was resected and a jejuno ascending colon anastamosis was done. Postoperative recovery was uneventful. DISCUSSION: This case report highlights an unrecognized complication of a giant Meckel's diverticulum. There are no clear guidelines on the management of an incidentally discovered MD though certain studies recommend resection of an incidental MD in males and individuals less than 50 years of age or when the MD is larger than 2cm or contains histologically abnormal tissue. Other meta analyses do not recommend routine resection. MD has been identified as a high risk region for ileal malignancy and its resection usually has minimal morbidity. A valid consent for opportunistic resection of a Meckel's diverticulum in any laparotomy would be discerning. CONCLUSION: Appropriate opportunistic resection of an incidental Meckel's diverticulum may prevent extensive surgical morbidity later. This case highlights the need to revisit guidelines for management of incidentally identified MD. PMID- 28735119 TI - A case series of pediatric seymour fractures related to hoverboards: Increasing trend with changing lifestyle. AB - BACKGROUND: Several recreational activities such as roller skating, skateboarding, and scooter riding create the risk for hand injuries, which are the fourth most commonly injured body part in relation to their use. Seymour first identified a specific pattern of digit injury as an open fracture affecting the distal phalangeal physis associated with nail avulsion from the eponychial fold. In this article, we report a series of Seymour fractures associated with misuse of the newly emerging recreational/transportation vehicle, the hoverboard. METHOD: The study includes a retrospective chart review of patients who presented to a tertiary hospital between December 2015 and October 2016 with a Seymour fracture caused while operating a hoverboard. RESULTS: A total of 13 patients were treated for Seymour fractures. The majority were male patients, and the group had a mean age of 10.3 years (+/-2.21). The affected digits were primarily the middle and ring fingers of the non-dominant hand. The injury mechanism reported by patients or families indicated that the child was operating the hoverboard in a sitting position with the hands grasping the wheel rim parts. CONCLUSION: We report a case series of a fracture pattern resulting from the improper/unsafe use of a hoverboard. This type of fracture occurs with a tremendous load of energy. Although improper use was a factor, design fault also plays a role in causing the injury. Parent awareness and supervision are important to prevent such injuries. PMID- 28735120 TI - Outpatient Lumbar Microdiscectomy in France: From an Economic Imperative to a Clinical Standard-An Observational Study of 201 Cases. AB - PURPOSE: The outpatient lumbar discectomy procedures have been established for more than 2 decades. However, especially in Europe, there are still obstacles to the development of these procedures, which may be related to medicoeconomic imperatives, and to several factors concerning both surgeons and patients. We describe our initial experience in introducing this method in our institution. METHODS: During a 3-year period, 201 patients met the criteria for ambulatory lumbar microdiscectomy. A dedicated fast-tracking unit provided preoperative patient education and immediate postoperative follow-up. A surgical consultation was organized 6 weeks after surgery, and a late satisfaction phone survey concerning ambulatory management was carried out after 6 months. RESULTS: The average total inpatient time was 10 hours and 12 minutes. One patient (0.5%) remained overnight because of an anxiety attack. No patients contacted the FT unit during the first night, and no complications occurred. All patients were reviewed in consultation around day 45: the average visual analog scale score was significantly reduced. At this early postoperative follow-up, 87.5% of patients were (very) satisfied with this procedure. At the day 180 survey, average visual analog scale scores were not significantly different from the day 45 data. In terms of return to normal activities of daily living, 120 patients (60%) had no limitation, 72 patients (36%) had minor or major limitations, and 8 (4%) were incapacitated. At this final evaluation, 8% of patients (n = 16) were very satisfied, 73% were satisfied (n = 146), 11% (n = 22) were partly satisfied, and 8% (n = 16) were not satisfied with the outpatient procedure. CONCLUSIONS: Reducing hospitalization for lumbar discectomies to a few hours is not a reduction in the quality of care. It is not necessarily simple to overcome the resistances of all protagonists, but placing the patient as the main actor of an integrated management plan is the key to transforming a medicoeconomic incentive into a clinical success. PMID- 28735122 TI - Ventral Lumbar Synovial Cyst Causing Cauda Equina Compression: Case Report and Literature Review. AB - BACKGROUND: Juxtafacet spinal cysts are cystic synovial lesions that often are indistinguishable clinically or radiologically and require histopathology analysis to confirm the diagnosis. Lumbar synovial cysts usually arising from the synovium of the facet joints. They have been described posterolaterally or rarely in the posterior midline. However, we describe the first synovial cyst ventral to the dural sac. CASE DESCRIPTION: We report a lumbar 3-4 lesion causing cauda equina compression in a 57-year-old man who presented with a 3-month history of low back pain and bilateral sciatica, intermittent urinary incontinence, and erectile dysfunction. Preoperative magnetic resonance imaging suggested prolapsed disc, after decompression, histological analysis of the fragment confirmed a synovial cyst. CONCLUSIONS: Hitherto synovial cysts have not been reported anterior to the dural sac. We describe a lumbar ventral cystic mass with cauda equina compression that mimicked a disc prolapse due to synovial metaplasia. The patient had urgent decompression with subsequent resolution of the symptoms. PMID- 28735121 TI - Survival Patterns of 5750 Stereotactic Radiosurgery-Treated Patients with Brain Metastasis as a Function of the Number of Lesions. AB - BACKGROUND: The number of brain metastases (BMs) plays an important role in the decision between stereotactic radiosurgery (SRS) and whole-brain radiation therapy. METHODS: We analyzed the survival of 5750 SRS-treated patients with BM as a function of BM number. Survival analyses were performed with Kaplan-Meier analysis as well as univariate and multivariate Cox proportional hazards models. RESULTS: Patients with BMs were first categorized as those with 1, 2-4, and 5-10 BMs based on the scheme proposed by Yamamoto et al. (Lancet Oncology 2014). Median overall survival for patients with 1 BM was superior to those with 2-4 BMs (7.1 months vs. 6.4 months, P = 0.009), and survival of patients with 2-4 BMs did not differ from those with 5-10 BMs (6.4 months vs. 6.3 months, P = 0.170). The median survival of patients with >10 BMs was lower than those with 2-10 BMs (6.3 months vs. 5.5 months, P = 0.025). In a multivariate model that accounted for age, Karnofsky Performance Score, systemic disease status, tumor histology, and cumulative intracranial tumor volume, we observed a ~10% increase in hazard of death when comparing patients with 1 versus 2-10 BMs (P < 0.001) or 10 versus >10 BMs (P < 0.001). When BM number was modeled as a continuous variable rather than using the classification by Yamamoto et al., we observed a step-wise 4% increase in the hazard of death for every increment of 6-7 BM (P < 0.001). CONCLUSIONS: The contribution of BM number to overall survival is modest and should be considered as one of the many variables considered in the decision between SRS and whole-brain radiation therapy. PMID- 28735123 TI - Surgery for Cerebellar Hemorrhage: A National Surgical Quality Improvement Program Database Analysis of Patient Outcomes and Factors Associated with 30-Day Mortality and Prolonged Ventilation. AB - OBJECTIVE: Primary cerebellar hemorrhage accounts for 10% of all intracranial hemorrhages. Given the confined space of the posterior fossa, cerebellar hemorrhage management sometimes necessitates suboccipital decompression and hematoma evacuation. In this study, we examine outcomes after surgery for primary cerebellar hemorrhage and identify risk factors associated with adverse outcomes. METHODS: A retrospective review of the 2005-2014 American College of Surgeons National Surgical Quality Improvement Program database was performed, with Current Procedural Terminology Code 61315 (suboccipital craniectomy or craniotomy for evacuation of cerebellar hemorrhage) queried between 2005 and 2014. Patient demographics, preoperative comorbidities, and 30-day outcomes were analyzed. Univariate and multivariate regression analyses were performed to identify predictors of mortality and adverse events. RESULTS: A total of 158 craniotomies were studied, with a 30-day mortality rate of 26.6%. The most common adverse events included ventilator dependence after 48 hours (48.7%) and pneumonia (24.1%). Almost one quarter (24.7%) of patients required additional operations, with 8.5% of patients undergoing repeat craniotomy. Death was associated with premorbid dependent functional status (P = 0.005), American Society of Anesthesiologists class (P = 0.010), and history of congestive heart failure (P = 0.031). Prolonged ventilation was associated with premorbid functional status (P = 0.043) and ventilator dependence (P = 0.007) before surgery. CONCLUSIONS: Cerebellar hemorrhage is associated with significant risk of mortality and ventilator dependence. In patients who require surgery, 30-day mortality risk remains high (26.6%), with functional status and American Society of Anesthesiologists class predictive of death. PMID- 28735124 TI - Inherent Tumor Characteristics That Limit Effective and Safe Resection of Giant Nonfunctioning Pituitary Adenomas. AB - BACKGROUND: Surgical treatment of giant pituitary adenomas is sometimes challenging. We present our surgical series of giant nonfunctioning adenomas to shed light on the limitations of effective and safe tumor resection. METHODS: The preoperative tumor characteristics, surgical approaches, outcome, and histology of giant nonfunctioning adenoma (>40 mm) in 128 consecutive surgical patients are reviewed. The follow-up period ranged from 19 to 113 months (mean 62.2 months). RESULTS: A transsphenoidal approach was used in the treatment of 109 patients and a combined transsphenoidal transcranial approach in 19 patients. A total of 93 patients (72.7%) underwent total resection or subtotal resection apart from the cavernous sinus (CS). The degree of tumor resection, excluding the marked CS invasion, was lower in tumors that were larger (P = 0.0107), showed massive intracranial extension (P = 0.0352), and had an irregular configuration (P = 0.0016). Permanent surgical complications developed in 28 patients (22.0%). Long term tumor control was achieved in all patients by single surgery, including 43 patients with adjuvant radiotherapy. Most tumors were histologically benign, with a low MIB-1 index (<3.0%) beside a few tumors mainly silent adenomas of pituitary specific transcription factor lineage. CONCLUSIONS: Irrespective of the surgical approach, massive intracranial extension, an irregular configuration, and marked CS invasion are inherent factors that independently limit effective resection. These high-risk tumors require an individualized therapeutic strategy. PMID- 28735125 TI - Management of Arteriovenous Malformations Associated with Developmental Venous Anomalies: A Literature Review and Report of 2 Cases. AB - BACKGROUND: Classification of cerebrovascular malformations has revealed intermediary lesions that warrant further review owing to their unusual presentation and management. We present 2 cases of arteriovenous malformation (AVM) associated with a developmental venous anomaly (DVA), and discuss the efficacy of previously published management strategies. METHODS: Two cases of AVMs associated with DVA were identified, and a literature search for published cases between 1980 and 2016 was conducted. Patient demographic data and clinical features were documented. RESULTS: In case 1, a 29-year-old female presenting with parenchymal hemorrhage and left homonymous hemianopia was found to have a right parieto-occipital AVM fed from the anterior cerebral, middle cerebral, and posterior cerebral arteries, with major venous drainage to the superior sagittal sinus. In case 2, imaging in a 34-year-old female evaluated for night tremors and incontinence revealed a left parietal AVM with venous drainage to the superior sagittal sinus. Including our 2 cases, 22 cases of coexisting AVMs and DVAs have been reported in the literature. At presentation, 68% had radiographic evidence of hemorrhage. Stereotactic radiosurgery was performed in 7 cases, embolization in 6 cases, surgical resection in 4 cases, and multimodal therapy in 5 cases. Radiography at follow-up demonstrated successful AVM obliteration in 67% of cases (12 of 18). CONCLUSIONS: Patients with coexisting AVMs and DVAs tend to have a hemorrhagic presentation. Contrary to traditional AVM management, in these cases it is important to preserve the draining vein via the DVA to ensure a safe, sustained circulatory outflow of the associated brain parenchyma while achieving safe AVM obliteration. PMID- 28735126 TI - Multilevel Spinal Segmental Fixation for Kyphotic Cervical Spinal Deformity in Pediatric Age Group-Report of Management in 2 Cases. AB - OBJECTIVE: We discuss the role of instability of multiple spinal segments including the atlantoaxial joint in the pathogenesis of cervical kyphotic deformity. MATERIAL AND METHODS: Two male patients (5 and 17 years old) had severe cervical kyphosis and presented with symptoms related to myelopathy. The patients underwent multisegmental spinal distraction and fixation that included atlantoaxial joint. No bone decompression was done. RESULTS: At a follow-up of >30 months, both patients had significant neurologic recovery. Investigations at follow-up showed successful arthrodesis of treated spinal segments. Although incomplete, there was recovery in kyphosis. CONCLUSIONS: Multisegmental spinal distraction and fixation can lead to reduction in kyphosis and relief from symptoms related to myelopathy. Role of spinal instability in general and atlantoaxial joint instability in particular in pathogenesis of cervical kyphosis need to be assessed on the basis of studies with a larger number of patients. PMID- 28735127 TI - The Fate of Patients with Adult Spinal Deformity Incurring Rod Fracture After Thoracolumbar Fusion. AB - OBJECTIVE: To report the outcome of adult spinal deformity (ASD) in patients with rod fracture (RF) after thoracolumbar fusion. METHODS: Retrospective review of prospective, multicenter database. Operative patients with ASD >=18 years old with RF after ASD surgery and with a minimum 6-month follow-up after RF were included. Health-related quality of life scores and radiographic alignment were compared with nonparametric paired and independent testing (P < 0.05). RESULTS: A total of 51 of 343 patients with ASD (14.9%) sustained a RF, of whom 44 (86.3%) had at least 6-month follow up after RF (mean age = 61.2 years, mean body mass index = 29.6 kg/m2). Mean total follow-up was 37.8 months (range 24.5-66.7 months). Interbody fusion was used in 26 cases of RF (59.1%) (transforaminal lumbar interbody fusion, n = 17 [65.4%], anterior lumbar interbody fusion, n = 5 [19.2%]). RF was symptomatic in 26 of 44 (59.1%) of patients and discovered incidentally in 18 of 44 patients (40.9%). Overall, 28 RFs were revised (63.6%); 12 of 23 (52.2%) unilateral RF and 16 of 21 (76.2%) bilateral RF at last follow up. Revision patients were significantly more likely to be symptomatic at the time of RF detection (78.6% vs. 25.0%, P = 0.0006), and had significantly worse Oswestry Disability Index and Scoliosis Research Society-22r pain scores. CONCLUSIONS: RFs were detected in 14.9% of patients with ASD and were most common at the L4-L5 and L5-S1 levels. Approximately 63.6% of patients underwent revision surgery. The decision to perform revision surgery may be based predominantly on symptoms referable to the RF, pain, and perceived disability, as radiographic parameters at the time of RF did not differ significantly between patients who did and did not undergo revision. PMID- 28735128 TI - A Computed Tomography-Based Comparison of Abnormal Vertebrae Pedicles Between Dystrophic and Nondystrophic Scoliosis in Neurofibromatosis Type 1. AB - OBJECTIVE: To explore the prevalence and distribution of abnormal vertebral pedicles in scoliosis secondary to neurofibromatosis type 1 (NF1-S) and to compare the abnormal vertebrae pedicles between dystrophic and nondystrophic scoliosis. METHODS: Using computed tomography images, we carefully measured 2652 vertebral pedicles from 56 patients with NF1-S with dystrophic scoliosis and 22 patients with NF1-S with nondystrophic scoliosis. Pedicle morphology was classified as follows: type A, a cancellous channel of >4 mm; type B, a cancellous channel of 2 to 4 mm; type C, a cancellous channel of <2 mm with an entirely cortical channel of >=2 mm; type D, a cortical channel of <2 mm; or type E, absent pedicle. Types B, C, D, and E were defined as abnormal. RESULTS: The total prevalence of abnormal vertebral pedicles in patients with NF1-S was as high as 67%, with type B comprising 39%, type C comprising 22%, type D comprising 4%, and type E comprising 2%. A significantly greater rate of abnormal pedicles was found in dystrophic scoliosis compared with nondystrophic scoliosis (70% vs. 59%, P < 0.0001). The upper thoracic spine (87%) is the most concentrated region of abnormal pedicles compared with the lower thoracic (73%) and lumbar spine (34%). CONCLUSIONS: There is a significantly high prevalence of abnormal pedicles in patients with NF1-S and an increased rate of abnormal pedicles in dystrophic scoliosis compared with nondystrophic ones. The described pedicle classification system could serve as an objective tool to guide preoperative assessment. PMID- 28735129 TI - Predictors of Recurrence and Complications After Chronic Subdural Hematoma Surgery: A Population-Based Study. AB - OBJECTIVE: To investigate predictors of recurrence and moderate to severe complications after burr-hole surgery for chronic subdural hematoma (cSDH). METHODS: A retrospective review was conducted in a Scandinavian single-center population-based cohort of 759 adult patients with cSDH operated with burr-hole surgery between January 1, 2005 and December 31, 2010. Possible predictors of recurrence and complications, assessed using a standardized reporting system of adverse events, were identified and analyzed in univariable analyses. Variables with a P value < 0.10 were included in a multivariable regression model. RESULTS: Recurrence was observed in 85 patients (11.2%), whereas moderate to severe complications were observed in 35 patients (4.6%). Bilateral hematoma (odds ratio [OR], 2.05; 95% confidence interval [CI], 1.25-3.35; P < 0.01) and largest hematoma diameter in millimeters (OR, 1.05; 95% CI, 1.01-1.09; P < 0.01) were independent predictors of recurrence in the multivariable model analysis. Glasgow Coma Scale (GCS) score of <13 (OR, 6.06; 95% CI, 2.72-13.51; P < 0.01) and Charlson Comorbidity Index (CCI) >1 (OR, 2.28; 95% CI, 1.10-4.75; P = 0.03) were independent predictors of moderate to severe complications. CONCLUSIONS: Recurrence after cSDH surgery is more often encountered in patients with radiologically more extensive disease reflected by bilateral hematoma and large hematoma diameter. On the other hand, moderate to severe complications are more often seen in patients in a worse clinical condition, reflected by decreased level of consciousness and more comorbidities. PMID- 28735131 TI - Mini-Craniotomy Under Local Anesthesia for Chronic Subdural Hematoma: An Effective Choice for Elderly Patients and for Patients in a Resource-Strained Environment. AB - BACKGROUND: Mini-craniotomy for chronic subdural hematoma (CSDH) is associated with lower rates of recurrence. However, the procedure is performed mostly with the patient under general anesthesia (GA) and therefore frequently requires an intensive care unit (ICU) facility, especially in the elderly population. Because of the unavailability of ICU beds, and to avoid GA, we started to perform this procedure with the patient under local anesthesia (LA). MATERIALS AND METHODS: This was a retrospective medical chart review conducted in the section of Neurosurgery at the Aga Khan Hospital in Karachi, Pakistan. The study duration was 1 year. We included patients aged 55 years or older undergoing surgery for CSDH. Clinical characteristics, hospital stay, and recurrence rates were compared between 2 groups, local versus general anesthesia. RESULTS: Thirty-five patients underwent mini-craniotomy for CSDH in the study period. Sixteen patients underwent mini-craniotomy under LA versus 19 patients for GA. Median age for the LA group was 67 years compared with 70 years in the GA group. Four patients from the LA group experienced postoperative complications versus 7 from the GA group. Only one patient in the LA group required an ICU bed in the postoperative period. There was no recurrence in LA group. The overall recurrence was 2.86%. CONCLUSIONS: Mini-craniotomy for CSDH under LA is an equally effective procedure compared with mini-craniotomy under GA. In addition, it minimizes the risks of GA in the elderly population and obviates the need of a postoperative ICU bed. It also reduces operative time and hospital stay as compared with GA. PMID- 28735130 TI - Bony Lateral Recess Stenosis and Other Radiographic Predictors of Failed Indirect Decompression via Extreme Lateral Interbody Fusion: Multi-Institutional Analysis of 101 Consecutive Spinal Levels. AB - OBJECTIVE: Although extreme lateral interbody fusion (XLIF) largely provides successful indirect decompression, some patients have recurrent same-level pain and functional disability. Identifying risk factors for this failure would facilitate better patient selection and improve outcomes. The aim of this study is to identify preoperative radiographic risk factors for failure of XLIF. METHODS: Patients undergoing XLIF were prospectively enrolled by 3 surgeons at 3 separate institutions. Radiographic variables measured included (1) anterior and posterior disc height, (2) foramen height and area, (3) central canal diameter, (4) central canal area, (5) right and left subarticular diameters, (6) facet arthropathy grade, and (7) presence of bony lateral recess stenosis. Patients failed indirect decompression if Oswestry Disability Index (ODI) scores did not improve by 20 points or revision surgery was required within 6 months postoperatively. Univariate and multivariate analyses were performed to identify radiographic predictors of failure of indirect decompression. RESULTS: Of the 45 patients (age 65.6 +/- 10.5 years; 14 male) involving 101 spinal levels included in this study, 13 (29%) failed indirect decompression. From univariate analysis, these patients had significantly smaller central canal diameter, foraminal height, and disc height (P < 0.05). In multivariate analysis of these parameters and those trending toward significance, bony lateral recess stenosis was the only significant independent predictor for failure of indirect decompression (coefficient, 0.55 [0.24-0.85]; P < 0.001). CONCLUSIONS: Bony lateral recess stenosis is an independent predictor for failure to achieve adequate spinal decompression via XLIF and thus may benefit from undergoing direct decompression. PMID- 28735132 TI - Asleep Robot-Assisted Surgery for the Implantation of Subthalamic Electrodes Provides the Same Clinical Improvement and Therapeutic Window as Awake Surgery. AB - OBJECTIVE: To study the impact of not performing awake clinical evaluation during the robot-assisted implantation of subthalamic nucleus deep brain stimulation (STN-DBS) electrodes on the stimulation parameters and clinical outcomes in patients with Parkinson disease (PD). METHODS: A total of 23 patients with PD underwent robot-assisted surgery for the bilateral implantation of STN-DBS electrodes. Thirteen patients received general anesthesia (GA) and a limited intraoperative evaluation (side effects only), and the other 10 patients received local anesthesia (LA) and a full evaluation. The primary endpoint was the therapeutic window (TW), defined as the difference between the mean voltage threshold for motor improvement and the mean voltage threshold for side effects in the active contacts at 12 months after surgery. Motor scores were measured as well. RESULTS: The TW was similar in the LA and GA groups, with mean +/- standard deviation values of 2.06 +/- 0.53 V and 2.28 +/- 0.99 V, respectively (P = 0.32). In the short term, the Unified Parkinson Disease Rating Scale (UPDRS) III score in the "off-drug, on-stim" condition fell to a similar extent in the LA and GA groups (by 40.3% and 49%, respectively; P = 0.336), as did the UPDRS III score in the "on-stim, on-drug" condition (by 57% and 70.7%, respectively; P = 0.36). CONCLUSIONS: Asleep, robot-assisted implantation of STN-DBS electrodes (with accurate identification of the STN and positioning of the DBS lead) produced the same motor results and TW as awake surgery. PMID- 28735133 TI - Neurologic Outcome After Resection of Parietal Lobe Including Primary Somatosensory Cortex: Implications of Additional Resection of Posterior Parietal Cortex. AB - OBJECTIVE: Postoperative neurologic outcomes after primary somatosensory cortex (S1) resection have not been well documented. This study was designed to evaluate the neurologic deterioration that follows resection of the S1 areas and to assess the risk factors associated with these morbidities. METHODS: We reviewed 48 consecutive patients with medically intractable epilepsy who underwent resection of the S1 and/or the adjacent cortex. The 48 patients were categorized into 4 groups according to the resected area as seen on postoperative magnetic resonance images: group 1 (resection of S1 only; n = 4), 2 (the posterior parietal cortex [PPC] only; n = 24), 3 (S1 and PPC; n = 10), and 4 (S1 and precentral gyrus; n = 10). RESULTS: After the resection of S1 areas, 19 patients (40%) experienced neurologic worsening, including 6 (13%) with permanent and 13 (27%) with transient deficits. Patients with permanent deficits included 2 with motor dysphasia, 1 with dysesthesia, 2 with equilibrium impairments, and 1 with fine movement disturbance of the hand. The overall and permanent neurologic risks were 25% and 0% in group 1, 17% and 4% in group 2, 80% and 20% in group 3, and 60% and 30% in group 4, respectively. Multivariate analysis determined that the resection of both S1 and PPC was the only significant risk factor for neurologic deficits (P = 0.002). CONCLUSIONS: The neurologic risk of the resection of S1 and/or its adjacent cortical areas was 40%. The additional resection of the PPC was significantly associated with the development of postoperative neurologic impairments. PMID- 28735134 TI - Intraventricular Meningioma Resection with Postoperative Ischemia of the Lateral Geniculate Nucleus. AB - BACKGROUND: Intraventricular meningiomas comprise 0.5%-3% of intracranial meningiomas. They often cause obstructive hydrocephalus and commonly are treated with surgical resection or stereotactic radiosurgery. OBJECTIVE: To describe the surgical approaches and resection techniques needed to approach intraventricular tumors while highlighting the eloquent anatomy and blood supply surrounding the ventricular system to avoid neurological injury. METHODS: Two cases of left atrial intraventricular meningiomas that were complicated by postoperative lateral geniculate nucleus ischemia and resultant temporary contralateral quadrantanopia are described. The safe surgical approaches to the atrium of lateral ventricles as well as the anatomy and blood supply to the lateral geniculate nucleus and optic radiation are discussed and illustrated. RESULTS: In both cases, the patients had complete resection of their tumors. They both ultimately made a good recovery after transient visual deficits. These cases provide useful demonstrations of eloquent anatomy of the ventricular walls and visual pathway anatomy. CONCLUSIONS: Care must be taken to avoid visual pathways along the lateral ventricle wall and the nearby arterial supply of the lateral geniculate nucleus from the choroidal arteries when resecting intraventricular tumors. PMID- 28735135 TI - Endoscope-Assisted Abscess Drainage Secondary to Endoscope-Assisted Transforaminal Lumbar Interbody Fusion: 1-Year Follow-Up. AB - INTRODUCTION: Endoscopic discectomy and fusions have been gaining popularity in the recent past and are noted to be safe for their application in elderly population. The procedure involves ultra-small incision for discectomy followed by placement of percutaneous screws in awake patients. Treatment of advanced spinal pathology with endoscope-assisted techniques is challenging. Although not common with the endoscopic approach, postoperative infection can be problematic, as there are no established guidelines on its management. METHODS: A 76-year-old female patient underwent lumbar 4-5 endoscopic-assisted transforaminal lumbar interbody fusion for severe degenerative changes leading to back and radicular leg pain. She did well postoperatively and was discharged home the following day. She presented to the outside hospital with new onset of severe back pain, sepsis, and positive methicillin-susceptible Staphylococcus aureus with blood culture and demonstrated no improvement while on antibiotics. RESULTS: Initial magnetic resonance imaging revealed postoperative changes only. With positive blood culture and localized pain, she was then offered to undergo a percutaneous drainage of the abscess. Under local anesthesia and intravenous sedation, a small pocket of collection was found along the endoscopic trajectory from previous surgery. After evacuation of the collection, the interbody device was irrigated with vancomycin through endoscope. Postoperatively, immediate symptomatic improvement was noted in back pain. She was discharged home on oxacillin and continues to do well at 12 months' follow-up with excellent fusion. CONCLUSIONS: The present case illustrates the successful treatment of a surgical-site infection after endoscope-assisted transforaminal lumbar interbody fusion via a repeat percutaneous endoscopic approach. PMID- 28735136 TI - Spinal Instability Predictive Scoring System for Subsequent Fracture After Bone Cement Augmentation in Patients with Osteoporotic Vertebral Compression Fracture. AB - OBJECTIVE: Bone cement augmentation procedures (vertebroplasty and kyphoplasty) are the primary treatments for osteoporotic vertebral compression fracture (VCF). However, these procedures are associated with various problems resulting in subsequent fracture. The purpose of this study was to evaluate the spinal instability factors related to subsequent fracture after vertebral augmentation procedures. METHODS: We retrospectively reviewed patients who underwent augmentation procedures for osteoporotic VCF. Between May 2011 and November 2014, 285 patients (vertebroplasty, n = 231; kyphoplasty, n = 54) were enrolled. Subsequent fractures were classified into 4 types based on the fracture patterns: 1) no subsequent fracture, 2) neofracture, 3) hammer fracture (new vertebral fractures involving another vertebra without a definitive history of trauma), and 4) kyphotic compression fracture. We analyzed subsequent fracture patterns and their occurrence rates according to factors that may induce subsequent fracture and developed a predictive scoring system with respect to the hammer fracture occurrence rate. We classified all cases into 4 groups (A,B,C,D) according to Spinal Instability Predictive Scoring System score. Groups A, B, C, and D were defined by total scores of 0~5, 6~10, 11~15, and 16~20, respectively. RESULTS: The subsequent fracture types for vertebroplasty were as follows: no subsequent fracture (n = 112; 48.28%); hammer fracture (n = 65; 28.02%); neofracture (n = 35; 15.09%); and kyphotic compression fracture (n = 19; 8.19%). According to the total scores, the occurrence rate of subsequent hammer fracture (no subsequent fracture, hammer fracture, neofracture, and kyphotic compression fracture) were as follows: group A (84.21%, 0%, 10.52%, and 5.26%), group B (64.58%, 10.45%, 12.5%, and 12.5%), group C (39.39%, 33.3%, 15.15%, and 12.12%), and group D (11.67%, 63.3%, 21.67%, and 3.33%). CONCLUSIONS: Predictive scores can be calculated and used to predict the possibility of subsequent fracture according to scores. Group D showed the highest predictive scores and will need more preventative treatment. PMID- 28735137 TI - Endonasal Operative Corridor Expansion by Sphenoidal Pneumosinus Dilatans in Tuberculum Sellae Meningiomas. AB - BACKGROUND: A retrospective cohort study of patients with tuberculum sellae meningioma (TSM)-associated sphenoidal pneumosinus dilatans (PSD) over a recent epoch was evaluated using a propensity-matched morphometric analysis. METHODS: A total of 38 patients with TSM and sphenoidal PSD were identified and matched by age and sex to 32 patients without tumors (controls). RESULTS: Overall, no significant difference between test and control groups was noted in sphenoid sinus size or other parameters; however, significantly greater mean distances from the posterior margin of the planum sphenoidale to the diaphragma sella (0.76 +/- 0.23 vs. 1.03 +/- 0.27, respectively; P = 0.0001) and angle between the planum sphenoidale to anterior face of sella turcica (113.41 +/- 10.58 vs. 123.21 +/- 12.55, respectively; P = 0.001) were seen in patients with TSM and PSD, suggestive of a selective expansion of the tuberculum sellae region. TSM/sphenoid sinus morphologies were divided into 3 types (A, B, and C) based on the extent of tumor and sinus morphology. There was progressive increase in tumor volume and anteroposterior sinus diameter from sphenoidal PSD types A-C, which influenced selection of surgical approach. CONCLUSIONS: This study suggests that TSM associated sphenoidal PSD leads to more selective splaying of the tuberculum sellae region rather than cumulative increase in sinus volume. This may lead to operative corridor expansion for endonasal access to TSM associated with sphenoidal PSD. A radiologic classification scheme for sphenoidal PSD associated with TSM is suggested that may aid surgical decision-making. PMID- 28735138 TI - Hemispheric Chronic Subdural Hematoma Concealing Subdural Metastases: Terrible Surprise Behind Routine Emergency Department Consultation. AB - The patient is a 79-year-old male, suffering from advanced metastatic prostate cancer, who developed a progressively worsening ideomotor slowing and was therefore referred to the emergency department of our institution. A plain axial computed tomography (CT) scan revealed a vast hemispheric subdural fluid collection, apparently a subdural hematoma. On closer inspection, and most of all, in hindsight, a tenuously isohyperdense signal irregularity at the frontal aspect of the fluid collection appears. Because of the declined general medical conditions and the paucity of the neurologic impairment, a high-dose, corticosteroid-based conservative strategy was performed. The total body CT scan for the routine oncologic follow-up of the prostate cancer scan fell at 20 days from the first CT of the emergency department. A second contrast-enhanced axial CT scan demonstrated the presence of 2 subdural metastases, presumably the initial pathogenesis of the subdural fluid collection. PMID- 28735139 TI - Cumulative Intracranial Tumor Volume and Number of Brain Metastasis as Predictors of Developing New Lesions After Stereotactic Radiosurgery for Brain Metastasis. AB - OBJECTIVES: To identify risk factors associated with early distant radiographic progression in patients undergoing stereotactic radiosurgery (SRS) for brain metastases (BM). METHODS: Following Institutional Review Board approval, data of 1427 patients (4283 BM lesions) who were treated by SRS at the Cleveland Clinic for 2000-2012 were collected. Local tumor progression (LTP), distant tumor progression (DTP), and radiographic radiation necrosis (RN) were the primary endpoints. Patient, imaging, radiosurgery, and tumor variables and follow-up data were collected. RESULTS: The median number of targets was 2 (range, 1-17); 45% of the patients had a single lesion. DTP was observed in 10% at 3 months and 19% at 6 months. Patients with 5-10 target lesions for SRS were more likely to develop new lesions at both 3 and 6 months compared to those with 2-4 lesions (odds ratio [OR], 0.83, 95% confidence interval [CI], 0.40-0.85 and OR, 0.85, 95% CI, 0.45 0.86 respectively; P < 0.05). Younger age (<65 years; P < 0.001), higher number of lesions (>1; P < 0.001), cumulative intracranial tumor volume (CITV) <2.75 cc (P = 0.023), type of SRS (upfront and salvage vs. boost; P < 0.001), and tumor pathology (radiosensitive; P < 0.001), were independent predictors of early distant tumor progression following SRS. CONCLUSIONS: The number of target lesions and low CITV are both independent predictors of early DTP following SRS for BM. Radiosensitive tumor histology, younger age (<65 years), and SRS without previous whole-brain radiation therapy (upfront or salvage) were also predictors of early DTP. PMID- 28735140 TI - Isolated Subcallosal Artery Infarction Secondary to Localized Cerebral Vasospasm of Anterior Communicating Artery Complex Following Subarachnoid Hemorrhage. AB - BACKGROUND: Subcallosal artery (ScA) infarction is a well-recognized but uncommon complication of surgical treatment of anterior communicating artery aneurysms. CASE DESCRIPTION: An elderly man presented with massive subarachnoid hemorrhage due to left posterior communicating artery aneurysm with thick clots in the anterior interhemispheric fissure. The aneurysm was coiled with balloon protection, and later, on the fifth day of ictus, the patient became acutely confused and developed memory disturbances. Magnetic resonance evaluation revealed typical infarcts in the anterior subcallosal region and fornix, confirming ScA infarction. Retrospective analysis of follow-up angiograms revealed focal isolated spasm of the anterior communicating artery artery and ScA, responding to intra-arterial milrinone infusion that was administered in view of neurologic worsening and clinical suspicion of cerebral vasospasm. CONCLUSION: Our case demonstrates a rare case of isolated ScA infarction induced by a local vasospasm and highlights the importance of its recognition. An early identification and intervention could potentially halt irreparable cerebral injury. PMID- 28735141 TI - Seizure Outcome of Patients with Magnetic Resonance Imaging-Negative Epilepsies: Still An Ongoing Debate. AB - BACKGROUND: Surgical results regarding MRI-negative epilepsy were presented and related clinical and histopathological parameters were discussed. METHODS: Thirty six MRI-negative epilepsy patients were retrospectively analyzed. Histopathological specimens were re-reviewed by 2 blind neuropathologists and re classified based on the current classifications. RESULTS: The mean age at surgery and seizure onset was 24.5 years and 9.3 years, respectively. Eight patients were younger than 18 years. Mean duration of seizures was 15.3 years. All but 2 underwent invasive monitorization. Eighteen patients had hypometabolism on FDG PET with temporal lobe involvement in majority (66.7%). Hypometabolism was found in all patients with hippocampal sclerosis (HS), which was present in 50% and 66.7% of focal cortical dysplasia (FCD) type I and II patients, respectively. The frontal lobe resection was the most frequent type of operation followed by resections in temporal, parietal and occipital lobes. In 7 patients, multilobar resection was performed. Histopathological diagnosis was FCD type I, II, III, HS, and gliosis in 14, 12, 2, 3 and 2 patients, respectively. The mean follow-up was 5.8 years. Seventeen patients were seizure free and favorable outcome (Engel's I and II) was found in 69.7%. FCD type I tend to have more favorable seizure outcome. Duration of epilepsy and hypometabolism on FDG-PET was significantly related to outcome, whereas involved lobe was not. CONCLUSIONS: Our results suggest it is worth pursuing resective surgery in adults as well as in children with drug-resistant epilepsy with normal MRI. PMID- 28735142 TI - Bifurcation Location and Growth of Aneurysm Size Are Significantly Associated with an Irregular Shape of Unruptured Intracranial Aneurysms. AB - BACKGROUND AND OBJECTIVE: Previous studies firmly proved that an irregular aneurysmal shape was associated strongly with intracranial aneurysm (IA) rupture, but it is unclear how irregularly shaped IAs form. We aimed to identify the factors related to irregular shape of IAs. METHODS: We retrospectively analyzed of consecutive patients evaluated or treated for IA at our institution from June 2015 to July 2016. According to the imaging morphology of aneurysm, the enrolled patients were divided into irregular and regular group. Demographic data and imaging data of the 2 groups were compared to identify the factors related to aneurismal irregular shape. RESULTS: There were 429 aneurysms (180 irregular and 249 regular aneurysms), including 315 unruptured aneurysms and 114 ruptured aneurysms. Most unruptured aneurysms occurred in the internal carotid arteries (53.3%), anterior communicating artery (10.8%), and posterior communicating artery (10.8%), anterior cerebral artery (5.4%), middle cerebral artery (9.8%), and posterior circulation (9.8%). In univariate analysis, for unruptured aneurysm, irregular aneurysmal shape was significantly related to aneurysm size (P = 0.009), aspect ratio (P = 0.003), size ratio (P = 0.002), and location at the bifurcation (P = 0.009) but not with smoking status, hypertension, hyperlipidemia, or diabetes mellitus. In multivariate logistic analysis, irregular aneurysms occurred mainly in unruptured aneurysms with a larger size (diameter >=5 mm; odds ratio [OR] 2.106; 95% confidence interval [CI] 1.183 3.749; P = 0.011); location at a bifurcation (OR 2.017; 95% CI 1.191-3.413; P = 0.006), and aspect ratio (>=0.8; OR 4.992; 95% CI 1.318-18.915; P = 0.018). CONCLUSIONS: Location at a bifurcation, an increased aneurysm size, and greater aspect ratio are significant independent factors associated with an irregular shape in unruptured IAs but not with smoking status, hypertension, hyperlipidemia, or diabetes mellitus. PMID- 28735143 TI - Transcranial low-level laser therapy improves brain mitochondrial function and cognitive impairment in D-galactose-induced aging mice. AB - Mitochondrial function plays a key role in the aging-related cognitive impairment, and photoneuromodulation of mitochondria by transcranial low-level laser therapy (LLLT) may contribute to its improvement. This study focused on the transcranial LLLT effects on the D-galactose (DG)-induced mitochondrial dysfunction, apoptosis, and cognitive impairment in mice. For this purpose, red and near-infrared (NIR) laser wavelengths (660 and 810 nm) at 2 different fluencies (4 and 8 J/cm2) at 10-Hz pulsed wave mode were administrated transcranially 3 d/wk in DG-received (500 mg/kg/subcutaneous) mice model of aging for 6 weeks. Spatial and episodic-like memories were assessed by the Barnes maze and What-Where-Which (WWWhich) tasks. Brain tissues were analyzed for mitochondrial function including active mitochondria, adenosine triphosphate, and reactive oxygen species levels, as well as membrane potential and cytochrome c oxidase activity. Apoptosis-related biomarkers, namely, Bax, Bcl-2, and caspase-3 were evaluated by Western blotting method. Laser treatments at wavelengths of 660 and 810 nm at 8 J/cm2 attenuated DG-impaired spatial and episodic-like memories. Also, results showed an obvious improvement in the mitochondrial function aspects and modulatory effects on apoptotic markers in aged mice. However, same wavelengths at the fluency of 4 J/cm2 had poor effect on the behavioral and molecular indexes in aging model. This data indicates that transcranial LLLT at both of red and NIR wavelengths at the fluency of 8 J/cm2 has a potential to ameliorate aging-induced mitochondrial dysfunction, apoptosis, and cognitive impairment. PMID- 28735144 TI - Entorhinal tau pathology disrupts hippocampal-prefrontal oscillatory coupling during associative learning. AB - A neural signature of asymptomatic preclinical Alzheimer's disease (AD) is disrupted connectivity between brain regions; however, its underlying mechanisms remain unknown. Here, we tested whether a preclinical pathologic feature, tau aggregation in the entorhinal cortex (EC) is sufficient to disrupt the coordination of local field potentials (LFPs) between its efferent regions. P301L mutant human tau or green fluorescent protein (GFP) was virally overexpressed in the EC of adult rats. LFPs were recorded from the dorsal hippocampus and prelimbic medial prefrontal cortex while the rats underwent trace eyeblink conditioning where they learned to associate 2 stimuli separated by a short time interval. In GFP-expressing rats, the 2 regions strengthened phase-phase and amplitude-amplitude couplings of theta and gamma oscillations during the interval separating the paired stimuli. Despite normal memory acquisition, this learning related, inter-region oscillatory coupling was attenuated in the tau-expressing rats while prefrontal phase-amplitude theta-gamma cross-frequency coupling was elevated. Thus, EC tau aggregation caused aberrant long-range circuit activity during associative learning, identifying a culprit for the neural signature of preclinical AD stages. PMID- 28735145 TI - Metabolic gene-targeted monitoring of non-starter lactic acid bacteria during cheese ripening. AB - Long ripened cheeses, such as Grana Padano (GP), a Protected Designation of Origin (PDO) Italian cheese, harbor a viable microbiota mainly composed of non starter lactic acid bacteria (NSLAB), which contribute to the final characteristics of cheese. The NSLAB species Lactobacillus rhamnosus, Lb. casei and Lb. paracasei are frequently found in GP, and form a closely related taxonomic group (Lb. casei group), making it difficult to distinguish the three species through 16S rRNA sequencing. SpxB, a metabolic gene coding for pyruvate oxidase in Lb. casei group, was recently used to distinguish the species within this bacterial group, both in pure cultures and in cheese, where it could provide an alternative energy source through the conversion of pyruvate to acetate. The aim of this work was to study the evolution of the metabolically active microbiota during different stages of GP ripening, targeting 16S rRNA to describe the whole microbiota composition, and spxB gene to monitor the biodiversity within the Lb. casei group. Furthermore, activation of pyruvate oxidase pathway was measured directly in cheese by reverse transcription real time PCR (RT-qPCR). The results showed that Lb. casei group dominates throughout the ripening and high-throughput sequencing of spxB allowed to identify four clusters inside the Lb. casei group. The dynamics of the sequence types forming the clusters were followed during ripening. Pyruvate oxidase pathway was expressed in cheese, showing a decreasing trend over ripening time. This work highlights how the composition of the microbiota in the early manufacturing stages influences the microbial dynamics throughout ripening, and how targeting of a metabolic gene can provide an insight into the activity of strains relevant for dairy products. PMID- 28735146 TI - Influence of electromagnetic pulse on the offspring sex ratio of male BALB/c mice. AB - Public concern is growing about the exposure to electromagnetic fields (EMF) and its effect on male reproductive health. Detrimental effect of EMF exposure on sex hormones, reproductive performance and sex-ratio was reported. The present study was designed to clarify whether paternal exposure to electromagnetic pulse (EMP) affects offspring sex ratio in mice. 50 male BALB/c mice aged 5-6 weeks were exposed to EMP daily for 2 weeks before mated with non-exposed females at 0d, 7d, 14d, 21d and 28d after exposure. Sex hormones including total testosterone, LH, FSH, and GnRH were detected using radioimmunoassay. The sex ratio was examined by PCR and agarose gel electrophoresis. The results of D0, D21 and D28 showed significant increases compared with sham-exposed groups. The serum testosterone increased significantly in D0, D14, D21, and D28 compared with sham-exposed groups (p<0.05). Overall, this study suggested that EMP exposure may lead to the disturbance of reproductive hormone levels and affect the offspring sex ratio. PMID- 28735147 TI - Neuropsychiatric aspects of frontal lobe meningioma. PMID- 28735148 TI - Mechanically-competent and cytocompatible polycaprolactone-borophosphosilicate hybrid biomaterials. AB - Organic-inorganic class II hybrid materials have domain sizes at the molecular level and chemical bonding between the organic and inorganic phases. We have previously reported the synthesis of class II hybrid biomaterials from alkoxysilane-functionalized polycaprolactone (PCL) and borophosphosilicate (B2O3 P2O5-SiO2) glass (BPSG) through a non-aqueous sol-gel process. In the present study, the mechanical properties and degradability of these PCL/BPSG hybrid biomaterials were studied and compared to those of their conventional composite counterparts. The compressive strength, modulus and toughness of the hybrid biomaterials were significantly greater compared to the conventional composites, likely due to the covalent bonding between the organic and inorganic phases. A hybrid biomaterial (50wt% PCL and 50wt% BPSG) exhibited compressive strength, modulus and toughness values of 32.2 +/- 3.5MPa, 573 +/- 85MPa and 1.54 +/- 0.03MPa, respectively; whereas the values for composite of similar composition were 18.8 +/- 1.6MPa, 275 +/- 28MPa and 0.76 +/- 0.03MPa, respectively. Degradation in phosphate-buffered saline was slower for hybrid biomaterials compared to their composite counterparts. Thus, these hybrid materials possess superior mechanical properties and more controlled degradation characteristics compared to their corresponding conventional composites. To assess in vitro cytocompatibility, MC3T3-E1 pre-osteoblastic cells were seeded onto the surfaces of hybrid biomaterials and polycaprolactone (control). Compared to polycaprolactone, cells on the hybrid material displayed enhanced spreading, focal adhesion formation, and cell number, consistent with excellent cytocompatibility. Thus, based on their mechanical properties, degradability and cytocompatibility, these novel biomaterials have potential for use as scaffolds in bone tissue engineering and related applications. PMID- 28735149 TI - Smoking relapse situations among a community-recruited sample of Spanish daily smokers. AB - INTRODUCTION: Relapse is a common factor within the behavior change process. However, there is scarce and limited knowledge of smoking relapse situations in population-based samples. The aim of this study was to identify smoking relapse situations among a sample of Spanish relapsers from the general population. METHODS: A sample of 775 relapsers was recruited among the general population using a snowball method. Participants completed a survey including sociodemographic, smoking-related and psychopathology variables. Smoking relapse situations were identified through specific questions assessing different aspects related to the last relapse episode. RESULTS: The majority of smoking relapse situations were attributed to positive affect (36.6%) and negative affect (34.3%), followed by lack of control (10.1%), smoking habit (6.7%), craving or nicotine withdrawal (6.3%), and social pressure (5.9%). Being unemployed and having a mental disorder in the past increased the likelihood of relapse in situations of negative affect. Being single and having quit smoking to save money were associated with an increased likelihood of relapse in situations of positive affect. CONCLUSIONS: Affect plays a significant role in smoking relapse among a community sample of unassisted Spanish smokers. Relapse may be much more of an affective and situational process than a habit, physiological or social pressure. Findings from this study may help develop tailored community smoking relapse prevention strategies or programs. PMID- 28735150 TI - Inverse relationship between urban green space and childhood autism in California elementary school districts. AB - Green space has a variety of health benefits. However, little is known about its impact on autism, the fastest-growing neurodevelopmental disorder in children. This study examined the relationship between green space and childhood autism prevalence. Autism count data in 2010 were obtained for 543 of ~560 public elementary school districts in California. Multiple types of green space were measured in each school district, including percentages of forest, grassland, and average tree canopy and near-road tree canopy. Their associations with autism prevalence were evaluated with negative binomial regression models and spatial regression models. We observed inverse associations between several green space metrics and autism prevalence in school districts with high road density, the highly urbanized areas, but not in others. According to negative binomial regression models, adjusted rate ratios (RR) for the relationships in these school districts between autism prevalence and green space metrics in 10% increments were as follows: for forest, RR=0.90 (95% confidence interval [CI]: 0.84-0.95); for grassland, RR=0.90 (95% CI: 0.83-0.97); for average tree canopy, RR=0.89 (95% CI: 0.83-0.95), and for near-road tree canopy, RR=0.81 (95% CI: 0.73 0.91). These results suggest that increases of 10% in forest, grassland, average tree canopy and near-road tree canopy are associated with a decrease in autism prevalence of 10%, 10% 11% and 19%, respectively. In contrast, urban land and road density were positively associated with autism prevalence. The results of spatial regression models were consistent with those obtained by negative binomial models, except for grassland. Our study suggests that green space, specifically tree cover in areas with high road density, may influence autism prevalence in elementary school children beneficially. Further studies are needed to investigate a potential causal relationship, and the major mechanisms that may underlie the beneficial associations with green space, such as buffering traffic related air pollution and noise. PMID- 28735151 TI - Do air pollution and neighborhood greenness exposures improve the predicted cardiovascular risk? AB - BACKGROUND: Numerous studies show associations between exposure to Particulate Matter and Cardiovascular disease (CVD). Current cardiovascular equations incorporate the major risk factors for CVD. The patients' environment, however, is not incorporated in these equations. METHODS: In a retrospective analysis, we assessed the contribution of neighborhood greenness and particulate matter (coarse-PM and PM<2.5MUm-PM2.5) to the development of CVD by analyzing the change in prediction abilities. We included members of the largest health-care provider in Southern-Israel, who had at least one cardiovascular risk factor (dyslipidemia, diabetes, hypertension or smokers). PM exposure and neighborhood greenness (Normalized Difference Vegetation Index-NDVI) were assessed by satellite-based models. We used pooled logistic mixed regressions to obtain the CVD risks including conventional risk factors (i.e. age, gender, blood-pressure, etc.) and measured the model performance with and without PM and NDVI. RESULTS: We included 23,110 subjects, of whom 12% had CVD. Coarse-PM exposure was associated with stroke and Myocardial-Infarction (MI) (OR 1.02,p<0.01 for both). NDVI was associated with MI: OR 0.72(p<0.01) for NDVI 0.1-0.2; and OR 0.52(p=0.270) for NDVI >0.2. The c-statistics slightly improved from 77.30% 77.40% for the prediction of MI (p=0.004) and from 75.60%-75.76% for the prediction of stroke (p=0.027). Calibration was fair in all models. The associations were partially mediated through the patients' comorbidities. CONCLUSION: The negligible improvement in the prediction performance, despite significant associations with PM and NDVI, may be due to partial mediation of these associations through the conventional cardiovascular risk factors, suggesting the importance in assessing the environmental effects on more basic physiological pathways when addressing the contribution to the cardiovascular risk. PMID- 28735153 TI - Self-monitoring systems for personalised health-care and lifestyle surveillance. AB - The quality of life and individual well-being are universally recognised as key factors in disease prevention. In particular, lifestyle interventions are effective tools for reducing the risk and incidence of major illnesses, such as cardiovascular diseases and metabolic disorders. On the other hand, patient role is progressively shifting from being a passive recipient of care towards being a co-producer of her/his health. In this frame, novel devices and systems able to help individuals in self-evaluation are expected to play a crucial role. In this special issue we focus on innovative methodologies and technologies devoted to individual self-assessment, oriented both to healthy people to maintain their well-being, and to diseased persons to improve their care. PMID- 28735152 TI - A systematic review of cardiovascular emergency department visits, hospital admissions and mortality associated with ambient black carbon. AB - BACKGROUND: Black carbon (BC) is a ubiquitous component of particulate matter (PM) emitted from combustion-related sources and is associated with a number of health outcomes. OBJECTIVES: We conducted a systematic review to evaluate the potential for cardiovascular morbidity and mortality following exposure to ambient BC, or the related component elemental carbon (EC), in the context of what is already known about the associations between exposure to fine particulate matter (PM2.5) and cardiovascular health outcomes. DATA SOURCES: We conducted a stepwise systematic literature search of the PubMed database and employed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for reporting our results. STUDY ELIGIBILITY CRITERIA: Studies meeting inclusion criteria (i.e., include a quantitative measurement of BC or EC used to characterize exposure and an effect estimate of the association of the exposure metric with ED visits, hospital admissions, or mortality due to cardiovascular disease) were evaluated for risk of bias in study design and results. STUDY APPRAISAL AND SYNTHESIS METHODS: Risk of bias evaluations assess some aspects of internal validity of study findings based on study design, conduct, and reporting and identify potential issues related to confounding or other biases. RESULTS: The results of our systematic review demonstrate similar results for BC or EC and PM2.5; that is, a generally modest, positive association of each pollutant measurement with cardiovascular emergency department visits, hospital admissions, and mortality. There is no clear evidence that health risks are greater for either BC or EC when compared to one another, or when either is compared to PM2.5. LIMITATIONS: We were unable to adequately evaluate the role of copollutant confounding or differential spatial heterogeneity for BC or EC compared to PM2.5. CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS: Overall, the evidence at present indicates that BC or EC is consistently associated with cardiovascular morbidity and mortality but is not sufficient to conclude that BC or EC is independently associated with these effects rather than being an indicator for PM2.5 mass. SYSTEMATIC REVIEW REGISTRATION NUMBER: Not available. PMID- 28735154 TI - Accuracy of C - Reactive protein as a bacterial infection marker in critically immunosuppressed patients: A systematic review and meta-analysis. AB - BACKGROUND: There is a need for a better understanding of the role of C-reactive protein (CRP) as a valid marker for the detection of bacterial infections in critically immunosuppressed patients. A high negative predictive value of CRP is also needed to rule out sepsis and bacterial infections in immunocompetent patients. However, few studies have evaluated the performance of CRP in immunocompromised hosts. The aim of the present study was to evaluate the performance of CRP as a marker of infection in critically immunosuppressed patients. METHODS: The inclusion criterion was immunosuppression for which CRP was used as a bacterial infection marker. Searches were performed in the Cochrane Register, MEDLINE, EMBASE, SCOPUS, Web OF Science, LILACS and CINAHL databases. We applied the Quality Assessment of Diagnostic Accuracy Studies tool 2 (QUADAS 2) to evaluate the quality of the articles and evaluated the test accuracy parameters using hierarchical summary receiver operating characteristic (HSROC) curves and bivariate random effect models. RESULTS: Only 13 of 21 studies produced quantitative results. We analyzed all studies using the random effects method (restricted maximum likelihood) and obtained a joint diagnostic odds ratio (DOR) of 3.04 (95% confidence interval [CI] 1.71-5.40) with heterogeneity (I2=91%, Q=181.48, p<0.001). Therefore, a bivariate model was applied. Analyzing the tuberculosis carrier, steroid user, or presence of opportunistic infection subgroups, as described in the proposal, was not possible due to the lack of information on these topics included in the articles. CONCLUSIONS: CRP appears to be a good screening tool for sepsis in critically immunosuppressed patients. Submitted PROSPERO 2015: CRD42015019329. PMID- 28735155 TI - Impact of restrictive fluid protocol on hypoxemia after aneurysmal subarachnoid hemorrhage. AB - PURPOSE: In patients with aneurysmal subarachnoid hemorrhage (aSAH), acute cardiac dysfunction and triple-H-therapy, can lead to hypoxemia. Our aim was to assess impact of a protocoled fluid restrictive approach on hypoxemia in these patients. METHODS: We included prospectively ICU patients with aSAH admitted within 24h after the bleed. The study was divided into 2 phases. The first phase, from January to December 2012, was designated as control group (group C). The second phase, from February 2014 to January 2015, was designated as study group (group S). Between these periods, a protocoled fluid intake approach was implemented to maintain as low as possible the cumulative fluid balances. RESULTS: Effective fluid restriction was obtained: at day 3 cumulative fluid balances were respectively for group C and group S, 1559+/-2402ml and 759+/ 1855ml (p=0.04); and 2211+/-4918ml vs 529+/-2806ml (p=0.04) at day 7. We observed reduction in proportion of hypoxemic patient in group S compared to group C, at day 3 (22% vs 40%, p=0.047) and at day 7 (28% vs 57%, p=0.007). CONCLUSIONS: Fluid restrictive management of patients with aSAH decreases number of hypoxemic patients at day 3 and day 7. PMID- 28735156 TI - Adaptive periodic paralysis allows weaning deep sedation overcoming the drowning syndrome in ECMO patients bridged for lung transplantation: A case series. AB - PURPOSE: Sedation in extracorporeal membrane oxygenation (ECMO) is challenging. Patients require deep sedation because of extremely high respiratory rates and increased work of breathing ("Drowning Syndrome") resulting in altered intra thoracic pressure and reduced pump flow associated with hemodynamic compromise and decreased oxygenation. However, deep sedation impedes essential active rehabilitation with physical therapy. METHODS: We reviewed data on 3 ECMO patients for whom we used a novel approach to replace continuous drips with periodic sedation/paralysis. Initially our patients were on high dose narcotics, propofol, and dexmedetomidine and unable to interact and breathe comfortably. IV narcotics were weaned over 24h and were replaced by methadone. Dexmedetomidine was continued in order to block hyperadrenergic events. Propofol was weaned at a prescribed rate. When patients demonstrated agitation, decreased pump flow and hemodynamic compromise, diazepam was given in combination with a paralytic. RESULTS: By replacing IV narcotic and propofol, with PRN diazepam and vecuronium, patients were off continuous drips in 1week and were able to actively participate in physical therapy. CONCLUSION: Allowing patients to wake up by rapid weaning of continuous narcotics and anesthetic agents using Dexmedetomidine and periodic paralysis to favorably alter hemodynamics is a successful method to wean deep sedation in ECMO. PMID- 28735157 TI - Effects of adhesions of amorphous Fe and Al hydroxides on surface charge and adsorption of K+ and Cd2+ on rice roots. AB - Iron (Fe) and aluminum (Al) hydroxides in variable charge soils attached to rice roots may affect surface-charge properties and subsequently the adsorption and uptake of nutrients and toxic metals by the roots. Adhesion of amorphous Fe and Al hydroxides onto rice roots and their effects on zeta potential of roots and adsorption of potassium (K+) and cadmium (Cd2+) by roots were investigated. Rice roots adsorbed more Al hydroxide than Fe hydroxide because of the greater positive charge on Al hydroxide. Adhesion of Fe and Al hydroxides decreased the negative charge on rice roots, and a greater effect of the Al hydroxide. Consequently, adhesion of Fe and Al hydroxides reduced the K+ and Cd2+ adsorption by rice roots. The results of attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR) and desorption of K+ and Cd2+ from rice roots indicated that physical masking by Fe and Al hydroxides and diffuse-layer overlapping between the positively-charged hydroxides and negatively-charged roots were responsible for the reduction of negative charge on roots induced by adhesion of the hydroxides. Therefore, the interaction between Fe and Al hydroxides and rice roots reduced negative charge on roots and thus inhibited their adsorption of nutrient and toxic cations. PMID- 28735158 TI - The criterion validity and intra-rater reliability of the Japanese version of the Functional Mobility Scale in children with cerebral palsy. AB - OBJECTIVE: The purpose of this study was to develop a Japanese version of the Functional Mobility Scale (FMS), and examine the criterion validity and intra rater reliability of the FMS in Japan. METHODS: The translation of the FMS was performed according to international standards for the translation of measurements. For criterion validity, 111 children with cerebral palsy (mean age; 12year 1mo+/-3year 7mo; range 5-18) were rated the Japanese version of the FMS and Gross Motor Function Classification System (GMFCS). For intra-rater reliability, the Japanese version of the FMS was rated twice by 24 parents of children with cerebral palsy by interview and/or telephone with a one- to two week interval between assessments. RESULTS: The criterion validity was confirmed with a strong correlation between GMFCS level and FMS scores (r2=-0.71 to -0.75). For intra-rater reliability, there was a substantial to excellent level of agreement (kappa=0.72-0.87). CONCLUSION: The study provides evidence of the criterion validity and intra-rater reliability of the Japanese version of the FMS as a measurement of mobility in children with cerebral palsy. PMID- 28735159 TI - Gender comparisons in children with ASD entering early intervention. AB - BACKGROUND: Males are diagnosed with Autism Spectrum Disorder (ASD) approximately four times as often as females. This has led to interest in recent years of potential under-diagnosis of females, as well as negative consequences for females with ASD due to under-identification. A number of potential explanations for gender bias in diagnosis are discussed including that females and males may present differently despite showing the same core symptoms. Previous research has shown inconsistent findings in comparisons between genders in young children with ASD for whom early intervention is vital. Thus, the aim of the present study was to investigate the social, communication, and cognitive functioning, as well as level of ASD symptoms, in a cohort of children who presented for early intervention to inform understanding of gender differences in this population, as well as to inform understanding of the mechanisms by which gender bias may occur. METHOD: Participants included 254 children (42 females) aged 29-74 months who completed measures of cognition, communication skills, adaptive behaviour, and ASD symptoms on entry to early intervention. RESULTS: Consistent with hypotheses, no significant gender differences were found both overall, and when split by functioning level. However, a similar ratio of males and females was found in both high- and low-functioning groups contrary to predictions. CONCLUSIONS: These results are consistent with some of the previous research that suggests gender differences may not be apparent in clinical samples at this young age. We highlight a need for further research that may use universal screening or longitudinal methods to understand the trajectory of development for females with ASD specifically. Such research could better inform timely and tailored intervention from the preschool years onwards. PMID- 28735160 TI - Longitudinal assessment of gait quality in children with bilateral cerebral palsy following repeated lower limb intramuscular Botulinum toxin-A injections. AB - BACKGROUND: Serial lower limb intramuscular Botulinum toxin-A (BoNT-A) injections are administered to children with bilateral spastic cerebral palsy (BCP) to reduce spasticity, improve walking and functional mobility, and delay the need for orthopaedic surgery. Gait quality is clinically assessed following BoNT-A with 2D video gait assessments (2DVGA) using the Edinburgh Visual Gait Score (EVGS). AIM: To determine the effect of three consecutive treatment cycles of lower limb intramuscular BoNT-A injections on gait quality using the EVGS in children with BCP by retrospectively reviewing repeated 2DVGA measures. METHODS AND PROCEDURES: Seventeen children with BCP and dynamic equinus (8 females and 9 males, age mean (SD), 4.0 (2.2) years, GMFCS I=2 and II=15) were included in the study after a retrospective audit of the records of the Queensland Children's Gait Laboratory (QCGL), Children's Health Queensland, Brisbane. The medical records of children who attended the QCGL between January 2001 and January 2016 were searched for eligibility. Children who had undertaken pre- and post treatment 2DVGA for the first three lower limb BoNT-A treatment cycles (6 assessments) were reviewed using the EVGS. BoNT-A treatments were administered 7.7 (2.3) months apart and post-BoNT-A reviews occurred 12.6 (6.7) weeks after injection. Mixed-effects linear regression assessed the change from baseline to each subsequent assessment (p<0.05). OUTCOMES AND RESULTS: EVGS reduced significantly by a mean of 2.4 points from pre- to post-BoNT-A in the first treatment cycle (p=0.001). Compared to baseline, mean total EVGS reduced significantly during the second (pre-BoNT-A -1.7 (p=0.020), post BoNT-A -2.8 (p<0.001)) and third (pre-BoNT-A -2.6 (p=0.001), post BoNT-A -2.4 (p=0.002)) treatment cycles. There was no difference in EVGS between post-BoNT-A in the first treatment cycle and scores for the second and third treatment cycles. CONCLUSIONS AND IMPLICATIONS: Improvements in gait quality were statistically significant, but did not reach the EVGS smallest real difference value of 4 points. Repeated lower limb intramuscular BoNT-A injections to improve gait quality in children with BCP should be reconsidered. PMID- 28735161 TI - Types of strain among family members of individuals with autism spectrum disorder across the lifespan. AB - BACKGROUND: Although increased caregiver strain is often found among family caregivers of individuals with autism spectrum disorder, it is still unclear as to how different types of strain relate to amount and types of caregiving across the lifespan. AIMS: The present study examined different types of strain (i.e. subjective internalized strain, subjective externalized strain, and objective strain) and how such strain relates to the amount of caregiving responsibilities. METHODS: Data was collected via online survey from a sample of 193 family caregivers of individuals with ASD from the United States, Canada, and the Republic of Ireland. Participants completed measures of strain and caregiving responsibilities, as well as coping, demographics, and services needed and received by the individual with ASD. RESULTS: Caregivers reported higher levels of objective strain than subjective, and caregiving responsibility was related to objective and subjective internalized strain. Coping style was strongly correlated with all types of strain, and unmet service needs were significantly related to objective and subjective internalized strain. Caregiving behaviors were only related to objective strain. CONCLUSION: The present results indicate that, although caregiving responsibility is related to objective and subjective internalized strain, the relationship is perhaps not as strong as the relationship between coping mechanisms and strain. Future research is needed to understand different types of strain and develop strategies to help caregivers. PMID- 28735162 TI - Tumor-infiltrating lymphocytes in breast cancer according to tumor subtype: Current state of the art. AB - The recent success of the immune checkpoint blockade in cancer immunotherapy has modified the treatment algorithms in a variety of aggressive neoplastic diseases. Nevertheless, optimal selection of ideal candidates to these drugs remains a challenge. The presence, location and composition of a pre-existing tumor immune infiltrate seem to impact on the benefit from these treatments. The association between the presence of baseline tumor-infiltrating lymphocytes (TIL) and patients' outcomes has been widely investigated in breast cancer, although immunotherapeutic strategies have historically been less successful with respect to other neoplastic diseases such as melanoma and kidney cancer. TIL extent varies and has different associations with outcomes in the various breast cancer subtypes. Furthermore, the presence of baseline high TIL has been associated with an increased benefit from some chemotherapeutic and targeted agents even though some conflicting results have been observed on this regard. This review aims to summarize the state of the art of TIL in breast cancer with a focus on their assessment, prevalence and clinical implications in the different subtypes. PMID- 28735163 TI - Multidimensional human capital formation in a developing country: Health, cognition and locus of control in the Philippines. AB - Economic success depends on multiple human capital stocks whose production is interrelated and occurs over many life stages. Yet, much empirical work fails to account for human capital's multidimensional nature and limits its focus to specific childhood stages. Using longitudinal data from the Philippines, I estimate a model of multidimensional human capital formation from birth through adulthood where health, cognitive, and noncognitive dimensions are jointly produced. I examine during which developmental stages parental investment is most influential and address the endogeneity of investment using a policy function where investment depends on child characteristics, exogenous conditions at birth and local prices. Findings imply that not only will early human capital disparities persist into adulthood without early remediation but also that cognitive gains yielded from early remediation will be lost without complementary investment in adolescence. Findings further suggest that interventions will be undervalued if their multidimensional effects are not accounted for. PMID- 28735164 TI - Vesicle trafficking in plant immunity. AB - To defend against extracellular pathogens, plants primarily depend on cell autonomous innate immunity due to the lack of the circulatory immune system including mobile immune cells. To extracellularly restrict or kill the pathogens, plant cells dump out antimicrobials. However, since antimicrobials are also toxic to plant cells themselves, they have to be safely delivered to the target sites in a separate vesicular compartment. In addition, because immune responses often requires energy otherwise used for the other metabolic processes, it is very important to properly control the duration and strength of immune responses depending on pathogen types. This can be achieved by regulating the sensing of immune signals and the delivery/discharge of extracellular immune molecules, all of which are controlled by membrane trafficking in plant cells. Soluble N ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) are now considered as the minimal factors that can merge two distinct membranes of cellular compartments. Hence, in this review, known and potential immune functions of SNAREs as well as regulatory proteins will be discussed. PMID- 28735165 TI - Development of selective attention in preschool-age children from lower socioeconomic status backgrounds. AB - Although differences in selective attention skills have been identified in children from lower compared to higher socioeconomic status (SES) backgrounds, little is known about these differences in early childhood, a time of rapid attention development. The current study evaluated the development of neural systems for selective attention in children from lower SES backgrounds. Event related potentials (ERPs) were acquired from 33 children from lower SES and 14 children from higher SES backgrounds during a dichotic listening task. The lower SES group was followed longitudinally for one year. At age four, the higher SES group exhibited a significant attention effect (larger ERP response to attended compared to unattended condition), an effect not observed in the lower SES group. At age five, the lower SES group exhibited a significant attention effect comparable in overall magnitude to that observed in the 4-year-old higher SES group, but with poorer distractor suppression (larger response to the unattended condition). Together, these findings suggest both a maturational delay and divergent developmental pattern in neural mechanisms for selective attention in young children from lower compared to higher SES backgrounds. Furthermore, these findings highlight the importance of studying neurodevelopment within narrow age ranges and in children from diverse backgrounds. PMID- 28735166 TI - Fidelity in school-based child sexual abuse prevention programs: A systematic review. AB - The aim of this study was to systematically review and evaluate the quality of the school-based child sexual abuse prevention education research in terms of implementation fidelity. A comprehensive literature search in PsycINFO, Medline, Education Resource Information Centre (ERIC) and the Cochrane Central Register of Controlled Trials was conducted. Articles included peer-reviewed, primary research studies related to the delivery of child sexual abuse prevention education programs within school settings published since 1996. In total, 3993 articles were identified and screened by two raters. Of those, 17 articles met the inclusion criteria. Implementation fidelity quality was assessed across the domains of: Intervention Design, Training Providers, Intervention Delivery, Intervention Receipt and Enactment of Skills, using the National Institute of Health Behavioral Change Consortium (NIHBCC) Fidelity Checklist. No study was identified as achieving high fidelity. Five studies (29%) reported including measures or processes to monitor implementation fidelity. There is an opportunity to improve the reporting of implementation fidelity related information within the school-based child sexual abuse prevention literature. This will allow more meaningful interpretations of treatment effects and increase confidence that changes attributed to the intervention are due to the intervention itself. Recommendations for such improvements are provided. PMID- 28735167 TI - First observation of metal ion-induced structural fluctuations of alpha-helical peptides by using diffracted X-ray tracking. AB - In order to analyze protein structural dynamics, we designed simple model peptides whose structures changed from random-coil to helix-bundle structures by forming stable hydrophobic core in the presence of metal ions. The strategy involved destabilizing a de novo designed three helix-bundle protein by substituting the residues present in its hydrophobic core with histidine and small amino acids. The conformational changes of peptides induced upon binding of Zn2+ to histidine were analyzed using circular dichroism spectroscopy, which revealed peptides, HA and HG, to be good candidates for further analyses. The diffracted X-ray tracking experiments showed that the structural fluctuations of both HA and HG were suppressed upon binding of Zn2+. We succeeded in observing the differences in fluctuations of HA and HG in solution between random-coil like and helix-bundle structures. The metal-binding energies determined using the angular diffusion coefficients were in good agreement with those determined using isothermal titration calorimetry. PMID- 28735168 TI - Impact of childhood adversities on depression in early adulthood: A longitudinal cohort study of 478,141 individuals in Sweden. AB - OBJECTIVE: Although the relationship between childhood adversity (CA) and depression is widely accepted, there is little information on what proportion of depression is attributable to CA. METHOD: We used a Swedish cohort of 478,141 individuals born in 1984-1988 in Sweden. Register-based CA indicators included parental death, parental substance abuse and psychiatric morbidity, parental criminality, parental separation, public assistance recipiency, child welfare intervention, and residential instability. Estimates of risk of depression, measured as retrieval of prescribed antidepressants and/or psychiatric care with a clinical diagnosis of depression, between 2006 and 2012 were calculated as Hazard Ratios (HR) with 95% confidence intervals (CI), using a Cox regression analysis. RESULTS: All CAs predicted depression in early adulthood. Furthermore, the predictive association between the CA indicators and depression was graded, with highest HRs observed for 4+ CAs (HR: 3.05 (95% CI 2.83-3.29)) for a clinical diagnosis for depression and HR: 1.32 (95% CI 1.25-1.41) for antidepressant medication after adjustments were made for important confounding factors. Of the studied CAs, child welfare intervention entailed highest HR for depression. CONCLUSION: Regardless of causality issues, children and youth with a history of multiple CA should be regarded as a high-risk group for depression by professionals in social, and health services that come into contact with this group. PMID- 28735169 TI - Aberrant link between empathy and social attribution style in borderline personality disorder. AB - In social interactions, we often need to quickly infer why other people do what they do. More often than not, we infer that behavior is a result of personality rather than circumstances. It is unclear how the tendency itself may contribute to psychopathology and interpersonal dysfunction. Borderline personality disorder (BPD) is characterized by severe interpersonal dysfunction. Here, we investigated if this dysfunction is related to the tendency to over-attribute behaviors to personality traits. Healthy controls and patients with BPD judged positive and negative behaviors presented within a situational constraint during functional magnetic resonance imaging. Before the experiment, we measured trait levels of empathy, paranoia, and need for cognition. Behaviorally, we found that empathy levels predicted the tendency to attribute behavior to traits in healthy controls, whereas in patients with BPD this relationship was significantly weakened. Whole brain analysis of group-by-empathy interaction revealed that when participants judged the behavior during the attribution phase, several brain regions implicated in mentalizing distinguished patients from controls: In healthy controls, neural activity scaled negatively with empathy, but this relationship was reversed in BPD patients. Due to the cross-sectional study design we cannot establish a causal link between empathy and social attributions. These findings indicate that the self-reported tendency to feel for others is related to the tendency to integrate situational information beyond personality. In BPD patients, by contrast, the association between empathy and attribution was significantly weaker, rendering empathy less informative in predicting the overall attribution style. PMID- 28735170 TI - Effects of different solvents on the conformations of apoptotic cytochrome c: Structural insights from molecular dynamics simulation. AB - Cytochrome c (cyt-c) upon binding with cardiolipin acquires peroxidase activity and is strictly connected to the pathogenesis of many human diseases including neurodegenerative and cardiovascular diseases. Interaction of cyt-c with cardiolipin mimics partial unfolding/conformational changes of cyt-c in different solvent environments. Dynamic pictures of these conformational changes of cyt-c are crucial in understanding their physiological roles in mitochondrial functions. Therefore, atomistic molecular dynamics (MD) simulations have been carried out to investigate the effect of different solvents (water, urea/water, MeOH and DMSO) on the structure and conformations of apoptotic cyt-c (Fe3+). Our study demonstrates that the structural changes in the protein are solvent dependent. The structural differences are observed majorly on the beta-sheets and alpha-helical conformations and the degree of their perturbation are specific to the solvent. Although a complete loss of beta-sheets (0%) is observed in MeOH and DMSO, by contrast, well preserved beta-sheets (3.84%) are observed in water and urea/water. A significant decrease in the alpha-helical contents is observed in MeOH (41.34%) and water (42.46%), a negligible alteration in DMSO (44.25%) and well preserved alpha-helical (45.19%) contents in urea/water. The distances between the residues critical for electron transfer are decreased considerably for DMSO. Further, the reduction in residue flexibility and the conformational space indicate that the collective motions of cyt-c are reduced when compared to other cosolvents. Essential dynamics analysis implies that the overall motions of cyt-c in water, MeOH and urea/water are involved in three to four eigenvectors and in first eigenvector in DMSO. Overall, we believe that MD simulations of cyt c in different solvents can provide a detailed microscopic understanding of the physiological roles, electron transport and peroxidase function in the early events of apoptosis which are hard to probe experiments. PMID- 28735171 TI - Encoding of coordination complexes with XML. AB - An in-silico system to encode structure, bonding and properties of coordination complexes is developed. The encoding is achieved through a semantic XML markup frame. Composition of the coordination complexes is captured in terms of central atom and ligands. Structural information of central atom is detailed in terms of electron status of valence electron orbitals. The ligands are encoded with specific reference to the electron environment of ligand centre atoms. Behaviour of ligands to form low or high spin complexes is accomplished by assigning a Ligand Centre Value to every ligand based on the electronic environment of ligand centre atom. Chemical ontologies are used for categorization purpose and to control different hybridization schemes. Complexes formed by the central atoms of transition metal, non-transition elements belonging to s-block, p-block and f block are encoded with a generic encoding platform. Complexes of homoleptic, heteroleptic and bridged types are also covered by this encoding system. Utility of the encoded system to predict redox electron transfer reaction in the coordination complexes is demonstrated with a simple application. PMID- 28735173 TI - Detached mindfulness reduced both depression and anxiety in elderly women with major depressive disorders. AB - We investigated the influence of detached mindfulness (DM) in treating symptoms of depression and anxiety among elderly women. Thirty-four elderly females (mean age: 69.23 years) suffering from moderate major depressive disorders (MDD) and treated with a standard medication (citalopram) at therapeutic doses were randomly assigned either to an intervention condition (DM; group treatment, twice weekly) or to a control condition (with leisure activities, twice weekly). At baseline (BL), four weeks later at study completion (SC), and four weeks after that at follow-up (FU), participants completed ratings for symptoms of depression and anxiety; experts blind to patients' group assignments rated patients' symptoms of depression. Symptoms of depression (self and experts' ratings) and anxiety declined significantly over time in the DM, but not in the control condition. Effects remained stable at FU. The pattern of results suggests that, compared to a control condition, a specific psychotherapeutic intervention such as DM can have a beneficial effect in elderly female patients with MDD. PMID- 28735172 TI - Exposure to intimate partner violence in utero and infant internalizing behaviors: Moderation by salivary cortisol-alpha amylase asymmetry. AB - Guided by the main tenets of contemporary models of the developmental origins of health and disease, this study evaluated whether individual differences in reactivity of the hypothalamic-pituitary-adrenal (HPA) axis and Sympathetic Nervous System (SNS) moderate the effect of prenatal exposure to trauma on internalizing and externalizing behaviors during infancy. Participants were a community sample of 182 mothers (M age=25years, 43% Caucasian, 33% Black/African American, 24% Biracial/Other) and their infants (59% girls; M age=11.8months). Each mother completed questionnaires that assessed IPV experienced during pregnancy and also reported on her infant's behavior problems. Infant saliva samples (later assayed for cortisol and sAA) were collected before and after a frustrating task (i.e., arm restraint). Results revealed that the association between in utero IPV and infant internalizing behaviors was most pronounced for infants with asymmetrical HPA-SNS (i.e., high-cortisol and low-sAA) reactivity to frustration, and least pronounced for infants with symmetrical HPA-SNS (i.e., low cortisol and low-sAA or high-cortisol and high-sAA) reactivity to frustration. Higher levels of externalizing behavior, in contrast, were associated with higher levels of prenatal IPV but unrelated to either cortisol or sAA reactivity to stress. Findings replicate documented associations between maternal IPV exposure during pregnancy and offspring risk. Moreover, findings advance our understanding of individual differences in the developmental origins of health and disease and provide additional evidence that assessing multiple stress biomarkers contributes to a more comprehensive understanding of individual vulnerability to adversity. PMID- 28735174 TI - Tetherless near-infrared control of brain activity in behaving animals using fully implantable upconversion microdevices. AB - Many nanomaterials can be used as sensors or transducers in biomedical research and they form the essential components of transformative novel biotechnologies. In this study, we present an all-optical method for tetherless remote control of neural activity using fully implantable micro-devices based on upconversion technology. Upconversion nanoparticles (UCNPs) were used as transducers to convert near-infrared (NIR) energy to visible light in order to stimulate neurons expressing different opsin proteins. In our setup, UCNPs were packaged in a glass micro-optrode to form an implantable device with superb long-term biocompatibility. We showed that remotely applied NIR illumination is able to reliably trigger spiking activity in rat brains. In combination with a robotic laser projection system, the upconversion-based tetherless neural stimulation technique was implemented to modulate brain activity in various regions, including the striatum, ventral tegmental area, and visual cortex. Using this system, we were able to achieve behavioral conditioning in freely moving animals. Notably, our microscale device was at least one order of magnitude smaller in size (~100 MUm in diameter) and two orders of magnitude lighter in weight (less than 1 mg) than existing wireless optogenetic devices based on light-emitting diodes. This feature allows simultaneous implantation of multiple UCNP-optrodes to achieve modulation of brain function to control complex animal behavior. We believe that this technology not only represents a novel practical application of upconversion nanomaterials, but also opens up new possibilities for remote control of neural activity in the brains of behaving animals. PMID- 28735175 TI - Cancer cell membrane-coated biomimetic platform for tumor targeted photodynamic therapy and hypoxia-amplified bioreductive therapy. AB - Modulating tumor microenvironment to amplify the therapeutic efficiency would be a novel strategy for effective cancer treatment. In this work, based on the TPZ loaded porphyrinic metal organic framework PCN-224 (PCN stands for porous coordination network), a cancer cell membrane-coated nanoplatform (TPZ@PCN@Mem) was fabricated for tumor targeted PDT and the successively resulting hypoxia amplified bioreductive therapy. After administration, TPZ@PCN@Mem exhibited the selective accumulation and long-term retention at tumor tissue due to the immune escape and homologous targeting endowed by the cancer membrane coating. Upon light irradiation, PCN-224-mediated toxic reactive oxygen species (ROS) were generated for PDT, and the resulting local hypoxia microenvironment would further accelerate the activation of TPZ for enhanced chemotherapy in 4T1 orthotopic tumor. The cascade synergistic therapeutic effects of TPZ@PCN@Mem could significantly suppress the primary tumor growth, and also inhibit its distal metastasis with minimal side effects. The study indicated an overwhelming superiority of utilizing this bioinspired strategy for tumor targeted PDT and hypoxia-activated bioreductive therapy, which provided a new insight for precise and effective tumor treatment. PMID- 28735176 TI - Reduced short-term variation following antenatal administration of betamethasone: Is reduced fetal size a predisposing factor? AB - OBJECTIVE: To assess the association between fetal size and the incidence of reduced short-term variability (STV) following bethametasone administration for fetal lung maturity. STUDY DESIGN: This was a retrospective, multicenter, cohort study conducted in two Tertiary University Units. Only uncomplicated singleton pregnancies admitted for threatened preterm labor between 26 and 34 weeks and submitted to betamethasone for fetal lung maturity were included. Delivery occurring within 72h from betamethasone administration represented criteria for exclusion. Computerized cardiotocography was carried out on a daily basis. Cases were identified by persistently reduced STV, defined as <5th percentile for gestational age and lasting for at least 72h after the first dose of betamethasone. The primary outcome was estimated fetal weight (EFW) at ultrasound in fetuses with normal and in those with persistently reduced STV. Pregnancy outcomes were also evaluated. RESULTS: Persistently reduced STV occurred in 33/405 of the included patients (8.1%). Compared to women with normal STV, those with persistently reduced STV had significantly lower EFW (1472+/-435 vs 1812+/ 532g, p 0.04), lower birthweight (2353+/-635 vs 2857+/-796g, p<0.01) and earlier gestational age at delivery (35.1+/-4.2 vs 37.3+/-2.4weeks, p<0.01), whereas all the other variables including gestational age on admission were comparable. CONCLUSIONS: Reduced STV following maternal betamethasone administration among appropriately grown fetuses seems to correlate with lower fetal size. Furthermore, fetuses with such abnormal response to steroids seem to carry a higher risk of perinatal complications, including lower birthweight and earlier gestational age at delivery. PMID- 28735177 TI - The visual system encodes others' direction of gaze in a first-person frame of reference. AB - The primate visual system contains specialised neural mechanisms for encoding the direction of others' gaze. A foundational question that we can ask in this domain concerns the frame of reference in which another person's gaze is represented. Electrophysiological recordings in macaque monkeys suggest that direction of gaze might be encoded relative to the observer (i.e., in a first person reference frame) or relative to the head or body of the stimulus (i.e., in a second person reference frame). Here we use sensory adaptation to gaze direction as a psychophysical tool to probe how this property of the environment is represented in the human visual system. We find that strong perceptual aftereffects occur following adaptation to images that share a common direction of gaze in the first person reference frame, but vary in their direction of gaze in the second person reference frame. In contrast, sensory aftereffects do not occur following adaptation to images that share a common direction of gaze in the second person reference frame. These findings suggest that the adaptive coding of gaze direction in the human visual system occurs primarily in a first-person coordinate system. These data also provide strong support for perceptual constancy in the context of perceived gaze direction, implying that the direction of others' attention is represented in the brain as a higher-level perceptual property abstracted from lower-level cues (e.g., iris position and head rotation). PMID- 28735178 TI - Development of a real-time prediction model of driver behavior at intersections using kinematic time series data. AB - As connected autonomous vehicles (CAVs) enter the fleet, there will be a long period when these vehicles will have to interact with human drivers. One of the challenges for CAVs is that human drivers do not communicate their decisions well. Fortunately, the kinematic behavior of a human-driven vehicle may be a good predictor of driver intent within a short time frame. We analyzed the kinematic time series data (e.g., speed) for a set of drivers making left turns at intersections to predict whether the driver would stop before executing the turn. We used principal components analysis (PCA) to generate independent dimensions that explain the variation in vehicle speed before a turn. These dimensions remained relatively consistent throughout the maneuver, allowing us to compute independent scores on these dimensions for different time windows throughout the approach to the intersection. We then linked these PCA scores to whether a driver would stop before executing a left turn using the random intercept Bayesian additive regression trees. Five more road and observable vehicle characteristics were included to enhance prediction. Our model achieved an area under the receiver operating characteristic curve (AUC) of 0.84 at 94m away from the center of an intersection and steadily increased to 0.90 by 46m away from the center of an intersection. PMID- 28735179 TI - Monitoring road safety development at regional level: A case study in the ASEAN region. AB - Persistent monitoring of progress, evaluating the results of interventions and recalibrating to achieve continuous improvement over time is widely recognized as being crucial towards the successful development of road safety. In the ASEAN (Association of Southeast Asian Nations) region there is a lack of well-resourced teams that contain multidisciplinary safety professionals, and specialists in individual countries, who are able to carry out this work effectively. In this context, not only must the monitoring framework be effective, it must also be easy to use and adapt. This paper provides a case study that can be easily reproduced; based on an updated and refined Road Safety Development Index (RSDI), by means of the RSR (Rank-sum ratio)-based model, for monitoring/reporting road safety development at regional level. The case study was focused on the road safety achievements in eleven Southeast Asian countries; identifying the areas of poor performance, potential problems and delays. These countries are finally grouped into several classes based on an overview of their progress and achievements regarding to road safety. The results allow the policymakers to better understand their own road safety progress toward their desired impact; more importantly, these results enable necessary interventions to be made in a quick and timely manner. Keeping action plans on schedule if things are not progressing as desired. This would avoid 'reinventing the wheel' and trial and error approaches to road safety, making the implementation of action plans more effective. PMID- 28735181 TI - Effects of cellulose degradation products on the mobility of Eu(III) in repositories for low and intermediate level radioactive waste. AB - The deep repository for low and intermediate level radioactive waste SFR in Sweden will contain large amounts of cellulosic waste materials contaminated with radionuclides. Over time the repository will be filled with water and alkaline conditions will prevail. In the present study degradation of cellulosic materials and the ability of cellulosic degradation products to solubilize and thereby mobilise Eu(III) under repository conditions has been investigated. Further, the possible immobilization of Eu(III) by sorption onto cement in the presence of degradation products has been investigated. The cellulosic material has been degraded under anaerobic and aerobic conditions in alkaline media (pH: 12.5) at ambient temperature. The degradation was followed by measuring the total organic carbon (TOC) content in the aqueous phase as a function of time. After 173days of degradation the TOC content is highest in the anaerobic artificial cement pore water (1547mg/L). The degradation products are capable of solubilising Eu(III) and the total europium concentration in the aqueous phase was 900MUmol/L after 498h contact time under anaerobic conditions. Further it is shown that Eu(III) is adsorbed to the hydrated cement to a low extent (<9MUmol Eu/g of cement) in the presence of degradation products. PMID- 28735180 TI - Cell Phone Use While Driving: Prospective Association with Emerging Adult Use. AB - Secondary task engagement such as cell phone use while driving is a common behavior among adolescents and emerging adults. Texting and other distracting cell phone use in this population contributes to the high rate of fatal car crashes. Peer engagement in similar risky driving behaviors, such as texting, could socially influence driver phone use behavior. The present study investigates the prospective association between peer and emerging adult texting while driving the first year after high school. Surveys were conducted with a national sample of emerging adults and their nominated peers. Binomial logistic regression analyses, adjusting for gender, race/ethnicity, parental education, and family affluence, showed that participants (n=212) with peers (n=675) who reported frequently texting while driving, were significantly more likely to text while driving the following year (odds ratio, 3.01; 95% CI, 1.19-7.59; P=0.05). The findings are consistent with the idea that peer texting behavior influences the prevalence of texting while driving among emerging adults. PMID- 28735182 TI - Fluidized-bed Fenton coupled with ceramic membrane separation for advanced treatment of flax wastewater. AB - Fluidized-bed Fenton coupled with ceramic membrane separation to treat the flax secondary effluent was investigated. The operating variables, including initial pH, dosage of H2O2 and Fe0, air flow rate, TMP and pore size, were optimized. The distributions of DOMs in the treatment process were analyzed. Under the optimum condition (600mgL-1H2O2, 1.4gL-1 Fe0, pH=3, 300Lh-1 air flow rate and 15psi TMP), the highest TOC and color removal efficiencies were 84% and 94% in the coupled reactor with 100nm ceramic membrane, reducing 39% of total iron with similar removal efficiency compared with Fluidized-bed Fenton. Experimental results showed that the ceramic membrane could intercept catalyst particles (average particle size >100nm), 10.4% macromolecules organic matter (AMW>20000Da) and 12.53% hydrophobic humic-like component. EEM-PARAFAC identified four humic-like (M1-M4) and one protein-like components (M5), and the fluorescence intensities of M1-M5 in the secondary effluent were 63.27, 63.05, 33.41, 16.71 and 0.72 QSE, respectively. After the coupled treatment, the removal efficiencies of M1(81%), M2(86%) were higher than M3, M4(63%, 61%). Pearson correlation analysis suggested that M1, M2 and M3 were the major contributors to the cake layer, and M4, M5 might more easily lead to pore blockages. PMID- 28735183 TI - Reductive dechlorination of trichloroethylene by polyvinylpyrrolidone stabilized nanoscale zerovalent iron particles with Ni. AB - We developed a novel stabilized nanoscale zerovalent iron (NZVI) particles with Ni using an electron conducting polymer, polyvinylpyrrolidone (PVP), to selectively dechlorinate trichloroethylene (TCE) to non-toxic intermediates. The size of the PVP stabilized NZVI-Ni ((PVP-NZVI-Ni), average diameter: ~20nm) is smaller than that of bare NZVI (50-80nm) due to the prevention of agglomeration of the resultant iron particles by PVP. PVP-NZVI-Ni showed a complete removal of TCE in 1h with superior dechlorination kinetics (kobs=5.702h-1) and ethane selectivity (98%), while NZVI-Ni showed 5 times slower dechlorination kinetics (1.218h-1). Other PVP-NZVI-metals (i.e., Cu, Sn, Co, and Mn) also enhanced the TCE dechlorination, but they were much slower (kobs=0.024-0.411h-1) than that of PVP-NZVI-Ni. In column test, PVP-NZVI-Ni exhibited better mobility (95% of PVP NZVI-Ni recovery in the eluent) than NZVI-Ni (1%). In addition, PVP-NZVI-Ni reductively transform TCE to ethane even under 10 cycles of repeated TCE dechlorination treatment. PMID- 28735184 TI - Synthesis of magnetic graphene oxide grafted polymaleicamide dendrimer nanohybrids for adsorption of Pb(II) in aqueous solution. AB - In this paper, using maleic anhydride and ethylenediamine as functional monomers, graphene oxide (GO) loaded magnetic Fe3O4 nanoparticles modified by (3 Aminopropyl) triethoxysilane as support, magnetic graphene oxide grafted polymaleicamide dendrimer (GO/Fe3O4-g-PMAAM) nanohybrids were fabricated by divergent method and magnetic separation technology. The obtained samples were characterized by transmission electron microscopy, X-ray diffraction, X-ray photoelectron spectroscopy, Fourier transform infrared spectroscopy, elementary analyzer and vibrating sample magnetometer. The effects of PMAAM generations, solution pH, Pb(II) initial concentration, temperature and contact time on the adsorption property of the samples for Pb(II) in aqueous solution were studied. The results demonstrated that nitrogen content and adsorption capacity of the as synthesized samples with amino terminal groups were all higher than their adjacent generations PMAAM with carboxyl terminal groups. Moreover, with increasing generations of PMAAM grafted on to the GO/Fe3O4, the nitrogen content and the adsorption capacity of the samples with the same terminal groups gradually increased. The maximum adsorption capacity of GO/Fe3O4-g-G3.0 for Pb(II) was 181.4mgg-1 at 298K. The rising of temperature was beneficial for the adsorption. The adsorption kinetics had a better agreement with pseudo-second order equation, and equilibrium data followed the Langmuir model. PMID- 28735185 TI - MIL-101(Cr)@GO for dispersive micro-solid-phase extraction of pharmaceutical residue in chicken breast used in microwave-assisted coupling with HPLC-MS/MS detection. AB - In this work, MIL-101(Cr)@GO (Graphite Oxide) was synthesized using a hydrothermal synthesis method and was applied as a dispersive micro-solid-phase extraction (D-MU-SPE) sorbent for the efficient concentration of four residual drugs (metronidazole, MNZ; tinidazole, TNZ; chloramphenicol, CAP; sulfamethoxazole, SMX). Meanwhile, the extraction process was optimized by combining it with microwave-assisted extraction. Factors affecting the D-MU-SPE efficiency, such as selection of sorbent materials, pH of the sample solution, salting-out effect, amount of used material, extraction time, desorption solvent and desorption time, were studied. Under the optimal extraction conditions, the linearity ranged from 10 to 1000ngkg-1 and 1-100ngkg-1 (r2>=0.9928) for the target analytes. The limits of detection were between 0.08 and 1.02ngkg-1, and the limits of quantitation were between 0.26 and 3.40ngkg-1. Additionally, the developed method also exhibited good precision (RSD<=2.5%), repeatability (RSD<=4.3%), high recoveries (88.9%-102.3%) and low matrix effects (78.2%-95.1%). The proposed method proved to be an efficient and reliable approach for the determination of the analytes. Finally, we successfully detected the four drugs in chicken breast. PMID- 28735186 TI - Development of a robust reporter gene assay to measure the bioactivity of anti-PD 1/anti-PD-L1 therapeutic antibodies. AB - Being regarded as the 'cancer panacea', the anti-PD-1/anti-PD-L1 monoclonal antibodies (mAbs) have become the R&D focus of biopharmaceutical industries. Several marketed such mAbs have been proved particularly effective in treating various cancers. However, the cell-based bioassay to measure the biological activities of the anti-PD-1/anti-PD-L1 mAbs as the lot release or stability test has been a great challenge to quality control laboratories due to the immunomodulating nature of the mAbs. Here, we describe the development and validation of a reporter gene assay consisting of two-cell systems to measure the bioactivity of the anti-PD-1/anti-PD-L1 mAbs. We have generated two cell lines, the CHO-PD-L1-CD3L cell line that stably expresses PD-L1 and the membrane anchored anti-CD3 single chain antibody fragment (scFv) named CD3L and the Jurkat PD-1-NFAT cell line that stably expresses PD-1 and the luciferase gene under the control of the NFAT response elements from the IL-2 promoter. The results show good dose-dependent responsiveness to the mAbs and excellent performance characteristics including specificity, accuracy and precision. The biological relevance of the assay, the passage stability of the two cell lines, and the capability of measuring various anti-PD-1/anti-PD-L1 mAbs render this assay applicable not only in lot release and stability test but also in characterization and development of new anti-PD1/anti-PD-L1 mAbs. PMID- 28735188 TI - Photoelectrochemical (PEC) studies on Cu2SnS3 (CTS) thin films deposited by chemical bath deposition method. AB - Cu2SnS3 (CTS) thin films have been successfully deposited on a cost-effective stainless steel substrate by simple and inexpensive chemical bath deposition (CBD) method. The films are deliberated in provisos of their structural, morphological, optical and photoelectrochemical (PEC) properties before and after annealing treatment, using various physico-chemical techniques. The XRD studies showed the formation of triclinic phase of CTS films with nanocrystalline structure. Also, the crystallinity is enhanced with annealing and the secondary phase of Cu2S observed. Raman analysis confirmed the formation of CTS compound with secondary Cu2S phase. The SEM images also discovered mostly tiny spherical grains and significant progress in the size of grains after annealing. The films possess direct transitions with band gap energies of 1.35eV and 1.31eV before and after annealing, respectively. The improved photoconversion efficiency of CTS thin film based PEC cell is explained with the help of theoretical modeling of energy band diagram and correspondent circuit model of the impedance spectra. PMID- 28735187 TI - Progress in targeting the BCL-2 family of proteins. AB - The network of protein-protein interactions among the BCL-2 protein family plays a critical role in regulating cellular commitment to mitochondrial apoptosis. Anti-apoptotic BCL-2 proteins are considered promising targets for drug discovery and exciting clinical progress has stimulated intense investigations in the broader family. Here, we discuss recent developments in small molecules targeting anti-apoptotic proteins and alternative approaches to targeting BCL-2 family interactions. These studies advance our understanding of the role of BCL-2 family proteins in physiology and disease, providing unique tools for dissecting these functions. The BCL-2 family of proteins is a prime example of targeting protein protein interactions and further chemical biology approaches will increase opportunities for novel targeted therapies in cancer, autoimmune and aging associated diseases. PMID- 28735189 TI - Studies on the role of unsaturation in the fatty acid surfactant molecule on the thermal conductivity of magnetite nanofluids. AB - To study the role of unsaturation in the surfactant molecule on the thermal conductivity of magnetite nanofluids, four different fatty acid (stearic, oleic, linoleic, and linolenic acids with different degree of unsaturation) coated magnetite nanoparticles of comparable size are prepared and dispersed in toluene. It is found that the nanofluid with the saturated fatty acid coated nanoparticles show larger viscosity than the fluid with the unsaturated fatty acid coated particles at all concentrations. Thermal conductivity studies show enhancement only above a critical concentration for all fluids. The critical concentration for thermal conductivity enhancement varies with the surfactant, possibly due to the difference in the degree of aggregation of the nanoparticles in the fluid, because of the difference in the conformation of the surfactant molecules on the nanoparticle's surface. The experimental thermal conductivity follows the Maxwell model at higher concentrations. From the overall studies, it is observed that the thermal conductivity of the fluids with aggregated or assembled nanoparticles shows slightly larger enhancement than that of the fluids with isolated particles. However, in the presence of a magnetic field, the fluids with isolated nanoparticles showed relatively larger enhancement, possibly due to the easy response of the isolated magnetite nanoparticles to the applied field. PMID- 28735190 TI - Surface complexation modeling of calcite zeta potential measurements in brines with mixed potential determining ions (Ca2+, CO32-, Mg2+, SO42-) for characterizing carbonate wettability. AB - This study presents experiment and surface complexation modeling (SCM) of synthetic calcite zeta potential in brine with mixed potential determining ions (PDI) under various CO2 partial pressures. Such SCM, based on systematic zeta potential measurement in mixed brines (Mg2+, SO42-, Ca2+ and CO32-), is currently not available in the literature and is expected to facilitate understanding of the role of electrostatic forces in calcite wettability alteration. We first use a double layer SCM to model experimental zeta potential measurements and then systematically analyze the contribution of charged surface species. Calcite surface charge is investigated as a function of four PDIs and CO2 partial pressure. We show that our model can accurately predict calcite zeta potential in brine containing a combination of four PDIs and apply it to predict zeta potential in ultra-low and pressurized CO2 environments for potential application in enhanced oil recovery in carbonate reservoirs. Model prediction reveals that calcite surface will be positively charged in all considered brines in pressurized CO2 environment (>1atm). The calcite zeta potential is sensitive to CO2 partial pressure in the various brine in the order of Na2CO3>Na2SO4>NaCl>MgCl2>CaCl2 (Ionic strength=0.1M). PMID- 28735191 TI - Newly designed diblock dispersant for powder stabilization in water-based suspensions. AB - A newly designed dispersant for water-based suspensions, ammonium poly(methacrylate)-block-poly(2-phenoxyethyl acrylate) (PMA-b-PBEA), is proposed in this study. According to the results of rheological analysis, the dispersion efficiency of this new dispersant is superior to that of the commercially available ammonium polyacrylate (PAA-NH4). The diblock structure of PMA-b-PBEA, which simultaneously contains a low-polar anchoring head group and a water dissociable stabilizing moiety, is the main cause for its extremely high efficiency for powder dispersion. The unique structure not only results in effective adsorption approximately double that of PAA-NH4, but also produces a low number of counter-ions that compress the electrical double layer and ruin powder stabilization. Based on Derjaquin-Landau-Verwey-Overbeek calculations, the large adsorbance of PMA-b-PBEA gives the powder, titania (TiO2) in this study, a high steric stabilization energy. In addition, PMA-b-PBEA provides TiO2 with a remarkably high electrostatic energy because it generates fewer counter-ions. This energy provides excellent dispersity of powder in the suspensions with a high solid content of 60wt% without showing any rheological hysteresis. PMID- 28735192 TI - Nozzle-jet printed flexible field-effect transistor biosensor for high performance glucose detection. AB - Printable electronics is a subject of great interest for low-cost, facile and environmentally-friendly large scale device production. But, it still remains challenging for printable biosensor development. Herein, we present the fabrication of nozzle-jet printed flexible field-effect transistor (FET) glucose biosensor. The silver source-drain electrodes and ZnO seed layers were printed on flexible substrate by nozzle-jet printer followed by ZnO nanorods (ZnO NRs) synthesis and glucose oxidase (GOx) immobilization. Utilization of nozzle-jet printing methods resulted in highly reproducible electrodes with well-defined vertical grown ZnO NRs for high GOx loading and enhanced glucose sensing performance in a wide glucose detection range. The stability, anti-interference ability, reproducibility, reusability, and applicability in human serum samples were also assessed. Overall, biosensor fabrication using nozzle-jet printer will not only provide large scale production of highly reproducible electrodes but also reduce the fabrication cost. Additionally, printed electrodes can be modified accordingly for different analyte detection. PMID- 28735193 TI - Fabrication of In2S3/Zn2GeO4 composite photocatalyst for degradation of acetaminophen under visible light. AB - A novel indium trisulfide/zinc germinate (In2S3/Zn2GeO4) composite was developed via a co-precipitation hydrothermal method. The as-prepared composite was characterized in detail by X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), and UV-vis diffuse reflectance spectroscopy (DRS). Zn2GeO4 nanorods work as the main photocatalyst while In2S3 nanoparticles deposited on them acts as the photosensitizer. The resulting In2S3/Zn2GeO4 heterogeneous photocatalyst not only has enhanced visible light absorption, but also improved photo-generated charge transfer efficiency with remarkably high efficiency in decomposing acetaminophen (APAP). The composite photocatalyst with the mass ratio of 30% In2S3 showed the best activity for APAP degradation under visible light, with performance far superior to that of In2S3, nitrogen-doped titanium dioxide (N-TiO2), Degussa P25, and Zn2GeO4. The influences of various parameters (i.e., catalyst dosage, solution pH, and initial concentration of APAP) and background interference (humic acid (HA) and bicarbonate (HCO3-)) on the photodegradation efficiency for APAP were also discussed. The mechanistic studies revealed that holes and superoxide radicals are mainly involved in the photodegradation of APAP by In2S3/Zn2GeO4 composite. A probable reaction mechanism of APAP degradation under visible light over In2S3/Zn2GeO4 heterojunction was proposed. PMID- 28735194 TI - Deposition-precipitation preparation of Ag/Ag3PO4/WO3 nanocomposites for efficient Visible-light degradation of rhodamine B under strongly acidic/alkaline conditions. AB - A series of novel visible-light-driven Ag/Ag3PO4/WO3 (AAPW) Z-scheme heterostructures were fabricated using a facile deposition-precipitation method followed by photo-reduction without adding any surfactant. To explore more deeply about the photocatalytic activity of AAPW nanocomposites under neutral and strongly acidic/alkaline conditions, we investigated their photocatalytic rhodamine B (RhB) efficiency at different pH value that was controlled by adding HNO3 or NaOH aqueous solution. It was found that as-prepared AAPW photocatalysts showed enhanced photocatalytic RhB efficiency under neutral and even strongly acidic/alkaline environment. The process of charge carrier separation and transfer in the AAPW nanocomposites and Z-scheme mechanism for RhB degradation were described in sufficient detail based on systematical characterizations and measurements. The silver particles introduced to build AAPW Z-scheme structure should contribute to more efficient charge separation, resulting in enhanced photocurrent response and photocatalytic activity. We expect thatthis work will provide systematic study concerning Z-scheme Ag/Ag3PO4/WO3 structure, and fulfill the research about photodegrade activity of catalyst under strongly acidic/alkaline conditions. PMID- 28735195 TI - Modified carbon fiber/magnetic graphene/epoxy composites with synergistic effect for electromagnetic interference shielding over broad frequency band. AB - The study on electromagnetic interference (EMI) shielding materials is a long standing project in civil and military areas. In this work, a novel kind of shielding material was fabricated and the shielding effectiveness (SE) over broad frequency was investigated. The epoxy (EP) resin was reinforced by reduced graphene oxide coated carbon fiber (rGO-CF, GCF) and Fe3O4 nanoparticles deposited rGO nanohybrids (magnetic graphene, MG). With only 0.5wt% of GCF and 9wt% of MG, the GCF/MG3/EP exhibited excellent SE (>30dB over 8.2-26.5GHz) and a maximum value of 51.1dB at 26.5GHz, which had a 31.7% increase than that of GCF/EP. The 3-aminopropyltriethoxysilane (APTES) modified MG (NMG) gained better dispersion in resin and could further increased absorbing property of composites. The synergistic effect between GCF and MG raised by 3D interpenetration structure of the ternary nanocomposite was favorable for high efficient shielding in wide frequency range. This composites show promise in lightweight and high-efficiency EMI shielding field. PMID- 28735196 TI - Molecular dynamics simulation of sodium dodecylsulfate (SDS) bilayers. AB - Sodium dodecylsulfate (SDS) - a simple single tailed surfactant (STS) can form stable vesicles from its micellar solution without any additives under the mediation of solid surfaces. To further understand the mechanism of this transition on the molecular level, molecular dynamics simulations are performed to study segments of SDS bilayers (as part of vesicles) in the bulk solution systematically, at the moment that the lower leaflet of bilayers already detached from solid surfaces. The SDS membrane would rather keep their bilayers structure than return to micelles when the initial interdigitated degree (deltai) between alkyl chains is more than 8.0+/-1.4%. And the interdigitated degree is always approaching to 31.7+/-2.0% while the equilibrium is reached. The aggregates behave as curved bilayers, planar bilayers, perforated bilayers, and micelles with the increase of the lower leaflet cross-sectional area. Besides, the structures of salt bridge and water bridge structures are formed between DS- and Na+ ions or water molecules, which contribute to the stability of SDS bilayers. The distribution difference of the salt bridges along the direction of S-O axis between the two leaflets leads to the asymmetry of the bilayers, which plays supplementary role to the formation of bilayers curvature. We expect that this work help to shed light on the understanding of interface phenomena and the mechanism of simple single-tailed surfactant vesicle self-assembly on the molecular level. PMID- 28735197 TI - Synthesis of porous polymer based solid amine adsorbent: Effect of pore size and amine loading on CO2 adsorption. AB - A series of porous polymers was synthesized by a suspension polymerization of divinylbenzene (DVB) and ethylene glycol dimethyl acrylate (EGDMA), which was further functionalized with polyethyleneimine (PEI) for CO2 capture. The results showed that the synthesized DVB and EGDMA (DE) copolymers were an effective support for loading PEI because of its larger pore size and specific surfaces area. It was found that DE (30, 10) loaded with 30wt% PEI exhibited a higher CO2 adsorption amount of 3.28mmol/g at 25 degrees C under dry condition. The CO2 adsorption capacity would decline gradually as the temperature continuously raised, for the reaction between CO2 and amine groups was an exothermic reaction. The kinetics study showed that Avrami kinetic model could accurately describe the whole CO2 adsorption process, suggesting that both physical adsorption and chemical adsorption were involved with the CO2 adsorption process. The intraparticle diffusion and Boyd's film diffusion models were applied to investigate the CO2 diffusion mechanism, the intraparticle diffusion model could well distinguish the rate-limiting step during CO2 adsorption process. This solid amine adsorbent could be regenerated with nitrogen stream at 75 degrees C, and it kept stable CO2 adsorption capacity after eight adsorption-desorption cycles. All these features indicated that this porous polymer based adsorbent has a high potential for CO2 capture and separation from flue gas. PMID- 28735198 TI - Impact of carbon quantum dots on dynamic properties of BSA and BSA/DPPC adsorption layers. AB - The effects of carbon quantum dots (CQDs) on the dynamic properties of bovine serum albumin (BSA) were investigated using pendant drop profile analysis method. Moreover, the effects of CQDs on the competitive adsorption of BSA and dipalmitoyl phosphatidylcholine (DPPC) were examined. CQDs reduce the fluorescence intensity of BSA and cause a red shift in fluorescence emission. The quenching constant at pH 4.3 is almost twice as large as that of the value obtained at pH 6.0. A small amount of CQDs does not influence the dynamic surface adsorption properties of BSA molecules. As the CQD concentration increases, a gradual increase in adsorption rate of BSA molecules is observed. Moreover, the addition of CQDs results in a significant transition of kinetic dependencies of surface elasticity of BSA solution when the CQD concentration exceeds a critical value. The appearance of the maximum surface elasticity value is probably attributed to the formation of tails and loops. When the dynamic surface properties are dominated by BSA molecules, the effects of CQDs on the surface properties of BSA/DPPC mixture are similar to those of BSA alone. However, when the surface film mainly consists of DPPC, CQDs can obviously change the interfacial properties of DPPC monolayer. PMID- 28735199 TI - One-pot synthesis of bismuth silicate heterostructures with tunable morphology and excellent visible light photodegradation performances. AB - Construction of a heterostructure to prolong the life of electron-hole pairs is a very important approach to endow it with excellent photodegradation performances. Particularly, one-pot synthesis of heterostructures with the same component but different crystal structures to form a proper band gap is still challenging. Herein, bismuth silicate (BSO) heterostructures are synthesized using a one-pot hydrothermal approach without adding any other inorganic components. The crystal phase, morphology, surface state, and photochemical properties of the BSO materials are precisely tuned to fabricate two kinds of bismuth silicate heterostructures: rod-like Bi2SiO5/Bi12SiO20 and flower-like Bi2SiO5/Bi4Si3O12 heterostructures. Thanks to the two heterostructures and clean surface, the optimized BSO material exhibits a highly active photocatalytic performance with a remarkable cycling stability. It photodegrades Rhodamine B under visible light irradiation as fast as 15min with the reaction rate constants k and ks to be 0.399min-1 and 0.698min-1Lm-2, respectively, which is up to 189 times faster than reported. PMID- 28735200 TI - Ion specific hydration in nano-confined electrical double layers. AB - We probe counter-ion specific effects in nano-confined electrical-double-layers (EDLs) by means of direct force measurements across a model slit pore in the extended surface forces apparatus. By variation of solution composition, we compare four different counter-ions with dissimilar hydration properties, namely Na+, K+, Cs+ as well as H3O+, all confined between (001) mica surfaces. We discuss the results in terms of a recently proposed pi-transition model, evoking hydrated ion layering as the recurrent structural element in highly confined EDLs. We demonstrate that the pi-transition essentially proceeds in multiple steps in coherence with the event of single- or multiple- hydrated-ion layering. PMID- 28735201 TI - Ultrasound Elastography of the Prostate Using an Unconstrained Modulus Reconstruction Technique: A Pilot Clinical Study. AB - A novel full-inversion-based technique for quantitative ultrasound elastography was investigated in a pilot clinical study on five patients for non-invasive detection and localization of prostate cancer and quantification of its extent. Conventional-frequency ultrasound images and radiofrequency (RF) data (~5 MHz) were collected during mechanical stimulation of the prostate using a transrectal ultrasound probe. Pre and post-compression RF data were used to construct the strain images. The Young's modulus (YM) images were subsequently reconstructed using the derived strain images and the stress distribution estimated iteratively using finite element (FE) analysis. Tumor regions determined based on the reconstructed YM images were compared to whole-mount histopathology images of radical prostatectomy specimens. Results indicated that tumors were significantly stiffer than the surrounding tissue, demonstrating a relative YM of 2.5+/-0.8 compared to normal prostate tissue. The YM images had a good agreement with the histopathology images in terms of tumor location within the prostate. On average, 76%+/-28% of tumor regions detected based on the proposed method were inside respective tumor areas identified in the histopathology images. Results of a linear regression analysis demonstrated a good correlation between the disease extents estimated using the reconstructed YM images and those determined from whole-mount histopathology images (r2=0.71). This pilot study demonstrates that the proposed method has a good potential for detection, localization and quantification of prostate cancer. The method can potentially be used for prostate needle biopsy guidance with the aim of decreasing the number of needle biopsies. The proposed technique utilizes conventional ultrasound imaging system only while no additional hardware attachment is required for mechanical stimulation or data acquisition. Therefore, the technique may be regarded as a non-invasive, low cost and potentially widely-available clinical tool for prostate cancer diagnosis. PMID- 28735202 TI - Effect of Wii FitTM exercise therapy on gait parameters in ankle sprain patients: A randomized controlled trial. AB - Ankle sprains are the most common sport related injuries. An alternative to physical therapy in the treatment of ankle sprains is home based exercise therapy. This study aims to compare the effectiveness of Wii FitTM exercise therapy in ankle sprain patients on temporal-spatial and kinematic gait parameters with a) conventional therapy and b) a control group not receiving exercise therapy. Ninety patients were randomly assigned to a Wii FitTM, physical therapy or control group. Temporal-spatial and kinematic gait parameters were assessed at baseline, 6 weeks and 6 months follow-up. All groups improved gait speed, cadence and step length between baseline and 6-week follow-up (P<0.036). Single support time improved only in the Wii FitTM group (P<0.001). Symmetry index of the single support time improved in the Wii FitTM group and physical therapy group (P<0.048). No between-group differences were found for temporal spatial gait parameters (P>0.050). Maximum plantar flexion improved in the physical therapy and control group between baseline and 6-week follow-up (P<0.035). However, none of the groups improved dorsiflexion (P>0.050). In conclusion, an unsupervised home-based 6-week Wii FitTM exercise therapy can be applied in ankle sprain patients. However, it was not more effective compared to physical therapy or no exercise therapy at all. PMID- 28735203 TI - Grape stalk application for caffeine removal through adsorption. AB - Concern over emerging pollutants presence in water resources is growing, justifying the search for alternative or additional techniques to those applied in conventional water treatment processes. Use of adsorption with agricultural wastes directly as adsorbents or as precursors for activated carbon synthesis is a viable method, combining removal efficiency, low cost and biodegradability of the material applied. This study investigated the employability of grape stalk, a waste from grape industrialization process without effective use, in caffeine removal from aqueous solution. Grape stalk was used in three different forms: raw with only grain size adjustment (GS), modified by phosphoric acid action (MGS) and as activated carbon (GSAC). In the first two cases parameters pH, residence time and adsorbent concentration were varied in order to find optimum batch process conditions. For GSAC, on the other hand, caffeine removal percentages were high even for the least amount of adsorbent that could be measured with acceptable accuracy, which did not justify concentration parameter variation. Better adsorption capacities were observed in acidic solutions, with optimum pH values being considered as 2.0 for GS and MGS and 4.0 for GSAC. Optimum residence time and adsorbent concentration were 40 min and 25 g L-1 (GS), 30 min and 15 g L 1 (MGS) and 30 min (GSAC). Moreover, equilibrium was evaluated through adsorption isotherms construction, which were best represented by Sips model, displaying determination coefficients R2 equal to 0.994, 0.999 and 0.987 and maximum adsorption capacities equal to 89.2, 129.6 and 916.7 mg g-1. Adsorbents particular characteristics such as specific surface areas and micropore volumes were also determined, resulting in 6.23, 4.21 and 1099.86 m2 g-1 and 0.003, 0.002 and 0.568 cm3 g-1 for GS, MGS and GSAC, respectively. PMID- 28735204 TI - Developing an ecosystem model of a floating wetland for water quality improvement on a stormwater pond. AB - An ecosystem model was developed to assist with designing and implementing a floating wetland (FW) for water quality management of urban stormwater ponds, focusing on nitrogen (N) removal. The model is comprised of three linked submodels: hydrology, plant growth, and nitrogen. The model was calibrated with the data that resulted from a FW constructed and implemented as part of an interdisciplinary pedagogical project on a university campus, titled "The Rain Project", which raised awareness of stormwater issues while investigating the potential application of green infrastructure for sustainable stormwater management. The FW had been deployed during the summer of 2015 (i.e., May through mid-September) on a major stormwater pond located at the center of the Fairfax Campus of George Mason University near Washington, D.C. We used the model to explore the impact of three design elements of FW (i.e., hydraulic residence time (HRT), surface area coverage, and primary productivity) on the function of FW. Model simulations showed enhanced N removal performance as HRT and surface area coverage increased. The relatively low macrophyte productivity observed indicates that, in the case of our pond and FW, N removal was very limited. The model results suggest that even full pond surface coverage would result in meager N removal (~6%) at a HRT of one week. A FW with higher plant productivity, more representative of that reported in the literature, would require only 10% coverage to achieve similar N removal efficiency (~7%). Therefore, macrophyte productivity appears to have a greater impact on FW performance on N removal than surface area coverage or pond HRT. The outcome of the study shows that this model, though limited in scope, may be useful in aiding the design of FW to augment the performance of degraded stormwater ponds in an effort to meet local water quality goals. PMID- 28735205 TI - Unconventional gas development facilitates plant invasions. AB - Vegetation removal and soil disturbance from natural resource development, combined with invasive plant propagule pressure, can increase vulnerability to plant invasions. Unconventional oil and gas development produces surface disturbance by way of well pad, road, and pipeline construction, and increased traffic. Little is known about the resulting impacts on plant community assembly, including the spread of invasive plants. Our work was conducted in Pennsylvania forests that overlay the Marcellus and Utica shale formations to determine if invasive plants have spread to edge habitat created by unconventional gas development and to investigate factors associated with their presence. A piecewise structural equation model was used to determine the direct and indirect factors associated with invasive plant establishment on well pads. The model included the following measured or calculated variables: current propagule pressure on local access roads, the spatial extent of the pre-development road network (potential source of invasive propagules), the number of wells per pad (indicator of traffic density), and pad age. Sixty-one percent of the 127 well pads surveyed had at least one invasive plant species present. Invasive plant presence on well pads was positively correlated with local propagule pressure on access roads and indirectly with road density pre-development, the number of wells, and age of the well pad. The vast reserves of unconventional oil and gas are in the early stages of development in the US. Continued development of this underground resource must be paired with careful monitoring and management of surface ecological impacts, including the spread of invasive plants. Prioritizing invasive plant monitoring in unconventional oil and gas development areas with existing roads and multi-well pads could improve early detection and control of invasive plants. PMID- 28735206 TI - Electrochemical treatment of biologically pre-treated dairy wastewater using dimensionally stable anodes. AB - In this work, electrochemical oxidation of aerobically pre-treated dairy wastewaters using IrO2-Pt coated dimensionally stable anodes was investigated. It was found that IrO2/Ti electrode outperforming Pt/Ti and IrO2-Pt/Ti at lower current densities, while Pt/Ti achieved better efficiency at higher current density. Among the different parameters which were studied, the current density was the most crucial for the efficiency of the process. A current density of 100 mA/cm2 led to almost complete removal of 3700 mg/L COD after 360 min of treatment using IrO2/Ti electrode and 0.2 M of sodium chloride while complete decolorization was achieved in less than 60 min. Electrolytes also found to significantly affect the process. More specific, the use of sodium chloride instead of sodium sulfate enhanced both COD and color removal due to the formation of active chlorine species. The effect of temperature was relative low; the process was favourable at elevated temperatures while increasing COD loading resulted in a decrease of COD and color removal. PMID- 28735207 TI - Nutrient balancing for phytoremediation enhancement of urea manufacturing raw wastewater. AB - Application of urea manufacturing wastewater to teak (Tectona grandis) trees, a fast growing tropical timber plants, is an environmentally-friendly and cost effective alternative for treatment of nitrogen-rich wastewater. However, the plant growth is strongly limited by lack of phosphorus (P) and potassium (K) elements when the plants are irrigated with wastewater containing high concentration of nitrogen (N). A greenhouse experiment was conducted to optimize the efficiency of teak-based remediation systems in terms of nutrient balance. Twelve test solutions consisted of 4 levels of P (95, 190, 570, 1140 mgL-1) and 3 levels of K (95, 190, 570 mgL-1) with a constant level of N (190 mgL-1) were applied to teak seedlings every four days during the study period. Evapotranspiration rate, nutrient removal percentage, leaf surface area, dry weight and nutrient contents of experimental plants were determined and compared with those grown in control solution containing only N (N:P:K = 1:0:0). Teak seedlings grown in units with 1:0.5:1 N:P:K ratio were highly effective at nutrient removal upto 47%, 48% and 49% for N, P and K, respectively. Removal efficiency of teak plants grown in other experimental units decreased with increasing P and K concentrations in test solutions. The lowest nutrient removal and plant growth were recorded in units with 1:6:0.5 N:P:K ratio which received the highest ratio of P to K. The findings indicated that teak seedlings functioned effectively as phytoremediation plants for N-rich wastewater treatment when they were being supplied with proper concentrations of P and K. PMID- 28735208 TI - Sectoral linkage analysis of three main air pollutants in China's industry: Comparing 2010 with 2002. AB - To investigate the driving forces of air pollution in China, the changes in linkages amongst inter-industrial air pollutant emissions were analyzed by hypothetical extraction method under the input-output framework. Results showed that the emissions of SO2, soot and dust from industrial sources increased by 56.46%, 36.95% and 11.69% respectively in 2010, compared with 2002. As major contributors to emissions, the power and gas sectors were responsible for the growing SO2 emissions, the nonmetal products sector for soot emissions, and the metals mining, smelting and pressing sectors for dust emissions. The increasing volume of emissions was mainly driven by the growing demand in the transport equipment and electrical equipment sectors. In addition, the expansion in the metals mining, smelting and pressing sectors could result in even more severe air pollution. Therefore, potential effective strategies to control air pollution in China are: (1) reducing the demand of major import sectors in the equipment manufacturing industry; (2) promoting R&D in low-emissions-production technologies to the power and gas sectors, the metals mining, smelting and pressing sectors, and the nonmetal products sector, and (3) auditing the considerable industrial scale expansion in the metals mining, smelting and pressing sectors and optimizing the industrial structure. PMID- 28735209 TI - Seasonal performance of denitrifying bioreactors in the Northeastern United States: Field trials. AB - Denitrifying bioreactors are increasingly being used for nitrate removal from agricultural drainage water. Filled with carbon substrates, often woodchips, denitrifying bioreactors provide a favorable anaerobic environment for denitrification. Despite performing well in loess soils in the Midwestern United States, field bioreactors have not yet been evaluated in shallow soils over glacial till that are characteristic for the Northeastern United States. This study, therefore, investigates the performance of bioreactors and provides design criteria for shallow soil with flashy discharges. Paired bioreactors, one filled with woodchips and one with a mixture of woodchip and biochar, were installed in tile drained fields in three landscapes in New York State. The bioreactors were monitored for a three-year period during which, the flow rate, temperature, nitrate (NO3--N), sulfate (SO42--S) and dissolved organic carbon (DOC) were measured. Results showed that the average NO3--N removal efficiency during the three years of observations was about 50%. The NO3--N removal rate ranged from 0 in winter to 72 g d-1 m-3 in summer. We found that biochar was only effective during the first year in enhancing denitrification, due to the ageing. An index for carbon availability related to NO3--N removal was developed. During winter, availability of the DOC was a limiting factor in bioreactor performance. Finally, to aid in the design of bioreactors, we developed generalizable relationships between the removal efficiency and hydraulic retention time and temperature. PMID- 28735210 TI - Moisture content prediction in poultry litter using artificial intelligence techniques and Monte Carlo simulation to determine the economic yield from energy use. AB - The objective of this study is to determine the economic return of poultry litter combustion in boilers to produce bioenergy (thermal and electrical), as this biomass has a high-energy potential due to its component elements, using fuzzy logic to predict moisture and identify the high-impact variables. This is carried out using a proposed 7-stage methodology, which includes a statistical analysis of agricultural systems and practices to identify activities contributing to moisture in poultry litter (for example, broiler chicken management, number of air extractors, and avian population density), and thereby reduce moisture to increase the yield of the combustion process. Estimates of poultry litter production and heating value are made based on 4 different moisture content percentages (scenarios of 25%, 30%, 35%, and 40%), and then a risk analysis is proposed using the Monte Carlo simulation to select the best investment alternative and to estimate the environmental impact for greenhouse gas mitigation. The results show that dry poultry litter (25%) is slightly better for combustion, generating 3.20% more energy. Reducing moisture from 40% to 25% involves considerable economic investment due to the purchase of equipment to reduce moisture; thus, when calculating financial indicators, the 40% scenario is the most attractive, as it is the current scenario. Thus, this methodology proposes a technology approach based on the use of advanced tools to predict moisture and representation of the system (Monte Carlo simulation), where the variability and uncertainty of the system are accurately represented. Therefore, this methodology is considered generic for any bioenergy generation system and not just for the poultry sector, whether it uses combustion or another type of technology. PMID- 28735212 TI - Externally controlled involuntary cognitions and their relations with other representations in consciousness. AB - Percepts and action-related urges often enter consciousness insuppressibly. The Reflexive Imagery Task (RIT) was developed to investigate how high-level cognitions (e.g., subvocalizations), too, can enter consciousness in this manner. Limitations of the paradigm include (a) that no data have confirmed subjects' introspections about the involuntary subvocalizations, and (b) that, in everyday life, adaptive responses to involuntary cognitions often depend on the nature of the other contents in consciousness. To address a and b, we developed an RIT in which subjects were presented with visual objects and instructed to not think of the object names. If a subvocalization did arise, however, subjects responded motorically only if the subvocalization rhymed with a word held in memory and if there was a visual "go" cue. Subjects successfully (on 0.83 of the trials) emitted this complex, "multi-determined" response, which provides evidence for the occurrence of the involuntary subvocalizations and illuminates the function of consciousness. PMID- 28735211 TI - Runoff initiation, soil detachment and connectivity are enhanced as a consequence of vineyards plantations. AB - Rainfall-induced soil erosion is a major threat, especially in agricultural soils. In the Mediterranean belt, vineyards are affected by high soil loss rates, leading to land degradation. Plantation of new vines is carried out after deep ploughing, use of heavy machinery, wheel traffic, and trampling. Those works result in soil physical properties changes and contribute to enhanced runoff rates and increased soil erosion rates. The objective of this paper is to assess the impact of the plantation of vineyards on soil hydrological and erosional response under low frequency - high magnitude rainfall events, the ones that under the Mediterranean climatic conditions trigger extreme soil erosion rates. We determined time to ponding, Tp; time to runoff, Tr; time to runoff outlet, Tro; runoff rate, and soil loss under simulated rainfall (55 mm h-1, 1 h) at plot scale (0.25 m2) to characterize the runoff initiation and sediment detachment. In recent vine plantations (<1 year since plantation; R) compared to old ones (>50 years; O). Slope gradient, rock fragment cover, soil surface roughness, bulk density, soil organic matter content, soil water content and plant cover were determined. Plantation of new vineyards largely impacted runoff rates and soil erosion risk at plot scale in the short term. Tp, Tr and Tro were much shorter in R plots. Tr-Tp and Tro-Tr periods were used as connectivity indexes of water flow, and decreased to 77.5 and 33.2% in R plots compared to O plots. Runoff coefficients increased significantly from O (42.94%) to R plots (71.92%) and soil losses were approximately one order of magnitude lower (1.8 and 12.6 Mg ha-1 h-1 for O and R plots respectively). Soil surface roughness and bulk density are two key factors that determine the increase in connectivity of flows and sediments in recently planted vineyards. Our results confirm that plantation of new vineyards strongly contributes to runoff initiation and sediment detachment, and those findings confirms that soil erosion control strategies should be applied immediately after or during the plantation of vines. PMID- 28735213 TI - Chemoselective synthesis and biological evaluation of arylated 2 (Trifluoromethyl) quinolines as nucleotide pyrophosphatase (NPPs) inhibitors. AB - A new approach to arylated 2-trifluoromethylquinolines based on novel regioselective Suzuki-Miyaura coupling reactions has been developed. Moreover, site-selective, chemo-selective amination reactions were performed. The new 2 trifluoromethylquinoline derivatives were tested as potential NPPs inhibitors and evaluated for their potential to inhibit two families of ecto-nucleotidases, i.e. NPPs and nucleoside triphosphate diphosphohydrolases (NTPDases). Several derivatives were active on a nanomolecular concentration. The results were validated based on docking studies to study the active binding site of the molecules. PMID- 28735214 TI - Indazole-based ligands for estrogen-related receptor alpha as potential anti diabetic agents. AB - Estrogen-related receptor alpha (ERRalpha) is an orphan nuclear receptor that has been functionally implicated in the regulation of energy homeostasis. Herein is described the development of indazole-based N-alkylthiazolidenediones, which function in biochemical assays as selective inverse agonists against this receptor. Series optimization provided several potent analogues that inhibited the recruitment of a co-activator peptide fragment in vitro (IC50s < 50 nM) and reduced fasted circulating insulin and triglyceride levels in a sub-chronic pre diabetic rat model when administered orally (10 mg/kg). A multi-parametric optimization strategy led to the identification of 50 as an advanced lead, which was more extensively evaluated in additional diabetic models. Chronic oral administration of 50 in two murine models of obesity and insulin resistance improved glucose control and reduced circulating triglycerides with efficacies similar to that of rosiglitazone. Importantly, these effects were attained without the concomitant weight gain that is typically observed with the latter agent. Thus, these studies provide additional support for the development of such molecules for the potential treatment of metabolic diseases. PMID- 28735215 TI - Estimation of individual axon bundle properties by a Multi-Resolution Discrete Search method. AB - A stable, accurate and robust-to-noise method for the estimation of the intra voxel bundle-wise diffusion properties for diffusion-weighted magnetic resonance imaging is presented. The proposed method overcomes some of the limitations of most of the multi-fiber algorithms in the literature and extends them to estimate the diffusion profiles, improving the estimation of the intra-voxel geometry at challenging microstructure configurations, that is to say: relatively small crossing angles, different voxel-wise anisotropic diffusion profiles and low SNR. The proposed methodology is based on four key novel ideas: (i) A Multi-Resolution Discrete-Search determines the orientation of the fiber bundles accurately and naturally constrains the sparsity on the recovered solutions; (ii) the determination of the number of fiber bundles using the F-test combined with a Rician bias correction; (iii) a Simultaneous Denoising and Fitting procedure that exploits the spatial redundancy of the axon bundles to achieve robustness with respect to noise; and (iv) a general framework for the estimation of the axial and radial diffusivity parameters independently for each voxel. A new useful evaluation metric is also proposed, which combines the information of the success rate in the estimated number of bundles and the angular error, avoiding in this way, some of the limitations these metrics have individually. A novel methodology for the evaluation of the methods on in-vivo data is also proposed. This work presents an extensive evaluation: the proposed methodology has been tested on state-of-the-art biophysical synthetic data for a variety of conditions, on the challenging spatially coherent phantom used on the HARDI reconstruction Challenge 2012, and on the recently released in-vivo MASSIVE data-set. Our results present significant improvements on the estimation of the number and orientation of the fiber bundles over the Spherical Deconvolution algorithm for multi-shell data, which is one of the most widely used multi-fiber algorithm. The results also show that, by the voxel-wise estimation of the diffusion profiles, the axial and radial diffusivity parameters are robustly estimated, being this essential for a better understanding of the individual bundle diffusion properties at challenging structural configurations. PMID- 28735216 TI - Elastic properties and strain-to-crack-initiation of calcium phosphate bone cements: Revelations of a high-resolution measurement technique. AB - Calcium phosphate cements (CPCs) should ideally have mechanical properties similar to those of the bone tissue the material is used to replace or repair. Usually, the compressive strength of the CPCs is reported and, more rarely, the elastic modulus. Conversely, scarce or no data are available on Poisson's ratio and strain-to-crack-initiation. This is unfortunate, as data on the elastic response is key to, e.g., numerical model accuracy. In this study, the compressive behaviour of brushite, monetite and apatite cements was fully characterised. Measurement of the surface strains was done using a digital image correlation (DIC) technique, and compared to results obtained with the commonly used built-in displacement measurement of the materials testers. The collected data showed that the use of fixed compression platens, as opposed to spherically seated ones, may in some cases underestimate the compressive strength by up to 40%. Also, the built-in measurements may underestimate the elastic modulus by up to 62% as compared to DIC measurements. Using DIC, the brushite cement was found to be much stiffer (24.3 +/- 2.3GPa) than the apatite (13.5 +/- 1.6GPa) and monetite (7.1 +/- 1.0GPa) cements, and elastic moduli were inversely related to the porosity of the materials. Poisson's ratio was determined to be 0.26 +/- 0.02 for brushite, 0.21 +/- 0.02 for apatite and 0.20 +/- 0.03 for monetite. All investigated CPCs showed low strain-to-crack-initiation (0.17-0.19%). In summary, the elastic modulus of CPCs is substantially higher than previously reported and it is concluded that an accurate procedure is a prerequisite in order to properly compare the mechanical properties of different CPC formulations. It is recommended to use spherically seated platens and measuring the strain at a relevant resolution and on the specimen surface. PMID- 28735217 TI - Zopiclone concentrations in oral fluid and blood after, administration of therapeutic doses of zopiclone. AB - PURPOSE: Little is known about the relationship between concentrations in oral fluid (OF) and blood for the widely prescribed hypnotic drug zopiclone. The purpose of this study was to investigate the usefulness of OF zopiclone concentrations to predict blood zopiclone concentrations in order to introduce OF testing as an alternative to more cumbersome blood testing. METHODS: 16 healthy young male volunteers received capsules of either 5 or 10mg zopiclone on two different study days separated by at least one week. Blood and OF were collected simultaneously at baseline and 9 times after intake of zopiclone on each study day. In addition an OF sample was collected 24-81h after intake. Lunch was served between samples taken 2.5 and 3.5h after intake. All samples were analysed for zopiclone, and the cut-off was 10ng/ml in blood and 0.2ng/ml in OF-buffer mixture. RESULTS: Zopiclone was detected in all OF samples during the study day. After 24-81h, all subjects were also positive for zopiclone in OF, except from three subjects ingesting the 5mg dose. In a single case zopiclone was detected in a baseline OF sample 14days after intake on an earlier study day. Zopiclone was detected in both OF and blood in 231 OF/blood pairs, and a significant but weak correlation between OF and blood concentration was seen (R2 of 0.30). The median (range) zopiclone OF/blood concentration ratio (ZOBCR) for all samples were 3.3 (0.8-18). The ZOBCR decreased when the OF volume increased. After 30 of 31 given doses of zopiclone, the ZOBCR was higher in samples collected before lunch than samples collected after lunch. DISCUSSION: Vast intra- and interindividual differences in ZOBCR were found, and the correlation between OF and blood concentration was less pronounced than reported in former studies. In accordance with earlier studies we found a negative correlation between ZOBCR and OF volume. The ZOBCR decreases in relation to recent intake of a meal, probably because stimulated saliva production causes "dilution" of saliva. OF zopiclone concentration appeared unsuitable for estimation of blood zopiclone concentration. Due to long detection time, analysis of zopiclone in OF might be useful to detect non-recent, previous intake. PMID- 28735218 TI - Strength of linguistic text evidence: A fused forensic text comparison system. AB - Compared to other forensic comparative sciences, studies of the efficacy of the likelihood ratio (LR) framework in forensic authorship analysis are lagging. An experiment is described concerning the estimation of strength of linguistic text evidence within that framework. The LRs were estimated by trialling three different procedures: one is based on the multivariate kernel density (MVKD) formula, with each group of messages being modelled as a vector of authorship attribution features; the other two involve N-grams based on word tokens and characters, respectively. The LRs that were separately estimated from the three different procedures are logistic-regression-fused to obtain a single LR for each author comparison. This study used predatory chatlog messages sampled from 115 authors. To see how the number of word tokens affects the performance of a forensic text comparison (FTC) system, token numbers used for modelling each group of messages were progressively increased: 500, 1000, 1500 and 2500 tokens. The performance of the FTC system is assessed using the log-likelihood-ratio cost (Cllr), which is a gradient metric for the quality of LRs, and the strength of the derived LRs is charted as Tippett plots. It is demonstrated in this study that (i) out of the three procedures, the MVKD procedure with authorship attribution features performed best in terms of Cllr, and that (ii) the fused system outperformed all three of the single procedures. When the token length is 1500, for example, the fused system achieved a Cllr value of 0.15. Some unrealistically strong LRs were observed in the results. Reasons for these are discussed, and a possible solution to the problem, namely the empirical lower and upper bound LR (ELUB) method is trialled and applied to the LRs of the best achieving fusion system. PMID- 28735219 TI - Electrodeposition to construct free-standing chitosan/layered double hydroxides hydro-membrane for electrically triggered protein release. AB - In this study, we report the electrodeposition of a chitosan/layered double hydroxides (LDHs) hydro-membrane for protein release triggered by an electrical signal. The electrodeposition was performed in a chitosan and insulin loaded LDHs suspension in the absence of salt. A free-standing chitosan/LDHs hydro-membrane was generated on the electrode with improved mechanical properties, which is dramatically different from the weak hydrogel deposited in the presence of salt. The amount of LDHs in the hydro-membrane affects the optical transmittance and multilayered structure of the hybrid membrane. Compared to the weak chitosan/LDHs hydrogel, the hydro-membrane has a higher insulin loading capacity and the release of insulin is relatively slow. By biasing electrical potentials to the hydro-membrane, the release behavior of insulin can be adjusted accordingly. In addition, the chitosan/LDHs hydro-membrane showed no toxicity to cells. Our results provide a facile method to construct a chitosan/LDHs hybrid multilayered hydro-membrane and suggest the great potential of the hydro-membrane in controlled protein release. PMID- 28735220 TI - Mesoporous calcium phosphate using casein as a template: Application to bovine serum albumin sorption. AB - Mesoporous hydroxyapatites were synthesized at room temperature using casein as a template, and key experimental factors, such as casein concentration, pH and extraction of casein in the final solids by washing and thermal treatment, were systematically investigated. The X-Ray Diffraction (XRD) patterns confirmed the synthesis of well-crystallized hydroxyapatite. The N2 adsorption/desorption isotherms were in agreement with the formation of mesoporous hydroxyapatite with a maximum surface area of 106m2g-1. Infrared spectroscopy and thermogravimetry analysis were performed to investigate the extraction of casein in water in the post-synthesis stage. Pure mesoporous hydroxyapatite exhibited good BSA adsorption capacity higher than the one obtained for conventional hydroxyapatite. PMID- 28735221 TI - Physicochemical properties of ionic and non-ionic biocompatible hydrogels in water and cell culture conditions: Relation with type of morphologies of bovine fetal fibroblasts in contact with the surfaces. AB - Cationic, anionic and non-ionic hydrogels having acrylamide polymer backbones were synthesized via free radical polymerization with N,N-methylenebisacrylamide (BIS) as crosslinker. The chemical structures of the hydrogels were characterized by Fourier Transform Infrared Spectroscopy (FTIR). Physicochemical properties such as swelling kinetic, maximum swelling capacity, volume phase transition temperature (VPTT) and wettability (static water contact angle) of hydrogels swollen in aqueous and cell culture medium, at room and cell culture temperatures were studied. In order to correlate the surface properties of the hydrogels and cellular adhesivity of bovine fetal fibroblasts (BFFs), cellular behaviour was analyzed by inverted fluorescence optical microscopy and atomic force microscopy (AFM). MTT assay demonstrated that the number of viable cells in contact with hydrogels does not significantly change in comparison to a control surface. Flattened and spindle-shaped cells and cell spheroids were the adopted morphologies during first days of culture on different hydrogels. Cell spheroids were easily obtained during the first 5days of culture in contact with PNIPAM-co 20%HMA (poly (N-isopropylacrylamide-co-20%N-acryloyl-tris (hydroxymethyl)aminomethane)) hydrogel surface. After 15days of culture all hydrogels showed high adhesion and visual proliferation. According to obtained results, non-ionic and hydrophilic surfaces with moderated wettability induce the formation of BFFs cell spheroids. These hydrogel surfaces could be used in clinical and biochemical treatments at laboratory level to cell growth and will allow generating the base for future biotechnologic platform. PMID- 28735222 TI - Effect of oleic acid on the properties of protein adsorbed layers at water/oil interfaces: An EPR study combined with dynamic interfacial tension measurements. AB - Multiphase food systems consist of complex interfacial layers where surface active molecules complete compete for adsorption and interact with one another affecting the interfacial properties and the behavior of the food systems involved. The present work focuses on the examination of interactions between proteins playing an which play an important role in milk-rich food systems (namely kappa-casein and beta-lactoglobulin) and oleic acid (an anionic surfactant abundant in food systems) at the oil/water interface. An interesting feature of this system is that the molecules interacting at the interface originate from different phases and do not transfer/dissolve significantly to the other phase. The systems were examined using Electron Paramagnetic Resonance (EPR) spectroscopy and Dynamic Interfacial Tension measurements (dynamic interfacial tension and dynamic interfacial dilatational rheology). This combination of experimental methods provided the dynamics of adsorption at the interface and the mechanical properties of the interface allowing valuable insight on the interactions of the different molecules. The above information was coupled with direct information on fatty acid mobility in the oil bulk phase and indirect information on the degree of relative fatty acid/protein adsorption at the interface by EPR. Overall a synergistic effect of the protein and fatty acid on decreasing interfacial tension of the oil/water interface was evidenced. The fatty acid interacted differently with the random coil kappa-casein and globular beta-lactoglobulin in terms of relative adsorption and in terms on its effect on mechanical properties. Thermal denaturation of beta-lactoglobulin affected the protein's interaction with the fatty acid due to conformational changes and exposure of non-polar sites. PMID- 28735223 TI - Isomeric separation and quantitation of di-(2-ethylhexyl) trimellitates and mono (2-ethylhexyl) trimellitates in blood by LC-MS/MS. AB - A new and fast HPLC-method for the simultaneous determination of tri-(2 ethylhexyl) trimellitate (TOTM or TEHTM), its diesters 2,4-di-(2-ethylhexyl) trimellitate (2,4-DEHTM), 1,4-di-(2-ethylhexyl) trimellitate (1,4-DEHTM), 1,2-di (2-ethylhexyl) trimellitate (1,2-DEHTM) and monoesters 1-mono-(2-ethylhexyl) trimellitate (1-MEHTM), 2-mono-(2-ethylhexyl) trimellitate (2-MEHTM) and 4-mono (2-ethylhexyl) trimellitate (4-MEHTM) together with di-(2-ethylhexyl) phthalate (DEHP) and its primary metabolite mono-(2-ethylhexyl) phthalate (MEHP) in blood was developed and validated. The analytes are extracted from blood using liquid liquid extraction and are chromatographically separated by reversed-phase HPLC using core shell material. Quantitative assessment was performed by ESI-tandem mass spectrometry in negative ionization mode using stable isotope dilution. In less than 30min six postulated primary metabolites of TOTM along with the DEHP metabolite MEHP can be selectively and sensitively quantified. Additionally, the method enables the determination of the parent plasticizers TOTM and DEHP. The detection limits in blood were found to range between 0.7-5.5MUg/L for all TOTM analytes. Precision and repeatability of the method were proven by relative standard deviations between 0.9% and 8.7%. TOTM, an alternative plasticizer to DEHP, is already increasingly used for medical devices. Nevertheless, data about the human metabolism of TOTM are still limited. The presented method is the first one enabling the simultaneous determination of the parent plasticizers TOTM and DEHP together with their primary degradation products (DEHTM, MEHTM, MEHP) and can thus be applied manifold including the investigation of the human metabolism of TOTM. PMID- 28735224 TI - Simultaneous quantification of cortisol and cortisone in urines from infants with packed-fiber solid-phase extraction coupled to HPLC-MS/MS. AB - Cortisol and cortisone are two important glucocorticoids in human body, their interconversion is controlled by two isotypes of 11beta-hydroxy steroid dehydrogenase (11beta-HSD1 and 11beta-HSD2). The ratio of urinary cortisol to cortisone can be used to assess the activity of 11beta-HSDs. An analytical method to quantify urinary cortisol and cortisone using high performance liquid chromatographic tandem mass spectrometry following a packed-fiber solid-phase extraction (PFSPE) was developed. The proposed method was validated and applied to determine the urinary cortisol and cortisone concentrations in infants. Linearity was observed in the range of 0.6-150ng/mL for cortisol and 0.8-200ng/mL for cortisone. The intra-day RSD was 2.4-4.5% for cortisol and 3.3-6.2% for cortisone. Inter-day RSD was 3.7-6.6% for cortisol and 4.3-8.2% for cortisone. The recovery was 97.8+/-4.6% for cortisol and 98.9+/-4.4% for cortisone. The established method is simple and efficient for the quantification of urinary cortisol and cortisone and for indirectly assessing the activity of 11beta hydroxy steroid dehydrogenase. PMID- 28735225 TI - No consistent cooling of the real hand in the rubber hand illusion. AB - In the rubber hand illusion (RHI), participants view a rubber hand that is stroked synchronously with their real, hidden hand. This procedure results in experiencing an increased sense of ownership over the rubber hand and demonstrates how multisensory information (vision, touch) can influence the sense of body ownership. However, it has also been suggested that a (lack of) sense of ownership over an own body part may in turn influence bodily processes. This suggestion has previously been supported by the observation that a decrease in skin temperature in the real hand correlated with ownership over the rubber hand. However, this finding has not been consistently replicated. Our lab has conducted several studies in which we recorded temperature of the hands during the RHI using various measures and in different circumstances, including continuous temperature measurements in a temperature-controlled room. An overall analysis of our results, covering five attempts to replicate the traditional RHI experiment and totalling 167 participants, does not show a reliable cooling of the real hand during the RHI. We discuss this failure to replicate and consider several possible explanations for inconsistencies between reports of hand temperature during the RHI. PMID- 28735226 TI - Perinatal fluoxetine effects on social play, the HPA system, and hippocampal plasticity in pre-adolescent male and female rats: Interactions with pre gestational maternal stress. AB - Selective serotonin reuptake inhibitor medications (SSRIs) are the first lines of treatment for maternal affective disorders, and are prescribed to up to 10% of pregnant women. Concern has been raised about how perinatal exposure to these medications affect offspring neurobehavioral outcomes, particularly those related to social interactions, as recent research has reported conflicting results related to autism spectrum disorder (ASD) risk in children prenatally exposed to SSRIs. Therefore, the aim of this work was to investigate the effects of perinatal exposure to the SSRI fluoxetine on social play behaviors and the hypothalamic pituitary adrenal system, using a model of pre-gestational maternal stress. We also investigated synaptic proteins in the CA2, CA3, and dentate gyrus of the hippocampus, as well as number of immature neurons in the granule cell layer, as both measures of plasticity in the hippocampus have been linked to social behaviors. In pre-adolescent male and female Sprague-Dawley rat offspring, main findings show that perinatal fluoxetine prevents the negative effect of maternal stress on sibling play behavior. However, perinatal fluoxetine increased social aggressive play with a novel conspecific in both sexes and decreased time grooming a novel conspecific in males only. Perinatal fluoxetine also increased serum corticosteroid binding globulin levels, 5-HT levels in the hippocampus, and pre-synaptic density assessed via synaptophysin in the dentate gyrus. Social interaction was significantly correlated with changes in plasticity in the CA2 region of the hippocampus. Pre-gestational maternal stress exposure resulted in significantly decreased rates of hippocampal neurogenesis and synaptophysin density in the dentate gyrus of pre-adolescent males, but not females. Together, these results further characterize the role of perinatal SSRIs, maternal stress prior to conception, and sex/gender on developing social behaviors and related plasticity in the hippocampus of pre-adolescent offspring. PMID- 28735227 TI - MicroRNA-27b inhibits cell proliferation in oral squamous cell carcinoma by targeting FZD7 and Wnt signaling pathway. AB - This study intended to investigate the role of microRNA-27b (miR-27b) in proliferation of oral squamous cell carcinoma (OSCC) cells and to explore the potential molecular mechanism. Cell proliferation was detected by MTT assay. The expression levels of miR-27b, Frizzled7 (FZD7), cyclin D1 and c-myc were detected by quantitative real time polymerase chain reaction (qRT-PCR). The protein expression level of FZD7 was detected by western blot analysis. The relationship between miR-27b and FZD7, and the activity of Wnt signaling pathway were determined using luciferase reporter assay. The miR-27b expression in OSCC cell lines was significantly decreased compared with control. Overexpression of miR 27b remarkably inhibited OSCC cell proliferation. Additionally, miR-27b could target and inhibit FZD7 expression and decrease the activity of Wnt signaling pathway.miR-27b could inhibit OSCC cell proliferation through inhibiting FZD7 and FZD7-mediated Wnt signaling pathway. PMID- 28735228 TI - The role of nitrogen uptake on the competition ability of three vineyard Saccharomyces cerevisiae strains. AB - Three vineyard strains of Saccharomyces cerevisiae, P301.4, P304.4 and P254.12, were assayed in comparison with a commercial industrial strain, QA23. The aim was to understand if nitrogen availability could influence strain competition ability during must fermentation. Pairwise-strain fermentations and co-fermentations with the simultaneous presence of the four strains were performed in synthetic musts at two nitrogen levels: control nitrogen condition (CNC) that assured the suitable assimilable nitrogen amount required by the yeast strains to complete the fermentation and low nitrogen condition (LNC) where nitrogen is present at very low level. Results suggested a strong involvement of nitrogen availability, as the frequency in must of the vineyard strains, respect to QA23, in LNC was always higher than that found in CNC. Moreover, in CNC only strain P304.4 reached the same strain frequency as QA23. P304.4 competition ability increased during the fermentation, indicating better performance when nitrogen availability was dropping down. P301.4 was the only strain sensitive to QA23 killer toxin. In CNC, when it was co-inoculated with the industrial strain QA23, P301.4 was never detected. In LNC, P301.4 after 12h accounted for 10% of the total population. This percentage increased after 48h (20%). Single-strain fermentations were also run in both conditions and the nitrogen metabolism further analyzed. Fermentation kinetics, ammonium and amino-acid consumptions and the expression of genes under nitrogen catabolite repression evidenced that vineyard yeasts, and particularly strain P304.4, had higher nitrogen assimilation rate than the commercial control. In conclusion, the high nitrogen assimilation rate seems to be an additional strategy that allowed vineyard yeasts successful competition during the growth in grape musts. PMID- 28735229 TI - Synthetic antibody mimics for the inhibition of protein-ligand interactions. AB - The rational/structure-based design and/or combinatorial development of molecules capable of selectively binding to a protein, represents a promising strategy for a range of biomedical applications, in particular the inhibition of disease associated protein-ligand interactions. The design of such protein binding molecules is often based on an antibody against the target protein, or involves the generation of smaller molecules that retain the binding characteristics of the antibody. Alternatively, protein binding molecules can be selected from protein libraries based on small, stably folded protein scaffolds presenting flexible loops, which are randomized in the libraries. In addition to recombinantly synthesized molecules, synthetic antibody paratope mimetic peptides have emerged as promising molecules for the design of antibody mimics. PMID- 28735230 TI - Granulometry, microbial composition and biological activity of dusts collected in French dairy farms. AB - BACKGROUND: Dairy working increases the prevalence of lower airway respiratory diseases, especially COPD and asthma. Epidemiological studies have reported that chronic inhalation of organic dusts released during specific daily tasks could represent a major risk factor for development of these pathologies in dairy workers. Knowledge on size, nature and biological activity of such organic dusts remain however limited. OBJECTIVE: To compare size distribution, microbial composition and cellular effects of dusts liberated by the spreading of straw bedding in five French dairy farms located in Brittany. RESULTS: Mechanized distribution of straw bedding generated a cloud of inhalable dusts in the five dairy farms' barns. Thoracic particles having a 3-7.5um size constituted 58.9 68.3% of these dusts. Analyses of thoracic dusts by next generation sequencing showed that the microbial dust composition differed between the five French farms, although Actinobacteria, Bacteroidetes, Firmicutes and Proteobacteria represent more than 97.5% of the bacterial phyla detected in each sample. Several bacteria genera comprising of human pathogenic species, such as Pseudomonas, Staphylococcus, Thermoactinomyces or Saccharopolyspora were identified. Cladosporium and Alternaria fungal genera, which are potent environmental determinants of respiratory symptoms, were detected in dusts collected in the five farms and their levels reached 15.5-51.1% and 9-24.7% of assignable fungal sequences in each sample, respectively. Finally, all dust samples significantly and strongly increased the expression of the pro-inflammatory TNF-alpha, IL 1beta, IL-6 and IL-8 cytokines at both mRNA and protein levels in human monocyte derived macrophages. Their effects were dose-dependent and detectable from 1ug/ml. The intensity of the macrophage responses however differed according to the samples. CONCLUSIONS: Our results strengthen the hypothesis that organic dusts released during the distribution of straw bedding are mainly constituted of thoracic particles which are small enough to deposit on lower bronchial epithelium of dairy farmers and induce inflammation. PMID- 28735231 TI - Exploring the association between heat and mortality in Switzerland between 1995 and 2013. AB - Designing effective public health strategies to prevent adverse health effect of hot weather is crucial in the context of global warming. In Switzerland, the 2003 heat have caused an estimated 7% increase in all-cause mortality. As a consequence, the Swiss Federal Office of Public Health developed an information campaign to raise public awareness on heat threats. For a better understanding on how hot weather affects daily mortality in Switzerland, we assessed the effect of heat on daily mortality in eight Swiss cities and population subgroups from 1995 to 2013 using different temperature metrics (daily mean (Tmean), maximum (Tmax), minimum (Tmin) and maximum apparent temperature (Tappmax)), and aimed to evaluate variations of the heat effect after 2003 (1995-2002 versus 2004-2013). We applied conditional quasi-Poisson regression models with non-linear distributed lag functions to estimate temperature-mortality associations over all cities (1995 2013) and separately for two time periods (1995-2002, 2004-2013). Relative risks (RR) of daily mortality were estimated for increases in temperature from the median to the 98th percentile of the warm season temperature distribution. Over the whole time period, significant temperature-mortality relationships were found for all temperature indicators (RR (95% confidence interval): Tappmax: 1.12 (1.05; 1.18); Tmax: 1.15 (1.08-1.22); Tmean: 1.16 (1.09-1.23); Tmin 1.23 (1.15 1.32)). Mortality risks were higher at the beginning of the summer, especially for Tmin. In the more recent time period, we observed a non-significant reduction in the effect of high temperatures on mortality, with the age group > 74 years remaining the population at highest risk. High temperatures continue to be a considerable risk factor for human health in Switzerland after 2003. More effective public health measures targeting the elderly should be promoted with increased attention to the first heat events in summer and considering both high day-time and night-time temperatures. PMID- 28735232 TI - Immunoglobulin-G4 related mastitis: A case report. AB - INTRODUCTION: IgG4-related mastitis (IgG4-RM) is exceedingly rare with only ten cases reported in the literature to date. Organs that are affected with IgG4 related disease (IgG4-RD) all share the same histopathological hallmarks consisting of dense lymphocytic infiltration, storiform fibrosis and obliterative phlebitis. PRESENTATION OF CASE: This case report highlights a case of IgG4-RM found incidentally in a 52-year-old woman during a routine breast screen and it explores the current literature about IgG4-RM and IgG4-RD. DISCUSSION: IgG4-RM and IgG4-RD, in general, is a new entity in the field of medicine and its aetiology is not well understood. In the literature, IgG4-RM often presents as a painless palpable breast lump in isolation or with other systemic manifestations. IgG4-RM is considered benign and has excellent prognosis post-conservative treatment with steroid or surgical excision. CONCLUSION: IgG4-RM is diagnosed exclusively on histological analysis. It is hard to distinguish IgG4-RD from malignant breast lesions purely on clinical examination and imaging studies. Increasing awareness of this condition among clinicians will assist them in managing patients better. Extensive whole body imaging is not recommended unless symptomatic. PMID- 28735233 TI - A model system to mimic environmentally active surface film roughness and hydrophobicity. AB - This work presents the development and initial assessment of a laboratory platform to allow quantitative studies on model urban films. The platform consists of stearic acid and eicosane mixtures that are solution deposited from hexanes onto smooth, solid substrates. We show that this model has distinctive capabilities to better mimic a naturally occurring film's morphology and hydrophobicity, two important parameters that have not previously been incorporated into model film systems. The physical and chemical properties of the model films are assessed using a variety of analytical instruments. The film thickness and roughness are probed via atomic force microscopy while the film composition, wettability, and water uptake are analyzed by Fourier transform infrared spectroscopy, contact angle goniometry, and quartz crystal microbalance, respectively. Simulated environmental maturation is achieved by exposing the film to regulated amounts of UV/ozone. Ultimately, oxidation of the film is monitored by the analytical techniques mentioned above and proceeds as expected to produce a utile model film system. Including variable roughness and tunable surface coverage results in several key advantages over prior model systems, and will more accurately represent native urban film behavior. PMID- 28735234 TI - Nano-cerium oxide functionalized biochar for phosphate retention: preparation, optimization and rice paddy application. AB - In this study, nano-cerium oxide functionalized maize straw biochar (Ce-MSB) was prepared and utilized to remove P from agricultural wastewater. Response Surface Model was applied to optimize the operating conditions. Moreover, Ce-MSB was applied to actual rice paddy column for the first time. Response Surface Model (RSM) showed higher materials ratio had positive effect on PO43- adsorption capacity, while higher pyrolysis temperature had negative effect. The maximum adsorption capacity of Ce-MSB for PO43- was 78 mg g-1, implying that Ce-MSB was an effective functionalized adsorbent for P removal. Paddy soil column experiment showed that application of Ce-MSB decreased total phosphorus concentration of surface water by 27.33% and increased total phosphors (TP) content of top soil by 7.22%. Further, Ce-MSB tends to increase rice plant height and leaf area. Therefore, Ce-MSB can be used as a promising functionalized biochar to reduce the risk of phosphorus loss from paddy field surface running water. PMID- 28735235 TI - Linear solvation energy relationship to predict the adsorption of aromatic contaminants on graphene oxide. AB - In this study, adsorption capability of aromatic contaminants on graphene oxide (GO) was predicted using linear solvation energy relationship (LSER) model for the first time. Adsorption data of 44 aromatic compounds collected from literature and our experimental results were used to establish LSER models with multiple linear regression. High value of R2 (0.919), strong robustness (QLoo2 = 0.862), and desirable predictability (Qext2 = 0.834) demonstrated the model worked well for predicting the adsorption of small aromatic contaminants (descriptor V<3.099) on GO. The adsorption process was governed by the ability of cavity formation and dispersion forces captured by vV and hydrogen-bond interactions captured by bB. Effect of equilibrium concentrations and properties of GO on the model were explored; and the results indicated that upon an increase of equilibrium concentration, the values of regression coefficients (a, b, v, e, and s) changed at different levels. The oxygen content normalization of logK0.001 decreased the value of b dramatically; however, no obvious changes of the model deduced by the surface area normalization of logK0.001 were witnessed. Overall, our study showed that LSER model provided a potential approach for exploring the adsorption of organic compounds on GO. PMID- 28735236 TI - Oxidation of Tris (2-chloroethyl) phosphate in aqueous solution by UV-activated peroxymonosulfate: Kinetics, water matrix effects, degradation products and reaction pathways. AB - The feasibility of UV-activated peroxymonosulfate (PMS) technology for the degradation of Tris (2-chloroethyl) phosphate (TCEP) in an aqueous solution was investigated in this study. The conditions of [PMS]0: [TCEP]0 = 20:1, T = 25 +/- 2 degrees C and pH = 5.5 +/- 0.5 cause a 94.6% removal of TCEP (1 mg L-1) after 30 min of Hg lamp irradiation. The effects of operating parameters (the oxidant doses, pH and presence of typical cations (Fe3+, Cu2+, Ni2+, NH4+), anions (Cl-, HCO3-, NO3-, HPO42-) and humic acid (HA)) were evaluated. It was found that an increase of the PMS dose and the presence of Fe3+ could accelerate the reaction, while the anions and HA inhibited the reaction. Meanwhile, TCEP removal in various water matrices was compared, and the order for TCEP removal was as follows: ultrapure water > tap water > synthetic water > secondary clarifier effluent > Jiuxiang river water. Twenty-two oxidation products were identified using an electrospray time-of-flight mass spectrometer, and the degradation pathways mainly involved radicals' addition and CO bond cleavage. Furthermore, ECOSAR analysis revealed that the intermediate products during the TCEP oxidation process were generally not harmful to three typical aquatic species. Hence, UV/PMS can be used as an efficient technology to treat TCEP-containing water and wastewaters. PMID- 28735237 TI - Effects of chronic exposure to cefadroxil and cefradine on Daphnia magna and Oryzias latipes. AB - Cefadroxil and cefradine have frequently been detected in surface waters, however toxicological studies in aquatic organisms have mostly been limited to acute lethal effects. In the present study, endocrine disruption caused by cefadroxil and cefradine, and its underlying mechanism were investigated by chronic exposure of Daphnia magna (21 d) and Oryzias latipes (120 d). In medaka fish, the effects on growth, mortality, and reproduction, as well as on the levels of hormones and genes related to the hypothalamic-pituitary-gonad (HPG) axis, were investigated after 120 d exposure. In D. magna, the chronic effects on growth were observed at the highest concentration of 83.0 mg L-1 cefadroxil and 80.8 mg L-1 cefradine. The growth of juvenile fish was significantly impaired by exposure to cefradine. Following exposure to cefadroxil and cefradine for 120 d, sex-dependent changes in E2 hormones were observed and their levels were supported by the regulation of genes along the HPG axis. We found that chronic exposure to cefadroxil and cefradine impaired growth and reproduction in a freshwater invertebrate and fish, and altered the levels of sex hormones and genes associated with the HPG axis in fish. PMID- 28735238 TI - The influence of heavy metals on toxicogenetic damage in a Brazilian tropical river. AB - Anthropogenic activities in tropical rivers favor the eutrophication process, which causes increased concentration of heavy metals. The presence and bioaccumulation of metals are directly related to the presence of genotoxic damage in aquatic organisms. Thus, we evaluated the presence of heavy metals (Fe, Zn, Cr, Cu and Al) and performed toxicogenetic tests in surface (S) and bottom (B) of water samples of the Poti river (Piaui/Brazil). Cytotoxicity and genotoxicity tests were performed in Allium cepa, and micronucleus (MN) and comet assay were performed in Oreochromis niloticus. The chemical analysis showed concentrations above the limit for Cu, Cr, Fe and Al according to Brazilian laws, characterizing anthropogenic disturbance in this aquatic environment. Toxicogenetic analysis presented significant cytotoxic, mutagenic and genotoxic effects in different exposure times and water layers (S and B), especially alterations in mitotic spindle defects, MN formations, nuclear bud and DNA strand breaks. Correlations between Fe and cytotoxicity, and Al and mutagenicity were statistically significant and point out to the participation of heavy metals in genotoxic damage. Therefore, Poti river water samples presented toxicogenetic effects on all bioindicators analyzed, which are most likely related to heavy metals pollution. PMID- 28735239 TI - Effects of a glyphosate-based herbicide in pejerrey Odontesthes humensis embryonic development. AB - Glyphosate-based herbicides (GBH) are the major pesticides used worldwide. Among them, the Roundup formulations are the most popular. Some aspects of GBH toxicity are well known, such as induction of oxidative stress. However, embryotoxicity is scarcely known. Therefore, the aim of the present study was to evaluate the effect of exposure to different Roundup Transorb R concentrations (0.36, 1.80, 3.62 and 5.43 mg glyphosate a.e./L) on Odontesthes humensis embryonic development. Embryos were sampled at three exposure times (48, 72 and 96 h). After 48 h, the stage of embryonic development and the number of somite pairs were analyzed; after 72 h, the percentage of pigmented embryos were evaluated and after 96 h, the eye diameter (ED) and the distance between eyes (DE) were measured. Mortality rates were daily calculated. Results show that Roundup exposure to all concentrations did not alter the endpoints evaluated at 48 and 72 h. On the other hand, exposure for 96 h to all concentrations induced a concentration-dependent reduction in ED and DE. Additionally, exposure to 5.43 mg a.e./L increased mortality. These findings indicate that Roundup has the potential to produce morphological alterations in fish embryos even at the lower and ecologically relevant concentration tested (0.36 mg a.e./L). This result corroborates the hypothesis that glyphosate alters the retinoic acid signaling pathway. Additionally, our findings indicate that exposure to high concentrations of Roundup (5.43 mg a.e./L) for 96 h causes high mortality rates of fish embryos. This is the first report of GBH embryotoxicity in an endemic fish of southern areas in South America. PMID- 28735241 TI - A new integrated approach to analyze bulk tank milk and raw milk filters for the presence of the E. coli serogroups frequently associated with VTEC status. AB - We optimized a combination of microbiological and molecular methods to quickly identify the presence of the O157 and the six non-O157 serogroups (O26, O45, O103, O111, O121 and O145) most frequently associated with VTEC status, at herd level. The lower detection limit of this methodology is 101CFU/ml for each of the serogroups tested. We tested 67 bulk tank milk (BTM) and raw milk filters (RMF) derived from dairy herds located in Lombardy and Trentino Alto Adige. We identified 3 positive samples and 20 positive samples out of 67 respectively in the BTM and RMF. Interestingly, several samples showed positivity for more than one serogroups at the same time. We also identified the presence of E. coli O45 and O121 for the first time in raw milk and raw milk filters. Once screened the seven serogroups of interest in our samples, we evaluated the real pathogenicity of our positive, non-O157 samples through two parallel molecular biology methods: virulence gene research by PCR, and HRMA and sequencing. The most frequently isolated serogroups in milk were O157 (2.64%), O103 (2.11%), and O145 (1.06%), while in RMF the frequencies were, respectively 14.92%, 4.48%, and 2.98%. Moreover, this is the first published report in Italy of positive recovery of O45 and O121 serogroups in milk and milk filters. The new diagnostic approach proposed investigate the presence of the O157 and big six non-O157 serogroups at farm level and not to identify VTEC hazard only once the product is processed and/or is ready to be consumed. PMID- 28735240 TI - Therapeutic effects of L-Cysteine in newborn mice subjected to hypoxia-ischemia brain injury via the CBS/H2S system: Role of oxidative stress and endoplasmic reticulum stress. AB - Neonatal hypoxic-ischemic (HI) injury is a major cause of neonatal death and neurological dysfunction. H2S has been shown to protect against hypoxia-induced injury and apoptosis of neurons. L-Cysteine is catalyzed by cystathionine-beta synthase (CBS) in the brain and sequentially produces endogenous H2S. The present study was designed to investigate whether L-Cysteine could attenuate the acute brain injury and improve neurobehavioral outcomes following HI brain injury in neonatal mice by releasing endogenous H2S. L-Cysteine treatment significantly attenuated brain edema and decreased infarct volume and neuronal cell death, as shown by a decrease in the Bax/Bcl-2 ratio, suppression of caspase-3 activation, and reduced phosphorylation of Akt and ERK at 72h after HI. Additionally, L Cysteine substantially up-regulated NF-E2-related factor 2 and heme oxygenase-1 expression. L-Cysteine also decreased endoplasmic reticulum (ER) stress associated pro-apoptotic protein expression. Furthermore, L-Cysteine had long term effects by protecting against the loss of ipsilateral brain tissue and improving neurobehavioral outcomes. Importantly, pre-treatment with a CBS inhibitor significantly attenuated the neuroprotection of L-Cysteine on HI insult. Thus, L-Cysteine exerts neuroprotection against HI-induced injury in neonates via the CBS/H2S pathway, mediated in part by anti-apoptotic effects and reduced oxidative stress and ER stress. Thus, L-Cysteine may be a promising treatment for HI. PMID- 28735242 TI - Transcriptomic analysis of the larva Taenia multiceps. AB - Taenia multiceps is an adult worm affiliated to Taeniidae family, Platyhelminthes phylum. The larvae of the parasite (Coenurus cerebralis) parasitic in the brain and spinal cord in domestic and wild ruminants or humans can led to a fatal central nervous system (CNS) disease. The aims of the present study were to define the transcriptome profiles of the larvae of T. multiceps by RNA-Seq approach, and to generate large functional gene datasets that could be used to predict the key molecular pathways linked to this cestode. Our results generated a total of 39,094,890 clean reads that were assembled from the sequence data in 90,833 contigs. Briefly, 70,253 unigenes with a mean length of 1492bp were formed. Based on a sequence similarity search against the databases (NR, Swissport, GO, COG, KEGG) using BLASTX with an E-value cutoff of 10-5, 40,465 of unigenes were identified as coding sequences (CDS) and 3261 were scanned by ESTScan. The present study carried out the transcriptome of the larval stage of T. multiceps, which provides a solid foundation for further studies in molecular biology and biochemistry as well as identification of candidate genes used in diagnosis and vaccine development. PMID- 28735243 TI - Interactions between Pteris vittata L. genotypes and a polycyclic aromatic hydrocarbon (PAH)-degrading bacterium (Alcaligenes sp.) in arsenic uptake and PAH dissipation. AB - The effects of two Pteris vittata L. accessions and a polycyclic aromatic hydrocarbon (PAH)-degrading bacterium (Alcaligenes sp.) on arsenic (As) uptake and phenanthrene dissipation were studied. The Alcaligenes sp. survived in the rhizosphere and improved soil As bioavailability with co-exposure. However, bacterial inoculation altered Pteris vittata L. stress tolerance, and substantially affected the As distribution in the rhizosphere of the two P. vittata accessions. Bacterial inoculation was beneficial to protect the Guangxi accession against the toxic effects, and significantly increased plant As and phenanthrene removal ratios by 27.8% and 2.89%, respectively. In contrast, As removal was reduced by 29.8% in the Hunan accession, when compared with corresponding non-inoculated treatments. We conclude that plant genotype selection is critically important for successful microorganism-assisted phytoremediation of soil co-contaminated with As and PAHs, and appropriate genotype selection may enhance remediation efficiency. PMID- 28735244 TI - Legacy and novel brominated flame retardants in interior car dust - Implications for human exposure. AB - Brominated flame retardants (BFRs) are organobromine compounds with an inhibitory effect on combustion chemistry tending to reduce the flammability of products. Concerns about health effects and environmental threats have led to phase-out or restrictions in the use of Penta-, Octa- and Deca-BDE technical formulations, increasing the demand for Novel BFRs (NBFRs) as replacements for the banned formulations. This study examined the occurrence of legacy and NBFRs in the dust from the interior of private cars in Thessaloniki, Greece, aged from 1 to 19 years with variable origin and characteristics. The determinants included 20 Polybrominated Diphenyl Ethers (PBDEs) (Di-to Deca-BDEs), four NBFRs such as Decabromodiphenylethane (DBDPE), 1,2-bis(2,4,6-tribromophenoxy)ethane (BTBPE), 2 ethylhexyl-2,3,4,5-tetrabromobenzoate (TBB), and bis(2-ethylhexyl)-3,4,5,6 tetrabromophthalate (TBPH), three isomers of hexabromocyclododecane (HBCD), and tetrabromobisphenol A (TBBPA). The concentrations of ?20PBDE ranged from 132 to 54,666 ng g-1 being dominated by BDE-209. The concentrations of ?4NBFRs ranged from 48 to 7626 ng g-1 and were dominated by DBDPE, the major substitute of BDE 209. HBCDs ranged between <5 and 1745 ng g-1, with alpha-HBCD being the most prevalent isomer Finally, the concentrations of TBBPA varied from <10 to 1064 ng g-1. The concentration levels and composition profiles of BFRs were investigated in relation to the characteristics of cars, such as year of manufacture, country of origin, and interior equipment (type of car seats, electronic and electrical components, ventilation, etc.). The average daily intakes of selected BFRs (BDE 47, BDE-99, BDE-153, BDE-209, TBB, BTBPE, TBPH, DBDPE, HBCDs and TBBPA) via ingestion and dermal absorption were estimated for adults and toddlers. The potential health risk due to BFRs was found to be several orders of magnitude lower than their corresponding reference dose (RfD) values. PMID- 28735245 TI - Association of 16 priority polycyclic aromatic hydrocarbons with humic acid and humin fractions in a peat soil and implications for their long-term retention. AB - To elucidate the environmental fate of polycyclic aromatic hydrocarbons (PAHs) once released into soil, sixteen humic acids (HAs) and one humin (HM) fractions were sequentially extracted from a peat soil, and sixteen priority PAHs in these humic substances (HSs) were analyzed. It was found that the total concentration of 16 PAHs (?16PAHs) increased evidently from HA1 to HA16, and then dramatically reached the highest value in HM. The trend of ?16PAHs in HAs relates to surface carbon and C-H/C-C contents, the bulk aliphatic carbon content and aliphaticity, as well as the condensation enhancement of carbon domains, which were derived from elemental composition, XPS, 13C NMR, as well as thermal analyses. HM was identified to be the dominant sink of 16 PAHs retention in soil, due to its aliphatic carbon-rich chemical composition and the highly condensed physical makeup of its carbon domains. This study highlights the joint roles of the physical and chemical properties of HSs in retention of PAHs in soil and the associated mechanisms; the results are of significance for PAH-polluted soil risk assessment and remediation. PMID- 28735247 TI - Can nurses rise to the public health challenge? How a novel solution in nurse education can address this contemporary question. AB - This paper raises the problem of how improvements in health outcomes, a key component in many governments' strategies, can be achieved. The work highlights a novel undergraduate educational approach which offers solutions to public health challenges within nursing. Against the backdrop of one UK university institution it discusses approaches that can guide nursing students towards a deeper understanding and engagement within the principles of public health. It then proposes how nurses can use their learning to become leaders of health improvement. PMID- 28735246 TI - Nurses' reports of staffing adequacy and surgical site infections: A cross sectional multi-centre study. AB - BACKGROUND: It is indicated that healthcare personnel's perceptions of the work environment may reflect the clinical outcomes for the patients they care for. However, the body of evidence is inconsistent when it comes to the association between work environment and surgical site infection. OBJECTIVES: The aim of this study is to examine the associations between nurse-reported characteristics of the work environment and incidence of surgical site infections after total hip arthroplasty. DESIGN AND SETTINGS: This is a cross-sectional multicentre study conducted in 16 Norwegian hospitals. PARTICIPANTS: Clinical outcomes for 2885 patients >18years that underwent total hip arthroplasty are combined with work environment descriptions from 320 nurses. MATERIALS AND METHODS: We combine data about surgical site infections from The Norwegian Surveillance System for Antibiotic Consumption and Healthcare-Associated Infections and hospital characteristics such as overall survival probability (from administrative patient data) and nurses' reports of characteristics of the work environment (from a multicentre survey among nurses in Norwegian hospitals). Stepwise mixed-effects logistic regression model was performed to examine the associations between characteristics of the work environment and surgical site infections. RESULTS: The incidence of surgical site infection among 2885 patients undergoing total hip arthroplasty in 16 Norwegian hospitals was 2.6%. Older age, elective procedures and high scores for staffing adequacy were associated with risk for surgical site infection. The association between high scores for adequate staffing and low risk for surgical site infections was present for patients that were admitted for an elective procedure, but not for patients admitted for a non-elective procedure. CONCLUSION: Our results show that the risk of surgical site infections after elective total hip arthroplasty was lower in hospitals where nurses assessed staffing as adequate. Our findings add to the existing literature that examines the linkage between work environment and clinical outcomes. PMID- 28735248 TI - Digital speakers in the digital era. PMID- 28735249 TI - To defer, or not to defer, that is the question. PMID- 28735250 TI - Registries, reality and complete revascularisation. PMID- 28735251 TI - Drug-coated balloons and in-stent restenosis: a new tale of an old story. PMID- 28735253 TI - How should I treat a patient with a symptomatic and severe low-flow low-gradient aortic stenosis and an incidental abdominal aortic aneurysm? PMID- 28735254 TI - How should I treat an Edwards SAPIEN 3 aortic valve embolisation during a transaortic transcatheter aortic valve implantation? PMID- 28735255 TI - Ascending aortic diameter and metabolic syndrome in Korean men. AB - This study aimed to evaluate the association of ascending aortic diameter (AAD) measured by low-dose chest CT (LDCT) and metabolic syndrome (MS) in Korean men. AAD was measured with LDCT in 1046 healthy Korean men (mean age 50.7+/-9.7 years, range 28 to 69 years) participating in medical health check-up in a university health promotion center. AAD was defined as the longest length measured from the left main coronary ostium to the level of the right pulmonary artery in the axial plane in LDCT. The association between AAD and MS was examined using logistic regression. The mean of AAD was significantly higher in cases with MS (37.2+/-4.2 mm) compared with those without MS (35.1+/-4.3 mm) (p<0.001). Logistic regression with AAD showed that ORs and 95% CI of MS in Q2 (1.72, 95% CI 1.23 to 2.53), Q3 (2.59, 95% CI 1.85 to 5.81) and Q4 (4.71, 95% CI 1.63 to 8.79) were significantly higher compared with Q1 (the lowest quartile). In variable (age, body surface area, total cholesterol, alanine aminotransferase, gamma-glutamyl transferase, smoking, alcohol intake and exercise) adjusted multiple linear regression analysis, Q4 (the highest quartile of AAD) was significantly associated with MS compared with Q1 (OR 4.52, 95% CI 1.67 to 9.87). In conclusion, AAD measured by LDCT is significantly associated with the prevalence of MS in Korean men. PMID- 28735256 TI - Comparison of multimodal intra-arterial treatment versus intravenous thrombolysis for hypertensive patients with severe large vessel cerebral infarction. AB - Since intravenous thrombolysis (IVT) is often associated with poor outcomes in hypertensive patients with severe acute cerebral infarction (ACI) due to occlusions of the internal carotid, basilar, or proximal middle cerebral artery, we evaluated whether multimodal intra-arterial treatment (IAT) might improve functional outcomes in this patient population. We retrospectively reviewed the charts of eligible patients who underwent multimodal IAT including intra-arterial thrombolysis, mechanical thrombectomy, balloon and/or stent angioplasty (IAT group) or IVT alone (IVT group). Outcomes included the revascularization rate 24 hours postprocedure, the frequency of survival at 7, 90, and 180 days postonset, and a measure of functional outcomes using the modified Rankin Scale (mRS). The IAT group included 62 patients and the IVT group included 31 patients. Multimodal IAT increased the revascularization rate at 24 hours (p<0.001) and the frequency of survival and functional independence (mRS <=2) at 7 days (p<0.001 and p=0.018, respectively), 90 days (both p<0.001), and 180 days (both p<0.001). Independent predictors of longer survival were treatment with multimodal IAT (HR 0.1; 95% CI 0.0 to 0.4; p<0.001) and revascularization (HR 0.1; 95% CI 0.0 to 0.4; p<0.001), whereas a longer duration from onset to treatment was a risk factor for death (HR 1.4; 95% CI 1.2 to 1.8; p<0.001). There was no significant between-group difference for symptomatic hemorrhagic transformation. This study found that for patients with severe hypertensive ACI with large vessel occlusions, multimodal IAT improved the outcomes, including early revascularization, survival, and functional outcome. PMID- 28735257 TI - Prognostic factors of overall survival and cancer-specific survival in patients with resected early-stage rectal adenocarcinoma: a SEER-based study. AB - The benefits of radiotherapy for colorectal cancer are well documented, but the impact of adjuvant radiotherapy on early-stage rectal adenocarcinoma remains unclear. This study aimed to identify predictors of overall survival (OS) and cancer-specific survival (CSS) in patients with stage II rectal adenocarcinoma treated with preoperative or postoperative radiation therapy. Patients with early stage rectal adenocarcinoma in the postoperative state were identified using the Surveillance, Epidemiology, and End Results database. The primary endpoints were OS and overall CSS. Stage IIA patients without radiotherapy had significantly lower OS and CSS compared with those who received radiation before or after surgery. Stage IIB patients with radiotherapy before surgery had significantly higher OS and CSS compared with patients in the postoperative or no radiotherapy groups. Patients with signet ring cell carcinoma had the poorest OS among all the groups. Multivariable analysis showed that ethnicity (HR, 0.388, p=0.006) and radiation before surgery (HR, 0.614, p=0.006) were favorable prognostic factors for OS, while age (HR, 1.064, p<0.001), race (HR, 1.599, p=0.041), stage IIB (HR, 3.011, p=0.011), and more than one tumor deposit (TD) (HR, 2.300, p=0.001) were unfavorable prognostic factors for OS. Old age (HR, 1.047, p<0.00 L), stage IIB (HR, 8.619, p=0.005), circumferential resection margin between 0.1 mm and 10 mm (HR, 1.529, p=0.039), and more than one TD (HR, 2.688, p=0.001) were unfavorable prognostic factors for CSS. This population-based study identified predictors of OS and CSS in patients with early-stage resected rectal adenocarcinoma, which may help to guide future management of this patient population. PMID- 28735258 TI - Risk of rehospitalisation and death for vulnerable New Zealand children. AB - OBJECTIVES: There is considerable need to improve the effectiveness of healthcare to reduce morbidity and mortality. Child hospitalisations are influenced by determinants of health, including the home environment. Our aims were: (1) To investigate whether children hospitalised with potentially avoidable conditions thought to be associated with the home have an increased risk of rehospitalisation and death, (2) To investigate whether children hospitalised with particular subgroups of potentially avoidable conditions have an increased risk of rehospitalisation and death, (3) To assess the usefulness of these subgroups for identifying at-risk children. DESIGN: We used four existing groups of potentially avoidable conditions developed based on expert opinion: 1. the potentially avoidable hospitalisations (PAH) group, associated with social/environmental conditions, 2. the potentially avoidable hospitalisations attributable (at least in part) to the home environment (PAHHE) group, 3. the crowding group, and 4. the Ministry of Health (MoH) group. We analysed national New Zealand hospital discharge data (2000-2014). Rehospitalisation and death were described using Kaplan-Meier curves. Group effectiveness for identifying at-risk children was assessed using Cox proportional hazard models with children hospitalised for non-PAH conditions as comparison. RESULTS: In total, 1425085 hospital admissions occurred, for 683115 unique children. Rehospitalisation was relatively common (71.0%). Death was rare (0.6%). All groups performed moderately well identifying at-risk children. Children with PAH have increased risk of rehospitalisation (adjusted HR (aHR):2.30-3.60) and death (aHR:3.07-10.44). PAH group had highest sensitivity (75.1%). The MoH group has the highest positive predictive value (rehospitalisation: 86.2%, death: 2.5%). CONCLUSIONS: Children in the MoH group are very likely to benefit from housing interventions. Rehospitalisation and early mortality are useful assessment measures. Rehospitalisation exerts a considerable burden, and child deaths are catastrophic. PMID- 28735259 TI - Observational study on the palatability and tolerability of oral prednisolone and oral dexamethasone in children in Saudi Arabia and the UK. AB - BACKGROUND: Short-course oral corticosteroids are routinely used to treat acute asthma and croup. We evaluated their tolerability and palatability in Saudi Arabian (SA) and UK children. METHODS: Prospective observational/interview study (3 months in each country). Palatability was evaluated using a 5-point facial Hedonicscale and tolerability by direct questioning of patient/parents. RESULTS: In SA, of 122 patients (2-10 years) recruited, 52 received prednisolone base tablets, 37 prednisolone sodium phosphate syrup and 33 received dexamethasone elixir. In the UK, of 133 patients (2-16 years), 38 received prednisolone base tablets (mainly crushed and dispersed), 42 prednisolone sodium phosphate soluble tablets and 53 received dexamethasone sodium phosphate oral solution.In both countries, dexamethasone had the highest palatability scores (SA mean: 1.97; UK mean: 3) and prednisolone base tablets had the lowest (SA mean: 1.12; UK mean: 1.39). Palatability scores improved for all formulations of prednisolone with each subsequent daily dose.In SA, prednisolone base tablets were associated with more nausea (24vs7 patients) and vomiting (5vs0 patients) than sodium phosphate syrup (p=0.008 and p=0.073, respectively). In the UK, vomiting occurred more frequently with prednisolone base (8 patients) than sodium phosphate soluble tablets (2 patients) (p=0.041).In both centres, dexamethasone was associated with less side effects. Vomiting (1vs0 patients), nausea (7vs3 patients) and abdominal pain (10vs8 patients) occurred more with dexamethasone sodium phosphate solution than dexamethasone elixir. CONCLUSIONS: Dexamethasone sodium phosphate solution was the most palatable preparation. Prednisolone base tablets were rated least palatable and were least well tolerated. Palatability scores improved with each dose taken. PMID- 28735261 TI - Protracted bacterial bronchitis: a common problem with no agreed solution. PMID- 28735260 TI - Aetiological investigations in early developmental impairment: are they worth it? AB - OBJECTIVE: To study the frequency a diagnosis is made in children with early developmental impairment (EDI), and the contribution made to diagnosis by specific investigations. DESIGN: Retrospective case note review. SETTING: Community, neurodisability and neurology department at a UK tertiary centre. PARTICIPANTS: Children referred to determine the aetiology of EDI where a cause was not evident on history and examination. Participants were divided into two groups: EDI and no additional features (EDI-) and EDI with additional features (EDI+). MAIN OUTCOME MEASURES: The frequency a cause was found for the child's EDI and which tests contributed to a diagnosis. RESULTS: 699 participants, 68.8% boys, median age at investigation 2 years 8 months (range 3 months to 11 years 5 months). 61 (8.7%) of participants had no investigations, and children with EDI- were less likely to be investigated (chi2=12.5, p<0.05). A diagnosis was made in 166 children (23.7%) and was more frequent in EDI+ (EDI- 9.9%, EDI+ 27.3%, chi2=19.0; p<0.05). Full blood count, zinc protoporphyrin, renal or liver function, bone profile, biotinidase, creatine kinase or lead level revealed no diagnoses. The following investigations found causes for EDI: MRI (23.1%), microarray (11.5%), Fragile X (0.9%), plasma amino acids (1.2%), urine organic acids (0.9%) and thyroid function tests (0.5%). CONCLUSIONS: The majority of 'screening' investigations for EDI do not contribute to a diagnosis, highlighting an area of cost saving for the NHS and reduced burden for patients and families. We propose a streamlined guideline for the investigation of EDI based on our data. PMID- 28735262 TI - Question 1: Effectiveness of melatonin in treating sleep problems in children with intellectual disability. PMID- 28735263 TI - Themes emerging from State of Child Health: UK and Australia. PMID- 28735264 TI - An unusual unilateral breast enlargement in a prepubertal girl. PMID- 28735265 TI - Filaggrin and childhood eczema. PMID- 28735266 TI - A curious case of PICC line knot formation. PMID- 28735267 TI - Acral self-healing collodion baby. PMID- 28735268 TI - Early surgery and neurodevelopmental outcomes of children born extremely preterm. AB - OBJECTIVES: To (1) compare the neurodevelopmental outcomes at 8 years of age of children born extremely preterm (EP) who underwent surgical procedures during the course of their initial hospital admission with those who did not and (2) compare the outcomes across eras, from 1991 to 2005. DESIGN: Prospective observational cohort studies conducted over three different eras (1991-1992, 1997 and 2005). Surviving EP children, who required surgical intervention during the primary hospitalisation, were assessed for general intelligence (IQ) and neurosensory status at 8 years of age. Major neurosensory disability comprised any of moderate/severe cerebral palsy, IQ less than -2 SD relative to term controls, blindness or deafness. RESULTS: Overall, 29% (161/546) of survivors had surgery during the newborn period, with similar rates in each era. Follow-up rates at 8 years were high (91%; 499/546), and 17% (86/499) of survivors assessed had a major neurosensory disability. Rates of major neurosensory disability were substantially higher in the surgical group (33%; 52/158) compared with those who did not have surgery (10%; 34/341) (OR 4.28, 95% CI 2.61 to 7.03). Rates of disability in the surgical group did not improve over time. After adjustment for relevant confounders, no specific surgical procedure was associated with increased risk of disability. IMPLICATIONS AND RELEVANCE: Major neurosensory disability at 8 years was higher in children born EP who underwent surgery during their initial hospital admission compared with those who did not. The rates of major neurosensory disability in the surgical cohort are not improving over time. PMID- 28735269 TI - Patient-family agreement on values and preferences for life-sustaining treatment: results of a multicentre observational study. AB - OBJECTIVES: To quantify agreement between patients and their family members on their own values and preferences for use or non-use of life-sustaining treatments for the patient. METHODS: Hospitalised patients aged 55 years or older with advanced pulmonary, cardiac, liver disease or metastatic cancer or aged 80 years or older from medical wards at 16 Canadian hospitals and their family members completed a questionnaire including eight items about values related to life sustaining treatment and a question about preferences for life-sustaining treatments. RESULTS: We recruited a total of 313 patient-family member dyads. Crude agreement between patients and family members about values related to life sustaining treatment was 42% across all eight items but varied widely: 20% when asking how important it was for the patient to respect the wishes of family members regarding their care; 72% when asking how important it was for the patient to be kept comfortable and suffer as little as possible. Crude agreement on preferences for life-sustaining treatment was 91% (kappa 0.60; 95%CI 0.45 to 0.75) when looking at preferences for cardiopulmonary resuscitation (CPR) versus no CPR but fell to 56% when including all five response options with varying degrees of resuscitative, medical or comfort options (kappa 0.39; 95%CI 0.31 to 0.47). CONCLUSIONS: There is appreciable disagreement between seriously ill hospitalised patients and family members in their values and preferences for life sustaining treatment. Strategies are needed to improve the quality of advance care planning, so that surrogates are better able to honour patient's wishes at the end of life. PMID- 28735270 TI - Subcutaneous levetiracetam for the management of seizures at the end of life. AB - OBJECTIVES: To report the results of a combined case series analysis of subcutaneous levetiracetam (Keppra) for the management of seizures in palliative care patients. METHODS: A comprehensive literature review on the use of subcutaneous levetiracetam was performed, and these data were combined with a prospective observational audit of its use in terminal care undertaken in a regional palliative care network. RESULTS: 7 papers were identified from the literature review-four case reports and three observational case series-reporting on a total of 53 cases where subcutaneous levetiracetam was administered.We report 20 further cases of subcutaneous levetiracetam administration from a prospective observational audit. Doses ranged from 250mg to 4000 mg daily. Oral to subcutaneous conversion ratios where stated were 1:1. Levetiracetam was reported as the sole administered antiepileptic drug (AED) in eight cases, and no seizures were reported until death in five cases. Five were switched back to enteral levetiracetam. In seven cases, levetiracetam was combined with AEDs to provide seizure control at the end of life. There was one report of a sterile abscess after 25 days of continuous subcutaneous administration. CONCLUSIONS: Combined analysis of 73 reported cases of subcutaneous levetiracetam suggests this treatment may have a role in the management of seizures at the end of life. However, randomised controlled trials are urgently needed to establish the efficacy and tolerability of subcutaneous levetiracetam administration. If proven to be safe and effective, subcutaneous levetiracetam offers the potential to prevent and treat seizures without causing unnecessary sedation at the end of life. PMID- 28735271 TI - A collaborative approach to facilitate professionals to support the breathless patient. AB - OBJECTIVES: Breathlessness is a major problem for people in their last weeks of life. Breathlessness is considered to be multidimensional with physical, psychological, emotional, social and spiritual factors all playing a part. It has been recognised that specific training to health professionals is beneficial in order to improve the care for patients with breathlessness.Breathlessness courses have tended to focus on senior nurses. A new flexible and collaborative training course was designed to include a wider range of nurses and other health professionals in hospital, hospice, primary care and community settings. The aim of the 'Practical Skills to Support the Breathless Patient' programme was to make patients and carers feel better supported in their breathlessness, for health professionals to develop confidence and skills in using proven interventions, and to adopt a flexible educational design that could be adapted to different contexts. METHODS: The course is learner-centred and teaching methods encourage interaction and participation via a mix of lectures and discussions with practical skills-focused, experiential workshops in smaller groups. Case study work was included to integrate learning with participants' practice environment. Evaluation is built in during the course, so adaptations can be made throughout to respond to changing learner needs. RESULTS: Participants reported increased confidence in terms of knowledge and applying this within everyday practice. The theory-practice dynamic worked well within each participant' specific work context in particular through the case study approach. CONCLUSIONS: The course developed a number of innovative approaches, such as multi-disciplinary learning groups, regular feedback loops, reflexive learning about putting theory into practice and long-term follow-up. Combining these elements increases professionals' confidence and sustains new clinical practice. PMID- 28735272 TI - Perceived nicotine content of reduced nicotine content cigarettes is a correlate of perceived health risks. AB - BACKGROUND: Reducing cigarette nicotine content may reduce smoking. Studies suggest that smokers believe that nicotine plays a role in smoking-related morbidity. This may lead smokers to assume that reduced nicotine means reduced risk, and attenuate potential positive effects on smoking behaviour. METHODS: Data came from a multisite randomised trial in which smokers were assigned to use cigarettes varying in nicotine content for 6 weeks. We evaluated associations between perceived and actual nicotine content with perceived health risks using linear regression, and associations between perceived nicotine content and perceived health risks with smoking outcomes using linear and logistic regression. FINDINGS: Perceived-not actual-nicotine content was associated with perceived health risks; compared with those perceiving very low nicotine, individuals who perceived low (beta=0.72, 95% CI 0.26 to 1.17), moderate (beta=1.02, 95% CI 0.51 to 1.53) or high/very high nicotine (beta=1.66, 95% CI 0.87 to 2.44) perceived greater health risks. Nevertheless, individuals perceiving low (OR=0.48, 95% CI 0.32 to 0.71) or moderate nicotine (OR=0.42, 95% CI 0.27 to 0.66) were less likely than those perceiving very low nicotine to report that they would quit within 1 year if only investigational cigarettes were available. Lower perceived risk of developing other cancers and heart disease was also associated with fewer cigarettes/day at week 6. CONCLUSIONS: Although the perception of reduced nicotine is associated with a reduction in perceived harm, it may not attenuate the anticipated beneficial effects on smoking behaviour. These findings have implications for potential product standards targeting nicotine and highlight the need to clarify the persistent harms of reduced nicotine combusted tobacco products. PMID- 28735274 TI - Automated dripping devices for vapers: RDTAs, bottomfeeders, squonk mods and dripboxes. PMID- 28735273 TI - Relationship between trying an electronic cigarette and subsequent cigarette experimentation in Scottish adolescents: a cohort study. AB - BACKGROUND: This study examines whether young never smokers in Scotland, UK, who have tried an e-cigarette are more likely than those who have not, to try a cigarette during the following year. METHODS: Prospective cohort survey conducted in four high schools in Scotland, UK during February/March 2015 (n=3807) with follow-up 1 year later. All pupils (age 11-18) were surveyed. Response rates were high in both years (87% in 2015) and 2680/3807 (70.4%) of the original cohort completed the follow-up survey. Analysis was restricted to baseline 'never smokers' (n=3001/3807), 2125 of whom were available to follow-up (70.8%). RESULTS: At baseline, 183 of 2125 (8.6%) never smokers had tried an e-cigarette and 1942 had not. Of the young people who had not tried an e-cigarette at baseline, 249 (12.8%) went on to try smoking a cigarette by follow-up. This compares with 74 (40.4%) of those who had tried an e-cigarette at baseline. This effect remained significant in a logistic regression model adjusted for smoking susceptibility, having friends who smoke, family members' smoking status, age, sex, family affluence score, ethnic group and school (adjusted OR 2.42 (95% CI 1.63 to 3.60)). There was a significant interaction between e-cigarette use and smoking susceptibility and between e-cigarette use and smoking within the friendship group. CONCLUSIONS: Young never smokers are more likely to experiment with cigarettes if they have tried an e-cigarette. Causality cannot be inferred, but continued close monitoring of e-cigarette use in young people is warranted. PMID- 28735275 TI - Tobacco price boards as a promotional strategy-a longitudinal observational study in Australian retailers. AB - BACKGROUND: Price boards in tobacco retailers are one of the few forms of tobacco promotion remaining in Australia. This study aimed to examine how these boards were used to promote products over a period of rapidly rising taxes. METHODS: Observations were made in a panel of 350 stores in Melbourne, Australia, in November of 2013 (just before) and in 2014 and 2015 (after 12.5% increases in tobacco duty). Fieldworkers unobtrusively noted the presence and characteristics of price boards, and the brand name, size and price of the product at the top of each board. RESULTS: Price boards were common in all store types apart from newsagent/lottery agents. The characteristics of the top-listed product changed notably over time: premium brands accounted for 66% of top-listed products in 2013, significantly declining to 43% in 2015, while packs of 20 cigarettes increased in prominence from 32% to 45%. The prevalence of packs of 20 cigarettes in budget market segments tripled from 2013 (13%) and 2014 (11%) to 32% in 2015, with no change in the proportion of packs that were under $A20 from 2014 (37%) to 2015 (36%). The rate of increase in the average price of the top-listed pack correspondingly flattened from 2014 to 2015 compared with 2013-2014. CONCLUSIONS: Price boards promote tobacco products in ways that undermine the effectiveness of tax policy as a means of discouraging consumption. Communication to consumers about prices should be restricted to information sheets provided to adult smokers on request at the point of sale. PMID- 28735276 TI - Mental health literacy in primary care: Canadian Research and Education for the Advancement of Child Health (CanREACH). AB - The effectiveness of a continuing education programme in paediatric psychopharmacology designed for primary healthcare providers was objectively measured based on the assumption that training would lead to measurable changes in referral patterns and established clinical measures of referred patients. Using established, valid and reliable measures of clinical urgency embedded in to a regional healthcare system since 2002, the referrals to child and adolescent psychiatric services of physicians who participated in the training (n=99) were compared pretraining and post-training, and to non-participating/untrained referring physicians (n=7753) making referrals over the same time period. Referrals were analysed for evidence of change based on frequencies and measures of clinical urgency. Participants of the training programme also completed standardised baseline and outcome self-evaluations. Congruent with participants self-reported evaluative reports of improved knowledge and practice, analysis of referral frequency and the clinical urgency of referrals to paediatric psychiatric services over the study period indicated that trained physicians made more appropriate referrals (clinically more severe) and reduced referrals to emergency services. Quantitative clinical differences as completed by intake clinicians blind to referrals from the study group designations were observed within the trained physician group pretraining and post-training, and between the trained physician group and the unexposed physician group. The results illustrate a novel model for objectively measuring change among physicians based on training in paediatric mental health management. PMID- 28735277 TI - Join the editorial board. PMID- 28735278 TI - Longer screening intervals are recommended following a negative HPV test in primary cervical screening. PMID- 28735279 TI - Value of screening for and treating pre-diabetes is reduced by low test accuracy and indirect evidence of impact on patient important outcomes. PMID- 28735280 TI - Duration of maintenance therapy for ANCA-associated vasculitis: more questions than answers. PMID- 28735281 TI - Bout of the corner men and not the boxers? Contextual effects flex their muscles. PMID- 28735284 TI - Infographics: Injury prevention exercise programmes: what are the perceptions of programme deliverers in the academy football setting? PMID- 28735283 TI - Practical precursors to reconsidering objective for physical activity in physical education. PMID- 28735285 TI - Synthesising 'best evidence' in systematic reviews when randomised controlled trials are absent: three tips for authors to add value for clinician readers. PMID- 28735282 TI - A systematic review of criteria used to define recovery from sport-related concussion in youth athletes. AB - OBJECTIVE: The Concussion in Sport Group guidelines recommend a multifaceted approach to help clinicians make return to sport decisions. The purpose of this study was to identify the most common multifaceted measures used to define clinical recovery from sport-related concussion in young athletes (high school and/or college level) and to summarise existing knowledge of criteria used to make return to sport decisions. DESIGN: Systematic review. DATA SOURCES: The PubMed (MEDLINE), SPORTDiscus and Embase electronic databases were searched from 1 January 2000 to 1 March 2017 by three independent reviewers. ELIGIBILITY CRITERIA: Inclusion criteria: elementary, high school and college age groups, and a specific definition of clinical recovery that required two or more measures. EXCLUSION CRITERIA: review articles, articles using the same sample population, case studies, non-English language and those that used one measure only or did not specify the recovery measures used. STUDY QUALITY: Study quality was assessed using the Downs and Black Criteria. RESULTS: Of 2023 publications, 43 met inclusion criteria. Included articles reported the following measures of recovery: somatic symptom resolution or return to baseline (100%), cognitive recovery or return to baseline (86%), no exacerbation of symptoms on physical exertion (49%), normalisation of balance (30%), normal special physical examination (12%), successful return to school (5%), no exacerbation of symptoms with cognitive exertion (2%) and normalisation of cerebral blood flow (2%). Follow-up to validate the return to sport decision was reported in eight (19%) articles. Most studies were case-control or cohort (level of evidence 4) and had significant risk of bias. CONCLUSION: All studies of sport-related concussion use symptom reports to define recovery. A minority of studies used multiple measures of outcome or had clearly defined recovery criteria, the most common being a combination of a self-reported symptom checklist and a computerised neurocognitive test. Future studies ideally should define recovery a priori using objective physiological measures in addition to symptom reports. PMID- 28735286 TI - Monitoring player fatigue status in the English Premier League. PMID- 28735287 TI - What is a symptomatic SLAP II tear? It is all about inclusion and exclusion criteria. PMID- 28735288 TI - Scapular dyskinesis increases the risk of future shoulder pain by 43% in asymptomatic athletes: a systematic review and meta-analysis. AB - BACKGROUND: It is unclear whether the presence of scapular dyskinesis increases the risk of developing shoulder pain in asymptomatic athletes. OBJECTIVES: To determine whether the presence of scapular dyskinesis in asymptomatic athletes increases the risk of developing shoulder pain by systematic review and meta analysis. METHODS: A systematic search was conducted in the Cochrane Library, Embase, PubMed, Cumulative Index to Nursing and Allied Health Literature, Allied and Complementary Medicine Database and SPORTDiscus. Prospective studies that assessed athletes for scapular dyskinesis and recorded incidents of shoulder pain were included. Study quality was assessed using the Downs and Black checklist. Meta-analysis was conducted to derive a pooled risk ratio (RR) for the development of shoulder pain in athletes with scapular dyskinesis compared with those without scapular dyskinesis. RESULTS: Five studies were included with a total of 419 athletes. Of the athletes with scapular dyskinesis, 35% (56/160) experienced shoulder pain during the follow-up, whereas 25% (65/259) of athletes without scapular dyskinesis experienced symptoms. The presence of scapular dyskinesis at baseline indicated a 43% increased risk of a shoulder pain event over a 9 to 24 months follow-up (RR=1.43, 95% CI 1.05 to 1.93). CONCLUSIONS: Athletes with scapular dyskinesis have 43% greater risk of developing shoulder pain than those without scapular dyskinesis. PMID- 28735289 TI - Prolonged Fever After ST-Segment Elevation Myocardial Infarction and Long-Term Cardiac Outcomes. AB - BACKGROUND: The biphasic inflammation after ST-segment elevation myocardial infarction (STEMI) plays an important role in myocardial healing and progression of systemic atherosclerosis. The purpose of this study is to investigate the impact of fever during the first and second phases of post-STEMI inflammation on long-term cardiac outcomes. METHODS AND RESULTS: A total of 550 patients with STEMI were enrolled in this study. Axillary body temperature (BT) was measured and maximum BTs were determined for the first (within 3 days: max-BT1-3d) and second (from 4 to 10 days after admission: max-BT4-10d) phases, respectively. Patients were followed for cardiac events (cardiovascular death, acute coronary syndrome, and rehospitalization for heart failure) for a median 5.3 years. During the follow-up period, 80 patients experienced cardiac events. A high max-BT4-10d was strongly associated with long-term cardiac events (hazard ratio, 95% CI) for a 1 degrees C increase in the max-BT4-10d: 2.834 (2.017-3.828), P<0.0001, whereas the max-BT1-3d was not associated with cardiac events (1.136 [0.731-1.742], P=0.57). Even after adjustment for coronary risk factors, estimated glomerular filtration rate, infarct size, pericardial effusion, and medications on discharge, fever during the second phase (max-BT4-10d >=37.1 degrees C) was significantly associated with future cardiac events (hazard ratio [95% CI] 2.900 [1.710-5.143], P<0.0001). CONCLUSIONS: Fever during the second phase but not the first phase of post-STEMI inflammation was a strong associated factor with worse long-term cardiac outcomes in patients after STEMI, suggesting the need to consider the optimal timing for anti-inflammatory strategies after STEMI. PMID- 28735290 TI - Membrane-Tethered Metalloproteinase Expressed by Vascular Smooth Muscle Cells Limits the Progression of Proliferative Atherosclerotic Lesions. AB - BACKGROUND: The MMP (matrix metalloproteinase) family plays diverse and critical roles in directing vascular wall remodeling in atherosclerosis. Unlike secreted type MMPs, a member of the membrane-type MMP family, MT1-MMP (membrane-type 1 MMP; MMP14), mediates pericellular extracellular matrix degradation that is indispensable for maintaining physiological extracellular matrix homeostasis. However, given the premature mortality exhibited by MT1-MMP-null mice, the potential role of the proteinase in atherogenesis remains elusive. We sought to determine the effects of both MT1-MMP heterozygosity and tissue-specific gene targeting on atherogenesis in APOE (apolipoprotein E)-null mice. METHODS AND RESULTS: MT1-MMP heterozygosity in the APOE-null background (Mmp14+/-Apoe-/- ) significantly promoted atherogenesis relative to Mmp14+/+Apoe-/- mice. Furthermore, the tissue-specific deletion of MT1-MMP from vascular smooth muscle cells (VSMCs) in SM22alpha-Cre(+)Mmp14F/FApoe-/- (VSMC-knockout) mice likewise increased the severity of atherosclerotic lesions. Although VSMC-knockout mice also developed progressive atherosclerotic aneurysms in their iliac arteries, macrophage- and adipose-specific MT1-MMP-knockout mice did not display this sensitized phenotype. In VSMC-knockout mice, atherosclerotic lesions were populated by hyperproliferating VSMCs (smooth muscle actin- and Ki67-double positive cells) that were characterized by a proinflammatory gene expression profile. Finally, MT1-MMP-null VSMCs cultured in a 3-dimensional spheroid model system designed to mimic in vivo-like cell-cell and cell-extracellular matrix interactions, likewise displayed markedly increased proliferative potential. CONCLUSIONS: MT1-MMP expressed by VSMCs plays a key role in limiting the progression of atherosclerosis in APOE-null mice by regulating proliferative responses and inhibiting the deterioration of VSMC function in atherogenic vascular walls. PMID- 28735293 TI - Speaking up against unsafe unprofessional behaviours: the difficulty in knowing when and how. PMID- 28735291 TI - Subclinical Atherosclerosis, Cardiac and Kidney Function, Heart Failure, and Dementia in the Very Elderly. AB - BACKGROUND: Heart failure (HF) and dementia are major causes of disability and death among older individuals. Risk factors and biomarkers of HF may be determinants of dementia in the elderly. We evaluated the relationship between biomarkers of cardiovascular disease and HF and risk of dementia and death. Three hypotheses were tested: (1) higher levels of high-sensitivity cardiac troponin T, N-terminal of prohormone brain natriuretic peptide, and cystatin C predict risk of death, cardiovascular disease, HF, and dementia; (2) higher levels of cardiovascular disease biomarkers are associated with increased risk of HF and then secondary increased risk of dementia; and (3) risk of dementia is lower among participants with a combination of lower coronary artery calcium, atherosclerosis, and lower high-sensitivity cardiac troponin T (myocardial injury). METHODS AND RESULTS: The Cardiovascular Health Study Cognition Study was a continuation of the Cardiovascular Health Study limited to the Pittsburgh, PA, center from 1998-1999 to 2014. In 1992-1994, 924 participants underwent magnetic resonance imaging of the brain. There were 199 deaths and 116 developed dementia before 1998-1999. Of the 609 participants eligible for the Pittsburgh Cardiovascular Health Study Cognition Study, 87.5% (n=532) were included in the study. There were 120 incident HF cases and 72% had dementia. In 80 of 87, dementia preceded HF. A combination of low coronary artery calcium score and low high-sensitivity cardiac troponin T was significantly associated with reduced risk of dementia and HF. CONCLUSIONS: Most participants with HF had dementia but with onset before HF. Lower high-sensitivity cardiac troponin T and coronary artery calcium was associated with low risk of dementia based on a small number of events. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00005133. PMID- 28735294 TI - Comparing family-based treatment with parent-focused treatment for adolescent anorexia nervosa. PMID- 28735295 TI - Azithromycin for episodes with asthma-like symptoms in young children aged 1-3 years. PMID- 28735292 TI - Pathogenesis of Hypertrophic Cardiomyopathy is Mutation Rather Than Disease Specific: A Comparison of the Cardiac Troponin T E163R and R92Q Mouse Models. AB - BACKGROUND: In cardiomyocytes from patients with hypertrophic cardiomyopathy, mechanical dysfunction and arrhythmogenicity are caused by mutation-driven changes in myofilament function combined with excitation-contraction (E-C) coupling abnormalities related to adverse remodeling. Whether myofilament or E-C coupling alterations are more relevant in disease development is unknown. Here, we aim to investigate whether the relative roles of myofilament dysfunction and E C coupling remodeling in determining the hypertrophic cardiomyopathy phenotype are mutation specific. METHODS AND RESULTS: Two hypertrophic cardiomyopathy mouse models carrying the R92Q and the E163R TNNT2 mutations were investigated. Echocardiography showed left ventricular hypertrophy, enhanced contractility, and diastolic dysfunction in both models; however, these phenotypes were more pronounced in the R92Q mice. Both E163R and R92Q trabeculae showed prolonged twitch relaxation and increased occurrence of premature beats. In E163R ventricular myofibrils or skinned trabeculae, relaxation following Ca2+ removal was prolonged; resting tension and resting ATPase were higher; and isometric ATPase at maximal Ca2+ activation, the energy cost of tension generation, and myofilament Ca2+ sensitivity were increased compared with that in wild-type mice. No sarcomeric changes were observed in R92Q versus wild-type mice, except for a large increase in myofilament Ca2+ sensitivity. In R92Q myocardium, we found a blunted response to inotropic interventions, slower decay of Ca2+ transients, reduced SERCA function, and increased Ca2+/calmodulin kinase II activity. Contrarily, secondary alterations of E-C coupling and signaling were minimal in E163R myocardium. CONCLUSIONS: In E163R models, mutation-driven myofilament abnormalities directly cause myocardial dysfunction. In R92Q, diastolic dysfunction and arrhythmogenicity are mediated by profound cardiomyocyte signaling and E-C coupling changes. Similar hypertrophic cardiomyopathy phenotypes can be generated through different pathways, implying different strategies for a precision medicine approach to treatment. PMID- 28735296 TI - Resumption of physical activity within 7 days of a concussion was associated with lower rates of persistent postconcussive symptoms (PPCS). PMID- 28735297 TI - Regulating the advertising of genetic tests in Europe: a balancing act. AB - Direct-to-consumer (DTC) genetic tests (GT) have provoked criticism over their potential adverse impact on public health. The European Parliament called for a ban on DTC advertising of GT during the debate for the adoption of a European Regulation on in vitro diagnostic medical devices. This proposal, however, was not ultimately retained in the final text. Instead, the regulation includes an article prohibiting misleading claims for this kind of advertising. These two different approaches raise questions about the optimal degree of regulation. Herein, we provide an overview of the ways GT have been advertised and related ethical issues. Subsequently, the laws regulating the advertising of GT at the European Union and national level are examined. Finally, recent regulatory developments are discussed. PMID- 28735299 TI - Identification of the first dominant mutation of LAMA5 gene causing a complex multisystem syndrome due to dysfunction of the extracellular matrix. AB - BACKGROUND: The laminin alpha 5 gene (LAMA5) plays a master role in the maintenance and function of the extracellular matrix (ECM) in mammalian tissues, which is critical in developmental patterning, stem cell niches, cancer and genetic diseases. Its mutations have never been reported in human disease so far. The aim of this study was to associate the first mutation in LAMA5 gene to a novel multisystem syndrome. METHODS: A detailed characterisation of a three generation family, including clinical, biochemical, instrumental and morphological analysis, together with genetics and expression (WES and RNAseq) studies, was performed. RESULTS: The heterozygous LAMA5 mutation c.9418G>A (p.V3140M) was associated with skin anomalies, impaired scarring, night blindness, muscle weakness, osteoarthritis, joint and internal organs ligaments laxity, malabsorption syndrome and hypothyroidism. We demonstrated that the mutation alters the amount of LAMA5 peptides likely derived from protein cleavage and perturbs the activation of the epithelial-mesenchymal signalling, producing an unbalanced expression of Sonic hedgehog and GLI1, which are upregulated in cells from affected individuals, and of ECM proteins (COL1A1, MMP1 and MMP3), which are strongly inhibited. Studies carried out using human skin biopsies showed alteration of dermal papilla with a reduction of the germinative layer and an early arrest of hair follicle downgrowth. The knock-in mouse model, generated in our laboratory, shows similar changes in the tissues studied so far. CONCLUSIONS: This is the first report of a disease phenotype associated with LAMA5 mutation in humans. PMID- 28735298 TI - FOXP1-related intellectual disability syndrome: a recognisable entity. AB - BACKGROUND: Mutations in forkhead box protein P1 (FOXP1) cause intellectual disability (ID) and specific language impairment (SLI), with or without autistic features (MIM: 613670). Despite multiple case reports no specific phenotype emerged so far. METHODS: We correlate clinical and molecular data of 25 novel and 23 previously reported patients with FOXP1 defects. We evaluated FOXP1 activity by an in vitro luciferase model and assessed protein stability in vitro by western blotting. RESULTS: Patients show ID, SLI, neuromotor delay (NMD) and recurrent facial features including a high broad forehead, bent downslanting palpebral fissures, ptosis and/or blepharophimosis and a bulbous nasal tip. Behavioural problems and autistic features are common. Brain, cardiac and urogenital malformations can be associated. More severe ID and NMD, sensorineural hearing loss and feeding difficulties are more common in patients with interstitial 3p deletions (14 patients) versus patients with monogenic FOXP1 defects (34 patients). Mutations result in impaired transcriptional repression and/or reduced protein stability. CONCLUSIONS: FOXP1-related ID syndrome is a recognisable entity with a wide clinical spectrum and frequent systemic involvement. Our data will be helpful to evaluate genotype-phenotype correlations when interpreting next-generation sequencing data obtained in patients with ID and/or SLI and will guide clinical management. PMID- 28735300 TI - Caveolin-1 expression as a prognostic marker in triple negative breast cancers of Asian women. AB - BACKGROUND: Triple-negative breast cancers (TNBCs) are defined by their lack of oestrogen receptor, progesterone receptor and epidermal growth factor receptor 2. Although heterogeneous, the majority are aggressive and treatment options are limited. Caveolin acts as tumour suppressor or promoter depending on the cancer type. AIM: In this study, we aimed to determine if the expression levels of the candidate biomarker caveolin-1 on stromal or tumour cells were associated with clinicopathological parameters and disease outcomes in TNBCs from an ethnically diverse cohort of Asian women. METHODS: Tumour specimens from 699 women with TNBC were subjected to immunohistochemical analysis of the frequency and intensity of caveolin-1 expression in tumour and stromal cells. A subset of 141 tumour samples also underwent Nanostring measurement of CAV1 mRNA. Results were correlated with clinicopathological parameters and disease outcomes. RESULTS: Expression of caveolin-1 in stromal cells was observed in 14.4% of TNBC cases. TNBCs of the basal-like phenotype (85% of samples) were significantly more likely to exhibit stromal cell caveolin-1 expression (p=0.028), as were those with a trabecular growth pattern (p=0.007). Lack of stromal caveolin-1 expression in both TNBCs and those with the basal-like phenotype was significantly associated with worse overall survival (p=0.009 and p=0.026, respectively): accordingly, increasing mRNA levels of CAV1 in TNBC samples predicted better overall survival. Caveolin-1 expression on TNBC tumour cells was not associated with clinical outcome. CONCLUSION: Stromal, but not tumoural, caveolin-1 expression is significantly associated with survival in Asian women with TNBC. PMID- 28735301 TI - Effect of faecal calprotectin assay variability on the management of inflammatory bowel disease and potential role of faecal S100A12. AB - AIMS: To prospectively evaluate whether between-assay variability of different faecal calprotectin (f-Cp) assays influences diagnostic accuracy for inflammatory bowel disease (IBD) in a cohort of patients with confirmed IBD and irritable bowel syndrome (IBS). To also evaluate the diagnostic accuracy of faecal S100A12 (f-S100A12) against f-Cp in the same patient cohort and assess whether f-S100A12 offers additional diagnostic value. METHODS: F-Cp using four commercially available f-Cp assays, f-S100A12 and blood biomarkers were measured in patients, recruited from the local IBD clinic, who had established IBS or active ulcerative colitis (UC) and Crohn's disease (CD). Diagnostic sensitivities and specificities for each assay and biomarker were calculated and compared. RESULTS: Median f-Cp levels in all assays were significantly higher in UC (347-884 ug/g; n=28) and CD (377-838 ug/g; n=15) compared with IBS (6-27 ug/g; n=17). Sensitivities and specificities at 50 ug/g were 94%-100% and 82%-100%, respectively. Median f S100A12 levels were significantly higher in UC (81.0 ug/g; IQR 38.3-159.8) and CD (47.2 ug/g; IQR 5.3-108.9) compared with IBS (0.7 ug/g; IQR 0.5-0.8). At 2.8 ug/g, f-S100A12 had a sensitivity of 97% and specificity of 94%. The blood biomarkers demonstrated sensitivities and specificities of 44%-63% and 80%-92%, respectively. CONCLUSIONS: The diagnostic sensitivity of the calprotectin assays was similar despite inter-kit variability in absolute values. There is a need for f-Cp assay standardisation, but in its absence assay-specific cut-off values may optimise their diagnostic performance. F-S100A12 demonstrated comparable sensitivity and specificity to f-Cp and although a research tool at present, may have a future role to play in the diagnosis and management of these patients. PMID- 28735302 TI - Autopsy interrogation of emergency medicine dispute cases: how often are clinical diagnoses incorrect? AB - AIMS: Emergency medicine is a 'high risk' specialty. Some diseases develop suddenly and progress rapidly, and sudden unexpected deaths in the emergency department (ED) may cause medical disputes. We aimed to assess discrepancies between antemortem clinical diagnoses and postmortem autopsy findings concerning emergency medicine dispute cases and to figure out the most common major missed diagnoses. METHODS: Clinical files and autopsy reports were retrospectively analysed and interpreted. Discrepancies between clinical diagnoses and autopsy diagnoses were evaluated using modified Goldman classification as major and minor discrepancy. The difference between diagnosis groups was compared with Pearson chi2 test. RESULTS: Of the 117 cases included in this study, 71 of cases (58 class I and 13 class II diagnostic errors) were revealed as major discrepancies (60.7%). The most common major diagnoses were cardiovascular diseases (54 cases), followed by pulmonary diseases, infectious diseases and so on. The difference of major discrepancy between the diagnoses groups was significant (p<0.001). Aortic dissection and myocardial infarction were the most common cause of death (15 cases for each disease) and the most common missed class I diagnoses (80% and 66.7% for each), higher than the average 49.6% of all class I errors of the study patients. CONCLUSIONS: High major disparities between clinical diagnoses and postmortem examinations exist in emergency medical disputes cases; acute aortic dissection and myocardial infarction are the most frequently major missed diagnoses that ED clinicians should pay special attention to in practice. This study reaffirmed the necessity and usefulness of autopsy in auditing death in EDs. PMID- 28735303 TI - Acid-fast bacterium detection and identification from paraffin-embedded tissues using a PCR-pyrosequencing method. AB - AIMS: Acid-fast bacterium (AFB) identification from formalin-fixed paraffin embedded (FFPE) tissues is challenging and may not be readily available to the clinical laboratory. A method to detect and identify AFB from FFPE tissues using PCR and pyrosequencing (PCR-Seq) was developed and evaluated. METHODS: The method was validated using spiked cell-clotted paraffin blocks before use with patients' specimens. DNA was extracted from tissue sections, and a 16S rRNA gene fragment was amplified and a signature sequence was produced on a PyroMark ID system. Sequences were aligned to established databases for AFB identification. Additional tissue sections were stained and examined for AFB. RESULTS: Both sensitivity and specificity were 100% on spiked cell-clotted blocks without cross reactivity with non-AFB. Of 302 FFPE tissues from patients, 116 (38%) were AFB stain positive; 83 (72%) of these had AFB identified. The 21 AFB identified included Mycobacterium tuberculosis complex (14 cases), Mycobacterium leprae (3), Mycobacterium genavense (2), Mycobacterium marinum-ulcerans group (3) and 17 other AFB (61). Thirteen cases were AFB-stain indeterminate and 4 were positive by the PCR-Seq method. Of the AFB stain-negative cases, 167 were negative and 6 were positive by PCR-Seq. CONCLUSIONS: The PCR-Seq method provided specific identification of various AFB species or complexes from FFPE tissues. PMID- 28735304 TI - Morphological and Molecular Characterization of Phoma complanata,a New Causal Agent of Archangelica officinalis Hoffm. in Poland. AB - The paper concerns the fungus Phoma complanata, isolated for the first time in Poland, from the roots and umbels of angelica (Archangelica officinalis) in 2009. The morphology of fungal isolates was tested on standard culture media. Moreover, the sequence analysis of ITS regions was conducted. Morphological similarity of P. complanata Polish isolates to the reference isolate obtained from CBS culture collection was determined and together with the molecular analysis confirmed the affiliation of the fungus to the species. PMID- 28735305 TI - Molecular Study of Indigenous Bacterial Community Composition on Exposure to Soil Arsenic Concentration Gradient. AB - Community structure of bacteria present in arsenic contaminated agricultural soil was studied with qPCR (quantitative PCR) and DGGE (Denaturing Gradient Gel Electrophoresis) as an indicator of extreme stresses. Copy number of six common bacterial taxa (Acidobacteria, Actinobacteria, alpha-, beta- and gamma Proteobacteria, Firmicutes) was calculated using group specific primers of 16S rDNA. It revealed that soil contaminated with low concentration of arsenic was dominated by both Actinobacteria and Proteobacteria but a shift towards Proteobacteria was observed with increasing arsenic concentration, and number of Actinobacteria eventually decreases. PCA (Principle Component Analysis) plot of bacterial community composition indicated a distinct resemblance among high arsenic content samples, while low arsenic content samples remained separated from others. Cluster analysis of soil parameters identifies three clusters, each of them was related to the arsenic content. Further, cluster analysis of 16S rDNA based DGGE fingerprint markedly distributed the soil bacterial populations into low (< 10 ppm) and high (> 10 ppm) arsenic content subgroups. Following analysis of diversity indices shows significant variation in bacterial community structure. MDS (Multi Dimensional Scaling) plot revealed distinction in the distribution of each sample denoting variation in bacterial diversity. Phylogenetic sequence analysis of fragments excised from DGGE gel revealed the presence of gamma-Proteobacteria group across the study sites. Collectively, our experiments indicated that gradient of arsenic contamination affected the shape of the soil bacterial population by significant structural shift. PMID- 28735306 TI - The Serological Surveillance of Hepatitis E virus among Hunters and Foresters in Eastern Poland. AB - The aim of the study was the analysis of the occurrence of specific antibodies against HEV among hunters and foresters who are at risk to be exposed. The study group consisted of 210 hunters (23-80 years old) and 60 foresters (22-64 years old). Anti-HEV IgG were present in 3.81% of the samples of the hunters and in 5% of the samples of the foresters. The statistical analysis shows no significant differences in the results anti-HEV IgG between the groups of hunters and foresters (p = 0.5278). Significantly higher anti-HEV IgG titers were found in the older age group (> 55 years old). PMID- 28735307 TI - Influence of Pseudomonas and Bacillus Strains Isolated from Lolium perenne Rhizospheric Soil in Vojvodina (Serbia) on Planth Growth and Soil Microbial Communities. AB - The aim of this study was the isolation of Pseudomonas sp. and Bacillus sp. strains from rhizospheric soil and monitoring the impact of two isolates denoted as P12 (Pseudomonas sp.) and B1 (Bacillus sp.) on the parameters of English ryegrass (Lolium perenne) yield and activity of the soil microbial communities. During 2012-2014, a plot experiment was set up following the randomized block system. Better effect on the plant growth was recorded with the use of Pseudomonas sp. P12 isolate than with Bacillus sp. B1. Positive effect on the increase in the total number of microorganisms, aminoheterotrophs and azotobacter was also achieved. Bacillus sp. B1 increased only the number of actimycetes. Both isolates positively affected dehydrogenase activity (DHA). PMID- 28735308 TI - Bactericidal Activity of Octenidine to Various Genospecies of Borrelia burgdorferi, Sensu Lato Spirochetes in Vitro and in Vivo. AB - The aim of our studies was to invent a reliable method for detection of the bactericidal activity of disinfectants against Borrelia burgdorferi in suspension (in vitro) and in cell line cultures (in vivo). In the suspension method, 0.01% octenidine at 20 degrees C and 35 degrees C was bactericidal to Borrelia afzeli; Borrelia garini, B. burgdorferi sensu stricto after 5 minutes treatment. Increase of the temperature to 35 degrees C speed up the bactericidal effect to 1 minute. The bactericidal action of octenidine towards B. burgdorferi spirochetes growing in fibroblasts was less effective and needed a longer time to kill them than in the suspension. PMID- 28735309 TI - Safety Evaluation of Enterocin Producer Enterococcus sp. Strains Isolated from Traditional Turkish Cheeses. AB - The purpose of this study was to determine the antimicrobial activity and occurrence of bacteriocin structural genes in Enterococcus spp. isolated from different cheeses and also investigate some of their virulence factors. Enterococcus strains were isolated from 33 different cheeses. Enterococcus faecium (6 strains) and Enterococcus faecalis (5 strains) enterocin-producing strains were identified by 16S rDNA analyses. Structural genes entA, entB, entP and entX were detected in some isolates. Multiple enterocin structural genes were found in 7 strains. None of the tested enterococci demonstrated anybeta haemolytic activity and only one strain had gelatinase activity. Six strains showed multiple antibiotic resistance patterns and in addition, vanA and several virulence genes were detected in many strains. Only E. faecalis MBE1-9 showed tyrosine decarboxylase activity and tdc gene was detected only in this strain. PMID- 28735310 TI - An Improve Protocol for PCR Using LM1 and LM2 Primers for Listeria monocytogenes Detection in Food Matrices. AB - Several studies have observed that a conventional PCR protocol using primers LM1 and LM2 for the identification of gene hlyA Listeria monocytogenes generates non specific PCR amplifications and false positives. For this reason in this study, we provide a modified PCR protocol that improves the specificity of the LM1 and LM2 primers. PMID- 28735311 TI - Erythromycin or Clindamycin - is it Still an Empirical Therapy against Streptococcus agalactiae in Patients Allergic to Penicillin? AB - Retrospective analysis of Streptococcus agalactiae antibiotic susceptibility isolated in 2010-2013 was performed. Penicillin was still the first-line antibiotic. Due to the high percentage of strains resistant to erythromycin and clindamycin empirical treatment with these antibiotics may not be effective. Lower resistance rate to erythromycin and clindamycin among strains isolated from infected pregnant women and newborns were observed than among strains isolated from samples from patients hospitalized in other departments (29% and 47% v. 46% and 63%). The increasing resistance rate might give a rise to a new epidemiological situation. PMID- 28735312 TI - Effect of Lyophilization on Survivability and Growth Kinetic of Trichoderma Strains Preserved on Various Agriculture By-Products. AB - Growth of four Trichoderma strains were tested on lignocellulosic by-products in solid state fermentation (SSF). The strains were also analyzed for their survival rate and growth after lyophilization on these carriers. All applied monocomponent and bicomponent media were substrates for the production and preservation of Trichoderma biomass. However, the maximum number of colony forming units (CFU/g dm) was acquired on bicomponent media based on dried grass and beet pulp or grass with corn cobs, when compared to monocomponent media. Although the process of lyophilization reduced the survival rate by 50%-60%, the actual number of viable cells in obtained biopreparations remained relatively high (0.58 * 108-1.68 * 108 CFU/g dm). The studied strains in the preserved biopreparations were characterized by a high growth rate, as evaluated in microcultures using the Bioscreen C system. PMID- 28735313 TI - Early KPC-Producing Klebsiella pneumoniae Bacteremia among Intensive Care Unit Patients Non-Colonized upon Admission. AB - Among 140 patients colonized by KPC-producing Klebsiella pneumoniae (KPC-Kp) between fourth and seventh day of Intensive Care Unit stay, 24 developed bacteraemia immediately after colonization. Colistin-resistance of the colonizing isolate was the factor significantly associated with early KPC-Kp bacteraemia (P < 0.001; OR 6.6, 95% CI 2.4-18.4), a worrisome finding since infections by colistin-resistant isolates is associated with increased mortality due to limited remaining therapeutic options. PMID- 28735314 TI - Gene Expression during BTEX Biodegradation by a Microbial Consortium Acclimatized to Unleaded Gasoline and a Pseudomonas putida Strain (HM346961) Isolated from It. AB - Pseudomonas putida strain (HM346961) was isolated from a consortium of bacteria acclimatized to unleaded gasoline-contaminated water. The consortium can efficiently remove benzene, toluene, ethylbenzene and xylene (BTEX) isomers, and a similar capability was observed with the P. putida strain. Proteome of this strain showed certain similarities with that of other strains exposed to the hydrocarbon compounds. Furthermore, the toluene di-oxygenase (tod) gene was up regulated in P. putida strain when exposed to toluene, ethylbenzene, xylene, and BTEX. In contrast, the tod gene of P. putida F1 (ATCC 700007) was up-regulated only in the presence of toluene and BTEX. Several differences in the nucleotide and protein sequences of these two tod genes were observed. This suggests that tod up-regulation in P. putida strain may partially explain their great capacity to remove aromatic compounds, relative to P. putida F1. Therefore, new tod and P. putida strain are promising for various environmental applications. PMID- 28735315 TI - The Diversity, Growth Promoting Abilities and Anti-microbial Activities of Bacteria Isolated from the Fruiting Body of Agaricus bisporus. AB - Agaricus bisporus plays an important role in ecological processes and is one of the most widely cultivated mushrooms worldwide. Mushroom growth-promoting bacteria have been isolated from casing soil and compost, but microorganisms in the fruiting body have received only a little attention. To get an overview of phylogenetic diversity of microorganisms in the fruiting body of A. bisporus, as well as to screen antimicrobial and mushroom growth-promoting strains, and eventually intensify mushroom production, we isolated and characterized microorganisms from the fruiting body of A. bisporus. In total, 55 bacterial strains were isolated, among which nine isolates represented Actinomycetes. All the isolates were analyzed by 16S rRNA gene RFLP and sixteen representative strains by 16S rRNA gene sequencing. According to the phylogenetic analysis, eleven isolates represented the Gram-positive Bacillus, Lysinibacillus, Paenibacillus, Pandorea and Streptomyces genera, and five isolates belonged to the Gram-negative Alcaligenes and Pseudomonas genera. The bacteria isolated from the fruiting body of A. bisporus had broad-spectrum antimicrobial activities and potential mushroom growth-promoting abilities. PMID- 28735316 TI - Biochar-rhizosphere interactions - A review. AB - Biochar is a solid material of biological origin obtained from the biomass carbonization, designed as a mean to reduce greenhouse gases emission and carbon sequestration in soils for a long time. Biochar has a wide spectrum of practical utilization and is applied as a promising soil improver or fertilizer in agriculture, or as a medium for soil or water remediation. Preparations of biochar increase plant growth and yielding when applied into soil and also improve plant growth conditions, mainly bio, physical and chemical properties of soil. Its physical and chemical properties have influence on bacteria, fungi and invertebrates, both in field and laboratory conditions. Such effects on rhizosphere organisms are positive or negative depending on biochar raw material origin, charring conditions, frequency of applications, applications method and doses, but long terms effects are generally positive and are associated mainly with increased soil biota activity. However, a risk assessment of biochar applications is necessary to protect the food production and soil environment. This should be accomplished by biochar production and characterization, land use implementation, economic analysis, including life cycle assessment, and environmental impact assessment. PMID- 28735317 TI - Genetic Characterization of a Novel Composite Transposon Carrying armA and aac(6) Ib Genes in an Escherichia coli Isolate from Egypt. AB - Aminoglycosides are used in treating a wide range of infections caused by Gram positive and Gram-negative bacteria; however, aminoglycoside resistance is common and occurs by several mechanisms. Among these mechanisms is bacterial rRNA methylation by the 16S rRNA methyl transferase (16S-RMTase) enzymes; but data about the spread of this mechanism in Egypt are scarce. Cephalosporins are the most commonly used antimicrobial agents in Egypt; therefore, this study was conducted to determine the frequency of 16S-RMTase among third generation cephalosporin-resistant clinical isolates in Egypt. One hundred and twenty three cephalosporin resistant Gram-negative clinical isolates were screened for aminoglycosides resistance by the Kirby Bauer disk diffusion method and tested for possible production of 16S-RMTase. PCR testing and sequencing were used to confirm the presence of 16S-RMTase and the associated antimicrobial resistance determinants, as well as the genetic region surrounding the armA gene. Out of 123 isolates, 66 (53.66%) were resistant to at least one aminoglycoside antibiotic. Only one Escherichia coli isolate (E9ECMO) which was totally resistant to all tested aminoglycosides, was confirmed to have the armA gene in association with blaTEM-1, blaCTX-M-15, blaCTX-M-14 and aac(6)-Ib genes. The armA gene was found to be carried on a large A/C plasmid. Genetic mapping of the armA surrounding region revealed, for the first time, the association of armA with aac(6)-Ib on the same transposon. In conclusion, the isolation frequency of 16S-RMTase was low among the tested aminoglycoside-resistant clinical samples. However, a novel composite transposon has been detected conferring high-level aminoglycosides resistance. PMID- 28735318 TI - Trends of Bloodstream Infections in a University Greek Hospital during a Three Year Period: Incidence of Multidrug-Resistant Bacteria and Seasonality in Gram negative Predominance. AB - The aim of the study was to assess the epidemiology, the incidence of multidrug resistant bacteria and bloodstream infections' (BSIs) seasonality in a university hospital. This retrospective study was carried out in the University General Hospital of Patras, Greece, during 2011-13 y. Blood cultures from patients with clinical presentation suggestive of bloodstream infection were performed by the BacT/ALERT System. Isolates were identified by Vitek 2 Advanced Expert System. Antibiotic susceptibility testing was performed by the disk diffusion method and E-test. Resistance genes (mecA in staphylococci; vanA/vanB/vanC in enterococci; blaKPC/blaVIM/blaNDM in Klebsiella spp.) were detected by PCR. In total, 4607 (9.7%) blood cultures were positive from 47451 sets sent to Department of Microbiology, representing 1732 BSIs. Gram-negative bacteria (52.3%) were the most commonly isolated, followed by Gram-positive (39.5%), fungi (6.6%) and anaerobes bacteria (1.8%). The highest contamination rate was observed among Gram positive bacteria (42.3%). Among 330 CNS and 150 Staphylococcus aureus, 281 (85.2%) and 60 (40.0%) were mecA-positive, respectively. From 113 enterococci, eight were vanA, two vanB and two vanC-positives. Of the total 207 carbapenem resistant Klebsiella pneumoniae (73.4%), 202 carried blaKPC, four blaKPC and blaVIM and one blaVIM. A significant increase in monthly BSIs' incidence was shown (R2: 0.449), which may be attributed to a rise of Gram-positive BSIs (R2: 0.337). Gram-positive BSIs were less frequent in spring (P < 0.001), summer (P < 0.001), and autumn (P < 0.001), as compared to winter months, while Gram-negative bacteria (P < 0.001) and fungi (P < 0.001) were more frequent in summer months. BSIs due to methicillin resistant S. aureus and carbapenem-resistant Gram negative bacteria increased during the study period. The increasing incidence of BSIs can be attributed to an increase of Gram-positive BSI incidence, even though Gram-negative bacteria remained the predominant ones. Seasonality may play a role in the predominance of Gram-negative's BSI. PMID- 28735319 TI - Intracellular Siderophore Detection in an Egyptian, Cobalt-Treated F. solani Isolate Using SEM-EDX with Reference to its Tolerance. AB - An Egyptian, plant pathogenic Fusarium solani isolate was grown on cobalt concentrations of 0, 50, 200, 500, 800, and 1000 ppm. The isolate survived concentrations up to 800 ppm, however failed to grow at 1000 ppm. Morphology and elemental analysis of the isolate under the investigated Co concentrations were studied using Scanning electron microscopy (SEM) and energy dispersive X-ray microanalysis (EDX). The isolate reserved its morphology up to a concentration of 200 ppm. Morphological distortions were dramatic at 500 and 800 ppm. EDX detected Co uptake through the hyphae, microconidia, macroconidia, and chlamydospores. Iron, calcium, and potassium were also detected. EDX results showed a linear relationship between Co% and Fe% up to a concentration of 500 ppm reflecting the possible ability of the isolate to synthesize intracellular siderophores storing iron and their release from the vacuoles. The participation of such siderophores in conferring tolerance against cobalt is discussed. At 800 ppm, the % of Fe was greatly reduced with an accompanying increase in morphological distortions and absence of microconidia. Increasing the implicated cobalt concentrations resulted in increasing the percentages of the chelated cobalt reflecting the possible implication of the cell wall as well as extracellular siderophores in the uptake of cobalt. The current results recommend the absence of cobalt in any control regime taken to combat the investigated F. solani isolate and highlights the accomplishment of biochemical, ultrastructural, and molecular studies on such isolate to approve the production of siderophores and the role of cell wall in cobalt uptake. PMID- 28735320 TI - In vitro Interaction between Fumonisin B1 and the Intestinal Microflora of Pigs. AB - The caecal chyme of pigs was incubated anaerobically in McDougall buffer with and without fumonisin B1 (5 MUg/ml) for 0, 24 and 48 h. The plate count agar technique was applied for enumerating the amount of bacteria including aerobic, anaerobic bacteria, coliform, Escherichia coli and Lactobacillus sp. The quantitative polymerase chain reaction was also performed to estimate the number of copies of the total bacteria, Lactobacillus, Bacteroides and Prevotella. No significant differences in the amount of bacterial groups between the experimental (buffer, chyme, and fumonisin B1) and control 1 groups (buffer + chyme) were observed in both methods. Fumonisin B1 and hydrolysed fumonisin B1 concentration were analysed by liquid chromatograghy - mass spectrometry. There was no significant difference in FB1 concentration between the experimental and the control 2 group (buffer and fumonisin B1) at 0 h incubation, 5.185 +/- 0.174 MUg/ml compared with 6.433 +/- 0.076 MUg/ml. Fumonisin B1 concentration in the experimental group was reduced to 4.080 +/- 0.065 MUg/ml at 24 h and to 2.747 +/- 0.548 MUg/ml at 48 h incubation and was significantly less than that of in the control group. Hydrolysed fumonisin B1 was detected after 24 h incubation (0.012 +/- 0 MUg/ml). At 48 h incubation time, hydrolysed fumonisin B1 concentration was doubled to 0.024 +/- 0.004 MUg/ml. These results indicate that fumonisin B1 can be metabolised by caecal microbiota in pigs though the number of studied bacteria did not change. PMID- 28735321 TI - Betaine Improves Polymer-Grade D-Lactic Acid Production by Sporolactobacillus inulinus Using Ammonia as Green Neutralizer. AB - The traditional CaCO3-based fermentation process generates huge amount of insoluble CaSO4 waste. To solve this problem, we have developed an efficient and green D-lactic acid fermentation process by using ammonia as neutralizer. The 106.7 g/L of D-lactic acid production and 0.89 g per g of consumed sugar were obtained by Sporolactobacillus inulinus CASD with a high optical purity of 99.7% by adding 100 mg/L betaine in the simple batch fermentation process. The addition of betaine was experimentally proven to protect cell at high concentration of ammonium ion, increase the D-lactate dehydrogenase specific activity and thus promote the production of D-lactic acid. PMID- 28735322 TI - Viral Infection of the Heart: Pathogenesis and Diagnosis. AB - Viral infections of the heart cause serious clinical problems, either as infectious myocarditis, which usually is a consequence of acute infection or as idiopathic dilated cardiomyopathy, resulting rather from a chronic infection. This minireview presents an up-to-date view on pathomechanisms of viral infection of the heart tissues, the role of immune system in controlling infectious process at its various stages and current possibilities of recognizing viral infection of the heart with use of both cardiological and virological methods. Our goal was to present the variety of known viral agents causing heart infection, level of complexity in mutual virus-cell interactions, and consequent clinical scenarios. PMID- 28735323 TI - Gas Gangrene of Different Origin Associated with Clostridium perfringens Type A in Three Patients Simultaneously Hospitalized in a Single Department of Orthopedics and Traumatology in Poland. AB - The objective of the study was to perform a comparative analysis of phenotypic and genetic similarity, determination of resistance profiles, detection of toxin encoding genes and molecular typing of Clostridium perfringens isolates originating from patients with gas gangrene. The study encompassed three patients with a clinical and microbiological diagnosis of gas gangrene who were hospitalized in one of the hospitals of the Kujawsko-Pomorskie province in the same period of time between 8th April 2015 and 20th April 2015. The three C. perfringens isolates studied had identical biochemical profiles. Two isolates had identical resistance patterns, while the third presented a different profile. Using the multiplex PCR method, all isolates showed the presence of cpa gene encoding alpha-toxin; furthermore, the presence of the cpb2 gene encoding beta2 toxin was confirmed in two isolates. Genotyping with the use of pulsed field gel electrophoresis (PFGE) indicated that the isolates originating from the three studied patients represent three genetically different restrictive patterns which corresponded to three different clones - clone A, clone B and clone C. As a result of the study, it is possible to conclude that the studied patients simultaneously hospitalized in a single Department of Orthopedics and Traumatology developed three different endogenous infections. PMID- 28735324 TI - Study of Acid Phosphatase in Solubilization of Inorganic Phosphates by Piriformospora indica. AB - Phosphorus is an essential plant macronutrient present in the soil. Only a small portion of phosphorus in soil is taken up by plants and the rest of it becomes unavailable to plants as it is immobilized. Phosphate solubilizing microorganisms play a vital role in converting the insoluble form of phosphates to the soluble form. The present paper reports the solubilization of tricalcium phosphate, rock phosphate, single super phosphate, zinc phosphate and aluminum phosphate by Piriformospora indica with the production of organic acids as well as acid phosphatase. The amount of phosphate released (4.73 mg ml-1) and titratable acidity (0.12%) was found to be the highest in the case of single super phosphate as compared to other phosphate sources. High performance liquid chromatography (HPLC) revealed the presence of oxalic acid, lactic acid, citric acid and succinic acid in the media. Highest phosphatase activity was observed with the cell membrane extract of the organism in the presence of zinc phosphate. PMID- 28735325 TI - Characterization of Endolithic Culturable Microbial Communities in Carbonate Rocks from a Typical Karst Canyon in Guizhou (China). AB - The endolithic environment is a ubiquitous habitat for microorganisms and a critical interface between biology and geology. In this study, a culture-based method and the phylogenetic analysis based on 16S rRNA and internal transcribed spacer (ITS) sequences were used to investigate the diversity of endolithic bacteria and fungi in two main types of carbonate rocks (namely dolomite and limestone) from Nanjiang Canyon in Guizhou karst area, China. The results of bacterial diversity indicated that all bacteria isolated from dolomite and limestone rocks were divided into 4 bacterial groups, including Proteobacteria, Actinobacteria, Firmicutes and Bacteroidetes. For these two kinds of rocks, Proteobacteria was the first dominant group, and Gammaproteobacteria occupied the greatest proportion which might be closely related to Pseudomonas in phylogeny to be the most dominant genera after isolation. Actinobacteria and Bacillus bacteria were also widespread in these two kinds of rock environments. There were only 9 and 8 strains of fungi isolated from dolomite and limestone respectively, which all belonged to Ascomycota. To the best of our knowledge, this is the first report on diversity of endolithic culturable bacteria and fungi in carbonate rocks in Guizhou karst region. These microorganisms may play an important and unprecedented role in the carbonate rock weathering during the long history of geological evolution. PMID- 28735326 TI - High Seroprevalence of CMV Among Women of Childbearing Age Implicates High Burden of Congenital Cytomegalovirus Infection in Poland. AB - Cytomegaloviruses are common worldwide, with variable frequency of infections. The infection in pregnancy may lead to pregnancy loss or serious sequelae for the child. To understand the risk posed by CMV in Poland we conducted cross-sectional study on women aged 15-49 basing on existing serum bank. Age dependent incidence, the rates of congenital infection and sequelae were modelled from sero prevalence, literature and demographic data. The overall anti-CMV IgG prevalence was 81.9% increasing from 74.3% in <30 years old to 94.3% in subjects 45+ years old. The lowest incidence was estimated at the age of 15 and the highest at the age 34 (3.8 and 8.95 respectively/100 women/year). The estimated rate of cCMV varies from 22.4 to 37.2 per 1000 live birth depending on the assumptions made. The proportion of cases due to secondary infection ranged from 34.8% to 49.9% accordingly. PMID- 28735327 TI - Genotyping and Clinicoepidemiological Characterization of Rotavirus Acute Gastroenteritis in Egyptian Children. AB - Group A rotavirus (RVA) acute gastroenteritis (AGE) is a common cause of severe childhood diarrhea. The dominant circulating RVA genotypes in a given region may vary between and within the geographic regions and from year to year. Our cross sectional study was designed to determine the burden of RVA genotypes among children with AGE admitted to referral Children Hospital at Egypt prior to implementation of the vaccine. Stool samples with clinico-epidemiological data were collected from 92 children <= 3 years-old with AGE. RVA G and P typing were performed with type-specific primers. RVA was detected in 48.9% of patients. Higher rates of RVA infections, 73.3% were detected in infants < 1 year-old. Breast-fed infants were significantly fewer in RVA positive group (P = 0.0006). Non-breastfeeding was a major risk factor for RVA AGE (OR 0.3, P = 0.02). RVA diarrhea occurred mostly in autumn and winter months (55.4% and 26.6%) with a significant difference in autumn (P = 0.0005) and was associated with vomiting and dehydration (OR; 1.66, P = 0.021 & 1.4, P = 0.03). RVA genotypes G1P[8] (26.7%), G9P[8] (20%) and G3P[8] (15.6%) were accounting for 62.3% of RVA AGE. G9 was significantly associated with mucus diarrhea, than G1 or G3 which were associated with watery diarrhea (P = 0.025). Also, G9 was significantly associated with loose stool for > 5 days (P = 0.006) and 54.4% of G9 patients had severe dehydration. The diversity of RVA strains detected in Nile Delta Egypt and emergence of G9 RVA highlight the need to apply vaccines against this genotype in Egypt. PMID- 28735328 TI - Molecular Characterization of Enteroviruses Isolated from Acute Flaccid Paralysis Cases in Poland, 1999-2014. AB - Enteroviruses (EVs) are among viral pathogens that can cause acute flaccid paralysis (AFP). This study represents an overview of EVs isolated through AFP surveillance in Poland between 1999 and 2014. The presence of enteroviruses was studied in stool samples that were collected from 747 AFP cases and their asymptomatic contacts. Fifty five (6.12%) cases of AFP were associated with enterovirus isolation. Out of the 55 positive cases, 40 were associated with detection of enterovirus in patient, and 15 with detection of EV in healthy contact, without positive detection in paralytic patient. Polioviruses were isolated from 35 AFP cases. The results of this study showed that about 43.6% of positive AFP cases were found in association with the isolation of non-polio enteroviruses (NPEV). A total of 12 different types of the species B were detected (CVA9, CVB1, CVB3, CVB4, CVB5, E3, E4, E9, E11, E13, E30), and one additional isolate represented the species enterovirus A (EV71). Among the 12 serotypes of species B, CVB3 and CVB5 were more frequently detected than others, representing 40% of the characterized isolates, followed by CVB4 (16%), E4 (8%), and E11(8%). Phylogenetic analysis revealed that strains from Poland had the closest genetic relationship with isolates previously identified in Europe (France, Finland, Denmark, Moldova) but also in other parts of the world (Tunisia, China, USA), suggesting wide distribution of these lineages. The paper provides information about NPEV circulation in Poland in the past 16 years, about its association with the AFP and it indicates the need for monitoring NPEV circulation even after the eradication of poliomyelitis. PMID- 28735329 TI - Antistaphylococcal Activity of Selected Thiourea Derivatives. AB - Five of thiourea derivatives were prepared using as a starting compound 3 (trifluoromethyl)aniline, 4-chloro-3-nitroaniline, 1,3-thiazol-2-amine, 2H-1,2,3 triazol-4-amine and commercial isothiocyanates. All compounds were evaluated in vitro for antimicrobial activity. Derivatives 2 and 3 showed the highest inhibition against Gram-positive cocci (standard and hospital strains). The observed MIC values were in the range of 0.5-8 MUg/ml. The products effectively inhibited the formation of biofilms of methicillin-resistant and standard strains of Staphylococcus epidermidis. Inhibitory activity of thioureas 2 and 3 against Staphylococcus aureus topoisomerase IV was studied. The examined compounds were nongenotoxic. PMID- 28735330 TI - Expiration Date Prediction of Biocontrol Agent Prepared with Bacillus subtilis B579 Using the Accelerated Aging Method. AB - The expiration date of biopesticidal products is an essential feature of their use and storage. In the present work, the expiration date of biocontrol agent was predicted using the accelerated aging method. The available bacteria in Bacillus subtilis B579 biocontrol agent were 3.7 +/- 0.2 * 1011 CFU/g. It is calculated that the expiration date of the agent was about 17 months at 25 degrees C. During this period, the available bacteria retained more than 90% of the value in the initial product. Thus, this work suggests the expiration date of biocontrol agents composed with spores could be estimated using the accelerated aging method. PMID- 28735331 TI - Evaluation of the Levels and Quality of Microbial Contamination in Medical Emergency Departments in Comparison to Other Workplaces. AB - Work in Hospital Emergency Departments (HEDs) exposes both the emergency ward staff and patients to infectious and in other way harmful biological agents. The results of this study shows the presence of pathogenic bacteria isolated by three different methods. It revealed 9.8% of pathogens detected by imprint method, 10.5% of pathogens by swabbing method, 17.6% and 22% in HEDs corridors and rooms, respectively, by air sampling method. In control workplaces (offices) pathogenic bacteria reached the level of 6.5% and 14.7% by imprint method and swabbing, respectively. The relatively low level of contamination by bacteria in HEDs may depend on the effectiveness of Standard Protective Precautions in the studied hospitals. PMID- 28735332 TI - The Usefulness of Biosynthetic Vascular Graft Omniflow II and Autologous Veins for the Treatment of Massive Infection of Dacron Vascular Graft with Enterococcus faecalis HLAR. AB - Infections of vascular grafts are the most severe complications in vascular surgery. We present the case of a 73-year-old male with infection of a dacron prosthesis with a strain of Enterococcus faecalis. The patient was treated with replacement of a full prosthesis with a combined graft constructed from Biosynthetic Vascular graft Omniflow and autologous veins. This graft is recommended for implantation in patients with a higher risk of infection. Our case is one of the first reported usage of this kind of graft in the aortic region and in a 2 years observation period no recurrence of infection was observed. PMID- 28735333 TI - Survival of Bacteria in Respiratory Protective Filters. AB - The aim of this study was to estimate the susceptibility of Staphylococcus hominis bacteria to the bacteriostatic agent in respiratory protective filters. Four types of filter media of different characteristics were tested. The number of bacteria was estimated by a culture-based method. It was proved that in treated filters the number of S. hominis was significantly reduced, even below the detection limit, while in untreated material bacteria were able to grow and multiply up to 100-fold within 8 hours. There was no correlation between filter structure and changes in the number of bacterial cells. PMID- 28735334 TI - Detection of Polioviruses in Sewage Using Cell Culture and Molecular Methods. AB - The work presented here demonstrates the utility of a two-step algorithm for environmental poliovirus surveillance based on: preselection of sewage samples tested for the presence of enteroviral genetic material-RT-PCR assay and detection of infectious viruses by cell culture technique (L20B for polioviruses and RD for polio and other non-polio enteroviruses). RD and L20B cell lines were tested to determine their sensitivity for isolation of viruses from environmental samples (sewage). Finally, we wanted to determine if sewage concentration affects the results obtained for RT-PCR and cell cultures. PMID- 28735335 TI - Evaluating the Effectiveness of a Health Promotion Intervention Program Among Physiotherapy Undergraduate Students. PMID- 28735336 TI - Acoustic Radiation Force Impulse (ARFI) Elastography and Serological Markers in Assessment of Liver Fibrosis and Free Portal Pressure in Patients with Hepatitis B. AB - BACKGROUND The aim of this study was to investigate the feasibility of using acoustic radiation force impulse (ARFI) elastography, AST-to-platelet ratio index (APRI), and FIB-4 in assessing liver fibrosis and free portal pressure in patients with hepatitis B. MATERIAL AND METHODS We enrolled 126 patients with hepatitis B who underwent liver surgery at the General Surgery Department of the First Affiliated Hospital of Shihezi University Medical School from February 2013 to August 2015. Preoperatively, shear wave velocity (SWV) of the liver was measured with the Siemens S2000 ultrasound system to reflect liver stiffness. Serological markers were collected and fibrosis indices APRI and FIB-4 were calculated. Intraoperatively, liver tissues were harvested and free portal pressure (FPP) was measured. Postoperatively, fibrosis of liver tissues was pathologically staged. RESULTS The results of SWV, APRI, FIB-4, and FPP were all correlated with the degree of liver fibrosis (Spearman correlation coefficients: r=0.777, P<0.001; r=0.526, P<0.001; r=0.471, P<0.001; p<0.000; r=0.675, p<0.000). Receiver operating characteristic curve (ROC) analysis showed that the areas under the curve (AUC) of ARFI, APRI, and FIB-4 in diagnosing liver fibrosis were 0.830, 0.768, and 0.717, respectively, for stage F>=1; 0.861, 0.773, and 0.754, respectively, for stage F>=2; 0.941, 0.793, and 0.779, respectively, for stage F>=3; and 0.945, 0.783, and 0.754, respectively, for stage F=4. SWV, APRI, and FIB-4 were all correlated with FPP (Pearson correlation coefficients: 0.387, P<0.001; 0.446, P<0.001; 0.419, P<0.001). CONCLUSIONS ARFI, APRI, and FIB-4 can assess liver fibrosis in patients with hepatitis B when assessing the portal venous pressure. The difference in diagnostic efficacy between the 3 was not significant. PMID- 28735337 TI - Thresholds of Toxicological Concern - Setting a threshold for testing below which there is little concern. AB - Low dose, low risk; very low dose, no real risk. Setting a pragmatic threshold below which concerns become negligible is the purpose of thresholds of toxicological concern (TTC). The idea is that such threshold values do not need to be established for each and every chemical based on experimental data, but that by analyzing the distribution of lowest or no-effect doses of many chemicals, a TTC can be defined - typically using the 5th percentile of this distribution and lowering it by an uncertainty factor of, e.g., 100. In doing so, TTC aims to compare exposure information (dose) with a threshold below which any hazard manifestation is very unlikely to occur. The history and current developments of this concept are reviewed and the application of TTC for different regulated products and their hazards is discussed. TTC lends itself as a pragmatic filter to deprioritize testing needs whenever real-life exposures are much lower than levels where hazard manifestation would be expected, a situation that is called "negligible exposure" in the REACH legislation, though the TTC concept has not been fully incorporated in its implementation (yet). Other areas and regulations - especially in the food sector and for pharmaceutical impurities - are more proactive. Large, curated databases on toxic effects of chemicals provide us with the opportunity to set TTC for many hazards and substance classes and thus offer a precautionary second tier for risk assessments if hazard cannot be excluded. This allows focusing testing efforts better on relevant exposures to chemicals. PMID- 28735338 TI - Undervaluation of suffering of experimental animals in Germany. PMID- 28735339 TI - IN vitro toxicology: From INtestine to braIN. PMID- 28735340 TI - Alternative approach to animal testing and cell cultures, according to European laws. PMID- 28735341 TI - The Effect of Nanosecond, High-Voltage Electric Pulses on the Shape and Permeability of Polymersome GUVs. AB - Polymersomes, vesicles composed of block copolymers, are promising candidates as membrane alternatives and functional containers, e.g., as potential carriers for functional molecules because of their stability and tunable membrane properties. In the scope of possible use for membrane protein delivery to cells by electrofusion, we investigated the cytotoxicity of such polymersomes as well as the effects of nanosecond electric pulses with variable repetition rate on the shape and permeability of polymersomes in buffers with different conductivities. The polymersomes did not show cytotoxic effects to CHO and B16-F1 cells in vitro in concentrations up to 250 ug/mL (for 48 h) or 1.35 mg/mL (for 60 min), which renders them suitable for interacting with living cells. We observed a significant effect of the pulse repetition rate on electrodeformation of the polymersomes. The electrodeformation was most pronounced in low conductivity buffer, which is favorable for performing electrofusion with cells. However, despite more pronounced deformation at higher pulse repetition rate, the electroporation performance of polymersomes was unaffected and remained in similar ranges both at 10 Hz and 10 kHz. This phenomenon is possibly due to the higher stability and rigidity of polymer vesicles, compared to liposomes, and can serve as an advantage (or disadvantage) depending on the aim in employing polymersomes such as stable membrane alternative architectures or drug vehicles. PMID- 28735342 TI - Cataract in the chronically exposed residents of the Techa riverside villages. AB - The present study is based on a retrospective analysis of archive data of the Clinical Department of the Urals Research Center for Radiation Medicine that has been established to examine and treat accidentally exposed residents of the Urals Region. All individuals included in this study were examined by an ophthalmologist. The study of cataract incidence has been conducted retrospectively for the period from 1951 till 2000 among chronically exposed residents of the Techa riverside villages (6343 persons). Individual accumulated absorbed doses to soft tissues (analogue of eye dose) reached 1.18 Gy (mean 0.12 Gy) while for 88.9% of the study group the dose did not exceed 0.1 Gy. There was no evidence of the influence of low-dose and low-dose rate on cataract incidence. Excess relative risk of cataract formation per 1 Gy was 0.40 (95% CI -0.43; 1.47). It is noted that 15% of all excess cases were registered in persons with soft tissue dose above 0.3 Gy, though their fraction among all examined persons was only 4.1%. Risk of cataract development significantly increased in exposed individuals with retinal angiosclerosis, diabetes and arterial hypertension. PMID- 28735343 TI - Exact probabilities for the indeterminacy of complex networks as perceived through press perturbations. AB - We consider the goal of predicting how complex networks respond to chronic (press) perturbations when characterizations of their network topology and interaction strengths are associated with uncertainty. Our primary result is the derivation of exact formulas for the expected number and probability of qualitatively incorrect predictions about a system's responses under uncertainties drawn form arbitrary distributions of error. Additional indices provide new tools for identifying which links in a network are most qualitatively and quantitatively sensitive to error, and for determining the volume of errors within which predictions will remain qualitatively determinate (i.e. sign insensitive). Together with recent advances in the empirical characterization of uncertainty in networks, these tools bridge a way towards probabilistic predictions of network dynamics. PMID- 28735344 TI - Treatment Outcome, Duration, and Costs: A Comparison of Performance Indicators Using Data from Eight Mental Health Care Providers in The Netherlands. AB - Assessing performance of mental health services (MHS) providers merely by their outcomes is insufficient. Process factors, such as treatment cost or duration, should also be considered in a meaningful and thorough analysis of quality of care. The present study aims to examine various performance indicators based on treatment outcome and two process factors: duration and cost of treatment. Data of patients with depression or anxiety from eight Dutch MHS providers were used. Treatment outcome was operationalized as case mix corrected pre-to-posttreatment change scores and as reliable change (improved) and clinical significant change (recovered). Duration and cost were corrected for case mix differences as well. Three performance indicators were calculated and compared: outcome as such, duration per outcome, and cost per outcome. The results showed that performance indicators, which also take process variability into account, reveal larger differences between MHS providers than mere outcome. We recommend to use the three performance indicators in a complementary way. Average pre-to-posttreatment change allows for a simple and straightforward ranking of MHS providers. Duration per outcome informs patients on how MHS providers compare in how quickly symptomatic relief is achieved. Cost per outcome informs MHS providers on how they compare regarding the efficiency of their care. The substantial variation among MHS providers in outcome, treatment duration and cost calls for further exploration of its causes, dissemination of best practices, and continuous quality improvement. PMID- 28735345 TI - Large facial lymphatic malformation treatment using sclerosing agent followed by surgical resection: clinical and pathology report. AB - Lymphatic malformations are rare slow-flow vascular malformations, with high tendency to appear in the head and neck region. The treatment of these lesions ranges from follow-up to sclerosing agent injection to surgical excision. The authors present a case of a new born with large extensive lingual and submandibular lymphatic malformation, for which the patient underwent tracheostomy and gastrostomy insertion. He was then treated successfully with sclerosing agent injections followed by surgical excision, with 7 years follow up. The second case presented is a two and a half baby with large lingual lymphatic malformation, treated successfully with doxycycline injections followed by intraoral excision of the lesion. Pathology of the excised lesion is then demonstrated, which shows for the first time the different layers affected by the sclerosing agent. PMID- 28735346 TI - Anatomical relation between nasal septum deviation and oropharynx volume in different facial patterns evaluated through cone beam computed tomography. AB - INTRODUCTION: The objective of this study was to establish the anatomical relation between nasal septum deviation (NSD) and oropharynx volume in different facial patterns using cone beam computed tomography (CBCT). METHODS: Ninety CBCT examinations were analyzed. InVivoDental software was used to evaluate cephalometric image reconstructions in terms of facial type, determined from cephalometric measurements indicative of growth direction; the presence of NSD was also evaluated. ITK-SNAP software was employed for delimitation of the oropharynx. Intra-examiner error methods were recorded. The results were subjected to parametric and non-parametric tests using Bioestat 5.0. RESULTS: A comparison of facial types revealed a significantly lower prevalence of NSD in the dolichofacial group compared with the brachyfacial and mesofacial groups (P = 0.0101 and 0.0149, respectively). In the total sample, there was a very strong positive relation between the presence of NSD and oropharynx space volume (P = 0.0162). The oropharynx volume was larger in all facial patterns in the presence of NSD. CONCLUSION: The presence of NSD was not associated with facial type, although the oropharynx volume in patients with NSD increased. Therefore, deviation of the septum influences oropharynx volume. PMID- 28735347 TI - The Impact of Eldercare on Adult Children's Health and Employment in Transitional China. AB - This paper explores the content and extent of the burden of caregiving for Chinese families in transition. It sets out to understand how Chinese families manage to balance family caregiving responsibilities with employment, the impact of the existing social institutions on family caregiving practices, and the risks that caregivers have to face. Data were collected from a sample of 214 workers from 14 manufacturing companies in an industrialized city in central China in 2013. Analysis revealed that common types of eldercare were assisting with activities of daily living and medical related care; middle aged employed respondents were most likely to be the caregivers to older family members; financial and time demands of care were challenging for caregivers, but women with more education and a secure job responded to the pressure of care giving better than those with less education and insecure jobs. An absence of workplace policies to support family caregivers was reported to create insecure employment conditions among middle aged workers. The findings imply an urgent need for legislative action and workplace policy that support family caregiving in China. PMID- 28735348 TI - Analysis of the CD8+ T cell anti-HIV activity in heterologous cell co-cultures reveals the benefit of multiple HLA class I matches. AB - CD8+ T lymphocytes can reduce the production of human immunodeficiency virus 1 (HIV-1) by CD4+ T cells by cytotoxic and non-cytotoxic mechanisms. To investigate the involvement of human leukocyte antigen (HLA) class I compatibility in anti HIV responses, we co-cultured primary CD8+ T cells, isolated from the peripheral blood of HIV-1-infected individuals, with panels of autologous and heterologous acutely HIV-1-infected primary CD4+ T cells. Altogether, CD8+ T cell anti-HIV activity was evaluated in more than 200 co-cultures. Marked heterogeneity in HIV 1 replication levels was observed among the co-cultures sharing a common CD8+ T cell source. The co-cultures that exhibited greater than 50% reduction in HIV production were found to have significantly increased numbers of matching HLA class I alleles (Yates chi-square = 54.21; p < 0.001). With CD8+ T cells from HIV controllers and asymptomatic viremic individuals, matching HLA-B and/or HLA-C alleles were more predictive of strong anti-HIV activity than matching HLA-A alleles. Overall, HLA class I genotype matches were more closely associated with CD8+ T cell anti-HIV activity than supertype pairings. Antibodies against HLA class I and CD3 reduced the CD8+ T cell anti-HIV activity. Stimulated CD8+ T cells exhibited increased anti-HIV activity and reduced dependency on HLA compatibility. These findings provide evidence that the maximal suppression of HIV replication by CD8+ T cells requires the recognition of multiple epitopes. These studies provide insight for HIV vaccine development, and the analytic approach can be useful for the functional characterization of HLA class I alleles and tentative HLA class I supertypes. PMID- 28735349 TI - Connecting the Dots Between Fatty Acids, Mitochondrial Function, and DNA Methylation in Atherosclerosis. AB - PURPOSE OF REVIEW: The quest for factors and mechanisms responsible for aberrant DNA methylation in human disease-including atherosclerosis-is a promising area of research. This review focuses on the role of fatty acids (FAs) as modulators of DNA methylation-in particular the role of mitochondrial beta-oxidation in FA induced changes in DNA methylation during the progression of atherosclerosis. RECENT FINDINGS: Recent publications have advanced the knowledge in all areas touched by this review: the causal role of lipids in shaping the DNA methylome, the associations between chronic degenerative disease and mitochondrial function, the lipid composition of the atheroma, and the relevance of DNA hypermethylation in atherosclerosis. Evidence is beginning to emerge, linking the dynamics of FA type abundance, mitochondrial function, and DNA methylation in the atheroma and systemically. In particular, this review highlights mitochondrial beta-oxidation as an important regulator of DNA methylation in metabolic disease. Despite the many questions still unanswered, this area of research promises to identify mechanisms and molecular factors that establish a pathological gene expression pattern in atherosclerosis. PMID- 28735350 TI - Inflammatory Joint Disorders and Neutrophilic Dermatoses: a Comprehensive Review. AB - Rheumatoid arthritis and spondyloarthritis are inflammatory joint disorders with an autoimmune pathogenesis and systemic involvement. The skin is one of the most frequently affected extraarticular sites with a number of manifestations or distinct diseases, including common conditions, such as rheumatoid nodules and psoriasis, and rare diseases like neutrophilic dermatoses. The latter are clinically characterised by polymorphic lesions, including pustules, bullae, abscesses, papules, nodules, plaques and ulcers, and histologically by neutrophil rich inflammatory infiltrates. Inflammatory joint disorders and neutrophilic dermatoses share a number of pathophysiological features related to their cytokine overexpression profile. Moreover, any organ system can be potentially involved in neutrophilic dermatoses, giving rise to the concept of neutrophilic disease. Among the extracutaneous manifestations of neutrophilic disease, joint involvement is regarded as the most common. It is not associated with erosions and disability and usually responds to treatment for skin involvement, consisting of systemic corticosteroids and, in refractory cases, immunosuppressants or biologics. Arthritis may also be the initial manifestation of rheumatoid arthritis or spondyloarthritis, which has a chronic or recurrent course and requires a continuous treatment with synthetic or biologic disease-modifying anti rheumatic drugs. If not properly treated, they may be associated with disability and reduced quality of life. Skin lesions occurring during the course of rheumatoid arthritis and spondyloarthritis require a multidisciplinary approach envisaging the collaboration of dermatologists and rheumatologists in order to achieve early diagnosis and treatment. Several biomarkers may help the clinician in the differential diagnosis of arthritis while histology is pivotal for the correct classification of the skin disease. However, in some cases, only regular follow-up allows a definite diagnosis. In this review article, we focus on the prototypic neutrophilic dermatoses like pyoderma gangrenosum, Sweet's syndrome, hidradenitis suppurativa and their syndromic forms as well as on their articular involvement, providing a simple approach for their diagnosis and therapy. PMID- 28735351 TI - Multiple correlation analyses revealed complex relationship between DNA methylation and mRNA expression in human peripheral blood mononuclear cells. AB - DNA methylation is an important regulator on the mRNA expression. However, a genome-wide correlation pattern between DNA methylation and mRNA expression in human peripheral blood mononuclear cells (PBMCs) is largely unknown. The comprehensive relationship between mRNA and DNA methylation was explored by using four types of correlation analyses and a genome-wide methylation-mRNA expression quantitative trait locus (eQTL) analysis in PBMCs in 46 unrelated female subjects. An enrichment analysis was performed to detect biological function for the detected genes. Single pair correlation coefficient (r T1) between methylation level and mRNA is moderate (-0.63-0.62) in intensity, and the negative and positive correlations are nearly equal in quantity. Correlation analysis on each gene (T4) found 60.1% genes showed correlations between mRNA and gene-based methylation at P < 0.05 and more than 5.96% genes presented very strong correlation (R T4 > 0.8). Methylation sites have regulation effects on mRNA expression in eQTL analysis, with more often observations in region of transcription start site (TSS). The genes under significant methylation regulation both in correlation analysis and eQTL analysis tend to cluster to the categories (e.g., transcription, translation, regulation of transcription) that are essential for maintaining the basic life activities of cells. Our findings indicated that DNA methylation has predictive regulation effect on mRNA with a very complex pattern in PBMCs. The results increased our understanding on correlation of methylation and mRNA and also provided useful clues for future epigenetic studies in exploring biological and disease-related regulatory mechanisms in PBMC. PMID- 28735352 TI - Long noncoding RNA expression profiles in chondrogenic and hypertrophic differentiation of mouse mesenchymal stem cells. AB - Long noncoding RNAs (lncRNAs) are important regulators for a variety of biological processes. Chondrogenic differentiation of mesenchymal stem cells (MSCs) is a crucial stage in chondrogenesis while chondrocyte hypertrophy is related to endochondral ossification and osteoarthritis. However, the effects of lncRNAs on chondrogenic and hypertrophic differentiation of mouse MSCs are unclear. To explore the potential mechanisms of lncRNAs during chondrogenesis and chondrocyte hypertrophy, microarray was performed to investigate the expression profiles of lncRNA and mRNA in MSCs, pre-chondrocytes, and hypertrophic chondrocytes. Then, we validated microarray data by RT-PCR and screened three lncRNAs from upregulating groups during chondrogenesis and chondrocyte hypertrophy respectively. After downregulating any of the above lncRNAs, we found that the expression of chondrogenesis-related genes such as Sox9 and Col2a1 and hypertrophy-related genes including Runx2 and Col10a1 was inhibited, respectively. Furthermore, the target genes of above lncRNAs were predicted by bioinformatics approaches. Gene ontology and Kyoto encyclopedia of genes and genome biological pathway analysis were also made to speculate the functions of above lncRNAs. In conclusion, the study first revealed the expression profile of lncRNAs in chondrogenic and hypertrophic differentiations of mouse MSCs and presented a new prospect for the underlying mechanisms of chondrogenesis and endochondral ossification. PMID- 28735353 TI - Non-Vitamin K Oral Anticoagulants (NOACs) and Their Reversal. AB - PURPOSE OF REVIEW: An 80-year-old man presents with an acute right hemiparesis and National Institutes of Health Stroke Scale (NIHSS) of 25, 14 h after taking dabigatran. Activated partial thromboplastin time (aPTT) is 42.8 s. Arteriogram demonstrates left internal carotid artery thrombosis. What is the appropriate management of this patient with acute ischemic stroke while on a NOAC? RECENT FINDINGS: Idarucizumab is a reversal agent approved for dabigatran, and two more reversal agents, andexanet alfa and aripazine, are currently in development for NOACs. In this article, we review currently available NOACs, their laboratory monitoring, and reversal agents. PMID- 28735354 TI - Transplantation sites for human and murine islets. AB - AIMS/HYPOTHESIS: Beta cell replacement is a potential cure for type 1 diabetes. In humans, islet transplants are currently infused into the liver via the portal vein, although this site has disadvantages. Here, we investigated alternative transplantation sites for human and murine islets in recipient mice, comparing the portal vein with quadriceps muscle and kidney, liver and spleen capsules. METHODS: Murine islets were isolated from C57BL6/J mice and transplanted into syngeneic recipients. Human islets were isolated and transplanted into either severe combined immunodeficiency (SCID) or recombination-activating gene 1 (RAG 1) immunodeficient recipient mice. All recipient mice were 8-12 weeks of age and had been rendered diabetic (defined as blood glucose concentrations >=20 mmol/l on two consecutive days before transplantation) by alloxan tetrahydrate treatment. Islets were transplanted into five different sites (portal vein, quadriceps muscle, kidney, liver and spleen capsules). Blood glucose concentrations were monitored twice weekly until mice were killed. Dose-response studies were also performed to determine the minimum number of islets required to cure diabetes ('cure' is defined for this study as random fed blood glucose of <15 mmol/l). RESULTS: For transplantation of murine islets into the different sites, the kidney yielded 100% success, followed by muscle (70%), portal vein (60%), spleen capsule (29%) and liver capsule (0%). For human islets, transplantation into the kidney cured diabetes in 75-80% of recipient mice. Transplantation into muscle and portal vein had intermediate success (both 29% at 2000 islet equivalents), while transplantation into liver and spleen capsule failed (0%). With increased islet mass, success rates for muscle grafts improved to 52-56%. CONCLUSIONS/INTERPRETATION: For both human and murine islets, equivalent or superior glucose lowering results were obtained for transplantation into skeletal muscle, compared with the portal vein. Unfortunately, kidney grafts are not feasible in human recipients. Skeletal muscle offers easier access and greater potential for protocol biopsies. This study suggests that human trials of muscle as a transplant site may be warranted. PMID- 28735355 TI - A systematic review of dental disease management in cancer patients. AB - INTRODUCTION: This systematic review aims to update on the prevalence of odontogenic-related infections and the efficacy of dental strategies in preventing dental-related complications in cancer patients since the 2010 systematic review. REVIEW METHOD: A literature search was conducted in the databases MEDLINE/PubMed and EMBASE for articles published between 1 January 2009 and 30 June 2016. Each study was assessed by 2 reviewers and the body of evidence for each intervention was assigned an evidence level. RESULTS: After examination of the abstracts and full-text articles, 59 articles satisfied the inclusion criteria. The weighted prevalence of dental infections and pericoronitis during cancer therapy was 5.4 and 5.3%, respectively. The frequency of dental-related infections during intensive chemotherapy after complete, partial, and minimal pre cancer dental evaluation/treatment protocols ranged from 0 to 4%. Protocols involving third molars extractions had the highest complications (40%). CONCLUSIONS: In view of the low prevalence of infections and the potential for complications after third molar extractions, it is suggested that partial dental evaluation/treatment protocols prior to intensive chemotherapy; whereby minor caries (within dentin), asymptomatic third molars or asymptomatic teeth without excessive probing depth (<8 mm), mobility (mobility I or II) or with periapical lesions of <5 mm were observed; is a viable option when there is insufficient time for complete dental evaluation/treatment protocols. The use of chlorhexidine, fluoride mouth rinses as well as composite resin, resin-modified glass ionomer cement (GIC), and amalgam restorations over conventional GIC in post head and neck radiation patients who are compliant fluoride users is recommended. PMID- 28735356 TI - Evaluation of anthelmintic antimicrobial and antioxidant activity of Chenopodium album. AB - The objective of this study was to evaluate the anthelmintic, antimicrobial and antioxidant activities of Chenopodium album against gastrointestinal nematodes of sheep and some pathogenic microbes. A worm motility inhibition assay was used for in vitro study, and a faecal egg count reduction assay was used for an in vivo study. Various concentrations ranging from 100 to 500 MUg/ml of the extract were subjected to antimicrobial screening by disc diffusion method against four selected bacterial (Staphylococcus aureus, Klebsiella pneumoniae, Pseudomonas multocida and Escherichia coli) and two fungal (Aspergillus flavus and Candida albicans) strains in order to estimate the medicinal potential of the herb. DPPH (1,1-diphenyl-2-picrylhydrazyl), riboflavin photo-oxidation, deoxyribose, lipid peroxidation assays were used for antioxidant activity. The extracts exhibited dose- and time-dependent anthelmintic effects on the Haemonchus contortus as compared to levamisole. The extract showed maximum inhibitory effect against S. aureus (28 +/- 0.14 mm), while as mild inhibitory effect was observed against E. coli among the selected microbial strains. The effect produced by the different extract concentrations was comparable with the standard antibacterial agent streptomycin sulphate and antifungal agent nystatin, which were used as effective positive control in the study. The antioxidant activity showed that the extracts exhibited scavenging effect in concentration-dependent manner on superoxide anion radicals and hydroxyl radicals leading to the conclusion that the plant has broad spectrum anthelmintic, antimicrobial and antioxidant activities and could be a potential alternative for treating various diseases. PMID- 28735357 TI - Promoting and Protecting Public Health: How the European Union Pharmacovigilance System Works. AB - This article provides an overview of the European Union pharmacovigilance system resulting from the rationalisation and strengthening delivered through the implementation of the revised pharmacovigilance legislation. It outlines the system aims, underlying principles, components and drivers for future change. At its core, the Pharmacovigilance Risk Assessment Committee is responsible for assessing all aspects of the risk management of medicinal products, thus ensuring that medicines approved for the European Union market are optimally used by maximising their benefits and minimising risks. The main objectives of the system are to promote and protect public health by supporting the availability of medicines including those that fulfil previously unmet medical needs, and reducing the burden of adverse drug reactions. These are achieved through a proactive, risk proportionate and patient-centred approach, with high levels of transparency and engagement of civil society. In the European Union, pharmacovigilance is now fully integrated into the life cycle of medicinal products, with the planning of pharmacovigilance activities commencing before a medicine is placed on the market, and companies encouraged to start planning very early in development for high-innovation products. After authorisation, information on the safety of medicines continues to be obtained through a variety of sources, including spontaneous reports of adverse drug reactions or monitoring real-world data. Finally, the measurement of the impact of pharmacovigilance activities, auditing and inspections, as well as capacity building ensure that the system undergoes continuous improvement and can always rely on the best methodologies to safeguard public health. PMID- 28735359 TI - Binding abstract concepts. AB - Binding theories assume that a stimulus and the response made to it are bound together in an event file (Hommel et al., Behav Brain Sci 24(05):849-937, 2001). Such bindings can occur even after single encounters. If the stimulus or parts of its features are repeated within the time frame in which the event file is still intact, the previously integrated response is retrieved. Stimulus-response binding can exist at a perceptual, conceptual or a response selection level (Henson et al., Trends Cogn Sci 18(7):376-384, 2014). The current experiments test whether the observed binding of concepts with responses can be extended from concrete to abstract concepts (detailedness) and whether abstract concepts can retrieve the previous response, in the absence of perceptual repetition. In the present experiment participants responded to a target feature (colour) while the detailedness of the stimulus was irrelevant to the task. The results showed a significant interaction of response relation and detailedness relation, even in the absence of perceptual repetition. This interaction is interpreted as evidence for response-retrieval due to abstract concept repetition. Thus, our data suggest a broader impact of binding mechanism on performance as even abstract concepts can be integrated into event-files and later modulate behaviour. PMID- 28735358 TI - IL-10 and TGF-beta unbalanced levels in neutrophils contribute to increase inflammatory cytokine expression in childhood obesity. AB - PURPOSE: Obesity is a multifactorial disease, associated with metabolic disorders, chronic low-grade inflammation, and impaired immunity. This study aimed to evaluate the childhood obesity-associated effects on neutrophil activation and cytokine production. METHODS: We evaluated activation and recognition markers and cytokine production in neutrophils from the peripheral blood of children with obesity and normal weight using multicolor flow cytometry. RESULTS: We demonstrate a higher frequency of neutrophils in childhood obesity group (CO) compared to normal-weight group (NW). Our data showed that neutrophils from CO group are capable of antigen recognition and presentation through higher expression of TLR-4 (CD284) and HLA-DR in comparison with neutrophils from NW. On the other hand, neutrophils from CO group are faulty to deliver co-stimulatory signals, through lower expression of co-stimulatory molecules. We showed an increased expression of IL-6, IL-1beta, IL-12, and TNF, and decreased expression of IL-8 and IL-10 by neutrophils from CO compared to NW, while TGF-beta is equivalently expressed in neutrophils from both groups. Despite this, we observed that TGF-beta/inflammatory cytokine ratio was significantly higher than the IL 10/inflammatory cytokine ratio only in CO group. Our analysis showed obesity altering the correlation profile for the expression of co-stimulatory, recognition, and activation molecules, as well as for cytokines by neutrophils, suggesting an association between lower IL-10 expression and inflammation in childhood obesity. CONCLUSIONS: The unbalance between the ratio of IL-10 and TGF beta expressions, the IL-10 lower expression, and changes in correlation profile seem to contribute with an inefficient regulation of inflammatory cytokine expression in childhood obesity. However, these changes still not may be considered the sole mechanism that directs inflammation during childhood obesity, once other molecules, pathways, and cells should be evaluated. PMID- 28735360 TI - Navigating the Future of Cardiovascular Drug Development-Leveraging Novel Approaches to Drive Innovation and Drug Discovery: Summary of Findings from the Novel Cardiovascular Therapeutics Conference. AB - PURPOSE: The need for novel approaches to cardiovascular drug development served as the impetus to convene an open meeting of experts from the pharmaceutical industry and academia to assess the challenges and develop solutions for drug discovery in cardiovascular disease. METHODS: The Novel Cardiovascular Therapeutics Summit first reviewed recent examples of ongoing or recently completed programs translating basic science observations to targeted drug development, highlighting successes (protein convertase sutilisin/kexin type 9 [PCSK9] and neprilysin inhibition) and targets still under evaluation (cholesteryl ester transfer protein [CETP] inhibition), with the hope of gleaning key lessons to successful drug development in the current era. Participants then reviewed the use of innovative approaches being explored to facilitate rapid and more cost-efficient evaluations of drug candidates in a short timeframe. RESULTS: We summarize observations gleaned from this summit and offer insight into future cardiovascular drug development. CONCLUSIONS: The rapid development in genetic and high-throughput drug evaluation technologies, coupled with new approaches to rapidly evaluate potential cardiovascular therapies with in vitro techniques, offer opportunities to identify new drug targets for cardiovascular disease, study new therapies with better efficiency and higher throughput in the preclinical setting, and more rapidly bring the most promising therapies to human testing. However, there must be a critical interface between industry and academia to guide the future of cardiovascular drug development. The shared interest among academic institutions and pharmaceutical companies in developing promising therapies to address unmet clinical needs for patients with cardiovascular disease underlies and guides innovation and discovery platforms that are significantly altering the landscape of cardiovascular drug development. PMID- 28735361 TI - Concentrations, Source Identification, and Lung Cancer Risk Associated with Springtime PM2.5-Bound Polycyclic Aromatic Hydrocarbons (PAHs) in Nanjing, China. AB - This study concentrated on the pollution level, sources, and lung cancer risk of PM2.5-bound polycyclic aromatic hydrocarbons (PAHs) in spring in Nanjing, China. The PM2.5 samples were collected in spring of the year 2016 in Nanjing. Sixteen United States Environmental Protection Agency priority PAHs were extracted and analyzed after sampling. The mean concentrations of PAHs and BaPeq were 3.98 +/- 1.01 and 0.29 +/- 0.08 ng/m3, respectively, which is a low level among results from regions worldwide. The diurnal variations of PAHs and BaPeq concentrations showed a relatively high level in the early morning, at the morning rush time of work and traffic transportation, and in the evening traffic peak hours. According to the results of diagnostic ratios, PAHs originated mainly from traffic exhaust, especially diesel vehicle emissions. In a single day, the highest inhalation exposure level was focused between 4 a.m. and 6 a.m., whereas the time between 12 a.m. to 2 p.m. in a day had the lowest exposure dose. Due to the inhalation exposure, the median values of incremental lung cancer risk in spring were estimated to be 7.08 * 10-9, 5.29 * 10-9, 3.53 * 10-8, 5.21 * 10-9, 7.21 * 10-9, 5.24 * 10-9, 3.01 * 10-8, and 5.40 * 10-9 for boys, male adolescents, male adults, male seniors, girls, female adolescents, female adults, and female seniors, respectively, indicating low potential lung cancer risk. PMID- 28735362 TI - The role of Sulforaphane in cancer chemoprevention and health benefits: a mini review. AB - Cancer is a multi-stage process resulting from aberrant signaling pathways driving uncontrolled proliferation of transformed cells. The development and progression of cancer from a premalignant lesion towards a metastatic tumor requires accumulation of mutations in many regulatory genes of the cell. Different chemopreventative approaches have been sought to interfere with initiation and control malignant progression. Here we present research on dietary compounds with evidence of cancer prevention activity that highlights the potential beneficial effect of a diet rich in cruciferous vegetables. The Brassica family of cruciferous vegetables such as broccoli is a rich source of glucosinolates, which are metabolized to isothiocyanate compounds. Amongst a number of related variants of isothiocyanates, sulforaphane (SFN) has surfaced as a particularly potent chemopreventive agent based on its ability to target multiple mechanisms within the cell to control carcinogenesis. Anti-inflammatory, pro-apoptotic and modulation of histones are some of the more important and known mechanisms by which SFN exerts chemoprevention. The effect of SFN on cancer stem cells is another area of interest that has been explored in recent years and may contribute to its chemopreventive properties. In this paper, we briefly review structure, pharmacology and preclinical studies highlighting chemopreventive effects of SFN. PMID- 28735363 TI - Routine follow-up radiographs for distal radius fractures are seldom clinically substantiated. AB - INTRODUCTION: The value of routine radiographs during follow-up after distal radius fractures is unclear. The aim of this study was to evaluate whether routine radiographs performed during the follow-up period in patients with a distal radius fracture influenced clinical decision making. METHODS: This retrospective cohort study included patients aged >=18 years who were treated for a distal radius fracture at four hospitals in The Netherlands in 2012. Demographic and clinical and radiographic characteristics were collected from medical records. RESULTS: 1042 patients were included. In 121 (14%) of the 841 radiographs, a clinical indication was reported. Treatment was affected by 22 (2.6%) radiographs, including 11 (1.5%) radiographs that were categorized as routine, 9 (1.2%) of which led to prolonged cast immobilization and 2 (0.2%) to surgery for conservatively treated patients. CONCLUSION: Although it is common practice to take radiographs after distal radius fractures, the study results indicate that routine radiographs seldom affect treatment. This finding should be weighed against the high health care costs associated with these fractures. We hope that the results of our study will trigger the awareness among surgeons that in the current practice, many radiographs are taken on routine without influencing clinical decision making and can probably be omitted. LEVEL OF EVIDENCE: Level III. PMID- 28735364 TI - Umbilical hernia repair in pregnant patients: review of the American College of Surgeons National Surgical Quality Improvement Program. AB - BACKGROUND: Umbilical hernias present commonly during pregnancy secondary to increased intra-abdominal pressure. As a result, umbilical hernia incarceration or strangulation may affect pregnant females. The purpose of this study is to detail the operative management and 30-day outcomes of umbilical hernias in pregnant patients using the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP). METHODS: All female patients undergoing umbilical hernia repair during pregnancy were identified within the ACS-NSQIP. Preoperative patient variables, intraoperative variables, and 30-day patient morbidity and mortality outcomes were investigated using a variety of statistical tests. RESULTS: A total of 126 pregnant patients underwent umbilical hernia repair from 2005 to 2014; 73 (58%) had incarceration or strangulation at the time of surgical intervention. The majority of patients (95%) underwent open umbilical hernia repair. Superficial surgical site infection was the most common morbidity in patients undergoing open umbilical hernia repair. CONCLUSIONS: Based on review of the ACS-NSQIP database, the incidence of umbilical hernia repair during pregnancy is very low; however, the majority of patients required repair for incarceration of strangulation. When symptoms develop, these hernias can be repaired with minimal 30-day morbidity to the mother. Additional studies are needed to determine the long-term recurrence rate of umbilical hernia repairs performed in pregnant patients and the effects of surgical intervention and approach on the fetus. PMID- 28735365 TI - An Update on the Use of Immunotherapy in the Treatment of Lymphoma. AB - PURPOSE OF REVIEW: Throughout the field of oncology, immunotherapy is moving further towards the first-line setting, and there is encouraging data for the use of these novel therapies in the management of lymphomas, utilizing treatments approved for both solid and hematologic malignancies. Herein, we review promising advances in this rapidly moving field from the past year. RECENT FINDINGS: In the last year, we have seen promising clinical data on engineered antibody therapies for the treatment of lymphomas, as well as further optimization of engineered antibody fragments fused onto linkers or chimeric T cell receptors, both of the modalities capable of transforming non-specific T cells into tumor-specific, serial killer cells. Here we will review the promising data on these advances in antibody-based therapies, as well as some of the immunomodulators and checkpoint blocking therapies that shown to have promising results in the treatment of lymphomas within the past year. PMID- 28735366 TI - Further validation of the affective bias test for predicting antidepressant and pro-depressant risk: effects of pharmacological and social manipulations in male and female rats. AB - RATIONALE: Affective biases are hypothesised to contribute to the cause and treatment of mood disorders. We have previously found that affective biases, associated with learning and memory, are observed following acute treatments with a range of antidepressant and pro-depressant manipulations. OBJECTIVE: This study aimed to test if similar biases are observed in male and female Sprague Dawley (SD) rats. We also test whether the stress hormone, corticosterone, induces a negative bias in the affective bias test (ABT) consistent with its putative role in the development of depression. We then use a meta-analysis to compare our findings with data published for the Lister Hooded rats. METHODS: The ABT uses a within-subject study design where animals learn to associate distinct digging substrates, encountered on different days, with the same value food reward. Exposure to one substrate is paired with a treatment manipulation (drug or environmental) and the other with a control condition. A preference test is used to test if the treatment has induced a positive or negative bias. RESULTS: Consistent with previous data, both male and female SD rats exhibit similar positive affective biases following treatment with the antidepressant, venlafaxine, and social play and negative affective biases following FG 7142 (benzodiazepine inverse agonist) and social stress. Acute treatment with corticosterone induced a negative bias. CONCLUSIONS: These data add to the translational validity of the ABT and suggest that corticosterone can induce a negative affective bias following acute treatment, an effect which may contribute to its long-term effects on mood. PMID- 28735367 TI - Short-term and long-term effects of diazepam on the memory for discrimination and generalization of scopolamine. AB - Benzodiazepines are among the most widely prescribed and misused psychopharmaceutical drugs. Although they are well-tolerated, they are also capable of producing amnestic effects similar to those observed after pharmacological or organic cholinergic dysfunction. To date, the effect of benzodiazepine diazepam on the memory for discrimination of anticholinergic drugs has not been reported. The aim of the present study was to analyze the immediate and long-term effects of diazepam on a drug discrimination task with scopolamine. Male Wistar rats were trained to discriminate between scopolamine and saline administration using a two-lever discrimination task. Once discrimination was acquired, the subjects were divided into three independent groups, (1) control, (2) diazepam, and (3) diazepam chronic administration (10 days). Subsequently, generalization curves for scopolamine were obtained. Additionally, the diazepam and control groups were revaluated after 90 days without having been given any other treatment. The results showed that diazepam produced a significant reduction in the generalization gradient for scopolamine, indicating an impairment of discrimination. The negative effect of diazepam persisted even 90 days after drug had been administered. Meanwhile, the previous administration of diazepam for 10 days totally abated the generalization curve and the general performance of the subjects. The results suggest that diazepam affects memory for the stimulus discrimination of anticholinergic drugs and does so persistently, which could be an important consideration during the treatment of amnesic patients with benzodiazepines. PMID- 28735368 TI - MDMA-induced indifference to negative sounds is mediated by the 5-HT2A receptor. AB - BACKGROUND: MDMA has been shown to induce feelings of sociability, a positive emotional bias and enhanced empathy. While previous research has used only visual emotional stimuli, communication entails more than that single dimension and it is known that auditory information is also crucial in this process. In addition, it is, however, unclear what the neurobiological mechanism underlying these MDMA effects on social behaviour is. Previously, studies have shown that MDMA-induced emotional excitability and positive mood are linked to the action on the serotonin (5-HT) 2A receptor. AIM: The present study aimed at investigating the effect of MDMA on processing of sounds (Processing of Affective Sounds Task (PAST)) and cognitive biases (Approach-Avoidance Task (AAT)) towards emotional and social stimuli and the role of 5-HT2A receptor in these effects. METHODS: Twenty healthy recreational users entered a 2 * 2, placebo-controlled, within subject study with ketanserin (40 mg) as pre-treatment and MDMA (75 mg) as treatment. Behavioural (PAST, AAT) measures were conducted 90 min after treatment with MDMA, respectively, 120 min after ketanserin. Self-report mood measures and oxytocin concentrations were taken at baseline and before and after behavioural tests. RESULTS: Findings showed that MDMA reduced arousal elicited by negative sounds. This effect was counteracted by ketanserin pre-treatment, indicating involvement of the 5-HT2 receptor in this process. MDMA did not seem to induce a bias towards emotional and social stimuli. It increased positive and negative mood ratings and elevated oxytocin plasma concentrations. The reduction in arousal levels when listening to negative sounds was not related to the elevated subjective arousal. CONCLUSION: It is suggested that this decrease in arousal to negative stimuli reflects potentially a lowering of defences, a process that might play a role in the therapeutic process. PMID- 28735369 TI - Ethylene sensitivity and relative air humidity regulate root hydraulic properties in tomato plants. AB - MAIN CONCLUSION: The effect of ethylene and its precursor ACC on root hydraulic properties, including aquaporin expression and abundance, is modulated by relative air humidity and plant sensitivity to ethylene. Relative air humidity (RH) is a main factor contributing to water balance in plants. Ethylene (ET) is known to be involved in the regulation of root water uptake and stomatal opening although its role on plant water balance under different RH is not very well understood. We studied, at the physiological, hormonal and molecular levels (aquaporins expression, abundance and phosphorylation state), the plant responses to exogenous 1-aminocyclopropane-1-carboxylic acid (ACC; precursor of ET) and 2 aminoisobutyric acid (AIB; inhibitor of ET biosynthesis), after 24 h of application to the roots of tomato wild type (WT) plants and its ET-insensitive never ripe (nr) mutant, at two RH levels: regular (50%) and close to saturation RH. Highest RH induced an increase of root hydraulic conductivity (Lpo) of non treated WT plants, and the opposite effect in nr mutants. The treatment with ACC reduced Lpo in WT plants at low RH and in nr plants at high RH. The application of AIB increased Lpo only in nr plants at high RH. In untreated plants, the RH treatment changed the abundance and phosphorylation of aquaporins that affected differently both genotypes according to their ET sensitivity. We show that RH is critical in regulating root hydraulic properties, and that Lpo is affected by the plant sensitivity to ET, and possibly to ACC, by regulating aquaporins expression and their phosphorylation status. These results incorporate the relationship between RH and ET in the response of Lpo to environmental changes. PMID- 28735370 TI - Gait and cognitive impairments in multiple sclerosis: the specific contribution of falls and fear of falling. AB - Our goal was to identify the specific contribution of fear of falling (FoF) and falls with quantitative gait impairments and cognition capabilities in multiple sclerosis (MS) patients. Patients were separated into four individual subgroups as to the presence of FoF and falls (i.e., fearless/non-fallers, fearless/fallers, FoF/non-fallers and FoF/fallers). The Falls Efficacy Scale International questionnaire was used to assess the level of concern of falling. Participants were defined as "fallers" and "non-fallers" based on their fall history. Spatio-temporal parameters of gait were analyzed using an electronic mat. Cognitive performance was assessed by a computerized cognitive battery of tests. The study included 540 MS patients, 47% were defined as fallers and 61.9% reported a FoF. Non-significant differences were found between the fearless/non fallers and fearless/fallers in all clinical, gait and cognitive scores. FoF/non fallers walked significantly slower compared to fearless MS individuals who had previously fallen. Furthermore, the same patient group exhibited a poorer performance in the motor skills cognitive subdomain. A significant reverse relationship was found between FoF and cognitive motor skills in the fallers and non-fallers groups. FoF characterizes a more disabling symptom than falling in the MS population. PMID- 28735372 TI - A Systematic Review and Taxonomy of Published Quality Criteria Related to the Evaluation of User-Facing eHealth Programs. AB - The purpose of this review was to identify and classify key criteria concepts related to the evaluation of user-facing eHealth programs. In line with the PRISMA statement methodology, computer searches of relevant databases were conducted for studies published between January 1, 2000 and March 1, 2016 that contained explicit quality criteria related to mHealth and eHealth products. Reference lists of included articles, review articles, and grey literature (e.g., books, websites) were searched for additional sources. A team of nine experts led by the first author was gathered to support the classification of these criteria. Identified criteria were extracted, grouped and organized using an inductive thematic analysis. Eighty-four sources - emanating from 26 different courtiers - were included in this review. The team extracted 454 criteria that were grouped into 11 quality domains, 58 criteria concepts and 134 concepts' sub-groups. Quality domains were: Usability, Visual Design, User Engagement, Content, Behavior Change/Persuasive Design, Influence of Social Presence, Therapeutic Alliance, Classification, Credibility/Accountability, and Privacy/Security. Findings suggest that authors around the globe agree on key criteria concepts when evaluating user-facing eHealth products. The high proportion of new published criteria in the second half of this review time-frame (2008-2016), and more specifically, the high proportion of criteria relating to persuasive design, therapeutic alliance and privacy/security within this time-frame, points to the advancements made in recent years within this field. PMID- 28735371 TI - Identifying Symptoms of Distress in Youth Living with Neurofibromatosis Type 1 (NF1). AB - Children and adolescents with Neurofibromatosis type 1 (NF1) are at increased risk for wide-ranging behavioral, developmental, and cognitive impairments and decreased quality of life. To date, no psychosocial screening tool has been developed to quickly assess the symptoms that 1) can be addressed during routine medical appointments in children with NF1, 2) can produce interpretable and actionable results, 3) can be integrated into medical care, and 4) can quickly identify patients at risk in order to better address that the provision of appropriate care are available. This study was conducted to test the overall usability of the Distress Thermometer (DT) and symptom checklist and concordance of DT ratings between pediatric patients, their caregivers and medical providers. Eighty youth (ages 7-21) living with NF1 completed the DT and an accompanying checklist. The findings of this study suggest the DT and symptom checklist was acceptable and feasible to complete in a clinic setting. A small subset reported high distress that required further assessment and intervention. Significant discordance between distress ratings of caregivers and children and healthcare providers was also found. Overall, the DT and accompanying symptom checklist provide important information to identify the presence of distress and contextualize the child's distress but is limited by not assessing whether these symptoms interfere with the child's daily life. PMID- 28735373 TI - Systematic Heuristic Evaluation of Computerized Consultation Order Templates: Clinicians' and Human Factors Engineers' Perspectives. AB - We assessed the usability of consultation order templates and identified problems to prioritize in design efforts for improving referral communication. With a sample of 26 consultation order templates, three evaluators performed a usability heuristic evaluation. The evaluation used 14 domain-independent heuristics and the following three supplemental references: 1 new domain-specific heuristic, 6 usability goals, and coded clinicians' statements regarding ease of use for 10 sampled templates. Evaluators found 201 violations, a mean of 7.7 violations per template. Minor violations outnumbered major violations almost twofold, 115 (57%) to 62 (31%). Approximately 68% of violations were linked to 5 heuristics: aesthetic and minimalist design (17%), error prevention (16%), consistency and standards (14%), recognition rather than recall (11%), and meet referrers' information needs (10%). Severe violations were attributed mostly to meet referrers' information needs and recognition rather than recall. Recorded violations yielded potential negative consequences for efficiency, effectiveness, safety, learnability, and utility. Evaluators and clinicians demonstrated 80% agreement in usability assessment. Based on frequency and severity of usability heuristic violations, the consultation order templates reviewed may impede clinical efficiency and risk patient safety. Results support the following design considerations: communicate consultants' requirements, facilitate information seeking, and support communication. While the most frequent heuristic violations involved interaction design and presentation, the most severe violations lacked information desired by referring clinicians. Violations related to templates' inability to support referring clinicians' information needs had the greatest potential negative impact on efficiency and safety usability goals. Heuristics should be prioritized in future design efforts. PMID- 28735374 TI - Changes in Global Transcriptional Profiling of Women Following Obesity Surgery Bypass. AB - BACKGROUND: Differential gene expression in peripheral blood mononuclear cells (PBMCs) after Roux-en-Y gastric bypass (RYGB) is poorly characterized. Markers of these processes may provide a deeper understanding of the mechanisms that underlie these events. The main goal of this study was to identify changes in PBMC gene expression in women with obesity before and 6 months after RYGB-induced weight loss. METHODS: The ribonucleic acid (RNA) of PBMCs from 13 obese women was analyzed before and 6 months after RYGB; the RNA of PBMCs from nine healthy women served as control. The gene expression levels were determined by microarray analysis. Significant differences in gene expression were validated by real-time quantitative polymerase chain reaction (RT-qPCR). RESULTS: Microarray analysis for comparison of the pre- and postoperative periods showed that 1366 genes were differentially expressed genes (DEGs). The main pathways were related to gene transcription; lipid, energy, and glycide metabolism; inflammatory and immunological response; cell differentiation; oxidative stress regulation; response to endogenous and exogenous stimuli; substrate oxidation; mTOR signaling pathway; interferon signaling; mitogen-activated protein kinases (MAPK), cAMP response element binding protein (CREB1), heat shock factor 1 (HSF1), and sterol regulatory element binding protein 1c (SREBP-1c) gene expression; adipocyte differentiation; and methylation. CONCLUSIONS: Six months after bariatric surgery and significant weight loss, many molecular pathways involved in obesity and metabolic diseases change. These findings are an important tool to identify potential targets for therapeutic intervention and clinical practice of nutritional genomics in obesity. PMID- 28735375 TI - Perioperative Practices Concerning One Anastomosis (Mini) Gastric Bypass: A Survey of 210 Surgeons. AB - BACKGROUND: There is currently little evidence available on the perioperative practices concerning one anastomosis/mini gastric bypass (OAGB/MGB) and no published consensus amongst experts. Even the published papers are not clear on these aspects. The purpose of this study was to understand various perioperative practices concerning OAGB/MGB. METHODS: Bariatric surgeons from around the world were invited to participate in a questionnaire-based survey. Only surgeons performing this procedure were included. RESULTS: Two hundred and ten surgeons from 39 countries with a cumulative experience of 68,442 procedures took the survey. Surgeons described a large number of absolute (n = 55) and relative contraindications (n = 59) to this procedure in their practice. Approximately 71.0% (n = 148/208), 70.0% (n = 147/208) and 65.0% (n = 137/209), respectively, routinely perform a preoperative endoscopy, screening for Helicobacter pylori and ultrasound scan of the abdomen. A minority (35.0%, n = 74/208) of the surgeons used a constant bilio-pancreatic limb (BPL) length for all the patients with remaining preferring to tailor the limb length to the patient and approximately half (49.0%, n = 101/206) routinely approximate diaphragmatic crura in patients with hiatus hernia. Some 48.5% (n = 101/208) and 40.0% (n = 53/205) surgeons, respectively, do not recommend routine iron and calcium supplementation. CONCLUSION: This survey is the first attempt to understand a range of perioperative practices with OAGB/MGB. The findings will help in identifying areas for future research and allow consensus building amongst experts with preparation of guidelines for future practice. PMID- 28735376 TI - The Socio-economic Impact of Bariatric Surgery. AB - INTRODUCTION: A recurring argument for bariatric surgery is cost savings due to sustained weight loss and reductions in comorbidities. However, studies prompting this argument tend to focus only on health care costs, and in some of them, cost changes after surgery have been modelled. The aim of this study was to generate real-world evidence on the socio-economic impact of bariatric surgery, by evaluating the effect on both direct and indirect costs. MATERIALS AND METHODS: Using real-world data from national registries, predictions of health care costs, social transfer payments and income were performed for a surgically treated individual and compared to those for a similar but non-surgically treated individual 3 years before and after surgery. Secondly, the relative risks for health care costs, social transfer payments and income of a surgical group compared with a non-surgical group were estimated. The non-surgical group was defined as being eligible for bariatric surgery but not undergoing it. RESULTS: Bariatric surgery was associated with higher, but insignificantly so, health care costs, primarily due to an increase in somatic inpatient services. A significant decrease in costs of drugs was seen, especially for anti-diabetic medication. Bariatric surgery had a slight positive effect on social transfer payments and no significant effect on income. CONCLUSIONS: There are no cost savings of bariatric surgery in the short run. Further real-world evidence over a longer period of time is needed to examine whether the higher health care costs will eventually be counterbalanced, making bariatric surgery a profitable intervention in a socio economic perspective. PMID- 28735377 TI - Study of the correlation between fengycin promoter expression and its production by Bacillus subtilis under different culture conditions and the impact on surfactin production. AB - This work aimed to rely expression of the fengycin promoter to fengycin production under different culture conditions. To this end, Bacillus subtilis BBG208, derived from BBG21, which is a fengycin overproducing strain carrying the green fluorescent protein (GFP) under the control of fengycin promoter, was used to assess the effects of different carbon and nitrogen sources on surfactin and fengycin production and the fengycin promoter expression. The data showed that some carbon sources oriented synthesis of one family of lipopeptides, while most of the nitrogen sources allowed high co-production of fengycin and surfactin. High expressions of promoter Pfen and fengycin synthesis were obtained with urea or urea + ammonium mixture as nitrogen source and mannitol as carbon source. Moreover, temperature, pH and oxygenation influenced their biosynthesis based on the nutrition conditions. Optimization of the production medium increased the fengycin production to 768 mg L-1, which is the highest level reported for this strain. This study defines the suitable nutrient conditions allowing as well the highest expression of the fengycin promoter and portrays the conditions relying on the fengycin and surfactin production. PMID- 28735378 TI - A phase I/II trial and pharmacokinetic study of mithramycin in children and adults with refractory Ewing sarcoma and EWS-FLI1 fusion transcript. AB - PURPOSE: In a preclinical drug screen, mithramycin was identified as a potent inhibitor of the Ewing sarcoma EWS-FLI1 transcription factor. We conducted a phase I/II trial to determine the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), and pharmacokinetics (PK) of mithramycin in children with refractory solid tumors, and the activity in children and adults with refractory Ewing sarcoma. PATIENTS AND METHODS: Mithramycin was administered intravenously over 6 h once daily for 7 days for 28 day cycles. Adult patients (phase II) initially received mithramycin at the previously determined recommended dose of 25 ug/kg/dose. The planned starting dose for children (phase I) was 17.5 ug/kg/dose. Plasma samples were obtained for mithramycin PK analysis. RESULTS: The first two adult patients experienced reversible grade 4 alanine aminotransferase (ALT)/aspartate aminotransferase (AST) elevation exceeding the MTD. Subsequent adult patients received mithramycin at 17.5 ug/kg/dose, and children at 13 ug/kg/dose with dexamethasone pretreatment. None of the four subsequent adult and two pediatric patients experienced cycle 1 DLT. No clinical responses were observed. The average maximal mithramycin plasma concentration in four patients was 17.8 +/- 4.6 ng/mL. This is substantially below the sustained mithramycin concentrations >=50 nmol/L required to suppress EWS-FLI1 transcriptional activity in preclinical studies. Due to inability to safely achieve the desired mithramycin exposure, the trial was closed to enrollment. CONCLUSIONS: Hepatotoxicity precluded the administration of a mithramycin at a dose required to inhibit EWS-FLI1. Evaluation of mithramycin in patients selected for decreased susceptibility to elevated transaminases may allow for improved drug exposure. PMID- 28735380 TI - The midline suboccipital subtonsillar approach to the cerebellomedullary cistern: how I do it. AB - BACKGROUND: Lesions lateral to the lower brainstem in an area extending from the foraminae of Luschka to the foramen magnum are rare and include different pathologies. There is no consensus on an ideal surgical approach. METHOD: To gain access to this area, we use the midline suboccipital subtonsillar approach (STA). This midline approach with unilateral retraction of the cerebellar tonsil enables entry into the cerebellomedullary cistern. CONCLUSIONS: The STA offers excellent access with a panoramic view of the cerebellomedullary cistern and its structures and therefore can be useful for a number of different pathologies in the lower petroclival area. PMID- 28735379 TI - Multidisciplinary management of clival chordomas; long-term clinical outcome in a single-institution consecutive series. AB - OBJECTIVE: Chordomas of the skull base have high recurrence rates even after radical resection and adjuvant radiotherapy. We evaluate the long-term clinical outcome using multidisciplinary management in the treatment of clival chordomas. METHODS: Between 1984 and 2015, 22 patients diagnosed with an intracranial chordoma were treated at the Karolinska University Hospital, Stockholm, Sweden. Sixteen of 22 were treated with Gamma Knife radiosurgery (GKRS) for tumour residual or progression during the disease course. Seven of 22 received adjuvant fractionated radiotherapy and 5 of these also received proton beam radiotherapy. RESULTS: Fifteen of 22 (68%) patients were alive at follow-up after a median of 80 months (range 22-370 months) from the time of diagnosis. Six were considered disease free after >10-year follow-up. The median tumour volume at the time of GKRS was 4.7 cm3, range 0.8-24.3 cm3. Median prescription dose was 16 Gy, range 12-20 Gy to the 40-50% isodose curve. Five patients received a second treatment with GKRS while one received three treatments. After GKRS patients were followed with serial imaging for a median of 34 months (range 6-180 months). Four of 16 patients treated with GKRS were in need of a salvage microsurgical procedure compared to 5/7 treated with conventional or proton therapy. CONCLUSION: After surgery, 7/22 patients received conventional and/or photon therapy, while 15/22 were treated with GKRS for tumour residual or followed with serial imaging with GKRS as needed upon tumour progression. With this multidisciplinary management, 5 and 10-year survivals of 82% and 50% were achieved, respectively. PMID- 28735381 TI - Characterization of the Sensorimotor Rhythm in 4-Month-Old Infants Born at Term and Premature. AB - The sensorimotor rhythm (SMR) is an electroencephalographic rhythm associated with motor and cognitive development observed in the central brain regions during wakefulness in the absence of movement, and it reacts contralaterally to generalized and hemibody movements. The purpose of this work was to characterize the SMR of 4-month-old infants, born either healthy at term or prematurely with periventricular leukomalacia (PVL). Two groups of infants were formed: healthy and premature with PVL. Their electroencephalograms (EEGs) were recorded in four conditions: rest, free movement, right-hand grasping and left-hand grasping, in order to explore general reactivity to free movement and contralateral reactivity in hand-grasping conditions. Associations between SMR, and cognitive and motor performance were analyzed. The healthy infants showed a SMR between 5.47 and 7.03 Hz, with clear contralateral reactivity to free movement and right-hand grasping. However, the premature infants with PVL did not show enough electroencephalographic characteristics to evidence the presence of SMR. Poor performance, characteristic of children with PVL, was related to low-frequency SMR, while good performance was associated with a higher frequency rhythm in the left hemisphere. The presence of SMR in the group of healthy infants could be considered a sign of health at this age. Thus, poor SMR evidence in the EEG of infants with PVL is probably a sign of brain immaturity or brain dysfunction. Our results provide data on infant SMR development that is needed to design neurofeedback protocols for infants with PVL. PMID- 28735382 TI - Combined Medication of Antiretroviral Drugs Tenofovir Disoproxil Fumarate, Emtricitabine, and Raltegravir Reduces Neural Progenitor Cell Proliferation In Vivo and In Vitro. AB - The application of combination antiretroviral therapy has greatly reduced the death rate from AIDS. However, up to 50% of patients on combination antiretroviral therapy develop HIV-associated neurocognitive disorders (HAND), which is associated with residual neuroinflammation and oxidative injury in the brain. Neural stem cells (NSCs) and progenitors play a vital role in repairing neuronal injuries. Therefore, we hypothesize that combination antiretroviral therapy may adversely affect NSCs/progenitors, contributing to the increasing prevalence of HAND. Here, we show that combined medication of three antiretroviral drugs tenofovir disoproxil fumarate (TDF), emtricitabine (FTC), and raltegravir (RAL) affects NSC homeostasis and progenitor proliferation in the mouse dentate gyrus (DG). Our results also show that TDF/FTC/RAL treatment prohibits proliferation and induces apoptosis of cultured mouse neural progenitor cells (NPCs), resulting in a reduction in the viability of NPCs. Moreover, we find that TDF, among the three drugs used in this combination antiretroviral treatment, accounts for most of the effects on neural progenitors. Together, our results offer a mechanistic explanation for the prevalence of HAND in AIDS patients treated with combination antiretroviral therapy. PMID- 28735383 TI - Brucellosis Causes Alteration in Trace Elements and Oxidative Stress Factors. AB - Brucellosis is regarded as one of the most common diseases among humans and livestock. In the present study, we aimed to assess the effect of this disease on the level of various cations including copper (Cu), manganese (Mn), zinc (Zn), and magnesium (Mg) as well as oxidative stress status in the serum of people suffering from brucellosis. The present case-study was carried out on 40 patients with brucellosis (case) and 20 healthy people (control). Blood specimens were taken from all the people and the level of essential trace elements and oxidative stress status were measured. The serum level of copper in the case group (165.39 +/- 43.19 MUg/dl) was significantly higher compared with that in the control group (122.12 +/- 28.88 MUg/dl). Whereas the serum level of zinc was significantly lower in the case group compared with that in the control group (76.47 +/- 28.88 vs. 92.85 +/- 23.16 MUg/dl). The manganese and magnesium serum levels did not differ significantly between the two groups. Furthermore, total antioxidant capacity level was significantly lower in the case group (122.12 +/- 28.22 MUmol/ml) than that in the control group (3.08 +/- 0.12 MUmol/ml) and the level of serum malondialdehyde was significantly higher in the case group (7.20 +/- 0.23 mmol/ml) than that in the control group (4.0 +/- 0.19 mmol/ml). Brucellosis can cause alteration in the serum level of essential trace elements. Moreover, the present study indicated that brucellosis produces oxidative stress in patients. PMID- 28735385 TI - Preparation of Decellularized Liver Scaffolds and Recellularized Liver Grafts. AB - Severe liver disease is the 12th leading cause of death in the USA, with organ transplantation often being the only viable option for treatment. However, due to the shortage of viable donor livers, it is estimated that over 1200 patients died in 2015 while waiting for liver transplantation. This highlights the need for alternative sources of viable organs. In this study, we describe a method that provides the groundwork for the development of functional liver grafts. The approach described here is for removal of cells from intact livers and subsequently repopulating them with functional liver cells. Briefly, rat livers are harvested and subjected to a series of perfusion decellularization steps using an anionic detergent such that an intact decellularized liver matrix (DLM) scaffold with preserved vascular architecture is obtained. Further, we describe methods to recellularize DLM scaffolds with adult primary hepatocytes, creating a liver graft that exhibits hepatic functions in vitro. PMID- 28735384 TI - Influence of Feeding Inorganic Vanadium on Growth Performance, Endocrine Variables and Biomarkers of Bone Health in Crossbred Calves. AB - The nutritional essentialities of transition element vanadium (V) as micro nutrient in farm animals have not yet been established, though in rat model, vanadium as vanadate has been reported to exert insulin-mimetic effect and shown to be needed for proper development of bones. The objective of this study was to determine the effect of V supplementation on growth performance, plasma hormones and bone health status in calves. Twenty-four crossbred calves (body weight 72.83 +/- 2.5 kg; age 3-9 months) were blocked in four groups and randomly assigned to four treatment groups (n = 6) on body weight and age basis. Experimental animals were kept on similar feeding regimen except that different groups were supplemented with either 0, 3, 6 or 9 ppm inorganic V/kg DM. Effect of supplementation during 150-day experimental period was observed on feed intake, body weight gain, feed efficiency, body measures, endocrine variables, plasma glucose and biomarkers of bone health status. Supplementation of V did not change average daily gain (ADG), dry matter intake (DMI), feed efficiency and body measures during the experimental period. During the post-V supplementation period plasma insulin-like growth factor-1 (IGF-1), triiodothyronine (T3) and thyroxin (T4) concentrations were increased and observed highest in 9 mg V/kg DM fed calves; however, levels of insulin, glucose, parathyroid hormone (PTH) and calcitonin hormones remained similar among calves fed on basal or V-supplemented diets. Bone alkaline phosphatase (Bone-ALP) concentration was increased (P < 0.05); however, plasma protein tyrosine phosphatase (PTP) level decreased (P < 0.05) in 6 and 9 mg V/kg DM supplemented groups. Plasma hydroxyproline (Hyp) and tartrate-resistant acid phosphatase (TRAP) concentration were unchanged by V supplementation. Blood V concentration showed positive correlation with supplemental V levels. These results suggest that V may play a role in modulation of the action of certain endocrine variables and biomarkers of bone health status in growing crossbred calves. PMID- 28735386 TI - The performance and microbial communities of biodegradation-electron transfer with sulfur metabolism integrated process for flue gas desulfurization wastewater treatment. AB - The biodegradation-electron transfer with sulfur metabolism integrated (BESI(r)) process was used for the treatment of real flue gas desulfurization wastewater. The BESI(r) process consists of an anaerobic activated sludge reactor, an anoxic activated sludge reactor, and an aerobic bio-film reactor. The performance of the integrated process was evaluated by the removal efficiencies of organics and nitrogen pollutants. The sulfate in the wastewater was used as an abundant sulfur source to drive the integrated process. The removal efficiencies of chemical oxygen demand, total organic carbon, ammonia nitrogen, and total nitrogen of the integrated process were 87.99, 87.04, 30.77, and 45.17%, respectively. High throughput 454-pyrosequencing was applied for the analysis of microbial communities in the integrated process. From the anaerobic activated sludge (Sample 1), anoxic activated sludge (Sample 2), and aerobic bio-film (Sample 3), totals of 1701, 1181, and 857 operational taxonomic units were obtained, respectively. The sulfur cycle was associated with the removal of organics and nitrogen pollutants. The sulfate-reducing bacteria participated in the organics removal in the anaerobic reactor, and the sulfide oxidation was related with the denitrification in the anoxic reactor. A complete nitrogen degradation chain was built in the integrated process. Through the degradation chain, the nitrogenous organic pollutants, ammonia nitrogen, and nitrate could be removed. The participant functional bacteria were also detected by pyrosequencing. PMID- 28735388 TI - Epigenetics and RNA Processing: Connections to Drought, Salt, and ABA? AB - There have been great research advances in epigenetics, RNA splicing, and mRNA processing over recent years. In parallel, there have been many advances in abiotic stress and Abscisic Acid (ABA) signaling. Here we overview studies that have examined stress-induced changes in the epigenome and RNA processing as well as cases where disrupting these processes changes the plant response to abiotic stress. We also highlight some examples where specific connections of stress or ABA signaling to epigenetics or RNA processing have been found. By implication, this also points out cases where such mechanistic connections are likely to exist but are yet to be characterized. In the absence of such specific connections to stress signaling, it should be kept in mind that stress sensitivity phenotypes of some epigenetic or RNA processing mutants maybe the result of indirect, pleiotropic effects and thus may perhaps not indicate a direct function in stress acclimation. PMID- 28735389 TI - The Fundamental Role of Reactive Oxygen Species in Plant Stress Response. AB - Chemical, physical, and biotic factors continuously vary in the natural environment. Such parameters are considered as stressors if the magnitude of their change exceeds the current acclimation norm of the plant. Activation of genetic programs allows for conditional expansion of the acclimation norm and depends on specific sensing mechanisms, intracellular communication, and regulation. The redox and reactive oxygen species (ROS) network plays a fundamental role in directing the acclimation response. These highly reactive compounds like H2O2 are generated and scavenged under normal conditions and participate in realizing a basal acclimation level. Spatial and temporal changes in ROS levels and redox state provide valuable information for regulating epigenetic processes, transcription factors (TF), translation, protein turnover, metabolic pathways, and cross-feed, e.g., into hormone-, NO-, or Ca2+-dependent signaling pathways. At elevated ROS levels uncontrolled oxidation reactions compromise cell functions, impair fitness and yield, and in extreme cases may cause plant death. PMID- 28735387 TI - Elevated Levels of Atypical Handedness in Autism: Meta-Analyses. AB - An elevated prevalence of atypical handedness (left-, mixed-, or non-right handedness) has been repeatedly reported in individuals with Autism Spectrum Disorder (ASD) compared to typically developing individuals. However, the exact magnitude of this difference as well as the presence of possible moderating factors remains unknown. Here, we present three sets of meta-analyses of studies that assessed the handedness prevalence among individuals with ASD, totaling 1199 individuals (n = 723 individuals with ASD and n = 476 typically developing individuals). Meta-analysis set 1 found that individuals with ASD are 3.48, 2.49, and 2.34 times more likely to be non-right-handed, left-handed, and mixed-handed compared to typically developing individuals, respectively. Meta-analysis set 2 found a 45.4%, 18.3%, and 36.1% prevalence of non-right-handedness, left handedness, and mixed-handedness, respectively, amongst individuals with ASD. The classification of handedness, the instrument used to measure handedness, and the main purpose of the study were found to moderate the findings of meta-analysis set 2. Meta-analysis set 3 revealed a trend towards weaker handedness for individuals with ASD. The elevated levels of atypical handedness in individuals with ASD could be attributed to atypicalities in cerebral structure and lateralization for language in individuals with ASD. PMID- 28735390 TI - The Role of Long Noncoding RNAs in Plant Stress Tolerance. AB - Plants must adapt to multiple biotic and abiotic stresses ; thus, sensing and responding to environmental signals is imperative for their survival. Moreover, understanding these responses is imperative for efforts to improve plant yield and consistency. Regulation of transcript levels is a key aspect of the plant response to environmental signals. Long noncoding RNAs (lncRNAs) have gained widespread attention in recent years with the advance of high-throughput sequencing technologies. As important biological regulators, lncRNAs have been implicated in a wide range of developmental processes and diseases in animals. However, knowledge of the role that lncRNAs play in plant stress tolerance remains limited. Here, we review recent studies on the identification, characteristics, classification, and biological functions of lncRNAs in response to various stresses, including bacterial pathogens, excess light, drought, salinity, hypoxia, extreme temperatures, and nitrogen/phosphate deficiency. We also discuss possible directions for future research. PMID- 28735391 TI - Toward a Resilient, Functional Microbiome: Drought Tolerance-Alleviating Microbes for Sustainable Agriculture. AB - In recent years, the utilization of novel sequencing techniques opened a new field of research into plant microbiota and was used to explore a wide diversity of microorganisms both inside and outside of plant host tissues, i.e., the endosphere and rhizosphere, respectively. An early realization from such research was that species richness and diversity of the plant microbiome are both greater than believed even a few years ago, and soil is likely home to the most abundant and diverse microbial habitats known. In most ecosystems sampled thus far, overall microbial complexity is determined by the combined influences of plant genotype, soil structure and chemistry, and prevailing environmental conditions, as well as the native "bulk soil" microbial populations from which membership is drawn. Beneficial microorganisms, traditionally referring primarily to nitrogen fixing bacteria, plant growth-promoting rhizobacteria, and mycorrhizal fungi, play a key role in major functions such as plant nutrition acquisition and plant resistance to biotic and abiotic stresses . Utilization of plant-associated microbes in food production is likely to be critical for twenty-first century agriculture, where arable cropland is limited and food, fiber, and feed productivity must be sustained or even improved with fewer chemical inputs and less irrigation. PMID- 28735392 TI - Mining and Quantifying In Vivo Molecular Interactions in Abiotic Stress Acclimation. AB - Stress acclimation is initialized by sensing the stressor, transducing the signal, and inducing the response. In particular, the signal transduction is driven by protein-protein interactions and the response might involve de novo complex formation, shifts in subcellular localization and, thus, transportation that is mediated by other proteins. The investigation of protein-protein interactions and their regulation upon abiotic stress is crucial for a deeper understanding of the underlying mechanisms. FRET measurements by sensitized emission allow for the analysis of protein-protein interactions in real time and have a high potential to provide new insights into the regulation of protein protein interaction with respect to subcellular localization and time. Within this section protocols are provided which allow for FRET analysis on the single cell level, the image acquisition procedure is described in detail and ImageJ plugins are suggested for the data evaluation. PMID- 28735393 TI - Generation of a Stress-Inducible Luminescent Arabidopsis and Its Use in Genetic Screening for Stress-Responsive Gene Deregulation Mutants. AB - In order to understand plant stress tolerance and its application, it is important to identify the signaling components involved in the stress-regulated gene expression. One initial step for this is generation of a stress-inducible luminescent Arabidopsis and its use in genetic mutant screening. Here, we describe how to generate a transgenic Arabidopsis line harboring a single copy of the STABILIZED1 (STA1) promoter-driven luciferase transgene (STA1p-LUC) as an example. STA1 is a pre-mRNA splicing factor Prp6p homolog and is induced by cold and heat stresses. In addition, generation of the STA1p-LUC mutant pool and a luminescence imaging-based screening for STA1p-LUC deregulated mutants are described. PMID- 28735394 TI - Detection of Differential DNA Methylation Under Stress Conditions Using Bisulfite Sequence Analysis. AB - DNA methylation is the most important epigenetic change affecting gene expression in plants grown under normal as well as under stress conditions. Therefore, researchers study differential DNA methylation under distinct environmental conditions and their relationship with transcriptome abundance. Up to date, more than 25 methods and techniques are available to detect DNA methylation based on different principles. Bisulfite sequencing method is considered as a gold standard since it is able to distinguish 5-methylcytosine from cytosine using the bisulfite treatment. Therefore, it is useful for qualitative and semiquantitative measurement of DNA methylation. However, the reliability of data obtaining from this technique is mainly depending on the efficiency of bisulfite conversion and number of sequencing clones representing the target-converted sequence. Therefore, it is labor intensive and time-consuming. Revolution of next generation DNA sequencing (NGS) has allowed researches to combine conventional bisulfite sequencing methods with high-throughput Illumina sequencing in a technique called whole genome bisulfite sequencing (WGBS). This technique allows a single nucleotide resolution of 5-methylcytosine on a genome scale. WGBS technique workflow involves DNA fragmentation, processing through end blunting, terminal A(s) addition at 3' end and adaptor ligation, bisulfite treatment, PCR amplification, sequencing libraries and assembling, and finally alignment with the reference genome and data analysis. Despite the fact that WGBS is more reliable than the conventional clone-based bisulfite sequencing, it is costly, requires large amount of DNA and its output data is not easily handled. PMID- 28735395 TI - ChIP-Seq Analysis for Identifying Genome-Wide Histone Modifications Associated with Stress-Responsive Genes in Plants. AB - Histone modifications represent the crux of epigenetic gene regulation essential for most biological processes including abiotic stress responses in plants. Thus, identification of histone modifications at the genome-scale can provide clues for how some genes are 'turned-on' while some others are "turned-off" in response to stress. This chapter details a step-by-step protocol for identifying genome-wide histone modifications associated with stress-responsive gene regulation using chromatin immunoprecipitation (ChIP) followed by sequencing of the DNA (ChIP seq). PMID- 28735396 TI - Isolation of Polysomal RNA for Analyzing Stress-Responsive Genes Regulated at the Translational Level in Plants. AB - Alteration of gene expression is an essential mechanism, which allows plants to respond and adapt to adverse environmental conditions. Transcriptome and proteome analyses in plants exposed to abiotic stresses revealed that protein levels are not correlated with the changes in corresponding mRNAs, indicating regulation at translational level is another major regulator for gene expression. Analysis of translatome, which refers to all mRNAs associated with ribosomes, thus has the potential to bridge the gap between transcriptome and proteome. Polysomal RNA profiling and recently developed ribosome profiling (Ribo-seq) are two main methods for translatome analysis at global level. Here, we describe the classical procedure for polysomal RNA isolation by sucrose gradient ultracentrifugation followed by highthroughput RNA-seq to identify genes regulated at translational level. Polysomal RNA can be further used for a variety of downstream applications including Northern blot analysis, qRT-PCR, RNase protection assay, and microarray based gene expression profiling. PMID- 28735397 TI - Global Proteomic Profiling and Identification of Stress-Responsive Proteins Using Two-Dimensional Gel Electrophoresis. AB - Global proteome profiling is a direct representation of the protein set in an organism, organ, tissues, or an organelle. One of the main objectives of proteomic analysis is the comparison and relative quantitation of proteins under a defined set of conditions. Two-dimensional gel electrophoresis (2-DE) has gained prominence over the last 4 decades for successfully aiding differential proteomics, providing visual confirmation of changes in protein abundance, which otherwise cannot be predicted from genome analysis. Each protein spot on 2-DE gel can be analyzed by its abundance, location, or even its presence or absence. This versatile gel-based method combines and utilizes the finest principle for separation of protein complexes by virtue of their charge and mass, visual mapping coupled with successful mass spectrometric identification of individual proteins. PMID- 28735398 TI - Phosphoproteomics Analysis for Probing Plant Stress Tolerance. AB - Protein phosphorylation is a key signaling mechanism during the plant biotic and abiotic stress response. Signaling cascades communicate between the cell surface, where the stress is perceived, and the nucleus, where a response can be enacted. Many of these signals involve the specific, transient phosphorylation of proteins by kinases, a signal which is usually amplified through cascades. The advent of high-throughput phosphoproteomics, pioneered mainly in yeast and mammalian cells, has made it possible to discover novel phosphorylation events rapidly and efficiently in a data-dependent manner and this has greatly enlarged our understanding of the plant's response to stress. This chapter describes a simple gel-free protocol for high-throughput phosphoproteomics, which is amenable to most labs engaged in plant stress research. PMID- 28735399 TI - Probing Posttranslational Redox Modifications. AB - Reactive molecular species (RMS) can damage DNA, lipids, and proteins but as signaling molecules they also affect the regulatory state of the cell. RMS consist of reactive oxygen (ROS), nitrogen (RNS), and carbonyl species (RCS). Besides their potentially destructive nature, RMS are able to modify proteins at the posttranslational level, resulting in regulation of structure, activity, interaction as well as localization. This chapter addresses methods to analyze and quantify posttranslational redox modifications in vitro and ex vivo, such as sulfenic acid generation of cysteine residues and oxidative carbonylation of proteins. In addition, by use of isothermal titration calorimetry, redox dependent interaction studies of proteins will be described. PMID- 28735400 TI - Zymographic Method for Distinguishing Different Classes of Superoxide Dismutases in Plants. AB - In plants, especially in chloroplasts, superoxide radical is generated when an electron is transferred to dimolecular O2 due to decreased activity of Photosystem I. The superoxide (O2-) radical accumulation is more rampant in plants exposed to abiotic stresses due to oxidation of photosystem components. Excessive superoxide radical accumulation will lead to oxidative damage to the cellular macromolecules. The ubiquitous superoxide dismutases (SODs) represent critical enzymatic antioxidant system present in cells, which can catalyze the disproportion of superoxide (O2-) radical rapidly into hydrogen peroxide (H2O2) and molecular oxygen. Depending on the metal cofactor present, the plant SODs are classified into Cu/ZnSOD, MnSOD, and FeSOD. The activity of SODs can be quantified zymographically. Additionally, using this method, different classes of SODs can be distinguished by using H2O2, KCN, and NaN3. PMID- 28735401 TI - Determination of Enzymes Associated with Sulfite Toxicity in Plants: Kinetic Assays for SO, APR, SiR, and In-Gel SiR Activity. AB - The amino acid cysteine plays a major role in plant response to abiotic stress by being the donor of elemental sulfur for the sulfuration of the molybdenum cofactor, otherwise the last step of ABA biosynthesis, the oxidation of abscisic aldehyde, is inactivated. Additionally, cysteine serves as a precursor for the biosynthesis of glutathione, the reactive oxygen species scavenger essential for redox status homeostasis during stress. Cysteine is generated by the sulfate reductive pathway where sulfite oxidase (SO; EC 1.8.3.1) is an important enzyme in the homeostasis of sulfite levels (present either as a toxic intermediate in the pathway or as a toxic air pollutant that has penetrated the plant tissue via the stomata). SO is localized to the peroxisomes and detoxifies excess sulfite by catalyzing its oxidation to sulfate. Here we show a kinetic assay that relies on fuchsin colorimetric detection of sulfite, a substrate of SO activity. This SO assay is highly specific, technically simple, and readily performed in any laboratory.5'-adenylylsulfate (APS) reductase (APR, E.C. 1.8.4.9) enzyme regulates a crucial step of sulfate assimilation in plants, algae and some human pathogens. The enzyme is upregulated in response to oxidative stress induced by abiotic stresses, such as salinity and hydrogen peroxide, to generate sulfite an intermediate for cysteine generation essential for the biosynthesis of glutathione, the hydrogen peroxide scavenger. Here we present two robust, sensitive, and simple colorimetric methods of APR activity based on sulfite determination by fuchsin.Sulfite reductase (SiR) is one of the key enzymes in the primary sulfur assimilation pathway. It has been shown that SiR is an important plant enzyme for protection plant against sulfite toxicity and premature senescence. Here we describe two methods for SiR activity determination: a kinetic assay using desalted extract and an in-gel assay using crude extract.Due to the energetically favorable equilibrium, sulfurtransferase (ST) activity measured as sulfite generation or consumption. Sulfite-generating ST activity is determined by colorimetric detection of SCN- formation at 460 nm as the red Fe(SCN)3 complex from cyanide and thiosulfate using acidic iron reagent. Sulfite consuming (MST) activity is detected as sulfite disappearance in the presence of thiocyanate (SCN-) or as SCN- disappearance. To abrogate interfering SO activity, total ST activities is detected by inhibiting SO activity with tungstate. PMID- 28735402 TI - Determination of Total Sulfur, Sulfate, Sulfite, Thiosulfate, and Sulfolipids in Plants. AB - In response to oxidative stress the biosynthesis of the ROS scavenger, glutathione is induced. This requires the induction of the sulfate reduction pathway for an adequate supply of cysteine, the precursor for glutathione. Cysteine also acts as the sulfur donor for the sulfuration of the molybdenum cofactor, crucial for the last step of ABA biosynthesis. Sulfate and sulfite are, respectively, the precursor and intermediate for cysteine biosynthesis and there is evidence for stress-induced sulfate uptake and further downstream, enhanced sulfite generation by 5'-phosphosulfate (APS) reductase (APR, EC 1.8.99.2) activity. Sulfite reductase (SiR, E.C.1.8.7.1) protects the chloroplast against toxic levels of sulfite by reducing it to sulfide. In case of sulfite accumulation as a result of air pollution or stress-induced premature senescence, such as in extended darkness, sulfite can be oxidized to sulfate by sulfite oxidase. Additionally sulfite can be catalyzed to thiosulfate by sulfurtransferases or to UDP-sulfoquinovose by SQD1, being the first step toward sulfolipid biosynthesis.Determination of total sulfur in plants can be accomplished using many techniques such as ICP-AES, high-frequency induction furnace, high performance ion chromatography, sulfur combustion analysis, and colorimetric titration. Here we describe a total sulfur detection method in plants by elemental analyzer (EA). The used EA method is simple, sensitive, and accurate, and can be applied for the determination of total S content in plants.Sulfate anions in the soil are the main source of sulfur, required for normal growth and development, of plants. Plants take up sulfate ions from the soil, which are then reduced and incorporated into organic matter. Plant sulfate content can be determined by ion chromatography with carbonate eluents.Sulfite is an intermediate in the reductive assimilation of sulfate to the essential amino acids cysteine and methionine, and is cytotoxic above a certain threshold if not rapidly metabolized and can wreak havoc at the cellular and whole plant levels. Plant sulfite content affects carbon and nitrogen homeostasis Therefore, methods capable of determining sulfite levels in plants are of major importance. Here we present two robust laboratory protocols which can be used for sulfite detection in plants.Thiosulfate is an essential sulfur intermediate less toxic than sulfite which is accumulating in plants in response to sulfite accumulation. The complexity of thiosulfate detection is linked to its chemical properties. Here we present a rapid, sensitive, and accurate colorimetric method based on the enzymatic conversion of thiosulfate to thiocyanate.The plant sulfolipid sulfoquinovosyldiacylglycerol (SQDG) accounts for a large fraction of organic sulfur in the biosphere. Aside from sulfur amino acids, SQDG represents a considerable sink for sulfate in plants and is the only sulfur-containing anionic glycerolipid that is found in the photosynthetic membranes of plastids. We present the separation of sulfolipids from other fatty acids in two simple ways: by one- and two-dimensional thin-layer chromatography. PMID- 28735403 TI - Determining Glutathione Levels in Plants. AB - Upon exposure to abiotic stresses, plants tend to accumulate excessive amounts of reactive oxygen species (ROS) that inturn react with cellular lipids, proteins, and DNA. Therefore, decreasing ROS accumulation is indispensible to survive under stress, which is accomplished by inducing enzymatic and nonenzymatic antioxidant defense pathways. Glutathione, particularly reduced glutathione (GSH), represents a principal anitioxidant that could decrease ROS through scavenging them directly or indirectly through ascorbate-glutathione cycle or GSH peroxidases. Glutathione content can be determined using HPLC or spectrophotometric assays. In this chapter, we provided detailed assays to determine total, reduced, and oxidized gluathione using spectrophotometric method. PMID- 28735405 TI - Profiling Abscisic Acid-Induced Changes in Fatty Acid Composition in Mosses. AB - In plants, change in lipid composition is a common response to various abiotic stresses. Lipid constituents of bryophytes are of particular interest as they differ from that of flowering plants. Unlike higher plants, mosses have high content of very long-chain polyunsaturated fatty acids. Such lipids are considered to be important for survival of nonvascular plants. Here, using abscisic acid (ABA )-induced changes in lipid composition in Physcomitrella patens as an example, a protocol for total lipid extraction and quantification by gas chromatography (GC) coupled with flame ionization detector (FID) is described. PMID- 28735404 TI - Porous Graphitic Carbon Liquid Chromatography-Mass Spectrometry Analysis of Drought Stress-Responsive Raffinose Family Oligosaccharides in Plant Tissues. AB - Drought is a major limiting factor in agriculture and responsible for dramatic crop yield losses worldwide. The adjustment of the metabolic status via accumulation of drought stress-responsive osmolytes is one of the many strategies that some plants have developed to cope with water deficit conditions. Osmolytes are highly polar compounds, analysis of whcih is difficult with typical reversed phase chromatography. Porous graphitic carbon (PGC) has shown to be a suitable alternative to reversed-phase stationary phases for the analysis of highly polar compounds typically found in the plant metabolome. In this chapter, we describe the development and validation of a PGC-based liquid chromatography tandem mass spectrometry (LC-MSn) method suitable for the target analysis of water-soluble carbohydrates, such as raffinose family oligosaccharides (RFOs). We present detailed information regarding PGC column equilibration, LC-MSn system operation, data analysis, and important notes to be considered during the steps of method development and validation. PMID- 28735406 TI - Detection of Free Polyamines in Plants Subjected to Abiotic Stresses by High Performance Liquid Chromatography (HPLC). AB - High-performance liquid chromatography (HPLC) is a sensitive, rapid, and accurate technique to detect and characterize various metabolites from plants. The metabolites are extracted with different solvents and eluted with appropriate mobile phases in a designed HPLC program. Polyamines are known to accumulate under abiotic stress conditions in various plant species and thought to provide protection against oxidative stress by scavenging reactive oxygen species. Here, we describe a common method to detect the free polyamines in plant tissues both qualitatively and quantitatively. PMID- 28735407 TI - Determination of Polyamines by Dansylation, Benzoylation, and Capillary Electrophoresis. AB - Polyamines are polycationic nitrogenous compounds that accumulate in plants exposed to abiotic stresses. In higher animals, they influence gene expression, brain development, and nerve growth and regeneration. Because of their known roles in plant stress responses, quantitative determination of polyamines is very important. Polyamines in their native form cannot be detected by optical and/or electrochemical methods as they do not show any structural features, and hence derivatization of polyamines is essential to make them to produce either chromophores or fluorescence. Here we describe various methods of derivatization using different labeling agents and suitable separation and detecting methods for a vast source of polyamines existing in living cells. PMID- 28735408 TI - Rapid Quantification of Abscisic Acid by GC-MS/MS for Studies of Abiotic Stress Response. AB - Drought and low water potential induce large increases in Abscisic Acid (ABA ) content of plant tissue. This increased ABA content is essential to regulate downstream stress resistance responses; however, the mechanisms regulating ABA accumulation are incompletely known. Thus, the ability to accurately quantify ABA at high throughput and low cost is important for plant stress research. We have combined and modified several previously published protocols to establish a rapid ABA analysis protocol using gas chromatography-tandem mass spectrometry (GC MS/MS). Derivatization of ABA is performed with (trimethylsilyl)-diazomethane rather than the harder to prepare diazomethane. Sensitivity of the analysis is sufficient that small samples of low water potential treated Arabidopsis thaliana seedlings can be routinely analyzed in reverse genetic studies of putative stress regulators as well as studies of natural variation in ABA accumulation. PMID- 28735409 TI - Silencing of Stress-Regulated miRNAs in Plants by Short Tandem Target Mimic (STTM) Approach. AB - In plants, microRNAs (miRNAs) regulate more than hundred target genes comprising largely transcription factors that control growth and development as well as stress responses. However, the exact functions of miRNA families could not be deciphered because each miRNA family has multiple loci in the genome, thus are functionally redundant. Therefore, an ideal approach to study the function of a miRNA family is to silence the expression of all members simultaneously, which is a daunting task. However, this can be partly overcome by Target Mimic (TM) approach that can knockdown an entire miRNA family. STTM is a modification of TM approach and complements it. STTMs have been successfully used in monocots and dicots to block miRNA functions. miR159 has been shown to be differentially regulated by various abiotic stresses including ABA in various plant species. Here, we describe in detail the protocol for designing STTM construct to block miR159 functions in Arabidopsis, with the potential to apply this technique on a number of other stress-regulated miRNAs in plants. PMID- 28735410 TI - Rhizosphere Sampling Protocols for Microbiome (16S/18S/ITS rRNA) Library Preparation and Enrichment for the Isolation of Drought Tolerance-Promoting Microbes. AB - Natural plant microbiomes are abundant and have a remarkably robust composition, both as epiphytes on the plant surface and as endophytes within plant tissues. Microbes in the former "habitat" face limited nutrients and harsh environmental conditions, while those in the latter likely lead a more sheltered existence. The most populous and diverse of these microbiomes are associated with the zone around the plant roots, commonly referred to as the rhizosphere. A majority of recent studies characterize these plant-associated microbiomes by community profiling of bacteria and fungi, using amplicon-based marker genes and next generation sequencing (NGS). Here, we collate a group of protocols that incorporate current best practices and optimized methodologies for sampling, handling of samples, and rRNA library preparation for variable regions of V5-V6 and V9 of the bacterial 16S ribosomal RNA (rRNA) gene, and the ITS2 region joining the 5.8S and 28S regions of the fungal rRNA gene. Samples collected for such culture-independent analyses can also be used for the actual isolation of microbes of interest, perhaps even those identified by the libraries described above. One group of microbes that holds promise for mediating plant stress incurred by drought are bacteria that are capable of reducing or eliminating the plant's perception of the stress through degradation of the gaseous plant hormone ethylene, which is abundantly produced in response to drought stimuli. This is accomplished by some types of soil bacteria that can produce the enzyme 1 aminocyclopropane-1-carboxylate (ACC) deaminase, which is the immediate precursor to ethylene. Here we provide a high-throughput protocol for screening of ACC deaminase-producing bacteria for the applied purpose of mitigating the impact of plant drought stress. PMID- 28735411 TI - Risk factors associated with postoperative recurrence and repeat surgery in Japanese patients with Crohn's disease. AB - PURPOSE: To avoid frequent surgery in patients with Crohn's disease, it is important to identify the risk factors for postoperative recurrence or repeat surgery. However, there have so far been few studies on this topic from Asian countries. In addition, the recent development of anti-tumor necrosis factor (TNF) therapy may have changed the risk factors. We aimed to identify the factors associated with postoperative recurrence and repeat surgery. METHODS: The postoperative courses of 168 patients were reviewed. We analyzed the cumulative postoperative recurrence and repeat surgery rates and identified the factors affecting these rates. RESULTS: Postoperative recurrence was observed in 70 patients, and the 1-, 3-, and 5-year cumulative recurrence rates were 17.1, 40.1, and 54.9%, respectively. The recurrence rate was significantly higher in patients with anal lesions and lower in patients newly treated with anti-TNF agents following surgery. In a multivariate analysis, the new introduction of anti-TNF agents was identified as an independent suppressor (hazard ratio 0.50, 95% confidence interval 0.28-0.88). Twenty-four patients underwent repeat surgery, and the 1-, 3-, and 5-year cumulative repeat surgery rates were 4.6, 11.2, and 18.7%, respectively. The surgery rate was significantly higher in patients with penetrating-type disease. In a multivariate analysis, penetrating-type disease (6.98, 2.37-23.35), anal lesions (4.40, 1.14-30.53), and first-time surgery (5.28, 1.17-17.93) were identified as independent risk factors. CONCLUSIONS: Anti TNF agents have the potential to prevent postoperative recurrence. The new introduction, dose escalation, or switching of anti-TNF agents is recommended in patients with some risk factors. PMID- 28735412 TI - Variability in attachment of the coracoacromial ligament in relation with its morphology. AB - PURPOSE: The coracoacromial ligament (CAL) presents with variable morphology and plays a significant role in the development of subacromial impingement syndrome. Sectioning the CAL has been suggested to relieve impingement of the rotator cuff. The aim of the current study was to investigate the CAL attachment in relation with ligament morphology. MATERIALS AND METHODS: The CAL was investigated in 220 cadaveric shoulders from 58 males and 59 females, with a median age of 82 years (range 53-102 years). CALs were classified according to three factors: (1) number of bands present; (2) shape; and (3) attachment to the acromial and coracoid processes. RESULTS: 35 (16%) CALs had a single band, 84 (38%) two bands, and 101 (46%) three or more bands. CAL shape was either broadband (14: 6%), quadrangular (21: 10%), Y-shaped (84: 38%), or multiple-banded (101: 46%). More ligaments were attached to the medial aspect of the acromion (60%) and medial end of the coracoid (75%) than those restricted to the anterior edge of the acromion (40%) and posterior aspect of the coracoid (25%). Multiple-banded ligaments attached significantly more medially at the acromion and coracoid processes, while single band ligament attachments were restricted to the anterior edge of the acromion and posterior aspect of the coracoid process. CONCLUSION: The CAL has variable morphology and attachments with interconnections to different structures around the shoulder. CALs with a medial acromial attachment may narrow the subacromial space leading to further shoulder impingement. PMID- 28735413 TI - Echocardiographic and hemodynamic assessment for predicting early clinical events in severe acute mitral regurgitation. AB - The diagnostic role of echocardiographic and hemodynamic assessment in acute mitral regurgitation (AMR) remains unclear. The central question of this study was to determine if echocardiographic and hemodynamic parameters can predict early clinical events in AMR. AMR was induced by percutaneously severing the mitral valve chordae tendineae in 39 Yorkshire pigs. Immediately after AMR induction, echocardiographic and hemodynamic exams were performed, and compared between those who died and those who survived within 30-days of the procedure. Echocardiographic indices of MR severity as well as the left atrial pressure showed significant differences between survivors and non-survivors in univariate analysis. Multi-variate logistic regression analysis revealed that echocardiography-derived regurgitant fraction and vena contracta as well as mean left atrial pressure could be used to segment the cohort into survivors and non survivors. Our study demonstrated, for the first time, that echocardiographic and hemodynamic assessment of AMR provides predictive information on early clinical events in a clinically relevant animal model of AMR. PMID- 28735414 TI - Bone mechanobiology in mice: toward single-cell in vivo mechanomics. AB - Mechanically driven bone (re)modeling is a multiscale process mediated through complex interactions between multiple cell types and their microenvironments. However, the underlying mechanisms of how cells respond to mechanical signals are still unclear and are at the focus of the field of bone mechanobiology. Traditionally, this complex process has been addressed by reducing the system to single scales and cell types. It is only recently that more integrative approaches have been established to study bone mechanobiology across multiple scales in which mechanical load at the organ level is related to molecular responses at the cellular level. The availability of mouse loading models and imaging techniques with improved spatial and temporal resolution has made it possible to track dynamic bone (re)modeling at the tissue and cellular level in vivo. Coupled with advanced computational models, the (re)modeling activities at the tissue scale can be associated with the mechanical microenvironment. However, methods are lacking to link the molecular responses of different cell types to their local mechanical microenvironment and bone (re)modeling activities occurring at the tissue scale. With recent improvements in "omics" technologies and single-cell molecular biology, it is now possible to sequence the complete genome and transcriptome of single cells. These technologies offer unique opportunities to comprehensively investigate the cellular transcriptional profiles within their specific microenvironment. By combining single-cell "omics" technologies with well-established tissue-scale models of bone mechanobiology, we propose a mechanomics approach to locally analyze the transcriptome of single cells with respect to their local 3D mechanical in vivo environment. PMID- 28735415 TI - CFD simulation of aerosol delivery to a human lung via surface acoustic wave nebulization. AB - Administration of drug in the form of particles through inhalation is generally preferable in the treatment of respiratory disorders. Conventional inhalation therapy devices such as inhalers and nebulizers, nevertheless, suffer from low delivery efficiencies, wherein only a small fraction of the inhaled drug reaches the lower respiratory tract. This is primarily because these devices are not able to produce a sufficiently fine drug mist that has aerodynamic diameters on the order of a few microns. This study employs computational fluid dynamics to investigate the transport and deposition of the drug particles produced by a new aerosolization technique driven by surface acoustic waves (SAWs) into an in silico lung model geometrically reconstructed using computed tomography scanning. The particles generated by the SAW are released in different locations in a spacer chamber attached to a lung model extending from the mouth to the 6th generation of the lung bronchial tree. An Eulerian approach is used to solve the Navier-Stokes equations that govern the airflow within the respiratory tract, and a Lagrangian approach is adopted to track the particles, which are assumed to be spherical and inert. Due to the complexity of the lung geometry, the airflow patterns vary as it penetrates deeper into the lung. High inertia particles tend to deposit at locations where the geometry experiences a significant reduction in cross section. Our findings, nevertheless, show that the injection location can influence the delivery efficiency: Injection points close to the spacer centerline result in deeper penetration into the lung. Additionally, we found that the ratio of drug particles entering the right lung is significantly higher than the left lung, independent of the injection location. This is in good agreement with this fact that the most of airflow enters to the right lobes. PMID- 28735416 TI - Super-resolution Microscopical Localization of Dopamine Receptors 1 and 2 in Rat Hippocampal Synaptosomes. AB - Although dopamine receptors D1 and D2 play key roles in hippocampal function, their synaptic localization within the hippocampus has not been fully elucidated. In order to understand precise functions of pre- or postsynaptic dopamine receptors (DRs), the development of protocols to differentiate pre- and postsynaptic DRs is essential. So far, most studies on determination and quantification of DRs did not discriminate between subsynaptic localization. Therefore, the aim of the study was to generate a robust workflow for the localization of DRs. This work provides the basis for future work on hippocampal DRs, in light that DRs may have different functions at pre- or postsynaptic sites. Synaptosomes from rat hippocampi isolated by a sucrose gradient protocol were prepared for super-resolution direct stochastic optical reconstruction microscopy (dSTORM) using Bassoon as a presynaptic zone and Homer1 as postsynaptic density marker. Direct labeling of primary validated antibodies against dopamine receptors D1 (D1R) and D2 (D2R) with Alexa Fluor 594 enabled unequivocal assignment of D1R and D2R to both, pre- and postsynaptic sites. D1R immunoreactivity clusters were observed within the presynaptic active zone as well as at perisynaptic sites at the edge of the presynaptic active zone. The results may be useful for the interpretation of previous studies and the design of future work on DRs in the hippocampus. Moreover, the reduction of the complexity of brain tissue by the use of synaptosomal preparations and dSTORM technology may represent a useful tool for synaptic localization of brain proteins. PMID- 28735417 TI - Design and Properties of an Immobilization Enzyme System for Inulin Conversion. AB - A commercial inulinase could convert inulin into fructose, which was optimized to be entrapped in the calcium alginate-gelatin beads with the immobilization yield of 86% for free inulinase activities. The optimum pH values and temperatures were 4.5 and 40 degrees C for the free enzyme and 5.0-5.5 and 45-50 degrees C for the immobilized enzyme. The kinetic parameters of V max and K m were 5.24 MUmol/min and 57.6 mg/mL for the free inulinase and 4.32 MUmol/min and 65.8 mg/mL for the immobilized inulinase, respectively. The immobilized enzyme retained 80% of its initial activities at 45 degrees C for 4 days, which could exhibit better thermal stability. The reuse of immobilized inulinase throughout the continuous batch operations was explored, which had better reusability of the immobilized biocatalyst. At the same time, the stability of immobilized enzyme in the continuous packed-bed bioreactor was estimated, which showed the better results and had its potential scale-up fructose production for inulin conversion. PMID- 28735418 TI - Gap junction communication between chromaffin cells: the hidden face of adrenal stimulus-secretion coupling. AB - From birth to death, catecholamine secretion undergoes continuous adjustments, allowing the organism to adapt to homeostasis changes. To cope with these stressful conditions, the neuroendocrine cells of the adrenal medulla play an immediate and crucial role. Chromaffin cell-driven catecholamine release is chiefly controlled by a neurogenic command that arises from the sympathetic nervous system, which releases acetylcholine at the splanchnic nerve terminal chromaffin cell synapses. In addition to receiving several synaptic inputs individually, chromaffin cells are coupled by gap junctions. This raises interesting questions about the usefulness and the role of the gap junctional coupling within the chromaffin tissue, considering that secretory function is efficiently completed by the neurogenic pathway. The findings that gap junctions contribute to catecholamine secretion, both ex vivo and in vivo, provide some early answers, but their involvement in other cellular functions still remains unexplored. This review summarizes the molecular and physiological evidence that gap junctions can act either as an accelerator or a brake of stimulus-secretion coupling and discusses this functional plasticity in the context of specific needs in circulating catecholamine levels. It introduces the concept of gap junctions as sympathetic activity sensors and guardians of the functional integrity of the chromaffin tissue. PMID- 28735419 TI - Modulation of human Kv4.3/KChIP2 channel inactivation kinetics by cytoplasmic Ca2. AB - The transient outward current (I to) in the human heart is mediated by Kv4.3 channels complexed with Kv channel interacting protein (KChIP) 2, a cytoplasmic Ca2+-binding EF-hand protein known to modulate Kv4.3 inactivation gating upon heterologous co-expression. We studied Kv4.3 channels co-expressed with wild-type (wt) or EF-hand-mutated (DeltaEF) KChIP2 in human embryonic kidney (HEK) 293 cells. Co-expression took place in the absence or presence of BAPTA-AM, and macroscopic currents were recorded in the whole-cell patch-clamp configuration with different free Ca2+ concentrations in the patch-pipette. Our data indicate that Ca2+ is not necessary for Kv4.3/KChIP2 complex formation. The Kv4.3/KChIP2 mediated current decay was faster and the recovery of Kv4.3/KChIP2 channels from inactivation slower with 50 MUM Ca2+ than with BAPTA (nominal Ca2+-free) in the patch-pipette. The apparent Ca2+-mediated slowing of recovery kinetics was still observed when EF-hand 4 of KChIP2 was mutated (DeltaEF4) but not when EF-hand 2 (DeltaEF2) was mutated, and turned into a Ca2+-mediated acceleration of recovery kinetics when EF-hand 3 (DeltaEF3) was mutated. In the presence of the Ca2+/calmodulin-dependent protein kinase II (CaMKII) inhibitor KN-93 cytoplasmic Ca2+ (50 MUM) induced an acceleration of Kv4.3/KChIP2 recovery kinetics, which was still observed when EF-hand 2 was mutated (DeltaEF2) but not when EF-hand 3 (DeltaEF3) or EF-hand 4 (DeltaEF4) was mutated. Our results support the notion that binding of Ca2+ to KChIP2 EF-hands can acutely modulate Kv4.3/KChIP2 channel inactivation gating, but the Ca2+-dependent gating modulation depends on CaMKII action. Our findings speak for an acute modulation of I to kinetics and frequency dependent I to availability in cardiomyocytes under conditions with elevated Ca2+ levels and CaMKII activity. PMID- 28735420 TI - Role of albumin and its modifications in glomerular injury. AB - Albuminuria is both a characteristic hallmark and a known risk factor for progressive glomerular disease. Although the molecular basis for a potential causative role for albuminuria in progressive chronic kidney disease remains poorly understood, there have been several recent advances in our understanding of the role of albumin, and its molecular modifications, in the development and progression of glomerular disease. This review discusses recent findings related to the ability of albumin and its associated factors to directly induce podocyte and glomerular injury. Additional recent studies confirming the ability and mechanisms by which podocytes endocytose albumin are also discussed. Lastly, we present several known molecular modifications in the albumin molecule itself, as well as substances bound to it, which may be important and potentially clinically relevant mediators of albumin-induced glomerular injury. These recent findings may create entirely new opportunities to develop novel future therapies directed at albumin that could potentially help reduce podocyte and renal tubular injury and slow the progression of chronic glomerular disease. PMID- 28735421 TI - Ammonia Released by Streptomyces aburaviensis Induces Droplet Formation in Streptomyces violaceoruber. AB - Streptomyces violaceoruber grown in co-culture with Streptomyces aburaviensis produces an about 17-fold higher volume of droplets on its aerial mycelium than in single-culture. Physical separation of the Streptomyces strains by either a plastic barrier or by a dialysis membrane, which allowed communication only by the exchange of volatile compounds or diffusible compounds in the medium, respectively, still resulted in enhanced droplet formation. The application of molecular sieves to bioassays resulted in the attenuation of the droplet-inducing effect of S. aburaviensis indicating the absorption of the compound. 1H-NMR analysis of molecular-sieve extracts and the selective indophenol-blue reaction revealed that the volatile droplet-inducing compound is ammonia. The external supply of ammonia in biologically relevant concentrations of >=8 mM enhanced droplet formation in S. violaceoruber in a similar way to S. aburaviensis. Ammonia appears to trigger droplet production in many Streptomyces strains because four out of six Streptomyces strains exposed to ammonia exhibited induced droplet production. PMID- 28735422 TI - Baerveldt(r) glaucoma implant surgery with the double scleral flap technique to prevent Hoffman elbow exposure. AB - OBJECTIVE: To compare the efficacy and safety of the Baerveldt(r) glaucoma implant (BGI) between a preserved donor scleral patch alone and double scleral flaps, comprising a preserved donor scleral patch and an autologous scleral pedicle flap. METHODS: This was an open-label retrospective study. We analyzed the cases of 52 consecutive patients (56 eyes) who underwent BGI surgery with the Hoffman elbow (#BG 102-350, Abbott) and were followed up for >1 year. Twenty-one eyes underwent BGI surgery with a preserved donor scleral patch alone (donor patch group), and the other 35 eyes underwent BGI surgery with a preserved donor scleral patch and an autologous scleral pedicle flap (double-flap group). The main outcome was the incidence of Hoffman elbow exposure associated with each surgical approach. RESULTS: Three patients in the donor-patch group (14.3%) developed Hoffman elbow exposure, whereas in the double-flap group, no cases had Hoffman elbow exposure (p = 0.048). CONCLUSIONS: The use of the double scleral flaps technique was more efficient in preventing Hoffman elbow exposure. PMID- 28735423 TI - The anticoagulant effect of heparin during radiofrequency ablation (RFA) in patients taking apixaban or rivaroxaban. AB - PURPOSE: Measuring the anticoagulant effect of heparin during radiofrequency ablation (RFA) in patients taking apixaban and rivaroxaban is challenging, since the activated coagulation time (ACT) does not seem to reflect the true anticoagulant activity of these drugs. We therefore evaluated coagulation properties of apixaban and rivaroxaban during RFA by different coagulation assays to better monitor periprocedural hemostasis. METHODS: The study included 90 patients (61 +/- 12 years) with atrial fibrillation who underwent RFA procedures. Patients received 20 mg rivaroxaban (n = 73) once or 5 mg apixaban (n = 17) twice daily 4 weeks prior to the procedure. During RFA, unfractionated heparin i.v. was given to maintain an ACT of 250-300 s. Blood samples were taken before and 10, 60, and 360 min after heparin administration. RESULTS: Heparin displayed a lower anti-Xa activity in rivaroxaban-treated patients compared to apixaban-treated patients. In contrast, D-dimer and prothrombin fragment F1+2 plasma levels indicated a higher activation of the coagulation cascade in apixaban/heparin than in rivaroxaban/heparin patients. This discordant coagulative state measured in vitro had no clinical impact in terms of bleeding or thromboembolic complications. CONCLUSION: We found different biochemical responses to rivaroxaban/heparin and apixaban/heparin during RFA. Precaution is necessary when monitoring periprocedural hemostasis in DOAC patients to avoid mismanagement. PMID- 28735424 TI - A novel 3D anatomic mapping approach using multipoint high-density voltage gradient mapping to quickly localize and terminate typical atrial flutter. AB - PURPOSE: The purposes of the study were to evaluate and characterize the cavotricuspid isthmus using multipoint high density voltage gradient mapping (HD VGM) to see if this would improve on current ablation techniques compared to standard cavotricuspid isthmus ablation techniques. METHODS: Group 1, 25 patients who underwent ablation using standard methods of 3D mapping and ablation, was compared to group 2, 33 patients undergoing ablation using HD-VGM and ablation. Using this method, we are able to identify the maximum voltage areas within isthmus and target it for ablation. Total procedure times, ablation times and number of lesions, distance ablated, and fluoroscopy times were compared. RESULTS: Fifty-eight patients were included in this study. Compared to group 1, in group 2, HD-VGM decreased the total ablation time 18.2 +/- 9.2 vs 8.3 +/- 4.0 min (p < 0.0001), total ablation lesions 22.7 +/- 18.8 vs 5.5 +/- 4.2 (p < 0.0001), and the length of the ablation lesions was significantly shorter 47.0 mm +/- 13 mm vs 32.6 mm +/- 10.0 mm (p < 0.0001). While the average length of the CTI was similar, 47.0 mm +/- 13 mm vs 46.1 mm +/- 10.0 mm (p 0.87), in group 2, only 71% of the isthmus was ablated. CONCLUSION: Multipoint high density voltage gradient mapping can help identify maximum voltage areas within the isthmus and when ablated can create bidirectional block with decreased ablation times and length of the lesion. PMID- 28735425 TI - Influence of Host Plant on Thaumetopoea pityocampa Gut Bacterial Community. AB - Microbial communities associated to the gut of insects are attracting an increasing interest, mainly because of their role in influencing several host life-traits. The characterization of the gut microbial community is pivotal for understanding insect ecology and, thus, to develop novel pest management strategies. The pine processionary moth, Thaumetopoea pytiocampa (Denis & Schiff.) (Lepidoptera: Thaumetopoeidae), is a severe defoliator of pine forests, able to feed on several pine species. In this work, we performed a metabarcoding analysis to investigate, for the first time, the diversity of the gut bacterial community of pine processionary larvae associated with three different host pine species (Pinus halepensis, Pinus nigra subsp. laricio, and Pinus pinaster). We found that the gut microbial community of T. pityocampa larvae collected on P. halapensis was different from that associated with larvae collected from P. nigra and P. pinaster. Moreover, the high presence of bacteria belonging to the genera Modestobacter, Delftia, and unidentified Methylobacteriaceae retrieved in larvae feeding on P. halapensis suggested that specific interactions can occur. Our results provide the evidence that different host plant differently impact on the microbiota diversity of T. pityocampa larvae, contributing to the general knowledge of this pest with information that could be useful in shaping the next generation of pest control strategies. PMID- 28735426 TI - Diet Versus Phylogeny: a Comparison of Gut Microbiota in Captive Colobine Monkey Species. AB - Both diet and host phylogeny shape the gut microbial community, and separating out the effects of these variables can be challenging. In this study, high throughput sequencing was used to evaluate the impact of diet and phylogeny on the gut microbiota of nine colobine monkey species (N = 64 individuals). Colobines are leaf-eating monkeys that fare poorly in captivity-often exhibiting gastrointestinal (GI) problems. This study included eight Asian colobines (Rhinopithecus brelichi, Rhinopithecus roxellana, Rhinopithecus bieti, Pygathrix nemaeus, Nasalis larvatus, Trachypithecus francoisi, Trachypithecus auratus, and Trachypithecus vetulus) and one African colobine (Colobus guereza). Monkeys were housed at five different captive institutes: Panxi Wildlife Rescue Center (Guizhou, China), Beijing Zoo, Beijing Zoo Breeding Center, Singapore Zoo, and Singapore Zoo Primate Conservation Breeding Center. Captive diets varied widely between institutions, but within an institution, all colobine monkey species were fed nearly identical or identical diets. In addition, four monkey species were present at multiple captive institutes. This allowed us to parse the effects of diet and phylogeny in these captive colobines. Gut microbial communities clustered weakly by host species and strongly by diet, and overall, colobine phylogenetic relationships were not reflected in gut microbiota analyses. Core microbiota analyses also identified several key taxa-including microbes within the Ruminococcaceae and Lachnospiraceae families-that were shared by over 90% of the monkeys in this study. Microbial species within these families include many butyrate producers that are important for GI health. These results highlight the importance of diet in captive colobines. PMID- 28735427 TI - Biomechanical evaluation of distal biceps tendon repair using tension slide technique and knotless fixation technique. AB - BACKGROUND: Acute distal biceps tendon ruptures are uncommon injuries that often affect young active males, typically resulting from an eccentric load on their dominant extremity. The purpose of this study was to compare pullout strength and tendon gapping in the tension slide technique (TST) versus a knotless fixation technique (KFT). METHODS: Two sets of experiments were performed using cadaveric elbow specimens. In the first experiment, eight elbows from different cadavers were tested to compare TST with a standard locking whipstitch with KFT, four elbows in each group, using a standard locking whipstitch. In the second experiment, 12 elbows were used to study the differences between TST with a standard locking whipstitch with KFT using suture tape reinforced whipstitch (RKFT), using the TST data from the first and second experiment. Each experiment evaluated gapping after cyclic loading and the second experiment also tested the construct to load to failure. RESULTS: Gapping for KFT with a standard locking whipstitch was 10.64 mm versus 2.69 mm for the TST after 1000 cycles (P = 0.016). A reinforced whipstitch significantly improved the failure to gap on the KFT with no significant difference in gapping when compared to TST after 3000 cycles (P = 0.36). The resultant gapping for TST and KST was 2.08 mm and 2.99 mm (P = 0.91), respectively. Load to failure for TST and KFT were 282 Nm and 328 Nm (P = 0.20), respectively. CONCLUSION: Bone-tendon gap resistance of a KFT repair of a torn distal biceps tendon is limited by suture technique. Using a tape reinforced locking whipstitch, the repair is as strong as TST repair. LEVELS OF EVIDENCE: Basic Science. PMID- 28735428 TI - Effects of low-intensity pulsed ultrasound on soft tissue micro-circulation in the foot. AB - PURPOSE: Low-intensity pulsed ultrasound (LIPUS) has been shown to accelerate bone healing and is considered to increase blood flow. The aim of this study was to assess changes in micro-circulation of the foots' soft tissue in response to LIPUS intervention. We hypothesised improved micro-circulation in response to LIPUS. METHODS: Micro-circulation was assessed in 2 mm and 8 mm-deep skin of 50 healthy volunteers using non-invasive laser-doppler spectrophotometry (O2C device). Measurements were performed before LIPUS-intervention (pre), directly after intervention (post) and 20, 40 and 60 minutes after LIPUS. RESULTS: All parameter of micro-circulation increased directly after LIPUS intervention at 8 mm depth. Participants with a low pre-intervention flow showed the largest changes (p < 0.001) with an increased post-flow of 38%. SO2 levels increased significantly after intervention (p = 0.045) and decreased after 60 minutes in comparison to pre-intervention status. rHb levels after 60 min were significantly higher in comparison to pre-intervention levels. CONCLUSION: In healthy volunteers, low-intensity pulsed ultrasound led to significant short-term changes in microcirculation of the foot. Younger subjects with a low pre-flow level and smokers showed a higher potential to increase blood flow after LIPUS. PMID- 28735429 TI - History of club-foot treatment; part II: tenotomy in the nineteenth century. AB - Clubfoot is one of the most common congenital orthopaedic anomalies and was described by Hippocrates in the year 400 BC. From manipulation in antiquity to splint and plaster in the Renaissance the treatment had improved before tenotomy. Tenotomy was tested during the 19th century and will be explained in this manuscript; the introduction of subcutaneous tenotomy of the Achilles tendon had focused the attention of surgeons on the surgical treatment of clubfeet. While this operation was very successful in the correction of equinus deformities due to poliomyelitis, cerebral palsy, and old injuries, it was not a panacea for the patient with the congenital clubfoot. To be successful, the forefoot adduction and inversion had to be corrected completely before correction of the equinus deformity could benefit the patient. For this reason operations were extended to include tenotomies of other tendons, particularly the anterior tibial tendon and incisions in the capsules of the talar joints. PMID- 28735430 TI - Approaches and fixation of the posterolateral fracture fragment in tibial plateau fractures: a review with an emphasis on rim plating via modified anterolateral approach. AB - PURPOSE: To review available approaches and fixation methods for posterolateral fracture fragment (PLF) in tibial plateau fracture, and to propose an algorithm to treat various types of plateau fractures which all involve the PLF. METHODS: This article reviews multiple surgical approaches for PLF and suggests an algorithm for suitable approach and fixation method according to PLF with combined plateau fracture. RESULTS: The modified anterolateral approach is a suitable single approach for fractures with a PLF combined with an anterolateral plateau fracture and for isolated posterolateral fracture fragments. For a multicolumn tibia plateau fracture involving the lateral, medial and posterior columns, dual approaches (modified anterolateral and posteromedial approach) can be used to access the entire plateau area. CONCLUSIONS: When considering approaches of this complex fracture pattern, one must consider local soft tissue condition, plateau fracture morphology, associated injuries, and fixation options. After review of multiple approaches described in the literature for PLF fixation, we can suggest an algorithm for the approach and fixation to treat tibial plateau fractures with posterolateral fracture fragments. PMID- 28735431 TI - A systematic review of primary Sjogren's syndrome in male and paediatric populations. AB - Primary Sjogren's syndrome (pSS) is a chronic multisystem autoimmune rheumatic disease characterised by female predominance. Although the disease is rare in the male and paediatric populations, it has been suggested that it may have a different disease phenotype, which has not been investigated before using a systematic approach. A systematic literature search of PubMed databases (updated to December 2016) was performed to identify all published data on the epidemiological, clinical and laboratory manifestations of pSS in the male and paediatric populations. The literature search of the male and paediatric pSS studies identified 2025 and 186 citations, respectively, out of which 7 and 5 fulfilled our inclusion criteria and were analysed further. The range of age at disease onset was 9.4-10.7 years for children and 39.4-56.9 years at diagnosis for male patients. We identified a prevalence of extra-glandular manifestations between 52.6-92.3% in the male population and 50.0-84.6% in children, while abnormal sialometry was only reported in the paediatric population, with a prevalence between 71.4 and 81.8%. There was a significant variation of positive serological markers, with anti-Ro antibodies reported between 15.7-75.0% and 36.4 84.6%, and anti-La antibodies between 5.6-51.7% and 27.3-65.4%, in the male and paediatric populations, respectively. The characteristics of pSS in the male and paediatric populations varied according to different studies. When compared to data available from pSS adult populations, children diagnosed with pSS reported less dryness and had a higher prevalence of parotitis, lymphadenopathy and systemic symptoms and male patients were younger at the time of diagnosis. This systematic review contributes to a better understanding of the epidemiology of pSS in rare populations. Large longitudinal cohort studies comparing male with female patients and adult with paediatric patients are needed. PMID- 28735432 TI - Eucalyptol, sabinene and cinnamaldehyde: potent inhibitors of salmonella target protein L-asparaginase. AB - Salmonella typhimurium is a severe threat to human life. The treatment became more difficult with the emergence of multidrug resistance. In the present in silico study, a novel drug target L-asparaginase was tested against three ligands eucalyptol, sabinene, and cinnamaldehyde, major components of cardamom, nutmeg, and cinnamon, respectively. The lowest docking score was obtained for sabinene followed by eucalyptol and cinnamaldehyde i.e. -5.648, -3.939 and -3.469. The docking score of sabinene is also better than the standard drug, Ciprofloxacin ( 4.661) and natural substrate L-asparagine (-5.497). The amino acid residues involved in interactions inside the binding pocket are threonine 115 and threonine 35. The ADMET profile studied, also suggests the potency of the test ligands as a drug candidate. The results suggest they could be safe alternatives of chemical compounds to treat infections and combat multidrug-resistant bacteria. PMID- 28735433 TI - Comments on: Cernes, R. & Zimlichman, R. Role of Paced Breathing for Treatment of Hypertension. Curr Hypertens Rep (2017) 19: 45. PMID- 28735434 TI - Quality assessment of groundwater from the south-eastern Arabian Peninsula. AB - Assessment of groundwater quality plays a significant role in the utilization of the scarce water resources globally and especially in arid regions. The increasing abstraction together with man-made contamination and seawater intrusion have strongly affected groundwater quality in the Arabia Peninsula, exemplified by the investigation given here from the United Arab Emirates, where the groundwater is seldom reviewed and assessed. In the aim of assessing current groundwater quality, we here present a comparison of chemical data linked to aquifers types. The results reveal that most of the investigated groundwater is not suitable for drinking, household, and agricultural purposes following the WHO permissible limits. Aquifer composition and climate have vital control on the water quality, with the carbonate aquifers contain the least potable water compared to the ophiolites and Quaternary clastics. Seawater intrusion along coastal regions has deteriorated the water quality and the phenomenon may become more intensive with future warming climate and rising sea level. PMID- 28735435 TI - Examination of honeys and flowers as soil element indicators. AB - Detection of soil element deficiencies is time consuming, requiring a major commitment for field work and analysis. Bees concentrate some elements in their honey which could allow soil element concentrations to be predicted without having to take large numbers of soil samples. We measured 14 element concentrations in soil, sunflower, acacia flower and honey samples from two different regions of Hungary. Across sites, the elements with significant correlation coefficients between honey and soil concentrations, in descending order of probability, were Cu > Ba >Sr = Ni > Zn > Mn = Pb >As. Bioconcentration from soil to honey was similar for areas with acacia and sunflower flowers. In the macroelements, it was the greatest for K, S and P and least for Mg and Na, and in the microelements, greatest for B, then Zn, then Cu, then As, Mo and Sr and least for Fe, Ba, Mn and Pb. It is concluded that in acacia and sunflower growing regions, honey can give an accurate estimate of soil element concentrations for Cu and Ba and provides relevant information for Sr, Ni, Zn, Mn, Pb and As. PMID- 28735436 TI - Assessing differences in macrofaunal assemblages as a factor of sieve mesh size, distance between samples, and time of sampling. AB - With increasing cascading effects of climate change on the marine environment, as well as pollution and anthropogenic utilization of the seafloor, there is increasing interest in tracking changes to benthic communities. Macrofaunal surveys are traditionally conducted as part of pre-incident environmental assessment studies and post-incident monitoring studies when there is a potential impact to the seafloor. These surveys usually characterize the structure and/or spatiotemporal distribution of macrofaunal assemblages collected with sediment cores; however, many different sampling protocols have been used. An assessment of the comparability of past and current survey methods was in need to facilitate future surveys and comparisons. This was the aim of the present study, conducted off the Oregon coast in waters 25-35 m deep. Our results show that the use of a sieve with a 1.0-mm mesh size gives results for community structure comparable to results obtained from a 0.5-mm mesh size, which allows reliable comparisons of recent and past spatiotemporal surveys of macroinfauna. In addition to our primary objective of comparing methods, we also found interacting effects of seasons and depths of collection. Seasonal differences (summer and fall) were seen in infaunal assemblages in the wave-induced sediment motion zone but not deeper. Thus, studies where wave-induced sediment motion can structure the benthic communities, especially during the winter months, should consider this effect when making temporal comparisons. In addition, some macrofauna taxa-like polychaetes and amphipods show high interannual variabilities, so spatiotemporal studies should make sure to cover several years before drawing any conclusions. PMID- 28735438 TI - Adenosine-assisted neurovascular surgery: initial case series and review of literature. AB - Cerebral aneurysms in complex anatomical locations and intraoperative rupture of aneurysms are challenging for neurosurgeons and anaesthetists alike. Mechanical and non-mechanical methods to reduce blood flow into aneurysms are well recognised techniques to facilitate aneurysm exclusion from the circulation. Mechanical methods like temporary clipping of parent arteries, carotid artery ligation and endovascular balloon occlusion are commonly used in clinical practice. However, non-mechanical techniques such as rapid ventricular pacing and adenosine-induced cardiac standstill with hypotension are still emerging strategies. The aim of this study is to report our units' experience in the use of adenosine in aneurysm clipping and arteriovenous malformation (AVM) resection and review the literature. The records of all patients who had adenosine-assisted clipping of intracranial aneurysms and AVM resections in our institute between November 2015 and December 2016 were extracted from prospectively maintained database. The following data were collected: patient demographics, comorbidities, size and location of the aneurysms or AVM, number of boluses and total dose of adenosine administered, duration of cardiac standstill and hypotension (systolic blood pressure < 60 mmHg), intraoperative and postoperative complications and outcome scores at discharge. Literature search on Embase and PubMed for the terms "adenosine and clipping", "adenosine and aneurysm" and "adenosine and AVM" was performed. Eight aneurysms and two AVMs were identified. While both AVMs were elective procedures, half of the aneurysm clippings were on urgent basis. We used adenosine safely with spontaneous return of rhythm in all cases. Temporary clips to the parent artery were applied for brief periods in 2 patients who had pre adenosine intraoperative rupture. We did not observe any immediate or late adverse events related to administration of adenosine. From our literature review, a total of ten case series and four case reports were identified. There were no reports on the use of adenosine in AVM resection. Transient adenosine induced asystole is a safe and effective technique in facilitating surgical treatment of complex aneurysms and AVMs. In addition, adenosine use reduces the need, duration, and associated complications of temporary clip applications to parent arteries. PMID- 28735437 TI - Prospective and retrospective study of videoconference telemedicine follow-up after elective neurosurgery: results of a pilot program. AB - Existing literature suggests that use of telemedicine during postoperative appointments can increase access to care and is valued by patients and providers alike. While research examining the clinical equivalency of telemedicine visits for postoperative care has been growing, few studies have reported on telemedicine follow-up after neurosurgery. This study examined if a videoconferencing visit could substitute for an in-person clinic visit for elective neurosurgical cases in the USA. This was a single-center prospective study of patients who underwent elective neurosurgical procedures (aneurysm clipping, resection of cavernous angiomas, resection of arterial venous malformation, microvascular decompression for trigeminal neuralgia and hemifacial spasm, and certain benign brain tumors) and were offered telemedicine follow-up care by an allied health professional during the first 90 days after neurosurgery. Prospective data was compared to a historical group of patients who underwent the same procedures and received in-person postoperative follow-up. Patients in the prospective group were contacted by telephone 2-6 weeks after surgery by a nurse practitioner and assessed using a standard template that included incidence of reported postoperative seizures, fever, and performance of activities of daily living. Primary outcome measures included percentage of patients accepting telemedicine, clinical and functional status, complications, patient satisfaction, patient travel time and distance, and rates of emergency room care or hospitalization within 90 days of discharge. Ninety-nine patients were included in the study, with 57 in the prospective group and 42 in the historical group. Of the 57 prospective patients, 47 accepted telemedicine in lieu of an in-person clinic visit. Emergency room visits and readmission rates at 30 and 90 days postoperatively did not differ significantly between the study groups, nor was there any significant difference in clinical variables that were recorded in the electronic medical record more than 80% of the time. This study demonstrates the safety and value of telemedicine as an alternative method of postoperative clinical care for patients undergoing elective neurosurgery. Telemedicine avoids unnecessary travel time and was welcomed by the majority of patients without compromising clinical or functional outcomes. PMID- 28735439 TI - Surgical Management of Periocular Cancers: High- and Low-Risk Features Drive Treatment. AB - PURPOSE OF REVIEW: Recent advances in the treatment of eyelid tumors have centered on the excision, evaluation of margins, role of sentinel lymph node biopsy, and adjunctive/adjuvant systemic and radiation therapy. The purpose of this review is to elaborate on these advances. RECENT FINDINGS: Mohs excision of basal cell carcinoma and squamous cell carcinoma continues to provide the greatest success in complete excision of the cancer, especially in those cases of high-risk disease including medial canthal location and recurrent disease. Sentinel lymph node biopsy has proven useful in the assessment of early regional metastasis in sebaceous cell carcinoma, melanoma, and Merkel cell carcinoma. The pathologic finding of perineural invasion is a high-risk feature in all periocular cancers, and adjuvant therapy should be considered. Targeted therapy shows great potential in situations that are not amenable to complete excision without sacrificing the globe. Identification of high- and low-risk features in eyelid cancers allows a stratified approach to treatment. While high-risk features may require adjuvant therapy, larger margins, and sentinel lymph node biopsy, low-risk features may allow topical therapy to adequately address the condition. Monoclonal antibodies and small molecule inhibitors show great promise in the treatment of extensive disease. PMID- 28735440 TI - New Hypofractionation Radiation Strategies for Glioblastoma. AB - PURPOSE OF REVIEW: Glioblastoma (GBM) is the most common and lethal primary brain tumor in adults, with a median survival of less than 2 years despite the standard of care treatment of 6 weeks of chemoradiotherapy. We review the data investigating hypofractionated radiotherapy (HFRT) in the treatment of newly diagnosed GBM. RECENT FINDINGS: Investigators have explored alternative radiotherapy strategies that shorten treatment duration with the goal of similar or improved survival while minimizing toxicity. HFRT over 1-3 weeks is already a standard of care for patients with advanced age or poor performance status. For young patients with good performance status, HFRT holds the promise of radiobiologically escalating the dose and potentially improving local control while maintaining quality of life. Through the use of shorter radiotherapy fractionation regimens coupled with novel systemic agents, improved outcomes for patients with GBM may be achieved. PMID- 28735441 TI - Pathology of Neuroendocrine Tumours of the Female Genital Tract. AB - Neuroendocrine tumours are uncommon or rare at all sites in the female genital tract. The 2014 World Health Organisation (WHO) Classification of neuroendocrine tumours of the endometrium, cervix, vagina and vulva has been updated with adoption of the terms low-grade neuroendocrine tumour and high-grade neuroendocrine carcinoma. In the endometrium and cervix, high-grade neoplasms are much more prevalent than low-grade and are more common in the cervix than the corpus. In the ovary, low-grade tumours are more common than high-grade carcinomas and the term carcinoid tumour is still used in WHO 2014. The term ovarian small-cell carcinoma of pulmonary type is included in WHO 2014 for a tumour which in other organs is termed high small-cell neuroendocrine carcinoma. Neuroendocrine tumours at various sites within the female genital tract often occur in association with other neoplasms and more uncommonly in pure form. PMID- 28735443 TI - Retinoic acid regulates avian lung branching through a molecular network. AB - Retinoic acid (RA) is of major importance during vertebrate embryonic development and its levels need to be strictly regulated otherwise congenital malformations will develop. Through the action of specific nuclear receptors, named RAR/RXR, RA regulates the expression of genes that eventually influence proliferation and tissue patterning. RA has been described as crucial for different stages of mammalian lung morphogenesis, and as part of a complex molecular network that contributes to precise organogenesis; nonetheless, nothing is known about its role in avian lung development. The current report characterizes, for the first time, the expression pattern of RA signaling members (stra6, raldh2, raldh3, cyp26a1, raralpha, and rarbeta) and potential RA downstream targets (sox2, sox9, meis1, meis2, tgfbeta2, and id2) by in situ hybridization. In the attempt of unveiling the role of RA in chick lung branching, in vitro lung explants were performed. Supplementation studies revealed that RA stimulates lung branching in a dose-dependent manner. Moreover, the expression levels of cyp26a1, sox2, sox9, rarbeta, meis2, hoxb5, tgfbeta2, id2, fgf10, fgfr2, and shh were evaluated after RA treatment to disclose a putative molecular network underlying RA effect. In situ hybridization analysis showed that RA is able to alter cyp26a1, sox9, tgfbeta2, and id2 spatial distribution; to increase rarbeta, meis2, and hoxb5 expression levels; and has a very modest effect on sox2, fgf10, fgfr2, and shh expression levels. Overall, these findings support a role for RA in the proximal distal patterning and branching morphogenesis of the avian lung and reveal intricate molecular interactions that ultimately orchestrate branching morphogenesis. PMID- 28735444 TI - Past, present and future of the climate and human health commission. AB - The following paper presents the history of the Climate and Human Health Commission at the International Society of Biometeorology after more than one decade since its creation. A brief history of the origins of the human biometeorology is revealed through some of the main research topics and publications of the founders of the society in this field. Secondly, it is presented as a brief review of the activities of the commission in the last 10 years, based on the reports that have periodically been submitted by members of the commission to the Bulletin of the society. A summary of the topics of interest on human biometeorology and the most frequent research topics are also described. Thirdly, the need of adapting human biometeorology contents, methods and techniques to a changing world is articulated according to some of the new environmental threats in the XXI century. Finally, a list of future actions and research lines collected through a form from members of the commission is presented. The paper concludes with the existence of great challenge for human biometeorology in order to transform biometeorological knowledge into specific services to improve the wellbeing of human beings. PMID- 28735445 TI - Characterizing prolonged heat effects on mortality in a sub-tropical high-density city, Hong Kong. AB - Extreme hot weather events are likely to increase under future climate change, and it is exacerbated in urban areas due to the complex urban settings. It causes excess mortality due to prolonged exposure to such extreme heat. However, there is lack of universal definition of prolonged heat or heat wave, which leads to inadequacies of associated risk preparedness. Previous studies focused on estimating temperature-mortality relationship based on temperature thresholds for assessing heat-related health risks but only several studies investigated the association between types of prolonged heat and excess mortality. However, most studies focused on one or a few isolated heat waves, which cannot demonstrate typical scenarios that population has experienced. In addition, there are limited studies on the difference between daytime and nighttime temperature, resulting in insufficiency to conclude the effect of prolonged heat. In sub-tropical high density cities where prolonged heat is common in summer, it is important to obtain a comprehensive understanding of prolonged heat for a complete assessment of heat-related health risks. In this study, six types of prolonged heat were examined by using a time-stratified analysis. We found that more consecutive hot nights contribute to higher mortality risk while the number of consecutive hot days does not have significant association with excess mortality. For a day after five consecutive hot nights, there were 7.99% [7.64%, 8.35%], 7.74% [6.93%, 8.55%], and 8.14% [7.38%, 8.88%] increases in all-cause, cardiovascular, and respiratory mortality, respectively. Non-consecutive hot days or nights are also found to contribute to short-term mortality risk. For a 7-day-period with at least five non-consecutive hot days and nights, there was 15.61% [14.52%, 16.70%] increase in all-cause mortality at lag 0-1, but only -2.00% [-2.83%, -1.17%] at lag 2-3. Differences in the temperature-mortality relationship caused by hot days and hot nights imply the need to categorize prolonged heat for public health surveillance. Findings also contribute to potential improvement to existing heat health warning system. PMID- 28735446 TI - Commentary for Special Issue of Prevention Science "Using Genetics in Prevention: Science Fiction or Science Fact?" AB - A growing number of prevention studies have incorporated genetic information. In this commentary, I discuss likely reasons for growing interest in this line of research and reflect on the current state of the literature. I review challenges associated with the incorporation of genotypic information into prevention studies, as well as ethical considerations associated with this line of research. I discuss areas where developmental psychologists and prevention scientists can make substantive contributions to the study of genetic predispositions, as well as areas that could benefit from closer collaborations between prevention scientists and geneticists to advance this area of study. In short, this commentary tackles the complex questions associated with what we hope to achieve by adding genetic components to prevention research and where this research is likely to lead in the future. PMID- 28735447 TI - Cost-Benefit Analysis of Two Child Abuse and Neglect Primary Prevention Programs for US States. AB - We assessed the US state-level budget and societal impact of implementing two child abuse and neglect (CAN) primary prevention programs. CAN cost estimates and data from two prevention programs (Child-Parent Centers and Nurse-Family Partnership) were combined with current population, cost, and CAN incidence data by US state. A cost-benefit mathematical model for each program by US state compared program costs with the future monetary value of benefits from reduced CAN. The models used a lifetime time horizon from government payer and societal perspectives. Both programs could potentially avert CAN among tens of thousands of children across the country. Lower costs from reduced CAN may substantially offset, but not always entirely eliminate, payers' program implementation cost. Results are sensitive to the rate of CAN in each US state. Given the considerable lifetime societal cost of CAN, including victims' lost work productivity, the programs were cost saving from the societal perspective in all US states using base case methods. This analysis represents an overall minimum return on payers' investment because averted CAN is just one of many positive health and educational outcomes associated with these programs and non-monetary benefits from reduced CAN were not included. Translating cost and effectiveness research on injury prevention programs for local conditions might increase decision makers' adoption of effective programs. PMID- 28735442 TI - Mechanisms regulating dendritic arbor patterning. AB - The nervous system is populated by diverse types of neurons, each of which has dendritic trees with strikingly different morphologies. These neuron-specific morphologies determine how dendritic trees integrate thousands of synaptic inputs to generate different firing properties. To ensure proper neuronal function and connectivity, it is necessary that dendrite patterns are precisely controlled and coordinated with synaptic activity. Here, we summarize the molecular and cellular mechanisms that regulate the formation of cell type-specific dendrite patterns during development. We focus on different aspects of vertebrate dendrite patterning that are particularly important in determining the neuronal function; such as the shape, branching, orientation and size of the arbors as well as the development of dendritic spine protrusions that receive excitatory inputs and compartmentalize postsynaptic responses. Additionally, we briefly comment on the implications of aberrant dendritic morphology for nervous system disease. PMID- 28735448 TI - Inhibitory effects of andrographolide on activated macrophages and adjuvant induced arthritis. AB - Andrographolide, a diterpenoid lactone obtained from plant Andrographis paniculata, is used in South Asian countries to relieve various inflammatory symptoms. To study the effects of this agent, the impact of andrographolide on production of inflammatory mediators were delineated in mouse peritoneal macrophages (PMphi). Inflammatory mediators like nitric oxide (NO), tumor necrosis factor (TNF)-alpha, interleukin-6 and related molecular mechanisms of andrographolide-mediated inhibition of enzymes/transcription factors were studied. In addition, the in vivo anti-inflammatory activity of andrographolide was evaluated in an adjuvant-induced arthritis rat model. The results indicated that andrographolide clearly inhibited the production of NO and TNF-alpha in lipopolysaccharide-activated PMphi in a dose-related manner. Immunoblot analyses revealed that andrographolide suppressed activation of both inducible NO synthase and cyclo-oxygenase-2 by directly targeting nuclear transcription factor (NF) kappaB. Complete Freund's Adjuvant-induced paw edema in rats was also significantly inhibited by andrographolide treatment. From the data, we concluded that andrographolide imparted anti-inflammatory effects by suppressing two key inflammatory enzymes and a signaling pathway that mediates expression of variety of inflammatory cytokines/agents in situ. It is plausible that eventually, after further toxicologic characterization, andrographolide might be useful as a drug for the clinical treatment of various inflammatory diseases like rheumatoid arthritis or diseases associated with joint pain. PMID- 28735450 TI - Prescription Drug Price Paradox: Cost Analysis of Canadian Online Pharmacies versus US Medicare Beneficiaries for the Top 100 Drugs. AB - BACKGROUND AND OBJECTIVES: Despite the introduction of Medicare Part D (MPD) and 2012 Affordable Care Act (ACA), patients have a cost burden due to increases in drug prices. To overcome cost barriers, some patients purchase their medications from Canadian online pharmacies as Canadian prescription drug prices are believed to be lower than US prescription drug prices. The objective of this study was to determine which top 100 Medicare drugs can be imported to the USA legally, and to determine which type of prescription drug would be more beneficial to be purchased from Canadian online pharmacies. Moreover, we also deemed it important to compare MPD beneficiary annual expenses with expenses patients would have when obtaining their prescriptions from Canadian online pharmacies. METHODS: We conducted a cost analysis from a patient perspective. A list of the top 100 Medicare drugs was compiled and information on drug prices was collected from three Canadian online pharmacies and four MPD plans in Virginia. The annual cost of each Medicare drug and percent change between Canadian online pharmacies and MPD were compared. RESULTS: A total of 78 drugs from the top 100 Medicare drugs were included in the final analysis. Seventy-six prescription drugs (97.4%) that could be purchased from Canadian online pharmacies showed a significantly lower average drug price percent change of -72.71% (P < 0.0001). The heart health/blood pressure subgroup had the highest number of drugs that could be purchased from Canadian online pharmacies. CONCLUSION: The majority of prescription drugs can be purchased at lower prices from Canadian online pharmacies when compared to Medicare beneficiaries' potential expenses. Purchasing medications from Canadian online pharmacies may be a viable option to address cost barriers. PMID- 28735449 TI - Therapy with omeprazole modulates regulatory T cell/T helper 17 immune response in children with duodenal ulcers. AB - The purpose of this study was to determine the effect of omeprazole on the regulatory T cell (Treg) and T helper 17 (Th17)-mediated response in patients with duodenal ulcers (DUs). DU patients were randomly divided into omeprazole and colloid bismuth subcitrate treatment groups. The ratios of Th17 and Treg in peripheral blood mononuclear cells (PBMCs) were measured. Cytokine production and Foxp3+- and RORgammat-positive cells were detected. The expressions of STAT3, p STAT3, STAT5 and p-STAT5 were detected by Western blot. The results showed that DU patients had an imbalanced Treg/Th17 response, as reflected by the higher IL 17 level and Th17 ratio and lower IL-10 level and Treg proportion in serum compared with those in the healthy volunteers. The administration of omeprazole to the patients significantly increased Treg and IL-10 levels and reduced Th17 and IL-17 levels. Omeprazole markedly increased the number of Foxp3-positive cells, decreased the number of RORgammat-positive cells and restored the balanced ratio of IL-10/IL-17 in the ulcer tissue. Interestingly, we observed a negative correlation between the ratios of Treg/Th17 and the pathological scores in damaged tissues. Of note, H. pylori-infected PBMCs showed decreased Treg and an increased Th17 proportion, which could be reversed by omeprazole. Finally, omeprazole increased the expression of p-STAT5 and reduced the level of p-STAT3 without any effects on the total expression of STAT5 and STAT3. Our data suggest that omeprazole treatment restores the equilibrium of the Treg/Th17-mediated response in DU patients. Moreover, the modulation of p-STAT3 and p-STAT5 expression by omeprazole induced balanced polarisation of Treg/Th17. PMID- 28735451 TI - Importance of ICPMS for speciation analysis is changing: future trends for targeted and non-targeted element speciation analysis. AB - This article is aimed at researchers interested in organic molecules which contain a heteroatom but who have never considered using inductively coupled plasma mass spectrometry (ICPMS) or who have used ICPMS for years and developed numerous methods for analysis of target elemental species. We try to illustrate (1) that ICPMS has been very useful for speciation analysis of metal(loid) target species and that there is now a trend to replace the costly detector with cheaper detection systems for routine target analysis, and (2) that ICPMS has been used and will be used even more in the future for non-targeted analysis of elements which are not normally associated with ICPMS analysis, such as non-metals such as sulfur, phosphorus, chlorine and fluorine. Graphical Abstract Starting with HPLC ICPMS for non-targeted analysis of heteroatom containing molecules, once target molecule is identified alternative detectors can be used for routine measurements. PMID- 28735452 TI - Characterization of polymeric substance classes in cereal-based beverages using asymmetrical flow field-flow fractionation with a multi-detection system. AB - Cereal-based beverages contain a complex mixture of various polymeric macromolecules including polysaccharides, peptides, and polyphenols. The molar mass of polymers and their degradation products affect different technological and especially sensory parameters of beverages. Asymmetrical flow field-flow fractionation (AF4) coupled with multi-angle light scattering (MALS) and refractive index detection (dRI) or UV detection (UV) is a technique for structure and molar mass distribution analysis of macromolecules commonly used for pure compound solutions. The objective of this study was to develop a systematic approach for identifying the polymer classes in an AF4//MALS/dRI/UV fractogram of the complex matrix in beer, a yeast-fermented cereal-based beverage. Assignment of fractogram fractions to polymer substance classes was achieved by targeted precipitations, enzymatic hydrolysis, and alignments with purified polymer standards. Corresponding effects on dRI and UV signals were evaluated according to the detector's sensitivities. Using these techniques, the AF4 fractogram of beer was classified into different fractions: (1) the low molar mass fraction was assigned to proteinaceous molecules with different degrees of glycosylation, (2) the middle molar mass fraction was attributed to protein polyphenol complexes with a coelution of non-starch polysaccharides, and (3) the high molar mass fraction was identified as a mixture of the cell wall polysaccharides (i.e., beta-glucan and arabinoxylan) with a low content of polysaccharide-protein association. In addition, dextrins derived from incomplete starch hydrolysis were identified in all fractions and over the complete molar mass range. The ability to assess the components of an AF4 fractogram is beneficial for the targeted design and evaluation of polymers in fermented cereal based beverages and for controlling and monitoring quality parameters. PMID- 28735453 TI - Comparing Oral Health Services Use in the Spanish and Immigrant Working Population. AB - We aim to analyze oral health services use and related factors in the immigrant working population compared to the Spanish counterparts. Cross-sectional study of working population (n = 8591) that responded Spanish National Health Survey (SNHS), 2011-2012. The association between oral health services use and migration status was estimated using logistic regression. Immigrant men presented a greater probability of oral health service use a year or more prior (aOR 1.63; 95% CI 1.26-2.02), independently of oral health, sociodemographic and socioeconomic characteristics. In immigrant women, greater probability of use of oral health services one year or more prior disappeared after adjusting for the same variables (aOR 1.15; 95% CI 0.91-1.45). Occupational social class and education level could explain better a high percentage of oral health service use one year or more prior in immigrant women but there is a persistent inequality in oral health service use in immigrant men. PMID- 28735454 TI - The Individual and Organizational Role of Physicians in Mitigating the Biological, Psychological and Social Health Consequences of Displacement. AB - The number of Internally Displaced People is growing globally with a significant number travelling to countries such as Canada. These individuals have unique health care needs that are significantly impacted by several social determinants of health, which provides a challenge to the physician as they must address the biological, psychological and social factors in order to effectively improve the health of this population. The physician must work at the individual, national, and international levels and collaborate with other health care workers in order to effectively address these complex health care issues. Some recent strategies that show promise in targeting these complex care issues include knowledge sharing among medical professionals, specialized treatment approaches including treatment through telemedicine as well as political advocacy. The application of strategies such as these, along with increased awareness and commitment from physicians, will work to improve health care and prevent negative health outcomes in this growing population. PMID- 28735455 TI - Examining the Role of Income Inequality and Neighborhood Walkability on Obesity and Physical Activity among Low-Income Hispanic Adults. AB - Obesity is a major public health issue affecting rising medical costs and contributing to morbidity and premature mortality. We aimed to identify factors that may play a role in obesity and physical activity at the individual and environmental/neighborhood levels. We analyzed data from an adult sample who were parents of students enrolled in a school-based health and wellness program. The sample was restricted to those who were Hispanic and whose children were on free/reduced lunch (n = 377). Dependent variables: body mass index (BMI); neighborhood walkability. Walk Score(r) was used to assess neighborhood walkability. Overall, 46% of participants were obese and 31% were overweight. The median age of respondents was 34 years, and the majority were female (88%) and married (59%). Participants who resided in a census tract with a higher relative income inequality (high, OR 2.54, 90% CI 1.154-5.601; moderate-high OR 2.527, 90% CI 1.324-4.821) and those who were unmarried (OR 1.807, 90% CI 1.119-2.917) were more likely to be obese versus normal weight. Overweight individuals that resided in areas that were walkable versus car-dependent averaged more days engaging in walking for at least 30-min (p <.05). Identifying individual and neighborhood factors associated with obesity can inform more targeted approaches to combat obesity at multiple ecological levels. The importance of understanding how neighborhood characteristics influence health-related and behavioral outcomes is further reinforced with the current findings. Identifying effective strategies to engage communities and organizations in creating, implementing, adopting, evaluating, and sustaining policy and/or environmental interventions will be needed to combat the obesity epidemic. PMID- 28735456 TI - Inferring foliar water uptake using stable isotopes of water. AB - A growing number of studies have described the direct absorption of water into leaves, a phenomenon known as foliar water uptake. The resultant increase in the amount of water in the leaf can be important for plant function. Exposing leaves to isotopically enriched or depleted water sources has become a common method for establishing whether or not a plant is capable of carrying out foliar water uptake. However, a careful inspection of our understanding of the fluxes of water isotopes between leaves and the atmosphere under high humidity conditions shows that there can clearly be isotopic exchange between the two pools even in the absence of a change in the mass of water in the leaf. We provide experimental evidence that while leaf water isotope ratios may change following exposure to a fog event using water with a depleted oxygen isotope ratio, leaf mass only changes when leaves are experiencing a water deficit that creates a driving gradient for the uptake of water by the leaf. Studies that rely on stable isotopes of water as a means of studying plant water use, particularly with respect to foliar water uptake, must consider the effects of these isotopic exchange processes. PMID- 28735457 TI - Impact of sentinel lymph node biopsy by ultrasound-guided core needle biopsy for patients with suspicious node positive breast cancer. AB - PURPOSE: The purpose of this study was to investigate the accuracy of preoperative diagnostic tools for axillary lymph nodes (LNs) staging of breast cancer. MATERIALS AND METHODS: A total of 2464 consecutive patients with operable breast cancer were prospectively identified at our institution between April 2012 and March 2017. Patients with suspicious axillary LN of breast cancer were assessed using preoperative ultrasound(US) or computed tomography (CT), underwent fine-needle aspiration cytology (FNA) or core needle biopsy (CNB). The inclusion criteria for both FNA and CNB were a cortical thickness >3 mm or abnormal morphological characteristics. Patients with biopsy-proven metastasis underwent axillary lymph node dissection (ALND), and those with a negative FNA or CNB underwent sentinel lymph node biopsy (SNB). If the SNB was positive, ALND was performed. Diagnostic accuracy for SNB was calculated for both FNA and CNB. In addition, the patients in this study were divided into two groups as follows: the cN0-FNA group (suspicious LN but negative FNA) and cN0-CNB group (suspicious LN but negative CNB). RESULTS: A number of patients with negative US/CT findings of LNs were 1406, with 744 undergoing FNA and 272 undergoing CNB for suspicious LNs. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were 65, 99, 99, 80, and 85% in FNA, and 87, 100, 100, 93 and 95% in CNB, respectively. SNB was performed in 172 (cN0-CNB group) of 272 CNB and 487 (cN0-FNA group) of 744 FNA patients. One hundred and seventy-two patients from the cN0-CNB group (Tis 6, T1 97, T2 66, T3 3 patients) treated with SNB were compared to 487 from the cN0-FNA group (Tis 21, T1 225, T2 233, T3 8 patients) in terms of number of LN metastasis. A number of patients with more than 3 positive SNB and positive LNs were 9 (5%) and 0 (0%) in cN0-CNB group, and 78 (16%) and 24 (5%) in cN0-FNA group, respectively. A number of patients who had complications such as haematoma and pain at the time of 7 to 14 days after CNB and FNA were 1 (0.5%) and 1 (0.5%) in cN0-CNB group, and were 0% and 0.2% in cN0 FNA group (p = 0.44), respectively. CONCLUSIONS: The preoperative diagnosis of axillary LNs was influenced by the diagnostic tool used. CNB is a reliable method for the preoperative diagnosis of LN metastasis. PMID- 28735458 TI - The efficacy of lapatinib and nilotinib in combination with radiation therapy in a model of NF2 associated peripheral schwannoma. AB - Neurofibromatosis type 2 (NF2), a neurogenetic condition manifest by peripheral nerve sheath tumors (PNST) throughout the neuroaxis for which there are no approved therapies. In vitro and in vivo studies presented here examine agents targeting signaling pathways, angiogenesis, and DNA repair mechanisms. In vitro dose response assays demonstrated potent activity of lapatinib and nilotinib against the mouse schwannoma SC4 (Nf2 -/-) cell line. We then examined the efficacy of everolimus, nilotinib, lapatinib, bevacizumab and radiation (RT) as mono- and combination therapies in flank and sciatic nerve in vivo NF2-PNST models. Data were analyzed using generalized linear models, two sample T-tests and paired T-tests, and linear regression models. SC4(Nf2 -/-) cells implanted in the flank or sciatic nerve showed similar rates of growth (p = 0.9748). Lapatinib, nilotinib and RT significantly reduced tumor growth rate versus controls in the in vivo flank model (p = 0.0025, 0.0062, and 0.009, respectively) whereas bevacizumab and everolimus did not. The best performers were tested in the in vivo sciatic nerve model of NF2 associated PNST, where chemoradiation outperformed nilotinib or lapatinib as single agents (nilotinib vs. nilotinib + RT, p = 0.0001; lapatinib versus lapatinib + RT, p < 0.0001) with no observed toxicity. There was no re-growth of tumors even 14 days after treatment was stopped. The combination of either lapatinib or nilotinib with RT resulted in greater delays in tumor growth rate than any modality alone. This data suggest that concurrent low dose RT and targeted therapy may have a role in addressing progressive PNST in patients with NF2. PMID- 28735459 TI - Diabetes and the hospitalized patient : A cluster analytic framework for characterizing the role of sex, race and comorbidity from 2006 to 2011. AB - In the US, one in four adults has two or more chronic conditions; this population accounts for two thirds of healthcare spending. Comorbidity, the presence of multiple simultaneous health conditions in an individual, is increasing in prevalence and has been shown to impact patient outcomes negatively. Comorbidities associated with diabetes are correlated with increased incidence of preventable hospitalizations, longer lengths of stay (LOS), and higher costs. This study focuses on sex and race disparities in outcomes for hospitalized adult patients with and without diabetes. The objective is to characterize the impact of comorbidity burden, measured as the Charlson Weighted Index of Comorbidities (WIC), on outcomes including LOS, total charges, and disposition (specifically, probability of routine discharge home). Data from the National Inpatient Sample (2006-2011) were used to build a cluster-analytic framework which integrates cluster analysis with multivariate and logistic regression methods, for several goals: (i) to evaluate impact of these covariates on outcomes; (ii) to identify the most important comorbidities in the hospitalized population; and (iii) to create a simplified WIC score. Results showed that, although hospitalized women had better outcomes than men, the impact of diabetes was worse for women. Also, non-White patients had longer lengths of stay and higher total charges. Furthermore, the simplified WIC performed equivalently in the generalized linear models predicting standardized total charges and LOS, suggesting that this new score can sufficiently capture the important variability in the data. Our findings underscore the need to evaluate the differential impact of diabetes on physiology and treatment in women and in minorities. PMID- 28735460 TI - The time dimension and the future of infertility treatments. PMID- 28735461 TI - Pneumonia and Streptococcus pneumoniae vaccine. AB - Pneumonia is an inflammatory disease of the lung, responsible for high morbidity and mortality worldwide. It is caused by bacteria, viruses, fungi, or other microorganisms. Streptococcus pneumoniae, a gram-positive bacterium with over 90 serotypes, is the most common causative agent. Moreover, comorbid factors including heart failure, renal disease, and pulmonary disease could increase the risk of pneumococcal pneumonia. Since the advent of the pneumococcal vaccine in the 1980s, the incidence of pneumonia has decreased significantly. However, current vaccines confer only limited protection against serotypes included in the vaccine. Thus, to overcome this limitation, new types of pneumococcal vaccines have been sought and under clinical trials. In this review, we discuss pneumonia and summarize the various types of pneumococcal vaccines in progress. PMID- 28735462 TI - Effect of decreased BCAA synthesis through disruption of ilvC gene on the virulence of Streptococcus pneumoniae. AB - Streptococcus pneumoniae (pneumococcus) is responsible for significant morbidity and mortality worldwide. It causes a variety of life-threatening infections such as pneumonia, bacteremia, and meningitis. In bacterial physiology, the metabolic pathway of branched-chain amino acids (BCAAs) plays an important role in virulence. Nonetheless, the function of IlvC, one of the enzymes involved in the biosynthesis of BCAAs, in S. pneumoniae remains unclear. Here, we demonstrated that downregulation of BCAA biosynthesis by ilvC ablation can diminish BCAA concentration and expression of pneumolysin (Ply) and LytA, and subsequently attenuate virulence. Infection with an ilvC mutant showed significantly reduced mortality and colonization in comparison with strain D39 (serotype 2, wild type), suggesting that ilvC can potentiate S. pneumoniae virulence due to adequate BCAA synthesis. Taken together, these results suggest that the function of ilvC in BCAA synthesis is essential for virulence factor and could play an important role in the pathogenesis of respiratory infections. PMID- 28735463 TI - Impact of pioglitazone on bone mineral density and bone marrow fat content. AB - : Pioglitazone use is associated with an increased risk of fractures. In this randomized, placebo-controlled study, pioglitazone use for 12 months was associated with a significant increase in bone marrow fat content at the femoral neck, accompanied by a significant decrease in total hip bone mineral density. The change in bone marrow fat with pioglitazone use was predominantly observed in female vs. male participants. INTRODUCTION: Use of the insulin sensitizer pioglitazone is associated with greater fracture incidence, although the underlying mechanisms are incompletely understood. This study aimed to assess the effect of pioglitazone treatment on femoral neck bone marrow (BM) fat content and on bone mineral density (BMD), and to establish if any correlation exists between the changes in these parameters. METHODS: In this double-blind placebo-controlled clinical trial, 42 obese volunteers with metabolic syndrome were randomized to pioglitazone (45 mg/day) or matching placebo for 1 year. The following measurements were conducted at baseline and during the treatment: liver, pancreas, and femoral neck BM fat content (by magnetic resonance spectroscopy), BMD by DXA, abdominal subcutaneous and visceral fat, and beta-cell function and insulin sensitivity. RESULTS: Results were available for 37 subjects who completed the baseline and 1-year evaluations. At 12 months, BM fat increased with pioglitazone (absolute change, +4.1%, p = 0.03), whereas BM fat content in the placebo group decreased non-significantly (-3.1%, p = 0.08) (p = 0.007 for the pioglitazone-placebo response difference). Total hip BMD declined in the pioglitazone group (-1.4%) and increased by 0.8% in the placebo group (p = 0.03 between groups). The change in total hip BMD was inversely and significantly correlated with the change in BM fat content (Spearman rho = -0.56, p = 0.01) in the pioglitazone group, but not within the placebo group (rho = -0.29, p = 0.24). Changes in BM fat with pioglitazone were predominantly observed in female vs. male subjects. CONCLUSIONS: Pioglitazone use for 12 months compared with placebo is associated with significant increase in BM fat content at the femoral neck, accompanied by a small but significant decrease in total hip BMD. PMID- 28735464 TI - Radiation dose reduction in thoracic and lumbar spine instrumentation using navigation based on an intraoperative cone beam CT imaging system: a prospective randomized clinical trial. AB - PURPOSE: Spine surgery still remains a challenge for every spine surgeon, aware of the potential serious outcomes of misplaced instrumentation. Though many studies have highlighted that using intraoperative cone beam CT imaging and navigation systems provides higher accuracy than conventional freehand methods for placement of pedicle screws in spine surgery, few studies are concerned about how to reduce radiation exposure for patients with the use of such technology. One of the main focuses of this study is based on the ALARA principle (as low as reasonably achievable). METHOD: A prospective randomized trial was conducted in the hybrid operating room between December 2015 and December 2016, including 50 patients operated on for posterior instrumented thoracic and/or lumbar spinal fusion. Patients were randomized to intraoperative 3D acquisition high-dose (standard dose) or low-dose protocol, and a total of 216 pedicle screws were analyzed in terms of screw position. Two different methods were used to measure ionizing radiation: the total skin dose (derived from the dose-area product) and the radiation dose evaluated by thermoluminescent dosimeters on the surgical field. RESULTS: According to Gertzbein and Heary classifications, low-dose protocol provided a significant higher accuracy of pedicle screw placement than the high-dose protocol (96.1 versus 92%, respectively). Seven screws (3.2%), all implanted with the high-dose protocol, needed to be revised intraoperatively. The use of low-dose acquisition protocols reduced patient exposure by a factor of five. CONCLUSION: This study emphasizes the paramount importance of using low dose protocols for intraoperative cone beam CT imaging coupled with the navigation system, as it at least does not affect the accuracy of pedicle screw placement and irradiates drastically less. PMID- 28735465 TI - Approximal morphology as predictor of approximal caries in primary molar teeth. AB - OBJECTIVE: To evaluate the predictive power of the morphology of the distal surface on 1st and mesial surface on 2nd primary molar teeth on caries development in young children. SAMPLE AND METHODS: Out of 101 3-to 4-year-old children from an on-going study, 62 children, for whom parents' informed consent was given, participated. Upper and lower molar teeth of one randomly selected side received a 2-day temporarily separation. Bitewing radiographs and silicone impressions of interproximal area (IPA) were obtained. One-year procedures were repeated in 52 children (84%). The morphology of the distal surfaces of the first molar teeth and the mesial surfaces on the second molar teeth (n=208) was scored from the occlusal aspect on images from the baseline resin models resulting in four IPA variants: concave-concave; concave-convex; convex-concave, and convex convex. Approximal caries on the surface in question was radiographically assessed as absent/present. RESULTS: Of the 52 children examined at follow-up, 31 children (60%) had 1-4 concave surfaces. In total 53 (25%) of the 208 surfaces were concave. A total of 22 children (43%) had 1-4 approximal lesions adding up to 59 lesions. Multiple logistic regression analyses disclosed that gender, surface morphology on one of the approximal surfaces (focus-surface), and adjacent-surface morphology were significantly related to caries development (p values <= 0.03). The odds ratio for developing caries in the focus surface/adjacent-surface in the four IPA variants were convex-convex, 1.0; convex concave, 5.5 (CI 2.0-14.7); concave-convex, 12.9 (CI 4.1-40.3); and concave concave, 15.7 (CI 5.1-48.3). CONCLUSION: Morphology of approximal surfaces in primary molar teeth, in particular both surfaces being concave, significantly influences the risk of developing caries. CLINICAL RELEVANCE: The concave morphology of approximal surfaces can predict future caries lesions supporting specific home-care and in-office preventive strategies. PMID- 28735466 TI - Comparative metabolic analysis in head and neck cancer and the normal gingiva. AB - OBJECTIVES: Chronic accumulation of lactate in malignant tumor tissue is associated with increased malignancy and radioresistance. For this study, biopsies of primary head and neck squamous cell carcinoma (HNSCC) and of the normal gingiva of the same patient were compared via metabolic profiling to the healthy gingiva from cancer-free patients. MATERIALS AND METHODS: Cryobiopsies of 140 HNSCC patients were used to determine ATP, lactate, and glucose concentrations of the tumor and normal gingiva via induced metabolic bioluminescence imaging (imBI). Additionally, these metabolites were quantified in a collective of 79 healthy (non-tumor-bearing) patients. Furthermore, tumor samples were analyzed via immunofluorescence imaging and quantitative real-time PCR for the expression of lactate and glucose transporters. RESULTS: There were significant differences in ATP concentrations detectable between the tumor, normal gingiva of tumor patients, and gingiva from healthy patients. Lactate concentrations were significantly increased in tumor tissue compared to the normal gingiva of tumor patients as well as the gingiva from healthy patients. Concerning glucose, there was a significant decrease in glucose concentrations detectable in the tumor biopsies compared to the normal gingiva of tumor patients. On the other hand, tumor samples from patients revealed significantly elevated relative expression levels of monocarboxylate transporters (MCT-1 and MCT-4), as well as glucose transporters (GLUT-1 and GLUT-3) compared to the corresponding normal gingiva of each patient. CONCLUSIONS: We could demonstrate that the lactate concentration in HNSCC correlates with primary tumor (T) stage. CLINICAL RELEVANCE: The aim of this study was to identify metabolic parameters to improve early cancer diagnosis, allow predictions on the degree of malignancy, and contribute to a personalized tumor therapy. PMID- 28735467 TI - Outcomes of preexisting diabetes mellitus in breast, colorectal, and prostate cancer. AB - PURPOSE: Preexisting diabetes is associated with increased morbidity and mortality in cancer. We examined the impact of incident cancer on the long-term outcomes of diabetes. METHODS: Using the United Kingdom Clinical Practice Research Datalink, we identified three cohorts of diabetes patients subsequently diagnosed with breast, colorectal, or prostate cancer, each matched to diabetic noncancer controls. Patients were required to have survived at least 1 year after cancer diagnosis (cases) or a matched index date (controls), and were followed up to 10 years for incident microvascular and macrovascular complications and mortality. Multivariate competing risks regression analyses were used to compare outcomes between cancer patients and controls. RESULTS: Overall, there were 3382 cancer patients and 11,135 controls with 59,431 person-years of follow-up. In adjusted analyses, there were no statistically significant (p <= 0.05) differences in diabetes complication rates between cancer patients and their controls in any of the three cancer cohorts. Combined, cancer patients were less likely (adjusted hazard ratio [HR] 0.88; 95% CI = 0.79-0.98) to develop retinopathy. Cancer patients were more likely to die of any cause (including cancer), but prostate cancer patients were less likely to die of causes associated with diabetes (HR 0.61; 95% CI = 0.43-0.88). CONCLUSIONS AND IMPLICATIONS: There is no evidence that incident cancer had an adverse impact on the long-term outcomes of preexisting diabetes. IMPLICATIONS FOR CANCER SURVIVORS: These findings are important for cancer survivors with preexisting diabetes because they suggest that substantial improvements in the relative survival of several of the most common types of cancer are not undermined by excess diabetes morbidity and mortality. PMID- 28735468 TI - The effect of water contamination and host-related factors on ectoparasite load in an insectivorous bat. AB - We examined the effects of sex, age, and reproductive state of the insectivorous bat Pipistrellus kuhlii on the abundance and prevalence of arthropod ectoparasites (Macronyssidae and Cimicidae) in habitats with either sewage polluted or natural bodies of water, in the Negev Desert, Israel. We chose water pollution as an environmental factor because of the importance of water availability in desert environments, particularly for P. kuhlii, which needs to drink on a daily basis. We predicted that parasite infestation rates would be affected by both environment and demographic cohort of the host. We found that female bats in the polluted site harbored significantly more mites than female bats in the natural site and that juveniles in the polluted site harbored significantly more cimicid individuals than juveniles in the natural site. We further found that age and sex (host-related factors) affected ectoparasite prevalence and intensity (i.e., the abundance of parasites) in the polluted site. Our results may suggest that the interaction between host-related and environment related factors affected parasite infestations, with females and young bats being more susceptible to ectoparasites when foraging over polluted water. This effect may be particularly important for bats that must drink or forage above water for other wildlife that depend on drinking water for survival. PMID- 28735469 TI - Phylogenetic relationships between Dicrocoelium chinensis populations in Japan and China based on mitochondrial nad1 gene sequences. AB - We carried out phylogenetic analyses of the relationships between Dicrocoelium chinensis populations in Japan and China using molecular markers. One hundred nine lancet flukes collected from Japan and China were identified as D. chinensis based on their testis orientation and the nucleotide sequences of their ribosomal ITS2. These flukes were analyzed phylogenetically using mitochondrial nad1 gene sequences. An analysis of molecular variance found that the percentage of variation between the countries was extremely high, indicating that the D. chinensis populations in Japan and China are differentiated genetically. D. chinensis mainly parasitizes wild sika deer, which is thought to originate in northeast Asia and to have colonized into Japan from the Eurasia continent in the Pleistocene glaciations. In addition, phylogenic analyses indicated that Japanese sika deer is genetically differentiated from Chinese population; therefore, we hypothesize that D. chinensis might have been introduced into Japan along with the migration of infected wild ruminants in the Pleistocene, and then the population became differentiated from the Chinese population. This study provides the nucleotide sequences of the nad1 gene of D. chinensis in Japan for the first time and shows that these sequences are useful for elucidating the phylogenetic relationships of the Dicrocoelium species prevalent in Asia. PMID- 28735471 TI - Effect of processing conditions on degree of hydrolysis, ACE inhibition, and antioxidant activities of protein hydrolysate from Acetes indicus. AB - Protein hydrolysate was prepared from Acetes indicus which is a major bycatch among non-penaeid prawn landings of India. Hydrolysis conditions (enzyme to substrate ratio and time) for preparing protein hydrolysates using alcalase enzyme were optimized by response surface methodology using central composite design. The optimum conditions for enzyme-substrate ratio (mL/100 g) of 1.57, 1.69, 1.60, 1.56, and 1.50 and for hydrolysis time of 97.18, 96.5, 98.15 min, 102.48, and 88.44 min were established for attaining maximum yield, degree of hydrolysis, 2,2-diphenyl-1-picrylhydrazyl, angiotensin I-converting enzyme inhibiting activity, and metal-chelating activity, respectively. ABTS radical scavenging activity and reducing power assay of optimized protein hydrolysate were found to be increased with the increase in concentration. The higher value of 7.04 (MUM Trolox/g), 87.95, and 77.24%, respectively for DPPH, ACE, and metal chelating activity indicated that the A. indicus protein hydrolysates have beneficial biological properties that could be well-utilized in the application of functional foods and nutraceuticals. Graphical abstract ?. PMID- 28735470 TI - Staged Reimplantation of a Total Hip Prosthesis After Co-infection with Candida tropicalis and Staphylococcus haemolyticus: A Case Report. AB - Fungal prosthetic joint infection is a rare complication in total joint arthroplasty. There are no established guidelines for management of these infections. We present a case of a 53-year-old male with a hip joint prosthesis co-infected with Candida tropicalis and Staphylococcus haemolyticus. A two-stage exchange arthroplasty was performed. The patient underwent implant removal, debridement, irrigation with saline solution and application of cement spacer impregnated with vancomycin followed by aggressive antimicrobial treatment in first stage. Complete eradication of infection was demonstrated by negative culture of sonicated cement spacer fluid and negative 16S rRNA and 18S rRNA gene PCR of sonicate fluid, synovial fluid and periprosthetic tissue samples. He underwent second-stage revision hip arthroplasty after 9 months of the first stage. At the latest follow-up, there was no evidence of recurrence of infection. This case illustrates the utility of sonication of biomaterials and molecular techniques for microbiological confirmation of absence of infection in staged surgeries which is required for a successful outcome. PMID- 28735473 TI - Low-concentration BPAF- and BPF-induced cell biological effects are mediated by ROS in MCF-7 breast cancer cells. AB - Reactive oxygen species (ROS) induced by bisphenol A (BPA) have been implicated in cellular oxidative damage and carcinogenesis. It is not known whether the potential alternatives of BPA, bisphenol AF (BPAF), and bisphenol F (BPF) can also induce ROS involved in mediating biological responses. This study evaluated the toxicity of BPAF and BPF on cell proliferation, DNA damage, intracellular calcium homeostasis, and ROS generation in MCF-7 human breast cancer cells. The results showed that BPAF at 0.001-1 MUM and BPF at 0.01-1 MUM significantly increased cell viability and at 25 and 50 MUM, both compounds decreased cell viability. At 0.01-10 MUM, both BPAF and BPF increased DNA damage and significantly elevated ROS and intracellular Ca2+ levels in MCF-7 cells. These biological effects were attenuated by the ROS scavenger N-acetylcysteine (NAC), indicating that ROS played a key role in the observed biological effects of BPAF and BPF on MCF-7 cells. These findings can deepen our understanding on the toxicity of BPAF and BPF, and provide basis data to further evaluate the potential health harm and establish environmental standard of BPAF and BPF. PMID- 28735472 TI - Assessment of soils contamination with veterinary antibiotic residues in Northern Poland using developed MAE-SPE-LC/MS/MS methods. AB - Among the wide range of compounds reaching the soil are the veterinary antimicrobials. Since no regulations regarding acceptable levels of drug concentrations in the environment exist, monitoring tests, particularly concerning soils, are carried out very rarely. This study presents a preliminary assessment of the contamination of agricultural soils in Northern Poland with seven antimicrobial veterinary medicines which has never been carried out before. Veterinary drugs were detected in 54% of the examined soil samples; the most commonly detected drugs were sulfonamides and trimethoprim. The highest indicated concentrations refer to enrofloxacin (57.0 MUg kg-1) and trimethoprim (47.8 MUg kg-1). The presence of these target drugs in the soil environment confirms the need for further monitoring studies. The analytical methods developed in this study are an excellent tool to achieve this goal and allow an estimation of the risk connected with the presence of veterinary antimicrobials in soils. PMID- 28735474 TI - Heterogeneous reaction of NO2 with soot at different relative humidity. AB - The influences of relative humidity (RH) on the heterogeneous reaction of NO2 with soot were investigated by a coated wall flow tube reactor at ambient pressure. The initial uptake coefficient (gamma initial) of NO2 showed a significant decrease with increasing RH from 7 to 70%. The gamma initial on "fuel rich" and "fuel-lean" soot at RH = 7% was (2.59 +/- 0.20) * 10-5 and (5.92 +/- 0.34) * 10-6, respectively, and it decreased to (5.49 +/- 0.83) * 10-6 and (7.16 +/- 0.73) * 10-7 at RH = 70%, respectively. Nevertheless, the HONO yields were almost independent of RH, with average values of (72 +/- 3)% for the fuel-rich soot and (60 +/- 2)% for the fuel-lean soot. The Langmuir-Hinshelwood mechanism was used to demonstrate the negative role of RH in the heterogeneous uptake of NO2 on soot. The species containing nitrogen formed on soot can undergo hydrolysis to produce carboxylic species or alcohols at high RH, accompanied by the release of little gas-phase HONO and NO. PMID- 28735475 TI - Antioxidant and antibacterial activities of Pelargonium asperum and Ormenis mixta essential oils and their synergistic antibacterial effect. AB - In this work, the chemical composition, the antioxidant, and the antibacterial activities of two Moroccan essential oils less studied, extracted from Pelargonium asperum and Ormenis mixta, were investigated. According to the gas chromatography coupled to mass spectrometry analysis, citronellol (25.07%), citronellyl ester (10.52%), geraniol (10.46%), and buthyl anthranilate (5.93%) were found to be the major components of P. asperum, while O. mixta was mainly composed of D-germacrene (11.46%), 1,8-cineole (10.28%), and cis-methyl isoeugenol (9.04%). Moreover, O. mixta essential oil exhibited an important antioxidant activity being significantly higher than that exhibited by P. asperum oil (P < 0.001). As regards the antimicrobial activity of both essential oils, the zones of growth inhibition and the minimum inhibitory concentration values showed that P. asperum essential oil was more active than that of O. mixta. Thereafter, the impact of the binary combination of essential oils on their antimicrobial effect was investigated against Staphylococcus aureus using the fractional inhibitory concentration index calculation. The results showed a promising synergistic antibacterial interaction between essential oils studied. PMID- 28735476 TI - Annual European Congress of Rheumatology : Madrid, Spain, 14-17 June 2017. PMID- 28735477 TI - Molecular Malfeasance Mediating Myeloid Malignancies: The Genetics of Acute Myeloid Leukemia. AB - A remarkable number of different, but recurrent, structural cytogenetic abnormalities have been observed in AML, and the 2016 WHO AML classification system incorporates numerous distinct entities associated with translocations or inversions, as well as others associated with single gene mutations into a category entitled "AML with recurrent genetic abnormalities." The AML classification is heavily reliant on cytogenetic and molecular information based on conventional genetic techniques (including karyotype, fluorescence in situ hybridization, reverse transcriptase polymerase chain reaction, single gene sequencing), but large-scale next generation sequencing is now identifying novel mutations. With targeted next generation sequencing panels now clinically available at many centers, detection of mutations, as well as alterations in epigenetic modifiers, is becoming part of the routine diagnostic evaluation of AML and will likely impact future classification schemes. PMID- 28735478 TI - Cytochemical Staining. AB - Historically, the diagnosis and classification of acute leukemia involved morphologic review of blasts in the peripheral blood and bone marrow smears and cytochemical staining. Cytochemical stains, which are enzymatic colorimetric reactions that occur in the cells of interest, were necessary to assign and confirm myeloid and lymphoid lineage. In the current WHO 2008 Classification of leukemia, immunophenotyping and cytogenetic analysis have largely replaced cytochemical staining in the characterization of acute leukemias. Nonetheless, cytochemical testing remains a useful adjunct assay for the proper classification of acute leukemia in a number of diagnostic settings. This chapter reviews the principles of the most common cytochemical stains, their procedures and guides to interpretation, and results in acute myeloid leukemia. PMID- 28735479 TI - Immunohistochemistry in Acute Myeloid Leukemia. AB - The World Health Organization's Classification of Tumours of Haematopoietic and Lymphoid Tissues (Swerdlow et al. (eds) WHO Classification of tumours of haematopoietic and lymphoid tissues, 4th edn. WHO Press, Lyon, 2008) created a classification scheme incorporating genetic, molecular, morphologic, and immunophenotypic characteristics. The diagnosis of acute myeloid leukemia requires equal to or greater than 20% blasts (except in some cases with specific cytogenetic abnormalities or in erythroleukemia). The diagnostic work up typically includes morphologic, cytochemical, and immunophenotypic features. This generally includes evaluation of the peripheral blood, bone marrow aspirate, and bone marrow trephine biopsy. As stated in the WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, "the contribution of an adequate bone marrow biopsy cannot be over stated" (Swerdlow et al. (eds) WHO Classification of tumours of haematopoietic and lymphoid tissues, 4th edn. WHO Press, Lyon, 2008). The evaluation of the bone marrow biopsy provided the necessary material for immunohistochemical studies used for both diagnosis and prognosis.The following text will focus on the utilization of immunohistochemical studies in the classification of acute myeloid leukemia. Other methodologies will be discussed elsewhere in this volume. PMID- 28735480 TI - Immunophenotyping by Multiparameter Flow Cytometry. AB - Multiparameter flow cytometry has become an indispensable tool for the diagnosis and classification of acute myeloid leukemia (AML). The basic method relies on the unique ability to detect immunophenotypic abnormalities on discrete subpopulations. The primary roles in the initial assessment of AML are to determine the immaturity of the leukemic population, define the lineage and the immunophenotypic aberrancies in blasts, and identify characteristic immunophenotypic features to predict important recurrent cytogenetic and genetic abnormalities and prognosis. The established immunophenotypic profile, a baseline "fingerprint," is used for follow-up assessment of residual disease. This chapter provides an overview of procedures for specimen processing, staining, and immunophenotyping of AML and describes our strategy for data analysis supplemented with illustrative case examples. PMID- 28735481 TI - Single-Cell Mass Cytometry of Acute Myeloid Leukemia and Leukemia Stem/Progenitor Cells. AB - Mass cytometry time-of-flight (CyTOF) empowers us to understand acute myeloid leukemia (AML) biology at the single-cell level. This technology, combined with advanced data-analysis methods, enables identification and characterization of the rare AML stem/progenitor cells that play key roles in drug resistance and AML relapse. Here we provide a protocol for AML sample preparation for CyTOF and keynotes emphasizing critical steps in and troubleshooting strategies for this procedure. PMID- 28735482 TI - Design and Application of Multiplex PCR Seq for the Detection of Somatic Mutations Associated with Myeloid Malignancies. AB - Targeted sequencing, in which only a selected set of genomic loci are sequenced, enables a much higher coverage of each target than what is obtained using whole genome or exome sequencing. Multiplex PCR offers a simple and affordable technique for specific capture of target regions and can be easily adapted to generate next-generation sequencing (NGS)-ready amplicons. Here we describe a multiplex PCR (MxPCR) approach for capturing 13 leukemia-associated mutation hotspots followed by MiSeq sequencing that enables robust detection of mutations with a variant allele fraction (VAF) as low as 0.8% (0.008) in blood DNA. PMID- 28735483 TI - AMLprofiler: A Diagnostic and Prognostic Microarray for Acute Myeloid Leukemia. AB - Acute myeloid leukemia is characterized by the proliferation and accumulation of immature hematopoietic cells of the myeloid lineage in the bone marrow. The disease is typified by diverse genetic abnormalities and marked heterogeneity both with regard to response to treatment and survival. The AMLprofiler is a qualitative in vitro diagnostic microarray developed by SkylineDx for use with Affymetrix technology. The AMLprofiler makes use of RNA chemistry and incorporates seven separate assays based on three different technologies cytogenetics, mutation, and expression analysis-to predict post-therapy survival rates in patients with acute myeloid leukemia. The assay has been validated for processing of bone marrow samples from which RNA is isolated within 48 h. The samples are subsequently processed using Affymetrix GeneChip reagent kits and analyzed on the Affymetrix GeneChip 3000Dx v2 system. The scanned AMLprofiler data is sent to a centralized server of SkylineDx via a secured Internet connection, and a diagnostic report is generated within 15 min. We have performed several AMLprofiler assays in our laboratory and found the data generated via this assay to be consistent with standard modalities. PMID- 28735484 TI - Microsphere-Based Assessment of DNA Methylation for AML Prognosis. AB - Epigenetic dysregulation, including aberrant methylation of cytosine residues in DNA, is a hallmark of cancer and clearly results in oncogenic cellular alterations such as transcriptional attenuation of tumor suppressors and genomic instability. A number of studies have examined DNA methylation alterations in patients with acute myeloid leukemia (AML) and have shown that analysis of multilocus methylation patterns can identify biologically distinct AML subclasses and can predict patient prognosis. In order to utilize the prognostic capability of methylation analysis in a clinical setting, we have developed a microsphere based HpaII tiny fragment enrichment by ligation-mediated PCR (xMELP) assay to interrogate the methylation state of genomic multiple loci along with a random forest-based classification algorithm that correlates DNA methylation status with patient prognosis. These tools can be easily implemented in a clinical molecular pathology laboratory and can be utilized for more accurate risk stratification of AML patients. PMID- 28735485 TI - Genome-Wide Analysis of DNA Methylation in Hematopoietic Cells: DNA Methylation Analysis by WGBS. AB - DNA methylation is a major epigenetic modification that regulates gene expression, genome imprinting, and development and has a role in diseases including cancer. There are various methods for whole-genome methylation profiling that differ in cost and resolution. Recent advances in high-throughput sequencing technologies coupled with bisulfite treatment enable absolute DNA methylation quantification and genome-wide single-nucleotide resolution analysis. In this chapter, we provide detailed protocols for whole-genome bisulfite sequencing (WGBS), which captures the complete methylome. Using WGBS, we are able to generate a reference DNA methylome for normal or malignant hematopoietic cells. PMID- 28735486 TI - Detection and Quantification of Acute Myeloid Leukemia-Associated Fusion Transcripts. AB - Real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR) based detection of abnormal fusion transcripts is an important strategy for the diagnosis and monitoring of patients with acute myeloid leukemia (AML) with t(8;21)(q22;q22); RUNX1-RUNX1T1, inv(16)(p13.1;q22); CBFB-MYH11 or t(15;17)(q22;q12); PML-RARA. In RT-qPCR assays, patient-derived cDNA is subjected to amplification using PCR primers directed against the fusion transcript of interest as well as a reference gene for normalization. Quantification is typically performed by constructing standard curves for each PCR run using a series of plasmid standards of known concentration that harbor the same fusion transcript or the same reference gene of interest. Fusion transcripts and reference gene copy numbers are then calculated in patient samples using these standard curves. The process of constructing standard curves is laborious and consumes additional reagents. In this chapter, we give the method details for a multiplex RT-qPCR strategy to detect and quantify the acute myeloid leukemia (AML)-associated fusion transcripts PML-RARA in patients with t(15;17) without the need for standard curves. This general method can also be applied to other AML-associated fusion transcripts such as CBFB-MYH11 and RUNX1-RUNX1T1. PMID- 28735487 TI - Targeted Next-Generation Sequencing of Acute Leukemia. AB - Mutation profiling of acute leukemias is a valuable tool for identifying genetic mutations with prognostic, predictive, therapeutic, and diagnostic utility. Technological advances, such as massively parallel sequencing, have allowed laboratories to assess for variation across dozens or hundreds of genes simultaneously with relatively low cost per target.Here, we describe a procedure for designing and using a TruSeq Custom Amplicon assay targeting genes involved in acute leukemias. This method is a fully customizable, amplicon-based assay for targeted resequencing, allowing interrogation of selected genomic regions of interest. The most readily available form of the assay allows sequencing of up to 1536 amplicons in a single reaction using a straightforward workflow. The ability to multiplex up to 1536 amplicons per reaction allows coverage of up to 650 kb of cumulative sequence and supports up to 96 samples per batch, depending on library size and desired sequencing depth. PMID- 28735488 TI - Bioinformatics Data Analysis of Next-Generation Sequencing Data from Heterogeneous Tumor Samples. AB - Tumor heterogeneity is a major challenge when it comes to treating cancer and also complicates research aimed at determining genetic sources for tumorigenesis. Leveraging high-throughput sequencing technology has been an effective approach for advancing our understanding of genetic diseases, and this type of data can also be used to better understand and make inferences about tumor heterogeneity. Here we describe the basics of genomics data analysis, as well as analysis pipelines for investigating tumor heterogeneity with next-generation sequencing data. PMID- 28735489 TI - A Zebrafish Model for Evaluating the Function of Human Leukemic Gene IDH1 and Its Mutation. AB - The recent advent of next-generation sequencing (NGS) has greatly accelerated identification of gene mutations in myeloid malignancies at unprecedented speed that will soon outpace their functional validation by conventional laboratory techniques and animal models. A high-throughput whole-organism model is useful for the functional validation of new mutations. We recently reported the use of zebrafish to evaluate the hematopoietic function of isocitrate dehydrogenase 1 (IDH1) and the effects of expressing human IDH1-R132H that is frequently identified in human acute myeloid leukemia (AML), in myelopoiesis, with a view to develop zebrafish as a model of AML. Here, we use IDH1 as an example to describe a comprehensive approach to evaluate hematopoietic gene function and the effects of mutations using zebrafish as a model. PMID- 28735490 TI - Measurement of Oncometabolites D-2-Hydroxyglutaric Acid and L-2-Hydroxyglutaric Acid. AB - We describe a liquid chromatography-tandem mass spectrometry assay for measurement of D-2-hydroxyglutaric acid and L-2-hydroxyglutaric acid. These metabolites are increased in specific inborn errors of metabolism and are now recognized as oncometabolites. The measurement of D-2-hydroxyglutarate in peripheral blood may be used as a biomarker for screening and follow-up of patients with IDH-mutated acute myeloid leukemia. PMID- 28735491 TI - Nanofluidic Allele-Specific Digital PCR Method for Quantifying IDH1 and IDH2 Mutation Burden in Acute Myeloid Leukemia. AB - Precise quantitation of allelic burden for a pathogenic mutation has diverse clinical and research applications but can be difficult to achieve with conventional qPCR-based techniques, especially at lower mutant allele frequencies. Digital PCR overcomes many of the limitations of qPCR and can be highly quantitative even for single-nucleotide variants, with distinct advantages over next-generation sequencing approaches. Here we describe a method combining the principles of TaqMan(r)-chemistry SNP genotyping with microfluidic digital PCR to generate a highly sensitive, quantitative allele-specific digital PCR assay for the six most common IDH1 and IDH2 mutations encountered in myeloid malignancy. The concept and approach could easily be applied to other suitable SNVs. PMID- 28735492 TI - Isolation of Biologically Active Exosomes from Plasma of Patients with Cancer. AB - A method for exosome isolation from human plasma was developed for rapid, high throughput processing of plasma specimens obtained from patients with cancer. This method removes the bulk of plasma proteins associated with exosomes and can be used for comparative examinations of exosomes and their content in serial specimens of patients' plasma, allowing for monitoring changes in exosome numbers, profiles, and functions in the course of cancer progression or during therapy. The plasma-derived exosomes can be recovered in quantities sufficient for the characterization of their morphology by transmission electron microscopy (TEM), size and concentration by qNano, protein/lipid ratios, nucleic acid extraction, molecular profiling by Western blots or immune arrays, and functional assays. PMID- 28735493 TI - Generating and Expanding Autologous Chimeric Antigen Receptor T Cells from Patients with Acute Myeloid Leukemia. AB - Adoptive transfer of genetically engineered T cells can lead to profound and durable responses in patients with hematologic malignancies, generating enormous enthusiasm among scientists, clinicians, patients, and biotechnology companies. The success of adoptive cellular immunotherapy depends upon the ability to manufacture good quality T cells. We discuss here the methodologies and reagents that are used to generate T cells for the preclinical study of chimeric antigen receptor T cell therapy for acute myeloid leukemia (AML). PMID- 28735494 TI - Trends in use of warfarin and direct oral anticoagulants in atrial fibrillation in Norway, 2010 to 2015. AB - PURPOSE: Since 2011, several direct oral anticoagulants (DOACs; dabigatran, rivaroxaban, apixaban) have been introduced as alternatives to warfarin for stroke prophylaxis in atrial fibrillation. We wanted to investigate changes in utilization of oral anticoagulants for atrial fibrillation in Norway following the introduction of DOACs. METHODS: Using nationwide registries, we identified all adults with pharmacy dispensings for warfarin or DOACs between January 2010 and December 2015 in Norway, and used ambulatory reimbursement codes to identify atrial fibrillation as indication. We defined incident use by a 1-year washout period. We describe trends in prevalent and incident use of warfarin and DOACs between 2010 and 2015, as well as patterns of treatment switching for incident users. RESULTS: One hundred twenty-nine thousand two hundred eighty-five patients filled at least one prescription for an oral anticoagulant for atrial fibrillation; the yearly number of incident users increased from 262 to 421 per 100,000 person-years; and the yearly share of incident users who initiated a DOAC increased to 82%. Half the prevalent users were on a DOAC by 2015. Within a year of drug initiation, 6, 12, 16 and 20% of incident users of apixaban, rivaroxaban, warfarin and dabigatran, respectively, switched oral anticoagulant. CONCLUSIONS: Use of DOACs for anticoagulation in atrial fibrillation became more prevalent between 2010 and 2015 in Norway, at the expense of warfarin. PMID- 28735495 TI - Neuroanatomical and resting state EEG power correlates of central hearing loss in older adults. AB - To gain more insight into central hearing loss, we investigated the relationship between cortical thickness and surface area, speech-relevant resting state EEG power, and above-threshold auditory measures in older adults and younger controls. Twenty-three older adults and 13 younger controls were tested with an adaptive auditory test battery to measure not only traditional pure-tone thresholds, but also above individual thresholds of temporal and spectral processing. The participants' speech recognition in noise (SiN) was evaluated, and a T1-weighted MRI image obtained for each participant. We then determined the cortical thickness (CT) and mean cortical surface area (CSA) of auditory and higher speech-relevant regions of interest (ROIs) with FreeSurfer. Further, we obtained resting state EEG from all participants as well as data on the intrinsic theta and gamma power lateralization, the latter in accordance with predictions of the Asymmetric Sampling in Time hypothesis regarding speech processing (Poeppel, Speech Commun 41:245-255, 2003). Methodological steps involved the calculation of age-related differences in behavior, anatomy and EEG power lateralization, followed by multiple regressions with anatomical ROIs as predictors for auditory performance. We then determined anatomical regressors for theta and gamma lateralization, and further constructed all regressions to investigate age as a moderator variable. Behavioral results indicated that older adults performed worse in temporal and spectral auditory tasks, and in SiN, despite having normal peripheral hearing as signaled by the audiogram. These behavioral age-related distinctions were accompanied by lower CT in all ROIs, while CSA was not different between the two age groups. Age modulated the regressions specifically in right auditory areas, where a thicker cortex was associated with better auditory performance in older adults. Moreover, a thicker right supratemporal sulcus predicted more rightward theta lateralization, indicating the functional relevance of the right auditory areas in older adults. The question how age-related cortical thinning and intrinsic EEG architecture relates to central hearing loss has so far not been addressed. Here, we provide the first neuroanatomical and neurofunctional evidence that cortical thinning and lateralization of speech-relevant frequency band power relates to the extent of age-related central hearing loss in older adults. The results are discussed within the current frameworks of speech processing and aging. PMID- 28735496 TI - Low-Level Prenatal Toxin Exposures and Breastfeeding Duration: A Prospective Cohort Study. AB - Introduction Maternal exposure to tobacco smoke is associated with shortened breastfeeding duration, but few studies have examined the effects on breastfeeding outcomes of low level exposures to other toxic chemicals. Moreover, it is unclear if passive smoking is associated with duration of breastfeeding. Our objective was therefore to examine the effect of low-level prenatal exposures to common environmental toxins (tobacco smoke, lead, and phthalates) on breastfeeding exclusivity and duration. Methods We conducted an analysis of data from the Health Outcomes and Measures of the Environment (HOME) Study. Serum and urine samples were collected at approximately 16 and 26 weeks gestation and at delivery from 373 women; 302 breastfed their infants. Maternal infant feeding interviews were conducted a maximum of eight times through 30 months postpartum. The main predictor variables for this study were gestational exposures to tobacco smoke (measured by serum cotinine), lead, and phthalates. Passive smoke exposure was defined as cotinine levels of 0.015-3.0 MUg/mL. Primary outcomes were duration of any and exclusive breastfeeding. Results Serum cotinine concentrations were negatively associated with the duration of any breastfeeding (29.9 weeks unexposed vs. 24.9 weeks with passive exposure, p = 0.04; and 22.4 weeks with active exposure, p = 0.12; p = 0.03 for linear trend), but not duration of exclusive breastfeeding. Prenatal levels of blood lead and urinary phthalate metabolites were not significantly associated with duration of any or exclusive breastfeeding. Conclusions Passive exposure to tobacco smoke during pregnancy was associated with shortened duration of any breastfeeding. PMID- 28735497 TI - Conceptual DFT analysis of the regioselectivity of 1,3-dipolar cycloadditions: nitrones as a case of study. AB - The regioselectivity of the 1,3-dipolar cycloaddition of a model nitrone with a set of dipolarophiles, presenting diverse electronic effects, is analyzed using conceptual density functional theory (DFT) methods. We deviate from standard approaches based on frontier molecular orbitals and formulations of the local hard/soft acid/base principle and use instead the dual descriptor. A detailed analysis is carried out to determine the influence of the way to calculate the dual descriptor, the computational procedure, basis set and choice of method to condensate the values of this descriptor. We show that the qualitative regioselectivity predictions depend on the choice of "computational conditions", something that indicates the danger of using black-box computational set-ups in conceptual DFT studies. PMID- 28735498 TI - Theoretical insight into the solvent effect of H2O and formamide on the cooperativity effect in HMX complex. AB - The cooperativity effects of the H-bonding interactions in HMX (1,3,5,7 tetranitro-1,3,5,7-tetrazacyclooctane)???HMX???FA (formamide), HMX???HMX???H2O and HMX???HMX???HMX complexes involving the chair and chair-chair HMX are investigated by using the ONIOM2 (CAM-B3LYP/6-31++G(d,p):PM3) and ONIOM2 (M06 2X/6-31++G(d,p):PM3) methods. The solvent effect of FA or H2O on the cooperativity effect in HMX???HMX???HMX are evaluated by the integral equation formalism polarized continuum model. The results show that the cooperativity and anti-cooperativity effects are not notable in all the systems. Although the effect of solvation on the binding energy of ternary system HMX???HMX???HMX is not large, that on the cooperativity of H-bonds is notable, which leads to the mutually strengthened H-bonding interaction in solution. This is perhaps the reason for the formation of different conformation of HMX in different solvent. Surface electrostatic potential and reduced density gradient are used to reveal the nature of the solvent effect on cooperativity effect in HMX???HMX???HMX. Graphical abstract RDG isosurface and electrostatic potential surface of HMX???HMX???HMX. PMID- 28735499 TI - An evaluation of the reliability of the characterization of the porous structure of activated carbons based on incomplete nitrogen adsorption isotherms. AB - The paper presents the results of research devoted to reliability evaluation of the analysis of results of the porous structure of activated carbons based on incomplete nitrogen adsorption isotherms using the BET, t-plot, and NLDFT methods, as well as the LBET method comprising the unique numerical fast multivariant procedure of adsorption system identification. The research involved the application of the nitrogen adsorption isotherms obtained for five samples of activated carbons produced from waste materials of organic origin by way of chemical activation with potassium hydroxide, sodium hydroxide, and potassium carbonate with the use of microwave heating. The analyses performed pointed to a good correlation between the results obtained using the BET, t-plot, NLDFT, and LBET methods. Moreover, the parameters of the porous structure determined using these methods based on incomplete adsorption isotherms of nitrogen are in fact as reliable as these methods allow. PMID- 28735500 TI - Adherence to COPD management guidelines in general practice? A review of the literature. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a progressive illness that is mostly managed in the general practice setting. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines are the international gold standard, and it is important to understand how these are being applied in general practice. AIMS: This review aimed to assess the current level of adherence to international best practice guidelines among general practitioners in relation to COPD. METHODS: PubMed and EMBASE searches (from 2012 to 2016) were performed and used the search terms guidelines, COPD, general practitioners, and primary care. Papers were excluded if they were not primary sources, were published before 2012, or did not pertain to a general practice setting. RESULTS: After applying set inclusion and exclusion criteria, 11 studies were retrieved. These papers were grouped under three categories: diagnosis, pharmacological, and non-pharmacological management, based on the GOLD guidelines. CONCLUSIONS: Current studies show significant variability in adherence to the GOLD guidelines. Barriers identified include lack of clarity, unfamiliarity with recommendations, and lack of familiarity with the guidelines. If general practice is expected to manage COPD and other chronic diseases, health service investment is needed to provide appropriate focused guidelines, to support their dissemination and resources to implement them in practice. PMID- 28735501 TI - Step by step guide to do a systematic review and meta-analysis for medical professionals. AB - INTRODUCTION: Systematic review and meta-analysis are statistical tools used to review researches performed on a same topic. They extract the collective effect of the studies performed on the topic of interest after statistically analysing the data of all the studies included. AIMS AND OBJECTIVES: Systematic reviews and meta-analysis are getting more and more popular in the medical field. Statistics is never the strong aspect of medical professionals, and facing a large number of statistical tests and values could be quite confusing for them. The aim of this article is to simplify these two very important research modalities for medical professionals. CONCLUSION: This article will provide a step-to-step guide for the medical colleagues to perform a meta-analysis if they are interested. PMID- 28735502 TI - Regenerative medicine in kidney disease: where we stand and where to go. AB - The kidney is a complex organ with more than 20 types of specialized cells that play an important role in maintaining the body's homeostasis. The epithelial tubular cell is formed during embryonic development and has little proliferative capacity under physiological conditions, but after acute injury the kidney does have regenerative capacity. However, after repetitive or severe lesions, it may undergo a maladaptation process that predisposes it to chronic kidney injury. Regenerative medicine includes various repair and regeneration techniques, and these have gained increasing attention in the scientific literature. In the future, not only will these techniques contribute to the repair and regeneration of the human kidney, but probably also to the construction of an entire organ. New mechanisms studied for kidney regeneration and repair include circulating stem cells as mesenchymal stromal/stem cells and their paracrine mechanisms of action; renal progenitor stem cells; the leading role of tubular epithelial cells in the tubular repair process; the study of zebrafish larvae to understand the process of nephron development, kidney scaffold and its repopulation; and, finally, the development of organoids. This review elucidates where we are in terms of current scientific knowledge regarding these mechanisms and the promises of future scientific perspectives. PMID- 28735504 TI - Low genetic diversity and functional constraint of miRNA genes participating pollen-pistil interaction in rice. AB - KEY MESSAGE: In this study, we sequenced and analyzed the expression and evolution of rice miRNA genes participating pollen-pistil interaction that is crucial to rice yield. Pollen-pistil interaction is an essential reproductive process for all flowering plants. While microRNAs (miRNAs) are important noncoding small RNAs that regulate mRNA levels in eukaryotic cells, there is little knowledge about which miRNAs involved in the early stages of pollen-pistil interaction in rice and how they evolve under this conserved process. In this study, we sequenced the small RNAs in rice from unpollinated pistil (R0), pistil from 5 min and 15 min after pollination, respectively, to identify known and novel miRNAs that are involved in this process. By comparing the corresponding mRNA-seq dataset, we identified a group of miRNAs with strong negative expression pattern with their target genes. Further investigation of all miRNA loci (MIRNAs) across 1083 public rice accessions revealed significantly reduced genetic diversity in MIRNAs with strong negative expression of their targets when comparing to those with little or no impact on targets during pollen-pistil interaction. Annotation of targets suggested that those MIRNAs with strong impact on targets were pronounced in cell wall related processes such as xylan metabolism. Additionally, plant conserved miRNAs, such as those with functions in gibberellic acid, auxin and nitrate signaling, were also with strong negative expression of their targets. Overall, our analyses identified key miRNAs participating pollen-pistil interaction and their evolutionary patterns in rice, which can facilitate the understanding of molecular mechanisms associated with seed setting. PMID- 28735503 TI - Association between allergic disease, sleep-disordered breathing, and childhood nocturnal enuresis: a population-based case-control study. AB - BACKGROUND: Little is known about the associations between allergic disease, sleep-disordered breathing (SDB), and childhood nocturnal enuresis (NE). We examined whether allergic disease and SDB were associated with childhood NE. METHODS: Data were assessed from the 2007-2012 Taiwan National Health Insurance Research Database. We enrolled 4308 children aged 5-18 years having NE diagnosis and age- and sex-matched 4308 children as the control group. The odds ratios of NE were calculated to determine an association with preexisting allergic disease and SDB. RESULTS: A total of 8616 children were included in the analysis. Prevalence of allergic diseases and SDB was significantly higher for the NE group than the control group (all p < 0.001). After adjusting odds ratios for potential confounding factors, except asthma, children with allergic rhinitis, atopic dermatitis, allergic conjunctivitis, and obstructive sleep apnea (OSA) had significantly higher odds of NE compared with children never diagnosed. With stratification for sex, girls with allergic rhinitis, atopic dermatitis, allergic conjunctivitis, OSA, and snoring had significantly higher odds of NE, compared with girls never diagnosed. Only boys with allergic rhinitis and OSA were associated with increased odds of NE. With stratification for age, children aged 5-12 years with allergic rhinitis, atopic dermatitis, allergic conjunctivitis, and OSA had significantly higher odds of NE compared with those never diagnosed. Odds of NE increased with the number of comorbid allergic diseases. CONCLUSIONS: Allergic diseases and SDB are associated with increased odds of childhood NE. The odds of NE increased with the number of comorbid allergic diseases present. PMID- 28735505 TI - Role of infarct location and pre-existing depression on cardiac baroreceptor sensitivity in subacute ischemic stroke. AB - Reduced cardiac baroreceptor sensitivity (BRS) after acute stroke is associated with worse outcome. The underlying mechanisms of reduced BRS are unclear. We evaluated cross correlation BRS (xBRS) in 184 patients with suspected acute ischemic stroke within 72 h of symptom onset. Among these patients, 22 had a transient ischemic attack (TIA) and 27 had a stroke mimic. Sixty-four age- and sex-matched ambulant control subjects without stroke were included. Compared with controls, xBRS was significantly lower in patients with ischemic stroke, TIA, and stroke mimics (4.6, 4.7, and 4.4, respectively, vs 6.6, p < 0.01). There was no difference in xBRS between right and left hemispheric infarctions (4.3 vs 4.9, p = 0.144), right and left insular infarctions (4.5 vs 5.3, p = 0.286), and insular infarction vs non-insular infarctions (4.7 vs 4.5, p = 0.996). Stroke patients with pre-existing depression/use of antidepressant medication had lower xBRS values than stroke patients with normal mental health (2.9 vs 4.8, p < 0.05). Control patients with depression also had lower xBRS compared to controls without depression (3.4 vs 5.9, p < 0.01). Our results suggest that decreased xBRS in the subacute phase after stroke is not associated with infarct localization. We found preliminary evidence for an association between pre-existing depression and use of antidepressant medication, and decreased BRS. PMID- 28735506 TI - Affection of immune cells by a C10orf2 mutation manifesting as mitochondrial myopathy and transient sensory transverse syndrome. PMID- 28735507 TI - Response to R-warfarin anticoagulant effect. PMID- 28735508 TI - Initiating insulin: How to help people with type 2 diabetes start and continue insulin successfully. PMID- 28735509 TI - Diagnostic utility of automated SureFISH (Dako Omnis) in the diagnosis of musculoskeletal translocation-related sarcomas. AB - Fluorescence in situ hybridization (FISH) is an essential tool for genetic diagnosis in daily pathological work. Almost full automation of FISH can be achieved with the recently released automated SureFISH platform (Dako Omnis, Agilent Technologies, Santa Clara, CA, USA). Its utility has been reported in HER2 amplification of breast and gastric carcinoma and ALK-rearranged lung cancer. Here, we examined the utility of automated SureFISH for the identification of rearrangement signals in translocation-related sarcomas (TRSs), including 11 EWSR1-rearranged and 10 synovial sarcoma cases, compared with non automated conventional FISH using the same specimens. The percentages of EWSR1 or SS18 split signals were higher in automated SureFISH than in conventional FISH in 13 of the 21 cases. On the other hand, 8 of the 21 cases showed the same or lower percentage of split signals in automated SureFISH. Both FISH approaches detected EWSR1 and SS18 split signals in more than 10% of tumor cells in all cases. The strongest advantage of automated SureFISH is its ability to reduce running time without sacrificing quality. Other advantages include improved signal sharpness with oligo probes and reduced ecological toxicity by avoiding formamide use. Automated SureFISH is an excellent tool for the genetic diagnosis of TRSs and contributes to their rapid definitive diagnosis. PMID- 28735511 TI - Infrared thermal imaging: a potential tool used in open colorectal surgery. AB - Aim of this pilot study was to assess blood perfusion of bowel in resection lines by means of the infrared thermal imaging in order to choose the best place for anastomosis. The paper brings a first experience with infrared thermal imaging used in colorectal surgery operation from initial observation of the patient with T3 adenomatous carcinoma with no lymph node metastasis. The obtained infrared images show a clear boundary between parts of the intestine with blood perfusion and without it. The proposed position of resection of colon identified by infrared camera is in accordance with routinely designated position. Infrared thermal imaging seems to be a complimentary diagnostic method to see the perfusion in colorectal surgery. PMID- 28735512 TI - Balloon dilatation of homograft conduits in the pulmonary position delays re intervention. PMID- 28735513 TI - Very early hepatocellular carcinoma in real-life practice: ablation or resection? A personal proposal. PMID- 28735510 TI - FXa inhibition by rivaroxaban modifies mechanisms associated with the pathogenesis of human abdominal aortic aneurysms. AB - AIMS: To evaluate if rivaroxaban, an oral factor Xa (FXa) inhibitor, could modify the expression in vitro of inflammatory and oxidative stress biomarkers in abdominal aortic aneurysmal (AAA) sites showing intraluminal thrombus. METHODS: AAA sites with intraluminal mural thrombus were obtained from six patients undergoing elective AAA repair. In addition, control abdominal aortic samples were obtained from six organ donors. AAA sites were incubated in the presence and absence of 50 nmol l-1 rivaroxaban. RESULTS: AAA sites showing thrombus demonstrated higher content of FXa than control. Interleukin-6 levels released from AAA [Control: median: 23.45 (interquartile range: 16.17-37.15) vs. AAA: median: 153.07 (interquartile range: 100.80-210.69) pg ml-1 mg tissue-1 , P < 0.05] and the expression levels of nitric oxide synthase 2 were significantly higher in AAA than in control. The protein expression level of NADPH oxidase subunits gp67-and gp91-phox, but did not gp47-phox, were also significantly higher in the AAA sites than in control. Addition of rivaroxaban to AAA sites explants significantly reduced the release of interleukin-6 [median: 51.61 (interquartile range: 30.87-74.03) pg ml-1 mg tissue-1 , P < 0.05 with respect to AAA alone] and the content of nitric oxide synthase 2, gp67 and gp91-phox NADPH subunits. The content of matrix metallopeptidase 9 was significantly higher in the AAA sites as compared to control. Rivaroxaban also reduced matrix metallopeptidase 9 content in AAA sites to similar levels to control. CONCLUSIONS: FXa inhibition by rivaroxaban exerted anti-inflammatory and antioxidative stress properties in human AAA sites, suggesting a role of FXa in these mechanisms associated with the pathogenesis of AAA. PMID- 28735514 TI - Laparoscopic associating liver partition and portal vein ligation for staged hepatectomy. PMID- 28735515 TI - Determination of cell fate in skeletal muscle following BMP gene transfer by in vivo electroporation. AB - We previously developed a novel method for gene transfer, which combined a non viral gene expression vector with transcutaneous in vivo electroporation. We applied this method to transfer the bone morphogenetic protein (BMP) gene and induce ectopic bone formation in rat skeletal muscles. At present, it remains unclear which types of cells can differentiate into osteogenic cells after BMP gene transfer by in vivo electroporation. Two types of stem cells in skeletal muscle can differentiate into osteogenic cells: muscle-derived stem cells, and bone marrow-derived stem cells in the blood. In the present study, we transferred the BMP gene into rat skeletal muscles. We then stained tissues for several muscle-derived stem cell markers (e.g., Pax7, M-cadherin), muscle regeneration related markers (e.g., Myod1, myogenin), and an inflammatory cell marker (CD68) to follow cell differentiation over time. Our results indicate that, in the absence of BMP, the cell population undergoes muscle regeneration, whereas in its presence, it can differentiate into osteogenic cells. Commitment towards either muscle regeneration or induction of ectopic bone formation appears to occur five to seven days after BMP gene transfer. PMID- 28735516 TI - DNMT1 regulates IL-6- and TGF-beta1-induced epithelial mesenchymal transition in prostate epithelial cells. AB - Multiple factors have been considered to play a role in the development of benign prostatic hyperplasia (BPH), including chronic inflammation, hormones, and epithelial-mesenchymal transition (EMT). Inflammation is regarded as one of the potential inducers of EMT. However, the mechanisms, modulating pro-inflammatory factors (IL-6 and TGF-beta1) induce EMT features, have not yet been studied in BPH. In this study, we investigated whether DNA methyltransferases1 (DNMT1) could regulate IL-6 and TGF-beta1 induce EMT. The expression of EMT features was analyzed in normal prostate epithelial cells (PrECs) and BPH1 cells. Real-time RT PCR and western blotting were used to examine the expression of EMT features in IL-6- and TGF-beta1-treated PrECs. Next, bisulfite sequencing PCR (BSP) methods were used to examine the DNA methylation level of the Cdh1 promoter region. The results showed that EMT features were increased in BPH1 cells, compared to PrECs. IL-6 and TGF-beta1 treatment induced EMT features, including decreased E-cadherin expression. The results of BSP revealed significant DNA hypermethylation at the promoter region of Cdh1 after IL-6 and TGF-beta1 exposure, which was rescued when pretreated with 5-Aza or TGF-beta1 antibody. Moreover, the protein expression and methyltransferase activity of DNMT1 were also increased after IL-6 and TGF-beta1 induction. Collectively, our study showed that IL-6 and TGF-beta1 could activate DNMT1 and directly regulate the expression of E-cadherin in PrECs, providing a potential therapeutic candidate for BPH. PMID- 28735517 TI - Metallothionein expression and synthesis in the testis of the lizard Podarcis sicula under natural conditions and following estrogenic exposure. AB - Metallothionein (MT) is the main protein involved in the homeostasis of metallic micronutrients and in cellular defence against heavy metals and reactive oxygen species. Found in almost all vertebrate tissues, MT presence and localization in the testis has been controversial. In the present study, by using in situ hybridization and immunohistochemical analysis we assessed the localization of both MT transcript and protein in Podarcis sicula testes during two different phases of the reproductive cycle: the autumnal resumption and the spring-early summer mating period. In addition, with the same methodological approach, we verified the effect of estradiol-17beta and nonylphenol, a potent xenoestrogen, on MT expression and synthesis. These results, the first collected in a non mammalian oviparous vertebrate, demonstrated that the expression profile of MT mRNA and protein changes during the reproductive cycle. In the fall resumption, MT transcripts are absent in spermatogonia and present in all the other cells of tubules, including spermatozoa; vice versa, the MT protein is evident only in spermatozoa and somatic cells. In the mating period, both MT transcripts and proteins are present in spermatogonia, spermatocytes and spermatids, whereas in the spermatozoa only the proteins are detected, thus suggesting that the MTs translated in the earlier germinal stages are stored up to spermatozoa. Results also demonstrated that in lizard testis the expression of MT gene undergoes a cell-specific regulation after estrogenic exposure; the possible role and the mechanism by which this regulation occurs have been discussed. PMID- 28735518 TI - The possible prognostic role of histone deacetylase and transforming growth factor beta/Smad signaling in high grade gliomas treated by radio-chemotherapy: a preliminary immunohistochemical study. AB - Glioblastoma (GBM) is the most common and aggressive tumor of the central nervous system. Unfortunately, patients affected by this disease have a very poor prognosis, due to high level of invasiveness and resistance to standard therapies. Although the molecular profile of GBM has been extensively investigated, the events responsible for its pathogenesis and progression remain largely unknown. Histone Deacetylases (HDAC) dependent epigenetic modifications and transforming growth factor (TGF)-beta/Smad pathway seem to play an important role in GBM tumorigenesis, resistance to common therapies and poor clinical outcome. The aim of this study was to evaluate the involvement and the possible interaction between these two molecular cascades in the pathogenesis and prognosis of GBM. Immunohistochemistry (IHC) was performed on microdissected GBM samples, collected from 14 patients (6 men and 8 women) ranging in age from 43 to 74 years. The patients were previously divided, on the basis of their overall survival (OS), into two groups: short and long OS. Patients with poor prognosis showed hyperexpression of HDAC4 and HDAC6, an activation of the TGF-beta/Smad pathway, with high levels of IL-13, Smad2, PDGF and MMP3 expression, compared to the long survivors. The short OS group exhibits a decrease in Smad 7 expression and also low levels of p21 immunostaining, which represents a common target of the two pathways. The IHC data was confirmed by quantitative analysis and Immunoblotting. Our preliminary results suggest that both HDAC4 and HDAC6 together with the TGF-beta/Smad pathway may be involved in progression of GBM and this cross talking could be a useful prognostic marker in this deadly disease. PMID- 28735519 TI - Expression of the HPV18/E6 oncoprotein induces DNA damage. AB - This study investigated possible variations in DNA damage in HeLa cells with silenced expression of the HPV/E6 oncogene compared with HeLa cells with normal expression of the E6 oncogene using the DNA breakage detection-fluorescence in situ hybridization (DBD-FISH) technique and a whole human genome DNA probe. The variable levels of DNA breaks present were measured quantitatively using image analysis after whole-genome DNA hybridization. HeLa cells with silenced expression of the HPV18/E6 oncogene showed a significant decrease in DNA damage compared with parental cells with normal expression of the E6 oncogene. These results were confirmed by alkaline comet assay. In conclusion, we demonstrated a decrease in DNA damage in HeLa clones associated with low expression of the HPV/E6 oncogene. The significance of this decrease regarding the HPV life cycle and carcinogenesis requires further exploration. PMID- 28735520 TI - Gemst: a taylor-made combination that reverts neuroanatomical changes in stroke. AB - In a single transient middle cerebral artery occlusion model of stroke and using immunohistochemical techniques, the effects of a new therapeutic approach named Gemst (a member of the Poly-L-Lysine innovative therapies) have been studied in the rat brain. The expression of inflammatory (CD45, CD11b), oxidative (NO tryptophan, NO2-tyrosine) and indoleamine 2, 3-dioxygenase pathway (kynurenic acid, 3-hydroxy anthranilic acid) markers has been evaluated in early and late phases of stroke. For this purpose, we have developed eight highly specific monoclonal antibodies directed against some of these markers. In the early phase (3 and 5 days of the stroke, we observed no effect of Gemst treatment (7.5 mg/day, subcutaneously for 3, 5 days). In the late phase (21 days) of stroke and exclusively in the ipsilateral side of non-treated animals an overexpression of kynurenic acid, 3-hydroxy anthranilic acid, CD45, CD11b, GFAP and ionized calcium binding adapter molecule 1 (IBA-1) was found. In treated animals, the overexpression of the four former markers was completely abolished whereas the overexpression of the two latter ones was decreased down to normal levels. Gemst reversed the pathological conditions of stroke to normal situations. Gemst exerts a multifunctional action: down-regulates the indoleamine 2, 3-dioxygenase pathway and abolishes brain infiltration, microglial activation and gliosis. Moreover, Gemst has no effect on the expression of doublecortin, a protein involved in neuronal migration. Gemst could be a new drug for the treatment of stroke since it reverses the pathological findings of stroke and normalizes brain tissue conditions following the ischemic insult. PMID- 28735521 TI - MyD88/ERK/NFkB pathways and pro-inflammatory cytokines release in periodontal ligament stem cells stimulated by Porphyromonas gingivalis. AB - The present study was aimed at investigating whether human Periodontal Ligament Stem Cells (hPDLSCs) were capable of sensing and reacting to lipopolysaccharide from Porphyromonas gingivalis (LPS-G) which is widely recognized as a major pathogen in the development and progression of periodontitis. At this purpose hPDLCs were stimulated with 5 MUg/mL LPS-G various times and the expression of toll-like receptor 4 (TLR4) was evaluated. Toll-like receptors (TLRs) play an essential role in innate immune signaling in response to microbial infections, and in particular TLR4, type-I transmembrane proteins, has been shown recognizing LPS-G. Our results put in evidence, in treated samples, an overexpression of TLR4 indicating that, hPDLSCs express a functional TLR4 receptor. In addition, LPS-G challenge induces a significant cell growth decrease starting from 24 h until 72 h of treatment. LPS-G leads the activation of the TLR4/MyD88 complex, triggering the secretion of proinflammatory cytokines cascade as: IL-1alpha, IL-8, TNF-alpha and beta and EOTAXIN. Moreover, the upregulation of pERK/ERK signaling pathways and NFkB nuclear translocation was evident. On the basis of these observations, we conclude that hPDLSCs could represent an appropriate stem cells niche modeling leading to understand and evaluate the biological mechanisms of periodontal stem cells in response to LPS-G, mimicking in vitro an inflammatory process occurring in vivo in periodontal disease. PMID- 28735522 TI - Characterization of the role of RILP in cell migration. AB - Rab-interacting lysosomal protein (RILP) is a regulator of late stages of endocytosis. Recent work proved that depletion of RILP promotes migration of breast cancer cells in wound healing assay, whereas its overexpression influences re-arrangements of actin cytoskeleton. Here, we further characterized the role of RILP in cell migration by analyzing several aspects of this process. We showed that RILP is fundamental also for migration of lung cancer cells regulating cell velocity. RILP silencing did not affect Golgi apparatus nor microtubules reorientation during migration. However, both RILP over-expression and expression of its mutated form, RILP-C33, impair cell adhesion and spreading. In conclusion, our results demonstrate that RILP has important regulatory roles in cell motility affecting migration velocity but also in cell adhesion and cell spreading. PMID- 28735523 TI - Histochemistry and immunolocalisation of glucokinin in antidiabetic plants used in traditional Mexican medicine. AB - Mexico is a megadiverse country that has 3,600 to 4,000 species of medicinal plants, of which approximately 800 are used to treat conditions related to diabetes mellitus (DM). DM is a chronic degenerative disease of energy metabolism that exists as two types: type 1 (DM1) and type 2 (DM2). DM is considered a public health problem that affects 7% of the Mexican population older than 20 years. DM is clinically controlled with hypoglycaemic drugs, alpha-glucosidase inhibitors, insulin secretion stimulants or the direct application of insulin. The hypoglycaemic effectiveness of specific molecules has been determined only for some medicinal plants in Mexico used to treat DM2. The presence of molecules called glucokinins, wich are similar to animal insulin molecules, has been reported in some plant species; glucokinins act as both growth factors and regulators of glucose metabolism in plants. Therefore, we hypothesized that the hypoglycaemic effectiveness of some of the popularly used species for the control of DM could be due to the presence of glucokinin, as reported for Bauhinia variegata. The goal of this work was to use histochemistry to detect, the accumulation of protein that is immunocytochemically compatible with glucokinin in slide sections of hypoglycaemic species used as remedies for DM2. The top fourteen most used medicinal plants in Mexico were selected for study via microscopic sections. Proteins were histochemically detected using naphthol blue black and Johansen's quadruple stain, and the immunocytochemical correspondence of the proteins with glucokinin was investigated using an insulin antibody. All species studied reacted positively to proteins and glucokinin in the same structures. The presence of glucokinin in these structures and the corresponding hypoglycaemic effects are discussed in the contex of the actions of other compounds. PMID- 28735524 TI - Characterization of cytoskeleton features and maturation status of cultured human iPSC-derived cardiomyocytes. AB - Recent innovations in stem cell technologies and the availability of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have opened new possibilities for studies and drug testing on human cardiomyocytes in vitro. Still, there are concerns about the precise nature of such 'reprogrammed' cells. We have performed an investigation using immunocytochemistry and confocal microscopy on several cellular features using commercially available hiPSC-CMs. For some selected developmentally regulated or cardiac chamber-specific proteins, we have compared the results from hiPSC-derived cardiomyocytes with freshly isolated, ventricular cardiomyocytes from adult rats. The results show that all typical cardiac proteins are expressed in these hiPSC-CMs. Furthermore, intercalated disc-like structures, calcium cycling proteins, and myofibrils are present. However, some of these proteins are only known from early developmental stages of the ventricular myocardium or the diseased adult heart. A heterogeneous expression pattern in the cell population was noted for some muscle proteins, such as for myosin light chains, or incomplete organization in sarcomeres, such as for telethonin. These observations indicate that hiPSC-CMs can be considered genuine human cardiomyocytes of an early developmental state. The here described marker proteins of maturation may become instrumental in future studies attempting the improvement of cardiomyocyte in vitro models. PMID- 28735525 TI - Oxygen tension-independent protection against hypoxic cell killing in rat liver by low sodium. AB - The role of Na+ in hypoxic injury was evaluated by a time-course analysis of damage in isolated livers perfused with N2-saturated buffer containing standard (143 mM) or low (25 mM) Na+ levels. Trypan blue uptake was used to detect non viable cells. Under hypoxia with standard-Na+, trypan blue uptake began at the border between pericentral areas and periportal regions and increased in the latter zone; using a low-Na+ buffer, no trypan blue zonation occurred but a homogenous distribution of dye was found associated with sinusoidal endothelial cell (SEC) staining. A decrease in hyaluronic acid (HA) uptake, index of SEC damage, was observed using a low-Na+ buffer. A time dependent injury was confirmed by an increase in LDH and TBARS levels with standard-Na+ buffer. Using low-Na+ buffer, SEC susceptibility appears elevated under hypoxia and hepatocytes was protected, in an oxygen independent manner. PMID- 28735526 TI - The biocompatibility of bone cements: progress in methodological approach. AB - The ideal bone graft substitute should have certain properties and there are many studies dealing with mixture of polymethylmetacrilate (PMMA) and beta tricalciumphospate (beta-TCP) presenting the best characteristics of both. Scanning Electron Microscopy (SEM), for ultra-structural data, resulted a very reliable in vivo model to better understand the bioactivity of a cement and to properly evaluate its suitability for a particular purpose. The present study aims to further improve the knowledge on osteointegration development, using both parameters obtained with the Environmental Scanning Electron Microscopy (ESEM) and focused histological examination. Two hybrid bone graft substitute were designed among ceramic and polymer-based bone graft substitutes. Based on beta TCP granules sizes, they were created with theoretical different osteoconductive properties. An acrylic standard cement was chosen as control. Cements were implanted in twelve New Zealand White (NZW) rabbits, which were sacrificed at 1, 2, 3, 6, 9 and 12 months after cement implantation. Histological samples were prepared with an infiltration process of LR white resin and then specimens were studied by X-rays, histology and Environmental Scanning Electron Microscopy (ESEM). Comparing the resulting data, it was possible to follow osteointegration's various developments resulting from different sizes of beta TCP granules. In this paper, we show that this evaluation process, together with ESEM, provides further important information that allows to follow any osteointegration at every stage of develop. PMID- 28735527 TI - Fibroblast activating protein-alpha expression in squamous cell carcinoma of the esophagus in primary and irradiated tumors: the use of archival FFPE material for molecular techniques. AB - There are numerous reports suggesting that fibroblast activating protein-alpha (FAP-alpha) plays an important role in invasion of various tumor types. We studied the expression pattern of FAP-alpha in esophageal squamous cell carcinoma (ESCC) patients who had not been treated primarily and those who had received neoadjuvant radiochemotherapy. Our goal was to establish whether readily available tissue specimens fixed in formalin and stored in paraffin blocks for years might still be a source of FAP-alpha RNA for PCR analysis. The study included 20 patients divided into two groups, 10 patients in each group. We evaluated the expression of FAP-alpha by PCR techniques in fresh frozen and in paraffin-embedded tissues, and compared it to the expression in non-cancer tissues. To detect the protein expression level of FAP-alpha in paraffin-embedded tissues we used chromogenic immunohistochemical (IHC) staining. Data were analyzed by t-test or the nonparametric Wilcoxon matched pair test using Statistica 12.5 software. We observed an increased level of the FAP-alpha gene and protein expression in cancer tissues when compared with their corresponding normal tissues. However, statistically significant differences were found only in the group of patients untreated before surgery. RNA extracted from paraffin embedded tissue sections had very low quality, especially in the context of degradation. FAP-alpha remains a highly altered participant of a complex microenvironment in esophageal squamous cell carcinoma, and its role in cell signaling requires further study. In this paper, we conclude that the use of a regular RT-PCR method for diagnostic purposes, which we have presented in an earlier paper, can be as good as qRT-PCR. Also, immunohistochemistry proved to be very useful and the only reliable method that can be used on formalin-fixed, paraffin-embedded tissues stored long term. PMID- 28735528 TI - Lipids: Evergreen autofluorescent biomarkers for the liver functional profiling. AB - Depending on their chemical nature, lipids can be classified in two main categories: hydrophilic, greatly contributing to membrane composition and subcellular organelle compartmentalization, and hydrophobic, mostly triglycerides, greatly enrolled in the storage and production of energy. In both cases, some lipid molecules can be involved as signaling agents in the regulation of metabolism and protective or damaging pathways in responses to harmful stimuli. These events could affect in particular the liver, because of its central role in the maintenance of lipid homeostasis. Lipids have been demonstrated to fluoresce, contributing to the overall emission signal of the liver tissue along with other endogenous fluorophores, relatable to energy metabolism and oxidative events. The mere estimation of the fluorescing lipid fraction in parallel with the other endogenous fluorophores, and with the common biochemical and histochemical biomarkers of tissue injury has been exploited to investigate the liver morpho-functional conditions in experimental hepatology. More interestingly, the fluorescing lipid fraction is greatly relatable to free fatty acids such as arachidonic, linoleic and linolenic acid, which are deserving increasing attention as precursors of products involved in several and complex signaling pathways. On these bases, the ability of autofluorescence to detect directly arachidonic acid and its balance with other unsaturated fatty acids may be exploited in the diagnosis and follow-up of fatty livers, helping to improve the personalization of the metabolic/lipidomic profiling. This could also contribute to elucidate the role of the injuring factors in the choice of suitable donors, and in the set-up of preservation procedures in liver transplantation. PMID- 28735529 TI - Spinel Ferrite Core-Shell Nanostructures by a Versatile Solvothermal Seed Mediated Growth Approach and Study of Their Nanointerfaces. AB - An easy, low-cost, repeatable seed-mediated growth approach in solvothermal condition has been proposed to synthesize bimagnetic spinel ferrite core-shell heterostructures in the 10-20 nm particle size range. Cobalt ferrite and manganese ferrite nanoparticles (CoFe2O4 and MnFe2O4) have been coated with isostructural spinel ferrites like maghemite/magnetite, MnFe2O4, and CoFe2O4 with similar cell parameters to create different heterostructures. The conventional study of the structure, morphology, and composition has been combined with advanced techniques in order to achieve details on the interface at the nanoscale level. Clear evidence of the heterostructure formation have been obtained (i) indirectly by comparing the 57Fe Mossbauer spectra of the core-shell samples and an ad hoc mechanical mixture and (ii) directly by mapping the nanoparticles' chemical composition by electron energy loss spectroscopy (EELS) and energy dispersive X-ray spectroscopy (EDX) in the scanning transmission electron microscopy mode (STEM). In addition, chemical-sensitive electron tomography in STEM-EDX mode has been applied in order to obtain detailed 3D images with a sub nanometer spatial resolution. PMID- 28735530 TI - Low-Temperature Oxygen Storage of CrIV-CrV Mixed-Valence YCr1-xPxO4-delta Driven by Local Condensation around Oxygen-Deficient Orthochromite. AB - The oxygen storage capability and related defect structure of tetrahedral orthochromite(V) compound YCr1-xPxO4 (x = 0, 0.3, 0.5, and 0.7) were investigated by employing thermal gravimetry and in situ X-ray spectroscopy for reversible oxygen store/release driven by heating-cooling cycles in the temperature range from 50 to 600 degrees C. YCr1-xPxO4 started releasing oxygen as heated from 50 degrees C under ambient atmosphere, with reduction of CrV to CrIV, while the reduced YCr1-xPxO4-delta phase was significantly reoxidized via absorbing oxygen by cooling to 50 degrees C under ambient atmosphere, recovering the original stoichiometric phase. Operando X-ray adsorption spectroscopy and first-principles calculations demonstrate that nonstoichiometric YCr1-xPxO4-delta phases were stabilized by forming linking polyhedral CrIV2O76- via corner sharing between oxygen-deficient CrIVO32- and adjacent CrIVO44-. YCr1-xPxO4 was found to have an extremely low reduction enthalpy of about 20 kJ mol-1 probably due to the relatively high reduction potential of high-valence-state Cr(V)/Cr(IV) redox pairs, thereby resulting in reversible oxygen storage in such a low-temperature region. PMID- 28735531 TI - Origami and Kirigami Nanocomposites. AB - The arts of origami and kirigami inspired numerous examples of macroscale hierarchical structures with high degree of reconfigurability and multiple functionalities. Extension of kirigami and origami patterning to micro-, meso-, and nanoscales enabled production of nanocomposites with unusual combination of properties, transitioning these art forms to the toolbox of materials design. Various subtractive and additive fabrication techniques applicable to nanocomposites and out-of-plane deformation of patterns enable a technological framework to negotiate often contradictory structural requirements for materials properties. Additionally, the long-searched possibility of patterned composites/parts with highly predictable set of properties/functions emerged. In this review, we discuss foldable/stretchable composites with designed mechanical properties, as exemplified by the negative Poisson's ratio, as well as optical and electrical properties, as exemplified by the sheet conductance, photovoltage generation, and light diffraction. Reconfiguration achieved by extrinsic forces and/or intrinsic stresses enables a wide spectrum of technological applications including miniaturized biomedical tools, soft robotics, adaptive optics, and energy systems, extending the limits of both materials engineering concepts and technological innovation. PMID- 28735533 TI - Kinetics of Photoelectrochemical Oxidation of Methanol on Hematite Photoanodes. AB - The kinetics of photoelectrochemical (PEC) oxidation of methanol, as a model organic substrate, on alpha-Fe2O3 photoanodes are studied using photoinduced absorption spectroscopy and transient photocurrent measurements. Methanol is oxidized on alpha-Fe2O3 to formaldehyde with near unity Faradaic efficiency. A rate law analysis under quasi-steady-state conditions of PEC methanol oxidation indicates that rate of reaction is second order in the density of surface holes on hematite and independent of the applied potential. Analogous data on anatase TiO2 photoanodes indicate similar second-order kinetics for methanol oxidation with a second-order rate constant 2 orders of magnitude higher than that on alpha Fe2O3. Kinetic isotope effect studies determine that the rate constant for methanol oxidation on alpha-Fe2O3 is retarded ~20-fold by H/D substitution. Employing these data, we propose a mechanism for methanol oxidation under 1 sun irradiation on these metal oxide surfaces and discuss the implications for the efficient PEC methanol oxidation to formaldehyde and concomitant hydrogen evolution. PMID- 28735532 TI - Transition-Metal-Free Decarboxylative Iodination: New Routes for Decarboxylative Oxidative Cross-Couplings. AB - Constructing products of high synthetic value from inexpensive and abundant starting materials is of great importance. Aryl iodides are essential building blocks for the synthesis of functional molecules, and efficient methods for their synthesis from chemical feedstocks are highly sought after. Here we report a low cost decarboxylative iodination that occurs simply from readily available benzoic acids and I2. The reaction is scalable and the scope and robustness of the reaction is thoroughly examined. Mechanistic studies suggest that this reaction does not proceed via a radical mechanism, which is in contrast to classical Hunsdiecker-type decarboxylative halogenations. In addition, DFT studies allow comparisons to be made between our procedure and current transition-metal catalyzed decarboxylations. The utility of this procedure is demonstrated in its application to oxidative cross-couplings of aromatics via decarboxylative/C-H or double decarboxylative activations that use I2 as the terminal oxidant. This strategy allows the preparation of biaryls previously inaccessible via decarboxylative methods and holds other advantages over existing decarboxylative oxidative couplings, as stoichiometric transition metals are avoided. PMID- 28735534 TI - Investigation and Application of a New Passive Sampling Technique for in Situ Monitoring of Illicit Drugs in Waste Waters and Rivers. AB - Illicit drugs constitute a class of emerging contaminants that has been drawing significant concern due to its potent pharmacological and biological activities. In this study, an in situ passive sampling approach that uses diffusive gradients in thin films (DGT) was successfully tested for measuring ketamine (KET), methamphetamine (METH), and amphetamine (AMP) in water. The diffusion coefficients of KET, METH, and AMP in diffusive gel were (8.13 +/- 0.12) * 10-6, (8.55 +/- 0.14) * 10-6, and (7.72 +/- 0.18) * 10-6 cm2 s-1 at 22 degrees C, respectively. The capacities of an XAD binding gel for KET, METH, and AMP were 92, 57, and 45 MUg per binding gel disc, which were suitable for long-term environmental monitoring. The DGT measurement of these drugs was not influenced by the pH (4 to 9) and the ionic strength (0.001 M - 0.1 M) and unaffected by the water flow, demonstrating the effectiveness of the XAD-based DGT for the in situ monitoring of illicit drugs. DGT samplers were deployed in a WWTP influent and natural rivers in Beijing, China. The ng L-1 levels of the drugs were high in the wastewater influent and low in river waters, with an insignificant fluctuation during the seven-day monitoring. The DGT-measured concentrations were comparable to the average concentrations determined by SPE method, which suggested that the average data measured by DGT could be substituted for high-frequency grab sampling. This study has demonstrated systematically for the first time that DGT is effective and accurate for monitoring illicit drugs in wastewater and surface waters, and provides a powerful tool to investigating the presence, transport, and environmental behaviors of these drugs in the aquatic ecosystem. PMID- 28735535 TI - Sodium Diisopropylamide in Tetrahydrofuran: Selectivities, Rates, and Mechanisms of Alkene Isomerizations and Diene Metalations. AB - Sodium diisopropylamide in tetrahydrofuran is an effective base for the metalation of 1,4-dienes and isomerization of alkenes. Dienes metalate via tetrasolvated sodium amide monomers, whereas 1-pentene is isomerized by trisolvated monomers. Facile, highly Z-selective isomerizations are observed for allyl ethers under conditions that compare favorably to those of existing protocols. The selectivity is independent of the substituents on the allyl ethers; rate and computational data show that the rates, mechanisms, and roles of sodium-oxygen contacts are substituent-dependent. The competing influences of substrate coordination and solvent coordination to sodium are discussed. PMID- 28735537 TI - Versatile Tetrablock Copolymer Scaffold for Hierarchical Colloidal Nanoparticle Assemblies: Synthesis, Characterization, and Molecular Dynamics Simulation. AB - A unique combination of molecular dynamics (MD) simulation and detailed size exclusion chromatography-multiangle light scattering (SEC-MALS) analysis is used to provide important a priori insights into the solution self-assembly of a well defined and symmetric tetrablock copolymer with two acrylic acid (AA) outer blocks, two polystyrene (PS) inner blocks, and a trithiocarbonate (TTC) central group, prepared by reversible addition-fragmentation chain transfer (RAFT) polymerization. SEC-MALS experiments show that the copolymer forms aggregates in both tetrahydrofuran and N,N-dimethylformamide (DMF), even in the presence of different salts, but not in 1,4-dioxane (dioxane). Combined with MD simulations, these results indicate that the AA units are the main cause of aggregation through intermolecular hydrogen bonding, with additional stabilization by the central TTC. The block copolymer chains self-assemble in dioxane by adding cadmium acetate, originating flowerlike inverse micelles with a cadmium acrylate core and the TTC groups in the outer surface of the PS corona. The micelles were used as nanoreactors in the templated synthesis of a single cadmium selenide (CdSe) quantum dot (QD) in the core of each micelle, whereas the shell TTC groups can be converted into thiol functions for further use of these units in hierarchical nanostructures. Only in dioxane where simulations and SEC-MALS suggest an absence of copolymer aggregates prior to cadmium acetate addition do well-dispersed and highly luminescent CdSe QDs form by templated synthesis. These results provide valuable insights into the self-assembly of RAFT copolymers in different solvent systems as it relates to the preparation of emissive QDs with polymer-spaced thiol functionality for binding to gold nanostructures. PMID- 28735536 TI - Five Electronic State Beyond Born-Oppenheimer Equations and Their Applications to Nitrate and Benzene Radical Cation. AB - We present explicit form of Adiabatic to Diabatic Transformation (ADT) equations and expressions of non-adiabatic coupling terms (NACTs) for a coupled five-state electronic manifold in terms of ADT angles between electronic wave functions. ADT matrices eliminate the numerical instability arising from singularity of NACTs and transform the adiabatic Schrodinger equation to its diabatic form. Two real molecular systems NO3 and C6H6+ (Bz+) are selectively chosen for the demonstration of workability of those equations. We examine the NACTs among the lowest five electronic states of the NO3 radical [X2A2' (12B2), A2E" (12A2 and 12B1) and B2E' (12A1 and 22B2)], in which all types of non-adiabatic interactions, that is, Jahn-Teller (JT) interactions, Pseudo Jahn-Teller (PJT) interactions, and accidental conical intersections (CIs) are present. On the other hand, lowest five electronic states of Bz+ [X2E1g (12B3g and 12B2g), B2E2g (12Ag and 12B1g), and C2A2u (12B1u)] depict similar kind of complex feature of non-adiabatic effects. For NO3 radical, the two components of degenerate in-plane asymmetric stretching mode are taken as a plane of nuclear configuration space (CS), whereas in case of Bz+, two pairs are chosen: One is the pair of components of degenerate in-plane asymmetric stretching mode, and the other one is constituted with one of the components each from out-of-plane degenerate bend and in-plane degenerate asymmetric stretching modes. We calculate ab initio adiabatic potential energy surfaces (PESs) and NACTs among the lowest five electronic states at the CASSCF level using MOLPRO quantum chemistry package. Subsequently, the ADT is performed using those newly developed equations to validate the positions of the CIs, evaluate the ADT angles and construct smooth, symmetric, and continuous diabatic PESs for both the molecular systems. PMID- 28735538 TI - Photophysics of the Singlet Oxygen Sensor Green Chromophore: Self-Production of 1O2 Explained by Molecular Modeling. AB - We report a combined computational and experimental study to rationalize the behavior of a well-known singlet oxygen (1O2) probe, that is, the chromophore of the Singlet Oxygen Sensor Green: a fluoresceine-based sensor. In particular, we evidence that the presence of an intramoleculer charge transfer state that is no more present upon reaction with 1O2 explains the fluorescence enhancement observed in the presence of reactive oxygen species. Furthermore, we also unequivocally show the photophysical pathways leading to the fluorescence enhancement of fluoresceine upon irradiation with UVA lights and also in the absence of any oxygen activator. More specifically, we evidence that the presence of a possible intersystem crossing upon population of higher energy singlet electronic excited states will lead to the population of the fluoresceine triplet manifold and hence to the self-production of 1O2. PMID- 28735539 TI - Strong Size Dependency on the Carrier and Photon Dynamics in InGaN/GaN Single Nanowalls Determined Using Photoluminescence and Ultrafast Transient Absorption Spectroscopy. AB - Here, we have demonstrated strong size dependency of quasi-equilibrium and nonequilibrium carrier and photon dynamics in InGaN/GaN single nanowalls using photoluminescence and transient absorption spectroscopy. We demonstrate that two dimensional carrier confinement, strain relaxation, and modified density of states lead to a reduced Stokes shift, smaller full width at half-maxima, increased exciton binding energy, and reduced nonradiative recombination. The ultrafast transient spectroscopy shows that carrier capture is a two-step process dominated by optical phonons and carrier-carrier scattering in succession. The carrier capture is a strongly size-dependent process and becomes slower due to modulation of the density of available states for progressively decreasing nanowall sizes. The slowest process is the electron-hole recombination, which is also extremely size-dependent and the rate increases by almost an order of magnitude in comparison to that of quantum-well structures. Electron-hole wave function overlap and modified density of states are among the key aspects in determining all the properties of these structures. PMID- 28735541 TI - Photoresponsive Foams Generated by a Rigid Surfactant Derived from Dehydroabietic Acid. AB - Innovation in the structure of surfactants is crucial to the construction of a surfactant-based system with intriguing properties. With dehydroabietic acid as a starting material, a nearly totally rigid azobenzene surfactant (R-azo-Na) was synthesized. The trans-R-azo-Na formed stable foams with half-lives of 636, 656, 976, and 872 min for 0.3, 1, 2, and 4 mmol.L-1 aqueous solutions, respectively. Under UV light irradiation, a fast collapse of the foams was observed, showing an in situ response. The excellent foam stability of trans-R-azo-Na leads to the extremely high photoresponsive efficiency. As revealed by dynamic surface tension and pulsed-field gradient NMR methods, an obvious energy barrier existed in the adsorption/desorption process of trans-R-azo-Na on the air/water interface. The foams formed by trans-R-azo-Na are thus stable against coarsening processes. The results reveal the unique photoresponsive behavior of a surfactant with a rigid hydrophobic skeleton and provide new insights into the structure causing aggregation of surfactants. PMID- 28735542 TI - All Inorganic Cesium Lead Iodide Perovskite Nanowires with Stabilized Cubic Phase at Room Temperature and Nanowire Array-Based Photodetectors. AB - Alluring optical and electronic properties have made organometallic halide perovskites attractive candidates for optoelectronics. Among all perovskite materials, inorganic CsPbX3 (X is halide) in black cubic phase has triggered enormous attention recently owing to its comparable photovoltaic performance and high stability as compared to organic and hybrid perovskites. However, cubic phase stabilization at room temperature for CsPbI3 still survives as a challenge. Herein we report all inorganic three-dimensional vertical CsPbI3 perovskite nanowires (NWs) synthesized inside anodic alumina membrane (AAM) by chemical vapor deposition (CVD) method. It was discovered that the as-grown NWs have stable cubic phase at room temperature. This significant improvement on phase stability can be attributed to the effective encapsulation of NWs by AAM and large specific area of these NWs. To demonstrate device application of these NWs, photodetectors based on these high density CsPbI3 NWs were fabricated demonstrating decent performance. Our discovery suggests a novel and practical approach to stabilize the cubic phase of CsPbI3 material, which will have broad applications for optoelectronics in the visible wavelength range. PMID- 28735540 TI - The n->pi* Interaction. AB - The carbonyl group holds a prominent position in chemistry and biology not only because it allows diverse transformations but also because it supports key intermolecular interactions, including hydrogen bonding. More recently, carbonyl groups have been found to interact with a variety of nucleophiles, including other carbonyl groups, in what we have termed an n->pi* interaction. In an n->pi* interaction, a nucleophile donates lone-pair (n) electron density into the empty pi* orbital of a nearby carbonyl group. Mixing of these orbitals releases energy, resulting in an attractive interaction. Hints of such interactions were evident in small-molecule crystal structures as early as the 1970s, but not until 2001 was the role of such interactions articulated clearly. These non-covalent interactions were first discovered during investigations into the thermostability of the proline-rich protein collagen, which achieves a robust structure despite a relatively low potential for hydrogen bonding. It was found that by modulating the distance between two carbonyl groups in the peptide backbone, one could alter the conformational preferences of a peptide bond to proline. Specifically, only the trans conformation of a peptide bond to proline allows for an attractive interaction with an adjacent carbonyl group, so when one increases the proximity of the two carbonyl groups, one enhances their interaction and promotes the trans conformation of the peptide bond, which increases the thermostability of collagen. More recently, attention has been paid to the nature of these interactions. Some have argued that rather than resulting from electron donation, carbonyl interactions are a particular example of dipolar interactions that are well-approximated by classical mechanics. However, experimental evidence has demonstrated otherwise. Numerous examples now exist where an increase in the dipole moment of a carbonyl group decreases the strength of its interactions with other carbonyl groups, demonstrating unequivocally that a dipolar mechanism is insufficient to describe these interactions. Rather, these interactions have important quantum-mechanical character that can be evaluated through careful experimental analysis and judicious use of computation. Although individual n >pi* interactions are relatively weak (~0.3-0.7 kcal/mol), the ubiquity of carbonyl groups across chemistry and biology gives the n->pi* interaction broad impact. In particular, the n->pi* interaction is likely to play an important role in dictating protein structure. Indeed, bioinformatics analysis suggests that approximately one-third of residues in folded proteins satisfy the geometric requirements to engage in an n->pi* interaction, which is likely to be of particular importance for the alpha-helix. Other carbonyl-dense polymeric materials like polyesters and peptoids are also influenced by n->pi* interactions, as are a variety of small molecules, some with particular medicinal importance. Research will continue to identify molecules whose conformation and activity are affected by the n->pi* interaction and will clarify their specific contributions to the structures of biomacromolecules. PMID- 28735543 TI - Effects of Chain Parameters on Kinetics of Photochromism in Acrylic-Spiropyran Copolymer Nanoparticles and Their Reversible Optical Data Storage. AB - Chemical bonding between photochromic compounds and polymer matrices will induce several consitions such as photostability, photoreversibility, elimination of dye aggregation, and undesirable negative photochromism. In such polymeric systems, the switching rate and photoisomerization are closely dependent on several parameters like chain flexibility, steric restrictions, polarity, and even proticity of the surrounding medium. Here, copolymerization of a synthesized spiropyran-based monomer with butyl acrylate (BA) and methyl methacrylate (MMA) comonomers was carried out with various compositions of MMA and BA through emulsion polymerization, and the corresponding photoisomerization kinetics were studied. Particle sizes and their distributions were analyzed by dynamic light scattering, and morphologies were investigated by scanning and transmission electron microscopic analyses. The results showed the particles are spherical with diameter 62-82 nm. Differential scanning calorimetric thermograms were employed to determine Tg of the prepared copolymers, which ranged from -23 to 93 degrees C. The kinetics of photoisomerization was then studied by UV-vis spectroscopy. Finally, a latex containing spiropyran/acrylic copolymer with Tg of about 0 degrees C and optimum rate of coloration and decoloration was considered in reversible optical data storage studies due to its fast photochromism and good film-formation properties. PMID- 28735544 TI - Facile Fabrication of Composite Electrospun Nanofibrous Matrices of Poly(epsilon caprolactone)-Silica Based Pickering Emulsion. AB - Functionalized matrices have been sought for their application in sensors, filtration, energy storage, catalysis, and tissue engineering. We report formation of an inorganic-organic composite matrix based on poly(epsilon caprolactone) (PCL) functionalized with hydrophobically modified silica (m silica) fabricated with reduced organic solvent usage. The matrix was obtained via electrospinning of a water-in-oil emulsion of PCL that was stabilized by judicious choice of m-silica as a Pickering agent resulting into an emulsifier free matrix. Inclusion of m-silica in PCL matrix resulted in enhancing tensile properties and cell proliferation efficiency. The electrospun composite matrix was free from any emulsifier or template polymer; thus any abrupt loss in mechanical properties was prevented when the matrix was subjected to aqueous conditions. The inorganic-organic biodegradable composite matrices thus produced using an emulsifier free emulsion find applications in tissue engineering and may further be evaluated for other areas including selective sorption and separation. PMID- 28735545 TI - Evaluation of Endocrine Disrupting Compounds Migration in Household Food Containers under Domestic Use Conditions. AB - Plasticizers and plastic monomers are commonly used in packaging. Most of them act as endocrine disrupters and are susceptible to migrate from the packaging to the food. We evaluated the migration of endocrine disrupting compounds from three different household food containers to four food simulants under different domestic treatments and for different periods of time, with the aim of reproducing real domestic conditions. The results showed that the migration to the simulants increased with the storage time, up to more than 50 times in certain cases. The heating power seemed to increase the migration processes (up to more than 30 times), and reusing containers produced an increase or decrease of the concentrations depending on the container type and the simulant. The concentrations found were lower than other concentrations reported (always less than 4000 pg/mL, down to less than 20 pg/mL), which might be a consequence of the domestic conditions used. PMID- 28735546 TI - Room-Temperature Quantum Ballistic Transport in Monolithic Ultrascaled Al-Ge-Al Nanowire Heterostructures. AB - Conductance quantization at room temperature is a key requirement for the utilizing of ballistic transport for, e.g., high-performance, low-power dissipating transistors operating at the upper limit of "on"-state conductance or multivalued logic gates. So far, studying conductance quantization has been restricted to high-mobility materials at ultralow temperatures and requires sophisticated nanostructure formation techniques and precise lithography for contact formation. Utilizing a thermally induced exchange reaction between single crystalline Ge nanowires and Al pads, we achieved monolithic Al-Ge-Al NW heterostructures with ultrasmall Ge segments contacted by self-aligned quasi one dimensional crystalline Al leads. By integration in electrostatically modulated back-gated field-effect transistors, we demonstrate the first experimental observation of room temperature quantum ballistic transport in Ge, favorable for integration in complementary metal-oxide-semiconductor platform technology. PMID- 28735547 TI - Nanoaramid Dressed Latex Particles: The Direct Synthesis via Pickering Emulsion Polymerization. AB - The direct synthesis of polymer microspheres modified by aramid nanofibers (ANFs) is an interesting challenge. This work describes a simple aqueous process to prepare polystyrene (PS)/ANF composite microspheres, where the specific ANF network was "dressed" on PS. ANF was derived from the copolymerization of terephthaloyl chloride, p-phenylene diamine, and methoxypolyethylene glycol and could be dispersed in water stably. We applied the as-synthesized ANF as a Pickering emulsifier in the o/w emulsion of styrene monomer. Radical polymerization was subsequently initiated in the Pickering emulsion system. The combination of ANF with polymer spheres was revealed by scanning electron microscopy (SEM) and thermal gravity analysis. The role of ANF in the monomer emulsion as well as in the polymerization was studied through SEM, optical microscopy, optical stability analyzer, and pulse nuclear magnetic resonance combined with the polymerization kinetic analysis. Moreover, we investigated the effects of other synthesis parameters, such as monomer type, monomer content, pH value, and salt concentration. PMID- 28735548 TI - Strain Driven Shape Evolution of Stacked (In,Ga)N Quantum Disks Embedded in GaN Nanowires. AB - The fabrication of nanowires with axial multiquantum wells or disks presenting a homogeneous size and shape distribution along the whole stack is still an unresolved challenge, despite being essential for narrowing their light emission bandwidth. In this work we demonstrate that the commonly observed change in the shape of the disks along the stacking direction proceeds in a systematic, predictable way. High- resolution transmission electron microscopy of stacked (In,Ga)N quantum discs embedded in GaN nanowires with diameters of ~40 nm and lengths of ~700 nm and finite element method calculations show that, contrary to what is normally assumed, this change is not related to the radial growth of the nanowires, which is shown to be negligible, but to the strain relaxation of the whole active region. A simple model is proposed to account for the experimental observations. The model assumes that each disk reaches an equilibrium shape that minimizes the overall energy of the system, given by the sum of the surface and strain energies of the disk itself and the barrier below. The strain state of the barrier is affected by the presence of the disk buried directly below in a way that depends on its shape. This gives rise to a cumulative process, which makes the aspect ratio of each quantum disk to be smaller compared to the disk grown just before, in qualitative agreement with the experimental observations. The obtained results imply that strain relaxation is an important factor to bear in mind for the design of multiquantum disks with controlled shape along the stacking direction in any lattice mismatched nanowire system. PMID- 28735549 TI - Correlations between community size and student perceptions of value. AB - INTRODUCTION: The purpose of this study was to determine if medical students' feeling of being valued was correlated to community size. The study, conducted in several communities in South Dakota, examined students' feeling of value relating to attending physicians, healthcare teams and patients. METHODS: Student value items were added to student satisfaction surveys sent out to students at the end of their primary clinical year and data collected from two graduating classes of students (n=114). Student responses were grouped by clinical campus and mean responses by community size were calculated. Additionally, student encounter logs were reviewed for study participants to gauge participation levels during clinical encounters. RESULTS: The degree to which students felt valued by their physician attending, the healthcare team and the patients decreased consistently as community size increased. Differences were statistically significant between students in the smallest and largest communities. Additionally, students in the community of 15 000 felt significantly more valued than students in the community of 170 000. Furthermore, there also appears to be a relationship between the percentage of participation in patient care by students and community size. Students in the smaller, rural communities participated at a higher percentage rather than observing. CONCLUSIONS: There appears to be a relationship between community size and the extent to which students feel value. The degree to which students felt valued decreased consistently as community size increased. Differences were statistically significant between students in the smallest communities and the two largest communities. Students in the smaller, rural communities participated at a higher percentage. Additional studies are needed to address whether students participate more as a result of feeling valued, or whether participation leads to an enhanced perception of value by students. PMID- 28735550 TI - One-year incidence of occupational accidents among agricultural workers in Oguzeli, Turkey. PMID- 28735551 TI - Quality of Pharmacist-Managed Anticoagulation Therapy in Long-Term Ambulatory Settings: A Systematic Review. AB - OBJECTIVE: To perform a systematic review to evaluate the quality of warfarin anticoagulation control in outpatient pharmacist-managed anticoagulation services (PMAS) compared with routine medical care (RMC). DATA SOURCES: MEDLINE, SCOPUS, EMBASE, IPA, CINAHL, and Cochrane CENTRAL, from inception to May 2017. Search terms employed: ("pharmacist-managed" OR "pharmacist-provided" OR "pharmacist led" OR "pharmacist-directed") AND ("anticoagulation services" OR "anticoagulation clinic" OR "anticoagulation management" OR "anticoagulant care") AND ("quality of care" OR "outcomes" OR "bleeding" OR "thromboembolism" OR "mortality" OR "hospitalization" OR "length of stay" OR "emergency department visit" OR "cost" OR "patient satisfaction"). STUDY SELECTION AND DATA EXTRACTION: Criteria used to identify selected articles: English language; original studies (comments, letters, reviews, systematic reviews, meta-analyses, editorials were excluded); warfarin use; outpatient setting; comparison group present; time in therapeutic range (TTR) included as a measure of quality of anticoagulant control; study design was not a case report. DATA SYNTHESIS: Of 177 articles identified, 25 met inclusion criteria. Quality of anticoagulation control was better in the PMAS group compared with RMC in majority of the studies (N = 23 of 25, 92.0%). Clinical outcomes were also favorable in the PMAS group as evidenced by lower or equal risk of major bleeding (N = 10 of 12, 83.3%) or thromboembolic events (N = 9 of 10, 90.0%), and lower rates of hospitalization or emergency department visits (N = 9 of 9, 100%). When reported, PMAS have also resulted in cost-savings in all (N=6 of 6, 100%) of studies. CONCLUSIONS: Compared with routine care, pharmacist-managed outpatient-based anticoagulation services attained better quality of anticoagulation control, lower bleeding and thromboembolic events, and resulted in lower health care utilization. PMID- 28735552 TI - A Prospective Study on the Effect of Sport Specialization on Lower Extremity Injury Rates in High School Athletes. AB - BACKGROUND: Sport specialization is associated with an increased risk of musculoskeletal lower extremity injuries (LEIs) in adolescent athletes presenting in clinical settings. However, sport specialization and the incidence of LEIs have not been investigated prospectively in a large population of adolescent athletes. PURPOSE: To determine if sport specialization was associated with an increased risk of LEIs in high school athletes. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: Participants (interscholastic athletes in grades 9-12) were recruited from 29 Wisconsin high schools during the 2015-2016 school year. Participants completed a questionnaire identifying their sport participation and history of LEIs. Sport specialization of low, moderate, or high was determined using a previously published 3-point scale. Athletic trainers reported all LEIs that occurred during the school year. Analyses included group proportions, odds ratios (ORs) and 95% CIs, and days lost due to injury (median and interquartile range [IQR]). Multivariate Cox proportional hazard ratios (HRs) with 95% CIs were calculated to investigate the association between the incidence of LEIs and sport specialization level. RESULTS: A total of 1544 participants (50.5% female; mean age, 16.1 +/- 1.1 years) enrolled in the study, competed in 2843 athletic seasons, and participated in 167,349 athlete-exposures. Sport specialization was classified as low (59.5%), moderate (27.1%), or high (13.4%). Two hundred thirty five participants (15.2%) sustained a total of 276 LEIs that caused them to miss a median of 7.0 days (IQR, 2.0-22.8). Injuries occurred most often to the ankle (34.4%), knee (25.0%), and upper leg (12.7%) and included ligament sprains (40.9%), muscle/tendon strains (25.4%), and tendinitis/tenosynovitis (19.6%). The incidence of LEIs for moderate participants was higher than for low participants (HR, 1.51 [95% CI, 1.04-2.20]; P = .03). The incidence of LEIs for high participants was higher than for low participants (HR, 1.85 [95% CI, 1.12-3.06]; P = .02). CONCLUSION: Athletes with moderate or high sport specialization were more likely to sustain an LEI than athletes with low specialization. Sports medicine providers need to educate coaches, parents, and interscholastic athletes regarding the increased risk of LEIs for athletes who specialize in a single sport. PMID- 28735553 TI - The Development and Validation of a Subjective Assessment Tool for the Hip in the Athletic Population. AB - BACKGROUND: No validated functional assessments are available that are designed specifically to evaluate the performance and function of the athletic hip. Subsections of some validated outcome assessments address recreation, but a full assessment dedicated to athletic hip function does not exist. Current hip scoring systems may not be sensitive to subtle changes in performance and function in an athletic, younger population. HYPOTHESIS: The patient-athlete subjective scoring system developed in this study will be validated, reliable, and responsive in the evaluation of hip function in the athlete. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: Based on the results of a pilot questionnaire administered to 18 athletic individuals, a final 10-item questionnaire was developed. Two hundred fifty competitive athletes from multiple sports completed the final questionnaire and 3 previously validated hip outcome assessments. Each athlete was self-assigned to 1 of 3 injury categories: (1) playing without hip/groin trouble; (2) playing, but with hip/groin trouble; and (3) not playing due to hip/groin trouble. The injury categories contained 196, 40, and 14 athletes, respectively. Correlations between the assessment scores and injury categories were measured. Responsiveness testing was performed in an additional group of 24 injured athletes, and their scores before and after intervention were compared. RESULTS: The Kerlan-Jobe Orthopaedic Clinic (KJOC) Athletic Hip Score showed high correlation with the modified Harris Hip Score, the Nonarthritic Hip Score, and the International Hip Outcome Tool. The new score stratified athletes by injury category, demonstrated responsiveness and accuracy, and varied appropriately with improvements in injury category after treatment of injuries. CONCLUSION: The new KJOC Athletic Hip Score is valid, reliable, and responsive for evaluation of the hip in an athletic population. The results support its use for the functional assessment of the hip in future studies. PMID- 28735554 TI - Magnetic resonance imaging in central nervous system vasculitis in a patient affected by crioglobulin-negative hepatitis C virus infection: A likely correlation. AB - A 56-year-old man with behavioural disorders and facial-brachio-crural right hemiparesis presented with a brain lesion studied with computed tomography, magnetic resonance imaging and brain biopsy, leading to the diagnosis of cerebral vasculitis. Hepatitis C virus (HCV) infection in a phase of activity, without cryoglobulins, was also detected. Brain biopsy, laboratory analysis and response to a specific therapy supported the diagnosis of central nervous system vasculitis that was HCV related. PMID- 28735555 TI - Parent Ratings of the Strengths and Difficulties Questionnaire: What Is the Optimum Factor Model? AB - To date, at least 12 different models have been suggested for the Strengths and Difficulties Questionnaire (SDQ). The current study used confirmatory factor analysis to examine the relative support for these models. In all, 1,407 Malaysian parents completed SDQ ratings of their children (age range = 5-13 years). Although the findings showed some degree of support for all 12 models, there was most support for an oblique six-factor model that included the five SDQ domains (emotional problems, conduct problems, hyperactivity, peer problems, and low prosocial behavior) and a positive construal factor comprising all the 10 SDQ positive worded items. The original proposed five-factor oblique model also showed good fit. The implications of the findings for understanding the results of past studies of the structural models of the parent version of the SDQ, and for clinical and research practice involving the SDQ are discussed. PMID- 28735556 TI - Quantitative Sensory Testing and Current Perception Threshold Testing in Patients With Chronic Pain Following Lower Extremity Fracture. AB - BACKGROUND: Chronic pain is a significant problem for patients with lower extremity injuries. While pain hypersensitivity has been identified in many chronic pain conditions, it is not known whether patients with chronic pain following lower extremity fracture report pain hypersensitivity in the injured leg. PURPOSE: To quantify and compare peripheral somatosensory function and sensory nerve activation thresholds in persons with chronic pain following lower extremity fractures with a cohort of persons with no history of lower extremity fractures. METHOD: This was a cross-sectional study where quantitative sensory testing and current perception threshold testing were conducted on the injured and noninjured legs of cases and both legs of controls. RESULTS: A total of 14 cases and 28 controls participated in the study. Mean time since injury at the time of testing for cases was 22.3 (standard deviation = 12.1) months. The warmth detection threshold ( p = .024) and nerve activation thresholds at 2,000 Hz ( p < .001) and 250 Hz ( p = .002), respectively, were significantly higher in cases compared to controls. CONCLUSION: This study suggests that patients with chronic pain following lower extremity fractures may experience hypoesthesia in the injured leg, which contrasts with the finding of hyperesthesia previously observed in other chronic pain conditions but is in accord with patients with nerve injuries and surgeries. This is the first study to examine peripheral sensory nerve function at the site of injury in patients with chronic pain following lower extremity fractures using quantitative sensory testing and current perception threshold testing. PMID- 28735557 TI - Long-Term Effects of Prematurity, Cumulative Medical Risk, and Proximal and Distal Social Forces on Individual Differences in Diurnal Cortisol at Young Adulthood. AB - This study examined the effects of prematurity, cumulative medical risk, and proximal and distal social forces on individual differences in the activity of the hypothalamic-pituitary-adrenal (HPA) axis in young adulthood. A prospective sample of 149 infants born healthy preterm (PT; n = 22), sick PT ( n = 93, medical illness, neurological illness, small for gestational age), and full term ( n = 34) was recruited from a Level III neonatal intensive care unit in southern New England between 1985 and 1989 and followed to age 23 years. Cumulative medical risk was indexed across seven assessment waves (spanning 17 years) using medical and neurological health status at birth, toddlerhood (ages 18 and 30 months), childhood (ages 4 and 8 years), and adolescence (ages 12 and 17 years). Distal risk included socioeconomic status (SES) at birth. Proximal social factors were indexed from assessments of the home environment and measures of child vulnerability and maternal self-esteem, involvement, and control style from birth, 4 years, 8 years, and 12 years. At age 23 years, five saliva samples were collected upon awakening, 45 min after waking, 4 hr after waking, 8 hr after waking, and bedtime (later assayed for cortisol). Results reveal effects of cumulative medical risk on the diurnal pattern of HPA axis activity, with moderating effects of SES and proximal social factors. Findings are discussed in terms of implications for contemporary theories related to developmental sensitivity and susceptibility to context and the developmental origins of health and disease theory. PMID- 28735558 TI - Nicotinic Receptor Abnormalities in the Cerebellar Cortex of Sudden Unexplained Fetal and Infant Death Victims-Possible Correlation With Maternal Smoking. AB - Nicotinic acetylcholine receptors (nAChRs) are cationic channels of the neuronal cell membrane, differentially expressed in the central nervous system which, when activated by endogenous acetylcholine or exogenous nicotine, are able to enhance cholinergic transmission. The aim of this study was to investigate in human perinatal age the immunohistochemical expression of the alpha7-nAChR subtype, given its involvement in neuronal differentiation and its significant vulnerability to the toxic effects of nicotine. Thirty fetuses (with a gestational age between 25 and 40 weeks) and 35 infants (1-6 months old), suddenly died of known (controls) and unknown causes (unexplained deaths), with smoking and nonsmoking mothers, were included in this study. A negative or low immunoexpression of alpha7-nAChRs, indicative of their inactivation, was observed in the granular layers of the cerebellar cortex in 66% of the sudden unexplained perinatal deaths and 11% of the controls. A high correlation was also observed between these findings and maternal smoking. Apart from the well-known adverse effects of nicotine exposure during pregnancy, it may also cause significant alterations in cerebellar cholinergic transmission in areas of the brain involved in vital functions. These events may give us insights into the pathogenetic mechanisms leading to sudden unexplained fetal and infant death. PMID- 28735559 TI - Effects of Intron 1 Sequences on Human PLP1 Expression: Implications for PLP1 Related Disorders. AB - Alterations in the myelin proteolipid protein gene ( PLP1) may result in rare X linked disorders in humans such as Pelizaeus-Merzbacher disease and spastic paraplegia type 2. PLP1 expression must be tightly regulated since null mutations, as well as elevated PLP1 copy number, both lead to disease. Previous studies with Plp1-lacZ transgenic mice have demonstrated that mouse Plp1 ( mPlp1) intron 1 DNA (which accounts for slightly more than half of the gene) is required for the mPlp1 promoter to drive significant levels of reporter gene expression in brain. However not much is known about the mechanisms that control expression of the human PLP1 gene ( hPLP1). Therefore this review will focus on sequences in hPLP1 intron 1 DNA deemed important for hPLP1 gene activity as well as a couple of "human-specific" supplementary exons within the first intron which are utilized to generate novel splice variants, and the potential role that these sequences may play in PLP1-linked disorders. PMID- 28735560 TI - Promotion of fracture healing by conjugated linoleic acid in rats. AB - BACKGROUND: The ability of fracture healing in Tibetans is significantly superior to Chinese Hans, which may attribute to factors from diet, altitude to physical conditions. Conjugated linoleic acid (CLA) is an important ingredient in Tibetan diet, playing a role in antioxidation, antiatherosclerosis, and decrease in body fat accumulation. Methods: This study further quantified CLA effect in fracture healing in rats using combined structural evaluation (X-ray and micro-computed tomography), biomechanical test, and histological examination. RESULTS: CLA could promote fracture healing with quicker development of trabecular connection, network and thickening and were more active at the stage of bony union and remodeling. The load to failure could reach 78.12 +/- 10.03 N, 41.4% stronger than the control by week 6 ( p = 0.0209). CONCLUSIONS: CLA improved the quality and mechanical strength of fracture healing in rats callus. The information may offer insight in development of new therapeutic strategies of fracture healing for general populations beyond Tibetans. PMID- 28735561 TI - Isolated revision of the acetabular component using alumina-on-alumina bearings without a metal sleeve: A preliminary study. AB - INTRODUCTION: There has been a debate on the use of ceramic-on-ceramic coupling with the retained femoral stem in isolated acetabular revision. The purpose of this study was to retrospectively review the results and complications of isolated revision of the acetabular component using alumina-on-alumina bearings. METHODS: Between August 2010 and December 2013, 22 patients (23 hips) with a mean age of 60.74 years (40-73) underwent isolated revision of the acetabular component from metal-on-polyethylene to alumina-on-alumina bearings without using a metal sleeve on the undamaged trunnion. All patients completed clinical and radiographic evaluation. RESULTS: At a mean follow-up of 3 years (2-5.5), all patients had a significant improvement in the clinical outcome, including Harris Hip Score (84.9 vs. 43, p < 0.001), West Ontario McMaster University Osteoarthritis Index Score (14.4 vs. 49.2, p < 0.001), and visual analogue pain score (1.42 vs. 6.63, p < 0.001). Complications included one aseptic loosening of the acetabular component and three noisy hips (click only). No fracture of the ceramic bearings, dislocation, infection, or squeaking noise were observed in any of the patients. CONCLUSION: Isolated revision of the acetabular component to alumina-on-alumina bearings on the undamaged trunnion may be considered if there is no available titanium sleeves. Our study showed a satisfactory early outcome with minimal complications. However, a longer term follow-up study is necessary. PMID- 28735562 TI - Diagnostic and Therapeutic Knowledge and Practices in the Management of Congenital Syphilis by Pediatricians in Public Maternity Hospitals in Brazil. AB - The study aimed to assess conformity with Brazil's standard protocol for diagnostic and therapeutic practices in the management of congenital syphilis by pediatricians in public maternity hospitals. A cross-sectional study was conducted in 2015 with 41 pediatricians working in all the public maternity hospitals in Teresina, the capital of Piaui State, Northeast Brazil, through self completed questionnaires. The study assessed the conformity of knowledge and practices according to the Brazilian Ministry of Health protocols. The study has made evident low access to training courses (54%) and insufficient knowledge of the case definition of congenital syphilis (42%) and rapid tests for syphilis (39%). Flaws were observed in the diagnostic workup and treatment of newborns. Requesting VDRL (88%) and correct treatment of neurosyphilis (88%) were the practices that showed the highest conformity with standard protocols. Low conformity with protocols leads to missed opportunities for identifying and adequately treating congenital syphilis. Based on the barriers identified in the study, better access to diagnostic and treatment protocols, improved recording on prenatal cards and hospital patient charts, availability of tests and medicines, and educational work with pregnant women should be urgently implemented, aiming to reverse the currently inadequate management of congenital syphilis and to curb its spread. PMID- 28735563 TI - A Gaussian Approximation Approach for Value of Information Analysis. AB - Most decisions are associated with uncertainty. Value of information (VOI) analysis quantifies the opportunity loss associated with choosing a suboptimal intervention based on current imperfect information. VOI can inform the value of collecting additional information, resource allocation, research prioritization, and future research designs. However, in practice, VOI remains underused due to many conceptual and computational challenges associated with its application. Expected value of sample information (EVSI) is rooted in Bayesian statistical decision theory and measures the value of information from a finite sample. The past few years have witnessed a dramatic growth in computationally efficient methods to calculate EVSI, including metamodeling. However, little research has been done to simplify the experimental data collection step inherent to all EVSI computations, especially for correlated model parameters. This article proposes a general Gaussian approximation (GA) of the traditional Bayesian updating approach based on the original work by Raiffa and Schlaifer to compute EVSI. The proposed approach uses a single probabilistic sensitivity analysis (PSA) data set and involves 2 steps: 1) a linear metamodel step to compute the EVSI on the preposterior distributions and 2) a GA step to compute the preposterior distribution of the parameters of interest. The proposed approach is efficient and can be applied for a wide range of data collection designs involving multiple non-Gaussian parameters and unbalanced study designs. Our approach is particularly useful when the parameters of an economic evaluation are correlated or interact. PMID- 28735564 TI - Synergistic effect of co-digestion to enhance anaerobic degradation of catering waste and orange peel for biogas production. AB - Catering waste and orange peel were co-digested using an anaerobic digestion process. Orange peel is difficult to degrade anaerobically due to the presence of antimicrobial agents such as limonene. The present study aimed to examine the feasibility of anaerobic co-digestion of catering waste with orange peel to provide the optimum nutrient balance with reduced inhibitory effects of orange peel. Batch experiments were conducted using catering waste as a potential substrate mixed in varying ratios (20-50%) with orange peel. Similar ratios were followed using green vegetable waste as co-substrate. The results showed that the highest organic matter degradation (49%) was achieved with co-digestion of catering waste and orange peel at a 50% mixing ratio (CF4). Similarly, the soluble chemical oxygen demand (sCOD) was increased by 51% and reached its maximum value (9040 mg l-1) due to conversion of organic matter from insoluble to soluble form. Biogas production was increased by 1.5 times in CF4 where accumulative biogas was 89.61 m3 t-1substrate compared with 57.35 m3 t-1substrate in the control after 80 days. The main reason behind the improved biogas production and degradation is the dilution of inhibitory factors (limonene), with subsequent provision of balanced nutrients in the co-digestion system. The tCOD of the final digestate was decreased by 79.9% in CF4, which was quite high as compared with 68.3% for the control. Overall, this study revealed that orange peel waste is a highly feasible co-substrate for anaerobic digestion with catering waste for enhanced biogas production. PMID- 28735565 TI - Can pharmacological manipulation of LTP favor the effects of motor rehabilitation in multiple sclerosis? AB - BACKGROUND: Synaptic plasticity, the basic mechanism of clinical recovery after brain lesion, can also remarkably influence the clinical course of multiple sclerosis (MS). Physical rehabilitation represents the main treatment option to promote synaptic long-term potentiation (LTP) and to enhance spontaneous recovery of neurological deficits. OBJECTIVES: To overview the role of pharmacological treatment and physical rehabilitation in modulating LTP and enhancing clinical recovery in MS. RESULTS: Drug-induced LTP enhancement can be effectively used to promote functional recovery, alone or combined with rehabilitation. Also, as inflammatory cytokines alter synaptic transmission and plasticity in MS, pharmacological resolution of inflammation can positively influence clinical recovery. Finally, physical exercise could be an independent factor able to preserve or enhance LTP reserve both influencing signaling pathways involved in plasticity induction and maintenance, and decreasing inflammation. FUTURE DIRECTIONS: Better knowledge of LTP determinants may be useful to design specific strategies to promote recovery after a relapse and to reduce the progressive neurological deterioration in MS patients. PMID- 28735566 TI - Attachment and Personality Disorders Among Child Molesters: The Role of Trust. AB - The present study investigated multivariate associations between attachment styles and personality disorders (PDs)-and the mediating role of trust-in a sample of child molesters ( n = 84) and a matched control group from the general community ( n = 80). Among child molesters, canonical correlation analysis revealed that two variates resembling avoidant and anxious attachment dimensions were associated with PD traits. Attachment avoidance was related to schizoid, schizotypal, and avoidant PDs, with a marginal contribution of antisocial PD. Attachment anxiety was related to borderline and histrionic PDs, with a marginal contribution of obsessive-compulsive PD. Paranoid and dependent PDs contributed to both variates. In the control group, a more general association between attachment insecurity and PDs emerged. Finally, mistrust significantly explained the associations between attachment and PDs in both samples. Future studies should examine whether treatment for PDs in child molesters could benefit from a focus on attachment and trust. PMID- 28735567 TI - Policy Research Challenges in Comparing Care Models for Dual-Eligible Beneficiaries. AB - Providing affordable, high-quality care for the 10 million persons who are dual eligible beneficiaries of Medicare and Medicaid is an ongoing health-care policy challenge in the United States. However, the workforce and the care provided to dual-eligible beneficiaries are understudied. The purpose of this article is to provide a narrative of the challenges and lessons learned from an exploratory study in the use of clinical and administrative data to compare the workforce of two care models that deliver home- and community-based services to dual-eligible beneficiaries. The research challenges that the study team encountered were as follows: (a) comparing different care models, (b) standardizing data across care models, and (c) comparing patterns of health-care utilization. The methods used to meet these challenges included expert opinion to classify data and summative content analysis to compare and count data. Using descriptive statistics, a summary comparison of the two care models suggested that the coordinated care model workforce provided significantly greater hours of care per recipient than the integrated care model workforce. This likely represented the coordinated care model's focus on providing in-home services for one recipient, whereas the integrated care model focused on providing services in a day center with group activities. The lesson learned from this exploratory study is the need for standardized quality measures across home- and community-based services agencies to determine the workforce that best meets the needs of dual-eligible beneficiaries. PMID- 28735568 TI - Turning a Blind Eye: Public Support of Emergency Housing Policies for Sex Offenders. AB - In this study, we examine the influences of citizen decision making in the context of four policy scenarios that would affect the living conditions of sex offenders (SOs) residing at an "emergency shelter" budget motel. We surveyed 773 citizens in an online survey about their support for four policy scenarios that would improve the living conditions of SOs: (a) at no cost to the respondent, (b) in exchange for a US$100 tax increase, and (c) by relocating SOs within the respondent's neighborhood (i.e., "in my backyard"/IMBY scenario). The fourth scenario involved moving nearby SOs into substandard housing located far away from the respondent (i.e., "not in my backyard"/NIMBY). While prior research finds that the public overwhelmingly supports punitive SO policies, we find that indifference is a mainstay of public opinion about improving SO housing conditions. That is, we find only modest levels of average support for any of the policy scenarios, and policy support decreased when increased taxes would be involved, compared with a "no cost" scenario. While no respondent characteristics significantly predicted policy support consistently across all four scenarios, some scenarios showed stark differences in support when considering specific respondent characteristics. Overall, these results suggest that what does affect support depends on the details of the policy being proposed, as well as who is considering the policy. We end by discussing the policy implications of our study for both policymakers and the public. PMID- 28735569 TI - Treatment of Moderate to Severe Psoriasis With High-Dose (450-mg) Secukinumab: Case Reports of Off-Label Use. AB - Treatment of moderate to severe psoriasis often requires systemic therapy, including biologics. Partial response to biologics and relapses are commonly managed with dose escalation. Secukinumab is a relatively new biologic that is currently used to treat moderate to severe psoriasis. There has been no literature published on dose escalation of secukinumab. This article describes the off-label use of a higher dose of secukinumab (450 mg every 4 weeks) instead of the standard dosing (300 mg every 4 weeks) in 2 patients with moderate to severe psoriasis. The first case involves a male patient with a high body mass index (BMI) (>=30 kg/m2) and severe psoriasis who was started on secukinumab at 450 mg following a partial response to treatment with the standard 300-mg dose. His psoriasis significantly improved with the higher dose of secukinumab. The second case discusses a female patient with treatment-resistant psoriasis and a BMI of 31.6 kg/m2 who initially achieved a complete remission with standard dosing of secukinumab. Later, her psoriasis relapsed and she was dose-escalated to secukinumab 450 mg in an attempt to recapture response, but this dose escalation was unsuccessful. In both cases, there were no adverse events observed with a higher dose of secukinumab. These cases demonstrate that dose escalation of secukinumab (450 mg rather than on-label 300 mg every 4 weeks) may be considered in selected patients with incomplete clearance, particularly for those with a high BMI. However, secukinumab dose escalation may not be as beneficial in patients with loss of efficacy. PMID- 28735570 TI - The challenge in the diagnosis and management of an advanced abdominal pregnancy in a resource-low setting: a case report. AB - BACKGROUND: Abdominal pregnancy is a rare form of ectopic pregnancy that is frequently left undiagnosed by inexperienced obstetricians and radiologists. It is associated with higher risk of maternal hemorrhage at any gestation and more at advanced gestation. CASE PRESENTATION: We present the case of a 22-year-old sub-Saharan African woman, gravida 3 para 0, who was diagnosed with advanced abdominal pregnancy of 25 weeks' gestation by a transvaginal ultrasound after the failure of two medical terminations of pregnancy in the first and second trimesters and a series of repeated obstetric ultrasounds showing intrauterine pregnancy. Laparotomy was done and her recovery was uneventful. CONCLUSIONS: The management of advanced abdominal pregnancy is more challenging as compared to earlier gestation so patients with failed medical termination of pregnancy should be critically analyzed for ectopic pregnancy as early as possible. PMID- 28735571 TI - Ethics review in compassionate use. AB - BACKGROUND: Compassionate use is the use of unapproved drugs outside of clinical trials. So far, compassionate use regulations have been introduced in the US, Canada, many European countries, Australia and Brazil, and treatment on a compassionate use basis may be performed in Japan and China. However, there are important differences between relevant regulations in individual countries, particularly that approval by a research ethics committee (institutional review board) is a requirement for compassionate use in some countries (e.g. the US, Spain, and Italy), but not in others (e.g. Canada, the UK, France, and Germany). DISCUSSION: The main objective of this article is to present aspects of compassionate use that are important for the discussion of the role of research ethics committees in the review of compassionate use. These aspects include the nature of compassionate use, potential risks to patients associated with the use of drugs with unproven safety and efficacy, informed consent, physicians' qualifications, and patient selection criteria. Our analysis indicates that the arguments for mandatory review substantially outweigh the arguments to the contrary. CONCLUSIONS: Approval by a research ethics committee should be obligatory for compassionate use. The principal argument against mandatory ethical review of compassionate use is that it is primarily a kind of treatment rather than biomedical research. Nonetheless, compassionate use is different from standard clinical care and should be subject to review by research ethics committees. First, in practice, compassionate use often involves significant research aspects. Second, it is based on unapproved drugs with unproven safety and efficacy. Obtaining informed consent from patients seeking access to unapproved drugs on a compassionate use basis may also be difficult. Other important problems include the qualifications of the physician who is to perform treatment, and patient selection criteria. PMID- 28735573 TI - Chemoattractant activity of tris-(hydroxymethyl)aminomethane for Brugia pahangi infective third-stage larvae. AB - Urocanic acid (UCA) is known as a major chemoattractant for Strongyloides stercoralis infective third-stage larvae (L3). Since Brugia pahangi is a skin penetrating parasitic nematode similar to S. stercoralis, UCA was expected to be a chemoattractant for B. pahangi L3. Thus, the chemoattractant activity of UCA for B. pahangi L3 was assessed. The chemotactic responses of B. pahangi L3 to UCA or acetic acid (CH3COOH) dissolved in amine solutions were assessed using an agar plate assay. A test solution of 200 mm UCA dissolved in aqueous 270 mm tris(hydroxymethyl)aminomethane (Tris) significantly attracted B. pahangi L3 compared with deionized water (DW), while neither a solution of 200 mm UCA dissolved in aqueous 230 mm ammonia (NH3) nor 290 mm triethylamine (TEA) significantly attracted L3. Similarly, a test solution of 200 mm CH3COOH dissolved with 200 mm Tris significantly attracted L3, but neither a test solution of 200 mm CH3COOH plus 200 mm NH3 nor 200 mm TEA attracted L3. Furthermore, L3 were significantly attracted to 200 mm Tris alone, compared with DW, but avoided 200 mm NH3 and 200 mm TEA. Moreover, the chemoattractant activity of Tris for L3 was observed even at a low concentration of 25 mm, and it was observed in a mild alkaline condition but not in an acidic condition. The present study reveals that Tris is a potential chemoattractant for B. pahangi L3 while UCA is not. This finding will contribute to an understanding of the mechanisms of skin-penetrating infection of filarial L3. PMID- 28735572 TI - Early nutritional intervention can improve utilisation of vegetable-based diets in diploid and triploid Atlantic salmon (Salmo salar L.). AB - The present study investigated nutritional programming in Atlantic salmon to improve utilisation of a vegetable-based diet. At first exogenous feeding, fry were fed either a marine-based diet (Diet Mstimulus, 80% fishmeal (FM)/4% fish oil (FO)) or a vegetable-based diet (Diet Vstimulus, 10% FM/0% FO) for 3 weeks. Subsequently, all fish were then fed under the same conditions with a commercial, marine-based, diet for 15 weeks and thereafter challenged with a second V diet (Diet Vchallenge, 10% FM/0% FO) for 6 weeks. Diploid and triploid siblings were run in parallel to examine ploidy effects. Growth performance, feed intake, nutrient utilisation and intestinal morphology were monitored. Fish initially given Diet Vstimulus (V-fish) showed 24 % higher growth rate and 23 % better feed efficiency compared with M-fish when later challenged with Diet Vchallenge. There was no difference in feed intake between nutritional histories, but increased nutrient retentions highlighted the improved utilisation of a V diet in V-fish. There were generally few significant effects of nutritional history or ploidy on enteritis scores in the distal intestine after the challenge phase as only V triploids showed a significant increase (P<0.05) in total score. The data highlighted that the positive effects were most likely a result of nutritional programming and the ability to respond better when challenged later in life may be attributed to physiological and/or metabolic changes induced by the stimulus. This novel study showed the potential of nutritional programming to improve the use of plant raw material ingredients in feeds for Atlantic salmon. PMID- 28735574 TI - Multicentre evaluation of a direct agglutination test prototype kit (DAT-LPC) for diagnosis of visceral leishmaniasis. AB - In this study, we assessed the sensitivity, specificity, and diagnostic accuracy of a previously developed direct agglutination test (DAT) using a freeze-dried antigen derived from Leishmania infantum promastigotes and composed in a prototype kit for visceral leishmaniasis (VL) diagnosis, named DAT-LPC. To evaluate DAT-LPC reproducibility, the kit was used to analyse 207 serum samples from VL patients and 80 serum samples from patients with other parasitic infections or healthy subjects in four laboratories from different public health institutions in Brazil. DAT-LPC showed sensitivity between 96.2 and 99.5% (P = 0.14), specificity ranging from 96.2 to 97.5% (P = 0.95), and diagnostic accuracy ranging from 96.5 to 99% (P = 0.34). The inter-laboratory reproducibility of qualitative results was classified as excellent (kappa index: 0.94-0.97). The reproducibility of the end-titre results in relation to the reference laboratory, ranged from 31 to 85%. These results demonstrate an excellent performance of the DAT-LPC, and validate it for the diagnosis of VL that could replace the immunofluorescent antibody test as the routine diagnostic test in the Brazilian public health system. PMID- 28735575 TI - Negotiating the complexities of exocrine and endocrine dysfunction in chronic pancreatitis. AB - Chronic pancreatitis is a chronic inflammatory disease of the pancreas characterised by irreversible morphological change and typically causing pain and/or permanent loss of function. This progressive, irreversible disease results in destruction of healthy pancreatic tissue and the development of fibrous scar tissue. Gradual loss of exocrine and endocrine function follows, along with clinical manifestations such as steatorrhoea, abdominal pain and diabetes. Nutrition in chronic pancreatitis has been described as a problem area and, until recently, there was little research on the topic. It is often asserted that >90 % of the pancreas must be damaged before exocrine insufficiency occurs; however, an exploration of the original studies from the 1970s found that the data do not support this assertion. The management of steatorrhoea with pancreatic enzyme replacement therapy is the mainstay of nutritional management, and early identification and treatment is a key. The presence of steatorrhoea, coupled with poor dietary intake (due to intractable abdominal pain, gastrointestinal side effects and often alcoholism) renders the chronic pancreatitis patients at considerable risk for undernutrition, muscle depletion and fat-soluble vitamin deficiency. Premature osteoporosis/osteopenia afflicts two-thirds of patients as a consequence of poor dietary intake of calcium and vitamin D, low physical activity, low sunlight exposure, heavy smoking, as well as chronic low-grade inflammation. Bone metabolism studies show increased bone formation as well as bone resorption in chronic pancreatitis, indicating that bone turnover is abnormally high. Loss of the pancreatic islet cells occurs later in the disease process as the endocrine cells are diffusely distributed throughout the pancreatic parenchyma. Patients may develop type 3c (pancreatogenic) diabetes, which is complicated by concurrent decreased glucagon secretion, and hence an increased risk of hypoglycaemia. Diabetes control is further complicated by poor diet, malabsorption and (for some) alcoholism, and therefore those with type 3c diabetes have clinical characteristics and therapeutic goals that are different from that of type 1 and type 2 diabetes patients. This review describes emerging research and clinical guidelines for nutrition in chronic pancreatitis. PMID- 28735576 TI - Society for Healthcare Epidemiology (SHEA) Mourns the Passing of Past Presidents. PMID- 28735577 TI - Growth performance and digestion of growing lambs fed diets supplemented with glycerol. AB - Two experiments were conducted to evaluate the effects of replacing corn with an increasing concentration of high-purity glycerol (>99%) on growth performance, economical efficiency, blood constituents and nutrient digestibility of growing lambs. In experiment one, 24 male lambs (initial BW=33.6+/-6.0 kg; age=6.75+/ 0.75 months) were randomly assigned to one of the three experimental treatments containing 0%, 5% or 10% glycerol to replace corn in concentrate. In experiment two, nine lambs (initial BW=44.7+/-2.2 kg, age=8.84+/-0.32 months) were used in a digestion trial with three treatments (three lambs per treatment) with glycerol replacing corn at 0%, 5% or 10% in the concentrate. Total dry matter (DM) intake decreased quadratically (P=0.003) with increasing concentration of glycerol in the diet. Lambs fed glycerol diets had greater average daily gain (P=0.005) and better feed efficiency (P=0.002) compared with the control. Feed costs were also reduced with glycerol inclusion. Glycerol supplementation did not affect serum concentrations of total protein, albumin, globulin, total lipid, cholesterol and glucose concentrations. Glycerol supplementation had no effect (P>0.05) on organic matter and CP digestion, but improved DM (P=0.0003), crude fiber (P=0.10), ether extract (P=0.0002) and nitrogen-free extract (P=0.05) digestion. In conclusion, glycerol can replace corn up to 10% of DM in the diets of growing lambs. PMID- 28735578 TI - Age-related differences of semen quality, seminal plasma, and spermatozoa antioxidative and oxidative stress variables in bulls during cold and warm periods of the year. AB - The aims of this study were to determine the presence and quantities of antioxidative status and oxidative stress (OS) variables in the seminal plasma and spermatozoa of bulls of varying age during cold and warm periods of the year, and to establish the correlation of these variables with semen quality parameters. The study was conducted on two groups each comprising nine Simmental bulls: one group contained younger animals (aged 2 to 4 years) and the second older animals (aged 5 to 10 years). Semen samples were collected using an artificial vagina for biochemical analysis. Seminal plasma and spermatozoa activities of total superoxide dismutase (TSOD), manganese superoxide dismutase (MnSOD), copper-zinc superoxide dismutase (CuZnSOD), catalase (CAT), selenium dependent glutathione peroxidase, reduced glutathione and concentrations of total protein (TP), thiobarbituric acid reactive substances (TBARS) and protein carbonyl content (PCC) were determined. Several antioxidants in seminal plasma were also determined: total glutathione peroxidase (TGSH-Px), selenium independent glutathione peroxidase (Non-SeGSH-Px), uric acid, albumins (ALB) and alkaline phosphatase (ALP). Significantly higher spermatozoa motility was observed during the cold v. warm period, and a significantly higher volume and total number of spermatozoa per ejaculate was observed in older than in younger bulls. Significantly higher values of ALP, TP and ALB were found in seminal plasma of older bulls than in younger bulls during the warm period. The seminal plasma of younger bulls showed significantly higher activities of TSOD, MnSOD, CuZnSOD, TGSH-Px and Non-SeGSH-Px. Younger bulls had significantly higher PCC concentration and activity of CAT in seminal plasma than older bulls during the cold period. Significantly higher concentrations of PCC and TBARS, and activities of TSOD, MnSOD and CuZnSOD were established in spermatozoa of the younger than in older bulls during the warm period. It could be concluded that antioxidative and OS variables differ significantly depending on bull age and time of year. Younger bulls were more sensitive to elevated ambient temperatures during the warm period, when the higher enzymatic antioxidative protection in seminal plasma and spermatozoa were insufficient to counteract the intensive oxidative processes in spermatozoa, which eventually resulted in decreased spermatozoa motility. The estimation of antioxidative and OS variables in seminal plasma and spermatozoa may have practical value for the assessment of bull semen quality. PMID- 28735579 TI - Directed threat imagery in generalized anxiety disorder. AB - BACKGROUND: Worrying has been suggested to prevent emotional and elaborative processing of fears. In cognitive-behavioral therapy (CBT), generalized anxiety disorder (GAD) patients are exposed to their fears during the method of directed threat imagery by inducing emotional reactivity. However, studies investigating neural correlates of directed threat imagery and emotional reactivity in GAD patients are lacking. The present functional magnetic resonance imaging (fMRI) study aimed at delineating neural correlates of directed threat imagery in GAD patients. METHOD: Nineteen GAD patients and 19 healthy controls (HC) were exposed to narrative scripts of either disorder-related or neutral content and were encouraged to imagine it as vividly as possible. RESULTS: Rating results showed that GAD patients experienced disorder-related scripts as more anxiety inducing and arousing than HC. These results were also reflected in fMRI data: Disorder related v. neutral scripts elicited elevated activity in the amygdala, dorsomedial prefrontal cortex, ventrolateral prefrontal cortex and the thalamus as well as reduced activity in the ventromedial prefrontal cortex/subgenual anterior cingulate cortex in GAD patients relative to HC. CONCLUSION: The present study presents the first behavioral and neural evidence for emotional reactivity during directed threat imagery in GAD. The brain activity pattern suggests an involvement of a fear processing network as a neural correlate of initial exposure during directed imagery in CBT in GAD. PMID- 28735580 TI - High-protein goat's milk diet identified through newborn screening: clinical warning of a potentially dangerous dietetic practice. AB - OBJECTIVE: Breast-feeding is an unequalled way of providing optimal food for infants' healthy growth and development and the WHO recommends that infants should be exclusively breast-fed for the first 6 months of life. For mothers who are unable to breast-feed or who decide not to, infant formulas are the safest alternative. Despite recommendations, it is possible that parents make potentially harmful nutritional choices for their children because of cultural beliefs or misinformation on infant nutrition. We describe a possible health risk of not breast-feeding, highlighting a potentially dangerous dietetic practice. Design/Setting/Subjects We report the case of a newborn who was fed with undiluted goat's milk because her mother could not breast-feed and was not aware of infant formulas. RESULTS: The dietary mistake was detected because of a positive expanded newborn screening result, characterized by severe hypertyrosinaemia with high methionine and phenylalanine levels, a pattern suggestive of severe liver impairment. The pattern of plasma amino acids was related to a goat's milk diet, because of its very different composition compared with human milk and infant formula. CONCLUSIONS: Our experience demonstrates that, when breast-feeding is not possible or is not exclusive, infants may be at risk of dangerous nutritional practices, including diets with very high protein content, such as a goat's milk diet. Families of not breast-fed infants may need appropriate advice on safe alternatives for infant nutrition to avoid the risks of inappropriate diets. PMID- 28735581 TI - Independent associations of dairy and calcium intakes with colorectal cancers in the Adventist Health Study-2 cohort. AB - OBJECTIVE: Results associating dairy and Ca intakes with colorectal cancer (CRC) risk have been mixed. Most previous analyses have suffered from confounding between dairy and Ca intakes. We examined independent associations between these variables, also dairy foods, and CRC incidence in a population with a large range of dairy intakes. DESIGN: Adventist Health Study-2 is a cohort study where subjects were enrolled 2002-2007. Proportional hazard regression analyses were performed to estimate hazard ratios (HR). Regression calibration was used to correct for dietary measurement error. SETTING: The population lived in all states of the USA. SUBJECTS: There were 77712 analytic subjects, all of whom were Seventh-day Adventists. Much of their dietary Ca came from non-dairy sources. SUBJECTS: During a mean follow-up of 7.8 years, 380 incident colon cancer and 111 incident rectal cancer cases were observed. RESULTS: Comparing extreme quintiles of intake in measurement error-corrected analyses, dairy intake (HR=0.31; 95 % CI 0.09, 0.88), independent of total Ca, was inversely related with risk of rectal cancer but gave little indication of association with colon cancer. However, total Ca intake (independent of dairy) was associated with risk of colon cancer (HR=0.55; 95 % CI 0.28, 0.98) and there was little indication of association with rectal cancer. Traditional regression analyses and associations with macronutrients from dairy generally supported these results. Milk intake was also negatively associated with CRC (HR=0.63; 95 % CI 0.43, 0.89). CONCLUSIONS: Dairy intake may decrease the risk of rectal cancer, and Ca may reduce risk of colon cancer and CRC. PMID- 28735582 TI - Health literacy and fruit and vegetable intake in rural Australia. AB - OBJECTIVE: Adequate fruit and vegetable intake is important in the prevention of chronic disease. Health literacy is associated with health outcomes but its role in dietary behaviour has received little attention. The present study investigated the association between a multidimensional measure of health literacy, sociodemographic characteristics, and fruit and vegetable intake in rural Australia. DESIGN: A cross-sectional survey on intake of fruits and vegetables (servings/d), demographic characteristics and health literacy profile using a nine-scale Health Literacy Questionnaire (HLQ). Associations between health literacy and fruit and vegetable intake were assessed using logistic regression. SETTING: A large rural area of Victoria. SUBJECTS: Adults residing in the Grampians region (n 1154; 61 % female, mean age 52 (sd 17) years). RESULTS: The HLQ scale 'Actively managing my health' predicted (OR; 95 % CI) fruit (2.31; 1.87, 2.84) and vegetable (1.81; 1.45, 2.26) intake. The scales 'Appraisal of health information' (fruits: 1.73; 1.41, 2.13; vegetables: 1.49; 1.20, 1.86), 'Social support for health' (fruits: 1.31; 1.06, 1.63; vegetables: 1.40; 1.10, 1.76) and 'Ability to find good health information' (fruits: 1.25; 1.05, 1.48; vegetables: 1.36; CI 1.13, 1.63) also predicted fruit and vegetable intake. These associations remained significant after adjusting for age, gender, educational attainment and having private health insurance. CONCLUSIONS: Health literacy, particularly being proactive, appraising information and having social support for health, is associated with greater fruit and vegetable intake. Future interventions should consider the health literacy needs of the community to improve fruit and vegetable intake. PMID- 28735583 TI - Fever and infections during pregnancy and psychosis-like experiences in the offspring at age 11. A prospective study within the Danish National Birth Cohort. AB - BACKGROUND: Maternal exposures to fever and infections in pregnancy have been linked to subsequent psychiatric morbidity in the child. This study examined whether fever and common infections in pregnancy were associated with psychosis like experiences (PLEs) in the child. METHODS: A longitudinal study of 46 184 children who participated in the 11-year follow-up of the Danish National Birth Cohort was conducted. Pregnant women were enrolled between 1996 and 2002 and information on fever, genitourinary infections, respiratory tract infection, and influenza-like illness during pregnancy was prospectively collected in two interviews during pregnancy. PLEs were assessed using the seven-item Adolescent Psychotic-Like Symptom Screener in a web-based questionnaire completed by the children themselves at age 11. RESULTS: PLEs were reported among 11% of the children. Multinomial logistic regression models with probability weights to adjust for potential selection bias due to attrition suggested that maternal fever, genitourinary infections and influenza-like illness were associated with a weak to moderate increased risk of subclinical psychosis-like symptoms in the offspring, whereas respiratory tract infections were not. No clear pattern was observed between the strengths of the associations and the timing of exposure, or the type of psychosis-like symptom. CONCLUSIONS: In this study, maternal exposures to fevers and common infections in pregnancy were generally associated with a subtle excess risk of PLEs in the child. A more pronounced association was found for influenza-like illness under an a priori definition, leaving open the possibility that certain kinds of infections may constitute important risk factors. PMID- 28735584 TI - Genomic differentiation between swamp and river buffalo using a cattle high density single nucleotide polymorphisms panel. AB - Buffalo (Bubalus bubalis) is an important livestock species in many tropical and subtropical regions. In recent decades, the interest in buffalo's milk have expanded and intensive buffalo farms start to emerge. However, breeding programs and population genetics information for this species is scarce or inexistent. The present study aims to test the suitability of the commercial high-density single nucleotide polymorphisms (SNP) genotyping panel, the Illumina BovineHD BeadChip, to estimate population genetics parameters, pedigree control and identification of common variants in major production candidate genes. From a total of 777 962 SNPs included in the panel, 20 479 were polymorphic in water buffalo at a call rate of 86% and an average expected heterozygosity (HE) of 0.306. From these, 357 were mapped within or around the flanking regions of several major candidate genes. A principal components analysis identified three different clusters, each representing pure swamp buffalo type, pure river buffalo type and admixed river buffalo. The hybrids between swamp and river buffalo were clearly identified as an intermediary cluster. The suitability of these SNPs data set for parentage and identity testing demonstrated that the combination of just 30 to 50 SNPs were enough to attain high probabilities of parentage exclusion (0.9999) in both types and identity (2.3*10-5 and 2.0*10-7) for river and swamp buffalo, respectively. Our analysis confirms the suitability of the BovineHD BeadChip to assess population structure, hybridization and identity of the water buffalo populations. PMID- 28735585 TI - Analyses of body weight patterns in growing pigs: a new view on body weight in pigs for frequent monitoring. AB - Frequent BW monitoring of growing pigs can be useful for identifying production (e.g. feeding), health and welfare problems. However, in order to construct a tool which will properly recognize abnormalities in pigs' growth a precise description of the growth process should be used. In this study we proposed a new model of pig growth accounting for daily fluctuations in BW. Body weight measurements of 1710 pigs (865 gilts and 843 barrows) originating from five consecutive batches from a Danish commercial farm were collected. Pigs were inserted into a large pen (maximum capacity=400) between November 2014 and September 2015. On average, each pig was observed for 42 days and weighed 3.6 times a day when passing from the resting to feeding area. Altogether, 243,160 BW measurements were recorded. A multilevel model of pig growth was constructed and fitted to available data. The BW of pigs was modeled as a quadratic function of time. A diurnal pattern was incorporated into the model by a cosine wave with known length (24 h). The model included pig effect which was defined as a random autoregressive process with exponential correlation. Variance of within-pigs error was assumed to increase with time. Because only five batches were observed, it was not possible to obtain the random effect for batch. However, in order to account for the batch effect the model included interactions between batch and fixed parameters: intercept, time, square value of time and cosine wave. The gender effect was not significant and was removed from the final model. For all batches, morning and afternoon peaks in the frequency of visits to the feeding area could be distinguished. According to results, pigs were lighter in the morning and heavier in the evening (minimum BW was reached around 1000 h and maximum around 2200 h). However, the exact time of obtaining maximum and minimum BW during the day differed between batches. Pigs had access to natural light and, therefore, existing differences could be explained by varying daylight level during observations periods. Because the diurnal amplitude for pig growth varied between batches from 0.9 to 1.4 kg, BW monitoring tools based on frequent measurements should account for diurnal variation in BW of pigs. This proposed description of growth will be built into a monitoring tool (a dynamic linear model) and applied to farm data in future studies. PMID- 28735586 TI - Cognitive development prior to onset of psychosis. AB - Schizophrenia patients commonly exhibit substantial and diffuse cognitive impairment. Evidence suggests that subtle cognitive deficits are already apparent in childhood and adolescence, many years prior to onset of psychosis. While there is almost unequivocal evidence of some degree of cognitive impairment in individuals who later develop schizophrenia, the literature remains inconclusive regarding the exact nature of this impairment and warrants careful review and interpretation. Meta-analytic findings suggest that individuals who later develop schizophrenia, but not related disorders, such as bipolar disorder, exhibit a premorbid IQ deficit of around 8 points. Several studies have also found evidence for premorbid deficits across most cognitive domains, such as language, processing speed and executive functions. Longitudinal studies, although rare, suggest that individuals who go on to develop schizophrenia may show a course of increasing cognitive impairment prior to onset of psychosis. While evidence regarding the etiology of premorbid deficits is scarce, common and rare genetic variants, as well as environmental factors such as obstetric complications and cannabis use may play an important role and warrant further examination. In this selected review, we give an overview of population-based studies on premorbid cognitive deficits in schizophrenia, with a special focus on evidence regarding the specificity, profile and course of these deficits. PMID- 28735587 TI - Black soldier fly as dietary protein source for broiler quails: meat proximate composition, fatty acid and amino acid profile, oxidative status and sensory traits. AB - In the perspective of improving the sustainability of meat production, insects have been rapidly emerging as innovative feed ingredient for some livestock species, including poultry. However, at present, there is still limited knowledge regarding the quality and sensory traits of the derived meat. Therefore, the present study tested the effect of a partial substitution of soya bean meal and oil with defatted black soldier fly (Hermetia illucens) larvae meal (H) in the diet for growing broiler quails (Coturnix coturnix japonica) on meat proximate composition, cholesterol, amino acid and mineral contents, fatty acid profile, oxidative status and sensory characteristics. To this purpose, three dietary treatments were designed: a control diet (C) and two diets (H1 and H2) corresponding to 10% and 15% H inclusion levels, respectively, were fed to growing quails from 10 to 28 days of age. At 28 days of age, quails were slaughtered and breast meat was used for meat quality evaluations. Meat proximate composition, cholesterol content and oxidative status remained unaffected by H supplementation as well as its sensory characteristics and off-flavours perception. Differently, with increasing the dietary H inclusion, the total saturated fatty acid and total monounsaturated fatty acid proportions raised to the detriment of the polyunsaturated fatty acid fraction thus lowering the healthiness of the breast meat. The H2 diet increased the contents of aspartic acid, glutamic acid, alanine, serine, tyrosine and threonine thus further enhancing the biological value of the meat protein. As a direct result of the dietary content of Ca and P, the meat of quails fed with the highest H level, displayed the highest Ca and the lowest P values. Therefore, meat quality evaluations confirmed H to be a promising insect protein source for quails. The only potential drawback from feeding H to broiler quails regarded the fatty acid profile of the meat, therefore requiring further research efforts to understand to what extent the fatty acid profile of H can be improved. PMID- 28735588 TI - Mode of action of Saccharomyces cerevisiae in enteric methane mitigation in pigs. AB - The objectives of this study were to determine the effect and mode of action of Saccharomyces cerevisiae (YST2) on enteric methane (CH4) mitigation in pigs. A total of 12 Duroc*Landrace*Yorkshire male finisher pigs (60+/-1 kg), housed individually in open-circuit respiration chambers, were randomly assigned to two dietary groups: a basal diet (control); and a basal diet supplemented with 3 g/YST2 (1.8*1010 live cells/g) per kg diet. At the end of 32-day experiment, pigs were sacrificed and redox potential (Eh), pH, volatile fatty acid concentration, densities of methanogens and acetogens, and expression of methyl coenzyme-M reductase subunit A gene were determined in digesta contents from the cecum, colon and rectum. Results showed that S. cerevisiae YST2 decreased (P<0.05) the average daily enteric CH4 production by 25.3%, lowered the pH value from 6.99 to 6.69 in the rectum, and increased the Eh value in cecum and colon by up to -55 mV (P<0.05). Fermentation patterns were also altered by supplementation of YST2 as reflected by the lower acetate, and higher propionate molar proportion in the cecum and colon (P<0.05), resulting in lower acetate : propionate ratio (P<0.05). Moreover, there was a 61% decrease in Methanobrevibacter species in the upper colon (P<0.05) and a 19% increase in the acetogen community in the cecum (P<0.05) of treated pigs. Results of our study concluded that supplementation of S. cerevisiae YST2 at 3 g/kg substantially decreased enteric CH4 production in pigs. PMID- 28735589 TI - Growth, meat and feed efficiency traits of lambs born to ewes submitted to energy restriction during mid-gestation. AB - The objective of this study was to evaluate the effects of the energy restriction of gestation of adult ewes from day 45 to day 115 on lamb live performance parameters, carcass and meat traits. In experiment I, dietary energy was restricted at 70% of the metabolizable energy (ME) requirements, after which ewes were re-fed ad libitum until lambing. In experiment II, dietary energy was restricted at 60% of the ME requirements, and ewes were re-fed to ME requirements until lambing. All ewes grazed together from the end of the restriction periods to weaning. Lambs were weaned and lot fed until slaughter. Feed intake, weight gain and feed efficiency were recorded, and body fat thickness and ribeye area (REA) were measured in the longissimus thoracis muscle. After slaughter, carcass weight and yield, fat depth, carcass and leg length, and frenched rack and leg weights and yields were determined. Muscle fiber type composition, Warner Bratzler shear force, pH and color were determined in the longissimus lumborum muscle. In experiment I, energy restriction followed by ad libitum feeding affected lamb birth weight (P0.05) were observed on later BW, REA, BF or carcass traits. Lambs born to non-restricted-fed ewes had higher (P<0.05) weight and yield of the frenched rack cut and their meat tended (P=0.11) to be tender compared with that of lambs from restricted ewes. The percentage of oxidative muscle fibers was lower for lambs born to non-restricted ewes (P<0.05); however, no effects of ewe treatment were observed on other muscle fiber types. For experiment II, energy restriction followed by ME requirements feeding, affected (P<0.01) pre-weaning live weight gain, weaning and final weights. Lambs from restricted ewes had higher (P<0.05) feed intake as % of leg weight and a trend to be less efficient (P=0.16) than lambs from unrestricted dams. Ribeye area and BF were not influenced by treatment. Treatment significantly affected slaughter weight, but had no effects on carcass yield and traits or on meat traits. The results obtained in both experiments indicate submitting ewes to energy restriction during gestation affects the performance of their progeny but the final outcome would depend on the ewe's re-feeding level during late gestation and the capacity of the offspring to compensate the in utero restriction after birth. PMID- 28735590 TI - Effects of psychological eating behaviour domains on the association between socio-economic status and BMI. AB - OBJECTIVE: The current study investigates potential pathways from socio-economic status (SES) to BMI in the adult population, considering psychological domains of eating behaviour (restrained eating, uncontrolled eating, emotional eating) as potential mediators stratified for sex. DESIGN: Data were derived from the population-based cross-sectional LIFE-Adult-Study. Parallel-mediation models were conducted to obtain the total, direct and indirect effects of psychological eating behaviour domains on the association between SES and BMI for men and for women. SETTING: Leipzig, Germany. SUBJECTS: We studied 5935 participants aged 18 to 79 years. RESULTS: Uncontrolled eating mediated the association between SES and BMI in men only and restrained eating in both men and women. Emotional eating did not act as mediator in this relationship. The total effect of eating behaviour domains on the association between SES and BMI was estimated as beta= 0.03 (se 0.02; 95 % CI -0.062, -0.003) in men and beta=-0.18 (se 0.02; 95 % CI 0.217, -0.138) in women. CONCLUSIONS: Our findings do not indicate a strong overall mediation effect of the eating behaviour domains restrained eating, uncontrolled eating and emotional eating on the association between SES and BMI. Further research on other pathways of this association is strongly recommended. Importantly, our findings indicate that, independent from one's social position, focusing on psychological aspects in weight reduction might be a promising approach. PMID- 28735591 TI - "We expect seniors to be able to prepare and recover from a cyclone as well as younger members of this community": Emergency Management's Expectations of Older Adults Residing in Aging, Remote Hamlets on Australia's Cyclone-Prone Coastline. AB - OBJECTIVE: To investigate the extent to which older residents feel they can remain "self-reliant" during future natural disasters and to compare the findings with the viewpoints of local policy-makers and with those charged with caring for the elderly both on a day-to-day basis and in times of crisis. METHODS: This study used an array of non-probability snowballing techniques to seek the participation of senior citizens over the age of 65 years, emergency services officers, community health carers, and local government disaster managers located in aging, remote, coastal Australian communities vulnerable to cyclones and storm surges. All respondents participated in either a face-to-face personal interview or a focus group, with senior citizens also completing a self-administered questionnaire. RESULTS: This research found a discrepancy between policy expectations and the experiences of both the elderly and those who care for them, as well as a lack of understanding with regard to the term "self-reliant." CONCLUSIONS: These results highlight the inability of older adults in aging, remote, coastal Australian communities to remain "self-reliant" in the future, impacting both disaster management policies and the future capacity of these communities to remain resilient. (Disaster Med Public Health Preparedness. 2018;12:14-18). PMID- 28735592 TI - The prevalence and service utilisation associated with mental and substance use disorders in Lao People's Democratic Republic: findings from a cross-sectional survey. AB - AIMS: An epidemiological survey was conducted to determine the prevalence of the mental and substance use disorders and ascertain patterns of mental health services utilisation in Lao People's Democratic Republic (Lao PDR) with the aim of evaluating existing gaps and opportunities in the provision of mental health services. METHODS: This study was a cross-sectional, household survey of adults living within Vientiane Capital province, Lao PDR. We collected data on participant demographics, mental and physical health status, family history of mental illness and exposure to potential risk factors. It also collected data on mental health service utilisation patterns, types of health professionals and treatment being accessed, barriers to treatment and perceived need for care. The MINI International Neuropsychiatric Interview (MINI v.6.0) was also administered to assess mental disorder prevalence. RESULTS: Age- and sex-standardised current prevalence of any disorder was estimated at 15.2% (95% CI 11.0-20.7). Alcohol dependence (5.5% (95% CI 3.2-9.6)), was the most prevalent followed by anxiety disorders (5.2% (95% CI 3.2-8.3)) and mood disorders (2.5% (95% CI 1.5-4.4)). 11.0% (95% CI 5.8-20.1) of participants with a mental and/or substance use disorder suffered from other comorbid disorders. A number of variables demonstrated significant effects in final logistic regression models, including family history, education and employment for mental disorders; and gender, numbers of hours worked per week and number of dependants for substance use disorders. Having a mental or substance use disorder was associated with an OR of 11.6 of suicidality over participants without a mental or substance use disorder (95% CI 2.8-58.5). Of the 101 participants who met criteria for a current mental or substance use disorder, only two (2.1% (95% CI 0.5-8.0)) had accessed services for their mental health in the past 12 months. No participants who had seen a health professional in the past 12 months reported getting as much help as they needed. The vast majority (89.2% (95% CI 76.5-95.4)) of participants meeting criteria for a current mental or substance use disorder reported that they had not experienced mental health problems in the past 12 months. CONCLUSIONS: This study presents the first epidemiological estimates for a range of mental and substance use disorders in the general population of the most populous province in Lao PDR. A large treatment gap exists for mental and substance use disorders in Lao PDR. This research adds value for health care and has been an important precursor to developing informed and targeted mental health policy, services and health system reform in Lao PDR. PMID- 28735593 TI - Virtual reality in the assessment and treatment of psychosis: a systematic review of its utility, acceptability and effectiveness. AB - Over the last two decades, there has been a rapid increase of studies testing the efficacy and acceptability of virtual reality in the assessment and treatment of mental health problems. This systematic review was carried out to investigate the use of virtual reality in the assessment and the treatment of psychosis. Web of Science, PsychInfo, EMBASE, Scopus, ProQuest and PubMed databases were searched, resulting in the identification of 638 articles potentially eligible for inclusion; of these, 50 studies were included in the review. The main fields of research in virtual reality and psychosis are: safety and acceptability of the technology; neurocognitive evaluation; functional capacity and performance evaluation; assessment of paranoid ideation and auditory hallucinations; and interventions. The studies reviewed indicate that virtual reality offers a valuable method of assessing the presence of symptoms in ecologically valid environments, with the potential to facilitate learning new emotional and behavioural responses. Virtual reality is a promising method to be used in the assessment of neurocognitive deficits and the study of relevant clinical symptoms. Furthermore, preliminary findings suggest that it can be applied to the delivery of cognitive rehabilitation, social skills training interventions and virtual reality-assisted therapies for psychosis. The potential benefits for enhancing treatment are highlighted. Recommendations for future research include demonstrating generalisability to real-life settings, examining potential negative effects, larger sample sizes and long-term follow-up studies. The present review has been registered in the PROSPERO register: CDR 4201507776. PMID- 28735594 TI - Facilitating Partnerships With Community- and Faith-Based Organizations for Disaster Preparedness and Response: Results of a National Survey of Public Health Departments. AB - OBJECTIVE: We identify characteristics of local health departments, which enhance collaborations with community- and faith-based organizations (CFBOs) for emergency preparedness and response. METHODS: Online survey data were collected from a sample of 273 disaster preparedness coordinators working at local health departments across the United States between August and December 2011. RESULTS: Using multiple linear regression models, we found that perceptions of CFBO trust were associated with more successful partnership planning (beta=0.63; P=0.02) and capacity building (beta=0.61; P=0.01). Employee layoffs in the past 3 years (beta=0.41; P=0.001) and urban location (beta=0.41; P=0.005) were positively associated with higher ratings of resource sharing between health agencies and CFBOs. Having 1-3 full-time employees increased the ratings of success in communication and outreach activities compared with health departments having less than 1 full-time employee (beta=0.33; P=0.05). Positive attitudes toward CFBOs also enhanced communication and outreach (beta=0.16; P=0.03). CONCLUSIONS: Staff-capacity factors are important for quick dissemination of information and resources needed to address emerging threats. Building the trust of CFBOs can help address large-scale disasters by improving the success of more involved activities that integrate the CFBO into emergency plans and operations of the health department and that better align with federal-funding performance measures. (Disaster Med Public Health Preparedness. 2018;12:57-66). PMID- 28735595 TI - Response to "Review of the Incidence of Traumatic Brain Injury". PMID- 28735596 TI - Cue reactivity towards bodies in anorexia nervosa - common and differential effects in adolescents and adults. AB - BACKGROUND: Aberrant reward mechanisms with regard to slim body shapes are discussed in patients with anorexia nervosa (AN). The aim of the present study was to examine of cue reactivity toward body shapes in AN via the late positive potential (LPP), an event-related electroencephalography (EEG) component. By including adolescents and adults, aspects of development and chronification could be studied (2 * 2 design). METHODS: Thirty-two female AN patients (19 adolescents and 13 adults) and 37 control participants (16 adolescents and 21 adults) were included. Standardized photographic stimuli showing women's bodies in underwear from five body mass index (BMI) categories (extremely underweight to extremely overweight) were presented. During picture evaluation, EEG activity was recorded (10-20 system). The LPP was measured in two time windows characterized by different topographies (450-700 ms: posterior; 1000-1300 ms: central). RESULTS: Regarding the posterior component, LPP amplitudes were clearly reduced in adult but not in adolescent patients; for both time windows the LPP showed differential patterns over BMI categories for patients and controls. Regarding the central component, a highly significant linear decrease from extremely underweight to extremely overweight body shapes was revealed in patients and no significant modulation in control participants. CONCLUSIONS: Adolescent and adult patients show increased sustained attention toward extremely underweight bodies. In chronically ill patients, this bias appears to be accompanied by generally reduced automatic attention. The LPP findings provide a differentiated picture of aberrant cue reactivity which could be interpreted as motivated attention toward body shapes in AN. PMID- 28735597 TI - Correlates and family aggregation of vitamin D concentrations in school-aged children and their parents in nine Mesoamerican countries. AB - OBJECTIVE: To determine the associations of sociodemographic characteristics, diet and outdoor activity as an indicator of sun exposure with serum 25 hydroxyvitamin D (25(OH)D) concentrations in children and their parents from Mesoamerica. We also quantified family aggregation of serum 25(OH)D. DESIGN: Cross-sectional study. Serum 25(OH)D concentrations were quantified using immunoassay. We compared the distribution of 25(OH)D concentrations in adults and children by levels of each correlate with the use of linear regression. Family aggregation was estimated using Pearson and intraclass correlation coefficients. SETTING: Capital cities of Guatemala, El Salvador, the Dominican Republic, Honduras, Nicaragua, Costa Rica, Panama and Belize, and Tuxtla Gutierrez in Mexico. SUBJECTS: Children (n 223) aged 7-12 years and 492 parents. RESULTS: Mean (sd) 25(OH)D concentrations in adults and children were 81.3 (21.1) and 79.5 (18.1) nmol/l, respectively. Prevalence of vitamin D deficiency (VDD; 25(OH)D <50 nmol/l) was 3.9 % among adults and 3.6 % among children. In adults, adjusted mean 25(OH)D concentrations were highest in Nicaragua (P<0.0001). Serum 25(OH)D was positively related to time spent gardening (P=0.03). Among children, 25(OH)D concentrations were positively associated with male sex (P=0.005), dairy intake (P=0.03) and mother's serum 25(OH)D concentrations (P<0.0001); and inversely associated with mother's BMI (P=0.02) and number of home assets (P=0.04). Family membership explained 31 % of the variability in 25(OH)D concentrations; aggregation was highest between mothers and children. CONCLUSIONS: VDD prevalence was low in this study. Sociodemographic characteristics, diet and outdoor activity predict serum 25(OH)D. Family aggregation of serum 25(OH)D is high between mothers and children. PMID- 28735598 TI - Developing and validating a nutrition knowledge questionnaire: key methods and considerations. AB - OBJECTIVE: To outline key statistical considerations and detailed methodologies for the development and evaluation of a valid and reliable nutrition knowledge questionnaire. DESIGN: Literature on questionnaire development in a range of fields was reviewed and a set of evidence-based guidelines specific to the creation of a nutrition knowledge questionnaire have been developed. The recommendations describe key qualitative methods and statistical considerations, and include relevant examples from previous papers and existing nutrition knowledge questionnaires. Where details have been omitted for the sake of brevity, the reader has been directed to suitable references. RESULTS: We recommend an eight-step methodology for nutrition knowledge questionnaire development as follows: (i) definition of the construct and development of a test plan; (ii) generation of the item pool; (iii) choice of the scoring system and response format; (iv) assessment of content validity; (v) assessment of face validity; (vi) purification of the scale using item analysis, including item characteristics, difficulty and discrimination; (vii) evaluation of the scale including its factor structure and internal reliability, or Rasch analysis, including assessment of dimensionality and internal reliability; and (viii) gathering of data to re-examine the questionnaire's properties, assess temporal stability and confirm construct validity. Several of these methods have previously been overlooked. CONCLUSIONS: The measurement of nutrition knowledge is an important consideration for individuals working in the nutrition field. Improved methods in the development of nutrition knowledge questionnaires, such as the use of factor analysis or Rasch analysis, will enable more confidence in reported measures of nutrition knowledge. PMID- 28735599 TI - Effectiveness of the MetSLIM lifestyle intervention targeting individuals of low socio-economic status and different ethnic origins with elevated waist-to-height ratio. AB - OBJECTIVE: To evaluate whether the lifestyle intervention MetSLIM targeting individuals of low socio-economic status of Turkish, Moroccan and Dutch origin was successful in improving waist circumference and other cardiometabolic risk factors, lifestyle behaviour and quality of life. DESIGN: A quasi-experimental intervention study (Netherlands Trial Register NTR3721). The intervention group participated in a 12-month combined dietary and physical activity programme. Examinations were performed at baseline and after 12 months. Participants underwent anthropometric measurements and blood withdrawal, and completed questionnaires on dietary intake, physical activity and quality of life. SETTING: Socio-economically deprived neighbourhoods in two Dutch cities, involving non blinded ethnicity-matched and gender-matched research assistants, dietitians and sports instructors. SUBJECTS: Mainly Turkish (49 %) and Dutch (36 %) subjects, aged 30-70 years, with a waist-to-height ratio of >0.5 (intervention, n 117; control, n 103). Dropout was 31 %. RESULTS: At 12 months, the intervention group showed greater improvements than the control group in waist circumference (beta= 3.3 cm, 95 % CI -4.7, -1.8, P<0.001) and other obesity measures. Additionally, greater reductions were observed for total cholesterol (beta=-0.33 mmol/l, 95 % CI -0.56, -0.10, P=0.005) and LDL cholesterol (beta=-0.35 mmol/l, 95 % CI -0.56, 0.14, P=0.001). Dietary changes were significant for fibre intake (beta=1.5 g/4184 kJ (1000 kcal), 95 % CI 0.3, 2.7, P=0.016). Compared with the control group, the intervention group reported a decrease in total minutes of physical activity (beta=-573 min/week, 95 % CI -1126, -21, P=0.042) and showed improvements in the quality-of-life domains 'health transition' and 'general health'. CONCLUSIONS: MetSLIM was shown to be effective in improving waist circumference, total and LDL cholesterol, and quality of life among Dutch and Turkish individuals living in deprived neighbourhoods. PMID- 28735600 TI - Evidence for increasing digestive and metabolic efficiency of energy utilization with age of dairy cattle as determined in two feeding regimes. AB - The changes taking place with age in energy turnover of dairy cattle are largely unknown. It is unclear whether the efficiency of energy utilization in digestion (characterized by faecal and methane energy losses) and in metabolism (characterized by urine and heat energy losses) is altered with age. In the present study, energy balance data were obtained from 30 lactating Brown Swiss dairy cows aged between 2 and 10 years, and 12 heifers from 0.5 to 2 years of age. In order to evaluate a possible dependence of age effects on diet type, half of the cattle each originated from two herds kept at the same farm, which were fed either on a forage-only diet or on the same forage diet but complemented with 5 kg/day of concentrate since their first calving. During 2 days, the gaseous exchange of the animals was quantified in open-circuit respiration chambers, followed by an 8-day period of feed, faeces, urine and milk collection. Daily amounts and energy contents were used to calculate complete energy balances. Age and feeding regime effects were analysed by parametric regression analysis where BW, milk yield and hay proportion in forage as consumed were considered as covariates. Relative to intake of gross energy, the availability of metabolizable energy (ME) increased with age. This was not the result of an increasing energy digestibility, but of proportionately lower energy losses with methane (following a curvilinear relationship with the greatest losses in middle-aged cows) and urine (continuously declining). The efficiency of utilization of ME for milk production (k l) increased with age. Potential reasons include an increase in the propionate-to-acetate ratio in the rumen because of a shift away from fibre degradation and methane formation as well as lower urine energy losses. The greater k l allowed older cows to accrete more energy reserves in the body. As expected, offering concentrate enhanced digestibility, metabolizability and metabolic utilization of energy. Age and feeding regime did not interact significantly. In conclusion, older cows seem to have digestive and metabolic strategies to use dietary energy to a certain degree more efficiently than younger cows. PMID- 28735602 TI - Skill sharing and delegation practice in two Queensland regional allied health cancer care services: a comparison of tasks. AB - Objective Delegation and skill sharing are emerging service strategies for allied health (AH) professionals working in Queensland regional cancer care services. The aim of the present study was to describe the consistency between two services for the types and frequency of tasks provided and the agreement between teams in the decision to delegate or skill share clinical tasks, thereby determining the potential applicability to other services.Methods Datasets provided by two similar services were collated. Descriptive statistical analyses were used to assess the extent of agreement.Results In all, 214 tasks were identified as being undertaken by the services (92% agreement). Across the services, 70 tasks were identified as high frequency (equal to or more frequently than weekly) and 29 as not high frequency (46% agreement). Of the 68 tasks that were risk assessed, agreement was 66% for delegation and 60% for skill sharing, with high-frequency and intervention tasks more likely to be delegated.Conclusions Strong consistency was apparent for the clinical tasks undertaken by the two cancer care AH teams, with moderate agreement for the frequency of tasks performed. The proportion of tasks considered appropriate for skill sharing and/or delegation was similar, although variation at the task level was apparent. Further research is warranted to examine the range of factors that affect the decision to skill share or delegate.What is known about the topic? There is limited research evidence regarding the use of skill sharing and delegation service models for AH in cancer care services. In particular, the extent to which decisions about task safety and appropriateness for delegation or skill sharing can be generalised across services has not been investigated.What does this paper add? This study investigated the level of clinical task consistency between two similar AH cancer care teams in regional centres. It also examined the level of agreement with regard to delegation and skill sharing to provide an indication of the level of local service influence on workforce and service model decisions.What are the implications for practitioners? Local factors have a modest influence on delegation and skill sharing decisions of AH teams. Practitioners need to be actively engaged in decision making at the local level to ensure the clinical service model meets local needs. However, teams should also capitalise on commonalities between settings to limit duplication of training and resource development through collaborative networks. PMID- 28735601 TI - Impact of equine assisted reproductive technologies (standard embryo transfer or intracytoplasmic sperm injection (ICSI) with in vitro culture and embryo transfer) on placenta and foal morphometry and placental gene expression. AB - Assisted reproductive technologies (ARTs) such as intracytoplasmic sperm injection (ICSI), in vitro embryo culture and embryo transfer (ET) may be associated with alterations in fetal and placental development. In horses, ET has been used for decades. More recently, in vitro embryo production by ICSI and in vitro culture, followed by embryo transfer (ICSI-C) has become an accepted method for clinical foal production. However, no information is available on the effects of ICSI-C or even of standard ET itself on placental and neonatal parameters in horses. We therefore evaluated placental and neonatal morphology and placental gene expression in reining- and cutting-type American Quarter Horse foals produced using different technologies. Thirty foals and placentas (naturally conceived (NC), ET and ICSI-C; 10 in each group) were examined morphometrically. The only parameter that differed significantly between groups was the length of the foal upper hindlimb, which was longer in ET and ICSI-C than in NC foals. Evaluation of placental mRNA expression for 17 genes related to growth and vascularisation showed no difference in gene expression between groups. These data indicate that within this population, use of ARTs was not associated with meaningful changes in foal or placental morphometry or in expression of the placental genes evaluated. PMID- 28735603 TI - The utility of single-item readiness screeners in middle school. AB - This study examined the benefit of utilizing one-item academic and one-item behavior readiness teacher-rated screeners at the beginning of the school year to predict end-of-school year outcomes for middle school students. The Middle School Academic and Behavior Readiness (M-ABR) screeners were developed to provide an efficient and effective way to assess readiness in students. Participants included 889 students in 62 middle school classrooms in an urban Missouri school district. Concurrent validity with the M-ABR items and other indicators of readiness in the fall were evaluated using Pearson product-moment correlation coefficients, with the academic readiness item having medium to strong correlations with other baseline academic indicators (r=+/-0.56 to 0.91) and the behavior readiness item having low to strong correlations with baseline behavior items (r=+/-0.20 to 0.79). Next, the predictive validity of the M-ABR items was analyzed with hierarchical linear regressions using end-of-year outcomes as the dependent variable. The academic and behavior readiness items demonstrated adequate validity for all outcomes with moderate effects (beta=+/-0.31 to 0.73 for academic outcomes and beta=+/-0.24 to 0.59 for behavioral outcomes) after controlling for baseline demographics. Even after controlling for baseline scores, the M-ABR items predicted unique variance in almost all outcome variables. Four conditional probability indices were calculated to obtain an optimal cut score, to determine ready vs. not ready, for both single-item M-ABR scales. The cut point of "fair" yielded the most acceptable values for the indices. The odd ratios (OR) of experiencing negative outcomes given a "fair" or lower readiness rating (2 or below on the M-ABR screeners) at the beginning of the year were significant and strong for all outcomes (OR=2.29 to OR=14.46), except for internalizing problems. These findings suggest promise for using single readiness items to screen for varying negative end-of-year student outcomes. PMID- 28735605 TI - The role of teacher behavior in children's relational aggression development: A five-wave longitudinal study. AB - The present article examined the development of relational aggression in middle childhood and the effects of observed teacher behavior on this development. Relying on social learning theory, we expected that teacher praise would slow down the increase of relational aggression, whereas teacher reprimands would promote the increase of relational aggression. A sample of 570 children (49% boys, Mage=7years and 5months, >95% Belgian) was followed from second to fourth grade. Teacher praise and reprimands were observed at the beginning of second grade. Child relational aggression was assessed using teacher and peer reports, collected at five points in time: at the beginning and end of the second grade, at the beginning and end of the third grade, and at the end of the fourth grade. Multilevel modeling showed that relational aggression generally increased from second to fourth grade. Moreover, when teachers displayed more praise, students' relational aggression increased at a slower rate; when teachers displayed more reprimands, students' relational aggression increased at a faster rate. Overall, the results stress the importance of supporting teachers to reduce reprimands and increase praise when interacting with children. PMID- 28735604 TI - Measuring home environments across cultures: Invariance of the HOME scale across eight international sites from the MAL-ED study. AB - The home environment provides the context for much of a child's early development. Examples of important aspects of the home environment include safety, cleanliness, and opportunities for cognitive stimulation. This study sought to examine the psychometric properties of an adapted form of the Home Observation for the Measurement of the Environment (HOME; Caldwell & Bradley, 1984, 2003) across the eight international sites of the MAL-ED project (Dhaka, Bangladesh; Vellore, India; Bhakatapur, Nepal; Naushahro Feroze, Pakistan; Fortaleza, Brazil; Loreto, Peru; Venda, South Africa; Haydom, Tanzania), to identify a factor structure that fit the data at all sites, and to derive a subset of items that could be used to examine home environmental characteristics across sites. A three-factor structure (i.e., Emotional and Verbal Responsivity; Clean and Safe Environment; Child Cleanliness) was identified, and partial measurement equivalence/invariance across sites was supported. Overall, these findings lend support for the use of portions of this abbreviated and adapted version of the HOME for use among heterogeneous, cross-cultural groups in low- and middle-income nations. PMID- 28735606 TI - Effects of the Self-Regulation Empowerment Program (SREP) on middle school students' strategic skills, self-efficacy, and mathematics achievement. AB - The current study examined the effectiveness of an applied self-regulated learning intervention (Self-Regulation Empowerment Program (SREP)) relative to an existing, school-based remedial mathematics intervention for improving the motivation, strategic skills, and mathematics achievement of academically at-risk middle school students. Although significant group differences in student self regulated learning (SRL) were not observed when using self-report questionnaires, medium to large and statistically significant group differences were observed across several contextualized, situation-specific measures of strategic and regulatory thinking. The SREP group also exhibited a statistically significant and more positive trend in achievement scores over two years in middle school relative to the comparison condition. Finally, SREP students and coaches reported SREP to be a socially-valid intervention, in terms of acceptability and importance. The importance of this study and critical areas for future research are highlighted and discussed. PMID- 28735607 TI - Similarities and dissimilarities between teachers' and students' relationship views in upper elementary school: The role of personal teacher and student attributes. AB - The present study aimed to advance insight into similarities and dissimilarities between teachers' and students' views of closeness and conflict in their dyadic relationship, and personal teacher and student attributes that contribute to these views. In total, 464 students (50.2% girls) and 62 teachers (67.5% females) from grades 4 to 6 participated in this study. Teachers filled out questionnaires about their background characteristics, self-efficacy (TSES), and student-teacher relationship perceptions (STRS) and students answered questions about their demographics and the student-teacher relationship quality (SPARTS). Peer nominations were used to measure students' internalizing and externalizing behavior. Tests for measurement invariance suggested that the conflict and closeness constructs both approximated similarity across students and teachers. Multilevel structural equation models furthermore indicated that students' relationship perceptions, and conflict in particular, were predicted by their own gender, socioeconomic status, and internalizing and externalizing behavior. Additionally, teaching experience negatively predicted students' perceived conflicts. Teachers' relationship perceptions were both predicted by their own characteristics (teaching experience) and student features (gender, socioeconomic status, and externalizing behavior). These predictors explained between 39% and 61% of the variance in student- and teacher-perceived closeness and conflict. Last, teachers' general self-efficacy was positively associated with mean levels of closeness, and negatively associated with mean levels of conflict across student-teacher dyads. PMID- 28735608 TI - School engagement trajectories in adolescence: The role of peer likeability and popularity. AB - This accelerated longitudinal study examined how peer status (i.e., peer likeability and popularity) is involved in adolescents' school engagement trajectories. A large sample of students was followed from Grades 7 to 11 (N=1116; Mage=13.79years). Students' school engagement and peer status were assessed using self-reports and peer nominations, respectively. Latent growth curve modeling revealed that different engagement dimensions were differentially associated with peer status. Likeability was positively related to both behavioral and emotional engagement in Grade 7, but not to behavioral and emotional disaffection. In contrast, popularity was related to less behavioral engagement and more behavioral disaffection at the start of secondary education, but not to emotional engagement and disaffection. Moreover, students' aggressive behavior moderated the relation between popularity and behavioral engagement in Grade 7, denoting the risk of popularity in combination with average and high levels of aggression. Results suggest that adolescents' popularity may interfere with meeting academic demands in general and with showing engagement in particular. PMID- 28735609 TI - Can teacher-child relationships alter the effects of early socioeconomic status on achievement in middle childhood? AB - Using data from the NICHD SECCYD (N=1053), we used two-level hierarchical linear models with site fixed effects to examine whether teacher-child closeness and conflict moderated associations between two indicators of early socioeconomic status (maternal education and family income) and standardized measures of children's math and reading achievement at 54months, 1st, 3rd, and 5th grades. Children whose mothers had lower levels of education and conflictual relationships with teachers exhibited lower reading achievement, on average, across elementary school. At the same time, children with less educated mothers who experienced increases in teacher-child closeness and decreases in teacher child conflict exhibited improvements in reading achievement across elementary school. Finally, low teacher-child closeness elevated the risk for poor math achievement posed by low family income. Implications for intervention design and development are discussed. PMID- 28735610 TI - Social, emotional, and behavioral screening: A comparison of two measures and two methods across informants. AB - The current study is a correlational design comparing a multiple-gate social, emotional, and behavioral (SEB) screening system with a single-gate SEB screening system using a common criterion variable. Teachers and parents of 105 preschool students completed the multiple-gate Preschool Behavior Screening System (PBSS; Feeney-Kettler, Kratochwill, & Kettler, 2009) and the single-gate Behavioral and Emotional Screening System (BESS; Kamphaus & Reynolds, 2007). The measures were evaluated using Cronbach's alpha, Pearson correlations with each other, and conditional probability indices to represent accuracy in predicting scores from the Achenbach System for Empirically Based Assessment (ASEBA; Achenbach & Rescorla, 2000). Results indicated the PBSS was internally consistent (alpha=0.87 to 0.97), teacher-parent agreement for both measures was in the expected range (r=0.05 to 0.40), and relations among scores from the measures were at the expected magnitudes and in the expected directions. Although both measures accurately predicted ASEBA results, the BESS was a better predictor for both groups of raters (i.e., teachers and parents) in most situations. The PBSS provided the advantage of also being a good predictor while providing internally consistent subscale scores that may be useful for intervention planning. The results are discussed including their implications for school psychologists seeking to select technically sound instruments that yield reliable scores from which valid inferences about SEB factors can be drawn. PMID- 28735611 TI - The SID Is 80 Years Old ....and Just Getting Started. PMID- 28735612 TI - Cutaneous Glucocorticoidogenesis and Cortisol Signaling Are Defective in Psoriasis. AB - Hannen et al. report that cutaneous glucocorticoidogenesis and expression of glucocorticoid receptors are inhibited in psoriatic skin. These findings substantiate the previous concept that deficient feedback of local proopiomelanocortin and glucocorticoids on cutaneous immunity contributes to inflammatory and autoimmune dermatoses. Restoration of efficient endogenous glucocorticoid signaling represents a realistic goal in treating psoriasis. PMID- 28735613 TI - Does Treatment of Psoriasis Reduce Cardiovascular Comorbidities? AB - Psoriasis has been associated with an increase in myocardial infarctions. Several registries have shown reductions in major adverse cardiovascular events in psoriasis patients and rheumatoid arthritis patients treated with tumor necrosis factor-alpha antagonists. Many assume that the reduction in cardiovascular events can be attributed to the anti-inflammatory effect of tumor necrosis factor blockers, but a 52-week study conducted by Bissonnette and coworkers failed to show a reduction in cardiovascular inflammation in psoriasis patients treated with adalimumab. Longer and larger studies are needed to explain why tumor necrosis factor-alpha blockade appears to reduce cardiovascular events in patients with severe psoriasis. PMID- 28735614 TI - Smokers versus Smoking: Is There Detection Bias for Keratinocyte Carcinomas? AB - Dusingize et al. used a prospective observational cohort study to demonstrate a decreased risk of basal cell carcinoma and an increased risk of squamous cell carcinoma among smokers. This association disappeared after stratifying for skin screening visits, demonstrating the important role of detection bias. In the absence of randomized clinical trials, well-designed and critically analyzed observational studies can provide similarly valuable evidence. PMID- 28735615 TI - New Mechanisms of ECM Production during Wound Healing: A Role for Parathyroid Hormone 2 Receptor Signaling. AB - Extracellular matrix deposition is required for wound healing. Studies by Sato et al. reveal a role for parathyroid hormone 2 receptor (PTH2R) in extracellular matrix production in wounds. Deficiencies in PTH2R or its ligand tuberoinfundibular peptide of 39 residues (TIP39) delayed repair, and TIP39 treatment accelerated healing. TIP39-PTH2R signaling induced decorin expression, which may explain the beneficial effects of PTH2R signaling on healing. These studies identify a novel role for PTH2R signaling in extracellular matrix production. PMID- 28735616 TI - Research Techniques Made Simple: An Introduction to Use and Analysis of Big Data in Dermatology. AB - Big data is a term used for any collection of datasets whose size and complexity exceeds the capabilities of traditional data processing applications. Big data repositories, including those for molecular, clinical, and epidemiology data, offer unprecedented research opportunities to help guide scientific advancement. Advantages of big data can include ease and low cost of collection, ability to approach prospectively and retrospectively, utility for hypothesis generation in addition to hypothesis testing, and the promise of precision medicine. Limitations include cost and difficulty of storing and processing data; need for advanced techniques for formatting and analysis; and concerns about accuracy, reliability, and security. We discuss sources of big data and tools for its analysis to help inform the treatment and management of dermatologic diseases. PMID- 28735617 TI - SnapshotDx Quiz: August 2017. PMID- 28735618 TI - Cells to Surgery Quiz: August 2017. PMID- 28735619 TI - Proceedings of the Ninth World Congress for Hair Research (2015). PMID- 28735620 TI - Let's Make Academic Radiology Great Again. PMID- 28735621 TI - Getting to grips with context and complexity - the case for realist approaches. PMID- 28735622 TI - Modeling RNA Secondary Structure with Sequence Comparison and Experimental Mapping Data. AB - Secondary structure prediction is an important problem in RNA bioinformatics because knowledge of structure is critical to understanding the functions of RNA sequences. Significant improvements in prediction accuracy have recently been demonstrated though the incorporation of experimentally obtained structural information, for instance using selective 2'-hydroxyl acylation analyzed by primer extension (SHAPE) mapping. However, such mapping data is currently available only for a limited number of RNA sequences. In this article, we present a method for extending the benefit of experimental mapping data in secondary structure prediction to homologous sequences. Specifically, we propose a method for integrating experimental mapping data into a comparative sequence analysis algorithm for secondary structure prediction of multiple homologs, whereby the mapping data benefits not only the prediction for the specific sequence that was mapped but also other homologs. The proposed method is realized by modifying the TurboFold II algorithm for prediction of RNA secondary structures to utilize basepairing probabilities guided by SHAPE experimental data when such data are available. The SHAPE-mapping-guided basepairing probabilities are obtained using the RSample method. Results demonstrate that the SHAPE mapping data for a sequence improves structure prediction accuracy of other homologous sequences beyond the accuracy obtained by sequence comparison alone (TurboFold II). The updated version of TurboFold II is freely available as part of the RNAstructure software package. PMID- 28735623 TI - Genes involved in leukotriene synthesis pathway are dynamically regulated during lung development in Rhesus monkeys. AB - BACKGROUND: Leukotrienes play critical roles in many inflammatory lung diseases and several antagonists of their receptors have been used in the clinical settings. However, the physiological functions of leukotrienes in lung development are still unclear. METHOD: The expression levels of 34 genes involved in leukotriene synthesis and function pathway in the lungs of Rhesus monkey during different developmental time points were determined on a MiSeq platform and analyzed by the reads per kilobase of transcript per million mapped reads (RPKM) method. RESULTS: The results showed that the expression levels of PLA2G1B, PLA2G10, PLA2G2D, ALOX5, and ALOX5AP increased dramatically in the lung of Rhesus monkey, reflecting the changes in the pulmonary environment after delivery. Additionally, the different expression patterns between molecules related to LTB4 and LTC4 synthesis suggested distinct roles of LTB4 and LTC4 in lung development. Finally, the constant expression of CysLT1 during the development process provided new information to the pharmaceutical basis of the use of leukotriene receptor antagonists in the clinical setting. CONCLUSION: The expression levels of several key genes involved in leukotriene synthesis changed dramatically during lung development in Rhesus monkeys, suggesting the potential roles of leukotrienes in lung development in this animal model. PMID- 28735624 TI - The effect of prostaglandin E2 receptor (PTGER2) activation on growth factor expression and cell proliferation in bovine endometrial explants. AB - The domestic animal endometrium undergoes regular periods of regeneration and degeneration during cycles of oestrus and dioestrus. If blastocyst implantation occurs in the uterus, the endometrium will prepare for pregnancy by changing its pattern of development to build a connection with the embryo to nourish it. Prostaglandin E2 (PGE2) secretion synchronized with endometrial growth in these processes and could be involved in endometrial growth. One of the PGE2 receptors (PTGER2) is present in endometrium and its increased expression accompanies with endometrial growth in above processes. However, the association between PTGER2 and endometrial growth remains unclear. Endometrial growth factors and cell proliferation is the foundation for endometrial growth. Therefore, in this study, the response of growth factors and cell proliferation essential for endometrial growth to PTGER2 activation were investigated in bovine endometrium. The results indicated that mRNA and protein expression of connective tissue growth factor (CTGF), fibroblast growth factor-2 (FGF-2), interleukin-8 (IL-8), transforming growth factor-beta1 (TGF-beta1), matrix metalloproteinase-2 (MMP-2), and vascular endothelial growth factor A (VEGFA) were up-regulated after PTGER2 activation by corresponding agonist butaprost (P < 0.05), and proliferation of endometrial epithelia and fibroblasts were induced in response to increased levels of proliferating cell nuclear antigen (PCNA), cytokeratin-18 (CK-18) and fibroblast specific protein 1 (FSP-1) expression in bovine endometrial explants in vitro (P < 0.05). PMID- 28735625 TI - Free fatty acid receptor (FFAR) agonists inhibit proliferation of human ovarian cancer cells. AB - Many cellular actions of omega-3 fatty acids are mediated by two G protein coupled receptors, FFA1 and FFA4, free fatty acid receptor (FFAR) family members that are activated by these dietary constituents. FFAR agonists inhibit proliferation of human prostate and breast cancer cells. Since omega-3 fatty acids can inhibit ovarian cancer cell growth, the current study tested the potential role of FFARs in the response. OVCAR3 and SKOV3 human ovarian cancer cell lines express mRNA for FFA1; FFA4 mRNA was detected at low levels in SKOV3 but not OVCAR3. Lysophosphatidic acid (LPA) and epidermal growth factor (EGF) stimulated proliferation of both cell lines; these responses were inhibited by eicosopentaneoic acid (EPA) and by GW9508, a synthetic FFAR agonist. The LPA antagonist Ki16425 also inhibited LPA- and EGF-induced proliferation; FFAR agonists had no further effect when added with Ki16425. The results suggest that FFARs are potential targets for ovarian cancer therapy. PMID- 28735626 TI - Differentiation of hMSC and hPDLSC induced by PGE2 or BMP-7 in 3D models. AB - Regenerative therapies of pathogenic tissue defects are gaining increasing importance in periodontology. Among others, the osteogenic effect of BMP-7 seems to play a major role in the development of teeth and alveolar bone. Human periodontal ligament stem cells (hPDLSC), as well as human mesenchymal stem cells (hMSC), show the ability to differentiate into various types of tissues. Regarding prostaglandin E2, many studies have confirmed that it is involved in the inflammation associated to periodontitis stimulating osteoclasts, which ultimately leads to resorption of tooth supporting bone. Herein, we aimed to investigate how PGE2 influences regenerative processes. The influence of PGE2 and BMP-7 on the osteogenic differentiation of hMSC and hPDLSC was determined in a 3D cell culture model using qRT-PCR, immunocytochemistry and REM. BMP-7 enhanced the expression of osteogenic markers in hMSC and lowered it in hPDLSC-TERT. BMP-7 had a lower osteogenic effect on hPDLSC-hTERT than on hMSC, while PGE2 decreases the osteogenic differentiation in both cell types, thus, inhibiting anabolic processes. Both cell types presented good proliferation and adhesion onto the scaffolds. The well-developed structural morphology and the support of osteogenic differentiation suggest that the scaffolds are potential candidate materials for bone regeneration. The positivity for Cap in hPDLSC and more in hMSC immunostaining samples indicates the initiation of neocementogenesis as part of periodontal regeneration. In conclusion, BMP7, in particular combined with MSC, seems to have a favourable application also in periodontal regeneration. Our results show that inflammation plays an important role in periodontal regeneration. PGE2 is a key mediator, which stimulates bone resorption also via a mechanism involving the inhibition of osteogenic differentiation of MSC as well as PDLSC. Therefore, regenerative approaches should always be conducted in combination with anti-inflammatory measures oriented to control inflammation. PMID- 28735627 TI - Inhibition of indoleamine 2,3-dioxygenase activity by fatty acids and prostaglandins: A structure function analysis. AB - Indoleamine 2,3-dioxygenase-1 (IDO-1) catalyses the first and rate-limiting step in the metabolism of L-tryptophan. Degradation of L-Trp leads to the production of several immunosuppressive metabolites, including N-formyl kynurenine and kynurenine (Kyn). Apart from a normal physiological role, IDO-1 has also been identified to play a crucial role in immune suppression and tumour induced tolerance. Indeed, many primary tumours express high levels of IDO-1 compared to normal cells of the same stroma. IDO-1 is accepted as being an inducible negative regulator of T cell viability, proliferation and activation. As such, IDO-1 has become a target of intense interest for pharmacological inhibition, for the treatment of cancer. We have previously demonstrated that AA and the prostaglandin metabolite, PGD2, repressed the IFNgamma mediated activity of IDO-1 in THP-1 cells and human monocytes. In this study, we characterise the structure function relationship of fatty acids and eicosanoids towards inhibition of IDO-1 activity in THP-1 cells and human monocytes. Using a commercial library of fatty acids, 55% of fatty acids inhibited IDO-1 activity. The activity of individual FAs was affected by chain length, number of double bonds and bond configuration. Interrogation of an AA derived eicosanoid library identified 13 PGs with significant inhibitory activity. A structure-function analysis revealed that the gamma position of the cyclopentenone ring, double bond in the alpha-beta position of the cyclopentenone ring, the presence of multiple OH groups in the side arm and the addition of an ethanolamide group, significantly increased the inhibitory activity of the PGs. Based on this data we have identified the structure of two possible compounds that may be even more potent pharmacological repressors of IDO 1. PMID- 28735628 TI - Novel algorithm including CA-125, HE4 and body mass index in the diagnosis of endometrial cancer. AB - OBJECTIVES: To evaluate the diagnostic and prognostic potential of preoperative serum CA-125 and HE4 levels in patients with endometrial cancer. METHODS: Prospective case-control study of 133 women who underwent surgical treatment at the University Medical Centre Ljubljana (64 patients with endometrial cancer, 69 control patients with prolapsed uterus or myoma). Serum CA-125 and HE4 levels were determined using electrochemiluminescent assays. RESULTS: Serum CA-125 and HE4 levels were significantly higher in patients with endometrial cancer, compared to the controls (p=2.67*10-4, 1.36*10-7, respectively). A diagnostic model that combines serum CA-125 and HE4 levels and body mass index separated patients with endometrial cancer from controls, with AUC of 0.804, sensitivity of 66.7%, and specificity of 84.6%. Serum HE4 levels showed good prognostic potential and stratified the patients according to presence/absence of deep myometrial invasion (p=0.001) or lymphovascular invasion (p=0.003), with AUCs of 0.78 and 0.81, respectively. In low-risk patients with grade 1 and 2 endometrioid cancer for whom lymphadenectomy can be avoided, HE4 allowed stratification according to deep myometrial invasion (p=3.39*10-4), with AUC of 0.84. Although median HE4 levels were higher in patients with lymphovascular invasion, this difference did not reach significance (p=0.06). CONCLUSIONS: A model based on preoperative serum CA-125 and HE4 levels and body mass index has good diagnostic accuracy for separation of patients with endometrial cancer and control patients. In patients with endometrial cancer, serum HE4 levels allow prediction of deep myometrial and lymphovascular invasion. PMID- 28735630 TI - Mandibular Advancement Devices: Tailoring New Treatments for Sleep Apnea Syndrome. PMID- 28735629 TI - Dose dense carboplatin paclitaxel improves progression free survival in patients with endometrial cancer. AB - OBJECTIVE: Pilot study to assess the value of weekly paclitaxel plus carboplatin every 3weeks (dose dense regimen, DD) compared to the standard 3-weekly protocol in the adjuvant setting for endometrial cancer. METHODS: Retrospective cohort study comparing consecutive patients with high and intermediate-high risk endometrial cancer, undergoing DD protocol (from 2011 to 2015) to a non overlapping historical cohort with similar characteristics who received treatment every three weeks (2008-2011). RESULTS: 122 patients with endometrial cancer were included in the study, of these, 61 patients received the dose dense protocol and 61 were treated with the standard 3-weekly protocol. After a median follow-up of 61.6months in the 3-weekly cohort, compared with 41.6months in the DD cohort, 40 progressions were recorded. 29 progressions were observed in women treated in the standard protocol, with a three years progression free survival (PFS) of 57.4%, compared to 11 progressions observed in patients in the DD schedule, with a three years PFS of 79.5% (P=0.03). Patients who were treated with the DD protocol were less likely to have progression events compared to the standard cohort with a hazard ratio of 0.4 on multivariate analysis (CI 95%, 0.2-0.8, P=0.01), had significantly less distant metastases (P=0.01), and had improved overall survival when diagnosed with advanced stage disease (P=0.02). Complaints of musculoskeletal pain were more frequent in the standard cohort (n=17, 27.9%) compared to the dose dense cohort (n=4, 6.6%), P=0.005. CONCLUSION: Preliminary data suggests that dose dense chemotherapy might be a reasonable and superior option for adjuvant treatment of endometrial cancer, compared to standard chemotherapy. PMID- 28735631 TI - Re: Wrong tooth extraction: an examination of 'Never Event' data. PMID- 28735632 TI - Traction with bilateral reverse eyelets: a simple technique for management of sagittal palatal fractures. PMID- 28735633 TI - Intraosseous spindle cell lipoma of the mandible: case report. AB - We describe what is to our knowledge the first reported intraosseous spindle cell lipoma of the mandible. It is the first spindle cell lipoma we have seen that shows dental resorption, and the largest that we have seen published (60*30*20mm). PMID- 28735635 TI - Re: Endoscopically-assisted extracapsular dissection of pleomorphic adenoma of the parotid gland through a postauricular sulcus approach in young patients. PMID- 28735634 TI - Management of upper and lower molars that are displaced into the neighbouring spaces. AB - Our aim was to describe our experience of retrieval of accidental displacements of upper and lower molars into neighbouring anatomical spaces. Thirteen patients were evaluated retrospectively in terms of age, sex, affected side, jaw (mandible or maxilla), surgeon's experience, whether the extracted teeth had erupted, which portion of the tooth or teeth was displaced, the anatomical space into which the fragment was displaced, postoperative complaints, timing of the retrieval, type of anaesthesia, and surgical approach. There were no significant differences in sex, affected side, which part of the tooth was displaced, whether the extracted teeth had erupted, type of anaesthesia, or timing of retrieval. We conclude that this condition should be treated, although follow-up alone may be an option. The intraoral lingual pouch approach for complications of mandibular third molars and the intraoral Caldwell-Luc operation for those in the maxilla could be successful options for retrieval. PMID- 28735636 TI - Severe distortion of an orbital titanium mesh implant after recurrent facial trauma: a potential threat to the orbital contents? AB - Titanium mesh implants have proved their effectiveness in the reconstruction of fractures of the orbital wall, and their compromise between stiffness and elasticity allows for optimal support of the orbital contents. However, after recurrent orbital trauma, these implants (even when properly positioned) can become a potential "penetrating object" that threatens the critical adjacent anatomical structures. We report the case of a patient with recurrent facial trauma whose orbit had previously been reconstructed with a titanium implant, and which resulted in severe deformation. PMID- 28735637 TI - Use of cyanoacrylate tissue adhesive to orientate histopathological specimens. PMID- 28735638 TI - Minimally-invasive removal of a screw in the mandibular condyle using computer assisted navigation. PMID- 28735639 TI - Free flap reconstruction for patients aged 85 years and over with head and neck cancer: clinical considerations for comprehensive care. AB - We aimed to identify and evaluate the clinical challenges involved in microvascular flap reconstructions of defects caused by resection of head and neck cancer among patients aged 85 and over. We designed a retrospective study of patients who were treated in the head and neck department of a tertiary referral centre from 2005 to 2015, and all patients aged 85 years and over who had reconstructions with microvascular flaps for head and neck cancer were entered into the study. A total of 24 patients fulfilled the criteria, of whom 15 were men and nine were women. The median (range) duration of stay in hospital was 23 (14-59) days. Eighteen patients had an American Society of Anesthesiologists (ASA) score grade II and six patients grade III. The median (range) operating time was 420 (310-705)minutes, and operative blood loss 550 (200-1500)ml. Sixteen patients had prophylactic tracheostomies, nine of whom developed postoperative surgical complications, seven associated with the tracheostomy (p=0.005). Resections of head and neck cancer and microvascular reconstructions in patients aged 85 and over are associated with a high incidence of postoperative complications. Medical complications tend to be associated with the tracheostomy while surgical complications are potentially associated with the ASA score. Although the morbidity is high, complex resections and microvascular reconstructions are successful with optimum recovery, and age did not seem to influence the outcome. However, it is necessary to avoid prophylactic tracheostomy if possible in these patients. PMID- 28735640 TI - Dose equivalents for second generation long-acting injectable antipsychotics: The minimum effective dose method. AB - BACKGROUND: The concept of dose equivalence of depot medication is important for many scientific and clinical purposes. METHODS: A systematic literature search on four second-generation antipsychotics available as long-acting injectable drugs and haloperidol was conducted. We used the minimum effective dose method which is based on randomized fixed dose studies where the smallest dose which was significantly more efficacious than placebo in the primary outcome was declared as minimum effective dose. We calculated equivalent doses from acute phase studies but we also reported the minimum effective doses found in relapse prevention studies. RESULTS: The acute phase minimum effective doses/olanzapine equivalents were: aripiprazole lauroxil 441mg (300mg aripiprazole)/4wks/0.71; aripiprazole 400mg/4weeks/0.95 (aripiprazole maintena); paliperidone palmitate 25mg/4weeks/0,06; risperidone 25mg/2weeks/0,12; RBP-7000 90mg/4weeks/0,21; olanzapine 210mg/2weeks/1. CONCLUSIONS: The minimum effective dose method is an operationalized and evidence-based approach for determining antipsychotic dose equivalence which can also be applied to long-acting injectable formulations. Doses may not have been chosen low enough to find the truly minimum effective dose. Comparisons with other methods will be necessary to come to ultimate conclusions. PMID- 28735641 TI - Risk and resilience brain networks in treatment-resistant schizophrenia. AB - BACKGROUND: Genes, molecules and neural circuits that are associated with, or confer risk to developing schizophrenia have been studied and mapped. It is hypothesized that certain neural systems may counterbalance familial risk of schizophrenia, and thus confer resilience to developing the disorder. This study sought to identify resting-state functional brain connectivity (rs-FC) representing putative risk or resilience endophenotypes in schizophrenia. METHODS: Resting-state functional magnetic resonance imaging (rs-fMRI) was performed in 42 individuals with treatment resistant schizophrenia (TRS), 16 unaffected first-degree family members (UFM) and 42 healthy controls. Whole-brain rs-FC networks were mapped for each individual and analysed graph theoretically to identify network markers associated with schizophrenia risk or resilience. RESULTS: The ~900 functional connections showing between-group differences were operationalized as conferring: i) resilience, ii) risk, or iii) precipitating risk and/or illness effects. Approximately 95% of connections belonged to the latter two categories, with substantially fewer connections associated with resilience. Schizophrenia risk primarily involved reduced frontal and occipital rs-FC, with patients showing additional reduced frontal and temporal rs-FC. Functional brain networks were characterized by greater local efficiency in UFM, compared to TRS and controls. CONCLUSIONS: TRS and UFM share frontal and occipital rs-FC deficits, representing a 'risk' endophenotype. Additional reductions in frontal and temporal rs-FC appear to be associated with risk that precipitates psychosis in vulnerable individuals, or may be due to other illness related effects, such as medication. Functional brain networks are more topologically resilient in UFM compared to TRS, which may protect UFM from psychosis onset despite familial liability. PMID- 28735642 TI - Development and psychometric properties of the Multidimensional Schizotypy Scale: A new measure for assessing positive, negative, and disorganized schizotypy. AB - This article reports on the development of a new self-report questionnaire measure of schizotypy - the Multidimensional Schizotypy Scale (MSS). Schizotypy offers a useful and unifying construct for understanding schizophrenia-spectrum psychopathology. Questionnaire measures have been widely used to assess schizotypy and have greatly informed our understanding of the construct. However, available measures suffer from a number of limitations, including lack of a clear conceptual framework, outdated wording, unclear factor structure, and psychometric shortcomings. The MSS is based on current conceptual models and taps positive, negative, and disorganized dimensions of schizotypy. The derivation sample included 6265 participants sampled from four universities and Amazon Mechanical Turk. A separate sample of 1000 participants from these sources was used to examine the psychometric properties of the final subscales. Scale development employed classical test theory, item response theory, and differential item function methods. The positive schizotypy and negative schizotypy subscales contain 26 items each, and the disorganized schizotypy subscale contains 25 items. The psychometric properties were almost identical in the derivation and validation samples. All three subscales demonstrated good to excellent reliability, high item-scale correlations, and good item and test curve characteristics. The MSS appears to provide a promising measure for assessing schizotypy. PMID- 28735643 TI - Disrupted relationship between "resting state" connectivity and task-evoked activity during social perception in schizophrenia. AB - Schizophrenia has been described as a self-disorder, whereas social deficits are key features of the illness. Changes in "resting state" activity of brain networks involved in self-related processing have been consistently reported in schizophrenia, but their meaning for social perception deficits remains poorly understood. Here, we applied a novel approach investigating the relationship between task-evoked neural activity during social perception and functional organization of self-related brain networks during a "resting state". "Resting state" functional MRI was combined with task-related functional MRI using a social perception experiment. Twenty-one healthy control participants (HC) and 21 out-patients with a diagnosis of schizophrenia (SCH) were included. There were no significant differences concerning age, IQ, education and gender between the groups. Results showed reduced "resting state" functional connectivity between ventromedial prefrontal cortex and dorsal posterior cingulate cortex in SCH, compared to HC. During social perception, neural activity in dorsal posterior cingulate cortex and behavioral data indicated impaired congruence coding of social stimuli in SCH. Task-evoked activity during social perception in dorsal posterior cingulate cortex co-varied with dorsal posterior cingulate cortex ventromedial prefrontal cortex functional connectivity during a "resting state" in HC, but not in SCH. Task-evoked activity also correlated with negative symptoms in SCH. These preliminary findings, showing disrupted prediction of social perception measures by "resting state" functioning of self-related brain networks in schizophrenia, provide important insight in the hypothesized link between self and social deficits. They also shed light on the meaning of "resting state" changes for tasks such as social perception. PMID- 28735644 TI - Fasting as possible complementary approach for polycystic ovary syndrome: Hope or hype? AB - Polycystic ovary syndrome (PCOS) is a common endocrine system disorder among women of reproductive age. In several cases, PCOS women show infertility or subfertility and other metabolic alteration, such as insulin resistance (InsR), dyslipidaemia, hyperinsulinemia and obesity. Despite the aetiology of the syndrome is still far from be elucidated, it could be considered the result of concurrent endocrine modifications, lifestyle factors and genetic background. In particular, accumulating evidence suggests that InsR and compensatory hyperinsulinemia play a pivotal pathogenic role in the hyperandrogenism of many PCOS phenotypes, which in turn have a clear detrimental effect on chronic anovulation. Different forms of fasting, such as intermittent fasting (IF, including alternate day fasting, or twice weekly fasting, for example) and periodic fasting (PF, lasting several days or longer every 2 or more weeks) are currently being tested in several in vitro and in vivo studies. Changes in the circulating levels of Insulin Growth Factor-1 (IGF-1), Insulin-like Growth Factor Binding Protein 1 (IGFBP1), glucose and insulin are typical effects of fasting which may play a key role on aging and metabolic homeostasis. Considering the paramount importance of InsR and compensatory hyperinsulinemia, different fasting regimens can reduce IGF-1, IGFBP1, glucose and insulin levels and consequently have beneficial effects on ovarian function, androgen excess and infertility in PCOS women. PMID- 28735645 TI - Psychiatric consultation in the collaborative care model: The "bipolar sieve" effect. AB - Around the world, psychiatrists are in exceptionally short supply. The majority of mental health treatment is delivered in primary care. In the United States, the Collaborative Care Model (CCM) addresses the shortfall of psychiatrists by providing indirect consultation in primary care. A Cochrane meta-analysis affirms the efficacy this model for depression and anxiety. However, our experience with the CCM suggests that most patients referred for consultation have problems far more complex than simple depression and anxiety. Based on preliminary data, we offer five linked hypotheses: (1) in an efficient collaborative care process, the majority of mental illnesses can be handled by providers who are less expensive and more plentiful than psychiatrists. (2) A majority of the remaining cases will be bipolar disorder variations. Differentiating these from PTSD, the most common alternative or comorbid diagnosis, is challenging and often requires a psychiatrist's input. (3) Psychiatric consultants can teach their primary care colleagues that bipolar diagnoses are estimations based on rigorously assessed probabilities, and that cases fall on a spectrum from unipolar to bipolar. (4) All providers must recognize that when bipolarity is missed, antidepressant prescription often follows. Antidepressants can induce bipolar mixed states, with extreme anxiety and potentially dangerous impulsivity and suicidality. (5) Psychiatrists can help develop clinical approaches in primary care that identify bipolarity and differentiate it from (or establish comorbidity with) PTSD; and psychiatrists can facilitate appropriate treatment, including bipolar-specific psychotherapies as well as use of mood stabilizers. PMID- 28735646 TI - Hyperhomocysteinemia and Age-related Macular Degeneration: Role of Inflammatory Mediators and Pyroptosis; A Proposal. AB - Age-related macular degeneration (AMD) and pyroptosis cause irreversible vascular changes in the eyes leading to central vision loss in patients. It is the most common eye disease affecting millions of people aged 50years or older, and is slowly becoming a major health problem worldwide. The disease mainly affects macula lutea, an oval-shaped pigmented area surrounding fovea near the center of retina, a region responsible for visual acuity. It is fairly a complex disease as genetics of patients, environmental triggers as well as risk factors such as age, family history of CVDs, diabetes, gender, obesity, race, hyperopia, iris color, smoking, diabetes, exposure to sun light and pyroptosis have all been clubbed together as probable causes of macular degeneration. Among genes that are known to play a role include variant polymorphisms in the complement cascade components such as CFH, C2, C3, and CFB as potential genetic risk factors. So far, AMD disease hypothesized theories have not resulted into the anticipated impact towards the development of effective or preventive therapies in order to help alleviate patients' suffering because, as of today, it is still unclear what actually initiates or leads to this dreaded eye condition. Based upon our extensive work on the metabolism of homocysteine (Hcy) in various disease conditions we, therefore, are proposing a novel hypothesis for AMD pathogenesis as we strongly believe that Hcy and events such as pyroptosis make a greater contribution to the overall etiology of AMD disease in a target population of susceptible hosts by inciting and accelerating the inherent inflammatory changes in the retina of these patients (Fig. 2). In this context, we further state that Hcy and pyroptosis should be considered as legitimate and valuable markers of retinal dysfunction as they not only aid and abet in the development but also in the progression of AMD in older people as discussed in this paper. This discussion should open up new avenues in tackling inflammatory and pyroptosis centered pathways that are up-regulated or solely promoted by Hcy interaction within the ocular compartment of AMD susceptible hosts. PMID- 28735647 TI - What is the underlying cause of type II diabetes? - Are cells protecting themselves against the reactivity of glucose? AB - Through the last couple of thousands of years, human food sources and availability have changed tremendously. Moving from a diet of hunter-gathers, consisting of nuts, fruits, tubers and meat, to the farmers' diet of vegetables, grains, milk and meat to this and last century, where among other processed foods there is the unlimited availability of refined sugar. This change in diet has been proposed as being the underlying reason for the dramatic increase in the prevalence of type II diabetes that we are observing worldwide in our time. The question is what is the underlying molecular cause of this disease? One possibility proposed here is that type II diabetes might be a consequence of our cells trying to protect themselves from too high intra-cellular concentration of the reactive compound glucose. PMID- 28735648 TI - Knowledge about dietary fibre and its health benefits: A cross-sectional survey of 2536 residents from across Croatia. AB - This cross-sectional study is aimed at identifying the level of understanding of the health benefits of dietary fibre in the prevention of disease, as well as the association between that understanding and fibre consumption in the Croatian population. We believe that nutritional knowledge is important for the consumption of healthy food which includes also a positive reflection on food habits and health. Only well-informed consumers can shop effectively for food rich in dietary fibre and thereby derive the health benefits that fibre can offer. We suppose the association between that understanding and fibre consumption in the Croatian population. However, this knowledge is not the only important determinant; food purchases are influenced by socioeconomic and demographic factors. Our hypothesis is that the level of knowledge about fibre and fibre consumption varies with age, gender, education level and urban or rural environment. It is our assumption that life styles, environmental conditions and education can affect the level of knowledge and perception about healthy eating habits. If this assumption is accurate, targeted education campaigns to educate and sensitise the population about fibre-rich foods and the health benefits of fibre is a priority. Public health programmes are urgently needed, particularly in rural areas, to sensitise the population to fulfill the recommended fibre intake, high-fibre food sources and the mechanisms by which fibre can help prevent disease. PMID- 28735649 TI - Dystonia as a patterned motor malflow. AB - The definition of dystonia has been renewed repeatedly but always within the context of overactive muscle contractions. In dystonia the muscles unnecessary for a motion fail to be adequately suppressed because of the loss of central motor control, resulting in inappropriate movements or abnormal postures ("overflow phenomenon"). This represents, however, only one side of the disrupted motor control. Some patients complain of the inability to activate muscles necessary for the intended task despite the lack of motor paresis, as best exemplified by the apraxia of eyelid opening. The author has ever coined the term "negative dystonia" for this phenomenon, which occurs hypothetically as a result of failed central motor flow and is often co-existent with overflow. Negative dystonia has a fixed pattern and sensory trick may be effective to ameliorate the symptom just as in the case of conventional dystonia. Hence we can speculate that the overflow and flow failure are the two sides of the same coin, both being caused by the loss of motor control. The current hypothesis is that dystonia is a representation of the patterned motor malflow (malicious flow) due to the loss of motor control. PMID- 28735650 TI - Prognostic utility of neuroinjury biomarkers in post out-of-hospital cardiac arrest (OHCA) patient management. AB - Despite aggressive intervention, patients who survive an out-of-hospital cardiac arrest (OHCA) generally have very poor prognoses, with nationwide survival rates of approximately 10-20%. Approximately 90% of survivors will have moderate to severe neurological injury ranging from moderate cognitive impairment to brain death. Currently, few early prognostic indicators are considered reliable enough to support patients' families and clinicians' in their decisions regarding medical futility. Blood biomarkers of neurological injury after OHCA may be of prognostic value in these cases. When most bodily tissues are oxygen-deprived, cellular metabolism switches from aerobic to anaerobic respiration. Neurons are a notable exception, however, being dependent solely upon aerobic respiration. Thus, after several minutes without circulating oxygen, neurons sustain irreversible damage, and certain measurable biomarkers are released into the circulation. Prior studies have demonstrated value in blood biomarkers in prediction of survival and neurologic impairment after OHCA. We hypothesize that understanding peptide biomarker kinetics in the early return of spontaneous circulation (ROSC) period, especially in the setting of refractory cardiac arrest, may assist clinicians in determining prognosis earlier in acute resuscitation. Specifically, during and after immediate resuscitation and return of ROSC, clinicians and families face a series of important questions regarding patient prognosis, futility of care and allocation of scarce resources such as the early initiation of extracorporeal cardiopulmonary resuscitation (ECPR). The ability to provide early prognostic information in this setting is highly valuable. Currently available, as well as potential biomarkers that could be good candidates in prognostication of neurological outcomes after OHCA or in the setting of refractory cardiac arrest will be reviewed and discussed. PMID- 28735651 TI - The effect of artesunate on short-term memory in Lyme borreliosis. AB - Lyme borreliosis is associated with memory deficits. While this may be related to cerebral infection by Borrelia bacteria, it may also be caused by concomitant co infection by Babesia protozoa. The anti-malarial artemisinin-derivative artesunate has been shown to be effective against a number of Babesia species and to have efficacy against human cerebral malaria. We hypothesised that concomitant administration of artesunate in Lyme borreliosis patients would help alleviate the severity of self-reported short-term memory impairment. This hypothesis was tested in a small pilot study in which patients were treated with both an intravenous antibiotic and oral artesunate (20mg four times per day); treatment was associated with a reduction in the severity of short-term memory difficulties (P?0.08). In light of these findings, we recommend that a formal randomised, placebo-controlled study be carried out. PMID- 28735652 TI - Boiling factors in the pot of type 1 diabetes mellitus management: the role of exercise. PMID- 28735653 TI - (Re)-wiring a brain with light: Clinical and visual processing findings after application of specific coloured glasses in patients with symptoms of a visual processing disorder (CVPD): Challenge of a possible new perspective? AB - The present investigation examined whether changes of electrophysiological late event related potential pattern could be used to reflect clinical changes from therapeutic intervention with coloured glasses in a group of patients with symptoms of central visual processing disorder. Subjects consisted of 13 patients with average age 16years (range 6-51years) with attention problems and learning disability, respectively. These patients were provided with specified coloured glasses which were required to be used during day time. Results indicated that specified coloured glasses significantly improved attention performance. Furthermore electrophysiological parameters revealed a significant change in the late event related potential distribution pattern (latency, amplitudes). This reflects a synchronization of together firing wired neural assemblies responsible for visual processing, suggesting an accelerated neuromaturation process when using coloured glasses. Our results suggest that the visual event related potentials measures are sensitive to changes in clinical development of patients with deficits of visual processing wearing appropriate coloured glasses. It will be discussed whether such a device might be useful for a clinical improvement of distraction symptoms caused by visual processing deficits. A model is presented explaining these effects by inducing the respiratory chain of the mitochondria such increasing the low energy levels of ATP of our patients. PMID- 28735654 TI - Chronic fatigue syndrome and idiopathic intracranial hypertension: Different manifestations of the same disorder of intracranial pressure? AB - Though not discussed in the medical literature or considered in clinical practice, there are similarities between chronic fatigue syndrome and idiopathic intracranial hypertension (IIH) which ought to encourage exploration of a link between them. The cardinal symptoms of each - fatigue and headache - are common in the other and their multiple other symptoms are frequently seen in both. The single discriminating factor is raised intracranial pressure, evidenced in IIH usually by the sign of papilloedema, regarded as responsible for the visual symptoms which can lead to blindness. Some patients with IIH, however, do not have papilloedema and these patients may be clinically indistinguishable from patients with chronic fatigue syndrome. Yet IIH is rare, IIH without papilloedema (IIHWOP) seems rarer still, while chronic fatigue syndrome is common. So are the clinical parallels spurious or is there a way to reconcile these conflicting observations? We suggest that it is a quirk of clinical measurement that has created this discrepancy. Specifically, that the criteria put in place to define IIH have led to a failure to appreciate the existence, clinical significance or numerical importance of patients with lower level disturbances of intracranial pressure. We argue that this has led to a grossly implausible distortion of the epidemiology of IIH such that the milder form of the illness (IIHWOP) is seen as less common than the more severe and that this would be resolved by recognising a connection with chronic fatigue syndrome. We hypothesise, therefore, that IIH, IIHWOP, lesser forms of IIH and an undetermined proportion of chronic fatigue cases are all manifestations of the same disorder of intracranial pressure across a spectrum of disease severity, in which this subset of chronic fatigue syndrome would represent the most common and least severe and IIH the least common and most extreme. PMID- 28735655 TI - An intramedullary nail coated with antibiotic and growth factor nanoparticles: An individualized state-of-the-art treatment for chronic osteomyelitis with bone defects. AB - Among various infections, chronic osteomyelitis is one of the most challenging in terms of treatment. This infection is more common among patients with open fractures and those who have undergone elective orthopedic procedures. The treatment of osteomyelitis requires high antibiotic doses and an aggressive and multifaceted surgical approach. The use of parenteral antibiotics alone, without debridement, is not sufficiently effective, due to the formation of sequestra and the low vascularity of the affected area. The surgical options available for patients with chronic osteomyelitis include sequestrectomy, curettage, and intramedullary reaming, although these procedures usually result in bone defects that require further surgical intervention. Polymethyl methacrylate or calcium phosphate beads, impregnated with antibiotics, are commonly placed in such cases; however, this option has several disadvantages, including the need for future removal of cement, uncontrollable local release of antibiotics, and the need for broad-spectrum agents. The resulting bone defects also require additional treatments involving vascularized fibula grafting, intramedullary nails, use of techniques like Masquelet and Ilizarov, and even soft tissue transfers. All of these methods have certain limitations, such as the eventual requirement of more than one surgical event. Certain growth factors aid in the development and vascularization of new bone, such as bone morphogenetic proteins (BMPs) and insulin-like growth factor I (IGF-1). We propose that nanoparticles of BMPs, IGL 1, and microorganism-specific antibiotics can be placed on the surface of intramedullary nails. These nanoparticles can be attached to various different polymeric materials such as poly(d,l-lactide), which is a biocompatible and biodegradable polymer, and can be positioned in several layers, to ensure controlled and systematic release. The placement of nanoparticles at the infection site alone will also ensure local delivery of the drugs only to the required areas. Moreover, these intramedullary nails will be useful for both infected non-unions and mal-unions. Over time, the nanoparticles will eradicate the infection and stimulate new healthy bone formation, whereas the intramedullary nail itself will provide constant stability and immobilization. This model provides new and revolutionary ideas for the development of individualized technologies in medicine. PMID- 28735656 TI - Around Manaslu Ultramarathon: Diarrhea Is Still the King. PMID- 28735657 TI - L-arginine Attenuates Hypobaric Hypoxia-Induced Increase in Ornithine Decarboxylase 1. AB - BACKGROUND: Chronic hypoxia-induced pulmonary hypertension and vascular remodeling have been shown to be associated with ornithine decarboxylase 1 (ODC1). However, few animal studies have investigated the role of ODC1 in acute hypoxia. OBJECTIVES: We investigated ODC1 gene expression, morphologic and functional changes, and the effect of L-arginine as an attenuator in lung tissues of rats exposed to acute hypobaric hypoxia at a simulated altitude of 6000 m. METHODS: Sprague-Dawley rats exposed to simulated hypobaric hypoxia (6000 m) for 24, 48, or 72 hours were treated with L-arginine (L-arginine group, 20 mg/100 g intraperitoneal; n=15) or untreated (non-L-arginine group, n=15). Control rats (n=5) were maintained at 2260 m in a normal environment for the same amount of time but were treated without L-arginine. The mean pulmonary artery pressure was measured by PowerLab system. The morphologic and immunohistochemical changes in lung tissue were observed under a microscope. The mRNA and protein levels of ODC1 were measured by real-time polymerase chain reaction and Western-blot, respectively. RESULTS: Hypobaric hypoxia induced pulmonary interstitial hyperemia and capillary expansion in the lungs of rats exposed to acute hypoxia at 6000 m. The mean pulmonary artery pressure and the mRNA and protein levels of ODC1 were significantly increased, which could be attenuated by treatment with L-arginine. CONCLUSIONS: L-arginine attenuates acute hypobaric hypoxia-induced increase in mean pulmonary artery pressure and ODC1 gene expression in lung tissues of rats. ODC1 gene contributes to the development of hypoxic pulmonary hypertension. PMID- 28735658 TI - Depression Among Older Adults: A 20-Year Update on Five Common Myths and Misconceptions. AB - Is depression among older adults symptomatically different than younger adults? Is it more common or chronic or difficult to treat? Is depression in late life more likely to be attributed to psychological problems? Twenty-years ago, Dan Blazer, a pioneer known for his groundbreaking work on depression in older adulthood, conducted an important review of the existing literature to refute five commonly held beliefs about depression in late life. Now, two decades later, we call upon selected articles that are representative of our current knowledge to provide an update and identify research priorities. The research consensus spanning the past 20 years suggests that when compared with their younger counterparts, depression in older adults is not more common and is not more often caused by psychological factors. Although some studies have suggested that depression in late life may be symptomatically different and characterized by a more somatic presentation, there is insufficient empirical evidence to conclude that depression presents differently across adulthood. Overall, older adults respond to psychological interventions as well as younger adults, although evidence suggests that antidepressants are less efficacious in late life. Finally, compared with middle-aged adults, depression in older adults is associated with a more chronic course (i.e., higher rate of relapse), which is likely moderated by medical comorbidity. This special article summarizes our current understanding of the nature and treatment of late-life depression and highlights areas of inquiry in need of further study. PMID- 28735659 TI - 2016: A historical year to Revista Portuguesa de Cardiologia. PMID- 28735661 TI - Paravesical (urachal) paraganglioma (PGL) presenting as hypertensive crisis during micturition, mimicking bladder PGL. PMID- 28735660 TI - Case detection and diagnosis of primary aldosteronism - The consensus of Taiwan Society of Aldosteronism. AB - BACKGROUND/PURPOSE: Even though the increasing clinical recognition of primary aldosteronism (PA) as a public health issue, its heightened risk profiles and the availability of targeted surgical/medical treatment being more understood, consensus in its diagnosis and management based on medical evidence, while recognizing the constraints of our real-world clinical practice in Taiwan, has not been reached. METHODS: The Taiwan Society of Aldosteronism (TSA) Task Force acknowledges the above-mentioned issues and reached this Taiwan PA consensus at its inaugural meeting, in order to provide updated information of internationally acceptable standards, and also to incorporate our local disease characteristics into the management of PA. RESULTS: When there is suspicion of PA, a plasma aldosterone to renin ratio (ARR) should be obtained initially. Patients with abnormal ARR will undergo confirmatory laboratory and image tests. Subtype classification with adrenal venous sampling (AVS) or NP-59 nuclear imaging, if AVS not available, to lateralize PA is recommended when patients are considered for adrenalectomy. The strengths and weaknesses of the currently available identification methods are discussed, focusing especially on result interpretation. CONCLUSION: With this consensus we hope to raise more awareness of PA among medical professionals and hypertensive patients in Taiwan, and to facilitate reconciliation of better detection, identification and treatment of patients with PA. PMID- 28735662 TI - 68Ga-DOTATOC and 18F-FDG PET/CT for identifying the primary lesions of suspected and metastatic neuroendocrine tumors: A prospective study in Taiwan. AB - BACKGROUND/PURPOSE: To investigate the diagnostic accuracy of 68Ga-DOTATOC and 18F-FDG PET/CT to identify the primary foci in Taiwanese patients with clinically suspected neuroendocrine tumors (NET) and NET of unknown primary site. METHODS: Patients with clinically suspected NET and NET of unknown primary site were eligible. All participants underwent a conventional workup (including CT, MR, endoscopic ultrasound), 68Ga-DOTATOC, and 18F-FDG PET/CT. The results of pathology and findings on clinical follow-up served as the gold standard. RESULTS: Among the 36 patients included in the study, we were able to identify the primary tumor in 17 participants (47.2%). The overall sensitivity values of 68Ga-DOTATOC, 18F-FDG, and conventional workup were 88%, 41%, and 53%, respectively, whereas the specificities were 100%, 100%, 68%, respectively. The areas under curve of 68Ga-DOTATOC, 18F-FDG, and conventional workup were 0.941, 0.706, and 0.607, respectively. 68Ga-DOTATOC was more sensitive than 18F-FDG and more specific than conventional workup. Treatment changes as a result of 68Ga DOTATOC PET/CT findings occurred in 12 (33.3%) of the 36 study participants. CONCLUSION: Our data confirm the usefulness of 68Ga-DOTATOC in the identification of NET. In addition, treatment modifications as a result of 68Ga-DOTATOC PET/CT findings were evident in approximately one third of NET patients. PMID- 28735663 TI - Histological Features of the Distal Third Metacarpal Bone in Thoroughbred Racehorses, With and Without Lateral Condylar Fractures. AB - A detailed histopathological study of the distal third metacarpal bone of Thoroughbred racehorses was undertaken to characterize lesions observed previously on magnetic resonance imaging (MRI). The bones were selected and grouped on the basis of MRI features. Representative sections in different planes were processed for histopathology. All lesions observed in the articular cartilage (AC) and subchondral bone (SCB) were recorded and graded with a scoring system, based partially on the Osteoarthritis Research Society International grading system. The scoring system included the severity of the lesion. Descriptive statistics and linear mixed effects models were performed. A positive correlation was observed between the severity of histopathological changes in the superficial and deeper osteochondral tissues, and between the number of race starts and AC score. Age was not correlated with AC or SCB score. A moderate variation in AC and SCB scores was observed between the groups; however, there were differences within individual bones. Bones with focal palmar necrosis (FPN) showed significant differences in the histological scoring of the AC compared with bones without FPN. Bones with incomplete fractures or larger areas of bone remodelling showed significant differences in SCB pathology when compared with bones with FPN. Haematoidin was detected in areas with excessive SCB and cancellous bone sclerosis and/or irregular bone density. This finding is suggestive of poor blood perfusion in these areas. PMID- 28735664 TI - Lingual Chondrolipoma in a Dog. AB - A 13-year-old female Yorkshire terrier was presented with difficulty swallowing because of a lingual mass, which had grown to a size of 0.8 * 0.8 * 0.8 cm in 1 month. Grossly, the mass was located in the lingual frenulum and the cut surface was grey-white in colour. Microscopically, the mass was unencapsulated and composed of lobules of mature adipose tissue and cartilaginous tissue with abundant basophilic myxoid matrix separated by fibrous connective tissue. Immunohistochemically, almost all of these cells were positive for vimentin and S100. Chondroid cells and their adjacent spindle cells were also positive for SOX9. Based on these findings, a diagnosis of chondrolipoma was made. To the best of our knowledge, this is the first report of a chondrolipoma originating as a primary tumour in the lingual frenulum of a dog. PMID- 28735665 TI - Prevalence of FoxP3+ Cells Does Not Correlate With Ki67 Expression in Canine Diffuse Large B-cell Lymphoma. AB - Diffuse large B-cell lymphoma (DLBCL) is the most common type of canine lymphoma and survival times are currently <1 year. Manipulation of the tumour microenvironment, of which the regulatory T cell (Treg) is a principal player, represents a potentially exciting way to curb the rapid proliferation of neoplastic cells. Tregs, characterized by the stable expression of the transcription factor FoxP3, suppress innate and adaptive arms of the immune response and represent a potential therapeutic target within neoplastic lymph nodes. This retrospective study explored the hypothesis that Tregs promote the proliferation of neoplastic large B cells, employing immunohistochemistry to assess both FoxP3 and Ki67 expression within canine lymph nodes. Fifty-seven biopsy samples of canine nodal DLBCL were examined. There were significantly fewer FoxP3+ cells in lymph nodes effaced by DLBCL than in reactive lymph nodes (27 versus 369 cells/mm2; Mann-Whitney U = 16, P = 0.011). There was no relationship between the number of intratumoural FoxP3+ cells and neoplastic cell proliferation (Spearman's rank r = 0.058, P = 0.670, 95% confidence interval). The results of this study show that FoxP3+ cells are reduced in lymph nodes effaced by DLBCL and that this change is unrelated to the expression of Ki67. This study also describes a robust digital method to standardize cell counts and facilitate future comparative studies. PMID- 28735666 TI - Detection of Papillomavirus DNA in Cutaneous Squamous Cell Carcinoma and Multiple Papillomas in Captive Reptiles. AB - Papillomaviruses (PVs) are small, non-enveloped DNA viruses that cause mucocutaneous tumours including squamous cell carcinoma (SCC) in man. In animals, evidence supports a causal role for PVs in the development of cutaneous and oral SCC in some species. In reptiles, three cases of papilloma or fibropapilloma have been associated with PV infection, but no association has been reported to date with SCC. Two cases of cutaneous epithelial tumours, multiple papillomas in a spiny-tailed lizard (Uromastyx acanthinura) and SCC in a Dumeril's boa (Acrantophis dumerili), were investigated by polymerase chain reaction. PV DNA was amplified from samples of both lesions. Typical microscopical features suggestive of PV infection (e.g. the presence of koilocytes) were observed in the lesions from the spiny-tailed lizard. This is the first report of an association between PV and SCC in reptiles. Further studies are needed to better clarify the role of PVs in these species and to characterize the PV strains involved. PMID- 28735667 TI - Immunohistochemical Expression of MCAM/CD146 in Canine Melanoma. AB - MCAM/CD146 (melanoma cell adhesion molecule/CD146) is a transmembrane immunoglobulin superfamily cell adhesion molecule involved in transendothelial migration and signal transduction. It is expressed in melanoma, squamous cell carcinoma, prostatic, ovarian, cervical and endometrial cancers and promotes tumour growth, angiogenesis and metastasis. Melanoma is the most common malignant oral tumour of dogs and also arises in the skin, nail bed and footpad. The aim of this study was to investigate the immunohistochemical expression of MCAM/CD146 in 51 canine melanomas, including oral, cutaneous and ocular tumours. Seventeen of the 51 (33.3%) cases were negative, eight (15.7%) were weakly positive, seven (13.7%) were moderately positive and 19 (37.3%) were strongly positive. MCAM/CD146 was expressed by both oral and cutaneous melanomas; however, the intensity and the extent of the immunoreactivity was higher in oral (P = 0.009) than in cutaneous tumours (P = 0.058). Most ocular melanomas did not express MCAM/CD146 (P = 0.256). Expression of MCAM/CD146 by canine melanomas may suggest the molecule as a target for treatment, especially in oral melanomas. PMID- 28735668 TI - Ovine Toxoplasmosis: A New Look at its Pathogenesis. AB - Conditions causing reproductive failure are a significant concern in the livestock industry, and amongst these, ovine toxoplasmosis is one of the most important. Despite decades of research, there remain gaps in knowledge about this disease, especially regarding the pathogenesis of abortion in sheep. As for other diseases causing ovine abortion, such as chlamydial abortion or border disease, the consequences of infection with Toxoplasma gondii depend largely on the stage of gestation, but the mechanisms involved are not well understood. Immunological modulation occurring during gestation has been proposed as the main mechanism accounting for this clinical variation. However, the extent and effect of such modulation has not yet been identified clearly in sheep and the involvement of other unknown factors has been proposed. Recent experimental studies have defined an unacknowledged clinical presentation of ovine toxoplasmosis, where abortions occur during the acute phase of infection, resulting in as high as 100% fetal loss in susceptible sheep. The pathogenesis of this clinical form differs from that of classically described ovine toxoplasmosis, and its pathological features resemble those of the perinatal syndrome known as cerebral palsy in man. A range of variables, including individual susceptibility, isolate virulence and infective dose, have been proposed as key factors in the development of one or the other of these clinical forms and warrants further investigation in this important disease. PMID- 28735669 TI - Lethal Gastric Mucosal Necrosis due to Administration of Oral Ferrous Bisglycinate Chelate to Suckling Piglets. AB - The oral application of a newly developed ferrous bisglycinate paste for suckling piglets at a dose of 180 mg/kg body weight led to increased death rates in 10% (n = 10) of Swiss test pig breeding farms (n = 100). Necropsy examination of suckling piglets (n = 12), selected randomly from the test farms with increased death rates, demonstrated severe gastric mucosal ulceration and necrosis. Due to the presence of crystalline iron surface coating within the gastric lesions, the iron was considered as the toxic principle and cause of death. To demonstrate the direct toxicity of ferrous bisglycinate, the paste was administered experimentally to a litter of suckling piglets (n = 11). Different time points (24, 48 and 72 h post partum) and doses (180 mg/kg and 360 mg/kg) were investigated. The manufacturer's recommended dose of 180 mg/kg corresponded to approximately 36 mg Fe/kg and to 6.4 % of the acute lethal dose50 of oral iron in rats. In all piglets the lesions were reproduced and most severe at the earliest time point (24 h post partum) and with the highest applied dose (360 mg/kg). The lesions were in accordance with those described from oral iron intoxication in man, suggesting pigs as an ideal animal model for oral iron toxicity studies. PMID- 28735670 TI - Concomitant Malignant Pulmonary Peripheral Nerve Sheath Tumour and Benign Cutaneous Peripheral Nerve Sheath Tumour in a Dog. AB - Peripheral nerve sheath tumours (PNSTs) are neoplastic growths derived from Schwann cells, perineural cells or both. Malignant PNSTs (MPNSTs) are uncommon in domestic animals. This report describes the concomitant occurrence of PNSTs in a 10-year-old female cocker spaniel with a clinical history of respiratory impairment. Grossly, there was a large infiltrative mass in the caudal lobe of the right lung; smaller nodules were observed in the other lobes of the right lung. Furthermore, a small encapsulated cutaneous nodule was observed on the left hindlimb. Histopathology of the pulmonary tumours revealed the proliferation of pleomorphic spindle-shaped cells with moderate mitotic index arranged in interwoven bundles and concentric Antoni A and Antoni B patterns; invasion of the adjacent pulmonary tissue was observed. The cutaneous nodule consisted of neoplastic mesenchymal cells in interwoven bundles with concentric whorls, but without the marked anisokaryosis, binucleation and infiltrative growth seen in the pulmonary tumour. Immunohistochemistry revealed that both tumours were immunoreactive for vimentin, glial fibrillary acidic protein and S100 protein, but were negative for factor VIII. These findings are indicative of a MPNST in the lung with a concomitant benign PNST in the limb. This case represents the first report of a primary MPNST in the lung of a dog. This neoplastic growth should be included in the differential diagnosis of primary malignant pulmonary tumours of dogs. PMID- 28735671 TI - Choroid Plexus Cyst in a Neonatal Burmeister's Porpoise (Phocoena spinipinnis). AB - Neuroectodermal developmental anomalies are reported rarely in cetaceans and central nervous system cysts are not described. We describe the gross, microscopical, histochemical and immunohistochemical features of a neuraxial myelencephalic cyst in a stranded neonatal Burmeister's porpoise (Phocoena spinipinnis). Grossly, a subdural, extra-axial, well-demarcated, yellow fluid filled cystic structure (1.9 * 1.6 * 1 cm) expanded the left foramen of Luschka, the left caudolateral cerebellar recess and the left cranioventral myelencephalon. The cyst displaced the ipsilateral ventral paraflocculus and distended the underlying cranial nerves IX, X, XI and XII. Microscopically, the cystic structure was lined by a monolayer of low cuboidal to flattened epithelium supported by a thin fibrovascular matrix. Immunohistochemistry (IHC) revealed strong and diffuse expression of AE1/AE3 and focal positivity for vimentin. IHC for epithelial membrane antigen, glial fibrillary acid protein, synaptophysin and S100 was negative. Based on these findings, an extra-axial cyst of the choroid plexus of the fourth ventricle (CCPFV) was diagnosed. The pathological relevance of the CCPFV in this case is uncertain. The cause of death involved severe perinatal interspecific (shark) trauma. The present case provides the first evidence of a neuroepithelial cyst in cetacean species. PMID- 28735672 TI - Cutaneous Angiolymphoid Hyperplasia in a Dog. AB - A 5-year-old male miniature dachshund was presented with a dermal nodule on the left forelimb that increased to 5 mm in diameter over a 2-month period. Grossly, the nodule was firm, and both the external and cut surfaces were homogeneously pale pink in colour. Microscopically, the nodule was comprised of mainly plump endothelial cells and inflammatory cells; among the latter, lymphocytes were predominant, with few scattered plasma cells, mast cells and macrophages. Lymphoid follicles with germinal centres were often observed. Mitotic figures were not observed amongst the endothelial cells. Immunohistochemically, the endothelial cells were positive for vimentin, factor VIII-related antigen and CD31, and the surrounding cells were positive for smooth muscle actin. Lymphocytes expressed CD3 or BLA36. These findings led to a diagnosis of cutaneous angiolymphoid hyperplasia. To the best of our knowledge, this is the first report of a cutaneous proliferative disorder comprising an admixture of proliferating vascular endothelial cells and lymphocytic infiltration with follicle formation in a dog. PMID- 28735673 TI - Pneumonia due to Talaromyces marneffei in a Dog from Southern Brazil with Concomitant Canine Distemper Virus Infection. AB - The pathological and molecular findings associated with Talaromyces marneffei induced pneumonia with concomitant infection by canine distemper virus (CDV) are described in a dog. The principal pathological alteration occurred in the lungs. Histopathology confirmed multifocal granulomatous pneumonia associated with numerous intralesional and intracellular septate fission cells consistent with T. marneffei. A molecular assay designed to amplify a partial fragment of the 18S rRNA gene of T. marneffei provided positive results from two fungal cultures derived from the lung. Sequencing and phylogenetic analyses confirmed the results of polymerase chain reaction (PCR). Furthermore, antigens of the CDV N protein were identified within the bronchial epithelium by immunohistochemistry and a PCR assay amplified the CDV N gene from hepatic and pulmonary fragments. Collectively, the pathological and molecular techniques confirmed a diagnosis of T. marneffei-induced pneumonia with concomitant infection by CDV. These findings represent the first description of pulmonary penicilliosis in the dog and extend the geographical niche of this emerging infectious pathogen. In this case, infection by CDV may have induced immunosuppression, which facilitated the development of pulmonary penicilliosis. PMID- 28735674 TI - Effect of Mouse Strain on Equine Herpesvirus 9 Infection. AB - The infectivity of equine herpesvirus (EHV)-9 has been studied in different animal models including immunocompromised animals. The current study focused on the infectivity of EHV-9 in different mouse strains (C3H, C57BL, DBA, BALB/c nu/nu, BALB/c and ICR) by intranasal inoculation of 2 * 106 plaque forming units (PFU). Various organs, including head and lungs, were collected 7 days post infection (dpi) to investigate microscopical lesions and the distribution of EHV 9 antigen. Immunopositivity of tissue sections was scored using ImageJ software. Open reading frame (ORF) 30 expression in lung tissues was quantified using quantitative reverse transcriptase polymerase chain reaction. Pathological examination revealed different degrees of rhinitis in the different mouse strains. Severe rhinitis was detected in C3H and BALB/c-nu/nu strains, moderate rhinitis was observed in C57BL and DBA strains and no lesions were detected in BALB/c mice. Immunopositivity for EHV-9 antigens was detected in the olfactory epithelium of C3H and BALB/c-nu/nu strains. Compared with C57BL, DBA, BALB/c nu/nu, ICR and BALB/c strains, the C3H strain showed greater expression of EHV-9 antigens in the brain. The proportion of areas with high positive to positive immunoreactivity for EHV-9 were 7.57, 3.42, 3.12, 2.51, 1.79 and 0.03% for C3H, C57BL, DBA, BALB/c-nu/nu, ICR and BALB/c strains, respectively. The proportions of areas with low positive to negative immunoreactivity were 92.42, 96.70, 96.87, 97.48, 98.16 and 99.96%, respectively. The highest relative expression levels for EHV-9 ORF30 in the lungs were in C3H mice. No significant differences in the expression of ORF30 were observed in other strains. In conclusion, of the strains examined, C3H, C57BL, DBA, BALB/c-nu/nu and ICR were the most susceptible to EHV 9 infection, and the BALB/c strain was less susceptible. PMID- 28735675 TI - Treatment of narcolepsy and other organic hypersomnias in children. AB - The comprehensive management of chronic disorders such as hypersomnias of childhood requires combining life-style changes with rational pharmacotherapy that is based on treating the symptoms that are most bothersome, the age, comorbidities, and metabolic and endocrine status of the patient. The excessive sleepiness of narcolepsy and idiopathic hypersomnia is best treated with dextroamphetamine or methylphenidate preparations or modafinil/armodafinil. Cataplexy treatment requires sodium oxybate, tricyclic agents, selective norepinephrine reuptake inhibitors or selective serotonin reuptake inhibitors. Sodium oxybate is approved only for adults, thus its use in children is only on an off-label basis. Dual therapy, with both anti-cataplectic and stimulant medications may be required, as is close monitoring for treatment-emergent side effects. PMID- 28735676 TI - A Case of Carcinocythemia: De Novo Hormone Receptor-positive Metastatic Breast Cancer Presenting With Circulating Tumor Cells Mimicking an Acute Leukemia. PMID- 28735677 TI - Genetic Risk Factors Associated With Antiemetic Efficacy of Palonosetron, Aprepitant, and Dexamethasone in Japanese Breast Cancer Patients Treated With Anthracycline-based Chemotherapy. AB - INTRODUCTION: Breast cancer patients often receive anthracycline-based chemotherapy, and chemotherapy-induced nausea and vomiting (CINV) remains one of the most uncomfortable and distressing adverse reactions. Poor control of CINV reduces the relative dose intensity of chemotherapy agents, which has been associated with poor clinical outcomes and shorter survival. The aim of the present study was to identify genetic risk factors associated with anthracycline based CINV. PATIENTS AND METHODS: We evaluated CINV attributable to anthracycline based chemotherapy in Japanese breast cancer patients treated with an antiemetic regimen that included palonosetron, aprepitant, and dexamethasone. Furthermore, we investigated the associations between CINV and single nucleotide polymorphisms in 6 candidate genes. RESULTS: Emesis episodes were rarely observed in the 125 patients included in the present survey (7.2%; n = 9); however, significant nausea occurred in more than one half of the patients (52.8%; n = 66). In particular, acute significant nausea was not effectively controlled. Multivariate logistic regression analysis revealed that the ABCG2 (rs2231142) AA genotype is significantly associated with acute significant nausea (odds ratio, 4.87; 95% confidence interval, 1.01-23.60; P = .049). CONCLUSION: The findings of the present study provide significant insights for developing personalized antiemetic strategies for breast cancer patients receiving anthracycline-based chemotherapy. PMID- 28735678 TI - All-ceramic inlay-retained fixed dental prostheses for replacing posterior missing teeth: A systematic review. AB - PURPOSE: To evaluate the current status of all-ceramic inlay-retained fixed dental prostheses (CIR-FDPs) for the replacement of posterior teeth. STUDY SELECTION: Screening of titles and abstracts, full-text analysis for inclusion eligibility, quality assessment, data extraction and evaluation of the scientific evidence were performed independently by two reviewers. The electronic databases MEDLINE/PubMed, EMBASE, Cochrane Central Register of Controlled Trials, and Compludoc were searched with no restriction to publication date or language. The quality of the studies was evaluated through: the original 'QDP' ('Questionnaire for selecting articles on Dental Prostheses') (for research papers); the 'Guidelines for managing overviews' of the Evidence-Based Medicine Working Group (for reviews); the Cochrane risk of bias tool; and the GRADE scale for grading scientific evidence. RESULTS: This review started with 4942 articles, which were narrowed down to 23 according to the selection criteria. The data was not statistically treated because of the heterogeneity of the studies. Zirconia-based CIR-FDPs may be recommended for restoring posterior single missing teeth, although the prosthesis/tooth bonded interface has yet to be improved. The addition of lateral wings to the classical inlay preparation seems promising. The weakest parts of CIR-FDPs are the connectors and retainers, while caries and endodontic problems are the most common biological complications. The fabrication of CIR-FDPs with monolithic zirconia may eliminate chipping problems. CONCLUSIONS: A three-unit CIR-FDP is a viable treatment option for replacing a posterior missing tooth. Appropriate case selection, abutment preparation and luting procedures may be decisive for clinical success. PMID- 28735679 TI - Soluble endoglin as a prognostic factor of the claudication distance improvement in patients with peripheral artery disease undergoing supervised treadmill training program. AB - Conservative therapy after complete revascularization is increasing in popularity in patients with peripheral artery disease (PAD). The aim of the present study was to find determinants of the improvement of walking abilities and endothelial function in patients with PAD undergoing supervised treadmill training program (STTP). The presented study enclosed 66 patients in the mean age 65.4 +/- 7.7 years with PAD who underwent a 3-month length STTP. We assessed the effect of following factors on the change of the flow-mediated dilatation value (DeltaFMD), maximal walking time (DeltaMWT), and pain-free walking time (DeltaPFWT). The evaluation included several biochemical and anthropometric indices with special insight into markers of angiogenesis, including soluble endoglin (sEng), platelet derived growth factor, and angiopoietin-2. Linear regression analysis for each of the variables and multi-factorial model analysis of variances was adopted to select the most influential determinants. The levels of sEng, a biomarker of several cardiovascular pathologies, were found to significantly predict the greater improvement of maximal walking time and pain-free walking time. Moreover, the linear regression analysis demonstrated, and analysis of variance confirmed that coronary artery disease and peracted endovascular interventions of lower limbs arteries are significant determinants of the better DeltaFMD improvement. On the contrary, treatment with beta-blockers and older age were poor predictors of DeltaFMD increase. In conclusion, the sEng level could serve as a determinant of walking abilities change after STTP in patients with PAD. The treatment with beta-blockers, the coexistence of coronary artery disease, and peracted endovascular interventions of lower limbs arteries are determinants of endothelial function. PMID- 28735681 TI - Young children will lie to prevent a moral transgression. AB - Children believe that it is wrong to tell lies, yet they are willing to lie prosocially to adhere to social norms and to protect a listener's feelings. However, it is not clear whether children will lie instrumentally to intervene on behalf of a third party when a moral transgression is likely to occur. In three studies (N=270), we investigated the conditions under which 5- to 8-year-olds would tell an "interventional lie" in order to misdirect one child who was seeking another child in a park. In Study 1, older children lied more when the seeker intended to steal a toy from another child than when the seeker intended to give cookies to the child. In Study 2, the transgression (stealing) was held constant, but harm to the victim was either emphasized or deemphasized. Children at all ages were more likely to lie to prevent the theft when harm was emphasized. In Study 3, harm to the victim was held constant and the act of taking was described as either theft or a positive action. Children at all ages were more likely to lie when the transgression was emphasized. We conclude that by 5years of age, children are capable of lying to prevent a moral transgression but that this is most likely to occur when both the transgression and the harm to the victim are salient. PMID- 28735680 TI - Dynamic Control of dNTP Synthesis in Early Embryos. AB - Exponential increase of cell numbers in early embryos requires large amounts of DNA precursors (deoxyribonucleoside triphosphates (dNTPs)). Little is understood about how embryos satisfy this demand. We examined dNTP metabolism in the early Drosophila embryo, in which gastrulation is preceded by 13 sequential nuclear cleavages within only 2 hr of fertilization. Surprisingly, despite the breakneck speed at which Drosophila embryos synthesize DNA, maternally deposited dNTPs can generate less than half of the genomes needed to reach gastrulation. The rest of the dNTPs are synthesized "on the go." The rate-limiting enzyme of dNTP synthesis, ribonucleotide reductase, is inhibited by endogenous levels of deoxyATP (dATP) present at fertilization and is activated as dATP is depleted via DNA polymerization. This feedback inhibition renders the concentration of dNTPs at gastrulation robust, with respect to large variations in maternal supplies, and is essential for normal progression of embryogenesis. PMID- 28735682 TI - Biosensors based on beta-galactosidase enzyme: Recent advances and perspectives. AB - Many industries are striving for the development of more reliable and robust beta galactosidase biosensors that exhibit high response rate, increased detection limit and enriched useful lifetime. In a newfangled technological atmosphere, a trivial advantage or disadvantage of the developed biosensor may escort to the survival and extinction of the industry. Several alternative strategies to immobilize beta-galactosidase enzyme for their utilization in biosensors have been developed in recent years in the quest of maximum utility by controlling the defects seen in the previous biosensors. The overwhelming call for on-line measurement of different sample constituents has directed science and industry to search for best practical solutions and biosensors are witnessed as the best prospect. The main objective of this paper is to serve as a narrow footbridge by comparing the literary works on the beta-galactosidase biosensors, critically analyze their use in the construction of best biosensor by showing the pros and cons of the predicted methods for the practical use of biosensors. PMID- 28735683 TI - Pain Management in Penile Prosthetic Surgery: A Review of the Literature. AB - INTRODUCTION: The literature on perioperative pain control and management in inflatable penile prosthesis placement is not firmly established. Because inflatable penile prosthesis placement is an elective procedure, pain can be one of the many issues that influence patient decision making. Pain control also presents a unique challenge to providers in an era of widespread opiate abuse. AIM: To review published data on pain management before, during, and after penile prosthetic surgery. METHODS: Peer-reviewed literature and conference abstracts were analyzed for all relevant publications related to this issue. RESULTS: The past several decades have seen a shift from general to local anesthesia for penile prosthetic surgery. This has been well characterized and is seen as successful with different local anesthetic options and techniques. To date, only one study has provided follow-up for longer than 1 week regarding postoperative pain management for prosthetic surgery. CONCLUSION: Perioperative pain management for the patient receiving a penile prosthetic is well characterized; postoperative pain management is not. Although periprocedural local anesthesia has been well described for penile prosthesis surgery, a standardized postoperative pain management plan does not exist. This review highlights the need for further characterization of postoperative pain and the subsequent development of an algorithmic approach for management. Reinstatler L, Shee K, Gross MS. Pain Management in Penile Prosthetic Surgery: A Review of the Literature. Sex Med Rev 2018;6:162-169. PMID- 28735684 TI - Micro-Denervation of the Spermatic Cord for Post-Vasectomy Pain Management. AB - INTRODUCTION: Post-vasectomy pain syndrome (PVPS) is a challenging problem for the practicing urologist because of its unclear pathophysiology and no clearly established protocol for evaluation or treatment. PVPS is defined as at least 3 months of chronic or intermittent scrotal content pain after a vasectomy procedure once other etiologies for the pain have been ruled out. AIM: To systematically review the current literature on the effectiveness of micro denervation of the spermatic cord (MDSC) for PVPS. METHODS: A systematic literature search using PubMed, Scopus, Medline, Embase, and Cochrane databases for all reports pertaining to PVPS using the Medical Subject Heading terms post vasectomy pain syndrome and micro-denervation of spermatic cord through February 2017. MAIN OUTCOME MEASURES: Scrotal content pain after MDSC for PVPS. RESULTS: There were nine retrospective studies evaluating MDSC for chronic testicular pain. After omitting repeated series, there were 213 patients who underwent MDSC for chronic orchialgia. Only one study specifically reviewed the outcomes of patients who underwent MDSC for PVPS. In this study, 17 patients underwent MSDC for PVPS, with 13 (76.5%) reporting complete relief of pain at their first follow up visit. The other four patients had significant improvement in pain and were satisfied with the results. Long-term follow-up data were not available for this study. CONCLUSION: MDSC remains a valuable approach with high success rates and should be considered for PVPS that is refractory to medical therapy. MDSC appears to have the most success for patients who experience a temporary relief from a cord block and can significantly improve the patient's quality of life and ability to return to daily activities. Tan WP, Levine LA. Micro-Denervation of the Spermatic Cord for Post-Vasectomy Pain Management. Sex Med Rev 2018;6:328 334. PMID- 28735685 TI - Utilizing circulating tumour DNA in radiation oncology. AB - Emerging technologies for detection of circulating tumour DNA (ctDNA) are expanding the possibilities for clinical impact to patients with localized, potentially curable cancer. For such patients, ctDNA analysis could aid in prognostication, prediction of treatment response, longitudinal monitoring for adaptive treatment, and evaluation of minimal residual disease. Radiation oncologists currently have few tools at their disposal for predicting or rapidly assessing treatment efficacy. By reflecting the genetic and epigenetic makeup of tumours as well as dynamic changes with treatment, ctDNA as a biomarker for radiation response could enable new personalized treatment approaches. In this review, we will discuss recent advances in ctDNA technologies and potential clinical applications of ctDNA analysis throughout the therapeutic course. Furthermore, we will consider how ctDNA analysis could someday guide radiotherapy prescriptions by revealing differences in tumour radiophenotype. PMID- 28735686 TI - Nicotine pretreatment reduced cocaine-induced CPP and its reinstatement in a sex- and dose-related manner in adult C57BL/6J mice. AB - Previous preclinical studies have shown that nicotine pretreatment during adolescence increases the reinforcing actions of cocaine. However, little is known about the effect of prior nicotine administration on cocaine-induced conditioned place preference (CPP) and its reinstatement in adult mice. Besides, little information is available regarding the role of sex in this cross-talk between nicotine and cocaine. Thus, we examined if nicotine administration during adulthood would differentially alter cocaine-induced CPP, its extinction and reinstatement in male versus female mice and if the dose of nicotine was important in this regard. To this end, mice were pretreated with saline or nicotine (0.25 or 1mg/kg; twice daily for seven days) and then tested for place preference before and after single and repeated conditioning with cocaine (15mg/kg). Mice were then exposed to extinction training and tested for reinstatement of CPP. Our results showed that male and female mice pretreated with saline and conditioned with cocaine each exhibited a robust CPP after a single cocaine conditioning. However, this response was blunted in mice pretreated with the lower but not higher dose of nicotine. Female mice pretreated with the lower dose nicotine also failed to show CPP after repeated conditioning. Reinstatement of cocaine-induced CPP was also blunted in these mice compared to their respective controls. Together, these results suggest that nicotine administration during adulthood exerts differential effects on cocaine-induced CPP and its reinstatement in male and female mice and the dose of nicotine is important in this regard. PMID- 28735688 TI - Here/In This Issue and There/Abstract Thinking: An App for That? Complexities of Smartphone Technology in Psychiatry. PMID- 28735687 TI - On the sequential separation and quantification of 237Np, 241Am, thorium, plutonium, and uranium isotopes in environmental and urine samples. AB - The implementation of the one-pass-through separation technique using two stacked chromatography columns of TEVA - TRU resins for the separation of 237Np, 241Am, thorium, plutonium and uranium from environmental and urine samples was investigated. The sequential separation technique proved to be successful and gave similar results to those obtained when using individual separations. The analysis time was considerably improved. The amount of chemical waste was also reduced by 50% and the use of HClO4 was avoided. The technique of ICP-MS was also investigated as a complementary technique to alpha-spectrometry. PMID- 28735689 TI - A Quiet Crisis: Pediatric Patients Waiting for Inpatient Psychiatric Care. PMID- 28735690 TI - Polypharmacy in Youth Treated With Antipsychotics: Do Antidepressants or Stimulants Add to the Risk for Type 2 Diabetes? PMID- 28735691 TI - Complexity and Parsimony in Natural History Studies of Children With Autism Spectrum Disorder. PMID- 28735692 TI - Network Psychiatry: Computational Methods to Understand the Complexity of Psychiatric Disorders. PMID- 28735693 TI - Concomitant Use of Atypical Antipsychotics With Other Psychotropic Medication Classes and the Risk of Type 2 Diabetes Mellitus. AB - OBJECTIVE: More than half of youth treated with atypical antipsychotic (AAP) medications are also treated with concomitant antidepressants or stimulants. This study assessed the association between antidepressant or stimulant use concomitant with AAPs and the risk of incident type 2 diabetes mellitus (T2DM). METHOD: Medicaid Analytic eXtract data were used to conduct a retrospective cohort study of youth (aged 5-20 years) who initiated AAP treatment. In AAP treated youth, concomitant antidepressant (selective serotonin reuptake inhibitors [SSRI]/serotonin-norepinephrine reuptake inhibitors [SNRIs], tricyclic/other cyclic antidepressants [TCAs], and other antidepressants) or stimulant use was assessed. The risk of incident T2DM was estimated using discrete time failure models, adjusting for disease risk score estimated using >125 baseline and time-dependent covariates. RESULTS: Among 73,224 AAP initiators, 43.0% had concomitant antidepressant use (76.4% were SSRI/SNRIs) and 43.8% had concomitant stimulant use. The study cohort had an average follow-up of 24.8 months (median = 22.0 months, interquartile range [IQR] = 10.0-38.0 months). In current AAP-treated youth, concomitant SSRI/SNRI (relative risk [RR] = 1.84, 95% CI = 1.30-2.59) or TCA use (RR = 2.75, 95% CI = 1.28-5.87) was associated with an increased risk of T2DM. By contrast, concomitant use of other antidepressants or stimulants with AAPs was not associated with an increased risk of T2DM. In concomitant users of AAPs and SSRI/SNRIs, the risk of T2DM increased with the duration of SSRI/SNRI use (RR = 2.35, 95% CI = 1.15-4.83 for >=180 days vs. 1-180 days) as well as with the cumulative SSRI/SNRI dose (RR = 1.99, 95% CI = 1.08-3.67 for >2,700 mg vs. 1-2,700 mg fluoxetine dose equivalents), after adjusting for the duration and cumulative dose of AAP use. By contrast, in concomitant users of AAPs and stimulants, neither duration nor cumulative dose of stimulants was associated with an increased risk of T2DM. CONCLUSION: In AAP treated Medicaid-insured youth, concomitant SSRI/SNRI use was associated with a heightened risk of T2DM, which intensified with increasing duration and dose. PMID- 28735694 TI - Depression and Violence in Adolescence and Young Adults: Findings From Three Longitudinal Cohorts. AB - OBJECTIVE: Despite recent research demonstrating associations between violence and depression in adults, links in adolescents are uncertain. This study aims to assess the longitudinal associations between young people's depression and later violent outcomes. METHOD: We used data from three cohorts with different measurements of depression exposures and subsequent violent outcomes. In a Dutch community cohort Research on Adolescent Development And Relationships (RADAR; N = 623) and a population-based British birth cohort Avon Longitudinal Study of Parents and Children (ALSPAC; N = 4,030), we examined the longitudinal links between adolescent depressive symptoms and violent behaviors from age 13 to 17 years. In a total Finnish birth cohort (FBC 1987; N = 57,526), we estimated risk of violent convictions in individuals clinically diagnosed with depression from age 15 to 27 years. RESULTS: During a mean follow-up period of 4 years, the adjusted odds ratio (aOR) of violent behaviors per unit of increase in depressive symptoms was 1.7 (95% CI = 1.2-2.5) in the Dutch RADAR community sample and 1.8 (95% CI = 1.4-2.3) in the British ALSPAC birth cohort. In the FBC 1987 cohort, the aOR of violent convictions was 2.1 (95% CI = 1.7-2.7) among individuals with a depression diagnosis compared with general population controls without depression. All risk estimates were adjusted for family socioeconomic status and previous violence. CONCLUSION: Consistent findings across three longitudinal studies suggest that clinical guidelines should consider recommending risk assessment for violence in young people with depression. The benefits of targeting risk management in subgroups by gender need further investigation. PMID- 28735695 TI - Variation in the Early Trajectories of Autism Symptoms Is Related to the Development of Language, Cognition, and Behavior Problems. AB - OBJECTIVE: The objectives of this study were to model more homogeneous subgroups within autism spectrum disorder (ASD) based on early trajectories of core symptoms; and to further characterize these subgroups in terms of trajectories of language, cognition, co-occurring (attention-deficit/hyperactivity disorder [ADHD]-related) traits and clinical outcome diagnosis. METHOD: Children (N = 203) referred for possible ASD at ages 1 to 4 years were assessed at three time points at intervals ranging from 9 months to 3 years. Assessments included standardized measures for ASD (Autism Diagnostic Observation Schedule [ADOS]), language (ADOS language item), nonverbal IQ (NV-IQ; different tests adequate to chronological/mental age), and parent-reported behavioral problems (Infant Toddler Social and Emotional Assessment, Child Behavior Checklist). RESULTS: Latent-class growth curve analysis with ADOS total scores led to the identification of three main stable and two small improving groups: a severe stable group (19.5% of sample)-the only group without considerable language improvement-showed persistent low NV-IQ and marked increase in attention problems over time; a moderate-stable group (21.7%) with below-average increasing NV-IQ; and a mild-stable group (48%) with stable-average NV-IQ and the highest scores on ADHD-related traits, whose ASD outcome diagnoses increased despite stable-low ASD scores. Two groups (each 5.4%) improved: one moved from severe to moderate ASD scores, and the other moved from moderate to mild/nonspectrum scores. Both of these groups improved on language, NV-IQ, and ADHD-related traits. CONCLUSION: Results support the high stability of ASD symptoms into various severity levels, but also highlight the significant contribution of non-ASD domains in defining and explaining the different ASD trajectories. PMID- 28735696 TI - The Network Structure of Posttraumatic Stress Symptoms in Children and Adolescents Exposed to Disasters. AB - OBJECTIVE: To evaluate current theoretical assumptions about the nature of pediatric posttraumatic stress disorder (PTSD) by examining the network structure of PTSD in a sample of youth exposed to disasters and testing for age differences. Network analysis provides the opportunity to identify "central" symptoms that might hold an outsized influence over others and are important targets for research and treatment. The authors hypothesized that particular symptoms would exhibit greater influence over others. They further hypothesized marked differences in symptom networks across children and adolescents. METHOD: Participants were 786 youth 8 to 13 years old (children) and 14 to 18 years old (adolescents) exposed to Hurricanes Katrina and Gustav who were assessed for PTSD symptoms using the University of California-Los Angeles PTSD Reaction Index for Children. Network models were computed and constructed using the R-package qgraph, which estimates associations between symptoms and forms graphic network models. RESULTS: Consistent with the hypotheses, the symptom network demonstrated meaningful variability across age, particularly in the strength of associations, and the relative importance of individual symptoms to the network as a whole. Results further demonstrated that symptoms cluster together in a manner that adds a unique perspective to current model conceptualizations. CONCLUSION: Network analysis is a potentially important additional conceptualization of psychopathology with related data analytic techniques. Results suggest that PTSD can be characterized as a web of interactions between symptoms. This work illuminates differences in the PTSD symptom network across development, such as the link between numbness of negative affect and amnesia in children, but not in teens, and how the critical symptoms within that network differ across childhood and adolescence. Network analysis could allow the re-envisioning of the nature of this complex disorder with new avenues for research and clinical practice. PMID- 28735697 TI - Disentangling Heterogeneity of Childhood Disruptive Behavior Problems Into Dimensions and Subgroups. AB - OBJECTIVE: Irritable and oppositional behaviors are increasingly considered as distinct dimensions of oppositional defiant disorder. However, few studies have explored this multidimensionality across the broader spectrum of disruptive behavior problems (DBPs). This study examined the presence of dimensions and distinct subgroups of childhood DBPs, and the cross-sectional and longitudinal associations between these dimensions. METHOD: Using factor mixture models (FMMs), the presence of dimensions and subgroups of DBPs was assessed in the Generation R Study at ages 6 (n = 6,209) and 10 (n = 4,724) years. Replications were performed in two population-based cohorts (Netherlands Twin Registry, n = 4,402, and Swedish Twin Study of Child and Adolescent Development, n = 1,089) and a clinical sample (n = 1,933). We used cross-lagged modeling in the Generation R Study to assess cross-sectional and longitudinal associations between dimensions. DBPs were assessed using mother-reported responses to the Child Behavior Checklist. RESULTS: Empirically obtained dimensions of DBPs were oppositional behavior (age 6 years), disobedient behavior, rule-breaking behavior (age 10 years), physical aggression, and irritability (both ages). FMMs suggested that one-class solutions had the best model fit for all dimensions in all three population-based cohorts. Similar results were obtained in the clinical sample. All three dimensions, including irritability, predicted subsequent physical aggression (range, 0.08-0.16). CONCLUSION: This study showed that childhood DBPs should be regarded as a multidimensional phenotype rather than comprising distinct subgroups. Incorporating multidimensionality will improve diagnostic accuracy and refine treatment. Future studies need to address the biological validity of the DBP dimensions observed in this study; herein lies an important opportunity for neuroimaging and genetic measures. PMID- 28735698 TI - Childhood Predictors of Adult Functional Outcomes in the Multimodal Treatment Study of Attention-Deficit/Hyperactivity Disorder (MTA). AB - OBJECTIVE: Recent results from the Multimodal Treatment Study of Attention Deficit/Hyperactivity Disorder (ADHD; MTA) have demonstrated impairments in several functioning domains in adults with childhood ADHD. The childhood predictors of these adult functional outcomes are not adequately understood. The objective of the present study was to determine the effects of childhood demographic, clinical, and family factors on adult functional outcomes in individuals with and without childhood ADHD from the MTA cohort. METHOD: Regressions were used to determine associations of childhood factors (age range 7 10 years) of family income, IQ, comorbidity (internalizing, externalizing, and total number of non-ADHD diagnoses), parenting styles, parental education, number of household members, parental marital problems, parent-child relationships, and ADHD symptom severity with adult outcomes (mean age 25 years) of occupational functioning, educational attainment, emotional functioning, sexual behavior, and justice involvement in participants with (n = 579) and without (n = 258) ADHD. RESULTS: Predictors of adult functional outcomes in ADHD included clinical factors such as baseline ADHD severity, IQ, and comorbidity; demographic factors such as family income, number of household members and parental education; and family factors such as parental monitoring and parental marital problems. Predictors of adult outcomes were generally comparable for children with and without ADHD. CONCLUSION: Childhood ADHD symptoms, IQ, and household income levels are important predictors of adult functional outcomes. Management of these areas early on, through timely treatments for ADHD symptoms, and providing additional support to children with lower IQ and from households with low incomes, could assist in improving adult functioning. PMID- 28735701 TI - Tainted. PMID- 28735700 TI - Sex Differences in the Relationship Between Conduct Disorder and Cortical Structure in Adolescents. AB - OBJECTIVE: Previous studies have reported reduced cortical thickness and surface area and altered gyrification in frontal and temporal regions in adolescents with conduct disorder (CD). Although there is evidence that the clinical phenotype of CD differs between males and females, no studies have examined whether such sex differences extend to cortical and subcortical structure. METHOD: As part of a European multisite study (FemNAT-CD), structural magnetic resonance imaging (MRI) data were collected from 48 female and 48 male participants with CD and from 104 sex-, age-, and pubertal-status-matched controls (14-18 years of age). Data were analyzed using surface-based morphometry, testing for effects of sex, diagnosis, and sex-by-diagnosis interactions, while controlling for age, IQ, scan site, and total gray matter volume. RESULTS: CD was associated with cortical thinning and higher gyrification in ventromedial prefrontal cortex in both sexes. Males with CD showed lower, and females with CD showed higher, supramarginal gyrus cortical thickness compared with controls. Relative to controls, males with CD showed higher gyrification and surface area in superior frontal gyrus, whereas the opposite pattern was seen in females. There were no effects of diagnosis or sex by-diagnosis interactions on subcortical volumes. Results are discussed with regard to attention-deficit/hyperactivity disorder, depression, and substance abuse comorbidity, medication use, handedness, and CD age of onset. CONCLUSION: We found both similarities and differences between males and females in CD cortical structure associations. This initial evidence that the pathophysiological basis of CD may be partly sex-specific highlights the need to consider sex in future neuroimaging studies and suggests that males and females may require different treatments. PMID- 28735699 TI - Establishing Clinical Cutoffs for Response and Remission on the Screen for Child Anxiety Related Emotional Disorders (SCARED). AB - OBJECTIVE: To determine optimal percent reduction and raw score cutoffs on the parent- and child-report Screen for Child Anxiety Related Emotional Disorders (SCARED) for predicting treatment response and remission among youth with anxiety disorders. METHOD: Data were obtained from youth (N = 438; 7-17 years old) who completed treatment in the Child/Adolescent Anxiety Multimodal treatment Study, a multisite, randomized clinical trial that examined the relative efficacy of medication (sertraline), cognitive-behavioral therapy (Coping Cat), their combination, and pill placebo for the treatment of separation anxiety disorder, generalized anxiety disorder, and social phobia. The parent- and youth-report SCARED were administered at pre- and posttreatment. Quality receiver operating characteristic methods evaluated the performance of various SCARED percent reduction and absolute cutoff scores in predicting treatment response and remission, as defined by posttreatment ratings on the Clinical Global Impression scales and the Anxiety Disorders Interview Schedule. RESULTS: Reductions of 55% on the SCARED-Parent and 50% on the SCARED-Youth optimally predicted treatment response. Posttreatment absolute raw scores of 10 (SCARED-Parent) and 12 (SCARED Youth) optimally predicted remission in the total sample, although separate SCARED-Parent cutoffs for children (12-13) and adolescents (9) showed greatest quality of efficiency. Each cutoff significantly predicted response and remission at 6-month follow-up. CONCLUSION: Results serve as guidelines for operationalizing treatment response and remission on the SCARED, which could help clinicians systematically monitor treatment outcomes of youth with anxiety disorders in a cost- and time-efficient manner. Clinical trial registration information-Child and Adolescent Anxiety Disorders (CAMS); http://clinicaltrials.gov/; NCT00052078. PMID- 28735703 TI - Ovarian mass-differentiating benign from malignant: the value of the International Ovarian Tumor Analysis ultrasound rules. AB - Ovarian cancer, the fifth most common cause of cancer death among women, has the highest mortality rate of all gynecologic cancers. General survival rate is <50% but can reach 90% if disease is detected early. Ultrasound is presently the best modality to differentiate between benign and malignant status. The patient with a malignant mass should be referred to an oncology surgeon since results have been shown to be superior to treatment by a specialist. Several ultrasound-based scoring systems exist for assessing the risk of an ovarian tumor to be malignant. The International Ovarian Tumor Analysis group published 2 such systems: the ultrasound Simple Rules and the Assessment of Different NEoplasias in the adneXa model. The Simple Rules classifies a tumor as benign, malignant, or indeterminate and the Assessment of Different NEoplasias in the adneXa model determines the risk for a tumor to be benign or malignant and, if malignant, the risk of various stages. Sensitivity of the Simple Rules and Assessment of Different NEoplasias in the adneXa model (using a cut-off of 10% to predict malignancy) are 92% and 96.5%, respectively, and specificities are 96% and 71.3%, respectively. These models are the best predictive tests for the preoperative classification of adnexal tumors. Their intent is to help the specialist make management decisions when faced with a patient with a persistent ovarian mass. The models are simple, are easy to use, and have been validated in multiple reports but not in the United States. We suggest they should be validated and widely introduced into medical practice in the United States. PMID- 28735702 TI - Quality measures in high-risk pregnancies: Executive Summary of a Cooperative Workshop of the Society for Maternal-Fetal Medicine, National Institute of Child Health and Human Development, and the American College of Obstetricians and Gynecologists. AB - Providers perceive current obstetric quality measures as imperfect and insufficient. Our organizations convened a "Quality Measures in High-Risk Pregnancies Workshop." The goals were to (1) review the current landscape regarding quality measures in obstetric conditions with increased risk for adverse maternal or fetal outcomes, (2) evaluate the available evidence for management of common obstetric conditions to identify those that may drive the highest impact on outcomes, quality, and value, (3) propose measures for high risk obstetric conditions that reflect enhanced quality and efficiency, and (4) identify current research gaps, improve methods of data collection, and recommend means of change. PMID- 28735704 TI - Effect of remote cesarean delivery on complications during hysterectomy: a cohort study. AB - BACKGROUND: Cesarean delivery is performed frequently worldwide, and follow-up studies that report complications at subsequent surgery are warranted. OBJECTIVES: The aim of the study was to investigate the association between a previous abdominal delivery and complications during a subsequent hysterectomy and to estimate the fraction of complications that are driven by the presence of adhesions. STUDY DESIGN: This was a longitudinal population-based register study of 25354 women who underwent a benign hysterectomy at 46 hospital units in Sweden 2000-2014. RESULTS: Adhesions were found in 45% of the women with a history of cesarean delivery. Organ injury affected 2.2% of the women. The risk of organ injury (adjusted odds ratio, 1.74; 95% confidence interval, 1.41-2.15) and postoperative infection (adjusted odds ratio, 1.26; 95% confidence interval, 1.15 1.39) was increased with previous cesarean delivery, irrespective of whether adhesions were present or not. The direct effect on organ injury by a personal history of cesarean delivery was estimated to 73%, and only 27% was mediated by the presence of adhesions. Previous cesarean delivery was a predictor of bladder injury (adjusted odds ratio, 1.86; 95% confidence interval, 1.40-2.47) and bowel injury (adjusted odds ratio, 1.83; 95% confidence interval, 1.10-3.03), but not ureter injury. A personal history of other abdominal surgeries was associated with bowel injury (adjusted odds ratio, 2.27; 95% confidence interval, 1.37 3.78), and the presence of endometriosis increased the risk of ureter injury (adjusted odds ratio, 2.15; 95% confidence interval, 1.34-3.44). CONCLUSION: Previous cesarean delivery is associated with an increased risk of complications during a subsequent hysterectomy, but the risk is only partly attributable to the presence of adhesions. Previous cesarean delivery and presence of endometriosis were major predisposing factors of organ injury at the time of the hysterectomy, whereas background and perioperative characteristics were of minor importance. PMID- 28735705 TI - Impact of preimplantation genetic screening on donor oocyte-recipient cycles in the United States. AB - OBJECTIVE: Our objective was to estimate the contribution of preimplantation genetic screening to in vitro fertilization pregnancy outcomes in donor oocyte recipient cycles. STUDY DESIGN: This was a retrospective cross-sectional study of US national data from the Society for Assisted Reproductive Technology Clinic Outcome Reporting System between 2005 and 2013. Society for Assisted Reproductive Technology Clinic Outcome Reporting relies on voluntarily annual reports by more than 90% of US in vitro fertilization centers. We evaluated pregnancy and live birth rates in donor oocyte-recipient cycles after the first embryo transfer with day 5/6 embryos. Statistical models, adjusted for patient and donor ages, number of embryos transferred, race, infertility diagnosis, and cycle year were created to compare live birth rates in 392 preimplantation genetic screening and 20,616 control cycles. RESULTS: Overall, pregnancy and live birth rates were significantly lower in preimplantation genetic screening cycles than in control cycles. Adjusted odds of live birth for preimplantation genetic screening cycles were reduced by 35% (odds ratio, 0.65, 95% confidence interval, 0.53-0.80; P < .001). CONCLUSION: Preimplantation genetic screening, as practiced in donor oocyte-recipient cycles over the past 9 years, has not been associated with improved odds of live birth or reduction in miscarriage rates. PMID- 28735707 TI - Do Intelligent Robots Need Emotion? AB - What is the place of emotion in intelligent robots? Researchers have advocated the inclusion of some emotion-related components in the information-processing architecture of autonomous agents. It is argued here that emotion needs to be merged with all aspects of the architecture: cognitive-emotional integration should be a key design principle. PMID- 28735708 TI - Brain and Social Networks: Fundamental Building Blocks of Human Experience. AB - How do brains shape social networks, and how do social ties shape the brain? Social networks are complex webs by which ideas spread among people. Brains comprise webs by which information is processed and transmitted among neural units. While brain activity and structure offer biological mechanisms for human behaviors, social networks offer external inducers or modulators of those behaviors. Together, these two axes represent fundamental contributors to human experience. Integrating foundational knowledge from social and developmental psychology and sociology on how individuals function within dyads, groups, and societies with recent advances in network neuroscience can offer new insights into both domains. Here, we use the example of how ideas and behaviors spread to illustrate the potential of multilayer network models. PMID- 28735706 TI - Amniotic fluid transcriptomics reflects novel disease mechanisms in fetuses with myelomeningocele. AB - BACKGROUND: Cell-free RNA in amniotic fluid supernatant reflects developmental changes in gene expression in the living fetus, which includes genes that are specific to the central nervous system. Although it has been previously shown that central nervous system-specific transcripts are present in amniotic fluid supernatant, it is not known whether changes in the amniotic fluid supernatant transcriptome reflect the specific pathophysiologic condition of fetal central nervous system disorders. In myelomeningocele, there is open communication between the central nervous system and amniotic fluid. OBJECTIVES: The purpose of this study was to identify molecular pathophysiologic changes and novel disease mechanisms that are specific to myelomeningocele by the analysis of amniotic fluid supernatant cell-free RNA in fetuses with open myelomeningocele. STUDY DESIGN: Amniotic fluid supernatant was collected from 10 pregnant women at the time of the open myelomeningocele repair in the second trimester (24.5+/-1.0 weeks); 10 archived amniotic fluid supernatant from sex and gestational age matched euploid fetuses without myelomeningocele were used as controls (20.9+/ 0.9 weeks). Differentially regulated gene expression patterns were analyzed with the use of human genome expression arrays. RESULTS: Fetuses with myelomeningocele had 284 differentially regulated genes (176 up- and 108 down-regulated) in amniotic fluid supernatant. Known genes that were associated with myelomeningocele (PRICKLE2, GLI3, RAB23, HES1, FOLR1) and novel dysregulated genes were identified in association with neurodevelopment and neuronal regeneration (up-regulated, GAP43 and ZEB1) or axonal growth and guidance (down regulated, ACAP1). Pathway analysis demonstrated a significant contribution of inflammation to disease and a broad influence of Wnt signaling pathways (Wnt1, Wnt5A, ITPR1). CONCLUSION: Transcriptomic analyses of living fetuses with myelomeningocele with the use of amniotic fluid supernatant cell-free RNA demonstrated differential regulation of specific genes and molecular pathways relevant to this central nervous system disorder, which resulted in a new understanding of pathophysiologic changes. The data also suggested the importance of pathways that involve secondary disease, such as inflammation, in myelomeningocele. These newly identified pathways may lead to hypotheses that can test novel therapeutic targets as adjuncts to fetal surgical repair. PMID- 28735710 TI - Comparison of two microextraction methods based on solidification of floating organic droplet for the determination of multiclass analytes in river water samples by liquid chromatography tandem mass spectrometry using Central Composite Design. AB - Two low density organic solvents based liquid-liquid microextraction methods, namely Vortex assisted liquid-liquid microextraction based on solidification of floating organic droplet (VALLME-SFO) and Dispersive liquid-liquid microextraction based on solidification of floating organic droplet(DLLME-SFO) have been compared for the determination of multiclass analytes (pesticides, plasticizers, pharmaceuticals and personal care products) in river water samples by using liquid chromatography tandem mass spectrometry (LC-MS/MS). The effect of various experimental parameters on the efficiency of the two methods and their optimum values were studied with the aid of Central Composite Design (CCD) and Response Surface Methodology(RSM). Under optimal conditions, VALLME-SFO was validated in terms of limit of detection, limit of quantification, dynamic linearity range, determination of coefficient, enrichment factor and extraction recovery for which the respective values were (0.011-0.219ngmL-1), (0.035 0.723ngmL-1), (0.050-0.500ngmL-1), (R2=0.992-0.999), (40-56), (80-106%). However, when the DLLME-SFO method was validated under optimal conditions, the range of values of limit of detection, limit of quantification, dynamic linearity range, determination of coefficient, enrichment factor and extraction recovery were (0.025-0.377ngmL-1), (0.083-1.256ngmL-1), (0.100-1.000ngmL-1), (R2=0.990-0.999), (35-49), (69-98%) respectively. Interday and intraday precisions were calculated as percent relative standard deviation (%RSD) and the values were <=15% for VALLME-SFO and DLLME-SFO methods. Both methods were successfully applied for determining multiclass analytes in river water samples. PMID- 28735709 TI - Interpersonal problems across levels of the psychopathology hierarchy. AB - We examined the relationship between psychopathology and interpersonal problems in a sample of 825 clinical and community participants. Sixteen psychiatric diagnoses and five transdiagnostic dimensions were examined in relation to self reported interpersonal problems. The structural summary method was used with the Inventory of Interpersonal Problems Circumplex Scales to examine interpersonal problem profiles for each diagnosis and dimension. We built a structural model of mental disorders including factors corresponding to detachment (avoidant personality, social phobia, major depression), internalizing (dependent personality, borderline personality, panic disorder, posttraumatic stress, major depression), disinhibition (antisocial personality, drug dependence, alcohol dependence, borderline personality), dominance (histrionic personality, narcissistic personality, paranoid personality), and compulsivity (obsessive compulsive personality). All dimensions showed good interpersonal prototypicality (e.g., detachment was defined by a socially avoidant/nonassertive interpersonal profile) except for internalizing, which was diffusely associated with elevated interpersonal distress. The findings for individual disorders were largely consistent with the dimension that each disorder loaded on, with the exception of the internalizing and dominance disorders, which were interpersonally heterogeneous. These results replicate previous findings and provide novel insights into social dysfunction in psychopathology by wedding the power of hierarchical (i.e., dimensional) modeling and interpersonal circumplex assessment. PMID- 28735711 TI - Stereoselective separation of beta-adrenergic blocking agents containing two chiral centers by countercurrent chromatography. AB - Four beta-adrenergic blocking agents, including 1-[(1-methylethyl)amino]-3 phenoxy-2-propanol (1), 1-[(1-methylethyl)amino]-3-(3-methylphenoxy)-2-propanol (2), 1,1'-[1,4-phenylenebis(oxy)]bis[3-[(1-methylethyl)amino]-2-propanol (3) and 1,1'-[(4-methyl-1,2-phenylene)bis(oxy)]bis[3-[(1-methylethyl)amino]-2-propanol (4), were stereoselectively separated by countercurrent chromatography using di-n hexyl l-tartrate and boric acid as chiral selector. The compounds (3) and (4) have four optical isomers since they contained two chiral centers. A two-phase solvent system composed of chloroform-0.05molL-1 of acetate buffer containing 0.10molL-1 of boric acid (1:1, v/v) was selected, in which 0.10molL-1 of di-n hexyl l-tartrate was added in the organic phase as chiral selector. 20-42mg of each racemate was stereoselectively separated by countercurrent chromatography in a single run with high purity of 96-98%, and the recovery of each separated compound reached around 87-93%. This is the first time report on successful stereoselective separation of optical isomeric compounds containing two chiral centers by countercurrent chromatography. At the same time, a chiral stationary phase was screened for analytical stereoselective separation of compounds (3) and (4) by high performance liquid chromatography. PMID- 28735712 TI - Analysis of polychlorinated dibenzo-p-dioxins and dibenzofurans in stack gas emissions by gas chromatography-atmospheric pressure chemical ionization-triple quadrupole mass spectrometry. AB - A gas chromatography coupled to triple-quadrupole mass spectrometry (GC (QqQ)MS/MS) including a soft-ionization through an atmospheric pressure chemical ionization (APCI) source based method was compared with the high resolution mass spectrometry (HRMS) standard reference method EN1948, for the analysis of polychlorinated dibenzo-p-dioxins and furans (PCDD/Fs) in stack gas emissions. The stack emission samples were collected, both, by manual method sampling (from 6 to 8h) and by long-term sampling systems (sampling time of several weeks). This work presents the first comparison of GC-(QqQ)MS/MS with APCI source with the European Standard EN1948 technique for stack gas emissions. Sample concentrations ranged from 0.5 to 596pg I-TEQ/Nm3. Comparative results in all investigated samples showed relative errors that were within +/-15%. These results make GC (QqQ)MS/MS with APCI suitable for the quantitative analysis of dioxins in the studied samples and create a real alternative tool to the reference sector GC HRMS instruments. PMID- 28735713 TI - Superparamagnetic graphene oxide-magnetite nanoparticle composites for uptake of actinide ions from mildly acidic feeds. AB - Super paramagnetic graphene oxide (GO) - Fe3O4 nanoparticle composites were prepared and characterized by conventional techniques such as XRD, SEM, EDX, FT IR, Raman, XPS, DLS and zeta potential, etc. TEM studies have confirmed nanoparticle nature of the composites. The GO-magnetic nanoparticle composites can be dispersed in mildly acidic aqueous solutions and get concentrated in a small volume under application of an external magnetic field. The composites were evaluated for the uptake of actinide ions such as Am3+, UO22+, Th4+ and Pu4+ from mildly acidic aqueous solutions. Am3+ sorption sharply increased with pH as the Kd values increased from about 10 at pH 1 to 105 at pH 3 beyond which a plateau in the Kd values was seen. Eu3+ displayed nearly comparable uptake behaviour to that of Am3+ while the uptake of other metal ions followed the trend: Pu(IV)>Th(IV)>>UO22+. The adsorption behaviour of Am3+ onto the graphene oxide - Fe3O4 nanoparticle composites fitted very well to the Langmuir as well as Temkin isotherm models. The desorption rate (using 1M HNO3) was fast and reusability study results were highly encouraging. The very high uptake values suggest possible application of the magnetic nanoparticles in radioactive waste remediation in natural ground water. PMID- 28735714 TI - Internal Urethrotomy With Intralesional Mitomycin C: An Effective Option for Endoscopic Management of Recurrent Bulbar and Bulbomembranous Urethral Strictures. AB - OBJECTIVE: To describe our experience with direct visual internal urethrotomy (DVIU) and mitomycin C (MMC) for recurrent bulbar and bulbomembranous urethral strictures of radiation and non-radiation-induced etiologies. METHODS: We reviewed our database of consecutive patients presenting to our tertiary care institution with recurrent bulbar and bulbomembranous urethral strictures who underwent DVIU with MMC from 2011 to 2016. Patients were stratified by radiation induced strictures (RIS) vs non-RIS. Cold-knife incisions were made at 12-, 3-, and 9-o'clock positions followed by intralesional injection of 10 mL MMC (0.4 mg/mL) in 0.2-0.4 mL aliquots and 1 month of postoperative daily clean intermittent catheterization (CIC). RESULTS: All 44 patients (RIS n = 18, non-RIS n = 26) failed prior endoscopic management or urethroplasty. Median stricture length was 2.0 cm (interquartile range [IQR] 1.0-2.5). Over a median follow-up of 25.8 months (IQR 12.9-47.2), 75.0% of patients (33/44) required no additional surgical intervention (RIS 12/18, 66.7%; non-RIS 21/26, 80.8%). Median time to stricture recurrence among those who recurred was 10.7 months (IQR 3.9-17.6; RIS 9.4 months, IQR 3.5-17.6; non-RIS 11.2 months, IQR 8.0-25.6). Four patients (RIS n = 2, non-RIS n = 2) elected to undergo urethroplasty for recurrence. A second DVIU with MMC was performed in the remaining recurrences (n = 7) with no further surgical intervention required in 37 of 40 of patients (92.5%) overall (RIS 14/16, 87.5%; non-RIS 23/24, 95.8%). No long-term complications were attributable to MMC. CONCLUSION: DVIU with MMC and short-term CIC for recurrent, short, bulbar and bulbomembranous urethral strictures is a safe endoscopic modality with promising early results. This approach may be useful for patients who are suboptimal candidates for open reconstruction. PMID- 28735715 TI - Thirty-day Morbidity of Abdominal Sacrocolpopexy Is Influenced by Additional Surgical Treatment for Stress Urinary Incontinence. AB - OBJECTIVE: To assess the impact of concurrent anti-incontinence procedure (AIP) at time of abdominal sacrocolpopexy (ASC) on 30-day complications, readmission, and reoperation. METHODS: The American College of Surgeons National Surgical Quality Improvement Program database from 2006 to 2013 was queried to identify patients who underwent ASC with or without AIP. We assessed baseline characteristics and 30-day perioperative outcomes including complications, readmission, and reoperation. RESULTS: There were 4793 patients who underwent ASC, of whom 1705 underwent concurrent AIP (35.6%). The majority of patients (4414, 92.1%) were treated by a gynecologist, but those treated by a urologist were older, had higher American Society of Anesthesiologists (ASA) class, and had increased frailty. Rates of 30-day postoperative urinary tract infection (UTI) and overall complication were higher among women who underwent concurrent AIP (4.75% vs 2.33%, P <.001; 7.74% vs 6.02%, P = .02). On multivariate analysis controlling for age, body mass index, approach, ASA physical status, modified frailty index, resident involvement, and surgeon specialty, AIP was associated with increased odds of UTI (odds ratio 2.20, 95% confidence interval 1.14-4.13, P = .02) and increased odds of overall complication (odds ratio 1.80, 95%confidence interval 1.10-2.93, P = .02). Thirty-day readmission and reoperation rates did not differ between the groups. CONCLUSION: AIP performed at the time of ASC are associated with higher rates of 30-day postoperative UTI but do not impact 30-day readmission or reoperation. The decision to perform AIP at the time of ASC should be made following a thorough discussion of the risks and benefits, including the potential for increased UTI with concurrent AIP. PMID- 28735716 TI - 69-Year-Old Man With Abdominal Pain and Obstipation. PMID- 28735717 TI - Real-Time Cineangiography Visualization of Cerebral Aneurysm Rupture in an Awake Patient: Anatomic, Physiological, and Functional Correlates. AB - Intracranial aneurysms are common and, on a population-based perspective, are a major cause of morbidity and mortality as a result of mass effect or rupture. Cerebral angiography is the primary technique used for the diagnosis of cerebral aneurysms, and the imaging data have additional utility for planning medical, endovascular, or surgical treatments. An extremely rare periprocedural complication of cerebral angiography is rupture of the aneurysm, either as a chance phenomenon or as a result of some physiologic change or mechanical effect. We report on a single awake, alert patient who experienced intraprocedural aneurysm rupture that was recorded in real time during diagnostic cerebral angiography and subsequently proved fatal. Rupture occurred shortly after the completion of contrast material injection into a semi-open vascular bed and appeared to be temporally unrelated to any supranormal change in systemic physiology. No therapeutic endovascular procedure was planned or attempted. From the high-quality sequential, frame-by-frame images, and electronic sedation and anesthesiology records, plus our own real-time observations (G.L., W.L.L.), we were able (for educational purposes) to reconstruct the time course of rupture of the aneurysm, the velocity and pattern of blood escaping the aneurysm and entering the subarachnoid space, and other physiologic and functional correlates (blood pressure changes, alterations in consciousness) that may be critical to our understanding of the mechanism and consequences of aneurysm rupture. PMID- 28735718 TI - Prevalence and Characteristics of Work Anxiety in Medical Rehabilitation Patients: A Cross-Sectional Observation Study. AB - OBJECTIVE: To investigate frequency, type, and characteristics of work anxieties in patients with somatic illness. DESIGN: Cross-sectional observation study. SETTING: Neurology, orthopedic, and cardiology rehabilitation clinics. PARTICIPANTS: Patients (N=1610; age, 18-65y) with work anxieties. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Patients who scored high on at least 2 of 9 items in the work-anxiety screening questionnaire and who reported impairment were investigated with a differential diagnostic interview on work anxieties and with the Mini-International Neuropsychiatric Interview on non-work-related common mental disorders. Patients also filled out a self-rating questionnaire on their subjective symptom load and sociodemographic data. RESULTS: Approximately 20% to 27% of the investigated inpatients in somatic rehabilitation (altogether n=393) received a work-anxiety diagnosis. Patients with orthopedic illness report highest work anxiety and have previous longest sick leave (20.6wk in the past 12mo). Patients with orthopedic illness suffer from work-related adjustment disorder with anxiety, social anxieties, and workplace phobias, whereas patients with cardiac illness are more often affected by hypochondriac anxieties. Anxieties of insufficiency and worrying occur equally in all indications. CONCLUSIONS: About a quarter of patients in somatic rehabilitation are in need of additional diagnostic attention owing to work anxieties. Differential diagnostic of work anxiety is needed for initiating adequate therapeutic action. Somatic rehabilitation physicians should be aware of work anxieties in their patients, especially in patients with orthopedic illness with previous long-term sick leave. PMID- 28735719 TI - Treatment With Chemotherapy and Cognitive Functioning in Older Adult Cancer Survivors. AB - OBJECTIVE: To investigate whether treatment of cancer with chemotherapy, as compared with surgery and radiation, differentially affects cognitive functioning in older adults. DESIGN: Latent class growth analysis approach. SETTING: Health and Retirement Study. PARTICIPANTS: Older adults (N=403) with a new diagnosis of cancer who were still alive 4 years after their diagnosis. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Cognition (degree of immediate recall and delayed recall of a word list). RESULTS: Findings indicated that 3 classes of cognitive functioning best fit the data, specifically high, middle, and low recall classes. Individuals treated with chemotherapy were significantly more likely to be in the high recall class, with no effect of receiving surgery or radiation. When interactions with demographic predictors were entered into the model, an Age * Treatment interaction was present such that individuals younger than 80 years were more likely to both receive chemotherapy and have high recall cognition. CONCLUSIONS: Three distinct classes of cognitive functioning emerged in older adults with cancer. Treatment with chemotherapy predicted likely membership in the high recall class in this sample of cancer survivors; however, this was due to an Age * Treatment interaction. Implications for understanding cognitive sequelae of cancer in late life are discussed. PMID- 28735720 TI - Randomized Controlled Trial to Examine the Impact of Aquatic Exercise Training on Functional Capacity, Balance, and Perceptions of Fatigue in Female Patients With Multiple Sclerosis. AB - OBJECTIVE: To assess the effects of an 8-week aquatic exercise training program on functional capacity, balance, and perceptions of fatigue in women with multiple sclerosis (MS). DESIGN: Randomized controlled design. SETTING: Referral center of an MS society. PARTICIPANTS: Women (N=32; mean age +/- SD, 36.4+/-8.2y) with diagnosed relapsing-remitting MS. After undergoing baseline testing by a neurologist, participants were allocated to either an intervention (aquatic training program, n=17) or a control group (n=15). INTERVENTIONS: The intervention consisted of an 8-week aquatic training program (3 supervised training sessions per week; session duration, 45-60min; 50%-75% estimated maximum heart rate). MAIN OUTCOME MEASURES: Six-minute walk test (6-MWT), balance (Berg Balance Scale [BBS]), and perceptions of fatigue (Modified Fatigue Impact Scale; [MFIS]) at baseline and after the 8-week intervention. Differences over time between the experimental and control groups were assessed by a 2*2 (group by time) repeated-measures analysis of variance. RESULTS: Thirty-two women completed the 8-week aquatic training intervention (experimental group, n=17; control group, n=15). All outcome measures improved in the experimental group: 6-MWT performance (pretest mean +/- SD, 451+/-58m; posttest mean +/- SD, 503+/-57m; P<.001); BBS (pretest mean +/- SD, 53.59+/-1.70; posttest mean +/- SD, 55.18+/ 1.18; P<.001), and MFIS (pretest mean +/- SD, 43.1+/-14.6; posttest mean +/- SD, 32.8+/-5.9; P<.01). A significant group-by-time interaction was evident between the experimental and control groups for 6-MWT (P<.001, partial eta2 [etap2]=.551), BBS (P<.001, etap2=.423), and MFIS (P<.001, etap2=.679). CONCLUSIONS: Aquatic exercise training improved functional capacity, balance, and perceptions of fatigue in women with MS. PMID- 28735721 TI - [The first moments of the carer: The process of becoming a caregiver of a dependent elderly relative]. AB - AIM: Describe the initial process through which people who imminently become caregivers of a dependent elderly relative. DESIGN: Qualitative study, for which its analysis has been directed by Grounded Theory principles. LOCATION: This study was conducted in the Health Districts of Jaen, during 2015 and 2016 at the community level. PARTICIPANTS AND/OR CONTEXTS: The recruitment was carried out by managers of the Health Centres of each Health District, who located the participants who met the inclusion criteria and invited them to participate in the study. METHOD: Eleven in-depth interviews were carried out, until saturation of information, on individuals who had been caring for an older relative with dependency for less than one year. RESULTS: Three phases have been described during this process. An initial phase of changes, in which the caregiver assumes new activities; a second phase full of emotions, in which the needs and consequences emerge in caregivers; and a third phase that emphasises acceptance as a coping strategy and uncertainty as an expectation of the future. DISCUSSION: The description of this process provides a comprehensive understanding of the experience of becoming a family caregiver, in order to help health professionals to adapt to the plans of care for this initial situation. PMID- 28735722 TI - [Is the introduction of clinical management programs for patients with chronic obstructive pulmonary disease useful? Comparison of the effectiveness of two interventions on the clinical progress and care received]. AB - OBJECTIVE: To evaluate the effectiveness of two management programs on patients with chronic obstructive pulmonary disease (COPD). DESIGN: A study with a quasi experimental design was used to evaluate the effectiveness of two interventions (I1, I2) for the care of patients with COPD after a mean follow-up of 31.2months. SETTING: Primary Care Centres in two Barcelona Health Areas and their referral hospitals. PARTICIPANTS: Patients with COPD selected by simple random sampling using any disease code corresponding to COPD. INTERVENTIONS: I1: Integrated management program that was optimised and coordinated the resources. Training was given, as well as quality control of spirometry. I2: Isolated interventions like a call-centre. Care circuits and computerised clinical notes were shared. MAIN MEASUREMENTS: Variables were recorded as regards lung function, severity, use of inhalers, lifestyles, quality of life, and exacerbations. RESULTS: Of the 393 patients evaluated at the beginning, 120 and 104 (I1 and I2, respectively) received the final evaluation. With I1, there was a reduction in patients who smoked (P=.034). Lung function and quality of life did not change significantly in either group, but shortness of breath was slightly worse. There was an increase in the correct use of inhalers, although it only reached 48% and 61% with interventions I1 and I2, respectively. The percentage of patients with exacerbations decreased with I1 compared to that of I2 (P<.001), and there were less hospital admissions due to exacerbations with I2 compared to I1 (P<.003]). CONCLUSIONS: Both interventions achieved significant improvements, and no overall worsening of a chronic and progressive disease as is COPD. PMID- 28735723 TI - A rate-independent continuum model for bone tissue with interaction of compressive and tensile micro-damage. AB - Low bone strength is a major risk factor for osteoporotic fractures and is only partially determined by clinical densitometry. Accumulated micro-damage induces residual strains, degrades elastic modulus and reduces bone strength independently of bone mineral density. Histologically, overloading of bone in compression and tension leads to distinct crack size, distribution and orientation which interact during combined loading scenarios. Statistics of rheological models can describe this process and reproduce experimental stress strain curves with an unprecedented realism, but are computationally expensive and therefore difficult to generalize to 3D. Accordingly, the aim of this work is to formulate a continuum damage model that describes the key features of bone micro-damage, namely the accumulation of residual strains, the degradation of elastic modulus and the reduction of strength in compression, tension and especially in their sequential application. The promising qualitative agreement of the model with the experiments will motivate a generalization to 3D and allow the biomechanical investigation of bones and bone-implant systems subjected to cyclic overloading in tension and/or compression. PMID- 28735724 TI - Evaluating community health workers' attributes, roles, and pathways of action in immigrant communities. AB - Community health workers (CHWs) are uniquely positioned to improve health outcomes in immigrant communities; however, research on appropriate metrics for evaluating CHW attributes and mechanisms of effectiveness are limited. The objective of this paper is to characterize CHW attributes and pathways of action using adapted measures, develop a scale using these measures, and explore how findings can inform future CHW research and practice. The study analyzed pre- and post-intervention group data from one quasi-experimental and three randomized controlled-design parent trials assessing the impact of CHW-led group and individual health coaching on various health outcomes in four New York City immigrant communities. We conducted descriptive, bi-variate and principal components analysis to develop a 13-item scale assessing CHW attributes, roles, and pathways of action. The sample included 437 individuals completing the intervention arm of a CHW study. We found CHWs were reported to affect change through a number of mechanisms and participants expressed substantial communal concordance with the CHWs in terms of country of birth, language, and culture. Principal components analysis with promax rotation identified 13 items with three factors and high Cronbach's alphas: 1) valued interpersonal attributes of the CHW (alpha=0.784); 2) CHW as a bridge to health and non-health resources (alpha=0.857); and 3) providing accessibility beyond health providers (alpha=0.904). Socio-demographic characteristics and differences in CHW pathways of action were identified by community. Study findings can guide improved selection and training of CHWs. Further, measures identified in the principal components analysis can be used to guide future CHW evaluation efforts. PMID- 28735725 TI - Susceptibility to cigarette smoking among middle and high school e-cigarette users in Canada. AB - There is a growing concern that the historic reductions in tobacco consumption witnessed in the past decades may be undermined by the rapid increase in e cigarette use. This study examined the association between e-cigarette use and future intention to smoke cigarettes among middle and high school students who had never smoked cigarettes. Data were drawn from the 2014-2015 Canadian Student Tobacco, Alcohol and Drugs Survey (n=25,637). A multivariable logistic regression model was used to examine the association between e-cigarette use and susceptibility to cigarette smoking. In addition, an inverse probability of treatment weighted regression adjustment method (doubly robust estimator), which models both the susceptibility to smoking and the probability of e-cigarette use, was conducted. About 10% of the students had ever tried an e-cigarette. There were higher rates of ever e-cigarette use among students in grades 10-12 (12.5%) than those in grades 7-9 (7.3%). Students who had ever tried an e-cigarette had higher odds of susceptibility to cigarette smoking (adjusted odds ratio=2.16, 95% confidence interval=1.80-2.58) compared to those that had never tried an e cigarette. Current use of an e-cigarette was associated with higher odds of smoking susceptibility (adjusted odds ratio=2.02, 95% confidence interval=1.43 2.84). Similar results were obtained from the doubly robust estimation. Among students who had never smoked cigarettes, e-cigarette use was associated with a higher susceptibility to cigarette smoking. PMID- 28735726 TI - Molecular adaptive convergence in the alpha-globin gene in subterranean octodontid rodents. AB - Tuco-tucos (Ctenomys) and related coruros (Spalacopus) are South American subterranean rodents. An energetically demanding lifestyle within the hypoxic/hypercapnic underground atmosphere may change the selective regime on genes involved in O2 transport in blood. In addition, some species of tuco-tucos may be found at high altitude, thus facing additional reductions in changes O2 availabily. We examined sequence variation in the alpha globin subunit gene of hemoglobine in these lineages, within a robust phylogenetic context. Using different approaches (classical and Bayesian maximum likelihood (PAML/Datamonkey) and alternatives methods (TreeSAAP)) we found at least 2 sites with evidence of positive selection in the basal branch of Octodontidae, but not in tuco-tucos. These results suggest some adaptive changes associated to fossoriality, but not strictly to life underground. PMID- 28735727 TI - Investigation of the role of DNA methylation in the expression of ERBB2 in human myocardium. AB - The ERBB2 gene encodes a transmembrane tyrosine kinase receptor that belongs to the epidermal growth factor receptor (EGFR) family. ERBB2 plays a pivotal role during heart development and is essential for normal cardiac function, particularly during episodes of cardiac stress. The monoclonal antibody drug trastuzumab is used for the therapy of breast cancers that overexpress ERBB2. The clinical use of trastuzumab is limited by the development of cardiotoxicity in some patients. Inter-individual differences in the expression of ERBB2 in cardiac tissue may impact the risk of cardiotoxicity. In this study, we examined whether DNA methylation status in the proximal promoter region of ERBB2 is associated to variable ERBB2 mRNA and ERBB2 protein expression in human myocardium. Complementary studies with ERBB2 gene reporter constructs and chromatin immunoprecipitation suggest that differential methylation in specific CpG sites modify the binding of Sp1 to the promoter of ERBB2. DNA methylation in the ERBB2 locus may contribute to the variable expression of ERBB2 in human myocardium. PMID- 28735728 TI - Artemisia argyi attenuates airway inflammation in ovalbumin-induced asthmatic animals. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Artemisia argyi is a traditional herbal medicine in Korea and commonly called as mugwort. It is traditionally used as food source and tea to control abdominal pain, dysmenorrhea, uterine hemorrhage, and inflammation. AIM OF THE STUDY: We investigated the effects of A. argyi (TOTAL) and dehydromatricarin A (DA), its active component on ovalbumin (OVA)-induced allergic asthma. MATERIALS AND METHODS: The animals were sensitized on day 0 and 14 by intraperitoneal injection of OVA with aluminum hydroxide. On day 21, 22 and 23 after the initial sensitization, the animals received an airway challenge with OVA for 1h using an ultrasonic nebulizer. TOTAL (50 and 100mg/kg) or DA (10 and 20mg/kg) were administered to mice by oral gavage once daily from day 18-23. Airway hyperresponsiveness (AHR) was measured 24h after final OVA challenge. RESULT: TOTAL and DA treated animals reduced inflammatory cell counts, cytokines and AHR in asthmatic animals, which was accompanied with inflammatory cell accumulation and mucus hypersecretion. Furthermore, TOTAL and DA significantly declined Erk phosphorylation and the expression of MMP-9 in asthmatic animals. CONCLUSION: In conclusion, we indicate that Total and DA suppress allergic inflammatory responses caused by OVA challenge. It was considered that A. argyi has a potential for treating allergic asthma. PMID- 28735729 TI - Protective effects of flavonoids isolated from Korean milk thistle Cirsium japonicum var. maackii (Maxim.) Matsum on tert-butyl hydroperoxide-induced hepatotoxicity in HepG2 cells. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Milk thistle leaves and flowers have been traditionally used as herbal remedy to alleviate liver diseases for decades. Korean milk thistle, Cirsium japonicum var. maackii (Maxim.) Matsum has been employed in traditional folk medicine as diuretic, antiphlogistic, hemostatic, and detoxifying agents. AIM OF THE STUDY: The aim of current investigation was to evaluate hepatoprotective properties of the MeOH extract of the roots, stems, leaves and flowers of Korean milk thistle as well as four isolated flavonoids, luteolin, luteolin 5-O-glucoside, apigenin and apigenin 7-O-glucuronide during t BHP-induced oxidative stress in HepG2 cells. MATERIALS AND METHODS: Hepatoprotective potential of the MeOH extracts and flavonoids derived from Korean milk thistle against t-BHP-induced oxidative stress in HepG2 cells were evaluated following MTT method. Incubating HepG2 cells with t-BHP markedly decreased the cell viability and increased the intracellular ROS generation accompanied by depleted GSH levels. Protein expression of heme oxygenase (HO-1) and nuclear factor-E2-related factor 2 (Nrf-2) was determined by Western blot. RESULTS: Our findings revealed that pretreating HepG2 cells with MeOH extracts and bioactive flavonoids significantly attenuated the t-BHP-induced oxidative damage, followed by increased cell viability in a dose-dependent manner. The results illustrate that excess ROS generation was reduced and GSH levels increased dose-dependently when HepG2 cells were pretreated with four flavonoids. Moreover, Western blotting analysis demonstrated that protein expressions of Nrf 2 and HO-1 were also up-regulated by flavonoids treatment. CONCLUSIONS: These results clearly demonstrate that the MeOH extracts and flavonoids from Korean milk thistle protected HepG2 cells against oxidative damage triggered by t-BHP principally by modulating ROS generation and restoring depleted GSH levels in addition to the increased Nrf-2/HO-1 signaling cascade. These flavonoids are potential natural antioxidative biomarkers against oxidative stress-induced hepatotoxicity. PMID- 28735730 TI - Impressic acid from Acanthopanax koreanum, possesses matrix metalloproteinase-13 down-regulating capacity and protects cartilage destruction. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Acanthopanax koreanum (Araliaceae) has been used in traditional medicine for enhancing vitality, rheumatism, and bone-related pains. But its activity on cartilage protection has not been known yet. AIM OF THE STUDY: Matrix metalloproteinase (MMP)-13 has an important role in degrading cartilage materials under pathologic conditions such as arthritis. The present study was designed to find the inhibitory activity of impressic acid on MMP-13 expression and cartilage protective action. MATERIALS AND METHODS: 70% ethanol extract of Acanthopanax koreanum leaves and impressic acid, a major constituent isolated from the same plant materials, were examined on MMP-13 down-regulating capacity in IL-1beta-treated human chondrocyte cell line (SW1353) and rabbit cartilage explants. RESULTS: In IL-1beta-treated SW1353 cells, impressic acid significantly and concentration-dependently inhibited MMP-13 expression at 0.5 10MUM. Impressic acid was found to be able to inhibit MMP-13 expression by blocking the phosphorylation of signal transducer and activator of transcription 1/-2 (STAT-1/-2) and activation of c-Jun and c-Fos among the cellular signaling pathways involved. Further, impressic acid was found to inhibit the expression of MMP-13 mRNA (47.7% inhibition at 10MUM), glycosaminoglycan release (42.2% reduction at 10MUM) and proteoglycan loss in IL-1-treated rabbit cartilage explants culture. In addition, a total of 21 lupane-type triterpenoids structurally-related to impressic acid were isolated from the same plant materials and their suppressive activities against MMP-13 expression were also examined. Among these derivatives, compounds 2, 3, 16, and 18 clearly down regulated MMP-13 expression. However, impressic acid was more potent than these derivatives in down-regulating MMP-13 expression. CONCLUSIONS: Impressic acid, its related triterpenoids, and A. koreanum extract have potential as therapeutic agents to prevent cartilage degradation by inhibiting matrix protein degradation. PMID- 28735731 TI - Marine debris in harbour porpoises and seals from German waters. AB - Records of marine debris in and attached to stranded harbour porpoises (Phocoena phocoena), harbour seals (Phoca vitulina) and grey seals (Halichoerus grypus) were studied comprising information on 6587 carcasses collected along the German coast between 1990 and 2014, the decomposition state allowed for necropsy in 1622 cases. Marine debris items were recorded in 31 carcasses including 14 entanglements (5 harbour porpoises, 6 harbour seals, 3 grey seals) and 17 cases of ingestion (4 harbour porpoises, 10 harbour seals, 3 grey seals). Objects comprised general debris (35.1%) and fishing related debris (64.9%). Injuries associated with marine debris included lesions, suppurative ulcerative dermatitis, perforation of the digestive tract, abscessation, suppurative peritonitis and septicaemia. This study is the first investigation of marine debris findings in all three marine mammal species from German waters. It demonstrates the health impacts marine debris can have, including severe suffering and death. The results provide needed information on debris burdens in the North and Baltic Seas for implementing management directives, such as the Marine Strategy Framework Directive (MSFD). PMID- 28735732 TI - Assessment of MRI issues for a new cerebral spinal fluid shunt, gravitational valve (GV). AB - PURPOSE: A gravitational valve (GV) may be used to treat hydrocephalus, offering possible advantages that include avoidance of over drainage and long-term complications. Because a GV is made from metal, there are potential safety and other problems related to the use of MRI. The objective of this investigation was to evaluate MRI-related issues (i.e., magnetic field interactions, heating, and artifacts) for a newly developed, metallic GV. METHODS: Tests were performed on the GV (GAV 2.0) using well-accepted techniques to assess magnetic field interactions (translational attraction and torque, 3-Tesla), MRI-related heating (1.5-T/64-MH and 3-T/128-MHz, whole body averaged SAR, 2.7-W/kg and 2.9-W/kg, respectively), artifacts (3-Tesla; gradient echo and T1-weighted, spin echo sequences), and possible functional changes related to exposures to different MRI conditions (exposing six samples each to eight different pulse sequences at 1.5 T/64-MHz and 3-T/128-MHz). RESULTS: Magnetic field interactions were not substantial (deflection angle 2 degrees , no torque) and heating was minor (highest temperature rise, >=1.9 degrees C, highest background temperature rise, >=1.7 degrees C). Artifacts on the gradient echo pulse sequence extended approximately 10mm from the size and shape of the GV. The different exposures to 1.5-T/64-MHz and 3-T/128-MHz conditions did not alter or damage the operational aspects of the GV samples. CONCLUSIONS: The findings demonstrated that MRI can be safely used in patients with this GV and, thus, this metallic implant is deemed acceptable or "MR Conditional" (i.e., using current labeling terminology), according to the conditions used in this study. PMID- 28735733 TI - Incidence, predictors, and outcomes associated with pneumothorax during cardiac electronic device implantation: A 16-year review in over 3.7 million patients. AB - BACKGROUND: Pneumothorax (PTX) is a potential complication of vascular access during cardiac implantable electronic device (CIED) procedures and is being scrutinized as a health care-acquired condition. OBJECTIVE: The purpose of this study was to determine the trends in PTX incidence in the United Stated over a 16 year period and to determine whether PTX is associated with increased mortality after adjustment for other factors. METHODS: Using weighted sampling in the largest inpatient health database in the United States (National Inpatient Sample), we evaluated data from patients with a primary procedure of CIED implantation from 1998 to 2013 who had at least 1 new vascular access (new or upgrade of prior CIED). The unadjusted and adjusted associations of PTX with mortality and other parameters were examined. RESULTS: Among 3,764,703 CIED procedures, PTX occurred in 47,839 cases (1.3%). The apparent incidence of PTX peaked at 1.6% in 2012 and 2013, although this result may have been affected by a concomitant decrease of inpatient (vs outpatient) CIED. PTX was significantly associated with pulmonary complications, chest tube insertion, length of stay, and costs. Mortality was statistically higher in patients with PTX (1.2% vs 0.7%; P <.001), a relationship that remained significant in a multivariate logistic regression analysis (odds ratio 1.50, 95% confidence interval 1.36-1.65; P <.001). Age >80 years, female gender, Caucasian race, chronic obstructive pulmonary disease, and dual-chamber (vs single-chamber) device were all associated with higher odds for PTX occurrence. Placement of a chest tube was a major determinant of worse outcomes and higher costs. CONCLUSION: PTX remains an important complication of CIED procedures and is associated with increased morbidity, mortality, and costs. PMID- 28735734 TI - Variation of High-Intensity Therapeutic Ultrasound (HITU) Pressure Field Characterization: Effects of Hydrophone Choice, Nonlinearity, Spatial Averaging and Complex Deconvolution. AB - Reliable acoustic characterization is fundamental for patient safety and clinical efficacy during high-intensity therapeutic ultrasound (HITU) treatment. Technical challenges, such as measurement variation and signal analysis, still exist for HITU exposimetry using ultrasound hydrophones. In this work, four hydrophones were compared for pressure measurement: a robust needle hydrophone, a small polyvinylidene fluoride capsule hydrophone and two fiberoptic hydrophones. The focal waveform and beam distribution of a single-element HITU transducer (1.05 MHz and 3.3 MHz) were evaluated. Complex deconvolution between the hydrophone voltage signal and frequency-dependent complex sensitivity was performed to obtain pressure waveforms. Compressional pressure (p+), rarefactional pressure (p ) and focal beam distribution were compared up to 10.6/-6.0 MPa (p+/p-) (1.05 MHz) and 20.65/-7.20 MPa (3.3 MHz). The effects of spatial averaging, local non linear distortion, complex deconvolution and hydrophone damage thresholds were investigated. This study showed a variation of no better than 10%-15% among hydrophones during HITU pressure characterization. PMID- 28735735 TI - Random Forest-Based Bone Segmentation in Ultrasound. AB - Ultrasound (US) imaging is a safe alternative to radiography for guidance during minimally invasive orthopedic procedures. However, ultrasound is challenging to interpret because of the relatively low signal-to-noise ratio and its inherent speckle pattern that decreases image quality. Here we describe a method for automatic bone segmentation in 2-D ultrasound images using a patch-based random forest classifier and several ultrasound specific features, such as shadowing. We illustrate that existing shadow features are not robust to changes in US acquisition parameters, and propose a novel robust shadow feature. We evaluate the method on several US data sets and report that it favorably compares with existing techniques. We achieve a recall of 0.86 at a precision of 0.82 on a test set of 143 spinal US images. PMID- 28735736 TI - Postoperative Pulmonary Complications Following Laparoscopy. AB - Postoperative pulmonary complications (PPCs) unrelated to anesthesia, especially hydropneumothorax, are rare after gynecologic laparoscopy. Hydropneumothorax can cause respiratory failure and be life-threatening, however. Awareness, prompt diagnosis, and timely intervention are crucial for clinical management. We review the literature for PPCs, including pneumothorax, hydrothorax, hydropneumothorax, and pleural effusion following laparoscopy, and also present a recent case of hydropneumothorax seen at our institution. PMID- 28735737 TI - A Novel Approach to Transmural Access to the Uterine Cavity in Cases of an Inaccessible Uterine Cavity: A Case Series. AB - Access to the uterine cavity can sometimes be a challenge or even impossible because of various causes such as prior surgery. We report our experience with a novel approach to this problem in 8 cases using ultrasound-guided transmural injection of dye; afterward, the cavity was successfully found in all cases by ultrasound-guided hysteroscopy following the colored epithelium. PMID- 28735738 TI - Mutation spectrum resulting in M13mp2 phage DNA exposed to N-nitrosoproline with UVA irradiation. AB - N-nitrosoproline (NPRO) is endogenously formed from proline and nitrite. In an effort to delineate the mechanism of NPRO-induced photomutagenicity, we investigated the mutagenic spectrum of NPRO on M13mp2 DNA with UVA irradiation. Following exposure to NPRO and UVA, the mutation frequency increased significantly in an NPRO and UVA dose-dependent manner. The sequence data derived from seventy of the mutants indicated that mutagenesis resulted mainly from an increase in single-base substitutions, the most frequent being GC to CG transversions. Non-clustering of the GC to CG mutations suggests that NPRO+UVA damage to DNA is random. These transversions may be caused by guanine adducts in DNA or in part by oxidatively modified guanine in DNA exposed to NPRO and UVA. PMID- 28735739 TI - Genome-wide bisulfite sensitivity profiling of yeast suggests bisulfite inhibits transcription. AB - Bisulfite, in the form of sodium bisulfite or metabisulfite, is used commercially as a food preservative. Bisulfite is used in the laboratory as a single-stranded DNA mutagen in epigenomic analyses of DNA methylation. Recently it has also been used on whole yeast cells to induce mutations in exposed single-stranded regions in vivo. To understand the effects of bisulfite on live cells we conducted a genome-wide screen for bisulfite sensitive mutants in yeast. Screening the deletion mutant array, and collections of essential gene mutants we define a genetic network of bisulfite sensitive mutants. Validation of screen hits revealed hyper-sensitivity of transcription and RNA processing mutants, rather than DNA repair pathways and follow-up analyses support a role in perturbation of RNA transactions. We propose a model in which bisulfite-modified nucleotides may interfere with transcription or RNA metabolism when used in vivo. PMID- 28735740 TI - DNA damage and the bystander response in tumor and normal cells exposed to X rays. AB - Monolayer and suspension cultures of tumor (BMG-1, CCRF-CEM), normal (AG1522, HADF, lymphocytes) and ATM-mutant (GM4405) human cells were exposed to X-rays at doses used in radiotherapy (high dose and high dose-rate) or radiological imaging (low dose and low dose-rate). Radiation-induced DNA damage, its persistence, and possible bystander effects were evaluated, based on DNA damage markers (gamma H2AX, p53ser15) and cell-cycle-specific cyclins (cyclin B1 and cyclin D1). Dose dependent DNA damage and a dose-independent bystander response were seen after exposure to high dose and high dose-rate radiation. The level of induced damage (expression of p53ser15, gamma-H2AX) depended on ATM status. However, low dose and dose-rate exposures neither increased expression of marker proteins nor induced a bystander response, except in the CCRF-CEM cells. Bystander effects after high-dose irradiation may contribute to stochastic and deterministic effects. Precautions to protect unexposed regions or to inhibit transmission of DNA damage signaling might reduce radiation risks. PMID- 28735741 TI - Apigenin prevents ultraviolet-B radiation induced cyclobutane pyrimidine dimers formation in human dermal fibroblasts. AB - Exposure to solar ultraviolet-B (UVB) radiation leads to the formation of cyclobutane pyrimidine dimers (CPDs). We investigated the protective effect of apigenin against UVB-induced CPDs formation in human dermal fibroblasts cells (HDFa). For this purpose, HDFa cells were treated with apigenin (15MUM) prior to UVB irradiation (20mJ/cm2); DNA damage and subsequent molecular end points were observed. Exposure to UVB radiation increased significant CPDs formation in HDFa cells and the frequencies of CPDs were reduced by treatment with apigenin (15MUM). UVB-induced CPDs downregulates the expression of nucleotide excision repair (NER) genes such as xeroderma pigmentosum complementation group C, B, G and F (XPC, XPB, XPG and XPF), transcription factor II human (TFIIH) and excision repair cross-complementation group 1 (ERCC1) in HDFa cells. Conversely, apigenin treatment restored UVB-induced loss of NER proteins in HDFa cells, which indicates its preventive effect against CPDs formation. Besides, single low dose UVB-exposure induced nuclear fragmentation, apoptotic frequency and apoptotic proteins expression (Bax and Caspase-3) have been prevented by the apigenin pretreatment. Furthermore, apigenin exhibits strong UV absorbance property and showed 10.08 SPF value. Thus, apigenin can protect skin cells against UVB-induced CPDs formation probably through its sunscreen effect. Hence, apigenin can be considered as an effective protective agent against UV induced skin damages. PMID- 28735742 TI - Genotoxicity of gemfibrozil in the gilthead seabream (Sparus aurata). AB - Widespread use of pharmaceuticals and suboptimal wastewater treatment have led to increased levels of these substances in aquatic ecosystems. Lipid-lowering drugs such as gemfibrozil, which are among the most abundant human pharmaceuticals in the environment, may have deleterious effects on aquatic organisms. We examined the genotoxicity of gemfibrozil in a fish species, the gilthead seabream (Sparus aurata), which is commercially important in southern Europe. Following 96-h waterborne exposure, molecular (erythrocyte DNA strand breaks) and cytogenetic (micronuclei and other nuclear abnormalities in cells) endpoints were measured. Gemfibrozil was positive in both endpoints, at environmentally relevant concentrations, a result that raises concerns about the potential genotoxic effects of the drug in recipient waters. PMID- 28735744 TI - In Reply. PMID- 28735745 TI - Procedure Volume in Orthognathic Surgery: The Surgeon or the Hospital? PMID- 28735743 TI - Exposure to meat-derived carcinogens and bulky DNA adduct levels in normal appearing colon mucosa. AB - INTRODUCTION: Meat consumption is a risk factor for colorectal cancer. This research investigated the relationship between meat-derived carcinogen exposure and bulky DNA adduct levels, a biomarker of DNA damage, in colon mucosa. METHODS: Least squares regression was used to examine the relationship between meat derived carcinogen exposure (PhIP and meat mutagenicity) and bulky DNA adduct levels in normal-appearing colon tissue measured using 32P-postlabelling among 202 patients undergoing a screening colonoscopy. Gene-diet interactions between carcinogen exposure and genetic factors relevant to biotransformation and DNA repair were also examined. Genotyping was conducting using the MassARRAY(r) iPLEX(r) Gold SNP Genotyping assay. RESULTS: PhIP and higher meat mutagenicity exposures were not associated with levels of bulky DNA adducts in colon mucosa. The XPC polymorphism (rs2228001) was found to associate with bulky DNA adduct levels, whereby genotypes conferring lower DNA repair activity were associated with higher DNA adduct levels than the normal activity genotype. Among individuals with genotypes associated with lower DNA repair (XPD, rs13181 and rs1799179) or detoxification activity (GSTP1, rs1695), higher PhIP or meat mutagenicity exposures were associated with higher DNA adduct levels. Significant interactions between the XPC polymorphism (rs2228000) and both dietary PhIP and meat mutagenicity on DNA adduct levels was observed, but associations were inconsistent with the a priori hypothesized direction of effect. CONCLUSION: Exposure to meat-derived carcinogens may be associated with increased DNA damage occurring directly in the colon among genetically susceptible individuals. PMID- 28735746 TI - Parallel Inhibitory and Excitatory Trigemino-Facial Feedback Circuitry for Reflexive Vibrissa Movement. AB - Animals employ active touch to optimize the acuity of their tactile sensors. Prior experimental results and models lead to the hypothesis that sensory inputs are used in a recurrent manner to tune the position of the sensors. A combination of electrophysiology, intersectional genetic viral labeling and manipulation, and classical tracing allowed us to identify second-order sensorimotor loops that control vibrissa movements by rodents. Facial motoneurons that drive intrinsic muscles to protract the vibrissae receive a short latency inhibitory input, followed by synaptic excitation, from neurons located in the oralis division of the trigeminal sensory complex. In contrast, motoneurons that retract the mystacial pad and indirectly retract the vibrissae receive only excitatory input from interpolaris cells that further project to the thalamus. Silencing this feedback alters retraction. The observed pull-push circuit at the lowest-level sensorimotor loop provides a mechanism for the rapid modulation of vibrissa touch during exploration of peri-personal space. PMID- 28735748 TI - Behaviorally Selective Engagement of Short-Latency Effector Pathways by Motor Cortex. AB - Blocking motor cortical output with lesions or pharmacological inactivation has identified movements that require motor cortex. Yet, when and how motor cortex influences muscle activity during movement execution remains unresolved. We addressed this ambiguity using measurement and perturbation of motor cortical activity together with electromyography in mice during two forelimb movements that differ in their requirement for cortical involvement. Rapid optogenetic silencing and electrical stimulation indicated that short-latency pathways linking motor cortex with spinal motor neurons are selectively activated during one behavior. Analysis of motor cortical activity revealed a dramatic change between behaviors in the coordination of firing patterns across neurons that could account for this differential influence. Thus, our results suggest that changes in motor cortical output patterns enable a behaviorally selective engagement of short-latency effector pathways. The model of motor cortical influence implied by our findings helps reconcile previous observations on the function of motor cortex. PMID- 28735747 TI - A Requirement for Mena, an Actin Regulator, in Local mRNA Translation in Developing Neurons. AB - During neuronal development, local mRNA translation is required for axon guidance and synaptogenesis, and dysregulation of this process contributes to multiple neurodevelopmental and cognitive disorders. However, regulation of local protein synthesis in developing axons remains poorly understood. Here, we uncover a novel role for the actin-regulatory protein Mena in the formation of a ribonucleoprotein complex that involves the RNA-binding proteins HnrnpK and PCBP1 and regulates local translation of specific mRNAs in developing axons. We find that translation of dyrk1a, a Down syndrome- and autism spectrum disorders related gene, is dependent on Mena, both in steady-state conditions and upon BDNF stimulation. We identify hundreds of additional mRNAs that associate with the Mena complex, suggesting that it plays broader role(s) in post-transcriptional gene regulation. Our work establishes a dual role for Mena in neurons, providing a potential link between regulation of actin dynamics and local translation. PMID- 28735749 TI - Initiation of Behavioral Response to Antidepressants by Cholecystokinin Neurons of the Dentate Gyrus. AB - Selective serotonin reuptake inhibitors (SSRIs) are the most commonly used class of antidepressant drugs, but the cellular and molecular mechanisms by which their therapeutic action is initiated are poorly understood. Here we show that serotonin 5-HT1B receptors in cholecystokinin (CCK) inhibitory interneurons of the mammalian dentate gyrus (DG) initiate the therapeutic response to antidepressants. In these neurons, 5-HT1B receptors are expressed presynaptically, and their activation inhibits GABA release. Inhibition of GABA release from CCK neurons disinhibits parvalbumin (PV) interneurons and, as a consequence, reduces the neuronal activity of the granule cells. Finally, inhibition of CCK neurons mimics the antidepressant behavioral effects of SSRIs, suggesting that these cells may represent a novel cellular target for the development of fast-acting antidepressant drugs. PMID- 28735750 TI - Partially Mixed Selectivity in Human Posterior Parietal Association Cortex. AB - To clarify the organization of motor representations in posterior parietal cortex, we test how three motor variables (body side, body part, cognitive strategy) are coded in the human anterior intraparietal cortex. All tested movements were encoded, arguing against strict anatomical segregation of effectors. Single units coded for diverse conjunctions of variables, with different dimensions anatomically overlapping. Consistent with recent studies, neurons encoding body parts exhibited mixed selectivity. This mixed selectivity resulted in largely orthogonal coding of body parts, which "functionally segregate" the effector responses despite the high degree of anatomical overlap. Body side and strategy were not coded in a mixed manner as effector determined their organization. Mixed coding of some variables over others, what we term "partially mixed coding," argues that the type of functional encoding depends on the compared dimensions. This structure is advantageous for neuroprosthetics, allowing a single array to decode movements of a large extent of the body. PMID- 28735751 TI - Structure of the Nav1.4-beta1 Complex from Electric Eel. AB - Voltage-gated sodium (Nav) channels initiate and propagate action potentials. Here, we present the cryo-EM structure of EeNav1.4, the Nav channel from electric eel, in complex with the beta1 subunit at 4.0 A resolution. The immunoglobulin domain of beta1 docks onto the extracellular L5I and L6IV loops of EeNav1.4 via extensive polar interactions, and the single transmembrane helix interacts with the third voltage-sensing domain (VSDIII). The VSDs exhibit "up" conformations, while the intracellular gate of the pore domain is kept open by a digitonin-like molecule. Structural comparison with closed NavPaS shows that the outward transfer of gating charges is coupled to the iris-like pore domain dilation through intricate force transmissions involving multiple channel segments. The IFM fast inactivation motif on the III-IV linker is plugged into the corner enclosed by the outer S4-S5 and inner S6 segments in repeats III and IV, suggesting a potential allosteric blocking mechanism for fast inactivation. PMID- 28735752 TI - Conformational Changes of CFTR upon Phosphorylation and ATP Binding. AB - The cystic fibrosis transmembrane conductance regulator (CFTR) is an anion channel evolved from an ATP-binding cassette transporter. CFTR channel gating is strictly coupled to phosphorylation and ATP hydrolysis. Previously, we reported essentially identical structures of zebrafish and human CFTR in the dephosphorylated, ATP-free form. Here, we present the structure of zebrafish CFTR in the phosphorylated, ATP-bound conformation, determined by cryoelectron microscopy to 3.4 A resolution. Comparison of the two conformations shows major structural rearrangements leading to channel opening. The phosphorylated regulatory domain is disengaged from its inhibitory position; the nucleotide binding domains (NBDs) form a "head-to-tail" dimer upon binding ATP; and the cytoplasmic pathway, found closed off in other ATP-binding cassette transporters, is cracked open, consistent with CFTR's unique channel function. Unexpectedly, the extracellular mouth of the ion pore remains closed, indicating that local movements of the transmembrane helices can control ion access to the pore even in the NBD-dimerized conformation. PMID- 28735754 TI - Correlation between pulmonary artery pressure and thoracic impedance: Insights from daily monitoring through an implanted device in chronic heart failure. AB - BACKGROUND: Thoracic impedance (TI) decrease and pulmonary artery pressure (PAP) elevation precede acute decompensation in congestive heart failure (HF). However, the relationship between TI and PAP has been studied only in the context of acute decompensation. METHODS: This prospective, observational study enrolled subjects with reduced ejection fraction HF, previously implanted with an ICD capable of measuring TI. Patients underwent implantation of a sensor for direct measurement of PAP (CardioMEMsTM). Both TI and PAP were remotely monitored daily during follow up. Investigators were blinded to PAP values during the first three months, then PAP was used as a guide to therapy. RESULTS: Ten patients were followed up for 405+/-141days (3720 patient-days). During hemodynamic guided therapy, diastolic PAP (dPAP) decreased from 27.8+/-10.2mmHg to 24.0+/-8.0mmHg (p<0.001); non-significant variations of TI were observed. A significant negative correlation was found between the variations of TI and PAP vs. baseline (p<0.001). Episodes of sustained increase of PAP preceded subsequent periods of TI decrease by 5.6+/-3.9days, but the former were poor predictors of the latter (sensitivity 0.37). CONCLUSIONS: Our study confirms the strict correlation that exists between left ventricular filling pressures and lung water content, estimated by dPAP and TI, respectively. However, dPAP acute variation analysis showed a limited value in predicting subsequent episodes of TI decrease. PMID- 28735755 TI - Protective effects of acute exercise prior to doxorubicin on cardiac function of breast cancer patients: A proof-of-concept RCT. AB - BACKGROUND: Preclinical studies have reported that a single treadmill session performed 24h prior to doxorubicin provides cardio-protection. We aimed to characterize the acute change in cardiac function following an initial doxorubicin treatment in humans and determine whether an exercise session performed 24h prior to treatment changes this response. METHODS: Breast cancer patients were randomized to either 30min of vigorous-intensity exercise 24h prior to the first doxorubicin treatment (n=13), or no vigorous exercise for 72h prior to treatment (control, n=11). Echocardiographically-derived left ventricular volumes, longitudinal strain, twist, E/A ratio, and circulating NT-proBNP, a marker of later cardiotoxicity, were measured before and 24-48h after the treatment. RESULTS: Following treatment in the control group, NT-proBNP, end diastolic and stroke volumes, cardiac output, E/A ratio, strain, diastolic strain rate, twist, and untwist velocity significantly increased (all p<=0.01). Whereas systemic vascular resistance (p<0.01) decreased, and ejection fraction (p=0.02) and systolic strain rate (p<0.01) increased in the exercise group only. Relative to control, the exercise group had a significantly lower NT-proBNP (p<0.01) and a 46% risk reduction of exceeding the cut-point used to exclude acute heart failure. CONCLUSION: The first doxorubicin treatment is associated with acutely increased NT-proBNP, echocardiographic parameters of myocardial relaxation, left ventricular volume overload, and changes in longitudinal strain and twist opposite in direction to documented longer-term changes. An exercise session performed 24h prior to treatment attenuated NT-proBNP release and increased systolic function. Future investigations should verify these findings in a larger cohort and across multiple courses of doxorubicin. PMID- 28735756 TI - Incidence and determinants of hyperkalemia and hypokalemia in a large healthcare system. AB - BACKGROUND: Hypo- and hyperkalemia in clinical settings are insufficiently characterized and large-scale data from Europe lacking. We studied incidence and determinants of these abnormalities in a large Swedish healthcare system. METHODS: Observational study from the Stockholm CREAtinine Measurements project, including adult individuals from Stockholm accessing healthcare in 2009 (n=364,955). Over 3-years, we estimated the incidence of hypokalemia, defined as potassium<3.5mmol/L, hyperkalemia, defined as potassium>5mmol/L, and moderate/severe hyperkalemia, defined as potassium>5.5mmol/L. Kidney function was assessed by estimated glomerular filtration rate (eGFR). RESULTS: Of 364,955 participants, 69.4% had 1-2 potassium tests, 16.7% had 3-4 tests and the remaining 13.9% had >4potassiumtests/year. Hypokalemia occurred in 49,662 (13.6%) individuals, with 33% recurrence. Hyperkalemia occurred in 25,461 (7%) individuals, with 35.7% recurrence. Moderate/severe hyperkalemia occurred in 9059 (2.5%) with 28% recurrence. The frequency of potassium testing was an important determinant of dyskalemia risk. The incidence proportion of hyperkalemia was higher in the presence of diabetes, lower eGFR, myocardial infarction, heart failure (HF), or use of renin angiotensin-aldosterone system inhibitors (RAASi). In adjusted analyses, women and use of loop/thiazide diuretics were associated with lower hyperkalemia risk. Older age, lower eGFR, diabetes, HF and use of RAASi were associated with higher hyperkalemia risk. On the other hand, women, younger age, higher eGFR and baseline use of diuretics were associated with higher hypokalemia risk. CONCLUSION: Hypo- and hyperkalemia are common in healthcare. Optimal RAASi and diuretics use and careful potassium monitoring in the presence of certain comorbidities, especially lower eGFR, is advocated. PMID- 28735753 TI - Genome Organization Drives Chromosome Fragility. AB - In this study, we show that evolutionarily conserved chromosome loop anchors bound by CCCTC-binding factor (CTCF) and cohesin are vulnerable to DNA double strand breaks (DSBs) mediated by topoisomerase 2B (TOP2B). Polymorphisms in the genome that redistribute CTCF/cohesin occupancy rewire DNA cleavage sites to novel loop anchors. While transcription- and replication-coupled genomic rearrangements have been well documented, we demonstrate that DSBs formed at loop anchors are largely transcription-, replication-, and cell-type-independent. DSBs are continuously formed throughout interphase, are enriched on both sides of strong topological domain borders, and frequently occur at breakpoint clusters commonly translocated in cancer. Thus, loop anchors serve as fragile sites that generate DSBs and chromosomal rearrangements. VIDEO ABSTRACT. PMID- 28735757 TI - The influence of training characteristics on the effect of exercise training in patients with coronary artery disease: Systematic review and meta-regression analysis. AB - BACKGROUND: Although exercise-based cardiac rehabilitation improves exercise capacity of coronary artery disease patients, it is unclear which training characteristic determines this improvement. Total energy expenditure and its constituent training characteristics (training intensity, session frequency, session duration and programme length) vary considerably among clinical trials, making it hard to compare studies directly. Therefore, we performed a systematic review and meta-regression analysis to assess the effect of total energy expenditure and its constituent training characteristics on exercise capacity. METHODS: We identified randomised controlled trials comparing continuous aerobic exercise training with usual care for patients with coronary artery disease. Studies were included when training intensity, session frequency, session duration and programme length was described, and exercise capacity was reported in peakVO2. Energy expenditure was calculated from the four training characteristics. The effect of training characteristics on exercise capacity was determined using mixed effects linear regression analyses. The analyses were performed with and without total energy expenditure as covariate. RESULTS: Twenty studies were included in the analyses. The mean difference in peakVO2 between the intervention group and control group was 3.97ml.min-1.kg-1 (p<0.01, 95% CI 2.86 to 5.07). Total energy expenditure was significantly related to improvement of exercise capacity (effect size 0.91ml.min-1.kg-1 per 100J.kg, p<0.01, 95% CI 0.77 to 1.06), no effect was found for its constituent training characteristics after adjustment for total energy expenditure. CONCLUSIONS: We conclude that the design of an exercise programme should primarily be aimed at optimising total energy expenditure rather than on one specific training characteristic. PMID- 28735758 TI - Left atrial fibrosis is associated with new-onset heart failure in patients with atrial fibrillation. PMID- 28735759 TI - Associations between tooth loss and prognostic biomarkers and the risk for cardiovascular events in patients with stable coronary heart disease. AB - BACKGROUND: Underlying mechanisms behind the hypothesized relationship between periodontal disease (PD) and coronary heart disease (CHD) have been insufficiently explored. We evaluated associations between self-reported tooth loss- a marker of PD- and prognostic biomarkers in 15,456 (97%) patients with stable CHD in the global STABILITY trial. METHODS AND RESULTS: Baseline blood samples were obtained and patients reported their number of teeth according to the following tooth loss levels: "26-32 (All)" [lowest level], "20-25", "15-19", "1-14", and "No Teeth" [highest level]. Linear and Cox regression models assessed associations between tooth loss levels and biomarker levels, and the relationship between tooth loss levels and outcomes, respectively. After multivariable adjustment, the relative biomarker increase between the highest and the lowest tooth loss level was: high-sensitivity C-reactive protein 1.21 (95% confidence interval, 1.14-1.29), interleukin 6 1.14 (1.10-1.18), lipoprotein-associated phospholipase A2 activity 1.05 (1.03-1.06), growth differentiation factor 15 1.11 (1.08-1.14), and N-terminal pro-B-type natriuretic peptide (NT-proBNP) 1.18 (1.11 1.25). No association was detected for high-sensitivity troponin T 1.02 (0.98 1.05). Some attenuation of the relationship between tooth loss and outcomes resulted from the addition of biomarkers to the multivariable analysis, of which NT-proBNP had the biggest impact. CONCLUSIONS: A graded and independent association between tooth loss and several prognostic biomarkers was observed, suggesting that tooth loss and its underlying mechanisms may be involved in multiple pathophysiological pathways also implicated in the development and prognosis of CHD. The association between tooth loss and cardiovascular death and stroke persisted despite comprehensive adjustment including prognostic biomarkers. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov; NCT00799903. PMID- 28735761 TI - Five new Associate Editors in the Editorial Team of PEC. PMID- 28735760 TI - First characterization of immunogenic conjugates of Vi negative Salmonella Typhi O-specific polysaccharides with rEPA protein for vaccine development. AB - Efficacious typhoid vaccines for young children will significantly reduce the disease burden in developing world. The Vi polysaccharide based conjugate vaccines (Vi-rEPA) against Salmonella Typhi Vi positive strains has shown high efficacy but may be ineffective against Vi negative S. Typhi. In this study, for the first time, we report the synthesis and evaluation of polysaccharide-protein conjugates of Vi negative S. Typhi as potential vaccine candidates. Four different conjugates were synthesized using recombinant exoprotein A of Pseudomonas aeruginosa (rEPA) and human serum albumin (HSA) as the carrier proteins, using either direct reductive amination or an intermediate linker molecule, adipic acid dihydrazide (ADH). Upon injection into mice, a significantly higher antibody titer was observed in mice administrated with conjugate-1 (OSP-HSA) (P=0.0001) and conjugate 2 (OSP-rEPA) (P<=0.0001) as compared to OSP alone. In contrast, the antibody titer elicited by conjugate 3 (OSPADH-HSA) and conjugate 4 (OSPADH-rEPA) were insignificant (P=0.1684 and P=0.3794, respectively). We conclude that reductive amination is the superior method to prepare the S. Typhi OSP glycoconjugate. Moreover, rEPA was a better carrier protein than HSA. Thus OSP-rEPA conjugate seems to be efficacious typhoid vaccines candidate, it may be evaluated further and recommended for the clinical trials. PMID- 28735762 TI - Parathyroidectomy for tertiary hyperparathyroidism: A systematic review. AB - OBJECTIVE: Analyze the efficacy and indications for parathyroidectomy as an intervention for tertiary hyperparathyroidism. DATA SOURCES: PubMed, MEDLINE, and Cochrane Library databases. REVIEW METHODS: A systematic literature search was performed using the. Original research articles in English were retrieved using the search terms ("tertiary hyperparathyroidism" OR "3HPT") AND "parathyroidectomy". Articles were analyzed in regards to their surgical indications, operative endpoints, comparison between different surgical interventions, characterization of disease recurrence rates, and evaluation of alternative medical management. RESULTS: Thirty studies met the criteria for inclusion. Among the studies that report indications for parathyroidectomy, persistent hypercalcemia as well as clinical manifestations of hypercalcemia despite medical therapy predicted which patients would eventually need surgical intervention. The majority of studies comparing the extent of parathyroidectomy recommended a more focused approach to parathyroidectomy when warranted. All studies found that parathyroidectomy was an effective treatment for 3HPT. Three studies discussed alternative conservative approaches. CONCLUSION: Interestingly, hyperparathyroidism alone is not an indication for surgery without other findings; rather, symptomatic hypercalcemia appears to be the main indication. Most studies recommend limited or subtotal parathyroidectomy for 3HPT. The operative endpoint of surgery is not necessarily a return of PTH to normal, but a >50% drop in PTH level even if PTH remains above normal. Additionally, "success" or "cure" is defined as normal calcium levels regardless of whether or not PTH is elevated. It appears the goal of surgery for 3HPT is not a normal PTH value, but a normal calcium level at least six months postoperatively. PMID- 28735763 TI - Platelet-rich plasma enhances bone union in posterolateral lumbar fusion: A prospective randomized controlled trial. AB - BACKGROUND CONTEXT: Platelet-rich plasma (PRP) accelerates bone union in vivo in a rodent model of spinal fusion surgery. However, PRP's effect on bone union after spinal surgery remains unclear. PURPOSE: The objective of this study was to evaluate the efficacy of PRP after posterolateral lumbar fusion (PLF) surgery. STUDY DESIGN/SETTING: Single-center prospective randomized controlled clinical trial with 2-year follow-up. PATIENT SAMPLE: The patient sample included a total 62 patients (31 patients in the PRP group or 31 patients in the control group). OUTCOME MEASURES: The outcome measures included the bone fusion rate, the area of bone fusion mass, the duration of bone fusion, and the clinical score using the visual analog scale (VAS). MATERIALS AND METHODS: We randomized 62 patients who underwent one- or two-level instrumented PLF for lumbar degenerative spondylosis with instability to either the PRP (31 patients) or the control (31 patients) groups. Platelet-rich plasma-treated patients underwent surgery using an autograft bone chip (local bone), and PRP was prepared from patient blood samples immediately before surgery; patients from the control group underwent PLF without PRP treatment. We assessed platelet counts and growth factor concentrations in PRP prepared immediately before surgery. The duration of bone union, the postoperative bone fusion rate, and the area of fusion mass were assessed using plain radiography every 3 months after surgery and by computed tomography at 12 or 24 months. The duration of bone fusion and the clinical scores for low back pain, leg pain, and leg numbness before and 3, 6, 12, and 24 months after surgery were evaluated using VAS. RESULTS: Data from 50 patients with complete data were included. The bone union rate at the final follow-up was significantly higher in the PRP group (94%) than in the control group (74%) (p=.002). The area of fusion mass was significantly higher in the PRP group (572 mm2) than in the control group (367 mm2) (p=.02). The mean period necessary for union was 7.8 months in the PRP group and 9.8 months in the control group (p=.013). In the PRP, the platelet count was 7.7 times higher and the growth factor concentrations were 50 times higher than those found in plasma (p<.05). There was no significant difference in low back pain, leg pain, and leg numbness in either group at any time evaluated (p>.05). CONCLUSIONS: Patients treated with PRP showed a higher fusion rate, greater fusion mass, and more rapid bone union after spinal fusion surgery than patients not treated with PRP. PMID- 28735764 TI - BMP-2/7 heterodimer strongly induces bone regeneration in the absence of increased soft tissue inflammation. AB - BACKGROUND CONTEXT: Bone morphogenetic protein (BMP)-2/7 heterodimer is a stronger inducer of bone regeneration than individual homodimers. However, clinical application of its potent bone induction ability may be hampered if its use is accompanied by excessive inflammatory reactions. PURPOSE: We sought to quantitatively evaluate bone induction and inflammatory reactions by BMP heterodimer and corresponding BMP homodimers using ultra-high resolution magnetic resonance imaging (MRI) and micro-computed tomography. STUDY DESIGN: An experimental animal study was carried out. METHODS: A total of 32 absorbable collagen sponge implantations into dorsal muscle were performed in rats of four different groups (control group, 0 ug BMP; recombinant human (rh)BMP-7 group, 3 ug rhBMP-7; rhBMP-2 group, 3 ug rhBMP-2; rhBMP-2/7 group, 3 ug rhBMP-2/7). Inflammatory reactions were evaluated by 11.7-T MRI (axial T2-weighted imaging using rapid acquisition with relaxation enhancement) at postoperative days 2 and 7. Bone volumes (BVs) of the induced ectopic bone were quantified at postoperative day 7. In addition, immunohistochemical staining for interleukin (IL)-1beta, IL-6, and tumor necrosis factor (TNF)-alpha was performed in samples obtained on postoperative day 2. Bone formation (BF)-to-inflammation (IM) ratios were calculated by dividing BVs by values of inflamed areas. RESULTS: At postoperative day 2, the mean volume of T2 high area on MRI scans in BMP-2 group was significantly larger than that in control group. In contrast, the BMP-2/7 had no difference in the mean volume of T2 high area compared with the control group; however, there was no difference between the BMP-2/7 compared with BMP-2 group. At postoperative day 7, the volumes of T2 high area were not different between the groups. Mean BV of the newly formed bone on postoperative day 7 was significantly greater in BMP-2/7 group than in BMP-7 groups. No new bone formation was observed in control group. BF-to-IM ratio in BMP-2/7 group was significantly higher than those in BMP-2 and BMP-7 homodimer groups. Immunohistochemistry experiments did not reveal differences in expression levels of IL-1beta, IL-6, or TNF-alpha in samples from BMP-2, BMP-7, and BMP-2/7 groups. CONCLUSIONS: This study demonstrated that BMP-2/7 heterodimer has stronger bone induction ability without accompanying increased inflammatory reactions (the increased BF-to-IM ratio) than those observed by BMP-2 or BMP-7 homodimers. These results suggest that BMP-2/7 heterodimer can be an alternative to BMP-2 and BMP-7 homodimers in clinical applications, although further translational studies, including whether lower doses of BMP heterodimer may produce similar bone formation compared with the BMP homodimers but produce a reduced inflammatory response, are required. PMID- 28735766 TI - Risk factor analysis for predicting vertebral body re-collapse after posterior instrumented fusion in thoracolumbar burst fracture. AB - BACKGROUND CONTEXT: In the posterior instrumented fusion surgery for thoracolumbar (T-L) burst fracture, early postoperative re-collapse of well reduced vertebral body fracture could induce critical complications such as correction loss, posttraumatic kyphosis, and metal failure, often leading to revision surgery. Furthermore, re-collapse is quite difficult to predict because of the variety of risk factors, and no widely accepted accurate prediction systems exist. Although load-sharing classification has been known to help to decide the need for additional anterior column support, this radiographic scoring system has several critical limitations. PURPOSE: (1) To evaluate risk factors and predictors for postoperative re-collapse in T-L burst fractures. (2) Through the decision-making model, we aimed to predict re-collapse and prevent unnecessary additional anterior spinal surgery. STUDY DESIGN: Retrospective comparative study. PATIENT SAMPLE: Two-hundred and eight (104 men and 104 women) consecutive patients with T-L burst fracture who underwent posterior instrumented fusion were reviewed retrospectively. Burst fractures caused by high-energy trauma (fall from a height and motor vehicle accident) with a minimum 1-year follow-up were included. The average age at the time of surgery was 45.9 years (range, 15-79). With respect to the involved spinal level, 95 cases (45.6%) involved L1, 51 involved T12, 54 involved L2, and 8 involved T11. Mean fixation segments were 3.5 (range, 2-5). Pedicle screw instrumentation including fractured vertebra had been performed in 129 patients (62.3%). OUTCOME MEASURES: Clinical data using self-report measures (visual analog scale score), radiographic measurements (plain radiograph, computed tomography, and magnetic resonance image), and functional measures using the Oswestry Disability Index were evaluated. METHODS: Body height loss of fractured vertebra, body wedge angle, and Cobb angle were measured in serial plain radiographs. We assigned patients to the re-collapse group if their body height loss progressed greater than 20% at any follow-up time compared with immediate postoperative body height loss; we assigned the remaining patients to the well-maintained group. The chi-square test and t test of SPSS were used for comparison of differences between two groups and multiple logistic regression analysis for risk factor evaluation. Through the decision tree analysis of statistical package R, a decision-making model was composed, and a cutoff value of revealed risk factors and re-collapse rate of each subgroup were identified. The present study wassupported by the University College of Medicine Research Fund (university to which authors belong). There was no external funding source for this study. The authors have no conflict of interest to declare. RESULTS: Re-collapse occurred in 31 of 208 patients (14.9%). In this group, age, the proportion of male gender, preoperative height loss, and preoperative wedge angle were significantly greater than the well-maintained group. Multivariable logistic regression analysis identified two independent risk factors: age (adjusted odds ratio 1.084, p=.002) and body height loss (adjusted odds ratio 1.065, p=.003). According to the decision-making tree, age (>43 years) was the most discriminating variable, andpreoperative body height loss (>54%) was the second. In this model, the re-collapse rate was zero in ages less than 43 years, and among those remaining, nearly 80% patients with greater than 54% of body height loss belonged to the re-collapse group. CONCLUSIONS: The independent predictors of re-collapse after posterior instrumented fusion for T-L burst fracture were the age at operation (>43 years old) and preoperative body height loss (>54%). Careful assessment using our decision-making model could help to predict re-collapse and prevent unnecessary additional spinal surgery for anterior column support, especially in young patients. PMID- 28735765 TI - Incidental durotomy during total en bloc spondylectomy. AB - BACKGROUND CONTEXT: The incidence of incidental durotomy (ID) during total en bloc spondylectomy (TES) tends to be higher than that during other spinal surgeries because of the peculiarities of TES, including its highly invasive nature, epidural tumor extension, and use in patients who often have complicated medical backgrounds. However, there have been no detailed reports on ID associated with TES. PURPOSE: The study aimed to investigate ID during TES in detail. STUDY DESIGN: This is a retrospective review of prospectively collected data. PATIENT SAMPLE: The study included 105 consecutive patients with spinal tumor who underwent TES between May 2010 and February 2015 (59 men, 46 women; mean age, 54.0 years [range, 14-75 years] at the time of surgery). OUTCOME MEASURES: Outcome measures included the incidence, risk factors, anatomical location, intraoperative maneuvers, and postoperative course of ID associated with TES. MATERIALS AND METHODS: Medical and operative records and imaging findings were reviewed. Univariate analysis and multivariable stepwise logistic regression models were used to identify independent risk factors for ID. RESULTS: Incidental durotomy occurred in 18 (17.1%) of the 105 patients. The univariate and multivariate analyses demonstrated that older age (adjusted odds ratio [aOR], 6.09; 95% confidence interval [CI], 1.17-31.76; p=.03), radiotherapy (RT) history (aOR, 5.31; 95% CI, 1.46-19.49; p=.01), and revision surgery (aOR, 19.42; 95% CI, 3.46-109.14; p<.01) were independent risk factors for ID. Incidental durotomy was more likely to occur during dissection of tumor tissues in proximity to the nerve root. Although all of the ID cases were primarily sutured and covered with polyglycolic acid mesh and fibrin glue spray, eight cases required additional intervention because of intractable postoperative cerebrospinal fluid leakage. Six of these eight had a history of RT. CONCLUSIONS: Our results may help better identify high-risk patients for ID during TES, which may aid surgeons with optimal surgical decision making and in counseling patients on perioperative complications. PMID- 28735767 TI - Measuring participation in patients with chronic back pain-the 5-Item Pain Disability Index. AB - BACKGROUND CONTEXT: Of the three broad outcome domains of body functions and structures, activities, and participation (eg, engaging in valued social roles) outlined in the World Health Organization's (WHO) International Classification of Functioning, Disability and Health (ICF), it has been argued that participation is the most important to individuals, particularly those with chronic health problems. Yet, participation is not commonly measured in back pain research. PURPOSE: The aim of this study was to investigate the construct validity of a modified 5-Item Pain Disability Index (PDI) score as a measure of participation in people with chronic back pain. STUDY DESIGN: A validation study was conducted using cross-sectional data. PATIENT SAMPLE: Participants with chronic back pain were recruited from a multidisciplinary pain center in Alberta, Canada. OUTCOME MEASURES: The outcome measure of interest is the 5-Item PDI. METHODS: Each study participant was given a questionnaire package containing measures of participation, resilience, anxiety and depression, pain intensity, and pain related disability, in addition to the PDI. The first five items of the PDI deal with social roles involving family responsibilities, recreation, social activities with friends, work, and sexual behavior, and comprised the 5-Item PDI seeking to measure participation. The last two items of the PDI deal with self care and life support functions and were excluded. Construct validity of the 5 Item PDI as a measure of participation was examined using Pearson correlations or point-biserial correlations to test each hypothesized association. RESULTS: Participants were 70 people with chronic back pain and a mean age of 48.1 years. Forty-four (62.9%) were women. As hypothesized, the 5-Item PDI was associated with all measures of participation, including the Participation Assessment with Recombined Tools-Objective (r=-0.61), Late-Life Function and Disability Instrument: Disability Component (frequency: r=-0.66; limitation: r=-0.65), Work and Social Adjustment Scale (r=0.85), a global perceived participation scale (r=0.54), employment status (r=-0.30), and the Usual Activity domain of the 15D (r=0.50). The expected correlations observed indicating a moderate or strong association provided supporting evidence for the construct validity of the 5-Item PDI as a measure of participation. The Oswestry Disability Index and the 5-Item PDI were also strongly correlated (r=0.70). The 5-Item PDI was associated to a lesser degree with depressive symptoms and resilience, as measured by the Hospital Anxiety and Depression Scale (HADS) (r=0.25) and the Connor-Davidson Resilience Scale (r=-0.28), as would be expected. No statistically significant association was found between the 5-Item PDI and the HADS Anxiety score. CONCLUSIONS: It is important that outcome measures of participation are included in back pain research to gauge the effects of painful spinal conditions and interventions on maintaining valued social roles. A simple, concise measure would be very useful for this purpose in clinical and research settings. The results of this study support the construct validity of the 5-Item PDI as a brief measure of participation in people with chronic back pain. These findings are likely most applicable to those with chronic back pain attending pain clinics and other tertiary centers for care. PMID- 28735768 TI - Cervical flexion and extension includes anti-directional cervical joint motion in healthy adults. AB - BACKGROUND CONTEXT: Anti-directional cervical joint motion has previously been demonstrated. However, quantitative studies of anti-directional and pro directional cervical flexion and extension motions have not been published. PURPOSE: This study aimed for a quantitative assessment of directional and anti directional cervical joint motion in healthy subjects. STUDY DESIGN: An observational study was carried out. PATIENTS SAMPLE: Eighteen healthy subjects comprised the study sample. OUTCOME MEASURES: Anti-directional and pro directional cervical flexion and extension motion from each cervical joint in degrees were the outcome measures. METHODS: Fluoroscopy videos of cervical flexion and extension motions (from neutral to end-range) were acquired from 18 healthy subjects. The videos were divided into 10% epochs of C0/C7 range of motion (ROM). The pro-directional and anti-directional motions in each 10% epoch were extracted, and the ratios of anti-directional motions with respect to the pro-directional motions (0%=no anti-directional movement) were calculated for joints and 10% epochs. RESULTS: The flexion and extension ROM for C0/C7 were 51.9 degrees +/-9.3 degrees and 57.2 degrees +/-12.2 degrees . The anti-directional motions of flexion and extension ROM constituted 42.8%+/-9.7% and 41.2%+/-8.2% of the respective pro-directional movements. For flexion, the first three joints (C0/C1, C1/C2, C2/C3) demonstrated larger ratios compared with the last three joints (C4/C5, C5/C6, C6/C7) (p<.03). For extension, C1/C2 and C2/C3 ratios were larger compared with C0/C1, C4/C5, and C5/C6 (p<.03). Comparisons between flexion and extension motions showed larger C0/C1 ratio but smaller C5/C6 and C6/C7 ratios in extension (p<.05). CONCLUSIONS: This is the first report of quantified anti-directional cervical flexion and extension motion. The anti-directional motion is approximately 40% of the pro-directional motion. The results document that large proportions of anti-directional cervical flexion and extension motions were normal. PMID- 28735769 TI - The Elderly are Less Likely to Receive Recommended Radical Radiotherapy for Non small Cell Lung Cancer. AB - AIMS: The National Institute for Healthcare Excellence recommends continuous hyperfractionated, accelerated radiotherapy (CHART), concurrent chemoradiation (cCRT) and stereotactic ablative radiotherapy (SABR) for appropriate patients with non-small cell lung cancer (NSCLC), but these are not universally available in all UK radiotherapy centres. Reduced access to these treatments may be contributing to reduced survival, with the concern that elderly patients are less likely to receive guideline-recommended therapy (GRT). MATERIALS AND METHODS: We report a prospective, UK national study of patients treated with curative-intent radiotherapy for NSCLC over a 2 month period. Clinical oncologists in all UK radiotherapy centres were contacted and asked to complete a proforma on all patients treated with curative-intent radiotherapy. RESULTS: Three hundred and seventeen records were returned from 82% of centres. Only 49% (95% confidence interval 43-55%) of patients received the GRT for their tumour type. Patients aged 70 years or over were less likely to access GRT than those under 70 years (40% compared with 60%, P = 0.001), both as a result of clinicians offering therapy less frequently (52% compared with 65%, P = 0.03) and a higher refusal of therapy (22% versus 8%, P = 0.02). A reluctance to travel to a different centre was a key component of these decisions. SABR was delivered to only 52% of suitable patients, mainly because it was not available in the local centre. CONCLUSIONS: In this study of UK curative-intent radiotherapy practice, a lack of local access seems to limit uptake of advanced radiotherapy techniques such as SABR, especially for patients aged over 70 years. PMID- 28735770 TI - To4, the first Tityus obscurus beta-toxin fully electrophysiologically characterized on human sodium channel isoforms. AB - Many scorpion toxins that act on sodium channels (NaScTxs) have been characterized till date. These toxins may act modulating the inactivation or the activation of sodium channels and are named alpha- or beta-types, respectively. Some venom toxins from Tityus obscurus (Buthidae), a scorpion widely distributed in the Brazilian Amazon, have been partially characterized in previous studies; however, little information about their electrophysiological role on sodium ion channels has been published. In the present study, we describe the purification, identification and electrophysiological characterization of a NaScTx, which was first described as Tc54 and further fully sequenced and renamed To4. This toxin shows a marked beta-type effect on different sodium channel subtypes (hNav1.1 hNav1.7) at low concentrations, and has more pronounced activity on hNav1.1, hNav1.2 and hNav1.4. By comparing To4 primary structure with other Tityus beta toxins which have already been electrophysiologically tested, it is possible to establish some key amino acid residues for the sodium channel activity. Thus, To4 is the first toxin from T. obscurus fully electrophysiologically characterized on different human sodium channel isoforms. PMID- 28735771 TI - Toxicosurveillance in the US opioid epidemic. PMID- 28735772 TI - Silicon to syringe: Cryptomarkets and disruptive innovation in opioid supply chains. AB - Cryptomarkets offer insight into the evolving interplay between online black markets and cartel-based distribution. The types and forms of heroin, fentanyl, and prescription drugs show wide diversification. In this commentary we describe changes in the conceptualizations, technologies and structures of drug supply chains in the 21st Century, with special attention to the role of cryptomarkets as tools, contexts, and drivers of innovation in public health research. PMID- 28735773 TI - Today's fentanyl crisis: Prohibition's Iron Law, revisited. AB - More than a decade in the making, America's opioid crisis has morphed from being driven by prescription drugs to one fuelled by heroin and, increasingly, fentanyl. Drawing on historical lessons of the era of National Alcohol Prohibition highlights the unintended, but predictable impact of supply-side interventions on the dynamics of illicit drug markets. Under the Iron Law of Prohibition, efforts to interrupt and suppress the illicit drug supply produce economic and logistical pressures favouring ever-more compact substitutes. This iatrogenic progression towards increasingly potent illicit drugs can be curtailed only through evidence-based harm reduction and demand reduction policies that acknowledge the structural determinants of health. PMID- 28735774 TI - Trends in hepatitis C antibody prevalence among Aboriginal and Torres Strait Islander people attending Australian Needle and Syringe Programs, 1996-2015. AB - BACKGROUND: Research indicates that hepatitis C antibody (anti-HCV) prevalence is higher among Australian Aboriginal and Torres Strait Islander (Aboriginal) than non-Aboriginal people who inject drugs (PWID). We examined trends in demographic and drug use characteristics and anti-HCV prevalence among Australian Needle and Syringe Program Survey (ANSPS) respondents by Aboriginal status from 1996 to 2015. METHODS: The ANSPS survey involved collecting demographic, behavioural data and a dried blood spot for anti-HCV testing. We used logistic regression to determine demographic and behavioural factors associated with testing anti-HCV positive in the following time-periods (1996-2000, 2001-2005, 2006-2010, 2011 2015) among Aboriginal and non-Aboriginal PWID respondents. RESULTS: Overall, there were 16,948 PWID, with 11% identifying as Aboriginal. The proportion of Aboriginal respondents increased from 7% in 1996-2000 to 16% in 2011-2015. Overall anti-HCV prevalence was significantly higher among Aboriginal (60%) than non-Aboriginal PWID (52%, p<0.01). Receptive syringe sharing (RSS) declined among non-Aboriginal PWID (p<0.001) over time, however among Aboriginal PWID, RSS remained stable (p=0.619). Factors independently associated with testing positive for anti-HCV among Aboriginal PWID in 2011-2015 were 16 or more years since first injection (adjusted odds ratio [AOR] 6.04, p<0.001), history of incarceration (AOR: 1.74, p=0.010) and currently or previously on opioid substitution therapy (AOR: 1.89, p=0.003). Compared to 1996-2000, testing anti-HCV positive was significantly associated with the time-periods: 2001-2005 (unadjusted odds ratio [OR]: 1.39, p<0.001), 2006-2010 (OR: 1.38, p<0.001) and 2011-2015 (OR: 1.25, p<0.001) among non-Aboriginal PWID; however this increase did not occur among Aboriginal PWID. CONCLUSION: The proportion of Aboriginal PWID attending Needle Syringe Programs appears to have increased. Overall, the prevalence of anti-HCV has remained higher among Aboriginal than non-Aboriginal PWID. Coupling increased access to NSPs with new interferon-free HCV treatments and culturally appropriate education and counselling services could influence new HCV infections among Aboriginal PWID. PMID- 28735775 TI - Heroin uncertainties: Exploring users' perceptions of fentanyl-adulterated and substituted 'heroin'. AB - BACKGROUND: The US is experiencing an unprecedented opioid overdose epidemic fostered in recent years by regional contamination of the heroin supply with the fentanyl family of synthetic opioids. Since 2011 opioid-related overdose deaths in the East Coast state of Massachusetts have more than tripled, with 75% of the 1374 deaths with an available toxicology positive for fentanyl. Fentanyl is 30 50X more potent than heroin and its presence makes heroin use more unpredictable. A rapid ethnographic assessment was undertaken to understand the perceptions and experiences of people who inject drugs sold as 'heroin' and to observe the drugs and their use. METHODS: A team of ethnographers conducted research in northeast Massachusetts and Nashua, New Hampshire in June 2016, performing (n=38) qualitative interviews with persons who use heroin. RESULTS: (1) The composition and appearance of heroin changed in the last four years; (2) heroin is cheaper and more widely available than before; and (3) heroin 'types' have proliferated with several products being sold as 'heroin'. These consisted of two types of heroin (alone), fentanyl (alone), and heroin-fentanyl combinations. In the absence of available toxicological information on retail-level heroin, our research noted a hierarchy of fentanyl discernment methods, with embodied effects considered most reliable in determining fentanyl's presence, followed by taste, solution appearance and powder color. This paper presents a new 'heroin' typology based on users' reports. CONCLUSION: Massachusetts' heroin has new appearances and is widely adulterated by fentanyl. Persons who use heroin are trying to discern the substances sold as heroin and their preferences for each form vary. The heroin typology presented is inexact but can be validated by correlating users' discernment with drug toxicological testing. If validated, this typology would be a valuable harm reduction tool. Further research on adaptations to heroin adulteration could reduce risks of using heroin and synthetic opioid combinations. PMID- 28735776 TI - Fentanyl in the US heroin supply: A rapidly changing risk environment. PMID- 28735777 TI - Heroin and fentanyl overdoses in Kentucky: Epidemiology and surveillance. AB - BACKGROUND: The study aims to describe recent changes in Kentucky's drug overdose trends related to increased heroin and fentanyl involvement, and to discuss future directions for improved drug overdose surveillance. METHODS: The study used multiple data sources (death certificates, postmortem toxicology results, emergency department [ED] records, law enforcement drug submissions, and prescription drug monitoring records) to describe temporal, geographic, and demographic changes in drug overdoses in Kentucky. RESULTS: Fentanyl- and heroin related overdose death rates increased across all age groups from years 2011 to 2015 with the highest rates consistently among 25-34-year-olds. The majority of the heroin and fentanyl overdose decedents had histories of substantial exposures to legally acquired prescription opioids. Law enforcement drug submission data were strongly correlated with drug overdose ED and mortality data. The 2016 crude rate of heroin-related overdose ED visits was 104/100,000, a 68% increase from 2015 (62/100,000). More fentanyl-related overdose deaths were reported between October, 2015, and September, 2016, than ED visits, in striking contrast with the observed ratio of >10 to 1 heroin-related overdose ED visits to deaths. Many fatal fentanyl overdoses were associated with heroin adulterated with fentanyl; <40% of the heroin overdose ED discharge records listed procedure codes for drug screening. CONCLUSIONS: The lack of routine ED drug testing likely resulted in underreporting of non-fatal overdoses involving fentanyl and other synthetic drugs. In order to inform coordinated public health and safety responses, drug overdose surveillance must move from a reactive to a proactive mode, utilizing the infrastructure for electronic health records. PMID- 28735778 TI - Yoga for Military Veterans with Chronic Low Back Pain: A Randomized Clinical Trial. AB - INTRODUCTION: Chronic low back pain (cLBP) is prevalent, especially among military veterans. Many cLBP treatment options have limited benefits and are accompanied by side effects. Major efforts to reduce opioid use and embrace nonpharmacological pain treatments have resulted. Research with community cLBP patients indicates that yoga can improve health outcomes and has few side effects. The benefits of yoga among military veterans were examined. DESIGN: Participants were randomized to either yoga or delayed yoga treatment in 2013 2015. Outcomes were assessed at baseline, 6 weeks, 12 weeks, and 6 months. Intention-to-treat analyses occurred in 2016. SETTING/PARTICIPANTS: One hundred and fifty military veterans with cLBP were recruited from a major Veterans Affairs Medical Center in California. INTERVENTION: Yoga classes (with home practice) were led by a certified instructor twice weekly for 12 weeks, and consisted primarily of physical postures, movement, and breathing techniques. MAIN OUTCOME MEASURES: The primary outcome was Roland-Morris Disability Questionnaire scores after 12 weeks. Pain intensity was identified as an important secondary outcome. RESULTS: Participant characteristics were mean age 53 years, 26% were female, 35% were unemployed or disabled, and mean back pain duration was 15 years. Improvements in Roland-Morris Disability Questionnaire scores did not differ between the two groups at 12 weeks, but yoga participants had greater reductions in Roland-Morris Disability Questionnaire scores than delayed treatment participants at 6 months -2.48 (95% CI= -4.08, -0.87). Yoga participants improved more on pain intensity at 12 weeks and at 6 months. Opioid medication use declined among all participants, but group differences were not found. CONCLUSIONS: Yoga improved health outcomes among veterans despite evidence they had fewer resources, worse health, and more challenges attending yoga sessions than community samples studied previously. The magnitude of pain intensity decline was small, but occurred in the context of reduced opioid use. The findings support wider implementation of yoga programs for veterans. TRIAL REGISTRATION: This study is registered at www.clinicaltrials.gov NCT02524158. PMID- 28735779 TI - A systematic review of variables associated with sleep paralysis. AB - Sleep paralysis is a relatively common but under-researched phenomenon. While the causes are unknown, a number of studies have investigated potential risk factors. In this article, we conducted a systematic review on the available literature regarding variables associated with both the frequency and intensity of sleep paralysis episodes. A total of 42 studies met the inclusion criteria. For each study, sample size, study site, sex and age of participants, sleep paralysis measure, and results of analyses looking at the relationship(s) between sleep paralysis and associated variable(s) were extracted. A large number of variables were associated with sleep paralysis and a number of themes emerged. These were: substance use, stress and trauma, genetic influences, physical illness, personality, intelligence, anomalous beliefs, sleep problems and disorders (both in terms of subjective sleep quality and objective sleep disruption), symptoms of psychiatric illness in non-clinical samples (particularly anxiety symptoms), and psychiatric disorders. Sleep paralysis appears to be particularly prevalent in post-traumatic stress disorder, and to a less degree, panic disorder. Limitations of the current literature, directions for future research, and implications for clinical practice are discussed. PMID- 28735780 TI - Electromyographic activity of the vastus intermedius muscle in patients with stiff-knee gait after stroke. A retrospective observational study. AB - Stiff-knee gait (SKG) in hemiplegic patients is often due to an inappropriate activity of the quadriceps femoris. However, there are no studies in literature addressing the vastus intermedius (VI) involvement in SKG. In this study, VI activity was analyzed in a sample of 46 chronic stroke patients with SKG, during spontaneous gait. VI activity was recorded by fine-wire electrodes inserted under ultrasound guidance then confirmed by electrical stimulation. The measured VI activity was compared to the normal reference pattern reported in literature and classified (e.g. premature, prolonged). The occurrences of abnormal activations during each sub-phase of the gait cycle were assessed. VI activity presented an abnormal timing in 96% of the sample. The most common pathological pattern (in 46% of the sample) was the combination of premature and prolonged VI activation. Nearly 20% of patients presented a continuous activity. A pathological activation in patients was found for 91% in mid stance, for more than 50% in terminal stance and pre-swing and for 37% and 70% in initial- and mid-swing. Results indicate that abnormal VI activity is frequent in patients with SKG. Hence, VI activity should be included in the assessment of SKG to assist in the clinical decision making processes. PMID- 28735781 TI - The Future of Fracture Risk Assessment in the Management of Osteoporosis. AB - There have been many advances in the field of osteoporosis that add to a greater understanding of skeletal integrity and the adverse effects menopause and aging have on bone. The World Health Organization, the International Osteoporosis Foundation, and numerous additional governmental and privately sponsored organizations, societies, and their respective task forces have provided guidance for the use of appropriate fracture assessment methodologies and fracture risk assessment tools, and for the prevention and management of osteoporosis. Despite these worldwide efforts, a majority of patients at high risk of fracture have not had bone density testing and are not diagnosed or offered osteoporosis treatment before or even after sustaining a fragility fracture. The future of fracture risk assessment and, in general, osteoporosis management requires health-care systems to develop customizable electronic medical record (EMR) systems that incorporate the tools necessary to identify patients at high fracture risk. As provided in the example of an advanced health-care osteoporosis model, an EMR can be fully customizable to identify fractures and patients at high risk of fracture, to assist clinicians in selecting the most efficacious osteoporosis treatments, and to provide long-term follow-up with or without serial bone density testing. Future fracture risk assessment models will likely be further refined by incorporating advanced fracture predictive technologies for integration into algorithms that have improved discrimination, calibration, risk reclassification capabilities, and clinical utility. These models will include accurate and reproducible bone biomarkers and genomic testing that will be automatically integrated into worldwide EMR systems for screening large numbers of at-risk populations and younger patients for future prediction and prevention of disease. The integration of this type of a fracture prediction model into future electronic medical record systems will result in the prevention of osteoporosis fractures. PMID- 28735782 TI - Editorial Commentary: Keeping the congenitally malformed heart in shape. PMID- 28735783 TI - Myocardial viability-State of the art: Is it still relevant and how to best assess it with imaging? AB - Despite major advances, ischemic cardiomyopathy (ICM) remains a significant cause of death and disability worldwide, with coronary artery disease (CAD) the leading cause of left ventricular (LV) systolic dysfunction. Coronary revascularization may improve LV function, heart failure symptoms and cardiovascular outcomes in high-risk patients with myocardial viability. Multiple imaging modalities have been utilized to detect viable myocardium and predict functional recovery following revascularization. Dobutamine stress echocardiography (DSE), nuclear imaging and cardiac MRI (CMR) are frequently used to assess viability. This review will summarize the extant literature on this topic, describe the role and methods for viability imaging in modern clinical practice, provide a patient centered perspective regarding the controversies surrounding the current utility of viability imaging, as well as discuss future directions. PMID- 28735784 TI - Cardiovascular effects of alcohol consumption. AB - Alcohol consumption has a major but complex impact on cardiovascular diseases. Both irregular and chronic heavy drinking occasions detrimentally impact on most major cardiovascular disease categories, whereas light to moderate drinking has been associated with beneficial effects on ischemic heart disease and ischemic stroke. Both detrimental and beneficial effects of alcohol consumption have been corroborated by biochemical pathways. The impact of alcohol consumption on cardiovascular disease should be evaluated within the context of other effects of alcohol on health. PMID- 28735785 TI - Effect of the Simultaneous Working Length Control during Root Canal Preparation on Postoperative Pain. AB - AIM: The aim of this study was to evaluate the effect of simultaneous length control during root canal preparation on postoperative pain compared with separate working length determination and root canal preparation. The design was a parallel-group, randomized, controlled trial with 2 arms. METHODS: Forty-four molar teeth were randomly divided into 2 groups (n = 22), a control group (separate length determination and root canal preparation) and a simultaneous length control during root canal preparation group. The following variables were recorded: age; gender; tooth number; preoperative pain on the visual analog scale; pain level on days 1, 3, 5, and 7; and analgesic intake after the procedure and initial/final percussion pain. The data were analyzed with the chi2 test, independent samples t test, and Mann-Whitney U test. RESULTS: The simultaneous length control during root canal preparation group resulted in lower postoperative pain levels on day 1 than did the control group (P < .05). Despite 2 patients' intake of postoperative analgesics in the control group, no patient needed to use postoperative analgesics in the simultaneous length control during root canal preparation group (P > .05). CONCLUSIONS: Simultaneous length control during root canal preparation as a non-pharmacologic strategy for reducing postoperative pain is a beneficial technique for preventing postoperative pain. PMID- 28735786 TI - Cone-beam Computed Tomographic Study of Root Anatomy and Canal Configuration of Molars in a Spanish Population. AB - INTRODUCTION: The aim of this study was to identify morphologic peculiarities of roots and analyze the root canal configuration in maxillary and mandibular first and second molars by means using cone-beam computed tomographic (CBCT) imaging in a Spanish population. METHODS: A total of 284 maxillary molars and 242 mandibular molars from 112 patients were examined in vivo by CBCT imaging; only untreated molars with healthy and fully matured apices were included in this study. Details regarding the number of roots, number of canals, and root canal configuration were recorded. RESULTS: Maxillary first and second molars had 3 roots in 97.2% and 79%, respectively. In mandibular molars, the frequency of 2 roots was 94% in first molars and 83% in second molars. The canal configuration of the palatal root was 100% Vertucci type I (1-1) in first and second molars. The distobuccal root showed a Vertucci type I configuration in 97% of first and 100% of maxillary second molars. The mesiobuccal root for first molars showed a Vertucci type II configuration (2-1) in 56.5% cases and Vertucci type IV (2-2) in 23.2%. For maxillary second molars, the Vertucci type I configuration reached 52.7%. In mandibular molars, the mesial root showed higher variability. Most frequent was the presence of 2 canals, Vertucci type II for first and second molars. In the distal root, the most common configuration was Vertucci type I in both molars. CONCLUSIONS: The greater percentage of fused roots was observed in maxillary molars. Vertucci type II configuration was more frequent than type IV in the mesial root of mandibular molars and the mesiobuccal root of maxillary molars. A third canal in the mesial root of first mandibular molars (6.7%) was higher than expected. PMID- 28735787 TI - Chemical-physical Properties and Apatite-forming Ability of Mineral Trioxide Aggregate Flow. AB - INTRODUCTION: This study aimed to analyze the chemical-physical properties, including pH, volumetric change, radiopacity, and apatite-forming ability in simulated body fluid, of a new tricalcium silicate material (MTA Flow; Ultradent Products Inc, South Jordan, UT). METHODS: MTA Flow was tested in comparison with MTA Angelus (Angelus, Londrina, PR, Brazil). The pH of soaking water was tested up to 168 hours in deionized water. In the solubility test, the root-end fillings of 20 acrylic teeth were scanned twice by micro-computed tomographic imaging before and after immersion in ultrapure water for 168 hours. In addition, using an aluminum step wedge, the radiopacity of each material was evaluated as recommended by international standards. The mean gray values of the test materials were measured using ImageJ software (National Institutes of Health, Bethesda, MD). The morphologic and chemical analyses of the material surface were performed using scanning electron microscopic energy-dispersive X-ray spectroscopic analysis after 28 days in Hank's balanced salt solution (HBSS). The data were analyzed using 2-way analysis of variance with the Student-Newman-Keuls test (P < .05). RESULTS: MTA Flow showed similar alkalizing activity to that of MTA Angelus. In the solubility test, both materials presented lower values without statistical differences. Both materials showed a marked alkalinizing activity within 3 hours, which continued for 168 hours. MTA Angelus showed statistically higher radiopacity values (P < .05). All materials showed the ability to nucleate calcium phosphate on their surface after 28 days in HBSS. CONCLUSIONS: MTA Flow showed remarkable alkalinizing capability, low solubility, good radiopacity, and the ability to form calcium phosphate deposits after being soaked in simulated body fluid, showing values similar to those of MTA Angelus. PMID- 28735788 TI - Effect of Mineral Trioxide Aggregate Apical Plug Thickness on Fracture Resistance of Immature Teeth. AB - INTRODUCTION: The aim of this study was to compare the fracture resistance of simulated immature teeth after using different thicknesses of mineral trioxide aggregate (MTA) apical plugs. METHODS: Fifty-two human maxillary anterior teeth were used. Five teeth were the positive control group; they were prepared using Peeso reamers to simulate immature teeth without any access cavity preparation. Access cavities of the 47 teeth were prepared, and the canals were instrumented with Peeso reamers. Five teeth served as the negative control; they were filled with calcium hydroxide. Forty-two teeth were divided into 3 groups; in groups 1, 2, and 3, MTA was placed into canals as a 3-mm and a 6-mm apical plug and a thorough canal length, respectively. The rest of the canals in groups 1 and 2 were filled with gutta-percha and AH Plus sealer (Dentsply DeTrey, Konstanz, Germany). After the storage period, the roots were covered with a polyether impression material and were embedded into self-curing resin blocks. Each specimen was then subjected to fracture testing using a universal testing machine. Data were analyzed using 1-way analysis of variance with the Tukey post hoc test for multiple comparisons. RESULTS: The negative group showed the lowest fracture resistance compared with the other groups. The 3-mm apical plug group showed the highest fracture resistance (P < .05). No significant differences were found between the 3-mm and 6-mm apical plug groups (P > .05). CONCLUSIONS: MTA should be used as an apical plug instead of root canal filling material to increase the fracture resistance of immature teeth. PMID- 28735789 TI - XP Shaper, A Novel Adaptive Core Rotary Instrument: Micro-computed Tomographic Analysis of Its Shaping Abilities. AB - INTRODUCTION: The aim of this study was to investigate the shaping abilities of the XP Shaper (FKG, La Chaux-de-Fonds, Switzerland) and compare the findings with Vortex Blue (Dentsply Tulsa Dental Specialties, Tulsa, OK) using micro-computed tomographic imaging. METHODS: Twenty matched, extracted, mandibular, central incisors with a single, oval canal were scanned preoperatively at 25-MUm resolution and postoperatively after instrumentation with either Vortex Blue in a crown-down manner up to size 30.04 or XP Shaper. The percent of untouched walls, changes in canal volume and surface area, the amount of dentin removed, debris remaining in the canal, and the preparation taper were determined. The total time required for instrumentation using each technique was calculated in seconds. Statistical analysis was used to compare between both groups using repeated measures multivariate analysis of variance with Bonferroni correction for post hoc comparison and independent sample t tests. RESULTS: The XP Shaper significantly increased the canal volume (F = 77.948, P < .001), surface area (F = 5.543, P = .030), and amount of dentin removed (F = 10.044, P = .001) and had significantly less untouched walls (38.6% +/- 8.1%) compared with VB (58.8% +/- 8.5%). There was less debris at all levels of the canal in the XP Shaper group. Results were almost significant (P = .059). The XP Shaper was also significantly faster in completing the mechanical preparation of the root canal space by almost 1 minute (t = 6.216, P < .001). CONCLUSIONS: The XP Shaper can expand beyond its core size to adapt to the anatomy of the root canal space. The XP Shaper can prepare and touch more canal walls in oval-shaped canals compared with Vortex Blue. However, the final preparation taper will vary according to the anatomy of the treated tooth. PMID- 28735790 TI - Patient-specific Finite Element Analysis of Fiber Post and Ferrule Design. AB - INTRODUCTION: A ferrule on anterior endodontic-treated teeth has been evaluated using clinical trials, in vitro tests, and finite element analysis (FEA). The patient-specific FEA with a nonuniform ferrule and nonlinear contact biting load associated with clinical validation can be used to predict failure. METHODS: A patient was selected with both maxillary central incisors with different ferrule designs who received endodontic treatment and restoration using a fiber post, composite core, and computer aided design and computer aided manufacturing lithium disilicate ceramic crowns. Strain gauges were attached to the buccal surfaces of both teeth to record ceramic strain during bite force recording for FEA validation. Cone-beam computed tomographic imaging was performed, and the Digital Imaging and Communication in Medicine files were exported to Mimics, 3 Matic (Materialise, Leuven, Belgium) and Patran (MSC Software, Santa Ana, CA) software to create a patient-specific FEA model. Bite load was applied using contact load applied by antagonist teeth (155 N). Mechanical properties were obtained from the literature. Modified von Mises equivalent stress was used for stress evaluation. RESULTS: Stresses on the dentin and fiber post on the left incisor, which had a nonuniform ferrule, were higher compared with the right incisor. The strain values recorded for the right central incisor (strain gauge =79.9 +/- 3.8 MUS and FEA = 69.5 MUS) and the left central incisor (strain gauge = 83.5 +/- 5.3 MUS and FEA = 73.9 MUS) validate the FEA analysis. CONCLUSIONS: FEA was validated with in vivo strain values measured at the buccal crown surfaces, supporting that the stress levels were realistic for investigation of the clinical performance of fiber posts. Maintaining a uniform ferrule was more favorable than a localized higher ferrule. PMID- 28735791 TI - Detection of Incomplete Root Fractures in Endodontically Treated Teeth Using Different High-resolution Cone-beam Computed Tomographic Imaging Protocols. AB - INTRODUCTION: The purpose of this study was to compare different high-resolution cone-beam computed tomographic (CBCT) imaging protocols in the diagnosis of incomplete root fractures of endodontically treated teeth. METHODS: Twenty single rooted human teeth were endodontically treated, and an incomplete root fracture was induced. The teeth were scanned with the CBCT unit PreXion 3D (Teracom, San Mateo, CA) operating at 2 different protocols: high resolution/standard (HI-STD) (19 seconds and 512 basis images) and high resolution/high density (HI-HI) (37 seconds and 1024 basis images). Three oral radiologists evaluated all images using multiplanar reconstructions. The diagnostic tests and the receiver operating characteristic (ROC) curve were calculated. RESULTS: The HI-STD and HI HI protocols presented an accuracy of 0.90 and 0.93, respectively, and both protocols had a sensitivity of 0.97. The HI-HI protocol showed a higher positive predictive value and slightly higher areas under the ROC curve. CONCLUSIONS: Both high-resolution imaging protocols presented high accuracy in the detection of incomplete root fracture of endodontically teeth. Thus, the HI-STD protocol should be indicated this reduces the radiation dose. PMID- 28735792 TI - Dynamic Torque and Vertical Force Analysis during Nickel-titanium Rotary Root Canal Preparation with Different Modes of Reciprocal Rotation. AB - INTRODUCTION: The purpose of the present study was to compare 2 modes of reciprocal movement (torque-sensitive and time-dependent reciprocal rotation) with continuous rotation in terms of torque and apical force generation during nickel-titanium rotary root canal instrumentation. METHODS: A custom-made automated root canal instrumentation and torque/force analyzing device was used to prepare simulated canals in resin blocks and monitor the torque and apical force generated in the blocks during preparation. Experimental groups (n = 7, each) consisted of (1) torque-sensitive reciprocal rotation with torque-sensitive vertical movement (group TqR), (2) time-dependent reciprocal rotation with time dependent vertical movement (group TmR), and (3) continuous rotation with time dependent vertical movement (group CR). The canals were instrumented with TF Adaptive SM1 and SM2 rotary files (SybronEndo, Orange, CA), and the torque and apical force were measured during instrumentation with SM2. The mean and maximum torque and apical force values were statistically analyzed using 1-way analysis of variance and the Tukey test (alpha = 0.05). RESULTS: The recordings showed intermittent increases of upward apical force and clockwise torque, indicating the generation and release of screw-in forces. The maximum upward apical force values in group TmR were significantly smaller than those in group CR (P < .05). The maximum torque values in clockwise and counterclockwise directions in groups TqR and TmR were significantly smaller than those in group CR (P < .05). CONCLUSIONS: Under the present experimental conditions using TF Adaptive instruments, both torque-sensitive and time-dependent reciprocal rotation generated significantly lower maximum torque and may have advantages in reducing stress generation caused by screw-in forces when compared with continuous rotation. PMID- 28735793 TI - Dentinal Microcrack Development after Canal Preparation: A Longitudinal in Situ Micro-computed Tomography Study Using a Cadaver Model. AB - INTRODUCTION: The purpose of this study was to evaluate the development of dentinal microcracks after root canal preparation with Reciproc and ProTaper Universal systems using an in situ cadaver model by means of a micro-computed tomography (micro-CT) imaging system. METHODS: At autopsy, 8 maxillary bone blocks having at least the first and second premolar teeth (n = 16) were excised, scanned at a resolution of 13.18 MUm, and randomly distributed into 2 groups (n = 8) according to the preparation protocol: Reciproc and ProTaper Universal systems. Root canals were prepared up to R25 and F2 instruments in the Reciproc and ProTaper Universal groups, respectively. After the preparation procedures, the specimens were scanned again, and the registered preoperative and postoperative cross-section images of the roots (n = 19,060) were screened to identify the presence of dentinal defects. RESULTS: In the Reciproc group, 9176 cross-section images were analyzed, and no crack was observed. In the ProTaper Universal group, 244 of 9884 cross-section slices (2.46%) had dentinal defects; however, all defects were already present in the corresponding preoperative images, indicating that no new microcrack was created after canal preparation. CONCLUSIONS: In situ root canal preparation of maxillary premolars with Reciproc and ProTaper Universal systems did not induce the formation of dentinal microcracks in a cadaver model as observed by micro-CT. PMID- 28735794 TI - Influence of Different Kinematics on Apical Extrusion of Irrigant and Debris during Canal Preparation Using K3XF Instruments. AB - INTRODUCTION: This in vitro study was designed to evaluate the amount of apically extruded irrigant and debris during root canal preparation using K3XF instruments (SybronEndo, Orange, CA) with different kinematics and using hand files with a step-back technique. METHODS: A total of 80 extracted mandibular premolars were selected and randomly assigned to 4 groups (n = 20). The root canals were instrumented with K-type stainless steel instruments using a step-back technique and with the K3XF system using the following kinematics: reciprocating motion, adaptive motion, and continuous rotation. Bidistilled water was used as an irrigant. Preweighed Eppendorf tubes were used to collect apically extruded debris during instrumentation. Extruded irrigant was collected from the drainage cannula using a plastic insulin syringe, and the volumes were recorded. After complete evaporation of the liquid inside the tube, the weight of extruded debris was determined for each specimen. Data were analyzed statistically using the Kruskal-Wallis and Mann-Whitney U tests at a significance level of P < .05. RESULTS: Hand file instrumentation was associated with a significantly greater extrusion of debris compared with the K3XF groups (P < .05). Among the different kinematics, the highest mean debris extrusion value was obtained with reciprocating motion and the least with continuous rotation, but this difference was not significant (P > .05). No significant differences were observed between groups in terms of irrigant extrusion (P > .05). CONCLUSIONS: Hand instrumentation extruded more debris than K3XF instruments that were used with different kinematics. All instrumentation kinematics were associated with apical debris and irrigant extrusion. PMID- 28735795 TI - Accuracy of 2 Endodontic Rotary Motors with Integrated Apex Locator. AB - INTRODUCTION: The purpose of this study was to evaluate in vitro the efficacy of both the electronic apex locator (EAL) and auto apical reverse (AAR) functions of the endodontic motor MM Control (Micro-Mega, Besancon Cedex, France) compared with Root ZX II (J Morita, Tokyo, Japan). METHODS: After cervical preflaring, the actual lengths (ALs) of 36 single-rooted teeth were obtained up to the apical foramen. The EAL measurements at the marks "APEX" and "0.5" of both devices were obtained using an alginate model. The teeth were divided randomly into 2 groups (n = 18), and root canal preparation was performed with rotary instruments using the AAR function (0.5 mark) of each motor. The length provided by the AAR was compared with the visual length after preparation (AL2). The differences between the electronic lengths and the respective visual measurements were assigned as negative for lower or positive when higher. The means of the absolute values and the percentages of distribution of the electronic measurements between devices were compared. RESULTS: There was no difference between the devices in terms of the means of the EAL measurements or AAR length (analysis of variance, P > .05). However, the EAL function of MM Control presented a greater percentage of measurements >1.01 mm longer than AL (chi-square, P < .01). The AAR function provided an acceptable apical limit in 83.3% of the cases for Root ZX and 77.8% of the cases for MM Control. CONCLUSIONS: The AAR function of both MM Control and Root ZX II provided an adequate apical limit of preparation in vitro. However, the use of only the EAL function of MM Control resulted in significantly more cases of overextended readings. PMID- 28735796 TI - Prevalence of Second Mesiobuccal Canals in Maxillary First Molars Detected Using Cone-beam Computed Tomography, Direct Occlusal Access, and Coronal Plane Grinding. AB - INTRODUCTION: The purpose of this study was to determine the prevalence of the second mesiobuccal canal (MB2) in 100 maxillary first molars using 3 independent methods and a combination method. METHODS: One hundred extracted human maxillary first molars were collected. The teeth were mounted in the maxillary first molar extraction sockets of a human cadaver head. A cone-beam computed tomographic (CBCT) scan was taken of each tooth. Two radiology faculty independently evaluated the CBCT volume for the presence of an MB2 canal. Additionally, teeth were accessed. If a canal was not found, a preoperative CBCT scan was viewed followed by a second attempt to locate an MB2 canal. Lastly, the mesiobuccal root was dissected by grinding in a coronal plane. RESULTS: A review of CBCT volumes found the presence of an MB2 canal 69% of the time. Accessing the tooth led to an MB2 detection of 78%. When a CBCT scan was viewed, this brought the access detection rate up to 87%. Coronal plane root grinding had an MB2 canal detection rate of 92%. Differences between each method were statistically significant. CONCLUSIONS: The results of this study show that an MB2 canal is present up to 92% of the time. Direct access of teeth found statistically significant more MB2 canals than viewing CBCT volumes alone (P = .032). Therefore, exposing every patient to a preoperative CBCT scan may not be appropriate. However, taking a CBCT scan when an MB2 canal is not found clinically can significantly increase the chances of finding an MB2 canal (P < .001). PMID- 28735797 TI - Characteristics, correlates, and assessment of psychosis in Parkinson disease without dementia. AB - INTRODUCTION: Considering that psychosis in Parkinson disease (PD) is associated with worse outcomes, including dementia, we aimed to study the characteristics, correlates, and assessment of PD psychosis in those without dementia. METHODS: 101 PD subjects without dementia (Montreal Cognitive Assessment >=21/30) were recruited to participate in a study of neuropsychiatric symptoms in PD. This study included a baseline standard neurological exam and common PD symptom assessments. Using the Scale for the Assessment of Positive Symptoms (SAPS) and separate assessment of visual illusions and sense of presence, NINDS-NIMH criteria for PD psychosis were applied. RESULTS: Of the 33 (32.7%) PD subjects who met diagnostic criteria for psychosis in PD, visual illusions were most common (72.7%), followed by visual hallucinations (39.4%). Adjusted for presence of REM sleep behavior disorder (RBD) (p = 0.097), use of dopamine agonists (OR = 3.7, p = 0.012) and greater autonomic symptom burden (OR = 1.1 (per 1-unit change in score on SCOPA-AUT), p = 0.012) were associated with greater risk of psychosis. Use of dopamine agonists (OR = 5.0, p = 0.007), higher MDS-UPDRS Part II score (OR = 1.1, p = 0.010), and presence of RBD (OR = 4.8, p = 0.012) were independent predictors of visual hallucinations and visual illusions. MDS-UPDRS item 1.2 score >=1 had highly correlated with the SAPS score (r = 0.65, p < 0.0001), but was 42% sensitive and 96% specific for identifying psychosis. CONCLUSION: This study confirms the association between dopamine agonists and psychosis in PD patients without dementia. The association of RBD, autonomic symptoms, and MDS-UPDRS Part II scores with psychosis underscore its link to brainstem dysfunction and greater PD motor symptom severity. PMID- 28735798 TI - The etiology of essential tremor: Genes versus environment. AB - INTRODUCTION: Essential tremor (ET) is characterized by bilateral upper limb action tremor. Here we review the pathophysiology (cerebral mechanisms) and etiology (genetic and environmental risk factors) of ET. METHODS: We reviewed the literature (until June 2017) by searching PubMed for relevant papers. RESULTS: The pathophysiology of ET involves oscillatory activity in the cortico-olivo cerebello-thalamic circuit, evidenced by electrophysiological and metabolic imaging. Possible underlying mechanisms include GABA-ergic dysfunction, cerebellar neurodegeneration, olivary dysfunction, or a combination. Genetic studies have examined affected ET families (linkage studies and whole-exome sequencing studies). These studies revealed several chromosomal regions and genes associated with ET, but the findings have not been replicated across different ET families. Genetic studies also assessed the sporadic occurrence of ET using genome wide genotyping of single nucleotide polymorphisms (SNP's) and candidate gene studies. Several SNP's are associated with ET, and this has been replicated across different cohorts. Interestingly, some of the involved genes are linked to the cerebellum and inferior olive. Environmental studies point to an association between ET and beta-carboline alkaloids (such as harmane), which have been found in the cerebellum. CONCLUSION: Genetic and environmental risk factors may influence cerebellar and/or olivary function, resulting in abnormal cortico-olivo cerebello-thalamic activity, and ultimately ET. PMID- 28735799 TI - Prior Knee Arthroscopy Does Not Influence Long-Term Total Knee Arthroplasty Outcomes and Survivorship. AB - BACKGROUND: Arthroscopic knee surgery frequently precedes total knee arthroplasty (TKA). There have been mixed data on the effect of prior arthroscopic surgery on results of TKA. The purpose of this study was to compare the 10-year Knee Society Score (KSS), survivorship, and complications of TKA in a cohort of patients who had a previous knee arthroscopy to a control cohort. METHODS: A retrospective review of 1315 TKAs who underwent a primary TKA between 2003 and 2004 was performed. Of these, 160 TKAs had previous arthroscopy (excluding ligamentous reconstruction). A matched cohort study 2:1 was carried out with a group of 320 controls (no prior surgery). Outcomes were assessed with the original KSS, range of-motion, complications, and survivorships. Mean follow-up was 9 years. RESULTS: The mean KSS increased from 36-84 in the arthroscopy group vs 35-86 in the control group (P = .5). The mean preoperative and postoperative range-of-motion was not different between groups (P = .2). The survivorship free of complication at 5 years was similar in both groups (94.3% in arthroscopy group vs. 95.3% in the control; P = .7) with infection in 2 controls and 3 arthroscopy cases (P = .2). The survivorships free of revision for aseptic loosening, revision for any reason, and reoperation were similar at 10 years (96.5%, 94.6%, and 89.2%, respectively, in the arthroscopy group vs 96.2%, 95.9%, and 91.5% in the control group). CONCLUSION: There were no significant differences between both groups. These data are reassuring and valuable in an era in which many candidates for TKA will have had previous arthroscopic knee surgery. PMID- 28735800 TI - Durability of Hemiarthroplasty for Pathologic Proximal Femur Fractures. AB - BACKGROUND: The hip is a common location for metastatic tumors. Due to the high loads placed through the proximal femur, surgery is often indicated to provide pain relief and restore function. Historically, these lesions are reconstructed with a hemiarthroplasty; however, there are few reports on the outcome of these reconstructions. The purpose of this study is to evaluate the outcome of hemiarthroplasty for the treatment of proximal femur metastatic disease, with a specific focus on the rates of conversion to total hip arthroplasty (THA). METHODS: One hundred ninety-nine patients (102 women, 97 men) were treated using a hemiarthroplasty to reconstruct the proximal femur for metastatic disease between 1992 and 2014. Mean age and body mass index were 62 years and 27.4 kg/m2, respectively. The most common site of primary disease was the breast (n = 63). The most common location for the metastatic disease was the femoral neck (n = 148). Mean follow-up for surviving patients was 4 years. RESULTS: Over the course of the study, 2 (1%) patients underwent conversion to a THA due to groin pain and degenerative changes. In addition, complications occurred in 12% of patients, most commonly a deep venous thrombosis (n = 5). Following the procedure, mean Harris Hip Score and Musculoskeletal Tumor Society 1993 scores were 73 and 63%, respectively. CONCLUSION: Reconstruction of the proximal femur with a hemiarthroplasty endoprosthesis provides a majority of patients with a durable means of reconstruction, with a low rate of conversion to THA. PMID- 28735801 TI - Prior Arthroscopy Leads to Inferior Outcomes in Total Hip Arthroplasty: A Match Controlled Study. AB - BACKGROUND: Total hip arthroplasty (THA) is one of the most common reoperations after hip arthroscopy. Although arthroscopy causes changes in the hip joint and the surrounding soft tissues that can make THA more challenging, previous reports on arthroscopy before THA have not demonstrated any significant effect on clinical outcomes. METHODS: Patients who underwent a THA following an ipsilateral hip arthroscopy were matched to a control group of THA patients with no history of ipsilateral hip surgery. Matching criteria were age within 5 years, sex, body mass index within 5, surgical approach, and robotic assistance. Harris Hip Score, Forgotten Joint Score-12, visual analog scale score, satisfaction, and postoperative complication and reoperation rates were compared at minimum 2-year follow-up. RESULTS: Thirty-five THA after arthroscopy patients were successfully matched to control patients. There were no significant differences in demographics between study groups. The THA after arthroscopy group had significantly lower Harris Hip Score, Forgotten Joint Score-12, and satisfaction at latest follow-up. They had higher visual analog scale score and complication rate in differences that closely approached significance. There was no significant difference in reoperation rate. CONCLUSION: A prior hip arthroscopy may adversely affect the clinical outcomes of THA. This potential risk should be considered when assessing the candidacy of a patient for hip arthroscopy. PMID- 28735802 TI - Correction of Patellofemoral Malalignment With Patellofemoral Arthroplasty. AB - BACKGROUND: The goal of patellofemoral arthroplasty (PFA) is to replace damaged cartilage and correct underlying deformities to reduce pain and prevent maltracking. We aimed to determine how PFA modifies patellar height, tilt, and tibial tuberosity-trochlear groove (TT-TG) distance. The hypothesis was that PFA would correct trochlear dysplasia or extensor mechanism malalignment. METHODS: The authors prospectively studied a series of 16 patients (13 women and 3 men) aged 64.9 +/- 16.3 years (range 41-86 years) who received PFA. All knees were assessed preoperatively and 6 months postoperatively using frontal, lateral, and "skyline" x-rays, and computed tomography scans to calculate patellar tilt, patellar height, and TT-TG distance. RESULTS: The interobserver agreement was excellent for all parameters (intraclass correlation coefficient >0.95). Preoperatively, the median patellar tilt without quadriceps contraction (QC) was 17.5 degrees (range 5.3 degrees -33.4 degrees ) and with QC was 19.8 degrees (range 0 degrees -52.0 degrees ). The median Caton-Deschamps index was 0.91 (range 0.80-1.22) and TT-TG distance was 14.5 mm (range 4.0-22.0 mm). Postoperatively, the median patellar tilt without QC was 0.3 degrees (range 15.3 degrees to 9.5 degrees ) and with QC was 6.1 degrees (range -11.5 degrees to 13.3 degrees ). The median Caton-Deschamps index was 1.11 (range 0.81-1.20) and TT-TG distance was 10.1 mm (range 1.8-13.8 mm). CONCLUSION: The present study demonstrates that beyond replacing arthritic cartilage, trochlear-cutting PFA improves patellofemoral congruence by correcting trochlear dysplasia and standardizing radiological measurements as patellar tilt and TT-TG. The association of lateral patellar facetectomy improves patellar tracking by reducing the patellar tilt. PMID- 28735803 TI - Transfusion Thresholds for Major Orthopedic Surgery: A Systematic Review and Meta analysis. AB - BACKGROUND: More than a million surgeries are performed annually in the United States for hip or knee arthroplasty or hip fracture stabilization. One-fifth of these patients have blood transfusions during their hospital stay. Increases in transfusion rates have caused concern about increased adverse events from unnecessary transfusions. METHODS: We systematically reviewed randomized trials examining the effect of restrictive vs liberal transfusion thresholds on patients having major orthopedic surgery. Study results were meta-analyzed with a random effects model and heterogeneity was tested with the I2 statistic. Study risk of bias was assessed using a modified Jadad scale and evidence strength was measured using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) system. RESULTS: A total of 504 published articles were screened, and 15 met inclusion criteria. The articles described 9 randomized trials, most comparing transfusion thresholds of 8 vs 10 g/dL hemoglobin. All involved hip or knee arthroplasty and/or hip fracture patients. Moderate-strength evidence suggested a reduction in need for transfusion (relative risk, 0.53; 95% confidence interval [CI], 0.39-0.71; I2 = 95%) and mean number of units transfused (-0.95 units, 95% CI, -1.48 to -0.41, I2 = 98%). There was a possible reduction in overall infections with more restrictive transfusion thresholds, although the result was not statistically significant (relative risk, 0.71; 95% CI, 0.47-1.06; I2 = 54%). Moderate-strength evidence suggested no differences in other clinical outcomes between the groups. Limitations included incomplete blinding, inconsistency, and imprecision. CONCLUSION: Moderate-strength evidence suggests that restrictive transfusion practices reduce utilization of transfusions and may decrease infections without increasing adverse outcomes in major orthopedic surgery. PMID- 28735804 TI - Effect of Type 2 Diabetes on In-Hospital Postoperative Complications and Mortality After Primary Total Hip and Knee Arthroplasty. AB - BACKGROUND: We aimed to compare in-hospital postoperative complications (IHPC) and in-hospital mortality between patients with and without type 2 diabetes mellitus (T2DM) undergoing primary total hip arthroplasty (THA) and total knee arthroplasty (TKA). METHODS: We analyzed data from the Spanish National Hospital Discharge Database, 2010-2014. We selected patients who had undergone THA (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] code 81.51) and TKA (code 81.54). Diabetic patients with THA and TKA were matched by year, age, sex, and the comorbidities included in the modified Elixhauser Comorbidity Index with a nondiabetic patient. RESULTS: We identified 115,234 THA patients and 195,355 TKA patients, 12.4% and 15.6% with T2DM, respectively. We matched 10,777 and 26,640 pairs of diabetic and nondiabetic patients. In T2DM patients who had undergone THA, the incidence of urinary tract infection was higher than in nondiabetic patients (1.50% vs 1.09%, P = .007), as was that of "any IHPC" (9.68% vs 8.98%, P = .038). In patients who had undergone TKA, the incidence of postoperative anemia was significantly higher in diabetic patients (4.90% vs 4.53, P = .040), as was that of urinary tract infection (0.80% vs 0.53%, P = .025) and "any IHPC" (7.30% vs 6.76%, P = .014). In both procedures, mean length of hospital stay was significantly higher in diabetic patients; for TKA, in-hospital mortality was higher in diabetic patients (0.09% vs 0.02%, P = .002). Previous comorbidities, age, and obesity predict a higher incidence of IHPC among diabetic patients. CONCLUSIONS: This study confirms the higher risk of IHPC among T2DM patients after joint arthroplasty. IHPC may result in a higher risk of mortality in patients undergoing TKA. PMID- 28735805 TI - Impact of Definition and Timeframe on Capturing Surgery-Related Readmissions After Primary Joint Arthroplasty. AB - BACKGROUND: Readmission rate has emerged as an important metric to measure quality, but varying definitions and timeframes are used. We aimed to evaluate the impact of different readmission definitions (postoperative vs postdischarge) and timeframes (30 vs 90-day) on capturing surgery-related readmissions after primary total joint arthroplasty. METHODS: Patients who underwent primary total hip or knee arthroplasty between January 1, 2013 and December 31, 2015 were included. The electronic medical records of readmitted patients were reviewed to determine whether a surgery-related event was most responsible for readmission. The performances of 4 definition-timeframe combinations in capturing surgery related readmissions were evaluated. RESULTS: A total of 2586 patients were included. Using both postoperative and postdischarge definitions, there were no differences in the proportion of readmissions that were surgery-related when comparing 30 and 90-day timeframes (postoperative: 71% vs 60%, P = .118; postdischarge: 68% vs 60%, P = .219). Greater proportion of readmissions between days 0 and 30 were for surgery-related reasons compared with readmissions between days 31 and 90 using both postoperative and postdischarge definitions (postoperative: 71% vs 47%, P = .005; postdischarge: 68% vs 49%, P = .022). Among 104 patients readmitted for surgery-related reasons within 1 year of discharge, 52% were readmitted within 30 days of surgery compared with 79% within 90 days (P < .001). Similarly, 53% and 81% of readmissions were captured by the 30 and 90 day postdischarge definitions, respectively (P < .001). CONCLUSION: A 90-day timeframe is superior in capturing surgery-related readmissions after total joint arthroplasty. Important Total hip and knee arthroplasty adverse events may be missed using a 30-day timeframe. PMID- 28735806 TI - Revisions of international consensus Fukuoka guidelines for the management of IPMN of the pancreas. AB - The management of intraductal papillary mucinous neoplasm (IPMN) continues to evolve. In particular, the indications for resection of branch duct IPMN have changed from early resection to more deliberate observation as proposed by the international consensus guidelines of 2006 and 2012. Another guideline proposed by the American Gastroenterological Association in 2015 restricted indications for surgery more stringently and recommended physicians to stop surveillance if no significant change had occurred in a pancreatic cyst after five years of surveillance, or if a patient underwent resection and a non-malignant IPMN was found. Whether or not it is safe to do so, as well as the method and interval of surveillance, has generated substantial debate. Based on a consensus symposium held during the meeting of the International Association of Pancreatology in Sendai, Japan, in 2016, the working group has revised the guidelines regarding prediction of invasive carcinoma and high-grade dysplasia, surveillance, and postoperative follow-up of IPMN. As the working group did not recognize the need for major revisions of the guidelines, we made only minor revisions and added most recent articles where appropriate. The present guidelines include updated information and recommendations based on our current understanding, and highlight issues that remain controversial or where further research is required. PMID- 28735807 TI - Imaging findings of axillary cystic lymphangioma in adult. PMID- 28735808 TI - Autoimmunity and its association with regulatory T cells and B cell subsets in patients with common variable immunodeficiency. AB - BACKGROUND: Common variable immunodeficiency (CVID) is one of the most prevalent symptomatic primary immunodeficiencies (PIDs), which manifests a wide clinical variability such as autoimmunity, as well as T cell and B cell abnormalities. METHODS: A total of 72 patients with CVID were enrolled in this study. Patients were evaluated for clinical manifestations and classified according to the presence or absence of autoimmune disease. We measured regulatory T cells (Tregs) and B-cell subsets using flow cytometry, as well as specific antibody response (SAR) to pneumococcal vaccine, autoantibodies and anti-IgA in patients. RESULTS: Twenty-nine patients (40.3%) have shown at least one autoimmune manifestation. Autoimmune cytopenias and autoimmune gastrointestinal diseases were the most common. A significant association was detected between autoimmunity and presence of hepatomegaly and splenomegaly. Among CVID patients, 38.5% and 79.3% presented a defect in Tregs and switched memory B-cells, respectively, whereas 69.0% presented CD21low B cell expansion. Among patients with a defect in Treg, switched memory and CD21low B cell, the frequency of autoimmunity was 80.0%, 52.2% and 55.0%, respectively. A negative correlation was observed between the frequency of Tregs and CD21low B cell population. 82.2% of patients had a defective SAR which was associated with the lack of autoantibodies. CONCLUSIONS: Autoimmunity may be the first clinical manifestation of CVID, thus routine screening of immunoglobulins is suggested for patients with autoimmunity. Lack of SAR in CVID is associated with the lack of specific autoantibodies in patients with autoimmunity. It is suggested that physicians use alternative diagnostic procedures. PMID- 28735809 TI - Antibiotic stewardship in perinatal and neonatal care. AB - The spread of antibiotic resistance due to the use and misuse of antibiotics around the world is now a major health crisis. Neonates are exposed to antibiotics both before and after birth, often empirically because of risk factors for infection, or for non-specific signs which may or may not indicate sepsis. There is increasing evidence that, apart from antibiotic resistance, the use of antibiotics in pregnancy and in the neonatal period alters the microbiome in the fetus and neonate with an increased risk of immediate and long-term adverse effects. Antibiotic stewardship is a co-ordinated program that promotes the appropriate use of antibiotics, improves patient outcomes, reduces microbial resistance, and decreases the spread of infections caused by multidrug-resistant organisms. This review addresses some of the controversies in antibiotic use in the perinatal period, examines opportunities for reduction of unnecessary antibiotic exposure in neonates, and provides a framework for antibiotic stewardship in neonatal care. PMID- 28735810 TI - Transesophageal Echocardiography Monitoring During Lung Transplantation. PMID- 28735812 TI - Reply to: "beta-blocker treatment of vascular disease in cocaine addiction". PMID- 28735811 TI - Improving hospital quality to reduce disparities in severe maternal morbidity and mortality. AB - Significant racial/ethnic disparities in maternal morbidity and mortality exist in the United States. Black women are 3-4 times more likely to die a pregnancy related death as compared with white women. Growing research suggests that hospital quality may be a critical lever for improving outcomes and narrowing disparities. This overview reviews the evidence demonstrating that hospital quality is related to maternal mortality and morbidity, discusses the pathways through which these associations between quality and severe maternal morbidity generate disparities, and concludes with a discussion of possible levers for action to reduce disparities by improving hospital quality. PMID- 28735814 TI - Tyrosine kinase inhibitors as modulators of trastuzumab-mediated antibody dependent cell-mediated cytotoxicity in breast cancer cell lines. AB - BACKGROUND: Trastuzumab is an anti-HER2 monoclonal antibody (mAb) therapy capable of antibody-dependent cell-mediated cytotoxicity (ADCC) and used in the treatment of HER2+ breast cancer. Through interactions with FcyR+ immune cell subsets, trastuzumab functions as a passive immunotherapy. The EGFR/HER2-targeting tyrosine kinase inhibitor (TKI) lapatinib and the next generation TKIs afatinib and neratinib, can alter HER2 levels, potentially modulating the ADCC response to trastuzumab. Using LDH-release assays, we investigated the impact of antigen modulation, assay duration and peripheral blood mononuclear cell (PBMC) activity on trastuzumab-mediated ADCC in breast cancer models of maximal (SKBR3) and minimal (MCF-7) target antigen expression to determine if modulating the ADCC response to trastuzumab using TKIs may be a viable approach for enhancing tumor immune reactivity. METHODS: HER2 levels were determined in lapatinib, afatinib and neratinib-treated SKBR3 and MCF-7 using high content analysis (HCA). Trastuzumab-mediated ADCC was assessed following treatment with TKIs utilising a colorimetric LDH release-based protocol at 4 and 12h timepoints. PBMC activity was assessed against non-MHC-restricted K562 cells. A flow cytometry-based method (CFSE/7-AAD) was also used to measure trastuzumab-mediated ADCC in medium-treated SKBR3 and MCF-7. RESULTS: HER2 antigen levels were significantly altered by the three TKIs in both cell line models. The TKIs significantly reduced LDH levels directly in SKBR3 cells but not MCF-7. Lapatinib and neratinib augment trastuzumab-related ADCC in SKBR3 but the effect was not consistent with antigen expression levels and was dependent on volunteer PBMC activity (vs. K562). A 12h assay timepoint produced more consistent results. Trastuzumab-mediated ADCC (PBMC:target cell ratio of 10:1) was measured at 7.6+/-4.7% (T12) by LDH assay and 19+/-3.2 % (T12) using the flow cytometry-based method in the antigen-low model MCF-7. CONCLUSIONS: In the presence of effector cells with high cytotoxic capacity, TKIs have the ability to augment the passive immunotherapeutic potential of trastuzumab in SKBR3, a model of HER2+ breast cancer. ADCC levels detected by LDH release assays are extremely low in MCF-7; the flow cytometry based CFSE/7-AAD method is more sensitive and consistent for the determination of ADCC in HER2-low models. PMID- 28735813 TI - Atypical memory B cells in human chronic infectious diseases: An interim report. AB - Immunological memory is a remarkable phenomenon in which survival of an initial infection by a pathogen leads to life-long protection from disease upon subsequent exposure to that same pathogen. For many infectious diseases, long lived protective humoral immunity is induced after only a single infection in a process that depends on the generation of memory B cells (MBCs) and long-lived plasma cells. However, over the past decade it has become increasingly evident that many chronic human infectious diseases to which immunity is not readily established, including HIV-AIDS, malaria and TB, are associated with fundamental alterations in the composition and functionality of MBC compartments. A common feature of these diseases appears to be a large expansion of what have been termed exhausted B cells, tissue-like memory B cells or atypical memory B cells (aMBCs) that, for simplicity's sake, we refer to here as aMBCs. It has been suggested that chronic immune activation and inflammation drive the expansion of aMBCs and that in some way aMBCs contribute to deficiencies in the acquisition of immunity in chronic infectious diseases. Although aMBCs are heterogeneous both within individuals and between diseases, they have several features in common including low expression of the cell surface markers that define classical MBCs in humans including CD21 and CD27 and high expression of genes not usually expressed by classical MBCs including T-bet, CD11c and a variety of inhibitory receptors, notably members of the FcRL family. Another distinguishing feature is their greatly diminished ability to be stimulated through their B cell receptors to proliferate, secrete cytokines or produce antibodies. In this review, we describe our current understanding of the phenotypic markers of aMBCs, their specificity in relation to the disease-causing pathogen, their functionality, the drivers of their expansion in chronic infections and their life span. We briefly summarize the features of aMBCs in healthy individuals and in autoimmune disease. We also comment on the possible relationship of human aMBCs and T-bet+, CD11c+ age/autoimmune-associated B cells, also a topic of this review volume. PMID- 28735815 TI - Intensive lifestyle intervention is particularly advantageous in poorly controlled type 2 diabetes. AB - BACKGROUND AND AIMS: It is unknown whether lifestyle change is effective in people with type 2 diabetes with inadequate glucose control. The aim of this study was to asses, in a group of people with type 2 diabetes, the impact of baseline values of glycosylated haemoglobin (HbA1c) on the effects of an intensive lifestyle intervention on metabolic, clinical and strength parameters. METHODS AND RESULTS: 222 people with type 2 diabetes with mean +/- standard deviation baseline HBA1c of 7.50% +/- 1.27 (range 5.1-12.7%), were enrolled in a 3-month structured multidisciplinary lifestyle intervention. Anthropometric, biochemical, clinical and fitness measurements were collected at baseline, at the end of the lifestyle intervention program and at two-year follow-up visit. Significant improvements in glycometabolic control (HbA1c: p <= 0.0001); anthropometric parameters (BMI p <= 0.0001; waist circumference: p <= 0.0001); and systemic blood pressure (p <= 0.0001) were observed both at the end of the three month intensive lifestyle program and at the two-year follow up visit. In addition, defined daily doses of hypoglycaemic treatment significantly decreased (p = 0.001). Fitness measures exhibited significant increments in the whole sample at the end of the intensive intervention program (p <= 0.0001). When patients were divided into tertiles considering the baseline value of HbA1c, the most marked improvements in HbA1c, blood glucose and triglycerides were observed in the group with inadequate glucose control (Hba1c >= 7.71%), both at the three month and two-year follow-ups. CONCLUSION: These results demonstrate that an intensive lifestyle intervention should be recommended for people with type 2 diabetes, particularly those with the most inadequate glycaemic control. REGISTRATION NUMBER: CURIAMO trial was registered in the Australian New Zealand Clinical Trials Registry, (ACTRN12611000255987). PMID- 28735816 TI - Lower risk of progression from prediabetes to diabetes with health checkup with lifestyle education: Japan Ningen Dock study. AB - BACKGROUND AND AIMS: To investigate whether the progression from prediabetes to diabetes is lower among those who undertake Ningen Dock (comprehensive health checkups with lifestyle education and doctor's consultation) than those who undertake basic mandatory occupational health checkups. METHODS AND RESULTS: Subjects aged 30-69 years with complete annual data from 2008 to 2012 for either Ningen Dock or basic health checkups were enrolled. Subjects with prediabetes (fasting plasma glucose 100-125 mg/dl or HbA1c 5.7-6.4%) at baseline were selected (14,928 in the comprehensive group and 10,433 in the basic group). The incidence of diabetes (fasting plasma glucose >= 126 mg/dl, HbA1c >= 6.5% or taking glucose-lowering drugs) and the reduction of risk factors were compared. After 4 years, 3226 cases of diabetes occurred among 25,361 subjects with prediabetes. The incidence of diabetes was lower in the comprehensive group than the basic group (2.9 vs. 3.8 cases/100 person-years, hazard ratio 0.75, 95% confidence interval 0.68-0.81 after adjustment). Moreover, more overweight subjects controlled their body mass index (16.2% vs. 13.2%) and more began a daily exercise habit (11.8% vs. 8.5%) in the comprehensive group than in the basic group. The incidence of diabetes was lower in subjects who could control their weight or start daily exercise at year 1 in the comprehensive group. CONCLUSION: Progression from prediabetes to diabetes was significantly lower in subjects undertaking a comprehensive health checkup with lifestyle education. Lifestyle education at health checkup for people with prediabetes might prevent progression to diabetes by reducing modifiable risk factors. PMID- 28735818 TI - Curcuminoids modify lipid profile in type 2 diabetes mellitus: A randomized controlled trial. AB - BACKGROUND: Type 2 diabetes (T2D) is an established risk factor for cardiovascular disease (CVD) and is associated with disturbed metabolism of lipids and lipoproteins. Curcuminoids are natural products with anti-diabetic and lipid-modifying actions but their efficacy in improving dyslipidemia in diabetic individuals has not been sufficiently studied. OBJECTIVE: To investigate the efficacy of supplementation with curcuminoids, plus piperine as an absorption enhancer, in improving serum lipids in patients with T2D. METHODS: In this 12 week randomized double-blind placebo-controlled trial, subjects with T2D (n=118) were assigned to curcuminoids (1000mg/day plus piperine 10mg/day) or placebo plus standard of care for T2D. Serum concentrations of lipids including total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), lipoprotein(a) [Lp(a)], and non-HDL-C were determined at baseline and at the end of trial. RESULTS: Between group comparison of change in the study parameters revealed significant reductions in serum levels of TC (-21.86+/-25.78 versus -17.06+/-41.51, respectively; p=0.023), non-HDL-C (-23.42+/-25.13 versus -16.84+/-41.42, respectively; p=0.014) and Lp(a) (-1.50+/-1.61 versus -0.34+/-1.73, respectively; p=0.001) and elevations in serum HDL-C levels (1.56+/-4.25 versus -0.22+/-4.62, respectively; p=0.048) in the curcuminoids group as compared with the placebo group (p<0.05). Serum TG and LDL-C changes did not show any significant difference between the study groups (p>0.05). CONCLUSION: Curcuminoids supplementation can reduce serum levels of atherogenic lipid indices including non-HDL-C and Lp(a). Therefore, curcuminoids supplementation could contribute to a reduced risk of cardiovascular events in dyslipidemic patients with T2D. PMID- 28735819 TI - Meta-analysis of the effects of Bifidobacterium preparations for the prevention and treatment of pediatric antibiotic-associated diarrhea in China. AB - Bifidobacterium preparations are increasingly used for pediatric antibiotic associated diarrhea (AAD) in China. The aim of this study was to review existing evidence on the efficacy of Bifidobacterium preparations for the prevention and treatment of pediatric AAD in China. Searches were performed with Medline, Embase, Cochrane Central Register of Controlled Trials, CNKI, and CBM databases. Thirty trials met the inclusion criteria. Of the 30 trials, five Bifidobacterium preparations were included. The preparations were all Bifidobacterium based, in combined with Lactobacillus, Enterococcus, Bacillus, Streptococcus or Clostridium strains. The pooled results of the 30 trials, which included 7225 participants, indicated a statistically significant association of Bifidobacterium preparations administration with reduction in pediatric AAD (odds ratio [OR], 0.33; 95% confidence interval [CI], 0.29-0.39; P<0.01). When the meta-analysis was re performed according to the trials explicitly aiming to prevent or treat pediatric AAD, respectively, the pooled results were similar (Bifidobacterium preparations use for preventing pediatric AAD (n=21): pooled OR, 0.34, 95% CI, 0.28-0.41, P<0.01; Bifidobacterium preparations use for treating pediatric AAD (n=9): pooled OR, 0.32, 95% CI, 0.23-0.43, P<0.01). Subgroup analyses which based on Bifidobacterium preparations variety, clinical condition, or participant's age also showed statistically significant benefit of adjunct Bifidobacterium preparations for the prevention and treatment of pediatric AAD in China. The pooled evidence suggested that Bifidobacterium preparations might be efficacious for the prevention and treatment of pediatric AAD in China. PMID- 28735820 TI - Evaluation of complementary-alternative medicine (CAM) questionnaire development for Indonesian clinical psychologists: A pilot study. AB - This study aimed to evaluate questionnaire development to measure the knowledge of Complementary-Alternative Medicine (CAM), attitudes towards CAM, CAM experiences, and CAM educational needs of clinical psychologists in Indonesia. A 26-item questionnaire was developed through an extensive literature search. Data was obtained from provisional psychologists from the Master of Professional Clinical Psychology programs at two established public universities in urban areas of Indonesia. To validate the questionnaire, panel reviews by executive members of the Indonesian Clinical Psychology Association (ICPA), experts in health psychology, and experts in public health and CAM provided their professional judgements. The self-reporting questionnaire consisted of four scales including: knowledge of CAM (6 items), attitudes towards CAM (10 items), CAM experiences (4 items), and CAM educational needs (6 items). All scales, except CAM Experiences, were assessed on a 7-point Likert scale. Sixty provisional psychologists were eligible to complete the questionnaire with a response rate of 73% (N=44). The results showed that the CAM questionnaire was reliable (Cronbach's coefficient alpha range=0.62-0.96; item-total correlation range=0.14-0.92) and demonstrated content validity. Following further psychometric evaluation, the CAM questionnaire may provide the evidence-based information to inform the education and practice of Indonesian clinical psychologists. PMID- 28735821 TI - Medical practitioners' attitudes towards animal assisted interventions. An Italian survey. AB - OBJECTIVES: The present study had a dual purpose: to obtain a comprehensive picture of the Italian medical practitioners' opinions, professional experiences, training needs and knowledge of Animal Assisted Interventions (AAI); and to provide a detailed description of the medical practitioners who are characterized by a strongly positive attitude towards AAI. METHODS: An online survey addressed to Italian medical practitioners was carried out using a 35-items structured questionnaire. Data obtained from the survey were analysed through appropriate summary statistics, analysis of variance (ANOVA) and logistic regression analysis. RESULTS: 670 medical practitioners participated in the online survey. Among them, 508 stated that they knew of AAI. 93.7% of these described themselves fully favourable towards the use of the human-animal relationship for therapeutic purposes, 84.4% defined themselves as confident and interested in studying the theme. A positive attitude towards AAI was greater in females, in people between 45 and 54 years old, in those who are pet owners and in those who believe that conferences are the most suitable tool to share information on AAI. CONCLUSIONS: The chance of having a positive attitude towards AAI is higher in respondents with specific characteristics. Data collected could be used as a starting point to promote and implement communication and training activities on AAI addressed to medical practitioners. PMID- 28735822 TI - Conservative management of a traumatic meniscal injury utilising osteopathy and exercise rehabilitation: A case report. AB - Meniscal injury is one of the most common knee soft tissue injuries, commonly affecting young athletes and an older, degenerative population. Treatment largely depends on the type and extent of the injury with arthroscopic repair or meniscectomy being mainstays. Although non-surgical approaches have been described, there is no published literature regarding a combination of indirect osteopathic techniques and rehabilitation in the management of these injuries. The current case report follows a 20-year-old male presenting with a 5-day history of acute knee pain, following trauma during an Australian Rules Football (AFL) match. An 8-week management plan of indirect osteopathic techniques and a tailored rehabilitation program was implemented. The Knee Injury and Osteoarthritis Outcome Score (KOOS) and the Lower Extremity Functional Scale (LEFS) questionnaires were utilised to measure outcomes. After the 8-week treatment and rehabilitation program, the patient had exceeded the minimum detectable change score for all outcome measures. This case report suggests that osteopathic manipulative treatment and rehabilitation may be an alternative, non surgical approach in the management of post-traumatic meniscal injuries. PMID- 28735823 TI - Comparison of remicade to curcumin for the treatment of Crohn's disease: A systematic review. AB - OBJECTIVE: The aim of this study was to review the literature to assess if there is evidence to support the use of Curcumin as a safe complementary therapy in treating Crohn's Disease (CD) in conjunction with Remicade. DESIGN: Systematic searches were performed by three researchers using electronic databases (ProQuest Medical Library, CINAHL Complete, and PUBMED) to locate and identify articles to meet a predetermined set of inclusion criteria. Specifically full text, peer reviewed articles published after 2007 were included if they studied human participants 18 years or older. RESULTS: Tumor necrosis factor-alpha (TNF-a) and Interleukin-1 (IL-1) levels increase in CD patients. Remicade reduces TNF-a in adults with CD. The issues are eventual loss of response (LOR) once IL-1 increases, and severe risks such as malignancy. CD patients using Curcumin saw a 55 point mean reduction in the Crohn's Disease Activity Index, reducing IL-1 and Crp. Plus it reduced TNF-a and PPMTase which improved colorectal cancer outcomes. CONCLUSIONS: LOR of Remicade occurs when IL-1 increases, and it can cause malignancy. Research shows Curcumin reduces IL-1 and improves cancer outcomes. Future research, using both Remicade and Curcumin, would have to be done, but preliminary data would suggest using both would reduce LOR. Curcumin, even by itself, was found to be a cheap and safe way to reduce CD symptoms and inflammatory markers. PMID- 28735817 TI - Osteosarcoma: Molecular Pathogenesis and iPSC Modeling. AB - Rare hereditary disorders provide unequivocal evidence of the importance of genes in human disease pathogenesis. Familial syndromes that predispose to osteosarcomagenesis are invaluable in understanding the underlying genetics of this malignancy. Recently, patient-derived induced pluripotent stem cells (iPSCs) have been successfully utilized to model Li-Fraumeni syndrome (LFS)-associated bone malignancy, demonstrating that iPSCs can serve as an in vitro disease model to elucidate osteosarcoma etiology. We provide here an overview of osteosarcoma predisposition syndromes and review recently established iPSC disease models for these familial syndromes. Merging molecular information gathered from these models with the current knowledge of osteosarcoma biology will help us to gain a deeper understanding of the pathological mechanisms underlying osteosarcomagenesis and will potentially aid in the development of future patient therapies. PMID- 28735824 TI - Effect of Qigong exercise on cognitive function, blood pressure and cardiorespiratory fitness in healthy middle-aged subjects. AB - OBJECTIVE: To investigate effects of Qigong exercise on cognitive function, blood pressure and cardiorespiratory fitness in healthy middle-aged subjects. METHODS: Study part 1 examined the effects of Qigong exercise in 12 subjects (5 males, 7 females, aged 52.2+/-7.1years) who performed Qigong for 8 weeks (60min sessions, 3 times/week). Study part 2 evaluated the detraining effects 12 weeks after cessation of Qigong. Cognitive function (Digit Span Forward and Backward Test, Trail Making Tests part A and B), blood pressure, and exercise performance were determined at baseline, immediately after the training programme, and after the detraining period. RESULTS: Qigong exercise showed a significant improvement of Trail Making Tests part A (p=0.04), systolic blood pressure (p=0.001), diastolic blood pressure (p=0.005), mean arterial pressure (p<0.001), and maximal workload (p=0.032). Twelve weeks after cessation, Trail Making Tests part A, systolic blood pressure, diastolic blood pressure, mean arterial pressure, and maximal workload had returned to baseline (p=0.050, 0.007, 0.001, 0.001, and 0.017, compared to after the training, respectively). CONCLUSION: These results suggest that Qigong exercise effectively improved attention, brain processing speed, blood pressure and maximal workload. However, these improvements disappeared 12 weeks after cessation of Qigong. Consequently, performing Qigong regularly is important to maintain related health effects. PMID- 28735825 TI - Dry needling in the management of myofascial trigger points: A systematic review of randomized controlled trials. AB - OBJECTIVE: This systematic review of randomized controlled trials aimed to examine the effectiveness of dry needling in the treatment of myofascial trigger points and to explore the impact of specific aspects of the technique on its effectiveness. METHODS: Relevant studies published between 2000 and 2015 were identified by searching PubMed, Scopus, The Cochrane Library and Physiotherapy Evidence Database. Studies identified by electronic searches were screened against a set of pre-defined inclusion criteria. RESULTS: Fifteen studies were included in this systematic review. The main outcomes that were measured were pain, range of motion, disability, depression and quality of life. The results suggest that dry needling is effective in the short term for pain relief, increase range of motion and improve quality of life when compared to no intervention/sham/placebo. There is insufficient evidence on its effect on disability, analgesic medication intake and sleep quality. CONCLUSIONS: Despite some evidence for a positive effect in the short term, further randomized clinical trials of high methodological quality, using standardized procedures for the application of dry needling are needed. PMID- 28735826 TI - affron(r) a novel saffron extract (Crocus sativus L.) improves mood in healthy adults over 4 weeks in a double-blind, parallel, randomized, placebo-controlled clinical trial. AB - BACKGROUND: In recent years phytotherapy has been explored as a source for alternative treatments for mood disorders. One potential candidate is saffron (Crocus sativus L.), whose main bioactive components are crocins and safranal. OBJECTIVES: The aim of this study was to investigate the efficacy of affron(r), a standardised stigmas extract from Crocus sativus L. for improving mood, stress, anxiety and sleep quality in healthy adults. METHODS: In this 3 arm study, 128 participants self-reporting low mood but not diagnosed with depression, were given affron(r) at 28mg/day, 22mg/day, or a placebo treatment in a randomized, double-blind, placebo-controlled trial for 4 weeks. Mood was measured at baseline and at the end of the study, using the POMS (primary outcome measure) and PANAS questionnaires, and the DASS-21 scale. Sleep was monitored using Sleep Quality Index (PSQI). RESULTS: Analysis indicated a significant decrease in negative mood and symptoms related to stress and anxiety at a 28mg/day dose (with a significant difference between 28mg/day and placebo on the POMS Total Mood Disturbance scale, p<0.001, d=-1.10), but no treatment effect at the 22mg/day dose. LIMITATIONS: The main weaknesses of this investigation were found in the self-reporting nature of both the screening and the testing. CONCLUSIONS: affron(r) increased mood, reduced anxiety and managed stress without side effects, offering a natural alternative to standard treatments. PMID- 28735827 TI - Efficacy and safety of Gegen Qinlian decoction for normalizing hyperglycemia in diabetic patients: A systematic review and meta-analysis of randomized clinical trials. AB - OBJECTIVES: A systematic review and meta-analysis was conducted to evaluate the efficacy and safety of Gegen Qinlian decoction (GQD) for normalizing hyperglycemia in T2DM patients by pooling all available RCTs. METHODS: All relevant RCTs were searched using the keywords: "GQD", "T2DM", "hyperglycemia" and "insulin" from the electronic databases including PubMed, EMBASE, Cochrane Library, Korean databases, Chinese medical databases, and Indian scientific database. Each RCT included the control (metformin) and experimental (GQD+metformin) groups. The outcome measures were the assessments of changes in the severity of diabetic symptoms such as "markedly effective" and "effective" (fasting plasma glucose levels: <7 and 7-9, respectively; 2h postprandial glucose levels: <8.3 and 8.3-10.5mmol/L, respectively) after 8 weeks of treatment in each RCT. RESULTS: There were 186 articles selected from the initial searches and 181 irrelevant and duplicate articles were removed. Finally, 5 relevant RCTs involving 499 patients were included in this review. The meta-analysis showed the odds ratio of favorable GQD effect on the marked effectiveness of glycemia (n=499, OR: 2.34, 95% CI: 1.63-3.37, P<0. In a subgroup analysis by GQD composition, 4 RCTs with original GQD composition also showed the odds ratio of the original GQD effect on the marked effectiveness of glycemia (n=339, OR: 2.58; 95% CI=1.65-4.02, P<0.0001) in comparison to the control group. All five studies used an appropriate method for randomization of the subjects but some of them included allocation concealment and blinding of patients and practitioners. There was no significant publication bias in the meta-analysis. CONCLUSION: The GQD and metformin had a synergistic effect on glycemic control in comparison to metformin alone as a T2DM therapy. More rigorous and larger studies are needed to confirm the therapeutic efficacy of GQD for hyperglycemia due to the moderate to high risk of bias in the 5 RCTs. PMID- 28735828 TI - Investigation of dietary supplements prevalence as complementary therapy: Comparison between hospitalized psoriasis patients and non-psoriasis patients, correlation with disease severity and quality of life. AB - OBJECTIVES: Psoriasis patients are often displeased with traditional medical treatments and they may self-prescribe dietary supplements as an alternative or complementary treatments. We aimed to investigate the prevalence of self medication of dietary supplements among psoriasis and non-psoriasis cases and its impact on disease severity and quality of life. DESIGN AND SETTING: This case control study evaluated 252 records of psoriasis patients and 245 non-psoriasis cases. Dietary supplementation over last 30days and characteristics, including age, age at onset of disease, co-morbidities, smoking and education were recorded. Psoriasis area and severity index (PASI) and dermatology quality of life index (DLQI) were calculated. P value less than 0.05 was considered as significant level. RESULTS: This study consisted 138 psoriasis (females; 54) and 138 non-psoriasis cases (females; 50), aged between 21 and 91 years. Among psoriasis patients, 72% reported using at least one of dietary supplements, which was different from non-psoriasis cases (25.36%, P=0.01). Multivitamin/mineral supplements (MVM) were the most frequent used dietary supplements (26.81%) and the most common reasons for the consumption of these supplements were to maintain and improve health. The consumption of folic acid (21.73%), omega-3 fatty acids or fish oil (10.14%), herbs (12.31%) and vitamin E (1.44%) had the most frequencies after MVM. No significant differences in PASI and DLQI were found among patients with consumption of different supplements (P>0.05). There was non significant and negative correlation between education and use of supplements (P=0.21, r=-0.02). CONCLUSIONS: Self-medicating of MVM over last 30days was prevalent among studied psoriasis patients. They took dietary supplements in order to improve and maintain their health. PMID- 28735829 TI - Comparative effects of 12 weeks of equipment based and mat Pilates in patients with Chronic Low Back Pain on pain, function and transversus abdominis activation. A randomized controlled trial. AB - BACKGROUND: Pilates method has been recommended for patients with chronic low back pain (CLBP) and the activation of transversus abdominis has been deemed to play an important role in the improvement of these patients. Nevertheless, the evidence of the activation of TrA in Pilates practitioners remains unclear. OBJECTIVE: To assess the effectiveness of 12 weeks of Pilates practice in disability, pain, kinesiophobia and transversus abdominis activation in patients with chronic nonspecific Low Back Pain. DESIGN: A randomized controlled trial was carried out. METHODS: A single-blind randomized controlled trial with repeated measures at 6 and 12 weeks was carried out. A total of ninety eight patients with low back pain were included and randomly allocated to a Pilates Mat group (PMG) equipment based with apparatus Pilates (PAG) or control group (CG). Roland Morris Disability Questionnaire (RMDQ), visual analog scale (VAS) Tampa Scale of Kinesiophobia (TSK), and transversus abdominis (TrA) activation assessed by real time ultrasound measurement (US) were assessed as outcome measures. RESULTS: Improvement were observed in both intervention groups in all the included variables at 6 and 12 weeks (p<0.001). Faster enhancement was observed in the equipment based Pilates group (p=0.007). CONCLUSIONS: Equipment based and mat Pilates modalities are both effective in the improvement of TaA activation in patients with CLBP with associate improvement on pain, function and kinesiophobia. Significant differences were observed after 12 weeks of intervention in PMG and PAG with faster improvement in PAG suggesting that, feedback provided by equipment could help in the interiorization of Pilates principles. PMID- 28735830 TI - "I just googled and read everything": Exploring breast cancer survivors' use of the internet to find information on complementary medicine. AB - OBJECTIVE: Breast cancer survivors often turn to the internet as an information resource when deciding whether to use complementary and alternative medicine (CAM) but their use of online CAM-related resources is poorly understood. The objective was to explore breast cancer survivors' use of the internet when making decisions about CAM use. DESIGN: A purposive sample of 11 breast cancer survivors (mean age=56) completed a quantitative questionnaire and a qualitative telephone interview. The theory of planned behaviour (TPB) was used to guide interview questions. Framework analysis and descriptive statistics were used. SETTING: United Kingdom. RESULTS: All participants found information on CAM using the internet and used some form of CAM after their diagnosis. Themes from the interviews went beyond the standard definitions of the TPB areas. Despite the lack of approval from their social network and healthcare team, participants used the internet to find information on CAM. Further, participants' cancer diagnosis changed their needs, transforming how they perceived and experienced the internet CONCLUSIONS: Participants' use of the internet was more complex than can easily be explained by the TPB and was inherently connected to the experience of self management for the consequences of cancer and its treatment. As breast cancer survivors may not disclose their use of the internet to their healthcare team, healthcare professionals need to be aware that the information available on the internet plays a factor in the decision-making process to use CAM. PMID- 28735832 TI - Mindfulness-based cognitive therapy for headache pain: An evaluation of the long term maintenance of effects. AB - OBJECTIVES: This study aimed to examine the durability of gain patterns following an 8-week Mindfulness-Based Cognitive Therapy (MBCT) for headache pain program. DESIGN: A secondary analysis of a randomized controlled trial was conducted. Participants (N=19) were individuals with headache pain who completed both the MBCT program as well as a 6-month follow-up assessment at a headache clinic or a university psychology clinic. Standardized measures of the primary outcomes (pain intensity and pain interference) and secondary outcomes (pain catastrophizing, mindfulness, activity engagement, pain willingness, and self-efficacy) were administered. Paired-samples t tests and effect sizes were examined. RESULTS: Significant (uncorrected ps<.05) pre- to post-treatment gains were found for pain intensity, pain interference, pain catastrophizing, activity engagement and self efficacy, and these gains were maintained at 6-months post-treatment. Effect sizes for the significant changes from pre- to post-treatment, and from pre treatment to follow-up were mostly consistent across epochs (.62<=ds<=-1.40), indicating steady maintenance of effects. Improvement in mindfulness and pain willingness was non-significant immediately post-treatment and at follow-up, with small effects observed. CONCLUSIONS: This study adds to a growing body of literature supporting the durability of MBCT for painful conditions. Results indicated a consistent pattern of maintenance of treatment-related gains across a number of key pain-related outcomes. Future research with a larger sample is needed to investigate the mechanisms underlying these continued gains in order to optimize targeted relapse-prevention. PMID- 28735831 TI - Wenxin Keli for Ventricular premature complexes with Heart failure: A Systematic Review and Meta-Analysis of Randomized Clinical Trials. AB - OBJECTIVE: To evaluate the efficacy and safety of Wenxin Keli (WXKL) alone or combined with Western medicine in treating ventricular premature complexes (VPCs) with heart failure (HF). METHODS: We searched five databases to identify relevant randomized controlled trials (RCTs) published before May 2016. Two review authors independently searched and screened the literature, extracted the data as well as assessed the methodological quality of the included studies by using criteria from the Cochrane Handbook, and analyzed via using Review Manager 5.3 software. RESULTS: Eight studies of WXKL were included. The results of the Meta-analysis showed that WXKL was more significant on the frequency of VPCs (MD=-427.08, 95% CI: -526.73~-327.43, P<0.01), left ventricular ejection fraction (LVEF) (MD= 4.12, 95% CI: 2.97~5.27, P<0.01), the total effect of VPCs (RR=0.48, 95% CI: 0.34~0.69, P<0.01) and 6-min walking test (MD=28.05, 95% CI: 19.56~36.54, P<0.01). The treatment group presented a significant reduction at left ventricular end-diastolic diameter (LVED) (MD=-3.94, 95% CI: -6.57~-1.31, P<0.01) when treatment time was 12 weeks, however, there was no statistical difference at 8 weeks. In addition, the included trials generally showed low methodological quality. CONCLUSIONS: Wenxin Keli may be effective and safe for treating VPCs and HF. However, further RCTs of larger scale, multi-center/country, longer follow-up periods, and higher quality are still required to verify the efficacy of Wenxin Keli in ventricular premature beat with heart failure. PMID- 28735833 TI - Cannabis use in people with Parkinson's disease and Multiple Sclerosis: A web based investigation. AB - OBJECTIVES: Cannabis has been used for medicinal purpose for thousands of years; however the positive and negative effects of cannabis use in Parkinson's disease (PD) and Multiple Sclerosis (MS) are mostly unknown. Our aim was to assess cannabis use in PD and MS and compare results of self-reported assessments of neurological disability between current cannabis users and non-users. METHODS: An anonymous web-based survey was hosted on the Michael J. Fox Foundation and the National Multiple Sclerosis Society webpages from 15 February to 15 October 2016. The survey collected demographic and cannabis use information, and used standardized questionnaires to assess neurological function, fatigue, balance, and physical activity participation. Analysis of variance and chi-square tests were used for the analysis. RESULTS: The survey was viewed 801 times, and 595 participants were in the final data set. Seventy-six percent and 24% of the respondents reported PD and MS respectively. Current users reported high efficacy of cannabis, 6.4 (SD 1.8) on a scale from 0 to 7 and 59% reported reducing prescription medication since beginning cannabis use. Current cannabis users were younger and less likely to be classified as obese (P < 0.035). Cannabis users reported lower levels of disability, specifically in domains of mood, memory, and fatigue (P<0.040). CONCLUSIONS: Cannabis may have positive impacts on mood, memory, fatigue, and obesity status in people with PD and MS. Further studies using clinically and longitudinally assessed measurements of these domains are needed to establish if these associations are causal and determine the long-term benefits and consequences of cannabis use in people with PD and MS. PMID- 28735834 TI - Retraction notice to "Secretory pathway Ca2+-ATPase isoform 1 knockdown promotes Golgi apparatus stress injury in a mouse model of focal cerebral ischemia reperfusion: In vivo and in vitro study" [Brain Res. 1642 (2016) 189-196]. PMID- 28735835 TI - Effect of scheduled second-look endoscopy on peptic ulcer bleeding: a prospective randomized multicenter trial. AB - BACKGROUND AND AIM: This study aimed to investigate the effectiveness of scheduled second-look endoscopy (EGD) with endoscopic hemostasis on peptic ulcer rebleeding and to identify the risk factors related to the need for second-look EGD. METHODS: We prospectively randomized patients who had endoscopically confirmed bleeding peptic ulcer with stigmata of active bleeding, visible vessel, or adherent clot into 2 groups between August 2010 and January 2013. Hemoclip application or thermal coagulation and/or epinephrine injection were allowed for initial endoscopic therapy. The same dosage of proton pump inhibitor was injected intravenously. The study group received scheduled second-look EGD 24 to 36 hours after the initial hemostasis, and further therapy was applied if endoscopic stigmata persisted, as above. Those patients who developed rebleeding underwent operation or radiologic intervention despite the additional endoscopic therapy. Outcome measures included rebleeding, amount of transfusion, duration of hospitalization, and mortality. RESULTS: After initial endoscopic hemostasis, 319 eligible patients were randomized into 2 groups. Sixteen (10.1%) and 9 (5.6%) patients developed rebleeding (P = .132), respectively. There was also no difference in surgical intervention (0, 0% vs 1, .6%, P >.999) or radiologic intervention (3, 1.9% vs 2, 1.2%, P = .683), median duration of hospitalization (6.0 vs 5.0 days, P = .151), amount of transfusion (2.4 +/- 1.7 vs 2.2 +/- 1.6 units, P = .276), and mortality (2, 1.3% vs 2, 1.2%, P > .999) between the 2 groups. Multivariate analysis showed that grades 3 to 4 of endoscopists' estimation to success of initial hemostasis, history of nonsteroidal anti inflammatory drug (NSAID) use, and larger amounts of blood transfusions (>=4 units of red blood cells) were the independent risk factors of rebleeding. CONCLUSIONS: A single EGD with endoscopic hemostasis is not inferior to scheduled second-look endoscopy in terms of reduction in rebleeding rate of peptic ulcer bleeding. Repeat endoscopy would be helpful in the patients with unsatisfactory initial endoscopic hemostasis, use of NSAIDs, and larger amounts of transfused blood. (Clinical trial registration number: KCT0000565; 4-2010-0348.). PMID- 28735836 TI - Importance of deformable image registration and biological dose summation in planning of radiotherapy retreatments. AB - The purpose of this study is to evaluate the effect of nonrigid and fractionation corrected dose summation on total doses in radiotherapy and to demonstrate the benefits of such dose summation on clinical decision-making for planning of retreatments. Dose summation of organs at risk (OARs) was investigated for 3 clinical cases with need of retreatment to the same site: head and neck, brain, and mediastinum. Three different summation methods over old and new radiotherapy treatment plans are presented and compared: (1) rigid raw sum with rigid registration of the planning images and direct dose summing; (2) deformable raw sum with deformable image registration and direct dose summing; and (3) deformable biological sum with deformable registration and takes into account the dose per fraction in biological manner in certain critical organs. In 2 cases, a user-defined dose downscaling is applied to take into account the time between the treatments and the healing from the radiation-induced effects. Of the 3 summation methods presented, the deformable biological sum was considered to offer the most biologically plausible account of the treatment. There were remarkable differences between near-maximum doses (D0.1cc) and dose-volume histogram (DVH) curves for OARs between different summation methods. The differences between deformable raw sum and rigid raw sum D0.1cc doses are in the range from -8 Gy to 2 Gy. Similarly, the deviation was from -14 Gy to 5 Gy for the deformable biological sum compared with the rigid raw sum. These differences come from incorrect summation of doses in the rigid raw sum case, and from the dose per fraction effect in biological summation. We conclude that computing the 3-dimensional deformable biological summation could be a valuable tool for treating patients with complex retreatments. It has the potential to assist the oncologist in refining plans for maximally curative doses while respecting appropriate tissue tolerances. PMID- 28735837 TI - Coronary artery calcification: From crystal to plaque rupture. AB - Epidemiological studies using coronary artery calcification measurement have linked calcification strongly with coronary events and mortality. Formerly considered as a passive age-related phenomenon, coronary artery calcification is now recognized as an active and regulated process. In fact, there is a local influence linked to the inflammation generated by the presence of oxidized lipids and, equally, a general influence from mineral metabolism factors, such as inorganic phosphate, calcium, pyrophosphate or fibroblast growth factor 23, which are regulators of cell differentiation and of phosphate and calcium deposition on the vascular layers. Despite active research in this field, no therapy is currently able to stop the progression of calcification. However, new data have provided a better understanding of atherosclerosis, enabling us to see calcification as a marker of the state of stability or instability of the atherosclerotic plaque, and opening new perspectives for atherosclerotic plaque imaging. PMID- 28735839 TI - Epidemiology of proximal humeral fractures: a detailed survey of 711 patients in a metropolitan area. AB - BACKGROUND: Literature lacks data concerning several epidemiologic aspects of proximal humeral fractures (PHFs). METHODS: This retrospective study included 711 consecutive patients (209 men, 502 women) who sustained a PHF in the last 3 years. Participants were divided into 2 groups, adults and children. Data regarding age, sex, date, and fracture side were collected. According to the mechanism of injury, we arbitrarily distinguished 7 subgroups. PHFs were classified according to the head-greater-lesser-shaft (HGLS)-Hertel classification and to the Salter-Harris classification using x-ray and computed tomography imaging. RESULTS: PHFs represent 5.03% of the overall fractures. The right side was involved in 389 patients (54.7%; P = .6). The mean age of male and female patients was 55.4 (standard deviation, 21.9) years and 67.0 (standard deviation, 16.1) years, respectively (P = .0001). Significant differences in the trauma mechanism between female patients (street/home low-energy trauma) and male patients (high-energy trauma) were found. A significant correlation between trauma mechanisms from 1 to 5 and fracture patterns H-G-L-S, HL-G-S, HGL-S, and HLS-G was observed. The occurrence of the same patterns significantly varied according to different age subgroups. Considering the pediatric population, a significant incidence of Salter-Harris 2 in both genders was found. No correlation was observed between the fracture patterns and the trauma mechanism. CONCLUSIONS: PHFs have a higher prevalence and incidence in females and in older age, respectively; they are more frequent in the winter months. In addition, male fractures are due to different traumatic events than those in females. A correlation between trauma and PHF pattern was evident only for adults. Some fracture patterns are correlated with different ranges of age in all patients. PMID- 28735838 TI - Cardiovascular effects of air pollution. AB - Air pollution is composed of particulate matter (PM) and gaseous pollutants, such as nitrogen dioxide and ozone. PM is classified according to size into coarse particles (PM10), fine particles (PM2.5) and ultrafine particles. We aim to provide an original review of the scientific evidence from epidemiological and experimental studies examining the cardiovascular effects of outdoor air pollution. Pooled epidemiological studies reported that a 10MUg/m3 increase in long-term exposure to PM2.5 was associated with an 11% increase in cardiovascular mortality. Increased cardiovascular mortality was also related to long-term and short-term exposure to nitrogen dioxide. Exposure to air pollution and road traffic was associated with an increased risk of arteriosclerosis, as shown by premature aortic and coronary calcification. Short-term increases in air pollution were associated with an increased risk of myocardial infarction, stroke and acute heart failure. The risk was increased even when pollutant concentrations were below European standards. Reinforcing the evidence from epidemiological studies, numerous experimental studies demonstrated that air pollution promotes a systemic vascular oxidative stress reaction. Radical oxygen species induce endothelial dysfunction, monocyte activation and some proatherogenic changes in lipoproteins, which initiate plaque formation. Furthermore, air pollution favours thrombus formation, because of an increase in coagulation factors and platelet activation. Experimental studies also indicate that some pollutants have more harmful cardiovascular effects, such as combustion derived PM2.5 and ultrafine particles. Air pollution is a major contributor to cardiovascular diseases. Promotion of safer air quality appears to be a new challenge in cardiovascular disease prevention. PMID- 28735840 TI - Critical shoulder angle is associated with full-thickness rotator cuff tears in patients with glenohumeral osteoarthritis. AB - BACKGROUND: Higher critical shoulder angle (CSA) is correlated with rotator cuff tears (RCTs), whereas lower CSA is associated with glenohumeral osteoarthritis (OA). Our goal was to investigate whether patients with concurrent glenohumeral OA and full-thickness RCTs demonstrate a higher CSA than patients with OA alone. METHODS: Using a 2-surgeon shoulder arthroplasty registry, we identified 31 patients with glenohumeral OA and full-thickness RCTs confirmed by plain radiography and magnetic resonance imaging, respectively. Sixty-two age- and gender-matched controls (1:2 ratio) with glenohumeral OA and an intact rotator cuff were identified from the same registry. Two independent observers evaluated the radiographs for CSA and acromiohumeral index. RESULTS: The average CSA was 30 degrees in the OA control group and 35 degrees in the concurrent RCT and OA group (P < .0001). Acromiohumeral index was comparable between the groups (P = .13). Interobserver reliability of the independent reviewers was excellent (kappa = 0.89; Rho = 0.95). The receiver operating characteristic curve for CSA demonstrated that a value >35 degrees was 90% specific and 52% sensitive for a full-thickness RCT in the setting of OA (area under curve = 0.84). CONCLUSION: Concurrent glenohumeral OA and full-thickness RCT are associated with greater CSA values compared with patients with glenohumeral OA alone. The CSA measurement may be useful in determining the need for magnetic resonance imaging to assess rotator cuff integrity in the arthritic population. PMID- 28735841 TI - The perioperative effects of chronic preoperative opioid use on shoulder arthroplasty outcomes. AB - HYPOTHESIS AND BACKGROUND: Chronic opioid therapy is an increasingly used modality for the treatment of osteoarthritis-associated pain. We hypothesized that chronic opioid use would be associated with adverse outcomes in shoulder arthroplasty. METHODS: A retrospective analysis of patients undergoing elective anatomic total shoulder arthroplasty (TSA) and reverse total shoulder arthroplasty (rTSA) at a single institution from 2012-2015 was performed. Patients were stratified by preoperative opioid use (nonusers, short-acting opioid users, and long-acting opioid users), and their postoperative clinical outcomes were assessed. RESULTS: We identified 262 patients (170 rTSA and 92 anatomic TSA), of whom 138 were using opioids preoperatively (82% short acting and 18% long acting). When non-opioid users, short-acting opioid users, and long acting opioid users were compared, mean total milligrams of morphine equivalents administered during postoperative hospitalization was significantly higher for those with preoperative opioid use (66.9 mg, 111.4 mg, and 208.3 mg, respectively; P < .001). In addition, postoperative visual analog scale pain scores were higher on postoperative day 0 (2.6, 3.2, and 3.9, respectively; P = .007), day 1 (4.0, 4.9, and 6.0, respectively; P < .001), and day 2 (3.0, 3.9, and 5.1, respectively; P < .001). Opioid use was not associated with a significantly increased hospital length of stay, complications, or readmission rates. For patients who completed 2-year follow-up, both the opioid user and non opioid user groups demonstrated similarly improved postoperative American Shoulder and Elbow Surgeons shoulder scores. CONCLUSION: A preoperative history of opioid use before shoulder arthroplasty was associated with significantly higher perioperative opioid consumption and visual analog scale scores. However, unlike in patients undergoing total knee or hip arthroplasty, preoperative opioid use was not associated with increased hospital length of stay, perioperative complications, or 90-day readmission rates for shoulder arthroplasty. PMID- 28735842 TI - Angled BIO-RSA (bony-increased offset-reverse shoulder arthroplasty): a solution for the management of glenoid bone loss and erosion. AB - BACKGROUND: Glenoid deficiency and erosion (excessive retroversion/inclination) must be corrected in reverse shoulder arthroplasty (RSA) to avoid prosthetic notching or instability and to maximize function, range of motion, and prosthesis longevity. This study reports the results of RSA with an angled, autologous glenoid graft harvested from the humerus (angled BIO-RSA). METHODS: A trapezoidal bone graft, harvested from the humeral head and fixed with a long-post baseplate and screws, was used to compensate for residual glenoid bone loss/erosion. For simple to moderate (<25 degrees ) glenoid defects, standardized instrumentation combined with some eccentric reaming (<15 degrees ) was used to reconstruct the glenoid and obtain neutral implant alignment. For severe (>25 degrees ) and complex (multiplanar) glenoid bone defects, patient-specific grafts and guides were used after 3-dimensional planning. Patients were reviewed with minimum 2 years of follow-up. Mean follow-up was 36 months (range, 24-81 months). Preoperative and postoperative measurements of inclination and version were performed in the plane of the scapula on computed tomography images. RESULTS: The study included 54 patients (41 women, 13 men; mean 73 years old). Fifteen patients had combined vertical and horizontal glenoid bone deficiency. Among E2/E3 glenoids, inclination improved from 37 degrees (range, 14 degrees to 84 degrees ) to 10.2 degrees (range -28 degrees to 36 degrees , P < .001). Among B2/C glenoids, retroversion improved from -21 degrees (range, -49 degrees to 0 degrees ) to -10.6 degrees (-32 degrees to 4 degrees , P = .06). Complete radiographic incorporation of the graft occurred in 94% (51 of 54). Complications included infection in 1 and clinical aseptic baseplate loosening in 2. Mild notching occurred in 25% (13 of 51) of patients. Constant-Murley and Subjective Shoulder Value assessments increased from 31 to 68 and from 30% to 83%, respectively (P < .001). CONCLUSION: Angled BIO-RSA predictably corrects glenoid deficiency, including severe (>25 degrees ) multiplanar deformity. Graft incorporation is predictable. Advantages of using an autograftharvested in situ include bone stock augmentation, lateralization, low donor-site morbidity, low relative cost, and flexibility needed to simultaneously correct posterior and superior glenoid defects. PMID- 28735843 TI - Does arm lengthening affect the functional outcome in onlay reverse shoulder arthroplasty? AB - BACKGROUND: The concept of onlay design reverse shoulder arthroplasty has been introduced to overcome complications observed with the traditional Grammont-type prosthesis. The aim of this study was to determine the influence of arm lengthening on the short-term clinical outcome in onlay reverse shoulder arthroplasty and investigate the effect of humeral tray offset positioning on arm lengthening and range of motion. METHODS: We retrospectively evaluated 56 patients undergoing reverse shoulder arthroplasty with the Aequalis Ascend Flex prosthesis (Tornier, Bloomington, MN, USA) at a minimum 2 years' follow-up. Arm lengthening was determined using bilateral scaled radiographs of the entire humerus. The Constant score and active range of motion were documented preoperatively and postoperatively. The relationship between arm lengthening, humeral tray offset position, and functional outcome was analyzed. RESULTS: The Constant score improved from 25.5 +/- 9.5 points to 71.5 +/- 13.8 points at a mean follow-up of 30.1 +/- 5.2 months. Mean postoperative anterior elevation was 145.2 degrees +/- 21.1 degrees , and external rotation was 30.7 degrees +/- 20.3 degrees . Arm lengthening exceeding 2.5 cm was related to a decrease in anterior elevation. We found a relationship between arm lengthening averaging 2.2 +/- 1.7 cm and increased Constant score values. Humeral tray positioning demonstrated no influence on the functional outcome. There was a trend toward increased arm lengthening in lateral offset positioning. CONCLUSIONS: Onlay reverse shoulder arthroplasty yields good short-term clinical results. In our population, arm lengthening averaging 1 to 2.5 cm was found to be the best compromise on postoperative range of motion. PMID- 28735844 TI - Hyperlipidemia increases the risk of retear after arthroscopic rotator cuff repair. AB - BACKGROUND: Hyperlipidemia (HL) has been identified as a risk factor for rotator cuff tear, but no studies have evaluated its effects on healing. The purpose of this study was to evaluate the effect of HL and statin use on rotator cuff healing after arthroscopic repair. METHODS: This was a retrospective review of 85 patients (86 shoulders) who underwent arthroscopic rotator cuff repair with postoperative ultrasound evaluation. Ultrasound findings were graded no retear, partial-thickness retear (PT), or full-thickness retear (FT). RESULTS: Average age was 62.1 years (45.3-74.3 years). On ultrasound evaluation, 65 shoulders (75.5%) had no retear, 14 (16.3%) had PT, and 7 (8.1%) had FT. There was no significant difference in retear rate by age, technique, or tissue quality. There were 33 patients (38.8%) who had the diagnosis of HL, and all were taking a statin medication. Compared with patients without HL, patients with HL had significantly higher rates of FT (18.1% vs. 1.9%; P < .001) and PT (27.2% vs. 9.4%; P < .001). The total retear rate (PT and FT) for HL patients was significantly higher at 45.5% (15/33) compared with the patients without HL at 11.3% (6/53), with an odds ratio of 6.5 (P < .001). There was no difference in retear rate by dosage or type of statin mediation. CONCLUSION: After arthroscopic rotator cuff repair, HL was a risk factor for retear. Further investigation is warranted on this topic, and these results may help in managing expectations after surgery. PMID- 28735845 TI - Anterior and posterior bands of the anterior bundle in the elbow ulnar collateral ligament: ultrasound anatomy. AB - BACKGROUND: The anterior oblique bundle (AOL) of the ulnar collateral ligament (UCL) is composed of anterior and posterior bands. This study evaluated the anatomy of the anterior and posterior bands in the AOL of the UCL for their separate visualization with ultrasound (US). METHODS: We dissected 18 cadaveric elbow joints and recorded the direction of each band from the lateral view to determine the proper position for the US transducer. To determine the proper inclination of the transducer, we measured the inclinations of each band at the proximal and distal insertions from the transverse view. A paired t test was used for comparisons between both bands. Values of P < .05 were considered statistically significant. RESULTS: The mean angles of the directions in the anterior and posterior bands were 10 degrees +/- 4 degrees and 24 degrees +/- 9 degrees , respectively. At the medial epicondyle, the mean inclination angles of both bands were 61 degrees +/- 5 degrees and 67 degrees +/- 5 degrees , respectively. At the sublime tubercle, the mean inclination angles of both bands were 14 degrees +/- 7 degrees and 44 degrees +/- 9 degrees , respectively. The inclination angles at the proximal ulna and the directions in both bands were significantly different (P < .001). CONCLUSIONS: This study shows that the directions of both bands and inclination angles of the bony attachments in both bands can assist with correct placement of the US transducer and allow for separate visualization of each band. PMID- 28735846 TI - Gartland types IIB and III supracondylar fractures of the humerus in children: is Blount's method effective and safe? AB - BACKGROUND: Blount's method is controversial for the treatment of Gartland types IIB and III supracondylar fracture of the humerus (SCFH) in children. The purpose of this study was to evaluate the clinical and radiologic outcomes and the failure and complication rates. METHODS: All types IIB and III SCFH treated with Blount's method from 2003-2013 were included in this retrospective single-center study. Clinical assessment was performed according to Flynn criteria. Baumann angle, anteversion angle, anterior humeral line, and humeroulnar angle were measured for radiographic assessment. RESULTS: Among 447 children with types IIB and III SCHF, 339 were treated according to Blount's method. There were 173 boys (51%), and the mean age was 6.3 years (1-14 years); 71% were type III. Mean time to surgery was 5.7 hours. According to Flynn criteria, results were satisfactory in 91% of cases. No compartment syndrome was encountered. There were 16 (4.7%) secondary displacements requiring surgical revision. Five (1.9%) children developed a cubitus varus deformity. At latest follow-up, the mean Baumann angle was 74.7 degrees (95% confidence interval, 74.1-75.3), the mean anteversion angle was 39.9 degrees (95% confidence interval, 39.5-40.3), the anterior humeral line was normal in 87.6% of cases, and the mean humeroulnar angle was 8.7 degrees . CONCLUSION: Blount's method is appropriate to manage types IIB and III SCFH, provided anatomic and stable reduction is obtained. PMID- 28735847 TI - Transcutaneous electrical nerve stimulation for postoperative pain relief after arthroscopic rotator cuff repair: a prospective double-blinded randomized trial. AB - BACKGROUND: Arthroscopic rotator cuff repair (ARCR) can be associated with significant postoperative pain. Concern for opioid abuse has led surgeons to identify alternative, efficacious methods of postoperative analgesia. To determine whether transcutaneous electrical nerve stimulation (TENS) can have a similarly beneficial effect after shoulder procedures, we conducted a prospective double-blinded randomized trial in patients undergoing outpatient ARCR. METHODS: All patients undergoing ARCR of a full-thickness rotator cuff tear by the senior authors were identified. Patients with a history of recent narcotic use or prior narcotic abuse and those under management of a pain control specialist were excluded. Patients were randomized into 2 groups, active or placebo TENS, and used the device for 4 sessions/day for 45 minutes/session for the first postoperative week. All patients received Percocet 5/325 mg (oxycodone/acetaminophen) for use as rescue pain pills. One-week narcotic consumption and visual analog scale pain scores were compared between groups. RESULTS: The final analysis included 37 patients (21 active,16 placebo). Baseline and procedural differences were not different between groups. At 1 week postoperatively, patients in the active group had significantly lower pain scores (3.6 +/- 2.1 vs. 5.8 +/- 1.2; P= .008). Postoperative Percocet consumption during the initial 48 hours (12.8 +/- 4.7 vs. 17.2 +/- 6.3; P = .020) and during the first week (25.2 +/- 9.9 vs. 33.8 +/- 14.3; P = .037) was also significantly lower in the active group. CONCLUSION: Results from this prospective double blinded randomized trial demonstrate that compared with placebo TENS, active TENS can result in significantly less pain and reduced opioid use in the immediate postoperative period after ARCR, suggesting that TENS may be potentially useful in a multimodal approach to managing postoperative pain. PMID- 28735848 TI - The outcomes and affecting factors after arthroscopic isolated subscapularis tendon repair. AB - BACKGROUND: This study evaluated clinical outcomes for isolated subscapularis tendon tears treated by arthroscopic repair, the factors affecting clinical outcomes, and changes in tendon structural integrity using magnetic resonance imaging. METHODS: Between 2005 and 2013, 45 patients with isolated subscapularis tendon tears were enrolled from two institutions. Clinical outcomes were assessed using the pain visual analog scale, American Shoulder and Elbow Surgeons, and Simple Shoulder Test scores. We evaluated factors affecting clinical outcomes: trauma history, tear classification, sex, age, symptom duration, preoperative fatty infiltration grade, cross-sectional area (CSA), cranial-transversal diameter, and caudal-transversal diameter. Subscapularis tendon integrity and fatty infiltration grade were evaluated using magnetic resonance imaging. RESULTS: No complications occurred except for tendon rerupture in 1 patient. No significant changes in tendon structural integrity occurred except for those related to CSA. Tendon structural integrity was significantly different between tears less than one-fourth of the entire subscapularis tendon and those exceeding one-fourth. However, there were no statistically significant differences in clinical outcomes between the 2 types of tear. Age was significantly associated with clinical outcomes, including Constant, American Shoulder and Elbow Surgeons, and Simple Shoulder Test scores. Men experienced better outcomes than women in Constant and Simple Shoulder Test scores. As the postoperative period progressed, the difference in CSA, cranial-transversal diameter, and caudal-transversal diameter decreased to the point of no statistical significance. CONCLUSION: Arthroscopic repair of isolated subscapularis tear provided significant functional improvements with a low rerupture rate. Age was significantly associated with clinical results. PMID- 28735849 TI - tDCS effects on word production: Limited by design? Comment on Westwood et al. (2017). PMID- 28735850 TI - Enhanced Energetic State and Protection from Oxidative Stress in Human Myoblasts Overexpressing BMI1. AB - The Polycomb group gene BMI1 is essential for efficient muscle regeneration in a mouse model of Duchenne muscular dystrophy, and its enhanced expression in adult skeletal muscle satellite cells ameliorates the muscle strength in this model. Here, we show that the impact of mild BMI1 overexpression observed in mouse models is translatable to human cells. In human myoblasts, BMI1 overexpression increases mitochondrial activity, leading to an enhanced energetic state with increased ATP production and concomitant protection against DNA damage both in vitro and upon xenografting in a severe dystrophic mouse model. These preclinical data in mouse models and human cells provide a strong rationale for the development of pharmacological approaches to target BMI1-mediated mitochondrial regulation and protection from DNA damage to sustain the regenerative potential of the skeletal muscle in conditions of chronic muscle wasting. PMID- 28735851 TI - Assessing beans as a source of intrinsic fiber on satiety in men and women with metabolic syndrome. AB - Dietary fiber is well-known for its satiety inducing properties. Adding fibers to mixed dishes is one way to increase fiber intake. However, adding fibers to foods versus including foods inherently containing fiber may reveal differing effects on satiety. The present study aimed to explore the satiety effects of adding fiber to a mixed meal versus using beans (Phaseolus vulgaris) as a source of intrinsic fiber in the meal. In this pilot study, 12 men and women with metabolic syndrome were randomly assigned to eat three standard meals in a crossover design on three different occasions that contained either no added fiber (control (NF)), extrinsic or added fiber (AF), or whole black beans as the source of intrinsic fiber (BN). Meals were matched for energy and macronutrient composition. Five hour postprandial subjective satiety was measured along with blood glucose, insulin, and the GI hormones, cholecystokinin (CCK) and peptide tyrosine tyrosine (PYY3-36). All meals induced fullness to a similar degree; however, the AF meal suppressed prospective consumption (F2,187 = 9.05, P = 0.0002) compared to the BN or NF meals. The NF meal tended to result in more satisfaction than the BN meal (F2,187 = 5.91, P = 0.003). The BN meal produced significantly higher postprandial CCK concentrations compared to the AF (F2,187 = 6.82, P = 0.001) and NF meals (F2,187 = 6.82, P = 0.002). Similar findings were observed for PYY3-36 response for BN > AF meal (F2,170 = 9.11, P < 0.0001). Postprandial insulin was significantly reduced after the BN meal, compared to the NF (F2,187 = 22.36, P < 0.0001) meal. These findings suggest that incorporating whole black beans into a meal has acute beneficial metabolic and GI hormone responses in adults with metabolic syndrome and are preferred over adding equivalent amounts of fiber from a supplement. PMID- 28735852 TI - Roles of quorum sensing molecules from Rhizobium etli RT1 in bacterial motility and biofilm formation. AB - Strain RT1 was isolated from root nodules of Lens culinaris (a lentil) and characterized as Rhizobium etli (a Gram-negative soil-borne bacterium) by 16S rDNA sequencing and phylogenetic analysis. The signaling molecules produced by R. etli (RT1) were detected and identified by high-performance liquid chromatography coupled with mass spectrometry. The most abundant and biologically active N-acyl homoserine lactone molecules (3-oxo-C8-HSL and 3-OH-C14-HSL) were detected in the ethyl acetate extract of RT1. The biological role of 3-oxo-C8-HSL was evaluated in RT1. Bacterial motility and biofilm formation were affected or modified on increasing concentrations of 3-oxo-C8-HSL. Results confirmed the existence of cell communication in RT1 mediated by 3-oxo-C8-HSL, and positive correlations were found among quorum sensing, motility and biofilm formation in RT1. PMID- 28735853 TI - A comparative study of genome organization and epigenetic mechanisms in model ciliates, with an emphasis on Tetrahymena, Paramecium and Oxytricha. AB - As a group of unicellular eukaryotes, ciliates offer a unique system to explore epigenetic regulation, mostly due to their nuclear dualism. Ciliates launched a successful radiation after their early evolutionary branching, therefore harboring an unexpectedly rich pool of diverse biological functions and mechanisms. In this review, we compare distinct features of different ciliates in mating type determination, genome organization, DNA methylation, and removal of internal eliminated sequences (IES), with emphasis on Tetrahymena, Paramecium and Oxytricha. Firstly, we review studies on mating type determination in Paramecium, one of the foundational phenomena that defined the field of epigenetics, and compare this process with that in Tetrahymena. Secondly, we showcase the high diversity in genome structure of several ciliates, such as genome size, gene copy numbers, genome rearrangement, etc. Thirdly, we present a brief description of features and potential functions of 5-methylcytosine (5mC) and N6-methyladenine (6mA) in ciliates so far studied. Fourthly, we describe both the initial and the continuously optimized scan RNA (scnRNA) model for IES elimination in Tetrahymena and contrast it with that in Paramecium and Oxytricha. Finally, we discuss the importance of integrative approaches to the study of epigenetic diversity in ciliates and provide possible directions for future research. PMID- 28735854 TI - Prevention and management of dementia: a priority for public health. PMID- 28735856 TI - Progress on dementia-leaving no one behind. PMID- 28735857 TI - Gill Livingston: transforming dementia prevention and care. PMID- 28735855 TI - Dementia prevention, intervention, and care. PMID- 28735858 TI - Asymmetric disease dynamics in multihost interconnected networks. AB - Epidemic spread in single-host systems strongly depends on the population's transmission network. However, little is known regarding the spread of epidemics across networks representing populations of multiple hosts. We explored cross species transmission in a multilayer network where layers represent populations of two distinct hosts, and disease can spread across intralayer (within-host) and interlayer (between-host) edges. We developed an analytic framework for the SIR epidemic model to examine the effect of (i) source of infection and (ii) between host asymmetry in infection probabilities, on disease risk. We measured risk as outbreak probability and outbreak size in a focal host, represented by one network layer. Numeric simulations were used to validate the analytic formulations. We found that outbreak probability is determined by a complex interaction between source of infection and between-host infection probabilities, whereas outbreak size is mainly affected by the non-focal host to focal host infection probability. Hence, inter-specific asymmetry in infection probabilities shapes disease dynamics in multihost networks. These results highlight the importance of considering multiple measures of disease risk and advance our understanding of disease spread in multihost systems. The study provides a flexible way to model disease dynamics in multiple hosts while considering contact heterogeneity within and between species. We strongly encourage empirical studies that include information on both cross-species infection rates and network structure of multiple hosts. Such studies are necessary to corroborate our theoretical results and to improve our understanding of multihost epidemiology. PMID- 28735860 TI - Are oral and maxillofacial surgery residents being adequately trained to care for pediatric patients? AB - OBJECTIVE: To evaluate whether current oral and maxillofacial surgery (OMS) residents are receiving adequate training and experience to perform specific surgical procedures and anesthesia for pediatric patients. STUDY DESIGN: A 17 question survey was sent electronically to fellows of the American Academy of Craniomaxillofacial Surgeons. Descriptive data for individual surgeons, their associated residency programs, and the quantity of specific pediatric procedures they performed were collected. Resident case load for inpatient and outpatient procedures and overall experience in medical, surgical, and anesthetic management of pediatric OMS patients were explored. RESULTS: Surveys were sent to 110 active fellows; 64 completed the questionnaire (58%). There were 59 male fellows and 5 female fellows, with a mean age of 50.4 years. Of those, 68.8% practice in an academic setting. Specifically, 93.8% take after-hours emergency calls covering adult and pediatric patients and 98.4% have admitting privileges at a children's hospital or a pediatric unit in an adult hospital. Their affiliated residency programs include required rotations in pediatrics or pediatric subspecialties. In their opinion, >90% of graduating OMS residents have the appropriate skill set to perform dentoalveolar procedures, outpatient anesthesia, orthognathic procedures, and alveolar bone grafts. However, residents have limited ability to reconstruct pediatric ramus-condyle unit with a costochondral graft. CONCLUSIONS: Results of this study indicate that, in the opinion of the respondents, graduates of OMS residency programs have adequate training to perform dentoalveolar procedures, outpatient anesthesia, orthognathic surgery, and alveolar bone grafts in pediatric procedures, but have limited experience with reconstruction of pediatric ramus-condyle unit via costochondral graft. PMID- 28735861 TI - Protective role of benzoselenophene derivatives of resveratrol on the induced oxidative stress in intestinal myofibroblasts and osteocytes. AB - Resveratrol (RE), a polyphenolic compound present in some food and plants, is characterized by anti-inflammatory and antioxidant properties. However, it is quickly metabolized with consequent loss of its efficacy. In this study, the antioxidant effect of 2-phenyl-benzoselenophene derivatives (VD0, VD1 and VD2) was detected in intestinal myofibroblast and osteocyte cell lines in which the oxidative stress was induced by GSH depletion or starvation, respectively. In fact, the oxidative stress is involved in pathogenesis of inflammatory bowel diseases (IBD) and in increased osteoclastogenesis in osteoporosis. Our results show that these derivatives have major antioxidant power in reducing and/or restoring radical oxygen species to control values than RE itself in both cell types. Moreover, derivatives have different antioxidant capacity in myofibroblasts and in osteocytes and this can be due to different degree of oxidative stress and structural characteristics of these compounds. Some of the synthesized RE analogs have shown anti-bacterial role in IBD and anti-resorptive activity in bone pathologies related to inflammatory and osteoporotic processes. Thus, we suggest benzoselenophene derivatives as good candidates for alternative therapy and/or therapeutic support in these pathologies. PMID- 28735859 TI - Computational Prediction of Position Effects of Apparently Balanced Human Chromosomal Rearrangements. AB - Interpretation of variants of uncertain significance, especially chromosomal rearrangements in non-coding regions of the human genome, remains one of the biggest challenges in modern molecular diagnosis. To improve our understanding and interpretation of such variants, we used high-resolution three-dimensional chromosomal structural data and transcriptional regulatory information to predict position effects and their association with pathogenic phenotypes in 17 subjects with apparently balanced chromosomal abnormalities. We found that the rearrangements predict disruption of long-range chromatin interactions between several enhancers and genes whose annotated clinical features are strongly associated with the subjects' phenotypes. We confirm gene-expression changes for a couple of candidate genes to exemplify the utility of our analysis of position effect. These results highlight the important interplay between chromosomal structure and disease and demonstrate the need to utilize chromatin conformational data for the prediction of position effects in the clinical interpretation of non-coding chromosomal rearrangements. PMID- 28735862 TI - Transcriptome analysis reveals temperature-regulated antiviral response in turbot Scophthalmus maximus. AB - Megalocytivirus is a severe pathogen to turbot (Scophthalmus maximus), a popular aquaculture species in many countries. In this study, we investigated the effect of temperature on the antiviral response of turbot at transcriptome level. We found that when turbot were infected with megalocytivirus RBIV-C1 at low temperatures (14 degrees C, 16 degrees C, and 18 degrees C), viral replication was undetectable or moderate and no fish mortality occurred; in contrast, when turbot were infected with RBIV-C1 at high temperatures (20 degrees C, 22 degrees C, and 24 degrees C), viral replication was robust and 100% host mortality was observed. During the course of viral infection, downward temperature shift curbed viral replication and augmented host survival, whereas upward temperature shift promoted viral replication and reduced host survival. Comparative transcriptome analyses were conducted to examine the whole-genome transcription of turbot infected with RBIV-C1 at 16 degrees C and 22 degrees C for 4 days (samples S16-4d and S22-4d, respectively) and 8 days (samples S16-8d and S22-8d, respectively). The results showed that compared to S22-4d and S22-8d, 1600 and 5927 upregulated unigenes of various functional categories were identified in S16-4d and S16-8d, respectively. Of these genes, 22 were immune related, most of which were detected in S16-8d and exhibited more genetic subtypes in S16-8d than in S16-4d. In addition, upregulated genes associated with cell junctions and cell membrane were also identified. These results indicate that temperature had a profound effect on the global transcription of turbot, which consequently affects the immune as well as physical resistance of the fish against viral infection. PMID- 28735863 TI - Structural insights into the specific recognition of DSR by the YTH domain containing protein Mmi1. AB - Meiosis is one of the most dramatic differentiation programs accompanied by a striking change in gene expression profiles in fission yeast Schizosaccharomyces pombe. Whereas a number of meiosis-specific transcripts are expressed untimely in mitotic cells, and the entry of meiosis will be blocked as the accumulation of meiosis-specific mRNAs in the mitotic cells. A YTH domain containing protein Mmi1 was identified as a pivotal effector in a post-transcriptional event termed selective elimination of meiosis-specific mRNAs. Mmi1 can recognize and bind a class of meiosis-specific transcripts expressed inappropriately in mitotic cells, which all contain a conservative region called DSR, as a mark to remove them in cooperation with nuclear exosomes. Here we report the 1.6 A resolution crystal structure of the Mmi1-YTH domain in complex with a high consensus hexanucleotide motif, which is multiple copied in the DSR region. Our structure observations, supported by site-directed mutations of key residues illustrate the mechanism for specific recognition of DSR-RNA by Mmi1. Moreover, different from other YTH domain family proteins, Mmi1-YTH domain has a distinctive RNA-binding properties although it has a similar fold as other ones. PMID- 28735864 TI - Identification of a DYRK1A-mediated phosphorylation site within the nuclear localization sequence of the hedgehog transcription factor GLI1. AB - GLI1 is a key downstream transcription effector of the Hedgehog (Hh) signaling pathway that is involved in promoting cell growth, differentiation and tissue patterning in embryonic development. GLI1 over-activation and its nuclear localization has also been linked to the increased aggressiveness of a number of cancers. It has previously been demonstrated that DYRK1A (dual-specificity tyrosine-regulated kinase 1A) can phosphorylate GLI1 and promote GLI1 nuclear localization and its transcriptional activity. Utilizing recombinant human GLI1 and DYRK1A proteins and phospho-peptide mass spectrometry, we demonstrated that GLI1 is phosphorylated by DYRK1A at Ser408, a phospho-site that falls within the putative nuclear localization sequence (NLS) of GLI1, suggesting a possible mechanistic role in modulating its translocation. Further, we showed that the Ser408 site on GLI1 was not phosphorylated in the presence of the selective DYRK1A inhibitor harmine. The data described herein provide the first identification of a DYRK1A-mediated site of phosphorylation on GLI1 within its NLS and may serve as a valuable mechanism for further understanding Hh signaling modulation. PMID- 28735865 TI - RPS27a enhances EBV-encoded LMP1-mediated proliferation and invasion by stabilizing of LMP1. AB - Epstein-Barr virus (EBV)-encoded latent membrane protein 1 (LMP1) is an oncoviral protein that plays a pivotal role in EBV-induced oncogenic transformation. The function of LMP1 in EBV-induced oncogenesis has been well studied. However, the molecular mechanisms underlying LMP1 protein stability remain poorly understood. In this study, we found that ribosomal protein s27a (RPS27a) regulates LMP1 stability by a tandem affinity purification analysis. RPS27a interacts directly with LMP1 in vitro and in vivo. Furthermore, overexpression of RPS27a increases the half-life of LMP1 in 293T cells, whereas downregulation of RPS27a using lentiviral shRNA technology accelerates the decrease in LMP1 protein level in EBV transformed B cells. We show that LMP1 ubiquitination via the proteasome is completely inhibited by overexpression of RPS27a. RPS27a also enhances LMP1 mediated proliferation and invasion, suggesting that RPS27a interacts with LMP1 and stabilizes it by suppressing proteasome-mediated ubiquitination. These results suggest that RSP27a could be a potential target in EBV-infected LMP1 positive cancer cells. PMID- 28735867 TI - Cleavage of the Interleukin-11 receptor induces processing of its C-terminal fragments by the gamma-secretase and the proteasome. AB - The cytokine Interleukin-11 (IL-11) signals through the membrane-bound IL-11 receptor (IL-11R), which is expressed in a cell-type specific manner. We have recently shown that the metalloprotease ADAM10 can cleave the IL-11R. The liberated soluble IL-11R (sIL-11R) ectodomain can bind its ligand, and the resulting IL-11/sIL-11R complex can activate cells that do not express the IL-11R (trans-signaling). In this study, we show that the remaining C-terminal fragment (CTF1) after ADAM10-mediated cleavage is subsequently cleaved within the membrane by the gamma-secretase complex, and that the resulting shorter CTF2 is further degraded by the proteasome. In contrast to other transmembrane receptors, e.g. Notch, we find no evidence that the IL-11R CTF can translocate into the nucleus to act as a transcription factor, suggesting that regulated intramembrane proteolysis of the IL-11R CTF acts as a mechanism to clear the plasma membrane from remaining protein fragments after cleavage of its ectodomain. PMID- 28735866 TI - MicroRNA-193-5p modulates angiogenesis through IGF2 in type 2 diabetic cardiomyopathy. AB - BACKGROUND: Patients with diabetic cardiomyopathy are often associated with increasing risk of heart failure. In this work, we used animal model to characterize the angiogenic effect of microRNA-193-5p, miR-193-5p in type 2 diabetic Goto-Kakizaki (GK) rats' myocardial microvascular endothelial cells, MMEC(GK). METHODS: MiR-193-5p in MMEC(GK) was compared to its expression in Wistar rat MMEC. In MMEC(GK), miR-193-5p was downregulated through viral infection. Its angiogenic effects on MMEC(GK) migration and proliferation were assessed by transwell and MTT assays, respectively. Downstream target of miR-193 5p, insulin growth factor 2 (IGF2), was assessed by dual-luciferase activity, qRT PCR and western blot assays, respectively. In miR-193-5p-downregulated MMEC(GK), IGF2 was further de-regulated to assess its mechanism in miR-193-5p downreuglation induced angiogenic regulation. RESULTS: MiR-193-5p is overexpressed in MMEC(GK). Its downregulation has significantly angiogenic effect by inducing migration and proliferation in MMEC(GK). IGF2 was demonstrated to be directly regulated by miR-193-5p in MMEC(GK). In addition, IGF2 inhibition in miR 193-5p-downregulated MMEC(GK)'s severely hindered cell migration and proliferation. CONCLUSION: MiR-193-5p is an active angiogenic factor in diabetic cardiomyopathy, possibly through inverse regulation on its downstream IGF2 gene. PMID- 28735868 TI - The thermal Z-isomerization-induced change in solubility and physical properties of (all-E)-lycopene. AB - The effect of Z-isomerization of (all-E)-lycopene on its solubility in organic solvents and physical properties was investigated. Lycopene samples containing different Z-isomer contents (23.8%, 46.9%, and 75.6% of total lycopene) were prepared from high-purity (all-E)-lycopene by thermal Z-isomerization in dichloromethane (CH2Cl2). As the Z-isomer content increased, the relative solubility of lycopene significantly improved. Although (all-E)-lycopene barely dissolved in ethanol (0.6 mg/L), the solubilities of lycopene containing 23.8%, 46.9%, and 75.6% Z-isomers were 484.5, 914.7, and 2401.7 mg/L, respectively. Furthermore, differential scanning calorimetry (DSC), powder X-ray diffraction (XRD), and scanning electron microscopy (SEM) analyses clearly indicated that (all-E)-lycopene was present in the crystal state, while Z-isomers of lycopene were present in amorphous states. A number of studies have suggested that Z isomers of lycopene are better absorbed in the human body than the all-E-isomer. This may be due to the change in solubility and physical properties of lycopene by the Z-isomerization. PMID- 28735869 TI - DHU1 negatively regulates UV-B signaling via its direct interaction with COP1 and RUP1. AB - Although DWD HYPERSENSITIVE TO UV-B 1 (DHU1) is reported to be a negative regulator in UV-B mediated cellular responses, its detailed role in UV-B signaling is still elusive. To further understand the action mechanism of DHU1 in UV-B response, physical and genetic interactions of DHU1 with various UV-B signaling components were investigated. Yeast two hybrid assay results suggested that DHU1 directly interacts with COP1 and RUP1, implying a functional connection with both COP1 and RUP1. In spite of the physical association between DHU1 and COP1, loss of DHU1 did not affect protein stability of COP1. Epistatic analysis showed that the functional loss of both DHU1 and UVR8 leads to alleviation of UV B hypersensitivity displayed in dhu1-1. Moreover, phenotypic studies with dhu1-1 cop1-6 and dhu1-1 hy5-215 revealed that COP1 and HY5 are epistatic to DHU1, indicating that UV-B hypersensitivity of dhu1-1 requires both COP1 and HY5. In the case of dhu1-1 rup1-1, UV-B responsiveness was similar to that of both dhu1-1 and rup1-1, implying that DHU1 and RUP1 are required for each other's function. Collectively, these results show that the role of DHU1 as a negative regulator in UV-B response may be derived from its direct interaction with COP1 by sequestering COP1 from the active UVR8-COP1 complex, resulting in a decrease in the COP1 population that positively participates in UV-B signaling together with UVR8. Furthermore, this inhibitory role of DHU1 in UV-B signaling is likely to be functionally connected to RUP1. This study will serve as a platform to further understand more detailed action mechanism of DHU1 in UV-B response and DHU1 mediated core UV-B signaling in Arabidopsis. PMID- 28735870 TI - Evaluation of the fetal cerebellum by magnetic resonance imaging. AB - Obstetric protocols dictate that the fetal cerebellum should always be assessed during sonograms during pregnancy. For various reasons, including technical limitations or inconclusive sonographic findings, suspicion of cerebellar abnormalities is one of the most common indications for prenatal magnetic resonance imaging (MRI). Although sonography is the imaging technique of choice to assess the cerebellum, MRI shows the anatomy of the posterior fossa and abnormalities in the development of the fetal cerebellum in greater detail and thus enables a more accurate prenatal diagnosis. We describe and illustrate the normal anatomy of the fetal cerebellum on MRI as well as the different diseases that can affect its development. Moreover, we review the most appropriate terminology to define developmental abnormalities, their differential diagnoses, and the role of MRI in the prenatal evaluation of the posterior fossa. PMID- 28735871 TI - A mathematical model for cell infiltration and proliferation in a chondral defect. AB - We develop a mathematical model to describe the regeneration of a hydrogel inserted into an ex vivo osteochondral explant. Specifically we use partial differential equations to describe the evolution of two populations of cells that migrate from the tissue surrounding the defect, proliferate, and compete for space and resources within the hydrogel. The two cell populations are chondrocytes and cells that infiltrate from the subchondral bone. Model simulations are used to investigate how different seeding strategies and growth factor placement within the hydrogel affect the spatial distribution of both cell types. Since chondrocyte migration is extremely slow, we conclude that the hydrogel should be seeded with chondrocytes prior to culture in order to obtain zonal chondrocyte distributions typical of those associated with healthy cartilage. PMID- 28735872 TI - Characterization of a novel cystatin type 2 from Rhipicephalus microplus midgut. AB - The Rhipicephalus (Boophilus) microplus is an exclusive bovine ectoparasite responsible for the transmission of pathogens that decrease meat, leather and milk productions. Cattle vaccination is an alternative to control tick infestations, but the discovery of potential antigens is still a challenge for researchers. Recently, our group performed a midgut transcriptome of engorged R. microplus tick, and out of 800 ESTs sequences one cystatin-coding sequence was identified and named Rmcystatin-4. In order to understand the physiological role of Rmcystatin-4, the aim of this work was the expression, purification and functional characterization of a novel type 2 cystatin from the tick R. microplus. Rmcystatin-4 gene expression was identified mostly in tick midgut suggesting its possible role in blood digestion control. Our data showed that rRmcystatin-4 was successfully expressed in active form using Pichia pastoris system and the purified inhibitor presented high selectivity to BmCl-1 (Ki = 0.046 nM). Moreover, rRmcystatin-4 was able to impaired BmCl-1 activity towards bovine hemoglobin. PMID- 28735873 TI - The therapeutic potential of purinergic signalling. AB - This review is focused on the pathophysiology and therapeutic potential of purinergic signalling. A wide range of diseases are considered, including those of the central nervous system, skin, kidney, musculoskeletal, liver gut, lower urinary tract, cardiovascular, airways and reproductive systems, the special senses, infection, diabetes and obesity. Several purinergic drugs are already on the market, including P2Y12 receptor antagonists for stroke and thrombosis, P2Y2 receptor agonists for dry eye, and A1 receptor agonists for supraventricular tachycardia. Clinical trials are underway for the use of P2X3 receptor antagonists for the treatment of chronic cough, visceral pain and hypertension, and many more compounds are being explored for the treatment of other diseases. Most experiments are 'proof of concept' studies on animal or cellular models, which hopefully will lead to further clinical trials. The review summarises the topic, mostly referring to recent review articles. PMID- 28735874 TI - Non ruptured severe aneurism of valsava sinus in a pregnant woman: A successful management. PMID- 28735875 TI - Comment on "Risk-based screening combined with a PCR-based test for group B streptococci diminishes the use of antibiotics in laboring women". PMID- 28735876 TI - Methods for automatic detection of artifacts in microelectrode recordings. AB - BACKGROUND: Extracellular microelectrode recording (MER) is a prominent technique for studies of extracellular single-unit neuronal activity. In order to achieve robust results in more complex analysis pipelines, it is necessary to have high quality input data with a low amount of artifacts. We show that noise (mainly electromagnetic interference and motion artifacts) may affect more than 25% of the recording length in a clinical MER database. NEW METHOD: We present several methods for automatic detection of noise in MER signals, based on (i) unsupervised detection of stationary segments, (ii) large peaks in the power spectral density, and (iii) a classifier based on multiple time- and frequency domain features. We evaluate the proposed methods on a manually annotated database of 5735 ten-second MER signals from 58 Parkinson's disease patients. COMPARISON WITH EXISTING METHODS: The existing methods for artifact detection in single-channel MER that have been rigorously tested, are based on unsupervised change-point detection. We show on an extensive real MER database that the presented techniques are better suited for the task of artifact identification and achieve much better results. RESULTS: The best-performing classifiers (bagging and decision tree) achieved artifact classification accuracy of up to 89% on an unseen test set and outperformed the unsupervised techniques by 5-10%. This was close to the level of agreement among raters using manual annotation (93.5%). CONCLUSION: We conclude that the proposed methods are suitable for automatic MER denoising and may help in the efficient elimination of undesirable signal artifacts. PMID- 28735877 TI - Dose comparison between TG-43-based calculations and radiochromic film measurements of the Freiburg flap applicator used for high-dose-rate brachytherapy treatments of skin lesions. AB - PURPOSE: Current high-dose-rate brachytherapy skin treatments with the Freiburg flap (FF) applicator are planned with treatment planning systems based on the American Association of Physicists in Medicine TG-43 data sets, which assume full backscatter conditions in dose calculations. The aim of this work is to describe an experimental method based on radiochromic film dosimetry to evaluate dose calculation accuracy during surface treatments with the FF applicator at different depths and bolus thicknesses. METHODS AND MATERIALS: Absolute doses were measured using a reference EBT3 radiochromic film dosimetry system within a Solid Water phantom at different depths (0, 0.5, 1, 2, and 3 cm) with respect to the phantom surface. The impact of bolus (up to 3-cm thickness) placed on top of the applicator was investigated for two clinical loadings created using Oncentra MasterPlan: 5 cm * 5 cm and 11 cm * 11 cm. RESULTS: For smaller loading and depths beyond 2 cm and for larger loading and depths beyond 1 cm, the dose difference was less than 3% (+/-4%). At shallower depths, differences of up to 6% (+/-4%) at the surface were observed if no bolus was added. The addition of 2-cm bolus for the smaller loading and 1 cm for larger loading minimized the difference to less than 3% (+/-4%). CONCLUSIONS: For typical FF applicator loading sizes, the actual measured dose was 6% (+/-4%) lower at the skin level when compared with TG-43. Additional bolus above the FF was shown to decrease the dose difference. The consideration of change in clinical practice should be carefully investigated in light of clinical reference data. PMID- 28735878 TI - IgA-mediated anti-glomerular basement membrane disease. A case report. PMID- 28735879 TI - Why contagious yawning does not (yet) equate to empathy. AB - Various studies and researchers have proposed a link between contagious yawning and empathy, yet the conceptual basis for the proposed connection is not clear and deserves critical evaluation. Therefore, we systematically examined the available empirical evidence addressing this association; i.e., a critical review of studies on inter-individual differences in contagion and self-reported values of empathy, differences in contagion based on familiarity or sex, and differences in contagion among individuals with psychological disorders, as well as developmental research, and brain imaging and neurophysiological studies. In doing so, we reveal a pattern of inconsistent and inconclusive evidence regarding the connection between contagious yawning and empathy. Furthermore, we identify study limitations and confounding variables, such as visual attention and social inhibition. Future research examining links between contagious yawning and empathy requires more rigorous investigation involving objective measurements to explicitly test for this connection. PMID- 28735881 TI - Recurrent, bilateral quadriceps tendon rupture due to indirect trauma in a patient with sickle cell trait: A case report. PMID- 28735880 TI - Age does not affect the outcome after digital nerve repair in children - A retrospective long term follow up. AB - BACKGROUND: Digital nerve injuries in children are not common, but they are considered to have an excellent prognosis, compared to adults, after nerve injury and repair. In studies including both children and adults age have been found to have an effect on outcome after nerve repair. METHODS: We investigated in a retrospective follow up study the long-time result after digital nerve injury and repair in children, 1-16 years of age (n = 38), and evaluate if age influences outcome. A group with young children, 1-10 years of age (n = 18), was compared with a group with older children, 11-16 years of age (n = 20). A clinical evaluation to evaluate sensation and grip strength was performed and questionnaires were used [Disability of the Arm, Shoulder and Hand (DASH), Cold Sensitivity Severity Scale (CISS), VAS-function and VAS-cosmetic] in median 40 months (range 12-131 months) after the injury and repair. RESULTS: All patient regained normal sensation. No correlations between age and monofilaments were found. Twenty children (52%) reported some problems with cold intolerance (i.e. CISS), but no other abnormal disability was found (i.e. DASH, VAS); again with no differences between the two groups. CONCLUSIONS: Children have an excellent long term recovery after a digital nerve repair and without any influence of age. PMID- 28735883 TI - Permeability modes in fluctuating lipid membranes with DNA-translocating pores. AB - Membrane pores can significantly alter not only the permeation dynamics of biological membranes but also their elasticity. Large membrane pores able to transport macromolecular contents represent an interesting model to test theoretical predictions that assign active-like (non-equilibrium) behavior to the permeability contributions to the enhanced membrane fluctuations existing in permeable membranes [Maneville et al. Phys. Rev. Lett. 82, 4356 (1999)]. Such high-amplitude active contributions arise from the forced transport of solvent and solutes through the open pores, which becomes even dominant at large permeability. In this paper, we present a detailed experimental analysis of the active shape fluctuations that appear in highly permeable lipid vesicles with large macromolecular pores inserted in the lipid membrane, which are a consequence of transport permeability events occurred in an osmotic gradient. The experimental results are found in quantitative agreement with theory, showing a remarkable dependence with the density of membrane pores and giving account of mechanical compliances and permeability rates that are compatible with the large size of the membrane pore considered. The presence of individual permeation events has been detected in the fluctuation time-series, from which a stochastic distribution of the permeation events compatible with a shot-noise has been deduced. The non-equilibrium character of the membrane fluctuations in a permeation field, even if the membrane pores are mere passive transporters, is clearly demonstrated. Finally, a bio-nano-technology outlook of the proposed synthetic concept is given on the context of prospective uses as active membrane DNA-pores exploitable in gen-delivery applications based on lipid vesicles. PMID- 28735882 TI - Antibiotic resistance and population structure of cystic fibrosis Pseudomonas aeruginosa isolates from a Spanish multi-centre study. AB - The first Spanish multi-centre study on the microbiology of cystic fibrosis (CF) was conducted from 2013 to 2014. The study involved 24 CF units from 17 hospitals, and recruited 341 patients. The aim of this study was to characterise Pseudomonas aeruginosa isolates, 79 of which were recovered from 75 (22%) patients. The study determined the population structure, antibiotic susceptibility profile and genetic background of the strains. Fifty-five percent of the isolates were multi-drug-resistant, and 16% were extensively-drug resistant. Defective mutS and mutL genes were observed in mutator isolates (15.2%). Considerable genetic diversity was observed by pulsed-field gel electrophoresis (70 patterns) and multi-locus sequence typing (72 sequence types). International epidemic clones were not detected. Fifty-one new and 14 previously described array tube (AT) genotypes were detected by AT technology. This study found a genetically unrelated and highly diverse CF P. aeruginosa population in Spain, not represented by the epidemic clones widely distributed across Europe, with multiple combinations of virulence factors and high antimicrobial resistance rates (except for colistin). PMID- 28735884 TI - From drop-shape analysis to stress-fitting elastometry. AB - Drop-shape analysis using pendant or sessile drops is a well-established experimental technique for measuring the interfacial or surface tension, and changes thereof. The method relies on deforming a drop by either gravity or buoyancy and fitting the Young-Laplace equation to the drop shape. Alternatively one can prescribe the shape and measure the pressure inside the drop or bubble using pressure tensiometry. However, when an interface with a complex microstructure is present, extra and anisotropic interfacial stresses may develop due to lateral interactions between the surface-active moieties, leading to deviations of the drop shape or even a wrinkling of the interface. To extract surface-material properties of these complex interfaces using drop-shape analysis or pressure tensiometry, the Young-Laplace law needs to be generalized in order to account for the extra and anisotropic stresses at the interface. In the present work, we review the different approaches that have been proposed to date to extract the surface tension as the thermodynamic state variable, as well as other rheological material properties such as the compression and the shear modulus. To evaluate the intrinsic performance of the methods, computer generated drops are subjected to step-area changes and then subjected to analysis using the different methods. Shape-fitting methods, now combined with an adequate constitutive method, do however perform rather poorly in determining the elastic stresses, especially at small area strains. An additional measurement o f the pressure or capillary-pressure tensiometry is required to improve the sensitivity. However, pressure-based methods still require the knowledge of the undeformed reference state, which may be difficult to achieve in practice. Moreover, it is not straightforward to judge from what point onwards one needs to go beyond the Young-Laplace equation. To overcome these limitations, a method based on stress fitting, which uses a local force balance method, is introduced here. One aspect of this new method is the use of the Chebyshev transform to numerically describe the contour shape of the drop interface. For all methods we present a detailed error analysis to evaluate if, and with what precision, surface material parameters can be extracted. Depending on the desired information, different ideal experimental conditions and most suitable methods are discussed, in addition to having a criterion to investigate if extra and anisotropic stresses matter. PMID- 28735885 TI - Surface hydrodynamics of viscoelastic fluids and soft solids: Surfing bulk rheology on capillary and Rayleigh waves. AB - From the recent advent of the new soft-micro technologies, the hydrodynamic theory of surface modes propagating on viscoelastic bodies has reinvigorated this field of technology with interesting predictions and new possible applications, so recovering its scientific interest very limited at birth to the academic scope. Today, a myriad of soft small objects, deformable meso- and micro structures, and macroscopically viscoelastic bodies fabricated from colloids and polymers are already available in the materials catalogue. Thus, one can envisage a constellation of new soft objects fabricated by-design with a functional dynamics based on the mechanical interplay of the viscoelastic material with the medium through their interfaces. In this review, we recapitulate the field from its birth and theoretical foundation in the latest 1980s up today, through its flourishing in the 90s from the prediction of extraordinary Rayleigh modes in coexistence with ordinary capillary waves on the surface of viscoelastic fluids, a fact first confirmed in experiments by Dominique Langevin and me with soft gels [Monroy and Langevin, Phys. Rev. Lett. 81, 3167 (1998)]. With this observational discovery at sight, we not only settled the theory previously formulated a few years before, but mainly opened a new field of applications with soft materials where the mechanical interplay between surface and bulk motions matters. Also, new unpublished results from surface wave experiments performed with soft colloids are reported in this contribution, in which the analytic methods of wave surfing synthetized together with the concept of coexisting capillary-shear modes are claimed as an integrated tool to insightfully scrutinize the bulk rheology of soft solids and viscoelastic fluids. This dedicatory to the figure of Dominique Langevin includes an appraisal of the relevant theoretical aspects of the surface hydrodynamics of viscoelastic fluids, and the coverage of the most important experimental results obtained during the three decades of research on this field. PMID- 28735886 TI - Effects of dietary propolis on the number and size of pleopadal egg, oxidative stress and antioxidant status of freshwater crayfish (Astacus leptodactylus Eschscholtz). AB - Four different crayfish diets; control, E1, E2 and E3, respectively containing 0, 1, 2 and 4% propolis, were tested to determine the effects of dietary propolis on the number and size of pleopadal egg, and malondialdehyde (MDA) level, superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) activities in the freshwater crayfish (Astacus leptodactylus). The crayfish were kept at 9.6+/ 5.3 degrees C water temperature and fed three times daily during a six month period The pleopodal egg number (from 7 to 9) produced per gram of the body weight and total pleopodal egg number (from 201 to 263) significantly increased (P<0.05) with the dietary propolis supplemantation. However, an increase in the dietary propolis led to a significant decrease (P<0.05) in the pleopodal egg size (from 3.22mm to 2.76mm). MDA level significantly (P<0.05) decreased in the hepatopancreas (from 4.78 to 3.04 nmol/g protein) and ovarium (from 3.52 to 1.98 nmol/g protein) of the crayfish fed with the increased dietary propolis level. On the other hand, an increase in the dietary propolis led to a significant increase (P<0.05) in SOD activities in hepatopancreas (from 21.8 to 41.1U/g protein) and ovarium (from 16.8 to 26.8U/g protein). However, CAT activities significantly decreased (P<0.05) in the hepatopancreas (from 23.8 to 18.9 nmol/g protein) and ovarium (from 21.8 to 17.5 nmol/g protein) of the crayfish fed with the increased dietary propolis level. Similarly, an increase in the dietary propolis caused a significant decrease (P<0.05) in GSH-Px activities in the hepatopancreas (from 21.8 to 41.1U/g protein) and ovarium (from 16.8 to 26.8U/g protein) with the formation of the pleopodal egg. The dietary propolis improves reproductive efficiency in the crayfish and decreases the oxidative stress under controlled hatchery conditions. PMID- 28735887 TI - Effect of pyrethroids on female genital system. Review. AB - Pyrethroids have been associated with a range of toxicological effects on various organs in animals.Recent animal studies suggest that neurodevelopmental, reproductive, and immunological effects may result following exposure to some pyrethroids at levels below those that induce overt signs of neurotoxicity. A variety of pyrethroids and their metabolites have the potential to affect the reproductive system. Dose-dependent effects on reproduction are associated with exposure across pyrethroid types. In mammals, permethrin and tetramethrin and cypermethrin have been found to be associated with adverse effects at high doses. Fenvalerate, deltamethrin, cypermethrin, caused morphometric and structural changes in the female genital organs. These pyrethroids affect ovulation, cause atresia of follicles, decrease the number of follicular cells, oocytes and corpora lutea and induce vesicular atrophy of the endometrial glands. The potential hormonal activity of pyrethroids showed that certain pyrethroids and their metabolites have multiple effects on the endocrine system. The level of steroid hormones, such as progesterone and estradiol, was inhibited. The pyrethorids may have the potential to mimic estrogens or to inhibit estrogen action. Some metabolites of pyrethroids, in particular permethrin and cypermethrin, are more likely to interact with the cellular estrogen receptors than the parent pyrethroids. Though several pyrethroids posses low toxicity, some pyrethroids, such as deltamethrin, cypermethrin, fenvalerate and bifenthrin have showed considerable toxicity. PMID- 28735888 TI - Differential expression of subunits of 20beta-hydroxysteroid dehydrogenase during gametogenesis in rainbow trout (Oncorhychus mykiss). AB - The patterns of expression of two subunits of 20beta-hydroxysteroid dehydrogenase (20beta-HSD), key enzyme involved in the biosynthesis and activation of steroid hormones, were examined in rainbow trout by using a combination of quantitative real-time PCR and in-situ hybridization. The expression of targeted genes was examined in mRNA extracted from different tissues at different gonadal stages in male and female trout. Both subunits of 20beta-HSD were found to be widely distributed in tissues. The highest expression of 20beta-HSD A was found in intestine followed by skin, stomach, liver and gills, whereas, the highest expression of 20beta-HSD B was observed in stomach followed by head kidney, ovary - at late vitellogenesis stage- and trunk kidney. In ovarian tissue 20beta-HSD A was highly expressed in mature oocytes, and the highest expression of 20beta-HSD B was in ovary at late vitellogenesis stage. There were no differences in the level of expression of either subunit among groups of rainbow trout at different stages of maturational competence. In male fish, 20beta-HSD A was highly expressed in testis stage I in contrast to 20beta-HSD B which was highly expressed in testis stage VIII. In situ- hybridization results showed that the 20beta-HSD gene was highly expressed in gastrointestinal organs, while only slightly expressed in the gonadal tissue of fish at stage 62day-post fertilization (dpf). Overall, the results confirm the ubiquitous presence of 20beta-HSD among tissues in rainbow trout with relatively minor fluctuations in expression associated with reproductive cycles which collectively suggests a wider metabolic role of these enzymes than just an association with the synthesis of control hormones for reproduction. PMID- 28735889 TI - Acute Promyelocytic Leukemia: A Perspective. AB - Treatment of patients with acute promyelocytic leukemia has significantly improved with the introduction of target specific agents all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) with long term survival a reality for the majority of patients. This can serve as a paradigm for cancer therapy where with the introduction of more potent target-specific drugs our reliance on the traditional cytotoxic agents is likely to diminish and less toxic and more effective regimens are likely to replace the current intensive chemotherapy regimens. PMID- 28735890 TI - Prognostic Validation of SKY92 and Its Combination With ISS in an Independent Cohort of Patients With Multiple Myeloma. AB - BACKGROUND: High risk and low risk multiple myeloma patients follow a very different clinical course as reflected in their PFS and OS. To be clinically useful, methodologies used to identify high and low risk disease must be validated in representative independent clinical data and available so that patients can be managed appropriately. A recent analysis has indicated that SKY92 combined with the International Staging System (ISS) identifies patients with different risk disease with high sensitivity. PATIENTS AND METHODS: Here we computed the performance of eight gene expression based classifiers SKY92, UAMS70, UAMS80, IFM15, Proliferation Index, Centrosome Index, Cancer Testis Antigen and HM19 as well as the combination of SKY92/ISS in an independent cohort of 91 newly diagnosed MM patients. RESULTS: The classifiers identified between 9% 21% of patients as high risk, with hazard ratios (HRs) between 1.9 and 8.2. CONCLUSION: Among the eight signatures, SKY92 identified the largest proportion of patients (21%) also with the highest HR (8.2). Our analysis also validated the combination SKY92/ISS for identification of three classes; low risk (42%), intermediate risk (37%) and high risk (21%). Between low risk and high risk classes the HR is >10. PMID- 28735891 TI - Versatile nature of hetero-chitosan based derivatives as biodegradable adsorbent for heavy metal ions; a review. AB - The polyfunctional chitosan can act as the biological macromolecule ligand not only for the adsorption and the recovery of metal ions from an aqueous media, but also for the fabrication of novel adsorbents which shows selectivity and better adsorption properties. The unmodified chitosan itself, a single cationic polysaccharide, has hydroxyl and amine groups carrying complex properties with the metal ions. In addition, the selectivity of metal ions, the adsorption efficiency and adsorption capacity of the adsorbent can be modified chemically. This review covers the synthetic strategies of chitosan towards the synthesis of hetero-chitosan based adsorbents via chemical modifications in past two decades. It also includes how chemical modification influences the metal adsorption with N, O, S and P containing chitosan derivatives. Hope this review article provides an opportunity for researchers in the future to explore the potential of chitosan as an adsorbent for removal of metal ions from wastewater. PMID- 28735892 TI - Clinical and Echocardiographic Correlates of Left Atrial Function Index: The Framingham Offspring Study. AB - BACKGROUND: Left atrial (LA) remodeling is a predictor of cardiovascular disease (CVD). We performed measurement of the LA function index (LAFI), a composite measure of LA structure and function, in a community-based cohort and here report the distribution and cross-sectional correlates of LAFI. METHODS: In 1,719 Framingham Offspring Study participants (54% women, mean age 66 +/- 9 years), we derived LAFI from the LA emptying fraction, left ventricular (LV) outflow tract velocity time integral, and indexed maximal LA volume. We used multivariable linear regression to assess the clinical and echocardiographic correlates of LAFI adjusting for age, sex, anthropometric measurements, and CVD risk factors. RESULTS: The average LAFI was 35.2 +/- 12.1. Overall, LAFI declined with advancing age (beta = -0.27, P < .001). LAFI was significantly higher (37.5 +/- 11.6) in a subgroup of participants free of CVD and CVD risk factors compared with those with either of these conditions (34.5 +/- 12.2). In multivariable models, LAFI was inversely related to antihypertensive use (beta = -1.26, P = .038), prevalent atrial fibrillation (beta = -4.46, P = .001), heart failure (beta = -5.86, P = .008), and coronary artery disease (beta = -2.01, P = .046). In models adjusting for echocardiographic variables, LAFI was directly related to LV ejection fraction (beta = 14.84, P < .001) and inversely related to LV volume (beta = -7.03, P < .001). CONCLUSIONS: LAFI was inversely associated with antihypertensive use and prevalent CVD and was related to established echocardiographic traits of LV remodeling. Our results offer normative ranges for LAFI in a white community-based sample and suggest that LAFI represents a marker of pathological atrial remodeling. PMID- 28735893 TI - Mechanistic and kinetic study on the reaction of methylperoxy radical with atomic iodine. AB - Singlet and triplet potential energy surfaces for the CH3O2 with I reaction have been investigated computationally to propose the reaction mechanisms and possible products. Multichannel RRKM theory and transition-state theory have been used to compute the overall and individual rate constants at 200-3000K and 10-14 1014Torr. On the singlet PES, addition-elimination, substitution and H abstraction mechanisms are located, and the addition-elimination mechanism is dominant. At 70Torr with N2 as bath gas, IM1(CH3OOI) formed by collisional stabilization is dominated at 200-300K, whereas CH2O and HIO are the major products at the temperatures between 350 and 3000K; The title reaction exhibits the typical falloff behavior. The results show that temperature and pressure affect the yield of products. Furthermore, the predicted rate constants at 298K 70Torr of N2 agree well with the available experimental values. On the triplet PES, the most favorable product should be CH3I+O2(3Sigma) at atmospheric condition. Other two pathways on the triplet PES will not compete with the pathways on the singlet PES in kinetically and thermodynamically. PMID- 28735894 TI - Geographical variation and trends in outcomes of laparoscopic spleen-preserving distal pancreatectomy with or without splenic vessel preservation: A meta analysis. AB - BACKGROUND: Distal pancreatectomy (DP) is performed to treat tumors of the pancreatic body and tail. Traditionally, splenectomy is performed with a DP, however, laparoscopic spleen-preserving DP (SPDP) using Warshaw's (splenic vessels ligation) or Kimura's (splenic vessels preservation) techniques have been reported. The clinical benefits of using either technique remain unclear. In this study, we conducted a meta-analysis to compare the clinical outcomes of patients undergoing Warshaw's and Kimura SPDP. This is the first study to evaluate the geographical variation in outcomes of Warshaw's and Kimura SPDP. METHODS: Databases of PubMed, Embase, and Cochrane library were used to identify studies reporting Warshaw's and Kimura SPDP. Clinical outcomes were compared. Pooled odds risk and weighted mean difference with 95% confidence interval were calculated using random effect models. RESULTS: Fourteen non-randomized controlled studies involving 945 patients met our selection criteria. 301 (31.9%) patients underwent Warshaw's SPDP; 644 (68.1%) underwent Kimura SPDP. Compared to Warshaw's SPDP, patients undergoing Kimura SPDP had a lower incidence of post-operative complications including spleen infarction (OR = 9.64, 95% CI = 5.79 to 16.05, P < 0.001) and gastric varices (OR = 11.88, 95% CI = 5.11 to 27.66, P < 0.001). The length of surgery was significantly shorter for Warshaw's SPDP (WMD = -18.12, 95%CI = -26.52 to -9.72, p < 0.001). Decreased blood loss was reported for patients undergoing Warshaw's SPDP (WMD = -59.72, 95%CI = -102.01 to -17.43, p = 0.006). There were no differences between the two groups' rates of conversion to an open procedure (P = 0.35), postoperative pancreatic fistula (P = 0.71), need for reoperation (P = 0.25), and length of hospital stay (P = 0.38). CONCLUSION: Both Warshaw's and Kimura are safe SPDP techniques. These data suggest Kimura SPDP is the preferred technique due to less risk of splenic infarct and gastric varices. Despite evidence of regional variation in volume performed (between Kimura and Warshaw's), there are no statistically significant differences in outcomes between these techniques. PMID- 28735895 TI - A Phosphosite within the SH2 Domain of Lck Regulates Its Activation by CD45. AB - The Src Family kinase Lck sets a critical threshold for T cell activation because it phosphorylates the TCR complex and the Zap70 kinase. How a T cell controls the abundance of active Lck molecules remains poorly understood. We have identified an unappreciated role for a phosphosite, Y192, within the Lck SH2 domain that profoundly affects the amount of active Lck in cells. Notably, mutation of Y192 blocks critical TCR-proximal signaling events and impairs thymocyte development in retrogenic mice. We determined that these defects are caused by hyperphosphorylation of the inhibitory C-terminal tail of Lck. Our findings reveal that modification of Y192 inhibits the ability of CD45 to associate with Lck in cells and dephosphorylate the C-terminal tail of Lck, which prevents its adoption of an active open conformation. These results suggest a negative feedback loop that responds to signaling events that tune active Lck amounts and TCR sensitivity. PMID- 28735896 TI - Argonaute CLIP Defines a Deregulated miR-122-Bound Transcriptome that Correlates with Patient Survival in Human Liver Cancer. AB - MicroRNA-122, an abundant and conserved liver-specific miRNA, regulates hepatic metabolism and functions as a tumor suppressor, yet systematic and direct biochemical elucidation of the miR-122 target network remains incomplete. To this end, we performed Argonaute crosslinking immunoprecipitation (Argonaute [Ago] CLIP) sequencing in miR-122 knockout and control mouse livers, as well as in matched human hepatocellular carcinoma (HCC) and benign liver tissue to identify miRNA target sites transcriptome-wide in two species. We observed a majority of miR-122 binding on 3' UTRs and coding exons followed by extensive binding to other genic and non-genic sites. Motif analysis of miR-122-dependent binding revealed a G-bulged motif in addition to canonical motifs. A large number of miR 122 targets were found to be species specific. Upregulation of several common mouse and human targets, most notably BCL9, predicted survival in HCC patients. These results broadly define the molecular consequences of miR-122 downregulation in hepatocellular carcinoma. PMID- 28735897 TI - RADX Promotes Genome Stability and Modulates Chemosensitivity by Regulating RAD51 at Replication Forks. AB - RAD51 promotes homology-directed repair (HDR), replication fork reversal, and stalled fork protection. Defects in these functions cause genomic instability and tumorigenesis but also generate hypersensitivity to cancer therapeutics. Here we describe the identification of RADX as an RPA-like, single-strand DNA binding protein. RADX is recruited to replication forks, where it prevents fork collapse by regulating RAD51. When RADX is inactivated, excessive RAD51 activity slows replication elongation and causes double-strand breaks. In cancer cells lacking BRCA2, RADX deletion restores fork protection without restoring HDR. Furthermore, RADX inactivation confers chemotherapy and PARP inhibitor resistance to cancer cells with reduced BRCA2/RAD51 pathway function. By antagonizing RAD51 at forks, RADX allows cells to maintain a high capacity for HDR while ensuring that replication functions of RAD51 are properly regulated. Thus, RADX is essential to achieve the proper balance of RAD51 activity to maintain genome stability. PMID- 28735898 TI - Genome-wide Single-Molecule Footprinting Reveals High RNA Polymerase II Turnover at Paused Promoters. AB - Transcription initiation entails chromatin opening followed by pre-initiation complex formation and RNA polymerase II recruitment. Subsequent polymerase elongation requires additional signals, resulting in increased residence time downstream of the start site, a phenomenon referred to as pausing. Here, we harnessed single-molecule footprinting to quantify distinct steps of initiation in vivo throughout the Drosophila genome. This identifies the impact of promoter structure on initiation dynamics in relation to nucleosomal occupancy. Additionally, perturbation of transcriptional initiation reveals an unexpectedly high turnover of polymerases at paused promoters-an observation confirmed at the level of nascent RNAs. These observations argue that absence of elongation is largely caused by premature termination rather than by stable polymerase stalling. In support of this non-processive model, we observe that induction of the paused heat shock promoter depends on continuous initiation. Our study provides a framework to quantify protein binding at single-molecule resolution and refines concepts of transcriptional pausing. PMID- 28735900 TI - Treatment with enzyme replacement therapy during pregnancy in a patient with Pompe disease. AB - Pregnancy is in general physically demanding, even more so for women with hereditary muscular diseases (HMDs). With increasing numbers of women with HMD reaching reproductive age, there is a growing need for research into what impact pregnancy can have on their clinical condition. A 25-year-old woman was diagnosed with Pompe disease at the age of 22 and began enzyme replacement therapy (ERT) right away. At the age of 25 she became pregnant. ERT was paused during the first trimester and recommenced throughout the second and third trimesters. Her clinical condition throughout the pregnancy remained stable. Delivery was uneventful, but prolonged and physically demanding. After delivery, cystitis further compromised her health, leaving her bedridden during early postpartum. In this case, continuing ERT during pregnancy resulted in a healthy outcome, with an uneventful pregnancy and delivery of a normal and healthy baby. However, data on pregnancy in women with Pompe disease are rare. PMID- 28735902 TI - Quality of Life Outcomes Following Treatment for Localized Prostate Cancer: What's New and What's Not. PMID- 28735901 TI - Mechanisms of pannexin1 channel gating and regulation. AB - Pannexins are a family of integral membrane proteins with distinct post translational modifications, sub-cellular localization and tissue distribution. Panx1 is the most studied and best-characterized isoform of this gene family. The ubiquitous expression, as well as its function as a major ATP release and nucleotide permeation channel, makes Panx1 a primary candidate for participating in the pathophysiology of CNS disorders. While many investigations revolve around Panx1 functions in health and disease, more recently, details started emerging about mechanisms that control Panx1 channel activity. These advancements in Panx1 biology have revealed that beyond its classical role as an unopposed plasma membrane channel, it participates in alternative pathways involving multiple intracellular compartments, protein complexes and a myriad of extracellular participants. Here, we review recent progress in our understanding of Panx1 at the center of these pathways, highlighting its modulation in a context specific manner. This article is part of a Special Issue entitled: Gap Junction Proteins edited by Jean Claude Herve. PMID- 28735903 TI - Genetics of non-syndromic childhood obesity and the use of high-throughput DNA sequencing technologies. AB - BACKGROUND: Childhood obesity is a serious public health problem associated with the development of several chronic diseases, such as type 2 diabetes mellitus, dyslipidemia, and hypertension. The elevated prevalence of obesity is mostly due to inadequate diet and lifestyle, but it is also influenced by genetic factors. OBJECTIVES: To review recent advances in the field of the genetics of obesity. We summarize the list of genes associated with the rare non-syndromic forms of obesity, and explain their function. Furthermore, we discuss the technologies that are available for the genetic diagnosis of obesity. RESULTS: Several studies reported that single gene variants cause Mendelian forms of obesity, determined by mutations of major effect in single genes. Rare, non-syndromic forms of obesity are a result of loss-of-function mutations in genes that act on the development and function of the hypothalamus or the leptin-melanocortin pathway. These variants disrupt enzymes and receptors that play a role in energy homeostasis, resulting in severe early-onset obesity and endocrine dysfunctions. Different approaches and technologies have been used to understand the genetic background of obesity. Currently, whole genome and whole exome sequencing are important diagnostic tools to identify new genes and variants associated with severe obesity, but other approaches are also useful at individual or population levels, such as linkage analysis, candidate gene sequencing, chromosomal microarray analysis, and genome-wide association studies. CONCLUSIONS: The understanding of the genetic causes of obesity and the usefulness and limitations of the genetic diagnostic approaches can contribute to the development of new personalized therapeutic targets against obesity. PMID- 28735899 TI - Mot1, Ino80C, and NC2 Function Coordinately to Regulate Pervasive Transcription in Yeast and Mammals. AB - Pervasive transcription initiates from cryptic promoters and is observed in eukaryotes ranging from yeast to mammals. The Set2-Rpd3 regulatory system prevents cryptic promoter function within expressed genes. However, conserved systems that control pervasive transcription within intergenic regions have not been well established. Here we show that Mot1, Ino80 chromatin remodeling complex (Ino80C), and NC2 co-localize on chromatin and coordinately suppress pervasive transcription in S. cerevisiae and murine embryonic stem cells (mESCs). In yeast, all three proteins bind subtelomeric heterochromatin through a Sir3-stimulated mechanism and to euchromatin via a TBP-stimulated mechanism. In mESCs, the proteins bind to active and poised TBP-bound promoters along with promoters of polycomb-silenced genes apparently lacking TBP. Depletion of Mot1, Ino80C, or NC2 by anchor away in yeast or RNAi in mESCs leads to near-identical transcriptome phenotypes, with new subtelomeric transcription in yeast, and greatly increased pervasive transcription in both yeast and mESCs. PMID- 28735904 TI - Short sleep duration is associated with B-type natriuretic peptide levels and predicts the death of Japanese patients with type 2 diabetes. AB - OBJECTIVE: To investigate the associations of sleep duration with all-cause mortality, glycemic control, and other clinical parameters of patients with type 2 diabetes. METHODS: From April 2013 to December 2015, we conducted a retrospective cohort study. Study participants were divided into three groups according to their sleep duration. Multiple regression analysis and Cox proportional hazards analysis were performed to assess the independent associations of sleep duration with clinical parameters and all-cause mortality. RESULTS: We enrolled 1233 patients who were then followed for 860 +/- 264 days. During the follow-up period, 20 patients (1.6%) died. Sleep duration inversely associated with plasma B-type natriuretic peptide levels (beta = -0.203, p = 0.012) in short (<7 h) sleepers, whereas it was positively associated with hemoglobin A1c levels (beta = 0.156, p = 0.021) in long (>=9 h) sleepers. Moreover, Cox proportional hazard analysis revealed that short sleep duration was a significant predictor of all-cause mortality (hazard ratio = 0.473; confidence interval 0.248-0.905, p = 0.024). CONCLUSION: Short sleep duration may serve as a prognostic indicator of mortality in Japanese patients with type 2 diabetes and may increase cardiovascular stress. Adequate sleep is essential for the management of type 2 diabetes. PMID- 28735905 TI - Awareness and knowledge of obstructive sleep apnea among the general population. AB - BACKGROUND: Obstructive sleep apnea (OSA) is an increasingly prevalent condition that remains largely undiagnosed. We aimed to assess the level of awareness and knowledge of OSA among the general population. METHODS: The Singapore Health 2 was a population-based study that comprised interview and health screening components. Out of 2720 subjects who completed the interview component, 2080 subjects gave consent for further health surveys. We contacted these subjects and conducted a structured telephone interview. RESULTS: We completed 1306 telephone interviews (response rate 62.8%). Two hundred and eighty-one (21.5%) respondents were aware of OSA, but only 170 (13.0%) respondents could define OSA correctly. A total of 77 (5.9%), 158 (12.1%), 150 (11.5%) and 110 (8.4%) respondents were able to correctly list at least one risk factor, symptom, health consequence and treatment options for OSA, respectively. The most common sources of information about OSA were traditional media such as newspapers (42.0%), internet (14.2%) or relatives and friends (14.6%). On multivariate analysis, respondents were more likely to define OSA correctly if they were older (>=61years), (odds ratio of 2.99, 95% Confidence Interval [CI]: 1.66-5.41), were Chinese as compared to Indians (odds ratio 2.63, 95% CI: 1.46-4.72), had higher levels of income (odds ratio 2.18, 95% CI 1.16-4.10) and post-secondary education (odds ratio 2.87, 95% CI: 1.28-6.45). CONCLUSION: Awareness and knowledge of OSA among the general population is currently poor. The effectiveness of ongoing health education campaigns to increase awareness should be monitored by examining temporal trends in public knowledge of sleep apnea. PMID- 28735906 TI - Predicting the presence of sleep-disordered breathing in children with Down syndrome. AB - OBJECTIVE: Sleep-disordered breathing (SDB) is highly prevalent in children with Down syndrome. Given the scarcity of resources and the presence of risk factors for SDB in this population, the objective of this study is to identify the clinical predictors of SDB, which would assist prioritization of children with Down syndrome for SDB evaluation. METHODS: A retrospective cohort study was conducted on children enrolled in the Down syndrome clinic at CHEO who underwent polysomnography in 2004-2014. Total apnea-hypopnea index (AHI) or obstructive AHI (OAHI) > 5 events/hour was considered clinically significant. Associations between SDB and concurrent diagnoses, referral reasons, and sleep symptoms assessed by questionnaire were examined using Pearson's chi-square test or Fisher's exact test as appropriate. Univariate and multivariate logistic regression analyses were used to examine the predictors of SDB. RESULTS: SDB was present in 42.9% of 119 children, with its highest prevalence at age 8 years. Symptoms were not significantly associated with AHI > 5 events/hour or OAHI > 5 events/hour. Gastroesophageal reflux was associated with lower odds of OAHI > 5 events/hour on univariate testing (odds ratio 0.16, 95% CI 0.04-0.72; p = 0.02) and multivariate analysis (odds ratio 0.05, 95% CI 0.0006-0.50; p = 0.002). CONCLUSIONS: SDB is highly prevalent at all ages in children with Down syndrome. Symptoms did not predict SDB in this population, although gastroesophageal reflux may mimic SDB, which indicates that clinicians should continue to perform ongoing surveillance for SDB throughout the lifespan of children with Down syndrome. PMID- 28735907 TI - The relationship between weight change and daytime sleepiness: the Sleep Heart Health Study. AB - OBJECTIVE: Through a causal framework, we aim to assess the association between weight change and daytime sleepiness, and the role of obstructive sleep apnoea (OSA) in this relationship. METHODS: From the Sleep Heart Health Study, we selected individuals who were: (1) 40-64 years old, with (2) body mass index (BMI) >=18.5 kg/m2, (3) no history of stroke, treatment for OSA, and tracheostomy at baseline. We used multiple linear regression to assess the relationship between five-year weight change and daytime sleepiness (assessed through Epworth Sleepiness Scale (ESS)) at five years, adjusting for daytime sleepiness, demographics, diabetes, subjective sleep duration, sleep disturbance, smoking status, weight, and use of antidepressants and benzodiazepines at baseline, in those with complete data (N = 1468). We further assessed the potential mediating role of OSA in this relationship. RESULTS: At baseline, the study participants were on average 55 years old, 46% males, with mean BMI 28 kg/m2; and 25% had ESS>10. ESS at five years worsened by 0.36 units (95% confidence interval (CI) 0.12-0.61, p = 0.004) with every 10-kg weight gain. When stratified by sex, this relationship was only found in women (0.55, 95% CI 0.25-0.86, p < 0.001; p interaction = 0.02). Approximately one-fifth of the relationship between weight change and daytime sleepiness was mediated by severity of OSA at five years. CONCLUSION: Weight gain has a detrimental effect on daytime sleepiness, mostly through pathways other than OSA. This study provides further evidence and understanding of the relationship between obesity and excessive daytime sleepiness. PMID- 28735908 TI - "I feel my arm shaking": partial cataplexy mistaken for drug-resistant focal epilepsy. PMID- 28735909 TI - Stereotyped episodes of aphasia and immobility: how cataplexy mimics stroke in an elderly patient. PMID- 28735910 TI - Prevalence of obstructive sleep apnea in patients with posttraumatic stress disorder and its impact on adherence to continuous positive airway pressure therapy: a meta-analysis. AB - OBJECTIVE: Although some authors have recently investigated the co-occurrence of posttraumatic stress disorder (PTSD) and obstructive sleep apnea (OSA), the topic remains insufficiently studied. The aim of this meta-analysis was to detect the pooled prevalence of OSA in PTSD and its impact on adherence to continuous positive airway pressure (CPAP) therapy. METHODS: We conducted a search for articles published until August 20, 2016, in PubMed, Embase, the Cochrane Library, and PsycINFO. The literature search identified 194 articles, and 12 studies were included in the meta-analysis. RESULTS: The pooled prevalence rates of OSA based on different apnea-hypopnea index (AHI) criteria in PTSD patients was 75.7% (95% confidence interval [CI] = 44.1-92.5%) (AHI >=5) and 43.6% (95% CI = 20.6-69.7%) (AHI >=10), respectively. Subgroup analysis showed that there was a significant difference between the prevalence of OSA in veterans with PTSD compared to nonveterans or mixed samples. Patients with PTSD and OSA demonstrated significantly lower adherence to CPAP therapy (regular use: g = -0.658, 95% CI = 0.856 to -0.460; time of average use per night: g = -0.873, 95% CI = -1.550 to 0.196) compared with those with OSA alone. CONCLUSIONS: OSA is commonly seen in patients with PTSD. Given its negative impact on the adherence to CPAP therapy, the possibility of OSA should be monitored carefully in patients with PTSD. PMID- 28735911 TI - Do gender and racial/ethnic disparities in sleep duration emerge in early adulthood? Evidence from a longitudinal study of U.S. adults. AB - OBJECTIVE: Gender and racial/ethnic disparities in sleep duration are well documented among the U.S. adult population, but we know little about how these disparities are shaped during the early course of adult life, a period marked by substantial changes in social roles that can influence time for sleep. METHODS: Prospective data was used from the National Longitudinal Survey of Youth 1997 (NLSY97), a U.S.-based representative sample of persons born between 1980 and 1984, who were first interviewed in 1997. Sleep duration was assessed in 2002, 2007/2008, 2009, 2010, and 2011. Random-coefficient models were estimated to examine gender and racial/ethnic disparities in trajectories of sleep duration across early adulthood as a function of educational experiences, employment, and family relationships. RESULTS: Sleep duration declined during early adulthood. Women reported shorter sleep than men from age 18 to 22, but slept longer than men by age 28. Black Young adults reported sleep durations similar to those of White young adults until age 24, after which blacks slept less than whites. Educational experiences and employment characteristics reduced gender and racial/ethnic disparities, but family relationships exacerbated them. CONCLUSION: This study is the first to establish the emergence of gender and racial/ethnic disparities in sleep duration during early adulthood. PMID- 28735913 TI - Gray matter abnormalities of the dorsal posterior cingulate in sleep walking. AB - OBJECTIVE: This study aimed to determine whether voxel-based analysis of T1 weighted magnetic resonance imaging (MRI) and diffusion tensor imaging is able to detect alterations of gray and white matter morphometry as well as measures of mean diffusivity and fractional anisotropy in patients with non-rapid eye movement parasomnia. METHODS: 3 Tesla MRI was performed in 14 drug-free, polysomnography-confirmed adult patients with non-rapid eye movement parasomnia (age: 29 +/- 4.2 years; disease duration 19.2 +/- 7.7 years) and 14 healthy subjects, matched for age and gender. Statistical parametric mapping was applied to objectively identify focal changes of MRI parameters throughout the entire brain volume. RESULTS: Statistical parametric mapping localized significant decreases of gray matter volume in the left dorsal posterior cingulate cortex (BA23) and posterior midcingulate cortex (BA24) in patients with non-rapid eye movement parasomnias compared to the control group (p < 0.001, corrected for multiple comparisons). No significant differences of mean diffusivity and fractional anisotropy measures were found between the non-rapid eye movement parasomnia group and the healthy control group. CONCLUSIONS: Recently, the simultaneous co-existence of arousal or wakefulness originating from the motor and cingulate cortices and persistent sleep in associative cortical regions was suggested as a functional framework of somnambulism. Gray matter volume decline in the dorsal posterior and posterior midcingulate cortex reported in this study might represent the neuroanatomical substrate for this condition. PMID- 28735912 TI - Sex and age differences in the associations between sleep behaviors and all-cause mortality in older adults: results from the National Health and Nutrition Examination Surveys. AB - OBJECTIVE: Our aim was to examine sex- and age-specific relationships of sleep behaviors with all-cause mortality rates. METHODS: A retrospective cohort study was conducted among 5288 adults (>=50 years) from the 2005-2008 National Health and Nutrition Examination Surveys who were followed-up for 54.9 +/- 1.2 months. Sleep duration was categorized as < 7 h, 7-8 h and >8 h. Two sleep quality indices were generated through factor analyses. 'Help-seeking behavior for sleep problems' and 'diagnosis with sleep disorders' were defined as yes/no questions. Sociodemographic covariates-adjusted Cox regression models were applied to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: A positive relationship was observed between long sleep and all-cause mortality rate in the overall sample (HR = 1.90, 95% CI: 1.38, 2.60), among males (HR = 1.48, 95% CI: 1.05, 2.09), females (HR = 2.32, 95% CI: 1.48, 3.61) and elderly (>=65 years) people (HR = 1.80, 95% CI: 1.30, 2.50). 'Sleepiness/sleep disturbance' (Factor I) and all-cause mortality rate were positively associated among males (HR = 1.22, 95% CI: 1.03, 1.45), whereas 'poor sleep-related daytime dysfunction' (Factor II) and all-cause mortality (HR = 0.75, 95% CI: 0.62, 0.91) were negatively associated among elderly people. CONCLUSIONS: Sex- and age specific relationships were observed between all-cause mortality rate and specific sleep behaviors among older adults. PMID- 28735914 TI - Companion of oral movements with limb movements in patients with sleep bruxism: preliminary findings. AB - BACKGROUND: Sleep bruxism (SB) patients show a higher incidence of leg movements than normal subjects. STUDY OBJECTIVES: The study aimed to characterize SB episodes and their relationships with limb movements (LMs). MATERIALS AND METHODS: Polysomnographic (PSG) recordings were performed on eight SB patients. The intervals between the onsets of adjacent SB episodes and LMs were determined and linear correlation analyses were used to estimate the relationship between the SB index and SB episodes in clusters. The Pearson chi2 and partitions of chi2 tests were used to analyze the differences in incidence of SB episodes and clusters in different sleep stages. RESULTS: A majority of SB episodes (85.05%) were found to be accompanied by LMs and among them, 70.52% SB episodes occurred with movements of both upper and lower limbs and most of LMs (70.54%) occurred before the onset of SB episodes. Most of SB episodes especially those accompanied by LMs occurred with microarousals or awakenings. Linear correlation analysis showed a positive correlation between the SB index and SB episodes in clusters (r2 = 0.7027, P = 0.0093). In addition, the percentage of SB episodes in clusters accompanied by LMs was significantly smaller than that of SB episodes not accompanied by LMs (chi2 test, P < 0.001) and the percentage of SB episodes in clusters during REM sleep was significantly smaller than that during NREM sleep (chi2 test, P < 0.0001). CONCLUSIONS: Most SB episodes might not be isolated events, but rather a part of a series of movements second to changes in arousal level. PMID- 28735915 TI - Changes in children's sleep domains between 2 and 3 years of age: the Ulm SPATZ Health Study. AB - OBJECTIVE: There is growing interest in the link between sleep habits and child health but reference values specific to toddlers as well as longitudinal data on sleep are scarce. We aimed to describe parent-reported child sleep habits and their intra-individual changes in two- to three-year-olds using data from a regional birth cohort study. METHODS: In the Ulm SPATZ Health Study, a birth cohort study conducted at Ulm, Southern Germany, with baseline examination from April 2012 to May 2013, the German version of the Children's Sleep Habits Questionnaire (CSHQ-DE) was used longitudinally at follow-ups at two and three years (N = 615 children). Descriptive statistics including intra-individual differences between three- and two-year scores were reported, the latter using the sign test. RESULTS: The sample-averaged total and subscale CSHQ scores differed only slightly between two and three years (max. Cohen's d = 0.39). Intra individual comparisons of the CSHQ subscales or single items revealed congruent but also opposing changes in items belonging to the same subscale. Whereas items on bedtime resistance generally improved, sleep duration shortened with older age. With regard to sleep anxiety, we found worsening in the item 'Afraid of sleeping in the dark' in about one-fifth of our children whereas other items on this CSHQ subscale showed an opposing trend with age. A similar opposing trend was detected within the subscale on night wakings. CONCLUSION: Our data provide initial descriptive information on sleep habits in toddlers. The high intra individual changes, partly in opposing directions which may be masked by aggregation, indicate a need for age- and item-specific analyses. PMID- 28735916 TI - Morbidity and mortality of middle-aged and elderly narcoleptics. AB - OBJECTIVES: The objective of the study was to evaluate the morbidities and mortality in a national group of middle-aged and elderly narcolepsy patients before and after the first diagnosis of the condition. METHODS: From the Danish National Patient Registry (NPR), 1174 patients (45.1% males) aged 20-59 years and 339 patients (44.8% males) aged 60+ who received a diagnosis of narcolepsy between 1998 and 2014 were compared, respectively, with 4716 and 1353 control citizens matched for age, gender and geography, who were randomly chosen from the Danish Civil Registration System Statistics. In the NPR, all morbidities are grouped into major WHO classes. RESULTS: Middle-aged and elderly patients had more health contacts before and after their narcolepsy diagnosis with respect to several disease domains: infections, neoplasm, endocrine/metabolic diseases/diabetes, mental/psychiatric, neurological (including epilepsy), eye, cardiovascular (hypertension, ischemic heart disease), respiratory (upper-airway infections, sleep apnea), gastrointestinal, musculoskeletal (including discopathies) and skin diseases. Narcolepsy patients had lower reproductive rates. Furthermore, patients showed significantly more health contacts due to the evaluation and control contacts for disease and symptoms. Patients suffered from significantly more multiple diseases than did controls. The 17-year hazard ratio mortality rates were 1.35 (95% CI, 0.94-1.95, p = 0.106) among 20-59 year-olds, and 1.38 (1.12-1.69, p = 0.002) among those aged 60+ years. CONCLUSION: There are higher rates of morbidity in several disease domains before and after a diagnosis of narcolepsy. Elderly narcolepsy patients have higher mortality rates. PMID- 28735917 TI - Mother-father agreement and one-year stability of children's sleep functioning. AB - OBJECTIVES: To (1) evaluate mother-father agreement of total sleep problems and specific sleep problem domains and (2) examine the one-year stability of children's sleep functioning, including cross-rater stability. METHODS: A community-based sample of 519 children (51% boys) in Spain was assessed in third grade and again 1 year later. At each time-point, both mothers and fathers provided ratings of sleep functioning using the Children's Sleep Habits Questionnaire (CSHQ). RESULTS: Sleep scores did not differ between mothers' and fathers' ratings. Cross-sectionally (at both time-points) and longitudinally (from grade 3 to grade 4), strong agreement was found between mothers' and fathers' ratings of total sleep problems, sleep habits, night wakings, and parasomnias. Lower agreement was found for daytime sleepiness and sleep onset delay. There was large effect size stability for both mothers' and fathers' ratings over the one-year period on the total sleep disturbance scale and most sleep subscales. CONCLUSIONS: This study provides the first evidence of strong mother-father agreement on subjective ratings of children's sleep functioning, both concurrently and over a one-year period, for overall sleep problems and certain sleep domains. However, agreement was far from identical, and further studies are needed to evaluate reasons for discrepancy and whether mother-father discrepancy in sleep functioning predicts children's functioning. More studies are needed that systematically include both mothers' and fathers' perspectives regarding children's sleep. PMID- 28735918 TI - A case of involuntary rhythmic and characteristic tapping sounds during sleep. PMID- 28735919 TI - Sleep disturbances at the time of a new diagnosis: a comparative study of human immunodeficiency virus patients, cancer patients, and general population controls. AB - OBJECTIVES: Sleep disturbances are a prevalent and troubling symptom of patients with highly stressful illnesses, such as human immunodeficiency virus (HIV) and cancer. The aim of this study was to compare the prevalence and incidence of sleep disturbances among persons with HIV, those with cancer, and the general population of Taiwan. METHODS: A matched cohort study design was used to compare the risk of sleep disturbances among three groups using reimbursement claims recorded in Taiwan's National Health Insurance Research Database (NHIRD). A total of 14,531 HIV-infected persons were compared with 1493 cancer patients and 1373 general population controls matched by gender and age. Cox proportional hazard regression models were used to test the hazard risk of sleep disturbances among the groups. RESULTS: The mean durations between the date of the initial HIV/cancer diagnosis and onset of sleep disturbances of HIV-infected persons, cancer patients, and controls were 1.7, 2.3, and 1.8 years, respectively. The risk of developing sleep disturbances was significantly higher in HIV-infected persons (adjusted hazard ratio [AHR] = 3.74, p < 0.001) and cancer patients (AHR = 2.72, p < 0.001) than in controls. HIV-infected persons had a 20% higher risk of sleep disturbances than cancer patients (AHR = 1.20, p < 0.001). CONCLUSIONS: HIV-infected persons exhibited a higher risk of developing sleep disturbances than cancer patients and general population controls. With efficacious treatments for sleep disturbances, we should focus on training and research programs for health care providers to intervene and treat earlier for the present and future health of cancer patients and HIV-infected persons. PMID- 28735920 TI - Risk of obstructive sleep apnea among patients with Cushing's syndrome: a nationwide longitudinal study. AB - OBJECTIVE: Previous studies have demonstrated the association between Cushing's syndrome (CS), obstructive sleep apnea (OSA), and the risk factors for OSA, but rarely provided the evidence within a large population. Using the Taiwan National Health Insurance Research Database, we attempted to investigate the association between CS and OSA, and to provide persuading evidences. METHODS: In our study, 1612 patients with CS and 1612 age-, sex-, and comorbidities-matched controls were included, and followed up to the end of 2011. Cases of OSA were identified during the follow-up. RESULTS: Among patients with CS, 53 developed OSA (incidence: 4.11 per thousand person-year) compared with 22 in the control group (incidence: 1.70 per thousand person-year) during the follow-up (p < 0.001). CS patients had a 2.82-fold higher risk of developing OSA (HR = 2.82; 95% CI: 1.67 4.77) in later life. DISCUSSION: Our study was the first longitudinal study to support the temporal association between CS and risk of OSA. Patients with CS were associated with an increased likelihood of OSA. Further studies would be required to investigate the exact underlying mechanisms between CS and OSA, and elucidate whether the prompt intervention for CS may reduce the risk of subsequent OSA. PMID- 28735921 TI - Frontal dysfunction in patients with restless legs syndrome performing a visual oddball task: an event-related potential source imaging study. AB - Restless legs syndrome (RLS) is a sensorimotor neurological disorder that is accompanied by the compelling urge to move one's legs, and unpleasant, disturbing sensations in the legs. Several neuropsychological studies have shown that RLS is associated with deficits in cognitive functions, such as attention, working memory, and frontal executive function, presumably due to abnormal frontal activities. However, the mechanism underlying the cognitive deficits in RLS patients is mostly unknown. To investigate the cortical origin of cognitive dysfunction in RLS, we analyzed the P2 and P3 event-related potential (ERP) components evoked by a visual oddball task using distributed cortical source localization via low-resolution brain electromagnetic tomography (LORETA) algorithm. A total of 17 female drug-naive RLS patients and 13 healthy volunteers were enrolled. Multichannel ERPs were recorded while performing a visual oddball task. We identified that the P2 and P3 ERP components were significantly reduced in RLS patients. These patients showed a reduction of the cortical current source densities in temporal periods corresponding to P2 and P3, compared to normal controls. Significant differences between RLS patients and normal controls were mainly found in the frontal region; that is, in the medial prefrontal cortex at the P2 epoch and the anterior cingulate cortex at the P3 epoch. Our neurophysiological results imply that the abnormal activities in the frontal region results in a cognitive deficit in RLS patients, which should be compared with neuropsychological evaluations in a further study. PMID- 28735922 TI - Prevalence of restless legs syndrome and associated factors in an otherwise healthy population: results from the Danish Blood Donor Study. AB - OBJECTIVE: Restless legs syndrome (RLS) is a neurological sensorimotor disorder characterized by uncomfortable sensations in the legs. RLS often occurs as a comorbid condition. Besides an increased risk of iron deficiency, blood donors are considered to be generally healthy. Blood donors are therefore an ideal population for studying factors associated with RLS occurrence, herein the role of iron. It is suggested that RLS is linked to sex, age, low socioeconomic status, unhealthy lifestyle, and iron deficiency. The objective of this study is therefore to estimate the RLS prevalence and identify associated biological, sociodemographic, economic, and lifestyle factors in a population of blood donors. METHODS: A total of 13,448 blood donors enrolled in the Danish Blood Donor Study from May 2015 to May 2016. RLS cases were identified using the validated Cambridge-Hopkins RLS-questionnaire. Logistic regression models were applied to assess the relationship between RLS and data on socially related factors collected using questionnaires and population registers. RESULTS: In this study, 7.2% women and 4.5% men were classified with RLS. RLS was associated with: female sex, high age, smoking, frequent alcohol consumption, and low education. RLS-related symptoms were associated with obesity, parity and donation intensity three years prior to inclusion among women. RLS was not related to: reduced plasma ferritin, employment status, and income. CONCLUSIONS: RLS is a frequent disorder in otherwise healthy individuals. The associations discovered in this study can be utilized in preventing or reducing RLS symptoms. PMID- 28735923 TI - Excessive daytime somnolence is associated with hypoglycemia in adult Latinos with type 2 diabetes mellitus. AB - OBJECTIVE: This study aimed to determine the frequency of sleep disorders in hypoglycemic diabetic patients and possible relationships with scores of sleep disorders and restless legs syndrome in mestizo population in Guayaquil, Ecuador. METHODS: A multicenter, cross-sectional study conducted at an outpatient endocrinology clinic in urban and rural Ecuador regions, included 290 participants with type 2 diabetes mellitus with severe hypoglycemic episodes, completed, validated, and culturally adapted sleep questionnaires to assess daytime sleepiness, risk of sleep apnea and restless legs syndrome. Logistic regression analysis was conducted to identify factors associated with severe hypoglycemia. RESULTS: The prevalence of EDS was 56.8%, RLS prevalence of 46.2%, and 38.6% prevalence of high risk Berlin score. Multivariate logistic regression indicated hypoglycemic T2DM in the range of 56-75 years old were more likely to have high ESS (p 0.0001). CONCLUSION: A high prevalence of sleep disorders in diabetic Latinos living in Ecuador was evidenced. The presence of somnolence in patients older than 56 years and high HbA1c levels should alert the clinician for the occurrence of hypoglycemic episodes. PMID- 28735924 TI - Obstructive sleep apnea: effect of comorbidities and positive airway pressure on all-cause mortality. AB - OBJECTIVE: Most studies have used cardiovascular and cerebrovascular disease (CVD) end-points to measure the effect of continuous positive airway pressure (CPAP), but pre-diagnostic morbidities involve a range of comorbidities that may influence the consequences of obstructive sleep apnea (OSA). We therefore aimed to evaluate all-cause total mortality after a diagnosis of OSA, the effect of CPAP in women and men, and the potential effect of major comorbidities. METHODS: We used national registry data as a historical cohort and included 22,135 OSA patients aged 20 years or more with comorbidity data three years before diagnosis and follow-up morbidity and mortality over a period of 17 years. RESULTS: A total of 8129 (37%) accepted CPAP for more than six months; 14,006 (63%) were CPAP non user/non-compliant. Those treated with CPAP tended to have higher mortality rates. Patients treated with CPAP were more likely to be male, elderly, suffer from diabetes, and present with more cardiovascular diseases than those not treated with CPAP. After a diagnosis of OSA, more patients in the CPAP-treated group developed cardiovascular complications. Female gender was associated with lower mortality, whereas age, diabetes type 2, and hypertension prior to OSA diagnosis were associated with negative effects on outcome. After an OSA diagnosis, male gender, age, diabetes (types 1 and 2), hypertension, and heart failure were all associated with greater mortality. CPAP treatment had a positive effect in middle-aged and elderly people, whereas CPAP in females had no effect on all-cause mortality. CONCLUSIONS: CPAP-treated patients present more comorbidities before and after diagnosis compared with non-treated/non-compliant patients, which explains the higher mortality in this group. CPAP treatment is associated with lower mortality rates in middle-aged and elderly (aged 60+ years) males, but only after adjustment for multiple comorbidities. No effect of CPAP treatment on all-cause mortality in female OSA patients was found. Males with OSA, older than 40 years, with comorbidities and a low educational level presented a particularly high mortality risk. PMID- 28735925 TI - Upper-airway flow limitation and transcutaneous carbon dioxide during sleep in normal pregnancy. AB - OBJECTIVE: Sleep during pregnancy involves a physiological challenge to provide sufficient gas exchange to the fetus. Enhanced ventilatory responses to hypercapnia and hypoxia may protect from deficient gas exchange, but sleep disordered breathing (SDB) may predispose to adverse events. The aim of this study was to analyze sleep and breathing in healthy pregnant women compared to non-pregnant controls, with a focus on CO2 changes and upper-airway flow limitation. METHODS: Healthy women in the third trimester and healthy non pregnant women with normal body mass index (BMI) were recruited for polysomnography. Conventional analysis of sleep and breathing was performed. Transcutaneous carbon dioxide (TcCO2) was determined for each sleep stage. Flow limitation was analyzed using the flattening index and TcCO2 values were recorded for every inspiration. RESULTS: Eighteen pregnant women and 12 controls were studied. Pregnancy was associated with shorter sleep duration and more superficial sleep. Apnea-hypopnea index, arterial oxyhemoglobin desaturation, flow-limitation, snoring or periodic leg movements were similar in the two groups. Mean SaO2 and minimum SaO2 were lower and average heart rate was higher in the pregnant group. TcCO2 levels did not differ between groups but variance of TcCO2 was smaller in pregnant women during non-rapid eye movement (NREM). TcCO2 profiles showed transient TcCO2 peaks, which seem specific to pregnancy. CONCLUSIONS: Healthy pregnancy does not predispose to SDB. Enhanced ventilatory control manifests as narrowing threshold of TcCO2 between wakefulness and sleep. Pregnant women have a tendency for rapid CO2 increases during sleep which might have harmful consequences if not properly compensated. PMID- 28735926 TI - Overlap Parasomnia Disorder in a case of Creutzfeldt-Jakob Disease. PMID- 28735927 TI - Predictors of sleep disturbances in the first year of life: a longitudinal study. AB - OBJECTIVE: The aim of this study was to identify early predictors of nocturnal awakenings and short sleep duration during the first year of life, in terms of sleep habits and patterns. We also analyzed the trend of nocturnal awakenings and total sleep duration from 3 to 12 months of age. METHODS: The parents of 704 infants (49.3% female) were interviewed during their first year of life. The interview included questions on infant sleep (eg, sleep habits, sleep duration, number of nocturnal awakenings) and maternal perception of infant sleep difficulties. RESULTS: The study results indicate that most of the infants at risk, with three or more nocturnal awakenings or <=10 h of total sleep duration in the early months of life, tend to display a similar pattern of sleep problems at 12 months. The main early predictors of sleep problems at 12 months were sleep duration, sleep initiation method, and nocturnal awakenings. More specifically, infants with three or more nocturnal awakenings or <=10 h of total sleep duration at 12 months were those with a higher number of awakenings during the night and a shorter sleep duration, at both three and six months. In addition, infants at risk for sleep problems at 12 months had an independent sleep initiation method at three months, whereas these same infants had a nonindependent sleep initiation method at six months. CONCLUSIONS: Our study identified the early predictors of sleep problems at 12 months. Caregivers should identify these early symptoms in infants to prevent possible sleep difficulties in later years. PMID- 28735928 TI - Efficacy and safety of almorexant in adult chronic insomnia: a randomized placebo controlled trial with an active reference. AB - BACKGROUND AND OBJECTIVES: The orally active dual OX1R and OX2R antagonist, almorexant, targets the orexin system for the treatment of primary insomnia. This clinical trial assessed the effect of almorexant on sleep maintenance and other sleep endpoints, and its safety and tolerability in adults. PATIENTS AND METHODS: Prospective, randomized, double-blind, placebo-controlled, active referenced trial in male and female adults aged 18-64 years with chronic, primary insomnia. Patients were randomized 1:1:1:1 to receive placebo, almorexant 100 mg, almorexant 200 mg, or zolpidem 10 mg (active reference) for 16 days. Primary efficacy assessments were objective (polysomnography-measured) and subjective (patient-recorded) wake time after sleep onset (WASO). Further sleep variables were also evaluated. RESULTS: From 709 randomized patients, 707 (mean age 45.4 years; 61.7% female) received treatment and 663 (93.8%) completed the study. A significant decrease versus placebo in median objective WASO was observed with almorexant 200 mg at the start and end of randomized treatment (-26.8 min and 19.5 min, respectively; both p < 0.0001); subjective WASO also decreased over the two-week treatment period (p = 0.0006). Objective and subjective total sleep time (TST) were increased with almorexant 200 mg (p < 0.0001). Almorexant 200 mg significantly reduced objective and subjective latency to persistent sleep and latency to sleep onset at initiation of therapy, and provided longer duration of sleep stages with no suppression of slow-wave sleep. No impaired next-day performance, rebound insomnia, or withdrawal effects were observed. Adverse events were similar with almorexant and placebo. CONCLUSION: Almorexant reduced time to sleep onset and maintained sleep without residual effects on next-day performance or safety concerns. This study provides further support for the role of the endogenous orexin system in insomnia disorder. CLINICALTRIALS. GOV REGISTRATION: NCT00608985. PMID- 28735929 TI - Electrophysiological and microstructural features of sleep in children at high risk for depression: a preliminary study. AB - OBJECTIVE: This preliminary study investigated electrophysiological and microstructural features of sleep in children and adolescents 4-18 years of age who were born to depressed mothers. METHODS: A total of 31 healthy subjects (15 male and 16 female) participated in the study. In this sample, 20 children born to mothers diagnosed with Major Depressive Disorder (MDD) were designated as "high-risk"; 11 children born to mothers without a personal history of depression were designated as "low-risk." Polysomnography including three-channel electroencephalography (EEG) was recorded for one night at the Pediatric Sleep Unit of the University Hospital of Lyon, France. Clinical and demographic data were collected. Sleep architectural parameters were analyzed. Sleep microstructure was assessed with the scoring of cyclic alternating pattern (CAP) and CAP measures were calculated. Spectral analysis was performed, and mean EEG band power was computed for each sleep stage. Sleep electrophysiological features (slow waves and sleep spindles) were detected, and related parameters were analyzed. Data were compared between high- and low-risk groups using Student t tests. RESULTS: A reduction in low-frequency spindle activity and slow spindles spatio-temporal characteristics over frontal and central derivations, and an altered distribution of CAP phase A subtypes (reduction of A1 over A2-3 ratio) were observed in the high-risk group relative to the low-risk group. CONCLUSION: Limited spindles generation and increased non-rapid eye movement sleep instability, observed in children born to depressed mothers, might reflect functional anomalies in cortical plasticity that could represent a pathogenic factor or an epiphenomenon for MDD. PMID- 28735930 TI - Brain atrophy in ageing: Estimating effects of blood glucose levels vs. other type 2 diabetes effects. PMID- 28735931 TI - Midterm Follow-up of Ureteral Embolization Using Vascular Plugs and N-Butyl Cyanoacrylate Glue. AB - This is a retrospective study of 9 consecutive female patients who underwent ureteral embolization via a "sandwich" technique with two vascular plugs and N butyl cyanoacrylate glue for ureteral fistulae unresponsive to urinary diversion. Average age was 61 years (range, 39-77 y), average duration of diversion was 48 days (range, 2-120 d), and average follow-up was 11 months (range, 4-23 mo). Seven patients (78%) experienced immediate resolution of urinary leakage, and the other 2 (22%) required unilateral repeat treatment for resolution of leakage. Symptom resolution lasted throughout the follow-up period for all patients. Bilateral internal iliac artery pseudoaneurysms developed in 1 patient and were treated with embolization and stent placement. PMID- 28735932 TI - Intercostal Hernia after Ablation of a Liver Tumor. PMID- 28735933 TI - Interventional Radiologists and Endovascular Therapy for Acute Ischemic Strokes. PMID- 28735934 TI - Percutaneous Lumen-Apposing Cholecystoduodenal Stent Insertion through a Pre existing Fistula for Internal Drainage of the Gallbladder in the Setting of Calculous Cholecystitis. PMID- 28735936 TI - Combined Surgical and Transhepatic Rendezvous Procedure for Relieving Anastomotic Biliary Obstruction in Children with Liver Transplants. AB - Four children (3 boys and 1 girl, age 1.4-9.4 y) presented 2-70 months after liver transplantation (mean 26 months) with high-grade narrowing at the surgical anastomosis that could not be crossed at percutaneous transhepatic cholangiography. Each patient was treated with a combined surgical and interventional radiology "rendezvous" procedure. Biliary drainage catheters were left in place for an average of 6 months after the procedure. At a mean 7.5 months after biliary drainage catheter removal, all children were catheter-free without clinical or biochemical evidence of biliary stricture recurrence. PMID- 28735935 TI - Catheter-Directed Thrombolysis in a Child with Bilateral Renal Artery Graft Thrombosis. AB - A 5-year-old boy with midaortic syndrome who had undergone aortic bypass and bilateral renal artery grafts presented to the emergency department 1 year after surgery with symptoms of nausea, vomiting, and abdominal pain. Because of delay in diagnosis of bilateral renal artery thrombosis, his condition progressed to anuric renal failure. He underwent catheter-directed thrombolysis 7 days after presentation with administration of tissue plasminogen activator and heparin infusion over a 24-hour period. There was successful resolution of thrombus and complete recovery of renal function to baseline. The patient had normal renal function at 6-month follow-up. PMID- 28735937 TI - Hemosuccus Pancreaticus. PMID- 28735938 TI - Women's Challenges in IR: #ILookLikeAnIR. PMID- 28735939 TI - Diagnostic Reference Levels Will Not Lead Us to "ALARA". PMID- 28735940 TI - Retrieval of a Long-Standing Inferior Vena Cava Filter Using the TightRail Rotating Dilator Sheath. PMID- 28735941 TI - Internal Coil Packing for Mesh Occlusion Device. PMID- 28735942 TI - Three-Dimensional to Three-Dimensional Image Fusion-Guided Thoracic Endovascular Aortic Repair without Iodine Injection. PMID- 28735943 TI - Percutaneous Plastic Stent Insertion for Treatment of Disconnected Pancreatic Duct. PMID- 28735944 TI - Case Report of Parabronchial Lung Metastasis Treated by Percutaneous Microwave Ablation in Combination with Bronchoscopic Endobronchial Saline Solution Cooling to Minimize Injury to a Bronchus. PMID- 28735945 TI - Invited commentary. PMID- 28735946 TI - Invited commentary. PMID- 28735947 TI - Invited commentary. PMID- 28735948 TI - Invited commentary. PMID- 28735949 TI - Hip flexor muscle dysfunction during walking at self-selected and fast speed in patients with aortoiliac peripheral arterial disease. AB - OBJECTIVE: Intermittent claudication aggravates physical function and is associated with an increased risk of death in patients with peripheral arterial disease (PAD). Previous studies on kinetic parameters (joint moment and power) of lower limbs in these patients have largely focused on the decline in the ankle plantar flexor moment and power at self-selected (SS) walking speed, which may not be an optimal condition to induce claudication pain. In the present study, we investigated the abnormalities in joint kinetic parameters in patients with PAD at both SS and at fast walking speeds. METHODS: We recruited 16 patients with aortoiliac PAD (4 unilateral and 12 bilateral) and 10 healthy controls. The participants were instructed to walk at SS and fast speeds along a 7-meter walkway embedded with a force plate. Spatiotemporal parameters and joint kinetic parameters of the lower limbs during the stance phase were recorded using a three dimensional motion analysis device. RESULTS: Compared with the controls, patients with PAD showed a significant reduction in their walking speed, step length, stride length, and cadence. Further, a reduction in peak hip flexor moment at fast walking speed and in peak hip flexor generation power was observed in both modes of walking. However, no significant between-group differences were observed for the peak ankle plantar flexor moment or power at either walking speed. Multiple regression analysis showed peak hip flexor generation power was a strong contributor to reduction at both SS and fast walking speeds in patients with PAD. CONCLUSIONS: Patients with aortoiliac PAD walk slowly and show reduced kinetic parameters of the hip joint at both SS and fast walking speeds. Our results suggest that hip flexor muscles may be a useful target for exercise training in patients with aortoiliac PAD. PMID- 28735950 TI - Associations between clinical diagnostic criteria and pretreatment patient reported outcomes measures in a prospective observational cohort of patients with neurogenic thoracic outlet syndrome. AB - OBJECTIVE: Neurogenic thoracic outlet syndrome (NTOS) is caused by dynamic compression of the brachial plexus at the level of the supraclavicular scalene triangle or the subcoracoid (pectoralis minor) space, or both. The purpose of this study was to characterize relationships between 14 clinical diagnostic criteria (CDC) and seven pretreatment patient-reported outcomes measures (PROMs) in a prospective cohort of patients with NTOS. METHODS: There were 183 new patient referrals between July 1 and December 31, 2015, with 150 (82%) meeting an established set of predefined CDC for NTOS. PROMs were evaluated across five domains: pain severity, functional disability, depression, quality of life, and pain catastrophizing. Linear regression and Pearson correlation statistics were used to analyze associations between CDC and PROMs. RESULTS: Mean +/- standard error patient age was 37.1 +/- 1.1 years (range, 12-66 years), and 107 (71%) were women. Five (3%) had a cervical rib, and 15 (10%) had recurrent NTOS. The most frequently positive CDC were neck or upper extremity pain (99%), upper extremity or hand paresthesia (94%), symptom exacerbation by arm elevation (97%), localized supraclavicular or subcoracoid tenderness to palpation (96%), and a positive 3 minute elevated arm stress test (94%; mean duration, 102.0 +/- 5.1 seconds). The number of positive CDC (mean, 9.6 +/- 0.1) correlated with the degree of tenderness to palpation and the duration of elevated arm stress test, as well as with PROMs for pain severity, functional disability, depression, physical quality of life, and pain catastrophizing (all P < .0001). PROMs across multiple domains were also strongly correlated with each other. Patients with clinically significant pain catastrophizing exhibited a greater level of functional disability than noncatastrophizing patients (P < .0001). CONCLUSIONS: This study illustrates the relative strengths of 14 CDC and seven PROMs to evaluate patients with NTOS, helping validate the selected CDC and highlighting the potential role of pain catastrophizing in functional disability. This cohort will provide valuable information on the utility of different CDC and PROMs to predict treatment outcomes. PMID- 28735952 TI - Invited commentary. PMID- 28735951 TI - Presentation, clinical features, and results of intervention in upper extremity fibromuscular dysplasia. AB - BACKGROUND: We present a case series of upper extremity fibromuscular dysplasia (UE FMD) consisting of 22 patients from two tertiary referral centers focusing on clinical presentation, diagnostic findings, and interventional outcomes. FMD is a noninflammatory, nonatherosclerotic arteriopathy that has a predisposition for middle-aged women. Involvement of the UE is thought to be rare. Patients with UE FMD can present with claudication or ischemia, or they can be incidentally diagnosed. The treatment approach is dictated by clinical presentation. METHODS: Data were collected of patients with UE FMD evaluated at two centers. Demographic data, presenting UE symptoms, UE arteries involved, FMD type, diagnostic method, physical examination findings, management, and outcomes were included. RESULTS: Twenty-two patients (29 limbs) were diagnosed with UE FMD. The brachial artery was most commonly involved (89.7% of affected limbs). More than half of limbs (n = 15 of 29 limbs [51.7%]) were asymptomatic, and of those who presented with symptoms, the most common symptoms were ischemic fingers or hand (31% of all affected limbs) and hand or arm claudication (27.6% of all affected limbs). UE FMD was noted on catheter angiography in 58.6% (n = 17 of 29 limbs), duplex ultrasound in 41.4% (n = 12 of 29 limbs), and computed tomography angiography in 27.6% (n = 8 of 29 limbs). Of the symptomatic limbs (n = 14), the majority were treated solely with medical therapy as the first intervention (57.1%). For symptomatic limbs treated with vascular intervention (n = 5), angioplasty was most commonly performed. Only 4 of the 14 limbs (28.6%) had complete symptomatic relief after the initial first intervention, in which 2 limbs were treated with medical therapy, 1 limb underwent angioplasty, and 1 limb had resolution of symptoms despite deferment of any therapy. Of the 10 limbs with residual symptoms after the first intervention, 6 limbs underwent a second intervention: angioplasty in 2 limbs initially treated medically (33.3%), surgical bypass in 2 limbs initially treated with angioplasty, surgical bypass in 1 limb initially treated with medical therapy, and sympathectomy in 1 limb (16.7%) initially treated with angioplasty. Both surgical bypass and angioplasty as secondary interventions resulted in complete symptom relief. CONCLUSIONS: Presenting symptoms for patients with UE FMD vary in severity from asymptomatic disease to digital ischemia. More than half of symptomatic limbs eventually require at least one invasive intervention for complete relief of symptoms. PMID- 28735953 TI - Twisting limbs after endovascular aortic aneurysm repair. PMID- 28735954 TI - Endarterectomy achieves lower stroke and death rates compared with stenting in patients with asymptomatic carotid stenosis. AB - BACKGROUND: It is currently unclear if carotid artery stenting (CAS) is as safe as carotid endarterectomy (CEA) for patients with significant asymptomatic stenosis. The aim of our study was to perform a systematic review and meta analysis of trials comparing CAS with CEA. METHODS: On March 17, 2017, a search for randomized controlled trials was performed in MEDLINE and Scopus databases with no time limits. We performed meta-analyses with Peto odds ratios (ORs) and 95% confidence intervals (CIs). Quality of evidence was assessed with the Grading of Recommendations Assessment, Development, and Evaluation method. The primary safety and efficacy outcome measures were stroke or death rate at 30 days and ipsilateral stroke at 1 year (including ipsilateral stroke and death rate at 30 days), respectively. Perioperative stroke, ipsilateral stroke, myocardial infarction (MI), and cranial nerve injury (CNI) were all secondary outcome measures. RESULTS: The systematic review of the literature identified nine randomized controlled trials reporting on 3709 patients allocated into CEA (n = 1479) or CAS (n = 2230). Stroke or death rate at 30 days was significantly higher for CAS (64/2176 [2.94%]) compared with CEA (27/1431 [1.89%]; OR, 1.57; 95% CI, 1.01-2.44; P = .044), with low level of heterogeneity beyond chance (I2 = 0%). Also, stroke rate at 30 days was significantly higher for CAS (63/2176 [2.90%]) than for CEA (26/1431 [1.82%]; OR, 1.63; 95% CI, 1.04-2.54; P = .032; I2 = 0%). MI at 30 days was nonsignificantly lower for CAS (12/1815 [0.66%]) compared with CEA (16/1070 [1.50%]; OR, 0.53; 95% CI, 0.24-1.14; P = .105; I2 = 0%); however, CNI at 30 days was significantly lower for CAS (2/1794 [0.11%]) than for CEA (33/1061 [3.21%]; OR, 0.13; 95% CI, 0.07-0.26; P < .00001; I2 = 0%). Regarding the long-term outcome of stroke or death rate at 30 days plus ipsilateral stroke during follow-up, this was significantly higher for CAS (79/2173 [3.64%]) than for CEA (35/1430 [2.45%]; OR, 1.51; 95% CI, 1.02-2.24; P = .04; I2 = 0%). Quality of evidence for all stroke outcomes was graded moderate. CONCLUSIONS: Among patients with asymptomatic stenosis undergoing carotid intervention, there is moderate-quality evidence to suggest that CEA had significantly lower 30-day stroke and also stroke or death rates compared with CAS at the cost of higher CNI and nonsignificantly higher MI rates. The long-term efficacy of CEA in ipsilateral stroke prevention, taking into account perioperative stroke and death, was preserved during follow-up. There is an urgent need for high-quality research before a firm recommendation is made that CAS is inferior or not to CEA. PMID- 28735955 TI - Current status of carbon dioxide angiography. AB - OBJECTIVE: Unfamiliarity of endovascular surgeons with carbon dioxide (CO2) angiography is one of the main reasons for its limited use. This review is intended to familiarize the reader with the principles and applications of that modality. METHODS: We conducted a comprehensive review of contemporary literature related to CO2 angiography and its use in the field of vascular and endovascular surgery, including technical details and diagnostic and interventional applications. RESULTS: Cardinal physicochemical characteristics of CO2 include buoyancy, ultralow viscosity, and nonmixing with blood. Because of the risk of neurotoxicity, intra-arterial CO2 angiography should only be performed below the diaphragm. Venous CO2 angiography can be performed anywhere in the torso and extremities. Ultralow viscosity enables intraprocedural imaging during vascular interventions without the need to exchange for an angiographic catheter. Benefits, advantages, and emerging applications of CO2 angiography are listed. Potential complications and their avoidance and troubleshooting are discussed. CONCLUSIONS: CO2 holds promise as an effective and versatile angiographic contrast agent. It is also a valuable modality for the guidance of endovascular interventions. Current availability of easy to use, safe, and portable CO2 delivery systems will likely expand the use of that modality even beyond the traditional indications of renal insufficiency and iodinated contrast allergy. PMID- 28735956 TI - Avoid the 4% penalty: Pace yourself into MIPS by October 2, 2017. PMID- 28735957 TI - Regarding "Standard endovascular aneurysm repair in patients with wide infrarenal aneurysm necks is associated with increased risk of adverse events". PMID- 28735958 TI - Reply. PMID- 28735959 TI - Regarding "Comparison of outcomes for double fenestrated endovascular aneurysm repair versus triple or quadruple fenestrated endovascular aneurysm repair in the treatment of complex abdominal aortic aneurysms". PMID- 28735960 TI - Reply. PMID- 28735961 TI - Binding of PmClipSP2 to microbial cell wall components and activation of the proPO-activating system in the black tiger shrimp Penaeus monodon. AB - Clip domain serine proteinases (ClipSPs) play an important role in the prophenoloxidase-activating (proPO) system. In the shrimp Penaeus monodon, the ClipSP PmClipSP2 has been previously shown to bind to microbial polysaccharides (LPS and beta-1,3-glucan) and likely activates the proPO system. To reveal the binding site of the PmClipSP2 protein, the N-terminal clip domain (Clip-PmClipSP) and C-terminal SP domain (SP-PmClipSP2) were separately cloned. The recombinant proteins were then assayed for their binding properties and involvement in proPO activation. According to the ELISA-based binding assay, rSP-PmClipSP2, but not rClip-PmClipSP, can bind immobilized LPS and beta-1,3-glucan as well as significantly activate PO activity. The binding site at the SP domain is proposed to have a pattern sequence (X-[PFY]-X-[AFILV]-[AFY]-[AITV]-X-[ILV]-X(5)-W-[IL]-X) that is located at the C-terminal region of the SP domain of PmClipSP2. Deletion of the pattern sequence abolished binding to LPS and beta-1,3-glucan. Conversely, a recombinant protein containing the pattern sequence (rPT-PmClipSP2-TRX) had the ability to bind to cell wall components, confirming that the pattern sequence at the C-terminus of PmClipSP2 is responsible for binding to microbes, subsequently leading to activation of the proPO cascade. PMID- 28735962 TI - Enhancement of antiviral capacity of transgenic silkworms against cytoplasmic polyhedrosis virus via knockdown of multiple viral genes. AB - Bombyx mori cytoplasmic polyhedrosis virus (BmCPV), a major pathogen of silkworms, causes serious economic losses in sericulture. The BmCPV genome contains 10 discrete dsRNA segments; among these, S1, S2, S3, S4, S6, and S7 encode virus structural proteins, whereas S5, S8, S9, and S10 encode nonstructural proteins. In an attempt to create an anti-BmCPV silkworm strain, we constructed transgenic RNAi vector pb-CNS for knockdown of S5, S8, S9, and S10, and pb-SNS targeting S1, S2, S4, S5, and S8. Transgenic silkworm line CNS and SNS were generated via microinjection of the practical diapause silkworm strain Furong. Following infection via the oral administration of a high dose of BmCPV, the mortality rates of the nontransgenic control, CNS, and SNS were 91%, 37%, and 41%, respectively. qPCR showed that the viral mRNA content in CNS and SNS was significantly lower than that in the nontransgenic line. The economic traits of CNS and SNS were not affected. These results suggest that the knockdown of multiple BmCPV genes significantly enhances the antiviral capacity of the silkworm. PMID- 28735963 TI - Selenium accelerates chicken dendritic cells differentiation and affects selenoproteins expression. AB - Selenium (Se) promotes immune cell differentiation and improves immune response. Antigen-presenting cells such as dendritic cells (DCs) play an important role in immune system, however, the impact of Se on DCs is still unclear. In this study, we successfully induced and cultured chicken DCs from peripheral blood mononuclear cells by incubating mononuclear cells with 50 ng/mL recombinant chicken granulocyte-macrophage colony stimulating factor and 10 ng/mL recombinant chicken interleukin-4 for total 9 days. In + Se group, we added 10-7 mol/L sodium selenite from the first day of cell culture. The results showed that Se supplementation expedited and increased the expression of cell surface markers including CD11c, CD40, CD86, and MHC II. Principal component analysis showed that the expression of selenoproteins SelW, SelK, Dio3, GPX1, GPX2, SelN, SelS, SelH in chicken DCs was highly correlated, and SelW had highest correlation with the cell surface markers MHC II and CD11c. In conclusion, Se accelerates the differentiation and maturation of chicken DCs. Se regulates the differentiation and maturation of chicken DCs by selenoproteins. Selenoproteins has closely correlated to surface markers of chicken DCs. PMID- 28735964 TI - Bovine A20 gene overexpression during bovine viral diarrhea virus-1 infection blocks NF-kappaB pathway in MDBK cells. AB - Viruses have developed cellular strategies to ensure progeny survival. One of the most interesting is immune camouflage, where the virus triggers a controlled intensity immune response that prevents total destruction of the infected cell, thus "winning time" for the virus. This study explored the regulatory contexts of the bovine A20 gene during bovine viral diarrhea virus (BVDV)-1 infection, using IL-8 as an immune-response sentinel molecule. Assessments were conducted through RT-qPCR, Western blotting, gene silencing/overexpression, luciferase assays, and the use of pharmacological inhibitors, among other approaches. The results demonstrated that a) BVDV-1 increased A20 levels in Madin-Darby bovine kidney cells, b) increased A20 led to decreased IL-8 expression, and c) the virus affected the NF-kappaB signaling pathway. Collectively, these data identify bovine A20 as a strong regulator of immune marker expression. In conclusion, this is the first report on BVDV-1 modulating bovine IL-8 activation through the NF kappaB/A20 pathway. PMID- 28735966 TI - Distribution and enrichment of trace metals in surface marine sediments in the Gulf of Pozzuoli and off the coast of the brownfield metallurgical site of Ilva of Bagnoli (Campania, Italy). AB - The distribution of metals in surface sediments of Gulf of Pozzuoli (GoP), embedding the former second Italian largest integrated steelworks of Bagnoli, was studied based on sediment dispersal, quality guidelines (SQGs) and quantitative pollution indices of the respective metals. As, Cd, Hg, Pb, Zn largely exceeded the limits. Hg had a mean of 5.8mg/kg, twentyfold higher the rule, accumulating primarily near Bagnoli site. The mean effective range quotient, m-ERM-Q, revealed a high potential for negative biological effects especially in the area nearby the Bagnoli site. The enrichment factor (EF) values were outstandingly high, >1.5 with values which were often >=100. The geoaccumulation index, Igeo, was very critical for Cr, Cu, Hg and Ni, showing an Igeo in the range of strongly polluted (45). The principal component analysis (PCA) and Pearson's correlation matrix (CM), excluded significant contribution from weathering products. PMID- 28735965 TI - Safety Profile and Immunologic Responses of a Novel Vaccine Against Shigella sonnei Administered Intramuscularly, Intradermally and Intranasally: Results From Two Parallel Randomized Phase 1 Clinical Studies in Healthy Adult Volunteers in Europe. AB - BACKGROUND: Approximately 164,000 deaths yearly are due to shigellosis, primarily in developing countries. Thus, a safe and affordable Shigella vaccine is an important public health priority. The GSK Vaccines Institute for Global Health (GVGH) developed a candidate Shigella sonnei vaccine (1790GAHB) using the Generalized Modules for Membrane Antigens (GMMA) technology. The paper reports results of 1790GAHB Phase 1 studies in healthy European adults. METHODS: To evaluate the safety and immunogenicity profiles of 1790GAHB, we performed two parallel, phase 1, observer-blind, randomized, placebo-controlled, dose escalation studies in France ("study 1") and the United Kingdom ("study 2") between February 2014 and April 2015 (ClinicalTrials.gov, number NCT02017899 and NCT02034500, respectively) in 18-45years old subjects (50 in study 1, 52 in study 2). Increasing doses of Alhydrogel adsorbed 1790, expressed by both O Antigen (OAg) and protein quantity, or placebo were given either by intramuscular route (0.059/1, 0.29/5, 1.5/25, 2.9/50, 5.9/100MUg of OAg/MUg of protein; study 1) or by intradermal (ID), intranasal (IN) or intramuscular (IM) route of immunization (0.0059/0.1, 0.059/1, 0.59/10MUg ID, 0.29/5, 1.2/20, 4.8/80MUg IN and 0.29/5MUg IM, respectively; study 2). In absence of serologic correlates of protection for Shigella sonnei, vaccine induced immunogenicity was compared to anti-LPS antibody in a population naturally exposed to S. sonnei. FINDINGS: Vaccines were well tolerated in both studies and no death or vaccine related serious adverse events were reported. In study 1, doses >=1.5/25MUg elicited serum IgG median antibody greater than median level in convalescent subjects after the first dose. No vaccine group in study 2 achieved median antibody greater than the median convalescent antibody. INTERPRETATION: Intramuscularly administered Shigella sonnei GMMA vaccine is well tolerated, up to and including 5.9/100MUg and induces antibody to the OAg of at least the same magnitude of those observed following natural exposure to the pathogen. Vaccine administered by ID or IN, although well tolerated, is poorly immunogenic at the doses delivered. The data support the use of the GMMA technology for the development of intramuscular multivalent Shigella vaccines. PMID- 28735967 TI - An undescribed species of putative Japanese Pyropia first appeared on the central coast of British Columbia, Canada, in 2015. PMID- 28735968 TI - Epidemiology and clinical features of Green pit viper (Trimeresurus trigonocephalus) envenoming in Sri Lanka. AB - Green pit viper is a venomous endemic snake in Sri Lanka. But little is known regarding its envenoming in the country. This study was carried out in order to find out epidemiology and clinical profile of its bites. A series of 17 patients with Sri Lankan Green pit viper (Trimeresurus trigonocephalus) bites was prospectively studied over 4 years. The mean age was 36 1/2 years (range 12-61 years) and comprised 14 (82%) males. Except one case, all bites occurred during day time (0600 h-1800 h) due to inadvertent provocation. In 13 cases (76%) bite took place in estates (tea or cinnamon) and 8 patients (47%) were estate workers. The bitten sites were upper limbs in 11 cases (65%) and lower limbs in 6 cases (35%). Ten patients (59%) brought the offending snake to the hospital and one patient was asymptomatic. Sixteen (94%) developed local envenoming features- 16 (94%) local pain and swelling, 6 (35%) local bleeding and lymphadenopathy and blistering in 4 (24%) patients. Systemic envenoming developed in 4 (24%) patients including 3 (18%) with coagulopathy that was treated with fresh frozen plasma. One (6%) patient developed bradycardia. Sri Lankan Green pit viper bites commonly occurs in estates and causes local envenoming frequently and coagulopathy occasionally. PMID- 28735969 TI - Temporal dynamics of reward anticipation in the human brain. AB - Reward anticipation is a complex process including cue evaluation, motor preparation, and feedback anticipation. The present study investigated whether these psychological processes were dissociable on neural dynamics in terms of incentive valence and approach motivation. We recorded EEG when participants were performing a monetary incentive delay task, and found a cue-P3 during the cue evaluation stage, a contingent negative variation (CNV) during the motor preparation stage, and a stimulus-preceding negativity (SPN) during the feedback anticipation stage. Critically, both the cue-P3 and SPN exhibited an enhanced sensitivity to gain versus loss anticipation, which was not observed for the CNV. Moreover, both the cue-P3 and SPN, instead of the CNV, for gain anticipation selectively predicted the participants' approach motivation as measured in a following effort expenditure for rewards task, particularly when reward uncertainty was maximal. Together, these results indicate that reward anticipation consists of several sub-stages, each with distinct functional significance, thus providing implications for neuropsychiatric diseases characterized by dysfunction in anticipatory reward processing. PMID- 28735970 TI - Blunted neural response to implicit negative facial affect in anorexia nervosa. AB - BACKGROUND: People with anorexia nervosa (AN) have difficulties in a wide range of social-emotional processes. Previous work suggests atypical involvement of the prefrontal cortex (PFC), amygdala, insula, and fusiform gyri during social emotional processing in AN. METHODS: Twenty women with AN and twenty healthy comparison (HC) women were presented with happy, fearful, and neutral faces during a functional magnetic resonance imaging study. Group differences were investigated in the following regions of interest: lateral PFC, amygdala, insula, and fusiform gyri. RESULTS: The HC participants showed significantly increased recruitment of the ventrolateral PFC and amygdala in the fearful > neutral contrast relative to the AN participants. The AN participants showed a significantly increased recruitment of a small cluster in the right posterior insula in the happy > neutral contrast. CONCLUSIONS: These findings are in line with the hypothesis that people with AN have a blunted response to negative and atypical exaggerated response to positive emotionally provoking stimuli. PMID- 28735971 TI - "Lacking warmth": Alexithymia trait is related to warm-specific thermal somatosensory processing. AB - Alexithymia is a personality trait involving deficits in emotional processing. The personality construct has been extensively validated, but the underlying neural and physiological systems remain controversial. One theory suggests that low-level somatosensory mechanisms act as somatic markers of emotion, underpinning cognitive and affective impairments in alexithymia. In two separate samples (total N=100), we used an established Quantitative Sensory Testing (QST) battery to probe multiple neurophysiological submodalities of somatosensation, and investigated their associations with the widely-used Toronto Alexithymia Scale (TAS-20). Experiment one found reduced sensitivity to warmth in people with higher alexithymia scores, compared to individuals with lower scores, without deficits in other somatosensory submodalities. Experiment two replicated this result in a new group of participants using a full-sample correlation between threshold for warm detection and TAS-20 scores. We discuss the relations between low-level thermoceptive function and cognitive processing of emotion. PMID- 28735973 TI - In vitro study on the regulation of cellular mRNA levels by changes in transcription rate and transcript stability in fish red blood cells. AB - The interplay of transcriptional and post-transcriptional processes in the regulation of gene expression has been extensively studied in mammals but little is known in other vertebrates so far. Most non-mammalian vertebrates are faced with environmental cues and stressors distinct from those experienced by mammals and thus it is likely that the gene expression strategies differ from those of mammals. Here we performed experiments to study in vitro the various levels of gene expression regulation in nucleated fish red blood cells. Three critical environmental cues frequently experienced by fish were chosen: exposure to hypoxia (2.5%), ambient water temperature increase by 10 degrees C (from 10 degrees C to 20 degrees C), and exposure to stress hormones (represented by the beta-adrenergic agonist isoproterenol). We found that beta-adrenergic stimulation increases the stability of the beta3b-adrenergic receptor (beta3b-ar) mRNA, suggesting that mRNA stability can play a role in the regulation of hormonal stress responses in fish. The beta3b-ar gene encodes a unique beta-adrenergic receptor subtype in fish red blood cells which controls the beta-Na+/H+ exchanger activity - an important component of responses to oxygen limitations. Our results furthermore show a yet undescribed link between the Hif1a signaling pathway and the beta-adrenergic receptor response. After beta-adrenergic stimulation, the transcription of hif1a was activated significantly after 4 hours of exposure. So far, such a response has only been described from mammalian species. This indicates that the beta-AR is fundamental to the molecular and physiological responses to hypoxia and that Hif1a might have additional functions than those already known. PMID- 28735974 TI - Characteristics of six small heat shock protein genes from Bactrocera dorsalis: Diverse expression under conditions of thermal stress and normal growth. AB - To explore the functions of small heat shock proteins (sHsps) in relation to thermal stress and development in Bactrocera dorsalis (Hendel), one of the most economically important pest species attacking a wide range of fruits and vegetables, six full-length cDNAs of sHsp genes (BdHsp17.7, 18.4, 20.4, 20.6, 21.6 and 23.8) were cloned, and the expression patterns in different developmental stages and tissues, as well as in response to both thermal and 20 hydroxyecdysone (20E) exposures, were examined using real time quantitative PCR. The open reading frames (ORFs) of six sHsps are 453, 489, 537, 543, 567 and 630bp in length, encoding proteins with molecular weights of 17.7, 18.4, 20.4, 20.6, 21.6 and 23.8kDa, respectively. BdHsp18.4 and BdHsp20.4 maintained lower expression levels in both eggs and larvae, whereas remarkably up-regulated after the larval-pupal transformation, suggesting that these two sHsps may be involved in metamorphosis. Significant tissue specificity exists among sHsps: the highest expression of BdHsp20.6 and BdHsp23.8 in the Malpighian tubules and ovary, respectively, versus a peak in the fat body for others. BdHsp20.4 and BdHsp20.6 were significantly up-regulated by thermal stress. In contrast, BdHsp18.4 and BdHsp23.8 reacted only to heat stress. BdHsp17.7 and BdHsp21.6 were insensitive to both heat and cold stresses. The degree of sHsps response depends on intensity of 20E treatment, i.e., dose and time. These results strongly suggest functional differentiation within the sHsp subfamily in B. dorsalis. The physiological function of sHsp members under thermal stress and normal growth remains the subjects of further investigation. PMID- 28735975 TI - Molecular characterization and expression profiles of myosin essential light chain gene in the Pacific oyster Crassostrea gigas. AB - In molluscs, muscle contraction is triggered by a direct binding of Ca2+ to myosin. The myosin essential light chain (MELC) provides the Ca2+ binding site and is of importance for motor function and regulation. In this study, the complete cDNA sequence of MELC gene of the Pacific oyster, Crassostrea gigas, was obtained, and the expression profiles were performed in different tissues and different embryo-larval development stages. The results showed that the full length of C. gigas MELC (CgMELC) cDNA was 659bp, containing a 5'-untranslated region of 73 bp, a 3'-untranslated region of 112bp. The open reading frame encoded a 157 amino acid peptide. The protein sequence of CgMELC contained a conserved EF-hand calcium binding motif, and showed a high sequence identity (68.4-100%) with other bivalves. Quantitative analysis of CgMELC mRNA in tissues indicated that CgMELC was expressed at the highest level in the striated adductor muscle, followed by the smooth adductor muscle and mantle. During the development of embryos and larvae, quantitative analysis and whole-mount in situ hybridization revealed that CgMELC was expressed starting from the blastula stage and abundantly expressed in trochophore and D-shaped larvae, indicating that CgMELC might also be involved in regulation of larval muscle system development. Our data provided valuable information for further researches on the function of MELC and regulation of muscle contraction in oysters. PMID- 28735976 TI - Predictive value of procalcitonin for intestinal ischemia and/or necrosis in pediatric patients with adhesive small bowel obstruction (ASBO). AB - PURPOSE: Evaluate serum procalcitonin (PCT) level as a predictor of intestinal ischemia or necrosis (IN) in patients with postoperative adhesive small bowel obstruction (ASBO). METHODS: Prospective cohort of consecutive patients with ASBO. Patients previously treated with antibiotics or septic were excluded. PCT was measured at the diagnosis of ASBO and every 24 h afterwards. MAIN OUTCOME: intestinal ischemia or necrosis (IN). RESULTS: Fifty-nine patients were included, 12 of whom were excluded; 47 patients remained in the study; male-to-female ratio = 1.9:1. MANAGEMENT: medical in 15 cases (32%) and surgical in 32 (68%). MAIN OUTCOME: Intestinal necrosis (IN) in 10 patients (21.3%). Mean PCT level was higher in patients with IN (15.11 ng/ml vs. 0.183 ng/ml, p=0.002), the proportion of patients with elevated PCT (>0.5 ng/dl) was higher in patients with IN (70% vs. 8.1%, p=<0.001, RR=26.4 with a 95% CI of 4.39-159.5). Elevated PCT levels at diagnosis had a 70% positive predictive value (PPV) and 91.8% negative predictive value (NPV) for prediction of IN. With a PCT value at diagnosis of >1.0 ng/dl, PPV was 87.5% and NPV, 92.3%. CONCLUSIONS: PCT levels are closely related to the presence of intestinal ischemia and necrosis in children with ASBO. LEVEL OF EVIDENCE: Study of Diagnostic Test, Level II. PMID- 28735977 TI - Isolated fallopian tube torsion with hydrosalpinx: Review of a debated management in a pediatric population. AB - PURPOSE: To quantify our experience with and assess the literature on diagnosis and management of isolated fallopian tube torsion (IFTT) with hydrosalpinx (HSX) in children. METHODS: A PubMed search was performed on pediatric cases of IFTT with HSX to provide a comprehensive review analyzing details and management of this association, focusing on the problem of fertility preservation. RESULTS: In addition to our 3 cases, 17 patients of pediatric IFTT associated with HSX were identified, for a total of 21 cases (median age 12.2 years). Menarchal status was present in 10/13 (76.9%); blood tests were reported in 9/20 (42%) showing leucocytosis in 7/9 (75%). Ultrasonography was performed in all cases except one. Laparoscopy was the surgical approach in 84.6% of the reported cases. The torsion was to the right in 36.8%, and to the left in 63.2% of the cases. In one case the torsion was bilateral and asynchronous. Performed procedures were salpingectomy (52.4%) and partial salpingectomy (14.3%); conservative management was reported in 33.3% of the cases. CONCLUSIONS: The literature describes different management techniques. Salpingectomy is the most frequently performed procedure but recently conservative management seems to be increasingly applied. A long-term study is necessary to define the most effective treatment for the preservation of future fertility in pediatric patients. TYPE OF STUDY: Treatment study (Retrospective Study): LEVEL IV. PMID- 28735978 TI - Ventilator-Induced Hiccups. PMID- 28735972 TI - Pyrimidine metabolism in schistosomes: A comparison with other parasites and the search for potential chemotherapeutic targets. AB - Schistosomes are responsible for the parasitic disease schistosomiasis, an acute and chronic parasitic ailment that affects >240 million people in 70 countries worldwide. It is the second most devastating parasitic disease after malaria. At least 200,000 deaths per year are associated with the disease. In the absence of the availability of vaccines, chemotherapy is the main stay for combating schistosomiasis. The antischistosomal arsenal is currently limited to a single drug, Praziquantel, which is quite effective with a single-day treatment and virtually no host-toxicity. Recently, however, the question of reduced activity of Praziquantel has been raised. Therefore, the search for alternative antischistosomal drugs merits the study of new approaches of chemotherapy. The rational design of a drug is usually based on biochemical and physiological differences between pathogens and host. Pyrimidine metabolism is an excellent target for such studies. Schistosomes, unlike most of the host tissues, require a very active pyrimidine metabolism for the synthesis of DNA and RNA. This is essential for the production of the enormous numbers of eggs deposited daily by the parasite to which the granulomas response precipitates the pathogenesis of schistosomiasis. Furthermore, there are sufficient differences between corresponding enzymes of pyrimidine metabolism from the host and the parasite that can be exploited to design specific inhibitors or "subversive substrates" for the parasitic enzymes. Specificities of pyrimidine transport also diverge significantly between parasites and their mammalian host. This review deals with studies on pyrimidine metabolism in schistosomes and highlights the unique characteristic of this metabolism that could constitute excellent potential targets for the design of safe and effective antischistosomal drugs. In addition, pyrimidine metabolism in schistosomes is compared with that in other parasites where studies on pyrimidine metabolism have been more elaborate, in the hope of providing leads on how to identify likely chemotherapeutic targets which have not been looked at in schistosomes. PMID- 28735979 TI - Using Functional Magnetic Resonance Imaging to Detect Preserved Function in a Preterm Infant with Brain Injury. AB - We studied developmental plasticity using functional magnetic resonance imaging (fMRI) in a preterm infant with brain injury on structural MRI. fMRI showed preserved brain function and subsequent neurodevelopment was within the normal range. Multimodal neuroimaging including fMRI can improve understanding of neural plasticity after preterm birth and brain injury. PMID- 28735980 TI - Amoxicillin Is the Most Cost-Effective Therapy for Acute Otitis Media: The Culmination of 40 Years of Research. PMID- 28735981 TI - Autoimmune Liver Disease in Children with Sickle Cell Disease. AB - OBJECTIVE: To assess the incidence, clinical features, and outcome of autoimmune liver disease (AILD) in patients with sickle cell disease (SCD). STUDY DESIGN: Single center retrospective review of patients with SCD with AILD referred between 1999 and 2015. RESULTS: Thirteen of 77 (17%) patients with SCD with hepatic dysfunction were diagnosed with AILD (median age 11, range, 3.4-16 years) with a female preponderance (77%). Acute hepatitis and insidious onset were the commonest presentations. Two patients (15%) presented with acute liver failure. In 2 patients (15%), parvovirus B19-induced transient red cell aplasia preceded the diagnosis of AILD. All patients were positive for antinuclear and/or smooth muscle autoantibodies. Six of 12 patients (50%) had cholangiopathy on cholangiogram suggesting autoimmune sclerosing cholangitis (ASC). Liver biopsy, performed in 11 patients without complications, showed interface hepatitis in 90%. Patients with AILD were treated with standard immunosuppression. After a median follow-up of 3.8 years (range, 0.2-14.3), 10 patients are alive (1 was transplanted 6.4 years after diagnosis); 2 are lost to follow-up; 1 died of subdural hemorrhage before starting treatment for AILD. Five (42%) achieved full and 4 (33%) partial biochemical remission. Ulcerative colitis, present in 4 patients (2 male patients, 3 with ASC) was diagnosed in 2 patients before and in 2 patients after the diagnosis of AILD. CONCLUSIONS: AILD is not uncommon in patients with SCD, affecting mainly female patients and responding satisfactorily to immunosuppressive treatment. Liver biopsy is helpful in confirming the diagnosis and can be safely performed in the absence of acute vaso-occlusive sickling episodes. Ulcerative colitis is common in the presence of ASC. PMID- 28735982 TI - A Standardized Donor Designation Ratio to Assess the Performance of Driver's License Agencies. AB - Evaluating Department of Motor Vehicles (DMV) locations based on the percent of patrons who register as donors does not account for individual characteristics that may influence willingness to donate. We reviewed the driver's licenses of 2997 randomly selected patients at an urban medical system to obtain donor designation, age, gender, and DMV location and linked patient addresses with census tract data on race, ethnicity, income, and education. We then developed a Standardized Donor Designation Ratio (SDDR) (ie, the observed number of donors at each DMV divided by the expected number of donors based on patient demographic characteristics). Overall, 1355 (45%) patients were designated as donors. Donor designation was independently associated with younger age, female gender, nonblack race, and higher income. Across 18 DMVs, the proportion of patients who were donors ranged from 30% to 68% and SDDRs ranged from 0.82 to 1.17. Among the 6 facilities in the lowest tertile by SDDR, 3 were in the lowest tertile by percent donation. In conclusion, there is a great deal of variation across DMVs in rates of organ donor designation. SDDRs that adjust for DMV patron characteristics are distinct measures that may more accurately describe the performance of DMVs in promoting organ donation. PMID- 28735983 TI - Factors Influencing the Willingness of Allied Health Students to Donate Organs or Tissues. AB - BACKGROUND: There has been an increase in the number of patients waiting for organ transplantation. METHODS: A questionnaire on knowledge and attitude toward organ donation was completed by 434 allied health students. RESULTS: Overall knowledge about the various aspects of organ donation was adequate and was higher among women and clinical students. Although the majority were willing to be living donors for their families, very few students supported deceased organ donation, and even fewer of them had thought about an organ donation card. Despite the good knowledge, an overall positive attitude toward deceased donation was held by only 44% of the students. In contrast, the attitude toward directed living organ donation to family members was favorable in 83.1% of the respondents, which seems to be influenced by cultural and sociodemographic factors. Our findings indicate that the most frequent cause of refusal to donate organs among students with negative attitudes was the mistrust of medical staff regarding brain death diagnosis (49.9%), followed by bodily concerns (18.1%) and religion (9.9%). Quite a few of our respondents supported commercial donation, which was attributed to the less knowledgeable groups. Respondents who were willing to donate organs indicated that the reason was for helping others and sympathy. This study identified that the main source of information about organ donation for the respondents was television, followed by relatives/friends and the internet. CONCLUSIONS: The misconception of the students toward deceased donation needs to be improved by integrating the concepts of brain death within the curriculum of allied health students. PMID- 28735984 TI - Preliminary Analysis of Competency Assessment of Organ Donation Coordinators in Hunan Province, China. AB - BACKGROUND: The organ donation coordinator is indispensable in the process of organ donation and transplantation. The competency of coordinators is closely related to the organ donation rate. OBJECTIVE: 1) To construct a competency assessment system for organ donation coordinators; and 2) to evaluate the competency level of coordinators in Hunan province. METHODS: We constructed the competency model framework for coordinators based on the McClelland competency model and then extracted and screened the competency indicators by interview and Delphi methods. Next, we determined the weight of the indicators by an analytic hierarchy process method. Finally, we evaluated the competency level of 42 coordinators in Hunan province with the use of our assessment system. RESULTS: 1) We constructed the competency evaluation system for organ donation coordinators, which included 6 dimensions and 21 competency indicators. 2) The average competency score of 42 coordinators was 79.43 +/- 8.51. Five coordinators were at qualified level (11.9%), 18 at moderate level (42.9%), 12 at good level (25.6%), and 7 at excellent level (16.7%). CONCLUSIONS: 1) This competency evaluation system for organ donation coordinators will provide scientific evidence for human resource management in health institutions. 2) The organ donation coordinators in Hunan were qualified, but their number was insufficient. PMID- 28735986 TI - Challenges for the Travelling Donor: Variability Between Donor Workup and Donor Surgery in the Canadian Kidney Paired Exchange Program. AB - BACKGROUND: A primary obstacle to providing renal transplantation is limited access to donated kidneys. The living-donor pool for renal allografts was greatly expanded through implementation of a kidney paired donation program. Whereas some programs ship donor kidneys to the site of renal transplantation, others send the donor to the site of transplantation. Performing the nephrectomy and transplantation at the same location may optimize functional renal outcomes, but preferred surgical approaches may differ between surgical teams performing the donor workup and donor surgery. Our objective was to identify incongruence between the surgery planned by the team that performed the donor's workup, and the surgery that took place at the site of donation. METHODS: A retrospective chart review was performed between the site of preoperative surgical planning, and the site of surgery for kidney donors in the Canadian kidney paired donation program. RESULTS: Fifty-one donors were preoperatively prepared in any of six Canadian provinces, and then underwent surgery in a different province. The surgical procedure performed for 31% of the patients' nephrectomies differed from the procedure suggested by the surgical team who conducted the preoperative workup. Half of these differences were between left laparoscopic and left laparoscopic hand-assisted, but the remainder included more substantial changes of sides and/or laparoscopic versus open procedures. CONCLUSION: Optimal patient care is challenged in a kidney paired donation program that uses the "traveling donor" approach due to differing surgical techniques selected by the surgeon at the site of donor workup and the surgeon at the site of donation. PMID- 28735985 TI - Attitude and Impact Factors Toward Organ Transplantation and Donation Among Transplantation Nurses in China. AB - BACKGROUND: Health workers' awareness and knowledge of transplantation medicine can improve people's sensitivity and reduce their degree of opposition to donations. The medical literature contains numerous examples of attitudes toward organ transplantation and donation aimed at university students or medical staff members, but rarely for transplantation nurses. OBJECTIVE: The purposes of the study were to investigate the attitudes toward organ transplantation and donation among transplantation nurses and to explore the impact factors. METHODS: The study was conducted in 37 transplantation surgery wards in 22 hospitals using cross-sectional approach. SPSS (International Business Machines Corporation, Armonk, New York, USA) 7.0 software was used to analysis descriptive and inferential statistics for data. RESULTS: Five hundred thirty-six effective questionnaires were received and the effective rate was 89.33%. Nurses' mean age was 28.40 years with a mean service length of 6.54 years. Among these nurses, 66.6% and 78.0% were willing to accept organ transplantation surgery for themselves and their relatives, respectively. Of these nurses, 33.4% would donate their organs after death; whereas 39.9% were uncertain. Only 38.2% were willing to register in the national organ donation system. Of these nurses, 28.2% were willing to sign the organ donation consent forms when their relatives became potential organ donors, and 45.7% were uncertain. Eight independent variables that affected nurses' attitudes toward donating their organs from most to least significant were: ratio of nurse to bed, title, employment form, age, length of service, position, monthly income, and the highest educational degree earned. Pearson correlation analysis showed a significant correlation among nurses' attitudes toward organ transplantation, organ donation, and online registration. CONCLUSION: The attitude toward donation and transplantation in the hospitals was not too optimistic, and an improvement in the training regarding transplantation and donation among nurses in China is necessary. Nurses are an important group who generate opinion in the patient population, and their negative attitudes can have a significant negative impact on society's attitudes toward organ donation. PMID- 28735987 TI - Estimated Nephron Number of the Donor Kidney: Impact on Allograft Kidney Outcomes. AB - BACKGROUND: Low birth weights have been associated with a reduction in nephron number with compensatory hypertrophy of existing glomeruli. The impact of donor birth weight as an estimate of nephron number on allograft function, however, has not been examined. METHODS: We collected donor birth weight, kidney weight, and volume from 91 living kidney donor-recipient pairs before nephrectomy and after 12, 36, and 60 months. Nephron number was calculated from donor birth weight and age. RESULTS: Donor birth weight, kidney weight/body surface area (BSA), and kidney volume showed a moderate positive correlation with allograft estimated glomerular filtration rate (eGFR) at 12 months (P < .05). Donor age showed a negative moderate correlation with allograft eGFR at 12 months (P = .015). The strongest correlation with allograft eGFR was observed for calculated donor kidney nephron number at 12, 36, and 60 months (R, 0.340, 0.305, and 0.476, respectively; P < .05). No impact was observed on allograft daily proteinuria of any investigated marker (P > .05). Recipients of donors with birth weight <2.5 kg had need of a significantly greater number of antihypertensive drugs (P < .05). CONCLUSIONS: Calculated nephron number from donor birth weight and age is suggested to be superior to donor kidney weight/BSA and volume regarding allograft function. Calculated nephron number could estimate expected eGFR and guide decision making in cases of impaired allograft function. PMID- 28735988 TI - Comparison of Both Sides for Retroperitoneal Laparoscopic Donor Nephrectomy: Experience From a Single Center in China. AB - BACKGROUND: Laparoscopic donor nephrectomy (LDN) has gradually become the main approach to obtain live donor kidneys. However, the shorter right renal vein limits its wider application. The aim of this study was to compare the outcomes of left- and right-side retroperitoneal LDN. METHODS: We reviewed the perioperative data of 527 consecutive donors receiving retroperitoneal pure LDN with a new method at our center between April 2009 and April 2014. The patients were divided into group A (the first 100 patients) and group B (the remaining 427 patients). A total of 423 cases of left donor surgery and 104 cases of right donor surgery were compared. The comparison of the laterality of LDN was also performed between group A and group B. RESULTS: This is currently the largest case series of LDN in our country. Although right-side LDN patients had longer operation time and a slightly higher incidence of intraoperative complications compared with left-side LDN patients, the operation time was shorter in both the groups compared with previous reports. In group B, patients undergoing right-side LDN had longer operation time and more frequent complications. Once the learning curve of 100 cases was completed, the incidence of complications and operation time were greatly reduced in both sides for LDN. There was no significant difference in the serum creatinine levels in recipients at 6 months of follow-up. CONCLUSIONS: Despite a slightly higher incidence of complications and longer operation time, right-side LDN can achieve equally safe and effective transplantation outcomes. This expands the source of potential donor kidneys. PMID- 28735989 TI - Outcome of Pretransplantation Therapeutic Plasma Exchange in Highly Sensitized Deceased-donor Kidney Transplant Recipients. AB - BACKGROUND: Sensitization is associated with a high rate of post-transplantation rejection. A desensitization protocol using therapeutic plasma exchange (TPE) was proposed to reduce anti-HLA antibody before transplantation, but there has been limited data regarding the efficacy of pretransplantation TPE in highly sensitized deceased-donor kidney transplantation (DDKT). METHODS: A retrospective cohort study of 142 patients who received DDKT was conducted and divided into two groups: a high-panel-reactive antibody (PRA) >50% group and a low-PRA <=50% group. The high-PRA group was sub-divided into those who received and did not receive pretransplantation TPE. Donor-specific anti-HLA antibodies (DSA) were also collected pretransplantation in the high-PRA group. RESULTS: The probability of acute rejection was 26, 4, and 9 cases/1000/person month in the high-PRA group with no TPE, the high-PRA group receiving TPE, and the low-PRA group, respectively (P = .0208). In the multivariable logistic regression analysis, the hazard ratio for graft rejection was 2.37 (95% confidence interval: 0.89 to 6.35) and 2.22 (95% confidence interval: 0.54 to 9.13) in the group of high-PRA who received TPE and high-PRA with no TPE, compared with the low-PRA group, respectively (P value not significant). The incidence of antibody-mediated rejection in 6 months in the DSA-positive subgroup was not different between those who received TPE or no TPE. CONCLUSION: Desensitization with TPE is a reasonable alternative for highly sensitized DDKT. Patients who received pretransplantation TPE had a lower incidence of acute rejection compared to the group that did not receive TPE. However, pretransplantation TPE alone was not effective in the prevention of acute rejection in recipients with DSA. PMID- 28735990 TI - Echocardiographic Pulmonary Hypertension Predicts Post-transplantation Renal Allograft Failure. AB - BACKGROUND: Pulmonary hypertension in the setting of renal transplantation has been associated with early allograft dysfunction and increased mortality, but this relationship has not been extensively studied. METHODS: We performed a retrospective cohort study of adult patients who underwent their first renal transplantation in the years 2003-2009 and had pre-transplantation echocardiograms. Pulmonary hypertension was defined as right ventricular systolic pressure >=40 mm Hg in the absence of left-sided valvular disease and/or left ventricular ejection fraction <=50%. Eighty-two of 205 patients (40%) met the inclusion criteria. The relationship between pulmonary hypertension and death censored allograft failure (hemodialysis dependence or retransplantation) and serum creatinine was assessed with the use of Cox hazard regression and generalized mixed models. RESULTS: The presence of pulmonary hypertension was associated with a 3-fold increase in the risk of death-censored allograft failure (95% confidence interval, 1.20-7.32; P = .02). Failure rates were 19% at 24 months and 51% at 96 months for those with pulmonary hypertension versus 7% at 24 months and 20% at 86 months for those without pulmonary hypertension (P = .01). Among those without graft failure, there was an increase in creatinine levels after transplantation (P = .01). Effect estimates were unchanged by adjustment for multiple covariates and when pulmonary hypertension was defined as right ventricular systolic pressure >=36 mm Hg. CONCLUSIONS: Pulmonary hypertension before renal transplantation carries a 3-fold increased risk of death-censored allograft failure. The relationship between the pulmonary circulation and renal allograft failure warrants further study. PMID- 28735991 TI - Lack of Impact of Hyperchloremia in Brain-Dead Organ Donors on the Onset of Kidney Allograft Function in the Recipients. AB - BACKGROUND: Hyperchloremia produces renal vasoconstriction and fall in glomerular filtration rate. In 90% of brain-dead organ donors, diabetes insipidus develops, characterized by inappropriate diuresis, hyperosmolality, and hyperchloremia. The aim of this study was to determine the relationship between the serum concentration of chlorides of the donor and the onset of the function of the kidney allograft in the recipient. METHODS: We retrospectively studied 213 donors and kidney allograft recipients. Serum creatinine concentrations and glomerular filtration rates on the 1st, 7th, and 30th days after transplantation of the recipients from hyperchloremic donors were compared with the recipients from normochloremic donors, as well as the incidences of acute tubular necrosis and delayed graft function. RESULTS: On the 1st day, serum creatinine concentrations of the recipients from hyperchloremic and normochloremic donors, respectively, were 448.2 +/- 212.1 MUmol/L and 502.2 +/- 197.8 MUmol/L (P = .1), on the 7th day, 168.6 +/- 102.6 MUmol/L and 196.9 +/- 120.6 MUmol/L (P = .13), and on the 30th day, 129.4 +/- 43.3 MUmol/L and 131.8 +/- 43.6 MUmol/L (P = .73). The differences were statistically significant. The groups also did not differ significantly in glomerular filtration rates and incidences of acute tubular necrosis and delayed graft function. CONCLUSIONS: In this study, no significant correlation between serum chloride concentrations of the organ donors and the onset of the function of kidney allografts in the recipients was found. PMID- 28735992 TI - Global Performance Status Score: A New Tool to Assess Physical Performance in Kidney Transplant Patients. AB - BACKGROUND: Information on physical performance in renal transplantation is limited because of the shortage of specifically designed evaluation instruments. Therefore, we elaborated and validated the Global Performance Status (GloPerSta) score to provide a new and comprehensive tool, exploring the different components of physical performance in kidney transplant patients. METHODS: We elaborated the GloPerSta score on the basis of the data obtained from a cross-sectional study, in which we evaluated the physical performance of a cohort of kidney transplant patients. The results of these analyses were weighted to describe the different contribution of any single test, via the generation of a structural equation model, resulting in the definition of the GloPerSta. Then, to internally validate this score, we studied its correlation with clinical parameters and quality of life (evaluated as KDQOL-SF, Kidney Disease Quality of Life-Short Form) in the same patient population. RESULTS: We enrolled 132 patients in whom the functional tests revealed a great heterogeneity. GloPerSta allowed the stratification of the patients in 3 different physical performance categories (low: score 0-11; medium: 12-22; high: 23-33). Internal validation showed that GloPerSta was directly and significantly correlated with the quality of life and allograft function, independent of the time from transplantation. CONCLUSIONS: The GloPerSta is a reliable tool to assess physical performance in a kidney transplant population. Its application might be of help in identifying patients needing intensive and personalized rehabilitation programs. PMID- 28735993 TI - Comparison of Clinical Outcomes Between Spousal and Living-related Donor Kidney Transplantation in Mainland China: A Single-center Experience. AB - Shortage of donors still is the major obstacle for kidney transplantation. Living related donors are the major resource of kidney transplantation at present. To expand the donor pool, spousal-donor kidney transplantation as one of the types of living-unrelated donors has been used to alleviate the organ shortage. A total of 116 living-kidney transplantations were retrospectively analyzed. We classified these recipients into two groups: a spousal-donor group (n = 50) and a living-related donor group (n = 66), and analyzed the outcome of transplantation. The Kaplan-Meier method was used for survival analysis with the log-rank test. The occurrence of delayed graft function and biopsy-proven acute rejection showed no significant difference between the two groups. Serum creatinine values at different times after transplantation in recipients with functioning grafts were similar in the two groups. Kaplan-Meier 3-year patient and graft survival rates were, respectively, 98% and 94% for the spousal donor group, and 98.5% and 95.5% for living-related donor group without significant difference. The demonstration of similar patient and graft survival of spousal-donor kidney transplantation compared with living-related donor kidney transplantation has made spousal-donor kidney transplantation an acceptable alternative for donor supply. PMID- 28735994 TI - Kidney Transplantation Using Gonadal Vein for Venous Anastomosis in Patients With Iliac Vein Thrombosis or Stenosis: A Series of Cases. AB - BACKGROUND: Kidney transplantation is the treatment of choice for patients with end-stage renal disease. The standard surgery uses the recipient's iliac vessels for vascular anastomosis. Thrombosis and/or stenosis of the iliac vein, which are possible complications of multiple vascular access points for dialysis, can be detected intraoperatively, constituting a surgical challenge. An infrequently reported option is the use of the gonadal vein. OBJECTIVES: This study aims to evaluate the outcomes of venous anastomosis in the gonadal vein in patients with iliac vein thrombosis and/or stenosis submitted to kidney transplantation. METHODS: We reviewed the records of five adult recipients with iliac vein thrombosis and/or stenosis detected intraoperatively during emergency kidney transplantation with deceased donor due to vascular access failure from February 2013 to December 2014. Antithrombotic prophylaxis was not performed. We evaluated the postoperative complications, length of stay, early graft echo-Doppler, and renal function during the first year postoperatively. RESULTS: Delayed graft function occurred in three cases. Two patients developed postoperative infection requiring antibiotics. One patient required reoperation due to post-renal biopsy complications. The mean length of stay was 31.2 days and the mean serum creatinine levels at discharge, at 6 months, and at 12 months postoperatively were 1.42 mg/dL, 0.86 mg/dL, and 0.82 mg/dL, respectively. All patients had normal ultrasonography. There were no losses of graft or deaths during follow-up. CONCLUSION: Venous anastomosis using the gonadal vein in kidney transplantation for patients with iliac vein thrombosis and/or stenosis showed good clinical and surgical results, showing this method to be a viable alternative to venous drainage in these complex patients. PMID- 28735995 TI - A Study on Adherence to Follow-up, Quality of Life, and Associated Factors Among Renal Transplant Recipients in China. AB - BACKGROUND: Adherence to follow-up is vital for the medical surveillance of the postoperative blood concentration, but relatively little research has examined it, and there is less study on relationships between adherence to follow-up and quality of life (QoL). We investigated the status of adherence to follow-up and QoL and associated factors among kidney transplantation recipients in China. METHODS: A cross-sectional study with the use of a Kidney Transplantation Recipient's Adherence to Follow-Up Questionnaire and a Quality of Life of Kidney Transplantation Recipients Questionnaire was conducted among 250 kidney transplantation recipients in Changsha, China, from January to March in 2015. RESULTS: The mean score for adherence to follow-up was 54.71 +/- 6.46. Time after transplantation was the only factor affecting adherence to follow-up scores (beta = -0.210; P < .05). The mean total score for QoL was 140.39 +/- 13.56; physical functioning, 23.72 +/- 3.33; psychologic functioning, 24.46 +/- 4.23; social functioning, 44.43 +/- 6.80; treatment, 24.81 +/- 2.97; and subjective satisfaction, 21.28 +/- 3.15. Multiple linear regression analysis showed that adherence to follow-up, economic level, job status, donor source, and original disease affected with QoL. CONCLUSIONS: Adherence to follow-up decreases with time after transplantation, and better compliance is associated with better QoL in all areas. Improvements in adherence to follow-up, income and reimbursement, psychologic guidance, and social support may increase QoL of kidney transplantat recipients. PMID- 28735996 TI - Effect of HLA Matching on Pediatric Renal Transplant Graft Survival in China. AB - INTRODUCTION: Kidney transplantation (KTX) has become one of the most effective therapies of choice for pediatric patients with end-stage renal disease (ESRD). The extent to which HLA mismatching influences graft survival following KTX has not been clarified. PATIENTS AND METHODS: The effect of HLA amino acid residue matching on graft survival was assessed in 36 pediatric patients in whom complete donor-recipient HLA data were available. HLA-A, -B, -DR and HLA-A+B+DR loci residue mismatches were separately analyzed. RESULTS: HLA-A, -B, -DR residue mismatches showed no significant statistical differences on kidney graft survival probability. When analyzing HLA-A+B+DR loci residue mismatches, the presence of 3 to 4 residue mismatches significantly increased the relative risk of graft rejection (P = .0292). PMID- 28735997 TI - Feasibility of BK Virus Real-Time PCR Testing in Renal Graft Biopsies With Negative SV40 Staining. AB - BACKGROUND: BK virus (BKV)-associated nephropathy (BKVAN) is often associated with renal graft dysfunction. When renal transplant recipients present with high clinical suspicion for BKVAN (high serum and urine BKV titer with graft dysfunction) but their graft biopsies stain negatively for BKV, non-correlated situations between the two tests often lead to a dilemma about how to treat them. METHODS: This retrospective investigation was conducted to determine how real time quantitative PCR (qPCR) for BKV, routinely applied to serum and urine, could be helpful in identifying the existing BKV in biopsy tissue stained negatively for BKV. RESULTS: DNA was extracted from each specimen through the use of five 10 MUm curls from the tissue block with use of the QIAamp DNA FFPE Tissue Kit (Qiagen), followed by BKV qPCR to determine copies of BKV/MUg of biopsy tissue DNA. Group 1 (11 negative renal controls for BKV) demonstrated 0 to 9 BKV copies/MUg DNA. Except for 3 focally staining cases showing low BKV, the remaining 10 positive renal controls in group 2 (13 positive transplant biopsies staining positively) demonstrated elevated BKV up to 160 million copies/MUg DNA. Group 3 transplants (13 uncertain transplants with negative BKV staining but positive liquid BKV) were negative for BKV (0-12 copies/MUg) in 4 of 13, had low BKV copies (36-346 copies/MUg) in 5 of 13, and had high BKV copies (17,240 526,945 copies/MUg) in 4 of 13 cases, through the use of qPCR. CONCLUSIONS: The data indicate that qPCR from paraffin-embedded tissue as a backup test is sensitive for ruling in/out BKV infection in renal transplant biopsies, particularly in uncertain cases. PMID- 28735998 TI - Assessment of Spleen Filtrate Function in Renal Transplant Recipients Using Technetium-99m Stannous Colloid Liver-Spleen Scan. AB - BACKGROUND: Functional hyposplenism (FH) is indicated by an anatomically present spleen that fails to take up radiolabeled colloid. The occurrence of FH has been reported in a small group of renal transplant recipients based on hematologic parameters. The aim of this study was to replicate this association in a larger group of renal transplant recipients with the use of technetium-99m-stannous colloid liver-spleen scan to assess the spleen function. METHODS: This survey based on single samples enrolled 101 unselected adult patients with functional kidney grafts >180 days after transplantation. All patients underwent 99mTc stannous colloid scan to assess spleen function as well as bone marrow uptake of radiocolloid along with an anatomic and blood flow study of the spleen and kidney with the use of Doppler sonography. RESULTS: The prevalence of hyposplenism was 32.7% (33/101) for the cohort, and increased uptake of radiocolloid by the bone marrow was seen in 9.9% (10/101). According to the multivariate analysis, the frequency of hyposplenism was significantly influenced by indirect bilirubin and hemoglobin, and direct bilirubin and neutrophil count remained as independent predictors of bone marrow uptake. CONCLUSIONS: This study demonstrated that a group of renal transplant recipients has FH. In addition, bone marrow uptake might be interpreted as liver dysfunction. In this situation, the small amount of contrast (spleen compared with liver) would leave hyposplenism undiagnosed. Further prospective and longitudinal clinical studies are needed to determine the clinical impact of this condition on the management of renal transplant recipients. PMID- 28735999 TI - Results of Real-time Multiplex Polymerase Chain Reaction Assay in Renal Transplant Recipients With Sterile Pyuria. AB - Urinary tract infections are a major cause of morbidity and hospitalization after renal transplantation. Patients treated with immunosuppressive drugs suffer not only from common uropathogens but also from opportunistic infections caused by unusual uropathogens. Sterile pyuria is associated with numerous infectious agents including viruses, fungi, and atypical or fastidious organisms. The objective of this study was to investigate the pathogens using real-time multiplex polymerase chain reaction (rtMPCR) assay in sterile pyuria of renal transplant recipients. In this prospective controlled study, pathogen detection was performed with rtMPCR assay on October 2016 in 60 patients with sterile pyuria who had undergone kidney transplantation. A total of 40 renal transplant patients were determined as the control group. Male-to-female ratio was same. The mean age of the subjects with sterile pyuria was 45.7 +/- 12.1 (25-74). The mean duration after transplantation was 28.8 +/- 3.97 (3-102) months. Pathogens were detected with rtMPCR in 61.7% of sterile pyuria group. This rate was significantly higher compared with the control group (P < .001). Two or more different pathogens were found in 13 (21.7%) patients in sterile pyuria group. The pathogens found included cytomegalovirus in 10 patients (19%), Gardnerella vaginalis and obligate anaerobes in 20 patients (38%), Ureaplasma spp in 17 patients (33%), Candida spp in 2 patients (4%), Mycoplasma hominis in one patient (2%), herpes simplex virus-2 in one patient (2%), and Trichomonas vaginalis in one patient (2%). Sterile pyuria may indicate the presence of genitourinary pathogens that cannot be detected with conventional urine culture method in renal transplantation patients. rtMPCR is an accurate and convenient method for detection of multiple potential pathogens of sterile pyuria in renal transplant patients. PMID- 28736000 TI - Renal Cell Carcinoma in Kidney Transplant Candidates. AB - BACKGROUND: An increased incidence of renal cell carcinoma (RCC) has been observed in patients with end-stage renal disease. However, the incidence of this pathological condition has not been studied adequately in kidney transplant candidates. The aim of this study was to examine the incidence of RCC and the clinical, imaging, and pathological characteristics in this population. METHODS: At our institution, the majority of kidney transplant candidates undergo a non contrast abdominal computerized tomography (CT) scan as a pre-transplant screening evaluation method. We retrospectively reviewed the medical data from 637 patients who were referred to our institution for kidney transplant evaluation during a period of 2 years. Of these, 174 were found ineligible and were excluded from the study; the final population consisted of 463 patients. Radical nephrectomy was proposed and performed in all the patients with findings highly suspicious of malignancy. RESULTS: A total of 20 patients had findings suspicious for kidney malignancy on non-contrast CT scan and underwent a total nephrectomy before transplantation. At the pathological examination, 13 patients had malignant lesions and 4 patients had benign lesions. All patients with malignancy were male, and 9 of 13 patients with malignancy had papillary RCC. CONCLUSIONS: This study confirms the increased incidence of RCC in kidney transplant candidates and underlines the utility of non-contrast CT scan without an intravenous contrast agent as a very useful screening tool in the pre operative evaluation of kidney transplant candidates. Hence, we recommend the implementation of routine screening with non-contrast CT scan in all kidney transplant candidates who undergo hemodialysis. PMID- 28736001 TI - Evaluating Retention of Skin Cancer Education in Kidney Transplant Recipients Reveals a Window of Opportunity for Re-education. AB - BACKGROUND: Skin cancer is the most common malignancy after solid organ transplant and can lead to significant morbidity. The likelihood of developing squamous cell carcinomas and melanomas is 100 and 2.4 times more likely, respectively, in kidney transplant recipients when compared with the general population. There are few data regarding the assessment and influence of solid organ transplant recipient (SOTR) knowledge of skin cancer and its effect on short- and long-term awareness and behavior. METHODS: The purpose of this study was to assess the baseline knowledge of SOTR immediately after transplantation, and then to reassess their knowledge following a 5-minute educational video. We also wanted to determine whether lifestyle modifications had been implemented 4 to 8 months after the intervention. RESULTS: Forty patients were enrolled within 2 months of transplantation. Eighty-seven percent of patients were renal transplant recipients, and 75% of patients were available for long-term follow up. There was a significant increase in knowledge in the immediate postintervention period, which was sustained at 4- to 8-month follow-up, as assessed by patient questionnaire. Patients appeared to be applying this knowledge by participating in lifestyle risk modification and positive sun protective behavior. CONCLUSIONS: Our study suggests that incorporating additional skin cancer education into the early transplant timeline (perhaps in the first one or two outpatient follow-up visits) with an easy to administer educational video and question and answer form increases patient knowledge and influences positive sun-protective behavior. PMID- 28736002 TI - High-flow Nasal Cannula Versus Noninvasive Ventilation for Treatment of Acute Hypoxemic Respiratory Failure in Renal Transplant Recipients. AB - OBJECTIVE: This study aimed to evaluate the outcomes of high-flow nasal cannula (HFNC) oxygen therapy compared with noninvasive ventilation (NIV) for the treatment of acute hypoxemic respiratory failure in renal transplant recipients. METHODS: Data were retrospectively collected from a tertiary intensive care unit (ICU) from July 1, 2011, to September 31, 2015. All renal recipients who had acute respiratory failure at that period of time were classified into the HFNC or NIV group depending on the initial form of respiratory support. RESULTS: A total of 38 patients were enrolled in this study. Twenty patients received HFNC and the other 18 received NIV as the initial respiratory support. The ICU mortality in the HFNC group was 5% (1 patient), compared with 22.2% (4 patients) in the NIV group (P = .083). The median length of the ICU stay was 12 days in the HFNC group, compared with 14 days in the NIV group (P = .297). The number of ventilator-free days at day 28 was significantly higher in the HFNC group than in the NIV group (26 +/- 3 vs 21 +/- 3; P < .001). The incidences of both pneumothorax (0% vs 22.2%; P = .042) and skin breakdown (0% vs 22.2%; P = .042) were significantly lower in the HFNC group. CONCLUSIONS: In renal transplant recipients with acute hypoxemic respiratory failure secondary to severe pneumonia, HFNC achieved outcomes similar to NIV. In addition, HFNC was associated with an increased number of ventilator-free days at day 28 and fewer complications. PMID- 28736003 TI - Kidney Graft Salvage Strategies for Vascular Complications During Kidney Transplantation: A Single-center Experience. AB - BACKGROUND: Kidney-related unknown vascular injuries are rare and usually diagnosed only after reperfusion. Hemorrhage that makes in situ reconstruction impossible can lead to graft loss. In an era of organ shortage and an increasing number of patients on the waiting list for transplantation, a kidney graft salvage procedure consisting of graft nephrectomy, reperfusion, reconstruction, and reimplantation should be undertaken whenever possible as a contribution to extending the organs available for transplantation. METHODS AND PATIENTS: From January 2010 to December 2015, in total five patients suffered from intraoperative or immediate postoperative vascular complication and were included for this retrospective analysis. Age, sex, etiology of kidney failure, delayed graft function, kind of vascular complications and therapy, presence of aortoiliac calcification, cold and warm ischemia time, and length of hospital stay were analyzed. RESULTS: By applying this "one-step-back" procedure in three consecutive patients and a structured in situ repair in two patients, all grafts were saved. Two of five patients developed delayed graft function requiring hemodialysis. At discharge, graft function was excellent in all five patients. Reconstructed vasculature showed 100% patency. CONCLUSION: These graft salvage strategies are safe with excellent outcome and should be considered in the event of an acute vascular complication during kidney transplantation. PMID- 28736004 TI - Lack of Association Between TGF-beta1 and MDR1 Genetic Polymorphisms and Cyclosporine-Induced Gingival Overgrowth in Kidney Transplant Recipients: A Meta analysis. AB - BACKGROUND: Gingival overgrowth (GO) induced by cyclosporine (CsA), one of the common complications after kidney transplantation, is associated with a genetic component. However, the effect of TGF-beta1 and MDR1 gene polymorphisms on the pathogenesis of CsA-induced GO remains to be determined. This study aimed to determine the association between TGF-beta1 and MDR1 gene polymorphisms and CsA induced GO in kidney transplant recipients. METHODS: The Pubmed, Embase, Cochrane Library, and Chinese CNKI (China National Knowledge Infrastructure) and Wanfang databases were comprehensively searched. Data were extracted and pooled results estimated from odds ratios (ORs) and 95% confidence intervals (CIs). In addition, quality assessment and publication bias of each eligible study were examined. RESULTS: Three trials focusing on the relationship between TGF-beta1 +869T>C and +915G>C and 3 studies on MDR1 C3435T gene polymorphisms and the onset of CsA induced GO were included. No association between the +869T>C polymorphism and CsA induced GO was found in the dominant model (TT+TC vs CC: OR, 0.77; 95% CI, 0.29 2.10; P = .614). In the recessive model, no association was found between the +915G>C polymorphism and CsA-induced GO (CC vs GG+GC: OR, 1.40; 95% CI, 0.81 2.43; P = .225). And in the dominant model, no significance was calculated between MDR1 C3435T gene polymorphisms and CsA-induced GO in kidney transplant recipients (TT vs CC+CT: OR, 1.14; 95% CI, 0.62-2.09; P = .68). CONCLUSIONS: No significant association exists between TGF-beta1 +869T>C, and +915G>C and MDR1 C3435T gene polymorphisms and the pathogenesis of CsA-induced GO in kidney transplant recipients. PMID- 28736005 TI - Benefits of Intraoperative Continuous Renal Replacement Therapy During Liver Transplantation in Patients With Renal Dysfunction. AB - BACKGROUND: Comparative outcomes of continuous renal replacement therapy during liver transplantation have not been investigated. We retrospectively compared the outcomes of intraoperative continuous renal replacement therapy with those of non dialytic conservative treatment in patients with pretransplant renal dysfunction. METHODS: We analyzed 240 transplantation patients with preoperative renal dysfunction (estimated glomerular filtration rate <60 mL/min/1.73 m2). RESULTS: Compared with the non-dialytic conservative treatment group (n = 98), the intraoperative continuous renal replacement therapy group (n = 142) experienced more severe critical illness (as indicated by Model for End-Stage Liver Disease score) and more severe preoperative renal dysfunction, as well as more frequent hepatic encephalopathy, ventilatory care, and intensive care unit admission (P < .005). There were also worse outcomes regarding patient survival, graft survival, recovery of renal function, and postoperative complications. However, the intraoperative continuous renal replacement therapy group significantly escaped volume overload (adjusted odds ratio, 0.396; 95% confidence interval, 0.223 0.703; P = .002) and unnecessary changes in serum sodium concentration >=10 mmol/L during surgery (adjusted odds ratio, 0.208; 95% confidence interval, 0.065 0.665; P = .008). CONCLUSIONS: Considering the more severe critical illness of the intraoperative continuous renal replacement therapy group but the low frequency of volume overload and serum sodium fluctuation, intraoperative continuous renal replacement therapy could be useful during liver transplantation in critically ill patients with renal dysfunction. Randomized, controlled studies that could demonstrate outcome benefits and indications of intraoperative continuous renal replacement therapy during liver transplantation are needed. PMID- 28736006 TI - Advantages of Epidural Analgesia on Pulmonary Functions in Liver Transplant Donors. AB - OBJECTIVE: Epidural analgesia (EA) has positive effects on anesthetic requirement, blood loss, postoperative analgesia, and pulmonary function tests (PFTs). The purpose of the present study was to investigate the effect of EA on postoperative PFTs in liver transplant donors (LTDs). METHODS: In the present study, 66 LTDs were classified as total intravenous anesthesia (TIVA) and TIVA+EA groups. Patient's age, sex, body mass index, induction and maintenance dose of propofol (IDP and MDP), operation duration, forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), FEV1/FVC ratio, visual analog scale (VAS), atelectasis scores, and lengths of intensive care unit (ICU) and hospital stays were recorded. RESULTS: In the TIVA+EA group, IPD, MPD, delta-FEV1 delta-FVC, VAS for all time, atelectasis score and length of hospital stay were significantly lower than in the TIVA group (P < .001 for all). Whereas VAS at the end of the operation was negatively correlated with delta-FEV1 and delta-FVC (r2 = 0.26 P < .001; r2 = 0.41 P < .001; respectively), it was positively correlated with atelectasis score and length of ICU stay (r2 = 0.49, P < .001; and r2 = 0.41, P < .001; respectively). Atelectasis score was positively correlated with length of ICU stay (r2 = 0.86, P < .001). CONCLUSIONS: Reduced anesthetic requirement, better postoperative analgesia, reduced atelectasis score, and preserved PFTs can be provided with the use of EA in LTDs. Positive effects of EA on anesthesia requirement, pain management and pulmonary function are associated with outcomes. PMID- 28736007 TI - Development and Validation of a Nomogram for Predicting Incidence of Early Allograft Dysfunction Following Liver Transplantation. AB - OBJECTIVE: Early allograft dysfunction (EAD) is frequent complication post-liver transplantation and is closely related to recipient's mortality and morbidity. We sought to develop a nomogram for predicting incidence of EAD. METHODS: Based on multivariate analysis of donor, recipient, and operation data of 199 liver transplants from deceased donors between 2013 and 2015, we identified 5 significant risk factors for EAD to build a nomogram. The model was subjected to prospective validation with a cohort of 42 patients who was recruited between January and June 2016. The predictive accuracy and discriminative ability were measured by area under the receiver operating characteristic curve (AUC). The agreement between nomogram prediction and actual observation was showed by the calibration curve. RESULTS: Incidence rate of EAD in the training set and validation cohort were 55.91% (104/199) and 54.76% (23/42), respectively. In the training set, according to the results of univariable and multivariable analysis, 5 independent risk factors including donor gender, donor serum gamma-glutamyl transpeptidase level, donor serum urea level, donor comorbidities (respiratory, cardiac, and renal dysfunction), and recipient Model for End-stage Liver Disease score were identified and assembled into the nomogram. The AUC of internal validation using bootstrap resampling and prospective validation using the external cohort of 42 patients was 0.74 and 0.60, respectively. The calibration curves for probability of EAD showed acceptable agreement between nomogram prediction and actual observation. According to the score table, the probability of EAD was under 30% when the total point tally was under 72. But when the total was up to 139, the risk of EAD increased to 60%. CONCLUSION: We've established and validated a nomogram that can provide individual prediction of EAD for liver transplant recipients. The practical prognostic model may help clinicians to qualify the liver graft accurately, making a more reasonable allocation of organs. PMID- 28736008 TI - Is Elective Status a Predictor of Poor Survival in Liver Retransplantation? AB - BACKGROUND: Orthotopic liver retransplantation (reLT) is considered to have poorer outcomes than primary transplantation. The objective of this study was to analyze the impact of medical urgency status as a predictor of patient survival after reLT. METHODS: Forty-nine patients who underwent reLT were included in this retrospective study. Urgent or elective status was based on the judgment of the surgical team, selected variables, and the Model for End-Stage Liver Disease score. Multivariate analysis was performed to identify variables associated with patient survival following reLT. RESULTS: Overall survival of the patient cohort was 57% at 1 year and 54.3% at 3 years after reTL. Survival in urgent-status patients was 68.8% and 63.4% at 1 and 3 years, respectively, whereas the survival rate for elective patients was 40.0% at both time points. Mortality was significantly associated with elective status (hazard ratio [HR], 2.42; P = .046) at 1 year, but was no longer significant (HR, 2.19; P < .069) after 3 years of follow-up. CONCLUSIONS: Elective status is associated with poorer outcome. Patient selection determines long-term survival more than any other single factor, so for patients designated to an elective status, prompt retransplantation should be encouraged. PMID- 28736009 TI - Beliefs of Living Donors About Recipients' End-Stage Liver Failure and Surgery for Organ Donation. AB - BACKGROUND: The concept of beliefs could provide a basis for how donors may perceive recipients' end-stage liver failure (ESLF) and surgery for organ donation. However, there is no such quantitative study. Therefore, the objective of this study was to explore beliefs of living donors about recipients' ESLF and surgery for organ donation. METHODS: The sample comprised 16 living donors who donated a part of their liver to a patient who had ESLF. The data were analyzed by following established procedures for inductive qualitative analysis. RESULTS: Analysis showed that donors' beliefs can be viewed in a number of groups. Beliefs about recipients' ESLF included diverse explanations for ESLF (blaming oneself and physicians) and physical symptoms (developmental slowing down). Beliefs about being a donor included reasons for being a donor (performing a good deed, being healed), barriers to being a donor (other people being ignorant and selfish), ways to manage these barriers (following one's gut feeling), and factors facilitating being a donor (the feeling that one does not have many people to leave behind). Beliefs about surgery for organ donation included physical effects (pain, feeling stiff). Beliefs about organ donation included views that general organ donation should be encouraged and that people's awareness should be raised. CONCLUSIONS: Existing psychological perspectives could help to interpret some beliefs. Nevertheless, other beliefs, not previously reported, could be considered as targets for individual consultations/psycho-educational programs for fostering emotional well-being. PMID- 28736010 TI - Predictors of Mortality in Living Donor Liver Transplantation. AB - BACKGROUND: Egypt has the highest prevalence of the world hepatitis C virus (HCV) load. Hence, the problem of end-stage liver disease (ESLD) is considered a huge burden on the community. Living donor liver transplantation (LDLT) is the only source of donation in Egypt till now. Survival rates had shown significant improvement in the past decades. This study provides analysis of the mortality rates and possible predictors of mortality following LDLT. It also aids in developing a practical and easy-to-apply risk index for prediction of early mortality. PATIENTS AND METHODS: This study is a retrospective study that was designed to analyze data from 128 adult patients with ESLD who underwent LDLT in the Liver Transplantation Unit at Faculty of Medicine, Cairo University. Early and late mortality were identified. All potential risk factors were tested using univariate regression for association with early and late mortality. Significant variables were then entered into a multivariable logistic regression model for identifying the predictors for mortality. RESULTS: Sepsis was the most common cause of early mortality. Early mortality and 1-year mortality were 29 (23%) and 23 (18%), respectively. Model for End-Stage Liver Disease (MELD) score, intraoperative packed red blood corpuscles (RBCs), and duration of intensive care unit (ICU) stay were found to be independently associated with early mortality. CONCLUSION: A MELD score >20, intraoperative transfusion >8 units of packed RBCs, and ICU stay >9 days are three independent predictors of early mortality. Their incorporation into a combined Risk Index can be used to improve outcomes of LDLT. PMID- 28736011 TI - Pediatric Donor to Adult Recipients in Donation After Cardiac Death Liver Transplantation: A Single-Center Experience. AB - BACKGROUND: The impact of using liver allografts from donors who are younger than 14 years at the time of donation after cardiac death (DCD) liver transplantation in terms of early allograft dysfunction (EAD) and graft survival is undefined. To determine if adults undergoing DCD liver transplantation who receive a graft from a donor age younger than or equal to 13 years have similar outcomes to recipients of organs from older than 18-year-old donors. METHODS: Records from adult patients undergoing DCD liver transplantation between March 2012 and December 2015 who received whole grafts from donors after cardiac death were reviewed. Patients with donors younger than or equal to 13 years (group 1) and older than 18 years (group 2) were compared for EAD rates, hepatic artery thrombosis (HAT), and graft survival. RESULTS: Records of 60 DCD liver transplantation patients were analyzed. The 90-day and 1-year graft survival rate of both groups was 90% versus 96% (P = .427) and 80% versus 84% (P = .668), respectively. The EAD rates of groups 1 and 2 were 30% versus 34% (P = .806). The incidence of HAT was 20% in group 1 compared with 12% in group 2 (P = .610). Also, 0.7% < graft to recipient weight ratio (GRWR) <0.8% was also usable for pediatric donor to adult recipients. CONCLUSIONS: Whole liver grafts from donors younger than or equal to 13 years can potentially be used in selected size-matched (GRWR >0.7%) DCD adult recipients. PMID- 28736012 TI - Sent Liver Grafts Do Not Have a Detrimental Impact on Post-transplant Outcome. AB - INTRODUCTION: "Sent livers" (SL) (interregional allocated organs) are considered extended donor criteria grafts. These grafts influence post-transplant outcome. In our donor allocation program, the number of allocated SLs is increasing. The aim of our study is to provide data supporting the possibility to enlarge the use of SLs through adequate donor-to-recipient matching. METHODS: A retrospective analysis was carried out from our prospective-collected database during 2014. RESULTS: Fifty-seven liver transplantations (LTs) were included: 22 SLs and 35 grafts procured by us (nSLs). Only donor risk index among donor characteristics showed a trend toward significant values (SL 1.901 vs nSL 1.726, P = .07). Among LT variables, the number of patients who received interleukin-2 inhibitor induction (SL 7 vs nSL 20, P < .05) and the presence of hepatocellular carcinoma (SL 50% vs nSL 34%, P < .05) reached statistical significance. One case of primary nonfunction occurred in the nSL group. No major retrieval injuries were observed. Retransplantation was performed in 6 cases (2 SLs and 4 nSLs). One patient in the SL group died after retransplantation. Graft survival rates at 1, 3, 6, and 12 months were 100%, 100%, 90%, 86% and 91%, 86%, 86%, 86% (P = .79) in SL and nSL groups, respectively. DISCUSSION: SL performance did not differ from that of nSL. SLs were usually allocated to noncritical candidates, and nSLs were transplanted more frequently in decompensated recipients. Despite this peculiar donor-recipient match, grafts survival was similar in the 2 groups of patients. PMID- 28736013 TI - Outcomes of Highly Sensitized Patients Undergoing Simultaneous Liver and Kidney Transplantation: A Single-Center Experience With Desensitization. AB - BACKGROUND: Preformed donor-specific human leukocyte antigen antibodies (DSAs) in patients undergoing simultaneous liver and kidney transplantation (SLKT) are an independent risk factor for poorer patient and renal allograft survival. The outcomes of patients highly sensitized (HS) against HLA antigens undergoing SLKT and select HS SLKT recipients undergoing desensitization at a high-volume desensitization center were investigated. METHODS: Seventy-five patients undergoing SLKT at a high-volume desensitization center between January 1, 2001, and December 31, 2015, were retrospectively reviewed. HS patients were defined by panel-reactive antibody (PRA) >30% (n = 17 patients), 11 of whom received pre- or perioperative desensitization with high-dose intravenous immunoglobulin (IVIG) +/ rituximab. RESULTS: HS patients had significantly higher class I and class II PRA (class I = 41.3% +/- 40.0% vs 2.5% +/- 6.3%; class II = 45.7% +/- 36.4% vs 1.0% +/- 2.9%; P < .001), were more likely to be female (P = .05), and more likely to have had a prior transplant (P = .03). HS patients demonstrated greater susceptibility to renal cell-mediated rejection (CMR) (23.5% vs 5.2%, P = .02) compared to nonsensitized patients. Higher renal antibody-mediated rejection (ABMR) was also observed in HS patients, 11.8% vs 3.4%, but did not reach significance (P = .18). Desensitization in select HS SLKT patients was well tolerated but did not improve patient and allograft survival or significantly curtail rejection. CONCLUSION: HS SLKT recipients demonstrated increased allograft rejection, particularly CMR, but patient and graft survival were not impacted in the first year post-transplant. Select HS SLKT patients tolerated desensitization with high-dose IVIG +/- rituximab and may have received additional immunoprotection against ABMR but survival was not affected. PMID- 28736014 TI - Efficacy and Safety of Generic Mycophenolate Mofetil (My-rept) 500-Milligram Tablets in Primary Liver Transplant Recipients. AB - BACKGROUND: Generic immunosuppressants may be cost-effective if clinical outcomes are equivalent to the brand-name medications. Mycophenolate mofetil in the form of My-rept may be cost-effective being a generic immunosuppressant, which is available as a 500-mg tablet as well as a 250-mg capsule (Chong Kun Dang Pharmaceutical Corporation, Seoul, Korea). OBJECTIVE: This study aimed to evaluate the efficacy, safety, cost-effectiveness, and convenience of My-rept 500 mg tablets in liver transplant recipients. SETTING: The setting was an outpatient liver transplantation clinic of a tertiary hospital in Korea. METHOD: A phase 4, single-center, open-label, noncomparative study was undertaken. A total of 50 patients were recruited. Acute transplant rejection, changes in blood chemistry, white blood cell count, assessments of renal function, occurrence of adverse drug reactions, and other characteristics of the patients were recorded for 24 weeks. After study termination, a satisfaction survey was conducted. RESULTS: All enrolled patients and their liver grafts had survived for 24 weeks post transplantation. No episodes of acute rejection were reported. Nine patients (18.8%) presented with adverse drug reactions that had been commonly reported with the use of other mycophenolate mofetil products, and no serious adverse drug reactions were reported. CONCLUSION: In conclusion, the My-rept 500-mg tablet appears to be feasible and convenient for administration to recipients of a liver transplant. PMID- 28736015 TI - Fibrosing Cholestatic Hepatitis C After Liver Transplantation: Therapeutic Options Before and After Introduction of Direct-Acting Antivirals: Our Experience and Literature Review. AB - BACKGROUND: Cirrhosis caused by hepatitis C is the most common indication for liver transplantation. The most aggressive form of hepatitis C virus (HCV) relapse after liver transplantation is fibrosing cholestatic hepatitis C, which can be observed in 2% to 15% of recipients. METHODS: Double therapy with peg interferon and ribavirin was characterized by low antiviral response, rapid fibrosis, and frequent graft failure within 1 year after surgery. RESULTS: Introduction of direct-acting antivirals for HCV treatment allows for more efficient therapy with less adverse reactions, including patients with fibrosing cholestatic hepatitis C. CONCLUSIONS: We present 4 (2.5%) cases of cholestatic viral hepatitis C recurrence in patients undergoing transplantation between 2006 and 2015 at the Transplantation Institute of Warsaw; during this period, 158 liver transplants were performed in patients with cirrhosis caused by HCV infection. PMID- 28736016 TI - Predictors of Non-adherence to Immunosuppressive Therapy in Asian Liver Transplant Recipients. AB - BACKGROUND: Adherence to immunosuppressive medications has been shown to affect post-transplant outcomes. We aimed to determine the level of adherence to immunosuppressive therapy in liver transplant (LT) recipients and to elucidate factors associated with it, as well as patient preferences on the dosing schedule. METHODS: LT recipients were recruited during transplant clinic follow up. A validated Morisky 8-item questionnaire was completed by patients to assess their adherence to immunosuppressive therapy. Adherence was determined by the sum of the responses to the questionnaire. Low, medium, and high adherence were defined by a Morisky score of >2, 1 to 2, and 0, respectively. Data on the patient's socio-economic and clinical background, dosing schedule of immunosuppressant medications, and patient preferences were included in the questionnaire. RESULTS: A total of 107 LT recipients were approached and 75 completed the questionnaire. The majority of patients (48/74, 64.9%) preferred a once-daily medication regimen. The proportion of high adherence was 24/75 (32.0%), medium adherence was 51/75 (42.7%), and low adherence was 19/75 (25.3%). Multivariate analysis showed younger age and post-transplant duration >5 years as independent predictors for low adherence. Among low-adherence patients, 16/19 (84.2%) patients were on a twice-daily regimen, and, of these, 14/16 (87.5%) preferred their medications to be reduced to once daily. CONCLUSIONS: A significant proportion (68%) of LT recipients had low to moderate adherence to medications, with younger age and longer post-transplant duration of >5 years as independent predictors. Early identification of at-risk patients is essential to allow implementation of measures to improve adherence. Simplifying medication regimens to once daily is a potential way to improve adherence. PMID- 28736017 TI - Long-term Outcomes for Liver Transplant Recipients in Terms of Hepatic Encephalopathy. AB - BACKGROUND: Liver transplantation (LT) is thought to resolve cognitive deficit due to hepatic encephalopathy (HE). The aim of this study was to determine the factors associated with the outcomes of patients with HE after LT. METHODS: The authors reviewed the medical records of 388 patients with HE who underwent LT from 1996 to 2014. RESULTS: There were 282 patients with grade 1-2 HE and 106 patients classified as grade 3-4. Patients in the latter group had a tendency for a more decompensated hepatic condition than patients with grade 1-2 HE. HE sequelae were only associated with grade 3-4 HE with borderline significance (P = .05). The cumulative 1-, 3-, and 5-year overall survival (OS) of patients with grade 1-2 HE were 81.9%, 77.3%, and 74.6%, whereas those of in patients with grade 3-4 HE were 77.4%, 73.3%, and 72.2%, respectively (P = .75). CONCLUSION: The sequelae of HE were only associated with the grade 3-4 HE. Aggressive treatment of HE prior to LT may prevent patients from deteriorating into high grade HE, which could further contribute to improving the outcomes after LT. PMID- 28736019 TI - Endomyocardial Biopsy via the Femoral Vein Using a Long, Curved Sheath. AB - BACKGROUND: Endomyocardial biopsy (EMB) has been defined as the gold standard method for surveillance of rejection after heart transplantation, and it has also been used in the diagnosis of myocarditis and the unknown causes of cardiomyopathies. The procedure, however, is not free from complications. Access through the jugular vein or the femoral vein is the standard approach. In this study, we performed biopsies by using a long, curved sheath and evaluated the rate of complications with this technique. METHODS: In this descriptive case series study, 97 EMBs were performed in 72 patients who were referred to a cardiovascular and medical research center in Tehran, Iran, between October 2011 and May 2013. The procedures were performed via the femoral approach by using a long bioptome with a long, curved sheath. RESULTS: Adequate specimens were obtained in 97.9% of the total EMBs, with an average of 5 fragments per procedure. No deaths occurred, and there were no cases of pericardial effusion, myocardial rupture, papillary muscle rupture, increase in the severity of tricuspid regurgitation, atrioventricular block, sustained and nonsustained ventricular tachycardia, or atrial fibrillation. There was one case of persistent right bundle branch block. CONCLUSIONS: Using a long, curved sheath can facilitate access to the interventricular septum compared with common sheaths and can be used safely in EMB via the femoral approach. PMID- 28736018 TI - Extracorporeal Life Support as a Bridge to Lung Transplantation in Patients With Acute Respiratory Failure. AB - BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is being used more often as a bridge to transplantation (BTT) in patients with acutely decompensated end stage lung disease in Korea. ECMO as a BTT may be the only rescue strategy for severe acute respiratory failure, but many centers still consider it to be a relative contraindication to lung transplantation because of its poor outcome. Because there are not enough lung donors, it is important to determine their optimal use. We reviewed and analyzed our experiences with the use of ECMO as a BTT in patients with acute respiratory failure. METHODS: This was a retrospective analysis of all patients with acutely decompensated end-stage lung disease treated with ECMO as a bridge to lung transplantation between March 2012 and February 2016. RESULTS: Of the 194 patients who underwent respiratory ECMO over a 4-year period, a BTT strategy was used for 19 patients (median age, 58 years) on our institution's lung transplantation waiting list (15 veno-venous, 3 veno-veno arterial, 1 veno-arterial). Fourteen patients (73.7%) were successfully bridged to transplantation; however, 3 died while on the waiting list and 2 returned to their baseline functions without transplantation. The overall in-hospital survival rate was 57.9% (11 of 19), including the 9 (64.3%) patients who underwent transplantation. CONCLUSIONS: Our findings support the view that well selected candidates with acutely decompensated end-stage lung disease may be safely bridged until a suitable donor is identified. ECMO is not able to reverse the course of patients; however, it could be a life-saving option for patients with acute respiratory failure requiring lung transplantation. PMID- 28736020 TI - Mechanism for the Instant Blood-Mediated Inflammatory Reaction in Rat Islet Transplantation. AB - OBJECTIVE: The purpose of this study was to investigate the mechanisms involved in the development of instant blood-mediated inflammatory reaction (IBMIR) triggered by pancreatic islet transplantation in an in vitro system. MATERIALS AND METHODS: Pancreatic islets were prepared and blood was taken from male and female Wistar rats. An in vitro heparinized tubing loop model on a rocking device that was placed in a 37 degrees C incubator was used to generate blood flow inside the loops. Rat blood was added to the device, and after a 60-minute incubation period, 800 islet equivalents were added to the system. Rat blood samples were taken for immediate hematologic analysis before circulation, before the addition of islets, and 5, 15, 30, and 60 minutes after the addition of islets. After 60 minutes, the blood in the tubing was filtered, and the filtrate was stained using hematoxylin and eosin for microscopic analysis. RESULTS: Following the addition of islets, the counts of platelets, white blood cells, and mononuclear cells were significantly decreased at 60 min (P < .05), and the plasma levels of thrombin-antithrombin complexes and complement C3a were significantly increased (P < .05). At 60 minutes after introduction of the islets, the thrombi and tissue in the remaining blood in the device consisted of a few islets with serious structural damage and incomplete capsules, and there were many microthrombi with a large number of infiltrating neutrophils around the islets. CONCLUSION: Our in vitro model of IBMIR was characterized by platelet consumption, activation of the coagulation and complement cascade systems, and leukocytic infiltration. PMID- 28736022 TI - Use of NanoICE for Procurement Achieves Better Cooling of Liver Grafts. AB - BACKGROUND: Rapid cooling at procurement after cross-clamping has been the cornerstone of organ preservation. NanoICE is a new form of ice that has emerged in the food industry and is providing more efficient cooling and preservation than regular ice. We hypothesize that the use of NanoICE will accelerate the cooling process of the allograft and will be able to maintain a steady low temperature without causing any significant histologic damage. METHODS: In this randomized pilot study, 14 pigs were used to study the liver core/surface cooling in a non-survival organ procurement operation. Animals were randomly assigned to 1 of 2 groups, each arm involving 7 pigs: (1) crushed-iced normal saline cooling method (control group) and (2) NanoICE cooling method (study group). Surface and core temperatures were measured with temperature probes, and liver biopsies were obtained before cross-clamping and 15 hours after preservation to assess for any evidence and degree of freezing injury. RESULTS: NanoICE was able to reduce and sustain lower core temperatures at 30 minutes, 60 minutes, and 15 hours, compared with crushed ice. The degree of histologic damage (reflecting cold injury) at 15 hours after flushing was not significantly different between the 2 methods. CONCLUSIONS: NanoICE cools the deeper liver parenchyma more quickly and sustains a cooler temperature than regular crushed ice without causing significantly histologic damage. Future research should focus on whether the effect of NanoICE has any impact on graft function and survival. PMID- 28736021 TI - Infectious Complications and Multidrug-Resistant Bacteria in Patients With Hematopoietic Stem Cell Transplantation in the First 12 Months After Transplant. AB - BACKGROUND: Hematopoietic stem cell transplantation (HSCT) has been used as treatment in different hematologic and solid malignancies. The aim of this study was to describe the frequency of infectious complications, microbiology, and outcome in patients undergoing HSCT in Mexico during the pre-engraftment period and the impact on mortality rates at 12 months. METHODS: We conducted a retrospective study of all hematologic malignancies that received HSCT from January 2009 and December 2014, at an oncology reference center. RESULTS: We included 210 patients: 144 autologous (69%) and 66 allogeneic HSCT (31%). There were 184 infections documented in 109 patients; incidence rate was 47.2 per 1000 neutropenia/days and 22.4 per 1000 hospitalization/days. The main infections reported were pneumonia (n = 40, 19%), bloodstream infections (n = 36, 17.1%), and central line-associated bloodstream infections (n = 28, 13.3%). There were 110 bacteria isolated, 31 were multidrug-resistant (26 were extended-spectrum beta-lactamase; Escherichia coli). There were 25 disseminated or complicated viral infections and 20 invasive fungal diseases. Fourteen patients died in the first 30 days (all related to the infectious process). In multivariate analysis leukemia, more than 2 chemotherapy regimens before transplant and pneumonia were related to 12-month mortality rates. CONCLUSIONS: Even though infectious processes are frequent in patients with HSCT, multidrug-resistant bacteria were not as frequent as supposed; however, when these microorganisms are involved, mortality rate is increased. It is important to be alert that patients with pneumonia have a significantly increased mortality risk in the first year. PMID- 28736023 TI - Protective Effects of Geniposide on Hepatic Ischemia/Reperfusion Injury. AB - BACKGROUND: Geniposide (GEN) is the major ingredient of Gardenia jasminoides Ellis, which has anti-inflammatory and anti-apoptotic activities and is widely used to treat ischemia disease. Inflammation and apoptosis play an important role in hepatic ischemia/reperfusion (I/R) injury. The current study was conducted to explore the effects of geniposide on hepatic I/R injury and its potential molecular mechanism in mice. METHODS: Fifty Sprague-Dawley rats were randomly divided into 5 groups: the sham group (sham), the hepatic I/R injury group (IRI) and the GEN groups (low, middle, and high). In the GEN and IRI groups, hepatic IRI by was induced by means of clamping the left and median liver lobes for 30 minutes with noninvasive endoclips. The GEN groups were pretreated with GEN (5, 10, 20 mg/kg) at 30 minutes before ischemia by use of intraperitoneal injection. Rats in the IRI group and sham group were administrated with same dosage of saline at the same time. After reperfusion for 6 hours, the hepatic pathology and the expression of alanine aminotransferase (ALT), AST aspartate aminotransferase, LDH lactic acid dehydrogenase, PI3K, AKT, p-AKT, m-TOR, Bax, BCL-2, interleukin (IL)-6, MCP-1, and tumor necrosis factor (TNF)-alpha were examined. RESULTS: Compared with the sham group, the IRI group had higher expression of ALT, AST, LDH, Bax, IL-6, MCP-1, and TNF-alpha and lower expression of BCL-2, PI3K, p-AKT, and mammalian target of rapamycin (mTOR), with more inflammatory cell infiltration, cellular swelling, and vacuolar degeneration. Compared with the IRI group, the GEN group had lower expression of ALT, AST, LDH, Bax, IL-6, MCP-1, and TNF-alpha and higher expression of BCL-2, PI3K, p-AKT, and mTOR, with less inflammatory cell infiltration, cellular swelling, and vacuolar degeneration. There were no differences in the expression of AKT among several groups. CONCLUSIONS: GEN can protect rats against hepatic I/R injury and partly relies on suppressing inflammation and apoptosis by inducing the activation of the PI3K/Akt/mTOR signaling pathway. PMID- 28736024 TI - Effects of Sildenafil and Tadalafil on Edema and Reactive Oxygen Species Production in an Experimental Model of Lung Ischemia-Reperfusion Injury. AB - BACKGROUND: Lung ischemia-reperfusion injury is characterized by formation of reactive oxygen species and cellular swelling leading to pulmonary edema and primary graft dysfunction. Phosphodiesterase 5 inhibitors could ameliorate lung ischemia-reperfusion injury by interfering in many molecular pathways. The aim of this work was to evaluate and compare the effects of sildenafil and tadalafil on edema and reactive oxygen species formation in an ex vivo nonhuman animal model of lung ischemia-reperfusion injury. METHODS: Thirty-two Wistar rats were distributed, treated, perfused and the cardiopulmonary blocks were managed as follows: control group: immediate excision and reperfusion without pretreatment; ischemia reperfusion group: treatment with dimethylsulfoxide 0.9% and excision 1 hour later; sildenafil group: treatment with sildenafil (0.7 mg/kg) and excision 1 hour later; and tadalafil group: treatment with tadalafil (0.15 mg/kg) and excision 2 hours later. All cardiopulmonary blocks except control group were preserved for 8 hours and then reperfused. Pulmonary arterial pressure, pulmonary venous pressure, and capillary filtration coefficient were measured. Reactive oxygen species were measured. RESULTS: Edema was similar between control and sildenafil groups, but significantly greater in the ischemia-reperfusion (P <= .04) and tadalafil (P <= .003) groups compared with the sildenafil group. The malondialdehyde levels were significantly lower in the sildenafil (P <= .001) and tadalafil (P <= .001) groups than the ischemia-reperfusion group. CONCLUSIONS: Administration of sildenafil, but not tadalafil, decreased edema in lung ischemia reperfusion injury. Both drugs decreased reactive oxygen species formation in a lung ischemia-reperfusion injury model. PMID- 28736025 TI - Locally Transplanted CD34+ Bone Marrow-Derived Cells Contribute to Vascular Healing After Vascular Injury. AB - INTRODUCTION: Vascular progenitor cells contribute to repair of injured vasculature. In this study, we aimed to investigate the role of bone marrow derived cells in the intimal formation after arterial injury. METHODS AND RESULTS: Balloon injury of the femoral artery of wild-type mice was followed by local delivery of bone marrow-derived cells from GFP transgenic mice. The arteries were collected 1, 4, 7, and 14 days after injury and studied for morphology, localization, and phenotypes of delivered cells. Bone marrow-derived cells were present in the intima only at the early stages of arterial injury and expressed endothelial progenitor cell markers (CD31, CD34, and VEGFR-2). In the areas where intima was thicker, bone marrow-derived cells differentiated to intimal smooth muscle cells but they did not fuse with intimal cells. Delivery of CD34+ cells contributed to a 1.5-fold inhibition of intimal hyperplasia. CONCLUSION: Bone marrow-derived endothelial cells differentiated but did not fuse with vascular smooth muscle cells at the early stages of intimal formation and contributed to intimal hyperplasia. PMID- 28736026 TI - Yogurt Feeding Induced the Prolongation of Fully Major Histocompatibility Complex Mismatched Murine Cardiac Graft Survival by Induction of CD4+Foxp3+ Cells. AB - Yogurt is a nutrient-rich food and the beneficial effects of yogurt on both health and immunomodulatory effects are well documented. In this pilot study, we investigated the effects of commercially produced yogurt R-1 on alloimmune responses in a murine cardiac transplantation model. The R-1 is produced by Meiji Co., Ltd., and contains live and active lactic acid bacteria (lactobacillus bulgaricus OLL1073R-1) mainly. CBA (H2k) mice underwent transplantation of a C57BL/6 (H2b; B6) heart and received oral administration of 1 mL, 0.1 mL, and 0.01 mL of R-1 from the day of transplantation until 7 days afterward. Additionally, we prepared one group of CBA recipients given 1 mL of R-1 sterilized by microwave for 7 days. Histological and immunohistochemical studies were performed. Naive CBA mice rejected B6 cardiac graft acutely (median survival time [MST]: 7 days). CBA recipients given of 1 mL of R-1 had significantly prolonged B6 allograft survival (MST, 27 days). However, other doses of 0.1 mL and 0.01 mL of R-1 did not prolonged allograft survival (MSTs, 9 days and 8.5 days, respectively). Also, CBA recipients administered microwaved R-1 had no prolongation of B6 allograft (MST, 9 days). Histological and immunohistochemical studies showed the cardiac allograft from R-1-exposed CBA recipients had preserved graft and vessel structure and the number of infiltrated CD4+, CD8+, and Foxp3+ cells in R-1-exposed CBA recipients increased, respectively. In conclusion, our findings imply that yogurt containing active lactic acid bacteria could change alloimmune responses partially and induce the prolongation of cardiac allograft survival via CD4+Foxp3+ regulatory cells. PMID- 28736027 TI - Suppression of Delayed Xenograft Rejection by Resveratrol in a Hamster-to-Rat Cardiac Transplantation Model. AB - BACKGROUND: Delayed xenograft rejection (DXR) is an insurmountable barrier for xenotransplantation. Previous studies reported that hamster hearts transplanted into rats undergo DXR and stop functioning after the cessation of immunosuppression. Herein, we investigated the effects of resveratrol on preventing DXR in a hamster-to-rat vascularized cardiac xenograft model. METHODS: Hamster hearts were engrafted into Lewis rat recipients. Recipient rats received a graft acceptance-inducing treatment of leflunomide and FK506 for 2 weeks to prevent acute xenograft rejection (AXR). Then, all recipient rats were randomly divided into two groups: one group was treated with 1% carboxymethyl cellulose vehicle (control group) and one group was treated with resveratrol (RES group). RESULTS: After cessation of FK506 and Lef in recipient rats, treatment with resveratrol prolonged the mean survival time from 8.5 days in the control group to 23.5 days. Compared with the control group, neutrophil infiltration in both cardiac muscle and blood vessel tissues of the grafts after resveratrol treatment was significantly reduced. Meanwhile, resveratrol treatment also significantly inhibited T-cell response along with increased production of cytokines including interleukin (IL)-4, IL-10, and decreased interferon (IFN)-gamma of recipients. Furthermore, in the RES group, immunoglobulin (Ig)M antibody production was markedly inhibited, while the production of IgG antibody and the frequency of B cells did not vary. CONCLUSION: Administration of resveratrol can markedly delay the emergence of DXR by inhibiting IgM secretion. PMID- 28736028 TI - Association Between Tacrolimus Pharmacokinetics and Cytochrome P450 3A5 and Multidrug Resistance Protein 1 Exon 21 Polymorphisms. AB - BACKGROUND: Individual differences in the pharmacokinetics (PK) of tacrolimus (TAC), an immunosuppressive drug, are reportedly associated with single nucleotide polymorphisms (SNPs) of cytochrome P450 (CYP) 3A5 and multidrug resistance protein 1 (MDR1). We determined the effect of SNPs in CYP3A5 and MDR1 exons 21 and 26 on TAC PK parameters. METHODS: Thirty-eight Japanese patients who underwent renal transplantation were genotyped for CYP3A5 and exons 21 and 26 of MDR1 with the use of polymerase chain reaction-restriction fragment length polymorphism analysis. TAC concentrations were determined 3 weeks after renal transplantation and PK parameters calculated. RESULTS: The area under the blood concentration-time curve (AUC) in CYP3A5 expressers was significantly higher than that in CYP3A5 nonexpressers (CYP3A5*3/*3). Patients with the MDR1 exon 21 A allele (G2677A) showed higher dose-adjusted AUC (AUC/D) and lower doses of TAC than those who did not possess that allele. Furthermore, patients with both CYP3A5*3/*3 and MDR1 G2677A showed significantly lower TAC doses and higher dose adjusted trough levels (C/D) and AUC/D than those without those genotypes. There was no significant association between MDR1 exon 26 polymorphism and the PK of TAC. CONCLUSIONS: Patients with both CYP3A5*3/*3 and MDR1 G2677A had higher blood TAC concentrations than those without those genotypes. Japanese patients should be carefully monitored for consideration of lower TAC doses, because 24% of Japanese patients have double mutations. PMID- 28736029 TI - Protective Role of Apelin Against Cyclosporine-Induced Renal Tubular Injury in Rats. AB - BACKGROUND: Cyclosporine (CsA) usually reduces glomerular filtration rate (GFR) but also can induce tubular injury without resulting in GFR reduction. Apelin is an endogenous ligand for the apelin receptor and has diverse physiologic roles related to hemodynamic or metabolic processes. We investigated the renoprotective role of apelin against CsA-induced tubular toxicity in rats. METHODS: Rats were given CsA (15 mg/kg/day) and/or apelin-13 (15 MUg/kg/day) for 7 days via subcutaneous injection. We performed serum and urinary assays of creatinine and neutrophil gelatinase-associated lipocalin (NGAL) to estimate renal injury and performed Western blotting for endothelial nitric oxide synthase and nuclear factor of activated T-cell cytoplasmic 1 (NFATc1) to document the underlying mechanism. RESULTS: The CsA-treated group showed increased urinary creatinine excretion, polyuria, and renal glycosuria without GFR reduction, suggesting adequate CsA-induced renal tubular injury. Urinary NGAL excretion also increased significantly in the CsA group. Conversely, apelin attenuated CsA-induced tubular injury and had no effect on urinary NGAL excretion. In histopathologic examination, the apelin-treated group had lower tubulo-interstitial injury scores compared with those in the CsA group. Regarding the effects of apelin, our results indicate that apelin provides protection against CsA-induced tubular injury by activating nitric oxide and/or the NFATc1 pathway. Notably, we also found that CsA inhibits renal glucose reabsorption by reducing Na+-K+ ATPase expression and that apelin reverses reduced renal glucose reabsorption by CsA in tubular cells. CONCLUSIONS: Our study demonstrates the renoprotective effect of apelin against CsA-induced renal tubular toxicity and provides novel insights into the effects of CsA and apelin on renal tubular cells. PMID- 28736030 TI - Erratum. PMID- 28736031 TI - Olanzapine induced neuroleptic malignant syndrome, treated with electroconvulsive therapy (ECT)-A case report. PMID- 28736032 TI - Central line-associated bloodstream infection rate elevation: Attributable to National Healthcare Safety Network surveillance definition changes, ongoing opportunities for infection prevention, or both? AB - Calendar year 2015 intensive care unit (ICU) central line-associated bloodstream infections (CLABSIs) from 1 hospital were reviewed using 2014 CLABSI surveillance definitions to assess the relative impact of definition changes and infection control practices on CLABSI rates. Increased ICU primary CLABSI rates were found to be a result of both surveillance definition changes and infection control practices. PMID- 28736034 TI - Salvianolic acid B promotes microglial M2-polarization and rescues neurogenesis in stress-exposed mice. AB - Although accumulating evidence suggests that activated microglia are associated with deficits in neurogenesis and contribute to the physiopathology of major depressive disorder, the role of microglia in treating depression remains poorly understood. Our previous study showed that salvianolic acid (SalB) has the regulation of neuroinflammatory responses and antidepressant-like effects. Here, we hypothesized that SalB's therapeutic effects occur because it modulates microglial phenotypes that are associated with neurogenesis. To test this hypothesis, we treated CMS-exposed C57BL/6 mice with SalB (20mg/kg, intraperitoneally, once daily) for 3weeks and investigated microglial phenotypic profiles and hippocampal neurogenesis. The results showed that the SalB treatment skewed M1 microglial polarization toward M2 activation in the hippocampus and cortex and remedied CMS-induced deficits in hippocampal neurogenesis. SalB (40uM) inhibited LPS-stimulated microglial M1 activation as well as induced M2 activation in vitro, and the cultured microglia with the SalB treatment showed enhanced neural precursor cell proliferation, differentiation, and survival. SalB treatment also ameliorated the depressive-like behaviors of the CMS-treated mice in sucrose preference, forced swimming, and tail suspension tests. These findings suggest a possible antidepressive mechanism for anti-inflammatory agents that is correlated with microglial polarization and hippocampal neurogenesis and which may provide a new microglia-targeted strategy for depression therapy. PMID- 28736033 TI - Acid-sensing T cell death associated gene-8 receptor expression in panic disorder. AB - BACKGROUND: While disruption of acid-base homeostasis has been pathoetiologically implicated in panic disorder (PD), the mechanism by which pH imbalance is translated to panic pathophysiology is poorly understood. Recently, in a translational rodent model of PD, we reported a role of microglial acid sensing G protein coupled receptor, T cell death associated gene-8 (TDAG8) in panic associated behavior and physiology. However, the clinical validity of the TDAG8 receptor has not been investigated. OBJECTIVE: To assess TDAG8 in PD, we evaluated TDAG8 receptor expression in adolescents and young adults with PD and healthy comparison subjects. METHODS: Relative expression of TDAG8 mRNA was determined in peripheral blood mononuclear cells from patients with PD, and compared to expression in healthy subjects. Linear models were utilized to evaluate the relationship between TDAG8 expression and panic disorder symptom severity scale (PDSS) score as well as other potential explanatory variables (e.g., CRP, body mass index, sex, age). Models were refined based on the estimated parameter significance, evidence of omitted variable bias and Bayesian/Akaike information criteria. RESULTS: Relative to healthy comparison subjects (n=17), expression of TDAG8 mRNA was significantly increased in patients with PD (n=15) (1.60+/-0.65 vs. 1.01+/-0.50, p=0.008). TDAG8 mRNA expression predicted PD symptom severity in a fixed effect model incorporating age and sex (p=0.003). CONCLUSIONS: Collectively, our results suggest greater TDAG8 expression in patients with PD compared to healthy subjects, and directly link TDAG8 expression and the severity of the PD symptoms. Further investigation of the TDAG8 receptor in panic pathophysiology is warranted. PMID- 28736035 TI - Propane-2-sulfonic acid octadec-9-enyl-amide, a novel PPARalpha/gamma dual agonist, protects against ischemia-induced brain damage in mice by inhibiting inflammatory responses. AB - Propane-2-sulfonic acid octadec-9-enyl-amide (N15), an analogue of oleoylethanolamide (OEA), is a novel PPARalpha/gamma dual agonist. Our previous studies verified the positive effects of OEA on the acute and delayed stages of cerebral ischemia. However, it is not clear whether N15 is effective against ischemic cerebral injury. In the present study, male Kunming mice were subjected to middle cerebral artery occlusion (MCAO). To evaluate its preventive effects, N15 (50, 100 or 200mg/kg, ip) was administered for 3days before ischemia. To evaluate its therapeutic effects, N15 (200mg/kg, ip) was administered 1h before reperfusion or 0, 1, 2 or 4h after reperfusion. Neurological deficit scores, infarct volume and the degree of brain oedema were determined at 24h after reperfusion. Blood brain barrier (BBB) disruption was evaluated by Evans blue (EB) and FITC-dextran leakages at 6h after reperfusion. The activation/inflammatory responses of microglia/macrophages were detected using immunohistochemistry and western blot. N15 pretreatment improved neurological dysfunction, reduced infarct volume and alleviated brain oedema in a dose dependent manner; the most effective dose was 200mg/kg. The therapeutic time window was within 2h after reperfusion. N15 treatment preserved the BBB integrity and suppressed the activation of microglia/macrophages. N15 inhibited inflammatory cytokine expression not only in MCAO mice but also in lipopolysaccharide (LPS)-stimulated BV-2 microglial cells. Additionally, N15 markedly decreased the phosphorylation levels of NF-kappaBp65, STAT3, and ERK1/2 both in vivo and in vitro. Furthermore, the PPARalpha antagonist MK886 or PPARgamma antagonist T0070907 respectively partly abolished the anti-inflammatory effects of N15 in vitro. Our findings demonstrated that N15 can exert neuroprotective effects against cerebral ischemic insult. Moreover, the neuroprotective effects of N15 on cerebral ischemia may be attributed to its anti inflammatory properties, at least in part, by enhancing PPARalpha/gamma dual signaling and inhibiting the activation of the NF-kappaB, STAT3, and ERK1/2 signaling pathways. These findings suggest that N15 may be a potential therapeutic choice for the prevention and treatment of ischemic stroke. PMID- 28736036 TI - [Regulation of the expression of coenzyme Q-synthesis complex during ageing]. AB - INTRODUCTION: Coenzyme Q is an essential component in the activity of the mitochondrial electron transport chain. Its synthesis involves, at least, a complex of ten different proteins. In this study, an attempt is made to determine the evolution of the expression of the genes involved in coenzyme Q synthesis during mouse ageing. MATERIAL AND METHODS: The messenger RNA (mRNA) of different organs, such as brain, liver, kidney and skeletal muscle from young (8 months), mature (18 months), and old (24 months) mice was extracted by using Trizol and was then analysed by real time PCR (qPCR) using specific primers for all the known components of the coenzyme Q-synthesis complex (COQ genes). RESULTS: Liver showed the highest age-dependent changes in mRNA levels of the different components of Q-synthesis complex, affecting the extent of the variation as well as the significance of the change. In most of the cases, mRNA levels of the different components were higher in mature animals compared to young and old animals. When mRNAs of young and old animals were compared, only minor reductions of mRNA levels were found. Kidney showed a pattern similar to that found in liver as regards the changes in expression, although with lower increases in mature animals than those observed in the liver. Brain and skeletal muscle showed low variations, with muscle being the tissue with less changes, although a pattern similar to that found in liver and kidney was found, with slight increases in mature animals. DISCUSSION: The results of this study indicate that ageing is an important factor affecting COQ gene expression, but its effect depends on the organ, and that mature animals show higher levels of mRNA than young and old animals. Taken into consideration the importance of coenzyme Q in cell metabolism and ageing, a more detailed study is needed to understand the gene regulation of the coenzyme Q-synthesis mechanisms during ageing. PMID- 28736037 TI - [Frequency of successful aging and frailty. Associated risk factors]. AB - OBJECTIVE: To determine the frequency of successful aging (SA) and its relationship with frailty in an elderly population. MATERIAL AND METHODS: An analytical cross-sectional study of subjects >=60 years of age seen as outpatients in a general hospital. Successful aging was defined as scores of >= 90 in the Barthel index and <= 2 in the Pfeiffer test. Frailty was determined using the Fried criteria. RESULTS: The study included 400 subjects (272 women and 128 men), with a mean age of 71.6+/-8.2 years. The SA frequency was 40.4%. frail status was statistically higher in non-successful aging subjects than in SA subjects (161.7 versus 7.9%; P<.001). Women were more frequently frail, while being a pensioner/retired and married were associated less frequently with frailty. CONCLUSIONS: Successful aging is associated with a lower level of frailty. PMID- 28736038 TI - Comparative study of the hypocholesterolemic and hypolipidemic activity of alginate and amidated alginate in rats. AB - Alginate is a copolymer of beta-d-mannuronate and alpha-l-guluronate, which are present in the cell wall of brown algae. The hypocholesterolemic and hypolipidemic activities of alginate and its derivative, which is prepared by a reaction with octadecylamine, were compared in rats fed diets containing cholesterol and palm fat at 10 and 50g/kg, respectively. Amidated alginate at 20g/kg significantly decreased serum cholesterol from 2.93 to 2.00MUmol/mL, serum triacylglycerols from 1.66 to 0.92MUmol/mL, hepatic cholesterol from 17.5 to 5.9MUmol/g, and total hepatic lipids from 67.4 to 51.7mg/g. Alginate at 20g/kg significantly reduced hepatic cholesterol to 13.1MUmol/g, but did not influence serum cholesterol, triacylglycerols, and total hepatic lipids. Amidated alginate significantly increased the faecal concentrations of neutral sterols from 98.7 to 122.4MUmol/g DM, but decreased faecal concentration of bile acids from 19.4 to 14.0MUmol/g DM. In samples of intestinal contents, taurine-conjugated bile acids dominated glycine conjugates. The supplementation of diets with cholesterol significantly increased the expression of hepatic cholesterol 7alpha-hydroxylase, especially in rats that received cholesterol without alginate or amidated alginate. In conclusion, amidated alginate is an effective hypocholesterolemic agent that is more efficient than its parent polysaccharide. PMID- 28736039 TI - Cloning, identification and characterization of a novel kappa-carrageenase from marine bacterium Cellulophaga lytica strain N5-2. AB - A novel kappa-carrageenase gene (Cly-kappa-car) was cloned and heterologously expressed from marine bacterium Cellulophaga lytica strain N5-2. The gene comprised an open reading frame of 1488bp encoding 495 amino acid residues. The deduced protein had a calculated molecular weight of 55.24kDa with an estimated isoelectric point of 9.90. Multiple alignment analysis revealed that Cly-kappa CAR shared identity with kappa-carrageenases from Zobellia sp. M-2 (46%), Zobellia galactanivorans (42%) and Rhodopirellula islandica (38%). Recombinant Cly-kappa-CAR (R-Cly-kappa-CAR) had maximum specific activity of 620.08U/mg at 35 degrees C, pH 7.0, 0.7% kappa-carrageenan and in the presence of 0.6% NaCl. It retained >75% of its initial activity after heat treatment below 35 degrees C for 2h. More than 50% of its activity was maintained after incubation at pH 5.0-8.0 and 4 degrees C for 6h. The Km and Vmax values for kappa-carrageenan were 0.94mg/ml and 13.42mM/min/mg, respectively. Thin layer chromatographic analysis of the R-Cly-kappa-CAR hydrolysis products revealed that the enzyme hydrolyzed kappa-carrageenan into neo-kappa-carraoctaose and neo-kappa-carrahexaose. R-Cly kappa-CAR is a novel kappa-carrageenase enzyme and could be a valuable tool to produce high degree of polymerization kappa-carrageenan oligosaccharides with various biological activities. PMID- 28736040 TI - Structural characteristics and prebiotic effects of Semen coicis resistant starches (type 3) prepared by different methods. AB - In order to investigate the effects of different preparation methods on Semen coicis resistant starch, the structural properties and prebiotic effects of autoclaving treatment-purified S. coicis resistant starch (GP-SRS3), ultrasonic autoclaving treatment-purified S. coicis resistant starch (UP-SRS3), enzyme autoclaving treatment-purified S. coicis resistant starch (EP-SRS3) and microwave moisture treatment-purified S. coicis resistant starch (MP-SRS3) were studied compared to high-amylose maize starch (HAMS). Fourier transform infrared spectroscopy and Solid-state 13C NMR spectroscopy showed all of SRS3 displayed B type crystallite structure, furthermore, MP-SRS3 and UP-SRS3 showed higher degree of ordered structure and degree of double helical structure compared to other samples. Field emission scanning electron microscopy showed MP-SRS3 displayed deeply layered strips and UP-SRS3 exhibited some cavities. Moreover, S. coicis resistant starch could promote the growth of Bifidobacteria adolescentis better compared to high-amylose maize starch, among these samples. MP-SRS3 exhibited best prebiotic effect, which was possible attributed to its rough surface and double helix structure. B. adolescentis displayed a higher survival rate to the simulated gastrointestinal tract environment in SRS3 medium than that in high amylose maize starch medium, especially MP-SRS3 and UP-SRS3, which partly contributed to its strips and cavities. Overall, MP-SRS3 could be regarded as a potential prebiotic to promote the growth of B. adolescentis for its structural trait. PMID- 28736041 TI - Construction of multilayer alginate hydrogel beads for oral delivery of probiotics cells. AB - Multilayer alginate hydrogel beads (MAHBs), which were prepared by emulsion method, had been fabricated via the ionic crosslinking between calcium ion (Ca2+) and carboxylic group of alginate and utilized as encapsulating material for oral delivery of a model probiotic bacteria Bifidobacterium breve. Optical and fluorescence microscopy obviously showed the microorganism cells were encapsulated in the core beads. The viability of B. breve cells encapsulated in MAHBs was significantly enhanced compared with ordinary free cultured ones, the top CFU per mL were (3.70+/-0.20)*107 and (2.61+/-0.22)*107 respectively. Meanwhile, B. breve cells encapsulated in MAHBs could still keep viability even after 12h' culture in the broth with pH value similar to gastric juice, while the free cultured cells had no activity in such culture condition. To test applicability of MAHBs for the delivery of microorganisms, a Gram-positive strain, Staphylococcus aureus, as well as a Gram-negative strain, Escherichia coli, were also employed and encapsulated in MAHBs. Similar to B. breve cells, the viability of encapsulated S. aureus cells and E. coli cells in extreme pH value environment were significantly promoted. In addition, a high alpha-amylase yielding efficiency Bacillus subtilis strain was found and encapsulated in MAHBs. Compared with control groups, MAHBs encapsulated B. subtilis cells produced more alpha-amylase after 240h' culture, while the release of this enzyme was sustained rather than the burst release like free cultured group, which means this system would not reduce metabolite yield while having long term sustained-release effect. In summary, MAHBs are favorable biological carrier, which has the potential of being applied to oral delivery of probiotics. PMID- 28736042 TI - Enhanced antibacterial efficacy of silver nanoparticles immobilized in a chitosan nanocarrier. AB - Herein, enhanced bactericidal activity of silver nanoparticles (Ag NPs) impregnated in chitosan nanocarriers is reported. The chitosan-based nanocarrier system for Ag NPs (Ag NP-Chi NC) was synthesized by ionotropic gelation of Ag NP chitosan with tripolyphosphate. The nanocarriers were characterized by UV-vis Spectroscopy, Transmission electron microscopy, Selected area electron diffraction pattern and Dynamic light scattering. The NCs exhibited superior antibacterial efficacy against both Gram negative and Gram positive bacteria in comparison to either chitosan or Ag NPs alone. The NCs interacted with bacteria causing irreparable membrane damage as revealed by Flow Cytometry studies. The present study demonstrates the potential of Ag NP-Chi NCs as an efficient antibacterial agent. PMID- 28736043 TI - Infectious Agents Trigger Trophic Cascades. AB - Most demonstrated trophic cascades originate with predators, but infectious agents can also cause top-down indirect effects in ecosystems. Here we synthesize the literature on trophic cascades initiated by infectious agents including parasitoids, pathogens, parasitic castrators, macroparasites, and trophically transmitted parasites. Like predators, infectious agents can cause density mediated and trait-mediated indirect effects through their direct consumptive and nonconsumptive effects respectively. Unlike most predators, however, infectious agents are not fully and immediately lethal to their victims, so their consumptive effects can also trigger trait-mediated indirect effects. We find that the frequency of trophic cascades reported for different consumer types scales with consumer lethality. Furthermore, we emphasize the value of uniting predator-prey and parasite-host theory under a general consumer-resource framework. PMID- 28736044 TI - High-dose influenza vaccine in nursing home residents: not to be sneezed at. PMID- 28736045 TI - Comparative effectiveness of high-dose versus standard-dose influenza vaccination on numbers of US nursing home residents admitted to hospital: a cluster randomised trial. AB - BACKGROUND: Immune responses to influenza vaccines decline with age, reducing clinical effectiveness. We compared the effect of the more immunogenic high-dose trivalent influenza vaccine with a standard-dose vaccine to identify the effect on reducing hospital admissions of nursing home residents in the USA. METHODS: We did a single-blind, pragmatic, comparative effectiveness, cluster-randomised trial with a 2 * 2 factorial design. Medicare-certified nursing homes in the USA located within 50 miles of a Centers for Disease Control and Prevention influenza reporting city were recruited, so long as the facilities were not located in a hospital, had more than 50 long-stay residents, had less than 20% of the population aged under 65 years, and were not already planning to administer the high-dose influenza vaccine to residents. Enrolled nursing homes were randomised to a facility-wide standard of care for the residents of either high dose or standard dose as the vaccine for the 2013-14 influenza season and half of each group were randomly allocated to free vaccines for staff. Individual residents were included in the analysis group if they were aged 65 years or older and were long-stay residents (ie, had been in the facility 90 days or more before commencing the influenza vaccination programme). The analysts and investigators with access to the raw data were masked to study group by coding the groups until after the analyses were complete. The primary outcome was hospital admissions related to pulmonary and influenza-like illness between Nov 1, 2013, and May 31, 2014, identified from Medicare hospital claims available for residents who were without private health insurance (ie, those who were considered Medicare fee-for service). We obtained data from the Centers for Medicare & Medicaid Services (CMS) and enrolled facilities. The analyses used marginal Poisson and Cox proportional hazards regression, accounting for clustering of residents within homes, on an intention-to-treat basis, adjusting for facility clustering and prespecified covariates. Safety data were voluntarily reported according to the standard of care. This trial is registered with ClinicalTrials.gov, number NCT01815268. FINDINGS: 823 facilities were recruited to the study between March and August, 2013, to participate in the trial, of which 409 facilities were randomised for residents to receive high-dose vaccine, and 414 facilities for residents to receive standard-dose vaccine. The facilities housed 92 269, of whom 75 917 were aged 65 years or older and 53 008 were also long-stay residents, and 38 256 were matched to Medicare hospital claims as of Nov 1, 2013. Staff vaccination rates did not differ between groups, so analyses focused on the high dose versus standard-dose vaccine comparison. On the basis of Medicare fee-for service claims, the incidence of respiratory-related hospital admissions was significantly lower in facilities where residents received high-dose influenza vaccines than in those that received standard-dose influenza vaccines (0.185 per 1000 resident-days or 3.4% over 6 months vs 0.211 per 1000 resident-days or 3.9% over 6 months; unadjusted relative risk of 0.888, 95% CI 0.785-1.005, 0=0.061, and adjusted relative risk 0.873, 0.776-0.982, p=0.023). INTERPRETATION: When compared with standard-dose vaccine, high-dose influenza vaccine can reduce risk of respiratory-related hospital admissions from nursing home residents aged 65 years and older. FUNDING: Sanofi Pasteur, Swiftwater, PA, USA. PMID- 28736046 TI - The optical imaging of tarantula hair corneal injury: One case report and review of the literature. AB - INTRODUCTION: Tarantulas belonging to the Theraphosidae family are more and more popular as family pets. Ocular injuries caused by tarantulas are reported in several articles. We hereby report the first known case of ocular injury caused by a tarantula in China and observed by anterior segment optical coherence tomography (AS-OCT). CASE: A 22-year-old girl was referred to our hospital with one-week history of red and irritated left eye after she grabbed her molting Chilean Rose Tarantula. Her best-corrected visual acuity was 20/20 on both eyes. Her left eyelid was slightly red and edema. Slit-lamp examination found that more than a dozen of microscopic barbed hairs embedded into the cornea. AS-OCT showed that barbed hairs embedded in the cornea in different direction and the length of the hairs ranged from 173MUm to 395MUm. The anterior chamber was quiet with normal fundus and intraocular pressure. Topical steroid treatment was prescribed and the response was good. No corneal opacity or intraocular inflammation was observed after topical steroid treatment for one month. CONCLUSIONS: As exotic pets become more and more popular, the importance of wearing ocular protection when handling tarantulas should be emphasized when they are sold. Tarantulas are unsuitable pet for children. When a patient presents with an unusual red eye, pet keeping history, spiders included, should be asked. PMID- 28736047 TI - Health risk assessment as an approach to manage an old landfill and to propose integrated solid waste treatment: A case study in Italy. AB - The aim of the present paper is to show how an approach based on human health risk analysis can be used as a decisional tool for the evaluation of impacts on population and for deciding between different waste treatment processes. The situation in which the increasing production of solid wastes cannot be confined in the old existing Municipal Solid Waste landfill (settled in Genoa, Liguria Region, Italy) is used as a case study. Risk assessment for human health due to air, surface water, groundwater and soil contamination is performed in different scenarios for the old landfill and compared with alternative Waste-to-Energy management solutions that consider thermal treatment by gasification of the total waste or gasification of the dry fraction coupled with anaerobic digestion of the wet fraction, plus biogas combustion with or without sludge and bottom ash/slag disposal in the old landfill. Hazard Index (HI) and Cancer Risk (CR) in case of operating landfill and under the suspected situation of failure of the sealing system, were respectively 1.15 and 1.1*10-7. Unacceptable HI were found due to groundwater contamination, while HI due to river pollution was slightly under the threshold. Vegetables ingestion was the most important pathway and ammonia the most responsible of toxic adverse effects. Fish ingestion and dermal contact with contaminated water were found to be the most important exposure pathways for carcinogenic risk, due mainly to BTEX. HI and CR in the supposed scenario of total waste gasification were respectively 9.4*10-1 and 1.1*10-5 while they were respectively 3.2*10-1 and 6*10-6 in case of gasification of the dry fraction. CR in both scenarios was over the threshold mainly due to dioxins, where milk and meat ingestion were found to be the highest risk pathways. Inhalation resulted as the highest not-carcinogenic risk exposure pathway, mainly due to NOx. Decision making was made by weighing up the different scenarios, and results suggested to definitively close the landfill and to eliminate gasification of the total waste as a possible waste treatment process. PMID- 28736048 TI - Long chain branching as an innovative up-cycling process of polypropylene post consumer waste - Possibilities and limitations. AB - Long chain branching (LCB) was used the first time as an innovative tool for value adding to PP from household post-consumer waste. Due to the highly improved melt properties, the possible application profile is extended and not only a "re cycling" process, even a real "up-cycling" is presented. The used PP was collected from commingled household polyolefin waste, which contained different types of PP and macromolecular impurities such as 10% of polyethylene with high density (PE-HD). In addition, a single PP waste fraction from cleaned beverage and yoghurt cups was manually sorted. The up-cycled PP from single polymer waste, as well as the post-consumer blend, showed pronounced strain hardening and increased melt strength, which was comparable to LCB-PP prepared from virgin PP. However, the up-cycled post-consumer blend showed weaker mechanical performance especially low elongation at break due to PE-HD. PMID- 28736049 TI - Development of a new approach based on midwave infrared spectroscopy for post consumer black plastic waste sorting in the recycling industry. AB - Waste sorting is key to the process of waste recycling. Exact identification of plastic resin and wood products using Near Infrared (NIR, 1-1.7um) sensing is currently in use. Yet, dark targets characterized by low reflectance, such as black plastics, are hard to identify by this method. Following the recent success of Midwave Infrared (MWIR, 3-12um) measurements to identify coloured plastic polymers, the aim of this study was to assess whether this technique is applicable to sorting black plastic polymers and wood products. We performed infrared reflectance contact measurements of 234 plastic samples and 29 samples of wood and paper products. Plastic samples included black, coloured and transparent Polyethylene Terephthalate (PET), Polyethylene (PE), Polyvinyl Chloride (PVC), Polypropylene (PP), Polylactic acid (PLA) and Polystyrene (PS). The spectral signatures of the black and coloured plastic samples were compared with clear plastic samples and signatures documented in the literature to identify the polymer spectral features in the presence of coloured material. This information was used to determine the spectral bands that best suit the sorting of black plastic polymers. The main NIR-MWIR absorption features of wood, cardboard and paper were identified as well according to the spectral measurements. Good agreement was found between our measurements and the absorption features documented in the literature. The new approach using MWIR spectral features appears to be useful for black plastics as it overcomes some of the limitations in the NIR region to identify them. The main limitation of this technique for industrial applications is the trade-off between the signal-to noise ratio of the sensor operating in standoff mode and the speed at which waste is moved under the sensor. This limitation can be resolved by reducing the system's spectral resolution to 16cm-1, which allows for faster spectra acquisition while maintaining a reasonable signal-to-noise ratio. PMID- 28736050 TI - Effects of aeration and leachate recirculation on methyl mercaptan emissions from landfill. AB - The issue of odorous volatile organic sulfur compound methyl mercaptan (MM) released from landfill sites cannot be ignored for its extremely low odor threshold and high toxicity. In this study, we focused on the formation and emission of MM in four lab-scaled simulated landfill reactors running in different operation modes, namely, R1 and R2, without leachate recirculation, running under anaerobic and semi-aerobic atmosphere, R3 and R4, with leachate recirculation, running under anaerobic and semi-aerobic atmosphere, respectively. From the perspective of odor abatement, the semi-aerobic operation mode can efficiently lower the emitted MM concentration by 87.4-94.9%, relative to the semi-aerobic operation mode. Furthermore, under semi-aerobic conditions, leachate recirculation substantially shortened the period of MM influence by 12.7%, thus reducing the risk of affecting the surrounding atmospheric environment. The formation of MM was dependent on the characteristics such as the volatile fatty acid concentration and chemical oxygen demand in the leachate and sulfide concentration of the refuse. Overall, MM release can be effectively controlled with semi-aerobic operation mode and leachate recirculation. PMID- 28736051 TI - Leachate pollution index as an effective tool in determining the phytotoxicity of municipal solid waste leachate. AB - Phytoremediation is a promising option for the treatment of municipal solid waste leachate. Combining the leachate pollution index with the phytotoxicity data will be useful in predicting the suitable concentration of leachate for the phytoremediation applications. Understanding the tolerant mechanisms of plants to leachate stress will further help to select the appropriate dose. The aim of the study was to investigate the effect of different concentrations of leachate on germination, growth, chlorophyll content and antioxidant enzyme activities in the plant Vigna unguiculata. The crude leachate has an LPI value of 31.99 with high concentration of organic matter, ammonia and dissolved solids. The results of the phytotoxicity study suggest that at lower concentrations the leachate enhanced the germination and promoted plant growth. Up to 5% concentration (v/v) of the leachate which had a LPI value of 11.84 the growth promotion was observed in V. unguiculata. This was made possible by the controlled modulation of reactive oxygen species through the enhanced antioxidant enzyme activities. However at higher concentration, the pollutants in leachate disrupt the enzyme activities and leads to the peroxidation of membrane lipids and significantly affected the plant growth. The study suggest that phytotoxic effects in plants are directly related to the LPI value and leachate with LPI values less than 10 are likely to promote plant growth and LPI values greater than 10 are likely to exert detrimental effect on the plant. PMID- 28736052 TI - [New oral anticoagulants in coronary artery disease]. AB - Antiplatelet therapy is essential for the prevention of recurrent cardiovascular events in stable and unstable coronary artery disease. Oral anticoagulants have been rarely used for treatment of coronary artery disease. The new direct oral anticoagulants offer various molecules and dosages and may be used in coronary artery disease. Dedicated studies are currently being conducted to confirm the optimal doses and the ideal association of antithrombotic drugs in different settings of coronary artery disease. PMID- 28736053 TI - Structure of Ligand-Bound Intermediates of Crop ABA Receptors Highlights PP2C as Necessary ABA Co-receptor. PMID- 28736054 TI - Low sensitivity of anion gap to detect clinically significant lactic acidosis in the emergency department. AB - INTRODUCTION: Lactic acidosis represents the pathologic accumulation of lactate and hydrogen ions. It is important to efficiently diagnose lactic acidosis as delayed treatment will lead to poor patient outcomes. As plasma lactate levels may not be rapidly available, some physicians may use elevated anion gaps to test for the need to measure lactate. All Edmonton metropolitan hospitals have Radiometer blood gas/electrolyte instruments in the ED or close by. As lactate is measured for each set of electrolytes, we were able to determine the effectiveness of a screening anion gap for lactic acidosis. METHODS: Two years of emergency department lactates and electrolytes from Edmonton's 5 metropolitan hospitals were analyzed. We determined the sensitivity, specificity and positive predictive value of detecting an elevated lactate, defined as >=2.5mmol/L or >=4mmol/L. RESULTS: Depending on the elevated anion gap cut-off and the definition of elevated lactate, between 40-80% of elevated lactates are missed. In general, the positive predictive value approaches 40% for AGs >=12mmol/L and 60% for AGs >=16mmol/L. CONCLUSIONS: Anion gap is an inadequate marker of lactic acidosis. We recommend that lactate be done with each set of electrolytes and/or blood gases. In this way lactic acidosis will not be missed. PMID- 28736055 TI - Monitoring urinary orosomucoid in patients undergoing cardiac surgery: A promising novel inflammatory marker. AB - BACKGROUND: Urinary biomarkers might provide non-invasive tool for monitoring of systemic processes. We aimed to investigate the time-course of urinary orosomucoid (u-ORM) excretion after cardiac surgery hypothesizing that u-ORM is an early and sensitive marker of systemic inflammatory activation. METHODS: During a 5-day follow-up study we monitored u-ORM levels in cardiovascular patients who underwent on-pump cardiac surgery (n=38). The patients baseline data were compared to healthy control individuals (n=40). u-ORM was measured by a newly developed automated turbidimetric assay and values were referred to urinary creatinine and expressed as u-ORM/u-CREAT (mg/mmol). RESULTS: The cardiovascular patients showed slightly increased baseline u-ORM excretion compared to healthy controls (0.29 vs 0.08mg/mmol, p<0.001). After cardiac surgery, a rapid 10-fold elevation in u-ORM/u-CREAT levels was found. The values remained high till the 3rd postoperative day, and they then decreased significantly (p<0.01) on the 5th day after surgery. u-ORM/u-CREAT mirrored well the perioperative tendency of hs CRP levels, but it did not follow the non-decreasing kinetics of serum ORM concentrations during the follow-up. u-ORM/u-CREAT correlated significantly (p<0.001) with inflammatory parameters (hs-CRP, se-ORM, WBC). CONCLUSIONS: We described u-ORM as an early and sensitive marker of inflammatory activation. The rapid elevation of u-ORM/u-CREAT after surgery and its postoperative kinetics could reflect the magnitude of inflammatory response better than serum ORM and similar to hs-CRP. u-ORM measurements might provide a novel non-invasive tool for real-time monitoring of systemic inflammation, however further investigations are required to confirm it. PMID- 28736056 TI - Variability of glycated hemoglobin levels in the first year post renal transplantation in patients without diabetes. AB - BACKGROUND: Glycated hemoglobin (HbA1c) is an alternative test used for the diagnosis and monitoring of diabetes in kidney transplant recipients. Immunosuppressive drugs are the most important risk factors related with changes in the glucose metabolism after transplant. It is still unknown if they impact on the variability of HbA1c. We assessed the variability of HbA1c levels in a group of renal transplant recipients without diabetes during the first year after transplant. METHODS: We estimated the variability of HbA1c in a group of 95 Brazilian kidney transplant recipients. Three EDTA whole blood samples were collected from each patient, one every four months for twelve months, totalizing 285 blood specimens. HbA1c values were measured by HPLC (Bio-Rad VariantTM II Turbo analyzer). Estimations were calculated according to Fraser and Harris method. RESULTS: There was no difference in HbA1c mean levels between men and women. Within-subject and between-subject biological variations were 4.42% and 7.05%, respectively. The reference change value calculated for HbA1c was 16.15% and the index of individuality was 0.63. CONCLUSIONS: Kidney transplant patients without diabetes presented higher HbA1c within-subject variation than individuals without diabetes from the general population. This should be considered when interpreting HbA1c results in the diagnosis and management of diabetes after kidney transplantation. PMID- 28736057 TI - Regional variation in breast cancer surgery: Results from the National Cancer Database (NCDB). AB - BACKGROUND: Early studies have shown significant regional differences in the utilization of breast-conserving therapy (BCT) and mastectomy with reconstruction. It is expected that with the passage of time and the adoption of national treatment guidelines, these disparities would disappear. METHODS: Patients with non-metastatic breast cancer who underwent surgery between 2004 and 2013 were analyzed using the National Cancer Database (NCDB). Trends in BCT and reconstruction were evaluated and multivariate logistic regression performed. RESULTS: The highest rate of BCT was in New England (69%) and the lowest in East South Central (49%), p < 0.001. The rate of reconstruction was highest in the Middle Atlantic (44%) and the lowest in East South Central (26%), p < 0.001. Compared to East South Central, the odds ratio (OR) for BCT in New England was 2.2 (95% CI 2.1-2.3), and the OR for reconstruction in Middle Atlantic was 1.7 (95% CI 1.6-1.8). CONCLUSION: There continue to be significant regional differences in breast surgery. PMID- 28736058 TI - Nipple-sparing mastectomy using a hemi-periareolar incision - Comment on the BREAST-Q analysis. PMID- 28736059 TI - Anti-Factor Xa measurements in acute care surgery patients to examine enoxaparin dose. AB - BACKGROUND: The purpose of this study was to determine if fixed dose enoxaparin prophylaxis provided effective anticoagulation for acute care surgery patients and to examine whether a real-time enoxaparin dose adjustment algorithm optimized anticoagulation. METHODS: Acute care surgical patients placed on enoxaparin prophylaxis 30 mg twice daily were recruited prospectively. Peak steady state aFXa levels were drawn with a goal peak aFXa range of 0.2-0.4 IU/ml. A real time dose adjustment algorithm was implemented for patients with out-of-range levels. RESULTS: Fifty five patients were included. 56.4% of patients had low aFXa levels (<0.2 IU/mL). Real-time enoxaparin dose adjustment significantly increased the proportion of patients who achieved in-range peak aFXa levels, compared to standard dosing (74.5% vs 41.8%, p < 0.001). Patients with initial inadequate peak aFXa levels had a higher rate of 90-day post-operative VTE, although not statistically significant (16.1% vs. 8.3%, p = 0.50). CONCLUSION: The majority of acute care surgery patients receive inadequate VTE prophylaxis with fixed enoxaparin dosing. PMID- 28736062 TI - Ecthyma gangrenosum as first manifestation of acute leukemia. PMID- 28736060 TI - Subtotal vs. total parathyroidectomy with autotransplantation for patients with renal hyperparathyroidism have similar outcomes. AB - BACKGROUND: The optimal surgery for patients with renal hyperparathyroidism has been controversial, as either subtotal parathyroidectomy (subtotal PTX) or total parathyroidectomy with auto-transplantation (total PTX-AT) may be employed. METHODS: Adult patients having subtotal PTX or total PTX-AT for secondary hyperparathyroidism were identified from the American College of Surgeons National Surgical Quality Improvement Program, 2005-2013. RESULTS: Of 1130 patients, the majority (n = 765, 68%) underwent subtotal PTX. Total PTX-AT was associated with longer operative time (median 150 vs. 120 min, p < 0.001). Rates of complications, reoperation, readmission, and 30-day mortality were not significantly different. After adjustment, the odds of having a complication [OR 0.97, p = 0.88] and being readmitted within 30 days [OR 0.86 p = 0.62] were similar between the two procedures. Total PTX-AT was associated with prolonged hospital stay [Adjusted mean 5.0 vs. 4.1 days; (RR) 1.22, p < 0.001] compared to subtotal PTX. CONCLUSIONS: Subtotal PTX and total PTX-AT have similar rates of complications, readmission, and 30-day mortality, but subtotal PTX is less likely to have extended hospital stay. These findings have important cost implications for patients, payers, and hospitals. PMID- 28736061 TI - Short-term reconsultation, hospitalisation, and death rates after discharge from the emergency department in patients with acute heart failure and analysis of the associated factors. The ALTUR-ICA Study. AB - BACKGROUND AND OBJECTIVES: The aim of this study was to define the following in patients with acute heart failure (AHF) discharged directly from accident and emergency (A&E): rates of reconsultation to A&E and hospitalisation for AHF, and all-cause death at 30 days, rate of combined event at 7 days and the factors associated with these rates. PATIENTS AND METHOD: The study included patients consecutively diagnosed with AHF during 2 months in 27 Spanish A&E departments who were discharged from A&E without hospitalisation. We collected 43 independent variables, monitored patients for 30 days and evaluated predictive factors for adverse events using Cox regression analysis. RESULTS: We evaluated 785 patients (78+/-9) years, 54.7% women). The rates of reconsultation, hospitalisation, and death at 30 days and the combined event at 7 days were: 26.1, 15.7, 1.7 and 10.6%, respectively. The independent factors associated with reconsultation were no endovenous diuretics administered in A&E (HR 2.86; 95% CI 2.01-4.04), glomerular filtration rate (GFR)<60ml/min/m2 (1.94; 1.37-2.76) and previous AHF episodes (1.48; 1.02-2.13); for hospitalisation these factors were no endovenous diuretics in A&E (2.97; 1.96-4.48), having heart valve disease (1.61; 1.04-2.48), blood oxygen saturation at arrival to A&E<95% (1.60; 1.06-2.42); and for the combined event no endovenous diuretics in A&E (3.65; 2.19-6.10), GFR<60ml/min/m2 (2.22; 1.31-3.25), previous AHF episodes (1.95; 1.04-3.25), and use of endovenous nitrates (0.13; 0.02-0.99). CONCLUSION: This is the first study in Spain to describe the rates of adverse events in patients with AHF discharged directly from A&E and define the associated factors. These data should help establish the most adequate approaches to managing these patients. PMID- 28736063 TI - Bladder cancer: Present and future. AB - Bladder cancer has a high incidence and involves high associated morbidity and mortality. Since its initial clinical suspicion, early diagnostic confirmation and multimodal treatment involve different medical specialties. For this reason, we consider it important to spread the current consensus for its management. Recent advances in immunology and Chemotherapy make it necessary to expose and reflect on future perspectives. PMID- 28736064 TI - New pathogenic variant in the NPR2 gene: Etiology of low size, macrocephaly and bone dysplasia in a male with acromesomelic dysplasia Maroteaux-type. PMID- 28736065 TI - Common variable immunodeficiency-associated granulomatous and lymphocytic interstitial lung disease successfully treated with a combination regimen of rituximab and azathioprine. PMID- 28736066 TI - Hypokalemia due to excessive cola consumption. PMID- 28736067 TI - Necrobiotic xanthogranuloma associated with monoclonal gammopathy of unknown significance. PMID- 28736068 TI - Gastrointestinal stromal tumour and second tumours: A literature review. AB - There are several tumours associated with gastrointestinal stromal tumour (GIST), most of them without an apparent family relationship; only 5% of them occur within the context of a family syndrome. In this article the corresponding literature about the former has been reviewed. A search in Pubmed was carried out, the methodology of which is described in detail in the body of the article. A total of 88 articles have been chosen for the review, next to the application of limits as well as a manual review. GIST patients have a twofold risk of developing a second tumour than the general population (4-33% of them develop a second neoplasm, either synchronic or metachronic). Most incident tumours associated with GIST are gastrointestinal and genitourinary tumours. In addition, patients with second tumours have a worse survival rate than those without second tumours. PMID- 28736069 TI - Differences between craving and health-related quality of life in patients with alcohol dependence with or without dual pathology in outpatient treatment: A descriptive study. AB - BACKGROUND AND OBJECTIVE: Dual diagnosis is the coexistence of an addictive disorder and another mental disorder. The objective is to estimate cravings and self-reported quality of life in a sample of patients with alcoholic dependence, with or without dual pathology, who attend an outpatient treatment centre. PATIENTS AND METHOD: A cross-sectional study of 112 patients (56 dual and 56 non dual), diagnosed with alcohol dependence according to DSM-IV-TR. The presence of cravings is determined by the Multidimensional Alcohol Craving Scale and quality of life through the SF-36 Health Questionnaire. RESULTS: There are no statistically significant differences in cravings in either subgroup; the latter tend to refer to lower alcohol cravings than non-dual patients. The dual patients have a worse quality of life in all categories evaluated, highlighting a worse quality of life in the categories: social function, emotional role, vitality and general health. Females present a lower quality of life emphasising those of social function and emotional role. No differences were detected in relation to cravings between the 2 groups. CONCLUSIONS: In order to perform a correct clinical and therapeutic approach for patients with alcohol dependence, we should consider focusing on the evaluation of cravings and quality of life. In order to perform a correct clinical and therapeutic approach for patients with alcohol dependence, it is necessary to consider cravings and quality of life, since these parameters are important for the evaluation of patients with alcohol dependence. PMID- 28736070 TI - Persistent hiccups in children after thoracic aggression. PMID- 28736071 TI - A disease-specific questionnaire for measuring patient-reported outcomes and experiences in the Swedish National Diabetes Register: Development and evaluation of content validity, face validity, and test-retest reliability. AB - OBJECTIVE: To describe the development and evaluation of the content and face validity and test-retest reliability of a disease-specific questionnaire that measures patient-reported outcomes and experiences for the Swedish National Diabetes Register for adult patients who have type 1 or type 2 diabetes. METHODS: In this methodological study, a questionnaire was developed over four phases using an iterative process. Expert reviews and cognitive interviews were conducted to evaluate content and face validity, and a postal survey was administered to evaluate test-retest reliability. RESULTS: The expert reviews and cognitive interviews found the disease-specific questionnaire to be understandable, with relevant content and value for diabetes care. An item-level content validity index ranged from 0.6-1.0 and a scale content validity/average ranged from 0.7-1.0. The fourth version, with 33 items, two main parts and seven dimensions, was answered by 972 adults with type 1 and type 2 diabetes (response rate 61%). Weighted Kappa values ranged from 0.31-0.78 for type 1 diabetes and 0.27-0.74 for type 2 diabetes. CONCLUSIONS: This study describes the initial development of a disease-specific questionnaire in conjunction with the NDR. Content and face validity were confirmed and test-retest reliability was satisfactory. PRACTICE IMPLICATIONS: With the development of this questionnaire, the NDR becomes a clinical tool that contributes to further understanding the perspectives of adult individuals with diabetes. PMID- 28736072 TI - Antibacterial activities of natural lichen compounds against Streptococcus gordonii and Porphyromonas gingivalis. AB - The oral bacteria not only infect the mouth and reside there, but also travel through the blood and reach distant body organs. If left untreated, the dental biofilm that can cause destructive inflammation in the oral cavity may result in serious medical complications. In dental biofilm, Streptococcus gordonii, a primary oral colonizer, constitutes the platform on which late pathogenic colonizers like Porphyromonas gingivalis, the causative agent of periodontal diseases, will bind. The aim of this study was to determine the antibacterial activity of eleven natural lichen compounds belonging to different chemical families and spanning from linear into cyclic and aromatic structures to uncover new antibiotics which can fight against the oral bacteria. The compounds were screened by broth microdilution assay. Three compounds were shown to have promising antibacterial activities where the depsidone core with certain functional groups constituted the best compound, psoromic acid, with the lowest MICs=11.72 and 5.86MUg/mL against S. gordonii and P. gingivalis, respectively. The compounds screened had promising antibacterial activity which might be attributed to some important functional groups as discussed in our study. The best compounds did not induce the death of gingival epithelial carcinoma cells (Ca9-22). These results introduce new compounds having potent antibacterial activities against oral pathogens causing serious medical complications. PMID- 28736073 TI - Post-eculizumab meningococcaemia in vaccinated patients. PMID- 28736075 TI - Editorial: Positive developments for JCIS. PMID- 28736074 TI - A novel genetic variant of Streptococcus pneumoniae serotype 11A discovered in Fiji. AB - OBJECTIVES: As part of annual cross-sectional Streptococcus pneumoniae carriage surveys in Fiji (2012-2015), we detected pneumococci in over 100 nasopharyngeal swabs that serotyped as '11F-like' by microarray. We examined the genetic basis of this divergence in the 11F-like capsular polysaccharide (cps) locus compared to the reference 11F cps sequence. The impact of this diversity on capsule phenotype, and serotype results using genetic and serologic methods were determined. METHODS: Genomic DNA from representative 11F-like S. pneumoniae isolates obtained from the nasopharynx of Fijian children was extracted and subject to whole genome sequencing. Genetic and phylogenetic analyses were used to identify genetic changes in the cps locus. Capsular phenotypes were evaluated using the Quellung reaction and latex agglutination. RESULTS: Compared to published 11F sequences, the wcwC and wcrL genes of the 11F-like cps locus are phylogenetically divergent, and the gct gene contains a single nucleotide insertion within a homopolymeric region. These changes within the DNA sequence of the 11F-like cps locus have modified the antigenic properties of the capsule, such that 11F-like isolates serotype as 11A by Quellung reaction and latex agglutination. CONCLUSIONS: This study demonstrates the ability of molecular serotyping by microarray to identify genetic variants of S. pneumoniae and highlights the potential for discrepant results between phenotypic and genotypic serotyping methods. We propose that 11F-like isolates are not a new serotype but rather are a novel genetic variant of serotype 11A. These findings have implications for invasive pneumococcal disease surveillance as well as studies investigating vaccine impact. PMID- 28736076 TI - Suppression of IgE-mediated mast cell activation and mouse anaphylaxis via inhibition of Syk activation by 8-formyl-7-hydroxy-4-methylcoumarin, 4MU8C. AB - Mast cells trigger IgE-mediated allergic reactions by releasing various allergic mediators. 8-Formyl-7-hydroxy-4-methylcoumarin, also called 4MU8C, was originally known as an inositol-requiring enzyme 1 (IRE1) suppressant, but no study has examined its relationship with mast cells and allergic diseases. Therefore, the purpose of this study was to determine whether 4MU8C is effective in suppressing allergic reactions in mast cells and in IgE-mediated allergic animal model. 4MU8C suppressed the degranulation of IgE-mediated mast cells (IC50=3.2MUM) and the production of cytokines such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-4 (IL-4) in a dose-dependent manner. 4MU8C also suppressed passive cutaneous anaphylaxis (PCA) in mice (ED50=25.1mg/kg). In an experiment on mast cell signaling pathways stimulated by antigen, the phosphorylation and activation of Syk was decreased by 4MU8C, and phosphorylation of downstream signaling molecules, such as linker for activated T cells (LAT), Akt, and the three MAP kinases, ERK, p38, and JNK, were suppressed. Mechanistic studies showed that 4MU8C inhibited the activity of Lyn and Fyn in vitro. Based on the results of those experiments, the suppressor mechanism of allergic reaction by 4MU8C involved reduced activity of Lyn and Fyn, which is pivotal in an IgE-mediated signaling pathway. In summary, for the first time, this study shows that 4MU8C inhibits Lyn and Fyn, thus suppressing allergic reaction by reducing the degranulation and the production of inflammatory cytokines. This suggests that 4MU8C can be used as a new medicinal candidate to control allergic diseases such as seasonal allergies and atopic dermatitis. PMID- 28736077 TI - Replication of the Zika virus in different iPSC-derived neuronal cells and implications to assess efficacy of antivirals. AB - Infections with the Zika virus (ZIKV) are responsible for congenital abnormalities and neurological disorders. We here demonstrate that ZIKV productively infects three types of human iPSC (induced pluripotent stem cells) derived cells from the neural lineage, i.e. cortical and motor neurons as well as astrocytes. ZIKV infection results in all three cell types in the production of infectious virus particles and induces cytopathic effects (CPE). In cortical and motor neurons, an Asian isolate (PRVABC59) produced roughly 10-fold more virus than the prototypic African strain (MR766 strain). Viral replication and CPE is efficiently inhibited by the nucleoside polymerase inhibitor 7-deaza-2'-C methyladenosine (7DMA). However, ribavirin and favipiravir, two molecules that inhibit ZIKV replication in Vero cells, did not inhibit ZIKV replication in the neuronal cells. These results highlight the need to assess the potential antiviral activity of novel ZIKV inhibitors in stem cell derived neuronal cultures. PMID- 28736078 TI - Patellar tendon in vivo regional strain with varying knee angle. AB - PURPOSE: Descriptive data on the aspects of site specific in vivo tendon strain with varying knee joint angle are non-existent. The present study determines and compares surface and deep layer strain of the patellar tendon during isometric contractions across a range of knee joint angles. METHODS: Male participants (age 22.0+/-3.4) performed ramped isometric knee extensions at knee joint angles of 90 degrees , 70 degrees , 50 degrees and 30 degrees of flexion. Strain patterns of the anterior and posterior regions of the patellar tendon were determined using real-time B-mode ultrasonography at each knee joint angle. Regional strain measures were compared using an automated pixel tracking method. RESULTS: Strain was seen to be greatest for both the anterior and posterior regions with the knee at 90 degrees (7.76+/-0.89% and 5.06+/-0.76%). Anterior strain was seen to be significantly greater (p<0.05) than posterior strain for all knee angles apart from 30 degrees , 90 degrees =(7.76vs. 5.06%), 70 degrees =(4.77vs. 3.75%), and 50 degrees =(3.74vs. 2.90%). The relative strain (ratio of anterior to posterior), was greatest with the knee joint angle at 90 degrees , and decreased as the knee joint angle reduced. CONCLUSIONS: The results from this study indicate that not only are there greater absolute tendon strains with the knee in greater flexion, but that the knee joint angle affects the regional strain differentially, resulting in greater shear between the tendon layers with force application when the knee is in greater degrees of flexion. These results have important implications for rehabilitation and training. PMID- 28736079 TI - Model-based cap thickness and peak cap stress prediction for carotid MRI. AB - A rupture-prone carotid plaque can potentially be identified by calculating the peak cap stress (PCS). For these calculations, plaque geometry from MRI is often used. Unfortunately, MRI is hampered by a low resolution, leading to an overestimation of cap thickness and an underestimation of PCS. We developed a model to reconstruct the cap based on plaque geometry to better predict cap thickness and PCS. We used histological stained plaques from 34 patients. These plaques were segmented and served as the ground truth. Sections of these plaques contained 93 necrotic cores with a cap thickness <0.62mm which were used to generate a geometry-based model. The histological data was used to simulate in vivo MRI images, which were manually delineated by three experienced MRI readers. Caps below the MRI resolution (n=31) were (digitally removed and) reconstructed according to the geometry-based model. Cap thickness and PCS were determined for the ground truth, readers, and reconstructed geometries. Cap thickness was 0.07mm for the ground truth, 0.23mm for the readers, and 0.12mm for the reconstructed geometries. The model predicts cap thickness significantly better than the readers. PCS was 464kPa for the ground truth, 262kPa for the readers and 384kPa for the reconstructed geometries. The model did not predict the PCS significantly better than the readers. The geometry-based model provided a significant improvement for cap thickness estimation and can potentially help in rupture-risk prediction, solely based on cap thickness. Estimation of PCS estimation did not improve, probably due to the complex shape of the plaques. PMID- 28736080 TI - The effect of ankle foot orthosis alignment on walking in individuals treated for traumatic lower extremity injuries. AB - Limb salvage surgeries are performed to treat a variety of lower limb pathologies and traumatic injuries. Individuals who have undergone limb salvage surgeries may require an ankle foot orthosis (AFO) to compensate for limb impairments and restore walking ability. Understanding the effects of AFO design parameters on gait biomechanics is important to refine AFO prescription criteria. In this study sagittal plane kinematic and kinetic data, muscle activity and alignment preference were examined as individuals treated for traumatic lower extremity injuries (N=12) walked over level ground with Plantarflexed (PF), Neutral, and Dorsiflexed (DF) aligned AFOs. A PF alignment resulted in earlier center of pressure progression (p<0.007) and a resulting decrease in both internal knee extensor moment (p<0.001) and quadriceps and soleus muscle activity (p<0.014) compared to the Neutral and DF alignments without affecting the lower limb support moment. A clear alignment preference was observed, with eight participants preferring the PF over the Neutral and DF alignments. The increase in internal knee extensor moment between the PF and DF alignments in the present study is consistent with previous investigations in other patient populations, suggesting a more DF aligned AFO may affect the knee joint moment similarly across patient populations. The results of this study suggest AFO alignment is an important design parameter that affects ankle and knee joint moments and muscle activity and should be carefully considered during AFO design and clinical fitting. PMID- 28736081 TI - Frizzled-7 mediates TGF-beta-induced pulmonary fibrosis by transmitting non canonical Wnt signaling. AB - : Pulmonary fibrosis is a progressive and often fatal lung disease characterized by fibroblast proliferation and excessive deposition of extracellular matrix. Both TGF-beta and Wnt signaling have been implicated in the regulation of organ fibrosis. However little is known about whether TGF-beta-induced gene expression changes in Wnt signaling pathway could predict disease progression. In the study, we investigated the interaction between TGF-beta and Wnt signaling in mediating pulmonary fibrosis by big data analysis, in vitro and in vivo experimental studies and clinical data analysis. We found that TGF-beta1 treatment induces a marked upregulation of Frizzled-7 (FZD7) in human lung fibroblasts. FZD7 expression is also increased in animal models of TGF-beta1-induced pulmonary fibrosis. TGF-beta1 upregulated FZD7 expression in a Smad3-dependent manner. Functionally, knockdown of FZD7 inhibits TGF-beta1-induced expression of alpha smooth muscle actin (alpha-SMA), collagen I (Col I), fibronectin and connective tissue growth factor (CTGF). FZD7 inhibition further attenuates TGF-beta1-induced pulmonary fibrosis in vivo. Finally our data demonstrated that FZD7 transmits non canonical Wnt signaling by interacting Wnt5A in the regulation of ECM expression. CONCLUSION: These results suggest that FZD7-targeted therapeutic strategies may be applicable for treating an array of fibrotic diseases. PMID- 28736082 TI - Differential proteome expression analysis of androgen-dependent and -independent pathways in LNCaP prostate cancer cells. AB - Prostate cancer (PC) is one of the leading causes of cancer death in men. It commonly develops in older males, but the number of younger men diagnosed with the disease has increased in recent years. Hormone therapies, such as chemical and surgical methods that inhibit androgen synthesis or androgen receptor (AR) activation, have been used for advanced disease. However, castration-resistant PC (CRPC), which exhibits androgen-independent mechanisms for activating AR, develops after a few years of such treatment and no therapy is available. In this study, we examined differences in the proteomes associated with the androgen dependent (DHT treatment) and -independent (FSK, forskolin treatment) AR signaling conditions in LNCaP prostate cancer cells. Moreover, we used EPI-001, which inhibits AR-mediated transcriptional activity, to examine whether the observed differences in protein expression were directly affected by AR-mediated mechanisms. A total of 213 protein spots were matched in our 2-dimensional gel electrophoresis (2DE) analysis and 8 proteins with significant expression changes in our 5 different treatment groups were identified by mass spectrometry. Among these proteins, expression levels of PEPCK-M, catalase, tubulin alpha chain, alpha-enolase, and endoplasmic reticulum resident protein 29 were significantly altered by DHT and the levels of HSP 90 and EF-Tu were changed by FSK. These changes were blocked by EPI-001 in DHT-regulated proteins, PEPCK-M, catalase, and tubulin alpha chain and FSK-regulated EF-Tu protein. The results from our immunohistochemical analysis using in vivo xenograft models were consistent with the 2DE data. We therefore report the first identification of differences in proteins that are significantly regulated under androgen-dependent and independent AR signaling conditions. Our findings could suggest a possible molecular mechanism through which AR is activated in the absence and/or presence of androgen, and might help explain the inhibitory action of EPI-001 on CRPC. PMID- 28736083 TI - Evolution to the early detection of severity. Where are we going? PMID- 28736084 TI - Increasing time to stop cardiopulmonary resuscitation in out of hospital cardiac arrest. PMID- 28736085 TI - Low cardiac output syndrome in the postoperative period of cardiac surgery. Profile, differences in clinical course and prognosis. The ESBAGA study. AB - OBJECTIVES: An analysis is made of the clinical profile, evolution and differences in morbidity and mortality of low cardiac output syndrome (LCOS) in the postoperative period of cardiac surgery, according to the 3 diagnostic subgroups defined by the SEMICYUC Consensus 2012. DESIGN: A multicenter, prospective cohort study was carried out. SETTING: ICUs of Spanish hospitals with cardiac surgery. PATIENTS: A consecutive sample of 2,070 cardiac surgery patients was included, with the analysis of 137 patients with LCOS. INTERVENTIONS: No intervention was carried out. RESULTS: The mean patient age was 68.3+/-9.3 years (65.2% males), with a EuroSCORE II of 9.99+/-13. NYHA functional class III-IV (52.9%), left ventricular ejection fraction<35% (33.6%), AMI (31.9%), severe PHT (21.7%), critical preoperative condition (18.8%), prior cardiac surgery (18.1%), PTCA/stent placement (16.7%). According to subgroups, 46 patients fulfilled hemodynamic criteria of LCOS (group A), 50 clinical criteria (group B), and the rest (n=41) presented cardiogenic shock (group C). Significant differences were observed over the evolutive course between the subgroups in terms of time subjected to mechanical ventilation (114.4, 135.4 and 180.3min in groups A, B and C, respectively; P<.001), renal replacement requirements (11.4, 14.6 and 36.6%; P=.007), multiorgan failure (16.7, 13 and 47.5%), and mortality (13.6, 12.5 and 35.9%; P=.01). The mean maximum lactate concentration was higher in cardiogenic shock patients (P=.002). CONCLUSIONS: The clinical evolution of these patients leads to high morbidity and mortality. We found differences between the subgroups in terms of the postoperative clinical course and mortality. PMID- 28736086 TI - Chronic depression and post-chikungunya rheumatological diseases: Is the IL 8/CXCL8 another associated mediator? PMID- 28736087 TI - Sphingomonads in Microbe-Assisted Phytoremediation: Tackling Soil Pollution. AB - Soil pollution has become a major concern in various terrestrial ecosystems worldwide. One in situ soil bioremediation strategy that has gained popularity recently is microbe-assisted phytoremediation, which is promising for remediating pollutants. Sphingomonads, a versatile bacteria group comprising four well-known genera, are ubiquitous in vegetation grown in contaminated soils. These Gram negative microbes have been investigated for their ability to induce innate plant growth-promoting (PGP) traits, including the formation of phytohormones, siderophores, and chelators, in addition to their evolutionary adaptations enabling biodegradation and microbe-assisted removal of contaminants. However, their capacity for bacterial-assisted phytoremediation has to date been undervalued. Here, we highlight the specific features, roles, advantages, and challenges associated with using sphingomonads in plant-microbe interactions, from the perspective of future phytotechnologies. PMID- 28736088 TI - Fetopathological examination for the fetuses with Down syndrome in Tunisia: Epidemiological study and associated malformations. AB - BACKGROUND: For Down syndrome (DS), traditional epidemiological studies to determine the prevalence, cause, and clinical significance of the syndrome have been conducted over the last 100 years. In Tunisia, the current work is the first in-depth study in epidemiology of DS from fetopathological data. AIM OF THE STUDY: The aim of this epidemiological study was to determine the impact of some feto-maternal characteristics in occurrence of DS and to search the frequency of associated congenital malformations with this syndrome. METHODS: Our retrospective study was realized for 144 fetuses with DS among 9321 autopsied fetuses in embryo-fetopathological service between 1994 and 2011. RESULTS: In our study, the majority of mothers (72.91%) were 35 years and older, with a statistically significant difference (p<10-6, OR=16.7, CI=8.7-32.4). The abnormalities of extremities (31%) were the most common fetal abnormalities followed by facial (23.51%) and digestive abnormalities (19.63%). CONCLUSION: One of the main conclusions of this research is that the most common risk factor for DS is maternal age. On the other hand, the type and the frequency of associated congenital anomalies with DS are still controversial. PMID- 28736089 TI - Long-term cognitive impairment and delirium in intensive care: A prospective cohort study. AB - BACKGROUND: Whilst there is a growing body of research exploring the effect of delirium in intensive care unit (ICU) patients, the relationship between patient delirium and long-term cognitive impairment has not been investigated in settings where low rates of delirium have been reported. OBJECTIVES: To assess the association between the incidence of delirium, duration of mechanical ventilation and long term cognitive impairment in general ICU patients. METHODS: Prospective cohort study conducted in a tertiary level ICU in Queensland, Australia. Adult medical and surgical ICU patients receiving >=12h mechanical ventilation were assessed for delirium on at least one day. Cognitive impairment was assessed at three and/or six-months using the: Repeatable Battery for the Assessment of Neuropsychological Status (RBANS); Trail Making Test (TMT) Part A and B; and Mini Mental State Examination (MMSE). RESULTS: Of 148 enrollees, 91 (61%) completed assessment at three and/or six months. Incidence of delirium was 19%, with 41% cognitively impaired at three months and 24% remaining impaired at six months. Delirium was associated with impaired cognition at six-months: mean TMT Part A scores (information processing speed) were 7.86s longer than those with no delirium (p=0.03), and mean TMT Part B scores (executive functioning) 24.0s longer (p=0.04). CONCLUSIONS: ICU delirium was positively associated with impaired information processing speed and executive functioning at six-months post-discharge for this cohort. Testing for cognitive impairment with RBANS and TMT should be considered due to its greater sensitivity in comparison to the MMSE. PMID- 28736090 TI - Never say never: Identification of acute pulmonary embolism on non-contrast computed tomography imaging. AB - Acute undifferentiated illness remains a critical challenge for the emergency physician. The diagnostic evaluation and treatment decisions on such severely ill patients often needs to be made in an expedited fashion. Situations occur wherein the ideal or recommended workup is not always feasible due to time or patient specific factors. We present two cases of patients with undifferentiated acute illness who had undergone non-contrast CT (computed tomography) scanning and subsequently had central pulmonary embolism identified upon careful review of their CT studies. PMID- 28736091 TI - A novel method for epistaxis management: Randomized clinical trial comparing nose clip with manual compression. PMID- 28736092 TI - Epidemiology and clinical outcomes of tuberculosis among homeless persons visiting emergency department in public hospital. PMID- 28736093 TI - Treatment of ED patients with bacteriuria/pyuria of clinically undetermined significance. PMID- 28736094 TI - From Japan to Europe: the importance to assess excessive daytime sleepiness in adults with ADHD symptoms. PMID- 28736095 TI - Predictors of CPAP failure in OSA/COPD overlap: in which direction one may look: Daytime hypercapnia and nocturnal hypoxia are independent predictors of early CPAP failure in patients with the OSA-COPD overlap syndrome. PMID- 28736096 TI - Pneumoperitoneum by Inguinal Laceration after Traffic Accident. AB - BACKGROUND: The leading cause of surgical pneumoperitoneum is hollow viscus perforation, which accounts for approximately 90% of cases. A nonsurgical etiology may account for up to about 10% of the causes of pneumoperitoneum. However, a pneumoperitoneum often poses significant management dilemmas for surgeons, especially when signs of peritonitis are absent or when the cause is unknown prior to laparotomy. We present the first case of pneumoperitoneum due to inguinal laceration without viscus perforation after a traffic accident. CASE REPORT: A 17-year-old male patient was admitted to the emergency department with a deep laceration of 7~8 cm with bleeding in the right inguinal region after a collision with a passenger car while riding a bicycle. The abdominal examination revealed diffuse abdominal tenderness on deep palpation without peritoneal signs. A chest radiograph showed no free gas below the diaphragm. On computed tomography angiography of the aorta, subcutaneous emphysema in the right inguinal and femoral areas and free air in the peritoneal cavity were observed. There was no bowel perforation in an exploratory laparotomy, but the right femoral sheath ruptured, and exposure of the femoral vessels into the peritoneal cavity was observed. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: A pneumoperitoneum can be caused by femoral sheath rupture without hollow viscus perforation in patients with a penetrating groin injury. Therefore, emergency physicians should not pursue solely abdominal/pelvic sources of a pneumoperitoneum in patients with a penetrating groin injury. PMID- 28736097 TI - Alcoholic Pellagra as a Cause of Altered Mental Status in the Emergency Department. AB - BACKGROUND: Pellagra, which is caused by a deficiency of niacin and tryptophan, the precursor of niacin, is a rare disease in developed countries where alcoholism is a major risk factor due to malnutrition and lack of B vitamins. Although pellagra involves treatable dementia and psychosis, it is often underdiagnosed, especially in developed countries. CASE REPORT: In Japan, a 37 year-old man presented to the emergency department with altered mental status and seizures. Wernicke encephalopathy and alcohol withdrawal were suspected. The patient was treated with multivitamins, which did not include nicotinic acid amide, and oral diazepam. Despite medical treatment, his cognitive impairment progressively worsened, and eventually, pellagra was suspected. His response to treatment with nicotinic acid amide was substantial, and he was discharged without any long-term sequelae. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Despite the treatable dementia and psychosis, pellagra is often underdiagnosed, especially in developed countries and alcoholic patients. Pellagra should be routinely suspected in alcoholic patients because the response to appropriate treatment is typically dramatic. PMID- 28736098 TI - Posterior canal wall reposition for management of cholesteatoma: Technique and results. AB - OBJECTIVE: The main goal of surgery in acquired middle ear cholesteatomas is the complete eradication of the disease with an ear free of discharge. This can be performed either by open or closed techniques with their benefits and drawbacks. We present the technique of reposition of the posterior canal wall for the management of cholesteatoma cases and its results and outcome. PATIENTS AND METHODS: This study included 31 patients with primary acquired middle ear cholesteatoma. The surgical technique included complete cortical mastoidectomy, wide posterior tympanotomy, dividing the bony posterior meatal wall with a micro sagittal saw and its removal, dissection and eradication of cholesteatoma, and repositioning the canal wall segment in its anatomical site. RESULTS: No significant intraoperative complication occurred. An injury to the dura occurred in one patient. Damage of the bony posterior canal wall occurred in two patients during saw cutting. Residual cholesteatoma was found in two patients. No dislocation or necrosis of the reconstructed posterior canal wall was noted and the new reconstructed external ear canal appeared to be of near normal size, shape, and contour. CONCLUSION: This technique provides optimal surgical exposure and access to areas that are difficult to reach by CWU approach, allows removal of the cholesteatoma without intraoperative complications, decreases the rate of residual cholesteatoma, restores near-normal anatomy of the external auditory canal, and avoids the sequelae of the open mastoid cavity. Therefore, it would be a feasible alternative to the standard CWU and CWD procedures. PMID- 28736099 TI - Selective anterior interosseous nerve conduction study: Coaxial needle versus surface electrode recordings. AB - OBJECTIVES: The aim is to determine which method provides the most selective motor nerve conduction of the anterior interosseous nerve (AIN), when the stimulation cannot be restricted to this nerve. METHODS: The AIN was stimulated at the elbow, along with the whole median nerve. The motor action potential (MAP) of the AIN was recorded with 2 different methods: 1 - a coaxial needle inserted in the pronator quadratus muscle (PQ); 2 - a pair of surface electrodes fixed on the PQ. Twenty-two controls and 4 patients with AIN palsy were studied with both methods. Two among the patients were also examined with a 3rd method involving a pair of surface electrodes fixed on the flexor pollicis longus. RESULTS: For controls, with needle recording, distal motor latency (DML) to the PQ was 4.2ms and PQ MAP amplitude was 15.0mV. With surface recording, distal motor latency (DML) to the PQ was 3.1ms and PQ compound MAP (CMAP) amplitude was 5.1mV. For patients, with needle recording, DML was normal, and MAP amplitude was drastically decreased as compared with controls, while with surface recording, DML and CMAP amplitude showed no substantial change. DISCUSSION AND CONCLUSIONS: These results demonstrate that recording with a coaxial needle electrode inserted in the PQ is the only method to provide a specific NCS of the AIN, and permit the diagnosis of isolated AIN lesions, which could otherwise be missed. PMID- 28736100 TI - Consensus document on the diagnosis and treatment of sexually transmitted diseases in adults, children and adolescents. AB - Sexually transmitted diseases (STDs) are one of the most common and universal problems of public health. Human immunodeficiency virus (HIV) and STD infections are clearly interrelated, and share risks, incidence and transmission mechanisms. The aim of this document is to inform health professionals about the current situation and management of STDs, which, because of their relevance, need greater care, both in the general population and in the population with HIV. These guidelines for STD treatment, although clinically oriented and focused especially on treatment, contain other aspects related to assessing and evaluating patients, as well as recommendations for diagnosis. PMID- 28736101 TI - Choice of antipsychotic to treat first-episode schizophrenia. PMID- 28736102 TI - Antipsychotic drugs for the acute treatment of patients with a first episode of schizophrenia: a systematic review with pairwise and network meta-analyses. AB - BACKGROUND: The first episode of schizophrenia is a pivotal phase of this debilitating illness. Which drug to use remains controversial without a summary of all direct or indirect comparisons of drugs. We did a systematic review with pairwise and network meta-analyses of efficacy and tolerability. METHODS: We searched MEDLINE, Embase, PsycINFO, Cochrane Library, PubMed, Biosis, and ClinicalTrials.gov for randomised controlled trials of antipsychotics for the acute treatment of first-episode schizophrenia, published up to Nov 17, 2016. Our primary outcome was overall change in symptoms. Secondary outcomes were change in positive and negative symptoms, categorical response to treatment, study dropout for any reason and for inefficacy of treatment, use of drugs to treat parkinsonian symptoms, weight gain, sedation, increase in prolactin release, overall functioning, and quality of life. We did the meta-analyses with a random effects model to calculate standardised mean differences (SMDs) or odds ratios (ORs) with 95% CIs. FINDINGS: We identified 19 relevant randomised controlled trials of 12 antipsychotic drugs that involved 2669 participants. 13 of the studies presented data on the primary outcome. For overall reduction of symptoms, amisulpride (SMD -0.37, 95% CI -0.61 to -0.14), olanzapine (-0.25, -0.39 to 0.12), ziprasidone (-0.25, -0.48 to -0.01), and risperidone (-0.14, -0.27 to 0.01) were significantly more efficacious than haloperidol, but the evidence was very low to moderate quality. Amisulpride was superior for reduction of symptoms to quetiapine (SMD -0.25, 95% CI -0.50 to -0.01). Olanzapine was superior to haloperidol and risperidone for reduction of negative symptoms. Several second generation antipsychotics were superior to haloperidol in terms of all-cause discontinuation. Olanzapine was associated with at least one use of drugs to treat parkinsonian symptoms and quetiapine with less akathisia than haloperidol, aripiprazole, risperidone, and olanzapine, but, again, evidence was very low to low quality. Molindone was superior to risperidone, haloperidol, and olanzapine in terms of weight gain, and superior to risperidone in terms of increase in prolactin release. INTERPREATION: Haloperidol seems to be a suboptimum treatment option for acute treatment of first-episode schizophrenia, but we found little difference between second-generation antipsychotics. The evidence was generally of low quality and the numbers of patients for each drug were small. Thus, the choice of treatment should be guided primarily by side-effects. FUNDING: German Federal Ministry of Education and Research. PMID- 28736103 TI - What Impact Do Chaplains Have? A Pilot Study of Spiritual AIM for Advanced Cancer Patients in Outpatient Palliative Care. AB - CONTEXT: Spiritual care is integral to quality palliative care. Although chaplains are uniquely trained to provide spiritual care, studies evaluating chaplains' work in palliative care are scarce. OBJECTIVES: The goals of this pre post study, conducted among patients with advanced cancer receiving outpatient palliative care, were to evaluate the feasibility and acceptability of chaplain delivered spiritual care, utilizing the Spiritual Assessment and Intervention Model ("Spiritual AIM"), and to gather pilot data on Spiritual AIM's effects on spiritual well-being, religious and cancer-specific coping, and physical and psychological symptoms. METHODS: Patients with advanced cancer (N = 31) who were receiving outpatient palliative care were assigned based on chaplains' and patients' outpatient schedules, to one of three professional chaplains for three individual Spiritual AIM sessions, conducted over the course of approximately six to eight weeks. Patients completed the following measures at baseline and post intervention: Edmonton Symptom Assessment Scale, Steinhauser Spirituality, Brief RCOPE, Functional Assessment of Chronic Illness Therapy-Spiritual (FACIT-Sp-12), Mini-Mental Adjustment to Cancer (Mini-MAC), Patient Dignity Inventory, Center for Epidemiological Studies-Depression (10 items), and Spielberger State Anxiety Inventory. RESULTS: From baseline to post-Spiritual AIM, significant increases were found on the FACIT-Sp-12 Faith subscale, the Mini-MAC Fighting Spirit subscale, and Mini-MAC Adaptive Coping factor. Two trends were observed, i.e., an increase in Positive religious coping on the Brief RCOPE and an increase in Fatalism (a subscale of the Mini-MAC). CONCLUSION: Spiritual AIM, a brief chaplain-led intervention, holds potential to address spiritual needs and religious and general coping in patients with serious illnesses. PMID- 28736104 TI - Opioid-Induced Constipation Relief From Fixed-Ratio Combination Prolonged-Release Oxycodone/Naloxone Compared With Oxycodone and Morphine for Chronic Nonmalignant Pain: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. AB - CONTEXT: Opioid-induced constipation (OIC) is one of the most frequent and severe adverse events (AEs) after treatment with opioids. Recent studies have indicated that fixed-ratio combination prolonged-release oxycodone/naloxone (OXN PR) could decrease OIC with similar pain relief compared with other opioids. OBJECTIVES: We systematically reviewed (PROSPERO registration numbers: CRD42016036244) the constipation relief of OXN PR compared with other opioids regardless of formulation, prolonged release, or extended release used for the relief of chronic pain. METHODS: Relevant studies were identified by searching PubMed, EMBASE, Web of Science, and the Cochrane library from inception to May 2016, with an update to December 2016. We quantitatively analyzed OIC (assessed by bowel function index [BFI]), pain intensity, and AEs. RESULTS: A total of 167 articles were identified from the databases. Finally seven studies with 3217 patients were included in our meta-analysis, including 1322 patients in OXN PR treatment groups and 1885 patients in prolonged-release oxycodone (OXY PR) or prolonged-release morphine (MOR PR) control group. The relative risk (RR) of OIC was decreased in OXN PR (RR 0.52, 95% CI 0.44; 0.62). Whether BFI was better or worse at baseline, the mean difference (MD) of BFI -17.48 95% CI -21.60; -13.36) was better after treatment with OXN PR with clinical importance at the end of intervention; moreover, the BFI of the OXN PR-treated group was closer to normal BFI scores. However, clinical BFI change from baseline to the end measurement only existed in patients when the baseline BFI was high (mean [SDs] 61.0 [23.39]-67.40 [19.51]), and the MD of the BFI was -15.96 (95% CI -25.56; -15.48). The RR of AEs was also smaller (RR 0.80; 95% CI 0.69-0.93), but the severity or duration of AEs was not reported. Pain intensity was also significantly decreased in the OXN PR treatment groups (MD -3.84, 95% CI -7.14; -0.55), although there was no clinically meaningful difference. CONCLUSION: For people with chronic pain, treatment with OXN PR decreases the incidence of OIC and provides intermediate-term bowel function improvement with clinical importance; in addition, pain relief is not weakened. The OIC after treatment with OXN PR for cancer-related pain and over the long term remains unknown. PMID- 28736105 TI - Policy Measures to Support Palliative Care at Home: A Cross-Country Case Comparison in Three European Countries. AB - CONTEXT: The proportion of people in need of palliative care worldwide is rising, and the majority wish to receive this care at home. Many countries have created policy measures to support palliative care at home. OBJECTIVE: To list and compare existing policy measures designed to support palliative care at home in addition to available primary care services in Belgium, France, and Germany. METHODS: A cross-country case comparison based on expert consultation, governmental policy documents, and relevant scientific literature. RESULTS: All three countries have policy measures that allow informal caregivers to adapt their working patterns or take leave of absence to provide care without losing employee rights; however, only Belgium offers specific paid palliative care leave. All three countries offer various allowances to people who are dying at home and their caregivers. Cost-reductions for out-of-pocket expenses are available, based on the level of care dependency in Germany and on prognosis in Belgium, but are not provided in France. Mobile home support teams exist in all three countries and are free of charge for patients and caregivers; but only in Belgium and Germany, there are specialist multidisciplinary palliative home care teams. Belgium and Germany provide respite care for palliative patients. CONCLUSION: European countries with similar contextual characteristics offer comparable policy measures to support palliative care at home in addition to the available primary care services. However, important differences exist in the criteria for access and the extent of what is offered. PMID- 28736106 TI - In vivo magnetic resonance approach to trimethyltin induced neurodegeneration in rats. AB - Trimethyltin (TMT) is commonly used to induce neurodegeneration in mice and rats; however, only scarce data of in vivo magnetic resonance (MR) spectroscopy and imaging characterizing TMT neurotoxicity are available. Our aim was to assess brain metabolite changes and brain atrophy by in vivo MR in the rat model of neurodegeneration induced by TMT. Adult male Wistar rats exposed to TMT (8mg/kg, i.p.) were used in the study. Proton MRS was applied on the dorsal hippocampus to reveal changes in neurochemical profile, and MR imaging was used to assess the volume of the entire hippocampus, ventricles and whole brain. Hippocampal levels of N-acetylaspartate (NAA), glutamate (Glu), total creatine (tCr) and taurine (Tau) significantly decreased, while the levels of myo-Inositol (mIns) and glutamine (Gln) significantly increased in TMT treated rats compared to controls. No changes in choline metabolites (tCho), glutathione (GSH), and GABA were observed. MR volumetry revealed a substantial loss of hippocampal mass, cerebral volume shrinkage and ventricular enlargement in the TMT treated group in comparison to the control group. To the best of our knowledge, this is the first study characterizing TMT induced neurodegeneration in the rat by in vivo MRS. Our findings suggest that TMT exposed rats may serve as a reliable animal model of neurodegeneration and MR based parameters could serve as potential in vivo biomarkers of therapeutic response. PMID- 28736107 TI - Cholinergic/opioid interaction in anterior cingulate cortex reduces the nociceptive response of vocalization in guinea pigs. AB - The anterior cingulate cortex (ACC) is crucial in the modulation of the sensory, affective and cognitive aspects of nociceptive processing. Also, it participates in the planning and execution of behavioral responses evoked by nociceptive stimuli via descending projections to the brainstem. In laboratory animals nociceptive experimental tests evaluate behavioral responses that preferentially express the sensory-discriminative or affective-motivational component of pain. The objective of this study was to investigate the participation of opioid and cholinergic neurotransmission in the ACC on different nociceptive responses in guinea pigs. We used nociceptive tests of formalin and vocalization evoked by peripheral noxious stimuli (electric shock) to evaluate the behavioral expression of the sensory-discriminative and affective motivational components, respectively. We verified that the microinjection of morphine (4.4nmol) in the ACC of guinea pigs promotes antinociception in the two experimental tests investigated. This effect is blocked by prior microinjection of naloxone (2.7nmol). On the other hand, the microinjection of carbachol (2.7nmol) in the ACC induces antinociception only in the vocalization test. This effect was prevented by prior microinjection of atropine (0.7nmol) and naloxone (2.7nmol). In fact, the blockade of u-opioids receptors with naloxone in ACC prevented the antinociceptive effect of carbachol in the vocalization test. Accordingly, we suggest that the antinociception promoted by carbachol was mediated by the activation of muscarinic receptors on local ACC opioid interneurons. The release of endogenous opioids seems to inhibited the expression of the behavioral response of vocalization. Therefore, we verified that the antinociceptive effect of morphine microinjection in ACC is broader and more robust than that promoted by carbachol. PMID- 28736109 TI - Electromyographic analysis of superior orbicularis oris muscle function in children surgically treated for unilateral complete cleft lip and palate. AB - PURPOSE: The aim of this study was to assess the electrical activity of the superior orbicularis oris muscle in children surgically treated for unilateral complete cleft lip and palate (UCCLP). MATERIAL AND METHODS: The sample comprised 45 patients 6.38-12.68 years of age with UCCLP and 40 subjects 6.61-11.71 years of age with no clefts. Electromyographical (EMG) recordings were taken with a DAB Bluetooth Instrument (Zebris Medical GmbH, Germany) in the rest position and during saliva swallowing, lip protrusion and reciprocal compression of the lips, as well as while producing the phonemes /p/, /b/, and /m/ combined with the vowel /a/. RESULTS: The electrical activity of the upper lip during saliva swallowing and lip compression was significantly greater in the cleft group. Similar resting level activity was observed in both groups. During the production of the /p/, /b/, and /m/ phonemes combined with the vowel /a/ the results showed no significant differences in the EMG activity between children with UCCLP and noncleft subjects. CONCLUSION: Patients with UCCLP have abnormal upper lip function characterized by increased activity of the superior orbicularis oris muscle during saliva swallowing and lip compression, and this may affect facial morphology. PMID- 28736110 TI - Effects of pre-load variations on hemodynamic parameters with a pulsatile autoregulated artificial heart during the early post-operative period. PMID- 28736111 TI - Metformin therapy reduces the risk of malignancy after heart transplantation. AB - BACKGROUND: Malignancy and diabetes mellitus (DM) cause significant morbidity and mortality after heart transplantation (HTx). Metformin, one of the most commonly used anti-diabetic drugs worldwide, has also been shown to exhibit anti-tumor activity. We therefore investigated the association between metformin therapy and malignancy after HTx. METHODS: The study population comprised 237 patients who underwent HTx between 1991 and 2016 and were prospectively followed-up. Clinical data were recorded on prospectively designed forms. The primary outcome was any cancer recorded during 15 years of follow-up. Treatment with metformin and the development of DM after HTx were assessed as time-dependent factors in the analyses. RESULTS: Of the 237 study patients, 85 (36%) had diabetes. Of the DM patients, 48 (56%) were treated with metformin. Kaplan-Meier survival analysis showed that, at 15 years after HTx, malignancy rate was 4% for DM patients treated with metformin, 62% for those who did not receive metformin and 27% for non-DM patients (log-rank test, p < 0.0001). Consistently, multivariate analysis showed that for DM patients, metformin therapy was independently associated with a significant 90% reduction (hazard ratio = 0.10; 95% confidence interval 0.02 to 0.40; p = 0.001) in the risk of the development of a malignancy. DM patients who were treated with metformin had a markedly lower risk (65%; p = 0.001) for the development of a malignancy or death after HTx as compared with non-DM patients. CONCLUSIONS: Our findings suggest that metformin therapy is independently associated with a significant reduction in the risk of malignancy after HTx. PMID- 28736108 TI - Chronic intermittent ethanol exposure selectively alters the expression of Galpha subunit isoforms and RGS subtypes in rat prefrontal cortex. AB - Chronic alcohol exposure induces pronounced changes in GPCR-mediated G-protein signaling. Recent microarray and RNA-seq analyses suggest associations between alcohol abuse and the expression of genes involved in G-protein signaling. The activity of G-proteins (e.g. Galphai/o and Galphaq) is negatively modulated by regulator of G-protein signaling (RGS) proteins which are implicated in drugs of abuse including alcohol. The present study used 7days of chronic intermittent ethanol exposure followed by 24h withdrawal (CIE) to investigate changes in mRNA and protein levels of G-protein subunit isoforms and RGS protein subtypes in rat prefrontal cortex, a region associated with cognitive deficit attributed to excessive alcohol drinking. We found that this ethanol paradigm induced differential expression of Galpha subunits and RGS subtypes. For example, there were increased mRNA and protein levels of Galphai1/3 subunits and no changes in the expression of Galphas and Galphaq subunits in ethanol-treated animals. Moreover, CIE increased the mRNA but not the protein levels of Galphao. Additionally, a modest increase in Galphai2 mRNA level by CIE was accompanied by a pronounced increase in its protein level. Interestingly, we found that CIE increased mRNA and protein levels of RGS2, RGS4, RGS7 and RGS19 but had no effect on the expression of RGS5, RGS6, RGS8, RGS12 or RGS17. Changes in the expression of Galpha subunits and RGS subtypes could contribute to the functional alterations of certain GPCRs following chronic ethanol exposure. The present study suggests that RGS proteins may be potential new targets for intervention of alcohol abuse via modification of Galpha-mediated GPCR function. PMID- 28736112 TI - Delayed stinging insect reactions. PMID- 28736113 TI - Titanium vs. polyetheretherketone (PEEK) interbody fusion: Meta-analysis and review of the literature. AB - Spinal interbody fusion is a standard and accepted method for spinal fusion. Interbody fusion devices include titanium (Ti) and polyetheretherketone (PEEK) cages with distinct biomechanical properties. Titanium and PEEK cages have been evaluated in the cervical and lumbar spine, with conflicting results in bony fusion and subsidence. Using Preferred Reporting Items for Systematic reviews and Meta-analyses (PRISMA) guidelines, we reviewed the available literature evaluating Ti and PEEK cages to assess subsidence and fusion rates. Six studies were included in the analysis, 3 of which were class IV evidence, 2 were class III, and 1 was class II. A total of 410 patients (Ti-228, PEEK-182) and 587 levels (Ti-327, PEEK-260) were studied. Pooled mean age was 50.8years in the Ti group, and 53.1years in the PEEK group. Anterior cervical discectomy was performed in 4 studies (395 levels) and transforaminal interbody fusion in 2 studies (192 levels). No statistically significant difference was found between groups with fusion (OR 1.16, 95% C.I 0.59-2.89, p=0.686, I2=49.7%) but there was a statistically significant the rate of subsidence with titanium (OR 3.59, 95% C.I 1.28-10.07, p=0.015, I2=56.9%) at last follow-up. Titanium and PEEK cages are associated with a similar rate of fusion, but there is an increased rate of subsidence with titanium cage. Future prospective randomized controlled trials are needed to further evaluate these cages using surgical and patient-reported outcomes. PMID- 28736114 TI - Flow diversion within seven days after stroke onset is associated with favorable outcome in anterior circulation stroke. AB - Anterior cerebral artery (ACA) flow diversion (FD), defined as ipsilateral mean velocity (MV) of at least 30% greater than the contralateral artery, could be seen an indirect sign of leptomeningeal collateralization in the setting of middle cerebral artery occlusion. The purpose of the study was to evaluate the association between dynamic FD and functional outcome in acute anterior stroke patients with large artery occlusion. Acute middle cerebral artery (MCA) or internal carotid artery (ICA) occlusive stroke patients within 12h were recruited. Transcranial Doppler ultrasound was done at baseline, 24h and 7d after onset and velocities of MCA and ACA were recorded. FD ratio was calculated by dividing the ipsilateral ACA MV by the contralateral ACA MV. FD was determined positive when FD ratio >=1.3. Outcome was assessed by 90-day modified Rankin's Scale (mRS). The association between FD at different time points and functional outcome were analyzed. 16 patients (median age of 67 and 75% were male) were recruited. FD ratio showed a trend of decline but did not reach statistical significance (p=0.056). The proportion of FD at baseline (p=0.026), 24h (p=0.001) and 7d (p=0.044) was significantly higher in patients with favorable outcome. Higher FD ratio at baseline (p=0.02) and 24h (p=0.003) were significantly associated with favorable outcome. These results suggested that FD ratio showed a trend of decline after stroke onset. Presence of FD within 7days was associated with favorable functional outcome in acute MCA/ICA occlusive stroke patients. PMID- 28736115 TI - Three-dimensional volumetric changes in the upper airway after maxillomandibular advancement in obstructive sleep apnoea patients and the impact on quality of life. AB - Obstructive sleep apnoea (OSA) is a sleep-related breathing disorder, characterized by repetitive airway obstructions, causing disruptive snoring and daytime sleepiness. Maxillomandibular advancement (MMA), which enlarges the upper airway, is a therapeutic surgical approach. However, no study has performed an upper airway sub-region analysis using validated three-dimensional (3D) anatomical and technical limits on cone beam computed tomography (CBCT). Hence, this prospective, observational trial was performed to evaluate 3D volumetric changes in the upper airway according to validated 3D cephalometric landmarks, before and after MMA, for all patients with a polysomnography diagnosis of OSA (apnoea-hypopnoea index (AHI) >=5). The secondary objective was to evaluate the impact of MMA on the AHI and in a subjective manner with the Epworth Sleepiness Scale (ESS) and OSA questionnaire. Eleven consecutive OSA patients were included. A significant volume increase in the oropharynx (P=0.002) and hypopharynx (P=0.02) was observed, in contrast to a non-significant volume reduction in the nasopharynx (P >0.05). The median AHI (P=0.03) and ESS score (P=0.004) decreased significantly as a result of surgery. In conclusion, MMA significantly enlarges the airway volume of the oropharynx and hypopharynx and is associated with improved quality of life. PMID- 28736116 TI - Central nervous system anomalies in craniofacial microsomia: a systematic review. AB - Extracraniofacial anomalies, including central nervous system (CNS) anomalies, may occur in craniofacial microsomia (CFM). This systematic review was performed to provide an overview of the literature on the prevalence and types of CNS anomalies and developmental disorders in CFM, in order to improve the recognition and possible treatment of these anomalies. A systematic search was conducted and data on the number of patients, patient characteristics, type and prevalence of CNS anomalies or developmental delay, and correlations between CFM and CNS anomalies were extracted. Sixteen papers were included; 11 of these described developmental disorders. The most common reported anomalies were neural tube defects, corpus callosum agenesis or hypoplasia, intracranial lipoma, Arnold Chiari malformations, hydrocephaly, ventriculomegaly, and cerebral hypoplasia. The prevalence of CNS anomalies in CFM varied from 2% to 69%. The prevalence of developmental disorders, such as intellectual disability, language or speech developmental delay, and neuropsychomotor delay, varied from 8% to 73%. This study suggests that CNS anomalies and developmental disorders are seen in a substantial proportion of patients with CFM. Further research should focus on determining which features of CFM are correlated with CNS anomalies to allow adequate screening and timely care. PMID- 28736117 TI - Modulation of dendritic cell and T cell cross-talk during aging: The potential role of checkpoint inhibitory molecules. AB - Dendritic cells (DCs) undergo continuous changes throughout life, and there is evidence that elderly DCs have a reduced capacity to stimulate T cells, which may contribute to impaired anti-tumour immune responses in elderly people with cancer. Changes in checkpoint inhibitory molecules/pathways during aging may be one mechanism that impairs the ability of elderly DCs to activate T cells. However, little is currently known regarding the combined effects of aging and cancer on DC and T cell inhibitory molecules/pathways. In this review, we discuss our current understanding of the influence of aging and cancer on key DC and T cell inhibitory molecules/pathways, the potential underlying cellular and molecular mechanisms contributing to their modulation, and the possibility of therapeutically targeting inhibitory molecules in elderly cancer patients. PMID- 28736118 TI - Guidelines for low intensity transcranial electrical stimulation - An overdue step in a fairly uncontrolled field. PMID- 28736119 TI - Close correlation between arterial and central venous lactate concentrations of children in shock: A cross-sectional study. AB - BACKGROUND: Arterial lactate (aLact) has been widely used to guide therapeutic decisions in children with shock. We evaluated the feasibility of central venous lactate (cvLact) in assessing aLact among children with shock. METHODS: Pairs of arterial and central venous samples for lactate concentrations were collected simultaneously during the shock and hemodynamically stable states. The results were analyzed by using a Cobas 8000 analyzer. RESULTS: Sixty-four blood paired samples were collected from 48 patients. The overall correlation between central venous and arterial lactate concentrations was r=0.962, p<0.0001, r2=0.965. The regression equation was aLact=(0.978*cvLact)-0.137. A similar correlation was found between central venous and arterial lactate concentrations during the states of shock and stable hemodynamics (r=0.970, p<0.0001, r2=0.966 and r=0.935, p<0.0001, r2=0.962, respectively). The mean difference between central venous and arterial lactate concentrations was 0.20mmol/l (95% CI: 0.08 to 0.32) and the limits of agreement were -0.74mmol/l (95% CI: -0.94 to -0.53) and 1.13 (95% CI: 0.93 to 1.34). CONCLUSIONS: In situations of shock where a central venous catheter is required, samples from a central vein present an acceptable and timely alternative to arterial samples for quantitating lactate concentrations. PMID- 28736120 TI - Aneurysmal degeneration of type B aortic dissections after thoracic endovascular aortic repair: A systematic review. AB - BACKGROUND: Promising results of thoracic endovascular aortic repair (TEVAR) in patients with complicated type B aortic dissection (TBAD) have been well documented. However, whereas early results have led many to hypothesize a benefit of TEVAR in uncomplicated patients, the natural history of TEVAR after the treatment of TBAD has yet to mature. In this review, we evaluated the available data to investigate whether longer term TEVAR warrants enthusiasm for all comers with TBAD. METHODS: A systematic review of the literature was performed searching specifically for studies assessing medium- and long-term outcomes after TEVAR for the treatment of TBAD. Studies were included if changes in aortic volume or diameter were recorded. Any publications recording only changes in mean aortic diameter across the study population were excluded. RESULTS: A total of 17 studies examining growth in the thoracic aorta were included. This event occurred in 6.6% to 84% of patients across studies. Six studies examined growth in the abdominal aorta after TEVAR, which occurred in 10% to 54% of patients. When viewed by chronicity, a significant number of patients treated for chronic and acute dissection experienced aneurysmal degeneration. CONCLUSIONS: Based on the available data to date, TEVAR for TBAD does not prevent aneurysmal degeneration of the thoracic or abdominal aorta. Therefore, the treatment of uncomplicated patients with this goal in mind is currently contrary to the available data. Given the variability of manuscript reporting styles for TBAD, the development of reporting standards is necessary to homogenize available data and to strengthen our understanding of this complex disease process. PMID- 28736121 TI - Potential of circulatory procalcitonin as a biomarker reflecting inflammation among South Indian diabetic foot ulcers. AB - OBJECTIVE: Diabetic foot ulcer (DFU), the major complication associated with diabetes mellitus, has been shown to precede amputation in up to 90% of cases. Recent data reveal that procalcitonin (PCT) is a valid marker for the diagnosis of bacterial infections compared with traditional markers like white blood cell count, C-reactive protein levels, and erythrocyte sedimentation rate in DFU patients. Furthermore, cytokines are proposed to act as modulators and mediators for the expression and release of PCT into the circulation. Hence, this preliminary study was conducted to evaluate the diagnostic accuracy of PCT compared with other traditional markers and to predict the association of PCT plasma levels with inflammatory cytokines and clinical parameters of incident diabetes among South Indian DFU subjects. METHODS: There were 185 subjects with type 2 diabetes mellitus (T2DM) selected in this cross-sectional study, subdivided into three groups: group I, control/T2DM subjects free from DFU (n = 75; male, 43; female, 32); group II, T2DM subjects with noninfected DFU (n = 34; male, 19; female, 15); and group III, T2DM subjects with infected DFU (IDFU; n = 76; male, 46; female, 30). Patients with IDFU were further divided into three subgroups as per the Infectious Diseases Society of America-International Working Group on the Diabetic Foot classification criteria: grade 2 (n = 27), grade 3 (n = 38), and grade 4 (n = 11). Subjects with type 1 diabetes, gestational diabetes, pneumonia, sepsis, inflammatory bowel disease, meningitis, or hematologic diseases and those who underwent surgery in the past 2 to 3 weeks were excluded from this study. For investigation of clinical parameters, blood samples were drawn from all the study subjects; plasma samples were used for estimating PCT by the enzyme-linked immunosorbent assay method. The profiling of plasma cytokines was carried out using a multiplex bead-based assay. Data are presented as mean +/ standard deviation for clinical and biochemical variables and as geometric mean with 95% confidence interval (CI) for cytokines. All analysis was done using the Statistical Package for the Social Sciences (version 20.0; IBM Corp, Armonk, NY); P < .05 was considered to be statistically significant. RESULTS: We found PCT to be a valid diagnostic marker for IDFU with higher sensitivity and specificity than other traditional markers. For PCT, the area under the receiver operating characteristic curve was found to be high (0.99; 95% CI, 0.96-1.0), followed by C reactive protein levels (0.78; 95% CI, 0.65-0.81), white blood cell count (0.76; 95% CI, 0.67-0.86), and erythrocyte sedimentation rate (0.74; 95% CI, 0.68-0.80) in IDFU subjects. We found the cutoff value of >=0.5 ng/mL to have 54% sensitivity and 100% specificity for PCT with a positive predictive value of 100% and a negative predictive value of 12% for IDFU diagnosis. Moreover, PCT circulatory levels showed a positive correlation with helper T-cell subtype 1 cytokines, such as interferon gamma (r = 0.21; P = .03) and interleukin 28A (r = 0.31; P = .003), and subtype 17 cytokines, such as interleukin 29/interferon lambda1 (r = 0.20; P = .037). CONCLUSIONS: PCT could be a valuable marker for diagnosis of T2DM patients with IDFU. PMID- 28736122 TI - Treatment of tibial nonunion with posterolateral bone grafting. AB - OBJECTIVES: Posterolateral bone grafting to treat nonunions of the distal two thirds of the tibia avoids the often traumatized and more tenuous anterior soft tissue envelope. Few modern reports of its effectiveness are available. We assessed whether posterolateral bone grafting leads to high union and low complication rates. METHODS: We conducted a retrospective review at a Level I trauma center. Our study group was 59 patients with distal two-thirds tibial fractures treated with posterolateral bone grafting. Patients included those with history of deep surgical site infection (SSI) before bone grafting (n=17), established nonunions (n=42), and impending nonunions associated with open fractures and bone gaps (n=17). All patients were followed for a minimum of 12 months unless they achieved union before that time point. Our primary outcome measurement was fracture union. Secondary outcome measurements were any complication associated with the approach and infection requiring return to the operating room. RESULTS: Fracture union was achieved in 44 (75%) of 59 patients without further intervention. The mean interval to union was 9.9 months (range, 3 22). Of 11 infected nonunions treated, nine progressed to union. Seventeen of 23 patients with defects >2cm, including defects up to 5.4cm without infection, were successfully treated. Two patients who underwent grafting at least 10 years after initial injury achieved union. No complications were associated with the approach (specifically, no wound breakdown, vascular injury, or tendon injury). Fourteen percent of patients experienced SSI after bone grafting. Seven of eight deep SSI occurred in patients with previous infection or positive intraoperative cultures. Only one (3%) of 36 patients without infection pre- or intraoperatively experienced SSI. CONCLUSIONS: Even in this relatively difficult patient cohort that included large bone gaps and history of infection, union was achieved at a relatively high rate with posterolateral bone graft. The approach seems to be safe, considering no known complications specifically associated with the approach occurred, and seems to reduce the risk of SSI in the absence of previous infection. PMID- 28736123 TI - Analysis of two treatment modalities for the prevention of vomiting after trauma: Orogastric tube or anti-emetics. AB - INTRODUCTION: Vomiting in the emergency department after trauma occurs frequently and might lead to aspiration of gastric content. An orogastric tube (OGT) is a way to prevent emesis. However, this is an inconvenient procedure and may actually trigger vomiting. Therefore, a change in policy was applied from preferably an OGT to the administration of anti-emetics in a selected population. The aim of this study was to analyse the prevention of vomiting in trauma patients after OGT or anti-emetics. MATERIALS AND METHODS: Retrospective cohort study. Data of all trauma patients presented at the crash room of the emergency department between July 1st 2013 and July 1st 2014 were collected from the local trauma registry and electronic patient documentation system and comprising 6 months preceding and 6 months after change of policy. Vomiting and nausea after trauma were recorded. Furthermore, complications such as aspiration and cardiac arrhythmias were documented. RESULTS: A total of 1446 patients were presented after trauma. 230 patients were promptly intubated. An additional 763 patients were fully responsive and did not complain of nausea. The remaining 453 patients were further analysed. 44 patients received OGT placement procedure and 409 patients received anti-emetics. Significant difference was found in patients vomiting after OGT placement or anti-emetics (20.5% vs. 2.7%; P<0.001). Patients who received anti-emetics were not more at risk for cardiac arrhythmias. After matched control analysis, there was still a significant difference was found. DISCUSSION AND CONCLUSION: Administration of anti-emetics is suitable and effective for the prevention of vomiting after trauma in this selected population, without an increased risk for complications. PMID- 28736124 TI - Implications of three-dimensional modeling of the proximal femur for cephalomedullary nailing: An Asian cadaver study. AB - PURPOSE: To determine the variability in the ideal entry point of cephalomedullary (CM) nail around the greater trochanter (GT) and the consequent conformity with the proximal femur by analyzing three-dimensional (3D) modeling and virtual implantation MATERIALS AND METHODS: A total of 105 cadaveric femurs (50 males and 55 females) underwent continuous 1.0mm slice computed tomography (CT) scans. CT images imported into Mimics(r) software to reconstruct the 3D model of the proximal femur and medullary canal. PFNA-II(r) was processed into a 3D model using a 3D-sensor at the actual size and optimally implanted in the proximal femur model using Mimics(r) software. The ideal entry point, nail conformity with the proximal femur, and the relationship between the entry point and adjacent structures were assessed. RESULTS: The ideal entry point was located a mean of 2.38mm (SD, 3.53mm) medial to the tip of GT. No lateral cortex impingement of the proximal femur occurred in the coronal plane based on the recommended point. However, a disparity in the sagittal plane between the proximal shaft and nail curvature was found in 47 models (44.8%). Rotation and magnification of the 3D model exposed all nails above the surface of the medial side of the GT. The proximal nail end was contained entirely within bone and circumferential endosteal cortical contact was present at the nail-bone interface. PMID- 28736125 TI - Minimally invasive treatment of displaced femoral shaft fractures with a teleoperated robot-assisted surgical system. AB - BACKGROUND: Minimally invasive surgical operation of intramedullary (IM) nailing is a standard technique for treating diaphyseal fractures. However, in addition to its advantages, there are some drawbacks such as the frequent occurrence of malalignment, physical fatigue and high radiation exposure to medical staff. The use of robotic and navigation techniques is promising treatments for femoral fractures. MATERIALS AND METHODS: This paper presents a novel robot-assisted manipulator for femoral shaft fracture reduction with indirect contact with the femur. An alternative clinical testing model was proposed for orthopedic surgeons to practice femoral fracture reduction. This model imitates the human musculoskeletal system in shape and functional performance. The rubber tube simulate muscles providing contraction forces, and the silicone simulates passive elasticity of muscles. Two-group experiments were performed for studying feasibility of the teleoperated manipulator. RESULTS: The average operative time was about 7min. In the first group experiments, the femur axial, antero-posterior (AP) and lateral views mean errors were 2.2mm, 0.7mm and 1.1mm, respectively, and their maximums were 3.0mm, 0.9mm and 1.5mm; the mean errors of rotation were 0.8 degrees around x-axis, 1.6 degrees around y-axis, 2.0 degrees around z-axis, and their maximums were 1.1 degrees , 2.2 degrees , 2.9 degrees , respectively. For the second group experiments, the femur axial, AP and lateral views mean errors were 1.8mm, 0.4mm and 0.8mm, respectively, and their maximums were 2.2mm, 0.7mm and 1.1mm; the mean errors of rotation were 1.2 degrees around x-axis, 1.6 degrees around y-axis, 1.9 degrees around z-axis, and their maximums were 2.4 degrees , 1.8 degrees , 2.7 degrees , respectively. Reduction for AP view displacement is easier than lateral (p<0.05) because of the tube-shaped anatomy and the muscle contraction forces. Errors around x-axis are smaller than those around y-, and z- axes (p<0.05), i.e., electro-mechanical actuator is easier to control than pneumatic. CONCLUSION: An experimental model for simulating human femoral characteristics was proposed. Experiments conducted on the artificial lower limb model demonstrated high reduction accuracy, safety, sufficient working space, and low radiation exposure of the proposed robot-assisted system. Thus, the minimally invasive teleoperated manipulator would have greater development prospect. PMID- 28736126 TI - Outcomes following osteosynthesis of periprosthetic hip fractures around cemented tapered polished stems. AB - We retrospectively reviewed outcomes of 79 patients with periprosthetic hip fractures around cemented tapered polished stem (CTPS) implants treated with osteosynthesis between January 1997 and July 2011. All patients underwent open reduction and fixation using a broad dynamic compression plate (DCP). Seventy two (91%) of fractures united. There were seven (9%) non-unions with failure of metal work, three (4%) as a result of infection and four (5%) due to mechanical failure. Significant subsidence (>5mm) of the implant was seen in seven (9%) of cases. Ten (13%) cases developed post-operative infection. Non-anatomic reduction and infection were identified as predictors of poor outcome. This is the largest series of a very specific group of periprosthetic fractures treated with osteosynthesis. Open reduction internal fixation with a broad dynamic compression plate for patients with periprosthetic hip fractures around the tip of cemented tapered polished stems is a suitable treatment provided there is no bone loss and the fracture can be precisely, anatomically, reduced and adequately fixed. PMID- 28736127 TI - A preformulation evaluation of a photosensitive surface active compound, explaining concentration dependent degradation. AB - A candidate drug within the cardiovascular area was identified during early research and evaluated for further development. The aim was to understand and explain the degradation mechanisms for the present compound. The stability of the active pharmaceutical ingredient (API) in solution and solid state was studied during different conditions. The bulk compound was exposed to elevated temperatures, increased relative humidity and stressed light conditions. Degradation of the drug in solutions was followed in the presence versus absence of ethylenediaminetetraacetic acid (EDTA), during aerobic versus anaerobic conditions, stored protected from light versus exposed to light and as a function of pH and concentration. It was possible to improve the stability by adding EDTA and completely abolish degradation by storing dissolved compound at anaerobic conditions. Solutions of API were stable between pH3 and 7, with some degradation at pH1, when stored protected from light and at 22 degrees C, but degrade rapidly when exposed to ambient light conditions. The degradation products were identified by mass spectroscopy. Degradation schemes were drawn. There was concentration dependence in the degradation of dissolved drug when exposed to light, showing a titration behavior that concurred with the measured critical micelle/aggregation concentration (CMC/CAC) of the compound. The compound was stable in solution during the investigated time period, at concentrations above CMC/CAC, where the molecule was protected from photodegradation when the compound aggregated. Below CMC/CAC, a significant degradation of the API occurred. This may be a potential explanation why other surface active compounds show concentration dependent degradation. The photosensitivity was also observed for the neutral compound in crystalline and amorphous form, as well as for the crystalline chloride salt of the drug. However, the degradation of amorphous form was faster compared to crystalline material. No difference was observed in the degradation pattern between the neutral form of the compound and the salt form of the drug. PMID- 28736128 TI - The effect of Pro NanoLipospheres (PNL) formulation containing natural absorption enhancers on the oral bioavailability of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) in a rat model. AB - The lipophilic phytocannabinoids cannabidiol (CBD) and Delta9 tetrahydrocannabinol (THC) show therapeutic efficacy in various medical conditions. Both molecules are poorly water soluble and subjected to extensive first pass metabolism in the gastrointestinal tract, leading to a limited oral bioavailability of approximately 9%. We have developed an advanced lipid based Self-Emulsifying Drug Delivery System termed Advanced Pro-NanoLiposphere (PNL) pre-concentrate. The PNL is composed of lipid and emulsifying excipients of GRAS status and are known to increase solubility and reduce Phase I metabolism of lipophilic active compounds. Advanced PNLs are PNLs with an incorporated natural absorption enhancers. These molecules are natural alkaloids and phenolic compounds which were reported to inhibit certain phase I and phase II metabolism processes. Here we use piperine, curcumin and resveratrol to formulate the Advanced-PNL formulations. Consequently, we have explored the utility of these Advanced-PNLs on CBD and THC oral bioavailability. Oral administration of CBD piperine-PNL resulted in 6-fold increase in AUC compared to CBD solution, proving to be the most effective of the screened formulations. The same trend was found in pharmacokinetic experiments of THC-piperine-PNL which resulted in a 9.3-fold increase in AUC as compared to THC solution. Our Piperine-PNL can be used as a platform for synchronized delivery of piperine and CBD or THC to the enterocyte site. This co-localization provides an increase in CBD and THC bioavailability by its effect at the pre-enterocyte and the enterocyte levels of the absorption process. The extra augmentation in the absorption of CBD and THC by incorporating piperine into PNL is attributed to the inhibition of Phase I and phase II metabolism by piperine in addition to the Phase I metabolism and P-gp inhibition by PNL. These novel results pave the way to utilize piperine-PNL delivery system for other poorly soluble, highly metabolized compounds that currently cannot be administered orally. PMID- 28736129 TI - Clinical and Radiological Predictors of Malignant Middle Cerebral Artery Infarction Development and Outcomes. AB - BACKGROUND: Optic nerve sheath diameter (ONSD) can predict intracranial hypertension and outcomes in severe traumatic brain injury. Its utility in middle cerebral artery (MCA) stroke is unknown. AIMS: We reviewed serial radiological measurements, including ONSD, in patients with MCA stroke undergoing decompressive craniectomy (DC) for malignant MCA syndrome and compared demographic, clinical, and radiological data with an age- and gender-matched group of nonmalignant MCA stroke patients. METHODS: Patients admitted to a large tertiary hospital in London, UK, between April 2012 and October 2016 with MCA infarction were identified through 2 data sources. We quantified ONSD, eyeball transverse diameter (ETD), ONSD/ETD ratio, midline shift (MLS), and infarct volume on computed tomography (CT). RESULTS: We identified 19 patients (mean age = 49.8 years [standard deviation = 12.5]) with malignant MCA stroke and 19 patients (47.8 years [16.0]) with nonmalignant MCA stroke. Mean ONSD, ONSD/ETD ratio, MLS, and infarct volume on initial CT all significantly increased after developing malignant MCA syndrome and decreased (except infarct volume, which increased) following DC (all Ps <.05). ONSD and ONSD/ETD ratios in the malignant group did not correlate with functional outcomes but were significantly higher on initial CT compared with the nonmalignant group (mean ONSD: 5.66 mm [.6] versus 4.97 mm [.5], P = .001; mean ONSD/ETD ratio: .25 [.03] versus .22 [.02], P = .002). CONCLUSIONS: ONSD, ONSD/ETD ratio, MLS, and infarct volume change dynamically in patients with malignant MCA infarction who undergo DC. An ONSD of more than 5.25 mm and an ONSD/ETD ratio of more than .232 on initial CT may identify MCA stroke patients at high risk of developing malignant MCA syndrome. PMID- 28736130 TI - In Response to Spinal Vascular Malformations in Children. PMID- 28736131 TI - Variation in Organization of Transient Ischemic Attack Care in The Netherlands. A Nationwide Survey Study. AB - BACKGROUND: Previous research has shown the importance of urgent initiation of antiplatelet therapy after transient ischemic attack (TIA) to reduce the risk of stroke. Many hospitals in the Netherlands have therefore implemented rapid pathways for assessment of patients with TIA. Dutch stroke guidelines lack clear directives for organization of TIA assessment and thus allow for variation. The aim of this study was to investigate variation in organization of TIA assessment in Dutch hospitals. METHODS: One neurologist per hospital (of 88 Dutch hospitals) with special interest in stroke was invited to participate in a web-based survey addressing the organization, content, and timing of TIA assessment. RESULTS: Seventy (80%) neurologists completed the survey, all of whom reported performing TIA assessment in their hospital. There was considerable variation in the method of application and the location of assessment. In 10% of the hospitals, patients with TIA are always admitted to the ward. The content of diagnostics is fairly similar, but hospitals vary in the extent of cardiological workup. Almost all hospitals aim for a swift start of assessment as directed by guidelines, but access time differs. Eighty-six percent of respondents reported that antiplatelet therapy is usually initiated before assessment, based on history. CONCLUSIONS: This study showed variation in organization of TIA assessment in Dutch hospitals, especially regarding location within the hospital, time to assessment after announcement, and cardiological workup. Further research is needed to investigate implications of this variation for quality of care. PMID- 28736132 TI - High On-Treatment Platelet Reactivity to Adenosine Diphosphate Predicts Ischemic Events of Minor Stroke and Transient Ischemic Attack. AB - BACKGROUND: This study aimed to evaluate the relationship between thromboelastography adenosine diphosphate maximum amplitude (TEG-ADPMA) and recurrent ischemic events in patients with minor ischemic stroke or high-risk transient ischemic attack (TIA). METHODS: A total of 265 patients received dual antiplatelet therapy were consecutively enrolled. High on-treatment platelet reactivity (HTPR) to ADP was assessed by TEG-ADPMA and detected the CYP2C19 genotype; recurrent ischemic events were followed up for 90 days after onset. The difference of recurrent ischemic events was analyzed with or without HTPR to ADP by the Kaplan-Meier, and further to determine the difference of recurrent ischemic events in each group according to TEG-ADPMA-based tertile distribution. RESULTS: A total of 23 (8.6%) patients had recurrent ischemic events. TEG-ADPMA greater than or equal to 48 mm had good predictive value. Whether these patients were divided into 2 groups or 3 groups, the HTPR to ADP group had higher risk of recurrent ischemic events than the normal on-treatment platelet reactivity to ADP group by the Kaplan-Meier (all, P < .05). The tertile distribution map showed that the results of recurrent ischemic events were statistically significant in the third tertile group compared with the other two groups (all, P < .03); also, the third tertile group had a higher rate of carriers of at least 1 CYP2C19 reduced-function allele than the other two groups (P < .05). CONCLUSIONS: In patients with minor ischemic stroke and high-risk TIA, the TEG-ADPMA could predict recurrent ischemic events and has auxiliary effect on clinical decision making. PMID- 28736133 TI - Knockdown of zif268 in the Posterior Dorsolateral Striatum Does Not Enduringly Disrupt a Response Memory of a Rewarded T-Maze Task. AB - Under certain conditions pavlovian memories undergo reconsolidation, whereby the reactivated memory can be disrupted by manipulations such as knockdown of zif268. For instrumental memories, reconsolidation disruption is less well established. Our previous, preliminary data identified that there was an increase in Zif268 in the posterior dorsolateral striatum (pDLS) after expression of an instrumental habit-like 'response' memory, but not an instrumental goal-directed 'place' memory on a T-maze task. Here, the requirement for Zif268 in the reconsolidation of a response memory was tested by knockdown of Zif268, using antisense oligodeoxynucleotide infusion into the pDLS, at memory reactivation. Zif268 knockdown reduced response memory expression 72H, but not 7d later. Western blotting revealed a non-significant increase in Zif268 in the pDLS in rats using response memories, but there was no change in Zif268 expression in the hippocampus following retrieval of a place memory. Zif268 expression increased in the basolateral amygdala after memory reactivation whether a response or place strategy was used during reactivation. We propose that Zif268 expression in the basolateral amygdala may be linked to prediction error, generated by the absence of reward at reactivation. Taken together, these results suggest a complex role for Zif268 in the maintenance of instrumental memories. PMID- 28736134 TI - Stimulus-evoked ERK-dependent phosphorylation of activity-regulated cytoskeleton associated protein (Arc) regulates its neuronal subcellular localization. AB - Activity-regulated cytoskeletal-associated protein (Arc) is implicated as a master regulator of long-term synaptic plasticity and memory formation in mammalian brain. Arc acts at synapses and within the nucleus, but the mechanisms controlling Arc localization and function are little known. As Arc transcription and translation are regulated by extracellularsignal-regulated kinase (ERK) signaling, we asked whether Arc protein itself is phosphorylated by ERK. GST fused Arc of rat origin was able to pull down endogenous ERK2 from rat hippocampal lysates. Using a peptide array, we show that ERK binds a non canonical docking (D) motif in the C-terminal domain of Arc, and this interaction is abolished by phosphorylation of Tyr309. Activated ERK2 phosphorylated bacterially expressed Arc in vitro at all five predicted sites, as confirmed by phospho-specific protein staining and LC-MS/MS analysis. In neuroblastoma cells expressing epitope tagged-Arc, we demonstrate ERK-dependent phosphorylation of Arc in response to activation of muscarinic cholinergic receptors with carbachol. Using phosphosite-specific antibodies, this stimulus-evoked phosphorylation was shown to occur on Ser206 located within the central hinge region of Arc. In cultured hippocampal neurons expressing phosphomutant Arc under control of the activity-dependent promoter, we show that Ser206 phosphorylation regulates the nuclear:cytosolic localization of Arc. Thus, the neuronal activity-induced phosphomimic exhibits enhanced cytosolic localization relative to phosphodeficient and wild-type Arc. Furthermore, enhanced Ser206 phosphorylation of endogenous Arc was detected in the dentate gyrus cytoskeletal fraction after induction of long-term potentiation (LTP) in live rats. Taken together, this work demonstrates stimulus-evoked ERK-dependent phosphorylation and regulation of Arc protein. PMID- 28736135 TI - Theta Neurofeedback Effects on Motor Memory Consolidation and Performance Accuracy: An Apparent Paradox? AB - Previous studies have shown that theta neurofeedback enhances motor memory consolidation on an easy-to-learn finger-tapping task. However, the simplicity of the finger-tapping task precludes evaluating the putative effects of elevated theta on performance accuracy. Mastering a motor sequence is classically assumed to entail faster performance with fewer errors. The speed-accuracy tradeoff (SAT) principle states that as action speed increases, motor performance accuracy decreases. The current study investigated whether theta neurofeedback could improve both performance speed and performance accuracy, or would only enhance performance speed at the cost of reduced accuracy. A more complex task was used to study the effects of parietal elevated theta on 45 healthy volunteers The findings confirmed previous results on the effects of theta neurofeedback on memory consolidation. In contrast to the two control groups, in the theta neurofeedback group the speed-accuracy tradeoff was reversed. The speed-accuracy tradeoff patterns only stabilized after a night's sleep implying enhancement in terms of both speed and accuracy. PMID- 28736136 TI - Prostaglandin E2 modulates presynaptic regulation of GnRH neurons via EP4 receptors in accordance with estrogen milieu. AB - Prostaglandin E2 (PGE2) promotes gonadotropin secretion by regulating the activity of neurons that release gonadotropin-releasing hormone (GnRH) in the hypothalamus. However, the mechanisms of action of PGE2 at these neurons have yet to be fully explored. We examined the effects of PGE2 on the generation of miniature excitatory postsynaptic currents (mEPSCs) at GnRH neurons as measured by whole-cell, patch-clamp recordings. GnRH neurons were identified in slices prepared from the preoptic areas of female GnRH-EGFP rats. Exposure to PGE2 significantly increased the frequency, but not the amplitude, of the mEPSCs generated on the day of proestrus, but neither frequency nor amplitude was altered on day 1 of diestrus. These data suggest that the action of PGE2 on mEPSC frequency varies depending on the stage of estrous. An estrogen-dependence of PGE2's action was further supported by the increased frequency, but not amplitude, of mEPSCs generated at GnRH neurons prepared from estrogen-primed ovariectomized rats. Conversely, PGE2 had no effect on mEPSC frequency or amplitude at GnRH neurons in cholesterol-treated rats. Subsequent experiments to identify candidate receptors for PG2E's action revealed that exposure to a PGE2 receptor 4 (EP4) agonist, but not EP1 or EP2 agonists, mimicked the effects achieved by PGE2 exposure. These effects of mEPSCs could be reversed using an EP4 antagonist, illustrating the specificity of the effect. Collectively, these data demonstrate that PGE2 can alter excitatory synaptic neurotransmission at GnRH neurons via EP4 signaling at presynaptic site(s) in an estrogen-dependent fashion during proestrus. PMID- 28736137 TI - Nogo presence is inversely associated with shifts in cortical microglial morphology following experimental diffuse brain injury. AB - Diffuse traumatic brain injury (TBI) initiates secondary pathology, including inflammation and reduced myelination. Considering these injury-related pathologies, the many states of activated microglia as demonstrated by differing morphologies would form, migrate, and function in and through fields of growth inhibitory myelin byproduct, specifically Nogo. Here we evaluate the relationship between inflammation and reduced myelin antigenicity in the wake of diffuse TBI and present the hypothesis that the Nogo-66 receptor antagonist peptide NEP(1-40) would reverse the injury-induced shift in distribution of microglia morphologies by limiting myelin-based inhibition. Adult male rats were subjected to midline fluid percussion sham or brain injury. At 2h, 6h, 1d, 2d, 7d, and 21d post injury, immunohistochemical staining was analyzed in sensory cortex (S1BF) for myelin antigens (myelin basic protein; MBP and CNPase), microglia morphology (ionized calcium-binding adapter protein; Iba1), Nogo receptor and Nogo. Pronounced reduction in myelin antigenicity was evident transiently at 1d post injury, as evidenced by decreased MBP and CNPase staining, as well as loss of white matter organization, compared to sham and later injury time points. Concomitant with reduced myelin antigenicity, injury shifted microglia morphology from the predominantly ramified morphology observed in sham-injured cortex to hyper-ramified, activated, fully activated, or rod. Changes in microglial morphology were evident as early as 2h post-injury, and remained at least until day 21. Additional cohorts of uninjured and brain-injured animals received vehicle or drug (NEP(1-40), i.p., 15min and 19h post-injury) and brains were collected at 2h, 6h, 1d, 2d, or 7d post-injury. NEP(1-40) administration further shifted distributions of microglia away from an injury-induced activated morphology toward greater proportions of rod and macrophage-like morphologies compared to vehicle-treated. By 7d post-injury, no differences in the distributions of microglia were noted between vehicle and NEP(1-40). This study begins to link secondary pathologies of white matter damage and inflammation after diffuse TBI. In the injured brain, secondary pathologies co-occur and likely interact, with consequences for neuronal circuit disruption leading to neurological symptoms. PMID- 28736138 TI - How viral genetic variants and genotypes influence disease and treatment outcome of chronic hepatitis B. Time for an individualised approach? AB - Chronic hepatitis B virus (HBV) infection remains a global problem. Several HBV genotypes exist with different biology and geographical prevalence. Whilst the future aim of HBV treatment remains viral eradication, current treatment strategies aim to suppress the virus and prevent the progression of liver disease. Current strategies also involve identification of patients for treatment, namely those at risk of progressive liver disease. Identification of HBV genotype, HBV mutants and other predictive factors allow for tailoured treatments, and risk-surveillance pathways, such as hepatocellular cancer screening. In the future, these factors may enable stratification not only of treatment decisions, but also of patients at risk of higher relapse rates when current therapies are discontinued. Newer technologies, such as next-generation sequencing, to assess drug-resistant or immune escape variants and quasi-species heterogeneity in patients, may allow for more information-based treatment decisions between the clinician and the patient. This article serves to discuss how HBV genotypes and genetic variants impact not only upon the disease course and outcomes, but also current treatment strategies. Adopting a personalised genotypic approach may play a role in future strategies to combat the disease. Herein, we discuss new technologies that may allow more informed decision-making for response guided therapy in the battle against HBV. PMID- 28736140 TI - How to better predict microvascular invasion and recurrence of hepatocellular carcinoma. PMID- 28736139 TI - Long-term response after stopping tenofovir disoproxil fumarate in non-cirrhotic HBeAg-negative patients - FINITE study. AB - BACKGROUND & AIMS: There is currently no virological cure for chronic hepatitis B but successful nucleos(t)ide analogue (NA) therapy can suppress hepatitis B virus (HBV) DNA replication and, in some cases, result in HBsAg loss. Stopping NA therapy often leads to viral relapse and therefore life-long therapy is usually required. This study investigated the potential to discontinue tenofovir disoproxil fumarate (TDF) therapy in HBeAg-negative patients. METHODS: Non cirrhotic HBeAg-negative patients who had received TDF for >=4years, with suppressed HBV DNA for >=3.5years, were randomly assigned to either stop (n=21) or continue (n=21) TDF monotherapy. Standard laboratory tests including HBV DNA viral load, HBsAg and alanine aminotransferase (ALT) measurements, and adverse event reporting were carried out during treatment and post-treatment follow-up for 144weeks. RESULTS: Of the patients who stopped TDF therapy, 62% (n=13) remained off-therapy to Week 144. Median HBsAg change in this group was 0.59log10IU/ml (range -4.49 to 0.02log10IU/ml) vs. 0.21log10IU/ml in patients who continued TDF therapy. Four patients (19%) achieved HBsAg loss. Patients stopping therapy had initial fluctuations in viral load and ALT; however, at Week 144, 43% (n=9) had either achieved HBsAg loss or had HBV DNA <2,000IU/ml. There were no unexpected safety issues identified with stopping TDF therapy. CONCLUSIONS: This controlled study demonstrated the potential for HBsAg loss and/or sustained virological response in non-cirrhotic HBeAg-negative patients stopping long-term TDF therapy. Lay summary: Nucleos(t)ide analogue (NA) is usually a life-long therapy for HBV patients. This randomised controlled study investigated the discontinuation of tenofovir disoproxil fumarate (TDF) therapy in HBeAg-negative patients. Of the patients who stopped TDF therapy, 62% remained off-therapy to Week 144, of which 43% of patients had achieved either HBsAg loss or HBV DNA <2,000IU/ml. This offers a potential for long-term HBV-suppressed patients without cirrhosis to stop NA therapy under strict surveillance. Clinical trial number: NCT01320943. PMID- 28736141 TI - Ammonia emission mitigation in food waste composting: A review. AB - Composting is a reliable technology to treat food waste (FW) and produce high quality compost. The ammonia (NH3) emission accounts for the largest nitrogen loss and leads to various environmental impacts. This review introduced the recent progresses on NH3 mitigation in FW composting. The basic characteristics of FW from various sources were given. Seven NH3 emission strategies proven effective in the literature were presented. The links between these strategies and the mechanisms of NH3 production were addressed. Application of hydrothermally treated C rich substrates, biochar or struvite salts had a broad prospect in FW composting if these strategies were proven cost-effective enough. Regulation of nitrogen assimilation and nitrification using biological additive had the potential to achieve NH3 mitigation but the existing evidence was not enough. In the end, the future prospects highlighted four research topics that needed further investigation to improve NH3 mitigation and nitrogen conservation in FW composting. PMID- 28736142 TI - Respiration adaptation of activated sludge under dissolved oxygen and hypochlorite stressed conditions. AB - In this work, the relationship between environmental disturbance and the recovery of activated sludge at a low dissolved oxygen of 0.5mg/l or in the presence of sodium hypochlorite of 1-15mg Cl2/gSS/d was examined. When microorganisms entered their physiological adaptation period, a sharp increase in endogenous respiration rate was observed. The activity recovery potential of sludge depended on the ratio of the endogenous respiration rate to the maximum respiration rate. A subsequent decrease in this ratio after a sharp increase indicates that the disturbance was recoverable. An increase in this ratio to a certain value, e.g., 0.35, suggests that the sludge system could not adapt to the new environments and thus was unrecoverable. In addition, the recoveries of sludge respiration and effluent quality were asynchronous, which was impacted by both sludge activity and operating conditions. These results provide a useful approach for the operation of activated sludge systems. PMID- 28736143 TI - Thermophilic membrane bioreactors: A review. AB - This study undertakes a state-of-the-art review on thermophilic membrane bioreactors (ThMBRs). Thermophilic aerobic membrane bioreactors (ThAeMBR) and thermophilic anaerobic membrane bioreactors (ThAnMBR) have been widely tested for various high-temperature industrial wastewater treatments at lab- and pilot-scale studies and full-scale applications. The biological and membrane performances of the ThAeMBRs and ThAnMBRs could be better, comparable or poorer, as compared to the mesophilic ones. In general, sludge yield was much lower, biodegradation kinetic was higher, and microbial community was less diversity in the ThAeMBR and ThAnMBR systems. The results from the literature show that ThMBR technology has demonstrated many advantages and is a promising technology for industrial wastewater treatment and sludge digestion. Furthermore, challenges and opportunities of various ThMBRs for industrial applications are identified and discussed. PMID- 28736144 TI - Evaluating the potential impact of hydrochar on the production of short-chain fatty acid from sludge anaerobic digestion. AB - In this study, waste activated sludge (WAS) was used as feedstock to generate hydrochars at different temperatures (220 degrees C and 260 degrees C) and their effect on sludge anaerobic digestion was evaluated. Experimental results showed that the maximum yield of short-chain fatty acid (SCFA) enhanced by hydrochar (220 degrees C) and hydrochar (260 degrees C) were 507.33 and 270.80mg chemical oxygen demand (COD)/L respectively, which were much higher than that in blank (141.49mg COD/L). Mechanism investigation confirmed that hydrochar remarkably accelerated the solubilization and hydrolysis of organic matters, enhanced the acidification of hydrolyzed products, and inhibited the activity of methanogenic bacteria as well as promoted the activities of key enzymes. Meanwhile, the organic matters especially humic substances existed in the hydrochar played an important role during anaerobic digestion. PMID- 28736145 TI - The thermochemical conversion of non-lignocellulosic biomass to form biochar: A review on characterizations and mechanism elucidation. AB - Biochar obtained from non-lignocellulosic biomass (NLBM) has attracted wide interests in various fields like pollutants removal, catalysis, and energy storage. However, the thermochemical conversion processes from NLBM to non lignocellulosic biochar (NLBC) have not been well summarized until now. To fill the knowledge gap, this review presents a systematical summary of NLBM characteristics, thermochemical behaviors of main components (e.g., C, O, N, P and metals), characterization methods for NLBC and conversion process, and the main applications of NLBC. Moreover, the vacancy and limitations of the current researches are pointed out to provide some guidance for future study. This review would contribute to deepen the understanding of NLBC, meanwhile optimize the efficient disposal and value-added utilization of NLBM wastes via thermochemical conversion. PMID- 28736146 TI - Lipid accumulation potential of oleaginous yeasts: A comparative evaluation using food waste leachate as a substrate. AB - In present study, the efficiency of three oleaginous yeasts i.e., Yarrowia lipolytica, Rhodotorula glutinis and Cryptococcus curvatus were compared for their lipid assimilation capacities using three different FW-leachates as a medium. The FW-leachates were collected from dry anaerobic digesters and diluted to achieve carbohydrate content of 25gL-1 prior to yeast inoculations. Around 5% of yeast cultures were individually mixed in three different FW-leachate mediums and incubated under 30 degrees C and 150rpm agitation for 6days. The Y. lipolytica produced high biomass with lipid contents of 49.0+/-2% on dry weight basis. Whereas, the acetic acid concentration of >6gL-1 inhibited the growth of R. glutinis. The study observed that the selection of appropriate FW-leachate composition is highly important for biolipid accumulation by oleaginous yeasts. PMID- 28736147 TI - Novel multifunctional plant growth-promoting bacteria in co-compost of palm oil industry waste. AB - Previously, a unique co-compost produced by composting empty fruit bunch with anaerobic sludge from palm oil mill effluent, which contributed to establishing a zero-emission industry in Malaysia. Little was known about the bacterial functions during the composting process and fertilization capacity of this co compost. We isolated 100 strains from the co-compost on 7 types of enumeration media and screened 25 strains using in vitro tests for 12 traits, grouping them according to three functions: plant growth promoting (fixation of nitrogen; solubilization of phosphorus, potassium, and silicate; production of 3 indoleacetic acid, ammonia, and siderophore), biocontrolling (production of chitinase and anti-Ganoderma activity), and composting (degradation of lignin, xylan, and cellulose). Using 16S rRNA gene sequence analysis, 25 strains with strong or multi-functional traits were found belong to the genera Bacillus, Paenibacillus, Citrobacter, Enterobacter, and Kosakonia. Furthermore, several strains of Citrobacter sedlakii exhibited a plant growth-stimulation in vivo komatsuna plant cultivation test. In addition, we isolated several multifunctional strains; Bacillus tequilensis CE4 (biocontrolling and composting), Enterobacter cloacae subsp. dissolvens B3 (plant growth promoting and biocontrolling), and C. sedlakii CESi7 (plant growth promoting and composting). Some bacteria in the co-compost play significant roles during the composting process and plant cultivation after fertilization, and some multifunctional strains have potential for use in accelerating the biodegradation of lignocellulosic biomass, protecting against Ganoderma boninense infection, and increasing the yield of palm oil. PMID- 28736148 TI - Risk and Protective Factors in the Lives of Transgender/Gender Nonconforming Adolescents. AB - PURPOSE: Research suggests that transgender and gender nonconforming (TGNC) youth may be at greatly increased risk of high-risk health behaviors compared with cisgender youth, but existing studies are limited by convenience samples and small numbers. This study uses a large school-based sample of adolescents to describe the prevalence of TGNC identity, associations with health risk behaviors and protective factors, and differences across birth-assigned sex. METHODS: This study analyzes existing surveillance data provided by 9th and 11th grade students in Minnesota in 2016 (N = 81,885). Students who were transgender, genderqueer, genderfluid, or unsure about their gender identity (TGNC) were compared with those who were not, using chi2 and t-tests. Outcome measures included four domains of high-risk behaviors and experiences and four protective factors. RESULTS: The prevalence of TGNC identity was 2.7% (n = 2,168) and varied significantly across gender, race/ethnicity, and economic indicators. Involvement in all types of risk behaviors and experiences was significantly higher, and reports of four protective factors were significantly lower among TGNC than cisgender youth. For example, almost two-thirds (61.3%) of TGNC youth reported suicidal ideation, which is over three times higher than cisgender youth (20.0%, chi2 = 1959.9, p < .001). Among TGNC youth, emotional distress and bullying experience were significantly more common among birth-assigned females than males. CONCLUSIONS: This research presents the first large-scale, population based evidence of substantial health disparities for TGNC adolescents in the United States, highlighting numerous multilevel points of intervention through established protective factors. Health care providers are advised to act as allies by creating a safe space for young people, bolstering protective factors, and supporting their healthy development. PMID- 28736149 TI - Methylmercury augments Nrf2 activity by downregulation of the Src family kinase Fyn. AB - Methylmercury (MeHg) is a potent developmental neurotoxicant that induces an oxidative stress response in the brain. It has been demonstrated that MeHg exposure increases nuclear factor erythroid 2-related factor 2 (Nrf2) activity. Nrf2 is a transcription factor that translocates to the nucleus in response to oxidative stress, and upregulates phase II detoxifying enzymes. Although, Nrf2 activity is augmented subsequent to MeHg exposure, it has yet to be established whether Nrf2 moves into the nucleus as a result. Furthermore, the potential effect MeHg might have on the non-receptor tyrosine kinase, Fyn, has not been addressed. Fyn phosphorylates Nrf2 in the nucleus, resulting in its inactivation, and consequent downregulation of the oxidative stress response. Here, we observe Nrf2 translocates to the nucleus subsequent to MeHg-induced oxidative stress. This response is concomitant with reduced Fyn expression and nuclear localization. Moreover, we detected an increase in phosphorylated Akt and glycogen synthase kinase 3 beta (GSK-3beta) at activating and inhibitory sites, respectively. Akt phosphorylates and inhibits GSK-3beta, which subsequently prevents Fyn phosphorylation to signal nuclear import. Our results demonstrate MeHg downregulates Fyn to maintain Nrf2 activity, and further illuminate a potential mechanism by which MeHg elicits neurotoxicity. PMID- 28736151 TI - Multi-loop nonlinear control design for performance improvement of LTI systems. AB - This paper puts forward a multi-loop nonlinear control (MLNC) strategy to overcome the limited performance of LTI controllers due to the so-called "waterbed" effect. According to "Bode's sensitivity integral", increasing the bandwidth or additional integral gain of LTI controller to improve the low frequency disturbance attenuation irrefutably increases the sensitivity to high frequency disturbances or measurement noise. Hence, it is impossible to attain the best of both worlds in the case of linear controllers. Therefore, with an aim to improve the transient and steady state performance of linear controllers, in this paper, a nonlinear control framework using circle criterion method and saturation nonlinearity, which adjusts the integral gain based on the error threshold, is discussed. The global asymptotic stability (GAS) of the MLNC strategy is theoretically proved using LaSalle's invariance principle and experimentally validated using measured frequency response function (FRF). Moreover, the performance of the MLNC strategy is compared with that of the multi loop linear control (MLLC) strategy on a benchmark magnetic levitation system for tracking application. The cumulative power spectral density (CPSD) of tracking error, which is used as the performance index to assess the overall closed loop performance, accentuates that MLNC can yield better steady state and transient performance compared to MLLC scheme. PMID- 28736150 TI - Prenatal environmental chemical exposures and longitudinal patterns of child neurobehavior. AB - BACKGROUND: Prenatal chemical exposures may adversely affect neurodevelopment, but few studies have examined the persistence of these associations. We examined whether associations between prenatal bisphenol A (BPA) or polybrominated diphenyl ether (PBDE) exposures persist or resolve as children age. METHODS: We followed 346 mother-child pairs (enrolled 2003-2006) from Cincinnati, OH from pregnancy until children were 8 years old. We measured BPA in urine collected at 16 and 26 weeks gestation and PBDE-47 in serum collected at 16 weeks gestation. We administered repeated measures of children's behavior, mental/psychomotor development, and IQ from ages 1-8 years. We determined if associations of BPA or PBDE-47 with child neurobehavior persisted or resolved as children aged using linear mixed models and estimated neurobehavioral measure reproducibility using intraclass correlation coefficients (ICCs). RESULTS: Higher BPA in girls and higher PBDE-47 in both boys and girls were associated with more externalizing behaviors; these associations persisted from ages 2-8 years (exposure*age interaction p-values>=0.36). Higher PBDE-47 concentrations were associated with decreases in MDI from ages 1-3 years (PBDE-47x age interaction p-value=0.03) and persistently lower IQ at ages 5 and 8 years (PBDE-47*age interaction p value=0.56). Mental/psychomotor abilities had fair reproducibility from ages 1-3 years (ICCs~0.4), cognitive abilities from ages 5 to 8 years had excellent reproducibility (ICCs=0.7-0.8), and parent-reported behaviors from ages 2-8 years had poor to good reproducibility (ICCs=0.38-0.59). CONCLUSIONS: Prenatal BPA and PBDE-47 concentrations were persistently associated with more externalizing behaviors. PBDE-47 concentrations were inversely associated with cognitive abilities that strengthened over time. PMID- 28736152 TI - Time-lapse culture with morphokinetic embryo selection improves pregnancy and live birth chances and reduces early pregnancy loss: a meta-analysis. AB - Embryo evaluation and selection is fundamental in clinical IVF. Time-lapse follow up of embryo development comprises undisturbed culture and the application of the visual information to support embryo evaluation. A meta-analysis of randomized controlled trials was carried out to study whether time-lapse monitoring with the prospective use of a morphokinetic algorithm for selection of embryos improves overall clinical outcome (pregnancy, early pregnancy loss, stillbirth and live birth rate) compared with embryo selection based on single time-point morphology in IVF cycles. The meta-analysis of five randomized controlled trials (n = 1637) showed that the application of time-lapse monitoring was associated with a significantly higher ongoing clinical pregnancy rate (51.0% versus 39.9%), with a pooled odds ratio of 1.542 (P < 0.001), significantly lower early pregnancy loss (15.3% versus 21.3%; OR: 0.662; P = 0.019) and a significantly increased live birth rate (44.2% versus 31.3%; OR 1.668; P = 0.009). Difference in stillbirth was not significant between groups (4.7% versus 2.4%). Quality of the evidence was moderate to low owing to inconsistencies across the studies. Selective application and variability were also limitations. Although time-lapse is shown to significantly improve overall clinical outcome, further high-quality evidence is needed before universal conclusions can be drawn. PMID- 28736153 TI - In-vitro study of gonadotrophin signaling pathways in human granulosa cells in relation to progesterone receptor expression. AB - In humans, data on gonadotrophin-activated (LH, HCG and FSH) progesterone receptor expression and signalling pathways involved in matrix metalloproteinases (MMPs) expression presumably linked to the follicle rupture, are limited. Our hypothesis is LH, HCG and FSH increase progesterone receptor expression in granulosa cells through different signalling pathways, leading to an increased expression of ADAMTS-1 and MMP3/10, which may mediate follicular rupture through the transcription factor, HIF1A. Human granulosa cells were isolated from follicular aspirates obtained from 22 healthy women participating in our IVF programme for male-factor infertility. Progesterone receptor and HIF1A expression was assessed by immunofluorescence, and PKA-PKC-PI3K- ERK1/2, ADAMTS-1 and MMP3/10 expression by Western blot in pre-ovulatory and in cultured granulosa cells. Results show that HCG, LH and FSH regulate progesterone receptor expression and activate PKA, PKC, PI3K and ERK1/2 signalling pathways in granulosa cells but progesterone receptor expression is only mediated by PKA, PKC and ERK pathways. HCG, FSH and LH regulated MMPs expression through progesterone receptors. Moreover, HCG-progesterone-receptor-dependent HIF1A expression stimulated MMP3/10 expression but not that of ADAMTS-1. These results suggest differential downstream progesterone receptor signalling, as progesterone receptor regulates MMP3/10 expression via HIF1A, which is not involved in ADAMTS 1 expression. PMID- 28736154 TI - Retinoic acid induces differentiation of buffalo (Bubalus bubalis) embryonic stem cells into germ cells. AB - Development of precise and reproducible culture system for in vitro differentiation of embryonic stem (ES) cells into germ cells counts as a major leap forward for understanding not only the remarkable process of gametogenesis, otherwise obscured by limited availability of precursor primordial germ cells (PGCs), but in finally treating the catastrophic infertility. Taking into account the significant role of retinoic acid (RA) during in vivo gametogenesis, we designed the present study to investigate the effects of its stimulation on directing the differentiation of ES cells into germ cells. The effects of RA were analyzed across dose-and-time upon various stages of gametogenesis like PGC induction, meiosis initiation and completion, haploid cell formation and development of the final gamete (oocyte and spermatozoa). Out of the series of RA doses (2, 4, 8, 16, 20 and 30MUM), 16MUM RA for 8day culture interval was found to induce highest expression of PGC- and meiosis-associated genes like DAZL, VASA, SYCP3, MLH1, TNP1/2 and PRM2, while mature germ cell genes like BOULE and TEKT1 (Spermatocyte markers), GDF9 and ZP2 (Oocyte markers) showed higher expression at 2MUM RA dose, suggesting functional concentration-gradient of RA activity. Immunocytochemistry revealed expression of germ lineage-specific markers like: c-KIT, DAZL and VASA (PGC-markers); SYCP3, MLH1 and PROTAMINE1 (Meiotic-markers); ACROSIN and HAPRIN (Spermatocyte-markers); and GDF9 and ZP4 (Oocyte-markers) in optimally differentiated embryoid bodies (EBs) and adherent cultures. We observed significantly reduced (p<0.05) concentration of 5-methyl-2 deoxycytidine in RA-differentiated EBs which is suggestive of the occurrence of methylation erasure. FACS analysis of optimally differentiated cultures detected 3.07% haploid cell population, indicating completion of meiosis. Oocyte-like structures (OLS) were obtained in adherent differentiated cultures. They had a big nucleus and a zona pellucida (ZP4) coat. They showed progression through 2 cell, 4-cell, 8-cell, morula and blastocyst-like structures upon extended culture beyond 14days. PMID- 28736155 TI - Integrin linked kinase regulates the transcription of AQP2 by NFATC3. AB - Two processes are associated with progressive loss of renal function: 1) decreased aquaporin-2 (AQP2) expression and urinary concentrating capacity (Nephrogenic Diabetes Insipidus, NDI); and 2) changes in extracellular matrix (ECM) composition, e.g. increased collagen I (Col I) deposition, characteristic of tubule-interstitial fibrosis. AQP2 expression is regulated by both the ECM-to intracellular scaffold protein integrin-linked kinase (ILK) by NFATc/AP1 and other transcription factors. In the present work, we used in vivo and in vitro approaches to examine ILK participation in NFATc3/AP-1-mediated increases in AQP2 gene expression. Both NFATc3 knock-out mice and ILK conditional-knockdown mice (cKD-ILK) display symptoms of NDI (polyuria and reduced AQP2 expression). NFATc3 is upregulated in the renal medulla tubular cells of cKD-ILK mice but with reduced nuclear localization. Inner medullary collecting duct mIMCD3 cells were subjected to ILK depletion and transfected with reporter plasmids. Pharmacological activators or inhibitors determined the effect of ILK activity on NFATc/AP-1-dependent increases in transcription of AQP2. Finally, mIMCD3 cultured on Col I showed reduced activity of the ILK/GSK3beta/NFATc/AQP2 axis, suggesting this pathway is a potential target for therapeutic treatment of NDI. PMID- 28736156 TI - Improving the economics of NASH/NAFLD treatment through the use of systems biology. AB - Nonalcoholic steatohepatitis (NASH) is a severe form of nonalcoholic fatty liver disease (NAFLD). We surveyed NASH therapies currently in development, and found a significant variety of targets and approaches. Evaluation and clinical testing of these targets is an expensive and time-consuming process. Systems biology approaches could enable the quantitative evaluation of the likely efficacy and safety of different targets. This motivated our review of recent systems biology studies that focus on the identification of targets and development of effective treatments for NASH. We discuss the potential broader use of genome-scale metabolic models and integrated networks in the validation of drug targets, which could facilitate more productive and efficient drug development decisions for the treatment of NASH. PMID- 28736157 TI - Prevention and treatment of the post-thrombotic syndrome. AB - Post-thrombotic syndrome (PTS) is a complication that develops in up to 50% of patients with deep vein thrombosis (DVT) and manifests as symptoms and signs of chronic venous insufficiency of varying severity. PTS negatively affects patient's quality of life and causes significant burden to the healthcare system. The risk for PTS development can be markedly reduced by preventing DVT and providing appropriate anticoagulation once it develops. Patients with extensive proximal (iliofemoral) DVT may benefit from invasive interventions, such as catheter-directed thrombolysis. The effectiveness of elastic compression stockings (ECS) for PTS prevention has not been conclusively demonstrated in randomized trials. Treatment of PTS is primarily based on ECS, exercise and lifestyle modifications. The effectiveness of various pharmacologic agents for PTS treatment remains controversial. Surgical or radiological interventions for vein reconstruction or revascularization may be considered in refractory cases. This review summarizes current evidence regarding prevention and treatment of PTS of the lower limbs in adults. PMID- 28736158 TI - Nanoliposomes carrying HER2/neu-derived peptide AE36 with CpG-ODN exhibit therapeutic and prophylactic activities in a mice TUBO model of breast cancer. AB - This study was designed to prepare and characterize nanoliposomal vaccine formulation encapsulating AE36 HER2/neu-derived peptide with or without CpG and evaluate the immunologic and therapeutic responses of that in BALB/c mice model of Her2 overexpressing breast cancer. AE36 was encapsulated in liposomes composed of DOTAP, DOPE and Cholesterol (DDC) or DD with. The formulations could induce both CD8+ and CD4+ responses and stimulate production of cytokines which was detected by Enzyme-linked immunospot assay (ELISpot) kits, cytotoxicity test and intracellular cytokine assay by flow cytometry. The formulation showed both therapeutic and prophylactic effects in BALB/c mice bearing Her2+ breast cancer. DDC+CpG showed the best effect in prophylactic study and DD+pG showed the best effect in therapeutic study, which both of them decreased the size of tumors significantly. The engineered nanoliposomes containing AE36 could be a candidate vaccine for the treatment or prophylaxis of HER2+ breast cancer and merits further investigation. PMID- 28736159 TI - A novel CCR-2/TLR-2 triggered signaling in murine peritoneal macrophages intensifies bacterial (Staphylococcus aureus) killing by reactive oxygen species through TNF-R1. AB - Macrophages are remarkably versatile in their ability to recognize and respond to a wide range of stimuli by expressing a variety of surface and intracellular receptors and triggering multiple signal transduction pathways. The onset of microbial infection is primarily determined by the initial contacts made by the microbes with the host macrophages. Although there prevail a relationship between the chemokine receptor and Toll like receptors during disease, particularly TLR-2 and CCR-2 signaling interdependence on each other has not been yet investigated during acute staphylococcal infection. Thus, the present study was aimed to trace possible interaction between CCR-2 and TLR-2 in peritoneal macrophages during acute Staphylococcus aureus infection. We found that neutralization of CCR-2 attenuates TLR-2 expression and restricts S. aureus burden but TLR-2 neutralization augments CCR-2 expression in macrophages, along with compromised host-derived reactive oxygen species production. S. aureus infection to CCR-2 intact but TLR-2 neutralized macrophages triggered production of IL-1beta, TNF alpha, IL-6, IFN-gamma, MCP-1 and expression of iNOS, TNFR-1 and GPx with concomitant decrease in IL-10 production. Further, study with NG-monomethyl-l arginine (L-NMMA) [iNOS blocker] and buthionine sulfoximine (BSO) [GPx blocker] revealed that S. aureus infection enhanced TLR-2 expression in CCR-2 intact and TLR-2 neutralized macrophages possibly via iNOS and TNFR-1 up regulation and GPx down regulation. Overall, our data indicate that targeting CCR-2 with neutralizing antibody in the early phase of S. aureus infection could restrict excessive inflammation with less compromised bacterial killing. It certainly would be a therapeutic strategy in S. aureus induced inflammatory and infective diseases. PMID- 28736161 TI - [Immortalization of erythroid progenitors for in vitro large-scale red cell production]. AB - Population ageing and increase in cancer incidence may lead to a decreased availability of red blood cell units. Thus, finding an alternative source of red blood cells is a highly relevant challenge. The possibility to reproduce in vitro the human erythropoiesis opens a new era, particularly since the improvement in the culture systems allows to produce erythrocytes from induced-Pluripotent Stem Cells (iPSCs), or CD34+ Hematopoietic Stem Cells (HSCs). iPSCs have the advantage of in vitro self-renewal, but lead to poor amplification and maturation defects (high persistence of nucleated erythroid precursors). Erythroid differentiation from HSC allows a far better amplification and adult-like hemoglobin synthesis. But the inability of these progenitors to self-renew in vitro remains a limit in their use as a source of stem cells. A major improvement would consist in immortalizing these erythroid progenitors so that they could expand indefinitively. Inducible transgenesis is the first way to achieve this goal. To date, the best immortalized-cell models involve strong oncogenes induction, such as c-Myc, Bcl-xL, and mostly E6/E7 HPV16 viral oncoproteins. However, the quality of terminal differentiation of erythroid progenitors generated by these oncogenes is not optimal yet and the long-term stability of such systems is unknown. Moreover, viral transgenesis and inducible expression of oncogenes raise important problems in term of safety, since the enucleation rate is not 100% and no nucleated cells having replicative capacities should be present in the final product. PMID- 28736162 TI - [Skin engineering for severe burns]. AB - Severe burned patients need definitive and efficient wound coverage. Outcome of massive burns has been improved by using cultured epithelial autografts (CEA). Despite fragility, percentages of success take, cost of treatment and long-term tendency to contracture, this surgical technique has been developed in few burn centres. First improvements were to combine CEA and dermis-like substitute. Cultured skin substitutes provide earlier skin closure and satisfying functional result. These methods have been used successfully in massive burns. Second improvement was to allow skin regeneration by using epidermal stem cells. Stem cells have capacity to differentiate into keratinocytes, to promote wound repair and to regenerate skin appendages. Human mesenchymal stem cells contribute to wound healing and were evaluated in cutaneous radiation syndrome. Skin regeneration and tissue engineering methods remain a complex challenge and offer the possibility of new treatment for injured and burned patients. PMID- 28736160 TI - Macrophage phenotype in response to ECM bioscaffolds. AB - Macrophage presence and phenotype are critical determinants of the healing response following injury. Downregulation of the pro-inflammatory macrophage phenotype has been associated with the therapeutic use of bioscaffolds composed of extracellular matrix (ECM), but phenotypic characterization of macrophages has typically been limited to small number of non-specific cell surface markers or expressed proteins. The present study determined the response of both primary murine bone marrow derived macrophages (BMDM) and a transformed human mononuclear cell line (THP-1 cells) to degradation products of two different, commonly used ECM bioscaffolds; urinary bladder matrix (UBM-ECM) and small intestinal submucosa (SIS-ECM). Quantified cell responses included gene expression, protein expression, commonly used cell surface markers, and functional assays. Results showed that the phenotype elicited by ECM exposure (MECM) is distinct from both the classically activated IFNgamma+LPS phenotype and the alternatively activated IL-4 phenotype. Furthermore, the BMDM and THP-1 macrophages responded differently to identical stimuli, and UBM-ECM and SIS-ECM bioscaffolds induced similar, yet distinct phenotypic profiles. The results of this study not only characterized an MECM phenotype that has anti-inflammatory traits but also showed the risks and challenges of making conclusions about the role of macrophage mediated events without consideration of the source of macrophages and the limitations of individual cell markers. PMID- 28736163 TI - Robotic-assisted laparoscopic MACE. AB - INTRODUCTION: The creation of a Malone antegrade continence enema (MACE) channel is an option to treat patients with neurologic conditions that result in fecal soiling or intractable constipation. It is typically performed in an open fashion through a midline incision or laparoscopically. The laparoscopic technique typically involves bringing the tip of the appendix to the skin whereas the open technique allows for imbrication of the cecum around the channel, which may improve continence and decrease the risk of perforation. Herein, we demonstrate a technique to create a MACE using both robotic-assisted and laparoscopic techniques that allows for imbrication of the channel without requiring an open incision. MATERIALS AND METHODS: Three robotic ports are placed in the midline and a fourth port is placed in the right lower quadrant at the location of the MACE stoma. Two mesenteric fenestrations are made along the appendix in order to imbricate the cecum around the channel. The tip of the appendix is then brought to through the laparoscopic port in the right lower quadrant, and matured to the skin. DISCUSSION: The MACE procedure can safely be performed using a robotic assisted technique that allows for imbrication of the cecum around the channel and improved cosmesis. PMID- 28736164 TI - Idiothetic Path Integration in the Fruit Fly Drosophila melanogaster. AB - After discovering a small drop of food, hungry flies exhibit a peculiar behavior in which they repeatedly stray from, but then return to, the newly discovered resource. To study this behavior in more detail, we tracked hungry Drosophila as they explored a large arena, focusing on the question of how flies remain near the food. To determine whether flies use external stimuli, we individually eliminated visual, olfactory, and pheromonal cues. In all cases, flies still exhibited a centralized search behavior, suggesting that none of these cues are absolutely required for navigation back to the food. To simultaneously eliminate visual and olfactory cues associated with the position of the food, we constructed an apparatus in which the food could be rapidly translated from the center of the arena. Flies continued to search around the original location, even after the food was moved to a new position. A random search model based on measured locomotor statistics could not reproduce the centered nature of the animal's trajectory. We conclude that this behavior is best explained by a form of path integration in which the flies use idiothetic cues to search near the location of the food. We argue that the use of path integration to perform a centered local search is not a specialization of Drosophila but rather represents an ancient behavioral mode that is homologous to the more elaborate foraging strategies of central place foragers such as ants. PMID- 28736165 TI - Intra-lineage Fate Decisions Involve Activation of Notch Receptors Basal to the Midbody in Drosophila Sensory Organ Precursor Cells. AB - Notch receptors regulate cell fate decisions during embryogenesis and throughout adult life. In many cell lineages, binary fate decisions are mediated by directional Notch signaling between the two sister cells produced by cell division. How Notch signaling is restricted to sister cells after division to regulate intra-lineage decision is poorly understood. More generally, where ligand-dependent activation of Notch occurs at the cell surface is not known, as methods to detect receptor activation in vivo are lacking. In Drosophila pupae, Notch signals during cytokinesis to regulate the intra-lineage pIIa/pIIb decision in the sensory organ lineage. Here, we identify two pools of Notch along the pIIa pIIb interface, apical and basal to the midbody. Analysis of the dynamics of Notch, Delta, and Neuralized distribution in living pupae suggests that ligand endocytosis and receptor activation occur basal to the midbody. Using selective photo-bleaching of GFP-tagged Notch and photo-tracking of photo-convertible Notch, we show that nuclear Notch is indeed produced by receptors located basal to the midbody. Thus, only a specific subset of receptors, located basal to the midbody, contributes to signaling in pIIa. This is the first in vivo characterization of the pool of Notch contributing to signaling. We propose a simple mechanism of cell fate decision based on intra-lineage signaling: ligands and receptors localize during cytokinesis to the new cell-cell interface, thereby ensuring signaling between sister cells, hence intra-lineage fate decision. PMID- 28736166 TI - Rhamnose-Containing Cell Wall Polymers Suppress Helical Plant Growth Independently of Microtubule Orientation. AB - Although specific organs in some plant species exhibit helical growth patterns of fixed or variable handedness, most plant organs are not helical. Here we report that mutations in Arabidopsis RHAMNOSE BIOSYNTHESIS 1 (RHM1) cause dramatic left handed helical growth of petal epidermal cells, leading to left-handed twisted petals. rhm1 mutant roots also display left-handed growth. Furthermore, we find that RHM1 is required to promote epidermal cell expansion. RHM1 encodes a UDP-L rhamnose synthase, and rhm1 mutations affect synthesis of the pectic polysaccharide rhamnogalacturonan-I. Unlike other mutants that exhibit helical growth of fixed handedness, the orientation of cortical microtubule arrays is unaltered in rhm1 mutants. Our findings reveal a novel source of left-handed plant growth caused by changes in cell wall composition that is independent of microtubule orientation. We propose that an important function of rhamnose containing cell wall polymers is to suppress helical twisting of expanding plant cells. PMID- 28736167 TI - An Actomyosin-Arf-GEF Negative Feedback Loop for Tissue Elongation under Stress. AB - In response to a pulling force, a material can elongate, hold fast, or fracture. During animal development, multi-cellular contraction of one region often stretches neighboring tissue. Such local contraction occurs by induced actomyosin activity, but molecular mechanisms are unknown for regulating the physical properties of connected tissue for elongation under stress. We show that cytohesins, and their Arf small G protein guanine nucleotide exchange activity, are required for tissues to elongate under stress during both Drosophila dorsal closure (DC) and zebrafish epiboly. In Drosophila, protein localization, laser ablation, and genetic interaction studies indicate that the cytohesin Steppke reduces tissue tension by inhibiting actomyosin activity at adherens junctions. Without Steppke, embryogenesis fails, with epidermal distortions and tears resulting from myosin misregulation. Remarkably, actomyosin network assembly is necessary and sufficient for local Steppke accumulation, where live imaging shows Steppke recruitment within minutes. This rapid negative feedback loop provides a molecular mechanism for attenuating the main tension generator of animal tissues. Such attenuation relaxes tissues and allows orderly elongation under stress. PMID- 28736168 TI - Light-Dependent Degradation of PIF3 by SCFEBF1/2 Promotes a Photomorphogenic Response in Arabidopsis. AB - Plant seedlings emerging from darkness into the light environment undergo photomorphogenesis, which enables autotrophic growth with optimized morphology and physiology. During this transition, plants must rapidly remove photomorphogenic repressors accumulated in the dark. Among them is PHYTOCHROME INTERACTING FACTOR 3 (PIF3), a key transcription factor promoting hypocotyl growth. Here we report that, in response to light activation of phytochrome photoreceptors, EIN3-BINDING F BOX PROTEINs (EBFs) 1 and 2 mediate PIF3 protein degradation in a manner dependent on light-induced phosphorylation of PIF3. Whereas PIF3 binds EBFs independent of light, the recruitment of PIF3-EBFs to the core SKP1-CUL1-F box protein (SCF) scaffold is facilitated by light signals or PIF3 phosphorylation. We also found that previously identified LIGHT-RESPONSE BRIC-A-BRACK/TRAMTRACK/BROAD (LRB) E3 ubiquitin ligases target phytochrome B (phyB) and PIF3 primarily under high-light conditions, whereas EBF1/2 vigorously target PIF3 degradation under wide ranges of light intensity without affecting the abundance of phyB. Both genetic and molecular data support that SCFEBF1/2 function as photomorphogenic E3s during seedling development. PMID- 28736169 TI - Protein Interaction Analysis Provides a Map of the Spatial and Temporal Organization of the Ciliary Gating Zone. AB - The motility and signaling functions of the primary cilium require a unique protein and lipid composition that is determined by gating mechanisms localized at the base of the cilium. Several protein complexes localize to the gating zone and may regulate ciliary protein composition; however, the mechanisms of ciliary gating and the dynamics of the gating components are largely unknown. Here, we used the BiFC (bimolecular fluorescence complementation) assay and report for the first time on the protein-protein interactions that occur between ciliary gating components and transiting cargoes during ciliary entry. We find that the nucleoporin Nup62 and the C termini of the nephronophthisis (NPHP) proteins NPHP4 and NPHP5 interact with the axoneme-associated kinesin-2 motor KIF17 and thus spatially map to the inner region of the ciliary gating zone. Nup62 and NPHP4 exhibit rapid turnover at the transition zone and thus define dynamic components of the gate. We find that B9D1, AHI1, and the N termini of NPHP4 and NPHP5 interact with the transmembrane protein SSTR3 and thus spatially map to the outer region of the ciliary gating zone. B9D1, AHI1, and NPHP5 exhibit little to no turnover at the transition zone and thus define components of a stable gating structure. These data provide the first comprehensive map of the molecular orientations of gating zone components along the inner-to-outer axis of the ciliary gating zone. These results advance our understanding of the functional roles of gating zone components in regulating ciliary protein composition. PMID- 28736170 TI - Overlap among Spatial Memories Triggers Repulsion of Hippocampal Representations. AB - Across the domains of spatial navigation and episodic memory, the hippocampus is thought to play a critical role in disambiguating (pattern separating) representations of overlapping events. However, it is not fully understood how and why hippocampal patterns become separated. Here, we test the idea that event overlap triggers a "repulsion" among hippocampal representations that develops over the course of learning. Using a naturalistic route-learning paradigm and spatiotemporal pattern analysis of human fMRI data, we found that hippocampal representations of overlapping routes gradually diverged with learning to the point that they became less similar than representations of non-overlapping events. In other words, the hippocampus not only disambiguated overlapping events but formed representations that "reversed" the objective similarity among routes. This finding, which was selective to the hippocampus, is not predicted by standard theoretical accounts of pattern separation. Critically, because the overlapping route stimuli that we used ultimately diverged (so that each route contained overlapping and non-overlapping segments), we were able to test whether the reversal effect was selective to the overlapping segments. Indeed, once overlapping routes diverged (eliminating spatial and visual similarity), hippocampal representations paradoxically became relatively more similar. Finally, using a novel analysis approach, we show that the degree to which individual hippocampal voxels were initially shared across route representations was predictive of the magnitude of learning-related separation. Collectively, these findings indicate that event overlap triggers a repulsion of hippocampal representations-a finding that provides critical mechanistic insight into how and why hippocampal representations become separated. PMID- 28736171 TI - Northern Elephant Seals Memorize the Rhythm and Timbre of Their Rivals' Voices. AB - The evolutionary origin of rhythm perception, a cognitive ability essential to musicality, remains unresolved [1-5]. The ability to perceive and memorize rhythmic sounds is widely shared among humans [6] but seems rare among other mammals [7, 8]. Although the perception of temporal metrical patterns has been found in a few species, this ability has only been demonstrated through behavioral training [9] (but see [10] for an example of spontaneous tempo coordination in a bonobo), and there is no experimental evidence to indicate its biological function. Furthermore, there is no example of a non-human mammal able to remember and recognize auditory rhythmic patterns among a wide range of tempi. In the northern elephant seal Mirounga angustirostris, the calls of mature males comprise a rhythmic series of pulses, with the call of each individual characterized by its tempo and timbre; these individual vocal signatures are stable over years and across contexts [11]. Here, we report that northern elephant seal males routinely memorize and recognize the unique tempo and timbre of their rivals' voices and use this rhythmic information to individually identify competitors, which facilitates navigation within the social network of the rookery. By performing playbacks with natural and modified vocalizations, we show that males are sensitive to call rhythm disruption independently of modification of spectral features and that they use both temporal and spectral cues to identify familiar rivals. While spectral features of calls typically encode individual identity in mammalian vocalizations [12], this is the first example of this phenomenon involving sound rhythm. PMID- 28736172 TI - Early Integration of Temperature and Humidity Stimuli in the Drosophila Brain. AB - The Drosophila antenna contains receptor neurons for mechanical, olfactory, thermal, and humidity stimuli. Neurons expressing the ionotropic receptor IR40a have been implicated in the selection of an appropriate humidity range [1, 2], but although previous work indicates that insect hygroreceptors may be made up by a "triad" of neurons (with a dry-, a cold-, and a humid-air-responding cell [3]), IR40a expression included only cold- and dry-air cells. Here, we report the identification of the humid-responding neuron that completes the hygrosensory triad in the Drosophila antenna. This cell type expresses the Ir68a gene, and Ir68a mutation perturbs humidity preference. Next, we follow the projections of Ir68a neurons to the brain and show that they form a distinct glomerulus in the posterior antennal lobe (PAL). In the PAL, a simple sensory map represents related features of the external environment with adjacent "hot," "cold," "dry," and "humid" glomeruli-an organization that allows for both unique and combinatorial sampling by central relay neurons. Indeed, flies avoided dry heat more robustly than humid heat, and this modulation was abolished by silencing of dry-air receptors. Consistently, at least one projection neuron type received direct synaptic input from both temperature and dry-air glomeruli. Our results further our understanding of humidity sensing in the Drosophila antenna, uncover a neuronal substrate for early sensory integration of temperature and humidity in the brain, and illustrate the logic of how ethologically relevant combinations of sensory cues can be processed together to produce adaptive behavioral responses. PMID- 28736173 TI - Low doses of 17alpha-ethinyl estradiol alter the maternal brain and induce stereotypies in CD-1 mice exposed during pregnancy and lactation. AB - Maternal care is critical for the survival, development and long-term success of offspring. Despite our current understanding of the role of endogenous estrogen in both maternal behavior and the maternal brain, the potential effects of exogenous estrogens on these endpoints remain poorly understood. Here, pregnant CD-1 mice were exposed to low doses of 17alpha-ethinyl estradiol (EE2), commonly used as a positive control in studies of other xenoestrogens, from day 9 of pregnancy until weaning. Using traditional maternal behavior assays, we document no significant changes in maternal behavior throughout the lactational period. However, EE2 induced increases in repetitive tail retrieval, which may indicate a stereotypy or obsessive compulsive (OCD)-like behavior. We also observed a significant reduction in tyrosine hydroxylase (TH) immunoreactivity in the ventral tegmental area (VTA), a region important for maternal motivation. These results suggest that pregnant adult females are not immune to the effects of this compound. PMID- 28736174 TI - Effects of cigarette smoke extracts on cell cycle, cell migration and endocrine activity in human placental cells. AB - Maternal smoking during pregnancy is known to be related to adverse pregnancy results associated with trophoblast proliferation and cell cycle progression. Moreover, many previous studies have shown that cigarette smoke is correlated with human chorionic gonadotropin beta (hCG-beta) subunit produced from syncytiotrophoblasts during pregnancy. Thus, we further investigated whether cigarette smoke extract (CSE) affects the cell proliferation, migration and endocrine hormone activity of JEG-3 human placental cancer cells. JEG-3 cell proliferation was significantly reduced by all CSEs in a concentration-dependent manner. Moreover, CSEs decreased proliferating cell nuclear antigen (PCNA) levels in JEG-3 cells in Western blot. Increased migration or invasion ability of JEG-3 cells following CSE treatment was also confirmed by a scratch or fibronectin invasion assay in vitro. Additionally, protein levels of E-cadherin as an epithelial maker were down-regulated, while the mesenchymal markers N-cadherin, snail and slug were up-regulated in a time-dependent manner. The metastasis marker, cathepsin D, was also down-regulated by CSE. Finally, CSEs significantly reduced the expression of hCG-beta protein in JEG-3 cells. Overall, these results indicate that exposure of placental cells to CSE deregulates the cell cycle by altering the expression of cell cycle-related proteins and stimulates cell metastatic ability by altering EMT markers and cathepsin D expression. CSE exposure may also decrease hCG-beta production as an endocrine marker, implying that cigarette smoke has adverse effects during pregnancy. PMID- 28736175 TI - Structural Basis for Receptor Selectivity by the Whitewater Arroyo Mammarenavirus. AB - Whitewater Arroyo virus belongs to the "New World" group of mammarenaviruses that reside in rodent reservoirs and are prevalent in North and South Americas. Clades B and A/B of New World mammarenaviruses use transferrin receptor 1 (TfR1) for entry. While all of these viruses use rodent-derived TfR1 orthologs, some can also use the human-TfR1 and thereby infect humans. Although we have structural information for TfR1 recognition by pathogenic virus, we do not know what the structural differences are between the receptor-binding domains of pathogenic and non-pathogenic viruses that allow some but not all viruses to utilize the human receptor for entry. The poor understanding of the molecular determinants of mammarenavirus host range, and thus pathogenicity, is partly due to the low sequence similarity between the receptor-binding domains from these viruses and the limited available structural information that preclude the use of modeling approaches. Here we present the first crystal structure of a receptor-binding domain of a non-pathogenic clade A/B mammarenavirus. This structure reveals the magnitude of structural differences within the receptor-binding domains of TfR1 tropic viruses. Our structural and sequence analyses indicate that the same structural incompatibilities with the human receptor equally affect both pathogenic and non-pathogenic mammarenaviruses. Non-pathogenic viruses do not have specific structural elements that prevent them from using the human receptor. Instead, the ability to utilize the human receptor directly depends on the extent of weak interactions throughout the receptor-binding site that in some viruses are sufficiently strong to overcome the structural incompatibilities. PMID- 28736176 TI - Crystal Structure of the C-terminal Domain of Human eIF2D and Its Implications on Eukaryotic Translation Initiation. AB - Protein synthesis is a key process in all living organisms. In eukaryotes, initiation factor 2 (eIF2) plays an important role in translation initiation as it selects and delivers the initiator tRNA to the small ribosomal subunit. Under stress conditions, phosphorylation of the alpha-subunit of eIF2 downregulates cellular protein synthesis. However, translation of certain mRNAs continues via the eIF2D-dependent non-canonical initiation pathway. The molecular mechanism of this process remains elusive. In addition, eIF2D plays a role in translation re initiation and ribosome recycling. Currently, there has been no structural information of eIF2D. We have now determined the crystal structure of the C terminal domains of eIF2D at 1.4-A resolution. One domain has the fold similar to that of eIF1, which is crucial for the scanning and initiation codon selection. The second domain has a known SWIB/MDM2 fold, which was not observed before in other translation initiation factors. Our structure reveals atomic details of inter-domain interactions in the C-terminal part of eIF2D and sheds light on the possible role of these domains in eIF2D during translation. PMID- 28736177 TI - The analgesic effect of non-pharmacological interventions to reduce procedural pain in preterm neonates. AB - BACKGROUND: Painful procedures are unavoidable in the medical care of preterm babies. The unpleasant experience during the neonatal period may contribute to hyperalgesia and poor neurodevelopment outcome later. Seeking effective interventions to reduce pain are strongly indicated for these very small premature babies. The aim of this study is to investigate if instilling breast milk (BM) or dextrose water into oral cavity can reduce the procedural pain of heel stick for preterm babies. METHODS: This is a prospective study; 20 premature neonates are enrolled. Each study case received heel stick 4 times. BM, 10% dextrose water (D10W), distilled water (placebo) and nothing (control group) were given one after the other in random order to the same patient before heel stick. Premature infant pain profile (PIPP) was used to assess the pain scores. The whole process consisted of 4 sections: a baseline period for 1 min, intervention period for 1 min, heel stick period for 20 s, and recovery period for 5 min. The primary outcome is to compare the PIPP scores in the 4 groups. RESULTS: Totally 20 babies completed this study. Median gestational age was 32 weeks 2 days (26 weeks 4 days-35 weeks 6 days) and median birth body weight was 1596 g (766-2435 g). The median PIPP scores and interquartile range at each time period were listed in the context. There are significant differences between BM/control group at all time periods, between BM/placebo group at 30-60 s, 1-2 min, and 2-3 min, and between D10W/control group at 0-30 s, 30-60 s, 3-4 min, and 4-5 min. There are no significant differences between BM/D10W, D10W/placebo, and placebo/control groups at any time periods. CONCLUSION: Giving something with taste such as BM or D10W is safe and effective in reducing the procedural pain of heel stick in preterm neonates; BM is the priority. PMID- 28736178 TI - Neonatal solid tumors. AB - BACKGROUND: Neonatal tumors are different from tumors of the older children and knowledge gained from treating older children can not be extrapolated to neonates. Neonates have immature physiology and their haematopoietic and immune systems are not fully developed and the response to therapy is unpredictable. Hence it is imperative to study these tumors as separate entity. The aim of this study is to analyse this rare set of tumors in terms of their incidence, clinical features and management. MATERIALS AND METHODS: All babies admitted in our hospital with tumors from January, 2011 to January 2016 were studied. Tumor-like conditions like haemangioma, lymphangioma and hamartomas were included. The age, sex distribution, type of tumor and management were studied. RESULTS: A total of 51 cases were registered out of which, 29 cases were haemangiomas and lymphangiomas. Of remaining 20 cases, 5 were benign ovarian cysts, 3 were neuroblastomas, 3 were congenital fibrosarcomas, 3 were sacrococcygeal teratomas. Wilm's tumor, congenital mesoblastic nephroma, haemangioendothelioma of liver and others formed the remaining six cases. CONCLUSION: Our study insists that the neonatal tumors are distinct subset of pediatric tumors, requiring careful selection of treatment modalities and most of the solid tumors can be successfully managed if diagnosed and treated early. Neonatal tumors are defined as tumors which are diagnosed before the first month of life. Some of them can be congenital (present at birth). Neonatal tumors are different from tumors in older children in terms of etiopathogenesis, behavior and response to therapy as well as long-term outcomes. PMID- 28736179 TI - Venous thromboembolism in burn patients is not prevented by chemoprophylaxis. AB - BACKGROUND: Venous thromboembolisms (VTE) including deep venous thrombosis and pulmonary embolism are serious complications following burn trauma. There are inconsistencies in the literature regarding thromboembolic prevention strategies and data suggests that complications occur despite chemoprophylaxis. OBJECTIVE: To determine the prevalence of deep venous thromboembolism and pulmonary embolism in burn patients who are actively being treated with VTE prophylaxis and to determine factors that help predict which anti-coagulated patients are at risk for VTE and may benefit from further treatment. MATERIALS AND METHODS: Retrospective analysis of burn data registry and patient Charts 1980-2012. RESULTS: Out of 1549 burn patients in the registry fifty patients (3.2%) had a VTE but charts were only available for 26 of these for further analysis. Of these, 12 patients (46%) had a VTE while on chemoprophylaxis and 14 (54%) without chemoprophylaxis. There were no differences between groups, but 90% of DVT complications occurred to Caucasian patients and none to Asians. The VTE group had significantly higher rate of inhalation injury, higher TBSA, longer hospital stay and ICU stay than matched controls. CONCLUSIONS: Chemoprophylaxis does not prevent VTEs. Burn severity predisposes to venous thromboembolic complications. PMID- 28736180 TI - Retreatment With Osimertinib Following Pneumonitis. PMID- 28736181 TI - Succinate accumulation impairs cardiac pyruvate dehydrogenase activity through GRP91-dependent and independent signaling pathways: Therapeutic effects of ginsenoside Rb1. AB - Altered mitochondrial oxidation increases vulnerability to cardiac ischemia/reperfusion (I/R) injury in metabolic disorders. However, the metabolic signaling responsible for the dysfunction remains partly unknown. We sought to test whether or not hypoxic succinate accumulation could inhibit pyruvate dehydrogenase (PDH) activity and subsequently aggravate I/R injury. Results showed that saturated fatty acid palmitate stimulation increased fatty acid oxidation and induced hypoxia in cardiomyocytes, leading to succinate accumulation. Intracellular succinate induced hypoxia inducible factor-1alpha (HIF-1alpha) expression and impaired PDH activity via upregulation of pyruvate dehydrogenase kinase 4 (PDK4) expression. Luciferase reporter assay showed that succinate increased PDK4 expression through gene promoter induction in a HIF 1alpha-dependent manner. Palmitate also induced the release of succinate into extracellular space. By activating GRP91, extracellular succinate induced the translocation of PKCdelta to mitochondria and further exacerbated PDH impairment. These results demonstrated that succinate impaired PDH activity via GPR91 dependent and independent pathways. Ginsenoside Rb1 (a major compound isolated from ginseng) and trimetazidine (fatty acid beta-oxidation inhibitor) prevented hypoxic succinate accumulation in cardiomyocytes and improved PDH activity by blocking succinate-associated HIF-1alpha activation and GPR91 signaling. Through improving PDH activity, Rb1 and trimetazidine prevented cardiac acidification, ameliorated mitochondrial dysfunction and thereby reduced apoptosis during hypoxia/reoxygenation insult. In isolated working rat hearts perfused with palmitate and in high-fat diet-fed mice, early intervention of Rb1 and trimetazidine reduced succinate production and resultantly increased heart resistance to ischemia/reperfusion injury. Taken together, our findings demonstrated that early intervention by targeting inhibition of succinate accumulation-induced PDH impairment is an effective strategy to alleviate I/R injury. PMID- 28736182 TI - Immune checkpoint therapy of mesothelioma: Pre-clinical bases and clinical evidences. AB - Treatment with immune-checkpoint blocking monoclonal antibody (mAb) is demonstrating a significant efficacy in different tumor types. Here, we discuss the impact of this promising approach in malignant mesothelioma (MM), a still dreadful disease in which medical treatment has been set on platinum based chemotherapy for decades with unsatisfactory results. PMID- 28736183 TI - Immunotherapy targeting immune check-point(s) in brain metastases. AB - Immunotherapy with monoclonal antibodies (mAb) directed to different immune check point(s) is showing a significant clinical impact in a growing number of human tumors of different histotype, both in terms of disease response and long-term survival patients. In this rapidly changing scenario, treatment of brain metastases remains an high unmeet medical need, and the efficacy of immunotherapy in these highly dismal clinical setting remains to be largely demonstrated. Nevertheless, up-coming observations are beginning to suggest a clinical potential of cancer immunotherapy also in brain metastases, regardless the underlying tumor histotype. These observations remain to be validated in larger clinical trials eventually designed also to address the efficacy of therapeutic mAb to immune check-point(s) within multimodality therapies for brain metastases. Noteworthy, the initial proofs of efficacy on immunotherapy in central nervous system metastases are already fostering clinical trials investigating its therapeutic potential also in primary brain tumors. We here review ongoing immunotherapeutic approaches to brain metastases and primary brain tumors, and the foreseeable strategies to overcome their main biologic hurdles and clinical challenges. PMID- 28736184 TI - Attitudes towards Zika virus infection among medical doctors in Aceh province, Indonesia. AB - Zika virus (ZIKV) infection, a public health emergency of international concern, has recently been confirmed in Indonesia. However, to date, there has been no study to assess how prepared healthcare workers in Indonesia are to confront this emerging infectious disease. The aim of this study was to assess the attitudes of medical doctors in Indonesia towards ZIKV infection and its associated explanatory variables. A cross-sectional self-administered online survey was conducted from 3 May to 3 June 2016 in Aceh province, Indonesia. A pre-tested questionnaire was used to collect data on doctors' attitudes towards ZIKV infection and a range of explanatory variables (basic demographic data, professional characteristics, workplace characteristics and facilities, and medical experience related to ZIKV infection). Associations between attitude and explanatory variables were assessed using multiple-step logistic regression. We received 631 responses, 424 (67.19%) of which were included in the final analysis. Approximately 64% (271) of doctors had a poor attitude towards ZIKV infection. Experience considering ZIKV infection as a differential diagnosis and attendance at a national conference was associated with a good attitude, with odds ratios (OR) of 3.93 (95% confidence interval [CI]: 1.15-13.49) and 1.69 (95% CI: 1.03-2.76), respectively. Unexpectedly, doctors who had attended an international conference and those working at places that had molecular diagnostic (polymerase chain reaction based testing) facilities had lower odds of having a good attitude (OR: 0.35 [95% CI: 0.15-0.84] and 0.42 [95% CI: 0.19 0.95], respectively). In conclusion, the attitude towards ZIKV infection is relatively poor among doctors in Aceh. Therefore, strategies for enhancing their capacity to respond to ZIKV infection are needed. The survey concept and tools were well accepted by the participants of this study, suggesting that this rapid assessment could be rolled out across the Indonesian archipelago and elsewhere to identify and regionally differentiate unmet needs of disease and outbreak preparedness. PMID- 28736185 TI - Effect of COA-Cl on transforming growth factor-beta1-induced epithelial mesenchymal transition in RLE/Abca3 cells. AB - Transforming growth factor (TGF)-beta1 has received much attention as a major inducer of epithelial-mesenchymal transition (EMT) in pathological conditions such as cancer and organ fibrosis. In this study, we examined the effect of a novel nucleic acid analog, COA-Cl, on TGF-beta1-induced EMT using RLE/Abca3, a cell line having alveolar type II cell-like phenotype. Changes in the cell morphology consistent with EMT were induced by TGF-beta1, whereas, this response was suppressed by co-treatment of the cells with COA-Cl. In addition, co treatment with COA-Cl abolished TGF-beta1-induced downregulation of cytokeratin 19 and upregulation of alpha-smooth muscle actin transcripts. In order to delineate the mechanism underlying the inhibitory effect of COA-Cl on TGF-beta1 induced EMT in RLE/Abca3 cells, we examined the role of zinc finger E-box binding homeobox (ZEB) family transcription factors in this phenomenon. Our results demonstrated that the treatment of cells with COA-Cl suppressed the TGF-beta1 mediated increase in the mRNA levels of ZEB2. Overall, it was concluded that COA Cl may have an inhibitory effect on TGF-beta1-induced EMT-like phenotypical changes in RLE/Abca3 cells via suppression of ZEB2 mRNA expression. PMID- 28736186 TI - Surgery no better than observation for localised prostate cancer. PMID- 28736187 TI - Protein biomarker for pancreatic ductal adenocarcinoma. PMID- 28736188 TI - Asparaginase-associated pancreatitis in childhood acute lymphoblastic leukaemia: an observational Ponte di Legno Toxicity Working Group study. AB - BACKGROUND: Survival for childhood acute lymphoblastic leukaemia surpasses 90% with contemporary therapy; however, patients remain burdened by the severe toxic effects of treatment, including asparaginase-associated pancreatitis. To investigate the risk of complications and risk of re-exposing patients with asparaginase-associated pancreatitis to asparaginase, 18 acute lymphoblastic leukaemia trial groups merged data for this observational study. METHODS: Patient files from 26 trials run by 18 trial groups were reviewed on children (aged 1.0 17.9 years) diagnosed with t(9;22)-negative acute lymphoblastic leukaemia between June 1, 1996, and Jan 1, 2016, who within 50 days of asparaginase exposure developed asparaginase-associated pancreatitis. Asparaginase-associated pancreatitis was defined by at least two criteria: abdominal pain, pancreatic enzymes at least three times the upper limit of normal (ULN), and imaging compatible with pancreatitis. Patients without sufficient data for diagnostic criteria were excluded. Primary outcomes were defined as acute and persisting complications of asparaginase-associated pancreatitis and risk of re-exposing patients who suffered an episode of asparaginase-associated pancreatitis to asparaginase. Data were collected from Feb 2, 2015, to June 30, 2016, and analysed and stored in a common database at Rigshospitalet, Copenhagen, Denmark. FINDINGS: Of 465 patients with asparaginase-associated pancreatitis, 33 (8%) of 424 with available data needed mechanical ventilation, 109 (26%) of 422 developed pseudocysts, acute insulin therapy was needed in 81 (21%) of 393, and seven (2%) of 458 patients died. Risk of assisted mechanical ventilation, need for insulin, pseudocysts, or death was associated with older age (median age for patients with complications 10.5 years [IQR 6.4-13.8] vs without complications 6.1 years [IQR 3.6-12.2], p<0.0001), and having one or more affected vital signs (fever, hypotension, tachycardia, or tachypnoea; 96 [44%] of 217 patients with affected vital signs vs 11 [24%] of 46 patients without affected vital signs, p=0.02). 1 year after diagnosis of asparaginase-associated pancreatitis, 31 (11%) of 275 patients still needed insulin or had recurrent abdominal pain or both. Both the risk of persisting need for insulin therapy and recurrent abdominal pain were associated with having had pseudocysts (odds ratio [OR] 9.48 [95% CI 3.01-35.49], p=0.0002 for insulin therapy; OR 11.79 [4.30-37.98], p<0.0001 for recurrent abdominal pain). Within 8 years of asparaginase-associated pancreatitis, risk of abdominal symptoms dropped from 8% (26 of 312) to 0% (0 of 35) but the need for insulin therapy remained constant (9%, three of 35). 96 patients were re-exposed to asparaginase, including 59 after a severe asparaginase-associated pancreatitis (abdominal pain or pancreatic enzymes at least three times the ULN or both lasting longer than 72 h). 44 (46%) patients developed a second asparaginase associated pancreatitis, 22 (52%) of 43 being severe. Risk of persisting need for insulin or abdominal pain after having had two versus one asparaginase-associated pancreatitis did not differ (three [7%] of 42 vs 28 [12%] of 233, p=0.51). Risk of a second asparaginase-associated pancreatitis was not associated with any baseline patient characteristics. INTERPRETATION: Since the risk of a second asparaginase-associated pancreatitis was not associated with severity of the first asparaginase-associated pancreatitis and a second asparaginase-associated pancreatitis did not involve an increased risk of complications, asparaginase re exposure should be determined mainly by the anticipated need for asparaginase for antileukaemic efficacy. A study of the genetic risk factors identifying patients in whom asparaginase exposure should be restricted is needed. FUNDING: The Danish Childhood Cancer Foundation and The Danish Cancer Society (R150-A10181). PMID- 28736189 TI - Neoadjuvant chemoradiotherapy for oesophageal cancer: Still looking for a challenger to the CROSS regimen. PMID- 28736190 TI - Molecular dynamics simulations of zinc oxide solubility: From bulk down to nanoparticles. AB - The solubility of metal oxides is one of the key descriptors for the evaluation of their potential toxic effects, both in the bulk form and in nanoparticulated aggregates. Current work presents a new methodology for the in silico assessment of the solubility of metal oxides, which is demonstrated using a well-studied system, ZnO. The calculation of the solubility is based on statistical thermodynamics tools combined with Density Functional Tight Binding theory for the evaluation of the free energy exchange during the dissolution process. Models of small ZnO clusters are used for describing the final dissolved material, since the complete ionic dissolution of ZnO is hindered by the formation of O2- anions in solution, which are highly unstable. Results show very good agreement between the computed solubility values and experimental data for ZnO bulk, up to 0.5 mg L 1 and equivalents of 50 MUg L-1 for the free Zn2+ cation in solution. However, the reference model for solid nanoparticles formed by free space nanoparticles can only give a limited quantitative solubility evaluation for ZnO nanoparticles. PMID- 28736191 TI - Clinical, histological, and ultrasound follow-up of breast reconstruction with one-stage muscle-sparing "wrap" technique: A single-center experience. AB - BACKGROUND: Prepectoral implant placement and complete coverage with porcine acellular matrix after mastectomy is a new concept in breast surgery presented in few cases in the literature. This paper aimed to present our single-center experience in one-stage breast reconstruction muscle-sparing "wrap" technique by evaluating clinical and aesthetic outcomes, ultrasound and histological examination, and patient quality of life. METHODS: From January 2014 to January 2017, 52 patients (40 unilateral, 12 bilateral) underwent one-stage muscle sparing breast reconstructions with Braxon(r) acellular dermal matrix and implant. In 3 patients, a surgical biopsy and histological examination with immunohistochemical analysis of the periprosthetic tissue were performed. All patients underwent breast ultrasound examination, and the occurrence of capsular contracture was assessed through the Baker classification and by measuring the mammary compliance scores with the Antoon Paar Mammary compliance system. Breast appearance was evaluated using a visual analogue scale (VAS) and in terms of quality of life using the EOCRT QLQ C-30 and QLQ BR-23 questionnaires. RESULTS: Early and late postoperative complications are reported. Histological and ultrasound evaluation showed a complete integration of the matrix. According to the VAS scale, the EOCRT QLQ C-30, and QLQ BR-23, patients' satisfaction resulted in a high score in terms of quality of life and aesthetic outcomes. CONCLUSION: The results of this new surgical technique in selected cases are promising in terms of effectiveness and low rate of postoperative complications, but further long-terms evaluations are required. PMID- 28736192 TI - The presence of PHB granules in cytoplasm protects non-halophilic bacterial cells against the harmful impact of hypertonic environments. AB - Numerous prokaryotes accumulate polyhydroxybutyrate (PHB) intracellularly as a storage material. It has also been proposed that PHB accumulation improves bacterial stress resistance. Cupriavidus necator and its PHB non-accumulating mutant were employed to investigate the protective role of PHB under hypertonic conditions. The presence of PHB granules enhanced survival of the bacteria after exposure to hypertonic conditions. Surprisingly, when coping with such conditions, the bacteria did not utilize PHB to harvest carbon or energy, suggesting that, in the osmotic upshock of C. necator, the protective mechanism of PHB granules is not associated with their hydrolysis. The presence of PHB granules influenced the overall properties of the cells, since challenged PHB free cells underwent massive plasmolysis accompanied by damage to the cell membrane and the leakage of cytoplasm content, while no such effects were observed in PHB containing bacteria. Moreover, PHB granules demonstrated "liquid like" properties indicating that they can partially repair and stabilize cell membranes by plugging small gaps formed during plasmolysis. In addition, the level of dehydration and changes in intracellular pH in osmotically challenged cells were less pronounced for PHB-containing cultures, demonstrating the important role of PHB for bacterial survival under hyperosmotic conditions. PMID- 28736193 TI - Relapsing fever causative agent in Southern Iran is a closely related species to East African borreliae. AB - We obtained two blood samples from relapsing fever patients residing in Jask County, Hormozgan Province, southern Iran in 2013. Sequencing of a partial fragment of glpQ from two samples, and further characterization of one of them by analyzing flaB gene, and 16S-23S spacer (IGS) revealed the greatest sequence identity with East African borreliae, Borrelia recurrentis, and Borrelia duttonii, and Borrelia microti from Iran. Phylogenetic analyses of glpQ, flaB, and concatenated sequences (glpQ, flab, and IGS) clustered these sequences amongst East African Relapsing fever borreliae and B. microti from Iran. However, the more discriminatory IGS disclosed a unique 8-bp signature (CAGCCTAA) separating these from B. microti and indeed other relapsing fever borreliae. In southern Iran, relapsing fever cases are mostly from localities in which O. erraticus ticks, the notorious vector of B. microti, prevail. There are chances that this argasid tick serves as a host and vector of several closely related species or ecotypes including the one we identified in the present study. The distribution of this Borrelia species remains to be elucidated, but it is assumed to be endemic to lowland areas of the Hormozgan Province, as well as Sistan va Baluchistan in the southeast and South Khorasan (in Persian: Khorasan-e Jonobi) in the east of Iran. PMID- 28736194 TI - The epigenetic drug Trichostatin A ameliorates experimental autoimmune encephalomyelitis via T cell tolerance induction and impaired influx of T cells into the spinal cord. AB - Multiple sclerosis is a T cell mediated chronic demyelinating disease of the central nervous system. Although currently available therapies reduce relapses, they do not facilitate tolerization of myelin antigen-specific T lymphocytes to ensure prolonged protection against multiple sclerosis. Here, we show that treatment of NOD mice with the histone deacetylase inhibitor, Trichostatin A affords robust protection against myelin peptide induced experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis. Protection was accompanied by histone hyperacetylation, and reduced inflammation and axonal damage in the spinal cord. Drug treatment diminished the generation of CD4+ memory T cells and induced tolerance in CD4+ T cells recognizing the immunizing myelin peptide. During the early immunization period, CD4+ T cells producing GM CSF+IFN-gamma, GM-CSF+IL-17A, as well as those expressing both IL-17A+IFN-gamma (double-producers) were detected in the secondary lymphoid organs followed by the appearance of cells producing IFN-gamma and GM-CSF. On the other hand, IFN-gamma producing Th1 cells appear first in the spinal cord followed by cells producing IL-17A and GM-CSF. Treatment with Trichostatin A substantially reduced the frequencies of all T cells secreting various lymphokines both in the periphery and in the spinal cord. These data indicate that epigenetic modifications induced by histone hyperacetylation facilitates T cell tolerance induction in the periphery leading to reduced migration of T cells to the spinal cord and mitigation of neuronal damage and improved clinical outcome. These results suggest that epigenetic modulation of the genome may similarly offer benefits to multiple sclerosis patients via abrogating the function of encephalitogenic T lymphocytes without exerting severe side effects associated with currently used disease-modifying therapies. PMID- 28736195 TI - Allelic difference in Mhc2ta confers altered microglial activation and susceptibility to alpha-synuclein-induced dopaminergic neurodegeneration. AB - Parkinson's Disease (PD) is a complex and heterogeneous neurodegenerative disease characterized by a progressive loss of dopaminergic neurons in the substantia nigra pars compacta and pathological intracellular accumulation of alpha synuclein (alpha-syn). In the vast majority of PD patients, the disease has a complex etiology, defined by multiple genetic and environmental risk factors. Common genetic variants in the human leukocyte-antigen (HLA) region have been associated to PD risk and the carriage of these can double the risk to develop PD. Among these common genetic variants are the ones that modulate the expression of MHCII genes. MHCII molecules encoded in the HLA-region are responsible for antigen presentation to the adaptive immune system and have a key role in inflammatory processes. In addition to cis-variants affecting MHCII expression, a transactivator encoded by the Mhc2ta gene is the major regulator of MHCII expression. We have previously identified variations in the promoter region of Mhc2ta, encoded in the VRA4 region, to regulate MHCII expression in rats. The expression of MHCII is known to be required in the response to alpha-syn. However, how the expression of MHCII affects the activation of microglial or the impact of physiological, differential Mhc2ta expression on degeneration of dopaminergic neurons has not previously been addressed. Here we addressed the implications of common genetic allelic variants of the major regulator of MHCII expression on alpha-syn-induced microglia activation and the severity of the dopaminergic neurodegeneration. We used a viral vector technology to overexpress alpha-syn in two rat strains; Dark agouti (DA) wild type and DA.VRA4-congenic rats. The congenic strain carries PVG alleles in the VRA4 locus and therefore displays lower Mhc2ta expression levels compared to DA rats. We analyzed the impact of this physiological differential Mhc2ta expression on gliosis, inflammation, degeneration of the nigro-striatal dopamine system and behavioral deficits after alpha-syn overexpression. We report that allelic variants of Mhc2ta differently modified the microglial activation in response to overexpression of human alpha-syn in rats. Overexpression of alpha-syn led to a larger denervation of the nigro-striatal system and significant behavioral deficits in DA.VRA4 congenic rats with lower Mhc2ta expression compared to DA rats. These results indicate that Mhc2ta is a key upstream regulator of the inflammatory response in PD pathology. PMID- 28736196 TI - Serological and molecular epidemiological outcomes after two decades of universal infant hepatitis B virus (HBV) vaccination in Nunavut, Canada. AB - Chronic hepatitis B virus (HBV) infection within the Canadian Arctic is considered endemic (>2% prevalence). Within the Arctic region of Nunavut, a vaccination program targeted at newborn infants was initiated approximately 20years ago, along with interim grade school catch-up programs, with the result that individuals born after 1980 are presumed vaccinated. This study investigates the effectiveness of these programs and is the first seroepidemiological survey to determine HBV prevalence in Nunavut in the post-vaccination era. Anonymized serum specimens scheduled for destruction following medical testing were collected between April 2013 and April 2014 from individuals granting consent. Specimens were tested for HBV antibodies, surface antigen (HBsAg), and HBV DNA to perform molecular characterization. Four thousand eight hundred and two specimens (13% of the population) were collected, with a resulting median age of 29years (range 1week to 93years). The prevalence of antibody to the HBV core protein was 9.4%; however, a 10-fold decrease in the rate of HBV exposure was noted among those born after 1980 compared to those born before (1.8% vs. 19.8%, p<0.01). HBsAg positivity was primarily documented in individuals born before 1980 (2.5%), although cases still occurred among the vaccine age cohort (0.3%). HBV subgenotype B5 (previously B6) was the most prevalent genotype observed (81.8%) indicating persistence of locally acquired infection. Vaccine-based antibody as the sole serological marker was evident in the vaccine age cohort, although the rate of decay with increasing age was much greater than predicted (less than 10% in those aged 5-19years). Nearly two decades after the advent of HBV vaccination in Nunavut, HBV prevalence has decreased to 1.2%, indicating non-endemic prevalence. However, the persistence of infection and a lower than expected prevalence of vaccine-based immunity in the vaccine age cohort will require further investigation to understand the causes and consequences. PMID- 28736197 TI - Characterization of an Escherichia coli-derived human papillomavirus type 16 and 18 bivalent vaccine. AB - Human papillomavirus (HPV) types 16 and 18 account for approximately 70% of cervical cancer worldwide. Neutralizing HPV prophylactic vaccines offer significant benefit, as they block HPV infection and prevent subsequent disease. However, the three licensed HPV vaccines that cover these two genotypes were produced in eukaryotic cells, which is expensive, particularly for low-income countries where HPV is highest. Here, we report a new HPV16 and -18 bivalent candidate vaccine produced from Escherichia coli. We used two strategies of N terminal truncation of HPV L1 proteins and soluble non-fusion expression to generate HPV16 and HPV18 L1-only virus-like particles (VLPs) in a scalable process. Through comprehensive characterization of the bivalent candidate vaccine, we confirm lot consistency in a pilot scale-up of 30L, 100L and 500L. Using cryo-EM 3D reconstruction, we found that HPV16 and -18VLPs present in a T=7 icosahedral arrangement, similar in shape and size to that of the native virions. This HPV16/18 bivalent vaccine shares comparable immunogenicity with the licensed vaccines. Overall, we show that the production of a HPV16/18 bivalent vaccine from an E. coli expression system is robust and scalable, with potentially good accessibility worldwide as a population-based immunization strategy. PMID- 28736198 TI - Characterization of Streptococcus pneumoniae invasive serotype 19A isolates from Argentina (1993-2014). AB - The aim of this study was to characterize Streptococcus pneumoniae serotype 19A isolates causing invasive pneumococcal disease in children, collected in Argentina between 1993 and 2014. A total of 176 isolates serotype 19A were analyzed. There was an increase in the proportion of serotype 19A isolates from 3% in 1993 to 6% in 2011, prior to the introduction of PCV13 in 2012, and from 2012 to 2014 its proportion gradually decreased. Penicillin resistance among serotype 19A isolates throughout the study period was 65.9%, but a significant increase was observed from 0% in 1993 to 87.5% in 2014. Genetic relationship of the isolates was determined by PFGE and selected strains were studied by MLST. Most of the isolates belonged to two clonal types: A (54.5%) and B (11.4%). Isolates of clonal type A were ST1131, a single locus variant of ST172 and accounted for 54% of the total collection. They were detected for the first time in our country in 1997 and most of them (93%) were penicillin non susceptible. Isolates of clonal type B were ST8121, a single locus variant of ST199, and were mainly susceptible to penicillin. These two clonal types are still in circulation and appear to be responsible for the dissemination of S. pneumoniae serotype 19A invasive isolates in our country. PMID- 28736199 TI - Decreased Hepatitis B vaccine response in pediatric patients with atopic dermatitis, psoriasis, and morphea. AB - Multiple groups of patients have been recognized for having high rates of non responders to the Hepatitis B vaccine including those with HIV, inflammatory bowel disease, and chronic kidney disease. These patients are at increased risk for infection due to both the nature of their underlying diseases and the immunosuppressive drugs they are commonly prescribed. Identification of groups with high non-response rates is essential in order to establish vaccination guidelines and prevent serious infections in already susceptible patients. We thus aimed to assess the rate of antibody response to the HBV vaccine in patients with psoriasis, atopic dermatitis, or morphea prior to starting immunosuppressive therapy. PMID- 28736200 TI - The web and public confidence in MMR vaccination in Italy. AB - Measles, mumps and rubella (MMR) vaccination coverage in Italy has been decreasing starting from 2012 and, at the present, none of the Italian regions has achieved the goal of 95% coverage target. A decision of the Court of Justice of Rimini in March 2012 that awarded vaccine-injury compensation for a case of autism has been indicated as a probable trigger event leading to a reduction of vaccine confidence in Italy. The aim of the study was to explore the relationship between MMR vaccination coverage to online search trends and social network activity on the topic "autism and MMR vaccine", during the period 2010-2015. A significant inverse correlation was found between MMR vaccination coverage and Internet search activity, tweets and Facebook posts. New media might have played a role in spreading misinformation. Media monitoring could be useful to assess the level of vaccine hesitancy and to plan and target effective information campaigns. PMID- 28736201 TI - Text message reminders for vaccination of adolescents with chronic medical conditions: A randomized clinical trial. AB - BACKGROUND: Many adolescents with chronic medical conditions (CMCs) are at risk of vaccine-preventable infection, yet are frequently under-vaccinated. Text message reminders, particularly those with embedded educational information, have been shown to increase general pediatric vaccination. Their use has not been studied specifically among adolescents with CMCs. METHODS: Eligible parents of adolescents with CMCs receiving care at one of 4 academically-affiliated pediatric clinics and requiring human papillomavirus (first dose), influenza, and/or pneumococcal polysaccharide vaccines were randomized in 4 consecutive cohorts to receive text message vaccine reminders with or without embedded educational information ("educational" vs. "plain" arm, respectively). Educational reminders, including one interactive message, addressed infection risk, vaccine safety/efficacy, and physician recommendations. Up to 5 weekly and 2 booster reminders were sent (October 2014-January 2015). Receipt of any needed vaccine and missed vaccination opportunities by 4, 12, and 24weeks after the initial reminder were compared between arms. RESULTS: Of randomized parents (n=295), 175 (59.3%) were Spanish-speaking; most had adolescents with CMCs who were 13-17years (n=229; 77.6%) and publically insured (n=272; 92.5%). Baseline demographics and parental vaccine beliefs were similar between arms. More adolescents in the plain vs. educational reminder arm received any needed vaccine by 4weeks (31.9% vs. 22.7%, adjusted relative risk [aRR] 1.47, 95% CI 1.01-2.14), but not by 12 or 24weeks. Plain reminders were noted in post hoc analyses to have a greater effect than educational reminders in certain sub-populations, including 11-12year-olds and those sent the initial reminder in early fall. Fewer adolescents in the plain vs. educational reminder arm had a missed vaccination opportunity by 4weeks (10.9% vs. 41.3%; aRR 0.21, 95% CI 0.07-0.60), but not by 12 or 24weeks. CONCLUSION: Plain text message vaccine reminders appear to have a positive effect compared to educational ones in the short-term and for certain families. TRIAL REGISTRATION: NCT02231957 (www.clinicaltrials.gov). PMID- 28736202 TI - Primary care team- and clinic level factors affecting HPV vaccine uptake. AB - OBJECTIVE: This study examined patient-, care team- and clinic-level factors associated with human papillomavirus (HPV) vaccine initiation and completion. METHODS: HPV vaccine initiation and completion rates among adolescents aged 9 18years were assessed using administrative data (n=38,277) from a large federally qualified health center serving predominantly Latino patients. Four clinics with particularly high and low adolescent HPV vaccine uptake were selected for in depth case study analyses. Semi-structured interviews with clinic leaders, providers, and support staff in these clinics (n=36) examined multilevel factors perceived as affecting vaccine initiation and completion. RESULTS: On average, less than half (45%) of patients had initiated the HPV vaccine; of these, 52% of patients completed all recommended doses. Vaccine uptake varied significantly across clinics but was higher among patients seen by providers specializing in pediatrics. Qualitative findings confirmed the importance of provider communication strategies but indicated that other health care team structures and processes also play an important role in vaccine uptake. Care team members in higher performing clinics were more likely to describe vaccination as a team effort rather than solely the provider's responsibility. Support staff in higher performing clinics also spent more time reviewing patient preventive care needs and preparing patients for the provider encounter. Clinic-level factors such as performance management systems and the use of immunization champions were described as important for developing an organizational climate supportive of vaccination. Tracking and reminder systems were described as important but insufficient for ensuring vaccine uptake in the absence of other supports. CONCLUSIONS: Efforts to improve HPV initiation and completion could benefit from additional attention to factors at the health care team and clinic levels. Interventions that target factors at multiple levels of influence are most likely to achieve higher vaccination rates. Quality monitoring programs may influence clinic investment in improving vaccination rates. PMID- 28736203 TI - Oral administration of visceral adipose tissue antigens ameliorates metabolic disorders in mice and elevates visceral adipose tissue-resident CD4+CD25+Foxp3+ regulatory T cells. AB - Obesity and type 2 diabetes are linked with chronic, low-grade inflammation in visceral adipose tissue (VAT). A unique population of VAT-resident CD4+Foxp3+ Tregs plays a crucial role in regulating VAT inflammation and metabolic homeostasis. VAT-resident Tregs display a highly restricted TCR repertoire, suggesting they recognize certain autoantigen(s) in VAT. A dramatic reduction of VAT-resident Tregs has been shown to closely correlate with obesity-related VAT chronic inflammation and metabolic disorders. Oral tolerance strategy may modulate inflammatory response to autoantigens by several mechanisms including induction of autoantigen-specific Tregs. Here, we explored the effects and cellular mechanism of oral administration of VAT pooled antigens on high-fat diet (HFD)-induced metabolic disorders in mice. Indeed, we found that oral treatment of VAT mixture antigens effectively inhibited gain in body weight and fat mass, ameliorated serum lipid parameters, and improved insulin sensitivity in HFD mice. This strategy was shown to significantly restore HFD-induced decrease of VAT resident Tregs, accompanied by a hampered M2-type to M1-type macrophages phenotypic switch as well as decreased CD8+ T cells infiltration in VAT. Thus, oral administration of VAT antigens may be a novel and safe strategy against obesity and its related metabolic disorders. PMID- 28736204 TI - Neural stability: A reflection of automaticity in reading. AB - Automaticity, the ability to perform a task rapidly with minimal effort, plays a key role in reading fluency and is indexed by rapid automatized naming (RAN) and processing speed. Yet little is known about automaticity's neurophysiologic underpinnings. The more efficiently sound is encoded, the more automatic sound processing can be. In turn, this automaticity could free up cognitive resources such as attention and working memory to help build an integrative reading network. Therefore, we hypothesized that automaticity and reading fluency correlate with stable neural representation of sounds, given a larger body of literature suggesting the close relationship between neural stability and the integrative function in the central auditory system. To test this hypothesis, we recorded the frequency-following responses (FFR) to speech syllables and administered cognitive and reading measures to school-aged children. We show that the stability of neural responses to speech correlates with RAN and processing speed, but not phonological awareness. Moreover, the link between neural stability and RAN mediates the previously-determined link between neural stability and reading ability. Children with a RAN deficit have especially unstable neural responses. Our neurophysiological approach illuminates a potential neural mechanism specific to RAN, which in turn indicates a relationship between synchronous neural firing in the auditory system and automaticity critical for reading fluency. PMID- 28736206 TI - BPAG1 in muscles: Structure and function in skeletal, cardiac and smooth muscle. AB - BPAG1, also known as Dystonin or BP230, belongs to the plakin family of proteins, which has multiple cytoskeleton-binding domains. Several BPAG1 isoforms are produced by a single BPAG1 genomic locus using different promoters and exons. For example, BPAG1a, BPAG1b, and BPAG1e are predominantly expressed in the nervous system, muscle, and skin, respectively. Among BPAG1 isoforms, BPAG1e is well studied because it was first identified as an autoantigen in patients with bullous pemphigoid, an autoimmune skin disease. BPAG1e is a component of hemidesmosomes, the adhesion complexes that promote dermal-epidermal cohesion. In the nervous system, the role of BPAG1a is also well studied because disruption of BPAG1a results in a phenotype identical to that of Dystonia musculorum (dt) mutants, which show progressive motor disorder. However, the expression and function of BPAG1 in muscles is not well studied. The aim of this review is to provide an overview of and highlight some recent findings on the expression and function of BPAG1 in muscles, which can assist future studies designed to delineate the role and regulation of BPAG1 in the dt mouse phenotype and in human hereditary sensory and autonomic neuropathy type 6 (HSAN6). PMID- 28736207 TI - Editorial Comment. PMID- 28736205 TI - Developmental and extrahepatic physiological functions of SREBP pathway genes in mice. AB - Sterol regulatory element-binding proteins (SREBPs), master transcriptional regulators of cholesterol and fatty acid synthesis, have been found to contribute to a diverse array of cellular processes. In this review, we focus on genetically engineered mice in which the activities of six components of the SREBP gene pathway, namely SREBP-1, SREBP-2, Scap, Insig-1, Insig-2, or Site-1 protease have been altered through gene knockout or transgenic approaches. In addition to the expected impacts on lipid metabolism, manipulation of these genes in mice is found to affect a wide array of developmental and physiologic processes ranging from interferon signaling in macrophages to synaptic transmission in the brain. The findings reviewed herein provide a blueprint to guide future studies defining the complex interactions between lipid biology and the physiologic processes of many distinct organ systems. PMID- 28736208 TI - Use of Transvaginal Mesh: What the Surgeon Should Consider. PMID- 28736209 TI - Histoplasmosis presenting as laryngeal ulcer in a post-renal transplant male: An unusual case from India. AB - Histoplasmosis has variable clinical presentation that mimics various benign and malignant lesions. It is more often associated with pulmonary lesions and disseminated form of disease. Herein, we report a rare case of localized laryngeal histoplasmosis in a 62-year-old Indian man who presented with hoarseness of voice and dysphagia. Post-renal transplant, he was on immunosuppressive drugs for last three years. Laryngoscopy revealed an ulceroproliferative growth at base of tongue, which was extending upto the pyriform fossa. Histopathology of laryngeal biopsy revealed numerous intracellular fungal yeast forms of Histoplasma that were subsequently confirmed serologically. The patient was put on oral itraconazole therapy and he responded well to the treatment with complete resolution of the disease. Early diagnosis and management of patient helps in preventing dissemination of the disease. PMID- 28736210 TI - Effects of positive expiratory pressure on chest wall volumes in subjects with stroke compared to healthy controls: a case-control study. AB - BACKGROUND: Alterations in respiratory system kinematics in stroke lead to restrictive pattern associated with decreased lung volumes. Chest physical therapy, such as positive expiratory pressure, may be useful in the treatment of these patients; however, the optimum intensity to promote volume and motion changes of the chest wall remains unclear. OBJECTIVE: To assess the effect of different intensities of positive expiratory pressure on chest wall kinematics in subjects with stroke compared to healthy controls. METHODS: 16 subjects with chronic stroke and 16 healthy controls matched for age, gender, and body mass index were recruited. Chest wall volumes were assessed using optoelectronic plethysmography during quiet breathing, 5 minutes, and recovery. Three different intensities of positive expiratory pressure (10, 15, and 20cmH2O) were administered in a random order with a 30 minutes rest interval between intensities. RESULTS: During positive expiratory pressure, tidal chest wall expansion increased in both groups compared to quiet breathing; however, this increase was not significant in the subjects with stroke (0.41 vs. 1.32L, 0.56 vs. 1.54L, 0.52 vs. 1.8L, at 10, 15, 20cmH2O positive expiratory pressure, for stroke and control groups; p<0.001). End-expiratory chest wall volume decreased in controls, mainly due to the abdomen, and increased in the stroke group, mainly due the pulmonary rib cage. CONCLUSION: Positive expiratory pressure administration facilitates acute lung expansion of the chest wall and its compartments in restricted subjects with stroke. Positive expiratory pressure intensities above 10cmH2O should be used with caution as the increase in end expiratory volume led to hyperinflation in subjects with stroke. PMID- 28736211 TI - Applying contemporary neuroscience in exercise interventions for chronic spinal pain: treatment protocol. AB - BACKGROUND: Nonspecific chronic spinal pain is a common problem within the chronic pain population and is characterized by high social, economic and personal impact. To date, therapists are still struggling in adequately treating these types of patients, as seen in the small and short-term benefits of frequently applied primary care treatments. It is remarkable that despite the well-documented presence of abnormalities in central nociceptive processing in nonspecific chronic spinal pain patients, the implementation of this knowledge in clinical practice is still nearly non-existent. METHODS: This paper provides the treatment protocol used in a large randomized controlled trial that aimed to assess the effectiveness of a modern neuroscience approach compared to usual care evidence-based physiotherapy. This comprehensive pain neuroscience treatment program combines pain neuroscience education and cognition-targeted exercise therapy. CONCLUSION: Based on previous small-scaled studies, this treatment protocol is expected to normalize central alterations by addressing central nervous system dysfunctions, psychological factors, as well as peripheral dysfunctions in a broader biopsychosocially-driven framework. PMID- 28736212 TI - Cardiovascular responses during resistance exercise after an aerobic session. AB - OBJECTIVE: To analyze the influence of previous aerobic exercise on cardiovascular responses during resistance exercise. METHODS: This is a crossover observational study. The sample included 19 normotensive men aged between 19 and 39 years. Subjects performed two experimental sessions in random order: resistance exercise (R: three sets of knee extension exercises with 40% of one repetition maximum) and aerobic exercise+resistance exercise (A+R: 30min of aerobic exercise followed by R protocol). In both sessions, blood pressure (BP) and heart rate were monitored beat-by-beat by finger photoplethysmography. RESULTS: After aerobic exercise in the A+R session, there was a maintenance of systolic BP -2 (95% CI: -6; 2) mmHg (P=0.35), diastolic 1 (95% CI: -2; 5) mmHg (P=0.40) and mean BP 0 (95% CI: -4; 4) mmHg (P=0.91) and an increase in heart rate 11 (95% CI: 7; 16)bpm (P<0.001). Diastolic and mean BP increased and peak heart rate was higher during resistance exercise in the A+R session compared to the R session. Differences between sessions: diastolic BP 7 (95% CI: 2; 12) mmHg (P=0.03); mean BP 8 (95% CI: 2; 13) mmHg (P=0.05); and peak heart rate 18 (95% CI: 13; 23)bpm (P<0.001). The increases in systolic BP during resistance exercise were similar between sessions 16 (95% CI: 6; 26) mmHg (P=0.43). CONCLUSION: Aerobic exercise before resistance exercise increased diastolic and mean BP and heart rate. However, due to the sample size of 19 individuals, the results must be interpreted with caution. PMID- 28736213 TI - Beyond expectations: The responses of the autonomic nervous system to visual food cues. AB - Self-report measures rely on cognitive and rational processes and may not, therefore, be the most suitable tools to investigate implicit or unconscious factors within a sensory experience. The responses from the autonomic nervous system (ANS), which are not susceptible to bias due to their involuntary nature, may provide a better insight. Expectations are important for the consumer-product interaction and should be considered. However, research using ANS responses has not focused thoroughly on expectations. Our aim was to investigate the mechanisms underlying ANS responses by evaluating the reactions to different images when expectations about a product are created (before tasting the product) and when they are confirmed and disconfirmed (after tasting the product). In a first study, seventy-five participants tasted four drinks (three identical soy-based drinks and one rice-based drink) and were told that they would be shown their main ingredient either before or after tasting. For the three identical drinks, the images shown were: worms, chocolate, and soy. Heart rate and skin conductance were measured during the procedure. The results showed that ANS responses followed similar patterns when images were presented before or after tasting. Heart rate decreased for all images, with the largest decrease found for chocolate and worms. Skin conductance increased, with the largest increase found for worms. To test whether the effects were solely caused by image perception, a second study was done in which forty participants only saw the images. The responses obtained were smaller and did not completely match those of the first study. In conclusion, it could be said that the ANS responses of the first study were a result of the sensory processing and defense mechanisms happening during the creation and (dis)confirmation of expectations. The second study confirmed that visual perception alone could not account for these effects and that it led to smaller changes. Hence, it seems that the context of use influences the patterns and magnitude of ANS responses to food cues. PMID- 28736214 TI - Genetic variants in gastric cancer: Risks and clinical implications. AB - Cancer is a multifactorial disease that involves many molecular alterations. Gastric cancer (GC) is the third leading cause of cancer death worldwide. GC is a highly heterogeneous disease with different molecular and genetics features. Therefore, this review focuses on an overview of the genetic aspects of gastric cancer by highlighting the important impact and role of deletions and/or duplications of chromosomal segments, genomic variants, H. pylori infection and interleukin variants, as found in gene expression and newly proposed molecular classification studies. The challenge is to better understand the mechanisms and different pathways that lead to the development and progression of GC. PMID- 28736216 TI - Pathogen-Induced TLR4-TRIF Innate Immune Signaling in Hematopoietic Stem Cells Promotes Proliferation but Reduces Competitive Fitness. AB - Bacterial infection leads to consumption of short-lived innate immune effector cells, which then need to be replenished from hematopoietic stem and progenitor cells (HSPCs). HSPCs express pattern recognition receptors, such as Toll-like receptors (TLRs), and ligation of these receptors induces HSPC mobilization, cytokine production, and myeloid differentiation. The underlying mechanisms involved in pathogen signal transduction in HSCs and the resulting biological consequences remain poorly defined. Here, we show that in vivo lipopolysaccharide (LPS) application induces proliferation of dormant HSCs directly via TLR4 and that sustained LPS exposure impairs HSC self-renewal and competitive repopulation activity. This process is mediated via TLR4-TRIF-ROS-p38, but not MyD88 signaling, and can be inhibited pharmacologically without preventing emergency granulopoiesis. Live Salmonella Typhimurium infection similarly induces proliferative stress in HSCs, in part via TLR4-TRIF signals. Thus, while direct TLR4 activation in HSCs might be beneficial for controlling systemic infection, prolonged TLR4 signaling has detrimental effects and may contribute to inflammation-associated HSPC dysfunction. PMID- 28736215 TI - Human iPSC Glial Mouse Chimeras Reveal Glial Contributions to Schizophrenia. AB - In this study, we investigated whether intrinsic glial dysfunction contributes to the pathogenesis of schizophrenia (SCZ). Our approach was to establish humanized glial chimeric mice using glial progenitor cells (GPCs) produced from induced pluripotent stem cells derived from patients with childhood-onset SCZ. After neonatal implantation into myelin-deficient shiverer mice, SCZ GPCs showed premature migration into the cortex, leading to reduced white matter expansion and hypomyelination relative to controls. The SCZ glial chimeras also showed delayed astrocytic differentiation and abnormal astrocytic morphologies. When established in myelin wild-type hosts, SCZ glial mice showed reduced prepulse inhibition and abnormal behavior, including excessive anxiety, antisocial traits, and disturbed sleep. RNA-seq of cultured SCZ human glial progenitor cells (hGPCs) revealed disrupted glial differentiation-associated and synaptic gene expression, indicating that glial pathology was cell autonomous. Our data therefore suggest a causal role for impaired glial maturation in the development of schizophrenia and provide a humanized model for its in vivo assessment. PMID- 28736217 TI - High-Content Screening in hPSC-Neural Progenitors Identifies Drug Candidates that Inhibit Zika Virus Infection in Fetal-like Organoids and Adult Brain. AB - Zika virus (ZIKV) infects fetal and adult human brain and is associated with serious neurological complications. To date, no therapeutic treatment is available to treat ZIKV-infected patients. We performed a high-content chemical screen using human pluripotent stem cell-derived cortical neural progenitor cells (hNPCs) and found that hippeastrine hydrobromide (HH) and amodiaquine dihydrochloride dihydrate (AQ) can inhibit ZIKV infection in hNPCs. Further validation showed that HH also rescues ZIKV-induced growth and differentiation defects in hNPCs and human fetal-like forebrain organoids. Finally, HH and AQ inhibit ZIKV infection in adult mouse brain in vivo. Strikingly, HH suppresses viral propagation when administered to adult mice with active ZIKV infection, highlighting its therapeutic potential. Our approach highlights the power of stem cell-based screens and validation in human forebrain organoids and mouse models in identifying drug candidates for treating ZIKV infection and related neurological complications in fetal and adult patients. PMID- 28736219 TI - Detection of mucous membrane pemphigoid autoantibodies by full-length BP180 enzyme-linked immunosorbent assay. PMID- 28736218 TI - Fluctuations in routine blood count might signal severe immune-related adverse events in melanoma patients treated with nivolumab. AB - BACKGROUND: Although nivolumab significantly prolongs survival of metastatic melanoma, about 10% of patients experience severe, even fatal immune-related adverse events (irAEs). Biomarkers to predict irAEs are, therefore, of great interest. OBJECTIVE: We aimed to correlate changes in routine blood count parameters to the occurrence of serious irAEs (grade 3/4 [G3/4] or lung/gastrointestinal [lung/GI] irAEs) in patients with melanoma who were treated with nivolumab. METHODS: We retrospectively analyzed data from 101 patient with melanoma treated with nivolumab from 8 institutes in Japan. We used logistic regression analyses to investigate associations between severe irAEs and fluctuations in routine blood count parameters (total white blood cell [WBC] count, relative neutrophil, monocyte, lymphocyte, and eosinophil count) during the treatment. Receiver-operating characteristic curve was used to determine a cutoff value for the blood count parameters and area under the curve (AUC). RESULTS: Univariate analysis revealed that G3/4 irAEs were associated with increased total WBC count (P=0.034, cutoff value=+27%, AUC=0.68, odds ratio [OR]=1.58) and decreased relative lymphocyte count (RLC, P=0.042, cutoff value= 23%, AUC=0.65, OR=1.65). However, multivariate analysis showed that the same factors, increased WBC count (P=0.014, cutoff value=+59.1%, AUC=0.79, OR=6.04) and decreased RLC (P=0.012, cutoff value=-32.3%, AUC=0.81, OR=5.01) were independent factors associated with lung/GI irAEs. CONCLUSIONS: Our results suggest that increased WBC count and decreased RLC are associated with G3/4 and lung/GI irAEs. Our analysis was based on the data point at which irAE occurrence was noticed and, therefore, these factors are not predictive, however, they could be a "signal" of severe irAE occurrence in patients with melanoma treated with nivolumab. PMID- 28736220 TI - Manufacturing of hydrogel biomaterials with controlled mechanical properties for tissue engineering applications. AB - : Hydrogels have been recognized as crucial biomaterials in the field of tissue engineering, regenerative medicine, and drug delivery applications due to their specific characteristics. These biomaterials benefit from retaining a large amount of water, effective mass transfer, similarity to natural tissues and the ability to form different shapes. However, having relatively poor mechanical properties is a limiting factor associated with hydrogel biomaterials. Controlling the biomechanical properties of hydrogels is of paramount importance. In this work, firstly, mechanical characteristics of hydrogels and methods employed for characterizing these properties are explored. Subsequently, the most common approaches used for tuning mechanical properties of hydrogels including but are not limited to, interpenetrating polymer networks, nanocomposites, self assembly techniques, and co-polymerization are discussed. The performance of different techniques used for tuning biomechanical properties of hydrogels is further compared. Such techniques involve lithography techniques for replication of tissues with complex mechanical profiles; microfluidic techniques applicable for generating gradients of mechanical properties in hydrogel biomaterials for engineering complex human tissues like intervertebral discs, osteochondral tissues, blood vessels and skin layers; and electrospinning techniques for synthesis of hybrid hydrogels and highly ordered fibers with tunable mechanical and biological properties. We finally discuss future perspectives and challenges for controlling biomimetic hydrogel materials possessing proper biomechanical properties. STATEMENT OF SIGNIFICANCE: Hydrogels biomaterials are essential constituting components of engineered tissues with the applications in regenerative medicine and drug delivery. The mechanical properties of hydrogels play crucial roles in regulating the interactions between cells and extracellular matrix and directing the cells phenotype and genotype. Despite significant advances in developing methods and techniques with the ability of tuning the biomechanical properties of hydrogels, there are still challenges regarding the synthesis of hydrogels with complex mechanical profiles as well as limitations in vascularization and patterning of complex structures of natural tissues which barricade the production of sophisticated organs. Therefore, in addition to a review on advanced methods and techniques for measuring a variety of different biomechanical characteristics of hydrogels, the new techniques for enhancing the biomechanics of hydrogels are presented. It is expected that this review will profit future works for regulating the biomechanical properties of hydrogel biomaterials to satisfy the demands of a variety of different human tissues. PMID- 28736221 TI - Scaffold curvature-mediated novel biomineralization process originates a continuous soft tissue-to-bone interface. AB - : A myriad of shapes are found in biological tissues, often naturally evolved to fulfill a particular function. In the field of tissue engineering, substrate geometry influences cell behavior and tissue formation in vitro, yet little is known how this translates to an in vivo scenario. Here we investigate scaffold curvature-induced tissue growth, without additional growth factors or cells, in an ovine animal model. We show that soft tissue formation follows a curvature driven tissue growth model. The highly organized endogenous soft matrix, potentially under mechanical strain, leads to a non-standard form of biomineralization, whereby the pre-existing organic matrix is mineralized without collagen remodeling and without an intermediate cartilage ossification phase. Micro- and nanoscale characterization of the tissue microstructure using histology, backscattered electron (BSE) and second-harmonic generation (SHG) imaging and synchrotron small angle X-ray scattering (SAXS) revealed (i) continuous collagen fibers across the soft-hard tissue interface on the tip of mineralized cones, and (ii) bone remodeling by basic multicellular units (BMUs) in regions adjacent to the native cortical bone. Thus, features of soft tissue-to bone interface resembling the insertion sites of ligaments and tendons into bone were created, using a scaffold that did not mimic the structural or biological gradients across such a complex interface at its mature state. This study provides fundamental knowledge for biomimetic scaffold design in the fields of bone regeneration and soft tissue-to-bone interface tissue engineering. STATEMENT OF SIGNIFICANCE: Geometry influences cell behavior and tissue formation in vitro. However, little is known how this translates to an in vivo scenario. Here we investigate the influence of scaffold mean surface curvature on in vivo tissue growth using an ovine animal model. Based on a multiscale tissue microstructure characterization, we show a seamless integration of soft tissue into newly formed bone, resembling the insertion sites of ligaments and tendons into bone. This interface was created using a scaffold without additional growth factors or cells that did not recapitulate the structural or biological gradients across such a complex tissue interface at its mature state. These findings have important implications for biomimetic scaffold design for bone regeneration and soft tissue to-bone interface tissue engineering. PMID- 28736222 TI - Hypermucoviscosity, rmpA, and aerobactin are associated with community-acquired Klebsiella pneumoniae bacteremic isolates causing liver abscess in Singapore. AB - INTRODUCTION: This retrospective study investigated the clinical etiology of community-acquired bacteremic Klebsiellapneumoniae infections, and characterized laboratory and genetic markers which may be associated with primary liver abscess (PLA). METHODS: Community-onset K. pneumoniae bacteremic episodes from 2010 to 2011 were identified from the laboratory information system. Isolates were retrieved for susceptibility testing, hypermucoviscosity testing, PCR-based serotyping (K1, K2 and K5) and PCR detection of virulence genes (rmpA, alls, kfu and aerobactin). Clinical data collected from electronic medical records included primary and secondary diagnoses, co-existing morbidities, antibiotic therapy, and in-patient mortality. RESULTS: 129 bacteremic episodes were identified. The most common primary infections were pneumonia (n = 24, 18.6%), primary liver abscess (n = 21, 16.3%) and urinary tract infections (n = 21, 16.3%). Hypermucoviscosity was present in 55 isolates (42.6%). The most commonly detected virulence genes were aerobactin (n = 63, 48.8%) and rmpA (n = 59, 45.7%). Isolates causing liver abscess were significantly associated with a positive string test, rmpA, aerobactin gene, and capsular serotype K1 (all p < 0.01), but not with capsular serotype K2, K5, kfu, or allS genes. The absence of a positive string test, rmpA, or aerobactin genes had a 97.3%-100% negative predictive value for PLA. The positive predictive values of the string test, rmpA, aerobactin genes, and serotype K1 for PLA ranged from 31.7% to 35.6%. CONCLUSION: In our study population, pneumonia and PLA were the most common sources of community-acquired bacteremia. Hypermucoviscosity, rmpA, aerobactin, and serotype K1 could be useful laboratory markers to alert clinicians to arrange abdominal imaging to detect liver abscess. PMID- 28736224 TI - Dichoptic training in adults with amblyopia: Additional stereoacuity gains over monocular training. AB - Dichoptic training is a recent focus of research on perceptual learning in adults with amblyopia, but whether and how dichoptic training is superior to traditional monocular training is unclear. Here we investigated whether dichoptic training could further boost visual acuity and stereoacuity in monocularly well-trained adult amblyopic participants. During dichoptic training the participants used the amblyopic eye to practice a contrast discrimination task, while a band-filtered noise masker was simultaneously presented in the non-amblyopic fellow eye. Dichoptic learning was indexed by the increase of maximal tolerable noise contrast for successful contrast discrimination in the amblyopic eye. The results showed that practice tripled maximal tolerable noise contrast in 13 monocularly well-trained amblyopic participants. Moreover, the training further improved stereoacuity by 27% beyond the 55% gain from previous monocular training, but unchanged visual acuity of the amblyopic eyes. Therefore our dichoptic training method may produce extra gains of stereoacuity, but not visual acuity, in adults with amblyopia after monocular training. PMID- 28736223 TI - Semaphorin 3A in Ankylosing Spondylitis. AB - BACKGROUND/PURPOSE: To determine serum semaphorin 3A (Sema 3A) levels in ankylosing spondylitis (AS). METHODS: Serum Sema 3A was measured in 46 AS patients and 30 healthy controls (HCs). For the patients, we recorded demographic data, disease activity, functional index & global assessment, detected human leukocyte antigen-B27 (HLA-B27), and measured erythrocyte sedimentation rate (ESR) & C-reactive protein (CRP). RESULTS: Sema 3A was higher in AS patients than in HCs (3.98 +/- 2.57 vs. 1.34 +/- 0.48 ng/ml, p = 0.013). Area under the curve (AUC) of standard receiver operating characteristic (ROC) has suggested that Sema 3A > 2 ng/ml is better to predict the higher Bath Ankylosing Spondylitis Disease Activity Index (BASDAI, > 4) than ESR or CRP. There were good correlations between higher Sema 3A and uveitis, Schober's test, as well as interstitial lung disease. AS patients undergoing anti-tumor necrosis factor therapies for 3 months exhibited a positive correlation of change in Sema 3A (DeltaSema 3A) with disease activity fluctuation [DeltaBASDAI, DeltaBath Ankylosing Spondylitis Functional Index (BASFI) and DeltaBath Ankylosing Spondylitis - Global score (BAS-G)]. CONCLUSION: Serum Sema 3A level was increased in AS patients and was inversely correlated to Schober's test. Serum Sema 3A is better as a bio-marker than ESR or CRP to correlate with high disease activity in AS patients, and it is also a good indicator for monitoring disease activity and functional status during anti-TNF treatment. Also, Sema 3A may be taken as a predictor for extra-articular presentations in AS, but this needs further study to elucidate. PMID- 28736225 TI - Variable effects of elevated egg yolk testosterone on different arms of the immune system in young quail. PMID- 28736226 TI - Rapid effects of the aromatase inhibitor fadrozole on steroid production and gene expression in the ovary of female fathead minnows (Pimephales promelas). AB - Cytochrome P450 aromatase catalyzes conversion of C19 androgens to C18 estrogens and is critical for normal reproduction in female vertebrates. Fadrozole is a model aromatase inhibitor that has been shown to suppress estrogen production in the ovaries of fish. However, little is known about the early impacts of aromatase inhibition on steroid production and gene expression in fish. Adult female fathead minnows (Pimephales promelas) were exposed via water to 0, 5, or 50ug fadrozole/L for a time-course of 0.5, 1, 2, 4, and 6h, or 0 or 50ug fadrozole/L for a time-course of 6, 12, and 24h. We examined ex vivo ovarian 17beta-estradiol (E2) and testosterone (T) production, and plasma E2 concentrations from each study. Expression profiles of genes known or hypothesized to be impacted by fadrozole including aromatase (cytochrome P450 [cyp] 19a1a), steriodogenic acute regulatory protein (star), cytochrome P450 side chain cleavage (cyp11a), cytochrome P450 17 alpha hydroxylase/17,20 lyase (cyp17), and follicle stimulating hormone receptor (fshr) were measured in the ovaries by quantitative real-time polymerase chain reaction (QPCR). In addition, broader ovarian gene expression was examined using a 15k fathead minnow microarray. The 5ug/L exposure significantly reduced ex vivo E2 production by 6h. In the 50ug/L treatment, ex vivo E2 production was significantly reduced after just 2h of exposure and remained depressed at all time-points examined through 24h. Plasma E2 concentrations were significantly reduced as early as 4h after initiation of exposure to either 5 or 50ug fadrozole/L and remained depressed throughout 24h in the 50ug/L exposure. Ex vivo T concentrations remained unchanged throughout the time-course. Expression of transcripts involved in steroidogenesis increased within the first 24h suggesting rapid induction of a mechanism to compensate for fadrozole inhibition of aromatase. Microarray results also showed fadrozole exposure caused concentration- and time-dependent changes in gene expression profiles in many HPG-axis pathways as early as 4h. This study provides insights into the very rapid effects of aromatase inhibition on steroidogenic processes in fish. PMID- 28736227 TI - Association between ROS production, swelling and the respirasome integrity in cardiac mitochondria. AB - Although mitochondrial Ca2+ overload and ROS production play a critical role in mitochondria-mediated cell death, a cause-effect relationship between them remains elusive. This study elucidated the crosstalk between mitochondrial swelling, ROS production, and electron transfer chain (ETC) supercomplexes in rat heart mitochondria in response to Ca2+ and tert-butyl hydroperoxide (TBH), a lipid-soluble organic peroxide. Results showed that ROS production induced by TBH was significantly increased in the presence of Ca2+ in a dose-dependent manner. TBH markedly inhibited the state 3 respiration rate with no effect on the mitochondrial swelling. Ca2+ exerted a slight effect on mitochondrial respiration that was greatly aggravated by TBH. Analysis of supercomplexes revealed a minor difference in the presence of TBH and/or Ca2+. However, incubation of mitochondria in the presence of high Ca2+ (1 mM) or inhibitors of ETC complexes (rotenone and antimycin A) induced disintegration of the main supercomplex, respirasome. Thus, PTP-dependent swelling of mitochondria solely depends on Ca2+ but not ROS. TBH has no effect on the respirasome while Ca2+ induces disintegration of the supercomplex only at a high concentration. Intactness of individual ETC complexes I and III is important for maintenance of the structural integrity of the respirasome. PMID- 28736228 TI - DBZ is a putative PPARgamma agonist that prevents high fat diet-induced obesity, insulin resistance and gut dysbiosis. AB - BACKGROUND: The nuclear receptor PPARgamma is an effective pharmacological target for some types of metabolic syndrome, including obesity, diabetes, nonalcoholic fatty liver disease, and cardiovascular disease. However, the current PPARgamma targeting thiazolidinedione drugs have undesirable side effects. Danshensu Bingpian Zhi (DBZ), also known as tanshinol borneol ester derived from Salvia miltiorrhiza, is a synthetic derivative of natural compounds used in traditional Chinese medicine for its anti-inflammatory activity. METHODS: In vitro, investigations of DBZ using a luciferase reporter assay and molecular docking identified this compound as a novel promising PPARgamma agonist. Ten-week-old C57BL/6J mice were fed either a normal chow diet (NCD) or a high-fat diet (HFD). The HFD-fed mice were gavaged daily with either vehicle or DBZ (50mg/kg or 100mg/kg) for 10weeks. The gut microbiota composition was assessed by analyzing the 16S rRNA gene V3+V4 regions via pyrosequencing. RESULTS: DBZ is an efficient natural PPARgamma agonist that shows lower PPARgamma-responsive luciferase reporter activity than thiazolidinediones, has excellent effects on the metabolic phenotype and exhibits no unwanted adverse effects in a HFD-induced obese mouse model. DBZ protects against HFD-induced body weight gain, insulin resistance, hepatic steatosis and inflammation in mice. DBZ not only stimulates brown adipose tissue (BAT) browning and maintains intestinal barrier integrity but also reverses HFD-induced intestinal microbiota dysbiosis. CONCLUSIONS: DBZ is a putative PPARgamma agonist that prevents HFD-induced obesity-related metabolic syndrome and reverse gut dysbiosis. GENERAL SIGNIFICANCE: DBZ may be used as a beneficial probiotic agent to improve HFD-induced obesity-related metabolic syndrome in obese individuals. PMID- 28736229 TI - Survival of Patients with Cutaneous Squamous Cell Carcinoma: Results of a Prospective Cohort Study. AB - Cutaneous squamous cell carcinoma (cSCC) is an increasing health burden in white populations. We prospectively assessed risk factors for tumor-specific and overall survival in 1,434 patients who underwent surgery for cSCC between January 24, 2005, and May 29, 2015. A total of 2,149 invasive cSCCs were analyzed. Univariate and multivariate survival analyses included tumor thickness, horizontal size, body site, histological differentiation, desmoplastic growth, history of multiple cSCCs, and immunosuppression. The primary endpoint was time to tumor-specific death. During a median follow-up period of 36.5 months (range = 0-137 months), 515 patients died; 40 because of cSCC (2.8%). Of those, 12 died because of visceral metastases and 28 because of tumor growth by local infiltration. On multivariate analyses, prognostic factors for tumor-specific survival were increased vertical tumor thickness (hazard ratio = 6.73; 95% confidence interval = 3.47-13.08; P < 0.0001), desmoplastic growth (hazard ratio = 4.14; 95% confidence interval = 2.68-9.83; P < 0.0001), and immunosuppression (hazard ratio = 2.07; 95% confidence interval = 1.04-4.12; P = 0.039). Defining a point list out of those factors and grouping them into four cohorts resulted in comprehensively separating survival curves (P < 0.001). Using a cut-off for tumor thickness of 6 mm or greater, the presence of desmoplastic growth and immunosuppression identifies patients at high risk for tumor-specific death. PMID- 28736231 TI - Serial or Parallel Metastasis of Cutaneous Melanoma? A Study of the German Central Malignant Melanoma Registry. AB - For more than a century the Halstedian hypothesis of contiguous metastasis from the primary tumor through the lymphatics to distant sites shaped lymph node surgery for melanoma. We challenge this dogma of serial metastatic dissemination. A single-center series of 2,299 patients with cutaneous metastatic melanoma was investigated to analyze overall survival and distant metastasis-free survival of stage IV patients with or without primary lymphatic metastasis. Results were then compared with those of 2,134 patients from three independent centers of the German Central Malignant Melanoma Registry. A multivariate binary logistic regression model was used to identify risk factors for the initial metastatic pathway. Distant metastasis-free survival (hazard ratio = 1.02; 95% confidence interval = 0.91-1.14; P = 0.76) and overall survival (HR = 1.09; 95% CI = 0.96 1.23; P = 0.177) did not differ between stage IV patients with primary hematogenous or primary lymphatic metastasis. Melanoma localization was the only significant risk factor for the initial metastatic pathway. These findings indicate that regional and distant metastases originate from the primary tumor itself in a rather parallel than serial fashion and could explain the lack of survival benefit associated with immediate complete lymph node dissection in sentinel lymph node-positive melanoma patients. PMID- 28736232 TI - Stage-Specific Embryonic Antigen-4 (SSEA-4) as a Distinguishing Marker between Eccrine and Apocrine Origin of Ducts of Sweat Glands. PMID- 28736230 TI - Pro-Inflammatory Chemokines and Cytokines Dominate the Blister Fluid Molecular Signature in Patients with Epidermolysis Bullosa and Affect Leukocyte and Stem Cell Migration. AB - Hereditary epidermolysis bullosa (EB) is associated with skin blistering and the development of chronic nonhealing wounds. Although clinical studies have shown that cell-based therapies improve wound healing, the recruitment of therapeutic cells to blistering skin and to more advanced skin lesions remains a challenge. Here, we analyzed cytokines and chemokines in blister fluids of patients affected by dystrophic, junctional, and simplex EB. Our analysis revealed high levels of CXCR1, CXCR2, CCR2, and CCR4 ligands, particularly dominant in dystrophic and junctional EB. In vitro migration assays demonstrated the preferential recruitment of CCR4+ lymphocytes and CXCR1+, CXCR2+, and CCR2+ myeloid cells toward EB-derived blister fluids. Immunophenotyping of skin-infiltrating leukocytes confirmed substantial infiltration of EB-affected skin with resting (CD45RA+) and activated (CD45RO+) T cells and CXCR2+ CD11b+ cells, many of which were identified as CD16b+ neutrophils. Our studies also showed that abundance of CXCR2 ligand in blister fluids also creates a favorable milieu for the recruitment of the CXCR2+ stem cells, as validated by in vitro and in-matrix migration assays. Collectively, this study identified several chemotactic pathways that control the recruitment of leukocytes to the EB-associated skin lesions. These chemotactic axes could be explored for the refinement of the cutaneous homing of the therapeutic stem cells. PMID- 28736234 TI - The Potential of Muse Cells for Regenerative Medicine of Skin: Procedures to Reconstitute Skin with Muse Cell-Derived Keratinocytes, Fibroblasts, and Melanocytes. PMID- 28736233 TI - Continued Increase in Melanoma Incidence across all Socioeconomic Status Groups in California, 1998-2012. AB - Melanoma incidence has been increasing in light-skinned populations worldwide, but the reasons for the increase have been controversial. Our prior assessment in California non-Hispanic whites showed substantial increases in invasive melanoma incidence for tumors of all thicknesses in all neighborhoods categorized by socioeconomic status (SES) between 1988-1992 and 1998-2002. To understand whether these trends continued, we updated our assessment to include the diagnosis period 2008-2012 and more accurate pathologic stage at diagnosis. We used the California Cancer Registry to calculate age-adjusted incidence rates for over 58,000 newly diagnosed melanomas. Incidence rates not only continued to rise over the 10-year period from 1998-2002 and 2008-2012 but also showed significant increases in almost all groups defined jointly by tumor thickness or stage at diagnosis and a small area (census tract) SES measure. The largest relative rate increases were seen for regional, distant, and ulcerated disease, especially among males living in the lowest SES neighborhoods. Considering tumor thickness and stage as proxies for time to screening detection and neighborhood SES as a proxy for health care access, we interpret this pattern to indicate continued, true increases in melanoma occurrence as opposed to a thin tumor phenomenon simply driven by improved access to care. PMID- 28736235 TI - HLA-A*26 Is Correlated With Response to Nivolumab in Japanese Melanoma Patients. PMID- 28736236 TI - Patients with Hidradenitis Suppurativa Have a High Psychiatric Disease Burden: A Finnish Nationwide Registry Study. AB - Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease of hair follicles that is associated with various comorbidities. To further clarify the associations between HS and psychiatric disorders, we conducted a nationwide retrospective study that included 4,381 patients with HS, and 39,554 with psoriasis and 43,248 with melanocytic nevi as controls. Patient data were obtained from the statutory Finnish Care Register for Health Care. The incidence of HS was 3.0/100,000 persons/year. At least one psychiatric diagnosis was found in 24.1% of the patients with HS compared with 19.1% of the patients with psoriasis (odds ratio 1.34; 95% confidence interval 1.24-1.46) and 13.5% of those with melanocytic nevi (odds ratio 2.04; confidence interval 1.88-2.22). Every mental disorder examined was significantly more frequent in HS than in the two other groups. Mental disorders were more common in women than in men with HS and psoriasis. The main finding of our study is that patients with HS have a higher risk of mental disorders than patients with psoriasis. Additionally, this study reveals that HS is associated with both schizophrenia (odds ratio 1.57; confidence interval 1.24-1.98) and bipolar disorder (odds ratio 1.81; confidence interval 1.47-2.23), findings that to our knowledge have not been reported previously. PMID- 28736237 TI - Editorial overview: Molecular neuroscience 2017. PMID- 28736238 TI - The Pursuit of Therapeutic Biomarkers with High-Throughput Cancer Cell Drug Screens. AB - In the last decade we have witnessed tremendous advances in our understanding of the landscape of the molecular alterations that underpin many of the most prevalent cancers, in the use of automated high-throughput platforms for high throughput drug screens in cancer cells, in the creation of more clinically relevant cancer cell models, and lastly in the development of more useful computational approaches in the pursuit of biomarkers of drug response. Separately, each of these improvements will undoubtedly lead to improvements in the treatment of cancer patients but to fulfill the promise of truly personalized cancer medicine, we must bring these disciplines together in a truly multidisciplinary fashion. PMID- 28736240 TI - Adduction of untested derived stimulus relations depends on environmental complexity. AB - The present research assessed adduction involving derived stimulus relations as a function of environmental complexity. In Group CA, four college students were trained with arbitrary-matching-to-sample discriminations that could have established four, 3-member stimulus classes. In Group EA, four other students were trained with discriminations that could have established four, 5-member classes. Neither group received derived-relations testing; instead, adduction was assessed immediately after the baseline discriminations were learned. The adduction assessment required participants to derive the untested CA (Group CA) or EA (Group EA) equivalence relations and combine them with their already learned math skills. All participants in Group CA showed above 90% accuracy during the adduction assessment, whereas only one of four Group EA participants responded in that manner. These results extend adduction to untested equivalence relations and clarify the environmental conditions under which such adduction is less likely to occur (i.e., with larger relational networks). PMID- 28736239 TI - beta-TrCP1 Is a Vacillatory Regulator of Wnt Signaling. AB - Simultaneous hyperactivation of Wnt and antioxidant response (AR) are often observed during oncogenesis. However, it remains unclear how the beta-catenin driven Wnt and the Nrf2-driven AR mutually regulate each other. The situation is compounded because many players in these two pathways are redox sensors, rendering bolus redox signal-dosing methods uninformative. Herein we examine the ramifications of single-protein target-specific AR upregulation in various knockdown lines. Our data document that Nrf2/AR strongly inhibits beta catenin/Wnt. The magnitude and mechanism of this negative regulation are dependent on the direct interaction between beta-catenin N terminus and beta TrCP1 (an antagonist of both Nrf2 and beta-catenin), and independent of binding between Nrf2 and beta-TrCP1. Intriguingly, beta-catenin positively regulates AR. Because AR is a negative regulator of Wnt regardless of beta-catenin N terminus, this switch of function is likely sufficient to establish a new Wnt/AR equilibrium during tumorigenesis. PMID- 28736241 TI - Oxytocin release via activation of TRPM2 and CD38 in the hypothalamus during hyperthermia in mice: Implication for autism spectrum disorder. AB - Oxytocin (OT) is a critical molecule for social recognition that mediates social and emotional behaviors. OT is released during stress and acts as an anxiolytic factor. To know the precise molecular mechanisms underlying OT release into the brain during stress is important. It has been reported that intracellular concentrations of free calcium in the hypothalamic neurons are elevated by simultaneous stimulation of cyclic ADP-ribose (cADPR) and heat. We have reported in vitro and in vivo data that supports the idea that release of OT in the brain of male mice is regulated by cADPR and fever in relation to stress conditions. 1) Significantly higher levels of OT release were observed in hypothalamus cultures isolated from subordinate mice in group-housed males compared to dominant males after cage-switch stress; 2) OT concentrations in micro-perfusates at the paraventricular nucleus upon perfusion stimulation with cADPR were enhanced in subordinate mice compared to dominant mice; 3) The OT concentration in the cerebrospinal fluid (CSF) was higher in endotoxin-shock mice with fever compared to controls with no body temperature increase; and 4) In mice exposed to new environmental stress, the CSF OT level transiently increased 5 min after exposure, while the rectal temperature increased from 36.6 degrees C to 37.8 degrees C from 5 to 15 min after exposure. In this review, we examine whether or not cADPR and hyperthermia co-regulate hypothalamic OT secretion during social stress through the elevation of intracellular free Ca2+ concentrations involved in CD38-dependent Ca2+ mobilization and TRPM2-dependent Ca2+ influx. Finally, we propose that the interaction between CD38 and TRPM2 seems to be a new mechanism for stress-induced release of OT, which may result in anxiolytic effects for temporal recovery from social impairments in children with autism spectrum disorder during hyperthermia. PMID- 28736242 TI - Suppression of cortical TRPM7 protein attenuates oxidative damage after traumatic brain injury via Akt/endothelial nitric oxide synthase pathway. AB - Neuronal death after traumatic brain injury (TBI) is a complex process resulting from a combination of factors, many of which are still unknown. Transient receptor potential melastatin 7 (TRPM7) is a transient receptor potential channel that has been demonstrated to mediate ischemic and traumatic neuronal injury in vitro. In the present study, TRPM7 was suppressed in the rat cerebral cortex by intracortical injections of viral vectors bearing shRNA specific for TRPM7 to investigate its potential role in an in vivo TBI model. We found that TRPM7 suppression significantly reduced brain edema, brain contusion volume and motor functional deficits, which was sustained for at least 2 weeks after the insult. These protective effects were accompanied by inhibited apoptosis in injured cortex. Also, TRPM7 suppression attenuated lipid peroxidation, decreased the expression of protein carbonyl, and preserved the endogenous antioxidant enzyme activities. The results of western blot analysis showed that TRPM7 suppression markedly increased the phosphorylation of Akt and endothelial nitric oxide synthase (eNOS). In addition, blocking Akt/eNOS pathway activation by the specific inhibitor LY294002 (LY, 10 MUL, 10 mmol/L) or L-NIO (0.5 mg/kg) partially reversed the protective effects of TRPM7 suppression and its anti oxidative activities. Taken together, these findings demonstrated that regional inhibition of TRPM7 in cerebral cortex exerts neuroprotective effects against TBI through activation of Akt/eNOS pathway. Thus, TRPM7 might represent a potential drug development target for the treatment of TBI. PMID- 28736243 TI - From insulin synthesis to secretion: Alternative splicing of type 2 ryanodine receptor gene is essential for insulin secretion in pancreatic beta cells. AB - Increases in the intracellular Ca2+ concentration in pancreatic islets, resulting from the Ca2+ mobilization from the intracellular source through the ryanodine receptor, are essential for insulin secretion by glucose. Cyclic ADP-ribose, a potent Ca2+ mobilizing second messenger synthesized from NAD+ by CD38, regulates the opening of ryanodine receptor. A novel ryanodine receptor mRNA (the islet type ryanodine receptor) was found to be generated from the type 2 ryanodine receptor gene by the alternative splicing of exons 4 and 75. The islet-type ryanodine receptor mRNA is expressed in a variety of tissues such as pancreatic islets, cerebrum, cerebellum, and other neuro-endocrine cells, whereas the authentic type 2 ryanodine receptor mRNA (the heart-type ryanodine receptor) was found to be generated using GG/AG splicing of intron 75 and is expressed in the heart and the blood vessel. The islet-type ryanodine receptor caused a greater increase in the Ca2+ release by caffeine when expressed in HEK293 cells pre treated with cyclic ADP-ribose, suggesting that the novel ryanodine receptor is an intracellular target for the CD38-cyclic ADP-ribose signal system in mammalian cells and that the tissue-specific alternative splicing of type 2 ryanodine receptor mRNA plays an important role in the functioning of the cyclic ADP-ribose sensitive Ca2+ release. PMID- 28736244 TI - The use of stable isotopes in the study of human pathophysiology. AB - The growing prevalence of metabolic diseases including fatty liver disease and Type 2 diabetes has increased the emphasis on understanding metabolism at the mechanistic level and how it is perturbed in disease. Metabolomics is a continually expanding field that seeks to measure metabolites in biological systems during a physiological stimulus or a genetic alteration. Typically, metabolomics studies provide total pool sizes of metabolites rather than dynamic flux measurements. More recently there has been a resurgence in approaches that use stable isotopes (e.g. 2H and 13C) for the unambiguous tracking of individual atoms through compartmentalised metabolic networks in humans to determine underlying mechanisms. This is known as metabolic flux analysis and enables the capture of a dynamic picture of the metabolome and its interactions with the genome and proteome. In this review, we describe current approaches using stable isotope labelling in the field of metabolomics and provide examples of studies that led to an improved understanding of glucose, fatty acid and amino acid metabolism in humans, particularly in relation to metabolic disease. Examples include the use of stable isotopes of glucose to study tumour bioenergetics as well as brain metabolism during traumatic brain injury. Lipid tracers have also been used to measure non-esterified fatty acid production whilst amino acid tracers have been used to study the rate of protein digestion on whole body postprandial protein metabolism. In addition, we illustrate the use of stable isotopes for measuring flux in human physiology by providing examples of breath tests to measure insulin resistance and gastric emptying rates. PMID- 28736245 TI - Early clinical observations on the use of imatinib mesylate in FOP: A report of seven cases. AB - BACKGROUND: Fibrodysplasia ossificans progressiva (FOP) is an ultrarare genetic disorder of progressive, disabling heterotopic ossification (HO) for which there is presently no definitive treatment. Research studies have identified multiple potential targets for therapy in FOP, and novel drug candidates are being developed for testing in clinical trials. A complementary approach seeks to identify approved drugs that could be re-purposed for off-label use against defined targets in FOP. One such drug is imatinib mesylate, a tyrosine kinase inhibitor originally developed for use in patients with chronic myeloid leukemia (CML). Imatinib has the desirable effect of attacking multiple targets involved in the early hypoxic and inflammatory stages of FOP flare-ups, including HIF1 alpha, PDGFRalpha, c-KIT, and multiple MAP kinases. RESULTS: Based on compelling biologic rationale, strong preclinical data, and a favorable safety profile, imatinib has been prescribed on an off-label basis in a non-trial setting in seven children with continuous FOP flare-ups, predominantly in the axial regions, and which were not responsive to standard-of-care regimens. Anecdotal reports in these seven isolated cases document that the medication was well-tolerated with a ubiquitous reported decrease in the intensity of flare-ups in the six children who took the medication. CONCLUSIONS: These early clinical observations support the implementation of clinical trials in children with uncontrolled FOP flare-ups to determine if imatinib may ameliorate symptoms or alter the natural history of this debilitating and life-threatening disease. PMID- 28736246 TI - In vitro osteoclastogenesis from Gaucher patients' cells correlates with bone mineral density but not with Chitotriosidase. AB - Gaucher disease (GD) is caused by mutations on the gene encoding for the lysosomal enzyme glucocerebrosidase. Type I GD (GD1) patients present anemia, hepatosplenomegaly and bone alterations. In spite of treatment, bone alterations in GD patients persist, including poor bone mineral density (BMD). Mechanisms leading to bone damage are not completely understood, but previous reports suggest that osteoclasts are involved. Chitotriosidase (CHIT) is the most reliable biomarker used in the follow up of patients, although its correlation with bone status is unknown. The aim of this work was to study the pro osteoclastogenic potential in patients and to evaluate its correlation with CHIT activity levels and clinical parameters. PBMCs from treated patients and healthy controls were cultured in the presence of M-CSF, and mature osteoclasts were counted. BMD, blood CHIT activity and serum levels of CTX, BAP, and cytokines were evaluated in patients. We found that blood CHIT activity and osteoclast differentiation were significantly increased in patients, but no correlation between them was observed. Interestingly, osteoclast numbers but not CHIT, presented a negative correlation with BMD expressed as Z-score. CTX, BAP and serum cytokines involved in bone remodeling were found altered in GD1 patients. These results show for the first time a correlation between osteoclast differentiation and BMD in GD1 patients, supporting the involvement of osteoclasts in the bone pathology of GD1. Our results also suggest that an altered immune response may play an important role in bone damage. PMID- 28736247 TI - Interleukin-1beta affects the phospholipid biosynthesis of fibroblast-like synoviocytes from human osteoarthritic knee joints. AB - OBJECTIVE: Phospholipids (PLs), together with hyaluronan and lubricin, are involved in boundary lubrication within human articular joints. Levels of lubricants in synovial fluid (SF) have been found to be associated with the health status of the joint. However, the biosynthesis and release of PLs within human joints remains poorly understood. This study contributes to our understanding of the effects of cytokines on the biosynthesis of PLs using cultured fibroblast-like synoviocytes (FLS) from human osteoarthritic knee joints. METHODS: Cultured FLS were stimulated with IL-1beta, TNFalpha, IL-6, or inhibitors of cell signaling pathways such as QNZ, SB203580 and SP600125 in the presence of stable isotope-labeled precursors of PLs. Lipids were extracted and quantified using electrospray ionization tandem mass spectrometry (ESI-MS/MS). RESULTS: Our analyses provide for the first time a detailed overview of PL species being synthesized by FLS. IL-1beta increased the biosynthesis of both phosphatidylethanolamine (PE) and PE-based plasmalogens. We show here that the NF kappaB, p38 MAPK and JNK signaling pathways are all involved in IL-1beta-induced PL biosynthesis. IL-6 had no impact on PLs, whereas TNFalpha increased the biosynthesis of all PL classes. CONCLUSION: The biosynthesis of various PLs is controlled by IL-1beta and TNFalpha. Our detailed PL species analysis revealed that FLS can partly contribute to the elevated PL levels found in human osteoarthritis (OA) SF. IL-1beta in particular stimulates PE and PE-based plasmalogens which can act as cell-protective antioxidants. These results suggest that during OA progression, FLS undergo alterations in their PL composition to adapt to the new diseased environment. PMID- 28736248 TI - Comparison of survival for partial vs. radical nephrectomy in young patients with T1a renal cell carcinoma treated at commission on cancer-accredited facilities and influence of comorbidities on treatment choice. AB - PURPOSE: There is a paucity of data comparing effects of partial nephrectomy (PN) vs. radical nephrectomy (RN) on overall survival in young patients. In this study, the National Cancer Database was used to evaluate the survival outcomes of those treated with PN and RN, and influence of comorbidities on surgical treatment (PN vs. RN) in young patients while accounting for Charlson-Deyo Comorbidity Score (CDCS). MATERIALS AND METHODS: Patients between 20 and 44 years old (n = 9,849) surgically treated for pT1a renal cell carcinoma between 2004 and 2013 were identified from the National Cancer Database. Kaplan-Meier log-rank analysis and Cox proportional hazards model were performed to compare overall survival and calculate the hazard ratio between those undergoing RN and PN. Binary logistic regression was used to calculate odds ratios for receiving RN compared to PN. The effect measures in all models were adjusted for potential confounding factors. RESULTS: After adjusting for comorbidities, PN offered an overall survival advantage over RN (P<0.001, hazard ratio = 0.464, 95% CI: 0.359 0.601) at a mean follow-up of 48.4 months (0-130.96), including young patients with no comorbidities (P<0.001). Compared to those with a CDCS = 0, patients were more likely to be treated with RN if they had a CDCS>1 (odds ratios = 2.049, 95% CI: 1.527-2.750). CONCLUSIONS: Young patients treated with PN demonstrate an overall survival advantage. This survival advantage is observed after an early follow-up even in those without comorbidities. It is still not clear if the survival advantage seen is due to treatment itself or selection bias. PMID- 28736249 TI - Identifying intermediate-risk candidates for active surveillance of prostate cancer. AB - PURPOSE: Although already established for very-low and low-risk (LR) prostate cancer (PCa), controversy remains around offering active surveillance (AS) to men with intermediate-risk (IR) PCa. As IR represents a broad spectrum of disease biology, there is a critical need to define eligibility criteria that will enable both patient and physician to accept AS as the best balance of competing risks. In this study, we aimed to identify predictors of progression to enable optimal patient selection. MATERIALS AND METHODS: In our AS cohort, men were assigned to risk categories according to the National Comprehensive Cancer Network (NCCN favorable and NCCN unfavorable) and the CAPRA classifications. Clinical, biochemical and pathological characteristics, progression to definitive invasive treatment, and pathologic progression on follow-up biopsies were compared among these groups. A multivariate Cox regression model was used to identify independent predictors of progression on AS. RESULTS: AS was the initial management option for 651 men, including 144 with IR PCa. During the median follow-up of 4.5 years (range: 0.6-19.1), 259 patients (39.7%) underwent definitive treatment. Further, 5- and 10-year predicted rates of intervention for IR patients were 50% and 66%, respectively. Treatment rates were no different between the NCCN LR and NCCN IR groups, but were higher in CAPRA IR compared to CAPRA LR groups (P = 0.025). NCCN unfavorable IR patients had a twofold increased risk of definitive intervention compared to favorable IR (hazard ratio [HR] = 2.07; 95% CI: 1.17-3.65; P = 0.01). In the entire cohort, the percentage of biopsy cores positive (continuous variable; P = 0.006) and ISUP grade 2 or higher on initial biopsy (P = 0.027) were independent predictors of cessation of AS on multivariate analysis. In the intermediate group, only the percentage of positive biopsy cores was an independent predictor (P = 0.021) of AS cessation. Only 1 IR patient developed metastatic disease (0.7%). Actuarial overall survival at 5 and 10 years was 98.6% and 94.1%, respectively. There were 2 PCa deaths at 18.7 and 19.1 years of follow-up. CONCLUSION: In all AS, increasing percentage of core involvement and presence of Gleason pattern 4 are predictors of increased risk of progression. For IR patients, the NCCN favorable criteria and CAPRA score predict those more likely to remain on AS. PMID- 28736250 TI - Change in prostate cancer presentation coinciding with USPSTF screening recommendations at a community-based urology practice. AB - OBJECTIVE: The benefits of prostate-specific antigen (PSA)-based prostate cancer screening are controversial. We sought to determine the change in prostate cancer presentation coinciding with the release of the United States Preventative Services Task Force recommendations against screening in a high-volume community based urology practice. METHODS: Characteristics of men presenting for an elevated PSA at a community urology practice from August 2011 to August 2015 were queried from a prospectively collected database. A retrospective analysis of presenting PSA, Gleason grade at biopsy, and prostatectomy as well as clinical and pathologic stage was performed. Kruskal-Wallis rank sum and chi-square tests were used for analysis. RESULTS: Referrals for elevated PSA decreased from 933 in year 1 to 816 by year 4 (12.5% decrease) with a concomitant reduction in biopsies performed in newly referred men from 461 to 356 (22.8% decrease, P = 0.02). The proportion of men presenting with PSAs>10 increased from 28.1% to 36.8% (P = 0.009). First-time biopsy-positivity rate increased from 48.4% to 62.4% with a rise in the proportion having Gleason>=7 from 51.6% to 69.7% (P = 0.0001). Of the 578 men who underwent radical prostatectomy, there was a 19.4% increase in Gleason>=7 tumors (P = 0.01). CONCLUSIONS: Our findings demonstrate a decrease in elevated PSA referrals, increase in PSA at the time of referral, decrease in detection of low-risk disease, and increase in detection of intermediate-/high risk disease in a high-volume, multisite, community-based urology practice, coinciding with the United States Preventative Services Task Force recommendations against PSA screening. PMID- 28736251 TI - Patient-centered approaches to creating understandable health information. AB - As care delivery shifts to further include patients in shared decision-making, patient-centered health information can balance the information asymmetry between patients and providers. Patient health literacy, numeracy, and graph literacy must match that of health information materials to create understandable health information that empowers patients to participate in shared decision-making. We consider an iterative approach focused on three key steps: assessment of the specific information needs of the selected patient community, assessment of that community's ability to receive and understand health information, and evaluation of the materials developed to assess effectiveness. This structured approach using validated tools maximizes the likelihood of meeting patient needs to improve health outcomes. PMID- 28736252 TI - Systemic therapy following metastasectomy for renal cell carcinoma: Using insights from other clinical settings to address unanswered questions. AB - Surgical resection for metastatic renal cell carcinoma (RCC) was first described several decades ago, but the appropriate role for surgery in coordinated multidisciplinary care has not been well-defined. The explosive development of new therapies for advanced RCC over the past 10 years has improved the outlook for patients, and there is now renewed interest in surgical metastasectomy for selected patients with metastatic RCC, moving away from the conventional dichotomy between surgery for local disease and systemic therapy for metastatic disease. Patients rendered disease-free after metastasectomy are at high risk of recurrence, but to date no postoperative medical treatment has been shown to be beneficial. Ongoing studies and relevant data will be reviewed to frame the multidisciplinary approach to patients with oligometastatic RCC and to outline future challenges and opportunities for advancing their care. PMID- 28736253 TI - Selective ER-alpha agonist alleviates vascular endothelial dysfunction in ovariectomized type 2 diabetic rats. AB - Postmenopausal diabetic women represent a specific risk group with a greater incidence of vascular deficits as compared with age-matched men or non-diabetic women. 17beta-estradiol is the mainstay therapy for menopause and associated complications; however, its vasculoprotective effect is lost in women with diabetes. Although, exact mechanism of dichotomous effect of estrogen has not been delineated but it may be due to, differential activation of ER-alpha and beta during disease conditions such as diabetes. Thus main objective of our study was to characterize the specific estrogen receptor which could be selectively targeted to achieve vasculoprotection in postmenopausal diabetic situation. A significant impairment in glycemic and lipid profile, decreased ACh-induced endothelium dependent relaxation, impaired endothelial integrity, and rise in inflammatory and oxidative stress markers were observed in ovariectomized type 2 diabetic rats as compared to sham rats. These markers were further correlated with aortic eNOS levels. Treatment with selective ER-alpha receptor agonist markedly while 17beta-estradiol partially ameliorated these alterations along with enhanced aortic eNOS levels. However, ER-beta agonist did not show any effect. Our data suggests that selective ER-alpha activation could be an important pharmacological target, to mimic the beneficial effect of estradiol in cardiovascular disorders, especially in postmenopausal diabetic state. PMID- 28736254 TI - Bisphenol A affects trophoblast invasion by inhibiting CXCL8 expression in decidual stromal cells. AB - Bisphenol A (BPA), an environmental endocrine-disrupting organic chemical, has been positively associated with the rate of implantation failure of in vitro fertilization. However, the underlying mechanisms remain unclear. To reveal the impact and the underlying mechanism of BPA on the crosstalk between trophoblast and decidual stromal cells (DSCs), we determined whether BPA was able to affect trophoblast invasion in vitro. We found that BPA significantly inhibited CXCL8 expression in DSCs, which hindered trophoblast invasion, and activated the phosphorylation of ERK in DSCs. U0126, an inhibitor of ERK activation, remarkably rescued trophoblast invasion and the inhibition of CXCL8 expression caused by BPA treatment. Moreover, the nuclear estrogen receptor antagonist ICI 182,780 and transmembrane G protein-coupled receptor GPR30 (membrane estrogen receptor) antagonist G15 significantly blocked the phosphorylation of ERK and reversed the reduction of trophoblast invasion. In brief, BPA activated ERK through nuclear and membrane estrogen receptors and inhibited CXCL8 expression in DSCs, thereby affecting their regulation of trophoblast invasion. PMID- 28736255 TI - Isoalantolactone derivative promotes glucose utilization in skeletal muscle cells and increases energy expenditure in db/db mice via activating AMPK-dependent signaling. AB - Augmenting glucose utilization and energy expenditure in skeletal muscle via AMP activated protein kinase (AMPK) is an imperative mechanism for the management of type 2 diabetes. Chemical derivatives (2a-2h, 3, 4a-4d, 5) of the isoalantolactone (K007), a bioactive molecule from roots of Inula racemosa were synthesized to optimize the bioactivity profile to stimulate glucose utilization in skeletal muscle cells. Interestingly, 4a augmented glucose uptake, driven by enhanced translocation of glucose transporter 4 (GLUT4) to cell periphery in L6 rat skeletal muscle cells. The effect of 4a was independent to phosphatidylinositide-3-kinase (PI-3-K)/Akt pathway, but mediated through Liver kinase B1 (LKB1)/AMPK-dependent signaling, leading to activation of downstream targets acetyl coenzyme A carboxylase (ACC) and sterol regulatory element binding protein 1c (SREBP-1c). In db/db mice, 4a administration decreased blood glucose level and improved body mass index, lipid parameters and glucose tolerance associated with elevation of GLUT4 expression in skeletal muscle. Moreover, 4a increased energy expenditure via activating substrate utilization and upregulated the expression of thermogenic transcription factors and mitochondrial proteins in skeletal muscle, suggesting the regulation of energy balance. These findings suggest the potential implication of isoalantolactone derivatives for the management of diabetes. PMID- 28736256 TI - A 25-Year-Old Woman With a Deceptive Pancreas Cyst: All Is Not as It Appears! PMID- 28736257 TI - Risk of depression among Bangladeshi type 2 diabetic patients. AB - OBJECTIVE: The objective of this study was to examine the strength and consistency of the relationship between depression and diabetes in Bangladeshi population. METHODS: The study was conducted at the medicine department of Bangabandhu Shiekh Mujib Medical University (BSMMU) during May 2012 to May 2013. Equal number of type 2 diabetes mellitus (T2DM) patients and non-diabetic subjects (patient attendants) were recruited from outpatient department matching for age (+/-2 years) and gender. Demographic and anthropometric data were collected from all the subjects. Depression was assessed using, Hospital Anxiety and Depression Scale (HADS) questionnaire. A subject with a score above 8 was considered as depressive. Baseline characteristics of diabetic and non-diabetic participants were compared using chi square test. Multivariable logistic regression was performed to assess the association between diabetes and depression adjusting for all plausible confounders in the model. RESULTS: 24.8% non-diabetic and 56.2% diabetic subjects were found to have depression. Statistically significant difference was found in income, waist-to-hip ratio between diabetic and non-diabetic subjects (P<0.001). Diabetic patients show 7 fold greater odds of having depression in comparison to their non-diabetic counterpart [OR 7.0, 95% CI (3.4, 14.3)]. Female gender appeared as significant predictor of depression [OR 4.3, 95% CI (2.1, 8.9)]. CONCLUSIONS: In Bangladeshi population, people with diabetes are 7 times more likely to have co-existing depression in comparison to non-diabetic subjects. Further studies are required to establish the nature of the relationship between depression and T2DM. PMID- 28736258 TI - Prevalence and trends of obesity among adult Sudanese individuals: Population based study. AB - AIM: The prevalence of obesity has increased across the globe in particular in Africa. The aim of this study was to determine the prevalence of obesity in Sudan. MATERIAL AND METHODS: Descriptive, cross sectional study recruited 7239 individuals. Demographic and clinical data were collected by an interview using a pretested standardised questionnaire. Anthropometric measurements including body weight, height and waist circumference have been taken using standardized techniques and calibrated equipment. Body mass index (BMI) has been calculated. RESULTS: Total of 7239 persons completed the questionnaires; the results showed that prevalence of obesity was found to be 21.2%, with a higher rate of obesity in females than males (26.3% versus 13.8%). The prevalence of central obesity was also higher in women (36.7%) than men (17.6%).The prevalence of overweight was 34.9%. The overall prevalence of overweight/obesity was 56.1%. Obesity determined by BMI was associated with hypertension and diabetes. While central obesity was associated with an increase in age, female, diabetes and hypertension. CONCLUSION: The prevalence of obesity was 21.2%. Obesity and central obesity have a higher prevalence among Sudanese women. Obesity and central obesity were associated with diabetes and hypertension. PMID- 28736259 TI - Molecular epidemiology and antimicrobial susceptibility of Clostridium difficile isolated from the Chinese People's Liberation Army General Hospital in China. AB - Clostridium difficile is a Gram-positive, spore-forming obligate anaerobe responsible for antibiotic-associated diarrhoea. Its virulence is associated with the production of endotoxins A and B and endospores, which can cause symptoms, such as diarrhoea, toxic megacolon, and pseudomembranous colitis. Given the increasing elderly population and the well-recognized problem of over-prescribing of broad-spectrum antibiotics, it is critical to have an understanding of molecular epidemiology and antimicrobial susceptibility in China. This study analyzed the toxin types and multilocus sequence typing (MLST) results of 74 clinical isolates of C. difficile after the glutamate dehydrogenase (GDH) screening test and anaerobic culture. The minimum inhibitory concentrations (MICs) of four different antibiotics were determined for all of the isolates, and the bacterial resistance mechanisms were investigated. Sixty-five strains (75%) were toxigenic, including 54 tcdA-positive, tcdB-positive, and cdtA/cdtB-negative strains (A+B+CDT-) and nine A-B+CDT- strains. Eleven strains (14.9%) were non toxigenic. All clinical isolates were classified into 26 MLST genotypes, with the predominant type being ST-54 (18.9%). All isolates were susceptible to vancomycin. The tetracycline, clindamycin, and levofloxacin resistance rates were 1.4%, 36.5%, and 20.3%, respectively. The expression of tet(M), erm(B), and mutations of gyrA and/or gyrB were observed in the tetracycline-, clindamycin-, and levofloxacin-resistant isolates, respectively. PMID- 28736260 TI - Soluble epoxide hydrolase activation by S-nitrosation contributes to cardiac ischemia-reperfusion injury. AB - Cardiac ischemia-reperfusion (I/R) injury always accompanies recanalization treatment for myocardial infarction. Here we found soluble epoxide hydrolase (sEH), which metabolizes cardioprotective epoxyeicosatrienoic acids into less effective diols, was rapidly activated during myocardial reperfusion in both mouse and rat models in expression-independent manner. Similar activation was mimicked by nitric oxide (NO) donor dose-dependently in vitro, along with an obvious induction of sEH S-nitrosation, a short-term post-translational modification, which diminished in sEH Cys-141-Ala mutant. In vivo, I/R induced sEH S-nitrosation could be reversed by NO synthase inhibitor L-NAME, with protective effect on cardiac dysfunction, which however vanished in sEH-/- mice. Further, a protective effect against I/R injury in the initial phase of reperfusion was observed in eNOS-/- mice, indicating inhibition of NO as a sEH based cardioprotective in early time of I/R injury. Besides, sEH inhibitor directly targeting on activated sEH during cardiac reperfusion significant reduced infarct size after I/R in vivo. In summary, our findings show the critical role of sEH S-nitrosation in cardiac I/R injury and inhibiting sEH S nitrosation may be a new therapeutic strategy clinically. PMID- 28736262 TI - BDNF - A key player in cardiovascular system. AB - Neurotrophins (NTs) were first identified as target-derived survival factors for neurons of the central and peripheral nervous system (PNS). They are known to control neural cell fate, development and function. Independently of their neuronal properties, NTs exert unique cardiovascular activity. The heart is innervated by sensory, sympathetic and parasympathetic neurons, which require NTs during early development and in the establishment of mature properties, contributing to the maintenance of cardiovascular homeostasis. The identification of molecular mechanisms regulated by NTs and involved in the crosstalk between cardiac sympathetic nerves, cardiomyocytes, cardiac fibroblasts, and vascular cells, has a fundamental importance in both normal heart function and disease. The article aims to review the recent data on the effects of Brain-Derived Neurotrophic Factor (BDNF) on various cardiovascular neuronal and non-neuronal functions such as the modulation of synaptic properties of autonomic neurons, axonal outgrowth and sprouting, formation of the vascular and neural networks, smooth muscle migration, and control of endothelial cell survival and cardiomyocytes. Understanding these mechanisms may be crucial for developing novel therapeutic strategies, including stem cell-based therapies. PMID- 28736261 TI - Genetic disruption of the cardiomyocyte circadian clock differentially influences insulin-mediated processes in the heart. AB - Cardiovascular physiology exhibits time-of-day-dependent oscillations, which are mediated by both extrinsic (e.g., environment/behavior) and intrinsic (e.g., circadian clock) factors. Disruption of circadian rhythms negatively affects multiple cardiometabolic parameters. Recent studies suggest that the cardiomyocyte circadian clock directly modulates responsiveness of the heart to metabolic stimuli (e.g., fatty acids) and stresses (e.g., ischemia/reperfusion). The aim of this study was to determine whether genetic disruption of the cardiomyocyte circadian clock impacts insulin-regulated pathways in the heart. Genetic disruption of the circadian clock in cardiomyocyte-specific Bmal1 knockout (CBK) and cardiomyocyte-specific Clock mutant (CCM) mice altered expression (gene and protein) of multiple insulin signaling components in the heart, including p85alpha and Akt. Both baseline and insulin-mediated Akt activation was augmented in CBK and CCM hearts (relative to littermate controls). However, insulin-mediated glucose utilization (both oxidative and non-oxidative) and AS160 phosphorylation were attenuated in CBK hearts, potentially secondary to decreased Inhibitor-1. Consistent with increased Akt activation in CBK hearts, mTOR signaling was persistently increased, which was associated with attenuation of autophagy, augmented rates of protein synthesis, and hypertrophy. Importantly, pharmacological inhibition of mTOR (rapamycin; 10days) normalized cardiac size in CBK mice. These data suggest that disruption of cardiomyocyte circadian clock differentially influences insulin-regulated processes, and provide new insights into potential pathologic mediators following circadian disruption. PMID- 28736264 TI - Mesenchymal stem/stromal cell extracellular vesicles: From active principle to next generation drug delivery system. AB - It has been demonstrated that the biological effector of mesenchymal stem/stromal cells (MSCs) is their secretome, which is composed of a heterogeneous pool of bioactive molecules, partially enclosed in extracellular vesicles (EVs). Therefore, the MSC secretome (including EVs) has been recently proposed as possible alternative to MSC therapy. The secretome can be considered as a protein based biotechnological product, it is probably safer compared with living/cycling cells, it presents virtually lower tumorigenic risk, and it can be handled, stored and sterilized as an Active Pharmaceutical/Principle Ingredient (API). EVs retain some structural and technological analogies with synthetic drug delivery systems (DDS), even if their potential clinical application is also limited by the absence of reproducible/scalable isolation methods and Good Manufacturing Practice (GMP)-compliant procedures. Notably, EVs secreted by MSCs preserve some of their parental cell features such as homing, immunomodulatory and regenerative potential. This review focuses on MSCs and their EVs as APIs, as well as DDS, considering their ability to reach inflamed and damaged tissues and to prolong the release of encapsulated drugs. Special attention is devoted to the illustration of innovative therapeutic approaches in which nanomedicine is successfully combined with stem cell therapy, thus creating a novel class of "next generation drug delivery systems." PMID- 28736265 TI - Preparing for Emerging Infectious Diseases in the Perinatal Population. AB - The unprecedented scale of the 2014-2015 Ebola virus outbreak in West Africa and the recent emergence and rapid spread of Zika virus infection and resultant neonatal sequelae show that the geographic range, spread, and effect of emerging infections are unpredictable. Lessons learned from analyzing the response of an academic medical center to care for pregnant women with suspected or confirmed Ebola virus disease can help health care professionals address future threats from emerging infections. PMID- 28736263 TI - Facile assembly and loading of theranostic polymersomes via multi-impingement flash nanoprecipitation. AB - Flash nanoprecipitation (FNP) has proven to be a powerful tool for the rapid and scalable assembly of solid-core nanoparticles from block copolymers. The process can be performed using a simple confined impingement jets mixer and provides an efficient and reproducible method of loading micelles with hydrophobic drugs. To date, FNP has not been applied for the fabrication of complex or vesicular nanoarchitectures capable of encapsulating hydrophilic molecules or bioactive protein therapeutics. Here, we present FNP as a single customizable method for the assembly of bicontinuous nanospheres, filomicelles and vesicular, multilamellar and tubular polymersomes from poly(ethylene glycol)-bl poly(propylene sulfide) block copolymers. Multiple impingements of polymersomes assembled via FNP were shown to decrease vesicle diameter and polydispersity, allowing gram-scale fabrication of monodisperse polymersomes within minutes. Furthermore, we demonstrate that FNP supports the simultaneous loading of both hydrophobic and hydrophilic molecules respectively into the polymersome membrane and aqueous lumen, and encapsulated enzymes were found to be released and remain active following vesicle lysis. As an example application, theranostic polymersomes were generated via FNP that were dual loaded with the immunosuppressant rapamycin and a fluorescent dye to link targeted immune cells with the elicited immunomodulation of T cells. By expanding the capabilities of FNP, we present a rapid, scalable and reproducible method of nanofabrication for a wide range of nanoarchitectures that are typically challenging to assemble and load with therapeutics for controlled delivery and theranostic strategies. PMID- 28736266 TI - Omega-3 Consumption During Pregnancy to Support Optimal Outcomes. AB - Long-chain omega-3 polyunsaturated fatty acids (n-3 LCPUFA), including docosahexaenoic acid, are components of cellular membranes that affect biological functioning. Most pregnant women consume inadequate amounts of n-3 LCPUFA and inadequately convert linolenic acid into docosahexaenoic acid. The purpose of this article is to educate nursing professionals on the importance of n-3 LCPUFA consumption during pregnancy and highlight the critical role of nursing professionals in supporting optimal consumption for improved metabolic, antioxidant, and anti-inflammatory potential. PMID- 28736267 TI - Gamma tocopherol-enriched supplement reduces sputum eosinophilia and endotoxin induced sputum neutrophilia in volunteers with asthma. AB - BACKGROUND: We and others have shown that the gamma tocopherol (gammaT) isoform of vitamin E has multiple anti-inflammatory and antioxidant actions and that gammaT supplementation reduces eosinophilic and endotoxin (LPS)-induced neutrophilic airway inflammation in animal models and healthy human volunteers. OBJECTIVE: We sought to determine whether gammaT supplementation reduces eosinophilic airway inflammation and acute neutrophilic response to inhaled LPS challenge in volunteers with asthma. METHODS: Participants with mild asthma were enrolled in a double-blinded, placebo-controlled crossover study to assess the effect of 1200 mg of gammaT daily for 14 days on sputum eosinophils, mucins, and cytokines. We also assessed the effect on acute inflammatory response to inhaled LPS challenge following gammaT treatment, focusing on changes in sputum neutrophilia, mucins, and cytokines. Mucociliary clearance was measured using gamma scintigraphy. RESULTS: Fifteen subjects with mild asthma completed both arms of the study. Compared with placebo, gammaT notably reduced pre-LPS challenge sputum eosinophils and mucins, including mucin 5AC and reduced LPS induced airway neutrophil recruitment 6 and 24 hours after challenge. Mucociliary clearance was slowed 4 hours postchallenge in the placebo group but not in the gammaT treatment group. Total sputum mucins (but not mucin 5AC) were reduced at 24 hours postchallenge during gammaT treatment compared with placebo. CONCLUSIONS: When compared with placebo, gammaT supplementation for 14 days reduced inflammatory features of asthma, including sputum eosinophils and mucins, as well as acute airway response to inhaled LPS challenge. Larger scale clinical trials are needed to assess the efficacy of gammaT supplements as a complementary or steroid-sparing treatment for asthma. PMID- 28736268 TI - Differential connectivity of gene regulatory networks distinguishes corticosteroid response in asthma. AB - BACKGROUND: Variations in drug response between individuals have prevented us from achieving high drug efficacy in treating many complex diseases, including asthma. Genetics plays an important role in accounting for such interindividual variations in drug response. However, systematic approaches for addressing how genetic factors and their regulators determine variations in drug response in asthma treatment are lacking. OBJECTIVE: We sought to identify key transcriptional regulators of corticosteroid response in asthma using a novel systems biology approach. METHODS: We used Passing Attributes between Networks for Data Assimilations (PANDA) to construct the gene regulatory networks associated with good responders and poor responders to inhaled corticosteroids based on a subset of 145 white children with asthma who participated in the Childhood Asthma Management Cohort. PANDA uses gene expression profiles and published relationships among genes, transcription factors (TFs), and proteins to construct the directed networks of TFs and genes. We assessed the differential connectivity between the gene regulatory network of good responders versus that of poor responders. RESULTS: When compared with poor responders, the network of good responders has differential connectivity and distinct ontologies (eg, proapoptosis enriched in network of good responders and antiapoptosis enriched in network of poor responders). Many of the key hubs identified in conjunction with clinical response are also cellular response hubs. Functional validation demonstrated abrogation of differences in corticosteroid-treated cell viability following siRNA knockdown of 2 TFs and differential downstream expression between good responders and poor responders. CONCLUSIONS: We have identified and validated multiple TFs influencing asthma treatment response. Our results show that differential connectivity analysis can provide new insights into the heterogeneity of drug treatment effects. PMID- 28736269 TI - Iodine-lithium-alpha-dextrin (ILalphaD) against Staphylococcus aureus skin infections: a comparative study of in-vitro bactericidal activity and cytotoxicity between ILalphaD and povidone-iodine. AB - BACKGROUND: As antimicrobial resistance continues to increase, revisiting old antimicrobial agents, modified to enhance efficacy and safety, becomes important. Iodine has been widely used for more than 150 years as a wound and skin disinfectant; it is an effective broad range bactericide and does not promote the development of resistant strains. The most important iodine-based agent is povidone-iodine (PVP-I) which provides excellent antibacterial activity. However, its safety profile has been questioned. AIM: To evaluate the in-vitro antibacterial efficacy and kinetic properties of a novel iodine-based compound, iodine lithium alpha-dextrin (ILalphaD), against Staphylococcus aureus, and compare the in-vitro cytotoxicity profiles of ILalphaD and PVP-I. METHODS: A minimum inhibitory concentration (MIC) microbroth dilution method was performed against 12 meticillin-resistant (MRSA) and eight meticillin-susceptible (MSSA) S. aureus clinical isolates using ILalphaD and PVP-I. Time-kill and post-antibiotic effect studies of ILalphaD provided rate-of-kill information. MTT cytotoxicity assays were performed using three cell lines, treated with MIC doses of ILalphaD and PVP-I. FINDINGS: The MIC values of ILalphaD and PVP-I against the MRSA strains were 125 mg/L and 31.25 mg/L, respectively. Time-kill and post-antibiotic effect studies of ILalphaD revealed a log10 reduction factor of 3 within 8 h of exposure at a 2 * MIC dose; the post-antibiotic effect was calculated at 5+/ 0.3h. Cell viability was affected slightly at the MIC dose of ILalphaD, while the MIC dose of PVP-I exerted a strong cell growth inhibitory effect of 90-95%. CONCLUSIONS: ILalphaD could be a promising solution against staphylococcal infections as it is effective, does not promote the development of resistant strains, and in-vitro testing indicates that it may be safer than PVP-I. Further studies are justified to determine whether ILalphaD overcomes the clinical limitations of PVP-I. PMID- 28736270 TI - Prevalence of, and risk factors for, carriage of carbapenem-resistant Enterobacteriaceae among hospitalized patients in Japan. AB - BACKGROUND: The prevalence of carbapenem-resistant Enterobacteriaceae (CRE) has been reported to be lower in Japan than in many other countries. However, extensive surveillance for CRE carriage has not been performed in Japan. AIM: To investigate the prevalence of CRE carriage in Japan among convalescent patients considered to be at high risk of being CRE carriers using an improved selective culture medium. METHODS: A cross-sectional survey was conducted in 22 acute care hospitals (ACHs) and 21 long-term care hospitals (LTCHs) in northern Osaka from December 2015 to January 2016. Patients who used incontinence aids, an enteral feeding tube or a urinary catheter were enrolled. Faecal specimens were examined using the newly developed M-ECC for imipenemase (IMP)-producing CRE, which is the most prevalent form of CRE in Japan. The positive isolates were analysed by polymerase chain reaction and sequencing. Risk factors associated with carriage were analysed by logistic regression. FINDINGS: Among 1507 patients, 184 (12.2%) carried CRE. The percentage of positive patients was significantly higher in LTCHs (14.9%) than in ACHs (3.6%) (P<0.001). Risk factors for CRE carriage were longer hospital stay [odds ratio (OR) 2.59; 95% confidence interval (CI) 1.87 3.60], enteral feeding (OR 3.03, 95% CI 2.08-4.42) and antibiotic exposure (OR 2.00, 95% CI 1.40-2.87). Among the 233 CRE isolates identified, 223 were IMP producers; the remaining isolates did not produce carbapenemase. CONCLUSIONS: This is the first Japanese report to demonstrate the significant spread of CRE in both ACHs and LTCHs using an improved selective medium. A coordinated regional approach may help to prevent further spread. PMID- 28736272 TI - Rheumatic paraneoplastic syndromes - A clinical link between malignancy and autoimmunity. AB - Paraneoplastic syndromes are rare but can have enormous clinical impact on diagnosis and outcome of neoplastic diseases. The rheumatologist should be familiar with a few typical musculoskeletal manifestations of malignancies to be able to diagnose them early for a timely initiation of anti-tumour therapies. This review describes the characteristic features of various paraneoplastic arthritides and vasculitides, cancer-associated myositis, hypertrophic osteoarthropathy, and tumour-induced osteomalacia. In addition, the current knowledge about underlying pathomechanisms of these syndromes is discussed. PMID- 28736273 TI - Novel insights into the pathogenesis of psoriasis. PMID- 28736271 TI - B cells and their cytokine activities implications in human diseases. AB - B cells are the only cell type that can give rise to antibody-producing cells, and the only cell type whose selective depletion can, today, lead to an improvement of a wide range of immune-mediated inflammatory diseases, including disorders not primarily driven by autoantibodies. Here, I discuss this paradoxical observation, and propose that the capacity of B cells to act as cytokine-producing cells explains how they can control monocyte activity and subsequently disease pathogenesis. Together with current data on the effect of anti-CD20 B cell-depleting reagents in the clinic, this novel knowledge on B cell heterogeneity opens the way for novel safer and more efficient strategies to target B cells. The forthcoming identification of disease-relevant B cell subsets is awaited to permit their monitoring and specific targeting in a personalized medicine approach. PMID- 28736274 TI - Biomarkers as a treatment guide in rheumatoid arthritis. AB - It is anticipated that biomarkers support rheumatologists to judge a group of patients that can improve the diagnosis and prognosis, and further facilitate appropriate and precise treatment with targeted therapy. In particular, biomarkers for predicting and monitoring response to biological disease modifying anti-rheumatic drugs (DMARDs) are demanding. Given the mechanism action of biological DMARDs is much more simple than the conventional synthetic DMARDs, a variety of approaches to find such biomarkers has been taken recent years. In this article, I will summarize the background for biomarker research and introduce recent topics in the research and the possible clinical applications of biomarkers to guide treatment in rheumatoid arthritis (RA). PMID- 28736276 TI - B-cells as therapeutic targets in neuro-inflammatory diseases. AB - B cells are an emerging therapeutic target in neuroinflammatory diseases. The anti-CD20 monoclonal antibody ocrelizumab was recently approved in the US as the first B-cell targeting immunomodulatory treatment for relapsing-remitting MS and primary progressive MS. In autoantibody-associated demyelinating syndromes such as neuromyelitis optica (NMO) and in myelin-oligodendrocyte-glycoprotein-(MOG) autoantibody-associated encephalomyelitis, B-cells are a logical target based on the pathogenesis of these antibody-mediated disorders. Furthermore, B cells and autoantibodies are promising targets in a variety of autoantibody-associated encephalitis syndromes such as N-methyl-d-aspartate receptor (NMDAR)-antibody encephalitis. PMID- 28736275 TI - Dendritic cells activation is associated with sustained virological response to telaprevir treatment of HCV-infected patients. AB - First anti-HCV treatments, that include protease inhibitors in conjunction with IFN-alpha and Ribavirin, increase the sustained virological response (SVR) up to 80% in patients infected with HCV genotype 1. The effects of triple therapies on dendritic cell (DC) compartment have not been investigated. In this study we evaluated the effect of telaprevir-based triple therapy on DC phenotype and function, and their possible association with treatment outcome. HCV+ patients eligible for telaprevir-based therapy were enrolled, and circulating DC frequency, phenotype, and function were evaluated by flow-cytometry. The antiviral activity of plasmacytoid DC was also tested. In SVR patients, myeloid DC frequency transiently decreased, and returned to baseline level when telaprevir was stopped. Moreover, an up-regulation of CD80 and CD86 on mDC was observed in SVR patients as well as an improvement of IFN-alpha production by plasmacytoid DC, able to inhibit in vitro HCV replication. PMID- 28736277 TI - Solving the pathogenesis of ankylosing spondylitis. PMID- 28736278 TI - Efficacy paradox and proportional contextual effect (PCE). AB - The "efficacy paradox" is when the effect of a treatment tested in an RCT, or evidence-based guideline advice, differs markedly from treatment benefits observed in clinical practice. This arises because in RCT reporting and guideline development treatment efficacy is judged by the separation of the treatment group from the placebo group (the specific treatment effect) whereas in clinical practice it is the overall treatment effect, which includes both specific and contextual responses, that patients experience. This paradox causes a disconnect between guidelines and clinical practice and ignores the importance of contextual response in clinical care. This article fully explains and discusses these issues and presents a possible way to reduce the paradox through an alteration in RCT reporting that shifts the focus to overall treatment benefit and the proportion ("proportional contextual effect") that is explained by placebo and contextual effects. PMID- 28736279 TI - miRNA meets plasma cells "How tiny RNAs control antibody responses". AB - We review the importance of small non-coding microRNAs for the generation of germinal center B cells and their differentiation in antibody-secreting plasma cells. In the last part, we briefly elucidate the role of microRNAs in some plasma cell disorders. PMID- 28736280 TI - The serine/threonine protein phosphatase 2A controls autoimmunity. AB - Protein phosphatase 2A (PP2A) is the first serine/threonine phosphatase recognized to contribute to human and murine lupus immunopathology. PP2A expression in SLE is controlled both epigenetically and genetically, and it is increased in patients with SLE, which contributes to decreased IL-2 production, decreased CD3zeta and increased FcRgamma expression on the surface of T cells, increased CREMalpha expression, hypomethylation of genes associated with SLE pathogenesis, and increased IL-17 production. beta regulatory subunit of PP2A regulates IL-2 deprivation-induced T cell death and is decreased in SLE patients. A mouse overexpressing PP2Ac in T cells displays peripheral granulocytosis, elevated IL-17 production, and develops glomerulonephritis when challenged. A mouse which lacks PP2Ac only in regulatory T cells develops severe autoimmunity and multiorgan inflammation because of loss of restraint on mTORC1 and inability of Foxp3+ cells to regulate conventional T cells. Targeting PP2A in T cell subsets may be therapeutic for SLE and other autoimmune diseases. PMID- 28736281 TI - Platycodin D suppressed LPS-induced inflammatory response by activating LXRalpha in LPS-stimulated primary bovine mammary epithelial cells. AB - Platycodin D (PLD), a triterpenoid saponin derived from the root of Platycodon grandiflorum, has been reported to possess anti-inflammatory activity. However, the protective effect of PLD on mastitis has not been reported. In the present study, we aim to investigate the anti-inflammatory feature of PLD on the primary bovine mammary epithelial cells (bMEC) challenged with LPS. The cell viability of bMEC was measured by MTT assay. The quantitative real-time polymerase chain reaction (qRT-PCR) was conducted to detect the gene expression of pro inflammatory cytokines and western blotting was carried out to measure the expression of LXRalpha and NF-kappaB. The results showed that PLD inhibited LPS induced TNF-alpha, IL-1beta, and IL-6 expression in LPS-stimulated bEMC. Meanwhile, PLD suppressed LPS-induced NF-kappaB activation. Furthermore, PLD was found to up-regulate the expression of LXRalpha. The inhibition of PLD on NF kappaB activation and inflammatory cytokines production were reversed by GGPP, the inhibitor of LXRalpha. In conclusion, our results suggested that PLD inhibited LPS-induced inflammatory response in bMEC by activating LXRalpha. PLD may be a potential therapeutic drug for mastitis. PMID- 28736282 TI - Imiquimod-induced psoriasis-like inflammation in differentiated Human keratinocytes: Its evaluation using curcumin. AB - Psoriasis is considered to be a systemic disease of immune dysfunction. It is still unclear what triggers the inflammatory cascade associated with psoriasis but recent evidences suggest the vital role of IL-23/IL-17A cytokine axis in etiology of psoriasis. Several studies have been conducted in psoriatic-like animal models but ethical issues and complexity surrounding it halts the screening of new anti-psoriatic drug candidates. Hence, in this study, we developed a new in-vitro model for psoriasis using imiquimod (IMQ) induced differentiated HaCaT cells which could be used for screening of new anti psoriatic drug candidates. The differentiated HaCaT cells were treated with IMQ (100MUM) to induce psoriatic like inflammation and its effect was investigated using a natural anti-psoriatic compound, curcumin. The proliferation of psoriatic like cells was inhibited by curcumin at 25 and 50uM concentrations. The psoriatic like cells decreased in number with increase in apoptotic and dead cells upon curcumin treatment. Curcumin inhibited the proliferation of IMQ-induced differentiated HaCaT cells (Psoriatic-like cells) by down-regulation of pro inflammatory cytokines, interleukin-17, tumor necrosis factor-alpha, interferon gamma, and interleukin-6. Apart from this, curcumin significantly enhanced the skin-barrier function by up-regulation of involucrin (iNV) and filaggrin (FLG), the regulators of epidermal skin barrier. The IMQ-induced differentiated HaCaT in vitro model recapitulated some aspects of the psoriasis pathogenesis similar to murine model. Henceforth, we conclude that this model may be used for rapid screening of anti-psoriatic drug candidates and warrant further mechanistic studies. PMID- 28736283 TI - Multicellular dosimetric chain for molecular radiotherapy exemplified with dose simulations on 3D cell spheroids. AB - PURPOSE: Absorbed radiation dose-response relationships are not clear in molecular radiotherapy (MRT). Here, we propose a voxel-based dose calculation system for multicellular dosimetry in MRT. We applied confocal microscope images of a spherical cell aggregate i.e. a spheroid, to examine the computation of dose distribution within a tissue from the distribution of radiopharmaceuticals. METHODS: A confocal microscope Z-stack of a human hepatocellular carcinoma HepG2 spheroid was segmented using a support-vector machine algorithm and a watershed function. Heterogeneity in activity uptake was simulated by selecting a varying amount of the cell nuclei to contain 111In, 125I, or 177Lu. Absorbed dose simulations were carried out using vxlPen, a software application based on the Monte Carlo code PENELOPE. RESULTS: We developed a schema for radiopharmaceutical dosimetry. The schema utilizes a partially supervised segmentation method for cell-level image data together with a novel main program for voxel-based radiation dose simulations. We observed that for 177Lu, radiation cross-fire enabled full dose coverage even if the radiopharmaceutical had accumulated to only 60% of the spheroid cells. This effect was not found with 111In and 125I. Using these Auger/internal conversion electron emitters seemed to guarantee that only the cells with a high enough activity uptake will accumulate a lethal amount of dose, while neighboring cells are spared. CONCLUSIONS: We computed absorbed radiation dose distributions in a 3D-cultured cell spheroid with a novel multicellular dosimetric chain. Combined with pharmacological studies in different tissue models, our cell-level dosimetric calculation method can clarify dose-response relationships for radiopharmaceuticals used in MRT. PMID- 28736284 TI - ADAM: A breathing phantom for lung SBRT quality assurance. AB - PURPOSE: Radiotherapy treatment of moving lesions is a challenging task in which different strategies can be used to adequately treat the tumor while sparing the surrounding tissue. The complexity of these strategies requires accurate and appropriate quality assurance tests. For this purpose, ADAM (Anthropomorphic Dynamic breAthing Model), a new phantom which simulates realistic patient breathing, was developed aiming to test the image quality and dose delivery in lung cancer treatments. MATERIALS AND METHODS: ADAM reproduces a male torso complete with a moving anterior chest wall and internal parts. The phantom's external body is printed with a 3D printer using acrylonitrile butadiene styrene. Internal lungs, ribs, spinal cord, and lung tumor (LT) are made of materials that simulate human tissues. Driven by an Arduino programmable board, the lungs can move along linear or elliptical paths while the anterior chest wall moves up and down. Phantom features and usability, reproducibility of LT position in the phantom chest, internal and external motion repeatability and tumor-to-surface motion correlation were investigated. RESULTS: Hounsfield Units of the employed materials demonstrates the phantom adequately simulates human tissues. Tests performed with the Synchrony system confirm ADAM's suitability for respiratory internal tracking. Reproducibility of the internal structure position is within 1mm as are internal and external motion repeatability. A strong positive correlation is found between the lung and chest wall positions (R2=0.999). CONCLUSIONS: ADAM demonstrates to be suitable to be employed with gating and tracking devices used in the treatment of moving lesions. PMID- 28736285 TI - Optimization of GATE simulations for whole-body planar scintigraphic acquisitions using the XCAT male phantom with 177Lu-DOTATATE biokinetics in a Siemens Symbia T2. AB - Simulations of planar whole body acquisitions in therapeutic procedures are often extensively time-consuming and therefore rarely used. However, optimising tools and variance reduction techniques can be employed to overcome this problem. In this paper, a variety of features available in GATE are explored and their capabilities to reduce simulation time are evaluated. For this purpose, the male XCAT phantom was used as a virtual patient with 177Lu-DOTATATE pharmacokinetic for whole body planar acquisition simulations in a Siemens Symbia T2 model. Activity distribution was divided into 8 compartments that were simulated separately. GATE optimization techniques included reducing the amount of time spent in both voxel and detector tracking. Some acceleration techniques led to a decrease of CPU-time by a factor of 167, while image statistics were kept constant. In that context, the simulation of therapeutic procedure imaging would still require 46days on a single CPU, but this could be reduced to hours on a dedicated cluster. PMID- 28736286 TI - Lack of immunotoxic effects of repeated exposure to atrazine associated with the adaptation of adrenal gland activation. AB - T cell-dependent IgM antibody production and natural killer cell (NKC) activity were assessed in SD rats orally administered atrazine for 28 days to males (0, 6.5, 25, or 100 mg/kg/day) or females (0, 3, 6, or 50 mg/kg/day), or 30 or 500 ppm in diet (3 or 51 mg/kg/day). Anti-asialo GM1 antibodies (NKC) and cyclophosphamide (antibody-forming cell assay [AFC]) served as positive controls. Pituitary (ACTH, prolactin), adrenal (corticosterone, progesterone, aldosterone), and gonadal (androgens, estrogens) hormones were assessed after 1, 7, and/or 28 days of treatment. Food intake and body weights were significantly reduced in the highest dosed males, and transiently affected in females. Urinary corticosterone levels were not increased in atrazine-treated groups in either sex at any time point measured (10, 22, or 24 days). Corticosterone and progesterone were elevated in males after a single atrazine dose >=6.5 mg/kg/day, but not after 7, 14, or 28 doses. There were no effects on adrenal, pituitary, or gonadal hormones in females. Atrazine did not suppress the AFC response or decrease NKC function after 28 days in males or females. Atrazine had no effect on spleen weights or spleen cell numbers in males or females, although thymus weights were elevated in males receiving the highest dose. The lack of immunotoxic effect of atrazine was associated with diminished adrenal activation over time in males, and no effects on adrenal hormones in females. PMID- 28736287 TI - Novel approach for selective reduction of NNN in cigarette tobacco filler and mainstream smoke. AB - Research conducted during past decades to reduce the level of the tobacco specific nitrosamine N-nitrosonornicotine (NNN) and its precursor nornicotine in tobacco yielded identification of three tobacco genes encoding for cytochrome P450 nicotine demethylases converting nicotine to nornicotine. We carried out trials to investigate the effect of using tobaccos containing three non functional nicotine demethylase genes on the selective reduction of NNN in cigarette tobacco filler and mainstream smoke. Our results indicate that the presence of non-functional alleles of the three genes reduces the level of nornicotine and NNN in Burley tobacco by 70% compared to the level observed in currently available low converter (LC) Burley tobacco varieties. The new technology, named ZYVERTTM, does not require a regular screening process, while a yearly selection process is needed to produce LC Burley tobacco seeds for NNN reduction. The reduction of NNN observed in smoke of blended prototype cigarettes is proportional to the inclusion level of tobacco having ZYVERTTM technology. Inclusion of Burley tobacco possessing the new trait into a typical American blend resulted in a selective reduction of NNN in cigarette smoke, while the levels of other Harmful and Potentially Harmful Constituents (HPHC) currently in the abbreviated list provided by the US Food and Drug Administration are statistically equivalent in comparison with the levels obtained in reference prototype cigarettes containing LC Burley. PMID- 28736288 TI - Rapid decay of transthoracic echocardiography skills at 1 month: A prospective observational study. AB - OBJECTIVE: Focused transthoracic echocardiography (FTTE) is an emerging tool in the management of critically ill patients, but the lack of adequate training models has limited the expansion of this technology. Although basic FTTE training courses have been shown to be sufficient in developing echocardiography skills, limited data exist regarding skill retention. In an effort to develop an adequate FTTE training model, we sought to determine the degree of skill retention after FTTE training. DESIGN: A prospective, observational study. SETTING: An academic center. PARTICIPANTS: Surgical residents and medical students: 31 subjects were enrolled from February to June 2016. RESULTS: Participants underwent a 2-hour FTTE course including didactics and a hands-on session measuring ejection fraction of left ventricle (LV) and inferior vena cava (IVC) diameter. Written knowledge and performance examinations applying FTTE were conducted before the course, immediately after, and at 1- and 3-month intervals, which were evaluated on a 0 to 9 scale and analyzed with paired t-tests. Performance examination scores obtaining the LV and IVC views preinitial and postinitial training increased from 1.7 to 6.5 (LV) and from 2.0 to 6.8 (IVC) (p < 0.01), decreased to 5.0 and 4.8, respectively, at 1 month (posttraining vs 1 month, p < 0.01), and did not significantly change at 3 months (5.4 and 5.0, respectively). Written examination scores increased from 42% to 62% (pretraining vs posttraining, p < 0.01), decreased to 48% in 1 month (posttraining vs 1 month, p < 0.01), and further decreased to 34% at 3 months (1 month vs 3 month, p < 0.01). CONCLUSIONS: Although a short training course appears sufficient to impart basic FTTE skills and knowledge, skills are significantly decayed at 1 month and knowledge continually decreases at 1 and 3 months. Future FTTE training models should consider the rapid degradation of knowledge and skills in determining frequency of refresher training and ongoing evaluation. PMID- 28736289 TI - Formation Mechanism and In Vitro Evaluation of Risperidone-Containing PLGA Microspheres Fabricated by Ultrafine Particle Processing System. AB - Ultrafine particle processing system (UPPS) was developed previously by our group to provide a new solution to microsphere fabrication. The UPPS was supposed to possess many featured advantages, but the microsphere formation mechanism during UPPS processing was still unknown. The objective of this study was to perform the formation mechanism investigation and in vitro evaluation on risperidone containing poly(d, l-lactic-co-glycolic acid) microspheres (RIS-PLGA MS) fabricated by UPPS. Evaporation profile and viscosity of the PLGA-containing solutions were considered as the critical factors for the microsphere formation mechanism and were determined in present study. The formation mechanism of RIS PLGA MS was put forward by semiquantitative analysis on the basis of the evaporation profile, viscosity, and scanning electron microscopy results. It was established that the evaporation profile and viscosity would have an impact on the evaporation velocity and PLGA molecular diffusion velocity during solidification process, resulting in different appearance of the microspheres. Furthermore, comprehensive in vitro evaluations of RIS-PLGA MS were conducted, including particle size distribution, micromeritics, morphology, drug loading, encapsulation efficiency, residual organic solvent, syringeability, and in vitro release behavior. The results revealed that RIS-PLGA MS was a promising candidate for intramuscular administration, and meanwhile UPPS was a qualified technology for microsphere production. PMID- 28736290 TI - Regulated proteolysis as an element of ER stress and autophagy: Implications for intestinal inflammation. AB - Endoplasmic reticulum (ER) stress and autophagy are tightly controlled cellular processes, which are responsible for maintaining protein homeostasis in a cell. Impairment of the interlinking pathways have been implicated in a number of human diseases, prominently in inflammatory bowel disease, where genetic variants in several independent autophagy and ER stress related loci have been associated to increased disease risk. Autophagy is a selective quality control process, which governs the integrity of the cell by removal of aged organelles and proteins via the lysosome, but recently has been shown to actively license the outcome of other signaling pathways by guiding the proteolytic removal of signaling protein complexes (adaptophagy). In this review, we summarize our knowledge on regulated proteolytic events involved in ER stress responses and autophagy, their interplay and potential regulatory effects with a particular focus on intestinal inflammation. This article is part of a Special Issue entitled: Proteolysis as a Regulatory Event in Pathophysiology edited by Stefan Rose-John. PMID- 28736291 TI - Clinical and Hemodynamic Correlates and Prognostic Value of VE/VCO2 Slope in Patients With Heart Failure With Preserved Ejection Fraction and Pulmonary Hypertension. AB - BACKGROUND: Impaired exercise capacity is one of the hallmarks of heart failure with preserved ejection fraction (HFpEF), but the clinical and hemodynamic correlates and prognostic value of exercise testing in patients with HFpEF is unknown. METHODS: Patients with HFpEF (left ventricular ejection fraction [LVEF] >=45%) and pulmonary hypertension underwent cardiopulmonary exercise test (CPX) to measure maximal (peak VO2) and submaximal (ventilatory equivalent for carbon dioxide [VE/VCO2] slope) exercise capacity. In addition, right heart catheterization was performed. Patients were grouped in tertiles based on the VE/VCO2 slope. Univariate and multivariate regression analyses were performed. A Cox regression analysis was performed to determine the mortality during follow up. RESULTS: We studied 88 patients: mean age 73 +/- 9 years, 67% female, mean LVEF 58%, median N-terminal pro-B-type natriuretic peptide (NT-proBNP) 840 (interquartile range 411-1938) ng/L. Patients in the highest VE/VCO2 tertile had the most severe HF, as reflected in higher New York Heart Association functional class and higher NT-proBNP plasma levels (all P < .05 for trend), whereas LVEF was similar between the groups. Multivariable regression analysis with backward elimination on invasive hemodynamic measurements showed that VE/VCO2 slope was independently associated with pulmonary vascular resistance (PVR). Cox regression analysis showed that increased VE/VCO2 slope (but not peak VO2) was independently associated with increased mortality. CONCLUSION: Increased VE/VCO2 slope was associated with more severe disease and higher PVR and was independently associated with increased mortality in patients with HFpEF. PMID- 28736292 TI - Reproductive features and use of an anti-inflammatory drug in estrus-induced dairy goats artificially inseminated in a standing position with cervix immobilization. AB - This study evaluated reproductive features and role of Flunixin-Meglumine at timed artificial insemination (AI), using a new technique of standing position with cervix immobilization. In Experiment 1, 10 goats (n=5 nulliparous [Null] and 5 pluriparous [Plu]) were evaluated after estrus induction by recorded reproductive parameters to define the ideal time for AI. In Experiment 2, goats were artificially inseminated 51-54h after sponge removal with frozen-thawed semen. At AI, 1mL saline (CONTROL; 18 Null and 14 Plu) or 50mg Flunixin-Meglumine (FLUNIXIN; 15 Null and 18 Plu) was administered i.m. Location of semen deposition was recorded for both groups. In Experiment 1, all sexual behavior and ovulatory parameters were similar between Null and Plu for estrus response and ovulation (100%), interval from sponge removal to ovulation (~64.2h), largest ovulatory follicle diameter (~6.6mm), and number of ovulations (~2.0). In Experiment 2, pregnancy rate was superior (P<0.01) for CONTROL (62.5%; 10 Null and 10 Plu) than FLUNIXIN (30.3%; 3 Null and 7 Plu) goats. Regardless of the treatment, intrauterine AI was more frequent (P<0.01) in Plu (100.0%; 32/32) than in Null (69.7%; 23/33) goats. Moreover, AI was more time-consuming (P<0.01) in Null (44+/ 37s; 4-139s) than in Plu (21+/-19s, 4-78s) goats. Therefore, administration of Flunixin-Meglumine at the time of AI adversely affected pregnancy rate. High rates of intrauterine cervical penetration were obtained, achieving good pregnancy rates in goats not receiving Flunixin-Meglumine. PMID- 28736293 TI - Zirconia-based versus metal-based single crowns veneered with overpressing ceramic for restoration of posterior endodontically treated teeth: 5-year results of a randomized controlled clinical study. AB - OBJECTIVES: The aim of this 5-year randomized controlled trial was to compare the longevity and clinical behavior of single posterior crowns made with pressable ceramic on zirconia and on metal frameworks, and if failures occur, to delineate the contributing factors. METHODS: 72 patients, who needed the covering of at least a molar and/or premolar, were included in the study. All teeth were endodontically treated, with absence of periapical lesion or active periodontitis. Ninety single crowns were made with zirconia or metal framework and covered with pressable veneering ceramics. Two independent examiners assessed the survival of restorations at 6 months, 1-4 and 5 years after restoration placement including periapical radiographs, intraoral photographs, and USPHS modified criteria. The statistical analyses were performed with the Kaplan-Meier method. RESULTS: One core fracture occurred in Zircad/Zirpress crowns and one metal ceramic crown was lost for root fracture. Chipping fracture of the veneering ceramic was detected in 2 metal-ceramic crowns and in 3 zirconia-based crowns. The Estimate Cumulative Survival (ECS) and the Estimate Cumulative Success (ECSs) with standard deviation (SE) were respectively 97,73+/-2,19 and 92,64+/-4,14 for zirconia-based crowns whereas 97,44+/-2,39 and 91,11+/-4,27 for porcelain fused to metal crowns. CONCLUSIONS: The present randomized controlled trial shows that the survival of zirconia-based and metal-based single crowns is similar over a follow-up period of 5 years. No significant differences in esthetic, functional and biological outcomes were demonstrated between the two groups. The main failure mode was the chipping fracture of the veneering ceramic in both materials. Study number on ClinicalTrial.gov NCT02758457. CLINICAL SIGNIFICANCE: According to the results of this clinical study, zirconia-based rehabilitations with overpressing veneering technique represent a valid alternative to metal-based for posterior single crown restorations. PMID- 28736294 TI - Enhanced neuroprotection of anthocyanin-loaded PEG-gold nanoparticles against Abeta1-42-induced neuroinflammation and neurodegeneration via the NF-KB /JNK/GSK3beta signaling pathway. AB - Amyloid-beta (Abeta1-42) plaques and neurofibrillary tangles (NFTs) are the main hallmarks considered to be associated with neuroinflammation in Alzheimer's disease (AD). Recently, nanoparticle-based targeted drug delivery approaches have been found to be a useful tool in the neurotherapeutics field. Therefore, we examined and compared the neuroprotective effect of anthocyanins alone and anthocyanin-loaded poly (ethylene glycol)-gold nanoparticles (PEG-AuNPs) in Abeta1-42-injected mouse and in vitro models of AD. We determined that anthocyanins alone or conjugated with PEG-AuNPs (AnPEG-AuNPs) reduced Abeta1-42 induced neuroinflammatory and neuroapoptotic markers via inhibiting the p-JNK/NF kappaB/p-GSK3beta pathway in both in vivo and in vitro AD models. However, anthocyanins loaded with PEG-AuNPs were more effective compared to anthocyanins alone. Taken together, these results demonstrate that PEG-coated gold anthocyanins nanoparticles could be a new therapeutic agent in the field of nanomedicine to prevent neurodegenerative diseases such as AD. PMID- 28736295 TI - Digital Multiplex Ligation-Dependent Probe Amplification for Detection of Key Copy Number Alterations in T- and B-Cell Lymphoblastic Leukemia. AB - Recurrent and clonal genetic alterations are characteristic of different subtypes of T- and B-cell lymphoblastic leukemia (ALL), and several subtypes are strong independent predictors of clinical outcome. A next-generation sequencing-based multiplex ligation-dependent probe amplification variant (digitalMLPA) has been developed enabling simultaneous detection of copy number alterations (CNAs) of up to 1000 target sequences. This novel digitalMLPA assay was designed and optimized to detect CNAs of 56 key target genes and regions in ALL. A set of digital karyotyping probes has been included for the detection of gross ploidy changes, to determine the extent of CNAs, while also serving as reference probes for data normalization. Sixty-seven ALL patient samples (including B- and T-cell ALL), previously characterized for genetic aberrations by standard MLPA, array comparative genomic hybridization, and/or single-nucleotide polymorphism array, were analyzed single blinded using digitalMLPA. The digitalMLPA assay reliably identified whole chromosome losses and gains (including high hyperdiploidy), whole gene deletions or gains, intrachromosomal amplification of chromosome 21, fusion genes, and intragenic deletions, which were confirmed by other methods. Furthermore, subclonal alterations were reliably detected if present in at least 20% to 30% of neoplastic cells. The diagnostic sensitivity of the digitalMLPA assay was 98.9%, and the specificity was 97.8%. These results merit further consideration of digitalMLPA as a valuable alternative for genetic work-up of newly diagnosed ALL patients. PMID- 28736296 TI - A New Targeted CFTR Mutation Panel Based on Next-Generation Sequencing Technology. AB - Searching for mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR) is a key step in the diagnosis of and neonatal and carrier screening for cystic fibrosis (CF), and it has implications for prognosis and personalized therapy. The large number of mutations and genetic and phenotypic variability make this search a complex task. Herein, we developed, validated, and tested a laboratory assay for an extended search for mutations in CFTR using a next-generation sequencing-based method, with a panel of 188 CFTR mutations customized for the Italian population. Overall, 1426 dried blood spots from neonatal screening, 402 genomic DNA samples from various origins, and 1138 genomic DNA samples from patients with CF were analyzed. The assay showed excellent analytical and diagnostic operative characteristics. We identified and experimentally validated 159 (of 188) CFTR mutations. The assay achieved detection rates of 95.0% and 95.6% in two large-scale case series of CF patients from central and northern Italy, respectively. These detection rates are among the highest reported so far with a genetic test for CF based on a mutation panel. This assay appears to be well suited for diagnostics, neonatal and carrier screening, and assisted reproduction, and it represents a considerable advantage in CF genetic counseling. PMID- 28736297 TI - 1alpha-Hydroxy derivatives of 7-dehydrocholesterol are selective liver X receptor modulators. AB - The nuclear receptors liver X receptor (LXR) alpha and LXRbeta are involved in the regulation of lipid metabolism, inflammation, immunity, cellular proliferation, and apoptosis. Oxysterols are endogenous LXR ligands, and also interact with other nuclear and membrane receptors. We previously reported that a phytosterol derivative with a 1alpha-hydroxy group acts as a potent LXR agonist with intestine-selective action and that 25-hydroxy and 26/27-hydroxy metabolites of 7-dehydrocholesterol (7-DHC) exhibit partial LXR agonism. In this study, we report that 1alpha-hydroxy derivatives of 7-DHC, 1alpha-OH-7-DHC and 1,25-(OH)2-7 DHC, act as LXR modulators. Luciferase reporter gene assays showed that 1alpha-OH 7-DHC activates LXRalpha and LXRbeta and that 1,25-(OH)2-7-DHC activates both LXRs and vitamin D receptor. Examination of cofactor peptide association showed that the 1alpha-hydroxy derivatives, specifically 1,25-(OH)2-7-DHC, induce association of coactivator/corepressor peptide in a different manner from the agonist T0901317. Docking modeling and alanine mutational analysis of LXRalpha demonstrated that 1,25-(OH)2-7-DHC interacts with LXRalpha residues in a manner distinct from potent agonists, such as T0901317 and 24(S),25-epoxycholesterol. 1alpha-OH-7-DHC and 1,25-(OH)2-7-DHC induced expression of LXR target genes in a cell type- and gene-selective manner. 1,25-(OH)2-7-DHC effectively suppressed lipopolysaccharide-stimulated proinflammatory gene expression in an LXR-dependent manner. Therefore, 1alpha-hydroxy derivatives, such as 1,25-(OH)2-7-DHC, are unique LXR modulators with selective agonistic activity and potent transrepression function. These oxysterols have potential as LXR-targeted therapeutics for inflammatory disease. PMID- 28736299 TI - N-acetylglucosamine, the building block of chitin, inhibits growth of Neurospora crassa. AB - N-acetylglucosamine (GlcNAc) is the monomer of the polysaccharide chitin, an essential structural component of the fungal cell wall and the arthropod exoskeleton. We recently showed that the genes encoding the enzymes for GlcNAc catabolism are clustered in several ascomycetes. In the present study we tested these fungi for growth on GlcNAc and chitin. All fungi, containing the GlcNAc gene cluster, could grow on GlcNAc with the exception of four independent Neurospora crassa wild-type isolates, which were however able to grow on chitin. GlcNAc even inhibited their growth in the presence of other carbon sources. Genes involved in GlcNAc catabolism were strongly upregulated in the presence of GlcNAc, but during growth on chitin their expression was not increased. Deletion of hxk-3 (encoding the first catabolic enzyme, GlcNAc-hexokinase) and ngt-1 (encoding the GlcNAc transporter) improved growth of N. crassa on GlcNAc in the presence of glycerol. A crucial step in GlcNAc catabolism is enzymatic conversion from glucosamine-6-phosphate to fructose-6-phosphate, catalyzed by the glucosamine-6-phosphate deaminase, DAM-1. To assess, if DAM-1 is compromised in N. crassa, the orthologue from Trichoderma reesei, Trdam1, was expressed in N. crassa. Trdam1 expression partially alleviated the negative effects of GlcNAc in the presence of a second carbon source, but did not fully restore growth on GlcNAc. Our results indicate that the GlcNAc-catabolism pathway is bypassed during growth of N. crassa on chitin by use of an alternative pathway, emphasizing the different strategies that have evolved in the fungal kingdom for chitin utilization. PMID- 28736298 TI - Calcitriol-mediated reduction in IFN-gamma output in T cell large granular lymphocytic leukemia requires vitamin D receptor upregulation. AB - Constitutively activated STAT1 and elevated IFN-gamma are both characteristic of T cell large granular lymphocytic leukemia (T-LGLL), a rare incurable leukemia with clonal expansion of cytotoxic T cells due to defective apoptosis. Interferon gamma (IFN-gamma) is an inflammatory cytokine that correlates with worse progression and symptomology in multiple autoimmune diseases and cancers. In canonical IFN-gamma-STAT1 signaling, IFN-gamma activates STAT1, a transcription factor, via phosphorylation of tyrosine residue 701 (p-STAT1). p-STAT1 then promotes transcription of IFN-gamma, creating a positive feedback loop. We previously found that calcitriol treatment of the TL-1 cell line, a model of T LGLL, significantly decreased IFN-gamma secretion and p-STAT1 while increasing the vitamin D receptor (VDR) protein. Here we further explore these observations. Using TL-1 cells, IFN-gamma decreased starting at 4h following calcitriol treatment, with a reduction in the intracellular and secreted protein levels as well as the mRNA content. A similar reduction in IFN-gamma transcript levels was observed in primary T-LGLL patient peripheral blood mononuclear cells (PBMCs). p STAT1 inhibition followed a similar temporal pattern and VDR upregulation inversely correlated with IFN-gamma levels. Using EB1089 and 25(OH)D3, which have high or low affinity for VDR, respectively, we found that the decrease in IFN gamma correlated with the ability of EB1089, but not 25(OH)D3, to upregulate VDR. However, both compounds inhibited p-STAT1; thus the reduction of p-STAT1 is not solely responsible for IFN-gamma inhibition. Conversely, cells treated with VDR siRNA exhibited decreased basal IFN-gamma production upon VDR knockdown in a dose dependent manner. Calcitriol treatment upregulated VDR and decreased IFN-gamma regardless of initial VDR knockdown efficiency, strengthening the connection between VDR upregulation and IFN-gamma reduction. Our findings suggest multiple opportunities to further explore the clinical relevance of the vitamin D pathway and the potential role for vitamin D supplementation in T-LGLL. PMID- 28736301 TI - FOXA transcriptional factor modulates insect susceptibility to Bacillus thuringiensis Cry1Ac toxin by regulating the expression of toxin-receptor ABCC2 and ABCC3 genes. AB - Cry toxins produced by Bacillus thuringiensis (Bt) are insecticidal proteins widely used in insect control. Recently, it was shown that ATP-binding cassette transporter proteins (ABC) such as ABCC2, ABCC3, ABCG1 and ABCA2 are implicated in the insecticidal action of Cry toxins as putative receptors. However, the transcriptional regulators involved in the expression of ABC transporter genes remain unknown. Sequence analysis of promoter regions of ABCC2 gene from Helicoverpa armigera and ABCC3 gene from Spodoptera litura Sl-HP cultured cells, revealed the potential participation of Forkhead box protein A (FOXA), a transcription factor that regulates the expression of genes through remodeling chromatin. To determine if FOXA was involved in regulating expression of ABCC2 and ABCC3 genes, the expression of FOXA, ABCC2 and ABCC3 was compared in Sl-HP cells that are sensitive to Cry1Ac toxin with those in S. frugiperda Sf9 cells that are not sensitive to the toxin. Expression levels of those genes were significantly higher in Sl-HP than in Sf9 cells. Transient expression of FOXA in Sf9 cells activated ABCC2 and ABCC3 transcription, which directly correlated with enhanced Cry1Ac-susceptibility in these cells. Silencing of FOXA gene expression by RNAi in H. armigera larvae resulted in a decreased expression of ABCC2 and ABCC3 without affecting expression of other Cry toxin receptor genes such as alkaline phosphatase, aminopeptidase or cadherin. Silencing of FOXA gene expression also resulted in a Cry1Ac-tolerant phenotype since lower mortality and higher pupation rate were observed in diet containing Cry1Ac protoxin in comparison with the control group. These results demonstrate that FOXA up regulates expression of the Cry1Ac-toxin receptor ABCC2 and ABCC3 genes, and that lower FOXA expression correlates with tolerance to Cry toxin in cell lines and in lepidopteran larvae. PMID- 28736300 TI - Towards an understanding of the molecular basis of effective RNAi against a global insect pest, the whitefly Bemisia tabaci. AB - In planta RNAi against essential insect genes offers a promising route to control insect crop pests, but is constrained for many insect groups, notably phloem sap feeding hemipterans, by poor RNAi efficacy. This study conducted on the phloem feeding whitefly Bemisia tabaci reared on tomato plants investigated the causes of low RNAi efficacy and routes to ameliorate the problem. Experiments using tomato transgenic lines containing ds-GFP (green fluorescent protein) revealed that full-length dsRNA is phloem-mobile, ingested by the insects, and degraded in the insect. We identified B. tabaci homologs of nuclease genes (dsRNases) in other insects that degrade dsRNA, and demonstrated that degradation of ds-GFP in B. tabaci is suppressed by administration of dsRNA against these genes. dsRNA against the nuclease genes was co-administered with dsRNA against two insect genes, an aquaporin AQP1 and sucrase SUC1, that are predicted to protect B. tabaci against osmotic collapse. When dsRNA constructs for AQP1, SUC1, dsRNase1 and dsRNase2 were stacked, insect mortality was significantly elevated to 50% over 6 days on artificial diets. This effect was accompanied by significant reduction in gene expression of the target genes in surviving diet-fed insects. This study offers proof-of-principle that the efficacy of RNAi against insect pests can be enhanced by using dsRNA to suppress the activity of RNAi-suppressing nuclease genes, especially where multiple genes with related physiological function but different molecular function are targeted. PMID- 28736302 TI - Beyond PEGylation: Alternative surface-modification of nanoparticles with mucus inert biomaterials. AB - Mucus is a highly hydrated viscoelastic gel present on various moist surfaces in our body including the eyes, nasal cavity, mouth, gastrointestinal, respiratory and reproductive tracts. It serves as a very efficient barrier that prevents harmful particles, viruses and bacteria from entering the human body. However, the protective function of the mucus also hampers the diffusion of drugs and nanomedicines, which dramatically reduces their efficiency. Functionalisation of nanoparticles with low molecular weight poly(ethylene glycol) (PEGylation) is one of the strategies to enhance their penetration through mucus. Recently a number of other polymers were explored as alternatives to PEGylation. These alternatives include poly(2-alkyl-2-oxazolines), polysarcosine, poly(vinyl alcohol), other hydroxyl-containing non-ionic water-soluble polymers, zwitterionic polymers (polybetaines) and mucolytic enzymes. This review discusses the studies reporting the use of these polymers or potential application to facilitate mucus permeation of nanoparticles. PMID- 28736303 TI - The good and the bad collagens of fibrosis - Their role in signaling and organ function. AB - Usually the dense extracellular structure in fibrotic tissues is described as extracellular matrix (ECM) or simply as collagen. However, fibrosis is not just fibrosis, which is already exemplified by the variant morphological characteristics of fibrosis due to viral versus cholestatic, autoimmune or toxic liver injury, with reticular, chicken wire and bridging fibrosis. Importantly, the overall composition of the ECM, especially the relative amounts of the many types of collagens, which represent the most abundant ECM molecules and which centrally modulate cellular functions and physiological processes, changes dramatically during fibrosis progression. We hypothesize that there are good and bad collagens in fibrosis and that a change of location alone may change the function from good to bad. Whereas basement membrane collagen type IV anchors epithelial and other cells in a polarized manner, the interstitial fibroblast collagens type I and III do not provide directional information. In addition, feedback loops from biologically active degradation products of some collagens are examples of the importance of having the right collagen at the right place and at the right time controlling cell function, proliferation, matrix production and fate. Examples are the interstitial collagen type VI and basement membrane collagen type XVIII. Their carboxyterminal propeptides serve as an adipose tissue hormone, endotrophin, and as a regulator of angiogenesis, endostatin, respectively. We provide an overview of the 28 known collagen types and propose that the molecular composition of the ECM in fibrosis needs careful attention to assess its impact on organ function and its potential to progress or reverse. Consequently, to adequately assess fibrosis and to design optimal antifibrotic therapies, we need to dissect the molecular entity of fibrosis for the molecular composition and spatial distribution of collagens and the associated ECM. PMID- 28736304 TI - Advances in cancer stem cell targeting: How to strike the evil at its root. AB - Cancer progression to metastatic stages is still unmanageable and the promise of effective anti-metastatic therapy remains largely unmet, emphasizing the need to develop novel therapeutics. The special focus here is on cancer stem cells (CSC) as the seed of tumor initiation, epithelial-mesenchymal transition, chemoresistance and, as a consequence, drivers of metastatic dissemination. We report on targeted therapies gearing towards the CSC's internal and membrane anchored markers using agents such as antibody derivatives, nucleic therapeutics, small molecules and genetic payloads. Another emphasis lies on novel proceedings envisaged to deliver current and prospective therapies to the target sites using newest viral and non-viral vector technologies. In this review, we summarize recent progress and remaining challenges in therapeutic strategies to combat CSC. PMID- 28736305 TI - Better With Ultrasound: Pleural Procedures in Critically Ill Patients. AB - Procedures designed to drain fluid or air from the pleural spaces can be technically challenging in patients who are critically ill, and are associated with significant complications. Many individual ultrasound techniques have been described, each with the goal of making pleural drainage procedures safer. This article presents a systemic approach for incorporating many of these tools into procedures such as diagnostic thoracentesis, therapeutic drainage, and pleural catheter insertion. A series of illustrative figures and narrated video presentations are included to demonstrate many of the described techniques. PMID- 28736306 TI - Cardiac Troponin Values in Patients With Acute Coronary Syndrome and Sleep Apnea: A Pilot Study. AB - BACKGROUND: An analysis of cardiac injury markers in patients with OSA who sustain an episode of acute coronary syndrome (ACS) may contribute to a better understanding of the interactions and impact of OSA in subjects with ACS. We compared peak cardiac troponin I (cTnI) levels in patients with OSA and patients without OSA who were admitted for ACS. METHODS: Blood samples were collected every 6 hours from the time of admission until two consecutive assays showed a downward trend in the cTnI assay. The highest value obtained defined the peak cTnI value, which provides an estimate of infarct size. RESULTS: We included 89 patients with OSA and 38 patients without OSA with an apnea-hypopnea index of a median of 32 (interquartile range [IQR], 20.8-46.6/h and 4.8 [IQR, 1.6-9.6]/h, respectively. The peak cTnI value was significantly higher in patients without OSA than in patients with OSA (median, 10.7 ng/mL [IQR, 1.78-40.1 ng/mL] vs 3.79 ng/mL [IQR, 0.37-24.3 ng/mL]; P = .04). The multivariable linear regression analysis of the relationship between peak cTnI value and patient group, age, sex, and type of ACS showed that the presence or absence of OSA significantly contributed to the peak cTnI level, which was 54% lower in patients with OSA than in those without OSA. CONCLUSIONS: The results of this study suggest that OSA has a protective effect in the context of myocardial infarction and that patients with OSA may experience less severe myocardial injury. The possible role of OSA in cardioprotection should be explored in future studies. PMID- 28736307 TI - Local striatal reward signals can be predicted from corticostriatal connectivity. AB - A defining feature of the basal ganglia is their anatomical organization into multiple cortico-striatal loops. A central tenet of this architecture is the idea that local striatal function is determined by its precise connectivity with cortex, creating a functional topography that is mirrored within cortex and striatum. Here we formally test this idea using both human anatomical and functional imaging, specifically asking whether within striatal subregions one can predict between-voxel differences in functional signals based on between voxel differences in corticostriatal connectivity. We show that corticostriatal connectivity profiles predict local variation in reward signals in bilateral caudate nucleus and putamen, expected value signals in bilateral caudate nucleus, and response effector activity in bilateral putamen. These data reveal that, even within individual striatal regions, local variability in corticostriatal anatomical connectivity predicts functional differentiation. PMID- 28736309 TI - Neural interactions mediating conflict control and its training-induced plasticity. AB - Cognitive control is of great plasticity. Training programs targeted on improving it have been suggested to yield neural changes in the brain. However, until recently, the relationship between training-induced brain changes and improvements in cognitive control is still an open issue. Besides, although the literature has attributed the operation of cognitive control to interactions between large-scale networks, the neural pathways directly associated with it remain unclear. The current study aimed to examine these issues by focusing on conflict processing. In particular, we employed a training program with a randomized controlled design. The main findings were as follows: 1) In behavior, the training group showed reduced conflict effect after training, relative to the control group; 2) In the pretest stage, the behavioral conflict effect was negatively correlated with a number of neural pathways, including the connectivity from the cingulo-opercular network (CON) to the cerebellum and to sub-regions of the dorsal visual network; 3) increase in the connectivity strength of several network interactions, such as the connectivity from the CON to the cerebellum and to the primary visual network, was associated with behavioral gains; 4) there were also nonlinear correlations between behavioral and neural changes. These findings highlighted a critical role of the modulation of CON on other networks in mediating conflict processing and its plasticity, and raised the significance of investigating nonlinear relationship in the field of cognitive training. PMID- 28736310 TI - Non-BOLD contrast for laminar fMRI in humans: CBF, CBV, and CMRO2. AB - Functional magnetic resonance imaging (fMRI) using the blood oxygenation level dependent (BOLD) contrast indirectly probes neuronal activity changes via evoked cerebral blood flow (CBF), cerebral blood volume (CBV) and cerebral metabolic rate of oxygen (CMRO2) changes. The gradient-echo BOLD signal is mostly sensitive to ascending veins in the tissue and to pial veins. Thereby, the achievable spatial specificity to neuronal activation is limited. Furthermore, the non linear interaction of CBF, CBV and CMRO2 can hamper quantitative interpretations of the BOLD signal across cortical depths with different baseline physiology. Measuring CBF, CBV or CMRO2 directly on a depth-dependent level has the potential to overcome these limitations. Here, we review these candidates of physiologically well-defined contrasts with the particular focus on arterial spin labeling (ASL), vascular space occupancy (VASO) and calibrated fMRI. These methods are reviewed with respect to their fMRI sequence parameter space and the applicability for neuroscientific studies in humans. We show representative results of depth-dependent 'non-BOLD-fMRI' in humans and their spatiotemporal characteristics. We conclude that non-BOLD methods are promising alternatives compared to conventional fMRI as they can provide improved spatial specificity, quantifiability and, hence, physiological interpretability as a function of cortical depth. At submillimeter resolution with inherently low signal-to-noise ratio (SNR), however, their use is still challenging. Nevertheless, we believe that 'non-BOLD-fMRI' is a useful alternative for depth-dependent investigations, by providing valuable insights into neurovascular coupling models that facilitate the interpretability of fMRI for neuroscientific applications. PMID- 28736308 TI - Laminar fMRI: What can the time domain tell us? AB - The rapid developments in functional MRI (fMRI) acquisition methods and hardware technologies in recent years, particularly at high field (>=7 T), have enabled unparalleled visualization of functional detail at a laminar or columnar level, bringing fMRI close to the intrinsic resolution of brain function. These advances highlight the potential of high resolution fMRI to be a valuable tool to study the fundamental processing performed in cortical micro-circuits, and their interactions such as feedforward and feedback processes. Notably, because fMRI measures neuronal activity via hemodynamics, the ultimate resolution it affords depends on the spatial specificity of hemodynamics to neuronal activity at a detailed spatial scale, and by the evolution of this specificity over time. Several laminar (<=1 mm spatial resolution) fMRI studies have examined spatial characteristics of the measured hemodynamic signals across cortical depth, in light of understanding or improving the spatial specificity of laminar fMRI. Few studies have examined temporal features of the hemodynamic response across cortical depth. Temporal features of the hemodynamic response offer an additional means to improve the specificity of fMRI, and could help target neuronal processes and neurovascular coupling relationships across laminae, for example by differences in the onset times of the response across cortical depth. In this review, we discuss factors that affect the timing of neuronal and hemodynamic responses across laminae, touching on the neuronal laminar organization, and focusing on the laminar vascular organization. We provide an overview of hemodynamics across the cortical vascular tree based on optical imaging studies, and review temporal aspects of hemodynamics that have been examined across cortical depth in high spatiotemporal resolution fMRI studies. Last, we discuss the limits and potential of high spatiotemporal resolution fMRI to study laminar neurovascular coupling and neuronal processes. PMID- 28736312 TI - Resting state functional connectivity correlates of emotional awareness. AB - Multiple neuroimaging studies have now linked emotional awareness (EA), as measured by the Levels of Emotional Awareness Scale (LEAS), with activation in regions of neural networks associated with both conceptualization (i.e., default mode network [DMN] regions) and interoception (i.e., salience network [SN] regions) - consistent with the definition of EA as one's ability to appropriately recognize, conceptualize, and articulate the emotions of self and other in fine grained, differentiated ways. However, no study has yet tested the hypothesis that greater LEAS scores are associated with greater resting state functional connectivity (FC) within these networks. Twenty-six adults (13 female) underwent resting state functional magnetic resonance imaging, and also completed the LEAS. Using pre-defined functional ROIs from the DMN and SN, we observed that LEAS scores were significantly positively correlated with FC between several regions of both of these networks, even when controlling for differences in general intelligence (IQ). These results suggest that higher EA may be associated with more efficient information exchange between brain regions involved in both interoception- and conceptualization-based processing, which could plausibly contribute to more differentiated bodily feelings and more fine-grained conceptualization of those feelings. PMID- 28736313 TI - Editorial. PMID- 28736311 TI - Imaging-wide association study: Integrating imaging endophenotypes in GWAS. AB - A new and powerful approach, called imaging-wide association study (IWAS), is proposed to integrate imaging endophenotypes with GWAS to boost statistical power and enhance biological interpretation for GWAS discoveries. IWAS extends the promising transcriptome-wide association study (TWAS) from using gene expression endophenotypes to using imaging and other endophenotypes with a much wider range of possible applications. As illustration, we use gray-matter volumes of several brain regions of interest (ROIs) drawn from the ADNI-1 structural MRI data as imaging endophenotypes, which are then applied to the individual-level GWAS data of ADNI-GO/2 and a large meta-analyzed GWAS summary statistics dataset (based on about 74,000 individuals), uncovering some novel genes significantly associated with Alzheimer's disease (AD). We also compare the performance of IWAS with TWAS, showing much larger numbers of significant AD-associated genes discovered by IWAS, presumably due to the stronger link between brain atrophy and AD than that between gene expression of normal individuals and the risk for AD. The proposed IWAS is general and can be applied to other imaging endophenotypes, and GWAS individual-level or summary association data. PMID- 28736314 TI - Expression and purification of single cysteine-containing mutant variants of the mouse prion protein by oxidative refolding. AB - The folding and aggregation of proteins has been studied extensively, using multiple probes. To facilitate such experiments, introduction of spectroscopically-active moieties in to the protein of interest is often necessary. This is commonly achieved by specifically labelling cysteine residues in the protein, which are either present naturally or introduced artificially by site-directed mutagenesis. In the case of the recombinant prion protein, which is normally expressed in inclusion bodies, the presence of the native disulfide bond complicates the correct refolding of single cysteine-containing mutant variants of the protein. To overcome this major bottleneck, a simple purification strategy for single tryptophan, single cysteine-containing mutant variants of the mouse prion protein is presented, with yields comparable to that of the wild type protein. The protein(s) obtained by this method are correctly folded, with a single reduced cysteine, and the native disulfide bond between residues C178 and C213 intact. The beta-sheet rich oligomers formed from these mutant variant protein(s) are identical to the wild type protein oligomer. The current strategy facilitates sample preparation for a number of high resolution spectroscopic measurements for the prion protein, which specifically require thiol labelling. PMID- 28736315 TI - The Spectrum of Triple-Negative Breast Disease: High- and Low-Grade Lesions. AB - Triple-negative breast cancer is viewed clinically as an aggressive subgroup of breast cancer. In fact, most triple-negative breast cancers are poor-prognosis tumors with a complex genomic landscape. However, triple-negative disease is vastly heterogeneous, encompassing multiple entities with marked genetic, transcriptional, histologic, and clinical differences, with neoplasms in this group ranging from low to high grade. Among the less common low-grade triple negative lesions, two large subgroups, both with a rather indolent behavior, can be distinguished: a low-grade triple-negative breast neoplasia family, which includes nonobligate precursors of triple-negative breast cancer, and, despite being low-grade, harbors the complex genomic landscape of usual triple-negative breast cancer, and the salivary gland-like tumors of the breast, lacking all the cardinal molecular features of conventional triple-negative breast cancer and underpinned by specific fusion genes or hotspot mutations, which may be of diagnostic and possibly therapeutic utility. Progression to high-grade triple negative breast cancer likely occurs in both subgroups but at different rates. In this review, we describe the heterogeneity of triple-negative disease, focusing on the histologic and molecular features of the low-grade lesions. Recognition that triple-negative breast cancer is an operational term and that triple negative disease is heterogeneous and includes low-grade forms driven by distinct sets of genetic alterations is germane to the successful implementation of precision medicine. PMID- 28736317 TI - Next-Generation Proteomics and Its Application to Clinical Breast Cancer Research. AB - Proteomics technology aims to map the protein landscapes of biological samples, and it can be applied to a variety of samples, including cells, tissues, and body fluids. Because the proteins are the main functional molecules in the cells, their levels reflect much more accurately the cellular phenotype and the regulatory processes within them than gene levels, mutations, and even mRNA levels. With the advancement in the technology, it is possible now to obtain comprehensive views of the biological systems and to study large patient cohorts in a streamlined manner. In this review we discuss the technological advancements in mass spectrometry-based proteomics, which allow analysis of breast cancer tissue samples, leading to the first large-scale breast cancer proteomics studies. Furthermore, we discuss the technological developments in blood-based biomarker discovery, which provide the basis for future development of assays for routine clinical use. Although these are only the first steps in implementation of proteomics into the clinic, extensive collaborative work between these worlds will undoubtedly lead to major discoveries and advances in clinical practice. PMID- 28736316 TI - Early Actions of Anti-Vascular Endothelial Growth Factor/Vascular Endothelial Growth Factor Receptor Drugs on Angiogenic Blood Vessels. AB - Tumors induce their heterogeneous vasculature by secreting vascular endothelial growth factor (VEGF)-A. Anti-VEGF/VEGF receptor (VEGFR) drugs treat cancer, but the underlying mechanisms remain unclear. An adenovirus expressing VEGF-A (Ad VEGF-A164) replicates the tumor vasculature in mice without tumor cells. Mother vessels (MV) are the first angiogenic vessel type to form in tumors and after Ad VEGF-A164. Multiday treatments with a VEGF trap reverted MV back to normal microvessels. We now show that, within hours, a single dose of several anti-VEGF drugs collapsed MV to form glomeruloid microvascular proliferations (GMP), accompanied by only modest endothelial cell death. GMP, common in many human cancers but of uncertain origin, served as an intermediary step in MV reversion to normal microvessels. The vasodisruptive drug combretastatin CA4 also targeted MV selectively but acted differently, extensively killing MV endothelium. Antivascular changes were quantified with a novel Evans blue dye assay that measured vascular volumes. As in tumors, Ad-VEGF-A164 strikingly increased endothelial nitric oxide synthase (eNOS) expression. The eNOS inhibitor N(G) Nitro-l-arginine methyl ester mimicked anti-VEGF/VEGFR drugs, rapidly collapsing MV to GMP. Inhibition of eNOS reduces synthesis of its vasodilatory product, nitric oxide, leading to arterial contraction. Patients and mice receiving anti VEGF/VEGFR drugs develop hypertension, reflecting systemic arterial contraction. Together, anti-VEGF/VEGFR drugs act in part by inhibiting eNOS, causing vasocontraction, MV collapse to GMP, and subsequent reversion of GMP to normal microvessels, all without extensive vascular killing. PMID- 28736319 TI - Robotic Ureteroplasty with Buccal Mucosa Graft for the Management of Complex Ureteral Strictures. AB - PURPOSE: Surgical management of proximal and mid ureteral strictures that are not amenable to primary excision and anastomosis is challenging. Although a buccal mucosa graft is commonly used during substitution urethroplasty, its use in substitution ureteroplasty is limited. We describe our technique of robotic ureteroplasty with a buccal mucosa graft to manage complex ureteral strictures and we report our outcomes. MATERIALS AND METHODS: We retrospectively reviewed the records of 12 patients who underwent robotic ureteroplasty with a buccal mucosa graft between September 2014 and June 2016. The indication for the procedure was a proximal or mid ureteral stricture not amenable to primary excision and anastomosis. The primary outcomes were clinical success, absent symptoms on ureteral pathology and radiological success, defined as absent ureteral obstruction on retrograde pyelography, renal scan and/or computerized tomography. RESULTS: Four of the 12 patients (33.3%) had a ureteropelvic junction stricture, 4 (33.3%) had a proximal stricture and 4 (33.3%) had a mid ureteral stricture. Eight of the 12 patients (66.7%) had previously undergone failed ureteral reconstruction. Median stricture length was 3 cm (range 2 to 5). Median operative time was 217 minutes (range 136 to 344) and mean estimated blood loss was 100 ml (range 50 to 200). Median length of stay was 1 day (range 1 to 6). At a median followup of 13 months (range 4 to 30) 10 of the 12 cases (83.3%) were clinically and radiologically successful. CONCLUSIONS: Robotic ureteroplasty with a buccal mucosa graft is associated with low inherent morbidity. It is an effective way to manage complex proximal and mid ureteral strictures. PMID- 28736318 TI - Prostate Specific Membrane Antigen Targeted 18F-DCFPyL Positron Emission Tomography/Computerized Tomography for the Preoperative Staging of High Risk Prostate Cancer: Results of a Prospective, Phase II, Single Center Study. AB - PURPOSE: We prospectively evaluated the diagnostic performance of prostate specific membrane antigen targeted 18F-DCFPyL positron emission tomography/computerized tomography in the preoperative staging of men at high risk for harboring metastatic prostate cancer despite a negative conventional staging evaluation. MATERIALS AND METHODS: Men with clinically localized high or very high risk prostate cancer were imaged with 18F-DCFPyL positron emission tomography/computerized tomography before undergoing radical prostatectomy with standardized pelvic lymph node dissection. The scans were interpreted by 2 blinded nuclear medicine readers and assessed for interreader variability as well as diagnostic accuracy for pelvic lymph node staging. Surgical pathology served as the reference standard to which 18F-DCFPyL scan findings were compared. RESULTS: A total of 25 men contributed analyzable data to this study. Seven of these patients (28%) were found to have 1 or more positive lymph nodes on surgical pathology. Sites of radiotracer uptake were identified in the prostate of all imaged patients. The 2 readers identified the same number of prostatic lesions in 22 patients (88%), of whom all had at least 1 intraprostatic lesion in common between the 2 reads. Additionally, the readers assigned the same N stage to 46 of 50 individual lymph node packets (92%). Following reconciliation of the relatively few discordant imaging reads, 7 patients (28%) were found to have 1 or more sites of radiotracer uptake in the pelvis consistent with N1 disease, resulting in 71.4% sensitivity (95% CI 29.0-96.3) and 88.9% specificity (95% CI 65.3-98.6). Analysis at the level of individual nodal packets resulted in 66.7% sensitivity (95% CI 29.9-92.5) and 92.7% specificity (95% CI 80.1-98.5). Three men (12%) had evidence of M1a disease. CONCLUSIONS: 18F-DCFPyL positron emission tomography/computerized tomography allowed for accurate detection of prostate cancer sites in men believed to have clinically localized disease based on conventional imaging. Our results support the need for a larger study to more precisely define the diagnostic accuracy of this novel molecular imaging test. PMID- 28736320 TI - Comparison of Urinary Tract Infection Rates Associated with Transurethral Catheterization, Suprapubic Tube and Clean Intermittent Catheterization in the Postoperative Setting: A Network Meta-Analysis. AB - PURPOSE: We performed a network meta-analysis of available randomized, controlled trials to elucidate the risks of urinary tract infection associated with transurethral catheterization, suprapubic tubes and intermittent catheterization in the postoperative setting. MATERIALS AND METHODS: PubMed(r), EMBASE(r) and Google ScholarTM searches were performed for eligible randomized, controlled trials from January 1980 to July 2015 that included patients who underwent transurethral catheterization, suprapubic tube placement or intermittent catheterization at the time of surgery and catheterization lasting up to postoperative day 30. The primary outcome of comparison was the urinary tract infection rate via a network meta-analysis with random effects model using the netmeta package in R 3.2 (www.r-project.org/). RESULTS: Included in analysis were 14 randomized, controlled trials in a total of 1,391 patients. Intermittent catheterization and suprapubic tubes showed no evidence of decreased urinary tract infection rates compared to transurethral catheterization. Suprapubic tubes and intermittent catheterization had comparable urinary tract infection rates (OR 0.903, 95% CI 0.479-2.555). On subgroup analysis of 10 randomized, controlled trials with available mean catheterization duration data in a total of 928 patients intermittent catheterization and suprapubic tube were associated with significantly decreased risk of urinary tract infection compared to transurethral catheterization when catheterization duration was greater than 5 days (OR 0.173, 95% CI 0.073-0.412 and OR 0.142, 95% CI 0.073-0.276, respectively). CONCLUSIONS: Transurethral catheterization is not associated with an increased urinary tract infection risk compared to suprapubic tubes and intermittent catheterization if catheterization duration is 5 days or less. However, a suprapubic tube or intermittent catheterization is associated with a lower rate of urinary tract infection if longer term catheterization is expected in the postoperative period. PMID- 28736321 TI - An Intraprostatic Modified Release Formulation of Antiandrogen 2-Hydroxyflutamide for Localized Prostate Cancer. AB - PURPOSE: We investigated the tolerability, safety and antitumor effects of a novel intraprostatic depot formulation of antiandrogen 2-hydroxyflutamide (in NanoZolid(r)) in men with localized prostate cancer. MATERIALS AND METHODS: Two clinical trials, LPC-002 and LPC-003, were performed in a total of 47 men. The formulation was injected transrectally into the prostate under ultrasound guidance. In LPC-002 the effects on prostate specific antigen and prostate volume were measured for 6 months in 24 patients. In LPC-003 antitumor effects were evaluated by histopathology and magnetic resonance imaging including spectroscopy during 6 or 8 weeks in 23 patients. In each study testosterone and 2 hydroxyflutamide in plasma were measured as well as quality of life parameters. RESULTS: In LPC-002 (mean dose 690 mg) a reduction was observed in prostate specific antigen and prostate volume. Average nadir prostate specific antigen and prostate volume were 24.9% and 14.0% below baseline, respectively. When increasing the dose in LPC-003 to 920 and 1,740 mg, average prostate specific antigen decreased 16% and 23% after 6 and 8 weeks, respectively. Magnetic resonance imaging and magnetic resonance spectroscopy showed morphological changes and a global reduction in metabolite concentrations following treatment, indicating an antitumor response. Injections did not result in hormone related side effects. Three serious adverse events were reported and all resolved with oral antibiotic treatment. CONCLUSIONS: Intraprostatic injections of 2 hydroxyflutamide depot formulations showed antitumor effects, and proved to be safe and tolerable. However, for better anticancer effects higher doses and better dose distribution are suggested. PMID- 28736322 TI - Clinical Outcomes of Chemotherapy Naive Men with Metastatic Castration Resistant Prostate Cancer and Low Baseline Prostate Specific Antigen Treated with Enzalutamide vs Placebo. AB - PURPOSE: Metastatic castration resistant prostate cancer with low baseline prostate specific antigen represents an early stage in the natural history of castration resistant prostate cancer progression (low volume disease), low prostate specific antigen producing disease or disease that is less dependent on androgen receptor biology (high volume disease). We analyzed outcomes in men with low prostate specific antigen and a high disease burden who received the oral androgen receptor inhibitor enzalutamide in the PREVAIL (Safety and Efficacy Study of Oral MDV3100 in Chemotherapy-Naive Patients with Progressive Metastatic Prostate Cancer) study. MATERIALS AND METHODS: In this exploratory analysis low baseline prostate specific antigen was defined as less than 10 ng/ml. Post hoc analyses included radiographic progression-free and overall survival in the once daily enzalutamide and placebo arms. Patients were stratified post hoc by high volume disease, defined as more than 4 bone metastases and/or visceral disease, and low volume disease, defined as 4 or fewer bone metastases with no visceral disease. RESULTS: Of 1,717 patients enrolled in PREVAIL 242 (14.1%) had low baseline prostate specific antigen, including 110 with high volume disease. Enzalutamide decreased the risk of radiographic progression relative to placebo in patients with low baseline prostate specific antigen (HR 0.20, 95% CI 0.10 0.42). This decrease was irrespective of tumor burden (high volume disease HR 0.17, 95% CI 0.06-0.51 and low volume disease HR 0.25, 95% CI 0.09-0.70). Median overall survival was not reached in patients with low baseline prostate specific antigen in either treatment arm. CONCLUSIONS: Chemotherapy naive men with metastatic castration resistant prostate cancer and low baseline prostate specific antigen irrespective of disease burden may benefit from enzalutamide. This indicates that targeting the androgen receptor signaling pathway is a therapeutic option in similar patients. PMID- 28736323 TI - Offspring neuroimmune consequences of maternal malnutrition: Potential mechanism for behavioral impairments that underlie metabolic and neurodevelopmental disorders. AB - Maternal malnutrition significantly increases offspring risk for both metabolic and neurodevelopmental disorders. Animal models of maternal malnutrition have identified behavioral changes in the adult offspring related to executive function and reward processing. Together, these changes in executive and reward based behaviors likely contribute to the etiology of both metabolic and neurodevelopmental disorders associated with maternal malnutrition. Concomitant with the behavioral effects, maternal malnutrition alters offspring expression of reward-related molecules and inflammatory signals in brain pathways that control executive function and reward. Neuroimmune pathways and microglial interactions in these specific brain circuits, either in early development or later in adulthood, could directly contribute to the maternal malnutrition-induced behavioral phenotypes. Understanding these mechanisms will help advance treatment strategies for metabolic and neurodevelopmental disorders, especially noninvasive dietary supplementation interventions. PMID- 28736325 TI - Traumatic Neuropathy of the Trigeminal Nerve in a College Trumpet Player: A Case Report. AB - : A 20-year-old college trumpet player presented with a 3-month history of upper lip numbness and worsening playing ability after a marching band performance. Examination demonstrated anesthesia of the upper lip that followed the borders of the trumpet mouthpiece. While playing, the patient had poor range and an airy tone quality. A prescription of complete embouchure rest for 6 weeks and a tailored return to play regimen resulted in resolution of upper lip numbness and improved trumpet playing. Neuropathy of the lip in a brass player is uncommon but highlights the uniqueness of injuries that may be sustained by performing artists. LEVEL OF EVIDENCE: V. PMID- 28736324 TI - Survival and neurological outcome in the elderly after in-hospital cardiac arrest. AB - BACKGROUND: There have been few studies of the outcome in elderly patients who have suffered in-hospital cardiac arrest (IHCA) and the association between cardiac arrest characteristics and survival. AIM: The aim of this large observational study was to investigate the survival and neurological outcome in the elderly after IHCA, and to identify which factors were associated with survival. METHODS: We investigated elderly IHCA patients (>=70years of age) who were registered in the Swedish Cardiopulmonary Resuscitation Registry 2007-2015. For descriptive purposes, the patients were grouped according to age (70-79, 80 89, and >=90years). Predictors of 30-day survival were identified using multivariable analysis. RESULTS: Altogether, 11,396 patients were included in the study. Thirty-day survival was 28% for patients aged 70-79 years, 20% for patients aged 80-89 years, and 14% for patients aged >=90years. Factors associated with higher survival were: patients with an initially shockable rhythm, IHCA at an ECG-monitored location, IHCA was witnessed, IHCA during daytime (8 a.m.-8 p.m.), and an etiology of arrhythmia. A lower survival was associated with a history of heart failure, respiratory insufficiency, renal dysfunction and with an etiology of acute pulmonary oedema. Patients over 90 years of age with VF/VT as initial rhythm had a 41% survival rate. We found a trend indicating a less aggressive care with increasing age during cardiac arrest (fewer intubations, and less use of adrenalin and anti-arrhythmic drugs) but there was no association between age and delay in starting cardiopulmonary resuscitation (CPR). In survivors, there was no significant association between age and a favourable neurological outcome (CPC score: 1-2) (92%, 93%, and 88% in the three age groups, respectively). CONCLUSIONS: Increasing age among the elderly is associated with a lower 30-day survival after IHCA. Less aggressive treatment and a worse risk profile might contribute to these findings. Relatively high survival rates among certain subgroups suggest that discussions about advanced directives should be individualized. Most survivors have good neurological outcome, even patients over 90 years of age. PMID- 28736326 TI - Tone-Inhibiting Insoles Enhance the Reciprocal Inhibition of Ankle Plantarflexors of Subjects With Hemiparesis After Stroke: An Electromyographic Study. AB - BACKGROUND: Spasticity is a common sequela of upper motor neuron pathology, such as cerebrovascular diseases and cerebral palsy. Intervention for spasticity of the ankle plantarflexors in physical therapy may include tone-inhibiting casting and/or orthoses for the ankle and foot. However, the physiological mechanism of tone reduction by such orthoses remains unclarified. OBJECTIVE: To investigate the electrophysiologic effects of tone-inhibiting insoles in stroke subjects with hemiparesis by measuring changes in reciprocal Ia inhibition (RI) in the ankle plantarflexor. DESIGN: An interventional before-after study. SETTING: Acute stroke unit or ambulatory rehabilitation clinic of a university hospital in Japan. PARTICIPANTS: Ten subjects (47-84 years) with hemiparesis and 10 healthy male control subjects (31-59 years) were recruited. METHODS: RI of the spastic soleus in response to the electrical stimulation of the deep peroneal nerve was evaluated by stimulus-locked averaging of rectified electromyography (EMG) of the soleus while subjects were standing. MAIN OUTCOME MEASUREMENTS: The magnitude of RI, defined as the ratio of the lowest to the baseline amplitude of the rectified EMG at approximately 40 milliseconds after stimulation, was measured while subjects were standing with and without the tone-inhibiting insole on the hemiparesis side. RESULTS: Enhancement of EMG reduction with the tone-inhibiting insole was significant (P < .05) in the subjects with hemiparesis, whereas no significant changes were found in controls. CONCLUSION: Tone-inhibiting insoles enhanced RI of the soleus in subjects after stroke, which might enhance standing stability by reducing unfavorable ankle plantarflexion tone. LEVEL OF EVIDENCE: III. PMID- 28736327 TI - Within-Session and Between-Session Reliability, Construct Validity, and Comparison Between Individuals With and Without Neck Pain of Four Neck Muscle Tests. AB - BACKGROUND: A variety of tests have been proposed to measure the performance of neck flexor muscles, but head-to-head comparisons hardly have been documented. OBJECTIVE: To compare reliability indexes, construct validity, and ability to discriminate between individuals with and without neck pain of 4 muscle tests (deep neck flexors endurance test [DNFET]; 2 variations of the craniocervical flexion test [CCFT1 and CCFT2]; and dynamometry). DESIGN: Reliability and validity study. SETTING: General community. PARTICIPANTS: A total of 66 participants, 33 with chronic idiopathic neck pain (mean +/- standard deviation pain intensity: 3.2 +/- 1.9) and 33 without neck pain, from the general population. METHODS/MAIN OUTCOME: Neck muscle functioning was assessed with the CCFT1, the CCFT2, the DNFET, and dynamometry on 2 separate sessions. Participants with neck pain also were assessed for pain intensity, disability, pain catastrophizing, and fear of movement. RESULTS: Relative reliability of all tests was at least moderate (intraclass correlation coefficient >= 0.62), whereas measurement error was high, particularly for the DNFET (95% minimum detectable change >= 23.00 seconds). All tests showed moderate correlation (r >= 0.3) with at least 2 pain-related measures and moderate-to-strong correlations with each other. Principal component analysis retained 2 factors explaining 68%-73% of the variance of the 4 muscle tests. Significant differences between groups were found for the DNFET and dynamometry (P < .05). CONCLUSION: The reliability indexes suggest that the DNFET and the CCFT may be more appropriate for group comparisons than for individual comparisons. The 4 tests seem to have construct validity, but they also seem to measure slightly different constructs. LEVEL OF EVIDENCE: III. PMID- 28736328 TI - Down regulation of miR-143 promotes radiation - Induced thymic lymphoma by targeting B7H1. AB - MicroRNA-143 has been implicated in tumor metastasis by directly targeting Bcl-2, and microRNA-143 expression is decreased in several human tumors. However, the expression and targets of miR-143 in radiation carcinogenesis remain unclear. We found that the expression of miR-143 is down-regulated and the expression of B7H1 (Pdcd1) is up-regulated in radiation-induced thymic lymphoma model in BALB/c mice. Additionally, overexpression of miR-143 strongly inhibited cell proliferation and increased cell apoptosis and its down-regulation promoted cell proliferation and reduced cell apoptosis. We also determined that there is an inverse correlation between miR-143 expression and B7H1 protein expression in radiation-induced thymic lymphoma samples, and miR-143 targets B7H1 in a 3'UTR dependent manner. In addition, we found that adenovirus over-expression of pre miR-143 reduced tumorigenesis in vivo. Finally, we conclude that down-regulated expression of miR-143 and up-regulation of its direct target B7H1 may indicate a novel therapeutic method for radiation-induced thymic lymphoma by increased expression of miR-143 or inhibition of B7H1. PMID- 28736329 TI - Cord blood eicosanoid signatures and newborn gestational age. AB - Beyond prostaglandins, the function of eicosanoids and other oxylipins in pregnancy and labor is poorly understood. In contrast to earlier work focusing on preterm infants, we investigated how oxylipin levels in newborns (measured in cord blood) vary during the last weeks of pregnancy in 190 mother-newborns (>=37 weeks of gestation) of the ENVIRONAGE birth cohort, Belgium. We found increased levels of PGE2 (p=0.003), PGF2alpha (p=0.042), 8,9-DHET (p=0.037), 11-HETE (p=0.034), and 15-HETrE (p=0.008) associated with full term pregnancy compared to early term labor. Furthermore, late vs early term was associated with increased levels of PGE2 (p=0.012) and TXB2 (p=0.033), while late vs full term was associated with decreased levels of 14,15-DHET (p=0.029), 11,12-DHET (p=0.033), and 5-HETE (p=0.045). To summarize, nine eicosanoids, derived via three enzymatic pathways, were significantly associated with gestational age. Eight of these were derived from arachidonic acid, and one from dihomo-gamma-linolenic acid. PMID- 28736330 TI - Impaired microglia fractalkine signaling affects stress reaction and coping style in mice. AB - Microglia, resident immune cells of the CNS are sensitive to various perturbations of the environment, such as stress exposure, and may be involved in translating these changes to behavior. Among the pathways mediating stress related neuronal cues to microglia, the fractalkine-fractalkine receptor (CX3CR1) signaling plays a crucial role. Using mice, in which the CX3CR1 gene was deleted, we explored hormonal and behavioral responses to acute and chronic stress along with changes in hypothalamic microglia. CX3CR1-/- animals display active escape in forced swim- and tail suspension tests, exaggerated neuronal activation in the hypothalamic paraventricular nucleus and increased corticosterone release in response to restraint. Analysis of Iba1 immunostaining of hypothalamic sections revealed stress-related reduction of microglia in CX3CR1-/- mice. Because microglia also contribute to energy balance regulation, we characterized metabolic phenotype of CX3CR1-/- mice. Comparison of respiratory exchange ratio did not show genotype effect on fuel preference, however, the energy expenditure was increased in CX3CR1-/- mice, which may be related to their active coping behavior. Microglia and fractalkine signaling has been repeatedly shown to be involved chronic stress-induced depressive state. CX3CR1-/- mice did not become anhedonic in the "two hit" chronic stress paradigm, confirming resistance of these animals to chronic stress-induced mood alterations. However, there was no difference in stress hormone levels, open field performance and hypothalamic microglia distribution between the genotypes. These results highlight differential involvement of microglia fractalkine signaling in controlling/integrating hormonal-, metabolic and behavioral responses to acute and chronic stress challenges. PMID- 28736331 TI - Microbial regulation of hippocampal miRNA expression: Implications for transcription of kynurenine pathway enzymes. AB - Increasing evidence points to a functional role of the enteric microbiota in brain development, function and behaviour including the regulation of transcriptional activity in the hippocampus. Changes in CNS miRNA expression may reflect the colonisation status of the gut. Given the pivotal impact of miRNAs on gene expression, our study was based on the hypothesis that gene expression would also be altered in the germ-free state in the hippocampus. We measured miRNAs in the hippocampus of Germ free (GF), conventional (C) and Germ free colonised (exGF) Swiss Webster mice. miRNAs were selected for follow up based on significant differences in expression between groups according to sex and colonisation status. The expression of miR-294-5p was increased in male germ free animals and was normalised following colonisation. Targets of the differentially expressed miRNAs were over-represented in the kynurenine pathway. We show that the microbiota modulates the expression of miRNAs associated with kynurenine pathway metabolism and, demonstrate that the gut microbiota regulates the expression of kynurenine pathway genes in the hippocampus. We also show a sex specific role for the microbiota in the regulation of miR-294-5p expression in the hippocampus. The gut microbiota plays an important role in modulating small RNAs that influence hippocampal gene expression, a process critical to hippocampal development. PMID- 28736332 TI - 5-Hydroxytryptamine 2A receptors of the dorsal raphe nucleus modulate panic-like behaviours and mediate fear-induced antinociception elicited by neuronal activation in the central nucleus of the inferior colliculus. AB - It has been established that chemical stimulation of the inferior colliculus (IC) of laboratory animals evokes fear-related defensive responses, which are considered panic attack-like behaviours. In addition, there is evidence that defensive reactions provoked by chemical stimulation of midbrain tectum neurons may induce an antinociceptive response. Morphologically, the IC receives projections from other mesencephalic structures, such as the dorsal raphe nucleus (DRN), a region rich in serotonergic neurons that play a critical role in the control of defensive behaviours. Moreover, this monoaminergic brainstem reticular nucleus is suggested to comprise the endogenous pain modulatory system. The aim of the present study was to investigate the role of DRN 5-hydroxytryptamine 2A (5 HT2A) receptors in Wistar rats by local microinjection of R-96544 (a selective antagonist of the 5-HT2A receptor) at doses of 5, 10 or 15nM on defensive reactions and fear-induced antinociception evoked by chemical stimulation of the central nucleus of the IC with NMDA (6, 9 or 12 nmol). Behavioural responses were analysed for 10min, and then the nociceptive threshold was measured at 10min intervals for 70min. The dose of 12nmol of NMDA was the most effective in causing panic attack-like defensive behaviours and much higher hypoalgesia. In addition, both effects were attenuated by pretreatment of the DRN with R-96544. These findings suggest the critical participation of DRN 5-HT2A receptors in the modulation of panic attack-like defensive behaviour and unconditioned fear induced antinociception organised by neurons in the central nucleus of the IC. PMID- 28736333 TI - Synthesis and characterization of a multifunctional gold-doxorubicin nanoparticle system for pH triggered intracellular anticancer drug release. AB - A nanoparticle drug carrier system has been developed to alter the cellular uptake and chemotherapeutic performance of an available chemotherapeutic drug. The system comprises of a multifunctional gold nanoparticle based drug delivery system (Au-PEG-PAMAM-DOX) as a novel platform for intracellular delivery of doxorubicin (DOX). Spherical gold nanoparticles were synthesized by a gold chloride reduction, stabilized with thiolated polyethylene glycol (PEG) and then covalently coupled with a polyamidoamine (PAMAM) G4 dendrimer. Further, conjugation of an anti-cancer drug doxorubicin to the dendrimer via amide bond resulted in Au-PEG-PAMAM-DOX drug delivery system. Acellular drug release studies proved that DOX released from Au-PEG-PAMAM-DOX at physiological pH was negligible but it was significantly increased at a weak acidic milieu. The intracellular drug release was monitored with confocal laser scanning microscopy analysis. In vitro viability studies showed an increase in the associated doxorubicin cytotoxicity not attributed to carrier components indicating the efficiency of the doxorubicin was improved, upon conjugation to the nano system. As such it is postulated that the developed pH triggered multifunctional doxorubicin-gold nanoparticle system, could lead to a promising platform for intracellular delivery of variety of anticancer drugs. PMID- 28736334 TI - TFOS DEWS II Introduction. PMID- 28736335 TI - TFOS DEWS II Definition and Classification Report. AB - The goals of the TFOS DEWS II Definition and Classification Subcommittee were to create an evidence-based definition and a contemporary classification system for dry eye disease (DED). The new definition recognizes the multifactorial nature of dry eye as a disease where loss of homeostasis of the tear film is the central pathophysiological concept. Ocular symptoms, as a broader term that encompasses reports of discomfort or visual disturbance, feature in the definition and the key etiologies of tear film instability, hyperosmolarity, and ocular surface inflammation and damage were determined to be important for inclusion in the definition. In the light of new data, neurosensory abnormalities were also included in the definition for the first time. In the classification of DED, recent evidence supports a scheme based on the pathophysiology where aqueous deficient and evaporative dry eye exist as a continuum, such that elements of each are considered in diagnosis and management. Central to the scheme is a positive diagnosis of DED with signs and symptoms, and this is directed towards management to restore homeostasis. The scheme also allows consideration of various related manifestations, such as non-obvious disease involving ocular surface signs without related symptoms, including neurotrophic conditions where dysfunctional sensation exists, and cases where symptoms exist without demonstrable ocular surface signs, including neuropathic pain. This approach is not intended to override clinical assessment and judgment but should prove helpful in guiding clinical management and research. PMID- 28736336 TI - TFOS DEWS II Sex, Gender, and Hormones Report. AB - One of the most compelling features of dry eye disease (DED) is that it occurs more frequently in women than men. In fact, the female sex is a significant risk factor for the development of DED. This sex-related difference in DED prevalence is attributed in large part to the effects of sex steroids (e.g. androgens, estrogens), hypothalamic-pituitary hormones, glucocorticoids, insulin, insulin like growth factor 1 and thyroid hormones, as well as to the sex chromosome complement, sex-specific autosomal factors and epigenetics (e.g. microRNAs). In addition to sex, gender also appears to be a risk factor for DED. "Gender" and "sex" are words that are often used interchangeably, but they have distinct meanings. "Gender" refers to a person's self-representation as a man or woman, whereas "sex" distinguishes males and females based on their biological characteristics. Both gender and sex affect DED risk, presentation of the disease, immune responses, pain, care-seeking behaviors, service utilization, and myriad other facets of eye health. Overall, sex, gender and hormones play a major role in the regulation of ocular surface and adnexal tissues, and in the difference in DED prevalence between women and men. The purpose of this Subcommittee report is to review and critique the nature of this role, as well as to recommend areas for future research to advance our understanding of the interrelationships between sex, gender, hormones and DED. PMID- 28736337 TI - TFOS DEWS II Epidemiology Report. AB - The subcommittee reviewed the prevalence, incidence, risk factors, natural history, morbidity and questionnaires reported in epidemiological studies of dry eye disease (DED). A meta-analysis of published prevalence data estimated the impact of age and sex. Global mapping of prevalence was undertaken. The prevalence of DED ranged from 5 to 50%. The prevalence of signs was higher and more variable than symptoms. There were limited prevalence studies in youth and in populations south of the equator. The meta-analysis confirmed that prevalence increases with age, however signs showed a greater increase per decade than symptoms. Women have a higher prevalence of DED than men, although differences become significant only with age. Risk factors were categorized as modifiable/non modifiable, and as consistent, probable or inconclusive. Asian ethnicity was a mostly consistent risk factor. The economic burden and impact of DED on vision, quality of life, work productivity, psychological and physical impact of pain, are considerable, particularly costs due to reduced work productivity. Questionnaires used to evaluate DED vary in their utility. Future research should establish the prevalence of disease of varying severity, the incidence in different populations and potential risk factors such as youth and digital device usage. Geospatial mapping might elucidate the impact of climate, environment and socioeconomic factors. Given the limited study of the natural history of treated and untreated DED, this remains an important area for future research. PMID- 28736340 TI - TFOS DEWS II pathophysiology report. AB - The TFOS DEWS II Pathophysiology Subcommittee reviewed the mechanisms involved in the initiation and perpetuation of dry eye disease. Its central mechanism is evaporative water loss leading to hyperosmolar tissue damage. Research in human disease and in animal models has shown that this, either directly or by inducing inflammation, causes a loss of both epithelial and goblet cells. The consequent decrease in surface wettability leads to early tear film breakup and amplifies hyperosmolarity via a Vicious Circle. Pain in dry eye is caused by tear hyperosmolarity, loss of lubrication, inflammatory mediators and neurosensory factors, while visual symptoms arise from tear and ocular surface irregularity. Increased friction targets damage to the lids and ocular surface, resulting in characteristic punctate epithelial keratitis, superior limbic keratoconjunctivitis, filamentary keratitis, lid parallel conjunctival folds, and lid wiper epitheliopathy. Hybrid dry eye disease, with features of both aqueous deficiency and increased evaporation, is common and efforts should be made to determine the relative contribution of each form to the total picture. To this end, practical methods are needed to measure tear evaporation in the clinic, and similarly, methods are needed to measure osmolarity at the tissue level across the ocular surface, to better determine the severity of dry eye. Areas for future research include the role of genetic mechanisms in non-Sjogren syndrome dry eye, the targeting of the terminal duct in meibomian gland disease and the influence of gaze dynamics and the closed eye state on tear stability and ocular surface inflammation. PMID- 28736341 TI - TFOS DEWS II iatrogenic report. AB - Dry eye can be caused by a variety of iatrogenic interventions. The increasing number of patients looking for eye care or cosmetic procedures involving the eyes, together with a better understanding of the pathophysiological mechanisms of dry eye disease (DED), have led to the need for a specific report about iatrogenic dry eye within the TFOS DEWS II. Topical medications can cause DED due to their allergic, toxic and immuno-inflammatory effects on the ocular surface. Preservatives, such as benzalkonium chloride, may further aggravate DED. A variety of systemic drugs can also induce DED secondary to multiple mechanisms. Moreover, the use of contact lens induces or is associated with DED. However, one of the most emblematic situations is DED caused by surgical procedures such as corneal refractive surgery as in laser-assisted in situ keratomileusis (LASIK) and keratoplasty due to mechanisms intrinsic to the procedure (i.e. corneal nerve cutting) or even by the use of postoperative topical drugs. Cataract surgery, lid surgeries, botulinum toxin application and cosmetic procedures are also considered risk factors to iatrogenic DED, which can cause patient dissatisfaction, visual disturbance and poor surgical outcomes. This report also presents future directions to address iatrogenic DED, including the need for more in-depth epidemiological studies about the risk factors, development of less toxic medications and preservatives, as well as new techniques for less invasive eye surgeries. Novel research into detection of early dry eye prior to surgeries, efforts to establish appropriate therapeutics and a greater attempt to regulate and oversee medications, preservatives and procedures should be considered. PMID- 28736342 TI - TFOS DEWS II Diagnostic Methodology report. AB - The role of the Tear Film and Ocular Surface Society (TFOS) Dry Eye Workshop (DEWS) II Diagnostic Methodology Subcommittee was 1) to identify tests used to diagnose and monitor dry eye disease (DED), 2) to identify those most appropriate to fulfil the definition of DED and its sub-classifications, 3) to propose the most appropriate order and technique to conduct these tests in a clinical setting, and 4) to provide a differential diagnosis for DED and distinguish conditions where DED is a comorbidity. Prior to diagnosis, it is important to exclude conditions that can mimic DED with the aid of triaging questions. Symptom screening with the DEQ-5 or OSDI confirms that a patient might have DED and triggers the conduct of diagnostic tests of (ideally non-invasive) breakup time, osmolarity and ocular surface staining with fluorescein and lissamine green (observing the cornea, conjunctiva and eyelid margin). Meibomian gland dysfunction, lipid thickness/dynamics and tear volume assessment and their severity allow sub-classification of DED (as predominantly evaporative or aqueous deficient) which informs the management of DED. Videos of these diagnostic and sub-classification techniques are available on the TFOS website. It is envisaged that the identification of the key tests to diagnose and monitor DED and its sub classifications will inform future epidemiological studies and management clinical trials, improving comparability, and enabling identification of the sub classification of DED in which different management strategies are most efficacious. PMID- 28736343 TI - TFOS DEWS II Management and Therapy Report. AB - The members of the Management and Therapy Subcommittee undertook an evidence based review of current dry eye therapies and management options. Management options reviewed in detail included treatments for tear insufficiency and lid abnormalities, as well as anti-inflammatory medications, surgical approaches, dietary modifications, environmental considerations and complementary therapies. Following this extensive review it became clear that many of the treatments available for the management of dry eye disease lack the necessary Level 1 evidence to support their recommendation, often due to a lack of appropriate masking, randomization or controls and in some cases due to issues with selection bias or inadequate sample size. Reflecting on all available evidence, a staged management algorithm was derived that presents a step-wise approach to implementing the various management and therapeutic options according to disease severity. While this exercise indicated that differentiating between aqueous deficient and evaporative dry eye disease was critical in selecting the most appropriate management strategy, it also highlighted challenges, based on the limited evidence currently available, in predicting relative benefits of specific management options, in managing the two dry eye disease subtypes. Further evidence is required to support the introduction, and continued use, of many of the treatment options currently available to manage dry eye disease, as well as to inform appropriate treatment starting points and understand treatment specificity in relation to dry eye disease subtype. PMID- 28736344 TI - TFOS DEWS II Clinical Trial Design Report. AB - The development of novel therapies for Dry Eye Disease (DED) is formidable, and relatively few treatments evaluated have been approved for marketing. In this report, the Subcommittee reviewed challenges in designing and conducting quality trials, with special reference to issues in trials in patients with DED and present the regulatory perspective on DED therapies. The Subcommittee reviewed the literature and while there are some observations about the possible reasons why so many trials have failed, there is no obvious single reason other than the lack of correlation between signs and symptoms in DED. Therefore the report advocates for conducting good quality studies, as described, going forward. A key recommendation for future studies is conduct consistent with Good Clinical Practice (GCP), including use of Good Manufacturing Practice (GMP) quality clinical trial material. The report also recommends that the design, treatments, and sample size be consistent with the investigational treatment, the objectives of the study, and the phase of development. Other recommendations for pivotal studies are a priori selection of the outcome measure, and an appropriate sample size. PMID- 28736345 TI - Preoperative Frailty Score for 30-Day Morbidity and Mortality After Cranial Neurosurgery. AB - BACKGROUND: Evaluating preoperative frailty is critical for guiding shared surgical decision-making. The purpose of this study was to develop a novel preoperative frailty index for classification of adverse outcomes following cranial neurosurgery procedures. METHODS: The American College of Surgeons National Surgical Quality Improvement Program database was queried for all cranial neurosurgery cases from 2006 to 2014. Sequential univariate and multivariate testing was used to identify significant independent predictors of 30-day mortality. Frailty scores were computed by summating across weighted predictors. Receiver operating characteristic curve analysis quantified the discriminative capacity of the frailty score for classifying mortality and other major adverse outcomes. RESULTS: List-wise exclusion of patients with incomplete datasets yielded a final sample of 27,098 patients (mortality rate = 3.9%). Multivariate regression testing identified 19 independent predictors of 30-day mortality. Receiver operating characteristic curve analysis revealed impressive outcome discrimination (area under the curve = 0.87, P < 0.001, optimal classification accuracy = 83.0%). Patients in the "high-risk" group (score >=4, n = 5155) had significantly increased risk for mortality (15.4%) and major adverse outcomes (32.0%) compared with patients in the "low-risk" group (n = 21,943, mortality = 1.2%, major adverse outcomes = 4.0%). The frailty score remained highly discriminative across all age groups examined. CONCLUSIONS: Neurosurgical patients undergo extensive preoperative evaluation, but the field currently lacks a robust bedside scoring system for quantifying patient frailty. In this study, we introduced a novel preoperative frailty index capable of classifying 30-day morbidity and mortality outcomes following cranial neurosurgeries. PMID- 28736347 TI - Efficacy of Closed Continuous Lumbar Drainage on the Treatment of Postcraniotomy Meningitis: A Retrospective Analysis of 1062 Cases. AB - BACKGROUND: Postcraniotomy meningitis is a severe complication in neurosurgery, and can result in high morbidity and mortality. Closed continuous lumbar drainage (CCLD) as an adjuvant method for treating postcraniotomy meningitis in adults is rarely assessed. This study aimed to evaluate the efficacy of CCLD in the treatment of postcraniotomy meningitis. METHODS: A total of 1062 patients older than 16 years with postcraniotomy meningitis were included, between January 2000 and December 2015. Of these, 474 received intravenous antibiotic therapy, steroid administration and adjuvant CCLD (experimental Group). The remaining 588 patients only received intravenous antibiotic and steroid therapies (control Group). Data were extracted from medical records. RESULTS: In the experimental group, meningitis-related mortality was 2.7%, and 77.4% individuals achieved a Glasgow Outcome Scale of 4-5. In the control group, meningitis-related mortality reached 11.6%, with only 61.1% of patients achieving a GOS of 4-5. The time to negative cerebrospinal fluid laboratory test and the duration of meningitis-related symptoms were significantly shorter in the experimental group compared with controls (P < 0.05). CONCLUSIONS: Intravenous antibiotic and steroid therapies, assisted by CCLD, can lead to lower mortality and improved Glasgow Outcome Scale score in patients with meningitis after craniotomy. Laboratory results negative for cerebrospinal fluid leak and meningitis-related symptom relief occurred faster in the experimental group. Intravenous antibiotic and steroid therapies combined with CCLD appear to be an effective and safe treatment for postcraniotomy meningitis. PMID- 28736346 TI - Shifting Treatment Paradigms for Ruptured Aneurysms from Open Surgery to Endovascular Therapy Over 25 Years. AB - BACKGROUND: Since the introduction of Gugliemi detachable coils in the early 1990s, major clinical studies have supported an increasing role for coil embolization of ruptured aneurysms. We assessed aneurysm location and treatment modality in aneurysmal subarachnoid hemorrhage (aSAH) over the past 25 years. METHODS: A prospective, institutional review board-approved aneurysm database was screened for patients presenting with aSAH from 1991 to 2016. Microsurgical and endovascular capabilities were present throughout. All patients underwent cerebral angiography prior to treatment. RESULTS: Data were available for 1306/1562 patients (83.6%) presenting with aSAH from 1991-2016. 72% were female, with average age 52.8 years, and average aneurysm size 8.0 mm. The most common vessel of origin was the anterior cerebral artery (37.3%), internal carotid artery (33.3%), and middle cerebral artery (14.6%). Posterior circulation accounted for 14.8% of the aneurysms. Open surgery was performed for 72.4% of aneurysms, endovascular treatment for 22.0%, and 5.7% were not treated. There was an increase in aneurysms treated by endovascular methods over 5-year intervals: 3.0% (1991-1996), 13.4% (1997-2001), 17.2% (2002-2006), 24.3% (2007-2011), and 41.9% (2012-2016). Posterior circulation aneurysms led this trend, increasing from 9.1% endovascular to 71.4%. Endovascular treatment increased from 2.9% and 1.4% of anterior cerebral artery and internal carotid artery aneurysms to 39.6% and 40.7%, respectively, in the most recent 5-year interval. By comparison, endovascular methods remained less commonly used for middle cerebral artery aneurysms (0% initially, now 22.0%). CONCLUSIONS: Endovascular treatment of ruptured intracranial aneurysms has steadily increased over the past 25 years at our major academic institution. This is consistent with positive data from clinical trials, advances in endovascular technology, and increasing experience of endovascular specialists. PMID- 28736348 TI - Pathologic Progression, Possible Origin, and Management of Multiple Primary Intracranial Neuroendocrine Carcinomas. AB - BACKGROUND: Primary intracranial neuroendocrine carcinomas (NECs) are extremely rare malignant tumors with no previous reports of multiple ones in the literatures. CASE DESCRIPTION: The clinical presentation, preoperative and reexamined magnetic resonance imaging findings, as well as histopathologic studies of a 56-year-old female subject with multiple intracranial NECs mimicking multiple intracranial meningiomas, who underwent 3 operations with left parietal craniotomy, right occipital parietal craniotomy, and left frontal craniotomy, separately and chronologically, are presented in this article. Noteworthy, the first and second tumors were confirmed as NECs exhibiting histologic characteristics of typical anaplastic meningiomas with features of whorl formation, while the third tumor was a typical NEC with features of organoid cancer nests. In other words, the first 2 lesions were diagnosed as meningioma as opposed to NEC. It was only after the third surgery that the pathology for the first 2 cases was reviewed and had a revised diagnosis. After the third surgical resection, the patient further received whole brain radiotherapy and systemic chemotherapy (temozolomide combined with YH-16). At her 10-month follow-up, the patient achieved a good outcome. CONCLUSIONS: Multiple primary intracranial NECs are extremely rare. The tumor might be of arachnoidal or leptomeningeal origin, with histologic patterns that might lead to transformation and/or progression. Maximal surgical resection is warranted for symptomatic mass effect. Postoperative adjuvant treatments including radiotherapy and chemotherapy should be a recommended therapeutic modality. PMID- 28736338 TI - TFOS DEWS II Tear Film Report. AB - The members of the Tear Film Subcommittee reviewed the role of the tear film in dry eye disease (DED). The Subcommittee reviewed biophysical and biochemical aspects of tears and how these change in DED. Clinically, DED is characterized by loss of tear volume, more rapid breakup of the tear film and increased evaporation of tears from the ocular surface. The tear film is composed of many substances including lipids, proteins, mucins and electrolytes. All of these contribute to the integrity of the tear film but exactly how they interact is still an area of active research. Tear film osmolarity increases in DED. Changes to other components such as proteins and mucins can be used as biomarkers for DED. The Subcommittee recommended areas for future research to advance our understanding of the tear film and how this changes with DED. The final report was written after review by all Subcommittee members and the entire TFOS DEWS II membership. PMID- 28736349 TI - Completion of the Circle of Willis Varies by Gender, Age, and Indication for Computed Tomography Angiography. AB - OBJECTIVE: The circle of Willis (CoW) is the foremost anastomosis and blood distribution center of the brain. Its effectiveness depends on its completion and the size and patency of its vessels. Gender-related and age-related anatomic variations in the CoW may play an important role in the pathogenesis of cerebrovascular diseases. In this study, we analyzed computed tomography angiograms (CTAs) to assess for differences in CoW completion related to gender, age, and indication for CTA. METHODS: A total of 834 CTAs were retrospectively analyzed for all CoW vessels to compare the incidence of complete CoW and variation frequency based on gender, age, and indication. RESULTS: The incidence of complete CoW was 37.1% overall. CoW completion showed a statistically significant decrease with increasing age for all age groups in both men (47.0%, 29.4%, 18.8%) and women (59.1%, 44.2%, 30.9%). Completion was greater in women (43.8%) than in men (31.2%) overall and for all age groups. These gender differences were all statistically significant except for the 18-39 years age group. The most frequent of the 28 CoW variations were absent posterior communicating artery (PCOM) bilaterally (17.1%), right PCOM (15.3%), and left PCOM (10.9%). Ischemic stroke and the 18-39 years age group of hemorrhagic stroke showed a statistically significant reduction in completion relative to trauma. CONCLUSIONS: The incidence of complete CoW is likely greater in women for all age groups and likely decreases with age in both genders. The most frequently absent vessel is likely the PCOM, either unilaterally or bilaterally. Completion may play a role in ischemic stroke and a subset of patients with hemorrhagic stroke. PMID- 28736350 TI - Antibiotic Prophylaxis in Endoscopic Endonasal Pituitary and Skull Base Surgery. AB - OBJECTIVE: Postoperative infection is a potentially dramatic consequence in endoscopic endonasal surgery. The aim of this study was to assess the efficacy of our intraoperative antibiotic prophylaxis by analyzing the risk factors of postoperative meningitis in our series. METHODS: Each endoscopic endonasal procedure performed since 1998 in patients with no preoperative infections and a follow-up longer than 30 days were included and retrospectively reviewed. Antibiotic protocol consisted in single antibiotic administration of ampicillin/sulbactam 3 g or cefazolin 2 g on induction; no postoperative administrations were performed after 2005. All cases of cerebrospinal fluid (CSF) leak, meningitis, and systemic infection were recorded. RESULTS: Two thousand thirty-two procedures matched the inclusion criteria (median age 50 years; range: 1-89 years, male/female ratio: 1:1.12). Intraoperative CSF leak occurred in 32.8% of the cases and postoperative CSF leak in 3.4%. The rate of meningitis was 0.69%; other systemic infections were observed in 0.44% of cases. Meningitis was statistically associated with intra- and postoperative CSF leak (P < 0.001). Other risk factors were the intradural extension of the tumors and their malignant histology. Extended approaches producing wide osteodural defects were correlated with a greater risk of meningitis (P < 0.001). CONCLUSIONS: All surgical maneuvers to prevent, detect, and quickly repair intra- and postoperative CSF leak are crucial to avoid postoperative meningitis. The proposed prophylaxis protocol is comparable in safety to those recommended in literature as assessed by the low rate of meningitis. PMID- 28736339 TI - TFOS DEWS II pain and sensation report. AB - Pain associated with mechanical, chemical, and thermal heat stimulation of the ocular surface is mediated by trigeminal ganglion neurons, while cold thermoreceptors detect wetness and reflexly maintain basal tear production and blinking rate. These neurons project into two regions of the trigeminal brain stem nuclear complex: ViVc, activated by changes in the moisture of the ocular surface and VcC1, mediating sensory-discriminative aspects of ocular pain and reflex blinking. ViVc ocular neurons project to brain regions that control lacrimation and spontaneous blinking and to the sensory thalamus. Secretion of the main lacrimal gland is regulated dominantly by autonomic parasympathetic nerves, reflexly activated by eye surface sensory nerves. These also evoke goblet cell secretion through unidentified efferent fibers. Neural pathways involved in the regulation of meibomian gland secretion or mucin release have not been identified. In dry eye disease, reduced tear secretion leads to inflammation and peripheral nerve damage. Inflammation causes sensitization of polymodal and mechano-nociceptor nerve endings and an abnormal increase in cold thermoreceptor activity, altogether evoking dryness sensations and pain. Long-term inflammation and nerve injury alter gene expression of ion channels and receptors at terminals and cell bodies of trigeminal ganglion and brainstem neurons, changing their excitability, connectivity and impulse firing. Perpetuation of molecular, structural and functional disturbances in ocular sensory pathways ultimately leads to dysestesias and neuropathic pain referred to the eye surface. Pain can be assessed with a variety of questionaires while the status of corneal nerves is evaluated with esthesiometry and with in vivo confocal microscopy. PMID- 28736351 TI - Intraoperative Ultrasound in Patients Undergoing Transsphenoidal Surgery for Pituitary Adenoma: Systematic Review [corrected]. AB - BACKGROUND: Transsphenoidal surgery is the gold standard for pituitary adenoma resection. However, despite advances in microsurgical and endoscopic techniques, some pituitary adenomas can be challenging to cure. OBJECTIVE: We sought to determine whether, in patients undergoing transsphenoidal surgery for pituitary adenoma, intraoperative ultrasound is a safe and effective technologic adjunct. METHODS: The PubMed database was searched between January 1996 and January 2016 to identify relevant publications that 1) featured patients undergoing transsphenoidal surgery for pituitary adenoma, 2) used intraoperative ultrasound, and 3) reported on safety or effectiveness. Reference lists were also checked, and expert opinions were sought to identify further publications. RESULTS: Ultimately, 10 studies were included, comprising 1 cohort study, 7 case series, and 2 case reports. One study reported their prototype probe malfunctioned, leading to false-positive results in 2 cases, and another study' prototype probe was too large to safely enter the sphenoid sinus in 2 cases. Otherwise, no safety issues directly related to use of intraoperative ultrasound were reported. In the only comparative study, remission occurred in 89.7% (61/68) of patients with Cushing disease in whom intraoperative ultrasound was used, compared with 83.8% (57/68) in whom it was not. All studies reported that surgeons anecdotally found intraoperative ultrasound helpful. CONCLUSIONS: Although there is limited and low quality evidence available, the use of intraoperative ultrasound appears to be a safe and effective technologic adjunct to transsphenoidal surgery for pituitary adenoma. Advances in ultrasound technology may allow for more widespread use of such devices. PMID- 28736352 TI - The Effect of Biocomposite Screws on Bone Regeneration in a Rat Osteoporosis Model. AB - OBJECTIVE: To evaluate the efficacy of biocomposite screws used in ovariectomy (OVX)-induced osteoporotic rats. METHODS: Twenty-four female Wistar rats (250-300 g, 12 weeks old) were divided into 4 groups: sham group (control), OVX-induced osteoporosis group (OVX), OVX and biodegradable poly(lactic-co-glycolic acid) (PLGA) without tricalcium phosphate (beta-TCP) screw insertion group (OVX/BSR), and OVX and biocomposite (PLGA with beta-TCP) screw insertion group (OVX/CSR). Three groups underwent bilateral OVX, and of these, 2 groups had 2 different types of screw inserted at the proximal tibia. At 25 weeks after OVX, the bilateral tibias were extracted. The extracted tibiae were scanned by ex vivo micro-computed tomography (CT) and stained with hematoxylin and eosin (H&E) and with Masson's trichrome stain for pathological assessment. RESULTS: Compared with the ovariectomized groups, the control group had the highest values for bone mineral density (BMD), bone volume (BV)/total volume (TV), and trabecular number (Tb.N) and the lowest values for trabecular thickness (Tb.Th) and trabecular separation (Tb.Sp). In the pairwise comparison among ovariectomized groups, the OVX/CSR group had significantly higher BMD, BV/TV, and Tb.N values than the other 2 groups (OVX and OVX/BSR) and significantly lower Tb.Sp. Micro-CT scans showed clear evidence of new trabecular formation near the screw insertion site in the OVX/CSR group only. Analyses of H&E- and Masson's trichrome-stained sections showed more and thicker trabecular bone around the implant in the OVX/CSR group compared with the OVX and OVX/BSR groups. CONCLUSIONS: Biocomposite screws can improve local bone quality and facilitate osteoconductivity in an osteoporotic rat model. PMID- 28736354 TI - Novel Technique of Percutaneous Fat Graft for Repair of Persistent Large Pseudomeningocele. AB - BACKGROUND: Pseudomeningocele is an uncommon but problematic complication in lumbar spine surgery. Initial conservative measures frequently are successful, but persistence requires additional management. The current surgical approach can involve a range of techniques, including blood patches, hydrogel/fibrin sealants, drains, open surgical repair of the dura, or a combination of the all techniques if symptoms persist. This report demonstrates a novel technique for repair via a percutaneous approach to deliver an autologous fat graft into the pseudomeningocele. CASE DESCRIPTION: A 64-year-old woman with a history of multiple complex lumbar spinal surgeries with previous durotomy had persistent positional headaches from an unresolved pseudomeningocele from L3 to L5. The defect and symptoms remained after all available surgical options were exhausted, including blood patches, hydrogel sealants (Duraseal), and open surgical repair with muscle and Gelfoam grafts. After autologous fat harvest, the patient underwent percutaneous repair of the pseudomeningocele with simultaneous aspiration of cerebrospinal fluid and injection of fat into the defect space. CONCLUSIONS: At 3 months postoperatively, the patient's symptoms were resolved with no clinical or radiographic findings of nerve root or thecal sac impingement and complete obliteration of the pseudomeningocele. This less-invasive approach offers the option of open surgical repair for persistent pseudomeningocele with the use of autologous graft material. PMID- 28736353 TI - Sport-Related Structural Brain Injury: 3 Cases of Subdural Hemorrhage in American High School Football. AB - BACKGROUND: The risk of sport-related concussion (SRC) has emerged as a major public health concern. In rare instances, sport-related head injuries can be even more severe, such as subdural hemorrhage, epidural hemorrhage, or malignant cerebral edema. Unlike SRCs, sport-related structural brain injury (SRSBI) is rare, may require neurosurgical intervention, and can lead to permanent neurologic deficit or death. Data characterizing SRSBI are limited, and many have recognized the need to better understand these catastrophic brain injuries. The goal of the current series is to describe, in detail, the presentation, management, and outcomes of examples of these rare injuries. CASE DESCRIPTION: During the fall of 2015, three high school football players presented with acute subdural hemorrhages following in-game collisions and were treated at our institution within a span of 2 months. For the 2 athletes who required surgical intervention, a previous SRC was sustained within 4 weeks before the catastrophic event. One year after injury, 2 players have returned to school, though with persistent deficits. One patient remains nonverbal and wheelchair bound. None of the athletes has returned to sports. CONCLUSIONS: Acute subdural hemorrhage resultant from an in-game football collision is rare. The temporal proximity of the reported SRSBIs to recent SRCs emphasizes the importance of return-to-play protocols and raises questions regarding the possibility of second impact syndrome. Although epidemiologic conclusions cannot be drawn from this small sample, these cases provide a unique opportunity to demonstrate the presentation, management, and long-term outcomes of SRSBI in American high school football. PMID- 28736355 TI - C2 Bone Erosion Secondary to Iatrogenic Pseudomeningocele: A Case Report and Description of a Novel Surgical Technique. AB - BACKGROUND: Pseudomeningoceles are a rare cause of bone erosions. Development of such erosions in the C2 vertebral body and the odontoid process can lead to life threatening instability. Treatment options to regain stability include atlantoaxial and occipitocervical fusion. For patients with a history of Chiari decompression and large C2 lesions, common fusion techniques are not always feasible. In addition, fusion surgery sacrifices physiologic motion and is therefore a disabling procedure, especially for young and active patients. CASE DESCRIPTION: We report a novel combined open operative and subsequent minimal invasive filling technique of several instable osteolytic/cystic areas within the C2 vertebra of a 28-year-old woman. The underlying cause for the lesions was a pseudomeningocele communicating with the vertebral body. This was an incidental finding 15 years after foramen magnum decompression with C1 and partial C2 laminectomy for Chiari malformation. Novel treatment included open posterior surgery with total laminectomy of the remaining C2 arch and refilling the odontoid with viscous beta tricalcium phosphate and polymethylmethacrylate bone cement. Postoperative 6- and 12-month follow-up computed tomography imaging showed a stable incorporation of the filling. CONCLUSIONS: Life-threatening fractures at the occipitocervical junction are rare and often are due to high impact trauma. Osteolytic changes at those bone compartments are a potential cause for pathologic fractures during normal daily activities. In this case, increased pressure on the bone due to a pseudomeningocele resulted in slow bone loss without symptoms. A novel combined technique of bone filling was applied successfully to stabilize the C2 vertebral bone. PMID- 28736356 TI - Finite Element Analysis of Influence of Axial Position of Center of Rotation of a Cervical Total Disc Replacement on Biomechanical Parameters: Simulated 2-Level Replacement Based on a Validated Model. AB - BACKGROUND: Finite element models have been widely used to predict biomechanical parameters of the cervical spine. Previous studies investigated the influence of position of rotational centers of prostheses on cervical biomechanical parameters after 1-level total disc replacement. The purpose of this study was to explore the effects of axial position of rotational centers of prostheses on cervical biomechanics after 2-level total disc replacement. METHODS: A validated finite element model of C3-C7 segments and 2 prostheses, including the rotational center located at the superior endplate (SE) and inferior endplate (IE), was developed. Four total disc replacement models were used: 1) IE inserted at C4-C5 disc space and IE inserted at C5-C6 disc space (IE-IE), 2) IE-SE, 3) SE-IE, and 4) SE-SE. All models were subjected to displacement control combined with a 50 N follower load to simulate flexion and extension motions in the sagittal plane. For each case, biomechanical parameters, including predicted moments, range of rotation at each level, facet joint stress, and von Mises stress on the ultra-high-molecular weight polyethylene core of the prostheses, were calculated. RESULTS: The SE-IE model resulted in significantly lower stress at the cartilage level during extension and at the ultra-high-molecular-weight polyethylene cores when compared with the SE-SE construct and did not generate hypermotion at the C4-C5 level compared with the IE-SE and IE-IE constructs. CONCLUSIONS: Based on the present analysis, the SE-IE construct is recommended for treating cervical disease at the C4-C6 level. This study may provide a useful model to inform clinical operations. PMID- 28736358 TI - [Emergence of methicillin-resistant Staphylococcus aureus SCCmec type IV/V epidemic clones in a large teaching hospital in China]. AB - OBJECTIVE: To investigate the staphylococcal cassette chromosome mec (SCCmec) genotype and molecular epidemiological characteristics of healthcare-associated methicillin-resistant Staphylococcus aureus (HA-MRSA) in a large teaching hospital in China. METHDOS: From January 2012 to December 2012, a total of 71 nonduplicate HA-MRSA were collected in a teaching hospital in Changsha, China. SCCmec types were determined by multiplex PCR, and Panton-Valentine leukocidin (PVL) gene was detected by PCR. The homology among the tested isolates was determined using pulsed-field gel electrophoresis (PFGE). RESULTS: Of the 71 HA MRSA isolates, 49 (69.0%) carried SCCmec III, 10 (14.1%) carried SCCmec IV, 3 (4.2%) carried SCCmec V and 3 (4.2%) carried SCCmec II; the remaining 6 isolates were not typeable by PCR. Compared with patients having SCCmec I/II/III MRSA infections, those with SCCmec IV/V MRSA infections had a significantly younger age and a similar duration of hospital stay before the first MRSA-positive culture and total hospital stay. PVL genes were strongly associated with SCCmec type IV/V MRSA infections. HA-SCCmec IV/V MRSA strains showed a greater susceptibility to rifampicin, gentamicin, levofloxacin, ciprofloxacin, and tetracycline than HA-SCCmec I/II/III MRSA strains. The 13 HA-SCCmec IV/V MRSA isolates formed one large group at the 55% similarity level. Three PFGE clusters with a similarity index of 85% or more were identified, and unique PFGE profiles were observed in 4 isolates. CONCLUSION: This is the first report of HA-MRSA isolates carrying SCCmec V in Chinese hospitals. SCCmec types IV and V MRSA clones have emerged in Chinese hospitals, which urges more rigorous surveillance of their spread in healthcare facilities in China. PMID- 28736357 TI - Incidence, Demographics, and Outcome of Traumatic Brain Injury in The Middle East: A Systematic Review. AB - BACKGROUND: Traumatic brain injury (TBI) is a serious global public health challenge. We aimed to assess the pattern of TBI in the Middle East, as reported in the last decade. METHODS: Literature searches were conducted on PubMed, MEDLINE, and Google scholar electronic databases. The search terms used in different combinations were epidemiology, incidence, case fatality, mortality, intracranial injury, brain injury, head injury, and the country names. Additional searches were conducted using reference lists of studies and review articles for selection of relevant articles. The search yielded 1082 articles; of which 701 duplicates and 346 articles were excluded. Thirty-five original studies met the inclusion criteria. Data were extracted using standardized Excel form and pilot tested. Median with interquartile range (IQR) was used to estimate the incidence rate and mortality of TBI. RESULTS: In the Middle East region, the median TBI incidence rate per capita was 45 (IQR, 38.5-367) per 100,000. The overall median emergency department-based TBI mortality, which included all age groups and all injury severities, was 10% (IQR, 7.75-15.75). We estimated the overall median mortality for head trauma studies based on emergency department admissions as 6% (IQR, 3-18) among all age groups and all injury severities. The overall TBI related median mortality in the intensive care unit-based studies was 25% (IQR, 15.5-47). CONCLUSIONS: The epidemiology of TBI in the Middle East remains understudied. The use of a globally recognized definition of TBI will contribute greatly to improve its reporting, analysis, and interpretation and to establish appropriate injury prevention programs. PMID- 28736359 TI - [Small intestinal cavernous hemangioma causing chronic hemorrhage: a case report]. AB - Small intestinal hemangioma is a rare condition that can be divided histologically into capillary, cavernous or mixed types, among which the cavernous type is the most common. Here we report a case of small intestinal cavernous hemangioma with chronic hemorrhage in 44-year-old man. The patient complained of weakness and dizziness for 2 years that aggravated 1 month before admission accompanied by intermittent melena. Laboratory tests suggest severe anemia, and computed tomography, gastroscopy and colonoscopy all revealed signs of anemia. Capsule endoscopy detected small intestinal erosions, bleeding lesions and prominent neoplasms. An exploratory laparotomy was performed, in which the segment of the jejunum with lesions was resected. Pathological examination of the resected jejunum identified the neoplasm as cavernous hemangioma of the small intestine, which was the cause of severe anemia. PMID- 28736360 TI - [S100A4, a potential therapeutic target on bladder cancer stem cells]. AB - OBJECTIVE: To observe the effect of S100A4 gene silencing mediated by small interfering RNA (siRNA) on the proliferation of bladder cancer stem cells (CSCs) and their capacity of xenograft tumor formation. METHODS: MB49 bladder cancer stem cells (MCSCs) were isolated and identified. The differentially expressed protein S100A4 was identified in MCSCs using isobaric tags for relative and absolute quantitation technology (iTRAQ). A siRNA targeting S100A4 was constructed and transfected into MCSCs, and its inhibitory effects on S100A4 expression in MCSCs were assessed with Western blotting and qPCR. The effects of siRNA-mediated S100A4 silencing on the proliferation and xenograft tumor formation ability of MCSCs were observed. RESULTS: Among the 65 differentially expressed proteins identified by iTRAQ combined with LC/MS/MS, S100A4 protein showed the most distinct differential expression in MCSCs. Transfection of MCSCs with S100A siRNA significantly inhibited the expressions of S100A4 at both mRNA and protein levels, caused obvious suppression of the cell proliferation, and attenuated the xenograft tumor formation ability of the cells in nude mice. CONCLUSION: S100A4 in MCSCs is associated with the recurrence and metastasis of bladder cancer. S100A4 may serve as a potential therapeutic target for eliminating bladder CSCs. PMID- 28736361 TI - [Effect of nucleolin silencing on differentiation of rat neural stem cells in vitro and the molecular mechanism]. AB - OBJECTIVE: To investigate the effect of nucleolin silencing on the differentiation of rat neural stem cells (NSCs) and the role of Wnt signaling pathway in mediating such effect. METHODS: Adenovirus vectors expressing small interfering RNA (siRNA) against nucleolin were constructed, verified, and packaged in HEK293A cells. The adenovirus was then transfected into NSCs isolated from neonatal SD rats and the differentiation of the NSCs was examined by detecting the expressions of neuron specific encloase (NSE) and glial fibrillary acidic protein (GFAP) using immunocytochemistry. The expressions of nucleolin, nestin, Wnt3, and beta-catenin in the cells were determined with Western blotting. RESULTS: Restriction endonuclease and sequencing analysis verified successful construction of the adenoviral vector expressing nucleolin siRNA (nucleolin-siRNA2). Infection of rat NSCs with nucleolin-siRNA2 significantly lowered nucleolin protein expression as compared with that in negative and blank control groups (P<0.05). The percentages of NSE-positive cells and GFAP-positive cells were significantly higher in NSCs infected with nucleolin-siRNA (P<0.01); the infection also resulted in obviously lowered expression of nestin protein and increased expressions of Wnt3 protein and beta-catenin nucleoprotein in the cells. CONCLUSIONS: Nucleolin silencing by adenovirus-mediated RNA interference induces the differentiation of NSCs into neurons and astrocytes, which is related with the activation of Wnt signaling pathway. PMID- 28736362 TI - [Small interfering RNA-mediated monocarboxylate transporter 1 silencing enhances sensitivity of nasopharyngeal carcinoma HNE1/DDP cells to cisplatin-induced apoptosis]. AB - OBJECTIVE: To investigate the effect of small interfering RNA (siRNA)-mediated silencing of monocarboxylate transporter 1 (MCT1) on the sensitivity of drug resistant nasopharyngeal carcinoma HNE1/DDP cells to cisplatin (DDP)-induced apoptosis and explore the possible mechanism. METHODS: The expression of MCT1 was analyzed in HNE1 and HNE1/DDP cells and in HNE1/DDP cells transfected with siRNA using Western blot. MTT assay was used to assess the inhibitory effect of different concentrations of DDP alone or in combination with MCT1 siRNA on the proliferation of HNE1/DDP cells. The apoptosis of cells treated with MCT1 siRNA or/and DDP (8 umol/L) was assessed using flow cytometry with PI staining, and the mitochondrial membrane potential was detected using JC-1 staining assay; the expressions of Mcl-1, Bak, Bcl-2, and Bax were analyzed using Western blotting. RESULTS: HNE1/DDP cells showed a high expression of MCT1, and MCT1 silencing using siRNA significantly increased the sensitivity of HNE1/DDP cells to DDP (P<0.05) and partly reversed DDP resistance of the cells. MCT1 silencing enhanced the sensitivity of HNE1/DDP cells to DDP-induced apoptosis. Treatment of HNE1/DDP cells with MCT1 siRNA combined with 8 umol/L DDP for 24 h resulted in an apoptotic rate of (51.23?2.86)%, significantly higher than that in cells treated with MCT1 siRNA or DDP alone (P<0.05). The combined treatment also reduced the mitochondrial membrane potential, down-regulated the expression of Mcl-1 and Bcl 2, and up-regulated the expression of Bax in the DDP-resistant cells. CONCLUSION: MCT1 siRNA can enhance the sensitivity of HNE1/DDP cells to DDP-induced apoptosis, the mechanism of which may involve the down-regulation of Mcl-1 and Bcl-2 and up-regulation of Bax expression. PMID- 28736363 TI - [Clinical characteristics and risk factors affecting outcomes of elderly patients with non-small cell lung cancer complicated by chronic obstructive pulmonary disease]. AB - OBJECTIVE: To investigate the clinical features, treatment strategy and risk factors affecting the prognosis of elderly patients with non-small cell lung cancer (NSCLC) complicated by chronic obstructive pulmonary disease (COPD). METHODS: We retrospectively analyzed the data of elderly patietns (>60 years) with newly diagnosed NSCLC complicated by COPD at the Geriatric Institution of General Hospital of PLA between January, 2000 and June, 2015. The clinical data collected included history of smoking, pulmonary function test results, initial treatments, TNM stage, chief complaints, comorbidities and laboratory tests. The Cox proportional hazards regression model was used to explore the prognostic factors in these patients. RESULTS: A total of 200 NSCLC patients were reviewed, of which 107 (53.5%) patients had the co-morbidity of COPD as confirmed by spirometry using bronchodilator test. The median survival of the patients with NSCLC complicated by COPD was 45.8 months with 1-, 3-, 5-, and 10-year survival rates of 80.4%, 55.4%, 41.0% and 20.0%, respectively. Stratification analysis showed that patients with COPD Gold grades 1 and 2 had a significant longer median overall survival (51.7 and 43.1 months, respectively) than those with grade 3/4 (16.9 months; P=0.020 and 0.043, respectively). Univariate and multivariate analyses using Cox proportional hazards regression model showed that an older age, a higher Gold grade, advanced disease stage (stages III and IV), squamous cell carcinoma, nonsurgical initial treatment, coughing and an elevated serum CEA level were independent risk factors for shorter survival of the patients. CONCLUSION: Multiple prognostic factors can affect the outcomes of elderly patients with NSCLC complicated by COPD, and a higher COPD Gold grade that fails to respond to treatment within 3 months is the independent risk factor for survival of the patients. PMID- 28736364 TI - [Angiotensin-(1-7) protects cardiac myocytes against high glucose-induced injury by inhibiting ClC-3 chloride channels]. AB - OBJECTIVE: To explore whether angiotensin-(1-7) [Ang-(1-7)] protects cardiac myocytes against high glucose (HG)-induced injury by inhibiting ClC-3 chloride channels. METHOD: H9c2 cardiac cells were exposed to 35 mmol/L glucose for 24 h to establish a cell injury model. The cells were treated with Ang-(1-7) or the inhibitor of chloride channel (NPPB) in the presence of HG for 24 h to observe the changes in HG-induced cell injury. Cell counter kit 8 (CCK-8) assay was used to test the cell viability, and the morphological changes of the apoptotic cells were detected using Hoechst 33258 staining and fluorescent microscopy. The intracellular level of reactive oxygen species (ROS) was examined by DCFH-DA staining, SOD activity in the culture medium was measured using commercial kits, and the mitochondrial membrane potential (MMP) of the cells was tested with rodamine 123 staining. The expression level of cardiac ClC-3 chloride channels was detected with Western blotting. RESULTS: Exposure of H9c2 cardiac cells to 35 mmol/L glucose for 24 h markedly enhanced the expressions of cardiac ClC-3 channel protein (P<0.01). Co-treatment of the cells with 1 umol/L Ang-(1-7) and HG for 24 h significantly attenuated HG- induced upregulation of ClC-3 channel protein expression (P<0.01). Co-treatment of the cells exposed to HG with 1 umol/L Ang-(1-7) or 100 umol/L NPPB for 24 h obviously ameliorated HG-induced injuries as shown by increased cell viability, enhanced SOD activity, decreased number of apoptotic cells, and reduced intracellular ROS generation and loss of MMP (P<0.01). CONCLUSION: ClC-3 channels are involved in HG-induced injury in cardiac cells. Ang-(1-7) protects cardiac cells against HG-induced injury by inhibiting ClC-3 channels. PMID- 28736365 TI - [Blighted ovum in subfertile patients undergoing assisted reproductive technology]. AB - OBJECTIVE: To explore the incidence and risk factors of blighted ovum in subfertile patients undergoing assisted reproductive technology (ART). METHODS: This retrospective analysis was conducted among 2378 patients who were pregnant following embryo transfer at our center from January, 2012 to December, 2015, including cases of early pregnancy losses and simultaneous live births. The cases with early pregnancy losses were divided into embryonic pregnancy and blighted ovum groups based on the presence or absence of an embryonic pole before dilation and curettage. The clinical data of the 3 groups were analyzed for comparisons of the maternal age, paternal age, BMI, AFC, basal FSH, bFSH/bLH, duration of infertility, Gn dosage, Gn days, serum estradiol on the day of HCG administration, endometrium thickness, number of oocyte retrieved, proportion of high-quality embryos transferred, serum beta-HCG value on the 10th to 14th days of embryo transfer, infertility type and miscarriage times. The incidences of blighted ovum were compared between cases with different cycles, embryo stages, infertile factors and methods of fertilization. RESULTS: Maternal age and paternal age, BMI, duration of infertility, infertility type and miscarriage times differed significantly between cases with blighted ovum and those with live births. Serum beta-HCG level was the lowest in blighted ovum group followed by embryonic pregnancy group and then by live birth group. Blastocyst transfer was associated with a significantly higher incidence of blighted ovum as compared with cleavage embryo transfer (11.6% vs 5.6%, P=0.000). No significant difference was found in the other parameters among the 3 groups (P>0.05). Adjusted logistic regression analysis showed that maternal age, beta-HCG level and blastocyst transfer were risk factors of blighted ovum. CONCLUSION: Advanced maternal age, low beta-HCG level and blastocyst transfer may increase the risk of blighted ovum possibly in association with gene imprinting errors during the early stage of embryo development. PMID- 28736366 TI - [Lactic acid inhibits the formation of semen-derived amyloid fibrils]. AB - OBJECTIVE: To investigate the inhibitory effect of lactic acid on semen-derived amyloid (SEVI) fibril formation. METHODS: PAP248-286 (2 mg/mL) was incubated with 4.0, 2.0, 1.0, 0.5, 0.25, and 0.125 mg/mL of lactic acid. After incubation for different times, aliquots were drawn from each sample for Thioflavin T (ThT) and Congo red staining to monitor semen-derived amyloid fibril formation. The beta sheet structure formation of PAP248-286 was measured by circular dichroism spectrum, and the morphology of amyloid fibrils incubated with or without lactic acid was observed with transmission electron microscopy (TEM). The enhancing effect of amyloid fibril incubated with lactic acid at different time points was determined using virus infection assay. PAP248-286 (2 mg/mL) was incubated with dilutions of vaginal secretion from healthy women, and amyloid fibril formation was detected with ThT and Congo red staining. RESULTS: Lactic acid inhibited SEVI fibril formation in a dose-dependent manner in vitro. Lactic acid at 0.5 mg/mL completely inhibited 2 mg/mL SEVI fibril formation within 48 h. After incubation for 48 h, lactic acid at 1 mg/mL inhibited the formation of beta-sheet structure of SEVI (2 mg/mL) and completely inhibited 2 mg/mL PAP248-286 aggregation as observed with TEM. In the presence of lactic acid, PAP248-286 lost the ability to enhance virus infection. Vaginal secretion inhibited SEVI fibril formation in a dose-dependent manner, and virtually no SEVI fibril occurred after incubation of 2 mg/mL PAP248-286 with 67% vaginal secretion. CONCLUSION: Lactic acid inhibits SEVI fibril formation in vitro. PMID- 28736367 TI - [Establishment of mouse model of bone metastasis of prostate cancer and breast cancer via femoral artery injection of tumor cells]. AB - OBJECTIVE: To explore an efficient and reliable method for establishing an animal model of bone metastasis of tumors. METHODS: Male C57BL/6J mice were randomized into 4 equal groups to receive injections of normal saline or prostate cancer RM 1 cell suspension via the femoral artery or the external iliac artery, and breast cancer 4T1-luc cells were injected in 15 female BALB/c mice via the femoral artery. The operation time, postoperative survival rate, and the tumor formation rates in the mice with two different injection methods were compared. The tumor metastasis in the mice was evaluated with in vivo imaging. RESULTS: The mean time for hemostasis time was 2.53?1.75 min in mice receiving tumor cell injection via the femoral artery, significantly shorter than that in mice with injections via the external iliac artery (4.70?1.63 min; P<0.05); the mean operation time was 14.67?2.16 min and 22.47?3.50 min in the two groups, respectively (P<0.05). At 21 days after the operation, the survival rate was 93.3% in femoral artery injection group, significantly higher than that in external iliac artery injection group (66.7%;P<0.05). The tumor metastasis rate was 100% in both groups. CONCLUSION: Injection of the tumor cells via the femoral artery is more suitable for establishing mouse models of bone metastasis of cancers. PMID- 28736368 TI - [Relationship between blood pressure variability and combined cardiovascular events in 5-10 years in hypertensive patients]. AB - OBJECTIVE: To explore the relationship between blood pressure variability (BPV) and combined cardiovascular events in 5-10 years in patients with hypertension. METHODS: A total of 367 hypertensive patients treated in our hospital from January, 2000 to January, 2005 were analyzed, and their BPV was assessed in comparison with 145 normotensive individuals. The hypertensive patients were classified into high BPV group and low BPV group, and the general clinical data and biochemical profiles were compared. The relationship between BPV and combined cardiovascular events of the patients within 5-10 years were explored. RESULTS: Compared with the normotensive individuals, the hypertensive patients showed significantly increased standard deviation and coefficient of variation of 24-h systolic blood pressure (SBP), 24-h diastolic blood pressrue (DBP), daytime SBP, daytime DBP, night-time SBP and night-time DBP (P<0.01). The percentages of drinking, smoking, diabetes and coronary heart disease were significantly higher in patients with high BPV than those with lower BPV (P<0.01 or 0.05); uric acid, homocysteine, urinary protein/creatinine ratio and urinary microalbumin increased more significantly in patients with high BPV (P<0.01 or 0.05). In addition, the combined cardiovascular events in 5-10 years were significantly higher in the patients with higher BPV than those with lower BPV (P<0.01 or 0.05). Logistic multivariate logistic regression analysis showed that alcohol, diabetes, coronary heart disease, uric acid and homocysteine were independent risk factors for cardiovascular events in hypertensive patients (P<0.01 or 0.05). CONCLUSION: In hypertensive patients, BPV is closely correlated with the long-term combined cardiovascular events, and a high BPV is associated with a greater likeliness of combined cardiovascular events. PMID- 28736369 TI - [An ultrasonographic study of the correlation between developmental dysplasia of the hip and congenital muscular torticollis in children]. AB - OBJECTIVE: To investigate the significance of early screening of pediatric developmental dysplasia of the hip (DDH) and congenital muscular torticollis (CMT) using ultrasonography and establish a simultaneous screening model for pediatric DDH and CMT. METHODS: From January, 2013 to January, 2016, a total of 5060 pediatric patients with suspected DDH and CMT underwent ultrasonic examinations. The diagnostic results of the two diseases were classified into different clinical types, and Chi-square test was used to analyze the one-way relationship between different types of DDH and CMT; correspondence analysis was used for multivariate analysis of the variables. Chi-square test was used to analyze the difference between the detection rates in suspected CMT patients and the normal population. RESULTS: GrafIIa type DDH was associated with mass-type CMT in the children (chi2=331.800, P<0.001). DDH of GrafIIb, GrafIIc, Graf III, and Graf IV types were related with non-tumor type of CMT. The children with a suspected diagnosis of CMT showed a significantly higher detection rate of DDH than the normal subjects (chi2=321.889, P<0.001). CONCLUSION: DDH is closely related with CMT. Early simultaneous screening of DDH and CMT can help to improve the early diagnosis rate of CMT in children. PMID- 28736370 TI - [Pregnancy and obstetric outcomes of fresh embryo transfer versus frozen-thawed embryo transfer in women below 35 years of age]. AB - OBJECTIVE: To compare the obstetric and perinatal outcomes between fresh embryo transfer (ET) and frozen-thawed ET (the "freeze-all" strategy) and evaluate the benefits of the "freeze-all" embryo strategy for young patients. METHODS: We reviewed a total of 2091 ET cycles performed between January, 2011 and December, 2015 in women aged 20-35 years, including 1295 fresh ET cycles and 796 frozen thawed ET cycles. The demographic characteristics, ovarian stimulation syndrome, clinical pregnancy rates, live birth rate and the obstetric outcomes (gestational age, preterm delivery rate and mean birth weight) were compared between the two groups. RESULTS: The mean age of the patients receiving frozen-thawed ET cycles had a significantly younger age than those having fresh ET cycles (29.5 vs 30.2 years, P<0.05); the patients undergoing frozen-thawed ET cycles also had significantly higher estradiol level on the day of trigger (12 973 pmol/L vs 8673 pmol/L) and a greater oocyte number retrieved (12.7 vs 8.7). The incidence of severe ovarian hyperstimulation syndrome was significantly lower in patients with frozen ET than those with fresh ET (P<0.05). No significant differences were found in the pregnancy rate (59.5% vs 56.0%; P>0.05), live birth rate (50.3% vs 47.0%; P>0.05), mean birth weight or gestational age between the two groups. CONCLUSIONS: The freeze-all policy produces similar pregnancy and obstetric outcomes with those of fresh ET. Our results support the hypothesis that the freeze-all strategy help to prevent OHSS with a good pregnancy rate. PMID- 28736371 TI - [Multifocal electroretinography for therapeutic effect evaluation of intravitreal injection Lucentis for wet age-related macular degeneration]. AB - OBJECTIVE: To evaluate the changes in retinal functions using multifocal electroretinography (mfERG) following intravitreal injection of Lucentis for treatment of wet age-related macular degeneration. METHODS: This prospective study was conducted in 14 patients (9 men and 5 women, 14 eyes) with wet age related macular degeneration receiving treatment with intravitreal injections of ranibizumab (Lucentis) in our hospital between October, 2014 and January, 2016. All the patients received the treatment following a 1+PRN protocol and after the initial injection, the patients were followed up monthly for 6 months to decide if additional injections were needed. The corrected visual acuity and mfERG findings of the patients were assessed before and at l, 3 and 6 months after the initial injection. RESULTS: At the last follow-up, the patients received injections for a mean of 2.86?1.58 times. The best corrected visual acuity (BCVA) at 1 month after the initial treatment was not significantly different from that before treatment (P=0.07), but showed significant improvements at 3 and 6 months (P<0.05). In mfERG, the implicit time of the 6 rings showed no significant decrease after the treatment, but the amplitude density of P1 and N1 in rings 1 and 2 improved significantly at 1, 3, and 6 months after the initial injection (P<0.05). CONCLUSION: Multifocal electroretinography can serve as a useful modality for evaluating visual function changes in patients receiving intravitreal injection of Lucentis for wet age-related macular degeneration. PMID- 28736372 TI - [Clinical value of apolipoprotein B versus low-density lipoprotein cholesterol in assessing risks of coronary artery disease]. AB - OBJECTIVE: To compare the value of apolipoprotein B (apoB) and low-density lipoprotein cholesterol (LDL-C) in assessing the risk of coronary heart disease in patients with inconsistent apoB and LDL-C levels. METHODS: In a total of 603 patients undergoing coronary angiography, apoB and LDL-C levels were categorized into high and low levels relative to the median levels of apoB and LDL-C, based on which the patients were divided into 4 groups with low apoB/low LDL-C, low apoB/high LDL-C, high apoB/low LDL-C, or high apoB/high LDL-C. According to the results of coronary angiography, we evaluated the number of coronary artery branches with lesions and the severity of coronary artery stenosis in the 4 groups to assess the correlation of apoB and LDL-C with cardiovascular risks. RESULTS: We found significant differences in the number of coronary artery branches with lesions and the severity of coronary artery stenosis among the 4 groups (P<0.05). The number of coronary artery branches involved and the severity of stenosis differed significantly between patients with consistently high and low apoB/LDL-C levels (P<0.005). Compared with those with low apoB/low LDL-C levels, the patients with high apoB/low LDL-C levels showed a significantly greater number of coronary artery branches with lesions (P=0.017) and more severe stenosis (P=0.034), but such differences were not found in patients with low apoB/high LDL-C levels. Pearson correlation analysis identified LDL-C and apoB as the risk factors for cardiovascular disease with areas under the ROC curve of 0.579 (P=0.014) and 0.589 (P=0.006), respectively. CONCLUSIONS: In patients with inconsistent levels of apoB and LDL-C, apoB and LDL-C levels are both risk factors of coronary heart disease in close relation with the disease severity. LDL-C and apoB are comparable for their important values in predicting the risk of coronary heart disease. PMID- 28736373 TI - [Relationship between hyperuricemia and adverse events in patients aged 40 years or older receiving rheumatic aortic valve replacement]. AB - OBJECTIVE: To explore the prognostic value of hyperuricemia for adverse events in patients >40 years old receiving valve replacement surgery for rheumatic aortic valve disease. METHDS: Consecutive middle-aged and elderly patients receiving aortic valve replacement surgery for rheumatic aortic valve disease between March, 2009 and July, 2013 were recruited in this study. The patients were divided into hyperuricemic group and normouricemic group based on their serum levels of uric acid, and the clinical data and adverse events within 1 year after the surgery were compared between the 2 groups. RESULTS: A total of 632 consecutive patients were recruited, including 381 patients with hyperuricemia and 251 with normouricemia. The in-hospital mortality rate was significantly higher in hyperuricemic group than in normouricemic group (7.6% vs 2.0%, P=0.002). Serum uric acid levels were negatively correlated with eGFR (r=-0.421, P<0.001) and positively correlated with C-reactive protein level (r=0.093, P=0.025). Multivariate analysis showed that hyperuricemia was independently associated with the in-hospital mortality (OR=3.07, 95%CI: 1.13-8.37, P=0.028) and mortality at 1 year after the surgery (HR=3.14, 95%CI: 1.30-7.62, P=0.011) after adjusting for potential risk factors including age, NYHA III-IV and postoperative acute kidney injury (AKI). Kaplan-Meier analysis showed that the cumulative rate of 1-year mortality after surgery was significantly higher in patients with hyperuricemia (Log-rank=11.73, P=0.001). CONCLUSION: Hyperuricemia is a predictor of in-hospital and one-year mortality in middle-aged and elderly patients following aortic valve replacement surgery for rheumatic aortic valve disease. PMID- 28736375 TI - [Expression of vasohibin-1 and MACC1 in lung squamous cell carcinoma and their clinicopathological significance]. AB - OBJECTIVE: To investigate the expressions of vasohibin-1 and MACC1 in lung squamous cell carcinoma (LSCC) and their associations with the clinicopathological characteristics of the patients. METHODS: The expressions of vasohibin-1 and MACC1 proteins were examined with immunohistochemistry in 160 LSCC tissues and 80 normal lung tissues. RESULTS: The positivity rates of vasohibin-1 and MACC1 proteins were 59.4% and 11.3% in LSCC tissues, respectively, which were significantly higher than the rates in normal lung tissues (57.5% and 8.8%, respectively; P<0.05). The expressions of vasohibin-1 and MACC1 proteins were significantly correlated with the tumor grades, lymph node metastasis, and TNM stages (all P<0.05). Spearman correlation analysis indicated a positive correlation between vasohibin-1 expression and MACC1 expressions (P<0.001). Kaplan-Meier survival analysis showed that LSCC patients with a positive expression of vasohibin-1 had significantly shorter overall survival time than those negative for vasohibin-1; the overall survival time was also significantly shorter in patients positive for MACC1 than in those negative for MACC1 (both P<0.05). Multivariate COX regression analysis indicated that positive expressions of vasohibin-1 and MACC1 protein and TNM stage were independent prognostic factors of LSCC. CONCLUSION: Aberrant expressions of vasohibin-1 and MACC1 may participate in the development and promote invasion and metastasis of LSCC. The combined detection of vasohibin-1 and MACC1 expression may provide important evidence for predicting the progression and prognosis of LSCC. PMID- 28736374 TI - [Low cement distribution index is a risk factor for refracture of the adjacent segments after percutaneous vertebroplasty]. AB - OBJECTIVE: To investigate the impact of cement distribution index on the occurrence of refracture in the adjacent segments after percutaneous vertebroplasty. METHODS: This retrospective analysis was conducted among 143 patients who received percutaneous vertebroplasty for osteoporotic vertebral compression fracture between April, 2011 and April, 2014. Of the 134 patients with complete follow-up data, 18 had adjacent segment fracture within 1 year following the surgeries (re-fracture group), and 116 patients without new fracture served as the control group. All the patients underwent X-ray examinations after the surgery and according to the position and shape, the cement in the vertebrae were classified into 5 types (I to V), and the volume cubage index was computed based on the cement volume and vertebral cubage. Age, gender, bone mineral density (BMD), cement distribution index, volume-cubage index, and cement leakage were evaluated in the 2 groups, and the variables with significant differences between the 2 groups were analyzed in Logistic regression analysis. RESULTS: BMD was significantly lower and the rate of cement leakage was significantly higher in the re-fracture group than in the control group (P<0.05). Significant difference was found in cement distribution index between the 2 groups (P<0.05) but not in age, gender, cement volume or volume-cubage index (P>0.05). Logistic regression analysis indicated that BMD, cement leakage and cement distribution index all significantly affected the occurrence of adjacent vertebral fractures following percutaneous vertebroplasty. CONCLUSION: A low BMD, cement leakage and a low cement distribution index are all risks factor of adjacent vertebral fracture after percutaneous vertebroplasty. PMID- 28736376 TI - [Protective effects of glycyrrhizic acid against lupus nephritis in MRL/lpr mice]. AB - OBJECTIVE: To investigate protective effect of glycyrrhizic acid (GA) against lupus nephritis in MRL/lpr mice and explore its underlying mechanisms. METHODS: Forty MRL/lpr mice were randomized equally into blank control group, dexamethasone (1.5 mg/kg) group, GA (20 mg/kg) group, and GA (40 mg/kg) group with corresponding treatments for 7 days, with 10 wild-type mice as the control group. Serum levels of uric acid and creatinine and inflammatory cytokines in the serum and kidney were tested after the treatments using enzyme-linked immunosorbent assays (ELISA). The pathological changes in the kidneys were detected using HE staining, and the protein expressions of NLRP3, ASC, caspase-1, IL-1beta, p-NF-kappaB, NF-kappaB, p-IkappaBalpha, and IkappaBalpha were detected with Western blotting. RESULTS: GA obviously decreased serum levels of uric acid and creatinine, decreased inflammatory cytokines in the serum and kidney, ameliorated renal pathologies and inhibited the expressions of NLRP3, ASC, caspase-1, IL-1beta, p-NF-kappaB, and p-IkappaBalpha proteins in MRL/lpr mice. CONCLUSION: GA has protective effects against lupus nephritis in MRL/lpr mice. PMID- 28736377 TI - [Association of RAS mutations in circulating cell-free DNA in the plasma with clinicopathological features of colorectal cancer]. AB - OBJECTIVE: To detect RAS mutations in the circulating cell-free DNA (cfDNA) in the plasma and explore the their correlation with the clinicopathological features in patients with colorectal cancer. METHODS: Real-time PCR was used to detect RAS mutations in plasma cfDNA and matched tumor tissue DNA samples from 71 colorectal cancer patients. The correlation of RAS mutations with the clinicopathological features of the patients were analyzed. RESULTS: Of the 71 patients with colorectal cancer, 23 (32.39%) showed RAS mutations in the cfDNA and 36 (50.7%) showed RAS mutations in tumor tissue DNA, with a concordance rate of 76.06% in the results between the two samples (Kappa=0.523). RAS mutations in the cfDNA were not related to the patients' age (P=0.072), gender (P=0.320), tumor stage (IVa and IVb, P=0.450), primary tumor position (P=0.324), lung metastasis (P=0.237), CEA level (P=0.284) or CA199 level (P=0.427). The positivity rate of RAS mutations in plasma cfDNA was significantly higher in patients with liver metastasis than those without liver metastasis (P=0.045). CONCLUSION: Plasma cfDNA can be a reliable source of diagnostic DNA to replace the tumor tissue DNA for diagnosis of RAS mutations. RAS mutations in plasma cfDNA occur more frequently in colorectal cancer patients with liver metastasis. PMID- 28736378 TI - [Optimization of emollient formulation for treating atopic dermatitis by skin physiological index testing]. AB - OBJECTIVE: To optimize the formulation of an emollient for treatment of atopic dermatitis prepared using ceramide, sodium hyaluronate, paeonol, and camellia seed oil. METHODS: The emollients with different ratios of the 4 components were designed according to the L9(34)orthogonal table with 4 factors and 3 levels. The efficacy of the prepared emollients was tested in 4-6 week-old BALB/c mouse models of atopic dermatitis to determine the optimal formulation of the emollient by evaluating skin water content, transepidermal water loss (TEWL), pharmacodynamics and skin irritation. RESULTS: Range analysis of the orthogonal table and analysis of variance showed that ceramide and camellia seed oil contents had the greatest impact on the skin water content and TEWL, respectively, and the optimal composition of the emollient contained the 4 components at the ratios of D1E1F1G1. Pharmacodynamic experiments showed that at high, medium and low doses, the emollient with the optimal formulation significantly improved the skin water content, pH and TEWL in the mice (P<0.05) with similar effects in the positive control group (P>0.05) and a skin irritation test score of 0. CONCLUSION: The emollient we prepared can significantly improve skin water content, pH and TEWL in the mouse model of atopic dermatitis without skin irritations. PMID- 28736379 TI - [Preparation of nanoparticles for sustained insulin release using poly (ethylene glycol) -poly (epsilon-caprolactone)-poly (N, N-diethylamino-2 ethylmethaerylate)]. AB - OBJECTIVE: To prepare an insulin-loaded nanoparticle assembled using pH-sensitive poly(ethylene glycol)-poly(epsilon-caprolactone)-poly(N,N-diethylamino-2 ethylmethaerylate) (mPEG-PCL-PDEAEMA) and investigate its performance of sustained insulin release in vitro and its hypoglycemic effects in diabetic rats. METHDOS: mPEG-PCL-PDEAEMA triblock copolymers with different hydrophobic lengths were synthesized by ring opening polymerization (ROP) combined with atom transfer radical polymerization (ATRP). The copolymers were characterized using Fourier transform Infrared (FT-IR) spectroscopy and proton nuclear magnetic resonance spectroscopy (1H-NMR). Insulin-loaded nanoparticles were prepared by nanoprecipitation technique, in which the reversible swelling of the pH-sensitive material was used for insulin loading and release. The obtained nanoparticles were further confirmed by dynamic light scattering (DLS) and transmission electron microscopy (TEM). The entrapment efficiency (EE%), drug loading (DL%) and in vitro release characteristics of the insulin- loaded nanoparticles were assessed using BCA protein assay kit. The hypoglycemic effects of the nanoparticles were evaluated by monitoring the glucose levels. RESULTS: The size of the nanoparticles decreased as pH value increased within the range of 1.2 to 7.4. Using copolymers mPEG5k-PCL13k- PDEAEMA10k and mPEG5k-PCL10k-PDEAEMA10k as the drug carriers, the nanoparticles prepared with an optimal insulin-coplymer mass ratio of 90% had an average size of 181.9?6.67 nm and 169?7.1 nm, maximal EE% of (81.99?1.77)% and (53.12?0.62)%, and maximal DL% of (42.46?0.53)% and (32.34?0.26)%, respectively. Compared with free insulin, the insulin-loaded nanoparticles was capable of sustained insulin release and the release rate was lowered as the hydrophobic length increases. In diabetic rats, the insulin-loaded nanoparticles based on mPEG5k-PCL13k- PDEAEMA10k maintained a sustained hypoglycemic effect for 48 h, which was significantly longer than the time of free insulin. CONCLUSION: The pH-sensitive triblock copolymer mPEG-PCL-PDEAEMA can serve as a promising candidate of carrier for sustained release of insulin. PMID- 28736380 TI - [Association of FasL-844T/C gene polymorphism with FasL expression in the nucleus pulposus of degenerative lumbar intervertebral discs]. AB - OBJECTIVE: To investigate the association of FasL-844T/C gene polymorphism with the magnetic resonance imaging (MRI) findings and FasL expression in the nucleus pulposus of degenerative lumbar intervertebral discs. METHODS: Lumbar MRI data, venous blood and nucleus pulposus were collected from 105 patients with lumbar disc herniation. The genotypes of FasL-844T/C gene of the patients were determined using matrix-assisted laser desorption ionization time-of-flight mass spectrometry. Immunohistochemistry was used to detect the expression of FasL in the nucleus pulposus of the degenerative lumbar intervertebral discs. RESULTS: Compared with CC genotype, TT genotype of FasL-844T/C gene was associated with a significantly increased score of lumbar disc degeneration (P=0.003) as observed in MRI scan. FasL expression in the nucleus pulposus differed significantly between patients of FASL-844CC genotype and those of FASL-844TT genotype (P=0.048), but not between those of FASL-844CC and FASL-844CT genotypes (P=0.264). No significant association was found between MRI findings and FasL expression in the nucleus pulposus of the lumbar intervertebral discs. CONCLUSION: FasL-844T/C gene polymorphism is correlated with the expression of FasL in the nucleus pulposus of the intervertebral disc in patients with lumbar disc herniation. MRI findings of the lumbar intervertebral discs do not correlate with the expression of FasL in the nucleus pulposus of the intervertebral discs. PMID- 28736381 TI - [Efficacy of ACEI in the treatment of hypertension and the effect of secondary prevention in patients complicated with coronary heart disease and stroke]. AB - OBJECTIVE: To investigate the efficacy of ACEI drugs in the treatment of hypertension patients and the effect of two levels of prevention of hypertension complicated with coronary heart disease and stroke. METHDOS: 210 cases of hypertension patients in our hospital from January 2012 to December 2015 were randomly divided into experimental group and control group, 105 cases in each group. According to the conventional symptomatic treatment, the experimental group was given lisinopril treatment, while control group was given the captopril treatment. Changes of blood pressure parameters and the level of baPWV in two groups were observed before and after treatment coronary heart disease and stroke, recurrence rate and death rate were compared in these two groups. RESULTS: No significant difference of SBP, DBP, PP and baPWV between two groups before treatment (P>0.05). The indexes of the two groups were significantly decreased after 1 months and 3 months, and the level of patients in the experimental group was lower than that of the control group (P<0.05). The recurrence rate in the experimental group was lower than those in the control group (P<0.05). CONCLUSIONS: ACEI drugs in the treatment of hypertension can effectively reduce the level of blood pressure, improve arterial elasticity function, reduce the recurrence rate and mortality rate of coronary heart disease and stroke. The effect of antihypertensive and two levels of prevention of hypertension complicated with coronary heart disease and stroke of lisinopril is positive. PMID- 28736382 TI - [Value of red blood cell distribution width in assessing the severity of acute pancreatitis]. AB - OBJECTIVE: To explore the value of red blood cell distribution width (RDW) in assessment of the severity of acute pancreatitis (AP). METHODS: This retrospective analysis was conducted among 527 patients with AP treated in our department from May, 2013 to May, 2016. According to the severity of the condition, the patients were classified into mild acute pancreatitis (MAP) group, moderately severe acute pancreatitis (MSAP) group and severe acute pancreatitis (SAP) group, with 105 subjects without AP as the control group. The demographic data and data of RDW were collected from all cases to evaluate the value of RDW in assessing the severity of AP in comparison with classic evaluation indicators glucose (Glu) and calcium (Ca). RESULTS: The patients with AP and the control subjects showed significant differences in RDW, Glu and Ca (P<0.05). RDW and Glu was significantly higher but Ca was significantly lower in SAP patients than in MAP and MSAP patients (P<0.05). Binary classification logistic regression analysis showed that Glu (P<0.05, OR=2.343), Ca (P<0.05, OR=2.182) and RDW (P<0.05, OR=3.374) were all independent risk factors for AP. The area under the ROC curve for predicting SAP decreased in the order of RDW (0.801), Glu (0.658), and Ca (0.227). CONCLUSION: RDW is a useful indicator for evaluation of the severity of AP. PMID- 28736383 TI - [Identification of a new 3.8kb deletional alpha thalassemia and detection of the deletion fragment]. AB - OBJECTIVE: To report the identification of a novel 3.8-kb deletion that caused alpha thalassemia and establish the method for detecting the deletion fragment. METHODS: Peripheral blood samples were collected from the proband and his mother for analysis of the hematological parameters and routine test for thalassemia genes. For the sample with an inconsistency between the genotyping results and phenotypic analysis results, a specific gap-PCR was employed to identify the rare or novel mutations. RESULTS: A novel 3814-bp deletion causing alpha thalassemia was found in the proband and his mother, who had genotypes of -alpha4.2/-alpha3.8 and alphaalpha/-alpha3.8, respectively. CONCLUSION: We identified a 3.8-kb deletion in the alpha-globin gene cluster that caused alpha thalassemia, and this finding enriches the alpha thalassemia gene mutation spectrum. Specific gap-PCR offers a convenient and efficient means for for detecting this deletion fragment. PMID- 28736384 TI - [Revisional surgery for nonstandard gastric bypass: a case report]. AB - Bariatric surgery is the most effective treatment for obesity with or without type 2 diabetes mellitus and its complications. With the growing incidence of type 2 diabetes mellitus, the number of hospitals performing bariatric surgery and surgical cases increase substantially. The problems in operation standardization, quality control of operation and postoperative management of the patients cause the failure in weight loss, hypoglycemia and severe complications, and revisional surgery is often required to correct the condition. We report a case of laparoscopic revisional surgery following nonstandard gastric bypass, and the reasons for failure of weight loss in first bariatric surgery, the current situation of bariatric surgery and revisional metabolic surgery were analyzed. This case demonstrates the clinical necessity of revisonal bariatric surgery and the importance of selection of the surgical approaches and indications. PMID- 28736386 TI - Stroke Prevention in Atrial Fibrillation in the Very Elderly: Anticoagulant Therapy Is No Longer a Sin. PMID- 28736385 TI - Thromboembolic Risk, Bleeding Outcomes and Effect of Different Antithrombotic Strategies in Very Elderly Patients With Atrial Fibrillation: A Sub-Analysis From the PREFER in AF (PREvention oF Thromboembolic Events-European Registry in Atrial Fibrillation). AB - BACKGROUND: Increasing age predisposes to both thromboembolic and bleeding events in patients with atrial fibrillation; therefore, balancing risks and benefits of antithrombotic strategies in older populations is crucial. We investigated 1-year outcome with different antithrombotic approaches in very elderly atrial fibrillation patients (age >=85 years) compared with younger patients. METHODS AND RESULTS: We accessed individual patients' data from the prospective PREFER in AF (PREvention oF thromboembolic events-European Registry in Atrial Fibrillation), compared outcomes with and without oral anticoagulation (OAC), and estimated weighed net clinical benefit in different age groups. A total of 6412 patients, 505 of whom were aged >=85 years, were analyzed. In patients aged <85 years, the incidence of thromboembolic events was 2.8%/year without OAC versus 2.3%/year with OAC (0.5% absolute reduction); in patients aged >=85 years, it was 6.3%/year versus 4.3%/year (2% absolute reduction). In very elderly patients, the risk of major bleeding was higher than in younger patients, but similar in patients on OAC and in those on antiplatelet therapy or without antithrombotic treatment (4.0%/year versus 4.2%/year; P=0.77). OAC was overall associated with weighted net clinical benefit, assigning weights to nonfatal events according to their prognostic implication for subsequent death (-2.19%; CI, -4.23%, -0.15%; P=0.036). We found a significant gradient of this benefit as a function of age, with the oldest patients deriving the highest benefit. CONCLUSIONS: Because the risk of stroke increases with age more than the risk of bleeding, the absolute benefit of OAC is highest in very elderly patients, where it, by far, outweighs the risk of bleeding, with the greatest net clinical benefit in such patients. PMID- 28736387 TI - Effect of Pregnancy on Ventricular and Aortic Dimensions in Repaired Tetralogy of Fallot. AB - BACKGROUND: The aim was to assess whether cardiovascular adaptation to pregnancy in women with repaired tetralogy of Fallot (TOF) adversely affects hemodynamic stability, in particular with respect to right ventricular (RV) dilatation, pulmonary regurgitation, or aortic root dilatation. METHODS AND RESULTS: This was a retrospective cohort study of women with repaired TOF with paired cardiovascular magnetic resonance scans before and after their first pregnancy (baseline RV end systolic volume index 49 mL/m2 and RV end diastolic volume index 118 mL/m2) matched with a comparison group of nulliparous women with TOF. Cases were matched for age at baseline cardiovascular magnetic resonance scan, time between follow-up of cardiovascular magnetic resonance scans, QRS duration, RV ejection fraction, and indexed RV end systolic and diastolic volume at baseline. Effect of pregnancy and time on parameters was assessed using mixed-effects modelling. Nineteen women with repaired TOF who had completed their first pregnancy were identified and matched with 38 nulliparous women. We observed no deleterious effects of pregnancy on RV volumes, aortic dimensions, or exercise data. There was an effect of pregnancy observed in both left ventricular end diastolic volume and left ventricular stroke volume, consistent with a sustained small increase in left ventricular stroke volume attributed to pregnancy (53-55 mL/m2). CONCLUSIONS: Women with repaired TOF and with mild-to-moderate RV dilatation considering pregnancy can be reassured that pregnancy is unlikely to cause deterioration in their cardiovascular status. We recommend that women are routinely assessed and followed up before and after pregnancy and that prepregnancy counseling is tailored to their individual clinical status. PMID- 28736388 TI - Physical Activity and Characteristics of the Carotid Artery Wall in High-Risk Patients-The SMART (Second Manifestations of Arterial Disease) Study. AB - BACKGROUND: Physical activity reduces the risk of vascular disease. This benefit is not entirely explained through an effect on vascular risk factors. We examined the relationship of physical activity and characteristics of the carotid artery wall in patients with vascular disease or risk factors. METHODS AND RESULTS: Cross-sectional analyses were performed in 9578 patients from the SMART (Second Manifestations of Arterial Disease) study, a prospective cohort study among patients with vascular disease or risk factors. Physical activity was assessed using questionnaires. Carotid intima-media thickness and carotid artery stenosis of both common carotid arteries was measured. In a subset of 3165 participants carotid diastolic diameter and distension were assessed. Carotid stiffness was expressed as the distensibility coefficient and Young's elastic modulus. Regression analyses adjusted for vascular risk factors showed that physical activity was inversely associated with diastolic diameter (fifth versus first quintile B=-0.13 mm; 95% CI, -0.21 to -0.05) and decreased risk of carotid artery stenosis (relative risk, 0.58; 95% CI, 0.48-0.69). A light level of physical activity was associated with less carotid stiffness (second versus first quintile; Young's elastic modulus B=-0.11 kPa-1*10-3; 95% CI, -0.16 to -0.06; distensibility coefficient B=0.93 kPa*103; 95% CI, 0.34-1.51), but there was no additional benefit with increasing levels of physical activity. In patients with vascular disease, physical activity was inversely associated with common carotid intima-media thickness, but not in patients with vascular risk factors. CONCLUSIONS: In patients with vascular disease or risk factors, increased physical activity was associated with smaller carotid diastolic diameter, decreased risk of carotid artery stenosis, and less carotid stiffness, but it only showed benefits on carotid intima-media thickness in patients with vascular disease. PMID- 28736389 TI - HIV testing experiences and their implications for patient engagement with HIV care and treatment on the eve of 'test and treat': findings from a multicountry qualitative study. AB - OBJECTIVE: In view of expanding 'test and treat' initiatives, we sought to elicit how the experience of HIV testing influenced subsequent engagement in HIV care among people diagnosed with HIV. METHODS: As part of a multisite qualitative study, we conducted in-depth interviews in Uganda, South Africa, Tanzania, Kenya, Malawi and Zimbabwe with 5-10 health workers and 28-59 people living with HIV, per country. Topic guides covered patient and provider experiences of HIV testing and treatment services. Themes were derived through deductive and inductive coding. RESULTS: Various practices and techniques were employed by health workers to increase HIV testing uptake in line with national policies, some of which affected patients' subsequent engagement with HIV services. Provider-initiated testing was generally appreciated, but rarely considered voluntary, with instances of coercion and testing without consent, which could lead to disengagement from care.Conflicting rationalities for HIV testing between health workers and their clients caused tensions that undermined engagement in HIV care among people living with HIV. Although many health workers helped clients to accept their diagnosis and engage in care, some delivered static, morally charged messages regarding sexual behaviours and expectations of clinic use which discouraged future care seeking. Repeat testing was commonly reported, reflecting patients' doubts over the accuracy of prior results and beliefs that antiretroviral therapy may cure HIV. Repeat testing provided an opportunity to develop familiarity with clinical procedures, address concerns about HIV services and build trust with health workers. CONCLUSION: The principles of consent and confidentiality that should underlie HIV testing and counselling practices may be modified or omitted by health workers to achieve perceived public health benefits and policy expectations. While such actions can increase HIV testing rates, they may also jeopardise efforts to connect people diagnosed with HIV to long-term care, and undermine the potential of test and treat interventions. PMID- 28736390 TI - 'Side effects' are 'central effects' that challenge retention in HIV treatment programmes in six sub-Saharan African countries: a multicountry qualitative study. AB - OBJECTIVES: To explore the bodily and relational experience of taking antiretroviral therapy (ART) and the subsequent effect on retention in HIV care in six sub-Saharan African countries. METHODS: In-depth interviews were conducted with 130 people living with HIV (PLHIV) who had initiated ART, 38 PLHIV who were lost to follow-up and 53 healthcare workers (HCWs) in Kenya, Uganda, Tanzania, Malawi, Zimbabwe and South Africa. PLHIV were purposely selected to include a range of HIV treatment histories. Deductive and inductive analysis was guided by aspects of practice theory; retention in HIV care following ART initiation was the practice of interest. RESULTS: PLHIV who were engaged in HIV care took ART every day, attended clinic appointments and ate as well as possible. For PLHIV, biomedical markers acted as reassurance for their positive treatment progression. However, many described ART side effects ranging from dizziness to conditions severe enough to prevent them from leaving home or caring for themselves or others. In all settings, the primary concern of HCW was ensuring patients achieved viral suppression, with management of side effects seen as a lower priority. Where PLHIV tolerated side effects, they were deemed the lesser of two evils compared with their pre-ART illnesses. Participants who reported feeling well prior to starting ART were often less able to tolerate side effects, and in many cases these events triggered their disengagement from HIV care. CONCLUSIONS: Retention in ART care is rarely an outcome of rational decision-making, but the consequence of bodily and relational experiences. Initiatives to improve retention should consider how bodily experiences of PLHIV relate to the rest of their lives and how this can be respected and supported by service providers to subsequently improve retention in care. PMID- 28736391 TI - 'I wanted to safeguard the baby': a qualitative study to understand the experiences of Option B+ for pregnant women and the potential implications for 'test-and-treat' in four sub-Saharan African settings. AB - OBJECTIVE: To explore what influences on engagement with Option B+ in four sub Saharan African settings. METHODS: In-depth interviews were conducted in 2015, with 22 HIV-positive women who had been pregnant since Option B+ was available, and 15 healthcare workers (HCWs) involved in HIV service delivery. Participants were purposely selected from four health and demographic surveillance sites in Malawi, Tanzania and Uganda. A thematic content analysis was conducted to investigate what influenced engagement with Option B+. RESULTS: Feeling 'ready' was key to pregnant women accepting antiretroviral treatment (ART) on the same day as diagnosis at antenatal clinic; this was influenced by previous knowledge of HIV-positive status, interactions with HCWs and relationship with their partners. The desire to protect their unborn infant was the main issue that motivated women to initiate treatment, temporarily over-riding barriers to starting ART. Many HCWs recognised that pressurising women into starting ART may lead them to stop treatment following delivery. However, their own responsibility to protect the infant sometimes drove HCWs to use strong persuasive techniques to initiate pregnant women onto ART as early as possible, occasionally causing women to disengage. CONCLUSIONS: Protecting the baby superseded feelings of unpreparedness for lifelong ART and may explain poor retention observed in Option B+ programmes. Women may benefit from more time to accept their status, and counselling on the long-term value of ART beyond the pregnancy and breastfeeding period. Strategies to promote readiness for same-day initiation of lifelong treatment are urgently needed, and may provide important lessons for universal test-and-treat implementation. PMID- 28736392 TI - 'I am treated well if I adhere to my HIV medication': putting patient-provider interactions in context through insights from qualitative research in five sub Saharan African countries. AB - OBJECTIVES: The nature of patient-provider interactions and communication is widely documented to significantly impact on patient experiences, treatment adherence and health outcomes. Yet little is known about the broader contextual factors and dynamics that shape patient-provider interactions in high HIV prevalence and limited-resource settings. Drawing on qualitative research from five sub-Saharan African countries, we seek to unpack local dynamics that serve to hinder or facilitate productive patient-provider interactions. METHODS: This qualitative study, conducted in Kisumu (Kenya), Kisesa (Tanzania), Manicaland (Zimbabwe), Karonga (Malawi) and uMkhanyakude (South Africa), draws upon 278 in depth interviews with purposively sampled people living with HIV with different diagnosis and treatment histories, 29 family members of people who died due to HIV and 38 HIV healthcare workers. Data were collected using topic guides that explored patient testing and antiretroviral therapy treatment journeys. Thematic analysis was conducted, aided by NVivo V.8.0 software. RESULTS: Our analysis revealed an array of inter-related contextual factors and power dynamics shaping patient-provider interactions. These included (1) participants' perceptions of roles and identities of 'self' and 'other'; (2) conformity or resistance to the 'rules of HIV service engagement' and a 'patient-persona'; (3) the influence of significant others' views on service provision; and (4) resources in health services. We observed that these four factors/dynamics were located in the wider context of conceptualisations of power, autonomy and structure. CONCLUSION: Patient-provider interaction is complex, multidimensional and deeply embedded in wider social dynamics. Multiple contextual domains shape patient-provider interactions in the context of HIV in sub-Saharan Africa. Interventions to improve patient experiences and treatment adherence through enhanced interactions need to go beyond the existing focus on patient-provider communication strategies. PMID- 28736393 TI - Traditional healers, faith healers and medical practitioners: the contribution of medical pluralism to bottlenecks along the cascade of care for HIV/AIDS in Eastern and Southern Africa. AB - OBJECTIVES: There are concerns that medical pluralism may delay patients' progression through the HIV cascade-of-care. However, the pathways of impact through which medical pluralism influence the care of people living with HIV (PLHIV) in African settings remain unclear. We sought to establish the manifestation of medical pluralism among PLHIV, and explore mechanisms through which medical pluralism contributes bottlenecks along the HIV care cascade. METHODS: We conducted a multicountry exploratory qualitative study in seven health and demographic surveillance sites in six eastern and southern African countries: Uganda, Kenya, Tanzania, Malawi, Zimbabwe and South Africa. We interviewed 258 PLHIV at different stages of the HIV cascade-of-care, 48 family members of deceased PLHIV and 53 HIV healthcare workers. Interviews were conducted using shared standardised topic guides, and data managed through NVIVO 8/10/11. We conducted a thematic analysis of healthcare pathways and bottlenecks related to medical pluralism. RESULTS: Medical pluralism, manifesting across traditional, faith-based and biomedical health-worlds, contributed to the care cascade bottlenecks for PLHIV through three pathways of impact. First, access to HIV treatment was delayed through the nature of health-related beliefs, knowledge and patient journeys. Second, HIV treatment was interrupted by availability of alternative options, perceived failed treatment and exploitation of PLHIV by opportunistic traders and healers. Lastly, the mixing of biomedical healthcare providers and treatment with traditional and faith-based options fuelled tensions driven by fear of drug-to-drug interactions and mistrust between providers operating in different health-worlds. CONCLUSION: Medical pluralism contributes to delays and interruptions of care along the HIV cascade, and mistrust between health providers. Region-wide interventions and policies are urgently needed in sub-Saharan Africa to minimise potential harm and consequences of medical pluralism for PLHIV. The role of sociocultural beliefs in mediating bottlenecks necessitate adoption of culture-sensitive approaches intervention designs and policy reforms appropriate to the context of sub-Saharan Africa. PMID- 28736394 TI - Changing forms of HIV-related stigma along the HIV care and treatment continuum in sub-Saharan Africa: a temporal analysis. AB - OBJECTIVES: Stigma remains pervasive for people living with HIV (PLHIV) in sub Saharan Africa, undermining care engagement. Using everyday, biographical and epochal temporalities, we explored the manifestation of stigma at different stages of the HIV care continuum in seven health and demographic surveillance sites in Eastern and Southern Africa. METHODS: Between 2015 and 2016, we conducted qualitative in-depth interviews with 264 PLHIV, 54 health providers and 48 family members of people who had died from HIV. Topic guides explored experiences of HIV testing, care and treatment services. Data were analysed thematically, aided by NVivo 10. RESULTS: In everyday time across these communities, stigma was evident in the presence of gossiping and the relative absence of supportive interpersonal discourse, which fuelled judicious disclosure. This was especially disruptive at testing, counselling and early antiretroviral therapy adherence stages of care. Biographical time framed everyday stigma events, highlighting the dilemma of disclosure in relation to sexual relationship norms, as well as the interfacing of age and healthcare continuum points. Epochal patriarchal relations gave a structural context to everyday and biographical stigma dynamics. Historical shifts to social acceptance of PLHIV within these communities, while positive, were complicated by stigma in everyday life and in respect of biographical goals like having a family. Moreover, low community-level resistance to HIV-related stigma jeopardised stigma reduction strategies. CONCLUSIONS: Despite improvements to HIV care services, stigma remains pervasive across the HIV care continuum in these sites. Context specific interventions are needed to address stigma and discrimination of PLHIV within the community and in health services, and greater reflection is required to ensure policies aiming to expand HIV treatment do not exacerbate stigma and result in negative HIV outcomes. PMID- 28736395 TI - Understanding the relationship between couple dynamics and engagement with HIV care services: insights from a qualitative study in Eastern and Southern Africa. AB - OBJECTIVE: To explore the interplay between couple dynamics and the engagement of people living with HIV (PLHIV) with HIV care and treatment services in three health and demographic surveillance sites in Tanzania, Malawi and South Africa. METHODS: A qualitative study was conducted involving 107 in-depth interviews with PLHIV with a range of HIV care and treatment histories, including current users of HIV clinics, and people not enrolled in HIV care. Interviews explored experiences of living with HIV and how and why they chose to engage or not with HIV services. Thematic analysis was conducted with the aid of NVivo 10. RESULTS: We found an interplay between couple dynamics and HIV care and treatment-seeking behaviour in Tanzania, Malawi and South Africa. Being in a relationship impacted on the level and type of engagement with HIV services in multiple ways. In some instances, couples living with HIV supported each other which improved their engagement with care and strengthened their relationships. The desire to fulfil societal expectations and attract a new partner, or have a baby with a new partner, or to receive emotional or financial support, strengthened on-going engagement with HIV care and treatment. However, fear of blame, abandonment or abuse resulted in unwillingness to disclose and often led to disputes or discord between couples. There was little evidence of intracouple understanding of each other's lived experiences with HIV, and we found that couples rarely interacted with the formal health system together. CONCLUSIONS: Couple dynamics influenced engagement with HIV testing, care and treatment for both partners through a myriad of pathways. Couple-friendly approaches to HIV care and treatment are needed that move beyond individualised care and which recognise partner roles in HIV care engagement. PMID- 28736396 TI - Using theories of practice to understand HIV-positive persons varied engagement with HIV services: a qualitative study in six Sub-Saharan African countries. AB - OBJECTIVES: This article considers the potential of 'theories of practice' for studying and understanding varied (dis)engagement with HIV care and treatment services and begins to unpack the assemblage of elements and practices that shape the nature and duration of individuals' interactions with HIV services. METHODS: We obtained data from a multicountry qualitative study that explores the use of HIV care and treatment services, with a focus on examining the social organisation of engagement with care as a practice and as manifested in the lives of people living with HIV in sub-Saharan Africa. The dataset comprised of 356 interviews with participants from six countries. RESULTS: We noted fluctuating interactions with HIV services in all countries. In line with theories of practice, we found that such varied engagement can be explained by (1) the availability, absence and connections between requisite 'materialities' (eg, health infrastructure, medicines), 'competencies' (eg, knowing how to live with HIV) and 'meanings' (eg, trust in HIV services, stigma, normalisation of HIV) and (2) a host of other life practices, such as working or parenting. These dynamics either facilitated or inhibited engagement with HIV services and were intrinsically linked to the discursive, cultural, political and economic fabric of the participating countries. CONCLUSION: Practice theory provides HIV researchers and practitioners with a useful vocabulary and analytical tools to understand and steer people's differentiated HIV service (dis)engagement. Our application of practice theory to engagement in HIV care, as experienced by HIV service users and providers in six sub-Saharan African countries, highlights the need for a practice-based approach in the delivery of differentiated and patient centred HIV services. PMID- 28736397 TI - Bottlenecks to HIV care and treatment in sub-Saharan Africa: a multi-country qualitative study. PMID- 28736398 TI - Engaging with HIV care systems: why space, time and social relations matter. PMID- 28736399 TI - Competency-based medical education studying live anatomy by ultrasound. PMID- 28736400 TI - What distinguishes a competent doctor in medical education? PMID- 28736401 TI - Success and survival conference: a novel idea to resonate an underutilized concept in medical education. PMID- 28736403 TI - Combating Health Disparities in Cambodian American Communities: A CBPR Approach to Building Community Capacity. AB - BACKGROUND: Cambodian Americans have higher rates of health problems compared with the general U.S. POPULATION: A relatively modest community capacity for collecting data contributes to these disparities. OBJECTIVES: To (1) further develop the Cambodian American community's capacity to design and conduct health research meaningful to their community via a community-based participatory research (CBPR) approach, (2) train and deploy bilingual community health workers (CHWs) to gather health-related data from their communities using mobile technology, and (3) measure the feasibility and effectiveness of our efforts. METHODS: A CBPR approach was used to engage leaders of Cambodian American communities in six states to identify their research needs, develop a short community health survey administered by CHWs, and conduct the survey using iPads programmed in Khmer spoken-language format. Administrative logs and surveys of CHWs and leaders measured feasibility and effectiveness of the project. RESULTS: CHWs, leaders, and community members reported largely positive experiences with the community health survey, despite poor/inconsistent Internet connectivity. The institutional capacity of Cambodian American community-based organizations to collect health-related data in their own communities was strengthened. Our efforts proved to be both feasible and effective. CONCLUSIONS: The use of mobile technology with spoken format can be a valuable tool in accessing input from vulnerable community members, including persons who may not be literate in any language. Trained CHWs, backed by dedicated and experienced community leaders, are an asset to their communities. Together, they are uniquely placed to make important contributions to the well-being of their community. PMID- 28736404 TI - Factors That Facilitate Addressing Social Determinants of Health Throughout Community-based Participatory Research Processes. AB - BACKGROUND: Community-based participatory research (CBPR) is one approach to addressing health disparities. Considering social conditions that foster disparate health outcomes is a strength of CBPR studies that move beyond a more narrow focus on modifying individual health behaviors. OBJECTIVE: This article examines factors that facilitate addressing the social determinants of health (SDH) throughout a CBPR process. METHODS: Conducting an extensive literature review of relevant key terms and, subsequently, using purposeful snowball sampling, we identified ten CBPR partnerships that addressed SDH and conducted semistructured interviews followed by qualitative content analysis. RESULTS: We identified factors that facilitate addressing SDH, which include commitment to SDH, community partner activism/engagement, partnership maturity, and government/political support. CONCLUSIONS: We present four lessons learned that can be useful to partnerships seeking to address health disparities at multiple ecological levels beyond individual-level change. We recommend that CBPR practitioners consider the role of SDH in CBPR studies involving health disparities. PMID- 28736405 TI - The Development of Culturally Appropriate Tobacco Prevention Videos Targeted Toward Somali Youth. AB - BACKGROUND: Approximately 18% of Somali youth in Minnesota intend to use tobacco in the next year and youth perceive that 64% of their peers smoke. High perceived prevalence increases tobacco use intentions and initiation, indicating that Somali youth-targeted tobacco prevention efforts are needed. OBJECTIVES: To develop a Somali youth-targeted tobacco prevention intervention using a community based participatory research (CBPR) approach. METHODS: Three focus groups were conducted to inform the development of a tobacco prevention intervention. Three tobacco prevention videos were developed. Twenty interviews were conducted to evaluate the videos. LESSONS LEARNED: It was essential to partner with Somali youth to develop the videos. Recruitment and development of the videos were facilitated through collaborating with trusted, existing community programs. CONCLUSIONS: A CBPR approach can be used to develop a culturally tailored intervention. It was important to involve academic and community partners in all stages of the research project. PMID- 28736406 TI - Using "Policy Briefs" to Present Scientific Results of CBPR: Farmworkers in North Carolina. AB - BACKGROUND: Using scientific results to inform policy that improves health and well-being of vulnerable community members is essential to community-based participatory research (CBPR). OBJECTIVES: We describe "policy briefs," a mechanism developed to apply the results of CBPR projects with migrant and seasonal farmworkers to policy changes. LESSONS LEARNED: Policy briefs are two page summaries of published research that address a single policy issue using language and graphics to make the science accessible to diverse audiences. Policy brief topics are selected by community advocates, based on collaborative research, and address a specific policy or regulation. Development is an iterative process of discussion with community representatives. Briefs have been used to provide information to advocates, state and national policymakers, and the public. CONCLUSIONS: Disseminating CBPR results to address policy is needed. Collaborating with community partners to produce policy briefs ensures that information about concerns and struggles reflects their priorities. PMID- 28736408 TI - A Culture of Understanding: Reflections and Suggestions from a Genomics Research Community Board. AB - There has been limited community engagement in the burgeoning field of genomics research. In the wake of a new discovery of genetic variants that increase the risk of kidney failure and are almost unique to people of African ancestry, community and clinical leaders in Harlem, New York, formed a community board to inform the direction of related research. The board advised all aspects of a study to assess the impact of testing for these genetic variants at primary care sites that serve diverse populations, including explaining genetic risk to participants. By reflecting on the board's experiences, we found that community voices can have tangible impact on research that navigates the controversial intersection of race, ancestry, and genomics by heightening vigilance, fostering clear communication between researchers and the community, and encouraging researchers to cede some control. Our reflections and work provide a strong justification for longitudinal community partnerships in genomics research. PMID- 28736407 TI - Implementing Physical Activity Recommendations in a Tri-Ethnic Rural Community through a Community-University Partnership. AB - BACKGROUND: A tri-ethnic rural community with limited resources and a university Prevention Research Center (PRC) developed a partnership to promote evidence based physical activity. OBJECTIVE: The purpose of this study was to investigate how a community-university partnership can disseminate and implement ?e Commu nity Guide's recommendations for increasing physical activity and create a model for other under-resourced communities experiencing high rates of chronic disease. METHODS: Qualitative data collected through 47 semistructured interviews, meeting minutes, and local newspaper articles were coded for themes and analyzed for patterns across the data. RESULTS: Implementation resulted in the creation of new paths and trails, increased walkability throughout the community, local park enhancements, and a community-wide campaign. Lessons learned included the importance of community-defined goals and outcomes, leadership, volunteerism, mutually beneficial goals, synergy, and having nontraditional partners. CONCLUSION: This research provides a community-university partnership model for implementing evidence-based strategies to increase physical activity in rural communities. PMID- 28736409 TI - Putting the Community back into Community Health Needs Assessments: Maximizing Partnerships Via Community-Based Participatory Research. AB - THE PROBLEM: The community health needs assessment (CHNA) mandate of the Patient Protection and Affordable Care Act (ACA) has the potential to make significant and sustainable change in the health of communities. However, to date many hospital-led assessments have used traditional, top-down data collection approaches that overemphasize individualized community member deficits and underutilize collaboration across sectors. PURPOSE: The purpose of this paper is to present the principles of community-based participatory research (CBPR) as a framework for conducting CHNAs in a way that mitigates the potential for harm, waste, and misrepresentation of community assets and needs that characterizes many existing CHNA processes, illustrating the power of applying CBPR partnerships to this process. KEY POINTS: CBPR is a framework to engage community members directly in research design, the collection and analysis of data, and the creation of action plans that address research findings. Key principles include collaborative involvement, establishment of empowering processes, and long-term commitment. A case example of an innovative community partnership demonstrates the power and challenges of taking a CBPR approach to the CHNA process. CONCLUSIONS: CBPR has incredible potential to be incorporated into ACA-mandated hospital CHNAs, leading to increased impact and shared power with community members. PMID- 28736410 TI - Using Local Data to Address Abandoned Property: Lessons Learned From a Community Health Partnership. AB - THE PROBLEM: A growing body of research highlights the role of the built environment in promoting or impeding health. This research suggests that environmental issues like abandoned properties exact a toll on physical and mental health. PURPOSE: We describe a community partnership aimed at improving community health through equitable land use policies and blight remediation. KEY POINTS: A collaboration between the University of Pittsburgh and Operation Better Block, Inc. (OBB), a community development corporation in Pittsburgh, was formed. We implemented an intervention to address property abandonment using data-driven techniques. In addition to successful advocacy for city-wide policies addressing abandonment, 80% of the properties that were part of our intervention were improved or addressed by the city. CONCLUSIONS: Balancing the needs of community and academic partners can be challenging, but our experiences suggest that community health partnerships to address built environmental issues may be an important conduit to health promotion. PMID- 28736411 TI - Community-Engaged Attribute Mapping: Exploring Resources and Readiness to Change the Rural Context for Obesity Prevention. AB - BACKGROUND: Individual risk factors for obesity are well-known, but environmental characteristics that influence individual risk, especially in rural communities, are not confirmed. Rural communities face unique challenges to implementing environmental strategies, such as walkability, aimed at supporting weight healthy lifestyles. Cooperative Extension, a community-embedded weight health partner, convened and engaged community members in self-exploration of local resources and readiness to change environmental characteristics perceived to promote unhealthy eating and inactivity. This approach leveraged Extension's mission, which includes connecting rural communities with land-grant university resources. OBJECTIVES: HEAL MAPPSTM (Healthy Eating Active Living Mapping Attributes using Participatory Photographic Surveys) was developed as a participatory action research methodology. Adopted by Extension community partners, HEAL MAPPSTM involved residents in photomapping, characterizing, and communicating lived experiences of their rural community, and prioritizing interventions to change the obesogenic context. METHODS: Extension educators serving rural communities in six Western U.S. states were trained to implement HEAL MAPPSTM. Extension engaged community members who mapped and evaluated their encounters with environmental attributes that shape their dietary and activity patterns. The method partnered residents with decision makers in identifying issues, assessing resources and readiness, and prioritizing locally relevant environmental strategies to reduce access disparities for rural populations with high obesity risk. CONCLUSIONS: HEAL MAPPSTM revealed differences in resource availability, accessibility, and affordability within and among rural communities, as well as in readiness to address the obesogenic context. Extension functioned successfully as the backbone organization, and local community health partner, cooperatively implementing HEAL MAPPSTM and engaging constituents in shaping weight healthy environments. PMID- 28736413 TI - An Innovative Methodological Approach to Building Successful Community Partnerships for Improving Insurance Coverage, Health, and Health Care in High Risk Communities. AB - BACKGROUND: More than 48% of U.S. children are racial/ethnic minorities, 21% are poor, and 6% are uninsured. It is unclear, however, what methods are most effective for identifying and engaging community partners in study enrollment of these children in high-risk communities. OBJECTIVE: Evaluate a new methodological approach to the screening, identification, and intervention study enrollment of uninsured minority children. METHODS: We developed, implemented, and evaluated a methodological approach consisting of four components: (1) identify communities with the highest proportions of low-income minority families with uninsured children, (2) hire minority research staff responsible for community engagement and data collection, (3) implement and evaluate a parent mentor (PM) intervention built on community partnerships and which creates jobs, and (4) successfully execute the research by engaging appropriate community partners. RESULTS: PMs were successfully recruited (n = 15) and trained (test scores significantly improved). Large numbers (n = 97) of appropriate, diverse community partners were engaged.The most productive community partners for recruitment were schools and childcare establishments, community-based organizations, discount and niche stores, supermarkets, and churches. Community partnerships resulted in 49,631 candidate participants screened and 329 enrolled in the study. The intervention was highly successful, with PMs significantly more effective and faster than traditional outreach/enrollment in insuring uninsured minority children, sustaining coverage, improving care access, reducing out-of-pocket costs, and achieving parental satisfaction and care quality, while saving $6,045 per child insured per year. CONCLUSIONS: This innovative, community-based methodology is highly effective, and could prove useful for community-based interventions targeting a variety of childhood and adult health, health-care, and equity issues. PMID- 28736414 TI - Community Interactive Research Workshop Series: Community Members Engaged as Team Teachers to Conduct Research. AB - BACKGROUND: Vietnamese women are diagnosed with cervical cancer at twice the rate of non-Hispanic White women and the highest compared to Chinese, Filipino, Korean, and Japanese women. ? e Vietnamese Women's Health Project, a community based participatory research partnership, was developed to address this concern. In earlier studies, community members received research training. OBJECTIVES: To describe how we developed an innovative curricular research training framework. Community members developed their own learning goals and activities, taught alongside a nurse scientist, and participated in a community interactive research workshop series. METHODS: Popular education principles were used to guide team teaching. Topics, learning goals, lesson plans, and an evaluation w ere de veloped t ogether. ? ree, 4 -5.5 h our workshops were hosted. Topics included qualitative research, art of hearing data, reflexivity, analysis, validity, and dissemination. Community members and a nurse scientist co-constructed knowledge through participatory methods. ?e workshops ran concurrent to the study timeline to inform community members' research activities and vice versa. A range from 8 to 20 participants attended the workshops, of which six community members were team teachers and three facilitated at each workshop. In an evaluation, team teachers reported workshop strengths: an empathetic and trusting learn ing environment, a sense of ownership in learning, a greater under standing of roles in research partnerships, and a feel ing of safety to conduct research with academic investigators. CONCLUSIONS: Academic investigators need to be aware that co-constructing knowledge is foundational to long-term sustainability of community-based participatory research partnership (CBPR) partnerships, but requires building team capacity to conduct research collaboratively. PMID- 28736416 TI - Editorial Note. PMID- 28736417 TI - Choosing Flourishing: Toward a More "Binocular" Way of Thinking about Disability. AB - There is a long-standing debate between people who can seem to be arguing "for" and "against" disability. Those arguing for have often been disability scholars and those arguing against have often been utilitarian philosophers. At least since the mid-2000s, some on both sides have sought to move beyond that debate, but that has proved difficult. Here I seek two small steps forward. One step is critical, and is aimed at we who line up "for" disability. Specifically, I suggest that the phrase "choosing disability" is misleading in at least two ways. First, when someone argues that she should be able to gestate a child who is, e.g., deaf, she does not view deafness as a disability, but as something more like an enhancement. Second, when someone else argues that no one should selectively abort fetuses with traits like deafness, she is not arguing for choosing deafness, but against making a choice based on the presence of a disabling trait. The other step is constructive, and aimed at those lined up on both sides. I suggest that we should adopt a more "binocular" approach to thinking about disability: one which, using the social and medical "lenses" on disability, helps us see it in more depth. If we get better at having a conversation about what disability is, rather than arguing for or against it, we can get better at promoting the flourishing of people with disabilities. PMID- 28736418 TI - The Complicated Relationship of Disability and Well-Being. AB - It is widely assumed that disability is typically a bad thing for those who are disabled. Our purpose in this essay is to critique this view and defend a more nuanced picture of the relationship between disability and well-being. We first examine four interpretations of the above view and argue that it is false on each interpretation. We then ask whether disability is thereby a neutral trait. Our view is that most disabilities are neutral in one sense, though we cannot make simple generalizations about disability's relationship to well-being in other important senses. After defending this view, we discuss its practical implications for selective abortion for disability, nondisabled people's interactions with disabled people, and the use of QALYs in health policy. PMID- 28736419 TI - How Not to Argue for Selective Reproductive Procedures. AB - Many bioethicists try to secure a moral requirement to select against disability, while wishing to avoid denigrating disabled people. Dan Brock's arguments are representative of this attempt. Brock argues that the harm of giving birth to a disabled child when an able child could be had in its stead is a "nonperson affecting harm." The harm is creating a world with less opportunity and more diminishment of opportunity. I argue that the presumptions that a life with disability is ceteris paribus a worse life, and that there is an inherent badness in living with a disability are contestable and fail to provide an argument that avoids the objections that disability scholars have voiced to reproductive selection against disability. PMID- 28736420 TI - Better Parenting through Biomedical Modification: A Case for Pluralism, Deference, and Charity. AB - In this paper, I will argue that the moral assessment of the prenatal selection and postnatal modification biotechnologies requires a nuanced approach, which pays close attention to the variety of sometimes conflicting parental roles and reasons involved in decisions for and against their use. I will focus on several related but distinct reasons that parents have, or give, for modifying existing children or selecting future children. Many of these reasons are expressed in terms of more effective parenting. Because there is a plurality of legitimate parental goals, I will conclude that assessing parental interventions requires us to adjudicate conflicts or tradeoffs among those goals. PMID- 28736421 TI - Pathological, Disabled, Transgender: The Ethics, History, Laws, and Contradictions in Models that Best Serve Transgender Rights. AB - This article addresses the precarious place of transgender and gender non-cis persons in relation to their discrimination-protections in recent legal, medical, and ethical policies in the United States. At present, there exists a contradiction such that trans persons are considered "pathological" enough that they are included in the latest iteration of the American Psychiatric Association's Diagnostic and Statistical Manual (DSM-V) as "gender dysphoric," but they are not included in the category of "disabled" under the Americans with Disabilities Act (ADA). As such, trans persons in America are subject to the stigma of pathology (albeit with medical treatment) without the full protections of the ADA. By contrast, transgender and non-cis-gender Americans find their queer cohorts who are HIV-positive to be fully protected by the ADA. We ask whether transgender and non-cis-gender persons should embrace their (already pathologized) personhood as a disability. Sometimes "choosing disability" affords more rights than it deploys stigma. PMID- 28736422 TI - Choosing Accommodations: Signed Language Interpreting and the Absence of Choice. AB - This paper carves out a topic space for discussion about the ethical question of whether input from signing Deaf consumers of interpreting services ought to be included in the provision of signed language interpreter accommodations. The first section provides background about disability accommodations and practices, including how signed language interpreting accommodations are similar and dissimilar to other kinds of disability accommodations. In the second section, I offer a personal narrative of my experience as a Deaf academic who has been excluded from the interpreter selection process, highlighting some of the harmful consequences of such exclusion. In the subsequent two sections, I describe and analyze the process of choosing interpreter accommodations, starting with the process of requesting signed language interpreters and the institutionalization of this process, followed by a brief overview of privacy and autonomy concerns from the standpoint of the signing Deaf consumer. The penultimate section considers some objections to the proposal of involving more consumer choice in signed language accommodations. I conclude the paper with some concrete suggestions for a more Deaf-centered, inclusive process for choosing interpreter accommodations. PMID- 28736423 TI - Choosing Disability, Visualizing Care. AB - This article explores how visual images of dependency and care reflect and reinforce perceptions of people who are ill, disabled, or otherwise dependent, those who sustain them, and the meaning of the work they do. Scenes of care are a valuable index for understanding cultural assumptions about who is deserving of care, how and where care should be given, and who is obligated to serve as a giver of care. It positions these images in the context of the emphasis, within the disability rights movement, on independence. I argue that the insistence on independence entails a form of what Lauren Berlant calls "cruel optimism"-desire for the very things that undermine happiness and well-being-because they rely on a willful disregard of the inevitable interdependency that is a fact of all human existence, as well as the particular forms of dependency that pertain to many disabled bodies. The end of the article considers works of visual art that challenge dominant modes for representing how care is given and received. If the invisibility of caregiving is one aspect of our willful forgetting that all bodies are dependent, I'll argue that visual images of care are an essential resource for recognizing and reimagining its status in our society. One desired outcome of such reconsideration would be to complicate the meaning of autonomy-as it relates to choosing disability-as well as how the work of caregiving is acknowledged and valued. PMID- 28736424 TI - Disability Bioethics: From Theory to Practice. PMID- 28736425 TI - CD133 Regulates IL-1beta Signaling and Neutrophil Recruitment in Glioblastoma. AB - CD133, a pentaspan transmembrane glycoprotein, is generally used as a cancer stem cell marker in various human malignancies, but its biological function in cancer cells, especially in glioma cells, is largely unknown. Here, we demonstrated that forced expression of CD133 increases the expression of IL-1beta and its downstream chemokines, namely, CCL3, CXCL3 and CXCL5, in U87MG glioma cells. Although there were no apparent changes in cell growth and sphere formation in vitro and tumor growth in vivo, in vitro trans-well studies and in vivo tumor xenograft assays showed that neutrophil recruitment was markedly increased by the ectopic expression of CD133. In addition, the clinical relevance between CD133 expression and IL-1beta gene signature was established in patients with malignant gliomas. Thus, these results imply that glioma cells expressing CD133 are capable of modulating tumor microenvironment through the IL-1beta signaling pathway. PMID- 28736427 TI - Ultrasonographic features of the normal filum terminale. AB - PURPOSE: The filum terminale (FT) is a fibrous band that connects the conus medullaris to the posterior body of the coccyx. Considering the advances of ultrasonography (US) technology and improvements in the resolution of US images, we aimed to re-establish the US features of the normal FT in infants younger than 6 months of age. METHODS: We retrospectively reviewed 30 spinal US scans, stored as video clips. The internal structure of the FT and the marginal echogenicity of the FT were assessed, and transverse and longitudinal US were compared. RESULTS: On US, a central echogenic line was defined in 18 (60%) normal FTs; however, there was no visible internal structure in 12 cases (40%). The marginal echogenicity of the FT was hyperechoic in eight cases (27%) in comparison with the cauda equina and was isoechoic in 22 cases (73%). In differentiating the normal FT from the surrounding nerve roots, transverse US was superior in 18 cases (60%), while longitudinal US was superior in two cases (7%). CONCLUSION: On US, the central canal of the FT was defined in 60% of normal FTs. Hyperechoic marginal echogenicity and the use of transverse US were helpful in distinguishing the normal FT from the nerve roots of the cauda equina. PMID- 28736426 TI - Modulation of Mitochondrial Membrane Potential and ROS Generation by Nicotinamide in a Manner Independent of SIRT1 and Mitophagy. AB - Nicotinamide (NAM) plays essential roles in physiology through facilitating NAD+ redox homeostasis. Importantly, at high doses, it protects cells under oxidative stresses, and has shown therapeutic effectiveness in a variety of disease conditions. In our previous studies, NAM lowered reactive oxygen species (ROS) levels and extended cellular life span in primary human cells. In the treated cells, levels of NAD+/NADH and SIRT1 activity increased, while mitochondrial content decreased through autophagy activation. The remaining mitochondria were marked with low superoxide levels and high membrane potentials (Deltapsim); we posited that the treatment of NAM induced an activation of mitophagy that is selective for depolarized mitochondria, which produce high levels of ROS. However, evidence for the selective mitophagy that is mediated by SIRT1 has never been provided. This study sought to explain the mechanisms by which NAM lowers ROS levels and increases Deltapsim. Our results showed that NAM and SIRT1 activation exert quite different effects on mitochondrial physiology. Furthermore, the changes in ROS and Deltapsim were not found to be mediated through autophagy or SIRT activation. Rather, NAM suppressed superoxide generation via a direct reduction of electron transport, and increased Deltapsim via suppression of mitochondrial permeability transition pore formation. Our results dissected the effects of cellular NAD+ redox modulation, and emphasized the importance of the NAD+/NADH ratio in the mitochondria as well as the cytosol in maintaining mitochondrial quality. PMID- 28736428 TI - Penile Doppler ultrasonography revisited. AB - Penile Doppler ultrasonography is a high-performing, noninvasive or minimally invasive imaging modality that allows the depiction of the normal anatomy and macroscopic pathologic changes in real time. Moreover, functional changes in penile blood flow, as seen in erectile dysfunction (ED), can be analyzed using color Doppler ultrasonography (CDUS). This review article describes the normal sonographic anatomy of the penis, the sonographic technique for evaluating ED, the normal phases of erection, and the various causes of ED. Additionally, we describe the interpretation of different parameters and findings on penile CDUS for the diagnosis and classification of ED, priapism, and Peyronie disease. PMID- 28736429 TI - Ultrasound-guided genitourinary interventions: principles and techniques. AB - Ultrasound (US) is often used to guide various interventional procedures in the genitourinary (GU) tract because it can provide real-time imaging without any radiation hazard. Moreover, US can clearly visualize the pathway of an aspiration or biopsy needle to ensure the safety of the intervention. US guidance also helps clinicians to access lesions via the transabdominal, transhepatic, transvaginal, transrectal, and transperineal routes. Hence, US-guided procedures are useful for radiologists who wish to perform GU interventions. However, US-guided procedures and interventions are difficult for beginners because they involve a steep initial learning curve. The purpose of this review is to describe the basic principles and techniques of US-guided GU interventions. PMID- 28736432 TI - Polycystic kidney disease: DZIP1L defines a new functional zip code for autosomal recessive PKD. PMID- 28736431 TI - Combined Blockade of T Cell Immunoglobulin and Mucin Domain 3 and Carcinoembryonic Antigen-Related Cell Adhesion Molecule 1 Results in Durable Therapeutic Efficacy in Mice with Intracranial Gliomas. AB - BACKGROUND Glioblastoma multiforme (GBM) evades immune surveillance by inducing immunosuppression via receptor-ligand interactions between immune checkpoint molecules. T cell immunoglobulin and mucin domain 3 (Tim-3) is a key checkpoint receptor responsible for exhaustion and dysfunction of T cells and plays a critical role in immunosuppression. Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) has been recently identified as a heterophilic ligand for Tim-3. MATERIAL AND METHODS We established an intracranial GBM model using C57BL/6 mice and GL261 cells, and treated the mice with single or combined monoclonal antibodies (mAbs) against Tim-3/CEACAM1. The CD4+, CD8+, and regulatory T cells in brain-infiltrating lymphocytes were analyzed using flow cytometry, and the effector function of T cells was assessed using ELISA. We performed a rechallenge by subcutaneous injection of GL261 cells in the "cured" (>90 days post-orthotopic tumor implantation) and naive mice. RESULTS The mean survival time in the control, anti-Tim-3, anti-CEACAM1, and combined treatment groups was 29.8, 43.4, 42.3, and 86.0 days, respectively, with 80% of the mice in the combined group becoming long-term survivors showing immune memory against glioma cells. Infiltrating CD4+ and CD8+ T cells increased and immunosuppressive Tregs decreased with the combined therapy, which resulted in a markedly elevated ratio of CD4+ and CD8+ cells to Tregs. Additionally, plasma IFN-gamma and TGF beta levels were upregulated and downregulated, respectively. CONCLUSIONS Our data indicate that combined blockade of Tim-3 and CEACAM1 generates robust therapeutic efficacy in mice with intracranial tumors, and provides a promising option for GBM immunotherapy. PMID- 28736430 TI - A Case of Type 1 Autoimmune Pancreatitis (AIP), a Form of IgG4-Related Disease (IgG4-RD). AB - BACKGROUND Type 1 autoimmune pancreatitis (AIP), also known as lymphoplasmacytic sclerosing pancreatitis (LPSP), is a rare cause of chronic pancreatitis, characterized by a fibro-inflammatory process. However, patients with AIP may have a good response to corticosteroid therapy. We describe a Tunisian patient with AIP that was confirmed to be an IgG4-related disease (IgG4-RD). CASE REPORT We describe a case of a 70-year-old man who was admitted to hospital for obstructive jaundice and abdominal pain. Serum liver function tests were abnormal and upper abdominal computed tomography (CT) imaging showed diffuse pancreatic swelling and strictures of the main pancreatic duct without any focal lesion. Pancreatico-biliary magnetic resonance imaging (MRI) showed a thickened rim surrounding the pancreatic duct Serum IgG4 levels were elevated, resulting in a diagnosis of IgG4-related AIP. The patient showed a good clinical, biochemical, and radiological response following steroid therapy in combination with azathioprine. CONCLUSIONS The diagnostic workup of IgG4-RD is complex and usually requires a combination of clinical examination, imaging, and serological analysis. As this case report has demonstrated, IgG4-RD should be considered in patients who present with pancreatitis or AIP, because of the favorable response to steroid therapy, particularly when treatment is initiated early. PMID- 28736433 TI - Diabetes mellitus: Complex interplay between metformin, AKI and lactic acidosis. PMID- 28736434 TI - Diabetic nephropathy: Restoring podocyte proteostasis in DN. PMID- 28736438 TI - Alternative splicing: A thermometer controlling gene expression. PMID- 28736437 TI - Dissecting evolution and disease using comparative vertebrate genomics. AB - With the generation of more than 100 sequenced vertebrate genomes in less than 25 years, the key question arises of how these resources can be used to inform new or ongoing projects. In the past, this diverse collection of sequences from human as well as model and non-model organisms has been used to annotate the human genome and to increase the understanding of human disease. In the future, comparative vertebrate genomics in conjunction with additional genomic resources will yield insights into the processes of genome function, evolution, speciation, selection and adaptation, as well as the quantification of species diversity. In this Review, we discuss how the genomics of non-human organisms can provide insights into vertebrate biology and how this can contribute to the understanding of human physiology and health. PMID- 28736439 TI - Genome organization: Tracking chromosomal conformation through the cell cycle. PMID- 28736436 TI - Heterogeneity in tuberculosis. AB - Infection with Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), results in a range of clinical presentations in humans. Most infections manifest as a clinically asymptomatic, contained state that is termed latent TB infection (LTBI); a smaller subset of infected individuals present with symptomatic, active TB. Within these two seemingly binary states, there is a spectrum of host outcomes that have varying symptoms, microbiologies, immune responses and pathologies. Recently, it has become apparent that there is diversity of infection even within a single individual. A good understanding of the heterogeneity that is intrinsic to TB - at both the population level and the individual level - is crucial to inform the development of intervention strategies that account for and target the unique, complex and independent nature of the local host-pathogen interactions that occur in this infection. In this Review, we draw on model systems and human data to discuss multiple facets of TB biology and their relationship to the overall heterogeneity observed in the human disease. PMID- 28736435 TI - Extracellular vesicles in renal disease. AB - Extracellular vesicles, such as exosomes and microvesicles, are host cell-derived packages of information that allow cell-cell communication and enable cells to rid themselves of unwanted substances. The release and uptake of extracellular vesicles has important physiological functions and may also contribute to the development and propagation of inflammatory, vascular, malignant, infectious and neurodegenerative diseases. This Review describes the different types of extracellular vesicles, how they are detected and the mechanisms by which they communicate with cells and transfer information. We also describe their physiological functions in cellular interactions, such as in thrombosis, immune modulation, cell proliferation, tissue regeneration and matrix modulation, with an emphasis on renal processes. We discuss how the detection of extracellular vesicles could be utilized as biomarkers of renal disease and how they might contribute to disease processes in the kidney, such as in acute kidney injury, chronic kidney disease, renal transplantation, thrombotic microangiopathies, vasculitides, IgA nephropathy, nephrotic syndrome, urinary tract infection, cystic kidney disease and tubulopathies. Finally, we consider how the release or uptake of extracellular vesicles can be blocked, as well as the associated benefits and risks, and how extracellular vesicles might be used to treat renal diseases by delivering therapeutics to specific cells. PMID- 28736440 TI - Repin1 deficiency in adipose tissue improves whole-body insulin sensitivity, and lipid metabolism. AB - BACKGROUND/OBJECTIVES: Replication initiator 1 (Repin1) gene encodes for a zinc finger protein and has been implicated in the regulation of adipocyte cell size and glucose transport in vitro. Here, we investigate the consequences of reduced adipose tissue (AT) Repin1 expression in vivo. SUBJECTS/METHODS: We have inactivated the Repin1 gene in adipose tissue (iARep-/-) at an age of 4 weeks using tamoxifen-inducible gene targeting strategies on the background of C57BL/6NTac mice. Furthermore, we differentiated human primary adipocytes derived from subcutaneous AT in vitro and knocked down REPIN1 using siRNA technique to measure glycerol release. RESULTS: Conditional Repin1 inactivation results in decreased AT mass, smaller adipocytes in both, subcutaneous and epigonadal AT compared to controls. Compared to controls, iARep-/- mice were more insulin sensitive, had better glucose tolerance and lower LDL-, HDL- and total cholesterol. Significantly lower AT expression of the Repin1 target genes Cd36 and Lcn2 may contribute to the phenotype of iARep-/- mice. Knockdown of REPIN1 in human in vitro differentiated adipocytes revealed an increased glycerol release. CONCLUSIONS: In conclusion, deficiency of Repin1 in AT causes alterations in AT morphology and function, which may underlay lower body weight and improved parameters of insulin sensitivity, glucose and lipid metabolism. PMID- 28736441 TI - Nationally representative equations that include resistance and reactance for the prediction of percent body fat in Americans. AB - BACKGROUND/OBJECTIVES: Resistance and reactance collected by bioelectrical impedance (BIA) can be used in equations to estimate percent body fat at relatively low cost and subject burden. To our knowledge, no such equations have been developed in a nationally representative sample. SUBJECTS/METHODS: Dual energy X-ray absorptiometry assessed percent body fat from the 1999 to 2004 National Health and Nutrition Survey was the criterion method for development of sex-specific percent body fat equations using up to 6467 males or 4888 females 8 49 years of age. Candidate variables were studied in multiple mathematical forms and interactions using the Least Absolute Shrinkage and Selection Operator. Models were fit in 2/3's of the data and validated in 1/3 of the data selected at random. Final coefficients, R2 values and root mean square error (RMSE) were estimated in the full data set. RESULTS: Models that included age, ethnicity, height, weight, BMI and BIA assessments (resistance, reactance and height2/resistance) had R2 values of 0.831 in men and 0.864 in women in the full data set. RMSE measurements were between 2 and 3 body fat percentage points, and all equations showed low bias across groups formed by age, race/ethnicity or body mass index category. The addition of triceps skinfold and waist circumference increased the R2 to 0.905 in males and 0.883 in females. Adding other anthropometrics (plus menses in females) had little impact on performance. Reactance and resistance alone (in multiple mathematical forms) performed poorly with R2~0.2. CONCLUSIONS: Equations that included BIA assessments along with demographic and anthropometric variables provided percent body fat assessments that had high generalizability, strong predictive ability and low bias. PMID- 28736442 TI - Family history of type 2 diabetes, abdominal adipocyte size and markers of the metabolic syndrome. AB - BACKGROUND/OBJECTIVES: A major risk factor of type 2 diabetes mellitus (T2DM) is a positive family history of diabetes. First degree relatives (FDR) of patients with T2DM are more insulin resistant and are reported to have larger abdominal subcutaneous adipocytes than adults without a family history. Our objectives were to assess whether FDR of T2DM are associated with larger abdominal adipocytes independent of age, sex and abdominal subcutaneous fat and to assess whether a family history of T2DM is also independently related to femoral adipocyte size, as well as visceral fat and fasting plasma triglyceride (TG) concentrations. METHODS: We extracted adipocyte size, body composition, plasma TG and demographic data of non-diabetic research participants of previous studies conducted in our laboratory. We ascertained the family history of T2DM from the electronic medical records. Multivariate regression analysis was used to assess whether FDR of T2DM are more likely to have other risk factors after adjusting for known covariates. RESULTS: Of 604 participants, 148 were FDR of T2DM. Although abdominal and femoral adipocyte size was greater in FDR of T2DM than those without a family history (0.74+/-0.33 vs 0.63+/-0.33 MUg lipid per cell, P<0.001; 0.81+/-0.29 vs 0.72+/-0.33 MUg lipid per cell, P=0.01, respectively), this was confounded by FDR of T2DM being older, having greater body mass index and percent body fat. A family history of T2DM was a significant predictor of abdominal adipocyte size after adjustment for age and body fat distribution parameters in females (total R2=0.5, P<0.0001), but not in males. A family history of T2DM was not independently predictive of femoral adipocyte size, visceral fat area or TG. CONCLUSIONS: Female FDR of T2DM have larger abdominal, but not femoral, adipocytes, even after accounting for age and body fat distribution. PMID- 28736443 TI - CLOCK 3111T/C genetic variant influences the daily rhythm of autonomic nervous function: relevance to body weight control. AB - BACKGROUND/OBJECTIVES: Humans carrying the genetic risk variant C at the circadian CLOCK (Circadian Locomotor Output Cycles Kaput) 3111T/C have been shown to have more difficulties to achieve desired weight loss than TT carriers. We tested the hypothesis that the daily rhythm of autonomic nervous function differs in CLOCK 3111C carriers, leading to reduced effectiveness in weight control. SUBJECTS/METHODS: We recruited 40 overweight/obese Caucasian women (body mass index>25), 20 carrying CLOCK 3111C (CC and TC) and 20 non-carriers with matched age and body mass index who participated in a dietary obesity treatment program of up to 30 weeks. Following the treatment, ambulatory electrocardiography was continuously monitored for up to 3.5 days when subjects underwent their normal daily activities. To assess autonomic function, heart rate variability analysis (HRV) was performed hourly to obtain mean inter-beat interval between two consecutive R waves (mean RR) and s.d. of normal-to-normal heartbeat intervals (SDNN), and two parasympathetic measures, namely, proportion of differences between adjacent NN intervals that are >50 ms (pNN50), and high-frequency (HF: 0.15-0.4 Hz) power. RESULTS: In the TT carriers, all tested HRV indices showed significant daily rhythms (all P-values <0.0001) with lower mean RR, SDNN, pNN50, and HF during the daytime as compared with the nighttime. The amplitudes of these rhythms except for SDNN were reduced significantly in the C carriers (mean RR: ~19.7%, P=0.001; pNN50: 58.1%, P=0.001; and HF: 41.1%, P=0.001). In addition, subjects with less weight loss during the treatment program had smaller amplitudes in the rhythms of mean RR (P<0.0001), pNN50 (P=0.007) and HF (P=0.003). Furthermore, the rhythmicity-weight loss associations were much stronger in the C carriers as compared to the TT carriers (mean RR: P=0.028, pNN50: P=0.0002; HF: P=0.015). CONCLUSIONS: The daily rhythm of parasympathetic modulation may play a role in the influence of the CLOCK variation on body weight control. PMID- 28736446 TI - Viral infection: When two become one. PMID- 28736444 TI - Lipid droplet remodelling and reduced muscle ceramides following sprint interval and moderate-intensity continuous exercise training in obese males. AB - BACKGROUND/OBJECTIVES: In obesity, improved muscle insulin sensitivity following exercise training has been linked to the lowering of diacylglycerol (DAG) and ceramide concentrations. Little is known, however, about how improved insulin action with exercise training in obese individuals relates to lipid droplet (LD) adaptations in skeletal muscle. In this study we investigated the hypothesis that short-term sprint interval training (SIT) and moderate-intensity continuous training (MICT) in obese individuals would increase perilipin (PLIN) expression, increase the proportion of LDs in contact with mitochondria and reduce muscle concentrations of DAGs and ceramides. METHODS: Sixteen sedentary obese males performed 4 weeks of either SIT (4-7 * 30 s sprints at 200% Wmax, 3 days week) or MICT (40-60 min cycling at ~65% VO2peak, 5 days per week), and muscle biopsies were obtained pre- and post-training. RESULTS: Training increased PLIN2 (SIT 90%, MICT 68%) and PLIN5 (SIT 47%, MICT 34%) expression in type I fibres only, and increased PLIN3 expression in both type I (SIT 63%, MICT 67%) and type II fibres (SIT 70%, MICT 160%) (all P<0.05). Training did not change LD content but increased the proportion of LD in contact with mitochondria (SIT 12%, MICT 21%, P<0.01). Ceramides were reduced following training (SIT -10%, MICT -7%, P<0.05), but DAG was unchanged. No training * group interactions were observed for any variables. CONCLUSIONS: These results confirm the hypothesis that SIT and MICT results in remodelling of LDs and lowers ceramide concentrations in skeletal muscle of sedentary obese males. PMID- 28736445 TI - Dietary fat and total energy intake modifies the association of genetic profile risk score on obesity: evidence from 48 170 UK Biobank participants. AB - BACKGROUND: Obesity is a multifactorial condition influenced by both genetics and lifestyle. The aim of this study was to investigate whether the association between a validated genetic profile risk score for obesity (GPRS-obesity) and body mass index (BMI) or waist circumference (WC) was modified by macronutrient intake in a large general population study. METHODS: This study included cross sectional data from 48 170 white European adults, aged 37-73 years, participating in the UK Biobank. Interactions between GPRS-obesity and macronutrient intake (including total energy, protein, fat, carbohydrate and dietary fibre intake) and its effects on BMI and WC were investigated. RESULTS: The 93-single-nucleotide polymorphism (SNP) GPRS was associated with a higher BMI (beta: 0.57 kg m-2 per s.d. increase in GPRS (95% confidence interval: 0.53-0.60); P=1.9 * 10-183) independent of major confounding factors. There was a significant interaction between GPRS and total fat intake (P(interaction)=0.007). Among high-fat-intake individuals, BMI was higher by 0.60 (0.52, 0.67) kg m-2 per s.d. increase in GPRS obesity; the change in BMI with GPRS was lower among low-fat-intake individuals (beta: 0.50 (0.44, 0.57) kg m-2). Significant interactions with similar patterns were observed for saturated fat intake (high beta: 0.66 (0.59, 0.73) versus low beta: 0.49 (0.42, 0.55) kg m-2, P(interaction)=2 * 10-4) and for total energy intake (high beta: 0.58 (0.51, 0.64) versus low beta: 0.49 (0.42, 0.56) kg m-2, P(interaction)=0.019), but not for protein intake, carbohydrate intake and fibre intake (P(interaction) >0.05). The findings were broadly similar using WC as the outcome. CONCLUSIONS: These data suggest that the benefits of reducing the intake of fats and total energy intake may be more important in individuals with high genetic risk for obesity. PMID- 28736447 TI - Prokaryotic Argonaute proteins: novel genome-editing tools? AB - Argonaute proteins constitute a highly diverse family of nucleic acid-guided proteins. They were first discovered in eukaryotes as key proteins in RNA interference systems, but homologous prokaryotic Argonaute proteins (pAgos) have also been found in archaea and bacteria. In this Progress article, we focus on long pAgo variants, a class of pAgos that are involved in nucleic acid-guided host defence against invading nucleic acids, and discuss the potential of pAgos in genome editing. PMID- 28736448 TI - Antimalarial drug discovery - approaches and progress towards new medicines. PMID- 28736449 TI - Interbacterial predation as a strategy for DNA acquisition in naturally competent bacteria. AB - This corrects the article DOI: 10.1038/nrmicro.2017.66. PMID- 28736450 TI - Screening survey of ocular, nasal, respiratory and skin symptoms in manicurists in Poland. AB - OBJECTIVES: Manicurists are exposed to various chemicals in nail and skin care products and may develop ocular, nasal, respiratory or skin adverse reactions to them. To investigate the occurrence of ocular, nasal, respiratory and skin problems among manicurists and to identify their causal factors, particularly allergic etiology and occupational origin. MATERIAL AND METHODS: Manicurists employed in beauty salons in the central region of Poland were invited to fill in the questionnaire and undergo medical examination, skin prick tests with common aeroallergens, patch tests with European Baseline Series and (Meth)Acrylates Series-Nails and spirometry. RESULTS: In the questionnaire adverse nasal symptoms were reported by 70%, ocular - by 58%, respiratory - by 42%, hand eczema - by 43% of manicurists. In the medical interview, the frequency of those complaints was lower: nasal ones - 41%, ocular - 24%, cough - 18%, hand skin dryness - 20%, hand eczema - 6%. Cough and hand skin dryness occurred significantly more frequently than in the case of controls. Contact allergy was found for 41% of manicurists and 35% of controls. The prevalence of nickel sensitization was high in both groups (38% and 27%, respectively). Only 3 manicurists reacted to (meth)acrylates. The frequency of atopic diseases was similar in compared groups. Irritant nasal and respiratory reactions were significantly more prevalent among manicurists (nasal - 18% vs. 2%, p < 0.01; respiratory - 18% vs. 1%, p < 0.001). Work-related nasal irritant reactions were finally diagnosed for 19%, ocular ones - for 13%, respiratory - for 18% and within hand skin - for 23% of manicurists. CONCLUSIONS: The frequency of workattributed irritant mucosal and skin symptoms among manicurists is high. Exposure to acrylates is an important source of mucosal irritant reactions while occlusive gloves cause irritation of hand skin. The prevalence of nickel allergy among Polish females is high. Int J Occup Med Environ Health 2017;30(6):887-896. PMID- 28736451 TI - Assessing musculoskeletal disorders among municipal waste loaders of Mumbai, India. AB - OBJECTIVES: The study aims to assess the impact of municipal waste loading occupation upon developing musculoskeletal disorders (MSDs) and thereby disabilities among waste loaders. Additionally, the study has identified the potential risk factors raising MSDs and disabilities. MATERIAL AND METHODS: A cross-sectional case-control design survey was conducted in 6 out of 24 municipal wards of Mumbai during March-September 2015. The study population consisted of municipal waste loaders (N = 180) and a control group (N = 180). The Standardized Modified Nordic questionnaire was adopted to measures the MSDs and thereby disabilities in the past 12 months. A Propensity Score Matching (PSM) method was applied to assess the impact of waste loading occupation on developing MSDs and disabilities. RESULTS: Waste loaders had a significantly higher risk of developing MSDs as well as disabilities than the control group particularly for low back, hip/ thigh upper back and shoulder. Propensity Score Matching results revealed that the MSDs were significantly higher among waste loaders for hip/thigh (22%), low back (19%), shoulder (18%), and upper back (15%) than matched control group. Likewise, MSDs-related disabilities were found to be significantly higher among waste loaders for low back (20%), hip/ thigh (18%) upper back (13%) and shoulder (8%) than the control group. Duration of work, substance use and mental health were found to be the potential psychosocial factors for developing the risk of MSDs and disabilities. CONCLUSIONS: The municipal waste loading occupation raised the risk of MSDs and related disabilities among waste loaders compared to the control group. The preventive and curative measures are strongly recommended to minimize the burden of MSDs and disabilities. Int J Occup Med Environ Health 2017;30(6):875-886. PMID- 28736452 TI - Replicates in high dimensions, with applications to latent variable graphical models. AB - In classical statistics, much thought has been put into experimental design and data collection. In the high-dimensional setting, however, experimental design has been less of a focus. In this paper, we stress the importance of collecting multiple replicates for each subject in this setting. We consider learning the structure of a graphical model with latent variables, under the assumption that these variables take a constant value across replicates within each subject. By collecting multiple replicates for each subject, we are able to estimate the conditional dependence relationships among the observed variables given the latent variables. To test the null hypothesis of conditional independence between two observed variables, we propose a pairwise decorrelated score test. Theoretical guarantees are established for parameter estimation and for this test. We show that our proposal is able to estimate latent variable graphical models more accurately than some existing proposals, and apply the proposed method to a brain imaging dataset. PMID- 28736453 TI - Recessions and the Costs of Job Loss. PMID- 28736454 TI - EARLY, LATE OR NEVER? WHEN DOES PARENTAL EDUCATION IMPACT CHILD OUTCOMES? AB - We estimate the causal effect of parents' education on their children's education and examine the timing of the impact. We identify the causal effect by exploiting the exogenous shift in (parents') education levels induced by the 1972 minimum school leaving age reform in England. Increasing parental education has a positive causal effect on children's outcomes that is evident in preschool assessments at age 4 and continues to be visible up to and including high-stakes examinations taken at age 16. Children of parents affected by the reform attain results around 0.1 standard deviations higher than those whose parents were not impacted. PMID- 28736455 TI - Using kaizen to improve employee well-being: Results from two organizational intervention studies. AB - Participatory intervention approaches that are embedded in existing organizational structures may improve the efficiency and effectiveness of organizational interventions, but concrete tools are lacking. In the present article, we use a realist evaluation approach to explore the role of kaizen, a lean tool for participatory continuous improvement, in improving employee well being in two cluster-randomized, controlled participatory intervention studies. Case 1 is from the Danish Postal Service, where kaizen boards were used to implement action plans. The results of multi-group structural equation modeling showed that kaizen served as a mechanism that increased the level of awareness of and capacity to manage psychosocial issues, which, in turn, predicted increased job satisfaction and mental health. Case 2 is from a regional hospital in Sweden that integrated occupational health processes with a pre-existing kaizen system. Multi-group structural equation modeling revealed that, in the intervention group, kaizen work predicted better integration of organizational and employee objectives after 12 months, which, in turn, predicted increased job satisfaction and decreased discomfort at 24 months. The findings suggest that participatory and structured problem-solving approaches that are familiar and visual to employees can facilitate organizational interventions. PMID- 28736456 TI - Activating Metal Sites for Biological Electron Transfer. AB - This review focuses on the unique spectroscopic features of the blue copper active sites. These reflect a novel electronic structure that activates the site for rapid long-range electron transfer in its biological function. The role of the protein in determining the geometric and electronic structure of this site is defined, as is its contribution to function. This has been referred to as the entatic/rack-induced state. These concepts are then extended to cytochrome c, which is also determined to be in an entatic state. PMID- 28736457 TI - Analysis of Receptor-Ligand Interactions. PMID- 28736458 TI - A Latent Class Analysis of Family Characteristics Linked to Youth Offending Outcomes. AB - OBJECTIVES: There were two aims to this study: firstly, to identify family subtypes of Singaporean youth offenders based on eight family variables. Secondly, the associations of these family subtypes with youth offending outcomes were tested. METHODS: With a sample of 3,744 youth, a latent class analysis was first conducted based on eight family variables. Multivariate analyses and a Cox regression were subsequently performed to analyze the associations of the family classes with age at first arrest, age at first charge, and recidivism. RESULTS: A three-class solution was found to have the best fit to the data: (1) intact functioning families had little family risk; (2) families with criminality had higher probabilities of family criminality, of drug/alcohol abuse, and of being nonintact; and (3) poorly managed families received the poorest parenting and were more likely to be nonintact. Youth offenders from the latter two classes were arrested and charged at younger ages. Additionally, they reoffended at a quicker rate. CONCLUSIONS: Family backgrounds matter for youth offending outcomes. Interventions have to be multifaceted and targeted at the family in order to mitigate the risk of young offenders from developing into pathological adult criminals. PMID- 28736459 TI - Final report on the key comparison, CCM.P-K15 in the pressure range from 1.0 * 10 4 Pa to 1.0 Pa. AB - The comparison CCM.P-K15 is a key comparison in pressure involving six laboratories in three regional metrological organizations (RMO). The measurand of the comparison is the accommodation coefficient of two spinning rotating gauge characterized in nitrogen from 0.1 mPa up to 1.0 Pa. The two transfer standards were circulated from November 2009 until March 2011. The circulation consisted of three loops, one for each RMO, and a new calibration by the pilot between each loop. The stability of one of the transfer standards was poor and was worse than expected based on the previous history of the transfer standard while the other transfer standard demonstrated good stability while circulated in Europe and America and a fair stability while circulated in Asia. All the participants demonstrated equivalence to the definition of pressure in their respective primary standards. PMID- 28736460 TI - Reference Correlation for the Viscosity of Carbon Dioxide. AB - A comprehensive database of experimental and computed data for the viscosity of carbon dioxide (CO2) was compiled and a new reference correlation was developed. Literature results based on an ab initio potential energy surface were the foundation of the correlation of the viscosity in the limit of zero density in the temperature range from 100 K to 2000 K. Guided symbolic regression was employed to obtain a new functional form that extrapolates correctly to T -> 0 K and to 10 000 K. Coordinated measurements at low density made it possible to implement the temperature dependence of the Rainwater-Friend theory in the linear in-density viscosity term. The residual viscosity could be formulated with a scaling term rhogamma /T the significance of which was confirmed by symbolic regression. The final viscosity correlation covers temperatures from 100 K to 2000 K for gaseous CO2, and from 220 K to 700 K with pressures along the melting line up to 8000 MPa for compressed and supercritical liquid states. The data representation is more accurate than with the previous correlations, and the covered pressure and temperature range is significantly extended. The critical enhancement of the viscosity of CO2 is included in the new correlation. PMID- 28736461 TI - Behavioral plasticity in response to perceived predation risk in breeding house wrens. AB - Predation is a significant cause of nest failure in passerine birds, and, thus, natural selection is expected to favor behavioral plasticity to allow birds to respond to perceived changes in predation risk. However, behavioral plasticity in response to perceived predation risk, and its potential fitness-related costs, are understudied. In a wild population of breeding house wrens (Troglodytes aedon), we tested the hypotheses that (1) birds show behavioral plasticity in response to perceived nest-predation risk to reduce self-risk or risk to offspring, but (2) this plasticity incurs fitness-related costs. We experimentally increased the perceived risk of nest predation by enlarging the diameter of the nestbox entrance from the standard 3.2 cm to 5.0 cm once incubation began. Unexpectedly, large-hole females spent significantly less time being vigilant than small-hole (control) females during late incubation. Both males and females also exhibited plasticity in their provisioning behavior. Large hole males increased and large-hole females decreased provisioning visits with increasing brood size, whereas small-hole males and females behaved similarly and were unaffected by brood size. Females did not show plasticity in their incubation or brooding behavior. Notwithstanding this behavioral plasticity in response to increased perceived predation risk, treatment had no effect on hatching success or early hatchling survival, nor did it affect nestling body condition or fledging success. We conclude, therefore, that house wrens show behavioral plasticity in response to perceived nest-predation risk, but that any short-term fitness-related costs associated with this flexibility appear negligible. PMID- 28736462 TI - Sequential Release of Multiple Drugs from Flexible Drug Delivery Films. AB - Sequential release of drugs aligned with the phases of tissue healing could reduce scarring. To achieve this aim, layered film devices comprising cellulose acetate phthalate (CAP) and Pluronic F-127 (Pluronic) were loaded with ketoprofen, quercetin, and pirfenidone. Citrate plasticizers were added to impart flexibility. Release of two or three drugs in sequence over several days was obtained for all multilayered devices tested. Mechanical analysis showed that elongation increased and modulus decreased with increasing plasticizer content. Release profiles can be tailored by order of layers, plasticizer concentration, and drug loaded, making CAP-Pluronic an appealing system for inhibiting scar tissue formation. PMID- 28736463 TI - Viscosity, density, and thermal conductivity of aluminum oxide and zinc oxide nanolubricants. AB - This paper presents liquid kinematic viscosity, density, and thermal conductivity measurements of eleven different synthetic polyolester-based nanoparticle nanolubricants (dispersions) at atmospheric pressure over the temperature range 288 K to 318 K. Aluminum oxide (Al2O3) and zinc oxide (ZnO) nanoparticles with nominal diameters of 127 nm and 135 nm, respectively, were investigated. A good dispersion of the spherical and non-spherical nanoparticles in the lubricant was maintained with a surfactant. Viscosity, density, and thermal conductivity measurements were made for the neat lubricant along with eleven nanolubricants with differing nanoparticle and surfactant mass fractions. Existing models were used to predict kinematic viscosity (+/-20%), thermal conductivity (+/-1%), and specific volume (+/-6%) of the nanolubricant as a function of temperature, nanoparticle mass fraction, surfactant mass fraction, and nanoparticle diameter. The liquid viscosity, density and thermal conductivity were shown to increase with respect to increasing nanoparticle mass fraction. PMID- 28736464 TI - The Generalized Higher Criticism for Testing SNP-Set Effects in Genetic Association Studies. AB - It is of substantial interest to study the effects of genes, genetic pathways, and networks on the risk of complex diseases. These genetic constructs each contain multiple SNPs, which are often correlated and function jointly, and might be large in number. However, only a sparse subset of SNPs in a genetic construct is generally associated with the disease of interest. In this article, we propose the generalized higher criticism (GHC) to test for the association between an SNP set and a disease outcome. The higher criticism is a test traditionally used in high-dimensional signal detection settings when marginal test statistics are independent and the number of parameters is very large. However, these assumptions do not always hold in genetic association studies, due to linkage disequilibrium among SNPs and the finite number of SNPs in an SNP set in each genetic construct. The proposed GHC overcomes the limitations of the higher criticism by allowing for arbitrary correlation structures among the SNPs in an SNP-set, while performing accurate analytic p-value calculations for any finite number of SNPs in the SNP-set. We obtain the detection boundary of the GHC test. We compared empirically using simulations the power of the GHC method with existing SNP-set tests over a range of genetic regions with varied correlation structures and signal sparsity. We apply the proposed methods to analyze the CGEM breast cancer genome-wide association study. Supplementary materials for this article are available online. PMID- 28736465 TI - Network Indicators of the Social Ecology of Adolescents in Relative and Non Relative Foster Households. AB - Though the presence, composition, and quality of social relationships particularly as found in family networks-has an important influence on adolescent well-being, little is known about the social ecology of youth in foster care. This study examined the social networks of foster youth participating in a large RCT of an intervention for siblings in foster care. Youth reported on the people they lived with and the relatives they were in contact with, which provided indicators of network size, composition, and relationship quality. Cluster analysis was used to identify five family network profiles for youth living in foster homes. Two identified subgroups reflected robust family networks where youth were living with relative caregiver(s) and related youth, and also reported multiple family ties outside the household, including with biological parents. The remaining three profiles reflected youth reports of fewer family connections within or beyond the foster household, with distinctions by whether they lived with siblings and/or reported having positive relationships with their mothers and/or fathers. The identified network profiles were validated using youth- and caregiver-reported measures of mental health functioning, with increased caregiver report of post-traumatic stress symptoms indicated for the three subgroups that were not characterized by a robust family network. PMID- 28736466 TI - Spatiotemporal aggregation for temporally extensive international microdata. AB - We describe a strategy for regionalizing subnational administrative units in conjunction with harmonizing changes in unit boundaries over time that can be applied to provide small-area geographic identifiers for census microdata. The availability of small-area identifiers blends the flexibility of individual microdata with the spatial specificity of aggregate data. Regionalizing microdata by administrative units poses a number of challenges, such as the need to aggregate individual scale data in a way that ensures confidentiality and issues arising from changing spatial boundaries over time. We describe a regionalization and harmonization strategy that creates units that satisfy spatial and other constraints while maximizing the number of units in a way that supports policy and research use. We describe this regionalization strategy for three test cases of Malawi, Brazil, and the United States. We test different algorithms and develop a semi-automated strategy for regionalization that meets data restrictions, computation, and data demands from end users. PMID- 28736467 TI - Stability of Gradient Field Corrections for Quantitative Diffusion MRI. AB - In magnetic resonance diffusion imaging, gradient nonlinearity causes significant bias in the estimation of quantitative diffusion parameters such as diffusivity, anisotropy, and diffusion direction in areas away from the magnet isocenter. This bias can be substantially reduced if the scanner- and coil-specific gradient field nonlinearities are known. Using a set of field map calibration scans on a large (29 cm diameter) phantom combined with a solid harmonic approximation of the gradient fields, we predicted the obtained b-values and applied gradient directions throughout a typical field of view for brain imaging for a typical 32 direction diffusion imaging sequence. We measured the stability of these predictions over time. At 80 mm from scanner isocenter, predicted b-value was 1 6% different than intended due to gradient nonlinearity, and predicted gradient directions were in error by up to 1 degree. Over the course of one month the change in these quantities due to calibration-related factors such as scanner drift and variation in phantom placement was <0.5% for b-values, and <0.5 degrees for angular deviation. The proposed calibration procedure allows the estimation of gradient nonlinearity to correct b-values and gradient directions ahead of advanced diffusion image processing for high angular resolution data, and requires only a five-minute phantom scan that can be included in a weekly or monthly quality assurance protocol. PMID- 28736468 TI - Multi-Atlas Spleen Segmentation on CT Using Adaptive Context Learning. AB - Automatic spleen segmentation on CT is challenging due to the complexity of abdominal structures. Multi-atlas segmentation (MAS) has shown to be a promising approach to conduct spleen segmentation. To deal with the substantial registration errors between the heterogeneous abdominal CT images, the context learning method for performance level estimation (CLSIMPLE) method was previously proposed. The context learning method generates a probability map for a target image using a Gaussian mixture model (GMM) as the prior in a Bayesian framework. However, the CLSSIMPLE typically trains a single GMM from the entire heterogeneous training atlas set. Therefore, the estimated spatial prior maps might not represent specific target images accurately. Rather than using all training atlases, we propose an adaptive GMM based context learning technique (AGMMCL) to train the GMM adaptively using subsets of the training data with the subsets tailored for different target images. Training sets are selected adaptively based on the similarity between atlases and the target images using cranio-caudal length, which is derived manually from the target image. To validate the proposed method, a heterogeneous dataset with a large variation of spleen sizes (100 cc to 9000 cc) is used. We designate a metric of size to differentiate each group of spleens, with 0 to 100 cc as small, 200 to 500cc as medium, 500 to 1000 cc as large, 1000 to 2000 cc as XL, and 2000 and above as XXL. From the results, AGMMCL leads to more accurate spleen segmentations by training GMMs adaptively for different target images. PMID- 28736469 TI - Improved Automatic Optic Nerve Radius Estimation from High Resolution MRI. AB - The optic nerve (ON) is a vital structure in the human visual system and transports all visual information from the retina to the cortex for higher order processing. Due to the lack of redundancy in the visual pathway, measures of ON damage have been shown to correlate well with visual deficits. These measures are typically taken at an arbitrary anatomically defined point along the nerve and do not characterize changes along the length of the ON. We propose a fully automated, three-dimensionally consistent technique building upon a previous independent slice-wise technique to estimate the radius of the ON and surrounding cerebrospinal fluid (CSF) on high-resolution heavily T2-weighted isotropic MRI. We show that by constraining results to be three-dimensionally consistent this technique produces more anatomically viable results. We compare this technique with the previously published slice-wise technique using a short-term reproducibility data set, 10 subjects, follow-up <1 month, and show that the new method is more reproducible in the center of the ON. The center of the ON contains the most accurate imaging because it lacks confounders such as motion and frontal lobe interference. Long-term reproducibility, 5 subjects, follow-up of approximately 11 months, is also investigated with this new technique and shown to be similar to short-term reproducibility, indicating that the ON does not change substantially within 11 months. The increased accuracy of this new technique provides increased power when searching for anatomical changes in ON size amongst patient populations. PMID- 28736470 TI - Structural-Functional Relationships Between Eye Orbital Imaging Biomarkers and Clinical Visual Assessments. AB - Eye diseases and visual impairment affect millions of Americans and induce billions of dollars in annual economic burdens. Expounding upon existing knowledge of eye diseases could lead to improved treatment and disease prevention. This research investigated the relationship between structural metrics of the eye orbit and visual function measurements in a cohort of 470 patients from a retrospective study of ophthalmology records for patients (with thyroid eye disease, orbital inflammation, optic nerve edema, glaucoma, intrinsic optic nerve disease), clinical imaging, and visual function assessments. Orbital magnetic resonance imaging (MRI) and computed tomography (CT) images were retrieved and labeled in 3D using multi-atlas label fusion. Based on the 3D structures, both traditional radiology measures (e.g., Barrett index, volumetric crowding index, optic nerve length) and novel volumetric metrics were computed. Using stepwise regression, the associations between structural metrics and visual field scores (visual acuity, functional acuity, visual field, functional field, and functional vision) were assessed. Across all models, the explained variance was reasonable (R2 ~ 0.1-0.2) but highly significant (p < 0.001). Instead of analyzing a specific pathology, this study aimed to analyze data across a variety of pathologies. This approach yielded a general model for the connection between orbital structural imaging biomarkers and visual function. PMID- 28736471 TI - Comparison of Multi-Fiber Reproducibility of PAS-MRI and Q-ball With Empirical Multiple b-Value HARDI. AB - Crossing fibers are prevalent in human brains and a subject of intense interest for neuroscience. Diffusion tensor imaging (DTI) can resolve tissue orientation but is blind to crossing fibers. Many advanced diffusion-weighted magnetic resolution imaging (MRI) approaches have been presented to extract crossing fibers from high angular resolution diffusion imaging (HARDI), but the relative sensitivity and specificity of approaches remains unclear. Here, we examine two leading approaches (PAS and q-ball) in the context of a large-scale, single subject reproducibility study. A single healthy individual was scanned 11 times with 96 diffusion weighted directions and 10 reference volumes for each of five b values (1000, 1500, 2000, 2500, 3000 s/mm2) for a total of 5830 volumes (over the course of three sessions). We examined the reproducibility of the number of fibers per voxel, volume fraction, and crossing-fiber angles. For each method, we determined the minimum resolvable angle for each acquisition. Reproducibility of fiber counts per voxel was generally high (~80% consensus for PAS and ~70% for q ball), but there was substantial bias between individual repetitions and model estimated with all data (~10% lower consensus for PAS and ~15% lower for q-ball). Both PAS and q-ball predominantly discovered fibers crossing at near 90 degrees, but reproducibility was higher for PAS across most measures. Within voxels with low anisotropy, q-ball finds more intra-voxel structure; meanwhile, PAS resolves multiple fibers at greater than 75 degrees for more voxels. These results can inform researchers when deciding between HARDI approaches or interpreting findings across studies. PMID- 28736472 TI - A radiative transfer equation-based image-reconstruction method incorporating boundary conditions for diffuse optical imaging. AB - Developing reconstruction methods for diffuse optical imaging requires accurate modeling of photon propagation, including boundary conditions arising due to refractive index mismatch as photons propagate from the tissue to air. For this purpose, we developed an analytical Neumann-series radiative transport equation (RTE)-based approach. Each Neumann series term models different scattering, absorption, and boundary-reflection events. The reflection is modeled using the Fresnel equation. We use this approach to design a gradient-descent-based analytical reconstruction algorithm for a three-dimensional (3D) setup of a diffuse optical imaging (DOI) system. The algorithm was implemented for a three dimensional DOI system consisting of a laser source, cuboidal scattering medium (refractive index > 1), and a pixelated detector at one cuboid face. In simulation experiments, the refractive index of the scattering medium was varied to test the robustness of the reconstruction algorithm over a wide range of refractive index mismatches. The experiments were repeated over multiple noise realizations. Results showed that by using the proposed algorithm, the photon propagation was modeled more accurately. These results demonstrated the importance of modeling boundary conditions in the photon-propagation model. PMID- 28736473 TI - Theoretical and Empirical Comparison of Big Data Image Processing with Apache Hadoop and Sun Grid Engine. AB - The field of big data is generally concerned with the scale of processing at which traditional computational paradigms break down. In medical imaging, traditional large scale processing uses a cluster computer that combines a group of workstation nodes into a functional unit that is controlled by a job scheduler. Typically, a shared-storage network file system (NFS) is used to host imaging data. However, data transfer from storage to processing nodes can saturate network bandwidth when data is frequently uploaded/retrieved from the NFS, e.g., "short" processing times and/or "large" datasets. Recently, an alternative approach using Hadoop and HBase was presented for medical imaging to enable co-location of data storage and computation while minimizing data transfer. The benefits of using such a framework must be formally evaluated against a traditional approach to characterize the point at which simply "large scale" processing transitions into "big data" and necessitates alternative computational frameworks. The proposed Hadoop system was implemented on a production lab-cluster alongside a standard Sun Grid Engine (SGE). Theoretical models for wall-clock time and resource time for both approaches are introduced and validated. To provide real example data, three T1 image archives were retrieved from a university secure, shared web database and used to empirically assess computational performance under three configurations of cluster hardware (using 72, 109, or 209 CPU cores) with differing job lengths. Empirical results match the theoretical models. Based on these data, a comparative analysis is presented for when the Hadoop framework will be relevant and non-relevant for medical imaging. PMID- 28736474 TI - Phenotype Analysis of Early Risk Factors from Electronic Medical Records Improves Image-Derived Diagnostic Classifiers for Optic Nerve Pathology. AB - We examine imaging and electronic medical records (EMR) of 588 subjects over five major disease groups that affect optic nerve function. An objective evaluation of the role of imaging and EMR data in diagnosis of these conditions would improve understanding of these diseases and help in early intervention. We developed an automated image-processing pipeline that identifies the orbital structures within the human eyes from computed tomography (CT) scans, calculates structural size, and performs volume measurements. We customized the EMR-based phenome-wide association study (PheWAS) to derive diagnostic EMR phenotypes that occur at least two years prior to the onset of the conditions of interest from a separate cohort of 28,411 ophthalmology patients. We used random forest classifiers to evaluate the predictive power of image-derived markers, EMR phenotypes, and clinical visual assessments in identifying disease cohorts from a control group of 763 patients without optic nerve disease. Image-derived markers showed more predictive power than clinical visual assessments or EMR phenotypes. However, the addition of EMR phenotypes to the imaging markers improves the classification accuracy against controls: the AUC improved from 0.67 to 0.88 for glaucoma, 0.73 to 0.78 for intrinsic optic nerve disease, 0.72 to 0.76 for optic nerve edema, 0.72 to 0.77 for orbital inflammation, and 0.81 to 0.85 for thyroid eye disease. This study illustrates the importance of diagnostic context for interpretation of image-derived markers and the proposed PheWAS technique provides a flexible approach for learning salient features of patient history and incorporating these data into traditional machine learning analyses. PMID- 28736475 TI - Virtual rough samples to test 3D nanometer-scale scanning electron microscopy stereo photogrammetry. AB - The combination of scanning electron microscopy for high spatial resolution, images from multiple angles to provide 3D information, and commercially available stereo photogrammetry software for 3D reconstruction offers promise for nanometer scale dimensional metrology in 3D. A method is described to test 3D photogrammetry software by the use of virtual samples-mathematical samples from which simulated images are made for use as inputs to the software under test. The virtual sample is constructed by wrapping a rough skin with any desired power spectral density around a smooth near-trapezoidal line with rounded top corners. Reconstruction is performed with images simulated from different angular viewpoints. The software's reconstructed 3D model is then compared to the known geometry of the virtual sample. Three commercial photogrammetry software packages were tested. Two of them produced results for line height and width that were within close to 1 nm of the correct values. All of the packages exhibited some difficulty in reconstructing details of the surface roughness. PMID- 28736476 TI - Best Practices for Building a Bimodal/Bilingual Child Language Corpus. AB - This article addresses the special challenges associated with collecting longitudinal samples of the spontaneous sign language and spoken language production by young bimodal bilingual children. We discuss the methods used in our study of children in the United States and Brazil. Since one of our goals is to observe both sign language and speech, as well as any language mixing, it is important for us to address issues of language choice and techniques for directing the child participant toward primary use of the target language in each session. Suggestions and guidelines for achieving this in effective yet respectful ways are presented. We are especially dependent on the participation, flexibility, and direction of our participant children's parents, who work with us to elicit samples that are genuinely representative of their children's linguistic abilities. We illustrate our procedures for training parents and other interlocutors in data-collection sessions. In return for their generous participation in our research, we address parents' questions and concerns about language development, especially in bimodal bilingual contexts. We take very seriously the need to negotiate with participants regarding their expectations for the use of the data they provide, and we abide by their wishes in this matter. The strategies presented here improve the quality of the investigations we can conduct by making the experiences of the participant families as pleasant as possible. PMID- 28736478 TI - Green's function modeling of response of two-dimensional materials to point probes for scanning probe microscopy. AB - A Green's function (GF) method is developed for interpreting scanning probe microscopy (SPM) measurements on new two-dimensional (2D) materials. GFs for the Laplace/Poisson equations are calculated by using a virtual source method for two separate cases of a finite material containing a rectangular defect and a hexagonal defect. The prescribed boundary values are reproduced almost exactly by the calculated GFs. It is suggested that the GF is not just a mathematical artefact but a basic physical characteristic of material systems, which can be measured directly by SPM for 2D solids. This should make SPM an even more powerful technique for characterization of 2D materials. PMID- 28736477 TI - Long-term exposure to elevated carbon dioxide does not alter activity levels of a coral reef fish in response to predator chemical cues. AB - ABSTRACT: Levels of dissolved carbon dioxide (CO2) projected to occur in the world's oceans in the near future have been reported to increase swimming activity and impair predator recognition in coral reef fishes. These behavioral alterations would be expected to have dramatic effects on survival and community dynamics in marine ecosystems in the future. To investigate the universality and replicability of these observations, we used juvenile spiny chromis damselfish (Acanthochromis polyacanthus) to examine the effects of long-term CO2 exposure on routine activity and the behavioral response to the chemical cues of a predator (Cephalopholis urodeta). Commencing at ~3-20 days post-hatch, juvenile damselfish were exposed to present-day CO2 levels (~420 MUatm) or to levels forecasted for the year 2100 (~1000 MUatm) for 3 months of their development. Thereafter, we assessed routine activity before and after injections of seawater (sham injection, control) or seawater-containing predator chemical cues. There was no effect of CO2 treatment on routine activity levels before or after the injections. All fish decreased their swimming activity following the predator cue injection but not following the sham injection, regardless of CO2 treatment. Our results corroborate findings from a growing number of studies reporting limited or no behavioral responses of fishes to elevated CO2. SIGNIFICANCE STATEMENT: Alarmingly, it has been reported that levels of dissolved carbon dioxide (CO2) forecasted for the year 2100 cause coral reef fishes to be attracted to the chemical cues of predators. However, most studies have exposed the fish to CO2 for very short periods before behavioral testing. Using long-term acclimation to elevated CO2 and automated tracking software, we found that fish exposed to elevated CO2 showed the same behavioral patterns as control fish exposed to present-day CO2 levels. Specifically, activity levels were the same between groups, and fish acclimated to elevated CO2 decreased their swimming activity to the same degree as control fish when presented with cues from a predator. These findings indicate that behavioral impacts of elevated CO2 levels are not universal in coral reef fishes. PMID- 28736479 TI - Molecular Dynamics Simulation of Trimer Self-Assembly Under Shear. AB - The self-assembly of patchy trimer particles consisting of one attractive site and two repulsive sites is investigated with nonequilibrium molecular dynamics simulations in the presence of a velocity gradient, as would be produced by the application of a shear stress on the system. As shear is increased, globular shaped micellar clusters increase in size and become more elongated. The globular clusters are also more stable at higher temperatures in the presence of shear than at equilibrium. These results help to increase our understanding of the effect of shear on self-assembly for a variety of applications. PMID- 28736480 TI - Engaging Students in Physical Education: Key Challenges and Opportunities for Physical Educators in Urban Settings. PMID- 28736481 TI - Gas Uptake of 3-D Printed Acrylonitrile Butadiene Styrene (ABS) Using a Vacuum Apparatus Designed for Absorption and Desorption Studies. AB - We describe a vacuum apparatus for determining the outgassing rate into vacuum, the diffusion coefficient, and the amount of gas absorbed for various materials. The diffusion coefficient is determined from a model applied to time-dependent desorption data taken using a throughput method. We used this method to determine the diffusion coefficient, D, for H2O in 3-D printed acrylonitrile butadiene styrene (ABS). We found DH2O = 8.3 * 10-8 cm2/s +/- 1.3 * 10-8 cm2/s (k = 1; 67% confidence interval) at 23.2 degrees C. This result was compared to the diffusion coefficient determined another by a gravimetric method, in which the sample weight was monitored as it absorbed gas from the atmosphere. The two methods agreed to within 3%, which is well within the uncertainty of the measurement. We also found that at least 80% of the atmospheric gas (air) absorbed by the ABS is water. The total amount of all atmospheric gas absorbed by ABS was about 0.35% by weight when exposed to ambient air in the laboratory, which was at a pressure of 101 kPa with a relative humidity of 57% at 22.2 degrees C. PMID- 28736482 TI - Unemployment Insurance and Disability Insurance in the Great Recession. AB - Social Security Disability Insurance (SSDI) awards rise during recessions. If marginal applicants are able to work but unable to find jobs, countercyclical Unemployment Insurance (UI) benefit extensions may reduce SSDI uptake. Exploiting UI extensions in the Great Recession as a source of variation, we find no indication that expiration of UI benefits causes SSDI applications and can rule out effects of meaningful magnitude. A supplementary analysis finds little overlap between the two programs' recipient populations: only 28% of SSDI awardees had any labor force attachment in the prior calendar year, and of those, only 4% received UI. PMID- 28736483 TI - Predicting Romantic Interest at Zero Acquaintance: Evidence of Sex Differences in Trait Perception but Not in Predictors of Interest. AB - We evaluated five competing hypotheses about what predicts romantic interest. Through a half-block quasi-experimental design, a large sample of young adults (i.e., responders; n = 335) viewed videos of opposite-sex persons (i.e., targets) talking about themselves and responders rated the targets' traits and their romantic interest in the target. We tested whether similarity, dissimilarity, or overall trait levels on mate value, physical attractiveness, life history strategy, and the Big-Five personality factors predicted romantic interest at zero acquaintance, and whether sex acted as a moderator. We tested the responders' individual perception of the targets' traits, in addition to the targets' own self-reported trait levels and a consensus rating of the targets made by the responders. We used polynomial regression with response surface analysis within multilevel modeling to test support for each of the hypotheses. Results suggest a large sex difference in trait perception; when women rated men, they agreed in their perception more often than when men rated women. However, as a predictor of romantic interest, there were no sex differences. Only the responders' perception of the targets' physical attractiveness predicted romantic interest; specifically, responders' who rated the targets' physical attractiveness as higher than themselves reported more romantic interest. PMID- 28736484 TI - The New Macromolecular Femtosecond Crystallography (MFX) Instrument at LCLS. PMID- 28736486 TI - The motivations, institutions and organization of university-industry collaborations in the Netherlands. AB - This study builds on the economics and organization literatures to explore whether and how institutions and organizational structure complement or substitute each other to create specific spaces of alignment where specific individual actors' motivations co-exist. Focusing on university-industry collaborations, the study examines whether and how different axes of alignment of university and industry motivations are integrated in projects with specific technological objectives and organizational structures, benefitting from the presence of specific institutions designed to facilitate collaboration. Empirically, the study relies on in-depth data on 30 university-industry collaborations in the Netherlands, and provides preliminary evidence that the technological objective and organizational structure of collaboration are malleable variables allowing the integration of both partners' objectives and expectations. Different institutional incentives for university-industry collaboration favor specific axes of alignment of motivations and certain types of collaborative projects' design. Hence, our exploratory results suggest that specific organizational and technological structures tend to prevail in the presence of specific institutions. PMID- 28736485 TI - Origin of rice (Oryza sativa L.) domestication genes. AB - A number of genes that contribute to the domestication traits of cultivated rice have been identified. These include Sh4, Rc, PROG1 and LABA1, which are associated with non-shattering rachis, white pericarp, erect growth and barbless awns, respectively. The mutations giving rise to the "domestication alleles" of these genes are either invariable in cultivated rice, or have variability that is strictly associated with the phenotypic trait. This observation forms the basis to those current rice domestication models that envisage a single origin for the domesticated phenotype. Such models assume that the domestication alleles are absent or rare in wild rice, emerged under cultivation and spread across all rice groups by introgressive hybridization. We examined whole-genome sequencing datasets for wild and cultivated rice to test the former two assumptions. We found that the rc and laba1 alleles occur in wild rice with broad geographical distribution, and reach frequencies as high as 13 and 15%, respectively. These results are in agreement with previous observations of the prog1 and sh4 domestication alleles in wild populations. We also show that the diversity of the genomic regions surrounding the rc, laba1, prog1 and sh4 alleles in wild accessions is greater than that in cultivated rice, suggesting that these alleles emerged prior to domestication. Our findings indicate that the possibility that independent rice groups obtained identical domestication alleles directly from the wild population needs to be considered. PMID- 28736487 TI - Development blocks in innovation networks: The Swedish manufacturing industry, 1970-2007. AB - The notion of development blocks (Dahmen, 1950, 1991) suggests the co-evolution of technologies and industries through complementarities and the overcoming of imbalances. This study proposes and applies a methodology to analyse development blocks empirically. To assess the extent and character of innovational interdependencies between industries the study combines analysis of innovation biographies and statistical network analysis. This is made possible by using data from a newly constructed innovation output database for Sweden. The study finds ten communities of closely related industries in which innovation activity has been prompted by the emergence of technological imbalances or by the exploitation of new technological opportunities. The communities found in the Swedish network of innovation are shown to be stable over time and often characterized by strong user-supplier interdependencies. These findings serve to stress how historical imbalances and opportunities are key to understanding the dynamics of the long run development of industries and new technologies. PMID- 28736488 TI - Quantification of GST and esterase activities in pyrethrin-resistant mosquitoes using pyrethroid-like fluorescent substrates. AB - Botanical pyrethrins and synthetic pyrethroids are highly potent and environmentally safe insecticides that are used to control a wide range of disease vector and pest arthropods. Unfortunately, resistance to these insecticides has been demonstrated in numerous medically important mosquito species. In this study adult Culex pipiens sensu lato were captured in agricultural and urban locations in Fresno County, California, and subsequently exposed to a commercial formulation of pyrethrin insecticide by ultra low volume spraying. Following insecticide exposure, two pyrethroid-like, fluorescent substrates (cis-DCVC and cis-TFMCVC) and CDNB were used to measure esterase and glutathione S-transferase (GST) activities in surviving mosquitoes. Elevated esterase activity (2.5-fold) was found in surviving urban mosquitoes at 12 h post pyrethrin exposure (in comparison to non-insecticide exposed control mosquitoes) when cis-TFMCVC was used as a substrate. Additionally, when CDNB was used as a substrate, 2.8-fold higher GST activity was found. A simple assay was established using our pyrethroid-like, fluorescent substrates that was able to detect low level esterase activities in homogenates made from individual mosquitoes. The cis TFMCVC-based assay suggested that esterase activity plays a role in pyrethrin resistance in urban mosquitoes in California. PMID- 28736489 TI - Challenges to promoting health for amateur athletes through anti-doping policy. AB - Anti-doping regulations are intended, at least in part, to promote the health of athletes. While most anti-doping efforts target elite and professional competitors, there have been recent moves by sport governing bodies to expand anti-doping testing to include amateur athletes. Drawing on previous critiques of anti-doping policies and illustrating cases, this article outlines five of the challenges to health promotion of applying the current detect and ban model to the amateur level of sport. I argue that the current approach is not effective and, in some ways, may undermine the goal of health promotion at the amateur level. In order to address these challenges, I propose alternative, health centred strategies that focus on athlete empowerment and choice through critical awareness of a variety of substances, associated risks and rewards, and the role of expertise in decision-making. PMID- 28736490 TI - Electromagnetic transduction therapy in non-specific low back pain: A prospective randomised controlled trial. AB - OBJECTIVES: A prospective randomised controlled trial to investigate the efficacy of electromagnetic transduction therapy (EMTT) for treatment of patients with non specific low back pain. DESIGN: Two groups with non-specific low back pain were either treated with conventional therapy alone over 6 weeks or in combination with 8 sessions of EMTT. RESULTS: In both intervention groups the low back pain related pain and the degree of disability decreased significantly at follow-up visits. Combination of EMTT and conventional therapy proved significant superior to conventional therapy alone. CONCLUSION: EMTT is a promising treatment in patients with non-specific low back pain. PMID- 28736491 TI - Next generalization of Cirtoaje's inequality. AB - In this paper, we classify sets of solutions of the next generalized Cirtoaje's inequality and its reverse, respectively. PMID- 28736492 TI - Comparison of Well-being of Older Adult Choir Singers and the General Population in Finland: A Case-Control Study. AB - Previous research suggests that singing in a choir as an older adult is associated with better quality of life (QOL). However, the degree to which sociodemographic variables and level of engagement in hobbies contribute to this relationship is largely unknown. The aim of the study was to compare quality of life (QOL) of older adult choir singers with a matched sample of older adults from the general population in Finland, taking into consideration sociodemographic, satisfaction with health, and level of engagement in hobbies (active, inactive). Case-control methods were used to match a sample of 109 older adult singers with a sample of 307 older adults from the general population. Tobit regression analysis with sociodemographic covariates was used to explore observed group differences in QOL as measured by two WHOQOL-Bref domains (psychological and physical). Probit regression analysis was used to examine the effect of sociodemographic variables and engagement in hobbies and on overall QOL and satisfaction with health. As expected, sociodemographic variables were strongly associated with physical and psychological QOL. After controlling for sociodemographic variables, the older choir singers reported significantly higher ratings on physical QOL, but not psychological QOL, compared to matched controls. Additional adjustment for satisfaction for health attenuated the results. When considering level of engagement in hobbies, older adult choir singers reported significantly higher overall QOL and satisfaction with health when compared to either controls who were either actively engaged in hobbies or not active in hobbies. These results suggest that singing in a choir as an older adult may promote well-being, even after accounting for sociodemographic and level of engagement in hobbies. PMID- 28736493 TI - Video as Data: From Transient Behavior to Tangible Recording. PMID- 28736494 TI - Josephson Arbitrary Waveform Synthesis With Multilevel Pulse Biasing. AB - We describe the implementation of new commercial pulse-bias electronics that have enabled an improvement in the generation of quantum-accurate waveforms both with and without low-frequency compensation biases. We have used these electronics to apply a multilevel pulse bias to the Josephson arbitrary waveform synthesizer and have generated, for the first time, a quantum-accurate bipolar sinusoidal waveform without the use of a low-frequency compensation bias current. This uncompensated 1 kHz waveform was synthesized with an rms amplitude of 325 mV and maintained its quantum accuracy over a1.5 mA operating current range. The same technique and equipment was also used to synthesize a quantum-accurate 1 MHz sinusoid with a 1.2 mA operating margin. In addition, we have synthesized a compensated 1 kHz sinusoid with an rms amplitude of 1 V and a 2.7 mA operating margin. PMID- 28736495 TI - Day-to-day Consistency in Positive Parent-Child Interactions and Youth Well Being. AB - The frequency of positive parent-child interactions is associated with youth adjustment. Yet, little is known about daily parent-child interactions and how day-to-day consistency in positive parent-child interactions may be linked to youth well-being. Using a daily diary approach, this study added to this literature to investigate whether and how day-to-day consistency in positive parent-child interactions was linked to youth depressive symptoms, risky behavior, and physical health. Participants were youth whose parents were employed in the IT division of a Fortune 500 company (N = 129, youth's mean age = 13.39, 55 % female), who participated in an 8 day daily diary study. Analyses revealed that, controlling for cross-day mean levels of positive parent-child interactions, older (but not younger) adolescents who experienced more consistency in positive interactions with parents had fewer depressive and physical health symptoms (e.g., colds, flu). The discussion focuses on the utility of daily diary methods for assessing the correlates of consistency in parenting, possible processes underlying these associations, and intervention implications. PMID- 28736496 TI - Analysis of heat loss mechanisms for mobile tent-type refuge alternatives. AB - Federal regulations require that refuge alternatives (RAs) be located within 305 m (1,000 ft) of the working face and spaced at one-hour travel distances in the outby area in underground coal mines, in the event that miners cannot escape during a disaster. The Mine Safety and Health Administration mandates that RAs provide safe shelter and livable conditions for a minimum of 96 hours while maintaining the apparent temperature below 35 degrees C (95 degrees F). The U.S. National Institute for Occupational Safety and Health used a validated thermal simulation model to examine the mechanisms of heat loss from an RA to the ambient mine and the effect of mine strata composition on the final internal dry bulb temperature (DBT) for a mobile tent-type RA. The results of these studies show that 51 percent of the heat loss from the RA to the ambient mine is due to radiation and 31 percent to conduction. Three mine width and height configurations and four mine strata compositions were examined. The final DBT inside the RA after 96 hours varied by less than 1 degrees C (1.8 degrees F) for the three mine width/height configurations and by less than 2 degrees C (3.6 degrees F) for the four mine strata compositions. PMID- 28736497 TI - Differences between the genomes of lymphoblastoid cell lines and blood-derived samples. AB - Lymphoblastoid cell lines (LCLs) represent a convenient research tool for expanding the amount of biologic material available from an individual. LCLs are commonly used as reference materials, most notably from the Genome in a Bottle Consortium. However, the question remains how faithfully LCL-derived genome assemblies represent the germline genome of the donor individual as compared to the genome assemblies derived from peripheral blood mononuclear cells. We present an in-depth comparison of a large collection of LCL- and peripheral blood mononuclear cell-derived genomes in terms of distributions of coverage and copy number alterations. We found significant differences in the depth of coverage and copy number calls, which may be driven by differential replication timing. Importantly, these copy number changes preferentially affect regions closer to genes and with higher GC content. This suggests that genomic studies based on LCLs may display locus-specific biases, and that conclusions based on analysis of depth of coverage and copy number variation may require further scrutiny. PMID- 28736498 TI - Insights on glicentin, a promising peptide of the proglucagon family. AB - Glicentin is a proglucagon-derived peptide mainly produced in the L-intestinal cells. While the roles of other members of the proglucagon family including glucagon-like peptide 1, glucagon-like peptide 2 and oxyntomodulin has been well studied, the functions and variation of glicentin in human are not fully understood. Experimental and clinical studies have highlighted its role in both intestinal physiology and glucose metabolism, pointing to its potential interest in a wide range of pathological states including gastrointestinal and metabolic disorders. Due to its structure presenting many similarities with the other proglucagon-derived peptides, its measurement is technically challenging. The recent commercialization of specific detection methods has offered new opportunities to go further in the understanding of glicentin physiology. Here we summarize the current knowledge on glicentin biogenesis and physiological roles. In the limelight of clinical studies investigating glicentin variation in human, we discuss future directions for potential applications in clinical practice. PMID- 28736499 TI - Living scaffolds for neuroregeneration. AB - Neural tissue engineers are exploiting key mechanisms responsible for neural cell migration and axonal path finding during embryonic development to create living scaffolds for neuroregeneration following injury and disease. These mechanisms involve the combined use of haptotactic, chemotactic, and mechanical cues to direct cell movement and re-growth. Living scaffolds provide these cues through the use of cells engineered in a predefined architecture, generally in combination with biomaterial strategies. Although several hurdles exist in the implementation of living regenerative scaffolds, there are considerable therapeutic advantages to using living cells in conjunction with biomaterials. The leading contemporary living scaffolds for neurorepair are utilizing aligned glial cells and neuronal/axonal tracts to direct regenerating axons across damaged tissue to appropriate targets, and in some cases to directly replace the function of lost cells. Future advances in technology, including the use of exogenous stimulation and genetically engineered stem cells, will further the potential of living scaffolds and drive a new era of personalized medicine for neuroregeneration. PMID- 28736500 TI - Comparative Proteomic Analysis of Three Chinese Hamster Ovary (CHO) Host Cells. AB - Chinese hamster ovary (CHO) cells have been widely used to express heterologous genes and produce therapeutic proteins in biopharmaceutical industry. Different CHO host cells have distinct cell growth rates and protein expression characteristics. In this study, the expression of about 1,307 host proteins in three sublines, i.e. CHO K1, CHO S and CHO/dihydrofolate reductase (dhfr)- , were investigated and compared using proteomic analysis. The proteins involved in cell growth, glycolysis, tricarboxylic acid cycle, transcription, translation and glycosylation were quantitated using Liquid chromatography tandem-mass spectrometry (LC-MS/MS). The key host cell proteins that regulate the kinetics of cell growth and the magnitude of protein expression levels were identified. Furthermore, several rational cell engineering strategies on how to combine the desired features of fast cell growth and efficient production of therapeutic proteins into one new super CHO host cell have been proposed. PMID- 28736502 TI - Comparison and Contrast of Two General Functional Regression Modeling Frameworks. AB - In this article, Greven and Scheipl describe an impressively general framework for performing functional regression that builds upon the generalized additive modeling framework. Over the past number of years, my collaborators and I have also been developing a general framework for functional regression, functional mixed models, which shares many similarities with this framework, but has many differences as well. In this discussion, I compare and contrast these two frameworks, to hopefully illuminate characteristics of each, highlighting their respecitve strengths and weaknesses, and providing recommendations regarding the settings in which each approach might be preferable. PMID- 28736501 TI - Design of Radioiodinated Pharmaceuticals: Structural Features Affecting Metabolic Stability towards in Vivo Deiodination. AB - Radioiodinated pharmaceuticals are convenient tracers for clinical and research investigations because of the relatively long half-lives of radioactive iodine isotopes (i.e., 123I, 124I, and 131I) and the ease of their chemical insertion. Their application in radionuclide imaging and therapy may, however, be hampered by poor in vivo stability of the C-I bond. After an overview of the use of iodine in biology and nuclear medicine, we present here a survey of the catabolic pathways for iodinated xenobiotics, including their biodistribution, accumulation, and biostability. We summarize successful rational improvements in the biostability and conclude with general guidelines for the design of stable radioiodinated pharmaceuticals. It appears to be necessary to consider the whole molecule, rather than the radioiodinated fragment alone. Iodine radionuclides are generally retained in vivo on sp2 carbon atoms in iodoarenes and iodovinyl moieties, but not in iodinated heterocycles or on sp3 carbon atoms. Iodoarene substituents also have an influence, with increased in vivo deiodination in the cases of iodophenols and iodoanilines, whereas methoxylation and difluorination improve biostability. PMID- 28736503 TI - "Do you see what I mean?" staff collaboration in eating disorder units during mealtimes. AB - BACKGROUND: Eating disorders are psychiatric illnesses with potentially life threatening consequences. Inpatient treatment is typically required for the most severely ill patients, who are often emaciated or significantly malnourished. A core therapeutic objective is to normalize eating patterns and facilitate weight gain. These goals guide the efforts of milieu therapeutic staff working with this patient group, who support renourishment through the positive manipulation of a structured environment, as well via relational aspects. However, there is a lack of empirical research exploring inpatient staff members' perspectives concerning various aspects of this work. This article explore staff's teamwork during mealtimes on inpatient eating disorder units. Specifically, we investigated the collaborative strategies employed to support core therapeutic goals of meal completion and normalized eating behavior, while concurrently maintaining a supportive, friendly atmosphere during mealtimes. METHODS: This was a exploratory qualitative study. Data was collected through 20 semi-structured in-depth interviews with staff members working on a specialized eating disorder unit. The interviews were performed after the conduction of meal time support. Cultural historical activity theory was used as the key theoretical tool for analysis. RESULTS: The analysis revealed three main themes: 1) strategic seating arrangements mediates division of labor, 2) the use of verbal and nonverbal communication as collaborative tools, and 3) the importance of experience as a collaborative resource. CONCLUSIONS: The present study found that mealtime collaborative strategies on inpatient EDUs were mainly of non-verbal nature, with level of experience as an important premise for staff collaboration. Greater awareness about how collegial collaboration is practiced may help staff members to learn routines and regulate scripts for mealtime practices. PMID- 28736505 TI - Estimating the cost-effectiveness of daclatasvir + sofosbuvir versus sofosbuvir + ribavirin for patients with genotype 3 hepatitis C virus. AB - BACKGROUND: As treatments for chronic hepatitis C are moving away from interferon containing regimens, the most appropriate allocation of resources to higher cost, interferon-free, direct-acting antiviral (DAA) regimens needs to be assessed. Hepatitis C virus (HCV) genotype 3 is associated with faster disease progression and has fewer treatment options, historically, than other HCV genotypes. This analysis aims to estimate the comparative cost-effectiveness of two recently licenced interferon-free regimens for the treatment of HCV genotype 3. METHODS: Utilising a published Markov model and results of a matching-adjusted indirect comparison of recently published clinical trial data (ALLY-3 and VALENCE, respectively), 12 weeks of treatment with daclatasvir + sofosbuvir (DCV + SOF) was compared to 24 weeks of treatment with sofosbuvir + ribavirin (SOF + RBV). UK specific model inputs were used to inform a cost-utility analysis of these regimens. RESULTS: In the base case analysis, DCV + SOF was found to be dominant over SOF + RBV in treatment-naive patients, patients that had previously been treated, and patients that are intolerant to, or ineligible for, interferon containing regimens. Given the low rates of treatment currently observed in the UK, DCV + SOF was also compared to no treatment in the interferon ineligible/intolerant patients, and may be considered cost-effective with an incremental cost-effectiveness ratio of L8817. CONCLUSIONS: When compared to 24 weeks of SOF + RBV, 12 weeks of treatment with DCV + SOF results in improved quality of life and reduced total costs, and therefore is likely to represent significant clinical and economic value as a treatment option for genotype 3 HCV infection. PMID- 28736504 TI - Pleomorphism and drug resistant cancer stem cells are characteristic of aggressive primary meningioma cell lines. AB - BACKGROUND: Meningioma tumors arise in arachnoid membranes, and are the most reported central nervous system (CNS) tumors worldwide. Up to 20% of grade I meningioma tumors reoccur and currently predictive cancer stem cells (CSCs) markers for aggressive and drug resistant meningiomas are scarce. METHODS: Meningioma tissues and primary cell lines were investigated using whole transcriptome microarray analysis, immunofluorescence staining of CSCs markers (including CD133, Sox2, Nestin, and Frizzled 9), and drug treatment with cisplatin or etoposide. RESULTS: Unsupervised hierarchical clustering of six meningioma samples separated tissues into two groups. Analysis identified stem cells related pathways to be differential between the two groups and indicated the de-regulation of the stem cell associated genes Reelin (RELN), Calbindin 1 (CALB1) and Anterior Gradient 2 Homolog (AGR2). Immunofluorescence staining for four tissues confirmed stemness variation in situ. Biological characterization of fifteen meningioma primary cell lines concordantly separated cells into two functionally distinct sub-groups. Pleomorphic cell lines (NG type) grew significantly faster than monomorphic cell lines (G type), had a higher number of cells that express Ki67, and were able to migrate aggressively in vitro. In addition, NG type cell lines had a lower expression of nuclear Caspase-3, and had a significantly higher number of CSCs co-positive for CD133+ Sox2+ or AGR2+ BMI1+. Importantly, these cells were more tolerant to cisplatin and etoposide treatment, showed a lower level of nuclear Caspase-3 in treated cells and harbored drug resistant CSCs. CONCLUSION: Collectively, analyses of tissues and primary cell lines revealed stem cell associated genes as potential targets for aggressive and drug resistant meningiomas. PMID- 28736506 TI - National disability-adjusted life years (DALYs) for 257 diseases and injuries in Ethiopia, 1990-2015: findings from the global burden of disease study 2015. AB - BACKGROUND: Disability-adjusted life years (DALYs) provide a summary measure of health and can be a critical input to guide health systems, investments, and priority-setting in Ethiopia. We aimed to determine the leading causes of premature mortality and disability using DALYs and describe the relative burden of disease and injuries in Ethiopia. METHODS: We used results from the Global Burden of Diseases, Injuries, and Risk Factors Study 2015 (GBD 2015) for non fatal disease burden, cause-specific mortality, and all-cause mortality to derive age-standardized DALYs by sex for Ethiopia for each year. We calculated DALYs by summing years of life lost due to premature mortality (YLLs) and years lived with disability (YLDs) for each age group and sex. Causes of death by age, sex, and year were measured mainly using Causes of Death Ensemble modeling. To estimate YLDs, a Bayesian meta-regression method was used. We reported DALY rates per 100,000 for communicable, maternal, neonatal, and nutritional (CMNN) disorders, non-communicable diseases, and injuries, with 95% uncertainty intervals (UI) for Ethiopia. RESULTS: Non-communicable diseases caused 23,118.1 (95% UI, 17,124.4 30,579.6), CMNN disorders resulted in 20,200.7 (95% UI, 16,532.2-24,917.9), and injuries caused 3781 (95% UI, 2642.9-5500.6) age-standardized DALYs per 100,000 in Ethiopia in 2015. Lower respiratory infections, diarrheal diseases, and tuberculosis were the top three leading causes of DALYs in 2015, accounting for 2998 (95% UI, 2173.7-4029), 2592.5 (95% UI, 1850.7-3495.1), and 2562.9 (95% UI, 1466.1-4220.7) DALYs per 100,000, respectively. Ischemic heart disease and cerebrovascular disease were the fourth and fifth leading causes of age standardized DALYs, with rates of 2535.7 (95% UI, 1603.7-3843.2) and 2159.9 (95% UI, 1369.7-3216.3) per 100,000, respectively. The following causes showed a reduction of 60% or more over the last 25 years: lower respiratory infections, diarrheal diseases, tuberculosis, neonatal encephalopathy, preterm birth complications, meningitis, malaria, protein-energy malnutrition, iron-deficiency anemia, measles, war and legal intervention, and maternal hemorrhage. CONCLUSIONS: Ethiopia has been successful in reducing age-standardized DALYs related to most communicable, maternal, neonatal, and nutritional deficiency diseases in the last 25 years, causing a major ranking shift to types of non communicable disease. Lower respiratory infections, diarrheal disease, and tuberculosis continue to be leading causes of premature death, despite major declines in burden. Non-communicable diseases also showed reductions as premature mortality declined; however, disability outcomes for these causes did not show declines. Recently developed non-communicable disease strategies may need to be amended to focus on cardiovascular diseases, cancer, diabetes, and major depressive disorders. Increasing trends of disabilities due to neonatal encephalopathy, preterm birth complications, and neonatal disorders should be emphasized in the national newborn survival strategy. Generating quality data should be a priority through the development of new initiatives such as vital events registration, surveillance programs, and surveys to address gaps in data. Measuring disease burden at subnational regional state levels and identifying variations with urban and rural population health should be conducted to support health policy in Ethiopia. PMID- 28736508 TI - 3-DOF Force-Sensing Motorized Micro-Forceps for Robot-Assisted Vitreoretinal Surgery. AB - In vitreoretinal surgery, membrane peeling is a prototypical task where a layer of fibrous tissue is delaminated off the retina with a micro-forceps by applying very fine forces that are mostly imperceptible to the surgeon. Previously we developed sensitized ophthalmic surgery tools based on fiber Bragg grating (FBG) strain sensors, which were shown to precisely detect forces at the instrument's tip in two degrees of freedom perpendicular to the tool axis. This paper presents a new design that employs an additional sensor to capture also the tensile force along the tool axis. The grasping functionality is provided via a compact motorized unit. To compute forces, we investigate two distinct fitting methods: a linear regression and a nonlinear fitting based on second-order Bernstein polynomials. We carry out experiments to test the repeatability of sensor outputs, calibrate the sensor and validate its performance. Results demonstrate sensor wavelength repeatability within 2 pm. Although the linear method provides sufficient accuracy in measuring transverse forces, in the axial direction it produces a root mean square (rms) error over 3 mN even for a confined magnitude and direction of forces. On the other hand, the nonlinear method provides a more consistent and accurate measurement of both the transverse and axial forces for the entire force range (0-25 mN). Validation including random samples shows that our tool with the nonlinear force computation method can predict 3-D forces with an rms error under 0.15 mN in the transverse plane and within 2 mN accuracy in the axial direction. PMID- 28736507 TI - National mortality burden due to communicable, non-communicable, and other diseases in Ethiopia, 1990-2015: findings from the Global Burden of Disease Study 2015. AB - BACKGROUND: Ethiopia lacks a complete vital registration system that would assist in measuring disease burden and risk factors. We used the Global Burden of Diseases, Injuries, and Risk Factors Study 2015 (GBD 2015) estimates to describe the mortality burden from communicable, non-communicable, and other diseases in Ethiopia over the last 25 years. METHODS: GBD 2015 mainly used cause of death ensemble modeling to measure causes of death by age, sex, and year for 195 countries. We report numbers of deaths and rates of years of life lost (YLL) for communicable, maternal, neonatal, and nutritional (CMNN) disorders, non communicable diseases (NCDs), and injuries with 95% uncertainty intervals (UI) for Ethiopia from 1990 to 2015. RESULTS: CMNN causes of death have declined by 65% in the last two-and-a-half decades. Injury-related causes of death have also decreased by 70%. Deaths due to NCDs declined by 37% during the same period. Ethiopia showed a faster decline in the burden of four out of the five leading causes of age-standardized premature mortality rates when compared to the overall sub-Saharan African region and the Eastern sub-Saharan African region: lower respiratory infections, tuberculosis, HIV/AIDS, and diarrheal diseases; however, the same could not be said for ischemic heart disease and other NCDs. Non communicable diseases, together, were the leading causes of age-standardized mortality rates, whereas CMNN diseases were leading causes of premature mortality in 2015. Although lower respiratory infections, tuberculosis, and diarrheal disease were the leading causes of age-standardized death rates, they showed major declines from 1990 to 2015. Neonatal encephalopathy, iron-deficiency anemia, protein-energy malnutrition, and preterm birth complications also showed more than a 50% reduction in burden. HIV/AIDS-related deaths have also decreased by 70% since 2005. Ischemic heart disease, hemorrhagic stroke, and ischemic stroke were among the top causes of premature mortality and age-standardized death rates in Ethiopia in 2015. CONCLUSIONS: Ethiopia has been successful in reducing deaths related to communicable, maternal, neonatal, and nutritional deficiency diseases and injuries by 65%, despite unacceptably high maternal and neonatal mortality rates. However, the country's performance regarding non communicable diseases, including cardiovascular disease, diabetes, cancer, and chronic respiratory disease, was minimal, causing these diseases to join the leading causes of premature mortality and death rates in 2015. While the country is progressing toward universal health coverage, prevention and control strategies in Ethiopia should consider the double burden of common infectious diseases and non-communicable diseases: lower respiratory infections, diarrhea, tuberculosis, HIV/AIDS, cardiovascular disease, cancer, and diabetes. Prevention and control strategies should also pay special attention to the leading causes of premature mortality and death rates caused by non-communicable diseases: cardiovascular disease, cancer, and diabetes. Measuring further progress requires a data revolution in generating, managing, analyzing, and using data for decision making and the creation of a full vital registration system in the country. PMID- 28736509 TI - "I'm Stuck": Women's Navigations of Social Networks and Prescription Drug Misuse in Central Appalachia. AB - This study utilizes anthropological analyses of kinship, care, gendered inequalities, and the state to examine how social networks affect women's substance use in a rural Appalachian county where the primary drug of choice is prescription opioids. Of 503 participants from a larger study of social networks among rural drug users, 16 women who reported using drugs with four or more other study participants (drug network members) were interviewed from November 2011 to February 2012. The purpose of interviews is to analyze the substance use patterns among participants who are highly connected in their networks. Female participants say they feel "stuck" in cycles of prescription drug misuse because of entrenchment in moral economies, intensive caretaking responsibilities, and violence from those in their networks. Although women demonstrate agency in their navigations of drug use, relationships, and economic and health inequalities, the factors that constrain women's actions culminate to create barriers for women accessing substance abuse treatment or decreasing substance use outside of treatment. This study adds to understandings of the relational and situational aspects of women's drug use and efforts to decrease use. Recognizing these aspects of women's lives will aid policies and programs in becoming more relevant to substance abusing women. (substance use; kinship; care; gendered inequalities; Appalachia). PMID- 28736512 TI - Attention to Individuals: Mixed Methods for N-of-1 Health Care Interventions. AB - In several ways, randomized controlled trials represent a high standard of rigor in clinical biomedical research. Randomized controlled trials fail, however, to yield knowledge applicable to specific individuals. This article presents a methodological rationale for a mixed methods approach to n-of-1 clinical studies that attends to the preferences and concerns of individuals while attaining high standards of qualitative and quantitative rigor. An illustrative research design involving a hypothetical music therapy intervention for a quality of life outcome is examined in some detail and a concluding argument is made that the proposed mixed methods approach is especially appropriate for early-stage research interventions intended to generate explanatory hypotheses. PMID- 28736510 TI - A genomic perspective on the generation and maintenance of genetic diversity in herbivorous insects. AB - Understanding the processes that generate and maintain genetic variation within populations is a central goal in evolutionary biology. Theory predicts that some of this variation is maintained as a consequence of adapting to variable habitats. Studies in herbivorous insects have played a key role in confirming this prediction. Here, we highlight theoretical and conceptual models for the maintenance of genetic diversity in herbivorous insects, empirical genomic studies testing these models, and pressing questions within the realm of evolutionary and functional genomic studies. To address key gaps, we propose an integrative approach combining population genomic scans for adaptation, genome wide characterization of targets of selection through experimental manipulations, mapping the genetic architecture of traits influencing fitness, and functional studies. We also stress the importance of studying the maintenance of genetic variation across biological scales-from variation within populations to divergence among populations-to form a comprehensive view of adaptation in herbivorous insects. PMID- 28736511 TI - Effects of Methylsulfonylmethane (MSM) on exercise-induced oxidative stress, muscle damage, and pain following a half-marathon: a double-blind, randomized, placebo-controlled trial. AB - BACKGROUND: Oxidative stress and muscle damage occur during exhaustive bouts of exercise, and many runners report pain and soreness as major influences on changes or breaks in training regimens, creating a barrier to training persistence. Methylsulfonylmethane (MSM) is a sulfur-based nutritional supplement that is purported to have pain and inflammation-reducing effects. To investigate the effects of MSM in attenuating damage associated with physical exertion, this randomized, double-blind, placebo-controlled study evaluated the effects of MSM supplementation on exercise-induced pain, oxidative stress and muscle damage. METHODS: Twenty-two healthy females (n = 17) and males (n = 5) (age 33.7 +/- 6.9 yrs.) were recruited from the 2014 Portland Half-Marathon registrant pool. Participants were randomized to take either MSM (OptiMSM(r)) (n = 11), or a placebo (n = 11) at 3 g/day for 21 days prior to the race and for two days after (23 total). Participants provided blood samples for measurement of markers of oxidative stress, and completed VAS surveys for pain approximately one month prior to the race (T0), and at 15 min (T1), 90 min (T2), 1 Day (T3), and 2 days (T4) after race finish. The primary outcome measure 8-hydroxy-2-deoxyguanine (8 OHdG) measured oxidative stress. Secondary outcomes included malondialdehyde (MDA) for oxidative stress, creatine kinase (CK) and lactate dehydrogenase (LDH) as measures of muscle damage, and muscle (MP) and joint pain (JP) recorded using a 100 mm Visual Analogue Scale (VAS). Data were analyzed using repeated and multivariate ANOVAs, and simple contrasts compared post-race time points to baseline, presented as mean (SD) or mean change (95% CI) where appropriate. RESULTS: Running a half-marathon induced significant increases in all outcome measures (p < 0.001). From baseline, 8-OHdG increased significantly at T1 by 1.53 ng/mL (0.86-2.20 ng/mL CI, p < 0.001) and T2 by 1.19 ng/mL (0.37-2.01 ng/mL CI, p < 0.01), and fell below baseline levels at T3 by -0.46 ng/mL (-1.18-0.26 CI, p > 0.05) and T4 by -0.57 ng/mL (-1.27-0.13 CI, p > 0.05). MDA increased significantly at T1 by 7.3 MUM (3.9-10.7 CI, p < 0.001). Muscle damage markers CK and LDH saw significant increases from baseline at all time-points (p < 0.01). Muscle and joint pain increased significantly from baseline at T1, T2, and T3 (p < 0.01) and returned to baseline levels at T4. Time-by-treatment results did not reach statistical significance for any outcome measure, however, the MSM group saw clinically significant (Delta > 10 mm) reductions in both muscle and joint pain. CONCLUSION: Participation in a half-marathon was associated with increased markers of oxidative stress, muscle damage, and pain. MSM supplementation was not associated with a decrease from pre-training levels of oxidative stress or muscle damage associated with an acute bout of exercise. MSM supplementation attenuated post-exercise muscle and joint pain at clinically, but not statistically significant levels. PMID- 28736514 TI - Design and Validation of Exoskeleton Actuated by Soft Modules toward Neurorehabilitation-Vision-Based Control for Precise Reaching Motion of Upper Limb. AB - We demonstrated the design, production, and functional properties of the Exoskeleton Actuated by the Soft Modules (EAsoftM). Integrating the 3D printed exoskeleton with passive joints to compensate gravity and with active joints to rotate the shoulder and elbow joints resulted in ultra-light system that could assist planar reaching motion by using the vision-based control law. The EAsoftM can support the reaching motion with compliance realized by the soft materials and pneumatic actuation. In addition, the vision-based control law has been proposed for the precise control over the target reaching motion within the millimeter scale. Aiming at rehabilitation exercise for individuals, typically soft actuators have been developed for relatively small motions, such as grasping motion, and one of the challenges has been to extend their use for a wider range reaching motion. The proposed EAsoftM presented one possible solution for this challenge by transmitting the torque effectively along the anatomically aligned with a human body exoskeleton. The proposed integrated systems will be an ideal solution for neurorehabilitation where affordable, wearable, and portable systems are required to be customized for individuals with specific motor impairments. PMID- 28736513 TI - Low cigarette smoking prevalence in peri-urban Peru: results from a population based study of tobacco use by self-report and urine cotinine. AB - BACKGROUND: A recent study found lower self-reported prevalence of tobacco smoking in a peri-urban area of Lima, Peru than previously reported in urban samples. These regions encompass substantial proportions of Peru's population - ones at greater risk of disease due to reduced healthcare access - but have been less often studied. We validate low smoking prevalence with urine cotinine and characterize chronic disease and lung function outcomes between non-, occasional, and daily smokers. METHODS: Data are from the CRONICAS Cohort Study, a population based longitudinal study in four low-resource Peruvian settings, which began in 2010. Of a baseline cohort of 2978 adults, we prospectively followed 2583 (87%) to determine prevalence of chronic illness. RESULTS: In a baseline sub-sample of 382 participants, median adjusted cotinine was 0.0 mcg/mg (IQR 0-0) for both self reported non-smokers and occasional smokers compared to 172.3 mcg/mg (IQR 0 709.2) for daily smokers. Creatinine-adjusted cotinine validated daily smoking prevalence of 4.7% at a cutoff of 100 mcg/mg. Kappa statistic for daily smoking and creatinine- adjusted cotinine >=100 mcg/mg was 0.65 (95% CI 0.47, 0.83), indicating substantial agreement. At baseline, we found 3.3% daily and 8.9% occasional smoking by self-report for the full cohort. Follow-up indicated little difference in chronic disease prevalence between groups. Daily smokers trended toward having a greater decline in FVC (-1%; 95% CI -2.9, 0.8) and FEV1 (-1.3%; 95% CI -3.2, 0.6) over 40 months when compared to non-smokers, whereas the decline in lung function for occasional smokers was similar compared to non smokers (-0.2% FVC; 95% CI -1.5, 1.0) and (0% FEV1; 95% CI -1.3, 1.3). CONCLUSIONS: Our data places Peru within a previously-described pattern of smoking found in much of Latin America, favoring occasional over daily smoking and low cigarette consumption. We determine that there are not significant differences between smoking groups concerning chronic disease outcomes. We favor distinguishing between daily and occasional smokers in order to accurately characterize these low-use populations. PMID- 28736515 TI - Heidelberg Neuro-Music Therapy Enhances Task-Negative Activity in Tinnitus Patients. AB - Background: Suffering from tinnitus causes mental distress in most patients. Recent findings point toward a diminished activity of the brain's default-mode network (DMN) in subjects with mental disorders including depression or anxiety and also recently in subjects with tinnitus-related distress. We recently developed a therapeutic intervention, namely the Heidelberg Neuro-Music Therapy (HNMT), which shows an effective reduction of tinnitus-related distress following a 1-week short-term treatment. This approach offers the possibility to evaluate the neural changes associated with the improvements in tinnitus distress. We previously reported gray matter (GM) reorganization in DMN regions and in primary auditory areas following HNMT in cases of recent-onset tinnitus. Here we evaluate on the same patient group, using functional MRI (fMRI), the activity of the DMN following the improvements tinnitus-related distress related to the HNMT intervention. Methods: The DMN activity was estimated by the task-negative activation (TNA) during long inter-trial intervals in a word recognition task. The level of TNA was evaluated twice, before and after the 1-week study period, in 18 treated tinnitus patients ("treatment group," TG), 21 passive tinnitus controls (PTC), and 22 active healthy controls (AC). During the study, the participants in TG and AC groups were treated with HNMT, whereas PTC patients did not receive any tinnitus-specific treatment. Therapy-related effects on DMN activity were assessed by comparing the pairs of fMRI records from the TG and PTC groups. Results: Treatment of the TG group with HNMT resulted in an augmented DMN activity in the PCC by 2.5% whereas no change was found in AC and PTC groups. This enhancement of PCC activity correlated with a reduction in tinnitus distress (Spearman Rho: -0.5; p < 0.005). Conclusion: Our findings show that an increased DMN activity, especially in the PCC, underlies the improvements in tinnitus related distress triggered by HNMT and identify the DMN as an important network involved in therapeutic improvements. PMID- 28736516 TI - Weaker Functional Connectivity Strength in Patients with Type 2 Diabetes Mellitus. AB - Type 2 diabetes mellitus (T2DM) is related to cognitive impairments and increased risk for dementia. Neuroimaging studies have demonstrated T2DM-related brain structural and functional changes which are partly associated to the cognitive decline. However, few studies focused on the early neuroimaging findingsin T2DM patients. In this study, a data-driven whole-brain resting state functional connectivity strength (rsFCS) methodwas used to evaluate resting functional changes in 53 T2DM patients compared with 55 matched healthy controls (HCs), and to detect the associations between the rsFCSchanges and cognitive functions in T2DM patients. The T2DM patients exhibited weaker long-range rsFCS in the right insula and weaker short-range rsFCS in the right supramarginalgyrus (SG) compared with the HCs. Additionally, seed-based functional connectivity (FC) analysis revealed weaker FC between the right insula and the bilateral superior parietal lobule (SPL), and between the right SG and the bilateral supplementary motor area (SMA)/right SPL in T2DM patientscompared with the HCs. In T2DM patients, negative correlation was found between the long-range rsFCS in the right insula and HbA1c levels; and the FC between the right SG and the bilateral SMA negatively correlated with TMT-A scores. Our results indicated that the rsFCS alteration occurredbefore obvious cognitive deficits in T2DM patients, which might be helpful for understanding the neuromechanism of cognitive declines in T2DM patients. PMID- 28736519 TI - Isolating Discriminant Neural Activity in the Presence of Eye Movements and Concurrent Task Demands. AB - A growing number of studies use the combination of eye-tracking and electroencephalographic (EEG) measures to explore the neural processes that underlie visual perception. In these studies, fixation-related potentials (FRPs) are commonly used to quantify early and late stages of visual processing that follow the onset of each fixation. However, FRPs reflect a mixture of bottom-up (sensory-driven) and top-down (goal-directed) processes, in addition to eye movement artifacts and unrelated neural activity. At present there is little consensus on how to separate this evoked response into its constituent elements. In this study we sought to isolate the neural sources of target detection in the presence of eye movements and over a range of concurrent task demands. Here, participants were asked to identify visual targets (Ts) amongst a grid of distractor stimuli (Ls), while simultaneously performing an auditory N-back task. To identify the discriminant activity, we used independent components analysis (ICA) for the separation of EEG into neural and non-neural sources. We then further separated the neural sources, using a modified measure-projection approach, into six regions of interest (ROIs): occipital, fusiform, temporal, parietal, cingulate, and frontal cortices. Using activity from these ROIs, we identified target from non-target fixations in all participants at a level similar to other state-of-the-art classification techniques. Importantly, we isolated the time course and spectral features of this discriminant activity in each ROI. In addition, we were able to quantify the effect of cognitive load on both fixation-locked potential and classification performance across regions. Together, our results show the utility of a measure-projection approach for separating task-relevant neural activity into meaningful ROIs within more complex contexts that include eye movements. PMID- 28736518 TI - Behavioral Effects of Systemic, Infralimbic and Prelimbic Injections of a Serotonin 5-HT2A Antagonist in Carioca High- and Low-Conditioned Freezing Rats. AB - The role of serotonin (5-hydroxytryptamine [5-HT]) and 5-HT2A receptors in anxiety has been extensively studied, mostly without considering individual differences in trait anxiety. Our laboratory developed two lines of animals that are bred for high and low freezing responses to contextual cues that are previously associated with footshock (Carioca High-conditioned Freezing [CHF] and Carioca Low-conditioned Freezing [CLF]). The present study investigated whether ketanserin, a preferential 5-HT2A receptor blocker, exerts distinct anxiety-like profiles in these two lines of animals. In the first experiment, the animals received a systemic injection of ketanserin and were exposed to the elevated plus maze (EPM). In the second experiment, these two lines of animals received microinjections of ketanserin in the infralimbic (IL) and prelimbic (PL) cortices and were exposed to either the EPM or a contextual fear conditioning paradigm. The two rat lines exhibited bidirectional effects on anxiety-like behavior in the EPM and opposite responses to ketanserin. Both systemic and intra-IL cortex injections of ketanserin exerted anxiolytic-like effects in CHF rats but anxiogenic-like effects in CLF rats. Microinjections of ketanserin in the PL cortex also exerted anxiolytic-like effects in CHF rats but had no effect in CLF rats. These results suggest that the behavioral effects of 5-HT2A receptor antagonism might depend on genetic variability associated with baseline reactions to threatening situations and 5-HT2A receptor expression in the IL and PL cortices. Highlights -CHF and CLF rats are two bidirectional lines that are based on contextual fear conditioning.-CHF rats have a more "anxious" phenotype than CLF rats in the EPM.-The 5-HT2A receptor antagonist ketanserin had opposite behavioral effects in CHF and CLF rats.-Systemic and IL injections either decreased (CHF) or increased (CLF) anxiety-like behavior.-PL injections either decreased (CHF) anxiety-like behavior or had no effect (CLF). PMID- 28736520 TI - Combined Effects of Feedforward Inhibition and Excitation in Thalamocortical Circuit on the Transitions of Epileptic Seizures. AB - The mechanisms underlying electrophysiologically observed two-way transitions between absence and tonic-clonic epileptic seizures in cerebral cortex remain unknown. The interplay within thalamocortical network is believed to give rise to these epileptic multiple modes of activity and transitions between them. In particular, it is thought that in some areas of cortex there exists feedforward inhibition from specific relay nucleus of thalamus (TC) to inhibitory neuronal population (IN) which has even more stronger functions on cortical activities than the known feedforward excitation from TC to excitatory neuronal population (EX). Inspired by this, we proposed a modified computational model by introducing feedforward inhibitory connectivity within thalamocortical circuit, to systematically investigate the combined effects of feedforward inhibition and excitation on transitions of epileptic seizures. We first found that the feedforward excitation can induce the transition from tonic oscillation to spike and wave discharges (SWD) in cortex, i.e., the epileptic tonic-absence seizures, with the fixed weak feedforward inhibition. Thereinto, the phase of absence seizures corresponding to strong feedforward excitation can be further transformed into the clonic oscillations with the increasing of feedforward inhibition, representing the epileptic absence-clonic seizures. We also observed the other fascinating dynamical states, such as periodic 2/3/4-spike and wave discharges, reversed SWD and clonic oscillations, as well as saturated firings. More importantly, we can identify the stable parameter regions representing the tonic-clonic oscillations and SWD discharges of epileptic seizures on the 2-D plane composed of feedforward inhibition and excitation, where the physiologically plausible transition pathways between tonic-clonic and absence seizures can be figured out. These results indicate the functional role of feedforward pathways in controlling epileptic seizures and the modified thalamocortical model may provide a guide for future efforts to mechanistically link feedforward pathways in the pathogenesis of epileptic seizures. PMID- 28736517 TI - Resolution of Cochlear Inflammation: Novel Target for Preventing or Ameliorating Drug-, Noise- and Age-related Hearing Loss. AB - A significant number of studies support the idea that inflammatory responses are intimately associated with drug-, noise- and age-related hearing loss (DRHL, NRHL and ARHL). Consequently, several clinical strategies aimed at reducing auditory dysfunction by preventing inflammation are currently under intense scrutiny. Inflammation, however, is a normal adaptive response aimed at restoring tissue functionality and homeostasis after infection, tissue injury and even stress under sterile conditions, and suppressing it could have unintended negative consequences. Therefore, an appropriate approach to prevent or ameliorate DRHL, NRHL and ARHL should involve improving the resolution of the inflammatory process in the cochlea rather than inhibiting this phenomenon. The resolution of inflammation is not a passive response but rather an active, highly controlled and coordinated process. Inflammation by itself produces specialized pro resolving mediators with critical functions, including essential fatty acid derivatives (lipoxins, resolvins, protectins and maresins), proteins and peptides such as annexin A1 and galectins, purines (adenosine), gaseous mediators (NO, H2S and CO), as well as neuromodulators like acetylcholine and netrin-1. In this review article, we describe recent advances in the understanding of the resolution phase of inflammation and highlight therapeutic strategies that might be useful in preventing inflammation-induced cochlear damage. In particular, we emphasize beneficial approaches that have been tested in pre-clinical models of inflammatory responses induced by recognized ototoxic drugs such as cisplatin and aminoglycoside antibiotics. Since these studies suggest that improving the resolution process could be useful for the prevention of inflammation-associated diseases in humans, we discuss the potential application of similar strategies to prevent or mitigate DRHL, NRHL and ARHL. PMID- 28736521 TI - Group-Level Progressive Alterations in Brain Connectivity Patterns Revealed by Diffusion-Tensor Brain Networks across Severity Stages in Alzheimer's Disease. AB - Alzheimer's disease (AD) is a chronically progressive neurodegenerative disease highly correlated to aging. Whether AD originates by targeting a localized brain area and propagates to the rest of the brain across disease-severity progression is a question with an unknown answer. Here, we aim to provide an answer to this question at the group-level by looking at differences in diffusion-tensor brain networks. In particular, making use of data from Alzheimer's Disease Neuroimaging Initiative (ADNI), four different groups were defined (all of them matched by age, sex and education level): G1 (N1 = 36, healthy control subjects, Control), G2 (N2 = 36, early mild cognitive impairment, EMCI), G3 (N3 = 36, late mild cognitive impairment, LMCI) and G4 (N4 = 36, AD). Diffusion-tensor brain networks were compared across three disease stages: stage I (Control vs. EMCI), stage II (Control vs. LMCI) and stage III (Control vs. AD). The group comparison was performed using the multivariate distance matrix regression analysis, a technique that was born in genomics and was recently proposed to handle brain functional networks, but here applied to diffusion-tensor data. The results were threefold: First, no significant differences were found in stage I. Second, significant differences were found in stage II in the connectivity pattern of a subnetwork strongly associated to memory function (including part of the hippocampus, amygdala, entorhinal cortex, fusiform gyrus, inferior and middle temporal gyrus, parahippocampal gyrus and temporal pole). Third, a widespread disconnection across the entire AD brain was found in stage III, affecting more strongly the same memory subnetwork appearing in stage II, plus the other new subnetworks, including the default mode network, medial visual network, frontoparietal regions and striatum. Our results are consistent with a scenario where progressive alterations of connectivity arise as the disease severity increases and provide the brain areas possibly involved in such a degenerative process. Further studies applying the same strategy to longitudinal data are needed to fully confirm this scenario. PMID- 28736522 TI - Gliotoxin Targets Nuclear NOTCH2 in Human Solid Tumor Derived Cell Lines In Vitro and Inhibits Melanoma Growth in Xenograft Mouse Model. AB - Deregulation of NOTCH2 signaling is implicated in a wide variety of human neoplasias. The current concept of targeting NOTCH is based on using gamma secretase inhibitors (GSI) to regulate the release of the active NOTCH intracellular domain. However, the clinical outcome of GSI remains unsatisfactory. Therefore we analyzed human solid tumor derived cell lines for their nuclear NOTCH activity and evaluated the therapeutic potential of the NOTCH2 transactivation inhibitor gliotoxin in comparison to the representative GSI DAPT. Electrophoretic mobility shift assays (EMSA) were used as a surrogate method for the detection of NOTCH/CSL transcription factor complexes. The effect of gliotoxin on cell viability and its clinical relevance was evaluated in vitro and in a melanoma xenograft mouse model. Cell lines derived from melanoma (518A2), hepatocellular carcinoma (SNU398, HCC-3, Hep3B), and pancreas carcinoma (PANC1) express high amounts of nuclear NOTCH2. Gliotoxin efficiently induced apoptosis in these cell lines whereas the GSI DAPT was ineffective. The specificity of gliotoxin was demonstrated in the well differentiated nuclear NOTCH negative cell line Huh7, which was resistant to gliotoxin treatment in vitro. In xenotransplanted 518A2 melanomas, a single day dosing schedule of gliotoxin was well tolerated without any study limiting side effects. Gliotoxin significantly reduced the tumor volume in early (83 mm3 vs. 115 mm3, p = 0.008) as well as in late stage (218 mm3 vs. 576 mm3, p = 0.005) tumor models. In conclusion, NOTCH2 appears to be a key target of gliotoxin in human neoplasias and gliotoxin deserves further evaluation as a potential therapeutic agent in cancer management. PMID- 28736523 TI - Sub-Minimum Inhibitory Concentrations of Rhubarb Water Extracts Inhibit Streptococcus suis Biofilm Formation. AB - Streptococcus suis is one of the most important swine pathogens, which can cause persistent infection by forming biofilms. In this study, sub-minimum inhibitory concentration (sub-MIC) of rhubarb water extracts were found to inhibit biofilm formation. Two-component signal transduction systems (TCSs), transcriptional regulators, and DNA binding proteins were compared under two conditions: (1) cells treated with sub-MIC rhubarb water extracts and (2) untreated cells. Using an isobaric tags for relative and absolute quantitation (iTRAQ) strategy, we found that TCSs constituent proteins of histidine kinase and response regulator were significantly down-regulated. This down-regulation can affect the transfer of information during biofilm formation. The transcriptional regulators and DNA binding proteins that can interact with TCSs and interrupt gene transcription were also significantly altered. For these reasons, the levels of protein expressions varied in different parts of the treated vs. untreated cells. In summary, rhubarb water extracts might serve as potential inhibitor for the control of S. suis biofilm formation. The change in TCSs, transcriptional regulators, and DNA binding proteins may be important factors in S. suis biofilm inhibition. PMID- 28736524 TI - Immune and Metabolic Regulation Mechanism of Dangguiliuhuang Decoction against Insulin Resistance and Hepatic Steatosis. AB - Dangguiliuhuang decoction (DGLHD) is a traditional Chinese medicine (TCM) formula, which mainly consists of angelica, radix rehmanniae, radix rehmanniae praeparata, scutellaria baicalensis, coptis chinensis, astragalus membranaceus, and golden cypress, and used for the treatment of diabetes and some autoimmune diseases. In this study, we explored the potential mechanism of DGLHD against insulin resistance and fatty liver in vivo and in vitro. Our data revealed that DGLHD normalized glucose and insulin level, increased the expression of adiponectin, diminished fat accumulation and lipogenesis, and promoted glucose uptake. Metabolomic analysis also demonstrated that DGLHD decreased isoleucine, adenosine, and cholesterol, increased glutamine levels in liver and visceral adipose tissue (VAT) of ob/ob mice. Importantly, DGLHD promoted the shift of pro inflammatory to anti-inflammatory cytokines, suppressed T lymphocytes proliferation, and enhanced regulatory T cells (Tregs) differentiation. DGLHD also inhibited dendritic cells (DCs) maturation, attenuated DCs-stimulated T cells proliferation and secretion of IL-12p70 cytokine from DCs, and promoted the interaction of DCs with Tregs. Further studies indicated that the changed PI3K/Akt signaling pathway and elevated PPAR-gamma expression were not only observed with the ameliorated glucose and lipid metabolism in adipocytes and hepatocytes, but also exhibited in DCs and T cells by DGLHD. Collectively, our results suggest that DGLHD exerts anti-insulin resistant and antisteatotic effects by improving abnormal immune and metabolic homeostasis. And DGLHD may be a novel approach to the treatment of obesity-related insulin resistance and hepatic steatosis. PMID- 28736526 TI - Age and Sex Interact to Mediate the Effects of Intermittent, High-Dose Ethanol Exposure on Behavioral Flexibility. AB - Human alcoholics have been shown to have impaired cognitive control over actions and increased reliance on habitual response strategies. While it is unclear in humans whether these differences predate ethanol exposure or result from chronic drinking, data from animal studies suggest that ethanol acts to promote the development of inflexible behaviors. Here, we investigated how intermittent exposure to high doses of ethanol impacts the ability to flexibly regulate behavior in a habit model. As adolescence, may represent a period of increased drug taking and developmental vulnerability that may impact adult behavior, we compared the effects of high-dose ethanol exposure during adolescence to exposure during adulthood in male and female rats. Our findings indicated that the effects of intermittent, high-dose ethanol exposure on habitual behavior is mediated by age and sex such that ethanol exposure during adolescence promoted the use of habitual response strategies in adult females, but not males, and that the opposite pattern emerged following intermittent, high-dose ethanol exposure in adult rats. PMID- 28736525 TI - Pharmaceutical Chaperones and Proteostasis Regulators in the Therapy of Lysosomal Storage Disorders: Current Perspective and Future Promises. AB - Different approaches have been utilized or proposed for the treatment of lysosomal storage disorders (LSDs) including enzyme replacement and hematopoietic stem cell transplant therapies, both aiming to compensate for the enzymatic loss of the underlying mutated lysosomal enzymes. However, these approaches have their own limitations and therefore the vast majority of LSDs are either still untreatable or their treatments are inadequate. Missense mutations affecting enzyme stability, folding and cellular trafficking are common in LSDs resulting often in low protein half-life, premature degradation, aggregation and retention of the mutant proteins in the endoplasmic reticulum. Small molecular weight compounds such as pharmaceutical chaperones (PCs) and proteostasis regulators have been in recent years to be promising approaches for overcoming some of these protein processing defects. These compounds are thought to enhance lysosomal enzyme activity by specific binding to the mutated enzyme or by manipulating components of the proteostasis pathways promoting protein stability, folding and trafficking and thus enhancing and restoring some of the enzymatic activity of the mutated protein in lysosomes. Multiple compounds have already been approved for clinical use to treat multiple LSDs like migalastat in the treatment of Fabry disease and others are currently under research or in clinical trials such as Ambroxol hydrochloride and Pyrimethamine. In this review, we are presenting a general overview of LSDs, their molecular and cellular bases, and focusing on recent advances on targeting and manipulation proteostasis, including the use of PCs and proteostasis regulators, as therapeutic targets for some LSDs. In addition, we present the successes, limitations and future perspectives in this field. PMID- 28736527 TI - Human COQ9 Rescues a coq9 Yeast Mutant by Enhancing Coenzyme Q Biosynthesis from 4-Hydroxybenzoic Acid and Stabilizing the CoQ-Synthome. AB - Coq9 is required for the stability of a mitochondrial multi-subunit complex, termed the CoQ-synthome, and the deamination step of Q intermediates that derive from para-aminobenzoic acid (pABA) in yeast. In human, mutations in the COQ9 gene cause neonatal-onset primary Q10 deficiency. In this study, we determined whether expression of human COQ9 could complement yeast coq9 point or null mutants. We found that expression of human COQ9 rescues the growth of the temperature sensitive yeast mutant, coq9-ts19, on a non-fermentable carbon source and increases the content of Q6, by enhancing Q biosynthesis from 4-hydroxybenzoic acid (4HB). To study the mechanism for the rescue by human COQ9, we determined the steady-state levels of yeast Coq polypeptides in the mitochondria of the temperature-sensitive yeast coq9 mutant expressing human COQ9. We show that the expression of human COQ9 significantly increased steady-state levels of yeast Coq4, Coq6, Coq7, and Coq9 at permissive temperature. Human COQ9 polypeptide levels persisted at non-permissive temperature. A small amount of the human COQ9 co-purified with tagged Coq6, Coq6-CNAP, indicating that human COQ9 interacts with the yeast Q-biosynthetic complex. These findings suggest that human COQ9 rescues the yeast coq9 temperature-sensitive mutant by stabilizing the CoQ synthome and increasing Q biosynthesis from 4HB. This finding provides a powerful approach to studying the function of human COQ9 using yeast as a model. PMID- 28736528 TI - Linking Ventilator Injury-Induced Leak across the Blood-Gas Barrier to Derangements in Murine Lung Function. AB - Mechanical ventilation is vital to the management of acute respiratory distress syndrome, but it frequently leads to ventilator-induced lung injury (VILI). Understanding the pathophysiological processes involved in the development of VILI is an essential prerequisite for improving lung-protective ventilation strategies. The goal of this study was to relate the amount and nature of material accumulated in the airspaces to biomarkers of injury and the derecruitment behavior of the lung in VILI. Forty-nine BALB/c mice were mechanically ventilated with combinations of tidal volume and end-expiratory pressures to produce varying degrees of overdistension and atelectasis while lung function was periodically assessed. Total protein, serum protein, and E-Cadherin levels were measured in bronchoalveolar lavage fluid (BALF). Tissue injury was assessed by histological scoring. We found that both high tidal volume and zero positive end-expiratory pressure were necessary to produce significant VILI. Increased BALF protein content was correlated with increased lung derecruitability, elevated peak pressures, and histological evidence of tissue injury. Blood derived molecules were present in the BALF in proportion to histological injury scores and epithelial injury, reflected by E-Cadherin levels in BALF. We conclude that repetitive recruitment is an important factor in the pathogenesis of VILI that exacerbates injury associated with tidal overdistension. Furthermore, the dynamic mechanical behavior of the injured lung provides a means to assess both the degree of tissue injury and the nature and amount of blood-derived fluid and proteins that accumulate in the airspaces. PMID- 28736529 TI - Detection of ROS Induced Proteomic Signatures by Mass Spectrometry. AB - Reversible and irreversible post-translational modifications (PTMs) induced by endogenously generated reactive oxygen species (ROS) in regulatory enzymes and proteins plays an essential role in cellular signaling. Almost all cellular processes including metabolism, transcription, translation and degradation have been identified as containing redox regulated proteins. Specific redox modifications of key amino acids generated by ROS offers a dynamic and versatile means to rapidly alter the activity or functional structure of proteins in response to biochemical, environmental, genetic and pathological perturbations. How the proteome responds to these stimuli is of critical importance in oxidant physiology, as it can regulate the cell stress response by reversible and irreversible PTMs, affecting protein activity and protein-protein interactions. Due to the highly labile nature of many ROS species, applying redox proteomics can provide a signature footprint of the ROS species generated. Ideally redox proteomic approaches would allow; (1) the identification of the specific PTM, (2) identification of the amino acid residue that is modified and (3) the percentage of the protein containing the PTM. New developments in MS offer the opportunity of a more sensitive targeted proteomic approach and retrospective data analysis. Subsequent bioinformatics analysis can provide an insight into the biochemical and physiological pathways or cell signaling cascades that are affected by ROS generation. This mini-review will detail current redox proteomic approaches to identify and quantify ROS induced PTMs and the subsequent effects on cellular signaling. PMID- 28736530 TI - Identification and Expression Profiling of Chemosensory Genes in Dendrolimus punctatus Walker. AB - Dendrolimus punctatus Walker is a serious pest affecting conifers in southern China. As extensive pesticide spraying is currently required to control D. punctatus, new control strategies are urgently needed. Chemosensory genes represent potential molecular targets for development of alternative pest control strategies, and the expression characteristics of these genes provide an indication of their function. To date, little information is available regarding chemosensory genes in D. punctatus or their expression profiles at different development stages and in various tissues. Here, we assembled and analyzed the transcriptomes of D. punctatus collected at different developmental stages and in a range of organs, using next-generation sequencing. A total of 171 putative chemosensory genes were identified, encoding 53 odorant binding proteins, 26 chemosensory proteins, 60 odorant receptors (OR), 12 gustatory receptors (GR), 18 ionotropic receptors (IR), and 2 sensory neuron membrane proteins (SNMPs). Expression analysis indicated that the antennae possess the largest number of highly expressed olfactory genes and that olfactory gene expression patterns in the eggs, larvae, and head were similar to one another, with each having moderate numbers of highly expressed olfactory genes. Fat body, ovary, midgut, and testis tissues also had similar olfactory gene expression patterns, including few highly expressed olfactory genes. Of particular note, we identified only two pheromone binding proteins and no pheromone receptors in D. punctatus, similar to our previous findings in Dendrolimus houi and Dendrolimus kikuchii, suggesting that insects of the Dendrolimus genus have different pheromone recognition characteristics to other Lepidopteran insects. Overall, this extensive expression profile analysis provides a clear map of D. punctatus chemosensory genes, and will facilitate functional studies and the development of new pest control methods in the future. PMID- 28736531 TI - Assessment of Hepatocellular Carcinoma Metastasis Glycobiomarkers Using Advanced Quantitative N-glycoproteome Analysis. AB - Hepatocelluar carcinoma (HCC) is one of the most common malignant tumors with high incidence of metastasis. Glycosylation is involved in fundamental molecular and cell biology process occurring in cancer including metastasis formation. In this study, lectin microarray, lectin blotting, lectin affinity chromatography and tandem 18O stable isotope labeling coupled with liquid chromatography-mass spectrometer (LC-MS) analysis were applied to quantify the changes in N-glycosite occupancy for HCC metastasis serum. Firstly, lectin microarray was used to screen glycoforms and Phaseolus vulgaris Leucoagglutinin (PHA-L) reactive structure (beta1,6-GlcNAc branched N-glycan) was found to be increased significantly in HCC patients with metastasis compared with those with non-metastasis. Then, PHA-L affinity glycoproteins were enriched followed by N-glycosite occupancy measurement with strategy of tandem 18O stable isotope labeling. 11 glycoproteins with significantly changed N-glycosite occupancy were identified, they were associated with cell migration, invasion and adhesion through p38 mitogen activated protein kinase signaling pathway and nuclear factor kappa B signaling pathway. Quantification of N-glycosite occupancy for PHA-L reactive glycoproteins could help to discover important glycoproteins of potential clinically significance in terms of HCC etiology. Also, understanding of N-glycosite occupancy alterations will aid the characterization of molecular mechanism of HCC metastasis as well as establishment of novel glycobiomarkers. PMID- 28736532 TI - A Memory of Early Life Physical Activity Is Retained in Bone Marrow of Male Rats Fed a High-Fat Diet. AB - Studies have reported opposing effects of high-fat (HF) diet and mechanical stimulation on lineage commitment of the bone marrow stem cells. Yet, how bone marrow modulates its gene expression in response to the combined effects of mechanical loading and a HF diet has not been addressed. We investigated whether early-life (before onset of sexual maturity at 6 weeks of age) voluntary physical activity can modulate the effects of a HF diet on male Sprague Dawley rats. In the bone marrow, early-life HF diet resulted in adipocyte hypertrophy and a pro inflammatory and pro-adipogenic gene expression profile. The bone marrow of the rats that undertook wheel exercise while on a HF diet retained a memory of the early-life exercise. This memory lasted at least 60 days after the cessation of the voluntary exercise. Our results are consistent with the marrow adipose tissue having a unique response to HF feeding in the presence or absence of exercise. PMID- 28736534 TI - Self-organizing Complex Networks: individual versus global rules. AB - We introduce a form of Self-Organized Criticality (SOC) inspired by the new generation of evolutionary game theory, which ranges from physiology to sociology. The single individuals are the nodes of a composite network, equivalent to two interacting subnetworks, one leading to strategy choices made by the individuals under the influence of the choices of their nearest neighbors and the other measuring the Prisoner's Dilemma Game payoffs of these choices. The interaction between the two networks is established by making the imitation strength K increase or decrease according to whether the last two payoffs increase or decrease upon increasing or decreasing K. Although each of these imitation strengths is selected selfishly, and independently of the others as well, the social system spontaneously evolves toward the state of cooperation. Criticality is signaled by temporal complexity, namely the occurrence of non Poisson renewal events, the time intervals between two consecutive crucial events being given by an inverse power law index MU = 1.3 rather than by avalanches with an inverse power law distribution as in the original form of SOC. This new phenomenon is herein labeled self-organized temporal criticality (SOTC). We compare this bottom-up self-organization process to the adoption of a global choice rule based on assigning to all the units the same value K, with the time evolution of common K being determined by consciousness of the social benefit, a top-down process implying the action of a leader. In this case self-organization is impeded by large intensity fluctuations and the global social benefit turns out to be much weaker. We conclude that the SOTC model fits the requests of a manifesto recently proposed by a number of European social scientists. PMID- 28736533 TI - Let-7b Regulates Myoblast Proliferation by Inhibiting IGF2BP3 Expression in Dwarf and Normal Chicken. AB - The sex-linked dwarf chicken is caused by the mutation of growth hormone receptor (GHR) gene and characterized by shorter shanks, lower body weight, smaller muscle fiber diameter and fewer muscle fiber number. However, the precise regulatory pathways that lead to the inhibition of skeletal muscle growth in dwarf chickens still remain unclear. Here we found a let-7b mediated pathway might play important role in the regulation of dwarf chicken skeletal muscle growth. Let-7b has higher expression in the skeletal muscle of dwarf chicken than in normal chicken, and the expression of insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3), which is a translational activator of IGF2, showed opposite expression trend to let-7b. In vitro cellular assays validated that let-7b directly inhibits IGF2BP3 expression through binding to its 3'UTR region, and the protein level but not mRNA level of IGF2 would be reduced in let-7b overexpressed chicken myoblast. Let-7b can inhibit cell proliferation and induce cell cycle arrest in chicken myoblast through let-7b-IGF2BP3-IGF2 signaling pathway. Additionally, let-7b can also regulate skeletal muscle growth through let-7b-GHR GHR downstream genes pathway, but this pathway is non-existent in dwarf chicken because of the deletion mutation of GHR 3'UTR. Notably, as the loss binding site of GHR for let-7b, let-7b has enhanced its binding and inhibition on IGF2BP3 in dwarf myoblast, suggesting that the miRNA can balance its inhibiting effect through dynamic regulate its binding to target genes. Collectively, these results not only indicate that let-7b can inhibit skeletal muscle growth through let-7b IGF2BP3-IGF2 signaling pathway, but also show that let-7b regulates myoblast proliferation by inhibiting IGF2BP3 expression in dwarf and normal chickens. PMID- 28736536 TI - Mind-Reading and Behavior-Reading against Agents with and without Anthropomorphic Features in a Competitive Situation. AB - Humans use two distinct cognitive strategies separately to understand and predict other humans' behavior. One is mind-reading, in which an internal state such as an intention or an emotional state is assumed to be a source of a variety of behaviors. The other is behavior-reading, in which an actor's behavior is modeled based on stimulus-response associations without assuming internal states behind the behavior. We hypothesize that anthropomorphic features are key for an observer switching between these two cognitive strategies in a competitive situation. We provide support for this hypothesis through two studies using four agents with different appearances. We show that only a human agent was thought to possess both the ability to generate a variety of behaviors and internal mental states, such as minds and emotions (Study 1). We also show that humans used mixed (opposing) strategies against a human agent and exploitative strategies against the agents with mechanical appearances when they played a repeated zero-sum game (Study 2). Our findings show that humans understand that human behavior is varied; that humans have internal states, such as minds and emotions; that the behavior of machines is governed by a limited number of fixed rules; and that machines do not possess internal mental states. Our findings also suggest that the function of mind-reading is to trigger a strategy for use against agents with variable behavior and that humans exploit others who lack behavioral variability based on behavior-reading in a competitive situation. PMID- 28736535 TI - Mind-Body Practice Changes Fractional Amplitude of Low Frequency Fluctuations in Intrinsic Control Networks. AB - Cognitive control impairment is a typical symptom largely reported in populations with neurological disorders. Previous studies have provided evidence about the changes in cognitive control induced by mind-body training. However, the neural correlates underlying the effect of extensive mind-body practice on cognitive control remain largely unknown. Using resting-state functional magnetic resonance imaging, we characterized dynamic fluctuations in large-scale intrinsic connectivity networks associated with mind-body practice, and examined their differences between healthy controls and Tai Chi Chuan (TCC) practitioners. Compared with a control group, the TCC group revealed significantly decreased fractional Amplitude of Low Frequency Fluctuations (fALFF) in the bilateral frontoparietal network, default mode network and dorsal prefrontal-angular gyri network. Furthermore, we detected a significant association between mind-body practice experience and fALFF in the default mode network, as well as an association between cognitive control performance and fALFF of the frontoparietal network. This provides the first evidence of large-scale functional connectivity in brain networks associated with mind-body practice, shedding light on the neural network changes that accompany intensive mind-body training. It also highlights the functionally plastic role of the frontoparietal network in the context of the "immune system" of mental health recently developed in relation to flexible hub theory. PMID- 28736537 TI - The Five Marks of the Mental. AB - The mental realm seems different to the physical realm; the mental is thought to be dependent on, yet distinct from the physical. But how, exactly, are the two realms supposed to be different, and what, exactly, creates the seemingly insurmountable juxtaposition between the mental and the physical? This review identifies and discusses five marks of the mental, features that set characteristically mental phenomena apart from the characteristically physical phenomena. These five marks (intentionality, consciousness, free will, teleology, and normativity) are not presented as a set of features that define mentality. Rather, each of them is something we seem to associate with phenomena we consider mental, and each of them seems to be in tension with the physical view of reality in its own particular way. It is thus suggested how there is no single mind-body problem, but a set of distinct but interconnected problems. Each of these separate problems is analyzed, and their differences, similarities and connections are identified. This provides a useful basis for future theoretical work on psychology and philosophy of mind, that until now has too often suffered from unclarities, inadequacies, and conflations. PMID- 28736538 TI - Agents and Patients in Physical Settings: Linguistic Cues Affect the Assignment of Causality in German and Tongan. AB - Linguistic cues may be considered a potent tool for focusing attention on causes or effects. In this paper, we explore how different cues affect causal assignments in German and Tongan. From a larger screening study, two parts are reported here: Part 1 dealt with syntactic variations, including word order (agent vs. patient in first/subject position) and case marking (e.g., as ergative vs. non-ergative in Tongan) depending on verb type (transitive vs. intransitive). For two physical settings (wood floating on water and a man breaking a glass), participants assigned causality to the two entities involved. In the floating setting, speakers of the two languages were sensitive to syntactic variations, but differed in the entity regarded as causative. In the breaking setting, the human agent was uniformly regarded as causative. Part 2 dealt with implicit verb causality. Participants assigned causality to subject or object of 16 verbs presented in minimal social scenarios. In German, all verbs showed a subject (agent) focus; in Tongan, the focus depended on the verb; and for nine verbs, the focus differed across languages. In conclusion, we discuss the question of domain specificity of causal cognition, the role of the ergative as causal marker, and more general differences between languages. PMID- 28736539 TI - Reviewing the Effectiveness of Music Interventions in Treating Depression. AB - Depression is a very common mood disorder, resulting in a loss of social function, reduced quality of life and increased mortality. Music interventions have been shown to be a potential alternative for depression therapy but the number of up-to-date research literature is quite limited. We present a review of original research trials which utilize music or music therapy as intervention to treat participants with depressive symptoms. Our goal was to differentiate the impact of certain therapeutic uses of music used in the various experiments. Randomized controlled study designs were preferred but also longitudinal studies were chosen to be included. 28 studies with a total number of 1,810 participants met our inclusion criteria and were finally selected. We distinguished between passive listening to music (record from a CD or live music) (79%), and active singing, playing, or improvising with instruments (46%). Within certain boundaries of variance an analysis of similar studies was attempted. Critical parameters were for example length of trial, number of sessions, participants' age, kind of music, active or passive participation and single- or group setting. In 26 studies, a statistically significant reduction in depression levels was found over time in the experimental (music intervention) group compared to a control (n = 25) or comparison group (n = 2). In particular, elderly participants showed impressive improvements when they listened to music or participated in music therapy projects. Researchers used group settings more often than individual sessions and our results indicated a slightly better outcome for those cases. Additional questionnaires about participants confidence, self-esteem or motivation, confirmed further improvements after music treatment. Consequently, the present review offers an extensive set of comparable data, observations about the range of treatment options these papers addressed, and thus might represent a valuable aid for future projects for the use of music-based interventions to improve symptoms of depression. PMID- 28736540 TI - Dutch-Cantonese Bilinguals Show Segmental Processing during Sinitic Language Production. AB - This study addressed the debate on the primacy of syllable vs. segment (i.e., phoneme) as a functional unit of phonological encoding in syllabic languages by investigating both behavioral and neural responses of Dutch-Cantonese (DC) bilinguals in a color-object picture naming task. Specifically, we investigated whether DC bilinguals exhibit the phonemic processing strategy, evident in monolingual Dutch speakers, during planning of their Cantonese speech production. Participants named the color of colored line-drawings in Cantonese faster when color and object matched in the first segment than when they were mismatched (e.g., , /laam4/ /lok3to4/, "blue camel;" , /hung4/ /lok3to4/, "red camel"). This is in contrast to previous studies in Sinitic languages that did not reveal such phoneme-only facilitation. Phonemic overlap also modulated the event-related potentials (ERPs) in the 125-175, 200-300, and 300-400 ms time windows, suggesting earlier ERP modulations than in previous studies with monolingual Sinitic speakers or unbalanced Sinitic-Germanic bilinguals. Conjointly, our results suggest that, while the syllable may be considered the primary unit of phonological encoding in Sinitic languages, the phoneme can serve as the primary unit of phonological encoding, both behaviorally and neurally, for DC bilinguals. The presence/absence of a segment onset effect in Sinitic languages may be related to the proficiency in the Germanic language of bilinguals. PMID- 28736542 TI - Modified Logistic Regression Approaches to Eliminating the Impact of Response Styles on DIF Detection in Likert-Type Scales. AB - Extreme response styles (ERS) is prevalent in Likert- or rating-type data but previous research has not well-addressed their impact on differential item functioning (DIF) assessments. This study aimed to fill in the knowledge gap and examined their influence on the performances of logistic regression (LR) approaches in DIF detections, including the ordinal logistic regression (OLR) and the logistic discriminant functional analysis (LDFA). Results indicated that both the standard OLR and LDFA yielded severely inflated false positive rates as the magnitude of the differences in ERS increased between two groups. This study proposed a class of modified LR approaches to eliminating the ERS effect on DIF assessment. These proposed modifications showed satisfactory control of false positive rates when no DIF items existed and yielded a better control of false positive rates and more accurate true positive rates under DIF conditions than the conventional LR approaches did. In conclusion, the proposed modifications are recommended in survey research when there are multiple group or cultural groups. PMID- 28736541 TI - Hallucinations in Healthy Older Adults: An Overview of the Literature and Perspectives for Future Research. AB - KEY POINTS ? Studies suggest a substantial minority of healthy older adults have hallucinatory experiences, in line with existing evidence on hallucinations in other age groups, though it is still unclear if hallucination prevalence increases or declines with age in older cohorts.? Stigma attached to both hallucinations and ageing leads to considerable under-reporting of these experiences in healthy older adults and may negatively bias how professionals, family members, and the public respond.? Why and when hallucinations in healthy older adults remit, persist, or progress to other clinical disorders remains poorly understood.? Current evidence points to a range of factors associated with hallucinations in older adults including decline in sensory or cognitive functioning, poor sleep, and psychosocial stressors (e.g., social isolation, loneliness, and bereavement), highlighting the need for accurate assessment and tailored interventions. Hallucinations, though common in youth and younger adults, are not the preserve of these age groups. Accumulating evidence shows that hallucinatory experiences are also present at surprisingly high rates in healthy older adults in the general community. Furthermore, stigma and misunderstanding of hallucinations, together with ageism, may lead to under reporting of these experiences by older adults, and misdiagnosis or mismanagement by health and mental health practitioners. Consequently, improved public and professional knowledge is needed about the nature and significance of hallucinations with advancing age. The purpose of this review is to provide a comprehensive overview, and critical analysis, of research on the prevalence, psychosocial, and neurobiological factors associated with hallucinations in people aged 60 years and over. To the best of our knowledge, this is the first review of its kind in the literature. The evidence supports a dynamic conceptualization of hallucinations, in which the emergence of hallucinations is viewed as a balance between the sensory, cognitive, or social impairments accompanying advancing age and the degree to which compensatory processes elicited by these impairments are successful. We briefly summarize the implications of the literature for aged care services and interventions, and stress that far more studies are needed in this important field of research. PMID- 28736544 TI - Non-suicidal Self-Injury in Eating Disordered Patients: Associations with Heart Rate Variability and State-Trait Anxiety. AB - Background: Non-suicidal self-injury (NSSI) is commonly present in individuals with eating disorders (EDs) and is often employed as a maladaptive emotion regulation strategy to avoid or abate negative emotions. One of the most prevalent negative emotions experienced by self-injurers is anxiety; however, this emotion has not been extensively studied in this population. Thus, the aim of our study was to investigate the influence of anxiety on NSSI in patients with ED from two different dimensions: state anxiety and trait anxiety. Methods: The study comprised a total of 66 females: 12 ED patients with NSSI, 32 ED patients without a history of NSSI, and 22 healthy controls. State and trait anxiety were assessed by means of State-Trait Anxiety Inventory (STAI-S-T) and physiological data [i.e., heart rate variability (HRV)] were collected. Results: STAI-trait scores were significantly higher in ED patients with NSSI than ED patients without NSSI. Furthermore, when conducting logistic regression analyses higher STAI-trait scores were associated with NSSI in ED patients. However, no differences in STAI-state scores and HRV were found between ED patients with and without NSSI. Discussion: The present findings suggest that anxiety as a trait is associated with the use of maladaptive strategies (i.e., NSSI) in ED patients. These results uphold the need to target trait anxiety in ED treatment in order to prevent possible NSSI behaviors. PMID- 28736543 TI - Oscillatory Correlates of Visual Consciousness. AB - Conscious experiences are linked to activity in our brain: the neural correlates of consciousness (NCC). Empirical research on these NCCs covers a wide range of brain activity signals, measures, and methodologies. In this paper, we focus on spontaneous brain oscillations; rhythmic fluctuations of neuronal (population) activity which can be characterized by a range of parameters, such as frequency, amplitude (power), and phase. We provide an overview of oscillatory measures that appear to correlate with conscious perception. We also discuss how increasingly sophisticated techniques allow us to study the causal role of oscillatory activity in conscious perception (i.e., 'entrainment'). This review of oscillatory correlates of consciousness suggests that, for example, activity in the alpha-band (7-13 Hz) may index, or even causally support, conscious perception. But such results also showcase an increasingly acknowledged difficulty in NCC research; the challenge of separating neural activity necessary for conscious experience to arise (prerequisites) from neural activity underlying the conscious experience itself (substrates) or its results (consequences). PMID- 28736545 TI - A Randomized, Controlled Trial of Mirror Therapy for Upper Extremity Phantom Limb Pain in Male Amputees. AB - OBJECTIVE: Phantom limb pain (PLP) is prevalent in patients post-amputation and is difficult to treat. We assessed the efficacy of mirror therapy in relieving PLP in unilateral, upper extremity male amputees. METHODS: Fifteen participants from Walter Reed and Brooke Army Medical Centers were randomly assigned to one of two groups: mirror therapy (n = 9) or control (n = 6, covered mirror or mental visualization therapy). Participants were asked to perform 15 min of their assigned therapy daily for 5 days/week for 4 weeks. The primary outcome was pain as measured using a 100-mm Visual Analog Scale. RESULTS: Subjects in the mirror therapy group had a significant decrease in pain scores, from a mean of 44.1 (SD = 17.0) to 27.5 (SD = 17.2) mm (p = 0.002). In addition, there was a significant decrease in daily time experiencing pain, from a mean of 1,022 (SD = 673) to 448 (SD = 565) minutes (p = 0.003). By contrast, the control group had neither diminished pain (p = 0.65) nor decreased overall time experiencing pain (p = 0.49). A pain decrement response seen by the 10th treatment session was predictive of final efficacy. CONCLUSION: These results confirm that mirror therapy is an effective therapy for PLP in unilateral, upper extremity male amputees, reducing both severity and duration of daily episodes. REGISTRATION: NCT0030144 ClinicalTrials.gov. PMID- 28736546 TI - ZB-16, a Novel GPR119 Agonist, Relieves the Severity of Streptozotocin Nicotinamide-Induced Diabetes in Rats. AB - GPR119 is involved in the regulation of incretin and insulin secretion, so the GPR119 agonists have been suggested as novel antidiabetic medications. The purpose of this work was to assess the influence of novel GPR119 agonist ZB-16 on the glucose utilization, insulin, and glucagon-like peptide-1 (GLP-1) secretion and the morphology of pancreas in rats with streptozotocin-nicotinamide-induced diabetes. 45 male Wistar rats were used in the study. The criteria of streptozotocin-nicotinamide-induced diabetes were blood glucose levels of 9-14 mmol/l measured in fasting conditions on the third day since administration of streptozotocin (65 mg/kg) and nicotinamide (230 mg/kg). Animals failed to reach the criteria were excluded from the experiment. The substances were administered per os once per day for 28 days. Measurements included blood glucose monitoring (every 7 days), glucose tolerance test (every 14 days), the assessment of insulin and GLP-1 levels in blood plasma (28 days after beginning), and the results of immunohistochemical staining of pancreas. It was found that ZB-16 (1 mg/kg per os, once a day) decreases the blood glucose levels under fasting conditions and improves the glucose utilization. These changes were associated with the increase in stimulated secretion of GLP-1 and insulin, accompanied by the growth of insulin-positive cells in pancreas. Thus, ZB-16 could be a promising antidiabetic drug for oral administration. PMID- 28736547 TI - Thyroid Involvement in Hepatitis C Virus-Infected Patients with/without Mixed Cryoglobulinemia. AB - Thyroid involvement is a common condition that can be recorded during the natural course of different systemic rheumatic diseases, including the mixed cryoglobulinemia (MC) syndrome or cryoglobulinemic vasculitis. MC is triggered by hepatitis C virus (HCV) chronic infection in the majority of cases; it represents the prototype of autoimmune-lymphoproliferative disorders complicating a significant proportion of patients with chronic HCV infection. HCV is both hepato and lymphotropic virus responsible for a great number of autoimmune/lymphoproliferative and/or neoplastic disorders. The complex of HCV related hepatic and extrahepatic manifestations, including MC and thyroid involvement, may be termed "HCV syndrome." Here, we describe the prevalence and clinico-serological characteristics of thyroid involvement, mainly autoimmune thyroiditis and papillary thyroid cancer, in patients with HCV syndrome with or without cryoglobulinemic vasculitis. PMID- 28736548 TI - Linking Only Aedes aegypti with Zika Virus Has World-Wide Public Health Implications. PMID- 28736549 TI - Cloning, Expression, Isotope Labeling, and Purification of Transmembrane Protein MerF from Mercury Resistant Enterobacter sp. AZ-15 for NMR Studies. AB - Mercury resistant (HgR) Enterobacter sp. AZ-15 was isolated from heavy metal polluted industrial wastewater samples near to districts Kasur and Sheikhupura, Pakistan. 16S rDNA ribotyping and phylogentic analysis showed 98% homology with already reported Enterobacter species. The merF gene encoding transmembrane protein-MerF was amplified from genomic DNA and ligated into pET31b+ vector using restriction endonucleases, SphI and XhoI. The genetic codons of merF gene encoding cysteine residues were mutated into codons, translating into serine residues by site-directed mutagenesis. Ketosteroid isomerase (KSI), a fusion tag which is present in pET31b+ vector, was used in the expression of merFm gene. KSI was used to drive the target peptide (MerFm) into inclusion bodies so that the peptide yield and purity were increased. The stable plasmid pET31b+:merFm was transformed into C43(DE3) E.coli cells. The high expression of uniformly 15N isotopically labeled-MerFm protein was induced with 1 mM IPTG. The purification of 15N-MerFm recombinant protein by Ni-NTA and size exclusion chromatography involved an unfolding/refolding procedure. The two-dimensional HSQC NMR spectra of MerFm protein showed the purity and correct number of resonances for each amide. 1H-15N HSQC NMR experiment also confirmed that no modification of the tryptophan residue occurred during cyanogen bromide cleavage. A small scale reservoir of Luria Bertani (LB) medium supplemented with 20 MUg/ml of HgCl2 showed 90% detoxification of Hg by Enterobacter sp. AZ-15. The accumulation of Hg on the cell surface of this strain was visualized by scanning electron microscopy (SEM) which confirmed its potential use in Hg-bioremediation. PMID- 28736550 TI - Probiotic Enterococcus mundtii Isolate Protects the Model Insect Tribolium castaneum against Bacillus thuringiensis. AB - Enterococcus mundtii strains isolated from the larval feces of the Mediterranean flour moth Ephestia kuehniella show antimicrobial activity against a broad spectrum of Gram-positive and Gram-negative bacteria. The in vitro probiotic characterization of one isolate revealed a high auto-aggregation score, a hydrophilic cell surface, tolerance for low pH, no hemolytic activity, and susceptibility to all tested antibiotics. We used the red flour beetle Tribolium castaneum, an established model organism, for the in vivo characterization of one probiotic E. mundtii isolate from E. kuehniella larvae. Tribolium castaneum larvae were fed orally with the probiotic isolate or the corresponding supernatant and then infected with either the entomopathogen Bacillus thuringiensis or Pseudomonas entomophila. Larvae exposed to the isolate or the supernatant showed increased survival following infection with B. thuringiensis but not P. entomophila. Heat treatment or treatment with proteinase K reduced the probiotic effect of the supernatant. However, the increased resistance attracts a fitness penalty manifested as a shorter lifespan and reduced fertility. T. castaneum has, pending on further research, the potential as an alternative model for the pre-screening of probiotics. PMID- 28736551 TI - Differential Phenotypes of Myeloid-Derived Suppressor and T Regulatory Cells and Cytokine Levels in Amnestic Mild Cognitive Impairment Subjects Compared to Mild Alzheimer Diseased Patients. AB - Alzheimer disease (AD) is the most prevalent form of dementia although the underlying cause(s) remains unknown at this time. However, neuroinflammation is believed to play an important role and suspected contributing immune parameters can be revealed in studies comparing patients at the stage of amnestic mild cognitive impairment (aMCI) to healthy age-matched individuals. A network of immune regulatory cells including regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) maintains immune homeostasis but there are very few data on the role of these cells in AD. Here, we investigated the presence of these cells in the blood of subjects with aMCI and mild AD (mAD) in comparison with healthy age-matched controls. We also quantitated several pro- and anti inflammatory cytokines in sera which can influence the development and activation of these cells. We found significantly higher levels of MDSCs and Tregs in aMCI but not in mAD patients, as well as higher serum IL-1beta levels. Stratifying the subjects based on CMV serostatus that is known to influence multiple immune parameters showed an absence of differences between aMCI subjects compared to mAD patients and healthy controls. We suggest that the increase in MDSCs and Tregs number in aMCI subjects may have a beneficial role in modulating inflammatory processes. However, this protective mechanism may have failed in mAD patients, allowing progression of the disease. This working hypothesis obviously requires testing in future studies. PMID- 28736552 TI - Asiatic Acid Exhibits Anti-inflammatory and Antioxidant Activities against Lipopolysaccharide and d-Galactosamine-Induced Fulminant Hepatic Failure. AB - Inflammation and oxidative stress are essential for the pathogenesis of fulminant hepatic failure (FHF). Asiatic acid (AA), which is a pentacyclic triterpene that widely occurs in various vegetables and fruits, has been reported to possess antioxidant and anti-inflammatory properties. In this study, we investigated the protective effects of AA against lipopolysaccharide (LPS) and d-galactosamine (GalN)-induced FHF and the underlying molecular mechanisms. Our findings suggested that AA treatment effectively protected against LPS/d-GalN-induced FHF by lessening the lethality; decreasing the alanine transaminase and aspartate aminotransferase levels, interleukin (IL)-1beta, IL-6, and tumor necrosis factor alpha production, malondialdehyde formation, myeloperoxidase level and reactive oxygen species generation (i.e., H2O2, NO, and [Formula: see text]), and increasing the glutathione and superoxide dismutase contents. Moreover, AA treatment significantly inhibited mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-kappaB) signaling pathway activation via the partial induction of programmed cell death 4 (PDCD4) protein expressions, which are involved in inflammatory responses. Furthermore, AA treatment dramatically induced the expression of the glutamate-cysteine ligase modifier subunit, the glutamate-cysteine ligase catalytic subunit, heme oxygenase-1, and NAD (P) H: quinoneoxidoreductase 1 (NQO1), which are largely dependent on activation of the nuclear factor-erythroid 2-related factor 2 (Nrf2) through the induction of AMP activated protein kinase (AMPK) and glycogen synthase kinase-3beta (GSK3beta) phosphorylation. Accordingly, AA exhibited protective roles against LPS/d-GalN induced FHF by inhibiting oxidative stress and inflammation. The underlying mechanism may be associated with the inhibition of MAPK and NF-kappaB activation via the partial induction of PDCD4 and upregulation of Nrf2 in an AMPK/GSK3beta pathway activation-dependent manner. PMID- 28736553 TI - Commentary: Basophil Activation-Dependent Autoantibody and Interleukin-17 Production Exacerbate Systemic Lupus Erythematosus. PMID- 28736554 TI - Differential Requirements for Src-Family Kinases in SYK or ZAP70-Mediated SLP-76 Phosphorylation in Lymphocytes. AB - In a synthetic biology approach using Schneider (S2) cells, we show that SLP-76 is directly phosphorylated at tyrosines Y113 and Y128 by SYK in the presence of ITAM-containing adapters such as CD3zeta, DAP12, or FcepsilonRgamma. This phosphorylation was dependent on at least one functional ITAM and a functional SH2 domain within SYK. Inhibition of Src-kinases by inhibitors PP1 and PP2 did not reduce SLP-76 phosphorylation in S2 cells, suggesting an ITAM and SYK dependent, but Src-kinase independent signaling pathway. This direct ITAM/SYK/SLP 76 signaling pathway therefore differs from previously described ITAM signaling. However, the SYK-family kinase ZAP70 required the additional co-expression of the Src-family kinases Fyn or Lck to efficiently phosphorylate SLP-76 in S2 cells. This difference in Src-family kinase dependency of SYK versus ZAP70-mediated ITAM based signaling was further demonstrated in human lymphocytes. ITAM signaling in ZAP70-expressing T cells was dependent on the activity of Src-family kinases. In contrast, Src-family kinases were partially dispensable for ITAM signaling in SYK expressing B cells or in natural killer cells, which express SYK and ZAP70. This demonstrates that SYK can signal using a Src-kinase independent ITAM-based signaling pathway, which may be involved in calibrating the threshold for lymphocyte activation. PMID- 28736555 TI - beta-Glucan Size Controls Dectin-1-Mediated Immune Responses in Human Dendritic Cells by Regulating IL-1beta Production. AB - Dectin-1/CLEC7A is a pattern recognition receptor that recognizes beta-1,3 glucans, and its stimulation initiates signaling events characterized by the production of inflammatory cytokines from human dendritic cells (DCs) required for antifungal immunity. beta-glucans differ greatly in size, structure, and ability to activate effector immune responses from DC; as such, small particulate beta-glucans are thought to be poor activators of innate immunity. We show that beta-glucan particle size is a critical factor contributing to the secretion of cytokines from human DC; large beta-glucan-stimulated DC generate significantly more IL-1beta, IL-6, and IL-23 compared to those stimulated with the smaller beta glucans. In marked contrast, the secretion of TSLP and CCL22 were found to be insensitive to beta-glucan particle size. Furthermore, we show that the capacity to induce phagocytosis, and the relative IL-1beta production determined by beta glucan size, regulates the composition of the cytokine milieu generated from DC. This suggests that beta-glucan particle size is critically important in orchestrating the nature of the immune response to fungi. PMID- 28736556 TI - Ras Signaling Inhibitors Attenuate Disease in Adjuvant-Induced Arthritis via Targeting Pathogenic Antigen-Specific Th17-Type Cells. AB - The Ras family of GTPases plays an important role in signaling nodes downstream to T cell receptor and CD28 activation, potentially lowering the threshold for T cell receptor activation by autoantigens. Somatic mutation in NRAS or KRAS may cause a rare autoimmune disorder coupled with abnormal expansion of lymphocytes. T cells from rheumatoid arthritis (RA) patients show excessive activation of Ras/MEK/ERK pathway. The small molecule farnesylthiosalicylic acid (FTS) interferes with the interaction between Ras GTPases and their prenyl-binding chaperones to inhibit proper plasma membrane localization. In the present study, we tested the therapeutic and immunomodulatory effects of FTS and its derivative 5-fluoro-FTS (F-FTS) in the rat adjuvant-induced arthritis model (AIA). We show that AIA severity was significantly reduced by oral FTS and F-FTS treatment compared to vehicle control treatment. FTS was as effective as the mainstay anti rheumatic drug methotrexate, and combining the two drugs significantly increased efficacy compared to each drug alone. We also discovered that FTS therapy inhibited both the CFA-driven in vivo induction of Th17 and IL-17/IFN-gamma producing "double positive" as well as the upregulation of serum levels of the Th17-associated cytokines IL-17A and IL-22. By gene microarray analysis of effector CD4+ T cells from CFA-immunized rats, re-stimulated in vitro with the mycobacterium tuberculosis heat-shock protein 65 (Bhsp65), we determined that FTS abrogated the Bhsp65-induced transcription of a large list of genes (e.g., Il17a/f, Il22, Ifng, Csf2, Lta, and Il1a). The functional enrichment bioinformatics analysis showed significant overlap with predefined gene sets related to inflammation, immune system processes and autoimmunity. In conclusion, FTS and F-FTS display broad immunomodulatory effects in AIA with inhibition of the Th17-type response to a dominant arthritogenic antigen. Hence, targeting Ras signal-transduction cascade is a potential novel therapeutic approach for RA. PMID- 28736557 TI - The Effect of Admission Renal Function on the Treatment and Outcome of Patients with Acute Coronary Syndrome. AB - BACKGROUND: Chronic kidney disease is a frequent comorbidity among patients with acute coronary syndrome (ACS). We aimed to evaluate treatment characteristics in ACS patients according to their renal function and to assess the effect of differences in therapy on clinical outcomes. METHODS: Included were patients with ACS enrolled in the biennial Acute Coronary Syndrome Israeli Surveys (ACSIS) during 2000-2013. Excluded were patients with cardiogenic shock at presentation. The estimated glomerular filtration rate (eGFR) was calculated using the simplified Modification of Diet in Renal Disease (MDRD) formula. The distribution of the eGFRs was divided into 4 categories (<45, 45-59.9, 60-74.9, and >=75 mL/min/1.73 m2). The primary endpoint was all-cause mortality at 1 year. RESULTS: A total of 13,194 patients with ACS were included. Patients with a reduced eGFR were less likely to be admitted to a coronary care unit and had lower rates of coronary angiograms and subsequent percutaneous coronary interventions. Furthermore, as the eGFR was lower, the patients were less frequently treated with aspirin, clopidogrel, beta-blockers, and ACE inhibitors/angiotensin receptor blockers. We demonstrated an inverse association between renal function and 1 year mortality, with the highest mortality rates observed in the group with the lowest eGFR (HR = 3.8, 95% CI 2.9-4.9, p < 0.0001). Differences in mortality remained significant following a multivariate analysis for all the baseline characteristics as well as for invasive and medical treatment (HR = 2.7, 95% CI 1.9-3.7, p < 0.0001). CONCLUSIONS: ACS patients with chronic kidney disease represent a high-risk group with an increased mortality risk. Despite this high risk, these patients are less frequently selected for an invasive treatment strategy and are less commonly treated with guideline-based medications. However, reduced renal function was associated with higher mortality regardless of the variations in therapy. PMID- 28736558 TI - Evaluation of the CRUSADE Risk Score for Predicting Major Bleeding in Patients with Concomitant Kidney Dysfunction and Acute Coronary Syndromes. AB - BACKGROUND: Kidney dysfunction (KD) has been associated with increased risk for major bleeding (MB) in patients with acute coronary syndromes (ACS) and may be in part related to an underuse of evidence-based therapies. Our aim was to assess the predictive ability of the Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA guidelines (CRUSADE) risk score in patients with concomitant ACS and chronic kidney disease. METHODS: We conducted a retrospective analysis of a prospective registry including 1,587 ACS patients. In-hospital MB was prospectively recorded according to the CRUSADE and Bleeding Academic Research Consortium (BARC) criteria. KD was defined as an estimated glomerular filtration rate <60 mL/min/1.73 m2. RESULTS: The predictive ability of the CRUSADE risk score was assessed by discrimination and calibration analyses. A total of 465 (29%) subjects had KD. In multivariate logistic regression analyses, we found high CRUSADE risk score values to be associated with a higher rate of in-hospital MB; however, among patients with KD, it was not associated with BARC MB. Regardless of the MB definition, the predictive ability of the CRUSADE score in patients with KD was lower: area under the curve (AUC) 0.71 versus 0.79, p = 0.03 for CRUSADE MB and AUC 0.65 versus 0.75, p = 0.02 for BARC MB. Hosmer-Lemeshow analyses showed a good calibration in all renal function subgroups for both MB definitions (all p values >0.3). CONCLUSIONS: The CRUSADE risk score shows a lower accuracy for predicting in-hospital MB in KD patients compared to those without KD. PMID- 28736559 TI - Levocarnitine Injections Decrease the Need for Erythropoiesis-Stimulating Agents in Hemodialysis Patients with Renal Anemia. AB - AIMS: The aim of this study was to evaluate the efficacy of levocarnitine injection for renal anemia in hemodialysis patients. METHODS: In this randomized controlled clinical trial, we randomly assigned patients on maintenance hemodialysis at our hospital to receive levocarnitine injections (n = 30) or no injection (n = 30) and monitored the patients during 12 months of treatment. In the treatment group, patients received an injection of levocarnitine 1,000 mg 3 times weekly after hemodialysis sessions. All patients received recombinant human erythropoietin as an erythropoiesis-stimulating agent (ESA). Response to ESA therapy was determined by calculating the erythropoietin responsiveness index (ERI; ESA dose.kg-1.g-1. dL-1.week-1). RESULTS: (1) The target levels of hemoglobin and hematocrit were maintained during the study period in both the levocarnitine group and the control group. (2) The dose of ESAs required to maintain these levels decreased gradually in the levocarnitine group and was significantly lower at 6 and 12 months than at study initiation. Furthermore, the dose of ESAs was significantly lower than that in the control group at 12 months. (3) The ERI showed a significant decrease at 6 and 12 months in the levocarnitine group, with a significant difference between the 2 groups at 12 months. CONCLUSION: Our results suggest that levocarnitine administration can reduce the dose of ESAs required in patients with renal anemia on hemodialysis and improve the response to ESA therapy. PMID- 28736560 TI - Nonparallel Progression of Left Ventricular Structure and Function in Long-Term Peritoneal Dialysis Patients. AB - BACKGROUND/AIMS: Left ventricular hypertrophy and dysfunction are key cardiovascular risk factors of patients on peritoneal dialysis (PD). The purpose of this study was to investigate the dynamic changes of left ventricular (LV) structure and function in patients on long-term PD. METHODS: Patients who underwent PD catheter insertions from January 2010 to December 2012 in our PD center were enrolled into this study. Cardiac structure and function of those patients were determined by echocardiography (4 times) at 12-month intervals. Patients' biochemical parameters, body mass index, blood pressure, urine output, ultrafiltration, and total fluid removal volume were collected. The use of antihypertensive drugs and active vitamin D3 was also recorded. RESULTS: A total of 40 patients were included. After 3 years of follow-up, patients' PD duration time, LV mass/height2.7 (p = 0.580), interventricular septal thickness (p = 0.216), left ventricular posterior wall thickness (p = 0.216), and LV ejection fraction (p = 0.270) did not show significant changes during the follow-up. In contrast, the E/A ratio (p = 0.004) and e' (p < 0.001) were statistically decreased, and the E/e' ratio (p = 0.006) was increased. Left atrial diameter was increased (p = 0.008), but the changes in left atrial diameter index did not reach statistical significance (p = 0.090). CONCLUSION: Long-term PD patients maintain stable LV structure and cardiac systolic function, but cardiac diastolic function declines over time. PMID- 28736561 TI - Recent Advances in Stroke Prevention in Patients with Atrial Fibrillation and End Stage Renal Disease. AB - BACKGROUND: Chronic kidney disease (CKD) is associated with a high prevalence of atrial fibrillation (AF), but in this population the risk/benefit ratio of anticoagulant therapy with vitamin K antagonists (VKA) for thromboprophylaxis is uncertain. SUMMARY: In end-stage renal disease (ESRD) patients undergoing hemodialysis, VKA seem less effective in stroke prevention than in the general population, with an increased risk of major bleeding. Recently, novel oral anticoagulant agents (NOACs) have proven to be effective for stroke prevention in AF and have demonstrated an improved safety profile compared to VKA. Limited data from post hoc analyses of controlled clinical trials suggest the safe and effective use of NOACs in patients with moderate renal impairment (i.e., estimated glomerular filtration rate, eGFR, between 30 and 50 mL/min). The question still remains whether NOACs can be used in patients with an eGFR <30 mL/min, since there are no studies addressing this subject. In fact, patients with CKD stage 4 and 5 were excluded from controlled clinical trials on anticoagulation therapy for stroke prevention in AF. Left atrial appendage (LAA) occlusion represents a nonpharmacological alternative for stroke prevention in patients with AF who are difficult to manage medically. Preliminary data indicate a similar efficacy and safety profile in patients with CKD compared to patients with normal renal function. KEY MESSAGES: Stroke prevention in patients with ESRD and AF represents a clinical challenge with poor evidence. LAA occlusion may become the standard of care for stroke prevention in patients with ESRD and AF. PMID- 28736562 TI - Brain Natriuretic Peptide Is a Marker of Fluid Overload in Incident Hemodialysis Patients. AB - BACKGROUND/AIMS: Brain natriuretic peptide (BNP) is secreted by cardiomyocytes under stretch condition. High blood levels are associated with decreased patient survival in heart failure patients and in hemodialysis (HD) patients. We report the monthly BNP change in the first months of HD therapy in incident patients and its relationship with fluid removal and cardiac history (CH). METHODS: All patients starting HD therapy in our unit from May 2008 to December 2012 were retrospectively analyzed. Every month (M1 to M6), BNP was assessed before a midweek dialysis session. CH, monthly pre- and postdialysis blood pressure, and postdialysis body weight were collected. RESULTS: A total of 236 patients were included in the analysis. The median BNP at HD start was 593 (175-1,433) pg/mL, with a significant difference between CH- and CH+ patients (291 vs. 731 pg/mL, p < 0.0001). Mortality was significantly higher in patients in the higher BNP tertile. BNP decreased significantly between M1 and M2 and then plateaued. The BNP change between M1 and M2 and between M1 and M6 was significantly correlated with the initial fluid removal. Applying stepwise multiple regression, the BNP change between M1 and M2 was significantly and independently related to fluid removal. The BNP level at M6 was also related to patient survival. CONCLUSIONS: We confirm that in incident HD patients, BNP level is related to fluid excess and cardiac status. The BNP decrease in the first months of HD therapy is related to fluid excess correction. BNP appears as an important tool to evaluate hydration status correction after HD onset. PMID- 28736563 TI - Estimated Glomerular Filtration Rate and 6-Minute Walk Distance in African Americans with Mild to Moderate Heart Failure. AB - BACKGROUND/AIMS: The 6-minute walk test is a measure of functional capacity in patients with heart failure (HF) or chronic kidney disease (CKD). The association between estimated glomerular filtration rate (eGFR) and 6-minute walk distance (6MWD) has not been investigated in African-Americans (AA), despite them having a higher incidence of CKD and chronic HF. Thus, our aim was to determine if eGFR was an independent predictor of 6MWD in AA >50 years of age with HF. METHODS: In this cross-sectional study, we examined the relationship between eGFR and 6MWD in 45 AA patients with HF from an urban outpatient HF clinic, using logistic regression with bootstrapping. RESULTS: The sample consisted of 53% females; mean age = 64.8 +/- 9 years, mean eGFR = 61.6 +/- 20 mL/min/1.73 m2, and mean 6MWD = 222 +/- 78 m. A decrease in eGFR by 10 mL/min/1.73 m2 was associated with 46% higher odds (p = 0.02) of a 6MWD <=200 m in an unadjusted model and 39-41% higher odds (p = 0.03) of a 6MWD <=200 m in adjusted models. CONCLUSION: A decrease in eGFR significantly predicted a shorter 6MWD in AA patients with HF. Therefore, a reduction in eGFR may be used as an early marker to identify and manage declining functional capacity in these patients. PMID- 28736564 TI - Characterization of an Animal Model to Study Risk Factors and New Therapies for the Cardiorenal Syndrome, a Major Health Issue in Our Aging Population. AB - BACKGROUND: The cardiorenal syndrome (CRS) is a major health problem in our aging population. The term was introduced to cover disorders of the kidneys and heart, whereby dysfunction of one organ may induce dysfunction of the other. As the natural history of the CRS is mostly slow, hence difficult to explore in clinical trials, adequate animal models combining cardiovascular and renal disease are required. Therefore, we developed and characterized a usable model for CRS type 4, i.e. chronic kidney disease (CKD) causing cardiac dysfunction. METHODS: CKD was induced in rats by supplementing the diet with adenine. During 8 weeks, several aspects of CRS were studied: CKD, mineral-bone disorder (MBD), cardiovascular disease, and (iron-deficiency) anemia. Hereto, the following parameters were monitored: serum creatinine, calcium, phosphate, FGF23, dynamic bone parameters, aortic Ca deposits, heart weight, serum NT-proANP, Hct, Hb, reticulocytes, spleen iron, and serum hepcidin. RESULTS: Animals developed a severe CKD together with a disturbed mineral balance as reflected by the increased serum creatinine and phosphorus levels and decreased serum calcium levels; and in association herewith aberrations in hormonal levels of FGF-23. In turn, the well-known and highly undesirable complications of CKD, i.e. high turnover bone disease and pathological vessel calcification were induced. Furthermore (iron-deficiency) anemia developed quickly. CONCLUSION: The animal model described in this article in many aspects mimics the human situation of the CRS type 4 and will be useful to concomitantly evaluate the effects of new treatment strategies on the various aspects of CRS. PMID- 28736565 TI - Urinary Osteopontin Predicts Incident Chronic Kidney Disease, while Plasma Osteopontin Predicts Cardiovascular Death in Elderly Men. AB - BACKGROUND AND OBJECTIVES: The matricellular protein osteopontin is involved in the pathogenesis of both kidney and cardiovascular disease. However, whether circulating and urinary osteopontin levels are associated with the risk of these diseases is less studied. DESIGN SETTING PARTICIPANTS AND MEASUREMENTS: A community-based cohort of elderly men (Uppsala Longitudinal Study of Adult Men [ULSAM]; n = 741; mean age: 77 years) was used to study the associations between plasma and urinary osteopontin, incident chronic kidney disease, and the risk of cardiovascular death during a median of 8 years of follow-up. RESULTS: There was no significant cross-sectional correlation between plasma and urinary osteopontin (Spearman rho = 0.07, p = 0.13). Higher urinary osteopontin, but not plasma osteopontin, was associated with incident chronic kidney disease in multivariable models adjusted for age, cardiovascular risk factors, baseline glomerular filtration rate, urinary albumin/creatinine ratio, and the inflammatory markers interleukin 6 and high-sensitivity C-reactive protein (odds ratio for 1 standard deviation [SD] of urinary osteopontin, 1.42, 95% CI 1.00-2.02, p = 0.048). Conversely, plasma osteopontin, but not urinary osteopontin, was independently associated with cardiovascular death (multivariable hazard ratio per SD increase, 1.35, 95% CI 1.14-1.58, p < 0.001, and 1.00, 95% CI 0.79-1.26, p = 0.99, respectively). The addition of plasma osteopontin to a model with established cardiovascular risk factors significantly increased the C-statistics for the prediction of cardiovascular death (p < 0.002). CONCLUSIONS: Higher urinary osteopontin specifically predicts incident chronic kidney disease, while plasma osteopontin specifically predicts cardiovascular death. Our data put forward osteopontin as an important factor in the detrimental interplay between the kidney and the cardiovascular system. The clinical implications, and why plasma and urinary osteopontin mirror different pathologies, remain to be established. PMID- 28736566 TI - Genome-Wide Linkage and Association Mapping of Halo Blight Resistance in Common Bean to Race 6 of the Globally Important Bacterial Pathogen. AB - Pseudomonas syringae pv. phaseolicola (Psph) Race 6 is a globally prevalent and broadly virulent bacterial pathogen with devastating impact causing halo blight of common bean (Phaseolus vulgaris L.). Common bean lines PI 150414 and CAL 143 are known sources of resistance against this pathogen. We constructed high resolution linkage maps for three recombinant inbred populations to map resistance to Psph Race 6 derived from the two common bean lines. This was complemented with a genome-wide association study (GWAS) of Race 6 resistance in an Andean Diversity Panel of common bean. Race 6 resistance from PI 150414 maps to a single major-effect quantitative trait locus (QTL; HB4.2) on chromosome Pv04 and confers broad-spectrum resistance to eight other races of the pathogen. Resistance segregating in a Rojo * CAL 143 population maps to five chromosome arms and includes HB4.2. GWAS detected one QTL (HB5.1) on chromosome Pv05 for resistance to Race 6 with significant influence on seed yield. The same HB5.1 QTL, found in both Canadian Wonder * PI 150414 and Rojo * CAL 143 populations, was effective against Race 6 but lacks broad resistance. This study provides evidence for marker-assisted breeding for more durable halo blight control in common bean by combining alleles of race-nonspecific resistance (HB4.2 from PI 150414) and race-specific resistance (HB5.1 from cv. Rojo). PMID- 28736567 TI - Dynamics of Calcium during In vitro Microspore Embryogenesis and In vivo Microspore Development in Brassica napus and Solanum melongena. AB - Calcium is widely known to have a role as a signaling molecule in many different processes, including stress response and activation of the embryogenic program. However, there are no direct clues about calcium levels during microspore embryogenesis, an experimental process that combines a developmental switch toward embryogenesis and the simultaneous application of different stressing factors. In this work, we used FluoForte, a calcium-specific fluorescent vital dye, to track by confocal microscopy the changes in levels and subcellular distribution of calcium in living rapeseed (B. napus) and eggplant (S. melongena) microspores and pollen grains during in vivo development, as well as during the first stages of in vitro-induced microspore embryogenesis in rapeseed. During in vivo development, a clear peak of cytosolic Ca2+ was observed in rapeseed vacuolate microspores and young pollen grains, the stages more suitable for embryogenesis induction. However, the Ca2+ levels observed in eggplant were dramatically lower than in rapeseed. Just after in vitro induction, Ca2+ levels increased specifically in rapeseed embryogenic microspores at levels dramatically higher than during in vivo development. The increase was observed in the cytosol, but predominantly in vacuoles. Non-embryogenic forms such as callus-like and pollen-like structures presented remarkably different calcium patterns. After the heat shock-based inductive treatment, Ca2+ levels progressively decreased in all cases. Together, our results reveal unique calcium dynamics in in vivo rapeseed microspores, as well as in those reprogrammed to in vitro embryogenesis, establishing a link between changes in Ca2+ level and subcellular distribution, and microspore embryogenesis. PMID- 28736569 TI - Deep Plant Phenomics: A Deep Learning Platform for Complex Plant Phenotyping Tasks. AB - Plant phenomics has received increasing interest in recent years in an attempt to bridge the genotype-to-phenotype knowledge gap. There is a need for expanded high throughput phenotyping capabilities to keep up with an increasing amount of data from high-dimensional imaging sensors and the desire to measure more complex phenotypic traits (Knecht et al., 2016). In this paper, we introduce an open source deep learning tool called Deep Plant Phenomics. This tool provides pre trained neural networks for several common plant phenotyping tasks, as well as an easy platform that can be used by plant scientists to train models for their own phenotyping applications. We report performance results on three plant phenotyping benchmarks from the literature, including state of the art performance on leaf counting, as well as the first published results for the mutant classification and age regression tasks for Arabidopsis thaliana. PMID- 28736568 TI - BdCIPK31, a Calcineurin B-Like Protein-Interacting Protein Kinase, Regulates Plant Response to Drought and Salt Stress. AB - Calcineurin B-like protein interacting protein kinases (CIPKs) are vital elements in plant abiotic stress signaling pathways. However, the functional mechanism of CIPKs has not been understood clearly, especially in Brachypodium distachyon, a new monocot model plant. In this study, BdCIPK31, a CIPK gene from B. distachyon was characterized. BdCIPK31 was downregulated by polyethylene glycol, NaCl, H2O2, and abscisic acid (ABA) treatments. Transgenic tobacco plants overexpressing BdCIPK31 presented improved drought and salt tolerance, and displayed hypersensitive response to exogenous ABA. Further investigations revealed that BdCIPK31 functioned positively in ABA-mediated stomatal closure, and transgenic tobacco exhibited reduced water loss under dehydration conditions compared with the controls. BdCIPK31 also affected Na+/K+ homeostasis and root K+ loss, which contributed to maintain intracellular ion homeostasis under salt conditions. Moreover, the reactive oxygen species scavenging system and osmolyte accumulation were enhanced by BdCIPK31 overexpression, which were conducive for alleviating oxidative and osmotic damages. Additionally, overexpression of BdCIPK31 could elevate several stress-associated gene expressions under stress conditions. In conclusion, BdCIPK31 functions positively to drought and salt stress through ABA signaling pathway. Overexpressing BdCIPK31 functions in stomatal closure, ion homeostasis, ROS scavenging, osmolyte biosynthesis, and transcriptional regulation of stress-related genes. PMID- 28736570 TI - Genome-Wide Identification and Functional Analysis of the Calcineurin B-like Protein and Calcineurin B-like Protein-Interacting Protein Kinase Gene Families in Turnip (Brassica rapa var. rapa). AB - The calcineurin B-like protein (CBL)-CBL-interacting protein kinase (CIPK) complex has been identified as a primary component in calcium sensors that perceives various stress signals. Turnip (Brassica rapa var. rapa) has been widely cultivated in the Qinghai-Tibet Plateau for a century as a food crop of worldwide economic significance. These CBL-CIPK complexes have been demonstrated to play crucial roles in plant response to various environmental stresses. However, no report is available on the genome-wide characterization of these two gene families in turnip. In the present study, 19 and 51 members of the BrrCBL and BrrCIPK genes, respectively, are first identified in turnip and phylogenetically grouped into three and two distinct clusters, respectively. The expansion of these two gene families is mainly attributable to segmental duplication. Moreover, the differences in expression patterns in quantitative real-time PCR, as well as interaction profiles in the yeast two-hybrid assay, suggest the functional divergence of paralog genes during long-term evolution in turnip. Overexpressing and complement lines in Arabidopsis reveal that BrrCBL9.2 improves, but BrrCBL9.1 does not affect, salt tolerance in Arabidopsis. Thus, the expansion of the BrrCBL and BrrCIPK gene families enables the functional differentiation and evolution of some new gene functions of paralog genes. These paralog genes then play prominent roles in turnip's adaptation to the adverse environment of the Qinghai-Tibet Plateau. Overall, the study results contribute to our understanding of the functions of the CBL-CIPK complex and provide basis for selecting appropriate genes for the in-depth functional studies of BrrCBL BrrCIPK in turnip. PMID- 28736571 TI - Evaluation of Quality Assessment Protocols for High Throughput Genome Resequencing Data. AB - Large-scale initiatives aiming to recover the complete sequence of thousands of human genomes are currently being undertaken worldwide, concurring to the generation of a comprehensive catalog of human genetic variation. The ultimate and most ambitious goal of human population scale genomics is the characterization of the so-called human "variome," through the identification of causal mutations or haplotypes. Several research institutions worldwide currently use genotyping assays based on Next-Generation Sequencing (NGS) for diagnostics and clinical screenings, and the widespread application of such technologies promises major revolutions in medical science. Bioinformatic analysis of human resequencing data is one of the main factors limiting the effectiveness and general applicability of NGS for clinical studies. The requirement for multiple tools, to be combined in dedicated protocols in order to accommodate different types of data (gene panels, exomes, or whole genomes) and the high variability of the data makes difficult the establishment of a ultimate strategy of general use. While there already exist several studies comparing sensitivity and accuracy of bioinformatic pipelines for the identification of single nucleotide variants from resequencing data, little is known about the impact of quality assessment and reads pre-processing strategies. In this work we discuss major strengths and limitations of the various genome resequencing protocols are currently used in molecular diagnostics and for the discovery of novel disease-causing mutations. By taking advantage of publicly available data we devise and suggest a series of best practices for the pre-processing of the data that consistently improve the outcome of genotyping with minimal impacts on computational costs. PMID- 28736572 TI - An index to characterize female career promotion in academic medicine. AB - BACKGROUND: Imbalances in female career promotion are a key factor of gender disparities at the workplace. They may lead to stress and stress-related diseases including burnout, depression or cardiovascular diseases. Since this problem cannot be generalized and varies between different fields, new approaches are needed to assess and describe the magnitude of the problem in single fields of work. METHODS: To construct a new index, operating figures of female and male medical students were collected for Germany in a period over 15 years and their progression throughout their studies towards specialization and academic chair positions. By the use of different female to male ratios (f:m), we constructed an index that describes the extend by which women can ascent in their academic career by using the field of academic medicine as an example. RESULTS: A medical student f:m ratio of 1.54 (52,366 female vs. 34,010 male) was found for Germany in 2013. In 1998, this f:m ratio was 0.999. In the same year (2013), the OB/GYN hospital specialists' f:m ratio was 1.566 (3347 female vs. 2137 male physicians) and 0.577 (516 female vs 894 male physicians) for ENT hospital specialists, respectively. The f:m ratios concerning chairs of OB/GYN and ENT were 0.105 and 0.1, respectively. Then an index was generated that incorporated these operating figures with the student f:m ratio as denominator and the chair f:m ratio as numerator while the hospital specialist f:m ratio served as a corrector in the numerator in order to adjust to the attraction of a given field to female physicians. As a result, the index was 0.044 for OB/GYN and 0.113 for ENT instead of ideally ~1 in a completely gender harmonized situation. CONCLUSION: In summary, a new index to describe female career advancement was established for academic medicine. By the use of this index, different academic and medical fields can now be compared to each other and future benchmarks could be proposed. Also, country differences may be examined using the proposed index and the success of specific funding programs. PMID- 28736573 TI - A rapid and efficient in vitro regeneration system for lettuce (Lactuca sativa L.). AB - BACKGROUND: Successful biotechnological improvement of crop plants requires a reliable and efficient in vitro regeneration system. Lettuce (Lactuca sativa L.), one the most important vegetable crops worldwide, is strongly genotype-dependent in terms of regeneration capacity, limiting the potential for biotechnological improvement of cultivars which show recalcitrance under currently available protocols. The effect of different nutrient sources, plant hormone combinations and activated charcoal supplementation on shoot induction efficiency was evaluated on the cultivar 'RSL NFR', which had previously shown poor regeneration efficiency. RESULTS: Multiple shoot organogenesis from cotyledon explants was recorded at the highest frequency and speed on Murashige and Skoog regeneration medium supplemented with 200 mg/l of activated charcoal, 3% sucrose, 10 mg/l benzylaminopurine and 0.5 mg/l naphthaleneacetic acid, which induced shoots through direct regeneration in 90.8 +/- 7.9% of explants. High shoot induction efficiency was also observed, albeit not quantified, when using this medium on some other cultivars. CONCLUSIONS: This activated charcoal-containing regeneration medium might offer a rapid and efficient option for direct shoot induction in some lettuce genotypes that do not respond well to common lettuce regeneration protocols. This is also the first report of the effect of activated charcoal in lettuce tissue culture. PMID- 28736575 TI - Identification of bifurcation transitions in biological regulatory networks using Answer-Set Programming. AB - BACKGROUND: Numerous cellular differentiation processes can be captured using discrete qualitative models of biological regulatory networks. These models describe the temporal evolution of the state of the network subject to different competing transitions, potentially leading the system to different attractors. This paper focusses on the formal identification of states and transitions that are crucial for preserving or pre-empting the reachability of a given behaviour. METHODS: In the context of non-deterministic automata networks, we propose a static identification of so-called bifurcations, i.e., transitions after which a given goal is no longer reachable. Such transitions are naturally good candidates for controlling the occurrence of the goal, notably by modulating their propensity. Our method combines Answer-Set Programming with static analysis of reachability properties to provide an under-approximation of all the existing bifurcations. RESULTS: We illustrate our discrete bifurcation analysis on several models of biological systems, for which we identify transitions which impact the reachability of given long-term behaviour. In particular, we apply our implementation on a regulatory network among hundreds of biological species, supporting the scalability of our approach. CONCLUSIONS: Our method allows a formal and scalable identification of transitions which are responsible for the lost of capability to reach a given state. It can be applied to any asynchronous automata networks, which encompass Boolean and multi-valued models. An implementation is provided as part of the Pint software, available at http://loicpauleve.name/pint. PMID- 28736574 TI - Elucidating the role of highly homologous Nicotiana benthamiana ubiquitin E2 gene family members in plant immunity through an improved virus-induced gene silencing approach. AB - BACKGROUND: Virus-induced gene silencing (VIGS) has been used in many plant species as an attractive post transcriptional gene silencing (PTGS) method for studying gene function either individually or at large-scale in a high-throughput manner. However, the specificity and efficiency for knocking down members of a highly homologous gene family have remained to date a significant challenge in VIGS due to silencing of off-targets. RESULTS: Here we present an improved method for the selection and evaluation of gene fragments used for VIGS to specifically and efficiently knock down members of a highly homologous gene family. Using this method, we knocked down twelve and four members, respectively of group III of the gene family encoding ubiquitin-conjugating enzymes (E2) in Nicotiana benthamiana. Assays using these VIGS-treated plants revealed that the group III E2s are essential for plant development, plant immunity-associated reactive oxygen species (ROS) production, expression of the gene NbRbohB that is required for ROS production, and suppression of immunity-associated programmed cell death (PCD) by AvrPtoB, an effector protein of the bacterial pathogen Pseudomons syringae. Moreover, functional redundancy for plant development and ROS production was found to exist among members of group III E2s. CONCLUSIONS: We have found that employment of a gene fragment as short as approximately 70 base pairs (bp) that contains at least three mismatched nucleotides to other genes within any 21-bp sequences prevents silencing of off-target(s) in VIGS. This improved approach in the selection and evaluation of gene fragments allows for specific and efficient knocking down of highly homologous members of a gene family. Using this approach, we implicated N. benthamiana group III E2s in plant development, immunity associated ROS production, and suppression of multiple immunity-associated PCD by AvrPtoB. We also unraveled functional redundancy among group III members in their requirement for plant development and plant immunity-associated ROS production. PMID- 28736576 TI - The impact of considering land intensification and updated data on biofuels land use change and emissions estimates. AB - BACKGROUND: The GTAP model has been used to estimate biofuel policy induced land use changes and consequent GHG emissions for more than a decade. This paper reviews the history of the model and database modifications and improvements that have occurred over that period. In particular, the paper covers in greater detail the move from the 2004 to the 2011 database, and the inclusion of cropland intensification in the modeling structure. RESULTS: The results show that all the changes in the global economy and agricultural sectors cause biofuels induced land use changes and associated emissions can be quite different using the 2011 database versus 2004. The results also demonstrate the importance of including land intensification in the analysis. The previous versions of GTAP and other similar models assumed that changes in harvested area equal changes in cropland area. However, FAO data demonstrate that it is not correct for several important world regions. The model now includes land intensification, and the resulting land use changes and emission values are lower as would be expected. CONCLUSIONS: Dedicated energy crops are not similar to the first generation feedstocks in the sense that they do not generate the level of market-mediated responses which we have seen in the first-generation feedstocks. The major market-mediated responses are reduced consumption, crop switching, changes in trade, changes in intensification, and forest or pasture conversion. These largely do not apply to dedicated energy corps. The land use emissions for cellulosic feedstocks depend on what we assume in the emissions factor model regarding soil carbon gained or lost in converting land to these feedstocks. We examined this important point for producing bio-gasoline from miscanthus. Much of the literature suggests miscanthus actually sequesters carbon, if grown on the existing active cropland or degraded land. We provide some illustrative estimates for possible assumptions. Finally, it is important to note the importance of the new results for the regulatory process. The current California Air Resources Board carbon scores for corn ethanol and soy biodiesel are 19.8 and 29.1, respectively (done with a model version that includes irrigation). The new model and database carbon scores are 12 and 18, respectively, for corn ethanol and soy biodiesel. Thus, the current estimates values are substantially less than the values currently being used for regulatory purposes. PMID- 28736577 TI - Optimization of proximity ligation assay (PLA) for detection of protein interactions and fusion proteins in non-adherent cells: application to pre-B lymphocytes. AB - BACKGROUND: Genetic abnormalities, including chromosomal translocations, are described for many hematological malignancies. From the clinical perspective, detection of chromosomal abnormalities is relevant not only for diagnostic and treatment purposes but also for prognostic risk assessment. From the translational research perspective, the identification of fusion proteins and protein interactions has allowed crucial breakthroughs in understanding the pathogenesis of malignancies and consequently major achievements in targeted therapy. METHODS: We describe the optimization of the Proximity Ligation Assay (PLA) to ascertain the presence of fusion proteins, and protein interactions in non-adherent pre-B cells. PLA is an innovative method of protein-protein colocalization detection by molecular biology that combines the advantages of microscopy with the advantages of molecular biology precision, enabling detection of protein proximity theoretically ranging from 0 to 40 nm. RESULTS: We propose an optimized PLA procedure. We overcome the issue of maintaining non-adherent hematological cells by traditional cytocentrifugation and optimized buffers, by changing incubation times, and modifying washing steps. Further, we provide convincing negative and positive controls, and demonstrate that optimized PLA procedure is sensitive to total protein level. The optimized PLA procedure allows the detection of fusion proteins and protein interactions on non-adherent cells. CONCLUSION: The optimized PLA procedure described here can be readily applied to various non-adherent hematological cells, from cell lines to patients' cells. The optimized PLA protocol enables detection of fusion proteins and their subcellular expression, and protein interactions in non-adherent cells. Therefore, the optimized PLA protocol provides a new tool that can be adopted in a wide range of applications in the biological field. PMID- 28736578 TI - The Dark Proteome Database. PMID- 28736579 TI - Changes of myocardial lipidomics profiling in a rat model of diabetic cardiomyopathy using UPLC/Q-TOF/MS analysis. AB - BACKGROUND: Diabetic cardiomyopathy (DCM) is a serious cardiac dysfunction induced by changes in the structure and contractility of the myocardium that are initiated in part by alterations in energy substrates. The underlying mechanisms of DCM are still under controversial. The observation of lipids, especially lipidomics profiling, can provide an insight into the know the biomarkers of DCM. The aim of our research was to detect changes of myocardial lipidomics profiling in a rat model of diabetic cardiomyopathy. METHODS: Diabetic cardiomyopathy was induced by feeding a high-sucrose/fat diet (HSFD) for 28 weeks and streptozotocin (30 mg/kg, intraperitoneally). The ultra-high-performance liquid chromatography (UPLC) coupled to quadruple time-of flight (QTOF) mass spectrometer was used to acquire and analyze the lipidomics profiling of myocardial tissue. Meanwhile, parameters of cardiac function were collected using cardiac catheterization, and the cardiac index was calculated, and fasting blood glucose and lipid levels were measured by an ultraviolet spectrophotometric method. RESULTS: We detected 3023 positive ion peaks and 300 negative ion peaks. Levels of phosphatidylcholine (PC) (22:6/18:2), PC (22:6/18:1), PC (20:4/16:1), PC (16:1/18:3), phosphatidylethanolamine (PE) (20:4/18:2), and PE (20:4/16:0) were down regulated, and PC (20:2/18:2), PC (18:0/16:0), and PC (20:4/18:0) were up regulated in DCM model rats, when compared with control rats. Cardiac functions signed as values of left ventricular systolic pressure, maximal uprising velocity of left ventricular pressure and maximal decreasing velocity of left ventricular pressure were injured by 21-44%, and the cardiac index was increased by 25%, and fasting blood glucose and lipids were increased by 34-368%. Meanwhile, the cardiac lipid-related biomarkers have significant correlation with changes of cardiac function and cardiac index. CONCLUSIONS: UPLC/Q-TOF/MS analysis data suggested changes of some potential lipid biomarkers in the development of cardiac dysfunction and hypertrophy of diabetic cardiomyopathy, which may serve as potential important targets for clinical diagnosis and therapeutic intervention of DCM in the future. PMID- 28736580 TI - Supportive and non-supportive interactions in families with a type 2 diabetes patient: an integrative review. AB - BACKGROUND: Type 2 diabetes and its management affect the patient and the close family potentially causing either psychological distress or increased sense of responsibility and collaboration in these families. Interactions between patient and family play an important role in maintaining lifestyle changes and diabetes self-management. The purpose of this integrative review was to summarise and assess published studies on the intra-family perspective of supportive and non supportive interactions in families with a type 2 diabetes patient. METHODS: Included in the review were published qualitative and quantitative studies that examined the intra-family perspective on supportive and non-supportive interactions. We searched the literature from 2000 to 2016 and the search strategy comprised the following databases: Cochrane, PubMed, CINAHL, Web of Science, PsycINFO and Psyc-ARTICLES as well as hand searching of reference lists. Quality assessment, data extraction and analysis were undertaken on all included studies. RESULTS: We identified five eligible research papers. Employing content analysis three categories describing interactions were refined: Impact of practical action, impact of emotional involvement, and impact of communication content. Supportive interactions included encouraging communication and family collaboration in managing diet, medications, and blood glucose checking. Non supportive interactions were visible irritation, nagging behaviour and refusing to share the burden of living with diabetes. CONCLUSION: The findings stress the importance of including both patient and family in clinical practice to target diabetes self-management adherence and well-being of the whole family. The majority of self-management occurs within the family environment. Therefore, the intra-family perspective of supportive and non-supportive interactions should be understood and addressed as the family members are interdependent and affected by each other. Future research assessing the impact of professional support and the family function will have the potential to improve the daily life and well-being of patients with type 2 diabetes as well as the whole family. PMID- 28736581 TI - The Remarkable Amphoteric Nature of Defective UiO-66 in Catalytic Reactions. AB - One of the major requirements in solid acid and base catalyzed reactions is that the reactants, intermediates or activated complexes cooperate with several functions of catalyst support. In this work the remarkable bifunctional behavior of the defective UiO-66(Zr) metal organic framework is shown for acid-base pair catalysis. The active site relies on the presence of coordinatively unsaturated zirconium sites, which may be tuned by removing framework linkers and by removal of water from the inorganic bricks using a dehydration treatment. To elucidate the amphoteric nature of defective UiO-66, the Oppenauer oxidation of primary alcohols has been theoretically investigated using density functional theory (DFT) and the periodic approach. The presence of acid and basic centers within molecular distances is shown to be crucial for determining the catalytic activity of the material. Hydrated and dehydrated bricks have a distinct influence on the acidity and basicity of the active sites. In any case both functions need to cooperate in a concerted way to enable the chemical transformation. Experimental results on UiO-66 materials of different defectivity support the theoretical observations made in this work. PMID- 28736582 TI - Multicast Delayed Authentication For Streaming Synchrophasor Data in the Smart Grid. AB - Multicast authentication of synchrophasor data is challenging due to the design requirements of Smart Grid monitoring systems such as low security overhead, tolerance of lossy networks, time-criticality and high data rates. In this work, we propose inf -TESLA, Infinite Timed Efficient Stream Loss-tolerant Authentication, a multicast delayed authentication protocol for communication links used to stream synchrophasor data for wide area control of electric power networks. Our approach is based on the authentication protocol TESLA but is augmented to accommodate high frequency transmissions of unbounded length. inf TESLA protocol utilizes the Dual Offset Key Chains mechanism to reduce authentication delay and computational cost associated with key chain commitment. We provide a description of the mechanism using two different modes for disclosing keys and demonstrate its security against a man-in-the-middle attack attempt. We compare our approach against the TESLA protocol in a 2-day simulation scenario, showing a reduction of 15.82% and 47.29% in computational cost, sender and receiver respectively, and a cumulative reduction in the communication overhead. PMID- 28736584 TI - Secondary Metabolites from the Leaves of the Medicinal Plant Goldenseal (Hydrastis canadensis). AB - The study presented herein constitutes an extensive investigation of constituents in Hydrastis canadensis L. (Ranunculaceae) leaves. It describes the isolation and identification of two previously unknown compounds, 3,4-dimethoxy-2 (methoxycarbonyl)benzoic acid (1) and 3,5,3'-trihydroxy-7,4'-dimethoxy-6,8-C dimethyl-flavone (2), along with the known compounds (+/-)-chilenine (3), (2R) 5,4'-dihydroxy-6-C-methyl-7-methoxy-flavanone (4), 5,4'-dihydroxy-6,8-di-C-methyl 7-methoxy-flavanone (5), noroxyhydrastinine (6), oxyhydrastinine (7) and 4',5' dimethoxy-4-methyl-3'-oxo-(1,2,5,6-tetrahydro-4H-1,3-dioxolo-[4',5':4,5] benzo[1,2-e]-1,2-oxazocin)-2-spiro-1'-phtalan (8). Compounds 3-8 have been reported from other sources, but this is the first report of their presence in H. canadensis extracts. A mass spectrometry based assay was employed to demonstrate bacterial efflux pump inhibitory activity against Staphylococcus aureus for 2, with an IC50 value of 180 +/- 6 MUM. This activity in addition to that of other bioactive compounds such as flavonoids and alkaloids, may explain the purported efficacy of H. canadensis for treatment of bacterial infections. Finally, this report includes high mass accuracy fragmentation spectra for all compounds investigated herein which were uploaded into the Global Natural Products Social molecular networking library and can be used to facilitate their future identification in H. canadensis or other botanicals. PMID- 28736583 TI - MicroRNA profiling of ovarian granulosa cell tumours reveals novel diagnostic and prognostic markers. AB - BACKGROUND: The aim of this study was to explore the clinical utility of microRNAs (miRNAs) as improved markers of ovarian granulosa cell tumours (GCTs) for cancer diagnosis and prognosis prediction. Current histopathological and genetic markers, such as the presence of a FOXL2 gene mutation to distinguish between the two major subtypes are not wholly accurate and as such novel biomarkers are warranted. METHODS: The miRNA expression profiles of five formalin fixed, paraffin-embedded (FFPE) adult-GCTs and five juvenile-GCTs were assessed using Affymetrix miRNA 3.0 Arrays and compared for differential expression. Ten miRNAs were assessed in an additional 33 FFPE tumours and four normal granulosa cell samples by quantitative RT-PCR, and their expression correlated to clinical information. RESULTS: MicroRNA array found 37 miRNAs as differentially expressed between the two GCT subtypes (p < 0.05, fold change >=2 and among these, miRs 138-5p, -184, -204-5p, -29c-3p, -328-3p and -501-3p were validated by RT-qPCR as differentially expressed between the two GCT subtypes (p < 0.05). In addition, the expression of miR-184 was predictive of tumour recurrence in adult-GCTs, specifically for patients diagnosed with stage I and II and stage I only disease (p < 0.001 and p < 0.05, respectively). CONCLUSIONS: This study is the first to report on global miRNA expression profiles of human ovarian GCTs using FFPE tumour samples. We have validated six miRNAs as novel markers for subtype classification in GCTs with low levels of miR-138-5p correlating with early tumour stage. Low miR-184 abundance was correlated with tumour recurrence in early stage adult-GCT patients as a candidate predictive biomarker. Further studies are now needed to confirm the clinical utility of these miRNAs as diagnostic and recurrence markers, and understand their possible roles in the pathogenesis of GCTs. PMID- 28736585 TI - Late onset asymptomatic pancreatic neuroendocrine tumor - A case report on the phenotypic expansion for MEN1. AB - BACKGROUND: Multiple endocrine neoplasia type 1 (MEN1) is a hereditary cancer syndrome associated with several endocrine as well as non-endocrine tumors and is caused by mutations in the MEN1 gene. Primary hyperparathyroidism affects the majority of MEN1 individuals by age 50 years. Additionally, MEN1 mutations trigger familial isolated hyperparathyroidism. We describe a seemingly unaffected 76-year-old female who presented to our Genetics Clinic with a family history of primary hyperparathyroidism and the identification of a pathogenic MEN1 variant. CASE PRESENTATION: The patient was a 76 year-old woman who appeared to be unaffected. She had a family history of a known MEN1 pathogenic variant. Molecular testing for the known MEN1 mutation c.1A > G, as well as, biochemical testing, MRI of the brain and abdomen were all performed using standard methods. Molecular testing revealed our patient possessed the MEN1 pathogenic variant previously identified in her two offspring. Physical exam revealed red facial papules with onset in her seventies, involving her cheeks, nose and upper lip. Formerly, she was diagnosed with rosacea by a dermatologist and noted no improvement with treatment. Clinically, these lesions appeared to be facial angiofibromas. Brain MRI was normal. However, an MRI of her abdomen revealed a 1.5 cm lesion at the tail of the pancreas with normal adrenal glands. Glucagon was mildly elevated and pancreatic polypeptide was nearly seven times the upper limit of the normal range. The patient underwent spleen sparing distal pancreatectomy and subsequent pathology was consistent with a well-differentiated pancreatic neuroendocrine tumor (pNET). CONCLUSIONS: Age-related penetrance and variable expressivity are well documented in families with MEN1. It is thought that nearly all individuals with MEN1 manifest disease by age 40. We present a case of late-onset MEN1 in the absence of the most common feature, primary hyperparathyroidism, but with the presence of a pNET and cutaneous findings. This family expands the phenotype associated with the c.1A > G pathogenic variant and highlights the importance of providing comprehensive assessment of MEN1 mutation carriers in families that at first blush may appear to have isolated hyperparathyroidism. PMID- 28736587 TI - The 29th Annual American Academy of Medical Acupuncture: Brief Highlights. PMID- 28736588 TI - The Regulation of the Practice of Acupuncture by Physicians in the United States. AB - Introduction: The landscape of acupuncture regulation has greatly evolved since the National Institutes of Health Consensus Statement in 1997. In recent decades, acupuncture treatment has become increasingly integrated with conventional medical care. Healthcare practitioners often utilize acupuncture as an adjunctive therapy to help alleviate symptoms of many conditions, such as nausea and pain. The popularity of this complementary and alternative modality has elevated the importance and urgency for states to regulate its practice and safety. Materials and Methods: The authors comprehensively examined the regulation of the practice of acupuncture by licensed physicians in the United States. Current statutes were evaluated with respect to those from past decades. Requirements were compared with the World Health Organization's recommendations for acupuncture basic training and safety. Results: Most physicians are permitted to practice acupuncture within the scope of their medical practices. Many states mandate that they complete additional education and training. Three states require that physicians obtain acupuncture licenses through the same process as non physicians. Compared to prior decades, many states have changed their requirements. Conclusions: This article provides current, individual state regulations for the practice of acupuncture by physicians. PMID- 28736586 TI - Photothermal Microscopy of Coupled Nanostructures and the Impact of Nanoscale Heating in Surface Enhanced Raman Spectroscopy. AB - The optical properties of plasmonic nanoparticles are strongly dependent on interactions with other nanoparticles, which complicates analysis for systems larger than a few particles. In this work we examined heat dissipation in aggregated nanoparticles, and its influence on surface enhanced Raman scattering (SERS), through correlated photothermal heterodyne imaging, electron microscopy and SERS measurements. For dimers the per particle absorption cross-sections show evidence of interparticle coupling, however, the effects are much smaller than those for the field enhancements that are important for SERS. For larger aggregates the total absorption was observed to be simply proportional to aggregate volume. This observation allows us to model light absorption and heating in the aggregates by assuming that the particles act as independent heat sources. The heat dissipation calculations show that very high temperatures can be created at the nanoparticle surface, and that the temperature decreases with increasing thermal conductivity of the surroundings. This is in agreement with the SERS measurements that show faster signal degradation for air compared to water environments. PMID- 28736589 TI - Dysbiosis, Spleen Qi, Phlegm, and Complex Difficulties. AB - The incidence of complex chronic health conditions is rising. Some of these conditions might have their roots in gut disturbances, which in Chinese Medicine would be categorized as Spleen and Stomach Qi Disharmonies. In this article, the author explores these issues from an integrative perspective and suggests areas where acupuncture techniques could be helpful. Five cases are described briefly to illustrate the use of acupuncture. PMID- 28736590 TI - Is Electroacupuncture Treatment More Effective in Somatic Tinnitus Than in Nonsomatic Tinnitus? AB - Background: In recent years, evidence has been accumulating linking subjective tinnitus to the somatosensory system. Somatic tinnitus is defined as tinnitus in which forceful contractions of jaw and neck muscles modulate the psychoacoustic attributes of tinnitus, such as pitch and loudness. Being a somatosensory-based treatment modality, needling might well be more effective for treating somatic than nonsomatic tinnitus. Objective: The aim of this study was to compare the outcomes of electroacupuncture (EA) treatment between patients with somatic and nonsomatic tinnitus. Materials and Methods: A single-blinded prospective study was carried wherein 27 patients with tinnitus were divided into either a somatic or a nonsomatic group, based on whether their tinnitus could be modulated by at least one of a series of forceful jaw and neck muscular contraction maneuvers. Tinnitus responses were evaluated after a single session of EA on selected acupoints for 30 minutes. Results: Seventeen of the 27 patients (63.0%) studied were found to have somatic tinnitus. Generalized estimating equation model analysis did not find any overall statistically significant difference in EA response between patients with somatic and nonsomatic tinnitus. However, patients with somatic tinnitus who were consistent in their responses to the muscular contraction maneuvers were more likely to improve with EA than variable responders to these maneuvers (62.5% versus 22.0%). Conclusions: EA did not provide increased benefits for patients with somatic tinnitus, compared to those with nonsomatic tinnitus overall. However, within the somatic tinnitus group, a subpopulation of patients appeared to be relatively more responsive to EA treatment. PMID- 28736591 TI - Immune Modulation and Treatment of Human Papilloma Virus-Related Warts with Energetics of Living Systems Acupuncture. AB - Background: Cutaneous warts are small skin lesions formed as a result of infection by the human papilloma virus (HPV). In the lesion, viral manipulation creates a microenvironment that favors virus survival and reproduction. Most lesions eventually regress, probably as a result of a Th1-mediated immune response. However, some warts fail to regress and become persistent. Objective: The efficacy of treatment of persistent HPV-caused warts with Energetics of Living Systems acupuncture and monitored immune system involvement was tested. Methods: Eighteen patients with persistent warts were recruited for the study; 9 received acupuncture treatment and 9 received placebo. Each patient was treated 4 times. Results: Clinical success was defined as total clearance of all lesions with no recurrence for 3 months. In the treatment group, clinical success was 36.6% versus 0% in the placebo group. In the treatment group, the level of interleukin (IL)-10 decreased. In a comparison of patients with cleared warts and overall patients with nonresponding warts, different expression levels of IL-8, IL-10, tumor necrosis factor-alpha, IL-6, and interferon-gamma were found, although these differences were not always statistically significant. Trends of differences (not significant) were observed in leukocyte levels. Acupuncture eliminated persistent warts in some of the patients, along with inducing changes in immunologic parameters. Conclusions: Taking the clinical and immunologic outcomes together, clearance of persistent warts following acupuncture might be due to a shift toward a Th1 immune response, or an anti-inflammatory effect against the lesion-induced microenvironment. PMID- 28736592 TI - A Multicenter Prospective Survey of Adverse Events Associated with Acupuncture and Moxibustion in Japan. AB - Background: There have been only a few prospective surveys on adverse events (AEs) in Japanese-style acupuncture practice, and these surveys were conducted only in a single college acupuncture clinic. Objective: The goal of this research was to assess the safety of acupuncture and moxibustion performed in educational facilities in Japan. Materials and Methods: This was a multicenter prospective survey, using paper reporting forms. It was conducted in eight acupuncture clinics affiliated with educational institutions. The subjects were outpatients attending the clinics. The main outcome measure was the number of reported adverse events. The study was conducted for 5-7 months at each facility between October 2014 and June 2015. Participating acupuncture practitioners were instructed to self-report AEs observed during and after treatment; patients were interviewed upon treatment completion. For returning patients, treatment was preceded by an interview survey regarding the AEs identified after the previous treatment session. A specialized 4-sheet questionnaire was used. Results: Two hundred and thirty-two acupuncture practitioners participated, 2180 patients received treatment, and there were 14,039 sessions, overall. In total, 847 (6.03%) AEs were reported. The most common AEs included subcutaneous bleeding and hematomas (370, 2.64%), followed by discomfort (109, 0.78%) and residual pain at insertion points (94, 0.67%). No infections or serious AEs were reported. Conclusions: Acupuncture and moxibustion performed in educational facilities in Japan were safe because most of the AEs reported were mild and transient. However, the risk cannot be defined definitely because the survey sample size was too small. PMID- 28736593 TI - Successful Treatment of Achilles Tendinopathy with Electroacupuncture: Two Cases. AB - Background: Achilles tendinopathy is a common injury for active patient populations and is challenging to treat. Acupuncture tendon-based therapy was first described in the Yellow Emperor's Classic of Internal Medicine. In modern times, specific techniques have been described poorly in the literature. The aim of this case report is to describe a new technique of acupuncture for the treatment of Achilles tendinopathy and provide 2 illustrative cases. Cases: Treatments for the 2 patients were performed in a deployed military treatment facility. SERIN(r) 0.25 mm * 40 mm needles placed at BL 60, BL 61, KI 3, and KI 4, with needles directed into the Achilles tendon of each patient. Needles were inserted until a firm catch of the needle entering the tendon was discerned. Energy was placed from KI 3(-) -> KI 4(+) and BL61 (-) -> BL 60(+) at 30 Hz for 15 minutes. Results: Both patients reported symptomatic reduction in Achilles tendinopathy pain and functional improvement following the described treatments. Conclusions: This case series describes two cases of successful Achilles tendinopathy therapy using direct tendon needle insertion with electrostimulation. This novel technique may provide an effective adjunct to traditional therapies in the treatment of Achilles tendinopathy. PMID- 28736595 TI - Abstracts and Commentaries on Key Articles in the Literature. PMID- 28736594 TI - How Do You Treat Osteoarthritis in Your Practice? PMID- 28736596 TI - Highlights of Modern Acupuncture Research: An Interview with Dr. Gerhard Litscher. PMID- 28736597 TI - Management of Fractures in the Edentulous Mandible. PMID- 28736598 TI - Development of a Virtual Reality Coping Skills Game to Prevent Post Hospitalization Smoking Relapse in Tobacco Dependent Cancer Patients. AB - Many hospitalized smokers return to smoking after hospital discharge even though continued smoking can compromise treatment effectiveness, reduce survival, increase risk of disease recurrence, and impair quality of life. After leaving a smoke-free hospital, patients encounter smoking cues at home, such as family members who smoke or emotional triggers such as stress, which can elicit powerful urges to smoke and lead to smoking relapse. Enabling smokers to experience such urges in a controlled setting while providing the ability to practice coping skills may be a useful strategy for building quitting self-efficacy. We are developing a virtual reality coping skills (VRCS) game to help hospitalized smokers practice coping strategies to manage these triggers in preparation for returning home after hospitalization. Our multidisciplinary team developed a prototype VRCS game using Second Life, a platform that allowed rapid construction of a virtual reality environment. The prototype contains virtual home spaces (e.g., living room, kitchen) populated with common triggers to smoke and a "toolkit" with scripted actions that enable the avatar to rehearse various coping strategies. Since eliciting and managing urges to smoke is essential to the game's utility as an intervention, we assessed the ability of the prototype virtual environment to engage former smokers in these scenarios. We recruited eight former smokers with a recent history of hospitalization and guided each through a VRCS scenario during which we asked the patient to evaluate the strength of smoking urges and usefulness of coping strategies. Initial data indicate that patients report high urges to smoke (mean = 8.8 on a 10 point scale) when their avatar confronted virtual triggers such as drinking coffee. Patients rated virtual practice of coping strategies, such as drinking water or watching TV, as very helpful (mean = 8.4 on a 10 point scale) in reducing these urges. With further development, this VRCS game may have potential to provide low cost, effective behavioral rehearsal to prevent relapse to smoking in hospitalized patients. PMID- 28736599 TI - [ATTITUDES TOWARDS SEXUAL COMMUNICATION BETWEEN PARENTS AND ADOLESCENTS IN PUERTO RICO]. AB - Communication between parents and adolescents about sexuality faces challenges due in part to sociocultural factors. This study aimed to document the attitudes of parents and adolescents about communication regarding sexuality. The results emanate from the baseline measurement of the Cuidalos Project. The presented data is part of a larger study that aimed to evaluate a web-based module to foster communications between parents and adolescents (13-17 years of age) on health related issues. In this article, we present the baseline data in which participants answered questions on their comfort when talking about sexual health issues. The sample was composed of 458 parent/adolescent dyads (n=916). We carried out a frequency and central tendency analysis of the gathered data. The average age for adolescents was 15 years of age, and 15% were sexually active. Adolescents reported better attitudes towards sexual communication than parents. Still, parents understood that they shared sufficient information on sexuality related topics. Parents and adolescents reported some level of difficulty and lack of comfort when talking about specific prevention methods. Results highlight the need to incorporate parents into interventions geared for adolescents and their sexual health. In Puerto Rico, it is necessary to develop programs that aim to reduce high-risk sexual activity among adolescents. PMID- 28736600 TI - Equivalence Tests: A Practical Primer for t Tests, Correlations, and Meta Analyses. AB - Scientists should be able to provide support for the absence of a meaningful effect. Currently, researchers often incorrectly conclude an effect is absent based a nonsignificant result. A widely recommended approach within a frequentist framework is to test for equivalence. In equivalence tests, such as the two one sided tests (TOST) procedure discussed in this article, an upper and lower equivalence bound is specified based on the smallest effect size of interest. The TOST procedure can be used to statistically reject the presence of effects large enough to be considered worthwhile. This practical primer with accompanying spreadsheet and R package enables psychologists to easily perform equivalence tests (and power analyses) by setting equivalence bounds based on standardized effect sizes and provides recommendations to prespecify equivalence bounds. Extending your statistical tool kit with equivalence tests is an easy way to improve your statistical and theoretical inferences. PMID- 28736601 TI - Classification review of dental adhesive systems: from the IV generation to the universal type. AB - Adhesive dentistry has undergone great progress in the last decades. In light of minimal-invasive dentistry, this new approach promotes a more conservative cavity design, which relies on the effectiveness of current enamel-dentine adhesives. Adhesive dentistry began in 1955 by Buonocore on the benefits of acid etching. With changing technologies, dental adhesives have evolved from no-etch to total etch (4th and 5th generation) to self-etch (6th, 7th and 8th generation) systems. Currently, bonding to dental substrates is based on three different strategies: 1) etch-and-rinse, 2) self-etch and 3) resin-modified glass-ionomer approach as possessing the unique properties of self-adherence to the tooth tissue. More recently, a new family of dentin adhesives has been introduced (universal or multi-mode adhesives), which may be used either as etch-and-rinse or as self-etch adhesives. The purpose of this article is to review the literature on the current knowledge for each adhesive system according to their classification that have been advocated by many authorities in most operative/restorative procedures. As noted by several valuable studies that have contributed to understanding of bonding to various substrates helps clinicians to choose the appropriate dentin bonding agents for optimal clinical outcomes. PMID- 28736603 TI - Effects of different kinds of beers on the surface roughness of glazed and polished methacrylate and Silorane-based composites: a 1-month study. AB - BACKGROUND: The aim of this in vitro study was to evaluate the effect of different kind of beers on the surface roughness of glazed and polished methacrylate- and Silorane-based resin composites after different immersion periods. METHODS: Methacrylate-based resin composites (Tetric N-Ceram, Ceram-X) and a Silorane-based resin composite (Filtek Silorane) were tested in the study. A total of 126 specimens (n=42 for each composite) were fabricated using a cylindrical custom metal mould. Surface roughness measurement was performed using a profilometer at baseline and after a 1-week and 1-month immersion in different kind of beers or distilled water. The results were analysed using repeated measure ANOVA and Tukey's HSD test (alpha=0.05). RESULTS: Repeated measure ANOVA results revealed that immersion period was a significant factor in the surface roughness of the tested specimens (p<0.001). The lowest surface roughness values were obtained with the specimens' polished Optidisc+BisCover LV. Regardless of the polishing systems used, Tetric N-Ceram showed the statistically lowest surface roughness values (p<0.05), whereas Filtek Silorane showed the highest surface roughness (p<0.001). CONCLUSION: The surface roughness values of the tested resin composites were affected by the polishing procedure used, the exposure time in the solutions and the type of composite resin. PMID- 28736602 TI - Radiographic technical quality of root canal treatment performed by a new rotary single-file system. AB - AIM: The aim of the present study was to evaluate radiographically the technical quality of root canal filling performed by postgraduate students with a new single-file Nickel-Titanium System (F6 Skytaper Komet) in clinical practice. METHODS: Records of 74 patients who had received endodontic treatment by postgraduate students at the School of Dentistry, Faculty of Medicine, University of Pavia in the period between September 2015 and April 2016 were collected and examined: the final sample consisted 114 teeth and 204 root canals. The quality of endodontic treatment was evaluated by examining the length of the filling in relation to the radiographic apex, the density of the obturation according to the presence of voids and the taper of root canal filling. Chi-squared analysis was used to determine statistically significant differences between the technical quality of root fillings according to tooth's type, position and curvature. RESULTS: The results showed that 75,49%, 82,84% and 90,69% of root filled canals had adequate length, density and taper respectively. CONCLUSIONS: Overall, the technical quality of root canal fillings performed by postgraduates students was acceptable in 60,78% of the cases. PMID- 28736604 TI - Comparison between three glass fiber post cementation techniques. AB - OBJECTIVE: The aim of this experimental study was to compare the traditional cement systems with those of the latest generation, to assess if indeed these could represent of viable substitutes in the cementation of indirect restorations, and in the specific case of endodontic posts. METHODS: The assessment of the validity of the cementing methods was performed according to the test of the push-out, conducted on sections obtained from the roots of treated teeth. The samples were divided into three groups. Group A (10 samples): etching for 30 seconds with 37% orthophosphoric acid (Superlux-Thixo-etch-DMG) combined with a dual-curing adhesive system (LuxaBond-Total Etch-DMG), dual-cured resin-composite cement (LuxaCore-DMG) and glass fiber posts (LuxaPost-DMG). Group B (10 samples): self-adhesive resin cement (Breeze-Pentron Clinical) and glass fiber posts (LuxaPost-DMG). Group C (10 samples): 3 steps light-curing, self etching, self-conditioning bonding agent (Contax-Total-etch-DMG), dual-cured resin-composite cement (LuxaCore-DMG) and glass fiber posts (LuxaPost-DMG). The survey was conducted by examining the breaking resistance of the post-cement tooth complex, subjected to a mechanical force. Statistical analysis was performed using SPSS Inc. ver. 13.0, Chicago, IL, USA. RESULTS: Group A values of bond strenth ranged from a minimum of 10.14 Mpa to a maximum value of 14.73 Mpa with a mean value of 12.58 Mpa. In Group B the highest value of bond strength was 6.54 Mpa and the minimum 5.55 Mpa. The mean value of the bond strength for the entire group was 6.58 Mpa. In Group C the highest bond strength was 6.59 Mpa whereas the lowest bond strength was 4.84 Mpa. Mean value of the bond strength of Group C was calculated at 5.7 Mpa. CONCLUSIONS: Etching with orthophosphoric acid combined with a dual-curing adhesive system and a dual-cured resin-composite cement was the technique that guaranteed the highest bond strength. Lowest bond strength values were obtained when dual self-adhesive cement was used. PMID- 28736605 TI - Minimally invasive orthodontics: elastodontic therapy in a growing patient affected by Dentinogenesis Imperfecta. AB - AIM: The aim of the study was to report the use of an elastodontic therapy in a growing patient affected by Dentinogenesis Imperfecta, second class malocclusion, deep bite and lower arch crowding from the deciduous dentition to permanent one. CASE REPORT: At first, the 5-year-old patient was treated with an elastodontic device known as "Nite-Guide". When the patient was 7 years old, during her first permanent molars and incisors eruption and after optimal house-practices, an Occlus-o-Guide Series G was placed at night and on daylight (two hours a day) performing exercises aimed to activate facial muscles and facilitate the deep bite reopening. At 9 years of age, with totally deep bite resolution, she used the Occluso-Guide only at night to hold down previous results and follow patient's dental growth. At 11 years of age, after successful teeth switching, we prescribed an Occlus-o-Guide Series N, which is functional for permanent dentition and guaranteed an eruptive guide for last dental elements. CONCLUSIONS: This clinic case could be considered an example of approach for all those patients with systemic and/or dental diseases that do not allow adequate dental retention, which is necessary for most orthodontic appliances; elastodontic devices do not require adequate dental retention and define a minimum intervention on the surfaces of the teeth. PMID- 28736606 TI - Mandibular bone regeneration after bone slat technique. AB - BACKGROUND: The reconstruction of alveolar ridges for implant placement is still a challenging surgical procedure, especially in the case of extensive vertical and horizontal bone atrophy. OBJECTIVE: The objective of the present study was to evaluate the quantity and quality of newly regenerated bone; clinically by means of direct clinical measuring, ridges augmented by autogenous cortical bone associated with autogenous particulate bone graft in the posterior lower jaw defect. METHODS: For the preliminary study, a bone defects in partially edentulous in patient aged 52 years were selected to receive horizontal ridge augumentation prior autolougous bone block and particulate graft. The donor site was the ramus of the same side. Prior the clinical evaluation, periapical X-ray and the cone beam computerized tomography (CBCT) was observed the quality, quantity and the stability the soft and hard tissue healing process, final result and the outcome. RESULT: The bone augmentation achieved with this technique created the ideal bone volume of hard and soft tissue, in quantity and quality, for placement of implants. CONCLUSION: The surgical technique was found to be easy in terms of technique and surgical trauma. PMID- 28736607 TI - Typical versus delayed speech onset influences verbal reporting of autistic interests. AB - BACKGROUND: The distinction between autism and Asperger syndrome has been abandoned in the DSM-5. However, this clinical categorization largely overlaps with the presence or absence of a speech onset delay which is associated with clinical, cognitive, and neural differences. It is unknown whether these different speech development pathways and associated cognitive differences are involved in the heterogeneity of the restricted interests that characterize autistic adults. METHOD: This study tested the hypothesis that speech onset delay, or conversely, early mastery of speech, orients the nature and verbal reporting of adult autistic interests. The occurrence of a priori defined descriptors for perceptual and thematic dimensions were determined, as well as the perceived function and benefits, in the response of autistic people to a semi structured interview on their intense interests. The number of words, grammatical categories, and proportion of perceptual/thematic descriptors were computed and compared between groups by variance analyses. The participants comprised 40 autistic adults grouped according to the presence (N = 20) or absence (N = 20) of speech onset delay, as well as 20 non-autistic adults, also with intense interests, matched for non-verbal intelligence using Raven's Progressive Matrices. RESULTS: The overall nature, function, and benefit of intense interests were similar across autistic subgroups, and between autistic and non-autistic groups. However, autistic participants with a history of speech onset delay used more perceptual than thematic descriptors when talking about their interests, whereas the opposite was true for autistic individuals without speech onset delay. This finding remained significant after controlling for linguistic differences observed between the two groups. CONCLUSIONS: Verbal reporting, but not the nature or positive function, of intense interests differed between adult autistic individuals depending on their speech acquisition history: oral reporting of intense interests was characterized by perceptual dominance for autistic individuals with delayed speech onset and thematic dominance for those without. This may contribute to the heterogeneous presentation observed among autistic adults of normal intelligence. PMID- 28736608 TI - Interrelationship between insistence on sameness, effortful control and anxiety in adolescents and young adults with autism spectrum disorder (ASD). AB - BACKGROUND: Both self-regulation and insistence on sameness (IS) are related to anxiety, which is a common feature of individuals with autism spectrum disorder (ASD). Here, we aimed to characterise the IS-self-regulation-anxiety interrelationship by investigating the potential contribution made by self regulation, assessed via effortful control (EC), to the IS-anxiety relationship in a sample of adolescents and young adults with ASD. METHOD: Seventy-one older adolescents and younger adults with ASD (49 males, 22 females; Mage = 18.71 years, SD = 2.51, range 14.42-24.81) completed the Adult Repetitive Behaviour Questionnaire-2, Effortful Control Scale of the Adult Temperament Questionnaire and the DSM-5 Dimensional Anxiety Scales. RESULTS: IS was associated with both EC (r = -.39, p = .001) and anxiety (r = .45, p < .001), and anxiety was in turn associated with EC (r = -.44, p < .001). To characterise the nature of this interrelationship, two mediation analyses were performed using the serial mediation model in PROCESS with 5000 resamples in bootstrapping. There was a significant indirect effect of EC on anxiety, through IS (b = -.06; BCa 95% CI [ .13, -.02]), and indirect effect on anxiety through EC (b = 1.62; BCa 95% CI [.59, 3.24]) with the mediators accounting for 29.07 and 26.04% of the total effect, respectively. CONCLUSIONS: Our study provides the first exploration of the IS-anxiety-self-regulation link in ASD. The finding that lower levels of self regulation are related both to anxiety and IS behaviours points to self regulation as a viable intervention target for both anxiety and IS behaviours. PMID- 28736609 TI - Shifting livelihood strategies in northern Nigeria - extensified production and livelihood diversification amongst Fulani pastoralists. AB - This paper presents an in-depth investigation of the livelihood strategies of Fulani pastoralists in north central Nigeria. Results show a diversified crop livestock system aimed at spreading risk and reducing cattle offtake, adapted to natural resource competition and insecurity by extensification, with further diversification into off-farm activities to spread risk, increase livelihood security and capture opportunities. However, significant costs were associated with extensification, and integration of crop and livestock enterprises was limited. Mean total income per capita in the study area was $554 or $1.52/person/day with 42% of households earning less than 1.25/person/day. Income levels were positively correlated with income diversity and price received per animal sold, rather than herd size. The outcomes of this livelihood strategy were favourable across the whole community, but when individual households are considered, there was evidence of moderate economic inequality in total income, cash income and herd size (Gini coefficient 0.32, 0.35 and 0.43 respectively). The poorest households were quite vulnerable, with low assets, income and income diversity. Implications for sustainability are discussed given the likelihood that the negative trends of reduced access to natural resources and insecurity will continue. PMID- 28736610 TI - Dog bite injuries to humans and the use of breed-specific legislation: a comparison of bites from legislated and non-legislated dog breeds. AB - BACKGROUND: The primary objective of this study was to investigate if differences in dog bite characteristics exist amongst legislated and non-legislated dog breeds listed under breed-specific legislation in Ireland (age when bitten, anatomical bite locations, triggers for biting, victim's relationship with the dog, geographical location and owner presence, history of aggression, reporting bite incident to authorities, medical treatment required following the bite, and type of bite inflicted). A second objective of the current study was to investigate dog control officer's enforcement and perceptions of current legislation. Data for statistical analyses were collated through a nationally advertised survey, with Pearson Chi-square and Fisher's Exact Test statistical methods employed for analyses. A total of 140 incident surveys were assessed comprising of non-legislated (n = 100) and legislated (n = 40) dog bite incidents. RESULTS: Legislated breeds were significantly more likely to be perceived as aggressive and less fearful as triggers for biting compared to non legislated breeds (P = 0.003). Non-legislated breeds were more likely to inflict a bite with the owner present on own property and on a business premises compared to legislated breeds (P = 0.036). Non-legislated breeds were more likely to not be reported to the authorities before (P = 0.009), and after (P = 0.032) the bite occurred compared to legislated breeds. There were no significant differences observed between both groups for; age when the victim was bitten, bite location, relationship with the dog, history of aggression, outcome for the dog, if the dog bit again, and seeing a professional trainer or behaviourist. No significant difference was observed between both legislated and non-legislated groups for medical treatment required following the bite, and the type of bite inflicted. CONCLUSION: The present study results did not observe evidence of any differences between legislated and non-legislated for both the medical treatment to victims required following the bite, and the type of bite inflicted. The significant differences in bites being reported to authorities, perceived triggers for biting, and biting locations suggests distinctly differing perceptions relating to risk between legislated and non-legislated dog breeds. Further consequences relating to the introduction of breed-specific legislation in Ireland are discussed. PMID- 28721200 TI - Protein-bound polyphenols create "ghost" band artifacts during chemiluminescence based antigen detection. AB - Antigen detection during Western blotting commonly utilizes a horseradish peroxidase-coupled secondary antibody and enhanced chemiluminescent substrate. We utilized this technique to examine the impact of green tea-derived polyphenols on the binding of egg white protein-specific IgE antibodies from allergic human plasma to their cognate antigens. Our experiments unexpectedly showed that green tea-derived polyphenols, when stably complexed with egg white proteins, caused "ghost" band formation in the presence of horseradish peroxide. This study suggests that caution should be taken when evaluating polyphenol-bound proteins by enhanced chemiluminescence Western blotting using horseradish peroxidase and demonstrates that protein-bound polyphenols can be a source of "ghost" band artifacts on Western blots. PMID- 28736612 TI - Adipose-derived stem cells: Comparison between two methods of isolation for clinical applications. AB - BACKGROUND: Adipose-derived stem cells are recognized as being an effective mesenchymal stem cell population with enormous potential in different fields of regenerative medicine and stem cell therapy. Although there is unanimous agreement on the harvesting procedure for adipose tissue, there are various protocols for adipose-derived stem cell isolation. The aim of this study was compare two methods of adipose-derived stem cells (ASCs) isolation, one based on a mechanical + enzymatic (ME) procedure and the other one exclusively mechanical (MC), in order to determine which one was superior to the other in accordance with current European and US legislation. METHODS: We reported step by step the two different methods ASCs isolation by comparing them. The ME procedure included the use of a centrifuge, an incubator and collagenase digestion solution (Collagenase NB 6 GMP Grade 17458; Serva GmbH, Heidelberg, Germany). The MC procedure was performed by vibrating shaker and centrifuge, both placed in a laminar airflow bench. RESULTS: With the ME procedure, a mean of 9.06 * 105 ASCs (range, 8.4 to 9.72 * 105; SD +/- 6.6 * 105) was collected, corresponding to 25.9% of the total number of harvested cells. With the MC procedure, a mean of 5 * 105 ASCs (range: 4.0 to 6.0 * 105; SD, +/-1 * 105) was collected, corresponding to 5% of the total number of harvested cells. CONCLUSION: Based on data collected, from the same amount of lipoaspirate the ME procedure allowed to isolate a greater number of ASCs (25,9%) compared to the MC one (5%). PMID- 28736613 TI - CD200 modulates macrophage cytokine secretion and phagocytosis in response to poly(lactic co-glycolic acid) microparticles and films. AB - Biocompatibility is a major concern for developing biomaterials used in medical devices, tissue engineering and drug delivery. Poly(lactic-co-glycolic acid) (PLGA) is one of the most widely used biodegradable materials, yet still triggers a significant foreign body response that impairs healing. Immune cells including macrophages respond to the implanted biomaterial and mediate the host response, which can eventually lead to device failure. Previously in our laboratory, we found that CD200, an immunomodulatory protein, suppressed macrophage inflammatory activation in vitro and reduced local immune cell infiltration around a biomaterial implant. While in our initial study we used polystyrene as a model material, here we investigate the effect of CD200 on PLGA, a commonly used biomaterial with many potential clinical applications. We fabricated PLGA with varied geometries, modified their surfaces with CD200, and examined macrophage cytokine secretion and phagocytosis. We found that CD200 suppressed secretion of the pro-inflammatory cytokine TNF-alpha and enhanced secretion of the anti inflammatory cytokine IL-10, suggesting a role for CD200 in promoting wound healing and tissue remodeling. In addition, we found that CD200 increased phagocytosis in both murine macrophages and human monocytes. Together, these data suggest that modification with CD200 leads to a response that simultaneously prevents inflammation and enhances phagocytosis. This immunomodulatory feature may be used as a strategy to mitigate inflammation or deliver drugs or anti inflammatory agents targeting macrophages. PMID- 28736614 TI - Tracheal granuloma 7 years after extubation. AB - Tracheal granuloma can cause severe stenosis long after extubation. When a patient with a history of endobronchial intubation has an intratracheal tumour, we should consider the possibility of this condition. PMID- 28736615 TI - Pulmonary arteriovenous malformations complicated by splenic infarction and abscess. AB - Pulmonary arteriovenous malformation (PAVM) is an abnormal blood vessel connecting a pulmonary artery and a vein, and is accompanied by paradoxical embolism to other organs due to a right-to-left shunt. We report the case of a 66 year-old woman with PAVM complicated by splenic infarction and abscess. Although the PAVM had been detected on a chest image 2 years previously, and she had been advised to have further investigations, she decided not to follow this further at the time. She then visited our hospital complaining of worsening dyspnoea on exertion. Detailed examinations revealed splenic infarction and abscessation due to PAVM. PAVM embolization was performed after antibiotic treatment. It is very rare for PAVM to be complicated by splenic infarction and abscess. Regardless of its size, embolization of a PAVM as soon as possible can reduce not only the risk of central nervous system complications, but also the risk of splenic infarction and abscess. PMID- 28736616 TI - MALDI-TOF MS contribution to the diagnosis of Campylobacter rectus multiple skull base and brain abscesses. AB - Campylobacter rectus is rarely associated with invasive infection. Both the isolation and the identification requirements of C. rectus are fastidious, probably contributing to an underestimation of its burden. We report the case of a 66-year-old man who developed several skull base and intracerebral abscesses after dental intervention. Campylobacter rectus was isolated from the brain biopsy. Within 45 minutes of reading the bacterial plate, the strain was accurately identified by MALDI-TOF MS. This rapid identification avoided the extra costs and delays present with 16S rRNA gene sequencing and allowed for a rapid confirmation of the adequacy of the empirical antibiotic treatment. PMID- 28736617 TI - An investigation of desalination by nanofiltration, reverse osmosis and integrated (hybrid NF/RO) membranes employed in brackish water treatment. AB - BACKGROUND: As an appropriate tool, membrane process is used for desalination of brackish water, in the production of drinking water. The present study aims to investigate desalination processes of brackish water of Qom Province in Iran. METHODS: This study was carried out at the central laboratory of Water and Wastewater Company of the studied area. To this aim, membrane processes, including nanofiltration (NF) and reverse osmosis (RO), separately and also their hybrid process were applied. Moreover, water physical and chemical parameters, including salinity, total dissolved solids (TDS), electric conductivity (EC), Na+1 and Cl-1 were also measured. Afterward, the rejection percent of each parameter was investigated and compared using nanofiltration and reverse osmosis separately and also by their hybrid process. The treatment process was performed by Luna domestic desalination device, which its membrane was replaced by two NF90 and TW30 membranes for nanofiltration and reverse osmosis processes, respectively. All collected brackish water samples were fed through membranes NF90-2540, TW30-1821-100(RO) and Hybrid (NF/RO) which were installed on desalination household scale pilot (Luna water 100GPD). Then, to study the effects of pressure on permeable quality of membranes, the simulation software model ROSA was applied. RESULTS: Results showed that percent of the salinity rejection was recorded as 50.21%; 72.82 and 78.56% in NF, RO and hybrid processes, respectively. During the study, in order to simulate the performance of nanofiltartion, reverse osmosis and hybrid by pressure drive, reverse osmosis system analysis (ROSA) model was applied. The experiments were conducted at performance three methods of desalination to remove physic-chemical parameters as percentage of rejections in the pilot plant are: in the NF system the salinity 50.21, TDS 43.41, EC 43.62, Cl 21.1, Na 36.15, and in the RO membrane the salinity 72.02, TDS 60.26, EC 60.33, Cl 43.08, Na 54.41. Also in case of the rejection in hybrid system of those parameters and ions included salinity 78.65, TDS 76.52, EC 76.42, Cl 63.95, and Na 70.91. CONCLUSIONS: Comparing rejection percent in three above-mentioned methods, it could be concluded that, in reverse osmosis process, ions and non-ion parameters rejection ability were rather better than nanofiltration process, and also better in hybrid compared to reverse osmosis process. The results reported in this paper indicate that the integration of membrane nanofiltration with reverse osmosis (hybrid NF/RO) can be completed by each other probably to remove salinity, TDS, EC, Cl, and Na. PMID- 28736618 TI - A 15q14 microdeletion involving MEIS2 identified in a patient with autism spectrum disorder. AB - We describe a 9-year-old male patient with a 15q14 microdeletion including MEIS2. The patient was born with a ventricular septal defect and submucosal cleft. Mild developmental disability and autism spectrum disorder diagnosed in childhood were also considered to be consequences of MEIS2 haploinsufficiency. The relatively mild developmental delay and lack of additional phenotypic features in this patient indicate that only MEIS2 plays an important role in the observed phenotypic features in the heterozygous state. PMID- 28736619 TI - The role of orthobiologics in foot and ankle surgery: Allogenic bone grafts and bone graft substitutes. AB - Orthobiologics are biological substances that are used therapeutically for their positive effects on healing skeletal and soft-tissue injuries. The array of orthobiological products currently available to the foot and ankle surgeon is wide, and includes bone allografts, bone substitutes, growth factors, and chondral scaffolds. Nonetheless, despite the surge in interest and usage of orthobiologics, there remains a relative paucity of research addressing their specific applications in foot and ankle surgery. In this review, we attempt to provide an overview of the literature on commonly available allogenic bone grafts and bone substitutes.There is Level II, III and IV evidence addressing allogenic bone grafts in primary arthrodesis and osteotomy procedures in foot and ankle surgery, which compares favourably with autogenic bone grafts in terms of fusion rates and clinical outcomes (often with fewer complications), and supports a Grade B recommendation for its use.Pertaining to bone substitutes, the multiplicity of products, coupled with a lack of large prospective clinical trials, makes firm recommendations difficult. Level II and IV studies of calcium phosphate and calcium sulphate products in displaced intra-articular calcaneal fractures have found favourable results in addressing bone voids, maintaining reduction and promoting union, meriting a Grade B recommendation. Evidence for TCP is limited to level IV studies reporting similarly good outcomes in intra articular calcaneal fractures, warranting a Grade C recommendation. The use of demineralised bone matrix products in hindfoot and ankle fusions has been described in Level II and III studies, with favourable results in achieving fusion and good clinical outcomes, supporting a Grade B recommendation for these indications.Overall, despite the general lack of high-level evidence in foot and ankle surgery, allogenic bone grafts and bone substitutes continue to hold front line roles in treating the bone defects encountered in trauma, tumour, and deformity correction surgery. However, more investigation is required before firm recommendations can be made. Cite this article: EFORT Open Rev 2017;2:272-280. DOI: 10.1302/2058-5241.2.160044. PMID- 28736620 TI - Peroneal tendon disorders. AB - Pathological abnormality of the peroneal tendons is an under-appreciated source of lateral hindfoot pain and dysfunction that can be difficult to distinguish from lateral ankle ligament injuries.Enclosed within the lateral compartment of the leg, the peroneal tendons are the primary evertors of the foot and function as lateral ankle stabilisers.Pathology of the tendons falls into three broad categories: tendinitis and tenosynovitis, tendon subluxation and dislocation, and tendon splits and tears. These can be associated with ankle instability, hindfoot deformity and anomalous anatomy such as a low lying peroneus brevis or peroneus quartus.A thorough clinical examination should include an assessment of foot type (cavus or planovalgus), palpation of the peronei in the retromalleolar groove on resisted ankle dorsiflexion and eversion as well as testing of lateral ankle ligaments.Imaging including radiographs, ultrasound and MRI will help determine the diagnosis. Treatment recommendations for these disorders are primarily based on case series and expert opinion.The aim of this review is to summarise the current understanding of the anatomy and diagnostic evaluation of the peroneal tendons, and to present both conservative and operative management options of peroneal tendon lesions. Cite this article: EFORT Open Rev 2017;2:281-292. DOI: 10.1302/2058-5241.2.160047. PMID- 28736621 TI - Percutaneous cement augmentation for osteoporotic vertebral fractures. AB - Thoracolumbar vertebral fracture incidents usually occur secondary to a high velocity trauma in young patients and to minor trauma or spontaneously in older people.Osteoporotic vertebral fractures are the most common osteoporotic fractures and affect one-fifth of the osteoporotic population.Percutaneous fixation by 'vertebroplasty' is a tempting alternative for open surgical management of these fractures.Despite discouraging initial results of early trials for vertebroplasty, cement augmentation proved its superiority for the treatment of symptomatic osteoporotic vertebral fracture when compared with optimal medical treatment.Early intervention is also gaining ground recently.Kyphoplasty has the advantage over vertebroplasty of reducing kyphosis and cement leak.Stentoplasty, a new variant of cement augmentation, is also showing promising outcomes.In this review, we describe the additional techniques of cement augmentation, stressing the important aspects for success, and recommend a thorough evaluation of thoracolumbar fractures in osteoporotic patients to select eligible patients that will benefit the most from percutaneous augmentation. A detailed treatment algorithm is then proposed. Cite this article: EFORT Open Rev 2017;2:293-299. DOI: 10.1302/2058-5241.2.160057. PMID- 28736622 TI - Nutrition and osteoporosis prevention for the orthopaedic surgeon: A wholefoods approach. AB - Osteoporosis is a prevalent and debilitating condition with no signs of subsiding. Rising numbers of people consuming nutrient-poor diets coupled with ageing populations and sedentary lifestyles appear to be the main drivers behind this.While the nutrients calcium and vitamin D have received most attention, there is growing evidence that wholefoods and other micronutrients have roles to play in primary and potentially secondary osteoporosis prevention.Until recently, calcium and vitamin D were regarded as the main nutrients essential to bone health but now there are emerging roles for iron, copper and selenium, among others.Fruit and vegetables are still not being eaten in adequate amounts and yet contain micronutrients and phytochemicals useful for bone remodelling (bone formation and resorption) and are essential for reducing inflammation and oxidative stress.There is emerging evidence that dried fruits, such as prunes, provide significant amounts of vitamin K, manganese, boron, copper and potassium which could help to support bone health.Just 50 g of prunes daily have been found to reduce bone resorption after six months when eaten by osteopaenic, postmenopausal women.Dairy foods have an important role in bone health. Carbonated drinks should not replace milk in the diet.A balanced diet containing food groups and nutrients needed for bone health across the whole lifecycle may help to prevent osteoporosis.Greater efforts are needed to employ preventative strategies which involve dietary and physical activity modifications, if the current situation is to improve. Cite this article: EFORT Open Rev 2017;2:300 308. DOI: 10.1302/2058-5241.2.160079. PMID- 28736623 TI - A literature review of cost-effectiveness of intravenous recombinant tissue plasminogen activator for treating acute ischemic stroke. AB - BACKGROUND: Intravenous recombinant tissue plasminogen activator (IV rtPA) is recommended treatment for acute ischemic stroke patients, but the cost effectiveness of IV rtPA within different time windows after the onset of acute ischemic stroke is not well reviewed. AIMS: To conduct a literature review of the cost-effectiveness studies about IV rtPA by treatment times. SUMMARY OF REVIEW: A literature search was conducted using MEDLINE, EMBASE, CINAHL and Cochrane Library, with the key words acute ischemic stroke, tissue plasminogen activator, cost, economic benefit, saving, and incremental cost-effectiveness analysis. The review is limited to original research articles published during 1995-2016 in English-language peer-reviewed journals. We found 16 studies meeting our criteria for this review. Nine of them were cost-effectiveness studies of IV rtPA treatment within 0-3 hours after stroke onset, 2 studies within 3-4.5 hours, 3 studies within 0-4.5 hours, and 2 study within 0-6 hours. IV rtPA is a cost saving or a cost-effectiveness strategy from most of the study results. Only one study showed incremental cost-effectiveness ratio of IV rtPA within one year was marginally above $50,000 per QALY threshold. IV rtPA within 0-3 hours after stroke led to cost savings for lifetime or 30 years, and IV rtPA within 3-4.5 hours after stroke increased costs but still was cost-effective. CONCLUSIONS: The literature generally showed that intravenous IV rtPA was a dominant or a cost effective strategy compared to traditional treatment for acute ischemic stroke patients without IV rtPA. The findings from the literature lacked generalizability because of limited data and various assumptions. PMID- 28736625 TI - Entering the molecular era of gastrointestinal oncology: current updates and challenges. PMID- 28736624 TI - Lyme and Dopaminergic Function: Hypothesizing Reduced Reward Deficiency Symptomatology by Regulating Dopamine Transmission. AB - The principal vector of Lyme disease in the United States is Ixodes scapularis: black legged or deer ticks. There is increased evidence that those infected may be plagued by anxiety or depression as well. Researchers have identified transcripts coding for two putative cytosolic sulfotransferases in these ticks, which recognized phenolic monoamines as their substrates. It is hypothesized that protracted Lyme disease sequelae may be due to impairment of dopaminergic function of the brain reward circuitry. The subsequent recombinant proteins exhibited sulfotransferase function against two neurotransmitters: dopamine and octopamine. This, in itself, can reduce dopamine function leading to many Reward Deficiency Syndrome behaviors, including depression and possibly, anxiety. In fact, it was shown that activity of Ixosc Sult 1 and Sult 2 in the Ixodid tick salivary glands might contain inactivation of the salivation signal through sulfonation of either dopamine or octopamine. This infraction results in a number of clinically observed mood changes, such as anxiety and depression. In fact, there are common symptoms observed for both Parkinson and Lyme diseases. The importance of understanding the mechanistic and neurobiological effects of Lyme on the central nervous system (CNS) provides the basis for pro-dopamine regulation as a treatment. WC 195. PMID- 28736626 TI - Molecular landscape and sub-classification of gastrointestinal cancers: a review of literature. AB - The historical approach of diagnosing cancer types based entirely on anatomic origin and histologic features, and the "one-size-fit-all" therapeutic approach, are inadequate in modern cancer treatment. From decades of research we now know that cancer is a highly heterogeneous disease driven by complex genetic or epigenetic alterations. The advent of various high throughput molecular tools has now enabled us to view and sub-classify each cancer type based on their distinct molecular features, in addition to histologic classification, with the promise of individualized treatment strategies tailored towards each specific subtype to improve patient outcomes. In this review, we have made an effort to systematically review the most up-to-date, leading literature in molecular analysis and/or subtyping of major gastrointestinal cancers. These include esophageal squamous cell carcinoma (ESCC), gastric cancer (GC) adenocarcinoma, pancreatic ductal adenocarcinoma (PDAC), hepatocellular carcinoma (HCC), gallbladder cancer (GBC), and colorectal cancer (CRC). For each cancer type we summarized the global mutational landscape, subgroup classification based on genomics, epigenetics, gene expression and/or proteomic analysis, and their salient clinicopathological features. We have highlighted the actionable mutations or mutational pathways that could help guide targeted therapies in the future. PMID- 28736628 TI - Predictive and prognostic biomarkers in personalized gastrointestinal cancer treatment. AB - Biomarkers play an important role in the detection and management of cancer patients. In gastrointestinal cancer, there is increasing interest in their development and validation according to specific tumor type. Prognostic biomarkers enable identification of patients with a more aggressive tumor evolution, while predictive biomarkers permit the identification of patients with a higher probability of responding or not to a specific treatment. Several biomarkers are currently widely employed in gastrointestinal cancers. These include rat sarcoma-2 virus (RAS) which is used to identify colorectal cancer (CRC) patients who will not respond to anti-epidermal growth factor receptor (EGFR) agents, while in gastric cancer, anti-human epidermal growth factor receptor 2 (HER2) therapy has been shown to only be active in HER2-positive patients. In pancreatic cancer, BRCA is a tool used to differentiate patients who are likely to respond to platinum-based combination therapies and to benefit from poly (ADP-ribose) polymerase (PARP) inhibitors. This review provides an update of the main biomarkers currently used in colorectal, gastric and pancreatic cancers, and reviews those that are being developed. PMID- 28736627 TI - Personalized and precision medicine: integrating genomics into treatment decisions in gastrointestinal malignancies. AB - The advent of next generation sequencing (NGS) technologies has advanced our understanding of the intrinsic biology of different gastrointestinal (GI) tumor types. The use of novel, more efficient sequencing platforms has improved turnaround times of sequencing results. This is providing real time opportunities to put precision medicine to the test. A number of early phase clinical trials are testing targeted therapies in unique molecularly characterized subsets of patients (baskets). While basket studies are gaining momentum, treatment failures serve to remind us that shifting from a histology-driven to a histology-agnostic approach is unlikely to be a failure-free strategy for a number of tumor types as recently learnt from vemurafenib failure in BRAF mutated metastatic colorectal cancer (mCRC). GI malignancies are clinically and molecularly heterogeneous. Unfortunately, development of biomarkers of response to therapy as well as targeted therapies for GI adenocarcinomas has fallen behind compared to other malignancies. Trastuzumab is the only FDA approved targeted therapy for GI adenocarcinomas for which a biomarker of response (HER2 amplifications) is available. In addition, RAS mutations are known to predict lack of response to epidermal growth factor receptor (EGFR) inhibitors in advanced colorectal cancer (CRC) patients. However, NGS has recently revealed that a number of actionable genetic aberrations are present at low prevalence across different GI malignancies. Prospective randomized clinical trials will determine whether matching actionable aberration with targeted therapy will contribute to improve survival in patients with GI malignancies. Here, we review current evidence for targeted therapies in GI malignancies, as well as application and pitfalls of NGS including tissue testing and liquid biopsies. PMID- 28736629 TI - Biologic therapy in esophageal and gastric malignancies: current therapies and future directions. AB - Biologic agents, including targeted antibodies as well as immunomodulators, are demonstrating unparalleled development and study across the entire spectrum of human malignancy. This review summarizes the current state of biologic therapies for esophageal, esophagogastric, and gastric malignancies, including those that target human epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), c-Met, mechanistic target of rapamycin (mTOR) and immunomodulators. We focus primarily on agents that have been included in phase II and III clinical trials in locally advanced, progressive, or metastatic esophageal and gastric malignancies. At this time, only two biologic therapies are recommended by the National Comprehensive Cancer Network (NCCN): trastuzumab for patients with esophageal/esophagogastric or gastric adenocarcinomas with HER2 overexpression and ramucirumab, a VEGFR-2 inhibitor, as a second-line therapy for metastatic disease. However, recent reports of increases in overall and progression-free survival for agents including pertuzumab, apatinib, and pembrolizumab will likely increase the use of targeted biologic therapy in clinical practice for esophageal and gastric malignancies. PMID- 28736630 TI - Current biologics for treatment of biliary tract cancers. AB - Biliary tract cancers (BTC) is a group of malignancies that arise from the epithelial cells of the biliary tree. These cancers are typically classified by anatomic site of origin: intrahepatic cholangiocarcinoma (IHCC) and extrahepatic cholangiocarcinoma (EHCC), and gallbladder cancer (GBC). To date, complete surgical resection remains the mainstay of treatment especially for earlier stage disease. Unfortunately, most patients present with advanced or metastatic disease, when systemic chemotherapy is the only treatment option. Due to the paucity of effective treatments, BTCs have a dismal prognosis. There is a tremendous need to better understand the disease biology, discover new therapies, and improve clinical outcomes for this challenging disease. Next-generation sequencing has produced a more accurate and detailed picture of the molecular signatures in BTCs. The three BTC histologic subtypes are, in fact, quite molecularly distinct. IHCC commonly contain FGFR2 fusions and IDH 1 and 2 mutations, whereas EHCC and GBC tend to carry mutations in EGFR, HER2, and MAPK pathway. In light of this emerging knowledge, clinical trials have become more biomarker-driven, which allows capturing of subsets of patients that are most likely to respond to certain therapies. Many new and promising targeted therapeutics are currently in the pipeline. Here we review the genetic landscape of BTCs while focusing on new molecular targets and targeted therapeutics currently being investigated in biomarker-driven clinical trials. PMID- 28736632 TI - Biologics in bowel cancer. AB - Colorectal cancer is the third most common cancer in the United States and second leading cause of cancer death with over 50,000 patients expected to die from their disease in 2017. For patients who present at diagnosis with advanced disease the standard treatment is systemic chemotherapy. Over the last decade a number of biologic therapies have emerged as viable treatment options for advance colorectal cancer. When these new drugs are combined with chemotherapy survival is prolonged, often without a detriment to quality of life. In this chapter we will review the most active biologic options for treatment of colorectal cancer and place them in the context of a rapidly growing field. PMID- 28736631 TI - Shifting paradigm of developing biologics for the treatment of pancreatic adenocarcinoma. AB - Pancreatic adenocarcinoma is still widely considered as a deadly disease even though there are substantial therapeutic developments in the past decade. Using combinational chemotherapy regimens, represented by gemcitabine plus nab paclitaxel and FOLFIRINOX, was able to improve overall survival in patients with advanced disease to a limited extent. It has been a challenge to develop targeted therapies that are focused on the neoplasm cells of pancreatic adenocarcinoma. Recently, targeting the stroma and immune compartments of pancreatic adenocarcinoma has shown promising results. The paradigm of biologics drug development therefore has been shifted by extending to these exciting areas. Although some of the preclinical and clinical researches in targeting the tumor microenvironment of pancreatic adenocarcinoma have shown promising results, others have resulted in controversial findings. Both comprehensive and in-depth researches on the basic science of the tumor microenvironment of pancreatic adenocarcinoma are thus warranted for the development of effective biologics that target the tumor microenvironment. Moreover, an ideal treatment for pancreatic adenocarcinoma shall be a combination of targeting both neoplastic cells and the tumor microenvironment. PMID- 28736633 TI - Biologics in gastrointestinal and pancreatic neuroendocrine tumors. AB - The development of biologic agents has ushered in a new era of precision medicine, opening the door to new therapeutic options designed to intelligently target cancer cells and their promoting factors, while leaving normal cells relatively unharmed. Biologics for the treatment of neuroendocrine tumors (NETs) have followed in the footsteps of regimens targeting pathways upregulated in other cancers, including the vascular endothelial growth factor (VEGF) and the mammalian target of rapamycin (mTOR). Through a number of clinical trials, the mTOR inhibitor everolimus and the receptor tyrosine kinase (RTK) inhibitor sunitinib were recently approved for NETs. Other biologics such as the VEGF-A inhibitor bevacizumab have also demonstrated promising clinical activity in NETs. Interestingly, though trials have demonstrated the efficacy of everolimus and sunitinib in extending progression-free survival (PFS) in NETs, objective response rates (RR) are uniformly low, indicating that the primary effect of these drugs is maintenance of stable disease. Due to the relatively indolent nature of the more common, well-differentiated variety of NETs, stable disease is often a reasonable goal for NET patients. Well-differentiated NETs have been shown to be poor responders to cytotoxic chemotherapy, underlining the important role of biologics in treating and managing NETs and their hormonal symptoms. Ongoing and future trials are investigating a wide variety of biologic compounds in NETs, including other RTK inhibitors, mTOR pathway inhibitors, and immune checkpoint inhibitors. Within this review, we will discuss major trials leading up to the FDA approval of everolimus and sunitinib for NETs, as well as other promising biologics currently under investigation in NET clinical trials. PMID- 28736634 TI - Gastrointestinal stromal tumors (GISTs): point mutations matter in management, a review. AB - The therapeutic implications of the genomic alterations seen within the drivers of gastrointestinal stromal tumors (GIST) are among the best understood in all of solid tumors. Sequencing of cKIT and PDGFRalpha should be considered standard practice for the treatment of GIST patients. In this article, we will review the common mutations and how they are utilized in clinical management. In addition, we will review the rare D842V PDGFRalpha mutation and the diverse molecular group that lacks a mutation in either cKIT or PDGFRalpha (wild-type GIST) which are best treated on clinical trial. Finally, we will look forward at the future therapies that are ever evolving for management of GIST. Taken together, the scientific advances in understanding the molecular basis of GIST validates the importance of knowing and understanding the mutations that are present in any one patient. PMID- 28736635 TI - Immunotherapy in gastrointestinal cancers. AB - Gastrointestinal (GI) cancers such as gastric, esophageal, pancreas, hepatobiliary, colorectal and anal cancers are a major cause of cancer related mortality worldwide. Traditional treatment options such as chemotherapy, surgery, radiation therapy, monoclonal antibodies and anti-angiogenic agents have been the backbone of treatment of GI cancers in various stages. Current cancer research is moving forward to incorporate immunotherapies in the treatment of GI cancers either as single agent or in combination with current available treatment modalities. This review summarizes the existing and ongoing immunotherapies in the treatment of GI cancers. PMID- 28736636 TI - Biological agents in gastrointestinal cancers: adverse effects and their management. AB - Biological therapy comprises agents that by virtue of their unique mechanisms of action, are able to specifically incite a response against or target malignant cells. They differ from conventional chemotherapy with regard to mechanisms of action, indications and side effect profile. Biologic agents have revolutionized therapy for a number of malignancies. In the setting of gastrointestinal (GI) malignancies, agents targeting vascular endothelial growth factor (VEGF), human epidermal growth factor receptor 2 (Her2/Neu) and epidermal growth factor receptor (EGFR) have proven to be invaluable additions to chemotherapy. However, these agents bring with them a set of side effects attributable to their unique mechanisms of action. The anti VEGF agents-bevacizumab, aflibercept and ramucirumab, can result in renal and vascular complications such as hypertension, arterial thrombotic events (ATE), proteinuria and GI perforations. The anti EGFR agents classically cause dermatological toxicities, in addition to hypomagnesemia, which can be dose limiting for patients. Trastuzumab, a monoclonal antibody that targets Her2/Neu, is known to cause cardiotoxicity, especially when used with anthracyclines. Use of immunotherapy agents such as nivolumab is associated with the development immune related adverse events (irAEs). The use of these agents is expected to increase over the next few years and it is crucial that patients and practitioners are aware of their adverse effects and current management strategies. This review highlights the adverse events associated with the use of biologic and immunologic therapies in GI cancers, their incidence and current management strategies. PMID- 28736637 TI - Primary and acquired resistance to biologic therapies in gastrointestinal cancers. AB - Improvements in the understanding of cancer biology have led to therapeutic advances in the treatment of gastrointestinal cancers. Drugs which target the vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) pathways have led the way in colon cancer. Monoclonal antibodies (mAbs) such as bevacizumab, ramucirumab, cetuximab, and panitumumab, have improved progression free survival and overall survival (OS) for colorectal cancers and were quickly adopted. Human epidermal growth factor receptor 2 (HER2) has demonstrated significant benefit for gastroesophageal cancers and in the setting of HER2 amplification, trastuzumab in combination with chemotherapy has become the standard of care. However, responses have not been as durable nor as robust as once hoped. Mechanisms of resistance for each of these biologic compounds have been hypothesized and are in the process of being better elucidated. This review will approach the innate and acquired mechanisms of resistance of the above compounds. Additionally, we will explore some ongoing clinical trials to capitalize on the mechanisms of resistance in the hopes of retaining the promise of targeting these pathways. PMID- 28736638 TI - Cost-effectiveness of precision medicine in gastrointestinal stromal tumor and gastric adenocarcinoma. AB - Over the past 20 years, with the incorporation of genetic sequencing and improved understanding regarding the mechanisms of cancer growth/metastasis, novel targets and their associated treatments have emerged in oncology and are now regularly incorporated into the clinical care of patients in the US. Novel, more tumor specific, non-chemotherapy agents, including agents that are commonly used in the treatment of patients with gastric adenocarcinoma (GA) and gastrointestinal stromal tumor (GIST), fall under a broader treatment strategy, termed "precision medicine". While diagnostic testing and associated treatments in metastatic GA (mGA) are costly and may produce marginal benefit, those associated with GIST, despite being costly, produce significant improvements in patient outcomes. Despite the significant difference in impact, the agents associated with these cancers have similar acquisition costs. In this paper, we will review the current literature regarding cost and cost-effectiveness associated with precision medicine diagnosis and treatment strategies for GA and GIST. PMID- 28736639 TI - Promising therapeutics of gastrointestinal cancers in clinical trials. AB - Many novel therapeutics are being developed for patients with cancers along the gastrointestinal (GI) tract. These emerging agents are frequently classified by their biological targets such as tumor growth pathways, tumor metabolism, microenvironment, etc. Some agents targeting cancer growth pathways are based on existing clinically validated therapeutic targets, such as regorafenib for hepatocellular carcinoma (HCC), while other agents focus on newly identified targets, such as FGFR fusions in cholangiocarcinoma. Drugs modifying the immunosuppressive tumor microenvironment have emerged as an attractive area of clinical investigation. Moreover, drugs targeting the stem-cell like qualities of cancer and the tight junction protein claudin 18.2 have generated quite a lot of excitement in the field. In this paper, we will systemically review the recent promising agents and therapeutic strategies in GI cancers. PMID- 28736640 TI - Systematic review and a meta-analysis of hospital and surgeon volume/outcome relationships in colorectal cancer surgery. AB - BACKGROUND: Numerous hospitals worldwide are considering setting minimum volume standards for colorectal surgery. This study aims to examine the association between hospital and surgeon volume on outcomes for colorectal surgery. METHODS: Two investigators independently reviewed six databases from inception to May 2016 for articles that reported outcomes according to hospital and/or surgeon volume. Eligible studies included those in which assessed the association hospital or surgeon volume with outcomes for the surgical treatment of colon and/or rectal cancer. Random effects models were used to pool the hazard ratios (HRs) for the association between hospital/surgeon volume with outcomes. RESULTS: There were 47 articles pooled (1,122,303 patients, 9,877 hospitals and 9,649 surgeons). The meta-analysis demonstrated that there is a volume-outcome relationship that favours high volume facilities and high volume surgeons. Higher hospital and surgeon volume resulted in reduced 30-day mortality (HR: 0.83; 95% CI: 0.78-0.87, P<0.001 & HR: 0.84; 95% CI: 0.80-0.89, P<0.001 respectively) and intra-operative mortality (HR: 0.82; 95% CI: 0.76-0.86, P<0.001 & HR: 0.50; 95% CI: 0.40-0.62, P<0.001 respectively). Post-operative complication rates depended on hospital volume (HR: 0.89; 95% CI: 0.81-0.98, P<0.05), but not surgeon volume except with respect to anastomotic leak (HR: 0.59; 95% CI: 0.37-0.94, P<0.01). High volume surgeons are associated with greater 5-year survival and greater lymph node retrieval, whilst reducing recurrence rates, operative time, length of stay and cost. The best outcomes occur in high volume hospitals with high volume surgeons, followed by low volume hospitals with high volume surgeons. CONCLUSIONS: High volume by surgeon and high volume by hospital are associated with better outcomes for colorectal cancer surgery. However, this relationship is non-linear with no clear threshold of effect being identified and an apparent ceiling of effect. PMID- 28736641 TI - Bone marrow tolerance during postoperative chemotherapy in colorectal carcinomas. AB - BACKGROUND: This study seeks to quantify and compare bone marrow tolerance during postoperative chemotherapy therapy between rectal cancer vs. colon cancer patients. During rectal cancer treatment, patients receive neoadjuvant chemoradiation (CRT) irradiation which can exacerbate the hematologic toxicity (HT) via incidental irradiation of the pelvic bone marrow (PBM) during myelosuppressive postoperative chemotherapy. In contrast, colon cancer patients receive the same postoperative myelosuppressive chemotherapy but do not routinely receive preoperative chemoradiation therapy. This comparison will help elucidate the lasting myelosuppressive effects of incidental pelvic bone marrow (PBM) irradiation on rectal cancer patients during neoadjuvant preoperative chemoradiation therapy. METHODS: Rectal cancer patients treated with preoperative CRT followed by postoperative 5-Fluorouracil and oxaliplatin (OxF) chemotherapy (n=35) were compared to colon cancer patients who received only postoperative OxF chemotherapy (n=42). End points were >= grade 3 hematologic toxicity (HT3) or hematologic event (HE) defined as >= grade 2 HT and a dose reduction in OxF. Wilcoxon rank sum test tested continuous variables and Chi-squared test measured differences in categorical variables. HT3 and HE probability during postoperative chemotherapy was estimated with Kaplan-Meier curves and Cox regression analysis. RESULTS: During OxF chemotherapy, 40.0% (n=14) of rectal cancer patients experienced HT3 compared to 26.1% (n=11) of colon cancer patients (P=0.4). HE was experienced by 48% (n=17) of rectal cancer patients compared to 36% (n=15) of colon cancer patients (P=0.36). Rectal cancer patients were likelier to experience HT3 on multivariable cox regression analysis, controlling for several clinical covariates, with a hazard ratio (HR) of 2.49, [(95% CI: 1.02-6.02), P=0.045] than colon cancer patients. While rectal cancer patients were more likely to experience HE than colon cancer patients on multivariable Cox regression analysis with a HR of 1.8 (95% CI: 0.95-3.75), this only trended in statistical significance, P=0.07. CONCLUSIONS: Rectal cancer patients are more likely than colon cancer patients to experience hematologic toxicities impacting the tolerance of standard of care chemotherapeutics during adjuvant therapy. Focused PBM sparing during radiation therapy for rectal cancer patients may improve tolerance of myelosuppressive chemotherapeutic agents delivered in the postoperative setting. PMID- 28736642 TI - Gemcitabine/nab-paclitaxel as second-line therapy following FOLFIRINOX in metastatic/advanced pancreatic cancer-retrospective analysis of response. AB - BACKGROUND: Given the tolerability of nPG in first-line therapy, we desired to evaluate the response and toxicity profiles of second-line gemcitabine with nab paclitaxel (nPG) following FOLFIRINOX. Methods: We retrospectively identified 30 patients who received first-line FOLFIRINOX for unresectable or metastatic pancreatic adenocarcinoma followed by second-line nPG. Response was evaluated by RECIST criteria and carbohydrate antigen 19-9 (CA19-9) change. RESULTS: Median age was 63 years with 77% percent having metastatic disease. Nineteen patients (63%) achieved PR based on CA19-9. Median overall survival (OS) with nPG was 12.4 months (mo) and median progression-free survival (PFS) was 3.7 mo. Median PFS and OS for patients with at least stable CA19-9 were 4.7 and 13.9 mo since initiation of nPG. Patients with an increased CA19-9 level during nPG had a shorter median PFS (1.4 mo) and OS (5.3 mo). A significant PFS difference was demonstrated in patients with at least stable disease as the best RECIST response versus in those with progressive disease (5.4 vs. 1.9 mo, P<0.001). Grade 3/4 adverse events include thrombocytopenia (33%), anemia (23%), nausea (17%), lymphopenia (7%), infectious complications (6%), diarrhea (3%), and neuropathy (3%). CONCLUSIONS: This study demonstrates a clinical benefit of second-line nPG. The study also suggests a possible use of CA19-9 to predict response to therapy. PMID- 28736643 TI - Comparison of efficacy and toxicity of FOLFIRINOX and gemcitabine with nab paclitaxel in unresectable pancreatic cancer. AB - BACKGROUND: Irinotecan, oxaliplatin and leucovorin-modulated fluorouracil (FOLFIRINOX) and the combination regimen of gemcitabine and nanoparticle albumin bound paclitaxel (GnP) (nab-PTX) improve the prognosis of patients with metastatic pancreatic cancer. However, no study has compared the efficacy of the two regimens. We compared retrospectively the efficacy and safety of the two regimens in patients with unresectable pancreatic cancer. METHODS: Thirty-eight patients with unresectable locally advanced or metastatic pancreatic cancer received FOLFIRINOX or GnP as first-line chemotherapy between December 2013 and September 2015. In the FOLFIRINOX group, patients received 85 mg/m2 oxaliplatin followed by 180 mg/m2 irinotecan and 200 mg/m2 L-leucovorin, and by 400 mg/m2 fluorouracil as a bolus and 2,400 mg/m2 fluorouracil as a 46-h continuous infusion every 14 days. In the GnP group, patients received 125 mg/m2 nab-PTX followed by 1 g/m2, and gemcitabine on days 1, 8 and 15, repeated every 28 days. RESULTS: Response rate was 6.3% in the FOLFIRINOX group and 40.9% in the GnP group (P=0.025). Median progression-free survival (PFS) was 3.7 months [95% confidence interval (CI), 3.0-4.5] in the FOLFIRINOX group and 6.5 months (95% CI, 6.2-6.9 months) in the GnP group (P=0.031). Drug toxicity in the GnP group was less than in the FOLFIRINOX group. CONCLUSIONS: Efficacy and safety of GnP compare favorably to those of FOLFIRINOX in patients with pancreatic cancer. Additional prospective trials are warranted. PMID- 28736644 TI - Overall and disease-free survival in patients treated with CRS + HIPEC with cisplatin and paclitaxel for gastric cancer with peritoneal carcinomatosis. AB - BACKGROUND: Our experience regarding cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) was reviewed in terms of overall survival (OS) and disease-free survival (DFS) in patients with synchronous peritoneal carcinomatosis (SPC) and metachronous peritoneal carcinomatosis (MPC) from gastric cancer (GC). METHODS: An analysis of prospectively collected data about patients who underwent CRS and HIPEC from July 2011 to July 2016 was carried out. Patients and tumor characteristics were taken into consideration together with pre and post-operative data. The outcomes concerned OS and DFS in both groups. RESULTS: A total of 17 cases were reported. All patients of SPC group underwent neoadjuvant chemotherapy, while all patients of MPC group underwent adjuvant chemotherapy subsequently to surgery of the primary tumor. The mean follow up period was 9 months (SD+/-9.5). Thirteen patients (76.5%) had SPC and four (23.5%) had MPC. The mean total Peritoneal Cancer Index (PCI) was 8.5 (SD+/-8.4). The mean PCI was 3.75 (SD+/-4.9) for SPC group and 16 (SD+/-9.5) for MPC (P=0.003). HIPEC regimen was cisplatin plus paclitaxel for fourteen patients (82.4%) and cisplatin plus mitomycin-C (MMC) for three patients (17.6%). OS was 16 months and 6 months respectively in patients with SPC and MPC (P=0.189). DFS was 11 months and 2 months respectively in the two groups (P=0.156). Patients with SPC patients and PCI >=12 were significantly different in terms of DFS from SPC with PCI <12 (P=0.001). Overall, twelve patients had postoperative major complications (CTCAE>2), in particular eight (61%) in SPC group while four (100%) in MPC group. Our study showed significantly better DFS for patients aged >60 years (P=0.016). CONCLUSIONS: HIPEC and CRS with cisplatin and paclitaxel in patients with PC from GC showed promising results in improving the DFS and the OS, particularly for patients with PCI <12 and for those aged >60. Although a high incidence of complications was revealed, especially in MPC group. PMID- 28736645 TI - Effect of Helicobacter pylori infection on outcomes in resected gastric and gastroesophageal junction cancer. AB - BACKGROUND: Helicobacter pylori (H pylori) infection is a known risk factor for gastric cancer (GC) and has been linked with gastroesophageal junction (GEJ) cancer. Studies examining the relationship between H. pylori infection, GC characteristics and prognosis are limited and have yielded conflicting results. We report on the clinicopathologic characteristics and oncologic outcomes of gastric and GEJ cancer patients with and without a history of H. pylori treated at our institution. METHODS: We retrospectively reviewed the medical records of patients over the age of 18 years who underwent curative resection for GEJ and GC at Mount Sinai Hospital between 2007 and 2012 who had histopathologic documentation of the presence or absence of H pylori infection. Demographic, clinical, pathologic, treatment characteristics and outcomes including recurrence free survival (RFS) and overall survival (OS) were compared. RESULTS: Ninety-five patients were identified. The majority of patients were male (61%), white (36%) or Asian (34%), with median age at diagnosis 64. Tumors were stage I (51%), stage II (23%), stage III (25%), and stage IV (1%). H pylori infection status was documented at the time of cancer diagnosis in 89 (94%) patients, and following cancer diagnosis and treatment in 6 (6%) patients. Younger age at diagnosis, Asian race and Lauren histologic classification were associated with H Pylori infection. H pylori positive patients exhibited higher 5-year OS and 5-year RFS compared to H pylori negative patients, though the difference was not statistically significant in either univariate or multivariate analyses. CONCLUSIONS: In this retrospective series of predominantly early stage GC and GEJ cancers, H. pylori positive patients were significantly younger at cancer diagnosis and were more frequently Asian compared to H. pylori negative patients. Other demographic and histologic classifications except for Lauren histologic classification were similar between the two groups. H pylori positive patients appeared to have improved outcomes compared to H. pylori negative patients. PMID- 28736646 TI - Sarcopenia related to neoadjuvant chemotherapy and perioperative outcomes in resected gastric cancer: a multi-institutional analysis. AB - BACKGROUND: This study's objective was to evaluate the change in sarcopenia score following neoadjuvant chemotherapy (NAC) and to correlate both sarcopenia and change in score with perioperative outcomes in patients with advanced resected gastric cancer. METHODS: Multi-institutional analysis of patients with gastric cancer who underwent NAC and resection from 2000-2015 was performed. Demographic and perioperative data were included. Sarcopenia score was defined as CT measurement of total psoas muscle at L3, stratified by height (m). Sarcopenia was defined as a score <385 mm2/m2 in women and <545 mm2/m2 in men. RESULTS: Of 36 patients, 19% were sarcopenic prior to NAC. Following NAC, 31% were sarcopenic, with 14% developing sarcopenia during NAC. One patient (3%) became non sarcopenic. There were no significant differences in patient, disease, or surgery characteristics between patients who were sarcopenic vs. not. Patients with sarcopenia were more likely to have post-operative complications (P=0.05). There was no significant difference in hospital stay (P=0.7402) or survival (P=0.2317). CONCLUSIONS: A significant number of patients with gastric cancer become sarcopenic during NAC. Although patients with sarcopenia were nearly twice as likely to develop post-operative complications, this did not appear to impact length of stay (LOS) or survival. PMID- 28736648 TI - The utility of positron emission tomography/computed tomography in target delineation for stereotactic body radiotherapy for liver metastasis from primary gastric cancer: an illustrative case report and literature review. AB - The liver is a common site for metastatic disease for many cancers. Radiation therapy is one means of treatment for liver metastases, especially for patients unable to undergo surgery or ineligible for systemic chemotherapy. In particular, stereotactic body radiotherapy (SBRT) has become an important option in the treatment of metastatic disease in the liver. SBRT delivers ablative doses of radiation in relatively few fractions. As such, precise and clear imaging plays an important role in maximizing disease control while minimizing normal tissue toxicity. We present a case that highlights the importance of using multiple imaging modalities for target volume delineation in stereotactic radiation treatment of liver metastases. PMID- 28736647 TI - An elderly man with remote history of metastatic melanoma now with localized pancreas cancer and new liver masses. PMID- 28736649 TI - Neoadjuvant transarterial radiation lobectomy for colorectal hepatic metastases: a small cohort analysis on safety, efficacy, and radiopathologic correlation. AB - Colorectal cancer patients have a high incidence of liver metastasis (ml-CRC). Surgical resection is the gold standard for treatment of hepatic metastasis but only a small percent of patients are traditional candidates based on disease extent and adequate size of the future liver remnant (FLR). Interventions such as portal vein embolization (PVE) and associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) are performed to increase FLR for operative conversion. Limitations to PVE include intrahepatic disease progression, portal vascular invasion, and utilization with concurrent chemotherapy. ALPPS is associated with a high morbidly and mortality. Radiation lobectomy (RL) with yttrium-90 (Y-90) delivers transarterial ablative brachytherapy to the future hepatectomy site which generates FLR hypertrophy similar or greater than PVE. Early results indicate that RL is safe, effective, and may offer unique benefits by providing cytoreduction of hepatic metastases which extends FLR hypertrophy time and allows FLR surveillance to gauge disease biology. A retrospective analysis of four patients with ml-CRC treated with RL prior to hepatectomy was performed to evaluate initial safety, efficacy, FLR hypertrophy, and radiopathologic correlation. Adverse events after RL and hepatectomy were evaluated. Imaging findings were analyzed for efficacy defined as FLR hypertrophy and disease control. Radiopathologic correlation was performed after histologic analysis. RL was well tolerated without major adverse events or hepatic decompensation. FLR hypertrophy ranged from 24.9% to 119% at mean follow up of three months. The majority of complications were related to surgical instrumentation of the FLR due to upstaging at time of surgery. Hepatectomy specimen histology demonstrated complete pathologic response in 50% of patients, 50% radiopathologic concordance rate, and no significant hepatic fibrosis. Initial experience with neoadjuvant RL for ml-CRC is safe and provides both durable disease control and FLR hypertrophy with concurrent chemotherapy. A 50% complete pathologic response rate raises the possibility of definitive chemoradiation in poor surgical candidates. Prospective investigation is required. PMID- 28736650 TI - A Salmonella Typhimurium outbreak linked to Vietnamese bread rolls in South Western Sydney, Australia, 2015. AB - INTRODUCTION: In September 2015, the South Western Sydney (SWS) Public Health Unit was notified of a cluster of Salmonella Typhimurium (STm) cases with a common multiple-locus variable-number tandem repeats analysis (MLVA) pattern. An investigation was conducted to identify a source and contain the outbreak. METHODS: The cluster was initially identified through routine geographic information system cluster scanning applied to the New South Wales Notifiable Conditions Management System. Additional cases were identified through a complaint to local council about a bakery. The bakery was inspected and 48 environmental and food swabs were collected for analysis. RESULTS: A total of 26 suspected cases were identified, of which 14 were interviewed. STm MLVA type 3-16 9-11-523 was identified in 19 of 26 case stool specimens. Most cases (12/14) consumed bread rolls containing pork or chicken with chicken liver pate and raw egg mayonnaise filling. Five cases identified a common bakery exposure. Environmental and food samples from the bakery isolated STm with an identical MLVA pattern. DISCUSSION: An STm cluster in SWS was investigated and found to be linked to Vietnamese bread rolls containing pork or chicken with chicken liver pate and raw egg mayonnaise filling. Confirmation of a distinct MLVA pattern among STm isolates from clinical, food and environmental samples provided evidence to establish an epidemiological link between the cases and the implicated premises and informed public health action to contain the outbreak. PMID- 28736651 TI - Adaptive Multi-scale Prognostics and Health Management for Smart Manufacturing Systems. AB - The Adaptive Multi-scale Prognostics and Health Management (AM-PHM) is a methodology designed to enable PHM in smart manufacturing systems. In application, PHM information is not yet fully utilized in higher-level decision making in manufacturing systems. AM-PHM leverages and integrates lower-level PHM information such as from a machine or component with hierarchical relationships across the component, machine, work cell, and assembly line levels in a manufacturing system. The AM-PHM methodology enables the creation of actionable prognostic and diagnostic intelligence up and down the manufacturing process hierarchy. Decisions are then made with the knowledge of the current and projected health state of the system at decision points along the nodes of the hierarchical structure. To overcome the issue of exponential explosion of complexity associated with describing a large manufacturing system, the AM-PHM methodology takes a hierarchical Markov Decision Process (MDP) approach into describing the system and solving for an optimized policy. A description of the AM-PHM methodology is followed by a simulated industry-inspired example to demonstrate the effectiveness of AM-PHM. PMID- 28736652 TI - Statistical properties of dynamic speckles from flowing Brownian scatterers in the vicinity of the image plane in optical coherence tomography. AB - A closed-form analytical expression is obtained for the spatio-temporal correlation function of the scattered radiation detected in fiber-based optical coherence tomography (OCT), assuming a clean optical system arrangement in the OCT sample arm. It is shown that the transverse flow component causes purely translational speckle motion with the predicted speckle velocity 2x higher than the velocity of the flowing particles as would be observed in the image plane under incoherent illumination. It is also shown that both speckle velocity and speckle radius do not depend on the position of the scattering volume relative to the focal plane, hence the derived correlation function is independent of the position of the scattering volume relative to the focal plane. Although the analytical results are obtained for a clean optical system arrangement, they can be used with high accuracy in most practical implementations of fiber based OCT. Validation experiments in control scattering phantoms with varying liquid viscosities show excellent agreement with the developed theoretical model, under both no-flow and flow conditions. Accurate viscosity determinations enabled by this methodology may have applications to non-invasive glucose measurements in medicine. PMID- 28736653 TI - Hemispheric differences in electrical and hemodynamic responses during hemifield visual stimulation with graded contrasts. AB - A multimodal neuroimaging technique based on electroencephalography (EEG) and functional near-infrared spectroscopy (fNIRS) was used with horizontal hemifield visual stimuli with graded contrasts to investigate the retinotopic mapping more fully as well as to explore hemispheric differences in neuronal activity, the hemodynamic response, and the neurovascular coupling relationship in the visual cortex. The fNIRS results showed the expected activation over the contralateral hemisphere for both the left and right hemifield visual stimulations. However, the EEG results presented a paradoxical lateralization, with the maximal response located over the ipsilateral hemisphere but with the polarity inversed components located over the contralateral hemisphere. Our results suggest that the polarity inversion as well as the latency advantage over the contralateral hemisphere cause the amplitude of the VEP over the contralateral hemisphere to be smaller than that over the ipsilateral hemisphere. Both the neuronal and hemodynamic responses changed logarithmically with the level of contrast in the hemifield visual stimulations. Moreover, the amplitudes and latencies of the visual evoked potentials (VEPs) were linearly correlated with the hemodynamic responses despite differences in the slopes. PMID- 28736655 TI - Comparison of vision through surface modulated and spatial light modulated multifocal optics. AB - Spatial-light-modulators (SLM) are increasingly used as active elements in adaptive optics (AO) systems to simulate optical corrections, in particular multifocal presbyopic corrections. In this study, we compared vision with lathe manufactured multi-zone (2-4) multifocal, angularly and radially, segmented surfaces and through the same corrections simulated with a SLM in a custom developed two-active-element AO visual simulator. We found that perceived visual quality measured through real manufactured surfaces and SLM-simulated phase maps corresponded highly. Optical simulations predicted differences in perceived visual quality across different designs at Far distance, but showed some discrepancies at intermediate and near. PMID- 28736654 TI - Enhancement of short coherence digital holographic microscopy by optical clearing. AB - In this work, we used a short coherence digital holographic microscopy system to demonstrate cross-talk noise suppression and imaging performance enhancement by optical clearing. Performance of the system on both phantom and in vitro porcine skin tissues before and after the treatment of 70% v./v. glycerol-saline solution was investigated. Our results showed that optical clearing effectively inhibits the cross-talk noise and improves the image quality in the deep of the in vitro porcine skin tissues. The imaging depth was increased by about 30% after topical application of the glycerol-saline solution for 30 min. PMID- 28736656 TI - Noise-bias and polarization-artifact corrected optical coherence tomography by maximum a-posteriori intensity estimation. AB - We propose using maximum a-posteriori (MAP) estimation to improve the image signal-to-noise ratio (SNR) in polarization diversity (PD) optical coherence tomography. PD-detection removes polarization artifacts, which are common when imaging highly birefringent tissue or when using a flexible fiber catheter. However, dividing the probe power to two polarization detection channels inevitably reduces the SNR. Applying MAP estimation to PD-OCT allows for the removal of polarization artifacts while maintaining and improving image SNR. The effectiveness of the MAP-PD method is evaluated by comparing it with MAP-non-PD, intensity averaged PD, and intensity averaged non-PD methods. Evaluation was conducted in vivo with human eyes. The MAP-PD method is found to be optimal, demonstrating high SNR and artifact suppression, especially for highly birefringent tissue, such as the peripapillary sclera. The MAP-PD based attenuation coefficient image also shows better differentiation of attenuation levels than non-MAP attenuation images. PMID- 28736657 TI - High temporal resolution aberrometry in a 50-eye population and implications for adaptive optics error budget. AB - We formed a database gathering the wavefront aberrations of 50 healthy eyes measured with an original custom-built Shack-Hartmann aberrometer at a temporal frequency of 236 Hz, with 22 lenslets across a 7-mm diameter pupil, for a duration of 20 s. With this database, we draw statistics on the spatial and temporal behavior of the dynamic aberrations of the eye. Dynamic aberrations were studied on a 5-mm diameter pupil and on a 3.4 s sequence between blinks. We noted that, on average, temporal wavefront variance exhibits a n-2 power-law with radial order n and temporal spectra follow a f-1.5 power-law with temporal frequency f. From these statistics, we then extract guidelines for designing an adaptive optics system. For instance, we show the residual wavefront error evolution as a function of the number of corrected modes and of the adaptive optics loop frame rate. In particular, we infer that adaptive optics performance rapidly increases with the loop frequency up to 50 Hz, with gain being more limited at higher rates. PMID- 28736658 TI - 3D reconstruction of cystoscopy videos for comprehensive bladder records. AB - White light endoscopy is widely used for diagnostic imaging of the interior of organs and body cavities, but the inability to correlate individual 2D images with 3D organ morphology limits its utility for quantitative or longitudinal studies of disease physiology or cancer surveillance. As a result, most endoscopy videos, which carry enormous data potential, are used only for real-time guidance and are discarded after collection. We present a computational method to reconstruct and visualize a 3D model of organs from an endoscopic video that captures the shape and surface appearance of the organ. A key aspect of our strategy is the use of advanced computer vision techniques and unmodified, clinical-grade endoscopy hardware with few constraints on the image acquisition protocol, which presents a low barrier to clinical translation. We validate the accuracy and robustness of our reconstruction and co-registration method using cystoscopy videos from tissue-mimicking bladder phantoms and show clinical utility during cystoscopy in the operating room for bladder cancer evaluation. As our method can powerfully augment the visual medical record of the appearance of internal organs, it is broadly applicable to endoscopy and represents a significant advance in cancer surveillance opportunities for big-data cancer research. PMID- 28736659 TI - High-dynamic-range fluorescence laminar optical tomography (HDR-FLOT). AB - Three-dimensional fluorescence laminar optical tomography (FLOT) can achieve resolutions of 100-200 um and penetration depths of 2-3 mm. FLOT has been used in tissue engineering, neuroscience, as well as oncology. The limited dynamic range of the charge-coupled device-based system makes it difficult to image fluorescent samples with a large concentration difference, limits its penetration depth, and diminishes the quantitative accuracy of 3D reconstruction data. Here, incorporating the high-dynamic-range (HDR) method widely used in digital cameras, we present HDR-FLOT, increasing penetration depth and improving the ability to image fluorescent samples with a large concentration difference. The method was tested using an agar phantom and a B6 mouse for brain imaging in vivo. PMID- 28736660 TI - Effect of higher-order aberrations and intraocular scatter on contrast sensitivity measured with a single instrument. AB - Higher-order aberrations (HOAs) and intraocular scatter lead to the degradation of image quality on the retina, and consequently deteriorate subjective visual performance. In this article, we modified an adaptive optics double-pass system to combine objective and subjective visual testing capabilities. Employing the modified DP system, we investigated the effects of HOAs and intraocular scatter on contrast sensitivity. Contrast sensitivity measurements were performed with HOAs either retained or corrected by adaptive optics, and with scatter either remaining at the natural eye-induced level or further enhanced by a set of three different scatter filters. Contrast sensitivity was found to be worse when HOAs were uncorrected or scatter increased. Quantitative analysis indicated that the joint effect of HOAs and scatter on contrast sensitivity was not a simple summation of each contributing factor, suggesting a potential compensatory mechanism between HOAs and intraocular scatter on contrast sensitivity. PMID- 28736661 TI - Brain tumor delineation enhanced by moxifloxacin-based two-photon/CARS combined microscopy. AB - Delineating brain tumor margin is critical for maximizing tumor removal while sparing adjacent normal tissue for better clinical outcome. We describe the use of moxifloxacin-based two-photon (TP)/coherent anti-Stokes Raman scattering (CARS) combined microscopy for differentiating normal mouse brain tissue from metastatic brain tumor tissue based on histoarchitectural and biochemical differences. Moxifloxacin, an FDA-approved compound, was used to label cells in the brain, and moxifloxacin-based two-photon microscopy (TPM) revealed tumor lesions with significantly high cellular density and invading edges in a metastatic brain tumor model. Besides, label-free CARS microscopy showed diminishing of lipid signal due to the destruction of myelin at the tumor site compared to a normal brain tissue site resulting in a complementary contrast for tumor detection. This study demonstrates that moxifloxacin-based TP/CARS combined microscopy might be advantageous for tumor margin identification in the brain that has been a long-standing challenge in the operating room. PMID- 28736663 TI - Three-dimensional OCT based guinea pig eye model: relating morphology and optics. AB - Custom Spectral Optical Coherence Tomography (SOCT) provided with automatic quantification and distortion correction algorithms was used to measure the 3-D morphology in guinea pig eyes (n = 8, 30 days; n = 5, 40 days). Animals were measured awake in vivo under cyclopegia. Measurements showed low intraocular variability (<4% in corneal and anterior lens radii and <8% in the posterior lens radii, <1% interocular distances). The repeatability of the surface elevation was less than 2 um. Surface astigmatism was the individual dominant term in all surfaces. Higher-order RMS surface elevation was largest in the posterior lens. Individual surface elevation Zernike terms correlated significantly across corneal and anterior lens surfaces. Higher-order-aberrations (except spherical aberration) were comparable with those predicted by OCT-based eye models. PMID- 28736662 TI - Can time-resolved NIRS provide the sensitivity to detect brain activity during motor imagery consistently? AB - Previous functional magnetic resonance imaging (fMRI) studies have shown that a subgroup of patients diagnosed as being in a vegetative state are aware and able to communicate by performing a motor imagery task in response to commands. Due to the fMRI's cost and accessibility, there is a need for exploring different imaging modalities that can be used at the bedside. A promising technique is functional near infrared spectroscopy (fNIRS) that has been successfully applied to measure brain oxygenation in humans. Due to the limited depth sensitivity of continuous-wave NIRS, time-resolved (TR) detection has been proposed as a way of enhancing the sensitivity to the brain, since late arriving photons have a higher probability of reaching the brain. The goal of this study was to assess the feasibility and sensitivity of TR fNIRS in detecting brain activity during motor imagery. Fifteen healthy subjects were recruited in this study, and the fNIRS results were validated using fMRI. The change in the statistical moments of the distribution of times of flight (number of photons, mean time of flight and variance) were calculated for each channel to determine the presence of brain activity. The results indicate up to an 86% agreement between fMRI and TR-fNIRS and the sensitivity ranging from 64 to 93% with the highest value determined for the mean time of flight. These promising results highlight the potential of TR fNIRS as a portable brain computer interface for patients with disorder of consciousness. PMID- 28736664 TI - Identification of melanoma cells: a method based in mean variance of signatures via spectral densities. AB - In this paper a new methodology to detect and differentiate melanoma cells from normal cells through 1D-signatures averaged variances calculated with a binary mask is presented. The sample images were obtained from histological sections of mice melanoma tumor of 4 [Formula: see text] in thickness and contrasted with normal cells. The results show that melanoma cells present a well-defined range of averaged variances values obtained from the signatures in the four conditions used. PMID- 28736665 TI - Airway compliance measured by anatomic optical coherence tomography. AB - Quantification of airway compliance can aid in the diagnosis and treatment of obstructive airway disorders by detecting regions vulnerable to collapse. Here we evaluate the ability of a swept-source anatomic optical coherence tomography (SSaOCT) system to quantify airway cross-sectional compliance (CC) by measuring changes in the luminal cross-sectional area (CSA) under physiologically relevant pressures of 10-40 cmH2O. The accuracy and precision of CC measurements are determined using simulations of non-uniform rotation distortion (NURD) endemic to endoscopic scanning, and experiments performed in a simplified tube phantom and ex vivo porcine tracheas. NURD simulations show that CC measurements are typically more accurate than that of the CSAs from which they are derived. Phantom measurements of CSA versus pressure exhibit high linearity (R2>0.99), validating the dynamic range of the SSaOCT system. Tracheas also exhibited high linearity (R2 = 0.98) suggestive of linear elasticity, while CC measurements were obtained with typically +/- 12% standard error. PMID- 28736666 TI - Enhancement of accuracy in shape sensing of surgical needles using optical frequency domain reflectometry in optical fibers. AB - We demonstrate a novel approach to enhance the precision of surgical needle shape tracking based on distributed strain sensing using optical frequency domain reflectometry (OFDR). The precision enhancement is provided by using optical fibers with high scattering properties. Shape tracking of surgical tools using strain sensing properties of optical fibers has seen increased attention in recent years. Most of the investigations made in this field use fiber Bragg gratings (FBG), which can be used as discrete or quasi-distributed strain sensors. By using a truly distributed sensing approach (OFDR), preliminary results show that the attainable accuracy is comparable to accuracies reported in the literature using FBG sensors for tracking applications (~1mm). We propose a technique that enhanced our accuracy by 47% using UV exposed fibers, which have higher light scattering compared to un-exposed standard single mode fibers. Improving the experimental setup will enhance the accuracy provided by shape tracking using OFDR and will contribute significantly to clinical applications. PMID- 28736667 TI - Changes in optical properties of electroporated cells as revealed by digital holographic microscopy. AB - Changes in optical and shape-related characteristics of B16F10 cells after electroporation were investigated using digital holographic microscopy (DHM). Bipolar rectangular pulses specific for electrochemotherapy were used. Electroporation was performed in an "off-axis" DHM set-up without using exogenous markers. Two types of cell parameters were monitored seconds and minutes after pulse train application: parameters addressing a specifically defined area of the cell (refractive index and cell height) and global cell parameters (projected area, optical phase shift profile and dry mass). The biphasic behavior of cellular parameters was explained by water and mannitol dynamics through the electropermeabilized cell membrane. PMID- 28736668 TI - In vivo photoacoustics and high frequency ultrasound imaging of mechanical high intensity focused ultrasound (HIFU) ablation. AB - The thermal effect of high intensity focused ultrasound (HIFU) has been clinically exploited over a decade, while the mechanical HIFU is still largely confined to laboratory investigations. This is in part due to the lack of adequate imaging techniques to better understand the in-vivo pathological and immunological effects caused by the mechanical treatment. In this work, we explore the use of high frequency ultrasound (US) and photoacoustics (PA) as a potential tool to evaluate the effect of mechanical ablation in-vivo, e.g. boiling histotripsy. Two mice bearing a neuroblastoma tumor in the right leg were ablated using an MRI-HIFU system conceived for small animals and monitored using MRI thermometry. High frequency US and PA imaging were performed before and after the HIFU treatment. Afterwards, the tumor was resected for further assessment and evaluation of the ablated region using histopathology. High frequency US imaging revealed the presence of liquefied regions in the treated area together with fragmentized tissue which appeared with different reflecting proprieties compared to the surrounding tissue. Photoacoustic imaging on the other hand revealed the presence of deoxygenated blood within the tumor after the ablation due to the destruction of blood vessel network while color Doppler imaging confirmed the blood vessel network destruction within the tumor. The treated area and the presence of red blood cells detected by photoacoustics were further confirmed by the histopathology. This feasibility study demonstrates the potential of high frequency US and PA approach for assessing in-vivo the effect of mechanical HIFU tumor ablation. PMID- 28736669 TI - Photoacoustic reflection artifact reduction using photoacoustic-guided focused ultrasound: comparison between plane-wave and element-by-element synthetic backpropagation approach. AB - Reflection artifacts caused by acoustic inhomogeneities constitute a major problem in epi-mode biomedical photoacoustic imaging. Photoacoustic transients from the skin and superficial optical absorbers traverse into the tissue and reflect off echogenic structures to generate reflection artifacts. These artifacts cause difficulties in the interpretation of images and reduce contrast and imaging depth. We recently developed a method called PAFUSion (photoacoustic guided focused ultrasound) to circumvent the problem of reflection artifacts in photoacoustic imaging. We already demonstrated that the photoacoustic signals can be backpropagated using synthetic aperture pulse-echo data for identifying and reducing reflection artifacts in vivo. In this work, we propose an alternative variant of PAFUSion in which synthetic backpropagation of photoacoustic signals is based on multi-angled plane-wave ultrasound measurements. We implemented plane wave and synthetic aperture PAFUSion in a handheld ultrasound/photoacoustic imaging system and demonstrate reduction of reflection artifacts in phantoms and in vivo measurements on a human finger using both approaches. Our results suggest that, while both approaches are equivalent in terms of artifact reduction efficiency, plane-wave PAFUSion requires less pulse echo acquisitions when the skin absorption is the main cause of reflection artifacts. PMID- 28736671 TI - Noninvasive in vivo monitoring of collagenase induced intracerebral hemorrhage by photoacoustic tomography. AB - Photoacoustic tomography (PAT) is an emerging noninvasive biomedical imaging modality that can be used for visualizing the structure and function of brain in high resolution. Here we report an application of PAT to imaging intracerebral hemorrhage (ICH) in a mouse model. In vivo photoacoustic images were obtained in mice with right basal ganglia hemorrhage induced by microinjection of collagenase. With multi-spectral light excitation, cortical vascular network was clearly revealed at 532 nm, and ICH associated hematoma lesions and perihemmatoma regions were accurately mapped over time at 750 nm and 875 nm, respectively. Our results suggest that PAT provides a unique tool for visualizing hemodynamics involved in brain diseases such as ICH. PMID- 28736670 TI - Wavefront sensorless adaptive optics OCT with the DONE algorithm for in vivo human retinal imaging [Invited]. AB - In this report, which is an international collaboration of OCT, adaptive optics, and control research, we demonstrate the Data-based Online Nonlinear Extremum seeker (DONE) algorithm to guide the image based optimization for wavefront sensorless adaptive optics (WFSL-AO) OCT for in vivo human retinal imaging. The ocular aberrations were corrected using a multi-actuator adaptive lens after linearization of the hysteresis in the piezoelectric actuators. The DONE algorithm succeeded in drastically improving image quality and the OCT signal intensity, up to a factor seven, while achieving a computational time of 1 ms per iteration, making it applicable for many high speed applications. We demonstrate the correction of five aberrations using 70 iterations of the DONE algorithm performed over 2.8 s of continuous volumetric OCT acquisition. Data acquired from an imaging phantom and in vivo from human research volunteers are presented. PMID- 28736672 TI - Handheld optical coherence tomography angiography. AB - We developed a handheld optical coherence tomography angiography (OCTA) system using a 100-kHz swept-source laser. The handheld probe weighs 0.4 kg and measures 20.6 * 12.8 * 4.6 cm3. The system has dedicated features for handheld operation. The probe is equipped with a mini iris camera for easy alignment. Real-time display of the en face OCT and cross-sectional OCT images in the system allows accurately locating the imaging target. Fast automatic focusing was achieved by an electrically tunable lens controlled by a golden-section search algorithm. An extended axial imaging range of 6 mm allows easy alignment. A registration algorithm using cross-correlation to register adjacent OCT B-frames with propagation from the central frame was used to effectively minimize motion artifacts in volumetric OCTA images captured in relatively short durations of 1 and 2.1 seconds. 2.5 * 2.5 mm (200 * 200 pixels) and 3.5 * 3.5 mm (300 * 300 pixels) retinal angiograms were demonstrated on two awake adult human subjects without the use of any mydriatic eye drops. PMID- 28736673 TI - Detection theory for accurate and non-invasive skin cancer diagnosis using dynamic thermal imaging. AB - Skin cancer is the most common cancer in the United States with over 3.5M annual cases. Presently, visual inspection by a dermatologist has good sensitivity (> 90%) but poor specificity (< 10%), especially for melanoma, which leads to a high number of unnecessary biopsies. Here we use dynamic thermal imaging (DTI) to demonstrate a rapid, accurate and non-invasive imaging system for detection of skin cancer. In DTI, the lesion is cooled down and the thermal recovery is recorded using infrared imaging. The thermal recovery curves of the suspected lesions are then utilized in the context of continuous-time detection theory in order to define an optimal statistical decision rule such that the sensitivity of the algorithm is guaranteed to be at a maximum for every prescribed false-alarm probability. The proposed methodology was tested in a pilot study including 140 human subjects demonstrating a sensitivity in excess of 99% for a prescribed specificity in excess of 99% for detection of skin cancer. To the best of our knowledge, this is the highest reported accuracy for any non-invasive skin cancer diagnosis method. PMID- 28736674 TI - Fluorescein as a topical fluorescent contrast agent for quantitative microendoscopic inspection of colorectal epithelium. AB - Fiber bundle microendoscopic imaging of colorectal tissue has shown promising results, for both qualitative and quantitative analysis. A quantitative image quality control and image feature extraction algorithm was previously designed for quantitative image feature analysis of proflavine-stained ex vivo colorectal tissue. We investigated fluorescein as an alternative topical stain. Images of ex vivo porcine, caprine, and human colorectal tissue were used to compare microendoscopic images of tissue topically stained with fluorescein and proflavine solutions. Fluorescein was shown to be comparable for automated crypt detection, with an average crypt detection sensitivity exceeding 90% using a combination of three contrast limit pairs. PMID- 28736675 TI - Simulation study on compressive laminar optical tomography for cardiac action potential propagation. AB - To measure the activity of tissue at the microscopic level, laminar optical tomography (LOT), which is a microscopic form of diffuse optical tomography, has been developed. However, obtaining sufficient recording speed to determine rapidly changing dynamic activity remains major challenges. For a high frame rate of the reconstructed data, we here propose a new LOT method using compressed sensing theory, called compressive laminar optical tomography (CLOT), in which novel digital micromirror device-based illumination and data reduction in a single reconstruction are applied. In the simulation experiments, the reconstructed volumetric images of the action potentials that were acquired from 5 measured images with random pattern featured a wave border at least to a depth of 2.5 mm. Consequently, it was shown that CLOT has potential for over 200 fps required for the cardiac electrophysiological phenomena. PMID- 28736676 TI - Label-free photoacoustic imaging of the cardio-cerebrovascular development in the embryonic zebrafish. AB - Zebrafish play an important role in biology, pharmacology, toxicology, and medicine. The cardio-cerebrovascular development of zebrafish is particularly critical to understand both brain disorders and cardiovascular diseases in human. In this paper, we applied optical resolution photoacoustic microscopy (ORPAM) to image the whole-body vasculature of the embryonic zebrafish with a special focus on the development of the cardio-cerebrovascular system. Using the intrinsic optical absorption contrast of the embryo, we successfully visualized the formation of the cardio-cerebrovascular network in high-resolution using a 10 * objective, and monitored the whole-body vascular development using a 4 * objective. In addition, we evaluated the impact of the eggshell and pigment inhibitor on the image quality. Our results suggest that ORPAM is capable of studying the cardio-cerebrovascular development of zebrafish in the embryonic stage, and thus has the potential to investigate the cardiovascular and cerebrovascular diseases of human in the future. PMID- 28736677 TI - No Evidence of On-farm Circulation of Avian Influenza H5 Subtype in Ca Mau Province, Southern Vietnam, March 2016 - January 2017. AB - BACKGROUND: Subtype H5N1 avian influenza viruses, both high pathogenicity and low pathogenicity, have been enzootic in Vietnam since 2001. The viruses are readily identified at live bird markets, but virus prevalence on smallholder poultry is typically zero or very low. If the true direction of the viral transmission chain is farm to market, it is unknown why farm prevalence should be low when market prevalence is moderate to high. METHODS: We established a cohort of 50 smallholder poultry farms in Ca Mau province in the Mekong Delta region of Vietnam. From March 2016 to January 2017, we collected naso-pharyngeal and cloacal samples from 156 ducks and 96 chickens. In addition, 126 environmental samples were collected. Samples were assayed for H5 subtype influenza by real time RT-PCR. Results/Discussion: None of the 378 collected samples were positive for H5 influenza. This is likely to mean that circulation of subtype H5 influenza viruses was low in Ca Mau in 2016. Detection of avian influenza on smallholder poultry farms is necessary to determine the directionality and association between farm prevalence and market prevalence of avian influenza viruses. Larger farm-level studies should be planned as these will be critical for determining the presence and strength of this association. PMID- 28736678 TI - Rapid Assessment Zika Virus Knowledge Among Clinical Specialists in Singapore: A Cross-sectional Survey. AB - INTRODUCTION: We report the results of a rapid assessment of Zika virus awareness among key clinical specialties in Singapore. METHODS: Between June 6 and June 19, 2016 we conducted an online survey of doctors working in obstetrics and gynaecology, neonatology and paediatrics in Singapore. The survey included 15 multiple choice questions to measure respondents' knowledge of Zika virus in four domains covering clinical and public health. RESULTS: A total of 110 survey responses (15% response rate) were obtained, 82% of respondents worked in the public sector. Overall, the median respondent score was 9.4 (Max score=15), with substantial variation (range: 3.5 - 14.7). Microcephaly and Guillain-Barre syndrome were recognised as causal complications of Zika virus infection by 99% and 50% of respondents respectively. Clinical features which could help differentiate Zika from Dengue were less well understood with 50% and 68% correctly identifying conjunctivitis and low grade fever respectively. Worryingly, 14% favoured non-steroidal anti-inflammatory drugs as part of treatment, without first excluding dengue as a diagnosis. Also, only 36% of respondents were aware of the current recommendation for preventing sexual transmission of Zika virus. Fewer than 50% were aware of the need for ophthalmological evaluation as part of congenital Zika virus infection. DISCUSSION: Our assessment demonstrates that there is good awareness of the clinical manifestation of Zika virus disease among key specialty doctors, but confusion with Dengue disease remains. It also highlights knowledge gaps in the prevention of sexually-transmitted Zika virus infection and the clinical management of congenital Zika virus infection in newborns. Our study identified strategic areas to improve communication to front-line doctors during public health response to the Zika epidemic. PMID- 28736679 TI - Chloroplast Genome Sequence Annotation of Dendrobium nobile (Asparagales: Orchidaceae), an Endangered Medicinal Orchid from Northeast India. AB - Orchidaceae constitutes one of the largest families of angiosperms. Owing to the significance of orchids in plant biology, market needs and current sustainable technology levels, basic research on the biology of orchids and their applications in the orchid industry is increasing. Although chloroplast (cp) genomes continue to be evolutionarily informative, there is very limited information available on orchid chloroplast genomes in public repositories. Here, we report the complete cp genome sequence of Dendrobium nobile from Northeast India (Orchidaceae, Asparagales), bearing the GenBank accession number KX377961, which will provide valuable information for future research on orchid genomics and evolution, as well as the medicinal value of orchids. Phylogenetic analyses using Bayesian methods recovered a monophyletic grouping of all Dendrobium species (D. nobile, D. huoshanense, D. officinale, D. pendulum, D. strongylanthum and D. chrysotoxum). The relationships recovered among the representative orchid species from the four subfamilies, i.e., Cypripedioideae, Epidendroideae, Orchidoideae and Vanilloideae, were consistent within the family Orchidaceae. PMID- 28736680 TI - Spatiotemporal Identification of Potential Tsunami Vertical Evacuation Sites: A Case Study of Shizuoka City, Japan. AB - INTRODUCTION: The city of Shizuoka directly faces the Nankai Trough (known for its tsunamigenic history), and is facing a potential tsunami threat. In this setting vertical evacuation can be of great significance in reducing loss of life. METHODS: We apply a GIS based method in order to identify sites that could be utilized for vertical evacuation within the existing building stock of the city, under two tsunami scenarios of 5 and 10 meters of run-up. For each building, we estimate the volume that is expected to be lost per scenario, as well as the number of people inside and how that number fluctuates over different times of the day. RESULTS: Using the criteria of 25% or less building volume loss and 6 cubic meters of volume per person, resulted in 2,046 potential sites for the 10 meter scenario and 1,643 potential sites for the 5 meter scenario, with the maximum amount of people that can potentially be accepted in these sites in the morning hours being 873,537 in the 10 meter scenario and 304,734 in the 5 meter scenario. DISCUSSION: Our approach has shown that there is a temporal aspect in tsunami vertical evacuation due to the movement of the local population throughout the day. the proposed method can be used for preliminary identification of potential vertical evacuation sites, however, it must be followed by further vulnerability and engineering assessments of buildings, in combination with accessibility and evacuation routing in order to reach a viable and complete evacuation plan. PMID- 28736681 TI - Integrating Environmental Monitoring and Mosquito Surveillance to Predict Vector borne Disease: Prospective Forecasts of a West Nile Virus Outbreak. AB - INTRODUCTION: Predicting the timing and locations of future mosquito-borne disease outbreaks has the potential to improve the targeting of mosquito control and disease prevention efforts. Here, we present and evaluate prospective forecasts made prior to and during the 2016 West Nile virus (WNV) season in South Dakota, a hotspot for human WNV transmission in the United States. METHODS: We used a county-level logistic regression model to predict the weekly probability of human WNV case occurrence as a function of temperature, precipitation, and an index of mosquito infection status. The model was specified and fitted using historical data from 2004-2015 and was applied in 2016 to make short-term forecasts of human WNV cases in the upcoming week as well as whole-year forecasts of WNV cases throughout the entire transmission season. These predictions were evaluated at the end of the 2016 WNV season by comparing them with spatial and temporal patterns of the human cases that occurred. RESULTS: There was an outbreak of WNV in 2016, with a total of 167 human cases compared to only 40 in 2015. Model results were generally accurate, with an AUC of 0.856 for short-term predictions. Early-season temperature data were sufficient to predict an earlier than-normal start to the WNV season and an above-average number of cases, but underestimated the overall case burden. Model predictions improved throughout the season as more mosquito infection data were obtained, and by the end of July the model provided a close estimate of the overall magnitude of the outbreak. CONCLUSIONS: An integrated model that included meteorological variables as well as a mosquito infection index as predictor variables accurately predicted the resurgence of WNV in South Dakota in 2016. Key areas for future research include refining the model to improve predictive skill and developing strategies to link forecasts with specific mosquito control and disease prevention activities. PMID- 28736682 TI - Standardized Approach to Quantitatively Measure Residual Limb Skin Health in Individuals with Lower Limb Amputation. AB - Objective: (1) Develop a standardized approach to quantitatively measure residual limb skin health. (2) Report reference residual limb skin health values in people with transtibial and transfemoral amputation. Approach: Residual limb health outcomes in individuals with transtibial (n = 5) and transfemoral (n = 5) amputation were compared to able-limb controls (n = 4) using noninvasive imaging (hyperspectral imaging and laser speckle flowmetry) and probe-based approaches (laser doppler flowmetry, transcutaneous oxygen, transepidermal water loss, surface electrical capacitance). Results: A standardized methodology that employs noninvasive imaging and probe-based approaches to measure residual limb skin health are described. Compared to able-limb controls, individuals with transtibial and transfemoral amputation have significantly lower transcutaneous oxygen tension, higher transepidermal water loss, and higher surface electrical capacitance in the residual limb. Innovation: Residual limb health as a critical component of prosthesis rehabilitation for individuals with lower limb amputation is understudied in part due to a lack of clinical measures. Here, we present a standardized approach to measure residual limb health in people with transtibial and transfemoral amputation. Conclusion: Technology advances in noninvasive imaging and probe-based measures are leveraged to develop a standardized approach to quantitatively measure residual limb health in individuals with lower limb loss. Compared to able-limb controls, resting residual limb physiology in people that have had transfemoral or transtibial amputation is characterized by lower transcutaneous oxygen tension and poorer skin barrier function. PMID- 28736683 TI - Progress Toward Optimizing Prosthetic Socket Fit and Suspension Using Elevated Vacuum to Promote Residual Limb Health. AB - Objective: Prosthetic sockets are custom made for each amputee, yet there are no quantitative tools to determine the appropriateness of socket fit. Ensuring a proper socket fit can have significant effects on the health of residual limb soft tissues and overall function and acceptance of the prosthetic limb. Previous work found that elevated vacuum pressure data can detect movement between the residual limb and the prosthetic socket; however, the correlation between the two was specific to each user. The overall objective of this work is to determine the relationship between elevated vacuum pressure deviations and prosthetic socket fit. Approach: A tension compression machine was used to apply repeated controlled forces onto a residual limb model with sockets of different internal volume. Results: The vacuum pressure-displacement relationship was dependent on socket fit. The vacuum pressure data were sensitive enough to detect differences of 1.5% global volume and can likely detect differences even smaller. Limb motion was reduced as surface area of contact between the limb model and socket was maximized. Innovation: The results suggest that elevated vacuum pressure data provide information to quantify socket fit. Conclusions: This study provides evidence that the use of elevated vacuum pressure data may provide a method for prosthetists to quantify and monitor socket fit. Future studies should investigate the relationship between socket fit, limb motion, and limb health to define optimal socket fit parameters. PMID- 28736684 TI - Multimodality Imaging Approaches for Evaluating Traumatic Extremity Injuries: Implications for Military Medicine. AB - Significance: Military service members are susceptible to traumatic extremity injuries that often result in limb loss. Tremendous efforts have been made to improve medical treatment that supports residual limb function and health. Despite recent improvements in treatment and novel prosthetic devices, many patients experience a wide range of clinical problems within residual limbs that can negatively impact the progress of rehabilitation programs while also impairing functional capacity and overall quality of life. Recent Advances: In addition to existing standard imaging modalities that are used for clinical evaluation of patients suffering from traumatic extremity injury, novel noninvasive imaging techniques are in development that may facilitate rapid and sensitive assessment of various aspects of traumatic extremity injuries and residual limb health. Critical Issues: Despite recent advances, there remains a clinical need for noninvasive quantitative imaging techniques that are capable of providing rapid objective assessments of residual limb health at the time of initial presentation as well as after various forms of medical treatment. Future Directions: Ongoing development of imaging techniques that allow for assessment of anatomical and physiological characteristics of extremities exposed to traumatic injury should greatly enhance the quality of patient care and assist in optimizing clinical outcomes. PMID- 28736685 TI - Reducing Variability of Perimetric Global Indices from Eyes with Progressive Glaucoma by Censoring Unreliable Sensitivity Data. AB - PURPOSE: Recent evidence suggests that increasing perimetric contrast all the way to 0 dB may not be clinically useful. This study examines whether raising the floor for point-wise sensitivities affects the ability of global indices to detect change. METHODS: Longitudinal data from eyes with progressive glaucoma were used. Point-wise sensitivities were censored at various cutoffs (12-19 dB). At each cutoff, mean deviations (MD) were recalculated using censored sensitivities, called censored mean deviation (CMD). Both MD and CMD were fitted using a linear model. MD and CMD rate of changes (signal) and the standard deviations (SD) of the residuals (noise) were obtained from the fitted models. The linear signal to noise ratio (LSNR) for MD (LSNRMD) and CMD (LSNRCMD) were compared. Additionally, at each cutoff, the ratios of LSNRCMD to LSNRMD were calculated and tested. RESULTS: CMD provided significantly (P <0.05) better LSNR than MD when using any point-wise sensitivity cutoff between 15-19 dB for progressing eyes. Moreover, the ratios of LSNRCMD to LSNRMD were significantly (P <0.05) greater than 1 at all cutoffs from 15-19 dB. CONCLUSION: This study demonstrates that censoring is an effective tool to reduce variability at low sensitivities for progressing eyes. TRANSLATIONAL RELEVANCE: This study suggests that 15-19 dB could be a more suitable endpoint for perimetric testing algorithms. PMID- 28736686 TI - Evaluating Changes in Ocular Redness Using a Novel Automated Method. AB - PURPOSE: To evaluate interobserver concordance in measured ocular redness among a group of raters using an objective computer-assisted method (ocular redness index [ORI]) and a group of clinicians using an ordinal comparative scale. METHODS: We conducted a prospective study to evaluate ocular redness in clinical photographs of 12 patients undergoing pterygium surgery. Photographs were acquired preoperatively, and at 1 week and 1 month postoperatively. One group of clinicians graded conjunctival redness in the photographs using an image-based comparative scale. A second group applied the ORI to measure redness in the same photographs. We evaluated redness change between time points, level of agreement among raters, and assessed redness score differences among observers within each group. RESULTS: Interobserver agreement using the image-based redness scale was 0.458 (P < 0.001). Interobserver agreement with the ORI was 0.997 (P < 0.001). We observed statistically significant differences among clinicians' measurements obtained with the image-based redness scale (P < 0.001). There were no significant differences among measurements obtained with the ORI (P = 0.27). We observed a significant change in redness between baseline and follow-up visits with all scoring methods. Detailed analysis of redness change was performed only in the ORI group due to availability of continuous scores. CONCLUSION: Our findings suggest that the ORI scores provide higher consistency among raters than ordinal scales, and can discriminate redness changes that clinical observers often can miss. TRANSLATIONAL RELEVANCE: The ORI may be a reliable alternative to measure ocular redness objectively in the clinic and in clinical trials. PMID- 28736687 TI - Tissue-Engineered Tendon for Enthesis Regeneration in a Rat Rotator Cuff Model. AB - Healing of rotator cuff (RC) injuries with current suture or augmented scaffold techniques fails to regenerate the enthesis and instead forms a weaker fibrovascular scar that is prone to subsequent failure. Regeneration of the enthesis is the key to improving clinical outcomes for RC injuries. We hypothesized that the utilization of our tissue-engineered tendon to repair either an acute or a chronic full-thickness supraspinatus tear would regenerate a functional enthesis and return the biomechanics of the tendon back to that found in native tissue. Engineered tendons were fabricated from bone marrow-derived mesenchymal stem cells utilizing our well-described fabrication technology. Forty three rats underwent unilateral detachment of the supraspinatus tendon followed by acute (immediate) or chronic (4 weeks retracted) repair by using either our engineered tendon or a trans-osseous suture technique. Animals were sacrificed at 8 weeks. Biomechanical and histological analyses of the regenerated enthesis and tendon were performed. Statistical analysis was performed by using a one-way analysis of variance with significance set at p < 0.05. Acute repairs using engineered tendon had improved enthesis structure and lower biomechanical failures compared with suture repairs. Chronic repairs with engineered tendon had a more native-like enthesis with increased fibrocartilage formation, reduced scar formation, and lower biomechanical failure compared with suture repair. Thus, the utilization of our tissue-engineered tendon showed improve enthesis regeneration and improved function in chronic RC repairs compared with suture repair. Clinical Significance: Our engineered tendon construct shows promise as a clinically relevant method for repair of RC injuries. PMID- 28736688 TI - The Top 50 Most Cited Articles in Cartilage Regeneration. AB - The aim of this study was to identify and analyze the top 50 most cited articles in cartilage regeneration. The impact of a scientific journal can be gauged by the total number of citations it has accrued. The top 50 most cited articles involving cartilage regeneration represent the most quoted level of evidence among this new subspecialty. This study aims to identify and analyze the 50 most cited articles in cartilage regeneration. The Web of ScienceTM citation indexing service was utilized to determine the most frequently cited articles published after 1956 containing "cartilage regeneration" in the "topic" or "title." The 50 most cited articles were included. The number of citations, year of publication, country of article origin, article institution, journal of publication, publication format, and authorship were then calculated for each article. The span of citations ranged from 1287 to 203 citations, with a mean of 361.02 citations per article in question. The articles originated from 11 countries, with the United States contributing 34 articles, followed by Japan with 5 articles. The articles were distributed across 34 high-impact journals. Biomaterials was the journal with the highest number of publications (seven articles) followed by the Journal of Orthopaedic Research (three articles). Of the 50 articles, 2 were clinical observational studies, 47 concerned basic science, and 1 was review article. The most cited articles involving cartilage regeneration are detected in both experimental and clinical research fields. The high ratio of basic science to clinical articles reflects the infancy of this relatively new specialty and that further clinical research is required in this area. PMID- 28736690 TI - Decellularization of Human Internal Mammary Artery: Biomechanical Properties and Histopathological Evaluation. AB - This study undertook to create small-diameter vascular grafts and assess their structure and mechanical properties to withstand arterial implantation. Twenty samples of intact human internal mammary arteries (IMAs) were collected and decellularized using detergent-based methods. To evaluate residual cellular and extracellular matrix (ECM) components, histological analysis was performed. Moreover, collagen typing and ECM structure were analyzed by Picrosirius red and Movat's pentachrome staining. Scanning electron microscopy was also applied to assess microarchitecture of both endothelial and adventitial surfaces of native and decellularized arterial samples. Furthermore, mechanical tests were performed to evaluate the rigidity and suture strength of the arteries. Human IMAs were completely decellularized in all three segments (proximal, middle, and distal). ECM proteins such as collagen and elastic fibers were efficiently preserved and no structural distortion in intima, media, and adventitial surfaces was observed. The parameters of the mechanical tests revealed no significant differences in the mechanical properties of decellularized arteries in comparison to native arteries with considerable strength, suture retention, and stress relaxation (Young's modulus [MPa] = 0.22 +/- 0.023 [native] and 0.22 +/- 0.015 [acellular]; and suture strength 0.56 +/- 0.19 [native] vs. 0.56 +/- 0.12 [acellular], respectively). Decellularized IMA represents a potential arterial scaffold as an alternative to autologous grafts for future arterial bypass surgeries. By this technique, microarchitecture and mechanical integrity of decellularized arteries were considerably similar to native arteries. The goal of this study was to introduce an efficient method for complete decellularization of human IMA and evaluate the ECM and biomechanical properties. PMID- 28736689 TI - Induced Pluripotent Stem Cells: Global Research Trends. AB - The induced pluripotent stem cell (iPSC) was first described more than 10 years ago and is currently used in various basic science and clinical research fields. The aim of this report is to examine the trends in research using iPSCs over the last 10 years. The 2006-2016 PubMed database was searched using the MeSH term "induced pluripotent stem cells." Only original research articles were selected, with a total of 3323 articles. These were classified according to research theme into reprogramming, differentiation protocols for specific cells and/or tissues, pathophysiological research on diseases, and discovery of new drugs, and then the trends over the years were analyzed. We also focused on 232 research publications on the pathophysiological causes of diseases and drug discovery with impact factor (IF; Thomson Reuters) of six or more. The IF of each article was summed up by year, by main target disease, and by country, and the total IF score was expressed as trends of research. The trends of research activities of reprogramming and differentiation on specific cells and/or tissues reached maxima in 2013/2014. On the other hand, research on pathophysiology and drug discovery increased continuously. The 232 articles with IF >=6 dealt with neurological, immunological/hematological, cardiovascular, and digestive tract diseases, in that order. The majority of articles were published from the United States, followed by Japan, Germany, and United Kingdom. In conclusion, iPSCs have become a general tool for pathophysiological research on disease and drug discovery. PMID- 28736691 TI - Prevalence and Risk Factors of Osteoporosis Among Jordanian Postmenopausal Women Attending the National Center for Diabetes, Endocrinology and Genetics in Jordan. AB - To assess the prevalence of osteoporosis and osteopenia among Jordanian postmenopausal women attending the National Center for Diabetes, Endocrinology, and Genetics (NCDEG), and to determine the potential associated risk factors. A cross-sectional study was conducted at (NCDEG) in Amman, Jordan. A total of 1079 Jordanian postmenopausal women aged between 45 and 84 years were included in this study that was conducted during the period between April 2013 and December 2014. All patients underwent bone mineral density measurement through dual-energy X-ray absorptiometry (DEXA) scan. DEXA scan was interpreted in terms of T score as per World Health Organization guidelines. The overall prevalence of osteoporosis and osteopenia was 37.5% and 44.6%, respectively. The maximum prevalence of osteoporosis was observed at the lumbar spine (32.4%) followed by the left femoral neck (14.4%), while the maximum prevalence of osteopenia was observed at the left femoral neck (56.1%) followed by the lumbar spine (41.3%). Patients with longer menopausal duration, normal or overweight body mass index, high parity, physical inactivity, positive family history of osteoporosis, inadequate sun exposure, high daily caffeine intake, low daily calcium intake, and delay in the age of menarche were all positively associated with osteoporosis. On the other hand, women with type 2 diabetes mellitus had lower risk of osteoporosis. There is a high prevalence of osteoporosis and osteopenia among Jordanian postmenopausal women. Necessary steps are needed for more public education and a wider dissemination of information about osteoporosis and its prevention. PMID- 28736692 TI - Evaluating the Impact of a HIV Low-Risk Express Care Task-Shifting Program: A Case Study of the Targeted Learning Roadmap. AB - In conducting studies on an exposure of interest, a systematic roadmap should be applied for translating causal questions into statistical analyses and interpreting the results. In this paper we describe an application of one such roadmap applied to estimating the joint effect of both time to availability of a nurse-based triage system (low risk express care (LREC)) and individual enrollment in the program among HIV patients in East Africa. Our study population is comprised of 16,513 subjects found eligible for this task-shifting program within 15 clinics in Kenya between 2006 and 2009, with each clinic starting the LREC program between 2007 and 2008. After discretizing follow-up into 90-day time intervals, we targeted the population mean counterfactual outcome (i. e. counterfactual probability of either dying or being lost to follow up) at up to 450 days after initial LREC eligibility under three fixed treatment interventions. These were (i) under no program availability during the entire follow-up, (ii) under immediate program availability at initial eligibility, but non-enrollment during the entire follow-up, and (iii) under immediate program availability and enrollment at initial eligibility. We further estimated the controlled direct effect of immediate program availability compared to no program availability, under a hypothetical intervention to prevent individual enrollment in the program. Targeted minimum loss-based estimation was used to estimate the mean outcome, while Super Learning was implemented to estimate the required nuisance parameters. Analyses were conducted with the ltmle R package; analysis code is available at an online repository as an R package. Results showed that at 450 days, the probability of in-care survival for subjects with immediate availability and enrollment was 0.93 (95% CI: 0.91, 0.95) and 0.87 (95% CI: 0.86, 0.87) for subjects with immediate availability never enrolling. For subjects without LREC availability, it was 0.91 (95% CI: 0.90, 0.92). Immediate program availability without individual enrollment, compared to no program availability, was estimated to slightly albeit significantly decrease survival by 4% (95% CI 0.03,0.06, p<0.01). Immediately availability and enrollment resulted in a 7 % higher in-care survival compared to immediate availability with non-enrollment after 450 days (95% CI-0.08,-0.05, p<0.01). The results are consistent with a fairly small impact of both availability and enrollment in the LREC program on incare survival. PMID- 28736693 TI - Squeezing effects applied in nonclassical superposition states for quantum nanoelectronic circuits. AB - Quantum characteristics of a driven series RLC nanoelectronic circuit whose capacitance varies with time are studied using an invariant operator method together with a unitary transformation approach. In particular, squeezing effects and nonclassical properties of a superposition state composed of two displaced squeezed number states of equal amplitude, but 180 degrees out of phase, are investigated in detail. We applied our developments to a solvable specific case obtained from a suitable choice of time-dependent parameters. The pattern of mechanical oscillation of the amount of charges stored in the capacitor, which are initially displaced, has exhibited more or less distortion due to the influence of the time-varying parameters of the system. We have analyzed squeezing effects of the system from diverse different angles and such effects are illustrated for better understanding. It has been confirmed that the degree of squeezing is not constant, but varies with time depending on specific situations. We have found that quantum interference occurs whenever the two components of the superposition meet together during the time evolution of the probability density. This outcome signifies the appearance of nonclassical features of the system. Nonclassicality of dynamical systems can be a potential resource necessary for realizing quantum information technique. Indeed, such nonclassical features of superposition states are expected to play a key role in upcoming information science which has attracted renewed attention recently. PMID- 28736694 TI - Biochemical properties of a new thermo- and solvent-stable xylanase recovered using three phase partitioning from the extract of Bacillus oceanisediminis strain SJ3. AB - The present study investigates the production and partial biochemical characterization of an extracellular thermostable xylanase from the Bacillus oceanisediminis strain SJ3 newly recovered from Algerian soil using three phase partitioning (TPP). The maximum xylanase activity recorded after 2 days of incubation at 37 degrees C was 20.24 U/ml in the presence of oat spelt xylan. The results indicated that the enzyme recovered in the middle phase of TPP system using the optimum parameters were determined as 50% ammonium sulfate saturation with 1.0:1.5 ratio of crude extract: t-butanol at pH and temperature of 8.0 and 10 degrees C, respectively. The xylanase was recovered with 3.48 purification fold and 107% activity recovery. The enzyme was optimally active at pH 7.0 and was stable over a broad pH range of 5.0-10. The optimum temperature for xylanase activity was 55 degrees C and the half-life time at this temperature was of 6 h. At this time point the enzyme retained 50% of its activity after incubation for 2 h at 95 degrees C. The crude enzyme resist to sodium dodecyl sulfate and beta mercaptoethanol, while all the tested ions do not affect the activity of the enzyme. The recovered enzyme is, at least, stable in tested organic solvents except in propanol where a reduction of 46.5% was observed. Further, the stability of the xylanase was higher in hydrophobic solvents where a maximum stability was observed with cyclohexane. These properties make this enzyme to be highly thermostable and may be suggested as a potential candidate for application in some industrial processes. To the best of our knowledge, this is the first report of xylanase activity and recoverey using three phase partitioning from B. oceanisediminis. PMID- 28736695 TI - Comparative evaluation of wastewater-treatment microbial fuel cells in terms of organics removal, waste-sludge production, and electricity generation. AB - Microbial fuel cells (MFCs) are devices that exploit living microbes for electricity generation coupled to organics degradation. MFCs are expected to be applied to energy-saving wastewater treatment (WWT) as alternatives to activated sludge reactors (ASRs). Although extensive laboratory studies have been performed to develop technologies for WWT-MFCs, limited information is available for comparative evaluation of MFCs and ASRs in terms of organics removal and waste sludge production. In the present study, laboratory WWT experiments were performed using cassette-electrode MFCs and ASRs that were continuously supplied either with artificial domestic wastewater (ADW) containing starch and peptone or with artificial industrial wastewater (AIW) containing methanol as the major organic matter. We found that these two types of WWT reactors achieved similar organics-removal efficiencies, namely, over 93% based on chemical oxygen demands for the ADW treatment and over 97% for the AIW treatment. Sludge was routinely removed from these reactors and quantified, showing that amounts of waste sludge produced in MFCs were approximately one-third or less compared to those in ASRs. During WWT, MFCs continuously generated electricity with Coulombic efficiencies of 20% or more. In reference to ASRs, MFCs are demonstrated to be attractive WWT facilities in terms of stable organics removal and low waste-sludge production. Along with the unnecessity of electric power for aeration and the generation of power during WWT, the results obtained in the present study suggest that MFCs enable substantial energy saving during WWT. PMID- 28736696 TI - Endobronchial lipoma causing progressive dyspnea. AB - We describe a 63-year-old male who presented with progressive exertional dyspnea, post-obstructive pneumonia and chest CT findings of an endobronchial lesion. Bronchoscopy revealed an endobronchial lipoma, which was resected using snare electrocautery. Complete resolution of the patient's symptoms was noted following bronchoscopic resection. PMID- 28736697 TI - Nasal application of petrolatum ointment - A silent cause of exogenous lipoid pneumonia: Successfully treated with prednisolone. AB - We report a case of exogenous lipoid pneumonia from chronic, extranasal use of petrolatum ointment (Vicks VapoRub in this case) for nasal decongestion in a young woman, presenting with cough, dyspnea and fever. Exogenous Lipoid pneumonia is a rare condition, underdiagnosed and is more prevalent in adults. Usually asymptomatic and diagnosed while evaluating predisposed patients who become clinically unstable or an abnormal lung shadow or during evaluation of rhinobronchial allergy. It is rarely reported from chronic use of petrolatum ointment extranasally and was diagnosed by transbronchial biopsy in the present case. She was found, retrospectively, to have been using petrolatum ointment, as an extranasal application since more than a year at bedtime. She didn't give history of using any other oil-based nasal topical vasoconstrictor preparations for sinusitis. Our patient was managed with discontinuation of further use of the petrolatum ointment and treatment with prednisolone apart from her regular treatment for chronic rhinobronchial allergy. Patient is stable without any further radiological deterioration during follow-up of one year. PMID- 28736699 TI - From Galapagos doves to passerines: Spillover of Haemoproteus multipigmentatus. AB - Haemoproteus (Haemoproteus) multipigmentatus, a haemosporidian parasite thought to be specific to columbiform birds, was detected in passeriform birds on Santiago Island in the Galapagos archipelago. We surveyed birds along an altitudinal gradient on the islands of Santa Cruz, Isabela and Santiago between June 2013 and July 2015. Molecular screening of 2254 individuals from 25 species of endemic and introduced birds revealed clusters of passerine birds positive for H. multipigmentatus on Santiago Island that coincide with captures of Galapagos doves at sampled sites. Of 507 individuals from 10 species of endemic passerines sampled on Santiago, 58 individuals from 6 species were found positive (11% prevalence). However, no gametocytes were found in the blood smears of positive passerines, suggesting that these species are not competent hosts for the parasite. All 31 doves captured were positive and gametocytes were found upon microscopic examination of all thin blood smears (averaging 357 gametocytes per 10,000 erythrocytes). These findings indicate parasite spillover from doves to passerines, but that passerines are possibly not competent hosts for further parasite transmission. The endemic Galapagos dove acts as a reservoir host for the introduced H. multipigmentatus, however the effect of this parasite on passerines has not been studied. We report on these findings because parasites can have large effects on individual host populations and on the ecology of a community, but may go undetected. PMID- 28736698 TI - Impact of automated ICA-based denoising of fMRI data in acute stroke patients. AB - Different strategies have been developed using Independent Component Analysis (ICA) to automatically de-noise fMRI data, either focusing on removing only certain components (e.g. motion-ICA-AROMA, Pruim et al., 2015a) or using more complex classifiers to remove multiple types of noise components (e.g. FIX, Salimi-Khorshidi et al., 2014 Griffanti et al., 2014). However, denoising data obtained in an acute setting might prove challenging: the presence of multiple noise sources may not allow focused strategies to clean the data enough and the heterogeneity in the data may be so great to critically undermine complex approaches. The purpose of this study was to explore what automated ICA based approach would better cope with these limitations when cleaning fMRI data obtained from acute stroke patients. The performance of a focused classifier (ICA AROMA) and a complex classifier (FIX) approaches were compared using data obtained from twenty consecutive acute lacunar stroke patients using metrics determining RSN identification, RSN reproducibility, changes in the BOLD variance, differences in the estimation of functional connectivity and loss of temporal degrees of freedom. The use of generic-trained FIX resulted in misclassification of components and significant loss of signal (< 80%), and was not explored further. Both ICA-AROMA and patient-trained FIX based denoising approaches resulted in significantly improved RSN reproducibility (p < 0.001), localized reduction in BOLD variance consistent with noise removal, and significant changes in functional connectivity (p < 0.001). Patient-trained FIX resulted in higher RSN identifiability (p < 0.001) and wider changes both in the BOLD variance and in functional connectivity compared to ICA-AROMA. The success of ICA-AROMA suggests that by focusing on selected components the full automation can deliver meaningful data for analysis even in population with multiple sources of noise. However, the time invested to train FIX with appropriate patient data proved valuable, particularly in improving the signal-to-noise ratio. PMID- 28736700 TI - Profiling and characterization of a longissimus dorsi muscle microRNA dataset from an F2 Duroc * Pietrain pig resource population. AB - To elucidate the effects of microRNA (miRNA) regulation in skeletal muscle of adult pigs, miRNA expression profiling was performed with RNA extracted from longissimus dorsi (LD) muscle samples from 174 F2 pigs (~ 5.5 months of age) from a Duroc * Pietrain resource population. Total RNA was extracted from LD samples, and libraries were sequenced on an Illumina HiSeq 2500 platform in 1 * 50 bp format. After processing, 232,826,977 total reads were aligned to the Sus scrofa reference genome (v10.2.79), with 74.8% of total reads mapping successfully. The miRDeep2 software package was utilized to quantify annotated Sus scrofa mature miRNAs from miRBase (Release 21) and to predict candidate novel miRNA precursors. Among the retained 295 normalized mature miRNA expression profiles ssc-miR-1, ssc miR-133a-3p, ssc-miR-378, ssc-miR-206, and ssc-miR-10b were the most abundant, all of which have previously been shown to be expressed in pig skeletal muscle. Additionally, 27 unique candidate novel miRNA precursors were identified exhibiting homologous sequence to annotated human miRNAs. The composition of classes of small RNA present in this dataset was also characterized; while the majority of unique expressed sequence tags were not annotated in any of the queried databases, the most abundantly expressed class of small RNA in this dataset was miRNAs. This data provides a resource to evaluate miRNA regulation of gene expression and effects on complex trait phenotypes in adult pig skeletal muscle. The raw sequencing data were deposited in the Sequence Read Archive, BioProject PRJNA363073. PMID- 28736701 TI - A comparative genome analysis of Cercospora sojina with other members of the pathogen genus Mycosphaerella on different plant hosts. AB - Fungi are the causal agents of many of the world's most serious plant diseases causing disastrous consequences for large-scale agricultural production. Pathogenicity genomic basis is complex in fungi as multicellular eukaryotic pathogens. Here, we report the genome sequence of C. sojina, and comparative genome analysis with plant pathogen members of the genus Mycosphaerella (Zymoseptoria. tritici (synonyms M. graminicola), M. pini, M. populorum and M. fijiensis - pathogens of wheat, pine, poplar and banana, respectively). Synteny or collinearity was limited between genomes of major Mycosphaerella pathogens. Comparative analysis with these related pathogen genomes indicated distinct genome-wide repeat organization features. It suggests repetitive elements might be responsible for considerable evolutionary genomic changes. These results reveal the background of genomic differences and similarities between Dothideomycete species. Wide diversity as well as conservation on genome features forms the potential genomic basis of the pathogen specialization, such as pathogenicity to woody vs. herbaceous hosts. Through comparative genome analysis among five Dothideomycete species, our results have shed light on the genome features of these related fungi species. It provides insight for understanding the genomic basis of fungal pathogenicity and disease resistance in the crop hosts. PMID- 28736702 TI - Cultivar-specific transcriptome prediction and annotation in Ficus carica L. AB - The availability of transcriptomic data sequence is a key step for functional genomics studies. Recently, a repertoire of predicted genes of a Japanese cultivar of fig (Ficus carica L.) was released. Because of the great phenotypic variability that can be found in this species, we decided to study another fig genotype, the Italian cv. Dottato, in order to perform comparative studies between the two cultivars and extend the pan genome of this species. We isolated, sequenced and assembled fig genomic DNA from young fruits of cv. Dottato. Then, putative gene sequences were predicted and annotated. Finally, a comparison was performed between cvs. Dottato and Horaishi predicted transcriptomes. Our data provide a resource (available at the Sequence Read Archive database under SRP109082) to be used for functional genomics of fig, in order to fill the gap of knowledge still existing in this species concerning plant development, defense and adaptation to the environment. PMID- 28736703 TI - Genome-wide miRNA, gene and methylation analysis of triple negative breast cancer to identify changes associated with lymph node metastases. AB - Triple negative breast cancer (TNBC) is a particularly important breast cancer subtype with an aggressive clinical phenotype that is associated with a higher likelihood of metastasis. This subtype is characterized by an absence of the estrogen (ER) and progesterone (PR) receptors, as well as the human epidermal growth factor receptor 2 (HER2/HER neu). The absence of the three receptors significantly reduces targeted treatment options for patients with TNBC and as such, there is an urgent need to identify novel treatment targets. Here, we provide detailed information regarding the design of a multi-platform dataset that describes genome-wide assessment of miRNA (assessed by microarray, GSE38167) and gene expression (assessed by microarray, GSE61723), as well as methylation (assessed by Illumina HM450K BeadChip, GSE78751) in TNBCs, matched normal adjacent tissues and matched lymph node metastases. The use of this multi platform dataset is likely to uncover novel markers and key pathways involved in progression to lymph node metastasis in TNBC. PMID- 28736705 TI - Polymorphic ventricular tachycardia due to change in pacemaker programming. PMID- 28736704 TI - Visualization of photoacoustic images in a limited-View measuring system using eigenvalues of a photoacoustic transmission matrix. AB - Photoacoustic imaging is a unique imaging method that involves extracting information from points at different depths, an advantage of ultrasound imaging, while maintaining functional information, a key feature of conventional photo imaging. This makes it easy to add functional images to ultrasound images by adding a laser pulse source to the conventional ultrasound imaging device and detecting a photo-ultrasound signal via a conventional ultrasound probe. One challenge when using normal one-dimensional (1D) probes and generating photoacoustic images is the limited-view problem, in which artefacts are observed due to the positions of the ultrasound transducers. In this study, we used a photoacoustic transmission matrix (PA-TM) for simulation and performed a verification test using a 1D probe and a phantom. The results confirmed that the eigenvalues of the PA-TM visualized the light absorber itself in the limited-view measurement system, which eliminates reconstruction artefacts and further scattering artefacts, and that visualization is possible by signal intensity amplification through further phase modulation. PMID- 28736706 TI - Pulmonary vein isolation for paroxysmal atrial fibrillation in a patient with stand-alone unroofed coronary sinus. PMID- 28736707 TI - Abnormal atrial strain with speckle-tracking echocardiography predicts the arrhythmic substrate of atypical right atrial flutter. PMID- 28736708 TI - Usefulness of a multi-spline duodecapolar catheter with smaller electrodes and closer spacings for mapping and ablation of Purkinje-related premature ventricular contraction and triggered ventricular fibrillation. PMID- 28736709 TI - Spatiotemporal characterization of the transition from sinus rhythm to ventricular fibrillation during an acute ischemic event in the intact human heart by whole-heart sock-mapping. PMID- 28736710 TI - Two apparently remote types of ventricular tachycardia from a single right bundle branch focal source. PMID- 28736711 TI - Left ventricular pseudoaneurysm as a complication of left ventricular summit premature ventricular contraction ablation. PMID- 28736712 TI - Successful ablation for non-pulmonary multi-foci atrial fibrillation/tachycardia in a patient with coronary sinus ostial atresia by transseptal puncture and epicardial approach. PMID- 28736713 TI - A subtype of idiopathic ventricular fibrillation and its relevance to catheter ablation and genetic variants. PMID- 28736714 TI - Correlation between functional electrical gaps identified by ultrahigh-density mapping and by late gadolinium enhancement cardiac magnetic resonance in repeat atrial fibrillation procedure. PMID- 28736715 TI - A case of liver abscess and fusobacterium septicemia. AB - Fusobacterium species are well described as the causative pathogen in Lemierre's syndrome, a suppurative thrombophlebitis of the jugular vein. However, they are less recognized for a unique variant of Lemierre's syndrome presenting with invasive intraabdominal infection and associated portal vein thrombosis. We describe a case of Fusobacterium nucleatum with hepatic abscess and septic pylephlebitis. PMID- 28736716 TI - Mucositis and oral infections secondary to gram negative rods in patients with prolonged neutropenia. AB - Patients with prolonged neutropenia are at risk for a variety of complications and infections including the development of mucositis and oral ulcers. The changes in oral flora during chemotherapy and its effects on the development of infections of the oral cavity have been studied with inconsistent results. However, there is evidence that supports the colonization of gram negative rods in patients undergoing chemotherapy. In this report, we present two leukemic patients who developed oral ulcers secondary to multi-drug resistant Pseudomonas aeruginosa. It is important to suspect multi-drug resistant gram negative rods in patients with prolonged neutropenia who develop gum infections despite appropriate antibiotic coverage. PMID- 28736717 TI - A case of suspected symptomatic Zika Neuroretinitis. PMID- 28736718 TI - Type 3 Gaucher disease, diagnostic in adulthood. PMID- 28736719 TI - Lipid profile in adult patients with Fabry disease - Ten-year follow up. AB - BACKGROUND: Fabry disease, an X-linked genetic condition, results from alpha galactosidase deficiency and increased accumulation of glycosphingolipids in cardiovascular tissues. Clinical manifestation includes vasculature associated complications. Hyperlipidaemia is one of the cardiovascular risk factors however it has never been well defined in Fabry disease. Enzyme Replacement Therapy (ERT) is available but its effect on serum cholesterol is unknown. The aim of this project was to assess the influence of long-term ERT on lipid profile in a large cohort of adult patients with Fabry disease. METHODS: This was a retrospective analysis of lipid profile results. Patients with Fabry disease were on ERT for 10 years, were not treated with statins and had no severe renal impairment. All patients had lipid profile measured before ERT was commenced and 6, 12, 24, 36, 48, 60, 120 months later. Statistical analysis included ANOVA, Student t-test and descriptive statistics. RESULTS: Among 72 patients, 40 were females (median age 45; range 29-75), 32 males (median age 46; range 20-69). There was no significant difference in total cholesterol or HDL-cholesterol measured at baseline before ERT was commenced and 6, 12, 24, 36, 48, 60 and 120 months after ERT was commenced in 72 patients (ANOVA; P = 0.673 and P = 0.883, respectively). Female patients on ERT had higher mean HDL-cholesterol as compared to female patients with Fabry disease who were asymptomatic and not treated (P >= 0.05). Total cholesterol between treated and non-treated female patients was comparable. Female patients on ERT have higher total cholesterol and HDL-cholesterol when compared to lipid results in male patients on ERT. Total cholesterol/HDL cholesterol ratio was low in female and male patients on ERT over 10 years. CONCLUSION: Adult patients with Fabry disease have remarkably elevated HDL cholesterol and as a result, elevated total cholesterol. It is possible that elevated HDL-cholesterol has a cardioprotective effect in patients with this condition. Long term ERT does not have a significant impact on lipid profile in female and male population with Fabry disease. PMID- 28736720 TI - Mitochondrial cardioencephalopathy due to a COQ4 mutation. PMID- 28736721 TI - Oddities Sporadic Neurofibroma of the Urinary Bladder. A Case Report. AB - Neurofibromas of the urinary bladder are an exceedingly rare entity and are considered mostly in conjunction with the disease of neurofibromatosis type 1. The fortuitous discovery of vesical plexiform neurofibromas without other stigmata of the disease is presented in a 57-year-old male patient. The course of his condition, modalities of investigation and a non-precedent treatment plan are demonstrated. PMID- 28736723 TI - Synthesis and characterization of bacterial cellulose and gelatin-based hydrogel composites for drug-delivery systems. AB - Bacterial cellulose and gelatin were successfully used to develop a hydrogel composite material. Hydrogel was synthesized by copolymerization between bacterial cellulose and gelatin. Scanning electron microscopy (SEM) images showed that the bacterial cellulose chain was uniform in size and shape. Glutaraldehyde was employed as a crosslinking agent. H-bonds were formed via the reaction between the amine and hydroxyl groups, which were the functional groups of the gelatin and bacterial cellulose, respectively. The hydrogel composite presented excellent properties in terms of its thermal stability, chemical resistance, and mechanical properties. Moreover, the swelling ratio of the hydrogel network, in water, was estimated to be 400-600%. Importantly, the hydrogel composite developed during this study is considered a good candidate for drug-delivery systems. PMID- 28736722 TI - Alterations in antioxidant system, mitochondrial biogenesis and autophagy in preeclamptic myometrium. AB - Preeclampsia is a pregnancy complication which causes significant maternal and fetal morbidity and mortality worldwide. Although intensive research has been performed in the last 40 years, the pathology of preeclampsia is still poorly understood. The present work is a comparative study of the myometrium of women with normal pregnancy, and those with late- and early-onset preeclampsia (n = 10 for each group). We observed significant changes in the levels of antioxidant enzymes, markers of mitochondrial biogenesis and autophagy proteins in preeclamptic myometrium. Levels of superoxide dismutase 1 and catalase were lower in both preeclamptic groups than the control group. In late-onset preeclampsia, expression levels of essential mitochondria-related proteins VDAC1, TFAM, hexokinase 1, PGC-1alpha and PGC-1beta, and autophagy marker LC3A, were significantly elevated. In the myometrium of the early-onset preeclampsia group OPA1 and Bcl-2 were up-regulated compared to those of the control (p < 0.05). These findings suggest that crucial molecular changes in the maternal myometrium occur with the development of preeclampsia. PMID- 28736724 TI - Biodecolorization of textile azo dye using Bacillus sp. strain CH12 isolated from alkaline lake. AB - Textile azo dye decolorizing bacteria were isolated from alkaline Lakes Abaya and Chamo using Reactive Red 239 (RR239) dye. Through subsequent screening process, strain CH12 was selected to investigate the effects of nutrient supplement, DO, pH, temperature, dye concentration and types on decolorization. Based on 16S rRNA gene sequence analysis, strain CH12 was identified as Bacillus sp. Decolorization efficiencies were significantly enhanced with carbon (>=98%) and organic nitrogen (~100%) supplements. Complete decolorization was also observed under anoxic and anaerobic conditions, and at the temperature of 30 degrees C and the pH of 10. However, the azo dye decolorization efficiency of strain CH12 was significantly reduced when NaNO3 (1-8%) was supplemented or under aerobic culturing condition (<=6%), indicating that RR239 was less preferred electron acceptor. Overall, strain CH12 can be a promising candidate for decolorization applications due to its potential to effectively decolorize higher RR239 concentrations (50-250 mg/L) and six additional dyes. PMID- 28736725 TI - Intraoperative Radiation Therapy: A Promising Treatment Modality in Head and Neck Cancer. AB - Every year, almost 62,000 are diagnosed with a head and neck cancer (HNC) and 13,000 will succumb to their disease. In the primary setting, intraoperative radiation therapy (IORT) can be used as a boost in select patients in order to optimize local control. Addition of external beam radiation to limited volumes results in improved disease control over surgery and IORT alone. In the recurrent setting, IORT can improve outcomes from salvage surgery especially in patients previously treated with external beam radiation. The use of IORT remains limited to select institutions with various modalities being currently employed including orthovoltage, electrons, and high-dose rate brachytherapy. Practically, execution of IORT requires a coordinated effort and careful planning by a multidisciplinary team involving the head and neck surgeon, radiation oncologist, and physicist. The current review summarizes common uses, outcomes, toxicities, and technical aspects of IORT in HNC patients. PMID- 28736726 TI - Social and Emotional Wellbeing Screening for Aboriginal and Torres Strait Islanders within Primary Health Care: A Series of Missed Opportunities? AB - BACKGROUND: Social and emotional wellbeing (SEWB) is a critical determinant of health outcomes for Indigenous Australians. This study examined the extent to which primary healthcare services (PHSs) undertake SEWB screening and management of Aboriginal and Torres Strait Islander clients, and the variation in SEWB screening and management across Indigenous PHS. METHODS: Cross-sectional analysis between 2012 and 2014 of 3,407 Indigenous client records from a non representative sample of 100 PHSs in 4 Australian states/territory was undertaken to examine variation in the documentation of: (1) SEWB screening using identified measurement instruments, (2) concern regarding SEWB, (3) actions in response to concern, and (4) follow up actions. Binary logistic regression was used to determine the factors associated with screening. RESULTS: The largest variation in SEWB screening occurred at the state/territory level. The mean rate of screening across the sample was 26.6%, ranging from 13.7 to 37.1%. Variation was also related to PHS characteristics. A mean prevalence of identified SEWB concern was 13% across the sample, ranging from 9 to 45.1%. For the clients where SEWB concern was noted, 25.4% had no referral or PHS action recorded. Subsequent internal PHS follow up after 1 month occurred in 54.7% of cases; and six-monthly follow up of referrals to external services occurred in 50.9% of cases. CONCLUSION: Our findings suggest that the lack of a clear model or set of guidelines on best practice for screening for SEWB in Indigenous health may contribute to the wide variation in SEWB service provision. The results tell a story of missed opportunities: 73.4% of clients were not screened and no further action was taken for 25.4% for whom an SEWB concern was identified. There was no follow up for just under half of those for whom action was taken. There is a need for the development of national best practice guidelines for SEWB screening and management, accompanied by dedicated SEWB funding, and training for health service providers as well as ongoing monitoring of adherence with the guidelines. Further research on barriers to screening and follow up actions is also warranted. PMID- 28736727 TI - Blood Lead Levels among Children in Yaounde Cameroon. AB - Blood lead levels (BLLs) are a useful indication of a population exposure to lead from environmental sources. No previous published study had reported BLLs in Cameroon. Our objective is to characterize exposure levels in children to inform policymakers of potential lead exposure sources. We tested the BLLs of 147 children aged 12 months to 6 years residing in Yaounde, Cameroon, and conducted an extensive questionnaire with their parents or guardians to characterize potential exposure sources. The geometric mean BLL among this population was 8.0 MUg/dl and arithmetic mean level was 8.7 MUg/dl. These levels are more than sixfold higher than the geometric mean BLL reported in the U.S. and more than fivefold higher than those reported in France. In addition, 88% of the children tested had lead levels greater than 5 MUg/dl. One limitation of the study is that the selection of the children sampled was not a random survey. The analysis of the responses to the questionnaire failed to uncover any specific exposure patterns. A statistically significant association was noted between the age of the child's home and the duration of exclusive breastfeeding with BLLs. The study points to a need for greater efforts to control sources of lead exposure in Cameroon. PMID- 28736728 TI - The Influence of Apical and Basal Defoliation on the Canopy Structure and Biochemical Composition of Vitis vinifera cv. Shiraz Grapes and Wine. AB - Defoliation is a commonly used viticultural technique to balance the ratio between grapevine vegetation and fruit. Defoliation is conducted around the fruit zone to reduce the leaf photosynthetic area, and to increase sunlight exposure of grape bunches. Apical leaf removal is not commonly practiced, and therefore its influence on canopy structure and resultant wine aroma is not well-studied. This study quantified the influences of apical and basal defoliation on canopy structure parameters using canopy cover photography and computer vision algorithms. The influence of canopy structure changes on the chemical compositions of grapes and wines was investigated over two vintages (2010-2011 and 2015-2016) in Yarra Valley, Australia. The Shiraz grapevines were subjected to five different treatments: no leaf removal (Ctrl); basal (TB) and apical (TD) leaf removal at veraison and intermediate ripeness, respectively. Basal leaf removal significantly reduced the leaf area index and foliage cover and increased canopy porosity, while apical leaf removal had limited influences on canopy parameters. However, the latter tended to result in lower alcohol level in the finished wine. Statistically significant increases in pH and decreases in TA was observed in shaded grapes, while no significant changes in the color profile and volatile compounds of the resultant wine were found. These results suggest that apical leaf removal is an effective method to reduce wine alcohol concentration with minimal influences on wine composition. PMID- 28736729 TI - Factors Promoting Development of Fibrosis in Crohn's Disease. AB - The concepts on the pathophysiology of intestinal fibrosis in Crohn's disease (CD) have changed in recent years. Some years ago fibrosis was regarded to be a consequence of long-standing inflammation with subsequent destruction of the gut wall matrix followed by scar formation and collagen deposition. Fibrosis in CD patients appeared to be an irreversible process that could hardly be influenced. Therefore, the main target in CD therapy was to control inflammation to avoid fibrosis development. Many of these assumptions seem to be only partially true. Inflammation may be a necessary prerequisite for the initiation of fibrosis. However, when the pathophysiologic processes that lead to fibrosis in CD patients have been initiated fibrosis development may be independent of inflammation and may continue even when inflammation is under good medical control. Fibrosis in CD also may be reversible. After strictureplasty local collagen deposits decrease or even disappear. With new animal models for intestinal fibrosis on the horizon, we need to spend more efforts on understanding the factors influencing fibrosis in CD patients to finally find specific therapies. In this context, it will be as important to find markers and quantitative imaging tools to have reliable endpoints for clinical trials in fibrosing CD. PMID- 28736730 TI - New Insight into microRNA Functions in Cancer: Oncogene-microRNA-Tumor Suppressor Gene Network. AB - Tumorigenesis is a multi-step and complex process with multi-factors involved. Deregulated oncogenes and tumor suppressor genes (TSGs) induced by genetic and epigenetic factors are considered as the driving force in the development and progression of cancer. Besides, microRNAs (miRNAs) act vital roles in tumorigenesis through regulating some oncogenes and TSGs. Interestingly, miRNAs are also regulated by oncogenes and TSGs. Considering the entangled regulation, here we propose a new insight into these regulation relationships in cancer: oncogene-miRNA-TSG network, which further emphasizes roles of miRNA, as well as highlights the network regulation among oncogene, miRNA, and TSG during tumorigenesis. The oncogene-miRNA-TSG network demonstrates that oncogenes and TSGs not only show functional synergy, but also there are regulatory relationships among oncogenes and TSGs during tumorigenesis, which could be mediated by miRNAs. In view of the oncogene-miRNA-TSG network involved in many oncogenes, miRNAs, and TSGs, as well as occurring in various tumor types, the anomaly of this network may be a common event in cancers and participates in tumorigenesis. This hypothesis broadens horizons of molecular mechanisms underlying tumorigenesis, and may provide a new promising venue for the prediction, diagnosis, and even therapy of cancer. PMID- 28736731 TI - A mixed methods systematic review of success factors of mhealth and telehealth for maternal health in Sub-Saharan Africa. AB - Access to health care is still limited for many women in sub-Saharan Africa (SSA), while it remains an important determinant of maternal mortality and morbidity. Information and communication technologies (ICTs), such as mhealth and telehealth, can help to facilitate this access by acting on the various obstacles encountered by women, be they socio-cultural, economic, geographical or organizational. However, various factors contribute to the success of mhealth and telehealth implementation and use, and must be considered for these technologies to go beyond the pilot project stage. The objective of this systematic literature review is to synthesize the empirical knowledge on the success factors of the implementation and use of telehealth and mhealth to facilitate access to maternal care in SSA. The methodology used is based on that of the Cochrane Collaboration, including a documentary search using standardized language in six databases, selection of studies corresponding to the inclusion criteria, data extraction, evaluation of study quality, and synthesis of the results. A total of 93 articles were identified, which allowed the inclusion of seven studies, six of which were on mhealth. Based on the framework proposed by Broens et al., we synthesized success factors into five categories: (I) technology, such as technical support to maintain, troubleshoot and train users, good network coverage, existence of a source of energy and user friendliness; (II) user acceptance, which is facilitated by factors such as unrestricted use of the device, perceived usefulness to the worker, adequate literacy, or previous experience of use ; (III) short- and long-term funding; (IV) organizational factors, such as the existence of a well-organized health system and effective coordination of interventions; and (V) political or legislative aspects, in this case strong government support to deploy technology on a large scale. Telehealth and mhealth are promising solutions to reduce maternal morbidity and mortality in SSA, but knowledge on how these interventions can succeed and move to scale is limited. Success factors identified in this review can provide guidance on elements that should be considered in the design and implementation of telehealth and mhealth for maternal health in SSA. PMID- 28736733 TI - A model for mHealth skills training for clinicians: meeting the future now. AB - We describe the current state of mHealth skills acquisition, education, and training available to clinical professionals in educational programs. We discuss how telemedicine experienced exponential growth due in large part to the ubiquity of the mobile phone. An outcome of this unprecedented growth has been the emergence of the need for technology skills training programs for clinicians that address extant curricula gaps. We propose a model to guide the development of future training programs that incorporate effective training strategies across five domains: (I) digital communication skills; (II) technology literacy and usage skills; (III) deploying telehealth products and services; (VI) regulatory and compliance issues; and (V) telehealth business case. These domains are discussed within the context of interprofessional teams and broader organizational factors. PMID- 28736732 TI - A systematic review of studies of web portals for patients with diabetes mellitus. AB - Patient web portals are password-protected online websites that offer patients 24 hour access to personal health information from anywhere with an Internet connection. Due to advances in health information technologies, there has been increasing interest among providers and researchers in patient web portals for use by patients with diabetes and other chronic conditions. This article, which is based upon bibliographic searches in PubMed, reviews web portals for patients with diabetes mellitus including patient web portals tethered to electronic medical records and web portals developed specifically for patients with diabetes. Twelve studies of the impact of patient web portals on the management of diabetes patients were identified. Three had a cross-sectional design, 1 employed mixed-methods, one had a matched-control design, 3 had a retrospective cohort design, and 5 were randomized controlled trials. Six (50%) of the studies examined web portals tethered to electronic medical records and the remainder were web portals developed specifically for diabetes patients. The results of this review suggest that secure messaging between adult diabetic patients and their clinician is associated with improved glycemic control. However, results from observational studies indicate that many diabetic patients do not take advantage of web portal features such as secure messaging, perhaps because of a lack of internet access or lack of experience in navigating web portal resources. Although results from randomized controlled trials provide stronger evidence of the efficacy of web portal use in improving glycemic control among diabetic patients, the number of trials is small and results from the trials have been mixed. Studies suggest that secure messaging between adult diabetic patients and their clinician is associated with improved glycemic control, but negative findings have also been reported. The number of randomized controlled trials that have examined the efficacy of web portal use in improving glycemic control among diabetic patients is still small. Additional research is needed to identify specific portal features that may impact quality of care or improve glycemic control. PMID- 28736734 TI - Compliance to self-monitoring of blood glucose among patients with type 2 diabetes mellitus and its influential factors: a real-world cross-sectional study based on the Tencent TDF-I blood glucose monitoring platform. AB - BACKGROUND: To investigate the compliance to self-monitoring of blood glucose (SMBG) among patients with type 2 diabetes mellitus (T2DM) and its influential factors. METHODS: The real-world SMBG use over 90 days among 415 T2DM patients were recorded by using a blood glucose monitoring platform (TDF-I, Tencent, China). Clinical features including age, sex, duration of diabetes, insulin treatment or not, and use of oral antidiabetic drugs were collected. Poor compliance was defined as the average frequency of weekly SMBG use over 90 days was below the criteria established by the physicians, and otherwise the patients were regarded as with good compliance. Factors affecting the SMBG compliance were analyzed by using independent sample t-test, Mann-Whitney U test, and multivariate logistic regression analysis. RESULTS: Only 57.6% of patients in the study cohort had good compliance to SMBG. Multivariate logistic regression models showed that only the duration of T2DM and the use of oral antidiabetic agents were independently associated with SMBG compliance; more specifically, patients with longer course of disease had poorer SMBG compliance, and those had used oral antidiabetic agents had poorer SMBG compliance. CONCLUSIONS: SMBG compliance in T2DM patients needs to be further improved. For patients with a longer course of disease and/or under oral antidiabetic medication, interventions such as patient education should be adopted to increase the SMBG compliance. PMID- 28736735 TI - Arginine and citrulline for the treatment of MELAS syndrome. AB - MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) syndrome is a maternally inherited mitochondrial disease with a broad spectrum of manifestations. In addition to impaired energy production, nitric oxide (NO) deficiency occurs in MELAS syndrome and leads to impaired blood perfusion in microvasculature that can contribute to several complications including stroke-like episodes, myopathy, and lactic acidosis. The supplementation of NO precursors, L-arginine and L-citrulline, increases NO production and hence can potentially have therapeutic utility in MELAS syndrome. L-citrulline raises NO production to a greater extent than L-arginine; therefore, L-citrulline may have a better therapeutic effect. The clinical effect of L citrulline has not yet been studied and clinical studies on L-arginine, which are limited, only evaluated the stroke-like episodes aspect of the disease. Controlled studies are still needed to assess the clinical effects of L-arginine and L-citrulline on different aspects of MELAS syndrome. PMID- 28736736 TI - Feedback-Driven Sensory Mapping Adaptation for Robust Speech Activity Detection. AB - Parsing natural acoustic scenes using computational methodologies poses many challenges. Given the rich and complex nature of the acoustic environment, data mismatch between train and test conditions is a major hurdle in data-driven audio processing systems. In contrast, the brain exhibits a remarkable ability at segmenting acoustic scenes with relative ease. When tackling challenging listening conditions that are often faced in everyday life, the biological system relies on a number of principles that allow it to effortlessly parse its rich soundscape. In the current study, we leverage a key principle employed by the auditory system: its ability to adapt the neural representation of its sensory input in a high-dimensional space. We propose a framework that mimics this process in a computational model for robust speech activity detection. The system employs a 2-D Gabor filter bank whose parameters are retuned offline to improve the separability between the feature representation of speech and nonspeech sounds. This retuning process, driven by feedback from statistical models of speech and nonspeech classes, attempts to minimize the misclassification risk of mismatched data, with respect to the original statistical models. We hypothesize that this risk minimization procedure results in an emphasis of unique speech and nonspeech modulations in the high-dimensional space. We show that such an adapted system is indeed robust to other novel conditions, with a marked reduction in equal error rates for a variety of databases with additive and convolutive noise distortions. We discuss the lessons learned from biology with regard to adapting to an ever-changing acoustic environment and the impact on building truly intelligent audio processing systems. PMID- 28736737 TI - Diffraction tomography with Fourier ptychography. AB - This paper presents a technique to image the complex index of refraction of a sample across three dimensions. The only required hardware is a standard microscope and an array of LEDs. The method, termed Fourier ptychographic tomography (FPT), first captures a sequence of intensity-only images of a sample under angularly varying illumination. Then, using principles from ptychography and diffraction tomography, it computationally solves for the sample structure in three dimensions. The experimental microscope demonstrates a lateral spatial resolution of 0.39 MUm and an axial resolution of 3.7 MUm at the Nyquist-Shannon sampling limit (0.54 and 5.0 MUm at the Sparrow limit, respectively) across a total imaging depth of 110 MUm. Unlike competing methods, this technique quantitatively measures the volumetric refractive index of primarily transparent and contiguous sample features without the need for interferometry or any moving parts. Wide field-of-view reconstructions of thick biological specimens suggest potential applications in pathology and developmental biology. PMID- 28736739 TI - Data and code for the exploratory data analysis of the electrical energy demand in the time domain in Greece. AB - We present data and code for visualizing the electrical energy data and weather-, climate-related and socioeconomic variables in the time domain in Greece. The electrical energy data include hourly demand, weekly-ahead forecasted values of the demand provided by the Greek Independent Power Transmission Operator and pricing values in Greece. We also present the daily temperature in Athens and the Gross Domestic Product of Greece. The code combines the data to a single report, which includes all visualizations with combinations of all variables in multiple time scales. The data and code were used in Tyralis et al. (2017) [1]. PMID- 28736738 TI - Preserving and restoring bone with continuous insulin infusion therapy in a mouse model of type 1 diabetes. AB - Those with type 1 diabetes (T1D) are more likely to suffer a fracture than age- and sex-matched individuals without diabetes, despite daily insulin therapy. In rodent studies examining the effect of bone- or glucose-targeting therapies on preventing the T1D-related decrease in bone strength, insulin co-therapy is often not included, despite the known importance of insulin signaling to bone mass accrual. Therefore, working toward a relevant pre-clinical model of diabetic bone disease, we assessed the effect of continuous subcutaneous insulin infusion (CSII) therapy at escalating doses on preserving bone and the effect of delayed CSII on rescuing the T1D-related bone deterioration in an established murine model of T1D. Osmotic minipumps were implanted in male DBA/2 J mice 2 weeks (prevention study) and 6 weeks (rescue study) after the first injection of streptozotocin (STZ) to deliver insulin at 0, 0.0625, 0.125, or 0.25 IU/day (prevention study; n = 4-5 per dose) and 0 or 0.25 IU/day (rescue study; n = 10 per group). CSII lasted 4 weeks in both studies, which also included age-matched, non-diabetic DBA/2 J mice (n = 8-12 per study). As the insulin dose increased, blood glucose decreased, body weight increased, a serum maker of bone resorption decreased, and a serum marker of bone formation increased such that each end point characteristic was linearly correlated with dose. There were insulin dose dependent relationships (femur diaphysis) with cross-sectional area of cortical bone and cortical thickness (micro-computed tomography) as well as structural strength (peak force endured by the mid-shaft during three-point bending). Likewise, trabecular bone volume fraction (BV/TV), thickness, and number (distal femur metaphysis) increased as the insulin dose increased. Delayed CSII improved glycated hemoglobin (HbA1c), but blood glucose levels remained relatively high (well above non-diabetic levels). Interestingly, it returned the resorption and formation markers to similar levels as those seen in non-T1D control mice. This apparent return after 4 weeks of CSII translated to a partial rescue of the structural strength of the femur mid-shaft. Delayed CSII also increased Tb.Th to levels seen in non-T1D controls but did not fully restore BV/TV. The use of exogenous insulin should be considered in pre-clinical studies investigating the effect of T1D on bone as insulin therapy maintains bone structure without necessarily lowering glucose below diabetic levels. PMID- 28736740 TI - Datasets of mung bean proteins and metabolites from four different cultivars. AB - Plants produce a wide array of nutrients that exert synergistic interaction among whole combinations of nutrients. Therefore comprehensive nutrient profiling is required to evaluate their nutritional/nutraceutical value and health promoting effect. In order to obtain such datasets for mung bean, which is known as a medicinal plant with heat alleviating effect, proteomic and metabolomic analyses were performed using four cultivars from China, Thailand, and Myanmar. In total, 449 proteins and 210 metabolic compounds were identified in seed coat; whereas 480 proteins and 217 metabolic compounds were detected in seed flesh, establishing the first comprehensive dataset of mung bean for nutraceutical evaluation. PMID- 28736741 TI - Elevated tumor mutational burden and prolonged clinical response to anti-PD-L1 antibody in platinum-resistant recurrent ovarian cancer. AB - *We report an ovarian cancer patient with a prolonged response to immunotherapy.*Comprehensive genomic profiling may detect patients who benefit from immunotherapy.*Mutational burden thresholds for ovarian cancer may be lower than other cancers. PMID- 28736743 TI - Oncolytic Adenovirus-Loaded Menstrual Blood Stem Cells Overcome the Blockade of Viral Activity Exerted by Ovarian Cancer Ascites. AB - Patients with ovarian cancer present peritoneal ascites at recurrence as a marker of disseminated disease and dismal prognosis. Oncolytic immunotherapy is an emerging approach for the treatment of disseminated cancer. In the present work, we constructed a novel oncolytic adenovirus, AR2011, to target malignant ovarian tumors. AR2011 exhibited a clear lytic effect in vitro in human ovarian cancer cell lines and malignant cells obtained from ascitic fluids (AFs) of patients with ovarian cancer. AR2011 activity was neutralized by antibodies present in 31 samples of patient-derived AFs. However, this blockade was overridden by preloading menstrual blood stem cells (MenSCs) with AR2011 (MenSC-AR), since AFs exerted no in vitro inhibitory effect on viral lytic activity under these conditions. Moreover, soluble factors present in AFs act as MenSC chemoattractants. MenSC-AR treatment of nude mice carrying established peritoneal carcinomatosis following administration of human ovarian cancer cells was able to inhibit tumor growth at levels similar to those observed with AR2011 alone. This study demonstrates that MenSCs can be used to override the blockade that AFs exert on viral oncolytic effects. PMID- 28736742 TI - Unique morphological characteristics of mitochondrial subtypes in the heart: the effect of ischemia and ischemic preconditioning. AB - RATIONALE: Three subsets of mitochondria have been described in adult cardiomyocytes - intermyofibrillar (IMF), subsarcolemmal (SSM), and perinuclear (PN). They have been shown to differ in physiology, but whether they also vary in morphological characteristics is unknown. Ischemic preconditioning (IPC) is known to prevent mitochondrial dysfunction induced by acute myocardial ischemia/reperfusion injury (IRI), but whether IPC can also modulate mitochondrial morphology is not known. AIMS: Morphological characteristics of three different subsets of adult cardiac mitochondria along with the effect of ischemia and IPC on mitochondrial morphology will be investigated. METHODS: Mouse hearts were subjected to the following treatments (N=6 for each group): stabilization only, IPC (3x5 min cycles of global ischemia and reperfusion), ischemia only (20 min global ischemia); and IPC and ischemia. Hearts were then processed for electron microscopy and mitochondrial morphology was assessed subsequently. RESULTS: In adult cardiomyocytes, IMF mitochondria were found to be more elongated and less spherical than PN and SSM mitochondria. PN mitochondria were smaller in size when compared to the other two subsets. SSM mitochondria had similar area to IMF mitochondria but their sphericity measures were similar to PN mitochondria. Ischemia was shown to increase the sphericity parameters of all 3 subsets of mitochondria; reduce the length of IMF mitochondria, and increase the size of PN mitochondria. IPC had no effect on mitochondrial morphology either at baseline or after ischemia. CONCLUSION: The three subsets of mitochondria in the adult heart are morphologically different. IPC does not appear to modulate mitochondrial morphology in adult cardiomyocytes. PMID- 28736745 TI - Jejunal Injury as a Rare Complication of Percutaneous Nephrolithotomy: Case Report. AB - Background: Colonic injury represents a rare complication of percutaneous nephrolithotomy (PCNL). Injury of the small bowel is very rare, with only anecdotal case reports in the literature. We report here a rare PCNL complication of jejunal perforation without concomitant colonic injury. Case Presentation: A 45-year-old male underwent PCNL for multiple left kidney stones. At the beginning of the procedure, we faced difficulty in achieving access, but after that the procedure was straightforward and ended smoothly. However, from the third day, the postoperative course became stormy with progressive development of picture of acute peritonitis. Laparotomy was mandatory and jejunal perforation was found and repaired. Conclusion: Although extremely rare, small bowel injury should be kept in mind during planning for percutaneous nephrolithotomy. Prompt diagnosis and active treatment should be undertaken without delay especially if picture of acute peritonitis is developed. PMID- 28736744 TI - Computational fluid dynamics study on the influence of an alternate ventilation configuration on the possible flow path of infectious cough aerosols in a mock airborne infection isolation room. AB - When infectious epidemics occur, they can be perpetuated within health care settings, potentially resulting in severe health care workforce absenteeism, morbidity, mortality, and economic losses. The ventilation system configuration of an airborne infection isolation room is one factor that can play a role in protecting health care workers from infectious patient bioaerosols. Though commonly associated with airborne infectious diseases, the airborne infection isolation room design can also impact other transmission routes such as short range airborne as well as fomite and contact transmission routes that are impacted by contagion concentration and recirculation. This article presents a computational fluid dynamics study on the influence of the ventilation configuration on the possible flow path of bioaerosol dispersal behavior in a mock airborne infection isolation room. At first, a mock airborne infection isolation room was modeled that has the room geometry and layout, ventilation parameters, and pressurization corresponding to that of a traditional ceiling mounted ventilation arrangement observed in existing hospitals. An alternate ventilation configuration was then modeled to retain the linear supply diffuser in the original mock airborne infection isolation room but interchanging the square supply and exhaust locations to place the exhaust closer to the patient source and allow clean air from supply vents to flow in clean-to-dirty flow paths, originating in uncontaminated parts of the room prior to entering the contaminated patient's air space. The modeled alternate airborne infection isolation room ventilation rate was 12 air changes per hour. Two human breathing models were used to simulate a source patient and a receiving health care worker. A patient cough cycle was introduced into the simulation, and the airborne infection dispersal was tracked in time using a multi-phase flow simulation approach. The results from the alternate configuration revealed that the cough aerosols were pulled by the exhaust vent without encountering the health care worker by 0.93 s after patient coughs and the particles were controlled as the aerosols' flow path was uninterrupted by an air particle streamline from patient to the ceiling exhaust venting out cough aerosols. However, not all the aerosols were vented out of the room. The remaining cough aerosols entered the health care worker's breathing zone by 0.98 s. This resulted in one of the critical stages in terms of the health care worker's exposure to airborne virus and presented the opportunity for the health care worker to suffer adverse health effects from the inhalation of cough aerosols. Within 2 s, the cough aerosols reentered and recirculated within the patient and health care worker's surroundings resulting in pockets of old contaminated air. By this time, coalescence losses decreased as the aerosol were no longer in very close proximity and their movement was primarily influenced by the airborne infection isolation room airflow patterns. In the patient and health care worker's area away from the supply, the fresh air supply failed to reach this part of the room to quickly dilute the cough aerosol concentration. The exhaust was also found to have minimal effect upon cough aerosol removal, except for those areas with high exhaust velocities, very close to the exhaust grill. Within 5-20 s after a patient's cough, the aerosols tended to break up to form smaller sized aerosols of less than one micron diameter. They remained airborne and entrained back into the supply air stream, spreading into the entire room. The suspended aerosols resulted in the floating time of more than 21 s in the room due to one cough cycle. The duration of airborne contagion in the room and its prolonged exposure to the health care worker is likely to happen due to successive coughing cycles. Hence, the evaluated alternate airborne infection isolation room is not effective in removing at least 38% particles exposed to health care worker within the first second of a patient's cough. PMID- 28736746 TI - Malakoplakia of the Prostate as a Mimicker of Prostate Cancer on Prostate Health Index and Magnetic Resonance Imaging-Fusion Prostate Biopsy: A Case Report. AB - Background: Isolated malakoplakia of the prostate is a rare inflammatory condition that has been clinically mistaken for prostatic malignancies. The development of Prostate Imaging Reporting and Data System (PI-RADS) classifications, and Prostate Health Index (PHI) has led to more accurate diagnosis of clinically significant disease and stratification of patients that may be at risk of prostate cancer. Case Presentation: We present a case of a 75 year-old male who was on follow-up with our hospital for elevated prostate specific antigen (PSA). He was admitted for an episode of urosepsis, which was treated with antibiotics and subsequently underwent further workup and was found to have a raised PHI, as well as a high PI-RADS classification and was later found to have malakoplakia based on histology of prostate tissue obtained during targeted magnetic resonance imaging (MRI)-guided fusion prostate biopsy. Conclusion: To our understanding, this is the first case where a prostate lesion has been labeled as a PI-RADS 5 lesion, with elevated PHI that has subsequently been proven histologically to be malakoplakia. An important possible confounder is the interval between the MRI and the episode of urosepsis and it is well known that urosepsis can affect the PSA and MRI result. We present this case to highlight the potential for a false diagnosis of prostate cancer, in spite of laboratory and radiological findings. PMID- 28736747 TI - Recurrent Dystrophic Calcification of the Prostatic Resection Cavity After Transurethral Resection of the Prostate: Clinical Presentation and Endoscopic Management. AB - Background: Dystrophic calcification (DC) can occur as a reaction to tissue damage and necrosis. So far, this has never been described as a complication after conventional transurethral resection of the prostate (TURP). Case Presentation: We report on a 59-year-old man who underwent uncomplicated monopolar TURP for lower urinary tract symptoms caused by benign prostatic hyperplasia. The patient showed an excellent course up to 5 weeks after the initial operation. Afterward he suffered from a rapid onset of irritative and obstructive voiding symptoms and pain. Complete DC of the prostatic resection cavity was found by cystoscopy and recurred quickly twice after Re-TURP despite anti-inflammatory treatment and normal urinary and metabolic findings. Complete recovery was only achieved by gently scraping off the calcifications avoiding further trauma to the residual prostatic tissue. Conclusion: In rare cases, delayed occurrence of irritative and obstructive voiding symptoms after TURP can be caused by DC of the prostatic resection cavity and might be misinterpreted as post-TURP infection. The pathomechanism of DC and the presented case suggest minimizing tissue trauma by cautious removal of calcifications rather than performing extensive Re-TURP. PMID- 28736748 TI - Troubleshooting for Ureteroscopy Complicated by Unexpected Guidewire Looping and Entrapment. AB - This report presents a bizarre and unusual case of looping and entrapment of a hydrophilic guidewire in the ureter of a 65-year-old woman with a stone in the lower ureter at the time of ureteroscopy and laser lithotripsy. We describe endourology maneuvers to remove the retained guidewire. Looping and entrapment of guidewire is a rare complication that urologists may face when they do not follow the basic principles of guidewire insertion. In that case, successful resolution is based both on surgeon's inspiration to apply the appropriate endourology maneuvers and availability of a variety of endourology tools in the theater. Both may lead urologists to avoid more invasive and morbid approaches for their patients. PMID- 28736749 TI - Synchronous Primary Renal Lymphoma and Renal Cell Carcinoma: Collision Tumors in the Same Kidney. AB - Background: Primary renal lymphoma (PRL) is an exceptionally rare disease with under 50 reported cases in the literature. PRL is an aggressive condition that can present with nonspecific symptoms and local invasion mimicking renal cell carcinoma (RCC). We present an unusual case involving a collision tumor between PRL and RCC. Case Presentation: The patient is a 62-year-old immunosuppressed man with an incidental left renal mass on cross-sectional imaging. Renal mass biopsy confirmed clear cell type RCC. He underwent robot-assisted, laparoscopic left radical nephrectomy for presumed RCC without evidence for extrarenal disease or discernable lymphadenopathy. Final pathology revealed a collision tumor, including PRL and RCC. Conclusion: To our knowledge, this is the first reported case within the literature describing a collision tumor between PRL and RCC. Although rare, it is important to consider PRL in the differential diagnosis of a solid renal mass, especially in patients with a prior history of transplantation and/or chronic immunosuppression. PMID- 28736750 TI - A Novel Defibrillation Tool: Percutaneously Delivered, Partially Insulated Epicardial Defibrillation. AB - INTRODUCTION: Epicardial defibrillation systems currently require surgical access. We aimed to develop a percutaneous defibrillation system with partially insulated epicardial coils to focus electrical energy on the myocardium and prevent or minimize extra-cardiac stimulation. METHODS: We tested 2 prototypes created for percutaneous introduction into the pericardial space via a steerable sheath. This included a partially-insulated defibrillation coil and a defibrillation mesh with a urethane balloon acting as an insulator to the face of the mesh not in contact with the epicardium. The average energy associated with a chance of successful defibrillation 75% of the time (ED75) was calculated for each experiment. RESULTS: Of 16 animal experiments, 3 pig experiments had malfunctioning mesh prototypes such that results were unreliable; these were excluded. Therefore, 13 animal experiments were analyzed - 6 canines (29.8+/ 4.0kg); 7 pigs (41.1+/-4.4kg). The overall ED75 was 12.8+/-6.7J (10.9+/-9.1J for canines; 14.4+/-3.9J in pigs [P=0.37]). The lowest ED75 obtained in canines was 2.5J while in pigs it was 9.5J. The lowest energy resulting in successful defibrillation was 2J in canines and 5J in pigs. There was no evidence of coronary vessel injury or trauma to extra-pericardial structures. CONCLUSION: Percutaneous, epicardial defibrillation using a partially insulated coil is feasible and appears to be associated with low defibrillation thresholds. Focusing insulation may limit extra-cardiac stimulation and potentially lower energy requirements for efficient defibrillation. PMID- 28736751 TI - Quantifying time-varying cellular secretions with local linear models. AB - Extracellular protein concentrations and gradients initiate a wide range of cellular responses, such as cell motility, growth, proliferation and death. Understanding inter-cellular communication requires spatio-temporal knowledge of these secreted factors and their causal relationship with cell phenotype. Techniques which can detect cellular secretions in real time are becoming more common but generalizable data analysis methodologies which can quantify concentration from these measurements are still lacking. Here we introduce a probabilistic approach in which local-linear models and the law of mass action are applied to obtain time-varying secreted concentrations from affinity-based biosensor data. We first highlight the general features of this approach using simulated data which contains both static and time-varying concentration profiles. Next we apply the technique to determine concentration of secreted antibodies from 9E10 hybridoma cells as detected using nanoplasmonic biosensors. A broad range of time-dependent concentrations was observed: from steady-state secretions of 230 pM near the cell surface to large transients which reached as high as 56 nM over several minutes and then dissipated. PMID- 28736752 TI - Inhibitory activity of a Concanavalin-isolated fraction from a glucosamine peptides reaction system against heat resistant E. coli. AB - Alcalase-derived gelatin hydrolysates were glycated with glucosamine in the presence (+) or absence (-) of transglutaminase (TGase), and their antimicrobial activities toward Escherichia coli AW 1.7 were studied. Glycation treatments were subjected to concanavalin A affinity chromatography to selectively collect the glycopeptide-enriched fractions and the changes in antimicrobial activity were determined. The minimum inhibitory concentration of glycated hydrolysates decreased by 1.2 times compared to the native hydrolysate, with no differences between (+) or (-) TGase treatments. No difference was observed in the dicarbonyl compound concentration between the two glycation methods except that 3 deoxyglucosone was greater in the TGase-mediated reaction. Concanavalin A retentate, but not the flow-through fractions, significantly improved the antimicrobial activity, however there was no difference between +TGase and -TGase glycated treatments. Purification of the retentate fraction from fluorescent compounds did not improve its antimicrobial activity. PMID- 28736753 TI - Combination of RT-PCR and proteomics for the identification of Crimean-Congo hemorrhagic fever virus in ticks. AB - Crimean-Congo hemorrhagic fever (CCHF) is an emerging tick-borne zoonotic disease caused by the CCHF virus (CCHFV). In this study, an experimental approach combining RT-PCR and proteomics was used for the identification and characterization of CCHFV in 106 ticks from 7 species that were collected from small ruminants in Greece. The methodological approach included an initial screening for CCHFV by RT-PCR followed by proteomics analysis of positive and control negative tick samples. This novel approach allowed the identification of CCHFV-positive ticks and provided additional information to corroborate the RT PCR findings using a different approach. Two ticks, Dermacentor marginatus and Haemaphysalis parva collected from a goat and a sheep, respectively were positive for CCHFV. The sequences for CCHFV RNA segments S and L were characterized by RT PCR and proteomics analysis of tick samples, respectively. These results showed the possibility of combining analyses at the RNA and protein levels using RT-PCR and proteomics for the characterization of CCHFV in ticks. The results supported that the CCHFV identified in ticks are genetic variants of the AP92 strain. Although the AP92-like strains probably do not represent a high risk of CCHF to the population, the circulation of genetically diverse CCHFV strains could potentially result in the appearance of novel viral genotypes with increased pathogenicity and fitness. PMID- 28736754 TI - Age-related macular degeneration in a randomized controlled trial of low-dose aspirin: Rationale and study design of the ASPREE-AMD study. AB - PURPOSE: Although aspirin therapy is used widely in older adults for prevention of cardiovascular disease, its impact on the incidence, progression and severity of age-related macular degeneration (AMD) is uncertain. The effect of low-dose aspirin on the course of AMD will be evaluated in this clinical trial. DESIGN: A sub-study of the 'ASPirin in Reducing Events in the Elderly' (ASPREE) trial, ASPREE-AMD is a 5-year follow-up double-blind, placebo-controlled, randomized trial of the effect of 100 mg daily aspirin on the course of AMD in 5000 subjects aged 70 years or older, with normal cognitive function and without cardiovascular disease at baseline. Non-mydriatic fundus photography will be performed at baseline, 3-year and 5-year follow-up to determine AMD status. PRIMARY OUTCOME MEASURES: The incidence and progression of AMD. Exploratory analyses will determine whether aspirin affects the risk of retinal hemorrhage in late AMD, and whether other factors, such as genotype, systemic disease, inflammatory biomarkers, influence the effect of aspirin on AMD. CONCLUSION: The study findings will be of significant clinical and public interest due to a potential to identify a possible low cost therapy for preventing AMD worldwide and to determine risk/benefit balance of the aspirin usage by the AMD-affected elderly. The ASPREE-AMD study provides a unique opportunity to determine the effect of aspirin on AMD incidence and progression, by adding retinal imaging to an ongoing, large-scale primary prevention randomized clinical trial. PMID- 28736755 TI - Risky Decision Making in Neurofibromatosis Type 1: An Exploratory Study. AB - BACKGROUND: Neurofibromatosis type 1 (NF1) is a monogenic disorder affecting cognitive function. About one third of children with NF1 have attentional disorders, and the cognitive phenotype is characterized by impairment in prefrontally-mediated functions. Mouse models of NF1 show irregularities in GABA release and striatal dopamine metabolism. We hypothesized that youth with NF1 would show abnormal behavior and neural activity on a task of risk-taking reliant on prefrontal-striatal circuits. METHODS: Youth with NF1 (N=29) and demographically comparable healthy controls (N=22), ages 8-19, were administered a developmentally sensitive gambling task, in which they chose between low-risk gambles with a high probability of obtaining a small reward, and high-risk gambles with a low probability of obtaining a large reward. We used functional magnetic resonance imaging (fMRI) to investigate neural activity associated with risky decision making, as well as age-associated changes in these behavioral and neural processes. RESULTS: Behaviorally, youth with NF1 tended to make fewer risky decisions than controls. Neuroimaging analyses revealed significantly reduced neural activity across multiple brain regions involved in higher-order semantic processing and motivation (i.e., anterior cingulate, paracingulate, supramarginal, and angular gyri) in patients with NF1 relative to controls during the task. We also observed atypical age-associated changes in neural activity in patients with NF1, such that during risk taking, neural activity tended to decrease with age in controls, whereas it tended to increase with age in patients with NF1. CONCLUSIONS: Findings suggest that developmental trajectories of neural activity during risky decision-making may be disrupted in youth with NF1. PMID- 28736756 TI - Advancing the Science of Myocardial Recovery With Mechanical Circulatory Support: A Working Group of the National, Heart, Lung, and Blood Institute. AB - The medical burden of heart failure (HF) has spurred interest in clinicians and scientists to develop therapies to restore the function of a failing heart. To advance this agenda, the National Heart Lung Blood Institute (NHLBI) convened a Working Group of experts on June 2-3, 2016 in Bethesda Maryland to develop recommendations for the NHLBI aimed at advancing the science of cardiac recovery in the setting of mechanical circulatory support (MCS). MSC devices effectively reduce volume and pressure overload that drives the cycle of progressive myocardial dysfunction, thereby triggering structural and functional reverse remodeling. Research in this field could be innovative in many ways and the Working Group specifically discussed opportunities associated with genome-phenome systems biology approaches, genetic epidemiology, bioinformatics and precision medicine at the population level, advanced imaging modalities including molecular and metabolic imaging, and developing minimally invasive surgical and percutaneous bioengineering approaches. These new avenues of investigations could lead to new treatments that target phylogenetically conserved pathways involved in cardiac reparative mechanisms. A central point that emerged from the NHLBI Working Group meeting was that the lessons learned from the MCS investigational setting can be extrapolated to the broader HF population. With the precedents set by the significant impact of studies of other well-controlled and tractable subsets on larger populations, such as the genetic work in both cancer and cardiovascular disease, the work to improve our understanding of cardiac recovery and resilience in MCS patients could be transformational for the greater HF population. PMID- 28736757 TI - Malaria parasite proteins involved in nutrient channels at the host erythrocyte membrane: advances and questions for future research. AB - Erythrocytes infected malaria parasites have increased permeability to nutrients and other solutes, as mediated by an unusual ion channel known as the plasmodial surface anion channel (PSAC). Although the increased permeability of infected erythrocytes was identified more than 70 years ago and subsequently characterized with tracer studies, its mechanism and role in parasite biology remained unclear until the introduction of patch-clamp methods and high-throughput screening technologies. These methods discovered and implicated PSAC as the primary mechanism, determined that this channel is essential for parasite development, led to identification of the channel's genes, and stimulated antimalarial drug discovery against this target. Despite these advances, many questions remain about this unusual parasite channel. Our review highlights some recent advances and describes important questions for future research. PMID- 28736758 TI - Vape shop retailers' perceptions of their customers, products and services: A content analysis. AB - INTRODUCTION: The popularity of electronic cigarettes (e-cigarettes) has spurred the growth of vape shops, but little is known about the retailers who may play an important role in the introduction and dissemination of vape products. In this paper we examine how retailers profile their customers and their perceptions of vaping, and the services their shops provide. METHODS: Semi-structured interviews were conducted with a convenience sample of retailers (n=77) located across southern California. Open-ended questions were coded and analyzed using a content analysis approach. RESULTS: Three themes emerged from the content analysis: who vapes, why people vape, and the vape shop environment. Retailers profiled customers as friendly, health conscious, and interested in tobacco cessation or cessation maintenance. Retailers believed e-cigarettes were used recreationally or as products that help curb other addictive behaviors. While most retailers reported positive experiences with vaping, some reported potentially negative experiences including failed cessation attempts, dual use of e-cigarettes and combustible cigarettes, and increased nicotine dependence. Retailers reported that they regularly answer questions about vaping and believe their shops function as social lounges that are tied to other recreational activities. CONCLUSIONS: Retailers attach certain characteristics to their clientele, perceive certain health benefits associated with vaping, and seek to establish their shops as places that provide guidance on vape products as well as shops with a recreational aesthetic. As vape shops grow in popularity, additional research on, and regulation of, these retailers will be necessary. Education campaigns are needed to inform retailers of the benefits and consequences of vaping. PMID- 28736759 TI - Forecasted trends in disability and life expectancy in England and Wales up to 2025: a modelling study. AB - BACKGROUND: Reliable estimation of future trends in life expectancy and the burden of disability is crucial for ageing societies. Previous forecasts have not considered the potential impact of trends in disease incidence. The present prediction model combines population trends in cardiovascular disease, dementia, disability, and mortality to forecast trends in life expectancy and the burden of disability in England and Wales up to 2025. METHODS: We developed and validated the IMPACT-Better Ageing Model-a probabilistic model that tracks the population aged 35-100 years through ten health states characterised by the presence or absence of cardiovascular disease, dementia, disability (difficulty with one or more activities of daily living) or death up to 2025, by use of evidence-based age-specific, sex-specific, and year-specific transition probabilities. As shown in the English Longitudinal Study of Ageing, we projected continuing declines in dementia incidence (2.7% per annum), cardiovascular incidence, and mortality. The model estimates disability prevalence and disabled and disability-free life expectancy by year. FINDINGS: Between 2015 and 2025, the number of people aged 65 years and older will increase by 19.4% (95% uncertainty interval [UI] 17.7-20.9), from 10.4 million (10.37-10.41 million) to 12.4 million (12.23-12.57 million). The number living with disability will increase by 25.0% (95% UI 21.3-28.2), from 2.25 million (2.24-2.27 million) to 2.81 million (2.72-2.89 million). The age standardised prevalence of disability among this population will remain constant, at 21.7% (95% UI 21.5-21.8) in 2015 and 21.6% (21.3-21.8) in 2025. Total life expectancy at age 65 years will increase by 1.7 years (95% UI 0.1-3.6), from 20.1 years (19.9-20.3) to 21.8 years (20.2-23.6). Disability-free life expectancy at age 65 years will increase by 1.0 years (95% UI 0.1-1.9), from 15.4 years (15.3 15.5) to 16.4 years (15.5-17.3). However, life expectancy with disability will increase more in relative terms, with an increase of roughly 15% from 2015 (4.7 years, 95% UI 4.6-4.8) to 2025 (5.4 years, 4.7-6.4). INTERPRETATION: The number of older people with care needs will expand by 25% by 2025, mainly reflecting population ageing rather than an increase in prevalence of disability. Lifespans will increase further in the next decade, but a quarter of life expectancy at age 65 years will involve disability. FUNDING: British Heart Foundation. PMID- 28736760 TI - Self-harm and violent criminality among young people who experienced trauma related hospital admission during childhood: a Danish national cohort study. AB - BACKGROUND: Development of a better understanding of subsequent pathways for individuals who experienced trauma during childhood might usefully inform clinicians and public health professionals regarding the causes of self-harm and interpersonal violence. We aimed to examine these risks during late adolescence and early adulthood among people admitted to hospital following injuries or poisonings during their childhood. METHODS: This national cohort study included Danish people born between Jan 1, 1977, and Dec 31, 1997, and was linked to the National Patient Register and Psychiatric Central Research Register to identify all people exposed to hospital admissions for injuries or poisonings due to self harm, interpersonal violence, or accidents before their 15th birthday. Linkage to these two registers and to the National Crime Register enabled ascertainment of self-harm and violent offending, respectively, as adverse outcomes at ages 15-35 years. Sex-specific incidence rate ratios (IRRs; relative risks) and cumulative incidence percentage values (absolute risks) were estimated. The confounding influence of parental socioeconomic status was also explored. FINDINGS: 1 087 672 Danish people were included in this study. The prevalence of any trauma-related hospital admission was 10% (105 753 per 1 087 672; males: 64 454 [11%]; females: 44 299 [8%]) and for both sexes, accident was by far the most prevalent of the categories assessed (males: 59 011 [11%]; females: 40 756 [8%]). Similar patterns of increased risk for self-harm and violent criminality were observed in both sexes, although the IRRs were consistently and significantly larger in women (self-harm: IRR 1.94 [95% CI 1.85-2.02]; violent criminality: 2.16 [1.97-2.36]) than in men (self-harm: 1.61 [1.53-1.69]; violent criminality: 1.58 [1.53-1.63]). Confounding by parental socioeconomic status explained little of the increased risks observed. For young adult men, the highest absolute risk observed was for violent offending among individuals admitted to hospital for interpersonal violence injury during childhood (cumulative incidence 25.0% [95% CI 21.2-28.9]). For young adult women, absolute risk was highest for repeat self-harm among those admitted to hospital following self-harm during childhood (cumulative incidence 21.4% [95% CI 19.8-23.1]). More frequent trauma-related hospital admissions in childhood, and being admitted multiple times for more than one reason, conferred substantial risk increases among young people, with especially steep gradients of this nature observed among women. INTERPRETATION: Trauma-related hospital admission early in life could be a useful marker for childhood distress that subsequently predicts internalised and externalised destructive behaviours among youths and young adults and might provide a timely opportunity for initiating family-oriented interventions. FUNDING: European Research Council. PMID- 28736761 TI - Phase II Study of Dovitinib in Patients Progressing on Anti-Vascular Endothelial Growth Factor Therapy. AB - BACKGROUND: Prior work identified the fibroblast growth factor (FGF) pathway as a mediator of resistance to anti-vascular endothelial growth factor (VEGF) therapy. We tested dovitinib, an inhibitor of both FGF and VEGF receptors, in patients progressing on anti-VEGF treatment. METHODS: Patients with measurable advanced colorectal or non-small cell lung cancer with progression despite anti-VEGF treatment within 56 days, good performance status and adequate organ function were eligible. A research tumor biopsy was followed by treatment with dovitinib 500 mg on a 5-day on/2-day off schedule for 28-day cycles. The primary endpoint of tumor response was evaluated every 2 cycles. Secondary endpoints included toxicity and 8-week disease control rate. Intratumor mRNA expression of angiogenic mediators was analyzed using a next generation sequencing based expression array. RESULTS: Ten patients treated previously with bevacizumab or ziv-aflibercept enrolled. The study closed with termination of dovitinib development. No responses were observed in 7 evaluable patients. The best response was stable disease in 1 patient. Common toxicities included gastrointestinal, metabolic, and biochemical derangements. All patients experienced at least one grade >= 3 treatment-related adverse event, most commonly fatigue, elevated GGT, and lymphopenia. Expression of multiple angiogenic mediators was common in tumors progressing on anti-VEGF therapy including high levels of FGFR1 and VEGFA. CONCLUSIONS: We found no evidence for the activity of dovitinib in patients who had recently progressed on anti-VEGF therapy and toxicities were significant. In tumors progressing despite anti-VEGF therapy, a multitude of pro-angiogenic mediators are expressed, including members of the FGF pathway. PMID- 28736762 TI - Confusion in the Study of Immune Reconstitution Inflammatory Syndrome. AB - As a consequence of late presentation for HIV care, a significant proportion of individuals develop immune reconstitution inflammatory syndrome (IRIS) soon after initiation of antiretroviral therapy. Incidence, predictors, and models of pathogenesis of IRIS vary in the literature. Here we discuss factors that may contribute to this lack of consensus. We propose that different pathogens drive different types of IRIS and suggest that these clinical conditions should be studied individually and not grouped under the general heading of "IRIS." PMID- 28736763 TI - Immunologic Effects of Maraviroc in HIV-Infected Patients with Severe CD4 Lymphopenia Starting Antiretroviral Therapy: A Sub-Study of the CADIRIS Trial. AB - BACKGROUND: We aimed to describe the mechanisms of immunological recovery and the effects of blocking CCR5 in patients starting ART with advanced HIV-infection. METHODS: This was a sub-study of a 48 week double-blind, clinical trial where patients starting ART with CD4+ cell counts <100 cells/uL were randomized to receive maraviroc or a placebo. CD4+ and CD8+ cell maturation phenotypes, expression of PD-1 and CCR5, and activation indices were measured at weeks 0, 4, 12, 24, and 48. The reactivity of CD4+ and CD8+cells with peptides of CMV and MTb, and with Staphylococcal enterotoxin B (SEB) was assessed by intracellular expression of IFNgamma, TNFalpha, and CD40 ligand at weeks 0, 4, and 12 of ART. RESULTS: Forty patients were included in the study (Maraviroc = 22; placebo = 18). Sustained increases in CD8+ cells and in proportions of CCR5+ CD4+ and CD8+ cells were observed in the maraviroc arm. Early increases in the proportions of activated (CD38+, HLA-DR+), PD-1+ CD4+, and CD8+ cells and more matured CD8+ cells, were observed in the maraviroc arm. T cell responses to CMV, MTb, and SEB did not differ by treatment arms. CONCLUSIONS: During antiretroviral therapy in advanced HIV infection, maraviroc retains mature, activated CCR5+ cells in circulation without impact on CD4+ T cell recovery or T cell reactivity to antigen or superantigen. PMID- 28736764 TI - Social Ecology and Diabetes Self-Management among Pacific Islanders in Arkansas. AB - Chronic diseases disproportionately affect ethnic and racial minorities. Pacific Islanders, including the Marshallese, experience some of the highest documented rates of type 2 diabetes. Northwest Arkansas is home to the largest population of Marshallese outside of the Republic of the Marshall Islands, and many migrants are employed by the local poultry industry. This migrant population continues to increase because of climate change, limited health care and educational infrastructure in the Marshall Islands, and the ongoing health effects of US nuclear testing. The US nuclear weapons testing program had extensive social, economic, and ecological consequences for the Marshallese and many of the health disparities they face are related to the nuclear fallout. Beginning in 2013, researchers using a community-based participatory (CBPR) approach began working with the local Marshallese community to address diabetes through the development and implementation of culturally appropriate diabetes self-management education in a family setting. Preliminary research captured numerous and significant environmental barriers that constrain self-management behaviors. At the request of our CBPR stakeholders, researchers have documented the ecological barriers faced by the Marshallese living in Arkansas through a series of qualitative research projects. Using the Social Ecological Model as a framework, this research provides an analysis of Marshallese health that expands the traditional diabetes self-management perspective. Participants identified barriers at the organizational, community, and policy levels that constrain their efforts to achieve diabetes self-management. We offer practice and policy recommendations to address barriers at the community, organizational, and policy level. PMID- 28736765 TI - Examining Characteristics of Hospitalizations in Heart Failure Patients: Results from the 2009 All-payer Data. AB - Heart failure (HF) is one of the most common chronic and disabling illnesses, resulting in high morbidity and mortality. Readmission rate, one key indicator of healthcare quality and healthcare utilization, is prevalent in HF patients. Inconsistent evidences exist about the impact of rural health disparities on HF patients' readmissions. The purpose of this explorative study was to examine the characteristics of hospitalized HF patients and factors related to readmissions in 2009. The results showed all-cause readmission rates were 13.6%, 23.6%, and 31.6% at 30-, 90- and 180-days respectively. The factors related readmissions included age, income, discharge/transfer status from index hospitalization, and comorbidity. Findings from this analysis suggested additional studies using multiple data sources are needed to have a comprehensive understanding of risk factors related HF patients' healthcare utilization. PMID- 28736766 TI - Feasibility Studies of a New Event Selection Method to Improve Spatial Resolution of Compton Imaging for Medical Applications. AB - A Compton imaging method for medical applications that includes new energy determination and data filtering techniques has been tested using several point sources with known emission lines. Using a prototype Compton camera, a distance of-closest approach technique has been employed to determine the initial energy of the incoming gammas and to ensure the reconstructed source position is within an acceptable distance from the known gamma source location. Further analysis is done by implementing a Compton line filtering technique, keeping only those interactions whose deposited energy in the first interaction matches the theoretical energy deposition predicted by the Compton equation. Using this new event filtering method, we see improvements in the full width at half maximum in the lateral profiles of gamma point sources of up to 70% over standard Compton imaging methods, as well as achievable spatial resolutions in the reconstructed images of better than 2 mm. In addition, this new Compton imaging method was able to reconstruct an extended source of gamma rays emitted during irradiation of a water tank with a clinical proton radiotherapy beam. PMID- 28736767 TI - Activation of mosquito complement antiplasmodial response requires cellular immunity. AB - The mosquito complement-like system is a major defense mechanism that limits Plasmodium infection. Ookinete midgut invasion results in irreversible damage to invaded cells and triggers epithelial nitration and complement activation. Several lines of evidence suggest that hemocytes participate in early antiplasmodial responses that target ookinetes, but their role remains unclear. The fate of hemocytes in response to Plasmodium infection was investigated by labeling this cell population in vivo. We found that midgut nitration triggers the local release of hemocyte-derived microvesicles (HdMv) into the basal labyrinth of the midgut. Several different strategies, such as gene silencing, immune priming, or systemic injection of polystyrene beads, were used to either enhance or reduce HdMv release. We provide direct experimental evidence that contact of hemocytes with the nitrated midgut basal surface triggers HdMv release and that this response is necessary for effective activation of mosquito complement. Our studies suggest that hemocyte-derived microvesicles may deliver some critical factor(s) that promote activation of thioester-containing protein 1, a key effector of the mosquito antiplasmodial immunity. PMID- 28736768 TI - Community engagement to address socio-ecological barriers to physical activity among African American breast cancer survivors. AB - BACKGROUND: With high rates of obesity, low levels of physical activity (PA), and lack of adherence to physical activity guidelines (PAGs) among African American (AA) breast cancer survivors (BCSs), culturally appropriate interventions that address barriers to participation in PA are needed. METHODS: To develop intervention content, members of an AA breast cancer support group participated in four 1-hour focus group discussions (related to the barriers to PA, strategies for overcoming them, and intervention content), which were audiotaped, transcribed, and analyzed. RESULTS: The support group collaborated with researchers to construct the Physical Activity Intervention Developed (PAID) to Prevent Breast Cancer, a multi-component (educational sessions; support group discussions; and structured, moderately intensive walking, strength training, and yoga), facilitated, 24-week program focused on reducing multi-level barriers to PA that promote benefits ('pay off') of meeting PAGs. CONCLUSIONS: Community engagement fostered trust, promoted mutuality, built collaboration, and expanded capacity of AA BCSs to participate in developing an intervention addressing individual, interpersonal, organizational, and community barriers to PA. PMID- 28736769 TI - Convolutional Neural Networks for Biomedical Text Classification: Application in Indexing Biomedical Articles. AB - Building high accuracy text classifiers is an important task in biomedicine given the wealth of information hidden in unstructured narratives such as research articles and clinical documents. Due to large feature spaces, traditionally, discriminative approaches such as logistic regression and support vector machines with n-gram and semantic features (e.g., named entities) have been used for text classification where additional performance gains are typically made through feature selection and ensemble approaches. In this paper, we demonstrate that a more direct approach using convolutional neural networks (CNNs) outperforms several traditional approaches in biomedical text classification with the specific use-case of assigning medical subject headings (or MeSH terms) to biomedical articles. Trained annotators at the national library of medicine (NLM) assign on an average 13 codes to each biomedical article, thus semantically indexing scientific literature to support NLM's PubMed search system. Recent evidence suggests that effective automated efforts for MeSH term assignment start with binary classifiers for each term. In this paper, we use CNNs to build binary text classifiers and achieve an absolute improvement of over 3% in macro F-score over a set of selected hard-to-classify MeSH terms when compared with the best prior results on a public dataset. Additional experiments on 50 high frequency terms in the dataset also show improvements with CNNs. Our results indicate the strong potential of CNNs in biomedical text classification tasks. PMID- 28736770 TI - Classification of Helpful Comments on Online Suicide Watch Forums. AB - Among social media websites, Reddit has emerged as a widely used online message board for focused mental health topics including depression, addiction, and suicide watch (SW). In particular, the SW community/subreddit has nearly 40,000 subscribers and 13 human moderators who monitor for abusive comments among other things. Given comments on posts from users expressing suicidal thoughts can be written from any part of the world at any time, moderating in a timely manner can be tedious. Furthermore, Reddit's default comment ranking does not involve aspects that relate to the "helpfulness" of a comment from a suicide prevention (SP) perspective. Being able to automatically identify and score helpful comments from such a perspective can assist moderators, help SW posters to have immediate feedback on the SP relevance of a comment, and also provide insights to SP researchers for dealing with online aspects of SP. In this paper, we report what we believe is the first effort in automatic identification of helpful comments on online posts in SW forums with the SW subreddit as the use-case. We use a dataset of 3000 real SW comments and obtain SP researcher judgments regarding their helpfulness in the contexts of the corresponding original posts. We conduct supervised learning experiments with content based features including n-grams, word psychometric scores, and discourse relation graphs and report encouraging F scores (~ 80 - 90%) for the helpful comment classes. Our results indicate that machine learning approaches can offer complementary moderating functionality for SW posts. Furthermore, we realize assessing the helpfulness of comments on mental health related online posts is a nuanced topic and needs further attention from the SP research community. PMID- 28736771 TI - On Interestingness Measures for Mining Statistically Significant and Novel Clinical Associations from EMRs. AB - Association rule mining has received significant attention from both the data mining and machine learning communities. While data mining researchers focus more on designing efficient algorithms to mine rules from large datasets, the learning community has explored applications of rule mining to classification. A major problem with rule mining algorithms is the explosion of rules even for moderate sized datasets making it very difficult for end users to identify both statistically significant and potentially novel rules that could lead to interesting new insights and hypotheses. Researchers have proposed many domain independent interestingness measures using which, one can rank the rules and potentially glean useful rules from the top ranked ones. However, these measures have not been fully explored for rule mining in clinical datasets owing to the relatively large sizes of the datasets often encountered in healthcare and also due to limited access to domain experts for review/analysis. In this paper, using an electronic medical record (EMR) dataset of diagnoses and medications from over three million patient visits to the University of Kentucky medical center and affiliated clinics, we conduct a thorough evaluation of dozens of interestingness measures proposed in data mining literature, including some new composite measures. Using cumulative relevance metrics from information retrieval, we compare these interestingness measures against human judgments obtained from a practicing psychiatrist for association rules involving the depressive disorders class as the consequent. Our results not only surface new interesting associations for depressive disorders but also indicate classes of interestingness measures that weight rule novelty and statistical strength in contrasting ways, offering new insights for end users in identifying interesting rules. PMID- 28736772 TI - On Quantifying Diffusion of Health Information on Twitter. AB - With the increasing use of digital technologies, online social networks are emerging as major means of communication. Recently, social networks such as Facebook and Twitter are also being used by consumers, care providers (physicians, hospitals), and government agencies to share health related information. The asymmetric user network and the short message size have made Twitter particularly popular for propagating health related content on the Web. Besides tweeting on their own, users can choose to retweet particular tweets from other users (even if they do not follow them on Twitter.) Thus, a tweet can diffuse through the Twitter network via the follower-friend connections. In this paper, we report results of a pilot study we conducted to quantitatively assess how health related tweets diffuse in the directed follower-friend Twitter graph through the retweeting activity. Our effort includes (1). development of a retweet collection and Twitter retweet graph formation framework and (2). a preliminary analysis of retweet graphs and associated diffusion metrics for health tweets. Given the ambiguous nature (due to polysemy and sarcasm) of health relatedness of tweets collected with keyword based matches, our initial study is limited to ~ 200 health related tweets (which were manually verified to be on health topics) each with at least 25 retweets. To our knowledge, this is first attempt to study health information diffusion on Twitter through retweet graph analysis. PMID- 28736773 TI - The Current State of Sensing, Health Management, and Control for Small-To-Medium Sized Manufacturers. AB - The development of digital technologies for manufacturing has been challenged by the difficulty of navigating the breadth of new technologies available to industry. This difficulty is compounded by technologies developed without a good understanding of the capabilities and limitations of the manufacturing environment, especially within small-to-medium enterprises (SMEs). This paper describes industrial case studies conducted to identify the needs, priorities, and constraints of manufacturing SMEs in the areas of performance measurement, condition monitoring, diagnosis, and prognosis. These case studies focused on contract and original equipment manufacturers with less than 500 employees from several industrial sectors. Solution and equipment providers and National Institute of Standards and Technology (NIST) Hollings Manufacturing Extension Partnership (MEP) centers were also included. Each case study involved discussions with key shop-floor personnel as well as site visits with some participants. The case studies highlight SME's strong need for access to appropriate data to better understand and plan manufacturing operations. They also help define industrially-relevant use cases in several areas of manufacturing operations, including scheduling support, maintenance planning, resource budgeting, and workforce augmentation. PMID- 28736774 TI - Phrase Based Topic Modeling for Semantic Information Processing in Biomedicine. AB - Given that unstructured data is increasing exponentially everyday, extracting and understanding the information, themes, and relationships from large collections of documents is increasingly important to researchers in many disciplines including biomedicine. Latent Dirichlet Allocation (LDA) is an unsupervised topic modeling technique based on the "bag-of-words" assumption that has been applied extensively to unveil hidden semantic themes within large sets of textual documents. Recently, it was extended using the "bag-of-n-grams" paradigm to account for word order. In this paper, we present an alternative phrase based LDA model to move from a bag of words or n-grams paradigm to a "bag-of-key-phrases" setting by applying a key phrase extraction technique, the C-value method, to further explore latent themes. We evaluate our approach by using a phrase intrusion user study and demonstrate that our model can help LDA generate better and more interpretable topics than those generated using the bag-of-n-grams approach. Given topic models essentially are statistical tools, an important problem in topic modeling is that of visualizing and interacting with the models to understand and extract new information from a collection. To evaluate our phrase based modeling approach in this context, we incorporate it in an open source interactive topic browser. Qualitative evaluations of this browser with biomedical experts demonstrate that our approach can aid biomedical researchers gain better and faster understanding of their document collections. PMID- 28736775 TI - A Multi-Label Classification Approach for Coding Cancer Information Service Chat Transcripts. AB - National Cancer Institute's (NCI) Cancer Information Service (CIS) offers online instant messaging based information service called LiveHelp to patients, family members, friends, and other cancer information consumers. A cancer information specialist (IS) 'chats' with a consumer and provides information on a variety of topics including clinical trials. After a LiveHelp chat session is finished, the IS codes about 20 different elements of metadata about the session in electronic contact record forms (ECRF), which are to be later used for quality control and reporting. Besides straightforward elements like age and gender, more specific elements to be coded include the purpose of contact, the subjects of interaction, and the different responses provided to the consumer, the latter two often taking on multiple values. As such, ECRF coding is a time consuming task and automating this process could help ISs to focus more on their primary goal of helping consumers with valuable cancer related information. As a first attempt in this task, we explored multi-label and multi-class text classification approaches to code the purpose, subjects of interaction, and the responses provided based on the chat transcripts. With a sample dataset of about 673 transcripts, we achieved example-based F-scores of 0.67 (for subjects) and 0.58 (responses). We also achieved label-based micro F-scores of 0.65 (for subjects), 0.62 (for responses), and 0.61 (for purpose). To our knowledge this is the first attempt in automatic coding of Live-Help transcripts and our initial results on the smaller corpus indicate promising future directions in this task. PMID- 28736776 TI - EmojiNet: Building a Machine Readable Sense Inventory for Emoji. AB - Emoji are a contemporary and extremely popular way to enhance electronic communication. Without rigid semantics attached to them, emoji symbols take on different meanings based on the context of a message. Thus, like the word sense disambiguation task in natural language processing, machines also need to disambiguate the meaning or 'sense' of an emoji. In a first step toward achieving this goal, this paper presents EmojiNet, the first machine readable sense inventory for emoji. EmojiNet is a resource enabling systems to link emoji with their context-specific meaning. It is automatically constructed by integrating multiple emoji resources with BabelNet, which is the most comprehensive multilingual sense inventory available to date. The paper discusses its construction, evaluates the automatic resource creation process, and presents a use case where EmojiNet disambiguates emoji usage in tweets. EmojiNet is available online for use at http://emojinet.knoesis.org. PMID- 28736777 TI - Cataloguing Treatments Discussed and Used in Online Autism Communities. AB - A large number of patients discuss treatments in online health communities (OHCs). One research question of interest to health researchers is whether treatments being discussed in OHCs are eventually used by community members in their real lives. In this paper, we rely on machine learning methods to automatically identify attributions of mentions of treatments from an online autism community. The context of our work is online autism communities, where parents exchange support for the care of their children with autism spectrum disorder. Our methods are able to distinguish discussions of treatments that are associated with patients, caregivers, and others, as well as identify whether a treatment is actually taken. We investigate treatments that are not just discussed but also used by patients according to two types of content analysis, cross-sectional and longitudinal. The treatments identified through our content analysis help create a catalogue of real-world treatments. This study results lay the foundation for future research to compare real-world drug usage with established clinical guidelines. PMID- 28736778 TI - Facile synthesis of black phosphorus-Au nanocomposites for enhanced photothermal cancer therapy and surface-enhanced Raman scattering analysis. AB - Black phosphorus (BP), a new type of two-dimensional nanomaterial, has attracted crucial attention in recent years owing to its excellent properties and great potential in various chemical, physical, and biological fields. In this study, BP nanosheets loaded with Au nanoparticles (BP-Au NSs) are obtained by a one-step facile synthetic method. The Au nanostructures can not only enhance the photothermal efficiency of the nanocomposites, but also endow BP-Au NSs with the potential to act as effective surface-enhanced Raman scattering (SERS) substrates for Raman biodetection. Cancer photothermal therapy (PTT) has been carried out in vitro and in vivo using BP-Au NSs as nanoagents. Under irradiation by an 808 nm laser, BP-Au NSs are capable of producing sufficient hyperthermia to destroy cancer cells, and the transplanted tumors in most of the tumor-bearing mice disappeared; BP-Au NSs are more effective than bare BP nanosheets. The PTT effect can also be monitored by a Raman technique that benefits from the high SERS activity of the BP-Au NSs. The molecular fingerprint features of breast tumors before and after PTT treatment were clearly identified using SERS analysis. The theranostic applications of BP-Au NSs exhibit promising potential in biomedicine. PMID- 28736779 TI - Visible light sensitization of benzoyl azides: cascade cyclization toward oxindoles via a non-nitrene pathway. AB - Visible light sensitization of benzoyl azides was examined in reaction with N phenylmethacrylamides to afford biologically important oxindoles and spirooxindoles via a cascade cyclization under mild reaction conditions. Mechanistic studies suggested a non-nitrene pathway, where triplet benzoyl azides act as the reactive intermediate. PMID- 28736780 TI - Surface-initiated synthesis of bulk-imprinted magnetic polymers for protein recognition. AB - Bulk imprinting of proteins was used combined with a grafting approach onto maghemite nanoparticles to develop a faster and simpler polymerization method for the synthesis of magnetic protein imprinted polymers with very high adsorption capacities and very strong affinity constants. PMID- 28736781 TI - Synthesis and biological properties of triazole-linked locked nucleic acid. AB - We have synthesized and studied the biological and biophysical properties of triazole-linked ribo and xylo locked nucleic acid (LNA). The combination of LNA with the Isobe triazole linkage gave high binding affinity when incorporated at the 3' or 5' termini of oligonucleotides, but low binding affinity at internal positions. Antisense oligonucleotides (ASOs) and siRNAs containing triazole dimers were highly active and nuclease resistant. Surprisingly, the xyloLNA modified siRNA was the most active of the series. PMID- 28736783 TI - Halogen effects on the solid-state packing of phenylalanine derivatives and the resultant gelation properties. AB - Phenylalanine is an important amino acid both biologically, essential to human health, and industrially, as a building block of artificial sweeteners. Our interest in this particular amino acid and its derivatives lies with its ability to form gels in a number of solvents. We present here the studies of the influence of halogen addition to the aromatic ring on the gelation properties and we analyse the crystal structures of a number of these materials to elucidate the trends in their behaviour based on the halogen addition to the aromatic group and the interactions that result. PMID- 28736782 TI - pH-Responsive de-PEGylated nanoparticles based on triphenylphosphine-quercetin self-assemblies for mitochondria-targeted cancer therapy. AB - We have developed mitochondria-targeted self-assembled nanoparticles (NPs) based on amphiphilic triphenylphosphine-quercetin (TPP-Que) conjugates, which were further modified by poly(ethylene glycol) via a pH-responsive coordination bond to form TQ-PEG NPs. And it is revealed that the TQ-PEG NPs were more effective therapeutic agents compared with Que in vitro and in vivo. PMID- 28736784 TI - A bioorthogonal fluorescent probe for mitochondrial hydrogen sulfide: new strategy for cancer cell labeling. AB - We report the application of a chemodosimeter 'turn on' fluorescent probe for detecting endogenous H2S formation in cancer cells. Mito-HS showed a bathochromic shift in the UV-vis-absorption spectrum from 355 nm to 395 nm in the presence of H2S. Furthermore, it showed an ~43-fold fluorescence enhancement at lambdaem = 450 nm in the presence of H2S (200 MUM). The cancer cell-specific fluorescence imaging reveals that Mito-HS has the ability to distinguish cancer cells from normal cells based on the level of endogenous H2S formation. In due course, Mito HS would be a powerful cancer biomarker based on its ability to estimate endogenous H2S formation in living cells. PMID- 28736786 TI - An enzyme-free flow cytometric bead assay for the sensitive detection of microRNAs based on click nucleic acid ligation-mediated signal amplification. AB - A versatile flow cytometric bead assay (FCBA) coupled with a completely enzyme free signal amplification mechanism is developed for the sensitive detection of microRNAs (miRNAs). This new strategy integrates click chemistry-mediated ligation chain reaction (CLCR) with hybridization chain reaction (HCR) for enzyme free signal amplification on magnetic beads (MBs), and a flow cytometer for the robust fluorescence readout of the MBs. Firstly, target miRNA can initiate CLCR on the surface of MBs based on the click chemical ligation between dibenzocyclooctyne (DBCO)- and azide-modified single-stranded DNA (ssDNA) probes, and the amount of ligated ssDNA sequences on the MBs will be proportional to the dosage of target miRNA. Afterward, each of the ligated ssDNA products can trigger a cascade chain reaction of hybridization events between two alternating fluorophore-tagged hairpin probes, resulting in another signal amplification pathway with an amplified accumulation of fluorophores on the MBs. Finally, the fluorophore-anchored MBs are directly and rapidly analyzed by using a flow cytometer without any separation or elution processes. Herein, the click nucleic acid ligation only occurs on the surface of MBs, so the nonspecific ligations are greatly inhibited compared with that of ligation reaction performed in homogeneous solution. Furthermore, the signal amplification by CLCR-HCR is highly efficient but totally enzyme-free, which may overcome the potential drawbacks of conventional enzyme-catalyzed signal amplification protocols and lead to a high sensitivity. The CLCR-HCR-based FCBA has pushed the detection limit of let-7a miRNA down to the femtomolar (fM) level, showing great potential in miRNA-related biological studies and disease diagnosis. PMID- 28736785 TI - Rapid and ultrasensitive detection of endocrine disrupting chemicals using a nanosensor-enabled cell-based platform. AB - Endocrine disrupting chemicals (EDCs) interact with estrogen receptors (ERs), causing a broad range of adverse health effects. Current assays for EDC activity are slow and often lack sensitivity. We report here an ultra-sensitive nanosensor that can detect estrogenic cellular changes in ER(+) MCF-7 cells rapidly (minutes) at several orders of magnitude lower than the generally used assays. Notably, the sensor responses at these ultra-low EDC levels correlated with an increased synthesis phase (S-phase) cell population of EDC-treated cells. The nanosensor was also able to detect binary EDC mixture effects, with synergism observed for bisphenol A (BPA) - 17beta-estradiol (E2), and antagonism for dicyclohexylphthalate (DCHP) - E2 and benzo(a)pyrene (BaP) - E2. PMID- 28736787 TI - Carbon quantum dots with intrinsic mitochondrial targeting ability for mitochondria-based theranostics. AB - We prepare for the first time a novel type of fluorescent carbon quantum dot (or carbon dot, CD) with intrinsic mitochondrial targeting ability by a one-step hydrothermal treatment of chitosan, ethylenediamine and mercaptosuccinic acid. The as-prepared CDs can realize mitochondrial imaging and mitochondria-targeted photodynamic cancer therapy without further modifications of other mitochondriotropic ligands (such as triphenylphosphine, TPP). Currently, many commercial mitochondrial probes suffer from the lack of modifiable groups, poor photostability, short tracking time, high cost and/or complicated staining procedures, which severely limit their applications in live-cell mitochondrial imaging. Compared to commercial mitochondrial probes such as MitoTrackers, our CDs exhibit remarkable features including ultra-simple and cost-effective synthesis, excellent photostability, facile storage, easy surface modification, wash-free and long-term imaging capability and negligible cytotoxicity. Besides, since mitochondria are susceptible to the reactive oxygen species generated during chemo-, photo- or radiotherapy, mitochondria-targeted cancer therapy has attracted much attention due to its satisfying anticancer efficiency. To test if the CDs can be used for mitochondria-targeted drug delivery, they were conjugated with a photosensitizer rose bengal (RB) and the resultant CDs-RB nanomissiles achieved efficient cellular uptake and mitochondrial targeting/accumulation, realizing mitochondria-targeted photodynamic therapy. We believe that the CD based nanotheranostics holds great promise in various biomedical applications. PMID- 28736788 TI - Characterisation of anticancer peptides at the single-cell level. AB - The development of efficacious anticancer therapeutics is difficult due to the heterogeneity of the cellular response to chemotherapy. Anticancer peptides (ACPs) are promising drug candidates that have been shown to be active against a range of cancer cells. However, few ACP studies focus on tumour single-cell heterogeneities. In order to address this need, we developed a microfluidic device and an imaging procedure that enable the capture, monitoring, and analysis of several hundred single cells for the study of drug response. MCF-7 human breast adenocarcinoma cells were captured in hydrodynamic traps and isolated in individual microchambers of less than 100 pL volume. With pneumatic valves, different sets of microchambers were actuated to expose the cells to various drugs. Here, the effect of three membranolytic ACPs - melittin, aurein 1.2 and aurein 2.2 - was investigated by monitoring the efflux of calcein from single MCF 7 cells. The loss of membrane integrity was observed with two different strategies that allow either focusing on one cell for mechanistic studies or parallel analysis of hundreds of individual cells. In general, the device is applicable to the analysis of the effect of various drugs on a large number of different cell types. The platform will enable us in the future to determine the origin of heterogeneous responses on pharmacological substances like ACPs within cell populations by combining it with other on-chip analytical methods. PMID- 28736790 TI - Foveal avascular zone area after macula-off rhegmatogenous retinal detachment repair: an optical coherence tomography angiography study. PMID- 28736789 TI - Spiritual distress and spiritual care in advanced heart failure. AB - As patients face serious and chronic illness, they are confronted with the realities of dying. Spiritual and existential issues are particularly prominent near the end of life and can result in significant distress. It is critical that healthcare professionals know how to address patients' and families' spiritual concerns, diagnose spiritual distress and attend to the deep suffering of patients in a way that can result in a better quality of life for patients and families. Tools such as the FICA spiritual history tool help clinicians invite patients and families to share their spiritual or existential concerns as well as sources of hope and meaning which can help them cope better with their illness. This article presents ways to help clinicians listen to the whole story of the patient and support patients in their care. PMID- 28736791 TI - Control of standing balance at leaning postures with functional neuromuscular stimulation following spinal cord injury. AB - This study systematically explored the potential of applying feedback control of functional neuromuscular stimulation (FNS) for stabilizing various erect and leaning standing postures after spinal cord injury (SCI). Perturbations ranging from 2 to 6% body weight were applied to two subjects with motor complete thoracic level SCI who were proficient at standing with implanted multichannel neural stimulators to activate the ankle, knee, hip and trunk muscles. The subjects stood with four different postures: erect, forward, forward-right and forward-left. Repeatable and controlled perturbations were applied in the forward, backward, rightward and leftward directions by linear actuators pulling on ropes attached to the subjects via a belt worn just above the waist. Upper extremity (UE) forces exerted on a stationary walker were measured with load cells attached to the handles. A feedback controller based on center of pressure (CoP) varied the stimulation levels to the otherwise paralyzed muscles so as to resist the effects of the perturbations. The effect of the feedback controller was compared to the case where only open-loop baseline stimulation was applied. This was done in terms of: (a) maximum resultant UE force exerted by the subjects on the walker, (b) maximum resultant CoP overshoot and (c) CoP root-mean-square deviation (RMSD). Feedback control resulted in significant reductions in the mean values of the majority of outcome values compared to baseline open-loop stimulation. Maximum resultant UE force was reduced by as much as 50% in one of the postures for one of the subjects. RMSD and maximum CoPs were reduced by as much as 75 and 70%, respectively, with feedback control. These results indicate that feedback control can be used to reject destabilizing disturbances in individuals with SCI using FNS not only for erect postures but also for leaning postures typically adopted during reaching while attempting various activities of daily living. PMID- 28736793 TI - Bacterial and Archaeal Diversity in Hypersaline Cyanobacterial Mats Along a Transect in the Intertidal Flats of the Sultanate of Oman. AB - Hypersaline intertidal zones are highly dynamic ecosystems that are exposed to multiple extreme environmental conditions including rapidly and frequently changing parameters (water, nutrients, temperature) as well as highly elevated salinity levels often caused by high temperatures and evaporation rates. Microbial mats in most extreme settings, as found at the coastline of the subtropical-arid Arabian Peninsula, have been relatively less studied compared to their counterparts around the world. We report, here, for the first time on the diversity of the bacterial and archaeal communities of marine microbial mats along an intertidal transect in a wide salt flat with strongly increased salinity employing Illumina MiSeq technology for amplicon sequencing of 16S rRNA gene fragments. Microbial communities were dominated by typical halotolerant to halophilic microorganisms, with clear shifts in community composition, richness, and diversity along the transect. Highly adapted specialists (e.g., Euhalothece, Salinibacter, Nanohaloarchaeota) were mainly found at the most extreme, upper tidal sites and less specialized organisms with wide tolerance ranges (e.g., Lyngbya, Rhodovibrio, Salisaeta, Halobacteria) in intermediate sites of the transect. The dominating taxa in the lower tidal sites were typical members of well-stabilized mats (e.g., Coleofasciculus, Anaerolineaceae, Thaumarchaeota). Up to 40% of the archaeal sequences per sample represented so far unknown phyla. In conclusion, the bacterial richness and diversity increased from upper towards lower tidal sites in line with increasing mat stabilization and functional diversity, opposed to that of cyanobacteria only and archaea, which showed their highest richness and diversity in upper tidal samples. PMID- 28736792 TI - Double-Injected Human Stem Cells Enhance Rehabilitation in TBI Mice Via Modulation of Survival and Inflammation. AB - Traumatic brain injury (TBI), a complicated form of brain damage, is a major cause of mortality in adults. Following mechanical and structural primary insults, a battery of secondary insults, including neurotransmitter-mediated cytotoxicity, dysregulation of calcium and macromolecule homeostasis, and increased oxidative stress, exacerbate brain injury and functional deficits. Although stem cell therapy is considered to be an alternative treatment for brain injuries, such as TBI and stroke, many obstacles remain. In particular, the time window for TBI treatment with either drugs or stem cells and their efficacy is still vague. Human placenta-derived mesenchymal stem cells (hpMSCs) have received extensive attention in stem cell therapy because they can be acquired in large numbers without ethical issues and because of their immune-modulating capacity and effectiveness in several diseases, such as Alzheimer's disease and stroke. Here, we tested the feasibility of hpMSCs for TBI treatment with an animal model and attempted to identify appropriate time points for cell treatments. Double injections at 4 and 24 h post-injury significantly reduced the infarct size and suppressed astrocyte and microglial activation around the injury. With reduced damage, double-injected mice showed enhanced anti-inflammatory- and TNF-alpha receptor 2 (TNFR2)-associated survival signals and suppressed pro-inflammatory and oxidative responses. In addition, double-treated TBI mice displayed restored sensory motor functions and reduced neurotoxic Abeta42 plaque formation around the damaged areas. In this study, we showed the extended therapeutic potentials of hpMSCs and concluded that treatment within an appropriate time window is critical for TBI recovery. PMID- 28736795 TI - Identifying characteristics and outcomes that are associated with fall-related fatalities: multi-year retrospective summary of fall deaths in older adults from 2005-2012. AB - BACKGROUND: Fall-related deaths continue to be the leading cause of accidental deaths in the older adult (65+ year) population. However, many fall-related fatalities are unspecified and little is known about the fall characteristics and personal demographics at the time of the fall. Therefore, this report describes the characteristics, circumstances and injuries of falls that resulted in older adult deaths in one U.S. County and explores the variables associated with fatal injuries from falls. METHODS: This is a continued retrospective analysis of 841older adults whose underlying cause of death was due to a fall over an 8-year period (2005-2012). Demographics and logistic regression of fall characteristics and injuries were analyzed. RESULTS: Falls that led to death most often occurred when walking in one's own home. Most of the residents in this study were community-dwellers who had previous comorbidities taking an average of six medications prior to their fall. Survival after a fall was on average 31 days. The two most common injuries after a fatal fall were hip fractures (54%), and head injuries (21%). A logistic regression identified two variables associated with hip fracture, advancing age (OR = 1.05, 95% confidence interval [CI] = 1.02 1.08) and diagnosis of a prior neurological condition (OR = 2.1, 95% CI = 1.4 3.1). Variables associated with head injuries included younger age (OR = .91, 95% CI = .89-.94), male gender (OR = 2.5, 95% CI = 1.7-3.8), prescribed anticoagulants (OR = 2.4, 95% CI = 1.5-3.9) and negative musculoskeletal comorbidity (OR = 1.9. 95% CI = 1.1-3.0). CONCLUSION: Hip fractures and head injuries were the most common injury after a fall that led to death in older adults greater than 65 years. There are opposing risk factors for older adults who incur a hip fracture compared to a head injury. Thus, health professionals will need to individualize prevention efforts to reduce fall fatalities. PMID- 28736794 TI - Tinea Capitis by Microsporum audouinii: Case Reports and Review of Published Global Literature 2000-2016. AB - Tinea capitis caused by Microsporum audouinii is reported herein from two Brazilian schoolchildren, which are brothers. Arthroconidia were evidenced on direct examination of scalp hair, and a fungus of the genus Microsporum was isolated from cultures of each patient. The isolated fungi were classified as M. audouinii by visualization of species-specific structures, including: pectinate hyphae, chlamydospores, and fusiform macroconidia, sterile growth with characteristic brown pigment in rice grains, and through DNA sequencing of the internal transcriber spacer region. Patients were refractory to ketoconazole, but the two cases had a satisfactory response to oral terbinafine. All M. audouinii infections described in this century were reviewed, and to our knowledge, this is the first literature description of this species from South America. Misidentification of M. audouinii with Microsporum canis can occur in this area, leading to erroneous data about the occurrence of this species. PMID- 28736796 TI - Longitudinal Research on Aging Drivers (LongROAD): study design and methods. AB - BACKGROUND: As an important indicator of mobility, driving confers a host of social and health benefits to older adults. Despite the importance of safe mobility as the population ages, longitudinal data are lacking about the natural history and determinants of driving safety in older adults. METHODS: The Longitudinal Research on Aging Drivers (LongROAD) project is a multisite prospective cohort study designed to generate empirical data for understanding the role of medical, behavioral, environmental and technological factors in driving safety during the process of aging. RESULTS: A total of 2990 active drivers aged 65-79 years at baseline have been recruited through primary care clinics or health care systems in five study sites located in California, Colorado, Maryland, Michigan, and New York. Consented participants were assessed at baseline with standardized research protocols and instruments, including vehicle inspection, functional performance tests, and "brown-bag review" of medications. The primary vehicle of each participant was instrumented with a small data collection device that records detailed driving data whenever the vehicle is operating and detects when a participant is driving. Annual follow-up is being conducted for up to three years with a telephone questionnaire at 12 and 36 months and in-person assessment at 24 months. Medical records are reviewed annually to collect information on clinical diagnoses and healthcare utilization. Driving records, including crashes and violations, are collected annually from state motor vehicle departments. Pilot testing was conducted on 56 volunteers during March-May 2015. Recruitment and enrollment were completed between July 2015 and March 2017. CONCLUSIONS: Results of the LongROAD project will generate much-needed evidence for formulating public policy and developing intervention programs to maintain safe mobility while ensuring well-being for older adults. PMID- 28736797 TI - Victimization Mediates the Longitudinal Association Between Depressive Symptoms and Violent Behaviors in Adolescence. AB - Despite evidence of a positive link between depressive symptoms and violent behaviors, the pathways underlying this longitudinal association remain unknown. Depressive symptoms might drive and reinforce victimization which in turn could increase risk of individuals becoming violent towards others. Thus, we tested whether victimization mediated the link between depressive symptoms and violent behaviors using a 6-year longitudinal study of a community sample of adolescents. The sample included 682 Dutch adolescents (54% boys) from an ongoing longitudinal study RADAR (Research on Adolescent Development and Relationships). From ages 13 to 18 years, depressive symptoms, victimization experiences, and violent behaviors were annually assessed. We conducted longitudinal mediation analyses to test pathways to violence in adolescents with depressive symptoms. Longitudinal analyses revealed that victimization mediated the association between depressive symptoms and violent behaviors from early to late adolescence. As part of this, we found that adolescents' depressive symptoms predicted victimization, and this victimization increased risk of subsequent violent behaviors. In conclusion, links between depressive symptoms and violent behaviors are potentially important to understand adolescent development. Decreasing the occurence of victimization is likely to be an important target for the prevention of violent behaviors in adolescents with depressive symptoms. PMID- 28736799 TI - RANKL-induced osteoclastogenesis is suppressed by 4-O-methylhonokiol in bone marrow-derived macrophages. AB - Magnolol, honokiol, and obovatol are well known bioactive constituents of the bark of Magnolia officinalis and have been reported to have beneficial effects in various diseases. We recently isolated a novel active compound, 4-O methylhonokiol (4-O-MH) from the ethanol extract of M. officinalis, which was previously reported to have pharmacological effects including anti-inflammatory, anti-oxidative, and anti-aging activities. Here, we examined the pharmacological properties of 4-O-MH on osteoblast (bone-forming cells) and osteoclast (bone resorbing cells) differentiation, and its underlying signaling pathways in primary cultured pre-osteoblasts and bone marrow macrophages. Our results showed that 4-O-MH did not affect cell viability in pre-osteoblasts and did not influence osteoblast differentiation and mineralized nodule formation, as assessed by alkaline phosphatase activity and Alizarin red staining. However, 4-O MH significantly inhibited TRAP-positive multinuclear osteoclasts and F-actin ring formation during Receptor activator of NF-kappaB ligand (RANKL)-mediated osteoclastogenesis without cytotoxicity. In addition, 4-O-MH suppressed RANKL induced critical factors (c-Fos, NF-ATc1, TRAP, and ITB3) for osteoclast differentiation and function. Furthermore, RANKL-mediated signaling, including ERK1/2, AKT, and NF-kB pathways was attenuated by 4-O-MH. Taken together, 4-O-MH has an inhibitory role in RANKL-mediated osteoclastogenesis but not osteoblast differentiation, and our findings also suggest that 4-O-MH is a potential therapeutic agent for bone-destructive diseases such as osteoporosis, alveolar bone resorption, and osteoarthritis. PMID- 28736800 TI - Editors' Introduction: Health Humanities: The Future of Pre-Health Education is Here. PMID- 28736798 TI - Sympathetic Under-Arousal and Externalizing Behavior Problems in Children with Autism Spectrum Disorder. AB - Children with autism spectrum disorder (ASD) commonly exhibit co-occurring externalizing behavior problems, which can impede learning opportunities and contribute significantly to caregiver stress. Substantial theory and research has linked under-arousal of the sympathetic nervous system to increased externalizing problems in children without ASD, but under-arousal has not been considered as an explanatory mechanism for individual differences among children with ASD. We tested the notion that lower electrodermal activity (EDA) would predict more externalizing problems in children with ASD, and considered the degree to which parent co-regulatory support could buffer this risk. Forty children with ASD between the ages of 4 and 11 years and their primary caregivers participated in a laboratory visit that included various play, compliance, and problem-solving regulatory tasks. EDA was measured through wireless wrist sensors, parental scaffolding was observed during a dyadic problem-solving task, and parents rated their children's externalizing behavior problems. As predicted, low EDA during the compliance-oriented tasks directly predicted higher child externalizing problems. Parental scaffolding moderated the link between under-arousal during the problem-solving regulatory tasks and externalizing problems such that the relation was observed in the context of low, but not high, support. Implications for relevant theories (e.g., fearlessness theory, stimulation-seeking theory) are discussed, and the potential for psychophysiological patterns to inform intervention with these children is considered. PMID- 28736801 TI - Childhood adversities and chronic conditions: examination of mediators, recall bias and age at diagnosis. AB - OBJECTIVES: The aim of this study was to (1) identify the influence of childhood socioeconomic status (CSES) on five chronic conditions: asthma, bronchitis, hypothyroid, migraine, and psychiatric disorders in later life; (2) determine the mediating role of childhood abuse (CA) in these associations, and (3) quantify recall bias due to respondent's mental health in these associations. METHODS: 10,325 men and women from the Tromso Study were followed for 13 years, and Poisson regression models were used. RESULTS: Low CSES was associated with a 16 23% higher risk of chronic conditions, and CA was associated with a 16-58% higher risk of chronic conditions (p < 0.05). A minor proportion of the association between CSES and CA (3.98%, p < 0.05); CSES and chronic conditions (5.54-8.71%, p < 0.05); and CA and chronic conditions (9.51-19.52%, p < 0.05), were driven by recall bias due to the respondent's mental health. CA mediated the association between CSES and chronic conditions (9.58-25.06%, p < 0.05). CONCLUSIONS: Low CSES and CA are associated with higher risk of chronic conditions in later life. A minor proportion of these associations are driven by recall bias. PMID- 28736802 TI - Psychotropic substances in house dusts: a preliminary assessment. AB - Psychotropic substances (PSs) are known to affect air and waters, while scarce attention has been paid to their occurrence in settled dusts although they can reach important concentrations there; moreover, no procedures have been developed for this specific purpose. In this study, a list of PSs (i.e., nicotine, cotinine, caffeine, cocaine, cannabinol, Delta9-tetrahydrocannabinol, cannabidiol, amphetamine, heroin, and methadone) were characterized in dusts from Rome and Fiumicino international airport, Italy, and from Ouargla city, Algeria. The analytical procedure, based on ultra-sonic bath extraction, silica column chromatography, and GC-MSD analysis, provided good recovery, uncertainty, sensitivity, and lack of interferences for all substances except amphetamine. In NIST SRM-2585 house dust, nicotine, cotinine, caffeine, cocaine, and cannabinol accounted for ~5.95, 0.87, 4.17, 7.0, and 2.2 MUg/g, respectively; on the other hand, methadone, tetrahydrocannabinol, cannabidiol, and heroin (all <0.025 MUg/g) were below the detection limit of the method. Two sites at the Fiumicino airport were affected by different loads of PSs (e.g., 0.76 and 2.80 ng/m2 of cocaine). In Ouargla, where dust was collected in a primary school and a dwelling, nicotine ranged from ~60 +/- 50 to ~86 +/- 89 ng/m2, cocaine was absent, and cannabinoids (0.35 +/- 0.43 ng/m2 as total) were found only in the home. In Rome, nicotine, caffeine, cocaine, and cannabinol reached ca. 700, 1470, 0.82, and 2.4 ng/m2, respectively, in a smokers' home, but they were ca. 1300, 25,000, 670, and 1700 ng/m2 in a non-smoker home. In conclusion, all dusts revealed the presence of illicit PSs. Further studies are necessary to understand the links between the PS amounts in airborne particulates and in dusts, as well as the PS origin and fate in interiors. PMID- 28736803 TI - Genetic and pathogenic analysis of a novel reassortant H5N6 influenza virus isolated from waterfowl in South Korea in 2016. AB - A novel reassortant highly pathogenic H5N6 influenza virus was isolated from waterfowl in South Korea in 2016. Seven genes of this virus originated from an H5N6 virus from China, whereas the remaining gene, PB1, was from an unknown virus. This virus productively infected pigs, which showed viral shedding through their noses and developed severe interstitial pneumonia. PMID- 28736804 TI - Study of the association between histo-blood group antigens and norovirus infection in Chinese children. AB - Human caliciviruses (HuCVs) have been recognized as a major cause of sporadic viral diarrhea in children, among which norovirus genotype GII.4 is the most prevalent genotype. Stool and saliva samples were collected from 295 children with acute diarrhea and 150 asymptomatic children at a hospital in China. The HuCV detection rate was 10.85% (32/295) among the children with acute diarrhea, and all of these 32 children were either HBGA secretors (12/32) or partial secretors (20/32). HuCV was detected in two (1.33%) of the 150 samples obtained from the asymptomatic children. Of the norovirus-GII.3-positive children, 60% had blood type O, but only 17.29% of the symptomatic patients had blood type O, indicating that type O individuals could be at higher risk of GII.3 infection. However, due to the limited number of individuals in this study, further studies with a larger number of subjects should be conducted to verify this hypothesis. PMID- 28736805 TI - Giant-cell arteritis: concordance study between aortic CT angiography and FDG PET/CT in detection of large-vessel involvement. AB - PURPOSE: The purpose of our study was to assess the concordance of aortic CT angiography (CTA) and FDG-PET/CT in the detection of large-vessel involvement at diagnosis in patients with giant-cell arteritis (GCA). METHODS: We created a multicenter cohort of patients with GCA diagnosed between 2010 and 2015, and who underwent both FDG-PET/CT and aortic CTA before or in the first ten days following treatment introduction. Eight vascular segments were studied on each procedure. We calculated concordance between both imaging techniques in a per patient and a per-segment analysis, using Cohen's kappa concordance index. RESULTS: We included 28 patients (21/7 women/men, median age 67 [56-82]). Nineteen patients had large-vessel involvement on PET/CT and 18 of these patients also presented positive findings on CTA. In a per-segment analysis, a median of 5 [1-7] and 3 [1-6] vascular territories were involved on positive PET/CT and CTA, respectively (p = 0.03). In qualitative analysis, i.e., positivity of the procedure suggesting a large-vessel involvement, the concordance rate between both procedures was 0.85 [0.64-1]. In quantitative analysis, i.e., per-segment analysis in both procedures, the global concordance rate was 0.64 [0.54-0.75]. Using FDG-PET/CT as a reference, CTA showed excellent sensitivity (95%) and specificity (100%) in a per-patient analysis. In a per-segment analysis, sensitivity and specificity were 61% and 97.9%, respectively. CONCLUSIONS: CTA and FDG-PET/CT were both able to detect large-vessel involvement in GCA with comparable results in a per-patient analysis. However, PET/CT showed higher performance in a per-segment analysis, especially in the detection of inflammation of the aorta's branches. PMID- 28736807 TI - Dermatoscopy of palmar wart with falooda seed appearance. PMID- 28736806 TI - A Skill Set for Supporting Displaced Children in Psychological Recovery After Disasters. AB - Helping children, adolescents, and families displaced following a natural disaster is a daunting task made more challenging by the relatively small research base to inform services and interventions. This paper describes the current literature pertaining to intervention practices used with displaced youth. Where gaps in the literature exist, we pull from the more general research on relocation and post-disaster intervention to assist practitioners in tailoring their efforts. Specifically discussed are ways to enhance youth resilience, to help youth build new social connections and adjust to change and uncertainty while coping with trauma-related symptoms, and to meet needs through the systems in which children are embedded. The need for focused attention to cultural factors is discussed with an emphasis on collaborating with culture brokers. PMID- 28736808 TI - Comparative cranial ontogeny of Tapirus (Mammalia: Perissodactyla: Tapiridae). AB - Skull morphology in tapirs is particularly interesting due to the presence of a proboscis with important trophic, sensory and behavioral functions. Several studies have dealt with tapir skull osteology but chiefly in a comparative framework between fossil and recent species of tapirs. Only one study examined an aspect of cranial ontogeny, development of the sagittal crest (Holbrook. J Zool Soc Lond 2002; 256; 215). Our goal is to describe in detail the morphological changes that occur during the postnatal ontogeny of the skull in two representative tapir species, Tapirus terrestris and Tapirus indicus, and to explore possible functional consequences of their developmental trajectories. We compared qualitative features of the skull on a growth series of 46 specimens of T. terrestris ordered on the basis of the sequence of eruption and tooth wear, dividing the sample into three age classes: class Y (very young juvenile), class J (from young juvenile to young adult) and class A (full and old adult). The qualitative morphological analysis consisted of describing changes in the series in each skull bone and major skull structure, including the type and degree of transformation (e.g. appearance, fusion) of cranial features (e.g. processes, foramina) and articulations (sutures, synchondroses, and synovial joints). We then measured 23 cranial variables in 46 specimens of T. terrestris that included the entire ontogenetic series from newborn to old adults. We applied statistical multivariate techniques to describe allometric growth, and compared the results with the allometric trends calculated for a sample of 25 specimens of T. indicus. Results show that the skull structure was largely conserved throughout the postnatal ontogeny in T. terrestris, so class Y was remarkably similar to class A in overall shape, with the most significant changes localized in the masticatory apparatus, specifically the maxillary tuber as a support of the large-sized permanent postcanine dentition, and correlated changes in diastemata, mandibular body, and sagittal and nuchal crests. In the nasal region, ontogenetic remodeling affected the space for the meatal diverticulum and the surfaces for the origin of the proboscis musculature. Overall, ontogenetic trajectories exhibited more negative allometric components in T. indicus than in T. terrestris, and they shared 47.83% of allometric trends. Tapirus indicus differed most significantly from T. terrestris in the allometry of postcanine toothrows, diastemata and mandibular body. Thus, some allometric trends seem to be highly conserved among the species studied, and the changes observed showed a strong functional and likely adaptive basis in this lineage of ungulates. PMID- 28736809 TI - Dose evaluation of Grid Therapy using a 6 MV flattening filter-free (FFF) photon beam: A Monte Carlo study. AB - PURPOSE: Spatially fractionated radiotherapy is a strategy to overcome the main limitation of radiotherapy, i.e., the restrained normal tissue tolerances. A well known example is Grid Therapy, which is currently performed at some hospitals using megavoltage photon beams delivered by Linacs. Grid Therapy has been successfully used in the management of bulky abdominal tumors with low toxicity. The aim of this work was to evaluate whether an improvement in therapeutic index in Grid Therapy can be obtained by implementing it in a flattening filter-free (FFF) Linac. The rationale behind is that the removal of the flattening filter shifts the beam energy spectrum towards lower energies and increase the photon fluence. Lower energies result in a reduction of lateral scattering and thus, to higher peak-to-valley dose ratios (PVDR) in normal tissues. In addition, the gain in fluence might allow using smaller beams leading a more efficient exploitation of dose-volume effects, and consequently, a better normal tissue sparing. METHODS: Monte Carlo simulations were used to evaluate realistic dose distributions considering a 6 MV FFF photon beam from a standard medical Linac and a cerrobend mechanical collimator in different configurations: grid sizes of 0.3 * 0.3 cm2 , 0.5 * 0.5 cm2 , and 1 * 1 cm2 and a corresponding center-to center (ctc) distance of 0.6, 1, and 2 cm, respectively (total field size of 10 * 10 cm2 ). As figure of merit, peak doses in depth, PVDR, output factors (OF), and penumbra values were assessed. RESULTS: Dose at the entrance is slightly higher than in conventional Grid Therapy. However, it is compensated by the large PVDR obtained at the entrance, reaching a maximum of 35 for a grid size of 1 * 1 cm2 . Indeed, this grid size leads to very high PVDR values at all depths (>= 10), which are much higher than in standard Grid Therapy. This may be beneficial for normal tissues but detrimental for tumor control, where a lower PVDR might be requested. In that case, higher valley doses in the tumor could be achieved by using an interlaced approach and/or adapting the ctc distance. The smallest grid size (0.3 * 0.3 cm2 ) leads to low PVDR at all depths, comparable to standard Grid Therapy. However, the use of very thin beams might increase the normal tissue tolerances with respect to the grid size commonly used (1 * 1 cm2 ). The gain in fluence provided by FFF implies that the important OF reduction (0.6) will not increase treatment time. Finally, the intermediate configuration (0.5 * 0.5 cm2 ) provides high PVDR in the first 5 cm, and comparable PVDR to previous Grid Therapy works at depth. Therefore, this configuration might allow increasing the normal tissue tolerances with respect to Grid Therapy thanks to the higher PVDR and thinner beams, while a similar tumor control could be expected. CONCLUSIONS: The implementation of Grid Therapy in an FFF photon beam from medical Linac might lead to an improvement of the therapeutic index. Among the cases evaluated, a grid size of 0.5 * 0.5 cm2 (1-cm-ctc) is the most advantageous configuration from the physics point of view. Radiobiological experiments are needed to fully explore this new avenue and to confirm our results. PMID- 28736810 TI - The effects of bacterial infection on human sperm nuclear protamine P1/P2 ratio and DNA integrity. AB - The purpose of this study was to detect the effects of bacterial infection on human sperm nuclear protamines and DNA fragmentation. In this study, 120 semen samples were collected from unselected male partners of couples consulting for infertility in infertility and obstetrics clinic. All the samples were screened bacteriologically according to World Health Organization guidelines, and also sperm parameters and DNA fragmentation were evaluated. The concentrations of protamines P1 and P2 were quantified using acid urea acrylamide gel electrophoresis. Of a total number of 120 sample, 36 (30%) of them were infected with bacteria. Nine species of bacteria belonging to five genera, Staphylococcus, Escherichia, Streptococcus, Enterococcus and Klebsiella, were identified. The comparison between infected (36) and noninfected (84) samples appeared the negative impact of bacterial infection on sperm parameters and P1/P2 ratios. The percentages of P1/P2 ratio abnormality were significantly higher in infected patients. Sperm concentration, motility, progression and chromatin condensation were significantly lower in infected patients (p < .010). Depending on these results, we concluded that the bacterial infections have significant negative effects on sperm chromatin condensation and protamine P1/P2 ratio. Moreover, the negative relationship between the bacterial infections and sperm parameters, such as concentration, motility and progressive motility, has been shown. PMID- 28736811 TI - Incidental finding of a membranous interventricular septum aneurysm. AB - We present the case of a 34-year-old female who was admitted to our hospital due to community-acquired pneumonia and had a transthoracic echocardiogram which revealed an aneurysm of the membranous interventricular septum. This was further investigated with a transesophageal echocardiogram which showed in detail the anatomical features of this very rare condition. PMID- 28736812 TI - Hair transplantation for the treatment of lichen planopilaris and frontal fibrosing alopecia: A report of two cases. AB - The efficacy of current medical treatments for lichen planopilaris (LPP) and its variant, frontal fibrosing alopecia (FFA), both lymphocyte-mediated primary cicatricial alopecias, is limited. Hair regrowth from scar tissue is usually not possible. Although hair transplantation restores the hairline and increases hair density in patients with cicatricial alopecia, the timing of the transplantation is crucial. Here, we report two Chinese patients with LPP or FFA who underwent the follicular unit extraction method of hair transplantation after the diseases were stabilised with therapy, with satisfactory results for 3-4 years of follow up. PMID- 28736813 TI - Use of the self-retaining Alexis ring retractor in transoral robotic surgery. AB - BACKGROUND: Ring retractors, such as the Alexis(r) wound retractor, are simple devices used in a wide range of surgical settings to provide atraumatic exposure while protecting wound edges. METHODS: Here, we describe the application of the Alexis(r) to provide access during transoral robotic surgery (TORS). CONCLUSION: Its ease of application and many benefits, including maximization of intraoral space and protection of perioral soft tissues, make this device an excellent adjunct for TORS procedures. PMID- 28736814 TI - Interactions between empathy and resting heart rate in early adolescence predict violent behavior in late adolescence and early adulthood. AB - BACKGROUND: Although resting heart rate (RHR) and empathy are independently and negatively associated with violent behavior, relatively little is known about the interplay between these psychophysiological and temperament-related risk factors. METHODS: Using a sample of 160 low-income, racially diverse men followed prospectively from infancy through early adulthood, this study examined whether RHR and empathy during early adolescence independently and interactively predict violent behavior and related correlates in late adolescence and early adulthood. RESULTS: Controlling for child ethnicity, family income, and child antisocial behavior at age 12, empathy inversely predicted moral disengagement and juvenile petitions for violent crimes, while RHR was unrelated to all measures of violent behavior. Interactive effects were also evident such that among men with lower but not higher levels of RHR, lower empathy predicted increased violent behavior, as indexed by juvenile arrests for violent offenses, peer-reported violent behavior at age 17, self-reported moral disengagement at age 17, and self reported violent behavior at age 20. CONCLUSIONS: Implications for prevention and intervention are considered. Specifically, targeting empathic skills among individuals at risk for violent behavior because of specific psychophysiological profiles may lead to more impactful interventions. PMID- 28736815 TI - A widespread cyanobacterium supported by polyphasic approach: proposition of Koinonema pervagatum gen. & sp. nov. (Oscillatoriales)1. AB - Several new genera originally classified as the genus Phormidium, a polyphyletic and taxonomically complex genus within the Oscillatoriales, were recently described. The simple morphology of Phormidium does not reflect its genetic diversity and the delimitation of a natural group is not possible with traditional classification systems based on morphology alone. Therefore, this study used morphological, ecological, and molecular approaches to evaluate four populations morphologically similar to Ammassolinea, Kamptonema, and Ancylothrix (simple, curved, and gradually attenuated at the ends trichome), found in subtropical and tropical Brazilian regions. 16S rRNA gene sequences grouped all the strains in a highly supported clade with other two European strains isolated from thermal springs surrounding areas. The 16S-23S ITS secondary structure corroborated the phylogenetic analysis with all the strains having similar structures. Consequently, a genetically well-defined and cryptic new genus, Koinonema gen. nov., is proposed containing the aquatic, mesophilic, and morphologically homogeneous new species, Koinonema pervagatum sp. nov. PMID- 28736816 TI - Antinociceptive Activity of Ent-Dihydrotucumanoic Acid Isolated from Gymnosperma glutinosum Spreng Less. AB - Preclinical Research The diterpene ent-dihydrotumanoic acid (DTA) was among the compounds isolated from Gymnosperma glutinosum (Spreng) Less (Asteraceae). There are no reports regarding the pharmacological effects of DTA. Cytotoxicity against cancer cells (1-250 uM), and the antibacterial (50-1400 uM) activity of DTA were evaluated using the MTT assay, and the minimum inhibitory concentration test, respectively. The antidiarrheal (1-100 mg/kg p.o.) and anti-inflammatory (2 mg/ear) effects of DTA were evaluated using castor oil and 12-O tetradecanoylphorbol-13-acetate, respectively. The antinociceptive and sedative effects of DTA (1-100 mg/kg p.o.) were evaluated using two models of chemically induced nociception, and the pentobarbital-induced sleeping time test, respectively. The antinociceptive mechanism of DTA was evaluated using the acetic acid writhing test with inhibitors related to pain processing pathways. The effects of DTA (10-100 mg/kg p.o.) on locomotor activity were evaluated using the rotarod test. DTA lacked cytotoxic activity (IC50 > 100 uM) on cancer cells, possessed moderate antibacterial effects against B. subtillis (MIC= 175 uM), moderate antidiarrheal and anti-inflammatory effects, and minimal vasorelaxant effects. In the formalin test, DTA showed antinociceptive effects in both phases. In the acetic acid test, DTA showed antinociceptive activity (ED50 = 50.2 +/- 5.6 mg/kg) with potency similar to that of naproxen (NPX; ED50 =33.7 +/- 4.5 mg/kg) an effect blocked by naloxone implicating an opioid mechanism. DTA also exerted antidiarrheal activity and showed no sedative effects or changes in locomotor activity in mice. Drug Dev Res 78 : 340-348, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28736817 TI - Pharmacokinetic-pharmacodynamic integration and modelling of oxytetracycline for the calf pathogens Mannheimia haemolytica and Pasteurella multocida. AB - A calf tissue cage model was used to study the pharmacokinetics (PK) and pharmacodynamics (PD) of oxytetracycline in serum, inflamed (exudate) and noninflamed (transudate) tissue cage fluids. After intramuscular administration, the PK was characterized by a long mean residence time of 28.3 hr. Based on minimum inhibitory concentrations (MICs) for six isolates each of Mannheimia haemolytica and Pasteurella multocida, measured in serum, integration of in vivo PK and in vitro PD data established area under serum concentration-time curve (AUC0-infinity )/MIC ratios of 30.0 and 24.3 hr for M. haemolytica and P. multocida, respectively. Corresponding AUC0-infinity /MIC ratios based on MICs in broth were 656 and 745 hr, respectively. PK-PD modelling of in vitro bacterial time-kill curves for oxytetracycline in serum established mean AUC0-24 hr /MIC ratios for 3log10 decrease in bacterial count of 27.5 hr (M. haemolytica) and 60.9 hr (P. multocida). Monte Carlo simulations predicted target attainment rate (TAR) dosages. Based on the potency of oxytetracycline in serum, the predicted 50% TAR single doses required to achieve a bacteriostatic action covering 48-hr periods were 197 mg/kg (M. haemolytica) and 314 mg/kg (P. multocida), respectively, against susceptible populations. Dosages based on the potency of oxytetracycline in broth were 25- and 27-fold lower (7.8 and 11.5 mg/kg) for M. haemolytica and P. multocida, respectively. PMID- 28736818 TI - Updating and identifying a novel mutation in the PMVK gene in classic porokeratosis of Mibelli. PMID- 28736819 TI - Evaluation of DNA methylation of inflammatory genes following treatment of chronic periodontitis: A pilot case-control study. AB - OBJECTIVE: To evaluate the influence of periodontal therapy on DNA methylation in patients with chronic periodontitis as compared to healthy individuals. MATERIAL AND METHODS: Twenty patients were enrolled into two groups: (i) 10 diagnosed as clinically healthy; and (ii) 10 diagnosed with chronic periodontitis. Clinical measures were recorded and gingival biopsies were harvested at baseline (both patient groups) and at 2 and 8 weeks post-baseline for diseased individuals. Molecular DNA methylation analysis was performed by pyrosequencing for the putative inflammation-associated genes LINE-1, COX-2, IFN-gamma and TNF-alpha. Random-intercept linear regression models were applied to evaluate methylation levels across groups at baseline and the methylation changes over time in the diseased and normal tissues. RESULTS: Periodontal therapy did not influence gene expression methylation of TNF-alpha, IFN-gamma and LINE-1 levels at normal and periodontitis sites over time. However, it significantly reduced COX-2 methylation levels comparable to healthy individuals at both 2 and 8 weeks post treatment (p < .05). CONCLUSIONS: Periodontal therapy resets the DNA methylation status of inflammatory gene for COX-2 in patients with periodontal disease. DNA methylation levels of TNF-alpha, IFN-gamma and LINE-1 were sustained in periodontitis sites despite therapy. Future studies should consider an expanded panel of inflammatory genes over time. (ClinicalTrials.gov NCT02835898). PMID- 28736820 TI - Disease-Causing Variants in the ATL1 Gene Are a Rare Cause of Hereditary Spastic Paraplegia among Czech Patients. AB - Variants in the ATL1 gene have been repeatedly described as the second most frequent cause of hereditary spastic paraplegia (HSP), a motor neuron disease manifested by progressive lower limb spasticity and weakness. Variants in ATL1 have been described mainly in patients with early onset HSP. We performed Sanger sequencing of all coding exons and adjacent intron regions of the ALT1 gene in 111 Czech patients with pure form of HSP and additional Multiplex-Ligation Probe Analysis (MLPA) testing targeting the ATL1 gene in 56 of them. All patients except seven were previously tested by Sanger sequencing of the SPAST gene with negative results. ATL1 diagnostic testing revealed only five missense variants in the ATL1 gene. Four of them are novel, but we suppose only two of them to be pathogenic and causal. The remaining variants are assumed to be benign. MLPA testing in 56 of sequence variant negative patients revealed no gross deletion in the ATL1 gene. Variants in the ATL1 gene are more frequent in patients with early onset HSP, but in general the occurrence of pathogenic variants in the ATL1 gene is low in our cohort, less than 4.5% and less than 11.1% in patients with onset before the age of ten. Variants in the ATL1 gene are a less frequent cause of HSP among Czech patients than has been previously reported among other populations. PMID- 28736821 TI - Testing for high-risk HPV in cervical and tonsillar paraffin-embedded tissue using a cartridge-based assay. AB - This study evaluates the suitability of Xpert HPV (Cepheid, Sunnyvale, CA, USA) test for cervical and tonsillar formalin-fixed paraffin-embedded (FFPE) tissue samples as compared to the tests currently used in diagnostics. Cervical biopsies and liquid cytology (LC) samples were collected from 48 women attending colposcopy. Biopsies were processed for histology and tested for hrHPV using Xpert HPV. LC samples were tested using Xpert and Hybrid Capture 2 (HC2; Qiagen, Hilden, Germany) tests. Also 29 archived tonsillar carcinoma samples were tested using Xpert, and the results were compared with histology and immunohistochemical p16INK4a (p16) staining. Among valid cervical LC samples 46.8% were hrHPV positive using Xpert test and 55.3% with HC2. The sensitivity of Xpert was 84.6% as compared to HC2, and overall test concordance was 91.5%. Test concordance between valid Xpert results from biopsies and LC samples was 84.6%. Among valid tonsillar samples 70.4% were hrHPV positive, and concordance of 96.3% was found between Xpert and p16 staining. To conclude, Xpert HPV test cartridge provides a convenient platform to test individual samples, including FFPE samples. Further studies are needed to establish whether test sensitivity is sufficient to reliably differentiate between hrHPV positive and hrHPV negative head and neck carcinomas. PMID- 28736822 TI - Congenital heart disease and cardiac procedural outcomes in patients with trisomy 21 and Turner syndrome. AB - Congenital heart disease (CHD) is present in approximately 50% of patients with trisomy 21 (T21) and Turner syndrome (TS). According to the American Academy of Pediatrics, every patient with these genetic disorders should have a postnatal echocardiogram. T21 is usually associated with atrioventricular (30%-60%), atrial (16%-21%), or ventricular septal defects (14%-27%). TS is usually associated with left-sided heart disease. However, the spectrum of CHD in these genetic disorders is wider than those mentioned lesions. More cardiac surgical procedures are offered to these patients and that has influenced positively their life expectancy for some CHD conditions. Single ventricular anatomy is associated with high mortality in these genetic disorders (49% in T21 and 83%-91% in TS). The goal of this article is to describe the spectrum of CHD, screening guidelines, and cardiac surgical outcomes in patients with T21 or TS with CHD. PMID- 28736823 TI - Distinct alignment of benzene derivatives in stretched polystyrene and polybutylacrylate gels: Specific polymer-solute interactions. AB - We have measured the alignment of a range of benzene derivatives in cross-linked polystyrene and poly(butyl acrylate) using a small number of residual dipolar couplings and simple geometric considerations. For apolar solutes in polystyrene and protic solutes in poly(butyl acrylate), the preferred molecular orientation does not coincide with the longest molecular axis (steric aligment). This behavior may be explained by specific pi-pi and hydrogen bonding interactions between solute and polymer, respectively, the latter being confirmed by molecular dynamics simulations. PMID- 28736824 TI - Evaluation of lumazine synthase from Bacillus anthracis as a presentation platform for polyvalent antigen display. AB - Polyvalent antigen display is an effective strategy to enhance the immunogenicity of subunit vaccines by clustering them in an array-like manner on a scaffold system. This strategy results in a higher local density of antigens, increased high avidity interactions with B cells and other antigen presenting cells, and therefore a more effective presentation of vaccine antigens. In this study, we used lumazine synthase (LS), an icosahedral symmetry capsid derived from Bacillus anthracis, as a scaffold to present 60 copies of a linear B cell epitope (PB10) from the ricin toxin fused to the C terminus of LS via four different linkers. We then investigated the effects of linker length, linker rigidity and formaldehyde crosslinking on the protein assembly, conformational integrity, thermal stability, in vitro antibody binding, and immunogenicity in mice. Fusion of the PB10 peptide onto LS, with varying linker lengths, did not affect protein assembly, thermal stability or exposure of the epitope, but had a minor impact on protein conformation. Formaldehyde crosslinking considerably improved protein thermal stability with only minor impact on protein conformation. All LS_PB10 constructs, when administered to mice by injection without adjuvant, elicited measurable anti-ricin serum IgG titers, although the titers were not sufficient to confer protection against a 10* lethal dose ricin challenge. This work sheds light on the biophysical properties, immunogenicity and potential feasibility of LS from B. anthracis as a scaffold system for polyvalent antigen display. PMID- 28736825 TI - Crystallization Caught in the Act with Terahertz Spectroscopy: Non-Classical Pathway for l-(+)-Tartaric Acid. AB - Crystal formation is a highly debated problem. This report shows that the crystallization of l-(+)-tartaric acid from water follows a non-classical path involving intermediate hydrated states. Analytical ultracentrifugation indicates solution clusters of the initial stages aggregate to form an early intermediate. Terahertz spectroscopy performed during water evaporation highlights a transient increase in the absorption during nucleation; this indicates the recurrence of water molecules that are expelled from the intermediate phase. Besides, a transient resonance at 750 GHz, which can be assigned to a natural vibration of large hydrated aggregates, vanishes after the final crystal has formed. Furthermore, THz data reveal the vibration of nanosized clusters in the dilute solution indicated by analytical ultracentrifugation. Infrared spectroscopy and wide-angle X-ray scattering highlight that the intermediate is not a crystalline hydrate. These results demonstrate that nanoscopic intermediate units assemble to form the first solvent-free crystalline nuclei upon dehydration. PMID- 28736826 TI - Impact of respiratory motion and acquisition settings on SPECT liver dosimetry for radioembolization. AB - PURPOSE: Respiratory motion may impose significant inaccuracies on emission activity estimation in quantitative SPECT. This effect may be a major issue in dosimetry as used in the management of liver radioembolization. The purpose of this study was to investigate the impact of respiratory motion on radioembolization liver dosimetry for different SPECT acquisition settings. METHODS: In a series of SPECT/CT Monte Carlo simulations using several digital XCAT phantoms, the following parameters were varied: breathing/nonbreathing, liver tumor size (0.3-35 ml) and location, patient properties (body mass index ranging from underweight to obese; male and female), acquisition time (10-30 s/view), collimator setup (High Sensitivity, High Resolution, Ultra High Resolution) and tumor VOI. The effect of applying a respiratory gating scheme was examined as well. RESULTS: Breathing decreased activity recovery and tumor/non tumor (T/N) ratios on average from 90% to 66%. VOIs based on SPECT images instead of breath-hold CT improved T/N values significantly. The most accurate results were obtained using a gating scheme combined with SPECT-based VOIs. Scan duration, body mass index, sex, and location all had a minor effect. Lung shunt fraction estimations were relatively unaffected by any of the varied parameters. CONCLUSIONS: Respiratory motion has a large effect on SPECT activity quantitation of liver tumors as used in radioembolization treatment planning and assessment. As compared with the other parameters that were varied in this study, respiration is the predominant degrading effect on image quantitation. Gating alleviates much of this detrimental effect. PMID- 28736829 TI - Clonal Analysis of Regulatory T Cell Defect in Patients with Autoimmune Polyendocrine Syndrome Type 1 Suggests Intrathymic Impairment. AB - Mutations in the autoimmune regulator gene disrupt thymic T cell development and negative selection, leading to the recessively inherited polyendocrine autoimmune disease autoimmune polyendocrine syndrome type 1 (APS-1). The patients also have a functional defect in the FOXP3+ regulatory T cell population, but its origin is unclear. Here, we have used T cell receptor sequencing to analyse the clonal relationship of major CD4+ T cell subsets in three patients and three healthy controls. The naive regulatory T cells showed little overlap with helper T cell subsets, supporting divergence in the thymus. The activated/memory regulatory T cell subset displayed more sharing with helper T cells, but was mainly recruited from the naive regulatory T cell population. These clonal patterns were very similar in both patients and controls. However, naive regulatory T cells isolated from the patients had a significantly longer T cell receptor complementarity determining region 3 than any other population, suggesting failure of thymic selection. These data indicate that the peripheral differentiation of regulatory T cells in APS-1 patients is not different from that in healthy controls. Rather, the patients' naive regulatory T cells may have an intrinsic defect imprinted already in the thymus. PMID- 28736830 TI - PCSK9 in context: A contemporary review of an important biological target for the prevention and treatment of atherosclerotic cardiovascular disease. AB - The identification of the critical role of proprotein convertase subtilisin/kexin type 9 (PCSK9) has rapidly led to the development of PCSK9 inhibition with monoclonal antibodies (mAbs). PCSK9 mAbs are already in limited clinical use and are the subject of major cardiovascular outcomes trials, which, if universally positive, could see much wider clinical application of these agents. Patients with familial hypercholesterolaemia are the most obvious candidates for these drugs, but other patients with elevated cardiovascular risk, statin intolerance or hyperlipoproteinaemia(a) may also benefit. PCSK9 mAbs, administered once or twice monthly, reduce LDL cholesterol levels by 50% to 70%, and appear to be safe and acceptable to patients over at least 2 years of treatment; however, treatment emergent adverse effects are not always identified in clinical trials, as well evidenced by statin myopathy. Inclisiran is a promising RNA-based therapy that promotes the degradation of PCSK9 mRNA transcripts and has similar efficacy to mAbs, but with a much longer duration of action. The cost-effectiveness and long term safety of therapies targeted at inhibiting PCSK9 remain to be demonstrated if they are to be used widely in coronary prevention. PMID- 28736828 TI - Genomic and metabolic characterization of a chromophobe renal cell carcinoma cell line model (UOK276). AB - Chromophobe renal cell carcinoma (ChRCC) represents 5% of all RCC cases and frequently demonstrates multiple chromosomal losses and an indolent pattern of local growth, but can demonstrate aggressive features and resistance to treatment in a metastatic setting. Cell line models are an important tool for the investigation of tumor biology and therapeutic drug efficacy. Currently, there are few ChRCC-derived cell lines and none is well characterized. This study characterizes a novel ChRCC-derived cell line model, UOK276. A large ChRCC tumor with regions of sarcomatoid differentiation was used to establish a spontaneously immortal cell line, UOK276. UOK276 was evaluated for chromosomal, mutational, and metabolic aberrations. The UOK276 cell line is hyperdiploid with a modal number of 49 chromosomes per cell, and evidence of copy-neutral loss of heterozygosity, as opposed to the classic pattern of ChRCC chromosomal losses. UOK276 demonstrated a TP53 missense mutation, expressed mutant TP53 protein, and responded to treatment with a small-molecule therapeutic agent, NSC319726, designed to reactivate mutated TP53. Xenograft tumors grew in nude mice and provide an in vivo animal model for the investigation of potential therapeutic regimes. The xenograft pathology and genetic analysis suggested that UOK276 was derived from the sarcomatoid region of the original tumor. In summary, UOK276 represents a novel in vitro and in vivo cell line model for aggressive, sarcomatoid-differentiated, TP53 mutant ChRCC. This preclinical model system could be used to investigate the novel biology of aggressive, sarcomatoid ChRCC and evaluate the new therapeutic regimes. PMID- 28736831 TI - Biomimetic Synthesis of Complex Flavonoids Isolated from Daemonorops "Dragon's Blood". AB - The dragonbloodins are a pair of complex flavonoid trimers that have been isolated from the palm tree Daemonorops draco, one of the sources of the ancient resin known as "dragon's blood". We present a short synthesis that clarifies their relative configurations and sheds light on their origin in Nature. This synthesis features biomimetic cascade reactions that involve both ionic and radical intermediates. The biogenetic relationships between dracorhodin, the dracoflavans C, and the dragonbloodins A1 and A2 are discussed. PMID- 28736832 TI - Three-dimensional echocardiography for predicting postoperative ventricular volumes after surgical ventricular reconstruction of left ventricular aneurysm: A case-based presentation. AB - Three-dimensional transthoracic echocardiography (3DTTE) may have a role in predicting final left ventricular volumes and clinical response after the surgical ventricular reconstruction (SVR) of left ventricular aneurysms and pseudoaneurysms. Left ventricle final volumes can be calculated through "virtual aneurysmectomy." We present a patient with a huge ventricular dilation combined with myocardial dissection, localized wall rupture, and aneurysm of the left ventricular apex after acute myocardial infarction in which accurate predictions from 3DTTE suggest potential clinical value. PMID- 28736833 TI - Isoindigo-Based Polymers with Small Effective Masses for High-Mobility Ambipolar Field-Effect Transistors. AB - So far, most of the reported high-mobility conjugated polymers are p-type semiconductors. By contrast, the advances in high-mobility ambipolar polymers fall greatly behind those of p-type counterparts. Instead of unipolar p-type and n-type materials, ambipolar polymers, especially balanced ambipolar polymers, are potentially serviceable for easy-fabrication and low-cost complementary metal oxide-semiconductor circuits. Therefore, it is a critical issue to develop high mobility ambipolar polymers. Here, three isoindigo-based polymers, PIID-2FBT, P1FIID-2FBT, and P2FIID-2FBT are developed for high-performance ambipolar organic field-effect transistors. After the incorporation of fluorine atoms, the polymers exhibit enhanced coplanarity, lower energy levels, higher crystallinity, and thus increased ue . P2FIID-2FBT exhibits n-type dominant performance with a ue of 9.70 cm2 V-1 s-1 . Moreover, P1FIID-2FBT exhibits a highly balanced uh and ue of 6.41 and 6.76 cm2 V-1 s-1 , respectively, which are among the highest values for balanced ambipolar polymers. Moreover, a concept "effective mass" is introduced to further study the reasons for the high performance of the polymers. All the polymers have small effective masses, indicating good intramolecular charge transport. The results demonstrate that high-mobility ambipolar semiconductors can be obtained by designing polymers with fine-tuned energy levels, small effective masses, and high crystallinity. PMID- 28736834 TI - Temporal bone chondroblastoma: Imaging characteristics with pathologic correlation. AB - BACKGROUND: Chondroblastoma commonly involves the temporal bone in the craniofacial region, but its imaging features have not been elucidated. This study aimed to describe the imaging features of temporal bone chondroblastoma with their pathologic correlation. METHODS: Radiopathologic correlation was performed in 5 patients with temporal bone chondroblastoma from our database and in 11 patients identified through a PubMed search. RESULTS: The cases of temporal bone chondroblastoma commonly involve the squamous part, temporal and infratemporal fossae, temporomandibular joint, and tympanic cavity, with the following features: high attenuation with calcification; heterogeneity; low signal intensity on T2-weighted imaging with enhancement; a smooth interface to the brain; and strong hypermetabolism on fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT. The heterogeneous low signal intensity on T2 weighted imaging was correlated with various histopathologic components, including calcification and hemosiderin deposition. CONCLUSION: Temporal bone chondroblastoma usually forms as an expansile, heterogeneous, hypermetabolic mass in the middle cranial fossa, frequently with low signal intensity on T2-weighted imaging, reflecting various degrees of calcification and hemosiderin deposition. PMID- 28736836 TI - Identification of adults with congenital heart disease of moderate or great complexity from administrative data. AB - INTRODUCTION: There is relatively sparse literature on the use of administrative datasets for research in patients with adult congenital heart disease (ACHD). The goal of this analysis is to examine the accuracy of administrative data for identifying patients with ACHD who died. METHODS: A list of the International Classification of Diseases codes representing ACHD of moderate- or great complexity was created. A search for these codes in the electronic health record of adults who received care in 2010-2016 was performed, and used state death records to identify patients who died during this period. Manual record review was completed to evaluate performance of this search strategy. Identified patients were also compared with a list of patients with moderate- or great complexity ACHD known to have died. RESULTS: About 134 patients were identified, of which 72 had moderate- or great-complexity ACHD confirmed by manual review, yielding a positive predictive value of 0.54 (95% CI 0.45, 0.62). Twenty six patients had a mild ACHD diagnosis. Thirty six patients had no identified ACHD on record review. Misidentifications were attributed to coding error for 19 patients (53%), and to acquired ventricular septal defects for 11 patients (31%). Diagnostic codes incorrect more than 50% of the time were those for congenitally corrected transposition, endocardial cushion defect, and hypoplastic left heart syndrome. Only 1 of 21 patients known to have died was not identified by the search, yielding a sensitivity of 0.95 (0.76, 0.99). CONCLUSION: Use of administrative data to identify patients with ACHD of moderate or great complexity who have died had good sensitivity but suboptimal positive predictive value. Strategies to improve accuracy are needed. Administrative data is not ideal for identification of patients in this group, and manual record review is necessary to confirm these diagnoses. PMID- 28736835 TI - Peptide mimetics of immunoglobulin A (IgA) and FcalphaRI block IgA-induced human neutrophil activation and migration. AB - The cross-linking of the IgA Fc receptor (FcalphaRI) by IgA induces release of the chemoattractant LTB4, thereby recruiting neutrophils in a positive feedback loop. IgA autoantibodies of patients with autoimmune blistering skin diseases therefore induce massive recruitment of neutrophils, resulting in severe tissue damage. To interfere with neutrophil mobilization and reduce disease morbidity, we developed a panel of specific peptides mimicking either IgA or FcalphaRI sequences. CLIPS technology was used to stabilize three-dimensional structures and to increase peptides' half-life. IgA and FcalphaRI peptides reduced phagocytosis of IgA-coated beads, as well as IgA-induced ROS production and neutrophil migration in in vitro and ex vivo (human skin) experiments. Since topical application would be the preferential route of administration, Cetomacrogol cream containing an IgA CLIPS peptide was developed. In the presence of a skin permeation enhancer, peptides in this cream were shown to penetrate the skin, while not diffusing systemically. Finally, epitope mapping was used to discover sequences important for binding between IgA and FcalphaRI. In conclusion, a cream containing IgA or FcalphaRI peptide mimetics, which block IgA induced neutrophil activation and migration in the skin may have therapeutic potential for patients with IgA-mediated blistering skin diseases. PMID- 28736837 TI - Acute effects of alcohol on sleep are mediated by components of homeostatic sleep regulatory system: An Editorial Highlight for 'Lesions of the basal forebrain cholinergic neurons attenuates sleepiness and adenosine after alcohol consumption' on page 710. AB - Alcohol causes adenosine buildup, which inhibits wake-active neurons via adenosine A1 receptors thus disinhibiting sleep active neurons and also stimulates sleep-active neurons via A2A receptors, causing sleep. This editorial highlights the study entitled, "Lesions of the basal forebrain cholinergic neurons attenuates sleepiness and adenosine after alcohol consumption" by Sharma and colleagues. They report that the wake-promoting basal forebrain (BF) cholinergic neurons play a crucial role in mediating acute alcohol-induced sleep via adenosinergic signaling. PMID- 28736838 TI - HTLV-1 carrier psoriasis patients treated by anti-IL-23/IL-17. PMID- 28736839 TI - The Neurotensin NTS1 Receptor Agonist PD149163 Produces Antidepressant-Like Effects in the Forced Swim Test: Further Support for Neurotensin as a Novel Pharmacologic Strategy for Antidepressant Drugs. AB - Preclinical Research Neurotensin is a nonbrain penetrant neuropeptide neurotransmitter that alters dopaminergic and serotonergic neurotransmission. Previous animal behavioral studies have demonstrated that intra-ventral tegmental administration of neurotensin and system administration of the selective neurotensin NTS1 receptor agonist, PD149163 produce antidepressant-like effects in a forced swim test and a differential reinforcement of low rate task, respectively. The present study sought to expand upon these past findings by assessing systemic administration of PD149163 in a forced swim test, a primary antidepressant preclinical screening model, in mice. The tricyclic antidepressant drug imipramine was tested for comparison, and both compounds were also assessed in an open field test. Both PD149163 and imipramine reduced time spent immobile, an antidepressant-like effect, in the forced swim test. The highest dose of each compound significantly reduced locomotor activity. These findings provide further evidence for the putative antidepressant effects for PD149163 and suggest that NTS1 receptor activation may be a novel pharmacologic strategy for antidepressant drug development. Drug Dev Res 78 : 196-202, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28736840 TI - ISSOP position statement on migrant child health. AB - Greater numbers of children are on the move than ever before. In 2015, the number of forcibly displaced people across the globe reached 65.3 million. Of the more than 1 million migrants, asylum seekers, and refugees who arrived in Europe in 2015, nearly one third were children, and 90,000 of these children were unaccompanied. Child migrants are among the most vulnerable, even after arriving at their destination. The health of migrant children is related to their health status before their journey, the conditions during their journey and at their destination, and the physical and mental health of their caregivers. These children may have experienced numerous forms of trauma including war, violence, separation from family, and exploitation. They may suffer from malnutrition and communicable diseases including vaccine-preventable diseases. Pregnant women, newborns, and unaccompanied minors are particularly vulnerable groups. Social isolation is a major risk factor for all migrant children that compound other health risks even after settlement in their new home. Lack of health information, language, and cultural differences serve as major barriers to adequate, timely, and appropriate healthcare. In spite the challenges they face, migrant children demonstrate remarkable resilience that can be nurtured to promote good mental and physical health. Migrant children, irrespective of their legal status, are entitled to healthcare of the same standard provided to children in the resident population, as stated in the UN Convention on the Rights of the Child. It is imperative that the health sector includes informed health workers who are able to identify the health risks and needs of these children and provide culturally competent care. In order to achieve this and promote the rights of migrant children to optimal health and well-being, ISSOP recommends that Programmes and activities designed to promote and protect migrant child health and well-being must be designed in collaboration with all sectors involved, including the education and social sectors, and should always include the voices of migrant children and their families. Health services should be readily available and easily accessible for preventive, maintenance, and curative care regardless of the child's legal status. Care should be of the same standard as care provided to the local population. Health information should be provided that is culturally sensitive and readily available in a language that migrant children and families can understand. Medical interpreters and cultural mediators should be available during healthcare encounters, and personnel working with migrants should receive training in cultural competence. Health professionals should not participate in age determination until methods with acceptable scientific and ethical standards have been developed. Professionals working with migrant children and families should have access to emotional support services. Evidence-based best practices in the care of migrant children should be identified and made widely available to health workers. An observatory should be established to study the factors leading to poor psychosocial and mental health in migrant children and youth. Paediatricians and paediatric societies should work to improve the sensitivity of their respective populations towards migrants, asylum seekers, and refugees. PMID- 28736841 TI - Outcomes of Blalock-Taussig shunts in current era: A single center experience. AB - OBJECTIVES: Mortality associated with the modified Blalock-Taussig shunt (MBTS) remains high despite advanced perioperative management. This study was formulated to provide data on (1) current indications, (2) outcomes, and (3) factors affecting mortality and morbidity. DESIGN: A retrospective single center chart review identified 95 children (excluding hypoplastic left heart lesions) requiring a MBTS. Mortality and major morbidity were analyzed using the Kaplan Meier method and risk factor analysis using Cox's proportional hazard regression. RESULTS: Median age was 8 (0-126) days, weight 3.1(1.7-5.4) kg. Seventy-three percent were neonates, 58% duct dependent and 73% had single ventricle physiology. Ninety-seven percent had a sternotomy approach for shunt placement with 70% receiving a 3.5 mm graft. Mean graft index (shunt cross sectional area [mm2 ]/BSA [m2 ]) was 44.39 +/- 8.04 and shunt size (mm) to body weight (kg) ratio 1.1 +/- 0.2. Hospital mortality was 12%, with an interval mortality of 6%. Shunt thrombosis/stenosis occurred in 23% and pulmonary over circulation in 30%, while shunt reoperation was required in 12% and catheter intervention in 8% of the cohort. At 1-year, survival was 82.0% (95% CI [72.7%, 88.4%]), and survival free of major morbidity 61.4% (95% CI [50.7%, 70.5%]). Duct dependency predisposed to mortality (P = .01, HR 6.74 [1.54, 29.53]) and composite outcome (mortality and major morbidity) (P = .04, HR 2.15, CI [1.036, 4.466]) and higher graft index to mortality (P = .005, HR 1.07 [1.02, 1.12]). CONCLUSIONS: The commonest indication for a MBTS in the current era was single ventricle palliation. Morbidity and mortality was considerable, partly explained by the higher at risk population. Alternative methods to maintain pulmonary blood flow in place of a MBTS requires further investigation. PMID- 28736842 TI - One-stage repair using a frozen elephant trunk technique for acute type A intramural hematoma with an ulcer-like projection in the dilated proximal descending aorta. PMID- 28736843 TI - Effectiveness of weekly azathioprine pulse in the treatment of chronic plaque psoriasis: an open-label study: reply to author. PMID- 28736844 TI - Newly Designed Silica-Containing Redox Nanoparticles for Oral Delivery of Novel TOP2 Catalytic Inhibitor for Treating Colon Cancer. AB - Although oral drug delivery is the most common route of drug administration, the conventional polymeric nanocarriers exhibit a low drug loading capacity and low stability in the gastrointestinal (GI) environments. In this study, a newly designed silica-containing redox nanoparticle (siRNP) with reactive oxygen species (ROS) scavenging capacity is developed as an ideal oral nanocarrier for a novel hydrophobic anticancer compound BNS-22 to treat colitis-associated colon cancer in vivo. Crosslinking of silica moieties significantly enhances the stability under acidic conditions and improves BNS-22 loading capacity of siRNP compared to the conventional redox nanoparticle. After oral administration to mice, BNS-22-loaded siRNP (BNS-22@siRNP) remarkably improves bioavailability and colonic tumor distribution of BNS-22. As the result, BNS-22@siRNP significantly inhibits the tumor progression in colitis-associated colon cancer mice compared to other control treatments. It is noteworthy that no systemic absorption of siRNP carrier is observed after oral administration. Interestingly, orally administered BNS-22@siRNP significantly suppresses the adverse effects of BNS-22 owing to its ROS scavenging capacity, and no other noticeable toxicities are observed in mice treated with BNS-22@siRNP although siRNP is localized in the GI tract. Our results indicate that siRNP is a promising oral drug nanocarrier for cancer therapy. PMID- 28736845 TI - Cytokine expression associated with Helicobacter pylori and Epstein-Barr virus infection in gastric carcinogenesis. AB - Helicobacter pylori and Epstein-Barr virus (EBV) infection, and associated cytokines are involved in gastric carcinogenesis. We investigated the expression of these cytokines and their relationship with clinicopathological characteristics. The study included specimens from 207 patients with gastric adenocarcinoma, 56 with chronic gastritis, 32 with metaplasia, and 30 with low grade epithelial dysplasia. Tissue microarrays were constructed and immunohistochemical staining for IL-1beta, IL-6, IL-10, IL-17, p16, p21, TNF alpha, and TNFR1 was performed. EBV and H. pylori infection status was determined. IL-1beta, IL-6, IL-17, p16, and p21 protein expression was significantly higher in adenocarcinoma cases than in the other cases (p < 0.05). EBV was only noted in adenocarcinoma (13 cases, 6.3%). The H. pylori infection rate in adenocarcinoma was significantly higher than that in the other cases (p < 0.005). IL-6 expression was associated with improved survival (p < 0.05), whereas IL-17 expression was associated with decreased survival (p < 0.05). IL-6 expression was inversely associated with angioinvasion, and disease stage (p < 0.05), whereas IL-17 expression was associated with disease stage (p < 0.05). IL 10 expression was correlated with IL-1beta and TNF-alpha expression, and p16 expression was correlated with IL-17 and EBV status. Our results indicate that IL 6 and IL-17 are associated with gastric carcinogenesis and may be considered prognostic factors. PMID- 28736846 TI - Time course of recovery of idiopathic vocal fold paralysis. AB - OBJECTIVES/HYPOTHESIS: To clarify the time course of recovery in patients with idiopathic vocal fold paralysis. STUDY DESIGN: Retrospective chart review. METHODS: Medical records for all patients with idiopathic vocal fold paralysis over a 10-year period were reviewed to obtain demographic and clinical information, including onset of disease and recovery of vocal function. Stroboscopic exams of patients who recovered voice were reviewed blindly to assess return of vocal fold motion. RESULTS: Thirty-eight of 55 patients (69%) recovered vocal function. Time course of recovery could be assessed in 34 patients who did not undergo injection augmentation. The mean time to recovery was 152.8 +/- 109.3 days (left, 179.8 +/- 111.3 days; right, 105.3 +/- 93.7 days; P = .088). Two-thirds of patients recovered within 6 months. Probability of recovery declined over time. Five of 22 patients who recovered voice had return of vocal fold motion; 17 did not. The mean time to recovery did not differ between these groups (return of motion, 127.4 +/- 132.3 days; no return of motion, 160.1 +/- 105.1 days; P = .290). CONCLUSIONS: Sixty-nine percent of patients with idiopathic vocal fold paralysis recovered vocal function, two thirds doing so within 6 months of onset. Age, gender, laterality, use of injection augmentation did not influence recovery rate. Declining probability of recovery over time leads us to consider framework surgery after 6 months in patients with idiopathic paralysis. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:148 152, 2018. PMID- 28736847 TI - Reproductive plasticity and landscape heterogeneity benefit a ground-nesting bird in a fire-prone ecosystem. AB - Disturbance is critical for the conservation of rangeland ecosystems worldwide and many of these systems are fire dependent. Although it is well established that restoring fire as an ecological process can lead to increased biodiversity in grasslands and shrublands, the underlying mechanisms driving community patterns are poorly understood for fauna in fire-prone landscapes. Much of this uncertainty stems from the paucity of studies that examine the effects of fire at scales relevant to organism life histories. We assessed the response of a non migratory ground-dwelling bird to disturbance (i.e., prescribed fire) and environmental stochasticity over the course of a 4-yr period, which spanned years of historic drought and record rainfall. Specifically, we investigated the nesting ecology of Northern Bobwhite (Colinus virginianus; hereafter Bobwhite) to illuminate possible avenues by which individuals respond to dynamic landscape patterns during a critical reproductive stage (i.e., nesting) in a mixed-grass shrubland in western Oklahoma, USA. We found that Bobwhites exhibited extreme plasticity in nest substrate use among time since fire categories (TSF) and subsequently maintained high nest survival (e.g., 57-70%). Bobwhites were opportunistic in nest substrate use among TSF categories (i.e., 72% of nest sites in shrubs in 0-12 months post fire compared to 71% in herbaceous vegetation in >36 months post fire), yet nesting decisions were first filtered by similar structural components (i.e., vertical and horizontal cover) within the vicinity of nest sites regardless of TSF category. Despite being a non-migratory and comparatively less mobile ground-nesting bird species, Bobwhites adjusted to dynamic vegetation mosaics on a fire-prone landscape under stochastic climatic conditions that culminated in stable and high nest survival. Broadly, our findings provide a unique depiction of organism response strategies to fire at scales relevant to a critical life-stage, a topic that has been previously understudied and poorly understood. We also demonstrate how doing so can better inform conservation practices aimed at restoring fire regimes on grassland and shrubland landscapes. PMID- 28736848 TI - The risk of colorectal neoplasia can be different according to the types of family members affected by colorectal cancer. AB - BACKGROUND AND AIM: A family history of colorectal cancer (CRC) is an important risk factor for CRC, but more detailed data are needed to prepare effective screening guidelines. We aimed to evaluate the risk of colorectal neoplasia (CRN) among individuals with different relatives affected by CRC (the first-degree relatives [FDRs] or the second-degree relatives or the first cousins) and to assess the effects of family histories according to age groups (30-39, 40-49, and >= 50 years). METHODS: A cross-sectional study was performed on 98 562 asymptomatic examinees aged >= 30 years who underwent colonoscopy as part of a health checkup. RESULTS: Mean age of the study population was 41.4 years, and the prevalence of CRN was 15.7%. Participants with >= 1 FDRs and >= 2 FDRs affected by CRC had a higher risk of CRN than those with no family history of CRC, while those with >= 1 second-degree relatives or first cousins affected did not. In the 30-39 and 40-49 years age groups, a family history of CRC in parents was a risk factor for CRN and advanced CRN, but not in siblings. By contrast, in the >= 50 age group, participants with affected siblings (reference group) had a significantly higher risk for advanced CRN than those with affected parents (adjusted odds ratio; 95% confidence interval: 0.39; 0.16-0.94 in father and 0.43; 0.18-0.995 in mother). CONCLUSIONS: The risk of CRN can be different according to the types of family members affected, and the impact of such family histories can be different according to age. PMID- 28736849 TI - Rounded and velvety epidermal naevus: Dermoscopic findings and literature review. PMID- 28736850 TI - Progressive ataxia and palatal tremor: Two autopsy cases of a novel tauopathy. AB - BACKGROUND: Sporadic progressive ataxia and palatal tremor is a rare syndrome characterized by mid- to late-adult-onset symptomatic palatal tremor and slowly progressive cerebellar ataxia. To date, there has been only one autopsy report, which described a novel 4-repeat tauopathy with hypertrophic olivary degeneration and tau-positive inclusions in olivary neurons and dystrophic neuritic processes termed glomeruloid bodies. We report on 2 additional autopsy cases. METHODS: Sections from selected paraffin-embedded brain regions were stained with hematoxylin and eosin/Luxol fast blue and processed for phosphorylated tau, 3 repeat tau, 4-repeat tau, neurofilament, glial fibrillary acid protein, phosphorylated alpha-synuclein, phosphorylated TAR DNA-binding protein 43, beta amyloid, and p62 immunohistochemistry. RESULTS: Two male patients were aged 74 and 64 years at onset. Both had clinical findings consistent with progressive ataxia and palatal tremor and T2 hyperintensity in the bilateral olives on MRI. Pathological findings included bilateral hypertrophic olivary degeneration accompanied by glomeruloid bodies, 3-repeat and 4-repeat tau-positive neuronal inclusions in the olive, and additional tauopathy in the midbrain, pons, and thalamus. Cerebellar cortical degeneration was extensive, but involvement of the dentate was minimal. P62-positive, but tau- and TAR DNA-binding protein 43 negative, inclusions in the cerebellum of 1 case was also a feature. CONCLUSIONS: Whereas our findings are largely in keeping with the previously published case report, we found a more extensive and mixed 3/4-repeat tauopathy and additional cerebellar p62 pathology, highlighting our incomplete understanding of the pathogenesis of this disease. (c) 2017 International Parkinson and Movement Disorder Society. PMID- 28736851 TI - Use of Fluorescence In Situ Hybridization Technology to Explain a Confusing Case of Vasa Previa. PMID- 28736852 TI - Successful medical treatment of an Aspergillus terreus mycetoma of the nostril/lip in a 16-year-old Fjord pony gelding with pituitary pars intermedia dysfunction. AB - BACKGROUND: Mycetoma is a chronic, proliferative lesion of cutaneous/subcutaneous tissue characterized by draining tracts and granules in the discharge caused by actinomycetes (actinomycetoma) or filamentous fungi (eumycotic mycetoma). OBJECTIVES: This case report describes the unusual finding of a cutaneous mycetoma of the lateral wing of the right nostril in a gelding. ANIMAL: A 16-year old Fjord gelding with suspected pituitary pars intermedia dysfunction (PPID) was presented for evaluation of a nonpainful, firm and raised mass involving the lateral wing of the right nostril and the lip. METHODS AND RESULTS: Cytological examination of the mass showed marked pyogranulomatous inflammation and histopathological examination revealed a fungal mycetoma. Fungal culture identified the causative organism as Aspergillus terreus, which is not known for its propensity to cause either dermal granulomas or mycetoma in domestic animals. Further investigation, including a TRH stimulation test, led to a diagnosis of PPID (Cushing's disease), which may have led to immunosuppression of the animal and increased susceptibility to infection. CONCLUSIONS AND CLINICAL IMPORTANCE: The horse was treated medically with pergolide for the PPID and oral potassium iodide for the fungal infection, with good therapeutic response and no relapse after five months. Surgical debridement or excision was not performed. To the best of the authors' knowledge, this is the first case report of a cutaneous mycetoma caused by A. terreus in a horse. PMID- 28736853 TI - Tai Chi for Risk of Falls. A Meta-analysis. AB - OBJECTIVES: To analyze the effectiveness of tai chi for falls prevention. DESIGN: Systematic review and meta-analysis. SETTING: Pubmed, Scopus, CINHAL, and Physiotherapy Evidence Database (PEDro) were searched to May 26, 2016. PARTICIPANTS: Older adult population and at-risk adults. INTERVENTION: Randomized controlled trials analyzing the effect of tai chi versus other treatments on risk of falls. MEASUREMENTS: The incidence rate ratio (IRR) for falls incidence and hazard ratio (HR) for time to first fall. RESULTS: The search strategy identified 891 potentially eligible studies, of which 10 met the inclusion criteria. There was high-quality evidence of a medium protective effect for fall incidence over the short term (IRR = 0.57; 95% CI = 0.46, 0.70) and a small protective effect over the long term (IRR = 0.87; 95% CI = 0.77, 0.98). Regarding injurious falls, we found very low-quality evidence of a medium protective effect over the short term (IRR = 0.50; 95% CI = 0.33, 0.74) and a small effect over the long term (IRR = 0.72; 95% CI = 0.54, 0.95). There was no effect on time to first fall, with moderate quality of evidence (HR = 0.98; 95% CI = 0.69, 1.37). CONCLUSION: In at risk adults and older adults, tai chi practice may reduce the rate of falls and injury-related falls over the short term (<12 months) by approximately 43% and 50%, respectively. Tai chi practice may not influence time to first fall in these populations. Due to the low quality of evidence, more studies investigating the effects of tai chi on injurious falls and time to first fall are required. PMID- 28736854 TI - Species packing in eco-evolutionary models of seasonally fluctuating environments. AB - As ecology and evolution become ever more entwined, many areas of ecological theory are being re-examined. Eco-evolutionary analyses of classic coexistence mechanisms are yielding new insights into the structure and stability of communities. We examine fluctuation-dependent coexistence models, identifying communities that are both ecologically and evolutionarily stable. Members of these communities possess distinct environmental preferences, revealing widespread patterns of limiting similarity. This regularity leads to consistent changes in the structure of communities across fluctuation regimes. However, at high amplitudes, subtle differences in the form of fluctuations dramatically affect the collapse of communities. We also show that identical fluctuations can support multiple evolutionarily stable communities - a novel example of alternative stable states within eco-evolutionary systems. Consequently, the configuration of communities will depend on historical contingencies, including details of the adaptive process. Integrating evolution into the study of coexistence offers new insights, while enriching our understanding of ecology. PMID- 28736856 TI - Divergent Regio- and Stereoselective Gold-catalyzed Synthesis of alpha Fluorosulfones and beta-Fluorovinylsulfones from Alkynylsulfones. AB - We developed a widely applicable, highly efficient synthesis of alpha fluorosulfone and beta-fluorovinylsulfone catalyzed by gold. Starting with alkynyl sulfone 1, an [Au]/HF/N-oxide system gives alpha-fluorosulfone 3 via a gold carbene intermediate, and, if no N-oxide is used, direct addition of HF to 1 gives vinyl sulfone 4 via a vinylfluoro gold intermediate. Both methods have good functional group tolerance and the reactions can be conducted in ambient atmosphere. PMID- 28736858 TI - Position and relative size of the vertebral artery according to age: Implications for internal jugular vein access. AB - AIM: The purpose of this retrospective observational study was to investigate the anatomical characteristics of the vertebral artery in pediatric patients using computed tomography images. METHODS: We evaluated anatomical characteristics of the right and left vertebral artery at the cricoid level and at a lower level, which was mid-level between the cricoid cartilage and the origin of vertebral artery from the subclavian artery. At each level, the cross-sectional areas of the vertebral artery and internal jugular vein, the relative size of vertebral artery to internal jugular vein, the minimum distance between them, and the extent of overlap between them were investigated. RESULTS: According to the chest computed tomography images of 344 patients, the sizes of internal jugular vein and vertebral artery were found to increase with age. On the other hand, the relative size of the vertebral artery to internal jugular vein was found to increase conversely with decreasing age. The distance between the vertebral artery and internal jugular vein increased with age at both sides and levels. The vertebral artery was mostly located at the medial side of the internal jugular vein, and overlapped with the internal jugular vein in at least 54% of the patients at the cricoid level and in 74% at the lower level. CONCLUSION: The theoretical risk of vertebral artery puncture is higher in younger children during internal jugular vein catheterization. PMID- 28736857 TI - Non-Covalent Assembly Method that Simultaneously Endows a Liposome Surface with Targeting Ligands, Protective PEG Chains, and Deep-Red Fluorescence Reporter Groups. AB - A new self-assembly method is used to rapidly functionalize the surface of liposomes without perturbing the membrane integrity or causing leakage of the aqueous contents. The key molecule is a cholesterol-squaraine-PEG conjugate with three important structural elements: a cholesterol membrane anchor, a fluorescent squaraine docking station that allows rapid and high-affinity macrocycle threading, and a long PEG-2000 chain to provide steric shielding of the decorated liposome. The two-step method involves spontaneous insertion of the conjugate into the outer leaflet of pre-formed liposomes followed by squaraine threading with a tetralactam macrocycle that has appended targeting ligands. A macrocycle with six carboxylates permitted immobilization of intact fluorescent liposomes on the surface of cationic polymer beads, whereas a macrocycle with six zinc(II) dipicolylamine units enabled selective targeting of anionic membranes, including agglutination of bacteria in the presence of human cells. PMID- 28736859 TI - Case of tumoral melanosis with a massive infiltration of CD163+ and CD68+ macrophages. PMID- 28736860 TI - Annual Research Review: DNA methylation as a mediator in the association between risk exposure and child and adolescent psychopathology. AB - BACKGROUND: DNA methylation (DNAm) is a potential mechanism for propagating the effects of environmental exposures on child and adolescent mental health. In recent years, this field has experienced steady growth. METHODS: We provide a strategic review of the current child and adolescent literature to evaluate evidence for a mediating role of DNAm in the link between environmental risks and psychopathological outcomes, with a focus on internalising and externalising difficulties. RESULTS: Based on the studies presented, we conclude that there is preliminary evidence to support that (a) environmental factors, such as diet, neurotoxic exposures and stress, influence offspring DNAm, and that (b) variability in DNAm, in turn, is associated with child and adolescent psychopathology. Overall, very few studies have examined DNAm in relation to both exposures and outcomes, and almost all analyses have been correlational in nature. CONCLUSIONS: DNAm holds potential as a biomarker indexing both environmental risk exposure and vulnerability for child psychopathology. However, the extent to which it may represent a causal mediator is not clear. In future, collection of prospective risk exposure, DNAm and outcomes - as well as functional characterisation of epigenetic findings - will assist in determining the role of DNAm in the link between risk exposure and psychopathology. PMID- 28736855 TI - 'Lnc'-ing Wnt in female reproductive cancers: therapeutic potential of long non coding RNAs in Wnt signalling. AB - : Recent discoveries in the non-coding genome have challenged the original central dogma of molecular biology, as non-coding RNAs and related processes have been found to be important in regulating gene expression. MicroRNAs and long non coding RNAs (lncRNAs) are among those that have gained attention recently in human diseases, including cancer, with the involvement of many more non-coding RNAs (ncRNAs) waiting to be discovered. ncRNAs are a group of ribonucleic acids transcribed from regions of the human genome, which do not become translated into proteins, despite having essential roles in cellular physiology. Deregulation of ncRNA expression and function has been observed in cancer pathogenesis. Recently, the roles of a group of ncRNA known as lncRNA have gained attention in cancer, with increasing reports of their oncogenic involvement. Female reproductive cancers remain a leading cause of death in the female population, accounting for almost a third of all female cancer deaths in 2016. The Wnt signalling pathway is one of the most important oncogenic signalling pathways which is hyperactivated in cancers, including female reproductive cancers. The extension of ncRNA research into their mechanistic roles in human cancers has also led to novel reported roles of ncRNAs in the Wnt pathway and Wnt-mediated oncogenesis. This review aims to provide a critical summary of the respective roles and cellular functions of Wnt-associated lncRNAs in female reproductive cancers and explores the potential of circulating cell-free lncRNAs as diagnostic markers and lncRNAs as therapeutic targets. LINKED ARTICLES: This article is part of a themed section on WNT Signalling: Mechanisms and Therapeutic Opportunities. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.24/issuetoc. PMID- 28736861 TI - Azadirachtin effects on mating success, gametic abnormalities and progeny survival in Drosophila melanogaster (Diptera). AB - BACKGROUND: Azadirachtin is a prominent natural pesticide and represents an alternative to conventional insecticides. It has been successfully used against insect pests. However, its effects on reproduction require further analysis. Here we investigated lethal and sublethal effects of azadirachtin, on treated adults in a model insect, Drosophila melanogaster (Meigen). Dose-mortality relationships as well as several parameters of reproduction (mating, spermatogenesis, oogenesis and fertility) were examined. RESULTS: Neem-Azal, a commercial formulation of azadirachtin, applied topically on newly emerged adults, increased mortality with a positive dose-dependent relationship. The LD50 (0.63 MUg) was determined 24 h after treatment using a non-linear regression. Adults surviving this dose had a mating success that was divided by 3 and a progeny production reduced by half when males were treated, and even more when females were treated. When combining probability of survival, of mating and reduced progeny, it appeared that LD50 induced a 98% reduction in reproductive rates. Reduced progeny was partially explained by the effect of adult treatment on gametes number and abnormalities. The number of cysts and the apical nuclei positions within the cysts decreased by 29.7% and 20%, respectively, in males. In females, the number of oocytes per ovary and the volume of basal oocytes also decreased by 16.1% and 32.4%, respectively. CONCLUSION: Azadirachtin causes significant toxic effects in both sexes and decreases the fecundity and fertility of D. melanogaster. Females are more sensitive to azadirachtin. (c) 2017 Society of Chemical Industry. PMID- 28736862 TI - Quality Management of Ultrasound Surveillance for Hepatocellular Carcinoma Under the Korean National Cancer Screening Program. AB - OBJECTIVES: The aim of this study was to investigate the quality of ultrasound (US) examinations for hepatocellular carcinoma surveillance under the Korean National Cancer Screening Program and to assess knowledge and experience about liver US of physicians who perform US examinations. METHODS: The investigation about the quality of liver US for hepatocellular carcinoma screening was based on the results of a nationwide quality assurance (QA) evaluation between 2012 and 2014 at all medical institutions participating in the National Cancer Screening Program. The QA evaluation was for personnel, equipment, education, and clinical images. Medical institutions with fewer than 60 of 100 points were considered to have failed the evaluation. Follow-up education in the form of a hands-on workshop was provided for physicians who worked in medical institutions that failed the QA evaluation. A questionnaire about basic knowledge and experience with US was administered during follow-up education. RESULTS: After the QA evaluation, 542 of 685 hospitals and 1340 of 1985 private clinics passed the test. The evaluation of private clinics and hospitals showed substantial differences in the frequency of adequacy or mean scores between the pass and fail groups for all QA items, even requirements. Among 233 participants in the hands on workshops, 187 physicians (80.2%) responded to the questionnaire. Results revealed that physicians had deficient knowledge and experience about liver US. CONCLUSIONS: The quality of liver US for hepatocellular carcinoma screening remains suboptimal. Education for physicians who perform liver US examinations is unsatisfactory in Korea. We should make an effort to improve the quality of liver US and teach basic US techniques to physicians. PMID- 28736863 TI - No associations established between single nucleotide polymorphisms in human Toll like receptor 2 and Toll-interacting protein and Staphylococcus aureus bloodstream infections. AB - Staphylococcus aureus bloodstream infections (SABSI) are associated with high morbidity and mortality. The Toll-like receptor 2 (TLR2) and Toll-interacting protein (TOLLIP) are important in recognition and regulation of human innate immunity response to S. aureus. Single nucleotide polymorphisms (SNPs) in the TLR2 and TOLLIP encoding genes have been associated with disease, including BSI. The aim of this study was to examine potential associations between a selection of SNPs in the genes encoding TLR2 and TOLLIP, and predisposition, severity, and outcome of SABSI. All patients >=18 years of age with at least one S. aureus positive blood culture collected from March 2011 through February 2014 at Akershus University Hospital, Lorenskog, Norway, were considered for inclusion. Patients attending elective orthopaedic surgery (total hip and knee replacements, lumbar surgery) served as a control group. The TLR2 Arg753Gln, TLR2 Pro631His, TOLLIP rs5743942, and rs5743867 polymorphisms were analysed using TaqMan SNP Genotyping Assays. A total of 209 SABSI patients and 295 controls were included. The TLR2 Arg753Gln and TLR2 Pro631His polymorphisms were infrequent with no homozygotes and <10% heterozygotes. The included TLR2 and TOLLIP polymorphisms were not associated with susceptibility to SABSI, severity, 30-day all-cause mortality, or SABSI caused by the clonal complex 30 (CC30) genotype. PMID- 28736864 TI - Brain tumor segmentation using holistically nested neural networks in MRI images. AB - PURPOSE: Gliomas are rapidly progressive, neurologically devastating, largely fatal brain tumors. Magnetic resonance imaging (MRI) is a widely used technique employed in the diagnosis and management of gliomas in clinical practice. MRI is also the standard imaging modality used to delineate the brain tumor target as part of treatment planning for the administration of radiation therapy. Despite more than 20 yr of research and development, computational brain tumor segmentation in MRI images remains a challenging task. We are presenting a novel method of automatic image segmentation based on holistically nested neural networks that could be employed for brain tumor segmentation of MRI images. METHODS: Two preprocessing techniques were applied to MRI images. The N4ITK method was employed for correction of bias field distortion. A novel landmark based intensity normalization method was developed so that tissue types have a similar intensity scale in images of different subjects for the same MRI protocol. The holistically nested neural networks (HNN), which extend from the convolutional neural networks (CNN) with a deep supervision through an additional weighted-fusion output layer, was trained to learn the multiscale and multilevel hierarchical appearance representation of the brain tumor in MRI images and was subsequently applied to produce a prediction map of the brain tumor on test images. Finally, the brain tumor was obtained through an optimum thresholding on the prediction map. RESULTS: The proposed method was evaluated on both the Multimodal Brain Tumor Image Segmentation (BRATS) Benchmark 2013 training datasets, and clinical data from our institute. A dice similarity coefficient (DSC) and sensitivity of 0.78 and 0.81 were achieved on 20 BRATS 2013 training datasets with high-grade gliomas (HGG), based on a two-fold cross-validation. The HNN model built on the BRATS 2013 training data was applied to ten clinical datasets with HGG from a locally developed database. DSC and sensitivity of 0.83 and 0.85 were achieved. A quantitative comparison indicated that the proposed method outperforms the popular fully convolutional network (FCN) method. In terms of efficiency, the proposed method took around 10 h for training with 50,000 iterations, and approximately 30 s for testing of a typical MRI image in the BRATS 2013 dataset with a size of 160 * 216 * 176, using a DELL PRECISION workstation T7400, with an NVIDIA Tesla K20c GPU. CONCLUSIONS: An effective brain tumor segmentation method for MRI images based on a HNN has been developed. The high level of accuracy and efficiency make this method practical in brain tumor segmentation. It may play a crucial role in both brain tumor diagnostic analysis and in the treatment planning of radiation therapy. PMID- 28736865 TI - Bioprotection of the built environment and cultural heritage. AB - The growth of microbial biofilms and various biomineralization phenomena can lead to the formation of stable layers and veneers on rocks known as 'rock varnishes' that can stabilize surfaces and protect from further weathering. This article describes the potential application of fungal systems for bioprotection of rock and mineral-based substrates and the evidence to support this concept of utilizing natural or engineered colonization and metabolic properties of fungi, including lichens. PMID- 28736867 TI - Volunteer peer support and befriending for carers of people living with dementia: An exploration of volunteers' experiences. AB - With ageing populations and greater reliance on the voluntary sector, the number of volunteer-led peer support and befriending services for carers of people with dementia in England is set to increase. However, little is known about the experiences of the volunteers who deliver these interventions, many of whom are former carers. Using in-depth semi-structured interviews with 10 volunteer peer supporters and befrienders, this exploratory study investigated volunteers' experiences of delivering the support, the types of relationships they form with carers and their perceptions of its impact upon them and on carers. Data were analysed using framework analysis. Findings showed that volunteers benefitted from their role due to the 'two-way' flow of support. Experiential similarity and having common interests with carers were considered important to the development of mutually beneficial relationships. Volunteers perceived that carers gained emotional and social support, which in turn improved the carers' coping ability. Being able to see positive changes to carers' lives was important for volunteers to gain enjoyment and satisfaction from their role. However, volunteers also identified challenges with their role, such as dealing with carers' emotions. Future research should investigate ways of reducing potential burden on volunteers and explore the impact of volunteering specifically on former carers of people with dementia. PMID- 28736866 TI - Antibacterial activity of fusion from biosynthesized acidocin/silver nanoparticles and its application for eggshell decontamination. AB - Bacteriocins from lactic acid bacteria (LAB) are useful to control the persistent development of pathogenic microorganisms in food and medicine fields. The bacteriocin acidocin was extracted from Lactobacillus acidophilus M1 that was isolated from fermented milk, purified using ammonium sulphate fractionation, and gel filtration column chromatography using Sephadex matrix and applied as a potential antibacterial agent. The molecular weight of the purified acidocin was estimated using SDS-PAGE to be 6.6 kDa. The acidocin was compared with silver nanoparticles (SNPs), biosynthesized by Aspergillus brasiliensis (niger) ATCC 16404, against two bacterial strains Bacillus cereus ATCC 14579 and Staphylococcus aureus ATCC 25923. Both acidocin and SNPs showed significance antibacterial effects using disc and well diffusion methods; the maximum antibacterial activity was proved against B. cereus from acidocin/SNPs composite using a ratio of 1/1 from each agent. The application of acidocin/SNPs composite as immersion solution, for disinfecting chicken eggshells, resulted in remarkable reduction in microbial load on the shells of 5.53 log10 CFU/eggshell. Results could provide an eco-friendly approach for potential antimicrobial composites to be used in food preservation and other health protection researches. PMID- 28736868 TI - High-Modulus Low-Cost Carbon Fibers from Polyethylene Enabled by Boron Catalyzed Graphitization. AB - Currently, carbon fibers (CFs) from the solution spinning, air oxidation, and carbonization of polyacrylonitrile impose a lower price limit of ~$10 per lb, limiting the growth in industrial and automotive markets. Polyethylene is a promising precursor to enable a high-volume industrial grade CF as it is low cost, melt spinnable and has high carbon content. However, sulfonated polyethylene (SPE)-derived CFs have thus far fallen short of the 200 GPa tensile modulus threshold for industrial applicability. Here, a graphitization process is presented catalyzed by the addition of boron that produces carbon fiber with >400 GPa tensile modulus at 2400 degrees C. Wide angle X-ray diffraction collected during carbonization reveals that the presence of boron reduces the onset of graphitization by nearly 400 degrees C, beginning around 1200 degrees C. The B doped SPE-CFs herein attain 200 GPa tensile modulus and 2.4 GPa tensile strength at the practical carbonization temperature of 1800 degrees C. PMID- 28736869 TI - Photon-Induced Near-Field Electron Microscopy of Eukaryotic Cells. AB - Photon-induced near-field electron microscopy (PINEM) is a technique to produce and then image evanescent electromagnetic fields on the surfaces of nanostructures. Most previous applications of PINEM have imaged surface plasmon polariton waves on conducting nanomaterials. Here, the application of PINEM on whole human cancer cells and membrane vesicles isolated from them is reported. We show that photons induce time-, orientation-, and polarization-dependent evanescent fields on the surfaces of A431 cancer cells and isolated membrane vesicles. Furthermore, the addition of a ligand to the major surface receptor on these cells and vesicles (epidermal growth factor receptor, EGFR) reduces the intensity of these fields in both preparations. We propose that in the absence of plasmon waves in biological samples, these evanescent fields reflect the changes in EGFR kinase domain polarization upon ligand binding. PMID- 28736870 TI - Alveolar bone resorption after primary tooth loss has a negative impact on straightforward implant installation in patients with agenesis of the lower second premolar. AB - OBJECTIVES: To compare the alveolar bone dimensions in patients with lower second premolar (P2) agenesis prior to and after primary molar loss on CT scans, and assess the possibility for straightforward implant placement. METHODS: Alveolar bone dimensions were evaluated on 150 mandibular CT scans in three groups: (i) agenesis of P2, with the primary tooth in situ, and regularly erupted first premolar (P1) and molar (M1) (AW); (ii) agenesis of P2, without the primary tooth in situ for >=3 m, but regularly erupted P1 and M1 (AWO); and (iii) P1, P2, and M1 regularly erupted (CTR). The possibility of straightforward placement of an implant 3.5 or 4.3 mm in O * 10 mm long was digitally simulated and compared to the actually performed treatment. RESULTS: Buccolingual width (7.3 +/- 2.0 mm) at the coronal aspect of the ridge in the AWO group was statistically significantly smaller comparing with both the AW (9.2 +/- 1.4 mm) and the CTR (9.5 +/- 1.1 mm) group; width reduction appeared to be mainly due to "collapse" of the buccal aspect of the ridge. Simulated straightforward placement of implants with a diameter of 3.5 or 4.3 mm was possible in 62% and 56% of the cases in the AWO vs. 86% and 84% in the AW group (p = .006 and .002, respectively). Straightforward implant placement was actually possible in all patients (22) in the AW group, while 28% (11 of 39) of the patients in the AWO group needed additional hard tissue augmentation. CONCLUSIONS: Significant dimensional differences exist in the alveolar ridge, especially in the coronal part, at lower P2 agenesis sites missing the primary tooth for >=3 m, when compared to P2 agenesis sites with the primary tooth in situ. It seems thus reasonable to advise that the primary second molar should be kept as long as possible, in order to facilitate straightforward implant installation and reduce the probability of additional bone augmentation procedures. PMID- 28736871 TI - Inequitable health service use in a Canadian paediatric population: A cross sectional study of individual- and contextual-level factors. AB - BACKGROUND: Health service use may be influenced by multilevel predisposing, enabling, and need factors but is equitable when driven by need. The study's objectives were as follows: (a) to investigate residential context's effect on child health service use and (b) to examine inequity of child health service use by testing for effect measure modification of need factors. METHODS: The sample of 1,451 children was from a prenatal cohort recruited from London, Ontario, between 2002 and 2004, with follow-up until children were toddler/preschooler aged. Individual-level data were linked by residential address to neighbourhood contextual-level data sourced from Statistics Canada. Multilevel logistic regression modelled factors associated with child health service use. Interaction terms were included in the model to test for effect measure modification of need factors by predisposing and enabling factors. RESULTS: Contextual-level factors were not associated with child health service use. Maternal parity and nativity to Canada modified the effect of the need factor, paediatric health condition, on health service use. Health condition's effect was lowest in children of Canadian born mothers with one child only (OR = 1.58, p = .04) and highest in children of Canadian-born mothers with three or more children (OR = 3.52, p < .01). Further, its effect was higher in children of Canadian-born mothers compared to children of mothers who migrated to Canada; however, odds ratios were not statistically significant for the latter. CONCLUSIONS: Results may inform future investigation of the potential inequity of health service use for subgroups of children whose mothers are of lower parity and not Canadian-born. An understanding of these inequities may inform future healthcare policy and care for paediatric populations. PMID- 28736872 TI - Global change and the distributional dynamics of migratory bird populations wintering in Central America. AB - Understanding the susceptibility of highly mobile taxa such as migratory birds to global change requires information on geographic patterns of occurrence across the annual cycle. Neotropical migrants that breed in North America and winter in Central America occur in high concentrations on their non-breeding grounds where they spend the majority of the year and where habitat loss has been associated with population declines. Here, we use eBird data to model weekly patterns of abundance and occurrence for 21 forest passerine species that winter in Central America. We estimate species' distributional dynamics across the annual cycle, which we use to determine how species are currently associated with public protected areas and projected changes in climate and land-use. The effects of global change on the non-breeding grounds is characterized by decreasing precipitation, especially during the summer, and the conversion of forest to cropland, grassland, or peri-urban. The effects of global change on the breeding grounds are characterized by increasing winter precipitation, higher temperatures, and the conversion of forest to peri-urban. During spring and autumn migration, species are projected to encounter higher temperatures, forests that have been converted to peri-urban, and increased precipitation during spring migration. Based on current distributional dynamics, susceptibility to global change is characterized by the loss of forested habitats on the non-breeding grounds, warming temperatures during migration and on the breeding grounds, and declining summer rainfall on the non-breeding grounds. Public protected areas with low and medium protection status are more prevalent on the non-breeding grounds, suggesting that management opportunities currently exist to mitigate near-term non-breeding habitat losses. These efforts would affect more individuals of more species during a longer period of the annual cycle, which may create additional opportunities for species to respond to changes in habitat or phenology that are likely to develop under climate change. PMID- 28736873 TI - Standardized molecular diagnostic tool for the identification of cryptic species within the Bemisia tabaci complex. AB - BACKGROUND: The whitefly Bemisia tabaci complex harbours over 40 cryptic species that have been placed in 11 phylogenetically distinct clades based on the molecular characterization of partial mitochondrial DNA COI (mtCOI) gene region. Four cryptic species are currently within the invasive clade, i.e. MED, MEAM1, MEAM2 and IO. Correct identification of these species is a critical step towards implementing reliable measures for plant biosecurity and border protection; however, no standardized B. tabaci-specific primers are currently available which has caused inconsistencies in the species identification processes. RESULTS: We report three sets of polymerase chain reaction (PCR) primers developed to amplify the mtCOI region which can be used for genotyping MED, MEAM1 and IO species, and tested these primers on 91 MED, 35 MEAM1 and five IO individuals. PCR and sequencing of amplicons identified a total of 21, six and one haplotypes in MED, MEAM1 and IO respectively, of which six haplotypes were new to the B. tabaci database. CONCLUSION: These primer pairs enabled standardization and robust molecular species identification via mtCOI screening of the targeted invasive cryptic species and will improve quarantine decisions. Use of this diagnostic tool could be extended to other species within the complex. (c) 2017 Society of Chemical Industry. PMID- 28736874 TI - The impact of changes in China's family patterns on family pension functions. AB - Using data from the Chinese census and the China Statistical Yearbook, this paper will analyze the historical changes and future trends of family households in China over the past 30 years and explore the changes of family pension functions and corresponding policies. Our analysis yielded 3 notable results. First, in family size miniaturization and structural simplification, 1- and 2-generation family households are the main body of contemporary China. Second, for family aging and changes in living patterns, which primarily manifest as an increase in; the proportion of elderly households and in middle-aged and elderly people in the family, the elderly model and the "multigenerational model" have become the 2 major residence models for the elderly in China. Third, nontraditional families have emerged in large numbers, such as the exclusively elderly family, empty nest family, grandparents family, Double Income, No Kids (DINK) family, older single family, and single-parent family. We argue that in the process of simplification, China's family structure is increasingly showing characteristics of networking. The change in family patterns entails the restoration of traditional functions and taking on new functions of the family by issuing relevant social policies. Only when these social policies are based on family functions and demands can they provide effective help to social members, particularly regarding the family's responsibilities to parent children and support the elderly. PMID- 28736875 TI - Assessment of unilateral ureter obstruction with multi-parametric MRI. AB - PURPOSE: Quantitative multi-parametric MRI (mpMRI) methods may allow the assessment of renal injury and function in a sensitive and objective manner. This study aimed to evaluate an array of MRI methods that exploit endogenous contrasts including relaxation rates, pool size ratio (PSR) derived from quantitative magnetization transfer (qMT), chemical exchange saturation transfer (CEST), nuclear Overhauser enhancement (NOE), and apparent diffusion coefficient (ADC) for their sensitivity and specificity in detecting abnormal features associated with kidney disease in a murine model of unilateral ureter obstruction (UUO). METHODS: MRI scans were performed in anesthetized C57BL/6N mice 1, 3, or 6 days after UUO at 7T. Paraffin tissue sections were stained with Masson trichrome following MRI. RESULTS: Compared to contralateral kidneys, the cortices of UUO kidneys showed decreases of relaxation rates R1 and R2 , PSR, NOE, and ADC. No significant changes in CEST effects were observed for the cortical region of UUO kidneys. The MRI parametric changes in renal cortex are related to tubular cell death, tubular atrophy, tubular dilation, urine retention, and interstitial fibrosis in the cortex of UUO kidneys. CONCLUSION: Measurements of multiple MRI parameters provide comprehensive information about the molecular and cellular changes produced by UUO. Magn Reson Med 79:2216-2227, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28736876 TI - Geriatric Cooperatives in Southwestern Ontario: A novel way of increasing inter sectoral partnerships in the care of older adults with responsive behaviours. AB - Established in 2010, Geriatric Cooperatives support the evolving Behavioural Supports Ontario (BSO) programme in the South West Local Health Integration Network. Geriatric Cooperatives bring together members representing relevant cross-sectoral services and are tasked with identifying system gaps associated with the BSO target population as well as developing work plans specific to their local area, leveraging local capacity, and co-ordinating and improving linkages between sectors and services. The purpose of this study was to evaluate the partnerships formed over time within these Cooperatives in order to inform their ongoing development and sustainability. In 2012 and in 2015, Geriatric Cooperative members were invited to complete the Partnership Self-Assessment Tool (PSAT), a valid and reliable tool for evaluating collaborative processes and identifying areas in need of improvement. Scoring the PSAT involves the calculation of mean scores (ranging from 1 to 5) for each of six dimensions describing effective collaboration; higher mean scores reflect better functioning. Two psychometrically sound versions of the PSAT exist; the shorter version (PSAT-S) scores fewer items in three dimensions. Survey response rates for the three Cooperatives that were evaluated in both 2012 and 2015 were 70% in 2012 and 36% in 2015; 57% of members who completed the survey in 2015 were new Cooperative members. Both years, more than 25% of respondents selected "don't know" for three of the nine items used to score the administration and management dimension. Both PSAT and PSAT-S mean dimension scores across both years reflected that more effort is needed to maximise collaborative potential. Use of the PSAT has promoted a better understanding of how partnerships are functioning. Knowledge of where more work is required along with effective strategies to overcome weak areas and gaps in functioning has the potential to ensure that these Cooperatives are successful. PMID- 28736877 TI - Authors' reply re: Long-term outcomes of transobturator tapes in women with stress urinary incontinence: E-TOT randomized controlled trial. PMID- 28736878 TI - Optimal positioning to image the subglottis during transnasal flexible laryngoscopy. PMID- 28736879 TI - Synthesis of Benzofurans and Indoles from Terminal Alkynes and Iodoaromatics Catalyzed by Recyclable Palladium Nanoparticles Immobilized on Siliceous Mesocellular Foam. AB - Herein, we report on the utilization of a heterogeneous catalyst, consisting of Pd nanoparticles supported on a siliceous mesocellular foam (Pd0 -AmP-MCF), for the synthesis of heterocycles. Reaction of o-iodophenols and protected o iodoanilines with acetylenes in the presence of a Pd nanocatalyst produced 2 substituted benzofurans and indoles, respectively. In general, the catalytic protocol afforded the desired products in good to excellent yields under mild reaction conditions without the addition of ligands. Moreover, the structure of the reported Pd nanocatalyst was further elucidated with extended X-ray absorption fine-structure spectroscopy, and it was proven that the catalyst could be recycled multiple times without significant loss of activity. PMID- 28736880 TI - Central nervous system infection due to Cryptococcus gattii sensu lato in India: Analysis of clinical features, molecular profile and antifungal susceptibility. AB - Cryptococcus gattii species complex has evolved as a pathogen in the last two decades causing infection among both immunocompetent and immunocompromised hosts. We aimed to analyse the clinical features of CNS infection caused by C. gattii sensu lato, molecular and antifungal susceptibility profile of this pathogen. Cases diagnosed to have CNS cryptococcosis were included in the study. Cryptococcus recovered from patient's specimen was identified by standard protocol. Species confirmation, mating type and molecular type determination were performed by PCR based methods. Antifungal susceptibility was tested in VITEK2C to amphotericin B, 5-flucytosine, fluconazole and voriconazole. Among 199 cases, 20 (10%) were due to C. gattii, comprising of 75% cryptococcal meningitis and 25% cryptococcoma cases. Young adult males were commonly affected. Headache and vomiting were prominent symptoms and 50% were immunocompromised. Among the isolates, 75%, 20% and 5% were C. tetragattii, C. gattii sensu stricto and C. bacillisporus respectively and all had mating type alpha. Four (20%) isolates of C. tetragattii and the only isolate of C. bacillisporus were resistant to fluconazole. The most common species isolated from south India is C. tetragattii. The study contributes to the epidemiology of C. gattii and reiterates the need for genotyping and antifungal susceptibility testing. PMID- 28736881 TI - Evidence of genetic factors involved in oral lichen planus pathogenesis. PMID- 28736882 TI - The clinical significance of monitoring the expression of the SIL-TAL1 fusion gene in T-cell acute lymphoblastic leukemia after allogeneic hematopoietic stem cell transplantation. AB - INTRODUCTION: SIL-TAL1 rearrangement is common in T-cell acute lymphoblastic leukemia (T-ALL). However, whether this fusion gene might be used as a reliable marker of minimal residual disease (MRD) following allogeneic stem cell transplantation (allo-HSCT) remains unknown METHODS: The clinical data of consecutive 29 patients with T-ALL who received allo-HSCT were collected. Their MRD were evaluated by SIL-TAL1, Wilms' tumor 1 (WT1) expression, and the leukemia associated immunophenotype (LAIP) . RESULTS: The median follow-up was 354 days (71-2111 days). Of the enrolled patients, 14 (87.5%) patients died of leukemia relapse. A total of 15 (51.7%) patients experienced relapse at a median of 90 days (60-540 days) after transplantation. The SIL-TAL1 expression of 16 patients converted from negative prior to transplantation to positive at 77 days (30-281 days) following transplantation; furthermore, 15 (93.8%) of them eventually experienced relapse. In the 15 relapsed patients, 13 (86.7%) had increased SIL TAL1 expression levels 30 days (11-220 days) earlier than the hematological relapse and the detection of abnormal WT1 and LAIP. CONCLUSION: We are the first to demonstrate the reliability of the SIL-TAL1 fusion gene as a good MRD marker for patients with T-ALL after allo-HSCT. PMID- 28736883 TI - Correction. PMID- 28736884 TI - Direct and Indirect Pathways From Adverse Childhood Experiences to High School Dropout Among High-Risk Adolescents. AB - Adverse childhood experiences (ACEs) are associated with an increased risk for school dropout. This study examined pathways from childhood adversity to school dropout through academic, behavioral, emotional, and social pathways. Data were collected prospectively from 728 adolescents and their caregivers who participated in the Longitudinal Studies of Child Abuse and Neglect and from child protective services records. Path analyses revealed a direct association between ACEs and dropout, as well as indirect effects through poor reading achievement and elevated externalizing problems. ACEs were associated with elevated internalizing problems, which were negatively associated with dropout. However, ACEs were not associated with peer influences. Implications of the identified mechanisms in the ACEs and school dropout association for future preventive interventions are discussed. PMID- 28736885 TI - Cutaneous squamous cell carcinoma of the scalp extending to the skull: A case report and review of the literature. AB - Squamous cell carcinoma (SCC) of the scalp has increased prevalence in older patients and often presents later in life. Mohs micrographic surgery remains the most effective treatment in most cases. Delayed presentation may result in localized bony invasion or distant metastases. We present a case of an elderly woman presenting with extension of SCC into the parietal bone of the skull. PMID- 28736886 TI - Size of thyroid carcinoma by histotype and variants: A population-based study in a mildly iodine-deficient area. AB - BACKGROUND: Data relating the size of thyroid cancer with histological types and variants are scarce. METHODS: All incident thyroid cancer diagnosed between 2003 and 2012 in a mildly iodine-deficient area were derived from a population-based tumor registry. Undifferentiated/anaplastic thyroid cancer and incidental cases were excluded. Major diameter of thyroid cancer, as assessed by pathological examination, was stratified in classes: <=10 mm; 11-20 mm; 21-40 mm; and >40 mm. For each class, absolute and relative frequencies of histological types were calculated. RESULTS: Tumors >20 mm were more frequent among follicular thyroid carcinoma (FTC) and Hurthle cell carcinoma than in other histotypes, with median size of 22.50 mm (95% confidence interval [CI] 16.71-28.29) and 25.00 mm (95% CI 17.04-32.96) in FTC and Hurthle cell carcinoma, respectively. Odds ratio for tumors >20 mm was significant for FTC and Hurthle cell carcinoma only (P < .0001). CONCLUSION: Among the histotypes and variants of differentiated thyroid cancer, FTC and Hurthle cell carcinoma are characterized by the largest size. PMID- 28736887 TI - First report of peste des petits ruminants virus lineage II in Hydropotes inermis, China. AB - In this study, we investigated an outbreak of peste des petits ruminants (PPR) at a Hydropotes inermis (water deer) farm in Anhui Province, China. These results demonstrated that PPR viruses (PPRVs) can infect H. inermis and also revealed that virulent lineage II PPRVs exist in China, where they have been responsible for the deaths of wild animals. The government should pay close attention to the threat of PPRV epidemiology in China. PMID- 28736888 TI - Alterations in cortical thickness in nonmedicated premature ejaculation patients: A morphometric MRI study. AB - PURPOSE: Premature ejaculation (PE) is one of the most common sexual dysfunctions in men. However, there has been little research evaluating alterations in brain structure related to PE. We aimed to investigate the characteristics of nonmedicated PE patients in terms of brain morphometry. MATERIALS AND METHODS: The sample consisted with 32 medication-naive adult men with clinical diagnosed PE and matched 31 healthy controls. All participants received diagnostic interviews and 3.0 Tesla MRI scans. Automatic segmentation processing of MRI structure images was performed using FreeSurfer software and cerebral cortical thickness between groups was compared. RESULTS: The PE group had thicker cortex in widespread regions, including the frontal, parietal and occipital lobe, and limbic system, compared with the healthy control group (P < 0.05). Moreover, the duration is negatively correlated with the mean cortical thickness of the right medial orbitofrontal cortex, right precentral gyrus and left superior frontal cortex (R2 = 0.29, P < 0.003; R2 = 0.163, P < 0.04; R2 = 0.2, P < 0.02), while the Premature Ejaculation Diagnostic Tool score is negatively correlated with the mean cortical thickness of the left caudal middle frontal cortex (R2 = 0.33, P < 0.005). CONCLUSION: The result highlights the structural features of PE and suggests the relationship with the severity of impairment is related to the severity of anatomic abnormality with the relevant brain region. These results support the value of imaging measures as markers for understanding the physiopathology of PE. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2018;47:656-662. PMID- 28736889 TI - Fast Adsorption of Soft Hydrogel Microspheres on Solid Surfaces in Aqueous Solution. AB - The real-time adsorption behavior of polymeric colloidal microspheres onto solid surfaces in aqueous solution was visualized for the first time using high-speed atomic force microscopy (HS-AFM) to reveal how the softness of the microspheres affects their dynamic adsorption. Studies that focus on the deformability of microspheres upon dynamic adsorption have not yet been reported, most likely on account of a lack of techniques that appropriately depict the dynamic adsorption and deformation behavior of individual microspheres at the nanoscale in real time. In this study, the deformability of microspheres plays a crucial role on the adsorption kinetics, that is, soft hydrogel microspheres adsorb faster than harder elastomeric or rigid microspheres. These results should provide insight towards development of new colloidal nanomaterials that exhibit effective adsorption on specific sites in aqueous solution. PMID- 28736890 TI - Insect frass in stored cereal products as a potential source of Lactobacillus sanfranciscensis for sourdough ecosystem. AB - AIM: Insect frass samples were collected from Drosophila melanogaster, Plodia interpunctella, Rhyzopertha dominica, Sitophilus granarius, Sitophilus oryzae, Sitophilus zeamais, Tribolium confusum and Tribolium castaneum to elucidate if they can be the origin of Type I sourdough micro-organisms (Lactobacillus sanfranciscensis and Candida milleri). METHODS AND RESULTS: Selective enrichments were carried out to isolate lactic acid bacteria (LBA) and yeast. A metagenetic analysis, targeted on bacterial 16S rRNA gene and fungal ITS region, was performed by using Illumina MiSeq protocol. In cultivation conditions, Lactococcus garvieae and Rhodotorula mucilaginosa were the most frequently species among LAB and yeasts respectively. The Next Generation Sequencing approach revealed that Enterobacteriaceae, Pseudomonadacae and Bacillaceae were the dominating taxa, accounting for 61% of the bacterial community. Lactobacillus genus showed a relative abundance of only 0.36%, but L. sanfranciscensis proved to be the species most frequent between lactobacilli and predominant in faecal samples of T. castaneum and T. confusum larvae. The core fungal microbiota was constituted by Saccharomycetales, Pleosporaceae and Nectriaceae that attained the 51% of recognized OTUs. While the most abundant yeast genus was Candida (17.1%), sequences belonging to C. milleri were not found. CONCLUSIONS: Frass released by the insects of stored cereal products can be the natural reservoir of L. sanfranciscensis. SIGNIFICANCE AND IMPACT OF THE STUDY: Insect dejections are potential sources of novel strains for controlled bakery productions. PMID- 28736892 TI - Anger Can Help: A Transactional Model and Three Pathways of the Experience and Expression of Anger. AB - Anger is a significant human emotion with far-reaching implications for individuals and relationships. We propose a transactional model of anger that highlights its relational relevance and potentially positive function, in addition to problematic malformations. By evolutionary design, physical, self concept, or attachment threats all similarly trigger diffuse physiological arousal, psychologically experienced as anger-emotion. Anger is first a signaling and motivational system. Anger is then formed to affirming, productive use or malformed to destructive ends. A functional, prosocial approach to anger organizes it for protective and corrective personal and relational adaptation. In our model, threat perception interacts with a person's view of self in relation to other to produce helpful or harmful anger. Inflated or collapsed views of self in relation to other produce distinct manifestations of destructive anger that are harmful to self, other, and relationship. Conversely, a balanced view of self in relation to other promotes constructive anger and catalyzes self, other, and relationship healing. Clinical use of the model to shape healing personal and relational contact with anger is explored. PMID- 28736891 TI - Heat-induced native dimerization prevents amyloid formation by variable domain from immunoglobulin light-chain REI. AB - : Amyloid light-chain (AL) amyloidosis is a protein-misfolding disease characterized by accumulation of immunoglobulin light chains (LCs) into amyloid fibrils. Dimerization of a full length or variable domain (VL ) of LC serves to stabilize the native state and prevent the formation of amyloid fibrils. We here analyzed the thermodynamic properties of dimerization and unfolding reactions by nonamyloidogenic VL from REI LC or its monomeric Y96K mutant using sedimentation velocity and circular dichroism. The data indicate that the equilibrium shifts to native dimerization for wild-type REI VL by elevating temperature due to the negative enthalpy change for dimer dissociation (-81.2 kJ.mol-1 ). The Y96K mutation did not affect the stability of the monomeric native state but increased amyloidogenicity. These results suggest that the heat-induced native homodimerization is the major factor preventing amyloid formation by wild-type REI VL . Heat-induced native oligomerization may be an efficient strategy to avoid the formation of misfolded aggregates particularly for thermostable proteins that are used at elevated temperatures under conditions where other proteins tend to misfold. DATABASE: Structural data are available in the Protein Data Bank under the accession numbers 5XP1 and 5XQY. PMID- 28736893 TI - Benchmarking density functional tight binding models for barrier heights and reaction energetics of organic molecules. AB - Density Functional Tight Binding (DFTB) models are two to three orders of magnitude faster than ab initio and Density Functional Theory (DFT) methods and therefore are particularly attractive in applications to large molecules and condensed phase systems. To establish the applicability of DFTB models to general chemical reactions, we conduct benchmark calculations for barrier heights and reaction energetics of organic molecules using existing databases and several new ones compiled in this study. Structures for the transition states and stable species have been fully optimized at the DFTB level, making it possible to characterize the reliability of DFTB models in a more thorough fashion compared to conducting single point energy calculations as done in previous benchmark studies. The encouraging results for the diverse sets of reactions studied here suggest that DFTB models, especially the most recent third-order version (DFTB3/3OB augmented with dispersion correction), in most cases provide satisfactory description of organic chemical reactions with accuracy almost comparable to popular DFT methods with large basis sets, although larger errors are also seen for certain cases. Therefore, DFTB models can be effective for mechanistic analysis (e.g., transition state search) of large (bio)molecules, especially when coupled with single point energy calculations at higher levels of theory. (c) 2017 Wiley Periodicals, Inc. PMID- 28736894 TI - Comparative development in Moenkhausia pittieri and Paracheirodon innesi (Ostariophysi: Characiformes) with comments on heterochrony and miniaturization in the Characidae. AB - Developmental heterochronies between the small-sized Moenkhausia pittieri and the miniature Paracheirodon innesi were determined by describing and comparing external morphological development in both species. Despite being classified as miniature, P. innesi was larger and more developed in the flexion and post flexion larval stages than M. pittieri. Broader patterns within the Characidae suggest that body size reduction in P. innesi is tied to accelerated development and higher growth rate along with early maturation and precocious cessation of growth, which are characteristic of miniature species. Comments on adipose-fin loss in Characidae as a consequence of developmental truncation are included. PMID- 28736895 TI - Independent association between age and circadian systolic blood pressure patterns in adults with hypertension. AB - Previous studies indicate a preliminary association between age and circadian blood pressure (BP) variation. This association would be affected by confounding factors in real-world populations. The authors investigated whether this is a convincingly independent association in a real-world population of adults with hypertension. Clinical data and findings of 24-hour ambulatory BP monitoring were obtained from 297 consecutive adults with hypertension (60.19+/-0.77 years). BP dipping patterns were categorized based on the percentage of nocturnal BP drop. Multivariate linear regression analysis identified an independent correlation between age and percentage of nocturnal systolic BPdrop (beta=-7.296; 95% CI, 10.430 to -4.162 [P<.001]). Reverse dippers were the oldest and extreme dippers were the youngest. A significant age difference was noted among patients grouped into four BP dipping patterns with and without adjustments for sex, body mass index, drugs, diabetes mellitus, smoking, 24-hour mean heart rate, and 24-hour mean systolic and diastolic BP. PMID- 28736896 TI - Studying Stepfamilies: Four Eras of Family Scholarship. AB - Historically, there have always been stepfamilies, but until the early 1970s, they remained largely unnoticed by social scientists. Research interest in stepfamilies followed shortly after divorce became the primary precursor to stepfamily formation. Because stepfamilies are structurally diverse and much more complex than nuclear families, they have created considerable challenges for both researchers and clinicians. This article examines four eras of stepfamily scholarship, tracing the development of research questions, study designs and methods, and conceptual frameworks from the mid-1970s to the present and drawing implications for the current state of the field. PMID- 28736897 TI - Taking culture seriously: Can we improve the developmental health and well-being of Australian Aboriginal children in out-of-home care? AB - BACKGROUND: Children in out-of-home care have well-documented health and developmental needs. Research suggests that Aboriginal children in care have unmet health and intervention needs. In metropolitan Sydney, Kari Aboriginal Resources Inc. (KARI), an Aboriginal organization, provides support to indigenous children in care, including clinical assessment and intervention. We wanted to determine the health and developmental needs of a subset of children in out-of home care with KARI, who had been in stable care for at least a year. We wanted to identify child, carer, and intervention characteristics that contributed to children doing well. We also wanted to identify enablers and barriers to providing culturally competent intervention. METHODS: We used mixed methods. From the KARI clinic database over the past 3 years, we identified children who had been in stable care with KARI for >12 months. We compared clinical measures and outcomes for these children with results from previous audits. We carried out a group discussion and key informant interviews with therapists and caseworkers to identify risk and resilience factors for each child, as well as enablers and barriers to culturally competent intervention. RESULTS: The health and developmental profile of the 26 children identified as being in stable care was similar to that of previous audits. Most (88%) were getting speech pathology intervention; one third were getting occupational therapy and psychological intervention; most children and their carers attended cultural programmes. The majority of children (25/26) improved in their developmental health. Caseworkers and therapists identified risk and resilience factors related to child, carer, and home characteristics. They also identified elements of good practice; systemic issues prevented some interventions from being carried out. CONCLUSIONS: There are challenges delivering a trauma-informed, culturally respectful service to Aboriginal children in out-of-home care in an urban setting, but it can be done if attention is paid to culture and the enablers and barriers are identified. PMID- 28736898 TI - Identification of positive selection signatures in pigs by comparing linkage disequilibrium variances. AB - Selection affects the patterns of linkage disequilibrium (LD) around the site of a beneficial allele with an increase in LD among the hitchhiking alleles. Comparing the differences in regional LD between pig populations could help to identify putative genomic regions with potential adaptations for economic traits. In this study, using Illumina Porcine SNP60K BeadChip genotyping data from 207 Chinese indigenous, 117 South American village and 408 Large White pigs, we estimated the variation of genome-wide LD between populations using the varld program. The top 0.1% standardized VarLD scores were used as a criterion for all comparisons, and compared with LD blocks, a total of four selection signatures on Sus scrofa chromosome (SSC) 7, 9, 13 and 14 were identified in all populations. These signatures overlapped with quantitative trait loci for linoleic acid content, age at puberty, number of muscle fibers per unit area, hip structure and body weight traits in pigs. Among them, one of the signatures (56.5-56.6 Mb on SSC7) in Large White pigs harbored the ADAMTSL3 gene, which is known to affect body length. The findings of this study seem to point toward recent selection in different pig populations. Further investigations are encouraged to confirm the selection signatures detected by varld in the present study. PMID- 28736899 TI - Trajectories of depressive and anxiety symptoms in older adults: a 6-year prospective cohort study. AB - OBJECTIVE: Depressive and anxiety symptoms are common in older adults, significantly affect quality of life, and are risk factors for Alzheimer's disease. We sought to identify the determinants of predominant trajectories of depressive and anxiety symptoms in cognitively normal older adults. METHOD: Four hundred twenty-three older adults recruited from the general community underwent Abeta positron emission tomography imaging, apolipoprotein and brain-derived neurotrophic factor genotyping, and cognitive testing at baseline and had follow up assessments. All participants were cognitively normal and free of clinical depression at baseline. Latent growth mixture modeling was used to identify predominant trajectories of subthreshold depressive and anxiety symptoms over 6 years. Binary logistic regression analysis was used to identify baseline predictors of symptomatic depressive and anxiety trajectories. RESULTS: Latent growth mixture modeling revealed two predominant trajectories of depressive and anxiety symptoms: a chronically elevated trajectory and a low, stable symptom trajectory, with almost one in five participants falling into the elevated trajectory groups. Male sex (relative risk ratio (RRR) = 3.23), lower attentional function (RRR = 1.90), and carriage of the brain-derived neurotrophic factor Val66Met allele in women (RRR = 2.70) were associated with increased risk for chronically elevated depressive symptom trajectory. Carriage of the apolipoprotein epsilon 4 allele (RRR = 1.92) and lower executive function in women (RRR = 1.74) were associated with chronically elevated anxiety symptom trajectory. CONCLUSION: Our results indicate distinct and sex-specific risk factors linked to depressive and anxiety trajectories, which may help inform risk stratification and management of these symptoms in older adults at risk for Alzheimer's disease. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28736900 TI - Depletion of Pax7+ satellite cells does not affect diaphragm adaptations to running in young or aged mice. AB - KEY POINTS: Satellite cell depletion does not affect diaphragm adaptations to voluntary wheel running in young or aged mice. Satellite cell depletion early in life (4 months of age) has minimal effect on diaphragm phenotype by old age (24 months). Prolonged satellite cell depletion in the diaphragm does not result in excessive extracellular matrix accumulation, in contrast to what has been reported in hind limb muscles. Up-regulation of Pax3 mRNA+ cells after satellite cell depletion in young and aged mice suggests that Pax3+ cells may compensate for a loss of Pax7+ satellite cells in the diaphragm. Future investigations should focus on the role of Pax3+ cells in the diaphragm during adaptation to exercise and ageing. ABSTRACT: Satellite cell contribution to unstressed diaphragm is higher compared to hind limb muscles, which is probably attributable to constant activation of this muscle to drive ventilation. Whether satellite cell depletion negatively impacts diaphragm quantitative and qualitative characteristics under stressed conditions in young and aged mice is unknown. We therefore challenged the diaphragm with prolonged running activity in the presence and absence of Pax7+ satellite cells in young and aged mice using an inducible Pax7CreER -R26RDTA model. Mice were vehicle (Veh, satellite cell replete) or tamoxifen (Tam, satellite cell-depleted) treated at 4 months of age and were then allowed to run voluntarily at 6 months (young) and 22 months (aged). Age-matched, cage-dwelling, Veh- and Tam-treated mice without wheel access served as activity controls. Diaphragm muscles were analysed from young (8 months) and aged (24 months) mice. Satellite cell depletion did not alter diaphragm mean fibre cross-sectional area, fibre type distribution or extracellular matrix content in young or aged mice, regardless of running activity. Resting in vivo diaphragm function was also unaffected by satellite cell depletion. Myonuclear density was maintained in young satellite cell depleted mice regardless of running, although it was modestly reduced in aged sedentary (-7%) and running (-19%) mice without satellite cells (P < 0.05). Using fluorescence in situ hybridization, we detected higher Pax3 mRNA+ cell density in both young and aged satellite cell-depleted diaphragm muscle (P < 0.05), which may compensate for the loss of Pax7+ satellite cells. PMID- 28736903 TI - A retrospective analysis of Impella use in all-comers: 1-year outcomes. AB - BACKGROUND: There are non-randomized data about the benefits of Impella use in the setting of cardiogenic shock. However, limited data exist to help guide clinicians about whether in the context of the intervention the device should be implanted early or late; how long the device should stay in; and how the mode of explant should be. METHODS: This is a retrospective, single center registry over 5 years comparing in-hospital outcomes and 1-year mortality in all-comers who had the Impella device placed early versus those who had the device placed late as a bailout. The primary endpoint was a composite of in-hospital all-cause mortality, major vascular, bleeding complications, and stroke. A secondary endpoint was 1 year mortality. RESULTS: Of 262 total patients, 181 (69.1%) had early and 81 (30.9%) had late Impella placement. Patients in the early group had a lower combined MACCE (17.1% vs 59.3%, P < 0.001) and in-hospital mortality (8.8% vs 48.1%, P < 0.001) compared to the late group. Major vascular (3.3% vs 2.5%, P = 1.0), bleeding complications (5.0% vs 7.4%, P = 0.57), and stroke (3.3% vs 7.4%, P = 0.20) were not significant between groups. Early Impella placement had lower 6 month (17.7% vs 53.1%, P < 0.001) and 1-year mortality rates (21.5% vs 53.1%, P < 0.001) compared to those in the late group. CONCLUSION: For patients with need for an Impella device, regardless of the indication, early implantation is associated with better in-hospital and 1-year outcomes as compared to when the device is implanted late as a bailout. PMID- 28736902 TI - Pseudoamniotic Band Syndrome After Fetoscopic Laser Ablation of Placental Anastomoses for Twin-Twin Transfusion Syndrome: Two Case Reports and Systematic Review. AB - Pseudoamniotic band syndrome is a rare complication that occurs after invasive procedures for complicated monochorionic twins. We report 2 cases of intrauterine recipient fetal death after laser therapy for twin-twin transfusion syndrome due to umbilical cord constriction by the amniotic band. PMID- 28736901 TI - Food waste conversion to microbial polyhydroxyalkanoates. AB - Polyhydroxyalkanoates (PHAs) are biopolymers with desirable material properties similar to petrochemically derived plastics. PHAs are naturally produced by a wide range of microorganisms as a carbon storage mechanism and can accumulate to significantly high levels. PHAs are an environmentally friendly alternative to their petroleum counterparts because they can be easily degraded, potentially reducing the burden on municipal waste systems. Nevertheless, widespread use of PHAs is not currently realistic due to a variety of factors. One of the major constraints of large-scale PHA production is the cost of carbon substrate for PHA producing microbes. The cost of production could potentially be reduced with the use of waste carbon from food-related processes. Food wastage is a global issue and therefore harbours immense potential to create valuable bioproducts. This article's main focus is to examine the state of the art of converting food derived waste into carbon substrates for microbial metabolism and subsequent conversion into PHAs. PMID- 28736904 TI - HRAS mutation in phacomatosis pigmentokeratotica without extracutaneous disease. PMID- 28736905 TI - Bacterial and fungal communities and contribution of physicochemical factors during cattle farm waste composting. AB - During composting, the composition of microbial communities is subject to constant change owing to interactions with fluctuating physicochemical parameters. This study explored the changes in bacterial and fungal communities during cattle farm waste composting and aimed to identify and prioritize the contributing physicochemical factors. Microbial community compositions were determined by high-throughput sequencing. While the predominant phyla in the bacterial and fungal communities were largely consistent during the composting, differences in relative abundances were observed. Bacterial and fungal community diversity and relative abundance varied significantly, and inversely, over time. Relationships between physicochemical factors and microbial community compositions were evaluated by redundancy analysis. The variation in bacterial community composition was significantly related to water-soluble organic carbon (WSOC), and pile temperature and moisture (p < .05), while the largest portions of variation in fungal community composition were explained by pile temperature, WSOC, and C/N (p < .05). These findings indicated that those parameters are the most likely ones to influence, or be influenced by the bacterial and fungal communities. Variation partitioning analyses indicated that WSOC and pile temperature had predominant effects on bacterial and fungal community composition, respectively. Our findings will be useful for improving the quality of cattle farm waste composts. PMID- 28736906 TI - Dental pulp stem cells and the management of neurological diseases: An update. AB - Medical research in regenerative medicine has brought promising perspectives for the use of stem cells in clinical trials. Stem cells are undifferentiated cells capable of multilineage differentiation and available in numerous sources in the human body. Dental pulp constitutes an attractive source of these cells since collecting mesenchymal stem cells from this site is a noninvasive practice that can be performed after a common surgical extraction of supernumerary or wisdom teeth. Thus, tissue sacrifice is very low and several cytotypes can be obtained owing to these cells' multipotency, in addition to the fact that they can be cryopreserved and stored for long periods. Mesenchymal stem cells have high proliferation rates, making them favorable for clinical application. These multipotent cells, present in biological waste, constitute an appropriate resource in the treatment of many neurological diseases. PMID- 28736907 TI - A rare case of lues maligna with ocular involvement presenting as an unmasking immune reconstitution inflammatory syndrome in a patient with HIV infection. PMID- 28736908 TI - BMP-7 ameliorates cobalt alloy particle-induced inflammation by suppressing Th17 responses. AB - Metal wear debris has been shown to activate an aseptic osteolytic process that causes failure in total joint arthroplasty (TJA). This osteolysis is characterized by a proinflammatory, self-propagating immune response involving primarily macrophages, dendritic cells, and activated osteoclasts, as well as T cells and B cells. The human bone morphogenic protein (BMP)-7, on the other hand, was shown to promote osteoblast survival, and reversed the downregulation of anabolic Smad proteins and Runx2 following cobalt injury. Therefore, we investigated the effect and mechanism of BMP-7 on the proinflammatory immune responses in osteoarthritis patients with previous TJA. Cobalt-treated monocytes/macrophages presented significantly elevated levels of interleukin 6 (IL-6) and tumor necrosis factor (TNF), both of which were suppressed by the addition of exogenous BMP-7. In patients with TJA, the serum BMP-7 level was inversely associated with the level of IL-6 and TNF secreted by monocytes/macrophages. Cobalt-treated monocytes/macrophages effectively supported Th17 inflammation, by an IL-6-dependent but not TNF-dependent mechanism. BMP-7, however, significantly suppressed cobalt-induced Th17 inflammation. In patients with TJA, the risk of osteolysis development was positively associated with the frequency of Th17 cells and negatively associated with the level of BMP-7. Together, these results demonstrated that BMP-7 could serve as a therapeutic agent in treating patients with metal wear debris-induced inflammation. PMID- 28736909 TI - A double-blinded, randomized, controlled, crossover evaluation of a zinc methionine supplement as an adjunctive treatment for canine atopic dermatitis. AB - BACKGROUND: Zinc is important for skin health and proper immune system function. HYPOTHESIS/OBJECTIVES: A zinc methionine, essential fatty acids (EFA) and biotin product (Zn supplement) was compared to an EFA and biotin product (control) in canine atopic dermatitis (CAD). ANIMALS: Twenty seven client-owned dogs with chronic CAD receiving ciclosporin or glucocorticoids. METHODS: A 24 week, randomized, double-blinded, controlled study with crossover at week 12 and 4 week period of allergy medication reduction at weeks 8 and 20. Evaluations included Canine Atopic Dermatitis Lesion Index (CADLI), pruritus Visual Analog Scale (VAS) and cytology sampling. RESULTS: In dogs receiving the zinc supplement and ciclosporin for eight weeks, 44% (n = 7) had significantly decreased CADLI from 11.9 to 6.0 (P = 0.0002) with no significant change in pruritus VAS (P = 1.0). In dogs receiving the zinc supplement and glucocorticoids for eight weeks, 55% (n = 6) had significantly decreased CADLI from 10.9 to 5.0 (P = 0.0043) and pruritus VAS from 7.4 to 3.2 (P = 0.0166). For dogs receiving either steroids or ciclosporin there was a reduction in use of such medications, for at least four weeks, in 63% of dogs receiving the zinc supplement and 37% of dogs receiving the control. This difference was not significant (P = 0.1027). Seventy eight percent of dogs were diagnosed and treated for superficial skin infections during the study. CONCLUSIONS AND CLINICAL IMPORTANCE: This study supports a potential benefit of adjunctive zinc methionine supplementation in CAD. Dogs receiving glucocorticoids may be more likely to benefit. Further studies are needed to substantiate these initial results. PMID- 28736910 TI - Longitudinal MR Spectroscopy Shows Altered Metabolism in Traumatic Brain Injury. AB - BACKGROUND AND PURPOSE: Brain trauma is known to result in heterogeneous patterns of tissue damage and altered neuronal and glial metabolism that evolve over time following injury; however, little is known on the longitudinal evolution of these changes. In this study, magnetic resonance spectroscopic imaging (MRSI) was used to map the distributions of altered metabolism in a single subject at five time points over a period of 28 months following injury. METHODS: Magnetic resonance imaging and volumetric MRSI data were acquired in a subject that had experienced a moderate traumatic brain injury (Glasgow Coma Scale 13) at five time points, from 7 weeks to 28 months after injury. Maps of N-acetylaspartate (NAA), total choline (Cho), and total creatine signal were generated and differences from normal control values identified using a z-score image analysis method. RESULTS: The z-score metabolite maps revealed areas of significantly reduced NAA and increased Cho, predominately located in frontal and parietal white matter, which evolved over the complete course of the study. A map of the ratio of Cho/NAA showed the greatest sensitivity to change, which indicated additional metabolic changes throughout white matter. The metabolic changes reduced over time following injury, though with abnormal values remaining in periventricular regions. CONCLUSIONS: The use of z-score image analysis for MRSI provides a method for visualizing diffuse changes of tissue metabolism in the brain. This image visualization method is of particularly effective for visualizing widespread and diffuse metabolic changes, such as that due to traumatic injury. PMID- 28736911 TI - Observational study of adherence to a traditional Mediterranean diet, sociocultural characteristics and cardiovascular disease risk factors of older Greek Australians from MEDiterranean ISlands (MEDIS-Australia Study): Protocol and rationale. AB - AIM: To describe the study protocol of the MEDiterranean ISlands-Australia (MEDIS Australia) Study modelled on the MEDIS Study conducted in Greece. The present study aims to explore adherence to the traditional Mediterranean diet pattern, determine enablers and barriers to adherence, explore the definition of Greek cuisine, and associations between adherence to the diet pattern and risk factors for cardiovascular disease (CVD) and metabolic syndrome in older Greek Australians originally from Greek islands and Cyprus. Now long-term immigrants, with at least 50 years in Australia, characteristics and risk factor profiles of older Greek islander-born Australians will be compared and contrasted to their counterparts living on Greek islands to evaluate the influence of migration on adherence. METHODS: The present study is an observational study of cross sectional design using a modified lifestyle and semi-quantitative food frequency questionnaire to capture sociodemographic, health, psychosocial and dietary characteristics, including cuisine, of 150 older Greek islander-born Australians. Anthropometric measures and medical history will be collected. Participants will be aged over 65 years, live independently, are originally from a Greek island and are free from CVD. RESULTS: Data collection is underway. CONCLUSIONS: Characteristics and behaviours associated with adherence, if identified, could be evaluated in future studies. For example, exploration of enablers or barriers to adherence to a Mediterranean dietary pattern in an Australian population. PMID- 28736912 TI - Performance of the Index of Dental Anxiety and Fear in a population-based sample of adults. AB - BACKGROUND: The Index of Dental Anxiety and Fear (IDAF-4C) was introduced to overcome the theoretical and practical shortcomings of previously developed dental fear measures. This new scale has not been tested on population samples other than in its country of origin, Australia. The aim of this study was to validate the IDAF-4C in a different cultural setting and to determine the prevalence and sociodemographic associations of dental anxiety. METHODS: A cross sectional study of a representative New Zealand adult population sample was undertaken. The questionnaire was mailed to 523 randomly-selected participants. Data were collected on sociodemographic characteristics, oral and general health care, and dental anxiety using both the IDAF-4C and the Dental Anxiety Scale (DAS). RESULTS: The response rate was 51.8%. The factor structure of the IDAF-4C was confirmed. The prevalence estimates for high dental anxiety and fear were 18.6% using the DAS and 13.0% using the IDAF-4C. Mean scores for the IDAF-4C and DAS were higher among episodic dental visitors and those without a recent dental visit. CONCLUSIONS: The performance of the IDAF-4C in this New Zealand community sample supports its use for dental anxiety measurement. PMID- 28736913 TI - A Community-Responsive Adaptation to Reach and Engage Latino Families Affected by Maternal Depression. AB - As family researchers and practitioners seek to improve the quality and accessibility of mental health services for immigrant families, they have turned to culturally adapted interventions. Although many advancements have been made in adapting interventions for such families, we have yet to understand how the adaptation can ensure that the intervention is reaching families identified to be in greatest need within a local system of care and community. We argue that reaching, engaging, and understanding the needs of families entails a collaborative approach with multiple community partners to ensure that adaptations to intervention content and delivery are responsive to the sociocultural trajectory of families within a community. We describe a cultural adaptation framework that is responsive to the unique opportunities and challenges of identifying and recruiting vulnerable families through community partnerships, and of addressing the needs of families by incorporating multiple community perspectives. Specifically, we apply these principles to the cultural adaptation of an intervention originally developed for low-income African American and White families facing maternal depression. The new intervention, Fortalezas Familiares (Family Strengths), was targeted to Latino immigrant families whose mothers were in treatment for depression in mental health and primary care clinics. We conclude with key recommendations and directions for how family researchers and practitioners can design the cultural adaptation of interventions to be responsive to the practices, preferences, and needs of underserved communities, including families and service providers. PMID- 28736914 TI - Internal diversification of non-Sub-Saharan haplogroups in Sahelian populations and the spread of pastoralism beyond the Sahara. AB - BACKGROUND: Today, African pastoralists are found mainly in the Sahel/Savannah belt spanning 6,000 km from west to east, flanked by the Sahara to the north and tropical rainforests to the south. The most significant group among them are the Fulani who not only keep cattle breeds of possible West Eurasian ancestry, but form themselves a gene pool containing some paternally and maternally-transmitted West Eurasian haplogroups. MATERIALS AND METHODS: We generated complete sequences for 33 mitogenomes belonging to haplogroups H1 and U5 (23 and 10, respectively), and genotyped 16 STRs in 65 Y chromosomes belonging to haplogroup R1b-V88. RESULTS: We show that age estimates of the maternal lineage H1cb1, occurring almost exclusively in the Fulani, point to the time when the first cattle herders settled the Sahel/Savannah belt. Similar age estimates were obtained for paternal lineage R1b-V88, which occurs today in the Fulani but also in other, mostly pastoral populations. Maternal clade U5b1b1b, reported earlier in the Berbers, shows a shallower age, suggesting another possibly independent input into the Sahelian pastoralist gene pool. CONCLUSIONS: Despite the fact that animal domestication originated in the Near East ~ 10 ka, and that it was from there that animals such as sheep, goats as well as cattle were introduced into Northeast Africa soon thereafter, contemporary cattle keepers in the Sahel/Savannah belt show uniparental genetic affinities that suggest the possibility of an ancient contact with an additional ancestral population of western Mediterranean ancestry. PMID- 28736915 TI - Anxiety symptoms and children's eye gaze during fear learning. AB - BACKGROUND: The eye region of the face is particularly relevant for decoding threat-related signals, such as fear. However, it is unclear if gaze patterns to the eyes can be influenced by fear learning. Previous studies examining gaze patterns in adults find an association between anxiety and eye gaze avoidance, although no studies to date examine how associations between anxiety symptoms and eye-viewing patterns manifest in children. The current study examined the effects of learning and trait anxiety on eye gaze using a face-based fear conditioning task developed for use in children. METHODS: Participants were 82 youth from a general population sample of twins (aged 9-13 years), exhibiting a range of anxiety symptoms. Participants underwent a fear conditioning paradigm where the conditioned stimuli (CS+) were two neutral faces, one of which was randomly selected to be paired with an aversive scream. Eye tracking, physiological, and subjective data were acquired. Children and parents reported their child's anxiety using the Screen for Child Anxiety Related Emotional Disorders. RESULTS: Conditioning influenced eye gaze patterns in that children looked longer and more frequently to the eye region of the CS+ than CS- face; this effect was present only during fear acquisition, not at baseline or extinction. Furthermore, consistent with past work in adults, anxiety symptoms were associated with eye gaze avoidance. Finally, gaze duration to the eye region mediated the effect of anxious traits on self-reported fear during acquisition. CONCLUSIONS: Anxiety symptoms in children relate to face-viewing strategies deployed in the context of a fear learning experiment. This relationship may inform attempts to understand the relationship between pediatric anxiety symptoms and learning. PMID- 28736916 TI - Hyaluronate effect on bacterial biofilm in ENT district infections: a review. AB - Bacterial resistance is a growing phenomenon which led the scientific community to search for new therapeutic targets, such as biofilm. A bacterial biofilm is a surface-associated agglomerate of microorganisms embedded in a self-produced extracellular polymeric matrix made of polysaccharides, nucleic acids, and proteins. Scientific literature offers several reports on a biofilm's role in infections regarding various body districts. The presence of a bacterial biofilm is responsible for poor efficacy of antibiotic therapies along with bacterial infections in ear, nose, and throat (ENT) districts such as the oral cavity, ear, nasal cavities, and nasal sinuses. In particular, bacterial biofilms are associated with recalcitrant and symptomatically more severe forms of chronic rhinosinusitis. As of today, there are no therapeutic options for the eradication of bacterial biofilm in ENT districts. Hyaluronic acid is a glycosaminoglycan composed of glucuronic acid and N-acetylglucosamine disaccharide units. Its efficacy in treating rhinosinusitis, whether or not associated with polyposis, is well documented, as well as results from its effects on mucociliary clearance, free radical production and mucosal repair. This review's aim is to evaluate the role of bacterial biofilms and the action exerted on it by hyaluronic acid in ENT pathology, with particular attention to the rhinosinusal district. In conclusion, this paper underlines how the efficacy of hyaluronate as an anti-bacterial biofilm agent is well demonstrated by in vitro studies; it is, however, only preliminarily demonstrated by clinical studies. PMID- 28736917 TI - True constructive interference in the steady state (trueCISS). AB - PURPOSE: To introduce a novel time-efficient method, termed true constructive interference in the steady state (trueCISS), that not only solves the problem of banding artifacts for balanced steady-state free precession (bSSFP) but also provides its genuine, that is, true, on-resonant signal. METHODS: After a compressed sensing reconstruction from a set of highly undersampled phase-cycled bSSFP scans, the local off-resonance, relaxation time ratio, and equilibrium magnetization are voxel-wise estimated using a dictionary-based fitting routine. Subsequently, on-resonant bSSFP images are generated using the previously estimated parameters. Due to the high undersampling factors used, the acquisition time is not prolonged with respect to a standard CISS acquisition. RESULTS: From a set of 16 phase-cycled SSFP scans in combination with an eightfold undersampling, both phantom and in vivo whole-brain experiments demonstrate that banding successfully can be removed. Additionally, trueCISS allows the derivation of synthetic bSSFP images with arbitrary flip angles, which enables image contrasts that may not be possible to acquire in practice due to safety constraints. CONCLUSION: TrueCISS offers banding-free bSSFP images with on resonant signal intensity and without requiring additional acquisition time compared to conventional methods. Magn Reson Med 79:1901-1910, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28736918 TI - Phase I, Randomized, Double-blind, Placebo-controlled, Single-dose, and Multiple dose Studies of Erenumab in Healthy Subjects and Patients With Migraine. AB - Monoclonal antibodies (mAbs) targeting calcitonin gene-related peptide (CGRP) signaling are being explored as prophylactic treatments for migraine. Erenumab (AMG 334) is the first potent, selective, and competitive human mAb antagonist of the CGRP receptor. We report the data from two phase I studies assessing the safety, pharmacokinetics (PK), and pharmacodynamics of single and multiple administrations of erenumab in healthy subjects and patients with migraine. The results indicate that the PK profile of erenumab is nonlinear from 1 mg to 70 mg and the linear portion of the clearance from 70 mg to 210 mg is consistent with other human immunoglobulin G2 antibodies. Single doses of erenumab resulted in >75% inhibition of capsaicin-induced dermal blood flow, with no apparent dose dependency for erenumab >=21 mg. Erenumab was generally well tolerated, with an acceptable safety profile, supporting further clinical development of erenumab for migraine prevention. PMID- 28736919 TI - A G326E substitution in the glutamate-gated chloride channel 3 (GluCl3) of the two-spotted spider mite Tetranychus urticae abolishes the agonistic activity of macrocyclic lactones. AB - BACKGROUND: The macrocyclic lactones abamectin and milbemectin are frequently used to control phytophagous mites such as Tetranychus urticae. Consequently, resistance has developed and was genetically linked with substitutions in the glutamate-gated chloride channel (GluCl) subunits TuGluCl1 and TuGluCl3. Here, we functionally validated a G326E substitution in TuGluCl3 by functional expression in Xenopus laevis oocytes followed by two-electrode voltage-clamp electrophysiology. RESULTS: Homomeric wild-type and mutated GluCl3 were successfully expressed. l-glutamic-acid-induced currents exhibited a rapid onset equal in both channels and EC50 for l-glutamic-acid was in the micromolar range (384.2 MUm and 292.7 MUm, respectively). Abamectin and milbemycin A4 elicited sustained currents in wild-type GluCl3, but the G326E substitution completely abolished the agonistic activity of macrocyclic lactones. CONCLUSION: A target site mutation in Tu GluCl3 contributes to avermectin resistance in T. urticae. However, given the multitude of channel genes and the potential additive or synergistic effects of mutations, to what extent mutations determine the often extremely strong resistance phenotype in the field deserves further study. (c) 2017 Society of Chemical Industry. PMID- 28736920 TI - Obtainment and evaluation of adjuvant effect of the aromatic geranyl derivative Filifolinone in bacterin of Piscirickettsia salmonis. PMID- 28736921 TI - Supplementary techniques for pain control during root canal treatment of lower posterior teeth with irreversible pulpitis: A systematic review and meta analysis. AB - The purpose of this systematic review and meta-analysis was to evaluate utilisation of supplementary techniques for pain control during root canal treatment of lower molars with irreversible pulpitis. The literature was searched using electronic databases up to year 2012. Seventeen studies with 1504 participants were included and each study compared experimental interventions with a standard treatment, i.e. the inferior alveolar nerve block. Changing the injection techniques or supplemental injection had no significant effect on pulp anaesthesia compared to the standard treatment (P = 1.00 or P = 0.14), whereas changing anaesthetic features and increasing anaesthetic volumes resulted in significantly higher rates of anaesthesia than those of the standard treatment (P = 0.03 and P = 0.007, respectively). Premedication with non-steroidal anti inflammatory drugs (NSAIDs) also significantly increased the success rate of anaesthesia (P = 0.001). Taken together, increased anaesthetic volumes and premedication with NSAIDs provide predictable anaesthesia and more pain control during endodontic treatment of lower molars with irreversible pulpitis. PMID- 28736922 TI - Effect of implantoplasty on fracture resistance and surface roughness of standard diameter dental implants. AB - OBJECTIVE: To assess the effect of implantoplasty on the fracture resistance, surface roughness, and macroscopic morphology of standard diameter (4.1 mm) external connection dental implants. MATERIALS AND METHODS: An in vitro study was conducted in 20 screw-shaped titanium dental implants with an external connection. In 10 implants, the threads and surface were removed and polished with high-speed burs (implantoplasty), while the remaining 10 implants were used as controls. The final implant dimensions were recorded. The newly polished surface quality was assessed by scanning electron microscopy (SEM) and by 3D surface roughness analysis using a confocal laser microscope. Finally, all the implants were subjected to a mechanical pressure resistance test. A descriptive analysis of the data was made. Also, Student's t tests were employed to detect differences regarding the compression tests. RESULTS: Implantoplasty was carried out for a mean time of 10 min and 48 s (standard deviation (SD) of 1 min 22 s). Macroscopically, the resulting surface had a smooth appearance, although small titanium shavings and silicon debris were present. The final surface roughness (Sa values 0.1 +/- 0.02 MUm) was significantly lower than that of the original (0.75 +/- 0.08 MUm Sa ) (p = .005). There was minimal reduction in the implant's inner body diameter (0.19 +/- 0.03 mm), and no statistically significant differences were found between the test and control implants regarding the maximum resistance force (896 vs 880 N, respectively). CONCLUSIONS: Implantoplasty, although technically demanding and time-consuming, does not seem to significantly alter fracture resistance of standard diameter external connection implants. A smooth surface with Sa values below 0.1 MUm can be obtained through the use of silicon polishers. A larger sample is required to confirm that implantoplasty does not significantly affect the maximum resistance force of standard diameter external connection implants. PMID- 28736923 TI - Applications of additive manufacturing in dentistry: A review. AB - Additive manufacturing (AM) or 3D printing has been hailed as the third industrial revolution as it has caused a paradigm shift in the way objects have been manufactured. Conventionally, converting a raw material to a fully finished and assembled, usable product comprises several steps which can be eliminated by using this process as functional products can be created directly from the raw material at a fraction of the time originally consumed. Thus, AM has found applications in several sectors including automotive, aerospace, printed electronics, and healthcare. AM is increasingly being used in the healthcare sector, given its potential to fabricate patient-specific customized implants with required accuracy and precision. Implantable heart valves, rib cages, and bones are some of the examples where AM technologies are used. A vast variety of materials including ceramics, metals, polymers, and composites have been processed to fabricate intricate implants using 3D printing. The applications of AM in dentistry include maxillofacial implants, dentures, and other prosthetic aids. It may also be used in surgical training and planning, as anatomical models can be created at ease using AM. This article gives an overview of the AM process and reviews in detail the applications of 3D printing in dentistry. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 2058 2064, 2018. PMID- 28736924 TI - Evaluation of spiral acquisition variants for functional imaging of human superior colliculus at 3T field strength. AB - PURPOSE: High-resolution functional magnetic resonance imaging of human subcortical brain structures is challenging because of their deep location in the cranium, and their comparatively weak blood oxygen level dependent responses to strong stimuli. Magnetic resonance imaging data for subcortical brain regions exhibit both low signal-to-noise ratio and low functional contrast-to-noise ratio. To overcome these challenges, this work evaluates the use of dual-echo spiral variants that combine outward and inward trajectories. Specifically, in in, in-out, and out-out combinations are evaluated. For completeness, single-echo spiral-in and parallel-receive-accelerated echo-planar-imaging sequences are also evaluated. METHODS: Sequence evaluation was based on comparison of functional contrast-to-noise ratio within retinotopically predefined regions of interest. Superior colliculus was chosen as sample subcortical brain region because it exhibits a strong visual response. All sequences were compared relative to a single-echo spiral-out trajectory to establish a within-session reference. RESULTS: In superior colliculus, the dual-echo out-out outperformed the reference trajectory by 55% in contrast-to-noise ratio, while all other trajectories had performance similar to the reference. The sequences were also compared in early visual cortex. Here, both dual-echo spiral out-out and in-out outperformed the reference by ~25%. CONCLUSION: Dual-echo spiral variants offer improved contrast to-noise ratio performance for high-resolution imaging for both superior colliculus and cortex. Magn Reson Med 79:1931-1940, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28736925 TI - Engineering a bzd cassette for the anaerobic bioconversion of aromatic compounds. AB - Microorganisms able to degrade aromatic contaminants constitute potential valuable biocatalysts to deal with a significant reusable carbon fraction suitable for eco-efficient valorization processes. Metabolic engineering of anaerobic pathways for degradation and recycling of aromatic compounds is an almost unexplored field. In this work, we present the construction of a functional bzd cassette encoding the benzoyl-CoA central pathway for the anaerobic degradation of benzoate. The bzd cassette has been used to expand the ability of some denitrifying bacteria to use benzoate as sole carbon source under anaerobic conditions, and it paves the way for future pathway engineering of efficient anaerobic biodegraders of aromatic compounds whose degradation generates benzoyl-CoA as central intermediate. Moreover, a recombinant Azoarcus sp. CIB strain harbouring the bzd cassette was shown to behave as a valuable biocatalyst for anaerobic toluene valorization towards the synthesis of poly-3 hydroxybutyrate (PHB), a biodegradable and biocompatible polyester of increasing biotechnological interest as a sustainable alternative to classical oil-derived polymers. PMID- 28736926 TI - Effects of testosterone enanthate treatment in conjunction with resistance training on thyroid hormones and lipid profile in male Wistar rats. AB - This study was conducted to determine the effects of 8-week administration of testosterone enanthate (TE) in conjunction with resistance training on thyroid hormones and lipid profiles. Sixty male adult Wistar rats were randomly divided into six groups: C: olive oil, RT: resistance training + olive oil, LD: TE (20 mg/kg), HD: TE (50 mg/kg), RT + LD: RT + TE (20 mg/kg), RT + HD: RT + TE (50 mg/kg). The RT consisted of climbing (5 reps/3 sets) a ladder carrying a load suspended from the tail. At the end, blood specimens were obtained from the orbital sinus and serum concentration of T4, T3, TSH and lipid profiles was determined. The serum concentration of TSH significantly increased in RT + HD group compared to C, and the serum concentration of T4 significantly decreased in LD, HD, RT + LD and RT + HD groups compared to the C and RT groups (p < .05). The concentration of HDL and cholesterol significantly decreased in HD and RT + HD groups compared with C group (p < .05). Both decreased T4 and increased TSH in the RT + HD group likely suggested a primary hypothyroidism as a complication of high-dose administration of testosterone enanthate along with resistance training. Alteration in lipid profile was another complication observed in rats received high doses of testosterone enanthate. PMID- 28736927 TI - Pituitary-thyroid axis development during the larval-juvenile transition in the pejerrey Odontesthes bonariensis. AB - The morphological development of the thyroid gland of pejerrey Odontesthes bonariensis during larval-juvenile transition was studied and related to whole body concentrations of thyroxine (T4 ) and tri-iodothyronine (T3 ). A complementary (c)DNA fragment of the thyroid-stimulating hormone beta-subunit (tshb) was sequenced and transcript levels quantified during this period. Follicles with eosinophilic and T4 -immunoreactive colloids were detected at hatching together with tshb transcript levels and whole-body concentrations of T4 and T3 hormones. Thyroid follicles were located in the subpharyngeal region associated with the ventral aorta below the hyoid bone. Follicle structure switched from the rounded form at hatching to oval in juveniles. Significant increase of follicle number per larva, mean colloidal area and total colloidal area was observed throughout development with maximum values at the end of the larval-juvenile transition. A significant decrease of tshb expression together with a significant increase in T4 and T3 whole-body concentrations was observed prior to achieving the juvenile phenotype. These results are in accordance with a negative feedback regulation of tshb expression by thyroid hormones and a possible association between thyroid hormone levels and the acceleration of metabolic processes necessary to complete metamorphosis. PMID- 28736928 TI - Mean platelet volume predicts prognosis in patients with diffuse large B-cell lymphoma. AB - To determine the prognostic value of baseline mean platelet volume (MPV) in diffuse large B-cell lymphoma (DLBCL) patients. We retrospectively analyzed 161 DLBCL patients who received R-CHOP chemotherapy. The associations between MPV and clinicopathological factors were assessed. A low MPV (MPV <= 9.1 fl, cut-off was calculated by receiver operating characteristics) was not associated with any other clinicopathological factors. Patients with MPV <= 9.1 fl experienced a shorter progression-free survival (PFS) (2-year PFS rate, 60.6% vs 84.0%, P = 0.003) and overall survival (OS) (2-year OS rate, 70.4% vs 87.9%, P = 0.030), compared with those with MPV > 9.1 fl. The multivariate analysis demonstrated that MPV <= 9.1 fl was an independent prognostic factor of OS (Hazard Ratio [HR] = 0.588, P = 0.045) and PFS (HR = 0.456, P = 0.010). Therefore, we demonstrated that low baseline MPV is an independent prognostic marker of poor outcome in patients with DLBCL. PMID- 28736929 TI - Impact of Cost-Sharing Increases on Continuity of Specialty Drug Use: A Quasi Experimental Study. AB - OBJECTIVE: To examine the impact of cost-sharing increases on continuity of specialty drug use in Medicare beneficiaries with multiple sclerosis (MS) or rheumatoid arthritis (RA). DATA SOURCES/STUDY SETTING: Five percent Medicare claims data (2007-2010). STUDY DESIGN: Quasi-experimental study examining changes in specialty drug use among a group of Medicare Part D beneficiaries without low income subsidies (non-LIS) as they transitioned from a 5 percent cost-sharing preperiod to a >=25 percent cost-sharing postperiod, as compared to changes among a disease-matched contemporaneous control group of patients eligible for full low income subsidies (LIS), who faced minor cost sharing (<=$6.30 copayment) in both the pre- and postperiods. DATA COLLECTION/EXTRACTION METHODS: Key variables were extracted from Medicare data. PRINCIPAL FINDINGS: Relative to the LIS group, the non-LIS group had a greater increase in incidence of 30-day continuous gaps in any Part D treatment from the lower cost-sharing period to the higher cost sharing period (MS, absolute increase = 10.1 percent, OR = 1.61, 95% CI 1.19 2.17; RA, absolute increase = 21.9 percent, OR = 2.75, 95% CI 2.15-3.51). The increase in Part D treatment gaps was not offset by increased Part B specialty drug use. CONCLUSIONS: Cost-sharing increases due to specialty tier-level cost sharing were associated with interruptions in MS and RA specialty drug treatments. PMID- 28736930 TI - Technical Note: Mobile accelerator guidance using an optical tracker during docking in IOERT procedures. AB - PURPOSE: Intraoperative electron radiation therapy (IOERT) involves the delivery of a high radiation dose during tumor resection in a shorter time than other radiation techniques, thus improving local control of tumors. However, a linear accelerator device is needed to produce the beam safely. Mobile linear accelerators have been designed as dedicated units that can be moved into the operating room and deliver radiation in situ. Correct and safe dose delivery is a key concern when using mobile accelerators. The applicator is commonly fixed to the patient's bed to ensure that the dose is delivered to the prescribed location, and the mobile accelerator is moved to dock the applicator to the radiation beam output (gantry). In a typical clinical set-up, this task is time consuming because of safety requirements and the limited degree of freedom of the gantry. The objective of this study was to present a navigation solution based on optical tracking for guidance of docking to improve safety and reduce procedure time. METHOD: We used an optical tracker attached to the mobile linear accelerator to track the prescribed localization of the radiation collimator inside the operating room. Using this information, the integrated navigation system developed computes the movements that the mobile linear accelerator needs to perform to align the applicator and the radiation gantry and warns the physician if docking is unrealizable according to the available degrees of freedom of the mobile linear accelerator. Furthermore, we coded a software application that connects all the necessary functioning elements and provides a user interface for the system calibration and the docking guidance. RESULT: The system could safeguard against the spatial limitations of the operating room, calculate the optimal arrangement of the accelerator and reduce the docking time in computer simulations and experimental setups. CONCLUSIONS: The system could be used to guide docking with any commercial linear accelerator. We believe that the docking navigator we present is a major contribution to IOERT, where docking is critical when attempting to reduce surgical time, ensure patient safety and guarantee that the treatment administered follows the radiation oncologist's prescription. PMID- 28736931 TI - Genetic Variants in HSD17B3, SMAD3, and IPO11 Impact Circulating Lipids in Response to Fenofibrate in Individuals With Type 2 Diabetes. AB - Individuals with type 2 diabetes (T2D) and dyslipidemia are at an increased risk of cardiovascular disease. Fibrates are a class of drugs prescribed to treat dyslipidemia, but variation in response has been observed. To evaluate common and rare genetic variants that impact lipid responses to fenofibrate in statin treated patients with T2D, we examined lipid changes in response to fenofibrate therapy using a genomewide association study (GWAS). Associations were followed up using gene expression studies in mice. Common variants in SMAD3 and IPO11 were marginally associated with lipid changes in black subjects (P < 5 * 10-6 ). Rare variant and gene expression changes were assessed using a false discovery rate approach. AKR7A3 and HSD17B13 were associated with lipid changes in white subjects (q < 0.2). Mice fed fenofibrate displayed reductions in Hsd17b13 gene expression (q < 0.1). Associations of variants in SMAD3, IPO11, and HSD17B13, with gene expression changes in mice indicate that transforming growth factor beta (TGF-beta) and NRF2 signaling pathways may influence fenofibrate effects on dyslipidemia in patients with T2D. PMID- 28736932 TI - Current practice of continence advisors in managing faecal incontinence in the United Kingdom: results of an online survey. AB - AIM: To investigate the current practice of continence advisors in the United Kingdom. METHOD: Continence advisors were contacted by email or letter to participate in a survey. The survey contained 27 questions which addressed the practice of each continence advisor, their knowledge of continence management and the adequacy of their training. RESULTS: Two hundred and twenty-six out of a total of 448 continence advisors (50.4%), responded. One hundred and seventy (76.9%) advisors treated both faecal and urinary incontinence, 51 (23.1%) treated urinary incontinence. Thirty-six advisors (16.1%) were lone workers and 130 (58.6%) had more than 10 years' experience. The majority of the advisors (75.6%) performed a digital rectal examination as part of their assessment. Regarding the management of faecal incontinence, 148 prescribed suppositories, 127 offered enemas and 147 advised on rectal irrigation. Most of the advisors taught pelvic floor exercises (n = 207) and urge resistance techniques (n = 188). One hundred and fifty-nine (87.4%) prescribed the Peristeen Coloplast(r) anal plug and 78 (47.6%) prescribed the Renew(r) anal insert. Eighty-nine advisors (42.6%) felt they had not been adequately trained to provide a bowel continence service. CONCLUSION: The majority of continence advisors in the UK manage faecal incontinence. They are able to initiate a broad range of conservative treatment options; however, almost half of the advisors who answered the survey felt inadequately trained and may be better supported by further training. PMID- 28736934 TI - Using social media to engage nurses in health policy development. AB - AIMS: To explore nurses' views on future priorities for the profession and to examine social media as an engagement tool to aid policy discussion and development. BACKGROUND: Nurses are often not directly involved in policy creation and some feel it is a process they cannot easily influence. METHODS: A descriptive mixed methods study of a Twitter chat hosted by the Chief Nursing Officer for Scotland was undertaken. Data were gathered using an analytics platform and NCapture software. The framework approach aided thematic analysis to draw out themes. RESULTS: Sixty-four people took part in the Twitter chat (#CNOScot) and posted 444 tweets. Nurses called for investment in technology, nursing research, education and mental health. Primary care and advanced practice roles to support older adults with complex health and social care needs were also seen as vital to develop further. CONCLUSION: Social media can help reach and engage nurses in policy discussion and ensure there is better continuity between policy and practice but some groups risk being excluded using this digital medium. IMPLICATIONS FOR NURSING MANAGEMENT: Nursing leaders should consider social media as one of many engagement strategies to ensure nurses and other stakeholders participate in policy debate that informs health strategy development. PMID- 28736933 TI - Disruption of oxidative balance in the gut of the western honeybee Apis mellifera exposed to the intracellular parasite Nosema ceranae and to the insecticide fipronil. AB - The causes underlying the increased mortality of honeybee colonies remain unclear and may involve multiple stressors acting together, including both pathogens and pesticides. Previous studies suggested that infection by the gut parasite Nosema ceranae combined with chronic exposure to sublethal doses of the insecticide fipronil generated an increase in oxidative stress in the midgut of honeybees. To explore the impact of these two stressors on oxidative balance, we experimentally infected bees with N. ceranae and/or chronically exposed to fipronil at low doses for 22 days, and we measured soluble reactive oxygen species (ROS) and ROS damage by quantifying both protein and lipid oxidation in the midgut. Our results revealed a disruption of the oxidative balance, with a decrease in both the amount of ROS and ROS damage in the presence of the parasite alone. However, protein oxidation was significantly increased in the N. ceranae/fipronil combination, revealing an increase in oxidative damage and suggesting higher fipronil toxicity in infected bees. Furthermore, our results highlighted a temporal order in the appearance of oxidation events in the intestinal cells and revealed that all samples tended to undergo protein oxidation during ageing, regardless of treatment. PMID- 28736935 TI - 3D Orientational Control in Self-Assembled Thin Films with Sub-5 nm Features by Light. AB - While self-assembled molecular building blocks could lead to many next-generation functional organic nanomaterials, control over the thin-film morphologies to yield monolithic sub-5 nm patterns with 3D orientational control at macroscopic length scales remains a grand challenge. A series of photoresponsive hybrid oligo(dimethylsiloxane) liquid crystals that form periodic cylindrical nanostructures with periodicities between 3.8 and 5.1 nm is studied. The liquid crystals can be aligned in-plane by exposure to actinic linearly polarized light and out-of-plane by exposure to actinic unpolarized light. The photoalignment is most efficient when performed just under the clearing point of the liquid crystal, at which the cylindrical nanostructures are reoriented within minutes. These results allow the generation of highly ordered sub-5 nm patterns in thin films at macroscopic length scales, with control over the orientation in a noncontact fashion. PMID- 28736936 TI - Invasive fungal infection following chemotherapy for acute myeloid leukaemia Experience from a developing country. AB - The incidence of invasive fungal infections (IFI) is believed to be higher in patients with acute myeloid leukaemia (AML) undergoing chemotherapy in non-HEPA filtered rooms. The aim of this study is to review the incidence of IFI in a large cohort of patients with AML treated at a single centre in India. Two hundred and twenty-two patients with AML treated with either induction chemotherapy or salvage chemotherapy between 2008 and 2013 were studied retrospectively. IFI was defined as per the revised EORTC-MSG criteria. Data on type of chemotherapy, prophylactic strategies, engraftment (ANC>500), the presence of IFI and survival were collected. IFI was diagnosed in 86 patients (38.7%) with proven IFI in 12 (5.4%). Use of posaconazole prophylaxis (P=.001) was the only factor associated with reduced incidence of IFI. Survival in patients with proven IFI was lower than those without proven IFI, but not statistically significant (59.4% vs 78.5%; P=.139). There is a high incidence of IFI during induction chemotherapy for acute myeloid leukaemia in developing countries. Posaconazole prophylaxis was associated with a significantly lower incidence of IFI. Optimal yet cost-effective strategies for prevention and early diagnosis of IFI are required to improve survival in patients undergoing chemotherapy for AML. PMID- 28736938 TI - Genetic variation in Pythium myriotylum based on SNP typing and development of a PCR-RFLP detection of isolates recovered from Pythium soft rot ginger. AB - : Pythium myriotylum is responsible for severe losses in both capsicum and ginger crops in Australia under different regimes. Intraspecific genomic variation within the pathogen might explain the differences in aggressiveness and pathogenicity on diverse hosts. In this study, whole genome data of four P. myriotylum isolates recovered from three hosts and one Pythium zingiberis isolate were derived and analysed for sequence diversity based on single nucleotide polymorphisms (SNPs). A higher number of true and unique SNPs occurred in P. myriotylum isolates obtained from ginger with symptoms of Pythium soft rot (PSR) in Australia compared to other P. myriotylum isolates. Overall, SNPs were discovered more in the mitochondrial genome than those in the nuclear genome. Among the SNPs, a single substitution from the cytosine (C) to the thymine (T) in the partially sequenced CoxII gene of 14 representatives of PSR P. myriotylum isolates was within a restriction site of HinP1I enzyme which was used in the PCR RFLP for detection and identification of the isolates without sequencing. The PCR RFLP was also sensitive to detect PSR P. myriotylum strains from artificially infected ginger without the need for isolation for pure cultures. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first study of intraspecific variants of Pythium myriotylum isolates recovered from different hosts and origins based on single nucleotide polymorphism (SNP) genotyping of multiple genes. The SNPs discovered provide valuable makers for detection and identification of P. myriotylum strains initially isolated from Pythium soft rot (PSR) ginger by using PCR-RFLP of the CoxII locus. The PCR-RFLP was also sensitive to detect P. myriotylum directly from PSR ginger sampled from pot trials without the need of isolation for pure cultures. PMID- 28736940 TI - Seven-year-olds' aggressive choices in a computer game can be predicted in infancy. AB - Concerns about the relationship between computer games and children's aggression have been expressed for decades, but it is not yet clear whether the content of such games evokes aggression or a prior history of aggression promotes children's interest in aggressive games. Two hundred and sixty-six 7-year-old children from a nationally representative longitudinal sample in the UK played a novel computer game (CAMGAME) in which the child's avatar encountered a series of social challenges that might evoke aggressive, prosocial or neutral behaviour. Aggressive choices during the game were predicted by well-known risk factors for aggressive conduct problems and the children's own early angry aggressiveness as infants. These findings suggest that children who are predisposed to aggression bring those tendencies to virtual as well as real environments. PMID- 28736939 TI - Fetal hemoglobin in sickle cell anemia: The Arab-Indian haplotype and new therapeutic agents. AB - Fetal hemoglobin (HbF) has well-known tempering effects on the symptoms of sickle cell disease and its levels vary among patients with different haplotypes of the sickle hemoglobin gene. Compared with sickle cell anemia haplotypes found in patients of African descent, HbF levels in Saudi and Indian patients with the Arab-Indian (AI) haplotype exceed that in any other haplotype by nearly twofold. Genetic association studies have identified some loci associated with high HbF in the AI haplotype but these observations require functional confirmation. Saudi patients with the Benin haplotype have HbF levels almost twice as high as African patients with this haplotype but this difference is unexplained. Hydroxyurea is still the only FDA approved drug for HbF induction in sickle cell disease. While most patients treated with hydroxyurea have an increase in HbF and some clinical improvement, 10 to 20% of adults show little response to this agent. We review the genetic basis of HbF regulation focusing on sickle cell anemia in Saudi Arabia and discuss new drugs that can induce increased levels of HbF. PMID- 28736941 TI - In vivo neutralization of alpha4 and beta7 integrins inhibits eosinophil trafficking and prevents lung injury during tropical pulmonary eosinophilia in mice. AB - Integrins regulate leukocyte trafficking during homeostasis and inflammatory conditions. However, the role of alpha4 and beta7 integrins in guiding eosinophil transmigration into the lungs during filarial manifestation of Tropical Pulmonary Eosinophilia (TPE) has not been explored. In this study, mice exhibiting TPE manifestations were administered with in vivo neutralizing antibodies against integrins alpha4 and beta7 or their combination and immuno-pathological parameters were evaluated. Results show an intact lung barrier, significantly lower lung inflammation and reduced eosinophil counts in the Bronchoalveolar lavage fluid and lungs of mice receiving anti-alpha4+ beta7 treatment. Reduced eosinophil peroxidase and beta-hexosaminidase activity, downregulation of inflammatory genes, lower production of inflammatory lipid intermediates like prostaglandins E2 and D2, leukotriene B4 and cysteinyl leukotrienes were also noted in anti-alpha4+ beta7 treated mice. Reduced accumulation of central memory, effector memory, regulatory T cells and lower production of IL-4, IL-5, and TGF beta were other cardinal features of anti-alpha4+ beta7 treated mice lungs. Flow cytometry-sorted lung eosinophils from anti-alpha4+ beta7 treated mice showed higher apoptotic potential, downregulated anti-apoptotic gene Bcl-2, and exhibited reduced F-actin polymerization and calcium influx as compared to IgG controls. In summary, neutralization of alpha4+ beta7 integrins impairs the transmigration, activation and survival of eosinophils and reduces TPE induced pathology in mice lungs. PMID- 28736942 TI - Glycaemic control and hypoglycaemia in people with type 2 diabetes switching from twice-daily basal insulin to once-daily insulin glargine 300 U/mL or insulin glargine 100 U/mL (EDITION 1 and EDITION 2 subgroup analysis). AB - In this post hoc analysis we compared glycaemic control and hypoglycaemia between insulin glargine 300 U/mL (Gla-300) and glargine 100 U/mL (Gla-100) administered once daily in people with type 2 diabetes (T2DM) from the EDITION 1 (basal plus mealtime insulin) and EDITION 2 (basal insulin plus oral antihyperglycaemic drugs) trials who were previously receiving twice-daily insulin. At randomization, 16.9% and 20.0% of people in EDITION 1 and 2, respectively, were receiving twice-daily basal insulin. Glycated haemoglobin change from baseline to Month 6 was similar over 6 months with Gla-300 or Gla-100 (least squares mean difference -0.01%; 95% confidence interval [CI] -0.27 to 0.24] in EDITION 1 and 0.16%; 95% CI -0.25 to 0.57, in EDITION 2). Participants previously receiving twice-daily insulin in EDITION 1 had a lower risk of confirmed (<=3.9 mmol/L [<=70 mg/dL]) or severe hypoglycaemia with Gla-300 vs Gla-100 at night (00:00 05:59 hours), but not at any time (24 hours); in EDITION 2 the risk was reduced at night and any time (24 hours). In conclusion, Gla-300 provided similar glycaemic control with less hypoglycaemia compared with Gla-100 in people with T2DM switching from twice-daily to once-daily basal insulin. PMID- 28736943 TI - Risk factors for wound complications in head and neck reconstruction: 773 free jejunal reconstruction procedures after total pharyngolaryngoesophagectomy. AB - BACKGROUND: Most studies that examined risk factors for wound complications after head and neck reconstruction analyzed various complications collectively. Moreover, they included a wide variety of resection areas and reconstruction materials. To overcome these limitations, both the resection area and reconstruction method were constrained in the present study. METHODS: Patients who underwent free jejunal graft reconstruction after pharyngolaryngoesophagectomy for hypopharyngeal cancer were enrolled. The outcomes of interest were abscesses, fistulas, and cervical skin flap necrosis. RESULTS: Abscesses, fistulas, and cervical skin flap necrosis developed in 19.3%, 11.3%, and 8.2% of 773 patients, respectively. A significant relationship was found between use of an open drain and abscess formation and between a longer operation time and cervical skin flap necrosis. CONCLUSION: Our findings suggest that use of an open drain, cardiovascular disease, and a longer operation time are significant risk factors for abscess formation, fistula formation, and cervical skin flap necrosis, respectively. PMID- 28736945 TI - Tim-1+ B cells suppress T cell interferon-gamma production and promote Foxp3 expression, but have impaired regulatory function in coronary artery disease. AB - Atherosclerosis and its associated coronary artery disease (CAD) represent another chronic low-grade inflammatory disorder. Regulatory B cells (Bregs) possess essential functions in maintaining peripheral tolerance and inhibiting pathogenic inflammation through IL-10. Here, we investigated one subset of Bregs, Tim-1+ B cell, and its role in atherosclerosis and CAD patients. In healthy individuals, IL-10-producing B cells were predominantly found in the Tim-1+ B cells. Upon stimulation of the B cell receptor (BCR) and Toll-like receptor 9 (TLR-9) by anti-BCR antibodies and CpG, respectively, the Tim-1+ B cells could further upregulate IL-10 expression. In contrast, the Tim-1+ B cells were present at normal frequency in CAD patients, but showed impaired capacity to upregulate IL-10 with or without BCR + CpG stimulation. The stimulated Tim-1+ B cells from healthy individuals also suppressed expression of interferon gamma (IFN-gamma), an atherogenic cytokine in T cells, in an IL-10-dependent fashion, and strongly promoted the expression of Foxp3 in naive CD4+ CD45RO- T cells. In contrast, the Tim-1+ B cells from CAD patients were unable to suppress IFN-gamma secretion, and only minimally increased the expression of Foxp3 in naive CD4+ CD45RO- T cells. Despite this, the frequency of Tim-1+ B cells in the atherosclerotic lesions from CAD patients was inversely correlated with the frequency of IFN-gamma-expressing T cells. Together, these results demonstrated that CAD patients presented an inflammatory disorder in regulatory B cells, which could be used as a therapeutic target. PMID- 28736944 TI - Short-term acipimox treatment is associated with decreased cardiac parasympathetic modulation. AB - AIMS: The nicotinic acid analogue acipimox is an antilipolytic agent, which acutely inhibits lipolysis and suppresses systemic levels of free fatty acids (FFA) and improves insulin sensitivity in obese patients. These effects of acipimox are transient due to a counter-regulatory increase in growth hormone levels that reverse the antilipolytic effect of acipimox. Hypopituitary patients constitute a viable model to study the growth hormone-independent effects of acipimox and the impact of isolated changes in FFA concentrations and insulin sensitivity on parasympathetic nervous activity. The aim of the present study was to investigate if pharmacological antilipolysis with acipimox acutely affects autonomic tone. METHODS: We studied heart rate variability as a measure of autonomic tone in eight hypopituitary men with and without acipimox treatment. The standard deviation of normal-to-normal intervals, root mean square of successive differences and high frequency were measured as heart rate variability parameters. The patients were studied in the basal and insulin-stimulated state with clamped plasma glucose on two occasions in a randomized, double-blind and placebo-controlled crossover study. RESULTS: Plasma glucose (4.7 vs. 4.9 mmol l-1 , P = 0.02) and serum FFA (0.05 vs. 0.41 mmol l-1 , P < 0.001) were significantly decreased during acipimox treatment. Acipimox had an inhibitory effect on standard deviation of normal-to-normal intervals (41.3 vs. 45.3 ms, P = 0.01), root mean square of successive differences (23.2 vs. 11 ms, P = 0.03) and high frequency (3.79 vs 3.60 ln (ms2 ), P = 0.02) and these effects were reversed during clamping. CONCLUSIONS: Short-term inhibition of lipolysis by acipimox treatment lowered circulating FFA levels, improved insulin sensitivity, and was accompanied by reduced parasympathetic tone. The effect of acipimox on the parasympathetic modulation was reversed by hyperinsulinaemia. PMID- 28736946 TI - Fast and reproducible in vivo T1 mapping of the human cervical spinal cord. AB - PURPOSE: To develop a fast and robust method for measuring T1 in the whole cervical spinal cord in vivo, and to assess its reproducibility. METHODS: A spatially nonselective adiabatic inversion pulse is combined with zonally oblique magnified multislice echo-planar imaging to produce a reduced field-of-view inversion-recovery echo-planar imaging protocol. Multi- inversion time data are obtained by cycling slice order throughout sequence repetitions. Measurement of T1 is performed using 12 inversion times for a total protocol duration of 7 min. Reproducibility of regional T1 estimates is assessed in a scan-rescan experiment on five heathy subjects. RESULTS: Regional mean (standard deviation) T1 was: 1108.5 (+/-77.2) ms for left lateral column, 1110.1 (+/-83.2) ms for right lateral column, 1150.4 (+/-102.6) ms for dorsal column, and 1136.4 (+/-90.8) ms for gray matter. Regional T1 estimates showed good correlation between sessions (Pearson correlation coefficient = 0.89 (P value < 0.01); mean difference = 2 ms, 95% confidence interval +/- 20 ms); and high reproducibility (intersession coefficient of variation approximately 1% in all the regions considered, intraclass correlation coefficient = 0.88 (P value < 0.01, confidence interval 0.71-0.95)). CONCLUSIONS: T1 estimates in the cervical spinal cord are reproducible using inversion-recovery zonally oblique-magnified multislice echo planar imaging. The short acquisition time and large coverage of this method paves the way for accurate T1 mapping for various spinal cord pathologies. Magn Reson Med 79:2142-2148, 2018. (c) 2017 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. PMID- 28736947 TI - Intraobserver and Interobserver Variability in Ultrasound Measurements of Thyroid Nodules. AB - OBJECTIVES: The purpose of this study was to assess the intraobserver and interobserver variability in ultrasound (US) measurements of thyroid nodules. METHODS: We performed a prospective study of the US examinations of 73 patients with 122 thyroid nodules greater than 5 mm in size. Ultrasound measurements in 4 dimensions (anteroposterior, transverse, longitudinal, and maximum diameters) and measurement of the estimated volume (using the ellipsoid formula) of each thyroid nodule were performed twice by 2 independent radiologists (A and B, with 10 years and 6 months of experience, respectively). The intraobserver and interobserver variability in measurements of thyroid nodules was assessed by a Bland-Altman analysis of agreement. The absolute values for intraobserver and interobserver variability were compared by a paired t test. RESULTS: The 95% intraobserver and interobserver limits of agreement for the anteroposterior, transverse, longitudinal, and maximum diameters and estimated volume of thyroid nodules were +/-18.2%, +/- 14.3%, and +/-21.0%; +/- 17.2%%, +/- 17.3%, and 18.2%; +/- 14.6%, +/- 15.5%, and +/-22.3%; +/- 13.8%, +/- 15.5%, and +/-19.6%; and +/-30.2%, +/- 27.7%, and +/-44.1%, respectively. The absolute values for intraobserver variability were lower than those for interobserver variability for all measurements. CONCLUSIONS: There was considerable intraobserver and interobserver variability in US measurement of thyroid nodules, which must be taken into account during follow-up US examinations of patients with thyroid nodules. PMID- 28736948 TI - Evaluating the efficacy of hydrogen peroxide vapour against foot-and-mouth disease virus within a BSL4 biosafety facility. AB - : An evaluation was made of the efficacy of 35% hydrogen peroxide vapour (HPV) against foot-and-mouth disease virus (FMDV) in a biosafety facility. Biological indicators (BIs) were produced using three serotypes of FMDV, all with a titre of >=106 TCID50 per ml. Fifteen BIs of each serotype were distributed across five locations, throughout a 30-m3 airlock chamber, producing a total of 45 BIs. Thirty-five percent HPV was generated and applied using a Bioquell vaporization module located in the centre of the chamber. After a dwell period of 40 min, the HPV was removed via the enclosures air handling system and the BIs were collected. The surfaces of the BIs were recovered into Glasgow's modified Eagle's medium (GMEM), cultivated in BHK21 Cl13 cell culture and analysed for evidence of cytopathic effect (CPE). No CPE was detected in any BI sample. Positive controls showed CPE. The experimentation shows that FMDV is susceptible to HPV decontamination and presents a potential alternative to formaldehyde. SIGNIFICANCE AND IMPACT OF THE STUDY: Foot-and-mouth disease virus (FMDV) is an important pathogen in terms of biosafety due to its infectious nature and wide range of host animals, such as cattle, sheep, goats and pigs. Outbreaks of FMDV can have a severe impact on livestock production, causing morbidity, mortality, reduced yields and trade embargoes. Laboratories studying FMDV must possess BSL4 robust bio-decontamination methods to prevent inadvertent release. Formaldehyde has been the primary agent for environmental decontamination, but its designation as a human carcinogen has led to a search for alternatives. This study shows 35% hydrogen peroxide vapour has the potential to be a rapid, effective, residue-free alternative. PMID- 28736949 TI - Simultaneous measurement of brain perfusion and labeling efficiency in a single pseudo-continuous arterial spin labeling scan. AB - PURPOSE: The aim of this study was to propose, optimize, and validate a pseudo continuous arterial spin labeling (pCASL) sequence for simultaneous measurement of brain perfusion and labeling efficiency. METHODS: The proposed sequence incorporates the labeling efficiency measurement into the postlabeling delay period of a conventional perfusion pCASL sequence by using the time-encoding approach. In vivo validation experiments were performed on nine young subjects by comparing it to separate perfusion and labeling efficiency sequences. Sensitivity of the proposed combined sequence for measuring labeling efficiency changes was further addressed by varying the flip angles of the pCASL labeling radiofrequency pulses. RESULTS: The proposed combined sequence decreased the perfusion signal by ~4% and a lower labeling efficiency (by ~10%) was found as compared to the separate sequences. However, the temporal signal-noise-ratio of the perfusion signal remained unchanged. When the pCASL flip angle was decreased to a suboptimal setting, a strong correlation was found between the combined and the separate sequences for the relative change in pCASL perfusion signal as well as for the relative change in labeling efficiency. High correlation was also observed between relative changes in perfusion signal and the measured labeling efficiencies. CONCLUSION: The proposed sequence allows simultaneous measurement of brain perfusion and labeling efficiency with high time-efficiency at the price of only a small compromise in measurement accuracy. The additional labeling efficiency measurement can be used to facilitate qualitative interpretation of pCASL perfusion images. Magn Reson Med 79:1922-1930, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28736950 TI - Impact of Interfacial Layers in Perovskite Solar Cells. AB - Perovskite solar cells (PCSs) are composed of organic-inorganic lead halide perovskite as the light harvester. Since the first report on a long-term-durable, 9.7 % efficient, solid-state perovskite solar cell, organic-inorganic halide perovskites have received considerable attention because of their excellent optoelectronic properties. As a result, a power conversion efficiency (PCE) exceeding 22 % was certified. Controlling the grain size, grain boundary, morphology, and defects of the perovskite layer is important for achieving high efficiency. In addition, interfacial engineering is equally or more important to further improve the PCE through better charge collection and a reduction in charge recombination. In this Review, the type of interfacial layers and their impact on photovoltaic performance are investigated for both the normal and the inverted cell architectures. Four different interfaces of fluorine-doped tin oxide (FTO)/electron-transport layer (ETL), ETL/perovskite, perovskite/hole transport layer (HTL), and HTL/metal are classified, and their roles are investigated. The effects of interfacial engineering with organic or inorganic materials on photovoltaic performance are described in detail. Grain-boundary engineering is also included because it is related to interfacial engineering and the grain boundary in the perovskite layer plays an important role in charge conduction, recombination, and chargecarrier life time. PMID- 28736951 TI - Component-Customizable Porous Rare-Earth-Based Colloidal Spheres towards Highly Effective Catalysts and Bioimaging Applications. AB - Multicomponent porous colloidal spheres are of interest because they not only show a combination of the properties associated with all different components, but also usually present synergy effects. However, a combination of different components in a single porous sphere is still greatly challenged due to the different precipitation behaviors of each component. In this work, we have developed a general synthetic route to prepare several categories of porous monodisperse rare-earth (RE)-based colloidal spheres with customizable elemental compositions and a uniform element distribution. The two-step synthetic strategy is based on the integration of coordination chemistry precipitation of RE ions and a subsequent ion-exchange process, which steers clear of obstacles, such as differences in solubility product constant, that are to be found in traditional co-precipitation methods. Our approach provides a new mixing mechanism to realize homogeneous distribution of each element within the porous spheres. An array of binary, ternary, and even senary RE colloidal porous spheres with diameters of 500 nm to 700 nm has been successfully synthesized. Taking advantage of their good dispersibility, porosity, and customizable components, these porous RE oxide spheres show excellent catalytic activity for the reduction of 4-nitrophenol, and promising application in single-phase multifunctional bioprobes. PMID- 28736952 TI - Validation of the albumin-bilirubin grade-based integrated model as a predictor for sorafenib-failed hepatocellular carcinoma. AB - BACKGROUND & AIMS: Sorafenib is the standard treatment for advanced hepatocellular carcinoma (HCC) but is challenging after treatment failure. Appropriate criteria for enrolling patients into second-line trials are still limited. In this study, we aimed to establish more objective criteria based on Albumin-Bilirubin (ALBI) grade to select patients with better post-progression survival (PPS) for second-line treatment. METHODS: Consecutive 404 advanced HCC patients receiving sorafenib were retrospectively enrolled. All patients were in Child-Pugh class A and BCLC stage C with either portal vein invasion or extrahepatic metastasis at the beginning of sorafenib treatment. Radiological evaluation based on mRECIST criteria and clinical assessments with compliance were performed on schedule. RESULTS: During the median follow-up period of 5.8 months, 310 patients developed progressive disease (PD) and 350 deaths occurred. The PD patients were randomized into derivation and validation cohorts by a 1:1 ratio. The independent predictors of poor PPS in derivation cohort were ALBI grade 3 at PD (hazard ratio [HR]=3.24, P = .002), new extrahepatic lesions (NEH) (HR=1.75, P = .011), and early PD within 4 months (HR=1.88, P = .037). ALBI-PD criteria were proposed by incorporating these three risk factors. In the validation cohort, PPS could be independently predicted by presence of early PD, NEH as well as ALBI grade 3 at PD. Patients within ALBI-PD criteria had significant longer median PPS than those beyond it even in Child-Pugh A (9.7 vs 4.9 months, P = .005) subpopulations. CONCLUSIONS: The ALBI-PD criteria can differentiate PPS and stratify the patients with advanced HCC for the second-line trials or salvage therapy. PMID- 28736953 TI - Neutropenia in kidney and liver transplant recipients: Risk factors and outcomes. AB - No studies have directly compared the key characteristics and outcomes of kidney (KTx) and liver transplantation (LTx) recipients with neutropenia. In this single center, retrospective, cohort study, we enrolled all adult patients who received a KTx or LTx between 2000 and 2011. Neutropenia was defined as 2 consecutive absolute neutrophil count (ANC) values <1500/mm3 in patients without preexisting neutropenia. The first neutropenia episode occurring during the first year post transplantation was analyzed. A total of 663 patients with KTx and 354 patients with LTx met the inclusion criteria. Incidence of neutropenia was 20% in KTx and 38% in LTx, respectively. High-risk CMV status and valganciclovir (VGCV) use were significant predictors of neutropenia for KTx recipients, but only VGCV use vs nonuse in LTx recipients. Neutropenia was associated with worse survival in KTx recipients (adjusted HR 1.95, 95% CI 1.18-3.22, P<.01), but not in LTx recipients (adjusted HR 0.75, 95% CI 0.52-1.10, P=.15). Sixteen acute rejection episodes were associated with preceding neutropenia in KTx recipients (HR 1.77, 95% CI 1.16-2.68, P=.007) and 24 acute rejection episodes in LTx recipients (HR 1.41, 95% CI 0.97-2.04, P=.07). Incidence of infection was similar in patients with and without neutropenia among KTx and LTx recipients. PMID- 28736954 TI - The impact of the bovine faecal microbiome on Escherichia coli O157:H7 prevalence and enumeration in naturally infected cattle. AB - AIMS: The objective of this study was to determine if the faecal microbiome has an association with Escherichia coli O157:H7 prevalence and enumeration. METHODS AND RESULTS: Pyrosequencing analysis of faecal microbiome was performed from feedlot cattle fed one of three diets: (i) 94 heifers fed low concentrate (LC) diet, (ii) 142 steers fed moderate concentrate (MC) diet, and (iii) 132 steers fed high concentrate (HC) diet. A total of 322 585 OTUs were calculated from 2,411,122 high-quality sequences obtained from 368 faecal samples. In the LC diet group, OTUs assigned to the orders Clostridiales and RF39 (placed within the class Mollicutes) were positively correlated with both E. coli O157:H7 prevalence and enumeration. In the MC diet group, OTUs assigned to Prevotella copri were positively correlated with both E. coli O157:H7 prevalence and enumeration, whereas OTUs assigned to Prevotella stercorea were negatively correlated with both E. coli O157:H7 prevalence and enumeration. In both the MC diet group and the HC diet group, OTUs assigned to taxa placed within Clostridiales were both positively and negatively correlated with both E. coli O157:H7 prevalence and enumeration. However, all correlations were weak. In both the MC diet group and the HC diet group, stepwise linear regression through backward elimination analyses indicated that these OTUs were significantly correlated (P < 0.001) with prevalence or enumeration, explaining as much as 50% of variability in E. coli O157:H7 prevalence or enumeration. CONCLUSIONS: Individual colonic bacterial species have little impact on E. coli O157:H7 shedding but collectively groups of bacteria were strongly associated with pathogen shedding. SIGNIFICANCE AND IMPACT OF THE STUDY: Bacterial groups in the bovine colon may impact faecal shedding of the zoonotic pathogen E. coli O157:H7, and manipulation of the intestinal microbiota to alter these bacteria may reduce shedding of this pathogen and foodborne illnesses. PMID- 28736955 TI - Does compliance with healthy lifestyle behaviours cluster within individuals in Australian primary school-aged children? AB - BACKGROUND: The 3 "movement behaviours" of sleep, screen time, and physical activity are associated with a wide range of health outcomes in children. This study examined whether these behaviours cluster together within individuals in Australian primary school children. METHODS: Three datasets including 4,449 9- to 11-year-old children were interrogated-(a) Obesity Prevention and Lifestyle (OPAL), (b) the International Study of Children, Obesity, Lifestyle and Environment (ISCOLE), and (c) the National Children's Nutrition and Physical Activity Survey (NCNPAS). The surveys measured movement behaviours using different instruments (accelerometry, use of time recall, and questionnaires) and different operationalizations of compliance. Observed frequencies of compliance with various combinations of guidelines were compared with expected frequencies based on the assumption of independence, using chi-square tests. RESULTS: Compliance with the sleep guidelines was relatively high (72%, 75%, and 79% in the OPAL, ISCOLE, and NCNPAS datasets, respectively), and compliance with the screen (18%, 35%, and 22%) and physical activity (33%, 57%, and 87%) guidelines was generally lower. Against expectation, there was no evidence of clustering in any of the datasets (p > .99). CONCLUSIONS: Compliance with movement behaviour guidelines does not cluster within individuals in 9- to 11-year-old Australian children. It may be unlikely that fostering compliance with one guideline will have a flow-on effect to the others. Temporal trade-offs (i.e., the need to choose one movement behaviour above another) in the 24-hr day may contribute to the lack of clustering. PMID- 28736956 TI - Nitrogen-Superdoped 3D Graphene Networks for High-Performance Supercapacitors. AB - An N-superdoped 3D graphene network structure with an N-doping level up to 15.8 at% for high-performance supercapacitor is designed and synthesized, in which the graphene foam with high conductivity acts as skeleton and nested with N superdoped reduced graphene oxide arogels. This material shows a highly conductive interconnected 3D porous structure (3.33 S cm-1 ), large surface area (583 m2 g-1 ), low internal resistance (0.4 Omega), good wettability, and a great number of active sites. Because of the multiple synergistic effects of these features, the supercapacitors based on this material show a remarkably excellent electrochemical behavior with a high specific capacitance (of up to 380, 332, and 245 F g-1 in alkaline, acidic, and neutral electrolytes measured in three electrode configuration, respectively, 297 F g-1 in alkaline electrolytes measured in two-electrode configuration), good rate capability, excellent cycling stability (93.5% retention after 4600 cycles), and low internal resistance (0.4 Omega), resulting in high power density with proper high energy density. PMID- 28736957 TI - Xenogeneic chimera-Generated by blastocyst complementation-As a potential unlimited source of recipient-tailored organs. AB - Blastocyst complementation refers to the injection of cells into a blastocyst. The technology allows for the creation of chimeric animals, which have the potential to be used as an unlimited source of organ donors. Pluripotent stem cells could be generated from a patient in need of a transplantation and injected into a large animal blastocyst (potentially of a pig), leading to the creation of organ(s) allowing immunosuppression-free transplantation. Various chimera combinations have already been generated, but one of the most recent steps leads to the creation of human-pig chimeras, which could be studied at an embryo stage. Although still far from clinical reality, the potential application is almost unlimited. The present review illustrates the historical steps of intra- and interspecific blastocyst complementation in rodents and large animals, specifically looking at its potential for generation of organ grafts. We also speculate on how it could change transplant indications, on its economic impact, and on the linked ethical concerns. PMID- 28736958 TI - Intraoperative indocyanine green fluorescent angiography-assisted modified superior gluteal artery perforator flap for reconstruction of sacral pressure sores. AB - Pressure sores are often observed in patients who are bedridden. They can be a severe problem not only for patients and their caregivers but also for plastic surgeons. Here, we describe a new method of superior gluteal artery perforator flap harvesting and anchoring with the assistance of intraoperative indocyanine green fluorescent angiography. In this report, we describe the procedure and outcomes for 19 patients with grades III and IV sacral pressure sores who underwent the operation between September 2015 and November 2016. All flaps survived, and two experienced wound-edge partial dehiscence. With the assistance of this imaging device, we were able to acquire a reliable superior gluteal artery perforator flap and perform modified operations with it that are safe, easy to learn and associated with fewer complications than are traditional. PMID- 28736959 TI - In vivo Raman spectroscopy-assisted early identification of potential second primary/recurrences in oral cancers: An exploratory study. AB - BACKGROUND: Higher rates of local recurrences and second primaries, ascribable to field cancerization, are known problem in oral cancers. The present study explored utility of identification of potential recurrences by Raman spectroscopy, which has been shown to identify oral precancers, cancers, and field cancerization in humans and micro-sized mechanical irritation-induced tumors in animals. METHODS: Raman spectra were acquired from tumor and contralateral normal mucosa in 99 patients with oral cancer who were then followed up for appearance of clinically apparent cancerous lesions. Misclassifications observed in subsequent multivariate statistical analysis between contralateral normal and tumor spectra were correlated with appearance of new malignant lesions. RESULTS: The patients with mismatched spectra had 1.5 times higher chances of developing local recurrence. The sensitivity of Raman spectroscopy in predicting the recurrences was 80% and the specificity was 29.7%. CONCLUSION: Findings provide proof-of-concept for Raman spectroscopy-based identification of sites that have higher propensity to progress to carcinomas before becoming clinically apparent. Prospective validation of Raman spectroscopy by including additional oral cavity subsites and use of multifiber bundles may improve rate of identification of recurrence-prone subjects. PMID- 28736961 TI - Changes in cytokine profiles following treatment with food allergen-specific sublingual immunotherapy in dogs with adverse food reactions. AB - BACKGROUND: Food allergen-specific sublingual immunotherapy (FA-SLIT) is considered to be a novel, safe and effective approach in dogs with adverse food reactions (AFR). HYPOTHESIS/OBJECTIVES: To investigate changes in key cytokines associated with FA-SLIT. ANIMALS: Eleven dogs with confirmed AFR. METHODS: Participants received either dose escalation of FA-SLIT or placebo over a six month period. Oral food challenge was performed at the beginning and end of the study, along with clinical examinations and collection of skin surface bacterial cytology and blood. Peripheral blood mononuclear cells were stimulated with the culprit food antigen. ELISA methods were used to quantify Interleukin (IL)-10, IFN-gamma, IL-4 and IL-17A in the supernatant of stimulated cells. RESULTS: IL-10 and IFN-gamma levels were significantly increased at the end of the study in the treatment group (T), compared with the placebo group (P), whereas no changes were found in IL-4 levels. IL-17A levels were decreased in both groups (but more profoundly in T). Bacterial scores on the skin were positively correlated with IL 17A and inversely correlated with IL-10 concentrations. Interleukins were not correlated with clinical scores. CONCLUSION AND CLINICAL IMPORTANCE: FA-SLIT may modulate the allergic response toward Th1 and Treg cell phenotypes, and induction of tolerance in dogs with AFR. Therefore, FA-SLIT may be a tool to desensitize dogs with AFR. However, more data on a larger number of cases and a broader panel of cytokines are needed to corroborate these findings, and to elucidate the mechanism of action for responses to FA-SLIT by dogs with AFR. PMID- 28736962 TI - Diagnosis and management of white-coat hypertension in children and adolescents: A Midwest Pediatric Nephrology Consortium study. AB - Although the definition of white-coat hypertension (WCH) in children and adolescents is clearly defined, little is known about how this condition is actually approached clinically. To better understand the contemporary approach to the diagnosis and management of WCH in pediatric patients, the authors surveyed the membership of the Midwest Pediatric Nephrology Consortium. Seventy-four faculty pediatric nephrologists responded to the survey. The survey results demonstrated uniformity in diagnosing WCH, including ambulatory blood pressure monitoring use in 93% of the respondents and a 75% adherence rate according to the 2014 American Heart Association scientific statement on pediatric ambulatory blood pressure monitoring. A total of 85% of respondents would not embark on further diagnostic evaluation once the WCH diagnosis was established, and none would initiate antihypertensive medications. There was a wide variety of practice habits in follow-up of WCH including frequency of office and out-of-office follow up blood pressure measurements, the setting and timing of physician follow-up, and the role of repeat ambulatory blood pressure monitoring. The results of this survey highlight the need for prospective studies aimed at establishing the optimal approach to pediatric patients with WCH. PMID- 28736963 TI - Breeding experiments and genome-wide association analysis elucidate two genetically different forms of non-syndromic congenital cleft lip and jaw in Vorderwald * Montbeliarde cattle. AB - Non-syndromic congenital cleft lip and jaw (CLJ) is a condition reported in Vorderwald * Montbeliarde cattle. The objective of the present study was to perform a genome-wide association study (GWAS) for 10 CLJ-affected and 50 unaffected Vorderwald * Montbeliarde cattle using the bovine Illumina high density bead chip to identify loci for this condition. Phenotypic classification of CLJ was based on a detailed recording of orofacial structures using computed tomography. A breeding experiment among CLJ-affected Vorderwald * Montbeliarde cattle and CLJ-affected Vorderwald * Montbeliarde cattle with unaffected Holsteins confirmed recessive inheritance and different loci for bilateral or left-sided versus right-sided CLJ. The GWAS for the five cases with right-sided CLJ gave a genome-wide signal on bovine chromosome (BTA) 29 at 16 Mb. For the four left-sided and one bilateral CLJ case, a genome-wide significant association was identified on BTA4 at 32 Mb. Two different loci are very likely to be involved in CLJ in Vorderwald * Montbeliarde cattle because experimental matings among affected cows and bulls with different types of CLJ did not result in CLJ affected progeny, and in addition, two different loci were also found through GWAS and mapped on two different bovine chromosomes. Validation in 346 Vorderwald * Montbeliarde cattle for the highly associated SNPs on BTA4 and 29 gave ratios of 33/346 (0.095, BTA4) and 6/346 (0.017, BTA29) homozygous mutant genotypes. Further studies should elucidate the responsible mutations underlying the different types of CLJ in Vorderwald * Montbeliarde cattle. PMID- 28736964 TI - Exceptionalism is not exceptional in relation to sexual and reproduction mechanisms: Contrasts of human and animal sexuality. AB - Speculation that the release of oxytocin by orgasm in the human female during coitus facilitates fertility by enhancing uterine sperm transport has been criticized as having no unequivocal empirical human evidence. However, a counter claim that this supports human "exceptionalism" as some form of uterine sperm transport occurs in other species. This is a misconception as it ignores that human uterine peristalsis, powered by contractions of the smooth muscle of the archimyometrium, facilitates sperm transport even without any systemic oxytocin involvement. Moreover, examination of various unique reproductive mechanisms in numerous animals also indicates that the claim is misjudged and rests on a biased interpretation of what "exceptionalism" means in this biological context. Ten chosen aspects of our sexuality are presented as being exceptional to humans. Clin. Anat. 30:940-945, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28736965 TI - Symptom burden as a driver of decisional regret in long-term oropharyngeal carcinoma survivors. AB - BACKGROUND: The purpose of this study was to characterize decisional regret and its association with symptom burden in a large cohort of oropharyngeal carcinoma (OPC) survivors. METHODS: A cross-sectional survey was administered to 1729 OPC survivors. Survey items included a multisymptom inventory and a validated decisional regret inventory. Associations between regret and symptom scores were analyzed to determine and rank symptom drivers of decisional regret. RESULTS: Nine hundred seventy-two patients responded reporting a low level of decisional regret overall, although 15.5% communicated "moderate to strong" regret. Overall symptom score and treatment group were statistically significant predictors of decisional regret. Relative to other symptoms, difficulty swallowing and feeling sad were the strongest drivers of decisional regret. CONCLUSION: OPC survivors provide a robust description of their long-term outcomes with 15.5% expressing "moderate to high" regret that was significantly associated with late symptom burden and multimodality treatment. Difficulty swallowing was the strongest driver of decisional regret. PMID- 28736967 TI - Corrigendum. PMID- 28736966 TI - Molecular characterization of nasal methicillin resistant Staphylococcus aureus isolates from workers of an automaker company in southeast Iran. AB - Colonization of methicillin resistant Staphylococccus aureus (MRSA) can occur more commonly in healthy people who live in close together or are in close physical contact with each other. Having knowledge about the molecular characteristics of these strains provides considerable discernment into the epidemiology of this important microorganism. A total of 806 nasal swabs were collected from healthy workers of an automaker company in the southeast of Iran and were analyzed to detect MRSA isolates. Multilocus sequence typing (MLST), spa typing, and detection of staphylococcal cassette chromosome mec (SCCmec) were performed. The presence of genes encoding Panton-Valentine Leukocidin (PVL) and Arginine Catabolic Mobile Element (ACME) were also investigated. Carriage rate of S. aureus was 20%. Among 10 identified MRSA, no acme was found while high prevalence of pvl (60%) was of great concern. Seven different spa types including five new ones were identified. The most frequent sequence type was the novel one; ST 3373 (n = 3), followed by each of ST22, ST88, ST859 (n = 2) and ST1955 (n = 1). MRSA isolates were clustered into two main clonal complexes; CC22 (n = 6) and CC88 (n = 4). Low genetic diversity with the dominance of CC22, SCCmecIV was found. Distribution of previously found hospital-associated MRSA was demonstrated among our isolates. PMID- 28736968 TI - Endocannabinoids in arthritis: current views and perspective. AB - Preclinical and clinical studies using cannabis-based therapy have been shown to provide both analgesia and anti-inflammatory effects, with an overall alleviation of clinical symptoms in animal models of arthritis, highlighting its promising therapeutic application for humans. Despite this, the development of cannabis based therapeutics remains in its infancy, with further investigation into its efficacy and safety profile in patients still required. This synopsis reviews the various components of the endocannabinoid system in health and disease and their potential as therapeutic targets. PMID- 28736969 TI - Correlating MRI with clinical evaluation in the assessment of disease activity of Takayasu's arteritis. AB - OBJECTIVES: To correlate magnetic resonance imaging (MRI) assessment of disease activity in patients with Takayasu's arteritis with the Indian Takayasu's activity score (ITAS). DESIGN, MATERIALS AND METHODS: We prospectively assessed 20 patients with Takayasu's arteritis from November 2010 to September 2011. RESULTS: We found a statistically significant association between MRI assessment of disease activity and ITAS with a P-value of 0.01. The MRI features suggesting active disease included wall thickening and enhancement. We also analyzed the association between MRI and clinical assessment which was also statistically significant at P = 0.037. CONCLUSION: Our study suggests that there is an association between MRI assessment of disease activity and the ITAS. MRI evaluation of disease activity of Takayasu's arteritis therefore goes hand in hand with ITAS 2010, ITAS - A, erythrocyte sedimentation rate and C-reactive protein. However this needs further investigation from future studies using serial assessments. PMID- 28736970 TI - Report from the 2016 University of California, San Francisco, Center for Reproductive Sciences retreat. PMID- 28736971 TI - Attitudes of Greek dentists towards repair of conservative restorations. An online survey. AB - OBJECTIVES: Repair versus replacement of a defective direct restoration is one important step for conserving tooth structure. This study was designed to collect information on the attitudes of Greek dentists towards repairing direct restorations. METHODS: An electronic questionnaire with 16 multiple-choice and rank-ordering questions was created online and its URL address was randomly emailed to 800 dentists in the area of Athens, Greece. The questionnaire remained open for 3 months, and after two reminder emails the data collected were analysed statistically to identify differences between clinician's sex or years of practicing dentistry, using the chi-square and Kruskal-Wallis tests at alpha = 0.05. RESULTS: Three-hundred and twenty dentists completed and submitted the questionnaire (response rate = 40%). A high proportion (86.8%) of the respondents reported that they routinely repair defective restorations, ranking the order of their frequency as 2.47 for amalgam and 2.41 for resin restorations. The reasons, with the highest ranks, for repairing amalgams were the restoration of bulk fractures (4.10) and restoration of marginal fractures (3.69). For repair of resin restorations, the reasons with the highest ranks were improving their colour (4.04) and removing marginal discoloration (3.99). Moreover, 94.1% of the respondents stated that they were enough, much and very much satisfied with the repair, 1 year after it was performed. CONCLUSIONS: A high percentage of Greek dentists are repairing defective direct restorations. There are discrepancies in the indications, techniques and materials used for repairs, such as bulk fractures and marginal restorations. Further studies on the efficacy of repairs, the criteria and procedure protocols are needed. Further, additional clinical education should be offered at the undergraduate or continuing education levels. PMID- 28736972 TI - Reduced risk of emergency admission for colorectal cancer associated with the introduction of bowel cancer screening across England: a retrospective national cohort study. AB - AIM: We wanted to find out if roll-out of the bowel cancer screening programme (BCSP) across England was associated with a reduced risk of emergency hospital admission for people presenting with colorectal cancer (CRC) during this period. METHOD: This is a retrospective cohort study of 27 763 incident cases of CRC over a 1-year period during the roll-out of screening across parts of England. The primary outcome was the number of emergency (unplanned) hospital admissions during the diagnostic pathway. The primary exposure was to those living in an area where the BCSP was active at the time of diagnosis. Patients were categorized into three exposure groups: BCSP not active (reference group), BCSP active < 6 months or BCSP active >= 6 months. RESULTS: The risk of emergency admission for CRC in England was associated with increasing age, female gender, comorbidity and social deprivation. After adjusting for these factors in logistic regression, the odds ratio (OR) for emergency admission in patients diagnosed >= 6 months after the start-up of local screening was 0.83 (CI 0.76-0.90). The magnitude of risk reduction was greatest for cases of screening age (OR 0.75; CI 0.63-0.90) but this effect was apparent also for cases outside the 60-69-year age group (OR 0.85; CI 0.77-0.94). Living in an area with active BCSP conferred no reduction in risk of emergency admission for people diagnosed with oesophagogastric cancer during the same period. CONCLUSION: The start-up of bowel cancer screening in England was associated with a substantial reduction in the risk of emergency admission for CRC in people of all ages. This suggests that the roll-out of the programme had indirect benefits beyond those related directly to participation in screening. PMID- 28736973 TI - Plasmacytoid dendritic cells and type I interferon in the immunological response against warts. AB - BACKGROUND: Plasmacytoid dendritic cells (pDCs) are the most potent producers of type I interferons (IFNs), and are involved in the pathogenesis of several cutaneous infectious (especially viral), inflammatory/autoimmune and neoplastic entities. Their role in the pathogenesis and regression of human papilloma virus (HPV)-induced skin lesions has not been well studied. AIM: To investigate pDC occurrence and activity in HPV-induced skin lesions, including inflamed and uninflamed warts as well as epidermodysplasia verruciformis (EDV)-associated lesions. METHODS: In total 20 inflamed and 20 uninflamed HPV-induced skin lesions (including 7 EDV lesions) were retrieved from our database, and the tissue was immunohistochemically tested for pDC occurrence and activity using anti-BDCA-2 and anti-MxA antibodies, respectively. RESULTS: pDCs were present in all 20 inflamed warts and absent from all 20 uninflamed cases. MxA expression was also diffuse and strong in 75% (15/20) inflamed warts, but not in any of the uninflamed warts. CONCLUSIONS: pDCs constitute a central component of the inflammatory host response in inflamed warts, possibly contributing to their regression through production of type I interferons. PMID- 28736974 TI - Topical sevoflurane for chronic venous ulcers infected by multi-drug-resistant organisms. AB - Several anaesthetic drugs have demonstrated antibacterial properties in vitro. Anaesthetics can primarily affect the cell wall of both susceptible and multi resistant bacteria. They may also have a synergistic effect with conventional antibiotics through an unknown mechanism. We present three cases of a chronic venous ulcer infected by multi-resistant bacteria refractory to conventional systemic antibiotics, including Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus (MRSA). Treatment with topical sevoflurane was performed for 1 month without systemic antibiotics. Patients with an MRSA infection showed progressive improvement with negative culture at the end of the treatment. Multi drug-resistant P. aeruginosa infection persisted at the end of treatment with positive culture. The local adverse events were mild and transient, including heat, pruritus and erythema. Topical sevoflurane may have an antibacterial effect on sensitive and multi-resistant strains. It can allow more complete surgical cleaning, leaving a cleaner wound with less fibrin and necrotic tissue. This decreases the bacterial colonisation and therefore the infectious risk, the bad smell and the exudation. The simultaneous use of conventional antibiotics and topical sevoflurane can have a synergistic antimicrobial effect. PMID- 28736976 TI - Living donor liver transplantation for neonatal fulminant hepatitis due to herpes simplex virus infection. AB - Although rare, ALF caused by disseminated HSV infection is associated with high mortality in the neonatal population. This condition is often diagnosed relatively late due to the absence of specific signs. We present a case involving a neonate with ALF submitted to living donor liver transplantation without a prior diagnosis. The patient had no skin or mucosal lesions, and IgM serology was negative for HSV-1 and HSV-2. Immunohistochemical staining of the liver explant was positive for herpes virus infection, and the patient subsequently received antiviral drug treatment, with a good outcome. Due to organ shortages and the rarity of the aforementioned condition, LT has seldom been reported for the treatment of ALF caused by herpes virus infection; however, LT may be the only option for neonates with fulminant hepatitis. The use of living donors in an urgent scenario is well established in Eastern countries and safely applicable for pediatric patients with ALF. PMID- 28736977 TI - Use of microbial indicators combined with environmental factors coupled with metrology tools for discrimination and classification of Luzhou-flavoured pit muds. AB - AIMS: Pit mud is essential for the quality and yield of Chinese Luzhou-flavoured liquor. A reliable and fast method based on the use of microbial indicators combined with environmental factors coupled with metrology tools is needed to discriminate and classify different maturity levels of Luzhou-flavoured pit muds. METHODS AND RESULTS: Firmicutes, Bacteroidetes, Actinobacteria, Lactobacillus, Bacillus, Methanosarcina, Methanocorpusculum, Methanoculleus and Clostridium kluyveri were microbial indicators in Luzhou-flavoured pit muds. They were detected by real-time quantitative PCR. Environmental factors investigated included moisture content, pH, total acid and ammonia nitrogen. Principal component analysis (PCA) and partial least square-discriminant analysis were employed to explore the structure of the data and construct discrimination and classification models by reduction in the data dimensionality. Pit muds were distinguished and classified as new, trend to-be aged and aged. Moisture content and pH were significantly negatively correlated with new pit mud, while pH, total acid, amino nitrogen, Firmicutes, Bacteroidetes, Actinobacteria, Methanosarcina, Methanoculleus and C. kluyveri were significantly positively correlated with aged pit mud. CONCLUSIONS: Microbial indicators combined with environmental factors coupled to metrology tools can reliably and quickly discriminate and classify different maturity levels of Luzhou-flavoured pit muds. SIGNIFICANCE AND IMPACT OF THE STUDY: Modern techniques and metrology tools verified the correctness of the traditional sensory evaluation used in controlling the quality of pit mud, and will contribute to distinguishing different maturity levels of Chinese Luzhou flavoured pit muds. PMID- 28736978 TI - CXCL8 promotes the invasion of human osteosarcoma cells by regulation of PI3K/Akt signaling pathway. AB - Chemokine cysteine-X-cysteine motif ligand 8 (CXCL8) is up-regulated in many malignancies, indicating that CXCL8 takes part in tumor progression. However, the expression and function of CXCL8 in osteosarcoma remained not fully elucidated. In this study, expressions of 12 cytokines and chemokines were measured in the serum from 12 of normal controls (NCs) and 25 of osteosarcoma patients. The human osteosarcoma cell line MG-63 was stimulated by recombinant CXCL8 to further analyze invasion, proliferation, apoptosis, cell cycles, cytokine secretions, and signaling pathways. We found that serum concentrations of CXCL8 and vascular endothelial growth factor were elevated in osteosarcoma patients in comparison with those in NCs. CXCL8 stimulation led to enhancement of invasion and suppression of late stage apoptosis in MG-63 cells. Moreover, secretions of MMPs by MG-63 cells were also increased upon stimulation. However, early stage apoptosis, proliferation, and cell cycles were not affected by CXCL8 treatment. Furthermore, CXCL8 stimulation induced elevations of phosphorylated PI3K and Akt, but not PKC or FAK. In conclusion, our findings suggested that CXCL8 enhanced the invasion and suppressed late stage apoptosis of osteosarcoma cells probably via influencing PI3K/Akt signaling pathway and elevating the expression of MMPs. CXCL8 may promote disease progression of osteosarcoma as a protumorigenic molecule, and may be served as a new therapeutic target for osteosarcoma. PMID- 28736979 TI - In vitro characteristics of Lactobacillus spp. strains isolated from the chicken digestive tract and their role in the inhibition of Campylobacter colonization. AB - Campylobacter jejuni/coli infections are the leading cause of bacterial diarrheal illnesses in humans. Many epidemiological studies indicate that improperly prepared meat from chickens that carry a high load of Campylobacter in their intestinal tracts is the key source of human infections. LAB, mainly members of the Lactococcus and Lactobacillus genera, increasingly have been tested as vehicles for the delivery of heterologous bacterial or viral antigens to animal mucosal immune systems. Thus, the objective of this study was to isolate, identify, and characterize Lactobacillus spp. strains isolated from chickens bred in Poland. Their ability to decrease the level of bird gut colonization by C. jejuni strain was also analyzed. First, the influence of the different chicken rearing systems was evaluated, especially the effect of diets on the Lactobacillus species that colonize the gut of chickens. Next, selected strains were analyzed in terms of their anti-Campylobacter activity in vitro; potential probiotic traits such as adhesion properties, bile and low pH tolerance; and their ability to grow on a defined carbon source. Given that improperly prepared chicken meat is the main source of human infection by Campylobacter, the selected strains were also assessed for their ability to inhibit Campylobacter colonization in the bird's intestine. These experiments revealed enormous physiological diversity among the Lactobacillus genus strains. Altogether, our results showed that L. plantarum strains isolated from the digestive tracts of chickens bred in Poland displayed some probiotic attributes in vitro and were able to decrease the level of bird gut colonization by C. jejuni strain. This suggests that they can be employed as vectors to deliver Campylobacter immunodominant proteins to the bird's immune system to strengthen the efficacy of in ovo vaccination. PMID- 28736981 TI - Ketoacidosis associated with SGLT2 inhibitor treatment: Analysis of FAERS data. AB - BACKGROUND: Regulatory agencies have concluded that sodium glucose cotransporter 2 (SGLT2) inhibitors lead to ketoacidosis, but published literature on this point remains controversial. METHODS: We searched the FDA Adverse Event Reporting System (FAERS) for reports of acidosis in patients treated with canagliflozin, dapagliflozin, or empagliflozin (from the date of each drug's FDA approval until May 15, 2015). We compared the number of SGLT2 inhibitor-related reports to reports of acidosis in patients treated with the 2 most commonly used DPP4 inhibitors: sitagliptin and saxagliptin. We estimated relative risks of acidosis by relating the number of reports to cumulative drug sales (a surrogate for patient exposure). RESULTS: FAERS contained 259 reports of acidosis (including 192 reports of ketoacidosis) for SGLT2 inhibitors compared with 477 reports of acidosis for DPP4 inhibitors (including 71 reports of ketoacidosis). Based on estimated patient exposure, the overall risk of developing acidosis was ~14-fold higher for SGLT2 inhibitors. Among 51 SGLT2 inhibitor-related reports with quantifiable metabolic information, 20 cases occurred in patients with type 1 diabetes (T1D), 25 in type 2 diabetes (T2D), and 6 in patients with unspecified type of diabetes. After excluding patients with T1D and focusing on patients identified as having T2D, we estimate that SGLT2 inhibitors were associated with ~7-fold increase in developing acidosis. Seventy-one percent had euglycemic ketoacidosis. CONCLUSIONS: Our results support the FDA's warning that SGLT2 inhibitors lead to ketoacidosis, as evidenced by an increased reporting rate for acidosis above that in a comparator population treated with DPP4 inhibitors. PMID- 28736982 TI - Understanding the Influence of Flow Velocity, Wall Motion Filter, Pulse Repetition Frequency, and Aliasing on Power Doppler Image Quantification. AB - OBJECTIVES: Although power Doppler imaging has been used to quantify tissue and organ vascularity, many studies showed that limitations in defining adequate ultrasound machine settings and attenuation make such measurements complex to be achieved. However, most of these studies were conducted by using the output of proprietary software, such as Virtual Organ computer-aided analysis (GE Healthcare, Kretz, Zipf, Austria); therefore, many conclusions may not be generalizable because of unknown settings and parameters used by the software. To overcome this limitation, our goal was to evaluate the impact of the flow velocity, pulse repetition frequency (PRF), and wall motion filter (WMF) on power Doppler image quantification using beam-formed ultrasonic radiofrequency data. METHODS: The setup consisted of a blood-mimicking fluid flowing through a phantom. Radiofrequency signals were collected using PRFs ranging from 0.6 to 10 kHz for 6 different flow velocities (5-40 cm/s). Wall motion filter cutoff frequencies were varied between 50 and 250 Hz. RESULTS: The power Doppler magnitude was deeply influenced by the WMF cutoff frequency. The effect of using different WMF values varied with the PRF; therefore, the power Doppler signal intensity was dependent on the PRF. Finally, we verified that power Doppler quantification can be affected by the aliasing effect, especially when using a PRF lower than 1.3 kHz. CONCLUSIONS: The WMF and PRF greatly influenced power Doppler quantification, mainly when flow velocities lower than 20 cm/s were used. Although the experiments were conducted in a nonclinical environment, the evaluated parameters are equivalent to those used in clinical practice, which makes them valuable for aiding the interpretation of related data in future research. PMID- 28736983 TI - Forgotten knowledge of the coronary-cameral connections and the rediscovery of their dynamic nature in development: The result of a misnomer, ambiguous use of nomenclature, and varied evaluation methods. PMID- 28736980 TI - Diverse roles for glycosaminoglycans in neural patterning. AB - The nervous system coordinates the functions of most multicellular organisms and their response to the surrounding environment. Its development involves concerted cellular interactions, including migration, axon guidance, and synapse formation. These processes depend on the molecular constituents and structure of the extracellular matrices (ECM). An essential component of ECMs are proteoglycans, i.e., proteins containing unbranched glycan chains known as glycosaminoglycans (GAGs). A defining characteristic of GAGs is their enormous molecular diversity, created by extensive modifications of the glycans during their biosynthesis. GAGs are widely expressed, and their loss can lead to catastrophic neuronal defects. Despite their importance, we are just beginning to understand the function and mechanisms of GAGs in neuronal development. In this review, we discuss recent evidence suggesting GAGs have specific roles in neuronal patterning and synaptogenesis. We examine the function played by the complex modifications present on GAG glycans and their roles in regulating different aspects of neuronal patterning. Moreover, the review considers the function of proteoglycan core proteins in these processes, stressing their likely role as co-receptors of different signaling pathways in a redundant and context-dependent manner. We conclude by discussing challenges and future directions toward a better understanding of these fascinating molecules during neuronal development. Developmental Dynamics 247:54-74, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 28736984 TI - Randomized, double-blinded, placebo-controlled pilot study on the effects of topical blackcurrant emulsion enriched in essential fatty acids, ceramides and 18 beta glycyrrhetinic acid on clinical signs and skin barrier function in dogs with atopic dermatitis. AB - BACKGROUND: Lipid-based emulsions can be useful for the management of canine atopic dermatitis (cAD). 18-beta glycyrrhetinic acid (GRA), a component of liquorice root, has anti-inflammatory and anti-pruritic effects. HYPOTHESIS/OBJECTIVES: To evaluate the effects of a topical lipid emulsion containing ceramides, fatty acids and GRA on clinical signs of cAD and skin barrier in a randomized, double-blinded, placebo-controlled trial. METHODS: Client owned (n = 45) dogs with nonseasonal, mild/moderate AD, received either treatment or placebo for three months. Skin lesions, pruritus, transepidermal water loss (TEWL) and global assessment (GA) were evaluated. RESULTS: Fourteen dogs receiving treatment and 14 receiving the placebo completed the study. After one month >=50% reduction in pruritus was seen in seven of 14 dogs (50%) in the Treatment group, and in two of 14 dogs (14.3%) in the Control group (P = 0.047). After two and three months, significant reduction in pruritus was not seen. For Canine Atopic Dermatitis Extent and Severity Index (CADESI), TEWL and GA, there were no significant findings over time or between groups. CONCLUSIONS AND CLINICAL RELEVANCE: The emulsion had some transient beneficial clinical effects. However, it was not effective in controlling pruritus as a monotherapy. Further studies should examine whether owner compliance was a factor in the steady decline of effect on pruritus scores. Further studies evaluating its role as an adjunctive therapy are indicated. PMID- 28736985 TI - Conducting Polymers Crosslinked with Sulfur as Cathode Materials for High-Rate, Ultralong-Life Lithium-Sulfur Batteries. AB - Low electrical conductivity and a lack of chemical confinement are two major factors that limit the rate performances and cycling stabilities of cathode materials in lithium-sulfur (Li-S) batteries. Herein, sulfur is copolymerized with poly(m-aminothiophenol) (PMAT) nanoplates through inverse vulcanization to form the highly crosslinked copolymer cp(S-PMAT) in which approximately 80 wt % of the feed sulfur is bonded chemically to the thiol groups of PMAT. A cp(S PMAT)/C-based cathode exhibits a high discharge capacity of 1240 mAh g-1 at 0.1 C and remarkable rate capacities of 880 mAh g-1 at 1 C and 600 mAh g-1 at 5 C. Moreover, it can retain a capacity of 495 mAh g-1 after 1000 deep discharge charge cycles at 2 C; this corresponds to a retention of 66.9 % and a decay rate of only 0.040 % per cycle. Such a remarkable rate performance is attributed to the highly conductive pathways of PMAT nanoplates, and the excellent cycling stability is ascribed mainly to the chemical confinement of sulfur through a large number of stable covalent bonds between sulfur and the thiol groups of PMAT. The results suggest that this strategy is a viable paradigm for the design and engineering of conducting polymers with reactive functional groups as effective electrode materials for high-performance Li-S batteries. PMID- 28736986 TI - Adolescent body mass index and risk of colon and rectal cancer in a cohort of 1.79 million Israeli men and women: A population-based study. AB - BACKGROUND: This study examined the association between the body mass index (BMI) in late adolescence and the risk of colon and rectal cancer. METHODS: This study analyzed a cohort of 1,087,358 Jewish men and 707,212 Jewish women who underwent health examinations at the ages of 16 to 19 years between 1967 and 2002 and were followed by linkage to the national cancer registry up to 2012. Cox regression was used to estimate hazard ratios (HRs) for cancer according to age- and sex adjusted BMI percentiles from the US Centers for Disease Control and Prevention (overweight, 85th percentile to <95th percentile; obesity, >=95th percentile). RESULTS: Over a median follow-up of 23 years, 2967 incidence cases of colorectal cancer, including 1977 among men (1403 in the colon and 574 in the rectum) and 990 among women (764 in the colon and 226 in the rectum), were identified. Overweight and obesity were associated with the risk for colon cancer among both men (HR for overweight, 1.53; 95% confidence interval [CI], 1.28-1.84; HR for obesity, 1.54; 95% CI, 1.15-2.06; statistically significant from a BMI of 23.4 kg/m2 [spline analysis]) and women (HR for overweight, 1.54; 95% CI, 1.22-1.93; HR for obesity, 1.51; 95% CI, 0.89-2.57; significant from a BMI of 23.6 kg/m2 ). Obesity, but not overweight, was associated with a risk for rectal cancer among men (HR, 1.71; 95% CI, 1.11-2.65; significant from a BMI of 29.6 kg/m2 ) and women (HR, 2.03; 95% CI, 0.90-4.58; significant from a BMI of 30.6 kg/m2 ). CONCLUSIONS: Being overweight or obese in adolescence was associated with an increased risk of subsequent colon cancers in men and women, whereas obesity was associated with rectal cancer. Cancer 2017;123:4022-30. (c) 2017 American Cancer Society. PMID- 28736988 TI - 'Hypoxia-inducible factor 1-alpha does not regulate osteoclastogenesis but enhances bone resorption activity via prolyl-4-hydroxylase 2'. PMID- 28736987 TI - Cardiac stress MRI evaluation of anomalous aortic origin of a coronary artery. AB - Myocardial ischemia is an insult that is primarily thought of in an adult population. However, there are several congenital and acquired cardiac lesions that may lead to myocardial ischemia in a pediatric population. One of the prominent congenital lesions is anomalous aortic origin of a coronary artery (AAOCA). Anomalous aortic origin of a coronary artery is one of the leading causes sudden cardiac death in pediatric and young adult patients, and thus the assessment of myocardial perfusion is of the utmost importance. Over the past decade, pharmacologic stress MRI has proven to be a highly sensitive and accurate diagnostic examination for qualifying myocardial perfusion in adults with coronary artery disease. This noninvasive imaging modality may be a useful tool in assessing the function impact of AAOCA on myocardial perfusion. PMID- 28736989 TI - Re: Long-term outcomes of transobturator tapes in women with stress urinary incontinence: E-TOT randomized controlled trial. PMID- 28736990 TI - Comparing the reported burn conditions for different severity burns in porcine models: a systematic review. AB - There are many porcine burn models that create burns using different materials (e.g. metal, water) and different burn conditions (e.g. temperature and duration of exposure). This review aims to determine whether a pooled analysis of these studies can provide insight into the burn materials and conditions required to create burns of a specific severity. A systematic review of 42 porcine burn studies describing the depth of burn injury with histological evaluation is presented. Inclusion criteria included thermal burns, burns created with a novel method or material, histological evaluation within 7 days post-burn and method for depth of injury assessment specified. Conditions causing deep dermal scald burns compared to contact burns of equivalent severity were disparate, with lower temperatures and shorter durations reported for scald burns (83 degrees C for 14 seconds) compared to contact burns (111 degrees C for 23 seconds). A valuable archive of the different mechanisms and materials used for porcine burn models is presented to aid design and optimisation of future models. Significantly, this review demonstrates the effect of the mechanism of injury on burn severity and that caution is recommended when burn conditions established by porcine contact burn models are used by regulators to guide scald burn prevention strategies. PMID- 28736991 TI - Bird beak drape technique for nose and lips ambulatory procedures. PMID- 28736992 TI - Microbiota, metabolome, and immune alterations in obese mice fed a high-fat diet containing type 2 resistant starch. AB - SCOPE: We examined the intestinal and systemic responses to incorporating a type 2 resistant starch (RS) into a high fat diet fed to obese mice. METHODS AND RESULTS: Diet-induced obese, C57BL/6J male mice were fed an HF diet without or with 20% (by weight) high-amylose maize resistant starch (HF-RS) for 6 weeks. Serum adiponectin levels were higher with RS consumption, but there were no differences in weight gain and adiposity. With HF-RS, the expression levels of ileal TLR2 and Reg3g and cecal occludin, TLR2, TLR4, NOD1 and NOD2 were induced; whereas colonic concentrations of the inflammatory cytokine IL-17A declined. The intestinal, serum, liver, and urinary metabolomes were also altered. HF-RS resulted in lower amino acid concentrations, including lower serum branched chain amino acids, and increased quantities of urinary di/trimethylamine, 3 indoxylsulfate, and phenylacetylglycine. Corresponding to these changes were enrichments in Bacteroidetes (S24-7 family) and certain Firmicutes taxa (Lactobacillales and Erysipelotrichaceae) with the HF-RS diet. Parabacteroides and S24-7 positively associated with cecal maltose concentrations. These taxa and Erysipelotrichaceae, Allobaculum, and Bifidobacterium were directly correlated with uremic metabolites. CONCLUSION: Consumption of RS modified the intestinal microbiota, stimulated intestinal immunity and endocrine-responses, and modified systemic metabolomes in obese mice consuming an otherwise obesogenic diet. PMID- 28736993 TI - Molecular characterization of Streptococcus pneumoniae, particularly serotype19A/ST320, which emerged in Krasnoyarsk, Russia. AB - Streptococcus pneumoniae, a common human pathogen, colonizes the nasopharynx and causes diseases including acute otitis media (AOM). Herein, pneumococcal serotype distributions in children before and after PCV7 vaccination and in patients with pneumococcal disease in Siberian Russia (Krasnoyarsk) are reported. Analyses included antimicrobial susceptibility testing, sequence typing (ST), pulsed field gel electrophoresis, virulence-related surface protein gene (VSG) typing with novel primers and structural analysis by scanning electron microscopy. In healthy children (HC) prior to administration of PCV7, drug-susceptible serotype23F/ST1500 was a major pneumococcal genotype. In the PCV7 trial, multidrug-resistant serotype19A/ST320 emerged in vaccinees after PCV7, exhibiting a PCV7-induced serotype replacement. Multidrug-resistant serotype19A/ST320 was evident in patients with AOM. Community-acquired pneumonia (CAP) isolates showed genetic similarities to the AOM (ST320) genotype, constituting a common non invasive AOM-CAP group. In contrast, meningitis isolates were more divergent. Overall, 25 ST types were identified; five (20%) of which were Krasnoyarsk native. Regarding VSGs, PI-1 (rlrA/rrgB), PI-2 (pitA/B), psrP and cbpA were present at 54.3%, 38.6%, 48.6%, and 95.7%, respectively, with two major VSG content types, PI-1- /PI-2- /psrP+ /cbpA+ and PI-1+ /PI-2+ /psrP- /cbpA+ , being found for HC and non-invasive diseases, respectively. A major clone of serotype19A/ST320 (PI-1+ /PI-2+ ) produced the longest pneumococcal wire (pilus) structures in colonies. ST1016 (PI-1- /PI-2- ) in HC had HEp-2 cell-adherent pili. These results suggest that serotype19A/ST320 and related genotypes, with the VSG content type PI-1+ /PI-2+ /psrP- /cbpA+ , emerged in vaccinees after PCV7 in Siberia, accompanying diseases in non-vaccinated children, and that some genotypes (serotypes19A/ST320 and 18/ST1016) produced novel pneumococcal structures, predicting their roles in colony formation and adherence. PMID- 28736994 TI - Intraoperative hemodynamic factors predicting early postoperative renal function in pediatric kidney transplantation. AB - BACKGROUND: The anesthetic management of kidney transplantation in children remains somewhat empirical. The goal of the present study was to investigate intraoperative hemodynamic factors affecting posttransplantation kidney function. METHODS: We performed a retrospective analysis of data from patients undergoing kidney transplantation in our pediatric teaching hospital from 2000 to 2014. Data collected included: donor and recipient demographic data, recipient comorbidities, fluids administered intraoperatively, and intraoperative blood pressure and central venous pressure. The main outcome of the study was the creatinine clearance at day 1 corrected to a body surface area of 1.73 m2. Analysis was performed using Classification Tree Analysis with 10-fold cross validation. RESULTS: One hundred and two patients were included. The following predictors of increased postoperative creatinine clearance at day 1 were identified: decreasing recipient weight, mean blood pressure-to-weight ratio 10 minutes after reperfusion, reduced cold ischemia duration, and increased intraoperative albumin infusion. Increased creatinine clearance was observed when mean blood pressure-to-weight ratio 10 minutes after reperfusion was >=4.3 in patients weighing 13-21 kg and >=2.5 in those >=22 kg. Overall, the model explained 64% (and at cross-validation 60%) of creatinine clearance variability at day 1. CONCLUSION: Intraoperative hemodynamics during kidney transplantation should be optimized in order to increase mean blood pressure according to values indicated by our analyses. Cold ischemia duration should be shortened as far as possible. PMID- 28736995 TI - Controlled Exposure of Bioactive Growth Factor in 3D Amyloid Hydrogel for Stem Cells Differentiation. AB - Amyloid based hydrogels can mimic the extracellular matrix and serve as matrices for tissue engineering both in vitro and in vivo. A pH responsive self-assembled amyloid hydrogel system is used to encapsulate various growth factors for driving stem cell differentiation toward neuronal lineage. Diffusion studies with fluorescence recovery after photobleaching and bulk release with the model protein fluorescein isothiocyanate-bovine serum albumin show that encapsulated protein molecules can be released in a sustained fashion from the hydrogel over a considerable period of time (30 d). Moreover, by modulating the porosity of the hydrogel by the simple addition of salt, the encapsulated protein molecules can be retained for a longer period of time within the hydrogel. Mesenchymal stem cells, when cultured in 3D amyloid hydrogels with growth factors fibroblast growth factor 8 and sonic hedgehog, show more neuron specific differentiation as compared to hydrogel alone. This higher differentiation potential of growth factor encapsulated amyloid hydrogels can be due to concomitant exposure of cells to biomechanical as well as biochemical cues during the course of differentiation. The present study suggests that amyloid based hydrogel can be exploited for controlled growth factor delivery as well as directed stem cell differentiation to neuron. PMID- 28736996 TI - Phytochemical Investigation, Antitumor Activity, and Hepatoprotective Effects of Acrocarpus fraxinifolius Leaf Extract. AB - Preclinical Research Nine known phenolic compounds were isolated from an aqueous methanolic extract of Acrocarpus fraxinifolius Weight and Arn leaves (AFL) family Fabaceae. This extract of AFL contained approximately 169 mg gallic acid/g as assessed by HPLC. The AFL extract had marginal antitumor activity (IC50 > 200 uL/mL) but showed a concentration-dependent hepatoprotective effect against CCl4 induced hepatotoxicity in vitro. Cell viability was increased, ALT and AST activity declined and reduced GSH concentration and SOD activity were restored as compared with silymarin. In vivo concurrent administration of AFL extract (500 mg/kg po) showed a hepatoprotective effect against gamma irradiation and CCl4 as evidenced by reduction of TNF-alpha, interleukin-6, malondialdehyde, nitric oxide, DNA fragmentation, caspase-3 activity, and downregulation of its m-RNA level and decreased proapoptotic protein Bax expression. AFL extract enhanced glutathione peroxidase, superoxide dismutase, and catalase activities, reduced glutathione concentrations and upregulated the expression of antiapoptotic Bcl-2. The extract could ameliorate hepatic injuries induced by gamma irradiation and CCl4 in rats suggesting potent hepatoprotective activity. Drug Dev Res 78 : 210 226, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28736997 TI - Distinct histopathologic features of radiation-induced chronic sinusitis. AB - BACKGROUND: Chronic rhinosinusitis (CRS) is a commonly observed sequela after radiation therapy to the paranasal sinuses. The histopathologic features of radiation-induced CRS have yet to be determined and may have major implications in disease management. METHODS: A structured histopathology report was utilized to analyze sinus tissue removed during functional endoscopic sinus surgery (FESS). Histopathology variables, Lund-Mackay score (LMS), and 22-item Sino-Nasal Outcome Test (SNOT-22) scores were compared among patients with radiation-induced CRS (CRSr), CRS without nasal polyps (CRSsNP), and CRS with nasal polyps (CRSwNP). RESULTS: Fifteen CRSr, 43 CRSsNP, and 56 CRSwNP patients who underwent FESS were analyzed. Compared with CRSsNP, CRSr cases had increased squamous metaplasia (40.0% vs 9.3%, p < 0.013) and subepithelial edema (53.3% vs. 2.3%, p < 0.001). Compared with CRSwNP, CRSr cases had fewer eosinophils per high-power field (20.0% vs 50.0%, p < 0.034), less basement membrane thickening (33.3% vs 76.8%, p < 0.002), and fewer eosinophil aggregates (0.0% vs 30.4%, p < 0.009). CRSr had significantly greater mean LMS (13.47 +/- 5.13 vs 7.07 +/- 4.79, p < 0.001) compared with CRSsNP. CONCLUSION: Radiation-induced CRS patients exhibited greater squamous metaplasia and subepithelial edema when compared with a cohort of patients with CRSsNP, and decreased eosinophilia and basement membrane thickening compared with a cohort of CRSwNP patients. CRSr cases demonstrated no difference in eosinophilia or neutrophilia compared with CRSsNP, and decreased eosinophilia compared with CRSwNP, lending further credence to the unique nature of radiation in the development of CRS in this patient group. These findings may have major implications with regard to extent of surgical intervention and medical management. PMID- 28736999 TI - Regulatory T cell subsets in peripheral blood of celiac disease patients and TLR2 expression: correlation with oxidative stress. AB - The study was carried out to study expression of Toll like receptors 2 (TLR2), natural/inducible Treg and Interferon-gamma alongside oxidative stress and understand their significance in pediatric samples. Influence of oxidative stress on Celiac Disease was analysed by evaluating lipid peroxidation, reduced glutathione, Glutathione peroxidase, etc. A comparison was performed among CD patients, CD patients on gluten free diet (GFD), and healthy controls. Peripheral nTregs exhibited a similar pattern of reduced numbers in CD and GFD cases when compared to healthy controls. On the other hand, inducible Tregs were much lower in GFD patients as compared to CD patients. Expression of TLR2 on iTregs was elevated in CD and GFD, however, expression on nTregs was unaltered in all the three groups. The inflammatory cytokine IFN-gamma positive Treg cells were found to be elevated in CD as compared to control group. Oxidative stress was elevated in CD as compared to healthy controls while that in GFD samples was lower in comparison to CD. The levels of LPO, activities of enzymes SOD and Catalase were higher in CD and GFD samples when compared to controls. However, enzyme Glutathione peroxidase and reduced glutathione levels declined in both CD and GFD groups as compared to controls. This report highlights the effect of elevated oxidative stress in CD on reduced traffic of iTregs toward periphery. A strong correlation was observed between the cytokine IFN-gamma and TLR2 expression in movement of iTregs in CD patients. PMID- 28736998 TI - Evasin-displaying lactic acid bacteria bind different chemokines and neutralize CXCL8 production in Caco-2 cells. AB - Chemokines are key signals in the immune system and play an important role as proinflammatory mediators in the pathology of inflammatory bowel disease and colorectal cancer, making them an important target for therapy. Recombinant lactic acid bacteria (LAB) were engineered to bind CC and CXC chemokines by displaying chemokine-binding proteins evasin-1, evasin-3 and evasin-4 on their surface. Evasin genes were cloned into lactococcal surface display vector and overexpressed in L. lactis NZ9000 and NZ9000DeltahtrA in fusion with secretion signal and surface anchor. Evasin-displaying bacteria removed from 15% to 90% of 11 different chemokines from the solution as determined with ELISA and Luminex multiplexing assays, whereby L. lactis NZ9000DeltahtrA proved more efficient. Lactobacillus salivarius ATCC 11741 was coated with L. . lactis-expressed evasin fusion protein, and its ability to bind chemokines was also confirmed. Evasin-3 displaying L. lactis removed 76.0% of IL-1beta-induced CXCL8 from the supernatant of Caco-2 epithelial cells. It also prevented secretion of CXCL8 from Caco-2 cells in a time-dependent manner when added before induction with IL-1beta. Evasin-displaying LAB have the ability to bind multiple chemokines simultaneously and exert synergistic activity. This innovative treatment approach therefore has the potential for mucosal therapy of inflammatory bowel disease or colorectal cancer. PMID- 28737000 TI - Chemoprofile and functional diversity of fungal and bacterial endophytes and role of ecofactors - A review. AB - Endophytes represent a hidden world within plants. Almost all plants that are studied harbor one or more endophytes, which help their host to survive against pathogens and changing adverse environmental conditions. Fungal and bacterial endophytes with distinct ecological niches show important biological activities and ecological functions. Their unique physiological and biochemical characteristics lead to the production of niche specific secondary metabolites that may have pharmacological potential. Identification of specific secondary metabolites in adverse environment can also help us in understanding mechanisms of host tolerance against stress condition such as biological invasions, salt, drought, temperature. These metabolites include micro as well as macromolecules, which they produce through least studied yet surprising mechanisms like xenohormesis, toxin-antitoxin system, quorum sensing. Therefore, future studies should focus on unfolding all the underlying molecular mechanisms as well as the impact of physical and biochemical environment of a specific host over endophytic function and metabolite elicitation. Need of the hour is to reshape the focus of research over endophytes and scientifically drive their ecological role toward prospective pharmacological as well as eco-friendly biological applications. This may help to manage these endophytes especially from untapped ecoregions as a useful undying biological tool to meet the present challenges as well as lay a strong and logical basis for any impending challenges. PMID- 28737001 TI - Papules on the arms and renal cell carcinoma. PMID- 28737002 TI - Nanofiltration-Enabled In Situ Solvent and Reagent Recycle for Sustainable Continuous-Flow Synthesis. AB - Solvent usage in the pharmaceutical sector accounts for as much as 90 % of the overall mass during manufacturing processes. Consequently, solvent consumption poses significant costs and environmental burdens. Continuous processing, in particular continuous-flow reactors, have great potential for the sustainable production of pharmaceuticals but subsequent downstream processing remains challenging. Separation processes for concentrating and purifying chemicals can account for as much as 80 % of the total manufacturing costs. In this work, a nanofiltration unit was coupled to a continuous-flow rector for in situ solvent and reagent recycling. The nanofiltration unit is straightforward to implement and simple to control during continuous operation. The hybrid process operated continuously over six weeks, recycling about 90 % of the solvent and reagent. Consequently, the E-factor and the carbon footprint were reduced by 91 % and 19 %, respectively. Moreover, the nanofiltration unit led to a solution of the product eleven times more concentrated than the reaction mixture and increased the purity from 52.4 % to 91.5 %. The boundaries for process conditions were investigated to facilitate implementation of the methodology by the pharmaceutical sector. PMID- 28737003 TI - Facilitators and barriers of participation in a longitudinal research on migrant families in Badalona (Spain): A qualitative approach. AB - Migrant populations are under-represented in health research. We conducted a community-based qualitative study with the aim to examine the willingness, barriers, facilitators and reasons for participating in longitudinal health research among migrants. In Badalona and Santa Coloma de Gramanet (Barcelona) from May to November 2014, 26 individual interviews and 8 discussion groups were conducted with a convenience sample of 76 migrants born in Colombia, Peru, Ecuador, Bolivia, Morocco, Pakistan and China; and 9 key informants. Grounded Theory methods and thematic analysis was used to analyse the data. Atlas-ti(R) software was used. Participants were willing to participate in health surveys and biological samples testing, and agreed to be re-contacted after 12 months. Participants agreed to the same participation for their children. Participants reported that undertaking biological samples and knowledge of the health status of their children were the greatest benefits of participation in health research. Barriers to participation reported by participants were language difficulties, time constraints and mobility issues. Facilitators of participation included offering complete and understandable information about the study objectives and procedures; offering interviewers with the same migrant background, gender, country of origin and socioeconomic status as participants; building trust through ensuring proximity, privacy and confidentiality; respecting cultural relationships; and receiving monetary compensation and test results. Focusing on migrant families instead of individuals may facilitate participation in the study. Despite being beneficial in general, receipt of monetary compensation, inclusion of questions related to sexual and reproductive health, and blood sample testing resulted in distrust for a small number of participants. The simultaneous use of several Internet tools was the most recommended tool for re contact. Those with higher risk of mobility, greater language barriers and less Internet use were more difficult to re-contact. Study findings will help to improve participation and retention of migrants in longitudinal research. PMID- 28737004 TI - Parent-child interactions and children with cerebral palsy: An exploratory study investigating emotional availability, functional ability, and parent distress. AB - BACKGROUND: Emotionally available parent-child relationships are supportive of child health and development. When a child has cerebral palsy, a range of child and parent factors can potentially impact the parent-child relationship; however, little research has specifically addressed this question. The aim of this study is to investigate links between parent-child emotional availability and both child functional abilities and parent distress in a sample of parents and children with cerebral palsy. METHODS: Twenty-three mothers (mean age 37.3+/-5.7 years) and their children (mean age 4.9+/-3.3 years) with cerebral palsy completed a 20 min videoed parent-child interaction, scored using the Emotional Availability Scales. Parents also completed the Depression Anxiety Stress Scale, the Paediatric Evaluation of Disability Inventory, and the Strengths and Difficulties Questionnaire. Correlational analyses were conducted, and qualitative observations were made. RESULTS: Parent-child dyads in which the parent reported depressive symptoms scored poorer on all aspects of parent-child emotional availability. Where parents reported experiencing anxiety or stress, increased parent hostility and decreased child responsiveness was found. There was no relationship between child functional abilities and either parent distress or parent-child emotional availability. Parent sensitivity, structuring, and nonintrusiveness were negatively associated with child peer problems. Both child responsiveness and child involvement were negatively associated with hyperactivity/inattention. Observations of video footage suggested that parent implementation of therapy strategies impacted negatively on parent-child emotional availability for some dyads. CONCLUSION: Findings from this study are consistent with the wider literature showing a link between parental depression and the parent-child relationship and extend this link to the cerebral palsy population. The importance of routine screening for parental mental health problems in early childhood intervention is highlighted by these findings. In addition, this study emphasizes the need to better understand how therapists support parents to implement therapeutic strategies to minimize negative impact on the developing parent-child relationship. PMID- 28737005 TI - Atomically Precise Gold Nanoclusters Accelerate Hydrogen Evolution over MoS2 Nanosheets: The Dual Interfacial Effect. AB - Hydrogen generation via electrocatalytic water splitting holds great promise for future energy revolution. It is desirable to design abundant and efficient catalysts and achieve mechanistic understanding of hydrogen evolution reaction (HER). Here, this paper reports a strategy for improving HER performance of molybdenum disulfide (MoS2 ) via introducing gold nanoclusters as a cocatalyst. Compared to plain MoS2 nanosheets, the Au25 (SR)18 /MoS2 nanocomposite exhibits enhanced HER activity with a small onset potential of -0.20 V (vs reversible hydrogen electrode) and a higher current density of 59.3 mA cm-2 at the potential of -0.4 V. In addition to the interfacial interaction between nanoclusters and MoS2 , the interface between the Au25 core and the surface ligands (thiolate vs selenolate) is also discovered to distinctly affect the catalytic performance. This work highlights the promise of metal nanoclusters in boosting the HER performance via tailoring the interfacial electronic interactions between gold nanoclusters and MoS2 nanosheets, as well as the interface between metal core and surface ligands. PMID- 28737006 TI - Unrecognized viral infections and chromosome abnormalities as a cause of fetal death - examination with fluorescence in situ hybridization, immunohistochemistry and polymerase chain reaction. AB - Fifteen to 50% of fetal deaths remain unexplained after post-mortem examination depending on inclusion criteria and classification systems. Our aim was to examine a selection of unexplained fetal deaths in order to investigate whether any common chromosome aberrations or viral infections were present. Reports from 351 fetal autopsies performed at the Department of Pathology and Medical Genetics at St. Olavs University Hospital from 2001 through 2010 were reviewed. Of these, 105 fetal deaths were classified as unexplained. Tissue samples from 30 cases were further examined with fluorescence in situ hybridization (FISH) to detect abnormalities in chromosomes 13, 18, and 21. The samples were also examined with immunohistochemistry (IHC) and polymerase chain reaction (PCR) to detect infections with cytomegalovirus, parvovirus B19, herpes simplex virus 1 and 2, enterovirus, and parechovirus. In two cases, a possible trisomy 13 mosaicism was found. No viruses were detected. In our selection of 30 unexplained cases, possible trisomy 13 mosaicism was found in two cases, and no viruses were detected. High degree of maceration and missing placental examination often complicate the investigation of fetal death, and extensive ancillary examinations do not necessarily contribute to a more specific diagnosis. PMID- 28737007 TI - Evaluating the efficacy of pentoxifylline in the treatment of oral submucous fibrosis: A meta-analysis. AB - Oral submucous fibrosis (OSMF), a potentially malignant oral cavity disorder that causes speech and mastication problems, lacks an established treatment regimen; moreover, no treatment can effectively reverse the course of OSMF. A meta analysis was conducted to investigate the efficacy of the peripheral vasodilator, pentoxifylline, in the treatment of OSMF. We searched five different databases for studies meeting our eligibility criteria (up to June 30, 2017). Statistical analyses were performed using RevMan 5.3 software. Three randomized controlled trials (247 OSMF patients) were selected. Pentoxifylline increased the objective sign maximal mouth opening (MMO; WMD: -4.59, 95% CI: -8.65, -0.53; p < 0.05) following short-term (under 1 month; WMD: -1.94, 95% CI: -3.12, -0.77; p < 0.05) and long-term (over 1 month; WMD: -5.44, 95% CI: -6.81, -4.07; p < 0.05) application. Pentoxifylline improved the subjective symptom burning sensation (WMD: -0.11, 95% CI: -0.17, -0.05; p < 0.05) only following long-term application (WMD: 0.42, 95% CI: 0.18, 0.96; p < 0.05). The efficacy on MMO and burning sensation increased with time. Although OSMF lacks definitive treatment modalities, our meta-analysis shows that pentoxifylline effectively improves the objective signs and subjective symptoms of OSMF and its therapeutic efficacy increases with time. PMID- 28737008 TI - Design and Synthesis of 4-Alkylidene-beta-lactams: Benzyl- and Phenethyl carbamates as Key Fragments to Switch on Antibacterial Activity. AB - The emergence of multidrug-resistant bacterial strains is particularly important in chronic pathologies such as cystic fibrosis (CF), in which persistent colonization and selection of resistant strains is favored by the frequent and repeated use of antibacterial agents. Staphylococcus aureus is a common pathogen in CF patients that has an associated increased multidrug resistance. In previous studies we demonstrated that the presence of a 4-alkylidene side chain directly linked to a beta-lactam appeared to strengthen the potency against S. aureus, especially against methicillin-resistant S. aureus (MRSA) strains. In the present study, 21 new 4-alkylidene-beta-lactams were synthesized and evaluated for antibacterial activity. We designed the new compounds to have aryl, benzyl, or phenethyl-carbamate groups on the C3 hydroxyethyl side chain. We found a correlation between biological activity and the nitrogen substituent of the carbamate group, and two phenethyl-carbamate beta-lactams were shown to be valuable antibacterial agents against selected linezolid-resistant strains, with a minimum inhibitory concentrations of 2-4 mg L-1 . PMID- 28737009 TI - Non-additive stabilization by halogenated amino acids reveals protein plasticity on a sub-angstrom scale. AB - It has been a long-standing goal to understand the structure-stability relationship of proteins, as optimal stability is essential for protein function and highly desirable for protein therapeutics. Halogenation has emerged as a minimally invasive strategy to probe the physical characteristics of proteins in solution, as well as enhance the structural stabilities of proteins for therapeutic applications. Although advances in synthetic chemistry and genetic code expansion have allowed for the rapid synthesis of proteins with diverse chemical sequences, much remains to be learned regarding the impact of these mutations on their structural integrity. In this contribution, we present a systematic study of three well-folded model protein systems, in which their structural stabilities are assessed in response to various hydrogen-to-halogen atom mutations. Halogenation allows for the perturbation of proteins on a sub angstrom scale, offering unprecedented precision of protein engineering. The thermodynamic results from these model systems reveal that in certain cases, proteins can display modest steric tolerance to halogenation, yielding non additive consequences to protein stability. The observed sub-angstrom sensitivity of protein stability highlights the delicate arrangement of a folded protein core structure. The stability data of various halogenated proteins presented herein should also provide guidelines for using halogenation as a strategy to improve the stability of protein therapeutics. PMID- 28737010 TI - Carbonate ooids of the Mesoarchaean Pongola Supergroup, South Africa. AB - Ooids from the Mesoarchaean Chobeni Formation, Pongola Supergroup, KwaZulu-Natal, South Africa are older than any ooids reported to date. They are made of dolomite and ankerite and show concentric, radial-concentric, micritic, and radial fabrics. Radial ooids are interpreted to have originated from high-Mg-calcite and probably formed by microbial activity in a low-energy regime, while concentric ooids had an aragonite precursor and formed biotically under agitated/high-energy environmental conditions. Micritic ooids formed via the recrystallization of concentric ooids. Ooids and other allochems, such as intraclasts and peloids, contain carbonaceous matter. The close association of carbonaceous matter within ooid cortices with metabolically important elements, such as N, S and P, as identified by nano-scale secondary ion mass spectrometry analysis, allows us to propose a biologically induced origin for some ooids. By analogy with modern examples, a variety of microbial communities probably played a role in carbonate precipitation and ooid formation. Shale-normalized rare earth element (REE) distribution patterns of ooids and other allochems show positive LaSN , GdSN and YSN anomalies, superchondritic Y/Ho ratios and depleted light rare earth elements (LREEs) relative to the heavy rare earth elements (HREEs), which resemble those of seawater. These anomalies are less pronounced than expected for an open marine setting, which is interpreted as evidence for deposition in restricted shallow marine environments. Non-seawater REE patterns in recrystallized matrix and pore- and vein-filling carbonate likely reflect redistribution of rare earth elements during post-depositional alteration and/or reflect differences in the elemental and REE compositions of diagenetic fluids. PMID- 28737011 TI - A distinctive patchy osteomalacia characterises Phospho1-deficient mice. AB - The phosphatase PHOSPHO1 is involved in the initiation of biomineralisation. Bones in Phospho1 knockout (KO) mice show histological osteomalacia with frequent bowing of long bones and spontaneous fractures: they contain less mineral, with smaller mineral crystals. However, the consequences of Phospho1 ablation on the microscale structure of bone are not yet fully elucidated. Tibias and femurs obtained from wild-type and Phospho1 null (KO) mice (25-32 weeks old) were embedded in PMMA, cut and polished to produce near longitudinal sections. Block surfaces were studied using 20 kV backscattered-electron (BSE) imaging, and again after iodine staining to reveal non-mineralised matrix and cellular components. For 3D characterisation, we used X-ray micro-tomography. Bones opened with carbide milling tools to expose endosteal surfaces were macerated using an alkaline bacterial pronase enzyme detergent, 5% hydrogen peroxide and 7% sodium hypochlorite solutions to produce 3D surfaces for study with 3D BSE scanning electron microscopy (SEM). Extensive regions of both compact cortical and trabecular bone matrix in Phospho1 KO mice contained no significant mineral and/or showed arrested mineralisation fronts, characterised by a failure in the fusion of the calcospherite-like, separately mineralising, individual micro volumes within bone. Osteoclastic resorption of the uncalcified matrix in Phospho1 KO mice was attenuated compared with surrounding normally mineralised bone. The extent and position of this aberrant biomineralisation varied considerably between animals, contralateral limbs and anatomical sites. The most frequent manifestation lay, however, in the nearly complete failure of mineralisation in the bone surrounding the numerous transverse blood vessel canals in the cortices. In conclusion, SEM disclosed defective mineralising fronts and extensive patchy osteomalacia, which has previously not been recognised. These data further confirm the role of this phosphatase in physiological skeletal mineralisation. PMID- 28737012 TI - Practical Ways to Achieve Targets in Diabetes Care 2017. AB - Ann M. Carracher, Payal H. Marathe, and Kelly L. Close are of Close Concerns (http://www.closeconcerns.com), a healthcare information company focused exclusively on diabetes and obesity care. Close Concerns publishes Closer Look, a periodical that brings together news and insights in these areas. Each month, the Journal of Diabetes includes this News feature, in which Carracher, Marathe, and Close review the latest developments relevant to researchers and clinicians. PMID- 28737013 TI - Anatomic variations of neck vessels and the course of pediatric internal jugular veins. AB - BACKGROUND: Landmark-guided internal jugular vein cannulation is difficult for pediatric patients but useful, especially when ultrasound equipment is unavailable. Therefore, it is important to define the adjacent anatomic characteristics of the pediatric internal jugular vein. METHODS: In 210 children the course of the internal jugular vein, and common carotid and vertebral arteries was measured from the level of the cricoid cartilage to the supraclavicular area using ultrasound. RESULTS: From the level of the cricoid cartilage to the supraclavicular area, vessel diameter increased with internal jugular vein increasing by 12%, and common carotid and vertebral arteries increasing by 5% each. From the level of the cricoid cartilage to the supraclavicular area, the number of patients with a medial common carotid artery position relative to the internal jugular vein increased, whereas those with a lateral position decreased; the number of patients with nonoverlapped common carotid artery-internal jugular vein increased, and those with totally overlapped decreased. In contrast, the overlapping status of vertebral artery-internal jugular vein changes oppositely. More than 97.14% of the vertebral artery lies lateral to the internal jugular vein at these levels. The minimal vertebral artery-internal jugular vein depth decreased from 0.46+/-0.20 to 0.37+/-0.19 cm. The angle from the internal jugular vein line to the horizontal line of the body was 83.35+/-9.04 degrees. CONCLUSION: The common carotid artery and internal jugular vein are farther apart as one moves down the neck, whereas the vertebral artery and internal jugular vein are getting together. Additionally, the diameter of the internal jugular vein increased. PMID- 28737014 TI - Clinical implementation of an exit detector-based dose reconstruction tool for helical tomotherapy delivery quality assurance. AB - PURPOSE: The aim of this study was to validate the accuracy of an exit detector based dose reconstruction tool for helical tomotherapy (HT) delivery quality assurance (DQA). METHODS AND MATERIAL: Exit detector-based DQA tool was developed for patient-specific HT treatment verification. The tool performs a dose reconstruction on the planning image using the sinogram measured by the HT exit detector with no objects in the beam (i.e., static couch), and compares the reconstructed dose to the planned dose. Vendor supplied (three "TomoPhant") plans with a cylindrical solid water ("cheese") phantom were used for validation. Each "TomoPhant" plan was modified with intentional multileaf collimator leaf open time (MLC LOT) errors to assess the sensitivity and robustness of this tool. Four scenarios were tested; leaf 32 was "stuck open," leaf 42 was "stuck open," random leaf LOT was closed first by mean values of 2% and then 4%. A static couch DQA procedure was then run five times (once with the unmodified sinogram and four times with modified sinograms) for each of the three "TomoPhant" treatment plans. First, the original optimized delivery plan was compared with the original machine agnostic delivery plan, then the original optimized plans with a known modification applied (intentional MLC LOT error) were compared to the corresponding error plan exit detector measurements. An absolute dose comparison between calculated and ion chamber (A1SL, Standard Imaging, Inc., WI, USA) measured dose was performed for the unmodified "TomoPhant" plans. A 3D gamma evaluation (2%/2 mm global) was performed by comparing the planned dose ("original planned dose" for unmodified plans and "adjusted planned dose" for each intentional error) to exit detector-reconstructed dose for all three "Tomophant" plans. Finally, DQA for 119 clinical (treatment length <25 cm) and three cranio-spinal irradiation (CSI) plans were measured with both the ArcCHECK phantom (Sun Nuclear Corp., Melbourne, FL, USA) and the exit detector DQA tool to assess the time required for DQA and similarity between two methods. RESULTS: The measured ion chamber dose agreed to within 1.5% of the reconstructed dose computed by the exit detector DQA tool on a cheese phantom for all unmodified "Tomophant" plans. Excellent agreement in gamma pass rate (>95%) was observed between the planned and reconstructed dose for all "Tomophant" plans considered using the tool. The gamma pass rate from 119 clinical plan DQA measurements was 94.9% +/- 1.5% and 91.9% +/- 4.37% for the exit detector DQA tool and ArcCHECK phantom measurements (P = 0.81), respectively. For the clinical plans (treatment length <25 cm), the average time required to perform DQA was 24.7 +/- 3.5 and 39.5 +/- 4.5 min using the exit detector QA tool and ArcCHECK phantom, respectively, whereas the average time required for the 3 CSI treatments was 35 +/- 3.5 and 90 +/- 5.2 min, respectively. CONCLUSION: The exit detector tool has been demonstrated to be faster for performing the DQA with equivalent sensitivity for detecting MLC LOT errors relative to a conventional phantom-based QA method. In addition, comprehensive MLC performance evaluation and features of reconstructed dose provide additional insight into understanding DQA failures and the clinical relevance of DQA results. PMID- 28737015 TI - Co-administration of caffeine and caffeic acid alters some key enzymes linked with reproductive function in male rats. AB - This study assessed the effects of caffeine combined with caffeic acid on some biomarkers of male reproductive function using normal albino Wistar rats. Rats were divided into four groups (n = 6) and treated for seven successive days; group 1 represents the control rats; group 2 rats were treated with 50 mg/kg body weight (BW) of caffeine only; group 3 rats were treated with 50 mg/kg BW of caffeic acid, while the rats in group 4 were cotreated with an equal combination of caffeine and caffeic acid. The results revealed significant increase in reproductive hormone, testicular and epididymal nitric oxide levels of the rats. Moreover, decreased oxidative stress in the testes and epididymides of the treated rats was evidenced by significant increase in total and nonprotein thiol levels, catalase and superoxide dismutase activities. Similarly, decreased testicular cholesterol level with concomitant elevation in testicular steroidogenic enzyme activities, glycogen and zinc levels were observed in the treated rats. No morphological changes were observed as revealed by the photomicrographs from light microscopy in treated rats. Nevertheless, the combination therapy exhibited additive/synergistic effect on these biochemical indices than when they were administered singly. This study suggests the combination therapy of caffeine and caffeic acid at the dose tested for improving male reproductive function. PMID- 28737016 TI - Grade I diastolic dysfunction and elevated left ventricular end-diastolic pressure: Mitral Doppler inflow, pulmonary vein atrial reversal, and the M-mode mitral B-bump. AB - Grade I diastolic dysfunction (DD) is generally associated with a normal mean left atrial pressure (LAP) and normal left ventricular end-diastolic pressure (LVEDP). The first hemodynamic alteration seen in DD, however, is the development of an elevated LVEDP with a persistent normal LAP. This is manifested by echocardiography as a continued mitral pulsed wave (PW) E/A <0.8 (Grade I DD), but with evidence of an elevated LVEDP. Such findings include alterations in PV flow, mitral PW inflow response to Valsalva maneuver, and also the presence of a B-bump on the mitral M-mode tracing. When assessing diastolic function, it may be clinically helpful to assess for this early hemodynamic manifestation of DD. PMID- 28737017 TI - High Efficiency Nonfullerene Polymer Solar Cells with Thick Active Layer and Large Area. AB - In this work, high-efficiency nonfullerene polymer solar cells (PSCs) are developed based on a thiazolothiazole-containing wide bandgap polymer PTZ1 as donor and a planar IDT-based narrow bandgap small molecule with four side chains (IDIC) as acceptor. Through thermal annealing treatment, a power conversion efficiency (PCE) of up to 11.5% with an open circuit voltage (Voc ) of 0.92 V, a short-circuit current density (Jsc ) of 16.4 mA cm-2 , and a fill factor of 76.2% is achieved. Furthermore, the PSCs based on PTZ1:IDIC still exhibit a relatively high PCE of 9.6% with the active layer thickness of 210 nm and a superior PCE of 10.5% with the device area of up to 0.81 cm2 . These results indicate that PTZ1 is a promising polymer donor material for highly efficient fullerene-free PSCs and large-scale devices fabrication. PMID- 28737018 TI - Increased myocardial native T1 relaxation time in patients with nonischemic dilated cardiomyopathy with complex ventricular arrhythmia. AB - PURPOSE: To study the relationship between diffuse myocardial fibrosis and complex ventricular arrhythmias (ComVA) in patients with nonischemic dilated cardiomyopathy (NICM). We hypothesized that NICM patients with ComVA would have a higher native myocardial T1 time, suggesting more extensive myocardial diffuse fibrosis. MATERIALS AND METHODS: We prospectively enrolled NICM patients with a history of ComVA (n = 50) and age-matched NICM patients without ComVA (n = 57). Imaging was performed at 1.5T with a protocol that included cine magnetic resonance imaging (MRI) for left ventricular (LV) function, late gadolinium enhancement (LGE) for focal scar, and native T1 mapping for diffuse fibrosis assessment. RESULTS: Global native T1 time was significantly higher in patients with NICM with ComVA when compared to patients with NICM without ComVA (1131 +/- 42 vs. 1107 +/- 45 msec, P = 0.006), and this finding remained after excluding segments with scar on LGE (1124 +/- 36 vs. 1102 +/- 44 msec, P = 0.006). Native T1 was similar in NICM patients with and without the presence of LGE (1121 +/- 39 vs. 1117 +/- 48 msec, P = 0.68) and mildly correlated with LV end-diastolic volume index (r = 0.27, P = 0.005), LV end-systolic volume index (r = 0.24, P = 0.01), and LV ejection fraction (r = -0.28, P = 0.003). Native T1 value for each 10-msec increment was an independent predictor of ComVA (odds ratio 1.14, 95% confidence interval 1.03-1.25; P = 0.008) beyond LV function and LGE. CONCLUSION: NICM patients with ComVA have higher native T1 compared to NICM without any documented ComVA. Native myocardial T1 is independently associated with ComVA, after adjusting for LV function and LGE. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:779-786. In memoriam: The authors are grateful for Dr. Josephson's inspiring guidance and contributions to this study. PMID- 28737020 TI - Bioactive Pimarane-Type Diterpenes from Marine Organisms. AB - Marine organisms represent an abundant sources of bioactive natural products with unique chemical structure. Pimarane diterpenes are a structurally diverse family of natural products with various biological activities and pharmacological properties. A prolific source of new marine-derived pimarane diterpenes have attracted considerable interest because of their unique structural diversity and varied biological activities, including antimicrobial, antitumor, and antiproliferative activities. This review provides a comprehensive overview of the structures, names, bioactivities, and references of 80 marine-derived pimarane-type natural products for the first time. PMID- 28737019 TI - Clinical outcomes for patients presenting with N3 head and neck squamous cell carcinoma: Analysis of the National Cancer Database. AB - BACKGROUND: There is a paucity of data regarding head and neck squamous cell carcinomas (HNSCCs) and N3 nodal disease. METHODS: Retrospective analysis of patients with N3 HNSCC identified in the National Cancer Database (NCDB) was performed. RESULTS: We identified 4867 patients with N3 HNSCC treated with primary surgery or chemoradiotherapy (CRT). Propensity-adjusted median survival was 54.2 and 44.8 months for surgery and CRT, respectively (P = .06). Oropharyngeal primary subsite demonstrated a survival advantage with surgery versus CRT with propensity-adjusted median survivals of 86.0 and 61.9 months, respectively (P < .05). CONCLUSION: Management of N3 HNSCC relies largely on CRT. Patients with N3 nodal disease with nonoropharyngeal primary tumors exhibit 5 year overall survival approaching 30% independent of initial treatment modality. Patients with oropharyngeal primaries exhibit improved outcomes with surgery largely influenced by the human papillomavirus (HPV)-negative subset. These data represent the most comprehensive analysis of N3 HNSCC outcomes and serves as a foundation for future research and clinical management. PMID- 28737022 TI - Anatomic types of anomalous aortic origin of a coronary artery: A pictorial summary. AB - Anomalous aortic origin of a coronary artery is a congenital abnormality of the origin or course of a coronary artery that arises from the aorta. As commonly seen in congenital heart disease, a wide spectrum of anatomic variability is seen and hence, it is important for clinicians to document the precise anatomy and course of the anomalous vessel. This article describes coronary artery nomenclature using computerized tomography angiography and virtual angioscopy. These details are important for decision making, useful for surgical planning, and may have prognostic implications. PMID- 28737021 TI - Infection therapy: the problem of drug resistance - and possible solutions. AB - The rising antibiotic resistance in major bacterial pathogens together with the breakdown of the antibiotic discovery platform creates a critical situation for infection therapy. Recent developments reviving new antibiotic discovery from defining chemical rules for membrane-passing compounds to isolation chips for soil bacteria and exploring the human microbiome for antibiotic-producing bacteria are discussed. The potential of bacteriocins, tailocins, phage lysins, phages, probiotics and commensal blends as alternatives to antibiotics is evaluated. PMID- 28737024 TI - [Foreword : Vulnerability, a legal category applied to the field of health care] PMID- 28737023 TI - Monodispersed Bioactive Glass Nanoclusters with Ultralarge Pores and Intrinsic Exceptionally High miRNA Loading for Efficiently Enhancing Bone Regeneration. AB - Bioactive glass nanoparticles (BGNs) have attracted much attention in drug delivery and bone tissue regeneration, due to the advantages including biodegradation, high bone-bonding bioactivity, and facile large-scale fabrication. However, the wide biomedical applications of BGNs such as efficient gene delivery are limited due to their poor pore structure and easy aggregation. Herein, for the first time, this study reports novel monodispersed bioactive glass nanoclusters (BGNCs) with ultralarge mesopores (10-30 nm) and excellent miRNA delivery for accelerating critical-sized bone regeneration. BGNCs with different size (100-500 nm) are fabricated by using a branched polyethylenimine as the structure director and catalyst. BGNCs show an excellent apatite-forming ability and high biocompatibility. Importantly, BGNCs demonstrate an almost 19 times higher miRNA loading than those of conventional BGNs. Additionally, BGNCs miRNA nanocomplexes exhibit a significantly high antienzymolysis, enhance cellular uptake and miRNA transfection efficiency, overpassing BGNs and commercial Lipofectamine 3000. BGNCs-mediated miRNA delivery significantly improves the osteogenic differentiation of bone marrow stromal stem cells in vitro and efficiently enhances bone formation in vivo. BGNCs can be a highly efficient nonviral vector for various gene therapy applications. The study may provide a novel strategy to develop highly gene-activated bioactive nanomaterials for simultaneous tissue regeneration and disease therapy. PMID- 28737025 TI - [Influence of initial protocolized treatment with steroids in length of stay and costs of community acquired pneumonia]. AB - OBJECTIVE: The aim of the study was to analyze the impact of steroid treatment in patients with community acquired pneumonia (CAP), both in length of stay and economical cost of admission at a clinical university hospital. METHODS: Prospective study of admitted patients with the diagnosis of CAP, both in Internal Medicine and Infectious diseases department. The study was conducted from January to march 2015; patients receiving steroids from diagnosis to end of antibiotic treatment were classified as group I; otherwise, they were considered in group II. Administration of steroids was done according to the criteria of the responsible. Cost was stablished according to CAP Diagnostic Related Group (DRG). RESULTS: Prevalence of patients younger than 65 year-old was higher in group I (p<0.05). In bivariate analyses, mean admission time was lower in group I (5.37 vs 8.88 days) (p<0.0005) and also economical cost (2,361 euros vs 3,907 euros) (p<0.0005). In multivariate analysis, factors independently associated to higher cost (>3,520 euros) were COPD (OR=2.602; 95% CI 1.074-6.305) and group II (patients with no steroids) (OR=6.2; p=0,007). CONCLUSIONS: No administration of steroids in patients with CAP was associated, together with COPD, with higher economical cost (evaluated by DRG/length of stay). PMID- 28737026 TI - Misconceptions of Spanish general practitioners' attitudes toward the management of urinary tract infections and asymptomatic bacteriuria: an internet-based questionnaire study. AB - OBJECTIVE: The diagnosis and management of urinary tract infections (UTI) vary widely across countries and practices. The objective of this study was to gain insight into general practitioners' (GP) perceptions on the current management of UTIs and asymptomatic bacteriuria in Spain. METHODS: Cross-sectional, internet based questionnaire study answered from July to September 2013. GPs affiliated with the largest Spanish scientific society in primary care (Sociedad Espanola de Medicina Familiar y Comunitaria) were invited to participate in the study. They were asked about the tests ordered in both uncomplicated and complicated UTIs and about the management in three clinical scenarios, depicting a 50-year woman with: 1. An uncomplicated UTI, 2. A complicated UTI, and 3. An asymptomatic bacteriuria. RESULTS: The questionnaire was completed by 1,239 GPs (6.7%). Urine cultures were reportedly requested by 26.3% of the GPs in uncomplicated UTIs and by 71.8% of the cases corresponding to the complicated UTIs whereas it was declared that dipsticks were the preferred tests in only uncomplicated UTIs (38.2%). A total of 22% and 13.2% of the GPs stated that they would withhold antibiotic therapy in patients with low-count and high-count asymptomatic bacteriuria, respectively. CONCLUSIONS: GPs have important misconceptions as to the indications for ordering urine cultures and in interpreting the definitions of common UTIs and treating UTIs and asymptomatic bacteriuria. The unnecessary use of antibiotics in patients with asymptomatic bacteriuria is considerable in Spain. PMID- 28737027 TI - ? PMID- 28737028 TI - [Chapter 1. Beyond the reification of vulnerability, thinking vulnerability as the subject capability] AB - In this introduction I will draw an overview of theories associated with the notion of care from feminist studies to clinical theory by articulating the concept of vulnerability to that of capability in Amartya Sen and showing the roots of capability theory in Aristotle and anti-utilitarian theories. PMID- 28737029 TI - Progress towards measles elimination in Bangladesh, 2000-2016. PMID- 28737030 TI - Enantioselective, Palladium-Catalyzed Conjugate Additions of Arylboronic Acids to Form Bis-benzylic Quaternary Stereocenters. AB - We report enantioselective, palladium-catalyzed conjugate additions of arylboronic acids to beta-aryl, beta,beta-disubstituted enones to generate ketones containing bis-benzylic quaternary stereocenters. A catalyst generated from palladium trifluoroacetate and (S)-4-tert-butyl-2-(2-pyridyl)oxazoline ligand ((S)-t-BuPyOx) promotes conjugate additions of a wide range of arylboronic acids to a variety of beta-aryl, beta,beta-disubstituted enones. Iterative addition of the arylboronic acid to minimize undesired protodeboronation pathways leads to efficient formation of the corresponding ketones containing bis-benzylic quaternary stereocenters in up to 92% yield and up to 93% enantioselectivity. PMID- 28737032 TI - Multilayer SnSb4-SbSe Thin Films for Phase Change Materials Possessing Ultrafast Phase Change Speed and Enhanced Stability. AB - A multilayer thin film, comprising two different phase change material (PCM) components alternatively deposited, provides an effective means to tune and leverage good properties of its components, promising a new route toward high performance PCMs. The present study systematically investigated the SnSb4-SbSe multilayer thin film as a potential PCM, combining experiments and first principles calculations, and demonstrated that these multilayer thin films exhibit good electrical resistivity, robust thermal stability, and superior phase change speed. In particular, the potential operating temperature for 10 years is shown to be 122.0 degrees C and the phase change speed reaches 5 ns in the device test. The good thermal stability of the multilayer thin film is shown to come from the formation of the Sb2Se3 phase, whereas the fast phase change speed can be attributed to the formation of vacancies and a SbSe metastable phase. It is also demonstrated that the SbSe metastable phase contributes to further enhancing the electrical resistivity of the crystalline state and the thermal stability of the amorphous state, being vital to determining the properties of the multilayer SnSb4-SbSe thin film. PMID- 28737031 TI - Ubiquitin Chain Enrichment Middle-Down Mass Spectrometry (UbiChEM-MS) Reveals Cell-Cycle Dependent Formation of Lys11/Lys48 Branched Ubiquitin Chains. AB - The dynamics of cellular signaling events are tightly regulated by a diverse set of ubiquitin chains. Recent work has suggested that branched ubiquitin chains composed of Lys11 and Lys48 isopeptide linkages play a critical role in regulating cell cycle progression. Yet, endogenous Lys11/Lys48 branched chains could not be detected. By combining a Lys11 linkage specific antibody with high resolution middle-down mass spectrometry (an approach termed UbiChEM-MS) we sought to identify endogenous Lys11/Lys48 branched ubiquitin chains in cells. Using asynchronous cells, we find that Lys11-linked branched chains can only be detected upon cotreatment with a proteasome and nonselective deubiquitinase inhibitor. Releasing cells from mitotic arrest results in a marked accumulation of Lys11/Lys48 branched chains in which branch points represent ~3-4% of the total ubiquitin population. This report highlights the utility of UbiChEM-MS in characterizing the architecture of Lys11 Ub chains under various cellular conditions and corroborates the formation of Lys11/Lys48 branched chains during mitosis. PMID- 28737033 TI - Rapid Identification of Meat Species by the Internal Extractive Electrospray Ionization Mass Spectrometry of Hemoglobin Selectively Captured on Functionalized Graphene Oxide. AB - Hemoglobin (Hb) present in the blood and meat juice samples was selectively adsorbed by graphene oxide (GO) particles functionalized with amylopectin (AP) and was sensitively detected by direct internal extractive electrospray ionization mass spectrometry (iEESI-MS) analysis for the identification of meat type. Various samples including the whole blood samples of chicken, duck, sheep, mouse, pigeon, turtledove, and meat juice mixtures were successfully identified based on the difference in molecular composition of Hb reflected in MS. The adulteration of sheep blood with only 2% chicken blood could be detected, which demonstrated the high chemical specificity of the approach. The established method is featured by the high speed of analysis (4 min per sample, including the analyte extraction and sample loading), high sensitivity, minimal sample preparation, and low sample consumption (0.9 MUL of whole blood or 300 mg of raw meat). In perspective, the reported method can be extended for the sensitive detection of trace analytes in complex matrices in broad molecular range by using the selective enrichment on functionalized graphene oxide particles followed by iEESI-MS analysis. PMID- 28737034 TI - Modification of the Poly(bisdodecylquaterthiophene) Structure for High and Predominantly Nonionic Conductivity with Matched Dopants. AB - Four p-type polymers were synthesized by modifying poly(bisdodecylquaterthiophene) (PQT12) to increase oxidizability by p-dopants. A sulfur atom is inserted between the thiophene rings and dodecyl chains, and/or 3,4-ethylenedioxy groups are appended to thiophene rings of PQT12. Doped with NOBF4, PQTS12 (with sulfur in side chains) shows a conductivity of 350 S cm-1, the highest reported nonionic conductivity among films made from dopant-polymer solutions. Doped with tetrafluorotetracyanoquinodimethane (F4TCNQ), PDTDE12 (with 3,4-ethylenedioxy groups on thiophene rings) shows a conductivity of 140 S cm-1. The converse combinations of polymer and dopant and formulations using a polymer with both the sulfur and ethylenedioxy modifications showed lower conductivities. The conductivities are stable in air without extrinsic ion contributions associated with PEDOT:PSS that cannot support sustained current or thermoelectric voltage. Efficient charge transfer, tighter pi-pi stacking, and strong intermolecular coupling are responsible for the conductivity. Values of nontransient Seebeck coefficient and conductivity agree with empirical modeling for materials with these levels of pure hole conductivity; the power factor compares favorably with prior p-type polymers made by the alternative process of immersion of polymer films into dopant solutions. Models and conductivities point to significant mobility increases induced by dopants on the order of 1-5 cm2 V-1 s-1, supported by field-effect transistor studies of slightly doped samples. The thermal conductivities were in the range of 0.2-0.5 W m-1 K-1, typical for conductive polymers. The results point to further enhancements that could be obtained by increasing doped polymer mobilities. PMID- 28737035 TI - Novel Wastewater-Based Epidemiology Approach Based on Liquid Chromatography Tandem Mass Spectrometry for Assessing Population Exposure to Tobacco-Specific Toxicants and Carcinogens. AB - Tobacco smoking remains an important public health issue worldwide. Assessment of exposure to tobacco-related toxicants and carcinogens at the population level is thus an essential population health indicator. This can be achieved by wastewater based epidemiology (WBE), which relies on the analysis of biomarkers in wastewater. However, required analytical methods for the simultaneous measurement of tobacco-related toxicants and carcinogens in wastewater are not available. In this study, a new analytical procedure was developed and validated to measure tobacco-related alkaloids, carcinogens, and their metabolites in raw wastewater, including anabasine (ANABA), anatabine (ANATA), cotinine (COT), trans-3' hydroxycotinine (COT-OH), N-nitrosoanabasine (NAB), N-nitrosoanatabine (NAT), N nitrosonornicotine (NNN), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), NNAL-N-beta glucuronide, and NNAL-O-beta-glucuronide. Different parameters were optimized for the solid-phase extraction procedure and instrumental analysis using liquid chromatography-tandem mass spectrometry. The optimized method was fully validated, resulting in acceptable within-run and between-run precision (<8% and <10% relative standard deviation, respectively) and accuracy (<9% and <13% bias, respectively). Method quantification limits were at 0.5-120 ng/L in wastewater. Target analytes were stable in wastewater at 4 and 20 degrees C over 24 h. The developed method was applied to wastewater samples from two Belgian cities. Average concentrations of COT, COT-OH, ANATA, ANABA, and NAT were 5200, 2600, 30, 10, and 0.6 ng/L, respectively, while NAB, NNN, NNK, and NNAL were not detected in the samples. With the developed robust analytical method, our study provided the first insight into the population exposure to both toxicants and carcinogens resulting from tobacco use. PMID- 28737036 TI - pH Change in Electroosmotic Flow Hysteresis. AB - Electroosmotic flow (EOF) or electro-osmosis has been shown to exhibit a hysteresis effect under displacement flow involving two solutions with different concentrations, i.e. the flow velocity for a high-concentration solution displacing a low-concentration solution is faster than the flow velocity in the reverse direction involving the same solution pair. On the basis of our recent numerical analysis, a pH change initiated at the interface between the two solutions has been hypothesized as the cause for the observed anomalies. We report the first experimental evidence of EOF hysteresis induced by a pH change in the bulk solution. pH-sensitive dye was employed to quantify the pH changes in the microchannel during EOF. The electric-field gradient across the boundary of two solutions generates an accumulation or depletion of a minority of pH governing ions such as hydronium (H3O+) ions, thus inducing pH variations across the microchannel. When a high-concentration solution displaced a lower concentration solution, a pH increase was observed, while the flow in the reverse direction induced a decrease in pH. This effect causes significant changes to the zeta potential and flow velocity. The experimental results show good quantitative agreement with numerical simulations. This work presents the experimental proof which validates the hypothesis of a pH change during electroomostic flow hysteresis as predicted by numerical analysis. The understanding of pH changes during EOF is crucial for accurate flow manipulation in microfluidic devices and maintenance of constant pH in biological and chemical systems under an electric field. PMID- 28737037 TI - Polyimide Aerogels Using Triisocyanate as Cross-linker. AB - A family of polyimide (PI)-based aerogels is produced using Desmodur N3300A, an inexpensive triisocyanate, as the cross-linker. The aerogels are prepared by cross-linking amine end-capped polyimide oligomers with the triisocyanate. The polyimide oligomers are formulated using 2,2'-dimethylbenzidine, 4,4' oxydianiline, or mixtures of both diamines, combined with 3,3',4,4' biphenyltetracarboxylic dianhydride, and are chemically imidized at room temperature. Depending on the backbone chemistry, chain length, and polymer concentration, density of the aerogels ranged from 0.06 to 0.14 g/cm3 and Brunauer-Emmett-Teller surface areas ranged from 350 to 600 m2/g. Compressive moduli of these aerogels were as high as 225 MPa, which are comparable to, or higher than, those previously reported prepared with similar backbone structures but with other cross-linkers. Because of their lower cost and commercial availability as cross-linker, the aerogels may have further potential as insulation for building and construction, clothing, sporting goods, and automotive applications, although lower-temperature stability may limit their use in some aerospace applications. PMID- 28737038 TI - Evolution of Aggregate Structure in Solutions of Anionic Monorhamnolipids: Experimental and Computational Results. AB - The evolution of solution aggregates of the anionic form of the native monorhamnolipid (mRL) mixture produced by Pseudomonas aeruginosa ATCC 9027 is explored at pH 8.0 using both experimental and computational approaches. Experiments utilizing surface tension measurements, dynamic light scattering, and both steady-state and time-resolved fluorescence spectroscopy reveal solution aggregation properties. All-atom molecular dynamics simulations on self assemblies of the most abundant monorhamnolipid molecule, l-rhamnosyl-beta hydroxydecanoyl-beta-hydroxydecanoate (Rha-C10-C10), in its anionic state explore the formation of aggregates and the role of hydrogen bonding, substantiating the experimental results. At pH 8.0, at concentrations above the critical aggregation concentration of 201 MUM but below ~7.5 mM, small premicelles exist in solution; above ~7.5 mM, micelles with hydrodynamic radii of ~2.5 nm dominate, although two discrete populations of larger lamellar aggregates (hydrodynamic radii of ~10 and 90 nm) are also present in solution in much smaller number densities. The critical aggregation number for the micelles is determined to be ~26 monomers/micelle using fluorescence quenching measurements, with micelles gradually increasing in size with monorhamnolipid concentration. Molecular dynamics simulations on systems with between 10 and 100 molecules of Rha-C10-C10 indicate the presence of stable premicelles of seven monomers with the most prevalent micelle being ~25 monomers and relatively spherical. A range of slightly larger micelles of comparable stability can also exist that become increasing elliptical with increasing monomer number. Intermolecular hydrogen bonding is shown to play a significant role in stabilization of these aggregates. In total, the computational results are in excellent agreement with the experimental results. PMID- 28737039 TI - Effect of Solvent Quality on Laminar Slip Flow Penetration of Poly(N isopropylacrylamide) Films with an Exploration of the Mass Transport Mechanism. AB - The effect of solvent quality on the slip flow penetration of polymer films was evaluated by monitoring small-molecule mass transport under varying laminar flow rates using Forster resonance energy transfer in combination with total internal reflectance fluorescence microscopy (FRET-TIRFM). For thin films of poly(N isopropylacrylamide) (pNIPAM), solvents with solvent quality ranging from good to poor were studied. The solvents used were composed of varying mole ratios of methanol and water in order to take advantage of the unique cononsolvency phenomenon of pNIPAM such that differences in the physicochemical properties of these solvents were insignificant for fluorescence detection. FRET quenching of a donor fluorophore covalently tethered on the substrate surface at the bottom of the pNIPAM film by a solution-confined acceptor was monitored as a function of time. Quenching curves were fit to a combined Taylor-Aris-Fickian mass transport model for the acceptor, rhodamine B (RhB) or 2-nitrobenzylaclohol (2-NBA), allowing apparent diffusion coefficients to be determined and used to assess slip flow penetration into the polymer film. An increase in the apparent diffusion coefficient of tracer molecules was observed with increasing laminar flow rate for all solvents, indicating that mass transport processes in the pNIPAM film are significantly perturbed by laminar slip flow penetration. In going from poor solvents, 31 mol % MeOH/H2O and 20 mol % MeOH/H2O, to the theta solvent, 13 mol % MeOH/H2O, and finally to a good solvent, 100% methanol, the slip length increases from 25 to 37 to 70 to 128 nm, with the corresponding percentage of the film penetrated by slip flow increasing from 19 to 27 to 42 to 57%, respectively. The apparent diffusion coefficients of the two acceptors, RhB and 2-NBA, which differ substantially in size and charge, in pNIPAM films under identical conditions were found to be of the same order of magnitude, albeit with a small difference (~10%) due to inherently different diffusive properties. Therefore, the dominant mechanism for the mass transport of small molecules in densely grafted thin pNIPAM brush films is suggested to be linear Fickian diffusion under the chosen laminar flow conditions with linear flow velocities ranging from 192 to 2952 MUm/s. High-quality fits to a Taylor-Aris-Fickian diffusion model of the experimental breakthrough curves obtained with both acceptor molecules further substantiate the proper use of this model and the validity of the FRET-TIRFM method. PMID- 28737041 TI - Comparable Consistency, Coherence, and Commonality of Measures of Cognitive Functioning Across Adulthood. AB - Increased age is associated with lower scores in many cognitive tests, but interpretation of those results is based on the assumption that the measurement at different ages is equivalent, such that the differences reflect quantitative rather than qualitative changes. The assumption of measurement equivalence was investigated by comparing adult age differences in the relations among alternative versions of the same tests, among different tests of the same ability, and among different cognitive abilities. Results from three independent data sets revealed that only modest age differences were apparent at each level, which implies that cognitive abilities have similar measurement properties at different ages in adulthood. PMID- 28737042 TI - Exploring the Evidence Base Behind Quality Measures. PMID- 28737043 TI - Health Care Providers and Managers: Seeking Concordance in the Discord. PMID- 28737045 TI - Pharmacist's Demand for Optimal Primary Care Service Delivery in a Community Pharmacy: The OPTiPharm Study. AB - BACKGROUND: The US population continues to expand providing the need for primary health care services. Community pharmacies integrated with medicine may provide greater access while providing high quality care. OBJECTIVE: To gauge pharmacists' demand for primary health care services delivered through community pharmacies. METHODS: An online survey was administered to determine community pharmacists' preferences for varying primary care services that could be offered in the community pharmacy setting. A Discrete Choice Experiment was employed to show pharmacists competing scenarios with varied primary care service offerings in the community pharmacy setting. Attributes evaluated were operation hours, service provider, medical records, service logistics, physical examinations, point-of-care diagnostic testing, preventative care, and drug prescribing. Respondents chose the scenario most likely to induce switching employment from base pharmacy to one providing advanced services. RESULTS: The optimal service delivery model from 291 community pharmacists comprised: inclusion of patient prescriptions and health information into the patient's medical record; provision of point of care testing and vital sign, including blood pressure, heart rate and breathing rate, and blood sugar and cholesterol measurement; and pharmacists prescribing (under physician oversight). Pharmacists were 4 times more likely to switch employment from their current pharmacy to their choice for advanced pharmacy services. Pharmacist demand was highest among those with a PharmD, less experience, working >40 hours per week, and in rural areas. CONCLUSIONS: This study provides empirical support for the model of pharmacists playing a greater role in the provision of primary care health services through community pharmacy settings. PMID- 28737040 TI - Potential of small-molecule fungal metabolites in antiviral chemotherapy. AB - Various viral diseases, such as acquired immunodeficiency syndrome, influenza, and hepatitis, have emerged as leading causes of human death worldwide. Scientific endeavor since invention of DNA-dependent RNA polymerase of pox virus in 1967 resulted in better understanding of virus replication and development of various novel therapeutic strategies. Despite considerable advancement in every facet of drug discovery process, development of commercially viable, safe, and effective drugs for these viruses still remains a big challenge. Decades of intense research yielded a handful of natural and synthetic therapeutic options. But emergence of new viruses and drug-resistant viral strains had made new drug development process a never-ending battle. Small-molecule fungal metabolites due to their vast diversity, stereochemical complexity, and preapproved biocompatibility always remain an attractive source for new drug discovery. Though, exploration of therapeutic importance of fungal metabolites has started early with discovery of penicillin, recent prediction asserted that only a small percentage (5-10%) of fungal species have been identified and much less have been scientifically investigated. Therefore, exploration of new fungal metabolites, their bioassay, and subsequent mechanistic study bears huge importance in new drug discovery endeavors. Though no fungal metabolites so far approved for antiviral treatment, many of these exhibited high potential against various viral diseases. This review comprehensively discussed about antiviral activities of fungal metabolites of diverse origin against some important viral diseases. This also highlighted the mechanistic details of inhibition of viral replication along with structure-activity relationship of some common and important classes of fungal metabolites. PMID- 28737046 TI - Instrumented Assessment of Physical Activity Is Associated With Muscle Function but Not With Muscle Mass in a General Population. AB - OBJECTIVES: Self-reported physical activity has shown to affect muscle-related parameters. As self-report is likely biased, this study aimed to assess the association between instrumented assessment of physical activity (I-PA) and muscle-related parameters in a general population. METHOD: Included were 156 young-to-middle-aged and 80 older community-dwelling adults. Seven days of trunk accelerometry (DynaPort MoveMonitor, McRoberts B.V.) quantified daily physical activity (i.e., active/inactive duration, number and mean duration of active/inactive periods, and number of steps per day). Muscle-related parameters included muscle mass, handgrip strength, and gait speed. RESULTS: I-PA was associated with handgrip strength in young-to-middle-aged adults and with gait speed in older adults. I-PA was not associated with muscle mass in either age group. DISCUSSION: The association between I-PA and muscle-related parameters was age dependent. The lack of an association between I-PA and muscle mass indicates the relevance of muscle function rather than muscle mass. PMID- 28737048 TI - Ototoxicity monitoring in children treated with platinum chemotherapy. AB - OBJECTIVE: To review the prevalence, mechanisms, clinical presentation, risk factors and implications of platinum-induced ototoxicity in paediatric cancer patients based on published evidence, discuss options for monitoring hearing in young children during treatment and review long-term follow-up guidelines. DESIGN: Narrative literature review. RESULTS: Children treated with cisplatin are at high risk of hearing loss and early, accurate identification of ototoxicity is important for medical decision making and hearing rehabilitation. Challenges of monitoring hearing in young children during cancer treatment and options for monitoring hearing are discussed. CONCLUSION: Hearing loss has important consequences for the survivors of childhood cancer including communication, learning, cognition and quality of life. Due to the presentation and configuration of ototoxic hearing loss, the test frequencies that are prioritised and the sequence of testing may differ from standard paediatric hearing evaluations. Hearing should be monitored during treatment and after completion of therapy. PMID- 28737047 TI - The role of mucoactive agents in the mechanically ventilated patient: a review of the literature. AB - INTRODUCTION: The management of airway secretions in the mechanically ventilated patient is a routine task throughout all intensive care units. The current treatment strategies are primarily based on anecdotal experiences rather than statistical evidence. Areas covered: This review article evaluates the data from published trials surrounding mucoactive agents and their use in the critically ill patient population. We completed an extensive search through PUBMED and CINAHL via EBSCO, along with the Cochran library to find all trials using mucoactive agents in the critically ill patient population. Expert commentary: Overall, the role of mucoactive agents in the intensive care unit is a field within pulmonary critical care that is in need of evidence-based recommendations. We feel that there is great opportunity for investigators to evaluate different mucoactive therapies in this patient population and to determine their effect on clinical outcomes. PMID- 28737049 TI - Primary small bowel adenocarcinoma: current view on clinical features, risk and prognostic factors, treatment and outcome. AB - Small bowel adenocarcinoma (SBA) is a rare but increasing cause of gastrointestinal malignancy, being both a diagnostic and therapeutic challenge. The goal of treatment is margin negative resection of a lesion and local lymphadenectomy, followed by modern adjuvant chemotherapy combinations in selected cases. Improved outcomes in patients with SBA are encouraging, but elucidation of mechanisms of carcinogenesis and risk factors as well as improved treatment for this malignancy is very needed. PMID- 28737050 TI - Efficacy of elagolix in the treatment of endometriosis. AB - INTRODUCTION: Much research has gone into developing medications that can be used to alleviate endometriosis-associated symptoms. In addition to already established medications, a new GnRH antagonist, elagolix, is in development. The novelty of this drug compared to other GnRH antagonists, is its nonpeptide structure, allowing it to be administered orally. Areas covered: We analyzed several Phase I, II and III clinical trials that have evaluated the safety and efficacy of this new medication. Expert opinion: Since many medications have been put on the market and have gained popularity for the treatment of endometriosis associated symptoms, the demonstration of equality or superiority of effect, tolerability, as well as patient compliance should be assessed when introducing a new drug. While elagolix may have an advantage over established GnRH agonists, in that it does not lead to a 'flare-up' effect, it too, takes a toll on bone mineral density. Nevertheless, studies have shown that this new oral GnRH antagonist is well tolerated, and the side effects have been described as 'mild or moderate'. However, in order to examine whether elagolix can compete with or even surpass established gold-standard medical treatments in this field, further studies that directly compare elagolix to said treatments, might be necessary. PMID- 28737051 TI - Pharmacokinetic/pharmacodynamic drug evaluation of benralizumab for the treatment of asthma. AB - INTRODUCTION: In many severe asthmatics, eosinophils cause inflammation and airways hyperresponsiveness, resulting in frequent exacerbations, impaired lung function, and reduced quality of life. Interleukin-5 (IL-5) is a key cytokine for eosinophil growth, differentiation, recruitment, activation, and survival. Anti IL-5-based therapies (mepolizumab and reslizumab are humanized monoclonal antibodies (hmAbs) that recognize free IL-5, benralizumab is a hmAb directed at the alpha subunit of the IL-5R) target the IL-5-signaling in eosinophilic asthma. Areas covered: The pharmacodynamic/pharmacokinetic profile of benralizumab and how it provided indications that permitted optimization of the design and timelines of the pivotal trials are described. Expert opinion: Benralizumab has the advantage over other anti-IL-5 therapies to target the IL-5Ralpha itself. Afucosylation enhances its interaction with its binding site and facilitates its pharmacological activity. Other benefits of benralizumab are fast (within 24 h) depletion of peripheral blood eosinophils, potent suppressive activity of bone marrow eosinophils and eosinophil precursors, tissue eosinophil apoptosis regardless of the presence of eosinophil survival factors and even at low IL-5R densities. The fact that benralizumab is dosed subcutaneously and is equally effective when given every eight weeks instead than every four weeks provides patients with convenience of self-administration and make it appealing for patients who dislike injections. PMID- 28737052 TI - The importance of model inputs and assumptions in conducting health technology assessments of novel drugs. PMID- 28737053 TI - Efficacy of baricitinib in the treatment of rheumatoid arthritis. AB - INTRODUCTION: although the outcome for patients with rheumatoid arthritis (ra) has improved in the past decades, adequate disease control cannot be achieved in a substantial proportion of patients. new drugs with a novel mechanism of action, may represent a valuable addition to the current armamentarium. Areas covered: This review focuses on the pharmacodynamics and pharmacokinetics of baricitinib. Furthermore, the article summarizes and comments the drug's efficacy and safety profile in RA patients. Expert opinion: Baricitinib is an oral targeted synthetic (ts) disease-modifying antirheumatic drug (DMARD) that mainly inhibits JAK1 and JAK2. Baricitinib monotherapy, or in combination with conventional synthetic (cs) DMARDs, has demonstrated its efficacy while having an acceptable safety profile in early active RA naive to DMARDs, and active RA with an inadequate response to csDMARDs and/or biologic (b)DMARDs. The future place of baricitinib in the management of RA patients will depend on several factors. However, baricitinib offer few advantages: oral administration, rapidity of action, efficacy in monotherapy and over adalimumab in one study and non-immunization. However, pending further safety data, current practice would be to start a bDMARD when the treatment target is not achieved with csDMARDs. Availability of additional long term safety data may influence prescribing decisions. PMID- 28737054 TI - Age Trajectories of Physical Health Among Older Adults of Mexican Descent: Implications of Immigrant Status, Age at Immigration, and Gender. AB - OBJECTIVE: This study examines consequences of immigrant status, age at immigration, and gender on age trajectories of activities of daily living (ADL) limitations and chronic conditions among older adults of Mexican descent. METHOD: This research draws on 7 waves of the Hispanic Established Populations for the Epidemiologic Study of the Elderly and employs growth curve models. RESULTS: All men had similar age trajectories of ADL limitations, regardless of immigrant status and age at immigration. All women experienced steeper increases in ADL limitations, although U.S.-born women and those who immigrated by age 19 had lower initial levels. Men who immigrated between ages 20 and 49 had steeper increases in chronic conditions, despite lower initial levels. U.S.-born women and those women who immigrated by age 50 had more chronic conditions at age 65. DISCUSSION: This study highlights the multidimensional nature of physical health by demonstrating that immigrant status-gender disparities can vary by the health outcome examined. PMID- 28737055 TI - What is taught about dementia in secondary schools? A survey of schools in Sussex, England (Innovative Practice). AB - Local dementia education initiatives exist in schools but it is unclear what the wider uptake of such programmes are. A self-created survey was sent to staff in a number of secondary schools (teaching ages 11-16) across Sussex, England. Sixty schools responded to the survey (response rate = 58%). While the majority of schools expressed an interest in including some form of dementia education within their school in the future, only nine schools (15%) currently had dementia education embedded within their curriculum. Despite government calls to reduce stigma and improve attitudes towards dementia, it seems very little is being taught in secondary schools on the topic. PMID- 28737056 TI - Quantification of human brain PDE4 occupancy by GSK356278: A [11C](R)-rolipram PET study. AB - We characterized the relationship between the plasma concentration of the phospodiesterase (PDE)-4 inhibitor GSK356278 and occupancy of the PDE4 enzyme in the brain of healthy volunteers, using the positron emission tomography (PET) tracer [11C](R)-rolipram. To this end, PET scans were acquired in eight male volunteers before and at 3 and 8 h after a single 14 mg oral dose of GSK356278. A metabolite-corrected arterial input function was used in conjunction with the dynamic PET emission data to estimate volumes of distribution (VT) from a two tissue compartment model. The administration of GSK356278 reduced [11C](R) rolipram whole brain VT by 17% at 3 h post-dose (p = 0.01) and by 4% at 8 h post dose. The mean plasma Cmax was 42.3 ng/ml, leading to a PDE4 occupancy of 48% at Tmax. The in vivo affinity of GSK356278 was estimated as EC50 = 46 +/- 3.6 ng/ml. We present the first report of a direct estimation of PDE4 blockade in the living human brain. In vivo affinity of GSK356278 for the PDE4, estimated in this early phase study, was combined with GSK356278 safety and tolerability data to decide on a therapeutic dose for future clinical development. PMID- 28737057 TI - Commercial Transactions in Children: The Case of Ghana. AB - The current article represents an examination of commercial transactions involving the sale of children in contemporary Ghana. It presents the results of a criminological analysis of 20 cases of commercial transactions in children in Ghana. It describes the sociodemographic characteristics of offenders and victims, victim-offender relationships, offender motivations, public reactions to the phenomenon, as well as the criminal justice system's responses to the crime. The data were extracted from Ghanaian print and electronic presses. The data show that more boys than girls were sold and that the ages of the victims ranged from 1 month to 19 years, although younger, prepubescent children were more likely to be sold than adolescents and younger adults. The results further show that the relationship between the offender and the child victim was a primary one, with parent-child relationships being dominant, followed by uncle-nephew. Pecuniary reasons were the primary motive for the crime, with offenders invariably expressing the need for money to satisfy pressing financial needs or personal enrichment. The data show that offenders were subject to prompt arrest, prosecution, and incarceration. A summary is provided for each of the 20 cases analyzed in the study. PMID- 28737058 TI - External Validity of Electronic Sniffers for Automated Recognition of Acute Respiratory Distress Syndrome. AB - INTRODUCTION: Automated electronic sniffers may be useful for early detection of acute respiratory distress syndrome (ARDS) for institution of treatment or clinical trial screening. METHODS: In a prospective cohort of 2929 critically ill patients, we retrospectively applied published sniffer algorithms for automated detection of acute lung injury to assess their utility in diagnosis of ARDS in the first 4 ICU days. Radiographic full-text reports were searched for "edema" OR ("bilateral" AND "infiltrate") and a more detailed algorithm for descriptions consistent with ARDS. Patients were flagged as possible ARDS if a radiograph met search criteria and had a PaO2/FiO2 or SpO2/FiO2 of 300 or 315, respectively. Test characteristics of the electronic sniffers and clinical suspicion of ARDS were compared to a gold standard of 2-physician adjudicated ARDS. RESULTS: Thirty percent of 2841 patients included in the analysis had gold standard diagnosis of ARDS. The simpler algorithm had sensitivity for ARDS of 78.9%, specificity of 52%, positive predictive value (PPV) of 41%, and negative predictive value (NPV) of 85.3% over the 4-day study period. The more detailed algorithm had sensitivity of 88.2%, specificity of 55.4%, PPV of 45.6%, and NPV of 91.7%. Both algorithms were more sensitive but less specific than clinician suspicion, which had sensitivity of 40.7%, specificity of 94.8%, PPV of 78.2%, and NPV of 77.7%. CONCLUSIONS: Published electronic sniffer algorithms for ARDS may be useful automated screening tools for ARDS and improve on clinical recognition, but they are limited to screening rather than diagnosis because their specificity is poor. PMID- 28737059 TI - Authors reply: delta HR/BT as a possible predictor of severity or mortality, not a predictor of bacterial infection. PMID- 28737060 TI - A Propensity Score-Matched Analysis of Inflammatory Response With Endovascular Aneurysm Sealing vs Endovascular Aneurysm Repair. AB - PURPOSE: To evaluate the risk of postimplantation syndrome associated with endovascular aneurysm sealing (EVAS) and endovascular aneurysm repair (EVAR) in patients treated for abdominal aortic aneurysm (AAA). METHODS: From December 2013 to May 2015, 41 AAA patients treated with EVAS (mean age 72+/-9 years; 38 men) and 63 with EVAR (mean age 74+/-10 years; 55 men) at a single center were retrospectively reviewed. To control for treatment selection bias, propensity score matching was used to compare outcomes by treatment mode. Main outcomes were postimplantation syndrome (defined as temperature >38 degrees C and leukocyte count >12,000/uL), inflammatory response markers [platelets and high-sensitivity C-reactive protein (hs-CRP)], and clinical complications through 30 days. RESULTS: In 39 matched patients per group, the incidences of postimplantation syndrome (p=0.07), mean body temperature (p=0.05), mean leukocyte count (p=0.003), and mean hs-CRP (p<0.001) were proportionally lower with EVAS vs EVAR. Serious adverse events (0% vs 12.8%, p=0.05) and endoleaks (0% vs 10.3%, p=0.13) through 30 days were less frequent with EVAS, but the group differences were not significantly different. The choice of endovascular graft material influenced postoperative and 30-day clinical outcomes, with greater overall risk observed with polyester stent-grafts. CONCLUSION: Endovascular aneurysm sealing is associated with a blunted systematic inflammatory response compared with EVAR. Polyester stent-grafts induce the greatest periprocedural inflammatory response. PMID- 28737061 TI - Functional and structural alterations in the migraine cerebellum. AB - The cerebellum plays an important role in pain processing but its function in headache and specifically in migraine is not known. We therefore compared 54 migraineurs with pairwise matched healthy controls in a magnetic resonance imaging study on neuronal cerebellar activity in response to nociceptive trigeminal sensation and also investigated possible structural alterations. Headache frequency, disease duration, and the proximity to a migraine attack were used as co-factors. Migraine patients showed functional and structural alterations in the posterior part of the cerebellum, namely crus I and crus II. Gray matter volume changes were seen on the right side whereas functional changes were ipsilateral to the stimulation, on the left side. Neuronal activity in the crus in response to trigeminal pain was modulated by migraine severity and the migraine phase. As the crus is strongly interconnected to higher cognitive areas in the temporal, frontal, and parietal part of the cortex our results suggest an specific cerebellar involvement in migraine. This is further supported by our finding of decreased connectivity from the crus to the thalamus and higher cortical areas in the patients. We therefore suggest an abnormally decreased inhibitory involvement of the migraine cerebellum on gating and nociceptive evaluation. PMID- 28737062 TI - Community-level electronic prescribing and adverse drug event hospitalizations among older adults. AB - This study sought to determine how the proportion of physicians using electronic prescribing in nine US states was associated with the hospitalization rate for adverse drug events among older adult patients. A discharge-level analysis of the relationship between county electronic prescribing and adverse drug event hospitalization rates was conducted. Data from the 2011 State Inpatient Databases, the Office of the National Coordinator Health IT Dashboard, and the Area Health Resource File were obtained for nine US states. The analysis examined the odds that a discharge for older adults would have been adverse drug event associated, versus other causes, using multivariable logistic regression models. After adjusting for patient, provider, health infrastructure, and community factors, the lowest county electronic prescribing rate quartile was associated with significantly greater odds of an adverse drug event hospitalization (odds ratio: 1.10; 95% confidence interval: 1.02-1.19). Early results indicate greater odds of adverse drug event hospitalizations among older adults living in counties with low electronic prescribing rates when compared to those in high electronic prescribing counties. PMID- 28737064 TI - The Effects of Delirium Prevention Guidelines on Elderly Stroke Patients. AB - This study aimed to evaluate the effectiveness of the delirium prevention interventions recommended by the Delirium Prevention Guidelines for Elderly Stroke Patients (DPGESP). The DPGESP comprises nine dimensions with 28 interventions, including risk factor assessment, orientation disorder prevention, sleeping pattern maintenance, sensory interventions, constipation, dehydration, hypoxia and infection prevention, pain management, and appropriate nutrition maintenance. This quasi-experimental study used a nonequivalent control group and a pretest-posttest design. The experimental and control groups each included 54 patients, and the participants were elderly patients who were admitted to the stroke unit. The study outcomes were the delirium incidence and severity, stroke impact, and length of hospitalization. Posttest values for delirium incidence, severity, stroke impact, and length of hospitalization were significantly improved in the experimental group. Implementation of the DPGESP had beneficial effects on the delirium incidence and severity, stroke impact, and length of hospitalization among elderly patients admitted to a stroke unit. PMID- 28737063 TI - Genetic diversity and antimicrobial resistance profile of Enterococcus faecalis isolated from broilers with vertebral osteomyelitis in Southeast Brazil. AB - Vertebral osteomyelitis (VO) is a worldwide emerging disease that affects broilers. Recently, the isolation of Enterococcus faecalis in cases of the disease has been described. This study aimed at determining the genetic diversity and antimicrobial resistance profile of 12 E. faecalis strains isolated from broilers with VO. Strains were isolated from nine flocks from six farms in a high density poultry production area in Southeast Brazil and were evaluated using multilocus sequence typing and phylogenetic analysis. Antimicrobial susceptibility tests and PCR were performed to detect antimicrobial resistance genes. E. faecalis isolates belonged to different sequence types (ST), six of which (ST49, ST100, ST116, ST202, ST249, and ST300) have been previously described. Strains ST708 and ST709 were newly identified in this study. Strain ST49 was most frequently isolated (50% of the flocks) from the analysed VO cases. No phylogenetic or phylogeographic relationship was found among the strains. The VO isolated E. faecalis strains showed highest resistance to aminoglycosides, mainly gentamicin (40%), but were highly susceptible to vancomycin (10%). Aminoglycoside resistance genes were detected in seven E. faecalis strains, and AAC6'-APH2" genes were most frequently detected. The results showed that E. faecalis strains isolated from recently reported VO cases were highly diverse genetically. The diversity of genotypes in circulation in the analysed flocks, without apparent relationship among them, raises questions on aetiopathogenesis of the disease in broilers and evolutionary aspects of E. faecalis. PMID- 28737065 TI - Postoperative stereotactic radiosurgery for limited brain metastases: are we ready for prime time? PMID- 28737066 TI - beta-Blockade in Heart Failure With Reduced Ejection Fraction: Does Heart Rate Control Influence Readmissions? AB - BACKGROUND: Raised resting heart rate (HR), >70 beats per minute (bpm), has been shown to be a risk factor for adverse cardiovascular outcomes and hospital readmissions, specifically in patients with heart failure with reduced ejection fraction (HF rEF). Given their mortality benefit, beta-blockers are recommended in HF rEF, with a goal to titrate to a maximum tolerated dose rather than a specific HR target. OBJECTIVE: To determine the impact of optimal HR control achievement prior to hospital discharge on hospital readmissions in patients with HF rEF receiving beta-blockade. METHODS: A retrospective study of patients admitted to 5 adult hospitals within a large urban health-care system, between 2013 and 2015, was conducted. Patients were identified via International Classification of Diseases, Ninth Revision ( ICD-9) coding for acute on chronic HF rEF. RESULTS: Of the 225 patients included, 20% achieved optimal HR control (n = 46, HR <70 bpm; n = 179, HR >=70 bpm) and only 15% received beta-blocker titration during hospital admission. Of note, 25% of patients receiving >=50% target dose (n = 79) and 28% receiving 100% target dose (n = 39) achieved optimal HR control. At 30 days, patients with an HR <70 bpm versus HR >=70 bpm exhibited similar readmission rates (9% vs 11%, respectively; P > .99) and ED visits (11% vs 8%, respectively; P = .57). CONCLUSIONS: Readmission rates were similar among patients with HF rEF despite the majority failing to achieve optimal HR control from beta-blockade. However, beta-blocker dosing remains suboptimal relative to guideline-recommended target doses. Opportunities exist for inpatient clinicians to optimize beta-blockade in an attempt to achieve HR control. PMID- 28737067 TI - Confirmed and Suspected Foreign Body Injuries in Children during 2008-2013: A Hospital-Based Single Center Study in Oulu University Hospital. AB - INTRODUCTION: Foreign body injuries are common in children. Most of them are not serious but they can be fatal. A suspected foreign body injury in a child results in a high rate of hospitalizations, exposure to radiation, and need for intervention. This study aimed to analyze the current epidemiology of in-hospital or out of hospital treated foreign object injuries and suspected foreign body injuries in children. MATERIAL AND METHODS: All children <16 years of age (N = 152) who suffered or were suspected to suffer (N = 63) from a foreign body injury and were treated in a pediatric trauma unit of Oulu University Hospital, Oulu, Finland, over a 6-year study period (2008-2013) were included. A comprehensive chart review was completed in order to evaluate injury history, age at the time of trauma, treatment and characteristics of the foreign objects. RESULTS: The majority (57.9%, N = 88) of the injuries were found in children <3 years of age. There was a male predominance (60.5%, N = 92). The most common anatomical site where the foreign body was found was the nose (28.9%, N = 44), followed by the esophagus (20.4%, N = 31) and the eye (11.2%, N = 17). Foreign objects were also found in the lower airways (10.5%, N = 16), ear (10.5%, N = 16), bowel (9.9%, N = 15), throat (3.9%, N = 6), stomach (3.9%, N = 6), and urethra (0.7%, N = 1). Various household items were the most common foreign bodies (33.6%, N = 51). Toys in particular caused 22.4% (N = 34) of the injuries. In-hospital intervention was necessary for 38.5% of the patients (N = 58). Intervention was needed in 39.7% (N = 25/63) of the patients who were suspected to suffer from foreign body but did not. There were no fatalities. CONCLUSION: Foreign body injuries treated at the pediatric trauma unit were most common in the youngest children (<3 years of age). Majority (61.8%, N = 94) of the patients were treated non-operatively, without any in-hospital intervention. PMID- 28737068 TI - Is Endocan an Inflammatory Marker or an Angiogenic Marker, or Both or None? PMID- 28737069 TI - Safety of Radial Access for Primary Percutaneous Intervention in Patients With ST Elevation Acute Myocardial Infarction: Results From a Low-Volume Center. AB - Radial access for primary percutaneous coronary intervention (pPCI) in patients with ST-elevation acute myocardial infarction (STEMI) is recommended in high volume experienced centers. This study investigated whether radial access for pPCI is safe even in a low-volume center. We performed radial access for pPCI in 171 patients. Major adverse cardiac events (total death, myocardial infarction, stroke) rate was 1.2%. The overall incidence of bleeding complications was 2.4%; there was no vascular complication at the access site. In patients with STEMI undergoing pPCI, the results of radial access in a low-volume center were acceptable. These findings support the safety of radial access in patients with STEMI. PMID- 28737070 TI - beta-Blockers on Discharge From Acute Atrial Fibrillation Are Associated With Decreased Mortality and Lower Cerebrovascular Accidents in Patients With Heart Failure and Reduced Ejection Fraction. AB - The benefits of beta-blockers in patients with heart failure (HF) with reduced ejection fraction (HFrEF) and atrial fibrillation (AF) are controversial. The Gulf Survey of Atrial Fibrillation Events was a prospective, multinational, observational registry of consecutive patients with AF recruited from the emergency department (ED). We studied the incidence of 6- and 12-month mortality, hospitalization for HF or AF, and stroke/transient ischemic attacks (TIAs) in patients with HFrEF, in relation to beta-blockers on discharge from the ED or the subsequent hospital stay. Of the 344 patients with HFrEF and AF in the GULF-SAFE, 177 patients (53%) were discharged on beta-blockers. Mortality was lower in those patients compared with the non-beta-blockers group at 6 and 12 months (odds ratios [ORs] 0.31, 95% CI [0.16-0.61]; OR 0.30, 95% CI [0.16-0.55]; P = .001 for both, respectively), so was the risk of stroke/TIAs. However, hospitalizations for AF increased in the beta-blockers group. Even after adjustment for several risk variables in 2 different models, the beneficial effect of beta-blockers on mortality persisted, at the cost of more hospitalization for AF. PMID- 28737071 TI - Inflammation and In-Stent Restenosis. PMID- 28737072 TI - The Effect of Metatarsal Padding on Pain and Functional Ability in Metatarsalgia. AB - BACKGROUND AND AIMS: Many kinds of insoles and pads are commonly used as a conservative treatment of metatarsalgia. However, earlier studies of insole treatment provide contradictory results, and the natural progression of metatarsalgia is still unknown. The aims of this study were to (1) determine whether simple custom-made metatarsal pad insoles reduce pain and improve functional ability, (2) find out patients' satisfaction with padding treatment, and (3) investigate predisposing factors for metatarsalgia. MATERIAL AND METHODS: All metatarsalgia patients provided with metatarsal pad insoles during a 2-year period at Kuopio University Hospital (n = 45) were included in the study and observed at least a year. In all, 25 patients were interviewed about their situation before and after treatment. The Numeric Rating Scale for pain and American Orthopaedic Foot & Ankle Society forefoot questionnaire included questions about predisposing factors, other diseases, exercise, work, shoes, and satisfaction with insoles. Foot X-rays taken from 45 patients during treatment were analyzed. RESULTS: The mean age of the patients was 56 years (range 34-84 years); 87% of them were women. In all, 47% of patients had osteoarthritic changes in the first metatarsophalangeal joint, and 42% had hallux valgus. In the interviewed subgroup (n = 25) body mass index was normal in 44%, and 36% were mildly overweight. High-heeled shoes were used by 40% daily, and 68% had done standing work for several years. Pain decreased significantly on the Numeric Rating Scale: 3.2 points in all patients ( p < 0.001), 3.1 points among women, and 4.25 points among men. The American Orthopaedic Foot & Ankle Society score improved 24.2 points in all patients ( p < 0.001, range 0-100), among women 19 points, and among men 29 points. CONCLUSION: Metatarsalgia affects mostly women and is often preceded by extensive use of high heels and standing work. Also, a high association of first metatarsophalangeal arthrosis and hallux valgus was found. Metatarsal pads reduce pain and improve the American Orthopaedic Foot & Ankle Society score. We recommend metatarsal padding as a safe and inexpensive alternative in treating metatarsalgia patients. PMID- 28737073 TI - Bleeding Pelvic Fracture Patients: Evolution of Resuscitation Protocols. AB - BACKGROUND AND AIMS: Massive transfusion protocol seems to improve outcome in massively bleeding trauma patients, but not pelvic fracture patients. The aim of this study was to evaluate the effect of massive transfusion protocol on the mortality and fluid resuscitation of shocked pelvic fracture patients. MATERIAL AND METHODS: This is a trauma register study from a single hospital. From the trauma registry patients with pelvic fracture, injury severity score >15, admission base excess below -5, age >15 years, blunt trauma, and primary admission from the scene were identified. Patients were divided into two groups: Group 1-pre-massive transfusion protocol (2006-2009) and Group 2-post-massive transfusion protocol (2010-2013). Basic characteristics and intensive care unit length of stay, mortality, and fluid resuscitation data were retrieved from the registry. Standardized mortality ratio was assessed using revised injury severity classification, version II methodology. RESULTS: Altogether, 102 patients were identified. Group 1 ( n = 56) and Group 2 ( n = 46) were comparable in their basic characteristics. The observed mortality was 35.7% and 26.1% in Groups 1 and 2, respectively. The standardized mortality ratio failed to reveal any difference between observed and expected mortality in either group. In the emergency room, the use of crystalloids decreased from 5.3 +/- 3.4 to 3.3 +/- 1.8 L ( p = 0.002) with increased use of fresh frozen plasma (2.9 +/- 4.4 vs 5.1 +/- 5.3, p = 0.007). CONCLUSION: No improvement in the adjusted survival of shocked pelvic fracture patients is apparent after implementation of massive transfusion protocol. Implementation of massive transfusion protocol is associated with a higher use of fresh frozen plasma and improved ratio of fresh frozen plasma:red blood cell toward the targeted 1:1 and decreased use of crystalloids. PMID- 28737074 TI - Intraoperative Tumor Perforation is Associated with Decreased 5-Year Survival in Colon Cancer: A Nationwide Database Study. AB - BACKGROUND: It is a widely held belief that intraoperative tumor perforation in colon cancer impairs survival and causes local recurrence, although the prognostic importance remains unclear. AIM: The aim of this study was to assess the effect of unintended intraoperative tumor perforation on postoperative mortality and long-term survival. MATERIAL AND METHODS: This national cohort study was based on data from a prospectively maintained nationwide colorectal cancer database. We included 16,517 colon cancer patients who were resected with curative intent from 2001 to 2012. RESULTS: Intraoperative tumor perforation produced a significantly impaired 5-year survival of 40% compared to 64% in non perforated colon cancer. Intraoperative tumor perforation was an independent risk factor for death, hazard ratio 1.63 (95% confidence interval: 1.4-1.94), with a significantly increased 90-day postoperative mortality of 17% compared to 7% in non-perforated tumors, p < 0.001. We showed that tumor fixation, emergency operations, and laparotomies were associated with an increased risk of intraoperative tumor perforation. CONCLUSION: This nationwide study demonstrates that intraoperative tumor perforation in colon cancer is associated with statistically significant reduced long-term survival and increased postoperative mortality. PMID- 28737075 TI - Socialization, Indifference, and Convenience: Exploring the Uptake of Influenza Vaccine Among Medical Students and Early Career Doctors. AB - The Chief Medical Officer recommends that all health care workers receive an influenza vaccination annually. High vaccination coverage is believed to be the best protection against the spread of influenza within a hospital, although uptake by health care workers remains low. We conducted semistructured interviews with seven medical students and nine early career doctors, to explore the factors informing their influenza vaccination decision making. Data collection and analysis took place iteratively, until theoretical saturation was achieved, and a thematic analysis was performed. Socialization was important although its effects were attenuated by participants' previous experiences and a lack of clarity around the risks and benefits of vaccination. Many participants did not have strong intentions regarding vaccination. There was considerable disparity between an individual's opinion of the vaccine, their intentions, and their vaccination status. The indifference demonstrated here suggests few are strongly opposed to the vaccination-there is potential to increase vaccination coverage. PMID- 28737076 TI - The communication skills and the empathic tendency levels of nursing students: a cross-sectional study. AB - BACKGROUND: The most basic component of communication skills is the complex and multidimensional skill of empathy. AIM: This study was conducted to assess the communication skills and empathic tendency levels of female nursing students Turkish university. METHODS: This cross-sectional study sample consisted of 342 nurse student. RESULTS: There was a significant difference between the classes in terms of communication skills (0.021, p < .05) but no significant difference in terms of the empathic tendency levels (0.712, p > .05). The mean communication skills score increased in the final year but empathic tendency levels did not increase with increasing school years. CONCLUSION: This result suggests that the empathic tendency level could not be increased with the courses in the curriculum in our study. The results suggest that empathic tendency levels were not increased with subsequent nursing coursework. Determining empathic predisposition levels prior to entry into nursing programs should therefore be considered. PMID- 28737077 TI - Systematic Screening of Adverse Reactions to Metal Debris after Recap-M2A-Magnum Metal-on-Metal Total Hip Arthroplasty. AB - BACKGROUND AND AIMS: An adverse reaction to metal debris is a known complication after large diameter head metal-on-metal total hip arthroplasty. However, the failure rate varies depending on the implant design. Therefore, we investigated the prevalence of adverse reaction to metal debris, as well as the symptoms and risk factors after undergoing a ReCap-M2a-Magnum large diameter head metal-on metal total hip arthroplasty. MATERIALS AND METHODS: Between 2005 and 2012, 1188 patients (1329 hips) underwent ReCap-M2a-Magnum total hip arthroplasty at our institution. Systematic screening for adverse reaction to metal debris was arranged using the Oxford Hip Score questionnaire, hip and pelvic radiographs, and assessments of the serum chromium and cobalt ion levels. Clinical evaluation and magnetic resonance imaging were performed for the symptomatic patients, as well as those with either chromium or cobalt ion levels ?5 ug/L. The prevalence of adverse reaction to metal debris after ReCap-M2a-Magnum total hip arthroplasty was assessed, and the risk factors for adverse reaction to metal debris were evaluated using logistic regression. The mean follow-up time was 5.2 (0.003-9.1) years. This study was an extension of a previous study conducted at our institution with 80 patients. RESULTS: In total, 33 patients (33 hips, 2.5% of all hips) required a revision operation due to adverse reaction to metal debris. Moreover, 157 hips exhibited definitive adverse reaction to metal debris, but a revision operation was not performed (157 of 1329 hips, 11.8% of all hips). Overall, 190 out of 1329 (14.3%) hips had definitive adverse reaction to metal debris. Pain, subluxation sensation, clicking, swelling, a small head size, and a fair/poor Oxford Hip Score were associated with definitive adverse reaction to metal debris. CONCLUSION: We found a high prevalence of adverse reaction to metal debris in the ReCap-M2a-Magnum total hip arthroplasty patients in this study; however, most of the patients did not require revision operations. PMID- 28737078 TI - Effect heating dwell time has on the retention of heavy metals in the structure of lightweight aggregates manufactured from wastes. AB - : The main objective of this paper was to study how effective thermal treatment is in the retention of different heavy metals (HMs) within the structure of artificial lightweight aggregates (LWAs). These LWAs were manufactured by washing aggregate sludge and sewage sludge. The consequence of increasing the heating dwell time whilst manufacturing these LWAs was also determined. Partitioning of the HMs (Cr, Ni, Cu, Zn, Cd and Pb) was studied by means of the optimized BCR sequential extraction procedure. Then, the leaching ratio (LRx,y) was calculated. Thermal treatment was totally effective for immobilizing most of the elements studied except for a part of the non-residual Zn and Cd fraction which could volatilize, and the fractions of Pb which were water- and acid-soluble, weakly adsorbed, exchangeable, and oxidable. These were more highly concentrated in the LWAs than in the initial waste mixture. The effect of increasing heating dwell time on the retention of heavy metals in the LWAs depended on both the chemical element studied and the heating dwell time. This study is very important since certain rises in the heating dwell time caused a decrease in retention of some specific heavy metals in the LWAs. ABBREVIATIONS: BCR-SEP: optimized BCR sequential extraction procedure; b.d.l: below the detection limit; F1: weakly adsorbed, exchangeable and water- and acid- soluble fraction; F2: reducible fraction; F3: oxidable fraction; F4: residual fraction; HM: heavy metal; ICP-MS: inductively coupled plasma-mass spectroscopy; LOI: loss on ignition; LWA: lightweight aggregate; LWA-5: lightweight aggregate sintered for 5 min; LWA-10: lightweight aggregate sintered for 10 min; LWA-20: lightweight aggregate sintered for 20 min; LWA-30: lightweight aggregate sintered for 30 min; LRx,y: leaching ratio of the element x in the fraction y; n.e: not established; S: compressive strength; SS: sewage sludge; WA24h: water absorption after 24 hours; WAS: washing aggregate sludge; W75S25: mixture of 75% (wt) of the dried washing aggregate sludge and 25% (wt) of the dried sewage sludge; rhob: loose bulk density; rhod: dry particle density; ?1 + 2 + 3: non-residual fraction; ?1 + 2 + 3 + 4: total concentration; ?2 + 3: reducible and oxidable fractions. PMID- 28737079 TI - Menstrual Education and Personal Hygiene Supplies to Empower Young Women in Haiti. AB - Recent studies report that Haitian women are concerned about unmet women's health issues. The Days for Girls (DfG) International program features women's health education and personal hygiene kits to ensure women understand the process of menstruation and sanitary hygiene practices. The aim was to train Haitian seamstresses to produce the DfG kits during an in-country workshop and investigate the perceived benefit of the DfG program in young women who used the DfG kits. Posttest only design was used to measure the effectiveness of DfG workshop and postsurvey to study perception of women using DfG kits. It was found that the workshop participants demonstrated an understanding of the DfG program (90% average). Forty-four young women (89.8%) who used the DfG hygiene kits for 2 months agreed that there is a need for feminine hygiene programs in Haiti and that the kits were easy to use and clean (97.1% and 92.1%, respectively). The DfG program could provide a cost-effective feminine hygiene program for Haiti and decrease waste from traditional hygiene products. PMID- 28737080 TI - SBR treatment of tank truck cleaning wastewater: sludge characteristics, chemical and ecotoxicological effluent quality. AB - A lab-scale activated sludge sequencing batch reactor (SBR) was used to treat tank truck cleaning (TTC) wastewater with different operational strategies (identified as different stages). The first stage was an adaptation period for the seed sludge that originated from a continuous fed industrial plant treating TTC wastewater. The first stage was followed by a dynamic reactor operation based on the oxygen uptake rate (OUR). Thirdly, dynamic SBR control based on OUR treated a daily changing influent. Lastly, the reactor was operated with a gradually shortened fixed cycle. During operation, sludge settling evolved from nearly no settling to good settling sludge in 16 days. The sludge volume index improved from 200 to 70 mL gMLSS-1 in 16 days and remained stable during the whole reactor operation. The average soluble chemical oxygen demand (sCOD) removal varied from 87.0% to 91.3% in the different stages while significant differences in the food to mass ratio were observed, varying from 0.11 (stage I) to 0.37 kgCOD.(kgMLVSS day)-1 (stage III). Effluent toxicity measurements were performed with Aliivibrio fischeri, Daphnia magna and Pseudokirchneriella subcapitata. Low sensitivity of Aliivibrio was observed. A few samples were acutely toxic for Daphnia; 50% of the tested effluent samples showed an inhibition of 100% for Pseudokirchneriella. PMID- 28737081 TI - Hypotension of ?110 mmHg is Associated with Increased Mortality in South African Patients After Trauma. AB - INTRODUCTION: This study used data from a prospectively maintained trauma database to assess the level of systolic blood pressure at which mortality rates for trauma begin to increase and to compare systolic blood pressure with base deficit as a predictor of outcome. METHODOLOGY: The Pietermaritzburg Metropolitan Trauma Service maintains a prospective digital trauma registry. All trauma patients admitted to the service for the period January 2012-January 2015 were included. Analysis was performed on systolic blood pressure relative to a number of selected markers of outcome and a variety of physiological parameters. RESULTS: Out of an original data set of 2974 trauma patients, a total of 169 elective patients, 799 patients with isolated traumatic brain injury, and 27 patients with incomplete data were excluded to leave a sample size of 2148 patients. Of these, 1830 (85.2%) were males and 318 (14.8%) were females. The mean age (standard deviation) was 31.8 (12.0) years. The median age (interquartile range) was 29 (23-37) years. There were 89 deaths in this cohort (4.1%). The median systolic blood pressure (interquartile range) was 123 (112 136) mmHg. The median base deficit was -1.4 (interquartile range: -4.5 to 1). The inflection curves below with fitted non-linear curve clearly show the upward change in mortality frequency around a systolic blood pressure of ?110 mmHg as well for a base deficit below -5. A cutoff of <110 for systolic blood pressure yields a high sensitivity and very high positive predictive value of 82% (95% confidence interval: 81-84) and 98% (95% confidence interval: 97-98), but low specificity (56%) and negative predictive value (12%), respectively. Similar optimal cutoff analysis for base deficit versus mortality suggests base deficit >4.8 as a good predictor area under the curve (0.82; 95% confidence interval: 0.75-0.88). This cutoff yields a high sensitivity of 80% (95% confidence interval: 78-82), moderate specificity of 75% (95% confidence interval: 62-85), very high positive predictive value of 98% (95% confidence interval: 97-99) but low negative predictive value of 17% (15-28). CONCLUSION: The data suggest that traumatic shock starts to become manifest at a systolic blood pressure of 110 mmHg and that a systolic blood pressure reading of 90 mmHg represents an advanced state of shock. Systolic blood pressure by itself is a poor predictor of mortality and outcome. Base deficit appears to be a far better predictor of mortality than systolic blood pressure. Future models to categorize shock will have to combine vital signs with biochemical markers of hypoperfusion. PMID- 28737083 TI - ? PMID- 28737082 TI - Myth, Manners, and Medical Ritual: Defensive Medicine and the Fetish of Antibiotics. AB - Given the global crisis of antimicrobial resistance, the continued misuse of antibiotics is perplexing, particularly despite persistent attempts to curb usage. This issue extends beyond traditional "wastage" areas, of livestock and community medicine, to hospitals, raising questions regarding the current principles of hospital practice. Drawing on five focus group discussions, we explore why doctors act in the ways they do regarding antibiotics, revealing how practices are done, justified, and perpetuated. We posit that antibiotic misuse is better understood in terms of social relations of fear, survival and a desire for autonomy; everyday rituals, performances, and forms of professional etiquette; and the mixed obligations evident in the health sector. Moreover, that antibiotic misuse presents as a case study of the broader problematic of defensive medicine. We argue that the impending global antibiotic crisis will involve understanding how medicine is built around certain logics of practice, many that are highly resistant to change. PMID- 28737084 TI - ? PMID- 28737085 TI - ? PMID- 28737086 TI - Prevalence, influencing factors, screening and diagnosis of delirium at stationary hospitalised patients in a Swiss acute Hospital. A pilot study AB - Background: Deliria have a massive effect on patients, from increased duration of hospitalization to higher mortality. Risk factors such as age, deprivation of substances, immobility as well as stress are known among others. Particularly in vulnerable persons minor factors can lead to a delirium. European studies report a prevalence rate between 17 % and 22 %, but can't be compared to the Swiss hospital system. No national delirium prevalence data in acute hospitals is known. Aim: On the one hand to measure the delirium prevalence in an acute hospital, to elaborate patient characteristics of delirium patients based on group comparison and to test sensitivity and specifity of the applied instruments, on the other hand to get information about the practicality of the study execution. Method: Delirium point prevalence measurement has been conducted in a prospective cross-sectional study. On one determined day data of patients have been collected by nurses in an acute hospital. Results: A prevalence point rate of 14 % (6 / 43) based on CAM has been identified. Significant differences were found between the groups in respect of age, discipline, number of ICD diagnoses, care dependency and in all the three delirium instruments. Delirium patients were not only longer hospitalized but had almost twice as many ICD diagnosed, were high-maintenance patients and mostly didn't claim to be in pain. Conclusion: This is the first prevalence study in a Swiss acute hospital. The utilized instruments are reliable and the study execution is practicable and could be conducted with a larger sample. Most known risk factors were confirmed. PMID- 28737088 TI - ? PMID- 28737087 TI - Getting home with artifical heart - what is the everyday life experience of people with mechanical circulatory Support. A qualitative study AB - Background: The growing number of mechanical circulatory support systems implanted with successful results in terms of quality of life and physical resilience means that more and more people are being discharged from hospital to live at home with an artificial heart. This puts high requirements on affected persons' disease and therapy management - a subject which has attracted very little qualitative research to date. Aim: This study therefore sought to shed light on how people with mechanical circulatory support experience their everyday lives. The aim was to document the subjective associations of those affected from an insider perspective. Methods: Following the interpretative phenomenological paradigm, narrative interviews were conducted with two female and eight male participants. For qualitative analysis, a multi-step process guided by the methodology of hermeneutic philosophy was used. Results: The qualitative data analysis revealed five main topic areas. These describe patients' state of health after implantation and the various adjustments, constraints and pressures necessitated by their illness and therapeutic requirements. On this basis, coping and management strategies are identified. Other significant aspects of patients' everyday lives are social interaction and environment and health care with an artificial heart. Conclusions: The findings add to our knowledge of the day-to day lives of people with mechanical circulatory support systems, giving us a better understanding of their specific situation. PMID- 28737090 TI - ? PMID- 28737089 TI - A guideline for adults with an indwelling urinary catheter in different health care Settings - methodological procedures AB - Background: People with an indwelling urinary catheter often suffer from complications and health care professionals are regularly confronted with questions about catheter management. Clinical guidelines are widely accepted to promote evidence-based practice. In the literature, the adaptation of a guideline is described as a valid alternative to the development of a new one. Aim: To translate a guideline for the care for adults with an indwelling urinary catheter in the acute and long term care setting as well as for home care. To adapt the guideline to the Swiss context. Method: In a systematic and pragmatic process, clinical questions were identified, guidelines were searched and evaluated regarding clinical relevance and quality. After each step, the next steps were defined. Results: An English guideline was translated, adapted to the local context and supplemented. The adapted guideline was reviewed by experts, adapted again and approved. After 34 months and an investment of a total of 145 man working days, a guideline for the care for people with an indwelling urinary catheter is available for both institutions. Conclusions: Translation and adaptation of a guideline was a valuable alternative to the development of a new one; nevertheless, the efforts necessary should not be underestimated. For such a project, sufficient professional and methodological resources should be made available to achieve efficient guideline work by a constant team. PMID- 28737091 TI - ? PMID- 28737093 TI - ? PMID- 28737092 TI - ? PMID- 28737094 TI - ? PMID- 28737095 TI - Impact of Body Mass Index on Complications and Survival after Surgery for Esophageal and Gastro-Esophageal-Junction Cancer. AB - BACKGROUND AND AIMS: The impact of body mass index on complications and survival in patients undergoing esophagectomy has been extensively studied with conflicting results. In this study, we assess the impact of body mass index on complications and survival following surgery for esophageal and gastro-esophageal junction cancer in a Danish population. MATERIAL AND METHODS: We identified 285 consecutive patients, who underwent curative-intended treatment for esophageal and gastro-esophageal-junction cancer in the period 2003-2010. We manually reviewed the electronic medical records of all patients included in the study. Body mass index was calculated as weight in kilograms divided by height in meters squared. We grouped patients according to their body mass index, using the World Health Organization definition, as underweight (body mass index < 18.5 kg/m2), normal weight (body mass index: 18.5-24.9 kg/m2), overweight (body mass index: 25 29.9 kg/m2), and obese (body mass index ? 30 kg/m2). RESULTS: Median age at surgery was 65 years (range: 27-84 years), of which 207 (72.6%) were males. Patients with the lowest body mass index and the obese patients seemed to have a higher frequency of minor complications. Anastomotic leakage occurred in less than 10% of the patients and was equally distributed across the groups as was the other major complications. There were no differences in the 1-, 2-, or 5-year survival rates between the four body mass index groups after adjustment for possible confounders. Five-year survival rates for the four body mass index groups were 31.8%, 28.7%, 27.9%, and 26.1%, respectively. CONCLUSION: Body mass index over 30 or under 18.5 does not seem to affect survival rates or the presence of serious postoperative complications following esophagectomy in patients with esophageal and gastro-esophageal-junction cancers not receiving neoadjuvant oncological treatment. PMID- 28737096 TI - As You Sow, So Shall You Reap: Gender-Role Attitudes and Late-Life Cognition. AB - Some studies have found that women outperform men in episodic memory after midlife. But is this finding universal, and what are the reasons? Gender differences in cognition are the result of biopsychosocial interactions throughout the life course. Social-cognitive theory of gender development posits that gender roles may play an important mediating role in these interactions. We analyzed country differences in the gender differential in cognition after midlife using data from individuals age 50 and above ( N = 226,661) from 27 countries. As expected, older women performed relatively better in countries characterized by more equal gender-role attitudes. This result was robust to cohort differences as well as reverse causality. The effect was partially mediated by education and labor-force participation. Cognition in later life thus cannot be fully understood without reference to the opportunity structures that sociocultural environments do (or do not) provide. Global population aging raises the importance of understanding that gender roles affect old-age cognition and productivity. PMID- 28737097 TI - Elevated Levels of Procalcitonin and Interleukin-6 are Linked with Postoperative Complications in Cardiac Surgery. AB - BACKGROUND: Cardiac surgery-associated acute kidney injury is a frequent and serious postoperative complication of cardiac surgery and is associated with an increased risk of morbidity, mortality, and length stay. In this study, we hypothesized that persistent elevation in inflammation in the first 48 h might be a powerful predictor of clinical outcome. Our aim was to elucidate the usefulness of interleukin-6 and procalcitonin postoperative levels in predicting mortality and renal complications in cardiac surgery patients. METHODS: A total of 122 cardiac surgery patients were enrolled. Procalcitonin and interleukin-6 concentrations were measured on the second postoperative day, and their levels were evaluated versus a number of conditions and endpoints. RESULTS: Procalcitonin has a good predictive value for adverse renal outcome (p < 0.05). Interleukin-6 has a good predictive value for 30 days and overall mortality in cardiac surgery population (p < 0.05). We did not observe a significant difference in procalcitonin and interleukin-6 levels among patients with different types of surgery and different extracorporeal circulation time, but the levels of both the molecules increase significantly depending on number of transfusions received by patients (p < 0.01). CONCLUSION: We speculated that procalcitonin and interleukin-6 could be two effective biomarkers. There is a possibility of having a combined inflammatory multi-biomarker panel, with procalcitonin for predicting renal outcome and interleukin-6 for predicting mortality. PMID- 28737098 TI - Abdominal Wall Morbidity Following Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy. AB - BACKGROUND: Incisional hernia formation has been reported as high as 20% within 1 year following midline laparotomy. Since hyperthermic intraperitoneal chemotherapy is likely to impair wound healing, we sought to investigate the incidence of incisional hernia formation and abdominal wall rupture following cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. METHODS: Consecutive patients with radiographic evidence of peritoneal metastases were scheduled for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy at the Comprehensive Cancer Center, University Hospital Tuebingen, Germany. Clinical data were retrospectively analyzed. RESULTS: Between May 2005 and May 2014, 271 patients underwent cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. Within follow-up, 19 (7%) incisional hernias and 11 (4%) abdominal wall ruptures were observed. Age ?70 years, cardio-pulmonary comorbidity, the presence of pseudomyxoma peritonei or mesothelioma, and postoperative abdominal wall rupture were detected as risk factors for hernia formation. However, Cox multivariate analysis only confirmed the presence of pseudomyxoma peritonei or mesothelioma and postoperative abdominal wall rupture as independent risk factors. CONCLUSION: Our data do not suggest that cytoreductive surgery and hyperthermic intraperitoneal chemotherapy is necessarily associated with a higher incidence of incisional hernia formation. However, patients suffering from pseudomyxoma peritonei or mesothelioma and patients with postoperative abdominal wall rupture seem to be at risk for developing incisional herniation. PMID- 28737099 TI - Concentrations and human health risk assessment of DDT and its metabolites in free-range and commercial chicken products from KwaZulu-Natal, South Africa. AB - Organochlorine pesticides such as dichlorodiphenyltrichloroethane (DDT) have been used in agriculture and for disease control purposes over many decades. Reports suggest that DDT exposure may result in a number of adverse effects in humans. In the KwaZulu-Natal Province of South Africa, DDT is sprayed annually in homes (indoor residual spraying) to control the mosquito vector of malaria. In the northern part of the Province, samples of free-range chicken meat (n = 48) and eggs (n = 13), and commercially produced chicken meat (n = 6) and eggs (n = 11), were collected and analysed. Of the free-range chicken meat samples, 94% (45/48) contained DDTs (SigmaDDTs median 6.1 ng/g wet weight [ww], maximum 79.1 ng/g ww). Chicken egg contents were also contaminated (SigmaDDTs in free-range eggs median 9544 ng/g ww, maximum 96.666 ng/g ww; and in commercial eggs median 1.3 ng/g ww, maximum 4.6 ng/g ww). The predominant DDT congener detected was p,p'-DDE in both free-range meat (>63%) and eggs (>66%), followed by p,p'-DDT and then p,p'-DDD. Based on estimated daily intake values, calculated human risk ratio (carcinogenic) values were >1 for DDTs detected in both free-range chicken products. Consumption of free-range eggs poses a particularly high health risk. PMID- 28737100 TI - Laser surgery versus radiotherapy for T1a glottic carcinoma: a meta-analysis of oncologic outcomes. AB - OBJECTIVES: A meta-analysis was conducted to compare oncologic outcomes for patients of T1a glottic carcinoma who were treated with laser surgery (LS) or radiotherapy (RT). METHODS: All related studies published up to October 2016 were acquired by searching PubMed, EMBASE, and Cochrane were conducted by two authors, with the index words: vocal, glottis, larynx, laser, surgery, cordectomy, radiotherapy, radiation, irradiation, carcinoma, and cancer. Relative studies which compared oncologic outcomes between LS and RT were included. RESULTS: A total of nine eligible studies were included for the analysis, which contained two prospective studies and seven retrospective studies. LS has increased larynx preservation (OR = 3.86, 95% CI = 1.47-10.13, p = .006) compared with RT group. No statistical difference was observed between LS group and RT group in terms of local control, overall survival, and disease-specific survival. There was a slight trend in terms of local control, overall survival, and disease-specific survival that all favored LS, although all data did not reach the level of statistical significance. CONCLUSIONS: The results of this meta-analysis indicate that LS may be a better option for the treatment of T1a glottic carcinoma because patients underwent LS may benefit from increased larynx preservation compared with RT. However, more multi-center randomized controlled trials would be urgently needed to prove these differences. PMID- 28737101 TI - Intervention to Prevent Falls: Community-Based Clinics. AB - PURPOSE: The purpose of this study was to document results of State funded fall prevention clinics on rates of self-reported falls and fall-related use of health services. METHODS: Older adults participated in community-based fall prevention clinics providing individual assessments, interventions, and referrals to collaborating community providers. A pre-post design compares self-reported 6 month fall history and fall-related use of health care before and after clinic attendance. RESULTS: Participants ( N = 751) were predominantly female (82%) averaging 81 years of age reporting vision (75%) and mobility (57%) difficulties. Assessments revealed polypharmacy (54%), moderate- to high-risk mobility issues (39%), and postural hypotension (10%). Self-reported preclinic fall rates were 256/751(34%) and postclinic rates were 81/751 (10.8%), ( p = .0001). Reported use of fall-related health services, including hospitalization, was also significantly lower after intervention. IMPLICATIONS: Evidence-based assessments, risk-reducing recommendations, and referrals that include convenient exercise opportunities may reduce falls and utilization of health care services. Estimates regarding health care spending and policy are presented. PMID- 28737103 TI - First Tarsometatarsal Joint Derotational Arthrodesis for Flexible Hallux Valgus: Results from Follow-Up of 3-8 Years. AB - PURPOSE: We report 3- to 8-year follow-up results for the first tarsometatarsal joint derotational arthrodesis. METHODS: A total of 70 patients (88 feet) with symptomatic flexible hallux valgus were operated between 2003 and 2009. In all, 66 patients (94.3%) with 84 (95.5%) feet were enrolled in retrospective analysis; of those, 58 (87.9%) patients with 76 (90.5%) feet were followed for a mean of 5.1 (range: 3.0-8.3) years. Preoperative, 6 week postoperative, and late follow up weightbearing radiographs were evaluated along with clinical examination and questionnaires. RESULTS: The mean hallux valgus angle improved 13.4 degrees (95% confidence interval: 11.6-15.1, p < .001) at the latest follow-up, while the mean intermetatarsal angle correction was 4.5 degrees (95% confidence interval: 3.7 5.2, p < .001). There were three (4.0%) nonunions, and seven (9.2%) feet needed reoperation during follow-up. CONCLUSION: First tarsometatarsal joint derotational arthrodesis is an effective procedure for correcting flexible hallux valgus deformity and provides a satisfactory long-term outcome. PMID- 28737102 TI - Comparative effectiveness of rivaroxaban in the treatment of nonvalvular atrial fibrillation. AB - Rivaroxaban is a direct oral anticoagulant (DOAC) approved for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation, a common arrhythmia. In this review, we summarize the effectiveness of rivaroxaban versus warfarin and the DOACs dabigatran, apixaban and edoxaban. The primary focus is on primary evidence from clinical trials, indirect comparison studies and real-world studies. While there are gaps in the literature, the evidence thus far indicates that rivaroxaban is superior to warfarin and similar to dabigatran, apixaban and edoxaban for the prevention of stroke or systemic embolism in patients with nonvalvular atrial fibrillation, although rivaroxaban may be associated with an elevated bleeding risk compared with other DOACs. PMID- 28737104 TI - Severe Postoperative Complications may be Related to Mesenteric Traction Syndrome during Open Esophagectomy. AB - BACKGROUND: During abdominal surgery, traction of the mesenterium provokes mesenteric traction syndrome, including hypotension, tachycardia, and flushing, along with an increase in plasma prostacyclin (PGI2). We evaluated whether postoperative complications are related to mesenteric traction syndrome during esophagectomy. METHODS: Flushing, hemodynamic variables, and plasma 6-keto PGF1alpha were recorded during the abdominal part of open ( n = 25) and robotically assisted ( n = 25) esophagectomy. Postoperative complications were also registered, according to the Clavien-Dindo classification. RESULTS: Flushing appeared in 17 (open) and 5 (robotically assisted) surgical cases ( p = 0.001). Mean arterial pressure was stable during both types of surgeries, but infusion of vasopressors during the first hour of open surgery was related to development of widespread (Grade II) flushing ( p = 0.036). For patients who developed flushing, heart rate and plasma 6-keto-PGF1alpha also increased ( p = 0.001 and p < 0.001, respectively). Furthermore, severe postoperative complications were related to Grade II flushing ( p = 0.037). CONCLUSION: Mesenteric traction syndrome manifests more frequently during open than robotically assisted esophagectomy, and postoperative complications appear to be associated with severe mesenteric traction syndrome. PMID- 28737105 TI - Future of Diabetes Technology. PMID- 28737106 TI - Disparities in the Prevalence of Unmet Needs and Their Consequences Among Black and White Older Adults. AB - OBJECTIVE: We document differential prevalence of need for assistance with personal, instrumental, and mobility tasks and adverse consequences of unmet needs, nursing home relocation, and mortality among Black and White older adults. METHOD: Data are from the National Health and Aging Trends Study. Using logistic and multinomial logistic regression, we determine whether race is predictive of reporting need or adverse consequence and test the role of race as a moderator of the relationship between baseline need and three 1-year outcomes. RESULTS: Black older adults are more likely to experience a consequence of unmet need (35.33% vs. 29.97%, p = .028) in unadjusted models. In adjusted models, we find no moderating effect of race on baseline need on nursing home placement (0.00, 95% confidence interval [CI] = [-2.43, 2.42], p = .991), mortality (0.73, 95% = [ 1.58, 0.11], p = .089), or a Round 2 consequence of unmet (-0.51, 95% CI = [ 1.15, 0.14], p = .121). DISCUSSION: This work highlights the complex relationship between race, need, unmet need, mortality, and nursing home entry. PMID- 28737107 TI - Characterization of Enterococcus faecalis isolates by chicken embryo lethality assay and ERIC-PCR. AB - Enterococcus faecalis is the major causative agent of amyloid arthropathy in chickens. Given the difficulty of estimating the risk from field strains, the embryo lethality assay (ELA) is proposed in this study as a model to predict the virulence of 68 avian E. faecalis strains. Additionally, Enterobacterial Repetitive Intergenic Consensus Polymerase Chain Reaction (ERIC-PCR) was used to characterize the genetic diversity of the E. faecalis strains. The ELA was performed 10 times with subsets of 7-8 E. faecalis strains each on a sample of 9987 eggs, including control groups. An estimated 3-24 colony-forming units were inoculated into the allantoic cavity of 10-day-old embryos. The embryonic mortality rate (EMR) was determined by means of candling the eggs over a period of seven days. The ELA was able to distinguish the virulence of the E. faecalis strains. Twenty-six strains were considered as avirulent strains with an EMR of below 40%. Five strains were highly virulent with an EMR above 80%. The remaining 37 strains were classified as strains of moderate virulence, causing an EMR between 40% and 80%. The highest EMR occurred three and four days post inoculation (p.i.). From the fourth day p.i., almost no embryonic mortality was observed. Therefore, the ELA could be optimized by reducing experiment duration to four days p.i. ERIC-PCR did not cluster the strains according to its virulence, although ERIC banding patterns revealed a considerable genetic diversity. In conclusion, the ELA can be considered a reliable and useful tool to predict the virulence of avian E. faecalis strains. PMID- 28737108 TI - Beliefs about emotion: implications for avoidance-based emotion regulation and psychological health. AB - People's beliefs about their ability to control their emotions predict a range of important psychological outcomes. It is not clear, however, whether these beliefs are playing a causal role, and if so, why this might be. In the current research, we tested whether avoidance-based emotion regulation explains the link between beliefs and psychological outcomes. In Study 1 (N = 112), a perceived lack of control over emotions predicted poorer psychological health outcomes (increased self-reported avoidance, lower well-being, and higher levels of clinical symptoms), and avoidance strategies indirectly explained these links between emotion beliefs and psychological health. In Study 2 (N = 101), we experimentally manipulated participants' emotion beliefs by leading participants to believe that they struggled (low regulatory self-efficacy) or did not struggle (high regulatory self-efficacy) with controlling their emotions. Participants in the low regulatory self-efficacy condition reported increased intentions to engage in avoidance strategies over the next month and were more likely to avoid seeking psychological help. When asked if they would participate in follow-up studies, these participants were also more likely to display avoidance-based emotion regulation. These findings provide initial evidence for the causal role of emotion beliefs in avoidance-based emotion regulation, and document their impact on psychological health-related outcomes. PMID- 28737109 TI - Clinical outcome prediction after thrombectomy of proximal middle cerebral artery occlusions by the appearance of lenticulostriate arteries on magnetic resonance angiography: A retrospective analysis. AB - Post-ischemic vasodynamic changes in infarcted brain parenchyma are common and range from hypo- to hyperperfusion. In the present study, appearance of the lenticulostriate arteries (LSAs) on postinterventional 3T time-of-flight (TOF) MRA suggestive for altered post-stroke vasodynamics following thrombectomy was investigated. Patients who underwent thrombectomy for a proximal MCA occlusion and for whom postinterventional 3T TOF-MRA (median at day 3) was available, were included in this retrospective analysis (n=98). LSA appearance was categorized into presence (LSA-sign+) or absence (LSA-sign-) of vasodilatation in the ischemic hemisphere. Functional outcome was determined using the modified Rankin scale (mRS). LSA-sign+ was observed in 64/98 patients. Hypertension (adjusted OR: 0.171, 95% CI: 0.046-0.645) and preinterventional IV rtPA (adjusted OR: 0.265, 95% CI: 0.088-0.798) were associated with absence of the LSA-sign+. In multivariate logistic regression, LSA-sign+ was associated with substantial neurologic improvement (adjusted OR: 10.18, 95% CI: 2.69-38.57) and good functional outcome (discharge-mRS <= 2, adjusted OR: 7.127, 95% CI: 1.913-26.551 and day 90 mRS <= 2, adjusted OR: 3.786, 95% CI: 1.026-13.973) after correcting for relevant confounders. For all clinical endpoints, model fit improved when including the LSA-sign term (p<0.05). Asymmetrical dilatation of LSAs following successful thrombectomy indicates favorable neurologic and mid-term functional outcomes. This may indicate preserved cerebral blood flow regulatory mechanisms. PMID- 28737110 TI - The Introduction of Adult Appendicitis Score Reduced Negative Appendectomy Rate. AB - BACKGROUND AND AIMS: Implementation of a clinical risk score into diagnostics of acute appendicitis may provide accurate diagnosis with selective use of imaging studies. The aim of this study was to prospectively validate recently described diagnostic scoring system, Adult Appendicitis Score, and evaluate its effects on negative appendectomy rate. MATERIAL AND METHODS: Adult Appendicitis Score stratifies patients into three groups: high, intermediate, and low risk of appendicitis. The score was implemented in diagnostics of adult patients suspected of acute appendicitis in two university hospitals. We analyzed the effects of Adult Appendicitis Score on diagnostic accuracy, imaging studies, and treatment. The study population was compared with a reference population of 829 patients suspected of acute appendicitis originally enrolled for the study of construction of the Adult Appendicitis Score. RESULTS: This study enrolled 908 patients of whom 432 (48%) had appendicitis. The score stratified 49% of all appendicitis patients into high-risk group with specificity of 93.3%. In the low risk group, prevalence of appendicitis was 7%. The histologically confirmed negative appendectomy rate decreased from 18.2% to 8.7%, p<0.001, compared to the original dataset. CONCLUSION: Adult Appendicitis Score is a reliable tool for stratification of patients into selective imaging, which results in low negative appendectomy rate. PMID- 28737111 TI - Habit in Personality and Social Psychology. AB - Habits are largely absent from modern social and personality psychology. This is due to outdated perspectives that placed habits in conflict with goals. In modern theorizing, habits are represented in memory as implicit context-response associations, and they guide responding in conjunction with goals. Habits thus have important implications for our field. Emerging research shows that habits are an important mechanism by which people self-regulate and achieve long-term goals. Also, habits change through specific interventions, such as changes in context cues. I speculate that understanding of habits also holds promise for reducing intergroup discrimination and for understanding lay theories of the causes for action. In short, by recognizing habit, the field gains understanding of a central mechanism by which actions persist in daily life. PMID- 28737112 TI - Preoperative Aspartate Aminotransferase-to-Platelet Ratio Index Predicts Perioperative Liver-Related Complications Following Liver Resection for Colorectal Cancer Metastases. AB - BACKGROUND AND AIMS: There are limited data on the potential role of preoperative non-invasive markers, specifically the aspartate-to-alanine aminotransferase ratio and the aspartate aminotransferase-to-platelet ratio index, in predicting perioperative liver-related complications after hepatectomy for colorectal cancer metastases. METHODS: Patients undergoing liver resection for colorectal cancer metastases in a European institution during 2003-2010 were retrospectively enrolled. Relevant data, such as neoadjuvant chemotherapy, preoperative liver function tests, and perioperative complications, were collected from medical records. The nontumorous liver parenchyma in the surgical specimens of 31 patients was re-evaluated. RESULTS: Overall, 215 patients were included. In total, 40% underwent neoadjuvant chemotherapy and 47% major resection, while 47% had perioperative complications (6% liver-related). In multivariate regression analysis, the aspartate aminotransferase-to-platelet ratio index was independently associated with liver-related complications (odds ratio: 1.149, p = 0.003) and perioperative liver failure (odds ratio: 1.155, p = 0.012). The latter was also true in the subcohort of patients with neoadjuvant chemotherapy (odds ratio: 1.157, p = 0.004) but not in those without such therapy (p = 0.062). The aspartate-to-alanine aminotransferase ratio was not related to liver-related complications (p = 0.929). The area under the receiver operating characteristics curve for the aspartate aminotransferase-to-platelet ratio index as a predictor of liver-related complications was 0.857 (p = 0.008) in patients with neoadjuvant chemotherapy. Increasing aspartate aminotransferase-to-platelet ratio index was observed with an increase in degrees of sinusoidal obstruction syndrome (p = 0.01) but not for fibrosis (p = 0.175) or steatosis (p = 0.173) in the nontumorous liver in surgical specimens. CONCLUSION: The preoperative aspartate aminotransferase-to-platelet ratio index, but not the aspartate-to-alanine aminotransferase ratio, predicts perioperative liver-related complications following hepatectomy due to colorectal cancer metastases, in particular after neoadjuvant chemotherapy. The aspartate aminotransferase-to-platelet ratio index is related to sinusoidal obstruction syndrome in the nontumorous liver. PMID- 28737113 TI - MicroRNAs: Roles in Regulating Neuroinflammation. AB - MicroRNAs (miRNAs) are small noncoding RNAs that broadly affect cellular and physiological function in all multicellular organisms. Here, the role of miRNAs in neuroinflammation is considered. miRNAs are 21- to 23-oligonucleotide RNAs that regulate translation of specific RNAs by binding to complementary regulatory RNA sequences, thereby causing mRNA degradation or sequestration. More than 5000 miRNAs likely exist in humans, and each miRNA binds an average of 200 RNAs. Specific immunomodulatory miRNAs can regulate a set of RNAs in a coordinated manner, suggesting that effective miRNA-based therapeutic manipulations for neuroinflammatory conditions may be revealed. For instance, miRNAs that preferentially inhibit translation of many cellular anti-inflammatory proteins could drive a pro-inflammatory response. Key pro-inflammatory ( miR-155, miR-27b, miR-326), anti-inflammatory ( miR-124, miR-146a, miR-21, miR-223), and mixed immunomodulatory ( let-7 family) miRNAs regulate neuroinflammation in various pathologies, including spinal cord injury, multiple sclerosis, ischemic stroke, and Alzheimer's disease. miRNAs represent a newly revealed layer of physiological complexity, the therapeutic benefits of which remain to be fully explored and exploited. In this review, we discuss the role of miRNAs in neuroinflammatory regulation and discuss how controlling miRNAs could alter cellular machinery to improve neuroinflammatory dynamics. PMID- 28737114 TI - Streptococcus constellatus causing multiple liver abscesses: an elusive pathogen. PMID- 28737116 TI - Apoptotic induction induces Leishmania aethiopica and L. mexicana spreading in terminally differentiated THP-1 cells. AB - Leishmaniasis develops after parasites establish themselves as amastigotes inside mammalian cells and start replicating. As relatively few parasites survive the innate immune defence, intracellular amastigotes spreading towards uninfected cells is instrumental to disease progression. Nevertheless the mechanism of Leishmania dissemination remains unclear, mostly due to the lack of a reliable model of infection spreading. Here, an in vitro model representing the dissemination of Leishmania amastigotes between human macrophages has been developed. Differentiated THP-1 macrophages were infected with GFP expressing Leishmania aethiopica and Leishmania mexicana. The percentage of infected cells was enriched via camptothecin treatment to achieve 64.1 +/- 3% (L. aethiopica) and 92 +/- 1.2% (L. mexicana) at 72 h, compared to 35 +/- 4.2% (L. aethiopica) and 36.2 +/- 2.4% (L. mexicana) in untreated population. Infected cells were co cultured with a newly differentiated population of THP-1 macrophages. Spreading was detected after 12 h of co-culture. Live cell imaging showed inter-cellular extrusion of L. aethiopica and L. mexicana to recipient cells took place independently of host cell lysis. Establishment of secondary infection from Leishmania infected cells provided an insight into the cellular phenomena of parasite movement between human macrophages. Moreover, it supports further investigation into the molecular mechanisms of parasites spreading, which forms the basis of disease development. PMID- 28737117 TI - Prevalence and correlates of traumatic brain injury (TBI) in older adults: results from the Well-being of the Singapore Elderly (WiSE) study. AB - BACKGROUND: Older adults are among the most susceptible to sustain traumatic brain injury (TBI). The study aimed to determine the (1) prevalence of TBI among older adults in Singapore, and (2) socio-demographic, lifestyle, and clinical correlates of TBI. METHODS: Data were extracted from the cross-sectional, Well being of the Singapore Elderly (WiSE) study. The study included 2,565 participants aged 60 years and above (Mean = 72.75, SD = 9.54). Information on TBI, socio-demographic, and lifestyle factors were collected using participant self-report and verified with the informant report where necessary. Disability was measured using the World Health Organization - Disability Assessment Schedule 2.0 (WHO-DAS 2.0). Data were analyzed using logistic regression analysis. RESULTS: The prevalence of TBI was 3.6%. Being female (vs. male) was found to be associated with decreased odds of having TBI. Having completed secondary education or lower (vs. tertiary education) was found to be associated with increased odds of having TBI. A history of fainting and diabetes were associated with the presence of TBI. Those with TBI were associated with higher disability scores on the WHO-DAS 2.0 than those without TBI. CONCLUSIONS: The current study provides information on the prevalence and associated factors of TBI in the older adult population in Singapore. Since TBI was associated with older adults with diabetes, they must be cautioned about fall risk. Also, given the association with disability, older adults with TBI are likely to require support and rehabilitative care to ensure good quality of life. PMID- 28737118 TI - Subjective cognitive decline is longitudinally associated with lower health related quality of life. AB - BACKGROUND: Subjective cognitive decline (SCD), the potentially earliest notable manifestation of preclinical Alzheimer's disease and other dementias, was consistently associated with lower quality of life in cross-sectional studies. The aim of this study was to investigate whether such an association persists longitudinally - particularly with health-related quality of life (HRQoL) in older individuals without cognitive impairment. METHODS: Data were derived from follow-up 2-6 of the prospective Germany Study on Ageing, Cognition and Dementia in Primary Care (AgeCoDe) covering a total six-year observation period. We used linear mixed effects models to estimate the effect of SCD on HRQoL measured by the EQ-5D visual analogue scale (EQ VAS). RESULTS: Of 1,387 cognitively unimpaired individuals aged 82.2 years (SD = 3.2) on average, 702 (50.6%) reported SCD and 230 (16.6%) with SCD-related concerns. Effect estimates of the linear mixed effects models revealed lower HRQoL in individuals with SCD (unadjusted: -3.7 points on the EQ VAS, 95%CI = -5.3 to -2.1; SE = 0.8; p < 0.001; adjusted: -2.9 points, 95%CI = -3.9 to -1.9; SE = 0.5; p < 0.001) than in individuals without SCD. The effect was most pronounced in SCD with related concerns (unadjusted: -5.4, 95%CI = -7.6 to -3.2; SE = 1.1; p < 0.001; adjusted: 4.3, 95%CI = -5.8 to -2.9, SE = 0.7; p < 0.001). CONCLUSION: SCD constitutes a serious issue to older cognitively unimpaired individuals that is depicted in persisting lower levels of HRQoL beyond depressive symptoms and functional impairment. Therefore, SCD should be taken seriously in clinical practice. PMID- 28737119 TI - Passive surveillance of United Kingdom bats for lyssaviruses (2005-2015). AB - Passive surveillance for lyssaviruses in UK bats has been ongoing since 1987 and has identified 13 cases of EBLV-2 from a single species; Myotis daubentonii. No other lyssavirus species has been detected. Between 2005 and 2015, 10 656 bats were submitted, representing 18 species, creating a spatially and temporally uneven sample of British bat fauna. Uniquely, three UK cases originate from a roost at Stokesay Castle in Shropshire, England, where daily checks for grounded and dead bats are undertaken and bat carcasses have been submitted for testing since 2007. Twenty per cent of Daubenton's bats submitted from Stokesay Castle since surveillance began, have tested positive for EBLV-2. Phylogenetic analysis reveals geographical clustering of UK viruses. Isolates from Stokesay Castle are more closely related to one another than to viruses from other regions. Daubenton's bats from Stokesay Castle represent a unique opportunity to study a natural population that appears to maintain EBLV-2 infection and may represent endemic infection at this site. Although the risk to public health from EBLV-2 is low, consequences of infection are severe and effective communication on the need for prompt post-exposure prophylaxis for anyone that has been bitten by a bat is essential. PMID- 28737120 TI - Psychometric properties of the Perceived Stress Scale in a sample of German dementia patients and their caregivers. AB - BACKGROUND: The aim of the present study was to investigate the psychometric characteristics of the Perceived Stress Scale (PSS) in a sample of dementia patients and their spousal caregivers. METHODS: We investigated the reliability and validity of the 14-item PSS in a sample of 80 couples, each including one spouse who had been diagnosed with mild to moderate dementia (mean age 75.55, SD = 5.85, 38.7% female) and one spousal caregiver (mean age 73.06, SD = 6.75, 61.3% female). We also examined the factor structure and sensitivity of the scale with regard to gender differences. RESULTS: Exploratory factor analysis of the PSS revealed a two-factor solution for the scale; the first factor reflected general stress while the second factor consisted of items reflecting the perceived ability to cope with stressors. A confirmatory factor analysis verified that the data were a better fit for the two-factor model than a one-factor model. The two factors of the PSS showed good reliability for patients as well as for caregivers ranging between alpha = 0.73 and alpha = 0.82. Perceived stress was significantly positively correlated with depressive symptomatology in both caregivers and patients. Mean PSS scores did not significantly differ between male and female patients nor did they differ between male and female caregivers. CONCLUSION: The present data indicate that the PSS provides a reliable and valid measure of perceived stress in dementia patients and their caregivers. PMID- 28737121 TI - The impact of cancer development on the risk of mycobacterial diseases among rheumatoid arthritis patients. AB - Mycobacterial diseases are prevalent in cancer and rheumatoid arthritis (RA) patients, especially those receiving tumor necrosis factor-alpha inhibitor (TNFi). However, the impact of cancer development on the risk of mycobacterial diseases among RA patients is unknown. Data from the Taiwan National Health Insurance Research Database were used to conduct a retrospective study to assess the occurrence of mycobacterial diseases in RA patients developing cancer (cancer positive), those using TNFi (TNFi-exposure), those with cancer and using TNFi (cancer-TNFi-comb), and those without cancer and not using TNFi (cancer-TNFi free). Cancer and TNFi exposure were time-dependent, and independent risk factors of mycobacterial diseases were assessed by Cox regression. Among 1344 RA patients diagnosed during 2000-2013, 68 (5.1%) developed cancer before their end points. The incidence rates of mycobacterial diseases in the cancer-positive (n = 56), TNFi-exposure (n = 290), cancer-TNFi-comb (n = 12), and cancer-TNFi-free (n = 986) subgroups were 6.7, 2.0, 7.6, and 1.3 per 1000 person-years, respectively. As compared with the cancer-TNFi-free group, the risk for mycobacterial diseases increased for the TNFi-exposure group (adjusted HR = 3.6, 95% confidence interval (95% CI) 1.1-11.5, P = 0.032) and remained high for cancer-positive (adjusted HR = 14.6, 95% CI 3.3-63.7, P < 0.001) after adjustment. This study suggested that cancer development increased the risk of mycobacterial diseases in RA patients, and risk assessment for this subgroup should be considered. PMID- 28737122 TI - Preserved heart function after left ventricular pressure overload in adult mice subjected to neonatal cardiac hypoplasia. AB - Intrauterine growth restriction in animal models reduces heart size and cardiomyocyte number at birth. Such incomplete cardiomyocyte endowment is believed to increase susceptibility toward cardiovascular disease in adulthood, a phenomenon referred to as developmental programming. We have previously described a mouse model of impaired myocardial development leading to a 25% reduction of cardiomyocyte number in neonates. This study investigated the response of these hypoplastic hearts to pressure overload in adulthood, applied by abdominal aortic constriction (AAC). Echocardiography revealed a similar hypertrophic response in hypoplastic hearts compared with controls over the first 2 weeks. Subsequently, control mice develop mild left ventricular (LV) dilation, wall thinning and contractile dysfunction 4 weeks after AAC, whereas hypoplastic hearts fully maintain LV dimensions, wall thickness and contractility. At the cellular level, controls exhibit increased cardiomyocyte cross-sectional area after 4 weeks pressure overload compared with sham operated animals, but this hypertrophic response is markedly attenuated in hypoplastic hearts. AAC mediated induction of fibrosis, apoptosis or cell cycle activity was not different between groups. Expression of fetal genes, indicative of pathological conditions, was similar in hypoplastic and control hearts after AAC. Among various signaling pathways involved in cardiac hypertrophy, pressure overload induces p38 MAP-kinase activity in hypoplastic hearts but not controls compared with the respective sham operated animals. In summary, based on the mouse model used in this study, our data indicates that adult hearts after neonatal cardiac hypoplasia show an altered growth response to pressure overload, eventually resulting in better functional outcome compared with controls. PMID- 28737123 TI - Development and Validation of Eco-Friendly Liquid Chromatographic and Spectrophotometric Methods for Simultaneous Determination of Coformulated Drugs: Phenylephrine Hydrochloride and Prednisolone Acetate. AB - Five simple, sensitive, and eco-friendly LC and UV spectrophotometric methods have been developed for the simultaneous determination of phenylephrine hydrochloride (PHE) and prednisolone acetate (PRD) in their combined dosage form. The first method was reversed-phase (RP) LC using methanol-water-heptane-1 sulfonic acid sodium salt (75 + 25 + 0.1, v/v/w) as a mobile phase. Separation was achieved using an XSelect HSS reversed-phase C18 analytical column (250 * 4.6 mm, 5um). The flow rate was 1.0 mL/min and UV detection was done at 230 nm. Quantification was achieved over the concentration ranges of 5-50 ug/mL for PHE and 2-90 ug/mL for PRD. Four spectrophotometric methods were proposed, namely dual wavelength, first derivative of ratio spectra, ratio difference, and mean centering of ratio spectra. Linearity was observed in the concentration ranges of 10-120 and 5-35 ug/mL for PHE and PRD, respectively, for the spectrophotometric methods. Green solvents were used in the proposed methods because they play a vital role in the analytical methods' influence on the environment. The suggested methods were validated regarding linearity, accuracy, and precision according to the International Conference on Harmonization guidelines, with satisfactory results. These methods could be used as harmless substitutes for routine analysis of the mentioned drugs, with no interference from excipients. PMID- 28737124 TI - Distribution and expression of brain-derived neurotrophic factor, nerve growth factor, and neurotrophic factor-3 in refractory epilepsy-associated focal cortical dysplasia. AB - OBJECTIVE: To investigate the expression and distribution of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and neurotrophic factor-3 (NT-3) in refractory epilepsy-associated type I focal cortical dysplasia (FCD I) and FCD IIA patients, and to explore their effects on pathogenesis of FCD I and FCD IIA. MATERIALS AND METHODS: 19 subjects who received surgery at the Department of Neurosurgery, First Affiliated Hospital, Fujian Medical University, China between June 2010 and May 2012, were enrolled in this study. They were pathologically diagnosed as FCD IIA (n = 7) and FCD I (n = 12) after surgery and were considered as two experimental groups. Temporal lobe samples of 10 subjects who had suffered craniocerebral injury but did not have nervous system disease were collected as a control group. Immunohistochemical methods and Western blot assays were used to detect the expression and distribution of BDNF, NGF, and NT-3 in temporal lobes, and differences in their expression and distribution were compared between experimental and control groups. RESULTS: BDNF expression was slightly higher in the FCD IIA group compared to that in the FCD I group and was significantly greater when compared with the control group. Compared with the control group, NGF and NT-3 expression was higher in the FCD groups. However, no significant difference was observed between the FCD IIA and FCD I group. CONCLUSION: Abnormal distribution and expression of BDNF, NGF, and NT-3 may play an important role in the mechanism of FCD I and FCD IIA-induced epilepsy.?. PMID- 28737125 TI - Taxanes in combination with platinum derivatives for the treatment of ovarian cancer during pregnancy: A literature review?. AB - Ovarian cancer is one of the most common types of solid carcinoma diagnosed during pregnancy. Taxane plus a platinum derivative is a combination therapy that is predominantly used in the treatment of ovarian cancer in non-pregnant women. Pregnancy adds various complexities to a course of treatment. In pregnant patients diagnosed with cancer during the first trimester, the risks of fetal malformations and fetal loss increase following the administration of cytotoxic drugs, and this is higher with multi-agent vs. single-agent chemotherapy (~ 25 vs. 10%). Exposure during the second and third trimester has little influence on teratogenic effects but increases the risk of intrauterine growth retardation, prematurity, low birth weight, and bone marrow toxicity. The present study aimed to review the maternal and fetal safety of treatment with taxane plus platinum derivatives for ovarian cancer during pregnancy. Relevant literature was retrieved from the Embase and PubMed databases using the search terms "ovarian cancer", "pregnancy", "taxane", "paclitaxel", "docetaxel", "platinum", "cisplatin", and "carboplatin". All available data up until September 2016 was synthesized, with no language restrictions. A total of 11 articles (including 13 pregnancies and 14 newborns) were retrieved that reported on the use of standard dose taxane and platinum chemotherapy, including 9 cases treated with paclitaxel and carboplatin, 3 cases treated with paclitaxel and cisplatin, and 1 case treated with docetaxel and cisplatin. In 13 of the 14 (92.9%) births included, a healthy neonate was born, with follow-up ranging from 2 to 160 months. The average weight of the neonates at the time of delivery was 2,442.1 g. In 7 of 9 the case reports that provided survival data, the mother was alive and disease free at the end of follow-up (ranging from 2 to 40 months). In conclusion, combination therapy with taxanes and a platinum derivative may play a significant role in the management of pregnant patients with ovarian cancer during the second and third trimester. Exposure to this combination of agents during the second and third trimester does not appear to have a significant bearing on fetal mortality and abortion.?. PMID- 28737126 TI - Compliance with vaccination against hepatitis A virus in Germany: A retrospective analysis?. AB - OBJECTIVES: To analyze compliance with vaccination against hepatitis A virus (HAV) in patients followed in general and pediatric practices in Germany. MATERIALS AND METHODS: The present study included 7,323 patients from 575 general practices and 3,962 patients from 111 pediatric practices. Patients were included if they had received the first dose of one of the two following vaccines against HAV: Havrix(r) or Vaqta(r), between 2011 and 2014. The immunization schedule of these vaccines consisted of two injections. Patients were considered compliant if they received the second dose at the recommended time or within a period of +/- 25% around the recommended time (tolerance period). RESULTS: Of the recruited patients, 61.1% received the second vaccine injection within the tolerance period. Individuals treated in pediatric practices had a higher likelihood of receiving the vaccine dose within the tolerance period compared to individuals treated in general practices (OR = 1.19; 95% CI: 1.06 - 1.35; p = 0.005). Furthermore, patients under the age of 18 years were more likely to be compliant than patients over the age of 30 years (OR = 1.53; 95% CI: 1.40 - 1.68; p < 0.001), while patients between 18 and 30 years (OR = 0.85; 95% CI: 0.77 - 0.93; p < 0.001) were the least likely to be compliant. CONCLUSION: Compliance with complete vaccination against HAV was low.?. PMID- 28737127 TI - Pharmacokinetics and safety of sacubitril/valsartan (LCZ696) in patients with mild and moderate hepatic impairment?. AB - OBJECTIVES: To assess the protein binding and pharmacokinetics of sacubitril/valsartan analytes (sacubitril, sacubitrilat, and valsartan) in an open-label, single oral dose (200 mg), parallel-group study in patients with mild and moderate hepatic impairment (Child-Pugh class A and B) and matched healthy subjects. METHODS: This study enrolled 32 subjects (n = 8 in each hepatic impairment and matched healthy subjects groups). Blood samples were collected at pre-determined time points to assess pharmacokinetics of sacubitril, sacubitrilat, and valsartan. Subjects with severe hepatic impairment were excluded as valsartan exposure is expected to be substantially increased in these patients. RESULTS: Sacubitril exposure (AUC) increased by 53% and 245% while the exposure to sacubitrilat was increased by 48% and 90% in patients with mild and moderate hepatic impairment, respectively. Sacubitril Cmax increased by 57% and 210% in mild and moderate hepatic impairment; however, for both sacubitrilat and valsartan, Cmax was unchanged. Valsartan AUC increased in patients with mild and moderate hepatic impairment by 19 - 109%, respectively. CONCLUSIONS: The increase in systemic exposures to all sacubitril/valsartan analytes correlated with the severity of liver disease. The plasma unbound fraction of sacubitrilat in patients with moderate hepatic impairment was slightly higher than in matched healthy subjects. This difference was not considered clinically significant. Safety assessments showed that sacubitril/valsartan was safe and well tolerated across all the study groups.?. PMID- 28737128 TI - Bioequivalence of two oseltamivir formulations in healthy Chinese volunteers?. AB - BACKGROUND: The aim of this study was to compare the bioavailability of a new generic formulation of oseltamivir 75-mg capsule (test) and a branded formulation Tamiflu(r) (reference) to meet regulatory criteria for marketing the test product in healthy Chinese male volunteers. METHODS: This single-dose, randomized-sequence, open-label, two-period crossover study was conducted in fasted healthy Chinese male volunteers, who first received a single oral dose of the test or reference formulation with a 7-day washout period, and then the alternative formulation. The study drug was administered after a 10-hour overnight fast. Blood samples were collected at baseline and at 0.25, 0.5, 0.75, 1.0, 1.5, 2, 4, 6, 8, 10, 12, 24, and 36 hours after administration of the study drug. Plasma concentrations of the parent oseltamivir and its metabolite oseltamivir carboxylate were determined using an LC-MS/MS method. The formulations were considered bioequivalent if the 90% confidence intervals (CIs) for the log-transformed values were within the predetermined equivalence range (70 - 143% for Cmax, 80 - 125% for AUC) according to the guidelines of the State Food and Drug Administration of China. Adverse events (AEs) were monitored throughout the study based on clinical parameters and patient reports. RESULTS: Characteristics of the 20 male volunteers included were as follows: mean age 23 (+/- 0.7, SD) years (range 21 - 24 years); weight 69 (+/- 7.1) kg (range 60 - 88 kg); height 177 (+/- 5.9) cm (range 168 - 192 cm). All included subjects completed the study. The mean geometric ratio between the test and reference formulations of oseltamivir was 99.5% (90% CI), 86.3 - 114.8%) for Cmax, 104.4% (95.7 - 113.9%) for AUC0-t, and 104.4% (95.6 - 113.9%) for AUC0-infinity. That of oseltamivir carboxylate was 103.7% (90% CI, 95.3 - 112.8%) for Cmax, 101.7% (96.6 - 107.1%) for AUC0 t, and 101.4% (96.5 - 106.5%) for AUC0-infinity. There was no significant difference in pharmacokinetic parameters between the two groups. Only 1 AE (nausea) occurred in 1 subject who received the test formulation; the AE resolved without any treatment. CONCLUSIONS: The result of this single-dose study indicated that the test formulation of oseltamivir capsule met the Chinese regulatory criteria for bioequivalence vs. the reference formulation in fasted healthy Chinese male volunteers.?. PMID- 28737129 TI - Association between polymorphisms in CTR1, CTR2, ATP7A, and ATP7B and platinum resistance in epithelial ovarian cancer. AB - The copper transporters CTR1, CTR2, ATP7A, and ATP7B regulate intracellular concentration of platinum by mediating its uptake and efflux in cells. We sought to explore the effect of genetic polymorphisms in CTR1, CTR2, ATP7A, and ATP7B on platinum resistance in patients suffering from epithelial ovarian cancer (EOC). A total of 152 Chinese EOC patients were enrolled in this study, all of whom underwent adjuvant chemotherapy using platinum and taxane after maximal debulking surgery. In total, 11 single-nucleotide polymorphisms (SNPs) in CTR1, CTR2, ATP7A, and ATP7B were genotyped in these patients. The CTR1 rs10981694 polymorphism was observed to be associated with carboplatin resistance, while patients with the rs10981694 G allele showed a significantly higher rate of carboplatin resistance (OR = 4.00, 95% CI 1.309 - 12.23, p < 0.01). In addition, we found that ATP7A rs2227291 was associated with cisplatin resistance and that carriers of the C allele were more sensitive to cisplatin (OR = 0.40, 95% CI: 0.17 - 0.94, p = 0.03). Our findings suggest that the CTR1 and ATP7A genetic polymorphisms could affect platinum resistance. The CTR1 and ATP7A genes might be considered a predictive marker for carboplatin and cisplatin resistance, respectively.?. PMID- 28737130 TI - Effect of pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer: A meta-analysis?. AB - INTRODUCTION: Pertuzumab, as an adjunctive therapy to trastuzumab and docetaxel, has been reported to be potentially beneficial for the treatment of human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. However, the results remain controversial. We conducted a systematic review and meta-analysis to evaluate the efficacy and safety of pertuzumab supplementation in patients with HER2-positive metastatic breast cancer. METHODS: Medline, SCOPUS, Google Scholar, Cochrane library databases, EMBASE, Springer, and Science Direct were systematically searched. Randomized controlled trials (RCTs) assessing the effect of pertuzumab + trastuzumab + docetaxel vs. trastuzumab + docetaxel on the treatment of HER2-positive metastatic breast cancer were included. Two investigators independently searched articles, extracted data, and assessed the quality of included studies. The primary outcomes were death, overall survival, and progression-free survival. Meta-analysis was performed using fixed- or random-effect model. RESULTS: Five RCTs involving 3,742 patients were included in the meta-analysis. Overall, compared with placebo and trastuzumab + docetaxel treatment, combination treatment of pertuzumab + trastuzumab + docetaxel treatment was associated with the significantly reduced death (hazard ratio (HR) = 0.67; 95% confidence interval (CI) = 0.57 - 0.78; p < 0.005) as well as improved overall survival (HR = 0.66; 95% CI = 0.35 - 0.67; p = 0.98) and progression-free survival (HR = 0.64; 95% CI = 0.58 - 0.71; p < 0.005). Moreover, pertuzumab supplementation did not increase the number of patients with reductions in the left ventricular ejection fraction (LVEF) of 10% or more (risk ratio (RR) = 0.70; 95% CI = 0.47 - 1.04; p = 0.07). CONCLUSION: Pertuzumab + trastuzumab + docetaxel treatment significantly reduced death, increased overall survival, and progression-free survival in patients with HER2-positive metastatic breast cancer compared to placebo and trastuzumab + docetaxel treatment, but showed no increased adverse events.?. PMID- 28737131 TI - Pharmacokinetics of flucloxacillin and its metabolites in patients with renal failure: Impact on liver toxicity?. AB - OBJECTIVE: The antimicrobial agent flucloxacillin is a potential cause of drug induced liver disease, but the underlying mechanisms for toxicity have not been fully elucidated. As in-vitro and in-vivo findings suggest that biotransformation products contribute to hepatotoxicity, the purpose of this study was to characterize formation and accumulation of its metabolites in patients with renal failure. METHODS: Twelve intensive care patients undergoing continuous venovenous hemofiltration received 4.0 g flucloxacillin as single and repeated infusion. Blood and dialysate samples were collected and analyzed for flucloxacillin and its metabolites by HPLC. RESULTS: The overall amounts of the flucloxacillin metabolites 5'-hydroxymethylflucloxacillin (5-OH-FX), 5' hydroxymethylflucloxacillin-penicilloic acid (5-OH-PA), and flucloxacillin penicilloic acid (FX-PA) produced varied considerably between patients, and accounted for 3.62 - 35.9% of total flucloxacillin concentration (flucloxacillin + metabolites) in the plasma. Clearance rates and sieving coefficients for 5-OH FX and FX-PA were comparable to that of the parent drug, although removal of 5-OH PA was decreased. Using an isolated perfused rat liver model we demonstrated that 5-OH-FX reached concentrations in the bile (240.5 +/- 84.2 nmoles/mL) that were sufficient to exert cytotoxic effects, unlike either of the two penicilloic acids. CONCLUSIONS: Based on data from perfused rat livers, high biliary concentrations of 5-OH-FX might also be observed in our patients explaining why LDH, bilirubin, and alkaline phosphatase were elevated in up to 8/12 patients after repeated infusion of flucloxacillin. Liver toxicity of flucloxacillin might therefore be observed in patients with renal impairment after continuously elevated 5-OH-FX levels.?. PMID- 28737132 TI - Differences in characteristics and outcomes between community- and hospital acquired acute kidney injury: A systematic review and meta-analysis?. AB - INTRODUCTION: No comprehensive review has examined the difference between community-acquired (CA) and hospital-acquired (HA) acute kidney injury (AKI) in terms of patient characteristics, in-hospital mortality, and hospital stay length. MATERIALS AND METHODS: We conducted a systematic review and meta-analysis of observational studies, using MEDLINE, EMBASE, Web of Science, Google Scholar, and the Cochrane Library from their inceptions to April 10, 2016. Observational studies that (1) were published in peer-reviewed journals; (2) compared CA-AKI with HA-AKI, irrespective of the AKI definition during the same period; and (3) investigated in-hospital mortality and length of hospital stay were studied. Differences in the patients' baseline characteristics were analyzed, and a meta analysis was conducted to compare the in-hospital mortality and length of hospital stay. RESULTS: Eight eligible observational studies with 17,939 patients were included. The systematic review showed that patients with CA-AKI had a significantly higher rate of AKI stage 3 compared with those with HA-AKI. The meta-analysis revealed that patients with CA-AKI showed significantly lower in hospital mortality (odds ratio (OR) = 2.79; Z = 8.22; 95% confidence interval (CI), 2.18 - 3.56; p < 0.001) and shorter length of hospital stay (OR = 2.55; Z = 5.81; 95% CI, 1.86 - 3.50; p < 0.001). Subanalyses of studies conducted in developing and developed countries showed that patients with CA-AKI had lower in hospital mortality and shorter length of hospital stay. Jackknife sensitivity analyses confirmed the replicability of these findings (p < 0.001). CONCLUSIONS: The results indicate that significant differences exist in clinical phenotypes between CA- and HA-AKI, even when standardized diagnosis criteria are used.?. PMID- 28737133 TI - Pretreatment with paricalcitol attenuates level and expression of matrix metalloproteinases in a rat model of renal ischemia-reperfusion injury?. AB - BACKGROUND: Ischemia-reperfusion injury (IRI) is a leading cause of acute kidney injury (AKI). The inflammatory response that drives IRI involves upregulation of matrix metalloproteinases (MMPs), which results in proteolytic degradation of renal microvascular matrix. Evidence suggests a potential protective role of active vitamin D on ischemic injury by downregulating MMPs. In the present study, we aimed to determine the expression and level of MMP-2 and MMP-9 in renal IRI model and the potential beneficial effect of paricalcitol on both level and expression of MMPs and tubular injury caused by IRI. MATERIALS AND METHODS: 20 Wistar albino rats were divided into three groups: sham-operated, ischemia reperfusion, and paricalcitol-pretreated. IRI model was induced by bilateral clamping of renal arteries for 45 minutes followed by 24 hours of reperfusion. The analysis of serum creatinine and levels of MMPs were performed after 24 hours of IRI. The effects of paricalcitol on the quantity and expression of MMP-2 and MMP-9 in renal tubular epithelial cells were investigated by enzyme-linked immunosorbent assay and immunohistochemistry, respectively. The pathological examinations were performed to score tubular damage by light microscopy. RESULTS: Creatinine levels decreased in the paricalcitol group, although this was not proven to be significant. Rats in the paricalcitol group showed significant decrease in both level and expression of MMPs and in tubular injury scores as compared to the IRI group. CONCLUSION: Paricalcitol may attenuate renal tubular injury caused by IRI by decreasing both level and expression of MMPs. Further studies are required to investigate the interplay between activated vitamin D and MMPs in AKI.?. PMID- 28737134 TI - WITHDRAWN: Nephrotic syndrome in primary myelofibrosis with renal extramedullary hematopoiesis and glomerulopathy in the JAK inhibitor era. AB - Ahead of Print article withdrawn by publisher. The publisher apologizes for any inconvenience this has caused. The article was scheduled for the journal "Clinical Nephrology. Case Studies" (issn 2196-5293). The article is available in PubmedCentral: https://www.ncbi.nlm.nih.gov/pubmed/29350220?. PMID- 28737135 TI - A flotation/sieving method to detect Echinococcus multilocularis and Toxocara spp. eggs in soil by real-time PCR. AB - Soil can be a source of human infection by many zoonotic helminth species including Echinococcus multilocularis and Toxocara spp. The prevention of alveolar echinococcosis could be greatly improved through the identification of at-risk areas. Yet very few data are available about the detection of E. multilocularis in soil, while more studies have been reported for Toxocara spp. Identification of soil contamination by E. multilocularis eggs requires the use of specific methods. This study describes the development of a method for the detection of E. multilocularis in soil samples with the concentration of eggs using a flotation/sieving method and detection by duplex real-time polymerase chain reaction (PCR). Toxocara spp. egg detection was also undertaken due to the widespread presence of this parasite in soil, despite it being considered less pathogenic. Method sensitivity of 100% was reached for the detection of 10 E. multilocularis eggs spiked in 10 g of soil. Concerning Toxocara spp., method sensitivity was lower but assumed to be due to the reduced effectiveness of the DNA extraction protocol. The parasitological status for E. multilocularis and Toxocara spp. of 63 carnivore fecal samples collected in highly endemic rural areas of France and of soil samples collected under and near these fecal samples was compared. The contamination of soil samples collected under positive fecal samples for E. multilocularis (n = 3) or Toxocara spp. (n = 19) confirmed the transfer of eggs from the definitive host to the environment. PMID- 28737137 TI - Point-of-Care Diagnosis in Pediatric Practice. PMID- 28737138 TI - Optimizing Bone Health in Cystic fibrosis: Success is the Sum of Small Efforts. PMID- 28737139 TI - The Confrontation of Fungal Sepsis in Neonates. PMID- 28737140 TI - Bone Mineral Density of Indian Children and Adolescents with Cystic Fibrosis. AB - OBJECTIVE: To document bone mineral density of children and adolescents with cystic fibrosis. DESIGN: Cross-sectional study. SETTING: Tertiary-care center of Northern India, July 2012 to August 2015. PARTICIPANTS: 52 children aged 6-18 years with cystic fibrosis and 62 healthy controls of similar age and sex. METHODS: Both patients and controls were stratified into two groups, as pre pubertal and peri-/post-pubertal, and compared for whole body bone mineral density, measured using dual energy X-ray absorptiometry. Serum levels of calcium, phosphate, alkaline phosphatase, 25-hydroxyvitamin D and parathyroid hormone were measured in children with cystic fibrosis. RESULTS: Compared with controls, the mean (SD) bone mineral density of children with cystic fibrosis was significantly lower in both the pre-pubertal (0.7 (0.1) g/cm2 vs 0.9 (0.1) g/cm2; P<0.001)) and peri-/post-pubertal groups (0.9 (0.1) g/cm2 vs 1.1 (0.1) g/cm2; P<0.001). Also, the mean (SD) bone mineral apparent density of pre-pubertal and peri-/post-pubertal cystic fibrosis patients was lower than the controls (P <0.001 and P= 0.01, respectively). Thirty-seven (71.2%) cystic fibrosis patients had serum 25-hydroxyvitamin D level below 15 ng/mL. CONCLUSION: Bone mineral density of children with cystic fibrosis was significantly lower than controls; majority of them were vitamin-D deficient. Intervening at an early stage of the disease and providing optimal therapy involving simultaneous management of the several factors affecting bone mineral accretion may be beneficial in improving bone health of these patients. PMID- 28737141 TI - Designing and Validation of a Hindi-language Parent Self-report Developmental Screening Tool. AB - AIM: To design and validate Hindi-language parent self-report developmental screening questionnaires for 9-month and 18-month-old Indian children. DESIGN: Cross-sectional study. SETTING: Tertiary-care pediatric hospital from April 2014 to March 2016. PARTICIPANTS: In each age group (9-month and 18-month), 45 children were enrolled for designing of questionnaires (30 for obtaining parental observations of current development and 15 for pre-testing). For validation of tool, 100 children (60 low risk and 40 high risk) were enrolled in each age group. METHODS: For designing, observations regarding current developmental milestones were obtained from parents and a list of all enumerated milestones was prepared. After detailed discussion by a team of developmental pediatricians, pediatric resident, clinical psychologist and language specialist, milestones were chosen for drafting of questionnaires. In each age group, drafts were pre tested and required modifications were done. The final questionnaires contained 20 items each to be scored on a Likert scale (total score ranging from 20 to 60, a lower score indicating a higher risk of developmental delay). These questionnaires were validated against Developmental Assessment Scale for Indian Infants (DASII), a gold standard instrument. RESULTS: On ROC analysis, the 9 month and 18-month screening tool had area under curve of 0.988 and 0.953, respectively, for detecting developmental delay. Score <=50 on the 9-months questionnaire had sensitivity of 100% and specificity of 87.2%. Score <=49 on the 18-months questionnaire had sensitivity of 91.4% and specificity of 88.7%. CONCLUSION: The new questionnaires have a promising role in developmental screening of children at the time of routine immunizations in our country. PMID- 28737142 TI - Prevention and Treatment of Vitamin D and Calcium Deficiency in Children and Adolescents: Indian Academy of Pediatrics (IAP) Guidelines. AB - JUSTIFICATION: Vitamin D deficiency (VDD) is being increasingly reported from India from all age-groups. Reports suggest that VDD affects all age groups, from neonates to adolescents. Further, habitually low calcium intakes are also reported in Indian children. Given the multiple guidelines, peculiarities of Indian circumstances, changing lifestyles, and lack of fortification, the Indian Academy of Pediatrics (IAP) felt the need for a Practice Guideline for Pediatricians for the prevention and treatment of vitamin D and calcium deficiency in children and adolescents. PROCESS: The 'Guideline for Vitamin D and Calcium in Children' committee was formed by the IAP in September 2016. A consultative committee meeting was held in November 2016 in Mumbai. Evidence from Indian and international studies and other previous published recommendations, which were pertinent to the Indian circumstances, were collated for the preparation of these guidelines. RESULTS: To present a practice guideline for pediatricians for the prevention and treatment of deficiency of vitamin D and calcium in the Indian context. RECOMMENDATIONS: For the prevention of rickets in premature infants, 400 IU of vitamin D and 150-220 mg/kg of calcium, and in neonates, 400 IU of vitamin D and 200 mg of calcium are recommended daily. For prevention of rickets and hypocalcemia in infants (after neonatal period) upto 1 year of age, and from 1-18 years, 400 IU and 600 IU vitamin D/day and 250-500 mg/day and 600-800 mg/day of calcium, respectively, are recommended. For treatment of rickets in premature neonates, infants upto 1 year and from 1-18 years, 1000 IU, 2000 IU and 3000-6000 IU of vitamin D daily, respectively, and elemental calcium of 70-80 mg/kg/day in premature neonates and 500-800 mg daily for all children over that age are recommended. Larger doses of vitamin D may be given from 3 months to 18 years of age as 60,000 IU/week for 6 weeks. PMID- 28737143 TI - Optimal Utilization of Pediatric Computed Tomography to Minimize Radiation Exposure: What the Clinician Must Know s. AB - The number of computed tomography (CT) scans being done for children all over the world is on the rise ever since the advent of Multi-Detector CT (MDCT). However, CT is a potential source of harmful ionizing radiation, and children are more susceptible to its adverse effects. It is essential for the pediatrician as well as the radiologist to be aware of some important principles and guidelines, by following which, radiation exposure to the child can be minimized to the bare essential. It is important to have knowledge of the valid and justifiable indications of CT for the child, the correct technique of performing the scan, and the new technological innovations now available on modern scanners that help to minimize radiation dose. PMID- 28737144 TI - Congenital Malformations to Birth Defects - The Indian Scenario. PMID- 28737145 TI - Congenital Hepatic Fibrosis with Polycystic Kidney Disease: An Unusual Cause of Neonatal Cholestasis. AB - Congenital hepatic fibrosis is characterized by hepatic fibrosis, portal hypertension, and renal cystic disease. Typical presentation of congenital hepatic fibrosis is in the form of portal hypertension, in adolescents and young adults. We present an unusual case of neonatal cholestasis with rapid deterioration within first 4 months of life, who was diagnosed to have congenital hepatic fibrosis with polycystic kidney disease on autopsy. PMID- 28737146 TI - Autoimmune Hypoglycemia in Type 1 Diabetes Mellitus. AB - BACKGROUND: Antibodies against exogenous insulin are common in type 1 diabetes mellitus patients. They can cause hypoglycemia, albeit uncommonly. CASE CHARACTERISTICS: A 14-year-old girl with type 1 diabetes mellitus presented with recurrent hypoglycemia. OUTCOME: High insulin, low C-peptide and raised insulin antibody levels documented during hypoglycemia. Plasmapheresis led to remission of hypoglycemia. MESSAGE: Antibodies to exogenous insulin should be considered as a cause of recurrent refractory hypoglycemia in type 1 diabetes mellitus patients. PMID- 28737147 TI - Brucella Causing Liver Abscess in a Child with Selective IgA Deficiency. AB - BACKGROUND: Brucella has been known to cause pyrexia of unknown origin. CASE CHARACTERISTICS: 9-year-old boy with fever and abdominal pain; multiple abscesses within the liver on ultrasonography. OBSERVATIONS: IgM Antibodies against Brucella were raised in his serum sample, and Brucella serum agglutination test was positive. Immunological work-up suggested selective IgA deficiency. Reduction in size following treatment with trimethoprim-sulphamethoxazole, amikacin and doxycycline. MESSAGE: Brucellosis should be considered as an etiology of liver abscess in patients not responding to conventional antibiotics. PMID- 28737148 TI - My Encounters with Children. PMID- 28737150 TI - Non-availability of Vaccines and Program Ownership. PMID- 28737149 TI - Plasma Hepcidin Levels in Healthy Children from Chandigarh, Northern India. AB - Hepcidin is a key molecule involved in iron homeostasis. We measured hepcidin levels in 50 healthy children from Chandigarh, Northern India for establishing normal ranges. Hepcidin ranges (19.96-36.6 ng/mL; 0-2 years) and (9.54-36.15 ng/mL; 2-6 years) with mean (SD) of 32.5 (4.84) ng/mL, and 31.13 (6.62) ng/mL respectively were noted in study participants. The mean (SD) and ranges for plasma hepcidin in boys and girls in the study was 31.01 (6.71) ng/mL (9.54-36.6 ng/mL) and 32.7 (4.14) ng/mL (19-36.2 ng/mL), respectively. PMID- 28737151 TI - Optimizing Antibiotic Therapy for Necrotizing Enterocolitis - Need of the Hour. PMID- 28737152 TI - A Plea for Fair Pricing of Vaccines. PMID- 28737153 TI - Remodel ICDS Centers as Early Child Care and Education Centers. PMID- 28737154 TI - Effect of dose and frequency of exposure to infectious stages on trematode infection intensity and success in mussels. AB - Marine parasites such as trematodes often compromise the fitness of their hosts. Such effects are generally considered to be density-dependent, i.e. the greater the infection intensity in the host, the greater the detrimental impact on host fitness. However, the mechanisms determining infection in marine hosts are still poorly understood. Here, we investigated the effect of cercarial dose and exposure frequency (single vs. trickle infections) of a marine trematode parasite, Himasthla elongata (Trematoda: Echinostomatidae), on infection intensity and success in its second intermediate host, the blue mussel Mytilus edulis, an abundant and widely distributed bivalve in European coastal waters. In our laboratory experiment, we tested 4 levels of parasite doses and showed that mussels faced higher parasite infection intensity at higher doses of cercarial exposure and that they acquired more infections when repeatedly exposed to smaller doses compared to a single high dose. However, the infection success of cercariae did not differ among 4 dose levels but was only significantly different between trickle and single exposures. This indicates that cercariae were not subjected to a dose-dependent regulation of their infectivity, suggesting that infection intensity in mussels is largely driven by factors mediating the abundance of infective stages. With the combined investigation of the effect of cercarial dose and exposure frequency at realistic dose levels, our study contributes to our currently very limited understanding of the determinants of infection intensity in marine hosts and highlights the usefulness of experimental studies in advancing our knowledge in this field. PMID- 28737155 TI - Dawestrema cycloancistrium (Monogenea) from the head pores of arapaimas. AB - Arapaima gigas is one of the main cultured fish species in South America, and monogenean parasites of this species cause large economic losses to fish farmers. During surveys of the parasites of cultured arapaimas from Mexiana Island in the Amazon River Delta, Rio Branco, in northwestern Brazilian Amazonia, and Yurimaguas, Peru, the monogenean Dawestrema cycloancistrium was found in the gills of A. gigas as well as in previously unreported sites, i.e. the head pores and chambers. The aim of this study was to investigate the transmission route of this parasite and its geographical distribution as well as to describe its morphology as observed by light and confocal imaging. Phalloidin labeling confirmed the presence of 2 prostatic reservoirs and showed muscular branches of fibers supporting haptoral sclerites. In arapaimas, the head connects to the gill chambers via 2 perforated scales located at the dorsolateral sides of the distal part of the head. The scales connect to thin channels and chambers situated in the proximal part of the head. These chambers are filled with cephalic mucus, which flows out to the environment through terminal pores. Adults and egg masses of monogeneans were found on the gills and inside the head pores and cavities of fish along with cephalic mucus. This indicates a specialized method of parasite transmission from adult fish to fingerlings during parental care (holding offspring in the mouth) or via head secretions, providing evidence of a new adapted mechanism of dispersion. PMID- 28737156 TI - Thyroid function of steatitis-affected Mozambique tilapia Oreochromis mossambicus from a sub-tropical African reservoir. AB - Thyroid function and nutritional indicators were measured in obese, steatitis affected Mozambique tilapia Oreochromis mossambicus from Loskop Reservoir (LR), South Africa. Plasma thyroid hormones (especially T3) and thyroid follicle histomorphology revealed high levels of activity in every aspect of the thyroid cascade measured in fish from LR compared to a reference population of steatitis free fish. Concurrent measurements of nutritional state including plasma lipids, liver lipid content and hepatocyte size showed that fish from LR had significant energy stores indicative of abundant nutritional intake. There were distinct sex and seasonal differences, with the highest plasma lipids and T3 levels observed in steatitis-affected females during spring and summer. Positive correlations were observed between plasma lipids (especially cholesterol) and T3 concentrations in fish from both populations, indicating a link between lipid metabolism and thyroid function. There was no direct evidence of thyroid disruption, but this cannot be ruled out until further research determines the factors that underlie the homeostatic shift leading to elevated plasma and liver lipids and T3 levels in steatitis-affected tilapia. PMID- 28737157 TI - Oral neoplasms in pickhandle barracuda Sphyraena jello from India. AB - We report the spontaneous occurrence of oral neoplasms in pickhandle barracuda Sphyraena jello Cuvier, 1829 from Parangipettai, on the southeast coast of India. A total of 11736 fish were examined, of which 43 were affected with oral tumours, with an overall prevalence of 0.37%. Gross and clinical symptoms included reddish to grayish-white distended tumourous growths on the gingiva, intra-oral bones and tongue. The tumours exhibited delayed eruption and intra- or extra-oral swelling, varied in consistency from extremely firm to fleshy and released mucinous material. The majority of tumours consisted of numerous clumped toothlets, but some included hardened tissues. Local area invasion/transmission was observed in most cases; however, necropsy examination revealed no gross evidence of distant metastasis into visceral organs. Radiographic examination of compound odontomas revealed distinct unilocular radio-opaque mini-toothlets surrounded by defined radiolucency, whereas complex odontomas exhibited unilocular and indistinct radio opaque masses within a much more extensive radiolucent zone. Histopathologically, the intra-oral tumour lesions were characterized by numerous imperfect (germ) toothlets consisting of a disorganized combination of dental tissues: pulp tissues with manifested and predominantly mixed hard dental tissues of immature dentine and enamel, numerous small to large and round to polyhedral ossicles embedded in hypocellular fibrous stromal tissues and sparsely spaced bland spindloid cells with cleft-like spaces of loose mucoid stroma. Histochemically, the neoplastic lesions stained positive for periodic acid-Schiff and Masson's trichrome. Based on the clinical and histological findings, the tumours were diagnosed as compound odontomas, complex odontomas, odontogenic myxomas, lingual myxomas and psammomatoid ossifying fibromas. PMID- 28737158 TI - Gastric lesions in dolphins stranded along the Eastern Adriatic coast. AB - Stranded cetaceans are often found with gastric lesions associated with the presence of parasites; most frequently, nematodes of the genus Anisakis and the heterophyd digenean trematode Pholeter gastrophilus. In this study, we present histopathology mainly (but not exclusively) related to these 2 parasite species. Macroscopically, lesions associated with the presence of Anisakis spp. were characterised by the presence of ulcers within the gastric mucosa, while the digenean P. gastrophilus was found within large submucosal fibrotic nodules in the gastric wall. Anisakis-induced alterations included severe ulcerative gastritis with mixed inflammatory infiltrate often associated with colonies of bacteria, and mild to moderate granulomatous gastritis with eosinophilic infiltrate. P. gastrophilus-associated lesions were characterised by fibrogranulomatous gastritis with mixed inflammatory infiltrate. Additionally, immunohistochemical (IHC) analysis of P. gastrophilus lesions was consistent with the histopathologic findings, revealing inflammation-mediated stimulation. IHC positive localisation of CD3+, iNOS+ and caspase-3+ cells suggests intensive accumulation of cytotoxic T-cells, proinflammatory cytokines and execution-phase of cell apoptosis at the parasitized area. In contrast, mechanical damage, rather than visible inflammatory response could be observed at the site of attachment of Braunina cordiformis recorded in 4 animals. Lesions not associated with the presence of parasites were mostly characterised by focal loss of superficial epithelial cells and accumulation of brown hemosiderin-like pigment or fibrous gastritis with lymphoplasmacytic infiltrate. In light of these results, we argue that observed 'tolerant' host-parasite interactions that led toward gastric lesions do not represent the cause of death and stranding of cetaceans included in this study. PMID- 28737159 TI - Health and Environmental Risk Assessment Project for bottlenose dolphins Tursiops truncatus from the southeastern USA. I. Infectious diseases. AB - From 2003 to 2015, 360 free-ranging Atlantic bottlenose dolphins Tursiops truncatus inhabiting the Indian River Lagoon (IRL, n = 246), Florida, and coastal waters of Charleston (CHS, n = 114), South Carolina, USA, were captured, given comprehensive health examinations, and released as part of a multidisciplinary and multi-institutional study of individual and population health. The aim of this review is to summarize the substantial health data generated by this study and to examine morbidity between capture sites and over time. The IRL and CHS dolphin populations are affected by complex infectious and neoplastic diseases often associated with immunologic disturbances. We found evidence of infection with cetacean morbillivirus, dolphin papilloma and herpes viruses, Chlamydiaceae, a novel uncultivated strain of Paracoccidioides brasiliensis (recently identified as the causal agent of dolphin lobomycosis/lacaziasis), and other pathogens. This is the first long-term study documenting the various types, progression, seroprevalence, and pathologic interrelationships of infectious diseases in dolphins from the southeastern USA. Additionally, the study has demonstrated that the bottlenose dolphin is a valuable sentinel animal that may reflect environmental health concerns and parallel emerging public health issues. PMID- 28737160 TI - Health and Environmental Risk Assessment Project for bottlenose dolphins Tursiops truncatus from the southeastern USA. II. Environmental aspects. AB - Bottlenose dolphins Tursiops truncatus are the most common apex predators found in coastal and estuarine ecosystems along the southeastern coast of the USA, where these animals are exposed to multiple chemical pollutants and microbial agents. In this review, we summarize the results of investigations of environmental exposures evaluated in 360 free-ranging dolphins between 2003 and 2015. Bottlenose dolphins inhabiting the Indian River Lagoon, Florida (IRL, n = 246), and coastal waters of Charleston, South Carolina (CHS, n = 114), were captured, given comprehensive health examinations, and released as part of a multidisciplinary and multi-institutional study of individual and population health. High concentrations of persistent organic pollutants including legacy contaminants (DDT and other pesticides, polychlorinated biphenyl compounds) as well as 'emerging' contaminants (polybrominated diphenyl ethers, perfluorinated compounds) were detected in dolphins from CHS, with lower concentrations in the IRL. Conversely, the concentrations of mercury in the blood and skin of IRL dolphins were among the highest reported worldwide and approximately 5 times as high as those found in CHS dolphins. A high prevalence of resistance to antibiotics commonly used in humans and animals was detected in bacteria isolated from fecal, blowhole, and/or gastric samples at both sites, including methicillin resistant Staphylococcus aureus (MRSA) at CHS. Collectively, these studies illustrate the importance of long-term surveillance of estuarine populations of bottlenose dolphins and reaffirm their important role as sentinels for marine ecosystems and public health. PMID- 28737161 TI - LiNbO3 surfaces from a microscopic perspective. AB - A large number of oxides has been investigated in the last twenty years as possible new materials for various applications ranging from opto-electronics to heterogeneous catalysis. In this context, ferroelectric oxides are particularly promising. The electric polarization plays a crucial role at many oxide surfaces, and it largely determines their physical and chemical properties. Ferroelectrics offer in addition the possibility to control/switch the electric polarization and hence the surface chemistry, allowing for the realization of domain-engineered nanoscale devices such as molecular detectors or highly efficient catalysts. Lithium niobate (LiNbO3) is a ferroelectric with a high spontaneous polarization, whose surfaces have a huge and largely unexplored potential. Owing to recent advances in experimental techniques and sample preparation, peculiar and exclusive properties of LiNbO3 surfaces could be demonstrated. For example, water films freeze at different temperatures on differently polarized surfaces, and the chemical etching properties of surfaces with opposite polarization are strongly different. More important, the ferroelectric domain orientation affects temperature dependent surface stabilization mechanisms and molecular adsorption phenomena. Various ab initio theoretical investigations have been performed in order to understand the outcome of these experiments and the origin of the exotic behavior of the lithium niobate surfaces. Thanks to these studies, many aspects of their surface physics and chemistry could be clarified. Yet other puzzling features are still not understood. This review gives a resume on the present knowledge of lithium niobate surfaces, with a particular view on their microscopic properties, explored in recent years by means of ab initio calculations. Relevant aspects and properties of the surfaces that need further investigation are briefly discussed. The review is concluded with an outlook of challenges and potential payoff for LiNbO3 based applications. PMID- 28737162 TI - Silk fiber reinforcement modulates in vitro chondrogenesis in 3D composite scaffolds. AB - The limited self-regenerative capacity of adult cartilage has steered the upsurge in tissue engineered replacements to combat the problem of osteoarthritis. In the present study, the potential of fiber-reinforced silk composites from mulberry (Bombyx mori) and non-mulberry (Antheraea assamensis) silk has been investigated for cartilage tissue engineering. The fabricated composites were physico chemically characterized and analyzed for cellular viability, proliferation, extracellular matrix formation and immunocompatibility. Both mulberry and non mulberry silk composites showed effective swelling (25%-30%) and degradation (10% 30%) behavior, owing to their interconnected porous nature. The non-mulberry fiber-reinforced composite scaffolds showed slower degradation (~90% mass remaining) than mulberry silk over a period of 28 days. The reinforcement of silk fibers within silk solution resulted in an increased compressive modulus and stiffness (nearly eight-fold). The biochemical analysis revealed significant increase in DNA content, sulphated glycosaminoglycan (sGAG) (~1.5 fold) and collagen (~1.4 fold) in reinforced composites as compared to pure solution scaffolds (p <= 0.01). Histological and immunohistochemical (IHC) staining corroborated enhanced deposition of sGAG and localization of collagen type II in fiber-reinforced composites. This was further substantiated by real time polymerase chain reaction studies, which indicated an up-regulation (~1.5 fold) of cartilage-specific gene markers namely collagen type II, sox-9 and aggrecan. The minimal secretion of tumor necrosis factor-alpha (TNF-alpha) by murine macrophages further demonstrated in vitro immunocompatibility of the scaffolds. Taken together, the results signified the potential of silk fiber-reinforced composite (particularly non-mulberry, A. assamensis) scaffolds as viable alternative biomaterial for cartilage tissue engineering. PMID- 28737163 TI - Plane-dependent ML scatter scaling: 3D extension of the 2D simulated single scatter (SSS) estimate. AB - Scatter correction is typically done using a simulation of the single scatter, which is then scaled to account for multiple scatters and other possible model mismatches. This scaling factor is determined by fitting the simulated scatter sinogram to the measured sinogram, using only counts measured along LORs that do not intersect the patient body, i.e. 'scatter-tails'. Extending previous work, we propose to scale the scatter with a plane dependent factor, which is determined as an additional unknown in the maximum likelihood (ML) reconstructions, using counts in the entire sinogram rather than only the 'scatter-tails'. The ML-scaled scatter estimates are validated using a Monte-Carlo simulation of a NEMA-like phantom, a phantom scan with typical contrast ratios of a 68Ga-PSMA scan, and 23 whole-body 18F-FDG patient scans. On average, we observe a 12.2% change in the total amount of tracer activity of the MLEM reconstructions of our whole-body patient database when the proposed ML scatter scales are used. Furthermore, reconstructions using the ML-scaled scatter estimates are found to eliminate the typical 'halo' artifacts that are often observed in the vicinity of high focal uptake regions. PMID- 28737164 TI - Nanofluidic chip for liquid TEM cell fabricated by parylene and silicon nitride direct bonding. AB - Despite the importance of nanofluidic transmission electron microscope (TEM) chips, a simple fabrication method has yet to be developed due to the difficulty of wafer bonding techniques using a nanoscale thick bonding layer. We present a simple and robust wafer scale bonding technique using parylene as a bonding layer. A nanoscale thick parylene layer was deposited on a silicon nitride (SiN) wafer and patterned to construct nanofluidic channels. The patterned parylene layer was directly bonded to another SiN wafer by thermal surface activation and bonding, with a bonding strength of ~3 MPa. Fourier transform infrared spectroscopy showed that carbon-oxygen bonds were generated by thermal activation. We demonstrated TEM imaging of gold nanoparticles suspended in liquid using the fabricated nanofluidic chip. PMID- 28737165 TI - Local integrals of motion in the two-site Anderson-Hubbard model. AB - It has been proposed that the states of fully many-body localized systems can be described in terms of conserved local pseudospins. Due to the multitude of ways to define these, the explicit identification of the optimally local pseudospins in specific systems is non-trivial. Given continuing intense interest in the role of disorder in strongly correlated systems, we consider the disordered Hubbard model. By studying a small system we provide concrete examples of the form of local integrals of motion in the Anderson-Hubbard model. Moreover, we are able not only to identify the most local choice but also to explore the nature of the distribution of possible choices. We track the evolution of the optimally localized pseudospins as hopping and interactions are varied to move the system away from the trivially localized atomic limit. PMID- 28737166 TI - Direct AFM observation of individual micelles, tile decorations and tiling rules of a dodecagonal liquid quasicrystal. AB - We performed an atomic force microscopy study of the dendron-based dodecagonal quasicrystal, the material that had been reported in 2004 as the first soft quasicrystal. We succeeded in orienting the 12-fold axis perpendicular to the substrate, which allowed the imaging of the quasiperiodic xy plane. Thus for the first time we have been able to obtain direct real-space information not only on the arrangement of the tiles, but also on their 'decorations' by the individual spherical micelles or 'nanoatoms'. The high-resolution patterns recorded confirm the square-triangle tiling, but the abundance of different nodes corresponds closely to random tiling rather than to any inflation rule. The previously proposed model of three types of decorated tiles, two triangular and one square, has been confirmed; the basic Frank-Kasper mode of alternating dense-sparse-dense sparse layer stacking along z is confirmed too, each of the four sublayers being 2 nm thick. The consecutive dense layers are seen to be rotated by 90 degrees , as expected. The 2 nm steps on the surface correspond to one layer of spheres, nonetheless with a dense layer always remaining on top, which implies a layer slip underneath and possibly the existence of screw dislocations. PMID- 28737167 TI - Polymer models with optimal good-solvent behavior. AB - We consider three different continuum polymer models, which all depend on a tunable parameter r that determines the strength of the excluded-volume interactions. In the first model, chains are obtained by concatenating hard spherocylinders of height b and diameter rb (we call them thick self-avoiding chains). The other two models are generalizations of the tangent hard-sphere and of the Kremer-Grest models. We show that for a specific value [Formula: see text], all models show optimal behavior: asymptotic long-chain behavior is observed for relatively short chains. For [Formula: see text], instead, the behavior can be parametrized by using the two-parameter model, which also describes the thermal crossover close to the theta point. The bonds of the thick self-avoiding chains cannot cross each other, and therefore the model is suited for the investigation of topological properties and for dynamical studies. Such a model also provides a coarse-grained description of double-stranded DNA, so that we can use our results to discuss under which conditions DNA can be considered as a model good-solvent polymer. PMID- 28737168 TI - Distribution of high-dimensional entanglement via an intra-city free-space link. AB - Quantum entanglement is a fundamental resource in quantum information processing and its distribution between distant parties is a key challenge in quantum communications. Increasing the dimensionality of entanglement has been shown to improve robustness and channel capacities in secure quantum communications. Here we report on the distribution of genuine high-dimensional entanglement via a 1.2 km-long free-space link across Vienna. We exploit hyperentanglement, that is, simultaneous entanglement in polarization and energy-time bases, to encode quantum information, and observe high-visibility interference for successive correlation measurements in each degree of freedom. These visibilities impose lower bounds on entanglement in each subspace individually and certify four dimensional entanglement for the hyperentangled system. The high-fidelity transmission of high-dimensional entanglement under real-world atmospheric link conditions represents an important step towards long-distance quantum communications with more complex quantum systems and the implementation of advanced quantum experiments with satellite links. PMID- 28737169 TI - Actomyosin drives cancer cell nuclear dysmorphia and threatens genome stability. AB - Altered nuclear shape is a defining feature of cancer cells. The mechanisms underlying nuclear dysmorphia in cancer remain poorly understood. Here we identify PPP1R12A and PPP1CB, two subunits of the myosin phosphatase complex that antagonizes actomyosin contractility, as proteins safeguarding nuclear integrity. Loss of PPP1R12A or PPP1CB causes nuclear fragmentation, nuclear envelope rupture, nuclear compartment breakdown and genome instability. Pharmacological or genetic inhibition of actomyosin contractility restores nuclear architecture and genome integrity in cells lacking PPP1R12A or PPP1CB. We detect actin filaments at nuclear envelope rupture sites and define the Rho-ROCK pathway as the driver of nuclear damage. Lamin A protects nuclei from the impact of actomyosin activity. Blocking contractility increases nuclear circularity in cultured cancer cells and suppresses deformations of xenograft nuclei in vivo. We conclude that actomyosin contractility is a major determinant of nuclear shape and that unrestrained contractility causes nuclear dysmorphia, nuclear envelope rupture and genome instability. PMID- 28737170 TI - High performance platinum single atom electrocatalyst for oxygen reduction reaction. AB - For the large-scale sustainable implementation of polymer electrolyte membrane fuel cells in vehicles, high-performance electrocatalysts with low platinum consumption are desirable for use as cathode material during the oxygen reduction reaction in fuel cells. Here we report a carbon black-supported cost-effective, efficient and durable platinum single-atom electrocatalyst with carbon monoxide/methanol tolerance for the cathodic oxygen reduction reaction. The acidic single-cell with such a catalyst as cathode delivers high performance, with power density up to 680 mW cm-2 at 80 degrees C with a low platinum loading of 0.09 mgPt cm-2, corresponding to a platinum utilization of 0.13 gPt kW-1 in the fuel cell. Good fuel cell durability is also observed. Theoretical calculations reveal that the main effective sites on such platinum single-atom electrocatalysts are single-pyridinic-nitrogen-atom-anchored single-platinum-atom centres, which are tolerant to carbon monoxide/methanol, but highly active for the oxygen reduction reaction. PMID- 28737173 TI - Coherent superpositions of three states for phosphorous donors in silicon prepared using THz radiation. AB - Superposition of orbital eigenstates is crucial to quantum technology utilizing atoms, such as atomic clocks and quantum computers, and control over the interaction between atoms and their neighbours is an essential ingredient for both gating and readout. The simplest coherent wavefunction control uses a two eigenstate admixture, but more control over the spatial distribution of the wavefunction can be obtained by increasing the number of states in the wavepacket. Here we demonstrate THz laser pulse control of Si:P orbitals using multiple orbital state admixtures, observing beat patterns produced by Zeeman splitting. The beats are an observable signature of the ability to control the path of the electron, which implies we can now control the strength and duration of the interaction of the atom with different neighbours. This could simplify surface code networks which require spatially controlled interaction between atoms, and we propose an architecture that might take advantage of this. PMID- 28737172 TI - Selective production of arenes via direct lignin upgrading over a niobium-based catalyst. AB - Lignin is the only large-volume renewable source of aromatic chemicals. Efficient depolymerization and deoxygenation of lignin while retaining the aromatic functionality are attractive but extremely challenging. Here we report the selective production of arenes via direct hydrodeoxygenation of organosolv lignin over a porous Ru/Nb2O5 catalyst that enabled the complete removal of the oxygen content from lignin. The conversion of birch lignin to monomer C7-C9 hydrocarbons is nearly quantitative based on its monomer content, with a total mass yield of 35.5 wt% and an exceptional arene selectivity of 71 wt%. Inelastic neutron scattering and DFT calculations confirm that the Nb2O5 support is catalytically unique compared with other traditional oxide supports, and the disassociation energy of Caromatic-OH bonds in phenolics is significantly reduced upon adsorption on Nb2O5, resulting in its distinct selectivity to arenes. This one pot process provides a promising approach for improved lignin valorization with general applicability. PMID- 28737171 TI - BRG1-SWI/SNF-dependent regulation of the Wt1 transcriptional landscape mediates epicardial activity during heart development and disease. AB - Epicardium-derived cells (EPDCs) contribute cardiovascular cell types during development and in adulthood respond to Thymosin beta4 (Tbeta4) and myocardial infarction (MI) by reactivating a fetal gene programme to promote neovascularization and cardiomyogenesis. The mechanism for epicardial gene (re )activation remains elusive. Here we reveal that BRG1, the essential ATPase subunit of the SWI/SNF chromatin-remodelling complex, is required for expression of Wilms' tumour 1 (Wt1), fetal EPDC activation and subsequent differentiation into coronary smooth muscle, and restores Wt1 activity upon MI. BRG1 physically interacts with Tbeta4 and is recruited by CCAAT/enhancer-binding protein beta (C/EBPbeta) to discrete regulatory elements in the Wt1 locus. BRG1-Tbeta4 co operative binding promotes optimal transcription of Wt1 as the master regulator of embryonic EPDCs. Moreover, chromatin immunoprecipitation-sequencing reveals BRG1 binding at further key loci suggesting SWI/SNF activity across the fetal epicardial gene programme. These findings reveal essential functions for chromatin-remodelling in the activation of EPDCs during cardiovascular development and repair. PMID- 28737174 TI - Inverted battery design as ion generator for interfacing with biosystems. AB - In a lithium-ion battery, electrons are released from the anode and go through an external electronic circuit to power devices, while ions simultaneously transfer through internal ionic media to meet with electrons at the cathode. Inspired by the fundamental electrochemistry of the lithium-ion battery, we envision a cell that can generate a current of ions instead of electrons, so that ions can be used for potential applications in biosystems. Based on this concept, we report an 'electron battery' configuration in which ions travel through an external circuit to interact with the intended biosystem whereas electrons are transported internally. As a proof-of-concept, we demonstrate the application of the electron battery by stimulating a monolayer of cultured cells, which fluoresces a calcium ion wave at a controlled ionic current. Electron batteries with the capability to generate a tunable ionic current could pave the way towards precise ion-system control in a broad range of biological applications. PMID- 28737176 TI - Room-temperature fabrication of a three-dimensional porous silicon framework inspired by a polymer foaming process. AB - A room-temperature routine for the fabrication of a three-dimensional silicon porous framework inspired by a polymer foaming process is introduced. The obtained micron-sized pores can be further modified by hydrothermal growth of nanowires to form a hierarchical porous composite framework. PMID- 28737177 TI - A metal-free cascade reaction of beta-halo-alpha,beta-unsaturated aldehydes and 1,4-dithiane-2,5-diols: synthesis of polycyclic 2-formylthiophenes. AB - A metal-free cascade reaction strategy has been developed for the synthesis of novel polycyclic 2-formylthiophenes from beta-halo-alpha,beta-unsaturated aldehydes and 1,4-dithiane-2,5-diols. A recyclable polymer supported organic base was used to perform the reaction process. This synthetic protocol was applied to synthesize several novel polycyclic thiophenes including steroidal D-ring annelated thiophene. Our synthetic strategy provides a high yield of thiophenes, avoids a tedious work-up procedure and minimizes the formation of waste. PMID- 28737178 TI - Electrokinetics and behavior near the interface of colloidal particles in non polar dispersions. AB - The electrokinetics and charging of nonpolar colloidal dispersions subjected to a voltage are investigated by electric current and optical measurements. From electric current measurements in response to an alternating triangular voltage with a peak value of a few hundred volts, we find that polystyrene toner particles are compacted near the electrodes and their charge increases by more than a factor of 20. The important increase of charge is interpreted by a mechanism in which counter charges, which are originally at the particle surface, are desorbed. Optical measurements performed under a dc voltage of the order of a few hundred volts demonstrate that the charge of the particles can again decrease or even be inverted. These phenomena are attributed to the movement of counter charged species from the interface layers onto the surface of the particles. The findings of this study are relevant for electrophoretic displays and liquid toner printing. PMID- 28737179 TI - Total synthesis of the dictyodendrins as an arena to highlight emerging synthetic technologies. AB - Covering: 1993-2017This review discusses the isolation, biological activity, and syntheses of the dictyodendrin class of natural products, covering the years 1993 2017. The dictyodendrins are a family of alkaloids isolated from marine sponges, Dictyodendrilla verongiformis and Ianthella sp., which possess a highly substituted pyrrolo[2,3-c]carbazole core at the phenol or quinone oxidation states. Dictyodendrins exhibit a wide range of biological activities, such as telomerase inhibition, BACE1 enzyme inhibition, and cytotoxicity against several cancer cell lines. The unique structure and interesting biological activities of dictyodendrins provided a platform for the application of novel synthetic methods including C-H insertion, C-H arylation, and electrocyclization cascades. PMID- 28737175 TI - Natural variation of macrophage activation as disease-relevant phenotype predictive of inflammation and cancer survival. AB - Although mouse models exist for many immune-based diseases, the clinical translation remains challenging. Most basic and translational studies utilize only a single inbred mouse strain. However, basal and diseased immune states in humans show vast inter-individual variability. Here, focusing on macrophage responses to lipopolysaccharide (LPS), we use the hybrid mouse diversity panel (HMDP) of 83 inbred strains as a surrogate for human natural immune variation. Since conventional bioinformatics fail to analyse a population spectrum, we highlight how gene signatures for LPS responsiveness can be derived based on an Interleukin-12beta and arginase expression ratio. Compared to published signatures, these gene markers are more robust to identify susceptibility or resilience to several macrophage-related disorders in humans, including survival prediction across many tumours. This study highlights natural activation diversity as a disease-relevant dimension in macrophage biology, and suggests the HMDP as a viable tool to increase translatability of mouse data to clinical settings. PMID- 28737180 TI - Direct arylation of inactivated benzene with aryl acyl peroxides toward biaryls. AB - A direct arylation of inactivated benzene with acyl peroxides was developed, affording biaryls in good to excellent yields. This transformation underwent a radical pathway under metal-free, base-free and additive-free conditions with good functional group compatibility. PMID- 28737181 TI - Poly(methylhydrosiloxane) as a green reducing agent in organophosphorus-catalysed amide bond formation. AB - Development of catalytic amide bond formation reactions has been the subject of the intensive investigations in the past decade. Herein we report an efficient organophosphorus-catalysed amidation reaction between unactivated carboxylic acids and amines. Poly(methylhydrosiloxane), a waste product of the silicon industry, is used as an inexpensive and green reducing agent for in situ reduction of phosphine oxide to phosphine. The reported method enables the synthesis of a wide range of secondary and tertiary amides in very good to excellent yields. PMID- 28737183 TI - New LnOCl (Ln = Sm, Nd) photocatalyst and novel cocatalytic effect on BiOCl in humid environment. AB - This is the first report on photocatalytic properties of LnOCl (Ln = Sm, Nd) compounds, and the novel cocatalytic effect on BiOCl in highly humid environments, evaluated via the photoremoval of nitric oxide (NO). PMID- 28737182 TI - Micro- and nano-patterned elastin-like polypeptide hydrogels for stem cell culture. AB - We show that submicron-sized patterns can be imprinted into soft, recombinant engineered protein hydrogels (here elastin-like proteins, ELP) by transferring wavy patterns from polydimethylsiloxane (PDMS) molds. The high-precision topographical tunability of the relatively stiff PDMS is translated to a bio responsive, soft material, enabling topographical cell response studies at elastic moduli matching those of tissues. Aligned and unaligned wavy patterns with mold periodicities of 0.24-4.54 MUm were imprinted and characterized by coherent anti-Stokes Raman scattering and atomic force microscopy. The pattern was successfully transferred down to 0.37 MUm periodicity (width in ELP: 250 +/- 50 nm, height: 70 +/- 40 nm). The limit was set by inherent protein assemblies (diameter: 124-180 nm) that formed due to lower critical solution temperature behavior of the ELP during molding. The width/height of the ELP ridges depended on the degree of hydration; from complete dehydration to full hydration, ELP ridge width ranged from 79 +/- 9% to 150 +/- 40% of the mold width. The surface of the ridged ELP featured densely packed protein aggregates that were larger in size than those observed in bulk/flat ELP. Adipose-derived stem cells (ADSCs) oriented along hydrated aligned patterns with periodicities >=0.60 MUm (height >=170 +/- 100 nm), while random orientation was observed for smaller distances/amplitudes, as well as flat and unaligned wavy ELP surfaces. Hence, micro-molding of ELP is a promising approach to create tissue-mimicking, hierarchical architectures composed of tunable micron-sized structures with nano sized protein aggregates, which opens the way for orthogonal screening of cell responses to topography and cell-adhesion ligands at relevant elastic moduli. PMID- 28737184 TI - A switchable electrochromism and electrochemiluminescence bifunctional sensor based on the electro-triggered isomerization of spiropyran/layered double hydroxides. AB - A bifunctional ultrathin film (UTF) electrode was fabricated based on layered double hydroxides (LDHs) and spiropyran (SP), which exhibited electrochromism and electrochemiluminescence (ECL) sensing behavior toward temperature and Zn2+ ions. PMID- 28737185 TI - Rationalising the effects of ionic liquids on a nucleophilic aromatic substitution reaction. AB - The nucleophilic aromatic substitution reaction between 1-fluoro-2,4 dinitrobenzene and ethanol was examined in a series of ionic liquids across a range of mole fractions. Temperature-dependent kinetic analyses were undertaken to determine the activation parameters for this reaction at the highest mole fraction. As the mole fraction of ionic liquid was increased, the rate constant of the reaction also increased, however the microscopic origin of the rate enhancement was shown to be different between different ionic liquids and also between different solvent compositions. These results indicate a balance between microscopic interactions that result in the observed solvent effects and a qualitative method for analysing such interactions is introduced. PMID- 28737186 TI - Ionic liquid [OMIm][OAc] directly inducing oxidation cleavage of the beta-O-4 bond of lignin model compounds. AB - We explored the oxidation reactions of lignin model compounds directly induced by ionic liquids under metal-free conditions. In this work, it was found that ionic liquid 1-octyl-3-methylimidazolium acetate as a solvent could promote the aerobic oxidation of lignin model compound 2-phenoxyacetophenone (1) and the yields of phenol and benzoic acid from 1 could be as high as 96% and 86%, respectively. A possible reaction pathway was proposed based on a series of control experiments. An acetate anion from the ionic liquid attacked the hydrogen from the beta-carbon thereby inducing the cleavage of the C-O bond of the aromatic ether. Furthermore, it was found that 2-(2-methoxyphenoxy)-1-phenylethanone (4) with a methoxyl group could also be transformed into aromatic products in this simple reaction system and the yields of phenol and benzoic acid from 4 could be as high as 98% and 85%, respectively. This work provides a simple way for efficient transformation of lignin model compounds. PMID- 28737187 TI - Recent advances in asymmetric total synthesis of prostaglandins. AB - Prostaglandins (PGs) are a series of hormone-like chemical messengers and play a critical role in regulating physiological activity. The diversified therapeutic activities and complex molecular architectures of PGs have attracted special attention, and huge progress has been made in asymmetric total synthesis and discovery of pharmaceutically useful drug candidates. In the last 10 years, several powerful syntheses have emerged as new solutions to the problem of building PGs and represent major breakthroughs in this area. This review highlights the advances in methodologies for the asymmetric total synthesis of prostaglandins. The application of these methodologies in the syntheses of medicinally useful prostaglandins is also described. The study has been carefully categorized according to the key procedures involved in the syntheses of various prostaglandins, aiming to give readers an easy understanding of this chemistry and provide insights for further improvements. PMID- 28737188 TI - [Late preterm, the ?forgotten? infants: A personal perspective]. PMID- 28737189 TI - [Pertussis vaccination in pregnancy: Security and effectiveness in the protection of the infant]. AB - Whooping cough is an immune preventable disease that can be life threatening. Despite infant immunization starting at 2 month of age, there are many cases and outbreaks in our country and also around the world, with a high risk of mortality specially in infants under 6 month of age. It has been proposed that antenatal vaccination with acellular pertussis component (Tdap) would be useful, safe and effective since it transfers a high antibody rate to the child, reducing the incidence of pertussis in this group by 85%. No higher incidence of adverse effects has been found in pregnant women with this vaccine. This strategy has been implemented in several developed and Latin American countries. The purpose of this manuscript is to review and discuss the benefits of antenatal vaccination with Tdap. It was concluded that maternal immunization with Tdap vaccine should be promoted to prevent infection and associated mortality in the less than 6 months of age by Bordetella pertussis. PMID- 28737190 TI - [Validation of the general help-seeking questionnaire for mental health problems in adolescents]. AB - : Help-seeking behavior is a protective factor in young people, essential for their mental health, well-being and development. However, some adolescents do not seek professional help when they need to. In this context, it is relevant to study the help-seeking behavior for mental health problems in adolescent population. OBJECTIVE: To adapt and validate the general help-seeking questionnaire for mental health problems in Chilean adolescents. SUBJECTS AND METHOD: Cross-sectional and correlational study of a non-random sample of 793 adolescent students, between 14 and 19 years old, from the city of Talca (Chile). The general help-seeking questionnaire, vignette version, (GHSQ-V) was administered after a transcultural adaptation and criterion validation. Descriptive statistics, exploratory factor analysis and non-parametric Mann Whitney U test were used for analysis. RESULTS: An exploratory analysis identified two factors regarding available sources of help: 1) informal sources; 2) formal sources. Reliability was calculated separately for each of the health problems, resulting alpha values ranging from 0.87 to 0.75. In addition, the scale showed significant association with the variables self-efficacy and depression in the hypothesized directions. Finally, significant differences were identified in the willingness to seek help by adolescent?s level of mental health literacy, for all mental health issues presented, except suicide. CONCLUSION: The adaptation of the GHSQ-V for Chilean adolescent and youth population is a valid and reliable instrument to measure willingness to seek help for mental health problems in our socio-cultural environment. PMID- 28737191 TI - [Stress in parents of hospitalized newborns in a neonatal intensive care unit]. AB - : The birth of a child that requires hospitalization in a Neonatal Intensive Care Unit (NICU) can be very stressful for parents. OBJECTIVE: To determine the stress level of parents of newborns (NB) hospitalized in a level III NICU in Santiago, and its association with clinical and sociodemographic variables. PATIENTS AND METHOD: Descriptive cross-sectional study. 373 admissions were evaluated. The sampling was non-probabilistic and included parents of RN admitted to the UPCN between 7 and 21 days of hospitalization. Only parents which have visited the RN at least three times were included. INSTRUMENTS: i) Questionnaire to obtain data which could not be obtained from the medical record; ii) Parental Stress Scale: Neonatal Intensive Care Unit (PSS:NICU) which measures the perception of parents about stressors from the physical and psychological environment of the UPCN. RESULTS: 100 parents of 59 hospitalized NB participated in the study. The average parental stress was 2.87+/-0.69. The subscale scores got higher was ?Relationship with the baby and parental role?. Complications in pregnancy, prenatal diagnosis or prenatal hospitalization, did not affect the stress level or the presence of prematurity, respiratory diseases, congenital malformations, genopathies or requirement of mechanical ventilation. CONCLUSIONS: Stress levels presented in parents are unrelated to gender and to the studied clinical variables. PMID- 28737192 TI - [Socioeconomical level and behavior in school-age children: the mediating role of parents]. AB - : A determinant of particular relevance in human development is the socioeconomic status (SES) and, specifically, low SES and poverty. Likewise, family environment is essential in the development of children and a potential mediator or moderator of the effect of broader social conditions. OBJECTIVE: To analyze the role of parenting stress as a mediating variable of the relationship between SES and both externalized and internalized behaviors in preschool children. SUBJECTS AND METHOD: Descriptive secondary base study based on the Longitudinal Survey of Chilean First Infancy that selected a stratified sample, representative by clusters, of 9.996 children from 3 to 5 years old and their caregivers, that completed a battery of instruments for measuring SES variables, parenting stress and externalized and internalized behaviors. The analysis used a linear model with least square estimate. As hypothesis testing, the Dm (an adaptation of the F test for multiple imputation method) was used. RESULTS: The mediation model of parenting stress in the relationship between SES and both externalized and internalized behaviors was confirmed for the latter; regarding externalized behaviors a model of moderation was observed, being the stress influence lower on the low SES. CONCLUSIONS: Parental stress showed a clear relationship with the presence of externalized and internalized behaviors, stronger than the SES. The relationship between SES and parenting stress is very important to understand the processes that affect children?s development. PMID- 28737193 TI - [Vertebral fractures in children with Type I Osteogenesis imperfecta]. AB - : Osteogenesis imperfecta (OI) is an hereditary disease affecting conective tissue, mainly associated to growth retardation and pathological fractures. OI type I (OI type I), is the mildest, most often, and homogeneous in its fenotype. Vertebral fractures are the most significant complications, associated to skeletical and cardiopulmonary morbidity. OBJECTIVES: To characterize clinically a cohort of children with OI type I. PATIENTS AND METHODS: A cohort of OI type I children younger than 20 year old was evaluated. Demographic, clinical, biochemical and radiological data were registered. RESULTS: Sixty seven patients were included, 55% male, 69% resident in the Metropolitan Region. The mean age of diagnose was 2.9 years, 70% presented vertebral fractures on follow-up, mostly thoracic, and 50% before the age of 5 years. Fifty percentage presented vertebral fractures at diagnose, which was about the age of 5 years. Bone metabolic parameters were in the normal range, without significant change at the moment of vertebral fractures. Calcium intake was found to be below American Academy of Pediatrics recommendations at the time of the first fracture. CONCLUSIONS: In this study OI type I has an early diagnose, and vertebral fractures show a high incidence, mostly in toddlers. Calcium intake was found to be below reccomended values, and should be closely supervised in these patients. PMID- 28737194 TI - [Face protective patches do not reduce facial pressure ulcers in a simulated model of non-invasive ventilation]. AB - : Noninvasive ventilation (NIV) frequently involves the development of facial pressure ulcers (FPU). Its prevention considers the empirical use of protective patches between skin and mask, in order to reduce the pressure exerted by it. OBJECTIVES: To evaluate the effect of protective patches on the pressure exerted by the facial mask, and its impact on the programmed ventilatory parameters. METHOD: Bilevel NIV simulated model using full face mask in phantom with a physiological airway (ALS PRO +) in supine position. Forehead, chin and cheekbones pressure were measured using 3 types of standard protective patches versus a control group using pressure sensors (Interlinks Electronics(r)). The values obtained with the protective patches-mask model were evaluated in the programmed variables maximum inspiratory flow (MIF)), expired tidal volume (Vte) and positive inspiratory pressure (IPAP), with Trilogy 100 ventilator, Respironics(r). The programming and recording of the variables was carried out in 8 opportunities in each group by independent operators. RESULTS: There was no decrease in facial pressure with any of the protective patches compared to the control group. Moltopren increased facial pressure at all support points (p < 0.001), increased leakage, it decreased MIF, Vte and IPAP (p < 0.001). Hydrocolloid patches increased facial pressure only in the left cheekbone, increased leakage and decreased MIF. Polyurethane patches did not produce changes in facial pressure or ventilatory variables. CONCLUSION: The use of protective patches of moltopren, hydrocolloid and polyurethane transparent did not contribute to the decrease of the facial pressure. A deleterious effect of the moltopren and hydrocolloid patches was observed on the administration of ventilatory variables, concluding that the non-use of the protective patches allowed a better administration of the programmed parameters. PMID- 28737195 TI - [Maternal postnatal depression and its impact on child neurodevelopment: a cohort study]. AB - : Post partum depresion (DPP) is the most frequent psquiatric disorder in pregnant woman and it may affect the neurodevelopment of their offspring. Our goal was to analyze the association between maternal depressive symptoms at 6 months after birth and child?s neurodevelopmental disorders at 18 months-old, in a homogeneous population characterized by low socioeconomic and cultural level. PATIENTS AND METHODS: A prospective cohort study was conducted. There were included 127 healthy postpartum women and their infants. A structured interview was performed which included patronymic data and family perception before discharge. Binomial monitoring took place at 6 months postpartum, when was applied the Beck test for depression and anxiety to mothers; children's neurodevelopment at 18 month-old was evaluated by Lezine Revised Brunet-test. RESULTS: The sample consisted of 125 women and their children. The mean age was 24.5 year old (SD 6.02); 30.6% had completed less than 6 years of formal education. The incidence of moderate to severe postpartum depression at 6 months after birth was 20%. The overall development score mean was 73.52 (SD 8.06) in the depression population and 76.97 (SD 8.07) in the population without depression (p = 0.04). The development coefficient was 69.08 (SD: 10.35) in the depression population and 74.11 (SD 0.67) in the population without depression (p = 0.01). CONCLUSIONS: The incidence of moderate to severe DPP was 20%. Persistent DPP in a vulnerable socio-economic context has impact on child development. PMID- 28737196 TI - [Results of a national program of pediatric heart transplantation: strengths and weakness]. AB - : Pediatric heart transplantation is an effective therapy to treat advanced heart failure in children. OBJECTIVES: To analyze the immediate and mid-term results of pediatric patients listed for heart transplantation. PATIENTS AND METHODS: Registration of patients admitted to our transplant protocol between October 2001 and July 2016 were reviewed, analyzing demographic data, diagnosis, status at the time of listing, waiting time until transplantation, donor data, use of ventricular assist device, hemodynamic data, complications and global mortality. RESULTS: Thirthy patients where included with a mean age of 9.4 years (1 month to 15 years). The most frequent diagnosis was dilated cardiomyopathy in 24 patients (80%). The status was I (urgency) in 19 cases and II in 11 cases. Ten patients died on the waiting list (33.3%) at an average of 52 days (13-139 days). Fourteen were transplanted (46.7%), with a waiting time of 199.6 days (4-586 days). Nine patients required mechanical support (30%). All patients received triple association of immunosuppression. One patient died 16 days post transplant due to primary graft failure (7.1%). The average follow-up was 43 months (0.5-159 months). Two patients died later on (82 and 55 months), both due to secondary rejection because of voluntary cessation of immunosuppressive therapy. Survival at 1 and 5 years was 93% and 74%, respectively. CONCLUSIONS: Our program has successfully transplanted 50% of patients enrolled, with good medium-term survival. A significant proportion of patients were listed as a medical emergency and 34.5% died on the waiting list. PMID- 28737197 TI - [Congenital hyperinsulinism of the newborn: a case report]. AB - : Congenital hyperinsulinism (CH) is the most frequent cause of persistent hypoglycemia in the newborn and it is characterized by an inappropriately elevated insulin level in presence of hypoglycemia. Initial management is medical treatment, but if it fails, partial pancreatectomy is the surgical procedure of choice. OBJECTIVE: To report a case of a newborn with CH to aware on this condition and update its multidisciplinary management. CASE REPORT: The case of a full term newborn with severe symptomatic hypoglycemia unresponsive to medical treatment is reported . Ultrasonography and abdominal MRI were normal, Gallium 68 PET/CT showed uptake in the body of the pancreas. Laparoscopic corporocaudal pancreatectomy was performed. The patient resolved hypoglycemia and was discharged without incidents. Genetic study was consistent with focal CH, confirmed later by biopsy. DISCUSSION: This case report exposes the clinical presentation of CH and its diagnosis. It emphasizes on the surgical treatment and the advantages of minimally invasive technique. PMID- 28737198 TI - [Tetany secondary to phosphate enema toxicity, case report]. AB - : Phosphate enemas are frequently used in the treatment of constipation. Errors in dosage and administration can lead to severe complications. OBJECTIVE: To report a case of severe toxicity of phosphate enemas in a child with no risk factors. CASE: 2 years old female, with functional constipation, was brought to emergency department because abdominal pain. She was diagnosed with fecal impaction and received half a bottle of Fleet Adult(r) (Laboratorio Synthon, Chile) two times, with no clinical resolution, deciding to start proctoclisis in pediatric ward. Soon after admission, she presented painful tetany, but alert and oriented. Patient was transferred to PICU where severe hyperphosphatemia and secondary hypocalcemia were confirmed. Her treatment included electrolyte correction; removal of residual phosphate enema and hyperhydration. Tetany resolved over 2 hours after admission and no other complications. Proctoclisis was performed and patient was discharged three days after admission with pharmacological management of constipation. CONCLUSION: Phosphate enemas may cause serious complications in children with no risk factors. Errors in dosage, administration and removal of the enema are causes of toxicity in this group. Pediatricians and health personnel must be aware of risks and signs of toxicity of phosphate enema. PMID- 28737199 TI - [Giant splenic cyst in a teenager girl: Case report]. AB - : Giant nonparasitic splenic epidermoid cysts are relatively uncommon. These lesions can lead abdominal pain, but most of then are asymptomatic, and they are discovered incidentally. We report a 13-y old female with a giant splenic epidermoid cystic, given the special interest of diagnostic and therapeutic decision-making of this rare entity. CASE REPORT: A 13-y old female with clinical history of abdominal pain since the last two months. On physical examination a firm, tender mass was palpable in left hypochondrium. Diagnosis of a large cystic splenic mass was made based on ultrasound and abdominal computed tomography scan. Splenectomy was performed, and histopathological-immunohistochemistry studies revealed findings suggestive of primary epithelial cyst. The post-operative clinical course was satisfactory and uneventful. CONCLUSIONS: Treatment of giant nonparasitic splenic cysts is surgical. Preserve splenic parenchyma must be the aim in an individualized decision-making. The different types of surgical modalities will be according to the diagnosis and clinical situation (cyst size, age, comorbidities). PMID- 28737200 TI - [Recurrent respiratory papillomatosis in a pediatric patient: case report]. AB - : Genetic variability related to the host immune system has been proposed as one of the most influential factors in the development of diseases caused by HPV. CLINICAL CASE: We report the case of a 5-year-old child in whom chronic laryngeal papillomatosis, probably acquired vertically during labor, was detected. The diagnosis of laryngeal papillomatosis was confirmed with a biopsy after a first surgery to remove the papillomas. The Derkay classification system was used to assess the severity of papillomatosis. Biopsy genotyping was performed by demonstrating HPV-6. Later, HLA-DQA1 * 0505, -DQB1 * 0301, -DRB1 * 1101 alleles were homozygous for HLA allele typing. CONCLUSIONS: Further studies are needed to identify the most prevalent HLA alleles in the Latino population and their potential association with genetic susceptibility in Recurrent Respiratory Papillomatosis. PMID- 28737201 TI - [Paniculitis as manifestation of prolonged febrile syndrome: Case report]. AB - : Fever of unknown origin (FUO) is defined as fever over 7 to 10 days without a diagnosis despite a complete initial study. The most frequent causes are infections, autoimmune and tumors. Even though most cases are self-limited there is a minority that has an underlying etiology with an ominous forecast, encouraging a systematized study. OBJECTIVE: To report a rare case of a boy who presented fever of unknown origin associated to panniculitis and was diagnosed of subcutaneous panniculitis-like-T cell lymphoma and to emphasis the importance of a sequential study of FUO, in order to reach a diagnosis in patients who need a timely intervention. CLINICAL CASE: A ten year old boy, previously healthy, presented subcutaneous nodular lesions of 2 month of evolution, located in abdominal region and extremities, given few symptoms, associated with prolonged fever. He was hospitalized for proper study, in first instance infectious and immune causes were discarded and through lesions biopsy the diagnose of subcutaneous panniculitis-like-T cell lymphoma was reached. CONCLUSION: When FUO is diagnosed, most prevalent causes must be discarded. Then, differential diagnosis, such as immune and neoplasic etiologies, have to be considered. If FUO is associated to elemental nodular lesions, biopsy must be indicated early, in order to find potential malignant cases, avoiding therapeutic delay. PMID- 28737202 TI - [Euglycemic ketosis in an adolescent with type 1 diabetes on insulin and dapaglifozin: Case report]. AB - : Dapagliflozin, an insulin-independent sodium-glucose cotransporter 2 inhibitor (SGLT2-I) induces glycosuria and reduces hyperglycemia in adults with type 2 diabetes. OBJECTIVE: To present an ?euglycemic? diabetic ketosis in an adolescent with type 1 diabetes (T1D) receiving dapagliflozin, to alert about the risk of a drug not approved in children nor in T1D. CASE REPORT: A 17 years old adolescent with T1D during 9 years, was started on dapagliflozin 10 mg / day to reduce insulin dose and weight. During 11 months on treatment, capillaries ketones were undetectable and she exhibited a reduction in body mass index 23.9 to 21.1 kg/m2, basal insulin 40 to 17 U, glycated hemoglobin 8.3 to 7.5%, capillary glucose 175 to 161 mg/dl and glucose variability (standard deviation) 85 to 77. Suddenly nausea and vomits appeared. The patient was on an insulin pump and well calibrated continuous glucose monitoring, showing stable glucose levels under 200 mg/dl, and an insulin bolus was delivered. Vomiting without hyperglycemia persisted; three hours later, she was severely dehydrated and fainting, with ketones 4.6 nmol/l and glucose 224 mg/dl. She received IV saline fluids, ondansetron, carbohydrates and several insulin boluses. Hydration and general condition improved soon, however despite several insulin doses, ketosis continued for 24 hours. It is remarkable that the pump was working well and the cannula was not changed. After the ketosis was resolved, she continued using the same cannula with good metabolic control. CONCLUSION: Euglycemic ketosis is a life-threatening condition that must be suspected. PMID- 28737203 TI - Pain insensitivity in a child with a de novo interstitial deletion of the long arm of the chromosome 4: Case report. AB - : Terminal and interstitial deletions of the distal segment of the long arm of chromosome 4 (Cr4q del) are not common genetic disorders. The severity of the phenotype is correlated with the size of the deletion because small deletions have little clinical impact, whereas large deletions are usually associated with multiple congenital anomalies, postnatal growth failure, and moderate to severe intellectual disability. Alteration in pain tolerance has not been included among these features, also in case of large deletions. The purpose of this report is to document a case of a child affected by interstitial Cr4q del, expressing pain insensitivity as clinical feature not previously described. We also offer a discussion on genetic disorders featuring pain insensitivity/indifference. CASE REPORT: A Caucasian girl aged 12 came to our observation for a developmental delay with multiple congenital abnormalities and moderate intellectual disability (IQ 47). A de novo interstitial Cr4 del between band q31.3 and q32.2 (Cr4 del q31.3 to q32.2) was found. The child also expresses no evidence of pain perception to injures which normally evoke pain. Consequently, she is affected by severe disability caused by painless injuries and self-injurious behaviours, such as excessive self-rubbing and scratching. The neurological examination manifested high pain threshold with preserved tactile sensitivity. CONCLUSIONS: This is the first report of pain insensitivity in a patient with a specific genetic deletion involving the interstitial region of the distal long arm of Cr4. Moreover, this report could serve as a useful model to better understand mechanisms of pain perception and its modulation. PMID- 28737204 TI - [Celiac disease, non celiac gluten sensitivity and wheat allergy: comparison of 3 different diseases triggered by the same food]. AB - Gluten and other related proteins of the wheat, rye and barley, have antigenic properties that may trigger adverse reactions in susceptible individuals. Celiac disease was the first pathology with clear causal association related to the intake of these proteins. Recently, wheat allergy and non celiac gluten sensitivity have been described. Although, clinical presentation and its relation with protein ingestion may be similar and elicit confusion, their pathogenic mechanism, diagnosis and treatment are quite different. Since the prevalence of these diseases is relatively high as a whole, it is essential that these become familiar to primary care doctors and general pediatricians, thus they will know how to differentiate and face them. The aim of this review is to compare the main aspects of epidemiology, pathofisiology, diagnosis and treatment of these 3 conditions. PMID- 28737205 TI - [Abdominal pain secondary to ileocecal fistulae by ingestion of multiple magnetic bodies: Clinical Case]. PMID- 28737206 TI - [Nephro-urological malformations in children with Down syndrome]. PMID- 28737207 TI - ? PMID- 28737208 TI - Pre-symptomatic (Baseline) computed tomography predicts invasive pulmonary aspergillosis in high-risk adult haemato-oncology patients. PMID- 28737209 TI - Lactate dehydrogenase as a prognostic marker in AL amyloidosis: expected or unexpected? PMID- 28737210 TI - Whole-body ultra-low dose computed tomography in comparison with spinal magnetic resonance imaging in the assessment of disease in multiple myeloma; Methodological issues on Diagnostic value. PMID- 28737211 TI - Closing in on the best supraglottic airway for paediatric anaesthesia? PMID- 28737212 TI - A genome-wide association study for equine recurrent airway obstruction in European Warmblood horses reveals a suggestive new quantitative trait locus on chromosome 13. AB - Recurrent airway obstruction (RAO), also known as heaves, is an asthma-like respiratory disease. Its development is strongly influenced by environmental risk factors such as sensitization and exposure to moldy hay, straw bedding and stabling indoors. A hereditary component has been documented in previous studies; however, so far no causative genetic variant that influences the risk of developing RAO has been identified. In this study, we revised an existing dataset and selected 384 horses for genotyping on the Affymetrix high-density equine SNP array. We performed an allelic case-control genome-wide association study, which revealed a suggestively significant association on equine chromosome 13 at 32 843 309 bp. This SNP is located in the protein-coding gene TXNDC11, which is possibly involved in the folding process of the multiprotein complexes DUOX1 and DUOX2. In humans, these proteins are known to take part in regulating the production of H2 O2 in the respiratory tract epithelium as well as in MUC5AC mucin expression. Therefore, TXNDC11 may be considered a functional candidate gene, and further research is needed to explore its potential role in RAO-affected horses. PMID- 28737213 TI - Identification of methylated GnTI-dependent N-glycans in Botryococcus brauni. AB - In contrast to mammals and vascular plants, microalgae show a high diversity in the N-glycan structures of complex N-glycoproteins. Although homologues for beta1,2-N-acetylglucosaminyltransferase I (GnTI), a key enzyme in the formation of complex N-glycans, have been identified in several algal species, GnTI dependent N-glycans have not been detected so far. We have performed an N glycoproteomic analysis of the hydrocarbon oils accumulating green microalgae Botryococcus braunii. Thereby, the analysis of intact N-glycopeptides allowed the determination of N-glycan compositions. Furthermore, insights into the role of N glycosylation in B. braunii were gained from functional annotation of the identified N-glycoproteins. In total, 517 unique N-glycosylated peptides have been identified, including intact N-glycopeptides that harbored N acetylhexosamine (HexNAc) at the nonreducing end. Surprisingly, these GnTI dependent N-glycans were also found to be modified with (di)methylated hexose. The identification of GnTI-dependent N-glycans in combination with N-glycan methylation in B. braunii revealed an uncommon type of N-glycan processing in this microalgae. PMID- 28737215 TI - Skin manifestations are common and associated with a higher prevalence of congenital abnormalities in Zika virus infection. PMID- 28737216 TI - Does developmental regression in autism spectrum disorder have biological origins? PMID- 28737214 TI - Decline in cellular function of aged mouse c-kit+ cardiac progenitor cells. AB - KEY POINTS: While autologous stem cell-based therapies are currently being tested on elderly patients, there are limited data on the function of aged stem cells and in particular c-kit+ cardiac progenitor cells (CPCs). We isolated c-kit+ cells from young (3 months) and aged (24 months) C57BL/6 mice to compare their biological properties. Aged CPCs have increased senescence, decreased stemness and reduced capacity to proliferate or to differentiate following dexamethasone (Dex) treatment in vitro, as evidenced by lack of cardiac lineage gene upregulation. Aged CPCs fail to activate mitochondrial biogenesis and increase proteins involved in mitochondrial oxidative phosphorylation in response to Dex. Aged CPCs fail to upregulate paracrine factors that are potentially important for proliferation, survival and angiogenesis in response to Dex. The results highlight marked differences between young and aged CPCs, which may impact future design of autologous stem cell-based therapies. ABSTRACT: Therapeutic use of c kit+ cardiac progenitor cells (CPCs) is being evaluated for regenerative therapy in older patients with ischaemic heart failure. Our understanding of the biology of these CPCs has, however, largely come from studies of young cells and animal models. In the present study we examined characteristics of CPCs isolated from young (3 months) and aged (24 months) mice that could underlie the diverse outcomes reported for CPC-based therapeutics. We observed morphological differences and altered senescence indicated by increased senescence-associated markers beta-galactosidase and p16 mRNA in aged CPCs. The aged CPCs also proliferated more slowly than their young counterparts and expressed lower levels of the stemness marker LIN28. We subsequently treated the cells with dexamethasone (Dex), routinely used to induce commitment in CPCs, for 7 days and analysed expression of cardiac lineage marker genes. While MEF2C, GATA4, GATA6 and PECAM mRNAs were significantly upregulated in response to Dex treatment in young CPCs, their expression was not increased in aged CPCs. Interestingly, Dex treatment of aged CPCs also failed to increase mitochondrial biogenesis and expression of the mitochondrial proteins Complex III and IV, consistent with a defect in mitochondria complex assembly in the aged CPCs. Dex-treated aged CPCs also had impaired ability to upregulate expression of paracrine factor genes and the conditioned media from these cells had reduced ability to induce angiogenesis in vitro. These findings could impact the design of future CPC-based therapeutic approaches for the treatment of older patients suffering from cardiac injury. PMID- 28737217 TI - Splenic rupture following temporary cessation of ibrutinib. PMID- 28737218 TI - Geographical foci and epidemiological changes of pemphigus vulgaris in four decades in Southeastern Brazil. PMID- 28737219 TI - Impacts of hydraulic redistribution on grass-tree competition vs facilitation in a semi-arid savanna. AB - A long-standing ambition in ecosystem science has been to understand the relationship between ecosystem community composition, structure and function. Differential water use and hydraulic redistribution have been proposed as one mechanism that might allow for the coexistence of overstory woody plants and understory grasses. Here, we investigated how patterns of hydraulic redistribution influence overstory and understory ecophysiological function and how patterns vary across timescales of an individual precipitation event to an entire growing season. To this end, we linked measures of sap flux within lateral and tap roots, leaf-level photosynthesis, ecosystem-level carbon exchange and soil carbon dioxide efflux with local meteorology data. The hydraulic redistribution regime was characterized predominantly by hydraulic descent relative to hydraulic lift. We found only a competitive interaction between the overstory and understory, regardless of temporal time scale. Overstory trees used nearly all water lifted by the taproot to meet their own transpirational needs. Our work suggests that alleviating water stress is not the reason we find grasses growing in the understory of woody plants; rather, other stresses, such as excessive light and temperature, are being ameliorated. As such, both the two layer model and stress gradient hypothesis need to be refined to account for this coexistence in drylands. PMID- 28737220 TI - Current state of pharmacovigilance in the Arab and Eastern Mediterranean region: results of a 2015 survey. AB - OBJECTIVES: This study describes the current state of pharmacovigilance systems in Arab and Eastern Mediterranean countries. METHODS: A descriptive cross sectional study was conducted between May and September 2015. Data were gathered from a standardized online survey sent to pharmacovigilance leadership identified as the official national contact for the WHO Programme for International Drug Monitoring. In countries with no specified pharmacovigilance programme or leadership, Ministry of Health officers responsible for drug safety policies were invited to participate in the survey. The survey measured three domains of pharmacovigilance performance using indicators that were defined and assigned scores a priori: 10 structural, 10 process, and seven impact indicators. Total scores were assigned to each domain of indicators, and countries were compared depending on their total performance score. KEY FINDINGS: Complete responses were received from 20 countries (of 24 total), representing an 83% response rate. Approximately 20% (n = 4) of respondents reported not having any pharmacovigilance programme in their country. In total, across the three primary pharmacovigilance performance domains, the mean score for the 20 countries in the survey was 28.9 [standard deviation(SD): 13.8] with a range from 4 to 48 (maximum possible score: 48). In the structural performance domain, which assessed the existence of key pharmacovigilance structures, systems and policies in each country, the mean score among respondents was 13.1 (SD: 5.7) and the scores ranged from 2 to 19 (maximum possible score: 19). In the process performance domain, which assessed the constellation of activities undertaken by pharmacovigilance programmes (including the collection, collation, analysis and evaluation of adverse drug event reports), the mean score among respondent countries was 9.1 (SD: 5.4) and the scores ranged from 0 to 17 (maximum possible score: 17). Finally, in the impact domain, which measured the scope of national efforts at promoting risk minimization and increasing awareness in use of potentially unsafe pharmaceutical products, the mean score was 6.8 (SD: 3.6) and scores ranged from 0 to 12 (maximum possible score: 12). CONCLUSIONS: The findings suggest wide disparities in pharmacovigilance systems in the region, underscoring the need for a multistakeholder effort in bolstering programme development and the necessity to build collaboration regionally and internationally to enhance capacity, improve public and healthcare provider awareness and assist in the development of pharmacovigilance systems still in their nascent stage. PMID- 28737221 TI - Development of paradoxical inflammatory disorders during treatment of psoriasis with TNF inhibitors: a review of published cases. AB - BACKGROUND: TNF inhibitors have proven to be effective and relatively safe in the management of psoriasis. While infections and certain malignancies are established as acknowledged side effects, paradoxical inflammatory, non neoplastic, noninfectious adverse events are being recognized less frequently. We aimed to identify published, peer-reviewed cases of paradoxical inflammatory, non neoplastic, noninfectious adverse events in psoriasis patients during TNF inhibitor therapy. METHODS: A literature search in MEDLINE was performed for articles published from inception through the 8th of June 2016 that reported suspected incidents fulfilling a predefined search strategy. In addition, articles identified by reference lists were added. RESULTS: A total of 295 cases from various organ systems among 13 269 patients were identified: 91 cases were related to infliximab, 101 cases were related to etanercept, and 102 cases were related to adalimumab. One case report was related to both etanercept and adalimumab. CONCLUSION: Induction of paradoxical non-neoplastic noninflammatory adverse events in psoriasis patients treated with a TNF inhibitor is worth recognizing. The amount of cases identified by this study suggests that continuous surveillance and research into these adverse effects is relevant. Nondermatologic paradoxical inflammatory reactions may be underreported. PMID- 28737222 TI - Bioinformatics analysis in menopause transition promotes distinct modulation in calvaria and bone marrow osteoblastic cells. AB - We read with great interest the recent report by Semeghini et al. (2017), Cell Biol Int, "Menopause transition promotes distinct modulation of mRNAs and miRNAs expression in calvaria and bone marrow osteoblastic cells," which appeared on 24 May 2017 in Cell Biology International. The results of the report are very helpful for us; however, from our perspective, the author's method in bioinformatics analysis is inappropriate: Student's t-test is an inappropriate statistical method for detecting differentially expressed mRNA or miRNA in osteoblastic cells from calvaria of ovariectomized rats compared to control or in osteoblastic cells from bone marrow of ovariectomized rats compared to control. PMID- 28737223 TI - A network meta-analysis of the clinical properties of various types of supraglottic airway device in children. AB - We conducted both conventional pairwise and Bayesian network meta-analyses to compare the clinical properties of supraglottic airway devices in children. We searched six databases for randomised clinical trials. Our primary end-points were oropharyngeal leak pressure, risk of insertion failure at first attempt, and blood staining risk. The risk of device failure, defined as the abandonment of the supraglottic airway device and replacement with a tracheal tube or another device, was also analysed. Sixty-five randomised clinical trials with 5823 participants were identified, involving 16 types of supraglottic airway device. Network meta-analysis showed that the i-gelTM, Cobra perilaryngeal airwayTM and Proseal laryngeal mask airway (LMA(r) -Proseal) showed statistically significant differences in oropharyngeal leak pressure compared with the LMA(r) -Classic, with mean differences (95% credible interval, CrI) of 3.6 (1.9-5.8), 4.6 (1.7 7.6) and 3.4 (2.0-4.8) cmH2 O, respectively. The i-gel was the only device that significantly reduced the risk of blood staining of the device compared with the LMA-Classic, with an odds ratio (95%CrI) of 0.46 (0.22-0.90). The risk (95%CI) of device failure with the LMA-Classic, LMA(r) -Unique and LMA-Proseal was 0.36% (0.14-0.92%), 0.49% (0.13-1.8%) and 0.50% (0.23-1.1%), respectively, whereas the risk (95%CI) of the i-gel and PRO-Breathe was higher, at 3.4% (2.5-4.7%) and 6.0% (2.8-12.5%), respectively. The risk, expressed as odds ratio (95%CrI), of insertion failure at first attempt, was higher in patients weighing < 10 kg at 5.1 (1.6-20.1). We conclude that the LMA-Proseal may be the best supraglottic airway device for children as it has a high oropharyngeal leak pressure and a low risk of insertion. Although the i-gel has a high oropharyngeal leak pressure and low risk of blood staining of the device, the risk of device failure should be evaluated before its routine use can be recommended. PMID- 28737224 TI - Hair loss associated with imatinib treatment: a dermoscopic study. PMID- 28737225 TI - Psychostimulant effect of dopaminergic treatment and addictions in Parkinson's disease. AB - BACKGROUND: Dopamine replacement therapy in PD has been associated with both behavioral addictions and dopamine addiction. OBJECTIVES: To investigate potential association between l-dopa induced neuropsychiatric fluctuations and addictions in PD. METHODS: A cohort of 102 patients with PD suffering from motor complications of l-dopa treatment was prospectively analyzed. We evaluated dopamine addiction, behavioral addictions, and neuropsychiatric fluctuations using the Ardouin scale of behavior in PD. RESULTS: Patients with (n = 51) or without (n = 51) neuropsychiatric fluctuations did not differ in age, disease duration, medication, or UPDRS III motor score during on and off drug condition. Patients with neuropsychiatric fluctuations had a higher H & Y stage in off-drug condition. A multivariate model showed that dopamine addiction (odds ratio: 8.9; P = 0.02) and behavioral addictions (odds ratio: 3.76; P = 0.033) were more frequent in the presence of neuropsychiatric fluctuations. Behavioral addictions and dopamine addiction were more frequent in the presence than in the absence of on-drug euphoria (46% vs. 13.9%; P < 0.001 and 27% vs 6.2 %; P = 0.003), while conversely, no association emerged between dopamine or behavioral addictions and presence of off-drug dysphoria. Patients with neuropsychiatric fluctuations had a poorer quality of life and a more frequent history of anxiety disorder. CONCLUSIONS: The psychostimulant effects of dopamine treatment during on-drug euphoria, rather than avoidance of off-drug dysphoria, appear to drive both behavioral addictions and abuse of medication. (c) 2017 International Parkinson and Movement Disorder Society. PMID- 28737226 TI - Laser-Induced Graphene Formation on Wood. AB - Wood as a renewable naturally occurring resource has been the focus of much research and commercial interests in applications ranging from building construction to chemicals production. Here, a facile approach is reported to transform wood into hierarchical porous graphene using CO2 laser scribing. Studies reveal that the crosslinked lignocellulose structure inherent in wood with higher lignin content is more favorable for the generation of high-quality graphene than wood with lower lignin content. Because of its high electrical conductivity (~10 Omega per square), graphene patterned on wood surfaces can be readily fabricated into various high-performance devices, such as hydrogen evolution and oxygen evolution electrodes for overall water splitting with high reaction rates at low overpotentials, and supercapacitors for energy storage with high capacitance. The versatility of this technique in formation of multifunctional wood hybrids can inspire both research and industrial interest in the development of wood-derived graphene materials and their nanodevices. PMID- 28737227 TI - Dasatinib-induced loss of eyebrows. PMID- 28737228 TI - Promising Thermoelectric Bulk Materials with 2D Structures. AB - Given that more than two thirds of all energy is lost, mostly as waste heat, in utilization processes worldwide, thermoelectric materials, which can directly convert waste heat to electricity, provide an alternative option for optimizing energy utilization processes. After the prediction that superlattices may show high thermoelectric performance, various methods based on quantum effects and superlattice theory have been adopted to analyze bulk materials, leading to the rapid development of thermoelectric materials. Bulk materials with two dimensional (2D) structures show outstanding properties, and their high performance originates from both their low thermal conductivity and high Seebeck coefficient due to their strong anisotropic features. Here, the advantages of superlattices for enhancing the thermoelectric performance, the transport mechanism in bulk materials with 2D structures, and optimization methods are discussed. The phenomenological transport mechanism in these materials indicates that thermal conductivities are reduced in 2D materials with intrinsically short mean free paths. Recent progress in the transport mechanisms of Bi2 Te3 -, SnSe-, and BiCuSeO-based systems is summarized. Finally, possible research directions to enhance the thermoelectric performance of bulk materials with 2D structures are briefly considered. PMID- 28737229 TI - Advances in transfusion medicine: gastrointestinal bleeding. AB - Gastrointestinal bleeding is a common medical and surgical emergency and is the second most common indication for red blood cell (RBC) transfusion in the UK. Most transfusion guidelines recommend the use of restrictive blood transfusion in stable gastrointestinal bleeding. This review explores the evidence supporting this practice, including whether it is safe in lower as well as upper gastrointestinal bleeding, and the risks of restrictive transfusion in patients with cardiovascular disease. There is a lack of evidence supporting the use of platelet and fresh frozen plasma transfusion in gastrointestinal bleeding. The aim of this review is to serve as a practical guide to transfusion in stable gastrointestinal bleeding. PMID- 28737230 TI - Endometrial cytopathology. An image analysis approach using the Ki-67 biomarker. AB - OBJECTIVE: To investigate the different identity and biological behaviour of endometrial benign epithelial and endometrial adenocarcinoma cell categories. METHODS: For this study, the imprint smears from three groups, 10 cases of disordered proliferative/benign hyperplastic endometrium, 21 cases of low-grade and eight cases of high-grade endometrial adenocarcinoma, were examined using image analysis and the Ki-67 biomarker. The plastic stem cell model was also applied. RESULTS: Among the examined groups, the nuclear area major axis ranged statistically different in the digitally measured Ki-67 positive endometrial epithelial and adenocarcinoma cells (P<.0001). Moreover, higher values of the cycling nuclear area major axis were observed in high-grade, as compared with the low-grade endometrial adenocarcinomas (P<.0001) and the cases of disordered/benign hyperplastic endometrium (P<.0001). Additionally, a Ki-67 increase pathway was observed in the benign endometrial lesions, and a relatively stable pathway was noticed in low- and high-grade endometrial adenocarcinomas. CONCLUSIONS: The different range of the nuclear area major axis among cycling endometrial epithelial and adenocarcinoma cells may correlate with their specific identity and biological behaviour. The different values of the cycling nuclear area major dimension may also be connected with the biological behaviour of the three examined groups. Moreover, the endometrial epithelial cells may follow a Ki 67 increase pathway, instead of the relatively stable pathway which the rapidly proliferating adenocarcinoma cells may use. Finally, the studied cell categories may exhibit different biology, because their stem cells may reside in different states of stemness. PMID- 28737231 TI - Rituximab in a risk-adapted treatment strategy gives excellent therapeutic results in nodular lymphocyte-predominant Hodgkin lymphoma. PMID- 28737232 TI - Chlorinated adenosine analogue induces AMPK and autophagy in chronic lymphocytic leukaemia cells during therapy. AB - 8-chloro-adenosine (8-Cl-Ado) is currently in phase-I clinical trials for acute myeloid leukaemia and chronic lymphocytic leukaemia (CLL). Previously, we demonstrated that treatment with 8-Cl-Ado leads to diminished ATP levels. We hypothesized that AMP-activated protein kinase (AMPK) signalling would be initiated in these cells, leading to induction of autophagy. AMPK activation and induction of autophagy were demonstrated during preclinical incubations in CLL cells with the analogues. Importantly, we extended similar observations in CLL lymphocytes during an 8-Cl-Ado phase-I trial. In conclusion, 8-Cl-Ado treatment induces autophagy in CLL lymphocytes in vitro as well as in vivo during clinical trial. PMID- 28737233 TI - Direct Observation of Inherent Atomic-Scale Defect Disorders responsible for High Performance Ti1-x Hfx NiSn1-y Sby Half-Heusler Thermoelectric Alloys. AB - Structural defects often dominate the electronic- and thermal-transport properties of thermoelectric (TE) materials and are thus a central ingredient for improving their performance. However, understanding the relationship between TE performance and the disordered atomic defects that are generally inherent in nanostructured alloys remains a challenge. Herein, the use of scanning transmission electron microscopy to visualize atomic defects directly is described and disordered atomic-scale defects are demonstrated to be responsible for the enhancement of TE performance in nanostructured Ti1-x Hfx NiSn1-y Sby half-Heusler alloys. The disordered defects at all atomic sites induce a local composition fluctuation, effectively scattering phonons and improving the power factor. It is observed that the Ni interstitial and Ti,Hf/Sn antisite defects are collectively formed, leading to significant atomic disorder that causes the additional reduction of lattice thermal conductivity. The Ti1-x Hfx NiSn1-y Sby alloys containing inherent atomic-scale defect disorders are produced in one hour by a newly developed process of temperature-regulated rapid solidification followed by sintering. The collective atomic-scale defect disorder improves the zT to 1.09 +/- 0.12 at 800 K for the Ti0.5 Hf0.5 NiSn0.98 Sb0.02 alloy. These results provide a promising avenue for improving the TE performance of state-of the-art materials. PMID- 28737234 TI - Formula supplementation in hospital and subsequent feeding at discharge among women who intended to exclusively breastfeed: An administrative data retrospective cohort study. AB - BACKGROUND: Among women who intend to exclusively breastfeed, it is important to identify mothers and their infants who have a greater risk of formula supplementation in hospital, and are unlikely to recover exclusive breastfeeding at discharge. We investigated factors associated with in-hospital formula feeding among healthy term infants born to women who intended to exclusively breastfeed, and among this group, predictors of infant feeding at discharge. METHODS: Retrospective cohort study utilizing routinely collected clinical data for women who intended to exclusively breastfeed and gave birth to healthy term infants in five hospitals in New South Wales, Australia, 2010-2013. Robust Poisson regression was used to obtain adjusted relative risks (aRR) for the associations between formula feeding in hospital, feeding at discharge, and associated factors. RESULTS: Of 24 713 mother-infant dyads in the study population, 16.5% received formula in hospital. After adjustment, the strongest predictors of formula supplementation were breastfeeding difficulties (aRR 2.90 [95% confidence interval {CI} 2.74-3.07]), Asian born mother (aRR 2.07 [95% CI 1.92-2.23]), and neonatal conditions (aRR 2.00 [95% CI 1.89-2.13]). Among infants who received formula (n=3998), 49.3% were fully breastfeeding at discharge, 33.1% partially breastfeeding, and 17.5% formula-only feeding. Compared with formula-only feeding, special care nursery admission (aRR 1.23 [95% CI 1.17-1.30]) and >=1 neonatal conditions (compared with none) were most strongly associated with fully breastfeeding at discharge (aRR 1.21 [95% CI 1.16-2.16]). CONCLUSION: Women and their infants who receive formula in hospital need additional support to attain exclusive breastfeeding by hospital discharge. Such support is especially needed for younger women, smokers, and women with breastfeeding difficulties. PMID- 28737235 TI - Does sensitivity to arousal improve the prognostic value of somatosensory evoked potentials in newborn infants? PMID- 28737236 TI - Diffuse large B cell lymphoma cell of origin by digital expression profiling in the REAL07 Phase 1-2 study. PMID- 28737237 TI - Subcortical shape analysis of progressive mild cognitive impairment in Parkinson's disease. AB - BACKGROUND: Cortical neural correlates of ongoing cognitive decline in Parkinson's disease (PD) have been suggested; however, the role of subcortical structures in longitudinal change of cognitive dysfunction in PD has not been fully investigated. Here, we used automatic analysis to explore subcortical brain structures in patients with PD with mild cognitive impairment that converts into PD with dementia. METHODS: One hundred eighty-two patients with PD with mild cognitive impairment were classified as PD with mild cognitive impairment converters (n = 74) or nonconverters (n = 108), depending on whether they were subsequently diagnosed with dementia in PD. We used surface-based analysis to compare atrophic changes of subcortical brain structures between PD with mild cognitive impairment converters and nonconverters. RESULTS: PD with mild cognitive impairment converters had lower cognitive composite scores in the attention and frontal executive domains than did nonconverters. Subcortical shape analysis revealed that PD with mild cognitive impairment converters had smaller local shape volumes than did nonconverters in the bilateral thalamus, right caudate, and right hippocampus. Logistic regression analysis showed that local shape volumes in the bilateral thalamus and right caudate were significant independent predictors of PD with mild cognitive impairment converters. In the PD with mild cognitive impairment converter group, thalamic local shape volume was associated with semantic fluency and attentional composite score. CONCLUSIONS: The present data suggest that the local shape volumes of deep subcortical structures, especially in the caudate and thalamus, may serve as important predictors of the development of dementia in patients with PD. (c) 2017 International Parkinson and Movement Disorder Society. PMID- 28737238 TI - The possible role of human papillomavirus infection in the development of lichen sclerosus. AB - Lichen sclerosus (LS) is a chronic inflammatory skin disease of unknown origin predominantly affecting the anogenital area that causes pruritus and pain and is associated with an increased risk of malignancy. In some cases, LS vanishes after application of imiquimod, raising the question whether human papillomavirus (HPV) may have an etiopathogenic role in anogenital LS. The databases MEDLINE and Embase were systematically searched using the PRISMA guidelines. Twenty-seven papers were included that reported the prevalence of HPV in LS and in LS associated with neoplasia. HPV was identified in 0-80% (median 22%) of all LS cases. The prevalence of HPV was higher among male patients with LS (median 29%) than among female patients (median 8%). HPV16 was the most prevalent genotype, but the distribution of genotypes indicates that even low-risk HPV can cause LS. The diverging detection rates are probably due to small sample sizes in the reviewed papers and different detection methods. Factors possibly underestimating the prevalence of HPV are a selective search for high-risk HPV, DNA destruction in fixed tissue, focally residing HPV, and possibly a clearing of HPV before the time of biopsy. Seventy-five percent of sexually active people acquire HPV during their lifetime, thus HPV alone is not a cause of LS. Genetic and immunological host factors and viral factors other than type are likely to contribute. Future studies should include patients with a short duration of symptoms, and biopsies should be multiple and fresh. PMID- 28737239 TI - Long-term use of dienogest in the treatment of painful symptoms in adenomyosis. AB - AIM: We aimed to investigate the safety and efficacy of dienogest (DNG), a progestational 19-norsteroid, administered for 52 weeks in patients with symptomatic adenomyosis. METHODS: A total of 130 patients with adenomyosis received 2 mg of DNG orally each day for 52 weeks. In cases of complicated anemia, patients were treated for anemia prior to receiving the medication. Adverse events and adverse drug reactions were evaluated. The patients' pain symptoms (dysmenorrhea and pelvic pain from adenomyosis) were assessed using a pain-scoring tool. This was a verbal rating scale comprising a 0-3-point pain severity score measuring disability to work, and an analgesics-usage score measuring need for analgesics. RESULTS: The most common adverse drug reactions included metrorrhagia (96.9%) and hot flush (7.7%). However, in most cases, metrorrhagia was tolerable and no clinically significant changes were observed concerning the incidence or severity of reactions during the 52-week treatment period. There were no serious adverse events. Both the pain-severity score and analgesics-usage score decreased after the start of treatment with DNG. The mean +/- standard deviation changes from baseline for the pain score were -3.4 +/- 1.8 at 24 weeks and -3.8 +/- 1.5 at 52 weeks, respectively. CONCLUSION: The long-term use of DNG was well-tolerated and effective in patients with symptomatic adenomyosis. PMID- 28737240 TI - In-gel and OFFGEL-based proteomic approach for authentication of meat species from minced meat and meat products. AB - BACKGROUND: Fraudulent mislabelling of processed meat products on a global scale that cannot be detected using conventional techniques necessitates sensitive, robust and accurate methods of meat authentication to ensure food safety and public health. In the present study, we developed an in-gel (two-dimensional gel electrophoresis, 2DE) and OFFGEL-based proteomic method for authenticating raw and cooked water buffalo (Bubalus bubalis), sheep (Ovis aries) and goat (Caprus hircus) meat and their mixes. RESULTS: The matrix-assisted liquid desorption/ionization time-of-flight mass spectrometric analysis of proteins separated using 2DE or OFFGEL electrophoresis delineated species-specific peptide biomarkers derived from myosin light chain 1 and 2 (MLC1 and MLC2) of buffalo sheep-goat meat mix in definite proportions at 98:1:1, 99:0.5:0.5 and 99.8:0.1:0.1 that were found stable to resist thermal processing. In-gel and OFFGEL-based proteomic approaches are efficient in authenticating meat mixes spiked at minimum 1.0% and 0.1% levels, respectively, in triple meat mix for both raw and cooked samples. CONCLUSIONS: The study demonstrated that authentication of meat from a complex mix of three closely related species requires identification of more than one species-specific peptide due to close similarity between their amino acid sequences. (c) 2017 Society of Chemical Industry. PMID- 28737241 TI - Factors associated with the severity of premenstrual syndrome among Iranian college students. AB - AIM: Premenstrual syndrome (PMS) is characterized by physical, cognitive, and behavioral symptoms that occur cyclically, from several days to 2 weeks before menses, which resolve either quickly or during the early days of menstruation. The aim of this study was to determine the factors associated with the severity of PMS in Iranian college students. METHODS: The cross-sectional study was performed among 298 college students (aged 18-35 years) with PMS, of whom, 271 college students completed the Iranian version of the Premenstrual Symptoms Screening Tool questionnaire to determine the severity of PMS. Factors associated with PMS severity were identified using linear regression analysis with a stepwise method. RESULTS: Factors associated with severity of PMS were age (years), family income (low vs high income), marital status (unmarried vs married), and familial history of dysmenorrhea or PMS after adjustment for dysmenorrheal severity with beta (95% confidence interval) of 0.31 (0.45-0.57), 11.6 (1.2-23.54), 3.2 (0.4-5.2), and 2.22 (0.04-4.4), respectively. CONCLUSION: In this study, factors associated with severity of PMS were age, marital status, family income, and familial history of PMS. We observed that some outcomes were consistent with some previously reported results, which indicates the need for further studies. PMID- 28737242 TI - Customers' perceptions of and satisfaction with medicine retail outlet services in Addis Ababa, Ethiopia: a cross-sectional study. AB - OBJECTIVES: The aim of this study was to assess customers' perceptions of and satisfaction with MRO services in Addis Ababa and to explore factors associated with their satisfaction and reasons for visits. METHODS: A cross-sectional survey was conducted among customers selected from 28 MROs in Addis Ababa, using multi stage sampling techniques. Simple descriptive statistics and multivariable logistic regression at 95% confidence interval were used for the analysis. KEY FINDINGS: Of 396 respondents, 324 (81.8%) visited MROs to purchase prescription medicines. A majority (338/396; 85.4%) of them perceived that pharmacists and druggists (pharmacy professionals) play a major role in healthcare delivery. A third (140/396; 35.4%) of the respondents agreed with the statement that pharmacy professionals are more concerned about patient care than about their business. Regarding reasons for visiting, being married was positively associated with buying over-the-counter, higher educational status was linked with more satisfaction. Overall, 56.8% (225/396) of the respondents reported that they were satisfied with the service provided by MROs. CONCLUSION: Customers of MROs had mixed perceptions of and satisfaction with the current service. Marital status and age were associated with the reason for visiting, while the educational level was associated with the level of satisfaction. The overall positive perceptions and satisfaction about MROs should be taken as an opportunity to promote and improve pharmaceutical services rendered in MROs, to ensure that the public is receiving maximum benefit. PMID- 28737243 TI - Investigating the genetic regulation of the expression of 63 lipid metabolism genes in the pig skeletal muscle. AB - A comprehensive and systematic view of the genetic regulation of lipid metabolism genes is still lacking in pigs. Herewith, we have investigated the genetic regulation of 63 porcine genes with crucial roles in the uptake, transport, synthesis and catabolism of lipids. With this aim, we have performed an expression QTL (eQTL) scan in 104 pigs with available genotypes for the Illumina Porcine SNP60 chip and microarray measurements of gene expression in the gluteus medius muscle. Analysis of the data with gemma software revealed 13 cis- and 18 trans-eQTL modulating the expression of 19 loci. Genes regulated by eQTL participated in a wide array of lipid metabolism pathways such as the beta oxidation of fatty acids, lipid biosynthesis and lipolysis, fatty acid activation and desaturation, lipoprotein uptake, apolipoprotein assembly and cholesterol trafficking. These data provide a first picture of the genetic regulation of loci involved in porcine lipid metabolism. PMID- 28737244 TI - Hypoxia: Animal experiments and clinical implications. AB - The developing fetus has some unique physiological properties that differ from properties in extra-uterine life. The fetus exists in a hypoxemic condition as a result of the presence of the placenta, which serves as a limiting interface between maternal and fetal circulation. In addition, the fetus is prone to be exposed to uterine contractions, which place it under a further hypoxic burden. Thus, the fetal response to hypoxic insults is important. There has been marked progression in the understanding of fetal physiology since the introduction of the 'chronic preparation model'. Based upon information from animal research, we now utilize medical technologies in daily medical care, for example, fetal heart rate monitoring and high-resolution ultrasonographic devices. In this review, we discuss the main findings in relation to fetal physiology and their clinical relevance. PMID- 28737245 TI - Exteroceptive stimuli override interoceptive state in reaction time control. AB - The processing of reaction time (RT) stimulus is modulated by its timing relative to the cardiac cycle. RT stimulus processing is also influenced by task irrelevant stimuli: a sensory stimulus speeds RT when it accompanies a cue to react in another sensory modality. Different theories have been proposed to explain this accessory stimulus effect (ASE). However, it is unclear whether the ASE interacts with the cardiac timing effect. In the present study, the relationship of the ASE, cardiac timing, and stimulus valence was examined. Fifty two subjects performed 400 trials of a simple RT task. Images of neutral and fear faces served as visual accessory stimuli; the RT stimulus was a 75 dB tone. Electrocardiography was recorded. Visual and auditory stimuli were presented at either cardiac systole or diastole. The stimulus onset asynchrony between visual and auditory stimuli was either 0 or 75 ms. Repeated measures ANOVAs showed that cardiac timing modulated RT, but only when accessory stimuli were absent. RT was shorter when the accessory stimulus preceded the imperative stimulus with respect to simultaneous presentation. The ASE was not influenced by visual stimulus valence or cardiac timing. Results indicate that the ASE overrides cardiac timing effects, suggesting a dynamic balance between exteroceptive stimuli and interoceptive states, and highlight the importance of embodied information processing. PMID- 28737246 TI - Prematurity, white matter, and cognition: support for leukocentrism. PMID- 28737247 TI - A single base deletion in the SLC45A2 gene in a Bullmastiff with oculocutaneous albinism. AB - Oculocutaneous albinism type 4 (OCA4) in humans and similar phenotypes in many animal species are caused by variants in the SLC45A2 gene, encoding a putative sugar transporter. In dog, two independent SLC45A2 variants are known that cause oculocutaneous albinism in Doberman Pinschers and several small dog breeds respectively. For the present study, we investigated a Bullmastiff with oculocutaneous albinism. The affected dog was highly inbred and resulted from the mating of a sire to its own grandmother. We obtained whole genome sequence data from the affected dog and searched specifically for variants in candidate genes known to cause albinism. We detected a single base deletion in exon 6 of the SLC45A2 gene (NM_001037947.1:c.1287delC) that has not been reported thus far. This deletion is predicted to result in an early premature stop codon. It was confirmed by Sanger sequencing and perfectly co-segregated with the phenotype in the available family members. We genotyped 174 unrelated dogs from diverse breeds, all of which were homozygous wildtype. We therefore suggest that SLC45A2:c.1287delC causes the observed oculocutaneous albinism in the affected Bullmastiff. PMID- 28737248 TI - Frost hardening and dehardening potential in temperate trees from winter to budburst. AB - We investigated how deciduous trees can adjust their freezing resistance in response to temperature during the progress of the ecodormancy phase, from midwinter to budburst. We regularly sampled twigs of four different temperate deciduous tree species from January to the leaf-out date. Using computer controlled freezers and climate chambers, the freezing resistance of buds was measured directly after sampling and also after the application of artificial hardening and dehardening treatments, simulating cold and warm spells. The thermal time to budburst in forcing conditions (c. 20 degrees C) was also quantified at each sampling as a proxy for dormancy depth. Earlier flushing species showed higher freezing resistance than late flushing species at either similar bud development stage or similar dormancy depth. Overall, freezing resistance and its hardening and dehardening potential dramatically decreased during the progress of ecodormancy and became almost nil during budburst. Our results suggest that extreme cold events in winter are not critical for trees, as freezing resistance can be largely enhanced during this period. By contrast, the timing of budburst is a critical component of tree fitness. Our results provide quantitative values of the freezing resistance dynamics during ecodormancy, particularly valuable in process-based species distribution models. PMID- 28737250 TI - Nodular lymphocyte predominant Hodgkin lymphoma in USA between 2000 and 2014: an updated analysis based on the SEER data. PMID- 28737249 TI - Haploidentical transplantation compared with matched sibling and unrelated donor transplantation for adults with standard-risk acute lymphoblastic leukaemia in first complete remission. AB - We retrospectively investigated outcomes of haploidentical donor (HID) transplant for adults with standard-risk acute lymphoblastic leukaemia (ALL) in first complete remission (CR1) compared with human leucocyte antigen (HLA)-matched sibling donor (MSD) and HLA-matched unrelated donor (MUD) transplants. A total of 348 adult patients were enrolled, including 127 HID, 144 MSD and 77 MUD recipients. The cumulative incidence of grade II-IV acute graft-versus-host disease (aGVHD) was 39.5%, 24.0% and 40.3% for HID, MSD and MUD, respectively (P = 0.020). However, there was no difference in grade III-IV aGVHD (11.4%, 7.7%, 13.5%, respectively, P = 0.468). The 5-year cumulative transplant-related mortality was 16.4%, 11.6% and 19.6% (P = 0.162), the 5-year relapse rate post transplantation was 14.8%, 21.1% and 16.7% (P = 0.231), the 5-year overall survival was 70.1%, 73.7% and 69.8% (P = 0.525), and the 5-year disease-free survival was 68.7%, 67.3% and 63.7%, respectively (P = 0.606). Furthermore, the 3 year GVHD-free, relapse-free survival was not different (50.8%, 54.9% and 52.2%, respectively, P = 0.847). Our results indicate that the outcomes of HID transplants are equivalent to those of MSD and MUD, and that HID transplantation is a valid alternative for standard-risk adults with ALL in CR1 who lack matched donors. PMID- 28737251 TI - A randomized controlled trial to study the efficacy of sulfasalazine for axial disease in ankylosing spondylitis. AB - AIM: To evaluate efficacy of sulfasalazine for axial ankylosing spondylosis. METHODS: 67 patients fulfilling the inclusion criteria were included and randomized into treatment and placebo group. RESULTS: Mean age in treatment group was 31 years (range: 17-60); placebo group was 30 years (18-46). Mean disease duration treatment group 8.4 years (range: 3-25) and placebo group was 8.3 years (3-19). Clinically significant improvement in ASDAS (DeltaASDAS > 1.1) seen in 15.1% of placebo and 67.7% in treatment group (P = 0.001). The mean +/- SD of DeltaASDAS in treatment group was 1.33 +/- 0.38 (range: 0.9-2.3) where as in placebo group it was 0.748 +/- 0.23 (0.4-1.3) with significant difference (P = 0.00). The mean +/- SD of DeltaBASDAI of treatment group was 3.29 +/- 0.97 (range: 1.5-5.5) placebo group was 1.47 +/- 0.99(0.5-4.5) with P = 0.00. The mean value of DeltaBASMI of drug group 3.29 +/- 0.97(range: 1.8-5) and of placebo group was 1.47 +/- 0.99 (0.6-3.7) with (P = 0.00). Clinical improvenent in (DeltaASDAS > 1.1) was observed in patients of both the groups with disease duration <= 4 years. However it was significantly higher in treatment group (P = 0.04). Highly significant improvement in (DeltaASDAS > 2) was observed in two of five patients in treatment group with disease duration <= 4 years. CONCLUSION: Sulfasalazine is effective in axial AS esp. in younger patients (< 25 years), disease duration < 4 years at the time of initiation of treatment and high disease activity (BASDAI > 7, CRP > 50 mg/L). This signifies early diagnosis and treatment is very important in management and prevention of disease progression. PMID- 28737252 TI - Japanese Clinical Practice Guide for Critical Obstetrical Hemorrhage (2017 revision). PMID- 28737254 TI - 1D and 2D NMR Spectroscopy of Bonding Interactions within Stable and Phase Separating Organic Electrolyte-Cellulose Solutions. AB - Organic electrolyte solutions (i.e. mixtures containing an ionic liquid and a polar, molecular co-solvent) are highly versatile solvents for cellulose. However, the underlying solvent-solvent and solvent-solute interactions are not yet fully understood. Herein, mixtures of the ionic liquid 1-ethyl-3 methylimidazolium acetate, the co-solvent 1,3-dimethyl-2-imidazolidinone, and cellulose are investigated using 1D and 2D NMR spectroscopy. The use of a triply 13 C-labelled ionic liquid enhances the signal-to-noise ratio for 13 C NMR spectroscopy, enabling changes in bonding interactions to be accurately pinpointed. Current observations reveal an additional degree of complexity regarding the distinct roles of cation, anion, and co-solvent toward maintaining cellulose solubility and phase stability. Unexpectedly, the interactions between the dialkylimidazolium ring C2 -H substituent and cellulose become more pronounced at high temperatures, counteracted by a net weakening of acetate cellulose interactions. Moreover, for mixtures that exhibit critical solution behavior, phase separation is accompanied by the apparent recombination of cation anion pairs. PMID- 28737253 TI - Circulating leucocytes perpetuate stroke-induced aortic dysfunction. AB - NEW FINDINGS: What is the central question of this study? Does a stroke event influence aortic endothelial function; and what is the role of peripheral circulating leucocytes in stroke on the vascular reactivity of the aorta? What is the main finding and its importance? In vitro co-culture experiments demonstrated that aortic endothelium-dependent relaxation was impaired when rat aortic rings were co-cultured with leucocytes stimulated with serum from stroke patients. Impaired vascular reactivity was not observed in aortic rings without leucocytes stimulated with serum from stroke patients or age-matched control patients with or without leucocytes. These data suggest that leucocyte-dependent altered aortic endothelium-dependent relaxation with stroke and the systemic consequences of stroke on vascular inflammation may occur in the aorta. Post-stroke inflammation has been linked to poor stroke outcomes. The vascular endothelium senses and responds to circulating factors, in particular inflammatory cytokines. Although stroke-associated local cerebrovascular dysfunction is well reported, the effects of a stroke on conduit artery function are not fully understood. We tested the hypothesis that serum from stroke patients triggers leucocyte-dependent aortic endothelial dysfunction that is associated with elevated concentrations of cytokines. Total leucocytes were isolated from healthy individuals, and the cells were incubated in serum from control subjects or stroke patients for 6 h. The quantity of cytokines in media was determined using an immunoassay. Vascular reactivity was determined by the rat aortic rings that were co-cultured with or without leucocytes and stimulated with serum samples from control subjects or stroke patients. Endothelium-dependent dilatation was significantly impaired in aortic rings co-cultured with leucocytes plus serum from stroke patients (50 +/- 30 versus 85 +/- 13%, P < 0.05) versus serum from control subjects. In contrast, no difference was observed in aortic function stimulated with serum from control subjects or stroke patients without total leucocytes. Likewise, total leucocyte derived cytokine concentrations were significantly increased in a time-dependent manner on stimulation with serum from stroke patients (P < 0.05). These observations support the concept that the increased response of leucocytes drives the development of stroke-associated vascular endothelial dysfunction. As such, pharmacologically targeting the source of inflammatory cytokines might alleviate stroke-associated peripheral vascular dysfunction. PMID- 28737255 TI - Efficient Organic Solar Cells with Non-Fullerene Acceptors. AB - Fullerene-free OSCs employing n-type small molecules or polymers as the acceptors have recently experienced a rapid rise with efficiencies exceeding 12%. Owing to the good optoelectronic and morphological tunabilities, non-fullerene acceptors exhibit great potential for realizing high-performance and practical OSCs. In this Review, recent exciting progress made in developing highly efficient non fullerene acceptors is summarized, mainly correlating factors like absorption, energy loss and morphology of new materials to their correspondent photovoltaic performance. PMID- 28737256 TI - Insula-based networks in professional musicians: Evidence for increased functional connectivity during resting state fMRI. AB - Despite considerable research on experience-dependent neuroplasticity in professional musicians, detailed understanding of an involvement of the insula is only now beginning to emerge. We investigated the effects of musical training on intrinsic insula-based connectivity in professional classical musicians relative to nonmusicians using resting-state functional MRI. Following a tripartite scheme of insula subdivisions, coactivation profiles were analyzed for the posterior, ventral anterior, and dorsal anterior insula in both hemispheres. While whole brain connectivity across all participants confirmed previously reported patterns, between-group comparisons revealed increased insular connectivity in musicians relative to nonmusicians. Coactivated regions encompassed constituents of large-scale networks involved in salience detection (e.g., anterior and middle cingulate cortex), affective processing (e.g., orbitofrontal cortex and temporal pole), and higher order cognition (e.g., dorsolateral prefrontal cortex and the temporoparietal junction), whereas no differences were found for the reversed group contrast. Importantly, these connectivity patterns were stronger in musicians who experienced more years of musical practice, including also sensorimotor regions involved in music performance (M1 hand area, S1, A1, and SMA). We conclude that musical training triggers significant reorganization in insula-based networks, potentially facilitating high-level cognitive and affective functions associated with the fast integration of multisensory information in the context of music performance. Hum Brain Mapp 38:4834-4849, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28737257 TI - Unilateral vestibular schwannoma and meningiomas in a patient with PIK3CA-related segmental overgrowth: Co-occurrence of mosaicism for 2 rare disorders. AB - A 28-year-old female with PIK3CA-related segmental overgrowth presented with headaches. She also had a unilateral vestibular schwannoma (VS), as well as 3 small (<2 cm) meningiomas, which according to the Manchester consensus diagnostic criteria for neurofibromatosis 2 (NF2) is sufficient for a clinical diagnosis. Analysis of blood revealed a mosaic PIK3CA c.2740G>A (p.Gly914Arg) mutation, confirming the diagnosis of PIK3CA-related overgrowth, but no mutations in NF2 were detected. Although VS has not previously been reported in PIK3CA-related segmental overgrowth, meningiomas have, raising the question of whether this patient's VS and meningiomas represent coincidental NF2 or phenotypic extension of her overgrowth syndrome. Genetic analysis of the VS revealed a heterozygous NF2 mutation c.784C>T (p.Arg262Ter) and loss of a portion of 22q, including NF2, SMARCB1, and LZTR1 genes. These results suggest that the patient has 2 different mosaic disorders, NF2 and PIK3CA-related overgrowth. The PIK3CA mutation was also present in the VS. Confirmation of the clinical diagnosis of mosaic NF2 in this patient has implications for monitoring and highlights the possibility of co occurrence of mosaicism for multiple rare disorders in a single patient. PMID- 28737259 TI - Homopolymer Nanolithography. AB - Future progress in nanoscience and nanotechnology necessitates further development of versatile, labor-, and cost-efficient surface patterning strategies. A new approach to nanopatterning is reported, which utilizes surface segregation of a smooth layer of an end-grafted homopolymer in a poor solvent. The variation in polymer grafting density yields a range of surface nanostructures, including randomly organized pinned spherical micelles, worm-like structures, networks, and porous films. The capability to use the polymer patterns for site-specific deposition of small molecules, polymers, or nanoparticles is shown. This versatile strategy enables patterning of curved surfaces with direct access to the substrate and no need in changing polymer composition to realize different surface patterns. PMID- 28737258 TI - Preclinical Alterations in Myocardial Microstructure in People with Metabolic Syndrome. AB - OBJECTIVE: Metabolic syndrome (MetS) can lead to myocardial fibrosis, diastolic dysfunction, and eventual heart failure. This study evaluated alterations in myocardial microstructure in people with MetS by using a novel algorithm to characterize ultrasonic signal intensity variation. METHODS: Among 254 participants without existing cardiovascular disease (mean age 42 +/- 11 years, 75% women), there were 162 with MetS, 47 with obesity without MetS, and 45 nonobese controls. Standard echocardiography was performed, and a novel validated computational algorithm was used to investigate myocardial microstructure based on sonographic signal intensity and distribution. The signal intensity coefficient (SIC [left ventricular microstructure]) was examined. RESULTS: The SIC was significantly higher in people with MetS compared with people with (P < 0.001) and without obesity (P = 0.04), even after adjustment for age, sex, body mass index, hypertension, diabetes mellitus, and the ratio of triglyceride (TG) to high-density lipoprotein (HDL) cholesterol (P < 0.05 for all). Clinical correlates of SIC included TG concentrations (r = 0.21, P = 0.0007) and the TG/HDL ratio (r = 0.2, P = 0.001). CONCLUSIONS: This study's findings suggest that preclinical MetS and dyslipidemia in particular are associated with altered myocardial signal intensity variation. Future studies are needed to determine whether the SIC may help detect subclinical diseases in people with metabolic disease, with the ultimate goal of targeting preventive efforts. PMID- 28737260 TI - Answer to the comment of manuscript CBIN.20170431-bioinformatics analysis in menopause transition promotes distinct modulation in calvaria and bone marrow osteoblastic cells. PMID- 28737261 TI - Does prolonged grief treatment foster posttraumatic growth? Secondary results from a treatment study with long-term follow-up and mediation analysis. AB - OBJECTIVES: Prolonged grief disorder (PGD) is a persistent and disabling kind of grief reaction that can be treated effectively with psychotherapeutic interventions. There has been limited investigation of whether these interventions can also enhance positive outcomes of bereavement, such as posttraumatic growth or benefit finding. DESIGN: As part of secondary analyses in a randomized controlled trial evaluating integrative cognitive-behavioural therapy for PGD (PG-CBT), the posttraumatic growth trajectories in 51 outpatients with clinically relevant prolonged grief symptoms were followed up from baseline up to 1.5 years. METHODS: Immediate treatment effects on posttraumatic growth in comparison with a waiting list control group were evaluated with univariate ANCOVA. Using mediation analysis, we examined the relation between symptom reduction and the short-term treatment effect on posttraumatic growth. For evaluating long-term outcome stability, the immediately treated group and the delayed treatment group were pooled. RESULTS: PG-CBT significantly fostered growth in patients suffering from PGD, with a controlled medium effect size of Cohen's d = 0.60 (completer analysis). This effect remained stable up to the 1.5 year follow-up. Grief symptom reduction mediated short-term treatment effects on posttraumatic growth. However, growth also partially mediated treatment effects on prolonged grief symptoms. CONCLUSIONS: Taken together, PG-CBT was effective in enhancing the participants' perception of posttraumatic growth, but the definite interaction between symptom reduction and posttraumatic growth remains unclear, as both seemed to influence each other's trajectory in the course of treatment. PRACTITIONER POINTS: Integrative CBT for prolonged grief disorder also fostered posttraumatic growth. Post-treatment and 1.5-year follow-up effect sizes for posttraumatic growth were moderate. Whether growth-enhancing techniques are useful in grief treatment needs further research. PMID- 28737263 TI - Lidocaine inhibits the proliferation of lung cancer by regulating the expression of GOLT1A. AB - OBJECTIVES: Lidocaine is the most commonly used local anaesthetic in clinical and can inhibit proliferation, suppress invasion and migration and induce apoptosis in human lung adenocarcinoma (LAD) cells. However, its specific downstream molecular mechanism is unclear. MATERIALS AND METHODS: LAD cell lines, A549 and H1299 cells, were treated with lidocaine. The proliferation was evaluated by the methylthiazolyldiphenyl-tetrazolium bromide (MTT) and bromodeoxyuridine (BrdU) assay. The expression level of related proteins was detected by real-time quantitative PCR (qPCR) and Western blot assay. RESULTS: The results indicated that lidocaine dose-dependently suppressed the proliferation of A549 and H1299 cells. In the LAD patients' samples, GOLT1A was upregulated and involved in the poor prognosis and higher grade malignancy. Additionally, GOLT1A mediates the function of lidocaine on repressing proliferation by regulating the cell cycle in A549 cells. CONCLUSIONS: Our findings suggest that lidocaine downregulates the GOLT1A expression to repress the proliferation of lung cancer cells. PMID- 28737262 TI - Overnight delivery of hypertonic saline by nasal cannula aerosol for cystic fibrosis. AB - AIM: Inhaled hypertonic saline increases mucociliary clearance, improves pulmonary function, and decreases exacerbations in cystic fibrosis (CF) but contributes to the already significant treatment burden of CF. Overnight delivery of inhaled medications via a specially designed nasal cannula-aerosol device (Trans-nasal Pulmonary Aerosol Delivery [tPAD]) is an alternative approach. Here, we test whether overnight inhalation of hypertonic saline via tPAD improves mucociliary clearance and assess the tolerability of the device. METHOD: In this study, 12 CF subjects inhaled 7% hypertonic saline (HS) for 8 h overnight using the tPAD system. Safety and tolerability were assessed and measurements of mucociliary and absorptive clearance (MCC/ABS) were performed after the treatment. Comparisons were made versus sham treatment where the same subjects wore the nasal cannula overnight but did not receive aerosol. RESULTS: Both the HS and sham treatments were well-tolerated. Only one subject did not complete the overnight HS treatment. There were no significant differences in MCC associated with HS inhalation at any time point (90 min, 3 h, 6 h) in any lung zone. Changes in FEV1 on both study days were similar. There were no differences in quality of sleep between HS and sham nights as assessed with the modified Leeds Sleep Evaluation Questionnaire (mLSEQ). Sino-Nasal Outcome Test (SNOT-14) questionnaires demonstrated significant increases (worsening) in 2/14 symptom categories with HS. CONCLUSIONS: The most likely cause for the failure to accelerate MCC was under-dosing of HS relative to the active transport of salt from the airways. PMID- 28737264 TI - Review article: the many potential roles of intestinal serotonin (5 hydroxytryptamine, 5-HT) signalling in inflammatory bowel disease. AB - BACKGROUND: Serotonin (5-hydroxytryptamine, 5-HT) is an important mediator of every major gut-related function. Recent investigations also suggest that 5-HT can influence the development and severity of inflammation within the gut, particularly in the setting of inflammatory bowel disease (IBD). AIM: To review the roles that the intestinal serotonin signalling system plays in gut function, with a specific focus on IBD. METHODS: We reviewed manuscripts from 1952 to 2017 that investigated and discussed roles for 5-HT signalling in gastrointestinal function and IBD, as well as the influence of inflammation on 5-HT signalling elements within the gut. RESULTS: Inflammation appears to affect every major element of intestinal 5-HT signalling, including 5-HT synthesis, release, receptor expression and reuptake capacity. Importantly, many studies (most utilising animal models) also demonstrate that modulation of selective serotonergic receptors (via agonism of 5-HT4 R and antagonism of 5-HT3 R) or 5-HT signal termination (via serotonin reuptake inhibitors) can alter the likelihood and severity of intestinal inflammation and/or its complicating symptoms. However, there are few human studies that have studied these relationships in a targeted manner. CONCLUSIONS: Insights discussed in this review have strong potential to lead to new diagnostic and therapeutic tools to improve the management of IBD and other related disorders. Specifically, strategies that focus on modifying the activity of selective serotonin receptors and reuptake transporters in the gut could be effective for controlling disease activity and/or its associated symptoms. Further studies in humans are required, however, to more completely understand the pathophysiological mechanisms underlying the roles of 5-HT in this setting. PMID- 28737265 TI - Letter to 'Uterine artery pseudoaneurysm bleeding one decade after caesarean section: A case report': Pseudoaneurysm anywhere and anytime. PMID- 28737266 TI - Nephrolithiasis: A complication of pediatric diabetic ketoacidosis. AB - OBJECTIVE: To determine the frequency of nephrolithiasis as a complication of diabetic ketoacidosis (DKA) in pediatrics. METHODS: We performed a retrospective chart review of patients with DKA admitted to a pediatric hospital between January 2009 and July 2016. We identified patients with nephrolithiasis during admission for DKA. RESULTS: We identified 395 episodes of DKA over 7.5 years. Nephrolithiasis developed as a complication of DKA in 3 of those admissions (0.8%). All three patients with nephrolithiasis were males with new onset type 1 diabetes, aged 11 to 16.5 years. They all developed symptoms of nephrolithiasis after transition to subcutaneous insulin. One patient had subsequent worsening acidosis that required an additional 24 hours of IV insulin administration. CONCLUSIONS: Nephrolithiasis is a rare complication of pediatric DKA, and should be considered in children with DKA who develop hematuria, flank pain, or suprapubic pain. Nephrolithiasis can increase insulin resistance due to increased pain and inflammation, so these patients should be monitored closely for recurrence of DKA. As patients with diabetes have increased risk of chronic kidney disease and nephrolithiasis can cause kidney injury, risk factors for nephrolithiasis should be identified and addressed to avoid subsequent kidney damage. PMID- 28737267 TI - Appearance and characterization of fruit image textures for quality sorting using wavelet transform and genetic algorithms. AB - : Images of four qualities of mangoes and guavas are evaluated for color and textural features to characterize and classify them, and to model the fruit appearance grading. The paper discusses three approaches to identify most discriminating texture features of both the fruits. In the first approach, fruit's color and texture features are selected using Mahalanobis distance. A total of 20 color features and 40 textural features are extracted for analysis. Using Mahalanobis distance and feature intercorrelation analyses, one best color feature (mean of a* [L*a*b* color space]) and two textural features (energy a*, contrast of H*) are selected as features for Guava while two best color features (R std, H std) and one textural features (energy b*) are selected as features for mangoes with the highest discriminate power. The second approach studies some common wavelet families for searching the best classification model for fruit quality grading. The wavelet features extracted from five basic mother wavelets (db, bior, rbior, Coif, Sym) are explored to characterize fruits texture appearance. In third approach, genetic algorithm is used to select only those color and wavelet texture features that are relevant to the separation of the class, from a large universe of features. The study shows that image color and texture features which were identified using a genetic algorithm can distinguish between various qualities classes of fruits. The experimental results showed that support vector machine classifier is elected for Guava grading with an accuracy of 97.61% and artificial neural network is elected from Mango grading with an accuracy of 95.65%. PRACTICAL APPLICATIONS: The proposed method is nondestructive fruit quality assessment method. The experimental results has proven that Genetic algorithm along with wavelet textures feature has potential to discriminate fruit quality. Finally, it can be concluded that discussed method is an accurate, reliable, and objective tool to determine fruit quality namely Mango and Guava, and might be applicable to in-line sorting systems. PMID- 28737268 TI - Comparison of two minimally invasive techniques for liver biopsy collection in dogs. AB - OBJECTIVES: High-quality biopsy is an essential factor for the successful diagnosis of canine liver disease. The aim of this study was to compare various aspects of biopsies obtained by two different techniques: pretied ligating loop and cup biopsy forceps. MATERIALS AND METHODS: Fifteen client-owned dogs underwent laparoscopic liver biopsies for diagnosis of liver disease. Biopsies were obtained from the same liver lobe using a pre-tied ligating loop and cup biopsy forceps. Biopsy weight, volume, histological value and surgical time were compared between the two techniques. Surgical complications were recorded. RESULTS: Samples obtained with the pre-tied ligating loop were significantly heavier and larger in volume than those obtained with cup biopsy forceps. Samples obtained with the ligating loop contained significantly more portal tracts and less crush and fragmentation artefacts. The time required to obtain a liver biopsy with the pre-tied ligating loop was approximately double that of the cup biopsy forceps technique. CLINICAL SIGNIFICANCE: The use of a pre-tied ligating loop is a good alternative to the cup biopsy forceps technique when acquiring laparoscopic liver biopsies in dogs. PMID- 28737269 TI - Concordance between self-reported and observer-rated anxiety severity in outpatients with anxiety disorders: The Leiden routine outcome monitoring study. AB - OBJECTIVES: Anxiety severity measures can be self-report or observer-rated. Although mostly these measures concur, they can diverge markedly. We examined concordance between two anxiety scales: the observer-rated Brief Anxiety Scale (BAS) and the self-report Brief Symptom Inventory 12-item version (BSI-12), and described associations between patient characteristics and discordance. DESIGN: The study used an observational design, using prospective data from 2,007 outpatients with DSM-IV-TR panic disorder with or without agoraphobia, agoraphobia without panic, social phobia, and/or generalized anxiety disorder. METHODS: Overall agreement was described using Pearson's product-moment correlation coefficient. Associations between patient characteristics and discordance (defined as |Z-BAS-Z-BSI-12| >= 1) were evaluated with univariable and multivariable multinomial logistic regression analyses. RESULTS: Overall correlation between BAS and BSI-12 was positive and strong (r = .59). Discordance occurred in 24.8% of patients ([Z-BAS >= Z-BSI-12 + 1] = 12.2%; [Z-BAS <= Z-BSI 12 - 1] = 12.6%). Patients with higher observed than self-reported anxiety severity did not differ from concordant patients. Patients with lower observed than self-reported anxiety severity more often had panic disorder, less often had social phobia, and had higher scores on cluster B and C personality characteristics than concordant patients. Lower observed than self-reported anxiety severity was best predicted by panic disorder, social phobia, and affective lability. CONCLUSIONS: Results demonstrate that the use of a single source of information gives a one-sided view of pathology. A multimethod approach is highly preferable, as this allows for assessment across different domains and through multiple sources of information, and as such, provides clinicians with vital information. PRACTITIONER POINTS: When assessing anxiety severity, the use of self-report measures provides additional information to observer-rated measures. In patients who have strong cluster B and C personality traits, anxiety severity might be overlooked, even by trained observers. The use of a multimethod assessment strategy is preferable in anxiety severity assessment. PMID- 28737270 TI - Hospital-ownership status and cesareans in the United States: The effect of for profit hospitals. AB - BACKGROUND: Given the increasing proportion of United States hospitals that are for-profit, we examined whether women who give birth in for-profit hospitals are more likely to have cesareans than women who give birth in not-for-profit hospitals. We hypothesized that cesareans are more likely to occur in for-profit hospitals because of the organizational emphasis on short-term financial indicators, including payment of shareholder dividends. METHODS: We used logistic regression and difference of means tests to analyze data from the Listening to Mothers III survey of women who gave birth in the United States in 2011 and 2012. RESULTS: Controlling for patient-level characteristics, we found that the odds of a woman's having a cesarean were two times higher in for-profit hospitals than in not-for-profit hospitals. We also found for-profit hospitals were significantly more likely to be members of multihospital systems and to have fewer full-time registered nurses and staff members per hospital bed. CONCLUSION: This research suggests that women who give birth in for-profit hospitals are more likely to have cesareans than women who give birth in not-for-profit hospitals. This information is important to women when deciding where to give birth. Knowing which hospital characteristics are associated with a greater likelihood of cesarean is helpful since hospital cesarean rates may be difficult to find. These findings are also informative for obstetric professionals, who can implement improvement initiatives to decrease cesarean rates and improve the overall quality of care for childbearing women in the United States. PMID- 28737271 TI - In vitro fertilization and pregnancy management in a woman with acquired idiopathic chylous ascites. AB - Acquired idiopathic chylous ascites is extremely rare in women of reproductive age. This is the first report describing successful infertility and pregnancy management in a patient with idiopathic chylous ascites. A 23-year-old woman presented with abdominal distention and was diagnosed with idiopathic fluid collection. A lymphogram revealed lymphatic leakage from the right renal hilum. Lymphatic-venous anastomosis of the thoracic duct was performed thrice, but the chylous ascites persisted. In vitro fertilization was performed because natural conception was not possible. Just prior to oocyte retrieval, transvaginal drainage of ascites was performed. In total, nine blastocysts were obtained and cryopreserved. Single frozen embryo transfer was performed, including hormone replacement therapy. The patient became pregnant and the ascites spontaneously decreased as the pregnancy progressed, finally disappearing around gestational week 20. A healthy baby was delivered transvaginally. Ascites began to reaccumulate on post-partum day 1 and returned to the pre-pregnancy level within a month. PMID- 28737272 TI - Dynamic coupling between fMRI local connectivity and interictal EEG in focal epilepsy: A wavelet analysis approach. AB - Simultaneous scalp EEG-fMRI recording is a noninvasive neuroimaging technique for combining electrophysiological and hemodynamic aspects of brain function. Despite the time-varying nature of both measurements, their relationship is usually considered as time-invariant. The aim of this study was to detect direct associations between scalp-recorded EEG and regional changes of hemodynamic brain connectivity in focal epilepsy through a time-frequency paradigm. To do so, we developed a voxel-wise framework that analyses wavelet coherence between dynamic regional phase synchrony (DRePS, calculated from fMRI) and band amplitude fluctuation (BAF) of a target EEG electrode with dominant interictal epileptiform discharges (IEDs). As a proof of concept, we applied this framework to seven patients with focal epilepsy. The analysis produced patient-specific spatial maps of DRePS-BAF coupling, which highlight regions with a strong link between EEG power and local fMRI connectivity. Although we observed DRePS-BAF coupling proximate to the suspected seizure onset zone in some patients, our results suggest that DRePS-BAF is more likely to identify wider 'epileptic networks'. We also compared DRePS-BAF with standard EEG-fMRI analysis based on general linear modelling (GLM). There was, in general, little overlap between the DRePS-BAF maps and GLM maps. However, in some subjects the spatial clusters revealed by these two analyses appeared to be adjacent, particularly in medial posterior cortices. Our findings suggest that (1) there is a strong time-varying relationship between local fMRI connectivity and interictal EEG power in focal epilepsy, and (2) that DRePS-BAF reflect different aspects of epileptic network activity than standard EEG-fMRI analysis. These two techniques, therefore, appear to be complementary. Hum Brain Mapp 38:5356-5374, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28737273 TI - Recovery free of heart failure after acute coronary syndrome and coronary revascularization. AB - AIMS: Previous studies have examined risk factors for the development of heart failure (HF) subsequent to acute coronary syndrome (ACS). Our study seeks to clarify the clinical variables that best characterize patients who remain free from HF after coronary artery bypass grafting (CABG) surgery for ACS to determine novel biological factors favouring freedom from HF in prospective translational studies. METHODS AND RESULTS: Nova Scotia residents (1995-2012) undergoing CABG within 3 weeks of ACS were included. The primary outcome was freedom from readmission to hospital due to HF. Descriptive statistics were generated, and a Cox proportional hazards model assessed outcome with adjustment for clinical characteristics. Of 11 936 Nova Scotians who underwent isolated CABG, 3264 (27%) had a recent ACS and were included. Deaths occurred in 210 (6%) of subjects prior to discharge. A total of 3054 patients were included in the long-term analysis. During follow-up, HF necessitating readmission occurred in 688 (21%) subjects with a hazard ratio of 12% at 2 years. The adjusted Cox model demonstrated significantly better freedom from HF for younger, male subjects without metabolic syndrome and no history of chronic obstructive pulmonary disease, renal insufficiency, atrial fibrillation, or HF. CONCLUSIONS: Our findings have outlined important clinical variables that predict freedom from HF. Furthermore, we have shown that 12% of patients undergoing CABG after ACS develop HF (2 years). Our findings support our next phase in which we plan to prospectively collect blood and tissue specimens from ACS patients undergoing CABG in order to determine novel biological mechanism(s) that favour resolution of post-ACS inflammation. PMID- 28737274 TI - Longitudinal dental maturation of children with complete unilateral cleft lip and palate: A case-control cohort study. AB - OBJECTIVES: Many reports suggest that children with cleft lip and palate (CLP) have delayed dental development and asymmetrical timing of tooth-pair formation. We aimed to investigate the dental maturation of permanent teeth in children with complete unilateral CLP (UCLP) and compare the findings with non-CLP children. SETTING AND SAMPLE POPULATION: This case-control study used 115 radiographs of children with complete UCLP and controls (non-CLP children matched on age, gender and ethnicity) from a hospital-based dental clinic in Singapore. MATERIAL AND METHODS: Orthopantomographs of 60 children with complete UCLP (5-9 years old) and 55 children (9-13 years old) from the same cohort were investigated using the Demirjian's method and compared with controls to determine if there were any differences in dental maturation with age. RESULTS: Delayed dental maturation was found in the 5- to 9-year-old children with UCLP compared to controls by 0.55 years (standard deviation: 0.75) (P<.001). There was no significant difference between the dental maturation of children with UCLP and controls in the 9- to 13 year-old group (P=.744). The group with UCLP had higher risk of asymmetrically developing tooth pairs than the control group for both age groups (P<.001). CONCLUSION: No difference in dental maturation between UCLP and controls in the 9 to 13-year-old group was found. However, there was diametrical difference in dental maturation in the 5- to 9-year-old group, which attenuated as they grew older. There was a consistently higher risk of asymmetrical tooth formation in children with UCLP than in controls. PMID- 28737275 TI - Thermally Activated Delayed Fluorescence in CuI Complexes Originating from Restricted Molecular Vibrations. AB - The mechanism of thermally activated delayed fluorescence (TADF) in molecules in aggregated or condensed solid states has been rarely studied and is not well understood. Nevertheless, many applications of TADF emitters are strongly affected by their luminescence properties in the aggregated state. In this study, two new isomeric tetradentate CuI complexes which simultaneously show aggregation induced emission (AIE) and TADF characteristics are reported for the first time. We provide direct evidence that effectively restricting the vibrations of individual molecules is a key requisite for TADF in these two CuI complexes through in-depth photophysical measurements combined with kinetic methods, single crystal analysis and theoretical calculations. These findings should stimulate new molecular engineering endeavours in the design of AIE-TADF active materials with highly emissive aggregated states. PMID- 28737276 TI - Age-related differences in the motor unit action potential size in relation to recruitment threshold. AB - Motor unit action potential size (MUAPsize ) versus recruitment threshold (RT) relationship analysis provides a non-invasive measure of motor unit (MU) hypertrophy; however, this method's ability to identify MU atrophy is unknown. This investigation sought to determine if MUAPsize versus RT relationship slope (APslope ) comparison could identify evidence of MU atrophy in older individuals. Surface electromyography signals were recorded from the first dorsal interosseous (FDI) of fourteen young (YG, age = 22.29 +/- 2.79 years) and ten older (OG, 61.0 +/- 2.0 years) subjects during a 50% maximal voluntary contraction (MVC) isometric trapezoidal muscle action. The signals were decomposed to yield a MUAPsize and RT for each MU. For each subject, the MUs recruited between 10% and 50% MVC were linearly regressed as a function of RT to calculate an individual APslope . FDI cross-sectional area (CSA) and echo intensity (EI) were quantified via ultrasonography. The mean APslope was lower for OG (0.033 +/- 0.010 mV %MVC-1 ) than YG (0.056 +/- 0.019 mV %MVC-1 ). OG and YG possessed similar CSAs (OG: 2.09 +/- 0.31 cm2 ; YG: 2.08 +/- 0.41 cm2 ); however, OG (53.25 +/- 7.56 AU) had greater EI than YG (43.87 +/- 7.59 AU). The lower OG mean APslope was due to smaller MUAPsizes of higher-threshold MUs, likely due to atrophy of muscle fibres that comprise those MUs. In support, similar CSA with greater EI indicated increased adipose and fibrous tissue and reduced contractile tissue in OG. Thus, MUAPsize versus RT relationship may provide a non-invasive measure of MU atrophy. PMID- 28737277 TI - Investigation of sensory profiles and hedonic drivers of emerging aquaculture fish species. AB - BACKGROUND: The aquaculture sector needs to increase the diversity fish species and their processed products to cover rising consumer demands. Candidates for this diversification have been identified to be meagre, greater amberjack, pikeperch and wreckfish. Yet scientific knowledge on their sensory profiles and consumer hedonic responses is scarce. The aim of the current study was to investigate these aspects, since they are essential for product development and market targeting. RESULTS: Species exhibited different sensory profiles with the exception of the odor/flavor profiles of meagre and greater amberjack, which were similar. Texture was more important than odor/flavor in explaining interspecies differences. Yet the hedonic responses were equally related to texture and odor/flavor. None of the species received negative hedonic scores. Both positive and negative hedonic drivers were identified within the odor/flavor and texture modalities. CONCLUSION: The distinct profiles of meagre, greater amberjack, pikeperch and wreckfish make these fish species valuable first materials for new product development and for covering markets with different sensory preferences. Differences in fish texture are more easily perceivable, yet small variations in fish odor/flavor can have a great impact on consumers' hedonic responses. (c) 2017 Society of Chemical Industry. PMID- 28737278 TI - Multicellular Vascularized Engineered Tissues through User-Programmable Biomaterial Photodegradation. AB - A photodegradable material-based approach to generate endothelialized 3D vascular networks within cell-laden hydrogel biomaterials is introduced. Exploiting multiphoton lithography, microchannel networks spanning nearly all size scales of native human vasculature are readily generated with unprecedented user-defined 4D control. Intraluminal channel architectures of synthetic vessels are fully customizable, providing new opportunities for next-generation microfluidics and directed cell function. PMID- 28737279 TI - Exercise capacity is not decreased in children who have undergone lung resection early in life for congenital thoracic malformations compared to healthy age matched children. AB - PURPOSE: The purpose of this study was to compare (i) the exercise capacity and (ii) lung function prior to and immediately post cardiopulmonary exercise tests (CPET) of children who underwent early life lung resection for Congenital Pulmonary Airway Malformations (CPAM) to healthy control children. METHOD: Eight children with CPAM (four males, age 9.6 +/- 1.8 years) and eight control children without respiratory disease (three males, age 9.4 +/- 1.4 years) performed a CPET on a cycle ergometer, during which maximal oxygen consumption (VO2max ) and heart rate were measured. Prior to and immediately post CPET, lung function measures including Nitrogen Multiple Breath Washout (MBW) and spirometry were performed. RESULTS: There were no significant between group differences in pre CPET lung function (P > 0.05) or maximal exercise capacity (VO2max CPAM: 39.4 mL. kg-1. min 1 , Control: 40.5 mL. kg-1. min-1 ). Post CPET, FEV1 was significantly lower in the CPAM group, with two participants diagnosed subsequently with exercise induced bronchospasm based on post-CPET spirometry and follow-up clinical investigations. CONCLUSION: Early life lung resection for CPAM does not appear to have negative implications for exercise capacity later in childhood. Clinicians should be aware that dyspnoea following exercise may be due to asthma rather than residual effects of CPAM in these children. PMID- 28737280 TI - Lack of adequate pneumococcal vaccination response in chronic lymphocytic leukaemia patients receiving ibrutinib. PMID- 28737281 TI - In situ evaluation of color stability and hardness' decrease of resin-based composites. AB - OBJECTIVE: To determine the color stability (CS) and hardness' decrease (HD) of two commercial resin-based composites (RBCs), after in situ staining conditions (SC). METHODS: Six disc-shaped specimens (6 * 2 mm) of two RBCs-Filtek Z350 XT (FZX) and IPS Empress Direct (IED)-were randomly distributed into palatal devices. Eight volunteers (aged 20-30 years) participated in this study. The in situ SC consisted of 400 mL consumption (2 * 200 mL/day) of water, orange juice, cola soda, and coffee and 140 mL consumption of red wine, 10 days each. CS was obtained by CIELAB color difference (DeltaE*) and HD (in %) by the Knoop method (50 g for 15 s), after curing (baseline) and after the in situ SC. Data were statistically analyzed at alpha = 0.05 significance level. RESULTS: For both RBCs, the coffee (5.7 +/- 0.5 for FZX; 5.9 +/- 1.3 for IED) and red wine (6.1 +/- 1.1 for FZX; 6.2 +/- 1.6 for IED) groups showed the highest DeltaE* while water the lowest (1.6 +/- 0.6 for FZX; 1.8 +/- 0.2 for IED). The highest HD was induced by red wine group for FZX (40.7 +/- 5.4) and by cola soda for IED (40.6 +/- 3.2) while the water groups (8.3 +/- 1.7 for FZX; 7.8 +/- 2.1 for IED) presented the lowest values for both RBCs. CONCLUSION: Both RBCs were affected by the in situ SC, but no significant differences for CS and HD were observed between them. Red wine and coffee showed higher discoloration potential. CLINICAL SIGNIFICANCE: This in situ study suggests that color stability and hardness' decrease of resin based composites were dependent on the type of consumed beverage and materials' composition. Patients with esthetic direct restorations should be aware of the degradative potential of them. PMID- 28737282 TI - Discrimination, gender and self-reported aesthetic problems among Brazilian Adults. AB - OBJECTIVES: To explore factors associated with discrimination in healthcare services and to assess whether discrimination based on dental aesthetics differs by sex. METHODS: Cross-sectional analysis based on a household survey carried out in a city in Southern Brazil. Fifteen primary health care (PHC) units with a dental team were randomly selected, and individuals who used the public services in the catchment areas of the PHC units were interviewed. The survey questionnaire included experiences with discrimination related to health services, sociodemographic and dental characteristics. Multiple logistic regressions were estimated with dental appearance as outcome. RESULTS: The final sample was composed of 433 individuals, with 15.2% reporting being discriminated in health services. Participants with >=20 teeth were significantly more likely to report discrimination than those with <20 teeth (16.6% vs 9.1%, respectively), and people with twisted and stained teeth reported more discrimination than those with white and aligned teeth (23.2% vs 9.9%, respectively). Overall, individuals with twisted and stained teeth were more likely to report discrimination (OR=3.13; 95% CI: 1.46-6.71). When the analyses were stratified by sex, women with twisted and stained teeth showed an OR=3.62 (95% CI: 1.55-8.46) and men OR=0.54 (95% CI: 0.05-6.18). CONCLUSION: Dental appearance may lead to discrimination in healthcare services, but this seems to be more important for women than men. PMID- 28737283 TI - Prevalence of hearing and vestibular loss in cystic fibrosis patients exposed to aminoglycosides. AB - AIM: Cystic Fibrosis (CF) patients frequently use aminoglycosides (AGS) to treat CF exacerbation due to colonization with Pseudomonas aeruginosa. Although AGS can cause vestibular and auditory sensory losses that can negatively impact quality of life, little is known about the prevalence of vestibular loss in this population. The aim of this study was to determine the prevalence of hearing loss and/or vestibular dysfunction in CF patients treated with AGS. METHODS: The relationship between hearing status and vestibular status was also investigated. Hearing was determined to be normal or abnormal based on pure tone air and bone conduction thresholds. Vestibular outcome was divided into four categories; normal, non-lateralized vestibular dysfunction, unilateral loss, and bilateral loss based on results of post head shaking testing, positional and positioning testing, bithermal calorics, sinusoidal, and rotational step testing. RESULTS: Of our cohort of 71 patients, 56 (79%) patients have vestibular system dysfunction while only 15 (21%) have normal vestibular system function. Overall, 16 patients (23%) have hearing loss. In considering the relationship between auditory and vestibular function, 12 (17%) demonstrated both normal hearing and normal vestibular function and 13 (18%) have both hearing loss and abnormal vestibular function. Of the 55 (78%) patients with normal hearing, 43 (61%) have vestibular dysfunction, while 3 (4%) of patients with normal vestibular function have hearing loss. CONCLUSION: These results suggest that monitoring hearing alone is insufficient to detect ototoxicity in CF patients being treated with systemic AGS. PMID- 28737285 TI - Role of endoscopic ultrasound-guided-fine needle aspiration biopsy in the diagnosis of lymphoma of the pancreas: A clinicopathological study of nine cases. AB - OBJECTIVE: Endoscopic ultrasound-guided-fine needle aspiration (EUS-FNA) is an established first-line procedure in the management of solid and cystic pancreatic masses. Lymphoma is an uncommon diagnosis in EUS-FNA of the pancreas, and it is more common for such a diagnosis to be because of secondary involvement of the pancreas by a lymphoproliferative disorder than for this to represent isolated primary pancreatic lymphoma (PPL). We present the clinical, EUS and cytological features of these lesions. MATERIAL AND METHODS: After obtaining approval from our Institutional Review Board (IRB), nine cases of lymphoma diagnosed on EUS-FNA at a tertiary care cancer centre over a period of 8 years from 2008 to 2016 were retrieved from our endoscopy and pathology archives. Rapid onsite evaluation (ROSE) was carried out by a trained cytopathologist in all these cases. Cell blocks were available in seven cases, and immunophenotyping was performed on cell blocks using the immunoperoxidase method. Flow cytometry was performed in two cases. RESULTS: The most frequent site of involvement was the head of the pancreas (n=5, 55.6%). Four out of nine cases were diagnosed as PPL (44.4%). Five cases were diagnosed as lymphoma secondarily involving the pancreas (55.6%). The most frequent diagnosis was diffuse large B-cell lymphoma (n=6, 66.7%), followed by Hodgkin's lymphoma (n=2, 22.2%) and peripheral T-cell lymphoma (n=1, 11.1%). CONCLUSION: EUS-FNA in experienced hands is a valuable diagnostic modality, in conjunction with ROSE, immunohistochemistry and flow cytometry, in the diagnosis and sub-typing of both primary and secondary pancreatic lymphoma. PMID- 28737284 TI - Antibody reactivity against Helicobacter pylori proteins in a sample of the Spanish adult population in 2008-2013. AB - BACKGROUND: Differences in Helicobacter pylori protein expression have been related to the risk of severe gastric diseases. In Spain, a marked geographic pattern in gastric cancer mortality has long been reported. OBJECTIVE: To characterize antibody reactivity patterns against 16 H. pylori proteins, by age, sex, and region of birth, in a large sample of the Spanish adult population. MATERIALS AND METHODS: Antibody reactivity was quantified by H. pylori multiplex serology in a sample from the control group of the multicase-control study MCC Spain. For this analysis, 2555 population-based controls were included. Each participant was classified as seropositive or seronegative for each protein according to specific cutoffs. Overall H. pylori seroprevalence was defined as positivity against >=4 proteins. Descriptive analyses by age, sex, and region of birth were performed for both seroprevalence and seroreactivity (continuous measure). Differences among groups were tested by logistic and linear regression models. RESULTS: Overall H. pylori seroprevalence increased with age in both sexes. For ages 55-74, seroprevalence was lower in women than in men (84% vs 92%, P<.001). Region of birth explained 7% of the variability in seroprevalence. Among H. pylori seropositive subjects, proteins with the highest seroprevalence were GroEL, NapA, HP231, and Omp. Seropositivity for most of the proteins increased or remained stable with age, rising mainly for CagA, GroEL, and HyuA in women. A clear cohort effect was not observed. CONCLUSIONS: This is the first study to describe the antibody patterns against 16 H. pylori proteins in the Spanish population. We found variability in the H. pylori antibody profiles according to both individual factors such as age and sex, and environmental factors such as the region of birth. The slightness of the reduction in seropositivity with decreasing age highlights the ongoing importance of this infection. PMID- 28737286 TI - Unexpected Chiro-Thermoresponsive Behavior of Helical Poly(phenylacetylene)s Bearing Elastin-Based Side Chains. AB - The thermoresponsive behavior of an elastin-based polymer can be altered by the polymeric macromolecular conformation. Thus, when the elastin basic amino acid sequence VPGVG is used as a pendant group of a poly(phenylacetylene) (PPA) its thermoresponsive behavior in water can be remotely detected through conformational changes on the formed helix. Circular dichroism at different temperatures shows an inversion of the first Cotton effect (450 nm) at 25.8 degrees C that matches with the cloud point temperature. The elastin-based side chain poly(phenylacetylene) shows an upper critical solution temperature with low pH and concentration dependency, not expected in elastin-based polymers. It was found that the polymer self-assembles in water into spherical nanoparticles with hydrodynamic diameters of 140 nm at the hydrophobic state. PMID- 28737287 TI - Internet and cell phone usage patterns among young adults with intellectual disabilities. AB - BACKGROUND: The risks and opportunities associated with the use of technologies are of growing research interest. Patterns of technology usage illuminate these opportunities and risks. However, no studies have assessed the usage patterns (frequency, duration, and intensity) and related factors in young people with intellectual disabilities. METHODS: Questionnaires on Internet and cell phone usage patterns, the Internet Over-Use Scale and the Cell-Phone Over-Use Scale, as well as the Beck Depression Inventory were filled out in one-on-one interviews of 216 youth with intellectual disabilities. RESULTS: Young people with disabilities make more social and recreational rather than educational use of these tools, and show higher rates of excessive use of both technologies than a comparison group of 410 young people without disabilities. Also, their overuse is associated with other unhealthy behaviors. CONCLUSION: The framework of support needs of people with disabilities should be considered to promote healthy Internet and cell phone use. PMID- 28737288 TI - Linkage disequilibrium among commonly genotyped SNP variants detected from bull sequence. AB - Genomic prediction utilizing causal variants could increase selection accuracy above that achieved with SNPs genotyped by currently available arrays used for genomic selection. A number of variants detected from sequencing influential sires are likely to be causal, but noticeable improvements in prediction accuracy using imputed sequence variant genotypes have not been reported. Improvement in accuracy of predicted breeding values may be limited by the accuracy of imputed sequence variants. Using genotypes of SNPs on a high-density array and non synonymous SNPs detected in sequence from influential sires of a multibreed population, results of this examination suggest that linkage disequilibrium between non-synonymous and array SNPs may be insufficient for accurate imputation from the array to sequence. In contrast to 75% of array SNPs being strongly correlated to another SNP on the array, less than 25% of the non-synonymous SNPs were strongly correlated to an array SNP. When correlations between non synonymous and array SNPs were strong, distances between the SNPs were greater than separation that might be expected based on linkage disequilibrium decay. Consistently near-perfect whole-genome linkage disequilibrium between the full array and each non-synonymous SNP within the sequenced bulls suggests that whole genome approaches to infer sequence variants might be more accurate than imputation based on local haplotypes. Opportunity for strong linkage disequilibrium between sequence and array SNPs may be limited by discrepancies in allele frequency distributions, so investigating alternate genotyping approaches and panels providing greater chances of frequency-matched SNPs strongly correlated to sequence variants is also warranted. Genotypes used for this study are available from https://www.animalgenome.org/repository/pub/;USDA2017.0519/. PMID- 28737290 TI - Integration of IR-808 Sensitized Upconversion Nanostructure and MoS2 Nanosheet for 808 nm NIR Light Triggered Phototherapy and Bioimaging. AB - Near infrared (NIR) light triggered phototherapy including photothermal therapy (PTT) and photodynamic therapy (PDT) affords superior outcome in cancer treatment. However, the reactive oxygen species (ROS) generated by NIR-excited upconversion nanostructure is limited by the feeble upconverted light which cannot activate PDT agents efficiently. Here, an IR-808 dye sensitized upconversion nanoparticle (UCNP) with a chlorin e6 (Ce6)-functionalized silica layer is developed for PDT agent. The two booster effectors (dye-sensitization and core-shell enhancement) synergistically amplify the upconversion efficiency, therefore achieving superbright visible emission under low 808 nm light excitation. The markedly amplified red light subsequently triggers the photosensitizer (Ce6) to produce large amount of ROS for efficient PDT. After the silica is endowed with positive surface, these PDT nanoparticles can be easily grafted on MoS2 nanosheet. As the optimal laser wavelength of UCNPs is consistent with that of MoS2 nanosheet for PTT, the invented nanoplatform generates both abundant ROS and local hyperthermia upon a single 808 nm laser irradiation. Both the in vitro and in vivo assays validate that the innovated nanostructure presents excellent cancer cell inhibition effectiveness by taking advantages of the synergistic PTT and PDT, simultaneously, posing trimodal (upconversion luminescence/computed tomography (CT)/magnetic resonance imaging (MRI) imaging capability. PMID- 28737289 TI - Comparison of PASL, PCASL, and background-suppressed 3D PCASL in mild cognitive impairment. AB - We compared three implementations of single-shot arterial spin labeled (ASL) perfusion magnetic resonance imaging: two-dimensional (2D) pulsed ASL (PASL), 2D pseudocontinuous ASL (PCASL), and background-suppressed (BS) 3D PCASL obtained in a cohort of patients with mild cognitive impairment (MCI) and elderly controls. Study subjects also underwent 18 F-fluorodeoxyglucose positron emission tomography (18 F-FDG PET). While BS 3D PCASL showed the lowest (P < 0.001) gray matter-white matter cerebral blood flow (CBF) contrast ratio, it provided the highest (P < 0.001) temporal signal-to-noise ratio. Mean relative CBF estimated using the PCASL methods in posterior cingulate cortex (PCC), precuneus, and hippocampus showed hypoperfusion in the MCI cohort compared to the controls consistent with hypometabolism measured by 18 F-FDG PET. BS 3D PCASL demonstrated the highest discrimination between controls and patients with effect size comparable to that seen with 18 F-FDG PET. 2D PASL did not demonstrate group differentiation with relative CBF in any ROI, whereas 2D PCASL demonstrated significant differences only in PCC and hippocampus. Mean global CBF values did not differ across methods and were highly correlated; however, the correlations were significantly higher (P < 0.001) when either the same labeling (PCASL) or the same acquisition strategy (2D) was used as compared to when both the labeling and readout methods differed. In addition, there were differences in regional distribution of CBF between the three modalities, which can be attributed to differences in sequence parameters. These results demonstrate the superiority of ASL with PCASL and BS 3D readout as a biomarker for regional brain function changes in MCI. Hum Brain Mapp 38:5260-5273, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28737291 TI - Nucleoside reverse transcriptase inhibitor-reducing strategies in HIV treatment: assessing the evidence. AB - Antiretroviral (ARV) therapy, comprising a backbone of two nucleos(t)ide reverse transcriptase inhibitors (NRTIs) plus another ARV, is the recognized standard of care (SOC), which has helped extend life expectancy in people living with HIV. In a quest to reduce lifelong drug exposure and minimize or avoid the toxicity of NRTIs, "NRTI-reducing" regimens have been investigated. This descriptive review assessing the results of NRTI-reducing strategies from the largest randomized trials focuses on virological efficacy, resistance, regimen safety (in terms of bone mineral density, renal function, lipids and central nervous system function) and simplicity. The review considers efficacy across various NRTI-sparing strategies, for example an integrase strand transfer inhibitor (INSTI) plus a ritonavir-boosted protease inhibitor (PI/r) or PI/r + lamivudine (3TC), in both naive and switch regimes. Of 10 key studies in treatment-naive adults assessing five NRTI-reducing strategies, only four studies demonstrated noninferiority vs. SOC [GARDEL, NEAT 001, AIDS Clinical Trials Group 5142 and PROGRESS]. In switch settings, 17 studies (10 randomized) were reviewed that used four strategies, including three studies assessing an INSTI plus a nonnucleoside reverse transcriptase inhibitor . Noninferiority of the NRTI-reducing arm was shown in six of 10 studies (ATLAS-M, SALT, DUAL, OLE, LATTE-2 and SWORD). In general, NRTI reducing therapy did not always result in an improvement in short- or long-term adverse events; however, in many cases, these endpoints were not reported. Some of these studies reported higher virological failure rates with more frequent emergence of resistance mutations. None of these NRTI-reducing strategies has been compared against a single-pill regimen, including those containing tenofovir alafenamide. Only strategies demonstrating noninferior efficacy, a benefit in safety/tolerability, and a favourable cost-efficacy ratio, preferably in a single pill, will eventually match the current SOC of triple ARV therapy. PMID- 28737292 TI - Obesity as a Disease: Why Ignore the Numbers? PMID- 28737293 TI - Reduced Prenatal Weight Gain and/or Augmented Postnatal Weight Gain Precedes Polycystic Ovary Syndrome in Adolescent Girls. AB - OBJECTIVE: Hepato-visceral fat excess is a feature of polycystic ovary syndrome (PCOS). Risk factors for such excess include low prenatal weight gain and high postnatal weight gain. This study examined whether adolescent PCOS was preceded by a relatively low birth weight and/or a relatively high BMI at diagnosis. METHODS: Study participants included 467 girls with PCOS (298 without obesity and 169 with obesity), diagnosed, respectively, in Spain and Germany; 87 healthy girls were controls. Z scores for weight at birth and BMI at PCOS diagnosis were derived, and their differences were calculated. RESULTS: Spanish girls with PCOS and without obesity and German girls with PCOS and obesity had mean birth weight z scores of -0.7 and 0.0, respectively, and mean BMI z scores of + 0.4 and +2.7, respectively, so that mean z score increments amounted to +1.1 and +2.6 (P < 0.001 vs. controls). CONCLUSIONS: PCOS in adolescent girls was preceded by marked z score increments between weight at birth and BMI at PCOS diagnosis, thus corroborating the notion that PCOS development is driven by a mismatch between prenatal weight gain and postnatal weight gain. PMID- 28737294 TI - A call to action towards an evidence-based approach to using verbal encouragement during maximal exercise testing. AB - By definition, maximal exercise testing inherently requires participants to give a maximal effort. This is an important practical issue as submaximal efforts can produce invalid test results. Verbal encouragement is commonly used to motivate participants to maintain or increase effort investment during maximal exercise testing. Accordingly, studies have reported significant increases in time to exhaustion of between 8% and 18% during VO2max and multistage shuttle run tests, and a significant 30.5 m mean increase in 6-min walk test distance. Significant improvements during shorter tests, such as the Wingate and 2-min walk tests, have not been observed however. Although participants typically perceive verbal encouragement positively during maximal exercise testing, around one-third have neutral or negative perceptions. Despite the ubiquity and importance of verbal encouragement during maximal exercise testing, surprisingly little research has investigated the characteristics of effective encouragement with respect to its content, timing and frequency. The only randomized controlled trial to investigate one of these issues observed that verbal encouragement delivered every 20 s increased time to exhaustion during VO2 max testing, but not every 60 or 180 s. Of particular concern is that several exercise testing guidelines have incorporated specific guidelines for the use of verbal encouragement, but not provided any theoretical or empirical justification, presumably because of the limited research to inform practice. Recent empirical research does provide some important insight into participant preference for the content and timing of verbal encouragement during maximal exercise testing; however, much more research is clearly required to establish comprehensive evidence-based guidelines. PMID- 28737295 TI - Towards a unified analysis of brain maturation and aging across the entire lifespan: A MRI analysis. AB - There is no consensus in literature about lifespan brain maturation and senescence, mainly because previous lifespan studies have been performed on restricted age periods and/or with a limited number of scans, making results instable and their comparison very difficult. Moreover, the use of nonharmonized tools and different volumetric measurements lead to a great discrepancy in reported results. Thanks to the new paradigm of BigData sharing in neuroimaging and the last advances in image processing enabling to process baby as well as elderly scans with the same tool, new insights on brain maturation and aging can be obtained. This study presents brain volume trajectory over the entire lifespan using the largest age range to date (from few months of life to elderly) and one of the largest number of subjects (N = 2,944). First, we found that white matter trajectory based on absolute and normalized volumes follows an inverted U-shape with a maturation peak around middle life. Second, we found that from 1 to 8-10 y there is an absolute gray matter (GM) increase related to body growth followed by a GM decrease. However, when normalized volumes were considered, GM continuously decreases all along the life. Finally, we found that this observation holds for almost all the considered subcortical structures except for amygdala which is rather stable and hippocampus which exhibits an inverted U-shape with a longer maturation period. By revealing the entire brain trajectory picture, a consensus can be drawn since most of the previously discussed discrepancies can be explained. Hum Brain Mapp 38:5501-5518, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28737297 TI - Correlates of frailty phenotype and frailty index and their associations with clinical outcomes. AB - OBJECTIVES: Frailty is a predictor of adverse health outcomes and can be measured across the life course, including among people living with HIV. The purpose of this study was to examine two commonly used measures of frailty - the frailty index (FI) and frailty phenotype - to assess common characteristics and to describe associations with multimorbidity, falls, and disability in people aging with HIV. METHODS: This was a cross-sectional observational study including 482 consecutive HIV-infected patients (mean age 53.9 +/- SD 6.9 years; 75% male) attending the multidisciplinary metabolic clinic at the University of Modena, Italy. Frailty was measured with the frailty phenotype and a 37-item FI. RESULTS: The mean FI score was 0.28+/-0.1 and frailty phenotype categories were: 3.1% frail, 51.9% pre-frail, and 45% robust. The duration of antiretroviral therapy was significantly different across levels of frailty as measured by both frailty tools (P < 0.01), but the nadir CD4 count was only significant for the FI (P = 0.01); current CD4 count was not significantly different across frailty levels using either tool. Both frailty measures were associated with multimorbidity; the FI was associated with Instrumental Activities of Daily Living impairment and falls history, whereas the frailty phenotype was not. CONCLUSIONS: The frailty phenotype and the FI demonstrated similar characteristics in patients at a tertiary-level HIV clinic. The FI had a stronger association with age, nadir CD4 count, comorbidities, falls, and disability. Integrating frailty assessments in clinical practice will be crucial for the development of interventions in age related conditions, including disability and falls, in older persons living with HIV. PMID- 28737298 TI - AMP-activated protein kinase is involved in induction of protective autophagy in astrocytes exposed to oxygen-glucose deprivation. PMID- 28737299 TI - Paediatric Workforce in the UK and the Wider Implications. PMID- 28737296 TI - Neurodevelopmental maturation as a function of irritable temperament: Insights From a Naturalistic Emotional Video Viewing Paradigm. AB - Few studies have investigated the neural systems involved in decreasing behavioral reactivity to emotional stimuli as children age. It has been suggested that this process may interact with temperament-linked variations in neurodevelopment to better explain individual differences in the maturation of emotion regulation. In this investigation, children ages 4 to 12 (n = 30, mean age = 7.62 years, SD = 1.71 years) and adults (n = 21, mean age = 26.67 years) watched clips from popular children's films containing positive, negative, or neutral emotional content during functional magnetic resonance imaging. Compared to adults, children demonstrated greater activation in subcortical and visual regions (hippocampus, thalamus, visual cortex, fusiform) during negative clips and greater activation of subcortical and prefrontal regions during positive clips (hippocampus, thalamus, caudate, ACC, OFC, superior frontal cortex). In children only, we found an age by temperament interaction in frontal and subcortical regions indicating that activation increased as a function of age in the most irritable children, but decreased as a function of age in the least irritable children. Findings were not present in the temperament domain of fear. Findings replicate and extend the existing irritability literature, indicating that healthy children highest in irritability may develop comparatively greater activation of the lateral prefrontal cortex in order to support adaptive regulation during emotional challenges. These results are discussed within the context of the emerging literature on the utility of complex, multidimensional, and naturalistic stimuli, which present a complementary alternative to understanding ecologically valid and sustained neural responses to emotionally evocative stimuli. Hum Brain Mapp 38:5307-5321, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28737300 TI - A Practical Approach to Hypothyroidism and Pregnancy. PMID- 28737301 TI - Vaccine-Preventable Admissions to an Irish Paediatric Intensive Care. AB - In the Republic of Ireland, the schedule of state-funded immunisation for children is comprehensive and includes diphtheria, pertussis, tetanus, pneumococcus, hepatitis B, meningococcus C, haemophilus B, polio, measles, rubella and mumps. Varicella and meningococcal B vaccines are commercially available but are not currently funded by the government. Each of the illnesses preventable by these vaccines can cause substantial morbidity, and rarely mortality, in infants and children. Our PICU continues to see serious illness due to avoidable infection. There were 39 admissions in a 4 year period, with 34 children surviving to discharge. Nine children were infected with pneumococcus, with 4 deaths. There was one case of pertussis, causing death. Most infections occurred in previously healthy children. These preventable conditions represent a significant burden on children, families, and on social and healthcare resources. PMID- 28737302 TI - An exploratory service-based study of Deliberate Self-Harm (DSH) in Ireland: 'A hidden population'? AB - The aim of this study was to investigate the nature and extent of deliberate self harm (DSH) amongst those attending national crisis centres in Ireland, and to assess clients' views of the service. A secondary analysis was undertaken of a large data set of clients presenting with DSH (n=823). Clients were predominantly female, under 25 and with self-cutting widely reported (73%). DSH co-occurred with suicidal ideation (SI) (42%) and/or a suicide attempt (SA) (35%). Males were significantly more likely to present with more severe problems, and to use more dramatic methods of DSH; more severe presenting issues were also significantly associated with a history of having friends who engage in DSH. The treatment completion rate was 36%. Clients reported overwhelmingly positive views about the service. This is the first study in Ireland to provide insights into a 'hidden population' of people who engage in DSH. A need for greater awareness of DSH and its links to suicidal ideation/behaviour is indicated. PMID- 28737303 TI - Comparing cardiovascular risk factors, disease and treatment in participants with rheumatoid arthritis and without arthritis in a population based stud. AB - Rheumatoid Arthritis (RA) is associated with a significant increase in mortality compared to the general population, with cardiovascular disease (CVD) the leading cause of death. The aim of this study is to compare the prevalence and treatment of modifiable CV risk factors and history of CVD in those with RA and those without arthritis in Ireland. Data from the Irish Longitudinal Study on Ageing (TILDA), a population-representative cohort study of people in Ireland aged 50 or over, was used. Participants with RA (n=457) were twice as likely to be obese (OR 2.02, 95% CI 1.99 to 2.06) compared to those without arthritis (n=4,063). Participants with RA were also more likely to be physically inactive (OR 1.73, 95% CI 1.69 to 1.76) and taking antihypertensive medication than those without arthritis. Exercise can have a beneficial impact on CVD and specific interventions to increase physical activity in those with RA may be warranted. PMID- 28737304 TI - Investigation and diagnostic formulation in patients admitted with transient loss of consciousness. AB - Several commonly completed tests have low diagnostic yield in the setting of transient loss of consciousness (T-LOC). We estimated the use and cost of inappropriate investigations in patients admitted with T-LOC and assessed if these patients were given a definitive diagnosis for their presentation. We identified 80 consecutive patients admitted with T-LOC to a university teaching hospital. Eighty-eight percent (70/80) had a computerized topography (CT) brain scan and 49% (34/70) of these scans were inappropriate based on standard guidelines. Almost half (17/80) of electroencephalograms (EEG) and 82% (9/11) of carotid doppler ultrasound performed were not based on clinical evidence of seizure or stroke respectively. Forty-four percent (35/80) of patients had no formal diagnosis documented for their presentation. Inappropriate investigation in T-LOC is very prevalent in the acute hospital, increasing cost of patient care. In addition, there is poor diagnostic formulation for T-LOC making recurrent events more likely in the absence of definitive diagnoses. PMID- 28737305 TI - The Hidden Burden of Outpatient Repeat PSA Testing in a Prospective Cohort. AB - PSA testing is widespread throughout Europe for diagnostic purposes and follow up. We performed a prospective outpatient cohort study of 250 men (2013-2015) in two hospital sites. Included were those men being followed up by urology with PSA blood testing. First appointments and those men in whom non-PSA tests were ordered by urology were excluded. The median age was 67.2yrs (46-88). Eighty-one point two percent of samples had a combination of 21 different serology tests at an added cost of >?18,000. Abnormal serology resulted in 53 referrals. Twenty-six six percent of correspondence referenced abnormal serology other than PSA. Follow up of non-PSA test results poses a challenge in an outpatient setting with failure to appropriately follow-up on abnormal results, increased costs, and medico-legal implications. There is currently no Irish legislature in place to safeguard hospital physicians. This study quantifies the levels of expenditure, resources and risk associated with ambulant PSA testing. PMID- 28737306 TI - The use of cold coagulation for the treatment of cervical intraepithelial neoplasia. AB - In 2015, Cold Coagulation was introduced as a treatment for cervical intraepithelial neoplasia (CIN) at our colposcopy clinic. We reviewed the 6-month follow up data of the first 200 women who underwent Cold Coagulation using cytology and HPV status as tests of cure (TOC). A random sample of 200 patients treated by Large Loop Excision of the Transformation Zone (LLETZ) during the same period was used to compare treatment outcome. Six months following treatment,173 (86.5%) of the women treated by CC and 167 (83.5%) treated by LLETZ had negative cytology. (x2= P>0.05). 148 (74%) treated by Cold Coagulation and 166 (83%) treated by LLETZ were HPV negative (x2= P<0.05). One hundred and thirty-nine (70%) women treated by Cold Coagulation and 152 (76%) treated with LLETZ had normal cytology and were HPV negative. This audit of our initial experience supports the observation that Cold Coagulation is as effective as LLETZ in the management of CIN when cervical cytology is used as a test of cure. PMID- 28737307 TI - Absorbable Polydioxanone (PDS) suture provides fewer wound complications than polyester (ethibond) suture in acute Tendo-Achilles rupture repair. AB - We prospectively studied acute Achilles tendon rupture in patients over a two 2 year period and reviewed the causes, outcome and complications. There were 53 patients included with acute Achilles rupture with minimum follow up period of 6 months. We compared the outcomes including infection rate and Boyden score between the two groups repaired by Polydioxanone and Polyester respectively. All infected cases had a suture repair using the polyester suture. The difference in the infection rate was highly significant between the 2 groups (p=0.001). All 34 patients (100%) in the PDS group had good / excellent results based on the Boyden clinical assessment. Conversely, only 16 patients 9(68.4%) had good or excellent results IN Polyester repair group. Patients treated with a non- absorbable suture (ethibond) material for repair had a higher incidence infection and worse Boyden scores than the absorbable PDS group. PMID- 28737308 TI - A Multicentre Study of Thromboprophylaxis in Pregnancy. AB - Venous thromboembolism (VTE) is a leading cause of maternal mortality. The risk increases with increasing maternal age, mode of delivery and medical co morbidities. Thromboprophylaxis with low molecular weight heparin (LMWH) has been shown to be both safe and efficacious. The aim of this study was to prospectively investigate the incidence of maternal risk factors in pregnant women admitted to hospital, to calculate their VTE risk status and to investigate if they were receiving appropriate thromboprophylaxis. All patients admitted to the participating hospitals on the day of investigation were assessed for risk of VTE on the basis of hospital chart review. Five Hundred and forty women were recruited from 16 hospitals. Almost 32% (31.7%) were receiving thromboprophylaxis with LMWH. Just under 80% of patients were on the correct thromboprophylaxis strategy as defined by the RCOG guideline but 49% were under-dosed. The odds of receiving appropriate thromboprophylaxis were significantly increased if the woman was >35 years 0or with parity>3. PMID- 28737309 TI - I Still Haven't Found What I'm Looking For... Bono, Google and Glaucoma Awareness. AB - The effect of celebrity diagnosis on public awareness of health conditions has already been well documented. In October 2014, Bono, the lead singer with U2, revealed publicly for the first time that he has glaucoma. This study aimed to analyze the impact of Bono's announcement on public awareness of glaucoma using Google Search trends as an indicator of public interest in the disease. Google Trends was used to examine Google Search activity for the term 'Glaucoma' between 2009 and 2015 in both Ireland and the United Kingdom. Trend analyses were performed using Microsoft Excel Version 14.3.5. Increased Google Search activity for 'Glaucoma' in October 2014 was found in both Ireland and the United Kingdom. A five-fold increase from the mean Google Search activity for this term was found in Ireland and a two-fold increase from the mean Google Search activity for this term was found in the United Kingdom. No such increase in Google Search activity occurred during each country's 2014 Glaucoma Awareness week. Google Trends is useful in medical research as a means of assessing public awareness of, and/or interest in, health related topics. Current approaches to glaucoma related health promotion in both Ireland and the United Kingdom have failed to yield an increase in on-line Google Search activity. While there was an increase in interest in glaucoma it is unclear whether this led to an increase in health seeking behaviour. PMID- 28737310 TI - A Case of Autoimmune Pancreatitis Presenting as a Deterioration in Glycaemic Control in a Patient with Pre-Existing Type 2 Diabetes. AB - We report a case of Type 1 autoimmune pancreatitis presenting as a rare cause of worsening hyperglycaemia in a patient with Type 2 diabetes and discuss the difficulties in differentiating this disease from pancreatic cancer. PMID- 28737311 TI - Amniotic band syndrome with pseudoarthrosis of tibia and fibula: A case report. AB - Constriction of the lower limb by congenital amniotic band has been proposed to explain the development of pseudoarthrosis of tibia and fibula. We report a case of amniotic band syndrome in a preterm infant with pseudoarthrosis of tibia and fibula. Simple release of constriction band with Z-plasty resulted in the growth of mature bone, replacing the pseudoarthrosis and hence did not require surgical amputation. Our case confirms the potential for bone growth in ABS, once the constricting band is released. Early limb preserving surgery with release of the constricting band with an intention to salvage the limb appears appropriate. PMID- 28737312 TI - Life After the Event: A Review of Basic Life Support Training for Parents Following Apparent Life-Threatening Events and Their Experience and Practices Following Discharge. AB - Apparent Life-Threatening Events (ALTEs) are a common presentation to paediatric hospitals and represent a significant cause of parental anxiety. Basic Life Support (BLS) training is recommended for all caregivers following ALTEs. This study aimed to assess the rate of caregiver BLS training and reviewed parents experience following discharge. Parents were interviewed by phone following discharge. Over the study period 25 children attended the Emergency Department with ALTE, 17/25 (68%) were trained and 13/17 (76%) were contactable for interview. All parents found training decreased their anxiety level and were interested in attending for re-training. BLS resuscitation was subsequently required by 2/13 (15%) of children. Non-medical grade monitors were in use by 10/13 (77%) of caregivers following discharge. Caregivers are eager to engage in BLS training and it effectively reduces their caregiver anxiety. We recommend an increase in instructor staff and use of group re-training post discharge. PMID- 28737313 TI - Adult attention deficit hyperactivity disorder and driving - risk, medication and fitness to drive. PMID- 28737314 TI - Immigrant health: laboratory reference ranges may differ from indigenous population's with potential for misinterpretation. PMID- 28737315 TI - A retrospective review of the management of patients with hidradenitis suppurativa in the Belfast health and social care trust, Northern Ireland. PMID- 28737316 TI - World-class healthcare - the children of Ireland deserve no less. PMID- 28737317 TI - [Determinants of enrolment and retention in mutual health organization in the region of Ziguinchor (Senegal)]. AB - Introduction: Despite the recognition of the role of Mutual Health Organization (MHO) as a mechanism to ensure the financial sustainability of health systems, recent studies have shown the existence of obstacles to enrolment and retention in these MHOs. The objective of this study was to examine the determinants of enrolment and retention in MHO in Senegal.Methods: Data collection was conducted from 22 June to 30 September 2015 in Ziguinchor, located 450 km from Dakar by stratified two-stage sampling (n = 912 households). The analysis was conducted by multiple logistic regression with selection of predictors in the Stepwise Backward method based on the likelihood ratio.Results: Low enrolment was significantly associated with rural residence, size of the household, low level of household head literacy and income, poor perception of the quality of care and distance from the nearest health facility. Low retention in MHO was also significantly associated with low household income, poor perception of quality of care, and presence of a person over the age of 60 years in the household.Conclusion: The determinants of enrolment and retention of consumers in MHO must be taken into account to ensure successful development of a Universal Health Coverage strategy. PMID- 28737318 TI - [Perceptions of a healthcare-associated infections reporting system in a Tunisian university hospital]. AB - Objective: The implementation of a healthcare-associated infections reporting system is a principal component of infection control and quality improvement policies in healthcare institutions. This study was designed to determine the perceptions of health professionals concerning implementation of a healthcare associated infections reporting system and to analyse factors influencing these perceptions.Methods: A descriptive cross-sectional study conducted in 2012 using a predefined, pre-tested and self-administered questionnaire in 380 health professionals working in 16 different departments of Farhat Hached University Hospital, Tunisia.Results: The majority of respondents (71.8%) reported that no healthcare-associated infections surveillance procedure had been implemented in their departments. However, most respondents (93%) recognised the value of implementation of a healthcare-associated infections reporting system in order to provide them with corrective actions (77%), to support the investigation of epidemic and emerging phenomena (49%) and to share experiences about the prevalence of healthcare-associated infections and their risk factors (44%).Conclusion: Staff training and development of a regulatory framework are essential to implementation and correct functioning of a healthcare-associated infections reporting system. PMID- 28737319 TI - [Sexual violence in urban environments: example in the city of Lubumbashi, Democratic Republic of the Congo]. AB - Introduction: Sexual violence, which is becoming increasingly recurrent in the Democratic Republic of the Congo, is a public health problem in Lubumbashi.Objective: The objective of this study was to determine the prevalence of sexual violence, the circumstances of occurrence and risk environments.Method: This was a retrospective, cross-sectional, descriptive study based on a document review of 116 female victims between the ages of 2 to 34 years attending the Kampemba General Hospital in Lubumbashi in 2013, generally for forensic examination.Results: The prevalence of sexual violence in Lubumbashi was 127 per 100,000 in the absence of any armed conflict. The frequency of sexual violence in Kampemba General Hospital was 3.35%. Victims of sexual violence were mostly young people (94%) aged 14 to 17 years (over 60% of cases), while the perpetrators of sexual violence were predominantly male (100%), civilians (98%) and adults (86.2%). 24% of pregnancies were observed among the victims and nearly 72% of cases of mental distress. Only 19.18% of cases of sexual violence were reported to the police.Conclusion: Gender-based sexual violence, which constitutes a denial of human rights and health remains a real public health problem in the DRC in general and especially in Lubumbashi. PMID- 28737320 TI - [Trends in caesarean section rates and places of delivery in Burkina Faso]. AB - Objective: The objective of this study was to evaluate the trends, mortality rates and places of caesarean section by level of care in Burkina Faso.Method: A retrospective study was conducted using data from Burkina Faso Ministry of Health annual health statistics and public hospital reports from 2000 to 2014. Linear regression was used to analyse caesarean section trends and mortality rates in District Hospitals (HD), Regional Hospitals (CHR) and University Hospitals (CHU).Results: From 2000 to 2014, the number of caesarean sections performed in Burkina Faso public hospitals increased almost tenfold from approximately 2,365 to 19,081, corresponding to a growth of the caesarean section rate from 0.5 to 2 per 100 deliveries. This growth was linear. Between 2000 and 2006, University Hospitals performed most of these caesarean sections. Starting from 2007, the majority of caesarean sections were performed by HD. The proportion of caesarean sections performed in Regional Hospitals remained almost constant, although the number of caesarean sections increased threefold. In 2014, HD performed 52% of caesarean sections, followed by University Hospitals (25%) and Regional Hospitals (23%). Analysis of mortality rates following caesarean section showed upward and downward trends, oscillating between 1 to 2% before 2008 and 0.15% in 2014. This same mortality trend was observed in each type of hospital.Conclusion: The results show an increase of better quality caesarean section rates, performed closer to the woman's home in Burkina Faso. The health care services decentralization policy and quality of care approaches have helped to achieve these results. PMID- 28737321 TI - ? PMID- 28737323 TI - [Complexity: concept and challenges for public health interventions]. AB - Introduction: Since 2000, the notion of "complex interventions" has been emerging in the health research field. "Complex interventions" and "complexity" are commonly used terms, but they are generally not defined. Conceptual ambiguities persist concerning the notion of complexity. The objective of this exploratory review is to characterize the notion of complexity: What is complexity? Where does this notion come from and what does it cover? What are the consequences of complexity in the health field?Methods: To clarify the concept of complexity, a narrative review was conducted in the fields of humanities and social science, managerial economics, psychology and healthcare.Results: The concept of complexity, that can be attributed to Edgar Morin, has been the subject of appropriations, adaptations, and operations in multiple areas. Complexity consists of understanding the factors influencing individual decisions. In the field of healthcare, the concept of complexity is used more pragmatically and is defined by objective characteristics of interventions (defined as complex) or their contexts for the practical purposes of evaluation.Discussion: The notions of complexity and complex interventions have implications for researchers and users of the results of research. In particular, the notion of complexity is designed to provide a better understanding of the mechanism of effectiveness of interventions, support transferability and use by actors and decision-makers. PMID- 28737322 TI - [What are the main factors assisting general practitioners in the development of educational strategies?] AB - General practitioners (GP) are in a special position to conduct educational strategies for their patients with chronic disease. Despite the GP's desire to be involved in patient education, this approach remains underdeveloped.Objective: To determine the factors required support the development of educational strategies in general practice from the GPs' perspective.Methods: Qualitative study based on a "modified nominal group technique" carried out among 21 GPs (not specifically trained in patient education) participating as investigators in an interventional study testing a structured educational strategy. The interventional study based on processes and tools specifically developed to suit general practice was held during their usual consultations. Thirty one patients with COPD were followed for 9 months.Results: GPs identified 23 specific factors restructured after the clarification-reformulation step in 6 main factors required for the development of educational strategies in general practice. The consensus revealed that reinforcement of initial and continuing medical training was the most frequently cited factor and was considered to be a priority. The development of inter- and intra-professional cooperation was the second leading factor to be taken into account.Conclusion: The improvement of GP training and the promotion of areas of cooperation could help GPs to develop educational strategies during their consultations. These results may provide insight to regional health agencies concerning the deployment of patient education in primary care. PMID- 28737324 TI - [Repeated BCG vaccine stockouts in France: local findings and consequences in a primary health care centre in Seine-Saint-Denis]. AB - France is the European country most severely impacted by BCG vaccine stockouts that started in 2013. After a brief history of French tuberculosis vaccine regulations, this article describes the dysfunctions induced by these shortages in a primary health care centre in Seine-Saint-Denis, the department with the highest incidence of tuberculosis in France.Field observations reveal two types of shortcomings in the institutional communication to healthcare professionals: incomplete communication on projected shortages and their duration; lack of technical information on BCG multidose vials for the Polish market replacing BCG SSI. We then report the consequences of this poor information on the performances of the primary health care centre and its workers.In the light of this situation, we propose ways to improve policy implementation, especially by creating bottom up communication channels from healthcare professionals towards health agencies. PMID- 28737325 TI - [Systemic lupus erythematosus: a French general hospital experience]. AB - Objectives: Systemic lupus erythematosus (SLE) is a disease requiring long-term follow-up. Most studies published in the literature concerned teaching hospitals. We wanted to study a population of SLE patients, their follow-up and therapeutic modalities in a general hospital in order to evaluate professional practices.Methods: We performed a descriptive and retrospective study with SLE patients followed at Centre Hospitalier Intercommunal Robert Ballanger in Aulnay sous Bois (Seine Saint-Denis) between March 2013 and March 2015.Results: Thirty nine patients were included with various forms of the disease: 77% presented arthritis, 67% had skin involvement, 44% had haematological disorders, 26% had serosal involvement, 13% had kidney involvement, 13% had neuropsychiatric disorders, 8% had digestive tract involvement and 2% had myocarditis. Thirty-five patients were treated with hydroxychloroquine and 12 were treated with immunosuppressive or biotherapy. Patients were seen 3 or 4 times a year as outpatients; 19 were hospitalized at least once in conventional wards and 27 were admitted at least once to a day hospital. Advice from a teaching hospital colleague was required for 6 patients, but only one patient was permanently followed in another hospital.Conclusion: Our patients had similar clinical features to those reported in large series, except for a lower prevalence of renal injuries. Therapeutic management was in accordance with guidelines, with frequent discussion with teaching hospitals. We identified measures to improve our follow-up?: more cardiovascular prevention, more vaccinations and adjustment of hydroxychloroquine monitoring. PMID- 28737326 TI - [Public health research: a policy able to address the challenges involved is essential]. PMID- 28737327 TI - [Proposal of standardised and logical templates for discharge letters and discharge summaries sent to general practitioners]. AB - Background: Communication between general practitioners (GPs) and hospitals is a weak point of the French health system. Unfortunately, hospital discharge documents, a keypoint for healthcare safety and efficiency, tend to be poorly defined. This study aimed to propose standardised and logical templates for discharge letters (DL) and discharge summaries (DS) with particular attention to GPs' needs.Methods: A Delphi methodology was conducted on the findings of a systematic review of the international literature. We recruited 28 experts including producers (hospital physicians and interns), recipients (GPs, head of the medical information department, patient representatives), and other professionals using discharge documents (representative of regional health administration for inspection and control, jurist, pharmacists).Results: A consensus was reached after two rounds of consultation. According to the experts, DS should ideally be available on the last day of hospitalization, but this is rarely possible. DL have therefore become the most important document for GPs. Two standardised and logical templates were submitted to the experts for validation. The templates were considered to be pertinent by the experts and were perceived as improving several key points such as writing and reading speed, communication between hospitals and community practitioners or safety of healthcare after discharge from hospital.Conclusion: DL and DS templates will be tested in pilot hospitals by an impact study. PMID- 28737328 TI - [Documenting a rehabilitation program using a logic model: an advantage to the assessment process]. AB - The cognitive and behavioral disorders after brain injury can result in severe limitations of activities and restrictions of participation. An interdisciplinary rehabilitation program was developed in physical medicine and rehabilitation at the Pitie-Salpetriere Hospital, Paris, France. Clinicians believe this program decreases activity limitations and improves participation in patients. However, the program's effectiveness had never been assessed. To do this, we had to define/describe this program. However rehabilitation programs are holistic and thus complex making them difficult to describe. Therefore, to facilitate the evaluation of complex programs, including those for rehabilitation, we illustrate the use of a theoretical logic model, as proposed by Champagne, through the process of documentation of a specific complex and interdisciplinary rehabilitation program. Through participatory/collaborative research, the rehabilitation program was analyzed using three "submodels" of the logic model of intervention: causal model, intervention model and program theory model. This should facilitate the evaluation of programs, including those for rehabilitation. PMID- 28737329 TI - [Mobile emergency care medical records audit: the need for Tunisian guidelines]. AB - Objective: This study was designed to assess the quality of the Gabes (Tunisia) mobile emergency care medical records and propose corrective actions.Materials and methods: A clinical audit was performed at the Gabes mobile emergency care unit (SMUR). Records of day, night and weekend primary and secondary interventions during the first half of 2014 were analysed according to a data collection grid comprising 56 criteria based on the SMUR guidelines and the 2013 French Society of Emergency Medicine evaluation guide. A non-conformance score was calculated for each section.Results: 415 medical records were analysed. The highest non-conformance rates (48.5%) concerned the "specificities of the emergency medical record" section. The lowest non-conformance rates concerned the surveillance data section (23.4%). The non-conformance score for the medical data audit was 24%.Conclusion: This audit identified minor dysfunctions that could be due to the absence of local guidelines concerning medical records in general and more specifically SMUR. Corrective measures were set up in the context of a short term and intermediate-term action plan. PMID- 28737330 TI - [Mobility of physicians in Europe: health policies and health care provision]. AB - Objective: To define the place of geographical mobility of physicians in medical demography policies in EU countries.Methods: Review of international migration assumptions in national projection models of numbers of physicians by broad categories of social protection systems in the EU.Results: Some countries fail to achieve medium-term projections of the number of physicians and those that do adopt the assumption of net migration, assume that they converge to zero. Migration is not considered to be a solution to the expected shortage of physicians, but rather a problem to be solved.Discussion: Three approaches to labour mobility are discussed: liberal, normative and ethical. The last approach appears to be the most popular by combining preservation of national interests with the World Health Organisation Global Code of Practice on the International Recruitment of Health Personnel. PMID- 28737331 TI - [Dispensing of oral anticancer drugs by retail pharmacies: professional requirements and recommendations]. AB - Objectives: As a result of organizational and therapeutic progress in the management of cancer, retail pharmacies are faced with numerous challenges in the follow-up of cancer patients. This study was designed to provide a better understanding of the way in which retail pharmacists define their role in the management of cancer patients and to identify actions that would promote more efficient coordination with other oncology professionals.Methods: Semi-structured qualitative interviews were conducted with retail pharmacists and data were analysed by thematic analysis.Results: The majority (53%) of retail pharmacists provide patients with explanations concerning their treatments. Participants in this study described in detail patients' questions concerning adverse effects (79%) as well as certain forms of alternative medicine (37%). Difficulties with an impact on patient follow-up were also reported, such as the lack of medical information concerning cancer treatments (21%) and their relationship with the hospital (26%).Conclusion: The availability of information tools shared by all healthcare professionals therefore appears to be essential to address the difficulties of follow-up of cancer patients by retail pharmacists. PMID- 28737332 TI - [Knowledge, attitudes and condom use skills among youth in Burkina Faso]. AB - Introduction: Condom use is recognized by the WHO as the only contraceptive that protects against both HIV / AIDS and unwanted pregnancies. But to be effective, condoms must be used consistently and correctly. The objective of this study was to assess young people's skills in male condom used, to identify the challenges faced by them when using condoms to better guide future interventions.Methods: Based on a two-level sampling representing 94,947 households within Bobo Dioulasso municipality, 573 youth aged between 15 and 24 were interviewed. This data collection was conducted from December 2014 to January 2015 in the three districts of the municipality. A questionnaire was used to assess the knowledge and attitudes of the youth.Results: Only 24% of surveyed know how to accurately use condoms despite their knowledge of condom effectiveness and although some of them are exposed to awareness-raising and information campaigns. Indeed, various handling errors and usage problems (breakage, slippage, leakage and loss of erection) had been identified during the oral demonstration performed by the surveyed. The older youth and with the highest level of education were the most likely to demonstrate increased skills in condom use. Moreover, girls were less competent than boys in terms of condom use.Conclusion: It is important to increase awareness-raising and information campaigns, adapting the content to the real needs of young people so as to transmit the skills required for effective prevention particularly in regard to condom use. PMID- 28737333 TI - Public health, health promotion and presidential election in France: break the barrier of good intentions. PMID- 28737334 TI - [Barriers to tuberculosis awareness and screening: a qualitative study in a French department]. AB - The incidence of tuberculosis in Seine-Saint-Denis is considerably higher than the national average. The north-west part of the department is particularly concerned. Screening teams encounter difficulties communicating on the disease, reaching the populations concerned and obtaining their adhesion to the screening proposal. The objective of this study was to identify and elucidate the obstacles to tuberculosis prevention and screening.A qualitative study was conducted based on observation of screening actions in Seine-Saint-Denis and semi-directive interviews with health professionals in charge of screening, community representatives and associations, and individuals from the population concerned.Obstacles to tuberculosis awareness and screening appear to be linked to the way in which screening is organized and implemented, and communication difficulties in relation to this disease. Three major obstacles were identified: the gap between the little attention paid to this disease and the sanitary crisis it can trigger in the event of an epidemic; the unsuitability of communication tools for the target population and their lack of attractiveness; maladjustment of screening actions to the local context.The study highlights the individual and social marginalization of the tuberculosis issue and the mechanisms producing this marginalization. It encourages the development of more interactive communication tools and modes, and increased awareness of the professionals involved in screening about field realities. PMID- 28737335 TI - [How to raise awareness about antibiotics and vaccination among French teenagers?] AB - Introduction: Bacterial resistance to antibiotics is a growing concern in Europe, vaccination coverage is inadequate, and young adults, who are the highest antibiotic consumers, have the lowest level of knowledge.Extension of the e-Bug project, a European educational school programme concerning microbes, antibiotics and vaccination, to 15-18-year-olds implies the development of educational resources based on social marketing to promote sustainable behavioural changes. The objectives of the present study, which is part of the needs assessment in France, are to explore the attitudes, knowledge and behaviour of 15-18-year-olds concerning antibiotics and vaccination and their health education needs.Methods: Individual semi-structured interviews were conducted using purposeful sampling of 15- to 18-year-olds, until data saturation, and were transcribed and analysed.Results: The results confirm that teenagers are high antibiotic consumers with poor knowledge. They are interested in their health, but less so in antibiotics and vaccination. Health information is mainly obtained from the Internet, but tends to be criticised. General practitioners play an important role in terms of health information and are also influenced by peers and family. Teenagers believe school should play an important role in health education, which they would prefer to be more interactive: debates, case-stories, sharing experience with peers, parents and health professionals, based on relevant concrete examples, via new technologies.Conclusion: Knowledge gaps revealed among young people during this survey confirm that this age-group should be targeted by a specifically tailored approach. Responders are receptive to information provided by reliable and easily accessible sources. High schools, as well as general practitioners, play an important role in health education in general for this age-group and particularly concerning antibiotics and vaccinations. The Internet is a relevant medium for disseminating information. Teaching should be interactive and take social influences (peers, family) into account. PMID- 28737337 TI - [Salt fluoridation and dental caries: state of the question]. AB - Objective: Dental caries remains a public health problem, particularly among socially deprived populations. In some developing countries, salt fluoridation programmes have been recently developed, but the use of fluoridated salt is limited worldwide and the level of evidence for its efficacy remains debated.Method: A literature review was conducted to identify epidemiological or clinical studies that have evaluated the effect of salt fluoridation on dental caries experiences in children.Results: After a literature search, 22 references were selected reporting data on the preventive effect of salt fluoridation programmes in Europe (Hungary, Switzerland, France, Germany) and South and Central America (Colombia, Mexico, Jamaica...). Data were mainly obtained from descriptive or retrospective epidemiological studies. The results indicate that, in the absence of topical fluoride support, salt fluoridation leads to a significant reduction in caries indexes among treated children compared to a control group. In a context of widespread use of fluoridated toothpastes, the additional effect achieved by salt fluoridation is limited. The prevalence of fluorosis is not markedly increased with fluoridated salt, but side effects were not always evaluated.Conclusion: Today, a salt fluoridation programme could be useful in areas in which fluoridated toothpastes are not widely used. The communication policy promoting the consumption of fluoridated salt is crucial to ensure the effectiveness of such a programme. PMID- 28737336 TI - [Reorientation of health services and health promotion: a review of the situation]. AB - The Ottawa Charter constitutes a major turning point in the world's vision of health, resources and the strategies to be implemented in order to respond to the populations expectations in this field. However, these expectations are no longer limited to the conventional biomedical concept of health, strongly care-oriented and focused on diseases. They currently integrate prevention of diseases and health promotion. Five main strategic actions have been identified to achieve these goals: 1) elaboration of public health policies; 2) creation of supportive environments; 3) strengthening of community actions; 4) development of individual skills; and 5) reorientation of health services. Almost 3 decades after the Ottawa Charter, what is the real orientation of health services in relation to health promotion? To answer this question, we will discuss the results of this approach, while analysing the multiple elements and factors that have contributed to these results, largely considered to have a mixed record in the literature. PMID- 28737338 TI - [Attitudes and practices towards seasonal influenza vaccination amongst French hospital staff]. AB - This survey intends to describe the attitudes towards vaccination amongst the hospital staff in the region of Castres, in the south-west of France, and their influenza vaccination coverage. A questionnaire was attached to all pay slips in March 2014 and 471 questionnaires were completed (return rate: 22.4%). Seasonal influenza vaccination coverage rate was similar to that reported in other French surveys. Paramedical personnel were less commonly immunized against influenza compared to medical personnel and age was the major factor associated with vaccination. Three quarters of the non-immunized hospital personnel did not wish to be vaccinated against influenza. Nearly 50% of respondents believed that healthcare personnel do not have to be role models regarding vaccination. The arguments considered most compelling in favour of vaccination are protection of the family, then patient protection and finally protection of other staff members. A demand for accurate scientific information was expressed by respondents, preferably delivered at their workplace. PMID- 28737339 TI - [Use of mobile applications by interns at Ibn-Rochd University Hospital in Casablanca, Morocco]. AB - Introduction: Mobile applications are now increasingly used by trainee and practising physicians due to the wide range of applications available in the field of healthcare and their ease of use. The objective of this study was to estimate the frequency and describe the use of these applications by interns at Ibn-Rochd University Hospital in Casablanca.Methods: A cross-sectional survey was conducted in December 2014 on a sample of Ibn-Rochd interns. Participants from multiple disciplines and medical specialties completed an anonymous self administered questionnaire.Results: One hundred and thirteen interns participated in the study with a 94.2% response rate: 95% of these interns had a smartphone and 85.2% had at least one healthcare mobile applications with an average of 3.57 applications per interns (SD = 3.14). Interns used these applications at least once a day and the most frequently downloaded applications were those devoted to diagnosis and patient care (61%). No statistically significant correlation was observed between the number of applications and the intern's specialty, the type of operating system used or the intern's gender.Conclusion: The use of healthcare mobile applications and the support they provide to Ibn-Rochd interns allowed an assessment of the importance of these new tools in medical training and practice. However, supervision and support by seniors are essential in view of the risks involved. PMID- 28737340 TI - [Healthcare-associated bacteraemia in intensive care units of Ibn Rochd University Hospital, Casablanca]. AB - Objective: This study was designed to determine the incidence of healthcare associated bacteraemia in intensive care units (ICU) of Ibn Rochd University Hospital, Casablanca, Morocco, the frequency of the bacterial strains isolated and their antibiotic resistance patterns.Methods: A prospective longitudinal study was conducted between May and July 2015 on patients admitted to the Ibn Rochd University Hospital ICU. The Comite technique des infections nosocomiales et des infections liees aux soins (CITNILS) definition of bacteraemia was used. Micro-organisms were isolated and identified according to standard bacteriology techniques. Antibiotic susceptibility testing was performed according to CLSI 2013 guidelines.Results: A total of 720 patients were hospitalised during the study period; 48 (6.7%) acquired healthcare-associated bacteraemia with an incidence ranging from 7.3/1,000 HD to 13.7/1,000 HD. Fifty-four bacteria were isolated: A. baumannii and K. pneumoniae each accounted for 18.5% of isolates. 66.7% of A. baumannii strains were resistant to imipenem and 20% of K. pneumoniae strains were ESBL+Conclusion: Healthcare-associated bacteraemia raises treatment problems due to multidrug-resistant bacteria, which is why regular surveillance is necessary to evaluate the time-course of these strains and the efficacy of prevention measures. PMID- 28737341 TI - [Regional differences in hospitalisations for complications of chronic hepatitis C in 2012]. AB - Objective: Only limited recent information is available concerning the regional incidence and prevalence of chronic hepatitis C (CHC), but this information is critical for optimal definition of public health policies for the management of hepatitis C. The objective of this study was to evaluate the feasibility of mapping potential regional differences in the prevalence of CHC and its complications using data from a health administrative database.Methods: The 2012 PMSI MCO hospital database contains information on diagnosis and healthcare resource use, essentially related to all hospitalisations in France. Hospital stays related to CHC were identified on the basis of ICD-10 disease codes. Hospital stays were classified according to stage of liver disease: non-cirrhotic liver disease, compensated cirrhosis, decompensated cirrhosis or hepatocellular carcinoma (HCC). All study variables were documented for each French administrative region in 2012.Results: In 2012, 12,040 patients were hospitalised in France for a reason related to CHC, corresponding to a standardised age- and gender- adjusted prevalence rate of 19.3/100,000 persons. The highest prevalences of CHC and HCC were observed in the Ile de France, Alsace and Provence-Alpes-Cote d'Azur regions.Conclusions: This study demonstrates the feasibility of using the PMSI database to identify regional differences in the prevalence of CHC. This information may be useful for planning regional healthcare resource provision for CHC. PMID- 28737342 TI - [Self-monitoring of blood glucose in France: data from a national survey]. AB - Objectives: To describe Self-Monitoring of Blood Glucose (SMBG) practices in France in patients with type 1 (T1DM) or type 2 (T2DM) diabetes, by estimating the proportion of patients performing SMBG at the recommended testing frequency and the proportion of patients complying with the current quality control guidelines on SMBG.Materials and methods: National cross-sectional study conducted in 238 pharmacies. A questionnaire was completed with adult diabetic patients buying SMBG devices or reagent strips for themselves, using a blood glucose meter for at least 6 months, treated with insulin or sulfonylurea/glinides +/- other oral hypoglycaemic agents (HA).Results: Data from 449 patients were analysed: 85 T1DM and 121 T2DM patients treated by multiple basal-bolus injections +/- HA (Group A and Group B), 123 T2DM patients treated by basal insulin +/- HA (Group C), 102 patients treated by other insulin regimens +/ HA (Group D) and 120 T2DM patients treated by sulfonylurea / glinides without insulin +/- other HA (Group E). The recommended test frequency was observed by 29.8%, 36.4%, 61.8% and 69.2% of patients in Group A, Group B, Group C, and Group E, respectively. The quality of self-monitoring was insufficient in terms of device cleaning, storage conditions/expiry date of reagent strips, or use of control solutions. Patients displayed a limited capacity to take decisions in relation to their SMBG results (Group A: 56.5%, Group B: 70.2%, Group C: 49.2%, Group E: 36.0%) and limited knowledge about their glucose targets (Group A: 81%, Group B: 80.5%, Group C: 68.6%, Group E: 73.7%).Conclusion: SMBG use and compliance with quality guidelines must be improved, but healthcare professionals and patients must also focus their efforts on education to interpret SMBG results. PMID- 28737343 TI - [Advanced practice nursing implementation strategies in hospital: a review of the literature]. AB - Objective: To analyse the factors of success and the obstacles to implementation of advanced practice nursing in the French health system.Methods: Review of the international literature concerning implementation of advanced practice nursing published between 2010 and 2016.Results: Of the 503 articles reviewed, 14 were included in this analysis, which showed that obstacles to implementation can be potentially transformed into advantages. Only one guideline was identified, the PEPPA (Participatory, Evidence-based, Patient-focused process for Advanced Practice Nursing (APN) role development). Four factors of successful implementation and evaluation of advanced practice nursing were identified: involvement of medical and paramedical personnel, supervisor and material support from administrative authorities, implementation of policies and regulation mechanisms and postgraduate university training.Conclusion: Implementation of advanced practice nursing in France should take into account the PEPPA guidelines used in Canada, in order to promote the success of these new roles in clinical practice. PMID- 28737344 TI - [Prevalence and associated factors of alcohol consumption among students of the Sousse region of Tunisia]. AB - Aim: This study was designed to assess the prevalence of alcohol consumption and factors associated with alcohol consumption among students of the Sousse region of Tunisia.Methods: This was a cross-sectional study conducted among 556 students of Sousse universities during the 2012-2013 academic year, using an anonymous self-report questionnaire. Data capture and statistical analysis were performed with SPSS software 18.0.Results: Our study population was composed of 268 males (48.2%) with a mean age of 21.8 +/- 2.1 years. Eighty-four students (15.1%) had consumed alcohol at least once. On multivariate analysis, male gender (OR = 6.94; 95%CI = [2.32-20.72]), smoking (OR = 13.21; 95%CI = [6.20-27.78]), drug use (OR = 32.22; 95%CI = [6.73-154.26]) and parental alcohol consumption (OR = 4.31; 95%CI = [1.70-10.91]) were the factors significantly associated with alcohol consumption among students.Conclusion: This study was designed to determine the characteristics of alcohol consumption among Tunisian students. Alcohol consumption levels were comparable to those reported in the general population and were significantly related to smoking and drug use.The next step of this study will consist of developing strategies to prevent risk behaviours in the student population. PMID- 28737345 TI - [High school student and skin bleaching in Cameroon]. AB - Introduction: Skin bleaching is a common practice in Africa, particularly in Cameroon. Studies show that it represents a danger for health, in terms of a demonstrated increased risk of dermatological diseases. However, increasing numbers of people are using skin bleaching in African cities, despite the fact that they are sometimes aware of the risk. This study proposed to transform the knowledge and perceptions of skin bleaching practices into educational strategies that can be used both by health professionals and educators. These strategies can also be used as preventive measures against skin bleaching among young schoolgirls.Methods: Data collection was based on a qualitative approach, in the form of a focus group discussion attended by 40 girls aged between 14 and 20 years, selected by convenient random sampling.Results: The results indicated that girls have an approximate knowledge about the consequences of skin bleaching on their health. On the contrary, they have a good knowledge about prevention, which can be used to develop a prevention strategy in order to reduce or eradicate skin bleaching, by educational awareness campaignsConclusion: These elements can be used as a basis for better prevention and health promotion in schools; so that students adopt healthy behaviours and to prevent those students at risk. PMID- 28737346 TI - [Economic hardship and fallout on households of the management of hydrocephalus in Benin]. AB - Objectives: The socioeconomic profile of households and families of children attending hospital for hydrocephalus were documented and analysed. Main costs related to diagnosis and care were reviewed. The emotional fallout and social well-being of families were also analysed.Methods: This retrospective cross sectional study (January 2006 to January 2015) was based on costs borne by households and families for neurosurgical care of children with hydrocephalus.Results: Sixty children (1 day to 12 years old) had been hospitalized for hydrocephalus in Cotonou-Benin. In 19 cases, the families were single-parent families.In 44 cases, the parents were self-employed workers or private company employees. Public servants, eligible for national health system assistance, accounted for a mere 16 cases. Twenty six children did not receive any financial support, whereas the total average care-related out-of-pocket expenditure for families during the hospital stay was approximately ?1,777 (1,117,500 FCFA), i.e. almost 14 times the average monthly income reported by the parents (82,600 FCFA - approximately ?120). After hospitalization, 31 mothers had lost their jobs and 21 couples experienced marital issues and their plans to have children. Twelve recent separations were recorded, as well as one indirect maternal death related to depression.Conclusion: In Benin Republic, surgical care for paediatric hydrocephalus represents catastrophic out-of-pocket expenditures for households and families and other living expenses. Families experience significant emotional fallout with effects on couple relationships and survival. PMID- 28737347 TI - [The fight against HIV/AIDS as a model of disease management in Sub-Saharan Africa?] AB - The inefficacy of health systems in Sub-Saharan Africa has now been clearly established. Analysis of the relative success of the management of HIV/AIDS can constitute an example of efficacy that could be extended to other fields. Based on a social and community approach, the example of HIV/AIDS can be used as a model of disease management, as it is distinguished by a fairly extensive management dimension, especially integrating socio-economic support. It is also characterized by the large place attributed to the patient and the family, and the community, as the main stakeholders. Without claiming to propose a miracle solution, this model, based on local sociocultural values and realities, constitutes a promising approach to health promotion in Sub-Saharan Africa. PMID- 28737349 TI - ? PMID- 28737348 TI - [Handling of cytostatics in oncology wards of an Algerian university hospital]. AB - Introduction: A study was conducted in the oncology wards of an Algerian university hospital in order to analyse cytostatic handling conditions.Materials and methods: Working conditions were evaluated in 2014 and then re-evaluated after opening of the cancer centre in 2015, using validated tools: professional questionnaire, ward monograph support and oncology ward audit support.The results were compared to clinical practice guidelines and oncology wards were classified according to the percentage compliance: non-compliance (< 69%), partial compliance (70-79%), substantial compliance (80-94%) and high compliance (95 100%). Exposure was evaluated by calculating the Cytotoxic Contact Index (CCI).Results: Oncology wards are situated in three hospitals. Reconstitution is performed in nonspecific treatment rooms with no collective protection measures. 62% of oncology units (oncology, gynaecology and haematology wards) were classified as level 2 and 3 exposure, requiring collective prevention measures.The level of compliance was very low (28%). All wards were classified as non-compliant for all items. Compliance essentially concerned training, quality control and hygiene measures. An improvement of cytostatic handling conditions was observed in 2015, concerning personnel training, recruitment of clinical pathologists and pharmacists, floorspace and hygiene of premises, storage of cytostatic agents and individual and collective protection equipment.Conclusion: In the light of this study, it appears relevant to improve cytostatic handling conditions by setting up a medical and environmental surveillance programme with the participation of all prevention personnel. PMID- 28737350 TI - ? PMID- 28737351 TI - ? PMID- 28737352 TI - [The role of a new syringe filter in harm reduction: the views of active injection drug users]. AB - Reducing the risks associated with drug injection is a core component of the Drug Harm Reduction Policy. In France, this strategy was implemented in the context of the AIDS epidemic in the 1980s. Unless appropriate hygienic precautions are taken, injecting drugs may cause infectious, bacterial or fungal diseases. French Health authorities promote the use of effective tools to help reduce the harm associated with drug injection. In this context, public authorities supported the evaluation of new drug injection paraphernalia. Two qualitative studies were carried out among injection drug users in order to assess the acceptability of new tools disseminated on an experimental basis. The main objective of the evaluation was to identify the criteria governing the adoption or rejection of injection paraphernalia. This paper focuses on the acceptability of a specific syringe filter which is a decisive tool to reduce the harm associated with drug injection. The results show that drug users accept or refuse to change their injecting behaviour depending on specific criteria not entirely associated with public health concerns. The information from these studies suggests that strategies designed to reduce the harm associated with drug injection must be based on these individual criteria and should provide personalized and long lasting assistance. PMID- 28737353 TI - [Neonaticides in France: analysis of 357 cases identified in the press (1993 2012)]. AB - Background and objectives: Despite easy access to contraception and child abandonment in France, neonaticides continue to occur and, although rare, are widely publicized. The objective of this study was to characterize neonaticides and their perpetrators over a twenty-year period in France based on cases reported in the press.Methods: 2,319 press articles describing the discovery of a newborn corpse in the regional and national press were extracted from electronic databases or other digital supports. A total of 357 neonaticides were described, corresponding to a mean annual rate of 2.34 per 100,000 births.Results: The mother was identified in 74% of cases. The corpse was usually discovered in the house or garden (35%, mostly in the rubbish bin and 6% in the freezer), but also in the wilds (31%). In almost one-quarter of cases, the mother had suffered a haemorrhage. Most neonates were killed by asphyxiation (35%), direct blows or being thrown out of a window (11%), or drowning (11%). Only 22% of neonates died without the mother's intervention, due to lack of care or neglect. Marked regional disparities were observed, even after calculation of regional rates. The mothers responsible (230 women due to 19 multiple neonaticides) had a mean age of 27.8 years and half of them had at least one other living child.Conclusions: Media coverage of neonaticides and access to electronic databases provide an opportunity to describe a rare phenomenon, for which it is difficult to collect sufficient sample sizes to allow analysis of the perpetrators and court rulings. PMID- 28737354 TI - [Do electronic cigarettes increase the risk of smoking among adolescents and young adults?] AB - Introduction: Electronic cigarette use is significantly higher among 15-24-year olds than in other age-groups. Electronic cigarettes, which may contain nicotine, could be a gateway to smoking initiation among young people. In this article, we reviewed the literature on smoking initiation or smoking enhancement by the use of e-cigarettes.Methods: We carried out a qualitative analysis in January 2016. We selected all longitudinal studies among adolescents or young adults using electronic cigarettes.Results: The analysis focused on 5 of the 544 articles identified, corresponding to five prospective observational studies. Four studies concluded that e-cigarette use was statistically associated with a high risk of smoking initiation. Young vapers were 8.3 (95% CI = 1.-58.6) to 12.7 (95% CI = 4.0-40.3) times more likely to initiate smoking at 1 year than non-vapers. Previous exposure to electronic cigarettes increased the risk of smoking conventional cigarettes by 14-year-old adolescents by 75% at 1 year follow up.Conclusion: Trying e-cigarettes during adolescence or young adulthood may have contributed to starting and continuation of smoking. However, these results must be interpreted cautiously due to methodological weaknesses. PMID- 28737355 TI - [The silent disappearance of PADHUE doctors: the end of a State injustice or a new form of exclusion?] AB - Up until recently in France, physicians who obtained their degrees outside the European Union had a specifically disadvantaged status, that was supposed to be eliminated by the end of 2016. Until that date, a selective qualification process authorized foreign physicians to "full practice". The deadline has been postponed to 2017 to resolve the complicated situations of certain doctors and to avoid tensions in hospital wards. These developments raise questions about the working conditions and motivations for migration of foreign medical doctors, particularly African doctors, who participate in the French healthcare system, and the obstacles to their integration. Does the disappearance of unequal working conditions constitute progress, or does suspension of access to full practice for PADHUE doctors from 2018 constitute a step backwards? Recent social science analyses, particularly on the motivations of African doctors for migration, show complex stakes. In a protectionist French healthcare system willing to maintain health coverage, out of phase with globalization that promotes transnational mobility, the closure of borders for medical doctors who obtained their degrees outside of Europe, that replaces inequality by exclusion, constitutes a subject of debate. PMID- 28737356 TI - [The Hospital, patients, health and territories Act and the recentralisation of the social and long term care sector]. AB - Hypothesis: The 2009 Hospital, Patients, Health and Territories Act crystallises a central government attempt to regain control over the social and long term care sector, which involves the utilisation of policy instruments borrowed from the hospital sector: capped budgets, agreements on targets and resources, competitive tendering or quasi-market mechanisms involving hospitals and services, etc. This paper is therefore based on the hypothesis of a recentralisation and healthicization of the social and long term care sector, with a key role for the regional health authorities.Method and data: 27 semi-structured interviews were conducted with actors operating within and outside the regional health agencies and thereafter analysed using Alceste. The aim was to describe and to analyse the positioning of the RHAs in relation to key actors of the social and long-term care sector in 2 regions in 2011.Results: Key issues for public organisations include the style of planning and knowhow transfer, while the professionals were chiefly concerned with the intensity of the ambulatory turn and needs analysis methodology. The compromises forged were related to types of democratic legitimacy, namely representative or participatory democracy.Conclusion: There is little evidence to support the initial hypothesis, namely the existence of a link between the creation of RHAs and a recentralisation of health policy between 2009 and 2013. One may rather suggest that a reconfiguration of the activities and resources of the actors operating at the centre (RHAs and conseils departementaux) and at the periphery (territorial units of the RHAs and third sector umbrella organisations) has occurred. PMID- 28737357 TI - [Health care access of Sub-Saharan African migrants living with chronic hepatitis B]. AB - Objective: The objective of this study was to analyse health care access of Sub Saharan African migrants living with chronic hepatitis B (CHB) in France.Methods: The ANRS-Parcours survey was a life-event survey conducted in 2012-2013 among Sub Saharan African migrants recruited by health care facilities managing CHB in the Paris region. Data were collected by face-to-face interview using a biographical grid and a standardized questionnaire.Results: 96.4% of the 619 participants basic health insurance coverage with CMU universal health insurance coverage in 18.6% of cases and AME state medical assistance in 23.4% of cases. One-third of basic health insurance beneficiaries did not have any complementary health insurance and 75.7% had long-term disease status. The median time to acquisition of health insurance cover after arrival in France was one year. 22.0% of participants reported delaying health care for financial reasons since their arrival in France and 9.7% reported being refused health care usually due to refusal of CMU or AME. Health care access was effective within one year of the diagnosis. Delayed health care access was more common among people without health insurance coverage in the year of diagnosis. Patients lost to follow-up for more than 12 months were rare.Conclusion: Sub-Saharan African migrants living with chronic hepatitis B rapidly access health insurance coverage and health care. However, barriers to health care access persist for some people, essentially due to absent or incomplete health insurance cover and refusal of care for AME or CMU beneficiaries. PMID- 28737358 TI - [Optimization of the HIS process mapping of the Military Instruction Hospital Mohammed V]. AB - Introduction: Development of process mapping is not easy, as, apart from identification of the key processes of the organization, mapping can hardly describe all of the interactions involved without becoming incomprehensible. In this context, the Rabat Military Hospital decided to review its process mapping to align it with the reference mapping proposed by the National Agency for Performance Support, which is designed to standardize and improve functional mapping of healthcare production systems.Methods: To assist the Military Hospital in this convergence process, this paper proposes the application of a convergence method on the current hospital process mapping, in order to guide hospital agents in the development of optimal process mapping, complying with guidelines for urbanization of information systems while remaining consistent with strategic guidelines.Results and discussion: The results obtained from application of this method to the initial hospital process mapping indicate a positive functional and organizational impact, particularly on optimization of the flow between processes. PMID- 28737359 TI - [Public spending on health and population health in Algeria: an econometric analysis]. AB - Objective: The objective of this study was to estimate the impact of public spending on health, among other determinants of health, on the health of the population in Algeria, using life expectancy (men and women) and infant mortality rates as indicators of health status.Methods: We conducted a longitudinal study over the period from 1974 to 2010 using the ARDL (Autoregressive Distributed Lags) approach to co-integration to estimate the short-term and long-term relationship.Results: Public spending on health has a positive, but not statistically significant impact, in the long and short term, on life expectancy (men and women). However, public spending significantly reduces the infant mortality rate. The long-term impact of the number of hospital beds is significant for the life expectancy of men, but not for women and infant mortality, but is significant for all indicators in the short-term relationship. The most important variables in improving the health of the population are real GDP per capita and fertility rate. PMID- 28737360 TI - [Capacity of response of the health system to the expectations of populations in zones exposed to results-based financing in Benin in 2015]. AB - Introduction: The increased use of results-based financing (RBF) services was the basis for this study designed to evaluate the contribution of RBF to the capacity of response of the health system to the population's expectations.Methods: This study, conducted in six Benin health zones randomly selected in two strata exposed to RBF (FBR_PRPSS and FBR_PASS) and one zone not exposed to RBF (Non_FBR), examined the seven dimensions of reactivity. A score, followed by weighting of their attributes, was used to calculate the index of reactivity (IR).Results: Sixty-seven health care units and 653 people were observed and interviewed. The FBR_PRPSS and FBR_PASS strata, managed by the new provisions of RBF, displayed good performances for the "rapidity of management" (70% and 80%) and "quality of the health care environment" dimensions, with a more marked improvement for the PRPSS model, which provides greater resources. Poor access to social welfare networks in the three strata led to renouncing of health care. The capacity of response to expectations was moderate and similar in the Non_FBR (IR = 0.53), FBR_PASS (IR = 0.62) and FBR_PRPSS (IR = 0.61) strata (p > 0.05).Conclusion: The FBR_PRPSS and FBR_PASS models have a non-significant effect on the capacity of response. Their success probably depends on the health system context, the combination of targeted interventions, such as universal health insurance, but also the importance and the use of the new resources that they provide. PMID- 28737361 TI - [Sex education in Tunisia: students' expectations and teachers' conceptions]. AB - Health education, as defined by the World Health Organization (WHO 1983), includes sex education. In Tunisia, there is a growing interest in sexuality issues, in contrast with the reigning conservative culture, challenging the taboos and restrictions imposed by religion. A global sex education strategy is therefore required in Tunisian in schools to help students understand their body and its biological functions, construct a real sexual identity and adopt behaviours that promote a healthy and low-risk lifestyle.In this study, we wonder whether the objectives defined by official programmes and conveyed by biology teachers are consistent with the expectations of their students in terms of sex education. This questionnaire-based survey, conducted among 95 biology teachers and 735 students, with an average age of 18 years, shows to what extent the objectives of biology teachers differ from the expectations of students, illustrating to what extent sex education needs to be adapted. PMID- 28737362 TI - [Ethnography of the determinants of eating behaviour in diabetic schooolchildren in Yaounde]. AB - Objective: Failure to comply with dietary recommendations exposes young insulin dependent diabetics to a risk of acute complications of diabetes and is a subject of major concern for health care professionals, who expected young diabetics to effectively adopt the recommended eating behaviour based on the revised diet. However, the revised diet initiated by health care professionals in Cameroon has been shown to have a limited efficacy. The objective of this study was to elucidate the motivations underlying poor compliance young diabetics with dietary recommendations and which simultaneously determine their eating behaviour.Methods: The study was conducted in Yaounde and was based on observations and biographical interviews with 13 students between the ages of 15 and 20 years with a diagnosis of diabetes for at least 6 months. Data were analysed by content analysis.Results: The results revealed negative perceptions of diabetes and treatment, encouraging young diabetics not to comply with the recommended eating and an influence of their social environment, i.e. school characteristics, peers and family, on their eating behaviour.Conclusion: The eating behaviour of young diabetics is determined equally by individual motivations related to their perceptions and social motivations. These motivations must be taken into account by health care professionals to promote better adherence of patients to dietary recommendations. PMID- 28737363 TI - [Dietary habits among type 2 diabetic patients attending the Abidjan Diabetes Centre]. AB - Objectives: The prevalence of diabetes is rapidly increasing in sub-Saharan Africa. Healthy lifestyle and dietary conditions play a key role in the control of blood sugar imbalance and cardiovascular complications of diabetes. This study was designed to describe the profile and dietary habits of type 2 diabetic patients attending the Abidjan Diabetes Centre (CADA), and to identify related factors.Methods: This cross-sectional, descriptive and analytic study was conducted in 2014 at the CADA. A total of 384 patients were included.Results: Patients had a mean age of 56.2 (SD: 11.7) years and had been living with diabetes for a mean duration of 8.6 years. Main comorbidities associated with diabetes were overweight (56.8%) and high blood pressure (45.3%). More than one half of patients (60.7%) did not have a good knowledge of the recommended diet for diabetics: 88.5% did not have regular meal times, 11.7% reported snacking and 61.5% had their meals outside of the home. In addition, 60.4% stated that, during the week preceding the survey, they had eaten at least one "not recommended" food, most commonly fatty meals and fried food (31.5%).Patients who did not know that eating fatty meals and fried food was not recommended for diabetics were 3 times more likely to each this type of food (p < 0.001).Conclusion: Strengthening nutritional support by therapeutic education sessions is a key strategy that should be implemented to improve dietary habits among type 2 diabetic patients in Ivory Coast. PMID- 28737364 TI - ? PMID- 28737366 TI - Metastatic grade III oligodendroglioma revealed by refractory thrombocytopenia. PMID- 28737365 TI - VIM thalamotomy in the treatment of Holmes' tremor secondary to HIV-associated midbrain lesion: a case report. AB - Holmes' tremor (rubral tremor, cerebellar outflow tremor) is characterized by rest, intention and postural tremor, often localized to one upper extremity, associated with ipsilateral dysmetria and dysdiadochokinesia. We describe a case of successful treatment of Holmes' tremor with unilateral nucleus ventralis intermedius (VIM) thalamotomy. The subject is a 43-year-old woman with unremarkable previous medical history. She presented with complete left hemiparesis in the context of human immunodeficiency syndrome and the magnetic resonance image disclosed a contrast-enhancing lesion in right brain peduncle, in topography of red nucleus. She developed a progressive rest, intention and postural tremor in left upper limb. She was submitted to a stereotactic biopsy and the tremor became worse. She performed awake right VIM thalamotomy, with immediate complete resolution of tremor. There were no complications after procedure, and the result is stable after six months. We highlight the role of thalamotomy in cases like ours, once patient recovered well and, due to HIV, will need further neuroimage studies to evaluate neurologic complications of HIV. Deep brain stimulation in such cases may interfere with coming neuroimage quality and may act like a foreign body. PMID- 28737367 TI - A rare case of a lipoma of the cranio-cervical junction in a middle-aged patient. PMID- 28737368 TI - Spindle cell oncocytoma of the pituitary gland. PMID- 28737369 TI - The mechanism behind rarely-encountered subdural hygroma formation following foramen magnum decompression. PMID- 28737370 TI - Spinal myxopapillary ependymoma presenting with low back pain and subarachnoid hemorrhage. PMID- 28737371 TI - A modified impact factor. PMID- 28737372 TI - Facile Synthesis of Different Morphologies of Cu2SnS3 for High-Performance Supercapacitors. AB - Cu2SnS3 is considered as an emerging potential candidate for electrode materials due to considerable interlayer spaces and tunnels in its crystal structures and excellent conducting ability. Ternary Cu2SnS3 as anode in lithium ion batteries has already been reported, but it is rarely mentioned to be applied in supercapacitors which is considered to be a complementary energy storage device for lithium ion batteries. It is an effective method to improve the electrochemical performance of materials by adjusting the morphology and microstructure of materials. In present study, ternary nanosheet-assembled Cu2SnS3 microspheres (M-CTS) and nanoparticles-like Cu2SnS3 (N-CTS) are synthesized via a facile solvothermal route. The results suggest that Cu2SnS3 microspheres (M-CTS) exhibit better capacitive performance compared with Cu2SnS3 (N-CTS) nanoparticles, which means that morphology does have a significant effect on the electrochemical reaction. M-CTS presents excellent supercapacitor performances with the high specific capacity of about 406 C g-1 at a current density of 1 A g-1 and achieves a high energy density of 85.6 W h kg-1 and power density of 720 W kg-1. The remarkable electrochemical performance of Cu2SnS3 can be attributed to the large specific surface area, smaller average pore size, and improved electrical conductivity. Our research indicates that it is very suitable for large-scale production and has enormous potential in the practical application of high-performance supercapacitors. PMID- 28737374 TI - Integrated SERS-Based Microdroplet Platform for the Automated Immunoassay of F1 Antigens in Yersinia pestis. AB - The development of surface-enhanced Raman scattering (SERS)-based microfluidic platforms has attracted significant recent attention in the biological sciences. SERS is a highly sensitive detection modality, with microfluidic platforms providing many advantages over microscale methods, including high analytical throughput, facile automation, and reduced sample requirements. Accordingly, the integration of SERS with microfluidic platforms offers significant utility in chemical and biological experimentation. Herein, we report a fully integrated SERS-based microdroplet platform for the automatic immunoassay of specific antigen fraction 1 (F1) in Yersinia pestis. Specifically, highly efficient and rapid immunoreactions are achieved through sequential droplet generation, transport, and merging, while wash-free immunodetection is realized through droplet-splitting. Such integration affords a novel multifunctional platform capable of performing complex multistep immunoassays in nL-volume droplets. The limit of detection of the F1 antigen for Yersinia pestis using the integrated SERS-based microdroplet platform is 59.6 pg/mL, a value approximately 2 orders of magnitude more sensitive than conventional enzyme-linked immunosorbent assays. This assay system has additional advantages including reduced sample consumption (less than 100 MUL), rapid assay times (less than 10 min), and fully automated fluid control. We anticipate that this integrated SERS-based microdroplet device will provide new insights in the development of facile assay platforms for various hazardous materials. PMID- 28737373 TI - Construction of a Multi-Cage-Based MOF with a Unique Network for Efficient CO2 Capture. AB - As a kind of MOFs, cage-based MOFs usually carry large voids and small windows, which are advantageous to the storage of small molecules that remain kinetically trapped inside the cages (confinement effect). By adjusting the size of windows via reticular synthesis, the cage-based MOFs can selectively capture and separate the suitable size molecules. Here, considering angle-directed and face-directed strategies, a novel multicage-based MOF NUM-3 with a new (3,4,5)-connected topology was successfully constructed in the mixed-ligands assembly. In the framework of NUM-3, there exist four different kinds of cages, which exhibit diverse polyhedral configurations. The four kinds of cages in the order ABCDDCBA as the minimum repeat unit form a 1D tortuous channel along the c axis. Based on the structure characteristics that the 1D channel exhibits different inner diameter (from 4.0 to13.0 A), NUM-3a (actived NUM-3) can capture CO2 over C2H4 and C2H6 by the size selectivity (the empirical kinetic diameters: CO2 < C2H4 < C2H6). In addition, it also exhibits commendable selectivity for CO2 over N2 and CH4. PMID- 28737375 TI - Matrix-Assisted Three-Dimensional Printing of Cellulose Nanofibers for Paper Microfluidics. AB - A cellulose nanofiber (CNF), one of the most attractive green bioresources, was adopted for construction of microfluidic devices using matrix-assisted three dimensional (3D) printing. CNF hydrogels can support structures printed using CAD design in a 3D hydrogel environment with the appropriate combination of rheological properties between the CNF hydrogel and ink materials. Amazingly, the structure printed freely in the bulky CNF hydrogels was able to retain its highly resolved 3D features in an ultrathin two-dimensional (2D) paper using a simple drying process. The dimensional change in the CNF hydrogels from 3D to 2D resulted from simple dehydration of the CNFs and provided transparent, stackable paper-based 3D channel devices. As a proof of principle, the rheological properties of the CNF hydrogels, the 3D structure of the ink, the formation of channels by evacuation of the ink, and the highly localized selectivity of the devices are described. PMID- 28737376 TI - Insight into c-di-GMP Regulation in Anammox Aggregation in Response to Alternating Feed Loadings. AB - Substrate concentrations generally fluctuate in wastewaters. However, how anammox biomass behaves to overcome the stress of alternating feed loadings remains unclear. Here, we combined long-term reactor operation, batch tests, 16S rRNA transcript sequencing, and metabolomics analysis to investigate the aggregation of anammox biomass under the regulation of c-di-GMP, a key second messenger, in response to alternating feed loadings. We demonstrated that the aggregation process was significantly faster under alternating loadings and was significantly correlated with higher levels of c-di-GMP and extracellular polymeric substances (EPS) production. The increase in c-di-GMP was positively correlated with a higher relative transcript expression level in the c-di-GMP pathway-dependent community. The targeted metabolomics results indicated that the increased production of fructose 6-phosphate and UDP-N-acetyl-d-glucosamine, the precursor substances for the synthesis of exopolysaccharides, was induced by higher levels of c-di-GMP. Consequently, the granulation process was accelerated via EPS production. Higher levels of intracellular hydrophobic amino acids were also positively correlated with increased extracellular protein levels, considering the significant increase in peptides under alternating loadings. On the basis of our findings, we believe that c-di-GMP regulation and EPS production of the anammox biomass are important mechanisms to enhance its tolerance against unfavorable feed stress. These results highlight the role of c-di-GMP in anammox biomass as it works to survive in unfavorable niches. PMID- 28737377 TI - Carbon Dot Based, Naphthalimide Coupled FRET Pair for Highly Selective Ratiometric Detection of Thioredoxin Reductase and Cancer Screening. AB - The fluorescence resonance energy transfer (FRET) mechanism has been established between carbon dots (CDs) and naphthalimide to monitor the activity of thioredoxin reductase (TrxR), which is often overexpressed in many cancer cells. The naphthalimide moiety was covalently attached to the surface of CDs through a disulfide linkage. In normal cell conditions (when devoid of high concentrations of TrxR), the CDs act as an energy donor and naphthalimide acts as an acceptor, which establishes the FRET pair as interpreted from the emission at lambdaem = 565 nm, when excited at lambdaex = 360 nm. However, contrary to this, the elevated levels of TrxR cause the breakage of disulfide bonds and consequently abolishes the FRET pair through the release of the naphthalimide moiety from the surface of CDs. This process was studied by monitoring of fluorescence intensity at lambdaem = 565 and 440 nm, when excited at the same wavelength (lambdaex = 360 nm). The TrxR based ratiometric quenching and enhancement of fluorescence intensity offers an interesting opportunity to monitor the enzyme activities and has many advantages over conventional monitoring of fluorescence intensity at a single wavelength to avoid interference of external factors. Fluorescence images of cancer cells in response to the nanosensor were visualized under a confocal microscope. Cytotoxicity study of nanosensor retards the growth of HeLa and MCF-7 cell lines in the presence of visible light. Therefore, the nanosensor also acts as a theranostic agent to diagnose as well as killing of cancer cells. PMID- 28737378 TI - Quantitative Mid-Infrared Cavity Ringdown Detection of Methyl Iodide for Monitoring Applications. AB - Methyl iodide is a toxic halocarbon with diverse industrial and agricultural applications, and it is an important ocean-derived trace gas that contributes to the iodine burden of the atmosphere. Quantitative analysis of CH3I is mostly based on gas chromatography coupled with mass spectrometry or electron capture detection (GC-MS/ECD) as of yet, which often limits the ability to conduct in situ high-frequency monitoring studies. This work presents an alternative detection scheme based on mid-infrared continuous wave cavity ringdown spectroscopy (mid-IR cw-CRDS). CH3I was detected at the RR2(15) rovibrational absorption transition at v = 3090.4289 cm-1; part of the corresponding v4 vibration band has been measured with Doppler-limited resolution for the first time. A line strength of S(T = 295 K) = (545 +/- 20) cm/mol, corresponding to a line center absorption cross-section sigmac(p = 0 bar) = (1.60 +/- 0.06) * 105 cm2/mol, and pressure-broadening coefficients gammap(Ar) = (0.094 +/- 0.002) cm 1/bar and gammap(N2) = (0.112 +/- 0.003) cm-1/bar have been determined. The performance of the detection system has been demonstrated with a tank-purging experiment and has been directly compared with a conventional GC-MS/ECD detection system. Quantitative detection with high reproducibility and continuous sampling is possible with a current noise-equivalent limit of detection of 15 ppb at 20 mbar absorption-cell pressure and 70 s averaging time. This limit of detection is suitable for practical applications in the ppm mixing ratio level range such as workplace monitoring, leak detection, and process studies. Natural environmental abundances are much lower, therefore possibilities for future improvement of the detection limit are discussed. PMID- 28737379 TI - An Enzyme-Free DNA Circuit-Assisted Graphene Oxide Enhanced Fluorescence Anisotropy Assay for MicroRNA Detection with Improved Sensitivity and Selectivity. AB - Graphene oxide (GO) has been proven as an outstanding fluorescence anisotropy (FA) amplifier. Yet the traditional GO amplified FA assays lack high sensitivity because of the 1:1 binding ratio between target and dye-modified probe. Herein, we report a new target-catalyzed hairpin assembly (CHA), an enzyme-free DNA circuit, assisted GO amplified FA strategy for microRNA-21 (miRNA-21) detection. In the presence of miRNA-21, the CHA was initiated and plenty of H1-H2 duplexes were produced continuously. The obtained H1-H2 duplex could induce the formation of a H1-H2-probe DNA (pDNA) complex by the toehold-mediated strand exchange reaction, which led the dye-modified pDNA to leave away from the GO surface, resulting in a decreased FA of the system. By monitoring the decrease of FA, miRNA-21 could be detected in the range of 0-16 nM. The limit of detection (LOD, 3sigma) was 47 pM, which was 194 times lower than that without CHA. In addition, the selectivity of this method has also been enhanced greatly as compared to that without CHA. Our method has great potential to be applied for detecting different types of targets and monitoring diverse molecular interactions by adapting the corresponding nucleotide sequence. PMID- 28737380 TI - Thermal Expansion Behavior in TcO2. Toward Breaking the Tc-Tc Bond. AB - The structure of TcO2 between 25 and 1000 degrees C has been determined in situ using X-ray powder diffraction methods and is found to remain monoclinic in space group P21/c. Thermal expansion in TcO2 is highly anisotropic, with negative thermal expansion of the b axis observed above 700 degrees C. This is the result of an anomalous expansion along the a axis that is a consequence of weakening of the Tc-Tc bonds. PMID- 28737381 TI - Cisplatin Binding Sites in Human H-Chain Ferritin. AB - The aim of this work is to identify the cisplatin binding sites on human H-chain ferritin. High-resolution X-ray crystallography reveals that cisplatin binds four distinct protein sites, that is, the side chains of His136 and Lys68, the side chain of His105, the side chain of Cys90 and the side chain of Cys102. These Pt binding sites are compared with those observed for the adduct that cisplatin forms upon encapsulation within horse spleen L-chain ferritin (87% identity with human L-chain ferritin). PMID- 28737382 TI - Solid-State Plasmonic Solar Cells. AB - Metallic nanoparticles such as silver and gold show localized surface plasmon resonances (LSPRs), which are associated with near-field enhancement effects in the vicinity of nanoparticles. Therefore, strong light-matter interaction is induced by the near-field enhancement effects of LSPRs. Because the resonant wavelength of LSPRs can be easily controlled by the size and shape of the metallic nanoparticles in the visible and near-infrared wavelength range, LSPRs have received considerable attention as optical antennae for light energy conversion systems such as solar cells. LSPRs decay very quickly as a result of light scattering and excitation of electron-hole pairs in the metal itself. However, in addition to the near-field enhancement effect, this light scattering and electron-hole pair excitation, which are known to cause loss of LSPRs, can be utilized as a solar cell enhancement mechanism. Here, we focus on plasmonic solid state solar cells. The mechanisms of the light scattering by LSPRs, near-field enhancement, and plasmon-induced charge separation based on electron-hole pair excitations can be clarified. We review the related studies from the viewpoint of these mechanisms rather than material science. PMID- 28737383 TI - Alternatives to Nuclear Overhauser Enhancement Spectroscopy Presat and Carr Purcell-Meiboom-Gill Presat for NMR-Based Metabolomics. AB - NMR metabolomics are primarily conducted with 1D nuclear Overhauser enhancement spectroscopy (NOESY) presat for water suppression and Carr-Purcell-Meiboom-Gill (CPMG) presat as a T2 filter to remove macromolecule signals. Others pulse sequences exist for these two objectives but are not often used in metabolomics studies, because they are less robust or unknown to the NMR metabolomics community. However, recent improvements on alternative pulse sequences provide attractive alternatives to 1D NOESY presat and CPMG presat. We focus this perspective on PURGE, a water suppression technique, and PROJECT presat, a T2 filter. These two pulse sequences, when optimized, performed at least on par with 1D NOESY presat and CPMG presat, if not better. These pulse sequences were tested on common samples for metabolomics, human plasma, and urine. PMID- 28737385 TI - A Synthetic Circuit for Mercury Bioremediation Using Self-Assembling Functional Amyloids. AB - Synthetic biology approaches to bioremediation are a key sustainable strategy to leverage the self-replicating and programmable aspects of biology for environmental stewardship. The increasing spread of anthropogenic mercury pollution into our habitats and food chains is a pressing concern. Here, we explore the use of programmed bacterial biofilms to aid in the sequestration of mercury. We demonstrate that by integrating a mercury-responsive promoter and an operon encoding a mercury-absorbing self-assembling extracellular protein nanofiber, we can engineer bacteria that can detect and sequester toxic Hg2+ ions from the environment. This work paves the way for the development of on-demand biofilm living materials that can operate autonomously as heavy-metal absorbents. PMID- 28737384 TI - Physicochemical Parameters Affecting the Electrospray Ionization Efficiency of Amino Acids after Acylation. AB - Electrospray ionization (ESI) is widely used in liquid chromatography coupled to mass spectrometry (LC-MS) for the analysis of biomolecules. However, the ESI process is still not completely understood, and it is often a matter of trial and error to enhance ESI efficiency and, hence, the response of a given set of compounds. In this work we performed a systematic study of the ESI response of 14 amino acids that were acylated with organic acid anhydrides of increasing chain length and with poly(ethylene glycol) (PEG) changing certain physicochemical properties in a predictable manner. By comparing the ESI response of 70 derivatives, we found that there was a strong correlation between the calculated molecular volume and the ESI response, while correlation with hydrophobicity (log P values), pKa, and the inverse calculated surface tension was significantly lower although still present, especially for individual derivatized amino acids with increasing acyl chain lengths. Acylation with PEG containing five ethylene glycol units led to the largest gain in ESI response. This response was maximal independent of the calculated physicochemical properties or the type of amino acid. Since no actual physicochemical data is available for most derivatized compounds, the responses were also used as input for a quantitative structure property relationship (QSPR) model to find the best physicochemical descriptors relating to the ESI response from molecular structures using the amino acids and their derivatives as a reference set. A topological descriptor related to molecular size (SPAN) was isolated next to a descriptor related to the atomic composition and structural groups (BIC0). The validity of the model was checked with a test set of 43 additional compounds that were unrelated to amino acids. While prediction was generally good (R2 > 0.9), compounds containing halogen atoms or nitro groups gave a lower predicted ESI response. PMID- 28737386 TI - Telomerase Inhibition and Human Telomeric G-Quadruplex DNA Stabilization by a beta-Carboline-Benzimidazole Derivative at Low Concentrations. AB - Guanine rich regions in DNA, which can form highly stable secondary structures, namely, G-quadruplex or G4 DNA structures, affect DNA replication and transcription. Molecules that stabilize G4 DNA have become important in recent years. In this study, G4 DNA stabilization, inhibition of telomerase, and anticancer activity of synthetic beta-carboline-benzimidazole derivatives (5a, 5d, 5h, and 5r) were studied. Among them, derivatives containing a 4 methoxyphenyl ring at C1 and a 6-methoxy-substituted benzimidazole at C3 (5a) were found to stabilize telomeric G-quadruplex DNA efficiently. The stoichiometry and interaction of a synthetic, beta-carboline-benzimidazole derivative, namely, 3-(6-methoxy-1H-benzo[d]imidazol-2-yl)-1-(4-methoxyphenyl)-9H-pyrido[3,4-b]indole (5a), with human intermolecular G-quadruplex DNA at low concentrations were examined using electrospray ionization mass spectrometry. Spectroscopy techniques indicate that 5a may intercalate between the two stacks of G-quadruplex DNA. This model is supported by docking studies. When cancer cells are treated with 5a, the cell cycle arrest occurs at the sub-G1 phase. In addition, an apoptosis assay and fluorescence microscopy studies using cancer cells indicate that 5a can induce apoptosis. Results of biochemical assays such as the polymerase chain reaction stop assay and telomerase activity assay indicate that 5a has the potential to stabilize G-quadruplex DNA, and thereby, it may interfere with in vitro DNA synthesis and decrease telomerase activity. The results of this study reveal that the beta-carboline-benzimidazole derivative (5a) is efficient in G-quadruplex DNA stabilization over double-stranded DNA, inhibits telomerase activity, and induces apoptosis in cancer cells. PMID- 28737387 TI - Self-Assembly of Lecithin and Bile Salt in the Presence of Inorganic Salt in Water: Mesoscale Computer Simulation. AB - The influence of inorganic salt on the structure of lecithin/bile salt mixtures in aqueous solution is studied by means of dissipative particle dynamics simulations. We propose a coarse-grained model of phosphatidylcholine and two types of bile salts (sodium cholate and sodium deoxycholate) and also take into account the presence of low molecular weight salt. This model allows us to study the system on rather large time and length scales (up to about ~20 MUs and 50 nm) and to reveal mechanisms of experimentally observed increasing viscosity upon increasing the low molecular weight salt concentration in this system. We show that increasing the low molecular weight salt concentration induces the growth of cylinder-like micelles formed in lecithin/bile salt mixtures in water. These wormlike micelles can entangle into transient networks displaying perceptible viscoelastic properties. Computer simulation results are in good qualitative agreement with experimental observations. PMID- 28737388 TI - Electronic and Optical Properties of Methylated Adamantanes. AB - Recent theoretical work has identified functionalized diamondoids as promising candidates for the tailoring of fluorescent nanomaterials. However, experiments confirming that optical gap tuning can be achieved through functionalization have, up until now, found only systems where fluorescence is quenched. We address this shortcoming by investigating a series of methylated adamantanes. For the first time, a class of functionalized diamondoids is shown to fluoresce in the gas phase. In order to understand the evolution of the optical and electronic structure properties with degree of functionalization, photoelectron spectroscopy was used to map the occupied valence electronic structure, while absorption and fluorescence spectroscopies yielded information about the unoccupied electronic structure and postexcitation relaxation behavior. The resulting spectra were modeled by (time-dependent) density functional theory. These results show that it is possible to overcome fluorescence quenching when functionalizing diamondoids and represent a significant step toward tailoring the electronic structure of these and other semiconductor particles in a manner suitable to applications. PMID- 28737389 TI - Glycosyl Cations versus Allylic Cations in Spontaneous and Enzymatic Hydrolysis. AB - Enzymatic prenyl and glycosyl transfer are seemingly unrelated reactions that yield molecules and protein modifications with disparate biological functions. However, both reactions employ diphosphate-activated donors and each proceed via cationic species: allylic cations and oxocarbenium ions, respectively. In this study, we explore the relationship between these processes by preparing valienyl ethers to serve as glycoside mimics that are capable of allylic rather than oxocarbenium cation stabilization. Rate constants for spontaneous hydrolysis of aryl glycosides and their analogous valienyl ethers were found to be almost identical, as were the corresponding activation enthalpies and entropies. This close similarity extended to the associated secondary kinetic isotope effects (KIEs), indicating very similar transition state stabilities and structures. Screening a library of over 100 beta-glucosidases identified a number of enzymes that catalyze hydrolysis of these valienyl ethers with kcat values up to 20 s-1. Detailed analysis of one such enzyme showed that ether hydrolysis occurs via the analogous mechanisms found for glycosides, and through a very similar transition state. This suggests that the generally lower rates of enzymatic cleavage of the cyclitol ethers reflects evolutionary specialization of these enzymes toward glycosides rather than inherent reactivity differences. PMID- 28737390 TI - Kinetic Isotope Effect Probes the Reactive Spin State, As Well As the Geometric Feature and Constitution of the Transition State during H-Abstraction by Heme Compound II Complexes. AB - What do experimentally measured kinetic isotope effects (KIEs) tell us about H abstraction reactions with multispin-state reactivity options? Using DFT calculations with tunneling corrections for experimentally studied H-abstraction reactions of porphyrin-Compound II species (Chem.-Eur. J. 2014, 20, 14437; Angew. Chem., Int. Ed. 2008, 47, 7321) with cyclohexane, dihydroanthracene (DHA), and xanthene (Xan), we show here that KIE is a selective probe that identifies the experimentally reactive spin state. At the same time, comparison of calculated and experimental KIE values permits us to determine the structural orientation of the transition states, as well as the presence/absence of an axial ligand, and the effect of porphyrin substituents. The studied compound II (Cpd II) species involve porphine, and porphyrin ligands with different meso-substituents, TPFPP (tetrakis(pentafluorophenyl)porphyrin dianion) and TMP (tetramesitylporphyrin dianion), with and without imidazole axial ligands. The DFT calculations reveal three potential pathways: quintet and triplet sigma-pathways (5Hsigma and 3Hsigma) that possess linear transition state (TS) structures, and a triplet pi pathway (3Hpi) having a bent TS structure. Without an axial ligand, the 5Hsigma pathways for these Cpd II complexes cross below the triplet states. The axial ligand raises the barriers for the quintet and triplet sigma-pathways and quenches any chances for two-state reactivity, thus proceeding via the 3Hpi pathway. All of these pathways exhibit characteristic KIE values: very large for 3Hpi (48-200), small for 5Hsigma (3-9), and intermediate for 3Hsigma (23-51). The calculated KIEs for (TPFPP)FeIV?O without an axial ligand reveal that 3Hsigma is the only pathway having a KIE that matches the experimental values, for the reactions with DHA and Xan (Angew. Chem., Int. Ed. 2008, 47, 7321). Indeed, theory shows that tunneling significantly lowers the 3Hsigma barrier rendering it the sole reactive state for the reaction. A prediction is made for the reactivity and KIE of (TMP)FeIV?O complex, and a comparison is made with the analogous nonheme complexes. PMID- 28737391 TI - Role of Dispersive Fluorous Interaction in the Solvation Dynamics of the Perfluoro Group Containing Molecules. AB - Perfluoro group containing molecules possess an important self-aggregation property through the fluorous (F...F) interaction which makes them useful for diverse applications such as medicinal chemistry, separation techniques, polymer technology, and biology. In this article, we have investigated the solvation dynamics of coumarin-153 (C153) and coumarin-6H (C6H) in ethanol (ETH), 2 fluoroethanol (MFE), and 2,2,2-trifluoroethanol (TFE) using the femtosecond upconversion technique and molecular dynamics (MD) simulation to understand the role of fluorous interaction between the solute and solvent molecules in the solvation dynamics of perfluoro group containing molecules. The femtosecond upconversion data show that the time scales of solvation dynamics of C6H in ETH, MFE, and TFE are approximately the same whereas the solvation dynamics of C153 in TFE is slow as compared to that of ETH and MFE. It has also been observed that the time scale of solvation dynamics of C6H in ETH and MFE is higher than that of C153 in the same solvents. MD simulation results show a qualitative agreement with the experimental data in terms of the time scale of the slow components of the solvation for all the systems. The experimental and simulation studies combined lead to the conclusion that the solvation dynamics of C6H in all solvents as well as C153 in ETH and MFE is mostly governed by the charge distribution of ester moieties (C?O and O) of dye molecules whereas the solvation of C153 in TFE is predominantly due to the dispersive fluorous interaction (F...F) between the perfluoro groups of the C153 and solvent molecules. PMID- 28737392 TI - Ligand Strain and Entropic Effects on the Binding of Macrocyclic and Linear Inhibitors: Molecular Modeling of Penicillopepsin Complexes. AB - Using extensive molecular dynamics simulations, we investigate the structure and dynamics of the complexes formed between penicillopepsin and two peptidomimetic inhibitors: a linear compound, isovaleryl(P4)-valine(P3)-asparagine(P2) leucine(P1)-phosphonate-phenylalanine(P1'), and its macrocylic analog that includes a methylene bridge between the Asn(P2) and Phe(P1') side chains. The macrocyclic inhibitor, which has a 420-fold stronger affinity than that of the acyclic one, has been considered to lower the entropic penalty for binding. To better understand this binding preference, the solution structure of the inhibitors is studied by molecular dynamics simulations. Subsequently, we assess the influence of the enzyme/inhibitor contacts, the enzyme-induced inhibitor strain, the variation of the ligand configurational entropy and the enzyme reorganization by combining molecular-mechanics Poisson-Boltzmann surface area and normal mode calculations with conformational entropy calculations. We find that there is no relevant entropic stabilization on the binding of the cyclic inhibitor with respect to the acyclic analog because the methylene bridge does not reduce appreciably the conformational flexibility of the free inhibitor. The most important factors explaining the stronger affinity of the macrocyclic inhibitor are the conformational filtering and the lower ligand strain induced by the methylene bridge. PMID- 28737393 TI - Continuous O2-Evolving MnFe2O4 Nanoparticle-Anchored Mesoporous Silica Nanoparticles for Efficient Photodynamic Therapy in Hypoxic Cancer. AB - Therapeutic effects of photodynamic therapy (PDT) are limited by cancer hypoxia because the PDT process is dependent on O2 concentration. Herein, we design biocompatible manganese ferrite nanoparticle-anchored mesoporous silica nanoparticles (MFMSNs) to overcome hypoxia, consequently enhancing the therapeutic efficiency of PDT. By exploiting the continuous O2-evolving property of MnFe2O4 nanoparticles through the Fenton reaction, MFMSNs relieve hypoxic condition using a small amount of nanoparticles and improve therapeutic outcomes of PDT for tumors in vivo. In addition, MFMSNs exhibit T2 contrast effect in magnetic resonance imaging (MRI), allowing in vivo tracking of MFMSNs. These findings demonstrate great potential of MFMSNs for theranostic agents in cancer therapy. PMID- 28737394 TI - l-Proline and RNA Duplex m-Value Temperature Dependence. AB - The temperature dependence of l-proline interactions with the RNA dodecamer duplex surface exposed after unfolding was quantified using thermal and isothermal titration denaturation monitored by uv-absorbance. The m-value quantifying proline interactions with the RNA duplex surface area exposed after unfolding was measured using RNA duplexes with GC content ranging between 17 and 83%. The m-values from thermal denaturation decreased with increasing GC content signifying increasingly favorable proline interactions with the exposed RNA surface area. However, m-values from isothermal titration denaturation at 25.0 degrees C were independent of GC content and less negative than those from thermal denaturation. The m-value from isothermal titration denaturation for a 50% GC RNA duplex decreased (became more negative) as the temperature increased and was in nearly exact agreement with the m-value from thermal denaturation. Since RNA duplex transition temperatures increased with GC content, the more favorable proline interactions with the high GC content duplex surface area observed from thermal denaturation resulted from the temperature dependence of proline interactions rather than the RNA surface chemical composition. The enthalpy contribution to the m-value was positive and small (indicating a slight increase in duplex unfolding enthalpy with proline) while the entropic contribution to the m-value was positive and increased with temperature. Our results will facilitate proline's use as a probe of solvent accessible surface area changes during biochemical reactions at different reaction temperatures. PMID- 28737395 TI - Kinetic Study of the Aroxyl-Radical-Scavenging Activity of Five Fatty Acid Esters and Six Carotenoids in Toluene Solution: Structure-Activity Relationship for the Hydrogen Abstraction Reaction. AB - A kinetic study of the reaction between an aroxyl radical (ArO*) and fatty acid esters (LHs 1-5, ethyl stearate 1, ethyl oleate 2, ethyl linoleate 3, ethyl linolenate 4, and ethyl arachidonate 5) has been undertaken. The second-order rate constants (ks) for the reaction of ArO* with LHs 1-5 in toluene at 25.0 degrees C have been determined spectrophotometrically. The ks values obtained increased in the order of LH 1 < 2 < 3 < 4 < 5, that is, with increasing the number of double bonds included in LHs 1-5. The ks value for LH 5 was 2.93 * 10-3 M-1 s-1. From the result, it has been clarified that the reaction of ArO* with LHs 1-5 was explained by an allylic hydrogen abstraction reaction. A similar kinetic study was performed for the reaction of ArO* with six carotenoids (Car-Hs 1-6, astaxanthin 1, beta-carotene 2, lycopene 3, capsanthin 4, zeaxanthin 5, and lutein 6). The ks values obtained increased in the order of Car-H 1 < 2 < 3 < 4 < 5 < 6. The ks value for Car-H 6 was 8.4 * 10-4 M-1 s-1. The ks values obtained for Car-Hs 1-6 are in the same order as that of the values for LHs 1-5. The results of detailed analyses of the ks values for the above reaction indicated that the reaction was also explained by an allylic hydrogen abstraction reaction. Furthermore, the structure-activity relationship for the reaction was discussed by taking the result of density functional theory calculation reported by Martinez and Barbosa into account. PMID- 28737396 TI - Azacyclo-indoles and Phenolics from the Flowers of Juglans regia. AB - Seven new azacyclo-indoles and phenolics and four known alkaloids were isolated from the flowers of Juglans regia. Spectroscopic and chromatographic data revealed that the structures of the new compounds are 5,6,11,12 tetrahydropyrrolo[1',2':1,2]azepino[4,5-b]indole-3-carbaldehyde (1), (+/-) 5,6,7,11c-tetrahydro-1H-indolizino[7,8-b]indol-3(2H)-one (2), (+/-)-9-hydroxy-5 oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-2-carboxamide (3), 5-(ethoxymethyl)-1 (4-hydroxyphenethyl)-1H-pyrrole-2-carbaldehyde (4), (+/-)-5,8-dihydroxy-4-(1H indol-3-yl)-3,4-dihydronaphthalen-1(2H)-one (5), (+/-)-4-(6-amino-9H-purin-9-yl) 5,8-dihydroxy-3,4-dihydronaphthalen-1(2H)-one (6), and (+/-)-4-(6-amino-9H-purin 9-yl)-5-hydroxy-3,4-dihydronaphthalen-1(2H)-one (7). The five pairs of enantiomers were resolved, and the absolute configurations of the enantiomers were assigned via electronic circular dichroism data. Compound 1 exhibited significant in vitro growth inhibition against the HCT-116, HepG2, BGC-823, NCI H1650, and A2780 cancer cell lines, with IC50 values of 2.87, 1.87, 2.28, 2.86, and 0.96 MUM, respectively, and low cytotoxicity toward normal IEC-6 cells, with a 79.6% survival rate at a 10 MUM concentration. PMID- 28737397 TI - Conformational Nonequilibrium Enzyme Kinetics: Generalized Michaelis-Menten Equation. AB - In a conformational nonequilibrium steady state (cNESS), enzyme turnover is modulated by the underlying conformational dynamics. On the basis of a discrete kinetic network model, we use an integrated probability flux balance method to derive the cNESS turnover rate for a conformation-modulated enzymatic reaction. The traditional Michaelis-Menten (MM) rate equation is extended to a generalized form, which includes non-MM corrections induced by conformational population currents within combined cyclic kinetic loops. When conformational detailed balance is satisfied, the turnover rate reduces to the MM functional form, explaining its general validity. For the first time, a one-to-one correspondence is established between non-MM terms and combined cyclic loops with unbalanced conformational currents. Cooperativity resulting from nonequilibrium conformational dynamics can be achieved in enzymatic reactions, and we provide a novel, rigorous means of predicting and characterizing such behavior. Our generalized MM equation affords a systematic approach for exploring cNESS enzyme kinetics. PMID- 28737398 TI - In Vivo Mechanisms of Intestinal Drug Absorption from Aprepitant Nanoformulations. AB - Over recent decades there has been an increase in the proportion of BCS class II and IV drug candidates in industrial drug development. To overcome the biopharmaceutical challenges associated with the less favorable properties of solubility and/or intestinal permeation of these substances, the development of formulations containing nanosuspensions of the drugs has been suggested. The intestinal absorption of aprepitant from two nanosuspensions (20 MUM and 200 MUM total concentrations) in phosphate buffer, one nanosuspension (200 MUM) in fasted state simulated intestinal fluid (FaSSIF), and one solution (20 MUM) in FaSSIF was investigated in the rat single-pass intestinal perfusion model. The disappearance flux from the lumen (Jdisapp) was faster for formulations containing a total concentration of aprepitant of 200 MUM than for those containing 20 MUM, but was unaffected by the presence of vesicles. The flux into the systemic circulation (Japp) and, subsequently, the effective diffusion constant (Deff) were calculated using the plasma concentrations. Japp was, like Jdisapp, faster for the formulations containing higher total concentrations of aprepitant, but was also faster for those containing vesicles (ratios of 2 and 1.5). This suggests that aprepitant is retained in the lumen when presented as nanoparticles in the absence of vesicles. In conclusion, increased numbers of nanoparticles and the presence of vesicles increased the rate of transport and availability of aprepitant in plasma. This effect can be attributed to an increased rate of mass transport through the aqueous boundary layer (ABL) adjacent to the gut wall. PMID- 28737399 TI - Rapid Characterization of the Human Breast Milk Lipidome Using a Solid-Phase Microextraction and Liquid Chromatography-Mass Spectrometry-Based Approach. AB - Human breast milk (HBM) is a biofluid consisting of various biomolecules such as proteins, lipids, carbohydrates, minerals and bioactive substances. Due to its unique and complex composition, HBM provides not only nutritional components required for the growth of the infant, but also additional protection against infections. Global insight into the composition of HBM is crucial to understanding the health benefits infants receive from breastfeeding and could be used to improve the composition of milk formula for babies that cannot be breastfed. To improve global profiling of the HBM lipidome, a new analytical approach based on solid-phase microextraction (SPME) and liquid chromatography mass spectrometry (LC-MS) was developed. The new extraction method allows for the rapid and simple extraction of a broad range of lipids directly from HBM samples. Moreover, the optimized two-step lipid extraction protocol ensures high lipidome coverage without using toxic solvents such as chloroform. The use of liquid chromatography-quadrupole time-of-flight mass spectrometry (LC-Q-TOF-MS) and an automated search of a lipid database allows comprehensive identification of the lipids contained in HBM. The demonstrated analytical approach based on SPME sample preparation and LC-Q-TOF-MS is rapid, free of toxic solvents, and suited for the qualitative analysis of the HBM lipid composition. PMID- 28737400 TI - Synthesis of Spirooxindoles via the tert-Amino Effect. AB - A new method is developed for the synthesis of spirooxindoles from amines and isatins via C-H functionalization. The reaction leverages the tert-amino effect to form an enolate-iminium intermediate via [1,5]-hydride shift followed by cyclization. Interestingly the hydride migrates to the N atom of a C?N, which is atypical for hydride additions to imines. PMID- 28737401 TI - Effect of Charged Group Spacer Length on Hydration State in Zwitterionic Poly(sulfobetaine) Brushes. AB - Effect of alkyl chain spacer length between the charged groups (CSL) in zwitterionic poly(sulfobetaine) (PSB) brushes on the hydration state was investigated. PSB brushes with ethyl (PMAES), propyl (PMAPS), or butyl (PMABS) CSL were prepared by surface-initiated atom transfer radical polymerization on silicon wafers. Hydration states of the PSB brushes in aqueous solutions and/or humid vapor were investigated by contact angle measurement, infrared spectroscopy, AFM observation, and neutron reflectivity. The PSB brushes are swollen in humid air and deionized water due to the hydration of the charged groups leading to the reduction of hydrated PSB brushes/water interfacial free energy. The hydrated PSB brushes exhibit clear interface with low interfacial roughness due to networking of the PSB brush chains through association of the SBs. The hydrated PSB brushes produce diffusive swollen layer in the presence of NaCl because of the charge screening followed by SB dissociation by the bound ions. The ionic strength sensitivity in the hydration got more significant with increasing the CSL in SBs because of the augmentation in partial charge by charged group separation. PMID- 28737402 TI - Ultrafast Hot Carrier Dynamics in GaN and Its Impact on the Efficiency Droop. AB - GaN is a key material for lighting technology. Yet, the carrier transport and ultrafast dynamics that are central in GaN light-emitting devices are not completely understood. We present first-principles calculations of carrier dynamics in GaN, focusing on electron-phonon (e-ph) scattering and the cooling and nanoscale dynamics of hot carriers. We find that e-ph scattering is significantly faster for holes compared to electrons and that for hot carriers with an initial 0.5-1 eV excess energy, holes take a significantly shorter time (~0.1 ps) to relax to the band edge compared to electrons, which take ~1 ps. The asymmetry in the hot carrier dynamics is shown to originate from the valence band degeneracy, the heavier effective mass of holes compared to electrons, and the details of the coupling to different phonon modes in the valence and conduction bands. We show that the slow cooling of hot electrons and their long ballistic mean free paths (over 3 nm at room temperature) are a possible cause of efficiency droop in GaN light-emitting diodes. Taken together, our work sheds light on the ultrafast dynamics of hot carriers in GaN and the nanoscale origin of efficiency droop. PMID- 28737404 TI - Silver-Catalyzed Tandem C=C Bond Hydroazidation/Radical Addition/Cyclization of Biphenyl Acetylene: One-Pot Synthesis of 6-Methyl Sulfonylated Phenanthridines. AB - A silver-catalyzed tandem carbon-carbon triple bond hydroazidation, radical addition, and cyclization of biphenyl acetylene is described under mild conditions, leading to the formation of 6-methyl sulfonylated phenanthridines in good yields. In this novel cascade reaction, most of the atoms are incorporated into the product without cleavage of the C=C bond. Mechanistic studies suggest the reaction should proceed through an iminyl radical reactive intermediate. PMID- 28737403 TI - Validation of Dissolution Testing with Biorelevant Media: An OrBiTo Study. AB - Dissolution testing with biorelevant media has become widespread in the pharmaceutical industry as a means of better understanding how drugs and formulations behave in the gastrointestinal tract. Until now, however, there have been few attempts to gauge the reproducibility of results obtained with these methods. The aim of this study was to determine the interlaboratory reproducibility of biorelevant dissolution testing, using the paddle apparatus (USP 2). Thirteen industrial and three academic laboratories participated in this study. All laboratories were provided with standard protocols for running the tests: dissolution in FaSSGF to simulate release in the stomach, dissolution in a single intestinal medium, FaSSIF, to simulate release in the small intestine, and a "transfer" (two-stage) protocol to simulate the concentration profile when conditions are changed from the gastric to the intestinal environment. The test products chosen were commercially available ibuprofen tablets and zafirlukast tablets. The biorelevant dissolution tests showed a high degree of reproducibility among the participating laboratories, even though several different batches of the commercially available medium preparation powder were used. Likewise, results were almost identicalbetween the commercial biorelevant media and those produced in-house. Comparing results to previous ring studies, including those performed with USP calibrator tablets or commercially available pharmaceutical products in a single medium, the results for the biorelevant studies were highly reproducible on an interlaboratory basis. Interlaboratory reproducibility with the two-stage test was also acceptable, although the variability was somewhat greater than with the single medium tests. Biorelevant dissolution testing is highly reproducible among laboratories and can be relied upon for cross-laboratory comparisons. PMID- 28737405 TI - Enhanced Gas Sensitivity and Sensing Mechanism of Network Structures Assembled from alpha-Fe2O3 Nanosheets with Exposed {104} Facets. AB - Network structures assembled from alpha-Fe2O3 nanosheets with exposed {104} facets were successfully prepared by heating Fe(NO3)3 solution containing polyvinylpyrrolidone (PVP) in air. The alpha-Fe2O3 nanosheet-based network structures demonstrate significantly higher response to ethanol and triethylamine than alpha-Fe2O3 commercial powders. The excellent sensing performances can be ascribed to the exposed (104) facet terminated with Fe atoms. A concept of the unsaturated Fe atoms serving as the sensing reaction active sites is thus proposed, and the sensing reaction mechanism is described at the atomic and molecular level for the first time in detail. The concept of the surface metal atoms with dangling bonds serving as active sites can deepen understanding of the sensing and other catalytic reaction mechanisms and provides new insight into the design and fabrication of highly efficient sensing materials, catalysts, and photoelectronic devices. PMID- 28737406 TI - Preclinical Effect of Absorption Modifying Excipients on Rat Intestinal Transport of Model Compounds and the Mucosal Barrier Marker 51Cr-EDTA. AB - There is a renewed interest from the pharmaceutical field to develop oral formulations of compounds, such as peptides, oligonucleotides, and polar drugs. However, these often suffer from insufficient absorption across the intestinal mucosal barrier. One approach to circumvent this problem is the use of absorption modifying excipient(s) (AME). This study determined the absorption enhancing effect of four AMEs (sodium dodecyl sulfate, caprate, chitosan, N-acetylcysteine) on five model compounds in a rat jejunal perfusion model. The aim was to correlate the model compound absorption to the blood-to-lumen clearance of the mucosal marker for barrier integrity, 51Cr-EDTA. Sodium dodecyl sulfate and chitosan increased the absorption of the low permeation compounds but had no effect on the high permeation compound, ketoprofen. Caprate and N-acetylcysteine did not affect the absorption of any of the model compounds. The increase in absorption of the model compounds was highly correlated to an increased blood-to lumen clearance of 51Cr-EDTA, independent of the AME. Thus, 51Cr-EDTA could be used as a general, sensitive, and validated marker molecule for absorption enhancement when developing novel formulations. PMID- 28737407 TI - Label-Free Monitoring of Single Molecule Immunoreaction with a Nanopipette. AB - The nanopipette has been employed for the single molecule analysis due to its advantage of easy fabrication and controllable diameter. Herein, we present that the single molecule immunoreaction could be monitored by using the quartz nanopipette through the discrimination of characteristic blockade current, which reflect the intrinsic character of the individual unlabeled protein molecules due to its heterogeneous motion in solution. Our methods show the ability to monitor the immunoreaction between single alpha-fetal protein (AFP) and its specific antibody in aqueous solution without any labeling. Our studies may open a new door to comprehensively understand the single molecule immunoreaction, which gain more insight into the molecular dynamic of elementary steps. PMID- 28737408 TI - Establishing the Trifluoromethylthio Radical Donating Abilities of Electrophilic SCF3-Transfer Reagents. AB - The recent recognition of the novel application of a few traditional electrophilic trifluoromethylthiolating reagents as SCF3 radical sources offers a remarkable new opportunity for the development of radical trifluoromethylthiolation reactions. Herein, the first trifluoromethylthio radical donating ability (Tt*DA) scale of electrophilic SCF3-transfer reagents has been developed. This scale is based on Y-SCF3 bond dissociation energies, which were obtained by density functional calculations (M06-2X). Single electron transfer is revealed to exhibit a substantial Y-SCF3 bond-weakening effect, thus significantly facilitating the SCF3 radical (*SCF3) release. The results may aid in future novel radical SCF3-transfer reagent design and new reaction development. PMID- 28737410 TI - Depth-Profiling the Nuclease Stability and the Gene Silencing Efficacy of Brush Architectured Poly(ethylene glycol)-DNA Conjugates. AB - PEGylation of an oligonucleotide using a brush polymer can improve its biopharmaceutical characteristics, including enzymatic stability and biodistribution. Herein, we quantitatively explore the nuclease accessibility of the nucleic acid as a function of "depth" toward the backbone of the brush polymer. It is found that protein accessibility decreases as the nucleotide is located closer to the backbone. Thus, by moving the conjugation point from the terminus of the nucleic acid strand to an internal position, much smaller brushes can be used to achieve the same level of steric shielding. This finding also makes it possible to assess antisense gene regulation efficiency of these brush DNA conjugates as a function of their nuclease stability. PMID- 28737409 TI - Low Buffer Capacity and Alternating Motility along the Human Gastrointestinal Tract: Implications for in Vivo Dissolution and Absorption of Ionizable Drugs. AB - In this study, we determined the pH and buffer capacity of human gastrointestinal (GI) fluids (aspirated from the stomach, duodenum, proximal jejunum, and mid/distal jejunum) as a function of time, from 37 healthy subjects after oral administration of an 800 mg immediate-release tablet of ibuprofen (reference listed drug; RLD) under typical prescribed bioequivalence (BE) study protocol conditions in both fasted and fed states (simulated by ingestion of a liquid meal). Simultaneously, motility was continuously monitored using water-perfused manometry. The time to appearance of phase III contractions (i.e., housekeeper wave) was monitored following administration of the ibuprofen tablet. Our results clearly demonstrated the dynamic change in pH as a function of time and, most significantly, the extremely low buffer capacity along the GI tract. The buffer capacity on average was 2.26 MUmol/mL/DeltapH in fasted state (range: 0.26 and 6.32 MUmol/mL/DeltapH) and 2.66 MUmol/mL/DeltapH in fed state (range: 0.78 and 5.98 MUmol/mL/DeltapH) throughout the entire upper GI tract (stomach, duodenum, and proximal and mid/distal jejunum). The implication of this very low buffer capacity of the human GI tract is profound for the oral delivery of both acidic and basic active pharmaceutical ingredients (APIs). An in vivo predictive dissolution method would require not only a bicarbonate buffer but also, more significantly, a low buffer capacity of dissolution media to reflect in vivo dissolution conditions. PMID- 28737411 TI - Can brief behavioral health interventions reduce suicidal and self-harm ideation in primary care patients? AB - OBJECTIVE: We examined whether brief behavioral health visits reduced suicidal and self-harm ideation among primary care patients and compared the effectiveness of interventions that targeted ideation directly (i.e., safety planning) with those that targeted ideation indirectly through management of underlying mental illness (e.g., behavioral activation). METHOD: We examined first- and last-visit data from 31 primary care patients with suicidal or self-harm ideation seen by behavioral health consultants. RESULTS: Patients reported significantly lower frequencies of suicidal and self-harm ideation at their final visit than at their initial visit. Patients whose ideation was targeted directly showed greater improvements than patients whose ideation was targeted indirectly. DISCUSSION: Although preliminary, results suggest mild to moderate suicidal ideation could be addressed in primary care through integration of behavioral health consultants into the medical team. (PsycINFO Database Record PMID- 28737412 TI - Integrated care clinic: Creating enhanced clinical pathways for integrated behavioral health care in a family medicine residency clinic serving a low income, minority population. AB - INTRODUCTION: Research examining the implementation and effectiveness of integrated behavioral health (BH) care in family medicine/primary care is growing. However, research identifying ways to consistently use integrated BH in busy family medicine/primary care settings with underserved populations is limited. This study describes 1 family medicine clinic's transformation into a fully integrated BH care clinic through the development of an Integrated Care Clinic (ICC) and enhanced clinical pathways to promote regular use of behavioral health clinicians (BHCs). METHOD: We implemented the ICC at the Broadway Family Medicine Clinic serving a low-income (<$25,000 annual income/year) and minority population (>70% African American) in Minnesota. We conducted a pre- and postevaluation of the ICC during regular clinic activity. RESULTS: Pilot findings indicated that the creation of ICC and the use of enhanced clinical pathways (e.g., 5-2-1-0 obesity prevention messages, Transitional Care Management, postpartum depression screening visits, warm hand-offs) to facilitate regular use of integrated BH care resulted in 6 integrated care visits per BHC per clinic half-day. In addition, changes in the behavioral/mental health therapy appointment time slot (from 60 to 30 min) reduced therapy no-show rates. Transitional Care Management (TCM) visits also showed improved pre- and postchanges in patient and clinician satisfaction and reductions in patient hospital readmission rates. DISCUSSION: The transformation into a fully integrated BH family medicine clinic through the creation of ICC and enhanced clinical pathways to facilitate regular integrated BH care showed promising pilot results. Future research is needed to examine associations between ICC and patient outcomes (e.g., weight, depressive symptoms). (PsycINFO Database Record PMID- 28737413 TI - Explaining general and specific factors in longitudinal, multimethod, and bifactor models: Some caveats and recommendations. AB - An increasing number of psychological studies are devoted to the analysis of g factor structures. One key purpose of applying g-factor models is to identify predictors or potential causes of the general and specific effects. Typically, researchers relate predictor variables directly to the general and specific factors using a classical mimic approach. However, this procedure bears some methodological challenges, which often lead to model misspecification and biased parameter estimates. We propose 2 possible modeling strategies to circumvent these problems: the multiconstruct bifactor and the residual approach. We illustrate both modeling approaches for the application of g-factor models to longitudinal and multitrait-multimethod data. Practical guidelines are provided for choosing an appropriate method in empirical applications, and the implications of this investigation for multimethod and longitudinal research are discussed. (PsycINFO Database Record PMID- 28737414 TI - The reciprocal relationship between depression and physical morbidity: The role of subjective age. AB - OBJECTIVES: The study aims to examine whether the reciprocal effects of physical morbidity and depression are moderated by subjective age-that is, individuals' perception of themselves as young or old. METHOD: Data from the first two waves of the Midlife in the United States study (1995-6, T1; 2004-6, T2; http://midus.wisc.edu/) were analyzed using a cross-lagged design. We assessed 3,591 individuals who participated in both waves and provided full data on all the relevant variables (mean age at T1 = 47.4). Depression and the number of chronic illnesses (the indicator of physical morbidity) were measured at both waves and were tested as predictors and outcomes in a cross-lagged model. The moderating role of subjective age was assessed by examining whether T1 variables interacted with subjective age in predicting T2 outcomes. RESULTS: Subjective age moderated the T1 depression-T2 morbidity relationship, so that the relationship was stronger for those with older subjective age. Subjective age did not moderate the T1 morbidity-T2 depression relationship. CONCLUSION: Older subjective age could be a risk factor for experiencing greater physical morbidity following depression. (PsycINFO Database Record PMID- 28737415 TI - Development and usability testing of a web-based decision support for users and health professionals in psychiatric services. AB - OBJECTIVE: Shared decision making (SMD) related to treatment and rehabilitation is considered a central component in recovery-oriented practice. Although decision aids are regarded as an essential component for successfully implementing SDM, these aids are often lacking within psychiatric services. The aim of this study was to use a participatory design to facilitate the development of a user-generated, web-based decision aid for individuals receiving psychiatric services. The results of this effort as well as the lessons learned during the development and usability processes are reported. METHOD: The participatory design included 4 iterative cycles of development. Various qualitative methods for data collection were used with potential end users participating as informants in focus group and individual interviews and as usability and pilot testers. RESULTS: Interviewing and testing identified usability problems that then led to refinements and making the subsequent prototypes increasingly user friendly and relevant. In each phase of the process, feedback from potential end users provided guidance in developing the formation of the web-based decision aid that strengthens the position of users by integrating access to information regarding alternative supports, interactivity between staff and users, and user preferences as a continual focus in the tool. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: This web-based decision aid has the potential to strengthen service users' experience of self-efficacy and control as well as provide staff access to user knowledge and preferences. Studies employing participatory models focusing on usability have potential to significantly contribute to the development and implementation of tools that reflect user perspectives. (PsycINFO Database Record PMID- 28737416 TI - Rejecting a bad option feels like choosing a good one. AB - Across 4,151 participants, the authors demonstrate a novel framing effect, attribute matching, whereby matching a salient attribute of a decision frame with that of a decision's options facilitates decision-making. This attribute matching is shown to increase decision confidence and, ultimately, consensus estimates by increasing feelings of metacognitive ease. In Study 1, participants choosing the more attractive of two faces or rejecting the less attractive face reported greater confidence in and perceived consensus around their decision. Using positive and negative words, Study 2 showed that the attribute's extremity moderates the size of the effect. Study 3 found decision ease mediates these changes in confidence and consensus estimates. Consistent with a misattribution account, when participants were warned about this external source of ease in Study 4, the effect disappeared. Study 5 extended attribute matching beyond valence to objective judgments. The authors conclude by discussing related psychological constructs as well as downstream consequences. (PsycINFO Database Record PMID- 28737417 TI - Benefits of positive relationship experiences for avoidantly attached individuals. AB - Attachment avoidance is characterized by discomfort with closeness and a reluctance to develop intimacy with romantic partners, which contribute to heightened general negativity and lower satisfaction and self-disclosure in and out of their relationships. Recent research, however, has begun to uncover circumstances in which romantic partners and positive relationships buffer more avoidantly attached individuals against deleterious individual and relationship outcomes. Across 3 studies, using a multimethod approach encompassing both experimental and dyadic longitudinal diary methods, we investigated the effects of positive, intimacy-related relationship experiences on more avoidant persons' positive and negative affect, relationship quality, self-disclosure, and attachment security immediately and over time. Results revealed that more avoidant individuals exhibit a reduction of general negative affect in particular (Studies 1-2) and report greater relationship quality (Studies 2-3) in response to positive relationship experiences, and, following intimacy-promoting activities with their partner, engage in greater self-disclosure over time and demonstrate decreased attachment avoidance 1 month later (Study 3). These findings identify novel circumstances in which more avoidant persons' negative expectations of relationships may be countered, and suggest that relatively simple techniques can have potentially important short- and long-term implications for more avoidant individuals and their relationships. (PsycINFO Database Record PMID- 28737418 TI - Charisma in everyday life: Conceptualization and validation of the General Charisma Inventory. AB - Although both scholars and lay people are fascinated with charismatic individuals, relatively few theorists have attempted to define charisma. Much of the empirical research examining charisma has focused on leadership. Even within that literature, however, theorists have focused on charisma's outcomes, leaving unarticulated what charisma actually is. Here, we tested an operational conceptualization of charisma in the context of everyday life. Specifically, we proposed that charisma is composed of the interpersonally focused dimensions of influence (the ability to guide others) and affability (the ability to make other people feel comfortable and at ease). We validated this conceptualization in a series of studies. In Studies 1-3, we used exploratory and confirmatory factor analyses to construct a short 6-item measure of charisma, the General Charisma Inventory. Next, in Study 4, we used round-robin evaluations and informant reports to establish the interpersonal nature of charisma. Finally, we examined the incremental validity of the scale in the context of dyadic interactions and tested the impact of charisma on perceptions of persuasiveness from voices. We found that (a) lay people possess a consensual conception of charisma; (b) charisma consists of a composition of quantifiable dimensions; (c) charisma is distinct from other constructs of interest to psychologists and leadership theorists; (d) charisma is observable; and (e) assessments of charisma predict real world outcomes. Thus, the current work not only comprehensively conceptualizes and measures charisma as an empirical construct, but also demonstrates its potential importance for the routine interactions that people experience every day. (PsycINFO Database Record PMID- 28737419 TI - Behavioral activation as a common mechanism of change across different orientations and disorders. AB - Behavioral activation is an effective treatment for depression, based on targeting deprivation of positive rewards. It becomes more and more evident that many forms of mental disorders and psychological suffering involve reduction of goal-driven and pleasant activities. This reduction leaves negative mental states free to take the center of consciousness, without being counterbalanced by positive feelings, memories, and experiences of agency, self-efficacy, competence, relaxation, energy, and satisfaction. Reduced activity can be found in disorders ranging from chronic pain to personality disorders and schizophrenia. We believed that the time was ripe to reason that behavioral activation, more than a treatment in itself, can be considered a fundamental mechanism of change in the psychotherapy for a wide range of dysfunctions, irrespective of the clinician's preferred orientation. In this special section, authors from diverse orientations describe how they integrate behavioral activation in their clinical practice, while providing rich and detailed clinical illustrations. We reflect that behavioral activation needs to be implemented in many forms of psychotherapy and for a wide range of disorders. Moreover, it has the potential to make treatment faster and maximize outcomes, as long as it is delivered under careful consideration of the therapy relationship. (PsycINFO Database Record PMID- 28737420 TI - Platforms and techniques used for biomarker assays: where are we now? PMID- 28737421 TI - Matrix effect management in liquid chromatography mass spectrometry: the internal standard normalized matrix effect. AB - LC-MS is becoming a standard for many applications, thanks to high sensitivity and selectivity; nevertheless, some issues are still present, particularly due to matrix effect (ME). Considering this, the use of optimal internal standards (ISs, usually stable-isotope labeled) is important, but not always possible because of cost or availability. Therefore, a deep investigation of the inter-lot variability of the ME and of the correcting power of the chosen IS (isotope labeled or not) is mandatory. While the adoption of isotopically labeled ISs considered as a 'gold standard' to mitigate ME impact on analytical results, there is not consensus about the standard technique to evaluate it during method validation. In this paper, currently available techniques to evaluate, reduce or counterbalance ME are presented and discussed. Finally, these techniques were summarized in a flowchart for a robust management of ME, particularly considering the concept of 'internal standard normalized ME'. PMID- 28737422 TI - The heights of biopharmaceutical complexity and the current reach of analytical instrumentation. PMID- 28737423 TI - Mass spectrometric techniques for the analysis of volatile organic compounds emitted from bacteria. AB - Bacteria are the main cause of many human diseases. Typical bacterial identification methods, for example culture-based, serological and genetic methods, are time-consuming, delaying the potential for an early and accurate diagnosis and the appropriate subsequent treatment. Nevertheless, there is a stringent need for in situ tests that are rapid, noninvasive and sensitive, which will greatly facilitate timely treatment of the patients. This review article presents volatile organic metabolites emitted from various micro-organism strains responsible for common bacterial infections in humans. Additionally, the manuscript shows the application of different analytical techniques for fast bacterial identification. Details of these techniques are given, which focuses on their advantages and drawbacks in using for volatile organic components analysis. PMID- 28737424 TI - Facilitator and Participant Use of Facebook in a Community-Based Intervention for Parents: The InFANT Extend Program. AB - BACKGROUND: Social networking sites such as Facebook afford new opportunities for behavior-change interventions. Although often used as a recruitment tool, few studies have reported the use of Facebook as an intervention component to facilitate communication between researchers and participants. The aim of this study was to examine facilitator and participant use of a Facebook component of a community-based intervention for parents. METHODS: First-time parent groups participating in the intervention arm of the extended Infant Feeding, Activity and Nutrition Trial (InFANT Extend) Program were invited to join their own private Facebook group. Facilitators mediated the Facebook groups, using them to share resources with parents, arrange group sessions, and respond to parent queries. Parents completed process evaluation questionnaires reporting on the usefulness of the Facebook groups. RESULTS: A total of 150 parents (from 27 first time parent groups) joined their private Facebook group. There were a mean of 36.9 (standard deviation 11.1) posts/group, with the majority being facilitator posts. Facilitator administration posts (e.g., arranging upcoming group sessions) had the highest average comments (4.0), followed by participant health/behavior questions (3.5). The majority of participants reported that they enjoyed being a part of their Facebook group; however, the frequency of logging on to their groups' page declined over the 36 months of the trial, as did their perceived usefulness of the group. CONCLUSIONS: Facebook appears to be a useful administrative tool in this context. Parents enjoyed being part of their Facebook group, but their reported use of and engagement with Facebook declined over time. PMID- 28737425 TI - Comparative study of root resorption of maxillary incisors in patients treated with lingual and buccal orthodontics. AB - OBJECTIVE: To compare the magnitude of external apical root resorption (EARR) of maxillary incisors in patients with mild to moderate anterior crowding, treated with lingual and conventional (labial) orthodontics. MATERIALS AND METHODS: The sample comprised 40 patients divided into two groups: lingual (20 patients) and conventional buccal brackets (20 patients). Patient ages ranged from 11 to 45 years, and the study included 12 men and 28 women. Apical root resorption was measured from periapical radiographs obtained at the beginning of treatment (T1) and at the end of the leveling phase (T2). Periapical radiographs were scanned and transferred to the CorelDraw X7 image-processing program, in which measurements of root lengths were performed. For intragroup and intergroup comparisons between the T1 and T2 phases, paired and independent t-tests, respectively, were used at 5% significance. RESULTS: There was significant apical root resorption for all teeth evaluated; the magnitude of the EARR (T2-T1) ranged from -0.35 mm to -0.63 mm in the lingual group, and from -0.66 mm to -0.85 mm in the conventional group. Although there was an intergroup variation in the magnitude of EARR observed, no statistically significant differences were found. Neither group presented any teeth with resorption >=1 mm. CONCLUSIONS: The magnitude of apical root resorption in maxillary incisors in patients with anterior crowding was similar regardless of orthodontic technique, lingual or conventional. Both techniques resulting in an apical rounding considered clinically insignificant. PMID- 28737426 TI - Posterior cranial base natural growth and development: A systematic review. AB - OBJECTIVE: To provide a synthesis of the published studies evaluating the natural growth and development of the human posterior cranial base (S-Ba). MATERIALS AND METHODS: The search was performed on MEDLINE, Embase, PubMed, and all EBM Reviews electronic databases. In addition, reference lists of the included studies were hand-searched. Articles were included if they analyzed posterior cranial-base growth in humans specifically. Study selection, data extraction, and risk of bias assessment were completed in duplicate. A meta-analysis was not justified. RESULTS: Finally, 23 published studies were selected: 5 cross-sectional and 18 cohort studies. Articles were published between 1955 and 2015, and all were published in English. The sample sizes varied between 20 and 397 individuals and consisted of craniofacial measurements from either living or deceased human skulls. Validity of the measurements was not determined in any of the studies, while six papers reported some form of reliability assessment. All the articles included multiple time points within the same population or data from multiple age groups. Growth of S-Ba was generally agreed to be from spheno-occipital synchondrosis growth. Basion displaced downward and backward and sella turcica moved downward and backward during craniofacial growth. Timing of cessation of S Ba growth was not conclusive due to limited identified evidence. CONCLUSIONS: Current evidence suggests that S-Ba is not totally stable, as its dimensions change throughout craniofacial growth and a minor dimensional change is observed even in late adulthood. PMID- 28737427 TI - The effect of different dietary levels of dl-methionine and dl-methionine hydroxy analogue on the antioxidant and immune status of young turkeys. AB - The hypothesis postulating that the antioxidant and immunological effects of dietary methionine (Met) in young turkeys (1-8 weeks of age) can be differentiated by level and source of Met was investigated in this study. A total of 544 female Hybrid Converter turkeys were divided into four groups and fed diets in which Met content was tailored through supplementation with dl methionine (dl-Met) or dl-methionine hydroxy analogue (MHA) to levels recommended by NRC (1994) (Groups dl-MetL and MHAL) and exceeding them by 50% (Groups dl-MetH and MHAH). Regardless of its source, the increased dietary Met content led to significantly higher body weight gains but had no effect on feed conversion rates. Moreover, an increased Met content lowered lipid peroxide concentrations in breast meat and increased selected indicators of the plasma antioxidant status like uric acid levels, activity of superoxide dismutase (SOD), glutathione (GSH) concentrations, the ferric-reducing ability of plasma (FRAP), increased immunoglobulin A (IgA) plasma levels and decreased interleukin 6 levels. In comparison with dl-Met, MHA decreased the activities of SOD and catalase, and GSH concentrations in plasma. A dosage by source interaction revealed that the lower MHA content was associated with the lowest plasma GSH concentrations, FRAP values and activities of SOD and catalase. The higher dietary MHA level resulted for most parameters similar values, except for a decrease in lipid peroxide concentrations and an increase in plasma IgA levels. It can be concluded that an increased dietary dl-Met and MHA content (about 150% of the recommendations given by NRC 1994) not only increased the growth rate of young turkeys but also improved their antioxidant status. MHA appears to be a less desirable source of dietary Met for young turkeys when the inclusion level of Met matches the current recommendations. Therefore, a further debate is needed to establish the dietary requirements for Met in poultry. PMID- 28737428 TI - Chromatographic determination of zonisamide, topiramate and sulpiride in plasma by a fluorescent 'turn-on' chemosensor. AB - AIM: Antiepileptics (AEDs) and antipsychotics are often coprescribed. Interactions between these drugs may affect both efficacy and toxicity. Therefore, drug monitoring is necessary for appropriate dosage adjustments. MATERIALS & METHODS: Specific 'turn-on' chemosensor, 4-chloro-7-nitrobenzofurazan is used for selective and sensitive determination of two AEDs: zonisamide (ZON) and topiramate (TOP) with the antipsychotic sulpiride (SUL) in epileptic patients' plasma followed by reversed-phase-HPLC separation without any interference. RESULTS: Linear behavior was observed in the range of 0.1-3 MUg/ml and 0.01-0.5 MUg/ml for the AEDs and SUL, respectively, with LOD of 33, 46 and 4 ng/ml and LOQ of 86, 93 and 9 ng/ml for ZON, TOP and SUL, respectively. The proposed method was successfully applied for determination of different pharmacokinetic parameters of ZON and TOP, and for clinical monitoring of the three drugs in healthy volunteers following oral administration. CONCLUSION: The developed method is suitable for the routine therapeutic drug monitoring of these drugs. PMID- 28737429 TI - HIF-1alpha inhibition by diethylstilbestrol and its polyacetal conjugate in hypoxic prostate tumour cells: insights from NMR metabolomics. AB - In this study, we have employed 1H NMR metabolomics to assess the metabolic responses of PC3 prostate tumour cells to hypoxia and to pharmacological HIF 1alpha inhibition by DES or its polyacetal conjugate tert-DES. Oxygen deprivation prompted a number of changes in intracellular composition and metabolic activity, mainly reflecting upregulated glycolysis, amino acid catabolism and other compensatory mechanisms used by hypoxic cells to deal with oxidative imbalance and energy deficit. Cell treatment with a non-cytotoxic concentration of DES, under hypoxia, triggered significant changes in 17 metabolites. Among these, lactate, phosphocreatine and reduced glutathione, whose levels showed opposite variations in hypoxic and drug-treated cells, emerged as possible markers of DES induced HIF-1alpha inhibition. Furthermore, the free drug had a much higher impact on the cellular metabolome than tert-DES, particularly concerning polyamine and pyrimidine biosynthetic pathways, known to be tightly involved in cell proliferation and growth. This is likely due to the different cell pharmacokinetics observed between free and conjugated DES. Overall, this study has revealed a number of unanticipated metabolic changes that inform on DES and tert-DES direct cellular effects, providing further insight into their mode of action at the biochemical level. PMID- 28737430 TI - Nivolumab for the treatment of bladder cancer. AB - INTRODUCTION: The checkpoint inhibitor nivolumab has recently demonstrated effectiveness against metatstatic urothelial carcinoma. Nivolumab is a fully human monoclonal antibody blocking PD-1 and thereby enhancing antitumour immune mechanisms. Areas covered: In this review, the authors describe the treatment of metastatic bladder cancer with nivolumab against the background of the standard treatment with cisplatin-based chemotherapy which can prolong overall survival from 3-6 months in untreated cases to over one year. Different combinations of cisplatin-based chemotherapy can further prolong survival by only a few months. The authors highlight that cancer immunotherapy by checkpoint inhibition offers potential to further prolong patient survival with limited and well manageable toxicity although serious immune-related adverse events may occur. Expert opinion: The response rate to nivolumab and other checkpoint inhibitors after first line chemotherapy remains under 30%. Patients unfit for cisplatin may benefit from first-line cancer immunotherapy. It is unclear which patients will respond and PD-1/PD-L1 expression alone is not a sufficiently reliable response marker. Treatment costs are extreme and further trials will have to clarify which subset of patients in which context of management will have a substantial benefit. PMID- 28737431 TI - The analysis of pneumatic atomization of Newtonian and non-Newtonian fluids for different medical nebulizers. AB - OBJECTIVE: The article contains results of the experimental studies on atomization process of inhaled drugs and aqueous solutions of glycerol with aqueous solutions of glycerol polyacrylamide (Rokrysol WF1) in pneumatic nebulizers. In experiments, the different concentration of aqueous solutions of glycerol polyacrylamide have been tested. In addition, the effect of nebulizer design on atomization process has been determined. The one of the main elements of medical pneumatic nebulizer is nebulizer cup. SIGNIFICANCE: The experiment with this scope is new and is very important from the point of view of aerosol therapy. METHODS: The results have been obtained by the use of the digital microphotography technique. In order to determine a physicochemical properties of tested liquids, a rheological measurements and measurements of the surface tension were carried out. RESULTS: The differences between characteristics of aerosol for the liquids have been observed. The analysis of the droplets size distributions shows that the different diameters of droplets for Newtonian and non-Newtonian fluids have been formed during atomization in pneumatic nebulizers equipped with different nebulizer cups. The effect of the mouthpiece location on the droplets diameters has been shown. CONCLUSIONS: Precise design of nebulizer and nebulizer cups, and also physicochemical properties of atomized liquids are of high importance in order to the effectiveness of drug delivery to patient's respiratory tracts. PMID- 28737432 TI - Integrin-targeted nano-sized polymeric systems for paclitaxel conjugation: a comparative study. AB - The generation of rationally designed polymer therapeutics via the conjugation of low molecular weight anti-cancer drugs to water-soluble polymeric nanocarriers aims to improve the therapeutic index. Here, we focus on applying polymer therapeutics to target two cell compartments simultaneously - tumour cells and angiogenic endothelial cells. Comparing different polymeric backbones carrying the same therapeutic agent and targeting moiety may shed light on any correlation between the choice of polymer and the anti-cancer activity of the conjugate. Here, we compared three paclitaxel (PTX)-bound conjugates with poly-l-glutamic acid (PGA, 4.9 mol%), 2-hydroxypropylmethacrylamide (HPMA, 1.2 mol%) copolymer, or polyethyleneglycol (PEG, 1:1 conjugate). PGA and HPMA copolymers are multivalent polymers that allow the conjugation of multiple compounds within the same polymer backbone, while PEG is a bivalent commercially available Food and Drug Administration (FDA)-approved polymer. We further conjugated PGA-PTX and PEG PTX with the integrin alphavbeta3-targeting moiety RGD (5.5 mol% and 1:1 conjugate, respectively). We based our selection on the overexpression of integrin alphavbeta3 on angiogenic endothelial cells and several types of cancer cells. Our findings suggest that the polymer structure has major effect on the conjugate's activity on different tumour compartments. A multivalent PGA-PTX-E [c(RGDfK)2] conjugate displayed a stronger inhibitory effect on the endothelial compartment, showing a 50% inhibition of the migration of human umbilical vein endothelial cell cells, while a PTX-PEG-E-[c(RGDfK)2] conjugate possessed enhanced anti-cancer activity on MDA-MB-231 tumour cells (IC50 = 20 nM versus IC50 300 nM for the PGA conjugate). PMID- 28737433 TI - Association and interaction between triglyceride-glucose index and obesity on risk of hypertension in middle-aged and elderly adults. AB - AIMS: To investigate the association between triglyceride-glucose(TyG) index and the risk of hypertension. METHOD: A cross-sectional study was conducted in Bengbu, China. The participants received relevant questionnaire survey, anthropometric tests, and laboratory examination. Multivariate logistic regression analysis was performed to estimate the possible association between TyG index and hypertension risk. The additive interaction evaluated by the relative excess risk due to interaction (RERI), attributable proportion due to interaction (AP), and synergy index(SI) was calculated. RESULTS: A total of 1777 participants (748 men and 1029 women) were investigated. There was a significant increase in the risk of hypertension and isolated systolic hypertension (ISH) when comparing the highest TyG index (the fourth quartile) to the lowest TyG index (the first quartile) and corresponding ORs were 2.446 (95% CI: 1.746-3.426) and 2.621(95%CI: 1.627-4.224), respectively. However, no significant relationship was observed between TyG index and isolated diastolic hypertension (IDH). In males, significant interactions between TyG index and WHtR (RERI:1.978, 95%CI: 0.162-3.792; AP: 0.359, 0.113-0.605; SI:1.782, 1.017-3.122), smoking (AP: 0.437, 95%CI: 0.048-0.825), family history of hypertension (AP:0.433, 95%CI: 0.203 0.662; SI:2.248, 95%CI: 1.333-3.791) were observed. As for females, there were also significant interactions between TyG index and WHtR (RERI:1.415, 95%CI: 0.693-2.136; AP: 0.198, 95%CI: 0.104-0.291; SI:1.298, 95%CI:1.101-1.530), family history of hypertension (RERI:1.744, 95%CI: 0.221-3.267; AP:0.405, 95%CI: 0.113 0.697) on risk of hypertension. CONCLUSIONS: Increased TyG index was significantly associated with higher risk of hypertension and ISH, but not for IDH in middle-aged and elderly adults. Our results also demonstrated interactions of TyG index and abdominal obesity and family history of hypertension on hypertension risk. PMID- 28737434 TI - Defining the timing of 25(OH)D rescue following nitrogen mustard exposure. AB - OBJECTIVE: Mass exposure to alkylating agents such as nitrogen mustard (NM), whether accidental or intentional as during warfare, are known to cause systemic toxicity and severe blistering from cutaneous exposure. Thus, establishing the timing and appropriate dose of any potential drug designed to reverse or impede these toxicities is critical for wound repair and survival. Our previous data demonstrates that a single intraperitoneal injection of low-dose 25 hydroxyvitamin D3 (25(OH)D) given as early as 1 h following NM exposure is sufficient to rescue mice from pancytopenia and death. However, the duration of time following exposure where intervention is still effective as a countermeasure is unknown. In this study, we sought to assess the maximal time permissible following NM exposure where 25(OH)D still affords protection against NM-induced cutaneous injury. Additionally, we determined if a higher dose of 25(OH)D would be more efficacious at time interval where low dose 25(OH)D is no longer effective. METHODS: Low (5 ng) and high (50 ng) doses of 25(OH)D were administered intraperitoneally to mice following exposure to topical NM to assess wound resolution and survival. Mice were imaged and weighed daily to measure wound healing and to monitor systemic toxicity. RESULTS: We demonstrated that 5 ng 25(OH)D administered as early as 1 h and as late as 24 h post-NM exposure is able to achieve 100% recovery in mice. In contrast, intervention at and beyond 48 h of NM exposure failed to achieve full recovery and resulted in >=60% death between days 6 and 12, demonstrating the critical nature of timely intervention with 25(OH)D at each respective dose. In order to circumvent the observed failure at >48 h exposure, we provided two consecutive doses of 5 ng or 50 ng of 25(OH)D at 48 h and 72 h post-NM exposure. Repeat dosing with 25(OH)D at 48 h and beyond led to marked improvement of lesion size with 75% recovery from mortality. CONCLUSIONS: The opportunity to use 25(OH)D as a medical countermeasure for NM induced toxicity has a finite of window for intervention. However, modifications such as repeat dosing can be an effective strategy to extend the intervention potential of 25(OH)D. PMID- 28737435 TI - Investigation on influence of Wurster coating process parameters for the development of delayed release minitablets of Naproxen. AB - The present work aims at studying process parameters affecting coating of minitablets (3 mm in diameter) through Wurster coating process. Minitablets of Naproxen with high drug loading were manufactured using 3 mm multi-tip punches. The release profile of core pellets (published) and minitablets was compared with that of marketed formulation. The core formulation of minitablets was found to show similarity in dissolution profile with marketed formulation and hence was further carried forward for functional coating over it. Wurster processing was implemented to pursue functional coating over core formulation. Different process parameters were screened and control strategy was applied for factors significantly affecting the process. Modified Plackett Burman Design was applied for studying important factors. Based on the significant factors and minimum level of coating required for functionalization, optimized process was executed. Final coated batch was evaluated for coating thickness, surface morphology, and drug release study. PMID- 28737437 TI - Once-weekly oral antidiabetic agent and treatment satisfaction. PMID- 28737436 TI - DNA methylation in the norepinephrine transporter gene promoter region is not associated with depression and hypertension. AB - OBJECTIVE: This study aims to detect the role of DNA methylation in norepinephrine transporter (NET) gene promoter region on the association between depression and hypertension. METHODS: A total of 162 subjects were categorized into four groups based on depression scores and blood pressure. DNA was extracted from peripheral white blood cells and methylation levels of nine CpG sites in NET gene promoter region were investigated by pyrosequencing. RESULTS: For each CpG site and the average value of nine CpG sites, there were no significant differences in DNA methylation of the NET gene promoter between healthy controls and patients with depression or hypertension. And there were no significant differences among groups after adjusting for age and body mass index. However, DNA methylation levels of the CpG sites adjacent to transcription start site tended to be low. In addition, CpG1.2-CpG5.2 were highly correlated with CpG4 as the first principle component, while CpG2 and the part of CpG1 and 3 were the second principle components. The total participants were clustered into three subgroups by hierarchical cluster analysis of methylated levels. CONCLUSION: Our study indicates that DNA methylation levels of nine CpG sites in NET gene promoter region are not associated with depression and hypertension. PMID- 28737438 TI - Prenatal exposure to angiotensin II increases blood pressure and decreases salt sensitivity in rats. AB - Renin angiotensin aldosterone system (RAAS) plays an essential role in the homeostatic control of arterial blood pressure, perfusion of tissues, and control of extracellular fluid. Its components are highly expressed in the developing kidney, general vasculature, brain, and heart. A modified intrauterine environment alters mechanisms controlling blood pressure (BP) and can lead to hypertension in the adult offspring and developmentally programmed RAAS can be involved in this process. There are very little data about the effects of increased angiotensin II (Ang II) concentrations during pregnancy on in utero development of the fetus. In our study, we administered Ang II to pregnant female rats via osmotic mini-pumps and evaluated the postnatal development and BP control in the offspring. To estimate possible developmental changes in sensitivity to salt, we exposed the offspring to a diet with increased salt content and measured plasma aldosterone levels and plasma renin activity. Increased Ang II during pregnancy raised BP in the offspring; however, salt sensitivity was decreased in comparison to controls. Relative weight of the left ventricle was decreased in the offspring prenatally exposed to Ang II, while relative kidney weight was reduced only in female offspring. Prenatal treatment led to increased aldosterone levels and decreased plasma renin activity, suggesting a complex physiological response. Our results suggest that conditions leading to upregulation of RAAS during pregnancy can influence the cardiovascular system of the fetus and have a long-term impact on the offspring's health. PMID- 28737439 TI - Systematic review and meta-analysis: is bowel preparation still necessary in small bowel capsule endoscopy? AB - INTRODUCTION: Optimal bowel preparation for small bowel capsule endoscopy(SBCE) is controversial. This meta-analysis aimed to investigate the effects of laxatives in SBCE. METHODS: A comprehensive literature search was conducted for studies investigating the use of laxatives in SBCE. The primary outcome was diagnostic yield(DY) for SB findings; secondary outcomes SB visualization quality(SBVQ) and completion rate(CR). Pooled odds ratios(ORs) with 95% confidence intervals(CIs) and number needed to treat(NNT) were calculated. RESULTS: Forty studies (4380 patients with laxatives, 2185 without) were included. Laxative use did not improve DY of SB findings overall (OR 1.11 (95%CI 0.85-1.44)) or for significant SB findings (OR 1.10 (95%CI 0.76-1.60)). However, SBVQ improved with the use of laxatives (OR 1.60 (95%CI 1.08-2.06)), NNT 14. The OR for completed SBCE was 1.30 (95%CI 0.95-1.78). Patients given polyethylene glycol(PEG) had lower DY than sodium phosphate(NaP). SBVQ improved more with NaP (NNT 7) than PEG (NNT 53). CONCLUSIONS: Laxatives do not significantly improve DY or CR in SBCE, but do improve SBQV. The use of laxatives may be beneficial in patients likely to have subtle findings. There are significant differences in methodology/definitions between studies, hence the need for standardized visualization scoring and recording of SBCE findings. PMID- 28737440 TI - Secukinumab improves scalp pain, itching, scaling and quality of life in patients with moderate-to-severe scalp psoriasis. AB - INTRODUCTION: Scalp psoriasis adversely affects patients' lives and is often resistant to treatment; however, it has not been a major focus of a clinical study. This analysis assessed the effect of secukinumab on patient-reported outcomes (PRO) of scalp psoriasis. METHODS: A randomized, double-blind, placebo controlled, multicenter study was conducted in 102 adult patients with moderate to-severe scalp psoriasis. Patients were randomized 1:1 to secukinumab 300 mg or placebo. Patients rated their scalp-related pain, itching and scaling using a 0 10 numeric rating scale (higher scores indicate greater severity). Scalp dermatitis-related quality of life (QOL) was assessed at baseline and then every 4 weeks using the Scalpdex. Analysis of covariance models examined PRO effect up to 12 weeks. RESULTS: Baseline scalp pain, itching and scaling mean (SD) values were 3.1 (3.00), 6.7 (2.60) and 7.3 (2.02) and similar for both treatment groups. At week 12, patients treated with secukinumab reported greater reduction in scalp pain (-1.98 vs. 0.61), itching (-4.07 vs. -0.04) and scaling (-5.76 vs. -0.95) as well as greater improvements in Scalpdex total scores (-39.62 vs. -7.91) compared with placebo (all p < .001). DISCUSSION/CONCLUSIONS: Secukinumab in moderate-to severe scalp psoriasis reduces scalp pain, itching, and scaling and improves patients' QOL. PMID- 28737441 TI - Irrigation during Laparoscopic Appendectomy for Complicated Appendicitis: Time to Review Current Guidelines. PMID- 28737442 TI - Parallelism experiments to evaluate matrix effects, selectivity and sensitivity in ligand-binding assay method development: pros and cons. AB - Parallelism is an essential experiment characterizing relative accuracy for a ligand-binding assay (LBA). By assessing the effects of dilution on the quantitation of endogenous analyte(s) in matrix, selectivity, matrix effects, minimum required dilution, endogenous levels of healthy and diseased populations and the LLOQ are assessed in a single experiment. This review compares and discusses all available approaches that can be used to assess key assay parameters for pharmacokinetic and biomarker LBAs, as well as the advantages and disadvantages of each approach. This review also summarizes a systematic approach that can apply to guide endogenous LBA method development and optimization with a suggested way to interpret parallelism data. PMID- 28737443 TI - Fertirrigation with sugarcane vinasse: Foreseeing potential impacts on soil and water resources through vinasse characterization. AB - This paper reports the characterization of the polluting potential of sugarcane vinasse, the main wastewater from ethanol production. Compositional data from vinasse samples collected from sugarcane biorefineries were used to predict negative effects on the soil, water resources and crops potentially associated with fertirrigation, the primary final destination of vinasse in Brazil. High risks of soil salinization were associated with the land disposal of vinasse, as evidenced by the high levels of total dissolved solids (TDS; >4,000 mg L-1) and electrical conductivity (>6.7 dS m-1). The high TDS levels coupled with the high biodegradable organic content of vinasse (>14 g L-1) also favor organic overloading events, leading to local anaerobiosis conditions. Conversely, soil sodification should not be observed in areas fertirrigated with sugarcane vinasse, given the low Na concentrations (<66 mg L-1) relative to Mg (>145.1 mg L 1) and Ca (>458.4 mg L-1) levels. Priority pollutants (Cu, Cr, Ni, Pb and Zn) and phytotoxic elements (Al and Fe) were also found in the analyzed samples; however, relevant environmental impacts should not be associated with these particular constituents. Overall, the relatively simple methodology used herein could efficiently replace massive field data collection to provide a basic understanding of the fate of vinasse in the environment in order to highlight the priority points to be considered in the management of this effluent. In summary, the prompt implementation of treatment plants in distilleries, in addition to a continuous and broad compositional characterization of vinasse, is essential to guarantee its adequate reuse. PMID- 28737444 TI - Evolving patterns in a collaboration network of global R&D on monoclonal antibodies. AB - We investigated the evolution process of collaborative inter-organizational network of the research and development (R&D) on monoclonal antibody (mAb) over the past 30 y. The annual detection of the collaboration network provides dynamics on network structures and relationship changes among different organizations. Our research showed continuous growth of the network's scale and complexity due to the constant entry of new organizations and the forging of new partnering relationships. The evolving topological features reveal a core periphery structure that became clearer over time and an increasing heterogeneity within the collaborative mAb R&D network. As measured by the number of network participants, dedicated biotechnology firms (DBFs) were the dominant organization form in the field of mAb development, but their average centrality was reduced during the period of 2004-2009, when pharmaceutical companies took over the positions of DBFs. Along with the network evolution, 2 waves of substitution on the leading positions were driven by technological innovations and mergers and acquisitions (M&A). In addition, this study analyzed organizational-level behaviors to help understand the evolution of network structures over the field of mAb development across the different technologically innovative or economic contexts. PMID- 28737445 TI - Preclinical pharmacokinetics and biodistribution studies of asenapine maleate using novel and sensitive RP-HPLC method. AB - AIM: Asenapine maleate (ASPM) is a newer antipsychotic drug available as a sublingual tablet in the market. EXPERIMENTAL: To investigate the pharmacokinetic and tissue distribution study of ASPM following oral administration in rats, reversed-phase HPLC method was developed and validated. RESULTS: ASPM was extracted from plasma and tissue matrix by liquid-liquid extraction technique and analyzed using mobile phase consisted of phosphate buffer pH 3.0 and acetonitrile (65:35% v/v). The method showed good linearity (10-500 ng/ml) with recovery 83 102%. In pharmacokinetics study, half-life was 32.74 +/- 7.51 h due to slow elimination of drug. The biodistribution study indicated preferential distribution of ASPM to highly perfused organs. CONCLUSION: The current method can be successfully applied for estimating the drug in various biological matrices. PMID- 28737446 TI - Quantitative in vitro phenotyping and prediction of drug interaction potential of CYP2B6 substrates as victims. AB - 1. Determination of fm, CYP for a compound is critical to assess the potential risk of a drug candidate as a victim of DDI. Several compounds are identified as CYP2B6 substrates, but the fm, CYP2B6 values are not determined quantitatively. 2. Two methods of reaction phenotyping, the chemical inhibition method and metabolism in rCYP enzymes, were used to determine the relative contributions of the enzymes. Chemical inhibition method was also conducted in the presence of BSA (0.5% w/v). 3. The results confirm with the earlier studies concerning the identity of the CYP2B6 enzyme. The fm, CYP2B6 values for artemisinin, bupropion, clopidogrel, ketamine, selegiline, sertraline and ticlopidine were 0.24, 0.28, 0.15, 0.45, 0.46, 0.42 and 0.54, respectively, in HLM determined by chemical inhibition method. The fm, CYP2B6 values for artemisinin, bupropion, clopidogrel, ketamine, selegiline, sertraline and ticlopidine were 0.46, 0.17, 0.15, 0.60, 0.51, 0.66 and 0.77, respectively, in HLM determined by chemical inhibition method in the presence of BSA (0.5% w/v). 4. Bupropion metabolism is majorly mediated by CYP2C19 (0.41) with a minor contribution from CYP2B6 (0.16) in the presence of BSA. Ticlopidine is a time-dependent inhibitor of both CYP2B6 and CYP2C19 that can inhibit the bupropion metabolism by 50-60%. PMID- 28737447 TI - PMab-52: Specific and Sensitive Monoclonal Antibody Against Cat Podoplanin for Immunohistochemistry. AB - Podoplanin (PDPN) is expressed in several normal tissues, such as lymphatic endothelial cells, podocytes of renal glomerulus, and type I alveolar cells of lung. PDPN activates platelet aggregation by binding to C-type lectin-like receptor-2 (CLEC-2) on platelet. Although monoclonal antibodies (mAbs) against human PDPN, mouse PDPN, rat PDPN, rabbit PDPN, dog PDPN, and bovine PDPN have been established, anticat PDPN (cPDPN) mAbs have not been developed. In this study, we immunized mice with Chinese hamster ovary (CHO)-K1 cell lines expressing cPDPN, and developed anti-cPDPN mAbs. One of the clones, PMab-52 (IgM, kappa), detected cPDPN specifically in flow cytometry and Western blot analysis. PMab-52 is also useful for detecting feline squamous cell carcinoma cells in immunohistochemical analysis. PMab-52 is expected to be useful for investigating the function of cPDPN in feline carcinomas. PMID- 28737449 TI - Molecular docking studies of fused coumarin derivatives as inhibitors of GlcN-6. AB - The biological activity of heterocyclic compounds depends on their structure, the type of hetero atoms in the ring and on the type of substituents present. In this paper, some heterocyclic compounds with coumarin moieties S1-S5 and novobiocin known as coumarin antibiotic were subjected to the molecular docking studies as important tools for drug discovery. Glucosamine-6-phosphate synthase is selected as a suitable target in this study. In silico studies reveal that all synthesized compounds S1-S5 are good inhibitors of GlcN-6 and the docking results are in agreement with in vitro antibacterial evaluation of compounds S1-S5. PMID- 28737448 TI - Mast Cell and M1 Macrophage Infiltration and Local Pro-Inflammatory Factors Were Attenuated with Incretin-Based Therapies in Obesity-Related Glomerulopathy. AB - BACKGROUND: The global increase of obesity parallels the obesity-related glomerulopathy (ORG) epidemic. Dipeptidyl peptidase 4 inhibitors and glucagon like peptide-1 receptor agonists were well recognized to attenuate renal injury independent of glucose control in diabetic nephropathy. There are limited studies focusing on their effects on ORG. We explored the effects of incretin-based therapies on early ORG and the inflammatory responses involved mainly concentrated on mast cell (MC) and macrophage (M) infiltration and local pro inflammatory factors. METHODS: ORG rat models were induced by high-fat diet and then divided into ORG vehicle, vildagliptin (3 mg/kg/day, qd) and liraglutide (200 MUg/kg, bid) treated groups. After 8 weeks of treatments, albuminuria, glomerular histology, renal inflammatory cell infiltration, and pro-inflammatory factors were analyzed. RESULTS: Early ORG model was demonstrated by albuminuria, glomerulomegaly, foot process fusion, and mesangial and endothelial mild proliferation. Incretin-based therapies limited body weight gain and improved insulin sensitivity. ORG was alleviated, manifested by decreased average glomerular area, attenuated mesangial and endothelial cell proliferation, and revived cell-to-cell propagation of podocytes, which contributed to reduced albuminuria. Compared with ORG vehicle, MC and M1 macrophage (pro-inflammatory) infiltration and M1/M2 ratio were significantly decreased; M2 macrophage (anti inflammatory) was not significantly increased after incretin-based treatments. Tumor necrosis factor-alpha (TNF-alpha) and IL-6 in renal cortex were significantly downregulated, while transforming growth factor-beta1 (TGF-beta1) remained unchanged. CONCLUSIONS: Incretin-based treatments could alleviate high fat diet-induced ORG partly through the systemic insulin sensitivity improvement and the attenuated local inflammation, mainly by the decrease of MC and M1 macrophage infiltration and reduction of TNF-alpha and IL-6. PMID- 28737450 TI - Initial Characterization of the Growth Stimulation and Heat-Shock-Induced Adaptive Response in Developing Lake Whitefish Embryos after Ionizing Radiation Exposure. AB - Ionizing radiation is known to effect development during early life stages. Lake whitefish (Coregonus clupeaformis) represent a unique model organism for examining such effects. The purpose of this study was to examine how ionizing radiation affects development in lake whitefish embryos and to investigate the presence of an adaptive response induced by heat shock. Acute exposure to 137Cs gamma rays was administered at five time points corresponding to major developmental stages, with doses ranging from 0.008 to 15.5 Gy. Chronic gamma-ray exposures were delivered throughout embryogenesis within a custom-built irradiator at dose rates between 0.06 and 4.4 mGy/day. Additionally, embryos were given a heat shock of 3, 6 or 9 degrees C prior to a single acute exposure. Radiation effects were assessed based on survival, development rate, morphometric measurements and growth efficiency. Embryos showed high resistance to acute exposures with an LD50/hatch of 5.0 +/- 0.7 Gy immediately after fertilization, increasing to 14.2 +/- 0.1 Gy later in development. Chronic irradiation at all dose rates stimulated growth, with treated embryos up to 60% larger in body mass during development compared to unirradiated controls. Chronic irradiation also accelerated the time-to-hatch. A heat shock administered 6 h prior to irradiation reduced mortality by up to 25%. Overall, low-dose chronic irradiation caused growth stimulation in developing lake whitefish embryos and acute radiation mortality was reduced by a heat-shock-induced adaptive response. PMID- 28737451 TI - Long-Term Quality of Life Outcomes Following Nissen Versus Toupet Fundoplication in Patients with Gastroesophageal Reflux Disease. AB - INTRODUCTION: Laparoscopic fundoplication is the gold standard treatment for gastroesophageal reflux disease (GERD) refractory to medical management. Although many studies have compared Nissen fundoplication (NF) to Toupet fundoplication (TF), it is unclear which operation provides the best long-term reflux control. The objective of this study was to evaluate long-term quality-of-life (QoL) outcomes after NF versus TF. METHODS: Clinical data from our single academic institutional foregut database were used to identify patients who underwent NF or TF (June 2010 to May 2016). Postoperative QoL was assessed through telephone at 1, 3, or 5 years postsurgery, using GERD-health related quality of life (GERD HRQL), Gastroparesis Cardinal Symptom Index (GCSI), and Eckardt Dysphagia scores. Proton pump inhibitor (PPI) use and satisfaction with surgery were also obtained. Trends in outcomes over time were analyzed by logistic regression or Cochran Armitage trend test. RESULTS: Our cohort included 155 TF and 161 NF patients. TF patients reported baseline dysphagia at higher rates (42.6% versus 19.9%; P < .001) and had worse preoperative esophageal dysmotility than NF patients. There were no significant differences in GERD-HRQL or GCSI scores between TF and NF patients at any time point postoperatively. Long-term satisfaction was equivalent between TF and NF patients 5 years postoperatively (70.0% versus 77.4%; P = .67). NF patients had higher Eckardt dysphagia scores 1 year after surgery compared to TF patients, but this difference was not present at 3 or 5 years postoperatively. Over time, PPI use increased and there was a trend toward increased GERD-HRQL scores in the TF group. CONCLUSIONS: Both TF and NF provide excellent long-term satisfaction for patients with GERD. NF and TF patients reported similar postoperative QoL scores. Our finding of increasing PPI use and a trend toward worsening GERD scores following TF warrants additional investigation regarding the long-term durability of TF. PMID- 28737452 TI - Memory rehabilitation for the working memory of patients with multiple sclerosis (MS). AB - OBJECTIVE: The main cognitive impairments in multiple sclerosis (MS) affect the working memory, processing speed, and performances that are in close interaction with one another. Cognitive problems in MS are influenced to a lesser degree by disease recovery medications or treatments,but cognitive rehabilitation is considered one of the promising methods for cure. There is evidence regarding the effectiveness of cognitive rehabilitation for MS patients in various stages of the disease. Since the impairment in working memory is one of the main MS deficits, a particular training that affects this cognitive domain can be of a great value. This study aims to determine the effectiveness of memory rehabilitation on the working memory performance of MS patients. METHOD: Sixty MS patients with cognitive impairment and similar in terms of demographic characteristics, duration of disease, neurological problems, and mental health were randomly assigned to three groups: namely, experimental, placebo, and control. Patients' cognitive evaluation incorporated baseline assessments immediately post-intervention and 5 weeks post-intervention. The experimental group received a cognitive rehabilitation program in one-hour sessions on a weekly basis for 8 weeks. The placebo group received relaxation techniques on a weekly basis; the control group received no intervention. RESULTS: The results of this study showed that the cognitive rehabilitation program had a positive effect on the working memory performance of patients with MS in the experimental group. These results were achieved in immediate evaluation (post-test) and follow-up 5 weeks after intervention. There was no significant difference in working memory performance between the placebo group and the control group. CONCLUSIONS: According to the study, there is evidence for the effectiveness of a memory rehabilitation program for the working memory of patients with MS. Cognitive rehabilitation can improve working memory disorders and have a positive effect on the working memory performance of these patients. PMID- 28737454 TI - Bioactivity of Epigallocatechin Gallate Nanoemulsions Evaluated in Mice Model. AB - The hypothesis that incorporation of epigallocatechin gallate (EGCG) into nanoemulsions may increase its bioactivity compared with EGCG aqueous solutions was examined in mice. After an in vitro study in a model system with stimulated gastrointestinal conditions, the following EGCG nanoemulsions were used in a mice experiment: Emulsion I: emulsion water in oil (W/O), which contained 0.23 mg/mL EGCG in aqueous phase; Emulsion II: emulsion oil in water (O/W), which contained 10% olive oil and 0.23 mg/mL esterified EGCG in fatty phase; and Emulsion III: emulsion O/W in water (W1/O/W2; 8:32:60), which contained 32% olive oil and 0.23 mg/mL EGCG in aqueous phase. After 2 h of mice administration by gavage with 0.1 mL of EGCG nanoemulsions, total antioxidant capacity (TAC) of plasma and some tissues (especially colon, jejunum, heart, spleen) was measured with Ferric Reducing Antioxidant Power (FRAP) and Oxygen Radical Absorbance Capacity (ORAC) assays. No toxic effects were observed after administration of 0.23 mg/mL esterified EGCG in CD1 mouse strain. The study concluded that administration of mice with the three EGCG nanoemulsions did not increase their TAC in specific tissues, compared with an aqueous EGCG solution at the same concentration. Nevertheless, the esterified EGCG emulsion (Emulsion II) exerted an increase in mice plasma compared with aqueous EGCG and showed higher values of TAC in several tissues, compared with Emulsions I and III. EGCG nanoemulsions could be considered a useful method in plethora functional food applications, but further research is required for safer results. PMID- 28737455 TI - [Difficulties in communication with parents of pediatric cancer patients during the transition to palliative care]. AB - INTRODUCTION: Adequate communication by medical personnel is especially important at certain points during the treatment of childhood cancer patients. AIM: To investigate the timing and manner of communication with parents concerning the introduction of palliative care in pediatric oncology. METHOD: Structured interviews, containing 14 questions, were carried out with physicians working in pediatric oncology (n = 22). Codes were generated inductively with the aid of Atlas.ti 6.0 software. RESULTS: Interviews show a tendency of a one-step transition to palliative care following curative therapy. Another expert is usually involved in communication, most likely a psychologist. Regarding communication, there are expressions utilized or avoided, such as expressing clarity, self-defense and empathy. The communication of death and dying was the most contradictory. CONCLUSION: This was the first investigation regarding communication in pediatric palliative care in Hungary. Our results show that a modern perspective of palliative communication is present, but necessitates more time to become entrenched. Orv Hetil. 2017; 158(30): 1175-1181. PMID- 28737453 TI - The metabolism and drug-drug interaction potential of the selective prostacyclin receptor agonist selexipag. AB - 1. The metabolism of selexipag has been studied in vivo in man and the main excreted metabolites were identified. Also, metabolites circulating in human plasma have been structurally identified and quantified. 2. The main metabolic pathway of selexipag in man is the formation of the active metabolite ACT-333679. Other metabolic pathways include oxidation and dealkylation reactions. All primary metabolites undergo subsequent hydrolysis of the sulphonamide moiety to their corresponding acids. ACT-333679 undergoes conjugation with glucuronic acid and aromatic hydroxylation to P10, the main metabolite detected in human faeces. 3. The formation of the active metabolite ACT-333679 is catalysed by carboxylesterases, while the oxidation and dealkylation reactions are metabolized by CYP2C8 and CYP3A4. CYP2C8 is the only P450 isoform catalysing the aromatic hydroxylation to P10. CYP2C8 together with CYP3A4 are also involved in the formation of several minor ACT-333679 metabolites. UGT1A3 and UGT2B7 catalyse the glucuronidation of ACT-333679. 4. The potential of selexipag to inhibit or induce cytochrome P450 enzymes or drug transport proteins was studied in vitro. Selexipag is an inhibitor of CYP2C8 and CYP2C9 and induces CYP3A4 and CYP2C9 in vitro. Also, selexipag inhibits the transporters OATP1B1, OATP1B3, OAT1, OAT3, and BCRP. However, due to its low dose and relatively low unbound exposure, selexipag has a low potential for causing drug-drug interactions. PMID- 28737456 TI - [Significance of the monitoring and screening for hereditary nonpolyposis colorectal carcinoma syndrome patients by presenting a case of a family tree]. AB - INTRODUCTION: Hereditary nonpolyposis colorectal carcinoma (HNPCC) is an autosomal dominant disease, which shows familial clustering. AIM: We would like to emphasize the importance of monitoring the HNPCC syndrome patients by presenting a case of a proven MMR gene mutation carrier and her family tree encompassing 10 years. MATERIALS AND METHOD: To screen a suspected HNPCC Hungarian family member we are taking thorough family histories. If the diagnosis of HNPCC was further supported by immunohistology and the microsatellite status, sequencing of the MMR genes was carried out. RESULTS: A novel mutation in exon 6 of the hMSH2 gene leading to the deletion of two nucleotide pairs [c.969 970delTC] was detected in our patient. During the 10-year follow-up period of our patient new HNPCC-associated tumors have developed in several family members. Conslusion: Close surveillance of the patient and its family members at risk was effective, although it requires compliance from the subjects. Orv Hetil. 2017; 158(30): 1182-1187. PMID- 28737457 TI - [Importance of gross deletions in the diagnosis of tuberous sclerosis complex: the first Hungarian cases]. AB - Tuberous sclerosis complex is a rare disease with high phenotypic heterogeneity, characterized by the appearance of multiplex hamartomas in the different organs. The disease is inherited by autosomal dominant manner, due to the mutations of two genes: the TSC1 or the TSC2. In this publication we present the cases of two young male and two middle-aged female patients, where pathogenetic differences of TSC1/TSC2 could not be verified by Sanger sequencing. However, multiplex ligation dependent probe amplification confirmed different sizes of deletions in different regions of the TSC2 gene. All patients carry the typical clinical signs of the disease. However, the individual phenotypic variability is very different. With this manuscript, we would like to draw attention to the relative frequent rate of gross gene deletions. Orv Hetil. 2017; 158(30): 1188-1194. PMID- 28737458 TI - [Vaginal birth after cesarean section in light of international opinions]. AB - INTRODUCTION: The tendency of increasing cesarean section rate has drawn worldwide attention. The vaginal birth after cesarean section is a useful method to decrease cesarean section rate at defined cases. AIM: Retrospective overview of factors resulting successful vaginal birth, labor/induction's condition, criterias, short and long term benefits and consequences. METHOD: Overview recommendations of international guidelines and publications' results concerned vaginal birth after cesarean section in "PubMed", "MEDLINE", "Cochrane" databases from 1996 to 2016. RESULTS: Reviewing results of recommendations and publications we can declare that statements are inconsistent, however the option of vaginal birth after cesarean section is appropriate for decrease complications and trend of increasing cesarean section rate. CONCLUSIONS: It would be important in our country to define a uniform recommendation regarding vaginal birth after cesarean section, with supporting evidence in obstetrical and gynecological practice. Orv Hetil. 2017; 158(30): 1168-1174. PMID- 28737459 TI - [The history of the Semmelweis research]. PMID- 28737460 TI - [Applied methods instead of autologous nerve transplantation in the reconstruction of nerve injuries on the hand]. AB - For a long time in the clinical practice the autologous nerve transplants are used in reconstruction of the segmental defects of injured hand nerves. The published outcomes, especially in case of the motor and mixed (sensory and motor) nerves, however, were not satisfactory. Hence, it remained a problem and in the focus of research. The author aimed to study this topic and drawing conclusions in his literary review publication. According to the recent results, the replacement of the autologous nerve transplants with other materials (e.g. nerve conduits, various allografts, etc.) has shown good outcomes in mixed nerves too, if the distance of the resected nerve ends do not exceed 6 mm and the diameter of the nerves were not more than 3-7 mm. The applications of these methods have shown poor results, if the defect and/or the nerve diameter were larger. So, in these cases the autologous nerve transplantation remains the optimal management in the future. Orv Hetil. 2017; 158(30): 1163-1167. PMID- 28737462 TI - Co-delivery of hydrophilic and hydrophobic drugs by micelles: a new approach using drug conjugated PEG-PCLNanoparticles. AB - Co-delivery strategy has been proposed to minimize the amount of each drug and to achieve the synergistic effect for cancer therapies. A conjugate of the antitumor drug, doxorubicin, with diblock methoxy poly (ethylene glycol)-poly caprolactone (mPEG-PCL) copolymer was synthesized by the reaction of mPEG-PCL copolymer with doxorubicin in the presence of p-nitrophenylchloroformate. The conjugated copolymer was characterized in vitro by 1H-NMR, FTIR, DSC and GPC techniques. Then, the doxorubicin conjugated mPEG-PCL(DOX-mPEG-PCL) was self-assembled into micelles in the presence of curcumin in aqueous solution. The resulting micelles were characterized further by various techniques such as dynamic light scattering (DLS) and atomic force microscopy (AFM).The encapsulation efficiency of doxorubicin and curcumin were 82.31 +/- 3.32 and 78.15 +/- 3.14%, respectively. The results revealed that the micelles formed by the DOX-mPEG-PCL with and without curcumin have spherical structure with average size of 116 and 134 nm respectively. The release behavior of curcumin and doxorubicin loaded to micelles were investigated in a different media. The release rate of micelles consisted of the conjugated copolymer was pH dependent as it was higher at lower pH than in neutral condition. Another feature of the conjugated micelles was a sustained release profile. The cytotoxicity of micelles were evaluated by MTT (3-(4, 5 dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide, atetrazole) assay on lung cancer A549 cell lines. In vitro cytotoxicity assay showed that the mPEG-PCL copolymer did not affect the growth of A549 cells. The cytotoxic activity of the micelles against A549 cells was greater than free doxorubicin and free curcumin. PMID- 28737463 TI - Prevalence of a New Variant OXA-204 and OXA-48 Carbapenemases Plasmids Encoded in Klebsiella pneumoniae Clinical Isolates in Tunisia. AB - Carbapenemase-producing Klebsiella pneumoniae strains have emerged as a major problem for healthcare systems. The aim of this study was to determine the role and diversity of plasmids harboring carbapenemases encoding genes from a collection of K. pneumoniae isolates recovered between July 2011 and January 2012, with decreased susceptibility to carbapenems. Imipenem (IPM), ertapenem (ETP), meropenem (MEM), and doripenem (DOR) minimum inhibitory concentrations (MICs) were determined by E-test. Carbapenemase production was detected with the modified Hodge test. beta-Lactamases encoding genes were amplified by PCR and sequenced. Plasmid incompatibility groups harbored by carbapenemases producers were investigated using the PCR-based replicon typing method and the clonal relationship of the isolates was investigated by pulse filed electrophoresis. IMP, ertapenem, meropenem, and doripenem MICs ranged between 0.25 and 16 mg/L. Carbapenemase activity was detected in 14 isolates. Two carbapenemases were identified: OXA-48 in 13 isolates and a new variant OXA-204 in 1 isolate, in combination with extended-spectrum beta-lactamases, CTX-M-1, CTX-M-9, CTX-M-14, CTX-M-15, and VEB-8. One isolate produced CMY-2. OXA-48 and the new variant OXA 204 were confirmed as transferable plasmid encoded. The carbapenemase-producing K. pneumoniae harbored plasmids of the A/C, LVPK, and L/M replicon types. Thirteen different pulso types were observed. Three pairs of isolates showed a clonal relatedness. This diversity in beta-lactamases, in pulso types and in plasmid content, shows the ability of OXA-type carbapenemase to disseminate. This is worrying for the control of the increase in antibiotic resistance frequency and necessitates that continuous investigations in the clinical setting remain a high priority to clarify the contribution of antimicrobial use into multiresistance bacterial dissemination. PMID- 28737464 TI - Acute glycemic and pressure responses of continuous and interval aerobic exercise in patients with type 2 diabetes. AB - BACKGROUND: Aerobic training has been widely indicated to patients with type 2 diabetes. However, there are still few studies comparing acute glycemic and blood pressure effects of different methods of aerobic training. The aim is to compare glycemic and pressure acute responses of continuous aerobic exercise to interval aerobic exercise in patients with type 2 diabetes. MATERIALS AND METHODS: This study is a randomized, crossover clinical trial. Fourteen patients with type 2 diabetes performed two sessions of aerobic training with different methods (continuous and interval). Continuous session had duration of 35 minutes with intensity of 85-90% of heart rate corresponding to anaerobic threshold (HRAT), while interval session had 45 minutes, with stimulus in intensity of 85-90% of HRAT with recovery in intensity under 85% of HRAT. Capillary glycemia, systolic and diastolic blood pressure were analyzed before and after the sessions. RESULTS: Patients were 63.5 +/- 9.8 years old. Glycemia was reduced in both sessions (p < 0.001). Only glycemia measured at 25 minutes after continuous session was not lower than pre-session values. Systolic blood pressure was also reduced in both sessions (p = 0.010) with similar behavior between them. In the diastolic blood pressure, there were differences only between the values measured immediately after exercise and the values measured 20 minutes (p = 0.002) and 30 minutes after exercise (p = 0.008). CONCLUSION: Both continuous and interval aerobic exercise, in a same intensity, are effective for glycemic and pressure acute reductions in individuals with type 2 diabetes. For patients with greater risk of hypertension, we believe that the interval method is safer. PMID- 28737465 TI - The effect of ozone gas sterilization on the properties and cell compatibility of electrospun polycaprolactone scaffolds. AB - The growing area of tissue engineering has the potential to alleviate the shortage of tissues and organs for transplantation, and electrospun biomaterial scaffolds are extremely promising devices for translating engineered tissues into a clinical setting. However, to be utilized in this capacity, these medical devices need to be sterile. Traditional methods of sterilization are not always suitable for biomaterials, especially as many commonly used biomedical polymers are sensitive to chemical-, thermal- or radiation-induced damage. Therefore, the objective of this study was to evaluate the suitability of ozone gas for sterilizing electrospun scaffolds of polycaprolactone (PCL), a polymer widely utilized in tissue engineering and regenerative medicine applications, by evaluating if scaffolds composed of either nanofibres or microfibres were differently affected by the sterilization method. The sterility, morphology, mechanical properties, physicochemical properties, and response of cells to nanofibrous and microfibrous PCL scaffolds were assessed after ozone gas sterilization. The sterilization process successfully sterilized the scaffolds and preserved most of their initial attributes, except for mechanical properties. However, although the scaffolds became weaker after sterilization, they were still robust enough to use as tissue engineering scaffolds and this treatment increased the proliferation of L929 fibroblasts while maintaining cell viability, suggesting that ozone gas treatment may be a suitable technique for the sterilization of polymer scaffolds which are significantly damaged by other methods. PMID- 28737466 TI - Association of AdipoQ single-nucleotide polymorphisms and smoking interaction with the risk of coronary heart disease in Chinese Han population. AB - AIMS: To investigate the impact of AdipoQ polymorphisms, and their additional interactions with smoking and drinking on coronary heart disease (CHD) risk based on Chinese population. METHODS: Hardy-Weinberg equilibrium (HWE) was performed using SNPStats (available online at http://bioinfo.iconcologia.net/SNPstats ). Generalized multifactor dimensionality reduction (GMDR) model was used to screen the best gene-gene and gene-environment interaction combinations. Logistic regression was performed to investigate association between four single nucleotide polymorphisms (SNPs) and CHD and the interaction effect between rs1501299 and smoking. RESULTS: Logistic analysis showed that CHD risks were higher in carriers with homozygous mutant of rs1501299 and rs2241766 than those with wild-type homozygotes, odds ratio (ORs) (95%CI) were 1.49 (1.19-1.95) and 1.71 (1.33-2.24), respectively, but CHD risks were lower in carriers with homozygous mutant of rs7649121 than those with wild-type homozygotes, OR (95%CI) was 0.72 (0.51-0.96). GMDR model indicated that there was a significant two-locus model (p = 0.0107) involving rs1501299 and current smoking, indicating a potential gene-environment interaction between rs1501299 and current smoking. Overall, the cross-validation consistency of this model was 9/10, and the testing accuracy was 60.11% (p = 0.0010). T-allele carriage had 42% prevalence, and one quarter of them were current smokers. Smokers with rs1501299-GT or TT genotype have the highest CHD risk, compared to never-smokers with rs1501299-GG genotype, OR (95%CI) was 3.56 (1.91-5.42), after adjustment for gender, age, alcohol status, and body mass index. But we did not find any significant gene-gene and gene-drinking interaction combinations in GMDR models. CONCLUSIONS: Polymorphisms in rs1501299 and rs2241766, and their additional interactions between rs1501299 and smoking were associated with increased CHD risks: polymorphism in rs7649121 was associated with decreased CHD risks. PMID- 28737467 TI - Once-weekly oral antidiabetic agent and treatment satisfaction. PMID- 28737468 TI - Economic evaluations of Haemophilus influenzae type b (Hib) vaccine: a systematic review. AB - AIMS: The World Health Organization (WHO) recommends the use of Haemophilus influenzae type b (Hib) conjugate vaccines, but China and Thailand have not used Hib vaccination in their national immunization programs. This systematic review aimed to update published economic evaluations of Hib vaccinations and to determine factors that potentially affected their cost-effectiveness. METHODS: Searches were performed from the inception until December 2015 using 13 databases: CAB direct; CEA registry; EconLit; EMBASE; E-library; NHSEED; PAHO; POPLINE; PubMed; Redalyc project; RePEc; SciELO; and WHOLIS. Reference lists of relevant studies and grey literature were also searched. Full economic evaluations of Hib vaccination with results of costs and outcomes were included. The WHO checklist was used to evaluate the quality of the included studies. Data from eligible studies were extracted using a standardized data collection form. RESULTS: Out of 830 articles, 27 were included. Almost half of the studies (12/27) were conducted in high-income countries. Twelve studies (12/27) investigated the Hib vaccine as an addition to the existing vaccination program. Most studies (17/27) examined a 3-dose schedule of Hib vaccine. Nineteen studies (19/27) reported the model used, where all were decision tree models. Most of the studies (23/27) demonstrated an economic value of Hib vaccination programs, key influential parameters being incidence rates of Hib disease and vaccine price. CONCLUSIONS: Hib vaccination programs are mostly found to be cost-effective across geographic regions and country income levels, and Hib vaccination is recommended for inclusion into all national immunization programs. The findings are expected to support policy-makers for making decisions on allocating limited resources of the Hib vaccination program effectively. PMID- 28737469 TI - Social and economic burden of recurrent urinary tract infections and quality of life: a patient web-based study (GESPRIT). AB - BACKGROUND: Uncomplicated lower urinary tract infections (UTIs) occur in approximately 50% of women, and 20-30% experience recurrent UTI. Data on UTIs and quality of life (QoL) in Europe are limited. METHODS: This was an anonymous, self administered web-based survey conducted in 5 countries (Germany, Switzerland, Poland, Russia and Italy), on adult women who had experienced recurrent UTI and were affected by acute UTI currently or within 4 weeks of study entry. Questions covered disease course; management; social and economic burden; education, income, and health insurance status. QoL was evaluated using the SF-12v2. RESULTS: Participants reported a mean of 5.15 UTI symptoms, ranging from 4.85 - 5.38 in Russia and Germany. There was a mean of 2.78 doctor visits per year (1.74 - 3.71 in Russia and Germany; p < 0.0001). 80.3% of participants had been treated with antibiotics, mean prescriptions ranged from 2.17 (Poland) to 3.36 (Germany) per person per year. A mean of 3.09 days sick leave due to UTIs, and 3.45 days of limited activities, were reported. Although 73.8% of participants had tried prophylaxis recurrence was common and associated with mental stress for a high proportion of women. CONCLUSIONS: Our results indicate that recurrent UTIs have a significant impact on QoL of women in Europe. PMID- 28737470 TI - Recent advances in circulating tumor cells and cell-free DNA in metastatic prostate cancer: a review. AB - INTRODUCTION: The treatment landscape of metastatic prostate cancer has changed dramatically over the past five years. As new discoveries are made and further novel therapies become available, there is a heightened urgency to develop biomarkers that can guide prognoses and predict therapy responses. Circulating tumor cells (CTCs) and cell-free circulating tumor DNA (ctDNA) in the blood have emerged as potential promising tumor avatars. Areas covered: In this review, we describe technological breakthroughs and clinical implementation of the CTCs and ctDNA. We also discuss the key challenges that must be overcome before circulating blood-based biomarkers can be universally adopted into the management of patients with metastatic prostate cancer. Expert commentary: Both CTCs and ctDNA have the potential to be incorporated into routine patient care, with increasing numbers of prospective trials incorporating them into clinical designs. CTCs and ctDNA will thus have an increasingly valuable role in augmenting our understanding of prostate cancer at a molecular level, aiding in prognostication of prostate cancer patients, acting as a surrogate for OS in clinical trials, and helping us prioritize our treatment selections by elucidating resistance mechanisms. PMID- 28737472 TI - Histone deacetylase HD2D is involved in regulating plant development and flowering time in Arabidopsis. AB - HD2D is one of the 4 plant specific HD2 family histone deacetylases (HDAC) identified in Arabidopsis and it is distantly related to the other HD2 members. At this time, little is known about the function of HD2D in plants. Here we provide evidence that HD2D is involved in the control of flowering time. Flowering was delayed in transgenic plants overexpressing HD2D and hd2d mutant plants flowered earlier compared with wild-type in both long day and short day conditions. Expression of several floral identity genes was altered in these plants. Taken together, our findings suggest that HD2D is a negative regulator of flowering that modulates the transition of vegetative to reproductive growth in a photoperiod independent manner. PMID- 28737471 TI - Quality control by trans-editing factor prevents global mistranslation of non protein amino acid alpha-aminobutyrate. AB - Accuracy in protein biosynthesis is maintained through multiple pathways, with a critical checkpoint occurring at the tRNA aminoacylation step catalyzed by aminoacyl-tRNA synthetases (ARSs). In addition to the editing functions inherent to some synthetases, single-domain trans-editing factors, which are structurally homologous to ARS editing domains, have evolved as alternative mechanisms to correct mistakes in aminoacyl-tRNA synthesis. To date, ARS-like trans-editing domains have been shown to act on specific tRNAs that are mischarged with genetically encoded amino acids. However, structurally related non-protein amino acids are ubiquitous in cells and threaten the proteome. Here, we show that a previously uncharacterized homolog of the bacterial prolyl-tRNA synthetase (ProRS) editing domain edits a known ProRS aminoacylation error, Ala-tRNAPro, but displays even more robust editing of tRNAs misaminoacylated with the non-protein amino acid alpha-aminobutyrate (2-aminobutyrate, Abu) in vitro and in vivo. Our results indicate that editing by trans-editing domains such as ProXp-x studied here may offer advantages to cells, especially under environmental conditions where concentrations of non-protein amino acids may challenge the substrate specificity of ARSs. PMID- 28737473 TI - Association between the high soluble fms-like tyrosine kinase-1 to placental growth factor ratio and adverse outcomes in asymptomatic women with early-onset fetal growth restriction. AB - OBJECTIVE: To assess whether the high soluble fms-like tyrosine kinase-1 (sFlt-1) to placental growth factor (PlGF) ratio is associated with adverse outcomes (e.g., HELLP syndrome [hemolysis, elevated liver enzymes, and low platelets], severe hypertension uncontrolled by medication, non-reassuring fetal status, placental abruption, pulmonary edema, growth arrest, maternal death, or fetal death) and a shorter duration to delivery in early-onset fetal growth restriction (FGR). METHODS: Thirty-four women with FGR diagnosed at <34.0 weeks were recruited. Serum angiogenic marker levels were estimated within 6 hours of a diagnosis of FGR. A receiver operating characteristic curve was used to determine the threshold of the sFlt-1/PlGF ratio to predict adverse outcomes. We used multivariable logistic regression analysis to examine the association between the sFlt-1/PlGF ratio and adverse outcomes. Finally, we used Kaplan-Meier analysis and the log-rank test to assess the probability of delay in delivery. RESULTS: Women who developed adverse outcomes within a week had a significantly higher sFlt-1/PlGF ratio than did those who did not develop complications. A cutoff value of 86.2 for the sFlt-1/PlGF ratio predicted adverse outcomes, with a sensitivity and specificity of 77.8% and 80.0%, respectively. Moreover, 58.4% of women with an sFlt-1/PlGF ratio >=86.2 versus 9.1% of those with an sFlt-1/PlGF ratio <86.2 delivered within a week of presentation (p < 0.001). In multivariate analyses, an sFlt-1/PlGF ratio >=86.2 (adjusted odds ratio 9.52; 95% confidence interval, 1.25-72.8) was associated with adverse maternal and neonatal outcomes. CONCLUSION: A high sFlt-1/PlGF ratio was associated with adverse outcomes and a shorter duration to delivery in early-onset FGR. PMID- 28737474 TI - Artemisia dracunculus Extracts Obtained by Organic Solvents and Supercritical CO2 Produce Cytotoxic and Antitumor Effects in Mice with L5178Y Lymphoma. AB - We investigated the cytotoxic and antitumor effects of nine leaf extracts from Artemisia dracunculus (Tarragon). Five extracts were obtained using different organic solvents and four by supercritical CO2. The cytotoxic effects were expressed as IC50 in 100, 80, 80, 100, and 80 MUg/mL by respective solvents: hexane, ethyl acetate, acetone, ethanol, and acetonitrile in L5178Y lymphoma cells. For supercritical CO2 extract A, IC50 was 100 MUg/mL; for extracts C and D, IC50 was 150 MUg/mL. The antitumor activity was assessed through a tumor growth inhibition test that measured ascites fluid volume and tumor cell counts of BALB/c mice (2 * 104 cells L5178Y i.p.). Twenty-four hours after inoculation, mice were treated with 100 mg/kg of acetonitrile extract or extract SF-A daily for 15 days in independent groups of five mice, using two administration routes. We observed tumor evolution with and without treatment. Without treatment, tumor evolution was 17,969 * 106 +/- 5485 L5178Y cells in 2.6 mL ascites volume, whereas the orally treated acetonitrile extract group showed 0.1 * 106 +/- 0.07 L5178Y cells (P < .05). The oral SF-A group showed 12.9 * 106 +/- 243 L5178Y cells, and intraperitoneal (i.p.)-treated SF-A group showed 0.1 * 106 +/- 0.05 L5178Y cells (P < .05) without any ascites volume development. The acetonitrile extract contains abundant polyphenols and possibly a flavone with antioxidant activity. The SF-A contains abundant alkamides. Both extracts are complexes and the identity of the compounds responsible for observed antitumor activity remains unknown. PMID- 28737475 TI - Ancient Ascaris DNA Sequences of Cytochrome B, Cytochrome C Oxidase Subunit 1, NADH Dehydrogenase Subunit 1, and Internal Transcribed Spacer 1 Genes from Korean Joseon Mummy Feces. AB - We analyzed Ascaris ancient DNA of cytochrome b, cytochrome c oxidase subunit 1, NADH dehydrogenase subunit 1, and internal transcribed spacer 1 genes extracted from the feces or precipitates of 15- to 18th-century Korean mummies. After multiple Ascaris genes in ancient samples were successfully amplified by polymerase chain reaction (PCR), consensus sequences could be determined by the alignment of the sequences of cloned PCR products. The obtained sequences of each gene were highly similar to those of Ascaris spp. reported thus far but were genetically distinct from Baylisascaris, Parascaris, and Toxascaris spp. The current report establishes that the genetic characteristics of the Ascaris spp. infecting pre-modern Korean societies were not uniform but were diverse to some degree. PMID- 28737476 TI - A high-fidelity method for genomic sequencing of single somatic cells reveals a very high mutational burden. AB - Postzygotic mutations in somatic cells lead to genome mosaicism and can be the cause of cancer, possibly other human diseases and aging. Somatic mutations are difficult to detect in bulk tissue samples. Here, we review the available assays for measuring somatic mutations, with a focus on recent single-cell, whole genome sequencing methods. Impact statement Somatic mutations cause cancer, possibly other diseases and aging. Yet, very little is known about the frequency of such mutations in vivo, their distribution across the genome, and their possible functional consequences other than cancer. Even in cancer, we do not know the heterogeneity of mutations within a tumor and if seemingly normal cells in its surroundings already have elevated mutation frequencies. Here, we review a new, whole genome amplification system that allows accurate quantification and characterization of single-cell mutational landscapes in human cells and tissues in relation to disease. PMID- 28737479 TI - Evaluation of brivaracetam: a new drug to treat epilepsy. AB - INTRODUCTION: High prevalence of therapy-resistant epilepsy demands development of anticonvulsants with new mechanisms of action. Brivaracetam is an analogue of levetiracetam which binds to the synaptic vesicle protein 2A (SV2A) and decreases release of excitatory neurotransmitters. Areas covered: Relevant published studies were searched for by predefined strategy in MEDLINE, EBSCO and SCINDEKS electronic databases. Brivaracetam is effective as adjunctive therapy for uncontrolled partial-onset seizures with or without secondary generalization in patients 16 years and older with epilepsy. It reduces baseline-adjusted focal seizure frequency per week from 7.3 to 12.8% over placebo. Adverse events rate in patients with brivaracetam is not higher than in patients with placebo. Expert opinion: Brivaracetam is an important step forward in the treatment of therapy resistant partial-onset seizures with or without secondary generalization. Its development was systematic and targeted. Due to its efficacy and excellent safety profile, it is likely that brivaracetam will be often prescribed. In future, efficacy and safety of brivaracetam should be tested in monotherapy settings and also in the first-line therapy of partial-onset seizures. PMID- 28737477 TI - Changes in duodenal enteroendocrine cells in patients with irritable bowel syndrome following dietary guidance. AB - The densities of enteroendocrine cells are abnormal in patients with irritable bowel syndrome (IBS); however, they tend to change toward normal levels in stomach, ileum, and colon following dietary guidance. The aim was to identify the types of duodenal enteroendocrine cells affected after receiving dietary guidance in the same group of patients with IBS. Fourteen patients with IBS and 14 control subjects were included. The patients received three sessions of dietary guidance. Both groups underwent gastroscopies at baseline, and again for the patients after 3-9 months (median, four months) from receiving dietary guidance. Tissue biopsies were collected from the descending part of the duodenum and were immunostained for all the types of enteroendocrine cells and were then quantified by using computerized image analysis. Using the Kruskal-Wallis non-parametric test with Dunn's test as a post-test, the results showed a significant difference in the secretin cell densities between control subjects and patients with IBS prior to and following dietary guidance ( P = 0.0001 and 0.011, respectively). The corresponding P values for cholecystokinin (CCK) cell densities were 0.03 and 0.42, respectively; gastric inhibitory peptide (GIP) cell densities were 0.06 and 0.43, respectively; serotonin cell densities were <0.0001 and 0.002, respectively; and for somatostatin cell densities were <0.0001 and 0.052, respectively. The Paired t-test showed a significant difference only in the serotonin ( P = 0.03) and somatostatin ( P < 0.0001) cell densities between IBS patients prior to and following dietary guidance. The changes in the cell densities of secretin, CCK, and GIP were not significant between IBS patients prior to and following dietary guidance. In conclusion, the densities of several duodenal enteroendocrine cells in IBS patients changed toward the values measured in control subjects following dietary guidance. The changes in serotonin and somatostatin cell densities may have contributed to the improvements in IBS symptoms, particularly pain and diarrhea. Impact statement Several contributing factors to the symptomology of irritable bowel syndrome (IBS) have been identified, such as abnormal densities of enteroendocrine cells and diet; however, the interactions between these factors have not been studied yet. The current study aims at exploring the dynamic changes between these two factors by studying the effect of using low fermentable oligo-, di-, monosaccharides and polyol (FODMAP) diet (known to improve IBS symptoms) through dietary guidance on the enteroendocrine cell densities in the duodenum. The findings showed that the densities of different enteroendocrine cells in the duodenum were abnormal before the patients received dietary guidance and tend to change/normalize after receiving guidance, which may have contributed in improving the symptoms of IBS. These findings highlight the importance of enteroendocrine cells in IBS pathophysiology and the mechanism behind the positive effect of low FODMAP dietary guidance in improving IBS symptoms and its usage as first step in the line of IBS management. PMID- 28737480 TI - Healthcare costs for allergic rhinitis patients on allergy immunotherapy: a retrospective observational study. AB - OBJECTIVE: Subcutaneous immunotherapy (SCIT) for allergic rhinitis (AR) has been shown to control symptoms for up to several years following treatment discontinuation, but the effect of SCIT on healthcare costs for commercially insured patients is unknown. The objective of this study was to compare healthcare costs and resource utilization for patients with AR who received SCIT compared with those who discontinued SCIT shortly after initiation. METHODS: This retrospective cohort study evaluated medical and pharmacy claims from the Optum Research Database from January 2009 through February 2014 for adults and pediatric patients with >7 (continuers) vs. <=7 (discontinuers) injection visits for SCIT within 60 days of initiation. RESULTS: After 1:1 propensity score matching, each cohort included 6710 patients. Continuers were less likely than discontinuers to use oral corticosteroids (27.7% vs. 29.6%, p = .018), or to have >=1 respiratory-related emergency room visit (5.4% vs. 6.5%, p = .008) and >=1 inpatient stay (1.1% vs. 1.7%; p = .002). Continuers were more likely than discontinuers to have >=1 AR-related office (98.8% vs. 94.6%, p < .001) or outpatient visit (2.4% vs. 1.7%, p = .002). Continuers had greater mean total AR related costs than discontinuers ($1918 vs. $646, p < .001). Unadjusted mean total respiratory-related costs were lower for continuers than discontinuers, although the difference was not statistically significant ($1589 vs. $1785, p = .077); when adjusted with a generalized linear model, these costs were significantly lower among continuers (p < .001). CONCLUSIONS: Continued SCIT use is associated with decreased emergency room visits and inpatient stays, decreased oral corticosteroid use, and lower respiratory-related costs, compared with early discontinuation. PMID- 28737482 TI - Corrigendum. PMID- 28737478 TI - Family matters: How MYC family oncogenes impact small cell lung cancer. AB - Small cell lung cancer (SCLC) is one of the most deadly cancers and currently lacks effective targeted treatment options. Recent advances in the molecular characterization of SCLC has provided novel insight into the biology of this disease and raises hope for a paradigm shift in the treatment of SCLC. We and others have identified activation of MYC as a driver of susceptibility to Aurora kinase inhibition in SCLC cells and tumors that translates into a therapeutic option for the targeted treatment of MYC-driven SCLC. While MYC shares major features with its paralogs MYCN and MYCL, the sensitivity to Aurora kinase inhibitors is unique for MYC-driven SCLC. In this review, we will compare the distinct molecular features of the 3 MYC family members and address the potential implications for targeted therapy of SCLC. PMID- 28737483 TI - Tissue Lesions Due to Spirorchiid Eggs in a Loggerhead Turtle ( Caretta caretta Linnaeus 1758) from Brazil: First Report Outside of the United States. AB - Spirorchiids (family Spirorchiidae Stunkard 1921) are a group of flukes that inhabit the circulatory system of turtles. Infection by members of the family Spirorchiidae involves egg deposition in the host bloodstream and accumulation in tissues, which cause inflammatory reactions and embolisms, leading or contributing to the death of the host. Reports of spirorchiid egg lesions in loggerhead turtles ( Caretta caretta Linnaeus, 1758) have only been reported from U.S. hosts. In the present report a female loggerhead sea turtle was found dead on the beach in the north part of the State of Rio de Janeiro, Brazil. During gross necropsy, no parasite egg nodule was found. But the microscopic analysis revealed a mild granulomatous inflammatory process due to eggs from the family Spirorchiidae and both Langhans giant cells and foreign-body giant cells in the heart, kidneys, intestines, lungs, and spleen. The present note is the first record of tissue lesions due to spirorchiid eggs in a loggerhead sea turtle outside the United States. PMID- 28737481 TI - Thermal response to firefighting activities in residential structure fires: impact of job assignment and suppression tactic. AB - Firefighters' thermal burden is generally attributed to high heat loads from the fire and metabolic heat generation, which may vary between job assignments and suppression tactic employed. Utilising a full-sized residential structure, firefighters were deployed in six job assignments utilising two attack tactics (1. Water applied from the interior, or 2. Exterior water application before transitioning to the interior). Environmental temperatures decreased after water application, but more rapidly with transitional attack. Local ambient temperatures for inside operation firefighters were higher than other positions (average ~10-30 degrees C). Rapid elevations in skin temperature were found for all job assignments other than outside command. Neck skin temperatures for inside attack firefighters were ~0.5 degrees C lower when the transitional tactic was employed. Significantly higher core temperatures were measured for the outside ventilation and overhaul positions than the inside positions (~0.6-0.9 degrees C). Firefighters working at all fireground positions must be monitored and relieved based on intensity and duration. Practitioner Summary: Testing was done to characterise the thermal burden experienced by firefighters in different job assignments who responded to controlled residential fires (with typical furnishings) using two tactics. Ambient, skin and core temperatures varied based on job assignment and tactic employed, with rapid elevations in core temperature in many roles. PMID- 28737484 TI - The effect of fiber and prebiotics on children's gastrointestinal disorders and microbiome. AB - INTRODUCTION: The bacteria received upon birth are the start of colonization of the approximately 1014 bacteria that are present in the mature human gastrointestinal tract, better known as the microbiota. The gut microbiota is implicated in gastrointestinal health, nutrient metabolism and benefits such as prevention of infection. Dietary fiber, including prebiotics, escape digestion in the small intestine and reach the colon intact, where they are partially or completely fermented by the gut microbiota. Areas covered: The possible interactions between dietary fiber, prebiotics and microbiota are discussed as well as how this relates to functional gastrointestinal disorders. During the first years of life the microbiota have not yet reached a stable state and is sensitive to disturbance by environmental factors. An imbalance in the microbiota early in life is found to be associated with several functional gastrointestinal disorders such as colic, functional abdominal pain, irritable bowel syndrome and constipation. Expert commentary: A better understanding of how gut microbial changes in early-life can impact gastrointestinal health might lead to new treatments or disease prevention. Nutritional strategies with fiber or prebiotics may support health due to modification of colonic microbiota composition and metabolic activity, for example by growth stimulation of Bifidobacterium and Lactobacillus. PMID- 28737485 TI - Risk-Taking During Feeding: Between- and Within-Population Variation and Repeatability Across Contexts Among Wild Zebrafish. AB - Behavioral responses are shaped by a complex interplay of extrinsic factors, such as predation and flow conditions, and intrinsic properties such as metabolic state. We investigated variations in boldness among four populations of zebrafish collected from widely varying habitat conditions across India. We measured feeding latencies of fish in four contexts: in a novel environment; in an environment with refuge and predators; in the presence of a shoal; and in the presence of a shoal and predators. The population from a high-flow and high predation habitat was significantly bolder than populations from low-predation and low-flow/stagnant habitats. Individuals were significantly bolder in the presence of shoal and predators than in the other contexts. In general, males were significantly bolder than females. Smaller individuals took greater risks to feed than larger individuals only within two populations. The high-predation, high-flow habitat fish also showed significantly lower between- and within individual variation in boldness than all the low-predation and low-flow populations. Furthermore, we found significantly repeatable responses across contexts within all populations, indicating behavioral consistency. Differences in response to variations in experimental contexts and stress and individual differences in metabolic rates could possibly explain the observed between- and within-individual variation among populations. PMID- 28737486 TI - 'No daddy', 'A kind of daddy': words used by donor conceived children and (aspiring) parents to refer to the sperm donor. AB - Research has shown that the recipients of donor sperm can experience difficulties finding appropriate language to refer to the donor. Based on two qualitative analysis techniques, namely word count and empirical discourse analysis, we studied the words used to refer to the donor in heterosexual and lesbian (aspiring) parents and in donor conceived children. Findings show that the words used in these households are highly diverse and have at least four different interlinked functions: (1) to position the donor in relation to the nuclear family; (2) to safeguard the role of the social parent; (3) to clarify family structure; and (4) to present a positive picture of the donor. Both parents and children consciously reflect on what words to use to refer to the donor. Although parents try to keep words like 'father' and 'daddy' out of the family narrative, children use these words. These findings show that it is important for healthcare personnel and policy makers to reflect on the careful use of terminology when they address questions around sperm donation because the terminology invokes specific meanings that have an effect on how the recipients and their children perceive the role of the donor. PMID- 28737487 TI - Task-dependent recurrent dynamics in visual cortex. AB - The capacity for flexible sensory-action association in animals has been related to context-dependent attractor dynamics outside the sensory cortices. Here, we report a line of evidence that flexibly modulated attractor dynamics during task switching are already present in the higher visual cortex in macaque monkeys. With a nonlinear decoding approach, we can extract the particular aspect of the neural population response that reflects the task-induced emergence of bistable attractor dynamics in a neural population, which could be obscured by standard unsupervised dimensionality reductions such as PCA. The dynamical modulation selectively increases the information relevant to task demands, indicating that such modulation is beneficial for perceptual decisions. A computational model that features nonlinear recurrent interaction among neurons with a task-dependent background input replicates the key properties observed in the experimental data. These results suggest that the context-dependent attractor dynamics involving the sensory cortex can underlie flexible perceptual abilities. PMID- 28737490 TI - Incarceration and infection: drug policy in the USA. PMID- 28737488 TI - Modulation of let-7 miRNAs controls the differentiation of effector CD8 T cells. AB - The differentiation of naive CD8 T cells into effector cytotoxic T lymphocytes upon antigen stimulation is necessary for successful antiviral, and antitumor immune responses. Here, using a mouse model, we describe a dual role for the let 7 microRNAs in the regulation of CD8 T cell responses, where maintenance of the naive phenotype in CD8 T cells requires high levels of let-7 expression, while generation of cytotoxic T lymphocytes depends upon T cell receptor-mediated let-7 downregulation. Decrease of let-7 expression in activated T cells enhances clonal expansion and the acquisition of effector function through derepression of the let-7 targets, including Myc and Eomesodermin. Ultimately, we have identified a novel let-7-mediated mechanism, which acts as a molecular brake controlling the magnitude of CD8 T cell responses. PMID- 28737491 TI - Safeguarding health in Europe's migrant hotspots. PMID- 28737492 TI - ASM Microbe 2017. PMID- 28737489 TI - NFATc2 enhances tumor-initiating phenotypes through the NFATc2/SOX2/ALDH axis in lung adenocarcinoma. AB - Tumor-initiating cells (TIC) are dynamic cancer cell subsets that display enhanced tumor functions and resilience to treatment but the mechanism of TIC induction or maintenance in lung cancer is not fully understood. In this study, we show the calcium pathway transcription factor NFATc2 is a novel regulator of lung TIC phenotypes, including tumorspheres, cell motility, tumorigenesis, as well as in vitro and in vivo responses to chemotherapy and targeted therapy. In human lung cancers, high NFATc2 expression predicted poor tumor differentiation, adverse recurrence-free and cancer-specific overall survivals. Mechanistic investigations identified NFATc2 response elements in the 3' enhancer region of SOX2, and NFATc2/SOX2 coupling upregulates ALDH1A1 by binding to its 5' enhancer. Through this axis, oxidative stress induced by cancer drug treatment is attenuated, leading to increased resistance in a mutation-independent manner. Targeting this axis provides a novel approach for the long-term treatment of lung cancer through TIC elimination. PMID- 28737493 TI - Cholera in Yemen. PMID- 28737496 TI - Claims of a cure for HIV come under fire. PMID- 28737499 TI - Tunable indirect-direct transition of few-layer SnSe via interface engineering. AB - Tin selenide (SnSe) is one of the best thermoelectric materials reported to date. The possibility of growing few-layer SnSe helped boost the interest in this long known, earth abundant material. Pristine SnSe in bulk, mono- and few-layer forms are reported to have indirect electronic bandgaps. Possible indirect-direct transition in SnSe is attractive for its optoelectronic-related applications. Based on the results from first principles density functional theory calculations, we carefully analyzed electronic band structures of bulk, and bilayer SnSe with various interlayer stackings. We report the possible stacking dependent indirect-direct transition of bilayer SnSe. By further analysis, our results reveal that it is the directionality of interlayer interactions that determine the critical features of their electronic band structures. In fact, by engineering the interface stacking between layers, it is possible to achieve few layer SnSe with direct electronic band gap. This study provides fundamental insights to design few-layer SnSe and SnSe heterostructures for electronic/optoelectronic applications, where the interface geometry plays a fundamental role in device performance. PMID- 28737500 TI - Quantum transport across van der Waals domain walls in bilayer graphene. AB - Bilayer graphene can exhibit deformations such that the two graphene sheets are locally detached from each other resulting in a structure consisting of domains with different van der Waals inter-layer coupling. Here we investigate how the presence of these domains affects the transport properties of bilayer graphene. We derive analytical expressions for the transmission probability, and the corresponding conductance, across walls separating different inter-layer coupling domains. We find that the transmission can exhibit a valley-dependent layer asymmetry and that the domain walls have a considerable effect on the chiral tunnelling properties of the charge carriers. We show that transport measurements allow one to obtain the strength with which the two layers are coupled. We perform numerical calculations for systems with two domain walls and find that the availability of multiple transport channels in bilayer graphene significantly modifies the conductance dependence on inter-layer potential asymmetry. PMID- 28737501 TI - Synthesis and enhanced microwave absorption properties: a strongly hydrogenated TiO2 nanomaterial. AB - Due to its improved physical and chemical performances, a strongly hydrogenated TiO2 was designed and produced successfully by using a sealing-transfer reduction method at a relatively low temperature (425 degrees C). The microstructures, electromagnetic and microwave absorbing properties were investigated in detail. Experimental results revealed that: (1) the minimum reflection loss (RL) value of the hydrogenated TiO2 up to -53.8 dB (99.999 99% of EM wave attenuation) was reached at 11.2 GHz, and the RL values below -20 dB (99%) were obtained in a frequency range of 7.3-16.8 GHz. (2) Compared to pristine TiO2 and black TiO2 in other reports, the present hydrogenated TiO2 exhibited greatly improved microwave absorption performance. Moreover, the mechanism was also discussed. It was demonstrated that the excellent microwave absorption performance of the black TiO2 arose from the strong dielectric loss, excellent impedance matching and attention loss due to associated relaxation and interfacial polarization. It is expected that the hydrogenated TiO2 exhibits great potential applications in the area of high performance microwave absorbing materials. In addition, it is believed that the black TiO2 @ magnetic metals composites will display an excellent microwave absorbing property. PMID- 28737502 TI - Intrinsic plasmarons in warm graphene. AB - Based on a self-consistent method, we predict theoretically that there exist intrinsic plasmarons in graphene at nonzero temperature, with a well defined mode, as shown by the result of Landau damping. We find that there are sharp differences between the discussed system and the QCD/QED system. Firstly, the thermal mass is proportional to [Formula: see text] but not [Formula: see text]. Secondly, at [Formula: see text], the fermion channel and plasmaron channel are nearly degenerate, and furthermore the energy difference between fermion and plasmaron becomes larger and larger with increasing q in the region [Formula: see text]. Thirdly, the fermion behaves as a 'relativistic particle' with nonzero mass, and the plasmaron exhibits an abnormal dispersion at moderate momentum. PMID- 28737503 TI - Directional connectivity in the EEG is able to discriminate wakefulness from NREM sleep. AB - : A reliable measure of consciousness is of great interest for various clinical applications including sleep studies and the assessment of depth of anaesthesia. A number of measures of consciousness based on the EEG have been proposed in the literature and tested in studies of dreamless sleep, general anaesthesia and disorders of consciousness. However, reliability has remained a persistent challenge. Despite considerable theoretical and experimental effort, the neural mechanisms underlying consciousness remain unclear, but connectivity between brain regions is thought to be disrupted, impairing information flow. OBJECTIVE: The objective of the current work was to assess directional connectivity between brain regions using directed coherence and propose and assess an index that robustly reflects changes associated with non-REM sleep. APPROACH: We tested the performance on polysomnographic recordings from ten healthy subjects and compared directed coherence (and derived features) with more established measures calculated from EEG spectra. We compared the performance of the different indexes to discriminate the level of consciousness at group and individual level. MAIN RESULTS: At a group level all EEG measures could significantly discriminate NREM sleep from waking, but there was considerable individual variation. Across all individuals, normalized power, the strength of long-range connections and the direction of functional links strongly correlate with NREM sleep stages over the experimental timeline. At an individual level, of the EEG measures considered, the direction of functional links constitutes the most reliable index of the level of consciousness, highly correlating with the individual experimental time line of sleep in all subjects. SIGNIFICANCE: Directed coherence provides a promising new means of assessing level of consciousness, firmly based on current physiological understanding of consciousness. PMID- 28737504 TI - Laser-driven coating of vertically aligned carbon nanotubes with manganese oxide from metal organic precursors for energy storage. AB - Carbon nanotubes-transition metal oxide systems are intensively studied due to their excellent properties for electrochemical applications. In this work, an innovative procedure is developed for the synthesis of vertically aligned multi walled carbon nanotubes (VACNTs) coated with transition metal oxide nanostructures. VACNTs are grown by plasma enhanced chemical vapor deposition and coated with a manganese-based metal organic precursor (MOP) film based on manganese acetate solution. Subsequent UV pulsed laser irradiation induces the effective heating-decomposition of the MOP leading to the crystallization of manganese oxide nanostructures on the VACNT surface. The study of the morphology, structure and composition of the synthesized materials shows the formation of randomly oriented MnO2 crystals, with few nanometers in size, and to their alignment in hundreds of nm long filament-like structures, parallel to the CNT's long axis. Electrochemical measurements reveal a significant increase of the specific capacitance of the MnO2-VACNT system (100 F g-1) as compared to the initial VACNT one (21 F g-1). PMID- 28737505 TI - Androgen-mediated sex bias impairs efficiency of leukotriene biosynthesis inhibitors in males. AB - Proinflammatory leukotrienes (LTs) are produced by 5-lipoxygenase (5-LO) aided by 5-LO-activating protein (FLAP). LT biosynthesis inhibitors are currently under clinical investigation as treatments for respiratory and cardiovascular diseases. Here, we have revealed a sex bias in the efficiency of clinically relevant LT biosynthesis inhibitors, showing that their effects are superior in females. We found that androgens cause these sex differences by impeding the LT-biosynthetic 5-LO/FLAP complex assembly. Lower doses of the FLAP inhibitor MK886 were required to reduce LTB4 levels in exudates of female versus male mice and rats. Following platelet-activating factor-induced shock, MK886 increased survival exclusively in female mice, and this effect was abolished by testosterone administration. FLAP inhibitors and the novel-type 5-LO inhibitors licofelone and sulindac sulfide exhibited higher potencies in human blood from females, and bioactive 5-LO/FLAP complexes were formed in female, but not male, human and murine leukocytes. Supplementation of female blood or leukocytes with 5alpha-dihydrotestosterone abolished the observed sex differences. Our data suggest that females may benefit from anti-LT therapy to a greater extent than males, prompting consideration of sex issues in LT modifier development. PMID- 28737507 TI - Leukotrienes and sex: strange bedfellows? AB - Leukotrienes are proinflammatory lipid mediators that have been shown to be upregulated in several diseases, including asthma, aspirin-exacerbated respiratory disease (AERD), inflammatory bowel disease, and acute respiratory distress syndrome. Leukotrienes have been explored as therapeutic targets for these diseases and others; however, leukotriene inhibitors have had limited success in the clinic. There are noted differences in the incidence of leukotriene-mediated diseases in males and females, but sex as a factor in the response to leukotriene inhibitors has not been fully explored. In this issue of the JCI, Pace and colleagues present evidence that there are sex-specific differences in the effectiveness of certain leukotriene inhibitors and link the differences in response to the presence of androgens. The results of this study indicate that sex needs to be taken into consideration in the future evaluation of leukotriene inhibitors to treat disease. PMID- 28737506 TI - Microglia and C9orf72 in neuroinflammation and ALS and frontotemporal dementia. AB - Amyotrophic lateral sclerosis (ALS) is a degenerative disorder that is characterized by loss of motor neurons and shows clinical, pathological, and genetic overlap with frontotemporal dementia (FTD). Activated microglia are a universal feature of ALS/FTD pathology; however, their role in disease pathogenesis remains incompletely understood. The recent discovery that ORF 72 on chromosome 9 (C9orf72), the gene most commonly mutated in ALS/FTD, has an important role in myeloid cells opened the possibility that altered microglial function plays an active role in disease. This Review highlights the contribution of microglia to ALS/FTD pathogenesis, discusses the connection between autoimmunity and ALS/FTD, and explores the possibility that C9orf72 and other ALS/FTD genes may have a "dual effect" on both neuronal and myeloid cell function that could explain a shared propensity for altered systemic immunity and neurodegeneration. PMID- 28737508 TI - Targeting NEK2 attenuates glioblastoma growth and radioresistance by destabilizing histone methyltransferase EZH2. AB - Accumulating evidence suggests that glioma stem cells (GSCs) are important therapeutic targets in glioblastoma (GBM). In this study, we identified NIMA related kinase 2 (NEK2) as a functional binding protein of enhancer of zeste homolog 2 (EZH2) that plays a critical role in the posttranslational regulation of EZH2 protein in GSCs. NEK2 was among the most differentially expressed kinase encoding genes in GSC-containing cultures (glioma spheres), and it was required for in vitro clonogenicity, in vivo tumor propagation, and radioresistance. Mechanistically, the formation of a protein complex comprising NEK2 and EZH2 in glioma spheres phosphorylated and then protected EZH2 from ubiquitination dependent protein degradation in a NEK2 kinase activity-dependent manner. Clinically, NEK2 expression in patients with glioma was closely associated with EZH2 expression and correlated with a poor prognosis. NEK2 expression was also substantially elevated in recurrent tumors after therapeutic failure compared with primary untreated tumors in matched GBM patients. We designed a NEK2 kinase inhibitor, compound 3a (CMP3a), which efficiently attenuated GBM growth in a mouse model and exhibited a synergistic effect with radiotherapy. These data demonstrate a key role for NEK2 in maintaining GSCs in GBM by stabilizing the EZH2 protein and introduce the small-molecule inhibitor CMP3a as a potential therapeutic agent for GBM. PMID- 28737509 TI - Astrocytic tight junctions control inflammatory CNS lesion pathogenesis. AB - Lesions and neurologic disability in inflammatory CNS diseases such as multiple sclerosis (MS) result from the translocation of leukocytes and humoral factors from the vasculature, first across the endothelial blood-brain barrier (BBB) and then across the astrocytic glia limitans (GL). Factors secreted by reactive astrocytes open the BBB by disrupting endothelial tight junctions (TJs), but the mechanisms that control access across the GL are unknown. Here, we report that in inflammatory lesions, a second barrier composed of reactive astrocyte TJs of claudin 1 (CLDN1), CLDN4, and junctional adhesion molecule A (JAM-A) subunits is induced at the GL. In a human coculture model, CLDN4-deficient astrocytes were unable to control lymphocyte segregation. In models of CNS inflammation and MS, mice with astrocyte-specific Cldn4 deletion displayed exacerbated leukocyte and humoral infiltration, neuropathology, motor disability, and mortality. These findings identify a second inducible barrier to CNS entry at the GL. This barrier may be therapeutically targetable in inflammatory CNS disease. PMID- 28737510 TI - Lymphocytes transiently expressing virus-specific T cell receptors reduce hepatitis B virus infection. AB - Adoptive transfer of T cells engineered to express a hepatitis B virus-specific (HBV-specific) T cell receptor (TCR) may supplement HBV-specific immune responses in chronic HBV patients and facilitate HBV control. However, the risk of triggering unrestrained proliferation of permanently engineered T cells raises safety concerns that have hampered testing of this approach in patients. The aim of the present study was to generate T cells that transiently express HBV specific TCRs using mRNA electroporation and to assess their antiviral and pathogenetic activity in vitro and in HBV-infected human liver chimeric mice. We assessed virological and gene-expression changes using quantitative reverse transcriptase PCR (qRT-PCR), immunofluorescence, and Luminex technology. HBV specific T cells lysed HBV-producing hepatoma cells in vitro. In vivo, 3 injections of HBV-specific T cells caused progressive viremia reduction within 12 days of treatment in animals reconstituted with haplotype-matched hepatocytes, whereas viremia remained stable in mice receiving irrelevant T cells redirected toward hepatitis C virus-specific TCRs. Notably, increases in alanine aminotransferase levels, apoptotic markers, and human inflammatory cytokines returned to pretreatment levels within 9 days after the last injection. T cell transfer did not trigger inflammation in uninfected mice. These data support the feasibility of using mRNA electroporation to engineer HBV TCR-redirected T cells in patients with chronic HBV infection. PMID- 28737511 TI - Astrocytes to the rescue! Glia limitans astrocytic endfeet control CNS inflammation. AB - The blood-brain barrier (BBB) and the glia limitans serve to prevent the migration of cells and other large molecules from the blood into the CNS. Neuroinflammatory diseases are characterized by disruption of the BBB and increased leukocyte infiltration into the CNS. In this issue of the JCI, Horng and colleagues demonstrate that astrocytes of the glia limitans induce tight junction formation in response to inflammatory cues, thereby tightening the border to limit the number of activated T cells infiltrating the CNS. Moreover, preventing the formation of this inducible barrier in mice increased disease severity in models of neuroinflammation. Together, the results of this study indicate that the inducible barrier of the glia limitans should be further explored as a therapeutic target. PMID- 28737512 TI - Thrombin promotes diet-induced obesity through fibrin-driven inflammation. AB - Obesity promotes a chronic inflammatory and hypercoagulable state that drives cardiovascular disease, type 2 diabetes, fatty liver disease, and several cancers. Elevated thrombin activity underlies obesity-linked thromboembolic events, but the mechanistic links between the thrombin/fibrin(ogen) axis and obesity-associated pathologies are incompletely understood. In this work, immunohistochemical studies identified extravascular fibrin deposits within white adipose tissue and liver as distinct features of mice fed a high-fat diet (HFD) as well as obese patients. Fibgamma390-396A mice carrying a mutant form of fibrinogen incapable of binding leukocyte alphaMbeta2-integrin were protected from HFD-induced weight gain and elevated adiposity. Fibgamma390-396A mice had markedly diminished systemic, adipose, and hepatic inflammation with reduced macrophage counts within white adipose tissue, as well as near-complete protection from development of fatty liver disease and glucose dysmetabolism. Homozygous thrombomodulin-mutant ThbdPro mice, which have elevated thrombin procoagulant function, gained more weight and developed exacerbated fatty liver disease when fed a HFD compared with WT mice. In contrast, treatment with dabigatran, a direct thrombin inhibitor, limited HFD-induced obesity development and suppressed progression of sequelae in mice with established obesity. Collectively, these data provide proof of concept that targeting thrombin or fibrin(ogen) may limit pathologies in obese patients. PMID- 28737514 TI - BAG3 plays a central role in proteostasis in the heart. AB - Proteinopathies are characterized by the accumulation of misfolded proteins, which ultimately interfere with normal cell function. While neurological diseases, such as Huntington disease and Alzheimer disease, are well characterized proteinopathies, cardiac diseases have recently been associated with alterations in proteostasis. In this issue of the JCI, Fang and colleagues demonstrate that mice with cardiac-specific deficiency of the co-chaperone protein BCL2-associated athanogene 3 (BAG3) develop dilated cardiomyopathy that is associated with a destabilization of small HSPs as the result of a disrupted interaction between BAG3 and HSP70. Together, the results of this study suggest that strategies to upregulate BAG3 during cardiac dysfunction may be beneficial. PMID- 28737513 TI - Loss-of-function mutations in co-chaperone BAG3 destabilize small HSPs and cause cardiomyopathy. AB - Defective protein quality control (PQC) systems are implicated in multiple diseases. Molecular chaperones and co-chaperones play a central role in functioning PQC. Constant mechanical and metabolic stress in cardiomyocytes places great demand on the PQC system. Mutation and downregulation of the co chaperone protein BCL-2-associated athanogene 3 (BAG3) are associated with cardiac myopathy and heart failure, and a BAG3 E455K mutation leads to dilated cardiomyopathy (DCM). However, the role of BAG3 in the heart and the mechanisms by which the E455K mutation leads to DCM remain obscure. Here, we found that cardiac-specific Bag3-KO and E455K-knockin mice developed DCM. Comparable phenotypes in the 2 mutants demonstrated that the E455K mutation resulted in loss of function. Further experiments revealed that the E455K mutation disrupted the interaction between BAG3 and HSP70. In both mutants, decreased levels of small heat shock proteins (sHSPs) were observed, and a subset of proteins required for cardiomyocyte function was enriched in the insoluble fraction. Together, these observations suggest that interaction between BAG3 and HSP70 is essential for BAG3 to stabilize sHSPs and maintain cardiomyocyte protein homeostasis. Our results provide insight into heart failure caused by defects in BAG3 pathways and suggest that increasing BAG3 protein levels may be of therapeutic benefit in heart failure. PMID- 28737516 TI - Pre-therapy Neural State of Bilateral Motor and Premotor Cortices Predicts Therapy Gain After Subcortical Stroke: A Pilot Study. AB - OBJECTIVE: The aim of the study was to examine whether neural state of spared motor and premotor cortices captured before a therapy predicts therapy-related motor gains in chronic subcortical stroke. DESIGN: Ten survivors, presenting chronic moderate upper limb impairment, underwent proton magnetic resonance spectroscopy, magnetic resonance imaging, clinical, and kinematics assessments before a 4-wk impairment-oriented training. Clinical/kinematics assessments were repeated after therapy, and motor gain was defined as positive values of clinical upper limb/elbow motion changes and negative values of trunk motion changes. Candidate predictors were N-acetylaspartate-neuronal marker, glutamate-glutamine indicator of glutamatergic neurotransmission, and myo-inositol-glial marker, measured bilaterally within the upper limb territory in motor and premotor (premotor cortex, supplementary motor area) cortices. Traditional predictors (age, stroke length, pre-therapy upper limb clinical impairment, infarct volume) were also investigated. RESULTS: Poor motor gain was associated with lower glutamate-glutamine levels in ipsilesional primary motor cortex and premotor cortex (r = 0.77, P = 0.01 and r = 0.78, P = 0.008, respectively), lower N acetylaspartate in ipsilesional premotor cortex (r = 0.69, P = 0.02), higher glutamate-glutamine in contralesional primary motor cortex (r = -0.68, P = 0.03), and lower glutamate-glutamine in contralesional supplementary motor area (r = 0.64, P = 0.04). These predictors outperformed myo-inositol metrics and traditional predictors (P ~ 0.05-1.0). CONCLUSIONS: Glutamatergic state of bilateral motor and premotor cortices and neuronal state of ipsilesional premotor cortex may be important for predicting motor outcome in the context of a restorative therapy. PMID- 28737517 TI - Intraoperative Detection of Persistent Endoleak by Detecting Residual Spontaneous Echocardiographic Contrast in the Aneurysmal Sac During Thoracic Endovascular Aortic Repair. AB - Persistent endoleaks may lead to adverse events after endovascular aortic repair. We prospectively examined the relationship between intraoperative residual spontaneous echocardiographic contrast (SEC) within the aneurysmal sac and the incidence of postoperative endoleaks in 60 patients undergoing thoracic endovascular aortic repair. Patients with SEC had a higher incidence of postoperative endoleaks than did patients without SEC within a few days postoperatively (60.0% vs 12.5%, respectively; P < .001) and at 6 months postoperatively (40.0% vs 2.5%, respectively; P < .001). Intraoperative confirmation of the absence of SEC may identify patients at low risk for persistent endoleaks after thoracic endovascular aortic repair. PMID- 28737518 TI - Dural Puncture Epidural Technique: Not So Fast. PMID- 28737515 TI - Cell biology of spinal cord injury and repair. AB - Spinal cord injury (SCI) lesions present diverse challenges for repair strategies. Anatomically complete injuries require restoration of neural connectivity across lesions. Anatomically incomplete injuries may benefit from augmentation of spontaneous circuit reorganization. Here, we review SCI cell biology, which varies considerably across three different lesion-related tissue compartments: (a) non-neural lesion core, (b) astrocyte scar border, and (c) surrounding spared but reactive neural tissue. After SCI, axon growth and circuit reorganization are determined by neuron-cell-autonomous mechanisms and by interactions among neurons, glia, and immune and other cells. These interactions are shaped by both the presence and the absence of growth-modulating molecules, which vary markedly in different lesion compartments. The emerging understanding of how SCI cell biology differs across lesion compartments is fundamental to developing rationally targeted repair strategies. PMID- 28737519 TI - In Response. PMID- 28737520 TI - Loss of Resistance Syringe: A Substitute for Cuff Pressure Manometer. PMID- 28737521 TI - Recommendations for Procedural Sedation Clinical Trials. PMID- 28737522 TI - Imaging Guidance for Thoracic Epidural Catheter Placement. PMID- 28737523 TI - Perioperative management of severe congenital protein C deficiency. AB - : Perioperative care of congenital protein C deficiency has not been well established. Here, we describe a patient with congenital protein C deficiency who underwent laparoscopic fundoplication and gastrostomy at 2 years of age. Preoperatively, we stopped warfarin, administered fresh frozen plasma, and activated protein C. These procedures were performed without bleeding or clotting events, and at 3 days after the procedures, we restarted warfarin. Several episodes of abdominal hemorrhage and purpura fulminans occurred 2-4 weeks postoperatively, and the events were managed conservatively. We conclude that an invasive procedure can be performed in patients with protein C deficiency with appropriate supportive therapy, and postoperative observation for a sufficient length of time is essential to minimize the risk of complications. PMID- 28737524 TI - Female athlete triad. AB - PURPOSE OF REVIEW: The obstetrician/gynecologist (ob/gyn) may be the first provider to have the opportunity to recognize and diagnose female athlete triad. This review will help the ob/gyn to understand the female athlete triad and what is new on this topic, how to screen and diagnose the condition and the ob/gyn's role in treatment. RECENT FINDINGS: Female athlete triad, also known as relative energy deficiency in sports, involves an interrelationship among energy availability, menstrual function and low bone density. When these components are not balanced, the health of the athlete is at risk. By using menstrual cycle as a vital sign, a careful medical history may alert you to this condition. The mainstay of treatment is achieving optimal energy balance and resumption of menses. This may involve dietary invention by increasing caloric intake or activity modification by limiting or restricting participation in sports. A multidisciplinary team, including the ob/gyn, athlete, coach, parents, sport nutritionist and sometimes psychiatrist/psychologist, is optimal for management. Medication may supplement but not replace treating the underlying condition. SUMMARY: The female athlete triad is an important disorder to identify, as early diagnosis and intervention may prevent long-term consequences, some of which may not be reversible if not diagnosed and treated. PMID- 28737525 TI - Death by "Snow"! A Fatal Forensic Case of Cocaine Leakage in a "Drug Mule" on Postmortem Computed and Magnetic Resonance Tomography Compared With Autopsy. AB - This forensic case presents unique postmortem imaging of a "drug mule" with fatal intoxication due to cocaine leakage on postmortem computed and magnetic resonance (MR) tomography compared with autopsy.Imaging by postmortem computed and MR tomography was performed before autopsy, histology, and toxicology were commissioned. Forensic imaging revealed 91 hyperdense, uniformly shaped body packs with signs of leakage, which was confirmed by autopsy. Postmortem MR imaging displayed the rarely described hypointense appearance of the body packs in T1- and T2-weighted sequences. Toxicology stated the dosage of cocaine intoxication as lethal.This case provides an opportunity to image internal cocaine drug containers on postmortem computed and MR tomography. The cause of death could be determined based on imaging and the radiological morphology of these packs by both imaging methods. PMID- 28737526 TI - Serial measurements of neutrophil gelatinase-associated lipocalin: prognostic value in patients with ST-segment elevation myocardial infarction treated with a primary percutaneous coronary intervention. AB - BACKGROUND: There are no previous data on serial changes in neutrophil gelatinase associated lipocalin (NGAL) levels in ST-segment elevation myocardial infarction (STEMI) patients before and after a primary percutaneous coronary intervention (pPCI). The aim of the present study was to evaluate the prognostic value of serial NGAL measurements in patients with STEMI treated by pPCI. MATERIALS AND METHODS: We identified 169 STEMI patients who underwent pPCI within 12 h of symptom onset and had plasma NGAL measurements before (pre-NGAL) and 6 h after (post-NGAL) pPCI. The primary endpoint was 30-day all-cause mortality, including cardiac death, whereas the secondary endpoint was the change in NGAL levels from before to after pPCI. RESULTS: The mean pre-NGAL and post-NGAL levels were 109.2+/-76.1 and 93.3+/-83.8 ng/ml, respectively. Thirty-day mortality occurred in 12 (7.1%) patients. In terms of changes in serial NGAL levels, post-NGAL levels were decreased in 132 (79%) patients. Patients with elevated post-NGAL levels showed increased mortality compared with patients with decreased post-NGAL levels (P=0.005). Multivariate analyses indicated that old age and high post-NGAL levels were independent risk factors for 30-day mortality. CONCLUSION: In a large percentage of STEMI patients, plasma post-pPCI NGAL levels were decreased compared with pre-pPCI NGAL levels, even with the administration of potentially nephrotoxic contrast medium. Post-NGAL levels seemed to be superior to pre-NGAL levels for the prediction of 30-day mortality outcome. PMID- 28737527 TI - Genitourinary vascularized composite allotransplantation. AB - PURPOSE OF REVIEW: Genitourinary vascularized allotransplantation (GUVCA) is gaining interest as a treatment option for patients with functional and aesthetic urogenital tissue loss. Only three cases have been done worldwide and research on the implementation and feasibility of this procedure is in an elementary state. RECENT FINDINGS: The psychosocial impact and ethical considerations with GUVCA are remote, particularly because of the intimate and personal nature of genital tissue. Though two of the three penile transplantation cases are considered successful, various unexpected factors and complications have been described alongside these successes. Treatment outcome depends on a complex combination of immunological, technical, and psychosocial components that will be different per individual case. Multidisciplinary evaluation and treatment protocols should be established to ensure that the quality of life in GUVCA recipients can be increased in a safe and ethical way. SUMMARY: Penile transplantation represents challenging new potential to improve phallus reconstruction in patients with severe genital tissue defects, but worldwide experience with GUVCA is limited. Controlled multicenter research is required to better define the risk/benefit ratio of this experimental yet promising treatment option. PMID- 28737529 TI - Observation About "Open Surgical Release of Posttraumatic Elbow Contracture in Children and Adolescents". PMID- 28737528 TI - Genetic variants of increased waist circumference in psychosis. AB - OBJECTIVE: We examined whether established metabolic risk genetic variants in the population confer a risk for increased waist circumference in patients with schizophrenia spectrum disorders and also an association with schizophrenia spectrum disorders irrespective of waist circumference. PATIENTS AND METHODS: We analyzed the association in (i) a case-case model in which patients with schizophrenia spectrum disorder with increased waist circumference (>=80 cm for women and >=94 cm for men) (n=534) were compared with patients with normal waist circumference (<80 cm for women; <94 cm for men) (n=124), and in (ii) a case control model in which schizophrenia spectrum disorder patients with increased waist circumference or irrespective of waist circumference were compared with population-derived controls (n=494) adjusted for age, sex, fasting glucose, smoking, and family history of diabetes. RESULTS: Genetic variants in five genes (MIA3, MRAS, P2RX7, CAMKK2, and SMAD3) were associated with increased waist circumference in patients with schizophrenia spectrum disorder (P<0.046). Genetic variants in three other genes (PPARD, MNTR1B, and NOTCH2) were associated with increased waist circumference in patients when compared with control individuals (P<0.037). Genetic variants in the PPARD, MNTR1B, NOTCH2, and HNF1B were nominally associated with schizophrenia spectrum disorder irrespective of waist circumference (P<0.027). No differences in waist circumference between specific psychosis diagnoses were detected. CONCLUSION: Increased waist circumference in patients with schizophrenia spectrum disorder may be explained, in part, by increased metabolic risk gene burden, and it indicates a shared genetic susceptibility to metabolic disorder and psychosis per se. Along these lines, common metabolic risk genetic variants confer a risk for increased waist circumference in patients with schizophrenia spectrum disorders. PMID- 28737530 TI - Ultrasound Characteristics of Clinically Dislocated But Reducible Hips With DDH. AB - BACKGROUND: Although ultrasound (US) is frequently used in diagnosis and management of infantile developmental dysplasia of the hip, precise ultrasonographic parameters of what constitutes a dislocation, subluxation etc remain poorly defined. The purpose of this study was (1) to describe the ultrasonographic characteristics of a large cohort of clinically dislocated but reducible hips and (2) to begin to develop ultrasonographic definitions for what constitutes a hip dislocation. METHODS: A retrospective review of prospectively collected data from an international multicenter study group on developmental dysplasia of the hip was conducted on all patients under 6 months of age with hip(s) that were dislocated at rest but reducible based on initial physical examination (ie, Ortolani positive). Femoral head coverage (FHC), alpha angle (alpha), and beta angle (beta) were measured on pretreatment US by the individual treating surgeon, and were recorded directly into the database. RESULTS: Based on 325 Ortolani positive hips, the median FHC on presentation was 10% with an interquartile range of 0% to 23%. A total of 126 of the 327 hips (39%) demonstrated 0% FHC. The 90th percentile was found to be at 33% FHC. Of 264 hips with sufficient alpha data, the median alpha was 43 degrees with an interquartile range from 37 to 49 degrees. The 90th percentile for alpha was at 54 degrees. A total of 164 hips had documented beta with a median of 66 degrees and an interquartile range of 57 to 79 degrees; the 90th percentile was at 94 degrees. CONCLUSIONS: Analysis of a large cohort of patients with dislocated but reducible hips reveals a median percent FHC of 10%, a median alpha of 43 degrees, and a median beta of 66 degrees on initial US. Using a threshold at the 90th percentile, a sensible ultrasonographic definition of a dislocated hip seems to be FHC<=33%, implying that FHC between 34% and 50% may be reasonably termed a subluxation. Although these findings are consistent with previous, smaller reports, further prospective research is necessary to validate these thresholds. LEVEL OF EVIDENCE: Level IV-diagnostic study.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/. PMID- 28737532 TI - Limbal Trocar-Cannulas for Complex Vitrectomy Surgery. PMID- 28737531 TI - Potential Causes of Elevated REE after High-Intensity Exercise. AB - INTRODUCTION: Resting energy expenditure (REE) increases after an intense exercise; however, little is known concerning mechanisms. PURPOSE: The purpose of this study was to determine effects of a single bout of moderate-intensity continuous (MIC) aerobic exercise, or high-intensity interval (HII) exercise on REE under energy balance conditions. METHODS: Thirty-three untrained premenopausal women were evaluated at baseline, after 8-16 wk of training, 22 h after either MIC (50% peak VO2) or HII (84% peak VO2). Participants were in a room calorimeter during and after the exercise challenge. Food intake was adjusted to obtain energy balance across 23 h. REE was measured after 22 h after all conditions. Twenty-three-hour urine norepinephrine concentration and serum creatine kinase activity (CrKact) were obtained. Muscle biopsies were obtained in a subset of 15 participants to examine muscle mitochondrial state 2, 3, and 4 fat oxidation. RESULTS: REE was increased 22 h after MIC (64 +/- 119 kcal) and HII (103 +/- 137 kcal). Markers of muscle damage (CrKact) increased after HII (9.6 +/ 25.5 U.L) and MIC (22.2 +/- 22.8 U.L), whereas sympathetic tone (urine norepinephrine) increased after HII (1.1 +/- 10.6 ng.mg). Uncoupled phosphorylation (states 2 and 4) fat oxidation were related to REE (r = 0.65 and r = 0.55, respectively); however, neither state 2 nor state 4 fat oxidation increased after MIC or HII. REE was not increased after 8 wk of aerobic training when exercise was restrained for 60 h. CONCLUSIONS: Under energy balance conditions, REE increased 22 h after both moderate-intensity and high-intensity exercise. Exercise-induced muscle damage/repair and increased sympathetic tone may contribute to increased REE, whereas uncoupled phosphorylation does not. These results suggest that moderate- to high-intensity exercise may be valuable for increasing energy expenditure for at least 22 h after the exercise. PMID- 28737533 TI - PROPHYLACTIC PREOPERATIVE LASER RETINOPEXY DOES NOT REDUCE THE OCCURRENCE OF RHEGMATOGENOUS RETINAL COMPLICATIONS IN MACULAR SURGERY. AB - PURPOSE: Knowledge on the utility of prophylactic 360 degrees laser retinopexy before pars plana vitrectomy in the absence of peripheral retinal pathology is limited. This study compares the occurrence of rhegmatogenous events in the setting of small-gauge pars plana vitrectomy with and without prophylactic preoperative laser. METHODS: Our multicenter, retrospective case-control analysis reviewed patients who underwent epiretinal membrane removal or macular hole repair through 23- or 25-gauge pars plana vitrectomy: 205 controls who did not receive prophylactic laser and 176 cases who received preoperative prophylactic laser retinopexy anterior to the equator. Main outcome measures were the rate and characteristics of postoperative retinal tears and detachments. Patients with previous pars plana vitrectomy or significant retinal disease were excluded. RESULTS: Of those patients with prophylactic laser and those without, there was no significant difference in the number of retinal breaks (1.7% vs. 0.49%, respectively; P = 0.339) or retinal detachments (0% vs. 0.49%, respectively; P = 1.00). Of the lasered group, there was one sclerotomy-related retinal break and two non-sclerotomy-related retinal breaks. Of the nonlasered group, there was one non-sclerotomy-related retinal break and one sclerotomy-related retinal detachment. CONCLUSION: Preoperative prophylactic peripheral laser retinopexy does not seem to offer an added benefit in the prevention of intraoperative and postoperative rhegmatogenous events. PMID- 28737534 TI - Considerations in the Understanding of Venous Outflow in the Retinal Capillary Plexus. PMID- 28737535 TI - Internal Limiting Membrane Retracting Door for Myopic Macular Holes. PMID- 28737537 TI - Global Perinatal Nursing Research: Sustainable Development Goals Update. PMID- 28737536 TI - From the Editors. PMID- 28737538 TI - Patient-Centered Culturally Sensitive Maternity Care Begins at Home. PMID- 28737539 TI - Hand Hygiene: A Back to Basics Global Health Initiative. PMID- 28737540 TI - Periviable Birth: More Issues Than Answers? PMID- 28737541 TI - Vaccine Culture in the Neonatal Intensive Care Unit: Good Habits Start Here. PMID- 28737542 TI - Addressing the Global Zika Epidemic Locally: An Interprofessional Model of Universal Screening at One Center. PMID- 28737543 TI - A Program Aimed at Reducing Anxiety in Pregnant Women Diagnosed With a Small-for Gestational-Age Fetus: Evaluative Findings From a Spanish Study. AB - The objective of this study was to evaluate the effect of anxiety-reducing techniques including music therapy, sophrology, and creative visualization in pregnant women with a fetus diagnosed as small for gestational age and improved fetal and neonatal weight. This was a quasi-experimental study with a nonrandomized clinical trial design. We compared 2 groups of pregnant women with a fetus diagnosed as small for gestational age with no abnormalities on Doppler studies. The control group (n = 93) received standard care, and the intervention group (n = 65), in addition to standard care, underwent a program of 6 sessions led by a midwife or nurse who taught anxiety-reduction techniques. The State Trait Anxiety Inventory (STAI) including trait and state subscales were completed by both groups at the start of the study, and only the STAI-State subscale was completed again at the end of the study. Comparisons between the 2 groups regarding fetal weight and centile and maternal STAI scores were performed using the t test and the chi test. There were no significant differences in the STAI Trait scores between the 2 groups. There were statistically significant differences in the intervention group's STAI-State score percentiles between the start and the end of the study, being lower at the end of the study (P < .001). There were significant differences between the 2 groups in fetal weight trajectory on the basis of fetal weight: the intervention group had a larger weight gain (P < .005). The program designed to reduce anxiety in pregnant women was effective at reducing anxiety in the women in the intervention group, leading to a favorable fetal weight trajectory in this group. PMID- 28737544 TI - Utilization of Large Data Sets in Maternal Health in Finland: A Case for Global Health Research. AB - In recent years, the use of large data sets, such as electronic health records, has increased. These large data sets are often referred to as "Big Data," which have various definitions. The purpose of this article was to summarize and review the utilization, strengths, and challenges of register data, which means a written record containing regular entries of items or details, and Big Data, especially in maternal nursing, using 4 examples of studies from the Finnish Medical Birth Register data and relate these to other international databases and data sets. Using large health register data is crucial when studying and understanding outcomes of maternity care. This type of data enables comparisons on a population level and can be utilized in research related to maternal health, with important issues and implications for future research and clinical practice. Although there are challenges connected with register data and Big Data, these large data sets offer the opportunity for timely insight into population-based information on relevant research topics in maternal health. Nurse researchers need to understand the possibilities and limitations of using existing register data in maternity research. Maternal child nurse researchers can be leaders of the movement to utilize Big Data to improve global maternal health. PMID- 28737546 TI - The Perinatal-Neonatal Care Journey for Parents of Preterm Infants: What Is Working and What Can be Improved. PMID- 28737545 TI - The Perinatal-Neonatal Care Journey for Parents of Preterm Infants: What Is Working and What Can Be Improved. AB - Preterm birth is traumatic for parents, but there are few reports of parents' views on how the healthcare journey can be improved. This secondary thematic analysis used focus group data from parent consultation on proposed neonatal services standards for Northern Ireland to discover parents' experiences and recommendations for the perinatal, neonatal, and home care phases. Parents of preterm infants (n = 40) described their healthcare journey as positive overall and were grateful for the caring and competent care providers they encountered. However, parents described experiences that varied in quality and family centeredness across the care journey from perinatal to home care. They noted inconsistencies in healthcare team communication and provider practices and reported receiving limited emotional and practical support at all phases. In the perinatal phase, parents described difficult situations of discovering medical problems leading to preterm birth. In the neonatal intensive care unit phase, they also experienced unmet needs for involvement in decision making, financial strain, and difficulty coping with transfers and discharge. Parents experienced emotional challenges and lack of support in the home care phase. Parents identified actions that health systems can take to improve the consistency of care and communication across all phases and settings to encourage better collaboration and transitions in care. PMID- 28737547 TI - Quality Improvement Initiative for Family-Centered Care in the Neonatal Intensive Care Unit of a Tertiary Hospital in South Africa. AB - The introduction of family-centered care in the neonatal intensive care unit was identified as a high priority to facilitate bonding and attachment with potential positive outcomes for the parents and infants. The aim of the study was, therefore, to develop and implement a quality improvement initiative to foster family-centered care in a tertiary neonatal intensive care unit from birth onward. A pretest posttest intervention design was used using mixed methods over 3 phases to determine the perceived level of family-centered care according to healthcare professionals and parents using self-administered questionnaires; to develop and implement a quality improvement initiative to enhance family-centered care in a neonatal intensive care unit using a nominal group technique, followed by the quality improvement process; and to evaluate the outcomes of the initiative by repeating the self-administered questionnaires to parents and staff. Various activities were introduced as part of the initiative such as early breastfeeding, early introduction of parents to their infant, open visitation policy, and involvement in caring activities. The perceived level of care according to staff and parents increased. It is expected to enhance bonding and attachment between the infants and their parents, with consequential long-term positive outcomes. PMID- 28737549 TI - Personalized Report Cards. PMID- 28737548 TI - Voluntourism: Who Are We Truly Helping? PMID- 28737550 TI - Intestinal cestodes. AB - PURPOSE OF REVIEW: Cestodes infections in humans are among the most prevalent parasitosis worldwide. Although tapeworm infection is often asymptomatic, they can be associated with a range of symptoms. The landscape of cestode infections is changing with rapid diagnosis techniques and advanced molecular diagnosis aiding in identification of species specific epidemiology. RECENT FINDINGS: Traditional descriptions of species by location have been challenged with molecular diagnostic techniques, which show variation in distribution of species, thought to be because of globalization and importation of disease. MAIN THEMES IN LITERATURE: Epidemiology, molecular diagnostic techniques. SUMMARY: Infection by tapeworms is often asymptomatic or accompanied by mild symptoms though can occasionally cause severe disease and contribute to anemia and malnutrition. Tapeworm infection is most prevalent in resource-poor countries but the distribution is worldwide. Epidemiology of infection is changing because of molecular diagnostics, which allow more accurate tracking of species. PMID- 28737551 TI - Vibrotactile Thresholds on the Mastoid and Forehead Position of Deaf Patients Using Radioear B71 and B81. AB - OBJECTIVES: The main objective of this study was to measure the vibrotactile thresholds on the mastoid process and forehead positions using patients with bilateral deafness and to compare the results from the two bone conduction vibrators Radioear B71 and B81. DESIGN: There is a possibility that the vibrotactile sensation on the skin makes it difficult to discriminate between sound and vibration. The risk is highest for patients who have bone conduction hearing thresholds in proximity to or worse than their vibrotactile thresholds. All measurements were performed similar to regular bone conduction threshold testing using an audiometer-driven bone conduction vibrator and pulsed warble tones, but the patients were instructed to respond only when feeling vibrations of the bone conduction vibrator instead of when hearing sound. Both the posterior forehead position and the mastoid process position on the temporal bone were tested for comparative reasons. In total, 16 patients participated in the study, 31% females and 69% males of age 29 to 77 years. All subjects were cochlear implant recipients, either uni- or bilaterally implanted. They were selected based on their audiogram data showing unmeasurable unaided hearing. RESULTS: The force level at which the vibrotactile thresholds were reached, increased with frequency from 125 up to 500 Hz, but remained constant for higher frequencies up to 2 kHz. A statistically significant difference was found between the 2 devices at 125 Hz at both the mastoid process and forehead position, where the vibrotactile threshold seem to be more sensitive for B71, possibly due to contribution of distortion components. There was no statistically significant difference in vibrotactile thresholds between the mastoid process and forehead position in absolute values (force level in dB re 1 uN), but in terms of hearing levels (dB HL) there was an average difference of 10 and 9 dB for B71 and B81, respectively. CONCLUSIONS: The results indicate that the vibrotactile thresholds can be confounded with bone conduction hearing thresholds measurements up to 500 Hz when using a standard audiometer and in particular when measuring on the forehead position. PMID- 28737552 TI - Two familial intrachromosomal insertions with maternal dup(6)(p22.3p25.3) or dup(2)(q24.2q32.1) in recombinant offspring. AB - In this study, we describe two patients with a recombinant chromosome secondary to a maternal intrachromosomal insertion. Patient 1 was a girl with dup(6)(p22.3p25.3). Patient 2 was a boy with dup(2)(q24.2q32.1). Both familial rearrangements were characterized by means of GTG-bands, fluorescence in-situ hybridization, and comparative genomic hybridization microarray analyses. Patient 1 had an ~23 Mb gain that involved the bands 6p22.3-6p25.3. Patient 2 had an ~23 Mb gain (cytobands 2q24.2-2q32.1) and a further ~1.9 Mb gain of 2p16.2-p16.3. The phenotype of each patient was in agreement with the typical 6p duplication or 2q24.2q32.1 duplication syndrome. The compound macular lesion in patient 1 suggests that retinal anomalies may be a part of the 6p trisomy phenotype. Among the 70 intrachromosomal insertions compiled here (including 68 from the literature), four were submicroscopic unbalanced insertions inherited from a balanced carrier and 66 were detectable on banded chromosomes (with or without array comparative genomic hybridization or other high-resolution assessment) and therefore spanned at least 5 Mb. Pericentric insertions are found in most chromosomes, whereas the paracentric ones are mainly observed in large and medium chromosome arms. That the former outnumber the latter in almost a 2 : 1 ratio appears to be related to the technique of diagnosis, size of the insertion, and size of the involved chromosome. Regardless of the apparent excess of carrier mothers, carriers of an intrachromosomal insertion beget almost twice as many children with a duplication than with a deletion. PMID- 28737553 TI - Complications After Body Contouring Surgery in Postbariatric Patients. AB - INTRODUCTION: Over recent years, body contouring procedures in postbariatric patients have been in exponentially growing demand resulting in high complication rates rendering a variety of ciphers in the literature. OBJECTIVE: The purpose of this study is to determine the complication rate in patients who have undergone body contouring surgery after bariatric surgery between June 2012 and March 2015 at Hospital de San Jose. METHODS: A cohort study including 153 individuals who underwent a total of 198 body contouring procedures after massive weight loss following bariatric surgery was conducted. Data on variables, such as complication rate according to the type of body contouring surgery, major and minor complications, weight of resected tissue, or intraoperation time, among other variables, were analyzed. RESULTS: A total of 198 procedures were performed in 153 patients. The mean (SD) age of the patients was 43.93 years (9.4 years). Of 198 procedures, 110 (55.5%) had complications. The rate for major complications was 13%, and for minor complications, 87%. Complication rates according to the type of operation were as follows: circumferential abdominal lipectomy, 55.7%; extended abdominal lipectomy, 53.7%; cruroplasty, 69%; breast surgery, 57%; and brachioplasty, 40%. Patients who presented with bleeding enough to require transfusion (P = 0.000) and with weight of the resected tissue greater than 2700 g in abdominoplasty (odds ratio, 3.26; 95% confidence interval, 1.48 7.1) had a higher complication rate. There were no thromboembolic events among this population. CONCLUSIONS: The overall complication rate was 55.5%. The great majority were minor complications. The thromboprophylaxis regimen used was 100% effective. PMID- 28737554 TI - Standardized Protocol for Virtual Surgical Plan and 3-Dimensional Surgical Template-Assisted Single-Stage Mandible Contour Surgery. AB - BACKGROUND: Mandible contour surgery, including reduction gonioplasty and genioplasty, has become increasingly popular in East Asia. However, it is technically challenging and, hence, leads to a long learning curve and high complication rates and often needs secondary revisions. The increasing use of 3 dimensional (3D) technology makes accurate single-stage mandible contour surgery with minimum complication rates possible with a virtual surgical plan (VSP) and 3 D surgical templates. This study is to establish a standardized protocol for VSP and 3-D surgical templates-assisted mandible contour surgery and evaluate the accuracy of the protocol. METHODS: In this study, we enrolled 20 patients for mandible contour surgery. Our protocol is to perform VSP based on 3-D computed tomography data. Then, design and 3-D print surgical templates based on preoperative VSP. The accuracy of the method was analyzed by 3-D comparison of VSP and postoperative results using detailed computer analysis. RESULT: All patients had symmetric, natural osteotomy lines and satisfactory facial ratios in a single-stage operation. The average relative error of VSP and postoperative result on the entire skull was 0.41 +/- 0.13 mm. The average new left gonial error was 0.43 +/- 0.77 mm. The average new right gonial error was 0.45 +/- 0.69 mm. The average pognion error was 0.79 +/- 1.21 mm. Patients were very satisfied with the aesthetic results. Surgeons were very satisfied with the performance of surgical templates to facilitate the operation. CONCLUSIONS: Our standardized protocol of VSP and 3-D printed surgical templates-assisted single-stage mandible contour surgery results in accurate, safe, and predictable outcome in a single stage. PMID- 28737555 TI - L-Shaped Septal Extension Spreader Graft for Improvement of Tip Symmetry in Unilateral Cleft Lip Nose Deformities. AB - INTRODUCTION: The unilateral cleft lip nose is characterized by numerous complex and interdependent deformities. Secondary rhinoplasty techniques aim to correct cleft lip nose deformities by using multiple maneuvers combining septum and nasal spine medialization and alar cartilage, as well as soft tissue mobilization and repositioning. Moreover, cartilage grafting is frequently used to restore adequate tip projection and nasal symmetry. We present a technique of cartilage grafting commonly used in noncleft rhinoplasties that we modified for cases of moderate cleft lip nose deformities. PATIENTS AND METHODS: We present a retrospective case study of 21 patients with moderate unilateral cleft lip nose deformities who underwent secondary septorhinoplasty with an L-shaped septal extension spreader graft combined with alar rim, alar batten graft, and soft tissue repositioning. Exclusion criteria were severe or complex septal deviation avoiding a stable fixation of the graft. Mean follow-up time was 28 months. Surgical outcomes were analyzed by anthropometric measurements of standardized preoperative and postoperative photographs. RESULTS: All parameters improved except for the nostril height. The height between the alar base and the dome defining dome symmetry, as well as the angles between the lower lateral cartilage and the alar base (alpha) defining the orientation of the alar rim, improved significantly. The mean ratios of cleft/noncleft side of the height between the alar base and the dome and alpha showed statistically significant improvements from 0.833 (preoperative) to 0.994 (postoperative) (P < 0.0001) and from 0.883 to 1.02 (P = 0.0038), respectively. CONCLUSIONS: The L-shaped septal extension spreader graft combined with alar batten graft and soft tissue repositioning is an option for secondary rhinoplasties in unilateral cleft lip nose deformities minimizing tip rigidity with significant improvement of the dome's height and its symmetry, as well as the alar side angle. PMID- 28737556 TI - Application of Epineural Sheath as a Novel Approach for Fat Volume Maintenance. AB - INTRODUCTION: Various methods have been suggested to improve fat graft survival and decrease graft loss. The exact mechanism of fat graft survival is still unclear, and new strategies are needed to further investigate it. MATERIALS AND METHODS: The efficacy of epineural sheath in fat volume maintenance was tested in rat model. Five experimental groups were created: group 1, fat graft without any coverage; group 2, epineural sheath tube alone; group 3, epineural sheath tube filled with fat graft; group 4, fat graft mixed with minced epineural sheath without any coverage; and group 5, fat graft covered with the epineural sheath patch. All grafts were implanted into the dorsal subcutaneous region and were followed for up to 12 weeks, when samples were harvested for hematoxylin and eosin and immunostaining for vascular endothelial growth factor expression and perilipin evaluation of fat viability. RESULTS: In groups 1 and 4, over 25% of graft loss was observed at first week, over 50% at third week, and 100% at sixth week postimplantation. The weight of fat graft within the epineural sheath tube and the weight of epineural tube (ET) alone were maintained up to 12 weeks postimplantation. The weight of fat graft within the epineural patch was maintained up to 6 weeks, but 50% of weight loss was observed between 6 and 12 weeks. Structure of the epineural sheath tubes and patches was intact, and no leakage of fat graft was observed. Based on hematoxylin and eosin staining, normal structure and integrity of the fat graft within the ET were preserved up to 12 weeks postimplantation. Characteristic adipocyte morphology was confirmed by perilipin staining, showing viable fat cells in groups 3 and 5 at 12 weeks. Increased vascular endothelial growth factor expression was observed in groups 2, 3, 4, and 5. CONCLUSIONS: Both, the ETs and epineural patches maintained 100% and 50% of fat graft weight at 12 weeks postimplantation, respectively. These results were confirmed by histology and immunostaining showing viable adipocytes within the epineural patches (6 weeks) and tubes (12 weeks). These results are encouraging and justify further evaluation of fat volume maintenance in preclinical large animal model in preparation to clinical application. PMID- 28737557 TI - Human and Autologous Adipose-derived Stromal Cells Increase Flap Survival in Rats Independently of Host Immune Response. AB - INTRODUCTION: There is a rising interest in adipose-derived stromal cells for clinical use; however, it is unknown whether freshly isolated stromal cells (SVF) or culture-expanded cells (ASCs) are more efficacious. We therefore aimed to compare the 2 cellular therapies in an in vivo model of angiogenesis, the ischemic flap in rats, which induces acute ischemia. We also aimed to determine the importance of cell presence and the host immune response. METHODS: A total of 96 rats (n = 12 in each group) were used, and in each rat, a caudally based random flap measuring 2 * 7 cm was made. The study was conducted in 3 phases. First, each rat was treated with human SVF cells, human ASCs, or vehicle. Second, each rat was treated with human SVF, human SVF lysate, or vehicle. Finally, each rat was treated with rat (autologous) SVF cells or vehicle. Flap survival, vessel density, and stromal cell retention were evaluated after 7 days. RESULTS: The mean survival rates for SVF treatment regardless of human or autologous origin were significantly increased as compared with the control group. Adipose stem/stromal cell and SVF lysate injection did not increase flap survival. Vessel density was increased for human and rat SVF and human ASC but not for SVF lysate. Human cells were not detected in the flaps after 7 days. CONCLUSIONS: Flap survival increased with SVF treatment regardless of human or autologous origin, suggesting that increased flap survival is independent of the host immune response. All cell injections lead to increased vessel density, but it did not necessarily lead to increased flap survival. Further research should elaborate which molecular events make SVF treatment more efficacious than ASC. PMID- 28737558 TI - Upper Extremity Patterns of Injury and Management at a Plastic and Reconstructive Surgery Referral Center in Mexico City. AB - BACKGROUND: Acute upper extremity injuries remain one of the most common consultations in the emergency departments for plastic surgery services. These injuries can affect a person's quality of life and negatively affect work-related or social interactions if not properly managed. We aim to evaluate our experience and management in a specialized referral center in Mexico City. METHODS: A retrospective review was performed. All patients with hand trauma managed by our service from July 2010 to June 2015 were included; their demographic characteristics were described as well as the most common patterns of injury, management, and outcome. RESULTS: A total of 4751 patients with injuries in the upper extremities were included, 77% were males with a mean age of presentation of 26.9 +/- 17.9 years; the age group most commonly affected was between 16 to 30 years (39%); 54% of the cases affected the right hand. Lacerative wounds were the most common mechanism of injury (60.7%), followed by blunt trauma (28.7%). Management was surgical in 87% of the cases. CONCLUSIONS: Upper extremity trauma encompasses a wide range of clinical presentations, from simple lacerations to catastrophic injuries that require extensive or multiple reconstructive procedures. The clear understanding of the trauma mechanisms and how they are related with certain patterns of injury might maximize awareness and guide a surgeon's management effectively. PMID- 28737559 TI - Complex Reconstruction After Sarcoma Resection and the Role of the Plastic Surgeon: A Case Series of 298 Patients Treated at a Single Center. AB - BACKGROUND: More than 1000 new patients present to the London Sarcoma Unit each year and between 5% and 10% require plastic surgery intervention. Advancements in radiotherapy and chemotherapy protocols combined with higher expectations for limb preservation has led to increased reconstructive challenges. Frequently, primary closure is achievable; however, larger tumors often require specialist reconstruction. STUDY DESIGN: A retrospective chart review of all referred patients from the London Sarcoma Unit requiring reconstruction between February 2006 and January 2015 was performed. Patients who underwent primary amputation were excluded. RESULTS: The total number of operations performed was 298 and the mean follow-up was 16 months (12-46 months). 51% of patients had major comorbidities. Patients could be separated into early (0-1 week postoperatively, n = 167) and late reconstructions (>1 week postoperatively, n = 131). 32 patients were reconstructed with skin grafts, 137 patients were managed with regional flaps and 129 patients were treated with free flaps. CONCLUSIONS: A patient with 3 or more major comorbidities resulted in a significantly increased risk of reconstructive failure (P < 0.05). Our experience has lead us to adhere to the following guidelines: (1) All patients should be reviewed in a multidisciplinary team meeting. (2) After primary excision, patients should be managed with a vacuum dressing until margins are clear. (3) Definitive reconstruction should be performed by a specialist reconstructive surgeon. PMID- 28737560 TI - Influence of Large-Volume Liposuction on Metabolic and Cardiovascular Health: A Systematic Review. AB - BACKGROUND: Evidence suggesting that adipose tissue is a metabolically active tissue has generated debate on the effects of large-volume liposuction (LVL) on metabolic and cardiovascular health. Given the inconsistency in the literature, the authors performed a systematic review to identify available evidence in order to elucidate the potential impact of LVL on metabolic markers and cardiovascular risk factors. METHODS: A PubMed search using relevant keywords was conducted. Articles were screened using predetermined inclusion and exclusion criteria. Large-volume liposuction was defined as greater than 3.5 L of lipoaspirate. All studies included evaluation of patients' preoperative and postoperative cardiovascular risk factors, inflammatory cytokines, and/or insulin resistance/sensitivity. Relevant studies were evaluated and assigned a level of evidence. RESULTS: A total of 12 studies that met the inclusion criteria were reviewed, of which 1 was a continuation of a previous study. All reports were prospective studies, 2 were randomized control trials, and 3 included a control group. A total of 364 patients were pooled for analysis. The mean volume of lipoaspirate was 7440 +/- 1934.9 mL. The mean body mass index at baseline and postliposuction was 30.7 and 28.4, respectively. Seven studies reported a trend toward decrease in total cholesterol levels with an overall mean reduction of 0.21 +/- 0.05 mmol/L from 4.6 +/- 0.79 mmol/L to 4.4 +/- 0.74 mmol/L. After LVL, leptin was reported to significantly decrease in 4 studies, and TNF-alpha was reported to significantly decrease in 2. Adiponectin was reported to significantly increase in 2 studies. IL-6 decreased significantly in 2 studies. Two studies included participants with type II diabetes mellitus, whereas 10 studies evaluated insulin sensitivity. Of these, 6 studies reported improvement in insulin sensitivity. Six studies represented level IV and 6 represented level II evidence. CONCLUSIONS: Liposuction is among the most common aesthetic procedures performed with advances that make it possible to remove considerable amount of adipose tissue within a short period. Current data, although conflicting, appear to support the notion that LVL can affect cardiovascular risk factors, metabolic balance, and insulin resistance in positive ways. Future research with prospective studies is needed to clarify the role of LVL in improving overall health. PMID- 28737561 TI - A Cadaver Study to Assess the Feasibility of a Cross-Nerve Transfer of the Infraorbital Nerve for Patients With Peripheral Infraorbital Nerve Injury. AB - BACKGROUND: Patients with facial fracture or head and neck surgery sometimes suffer from infraorbital nerve injury. This injury results in severe hemilateral numbness in the midfacial area. The infraorbital nerve ends with two major branches; the infra nasal branch (INB) and superior labial branch (SLB). In this study, we assessed the feasibility of cross-nerve transfer of the INB and SLB based on a cadaver study. METHODS: The INB/SLB from a total 20 sides of 10 cadavers (2 men and 8 women; average age, 79.9 years) were dissected. The distribution patterns of the INB and SLB, the distance between the INB/SLB and the piriform aperture, and the shortest distance between the INB/SLB were estimated. RESULTS: Three distribution patterns of the INB and SLB were observed, that is type A (65%); only the INB is thick enough for a nerve transfer, type B (20%); only the SLB is thick enough for a nerve transfer, and a combination of types A and B (15%). The distance between the INB, SLB and the piriform aperture was on average 8.61 and 10.81 mm in each. The shortest distance between the INB and SLB was on average 11.34 +/- 3.7 mm. CONCLUSIONS: The INB and SLB existed in all the specimens and could be found approximately 1 cm below the piriform aperture. The average distance between the INB and SLB was approximately 11 mm. These results imply the feasibility of a cross-nerve transfer of the distal part of the infraorbital nerve. PMID- 28737562 TI - Dynamic Cleft Maxillary Orthopedics and Periosteoplasty. AB - In 1985 this cleft team, dissatisfied with the treatment and results from cleft lip and palate repair, began a longitudinal long-term study using dynamic maxillary orthopedics and periosteoplasty as was originally described by Drs Millard and Latham. All cases were carefully documented through adolescence, including clinical assessments, orthodontic, radiographic, and cephalometric analyses. In 1998, in this journal, we published our data on 35 complete unilateral and 10 complete bilateral cleft patients. At that time facial growth was following normal cephalometric patterns. Crossbites were dental and treated with orthodontics. There was radiologic evidence of bone within the alveolus with elimination of the oronasal fistula, and facial aesthetics revealed soft faded scars and balanced noses.That publication was a preliminary study with the intent to provide long-term results when full facial growth was achieved. This article reports on 25 patients from the initial cohort (20 unilateral and 5 bilateral) that we were able to closely follow up for 25 years, with the same clinical team, making it the longest study of its kind.At this stage, data revealed continued growth of the midface both vertically and horizontally. Secondary alveolar cleft bone grafting when required was in small aliquots placed into well-healed tissue, and orthodontic movement of teeth was through a consolidated alveolus. Orthognathic procedures were performed in 2 of 5 bilateral and 0 of 20 unilateral cases.We concluded that in this cohort, dynamic maxillary orthopedics and periosteoplasty, despite controversy in the literature, did not negatively impact facial growth and provided the benefit of early structural normalization and social integration by consolidation of the maxilla, closure of the oronasal fistula, tension free closure of the lip, and by balancing the nose. PMID- 28737563 TI - Reverse Distal Transverse Palmar Arch in Distal Digital Replantation. AB - BACKGROUND: Refinements in microsurgery have made distal finger replantation an established technique with high success rates and good functional and aesthetic outcomes. However, it still represents a technically demanding procedure due to the small vessel caliber and frequent lack of vessel length, requiring the use of interpositional venous grafts in some instances. We describe a new technique for anastomosis in fingertip replantation, whereby the need for venous grafts is eliminated. METHODS: Applying the reverse distal transverse palmar arch technique, 11 cases of distal digital replantation were performed between January 2011 and July 2016. The described procedure was used for arterial anastomosis in 10 cases and arteriovenous shunting for venous drainage in 1 case. A retrospective case review was conducted. The technical description and clinical outcome evaluations are presented. RESULTS: Ten of the 11 replanted digits survived, corresponding to an overall success rate of 91%. One replant failed due to venous insufficiency. Blood transfusions were not required for any of the patients. Follow-up (range, 1.5-5 months) revealed near-normal range of motion and good aesthetic results. All of the replanted digits developed protective sensation. The average length of hospital admission was 5 days. All patients were satisfied with the results and were able to return to their previous work. CONCLUSIONS: The use of the reverse distal transverse palmar arch is a novel and reliable technique in distal digital replantation when an increase in vessel length is required, allowing for a tension-free arterial repair without the need for vein grafts. PMID- 28737564 TI - Localized Leg Volume Index: A New Method for Body Type-Corrected Evaluation of Localized Leg Lymphedematous Volume Change. AB - BACKGROUND: Volume measurement is one of the most common evaluations for lower extremity lymphedema. However, volume comparison between different patients with different physique may be inappropriate, and it is difficult to evaluate localized limb volume change using leg volume evaluation. METHODS: Localized leg volumes (Vk, k = 1-5) and localized leg volume indices (LEVIk) at 5 points (1, thigh; 2, knee; 3, lower leg; 4, ankle; 5, foot) of 106 legs of 53 examinees with no leg edema were calculated based on physical measurements, leg circumferences and lengths, and body mass index (BMI). Interrater and intrarater reliabilities of LEVIk were assessed, and Vk and LEVIk were compared between lower BMI (BMI < 22 kg/m) group and higher BMI (BMI >= 22 kg/m) group. RESULTS: Interrater and intrarater reliabilities of LEVIk were all high (all: r > 0.98). Between lower and higher BMI groups, significant differences were observed in all Vk: V1 (P = 3.7 * 10), V2 (P = 4.7 * 10), V3 (P = 4.5 * 10), V4 (P = 1.6 * 10), and V5 (P = 2.4 * 10). Regarding LEVI between groups, significant differences were seen in LEVI3 (P = 0.009), LEVI4 (P = 0.004), and LEVI5 (P = 1.3 * 10); no significant difference was seen in LEVI1 (P = 0.23) or LEVI2 (P = 0.51). CONCLUSIONS: Localized leg volume index is a highly reproducible and convenient method for evaluation of localized volume change of the lower extremity, which is less affected by body type compared with leg volumetry. PMID- 28737565 TI - Use of Resuscitative Endovascular Balloon Occlusion of the Aorta in a Multidisciplinary Approach. AB - The usage of resuscitative endovascular balloon occlusion of the aorta, also known as aortic balloon occlusion, is an emerging method for bleeding control as a bridge to definitive treatment in trauma management. We describe a trauma case where resuscitative endovascular balloon occlusion of the aorta was used as part of the EndoVascular hybrid Trauma and bleeding Management concept to facilitate transient hemorrhage control and thereby to permit damage control surgery. The case is an illustration of the adoption of a multidisciplinary approach. PMID- 28737566 TI - High Flow Nasal Cannula, A Novel Approach to Airway Management in Awake Craniotomies. PMID- 28737567 TI - Annual Scientific Meeting of Neuroanaesthesia and Critical Care Society of Great Britain and Ireland, 2017: A Report. PMID- 28737568 TI - Systematic Review: Nutrition and Physical Activity in the Management of Paediatric Nonalcoholic Fatty Liver Disease. AB - OBJECTIVES: The aim of the study was to evaluate efficacy of nutrition and physical activity interventions in the clinical management of paediatric nonalcoholic fatty liver disease. The prevalence of paediatric nonalcoholic fatty liver disease continues to rise alongside childhood obesity. Weight loss through lifestyle modification is currently first-line treatment, although supplementation of specific dietary components may be beneficial. METHODS: Medline, CINAHL, EMBASE, Scopus, and Cochrane Libraries were systematically searched to identify randomized controlled trials assessing nutritional and physical activity interventions. Primary outcome measures were changes to liver biomarkers assessed by imaging, histology, or serum liver function tests. Study quality was evaluated using the American Dietetic Association Quality Criteria Checklist. RESULTS: Fifteen articles met eligibility criteria investigating nutritional supplementation (vitamin E [n = 6], probiotics [n = 2], omega-3 fatty acids [n = 5]), dietary modification (low glycaemic load [n = 1] and reducing fructose intake [n = 1]). No randomized controlled trials examining physical activity interventions were identified. Vitamin E was ineffective at improving alanine transaminase levels, whereas omega-3 fatty acids decreased hepatic fat content. Probiotics gave mixed results, whereas reduced fructose consumption did not improve primary outcome measures. A low glycaemic load diet and a low-fat diet appeared equally effective in decreasing hepatic fat content and transaminases. Most studies were deemed neutral as assessed by the American Dietetic Association Quality Criteria Checklist. CONCLUSIONS: The limited evidence base inhibits the prescription of specific dietary and/or lifestyle strategies for clinical practice. General healthy eating and physical activity guidelines, promoting weight loss, should remain first-line treatment until high quality evidence emerges that support specific interventions that offer additional clinical benefit. PMID- 28737569 TI - Elevated Hemoglobin Level Is Associated With Advanced Fibrosis in Pediatric Nonalcoholic Fatty Liver Disease. AB - OBJECTIVES: Hemoglobin (Hb) and red blood cell distribution width (RDW) have been reported to be a risk marker of metabolic syndrome and nonalcoholic fatty liver disease (NAFLD). No study exists on pediatric populations. We aimed to determine the association between hematological parameters, and the severity of disease in children with biopsy-proven NAFLD. METHODS: A total of 117 children (85 boys, mean age 12 years) with ultrasound evidence of NAFLD undergoing liver biopsy for diagnosis of nonalcoholic steatohepatitis (NASH), were prospectively enrolled between January 2011 and May 2013 in the setting of a tertiary care center. Children were screened for routine hematological and metabolic parameters, and causes of liver steatosis other than nonalcoholic were excluded, before liver biopsy was performed. RESULTS: A total of 41 NAFLD (boys 29, mean age 11.2 years) and 76 NASH (boys 56, mean age 12.8 years) children were studied. Alanine transaminase levels were significantly higher in NASH group compared with NAFLD group (P = 0.05), and homeostatic model assessment of insulin resistance and triglycerides levels (P = 0.03 and 0.02, respectively). Regarding hematological components: red cell count, Hb, hematocrit, and RDW values were all significantly higher in NASH group compared with NAFLD group (P < 0.05 for each parameter). CONCLUSIONS: Children with NASH were more likely to have high levels of RDW compared to those with steatosis only. Moreover, NASH was associated with higher red cell count, Hb, and hematocrit. If confirmed in future follow-up studies, hematological parameters may be introduced in algorithms for NASH risk prediction. PMID- 28737570 TI - Clinical Presentation of Acute Gastroenteritis in Children With Functional Abdominal Pain Disorders. AB - Visceral hypersensitivity and abnormal coping are common in children with functional abdominal pain disorders (FAPDs). Thus, it would be expected that children with visceral hypersensitivity would report more pain if their gut is acutely inflamed. The aim of the study was to compare clinical symptoms and somatization of children with and without FAPDs at time of an episode of acute gastroenteritis. Seventy children with acute gastroenteritis and their parents completed the Rome III Diagnostic Questionnaire for Pediatric Functional GI Disorders and the Children's Somatization Inventory. Twenty-one percent of children were diagnosed with an FAPD. Children with FAPDs showed significantly more nongastrointestinal somatic symptoms than children without FAPDs. There were no significant differences in abdominal pain, nausea, vomiting, or school absenteeism between both groups at time of consultation. PMID- 28737571 TI - Breast-feeding and Infant Hospitalization for Infections: Large Cohort and Sibling Analysis. AB - OBJECTIVES: Breast-feeding may protect against infections, but its optimal duration remains controversial. We aimed to study the association of the duration of full and any breast-feeding with infections the first 18 months of life. METHODS: The Norwegian Mother and Child study (MoBa) is a prospective birth cohort which recruited expecting mothers giving birth from 2000 to 2009. We analyzed data from the full cohort (n = 70,511) and sibling sets (n = 21,220) with parental report of breast-feeding and infections. The main outcome measures were the relative risks (RRs) for hospitalization for infections from 0 to 18 months by age at introduction of complementary foods and duration of any breast feeding. RESULTS: Although we found some evidence for an overall association between longer duration of full breast-feeding and lower risk of hospitalizations for infections, 7.3% of breast-fed children who received complementary foods at 4 to 6 months of age compared to 7.7% of those receiving complementary foods after 6 months were hospitalized (adjusted RR 0.95, 95% confidence interval 0.88-1.03). Higher risk of hospitalization was observed in those breast-fed 6 months or less (10.0%) compared to >=12 months (7.6%, adjusted RR 1.22, 95% confidence interval 1.14-1.31), but with similar risks for 6 to 11 months versus >=12 months. Matched sibling analyses, minimizing the confounding from shared maternal factors, showed nonsignificant associations and were generally weaker compared with the cohort analyses. CONCLUSIONS: Our results support the recommendation to fully breast feed for 4 months and to continue breast-feeding beyond 6 months, and suggest that protection against infections is limited to the first 12 months. PMID- 28737572 TI - European Society for Paediatric Gastroenterology, Hepatology and Nutrition Guidelines for the Evaluation and Treatment of Gastrointestinal and Nutritional Complications in Children With Neurological Impairment. AB - OBJECTIVES: Feeding difficulties are frequent in children with neurological impairments and can be associated with undernutrition, growth failure, micronutrients deficiencies, osteopenia, and nutritional comorbidities. Gastrointestinal problems including gastroesophageal reflux disease, constipation, and dysphagia are also frequent in this population and affect quality of life and nutritional status. There is currently a lack of a systematic approach to the care of these patients. With this report, European Society of Gastroenterology, Hepatology and Nutrition aims to develop uniform guidelines for the management of the gastroenterological and nutritional problems in children with neurological impairment. METHODS: Thirty-one clinical questions addressing the diagnosis, treatment, and prognosis of common gastrointestinal and nutritional problems in neurological impaired children were formulated. Questions aimed to assess the nutritional management including nutritional status, identifying undernutrition, monitoring nutritional status, and defining nutritional requirements; to classify gastrointestinal issues including oropharyngeal dysfunctions, motor and sensory function, gastroesophageal reflux disease, and constipation; to evaluate the indications for nutritional rehabilitation including enteral feeding and percutaneous gastrostomy/jejunostomy; to define indications for surgical interventions (eg, Nissen Fundoplication, esophagogastric disconnection); and finally to consider ethical issues related to digestive and nutritional problems in the severely neurologically impaired children. A systematic literature search was performed from 1980 to October 2015 using MEDLINE. The approach of the Grading of Recommendations Assessment, Development, and Evaluation was applied to evaluate the outcomes. During 2 consensus meetings, all recommendations were discussed and finalized. The group members voted on each recommendation using the nominal voting technique. Expert opinion was applied to support the recommendations where no randomized controlled trials were available. PMID- 28737573 TI - Investigating the Impact of Different Suspicion of Infection Criteria on the Accuracy of Quick Sepsis-Related Organ Failure Assessment, Systemic Inflammatory Response Syndrome, and Early Warning Scores. AB - OBJECTIVE: Studies in sepsis are limited by heterogeneity regarding what constitutes suspicion of infection. We sought to compare potential suspicion criteria using antibiotic and culture order combinations in terms of patient characteristics and outcomes. We further sought to determine the impact of differing criteria on the accuracy of sepsis screening tools and early warning scores. DESIGN: Observational cohort study. SETTING: Academic center from November 2008 to January 2016. PATIENTS: Hospitalized patients outside the ICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Six criteria were investigated: 1) any culture, 2) blood culture, 3) any culture plus IV antibiotics, 4) blood culture plus IV antibiotics, 5) any culture plus IV antibiotics for at least 4 of 7 days, and 6) blood culture plus IV antibiotics for at least 4 of 7 days. Accuracy of the quick Sepsis-related Organ Failure Assessment score, Sepsis-related Organ Failure Assessment score, systemic inflammatory response syndrome criteria, the National and Modified Early Warning Score, and the electronic Cardiac Arrest Risk Triage score were calculated for predicting ICU transfer or death within 48 hours of meeting suspicion criteria. A total of 53,849 patients met at least one infection criteria. Mortality increased from 3% for group 1 to 9% for group 6 and percentage meeting Angus sepsis criteria increased from 20% to 40%. Across all criteria, score discrimination was lowest for systemic inflammatory response syndrome (median area under the receiver operating characteristic curve, 0.60) and Sepsis-related Organ Failure Assessment score (median area under the receiver operating characteristic curve, 0.62), intermediate for quick Sepsis-related Organ Failure Assessment (median area under the receiver operating characteristic curve, 0.65) and Modified Early Warning Score (median area under the receiver operating characteristic curve 0.67), and highest for National Early Warning Score (median area under the receiver operating characteristic curve 0.71) and electronic Cardiac Arrest Risk Triage (median area under the receiver operating characteristic curve 0.73). CONCLUSIONS: The choice of criteria to define a potentially infected population significantly impacts prevalence of mortality but has little impact on accuracy. Systemic inflammatory response syndrome was the least predictive and electronic Cardiac Arrest Risk Triage the most predictive regardless of how infection was defined. PMID- 28737574 TI - Is There a Role for Enterohormones in the Gastroparesis of Critically Ill Patients? AB - OBJECTIVES: Delayed gastric emptying occurs in critically ill patients and impairs the delivery, digestion, and absorption of enteral feeding. A pathophysiologic role of the enterohormones peptide YY and ghrelin is supported by preclinical data. To compare the circulating plasma levels of peptide YY and ghrelin in control subjects and in critically ill patients, during feeding and fasting, and to search for a correlation with gastric emptying. DESIGN: A prospective observational trial. SETTINGS: Mixed ICU of an academic hospital. SUBJECTS: Healthy volunteers and patients expected to stay in ICU for at least 3 days in whom enteral nutrition was indicated. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Plasma peptide YY and ghrelin (enzyme-linked immunosorbent assay) were measured once in 10 fasting volunteers (controls) and daily from admission until day 5 of the ICU stay in 30 critically ill patients (median [interquartile range] age 63 [57-67] yr, median [interquartile range] Acute Physiology and Chronic Health Evaluation II score 21 [14-24]). Eight patients could not be fed (fasting group). In fed patients, 13 never had a gastric residual volume higher than 250 mL (low gastric residual volume group), in contrast to the high gastric residual volume group (n = 9). The plasma levels of peptide YY did not differ between patients (6.4 [0-18.1] pg/mL) and controls (4.8 [0.3-17.7] pg/mL). Ghrelin levels were lower in patients than in control (213 [54.4-522.7] vs 1,435 [1,321.9-1,869.3] pg/mL; p < 0.05). Plasma peptide YY or ghrelin did not differ between fasting and fed patients or between the high and low gastric residual volume groups. CONCLUSIONS: In critically ill patients, plasma concentration of ghrelin significantly differs from that of controls, irrespective of the feeding status. No correlation was found between the temporal profile of ghrelin or peptide YY plasma concentration with bedside functional assessment of gastric emptying. PMID- 28737575 TI - Diabetes Is Not Associated With Increased 90-Day Mortality Risk in Critically Ill Patients With Sepsis. AB - OBJECTIVES: To determine the association of pre-existing diabetes, hyperglycemia, and hypoglycemia during the first 24 hours of ICU admissions with 90-day mortality in patients with sepsis admitted to the ICU. DESIGN: We used mixed effects logistic regression to analyze the association of diabetes, hyperglycemia, and hypoglycemia with 90-day mortality (n = 128,222). SETTING: All ICUs in the Netherlands between January 2009 and 2014 that participated in the Dutch National Intensive Care Evaluation registry. PATIENTS: All unplanned ICU admissions in patients with sepsis. INTERVENTIONS: The association between 90-day mortality and pre-existing diabetes, hyperglycemia, and hypoglycemia, corrected for other factors, was analyzed using a generalized linear mixed effect model. MEASUREMENTS AND MAIN RESULTS: In a multivariable analysis, diabetes was not associated with increased 90-day mortality. In diabetes patients, only severe hypoglycemia in the absence of hyperglycemia was associated with increased 90-day mortality (odds ratio, 2.95; 95% CI, 1.19-7.32), whereas in patients without pre existing diabetes, several combinations of abnormal glucose levels were associated with increased 90-day mortality. CONCLUSIONS: In the current retrospective large database review, diabetes was not associated with adjusted 90 day mortality risk in critically ill patients admitted with sepsis. PMID- 28737576 TI - Hereditary Leiomyomatosis and Renal Cell Carcinoma Syndrome Combined With Adrenocortical Carcinoma on 18F-FDG PET/CT. AB - Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome is a recognized distinct phenotypic variant of multiple cutaneous and uterine leiomyomatosis. The present case reports an extremely rare case of HLRCC syndrome combined with adrenocortical carcinoma. The case suggests that HLRCC should be considered in any young patient with bulky uterine leiomyomas and renal cell cancer, and F-FDG PET/CT can help detect unexpected additional primary malignancy in a patient with known cancer. PMID- 28737577 TI - Vertebral Myeloma Mimicking Prostatic Carcinoma Metastasis in 68Ga-PSMA PET/CT. AB - Ga-PSMA PET/CT was performed in a 75-year-old man with newly diagnosed prostate cancer because of an equivocal lesion in the spine both on Tc-bone-SPECT/CT and MRI. Because of increased PSMA activity on PET/CT, the bone lesion was interpreted as metastasis from prostate cancer. Later, the patient was diagnosed as having monoclonal gammopathy of unknown significance. A biopsy was performed, and histological examination revealed multiple myeloma with PSMA expression in the neovessels but no metastatic prostate cancer cells. The patient was downstaged, and the treatment was changed accordingly. This case illustrates the importance of biopsies from PSMA PET-positive lesions. PMID- 28737578 TI - Re: 18F-FDG PET/CT Versus Contrast-Enhanced CT for Staging and Prognostic Prediction in Patients With Salivary Gland Carcinomas. PMID- 28737579 TI - Prostate-Specific Membrane Antigen-Targeted Imaging With [18F]DCFPyL in High Grade Gliomas. AB - High-grade gliomas (World Health Organization grade III-IV) are highly lethal primary brain tumors. Imaging modalities, including MRI and FDG PET, provide a limited ability to differentiate treatment effects (such as radiation necrosis) from recurrent or residual tumor. As the first step in validating the applicability of prostate-specific membrane antigen (PSMA)-targeted imaging in high-grade gliomas, we evaluated the ability of the PSMA-targeted small molecule [F]DCFPyL (2-(3-(1carboxy-5-(6-[F]fluoro-pyridine-3-carbonyl)-amino]-pentyl) ureido)-pentanedioic acid) to image high-grade gliomas in a series of 3 prospectively recruited patients. We found [F]DCFPyL binds PSMA in the neovasculature of glioblastoma multiforme and tumor cells of anaplastic astrocytoma. PMID- 28737580 TI - Nivolumab-Induced Development of Pulmonary Sarcoidosis in Renal Cell Carcinoma. AB - A 64-year-old woman with metastatic clear cell renal carcinoma who had been on nivolumab immunotherapy for 10 months was referred for a FDG PET scan to monitor disease progress. New bilateral mediastinal and hilar FDG-avid lymphadenopathy was noted. Pathology on subsequent mediastinal nodal biopsy showed well-formed epithelioid granulomas with no evidence of malignancy consistent with sarcoidosis. This case illustrates that pulmonary sarcoidosis can be induced by immunotherapy in the treatment of renal cell carcinoma. PMID- 28737581 TI - Intense 99mTc-MDP Activity in an Elongated Sagging Gallbladder With a Partially Calcified Gallstone. AB - Intense activity was noted in the right middle abdomen on whole-body Tc-MDP bone scan images, which were obtained in a 78-year-old woman who had back pain. Further SPECT/CT images demonstrated that the intense activity was located in an elongated gallbladder. Partially calcified gallstone was also revealed on SPECT/CT images. Unexpectedly, the gallbladder activity was from the radioactive bile inside the gallbladder lumen, whereas the partially calcified gallstone was relatively photopenic. PMID- 28737582 TI - A nutritional approach for managing irritable bowel syndrome. AB - PURPOSE OF REVIEW: Irritable bowel syndrome (IBS) is the most common functional gastrointestinal disorder (FGID) encountered by the pediatrician and consultant. The primary focus of this review is to provide an update on beneficial nutritional interventions for managing this patient population with discussion on gut microbiome effects. RECENT FINDINGS: A common complaint among the pediatric population is IBS-related recurrent abdominal pain. The prevalence of IBS is estimated to range between 6 and 14% and is defined by the Rome III criteria for FGIDs. Recent studies highlight the role of nutritional interventions in mitigating symptoms of IBS. Although eliminating foods that aggravate IBS gastrointestinal symptoms have become a main nutritional approach for acute management of IBS, recent literature reflects how this may impact the gut microbiome and potentially have long-term implications. SUMMARY: There are emerging studies suggesting IBS symptomatic improvement with different dietary interventions in the pediatric population, but most of what is known at this time has been extrapolated from the adult literature. PMID- 28737583 TI - Callosal injury-induced working memory impairment: a computational network modeling study. AB - Mild traumatic brain injury (mTBI) often results in working memory (WM) impairment, but the mechanistic relationship between the two remains elusive. We used a computational model of two cortical neuronal networks linked by myelinated callosal axons with distance-dependent conduction delays to simulate callosal dysfunction in mTBI and quantify its impact on WM. WM maintenance and termination in the model network depended on short-term synaptic plasticity. In injured networks, WM duration depended on the extent of callosal injury, consistent with clinical data. The model provides a framework for studying callosal injury induced neurobehavioral alterations following mTBI, and, to the best of our knowledge, is the first computational model to address mTBI-induced WM impairment. PMID- 28737584 TI - Update on new muscle glycogenosis. AB - PURPOSE OF REVIEW: The field of muscle glycogenoses has progressed in recent years by the identification of new disorders, and by reaching a better understanding of pathophysiology of the disorders and the physiology of glycogen metabolism. RECENT FINDINGS: In this review, we describe the clinical and pathological features of the three most recently described muscle glycogenoses caused by recessive mutations in GYG1, RBCK1 and PGM1. The three involved enzymes play different roles in glycogen metabolism. Glycogenin-1 (GYG1) is involved in the initial steps of glycogen synthesis, whereas phosphoglucomutase catalyzes two metabolic pathways; the connection between galactose and glycogen on one side, and glucose metabolism on the other side. The metabolic consequences of mutations in the ubiquitin ligase gene RBCK1 are still poorly understood. GYG1 deficiency has been associated with cardiomyopathies with abnormal storage material in the heart, but most cases present with a polyglucosan body myopathy without cardiac involvement. SUMMARY: The recent identification of new glycogenosis not only allows to improve the knowledge of glycogen metabolism, but also builds bridges with protein glycosylation and immune system. PMID- 28737586 TI - Comparison of Acute Physiological and Psychological Responses Between Moderate Intensity Continuous Exercise and Three Regimes of High-Intensity Interval Training. AB - Olney, N, Wertz, T, LaPorta, Z, Mora, A, Serbas, J, and Astorino, TA. Comparison of acute physiological and psychological responses between moderate-intensity continuous exercise and three regimes of high intensity interval training. J Strength Cond Res 32(8): 2130-2138, 2018-High-intensity interval training (HIIT) elicits similar physiological adaptations as moderate-intensity continuous training (MICT) despite less time commitment. However, there is debate whether HIIT is more aversive than MICT. This study compared physiological and perceptual responses between MICT and 3 regimes of HIIT. Nineteen active adults (age = 24.0 +/- 3.3 years) unfamiliar with HIIT initially performed ramp exercise to exhaustion to measure maximal oxygen uptake (V[Combining Dot Above]O2max) and determine workload for subsequent sessions, whose order was randomized. Sprint interval training (SIT) consisted of six 20-second bouts of "all-out" cycling at 140% of maximum watts (Wmax). Low-volume HIIT (HIITLV) and high-volume HIIT (HIITHV) consisted of eight 60-second bouts at 85% Wmax and six 2-minute bouts at 70% Wmax, respectively. Moderate-intensity continuous training consisted of 25 minutes at 40% Wmax. Across regimes, work was not matched. Heart rate (HR), V[Combining Dot Above]O2, blood lactate concentration (BLa), affect, and rating of perceived exertion (RPE) were assessed during exercise. Ten minutes postexercise, Physical Activity Enjoyment (PACES) was measured via a survey. Results revealed significantly higher (p <= 0.05) V[Combining Dot Above]O2, HR, BLa, and RPE in SIT, HIITLV, and HIITHV vs. MICT. Despite a decline in affect during exercise (p < 0.01) and significantly lower affect (p <= 0.05) during all HIIT regimes vs. MICT at 50, 75, and 100% of session duration, PACES was similar across regimes (p = 0.65), although it was higher in women (p = 0.03). Findings from healthy adults unaccustomed to interval training demonstrate that HIIT and SIT are perceived as enjoyable as MICT despite being more aversive. PMID- 28737587 TI - Influence of Tactical and Situational Variables on Offensive Sequences During Elite Football Matches. AB - Sarmento, H, Figueiredo, A, Lago-Penas, C, Milanovic, Z, Barbosa, A, Tadeu, P, and Bradley, PS. Influence of tactical and situational variables on offensive sequences during elite football matches. J Strength Cond Res 32(8): 2331-2339, 2018-This study examined the influence of tactical and situational variables on offensive sequences during elite football matches. A sample of 68 games and 1,694 offensive sequences from the Spanish La Liga, Italian Serie A, German Bundesliga, English Premier League, and Champions League were analyzed using chi and logistic regression analyses. Results revealed that counterattacks (odds ratio [OR] = 1.44; 95% confidence interval [CI]: 1.13-1.83; p < 0.01) and fast attacks (OR = 1.43; 95% CI: 1.11-1.85; p < 0.01) increased the success of an offensive sequence by 40% compared with positional attacks. The chance of an offensive sequence ending effectively in games from the Spanish, Italian, and English Leagues were higher than that in the Champions League. Offensive sequences that started in the preoffensive or offensive zones were more successful than those started in the defensive zones. An increase of 1 second in the offensive sequence duration and an extra pass resulted in a decrease of 2% (OR = 0.98; 95% CI: 0.98-0.99; p < 0.001) and 7% (OR = 0.93; 95% CI: 0.91-0.96; p < 0.001), respectively, in the probability of its success. These findings could assist coaches in designing specific training situations that improve the effectiveness of the offensive process. PMID- 28737588 TI - Longer Concentric Action Increases Muscle Activation And Neuromuscular Fatigue Responses In Protocols Equalized By Repetition Duration. AB - The aim of this study was to investigate the impact of protocols equalized by the repetition duration but composed of different concentric and eccentric durations on muscle activation and neuromuscular fatigue. Seventeen males with previous experience in resistance training performed 3 training protocols (A - 2s con : 4s ecc; B - 3s con : 3s ecc; and C - 4s con : 2s ecc) with the Smith machine bench press exercise, all with 3 sets, 6 repetitions, 3 minutes' rest, and 60% of 1RM. The normalized root mean square of the electromyographic signal (EMGRMS) and mean frequency electromyography (EMGMF) for pectoralis major and triceps brachii muscles were calculated for 2nd and 5th repetitions in each set. The results showed an EMGMF decrease across the repetitions accompanied by a progressive increase of the EMGRMS across the repetitions for all protocols and muscles. The EMGRMS was higher in Protocol C when compared with Protocol A and B for pectoralis major. The EMGMF was lower in Protocols B and C than in Protocol A for pectoralis major throughout the sets and repetitions. A higher EMGRMS and a lower EMGMF were observed in Protocols B and C compared to Protocol A for triceps brachii, solely in the 5th repetition . In conclusion, training protocols conducted with the same repetition duration, but with different concentric and eccentric durations, produce distinct muscle activation and neuromuscular fatigue responses, in which performing longer concentric durations could be the more appropriate strategy to increase muscle activation and neuromuscular fatigue. PMID- 28737585 TI - Biomarkers in Sports and Exercise: Tracking Health, Performance, and Recovery in Athletes. AB - Biomarker discovery and validation is a critical aim of the medical and scientific community. Research into exercise and diet-related biomarkers aims to improve health, performance, and recovery in military personnel, athletes, and lay persons. Exercise physiology research has identified individual biomarkers for assessing health, performance, and recovery during exercise training. However, there are few recommendations for biomarker panels for tracking changes in individuals participating in physical activity and exercise training programs. Our approach was to review the current literature and recommend a collection of validated biomarkers in key categories of health, performance, and recovery that could be used for this purpose. We determined that a comprehensive performance set of biomarkers should include key markers of (a) nutrition and metabolic health, (b) hydration status, (c) muscle status, (d) endurance performance, (e) injury status and risk, and (f) inflammation. Our review will help coaches, clinical sport professionals, researchers, and athletes better understand how to comprehensively monitor physiologic changes, as they design training cycles that elicit maximal improvements in performance while minimizing overtraining and injury risk. PMID- 28737589 TI - Validity of a taekwondo specific test to measure vo2peak and the heart rate deflection point. AB - This study investigated whether the progressive specific taekwondo test (PSTT) is a valid test to measure peak oxygen consumption (VO2PEAK) and the heart rate deflection point (HRDP) in taekwondo athletes. Eighteen male black belt athletes (25.3 +/- 4.8 years; 8.2 +/- 4.7 years of practice; 171.8 +/- 4.7 cm; 76.1 +/- 8.2 kg, and 13.1 +/- 2.9% body fat) involved in regional and national level competitions performed the PSTT and an incremental treadmill test (IT). The following variables were analyzed: VO2PEAK, respiratory quotient, oxygen consumption at the HRDP (VO2HRDP), peak heart rate (HRPEAK), HRDP, and peak post test blood lactate concentration. During the PSTT the peak kick frequency (FKPEAK) and kick frequency at the HRDP (FKHRDP) was also obtained. During the IT, the peak speed and the speed at the HRDP were identified by the DMAX method (the first and last points of the curve were connected by a straight line and the most distant point of the curve to the line was considered as the heart rate deflection point). No differences were observed between VO2 responses during the PSTT and IT (p>0.05). VO2PEAK and VO2HRDP presented bias (1.3 ml.kg.min and -0.78 ml.kg.min, respectively) derived from the Bland & Altman plots, with the 95% limits of agreement indicating that the differences between the two measures can reach 11% for VO2PEAK and 17% for VO2HRDP. The PSTT is a valid tool to assess aerobic power and capacity in taekwondo athletes based on direct comparisons to a treadmill test. The test presents more specific variables for the assessment and training of taekwondo athletes, such as FKPEAK and FKHRDP, which can be used to determine and control the effects of training and help coaches in prescribing training programs. PMID- 28737590 TI - Fiber Type Composition And Rate Of Force Development In Endurance And Resistance Trained Individuals. AB - The purpose of the study was to investigate the relationship between muscle fiber composition and the rate of force development (RFD) in well-trained individuals with different training background. Thirty-eight young males with different training background participated: 9 endurance runners, 10 power-trained, 9 strength-trained, and 10 sedentary. They performed maximal isometric leg press for the measurement of RFD. Body composition (dual x-ray absorptiometry) and vastus lateralis fiber type composition was also evaluated. When all participants were examined as a group, moderate correlations were found between the percent of type II muscle fibers and RFD between 100-600ms (r: 0.321 - 0.497, p<0.05). The correlation coefficients were higher for the cross-sectional area (CSA) and the %CSA of type II and IIx muscle fibers (r: 0.599 - 0.847, p<0.001). For the power group, RFD up to 250ms was highly correlated with % type IIx muscle fibers and type IIx fiber CSA (r: 0.670 - 0.826, p<0.05), as well as with %CSA of type IIx fibers (r: 0.714 - 0.975, p<0.05). Significant correlations were found between the relative RFD (.kg lower extremities lean mass) and CSA-%CSA of type II and IIx fibers for the power group (r: 0.676 - 0.903, p<0.05). No significant correlations were found between muscle morphology and RFD for the other groups. In conclusion, the present data suggest that there is a strong link between the type IIx muscle fibers and early RFD and relative RFD in power-trained participants. Type II fibers seem to be moderately linked with RFD in non-power trained individuals. PMID- 28737592 TI - Dilation Time in Endoscopic Papillary Balloon Dilation for Common Bile Duct Stones. AB - BACKGROUND: To assess the short-term outcomes after endoscopic sphincterotomy (EST) plus endoscopic papillary balloon dilation (EPBD) versus EPBD alone and appropriate balloon dilation time in EPBD alone. MATERIALS AND METHODS: A total of 413 patients with common bile duct stones (CBDSs) were included in the EST plus EPBD group and 84 were in the EPBD alone group. We retrospectively evaluated the safety and efficacy between EST plus EPBD and EPBD alone group. The patients in EPBD alone group were assigned to dilation time >=5 minutes group (n=35) and time <5 minutes group (n=49). Further, we preliminarily discussed the influence of balloon dilation time on the procedure-related complications. RESULTS: Compared with EST plus EPBD, the patients in EPBD alone group were younger [56.6 (range: 18 to 95) vs. 65.1 (24 to 92) y; P=0.006], had smaller diameter of the largest stone [10.4 (range: 3 to 20) vs. 12.3 (5 to 30) mm; P<0.001] and were lesser frequently performed with jaundice [22 (26.2%) vs. 189 (45.8%); P=0.001]. The mean duration of postoperative hospital stay in EPBD alone group was significantly shorter than EST plus EPBD group [6.3 (range: 1 to 18) vs. 9.2 (1 to 44) d; P<0.001]. The patients in EPBD alone group had higher risk of post endoscopic retrograde cholangiopancreatography pancreatitis than EST plus EPBD group [11 (13.1%) vs. 22 (5.3%); P=0.009]. Patients in the dilation time <5 minutes group had higher risk to suffer from postoperative pancreatitis than the EST plus EPBD group [9 (18.4%) vs. 22 (5.3%); P=0.002], while patients in the dilation time >=5 minutes group had less procedure-related hemorrhage than the EST plus EPBD group [0 vs. 36 (8.7%); P=0.047]. CONCLUSION: Long balloon dilation time in EPBD alone is safe and effective in treating CBDSs. PMID- 28737591 TI - HIV Incidence and Predictors of HIV Acquisition From an Outside Partner in Serodiscordant Couples in Lusaka, Zambia. AB - OBJECTIVE: Evaluate the incidence and predictors of HIV acquisition from outside partners in serodiscordant couples. METHODS: Demographic, behavioral, and clinical exposures were measured quarterly in a cohort of serodiscordant cohabiting couples in Zambia from 1995 to 2012 (n = 3049). Genetic analysis classified incident infections as those acquired from the study partner (linked) or acquired from an outside partner (unlinked). Factors associated with time to unlinked HIV infection were evaluated using multivariable Cox proportional hazards regression stratified by sex. RESULTS: There were 100 unlinked infections in couples followed for a median of 806 days. Forty-five infections occurred in women [1.85/100 couple-years; 95% confidence interval (CI): 1.35 to 2.47]. Risk of female unlinked infection (vs. nonseroconverting females) was associated with reporting being drunk weekly/daily vs. moderate/nondrinkers at baseline [adjusted hazard ratio (aHR) = 5.44; 95% CI: 1.03 to 28.73], genital ulcers (aHR = 6.09; 95% CI: 2.72 to 13.64), or genital inflammation (aHR = 11.92; 95% CI: 5.60 to 25.37) during follow-up adjusting for age, years cohabiting, income, contraceptive use, previous pregnancies, history of sexually transmitted infections, and condomless sex with study partner. Fifty-five infections occurred in men (1.82/100 couple-years; 95% CI: 1.37 to 2.37). Risk of male unlinked infection was associated with genital inflammation (aHR = 8.52; 95% CI: 3.82 to 19.03) or genital ulceration (aHR = 2.31; 95% CI: 2.05 to 8.89), reporting >=1 outside sexual partner (aHR = 3.86; 95% CI: 0.98 to 15.17) during follow-up, and reporting being drunk weekly/daily vs. moderate/nondrinkers at baseline (aHR = 3.84; 95% CI: 1.28 to 11.55), controlling for age, income, circumcision status, and history of sexually transmitted infection. CONCLUSIONS: Predictors of unlinked infection in serodiscordant relationships were alcohol use, genital inflammation, and ulceration. Causes of genital inflammation and ulceration should be screened for and treated in HIV-negative individuals. Counseling on risk of alcohol use and sex with outside partners should be discussed with couples where 1 or both are HIV-negative, including in counseling on use of pre exposure prophylaxis to prevent HIV acquisition in the HIV-negative partner (when feasible and affordable). PMID- 28737593 TI - A Teachable Moment After Orthopaedic Fracture in the Smoking Patient: A Randomized, Controlled Trial. AB - OBJECTIVES: To assess whether education during hospitalization after an acute fracture changes patient attitudes toward smoking-related complications and to assess whether this change persists into the first outpatient follow-up visit. DESIGN: Prospective, randomized, controlled trial. SETTING: Level 1 trauma center. PATIENTS: Inpatients with fractures who identified as smokers: 40 assessed for inclusion and randomized, 30 completed inpatient assessments, and 20 completed outpatient follow-up. INTERVENTION: An educational intervention by the researcher to teach the patient about the harms of smoking regarding fracture healing. MAIN OUTCOME MEASURES: A novel questionnaire to assess the intervention via Likert scale responses, evaluating perceived risk, affective response, and self-role. RESULTS: Education resulted in an increase in perceived risk and affective response within the cohort and an increase in perceived risk when compared with control subjects. No significant differences persisted into outpatient follow-up. CONCLUSIONS: This trial demonstrated that a teachable moment can have an early effect on certain attitudes toward smoking after an acute fracture. These changes did not persist at the first follow-up visit. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence. PMID- 28737594 TI - Identifying Risk for Acute Kidney Injury in Infants and Children Following Cardiac Arrest. AB - OBJECTIVES: Our goal was to identify risk factors for acute kidney injury in children surviving cardiac arrest. DESIGN: Retrospective analysis of a public access dataset. SETTING: Fifteen children's hospitals associated with the Pediatric Emergency Care Applied Research Network. PATIENTS: Two hundred ninety six subjects between 1 day and 18 years old who experienced in-hospital or out-of hospital cardiac arrest between July 1, 2003, and December 31, 2004. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Our primary outcome was development of acute kidney injury as defined by the Acute Kidney Injury Network criteria. An ordinal probit model was developed. We found six critical explanatory variables, including total number of epinephrine doses, postcardiac arrest blood pressure, arrest location, presence of a chronic lung condition, pH, and presence of an abnormal baseline creatinine. Total number of epinephrine doses received as well as rate of epinephrine dosing impacted acute kidney injury risk and severity of acute kidney injury. CONCLUSIONS: This study is the first to identify risk factors for acute kidney injury in children after cardiac arrest. Our findings regarding the impact of epinephrine dosing are of particular interest and suggest potential for epinephrine toxicity with regard to acute kidney injury. The ability to identify and potentially modify risk factors for acute kidney injury after cardiac arrest may lead to improved morbidity and mortality in this population. PMID- 28737595 TI - Time of Admission to the PICU and Mortality. AB - OBJECTIVES: To evaluate for any association between time of admission to the PICU and mortality. DESIGN: Retrospective cohort study of admissions to PICUs in the Virtual Pediatric Systems (VPS, LLC, Los Angeles, CA) database from 2009 to 2014. SETTING: One hundred and twenty-nine PICUs in the United States. PATIENTS: Patients less than 18 years old admitted to participating PICUs; excluding those post cardiac bypass. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 391,779 admissions were included with an observed PICU mortality of 2.31%. Overall mortality was highest for patients admitted from 07:00 to 07:59 (3.32%) and lowest for patients admitted from 14:00 to 14:59 (1.99%). The highest mortality on weekdays occurred for admissions from 08:00 to 08:59 (3.30%) and on weekends for admissions from 09:00 to 09:59 (4.66%). In multivariable regression, admission during the morning 06:00-09:59 and midday 10:00-13:59 were independently associated with PICU death when compared with the afternoon time period 14:00-17:59 (morning odds ratio, 1.15; 95% CI, 1.04-1.26; p = 0.006 and midday odds ratio, 1.09; 95% CI; 1.01-1.18; p = 0.03). When separated into weekday versus weekend admissions, only morning admissions were associated with increased odds of death on weekdays (odds ratio, 1.13; 95% CI, 1.01-1.27; p = 0.03), whereas weekend admissions during the morning (odds ratio, 1.33; 95% CI, 1.14-1.55; p = 0.004), midday (odds ratio, 1.27; 95% CI, 1.11-1.45; p = 0.0006), and afternoon (odds ratio, 1.17; 95% CI, 1.03-1.32; p = 0.01) were associated with increased risk of death when compared with weekday afternoons. CONCLUSIONS: Admission to the PICU during the morning period from 06:00 to 09:59 on weekdays and admission throughout the day on weekends (06:00-17:59) were independently associated with PICU death as compared to admission during weekday afternoons. Potential contributing factors deserving further study include handoffs of care, rounds, delays related to resource availability, or unrecognized patient deterioration prior to transfer. PMID- 28737596 TI - Creating a Controlled Arterio-Venous Shunt by Reversing the Extracorporeal Membrane Oxygenation Blood Flow: A Strategy for Weaning Patients Off Veno Arterial Extracorporeal Membrane Oxygenation. AB - OBJECTIVES: To assess whether reversing the veno-arterial extracorporeal membrane oxygenation blood flow (thereby creating a controlled arterio-venous shunt) can be used to wean children off extracorporeal membrane oxygenation. The standard practice for weaning patients off VA extracorporeal membrane oxygenation is to gradually reduce the blood flows delivered through the extracorporeal membrane oxygenation pump to a minimum level followed by either insertion of an "arterio venous bridge" and clamping of the blood flow to the patient or direct decannulation. "Pump controlled retrograde flow trial off" is a technique where the revolutions in the centrifugal pump are reduced to the point where the patient will drive the blood retrograde through the extracorporeal membrane oxygenation circuit, effectively turning the circuit into a controlled arterio venous shunt. The revolutions per minute control the amount of shunt flow. This eliminates any cardiorespiratory support the extracorporeal membrane oxygenation circuit may provide to the patient. DESIGN: Feasibility study. SETTING: Pediatric intensive care. PATIENTS: Extracorporeal membrane oxygenation-dependent pediatric patients, who were ready for weaning, and possible separation from extracorporeal membrane oxygenation entered the trial. INTERVENTION: Pump controlled retrograde flow trial off. MEASUREMENT AND MAIN RESULTS: During 2016, pump controlled retrograde flow trial off was used in 17 patients, for a total of 23 episodes. One episode was unsuccessful in a patient with a body weight of 2.2 kg, where cardiac output was insufficient to provide blood flow to both body and extracorporeal membrane oxygenation circuit, though from 2.8 kg body weight upward, the technique was tolerated. The duration of pump controlled retrograde flow trial off was 15 minutes to 2.5 hours. Five cases led to a continuation of the extracorporeal membrane oxygenation run, as they were not ready to be decannulated. Fifteen patients were decannulated after the pump controlled retrograde flow trial off. No patient needed to be recommenced on extracorporeal membrane oxygenation after decannulation. CONCLUSIONS: Pump controlled retrograde flow trial off is an easy to use and easily reversible technique to assess patient readiness for separation from extracorporeal membrane oxygenation. Given pump controlled retrograde flow trial off can easily be stopped and-in our experience-is not associated with complications, it lowers the threshold to attempt coming off extracorporeal membrane oxygenation and facilitates accurate assessment of whether a patient will need further ongoing extracorporeal membrane oxygenation support. PMID- 28737597 TI - A Prospective Study of the Association Between Clinically Significant Bleeding in PICU Patients and Thrombocytopenia or Prolonged Coagulation Times. AB - OBJECTIVE: There are no proven methods to predict the risk of clinically significant bleeding in the PICU. A retrospective study identified platelet count as a risk marker for clinically significant bleeding. We conducted a study to examine any association of platelet count, international normalized ratio, and activated partial thromboplastin time with bleeding risk in PICU patients. DESIGN: Prospective observational cohort study. SETTING: The PICU at the Children's Hospital of Eastern Ontario, a university-affiliated tertiary care pediatric center. PATIENTS: Consecutive patients admitted to the PICU. Exclusion criteria were prior inclusion, admission with bleeding, inherited bleeding disorders, weight less than 3 kg, and age less than 60 days or 18 years or more. INTERVENTIONS: There were no interventions in this observational study. MEASUREMENTS AND MAIN RESULTS: Patients were monitored in real time for clinically significant bleeding, using a broadly inclusive definition of clinically significant bleeding, for up to 72 hours after admission to the PICU, or until death or discharge. All measurements of platelet count, international normalized ratio, and activated partial thromboplastin time obtained during the study period were included as time-varying covariates in Cox proportional hazard models. Two hundred thirty-four patients were eligible, and 25 (11%) had one or more episodes of clinically significant bleeding. Platelet count was associated with increased hazard of clinically significant bleeding (hazard ratio, 0.96 per 10 * 10/L increase in platelet count; 95% CI (0.93-0.997; p = 0.03). Increasing hazard for clinically significant bleeding was seen with decreasing platelet count. Neither international normalized ratio nor activated partial thromboplastin time was significantly associated with clinically significant bleeding. CONCLUSIONS: There is a statistically significant association in PICU patients between decrease in platelet count and clinically significant bleeding, and this association is stronger with lower platelet counts. Further study is required to determine whether platelet transfusion can reduce bleeding risk. International normalized ratio and activated partial thromboplastin time do not predict clinically significant bleeding, and these tests should not be used for this purpose in a general PICU patient population. PMID- 28737598 TI - Epidemiology and Outcomes of Cardiac Arrest in Pediatric Cardiac ICUs. AB - OBJECTIVES: In-hospital cardiac arrest occurs in 2.6-6% of children with cardiac disease and is associated with significant morbidity and mortality. Much remains unknown about cardiac arrest in pediatric cardiac ICUs; therefore, we aimed to describe cardiac arrest epidemiology in a contemporary multicenter cardiac ICU cohort. DESIGN: Retrospective analysis within the Pediatric Cardiac Critical Care Consortium clinical registry. SETTING: Cardiac ICUs within 23 North American hospitals. PATIENTS: All cardiac medical and surgical patients admitted from August 2014 to July 2016. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: There were 15,908 cardiac ICU encounters (6,498 medical, 9,410 surgical). 3.1% had cardiac arrest; rate was 4.8 cardiac arrest per 1,000 cardiac ICU days. Medical encounters had 50% higher rate of cardiac arrest compared with surgical encounters. Observed (unadjusted) cardiac ICU cardiac arrest prevalence varied from 1% to 5.5% among the 23 centers; cardiac arrest per 1,000 cardiac ICU days varied from 1.1 to 10.4. Over half cardiac arrest occur within 48 hours of admission. On multivariable analysis, prematurity, neonatal age, any Society of Thoracic Surgeons preoperative risk factor, and Society of Thoracic Surgeons European Association for Cardio-Thoracic Surgery mortality category 4, 5 had strongest association with surgical encounter cardiac arrest. In medical encounters, independent cardiac arrest risk factors were acute heart failure, prematurity, lactic acidosis greater than 3 mmol/dL, and invasive ventilation 1 hour after admission. Median cardiopulmonary resuscitation duration was 10 minutes, return of spontaneous circulation occurred in 64.5%, extracorporeal cardiopulmonary resuscitation in 27.2%. Unadjusted survival was 53.2% in encounters with cardiac arrest versus 98.2% without. Medical encounters had lower survival after cardiac arrest (37.7%) versus surgical encounters (62.5%); Norwood patients had less than half the survival after cardiac arrest (35.6%) compared with all others. Unadjusted survival after cardiac arrest varied greatly among 23 centers. CONCLUSIONS: We provide contemporary epidemiologic and outcome data for cardiac arrest occurring in the cardiac ICU from a multicenter clinical registry. As detailed above, we highlight high-risk patient cohorts and periods of time that may serve as targets for research and quality improvement initiatives aimed at cardiac arrest prevention. PMID- 28737599 TI - Interhospital Transport of Children Undergoing Cardiopulmonary Resuscitation: A Practical and Ethical Dilemma. AB - OBJECTIVES: To discuss risks and benefits of interhospital transport of children in cardiac arrest undergoing cardiopulmonary resuscitation. DESIGN: Narrative review. RESULTS: Not applicable. CONCLUSIONS: Transporting children in cardiac arrest with ongoing cardiopulmonary resuscitation between hospitals is potentially lifesaving if it enables access to resources such as extracorporeal support, but may risk transport personnel safety. Research is needed to optimize outcomes of patients transported with ongoing cardiopulmonary resuscitation and reduce risks to the staff caring for them. PMID- 28737600 TI - An Interprofessional Quality Improvement Initiative to Standardize Pediatric Extubation Readiness Assessment. AB - OBJECTIVES: Establishing protocols to wean mechanical ventilation and assess readiness for extubation, with the goal of minimizing morbidity associated with extubation failure and prolonged mechanical ventilation, have become increasingly important in contemporary PICUs. The aim of this quality improvement initiative is to establish a respiratory therapist-led daily spontaneous breathing trial protocol to standardize extubation readiness assessment and documentation in our PICU. DESIGN: A quality improvement project. SETTING: Single center, tertiary care Children's Hospital PICU. PATIENTS: All intubated patients admitted to PICU requiring conventional mechanical ventilation between February 2013 and January 2016. INTERVENTIONS: A working group of pediatric intensivists, respiratory therapists, nurses, and information technology specialists established the protocol, standardized documentation via the electronic medical record, and planned education. Daily spontaneous breathing trial protocol implementation began in February 2015. All patients on mechanical ventilation were screened daily at approximately 4 AM by a respiratory therapist to determine daily spontaneous breathing trial eligibility. If all screening criteria were met, patients were placed on continuous positive airway pressure of 5 cm H2O with pressure support of 8 cm H2O for up to 2 hours. If tolerated, patients would be extubated to supplemental oxygen delivered via nasal cannula in the morning, after intensivist approval. Daily audits were done to assess screening compliance and accuracy of documentation. MEASUREMENTS AND MAIN RESULTS: We analyzed data from 398 mechanically ventilated patients during daily spontaneous breathing trial period (February 2015-January 2016), compared with 833 patients from the pre-daily spontaneous breathing trial period (February 2013-January 2015). During the daily spontaneous breathing trial period, daily screening occurred in 92% of patients. Extubation failure decreased from 7.8% in the pre-daily spontaneous breathing trial period to 4.5% in daily spontaneous breathing trial period. The use of high-flow nasal cannula slightly increased during the project, while there was no change in duration of mechanical ventilation or the use of noninvasive ventilation. CONCLUSIONS: An interprofessionally developed respiratory therapist led extubation readiness protocol can be successfully implemented in a busy tertiary care PICU without adverse events. PMID- 28737602 TI - Treatment of Congenital Thrombotic Thrombocytopenia Purpura: A New Paradigm. AB - Congenital thrombotic thrombocytopenia purpura (cTTP) is a very rare disorder worldwide. Standard treatment of recognized cases has been to administer fresh frozen plasma as the source of ADAMTS13, to replenish the absent ADAMTS13 enzyme. An alternative source, a plasma-derived factor VIII concentrate used for hemophilia A, and found to contain this enzyme, was reported to be effective in 1 patient in the United States. We now report details on a US cohort of 8 cTTP patients who have been successfully treated for varying periods with a marketed antihemophilic factor concentrate Koate-DVI. This biological product has been used successfully on demand in varying doses to treat acute exacerbations, as well as prophylactically (3 to 6 U ADAMTS13 every 3 to 21 d). Self-infused at home, in lieu of fresh frozen plasma therapy in the hospital setting, this product has effectively prevented episodes of thrombocytopenia, microangiopathic hemolytic anemia, and the concomitant organ damage in these patients. This specific virus inactivated product can be used to prevent further manifestations of this congenital enzyme deficiency. PMID- 28737601 TI - New Ways to Detect Pediatric Sickle Cell Retinopathy: A Comprehensive Review. AB - Sickle retinopathy reflects disease-related vascular injury of the eye, which can potentially result in visual loss from vitreous hemorrhage or retinal detachment. Here we review sickle retinopathy among children with sickle cell disease, describe the epidemiology, pediatric risk factors, pathophysiology, ocular findings, and treatment. Newer, more sensitive ophthalmological imaging modalities are available for retinal imaging, including ultra-widefield fluorescein angiography, spectral-domain optical coherence tomography, and optical coherence tomography angiography. Optical coherence tomography angiography provides a noninvasive view of retinal vascular layers that could previously not be imaged and can be quantified for comparative or prospective analyses. Ultra-widefield fluorescein angiography provides a more comprehensive view of the peripheral retina than traditional imaging techniques. Screening for retinopathy by standard fundoscopic imaging modalities detects a prevalence of approximately 10%. In contrast, these more sensitive methods allow for more sensitive examination that includes the retina perimeter where sickle retinopathy is often first detectable. Use of these new imaging modalities may detect a higher prevalence of early sickle pathology among children than has previously been reported. Earlier detection may help in better understanding the pathogenesis of sickle retinopathy and guide future screening and treatment paradigms. PMID- 28737603 TI - Deceased-Donor Liver Size and the Sex-Based Disparity in Liver Transplantation. PMID- 28737604 TI - The Democratization of Genomic Inquiry Empowers Our Understanding of Nephrotic Syndrome. PMID- 28737605 TI - Glomerulus-on-a-Chip. Life Up. PMID- 28737606 TI - Visual Acuity and Contrast Sensitivity Development in Children: Sweep Visually Evoked Potential and Psychophysics. AB - PURPOSE: The purpose of this study was to investigate the development of visual acuity (VA) and contrast sensitivity in children as measured with objective (sweep visually evoked potential) and subjective, psychophysical techniques, including signal detection theory (SDT), which attempts to control for differences in criterion or behavior between adults and children. Furthermore, this study examines the possibility of applying SDT methods with children. METHODS: Visual acuity and contrast thresholds were measured in 12 children 6 to 7 years old, 10 children 8 to 9 years old, 10 children 10 to 12 years old, and 16 adults. For sweep visually evoked potential measurements, spatial frequency was swept from 1 to 40 cpd to measure VA, and contrast of sine-wave gratings (1 or 8 cpd) was swept from 0.33 to 30% to measure contrast thresholds. For psychophysical measurements, VA and contrast thresholds (1 or 8 cpd) were measured using a temporal two-alternative forced-choice staircase procedure and also with a yes-no SDT procedure. Optotype (logMAR [log of the minimum angle of resolution]) VA was also measured. RESULTS: The results of the various procedures were in agreement showing that there are age-related changes in threshold values and logMAR VA after the age of 6 years and that these visual functions do not become adult-like until the age of 8 to 9 years at the earliest. It was also found that children can participate in SDT procedures and do show differences in criterion compared with adults in psychophysical testing. CONCLUSIONS: These findings confirm a slightly later development of VA and contrast sensitivity (8 years or older) and indicate the importance of using SDT or forced-choice procedures in any developmental study to attempt to overcome the effect of criterion in children. PMID- 28737607 TI - A Standardized Arabic Reading Acuity Chart: The Balsam Alabdulkader-Leat Chart. AB - PURPOSE: The aim of this study was to develop and validate the first standardized Arabic continuous text near-visual-acuity chart, the Balsam Alabdulkader-Leat (BAL) chart. METHODS: Three versions of the BAL chart were created from previously validated sentences. Reading acuity (RA) and reading speed in standard length words per minute (SLWPM) were measured for three versions of the BAL chart and three English charts (MNREAD, Colenbrander, and Radner) for 86 bilingual adults with normal vision aged 15 to 59 years. The RA and SLWPM were compared using analysis of variance. To analyze agreement between the charts, Bland-Altman plots were used. Normal visual acuity (0.00 logMAR [log minimum angle of resolution]) was calibrated for the BAL chart with linear regression analysis. RESULTS: Average RAs for BAL1, BAL2, and BAL3 were 0.62, 0.64 and 0.65 log-point print, respectively, which were statistically significantly different (repeated measures analysis of variance, P < .05), but not considered clinically significant. The coefficients of agreement for RA between the BAL charts were 0.054 (between 1 and 2), 0.061 (between 2 and 3), and 0.059 (between 1 and 3). Linear regression between the average RA for the BAL chart and the MNREAD and Radner charts showed that 0.7 log-point size at 40 cm is equivalent to 0.00 logMAR, and the new BAL chart was labeled accordingly. Mean SLWPM for the BAL charts was 201, 195, and 195 SLWPM, respectively, and for the Colenbrander, MNREAD, and Radner charts was 146, 171, and 146, respectively. The coefficients of agreement for log-SLWPM between BAL1 and BAL2, BAL2 and BAL3, and BAL1 and BAL3 were 0.063, 0.064, and 0.057 log-SLWPM, respectively. CONCLUSIONS: The BAL chart showed high interchart agreement. It is recommended for accurate near performance measures in Arabic for both research and clinical settings. PMID- 28737609 TI - The Effects of Supplementary Low-Load Blood Flow Restriction Training on Morphological and Performance-Based Adaptations in Team Sport Athletes. AB - Scott, BR, Peiffer, JJ, and Goods, PSR. The effects of supplementary low-load blood flow restriction training on morphological and performance-based adaptations in team sport athletes. J Strength Cond Res 31(8): 2147-2154, 2017 Low-load resistance training with blood flow restriction (BFR) may be a method to enhance muscular development even in trained athletes. This study aimed to assess whether supplemental low-load BFR training can improve muscle size, strength, and physical performance characteristics in team sport athletes. Twenty-one semiprofessional Australian football athletes were assessed for 3-repetition maximum (3RM) and muscular endurance in the back squat, vastus lateralis muscle architecture, and performance in sprint and vertical jump tasks. Participants then undertook a 5-week training program, consisting of normal high-load resistance training supplemented by low-load squats with (LLBFR) or without (LL) BFR. Participants also performed regular conditioning and football training during this period. After the training intervention, participants again completed the pretraining testing battery. Squat 3RM and endurance increased from pretraining levels in both LL (3RM = 12.5% increase; endurance = 24.1% increase; p <= 0.007) and LLBFR (3RM = 12.3% increase; endurance = 21.2% increase; p = 0.007) groups, though there were no between-group differences. No post-training changes were observed for muscle architecture, or performance in sprinting and jumping tasks. Although squat 3RM and endurance performance increased in both groups, adding BFR during supplemental exercise did not enhance these responses. Similarly, there were no large differences in the assessments of sprint, acceleration, and jumping performance between the groups after training. These findings suggest that although LLBFR did not negatively affect adaptive responses to resistance training, this training strategy may not provide added benefit for healthy Australian football athletes already undertaking a rigorous training schedule. PMID- 28737610 TI - Influence of Match Location, Quality of Opponents, and Match Status on Movement Patterns in Brazilian Professional Football Players. AB - Aquino, R, Munhoz Martins, GH, Palucci Vieira, LH, and Menezes, RP. Influence of match location, quality of opponents and match status on movement patterns in brazilian professional football players. J Strength Cond Res 31(8): 2155-2161, 2017-The aim of this study was to examine the independent and interactive effects of match location, quality of opponents, and match status on the movement patterns in a professional Brazilian football team. Sixteen matches of the fourth division Brazilian Championship of 2015 were analyzed during the competitive stages (classifier, 8 matches; octave-finals, 2 matches; quarterfinals, 2 matches; semifinals, 2 matches; and finals, 2 matches). A 5-Hz Global Positioning System Sports QSTARZ was used to record the total distance (TD), maximum speed (VMAX), average speed (VAVERAGE), and frequency of high-intensity activities (HIA). The Student's t-test for independent samples showed significantly higher values (p <= 0.05) of VMAX, VAVERAGE, and HIA in home matches when compared with away matches. Comparing the quality of opponents, statistically higher values of TD, VMAX, and HIA were found when the team played against strong opponents. Regarding match status, 1-way analysis of variance demonstrated that when the team won presented significantly higher values of TD, VMAX, VAVERAGE, and HIA compared with matches when the team lost. There were no substantial interactive effects of match situational variables on movement patterns. Finally, multiple linear regression showed that the variable quality of opponents has a higher relative contribution to the variance in HIA (19%) than match status (16%) and match location (4%). In particular, the results indicate that physical performance in professional football is influenced by match situational variables, resulting in a change in the team's style of play. PMID- 28737608 TI - A Randomized Trial of Soft Multifocal Contact Lenses for Myopia Control: Baseline Data and Methods. AB - SIGNIFICANCE: The Bifocal Lenses In Nearsighted Kids (BLINK) study is the first soft multifocal contact lens myopia control study to compare add powers and measure peripheral refractive error in the vertical meridian, so it will provide important information about the potential mechanism of myopia control. PURPOSE: The BLINK study is a National Eye Institute-sponsored, double-masked, randomized clinical trial to investigate the effects of soft multifocal contact lenses on myopia progression. This article describes the subjects' baseline characteristics and study methods. METHODS: Subjects were 7 to 11 years old, had -0.75 to -5.00 spherical component and less than 1.00 diopter (D) astigmatism, and had 20/25 or better logMAR distance visual acuity with manifest refraction in each eye and with +2.50-D add soft bifocal contact lenses on both eyes. Children were randomly assigned to wear Biofinity single-vision, Biofinity Multifocal "D" with a +1.50-D add power, or Biofinity Multifocal "D" with a +2.50-D add power contact lenses. RESULTS: We examined 443 subjects at the baseline visits, and 294 (66.4%) subjects were enrolled. Of the enrolled subjects, 177 (60.2%) were female, and 200 (68%) were white. The mean (+/- SD) age was 10.3 +/- 1.2 years, and 117 (39.8%) of the eligible subjects were younger than 10 years. The mean spherical equivalent refractive error, measured by cycloplegic autorefraction was -2.39 +/- 1.00 D. The best-corrected binocular logMAR visual acuity with glasses was +0.01 +/- 0.06 (20/21) at distance and -0.03 +/- 0.08 (20/18) at near. CONCLUSIONS: The BLINK study subjects are similar to patients who would routinely be eligible for myopia control in practice, so the results will provide clinical information about soft bifocal contact lens myopia control as well as information about the mechanism of the treatment effect, if one occurs. PMID- 28737611 TI - Can Resistance Training Enhance the Rapid Force Development in Unloaded Dynamic Isoinertial Multi-Joint Movements? A Systematic Review. AB - Van Hooren, B, Bosch, F, and Meijer, K. Can resistance training enhance the rapid force development in unloaded dynamic isoinertial multi-joint movements? A systematic review. J Strength Cond Res 31(8): 2324-2337, 2017-The objectives of this systematic review were to (a) evaluate whether resistance training can improve the rapid force development in unloaded dynamic isoinertial multi-joint movements and (b) investigate whether these effects differ between untrained/recreationally trained and well-trained individuals. Four electronic databases were screened for studies that measured the effects of resistance training on rapid force development in unloaded dynamic isoinertial multi-joint movements. Twelve studies with a total of 271 participants were included. 10/26 (38%) and 6/14 (43%) of the measures of rapid force development in unloaded dynamic isoinertial multi-joint movements significantly improved following training in the untrained/recreationally trained and well-trained individuals, respectively. Additionally, 7/14 (50%) and 3/12 (25%) of the measures significantly improved during a countermovement and squat jump in the untrained/recreationally trained individuals and 4/6 (67%) and 2/8 (25%) significantly improved during a countermovement and squat jump in the well trained individuals, respectively. These findings indicate that resistance training has a limited transfer to rapid force development in unloaded dynamic isoinertial multi-joint movements, especially for well-trained individuals and in movements without a countermovement. Furthermore, rapid force development has likely a limited transfer from movements with countermovement to movements without a countermovement and from bilateral movements to unilateral movements. Therefore, it is important to specifically mimic the actual sport movement in order to maximize the transfer of training and testing. PMID- 28737612 TI - Interpreting Data and Concluding in Science: Cautious Consideration of the Methodological Design and Risks of Spreading Inappropriate Information. PMID- 28737613 TI - Workload Assessment in Soccer: An Open-Minded, Critical Thinking Approach is Needed. PMID- 28737614 TI - In Response to Determinants of Olympic Fencing Performance and Implications for Strength and Conditioning Training: Erratum. PMID- 28737615 TI - Acute Wound Complications After Total Knee Arthroplasty: Prevention and Management. AB - Normal wound healing with avoidance of early wound complications is critical to the success of total knee arthroplasty. The severity of acute complications includes less morbid problems, such as quickly resolved drainage and small superficial eschars, to persistent drainage and full-thickness tissue necrosis, which may require advanced soft-tissue coverage. To achieve proper healing, surgeons must respond to persistent drainage by addressing modifiable patient risk factors, using meticulous surgical technique, and implementing an algorithmic approach to treatment. PMID- 28737616 TI - The Role of Therapeutic Modalities in Surgical and Nonsurgical Management of Orthopaedic Injuries. AB - Rehabilitation professionals often use therapeutic modalities as a component of the surgical and nonsurgical management of orthopaedic injuries. Myriad therapeutic modalities, including cryotherapy, thermotherapy, ultrasonography, electrical stimulation, iontophoresis, and laser therapy, are available. Knowledge of the scientific basis of each modality and the principles of implementation for specific injuries enables musculoskeletal treatment providers to prescribe these modalities effectively. The selection of specific therapeutic modalities is based on their efficacy during a particular phase of rehabilitation. Therapeutic modalities are an adjunct to standard exercise and manual therapy techniques and should not be used in isolation. PMID- 28737617 TI - Management of Acetabular Fractures in the Elderly. AB - The incidence of acetabular fractures in the elderly population is increasing. Fractures in this population differ from those in younger patients, with more frequent involvement of the anterior column, more comminution, and more severe articular impaction in elderly patients. Although acetabular fractures in geriatric patients are more likely the result of low-energy trauma, outcomes are generally poorer than those in young patients. Multiple management options have been proposed, but no intervention has become the standard of care for these fractures in the elderly. Patient characteristics (eg, prior ambulation status, functional capacity, bone quality), the nature of the fracture, and the experience of the treating orthopaedic surgeon all must be considered when choosing among nonsurgical treatment, percutaneous fixation, open reduction and internal fixation, and immediate or delayed arthroplasty. Each treatment option has the potential for satisfactory results in properly selected patients. PMID- 28737618 TI - Evaluation of Ulnar-sided Wrist Pain. AB - Determining the etiology of ulnar-sided wrist pain is often challenging. The condition may be acute or chronic, and differential diagnoses include injuries to the ulnar carpal bones, ligament tears, tendinitis, vascular conditions, osteoarthritis and systemic arthritis, and ulnar nerve compression. An anatomically based, methodical physical examination coupled with provocative maneuvers, including piano key, ulnar impaction, shuck, foveal stress, and extensor carpi ulnaris synergy tests, further defines the differential diagnosis. Diagnostic imaging used in the evaluation of ulnar-sided wrist pain includes plain radiographs and MRI with or without arthrography. Wrist arthroscopy is becoming increasingly important in the diagnosis and management of ulnar-sided intra-articular wrist pathology. PMID- 28737619 TI - Revision Total Elbow Arthroplasty. AB - Despite recent technologic advances, total elbow arthroplasty has complication rates higher than that of total joint arthroplasty in other joints. With new antirheumatic treatments, the population receiving total elbow arthroplasty has shifted from patients with rheumatoid arthritis to those with posttraumatic arthritis, further compounding the high complication rate. The most common reasons for revision include infection, aseptic loosening, fracture, and component failure. Common mechanisms of total elbow arthroplasty failure include infection, aseptic loosening, fracture, component failure, and instability. Tension band fixation, allograft struts with cerclage wire, and/or plate and screw constructs can be used for fracture stabilization. PMID- 28737620 TI - Sarcoidosis Following Anti-PD-1 and Anti-CTLA-4 Therapy for Metastatic Melanoma. AB - Immune checkpoint inhibitors represent the newest treatment for stage IV melanoma. These agents are generally well tolerated, however severe immune related adverse effects have been noted in a small, but clinically significant percentage of patients. Specifically, sarcoidosis is a known potential complication following anti-CTLA-4 therapy. We present 2 cases of pulmonary and cutaneous sarcoidosis developing in patients with stage IV melanoma. Both patients were treated with ipilimumab and anti-PD-1 therapy, and both experienced good oncologic responses to treatment; neither had evidence of preexisting sarcoidosis. Of note, both patients developed sarcoidosis only after undergoing immune checkpoint inhibitor therapy. In 1 patient, sarcoidosis developed after initiation of anti-PD-1 therapy, 3 months after the last dose of anti-CTLA-4 monotherapy, suggesting a synergistic immune dysmodulating effect of both checkpoint inhibitors. Ultimately, both patients' symptoms and radiologic findings resolved with corticosteroid treatment, and both patients have tolerated retreatment with PD-1 inhibitors. Sarcoidosis is a rare complication of immune checkpoint inhibitors and can manifest with severe pulmonary manifestations. However, sarcoidosis in this setting is responsive to corticosteroids and does not necessarily recur with retreatment. It is yet unclear whether the development of sarcoidosis in these patients represents unmasking of preexisting autoimmune tendencies or is a marker of oncologic response. PMID- 28737621 TI - Baroreflex activation therapy: a new approach to the management of advanced heart failure with reduced ejection fraction. AB - : Chronic heart failure is a common clinical condition characterized by persistent excessive sympathetic nervous system activation. The derangement of the sympathetic activity has relevant implications for disease progression and patient survival. Aiming to positively impact patient outcome, autonomic nervous system modulatory therapies have been developed and tested in animal and clinical studies. As a general gross assumption, direct vagal stimulation and baroreflex activation are considered equivalent. This assumption does not take into account the fact that direct cervical vagal nerve stimulation involves activation of both afferent and efferent fibers innervating not only the heart, but the entire visceral system, leading to undesired responses to and from this compartment. The different action of baroreflex activation is based on generating a centrally mediated reduction of sympathetic outflow and increasing parasympathetic activity to the heart via a physiological reflex pathway. Thus, baroreflex activation rebalances the unbalanced autonomic nervous system via a specific path. Independent and complementary investigations have shown that sympathetic nerve activity can be rebalanced via control of the arterial baroreflex in heart failure patients.Results from recent pioneering research studies support the hypothesis that baroreflex activation can add significant therapeutic benefit on top of guideline-directed medical therapy in patients with advanced heart failure. In the present review, baroreflex activation therapy results are discussed, focusing on critical aspects like patient selection rationale to support clinician orientation in opting for baroreflex activation therapy when, on top of current guideline-directed medical treatment, other therapies are to be considered. PMID- 28737622 TI - Changes in the Nature and Severity of Invasive Pneumococcal Disease in Children Before and After the Seven-valent and Thirteen-valent Pneumococcal Conjugate Vaccine Programs in Calgary, Canada. AB - BACKGROUND: Since the introduction of childhood pneumococcal conjugate vaccines, invasive pneumococcal disease (IPD) incidence has decreased in children and the predominant serotypes causing disease have changed. This study describes changes in the clinical features of IPD in children (<18 years) before and after the conjugate vaccine introduction. METHODS: The Calgary Area Streptococcus pneumoniae Epidemiology Research study collects information on all IPD cases in Calgary, Alberta, Canada. Descriptive and regression analyses were used to compare IPD in the pre-vaccine (January 2000 to August 2002), post-7-valent protein-polysaccharide conjugate vaccine (September 2002 to June 2010) and post 13-valent protein-polysaccharide conjugate vaccine (PCV13) (July 2010 to December 2015) periods; intensive care unit and inpatient admissions were outcome measures. RESULTS: The incidence of IPD in children (<18 years) decreased from an average of 17 cases/100,000/yr in 2000-2001 to 4 cases/100,000/yr in 2015. The median age of children presenting with IPD shifted from 2.0 years (interquartile range: 2.5) in the pre-vaccine period to 3.9 years (interquartile range: 6.2) in the post-PCV13 period. The proportion of children with a comorbidity that is an indication for pneumococcal vaccination did not change. Invasive disease with focus (meningitis, pneumonia, empyema, peritonitis) compared with invasive disease with bacteremia only increased from 44.6% in pre-vaccine to 64.0% and 61.4% in the post-7-valent protein-polysaccharide conjugate vaccine and post PCV13 periods, respectively (P = 0.017). Having IPD in the post-PCV13 period compared with the pre-vaccine period was associated with an increased odds of hospitalization [Odds ratio (OR): 2.9; 95% Confidence Interval (CI): 1.4-6.2]. CONCLUSIONS: Clinical features of IPD have changed since pneumococcal conjugate vaccines were introduced, with a shift toward more focal infections requiring hospitalization. Although overall IPD cases have declined, disease that does occur appears to be more severe. PMID- 28737623 TI - An Observational Study of Severe Pertussis in 100 Infants <=120 Days of Age. AB - BACKGROUND: Pertussis in young infants is a unique, severe, afebrile, cough illness that is frequently fatal. METHODS: All pertussis cases <=120 days of age admitted to a pediatric intensive care unit in California between October 1, 2013, and April 25, 2015, were evaluated. RESULTS: Of 100 pertussis patients <=120 days of age admitted to pediatric intensive care unit, there were 5 deaths. The white blood cell counts in the fatal cases were significantly higher than in the nonfatal cases. Thirty-four percent of patients were intubated, 18% received inotropic and/or vasoactive support, 22% received steroid, 4% received extracorporal membrane oxygenation, and 3% underwent exchange blood transfusion. The median age at the time of illness onset in the patients who died was 23 days. CONCLUSIONS: These data, as well as data from previous California studies, suggest updated strategies for the management of severe pertussis. These include perform serial white blood cell counts, treat all presumptive cases with azithromycin, evaluate for pulmonary hypertension, intubate and administer oxygen for apneic episodes and administer inotropic/vasoactive agents for cardiogenic shock. Do not administer steroids or nitric oxide. Criteria for exchange blood transfusion therapy for leukocytosis with lymphocytosis are suggested. PMID- 28737624 TI - Palpebral Anthrax. AB - A 13-year-old male patient presented with a complaint of swelling of the left eye starting 3 days ago. Bullous lesion and purulent discharge were present on his left eyelids. Bacillus anthracis was shown in culture and diagnosis was confirmed. Oculocutaneous anthrax is a rare condition, but the diagnosis should be considered in patients with a painless necrotizing ulcer. PMID- 28737625 TI - A National Seroepidemiologic Survey of Pertussis Among School Children in Taiwan. AB - BACKGROUND: In 2009, a booster dose of acellular pertussis vaccine for children at or before entry to elementary school was added to the national immunization program in Taiwan, which includes pertussis vaccination at 2, 4, 6 and 18 months of age. In 2013, a study to assess the level of humoral immunity against pertussis in elementary and junior high school children and adolescents was conducted. METHODS: A multistage stratified systematic sampling method was applied to randomly selected grade 1 to 9 school children for testing. Serum samples were tested for IgG antibodies to Bordetella pertussis using commercial enzyme-linked immunosorbent assay kits. The study collected information on sociodemographic characteristics, vaccination history, sibling number and disease history of pertussis. RESULTS: The study recruited 2782 school children from 58 schools around the country. By questionnaire, only 1% (28/2782) students had history of pertussis. The overall positivity rate of anti-B. pertussis IgG was 42.5%, and the rates were not different between the 5 geographical areas (range from 39.6% to 44.6%, P = 0.375). Age-stratified data showed that the positivity rates were 43.6-48.8% among grade 1-3 students, 26.6-28.7% in grade 4-5 students and increased progressively from 39.4% to 51.3% in grade 6-9 students. The overall positivity rate was significantly higher in the nonbooster group (46.4% versus 38.6%, P < 0.01). CONCLUSION: The prevalence of anti-B. pertussis antibody was 42.5% in grade 1-9 students under the current vaccination program in Taiwan. Antibody induced by the booster vaccination before entry of primary school waned rapidly in 3-4 years. Rapid waning of anti-B. pertussis antibody may explain the resurgence of whooping cough in recent decades. Additional booster doses should be considered in adolescents and adults. PMID- 28737626 TI - Perinatal Chikungunya Virus-associated Encephalitis Leading to Postnatal-Onset Microcephaly and Optic Atrophy. AB - Chikungunya virus is capable of affecting the nervous system of children and adults. We describe a case of sepsis and encephalitis triggered by this agent in a newborn whose mother developed symptoms of acute infection 2 days before delivery. Consequently, the infant had severe encephalitis that evolved with postnatal-onset microcephaly, bilateral optic atrophy, epilepsy and cerebral palsy. PMID- 28737627 TI - Direct and Indirect Effectiveness of the 10-Valent Pneumococcal Conjugate Vaccine Against Carriage in a Cluster Randomized Trial. AB - Finnish invasive pneumococcal disease (FinIP) vaccine trial was designed to evaluate effectiveness of 10-valent pneumococcal conjugate vaccine (PHiD-CV10; GSK; Rixensart, Belgium). We conducted 2 satellite studies to evaluate ten-valent Pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10) effectiveness against pneumococcal carriage in FinIP-vaccinated children (long term direct and indirect effectiveness combined) and in their unvaccinated siblings (indirect effectiveness within the family). FinIP was a cluster randomized trial, where >47,000 children <19 months of age were recruited in 2009 2010. Children received PHiD-CV10 in 2/3, and control vaccine in 1/3 of clusters according to age-specific infant and catch-up schedules. We obtained nasopharyngeal samples from subgroups of FinIP-vaccinated children at 3-5 years of age in 2013 and their unvaccinated older siblings in 2011 and 2013, and compared carriage in PHiD-CV10 clusters to control clusters in parallel. National Vaccination Programme with PHiD-CV10 for all 3-month-old children started in 2010 resulting in 92% vaccination coverage. To investigate indirect effects, over 2200 nasopharyngeal swabs were obtained during each round from unvaccinated older siblings. In 2011, we observed a 29% (95% confidence interval: 6-47) reduction in vaccine-type carriage in siblings of PHiD-CV10 participants vaccinated according to infant schedules. Vaccine-type carriage prevalences were low with no differences observed in 2013, 3 years after PHiD-CV10 introduction. For estimation of combined direct and indirect effectiveness, 1550 swabs from FinIP vaccinated children were obtained in 2013. We observed a reduction of 54% (95% confidence interval: 34-68) in vaccine-type carriage in PHiD-CV10-vaccinated children. This study was the first randomized trial to show the indirect effect of extended valency pneumococcal conjugate vaccination on carriage. Also, long term effectiveness against vaccine-type carriage was demonstrated in vaccinated children. PMID- 28737628 TI - Becoming Fully Engaged. PMID- 28737629 TI - Join the Orthopaedic Nursing Journal Team. PMID- 28737630 TI - First in the Nation: One Unit's Journey to Achieving Fragility Fracture Certification. AB - Osteoporosis is related to more than 2 million fractures and $19 billion in healthcare costs each year (). A fragility fracture (FF) is a low-energy fracture of the distal radius, proximal humerus, ankle, or proximal femur (hip) from minimal trauma such as a fall from a standing height. In addition to cost, FFs often result in the loss of independence and productivity (). In 2015, our orthopaedic unit received the first certification ever awarded for FFs. Fragility fracture certification is a new certification demonstrating that a healthcare facility complies with national patient care standards and uses evidence-based practice guidelines to deliver quality outcomes. Orthopaedic nurses have a critical role in optimizing future bone health and fracture prevention. Our story describes the process and challenges faced becoming the first organization in the nation to be successfully surveyed for The Joint Commission's Fragility Fracture Certification. PMID- 28737631 TI - First in the Nation: One Unit's Journey to Achieving Fragility Fracture Certification. PMID- 28737633 TI - Transgender Individuals and Osteoporosis Prevention. PMID- 28737632 TI - Transgender Individuals and Osteoporosis Prevention. AB - BACKGROUND: Risk behaviors and hormone use place transgender individuals (TIs) in jeopardy for osteoporosis. PURPOSE: The purpose of this study was to expand the science about the knowledge, health beliefs, and osteoporosis (OP) preventing behaviors of TIs. METHODS: This was a mixed-methods pilot study of a convenience sample of 31 TIs 30 years and older. Participants completed an online Osteoporosis Bone Health Survey. Fifteen participants were randomly selected for an interview to describe their perceptions of bone health. RESULTS: Transgender individuals performed poorly on the knowledge measure. There were no significant findings for osteoporosis health beliefs. Participants' daily dietary dairy calcium intake was 800 mg and daily walking activity was 17 minutes. Perceptions of bone health revealed two essential elements, knowing and doing. CONCLUSION: Determining TIs' bone health perception is important because of their unique healthcare issues. Healthcare providers need to be aware of TIs' bone health needs to help enhance TIs' OP knowledge, health beliefs, and preventing behaviors. PMID- 28737634 TI - Noise Reduction to Reduce Patient Anxiety During Cast Removal: Can We Decrease Patient Anxiety With Cast Removal by Wearing Noise Reduction Headphones During Cast Saw Use? AB - BACKGROUND: Noise reduction headphones decrease the sound during cast removal. Their effectiveness in decreasing anxiety has not been studied. PURPOSE: Compare pediatric patients' anxiety levels during cast removal with and without utilization of noise reduction headphones combined with use of a personal electronic device. METHODS: Quality improvement project. Patients randomly assigned to noise reduction headphone group or standard care group during cast removal. Faces, Legs, Activity, Cry, and Consolability Scale and heart rate were evaluated prior to, during, and after cast removal. Data were compared across groups. RESULTS: Fifty patients were included; 25 per group. No difference detected between the 2 groups in Faces, Legs, Activity, Cry, and Consolability Scale score prior to (p = .05) or after cast removal (p = .30). During cast removal, the headphone group had lower FLACC Scale scores (p = .03). Baseline heart rate was lower in the headphone group prior to (p = .02) and after (p = .005) cast removal with no difference during cast removal (p = .24). CONCLUSION: Utilizing noise reduction headphones and a personal electronic device during the cast removal process decreases patient anxiety. PMID- 28737635 TI - Reducing Length of Stay, Direct Cost, and Readmissions in Total Joint Arthroplasty Patients With an Outcomes Manager-Led Interprofessional Team. AB - The purpose of this quality improvement project was to determine whether an outcomes manager-led interprofessional team could reduce length of stay and direct cost without increasing 30-day readmission rates in the total joint arthroplasty patient population. The goal was to promote interprofessional relationships combined with collaborative practice to promote coordinated care with improved outcomes. Results from this project showed that length of stay (total hip arthroplasty [THA] reduced by 0.4 days and total knee arthroplasty [TKA] reduced by 0.6 days) and direct cost (THA reduced by $1,020 per case and TKA reduced by $539 per case) were significantly decreased whereas 30-day readmission rates of both populations were not significantly increased. PMID- 28737636 TI - Reducing Length of Stay, Direct Cost, and Readmissions in Total Joint Arthroplasty Patients With an Outcomes Manager-Led Interprofessional Team. PMID- 28737637 TI - Self-Reported Rates of Adherence to Aspirin Prescribed as an Antithrombotic Therapy Following Postoperative Total Joint Replacement. AB - BACKGROUND: Patients may not understand the importance of medication adherence when discharged with aspirin (ASA) as an anticoagulant for venous thromboembolism (VTE) prophylaxis after joint replacement surgery. PURPOSE: The purpose of this study was to examine self-reported rates of adherence to postoperative use of ASA for VTE prophylaxis. METHODS: This was an exploratory, descriptive study using a convenience sample of 99 participants. Adherence was measured with a 4-question self-reporting tool. RESULTS: Thirty-seven percent were male and 76% were Caucasian, and median age was 63 years. Ninety-two percent had the dosage correct, 76% knew how long to take the medication, and 100% of the sample was still taking the ASA; 40% had forgotten to take 1 or more doses of the medication. No associations were noted. Overall compliance was 44%. CONCLUSION: A significant number missed 1 or more doses. This is an opportunity for nurses to work with patients on innovative ways to improve adherence. PMID- 28737639 TI - Motor Control Exercise for Chronic Nonspecific Low Back Pain. PMID- 28737638 TI - A Bone Health Intervention for Chinese Immigrants in Santa Clara County. AB - BACKGROUND: Among Chinese immigrants, osteoporosis is undertreated, misdiagnosed, and a leading cause of fragility fractures. In orthopaedic surgery departments, prevention education and health behavior change programs are necessary to improve their bone health. PURPOSE: The purpose of this study was to examine the effectiveness of an osteoporosis prevention education program on participants' self-efficacy with regard to exercise and nutrition when provided by an orthopaedic surgery team during an annual Chinese Health Fair in Santa Clara County, CA. METHODS: This pilot study used a single-group pretest and posttest design. Chinese immigrants at risk of osteoporosis were recruited during a 1-day health fair. The Bone Health Intervention (BHI) included orthopaedic surgeon consultation, visual aids including osteoporosis images and bone models, a video that included a discussion on calcium and vitamin D in the Chinese diet and culturally-acceptable exercise, and osteoporosis educational handouts. The Osteoporosis Self-Efficacy Scale (OSES) was utilized to measure participants' confidence in the ability to participate in self-care behaviors related to physical activity and calcium intake before and after the intervention. Paired t tests were used to compare participants' OSES scores pre- and postintervention. RESULTS: There was a significant increase in mean OSES scores postintervention, indicating that the intervention could be an effective method of increasing participants' self-efficacy regarding calcium intake and time spent in exercising. CONCLUSION: These results indicate that a culturally meaningful education program can potentially reduce fragility fracture risk. Orthopaedic health providers are ideal candidates to deliver preventive care education to improve outcomes for Chinese immigrants. PMID- 28737640 TI - Tibial Plateau Fracture. PMID- 28737641 TI - Tibial Plateau Fracture. PMID- 28737642 TI - Medical Errors, Passing Along Nursing Knowledge, and Stress and Burnout: Three Books. PMID- 28737643 TI - New Certificants, January to March 2017. PMID- 28737646 TI - CRP/Albumin Ratio: An Early Predictor of Steroid Responsiveness in Acute Severe Ulcerative Colitis. AB - INTRODUCTION: Identifying hospitalized patients with acute severe ulcerative colitis (ASUC) who will be refractory to corticosteroid therapy and require rescue therapy remains difficult. Hypoalbuminemia worsens with time during hospitalization and is associated with rapid clearance of and reduced response to infliximab (IFX) rescue. Early use of rescue therapy may therefore be more effective. Simple clinical and laboratory predictors of corticosteroid responsiveness would facilitate earlier use of rescue therapy. MATERIALS AND METHODS: Retrospective study of a prospectively maintained database of 3600 patients attending a single center was conducted. Patients with histologically confirmed ulcerative colitis admitted with ASUC over a 5-year period from January 2010 to December 2014 were identified. All patients initially received intravenous corticosteroids. Patient demographics were collected; C-reactive protein (CRP) and albumin levels were recorded at baseline and during admission. Receiver operating characteristic statistics were used to determine the optimal stool frequency, CRP, albumin, and CRP/albumin ratio (CAR) to predict steroid response. RESULTS: A total of 124 ASUC patients were admitted during a 5-year period. Median follow-up was 2.3 years. A total of 62 patients (50%) were steroid responsive, 55 patients (44%) received rescue IFX, 22 patients (18%) required colectomy within 30 days of admission, whereas a further 14 (11%) required colectomy during follow-up. By receiver operating characteristic statistics, day 3 CAR was a more accurate marker of steroid responsiveness than day 3 CRP or day 3 albumin alone [area under curve=0.75 (P<0.001)]. The optimal CAR to predict response to steroids on day 3 was 0.85 (sensitivity 70%, specificity 76%). When combined with D3 stool frequency, specificity improved to 83%. If at day 3, CAR was >0.85 and stool frequency was >3, the relative risk of steroid nonresponse was significantly raised at 3.9 (95% confidence interval, 2.1-7.2). CONCLUSIONS: Raised D3 CAR is an early predictor of steroid-refractory ASUC. When combined with D3 stool frequency, its predictive ability improves. In patients with predicted steroid nonresponse, early introduction of rescue IFX at this stage may be more effective, before serum albumin falls profoundly. PMID- 28737645 TI - Risk of Cancer Recurrence Among Individuals Exposed to Antitumor Necrosis Factor Therapy: A Systematic Review and Meta-Analysis of Observational Studies. AB - BACKGROUND: Patients with immune-mediated disorders such as ankylosing spondylitis, inflammatory bowel disease, psoriasis and rheumatoid arthritis are increasingly treated with tumor necrosis factor (TNF) inhibitors. The safety of anti-TNF therapy in patients with a history of cancer requires further evaluation. We conducted a systematic review and a meta-analysis of observational studies including patients with a history of cancer exposed to anti-TNF therapy assessing for a risk of new cancer or cancer recurrence. MATERIALS AND METHODS: A computerized literature search of MEDLINE, Google scholar, and Cochrane Database of Systematic Reviews was performed through September 1, 2015. Study characteristics, quality, and risk of bias were assessed. Random-effects model meta-analyses were used to estimate the risk of new cancer development or cancer recurrence. RESULTS: Nine English-language observational studies including patients with a history of cancer and exposed to anti-TNF therapy were idenitifed. The pooled incidence rate ratio of new or recurrent cancer among individuals with a history of cancer exposed to anti-TNF therapy was not significantly different compared with control therapies (incidence rate ratio, 0.90; 95% confidence interval, 0.59-1.37). Subgroup analyses were performed according to disease type, underlying cancer diagnosis, time to initiation of anti-TNF therapy and study quality. Heterogeneity of study populations, heterogeneity of the included cancer subtypes and utilization of observational studies limits the study quality. CONCLUSIONS: The risk of new cancer or cancer recurrence among patients with a history of cancer and use of anti-TNF therapy is similar to the risk with nonbiological disease modifying therapies. These results support the use of anti-TNF medications in select populations despite prior diagnosis of cancer. PMID- 28737647 TI - Risk Factors for 30-day Hospital Readmission for Diverticular Hemorrhage. AB - INTRODUCTION: The 2010 Affordable Care Act introduced the Hospital Readmissions Reduction Program to reduce health care utilization. Diverticular disease and its complications remain a leading cause of hospitalization among gastrointestinal disease. We sought to determine risk factors for 30-day hospital readmissions after hospitalization for diverticular bleeding. MATERIALS AND METHODS: We utilized the 2013 National Readmission Database sponsored by the Agency for Healthcare Research and Quality focusing on hospitalizations with the primary or secondary discharge diagnosis of diverticular hemorrhage or diverticulitis with hemorrhage. We excluded repeat readmissions, index hospitalizations during December and those resulting in death. Our primary outcome was readmission within 30 days of index hospital discharge. Secondary outcomes of interest included medical and procedural comorbid risk factors. The data were analyzed using logistic regression analysis. RESULTS: In total, 29,090 index hospitalizations for diverticular hemorrhage were included. There were 3484 (12%) 30-day readmissions with recurrent diverticular hemorrhage diagnosed in 896 (3%).Index admissions with renal failure [odds ratio (OR), 1.31; 95% confidence interval (CI), 1.19-1.43], congestive heart failure (OR, 1.30; 95% CI, 1.17-1.43), chronic pulmonary disease (OR, 1.19; 95% CI, 1.09-1.29), coronary artery disease (OR, 1.12; 95% CI, 1.03-1.21), atrial fibrillation (OR, 1.12; 95% CI, 1.02-1.22) cirrhosis (OR, 1.95; 95% CI, 1.29-2.93, performance of blood transfusion (OR, 1.23; 95% CI, 1.15-1.33), and abdominal surgery (OR, 1.24; 95% CI, 1.03-1.49) had increased risk of 30-day readmission. CONCLUSIONS: The 30-day readmission rate for diverticular hemorrhage was 12% with multiple identified comorbidities increasing readmission risk. PMID- 28737648 TI - Who is Responsible for What Happens Before, During, and After Colonoscopy? Results of a National Survey of Primary Care Physicians. AB - BACKGROUND AND AIMS: Primary care providers (PCPs) play a critical role in colon cancer screening by initiating referrals to gastroenterologists for colonoscopy, but little is known about their role in pre-colonoscopy bowel preparation selection and pre-colonoscopy follow-up care. This study aimed to better understand coordination of care between PCPs and gastroenterologists as well as the current availability of "open-access" screening colonoscopy. METHODS: A multiple-choice survey was developed to assess PCPs' experiences with open-access colonoscopy, their involvement in the pre-colonoscopy process, and follow-up after colonoscopy. The survey was distributed electronically to a nationally representative sample of PCPs, via the American College of Physicians (ACP) Research Center's Internal Medicine Insider Research Panel. RESULTS: Of 442 PCPs invited to participate, 210 responded (response rate, 210/442, 48%), and 29 were ineligible (spent <25% of their time on clinical care or placed no referrals to colonoscopy), yielding 181 completed surveys. A total of 39% reported that open access was "rarely" or "never" available in their practice setting. The majority reported that pre-colonoscopy care was coordinated by gastroenterologists rather than PCPs. For example, 93% reported that gastroenterologists were responsible for bowel preparation selection in their practice setting. Post-colonoscopy, 54% of PCPs reported that they were responsible for ordering subsequent colonoscopies. CONCLUSIONS: PCPs frequently coordinate follow-up care postprocedure but play a relatively minor role in the pre-colonoscopy bowel preparation process. Open access availability for screening colonoscopy remains limited in this national sample of PCPs. PMID- 28737649 TI - Race, Age, and Geography Impact Hepatitis C Genotype Distribution in the United States. AB - GOALS: To determine the impact of geography and patient characteristics on hepatitis C virus (HCV) genotype and subtype distribution in a large sample of patients under routine clinical care BACKGROUND:: HCV genotype impacts disease course and response to treatment. Although several studies have reported genotype distribution within specific US populations, there are no comprehensive descriptions in large, geographically diverse cohorts. STUDY: Using data from the Chronic Hepatitis Cohort Study, we present the distribution of HCV genotypes (GT) and subtypes (ST) among a racially diverse cohort of over 8000 HCV-infected patients from four large US health systems. RESULTS: Genotype distribution varied significantly by geographic and demographic factors. In age-adjusted analyses, African American patients had significantly higher prevalence of GT1 (85%) than other racial categories, largely driven by a markedly higher proportion of GT1 subtype b (~34%) than in Asian/other (24%) and white (21%) patients. GT3 represented an increasing proportion of infections as birth decade progressed, from 4% in patients born before 1946 to 18% of those born after 1976. Within the cohort of "living/uncured" patients, highly elevated alanine aminotransferase (>2 times the upper limit of normal) was significantly more common in GT3 patients, whereas Fibrosis-4 Index scores indicative of cirrhosis were most common in the combined group of GT4&6 patients. CONCLUSION: Distribution of HCV genotypes and subtypes in the United States is more variable than suggested by previous national-level estimates and single-center studies. "Real-world" prevalence data may improve targeting of prevention, screening, and treatment efforts for hepatitis C. PMID- 28737650 TI - Thalidomide in Transfusion Dependent Thalassemia: Hope or Hype. PMID- 28737651 TI - From the Editor. PMID- 28737652 TI - Case in Health Care Management. PMID- 28737653 TI - Excellence and Efficiency Through a Structured Large Scale Approach: The Hospital Do Rim in Sao Paulo, Brazil. PMID- 28737655 TI - Contraception for Transplant Patients. PMID- 28737656 TI - Elisa Gordon, PhD, MPH: Professor, Comprehensive Transplant Center, Department of Surgery; Center for Healthcare Studies, Institute for Public Health and Medicine; and Center for Bioethics and Medical Humanities, Department of Medical Education, Feinberg School of Medicine, Northwestern University, Chicago, IL. PMID- 28737657 TI - Intensive Care Solely to Facilitate Organ Donation-New Challenges. PMID- 28737658 TI - Regulation of Clinical Xenotransplantation-Time for a Reappraisal. AB - The continual critical shortage of organs and cells from deceased human donors has stimulated research in the field of cross-species transplantation (xenotransplantation), with the pig selected as the most suitable potential source of organs. Since the US Food and Drug Administration concluded a comprehensive review of xenotransplantation in 2003, considerable progress has been made in the experimental laboratory to improve cell and organ xenograft survival in several pig-to-nonhuman primate systems that offer the best available models to predict clinical outcomes. Survival of heart, kidney, and islet grafts in nonhuman primates is now being measured in months or even years. The potential risks associated with xenotransplantation, for example, the transfer of an infectious microorganism, that were highlighted in the 2003 Food and Drug Administration guidance and subsequent World Health Organization consensus documents have been carefully studied and shown to be either less likely than previously thought or readily manageable by donor selection or recipient management strategies. In this context, we suggest that the national regulatory authorities worldwide should re-examine their guidelines and regulations regarding xenotransplantation, so as to better enable design and conduct of safe and informative clinical trials of cell and organ xenotransplantation when and as supported by the preclinical data. We identify specific topics that we suggest require reconsideration. PMID- 28737659 TI - Summary of Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline on the Evaluation and Care of Living Kidney Donors. AB - Kidney Disease: Improving Global Outcomes (KDIGO) engaged an evidence review team and convened a work group to produce a guideline to evaluate and manage candidates for living kidney donation. The evidence for most guideline recommendations is sparse and many "ungraded" expert consensus recommendations were made to guide the donor candidate evaluation and care before, during, and after donation. The guideline advocates for replacing decisions based on assessments of single risk factors in isolation with a comprehensive approach to risk assessment using the best available evidence. The approach to simultaneous consideration of each candidate's profile of demographic and health characteristics advances a new framework for assessing donor candidate risk and for defensible shared decision making. PMID- 28737660 TI - Renal Protection Mediated by Hypoxia Inducible Factor-1alpha Depends on Proangiogenesis Function of miR-21 by Targeting Thrombospondin 1. AB - BACKGROUND: Angiogenesis contributes to the repair process after renal ischemia/reperfusion (I/R) injury. In the present study, we tested the role of miR-21 in the angiogenesis induced by hypoxia inducible factor (HIF)-1alpha through inhibiting a predicted target gene thrombospondin 1 (TSP-1). METHODS: To stabilize HIF-1alpha, hypoxia (1% O2 for 24 hours) was performed in human umbilical vein endothelial cells and cobalt chloride (CoCl2) was pretreated intraperitoneally 24 hours before renal I/R in mice. Locked nucleic acid modified anti-miR-21 and scrambled control was transfected with hypoxic cells or delivered into the mice via tail vein 1 hour before CoCl2 injection. The kidneys and blood were collected at 24 hours after reperfusion. RESULTS: HIF-1alpha induced by hypoxia and CoCl2 upregulated vascular endothelial growth factor and miR-21, and increased angiogenesis. It was found that expression of TSP-1 was inversely related with miR-21 in vitro and in vivo. Targeting of TSP-1 by miR-21 was further confirmed in vitro. Furthermore, HIF-1alpha improved renal function, accompanied with increased angiogenesis after I/R injury in mice. The protective effect of HIF-1alpha was attenuated by inhibition of miR-21. CONCLUSIONS: HIF 1alpha induced angiogenesis by upregulating not only vascular endothelial growth factor but also miR-21 via inhibiting a novel target gene TSP-1. Both of them may contribute to the protective effect of HIF-1alpha on renal I/R injury. PMID- 28737662 TI - The Authors' Response. PMID- 28737661 TI - Toward Establishing Core Outcome Domains For Trials in Kidney Transplantation: Report of the Standardized Outcomes in Nephrology-Kidney Transplantation Consensus Workshops. AB - BACKGROUND: Treatment decisions in kidney transplantation requires patients and clinicians to weigh the benefits and harms of a broad range of medical and surgical interventions, but the heterogeneity and lack of patient-relevant outcomes across trials in transplantation makes these trade-offs uncertain, thus, the need for a core outcome set that reflects stakeholder priorities. METHODS: We convened 2 international Standardized Outcomes in Nephrology-Kidney Transplantation stakeholder consensus workshops in Boston (17 patients/caregivers; 52 health professionals) and Hong Kong (10 patients/caregivers; 45 health professionals). In facilitated breakout groups, participants discussed the development and implementation of core outcome domains for trials in kidney transplantation. RESULTS: Seven themes were identified. Reinforcing the paramount importance of graft outcomes encompassed the prevailing dread of dialysis, distilling the meaning of graft function, and acknowledging the terrifying and ambiguous terminology of rejection. Reflecting critical trade offs between graft health and medical comorbidities was fundamental. Contextualizing mortality explained discrepancies in the prioritization of death among stakeholders-inevitability of death (patients), preventing premature death (clinicians), and ensuring safety (regulators). Imperative to capture patient reported outcomes was driven by making explicit patient priorities, fulfilling regulatory requirements, and addressing life participation. Specificity to transplant; feasibility and pragmatism (long-term impacts and responsiveness to interventions); and recognizing gradients of severity within outcome domains were raised as considerations. CONCLUSIONS: Stakeholders support the inclusion of graft health, mortality, cardiovascular disease, infection, cancer, and patient reported outcomes (ie, life participation) in a core outcomes set. Addressing ambiguous terminology and feasibility is needed in establishing these core outcome domains for trials in kidney transplantation. PMID- 28737663 TI - The Author's Response. PMID- 28737664 TI - sMap3D Corneo-Scleral Topographer Repeatability in Scleral Lens Patients. AB - OBJECTIVES: To determine repeatability of measurements using the sMap3D Corneo Scleral Topographer in patients presenting for scleral lens fitting. METHODS: As part of our standard clinical evaluation, 25 eyes of 23 patients who presented for scleral lens fitting were examined twice in the same day with the sMap3D in this retrospective study. Sagittal height (SAG), sMap3D principal toricity magnitude (as calculated by the instrument software), and steep axis location were measured at a 16-mm chord diameter. Up gaze, primary, and down gaze positions of each eye were imaged and "stitched" by the instrument software into a single corneoscleral topography map from which the measurements were derived. RESULTS: The mean difference in SAG between the 2 examinations was 14 MUm with an SD of 55 MUm. Sixty-eight percent of cases had a difference of <=50 MUm, and 95% of cases had a difference of <=100 MUm. The mean difference in sMap3D principal toricity magnitude between examinations was 0.15 diopter (D) with an SD of 0.38 D. Eighty-four percent of cases had a difference of <=0.5 D, and all cases had a difference of <1 D. Mean toric axis difference between examinations was 2.5 degrees with an SD of 18.4 degrees . Sixty-four percent of cases had an axis difference of <=10 degrees , and 84% had an axis difference of <=15 degrees . CONCLUSIONS: The sMap3D measurements are repeatable with regard to scleral toricity and SAG values at a 16-mm diameter and thus would be suitable to use for scleral lens fitting. PMID- 28737665 TI - Refractive and Corneal Aberrometric Changes After Crescentic Lamellar Wedge Resection in Pellucid Marginal Degeneration. AB - OBJECTIVE: To evaluate the effectiveness of crescentic corneal lamellar wedge resection for the treatment of pellucid marginal degeneration (PMD) in improving refractive, visual, and corneal aberrometry. METHODS: The study included 10 eyes of 10 patients who had undergone corneal lamellar wedge resection for PMD. Pellucid marginal degeneration was diagnosed based on the clinical signs and corneal topography. The corneal aberrometry was evaluated with Sirius corneal topography. RESULTS: The mean follow-up period was 14.1 months (range, 9-24 months). Uncorrected visual acuity was improved in nine eyes and remained unchanged in 1 case, whereas best-corrected visual acuity was improved in all eyes postoperatively. By vector analysis, the overall mean astigmatic drift at the last visit was calculated to be 13.0+/-6.3 diopters (D). At last visit, significant reductions were found for all aberrometric measurements. However, the differences were not significant for the measurements of trefoil (P=0.189). CONCLUSIONS: Corneal lamellar wedge resection is a favorable surgical option for management of PMD, allowing for improved visual acuity, keratometric cylinder, and corneal aberrations. PMID- 28737666 TI - The Role of AOPP in Age-Related Bone Loss and the Potential Benefits of Berry Anthocyanins. AB - Age-related bone loss is a major factor in osteoporosis and osteoporotic fractures among the elderly. Because bone homeostasis involves a balance between bone formation and resorption, multiple mechanisms may induce age-dependent changes in bone. Oxidative stress is one such factor that contributes to the pathology of aging-associated osteoporosis (AAO). Advanced oxidation protein products (AOPP) are a biomarker of oxidant-mediated protein damage, and can also act to increase the production of reactive oxygen species (ROS), thereby perpetuating oxidative damage. AOPP is a relatively novel marker of oxidative stress, and its role in bone aging has not been fully elucidated. Furthermore, it has been theorized that dietary antioxidants may decrease AOPP levels, thereby reducing AAO risk, but a limited number of studies have been specifically targeted at addressing this hypothesis. Therefore, the objective of this review is to examine the findings of existing research on the role of AOPP in age related bone loss, and the potential use of dietary antioxidants to mitigate the effects of AAOP on age-related bone loss. Cross-sectional studies have delivered mixed results, showing that AOPP levels are inconsistently associated with bone loss and aging. However, in vitro studies have documented multiple mechanisms by which AOPP may lead to bone loss, including upregulation of the JNK/p38 MAPK signaling pathways as well as increasing expression of sclerostin and of receptor activator of NFkappaB ligand (RANKL). Studies also indicate that antioxidants especially berry anthocyanins-may be an effective dietary agent to prevent aging associated bone deterioration by inhibiting the formation of AOPP and ROS. However, the understanding of these pathways in AAO has largely been based on in vitro studies, and should be examined in further animal and human studies in order to inform recommendations regarding dietary anthocyanin use for the prevention of AAO. PMID- 28737667 TI - Prenatal Vitamin D Intake, Cord Blood 25-Hydroxyvitamin D, and Offspring Body Composition: The Healthy Start Study. AB - Vitamin D deficiency in pregnancy may be associated with increased offspring adiposity, but evidence from human studies is inconclusive. We examined associations between prenatal vitamin D intake, 25-hydroxyvitamin D (25(OH)D) in cord blood, and offspring size and body composition at birth and 5 months. Participants included 605 mother-offspring dyads from the Healthy Start study, an ongoing, pre-birth prospective cohort study in Denver, Colorado, USA. Prenatal vitamin D intake was assessed with diet recalls and questionnaires, and offspring body composition was measured via air displacement plethysmography at birth and 5 months. General linear univariate models were used for analysis, adjusting for maternal age, race/ethnicity, pre-pregnancy body mass index (BMI), offspring sex, and gestational age at birth. Non-Hispanic white race, lower pre-pregnancy BMI, higher prenatal vitamin D intake, and summer births were associated with higher cord blood 25(OH)D. Higher 25(OH)D was associated with lower birthweight (beta = 6.22, p = 0.02), but as maternal BMI increased, this association became increasingly positive in direction and magnitude (beta = 1.05, p = 0.04). Higher 25(OH)D was also associated with lower neonatal adiposity (beta = -0.02, p < 0.05) but not after adjustment for maternal BMI (beta = -0.01, p = 0.25). Cord blood 25(OH)D was not associated with offspring size or body composition at 5 months. Our data confirm the hypothesis that vitamin D exposure in early life is associated with neonatal body size and composition. Future research is needed to understand the implications of these associations as infants grow. PMID- 28737668 TI - Effect of Patulin from Penicillium vulpinum on the Activity of Glutathione-S Transferase and Selected Antioxidative Enzymes in Maize. AB - The mycotoxin patulin (PAT) was purified from Penicillium vulpinum CM1 culture that has been isolated from a soil cultivated with maize. The effect of PAT and of a fungal culture filtrate on the activities of glutathione-S-transferase (GST) and some antioxidant enzymes viz. ascorbate peroxidase (APX), glutathione reductase (GR), dehydroascorbate reductase (DHAR) and monodehydroascorbate reductase (MDHAR) was investigated in roots and shoots of 8-day-old maize seedlings. PAT and culture filtrate caused significant reduction effects in a dose-related manner on the total GST activity. Upon application of the high PAT concentration (25 MUg.mL-1) and of the concentrated fungal filtrate (100%, v/v), the reduction in GST activity of roots was 73.8-76.0% and of shoots was 60-61.7%. Conversely, significant increases in the activities of antioxidant enzymes were induced. Application of 25 MUg.PAT.mL-1 increased APX, GR, DHAR, and MDHAR activity of root by 2.40-, 2.00-, 1.24-, and 2.16-fold, respectively. In shoots, the enzymatic activity was increased by 1.57-, 1.45-, 1.45-, and 1.61-fold, respectively. Similar induction values of the enzymatic activity were obtained upon application of the concentrated fungal filtrate. This is the first report describing the response of GST and antioxidant enzyme activities of plant cells to PAT toxicity. PMID- 28737669 TI - Molecular Dynamics Simulations of the Host Defense Peptide Temporin L and Its Q3K Derivative: An Atomic Level View from Aggregation in Water to Bilayer Perturbation. AB - Temporin L (TempL) is a 13 residue Host Defense Peptide (HDP) isolated from the skin of frogs. It has a strong affinity for lipopolysaccharides (LPS), which is related to its high activity against Gram-negative bacteria and also to its strong tendency to neutralize the pro-inflammatory response caused by LPS release from inactivated bacteria. A designed analog with the Q3K substitution shows an enhancement in both these activities. In the present paper, Molecular Dynamics (MD) simulations have been used to investigate the origin of these improved properties. To this end, we have studied the behavior of the peptides both in water solution and in the presence of LPS lipid-A bilayers, demonstrating that the main effect through which the Q3K substitution improves the peptide activities is the destabilization of peptide aggregates in water. PMID- 28737670 TI - Motor Control Training for the Shoulder with Smart Garments. AB - Wearable technologies for posture monitoring and posture correction are emerging as a way to support and enhance physical therapy treatment, e.g., for motor control training in neurological disorders or for treating musculoskeletal disorders, such as shoulder, neck, or lower back pain. Among the various technological options for posture monitoring, wearable systems offer potential advantages regarding mobility, use in different contexts and sustained tracking in daily life. We describe the design of a smart garment named Zishi to monitor compensatory movements and evaluate its applicability for shoulder motor control training in a clinical setting. Five physiotherapists and eight patients with musculoskeletal shoulder pain participated in the study. The attitudes of patients and therapists towards the system were measured using standardized survey instruments. The results indicate that patients and their therapists consider Zishi a credible aid for rehabilitation and patients expect it will help towards their recovery. The system was perceived as highly usable and patients were motivated to train with the system. Future research efforts on the improvement of the customization of feedback location and modality, and on the evaluation of Zishi as support for motor learning in shoulder patients, should be made. PMID- 28737672 TI - Mesoporous Silica Nanoparticles as Drug Delivery Vehicles in Cancer. AB - Even though cancer treatment has improved over the recent decades, still more specific and effective treatment concepts are mandatory. Surgical removal is not always possible, metastases are challenging and chemo- and radiotherapy can not only have severe side-effects but also resistances may occur. To cope with these challenges more efficient therapies with fewer side-effects are required. One promising approach is the use of drug delivery vehicles. Here, mesoporous silica nanoparticles (MSN) are discussed as biodegradable drug carrier to improve efficacy and reduce side-effects. MSN excellently fulfill the criteria for nanoparticulate carriers: their distinct structure allows high loading capacity and a plethora of surface modifications. MSN synthesis permits fine-tuning of particle and pore sizes. Moreover, drug release can be tailored through various gatekeeper systems which are for example pH-sensitive or redox-sensitive. Furthermore, MSN can either enter tumors passively by the enhanced permeability and retention effect or can be actively targeted by various ligands. PEGylation prolongs circulation time and availability. A huge advantage of MSN is their explicitly low toxic profile in vivo. Yet, clinical translation remains challenging. Overall, mesoporous silica nanoparticles are a promising tool for innovative, more efficient and safer cancer therapies. PMID- 28737673 TI - Magnetic Nanoemulsions: Comparison between Nanoemulsions Formed by Ultrasonication and by Spontaneous Emulsification. AB - Nanoemulsions are particularly suitable as a platform in the development of delivery systems. The type of nanoemulsion with a higher stability will offer an advantage in the preparation of a delivery system for lipophilic drugs. Nanoemulsions can be fabricated by different processing methods, which are usually categorized as either high- or low-energy methods. In this study, a comparison between two methods of preparing magnetic oil-in-water (O/W) nanoemulsions is described. The nanoemulsions were formed by sonication (the high energy method) or by spontaneous emulsification (the low-energy method). In both cases, the oil phase was olive oil, and a phospholipid and a pegylated phospholipid were used as emulsifiers. To favor the comparison, the amounts of the components were the same in both kinds of nanoemulsions. Moreover, nanoemulsions were loaded with hydrophobic superparamagnetic nanoparticles and indomethacin. In vitro, releases studies indicated a short drug burst period followed by a prolonged phase of dissolutive drug release. The Korsmeyer-Peppas model can fit the associated kinetics. The results showed that such nanoemulsions are suitable as a platform in the development of delivering systems for lipophilic drugs. The long-term stability was also examined at different temperatures, as well as the interaction with plasma proteins. Nanoemulsion obtained by the low-energy method showed a great stability at 4 degrees C and at ambient temperature. Its size and polydispersity did not change over more than two months. The spontaneous emulsification method therefore has great potential for forming nanoemulsion-based delivery systems. PMID- 28737671 TI - Age-Related Loss of Cohesion: Causes and Effects. AB - Aneuploidy is a leading genetic cause of birth defects and lower implantation rates in humans. Most errors in chromosome number originate from oocytes. Aneuploidy in oocytes increases with advanced maternal age. Recent studies support the hypothesis that cohesion deterioration with advanced maternal age represents a leading cause of age-related aneuploidy. Cohesin generates cohesion, and is established only during the premeiotic S phase of fetal development without any replenishment throughout a female's period of fertility. Cohesion holds sister chromatids together until meiosis resumes at puberty, and then chromosome segregation requires the release of sister chromatid cohesion from chromosome arms and centromeres at anaphase I and anaphase II, respectively. The time of cohesion cleavage plays an important role in correct chromosome segregation. This review focuses specifically on the causes and effects of age related cohesion deterioration in female meiosis. PMID- 28737674 TI - Pinhole Zone Plate Lens for Ultrasound Focusing. AB - The focusing capabilities of a pinhole zone plate lens are presented and compared with those of a conventional Fresnel zone plate lens. The focusing properties are examined both experimentally and numerically. The results confirm that a pinhole zone plate lens can be an alternative to a Fresnel lens. A smooth filtering effect is created in pinhole zone plate lenses, giving rise to a reduction of the side lobes around the principal focus associated with the conventional Fresnel zone plate lens. The manufacturing technique of the pinhole zone plate lens allows the designing and constructing of lenses for different focal lengths quickly and economically and without the need to drill new plates. PMID- 28737675 TI - 3D Reconstruction of Space Objects from Multi-Views by a Visible Sensor. AB - In this paper, a novel 3D reconstruction framework is proposed to recover the 3D structural model of a space object from its multi-view images captured by a visible sensor. Given an image sequence, this framework first estimates the relative camera poses and recovers the depths of the surface points by the structure from motion (SFM) method, then the patch-based multi-view stereo (PMVS) algorithm is utilized to generate a dense 3D point cloud. To resolve the wrong matches arising from the symmetric structure and repeated textures of space objects, a new strategy is introduced, in which images are added to SFM in imaging order. Meanwhile, a refining process exploiting the structural prior knowledge that most sub-components of artificial space objects are composed of basic geometric shapes is proposed and applied to the recovered point cloud. The proposed reconstruction framework is tested on both simulated image datasets and real image datasets. Experimental results illustrate that the recovered point cloud models of space objects are accurate and have a complete coverage of the surface. Moreover, outliers and points with severe noise are effectively filtered out by the refinement, resulting in an distinct improvement of the structure and visualization of the recovered points. PMID- 28737676 TI - High Dose Ascorbate Causes Both Genotoxic and Metabolic Stress in Glioma Cells. AB - We have previously shown that exposure to high dose ascorbate causes double stranded breaks (DSBs) and a build-up in S-phase in glioblastoma (GBM) cell lines. Here we investigated whether or not this was due to genotoxic stress as well as metabolic stress generated by exposure to high dose ascorbate, radiation, ascorbate plus radiation and H2O2 in established and primary GBM cell lines. Genotoxic stress was measured as phosphorylation of the variant histone protein, H2AX, 8-oxo-7,8-dihydroguanine (8OH-dG) positive cells and cells with comet tails. Metabolic stress was measured as a decrease in NADH flux, mitochondrial membrane potential (by CMXRos), ATP levels (by ATP luminescence) and mitochondrial superoxide production (by mitoSOX). High dose ascorbate, ascorbate plus radiation, and H2O2 treatments induced both genotoxic and metabolic stress. Exposure to high dose ascorbate blocked DNA synthesis in both DNA damaged and undamaged cell of ascorbate sensitive GBM cell lines. H2O2 treatment blocked DNA synthesis in all cell lines with and without DNA damage. DNA synthesis arrest in cells with damaged DNA is likely due to both genotoxic and metabolic stress. However, arrest in DNA synthesis in cells with undamaged DNA is likely due to oxidative damage to components of the mitochondrial energy metabolism pathway. PMID- 28737677 TI - Double-Layer Compressive Sensing Based Efficient DOA Estimation in WSAN with Block Data Loss. AB - Accurate information acquisition is of vital importance for wireless sensor array network (WSAN) direction of arrival (DOA) estimation. However, due to the lossy nature of low-power wireless links, data loss, especially block data loss induced by adopting a large packet size, has a catastrophic effect on DOA estimation performance in WSAN. In this paper, we propose a double-layer compressive sensing (CS) framework to eliminate the hazards of block data loss, to achieve high accuracy and efficient DOA estimation. In addition to modeling the random packet loss during transmission as a passive CS process, an active CS procedure is introduced at each array sensor to further enhance the robustness of transmission. Furthermore, to avoid the error propagation from signal recovery to DOA estimation in conventional methods, we propose a direct DOA estimation technique under the double-layer CS framework. Leveraging a joint frequency and spatial domain sparse representation of the sensor array data, the fusion center (FC) can directly obtain the DOA estimation results according to the received data packets, skipping the phase of signal recovery. Extensive simulations demonstrate that the double-layer CS framework can eliminate the adverse effects induced by block data loss and yield a superior DOA estimation performance in WSAN. PMID- 28737678 TI - An Update on Jacalin-Like Lectins and Their Role in Plant Defense. AB - Plant lectins are proteins that reversibly bind carbohydrates and are assumed to play an important role in plant development and resistance. Through the binding of carbohydrate ligands, lectins are involved in the perception of environmental signals and their translation into phenotypical responses. These processes require down-stream signaling cascades, often mediated by interacting proteins. Fusing the respective genes of two interacting proteins can be a way to increase the efficiency of this process. Most recently, proteins containing jacalin related lectin (JRL) domains became a subject of plant resistance responses research. A meta-data analysis of fusion proteins containing JRL domains across different kingdoms revealed diverse partner domains ranging from kinases to toxins. Among them, proteins containing a JRL domain and a dirigent domain occur exclusively within monocotyledonous plants and show an unexpected high range of family member expansion compared to other JRL-fusion proteins. Rice, wheat, and barley plants overexpressing OsJAC1, a member of this family, are resistant against important fungal pathogens. We discuss the possibility that JRL domains also function as a decoy in fusion proteins and help to alert plants of the presence of attacking pathogens. PMID- 28737680 TI - Mapping Quantitative Trait Loci (QTL) for Resistance to Late Blight in Tomato. AB - Late blight caused by Phytophthora infestans (Montagne, Bary) is a devastating disease of tomato worldwide. There are three known major genes, Ph-1, Ph-2, and Ph-3, conferring resistance to late blight. In addition to these three genes, it is also believed that there are additional factors or quantitative trait loci (QTL) conferring resistance to late blight. Precise molecular mapping of all those major genes and potential QTL is important in the development of suitable molecular markers and hence, marker-assisted selection (MAS). The objective of the present study was to map the genes and QTL associated with late blight resistance in a tomato population derived from intra-specific crosses. To achieve this objective, a population, derived from the crossings of NC 1CELBR * Fla. 7775, consisting of 250 individuals at F2 and F2-derived families, were evaluated in replicated trials. These were conducted at Mountain Horticultural Crops Reseach & Extension Center (MHCREC) at Mills River, NC, and Mountain Research Staion (MRS) at Waynesville, NC in 2011, 2014, and 2015. There were two major QTL associated with late blight resistance located on chromosomes 9 and 10 with likelihood of odd (LOD) scores of more than 42 and 6, explaining 67% and 14% of the total phenotypic variation, respectively. The major QTLs are probably caused by the Ph-2 and Ph-3 genes. Furthermore, there was a minor QTL on chromosomes 12, which has not been reported before. This minor QTL may be novel and may be worth investigating further. Source of resistance to Ph-2, Ph-3, and this minor QTL traces back to line L3707, or Richter's Wild Tomato. The combination of major genes and minor QTL may provide a durable resistance to late blight in tomato. PMID- 28737679 TI - Modernization of Enoxaparin Molecular Weight Determination Using Homogeneous Standards. AB - Enoxaparin is a low-molecular weight heparin used to treat thrombotic disorders. Following the fatal contamination of the heparin supply chain in 2007-2008, the U.S. Pharmacopeia (USP) and U.S. Food and Drug Administration (FDA) have worked extensively to modernize the unfractionated heparin and enoxaparin monographs. As a result, the determination of molecular weight (MW) has been added to the monograph as a measure to strengthen the quality testing and to increase the protection of the global supply of this life-saving drug. The current USP calibrant materials used for enoxaparin MW determination are composed of a mixture of oligosaccharides; however, they are difficult to reproduce as the calibrants have ill-defined structures due to the heterogeneity of the heparin parent material. To address this issue, we describe a promising approach consisting of a predictive computational model built from a library of chemoenzymatically synthesized heparin oligosaccharides for enoxaparin MW determination. Here, we demonstrate that this test can be performed with greater efficiency by coupling synthetic oligosaccharides with the power of computational modeling. Our approach is expected to improve the MW measurement for enoxaparin. PMID- 28737681 TI - Nutrient and Total Polyphenol Contents of Dark Green Leafy Vegetables, and Estimation of Their Iron Bioaccessibility Using the In Vitro Digestion/Caco-2 Cell Model. AB - Dark green leafy vegetables (DGLVs) are considered as important sources of iron and vitamin A. However, iron concentration may not indicate bioaccessibility. The objectives of this study were to compare the nutrient content and iron bioaccessibility of five sweet potato cultivars, including three orange-fleshed types, with other commonly consumed DGLVs in Ghana: cocoyam, corchorus, baobab, kenaf and moringa, using the in vitro digestion/Caco-2 cell model. Moringa had the highest numbers of iron absorption enhancers on an "as-would-be-eaten" basis, beta-carotene (14169 MUg/100 g; p < 0.05) and ascorbic acid (46.30 mg/100 g; p < 0.001), and the best iron bioaccessibility (10.28 ng ferritin/mg protein). Baobab and an orange-fleshed sweet potato with purplish young leaves had a lower iron bioaccessibility (6.51 and 6.76 ng ferritin/mg protein, respectively) compared with that of moringa, although these three greens contained similar (p > 0.05) iron (averaging 4.18 mg/100 g) and beta-carotene levels. The ascorbic acid concentration of 25.50 mg/100 g in the cooked baobab did not enhance the iron bioaccessibility. Baobab and the orange-fleshed sweet potato with purplish young leaves contained the highest levels of total polyphenols (1646.75 and 506.95 mg Gallic Acid Equivalents/100 g, respectively; p < 0.001). This suggests that iron bioaccessibility in greens cannot be inferred based on the mineral concentration. Based on the similarity of the iron bioaccessibility of the sweet potato leaves and cocoyam leaf (a widely-promoted "nutritious" DGLV in Ghana), the former greens have an added advantage of increasing the dietary intake of provitamin A. PMID- 28737683 TI - Increased Risk of Drug-Induced Hyponatremia during High Temperatures. AB - PURPOSE: To investigate the relationship between outdoor temperature in Sweden and the reporting of drug-induced hyponatremia to the Medical Products Agency (MPA). METHODS: All individual adverse drug reactions (ADR) reported to MPA from 1 January 2010 to 31 October 2013 of suspected drug-induced hyponatremia and random controls were identified. Reports where the ADR had been assessed as having at least a possible relation to the suspected drug were included. Information on administered drugs, onset date, causality assessment, sodium levels, and the geographical origin of the reports was extracted. A case crossover design was used to ascertain the association between heat exposure and drug-induced hyponatremia at the individual level, while linear regression was used to study its relationship to sodium concentration in blood. Temperature exposure data were obtained from the nearest observation station to the reported cases. RESULTS: During the study period, 280 reports of hyponatremia were identified. More cases of drug-induced hyponatremia were reported in the warmer season, with a peak in June, while other ADRs showed an opposite annual pattern. The distributed lag non-linear model indicated an increasing odds ratio (OR) with increasing temperature in the warm season with a highest odds ratio, with delays of 1-5 days after heat exposure. A cumulative OR for a lag time of 1 to 3 days was estimated at 2.21 at an average daily temperature of 20 degrees C. The change in sodium per 1 degrees C increase in temperature was estimated to be 0.37 mmol/L (95% CI: -0.02, -0.72). CONCLUSIONS: Warm weather appears to increase the risk of drug-induced hyponatremia. PMID- 28737684 TI - Angular Rate Sensing with GyroWheel Using Genetic Algorithm Optimized Neural Networks. AB - GyroWheel is an integrated device that can provide three-axis control torques and two-axis angular rate sensing for small spacecrafts. Large tilt angle of its rotor and de-tuned spin rate lead to a complex and non-linear dynamics as well as difficulties in measuring angular rates. In this paper, the problem of angular rate sensing with the GyroWheel is investigated. Firstly, a simplified rate sensing equation is introduced, and the error characteristics of the method are analyzed. According to the analysis results, a rate sensing principle based on torque balance theory is developed, and a practical way to estimate the angular rates within the whole operating range of GyroWheel is provided by using explicit genetic algorithm optimized neural networks. The angular rates can be determined by the measurable values of the GyroWheel (including tilt angles, spin rate and torque coil currents), the weights and the biases of the neural networks. Finally, the simulation results are presented to illustrate the effectiveness of the proposed angular rate sensing method with GyroWheel. PMID- 28737682 TI - Cadmium Handling, Toxicity and Molecular Targets Involved during Pregnancy: Lessons from Experimental Models. AB - Even decades after the discovery of Cadmium (Cd) toxicity, research on this heavy metal is still a hot topic in scientific literature: as we wrote this review, more than 1440 scientific articles had been published and listed by the PubMed.gov website during 2017. Cadmium is one of the most common and harmful heavy metals present in our environment. Since pregnancy is a very particular physiological condition that could impact and modify essential pathways involved in the handling of Cd, the prenatal life is a critical stage for exposure to this non-essential element. To give the reader an overview of the possible mechanisms involved in the multiple organ toxic effects in fetuses after the exposure to Cd during pregnancy, we decided to compile some of the most relevant experimental studies performed in experimental models and to summarize the advances in this field such as the Cd distribution and the factors that could alter it (diet, binding-proteins and membrane transporters), the Cd-induced toxicity in dams (preeclampsia, fertility, kidney injury, alteration in essential element homeostasis and bone mineralization), in placenta and in fetus (teratogenicity, central nervous system, liver and kidney). PMID- 28737685 TI - Microcystin Prevalence throughout Lentic Waterbodies in Coastal Southern California. AB - Toxin producing cyanobacterial blooms have increased globally in recent decades in both frequency and intensity. Despite the recognition of this growing risk, the extent and magnitude of cyanobacterial blooms and cyanotoxin prevalence is poorly characterized in the heavily populated region of southern California. Recent assessments of lentic waterbodies (depressional wetlands, lakes, reservoirs and coastal lagoons) determined the prevalence of microcystins and, in some cases, additional cyanotoxins. Microcystins were present in all waterbody types surveyed although toxin concentrations were generally low across most habitats, as only a small number of sites exceeded California's recreational health thresholds for acute toxicity. Results from passive samplers (Solid Phase Adsorption Toxin Tracking (SPATT)) indicated microcystins were prevalent throughout lentic waterbodies and that traditional discrete samples underestimated the presence of microcystins. Multiple cyanotoxins were detected simultaneously in some systems, indicating multiple stressors, the risk of which is uncertain since health thresholds are based on exposures to single toxins. Anatoxin-a was detected for the first time from lakes in southern California. The persistence of detectable microcystins across years and seasons indicates a low level, chronic risk through both direct and indirect exposure. The influence of toxic cyanobacterial blooms is a more complex stressor than presently recognized and should be included in water quality monitoring programs. PMID- 28737686 TI - Comparison of Two Stationary Phases for the Determination of Phytosterols and Tocopherols in Mango and Its By-Products by GC-QTOF-MS. AB - Two different gas chromatography coupled to quadrupole-time of flight mass spectrometry (GC-QTOF-MS) methodologies were carried out for the analysis of phytosterols and tocopherols in the flesh of three mango cultivars and their by products (pulp, peel, and seed). To that end, a non-polar column ((5%-phenyl) methylpolysiloxane (HP-5ms)) and a mid-polar column (crossbond trifluoropropylmethyl polysiloxane (RTX-200MS)) were used. The analysis time for RTX-200MS was much lower than the one obtained with HP-5ms. Furthermore, the optimized method for the RTX-200MS column had a higher sensibility and precision of peak area than the HP-5ms methodology. However, RTX-200MS produced an overlapping between beta-sitosterol and Delta5-avenasterol. Four phytosterols and two tocopherols were identified in mango samples. As far as we are concerned, this is the first time that phytosterols have been studied in mango peel and that Delta5-avenasterol has been reported in mango pulp. alpha- and gamma-tocopherol were determined in peel, and alpha-tocopherol was the major tocopherol in this fraction (up to 81.2%); however, only alpha-tocopherol was determined in the pulp and seed. The peel was the fraction with the highest total concentration of phytosterols followed by seed and pulp, and "Sensacion" was the cultivar with the highest concentration of total phytosterols in most cases. There were no significant differences between quantification of tocopherols with both columns. However, in most cases, quantification of phytosterols was higher with RTX-200MS than with HP-5ms column. PMID- 28737687 TI - New Cinchona Oximes Evaluated as Reactivators of Acetylcholinesterase and Butyrylcholinesterase Inhibited by Organophosphorus Compounds. AB - For the last six decades, researchers have been focused on finding efficient reactivators of organophosphorus compound (OP)-inhibited acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). In this study, we have focused our research on a new oxime scaffold based on the Cinchona structure since it was proven to fit the cholinesterases active site and reversibly inhibit their activity. Three Cinchona oximes (C1, C2, and C3), derivatives of the 9 oxocinchonidine, were synthesized and investigated in reactivation of various OP inhibited AChE and BChE. As the results showed, the tested oximes were more efficient in the reactivation of BChE and they reactivated enzyme activity to up to 70% with reactivation rates similar to known pyridinium oximes used as antidotes in medical practice today. Furthermore, the oximes showed selectivity towards binding to the BChE active site and the determined enzyme-oxime dissociation constants supported work on the future development of inhibitors in other targeted studies (e.g., in treatment of neurodegenerative disease). Also, we monitored the cytotoxic effect of Cinchona oximes on two cell lines Hep G2 and SH-SY5Y to determine the possible limits for in vivo application. The cytotoxicity results support future studies of these compounds as long as their biological activity is targeted in the lower micromolar range. PMID- 28737689 TI - Highly Efficient Near Infrared Photothermal Conversion Properties of Reduced Tungsten Oxide/Polyurethane Nanocomposites. AB - In this work, novel WO3-x/polyurethane (PU) nanocomposites were prepared by ball milling followed by stirring using a planetary mixer/de-aerator. The effects of phase transformation (WO3 -> WO2.8 -> WO2.72) and different weight fractions of tungsten oxide on the optical performance, photothermal conversion, and thermal properties of the prepared nanocomposites were examined. It was found that the nanocomposites exhibited strong photoabsorption in the entire near-infrared (NIR) region of 780-2500 nm and excellent photothermal conversion properties. This is because the particle size of WO3-x was greatly reduced by ball milling and they were well-dispersed in the polyurethane matrix. The higher concentration of oxygen vacancies in WO3-x contribute to the efficient absorption of NIR light and its conversion into thermal energy. In particular, WO2.72/PU nanocomposites showed strong NIR light absorption of ca. 92%, high photothermal conversion, and better thermal conductivity and absorptivity than other WO3/PU nanocomposites. Furthermore, when the nanocomposite with 7 wt % concentration of WO2.72 nanoparticles was irradiated with infrared light, the temperature of the nanocomposite increased rapidly and stabilized at 120 degrees C after 5 min. This temperature is 52 degrees C higher than that achieved by pure PU. These nanocomposites are suitable functional materials for solar collectors, smart coatings, and energy-saving applications. PMID- 28737688 TI - Canadian Potential Healthcare and Societal Cost Savings from Consumption of Pulses: A Cost-Of-Illness Analysis. AB - Consumption of dietary pulses, including beans, peas and lentils, is recommended by health authorities across jurisdictions for their nutritional value and effectiveness in helping to prevent and manage major diet-related illnesses of significant socioeconomic burden. The aim of this study was to estimate the potential annual healthcare and societal cost savings relevant to rates of reduction in complications from type 2 diabetes (T2D) and incidence of cardiovascular disease (CVD) following a low glycemic index (GI) or high fiber diet that includes pulses, or 100 g/day pulse intake in Canada, respectively. A four-step cost-of-illness analysis was conducted to: (1) estimate the proportions of individuals who are likely to consume pulses; (2) evaluate the reductions in established risk factors for T2D and CVD; (3) assess the percent reduction in incidences or complications of the diseases of interest; and (4) calculate the potential annual savings in relevant healthcare and related costs. A low GI or high fiber diet that includes pulses and 100 g/day pulse intake were shown to potentially yield Can$6.2 (95% CI $2.6-$9.9) to Can$62.4 (95% CI $26-$98.8) and Can$31.6 (95% CI $11.1-$52) to Can$315.5 (95% CI $110.6-$520.4) million in savings on annual healthcare and related costs of T2D and CVD, respectively. Specific provincial/territorial analyses suggested annual T2D and CVD related cost savings that ranged from up to Can$0.2 million in some provinces to up to Can$135 million in others. In conclusion, with regular consumption of pulse crops, there is a potential opportunity to facilitate T2D and CVD related socioeconomic cost savings that could be applied to Canadian healthcare or re assigned to other priority domains. Whether these potential cost savings will be offset by other healthcare costs associated with longevity and diseases of the elderly is to be investigated over the long term. PMID- 28737690 TI - Synthesis, Physico-chemical Characterization, Crystal Structure and Influence on Microbial and Tumor Cells of Some Co(II) Complexes with 5,7-Dimethyl-1,2,4 triazolo[1,5-a]pyrimidine. AB - Three complexes, namely [Co(dmtp)2(OH2)4][CoCl4] (1), [Co(dmtp)2Cl2] (2) and [Co(dmtp)2(OH2)4]Cl2?2H2O (3) (dmtp: 5,7-dimethyl-1,2,4-triazolo[1,5 a]pyrimidine), were synthesized and characterized by spectral (IR, UV-Vis-NIR), and magnetic measurements at room temperature, as well as single crystal X-ray diffraction. Complex (1) crystallizes in monoclinic system (space group C2/c), complex (2) adopts an orthorhombic system (space group Pbca), and complex (3) crystallizes in triclinic system (space group P1). Various types of extended hydrogen bonds and pi-pi interactions provide a supramolecular architecture for all complexes. All species were evaluated for antimicrobial activity towards planktonic and biofilm-embedded microbial cells and influence on HEp-2 cell viability, cellular cycle and gene expression. PMID- 28737691 TI - Coagulopathy in the Setting of Mild Traumatic Brain Injury: Truths and Consequences. AB - Mild traumatic brain injury (mTBI) is a common, although poorly-defined clinical entity. Despite its initially mild presentation, patients with mTBI can rapidly deteriorate, often due to significant expansion of intracranial hemorrhage. TBI associated coagulopathy is the topic of significant clinical and basic science research. Unlike trauma-induced coagulopathy (TIC), TBI-associated coagulopathy does not generally follow widespread injury or global hypoperfusion, suggesting a distinct pathogenesis. Although the fundamental mechanisms of TBI-associated coagulopathy are far from clearly elucidated, several candidate molecules (tissue plasminogen activator (tPA), urokinase plasminogen activator (uPA), tissue factor (TF), and brain-derived microparticles (BDMP)) have been proposed which might explain how even minor brain injury can induce local and systemic coagulopathy. Here, we review the incidence, proposed mechanisms, and common clinical tests relevant to mTBI-associated coagulopathy and briefly summarize our own institutional experience in addition to identifying areas for further research. PMID- 28737692 TI - Salt Reductions in Some Foods in The Netherlands: Monitoring of Food Composition and Salt Intake. AB - BACKGROUND AND OBJECTIVES: High salt intake increases blood pressure and thereby the risk of chronic diseases. Food reformulation (or food product improvement) may lower the dietary intake of salt. This study describes the changes in salt contents of foods in the Dutch market over a five-year period (2011-2016) and differences in estimated salt intake over a 10-year period (2006-2015). METHODS: To assess the salt contents of foods; we obtained recent data from chemical analyses and from food labels. Salt content of these foods in 2016 was compared to salt contents in the 2011 version Dutch Food Composition Database (NEVO, version 2011), and statistically tested with General Linear Models. To estimate the daily dietary salt intake in 2006, 2010, and 2015, men and women aged 19 to 70 years were recruited through random population sampling in Doetinchem, a small town located in a rural area in the eastern part of the Netherlands. The characteristics of the study population were in 2006: n = 317, mean age 49 years, 43% men, in 2010: n = 342, mean age 46 years, 45% men, and in 2015: n = 289, mean age 46 years, 47% men. Sodium and potassium excretion was measured in a single 24 h urine sample. All estimates were converted to a common metric: salt intake in grams per day by multiplication of sodium with a factor of 2.54. RESULTS: In 2016 compared to 2011, the salt content in certain types of bread was on average 19 percent lower and certain types of sauce, soup, canned vegetables and legumes, and crisps had a 12 to 26 percent lower salt content. Salt content in other types of foods had not changed significantly. Between 2006, 2010 and 2015 the estimated salt intake among adults in Doetinchem remained unchanged. In 2015, the median estimated salt intake was 9.7 g per day for men and 7.4 g per day for women. As in 2006 and 2010, the estimated salt intake in 2015 exceeded the recommended maximum intake of 6 g per day set by the Dutch Health Council. CONCLUSION: In the Netherlands, the salt content of bread, certain sauces, soups, potato crisps, and processed legumes and vegetables have been reduced over the period 2011-2016. However, median salt intake in 2006 and 2015 remained well above the recommended intake of 6 g. PMID- 28737693 TI - A Context-Driven Model for the Flat Roofs Construction Process through Sensing Systems, Internet-of-Things and Last Planner System. AB - The main causes of building defects are errors in the design and the construction phases. These causes related to construction are mainly due to the general lack of control of construction work and represent approximately 75% of the anomalies. In particular, one of the main causes of such anomalies, which end in building defects, is the lack of control over the physical variables of the work environment during the execution of tasks. Therefore, the high percentage of defects detected in buildings that have the root cause in the construction phase could be avoidable with a more accurate and efficient control of the process. The present work proposes a novel integration model based on information and communications technologies for the automation of both construction work and its management at the execution phase, specifically focused on the flat roof construction process. Roofs represent the second area where more defects are claimed. The proposed model is based on a Web system, supported by a service oriented architecture, for the integral management of tasks through the Last Planner System methodology, but incorporating the management of task restrictions from the physical environment variables by designing specific sensing systems. Likewise, all workers are integrated into the management process by Internet-of Things solutions that guide them throughout the execution process in a non intrusive and transparent way. PMID- 28737695 TI - Predictive Structure and Topology of Peroxisomal ATP-Binding Cassette (ABC) Transporters. AB - The peroxisomal ATP-binding Cassette (ABC) transporters, which are called ABCD1, ABCD2 and ABCD3, are transmembrane proteins involved in the transport of various lipids that allow their degradation inside the organelle. Defective ABCD1 leads to the accumulation of very long-chain fatty acids and is associated with a complex and severe neurodegenerative disorder called X-linked adrenoleukodystrophy (X-ALD). Although the nucleotide-binding domain is highly conserved and characterized within the ABC transporters family, solid data are missing for the transmembrane domain (TMD) of ABCD proteins. The lack of a clear consensus on the secondary and tertiary structure of the TMDs weakens any structure-function hypothesis based on the very diverse ABCD1 mutations found in X-ALD patients. Therefore, we first reinvestigated thoroughly the structure function data available and performed refined alignments of ABCD protein sequences. Based on the 2.85 A resolution crystal structure of the mitochondrial ABC transporter ABCB10, here we propose a structural model of peroxisomal ABCD proteins that specifies the position of the transmembrane and coupling helices, and highlight functional motifs and putative important amino acid residues. PMID- 28737697 TI - Worldwide Regulations of Standard Values of Pesticides for Human Health Risk Control: A Review. AB - Abstract: The impact of pesticide residues on human health is a worldwide problem, as human exposure to pesticides can occur through ingestion, inhalation, and dermal contact. Regulatory jurisdictions have promulgated the standard values for pesticides in residential soil, air, drinking water, and agricultural commodity for years. Until now, more than 19,400 pesticide soil regulatory guidance values (RGVs) and 5400 pesticide drinking water maximum concentration levels (MCLs) have been regulated by 54 and 102 nations, respectively. Over 90 nations have provided pesticide agricultural commodity maximum residue limits (MRLs) for at least one of the 12 most commonly consumed agricultural foods. A total of 22 pesticides have been regulated with more than 100 soil RGVs, and 25 pesticides have more than 100 drinking water MCLs. This research indicates that those RGVs and MCLs for an individual pesticide could vary over seven (DDT drinking water MCLs), eight (Lindane soil RGVs), or even nine (Dieldrin soil RGVs) orders of magnitude. Human health risk uncertainty bounds and the implied total exposure mass burden model were applied to analyze the most commonly regulated and used pesticides for human health risk control. For the top 27 commonly regulated pesticides in soil, there are at least 300 RGVs (8% of the total) that are above all of the computed upper bounds for human health risk uncertainty. For the top 29 most-commonly regulated pesticides in drinking water, at least 172 drinking water MCLs (5% of the total) exceed the computed upper bounds for human health risk uncertainty; while for the 14 most widely used pesticides, there are at least 310 computed implied dose limits (28.0% of the total) that are above the acceptable daily intake values. The results show that some worldwide standard values were not derived conservatively enough to avoid human health risk by the pesticides, and that some values were not computed comprehensively by considering all major human exposure pathways. PMID- 28737694 TI - The Role of p16INK4a Pathway in Human Epidermal Stem Cell Self-Renewal, Aging and Cancer. AB - The epidermis is a self-renewing tissue. The balance between proliferation and differentiation processes is tightly regulated to ensure the maintenance of the stem cell (SC) population in the epidermis during life. Aging and cancer may be considered related endpoints of accumulating damages within epidermal self renewing compartment. p16INK4a is a potent inhibitor of the G1/S-phase transition of the cell cycle. p16INK4a governs the processes of SC self-renewal in several tissues and its deregulation may result in aging or tumor development. Keratinocytes are equipped with several epigenetic enzymes and transcription factors that shape the gene expression signatures of different epidermal layers and allow dynamic and coordinated expression changes to finely balance keratinocyte self-renewal and differentiation. These factors converge their activity in the basal layer to repress p16INK4a expression, protecting cells from senescence, and preserving epidermal homeostasis and regeneration. Several stress stimuli may activate p16INK4a expression that orchestrates cell cycle exit and senescence response. In the present review, we discuss the role of p16INK4a regulators in human epidermal SC self-renewal, aging and cancer. PMID- 28737699 TI - Efficient Retrieval of Massive Ocean Remote Sensing Images via a Cloud-Based Mean Shift Algorithm. AB - The rapid development of remote sensing (RS) technology has resulted in the proliferation of high-resolution images. There are challenges involved in not only storing large volumes of RS images but also in rapidly retrieving the images for ocean disaster analysis such as for storm surges and typhoon warnings. In this paper, we present an efficient retrieval of massive ocean RS images via a Cloud-based mean-shift algorithm. Distributed construction method via the pyramid model is proposed based on the maximum hierarchical layer algorithm and used to realize efficient storage structure of RS images on the Cloud platform. We achieve high-performance processing of massive RS images in the Hadoop system. Based on the pyramid Hadoop distributed file system (HDFS) storage method, an improved mean-shift algorithm for RS image retrieval is presented by fusion with the canopy algorithm via Hadoop MapReduce programming. The results show that the new method can achieve better performance for data storage than HDFS alone and WebGIS-based HDFS. Speedup and scaleup are very close to linear changes with an increase of RS images, which proves that image retrieval using our method is efficient. PMID- 28737696 TI - Targeting Platelets for the Treatment of Cancer. AB - The majority of cancer-associated mortality results from the ability of tumour cells to metastasise leading to multifunctional organ failure and death. Disseminated tumour cells in the blood circulation are faced with major challenges such as rheological shear stresses and cell-mediated cytotoxicity mediated by natural killer cells. Nevertheless, circulating tumour cells with metastatic ability appear equipped to exploit host cells to aid their survival. Despite the long interest in targeting tumour-associated host cells such as platelets for cancer treatment, the clinical benefit of this strategy is still under question. In this review, we provide a summary of the latest mechanistic and clinical evidence to evaluate the validity of targeting platelets in cancer. PMID- 28737698 TI - Platycodon grandiflorus Root Extract Improves Learning and Memory by Enhancing Synaptogenesis in Mice Hippocampus. AB - Platycodon grandiflorus (Jacq.) A.DC. (PG) has long been used as an ingredient of foods and is known to have beneficial effects on cognitive functions as well. The present study examined the effect of each PG extract (PGE) from root, aerial part, and seeds on cognitive functions in mice. Changes in spatial learning and memory using a Y-maze test, and markers of adult hippocampal neurogenesis and synaptogenesis were examined. Moreover, changes in neuritogenesis and activation of the ERK1/2 pathway were investigated. Results indicated that mice administered PGE (root) showed increased spontaneous alternation in the Y-maze test and synaptogenesis in the hippocampus. In addition, PGE (root) and platycodin D, the major bioactive compound from the PG root, significantly stimulated neuritic outgrowth by phosphorylation of the ERK1/2 signaling pathway in vitro. These results indicate that the PGE (root), containing platycodin D, enhances cognitive function through synaptogenesis via activation of the ERK1/2 signaling pathway. PMID- 28737700 TI - A Novel Brominated Alkaloid Securidine A, Isolated from the Marine Bryozoan Securiflustra securifrons. AB - A novel brominated alkaloid, Securidine A, was isolated from the cold water marine bryozoan Securiflustra securifrons. Securidine A was isolated using semi preparative HPLC, and the structure was elucidated by spectroscopic methods. The isolated Securidine A was tested for cytotoxic, antibacterial, and anti-diabetic activities as well as for its potential for inhibition of biofilm formation. No significant biological activity was observed in the applied bioassays, thus expanded bioactivity profiling is required, in order to reveal any potential applications for Securidine A. PMID- 28737702 TI - A Novel and Practical Chromatographic "Fingerprint-ROC-SVM" Strategy Applied to Quality Analysis of Traditional Chinese Medicine Injections: Using KuDieZi Injection as a Case Study. AB - Fingerprinting is widely and commonly used in the quality control of traditional Chinese medicine (TCM) injections. However, current studies informed that the fingerprint similarity evaluation was less sensitive and easily generated false positive results. For this reason, a novel and practical chromatographic "Fingerprint-ROC-SVM" strategy was established by using KuDieZi (KDZ) injection as a case study in the present article. Firstly, the chromatographic fingerprints of KDZ injection were obtained by UPLC and the common characteristic peaks were identified with UPLC/Q-TOF-MS under the same chromatographic conditions. Then, the receiver operating characteristic (ROC) curve was used to optimize common characteristic peaks by the AUCs value greater than 0.7. Finally, a support vector machine (SVM) model, with the accuracy of 97.06%, was established by the optimized characteristic peaks and applied to monitor the quality of KDZ injection. As a result, the established model could sensitively and accurately distinguish the qualified products (QPs) with the unqualified products (UPs), high-temperature processed samples (HTPs) and high-illumination processed samples (HIPs) of KDZ injection, and the prediction accuracy was 100.00%, 93.75% and 100.00%, respectively. Furthermore, through the comparison with other chemometrics methods, the superiority of the novel analytical strategy was more prominent. It indicated that the novel and practical chromatographic "Fingerprint ROC-SVM" strategy could be further applied to facilitate the development of the quality analysis of TCM injections. PMID- 28737701 TI - Application of Extrusion-Based Hydrogel Bioprinting for Cartilage Tissue Engineering. AB - Extrusion-based bioprinting (EBB) is a rapidly developing technique that has made substantial progress in the fabrication of constructs for cartilage tissue engineering (CTE) over the past decade. With this technique, cell-laden hydrogels or bio-inks have been extruded onto printing stages, layer-by-layer, to form three-dimensional (3D) constructs with varying sizes, shapes, and resolutions. This paper reviews the cell sources and hydrogels that can be used for bio-ink formulations in CTE application. Additionally, this paper discusses the important properties of bio-inks to be applied in the EBB technique, including biocompatibility, printability, as well as mechanical properties. The printability of a bio-ink is associated with the formation of first layer, ink rheological properties, and crosslinking mechanisms. Further, this paper discusses two bioprinting approaches to build up cartilage constructs, i.e., self supporting hydrogel bioprinting and hybrid bioprinting, along with their applications in fabricating chondral, osteochondral, and zonally organized cartilage regenerative constructs. Lastly, current limitations and future opportunities of EBB in printing cartilage regenerative constructs are reviewed. PMID- 28737703 TI - Autophagy and Human Neurodegenerative Diseases-A Fly's Perspective. AB - Neurodegenerative diseases in humans are frequently associated with prominent accumulation of toxic protein inclusions and defective organelles. Autophagy is a process of bulk lysosomal degradation that eliminates these harmful substances and maintains the subcellular environmental quality. In support of autophagy's importance in neuronal homeostasis, several genetic mutations that interfere with autophagic processes were found to be associated with familial neurodegenerative disorders. In addition, genetic mutations in autophagy-regulating genes provoked neurodegenerative phenotypes in animal models. The Drosophila model significantly contributed to these recent developments, which led to the theory that autophagy dysregulation is one of the major underlying causes of human neurodegenerative disorders. In the current review, we discuss how studies using Drosophila enhanced our understanding of the relationship between autophagy and neurodegenerative processes. PMID- 28737704 TI - Toxicity at the Edge of Life: A Review on Cyanobacterial Toxins from Extreme Environments. AB - Cyanotoxins are secondary metabolites produced by cyanobacteria, of varied chemical nature and toxic effects. Although cyanobacteria thrive in all kinds of ecosystems on Earth even under very harsh conditions, current knowledge on cyanotoxin distribution is almost restricted to freshwaters from temperate latitudes. In this review, we bring to the forefront the presence of cyanotoxins in extreme environments. Cyanotoxins have been reported especially in polar deserts (both from the Arctic and Antarctica) and alkaline lakes, but also in hot deserts, hypersaline environments, and hot springs. Cyanotoxins detected in these ecosystems include neurotoxins-anatoxin-a, anatoxin-a (S), paralytic shellfish toxins, beta-methylaminopropionic acid, N-(2-aminoethyl) glycine and 2,4 diaminobutyric acid- and hepatotoxins -cylindrospermopsins, microcystins and nodularins-with microcystins being the most frequently reported. Toxin production there has been linked to at least eleven cyanobacterial genera yet only three of these (Arthrospira, Synechococcus and Oscillatoria) have been confirmed as producers in culture. Beyond a comprehensive analysis of cyanotoxin presence in each of the extreme environments, this review also identifies the main knowledge gaps to overcome (e.g., scarcity of isolates and -omics data, among others) toward an initial assessment of ecological and human health risks in these amazing ecosystems developing at the very edge of life. PMID- 28737705 TI - Emotion Recognition from Chinese Speech for Smart Affective Services Using a Combination of SVM and DBN. AB - Accurate emotion recognition from speech is important for applications like smart health care, smart entertainment, and other smart services. High accuracy emotion recognition from Chinese speech is challenging due to the complexities of the Chinese language. In this paper, we explore how to improve the accuracy of speech emotion recognition, including speech signal feature extraction and emotion classification methods. Five types of features are extracted from a speech sample: mel frequency cepstrum coefficient (MFCC), pitch, formant, short-term zero-crossing rate and short-term energy. By comparing statistical features with deep features extracted by a Deep Belief Network (DBN), we attempt to find the best features to identify the emotion status for speech. We propose a novel classification method that combines DBN and SVM (support vector machine) instead of using only one of them. In addition, a conjugate gradient method is applied to train DBN in order to speed up the training process. Gender-dependent experiments are conducted using an emotional speech database created by the Chinese Academy of Sciences. The results show that DBN features can reflect emotion status better than artificial features, and our new classification approach achieves an accuracy of 95.8%, which is higher than using either DBN or SVM separately. Results also show that DBN can work very well for small training databases if it is properly designed. PMID- 28737707 TI - An Appropriate Modulation of Lymphoproliferative Response and Cytokine Release as Possible Contributors to Longevity. AB - The decrease in the proliferative response of lymphocytes is one of the most evident among the age-related changes of the immune system. This has been linked to a higher risk of mortality in both humans and experimental animals. However, long-lived individuals, in spite of optimally maintaining most of the functions of the immune system, also seem to show an impaired proliferative response. Thus, it was hypothesized that these individuals may have distinct evolution times in this proliferation and a different modulatory capacity through their cytokine release profiles. An individualized longitudinal study was performed on female ICR-CD1 mice, starting at the adult age (40 weeks old), analyzing the proliferation of peritoneal leukocytes at different ages in both basal conditions and in the presence of the mitogen Concanavalin A, for 4, 24 and 48 h of culture. The cytokine secretions (IL-2, IL-17, IL-1beta, IL-6, TNF-alpha and IL-10) in the same cultures were also studied. Long-lived mice show a high proliferative capacity after short incubation times and, despite experiencing a functional decline when they are old, are able to compensate this decrease with an appropriate modulation of the lymphoproliferative response and cytokine release. This could explain their elevated resistance to infections and high longevity. PMID- 28737708 TI - Functional Comparison for Lipid Metabolism and Intestinal and Fecal Microflora Enzyme Activities between Low Molecular Weight Chitosan and Chitosan Oligosaccharide in High-Fat-Diet-Fed Rats. AB - The present study investigated and compared the regulatory effects on the lipid related metabolism and intestinal disaccharidase/fecal bacterial enzyme activities between low molecular weight chitosan and chitosan oligosaccharide in high-fat-diet-fed rats. Diet supplementation of low molecular weight chitosan showed greater efficiency than chitosan oligosaccharide in suppressing the increased weights in body and in liver and adipose tissues of high-fat-diet-fed rats. Supplementation of low molecular weight chitosan also showed a greater improvement than chitosan oligosaccharide in imbalance of plasma, hepatic, and fecal lipid profiles, and intestinal disaccharidase activities in high-fat-diet fed rats. Moreover, both low molecular weight chitosan and chitosan oligosaccharide significantly decreased the fecal microflora mucinase and beta glucuronidase activities in high-fat-diet-fed rats. These results suggest that low molecular weight chitosan exerts a greater positive improvement than chitosan oligosaccharide in lipid metabolism and intestinal disaccharidase activity in high-fat-diet-induced obese rats. PMID- 28737706 TI - Redox Properties of Tryptophan Metabolism and the Concept of Tryptophan Use in Pregnancy. AB - During pregnancy, tryptophan (Trp) is required for several purposes, and Trp metabolism varies over time in the mother and fetus. Increased oxidative stress (OS) with high metabolic, energy and oxygen demands during normal pregnancy or in pregnancy-associated disorders has been reported. Taking the antioxidant properties of Trp and its metabolites into consideration, we made four hypotheses. First, the use of Trp and its metabolites is optional based on their antioxidant properties during pregnancy. Second, dynamic Trp metabolism is an accommodation mechanism in response to OS. Third, regulation of Trp metabolism could be used to control/attenuate OS according to variations in Trp metabolism during pregnancy. Fourth, OS-mediated injury could be alleviated by regulation of Trp metabolism in pregnancy-associated disorders. Future studies in normal/abnormal pregnancies and in associated disorders should include measurements of free Trp, total Trp, Trp metabolites, and activities of Trp degrading enzymes in plasma. Abnormal pregnancies and some associated disorders may be associated with disordered Trp metabolism related to OS. Mounting evidence suggests that the investigation of the use of Trp and its metabolites in pregnancy will be meanful. PMID- 28737710 TI - Cytoprotective Effect of the UCP2-SIRT3 Signaling Pathway by Decreasing Mitochondrial Oxidative Stress on Cerebral Ischemia-Reperfusion Injury. AB - Recovered blood supply after cerebral ischemia for a certain period of time fails to restore brain function, with more severe dysfunctional problems developing, called cerebral ischemia-reperfusion injury (CIR). CIR involves several extremely complex pathophysiological processes in which the interactions between key factors at various stages have not been fully elucidated. Mitochondrial dysfunction is one of the most important mechanisms of CIR. The mitochondrial deacetylase, sirtuin 3 (SIRT3), can inhibit mitochondrial oxidative stress by deacetylation, to maintain mitochondrial stability. Uncoupling protein 2 (UCP2) regulates ATP (Adenosine triphosphate) and reactive oxygen species production by affecting the mitochondrial respiratory chain, which may play a protective role in CIR. Finally, we propose that UCP2 regulates the activity of SIRT3 through sensing the energy level and, in turn, maintaining the mitochondrial steady state, which demonstrates a cytoprotective effect on CIR. PMID- 28737711 TI - The Effects of Artemisinin on the Cytolytic Activity of Natural Killer (NK) Cells. AB - Artemisinin, a chemical compound used for the treatment of malaria, has been known to show anti-cancer activity. However, the effect of this chemical on natural killer (NK) cells, which are involved in tumor killing, remains unknown. Here, we demonstrate that artemisinin exerts a potent anti-cancer effect by activating NK cells. NK-92MI cells pre-treated with artemisinin were subjected to a cytotoxicity assay using K562 cells. The results showed that artemisinin significantly enhances the cytolytic activity of NK cells in a dose-dependent manner. Additionally, the artemisinin-enhanced cytotoxic effect of NK-92MI cells on tumor cells was accompanied by the stimulation of granule exocytosis, as evidenced by the detection of CD107a expression in NK cells. Moreover, this enhancement of cytotoxicity by artemisinin was also observed in human primary NK cells from peripheral blood. Our results suggest that artemisinin enhances human NK cell cytotoxicity and degranulation. This is the first evidence that artemisinin exerts antitumor activity by enhancing NK cytotoxicity. Therefore, these results provide a deeper understanding of the action of artemisinin and will contribute to the development and application of this class of compounds in cancer treatment strategies. PMID- 28737712 TI - An Investigation of Sensory Specific Satiety and Food Size When Children Consume a Whole or Diced Vegetable. AB - Children's vegetable consumption is often lower than that needed to promote optimal health and development, and practical approaches for increasing vegetable consumption are needed. Sensory Specific Satiety (SSS) reduces the liking and consumption of a consumed food over the course of an eating occasion and is an important factor in meal termination. The present study aimed to investigate the development of SSS when children ate vegetables of different sizes. The absence of SSS would be an encouraging sign to provide children more vegetables during a meal. Seventy-two children (33 boys, ages 8.8 +/- 1.5 years) were recruited from Australian primary schools. Participating children consumed either whole or diced carrots for a maximum period of 10-min from a 500 g box. Cucumber was used as a control vegetable. Children's liking of carrots and cucumber was measured with a 5-point child friendly hedonic scale prior to and after carrot consumption. In comparison to cucumber, liking for neither diced (p = 0.57) nor whole carrots (p = 0.18) changed during ad libitum consumption of carrots, indicating that SSS did not occur. However, children (n = 36) who finished eating carrots within the 10 min time limit, spent more time eating the whole carrots compared to the diced carrots (p < 0.05), which tended to result in a higher consumption of whole carrots (p < 0.06). This suggests that, in order to increase vegetable consumption, it is better to present children whole carrots than diced carrots. These findings might aid in the development of strategies to promote children's greater vegetable consumption. PMID- 28737714 TI - Parametric Loop Division for 3D Localization in Wireless Sensor Networks. AB - Localization in Wireless Sensor Networks (WSNs) has been an active topic for more than two decades. A variety of algorithms were proposed to improve the localization accuracy. However, they are either limited to two-dimensional (2D) space, or require specific sensor deployment for proper operations. In this paper, we proposed a three-dimensional (3D) localization scheme for WSNs based on the well-known parametric Loop division (PLD) algorithm. The proposed scheme localizes a sensor node in a region bounded by a network of anchor nodes. By iteratively shrinking that region towards its center point, the proposed scheme provides better localization accuracy as compared to existing schemes. Furthermore, it is cost-effective and independent of environmental irregularity. We provide an analytical framework for the proposed scheme and find its lower bound accuracy. Simulation results shows that the proposed algorithm provides an average localization accuracy of 0.89 m with a standard deviation of 1.2 m. PMID- 28737709 TI - Regulation and Modulation of Human DNA Polymerase delta Activity and Function. AB - This review focuses on the regulation and modulation of human DNA polymerase delta (Pol delta). The emphasis is on the mechanisms that regulate the activity and properties of Pol delta in DNA repair and replication. The areas covered are the degradation of the p12 subunit of Pol delta, which converts it from a heterotetramer (Pol delta4) to a heterotrimer (Pol delta3), in response to DNA damage and also during the cell cycle. The biochemical mechanisms that lead to degradation of p12 are reviewed, as well as the properties of Pol delta4 and Pol delta3 that provide insights into their functions in DNA replication and repair. The second focus of the review involves the functions of two Pol delta binding proteins, polymerase delta interaction protein 46 (PDIP46) and polymerase delta interaction protein 38 (PDIP38), both of which are multi-functional proteins. PDIP46 is a novel activator of Pol delta4, and the impact of this function is discussed in relation to its potential roles in DNA replication. Several new models for the roles of Pol delta3 and Pol delta4 in leading and lagging strand DNA synthesis that integrate a role for PDIP46 are presented. PDIP38 has multiple cellular localizations including the mitochondria, the spliceosomes and the nucleus. It has been implicated in a number of cellular functions, including the regulation of specialized DNA polymerases, mitosis, the DNA damage response, mouse double minute 2 homolog (Mdm2) alternative splicing and the regulation of the NADPH oxidase 4 (Nox4). PMID- 28737713 TI - Quality Assessment of Gentiana rigescens from Different Geographical Origins Using FT-IR Spectroscopy Combined with HPLC. AB - Gentiana rigescens is a precious herbal medicine in China because of its liver protective and choleretic effects. A method for the qualitative identification and quantitative evaluation of G. rigescens from Yunnan Province, China, has been developed employing Fourier transform infrared (FT-IR) spectroscopy and high performance liquid chromatography (HPLC) with the aid of chemometrics such as partial least squares discriminant analysis (PLS-DA) and support vector machines (SVM) regression. Our results indicated that PLS-DA model could efficiently discriminate G. rigescens from different geographical origins. It was found that the samples which could not be determined accurately were in the margin or outside of the 95% confidence ellipses. Moreover, the result implied that geographical origins variation of root samples were more obvious than that of stems and leaves. The quantitative analysis was based on gentiopicroside content which was the main active constituent in G. rigescens. For the prediction of gentiopicroside, the performances of model based on the parameters selected through grid search algorithm (GS) with seven-fold cross validation were better than those based on genetic algorithm (GA) and particle swarm optimization algorithm (PSO). For the SVM-GS model, the result was satisfactory. FT-IR spectroscopy coupled with PLS-DA and SVM-GS can be an alternative strategy for qualitative identification and quantitative evaluation of G. rigescens. PMID- 28737716 TI - Editorial for Special Issue: Approaches to Top-Down Proteomics: In Honour of Prof. Patrick H. O'Farrell. AB - Presaging the current discipline of Proteomics, Prof Patrick H. O'Farrell recognized the critical need for detailed protein analyses to dissect and thereby understand molecular mechanisms. [...]. PMID- 28737717 TI - Synthesis and Ion-Exchange Properties of Graphene Th(IV) Phosphate Composite Cation Exchanger: Its Applications in the Selective Separation of Lead Metal Ions. AB - In this study, graphene Th(IV) phosphate was prepared by sol-gel precipitation method. The ion-exchange behavior of this cation-exchanger was studied by investigating properties like ion-exchange capacity for various metal ions, the effect of eluent concentration, elution behavior, and thermal effect on ion exchange capacity (IEC). Several physicochemical properties as Fourier transform infrared (FTIR) spectroscopy, X-ray diffraction (XRD) study, thermal studies, scanning electron microscopy (SEM) and transmission electron microscopy (TEM) studies were also carried out. The material possessed an IEC of 1.56 meq.dry.g-1 of the exchanger and was found to be nano-composite. The selectivity studies showed that the material is selective towards Pb(II) ions. The selectivity of this cation-exchanger was demonstrated in the binary separation of Pb(II) ions from mixture with other metal ions. The recovery was found to be both quantitative and reproducible. PMID- 28737718 TI - Experimental Study on the Health Benefits of Garden Landscape. AB - To mitigate the negative effects of modern cities on health, scientists are focusing on the diverse benefits of natural environments; a conceptual approach to use gardens for promoting human health is being attempted. In this study, the effects of the visual landscape of a traditional garden on psychological and physiological activities were investigated. Eighteen male and female adults participated in this indoor experiment (mean age, 26.7 years). Twelve different landscape images for city and garden were presented continuously for 90 s. In the time series changes of oxygenated hemoglobin (O2Hb), different patterns of changes were observed between the city and garden. The mean O2Hb values increased for the city landscapes, whereas they decreased for the garden landscapes both in the left and right prefrontal cortices. Significant differences in the negative psychological states of tension, fatigue, confusion, and anxiety were observed between the city and garden landscapes. Important differences in the physiological and psychological responses to the two different landscapes were also detected between male and female participants, providing valuable clues to individual differences in the health benefits of natural landscapes. To validate the use of gardens as a resource for promoting health in urban dwellers, further scientific evidence, active communication, and collaboration among experts in the relevant field are necessary. PMID- 28737715 TI - Latency, Integration, and Reactivation of Human Herpesvirus-6. AB - Human herpesvirus-6A (HHV-6A) and human herpesvirus-6B (HHV-6B) are two closely related viruses that infect T-cells. Both HHV-6A and HHV-6B possess telomere-like repeats at the terminal regions of their genomes that facilitate latency by integration into the host telomeres, rather than by episome formation. In about 1% of the human population, human herpes virus-6 (HHV-6) integration into germline cells allows the viral genome to be passed down from one generation to the other; this condition is called inherited chromosomally integrated HHV-6 (iciHHV-6). This review will cover the history of HHV-6 and recent works that define the biological differences between HHV-6A and HHV-6B. Additionally, HHV-6 integration and inheritance, the capacity for reactivation and superinfection of iciHHV-6 individuals with a second strain of HHV-6, and the role of hypomethylation of human chromosomes during integration are discussed. Overall, the data suggest that integration of HHV-6 in telomeres represent a unique mechanism of viral latency and offers a novel tool to study not only HHV-6 pathogenesis, but also telomere biology. Paradoxically, the integrated viral genome is often defective especially as seen in iciHHV-6 harboring individuals. Finally, gaps in the field of HHV-6 research are presented and future studies are proposed. PMID- 28737719 TI - Development of Poly(lactic acid)/Chitosan Fibers Loaded with Essential Oil for Antimicrobial Applications. AB - Cinnamon essential oil (CEO) was successfully encapsulated into chitosan (CS) nanoparticles at different loading amounts (1%, 1.5%, 2%, and 2.5% v/v) using oil in-water (o/w) emulsion and ionic-gelation methods. In order to form active packaging, poly(lactic acid) (PLA) was used to fabricate PLA/CS-CEO composite fibers using a simple electrospinning method. The shape, size, zeta potential, and encapsulation efficacy of the CS-CEO nanoparticles were investigated. The composition, morphology, and release behavior of the composite fibers were investigated. PLA/CS-CEO-1.5 showed good stability and favorable sustained release of CEO, resulting in improved antimicrobial activity compared to the other blends. The PLA/CS-CEO fibers showed high long-term inactivation rates against Escherichia coli and Staphylococcus aureus due to the sustained release of CEO, indicating that the developed PLA/CS-CEO fibers have great potential for active food packaging applications. PMID- 28737720 TI - A Simple and Highly Sensitive Thymine Sensor for Mercury Ion Detection Based on Surface Enhanced Raman Spectroscopy and the Mechanism Study. AB - Mercury ion (Hg2+) is recognized as one of the most toxic metal ions for the environment and for human health. Techniques utilized in the detection of Hg2+ are an important factor. Herein, a simple thymine was successfully employed as the surface enhanced Raman spectroscopy sensor for Hg2+ ion detection. The limit of detection (LOD) of the developed sensor is better than 0.1 nM (0.02 ppb). This sensor can also selectively distinguish Hg2+ ions over 7 types of alkali, heavy metal and transition-metal ions. Moreover, the LOD of the sensor can even achieve 1 ppb in practical application in the nature system, which is half the maximum allowable level (10 nM, 2 ppb) stipulated in the US Environmental Protection Agency standard. Further investigation of the thymine-Hg2+-thymine coordination mechanism provides a possible means of detecting other metal ions by replacing the metal ion-specific ligands. This work paves the way for the detection of toxic metal ions and environmental problems. PMID- 28737721 TI - Pyranopyran-1,8-dione, an Active Compound from Vitices Fructus, Attenuates Cigarette-Smoke Induced Lung Inflammation in Mice. AB - Previously, we isolated and identified pyranopyran-1,8-dione (PPY) from Viticis Fructus, as a bioactive compound possessing anti-inflammatory properties. The present study was aimed to evaluate the preventive benefit of PPY on cigarette smoke (CS)-induced lung inflammation. C57BL/6 mice were exposed to CS for 2 weeks while PPY was administrated by oral injection 2 h before CS exposure. To validate the anti-inflammatory effects of PPY, the numbers of immune cells in the bronchoalveolar lavage fluid were counted. Proinflammatory cytokines (Tumor necrosis factor-alpha: TNF-alpha, IL-6) and keratinocyte chemokine (KC/CXCL1) were also measured. Histopathologic analysis and cellular profiles showed that inflammatory cell infiltrations were significantly decreased in peribronchial and perivascular area by PPY treatment. The alveolar destruction by CS was markedly ameliorated by PPY treatment. In addition, the TNF-alpha, IL-6, and KC levels were declined in the PPY groups. These observations suggest that PPY has a preventive potential for lung inflammatory diseases. PMID- 28737722 TI - Induction of a Regulatory Phenotype in CD3+ CD4+ HLA-DR+ T Cells after Allogeneic Mixed Lymphocyte Culture; Indications of Both Contact-Dependent and -Independent Activation. AB - Although the observation of major histocompatibility complex II (MHCII) receptors on T cells is longstanding, the explanation for this occurrence remains enigmatic. Reports of an inducible, endogenous expression exist, as do studies demonstrating a protein acquisition from other cells by mechanisms including vesicle transfer. Irrespective of origin, the presence of the human MHCII isotype, human leukocyte antigen DR (HLA-DR), potentially identifies a regulatory T cell population. Using an allogeneic mixed lymphocyte culture (MLC) to induce an antigen-specific immune response, the role of antigen-presenting cells (APCs) for the presence of HLA-DR on cluster of differentiation 3(CD3)+ CD4+ T cells was evaluated. Moreover, a functional phenotype was established for these T cells. It was demonstrated that APCs were essential for HLA-DR on CD3+ CD4+ T cells. Additionally, a regulatory T cell phenotype was induced in CD3+ CD4+ HLA-DR+ responder T cells with an expression of CD25, CTLA-4, CD62L, PD-1, and TNFRII. This phenotype was induced both with and without physical T cell:APC contact, which could reveal novel indications about its functionality. To further investigate contact-independent communication, a phenotype of the small cell derived vesicles from the MLCs was determined. Yet heterogeneous, this vesicle phenotype displayed contact-dependent differences, providing clues about their intended function in cellular communication. PMID- 28737723 TI - Role of G Protein-Coupled Receptors in the Regulation of Structural Plasticity and Cognitive Function. AB - Cognition and other higher brain functions are known to be intricately associated with the capacity of neural circuits to undergo structural reorganization. Structural remodelling of neural circuits, or structural plasticity, in the hippocampus plays a major role in learning and memory. Dynamic modifications of neuronal connectivity in the form of dendritic spine morphology alteration, as well as synapse formation and elimination, often result in the strengthening or weakening of specific neural circuits that determine synaptic plasticity. Changes in dendritic complexity and synapse number are mediated by cellular processes that are regulated by extracellular signals such as neurotransmitters and neurotrophic factors. As many neurotransmitters act on G protein-coupled receptors (GPCRs), it has become increasingly apparent that GPCRs can regulate structural plasticity through a myriad of G protein-dependent pathways and non canonical signals. A thorough understanding of how GPCRs exert their regulatory influence on dendritic spine morphogenesis may provide new insights for treating cognitive impairment and decline in various age-related diseases. In this article, we review the evidence of GPCR-mediated regulation of structural plasticity, with a special emphasis on the involvement of common as well as distinct signalling pathways that are regulated by major neurotransmitters. PMID- 28737724 TI - Time-dependent Inhibition of CYP2C8 and CYP2C19 by Hedera helix Extracts, A Traditional Respiratory Herbal Medicine. AB - The extract of Hedera helix L. (Araliaceae), a well-known folk medicine, has been popularly used to treat respiratory problems, worldwide. It is very likely that this herbal extract is taken in combination with conventional drugs. The present study aimed to evaluate the effects of H. helix extract on cytochrome P450 (CYP) enzyme-mediated metabolism to predict the potential for herb-drug interactions. A cocktail probe assay was used to measure the inhibitory effect of CYP. H. helix extracts were incubated with pooled human liver microsomes or CYP isozymes with CYP-specific substrates, and the formation of specific metabolites was investigated to measure the inhibitory effects. H. helix showed significant inhibitory effects on CYP2C8, CYP2C19 and CYP2D6 in a concentration-dependent manner. In recombinant CYP2C8, CYP2C19 and CYP2D6 isozymes, the IC50 values of the extract were 0.08 +/- 0.01, 0.58 +/- 0.03 and 6.72 +/- 0.22 mg/mL, respectively. Further investigation showed that H. helix extract has a positive time-dependent inhibition property on both CYP2C8 and CYP2C19 with IC50 shift value of 2.77 +/- 0.12 and 6.31 +/- 0.25, respectively. Based on this in vitro investigation, consumption of herbal medicines or dietary supplements containing H. helix extracts requires careful attention to avoid any CYP-based interactions. PMID- 28737725 TI - Optimization of the Silver Nanoparticles PEALD Process on the Surface of 1-D Titania Coatings. AB - Plasma enhanced atomic layer deposition (PEALD) of silver nanoparticles on the surface of 1-D titania coatings, such as nanotubes (TNT) and nanoneedles (TNN), has been carried out. The formation of TNT and TNN layers enriched with dispersed silver particles of strictly defined sizes and the estimation of their bioactivity was the aim of our investigations. The structure and the morphology of produced materials were determined using X-ray photoelectron spectroscopy (XPS) and scanning electron miscroscopy (SEM). Their bioactivity and potential usefulness in the modification of implants surface have been estimated on the basis of the fibroblasts adhesion and proliferation assays, and on the basis of the determination of their antibacterial activity. The cumulative silver release profiles have been checked with the use of inductively coupled plasma-mass spectrometry (ICPMS), in order to exclude potential cytotoxicity of silver decorated systems. Among the studied nanocomposite samples, TNT coatings, prepared at 3, 10, 12 V and enriched with silver nanoparticles produced during 25 cycles of PEALD, revealed suitable biointegration properties and may actively counteract the formation of bacterial biofilm. PMID- 28737726 TI - Synthesis and Biological Evaluation of Ginsenoside Compound K Derivatives as a Novel Class of LXRalpha Activator. AB - Compound K is one of the active metabolites of Panaxnotoginseng saponins, which could attenuate the formation of atherosclerosis in mice modelsvia activating LXRalpha. We synthesized and evaluated a series of ginsenoside compound K derivatives modified with short chain fatty acids. All of the structures of this class of ginsenoside compound K derivative exhibited comparable or better biological activity than ginsenoside compound K. Especially structure 1 exhibited the best potency (cholesteryl ester content: 41.51%; expression of ABCA1 mRNA: 319%) and low cytotoxicity. PMID- 28737727 TI - Patterns Associated with Adult Mandibular Fractures in Southern Taiwan-A Cross Sectional Retrospective Study. AB - Purpose: This study aimed to determine the patterns associated with adult mandibular fractures from a Level-I trauma center in southern Taiwan. Methods: The data of adult trauma patients admitted between 1 January 2009 and 31 December 2014 were retrieved from the Trauma Registry System and retrospectively reviewed. Fracture site and cause of injury were categorized into groups for comparison, and corresponding odds ratios (ORs) and 95% confidence intervals (CIs) were obtained by multivariate logistic regression. Results: Motorcycle accidents were the most common cause of mandibular fractures (76.3%), followed by falls (10.9%), motor vehicle accidents (4.8%), and being struck by/against objects (4.5%). Of the 503 cases of mandibular fractures, the condylar neck and head were the most common sites (32.0%), followed by the parasymphysis (21.7%), symphysis (19.5%), angle and ramus (17.5%), and body (9.3%). The location of mandibular fractures in patients who had motorcycle accidents was similar to that in all patients. Motor vehicle accidents resulted in a significantly higher number of body fractures (OR 3.3, 95% CI 1.24-8.76, p = 0.017) and struck injury in a significantly higher number of angle and ramus fractures (OR 3.9, 95% CI 1.48-10.26, p = 0.006) compared to motorcycle accidents. The helmet-wearing status and body weight were not associated with the location of mandibular fractures in motorcycle accidents. Conclusions: Our study revealed that the anatomic fracture sites of mandible were specifically related to different etiologies. In southern Taiwan, motorcycle accidents accounted for the major cause of mandibular fractures and were associated with the condylar neck and head as the most frequent fracture sites. In contrast, motor vehicle accidents and struck injuries tended to cause more body fracture as well as angle and ramus fracture compared to motorcycle accidents. Furthermore, the status of helmet-wearing and body weight were not associated with the location of mandible fractures caused by motorcycle accidents. PMID- 28737728 TI - Neighbor Affinity-Based Core-Attachment Method to Detect Protein Complexes in Dynamic PPI Networks. AB - Protein complexes play significant roles in cellular processes. Identifying protein complexes from protein-protein interaction (PPI) networks is an effective strategy to understand biological processes and cellular functions. A number of methods have recently been proposed to detect protein complexes. However, most of methods predict protein complexes from static PPI networks, and usually overlook the inherent dynamics and topological properties of protein complexes. In this paper, we proposed a novel method, called NABCAM (Neighbor Affinity-Based Core Attachment Method), to identify protein complexes from dynamic PPI networks. Firstly, the centrality score of every protein is calculated. The proteins with the highest centrality scores are regarded as the seed proteins. Secondly, the seed proteins are expanded to complex cores by calculating the similarity values between the seed proteins and their neighboring proteins. Thirdly, the attachments are appended to their corresponding protein complex cores by comparing the affinity among neighbors inside the core, against that outside the core. Finally, filtering processes are carried out to obtain the final clustering result. The result in the DIP database shows that the NABCAM algorithm can predict protein complexes effectively in comparison with other state-of-the-art methods. Moreover, many protein complexes predicted by our method are biologically significant. PMID- 28737729 TI - Geographic Distribution and Temporal Trends of HIV-1 Subtypes through Heterosexual Transmission in China: A Systematic Review and Meta-Analysis. AB - Background: Heterosexual transmission (HST) has become the current predominant transmission pathways of the HIV-1 epidemic in China. The aim of this study was to explore the geographic and dynamic change of HIV-1 subtypes through HST in China from published studies. Methods: Several electronic databases were searched to identify the studies, and the overall prevalence of HIV-1 subtypes was estimated by a meta-analysis method. Subgroup analysis was conducted by study region and time period. Publication bias was evaluated using Egger's test. The chi2 test was used to evaluate the proportion differences among subgroups. Sensitivity analysis was carried out to assess the stability of the overall prevalence estimates. Results: 42 studies were included in our final analysis. The overall prevalence of CRF01_AE was 46.34% (95% CI: 40.56-52.17%), CRF07_BC was 19.16% (95% CI: 15.02-23.66%), B/B' was 13.25% (95% CI: 9.68-17.25%), CRF08_BC was 10.61% (95% CI: 7.08-14.70%), and C was 4.29% (95% CI: 1.85-7.48%). In subgroup analysis, the prevalence of CRF01_AE and CRF07_BC increased, while the prevalence of B/B' decreased over time, whereby the prevalence of CRF07_BC and CRF08_BC have exceeded that of B/B' since 2010. A significant higher prevalence of CRF01_AE was found in the South provinces, CRF07_BC in East provinces, CRF08_BC and C in Southwest provinces, and B/B' in North provinces. Conclusions: The HIV-1 prevalent strains have evolved into complicated and diverse subtypes, and the proportion of HIV-1 subtypes through HST has changed constantly in different regions and periods in China. This highlights the urgent need to vigorously strengthen the prevention and control of the HIV-1 epidemic. PMID- 28737730 TI - Sildenafil in Infants and Children. AB - Pulmonary arterial hypertension (PAH) management has been transformed in recent times with the advent of cheap and effective diagnostic tools and therapy. Sildenafil, a phosphodiesterase-V inhibitor, has been at the centre of this treatment, and its success in treating PAH has led to its widespread uptake in adult and paediatric pulmonary hypertension (PH), as a first line treatment choice. This might apply to persistent pulmonary hypertension of the newborn (PPHN) or bronchopulmonary dysplasia, as well as to more complex diseases, such as idiopathic pulmonary hypertension. Although recent data regarding long-term mortality and the repeal of Food and Drug Administration (FDA) approval has complicated the issue, Sildenafil continues to be the major treatment option for paediatric PH for patients in a variety of contexts, and this does not seem likely to change in the foreseeable future. In this review, we provide a summary of pulmonary hypertension in infants and children and the use of Sildenafil for such diseases. PMID- 28737731 TI - Study on Chemical Profile and Neuroprotective Activity of Myrica rubra Leaf Extract. AB - The chemical profile of Myrica rubra (a native species in China) leaf extract was investigated by UPLC-PDA-HRMS, and the neuroprotective activity of two characteristic constituents, myricanol and myricetrin, was evaluated with N2a cells using H2O2-inducedoxidative challenge through a series of methods, e.g., MTT assay, ROS assay and [Ca2+]i assay. Among the 188 constituents detected in the extract of Myrica rubra leaf, 116 were identified definitely or tentatively by the comprehensive utilization of precise molecular weight and abundant multistage fragmentation information obtained by quadrupole orbitrap mass spectrometry. In addition, 14 potential new compounds were reported for the first time. This work established an example for the research of microconstituents in a complex analyte and revealed that suppression of H2O2-induced cytotoxicity in N2a cells was achieved by the pretreatment with myricanol. The evidence suggested myricanol may potentially serve as a remedy for prevention and therapy of neurodegenerative diseases induced by oxidative stress. PMID- 28737732 TI - The Role of Heart-Rate Variability Parameters in Activity Recognition and Energy Expenditure Estimation Using Wearable Sensors. AB - Human-activity recognition (HAR) and energy-expenditure (EE) estimation are major functions in the mobile healthcare system. Both functions have been investigated for a long time; however, several challenges remain unsolved, such as the confusion between activities and the recognition of energy-consuming activities involving little or no movement. To solve these problems, we propose a novel approach using an accelerometer and electrocardiogram (ECG). First, we collected a database of six activities (sitting, standing, walking, ascending, resting and running) of 13 voluntary participants. We compared the HAR performances of three models with respect to the input data type (with none, all, or some of the heart rate variability (HRV) parameters). The best recognition performance was 96.35%, which was obtained with some selected HRV parameters. EE was also estimated for different choices of the input data type (with or without HRV parameters) and the model type (single and activity-specific). The best estimation performance was found in the case of the activity-specific model with HRV parameters. Our findings indicate that the use of human physiological data, obtained by wearable sensors, has a significant impact on both HAR and EE estimation, which are crucial functions in the mobile healthcare system. PMID- 28737733 TI - A Secure and Verifiable Outsourced Access Control Scheme in Fog-Cloud Computing. AB - With the rapid development of big data and Internet of things (IOT), the number of networking devices and data volume are increasing dramatically. Fog computing, which extends cloud computing to the edge of the network can effectively solve the bottleneck problems of data transmission and data storage. However, security and privacy challenges are also arising in the fog-cloud computing environment. Ciphertext-policy attribute-based encryption (CP-ABE) can be adopted to realize data access control in fog-cloud computing systems. In this paper, we propose a verifiable outsourced multi-authority access control scheme, named VO-MAACS. In our construction, most encryption and decryption computations are outsourced to fog devices and the computation results can be verified by using our verification method. Meanwhile, to address the revocation issue, we design an efficient user and attribute revocation method for it. Finally, analysis and simulation results show that our scheme is both secure and highly efficient. PMID- 28737734 TI - Storage of Fruits and Vegetables in Refrigerator Increases their Phenolic Acids but Decreases the Total Phenolics, Anthocyanins and Vitamin C with Subsequent Loss of their Antioxidant Capacity. AB - It is of paramount importance for consumers, scientists and industrialists to understand how low-temperature storage of food items affects their bioactive compounds and properties. This study evaluated the effects of cold storage on total phenolics (TP), phenolic acids profile (PA), total anthocyanins (TA), total ascorbic acid (Vit. C) and antioxidant activity (AA) of 19 fruits and vegetables, collected from local Indian markets and stored in refrigerator (4 degrees C) during 15 days. Content of TP was highest in dill and amaranth and decreased (up to 29.67%) with storage. Leafy vegetables (amaranth, dill, onion, fenugreek and spinach) contained higher amounts of the 12 PA revealed by UPLC-UV; ellagic, gallic, sinapic and vanillic acids levels were the highest; chlorogenic acid (rho = 0.423), syringic acid (rho = 0.403) and sinapic acid (rho = 0.452) mostly correlated with TP; and the PA increased during storage. Highest contents of Vit C estimated by AOAC, DCPIP and DNP methods were found in amaranth, dill and pomegranate, and decreased with storage. Pomegranate showed highest TA levels and low-temperature storage did not significantly increase TA, which was the largest contributor of TP in fruits and vegetables (rho = 0.661). Storage induced a drastic decrease of AA, which mostly correlated with TP (rho = 0.808, 0.690 and 0.458 for DPPH, ABTS and FRAP assays, respectively). Spearman's correlation confirmed by principal component analysis demonstrated that dill, pomegranate and amaranth had the highest overall antioxidant capacity, whereas orange juice and carrot showed the lowest. The results provide support for a key-role of TP, followed by Vit. C and TA in antioxidant capacity of fruits and vegetables, which could be interesting dietary sources of natural antioxidants for prevention of diseases caused by oxidative stress. PMID- 28737736 TI - Tomato development: MADS-box engineering. PMID- 28737735 TI - The Putative Histone Methyltransferase DOT1 Regulates Aflatoxin and Pathogenicity Attributes in Aspergillus flavus. AB - Lysine methyltransferases transfer methyl groups in specific lysine sites, which regulates a variety of important biological processes in eukaryotes. In this study, we characterized a novel homolog of the yeast methyltransferase DOT1 in A. flavus, and observed the roles of dot1 in A. flavus. Deletion of dot1 showed a significant decrease in conidiation, but an increase in sclerotia formation. A change in viability to multiple stresses was also found in the Deltadot1 mutant. Additionally, aflatoxin (AF) production was found severely impaired in the Deltadot1 mutant. Further analysis by qRT-PCR revealed that the transcription of AF structural genes and their regulator gene aflS were prominently suppressed in the Deltadot1 mutant. Furthermore, our data revealed that Dot1 is important for colonizing maize seeds in A. flavus. Our research indicates that Dot1 is involved in fungal development, aflatoxin biosynthesis and fungal virulence in A. flavus, which might provide a potential target for controlling A. flavus with new strategies. PMID- 28737737 TI - Tropical forest conservation: Developing without deforestation. PMID- 28737738 TI - The innate immune receptor NLRP12 maintains intestinal homeostasis by regulating microbiome diversity. PMID- 28737739 TI - Clonal expansion shapes the human Vdelta1T cell receptor repertoire. PMID- 28737740 TI - Complement factor P: promoting the antibacterial activity of natural killer cells. PMID- 28737743 TI - Development of gene therapies-lessons from nusinersen. AB - The nusinersen development and approval process provide important lessons regarding the pathway to marketing approval for gene therapies. These lessons emphasize rigorous clinical trial design, flexibility in trial design and analysis, a collaborative effort with regular communications between the drug developer and the Food and Drug Administration (FDA), and use of FDA's expedited programs. These lessons are critical to the development of gene therapies for the treatment of serious or life-threatening rare diseases. PMID- 28737742 TI - Systemic transport of trans-zeatin and its precursor have differing roles in Arabidopsis shoots. AB - Organ-to-organ signal transmission is essential for higher organisms to ensure coordinated biological reactions during metabolism and morphogenesis. Similar to organs in animals, plant organs communicate by various signalling molecules. Among them, cytokinins, a class of phytohormones, play a key role as root-to shoot long-distance signals, regulating various growth and developmental processes in shoots1,2. Previous studies have proposed that trans-zeatin riboside, a type of cytokinin precursor, is a major long-distance signalling form in xylem vessels and its action depends on metabolic conversion via the LONELY GUY enzyme in proximity to the site of action3-5. Here we report an additional long-distance signalling form of cytokinin: trans-zeatin, an active form. Grafting between various cytokinin biosynthetic and transportation mutants revealed that root-to-shoot translocation of trans-zeatin, a minor component of xylem cytokinin, controls leaf size but not meristem activity-related traits, whereas that of trans-zeatin riboside is sufficient for regulating both traits. Considering the ratio of trans-zeatin to trans-zeatin-riboside in xylem and their delivery rate change in response to environmental conditions, this dual long distance cytokinin signalling system allows plants to fine-tune the manner of shoot growth to adapt to fluctuating environments. PMID- 28737741 TI - Rapidly inducible Cas9 and DSB-ddPCR to probe editing kinetics. AB - We developed a chemically inducible Cas9 (ciCas9) and a droplet digital PCR assay for double-strand breaks (DSB-ddPCR) to investigate the kinetics of Cas9-mediated generation and repair of DSBs in cells. ciCas9 is a rapidly activated, single component Cas9 variant engineered by replacing the protein's REC2 domain with the BCL-xL protein and fusing an interacting BH3 peptide to the C terminus. ciCas9 can be tunably activated by a compound that disrupts the BCL-xL-BH3 interaction within minutes. DSB-ddPCR demonstrates time-resolved, highly quantitative, and targeted measurement of DSBs. Combining these tools facilitated an unprecedented exploration of the kinetics of Cas9-mediated DNA cleavage and repair. We find that sgRNAs targeting different sites generally induce cleavage within minutes and repair within 1 or 2 h. However, we observe distinct kinetic profiles, even for proximal sites, and this suggests that target sequence and chromatin state modulate cleavage and repair kinetics. PMID- 28737744 TI - Delivering advanced therapies: the big pharma approach. AB - After two decades of focused development and some recent clinical successes, cell and gene therapy (CGT) is emerging as a promising approach to personalized medicines. Genetically engineered cells as a medical modality are poised to stand alongside or in combination with small molecule and biopharmaceutical approaches to bring new therapies to patients globally. Big pharma can have a vital role in industrializing CGT by focusing on diseases with high unmet medical need and compelling genetic evidence. Pharma should invest in manufacturing and supply chain solutions that deliver reproducible, high-quality therapies at a commercially viable cost. Owing to the fast pace of innovation in this field proactive engagement with regulators is critical. It is also vital to understand the needs of patients all along the patient care pathway and to establish product pricing that is accepted by prescribers, payers and patients. PMID- 28737746 TI - DNA computing: Spatially localized DNA domino. PMID- 28737745 TI - Electromagnetized gold nanoparticles mediate direct lineage reprogramming into induced dopamine neurons in vivo for Parkinson's disease therapy. AB - Electromagnetic fields (EMF) are physical energy fields generated by electrically charged objects, and specific ranges of EMF can influence numerous biological processes, which include the control of cell fate and plasticity. In this study, we show that electromagnetized gold nanoparticles (AuNPs) in the presence of specific EMF conditions facilitate an efficient direct lineage reprogramming to induced dopamine neurons in vitro and in vivo. Remarkably, electromagnetic stimulation leads to a specific activation of the histone acetyltransferase Brd2, which results in histone H3K27 acetylation and a robust activation of neuron specific genes. In vivo dopaminergic neuron reprogramming by EMF stimulation of AuNPs efficiently and non-invasively alleviated symptoms in mouse Parkinson's disease models. This study provides a proof of principle for EMF-based in vivo lineage conversion as a potentially viable and safe therapeutic strategy for the treatment of neurodegenerative disorders. PMID- 28737747 TI - A spatially localized architecture for fast and modular DNA computing. AB - Cells use spatial constraints to control and accelerate the flow of information in enzyme cascades and signalling networks. Synthetic silicon-based circuitry similarly relies on spatial constraints to process information. Here, we show that spatial organization can be a similarly powerful design principle for overcoming limitations of speed and modularity in engineered molecular circuits. We create logic gates and signal transmission lines by spatially arranging reactive DNA hairpins on a DNA origami. Signal propagation is demonstrated across transmission lines of different lengths and orientations and logic gates are modularly combined into circuits that establish the universality of our approach. Because reactions preferentially occur between neighbours, identical DNA hairpins can be reused across circuits. Co-localization of circuit elements decreases computation time from hours to minutes compared to circuits with diffusible components. Detailed computational models enable predictive circuit design. We anticipate our approach will motivate using spatial constraints for future molecular control circuit designs. PMID- 28737749 TI - Wearable electronics: Nanomesh on-skin electronics. PMID- 28737748 TI - Inflammation-free, gas-permeable, lightweight, stretchable on-skin electronics with nanomeshes. AB - Thin-film electronic devices can be integrated with skin for health monitoring and/or for interfacing with machines. Minimal invasiveness is highly desirable when applying wearable electronics directly onto human skin. However, manufacturing such on-skin electronics on planar substrates results in limited gas permeability. Therefore, it is necessary to systematically investigate their long-term physiological and psychological effects. As a demonstration of substrate-free electronics, here we show the successful fabrication of inflammation-free, highly gas-permeable, ultrathin, lightweight and stretchable sensors that can be directly laminated onto human skin for long periods of time, realized with a conductive nanomesh structure. A one-week skin patch test revealed that the risk of inflammation caused by on-skin sensors can be significantly suppressed by using the nanomesh sensors. Furthermore, a wireless system that can detect touch, temperature and pressure is successfully demonstrated using a nanomesh with excellent mechanical durability. In addition, electromyogram recordings were successfully taken with minimal discomfort to the user. PMID- 28737750 TI - Room-temperature continuous-wave lasing from monolayer molybdenum ditelluride integrated with a silicon nanobeam cavity. AB - Monolayer transition-metal dichalcogenides (TMDs) have the potential to become efficient optical-gain materials for low-energy-consumption nanolasers with the smallest gain media because of strong excitonic emission. However, until now TMD based lasing has been realized only at low temperatures. Here we demonstrate for the first time a room-temperature laser operation in the infrared region from a monolayer of molybdenum ditelluride on a silicon photonic-crystal cavity. The observation is enabled by the unique combination of a TMD monolayer with an emission wavelength transparent to silicon, and a high-Q cavity of the silicon nanobeam. The laser is pumped by a continuous-wave excitation, with a threshold density of 6.6 W cm-2. Its linewidth is as narrow as 0.202 nm with a corresponding Q of 5,603, the largest value reported for a TMD laser. This demonstration establishes TMDs as practical materials for integrated TMD-silicon nanolasers suitable for silicon-based nanophotonic applications in silicon transparent wavelengths. PMID- 28737751 TI - Controlling energy flow in multimetallic nanostructures for plasmonic catalysis. AB - It has been shown that photoexcitation of plasmonic metal nanoparticles (Ag, Au and Cu) can induce direct photochemical reactions. However, the widespread application of this technology in catalysis has been limited by the relatively poor chemical reactivity of noble metal surfaces. Despite efforts to combine plasmonic and catalytic metals, the physical mechanisms that govern energy transfer from plasmonic metals to catalytic metals remain unclear. Here we show that hybrid core-shell nanostructures in which a core plasmonic metal harvests visible-light photons can selectively channel that energy into catalytically active centres on the nanostructure shell. To accomplish this, we developed a synthetic protocol to deposit a few monolayers of Pt onto Ag nanocubes. This model system allows us to conclusively separate the optical and catalytic functions of the hybrid nanomaterial and determine that the flow of energy is strongly biased towards the excitation of energetic charge carriers in the Pt shell. We demonstrate the utility of these nanostructures for photocatalytic chemical reactions in the preferential oxidation of CO in excess H2. Our data demonstrate that the reaction occurs exclusively on the Pt surface. PMID- 28737754 TI - Organ communication: Cytokinins on the move. PMID- 28737753 TI - Metabolic control of the scaffold protein TKS5 in tissue-invasive, proinflammatory T cells. AB - Pathogenic T cells in individuals with rheumatoid arthritis (RA) infiltrate non lymphoid tissue sites, maneuver through extracellular matrix and form lasting inflammatory microstructures. Here we found that RA T cells abundantly express the podosome scaffolding protein TKS5, which enables them to form tissue-invasive membrane structures. TKS5 overexpression was regulated by the intracellular metabolic environment of RA T cells-specifically, by reduced glycolytic flux that led to deficiencies in ATP and pyruvate. ATPlopyruvatelo conditions triggered fatty acid biosynthesis and the formation of cytoplasmic lipid droplets. Restoration of pyruvate production or inhibition of fatty acid synthesis corrected the tissue-invasiveness of RA T cells in vivo and reversed their proarthritogenic behavior. Thus, metabolic control of T cell locomotion provides new opportunities to interfere with T cell invasion into specific tissue sites. PMID- 28737752 TI - Mechanical strain sensing implicated in cell shape recovery in Escherichia coli. AB - The shapes of most bacteria are imparted by the structures of their peptidoglycan cell walls, which are determined by many dynamic processes that can be described on various length scales ranging from short-range glycan insertions to cellular scale elasticity1-11. Understanding the mechanisms that maintain stable, rod-like morphologies in certain bacteria has proved to be challenging due to an incomplete understanding of the feedback between growth and the elastic and geometric properties of the cell wall3,4,12-14. Here, we probe the effects of mechanical strain on cell shape by modelling the mechanical strains caused by bending and differential growth of the cell wall. We show that the spatial coupling of growth to regions of high mechanical strain can explain the plastic response of cells to bending4 and quantitatively predict the rate at which bent cells straighten. By growing filamentous Escherichia coli cells in doughnut shaped microchambers, we find that the cells recovered their straight, native rod shaped morphologies when released from captivity at a rate consistent with the theoretical prediction. We then measure the localization of MreB, an actin homologue crucial to cell wall synthesis, inside confinement and during the straightening process, and find that it cannot explain the plastic response to bending or the observed straightening rate. Our results implicate mechanical strain sensing, implemented by components of the elongasome yet to be fully characterized, as an important component of robust shape regulation in E. coli. PMID- 28737755 TI - Biphasic growth dynamics control cell division in Caulobacter crescentus. AB - Cell size is specific to each species and impacts cell function. Various phenomenological models for cell size regulation have been proposed, but recent work in bacteria has suggested an 'adder' model, in which a cell increments its size by a constant amount between each division. However, the coupling between cell size, shape and constriction remains poorly understood. Here, we investigate size control and the cell cycle dependence of bacterial growth using multigenerational cell growth and shape data for single Caulobacter crescentus cells. Our analysis reveals a biphasic mode of growth: a relative timer phase before constriction where cell growth is correlated to its initial size, followed by a pure adder phase during constriction. Cell wall labelling measurements reinforce this biphasic model, in which a crossover from uniform lateral growth to localized septal growth is observed. We present a mathematical model that quantitatively explains this biphasic 'mixer' model for cell size control. PMID- 28737756 TI - Overexpression of zinc finger protein 687 enhances tumorigenic capability and promotes recurrence of hepatocellular carcinoma. AB - Zinc finger protein 687 (ZNF687), identified as a C2H2 zinc finger protein, has been found to be mutated and upregulated in giant cell tumor of bone and acute myeloid leukemia, suggesting an oncogenic role for ZNF687 in cancer. However, the clinical significance and precise role of ZNF687 in cancer progression are largely unknown. Herein, we report that ZNF687 was markedly upregulated in hepatocellular carcinoma (HCC) cell lines and HCC tissues, and was significantly correlated with relapse-free survival in HCC. ZNF687 overexpression greatly enhanced HCC cell capability for tumorsphere formation, invasion and chemoresistance in vitro, whereas inhibiting ZNF687 reduced these capabilities and inhibited HCC cell tumorigenic capability in vivo. Importantly, extreme limiting dilution analysis revealed that even 1 * 102 ZNF687-transduced cells could form tumors in vivo, indicating that ZNF687 contributes to HCC recurrence. Moreover, we demonstrate that ZNF687 transcriptionally upregulated the expression of the pluripotency-associated factors BMI1, OCT4 and NANOG by directly targeting their promoters. Therefore, our results suggest that ZNF687 has a promoter role in regulating HCC progression, which provides a potential therapeutic target for HCC in humans. PMID- 28737757 TI - Non-canonical WNT/PCP signalling in cancer: Fzd6 takes centre stage. AB - Frizzled receptors are the mediators of the wnt canonical and non-canonical pathways, which play fundamental roles in cell differentiation and organism development. A large body of work indicates that dysregulation of wnt signalling is a feature of oncogenic transformation, but most of the studies published so far focus on the assessment of the consequences of aberrations of the canonical pathway in human cancer. In this review, we discuss the emerging role of the wnt non-canonical pathway regulated by frizzled receptor 6 (Fzd6) in the pathogenesis of different types of human malignancies. The function played by Fzd6 in the physiology of normal and cancer cells has been highlighted in the view that an increased knowledge of the signalling pathways upstream and downstream of this receptor could ultimately result in the identification of new targets for cancer therapy. PMID- 28737758 TI - Real-world experience with 0.2 MUg/day fluocinolone acetonide intravitreal implant (ILUVIEN) in the United Kingdom. AB - AimsTo compare safety outcomes and visual function data acquired in the real world setting with FAME study results in eyes treated with 0.2 MUg/day fluocinolone acetonide (FAc).MethodsFourteen UK clinical sites contributed to pseudoanonymised data collected using the same electronic medical record system. Data pertaining to eyes treated with FAc implant for diabetic macular oedema (DMO) was extracted. Intraocular pressure (IOP)-related adverse events were defined as use of IOP-lowering medication, any rise in IOP>30 mm Hg, or glaucoma surgery. Other measured outcomes included visual acuity, central subfield thickness (CSFT) changes and use of concomitant medications.ResultsIn total, 345 eyes had a mean follow-up of 428 days. Overall, 13.9% of patients required IOP lowering drops (included initiation, addition and switching of current drops), 7.2% had IOP elevation >30 mm Hg and 0.3% required glaucoma surgery. In patients with prior steroid exposure and no prior IOP-related event, there were no new IOP related events. In patients without prior steroid use and without prior IOP related events, 10.3% of eyes required IOP-lowering medication and 4.3% exhibited IOP >30 mm Hg at some point during follow-up. At 24 months, mean best-recorded visual acuity increased from 51.9 to 57.2 letters and 20.8% achieved >=15-letter improvement. Mean CSFT reduced from 451.2 to 355.5 MUm.ConclusionsWhile overall IOP-related emergent events were observed in similar frequency to FAME, no adverse events were seen in the subgroup with prior steroid exposure and no prior IOP events. Efficacy findings confirm that the FAc implant is a useful treatment option for chronic DMO. PMID- 28737759 TI - Outcome of universal newborn eye screening with wide-field digital retinal image acquisition system: a pilot study. AB - PurposeTo evaluate the outcome of universal newborn eye screening with wide-field digital retinal imaging (WFDRI) system.MethodsIn this pilot study, we examined 1152 apparently healthy newborn infants in the obstetrics and gynecology ward of a civil hospital in Eastern India over 1.5 years. The examination included external eye examination, red reflex test and fundus imaging by WFDRI (RetCam II, Clarity medical system, Pleasanton, CA, USA) by a trained optometrist. The pathologies detected, net monetary gain and skilled manpower saved were documented. The results were compared with three similar studies thus far published in the literature.ResultsOcular abnormality of any kind was seen in 172 (14.93%) babies. Retinal hemorrhage in 153 babies (88.9% of all abnormal findings) was the most common abnormality; it was bilateral in 118 (77.12%) babies and 4 babies had foveal hemorrhage. Other abnormalities included vitreous hemorrhage (n=1), congenital glaucoma (n=2), uveal coloboma (n=2), retinopathy mimicking retinopathy of prematurity (n=2), and cystic fovea (n=3). The retinal hemorrhages resolved spontaneously in all eyes. One baby with congenital glaucoma received surgery and the other was treated medically. The benefits included savings in skilled manpower, a net monetary gain of INR 4.195 million (US$ 62,612) and skilled manpower saving by 319.4 h.ConclusionsThe universal neonatal eye screening using WFDRI detected pathologies that needed immediate care or regular follow up; saved skilled manpower with a net monetary gain. But compared to a red reflex test the benefits were marginal in terms of detecting treatment warranting ocular pathologies. PMID- 28737761 TI - GLUTAMATE RECEPTOR-LIKE channels are essential for chemotaxis and reproduction in mosses. AB - Glutamate receptors are well characterized channels that mediate cell-to-cell communication during neurotransmission in animals, but their functional role in organisms without a nervous system remains unclear. In plants, genes of the GLUTAMATE RECEPTOR-LIKE (GLR) family have been implicated in defence against pathogens, reproduction, control of stomata aperture and light signal transduction. However, the large number of GLR genes present in angiosperm genomes (20 to 70) has prevented the observation of strong phenotypes in loss-of function mutants. Here we show that in the basal land plant Physcomitrella patens, mutation of the GLR genes GLR1 and GLR2 causes failure of sperm cells to target the female reproductive organs. In addition, we show that GLR genes encode non-selective Ca2+-permeable channels that can regulate cytoplasmic Ca2+ and are needed to induce the expression of a BELL1-like transcription factor essential for zygote development. Our work reveals functions for GLR channels in sperm chemotaxis and transcriptional regulation. Sperm chemotaxis is essential for fertilization in both animals and early land plants such as bryophytes and pteridophytes. Therefore, our results suggest that ionotropic glutamate receptors may have been conserved throughout plant evolution to mediate cell-to-cell communication during sexual reproduction. PMID- 28737760 TI - Channel opening and gating mechanism in AMPA-subtype glutamate receptors. AB - AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid)-subtype ionotropic glutamate receptors mediate fast excitatory neurotransmission throughout the central nervous system. Gated by the neurotransmitter glutamate, AMPA receptors are critical for synaptic strength, and dysregulation of AMPA receptor-mediated signalling is linked to numerous neurological diseases. Here we use cryo-electron microscopy to solve the structures of AMPA receptor-auxiliary subunit complexes in the apo, antagonist- and agonist-bound states and determine the iris-like mechanism of ion channel opening. The ion channel selectivity filter is formed by the extended portions of the re-entrant M2 loops, while the helical portions of M2 contribute to extensive hydrophobic interfaces between AMPA receptor subunits in the ion channel. We show how the permeation pathway changes upon channel opening and identify conformational changes throughout the entire AMPA receptor that accompany activation and desensitization. Our findings provide a framework for understanding gating across the family of ionotropic glutamate receptors and the role of AMPA receptors in excitatory neurotransmission. PMID- 28737762 TI - Mechanism of host substrate acetylation by a YopJ family effector. AB - The Yersinia outer protein J (YopJ) family of bacterial effectors depends on a novel acetyltransferase domain to acetylate signalling proteins from plant and animal hosts. However, the underlying mechanism is unclear. Here, we report the crystal structures of PopP2, a YopJ effector produced by the plant pathogen Ralstonia solanacearum, in complex with inositol hexaphosphate (InsP6), acetyl coenzyme A (AcCoA) and/or substrate Resistance to Ralstonia solanacearum 1 (RRS1 R)WRKY. PopP2 recognizes the WRKYGQK motif of RRS1-RWRKY to position a targeted lysine in the active site for acetylation. Importantly, the PopP2-RRS1-RWRKY association is allosterically regulated by InsP6 binding, suggesting a previously unidentified role of the eukaryote-specific cofactor in substrate interaction. Furthermore, we provide evidence for the reaction intermediate of PopP2-mediated acetylation, an acetyl-cysteine covalent adduct, lending direct support to the 'ping-pong'-like catalytic mechanism proposed for YopJ effectors. Our study provides critical mechanistic insights into the virulence activity of YopJ class of acetyltransferases. PMID- 28737764 TI - Paired related homeobox protein 1 regulates PDGF-induced chemotaxis of hepatic stellate cells in liver fibrosis. AB - Activation of the platelet-derived growth factor (PDGF)/PDGF beta receptor (PDGFbetaR) axis has a critical role in liver fibrosis. However, the mechanisms that regulate the PDGF signaling are yet to be elucidated. The present study demonstrates that paired related homeobox protein 1 (Prrx1) is involved in PDGF dependent hepatic stellate cell (HSCs) migration via modulation of the expression of metalloproteinases MMP2 and MMP9. PDGF elevated the level of Prrx1 through the activation of ERK/Sp1 and PI3K/Akt/Ets1 pathways. In vivo, an adenoviral-mediated Prrx1 shRNA administration attenuated liver fibrosis in thioacetamide-induced fibrotic models. These studies reveal a role of Prrx1 as a modulator of PDGF dependent signaling in HSCs, and inhibiting its expression may offer a therapeutic approach for hepatic fibrosis. PMID- 28737763 TI - Melanoma subtypes demonstrate distinct PD-L1 expression profiles. AB - PD-L1 expression in the tumor immune microenvironment is recognized as both a prognostic and predictive biomarker in patients with cutaneous melanoma, a finding closely related to its adaptive (IFN-gamma-mediated) mechanism of expression. Approximately 35% of cutaneous melanomas express PD-L1, however, the expression patterns, levels, and prevalence in rarer melanoma subtypes are not well described. We performed immunohistochemistry for PD-L1 and CD8 on 200 formalin-fixed paraffin-embedded specimens from patients with acral (n=16), mucosal (n=36), uveal (n=103), and chronic sun-damaged (CSD) (n=45) melanomas (24 lentigo maligna, 13 'mixed' desmoplastic, and 8 'pure' desmoplastic melanomas). CD8+ tumor-infiltrating lymphocyte (TIL) densities were characterized as mild, moderate, or severe, and their geographic association with PD-L1 expression was evaluated. Discrete lymphoid aggregates, the presence of a spindle cell morphology, and the relationship of these features with PD-L1 expression were assessed. PD-L1 expression was observed in 31% of acral melanomas, 44% of mucosal melanomas, 10% of uveal melanomas, and 62% of CSD melanomas (P<0.0001). Compared to our previously characterized cohort of cutaneous melanomas, the proportion of PD-L1(+) tumors was lower in uveal (P=0.0002) and higher in CSD (P=0.0073) melanomas, while PD-L1 expression in the acral and mucosal subtypes was on par. PD-L1 expression in all subtypes correlated with a moderate-severe grade of CD8+ TIL (all, P<0.003), supporting an adaptive mechanism of expression induced during the host antitumor response. The tumor microenvironments observed in CSD melanomas segregated by whether they were the pure desmoplastic subtype, which showed lower levels of PD-L1 expression when compared to other CSD melanomas (P=0.047). The presence of lymphoid aggregates was not associated with the level of PD-L1 expression, while PD-L1(+) cases with spindle cell morphology demonstrated higher levels of PD-L1 than those with a nested phenotype (P<0.0001). Our findings may underpin the reported clinical response rates for anti-PD-1 monotherapy, which vary by subtype. PMID- 28737765 TI - Adrenocorticotropic hormone and 1,25-dihydroxyvitamin D3 enhance human osteogenesis in vitro by synergistically accelerating the expression of bone specific genes. AB - To improve definition of the physical and hormonal support of bone formation, we studied differentiation of human osteoblasts in vitro at varying combinations of ACTH, 1alpha,25-dihydroxyvitamin D3 (1,25(OH)2D), and extracellular calcium, with and without added cortisol. Bone mineralization, alkaline phosphatase activity, and osteoblast-specific markers RunX2, osterix, and collagen I increased with 10 pM ACTH, 10 nM 1,25(OH)2D, or at 2 mM calcium with important synergistic activity of combinations of any of these stimuli. Signals induced by ACTH at 10-30 min included cAMP, TGF-beta, and Erk1/2 phosphorylation. Affymetrix gene expression analysis showed that 2 h treatment of ACTH or 1,25(OH)2D increased the expression of bone regulating and structural mRNAs, including collagen I, biglycan, the vitamin D receptor, and TGF-beta. Accelerating expression of these bone-specific genes was confirmed by quantitative PCR. Expression of 1,25(OH)2D 1alpha hydroxylase (1alpha-hydroxylase) increased with 1,25(OH)2D, ACTH, and extracellular calcium from 0.5 to 2 mM. Unlike renal 1alpha-hydroxylase, in osteoblasts, 1alpha-hydroxylase activity is independent of parathyroid hormone. In keeping with calcium responsivity, calcium-sensing receptor RNA and protein increased with 10 nM ACTH or 1,25(OH)2D. Inclusion of 200 nM cortisol or 10 nM ACTH in differentiation media blunted osteoblasts alkaline phosphatase response to 1,25(OH)2D and calcium. Our results point to the importance of ACTH in bone maintenance and that extra skeletal (renal) 1,25(OH)2D is required for bone mineralization despite 1alpha-hydroxylase expression by osteoblasts. PMID- 28737767 TI - Sensitive and non-invasive method for the in vivo analysis of membrane permeability in small animals. AB - Tissue membranes are boundaries that isolate organs or cavities in the body. These semi-permeable membranes are responsible for passive protection that acts through the regulation of nutrient absorption, secretion and filtration of small molecules. These functions could be altered as a consequence of inflammation or trauma, which in turn could lead to changes in permeability, allowing the entrance of toxins, antigens, proteins or facilitating the spread of tumors. Membrane permeability therefore plays an important role in numerous diseases. However, current experimental techniques that are available to quantify membrane permeability in small animals have limited precision and temporal specificity. Improvements in such measurements would lead to a deeper understanding of disease pathogenesis and this may accelerate the development of specific therapies. The study reported here concerns the efficacy of a novel, non-invasive imaging analysis-based measurement method that significantly improves the quantification of tissue membrane permeability in small animals, while at the same time mitigating the adverse effects experienced by the animals under study. PMID- 28737766 TI - Endothelial fibrosis induced by suppressed STAT3 expression mediated by signaling involving the TGF-beta1/ALK5/Smad pathway. AB - During systemic inflammatory pathologies, mediators of inflammation circulate in the bloodstream and interact with endothelial cells (ECs), resulting in endothelial dysfunction that maintains and enhances the pathological condition. Inflammatory mediators change the protein expression profile of ECs, which become activated fibroblasts via endothelial-to-mesenchymal transition. This process is characterized by downregulated endothelial proteins and strongly upregulated fibrotic-specific genes and extracellular matrix-forming proteins. The main inductor of endothelial fibrosis is transforming growth factor-beta1 (TGF-beta1), which acts through the TGF-beta1/activin receptor-like kinase 5 (ALK5)/Smads intracellular signaling pathway. The signal transducer and activator of transcription 3 (STAT3) is also involved in fibrosis in several tissues (e.g. heart and vascular system), where STAT3 signaling decreases TGF-beta1-induced responses by directly interacting with Smad proteins, suggesting that decreased STAT3 could induce TGF-beta1-mediated fibrosis. However, it is unknown if suppressed STAT3 expression induces EC fibrosis through a mechanism involving the TGF-beta signaling pathway. The present study evaluated the fibrotic actions of STAT3 suppression in ECs and investigated TGF-beta1/ALK5/Smad4 signaling pathway participation. Suppressed STAT3 expression stimulated fibrotic conversion in ECs, as mediated by protein expression reprograming that decreased endothelial marker expression and increased fibrotic and extracellular matrix protein levels. The potential mechanism underlying these changes was dependent on TGF-beta1 secretion, the ALK5 activation pathway, and Smad4 translocation into the nucleus. We conclude that suppressed STAT3 expression converts ECs into activated fibroblasts via TGF-beta1/ALK5/Smad4 signaling pathway involvement. PMID- 28737768 TI - ARID1A-mutated ovarian cancers depend on HDAC6 activity. AB - ARID1A, encoding a subunit of the SWI/SNF chromatin-remodelling complex, is the most frequently mutated epigenetic regulator across all human cancers. ARID1A and TP53 mutations are typically mutually exclusive. Therapeutic approaches that correlate with this genetic characteristic remain to be explored. Here, we show that HDAC6 activity is essential in ARID1A-mutated ovarian cancers. Inhibition of HDAC6 activity using a clinically applicable small-molecule inhibitor significantly improved the survival of mice bearing ARID1A-mutated tumours. This correlated with the suppression of growth and dissemination of ARID1A-mutated, but not wild-type, tumours. The dependence on HDAC6 activity in ARID1A-mutated cells correlated with a direct transcriptional repression of HDAC6 by ARID1A. HDAC6 inhibition selectively promoted apoptosis of ARID1A-mutated cells. HDAC6 directly deacetylates Lys120 of p53, a pro-apoptotic post-translational modification. Thus, ARID1A mutation inactivates the apoptosis-promoting function of p53 by upregulating HDAC6. Together, these results indicate that pharmacological inhibition of HDAC6 is a therapeutic strategy for ARID1A-mutated cancers. PMID- 28737769 TI - Local lung hypoxia determines epithelial fate decisions during alveolar regeneration. AB - After influenza infection, lineage-negative epithelial progenitors (LNEPs) exhibit a binary response to reconstitute epithelial barriers: activating a Notch dependent DeltaNp63/cytokeratin 5 (Krt5) remodelling program or differentiating into alveolar type II cells (AEC2s). Here we show that local lung hypoxia, through hypoxia-inducible factor (HIF1alpha), drives Notch signalling and Krt5pos basal-like cell expansion. Single-cell transcriptional profiling of human AEC2s from fibrotic lungs revealed a hypoxic subpopulation with activated Notch, suppressed surfactant protein C (SPC), and transdifferentiation toward a Krt5pos basal-like state. Activated murine Krt5pos LNEPs and diseased human AEC2s upregulate strikingly similar core pathways underlying migration and squamous metaplasia. While robust, HIF1alpha-driven metaplasia is ultimately inferior to AEC2 reconstitution in restoring normal lung function. HIF1alpha deletion or enhanced Wnt/beta-catenin activity in Sox2pos LNEPs blocks Notch and Krt5 activation, instead promoting rapid AEC2 differentiation and migration and improving the quality of alveolar repair. PMID- 28737770 TI - Tissue-specific CTCF-cohesin-mediated chromatin architecture delimits enhancer interactions and function in vivo. AB - The genome is organized via CTCF-cohesin-binding sites, which partition chromosomes into 1-5 megabase (Mb) topologically associated domains (TADs), and further into smaller sub-domains (sub-TADs). Here we examined in vivo an ~80 kb sub-TAD, containing the mouse alpha-globin gene cluster, lying within a ~1 Mb TAD. We find that the sub-TAD is flanked by predominantly convergent CTCF-cohesin sites that are ubiquitously bound by CTCF but only interact during erythropoiesis, defining a self-interacting erythroid compartment. Whereas the alpha-globin regulatory elements normally act solely on promoters downstream of the enhancers, removal of a conserved upstream CTCF-cohesin boundary extends the sub-TAD to adjacent upstream CTCF-cohesin-binding sites. The alpha-globin enhancers now interact with the flanking chromatin, upregulating expression of genes within this extended sub-TAD. Rather than acting solely as a barrier to chromatin modification, CTCF-cohesin boundaries in this sub-TAD delimit the region of chromatin to which enhancers have access and within which they interact with receptive promoters. PMID- 28737771 TI - Obesity alters the lung myeloid cell landscape to enhance breast cancer metastasis through IL5 and GM-CSF. AB - Obesity is associated with chronic, low-grade inflammation, which can disrupt homeostasis within tissue microenvironments. Given the correlation between obesity and relative risk of death from cancer, we investigated whether obesity associated inflammation promotes metastatic progression. We demonstrate that obesity causes lung neutrophilia in otherwise normal mice, which is further exacerbated by the presence of a primary tumour. The increase in lung neutrophils translates to increased breast cancer metastasis to this site, in a GM-CSF- and IL5-dependent manner. Importantly, weight loss is sufficient to reverse this effect, and reduce serum levels of GM-CSF and IL5 in both mouse models and humans. Our data indicate that special consideration of the obese patient population is critical for effective management of cancer progression. PMID- 28737772 TI - Cortical forces and CDC-42 control clustering of PAR proteins for Caenorhabditis elegans embryonic polarization. AB - Cell polarization enables zygotes to acquire spatial asymmetry, which in turn patterns cellular and tissue axes during development. Local modification in the actomyosin cytoskeleton mediates spatial segregation of partitioning-defective (PAR) proteins at the cortex, but how mechanical changes in the cytoskeleton are transmitted to PAR proteins remains elusive. Here we uncover a role of actomyosin contractility in the remodelling of PAR proteins through cortical clustering. During embryonic polarization in Caenorhabditis elegans, actomyosin contractility and the resultant cortical tension stimulate clustering of PAR-3 at the cortex. Clustering of atypical protein kinase C (aPKC) is supported by PAR-3 clusters and is antagonized by activation of CDC-42. Cortical clustering is associated with retardation of PAR protein exchange at the cortex and with effective entrainment of advective cortical flows. Our findings delineate how cytoskeleton contractility couples the cortical clustering and long-range displacement of PAR proteins during polarization. The principles described here would apply to other pattern formation processes that rely on local modification of cortical actomyosin and PAR proteins. PMID- 28737773 TI - The incidence of atrial fibrillation among patients with AL amyloidosis undergoing high-dose melphalan and stem cell transplantation: experience at a single institution. PMID- 28737774 TI - Outcomes of salvage autologous stem cell transplantation for multiple myeloma with cytopenias and exposure to novel agents. PMID- 28737777 TI - Post-synthetic transformation of a Zn(ii) polyhedral coordination network into a new supramolecular isomer of HKUST-1. AB - A Zn-based porphyrin containing metal-organic material (porphMOM-1) was transformed into a novel Cu-based porphyrin-encapsulating metal-organic material (porph@HKUST-1-beta) via a one-pot post-synthetic modification (PSM) process involving both metal ion exchange and linker installation of trimesic acid. HKUST 1-beta is the first example of yao topology and is to our knowledge the first supramolecular isomer of the archetypal coordination network HKUST-1. PMID- 28737776 TI - Therapeutic salivary monitoring of IV busulfan in patients undergoing hematopoietic stem cell transplantation: a pilot study. AB - Individual therapeutic monitoring of busulfan (BU) minimizes its toxicity and improves the therapeutic outcomes during hematopoietic stem cell transplantation (HSCT). For individual dose adjustment, several blood collections are performed that are uncomfortable for patients. The aim of this pilot study was to validate a laboratory method for quantification of BU in saliva and to present the results obtained using this protocol in HSCT patients. We performed analyses of selectivity, precision and accuracy of saliva with standard concentrations of BU using ultra-high-performance liquid chromatography with diode array detection. We also determined salivary and plasmatic concentrations of BU in six HSCT patients. Saliva exhibited excellent selectivity, precision and accuracy for quantification of BU. In the patient samples, significant correlations were noted between plasmatic and salivary concentrations of BU (r=0.97, P<0.001 in the test dose; r=0.93, P<0.001 in the adjusted dose). Passing &Bablok regression revealed good agreement between the two methods (R2=0.956 for test dose; R2=0.927 for adjusted dose). In conclusion, the saliva is safe for laboratory BU measurement. The good agreement with plasma encourages further clinical studies using saliva for BU therapeutic monitoring. PMID- 28737778 TI - Intense redox-driven chiroptical switching with a 580 mV hysteresis actuated through reversible dimerization of an azoniahelicene. AB - Electrochemical reduction of an azoniahelicene affords a dimer, accompanied by a strong change in the electronic circular dichroism. The fast dimerisation event leads to a >500 mV shift of the oxidation potential, affording a large area of bistability, where the chiroptical signal only depends on the redox history. PMID- 28737779 TI - The nature of intermolecular interactions in pyridinium-anion-beta hexachlorocyclohexane molecular crystals. AB - The nature of intermolecular interactions in different molecular crystal configurations formed by pyridinium cations, chloride or bromide anions as well as beta-hexachlorocyclohexane (beta-HCH) molecules has been investigated using high level ab initio quantum chemistry methods. Several molecular subsystems taken from the crystal unit cell were considered and their supramolecular energy stability was analyzed in detail using high level density-fitting local electron correlation (DF-LMP2 and DF-LCCSD(T)) methods together with the aug-cc-pVTZ basis set. In order to elucidate the nature of the intermolecular interactions between different fragments, the symmetry adapted perturbation theory (SAPT) method up to "2+3" truncation expansion was applied. The SAPT analysis has shown that the "simple" pair model of a halide anion-beta-HCH complex is not adequate to properly describe the stability of the crystals, since the charge polarization induced by the cation counterpart on the halide anion significantly changes the nature and the magnitude of the anion-beta-HCH interaction. PMID- 28737775 TI - Fertility preservation issues in pediatric hematopoietic stem cell transplantation: practical approaches from the consensus of the Pediatric Diseases Working Party of the EBMT and the International BFM Study Group. AB - Fertility preservation is an urgent challenge in the transplant setting. A panel of transplanters and fertility specialists within the Pediatric Diseases Working Party of the European Society for Blood and Marrow Transplantation (EBMT) and the International BFM Study Group provides specific guidelines. Patients and families should be informed of possible gender- and age-specific cryopreservation strategies that should be tailored according to the underlying disease, clinical condition and previous exposure to chemotherapy. Semen collection should be routinely offered to all postpubertal boys at the diagnosis of any disease requiring therapy that could potentially impair fertility. Testicular tissue collection might be offered to postpubertal boys; nevertheless, its use has been unsuccessful to date. Oocyte collection after hormonal hyperstimulation should be offered to postpubertal girls facing gonadotoxic therapies that could be delayed for the 2 weeks required for the procedure. Ovarian tissue collection could be offered to pre-/post-pubertal girls. Pregnancies have been reported after postpubertal ovarian tissue reimplantation; however, to date, no pregnancy has been reported after the reimplantation of prepubertal ovarian tissue or in vitro maturation of pre-/post-pubertal ovarian tissue. Possible future advances in reproductive medicine could change this scenario. Health authorities should prioritize fertility preservation projects in pediatric transplantation to improve patient care and quality of life. PMID- 28737780 TI - Ultra low lattice thermal conductivity and high carrier mobility of monolayer SnS2 and SnSe2: a first principles study. AB - Using density functional theory, we systematically investigate the lattice thermal conductivity and carrier mobility of monolayer SnX2 (X = S, Se). The room temperature ultra low lattice thermal conductivities found in monolayer SnS2 (6.41 W m-1 K-1) and SnSe2 (3.82 W m-1 K-1) are attributed to the low phonon velocity, low Debye temperature, weak bonding interactions, and strong anharmonicity in monolayer SnX2. The predicted values of lattice thermal conductivity are lower than those of other two-dimensional materials such as stanene, phosphorene, monolayer MoS2, and bulk SnX2. High phonon-limited carrier mobilities are obtained for the monolayer SnX2. For example, the electron mobility of monolayer SnS2 is 756.60 cm2 V-1 s-1 and the hole mobility is 187.44 cm2 V-1 s-1. The electron mobility of these monolayers is higher than their hole mobility due to the low effective mass of electrons and low deformation constants, which makes them n-type materials. Due to their ultra low lattice thermal conductivities coupled with high carrier mobilities, monolayer SnX2 materials may be promising materials for thermoelectric applications. PMID- 28737781 TI - Synthesis of hollow Cu1.8S nano-cubes for electromagnetic interference shielding. AB - The applications of inorganic semiconductor nano-structures as electromagnetic interference (EMI) shielding materials have been scarcely researched. Herein, we have designed hollow Cu1.8S nano-cubes via a mild anion exchange and etching process. These 30 wt% hollow Cu1.8S nano-cubes loaded in wax can display 30 dB of EMI shielding effectiveness (SE) in the whole tested frequency range of 2-18 GHz with a sample thickness of only 1 mm. This good EMI shielding performance can be attributed to the high electric conductivity, which leads to a high dielectric constant. This research opens up the possibility for the applications of inorganic semiconductor nano-structures as lightweight EMI shielding materials, especially in the areas of aerospace, automobile and sophisticated electronics. PMID- 28737782 TI - Ferrocene-cinchona hybrids with triazolyl-chalcone linkers act as pro-oxidants and sensitize human cancer cell lines to paclitaxel. AB - Recently, we demonstrated that ferrocene-containing compounds with a cinchona moiety displayed marked anticancer activity. Here we report on the effects of the most promising isomers encompassing quinine- (compounds 4 and 5) and quinidine epimers (compounds 6 and 7) - synthesized using improved methods providing controlled diastereoselectivity - in three different human multidrug resistant (MDR) cancer cell lines and their sensitive counterparts (non-small cell lung carcinoma NCI-H460/R/NCI-H460, colorectal carcinoma DLD1-TxR/DLD1 and glioblastoma U87-TxR/U87). We observed that the presence of the MDR phenotype did not diminish the activity of the compounds suggesting that ferrocene quinine- and quinidine-epimers are not substrates for P-glycoprotein, which has been indicated as a major mechanism of MDR in the cell lines used. Considering that metal-based anticancer agents mainly act by increasing ROS production, we investigated the potential of ferrocene-quinidine epimers to generate ROS. We found that 6 and 7 more readily increased ROS production and induced mitochondrial damage in MDR cancer cells. According to cell death analysis, 6 and 7 were more active against MDR cancer cells showing collateral sensitivity. In addition, our data suggest that these compounds could act as inhibitors of autophagy. Importantly, simultaneous treatments of 6 and 7 with paclitaxel (PTX) increased the sensitivity of MDR cancer cells to PTX. In conclusion, the ferrocene-quinidine epimers, besides being selective towards MDR cancer cells, could also possess potential to overcome PTX resistance. PMID- 28737783 TI - Fluorination-enriched electronic and magnetic properties in graphene nanoribbons. AB - The feature-rich electronic and magnetic properties of fluorine-doped graphene nanoribbons are investigated by the first-principles calculations. They arise from the cooperative or competitive relations among the significant chemical bonds, finite-size quantum confinement and edge structure. There exist C-C, C-F, and F-F bonds with multi-orbital hybridizations. Fluorine adatoms can create p type metals or concentration- and distribution-dependent semiconductors, depending on whether the pi bonding is seriously suppressed by the top-site chemical bonding. Furthermore, five kinds of spin-dependent electronic and magnetic properties cover the non-magnetic and ferromagnetic metals, non-magnetic semiconductors, and anti-ferromagnetic semiconductors with/without spin splitting. The diverse essential properties are clearly revealed in the spatial charge distribution, spin density, and orbital-projected density of states. PMID- 28737785 TI - How to obtain Pt(iv) complexes suitable for conjugation to nanovectors from the oxidation of [PtCl(terpyridine)]. AB - Oxidation of [Pt(II)Cl(terpy)]+ (terpy = 2,2':6',2''-terpyridine) has been attempted with several oxidizing agents and under different experimental conditions in order to obtain a Pt(iv) complex suitable for the conjugation to nanovectors to be used in drug delivery targeting for anticancer therapy. The best compromise in terms of yield and purity of the final complex was obtained by microwave-assisted reaction at 70 degrees C in 50% aqueous H2O2 for 2 h. Under these conditions the quantitative formation of [Pt(IV)Cl(OH)2(terpy)]+ was observed. The subsequent synthetic steps were, (i) functionalization of [Pt(IV)Cl(OH)2(terpy)]+ in the axial position with succinic anhydride to obtain [Pt(IV)Cl(OH)(succinato)(terpy)]+ and (ii) reaction of the latter with nonporous silica nanoparticles (SNPs) with an external shell containing primary amino groups to obtain a nanovector able to transport the Pt(iv) antitumor prodrug in the form of a conjugate Pt-SNP. Finally, the antiproliferative activity and cell accumulation of [Pt(II)Cl(terpy)]+, [Pt(IV)Cl(OH)2(terpy)]+, and the Pt-SNP conjugate were measured on three cancer cell lines. Despite highly effective accumulation of Pt-SNP in cells, a modest increase in activity was observed with respect to the molecular species. Further experiments showed that the Pt-SNP conjugate can release [Pt(II)Cl(terpy)]+ upon reduction, but this metabolite may undergo hydrolysis, and the resulting aquo complex could coordinate once again the free amino groups of the SNPs. In the resulting tetraamine form, the Pt(ii) complex conjugated to the SNPs cannot completely perform its antiproliferative activity. PMID- 28737786 TI - Fluorescence emission originated from the H-aggregated cyanine dye with chiral gemini surfactant assemblies having a narrow absorption band and a remarkably large Stokes shift. AB - We demonstrate that the fluorescence emission that originated from a cyanine dye forming H-aggregates with a narrow absorption band and a remarkably large Stokes shift can be induced by symmetry breaking. The H-aggregate formation was successfully induced using chirally assembled cationic gemini surfactants with enantiomeric tartrate counterions as templates in water. PMID- 28737787 TI - Coming full circle: constructing a [Gd6] wheel dimer by dimer and the importance of spin topology. AB - The syntheses, structures, magnetic and thermodynamic properties of three related triethanolamine-based GdIII complexes are described. The smallest, a dimer ([Gd2]), can be viewed as the subunit from which the two larger complexes, a linear tetramer ([Gd2]2) and a cyclic hexamer ([Gd2]3), are composed by further deprotonation of the triethanolamine ligand. In all cases, nearest neighbour magnetic ions are weakly correlated by antiferromagnetic isotropic exchange, whose strength does not change significantly from one complex to another; J ranging from -0.10 to -0.13 cm-1. Therefore, rather than the strength of the coupling, it is the spin topology that is the dominant factor in determining the differences between the physical properties - specifically, the nuclearity and the transition from open (dimer and tetramer) to cyclic (hexamer) boundary conditions. Indeed the hexanuclear wheel reaches the continuum limit of classical Heisenberg spin chains. In terms of the magnetocaloric properties, the smaller the nuclearity, the larger the magnetic entropy and adiabatic temperature changes. PMID- 28737788 TI - A multiscale agent-based framework integrated with a constraint-based metabolic network model of cancer for simulating avascular tumor growth. AB - In recent years, many efforts have been made in the field of computational modeling of cancerous tumors, in order to obtain a better understanding and predictions of their growth patterns. Furthermore, constraint-based modeling of metabolic networks has become increasingly popular, which is appropriate for the systems-level reconstruction of cell physiology. The goal of the current study is to integrate a multiscale agent-based modeling framework with a constraint-based metabolic network model of cancer cells in order to simulate the three dimensional early growth of avascular tumors. In order to develop the integrated model, a previously published generic metabolic network model of cancer cells was introduced into a multiscale agent-based framework. This model is initiated with a single tumor cell. Nutrients can diffuse through the simulation space and the cells uptake or excrete metabolites, grow, proliferate or become necrotic based on certain defined criteria and flux values of particular reactions. The simulation was run for a period of 20 days and the plots corresponding to various features such as the growth profile and necrotic core evolution were obtained. These features were compared with the ones observed in other (experimental) studies. One interesting characteristic of our modeling is that it provides us with the ability to predict gene expression patterns through different layers of a tumor, which can have important implications, especially in drug target selection in the field of cancer therapy. PMID- 28737789 TI - A model for the effect of bulk liquid viscosity on cavitation bubble dynamics. AB - A new model of single cavitation bubble dynamics has been developed to include the effect of bulk liquid viscosity in addition to the effects of evaporation/condensation of water vapor, thermal conduction and the compressibility of a liquid. In this study, the liquid viscosity is divided into two parts: viscosity at the bubble interface (MU') and viscosity of the bulk liquid (MU). A set of numerical calculations with and without MU has been completed under different viscosities (0.001-0.014 Pa s) to quantitatively analyze the effect of MU on single cavitation bubble dynamics. The results show that the effect can be negligible for small viscosities, but it should be taken into account for relatively high viscosities. PMID- 28737790 TI - Tuning the gap of lead-based halide perovskites by introducing superalkali species at the cationic sites of ABX3-type structure. AB - We study with scalar relativistic density functional theory (DFT) calculations the effect of changes in the ionicity of the bonding mechanism and charge donation on the structure and electronic properties of new lead halide perovskites which show promising performance in optoelectronic applications as long-wave infrared detectors and thermoelectrics. Our results provide evidence that the band gap of these compounds can be tuned upon the introduction of appropriate superalkali moieties at the cationic A-sites in the CsPbI3-type structure. The computed band gap is 0.36 eV (direct) and 0.41 eV (indirect) for [Li3O]PbI3 and [Li3S]PbI3, respectively. By changing the chemical environment in the Pb-halide perovskite structure, we see drastic changes in the shape of both valence and conduction bands, as compared to CsPbI3. Introducing superalkali cations produces extra electronic states close to the Fermi level which arise from the formation of delocalized energy states, where a strong hybridization is identified between Pb and Li s-states near the top of the valence band. This can promote the hole mobility and increase the exciton diffusion length at longer wavelengths. Berry phase calculations show rather significant spontaneous polarization of 34 and 15 MUC cm-2 along the x-axis in both [Li3O]PbI3 and [Li3S]PbI3, indicative of ferroelectric behavior. PMID- 28737791 TI - Aqueous ionic liquids and their influence on peptide conformations: denaturation and dehydration mechanisms. AB - Low concentrated aqueous ionic liquids (ILs) and their influence on protein structures have attracted a lot of interest over the last few years. This can be mostly attributed to the fact that aqueous ILs, depending on the ion species involved, can be used as protein protectants or protein denaturants. Atomistic molecular dynamics (MD) simulations are performed in order to study the influence of different aprotic ILs on the properties of a short hairpin peptide. Our results reveal distinct binding and denaturation effects for 1-ethyl-3 methylimidazolium (EMIM) in combination with different anions, namely, chloride (CL), tetrafluoroborate (BF4) and acetate (ACE). The simulation outcomes demonstrate that the studied ILs with larger anions reveal a more pronounced accumulation behavior of the individual ion species around the peptide, which is accomplished by a stronger dehydration effect. We can relate these findings to the implications of the Kirkwood-Buff theory, which provides a thermodynamic explanation for the denaturation strength in terms of the IL accumulation behavior. The results for the spatial distribution functions, the binding energies and the local/bulk partition coefficients are in good agreement with metadynamics simulations in order to determine the energetically most stable peptide conformations. The free energy landscapes indicate a decrease of the denaturation strength in the order EMIM/ACE, EMIM/BF4 and EMIM/CL, which coincides with a decreasing size of the anion species. An analysis of the potential binding energies reveals that this effect is mainly of enthalpic nature. PMID- 28737792 TI - Ferromagnetic resonance of NiCoFe2O4 nanoparticles and microwave absorption properties of flexible NiCoFe2O4-carbon black/poly(vinyl alcohol) composites. AB - The effect of cationic disorder and particle morphology on the ferromagnetic resonance (FMR) of NiCoFe2O4 nanoparticles (NPs) and the electromagnetic shielding effectiveness of flexible composites (wherein the nanoparticles are used as fillers) has been presented. Upon annealing at 1000 degrees C, spherical, ~25 nm, single crystalline (as-prepared) NPs are transformed into octahedral, ~200 nm, polycrystalline (annealed) NPs and change the cationic distribution significantly. The effect of shape, size and cationic distribution on the resonance properties has been discussed using the randomly-oriented anisotropic-axis model. The temperature dependent evolution of FMR spectra has been found to be consistent with a Bloch spin-relaxation model. Analysis of the FMR spectra reveals that NiCoFe2O4 nanoparticles have a large internal magnetic field along with broad FMR linewidths of ~2-3 kOe, signifying high magnetic losses that are essential for the absorption of electromagnetic (EM) waves. Next, NiCoFe2O4-carbon black (NCF-CB) hybrids grafted in a PVA matrix, as flexible composite films with a thickness of ~1.5 mm, are assessed for EM wave absorption properties in the range of 8-18 GHz. As compared to annealed-NCF-CB/PVA (21 dB, ~99.5%), the as-prepared-NCF-CB/PVA composite film exhibits significantly large SE of 27 dB (~99.9% attenuation of the EM wave), with a dominant contribution from absorption (SEA ~ 21 dB). The electrical conductivity, the electric modulus, and Cole-Cole plots reveal that the dielectric losses in the as-prepared-NCF CB/PVA have significant contributions from cationic disorder and particle size, as compared to the annealed-NCF-CB/PVA composites. Cationic disorder increases the d-d electron transition probability between adjacent ionic pairs such as Co2+/Fe3+ and a reduced particle size creates large interfacial polarization in the as-prepared NCF/CB hybrids. Considerably large values of the Landes g-factor, magnetic anisotropy and better impedance matching indicate a dominant magnetic loss contribution in ap-NCF (g = 4.5) as compared to an-NCF (g = 2.5) at 300 K. PMID- 28737793 TI - Asymmetric synthesis of isoquinolinonaphthyridines catalyzed by a chiral Bronsted acid. AB - A catalytic asymmetric method for the synthesis of chiral isoquinolinonaphthyridines has been developed. A chiral disulfonimide catalyzes a redox cyclization reaction between 2-methyl-3-aldehydeazaarenes and 1,2,3,4 tetrahydroisoquinolines to deliver a range of isoquinolinonaphthyridines with good to high yields (up to 91%) and up to 92 : 8 er. PMID- 28737794 TI - Heterogeneous enantioselective synthesis of chromans via the oxa-Michael-Michael cascade reaction synergically catalyzed by grafted chiral bases and inherent hydroxyls on mesoporous silica surface. AB - A heterogeneous enantioselective oxa-Michael-Michael reaction for the synthesis of chromans has been developed on a heterogeneous acid-base synergic catalyst with inherent silica as acidic sites and immobilized chiral amines as basic sites. Final products were afforded in selectivity of up to 98% and ee of 97% from 2-nitrovinyl phenol and 3-methyl-2-butenal. The heterogeneous synergistic catalytic mechanism has also been studied. PMID- 28737795 TI - A DNA nanoribbon as a potent inhibitor of metallo-beta-lactamases. AB - We discovered a promising metallo-beta-lactamase inhibitor, a DNA nanoribbon, by enzymatic kinetics and isothermal titration calorimetry evaluations. Atomic force microscopy, gel electrophoresis, competitive binding experiments, circular dichroic and thermal denaturation studies suggested that the DNA nanoribbon could bind to the enzyme through a minor groove. PMID- 28737797 TI - Cation distribution dependent magnetic properties in CoCr2-xFexO4 (x = 0.1 to 0.5): EXAFS, Mossbauer and magnetic measurements. AB - In this report, we have examined the evolution of the structure and rich magnetic transitions such as a paramagnetic to ferrimagnetic phase transition at the Curie temperature (TC), spiral ordering temperature (TS) and lock-in temperature (TL) observed in the CoCr2O4 spinel multiferroic after substituting Fe. The crystal structure, microstructure and cation distribution among the tetrahedral (A) and octahedral (B) sites in the spinel lattice are characterised by X-ray diffraction, transmission electron microscopy, Extended X-ray Absorption Fine Structure (EXAFS) and Mossbauer spectroscopy. Due to the same radial distances of the first coordination shell in both tetrahedral and octahedral environments observed in EXAFS spectra, the position of the second coordination shell specifies the preference of more Fe ions towards the A site at x = 0.1. At x = 0.5, more Fe ions favour the B site. The cation distribution quantitatively obtained from the Mossbauer spectral analysis shows that while 60% of Fe ions occupy the A site in x = 0.1, 40% occupy it in x = 0.5. Surprisingly at x = 0.3, Fe ions are distributed equally among the A and B sites. dc magnetization reveals an increase in TC from 102 K to 200 K and in TS from 26 to 40 K with an increase in Fe concentration, indicating an enhancement in A-B exchange interaction at the expense of B-B. No report has until now demonstrated such an enhancement in TS either in pure or in doped CoCr2O4. Furthermore, frequency-dependent ac susceptibility (chi) data fitted with different phenomenological models such as the Neel-Arrhenius, Vogel-Fulcher and power law confirm a spin-glass and/or cluster-glass behaviour in nanoparticles of CoCr2-xFexO4. PMID- 28737798 TI - Correction: Breath figure in non-aqueous vapor. AB - Correction for 'Breath figure in non-aqueous vapor' by Jianyun Ding et al., Soft Matter, 2013, 9, 506-514. PMID- 28737799 TI - Slow magnetic relaxation in five-coordinate spin-crossover cobalt(ii) complexes. AB - We present the first examples of the coexistence of field induced slow magnetic relaxation and spin-crossover observed in five-coordinate cobalt(ii) complexes [Co(12-TMC)(CH3CN)](X)2 (12-TMC = 1,4,7,10-tetramethyl-1,4,7,10 tetraazacyclododecane, X = BF4-, 1; PF6-, 2). The direct-current (dc) magnetic data show a gradual and incomplete spin-crossover at high temperature. 1 and 2 display frequency- and temperature-dependent alternating-current (ac) magnetic susceptibility under an applied dc field of 2500 Oe, which originates from the S = 1/2 spin state of Co(ii) ions. PMID- 28737800 TI - C-H addition reactivity of 2-phenylpyridine and 2,2'-bipyridine with pentaphenylborole. AB - The reactions of pentaphenylborole with pyridines with a pendent aryl group in the 2-position, specifically 2-phenylpyridine and 2,2'-bipyridine, readily afforded adducts. Upon thermolysis, the adducts converted to ortho C-H addition products with the two substituents introduced onto the diene on the boracyclic carbon atoms adjacent to boron in a syn fashion. Photolysis of the syn 2 phenypyridine product led to isomerization to the anti conformer which did not readily occur for the 2,2'-bipyridine complex. Such C-H bond reactivity is uncommon for main group elements and provides insight into methodologies to access boron frameworks. PMID- 28737801 TI - Optical properties and mechanofluorochromism of new BODIPY dyes based on the pyridine-pyrimidine hybrid structure. AB - A new family of BODIPY dyes (PPB1-4) based on the pyridine-pyrimidine hybrid structure has been synthesized. These dyes show high cyan fluorescence in hexane with quantum yields (Phif) ranging from 0.33 to 0.90. Interestingly, moderate fluorescence of PPB1-4 is observed in the solid state (Phif, 0.11-0.26). X-ray structure analysis demonstrates that H-aggregation should be responsible for the red-shifted and quenched emission in the solid state. Moreover, PPB1-4 show high contrast and reversible mechanochromic fluorescence based on the proposed mechanism of mechanical stimuli triggered dimer dissolution and formation. In addition, rewritable mechanochromic fluorescence recording media fabricated with PPB4 have been successfully achieved. PMID- 28737802 TI - Accurate prediction of energetic properties of ionic liquid clusters using a fragment-based quantum mechanical method. AB - Accurate prediction of physicochemical properties of ionic liquids (ILs) is of great significance to understand and design novel ILs with unique properties. This study employed the electrostatically embedded generalized molecular fractionation (EE-GMF) method for accurate energy calculation of IL clusters. The accuracy and efficiency of the EE-GMF method are systematically assessed at different ab initio levels (including HF, DFT and MP2) with diverse basis sets. With the fixed charge model for the embedding field, the deviations of the EE-GMF approach from conventional full system calculations are within 2.58 kcal mol-1 for all IL clusters with up to 30 ion pairs (720 atoms), tested in this study. Moreover, this linear-scaling fragment quantum mechanical (QM) method can significantly reduce the total computational cost for post-HF methods. The EE-GMF approach is well-suited for studying the energetic, structural and dynamical properties of ILs using high-level ab initio theories. PMID- 28737803 TI - Concerted transfer of multiple protons in acid-water clusters: [(HCl)(H2O)]2 and [(HF)(H2O)]4. AB - Molecular dynamics simulations using directly ab initio potentials are carried out for the ionically bonded clusters [(Cl-)(H3O+)]2 and [(F-)(H3O+)]4 to explore their transitions to the hydrogen-bonded [(HCl)(H2O)]2 and [(HF)(H2O)]4 structures during the first picosecond of simulation. Both the ionic and the H bonded structures that are formed are highly symmetric. It is found that proton transfers are concerted in all trajectories for [(Cl-)(H3O+)]2. For [(F )(H3O+)]4, the fully concerted mechanism is dominant but partially concerted transfers of two or three protons at the same time also occur. The concerted mechanism also holds for the reverse process of ionization of neutral acid molecules. It is suggested that the high symmetry of the ionic and the H-bonded structures plays a role in the preference for concerted transfers. Possible implications of the results for proton transfers in other systems are discussed. PMID- 28737804 TI - Modulation of in:out and out:out conformations in [X.X'.X''] phosphatranes by Lewis acids. AB - A theoretical study of [X.X'.X'']phosphatrane:Lewis acid complexes has been carried out in order to analyze how the in:out and out:out conformations can be modulated by the interaction with Lewis acids (LA). It has been found that in:out structures are more stable in larger systems i.e. in [4.4.3]:LA and [4.4.4]:LA than in [3.3.3]:LA and [4.3.3]:LA. The results obtained for the relative energies in conjunction with electron density properties showed that upon complexation, in:out conformers become more stable with the increasing acidity of the corresponding Lewis acid. In fact, the binding energies found for in:out complexes are larger than those obtained for out:out complexes. The complexes with the largest relative energy favoring the in:out structure correspond to those with charged Lewis acids, followed by the complexes with ClF. In all cases, the complexes are cooperative, reaching a maximum value of 168.5 kJ mol-1 for the [4.3.3]:F+ complex. PMID- 28737805 TI - Nonhelical heterometallic [Mo2M(npo)4(NCS)2] string complexes (M = Fe, Co, Ni) with high single-molecule conductance. AB - Using the planar 1,8-naphthyridin-2(1H)-one (Hnpo) ligand, novel nonhelical HMSCs [Mo2M(npo)4(NCS)2] (M = Fe, Co, Ni) were synthesised and they exhibited high single-molecule conductance. PMID- 28737806 TI - Whole blood Fe isotopic signature in a sub-Saharan African population. AB - The Fe isotopic composition of an individual's whole blood has recently been shown to be an interesting clinical indicator of Fe status. The present study aimed to evaluate the influence of several endemic characteristics of a representative population of the South Kivu province, an Fe-rich volcanic African region, on the whole blood Fe isotopic composition. Both diabetes mellitus and the ferroportin Q248H mutation are very common in Africa and are strongly associated with impairments in Fe metabolism. Fe isotopic analysis of whole blood samples was carried out using multi-collector inductively coupled plasma-mass spectrometry (after chromatographic isolation of the target element). Forty-two male subjects (between 48 and 59 years old) living in Bukavu (South Kivu) were enrolled in this study. Among the selected population, wild-type subjects and subjects presenting the ferroportin Q248H mutation (heterozygotes and homozygotes) were included. Within each group, diabetic and non-diabetic patients were considered. The whole blood delta56Fe value ranged from -3.090/00 to 2.410/00. The delta56Fe value shows a significant negative correlation with the ferritin concentration. No correlation could be established between the whole blood delta56Fe value and the transferrin concentration, transferrin saturation or serum Fe concentration. The ferroportin Q248H mutation did not seem to have affected the whole blood Fe isotopic signature. The whole blood delta56Fe values were significantly higher in diabetic subjects than in non-diabetic subjects and showed a significant negative correlation with body mass index (BMI) values. PMID- 28737807 TI - NPY binds with heme to form a NPY-heme complex: enhancing peroxidase activity in free heme and promoting NPY nitration and inactivation. AB - Neuropeptide Y (NPY) is a member of the pancreatic peptide family of neuropeptides that play a crucial role in numerous central and peripheral nervous system responses. Recently, it has been shown that NPY protects cells against neurotoxic damage from beta-amyloid peptides (Abeta) in Alzheimer's disease (AD). Heme is a common factor linking several metabolic perturbations in AD and altered heme metabolism has been shown to be related to the pathologies of AD. Thus, heme may have a chance to act on NPY and potentially counteract its function. To explore this, UV-visible spectroscopy, fluorescence spectroscopy and differential pulse voltammetry (DPV) were used to demonstrate that NPY can bind with heme to form a NPY-heme complex and the binding enhances the peroxidase activity of heme. Dot blotting results indicate that NPY is easily nitrated upon binding with heme when H2O2 and NO2- are present. Furthermore, LC-MS/MS results confirm that tyrosine36 (Tyr36), an important amino acid residue of NPY in binding and activating neuropeptide receptors, can be nitrated during the nitration process. Thereafter, we used mutant peptide NPY(3N) (Tyr36 replaced by 3-nitrotyrosine) to investigate the impact of nitration on the structure and bioactivity of the peptide. Our results show that Tyr36 nitration destabilizes the alpha-helix conformation of the peptide, and counteracts NPY-induced inhibition of cAMP accumulation in SK-N-MC cells. Collectively, these data imply that the self association of NPY with heme potentially induces tyrosine nitration, destroys the active monomeric conformation of the peptide and thereby counteracts its bioactivity. PMID- 28737808 TI - Full-spectrum volumetric solar thermal conversion via photonic nanofluids. AB - Volumetric solar thermal conversion is an emerging technique for a plethora of applications such as solar thermal power generation, desalination, and solar water splitting. However, achieving broadband solar thermal absorption via dilute nanofluids is still a daunting challenge. In this work, full-spectrum volumetric solar thermal conversion is demonstrated over a thin layer of the proposed 'photonic nanofluids'. The underlying mechanism is found to be the photonic superposition of core resonances, shell plasmons, and core-shell resonances at different wavelengths, whose coexistence is enabled by the broken symmetry of specially designed composite nanoparticles, i.e., Janus nanoparticles. The solar thermal conversion efficiency can be improved by 10.8% compared with core-shell nanofluids. The extinction coefficient of Janus dimers with various configurations is also investigated to unveil the effects of particle couplings. This work provides the possibility to achieve full-spectrum volumetric solar thermal conversion, and may have potential applications in efficient solar energy harvesting and utilization. PMID- 28737809 TI - Hybrid density functional theory modeling of Ca, Zn, and Al ion batteries using the Chevrel phase Mo6S8 cathode. AB - Hybrid density functional theory (DFT) is used to study the Chevrel phase Mo6X8 (X = S, Se, Te) as a promising cathode material intercalated with various metal ions (M = Li, Na, Be, Mg, Ca, Sr, Ba, Zn, Al). Electronic properties and voltages are calculated for each case. Ca ions are predicted to produce a voltage output ranging from 1.8-2.1 V, comparable to the voltage calculated for Li ions while providing two electrons per transferred ion. The highest voltage is determined to result when the chalcogen X in Mo6X8 is S, over Se or Te. Additionally, a comparison of the local-density approximation (LDA), the Perdew-Burke-Ernzerhof (PBE), the Hubbard U corrected GGA-PBE (PBE+U), the meta-GGA modified Becke Johnson (mBJ), and the hybrid Heyd-Scuseria-Ernzerhof (HSE) functionals are made. The electronic structure determined with HSE is taken as the most reliable, and PBE and LDA can provide reasonable approximations. The PBE+U approach yields an erroneous band gap and should be avoided. The voltages calculated with HSE are in excellent agreement with available experimental data. PMID- 28737810 TI - Ionic diffusion and proton transfer in aqueous solutions of alkali metal salts. AB - We report on a series of ab initio molecular dynamics investigations on LiCl, NaCl, and KCl aqueous solutions under the effect of static electric fields. We have found that although in low-to-moderate field intensity regimes the well known sequence of cationic mobilities MU(K+) > MU(Na+) > MU(Li+) (i.e., the bigger the cation the higher the mobility) is recovered, from intense field strengths this intuitive rule is no longer verified. In fact, field-induced water molecular dissociations lead to more complex phenomena regulating the standard migration properties of the simplest monovalent cations. The water dissociation threshold is lowered from 0.35 V A-1 to 0.25 V A-1 by the presence of charged species in all samples. However, notwithstanding a one-stage process of water ionization and proton conduction takes place at 0.25 V A-1 in the electrolyte solutions where "structure maker" cations are present (i.e., LiCl and NaCl), the KCl aqueous solution shows some hindrance in establishing a proton conductive regime, which is characterized by the same proton conduction threshold of neat water (i.e., 0.35 V A-1). In addition, it turns out that protons flow easily in the LiCl (sigmap = 3.0 S cm-1) solution and then - in descending order - in the NaCl (sigmap = 2.5 S cm-1) and KCl (sigmap = 2.3 S cm-1) electrolyte solutions. The protonic conduction efficiency is thus inversely proportional to the ionic radii of the cations present in the samples. Moreover, Cl- anions act as a sort of "protonic well" for high field intensities, further lowering the overall proton transfer efficiency of the aqueous solutions. As a consequence, all the recorded protonic conductivities are lower than that for neat water (sigmap = 7.8 S cm-1), which strongly indicates that devices exploiting the proton transfer ability should be designed so as to minimize the presence of ionic impurities. PMID- 28737811 TI - Extremely low catalyst loading for electroless deposition on a non-conductive surface by a treatment for reduced graphene oxide. AB - Enhancement of electroless deposition using reduced-graphene-oxide (rGO) coating for a conductive surface on the non-conductive substrate is proposed and demonstrated. We confirmed that the rGO treatment enhanced the Pd catalytic activity and achieved a sufficient rate in electroless deposition with extremely low Pd loading (3.94 * 10-2 MUg cm-2). PMID- 28737812 TI - A DFT mechanistic study of the organocatalytic asymmetric reaction of aldehydes and homophthalic anhydride. AB - The first DFT study of the cycloaddition of benzaldehyde with homophthalic anhydride under the influence of a bifunctional organocatalyst is reported. The catalyst first binds and then deprotonates the anhydride, leading to a squaramide bound enolate, which then adds to the aldehyde with activation of the electrophile by the catalyst's ammonium ion. PMID- 28737813 TI - The synthesis of CuyMnzAl1-zOx mixed oxide as a low-temperature NH3-SCR catalyst with enhanced catalytic performance. AB - A new type of low-temperature selective catalytic reduction (SCR) catalyst, CuyMnzAl1-zOx, derived from layered double hydroxides is presented in this contribution. By tuning the Cu/Mn/Al ratio, the optimal catalyst Cu2Mn0.5Al0.5Ox resulted in a NOx conversion of 91.2% at 150 degrees C, which is much higher than that of all other control catalysts, Cu2AlOx (71.1%), Cu-Mn/gamma-Al2O3 (65.23%), and Mn/gamma-Al2O3 (59.32%). All samples were characterized in detail using various physico-chemical techniques including XRD, BET, FTIR, TEM, H2-TPR, NH3-TPD, and XPS analyses, and the results revealed that the superior catalytic performance of the Cu2Mn0.5Al0.5Ox catalyst can be attributed to its high specific surface area, high reducibility of MnO2 and CuO species, abundance of surface acid sites, and the good dispersion of MnO2 and CuO species. FTIR analyses of pyridine adsorbed samples revealed that the catalytic activity is proportional to the amount of Lewis acid sites. Cu2Mn0.5Al0.5Ox also showed much higher resistance to 100 ppm SO2 and 5% H2O than the control catalysts. The poisoning mechanism and the regenerability of the Cu2Mn0.5Al0.5Ox catalyst was also investigated. In all, compared with the control catalysts of Cu2AlOx, Cu Mn/gamma-Al2O3, and Mn/gamma-Al2O3, the newly designed Cu2Mn0.5Al0.5Ox catalyst is not only more active at low temperatures (100-250 degrees C), but is also relatively more robust in the presence of SO2 and H2O. PMID- 28737814 TI - Synthesis and characterization of 1'-(diphenylphosphino)-1-isocyanoferrocene, an organometallic ligand combining two different soft donor moieties, and its Group 11 metal complexes. AB - The development of a practical synthesis of 1'-(diphenylphosphino)-1 aminoferrocene (2) and its P-borane adduct (2B) allowed the facile preparation of 1'-(diphenylphosphino)-1-isocyanoferrocene (1). This compound combining two specific soft-donor moieties was studied as a ligand for univalent Group 11 metal ions. The reactions of 1 with AgCl at 1 : 1 and 2 : 1 molar ratios only led to the coordination polymer [Ag2(MU-Cl)2(MU(P,C)-1)]n (6), while those with Ag[SbF6] provided the dimer [Ag2(Me2CO-kappaO)2(MU(P,C)-1)2][SbF6]2 and the quadruply bridged disilver complex [Ag2(MU(P,C)-1)4][SbF6]2 (8), respectively. Addition of 1 to [AuCl(tht)] (tht = tetrahydrothiophene) afforded the mono- and the digold complex, [AuCl(1-kappaP)] (9) and [(MU(P,C)-1)(AuCl)2] (10), depending on the reaction stoichiometry. Finally, the reaction of 1 with [Au(tht)2][SbF6] or halogenide removal from 9 with AgNTf2 led to cationic dimers [Au2(MU(P,C)-1)2]X2 (11, X = SbF6 (a) or NTf2 (b)). Catalytic tests in the Au-mediated isomerization of (Z)-3-methylpent-2-en-4-yn-1-ol to 2,3-dimethylfuran revealed that 11a and 11b are substantially less catalytically active than their analogues containing 1' (diphenylphosphino)-1-cyanoferrocene as the ligand, most likely due to a stronger coordination of the isonitrile moiety, which prevents dissociation of the dimeric complexes into catalytically active monomeric species. PMID- 28737815 TI - Isofraxidin, a coumarin component improves high-fat diet induced hepatic lipid homeostasis disorder and macrophage inflammation in mice. AB - Isofraxidin (IF) is a coumarin compound produced in the functional foods Siberian ginseng and Apium graveolens. The first objective of this study was to investigate the protective effects and putative methods of IF in combating lipotoxicity in vitro and in vivo. Oleic acid was used to induce lipid turbulence in human hepatoma cells (HepG2). Alterations in triglyceride metabolism, inflammation and oxidative status were monitored. Results show that IF mainly reduced triglyceride accumulation, TNF-alpha release and ROS activation in metabolic disordered cells. Next, a high-fat diet, which induced a non-alcoholic fatty liver disease, was used to evaluate the therapeutic action of IF. Our results show that treatment with IF significantly inhibited the high-fat diet induced elevation in body weight, liver weight, lipid metabolism (TG, TC and HDL C) and hepatic injury in mice. In biochemical terms, treatment with IF resulted in enhanced phosphorylation of AMPKalpha and ACC, as well as reduced hepatic expression of FAS and HMGC, suggesting that lipogenesis was compromised. We also found robust evidence that treatment with IF significantly depleted infiltrating inflammatory cells (F4/80+ Kupffer cells and CD68+ macrophages) and inflammatory cytokine release (TNFalpha and IL-6). Moreover, the anti-inflammatory activity in IF-treated hepatic tissue correlated with down-regulation of TLR4 expression and NF-kappaB transcription. In sum, these results suggest that IF might play a protective role against lipid metabolism disorder induced by a high-fat diet via inhibition of lipid production and inflammation in the liver. PMID- 28737816 TI - Protein stability and dynamics influenced by ligands in extremophilic complexes - a molecular dynamics investigation. AB - In this study, we explore the structural and dynamic adaptations of the Tryptophan synthase alpha-subunit in a ligand bound state in psychrophilic, mesophilic and hyperthermophilic organisms at different temperatures by MD simulations. We quantify the global and local fluctuations in the 40 ns time scale by analyzing the root mean square deviation/fluctuations. The distinct behavior of the active site and loop 6 is observed with the elevation of temperature. Protein stability relies more on electrostatic interactions, and these interactions might be responsible for the stability of varying temperature evolved proteins. The paper also focuses on the effect of temperature on protein dynamics and stability governed by the distinct behavior of the ligand associated with its retention, binding and dissociation over the course of time. The integration of principle component analysis and a free energy landscape was useful in identifying the conformational space accessible to ligand bound homologues and how the presence of the ligand alters the conformational and dynamic properties of the protein. PMID- 28737818 TI - Di- vs. tetra-substituted quinonediimines: a drastic effect on coordination chemistry. AB - We describe the first isolation of N,N'-disubstituted benzoquinonediimines (QDIs) 2 which revealed drastically different properties compared to N,N',N'',N''' tetrasubstituted QDIs 1 due to the absence of N-substituents in the "upper part" of the molecule. Three major differences could be highlighted thanks to the present joint experimental and theoretical investigation: (1) the metalation with different metal precursors revealed a specific behaviour in coordination chemistry giving access to novel complexes with unprecedented stoichiometry and remarkable absorption properties. More specifically, a new monoplatinum complex that is able to absorb light from the UV up to the NIR region because of its unique delocalization pathway across the metal centre was obtained; (2) this new class of di-substituted QDIs showed an exceptionally broad pKa range (DeltapKa~ 8) that could be explained by the possible tuning of the basicity of each imine which is now attainable; (3) these quinones could be used as reagents in organic synthesis to form the previously unknown N,N',N'',N'''-tetrasubstituted QDIs with tuneable substituents (aryl vs. alkyl), previously unknown, as a new ligand for coordination chemistry. PMID- 28737819 TI - Insertion reactions of small unsaturated molecules in the N-B bonds of boron guanidinates. AB - We report here 1,1- and 1,2-insertion reactions of small unsaturated molecules in the N-B bonds of two boron guanidinates, (Me2N)C(NiPr)2BCy2 (1) and {iPr(H)N}C(NiPr){N(p-tBu-C6H4)}BCy2 (2), and two bisboron guanidinates(2-), {iPr(BCy2)N}C(NiPr){N(p-tBu-C6H4)}BCy2 (3) and {iPr(C8H14B)N}C(NiPr){N(p-Me C6H4)}BC8H14 (4), the latter being prepared for the first time by double deprotonation of the corresponding guanidine with the 9-borabicyclo[3.3.1]nonane dimer, (H-BC8H14)2. Compounds 1-4 easily insert aromatic isonitriles, XylNC (Xyl = 2,6-Me2-C6H3) and (p-MeO-C6H4)NC, to give the expected diazaboroles 5-12, some of them being structurally characterised by X-ray diffraction. Interestingly, the BC8H14 derivatives 11 and 12 are in a fast temperature-dependent equilibrium with the de-insertion products, whose thermodynamic parameters are reported here. A correlation between these equilibria and the puckered heterocyclic structure found in the solid state for 11, and confirmed by DFT calculations, is also established. Reactions of the aforementioned guanidinates with CO are more sluggish or even precluded, and only one product, {iPr(H)N}C{N(p-tBu C6H4)}(NiPr)(CO)BCy2 (13), could be isolated in moderate yields. The 1,2 insertions of benzaldehyde in compounds 1, 2 and 4 are reversible reactions in all cases, and only one of the insertion products, {iPr(H)N}C{N(p-tBu C6H4)}(NiPr)(PhHCO)BCy2 (16a), was isolated and diffractrometrically characterised. Likewise, CO2 reversibly inserts into a N-B bond of 2 to give {iPr(H)N}C{N(p-tBu-C6H4)}(NiPr)(CO2)BCy2 (19) with a conversion of ca. 9%. In all these equilibria, de-insertion is always favoured upon increasing the temperature. PMID- 28737820 TI - Effect of substrate concentrations on the aggregation behavior and dynamic oscillatory properties of self-oscillating block copolymers. AB - We developed a novel type of block copolymer, named the self-oscillating block copolymer, which exhibits autonomous assembly and disassembly driven by the dissipative structures formed by the oscillatory Belousov-Zhabotinsky (BZ) reaction. In a catalyst-free BZ solution, this polymer undergoes autonomous structural changes following the periodic redox changes of a metal catalyst incorporated into the polymer side chain. However, until now, a detailed study of the relationship between the dynamic structural changes and polymer solution conditions has not been conducted. We investigated the effect of substrate concentrations of the BZ reaction and the addition of salts on the equilibrium structures as well as the oscillatory properties of the self-oscillating block copolymers. We clarified that the substrate concentrations and the addition of specific salts significantly modulate dynamic assembly and disassembly of block copolymers. PMID- 28737821 TI - Structure and reactivity of [RuII(terpy)(N^N)Cl]Cl complexes: consequences for biological applications. AB - The crystal structures of [RuII(terpy)(bipy)Cl]Cl.2H2O and [RuII(terpy)(en)Cl]Cl.3H2O, where terpy = 2,2':6',2''-terpyridine, bipy = 2,2' bipyridine and en = ethylenediamine, were determined and compared to the structure of the complexes in solution obtained by multi-nuclear NMR spectroscopy in DMSOd-6 as a solvent. In aqueous solution, both chlorido complexes aquate fully to the corresponding aqua complexes, viz. [RuII(terpy)(bipy)(H2O)]2+ and [RuII(terpy)(en)(H2O)]2+, within ca. 2 h and ca. 2 min at 37 degrees C, respectively. The spontaneous aquation reactions can only be suppressed by chloride concentrations as high as 2 to 4 M, i.e. concentrations much higher than that found in human blood. The corresponding aqua complexes are characterized by pKa values of ca. 10 and 11, respectively, which suggest a more labile coordinated water molecule in the case of the [RuII(terpy)(en)(H2O)]2+ complex. Substitution reactions of the aqua complexes with chloride, cyanide and thiourea show that the [RuII(terpy)(en)(H2O)]2+ complex is 30-60 times more labile than the [RuII(terpy)(bipy)(H2O)]2+ complex at 25 degrees C. Water exchange reactions for both complexes were studied by 17O-NMR and DFT calculations (B3LYP(CPCM)/def2tzvp//B3LYP/def2svp and omegaB97XD(CPCM)/def2tzvp//B3LYP/def2svp). Thermal and pressure activation parameters for the water exchange and ligand substitution reactions support the operation of an associative interchange (Ia) process. The difference in reactivity between these complexes can be accounted for in terms of pi-back bonding effects of the terpy and bipy ligands and steric hindrance on the bipy complex. Consequences for eventual biological application of the chlorido complexes are discussed. PMID- 28737822 TI - Liquid crystal templating as an approach to spatially and temporally organise soft matter. AB - Chemistry quickly moves from a molecular science to a systems science. This requires spatial and temporal control over the organisation of molecules and molecular assemblies. Whilst Nature almost by default (transiently) organises her components at multiple different length scales, scientists struggle to realise even relatively straightforward patterns. In the past decades, supramolecular chemistry has taught us the rules to precisely engineer molecular assembly at the nanometre scale. At higher length scales, however, we are bound to top-down nanotechnology techniques to realise order. For soft, biological matter, many of these top-down techniques come with serious limitations since the molecules generally show low susceptibilities to the applied stimuli. A new method is based on liquid crystal templating. In this hierarchical approach, a liquid crystalline host serves as the scaffold to order polymers or assemblies. Being a liquid crystal, the host material can be ordered at many different length scales and on top of that, is highly susceptible to many external stimuli, which can even be used to manipulate the liquid crystal organisation in time. As a result, we anticipate large control over the organisation of the materials inside the liquid crystalline host. Recently, liquid crystal templating was also realised in water. This suddenly makes this tool highly applicable to start organising more delicate biological materials or even small organisms. We review the scope and limitations of liquid crystal templating and look out to where the technique may lead us. PMID- 28737823 TI - Overexpression of non-SMC condensin I complex subunit G serves as a promising prognostic marker and therapeutic target for hepatocellular carcinoma. AB - The non-SMC condensin I complex subunit G (NCAPG) that organizes the coiling topology of individual chromatids, represents an overexpressed antigen in various types of cancer, and also contributes to restructuring chromatin into rod-shaped mitotic chromosomes and ensuring the segregation of sister chromatid during cell division. In this study, we investigated the association between NCAPG expression and the biological behavior of hepatocellular carcinoma (HCC) to further explore the potential of NCAPG as a therapeutic target. The expression of NCAPG was detected in human HCC cell lines and tumor samples. The effects of NCAPG on the cell cycle, apoptosis and metastasis were investigated by various assays. NCAPG was found to be overexpressed in HCC compared with the adjacent normal tissue (P<0.001), and high levels of NCAPG expression were found to significantly correlate with recurrence, the time of recurrence, metastasis, differentiation and TNM stage. Furthermore, an elevated expression of NCAPG was associated with a poor overall survival (P<0.05). In addition, in vitro experiments further confirmed the ex vivo data; i.e., the knockdown of NCAPG expression reduced HCC cell viability, but induced apoptosis and arrested the cells at the S phase of the cell cycle. The knockdown of NCAPG expression also inhibited tumor cell migration and the cell invasive capacity in vitro. At the protein level, the knockdown of NCAPG expression upregulated Bax, cleaved caspase-3 and E-cadherin, but downregulated cyclin A1, CDK2, Bcl-2, N-cadherin and HOXB9 expression, suggesting that the knockdown of NCAPG expression suppressed tumor cell epithelial-mesenchymal transition. On the whole, this study demonstrates that NCAPG plays an important role in the development and progression of HCC, and that it may be a novel therapeutic target for patients with HCC. PMID- 28737824 TI - Inhibitory effects of 1,25(OH)2D3 on the proliferation of hepatocellular carcinoma cells through the downregulation of HDAC2. AB - The inhibitory effects of 1,25(OH)2D3 on the proliferation of a variety of cancer cell lines have been extensively reported. However, the underlying mechanisms remain largely unknown. In the present study, the effects of 1,25(OH)2D3 on the in vitro proliferation of human hepatocellular carcinoma HepG2 cells and the mechanism involved were investigated. Flow cytometry and MTT assay revealed that 1,25(OH)2D3 inhibited cell proliferation in vitro. Western blotting and real-time PCR indicated that 1,25(OH)2D3 upregulated the expression of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) and attenuated that of histone deacetylase 2 (HDAC2). Knockdown of HDAC2 completely mimicked the effects of 1,25(OH)2D3 on PTEN gene expression. The influence of 1,25(OH)2D3 on PTEN expression was reversed in the cells treated with a recombinant pEGFP-LV2-HDAC2 plasmid. Akt phosphorylation, which was downregulated by 1,25(OH)2D3 treatment, was promoted by HDAC2 overexpression. These findings revealed that 1,25(OH)2D3 inhibited cell growth possibly by HDAC2-mediated PTEN upregulation, Akt deactivation, and inhibition of the PI3K/Akt signaling pathway. PMID- 28737825 TI - Combination of rapamycin and garlic-derived S-allylmercaptocysteine induces colon cancer cell apoptosis and suppresses tumor growth in xenograft nude mice through autophagy/p62/Nrf2 pathway. AB - The natural plant-derived product S-allylmercapto-cysteine (SAMC) has been studied in cancer therapy as a single and combination chemotherapeutic agent. The present study was employed to verify the combination use of SAMC and rapamycin that is the mTOR inhibitor with anticancer ability but has limited efficacy due to drug resistance, and to explore the underlying mechanisms. We combined rapamycin and SAMC for colorectal cancer treatment in the HCT-116 cancer cells and a xenograft murine model. The in vivo study was established by xenografting HCT-116 cells in BALB/c nude mice. It was found that the combination therapy had enhanced tumor-suppressing ability with the upregulation of the Bax/Bcl-2 ratio as a consequence of activated apoptosis, inhibition of autophagic activity and prevention of Akt phosphorylation. The rapamycin and SAMC combination activated antioxidant transcription expressions of Nrf2 and downstream gene NQO1. Concomitantly, autophagosome cargo p62 was downregulated, indicating that the p62 played a negative-regulatory role between Nrf2 and autophagy. Our results show that the combination of SAMC and rapamycin enhanced the anticancer ability, which could be used for the treatment of colorectal cancer. The underling mechanism of autophagy/p62/Nrf2 pathway discovered may provide a new direction for drug development, especially for traditional Chinese medicines. PMID- 28737826 TI - Comparison of isolation methods of exosomes and exosomal RNA from cell culture medium and serum. AB - Exosomes are cell-derived vesicles and are abundant in biological fluids; they contain RNA molecules which may serve as potential diagnostic biomarkers in 'precision medicine'. To promote the clinical application of exosomal RNA (exoRNA), many isolation methods must be compared and validated. Exosomes in cell culture medium (CCM) and serum may be isolated using ultracentrifugation (UC), ExoQuick or Total Exosome Isolation Reagent (TEI), and exoRNA may be extracted using TRIzol-LS, SeraMir, Total Exosome RNA Isolation (TER), HiPure Liquid RNA/miRNA kit (HLR), miRNeasy or exoRNeasy. ExoRNA was assessed using NanoDrop, Bioanalyzer 2100, quantitative polymerase chain reaction and high-throughput sequencing. UC showed the lowest recovery of particles, but the highest protein purity for exosome isolation. For isolation of exoRNA, we found that combinations of the TEI and TER methods resulted in high extraction efficiency and purity of small RNA obtained using CCM. High yield and a narrow size distribution pattern of small RNA were shown in exoRNA isolated by exoRNeasy from serum. In RNA profile analysis, the small RNA constituent ratio, miRNA content and amount varied as a result of methodological differences. This study showed that different methods may introduce variations in the concentration, purity and size of exosomes and exoRNA. Herein we discuss the advantages and disadvantages of each method and their application to different materials, therefore providing a reference according to research design. PMID- 28737828 TI - TAZ inhibition restores sensitivity of cisplatin via AKT/mTOR signaling in lung adenocarcinoma. AB - The cisplatin-based doublet remains the foundation of treatment for the majority of patients with advanced non-small cell lung cancer (NSCLC), however, many patients exhibit acquired drug resistance. Transcriptional co-activator with PDZ binding motif (TAZ) is an oncogene in lung cancer, important for lung tumorigenesis and metastasis. Recently, it was revealed that TAZ upregulation confers resistance against a diverse range of cytotoxic agents. The present study aimed to investigate whether TAZ is involved in cisplatin sensitivity in lung adenocarcinoma. In the present study, we investigated TAZ expression in lung adenocarcinoma tissues and cell lines with western blot and RT-PCR analyses. By knocking down TAZ using short hairpin RNAs in cisplatin-resistant A549 and H460 cells, cell proliferation and apoptosis were assessed by BrdUrd labeling and flow cytometric analysis, respectively. The IC50 value of cisplatin was also assessed with CCK-8 assays. The western blotting for AKT, p-AKT, S6K and p-S6K were performed in cells with TAZ knockdown or overexpression. When the AKT/mTOR pathway was blocked in A549 and H460 with TAZ overexpression, cisplatin sensitivity was assessed by IC50 value. High expression of TAZ was found in lung adenocarcinoma tissues and cell lines, which were associated with cisplatin resistance. Knockdown of TAZ using shRNAs confered decreasing proliferation, increasing apoptosis and enhanced cisplatin sensitivity in cisplatin-resistant cells. Additionally, TAZ knockdown decreased the AKT/mTOR pathway expression. Overexpression of TAZ increased p-AKT and p-S6K, which was inhibited by siAKT. Furthermore, we found that the inhibition of the AKT/mTOR pathway rescued the cells from cisplatin resistance caused by TAZ overexpression. Our data revealed that TAZ inhibition restores sensitivity of cisplatin in lung adenocarcinoma, which was, at least in part, AKT/mTOR signaling pathway-dependent. TAZ may be a potent therapeutic target for NSCLC in combination with conventional chemotherapy. PMID- 28737827 TI - Cytotoxic and chemosensitization effects of Scutellarin from traditional Chinese herb Scutellaria altissima L. in human prostate cancer cells. AB - Scutellaria altissima L. is a common traditional Chinese medicine used to treat inflammation in some countries. Scutellarin, an active major flavone glycoside isolated from the traditional Chinese medicine Scutellaria altissima L., has been shown to offer various beneficial biochemical effects on cerebrovascular diseases and inflammation. However, the antiproliferative effects of Scutellarin in prostate cancer and the underlying mechanism are not fully elucidated. In the present study, we aimed to ascertain whether Scutellarin inhibits cancer cell growth and to further explore the molecular mechanism. Scutellarin enhanced the sensitivity of prostate cancer cells to cisplatin. MTT assays revealed that cell viability was significantly decreased in the prostate cancer cells treated with Scutellarin. Flow cytometric analysis indicated that Scutellarin suppressed cell proliferation by promoting G2/M arrest and inducing apoptosis. We employed western blotting to delineate the underlying mechanisms involved in the G2/M arrest and apoptosis. Comet assay and gammaH2AX immunocytochemistry were used to detect levels of DNA damage in PC3 cells exposed to Scutellarin and/or cisplatin. Our data revealed that Scutellarin significantly induced prostate cancer cell apoptosis by activating the caspase cascade. An increase in the Bax/Bcl-2 ratio, depolarization of mitochondrial membrane potential and cell cycle arrest at G2/M phase were accompanied by the apoptosis induction. Additionally, Scutellarin altered the protein expression of cell cycle and apoptosis regulatory genes by downregulating Cdc2, cyclin B1 and Bcl-2 and upregulating caspase-3, caspase-9 and Bax in prostate cancer cells. Furthermore, Scutellarin sensitized PC3 cells to cisplastin treatment in a dose-dependent manner. Taken together, our data confirmed the cytotoxicity of Scutellarin against prostate cancer PC3 cells and provide new findings in regards to Scutellarin sensitizing prostate cancer cells to chemotherapy. Our findings suggest that Scutellarin has potential to be used as a novel antineoplastic therapeutic candidate for prostate cancer patients. PMID- 28737829 TI - Expression profile of circular RNAs in human gastric cancer tissues. AB - Circular RNAs (circRNAs) represent a newly identified class of non-coding RNA molecules, which interfere with gene transcription by adsorbing microRNAs (miRNAs). CircRNAs serve important roles in disease development and have the potential to serve as a novel class of biomarkers for clinical diagnosis. However, the role of circRNAs in the occurrence and development of gastric cancer (GC) remains unclear. In the present study, the expression profiles of circRNAs were compared between GC and adjacent normal tissues using a circRNA microarray, following which quantitative polymerase chain reaction (qPCR) was used to confirm the results of the circRNA microarray. Compared with the adjacent, normal mucosal tissues, 16 circRNAs were upregulated and 84 circRNAs were downregulated in GC. A total of 10 circRNAs were selected for validation in three pairs of GC and adjacent noncancerous tissues. The qPCR results were consistent with the findings of the microarray-based expression analysis. Of the circRNAs studied, only circRNA-0026 (hsa_circ_0000026) exhibited significantly different expression in GC (2.8-fold, P=0.001). Furthermore, online Database for Annotation, Visualization and Integrated Discovery annotation was used to predict circRNA targeted miRNA-gene interactions. The analysis revealed that circRNA-0026 may regulate RNA transcription, RNA metabolism, gene expression, gene silencing and other biological functions in GC. In conclusion, differential expression of circRNAs may be associated with GC tumorigenesis, and circRNA-0026 is a promising biomarker for GC diagnosis and targeted therapy. PMID- 28737830 TI - Role of triosephosphate isomerase and downstream functional genes on gastric cancer. AB - Triosephosphate isomerase (TPI) is highly expressed in many types of human tumors and is involved in migration and invasion of cancer cells. However, TPI clinicopathological significance and malignant function in gastric cancer (GC) have not been well defined. The present study aimed to examine TPI expression in GC tissue and its biological functions. Furthermore, we investigated its downstream genes by gene chip technology. Our results showed that TPI expression was higher in gastric cancer tissues than adjacent tissues, although no statistical differences were found between TPI expression and clinicopathological factors. TPI overexpression in human gastric carcinoma cell line BGC-823 enhanced cell proliferation, invasion and migration, but did not change cell cycle distribution, while TPI knockdown suppressed proliferation, invasion and migration, induced apoptosis and increased G2/M arrest of human gastric carcinoma cell line MGC-803. Since the cell division cycle associated 5 (CDCA5) was identified as the one with the most decreased expression after TPI knockdown, we investigated its role in MGC-803 cells. The results showed that CDCA5 knockdown also inhibited proliferation, migration, induced apoptosis and increased G2/M arrest similarly to TPI knockdown. CDCA5 overexpression promoted MGC-803 cell proliferation, clone formation and migration abilities. These results indicated that TPI expression level might affect GC cell behavior, suggesting that both TPI and CDCA5 might be considered as potential tumor markers related with GC development and might be potential new targets in GC treatment. PMID- 28737831 TI - Royal jelly lipophilic fraction induces antiproliferative effects on SH-SY5Y human neuroblastoma cells. AB - Royal jelly (RJ) is one the most important bee product because it strongly influences the larval development in the hive, including the queen bee. In literature, RJ is known for its antioxidant, immunoregulatory, antifungal, antibiotical, erythropoietic, hypoglycemic, anticholesteremic, antithyroidic, anti-osteoporotic and estrogenic properties. However, it is surprising how rare the scientific evidence about RJ antineoplastic capacity are. That being said, we investigated, for the first time, the in vitro bioactivity of six different RJs on the growth of three different mammalian cell lines: immortalized murine myoblasts (C2C12), human prostate cancer (PC3) and human neuroblastoma (SH-SY5Y). These studies were performed treating the cells with the only lipophilic, or hydrophilic, fraction of the RJs, a scientific approach never performed before. Moreover, chemical and protein profiles of all RJs were finely characterized, in qualitative and quantitative terms, by GC-MS and 1D-SDS-PAGE, respectively, in order to give a complete framework to the research. Despite the deep differences we found in the composition of each sample, unexpectedly, RJs showed comparable or very similar biological effects. In particular, our attention was captured by the extraordinary antiproliferative activity of the lipophilic extract of all RJs against SH-SY5Y cells, suggesting a potential medical application of this bee product to prevent the onset and slow down the growth of human neuroblastoma. PMID- 28737832 TI - Self-Assembled Polyprodrug Amphiphile for Subcutaneous Xenograft Tumor Inhibition with Prolonged Acting Time In Vivo. AB - Polymeric drug delivery system termed as "polyprodrug amphiphile" poly(2 methylacryloyloxyethyl phosphorylcholine)-b-poly(10-hydroxy-camptothecin methacrylate (pMPC-b-pHCPT) is developed for the prolonged-acting cancer therapy. It is obtained by two-step reversible addition-fragmentation chain transfer polymerization of zwitterionic monomer MPC and an esterase-responsive polymerizable prodrug methacrylic anhydride-CPT, respectively. This diblock polymer is composed of both antifouling (pMPC) and bioactive (pHCPT) segments and the drug is designed as a building block to construct the polymer skeleton directly. Due to its distinct amphiphilicity, the polymer can self-assemble into micelles with different dynamic sizes by facilely tuning the ratio of MPC/HCPT under physiological conditions. The outer pMPC shell is superhydrophilic to form dense hydrate layer preventing the nanosystem from unwanted nonspecific protein adsorption, which is the main lead cause of the rapid clearance of nanoparticles in vivo, thus facilitating the accumulation of drugs in tumor sites via enhanced permeability and retention effect. The configuration of the polyprodrug amphiphile is confirmed by several measurements. The resistance to albumin adsorption, prolonged plasma retention time, accumulation in tumor sites, and anticancer activity of the micelles is also investigated in vitro and in vivo. This novel amphiphile can be expected as a promising agent for the passive targeted prolonged-acting cancer therapy. PMID- 28737833 TI - The natural history of oviposition on a ginkgophyte fruit from the Middle Jurassic of northeastern China. AB - A distinctive pattern of oviposition lesions occurs on a ginkgoalean seed, Yimaia capituliformis, which likely was inflicted by a kalligrammatid lacewing with a long, sword-like, plant-piercing ovipositor. This newly recorded oviposition type, DT272, occurs in the 165 million-year-old Jiulongshan Formation, of Middle Jurassic age, in Northeastern China. DT272 consists from three to seven, approximately equally spaced lesions with surrounding callus tissue, the fabricator of which targeted fleshy outer and inner tissues of a ginkgophyte fruit. This distinctive damage also is known from the fleshy attachment pad surfaces of basal bennettitalean bracts. Examination of the life history of this probable ginkgoalean-kalligrammatid oviposition interaction indicates that the spacing of the eggs in substrate tissues disfavored inter-larval contact, but little can be said of defense and counterdefense strategies between the plant host and the newly hatched immatures. PMID- 28737834 TI - Vitamin K antagonists versus low-molecular-weight heparin for the long term treatment of symptomatic venous thromboembolism. AB - BACKGROUND: People with venous thromboembolism (VTE) generally are treated for five days with intravenous unfractionated heparin or subcutaneous low-molecular weight heparin (LMWH), followed by three months of vitamin K antagonists (VKAs). Treatment with VKAs requires regular laboratory measurements and carries risk of bleeding; some patients have contraindications to such treatment. Treatment with LMWH has been proposed to minimise the risk of bleeding complications. This is the second update of a review first published in 2001. OBJECTIVES: The purpose of this review was to evaluate the efficacy and safety of long term treatment (three months) with LMWH versus long term treatment (three months) with VKAs for symptomatic VTE. SEARCH METHODS: For this update, the Cochrane Vascular Information Specialist searched the Specialised Register (last searched November 2016) and the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 10), The Cochrane Vascular Information Specialistalso searched clinical trials registries for ongoing studies. SELECTION CRITERIA: Randomised controlled trials comparing LMWH versus VKA for long treatment (three months) of symptomatic VTE. Two review authors independently evaluated trials for inclusion and methodological quality. DATA COLLECTION AND ANALYSIS: Review authors independently extracted data and assessed risk of bias. We resolved disagreements by discussion and performed meta-analysis using fixed-effect models with Peto odds ratios (Peto ORs) and 95% confidence intervals (CIs). Outcomes of interest were recurrent VTE, major bleeding, and mortality. We used GRADE to assess the overall quality of evidence supporting these outcomes. MAIN RESULTS: Sixteen trials, with a combined total of 3299 participants fulfilled our inclusion criteria. According to GRADE, the quality of evidence was moderate for recurrent VTE, low for major bleeding, and moderate for mortality. We downgraded the quality of the evidence for imprecision (recurrent VTE, mortality) and for risk of bias and inconsistency (major bleeding).We found no clear differences in recurrent VTE between LMWH and VKA (Peto OR 0.83, 95% confidence interval (CI) 0.60 to 1.15; P = 0.27; 3299 participants; 16 studies; moderate-quality evidence). We found less bleeding with LMWH than with VKA (Peto OR 0.51, 95% CI 0.32 to 0.80; P = 0.004; 3299 participants; 16 studies; low-quality evidence). However, when comparing only high-quality studies for bleeding, we observed no clear differences between LMWH and VKA (Peto OR 0.62, 95% CI 0.36 to 1.07; P = 0.08; 1872 participants; seven studies). We found no clear differences between LMWH and VKA in terms of mortality (Peto OR 1.08, 95% CI 0.75 to 1.56; P = 0.68; 3299 participants; 16 studies; moderate-quality evidence). AUTHORS' CONCLUSIONS: Moderate-quality evidence shows no clear differences between LMWH and VKA in preventing symptomatic VTE and death after an episode of symptomatic DVT. Low quality evidence suggests fewer cases of major bleeding with LMWH than with VKA. However, comparison of only high-quality studies for bleeding shows no clear differences between LMWH and VKA. LMWH may represent an alternative for some patients, for example, those residing in geographically inaccessible areas, those who are unable or reluctant to visit the thrombosis service regularly, and those with contraindications to VKA. PMID- 28737835 TI - PDMS/glass hybrid device with a reusable carbon electrode for on-line monitoring of catecholamines using microdialysis sampling coupled to microchip electrophoresis with electrochemical detection. AB - On-line separations-based sensors employing microdialysis (MD) coupled to microchip electrophoresis (ME) enable the continuous monitoring of multiple analytes simultaneously. Electrochemical detection (EC) is especially amenable to on-animal systems employing MD-ME due to its ease of miniaturization. However, one of the difficulties in fabricating MD-ME-EC systems is incorporating carbon working electrodes into the device. In this paper, a novel fabrication procedure is described for the production of a PDMS/glass hybrid device that is capable of integrating hydrodynamic MD flow with ME-EC using a flow-gated interface and a pyrolyzed photoresist film carbon electrode. This fabrication method enables the reuse of carbon electrodes on a glass substrate, while still maintaining a good seal between the PDMS and glass to allow for pressure-driven MD flow. The on-line MD-ME-EC device was characterized in vitro and in vivo for monitoring analytes in the dopamine metabolic pathway. The ultimate goal is to use this device and associated instrumentation to perform on-animal, near-real time in vivo monitoring of catecholamines. PMID- 28737836 TI - Parenting and Cortisol in Infancy Interactively Predict Conduct Problems and Callous-Unemotional Behaviors in Childhood. AB - This study examines observed maternal sensitivity, harsh-intrusion, and mental state talk in infancy as predictors of conduct problems (CP) and callous unemotional (CU) behaviors in middle childhood, as well as the extent to which infants' resting cortisol and cortisol reactivity moderate these associations. Using data from the Family Life Project (n = 1,292), results indicate that maternal sensitivity at 6 months predicts fewer CP at first grade, but only for infants who demonstrate high levels of cortisol reactivity. Maternal harsh intrusion predicts fewer empathic-prosocial behaviors, a component of CU behaviors, but only for infants who demonstrate high resting cortisol. Findings are discussed in the context of diathesis-stress and differential susceptibility models. PMID- 28737837 TI - Drug survival and reasons for discontinuation of the first biological disease modifying antirheumatic drugs in Thai patients with rheumatoid arthritis: Analysis from the Thai Rheumatic Disease Prior Authorization registry. AB - AIM: To evaluate and compare the retention rate of biological disease-modifying antirheumatic drugs (bDMARDs) in real-life practice and identify risk factors related to remission and drug discontinuation in patients with rheumatoid arthritis (RA). METHOD: A total of 256 patients fulfilling criteria for RA and starting bDMARD between December 2009 and October 2014 were selected from the Rheumatic Disease Prior Authorization registry. Baseline demographic and clinical data were recorded. The cumulative probability of bDMARD discontinuation over 5 years of follow-up and factors associated with RA remission and bDMARD withdrawal were analyzed. RESULTS: Almost half (46%) of patients were initially treated with rituximab (RTX), with 33% treated with etanercept (ETN) and 21% with infliximab (IFX). Fewer than 10% were subsequently switched to a second bDMARD. The 1- and 5 year remission rates in patients continuing their first bDMARD were 7.2% and 21.5%, respectively. At 5 years, the drug survival rates for RTX, ETN and IFX were 50%, 25% and 22%, respectively. Multivariate analysis showed that RTX was significantly associated with highest drug survival. Relative to RTX, the hazard ratios for discontinuation of IFX and ETN were 2.60 (95% confidence interval [CI] 1.53-4.42) and 2.15 (95% CI 1.36-3.42), respectively. Thirty-nine percent of patients stopped treatments, due to inadequate response (42%), serious adverse events (22%), nonadherence (14%) or remission/low disease activity (13%). CONCLUSION: Over 5 years, only one-third of patients continued using their first bDMARD. The leading cause of drug discontinuation was inadequate response. PMID- 28737838 TI - Improved bacterial identification directly from urine samples with matrix assisted laser desorption/ionization time-of-flight mass spectrometry. AB - BACKGROUND: Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) contributes to rapid identification of pathogens in the clinic but has not yet performed especially well for Gram-positive cocci (GPC) causing complicated urinary tract infection (UTI). The goal of this study was to investigate the possible clinical use of MALDI-TOF MS as a rapid method for bacterial identification directly from urine in complicated UTI. METHODS: MALDI-TOF MS was applied to urine samples gathered from 142 suspected complicated UTI patients in 2015-2017. We modified the standard procedure (Method 1) for sample preparation by adding an initial 10 minutes of ultrasonication followed by centrifugation at 500 g for 1 minutes to remove debris such as epithelial cells and leukocytes from the urine (Method 2). RESULTS: In 133 urine culture-positive bacteria, the rate of corresponded with urine culture in GPC by MALDI-TOF MS in urine with standard sample preparation (Method 1) was 16.7%, but the modified sample preparation (Method 2) significantly improved that rate to 52.2% (P=.045). Method 2 also improved the identification accuracy for Gram-negative rods (GNR) from 77.1% to 94.2% (P=.022). The modified Method 2 significantly improved the average MALDI score from 1.408+/-0.153 to 2.166+/-0.045 (P=.000) for GPC and slightly improved the score from 2.107+/-0.061 to 2.164+/-0.037 for GNR. CONCLUSION: The modified sample preparation for MALDI-TOF MS can improve identification accuracy for complicated UTI causative bacteria. This simple modification offers a rapid and accurate routine diagnosis for UTI, and may possibly be a substitute for urine cultures. PMID- 28737840 TI - Contents: Proteomics 4/2007. PMID- 28737839 TI - Moving an Evidence-Based Parenting Program Into the Community. AB - Attachment and Biobehavioral Catch-up (ABC) is a parenting program developed to enhance sensitivity among parents of infants who experience early adversity. In several randomized clinical trials, the intervention's efficacy has been demonstrated. Moving interventions into the community with adequate fidelity is challenging, though, and intervention effects are often much smaller than when tested in randomized clinical trials. To enhance the likelihood that ABC is delivered with high fidelity, a microanalytic fidelity assessment was developed. Using this fidelity tool as a central component of training, supervision, and certification, changes in parent sensitivity for 108 families with children ages 6 months to 2 years were as large as those seen in laboratory settings. These findings are discussed with regard to implications for moving other evidence based interventions into the community. PMID- 28737841 TI - The effect of sucrose addition at dosage stage on the foam attributes of a bottle fermented English sparkling wine. AB - BACKGROUND: Approximately two-thirds of wine produced in the UK is bottle fermented sparkling wine. Effervescence and foamability are key features used to assess English sparkling wine (ESW) quality. A critical, yet understudied, area of research is the potential for dosage to influence foam behaviour via associated changes in wine viscosity. RESULTS: In this study, dosage treatments of five increasing levels of sucrose (from 0 to 31 g L-1 ) were added to an ESW. After storage, the foamability attributes of the wines were analysed via an adapted Mosalux method and a novel image analysis method combined with free pour of the wine. Results indicate that increasing sucrose concentration improved foam formation, but reduced foam stability, likely due to the sucrose added causing a modification in wine viscosity. CONCLUSIONS: These results highlight the impact that dosage treatments can have on the quality of foam produced upon pouring, and therefore have the potential to inform future sparkling winemaking practices. (c) 2017 Society of Chemical Industry. PMID- 28737842 TI - Network meta-analysis of disconnected networks: How dangerous are random baseline treatment effects? AB - In network meta-analysis, the use of fixed baseline treatment effects (a priori independent) in a contrast-based approach is regularly preferred to the use of random baseline treatment effects (a priori dependent). That is because, often, there is not a need to model baseline treatment effects, which carry the risk of model misspecification. However, in disconnected networks, fixed baseline treatment effects do not work (unless extra assumptions are made), as there is not enough information in the data to update the prior distribution on the contrasts between disconnected treatments. In this paper, we investigate to what extent the use of random baseline treatment effects is dangerous in disconnected networks. We take 2 publicly available datasets of connected networks and disconnect them in multiple ways. We then compare the results of treatment comparisons obtained from a Bayesian contrast-based analysis of each disconnected network using random normally distributed and exchangeable baseline treatment effects to those obtained from a Bayesian contrast-based analysis of their initial connected network using fixed baseline treatment effects. For the 2 datasets considered, we found that the use of random baseline treatment effects in disconnected networks was appropriate. Because those datasets were not cherry picked, there should be other disconnected networks that would benefit from being analyzed using random baseline treatment effects. However, there is also a risk for the normality and exchangeability assumption to be inappropriate in other datasets even though we have not observed this situation in our case study. We provide code, so other datasets can be investigated. PMID- 28737843 TI - Non-steroidal anti-inflammatory drugs (NSAIDs) for cancer-related pain in children and adolescents. AB - BACKGROUND: Pain is a common feature of childhood and adolescence around the world, and for many young people, that pain is chronic. The World Health Organization (WHO) guidelines for pharmacological treatments for persisting pain in children acknowledge that pain in children is a major public health concern of high significance in most parts of the world. Views on children's pain have changed over time and relief of pain is now seen as important. In the past, pain was largely dismissed and was frequently left untreated, and it was assumed that children quickly forgot about painful experiences.We designed a suite of seven reviews in chronic non-cancer pain and cancer pain (looking at antidepressants, antiepileptic drugs, non-steroidal anti-inflammatory drugs, opioids, and paracetamol as priority areas) to review the evidence for children's pain using pharmacological interventions.As one of the leading causes of mortality and morbidity for children and adolescents in the world today, childhood cancer (and its associated pain) is a major health concern. Specific mortality and morbidity data relating to children are not currently identified. All childhood cancer rates are on the rise; for example, in the USA approximately 10,380 children aged under 15 years were expected to be diagnosed with cancer by the end of 2016. However, with survival rates also increasing, over 80% of paediatric cancer patients are expected to survive for five years or more, thus identifying the need to address pain management in this population.Cancer pain in infants, children, and adolescents is primarily nociceptive pain with negative long term effects. Cancer-related pain is generally caused directly by the tumour itself such as compressing on the nerve or inflammation of the organs. Cancer-related pain generally occurs as a result of perioperative procedures, nerve damage caused by radiation or chemotherapy treatments, or mucositis. However, this review focused on pain caused directly by the tumour itself such as nerve infiltration, external nerve compression, and other inflammatory events.Non steroidal anti-inflammatory drugs (NSAIDs) are used to treat pain, reduce fever, and for their anti-inflammatory properties. They are commonly used within paediatric pain management. NSAIDs are currently licensed for use in western countries, however not approved for infants aged under three months. Primary adverse effects include gastrointestinal issues and possible renal impairment with long term use. Other adverse effects in children include diarrhoea, headache, nausea, constipation, rash, dizziness, and abdominal pain. OBJECTIVES: To assess the analgesic efficacy, and adverse events, of non-steroidal anti inflammatory drugs (NSAIDs) used to treat cancer-related pain in children and adolescents aged from birth and 17 years, in any setting. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online, MEDLINE via Ovid, and Embase via Ovid from inception to 21 February 2017. We also searched the reference lists of retrieved studies and reviews, and searched online clinical trial registries. SELECTION CRITERIA: Randomised, double-blind trials of any dose, and any route, treating cancer-related pain in children and adolescents, comparing NSAIDs with placebo or an active comparator. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for eligibility. We planned to use dichotomous data to calculate risk ratio and number needed to treat for one additional event, using standard methods. We assessed GRADE (Grading of Recommendations Assessment, Development and Evaluation) and planned to create a 'Summary of findings' table. MAIN RESULTS: No studies were eligible for inclusion in this review (very low quality evidence). We downgraded the quality of evidence by three levels due to the lack of data reported for any outcome. AUTHORS' CONCLUSIONS: There is no evidence from randomised controlled trials that non-steroidal anti-inflammatory drugs (NSAIDs) reduce cancer-related pain in children and adolescents. This means that no reliance or conclusions can be made about efficacy or harm in the use of NSAIDs to treat chronic cancer-related pain in children and adolescents. PMID- 28737844 TI - Dentistry's Pay Gap. PMID- 28737848 TI - Dental Student Research. PMID- 28737849 TI - Antifungal Activity of AlkaloidsAgainst Candida albicans. AB - Candida albicans is a pathogen in the mouth responsible for opportunisticinfections that are usually harmless. Natural products have been used to developseveral drugs, mostly anticancer and anti-infective agents. Among these, alkaloidshave been studied for their medicinal properties. In this study, we examined theirantifungal activity against C. albicans in vitro. Among the alkaloids studied in thiswork, berberine hydrochloride showed the best activity against C. albicans. PMID- 28737850 TI - Prevalence of EnamelMarkings on Third Molars. AB - The purpose of this study was to measure the prevalence of enamelmarkings in routinely extracted third molars. One hundred donated third molarswere examined. All had some marking(s). Caries was almost universal; whitesnowcapping of cusps and ridges was extremely common; pit and valley defectswere very common; spots and bands were very common, most were white;horizontal grooves were common; linear enamel hypoplasia, considered to be a truedevelopmental defect, was rare. PMID- 28737851 TI - NonodontogenicSources of Dental Pain. AB - Nonodontogenic sources of dental pain can be extremelychallenging to diagnose. It is critical to establish a proper diagnosis to ensure thattreatment is directed toward the source of the pain rather than the site of the pain. PMID- 28737852 TI - Data Backup: What's Your Risk Tolerance? PMID- 28737853 TI - Basic Life Support Course, AEDs and MedicalEmergency Kits. PMID- 28737854 TI - Short-and long-term harm resulting from inappropriate antibiotic prescription in childhood and adolescence. PMID- 28737855 TI - Discontinuation of pediatric trials. PMID- 28737856 TI - The principle of synchronicity-equivalence and chronomedicine: relevance and methodological exploration. PMID- 28737857 TI - Seroprevalence of Bordetella pertussis among vaccinated and unvaccinated pregnant women and newborn infants in a university hospital of Buenos Aires. AB - INTRODUCTION: Pertussis is a highly contagious disease caused by Bordetella pertussis. It poses a high morbidity and mortality rate, especially among infants younger than 6 months old. In Argentina, pertussis incidence and mortality have increased over the past three decades. OBJETIVE: To establish Bordetella pertussisantibody titers among pregnant women in their third trimester and among newborn infants, as measured in cord blood. METHODS: This was an observational, cross-sectional study. The study started in 2011; at that time, pertussis vaccination was not mandatory for pregnant women as per the national immunization schedule, only optional. Maternal antibodies were measured in the last trimester of pregnancy for women and in cord blood for newborn infants. Antibody titers were determined using Abcam's anti-Bordetella pertussis toxin (PT) IgG in vitro ELISA kit. The chi2 test was used to compare prevalence rates. RESULTS: The study included 111 mother-newborn infant dyads; 35 infants from unvaccinated mothers (before the introduction of the vaccine) and 76 from vaccinated mothers. Positive IgG antibodies were found in 92% (70/76) of infants born from vaccinated mothers whereas 100% (35/35) of infants born from unvaccinated mothers had negative results for antibodies; p < 0.001. CONCLUSION: In the vaccinated population of this study, 92% of infants had positive IgG antibodies. This study supports the need for maternal immunization against Bordetella pertussis to provide protection to newborn infants. PMID- 28737858 TI - The effects of pneumococcal conjugate vaccine (PCV7 and PCV13) on Turkish children with invasive pneumococcal disease: a single center experience. AB - INTRODUCTION: The aim of this prospective single-center study was to determine the changings in incidence of invasive pneumococcal disease (IPD), serotype distribution and the antimicrobial resistance patterns of S. pneumoniae in children with IPD after the period (1 to 7 years) of vaccination with PCV7 (2008) and PCV13 (2011). POPULATION AND METHODS: The study was conducted on 39 Turkish children with IPD between ages 1 month and 18 years in Ankara, Turkey. Streptococcus pneumoniae was identified using standard laboratory procedures from blood, cerebrospinal fluid (CSF), pleural fluid, and other sterile body fluids and tissues. S. pneumoniae isolates were tested for resistance to penicilin and ceftriaxone using the E-test methodology. Serotypes of the isolates were determined by Quellung reaction. RESULTS: The overall annual incidence rate of IPD decreased significantly from 7.71 (95% CI, 1.99-13.4) to 1.58 (95% CI, 0.6 3.77; RRR=-79.5; p=0.006) per 100 000 population among <=5 years of age without underlying disease. During the overall study period, the PCV7-serotypes and PCV13 serotypes represented 27.8% and 63.8% of isolates, respectively. PCV13-serotypes made up 81.8% of cases of IPD in the pre-PCV13 era and decreased to 56% in the 4 years after PCV13. The penicillin and ceftriaxone (for meningitis) resistance rates were 48.5% and 9.1%, respectively. CONCLUSIONS: This is the first study about the changing pattern of the incidence of IPD in Turkish children after the implementation of the PCV7 and PCV13 in Turkish national vaccine schedule and a prominent decrease in incidence of IPD has seen after the implementation of PCV13. PMID- 28737859 TI - Association between dietary glycemic load and metabolic syndrome in obese children and adolescents. AB - OBJETIVE: To study the association between the metabolic syndrome (MS) and the glycemic load (GL) of food intake among obese children and adolescents seen in consultation by the endocrinology team in a pediatric referral hospital in Lima, Peru. POPULATION AND METHOD: Cross-sectional study among obese children and adolescents (body mass index >= 95 percentile), 10-15 years old. The MS was classified according to criteria of the International Diabetes Federation. A 24 hour reminder was used, and the overall and per meal GL was calculated. The association between the GL tertiles (comparison with the lower tertile) and the MS was assessed using prevalence ratios adjusted by demographic outcome measures, family history, physical activity and total carbohydrate consumption in Poisson regression models with a robust variance. RESULTS: Out of 273 obese children and adolescents, 52.4% were male and 94.9% did not engage in any physical activity. Glycemic load median value was 213 (164.8-287.4) and the daily calorie intake value was 2275 (1851-3024) kcal, consisting mainly of carbohydrates (62%). MS prevalence was 22.3%; the most prevalent components were abdominal obesity (81.7%) and low values of high density lipoprotein (HDL) (63.7%). Lastly, an association was observed between a high consumption of GL and the risk of developing MS (aRP 4.5; 95% CI: 1.3-15.3). CONCLUSIONS: There is an association between a high consumption of GL and the presence of MS among obese children and adolescents. PMID- 28737860 TI - Natural history of immunoglobulin E-mediated cow's milk allergy in a population of Argentine children. AB - INTRODUCTION: Cow's milk protein allergy is the most common allergy in pediatrics. Immunoglobulin E (IgE)-mediated cow's milk allergy poses a higher risk for life and a worse prognosis. OBJETIVES: To describe the course of IgE mediated cow's milk protein allergy and risk factors associated with disease persistence. PATIENTS AND METHODS: This was a descriptive, retrospective study conducted in patients seen at the Division of Pediatric Allergy of Hospital Italiano between June 2006 and June 2012 who had been diagnosed with IgE-mediated cow's milk allergy. RESULTS: Out of the 72 patients with IgE-mediated cow's milk allergy, 39 (54%) were boys. Patients' average age at the time of diagnosis was 5.19 +/- 3.7months old; the most common symptoms were urticaria and vomiting. Rhinitis and asthma were the most commonly observed concomitant atopic diseases. In the study period, 54.5% of patients developed tolerance at an average age of 32 months old. An 8-mm papule in the skin prick test and casein sensitization were associated with disease persistence. CONCLUSION: Overall, 54.5% of patients developed tolerance at 32 months old. A significant association was observed between papule size at the time of diagnosis and casein sensitization and disease persistence. PMID- 28737861 TI - Effects of 25 hydroxy vitamin D levels on the severity and asthma control in school age asthma patients. AB - BACKGROUND: The objective was to determine vitamin D levels in patients between the ages 6 and 18 years, followed for asthma, and the relation between vitamin D levels and asthma control and severity. MATERIALS AND METHODS: Patients with asthma and healthy volunteers between the ages 6 and 18 years were enrolled into the study as patient and control groups, respectively. Patient demographic information and clinical findings were recorded; a respiratory function test was performed. Body mass index (BMI), 25(OH) D,calcium, phosphorus, alkaline phosphatase, total IgE and eosinophil levels were determined for all patients. Asthma severity and control conditions were established based on GINA (Global Initiative for Asthma) criteria. RESULTS: Seventy two patients with asthma and 66 healthy children were included. Compared to the control group, decreased serum vitamin D levels were detected in patient group. Thirty eight (52.8%) patients in asthma patient group had vitamin D defficiency; in this group, asthma control was poor and asthma severity was significantly higher. No significant correlation was found between vitamin D levels and gender, obesity, respiratory functions, skin test, serum eosinophil and total IgE levels. CONCLUSION: The frequency of vitamin D deficiency and insufficiency was higher in children with asthma, compared to the controls. Lower levels of vitamin D are associated with poor asthma control and increased asthma severity. PMID- 28737862 TI - Neonatal mortality in Argentina. Situation analysis from 2005 to 2014. AB - INTRODUCTION: Neonatal mortality (NM) refers to deaths occurring between birth and 27 days of life. This component of infant mortality has shown the least reduction over the past 50 years. The objective of this study was to analyze the course and characteristics of NM in Argentina. POPULATION AND METHODS: This was a descriptive, ecological study of NM in Argentina conducted between 2005 and 2014 to analyze its course, causes, and the relevance of prematurity and a low birth weight. Records of the Health Statistics and Information Department of the Ministry of Health of Argentina were used. RESULTS: The neonatal mortality rate reduced by 19.2% (2005: 8.90/00; 2014: 7.20/00); the early component (between birth and 6 days of life), by 20% (2005: 6.50/00; 2014: 5.20/00); and the late component (between 7 and 27 days of life), by 13% (2005: 2.30/00; 2014: 20/00). Disorders originating in the perinatal period and congenital malformations were the cause of more than 95% of neonatal deaths in this period. The relative significance of disorders originating in the perinatal period reduced, but that of congenital malformations increased. Preterm and low birth weight live births had the greatest risk of neonatal death. A younger gestational age and a lower birth weight resulted in a lower reduction of specific neonatal mortality rate. CONCLUSION: In the past 10 years, NM has reduced significantly. Disorders originating in the perinatal period and congenital malformations were the cause of almost all deaths in this age group. NM was associated with a low birth weight and prematurity. PMID- 28737863 TI - Tendencia de los egresos hospitalarios por enfermedades infecciosas intestinales en ninos en Argentina, 2005-2013. AB - INTRODUCTION: Acute diarrhea is one of the most serious public health problems in developing countries because it is generally associated with unfavorable living conditions. The objective of this study was to analyze trends in hospital discharges for intestinal infectious disease in children under age 5 recorded in official public hospitals from Argentina in the 2005-2013 period. POPULATION AND METHODS: This was an ecological, time-series study based on data provided by the Health Statistics and Information Department, at a national and regional level. Specific hospital discharge rates were estimated, and seasonal behavior and trends were analyzed in relation to this event. RESULTS: In Argentina, 2 521 729 patients under age 5 were discharged in this period; of these, 9.0% were diagnosed with intestinal infectious disease. Children under age 1 accounted for a third of hospitalizations; two annual peaks (summer and winter) were observed in the seasonality analysis. Overall, a downward trend was observed, with a mild increase in the 2007-2009 period. Rates were up to 3 or 4 times higher in Northwest and Northeast Argentina than in the Pampa region. CONCLUSION: Hospital discharges for intestinal infectious disease in the public subsector account for approximately 10% of all discharges of children under age 5. This event shows a seasonal pattern, with a slightly downward trend over the past years in spite of its heterogeneous distribution across the different Argentine regions. PMID- 28737864 TI - Measuring adverse events in pediatric inpatients with the Global Trigger Tool. AB - INTRODUCTION: The safety of inpatients is a priority in the health care system. The Global Trigger Tool seems to be suitable to estimate the incidence of adverse events (AE) in pediatric inpatients. OBJETIVES: To describe the incidence and categories of AE in pediatric inpatients using the Global Trigger Tool and to identify risk factors associated to their development. POPULATION AND METHODS: Retrospective study. Medical records of 200 patients hospitalized at Hospital Elizalde during 2013 were included. Outcome measures: number of AE/100 admissions and distribution of harm. A chi2 test, Student's t test and Pearson's correlation test were carried out. Significance level = p < 0.05. RESULTS: The study detected 289 triggers (1.4/patient); 52 AEs (26 AEs/100 patients, 95% CI: 20.4-32.5). There was at least one AE every 36 patients; 7 patients had more than one AE; 45 AEs were in the E and F categories (temporary harm). Medical care triggers were associated to AEs (OR 8.1; 95% CI: 3.7-17.3, p < 0.001). A positive correlation was found between the number of triggers and the number of AEs per patient (R= 0.46; p < 0.001). Being hospitalized in a closed unit (OR 2.8; 95% CI: 1.2-6.5; p= 0.03) and a longer hospital stay were associated to AEs (p < 0.001). CONCLUSION: An AE frequency of 26% was identified, and most AEs resulted in temporary harm. The presence of AEs was associated to hospitalization in a closed unit, longer hospital stay, higher number of triggers and general care triggers. PMID- 28737865 TI - Unusual increase of cases of myelitis in a pediatric hospital in Argentina. AB - INTRODUCTION: The association between enterovirus D68 and acute flaccid myelitis was first described in the United States in 2014. Since then, sporadic cases have been reported in Canada and Europe. This study describes a series of cases of acute flaccid myelitis at Hospital de Pediatria "Prof. Dr. Juan P. Garrahan," in Buenos Aires, Argentina, during 2016. METHODS: Descriptive, retrospective study. All patients with acute flaccid myelitis and lesions in the spinal cord involving the gray matter, as observed in the magnetic resonance imaging (MRI) scan, hospitalized from 04/01/2016 to 07/01/2016, were included in the study. Samples of nasopharyngeal secretions, fecal swabs and cerebrospinal fluid were collected and processed to look for the causative agent. RESULTS: Ten patients were included. The median age was 4 years old (range from 3 months to 5 years old). Eight patients had a self-limiting febrile condition before the onset of neurological symptoms. Neurological findings were flaccid weakness in, at least, one limb, cervical paralysis (n= 2) and facial paralysis (n= 2). All patients had longitudinal lesions in the spinal cord, with gray matter involvement, mainly in the anterior horn. In all cases, a lumbar puncture (spinal tap) was performed. Pleocytosis was observed in 7 patients. In four children, enterovirus D68 was identified in nasopharyngeal secretions, and in one, it was detected in the cerebrospinal fluid. Neurological deficit persisted in all patients at the time of discharge. CONCLUSIONS: The first outbreak of acute flaccid myelitis associated to enterovirus D68 is reported in Argentina. Active epidemiological surveillance will help to determine the true incidence, epidemiology and etiology of this disease. PMID- 28737866 TI - Algorithms imaging tests comparison following the first febrile urinary tract infection in children. AB - OBJETIVES: To compare the diagnostic sensitivity, costs and radiation doses of imaging tests algorithms developed by the Argentine Society of Pediatrics in 2003 and 2015, against British and American guidelines after the first febrile urinary tract infection (UTI). POPULATION AND METHODS: Inclusion criteria: children <= 2 years old with their first febrile UTI and normal ultrasound, voiding cystourethrography and dimercaptosuccinic acid scintigraphy, according to the algorithm established by the Argentine Society of Pediatrics in 2003, treated between 2003 and 2010. The comparisons between algorithms were carried out through retrospective simulation. RESULTS: Eighty (80) patients met the inclusion criteria; 51 (63%) had vesicoureteral reflux (VUR); 6% of the cases were severe. Renal scarring was observed in 6 patients (7.5%). Cost: ARS 404,000. Radiation: 160 millisieverts. With the Argentine Society of Pediatrics' algorithm developed in 2015, the diagnosis of 4 VURs and 2 cases of renal scarring would have been missed. The cost of this omission would have been ARS 301,800 and 124 millisieverts of radiation. British and American guidelines would have missed the diagnosis of all VURs and all cases of renal scarring, with a related cost of ARS 23,000 and ARS 40,000, respectively and 0 radiation. CONCLUSION: Intensive protocols are highly sensitive to VUR and renal scarring, but they imply high costs and doses of radiation, and result in questionable benefits. PMID- 28737867 TI - Pediatric dermatopathology: an overview. AB - Dermatopathology is a subspecialty of pathology and dermatology involving correlation of clinical information with microscopic observations of skin biopsies to provide diagnostic information. Pediatric dermatology is a subspecialty of dermatology for which specific points need to be known for evaluating and managing skin disorders in children. The histopathological approach and other important factors for definitive diagnoses in pediatric dermatopathology are reviewed. Skin diseases in children are not necessarily smaller versions of those that develop in adults and some diaseases may be confined to pediatric age group. An experienced team of dermatology and pathology increases the success of skin biopsies in pediatric dermatology besides the excellent technical skills. The histopathologic findings of skin lesions in children should be evaluated by pediatric pathologists, who have a specific interest for pediatric dermatopathology, in close collaboration with pediatric dermatologists. PMID- 28737868 TI - Languaje: what makes us humans. AB - Pediatrician carry out the surveillance of language in preschool children as one of the components of child development (language, fine and gross motor skills, etc.). However, language is more than that. The process of transformation of the magic meaning on the word present in the initial stages of human evolution (Myth period) into a new, symbolic meaning as representative of the object (Logos period) took around 40,000 years. With the mastering of language, man was capable of thinking; from then onwards, these two functions, thought and language, became inextricably linked, the evolved hand in hand. But this achievement had a high price : the alienation of man from nature. Hence, language became a social construction which, far from representing the objects of nature, was capable of assigning attributes and meaning to the objects themselves. Language can be used as a commercial strategy (making the words value and cost indistinguishable). According to Lacan, language is also a part of the subject, we are constructed by language. By promoting language in children we contribute to the promotion of the child as a person, as an individual and as a social being. PMID- 28737869 TI - Management of cirrhotic ascites in children. Review and recommendations. Part 1: Pathophysiology, diagnostic evaluation, hospitalization criteria, treatment, nutritional management. AB - Ascites is a major complication of cirrhosis. There are several evidence-based articles and guidelines for the management of adults, but few data have been published in relation to children. In the case of pediatric patients with cirrhotic ascites (PPCA), the following questions are raised: How are the clinical assessment and ancillary tests performed? When is ascites considered refractory? How is it treated? Should fresh plasma and platelets be infused before abdominal paracentesis to prevent bleeding? What are the hospitalization criteria? What are the indicated treatments? What complications can patients develop? When and how should hyponatremia be treated? What are the diagnostic criteria for spontaneous bacterial peritonitis? How is it treated? What is hepatorenal syndrome? How is it treated? When should albumin be infused? When should fluid intake be restricted? The recommendations made here are based on pathophysiology and suggest the preferred approach to its diagnostic and therapeutic aspects, and preventive care. PMID- 28737870 TI - Analysis of acid-labile subunit and its usefulness in pediatrics. AB - The acid-labile subunit (ALS) is an 85 kDa glycoprotein that belongs to the leucine-rich repeat superfamily. It mainly circulates in serum bound to a high molecular weight ternary complex. The main and most widely studied function of ALS is to prolong the half-life of the binary complex formed by insulin-like growth factors type 1 and 2 and its transport proteins 3 and 5. ALS serum levels are lower in neonates, reach a peak in late puberty, and then slowly decrease throughout adulthood. ALS deficiency has consequences on growth, hydrocarbon and bone metabolism, and, in some cases, it affects pubertal development. To date, 25 patients with complete ALS deficiency due to IGFALS gene mutations have been found. PMID- 28737871 TI - Normoblastemia multinuclear en un recien nacido secundaria a hipoxia. AB - Normoblasts may be seen in peripheral blood smear of newborns. The number of normoblasts per 100 white blood cells is generally in the range of 0-10.They can be seen more common than usual in hypoxic condition, because intrauterine hypoxia increases the production of red blood cells. However, multinucleated normoblasts in a newborn caused by hypoxia haven't been reported before. We present a newborn with multinucleated normoblasts secondary to intrauterine hypoxia. This case is important; because it is the first time multinucleated normoblasts in peripheral blood smear of a hypoxic newborn has been detected. PMID- 28737872 TI - [Loeys-Dietz Syndrome, 3 generations, 4 familial cases]. AB - Loeys-Dietz Syndrome is an autosomal dominant disease with aortic aneurysms, arterial tortuosity with hypertelorism and bifid uvula. We describe four familial cases within three generations. The diagnosis, surgical management and followup will be addressed. PMID- 28737873 TI - Two novel mutations in the glycine decarboxylase gene in a boy with classic nonketotic hyperglycinemia: case report. AB - Nonketotic hyperglycinemia is an extremely rare autosomal recessively inherited glycine encephalopathy caused by a deficiency in the mitochondrial glycine cleavage system, which leads to severe clinical symptoms. Nonketotic hyperglycinemia is characterized by complex and diverse phenotypes, such as hypotonia, seizures, cognitive impairment, developmental delays and myoclonic jerks that may lead to apnea and even death. Here we report a 1-year-old boy with myoclonic seizures, hypotonia and coma; he had elevated plasma and cerebrospinal fluid glycine levels, and cerebrospinal fluid/plasma glycine ratio was 0.24. Two novel heterozygous mutations confirm the diagnosis of nonketotic hyperglycinemia. One is a missense mutation c.2516A>G (p.Y839C) and the other one is a splicing mutation c.2457+2T>A in the GLDC gene. PMID- 28737874 TI - [Brain abscess in children: ten years of experience in a third level pediatric hospital]. AB - Brain abscess is a focal infection that occurs with a frequency of 0.3-1.3 cases per 100,000 people/year. We describe the epidemiology, clinical and microbiology characteristics of 38 children diagnosed with brain abscess hospitalized between 4/1/2005 and 12/31/2015 at Hospital de Pediatria "Prof. Dr. Juan P. Garrahan" in Buenos Aires City. Twenty-four patients were male. The median age was 132 months. Predisposing factors were detected in 25 children. The median evolution from onset of symptoms to the visit was 7 days. There were 27 cases with single lesions. Surgical drainage was performed in 34 patients. The most frequent bacteria were anaerobes, Streptococcus viridans and Staphylococcus aureus. The median of antibiotic treatment was 56 days and the median of hospitalization was 43 days. The lethality was 3%. PMID- 28737875 TI - [Intestinal cystic duplication. Case report]. AB - Intestinal cystic duplications are rare congenital anomalies, with an estimated incidence of approximately 1:4500 autopsies. The etiopathogenesis is uncertain. These duplications are cystic, tubular or diverticular structures lined with gastrointestinal mucosa. They share a common smooth muscle wall with the gastrointestinal tract but usually their lumens do not communicate with each other. Gastric duplication cysts represent 7-9% of the gastrointestinal tract duplication. They can be diagnosed prenatally by fetal ultrasound; magnetic resonance imaging characterizes the cyst and excludes other malformations. Postnatal ultrasound shows a characteristic double walled cyst. Newborns are usually asymptomatic, although nonspecific gastrointestinal symptoms, intestinal obstruction due to mass effect, volvulus or infection are described. In asymptomatic patients, clinical follow-up and periodic image controls are recommended. Elective surgical resection is the treatment of choice, using minimally invasive technique whenever possible. A case of prenatally suspected intestinal cystic duplication is presented. PMID- 28737876 TI - [Acute pericarditis, complicated by pericardial effusion in a pediatric patient: case report]. AB - Acute pericarditis is the most common disease of the pericardium encountered in clinical practice. It is diagnosed in 0.1% of all admissions and 5% of emergency room admissions for chest pain. In developed countries, it is usually due to a benign cause. Idiopathic and infectious pericarditis are more common than secondary to surgical pericardiotomy or neoplastic causes, whereas tuberculosis is the dominant cause in developing countries. The most common symptoms of pericarditis are characteristic chest pain and fever. Since pericarditis presents a benign outcome because of self-limiting and good response to conventional anti inflammatory therapy, it can be safely managed on outpatient basis unless a specific cause is suspected or the patient has high-risk features to avoid complications such as pericardial effusion, cardiac tamponade or recurrent pericarditis. We report a case of pericarditis, diagnosed 9 months after surgical closure of an atrial septal defect, in a 7-year-old boy with favorable evolution. PMID- 28737877 TI - [Neisseria gonorrhoeae: an infrequent causal agent of periorbital cellulitis in a child]. AB - Periorbital cellulitis is a very common disease in pediatric population, it describes an infection involving the adjacent soft tissues anterior to the orbital septum. Pathogens involved are generally Gram-positive cocci after introduction of Haemophilus influenzae vaccine. We report a case of Neisseria gonorrhoeae periorbital cellulitis associated with bacterial conjunctivitis in a child. There are few cases reported in the literature with this microorganism as the causal agent. With this case, we would like to emphasize the importance to do a culture of the ocular secretion (if it exists) because this allowed us to determine an infrequent agent of this disease. PMID- 28737878 TI - [Unusual case of food protein-induced enterocolitis syndrome]. AB - Food protein-induced enterocolitis syndrome is a nonimmunoglobulin E mediated gastrointestinal food hypersensitivity that manifests as profuse, repetitive vomiting, pallor and hypotonia, often with diarrhea leading to severe dehydration and lethargy (sepsis-like symptoms) in the acute setting. An oral food challenge is sometimes performed to confirm the diagnosis and treatment consists of elimination of the food trigger(s) from the diet. We report a case of a 3 monthsold infant with several episodes of food protein-induced enterocolitis syndrome after taking infant formula milk with tolerance of another trademark. Differences in the composition of its ingredients could be the cause of the sensitization. PMID- 28737879 TI - [Visceral leishmaniasis. Pediatric case report]. AB - La leishmaniasis es una enfermedad causada por parasitos obligados intracelulares pertenecientes al genero Leishmania y que reconoce tres formas clinicas principales: cutanea, visceral y mucocutanea. Es una patologia del grupo de las "enfermedades desatendidas". Es la unica enfermedad tropical transmitida a traves de vectores que se ha mantenido endemica por decadas en el sur de Europa. La leishmaniasis visceral representa la forma mas grave. Se caracteriza por fiebre, perdida de peso, anemia y hepatoesplenomegalia. Su periodo de incubacion oscila entre 2 semanas y 18 meses. La leishmaniasis se considera una enfermedad reemergente a nivel mundial. Algunos de los factores que favorecen esta situacion son los cambios en las condiciones climaticas, migraciones y urbanizaciones deficitarias en saneamiento ambiental. Se presenta el caso de un nino europeo que estaba vacacionando en Cordoba y fue derivado a nuestro Hospital por fiebre y pancitopenia, lo que genero un abordaje multidisciplinario con resolucion clinica favorable. PMID- 28737880 TI - [Pheochromocytoma presenting with secondary enuresis in a 13-year-old girl]. AB - Pheochromocytoma is a rare tumor which is infrequent in children. Although the clinical presentation in children can be atypical, the classic symptoms are headache, sweating and tachycardia. Hypertension is often a constant sign in most patients. There are few cases in literature reporting pheochromocytoma presented with polyuria. We present a 13-year-old girl who came to the Pediatric Nephrologist due to a year of evolution of secondary enuresis. When her blood pressure was taken, she was above the 99th percentile that corresponds to her age and her height that is why she was admitted for treatment and diagnostic study. PMID- 28737881 TI - [Bronchial mucoepidermoid carcinoma in childhood. Case report]. AB - Bronchial tumors are rare in children. Most of them are malignant, being the carcinoid tumor the most common. Less frequently the mucoepidermoid carcinoma is found in the tracheobronchial tree. Mucoepidermoid carcinoma accounts for 0.1 to 0.2% of all malignant bronchopulmonary tumors. It manifests with symptoms of airway obstruction and/or recurrent pneumonias. Early diagnosis and appropriate treatment are of great importance in the prognosis. Bronchoscopy with biopsy of the endobronchial mass is the method of choice to confirm the diagnosis. Treatment consists of surgical resection of the lesion. We present an 11-year-old girl with dyspnea on exertion and cough due to a low malignant mucoepidermoid arcinoma of the ronchi. We describe the clinical manifestations, the diagnostic methods and the treatment of this rare neoplasia in pediatrics. PMID- 28737882 TI - [Training of resident physicians in the recognition and treatment of an anaphylaxis case in pediatrics with simulation models]. AB - OBJETIVE: To evaluate the performance of resident physicians in diagnosing and treating a case of anaphylaxis, six months after participating in simulation training exercises. METHODS: Initially, a group of pediatric residents were trained using simulation techniques in the management of critical pediatric cases. Based on their performance in this exercise, participants were assigned to one of 3 groups. At six months post-training, 4 residents were randomly chosen from each group to be re-tested, using the same performance measure as previously used. RESULTS: During the initial training session, 56 of 72 participants (78%) correctly identified and treated the case. Six months after the initial training, all 12 (100%) resident physicians who were re-tested successfully diagnosed and treated the simulated anaphylaxis case. CONCLUSIONS: The training through simulation techniques allowed correction or optimization of the treatment of simulated anaphylaxis cases in resident physicians evaluated after 6 months of the initial training. PMID- 28737883 TI - [Infants, children, adolescents and screens: what's new?] PMID- 28737884 TI - [Deficiencia de hierro y anemia ferropenica. Guia para su prevencion, diagnostico y tratamiento. PMID- 28737886 TI - Ex Vivo Rat Eye Model for Investigating Transport of Next Generation Precision Polyester Nanosystems. AB - We present for the first time a robust ex vivo rat eye model for investigating the transport of precision-polyester nanosystems (P2Ns) across the blood-retinal barrier, intended for systemic administration. The P2Ns-GA actively transport exploiting transferrin receptors present in the inner retinal barrier and colocalize in ganglion cells. Such delivery approaches have the potential to deliver drugs to posterior segments of the eye, which is still a major challenge in treating posterior ocular disorders. PMID- 28737885 TI - Classics in Chemical Neuroscience: Memantine. AB - Memantine was the first breakthrough medication for the treatment of moderate to severe Alzheimer's disease (AD) patients and represents a fundamentally new mechanism of action (moderate-affinity, uncompetitive, voltage-dependent, N methyl-d-aspartate (NMDA) receptor antagonist that exhibits fast on/off kinetics) to modulate glutamatergic dysfunction. Since its approval by the FDA in 2003, memantine, alone and in combination with donepezil, has improved patient outcomes in terms of cognition, behavioral disturbances, daily functioning, and delaying time to institutionalization. In this review, we will highlight the historical significance of memantine to AD (and other neuropsychiatric disorders) as well as provide an overview of the synthesis, pharmacology, and drug metabolism of this unique NMDA uncompetitive antagonist that clearly secures its place among the Classics in Chemical Neuroscience. PMID- 28737887 TI - Enhanced Triboelectric Nanogenerators Based on MoS2 Monolayer Nanocomposites Acting as Electron-Acceptor Layers. AB - As one of their major goals, researchers attempting to harvest mechanical energy efficiently have continuously sought ways to integrate mature technologies with cutting-edge designs to enhance the performances of triboelectric nanogenerators (TENGs). In this research, we introduced monolayer molybdenum-disulfide (MoS2) into the friction layer of a TENG as the triboelectric electron-acceptor layer in an attempt to dramatically enhance its output performance. As a proof of the concept, we fabricated a vertical contact-separation mode TENG containing monolayer MoS2 as an electron-acceptor layer and found that the TENG exhibited a peak power density as large as 25.7 W/m2, which is 120 times larger than that of the device without monolayer MoS2. The mechanisms behind the performance enhancement, which are related to the highly efficient capture of triboelectric electrons in monolayer MoS2, are discussed in detail. This study indicates that monolayer MoS2 can be used as a functional material for efficient energy harvesting. PMID- 28737889 TI - Application of Resonance Ionization Mass Spectrometry for Ultratrace Analysis of Technetium. AB - This work shows the ability of resonance ionization mass spectrometry (RIMS) to determine 99gTc at the ultratrace level. The characterization of the prepared samples by X-ray photoelectron spectroscopy (XPS) and optimization of the RIMS setup for this purpose, as well as the application of the RIMS method to a soil sample, are presented in this article. 97Tc was used as a tracer isotope to determine the amount of 99gTc in a soil sample with RIMS. With 8.8 * 1010 atoms of 97Tc as the tracer, the concentration of 99gTc was found to be 1.5 * 109 atoms per gram of dried sample material, demonstrating the sensitivity of the method. Furthermore, it could be shown that the 97Tc solution contained 98Tc as well. This is the first time that 97,98,99gTc have been simultaneously measured with RIMS. PMID- 28737888 TI - Discovery of Novel Proline-Based Neuropeptide FF Receptor Antagonists. AB - The neuropeptide FF (NPFF) system has been implicated in a number of physiological processes including modulating the pharmacological activity of opioid analgesics and several other classes of drugs of abuse. In this study, we report the discovery of a novel proline scaffold with antagonistic activity at the NPFF receptors through a high throughput screening campaign using a functional calcium mobilization assay. Focused structure-activity relationship studies on the initial hit 1 have resulted in several analogs with calcium mobilization potencies in the submicromolar range and modest selectivity for the NPFF1 receptor. Affinities and potencies of these compounds were confirmed in radioligand binding and functional cAMP assays. Two compounds, 16 and 33, had good solubility and blood-brain barrier permeability that fall within the range of CNS permeant candidates without the liability of being a P-glycoprotein substrate. Finally, both compounds reversed fentanyl-induced hyperalgesia in rats when administered intraperitoneally. Together, these results point to the potential of these proline analogs as promising NPFF receptor antagonists. PMID- 28737890 TI - A Difluoroboron beta-Diketonate Probe Shows "Turn-on" Near-Infrared Fluorescence Specific for Tau Fibrils. AB - Tau aggregation in neuronal cells has recently received significant attention as a robust predictor of the progression of Alzheimer's disease (AD) because of its proven correlation with the degree of cognitive impairment in AD patients. Accordingly, noninvasive imaging of tau aggregates has been highlighted as a promising diagnostic tool for AD. We have previously identified a tau-specific "turn-on" near-infrared fluorescent (NIRF) probe (1), and, in this study, structural modification was performed to optimize its physicochemical as well as fluorescence properties. Thus, a series of fluorescent dyes (2a-2j) composed of a variously substituted difluoroboron beta-diketonate and an N,N-dimethylaniline moiety linked by a length-extendable pi-bridge were prepared. Among those, isobutyl-substituted difluoroboron beta-ketonate with a pi-conjugated 1,4 butadienyl linker (2e) showed the most promising properties as a tau-specific NIRF probe. Compared with 1, the "turn-on" fluorescence of 2e was more specific to tau fibrils, and it showed 8.8- and 6.2-times higher tau-over-Abeta and tau over-BSA specificity, respectively. Also, the fluorescence intensity of 2e upon binding to tau fibrils was substantially higher (~2.9 times) than that observed from 1. The mechanism for tau-specificity of 2e was investigated, which suggested that the molecular rotor-like property of 2e enables specific recognition of the microenvironment of tau aggregates to emit strong fluorescence. In transgenic cell lines stably expressing GFP-tagged tau proteins, 2e showed good colocalization with tau-GFP. Moreover, the fluorescence from 2e exhibited almost complete overlap with p-Tau antibody staining in the human AD brain tissue section. Collectively, these observations demonstrate the potential of 2e as a tau-specific fluorescent dye in both in vitro and ex vivo settings. PMID- 28737891 TI - Dynamic Chemistry-Based Sensing: A Molecular System for Detection of Saccharide, Formaldehyde, and the Silver Ion. AB - Development of artificial complex molecular systems is of great importance in understanding complexity in natural processes and for achieving new functionalities. One of the strategies is to create them via optimized utilization of noncovalent interactions and dynamic covalent bonds. We report here on a new complex molecular system, which was constructed by integrating the multiple interactions containing a dynamic covalent interaction between 1,2-diol and boronic acid, a coordination interaction between the silver ion and pyridyl, and an easy accessible reaction between secondary amine and formaldehyde. By employing the three dynamic interactions, a pyrene (Py) labeled fluorophore, PPB, was designed and synthesized. The compound reacts with fructose (F), a monosaccharide, in aqueous phase and produces a fluorescent adduct, PPB-F, which can be further used as a sensing platform for formaldehyde (FA) and the silver ion. The respective dynamic interactions are accompanied with color changes due to the reversible switching between Py-monomer emission and excimer emission. The respective experimental detection limits (DLs) for the three analytes are much lower than 0.2 mM, 0.1 mM, and 2.5 MUM, respectively. The presence of relevant compounds or ions shows little effect upon the sensing. No doubt, the results as presented show that the integration of supramolecular interactions including dynamic covalent bonds can be employed as a general strategy to develop new functional molecular systems or materials. PMID- 28737892 TI - Automated in Situ Measurement of Gas Solubility in Liquids with a Simple Tube-in Tube Reactor. AB - Data on the solubilities of gases in liquids are foundational for assessing a variety of multiphase separations and gas-liquid reactions. Taking advantage of the tube-in-tube reactor design built with semipermeable Teflon AF-2400 tubes, liquids can be rapidly saturated without direct contacting of gas and liquid. The gas solubility can be determined by performing steady-state flux balances of both the gas and liquid flowing into the reactor system. Using this type of reactor, a fully automated strategy has been developed for the rapid in situ measurement of gas solubilities in liquids. The developed strategy enables precise gas solubility measurements within 2-5 min compared with 4-5 h using conventional methods. This technique can be extended to the discrete multipoint steady-state and continuous ramped-multipoint data acquisition methods. The accuracy of this method has been validated against several gas-liquid systems, showing less than 2% deviation from known values. Finally, this strategy has been extended to measure the temperature dependence of gas solubilities in situ and to estimate the local enthalpy of dissolution across a defined temperature range. PMID- 28737893 TI - Uncondensed Graphitic Carbon Nitride on Reduced Graphene Oxide for Oxygen Sensing via a Photoredox Mechanism. AB - Melon, a polymeric, uncondensed graphitic carbon nitride with a two-dimensional structure, has been coupled with reduced graphene oxide (rGO) to create an oxygen chemiresistor sensor that is active under UV photoactivation. Oxygen gas is an important sensor target in a variety of areas including industrial safety, combustion process monitoring, as well as environmental and biomedical fields. Because of the intimate electrical interface formed between melon and rGO, charge transfer of photoexcited electrons occurs between the two materials when under UV (lambda = 365 nm) irradiation. A photoredox mechanism wherein oxygen is reduced on the rGO surface provides the basis for sensing oxygen gas in the concentration range 300-100 000 ppm. The sensor response was found to be logarithmically proportional to oxygen gas concentration. DFT calculations of a melon-oxidized graphene composite found that slight protonation of melon leads to charge accumulation on the rGO layer and a corresponding charge depletion on the melon layer. This work provides an example of a metal-free system for solid-gas interface sensing via a photoredox mechanism. PMID- 28737894 TI - Dual Role of Gold Nanorods: Inhibition and Dissolution of Abeta Fibrils Induced by Near IR Laser. AB - Extracellular plaques of amyloid beta (Abeta) fibrils and neurofibrillary tangles are known to be associated with neurological diseases such as Alzheimer's disease. Studies have shown that spherical nanoparticles inhibit the formation of Abeta fibrils by intercepting the nucleation and growth pathways of fibrillation. In this report, gold nanorods (AuNRs) are used to inhibit the formation of Abeta fibrils and the shape-dependent plasmonic properties of AuNRs are exploited to faciliate faster dissolution of mature Abeta fibrils. Negatively charged, lipid (DMPC) stabilized AuNRs inhibit the formation of fibrils due to selective binding to the positevly charged amyloidogenic sequence of Abeta protein. The kinetics of inhibition is characterized by thioflavin T (ThT) fluorescence, transmission electronic microscopy (TEM), atomic force microscopy (AFM), and attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR). An increase in the aspect ratio of DMPC-AuNR in the range of 2.2-4.2 decreased the fibrils content proportionally. Further, the fibrils content is decreased by increasing the concentration of AuNR for all aspect ratios. As AuNR absorb near-infrared (NIR) light and creates a localized hotspot, NIR laser (800 nm) is applied for 2 min to facilitate the thermal dissolution of mature Abeta fibrils. Majority of Abeta fibrils are disintegrated into smaller fragments after exposure to NIR in the presence of AuNR. Thus, the DMPC-AuNRs exhibit a dual effect: inhibition of fibrillation and NIR laser facilitated dissolution of mature amyloid fibrils. This study essentially provides guidelines to design efficient nanoparticle-based therapeutics for neurodegenerative diseases. PMID- 28737895 TI - Cell Wall Remodeling of Staphylococcus aureus in Live Caenorhabditis elegans. AB - Peptidoglycan (PG) scaffolds are critical components of bacterial cell walls. They counter internal turgor pressure to prevent lysis and protect against external insults. It was recently discovered that various types of bacteria release large quantities of PG building blocks (d-amino acids) into their surrounding medium. Contrarily, cultured bacteria were also found to incorporate d-amino acids (both natural and synthetic) from the medium directly into their PG scaffold. These two processes may potentially function, in concert, to metabolically remodel PG in live host organisms. However, demonstration that bacteria can decorate their cell surfaces with exogenous d-amino acids was limited to in vitro culture conditions. We present the first evidence that bacteria remodel their PG with exogenous d-amino acids in a live host animal. A tetrazine click partner was conjugated onto the side chain of a d-amino acid to capture incorporation into the bacterial PG scaffold using a complementary click reactive fluorophore. Staphylococcus aureus infected Caenorhabditis elegans treated with exogenous d-amino acids readily revealed in vivo PG labeling. These results suggest that extracellular d-amino acids may provide pathogens with a mode of late-stage in vivo cell-surface remodeling. PMID- 28737896 TI - Interfacial Shear Strength and Adhesive Behavior of Silk Ionomer Surfaces. AB - The interfacial shear strength between different layers in multilayered structures of layer-by-layer (LbL) microcapsules is a crucial mechanical property to ensure their robustness. In this work, we investigated the interfacial shear strength of modified silk fibroin ionomers utilized in LbL shells, an ionic cationic pair with complementary ionic pairing, (SF)-poly-l-glutamic acid (Glu) and SF-poly-l-lysine (Lys), and a complementary pair with partially screened Coulombic interactions due to the presence of poly(ethylene glycol) (PEG) segments and SF-Glu/SF-Lys[PEG] pair. Shearing and adhesive behavior between these silk ionomer surfaces in the swollen state were probed at different spatial scales and pressure ranges by using functionalized atomic force microscopy (AFM) tips as well as functionalized colloidal probes. The results show that both approaches were consistent in analyzing the interfacial shear strength of LbL silk ionomers at different spatial scales from a nanoscale to a fraction of a micron. Surprisingly, the interfacial shear strength between SF-Glu and SF Lys[PEG] pair with partially screened ionic pairing was greater than the interfacial shear strength of the SF-Glu and SF-Lys pair with a high density of complementary ionic groups. The difference in interfacial shear strength and adhesive strength is suggested to be predominantly facilitated by the interlayer hydrogen bonding of complementary amino acids and overlap of highly swollen PEG segments. PMID- 28737897 TI - Biogenic Hydroxyapatite: A New Material for the Preservation and Restoration of the Built Environment. AB - Ordinary Portland cement (OPC) is by weight the world's most produced man-made material and is used in a variety of applications in environments ranging from buildings, to nuclear wasteforms, and within the human body. In this paper, we present for the first time the direct deposition of biogenic hydroxyapatite onto the surface of OPC in a synergistic process which uses the composition of the cement substrate. This hydroxyapatite is very similar to that found in nature, having a similar crystallite size, iron and carbonate substitution, and a semi crystalline structure. Hydroxyapatites with such a structure are known to be mechanically stronger and more biocompatible than synthetic or biomimetic hydroxyapatites. The formation of this biogenic hydroxyapatite coating therefore has significance in a range of contexts. In medicine, hydroxyapatite coatings are linked to improved biocompatibility of ceramic implant materials. In the built environment, hydroxyapatite coatings have been proposed for the consolidation and protection of sculptural materials such as marble and limestone, with biogenic hydroxyapatites having reduced solubility compared to synthetic apatites. Hydroxyapatites have also been established as effective for the adsorption and remediation of environmental contaminants such as radionuclides and heavy metals. We identify that in addition to providing a biofilm scaffold for nucleation, the metabolic activity of Pseudomonas fluorescens increases the pH of the growth medium to a suitable level for hydroxyapatite formation. The generated ammonia reacts with phosphate in the growth medium, producing ammonium phosphates which are a precursor to the formation of hydroxyapatite under conditions of ambient temperature and pressure. Subsequently, this biogenic deposition process takes place in a simple reaction system under mild chemical conditions and is cheap and easy to apply to fragile biological or architectural surfaces. PMID- 28737898 TI - Systematic Thermodynamics of Layered Perovskites: Ruddlesden-Popper Phases. AB - Perovskite, CaTiO3, is the prototype of an extensive group of materials. They are capable of considerable chemical modification, with the further capability of undergoing structural modification by the intercalation of thin sheets of intrusive materials (both inorganic and organic) between the cubic perovskite layers, to form a range of "layered" perovskites. These changes bring about alterations in their electronic, structural, and other properties, permitting some "tuning" toward specific ends. This paper collects the limited known thermodynamic data for layered perovskites of various chemical compositions and demonstrates by example that the thermodynamic layer values are substantially additive. This additivity may be exploited by summing properties of the constituent oxides, by adding differences between adjacent compositions within a series, or even by substitution of oxides for one another, thus permitting prediction beyond the known range of compositions. Strict additivity implies full reversibility so that the additive product may be unstable and may undergo structural changes, producing materials with new and potentially useful properties such as ferroelectricity, polarity, giant magnetoresistance, and superconductivity. PMID- 28737899 TI - alpha-Amino Acid Derived Benzimidazole-Linked Rhodamines: A Case of Substitution Effect at the Amino Acid Site toward Spiro Ring Opening for Selective Sensing of Al3+ Ions. AB - alpha-Amino acid derived benzimidazole-linked rhodamines have been synthesized, and their metal ion sensing properties have been evaluated. Experimentally, l valine- and l-phenylglycine-derived benzimidazole-based rhodamines 1 and 2 selectively recognize Al3+ ion in aqueous CH3CN (CH3CN/H2O 4/1 v/v, 10 mM tris HCl buffer, pH 7.0) over the other cations by exhibiting color and "turn-on" emission changes. In contrast, glycine-derived benzimidazole 3 remains silent in the recognition event and emphasizes the role of alpha-substitution of amino acid undertaken in the design. The fact has been addressed on the basis of the single crystal X-ray structures and theoretical calculations. Moreover, pink 1.Al3+ and 2.Al3+ ensembles selectively sensed F- ions over other halides through a discharge of color. Importantly, compounds 1 and 2 are cell permeable and have been used as imaging reagents for the detection of Al3+ uptake in human lung carcinoma cell line A549. PMID- 28737901 TI - Addition and Correction to Complete Field Guide to Asymmetric BINOL-Phosphate Derived Bronsted Acid and Metal Catalysis: History and Classification by Mode of Activation; Bronsted Acidity, Hydrogen Bonding, Ion Pairing, and Metal Phosphates. PMID- 28737900 TI - Accumulation of Charantin and Expression of Triterpenoid Biosynthesis Genes in Bitter Melon (Momordica charantia). AB - Charantin, a natural cucurbitane type triterpenoid, has been reported to have beneficial pharmacological functions such as anticancer, antidiabetic, and antibacterial activities. However, accumulation of charantin in bitter melon has been little studied. Here, we performed a transcriptome analysis to identify genes involved in the triterpenoid biosynthesis pathway in bitter melon seedlings. A total of 88,703 transcripts with an average length of 898 bp were identified in bitter melon seedlings. On the basis of a functional annotation, we identified 15 candidate genes encoding enzymes related to triterpenoid biosynthesis and analyzed their expression in different organs of mature plants. Most genes were highly expressed in flowers and/or fruit from the ripening stages. An HPLC analysis confirmed that the accumulation of charantin was highest in fruits from the ripening stage, followed by male flowers. The accumulation patterns of charantin coincide with the expression pattern of McSE and McCAS1, indicating that these genes play important roles in charantin biosynthesis in bitter melon. We also investigated optimum light conditions for enhancing charantin biosynthesis in bitter melon and found that red light was the most effective wavelength. PMID- 28737902 TI - Absorption of Low-Energy UV Radiation by Human Telomere G-Quadruplexes Generates Long-Lived Guanine Radical Cations. AB - Telomeres, which are involved in cell division, carcinogenesis, and aging and constitute important therapeutic targets, are prone to oxidative damage. This propensity has been correlated with the presence of guanine-rich sequences, capable of forming four-stranded DNA structures (G-quadruplexes). Here, we present the first study on oxidative damage of human telomere G-quadruplexes without mediation of external molecules. Our investigation has been performed for G-quadruplexes formed by folding of GGG(TTAGGG)3 single strands in buffered solutions containing Na+ cations (TEL21/Na+). Associating nanosecond time resolved spectroscopy and quantum mechanical calculations (TD-DFT), it focuses on the primary species, ejected electrons and guanine radicals, generated upon absorption of UV radiation directly by TEL21/Na+. We show that, at 266 nm, corresponding to an energy significantly lower than the guanine ionization potential, the one-photon ionization quantum yield is 4.5 * 10-3. This value is comparable to that of cyclobutane thymine dimers (the major UV-induced lesions) in genomic DNA; the quantum yield of these dimers in TEL21/Na+ is found to be (1.1 +/- 0.1) * 10-3. The fate of guanine radicals, generated in equivalent concentration with that of ejected electrons, is followed over 5 orders of magnitude of time. Such a quantitative approach reveals that an important part of radical cation population survives up to a few milliseconds, whereas radical cations produced by chemical oxidants in various DNA systems are known to deprotonate, at most, within a few microseconds. Under the same experimental conditions, neither one-photon ionization nor long-lived radical cations are detected for the telomere repeat TTAGGG in single-stranded configuration, showing that secondary structure plays a key role in these processes. Finally, two types of deprotonated radicals are identified: on the one hand, (G-H2)* radicals, stable at early times, and on the other hand, (G-H1)* radicals, appearing within a few milliseconds and decaying with a time constant of ~50 ms. PMID- 28737903 TI - Transition Metal Functionalization of P4 Using a Diarylgermylene Anchor. AB - The manipulation of white phosphorus (P4) has been a long-standing challenge for chemists. While the holy grail remains at finding a method to catalytically activate and functionalize P4 to yield new organophosphorus compounds, fundamental research lies in developing procedures to control the reactivity of elemental phosphorus. In this work, Lewis acidic transition metal moieties M(CO)5 (M = Cr, Mo, W) and AuCl react with P4 derivatized with a low valent germanium compound. For both M(CO)5 and AuCl, bis-functionalized products can be formed; however the monosubstituted derivatives are found to be more stable, and the decomposition can be monitored by 31P{1H} NMR spectroscopy. The selective reactivity of white phosphorus, once a P-P bond has been activated, is a key step in yielding new organophosphorus compounds. PMID- 28737904 TI - Ni-Catalyzed Regioselective 1,2-Dicarbofunctionalization of Olefins by Intercepting Heck Intermediates as Imine-Stabilized Transient Metallacycles. AB - We disclose a strategy for Ni-catalyzed dicarbofunctionalization of olefins in styrenes by intercepting Heck C(sp3)-NiX intermediates with arylzinc reagents. This approach utilizes a readily removable imine as a coordinating group that plays a dual role of intercepting oxidative addition species derived from aryl halides and triflates to promote Heck carbometalation and stabilizing the Heck C(sp3)-NiX intermediates as transient metallacycles to suppress beta-hydride elimination and facilitate transmetalation/reductive elimination steps. This method affords diversely substituted 1,1,2-triarylethyl products that occur as structural motifs in various natural products. PMID- 28737905 TI - Metabolism of T-2 Toxin in Farm Animals and Human In Vitro and in Chickens In Vivo Using Ultra High-Performance Liquid Chromatography- Quadrupole/Time-of Flight Hybrid Mass Spectrometry Along with Online Hydrogen/Deuterium Exchange Technique. AB - After being incubated with animal and human liver microsomes, metabolites of phase I and II were investigated. A comparison was performed by ultrahigh performance liquid chromatography-quadrupole/time-of-flight coupled to mass spectrometry (UHPLC-Q/TOF). Consequently, a total of four phase I metabolites and three glucuronide binding metabolites of T-2 toxin were discovered. Although a significant metabolic difference was observed among six species, HT-2 toxin was the major product in all species. In addition, the in vivo metabolism of T-2 toxin after oral administration was also investigated in chickens, In total, 18 metabolites were detected, of which 13 were novel, to our knowledge, and reported for the first time. To elucidate the structures of these metabolites, besides accurate mass data from their MS and MS2 spectra, online hydrogen/deuterium (H/D) exchange technique was also carried out. These new metabolites were regarded as 3'-hydroxy-T-2 3-sulfate, 3'-hydroxy-HT-2 3-sulfate, 4'-hydroxy-HT-2, 3',4' dihydroxy-HT-2, 4'-carboxyl-T-2, 4'-carboxyl-HT-2, 4'-carboxyl-4'-hydroxy-T-2, and their isomers, implying that T-2 toxin was metabolized more extensively in animals than previously thought. Furthermore, 3'-hydroxy-HT-2, 4'-carboxyl-T-2, 3'-hydroxy-T-2, HT-2 toxin, and neosolaniol were identified to be the major metabolites of T-2 toxin in chickens. The present study expands existing knowledge about T-2 toxin metabolism, informing assessments of the impact T-2 toxin exposure and metabolism on health. PMID- 28737906 TI - Role of Protein Dimeric Interface in Allosteric Inhibition of N-Acetyl-Aspartate Hydrolysis by Human Aspartoacylase. AB - The results of molecular modeling suggest a mechanism of allosteric inhibition upon hydrolysis of N-acetyl-aspartate (NAA), one of the most abundant amino acid derivatives in brain, by human aspartoacylase (hAsp). Details of this reaction are important to suggest the practical ways to control the enzyme activity. Search for allosteric sites using the Allosite web server and SiteMap analysis allowed us to identify substrate binding pockets located at the interface between the subunits of the hAsp dimer molecule. Molecular docking of NAA to the pointed areas at the dimer interface predicted a specific site, in which the substrate molecule interacts with the Gly237, Arg233, Glu290, and Lys292 residues. Analysis of multiple long-scaled molecular dynamics trajectories (the total simulation time exceeded 1.5 MUs) showed that binding of NAA to the identified allosteric site induced significant rigidity to the protein loops with the amino acid side chains forming gates to the enzyme active site. Application of the protein dynamical network algorithms showed that substantial reorganization of the signal propagation pathways of intersubunit communication in the dimer occurred upon allosteric NAA binding to the remote site. The modeling approaches provide an explanation to the observed decrease of the reaction rate of NAA hydrolysis by hAsp at high substrate concentrations. PMID- 28737907 TI - In Situ Solid-Gas Reactivity of Nanoscaled Metal Borides from Molten Salt Synthesis. AB - Metal borides have mostly been studied as bulk materials. The nanoscale provides new opportunities to investigate the properties of these materials, e.g., nanoscale hardening and surface reactivity. Metal borides are often considered stable solids because of their covalent character, but little is known on their behavior under a reactive atmosphere, especially reductive gases. We use molten salt synthesis at 750 degrees C to provide cobalt monoboride (CoB) nanocrystals embedded in an amorphous layer of cobalt(II) and partially oxidized boron as a model platform to study morphological, chemical, and structural evolutions of the boride and the superficial layer exposed to argon, dihydrogen (H2), and a mixture of H2 and carbon dioxide (CO2) through a multiscale in situ approach: environmental transmission electron microscopy, synchrotron-based near-ambient pressure X-ray photoelectron spectroscopy, and near-edge X-ray absorption spectroscopy. Although the material is stable under argon, H2 triggers at 400 degrees C decomposition of CoB, leading to cobalt(0) nanoparticles. We then show that H2 activates CoB for the catalysis of CO2 methanation. A similar decomposition process is also observed on NiB nanocrystals under oxidizing conditions at 300 degrees C. Our work highlights the instability under reactive atmospheres of nanocrystalline cobalt and nickel borides obtained from molten salt synthesis. Therefore, we question the general stability of metal borides with distinct compositions under such conditions. These results shed light on the actual species in metal boride catalysis and provide the framework for future applications of metal borides in their stability domains. PMID- 28737908 TI - Edible Nanoencapsulation Vehicles for Oral Delivery of Phytochemicals: A Perspective Paper. AB - Edible nanoencapsulation vehicles (ENVs) designed for the delivery of phytochemicals have gained increasing research interest. The major driving force for this trend is the potential bioavailability enhancement effect for phytochemicals when delivered via ENVs. ENVs affect the bioefficacy of phytochemicals by influencing their dispersion and gastrointestinal stability, rate and site of release, transportation efficiency across the endothelial layer, systemic circulation and biodistribution, and regulation of gut microflora. Enhanced bioefficacy can be achieved by rational design of the size, surface property, matrix materials, and compartment structure of ENVs according to properties of phytochemicals. Future investigations may lay particular emphasis on examining the relevance between results gained by in vitro digestion simulations and those obtained via in vivo digestion simulations, structural evolutions of ENVs during digestion and absorption, impacts of ENVs on the metabolism of phytochemicals, and using ENVs for deciphering the reciprocal interactions between phytochemicals and gut microbiota. PMID- 28737910 TI - Raman and IR Spectroscopy Studies on Propane at Pressures of Up to 40 GPa. AB - Raman and IR spectroscopy studies on propane were performed at pressures of up to 40 GPa at ambient temperatures using the diamond anvil cell technique. Propane undergoes three phase transitions at 6.4(5), 14.5(5), and 26.5(5) GPa in Raman spectroscopy and at 7.0(5), 14.0(5), and 27.0(5) GPa in IR spectroscopy. The phase transitions were identified using the Raman and IR splitting modes and the appearance or disappearance of peaks, which clearly corresponded to the changes in the frequencies of the modes as the pressure changed. Our results demonstrate the complex high-pressure behavior of solid propane. PMID- 28737911 TI - Platform for Unified Molecular Analysis: PUMA. AB - We introduce a free platform for chemoinformatic-based diversity analysis and visualization of chemical space of user supplied data sets. Platform for Unified Molecular Analysis (PUMA) integrates metrics used to characterize compound databases including visualization of chemical space, scaffold content, and analysis of chemical diversity. The user's input is a file with SMILES, database names, and compound IDs. PUMA computes molecular properties of pharmaceutical relevance, Murcko scaffolds, and diversity analysis. The user can interactively navigate through the graphs and export image files and the raw data of the diversity calculations. The platform links two public online resources: Consensus Diversity Plots for the assessment of global diversity and Activity Landscape Plotter to analyze structure-activity relationships. Herein, we describe the functionalities of PUMA and exemplify its use through the analysis of compound databases of general interest. PUMA is freely accessible at the authors web-site https://www.difacquim.com/d-tools/ . PMID- 28737909 TI - Inhibitory Kappa B Kinase alpha (IKKalpha) Inhibitors That Recapitulate Their Selectivity in Cells against Isoform-Related Biomarkers. AB - IKKbeta plays a central role in the canonical NF-kB pathway, which has been extensively characterized. The role of IKKalpha in the noncanonical NF-kB pathway, and indeed in the canonical pathway as a complex with IKKbeta, is less well understood. One major reason for this is the absence of chemical tools designed as selective inhibitors for IKKalpha over IKKbeta. Herein, we report for the first time a series of novel, potent, and selective inhibitors of IKKalpha. We demonstrate effective target engagement and selectivity with IKKalpha in U2OS cells through inhibition of IKKalpha-driven p100 phosphorylation in the noncanonical NF-kB pathway without affecting IKKbeta-dependent IKappa-Balpha loss in the canonical pathway. These compounds represent the first chemical tools that can be used to further characterize the role of IKKalpha in cellular signaling, to dissect this from IKKbeta and to validate it in its own right as a target in inflammatory diseases. PMID- 28737912 TI - Molecular Structure, Equilibrium Conformation, and Ring-Puckering Motion in 1,1,3,3-Tetramethylcyclobutane. An Electron-Diffraction Investigation Augmented by Molecular Orbital and Normal Coordinate Calculations. AB - The molecule cyclobutane (CB) has a nonplanar carbon skeleton folded around a line connecting diagonally opposite atoms. The puckering angle (the change from planarity) of ~30 degrees is generally attributed to steric repulsion between the four sets of adjacent methylene groups that would be opposed in a planar ring and is relieved by the puckering. According to this criterion, a similar molecule, 1,1,3,3-tetramethylcyclobutene (TMCB), in which adjacent methylene groups do not exist, would be expected to have a planar ring in the equilibrium form. We have investigated the structure of TMCB to test this expectation. Two models were designed for the tests: one having D2h symmetry (planar ring) and one of C2v symmetry (nonplanar ring). Each model incorporated the dynamics of large amplitude bending around a line joining the methylene groups. Our results suggest the D2h model is to be preferred. Dynamic averages (rg/A; ?g/deg) of the more important distances and angles in the D2h model with estimated 2sigma uncertainties, are as follows. = 1.105 (5), C1-C5 = 1.524 (10), C1-C2 = 1.559 (11), C2-C1-C4 = 87.4 (8), C1-C2-C3 = 92.0 (7), C5-C1-C6 = 109.0 (13), and C2-C1-C5 = 115.8 (8). The large-amplitude bending of the ring leads to a thermal average value of the folding angle equal to 177.1 degrees . The results, including the differences between TMCB and CB, are discussed. PMID- 28737914 TI - Density Functional Theory Study on the Complexation of NOTA as a Bifunctional Chelator with Radiometal Ions. AB - 1,4,7-Triazacyclononane-1,4,7-triacetic acid (NOTA) is a key bifunctional chelator utilized for the complexation of metal ions in radiopharmaceutical applications; the ability of these chelators depends on the strength of their binding with ions. The focus of the present work is to evaluate the complexation of Cu2+, Ga3+, Sc3+, and In3+ radiometal ions with NOTA using density functional theory (B3LYP functional) and 6-311+G(2d,2p)/DGDZVP basis sets. The significant role of ion-water interactions in the chelation interaction energies in solution reflects the competition between ion-water and NOTA-ion interaction in the chelation process. There is reasonable agreement between experimental and theoretical binding constants, geometries, and 1H NMR chemical shifts. Chelation interaction energies, Gibbs free energies, and entropies in solution show that the NOTA-Ga3+ and NOTA-Cu2+ are the most and least stable complexes, respectively. The natural atomic charges and second order perturbation analysis reveal charge transfer between NOTA and radiometal ions. The theoretical 1H NMR chemical shifts of NOTA are in good agreement with experiment; these values are influenced by the presence of the ions, which have a deshielding effect on the protons of NOTA. Global scalar properties such as EHOMO/ELUMO, DeltaELUMO-HOMO, and chemical hardness/softness confirm that the NOTA-Cu2+ complex, which has a singly occupied molecular orbital, has the lowest DeltaELUMO-HOMO value, the least chemical hardness, and the highest chemical softness. The significant variation of the hardness and DeltaELUMO-HOMO values of the complexes can be attributed to the different positions of the metal ions on the periodic table. This study affirms that, among the radiometal ions, Ga3+ can be used to effectively radiolabel NOTA chelator for radiopharmaceutical usage as it binds most stably with NOTA. PMID- 28737913 TI - UPLC-Q-Exactive Orbitrap/MS-Based Lipidomics Approach To Characterize Lipid Extracts from Bee Pollen and Their in Vitro Anti-Inflammatory Properties. AB - Bee pollen (BP) is collected by honeybees from flower pollen mixed with nectar and its secretions with extensive nutritional and therapeutic properties. Lipids are known to be critical contributors for the therapeutic effects of BP and vary depending on different plant sources; however, lipid profiles of BP are not available. Here, an UPLC-Q-Exactive Orbitrap/MS method was established for comprehensive lipidomics analysis of BP derived from three major nectar plants (Brassica campestris L., Camellia sinensis L., and Nelumbo nucifera Gaertn.). A total of nine lipid classes, including phosphatidylcholine (41 species), phosphatidylethanolamine (43 species), phosphatidylglycerol (9 species), phosphatidylserine (10 species), lysophosphatidylcholine (12 species), ceramide (8 species), diglyceride (27 species), triglyceride (137 species), and fatty acids (47 species), were first identified and quantified in the three BPs. In vitro anti-inflammatory activity was also discovered in the lipid extracts of three BPs, which has potential relevance to the abundance of phospholipids and unsaturated fatty acids in BP. Our comprehensive lipidomics profiling and in vitro anti-inflammatory properties of BP provide evidence for its future application. PMID- 28737915 TI - Extended Study on Crystal Growth and Viscosity in Ge-Sb-Se Bulk Glasses and Thin Films. AB - Crystal growth rates in Ge18Sb28Se54 bulk glass and thin film were measured using optical and scanning electron microscopy under isothermal conditions. The studied temperature region was 255-346 degrees C and 254-286 degrees C for bulk glass and thin film, respectively. The compact crystalline layer growing from the surface into the amorphous core was formed in bulk glasses and no bulk crystallization was observed. In the case of thin films, needle-shape crystals were formed. The crystalline layer and needle-shape crystals grew linearly with time that corresponds to a crystal growth controlled by the crystal-liquid interface kinetics. In the narrow temperature range, crystal growth rates exhibit simple exponential behavior, so the activation energies of crystal growth for the studied temperature regions were estimated (EG = 294 +/- 6 kJ/mol for bulk glass and EG = 224 +/- 12 kJ/mol for thin film). Viscosity of Ge18Sb28Se54 material was measured in the region of the undercooled melt and glass. The extrapolation of viscosity data into the immeasurable, but important, temperature range is discussed. The experimental growth data were combined with melting and viscosity data and the appropriate growth models were proposed to describe crystal growth in a wide temperature region. The standard crystal growth models are based on a simple proportionality of the crystal growth rate to the viscosity (u ? eta-1). This simple proportionality holds for the bulk material. Nevertheless, in the thin films the decoupling of the crystal growth rate from the inverse viscosity occurs, and the standard kinetic growth models need to be corrected. Such corrections provide better description of experimental data and more realistic value of the parameter describing the mean interatomic distance in the crystal liquid interface layer, where the crystal growth takes place. PMID- 28737916 TI - The Conjugated Double Bond of Coniferyl Aldehyde Is Essential for Heat Shock Factor 1 Mediated Cytotoprotection. AB - Coniferyl aldehyde (1) is previously reported as a potent inducer of heat shock factor 1 (HSF1). Here, we further examined the active pharmacophore of 1 for activation of HSF1 using the derivatives coniferyl alcohol (2), 4-hydroxy-3 methoxyphenylpropanal (3), and 4-hydroxy-3-methoxyphenylpropanol (4). Both 1 and 2 resulted in increased survival days after a lethal radiation (IR) dose. The decrease in bone marrow (BM) cellularity and Ki67-positive BM cells by IR was also significantly restored by 1 or 2 in mice. These results suggested that the vinyl moiety of 1 and 2 is necessary for inducing HSF1, which may be useful for developing small molecules for cytoprotection of normal cells against damage by cytotoxic drugs and radiation. PMID- 28737917 TI - Antagonistic Interplay Between an Intermolecular CH...O and an Intramolecular OH...O Hydrogen Bond in a 1:1 Complex Between 1,2-Cyclohexanedione and Chloroform: A Combined Matrix Isolation Infrared and Quantum Chemistry Study. AB - Matrix isolation infrared spectra of a weak C-H...O hydrogen-bonded complex between the keto-enol form of 1,2-cyclohexanedione (HCHD) and chloroform have been measured. The spectra reveal that the intramolecular O-H...O H-bond of HCHD is weakened as a result of complex formation, manifesting in prominent blue shift (~23 cm-1) of the nuO-H band and red shifts (~7 cm-1) of nuC?O bands of the acceptor (HCHD). The nuC-H band of donor CHCl3 undergoes a large red shift of ~33 cm-1. Very similar spectral effects are also observed for formation of the complex in CCl4 solution at room temperature. Our analysis reveals that out of several possible iso-energetic conformational forms of the complex, the one involving antagonistic interplay between the two hydrogen bonds (intermolecular C H...O and intramolecular O-H...O) is preferred. The combined experimental and calculated data presented here suggest that in condensed media, conformational preferences are guided by directional hyperconjugative charge transfer interactions at the C-H...O hydrogen bonding site of the complex. PMID- 28737918 TI - Reactive, Inelastic, and Dissociation Processes in Collisions of Atomic Oxygen with Molecular Nitrogen. AB - We report the results of detailed calculations of reactive, inelastic, and dissociative processes in collisions of atomic oxygen with molecular nitrogen in their respective electronic ground states. Cross sections are calculated as a function of collision energy in the range 0.001-10 eV, considering the whole rovibrational ladder. Some problems related to the vibrational energy levels of the asymptotes of 3A" and 3A' potential energy surfaces used in this work are solved by an appropriate scaling at the level of cross sections. The results are compared with data in the literature, obtaining excellent agreement with experimental thermal data for reactive processes on a very large temperature range, and reasonable agreement with indirect dissociative data. Significant discrepancies are observed with previous reactive state-to-state results calculated on less detailed potential energy surfaces. Inelastic results are compatible with extrapolation of experimental thermal rate coefficient for temperatures higher than 4500 K but completely fail to reproduce experimental data at room temperature. The issue is discussed, indicating the reasons and possible solutions to the problem, and a resonable rate coefficient is obtained combining experimental and theoretical results in the range 300-20000 K. Complete, accurate fits are provided for both reactive and dissociative state-to state rate coefficients to use them in applicative numerical codes concerning air kinetics. PMID- 28737919 TI - Proton-Detected NMR Spectroscopy of Nanodisc-Embedded Membrane Proteins: MAS Solid-State vs Solution-State Methods. AB - The structural and dynamical characterization of membrane proteins in a lipid bilayer at physiological pH and temperature and free of crystal constraints is crucial for the elucidation of a structure/dynamics-activity relationship. Toward this aim, we explore here the properties of the outer-membrane protein OmpX embedded in lipid bilayer nanodiscs using proton-detected magic angle spinning (MAS) solid-state NMR at 60 and 110 kHz. [1H,15N]-correlation spectra overlay well with the corresponding solution-state NMR spectra. Line widths as well as line intensities in solid and solution both depend critically on the sample temperature and, in particular, on the crossing of the lipid phase transition temperature. MAS (110 kHz) experiments yield well-resolved NMR spectra also for fully protonated OmpX and both below and above the lipid phase transition temperature. PMID- 28737921 TI - Investigation of Mass-Produced Substrates for Reproducible Surface-Enhanced Raman Scattering Measurements over Large Areas. AB - Surface-enhanced Raman scattering (SERS) is a versatile spectroscopic technique that suffers from reproducibility issues and usually requires complex substrate fabrication processes. In this article, we report the use of a simple mass production technology based on Blu-ray disc manufacturing technology to prepare large area SERS substrates (~40 mm2) with a high degree of homogeneity (+/-7% variation in Raman signal) and enhancement factor of ~6 * 106. An industrial high throughput injection molding process was used to generate periodic microstructured polymer substrates coated with a thin Ag film. A short chemical etching step produces a highly dense layer of Ag nanoparticles at the polymer surface, which leads to a large and reproducible Raman signal. Finite difference time domain simulations and cathodoluminescence mapping experiments suggest that the sample microstructure is responsible for the generation of SERS active nanostructures around the microwells. Comparison with commercial SERS substrates demonstrates the validity of our method to prepare cost-efficient, reliable, and sensitive SERS substrates. PMID- 28737922 TI - Disentangling the Complex Vibrational Spectrum of the Protonated Water Trimer, H+(H2O)3, with Two-Color IR-IR Photodissociation of the Bare Ion and Anharmonic VSCF/VCI Theory. AB - Vibrational spectroscopy of the protonated water trimer provides a stringent constraint on the details of the potential energy surface (PES) and vibrational dynamics governing excess proton motion far from equilibrium. Here we report the linear spectrum of the cold, bare H+(H2O)3 ion using a two-color, IR-IR photofragmentation technique and follow the evolution of the bands with increasing ion trap temperature. The key low-energy features are insensitive to both D2 tagging and internal energy. The D2-tagged D+(D2O)3 spectrum is reported for the first time, and the isotope dependence of the band pattern is surprisingly complex. These spectra are reproduced by large-scale vibrational configuration interaction calculations based on a new full-dimensional PES, which treat the anharmonic effects arising from large amplitude motion. The results indicate such extensive mode mixing in both isotopologues that one should be cautious about assigning even the strongest features to particular motions, especially for the absorptions that occur close to the intramolecular bending mode of the water molecule. PMID- 28737923 TI - Cosilencing Intestinal Transglutaminase-2 and Interleukin-15 Using Gelatin-Based Nanoparticles in an in Vitro Model of Celiac Disease. AB - In this study, we have developed a type B gelatin nanoparticle based siRNA delivery system for silencing of intestinal transglutaminase-2 (TG2) and interleukin-15 (IL-15) genes in cultured human intestinal epithelial cells (Caco 2) and murine alveolar macrophage cells (J774A.1). Small interfering RNA (siRNA) targeting the TG2 or IL-15 gene was encapsulated within gelatin nanoparticles using ethanol-water solvent displacement method. Size, charge, and morphology of gelatin nanoparticles were evaluated using a Zetasizer instrument and transmission electron microscopy. siRNA encapsulation efficiency was determined using an siRNA specific stem-loop quantitative polymerase chain reaction (qPCR) assay. Cellular uptake of siRNA-containing gelatin nanoparticles was determined using fluorescent microscopy and stem-loop qPCR assay. siRNA loading in the RISC (RNA-induced silencing complex) was determined by immunoprecipitation of argonaute 2 (AGO2) protein followed by stem-loop qPCR for siRNA quantification. Gene expression analysis of TG2, IL-15, and the proinflammatory cytokines, tumor necrosis factor alpha (TNF-alpha) and interferon gamma (IFN-gamma), was performed using qPCR assays. Efficacy of silencing TG2 and IL-15 knockdown was evaluated in an in vitro model of celiac disease by utilizing immunogenic alpha-gliadin peptide p31-43 in cultured J774A.1 cells. siRNA-containing gelatin nanoparticles were spherical in shape with mean particle size and charge of 217 +/- 8.39 nm and -6.2 +/- 0.95 mV, respectively. siRNA loading efficiency within gelatin nanoparticles was found to be 89.3 +/- 3.05%. Evaluations of cellular uptake using fluorescent microscopy showed rapid internalization of gelatin nanoparticles within 2 h of dosing, with cytosolic localization of delivered siRNA in Caco-2 cells. Gelatin nanoparticles showed greater intracellular siRNA exposure with a longer half-life, when compared to Lipofectamine-mediated siRNA delivery. Approximately 0.1% of total intracellular siRNA was associated in the RISC complex. A maximum knockdown of 60% was observed at 72 h post siRNA treatment for both TG2 and IL-15 genes, which corresponded to ~200 copies of RISC associated siRNA. Further, efficacy of gelatin nanoparticle mediated knockdown of TG2 and IL-15 mRNA was tested in an in vitro model of celiac disease. Significant suppression in the levels of proinflammatory cytokines (TNF-alpha and IFN-gamma) was observed in p31-43 stimulated J774A.1 cells upon either IL-15 or IL-15 + TG2 siRNA treatment. The results from this study indicate that gelatin nanoparticle mediated TG2 and IL-15 siRNA gene silencing is a very promising approach for the treatment of celiac disease. PMID- 28737924 TI - Linking pH, Temperature, and K+ Concentration for DNA i-Motif Formation. AB - The conformation a particular DNA segment assumes depends upon its sequence context and the environment under which it is prepared. To complement our findings with G-rich sequences related to the human telomere, we have been investigating the pH induced transition from single strand to i-motif for sequences related to the human telomere C-rich strand. We have carried out titrations of (CCCTAA)4 from pH 7.0 to pH 5.0 at temperatures ranging from 15 to 45 degrees C at 115 mM K+ and at K+ concentrations ranging from 15 to 215 mM at 25 degrees C. Circular dichroism (CD) spectra were determined to monitor the transition. The pH at the midpoint of the proton induced transition, pHmp, is dependent upon both temperature and [K+]. Wyman-type plots of log K vs pH yielded linear correlations and the slopes of those lines, DeltaQ, were also linearly dependent on [K+] and T. For these studies, DeltaQ represents the minimum number of protons that must be added to the oligomer to induce the initial folding. These results are consistent with Le Chatelier's principle. Optical melting studies were also carried out for (CCCTAA)4 at pH 5.0 and [K+] ranging from 15 to 315 mM. Linear correlations between the temperature at the midpoint of the transition, Tm, and log [K+] allowed determination of the differential ion binding term, DeltanK+. These linkages between pH, temperature, and [K+] can be utilized to design i-motif forming DNA oligomers with highly tunable properties. PMID- 28737925 TI - Lipid Bilayer-Gated Mesoporous Silica Nanocarriers for Tumor-Targeted Delivery of Zoledronic Acid in Vivo. AB - Zoledronic acid (ZOL) is a nitrogen-containing bisphosphonate used for the treatment of bone diseases and calcium metabolism. Anticancer activity of ZOL has been established, but its extraskeletal effects are limited due to its rapid uptake and accumulation to bone hydroxyapatite. In this work, we report on the development of tethered lipid bilayer-gated mesoporous silica nanocarriers (MSNs) for the incorporation, retention, and intracellular delivery of ZOL. The in vitro anticancer activity of ZOL-loaded nanocarriers was evaluated by cell viability assay and live-cell imaging. For in vivo delivery, the nanocarriers were tagged with folic acid to boost the affinity for breast cancer cells. Histological examination of the liver revealed no adverse off-target effects stemming from the nanocarriers. Importantly, nonspecific accumulation of ZOL within bone was not observed, which indicated in vivo stability of the tethered lipid bilayers. Further, the intravenously administered ZOL-loaded nanocarriers showed tumor growth suppression in breast cancer xenograft-bearing mice. PMID- 28737926 TI - Geometric Shape Regulation and Noncovalent Synthesis of One-Dimensional Organic Luminescent Nano-/Micro-Materials. AB - Noncovalent synthesis of one-dimensional (1D) organic nano-/micro-materials with controllable geometric shapes or morphologies and special luminescent and electronic properties is one of the greatest challenges in modern chemistry and material science. Control of noncovalent interactions is fundamental for realizing desired 1D structures and crucial for understanding the functions of these interactions. Here, a series of thiophene-fused phenazines composed of a halogen-substituted pi-conjugated plate and a pair of flexible side chains is presented, which displays halogen-dependent 1D self-assemblies. Luminescent 1D twisted wires, straight rods, and zigzag wires, respectively, can be generated in sequence when the halogen atoms are varied from the lightest F to the heaviest I. It was demonstrated that halogen-dependent anisotropic noncovalent interactions and mirror-symmetrical crystallization dominated the 1D-assembly behaviors of this class of molecules. The methodology developed in this study provides a potential strategy for constructing 1D organic materials with unique optoelectronic functions. PMID- 28737927 TI - A Facile, Nonreactive Hydrogen Peroxide (H2O2) Detection Method Enabled by Ion Chromatography with UV Detector. AB - Hydrogen peroxide (H2O2) is ubiquitous in the natural environment, and it is now widely used for pollutant control in water and wastewater treatment processes. However, current analytical methods for H2O2 inevitably require reactions between H2O2 and other reactants to yield signals and are thus likely subjective to the interferences of coexisting colored, oxidative, and reductive compounds. In order to overcome these barriers, we herein for the first time propose to analyze H2O2 by ion chromatography (IC) using an ultraviolet (UV) detector. The proposal is based on two principles: first, that H2O2 can deprotonate to hydroperoxyl ion (HO2-) when eluent pH is higher than the acid-dissociation coefficient of H2O2 (pKa = 11.6); and second, that after separation from other compounds via IC column, H2O2 can be quantified by a UV detector. Under favorable operating conditions, this method has successfully achieved acceptable recoveries (>91%) of H2O2 dosed to ultrapure and natural waters, a calibration curve with R2 > 0.99 for a wide range of H2O2 concentrations from 0.1 to 50 mg/L and a method detection limit of 0.027 mg/L. In addition, this approach was shown to be capable of distinguishing H2O2 from anions (e.g., fluoride and chloride) and organics (e.g., glycolate) and monochloramine, suggesting that it is insensitive to many neighboring compounds as long as they do not react quickly with H2O2. Hence, this study proves the combination of IC and UV detector a facile and reliable method for H2O2 measurement. PMID- 28737928 TI - Electron Beam Etching of CaO Crystals Observed Atom by Atom. AB - With the rapid development of nanoscale structuring technology, the precision in the etching reaches the sub-10 nm scale today. However, with the ongoing development of nanofabrication the etching mechanisms with atomic precision still have to be understood in detail and improved. Here we observe, atom by atom, how preferential facets form in CaO crystals that are etched by an electron beam in an in situ high-resolution transmission electron microscope (HRTEM). An etching mechanism under electron beam irradiation is observed that is surprisingly similar to chemical etching and results in the formation of nanofacets. The observations also explain the dynamics of surface roughening. Our findings show how electron beam etching technology can be developed to ultimately realize tailoring of the facets of various crystalline materials with atomic precision. PMID- 28737929 TI - Enhanced Degradation of TCE on a Superfund Site Using Endophyte-Assisted Poplar Tree Phytoremediation. AB - Trichloroethylene (TCE) is a widespread environmental pollutant common in groundwater plumes associated with industrial manufacturing areas. We had previously isolated and characterized a natural bacterial endophyte, Enterobacter sp. strain PDN3, of poplar trees, that rapidly metabolizes TCE, releasing chloride ion. We now report findings from a successful three-year field trial of endophyte-assisted phytoremediation on the Middlefield-Ellis-Whisman Superfund Study Area TCE plume in the Silicon Valley of California. The inoculated poplar trees exhibited increased growth and reduced TCE phytotoxic effects with a 32% increase in trunk diameter compared to mock-inoculated control poplar trees. The inoculated trees excreted 50% more chloride ion into the rhizosphere, indicative of increased TCE metabolism in planta. Data from tree core analysis of the tree tissues provided further supporting evidence of the enhanced rate of degradation of the chlorinated solvents in the inoculated trees. Test well groundwater analyses demonstrated a marked decrease in concentration of TCE and its derivatives from the tree-associated groundwater plume. The concentration of TCE decreased from 300 MUg/L upstream of the planted area to less than 5 MUg/L downstream of the planted area. TCE derivatives were similarly removed with cis 1,2-dichloroethene decreasing from 160 MUg/L to less than 5 MUg/L and trans-1,2 dichloroethene decreasing from 3.1 MUg/L to less than 0.5 MUg/L downstream of the planted trees. 1,1-dichloroethene and vinyl chloride both decreased from 6.8 and 0.77 MUg/L, respectively, to below the reporting limit of 0.5 MUg/L providing strong evidence of the ability of the endophytic inoculated trees to effectively remove TCE from affected groundwater. The combination of native pollutant degrading endophytic bacteria and fast-growing poplar tree systems offers a readily deployable, cost-effective approach for the degradation of TCE, and may help mitigate potential transfer up the food chain, volatilization to the atmosphere, as well as direct phytotoxic impacts to plants used in this type of phytoremediation. PMID- 28737930 TI - Self-Collapse Lithography. AB - We report a facile, high-throughput soft lithography process that utilizes nanoscale channels formed naturally at the edges of microscale relief features on soft, elastomeric stamps. Upon contact with self-assembled monolayer (SAM) functionalized substrates, the roof of the stamp collapses, resulting in the selective removal of SAM molecules via a chemical lift-off process. With this technique, which we call self-collapse lithography (SCL), sub-30 nm patterns were achieved readily using masters with microscale features prepared by conventional photolithography. The feature sizes of the chemical patterns can be varied continuously from ~2 MUm to below 30 nm by decreasing stamp relief heights from 1 MUm to 50 nm. Likewise, for fixed relief heights, reducing the stamp Young's modulus from ~2.0 to ~0.8 MPa resulted in shrinking the features of resulting patterns from ~400 to ~100 nm. The self-collapse mechanism was studied using finite element simulation methods to model the competition between adhesion and restoring stresses during patterning. These results correlate well with the experimental data and reveal the relationship between the line widths, channel heights, and Young's moduli of the stamps. In addition, SCL was applied to pattern two-dimensional arrays of circles and squares. These chemical patterns served as resists during etching processes to transfer patterns to the underlying materials (e.g., gold nanostructures). This work provides new insights into the natural propensity of elastomeric stamps to self-collapse and demonstrates a means of exploiting this behavior to achieve patterning via nanoscale chemical lift-off lithography. PMID- 28737931 TI - Semiordered Hierarchical Metallic Network for Fast and Large Charge-Induced Strain. AB - Nanoporous metallic actuators for artificial muscle applications are distinguished by combining the low operating voltage, which is otherwise reserved for polymer-based actuators with interesting values of strain amplitude, strength, and stiffness that are comparable of those of piezoceramics. We report a nanoporous metal actuator with enhanced strain amplitude and accelerated switching. Our 3D macroscopic metallic muscle has semiordered and hierarchical nanoporous structure, in which MUm-sized tubes align perpendicular with the sample surface, while nm-sized ligaments consist of the tube walls. This nanoarchitecture combines channels for fast ion transportation with large surface area for charge storage and strain generation. The result is a record reversible strain amplitude of 1.59% with a strain rate of 8.83 * 10-6 s-1 in the field of metallic based actuators. A passive hydroxide layer is self-grown on the metal surface, which not only contributes a supercapacitive layer, but also stabilizes the nanoporous structure against coarsening, which guarantees sustainable actuation beyond ten-thousand cycles. PMID- 28737932 TI - Ins and Outs in Environmental and Occupational Safety Studies of Asthma and Engineered Nanomaterials. AB - According to the Centers for Disease Control and Prevention, approximately 25 million Americans suffer from asthma. The disease total annual cost is about $56 billion and includes both the direct and indirect costs of medications, hospital stays, missed work, and decreased productivity. Air pollution with xenobiotics, bacterial agents, and industrial nanomaterials, such as carbon nanotubes, contribute to the exacerbation of this condition and are a point of particular attention in environmental toxicology as well as in occupational health and safety research. Mast cell degranulation and activation of Th2 cells triggered either by allergen-specific immunoglobulin E (IgE) or by alternative mechanisms, such as locally produced neurotransmitters, underlie the pathophysiological process of airway constriction during an asthma attack. Other immune and non immune cell types, including basophils, eosinophils, Th1, Th17, Th9, macrophages, dendritic cells, and smooth muscle cells, are involved in the inflammatory and allergic responses during asthma, which, under chronic conditions, may progress without mast cells, the key trigger of the acute asthma attack. To decipher complex molecular, cellular, and genetic mechanisms, many researchers have attempted to develop in vitro and in vivo models to study asthma. Herein, we summarize the advantages and disadvantages of various models and their applicability to nanoparticle evaluation in asthma research. We further suggest that a framework for both in vitro and in vivo methods should be used to study the impact of engineered nanomaterials on asthma etiology, pathophysiology, and treatment. PMID- 28737933 TI - Efficient Application of Continuous Fractional Component Monte Carlo in the Reaction Ensemble. AB - A new formulation of the Reaction Ensemble Monte Carlo technique (RxMC) combined with the Continuous Fractional Component Monte Carlo method is presented. This method is denoted by serial Rx/CFC. The key ingredient is that fractional molecules of either reactants or reaction products are present and that chemical reactions always involve fractional molecules. Serial Rx/CFC has the following advantages compared to other approaches: (1) One directly obtains chemical potentials of all reactants and reaction products. Obtained chemical potentials can be used directly as an independent check to ensure that chemical equilibrium is achieved. (2) Independent biasing is applied to the fractional molecules of reactants and reaction products. Therefore, the efficiency of the algorithm is significantly increased, compared to the other approaches. (3) Changes in the maximum scaling parameter of intermolecular interactions can be chosen differently for reactants and reaction products. (4) The number of fractional molecules is reduced. As a proof of principle, our method is tested for Lennard Jones systems at various pressures and for various chemical reactions. Excellent agreement was found both for average densities and equilibrium mixture compositions computed using serial Rx/CFC, RxMC/CFCMC previously introduced by Rosch and Maginn (Journal of Chemical Theory and Computation, 2011, 7, 269-279), and the conventional RxMC approach. The serial Rx/CFC approach is also tested for the reaction of ammonia synthesis at various temperatures and pressures. Excellent agreement was found between results obtained from serial Rx/CFC, experimental results from literature, and thermodynamic modeling using the Peng Robinson equation of state. The efficiency of reaction trial moves is improved by a factor of 2 to 3 (depending on the system) compared to the RxMC/CFCMC formulation by Rosch and Maginn. PMID- 28737934 TI - The Combined QSAR-ICE Models: Practical Application in Ecological Risk Assessment and Water Quality Criteria. PMID- 28737935 TI - The Current State of Peptide Drug Discovery: Back to the Future? AB - Over the past decade, peptide drug discovery has experienced a revival of interest and scientific momentum, as the pharmaceutical industry has come to appreciate the role that peptide therapeutics can play in addressing unmet medical needs and how this class of compounds can be an excellent complement or even preferable alternative to small molecule and biological therapeutics. In this Perspective, we give a concise description of the recent progress in peptide drug discovery in a holistic manner, highlighting enabling technological advances affecting nearly every aspect of this field: from lead discovery, to synthesis and optimization, to peptide drug delivery. An emphasis is placed on describing research efforts to overcome the inherent weaknesses of peptide drugs, in particular their poor pharmacokinetic properties, and how these efforts have been critical to the discovery, design, and subsequent development of novel therapeutics. PMID- 28737936 TI - A(II)GeTeO6 (A = Mn, Cd, Pb): Non-Centrosymmetric Layered Tellurates with PbSb2O6 Related Structure. AB - A(II)GeTeO6 (A = Mn, Cd, Pb), new non-centrosymmetric (NCS) honeycomb-layered tellurates, were synthesized and characterized. A(II)GeTeO6 (A = Mn, Cd, Pb) crystallize in trigonal space group P312 (No. 149) of edge-sharing Ge4+O6 and Te6+O6 octahedra, which form honeycomb-like-layers in the ab-plane with A(II) (A = Mn, Cd, Pb) cations located between the layers. Their crystal structures are PbSb2O6-related, and the ordering of Ge4+ and Te6+ in octahedral environment breaks the inversion symmetry of the parent PbSb2O6 structure. The size of A(II) cation in six coordination is an important factor to stabilize PbSb2O6-based structure. Temperature-dependent optical second harmonic generation measurements on A(II)GeTeO6 confirmed non-centrosymmetric character in the entire scanned temperature range (0 to 600 degrees C). The materials exhibit a powder SHG efficiency of ~0.37 and ~0.21 times of KH2PO4 for PbGeTeO6 and CdGeTeO6, respectively. Magnetic measurements of MnGeTeO6 indicate anti-ferromagnetic order at TN ~ 9.4 K with Weiss temperature of -22.47 K. PMID- 28737937 TI - Asymmetric Hydrogen Bonding Catalysis for the Synthesis of Dihydroquinazoline Containing Antiviral, Letermovir. AB - A weak Bronsted acid-catalyzed asymmetric guanidine aza-conjugate addition reaction has been developed. C2-symmetric, dual hydrogen-bond donating bistriflamides are shown to be highly effective in activating alpha,beta unsaturated esters toward the intramolecular addition of a pendant guanidinyl nucleophile. Preliminary mechanistic investigation, including density functional theory calculations and kinetics studies, support a conjugate addition pathway as more favorable energetically than an alternative electrocyclization pathway. This methodology has been successfully applied to the synthesis of the 3,4 dihydroquinazoline-containing antiviral, Letermovir, and a series of analogues. PMID- 28737938 TI - Heterogeneous Photo-oxidation of SO2 in the Presence of Two Different Mineral Dust Particles: Gobi and Arizona Dust. AB - The impact of authentic mineral dust particles sourced from the Gobi Desert (GDD) on the kinetic uptake coefficient of SO2 was studied under varying environments (humidity, O3, and NOx) using both an indoor chamber and an outdoor chamber. There was a significant increase in the kinetic uptake coefficient of SO2 (gammaSO42-,light) for GDD particles under UV light compared to the value (gammaSO42-,dark) under dark conditions at various relative humidities (RH) ranging from 20% to 80%. In both the presence and the absence of O3 and NOx, gammaSO42-,light and gammaSO42-,dark greatly increased with increasing RH. The resulting gammaSO42-,light of GDD particles was also compared to that of Arizona Test Dust (ATD) particles. The gammaSO42-,light values of GDD were 2 to 2.5 times greater than those of ATD for all RH levels. To understand the photocatalytic act of dust particles, both GDD and ATD were characterized for the metal element composition of fresh particles, the aerosol acidity of aged particles, and the hygroscopic properties of both fresh and aged particles. We conclude that the difference in the formation of sulfate between GDD and ATD particles is regulated mainly by the quantity of the semiconductive metals in dust particles and partially by hygroscopic properties. PMID- 28737939 TI - Several [Gd-M] Heterometal-Organic Frameworks with [Gdn] as Nodes: Tunable Structures and Magnetocaloric Effect. AB - Tunable structures and magnetocaloric effect (MCE) of seven MOFs with [Gdn] as nodes are explored. The [Gdn] node is realized from mononuclear [Gd] to binuclear paddle-wheel [Gd2], tetranuclear tetrahedral [Gd4], and pentanuclear trigonal bipyramidal [Gd5]. Meanwhile, the magnetic entropy changes from 19.4 to 46.0 J.kg 1.K-1. The results reveal that the effect of magnetic density on MCE plays a dominant role for Gd3+-based compounds, and high spin ground state of Mn2+ (S = 5/2) is more favorable to achieve high MCE than that with Zn2+, Co2+, and Ni2+ (Co2+, S = 3/2; Ni2+, S = 1). To our knowledge, it is the first report that MCE is controlled by various clusters as nodes in MOFs. PMID- 28737941 TI - Unveiling the Catalytic Role of B-Block Histidine in the N-S Acyl Shift Step of Protein Splicing. AB - Protein splicing is a post-translational modification that involves the excision of a segment denoted as "intein" and the joining of its two flanking segments. The process is autocatalytic, making inteins appealing for many applications in biotechnology, bioengineering, or medicine. The canonical mechanism of protein splicing is composed of four sequential steps, and is initialized by an N-S or N O acyl shift to form a linear ester. It is well-established that a histidine, the most conserved amino acid in all inteins, catalyzes this initial step, even though its role remains to be understood. In this study, we combine molecular dynamics simulations and quantum mechanics/molecular mechanics (QM/MM) hybrid calculations to investigate the alternative reaction pathways proposed for the N S acyl shift in Mycobacterium tuberculosis RecA intein. The results rule out the histidine acting as a base and activating the side chain of Cys1; instead, an aspartate performs this action. In the reaction mechanism proposed herein, denoted as the "Asp422 activated" mechanism, two sequential roles are attributed to the histidine: (i) ground-state destabilization by straining the scissile peptide bond and (ii) protonation of the leaving amide group. In summary, the study provides relevant data to understand the catalytic role of this histidine, and proposes a reaction pathway for the N-S acyl shift reaction in protein splicing that fits with the available experimental data. PMID- 28737940 TI - Defining the Structural Basis for Allosteric Product Release from E. coli Dihydrofolate Reductase Using NMR Relaxation Dispersion. AB - The rate-determining step in the catalytic cycle of E. coli dihydrofolate reductase is tetrahydrofolate (THF) product release, which can occur via an allosteric or an intrinsic pathway. The allosteric pathway, which becomes accessible when the reduced cofactor NADPH is bound, involves transient sampling of a higher energy conformational state, greatly increasing the product dissociation rate as compared to the intrinsic pathway that obtains when NADPH is absent. Although the kinetics of this process are known, the enzyme structure and the THF product conformation in the transiently formed excited state remain elusive. Here, we use side-chain proton NMR relaxation dispersion measurements, X ray crystallography, and structure-based chemical shift predictions to explore the structural basis of allosteric product release. In the excited state of the E:THF:NADPH product release complex, the reduced nicotinamide ring of the cofactor transiently enters the active site where it displaces the pterin ring of the THF product. The p-aminobenzoyl-l-glutamate tail of THF remains weakly bound in a widened binding cleft. Thus, through transient entry of the nicotinamide ring into the active site, the NADPH cofactor remodels the enzyme structure and the conformation of the THF to form a weakly populated excited state that is poised for rapid product release. PMID- 28737942 TI - The Role of Rydberg-Valence Coupling in the Ultrafast Relaxation Dynamics of Acetone. AB - The electronic structure of excited states of acetone is represented by a Rydberg manifold that is coupled to valence states which provide very fast and efficient relaxation pathways. We observe and characterize the transfer of population from photoexcited Rydberg states (6p, 6d, 7s) to a whole series of lower Rydberg states (3p to 4d) and a simultaneous decay of population from these states. We obtain these results with time-resolved photoelectron-photoion coincidence (PEPICO) detection in combination with the application of Bayesian statistics for data analysis. Despite the expectedly complex relaxation behavior, we find that a simple sequential decay model is able to describe the observed PEPICO transients satisfactorily. We obtain a slower decay (~320 fs) from photoexcited states compared to a faster decay (~100 fs) of states that are populated by internal conversion, demonstrating that different relaxation dynamics are active. Within the series of Rydberg states populated by internal conversion, the decay dynamics seem to be similar, and a trend of slower decay from lower states indicates an increasingly higher energy barrier along the decay pathway for lower states. The presented results agree all in all with previous relaxation studies within the Rydberg manifold. The state-resolved observation of transient population ranging from 3p to 4d can serve as reference for time-dependent simulations. PMID- 28737943 TI - t-BuOK-Mediated Oxidative Dehydrogenative C(sp3)-H Arylation of 2-Alkylazaarenes with Nitroarenes. AB - The first transition-metal free and regioselective C(sp3)-H arylation of 2 alkylazaarenes with nitroarenes has been achieved via t-BuOK-mediated dehydrogenative C(sp3)-C(sp2) coupling. This reaction provides an efficient access to the biologically important and synthetically useful 2-benzyl substituted azaarenes under mild conditions without the need of prefunctionalization of 2-alkylazaarenes or using the specialized arylating agents. PMID- 28737945 TI - Preliminary PET Study of 18F-FC119S in Normal and Alzheimer's Disease Models. AB - To evaluate the efficacy of 18F-FC119S as a positron emission tomography (PET) radiopharmaceutical for the imaging of Alzheimer's disease (AD), we studied the drug absorption characteristics and distribution of 18F-FC119S in normal mice. In addition, we evaluated the specificity of 18F-FC119S for beta-amyloid (Abeta) in the AD group of an APP/PS1 mouse model and compared it with that in the wild-type (WT) group. The behavior of 18F-FC119S in the normal mice was characteristic of rapid brain uptake and washout patterns. In most organs, including the brain, 18F FC119S reached its maximum concentration within 1 min and was excreted via the intestine. Brain PET imaging of 18F-FC119S showed highly specific binding of the molecule to Abeta in the cortex and hippocampus. The brain uptake and binding values for the AD group were higher than those for the WT group. These results indicated that 18F-FC119S would be a candidate PET imaging agent for targeting Abeta plaque. PMID- 28737944 TI - In Situ-Generated Glycinyl Chloroaminals for a One-Pot Synthesis of Non proteinogenic alpha-Amino Esters. AB - An acetyl chloride-mediated cascade transformation involving a primary carbamate, ethyl glyoxylate, and various types of nucleophiles is reported for the synthesis of orthogonally protected alpha-amino esters. These reactions proceeded rapidly to afford the pivotal alpha-chloroglycine intermediate in excellent yields, which can be directly functionalized in situ with various types of nucleophiles. A mild and unique AcOH(cat.)/AcCl system was found to promote an autocatalytic-like condensation and facilitate the multicomponent assembly of non-proteinogenic alpha-amino esters. To better understand this one-pot transformation and the orchestration of the components' condensations, the investigation of a broader scope of nucleophiles and some kinetic studies are presented. Our findings suggest that the halogenation step toward the formation of alpha-chloroglycine is the rate-determining step likely proceeding through the formation of N-carbamoyl iminium. Also, the initial kinetic profiling for the nucleophilic substitution supports an SN1-like (SN2C+) mechanism in which nucleophiles add to the iminium chloride tight ionic pair. These results lead ultimately to the design of a new protocol in which an achiral hydrogen bond donor thiourea catalyst was utilized to enhance the reaction scope and enable silylated nucleophiles to be efficiently exploited to synthesize novel non-proteinogenic alpha-amino esters. PMID- 28737947 TI - A Reactive Eremophilane and Its Antibacterial 2(1H)-Naphthalenone Rearrangement Product, Witnesses of a Microbial Chemical Warfare. AB - Two sesquiterpenes, 4-epi-microsphaeropsisin (1) and a dihydrofurano-2(1H) naphthalenone (variabilone, 2) which represents a new skeleton, were isolated from endophytic fungus Paraconiothyrium variabile. Reactivity studies showed that eremophilane 1 is a precursor of 2 through acid-promoted methyl 1,2-migration and aromatization. An electrophilic intermediate of this transformation was intercepted by N-acetylcysteamine, a biomimetic nucleophile. Only compound 2 was antibacterial against endophytic bacterium Bacillus subtilis (coisolated with P. variabile), suggesting a role in the microbial competition in plants. PMID- 28737946 TI - Structure-Guided Optimization of HIV Integrase Strand Transfer Inhibitors. AB - Integrase mutations can reduce the effectiveness of the first-generation FDA approved integrase strand transfer inhibitors (INSTIs), raltegravir (RAL) and elvitegravir (EVG). The second-generation agent, dolutegravir (DTG), has enjoyed considerable clinical success; however, resistance-causing mutations that diminish the efficacy of DTG have appeared. Our current findings support and extend the substrate envelope concept that broadly effective INSTIs can be designed by filling the envelope defined by the DNA substrates. Previously, we explored 1-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamides as an INSTI scaffold, making a limited set of derivatives, and concluded that broadly effective INSTIs can be developed using this scaffold. Herein, we report an extended investigation of 6-substituents as well the first examples of 7 substituted analogues of this scaffold. While 7-substituents are not well tolerated, we have identified novel substituents at the 6-position that are highly effective, with the best compound (6p) retaining better efficacy against a broad panel of known INSTI resistant mutants than any analogues we have previously described. PMID- 28737948 TI - A Global Catastrophic Biological Risk Is Not Just About Biology. PMID- 28737949 TI - Effects of Autogenous Bone Marrow Aspirate Concentrate on Radiographic Integration of Femoral Condylar Osteochondral Allografts. AB - BACKGROUND: Transplantation of fresh osteochondral allografts (OCAs) is an attractive treatment option for symptomatic articular cartilage lesions in young, healthy patients. Because the lack of OCA bone integration can be a cause of treatment failure, methods for speeding and enhancing OCA bone integration to mitigate this potential complication are highly desirable. PURPOSE: To determine if autogenous bone marrow aspirate concentrate (BMC) treatment of large femoral condylar OCAs would be associated with superior radiographic OCA bone integration compared with nontreated allografts during the critical first 6 months after surgery. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: A review of patients enrolled in a prospective registry who were treated with transplantation of large OCAs to one or both femoral condyles at our institution from March 12, 2013 to March 14, 2016 was performed. Patients were stratified into 2 groups based on BMC treatment versus no BMC treatment; the treatment was nonrandomized and was rooted in a shift in practice and a continuing effort to optimize OCA transplantation at our institution. Patients were excluded if they did not have orthogonal view radiographs performed at 6 weeks, 3 months, and 6 months postoperatively. Each condyle undergoing OCA transplantation was assessed individually by an independent musculoskeletal radiologist, who was blinded to the treatment group and time point. OCAs were assessed with respect to graft integration (0%-100%; 0 = no integration, 100 = complete integration) and degree of sclerosis (0-3; 0 = normal, 1 = mild sclerosis, 2 = moderate sclerosis, and 3 = severe sclerosis) of the graft at each time point. RESULTS: This study identified 17 condyles in 15 patients who underwent OCA transplantation without BMC and 29 condyles in 22 patients who underwent OCA transplantation with BMC. The BMC group had significantly ( P = .033) higher graft integration scores at 6 weeks, 3 months, and 6 months after surgery. Graft sclerosis was significantly ( P = .017) less in the BMC group at 6 weeks and 3 months, with no significant difference at 6 months after surgery. When combining the groups to examine the influence of smoking on graft integration, nonsmokers had significantly ( P = .007) higher graft integration scores at 6 months. CONCLUSION: Large femoral condylar OCAs treated with autogenous BMC before implantation showed superior radiographic integration to bone and less sclerosis during the initial 6-month postoperative period. BMC treatment of OCAs may mitigate the failure of OCA bone healing. PMID- 28737950 TI - Corrigendum. PMID- 28737952 TI - The Challenge of Global Catastrophic Biological Risks. PMID- 28737951 TI - Monitoring of small bowel Crohn's disease. AB - INTRODUCTION: In recent years, the therapeutic paradigm in Crohn's disease has shifted from a mere symptom-oriented approach, to aiming to healing of the underlying inflammation and prevention of long-term structural complications. Such 'treat-to-target' approach may allow for a more stable disease course with less hospitalizations, lower requirement for surgery and improved quality of life. In Crohn's disease, the small bowel is affected in the majority of patients; frequently, Crohn's involves only the small bowel, which remains inaccessible to conventional ileocolonoscopic techniques. Thus, non-invasive monitoring techniques are crucial for accurate disease assessment. Areas covered: This review addresses the indications and clinical implications of non-invasive small bowel monitoring modalities (magnetic resonance enterography, intestinal ultrasound, capsule endoscopy) in the assessment and management of Crohn's disease. Expert commentary: This review addresses the limitations of the current knowledge and future areas of research, including the possible utilization of transmural healing as an imaging target and the need to establish clear quantitative target values to guide treatment by imaging findings in Crohn's disease. PMID- 28737953 TI - Metabolic factors and oxidative stress in osteoarthritis: a case-control study. AB - Previous studies suggest that metabolic disturbances might be involved in the development of osteoarthritis (OA). Associations have been found between the individual components of metabolic syndrome (MetS) and OA. MetS has been associated with increased oxidative stress (OxS). The study aimed to clarify the role of MetS components in OA and to evaluate the levels of OxS in OA patients and in age-matched controls. Fifty-five patients with end-stage OA (age 63 +/- 7 years) prior to hip or knee joint replacement surgery and 55 age-, gender- and body mass index matched controls (61 +/- 8 years) were enrolled in the study. Serum levels of glucose, insulin, c-peptide, cholesterols and OxS markers were recorded. Homeostasis model assessment for insulin resistance was used as the proxy measure of insulin resistance. Radiographic severity was assessed using the Kellgren-Lawrence score. The OA patients had higher total peroxide concentration and oxidative stress index [488 (250-612) MUmol/L vs. 326 (168-442) MUmol/L, p = .011 and 34 (17-51) vs. 20 (11-28), p = .002, respectively] and decreased total antioxidant capacity (1.49 +/- 0.27 vs. 1.66 +/- 0.27 mmol trolox equivalent/L, p= .008) compared with the controls. In addition, OA group had significantly higher level of C-peptide compared with the controls [1.8 (0.94-2.47) vs. 1.3 (0.46-1.42) ng/mL, p < .001, respectively]. Furthermore, OA radiographic severity was independently associated with LDL-cholesterol (p = .007) and oxidized LDL (p = .022). This study demonstrates that end-stage OA patients have increased levels of OxS and decreased antioxidant capacity. OA is associated with impaired lipid metabolism and dysglycemia. Our results underline the importance OxS and metabolic disturbances in the pathogenesis of OA. PMID- 28737954 TI - An App a Day Keeps the Doctor Away: Guided Education and Training via Smartphones in Subthreshold Post Traumatic Stress Disorder. AB - Post traumatic stress disorder (PTSD) symptoms are common in military service members (SMs), but stigma can impede treatment initiation. Smartphone applications (apps) are available anywhere, anytime, with the potential to both mitigate the impact of stigma and reduce PTSD symptom severity. We provided 144 SMs or family members, with subthreshold PTSD symptoms (PTSD Checklist [PCL] scores of 28-49), with apps promoting psychoeducation, social engagement, and relaxation and randomized them to 6 weeks of resilience enhancement (brief cognitive-behavioral session, followed by daily text messages directing app use) or a control group (daily text messages of inspirational quotes). Participants (54 percent males, 87 percent SMs) in both groups reported reductions in PTSD, anxiety, and depression symptoms during the 6-week intervention, which were sustained at 3 months, but exhibited partial rebound at 6-12 months. Our preliminary results suggest that app use, with or without specific direction, feasibly and effectively reduces symptom severity. Future studies should consider a longer intervention, enhanced compliance tracking, or boosters to sustain benefits. PMID- 28737955 TI - Meta-analysis of the Risk of Infections After Anterior Cruciate Ligament Reconstruction by Graft Type. AB - BACKGROUND: An infection after anterior cruciate ligament (ACL) reconstruction is a relatively rare but challenging complication. There are no meta-analyses comparing the incidence of infections after ACL reconstruction with the various available graft choices. PURPOSE: To compare the incidence of infections after ACL reconstruction with bone-patellar tendon-bone (BPTB) autografts compared with hamstring autografts, with a secondary aim of comparing the incidence of infections after reconstruction with autografts compared with allografts. STUDY DESIGN: Meta-analysis. METHODS: A systematic review was performed to identify level 1 and 2 studies that reported the incidence of infections by graft type after ACL reconstruction. Studies that evaluated patients undergoing primary ACL reconstruction with an autograft, allograft, or combination of autograft and allograft and reported the number of postoperative infections by graft type utilized were considered for inclusion. Studies were excluded if they included revision ACL reconstruction or did not specify the number of infections by graft type. Study findings were reviewed, and meta-analysis was performed when data were sufficiently homogeneous. RESULTS: Twenty-one studies meeting criteria were identified from the literature review. Meta-analysis revealed a significant difference in the incidence of deep infections between BPTB autografts and hamstring autografts, with the BPTB group displaying a 77% lower incidence of infections compared with the hamstring group (relative risk [RR], 0.23; 95% CI, 0.097-0.54). The incidence of infections was 66% lower with BPTB autografts compared with all other graft types, with a pooled RR of 0.33 (95% CI, 0.15 0.71). There was no significant difference in the incidence of infections after ACL reconstruction with autografts compared with allografts (RR, 1.035; 95% CI, 0.589-1.819). CONCLUSION: The findings of this meta-analysis demonstrate a significantly lower incidence of deep infections after ACL reconstruction with BPTB autografts compared with hamstring autografts but not compared with allografts. CLINICAL RELEVANCE: Although the overall infection rate after ACL reconstruction is relatively low, the significantly higher rate of infections with hamstring autografts compared with BPTB autografts should be a consideration when discussing graft choices for ACL reconstruction. PMID- 28737956 TI - Hypophonia as a sign of thalamus lesion: a case report. AB - Hypophonia is a neurological sign usually seen after brainstem or peripheral damage, either at the recurrent laryngeal nerve or vocal cord level. However, it has been described as a sign of supratentorial strokes in a few studies, specifically when anterior and ventral thalamic involvement is reported. In addition, it is a prominent sign of other neurological disorders such as Parkinson disease and other extrapyramidal conditions. We describe a case of hypophonia secondary to a left thalamic hemorrhage, after a careful search of other potential causes of this deficit, and we discuss the underlying neuroanatomical circuits. PMID- 28737957 TI - Investigating factors influencing pedestrian injury severity at intersections. AB - OBJECTIVE: Vehicle crashes that involve pedestrians at intersections have been reported occasionally. Pedestrian injury severity in these crashes is significantly related to driver and pedestrian attributes, vehicle characteristics, and the geometry of intersections. Identifying factors associated with pedestrian injury severity (PIS) is critical for reducing crashes and improving safety. For developing the proposed probit models, drivers involved in crashes are classified into 3 groups: young drivers (16 <= age <= 24), middle aged drivers (25 <= age <= 64), and older drivers (age >= 65). This study determines that PIS is significantly but differently affected by these grouped drivers with different sets of explanatory variables. METHODS: A total of 2,614 crash records (2011-2012) at intersections in Cook County, Illinois, were collected. An ordered probit modeling approach was employed to develop the proposed model and examine factors influencing PIS. The likelihood ratio test was used to assess model performance. Elasticity analysis was conducted to interpret the marginal effect of contributing factors on PIS associated with different driver groups by age. RESULTS: The results show that 4 independent variables, including pedestrian age, vehicle type, point of first contact, and weather condition, significantly affect PIS at intersections for all drivers. Two additional independent variables (i.e., number of vehicles and traffic type) affect PIS for young and middle-aged drivers, and 2 other variables (i.e., divided type and hit-and-run related) are significant to PIS for both young and older drivers. CONCLUSIONS: The independent variables significant to PIS at intersections for young, middle-aged, and older driver groups were identified and the marginal effect of each variable to the likelihood of PIS were assessed. PMID- 28737958 TI - State- and trait-like variation in morning and evening components of morningness eveningness in winter depression. AB - PURPOSE: Evening preference (eveningness) can be a risk factor for depression and a shift toward morning preference (morningness) can occur in response to treatment. A study of winter depression provides possibility to longitudinally evaluate state- and trait-like variation in morningness-eveningness during treatment in winter and remission in summer. MATERIAL AND METHODS: Female patients with winter depression and controls without a psychiatric history (n = 54 and 32 with mean age +/- standard deviation of 34.4 +/- 11.0 and 35.7 +/- 9.5 years, respectively) were treated with two-hour bright light for a week during winter period. Some of them (n = 40 and 19, respectively) were then restudied in summer. Measures obtained during the winter period from patients before and after treatment were compared to those obtained from controls and from the same patients in the summer period. Among compared measures, there were self assessments of state- and trait-like differences in morning and evening components of morningness-eveningness. RESULTS: The groups of depressed patients and controls differed in self-assessments of morning but not evening component of morningness-eveningness. The difference in state-like variation in morning component became non-significant after treatment and in summer. On the other hand, trait-like variation in this component demonstrated adequate test-retest (winter-summer) reliability, i.e. a shift toward trait-like eveningness persisted in patients in the summer. CONCLUSIONS: The observed normalization of state-like variation in morning component of morning-evening preference can be mainly explained by the disappearance of such depressive symptoms as lack of energy, social withdrawal, loss of interest in once enjoyable activities, etc. PMID- 28737959 TI - Influence of patient related factors on number of mesenchymal stromal cells reached after in vitro culture expansion for clinical treatment. AB - BACKGROUND: Number of stromal cells injected in patients with ischaemic heart disease (IHD) may be of importance for the treatment efficacy, which in turn may be influenced by various patient-related factors. In this study, we investigate whether patient-related factors influence the number of autologous stromal cells reached after in vitro culture expansion for clinical therapy. METHODS: Culture expansion data from 111 patients with IHD treated with autologous stromal cells in three clinical trials were used. We correlated the final cell count after two passages of cultivation with different patient factors. RESULTS: There was a significant relation between body mass index (BMI) and the number of adipose derived stromal cells (ASCs) reached after culture expansion and for all patients included into the three studies (r = 0.375, p = .019 and r = 0.200, p = .036, respectively). Moreover, there was a significantly higher number of ASCs reached in patients with hypertension compared to those without hypertension and for all patients overall (68.8 +/- 39.6 * 106 vs. 39.1 +/- 23.6 * 106, p = .020 and 62.0 +/- 55.0 * 106 vs. 29.0 +/- 19.3 * 106, p < .001, respectively). The same tendency was seen with bone marrow derived mesenchymal stromal cells (MSCs) in patients with hypertension compared to those without hypertension (58.4 +/- 61.8 * 106 vs. 22.6 +/- 13.3 * 106, p < .001) and in males compared to females (56.4 +/- 61.5 * 106 vs. 30.9 +/- 27.9 * 106, p = .041). Moreover, a significant negative correlation between left ventricular ejection fraction and number of MSCs was found (r = -0.287, p = .017). CONCLUSIONS: Patient related factors such as BMI, hypertension and gender may influence the number of MSCs reached after in vitro culture expansion. PMID- 28737961 TI - Metacercaria Infection Status of Fishborne Zoonotic Trematodes, Except for Clonorchis sinensis in Fish from the Heilongjiang Province, China. AB - To investigate the metacercarial infections of fishborne zoonotic trematodes (FZT), a total of 6815 freshwater fish (in representing 13 species of 5 families) were collected from Songhua river (n = 2636), Nenjiang river (n = 1935), Mudanjiang river (n = 301), and other lakes or ponds (n = 1943) in 36 representative regions in Heilongjiang Province, China, from August 2012 to December 2015. Metacercariae of four FZT species, that is, Clonorchis sinensis, Metorchis orientalis, Isthmiophora hortensis, and Metagonimus yokogawai, metacercariae were detected in the examination by the artificial digestion method. As the partial data for C. sinensis were previously reported, the remaining three FZT species are to be treated in this study. The overall prevalence of M. orientalis, I. hortensis, and M. yokogawai, metacercariae was 10.54%, 0.28%, and 1.35%, respectively. Metacercariae of M. orientalis were detected in seven fish species, that is, Pseudorasbora parva, Hemiculter leucisculus, Saurogobio dabryi, Rhynchocypris lagowskii, Carassius auratus, Rhodeus ocellatus and Perccottus glehnii. Their prevalences were the highest in false dace, P. parva (26.81%), and in fish from Songhua river (17.94%). Metacercariae of I. hortensis were detected in only one fish species, Misgurnus anguillicaudatus, from Nenjiang river only. Metacercariae of M. yokogawai were detected in three fish species, that is, P. parva, H. leucisculus and S. dabryi. Their prevalences were the highest in sharpbelly, H. leucisculus (6.05%), and in fish from Mudanjiang river (5.65%). This study first demonstrated the existence of M. orientalis, I. hortensis, and M. yokogawai in freshwater fish from Heilongjiang Province, posing a major public health concern. Eight fish species, namely M. anguillicaudatus, P. parva, H. leucisculus, S. dabryi, R. lagowskii, C. auratus, R. ocellatus, and P. glehnii, cannot be eaten raw. Moreover, the findings of this study not only extended the second intermediate host range of FZT, but also improve the information of the distribution of FZT in China. PMID- 28737962 TI - Can You Hear Me Now? Importance of Assessing Patients' Cancer Care Experiences. PMID- 28737963 TI - 2017 ASCO Quality Care Symposium: Nurturing a New and Growing Community of Practitioners. PMID- 28737960 TI - Optimization and Interpretation of Serial QuantiFERON Testing to Measure Acquisition of Mycobacterium tuberculosis Infection. AB - RATIONALE: Conversion from a negative to positive QuantiFERON-TB test is indicative of Mycobacterium tuberculosis (Mtb) infection, which predisposes individuals to tuberculosis disease. Interpretation of serial tests is confounded by immunological and technical variability. OBJECTIVES: To improve the consistency of serial QuantiFERON-TB testing algorithms and provide a data-driven definition of conversion. METHODS: Sources of QuantiFERON-TB variability were assessed, and optimal procedures were identified. Distributions of IFN-gamma response levels were analyzed in healthy adolescents, Mtb-unexposed control subjects, and patients with pulmonary tuberculosis. MEASUREMENTS AND MAIN RESULTS: Individuals with no known Mtb exposure had IFN-gamma values less than 0.2 IU/ml. Among individuals with IFN-gamma values less than 0.2 IU/ml, 0.2-0.34 IU/ml, 0.35-0.7 IU/ml, and greater than 0.7 IU/ml, tuberculin skin test positivity results were 15%, 53%, 66%, and 91% (P < 0.005), respectively. Together, these findings suggest that values less than 0.2 IU/ml were true negatives. In short-term serial testing, "uncertain" conversions, with at least one value within the uncertainty zone (0.2-0.7 IU/ml), were partly explained by technical assay variability. Individuals who had a change in QuantiFERON-TB IFN gamma values from less than 0.2 to greater than 0.7 IU/ml had 10-fold higher tuberculosis incidence rates than those who maintained values less than 0.2 IU/ml over 2 years (P = 0.0003). By contrast, "uncertain" converters were not at higher risk than nonconverters (P = 0.229). Eighty-seven percent of patients with active tuberculosis had IFN-gamma values greater than 0.7 IU/ml, suggesting that these values are consistent with established Mtb infection. CONCLUSIONS: Implementation of optimized procedures and a more rigorous QuantiFERON-TB conversion definition (an increase from IFN-gamma <0.2 to >0.7 IU/ml) would allow more definitive detection of recent Mtb infection and potentially improve identification of those more likely to develop disease. PMID- 28737964 TI - Laparoscopic Duhamel Procedure with Ex-Anal Rectal Transection for Right-Sided Hirschsprung's Disease. AB - BACKGROUND: Increased defecation frequency and soiling are common complications of surgery for right-sided Hirschsprung's disease (HD). Though the laparoscopic Duhamel procedure is a favorable option in right-sided HD, the conventional laparoscopic technique is time consuming and has complications that are associated with the reservoir. In this study, we described a modified laparoscopic Duhamel technique with ex-anal rectal transection combined with the Deloyer's procedure for right-sided HD. MATERIALS AND METHODS: Between March 2010 and January 2015, 18 right-sided HD underwent this modified laparoscopic Duhamel procedure (MLDP). The main modifications were to mobilize the colon and to dissect the retrorectal space under laparoscopy, pull out, and transect ex-anally by using a linear stapling device through a transverse incision on posterior wall of the rectum. Seven age-matched patients who underwent a conventional laparoscopic Duhamel procedure (CLDP) between March 2008 and December 2010 were included as the control group. Demographics, surgical procedures, operative data, postoperative complications, and clinical outcomes were compared between these two groups. RESULTS: Operative time was significantly shorter in the MLDP group (150 minutes versus 195 minutes; P = .03). There was no significant difference in mean timespan to obtain a normal defecation frequency (3.8 months versus 3.6 months), incidence of soiling (11.1% versus 14.3%; P = .34), and constipation (5.6% versus 14.3%; P = .69). Pouchitis were not found in the MLDP group, whereas 2 patients in the CLDP group (28.6%) presented with pouchitis and intractable diarrhea, requiring spur division. The incidence of postoperative enterocolitis was not significantly different in the two groups (11.1% in MLDP versus 14.3% in CLDP; P = .68). All 22 patients had a normal defecation over 4 years of age. CONCLUSIONS: Laparoscopic Duhamel with ex-anal rectal transection is a simple, easy-to-learn, and effective procedure for right-sided HD. It has low postoperative pouchitis because of a short pouch. PMID- 28737965 TI - Comparison of three competitive immunoassays for measurement of TSH receptor antibodies in patients with Graves' disease. AB - Thyrotropin (TSH) receptor antibodies (TRAb) mediate the hyperthyroidism of Graves' disease (GD). The aim of the study was to compare the diagnostic performance and assay agreement between three immunoassays for the measurement of TRAb in patients with newly diagnosed GD. TRAb was measured with three different assays [H-TRAb (BRAHMS Diagnostica), M22-Man (RSR Limited) and M22-Aut (Roche Diagnostics)] in 387 participants who were recruited from two Danish population based studies and diagnosed with GD (n = 101), multinodular toxic goitre (n = 88), primary autoimmune hypothyroidism (n = 100) or included as controls (n = 98). Coefficient of variation for duplicate measurements with each of the three assays were H-TRAb: 3.6%, M22-Man: 9.4%, M22-Aut: 7.7%. Frequency of TRAb positivity in patients with GD were H-TRAb: 95%, M22-Man: 94%, M22-Aut: 96%. Receiver operating characteristic analysis revealed a high sensitivity (H-TRAb: 95%, M22-Man: 93%, M22-Aut: 95%) and specificity (H-TRAb: 99%, M22-Man: 99%, M22 Aut: 97%) for the diagnosis of GD with all assays. Comparison of TRAb levels showed inter-assay variability and values were considerably lower with the M22 Man assay. All TRAb assays showed a high diagnostic performance for GD, but a high inter-assay variability was observed limiting the use of different assays in clinical monitoring of patients with GD. PMID- 28737966 TI - Effect of obesity on sinonasal disease in asthma. AB - OBJECTIVE: Sinonasal disease can contribute to poor asthma control. There are reports that link obesity with an increased prevalence of sinonasal disease, but no studies evaluating the severity of sinonasal disease in obese asthmatics, and how this impacts asthma control. The purpose of the current study was to determine if obesity is associated with increased severity of sinonasal disease, and/or affects response to nasal corticosteroid treatment in asthma. METHODS: This study included 236 adults participating in a 24-week randomized, double masked, placebo-controlled study of nasal mometasone for the treatment of poorly controlled asthma. Sinonasal disease severity was assessed using validated questionnaires, and compared in participants of differing BMIs. Eosinophilic inflammation was assessed using markers in nasal lavage, serum and exhaled nitric oxide. Response to treatment was compared in different BMI groups. RESULTS: Obesity had no effect on the severity of sinonasal disease symptoms in asthmatics (Sino-Nasal Outcome Test 22 (SNOT 22) score [mean +/- SD] 35.4 +/- 18.5, 40.2 +/- 22.8, and 39.1 +/- 21.7, p = 0.43, in lean, overweight and obese participants), nor on nasal, bronchial or systemic markers of allergic inflammation. Nasal steroids had some limited effects on symptoms, lung function and inflammatory markers in lean participants, but no detectable effect was found in obese patients. CONCLUSIONS: Obesity does not affect severity of sinonasal disease in patients with asthma; the association of sinonasal disease symptoms with increased asthma severity and markers of Type 2 inflammation are consistent across all BMI groups. The response of obese patients to nasal corticosteroids requires further study. PMID- 28737967 TI - Integral membrane proteins: bottom-up, top-down and structural proteomics. AB - INTRODUCTION: Integral membrane proteins and lipids constitute the bilayer membranes that surround cells and sub-cellular compartments, and modulate movements of molecules and information between them. Since membrane protein drug targets represent a disproportionately large segment of the proteome, technical developments need timely review. Areas covered: Publically available resources such as Pubmed were surveyed. Bottom-up proteomics analyses now allow efficient extraction and digestion such that membrane protein coverage is essentially complete, making up around one third of the proteome. However, this coverage relies upon hydrophilic loop regions while transmembrane domains are generally poorly covered in peptide-based strategies. Top-down mass spectrometry where the intact membrane protein is fragmented in the gas phase gives good coverage in transmembrane regions, and membrane fractions are yielding to high-throughput top down proteomics. Exciting progress in native mass spectrometry of membrane protein complexes is providing insights into subunit stoichiometry and lipid binding, and cross-linking strategies are contributing critical in-vivo information. Expert commentary: It is clear from the literature that integral membrane proteins have yielded to advanced techniques in protein chemistry and mass spectrometry, with applications limited only by the imagination of investigators. Key advances toward translation to the clinic are emphasized. PMID- 28737968 TI - Pattern of Tumor Shrinkage during Neoadjuvant Chemotherapy Is Associated with Prognosis in Low-Grade Luminal Early Breast Cancer. AB - Purpose To evaluate the association between tumor shrinkage patterns shown with magnetic resonance (MR) imaging during neoadjuvant chemotherapy (NAC) and prognosis in patients with low-grade luminal breast cancer. Materials and Methods This retrospective study was approved by the institutional review board and informed consent was obtained from all subjects. The low-grade luminal breast cancer was defined as hormone receptor-positive and human epidermal growth factor receptor 2-negative with nuclear grades 1 or 2. The patterns of tumor shrinkage as revealed at MR imaging were categorized into two types: concentric shrinkage (CS) and non-CS. Among 854 patients who had received NAC in a single institution from January 2000 to December 2009, 183 patients with low-grade luminal breast cancer were retrospectively evaluated for the development set. Another data set from 292 patients who had received NAC in the same institution between January 2010 and December 2012 was used for the validation set. Among these 292 patients, 121 patients with low-grade luminal breast cancer were retrospectively evaluated. Results In the development set, the median observation period was 67.9 months. Recurrence was observed in 31 patients, and 16 deaths were related to breast cancer. There were statistically significant differences in both the disease-free survival (DFS) and overall survival (OS) rates between patterns of tumor shrinkage (P < .001 and P < .001, respectively). Multivariate analysis demonstrated that the CS pattern had the only significant independent association with DFS (P = .001) and OS (P = .009) rate. In the validation set, the median follow-up period was 56.9 months. Recurrence was observed in 20 patients (16.5%) and eight (6.6%) deaths were related to breast cancer. DFS rate was significantly longer in patients with the CS pattern (72.8 months; 95% confidence interval [CI]: 69.9, 75.6 months) than in those with the non-CS pattern (56.0 months; 95% CI: 49.1, 62.9 months; P <= .001). The CS pattern was associated with an excellent prognosis (median OS, 80.6 months; 95% CI: 79.3, 81.8 months vs 65.0 months; 95% CI: 60.1, 69.8 months; P = .004). Multivariate analysis demonstrated that the CS pattern had the only significant independent association with DFS (P = .007) and OS (P = .037) rates. Conclusion The CS pattern as revealed at MR imaging during NAC had the only significant independent association with prognosis in patients with low-grade luminal breast cancer. (c) RSNA, 2017. PMID- 28737969 TI - High Hydrostatic Pressure Extract of Ginger Exerts Antistress Effects in Immobilization-Stressed Rats. AB - Stress contributes to physiological changes such as weight loss and hormonal imbalances. The aim of the present study was to investigate antistress effects of high hydrostatic pressure extract of ginger (HPG) in immobilization-stressed rats. Male Sprague-Dawley rats (n = 24) were divided into three groups as follows: control (C), immobilization stress (2 h daily, for 2 weeks) (S), and immobilization stress (2 h daily, for 2 weeks) plus oral administration of HPG (150 mg/kg body weight/day) (S+G). Immobilization stress reduced the body weight gain and thymus weight by 50.2% and 31.3%, respectively, compared to the control group. The levels of serum aspartate transaminase, alanine transaminase, and corticosterone were significantly higher in the stress group, compared to the control group. Moreover, immobilization stress elevated the mRNA levels of tyrosine hydroxylase (Th), dopamine beta-hydroxylase (Dbh), and cytochrome P450 side-chain cleavage (P450scc), which are related to catecholamine and corticosterone synthesis in the adrenal gland. HPG administration also increased the body weight gain and thymus weight by 12.7% and 16.6%, respectively, compared to the stress group. Furthermore, the mRNA levels of Th, Dbh, phenylethanolamine N-methyltransferase, and P450scc were elevated by the HPG treatment when compared to the stress group. These results suggest that HPG would have antistress effects partially via the reversal of stress-induced physiological changes and suppression of mRNA expression of genes related to corticosterone and catecholamine synthetic enzymes. PMID- 28737970 TI - The photocatalytic degradation of methylene blue by green semiconductor films that is induced by irradiation by a light-emitting diode and visible light. AB - : This study develops a low-energy rotating photocatalytic contactor (LE-RPC) that has Cu-doped TiO2 films coated on stainless-steel rotating disks, to experimentally evaluate the efficiency of the degradation and decolorization of methylene blue (MB) under irradiation from different light sources (visible 430 nm, light-emitting diode [LED] 460 nm, and LED 525 nm). The production of hydroxyl radicals is also examined. The experimental results show that the photocatalytic activity of TiO2 that is doped with Cu2+ is induced by illumination with visible light and an LED. More than 90% of methylene blue at a 10 mg/L concentration is degraded after illumination by visible light (430 nm) for 4 hr at 20 rpm. This study also demonstrates that the quantity of hydroxyl radicals produced is directly proportional to the light energy intensity. The greater the light energy intensity, the greater is the number of hydroxyl radicals produced. IMPLICATIONS: The CuO-doped anatase TiO2 powder was successfully synthesized in this study by a sol-gel method. The catalytic abilities of the stainless-steel film were enhanced in the visible light regions. This study has successfully modified the nano-photocatalytic materials to drop band gap and has also successfully fixed the nano-photocatalytic materials on a substratum to effectively treat dye wastewater in the range of visible light. The results can be useful to the development of a low-energy rotating photocatalytic contactor for decontamination purposes. PMID- 28737971 TI - Fluticasone Furoate, Vilanterol, and Lung Function Decline in Patients with Moderate Chronic Obstructive Pulmonary Disease and Heightened Cardiovascular Risk. AB - RATIONALE: Many patients with chronic obstructive pulmonary disease (COPD) have an accelerated loss of lung function. It is unclear whether drug treatment can modify this in patients with moderately severe disease. OBJECTIVES: In a prespecified analysis of the key secondary outcome in SUMMIT (Study to Understand Mortality and Morbidity), we investigated whether the inhaled corticosteroid fluticasone furoate (FF; 100 MUg), the long-acting beta-agonist vilanterol (VI; 25 MUg), or their combination (FF/VI) modified the rate of decline in FEV1 compared with placebo. We also investigated how baseline covariates affected this decline. METHODS: Spirometry was measured every 12 weeks in this event-driven, randomized, placebo-controlled trial of 16,485 patients with moderate COPD and heightened cardiovascular risk. An average of seven spirometric assessments per subject among the 15,457 patients with at least one on-treatment measurement were used in the analysis of rate of FEV1 decline. All statistical comparisons are considered nominal. MEASUREMENTS AND MAIN RESULTS: The adjusted rates of FEV1 decline were -46 ml/yr (-3.0% of baseline) with placebo, -47 ml/yr (-3.1%) with VI, -38 ml/yr (-2.5%) with FF, and -38 ml/yr (-2.3%) with FF/VI. FF-containing regimens had lower rates of decline than placebo (P < 0.03), and FF/VI had a lower rate of decline than VI alone (P < 0.005). The FEV1 decline was faster in current smokers, those with a lower body mass index, males, and patients with established cardiovascular disease. CONCLUSIONS: In patients with moderate COPD and heightened cardiovascular risk, FF alone or in combination with VI appears to reduce the rate of FEV1 decline. Clinical trial registered with www.clinicaltrials.gov (NCT01313676). PMID- 28737972 TI - Identifying Health Information Technology Needs of Oncologists to Facilitate the Adoption of Genomic Medicine: Recommendations From the 2016 American Society of Clinical Oncology Omics and Precision Oncology Workshop. AB - At the ASCO Data Standards and Interoperability Summit held in May 2016, it was unanimously decided that four areas of current oncology clinical practice have serious, unmet health information technology needs. The following areas of need were identified: 1) omics and precision oncology, 2) advancing interoperability, 3) patient engagement, and 4) value-based oncology. To begin to address these issues, ASCO convened two complementary workshops: the Omics and Precision Oncology Workshop in October 2016 and the Advancing Interoperability Workshop in December 2016. A common goal was to address the complexity, enormity, and rapidly changing nature of genomic information, which existing electronic health records are ill equipped to manage. The subject matter experts invited to the Omics and Precision Oncology Workgroup were tasked with the responsibility of determining a specific, limited need that could be addressed by a software application (app) in the short-term future, using currently available genomic knowledge bases. Hence, the scope of this workshop was to determine the basic functionality of one app that could serve as a test case for app development. The goal of the second workshop, described separately, was to identify the specifications for such an app. This approach was chosen both to facilitate the development of a useful app and to help ASCO and oncologists better understand the mechanics, difficulties, and gaps in genomic clinical decision support tool development. In this article, we discuss the key challenges and recommendations identified by the workshop participants. Our hope is to narrow the gap between the practicing oncologist and ongoing national efforts to provide precision oncology and value-based care to cancer patients. PMID- 28737973 TI - Current Treatment Landscape of Advanced Papillary Renal Cancer. PMID- 28737974 TI - Quality Improvement in the Era of Big Data. PMID- 28737975 TI - Charting the Future of Cancer Health Disparities Research: A Position Statement From the American Association for Cancer Research, the American Cancer Society, the American Society of Clinical Oncology, and the National Cancer Institute. PMID- 28737976 TI - On Defining Global Catastrophic Biological Risks. PMID- 28737978 TI - Risk of violence among patients in psychiatric treatment: results from a national census. AB - BACKGROUND: Adverse media coverage of isolated incidents affects the public perception of the risk of violent behavior among people with mental illness. However, the risk of violence is studied most frequently among inpatients, which falsely exaggerates the prevalence of people with mental illness because the majority of individuals receive treatment as outpatients. AIM: To estimate the prevalence of the risk of violence among inpatients and outpatients in psychiatric treatment, as well as the associations with gender, age, socio economic status and co-morbid substance use disorders in all major diagnostic categories. METHODS: We conducted a national census of patients in specialist mental health services in Norway, which included 65% of all inpatients (N = 2,358) and 60% of all outpatients (N = 23,124). RESULTS: The prevalence of the risk of violence was 32% among inpatients and 8% among outpatients, where 80% of the patients in specialist mental health services were outpatients. If we weight the prevalence rates accordingly, less than 2% of the patients in specialist mental health services had a high risk of violent behavior. CONCLUSIONS: The stigma attached to those with mental illness is not consistent with the absence or low to modest risk of violent behavior in 98% of the patient group. Substance use disorders must be given priority in the treatment of all patient groups. Mental health care in general and interventions that target violent behavior in particular should address the problems and needs of these patients better, especially those who are unemployed, have a low level of education and have a background of being a refugee or an immigrant. PMID- 28737979 TI - HECT Domain and RCC1-Like Domain-Containing Protein 5 (HERC-5) Gene Polymorphisms in HIV-1-Infected Individuals: A Study from India. AB - HECT domain and RCC1-like domain-containing protein 5 (HERC-5) is one of the novel host restriction factors that is known to inhibit HIV release in vitro. Polymorphisms in other host restriction factors have been associated with HIV infection and disease progression. However, no report is available on the HERC-5 polymorphism in HIV-infected individuals. We studied the HERC-5 gene polymorphism in HIV-infected individuals and explored whether it is associated with different disease outcomes. Genomic DNA was isolated from 41 HIV-1 progressors, 39 long term nonprogressors, and 74 HIV seronegative healthy donors for amplification of HERC5 Exon-18 and other regulatory regions followed by sequencing. We found no genetic variation in the known single-nucleotide polymorphism (SNP)-rs34457268 (Exon-18) of HERC-5 in HIV-infected individuals. Instead, a synonymous mutation at rs6857425 (T-C) was present in the same region among all study groups (p > .05), irrespective of their HIV status. We further noted two novel SNPs in Intron 18 region. To the best of our knowledge, this is first study to report the HERC5 gene polymorphism among HIV-infected groups. PMID- 28737980 TI - Nitration of H2B histone elicits an immune response in experimental animals. AB - Histone H2B is an autoantigen that appears in circulation due to altered apoptosis/or insufficient clearance and is likely to be involved in the induction and progression of autoimmune diseases since modified-H2B is immunogenic. Our studies demonstrate that tyrosines of H2B histone spontaneously converts to free and nitrotyrosine bound protein in vivo. Commercially available H2B histone was modified with peroxynitrite in vitro. Modified H2B was found to be more immunogenic than native form in experimental animals. Furthermore, the sera of rabbits were analyzed for the native and modified forms of the H2B histone. The binding specificity of autoantibodies was characterized by competitive enzyme linked immunosorbent assay (ELISA) and band shift assay. The free 3-nitrotyrosine in systemic lupus erythematosus sera was quantified by high-performance liquid chromatography. Peroxynitrite-modified H2B induced high titre antibodies as compared to native form which were directly proportional to the nitrotyrosine content. Furthermore, the induced antibodies showed specificity towards the immunogen and cross-reacted with tyrosine-nitrated proteins. ELISA showed preferential binding of induced anti-peroxynitrite modified H2B antibodies to modified H2B as compared to native H2B. The present study shows that peroxynitrite modification of self-antigen(s) generates neoepitopes capable of inducing modified-H2B autoantibodies in experimental animals. PMID- 28737981 TI - Contact Forces Acting on Large Femoral Osteochondral Allografts During Forced Knee Extension. AB - BACKGROUND: A single cylindrical graft plug is commonly used for large focal femoral defects during osteochondral allograft (OCA) transplantation. Excessive contact force (CF) on a proud plug could compromise initial healing. CFs during forced knee extension are of particular interest because this maneuver is used by therapists to restore early postoperative range of motion. HYPOTHESIS: A proud OCA plug will significantly increase the CF and significantly decrease the knee extension angle (KEA). STUDY DESIGN: Controlled laboratory study. METHODS: Eleven human knee specimens had miniature load cells installed in both femoral condyles at standardized locations representative of clinical defects. Each load cell had a 20-mm-diameter cylinder of native bone/cartilage attached at its precise anatomic location. Four spacers, 0.5 mm in thickness, were inserted sequentially between each load cell and its mounting bracket to create proud plug conditions of 0.5 to 2 mm. Measurements of the CF and KEA were recorded at extension moment levels up to 8 N.m. RESULTS: At 8 N.m, the mean CFs for flush plugs were 149 +/- 18 N (lateral) and 34 +/- 13 N (medial). The mean increases in the medial CF (compared with flush) for 0.5-mm, 1-mm, 1.5-mm, and 2-mm proud conditions were 31 N (+91%), 64 N (+188%), 111 N (+325%), and 154 N (+451%), respectively. Corresponding increases for lateral proud plugs were 55 N (+37%), 120 N (+81%), 162 N (+109%), and 210 N (+141%), respectively. The CFs (and CF increases) for lateral grafts were significantly ( P < .05) higher than corresponding values for medial grafts at each proudness condition. Medial plug proudness had no consistent effect on the KEA. A 1-mm proud lateral plug significantly reduced the KEA by -1.6 degrees (0 N.m) and -0.9 degrees (2 N.m). CONCLUSION: Graft proudness of only 0.5 mm significantly increased CFs during forced knee extension, emphasizing the surgical precision necessary to achieve normal CF levels. CLINICAL RELEVANCE: It is believed that some amount of CF is beneficial in the early stages of graft healing, and our findings suggest that forced knee extension may be well suited for this purpose. However, the surgeon should be aware that large extension moments can also generate relatively high CFs, especially if the plug is proud. PMID- 28737982 TI - Knocking on prison's door: a 10-fold rise in the number of psychotic prisoners in Finland during the years 2005-2016. AB - BACKGROUND: As in many European countries, Finnish psychiatric services experienced a rapid process of deinstitutionalization in the 1990s. In recent decades, the decrease in numbers of psychiatric hospital beds has in several countries been found to be linked with increasing criminality among severely mentally ill individuals. It has been concluded that deinstitutionalization could be the main reason for this development. AIM: To investigate whether the prevalence of severely mentally ill persons to prison is a growing trend also in Finland. METHODS: We searched for the annual data in electronic case files of all prisoners about the ICD-10 diagnostic group of the most severe psychotic disorders. We also searched for the comorbid substance use disorders. Psychotic disorders due to substance abuse only were excluded from this study. RESULTS: During the years 2005-2016, a rapid 10-fold increase in psychotic disorders has occurred in Finnish prisons. In 2016, 185 prisoners (5.9% of all Finnish prisoners) were diagnosed as having a psychotic disorder that was not induced by substance abuse. The causes of this dramatic change are unclear. Comorbid substance abuse disorders were detected in only 39.5% of these prisoners and therefore substance abuse can only partly explain the increasing criminality of the severely mentally ill persons. 80.5% of psychotic disorders were diagnosed in Psychiatric Hospital for prisoners and 19.5% in prison policlinic services. CONCLUSION: Trans-institutionalization has become a serious challenge for the Finnish criminal justice and mental health systems. Further studies are needed to detect the causes of this change. More specialized services for severely mentally ill persons are needed both in the community psychiatry and also inside the prison services. PMID- 28737983 TI - Advancing Patient Care Through Specialty Pharmacy Services in an Academic Health System. AB - BACKGROUND: With the rapid growth of specialty pharmacies, including those within academic health systems, pharmacists have the opportunity to improve patient care through the management of specialty medications. Specialty pharmacists within academic health systems are uniquely positioned to overcome restrictions to medication access, financial constraints, and provider burdens that often lead to obstacles for patients to start and maintain necessary treatments. The Vanderbilt Specialty Pharmacy (VSP) model at Vanderbilt University Medical Center (VUMC) provides an example of a patient-centered, collaborative care prototype that places pharmacists directly into specialty clinics to assist with comprehensive management of patients on specialty medications. PROGRAM DESCRIPTION: VSP integrates specialty pharmacy services within existing specialty clinics based on the needs of each individual clinic. Each clinic is staffed with at least 1 clinical pharmacist and 1 pharmacy technician. The pharmacist is integrally involved in medication selection, initiation, and monitoring. The specialty pharmacy team ensures appropriate medication access and cost, provides extensive medication education, ensures patients are adherent to treatment, and coordinates care between patients and providers using the electronic medical record. OBSERVATIONS: Integration of pharmacists within specialty clinics at VUMC benefits providers, the health system, and patient care. This model has demonstrated decreased provider and clinic burden, decreased time to medication approval and initiation, excellent patient and provider satisfaction, substantial patient cost savings, optimal medication adherence, and overall improved continuity of care for patients on specialty medications. Since its inception in 2011, VSP has integrated 24 clinical pharmacists and 17 pharmacy technicians into 20 specialty clinics, with continued quarterly growth. IMPLICATIONS: The VSP model advances the role of pharmacists in managing patients on specialty medications in collaboration with providers. The integrated collaborative approach as presented by VSP represents a best practices model for those establishing and advancing specialty pharmacy services within academic health systems. DISCLOSURES: No outside funding supported this study. The authors have nothing to disclose. Study concept and design were principally contributed by Bagwell and Newman, along with the other authors. Lee took the lead in data collection, along with Carver, Bagwell, Kelley, and Newman. Data interpretation was performed by Carver, Kelley, Lee, and Bagwell, with assistance from Newman. The manuscript was written by Bagwell, Carver, Kelley, and Lee and revised primarily by Bagwell, along with the other authors. PMID- 28737984 TI - Evaluating the Training, Responsibilities, and Practices of P&T Committee Members and Nonmember Contributors. AB - BACKGROUND: Pharmacy and therapeutics (P&T) committees are responsible for managing drug formularies in numerous health care settings. Although pharmacy practice and health care organizations provide general recommendations of responsibilities and skills for members and nonmember contributors of P&T committees, the study investigators hypothesized that there is diversity in the training, responsibilities, and practices of these members and contributors. OBJECTIVE: To describe the training, responsibilities, and practices of members and nonmember contributors of P&T committees in a variety of health care settings, using an online survey. METHODS: In December 2015, an online survey was delivered to clinicians who were considered likely to be involved in P&T committee service from hospitals ranked by U.S. News & World Report and a convenience sample of clinicians practicing in managed care settings. The survey instrument was designed to assess various domains and perceptions of P&T committee processes. RESULTS: Sixty-nine respondents representing various health care delivery settings in the United States were eligible for and completed the survey. The majority of the respondents were pharmacists (94.2%), and 72.5% of the respondents were P&T committee members. The remainder of the respondents were nonmember P&T committee contributors. Approximately 60% of the respondents had served in P&T committee roles for >= 10 years. Specialized postgraduate training incorporating literature evaluation and formulary management was possessed by 21.7% and 17.4% of the respondents, respectively; however, most of the respondents received on-the-job training. Approximately half of the respondents were responsible for preparation of P&T committee documents, and 58% reported that nonmember contributors typically write and prepare these documents. Skill in literature evaluation was the most important criterion in selecting authors of P&T committee documents, while 10.1% of the respondents indicated that their committees did not use any criteria for author selection. When authoring documents, primary literature was routinely consulted by 89.5% of the respondents. Most of the respondents (84.1%) used an organization-specific document template, while 5.8% of the respondents indicated that they prepared documents with no defined process. The most highly ranked factor that could have a perceived beneficial effect on P&T committee functions were guidelines on the authoring and reviewing of P&T committee documents. CONCLUSIONS: The survey of P&T committee members and nonmember contributors used in this study identified current training, responsibilities, and practices that can inform recommendations for standards in these domains. Findings suggest opportunities for improvement in achieving best practice recommendations to ensure evidence-based decision making by P&T committees. DISCLOSURES: No outside funding supported this study. At the time of this study, Kelly was employed by Global Account Management Group (GAMG), which provides consulting services to the hospital and health services industry. As an employee of GAMG, Kelly has served on various advisory boards. All fees for consulting work were paid to GAMG and were primarily related to training or the federal market (e.g., Department of Defense or the Department of Veterans Affairs) and have no association with this study. Rodriguez and Moody report no conflicts of interest. All authors contributed to study concept and design. Rodriguez took the lead in data collection, assisted by the other authors. Data interpretation was performed by Rodriguez, along with Kelly and Moody. The manuscript was written and revised primarily by Rodriguez, along with the other authors. PMID- 28737986 TI - Real-World Adherence and Persistence to Oral Disease-Modifying Therapies in Multiple Sclerosis Patients Over 1 Year. AB - BACKGROUND: Disease-modifying therapies (DMTs) are indicated to reduce relapse rates and slow disease progression for relapsing-remitting multiple sclerosis (MS) patients when taken as prescribed. Nonadherence or non-persistence in the real-world setting can lead to greater risk for negative clinical outcomes. Although previous research has demonstrated greater adherence and persistence to oral DMTs compared with injectable DMTs, comparisons among oral DMTs are lacking. OBJECTIVE: To compare adherence, persistence, and time to discontinuation among MS patients newly prescribed the oral DMTs fingolimod, dimethyl fumarate, or teriflunomide. METHODS: This retrospective study used MarketScan Commercial and Medicare Supplemental claims databases. MS patients with >= 1 claim for specified DMTs from April 1, 2013, to June 30, 2013, were identified. The index drug was defined as the first oral DMT within this period. To capture patients newly initiating index DMTs, patients could not have a claim for their index drugs in the previous 12 months. Baseline characteristics were described for patients in each treatment cohort. Adherence, as measured by medication possession ratio (MPR) and proportion of days covered (PDC); persistence (30-day gap allowed); and time to discontinuation over a 12-month follow-up period were compared across treatment cohorts. Adjusted logistic regression models were used to examine adherence, and Cox regression models estimated risk of discontinuation. RESULTS: 1,498 patients newly initiated oral DMTs and met study inclusion criteria: fingolimod (n = 185), dimethyl fumarate (n = 1,160), and teriflunomide (n = 143). Patients were similar across most baseline characteristics, including region, relapse history, and health care resource utilization. Statistically significant differences were observed across the treatment cohorts for age, gender, previous injectable/infused DMT use, and comorbidities. Adherence and time to discontinuation were adjusted for age, gender, region, previous oral and injectable/infused DMT use, relapse history, and Charlson Comorbidity Index score. Relative to fingolimod patients, dimethyl fumarate and teriflunomide patients were significantly less likely to have an MPR >= 80% (OR = 0.18; 95% CI = 0.09-0.36; P < 0.001 and OR = 0.19; 95% CI = 0.08-0.42; P < 0.001, respectively). Similarly, relative to fingolimod patients, dimethyl fumarate and teriflunomide patients were significantly less likely to have PDC >= 80% (OR = 0.47; 95% CI = 0.33-0.67; P < 0.001 and OR = 0.37; 95% CI = 0.23-0.59; P < 0.001, respectively). Additionally, the HR for discontinuation was about 2 times greater for dimethyl fumarate (HR = 1.93; 95% CI = 1.44-2.59; P < 0.001) and teriflunomide patients (HR = 2.27; 95% CI = 1.57-3.28; P < 0.001) compared with fingolimod. CONCLUSIONS: In a real-world setting, patients taking fingolimod had better adherence and persistence compared with patients taking other oral DMTs over 12 months. Coupled with clinical factors, medication adherence and persistence should be important considerations when determining coverage decisions for MS patients. DISCLOSURES: This research was funded by Novartis Pharmaceuticals. Johnson, Lin, Ko, and Herrera are employed by Novartis Pharmaceuticals and own Novartis stock. Huanxue Zhou is employed by KMK Consulting, which provides consulting services to Novartis. Study concept and design were contributed by Johnson, Lin, Ko, and Herrera. Zhou collected the data, and data interpretation was performed by Johnson, Lin, Ko, and Herrera. All authors were involved in manuscript revision. The abstract for this study was presented at the AMCP Nexus 2015; October 26-29, 2015; Orlando, Florida. PMID- 28737985 TI - Evaluation of Patient Migration Patterns and Related Health Care Costs Within a National Medicare Advantage Prescription Drug Plan After Implementation of an Oxycodone HCl Extended-Release Access Restriction. AB - BACKGROUND: Health plans use formulary restrictions (e.g., prior authorization, step therapy, tier change, nonformulary status) in an effort to control cost and promote quality, safety, and appropriate prescription utilization. Some Medicare payers perceive that the inclusion of certain agents, such as branded oxycodone HCl extended-release tablets (OERs), on their formularies is associated with attracting high-cost members to the plan. OBJECTIVE: To evaluate disenrollment rates, patient migration, and subsequent health care costs among OER users who disenrolled from a national Medicare Advantage Prescription Drug plan (study MAPD) in the plan year following OER nonformulary restriction. METHODS: A retrospective, longitudinal cohort study using IMS pharmacy and medical claims data between July 1, 2011, and December 31, 2014, was conducted. In the study MAPD, adults aged >= 18 years who were chronic OER users with >= 2 OER claims 6 months before the nonformulary restriction date on January 1, 2013 (index date) and with continuous activity in pharmacy and medical claims for 6 months pre- and post-index were included in the study. Comparison years of 2012 and 2014 prerestriction/postrestriction were selected. All groups were followed for 6 months postindex. Year-to-year disenrollment rates of OER patients and the overall plan, as well as patient characteristics and costs of those who disenrolled from and those who remained with the plan, were measured. Costs were compared using a difference-in-differences approach. RESULTS: This study identified 2,935 eligible OER users from the study-MAPD population after imposing nonformulary restrictions on OERs on January 1, 2013. Mean age was 62.1 years, and 59.8% were female. The mean Charlson Comorbidity Index score was 1.83 for those 1,001 patients with medical claims data. For comparison years 2012 (prerestriction) and 2014 (postrestriction), 2,248 and 2,222 OER patients were identified, respectively. Patient characteristics were similar across patient cohorts in all 3 study years. Disenrollment rates for OER users (12.9%, 5.5%, and 14.3% for years 2012, 2013, and 2014, respectively) were lower or similar to those of the overall plan (18.3%, 7.6%, and 14.1%, respectively, for the same 3 years). Approximately 40% of OER users who disenrolled from the study-MAPD migrated to plans also imposing a nonformulary restriction on OERs, while about 25% moved to plans with less restrictive OER coverage. The majority (59.9%) of patients continued OER use irrespective of their disenrollment from the study MAPD in 2013. Although a nonsignificant decrease ($117; P = 0.340) in per patient per month (PPPM) cost was observed among OER patients postrestriction (from 2012 to 2013), the difference-in-difference analysis indicated a net postrestriction increase of $124 (P = 0.461) in PPPM for OER patients. CONCLUSIONS: This study found little evidence to support any consistent directional effect on patient enrollment behavior as a result of an OER non-formulary restriction. Implementation of an OER nonformulary restriction did not lead to higher OER patient disenrollment or lower patient costs in the study-MAPD. DISCLOSURES: Funding for this study was provided by Purdue Pharma. De, Chen, and Wade are employees of QuintilesIMS, a for-profit company that was contracted by Purdue Pharma to undertake this research. Sweet was a paid consultant for Purdue Pharma at the time of this study. Study concept and design were contributed by Chen, Wade, and De. Chen, De, and Wade collected the data, which were interpreted by all the authors. The manuscript was written by Chen and De, along with Sweet and Wade, and revised by all the authors. PMID- 28737987 TI - Factors Associated with Patient Preferences for Disease-Modifying Therapies in Multiple Sclerosis. AB - BACKGROUND: Treatment adherence in patients with multiple sclerosis (MS) is essential to reduce the rate of acute neurological attacks, severity of relapses, and hospitalizations and to slow its progression. Adherence rates in MS patients have been shown to be affected by multiple factors, including physical or cognitive difficulties, perceived lack of treatment efficacy, treatment-related adverse events, injection anxiety, and frequency of administration. OBJECTIVE: To elicit the preferences of MS patients for noneconomic and economic attributes of current disease-modifying therapies (DMTs). METHODS: We used conjoint analysis to estimate preferences from a convenience sample through a web-based online survey. Patients were invited to participate in the study using web portals and newsletters for MS patients. The conjoint survey included the following 6 attributes: (1) overall efficacy based on autoimmune disease progression stabilization; (2) acute increase in disease activity (flare-up); (3) rate of respiratory tract infections; (4) rate of serious respiratory tract infections (leading to hospitalization); (5) medication use; and (6) patient monthly out-of pocket medication costs. Using a fractional factorial design, 24 product profiles were created. Each respondent reviewed a random selection of 8 profiles. With each profile, subjects were asked to indicate their likelihood to try the hypothetical products on a scale from 0 to 100. Random effects linear regression was used to elicit preferences. RESULTS: After exclusion of respondents with incomplete information, data from 129 subjects were included in the analysis. The overall relative importance of each attribute for the ranges presented were (1) 38.4% for monthly out-of-pocket cost; (2) 21.5% for route and frequency of administration; (3) 15.9% for risk of hospitalization by infection; (4) 11.9% for risk of respiratory tract infection; (5) 7.4% for risk of flare-ups; and (6) 5.0% for disease progression stabilization. Preference weights indicated that subjects favored subcutaneous (beta coefficient [beta] = -2.26, 95% CI = -4.22 to -0.22) and oral administration (beta = 7.93, 95% CI = 5.95 to 10.2) over intramuscular (beta = -5.67, 95% CI = -8.67 to -3.56), but no significant differences were found between subcutaneous over intramuscular administration. Monthly out-of pocket cost was the most influential attribute, with an overall relative importance of 38%. The most preferred level was $75 (beta = 12.85, 95% CI = 10.64 to 15.06) followed by $150 (beta = 3.41, 95% CI = 0.98 to 5.84) when compared between $75, $150, $300, and $450 a month. CONCLUSIONS: Conjoint analysis proved to be a convenient tool to quantify respondents' relative preferences for DMT characteristics. Respondents gave higher weight to DMT monthly out-of-pocket costs and mode of administration than to adverse effects or efficacy. These findings may assist in the development of DMT cost-sharing strategies and shared decision making at the point of care. DISCLOSURES: No outside funding supported this study. The authors declare no potential conflicts of interest. Study concept and design were contributed by Hincapie and Burns. Data were collected by Hincapie and Burns, and interpreted by all the authors. The manuscript was written by Hincapie, Penm, and Burns and revised by Penm, Hincapie, and Burns. At the time of data collection, Burns was a PhD candidate at The University of Oklahoma, College of Pharmacy. PMID- 28737988 TI - Patterns of Care for Biologic-Dosing Outliers and Nonoutliers in Biologic-Naive Patients with Rheumatoid Arthritis. AB - BACKGROUND: Although most biologic medications for patients with rheumatoid arthritis (RA) have recommended fixed dosing, actual biologic dosing may vary among real-world patients, since some patients can receive higher (high-dose outliers) or lower (low-dose outliers) doses than what is recommended in medication package inserts. OBJECTIVE: To describe the patterns of care for biologic-dosing outliers and nonoutliers in biologic-naive patients with RA. METHODS: This was a retrospective, longitudinal cohort study of patients with RA who were not pregnant and were aged >= 18 and < 90 years from an integrated health care delivery system. Patients were newly initiated on adalimumab (ADA), etanercept (ETN), or infliximab (IFX) as index biologic therapy between July 1, 2006, and February 28, 2014. Outlier status was defined as a patient having received at least 1 dose < 90% or > 110% of the approved dose in the package insert at any time during the study period. Baseline patient profiles, treatment exposures, and outcomes were collected during the 180 days before and up to 2 years after biologic initiation and compared across index biologic outlier groups. Patients were followed for at least 1 year, with a subanalysis of those patients who remained as members for 2 years. RESULTS: This study included 434 RA patients with 1 year of follow-up and 372 RA patients with 2 years of follow-up. Overall, the vast majority of patients were female (~75%) and had similar baseline characteristics. Approximately 10% of patients were outliers in both follow-up cohorts. ETN patients were least likely to become outliers, and ADA patients were most likely to become outliers. Of all outliers during the 1-year follow-up, patients were more likely to be a high-dose outlier (55%) than a low dose outlier (45%). Median 1- and 2-year adjusted total biologic costs (based on wholesale acquisition costs) were higher for ADA and ETA nonoutliers than for IFX nonoutliers. Biologic persistence was highest for IFX patients. Charlson Comorbidity Index score, ETN and IFX index biologic, and treatment with a nonbiologic disease-modifying antirheumatic drug (DMARD) before biologic initiation were associated with becoming high- or low-dose outliers (c-statistic = 0.79). CONCLUSIONS: Approximately 1 in 10 study patients with RA was identified as a biologic-dosing outlier. Dosing outliers did not appear to have better clinical outcomes compared with nonoutliers. Before initiating outlier biologic dosing, health care providers may better serve their RA patients by prescribing alternate DMARD therapy. DISCLOSURES: This study was sponsored by Janssen Scientific Affairs. It is the policy of Janssen Scientific Affairs to publish all sponsored studies unless they are exploratory studies or are determined a priori for internal use only (e.g., to inform business decisions). Meyer is an employee of Janssen Scientific Affairs and a stockholder in Johnson and Johnson, its parent company. Delate and Jenkins have nothing to disclose. Study concept and design were contributed by Delate and Meyer. Delate took the lead in data collection, along with Jenkins. All authors participated in data analysis. The manuscript was written primarily by Delate, along with Meyers and Jenkins, and was revised by Meyer, along with Delate and Jenkins. PMID- 28737989 TI - Incremental Effect of the Addition of Prescriber Restrictions on a State Medicaid's Pharmacy-Only Patient Review and Restriction Program. AB - BACKGROUND: Patient review and restriction programs (PRRPs), used by state Medicaid programs to limit potential abuse and misuse of opioids and related controlled medications, often restrict members to a single pharmacy for controlled medications. While most states use a restricted pharmacy access model, not all states include restricted prescriber access. Oklahoma Medicaid (MOK) added a restricted prescriber access feature to its PRRP in July 2014. OBJECTIVE: To evaluate the incremental effect that the addition of a prescriber restriction to MOK's pharmacy-only PRRP had on the pharmacy and resource utilization of the enrolled members. METHODS: MOK members with at least 6 months of enrollment in the pharmacy-only PRRP were restricted to a maximum of 3 prescribers for controlled substances in July 2014 and were identified as "cases." Using a propensity score method, cases were matched to controls from the MOK non-PRRP enrolled population based on demographics and baseline health care utilization. Data from January 1, 2014, through December 31, 2014, were evaluated. Each member's monthly health care resource utilization, defined in terms of medical and pharmacy costs, prescription counts, and opioid use per member per month (PMPM), was analyzed. A difference-indifferences (DID) regression estimated the change in resource utilization following the July 2014 policy change. RESULTS: This study included 378 controls and 126 cases after propensity matching. No differences were noted for daily morphine equivalents, benzodiazepine prescriptions, or maintenance prescriptions. There were decreases in mean PMPM use for both groups for short-acting opioid (SAO) claims (P < 0.001), overall opioid claims (P = 0.007 for controls and P < 0.001 for cases), prescribers (P = 0.01 for controls and P < 0.001 for cases), and number of pharmacies for cases (P < 0.001). DID analyses indicated that cases had a larger decrease in mean SAO claims (difference: -0.15, 95% CI: -0.25 to -0.04, P = 0.008); prescribers (difference: -0.25, 95% CI: -0.36 to -0.15, P < 0.001); and pharmacies (difference: -0.20, 95% CI: -0.28 to -0.13, P < 0.001) relative to controls. The difference for overall opioid claims was greater for cases than controls but did not reach statistical significance (difference: -0.12, 95% CI: -0.25 to 0.00, P = 0.050). CONCLUSIONS: Although there was no evidence that overall opioid claims were affected, the addition of prescriber restrictions may have resulted in an incremental change to SAO, prescriber, and pharmacy use in the PRPP population. Use of PRRPs may be an effective tool in reducing inappropriate use of prescription opioids within payer systems. The question remains whether these changes result in long-term changes to behavior outside the payer system. Future research into the effects of PRRPs on patient behavior beyond the payer system is needed. DISCLOSURES: No outside funding supported this research. All authors disclose either employment by the Oklahoma Health Care Authority or contractual work for this employer. In addition, Keast discloses unrelated funding through unrestricted research grants from Gilead Sciences and Purdue Pharma. Study concept and design were contributed by Keast and Pham, along with Teel and Nesser. Keast and Pham collected the data, along with Teel, and data interpretation was provided by Keast and Pham, with assistance from Teel and Nesser. The manuscript was written primarily by Keast, along with Pham and Teel, and revised by all the authors. PMID- 28737990 TI - Cost-Effectiveness of Novel Agents in Medicare Patients with Multiple Myeloma: Findings from a U.S. Payer's Perspective. AB - BACKGROUND: Since multiple myeloma (MM) incurs a substantial economic burden in care management, more and more discussion has been generated in recent years about the costs of novel antimyeloma drugs and their associated value. Because of these costs, economic assessment that quantifies value of care over the long-term is essential. OBJECTIVE: To determine the cost-effectiveness (measured as cost per life-year saved) of front-line novel agent-based therapy use among a cohort of elderly patients with MM in a real-world setting. METHODS: We identified 2,551 elderly patients with advanced MM from 2000 to 2009 who initiated novel agent based therapy (bortezomib, lenalidomide, or thalidomide) or chemotherapy from the Surveillance, Epidemiology, and End Results-Medicare linked data. Patients were characterized according to age at diagnosis, sex, race, geographic region, marital status, socioeconomic status, comorbidities, and receipt of novel agents. Twenty-month cost of care and overall survival related to MM were compared between patients treated with novel agent-based therapy and patients treated with chemotherapy. A net monetary benefit approach and corresponding cost effectiveness acceptability curves were used to evaluate the cost-effectiveness of novel agent-based therapy. RESULTS: Overall, average 12-month MM total costs were 2.03 times higher for novel agent-based therapy ($144,665) than for chemotherapy ($47,750). Antimyeloma pharmacy costs represented about 31% ($45,095) of total MM costs for patients treated with novel agents but represented about 19% ($8,921) of total MM costs for patients treated with chemotherapy. Twelve-month survival rates increased significantly among patients receiving novel agents compared with patients receiving chemotherapy. In the incremental net monetary benefit analysis, after adjusting for potential covariates, patient use of novel agents was only cost-effective compared with chemotherapy when the willingness-to-pay thresholds were high, at about $230,000. CONCLUSIONS: Given the most common treatment practices in the United States, the use of novel agent-based therapy is not cost-effective at its current level of cost and effectiveness. Future studies should evaluate the generalizability of these results by evaluating cost-effectiveness of novel agent-based therapy use in different patient populations. DISCLOSURES: Funding for this study was contributed by the Agency for Healthcare Research and Quality (R01-H5018956). The authors have nothing to disclose. Study concept and design were contributed by Chen, Lairson, and Du, along with Chan. Chen and Du took the lead in data collection, along with Lairson and Huo. Data interpretation was performed by Chen, Chan, and Du, along with Lairson and Huo. The manuscript was written by Chen, along with Du, Lairson, Chan, and Huo, and revised by primarily by Du, along with Lairson, Huo, Chen, and Chan. PMID- 28737991 TI - Lowering Cost Share May Improve Rates of Home Glucose Monitoring Among Patients with Diabetes Using Insulin. AB - BACKGROUND: Not much is known about the extent to which lower cost share for blood glucose strips is associated with persistent filling. OBJECTIVE: To evaluate the relationship between cost sharing for blood glucose testing strips and continued use of testing strips. METHODS: This is a retrospective observational study using medical and pharmacy claims data integrated with laboratory hemoglobin A1c (A1c) values for patients using insulin and blood glucose testing strips. Diabetic patients using insulin who had at least 1 fill of blood glucose testing strips between 2010 and 2012 were included. Patients were divided into a low cost-share group (out-of-pocket cost percentage of total testing strip costs over a 1-year period from the initial fill < 20%; n = 3,575) and a high cost-share group (out-of-pocket cost percentage >= 20%; n = 3,580). We compared the likelihood of continued testing strip fills after the initial fill between the 2 groups by using modified Poisson regression models. RESULTS: Patients with low cost share had higher rates of continued testing strip fills compared with those with high cost share (89% vs. 82%, P < 0.001). Lower cost share was associated with greater probability of continued fills (adjusted risk ratio [aRR] = 1.05, 95% CI = 1.03-1.07, P < 0.001). Other patient characteristics associated with continued fills included type 1 diabetes diagnosis, types of insulin regimens, and health insurance plan type. In a subset analysis of patients whose A1c values at baseline were above the target level (8%) set by the National Committee for Quality Assurance guidelines, we saw a slight increase in magnitude of relationship between cost share and continued fills (RR = 1.06, 95% CI = 1.03-1.10, P < 0.01). CONCLUSIONS: There was a statistically significant association between cost share for testing strips and continued blood glucose self-monitoring. Among patients not achieving A1c control at baseline, there was an increase in the magnitude of relationship. Lowering cost share for testing strips can remove a barrier to persistence in diabetes self-management. DISCLOSURES: Funding for this study was provided by Anthem, which had no role in the study design, data interpretation, or preparation or review of the manuscript. The decision to publish was strictly that of the authors. Xie, Agiro, and DeVries are employees of HealthCore, a wholly owned subsidiary of Anthem. Bowman is an employee of Anthem. Study concept and design were contributed by all the authors. Xie took the lead in data collection, along with Agiro, and data interpretation was performed by all the authors. The manuscript was written by Xie and Agiro, along with DeVries, and revised by Xie, Agiro, and Devries, along with Bowman. PMID- 28737992 TI - Temporal Trends in Use of Biologic DMARDs for Rheumatoid Arthritis in the United States: A Cohort Study of Publicly and Privately Insured Patients. AB - BACKGROUND: Ten biologic disease-modifying antirheumatic drugs (bDMARDs) are available as treatment for rheumatoid arthritis (RA), but relatively little is known about population-level time trends in the use of these agents. OBJECTIVE: To describe time trends in the use of bDMARDs in RA patients with private or public insurance in the United States. METHODS: Claims data from private (Optum Clinformatics, 2004-2015) and public (Medicaid Analytic eXtract [MAX], 2000-2010) insurance programs were used. Patients with RA diagnosis codes and continuous health plan enrollment for 1-year baseline and 1-year follow-up periods were identified into 2 separate cohorts: (1) patients not using any bDMARD or (2) patients using a single bDMARD during the baseline period. Initiation of the first bDMARD from group 1 and switch to a second bDMARD from group 2 was identified as the outcome of interest during the 1-year follow-up period. Using mixed-effects regression models, we calculated yearly rates of initiation and switch for bDMARDs, adjusted for case-mix. We also described the proportion of all initiations and switches accounted for by each agent. RESULTS: There were 113,031 RA patients with public insurance and 97,751 RA patients with private insurance who were included in the study. The rates of initiation of bDMARDs (per 100 patients) increased significantly over time in Medicaid data for incident RA patients (from 1.1 to 3.1, P = 0.0006) and prevalent RA patients (from 4.6 to 10.9, P = 0.008). In Optum Clinformatics data, the rates were stable, with 7.7 to 8.3 per 100 incident RA patients (P = 0.10) and 11.0 to 11.5 per 100 prevalent RA patients (P = 0.12). The rates of switching (per 100 patients) increased over time from 6.4 to 16.0 (P = 0.04) in Medicaid data and 9.1 to 17.0 (P = 0.00003) in Optum Clinformatics data. Use of etanercept as the most common first-line agent was stable at approximately 50% of all biologic initiations, but use of infliximab decreased and the use of newer agents increased. CONCLUSIONS: More RA patients used bDMARDs in recent years, and use of newer agents, including certolizumab, golumumab, and tocilizuamab, is rising, which highlights a need for further comparative safety and effectiveness research of these agents to better guide evidence-based decision making. DISCLOSURES: This study was supported by an investigator-initiated research grant from Pfizer. The study was conducted by the authors independent of the sponsor. The sponsor was given the opportunity to make nonbinding comments on a draft of the manuscript, but the authors retained the right of publication and determined the final wording. Solomon receives salary support through research support to his hospital from Amgen, Pfizer, AstraZeneca, Genentech, Lilly, Bristol-Myers Squibb, and CORRONA. Kim receives research grants from AstraZeneca, Lilly, Pfizer, Bristol-Myers Squibb, and Genentech. Desai receives research grants from Merck. Study concept and design were contributed by Desai and Kim. Liu took the lead in data collection, along with Jin, Desai, and Kim. All authors contributed equally in the interpretation of the results. The manuscript was written and revised primarily by Desai, along with Kim and the other authors. PMID- 28737993 TI - The Effect of Formulary Restrictions on Patient and Payer Outcomes: A Systematic Literature Review. AB - BACKGROUND: Formulary restrictions are implemented to reduce pharmacy costs and ensure appropriate use of pharmaceutical products. As adoption of formulary restrictions increases with rising pharmacy costs, there is a need to better understand the potential effect of formulary restrictions on patient and payer outcomes. OBJECTIVE: To conduct a systematic literature review that assesses the effect of formulary restrictions on the following outcomes: medication adherence, clinical outcomes, treatment satisfaction, drug utilization, health care resource utilization, and economic outcomes. METHODS: Studies published in 2005 or later were identified from the MEDLINE, Embase, and Cochrane databases and the National Health Service Economic Evaluation Database, using 2 sets of search terms. A total of 17 formulary restriction terms (e.g., step therapy [ST] and prior authorization [PA]) and 55 outcome terms were included, resulting in 935 unique search term combinations. Two reviewers independently conducted analyses of the titles, abstracts, and full-text articles. The search was limited to English language articles that evaluated the effect of ST and/or PA placed by U.S. third party payers on the following outcomes: patient outcomes (medication adherence, clinical outcomes, and treatment satisfaction) and payer outcomes (drug utilization, health care resource utilization, and economic outcomes). RESULTS: Of 2,321 reviewed articles, 59 articles met the study inclusion criteria. The included studies assessed the effect of ST (n = 18), PA (n = 35), or both (n = 6) on medication adherence (n = 14), clinical outcomes (n = 12), treatment satisfaction (n = 2), drug utilization (n = 39), health care resource utilization (n = 18), and economic outcomes (n = 42). The 59 articles measured 164 outcomes across the patient, health care resource utilization, and economic outcome categories of interest. Of the total number of outcomes, 50.6% (n = 83) were negative in direction or were unfavorable, whereas 40.2% (n = 66) were positive in direction or were favorable, when the perspectives of patients and payers were considered. Of the total number of drug utilization outcomes reported (n = 46), the majority showed lower drug utilization (> 90%). However, in some of the articles, pharmacy cost savings resulting from lower drug utilization appeared to be offset by increased medical costs. CONCLUSIONS: Formulary coverage decisions may have unintended consequences on patient and payer outcomes despite lower drug utilization and pharmacy cost savings; therefore, careful evaluation of restrictions before policy implementation and continued reevaluation after implementation is warranted. DISCLOSURES: This study was funded by Novartis Pharmaceuticals. Park and Ko are employed by Novartis Pharmaceuticals in East Hanover, New Jersey, and Ko holds stock in Novartis. Raza, George, and Agrawal are employed by Novartis Healthcare in Hyderabad, India. Study concept and design were contributed primarily by Park and Ko, along with the other authors. Raza, George, and Agrawal collected the data, along with Park and Ko. Data interpretation was performed by Agrawal, Raza, George, Park, and Ko. The manuscript was written and revised by Raza, George, and Park, along with Ko and Agrawal. Results from this systematic literature review were presented at the AMCP Annual Meeting 2016; San Francisco, California; April 19-22, 2016. PMID- 28737994 TI - Impact of a Patient Support Program on Patient Adherence to Adalimumab and Direct Medical Costs in Crohn's Disease, Ulcerative Colitis, Rheumatoid Arthritis, Psoriasis, Psoriatic Arthritis, and Ankylosing Spondylitis. AB - BACKGROUND: AbbVie provides a free-to-patient patient support program (PSP) to assist adalimumab-treated patients with medication costs, nurse support, injection training, pen disposal, and medication reminders. The impact of these services on patient adherence to adalimumab and direct medical costs associated with autoimmune disease has not been assessed. OBJECTIVE: To quantify the relationship between participation in a PSP and outcomes (adalimumab adherence, persistence, and direct medical costs) in patients initiating adalimumab treatment. METHODS: A longitudinal, retrospective, cohort study was conducted using patient-level data from the PSP combined with Symphony Health Solutions administrative claims data for patients initiating adalimumab between January 2008 and June 2014. The sample included patients aged >= 18 years with a diagnosis of Crohn's disease, ulcerative colitis, rheumatoid arthritis, psoriasis, psoriatic arthritis, or ankylosing spondylitis who were biologic-naive before initiation of adalimumab. Patients who enrolled in the PSP (PSP cohort) were matched to those who did not enroll (non-PSP cohort) based on age, sex, year of treatment initiation, comorbidities, diagnosis, and initiation at a specialty pharmacy. For the PSP cohort, the index date was assigned as the earliest date of PSP enrollment, and time to enrollment following adalimumab initiation was used to assign index dates for the non-PSP cohort. All patients were required to have evidence of medical and pharmacy coverage for at least 6 months before and after their first adalimumab claim and at least 12 months after their index date. Adherence (proportion of days covered during the 12 months following PSP opt-in [index date]) was compared between cohorts using t-tests. Persistence was assessed using survival analysis of discontinuation rates. Medical costs for emergency department, inpatient, physician, and outpatient visits (all-cause and disease-related) and total costs (medical plus drug costs) were compared at 12 months following the index date using t-tests. RESULTS: A total of 2,386 patients were included in the study and were allocated to the PSP (n = 1,199) and non-PSP (n = 1,187) cohorts. Baseline characteristics were similar between cohorts. During the follow-up period, adalimumab adherence was 14% greater in the PSP cohort than for the non-PSP cohort (67.0% vs. 58.8%; P < 0.001). The discontinuation rate for adalimumab was 14% lower in the PSP cohort compared with the non-PSP cohort (39.7% vs. 46.2%; P = 0.001). Univariate analyses showed that PSP patients had 23% lower 12-month medical costs (excluding costs for biologic treatment) than did non-PSP patients ($18,322 vs. $23,679; P = 0.003). Disease related medical costs were 22% lower for PSP than for non-PSP patients ($8,001 vs. $10,202; P = 0.045). Total costs were 10% lower for PSP than for non-PSP patients ($35,741 vs. $39,713; P = 0.030). CONCLUSIONS: Patient enrollment in the PSP was associated with greater adherence, improved persistence, and reduced medical (all-cause and disease-related) and total health care costs for patients receiving adalimumab therapy. DISCLOSURES: Design, study conduct, and financial support for this study were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the abstract. All authors contributed to the development of the publication and maintained control over the final content. Rubin has received consulting fees or research support from AbbVie, Amgen, Emmi, Genentech, Ironwood, Janssen, Pfizer, Prometheus, Shire, and Takeda. Skup and Mittal are employees and stockholders of AbbVie. Chao was an employee of AbbVie at the time of the study and may hold AbbVie stock. Johnson and Davis are employees of Medicus Economics, which received payment from AbbVie to participate in this research. Study concept and design were contributed by Rubin, Mittal, Chao, and Skup, along with Davis and Johnson. Davis and Johnson took the lead in data collection, with assistance from the other authors, and data interpretation was performed by Rubin, Mittal, Chao, and Skup, with assistance from Davis and Johnson. All authors contributed to the writing and revision of the manuscript. The abstract for this study was published as Rubin DT, Skup M, Davis M, Johnson S, Chao J. Impact of AbbVie's patient support program on resource costs in Crohn's disease, ulcerative colitis, rheumatoid arthritis, psoriasis, psoriatic arthritis, and ankylosing spondylitis. J Manag Care Spec Pharm. 2015;21(Suppl 4a):S74-75 (poster presentation at Academy of Managed Care, 27th Annual Meeting and Expo; April 7-10, 2015; San Diego, CA) and as abstract 2339 in Arthritis Rheumatol. 2015;67(Suppl 10; poster presentation at American College of Rheumatology 2015 ACR/AHRP Annual Meeting; November 7-11, 2015; San Francisco, CA). PMID- 28737995 TI - Factors in the 4-week Acceptance of a Computer-Based, Chronic Disease Self Monitoring System in Patients with Type 2 Diabetes Mellitus and/or Hypertension. AB - BACKGROUND: Health information technology (HIT) interventions developed to support patients' self-care for chronic diseases have become popular, but people may not always accept and sustain their use. INTRODUCTION: This study examined factors that affected patients' acceptance of a computer-based, chronic disease self-monitoring system over a 4-week period. MATERIALS AND METHODS: A research model was developed to test the relationships between the perceived usefulness, perceived ease of use, attitude, and subjective norm and the patients' behavioral intention to use the system (i.e., acceptance). Data were collected with surveys of 42 patients with type 2 diabetes mellitus and/or hypertension at baseline, 2 weeks after implementation, and 4 weeks after implementation. Path analysis was used for model testing. RESULTS: Perceived usefulness affected behavioral intention indirectly at 2 weeks and directly at 4 weeks; perceived ease of use affected behavioral intention indirectly at 2 and 4 weeks; attitude directly affected behavioral intention at 2 weeks; and subjective norm affected behavioral intention indirectly at 2 weeks and directly at baseline and at 4 weeks. CONCLUSIONS: Patients' acceptance of HIT is affected by the factors proposed in our research model. It is suggested that healthcare stakeholders consider and address the effects of these factors and their variations over time before implementing HIT. PMID- 28737997 TI - Adolescent and Young Adult Cancer Survivors' Experiences of the Healthcare System: A Qualitative Study. AB - PURPOSE: To qualitatively examine the experiences of diagnosis and treatment, and attitudes toward ongoing healthcare of adolescent and young adult (AYA) survivors of AYA cancer, to determine barriers to healthcare engagement in the early survivorship period. METHODS: Forty-two participants aged between 15 and 25 years were recruited between February 2013 and October 2015 as part of a larger Australia-wide study. This study analyzed data collected through a semistructured telephone interview. Interviews were recorded and transcribed verbatim and then coded line-by-line. Data were analyzed for emergent themes using the qualitative software NVivo. RESULTS: Many participants demonstrated a good understanding of their cancer diagnosis and treatment. Participants expressed high levels of confidence in their healthcare teams and demonstrated a conscientious approach to their ongoing cancer-specific and general healthcare. However, most AYAs had expectations of the cancer journey that differed from the realities of their experiences. CONCLUSIONS: The results further highlight the crucial role of healthcare professionals in ensuring AYA cancer patients have accurate expectations of diagnosis and treatment, and develop a strong working knowledge of their disease that is maintained into survivorship. AYA cancer survivors may require ongoing education and support to stay engaged with long-term follow-up care. PMID- 28737996 TI - Integrating Palliative and Oncology Care for Patients with Advanced Cancer: A Quality Improvement Intervention. AB - BACKGROUND: Practice guidelines recommend palliative care for patients with advanced cancer, but gaps in access and quality of care persist. OBJECTIVE: To increase goals-of-care (GOC) communication for hospitalized patients with Stage IV cancer. METHODS: An interdisciplinary team designed a quality improvement intervention to enhance oncology palliative care, including training in communication skills and triggers for palliative care consults. SETTING/SUBJECTS: All adult inpatients with Stage IV cancer and unplanned admission at an 804-bed hospital affiliated with a National Cancer Institute (NCI) Comprehensive Cancer Center. MEASUREMENTS: The primary quality measure was the percentage of patients with Stage IV cancer who had a GOC discussion during hospitalization; secondary measures included screening for pain, dyspnea, spiritual needs, and outcomes of intensive care, hospice, and 30-day readmission. RESULTS: In the 11-month study period, n = 330, Stage IV cancer patients were hospitalized. Comparing the first three months with the final three months, rates of GOC discussion increased from 29% to 48% (p = 0.013), and specialty palliative care consultation increased from 18% to 33%, (p = 0.026). Rates of symptom screening, intensive care unit transfer, hospice, and 30-day re-admission did not change overall. However, patients with specialty palliative care more frequently had pain screening (91% vs. 81%, p = 0.020), spiritual assessment (48% vs. 10%, p < 0.001), and hospice referral (39% vs. 9%, p < 0.001), and they were less likely to be re-admitted within 30 days (12% vs. 21%, p = 0.059). DISCUSSION: Interdisciplinary quality improvement was effective to increase GOC discussions and palliative care consults for patients with Stage IV cancer. PMID- 28737998 TI - Examination of the Patient-Focused Impact of Cancer Telegenetics Among a Rural Population: Comparison with Traditional In-Person Services. AB - BACKGROUND: Telecommunication models promise to improve access to cancer genetic counseling. Little is known about their impact among the geographically underserved. This work examined knowledge and emotional outcomes and attitudes/beliefs regarding cancer telegenetic services (via live-interactive videoconferencing) in Maine. MATERIALS AND METHODS: Cancer telegenetic patients seen at two remote sites and control (in-person) patients responded to pre /postsurveys assessing care impact on hereditary breast and ovarian cancer (HBOC) knowledge and emotional health, ease of access to services, and telegenetics satisfaction/acceptability. RESULTS: 158/174 (90%) participants returned pre- and immediate postcounseling surveys (90 remote and 68 in-person). Fewer returned 1 month postsurveys. Remote patients were older with lower education levels, more likely to live in rural counties and to have cancer histories. The two groups were matched relative to gender, race, and health insurance status. HBOC knowledge improved equally in both groups pre- versus immediately postcounseling and was maintained at 1 month in both groups. Decreased anxiety was evident postcounseling with no significant difference between groups. Depression improved significantly in remote patients immediately postcounseling; 1-month depression measures were lower in both groups. The availability of telegenetics eased transportation needs/work absences, and patients reported satisfaction with telecommunication quality. Despite overall acceptance of telegenetics, 32% of remote patients noted preference for in-person care. CONCLUSIONS: There were few differences in HBOC knowledge and emotional outcomes comparing traditional in person cancer genetic services with telegenetics, and satisfaction with/acceptance of this model was high. These data relate to scalability of cancer telegenetics in rural regions regionally and nationally. PMID- 28737999 TI - Effect of laparotomy on the pituitary-adrenal axis in dogs. AB - OBJECTIVE To assess effects of major abdominal surgery on serum cortisol and aldosterone and plasma canine ACTH (cACTH) concentrations. ANIMALS 39 healthy dogs undergoing laparotomy during veterinary student surgical laboratories. PROCEDURES Blood samples were obtained before and at completion of surgery. Serum cortisol and aldosterone and plasma cACTH concentrations were measured by use of validated radioimmunoassays. Changes in concentrations (postoperative concentration minus preoperative concentration) were calculated. Data were analyzed by use of the Wilcoxon signed rank test, Pearson correlation analysis, and Mann-Whitney rank sum test. RESULTS Cortisol, aldosterone, and cACTH concentrations increased significantly from before to after surgery. Although cortisol and aldosterone concentrations increased in almost all dogs, cACTH concentrations decreased in 6 of 32 (19%) dogs. All dogs had preoperative cortisol concentrations within the reference range, but 24 of 39 (62%) dogs had postoperative concentrations above the reference range. A correlation between the change in cACTH concentration and the change in cortisol concentration was not detected. CONCLUSIONS AND CLINICAL RELEVANCE Laparotomy caused a significant increase in serum cortisol and aldosterone concentrations. In most dogs, but not all dogs, plasma cACTH concentrations increased. Lack of correlation between the change in cACTH concentration and the change in cortisol concentration suggested that increased postoperative cortisol concentrations may have been attributable to ACTH-independent mechanisms, an early ACTH increase that caused a sustained cortisol release, or decreased cortisol clearance. Further studies are indicated to evaluate the effects of various anesthetic protocols and minimally invasive surgical techniques on the stress response. PMID- 28738000 TI - Comparison of cardiac output measured by use of computed tomography and thermodilution in dogs. AB - OBJECTIVE To compare cardiac output (CO) measured by use of CT coronary angiography and thermodilution (criterion-referenced standard) at various CO values, record adverse effects, and determine the time needed to measure CO. ANIMALS 5 healthy purpose-bred Beagles (2 males and 3 females). PROCEDURES A prospective nonrandomized crossover study was conducted. Dogs were premedicated with butorphanol tartrate (0.2 mg*kg-1, IM). Anesthesia was induced by IV administration of etomidate (1 to 2 mg*kg-1) and midazolam (0.25 mg*kg-1). Orotracheal intubation was performed, and anesthesia was maintained by administration of isoflurane. The CO was determined by use of thermodilution and by use of CT at 3 CO values. Dobutamine was infused at various rates to obtain the 3 CO values. RESULTS 13 values were obtained and analyzed. The mean +/- SD difference between methods was 0.09 +/- 0.71 L*min-1 (95% confidence interval [CI], 0.52 to -0.34 L*min-1). Only 1 of 13 values was located on the 100% agreement line (ie, 0 line), 7 of 13 values were located within the 95% CI, and 5 of 13 values were outside the 95% CI. CONCLUSIONS AND CLINICAL RELEVANCE For this study, there was poor agreement between the 2 methods. The 95% CI interval was 0.52 to -0.34 L*min-1, and 5 of 13 values were outside the 95% CI. Therefore, results for the CT method appeared to be inappropriate for use in making clinical decisions. PMID- 28738002 TI - Effects of storage conditions on results for quantitative and qualitative evaluation of proteins in canine urine. AB - OBJECTIVE To investigate effects of storage conditions on the canine urine protein-to-creatinine ratio (UPC) and on SDS-agarose gel electrophoresis (AGE) of urinary proteins. SAMPLE Urine specimens from 20 proteinuric (UPC > 0.5) and 20 nonproteinuric (UPC <= 0.2) dogs. PROCEDURES UPC and SDS-AGE were performed on urine specimens stored at room temperature (20 degrees C) and 4 degrees C for up to 5 days and at -20 degrees and -80 degrees C for up to 360 days; some specimens were subjected to 3 freeze-thaw cycles. Results were compared with those obtained for fresh urine specimens. RESULTS UPC was not affected by storage at room temperature or by freezing. A decrease in UPC was observed for specimens from nonproteinuric dogs after 5 days at 4 degrees C (10%) and from both groups after 90 days at -20 degrees and -80 degrees C (<= 20% and <= 15%, respectively). The SDS-AGE profiles revealed no visual changes regardless of duration of storage for specimens stored at room temperature, 4 degrees C, and 80 degrees C, except for 1 profile after 360 days at -80 degrees C. Repeated freeze-thaw cycles did not affect SDS-AGE profiles. Appearance or strengthening of high-molecular-weight bands that could alter interpretation was evident in SDS AGE profiles after storage at -20 degrees C for >= 15 days (31/40 dogs). CONCLUSIONS AND CLINICAL RELEVANCE Storage of urine at -20 degrees or -80 degrees C for up to 1 year influenced the UPC without affecting clinical interpretation. Storage of urine specimens at -20 degrees C impaired visual analysis of SDS-AGE. When SDS-AGE cannot be performed on fresh or recently refrigerated urine specimens, storage at -80 degrees C is recommended. PMID- 28738003 TI - Pharmacokinetics and egg residues after oral administration of a single dose of meloxicam in domestic chickens (Gallus domesticus). AB - OBJECTIVE To determine the pharmacokinetics of meloxicam in domestic hens and duration and quantity of drug residues in their eggs following PO administration of a single dose (1 mg of meloxicam/kg). ANIMALS 8 healthy adult White Leghorn hens. PROCEDURES Hens were administered 1 mg of meloxicam/kg PO once. A blood sample was collected immediately before and at intervals up to 48 hours after drug administration. The hens' eggs were collected for 3 weeks after drug administration. Samples of the hens' plasma, egg whites (albumen), and egg yolks were analyzed by high-performance liquid chromatography. RESULTS The half-life, maximum concentration, and time to maximum concentration of meloxicam in plasma samples were 2.8 hours, 7.21 MUg/mL, and 2 hours, respectively. Following meloxicam administration, the drug was not detected after 4 days in egg whites and after 8 days in egg yolks. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that meloxicam administered at a dose of 1 mg/kg PO in chickens appears to maintain plasma concentrations equivalent to those reported to be therapeutic for humans for 12 hours. The egg residue data may be used to aid establishment of appropriate drug withdrawal time recommendations. PMID- 28738004 TI - Bone marrow cell composition and morphology in healthy juvenile female New Zealand White rabbits (Oryctolagus cuniculus). AB - OBJECTIVE To provide contemporary preliminary guidelines for the morphological evaluation of bone marrow in conjunction with CBC results for healthy juvenile (3 to 6-month-old) female New Zealand White rabbits (Oryctolagus cuniculus). ANIMALS 22 female New Zealand White rabbits. PROCEDURES Each rabbit was sedated, and a blood sample (3 mL) was collected from an ear artery for a CBC, after which the rabbit was euthanized. Within 5 minutes after euthanasia, bone marrow samples were obtained from the femur for cytologic and histologic evaluation. Bone marrow specimens for cytologic evaluation were stained with modified Wright stain, and those for histologic evaluation were stained with either H&E or Prussian blue stain. RESULTS The CBC results were within published reference ranges for all rabbits except 4, each of which had mild leukopenia. Cytologic assessment of bone marrow revealed a median myeloid-to-erythroid ratio of 0.7 and 2.8 megakaryocytes/low-power field (magnification, 100X), and the median percentages of lymphocytes, plasma cells, and macrophages were 11.5%, 0.1%, and 0%, respectively. The myeloid-to-erythroid ratio was not significantly correlated with any CBC variable. On histologic evaluation of bone marrow, the cellularity ranged from 30% to 50%, there were 2.1 to 7.7 megakaryocytes/hpf (magnification, 400X), and no iron stores were visible in H&E or Prussian blue-stained specimens. CONCLUSIONS AND CLINICAL RELEVANCE Results of the present study provided contemporary preliminary guidelines for the evaluation of bone marrow in healthy laboratory rabbits. PMID- 28738005 TI - Accuracy and repeatability of long-bone replicas of small animals fabricated by use of low-end and high-end commercial three-dimensional printers. AB - OBJECTIVE To assess the repeatability and accuracy of polymer replicas of small, medium, and large long bones of small animals fabricated by use of 2 low-end and 2 high-end 3-D printers. SAMPLE Polymer replicas of a cat femur, dog radius, and dog tibia were fabricated in triplicate by use of each of four 3-D printing methods. PROCEDURES 3-D renderings of the 3 bones reconstructed from CT images were prepared, and length, width of the proximal aspect, and width of the distal aspect of each CT image were measured in triplicate. Polymer replicas were fabricated by use of a high-end system that relied on jetting of curable liquid photopolymer, a high-end system that relied on polymer extrusion, a triple-nozzle polymer extrusion low-end system, and a dual-nozzle polymer extrusion low-end system. Polymer replicas were scanned by use of a laser-based coordinate measurement machine. Length, width of the proximal aspect, and width of the distal aspect of the scans of replicas were measured and compared with measurements for the 3-D renderings. RESULTS 129 measurements were collected for 34 replicas (fabrication of 1 large long-bone replica was unsuccessful on each of the 2 low-end printers). Replicas were highly repeatable for all 3-D printers. The 3-D printers overestimated dimensions of large replicas by approximately 1%. CONCLUSIONS AND CLINICAL RELEVANCE Low-end and high-end 3-D printers fabricated CT-derived replicas of bones of small animals with high repeatability. Replicas were slightly larger than the original bones. PMID- 28738006 TI - Effect of lidocaine on inflammation in equine jejunum subjected to manipulation only and remote to intestinal segments subjected to ischemia. AB - OBJECTIVE To examine effects of continuous rate infusion of lidocaine on transmural neutrophil infiltration in equine intestine subjected to manipulation only and remote to ischemic intestine. ANIMALS 14 healthy horses. PROCEDURES Ventral midline celiotomy was performed (time 0). Mild ischemia was induced in segments of jejunum and large colon. A 1-m segment of jejunum was manipulated by massaging the jejunal wall 10 times. Horses received lidocaine (n = 7) or saline (0.9% NaCl) solution (7) throughout anesthesia. Biopsy specimens were collected and used to assess tissue injury, neutrophil influx, cyclooxygenase expression, and hypoxia-inducible factor 1alpha (HIF-1alpha) expression at 0, 1, and 4 hours after manipulation and ischemia. Transepithelial resistance (TER) and mannitol flux were measured by use of Ussing chambers. RESULTS Lidocaine did not consistently decrease neutrophil infiltration in ischemic, manipulated, or control tissues at 4 hours. Lidocaine significantly reduced circular muscle and overall scores for cyclooxygenase-2 expression in manipulated tissues. Manipulated tissues had significantly less HIF-1alpha expression at 4 hours than did control tissues. Mucosa from manipulated and control segments obtained at 4 hours had lower TER and greater mannitol flux than did control tissues at 0 hours. Lidocaine did not significantly decrease calprotectin expression. Severity of neutrophil infiltration was similar in control, ischemic, and manipulated tissues at 4 hours. CONCLUSIONS AND CLINICAL RELEVANCE Manipulated jejunum did not have a significantly greater increase in neutrophil infiltration, compared with 4-hour control (nonmanipulated) jejunum remote to sites of manipulation, ischemia, and reperfusion. Lidocaine did not consistently reduce neutrophil infiltration in jejunum. PMID- 28738007 TI - Comparison of intraosseous pentobarbital administration and thoracic compression for euthanasia of anesthetized sparrows (Passer domesticus) and starlings (Sturnus vulgaris). AB - OBJECTIVE To compare intraosseous pentobarbital treatment (IPT) and thoracic compression (TC) on time to circulatory arrest and an isoelectric electroencephalogram (EEG) in anesthetized passerine birds. ANIMALS 30 wild caught adult birds (17 house sparrows [Passer domesticus] and 13 European starlings [Sturnus vulgaris]). PROCEDURES Birds were assigned to receive IPT or TC (n = 6/species/group). Birds were anesthetized, and carotid arterial pulses were monitored by Doppler methodology. Five subdermal braided-wire electrodes were used for EEG. Anesthetic depth was adjusted until a continuous EEG pattern was maintained, then euthanasia was performed. Times from initiation of euthanasia to cessation of carotid pulse and irreversible isoelectric EEG (indicators of death) were measured. Data (medians and first to third quartiles) were summarized and compared between groups within species. Necropsies were performed for all birds included in experiments and for another 6 birds euthanized under anesthesia by TC (4 sparrows and 1 starling) or IPT (1 sparrow). RESULTS Median time to isoelectric EEG did not differ significantly between treatment groups for sparrows (19.0 and 6.0 seconds for TC and IPT, respectively) or starlings (88.5 and 77.5 seconds for TC and IPT, respectively). Median times to cessation of pulse were significantly shorter for TC than for IPT in sparrows (0.0 vs 18.5 seconds) and starlings (9.5 vs 151.0 seconds). On necropsy, most (14/17) birds that underwent TC had grossly visible coelomic, pericardial, or perihepatic hemorrhage. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that TC might be an efficient euthanasia method for small birds. Digital pressure directly over the heart during TC obstructed venous return, causing rapid circulatory arrest, with rupture of the atria or vena cava in several birds. The authors propose that cardiac compression is a more accurate description than TC for this procedure. PMID- 28738008 TI - Randomized placebo-controlled study of the effects of Yunnan Baiyao on hemostasis in horses. AB - OBJECTIVE To determine effects of oral administration of Yunnan Baiyao on platelet activation, coagulation, and fibrinolysis in healthy horses. ANIMALS 12 healthy adult horses. PROCEDURES In a randomized blinded crossover study that included a 4-week washout period between treatments, horses were orally administered a paste containing Yunnan Baiyao (15 mg/kg) or placebo at 12-hour intervals for 3 days. Blood samples were collected before start of treatment (time 0) and at 24 and 72 hours for a CBC, measurement of fibrinogen concentration, coagulation screening tests, and a panel of assays to assess platelet activation (including ADP- and collagen-induced aggregation and closure times, flow-cytometric variables of platelet-leukocyte aggregates, platelet membrane P-selectin and phosphatidylserine expression, and microparticle release), von Willebrand factor (vWF) concentration, and cofactor activity. In addition, thrombelastography was used to evaluate fibrin formation in tissue factor-activated whole blood and plasma and to assess tissue plasminogen activator-induced plasma fibrinolysis. For each treatment, values obtained before and 72 hours after start of administration were compared by use of Wilcoxon signed rank tests. RESULTS Yunnan Baiyao treatment had no significant effect on any hemostatic variable, compared with results for the placebo treatment. CONCLUSIONS AND CLINICAL RELEVANCE Administration of Yunnan Baiyao at a dosage typically used in clinical practice had no effect on in vitro measures of platelet or vWF function and no enhancement of fibrin-clot formation or stability. Any hemostatic actions of Yunnan Baiyao may require higher dosages or result from cell-surface interactions at sites of vascular and tissue injury not examined in this study. PMID- 28738009 TI - Morphological evaluation of clefts of the lip, palate, or both in dogs. AB - OBJECTIVE To systematically characterize the morphology of cleft lip, cleft palate, and cleft lip and palate in dogs. ANIMALS 32 client-owned dogs with clefts of the lip (n = 5), palate (23), or both (4) that had undergone a CT or cone-beam CT scan of the head prior to any surgical procedures involving the oral cavity or face. PROCEDURES Dog signalment and skull type were recorded. The anatomic form of each defect was characterized by use of a widely used human oral cleft classification system on the basis of CT findings and clinical images. Other defect morphological features, including shape, relative size, facial symmetry, and vomer involvement, were also recorded. RESULTS 9 anatomic forms of cleft were identified. Two anatomic forms were identified in the 23 dogs with cleft palate, in which differences in defect shape and size as well as vomer abnormalities were also evident. Seven anatomic forms were observed in 9 dogs with cleft lip or cleft lip and palate, and most of these dogs had incisive bone abnormalities and facial asymmetry. CONCLUSIONS AND CLINICAL RELEVANCE The morphological features of congenitally acquired cleft lip, cleft palate, and cleft lip and palate were complex and varied among dogs. The features identified here may be useful for surgical planning, developing of clinical coding schemes, or informing genetic, embryological, or clinical research into birth defects in dogs and other species. PMID- 28738010 TI - Effects of the alpha2-adrenoceptor agonist medetomidine on the distribution and clearance of alfaxalone during coadministration by constant rate infusion in dogs. AB - OBJECTIVE To assess the possible impact of medetomidine on concentrations of alfaxalone in plasma, when coadministered as a constant rate infusion (CRI) to dogs, and to determine the possible impact of medetomidine on the cardiopulmonary effects of alfaxalone during CRI. ANIMALS 8 healthy adult Beagles. PROCEDURES 3 treatments were administered in a randomized crossover design as follows: 1 = saline (0.9% NaCl) solution injection, followed in 10 minutes by induction of anesthesia with alfaxalone (loading dose, 2.4 mg/kg; CRI, 3.6 mg/kg/h, for 60 minutes); 2 = medetomidine premedication (loading dose, 4.0 MUg/kg; CRI, 4.0 MUg/kg/h), followed by alfaxalone (as in treatment 1); and, 3 = medetomidine (as in treatment 2) and MK-467 (loading dose, 150 MUg/kg; CRI, 120 MUg/kg/h), followed by alfaxalone (as in treatment 1). The peripherally acting alpha2 adrenoceptor antagonist MK-467 was used to distinguish between the peripheral and central effects of medetomidine. Drugs were administered IV via cephalic catheters, and there was a minimum of 14 days between treatments. Cardiopulmonary parameters were measured for 70 minutes, and jugular venous blood samples were collected until 130 minutes after premedication. Drug concentrations in plasma were analyzed with liquid chromatography-tandem mass spectrometry. RESULTS The characteristic cardiovascular effects of medetomidine, such as bradycardia, hypertension, and reduction in cardiac index, were obtunded by MK-467. The concentrations of alfaxalone in plasma were significantly increased in the presence of medetomidine, indicative of impaired drug distribution and clearance. This was counteracted by MK-467. CONCLUSIONS AND CLINICAL RELEVANCE The alteration in alfaxalone clearance when coadministered with medetomidine may be attributed to the systemic vasoconstrictive and bradycardic effects of the alpha2 adrenoceptor agonist. This could be clinically important because the use of alpha2-adrenoceptor agonists may increase the risk of adverse effects if standard doses of alfaxalone are used. PMID- 28738011 TI - Associations between gastric dilatation-volvulus in Great Danes and specific alleles of the canine immune-system genes DLA88, DRB1, and TLR5. AB - OBJECTIVE To determine whether specific alleles of candidate genes of the major histocompatibility complex (MHC) and innate immune system were associated with gastric dilatation-volvulus (GDV) in Great Danes. ANIMALS 42 healthy Great Danes (control group) and 39 Great Danes with >= 1 GDV episode. PROCEDURES Variable regions of the 2 most polymorphic MHC genes (DLA88 and DRB1) were amplified and sequenced from the dogs in each group. Similarly, regions of 3 genes associated with the innate immune system (TLR5, NOD2, and ATG16L1), which have been linked to inflammatory bowel disease, were amplified and sequenced. Alleles were evaluated for associations with GDV, controlling for age and dog family. RESULTS Specific alleles of genes DLA88, DRB1, and TLR5 were significantly associated with GDV. One allele of each gene had an OR > 2 in the unadjusted univariate analyses and retained a hazard ratio > 2 after controlling for temperament, age, and familial association in the multivariate analysis. CONCLUSIONS AND CLINICAL RELEVANCE The 3 GDV-associated alleles identified in this study may serve as diagnostic markers for identification of Great Danes at risk for GDV. Additional research is needed to determine whether other dog breeds have the same genetic associations. These findings also provided a new target for research into the etiology of, and potential treatments for, GDV in dogs. PMID- 28738012 TI - Evaluation of protein kinase CK2 as a therapeutic target for squamous cell carcinoma of cats. AB - OBJECTIVE To investigate protein kinase CK2 (CK2) expression in squamous cell carcinoma (SCC) of cats and to examine effects of CK2 downregulation on in vitro apoptosis and viability in SCC. SAMPLE Biopsy specimens of oral mucosa and testis and blood samples from clinically normal cats, biopsy specimens of oral SCC from cats, and feline SCC (SCCF1) and mammary gland carcinoma (K12) cell lines. PROCEDURES Immunohistochemical labeling for CK2alpha was performed on biopsy specimens. Sequences of the CK2alpha subunit gene and CK2alpha' subunit gene in feline blood and feline cancer cell lines were determined by use of PCR and reverse-transcription PCR assays followed by direct Sanger sequencing. Specific small interfering RNAs (siRNAs) were developed for feline CK2alpha and CK2alpha'. The SCCF1 cells were treated with siRNA and assessed 72 hours later for CK2alpha and CK2alpha' expression and markers of apoptosis (via western blot analysis) and for viability (via 3-[4,5-dimethylthiazol-2-yl]-5-[3-carboxymethoxyphenyl]-2-[4 sulfophenyl]-2H-tetrazolium assays). RESULTS CK2alpha was expressed in all feline oral mucosa samples and 7 of 8 oral SCC samples. Expression of CK2alpha and CK2alpha' was successfully downregulated in SCCF1 cells by use of siRNAs, which resulted in decreased viability and induction of apoptosis. CONCLUSIONS AND CLINICAL RELEVANCE In this study, CK2 appeared to be a promising therapeutic target for SCCs of cats. A possible treatment strategy for SCCs of cats would be RNA interference that targets CK2. PMID- 28738013 TI - Commentary on Duan et al.: A Retrospective Study of Peroral Endoscopic Full Thickness Myotomy in Patients with Severe Achalasia. PMID- 28738014 TI - Enhancer of zeste homologue 2 (EZH2) expression in synovial sarcomas as a promising indicator of prognosis. AB - Synovial sarcoma (SS) is a type of soft-tissue sarcoma, often linked to poor survival. Although overexpression of enhancer of zeste homologue 2 (EZH2) has been associated with poor prognosis in different tumors, a few studies investigated this link in SS. Here, we analyzed the relationship between EZH2 expression and prognostic factors in SS. We included 29 patients with SS. Immunostaining of EZH2 was performed with (D2C9) XPTM Rabbit mAb antibody, and the results were classified as low EZH2 expression (negative or weak expression) and high EZH2 expression category (moderate or strong expression). Analysis of survival in relation to prognostic factors was performed with Kaplan-Meier survival curves and Cox proportional hazard regression analysis. Our sample included 19/29 female and 10/29 male patients, with age range 16-63 years. The tumor diameter ranged from 2 to 15 cm. Necrosis was observed in 15/29 cases. Sixteen cases had >10 mitoses per 50 high-power fields (HPFs). Out of 29 cases, 14 showed low and 15 had high EZH2 expression. Statistically significant results were obtained for the association between the presence of metastasis and necrosis (p = 0.042), high EZH2 expression and distant metastasis (p = 0.018), high EZH2 expression and necrosis (p = 0.016), and high EZH2 expression and the tumor size >5 cm versus tumor size <=5 cm (p = 0.014). Patients with all of the following: the tumor size <=5 cm, low EZH2 expression, and without necrosis and distant metastasis had significantly longer survival time. Our results are consistent with previous studies, suggesting that EZH2 overexpression is an indicator of poor prognosis in SS. PMID- 28738015 TI - Observational study to estimate the changes in the effectiveness of bacillus Calmette-Guerin (BCG) vaccination with time since vaccination for preventing tuberculosis in the UK. AB - BACKGROUND: Until recently, evidence that protection from the bacillus Calmette Guerin (BCG) vaccination lasted beyond 10 years was limited. In the past few years, studies in Brazil and the USA (in Native Americans) have suggested that protection from BCG vaccination against tuberculosis (TB) in childhood can last for several decades. The UK's universal school-age BCG vaccination programme was stopped in 2005 and the programme of selective vaccination of high-risk (usually ethnic minority) infants was enhanced. OBJECTIVES: To assess the duration of protection of infant and school-age BCG vaccination against TB in the UK. METHODS: Two case-control studies of the duration of protection of BCG vaccination were conducted, the first on minority ethnic groups who were eligible for infant BCG vaccination 0-19 years earlier and the second on white subjects eligible for school-age BCG vaccination 10-29 years earlier. TB cases were selected from notifications to the UK national Enhanced Tuberculosis Surveillance system from 2003 to 2012. Population-based control subjects, frequency matched for age, were recruited. BCG vaccination status was established from BCG records, scar reading and BCG history. Information on potential confounders was collected using computer-assisted interviews. Vaccine effectiveness was estimated as a function of time since vaccination, using a case-cohort analysis based on Cox regression. RESULTS: In the infant BCG study, vaccination status was determined using vaccination records as recall was poor and concordance between records and scar reading was limited. A protective effect was seen up to 10 years following infant vaccination [< 5 years since vaccination: vaccine effectiveness (VE) 66%, 95% confidence interval (CI) 17% to 86%; 5-10 years since vaccination: VE 75%, 95% CI 43% to 89%], but there was weak evidence of an effect 10-15 years after vaccination (VE 36%, 95% CI negative to 77%; p = 0.396). The analyses of the protective effect of infant BCG vaccination were adjusted for confounders, including birth cohort and ethnicity. For school-aged BCG vaccination, VE was 51% (95% CI 21% to 69%) 10-15 years after vaccination and 57% (95% CI 33% to 72%) 15 20 years after vaccination, beyond which time protection appeared to wane. Ascertainment of vaccination status was based on self-reported history and scar reading. LIMITATIONS: The difficulty in examining vaccination sites in older women in the high-risk minority ethnic study population and the sparsity of vaccine record data in the later time periods precluded robust assessment of protection from infant BCG vaccination > 10 years after vaccination. CONCLUSIONS: Infant BCG vaccination in a population at high risk for TB was shown to provide protection for at least 10 years, whereas in the white population school-age vaccination was shown to provide protection for at least 20 years. This evidence may inform TB vaccination programmes (e.g. the timing of administration of improved TB vaccines, if they become available) and cost-effectiveness studies. Methods to deal with missing record data in the infant study could be explored, including the use of scar reading. FUNDING: The National Institute for Health Research Health Technology Assessment programme. During the conduct of the study, Jonathan Sterne, Ibrahim Abubakar and Laura C Rodrigues received other funding from NIHR; Ibrahim Abubakar and Laura C Rodrigues have also received funding from the Medical Research Council. Punam Mangtani received funding from the Biotechnology and Biological Sciences Research Council. PMID- 28738018 TI - Nurture trumps nature! AB - Mutation-associated infections in one individual are prevented in relatives with the same mutation by a compensatory adaptive immune response. PMID- 28738016 TI - Eomesodermin promotes the development of type 1 regulatory T (TR1) cells. AB - Type 1 regulatory T (TR1) cells are Foxp3- interleukin-10 (IL-10)-producing CD4+ T cells with potent immunosuppressive properties, but their requirements for lineage development have remained elusive. We show that TR1 cells constitute the most abundant regulatory population after allogeneic bone marrow transplantation (BMT), express the transcription factor Eomesodermin (Eomes), and are critical for the prevention of graft-versus-host disease. We demonstrate that Eomes is required for TR1 cell differentiation, during which it acts in concert with the transcription factor B lymphocyte-induced maturation protein-1 (Blimp-1) by transcriptionally activating IL-10 expression and repressing differentiation into other T helper cell lineages. We further show that Eomes induction in TR1 cells requires T-bet and donor macrophage-derived IL-27. Thus, we define the cellular and transcriptional control of TR1 cell differentiation during BMT, opening new avenues to therapeutic manipulation. PMID- 28738017 TI - Distinct oxysterol requirements for positioning naive and activated dendritic cells in the spleen. AB - Correct positioning of dendritic cells (DCs) is critical for efficient pathogen encounter and antigen presentation. Epstein-Barr virus-induced gene 2 (EBI2) has been identified as a chemoattractant receptor required for naive CD4+DCIR2+ DC positioning in response to 7alpha,25-hydroxycholesterol (7alpha,25-HC). We now provide evidence that a second EBI2 ligand, 7alpha,27-HC, is involved in splenic DCIR2+ DC positioning and homeostasis. Cyp27a1, the enzyme uniquely required for 7alpha,27-HC synthesis, is expressed by stromal cells in the region of naive DC localization. After activation, DCIR2+ DCs move into the T cell zone. We find that EBI2 is rapidly up-regulated in DCIR2+ DCs under certain activation conditions, and positioning at the B-T zone interface depends on EBI2. Under conditions of type I interferon induction, EBI2 ligand levels are elevated, causing activated DCIR2+ DCs to disperse throughout the T zone. Last, we provide evidence that oxysterol metabolism by Batf3-dependent DCs is important for EBI2 dependent positioning of activated DCIR2+ DCs. This work indicates that 7alpha,27 HC functions as a guidance cue in vivo and reveals a multitiered role for EBI2 in DC positioning. Deficiency in this organizing system results in defective CD4+ T cell responses. PMID- 28738019 TI - Barrier busting yeast brew trouble in the gut. AB - Saccharomyces cerevisiae, a common yeast in the gut, induces uric acid production by intestinal epithelium, leading to decreased barrier function and increased colitis in mouse models. PMID- 28738021 TI - Commensal bacteria (ab)use CD8+ T cells to induce insulin resistance. AB - Type I interferon-dependent expansion of intrahepatic CD8+ T cells promotes systemic insulin resistance in obesity. PMID- 28738020 TI - Resident memory T cells in the skin mediate durable immunity to melanoma. AB - Tissue-resident memory T (TRM) cells have been widely characterized in infectious disease settings; however, their role in mediating immunity to cancer remains unknown. We report that skin-resident memory T cell responses to melanoma are generated naturally as a result of autoimmune vitiligo. Melanoma antigen-specific TRM cells resided predominantly in melanocyte-depleted hair follicles and were maintained without recirculation or replenishment from the lymphoid compartment. These cells expressed CD103, CD69, and CLA (cutaneous lymphocyte antigen), but lacked PD-1 (programmed cell death protein-1) or LAG-3 (lymphocyte activation gene-3), and were capable of making IFN-gamma (interferon-gamma). CD103 expression on CD8 T cells was required for the establishment of TRM cells in the skin but was dispensable for vitiligo development. CD103+ CD8 TRM cells were critical for protection against melanoma rechallenge. This work establishes that CD103-dependent TRM cells play a key role in perpetuating antitumor immunity. PMID- 28738023 TI - Cluster assembly route to a novel octagonal two-dimensional ZnO monolayer. AB - To explore the possibility of cluster assembly resulting in a two-dimensional (2D) stable monolayer of ZnO, a systematic study is performed on the structural evolution of bare and passivated stoichiometric clusters of [Formula: see text] [Formula: see text], [Formula: see text], using density-functional-theory-based first principles electronic structure calculations. The changes in hybridization are investigated with the aid of the site-projected partial density of states and partial charge density, while the effect of passivation and size on the ionicity of the cluster is studied using Bader charge analysis. The structural and chemical properties are found to be influenced by the coordination number of atoms in the clusters irrespective of the coordinating species. The physical parameters and hybridization of the states for the clusters on passivation resemble those of the bulk. Passivation thus provides an environment that leads to the stability of the clusters. Cluster assembly using the stable cluster geometries of passivated clusters (without the passivating atoms) has been shown to lead to stable 2D structures. This stability has been studied on the basis of binding energy, vibrational frequency, phonon dispersion and thermal properties. A new octagonal 2D monolayer planar geometry of ZnO is predicted. PMID- 28738022 TI - Werner syndrome: a model for sarcopenia due to accelerated aging. AB - Werner syndrome (WS) is a rare inheritable progeroid syndrome caused by a mutation in the WRN gene. Although WS has been described as a characteristic appearance of very slender extremities with a stocky trunk, few studies have investigated the loss of muscle mass, fat mass distribution (body composition), and mobility according to age and sex. Therefore, the aim of this study was to precisely describe the body composition in WS. Nine Japanese patients with WS (four males and five females; mean age 48+/-8.8 years) were recruited. Body composition was examined by dual-energy X-ray absorptiometry and computed tomography (CT). The hand grip strength and mobility were evaluated using the two step test, stand-up test and 25-question geriatric locomotive function scale (GLFS). The mean skeletal muscle index (SMI) was 4.0+/-0.6 kg/m2. SMI of all patients met the criteria of sarcopenia, even though some patients were aged < 40 years. All patients also showed deceased mobility. In conclusion, these results indicate that all patients with WS, even those aged < 40 years, had already lost muscle mass to the level of sarcopenia. Continued research on sarcopenia in WS might facilitate the discovery of novel mechanisms and development of new treatment strategies for sarcopenia. PMID- 28738024 TI - Evaluation of Irradiated Corneas Using Scatterometry and Light and Electron Microscopy. AB - OBJECTIVE: To determine if sterilization of donor corneas by irradiation alters optical, histologic, or ultrastructural tissue characteristics. METHODS: Blinded assessment of 10 irradiated and 10 nonirradiated donor corneas by a scatterometer used to objectively measure backscattered corneal light. Light and electron microscopy were performed on samples from both groups. RESULTS: The mean scattering of the nonirradiated (control) corneas was significantly lower (0.0060 +/- 0.0034, mean +/- SD) than the scattering of the irradiated corneas (0.023 +/- 0.0078; P = 0.0001). There was no statistical difference between ages, days in storage, or central corneal thickness of the 2 groups. Light microscopic evaluation revealed attenuation of the irradiated corneal epithelium with superficial stromal clefting. Transmission electron microscopy demonstrated similar fibril diameter in the nonirradiated and irradiated corneas. Although the mean interfibrillar distance was similar between the nonirradiated and irradiated groups, the interfibrillar distance in the superficial stroma was increased in the nonirradiated compared with the irradiated groups (15.4 +/- 2.4 vs. 11.8 +/- 0.98 nm; P <= 0.05). CONCLUSIONS: Our data quantitatively support increased light scatter after irradiation, which cannot be attributed to increased corneal thickness. Irradiation alters the histology of the epithelium and the ultrastructure of the superficial corneal stroma. Increased light scatter because of epithelial changes would not be expected to impact postoperative visual function. However, increased light scatter because of stromal changes may affect postoperative visual function if used for optical corneal rehabilitation. Further investigation is warranted to determine whether attenuated epithelium or superficial stromal changes are the cause of increased light scatter in the irradiated corneal tissue. PMID- 28738025 TI - Fork Head Box Class O1 (FOXO1) Activates Bim Expression to Mediate Cardiac Apoptosis in Chronic Intermittent Hypoxia-Induced Cardiac Hypertrophy. PMID- 28738026 TI - Effect of red blood cell storage time on markers of hemolysis and inflammation in transfused very low birth weight infants. AB - BackgroundProlonged storage of transfused red blood cells (RBCs) is associated with hemolysis in healthy adults and inflammation in animal models. We aimed to determine whether storage duration affects markers of hemolysis (e.g., serum bilirubin, iron, and non-transferrin-bound iron (NTBI)) and inflammation (e.g., interleukin (IL)-8 and monocyte chemoattractant protein (MCP)-1) in transfused very low birth weight (VLBW) infants.MethodsBlood samples from 23 independent transfusion events were collected by heel stick before and 2-6 h after transfusion.ResultsSerum iron, total bilirubin, NTBI, and MCP-1 levels were significantly increased after transfusion of RBCs (P<0.05 for each comparison). The storage age of transfused RBCs positively correlated with increases in NTBI following transfusion (P<0.001; R2=0.44). No associations between storage duration and changes in the other analytes were observed.ConclusionTransfusion of RBCs into VLBW infants is associated with increased markers of hemolysis and the inflammatory chemokine MCP-1. RBC-storage duration only correlated with increases in NTBI levels following transfusion. NTBI was only observed in healthy adults following 35 days of storage; however, this study suggests that VLBW infants are potentially more susceptible to produce this pathological form of iron, with increased levels observed after transfusion of only 20-day-old RBCs. PMID- 28738027 TI - N-terminal B-type natriuretic peptide urinary concentrations and retinopathy of prematurity. AB - BackgroundTo validate the findings of a single-center pilot study showing elevated urinary N-terminal B-type natriuretic peptide (NTproBNP) concentrations in preterm infants subsequently developing severe retinopathy of prematurity (ROP) in a multicenter setting across eight European and Middle East countries.MethodsProspective observational study in 967 preterm infants <30 weeks' gestational age assessing the capacity of urinary NTproBNP on days of life (DOLs) 14 and 28 to predict ROP requiring treatment.ResultsUrinary NTproBNP concentrations were markedly elevated in infants who developed ROP requiring treatment (n=94) compared with survivors without ROP treatment (n=837), at both time points (median (interquartile range) DOL14: 8,950 (1,925-23,783) vs. 3,083 (1,193-17,393) vs. 816 (290-3,078) pg/ml, P<0.001) and DOL28 (2,203 (611-4,063) vs. 1,671 (254-11,340) vs. 408 (162-1,126) pg/ml, P<0.001). C-statistic of NTproBNP for treated ROP or death was 0.731 (95% confidence interval 0.654-0.774) for DOL14 and 0.683 (0.622-0.745) for DOL28 (P<0.001). Threshold scores were calculated, potentially enabling around 20% of infants with low NTproBNP scores never to be screened with ophthalmoscopy.ConclusionThere is a strong association between early urinary NTproBNP and subsequent ROP development, which can be used to further refine subgroups of patients with high or low risk of severe ROP. PMID- 28738028 TI - EBV-HLH children with reductions in CD4+ T cells and excessive activation of CD8+ T cells. AB - BackgroundIn this report, we analyzed the number and activation profiles of T cells in Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV HLH) patients and assessed their value for the diagnosis of EBV-HLH.MethodsWe compared the quantity of CD4+ T cells and CD8+ T cells in peripheral blood among HLH patients, a sepsis group, and healthy controls. We then analyzed variations in the activation marker in CD4+ T and CD8+ T cells.ResultsThe percentage of CD4+ T cells decreased in the EBV-HLH patients when compared with healthy controls, which induced significant differences in the ratio of CD4+ T cells/CD8+ T cells. The percentage of CD4+HLA-DR+ T cells, CD8+CD69+ T cells, CD8+HLA-DR+ T cells, and CD8+HLA-DR+ T cells/CD4+CD25+ T cells increased in EBV-HLH patients when compared with that in healthy controls. Compared with EBV-HLH survivors, the median percentage of CD4+CD25+ T cells (7.9 vs. 3.0) were decreased, but the ratios of CD8+HLA-DR+T cells/CD4+CD25+T cells (6.3 vs. 20.3) were increased in the dead patients.ConclusionsThere was a reduction in CD4+ T cells and abnormal activation of CD8+ T cells in the EBV-HLH patients. The percentage of CD4+CD25+ T cells and the ratios of CD8+HLA-DR+ T cells/CD4+CD25+ T cells in EBV-HLH patients had a relation to the prognosis of the disease. PMID- 28738029 TI - Confronting Compassion Fatigue: Assessment and Intervention in Inpatient Oncology?. AB - BACKGROUND: A notable variation among patient satisfaction scores with nursing care was identified. Contributing factors were examined and revealed significant negative correlations between the unit death rate and surviving patients' satisfaction scores. Compassion fatigue (CF) was hypothesized to be a major contributing factor.?. OBJECTIVES: The objective was to address CF in RNs and oncology care associates (assistive personnel) by developing an intervention to provide bereavement support to staff after patient deaths.?. METHODS: A mixed methods sequential design was used. Instruments included the Professional Quality of Life scale and Press Ganey survey results. Univariate descriptive statistics, frequencies, an independent t test, and an analysis of covariance were used for data analysis.?. FINDINGS: The preintervention results revealed average compassion satisfaction and secondary traumatic stress scores and low burnout scores. No significant difference was noted between pre- and postintervention CF scores. Patients' perception of nurses' skills improved significantly in the second quarter of 2015. PMID- 28738030 TI - Delivery of ?Clinical Services: Mobilizing Advanced Practice Providers to Enhance Patient Care. AB - Advanced practice providers (APPs) are increasingly being used in a variety of healthcare settings to provide care, treatment, and services to patients with cancer. They are also being deployed to acute oncologic settings to enhance patient care delivery and address the ever-evolving needs of patients in academic medicine. In response, the University of Texas MD Anderson Cancer Center developed a series of innovative clinical programs staffed by acute care APPs. These provide an opportunity to rapidly adapt to the acute care needs of patients with cancer while fostering the professional development of APPs within the full scope of their oncologic clinical practice.?. PMID- 28738031 TI - Perioperative Care Implementation: Evidence-Based Practice for Patients With Pancreaticoduodenectomy Using the Enhanced Recovery After Surgery Guidelines ?. AB - BACKGROUND: Pancreatic adenocarcinoma is an aggressive cancer that carries a poor prognosis. Pancreaticoduodenectomy (PD) offers the only potential cure, but the associated morbidity is high. The Enhanced Recovery After Surgery (ERAS) evidence based guidelines for perioperative care for PD can be used to reduce variations in practice.?. OBJECTIVES: The primary aim was to evaluate the feasibility of the ERAS guidelines for patients undergoing PD. Secondary aims were to assess length of stay (LOS), readmission within 30 days, 30-day mortality, and total surgical complication rates.?. METHODS: Guideline feasibility was evaluated by percentage completion and compliance to each of the perioperative phases of the guideline. Hospital LOS, 30-day readmission, 30-day mortality, and total surgical complication rates were compared before and after ERAS implementation. ?. FINDINGS: The ERAS guidelines were feasible and safely implemented with no change in LOS, readmission, morbidity, and mortality rates. PMID- 28738032 TI - Nurse-Administered Hand Massage: Integration Into an Infusion Suite's Standard of Care?. AB - BACKGROUND: Nurse-delivered hand massage is a safe and effective intervention that has potential for positively affecting nursing and patient outcomes.?. OBJECTIVES: Nurses in a National Cancer Institute-designated academic health center outpatient chemotherapy infusion suite were taught how to administer a hand massage to strengthen the nurse-patient relationship and improve patient experience, comfort, satisfaction, stress, and anxiety.?. METHODS: A pre /postimplementation group comparison design was used. Patients in both groups completed self-reported measures of stress, comfort, satisfaction, and anxiety. Nurses completed Likert-type scales pre- and postimplementation on the perceived benefits of hand massage to the patient and nursing practice, impact on patient anxiety, and preparation in providing a hand massage.?. FINDINGS: A positive trend was seen in all indicators. Patients who received a hand massage had a statistically significant improvement in comfort (p = 0.025) compared to those who did not. A statistically significant improvement was seen in all nurse indicators pre- to postimplementation. PMID- 28738033 TI - How Can I Implement Accurate Delirium Screening and Prevention Practices? AB - As a clinical nurse specialist (CNS), I am tasked with improving patient outcomes through collaborative research, evidence-based practice, and process improvement efforts that affect the quality and safety of patient care. However, I have learned over time that it is not enough to simply incorporate the latest evidence into organizational policies and procedures; it has to be followed in practice. ?. PMID- 28738034 TI - Cancer-Associated Thrombosis: Improving Patient Adherence to Low-Molecular-Weight Heparin Therapy. AB - Although evidence-based treatment guidelines recommend low-molecular-weight heparin (LMWH) monotherapy for cancer-associated thrombosis (CAT), adherence to outpatient treatment guidelines for CAT still needs improvement. One of the challenges that clinicians face in treating CAT with LMWH is patient preference for oral anticoagulants over daily LMWH injections. This article aims to provide oncology nurses with practical advice on patient education to increase patient acceptance of and adherence to LMWH treatment for CAT. PMID- 28738035 TI - Palliative Care and Phase 1 Trials: Intervention to Improve Quality of Life and Provide Education?. AB - BACKGROUND: Patients in phase 1 clinical trials often have significant symptom burdens and quality-of-life concerns that increase as they progress along the cancer trajectory and experience drug toxicities from the clinical trial. ?. OBJECTIVES: The interdisciplinary intervention described is aimed at providing optimum palliative care to support patients with solid tumors participating in a phase 1 clinical trial.?. METHODS: The intervention includes a baseline evaluation using quantitative surveys, a comprehensive palliative care assessment by a research nurse based on patient baseline evaluation, and a goals-of-care discussion by the treating oncologist. The second component includes an interdisciplinary meeting where palliative care recommendations are made, followed by two patient education sessions.?. FINDINGS: The initial experience with the palliative care intervention suggests a need for support for this population, as well as potential benefits from integrating palliative care for patients enrolled in phase 1 clinical trials. PMID- 28738036 TI - Cannabis Guidelines?. AB - Cannabis has been used for centuries in the treatment of medical conditions. Cannabis has been recommended for appetite, anxiety, depression, sleep, and migraines. However, the stigma associated with cannabis as a recreational drug has created challenges to the legitimacy and social acceptance of cannabis for medical purposes in the United States. PMID- 28738037 TI - Mosaicism: Implications for Genetic Counseling and Medical Management. AB - Mosaicism describes the presence of two or more populations of cells with different genotypes in one individual that have developed from a single fertilized egg. This article reviews the various clinical presentations of mosaicism associated with hereditary cancer syndromes and the challenges in providing patients and their families with appropriate genetic testing, as well as provides recommendations for cancer presentation and early detection. Management of mosaicism is based on personal and family history, along with genetic testing results. ?. PMID- 28738038 TI - Nurse Education and Survivorship: Building the Specialty Through Training and Program Development?. AB - BACKGROUND: As the number of cancer survivors in the United States continues to grow, the need to educate healthcare providers in the components of survivorship care remains a challenge in the current healthcare system. Survivors have unique concerns and follow-up requirements that are key to minimizing their risks for recurrence and supporting quality of life.?. OBJECTIVES: This article describes the impact of the curriculum, faculty, and teaching methods for an educational program to prepare nurses to provide cancer survivorship care.?. METHODS: Mixed methods with quantitative and qualitative approaches were used.?. FINDINGS: Course content and faculty received high scores in the evaluations. Analysis of the most common goals implemented by participants after the course focused on providing professional education, planning the process for survivorship care, and implementing treatment summaries and survivorship care plans. PMID- 28738039 TI - Chemotherapy Extravasation: Establishing a National Benchmark for Incidence Among Cancer Centers. AB - BACKGROUND: Given the high-risk nature and nurse sensitivity of chemotherapy infusion and extravasation prevention, as well as the absence of an industry benchmark, a group of nurses studied oncology-specific nursing-sensitive indicators. ?. OBJECTIVES: The purpose was to establish a benchmark for the incidence of chemotherapy extravasation with vesicants, irritants, and irritants with vesicant potential.?. METHODS: Infusions with actual or suspected extravasations of vesicant and irritant chemotherapies were evaluated. Extravasation events were reviewed by type of agent, occurrence by drug category, route of administration, level of harm, follow-up, and patient referrals to surgical consultation.?. FINDINGS: A total of 739,812 infusions were evaluated, with 673 extravasation events identified. Incidence for all extravasation events was 0.09%. PMID- 28738040 TI - Clinical Nurse Consultant Support: Management of Patients With Melanoma Receiving Immunotherapy ?and Targeted Therapy?. AB - BACKGROUND: Targeted therapy and immunotherapy agents for advanced melanoma are associated with novel toxicities. Melanoma clinical nurse consultants (CNCs) provide multifaceted clinical care.?. OBJECTIVES: The objective was to evaluate the type of support, excluding clinic and inpatient care, provided by CNCs for patients not enrolled in a clinical trial.?. METHODS: A prospective review of CNC support provided during a 12-week period was conducted.?. FINDINGS: From May to August 2015, 105 patients attended clinic, and 72 received CNC support. Initial patient encounters with CNCs were documented (n = 150), as well as additional interactions (n = 291). The most common problem identified per initial encounter was symptom/drug toxicity. The most common therapy-related concern was related to anti-programmed cell death protein 1 immunotherapy and BRAF plus MEK inhibition. CNC interventions commonly involved clinical advice and counseling and care coordination. PMID- 28738041 TI - Catheter-Associated Urinary Tract Infections: Implementing a Protocol to Decrease Incidence in Oncology Populations?. AB - BACKGROUND: The impact of catheter-associated urinary tract infections (CAUTIs) on immunocompromised patients with cancer requires preventive intervention from bedside nurses.?. OBJECTIVES: This protocol aims to prevent CAUTIs in the inpatient oncology population by implementing an evidence-based, nurse-driven protocol for discontinuing indwelling urinary catheters (IUCs).?. METHODS: Following a literature review of 34 articles, a nurse-driven CAUTI prevention protocol was developed and implemented on two 26-bed oncology units. Unit staff were educated on the protocol and use of the audit tool.?. FINDINGS: Although CAUTI rates remained unchanged, infections per 1,000 IUC days decreased, and adherence among oncology nurses rose 66%-90% within the first two months. The protocol encouraged preventive intervention from RNs to protect patients with cancer from CAUTIs. PMID- 28738042 TI - Cognitive Screening: Using the Clock-Drawing Test to Assess for Preexisting Deficits in Older Women Diagnosed With Breast Cancer?. AB - BACKGROUND: Older women diagnosed with breast cancer may also have preexisting cognitive deficits.?. OBJECTIVES: The aim of the current study is to describe errors on the clock-drawing test (CDT), which is used to screen for preexisting cognitive deficits in older women diagnosed with breast cancer.?. METHODS: This descriptive study included a convenience sample of women aged 69 years or older with a diagnosis of breast cancer. The CDT was used to screen for cognitive deficits, such as size of the clock, graphic difficulties, stimulus-bound response, conceptual deficit, spatial and/or planning deficit, and perseveration. Data were analyzed by the Rouleau qualitative error analysis.?. FINDINGS: Many older adult patients exhibit some abnormality on the CDT. Most abnormalities were spatial/planning difficulties. Cognitive screening should be included in the comprehensive assessment of older adults diagnosed with breast cancer to screen for preexisting cognitive limitations. PMID- 28738043 TI - The Next Journey: Moving Forward After Cancer Diagnosis and Treatment?. AB - Oncology healthcare providers have an obligation to support cancer survivors, not just during active treatment, but also long after they have completed therapy. By providing survivorship care education and establishing programs using evidence based practice, the specific needs and resources required to aid survivors in this new transition and journey can be identified. Survivors need to be guided, informed, and have their unique needs addressed. PMID- 28738044 TI - Survivorship Model of Care: Development and Implementation of a Nurse Practitioner-Led Intervention for Patients With Breast Cancer?. AB - BACKGROUND: Despite a call for action to improve survivorship care, no optimal model of care exists. ?. OBJECTIVES: To develop and evaluate the feasibility of a nurse practitioner (NP)-led model of care for survivorship visits after initial therapy. ?. METHODS: Patients received an NP-led survivorship bridge visit (NPSBV) following treatment for early-stage breast cancer. A cross-sectional survey was used to evaluate responses to the NPSBV and patient satisfaction with care. Satisfaction with usual care was evaluated in a comparison of patient groups. Differences were assessed with a chi-square test or Fisher's exact test.?. FINDINGS: Of 166 surveys, 118 were returned. The NPSBV met feasibility with a high attendance rate and had high acceptability and satisfaction rates. NPSBV patients were more likely to report that their team always cared as much as they did about their health compared to controls. Most patients would recommend the NPSBV to others. PMID- 28738045 TI - Camp Raising Spirits: An Oncology Nursing Society Chapter Leadership Success Story?. AB - Oncology Nursing Society (ONS) members share a unique passion for the people they serve and frequently commit to projects that make a difference. Camp Raising Spirits, a weekend retreat for adults with cancer, has made a difference in southwestern Pennsylvania for hundreds of people with cancer and their caregivers for 24 consecutive years. This article will describe how an ONS chapter capitalized on the leadership attributes of partnership, creativity, and commitment to sustain an important community service program. ?. PMID- 28738046 TI - Safety Culture: Establishing Processes to Support Trust and Accountability for Risk Reduction ?. AB - Oncology nurses are tasked with developing skills that enable vigilant risk surveillance through situational awareness. However, care distractions, task interruptions, increased workloads, and time constraints are common challenges that compete with the ability to provide optimal safe care. A commitment to safety is a professional and organizational expectation, and being empowered to overcome safety-related challenges necessitates multilevel and interprofessional accountability.?. PMID- 28738047 TI - Chemomobilization: Overview of an Educational Quality Improvement Project for Recipients of Autologous Stem Cell Transplantation?. AB - BACKGROUND: In preparation for an autologous stem cell transplantation, patients undergo chemomobilization; however, a dearth of standardized, evidence-based patient education on chemomobilization exists in the literature and in practice.?. OBJECTIVES: The purpose of this quality improvement educational initiative is to identify an ?evidence-based approach to appraise the educational needs of patients and their caregivers and to enhance chemomobilization education. ?. METHODS: A review of the literature related to chemomobilization was conducted, as well as an informal survey of educational practices at five ?National Cancer Institute-designated comprehensive cancer centers. A 14-item survey was administered to 50 patients who underwent chemomobilization to assess their educational needs, experiences, and preferences. ?. FINDINGS: Patients prefer written information to review. Receiving verbal education from reliable healthcare providers in a structured format may enhance effective comprehension and retention. Patients identified timing, process, side effects, and expectations about chemomobilization as the most important topics to include in education. PMID- 28738048 TI - Scalp Cooling: The Prevention of Chemotherapy-Induced Alopecia?. AB - Hair loss (alopecia) from chemotherapy is one of the most feared side effects of many patients, particularly women. Many patients and their healthcare providers believe that cryotherapy can help prevent or mitigate these changes. Scalp cooling has been used for more than 30 years to prevent alopecia caused by chemotherapy, particularly taxanes and anthracyclines. This article presents an overview of the evidence for this strategy, as well as its impact on nursing care provision. PMID- 28738049 TI - Atypical Hemolytic Uremic Syndrome: Achieving Positive Patient Outcomes With Early Diagnosis and Appropriate Management?. AB - BACKGROUND: Atypical hemolytic uremic syndrome (aHUS), a condition found in adult and pediatric populations, can be idiopathic or acquired as a result of major systemic changes. aHUS presents with a wide array of symptoms that can be attributed to other less dangerous conditions. Because of its complex nature and rare occurrence, it is typically diagnosed in later stages and with multiple organ involvement.?. OBJECTIVES: This article provides an overview of aHUS and available interventions. ?. METHODS: Current aHUS literature was reviewed, and implications for nursing care were identified.?. FINDINGS: Early diagnosis is crucial to achieve positive patient outcomes. The difference in pathology among the different thrombotic microangiopathies and their appropriate management must be understood. Although aHUS requires a multidisciplinary approach, nurses play a crucial role in assessing disease progression and identifying possible complications. PMID- 28738050 TI - Intralesional Therapy: Consensus Statements for Best Practices in Administration From the Melanoma Nursing Initiative?. AB - BACKGROUND: Talimogene laherparepvec (T-VEC) is the first intralesional therapy for melanoma approved by the U.S. Food and Drug Administration. This oncolytic viral immunotherapy has improved outcomes for patients with locoregional recurrent melanoma and is showing promise in combination with systemic therapies. ?. OBJECTIVES: This article aims to provide oncology nurses with expert guidance on best practices in incorporating intralesional therapy for patients diagnosed with melanoma in practice. ?. METHODS: Members of the Melanoma Nursing Initiative explored issues related to administration of T-VEC in melanoma. The current literature and clinical experiences were reviewed. ?. FINDINGS: The author offers a care step pathway (CSP) and commentary detailing best practices in infection control, drug storage, pharmacy interface, patient flow, space/staff allocation, patient education, and adverse event management with T-VEC. The CSP will help nurses improve patient outcomes and streamline the workflow with this novel therapeutic approach. PMID- 28738052 TI - Collaborative Care in Melanoma: The Essential Role of the Nurse?. AB - This article provides perspective from medical oncologists on the importance of this supplement from the Melanoma Nursing Initiative. The authors (a) delineate the challenges inherent in addressing adverse event (AE) management with newer melanoma therapies, particularly in the community setting; (b) illustrate how advanced practice providers with extensive clinical trial experience in melanoma are in a key position to set the agenda and educate colleagues on best practices in AE management; and PMID- 28738051 TI - BRAF/MEK ?Inhibitor Therapy: Consensus Statement From the Faculty of the Melanoma Nursing Initiative on Managing Adverse Events and Potential Drug Interactions. AB - BACKGROUND: BRAF/MEK inhibitor therapy improves outcomes in BRAF V600E- and V600K mutated unresectable or metastatic melanoma. However, these regimens are associated with adverse events (AEs) that may lead to unnecessary drug modifications and discontinuations or potentially serious sequelae. In addition, drug-drug interactions (DDIs) may result in AEs or altered therapeutic efficacy.?. OBJECTIVES: This article presents consensus statements to guide nurses in the prevention, recognition, and management of AEs and potential DDIs associated with BRAF/MEK inhibitor therapy. ?. METHODS: Members of the Melanoma Nurse Initiative reviewed the current literature and clinical experience related to AEs and DDIs associated with BRAF/MEK inhibitor therapy. ?. FINDINGS: The care step pathways provided for select AEs represent a proactive, comprehensive nursing care plan to support optimal patient outcomes. Recommendations are also offered for preventing and managing DDIs. PMID- 28738053 TI - Promoting Oral Therapy Adherence: Consensus Statements From the Faculty of the Melanoma Nursing Initiative on Oral Melanoma Therapies?. AB - BACKGROUND: Inhibitors of BRAF and the downstream signaling protein MEK have improved outcomes for patients with BRAF-mutant advanced malignant melanoma. Despite their ease of administration, these oral therapies pose adherence challenges. ?. OBJECTIVES: This article aims to increase awareness of causes of nonadherence to oral targeted therapies in advanced malignant melanoma and to provide oncology nurses with strategies to address these nonadherence issues. ?. METHODS: Members of the Melanoma Nursing Initiative explored issues related to adherence to targeted therapies in advanced malignant melanoma. The current literature and clinical experience were reviewed. ?. FINDINGS: The authors present a care step pathway focused on increased patient engagement and rapid identification and optimal management of toxicities to avoid toxicity-related nonadherence. Other causes for nonadherence and employment of individualized strategies to support patient adherence are addressed. PMID- 28738054 TI - Ipilimumab-Based? Therapy: Consensus Statement From the Faculty of the Melanoma Nursing Initiative on Managing Adverse Events With Ipilimumab Monotherapy and Combination Therapy With Nivolumab. AB - BACKGROUND: Ipilimumab (Yervoy(r)) therapy improves outcomes in patients with resected stage III melanoma, and ipilimumab alone or combined with nivolumab (Opdivo(r)) does so in those with unresectable or metastatic melanoma. These immunotherapies are associated with immune-related adverse events (irAEs). With prompt recognition and appropriate management, serious sequelae or unnecessary treatment discontinuation can be prevented.?. OBJECTIVES: This article presents consensus statements to guide oncology nurses in the recognition and management of irAEs associated with ipilimumab and nivolumab. ?. METHODS: Members of the Melanoma Nursing Initiative reviewed the current literature and clinical experience regarding nursing interventions related to irAEs associated with ipilimumab or ipilimumab and nivolumab therapy.?. FINDINGS: The care step pathways provided represent a proactive, evidence-based, and comprehensive plan to support optimal patient outcomes. PMID- 28738055 TI - PD-1 Inhibitor Therapy: Consensus Statement From the Faculty of the Melanoma Nursing Initiative on Managing Adverse Events?. AB - BACKGROUND: Programmed cell death protein 1 (PD-1) inhibitor therapies are now a standard treatment for advanced melanoma and other tumor types. The immune related adverse events (irAEs) associated with PD-1 inhibitor therapy are drastically different from the AEs associated with chemotherapy. Because these irAEs reflect immune system activation rather than side effects of therapy, nurses should be cognizant of the range of organ systems potentially affected as well as likely clinical presentations.?. OBJECTIVES: This article presents consensus statements to guide nurses in the recognition and management of irAEs associated with PD-1 inhibitor monotherapy for advanced melanoma.?. METHODS: Members of the Melanoma Nursing Initiative discussed the current literature and clinical experience regarding nursing interventions related to irAEs associated with PD-1 inhibitor therapy.?. FINDINGS: The care step pathways provided for select irAEs represent a proactive, comprehensive nursing care plan to support optimal outcomes for patients receiving PD-1 inhibitor therapy. PMID- 28738056 TI - Advances in Melanoma: The Rationale for the Melanoma Nursing Initiative?. AB - This article provides an overview of this supplement, outlining the needs assessment process the Melanoma Nursing Initiative (MNI) used to determine the immunotherapy and targeted therapy topics for discussion as well as the process for developing the consensus statements. The article provides specific discussion of a unique feature of the MNI, the care step pathways (CSPs) for management of adverse events (AEs) associated with melanoma therapies, and looks to the future in terms of the potential benefits of engaging and enabling oncology nurses to adopt a standardized approach to AE management and adherence promotion for melanoma therapies. PMID- 28738057 TI - The fatty liver index as a predictor of incident chronic kidney disease in a 10 year prospective cohort study. AB - BACKGROUND: Although non-alcoholic fatty liver disease (NAFLD) is considered to be associated with chronic kidney disease (CKD), long-term follow up data is lacking. We investigated whether NAFLD, as determined by the fatty liver index (FLI), could predict incident CKD in 10-year prospective cohort study. We also assessed the clinical utility of FLI to predict the development of CKD. METHODS: 6,238 adults aged 40 to 69 years without baseline CKD from the Ansan-Ansung cohort were examined. Patients were classified according to FLI as follows: FLI<30, no NAFLD; FLI>=60, NAFLD; and 30<= FLI<60, intermediate. Incident CKD was defined as estimated glomerular filtration rate (eGFR) <60 ml/min per 1.73 m2. The clinical utility of FLI in predicting incident CKD was estimated via area under the receiver-operating characteristic curve (AUC), net reclassification improvement (NRI), and integrated discrimination improvement (IDI) analyses. RESULTS: During an average of 10 years of follow-up, 724 subjects (15.21%) developed CKD. The adjusted hazard ratio [95% confidence interval (CI)] for incident CKD increased in a graded manner with FLI increased (<30 vs. 30-59 vs. >=60 = 1 vs. 1.17 [0.997-1.375] vs. 1.459 [1.189-1.791], respectively, P for trend = 0.0012). Incorporation of FLI into traditional risk factors of CKD significantly increased prediction of incident CKD based on NRI (17%; 95% CI, 8.9 25%; P-value <0.001) and IDI (0.002; 95% CI, 0.0046-0.0143; P-value = 0.046). CONCLUSIONS: FLI, a surrogate marker of NAFLD, was an independent risk factor for incident CKD. FLI provides meaningful incremental risk reclassification beyond that of conventional risk factors of CKD. PMID- 28738058 TI - Establishing a library of resources to help people understand key concepts in assessing treatment claims-The "Critical thinking and Appraisal Resource Library" (CARL). AB - BACKGROUND: People are frequently confronted with untrustworthy claims about the effects of treatments. Uncritical acceptance of these claims can lead to poor, and sometimes dangerous, treatment decisions, and wasted time and money. Resources to help people learn to think critically about treatment claims are scarce, and they are widely scattered. Furthermore, very few learning-resources have been assessed to see if they improve knowledge and behavior. OBJECTIVES: Our objectives were to develop the Critical thinking and Appraisal Resource Library (CARL). This library was to be in the form of a database containing learning resources for those who are responsible for encouraging critical thinking about treatment claims, and was to be made available online. We wished to include resources for groups we identified as 'intermediaries' of knowledge, i.e. teachers of schoolchildren, undergraduates and graduates, for example those teaching evidence-based medicine, or those communicating treatment claims to the public. In selecting resources, we wished to draw particular attention to those resources that had been formally evaluated, for example, by the creators of the resource or independent research groups. METHODS: CARL was populated with learning-resources identified from a variety of sources-two previously developed but unmaintained inventories; systematic reviews of learning-interventions; online and database searches; and recommendations by members of the project group and its advisors. The learning-resources in CARL were organised by 'Key Concepts' needed to judge the trustworthiness of treatment claims, and were made available online by the James Lind Initiative in Testing Treatments interactive (TTi) English (www.testingtreatments.org/category/learning-resources).TTi English also incorporated the database of Key Concepts and the Claim Evaluation Tools developed through the Informed Healthcare Choices (IHC) project (informedhealthchoices.org). RESULTS: We have created a database of resources called CARL, which currently contains over 500 open-access learning-resources in a variety of formats: text, audio, video, webpages, cartoons, and lesson materials. These are aimed primarily at 'Intermediaries', that is, 'teachers', 'communicators', 'advisors', 'researchers', as well as for independent 'learners'. The resources included in CARL are currently accessible at www.testingtreatments.org/category/learning-resources. CONCLUSIONS: We hope that ready access to CARL will help to promote the critical thinking about treatment claims, needed to help improve healthcare choices. PMID- 28738059 TI - Predicting diabetes mellitus using SMOTE and ensemble machine learning approach: The Henry Ford ExercIse Testing (FIT) project. AB - Machine learning is becoming a popular and important approach in the field of medical research. In this study, we investigate the relative performance of various machine learning methods such as Decision Tree, Naive Bayes, Logistic Regression, Logistic Model Tree and Random Forests for predicting incident diabetes using medical records of cardiorespiratory fitness. In addition, we apply different techniques to uncover potential predictors of diabetes. This FIT project study used data of 32,555 patients who are free of any known coronary artery disease or heart failure who underwent clinician-referred exercise treadmill stress testing at Henry Ford Health Systems between 1991 and 2009 and had a complete 5-year follow-up. At the completion of the fifth year, 5,099 of those patients have developed diabetes. The dataset contained 62 attributes classified into four categories: demographic characteristics, disease history, medication use history, and stress test vital signs. We developed an Ensembling based predictive model using 13 attributes that were selected based on their clinical importance, Multiple Linear Regression, and Information Gain Ranking methods. The negative effect of the imbalance class of the constructed model was handled by Synthetic Minority Oversampling Technique (SMOTE). The overall performance of the predictive model classifier was improved by the Ensemble machine learning approach using the Vote method with three Decision Trees (Naive Bayes Tree, Random Forest, and Logistic Model Tree) and achieved high accuracy of prediction (AUC = 0.92). The study shows the potential of ensembling and SMOTE approaches for predicting incident diabetes using cardiorespiratory fitness data. PMID- 28738060 TI - Community detection in sequence similarity networks based on attribute clustering. AB - Networks are powerful tools for the presentation and analysis of interactions in multi-component systems. A commonly studied mesoscopic feature of networks is their community structure, which arises from grouping together similar nodes into one community and dissimilar nodes into separate communities. Here, the community structure of protein sequence similarity networks is determined with a new method: Attribute Clustering Dependent Communities (ACDC). Sequence similarity has hitherto typically been quantified by the alignment score or its expectation value. However, pair alignments with the same score or expectation value cannot thus be differentiated. To overcome this deficiency, the method constructs, for pair alignments, an extended alignment metric, the link attribute vector, which includes the score and other alignment characteristics. Rescaling components of the attribute vectors qualitatively identifies a systematic variation of sequence similarity within protein superfamilies. The problem of community detection is then mapped to clustering the link attribute vectors, selection of an optimal subset of links and community structure refinement based on the partition density of the network. ACDC-predicted communities are found to be in good agreement with gold standard sequence databases for which the "ground truth" community structures (or families) are known. ACDC is therefore a community detection method for sequence similarity networks based entirely on pair similarity information. A serial implementation of ACDC is available from https://cmb.ornl.gov/resources/developments. PMID- 28738061 TI - Magnetic resonance imaging and tensor-based morphometry in the MPTP non-human primate model of Parkinson's disease. AB - Parkinson's disease (PD) is the second most common neurodegenerative disorder producing a variety of motor and cognitive deficits with the causes remaining largely unknown. The gradual loss of the nigrostriatal pathway is currently considered the pivotal pathological event. To better understand the progression of PD and improve treatment management, defining the disease on a structural basis and expanding brain analysis to extra-nigral structures is indispensable. The anatomical complexity and the presence of neuromelanin, make the use of non human primates an essential element in developing putative imaging biomarkers of PD. To this end, ex vivo T2-weighted magnetic resonance images were acquired from control and 1-methyl-4 phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated marmosets. Volume measurements of the caudate, putamen, and substantia nigra indicated significant atrophy and cortical thinning. Tensor-based morphometry provided a more extensive and hypothesis free assessment of widespread changes caused by the toxin insult to the brain, especially highlighting regional cortical atrophy. The results highlight the importance of developing imaging biomarkers of PD in non-human primate models considering their distinct neuroanatomy. It is essential to further develop these biomarkers in vivo to provide non-invasive tools to detect pre-symptomatic PD and to monitor potential disease altering therapeutics. PMID- 28738062 TI - Analysis of novel RUNX2 mutations in Chinese patients with cleidocranial dysplasia. AB - Cleidocranial dysplasia (CCD) is an autosomal dominant inheritable skeletal disorder characterized by cranial dysplasia, clavicle hypoplasia and dental abnormalities. This disease is mainly caused by heterozygous mutations in RUNX2, a gene that encodes an osteoblast-specific transcription factor. In the present study, mutational analyses of RUNX2 gene were performed on four unrelated Chinese patients with CCD. Four different RUNX2 mutations were detected in these patients, including one nonsense mutation (c.199C>T p.Q67X) and three missense mutations (c.338T>G p.L113R, c.557G>C p.R186T and c.673C>T p.R225W). Among them, two mutations (c.199C>T p.Q67X and c.557G>C p.R186T) were novel and the other two had been reported in previous literatures. Except for Q67X mutation located in the Q/A domain, other three mutations were clustered within the highly conserved Runt domain. Green fluorescent protein (GFP) and RUNX2 fusion protein analyses in vitro showed that nuclear accumulation of RUNX2 protein was disturbed by Q67X mutation, while the other two mutations (c.338T>G p.L113R and c.557G>C p.R186T) had no effects on the subcellular distribution of RUNX2. Luciferase reporter assay demonstrated that all the three novel RUNX2 mutations significantly reduced the transactivation activity of RUNX2 on osteocalcin promoter. Our findings enrich the evidence of molecular genetics that the mutations of RUNX2 gene are responsible for CCD. PMID- 28738063 TI - Atypical speech versus non-speech detection and discrimination in 4- to 6- yr old children with autism spectrum disorder: An ERP study. AB - Previous event-related potential (ERP) research utilizing oddball stimulus paradigms suggests diminished processing of speech versus non-speech sounds in children with an Autism Spectrum Disorder (ASD). However, brain mechanisms underlying these speech processing abnormalities, and to what extent they are related to poor language abilities in this population remain unknown. In the current study, we utilized a novel paired repetition paradigm in order to investigate ERP responses associated with the detection and discrimination of speech and non-speech sounds in 4- to 6-year old children with ASD, compared with gender and verbal age matched controls. ERPs were recorded while children passively listened to pairs of stimuli that were either both speech sounds, both non-speech sounds, speech followed by non-speech, or non-speech followed by speech. Control participants exhibited N330 match/mismatch responses measured from temporal electrodes, reflecting speech versus non-speech detection, bilaterally, whereas children with ASD exhibited this effect only over temporal electrodes in the left hemisphere. Furthermore, while the control groups exhibited match/mismatch effects at approximately 600 ms (central N600, temporal P600) when a non-speech sound was followed by a speech sound, these effects were absent in the ASD group. These findings suggest that children with ASD fail to activate right hemisphere mechanisms, likely associated with social or emotional aspects of speech detection, when distinguishing non-speech from speech stimuli. Together, these results demonstrate the presence of atypical speech versus non speech processing in children with ASD when compared with typically developing children matched on verbal age. PMID- 28738064 TI - Species A rotavirus NSP3 acquires its translation inhibitory function prior to stable dimer formation. AB - Species A rotavirus non-structural protein 3 (NSP3) is a translational regulator that inhibits or, under some conditions, enhances host cell translation. NSP3 binds to the translation initiation factor eIF4G1 and evicts poly-(A) binding protein (PABP) from eIF4G1, thus inhibiting translation of polyadenylated mRNAs, presumably by disrupting the effect of PABP bound to their 3'-ends. NSP3 has a long coiled-coil region involved in dimerization that includes a chaperone Hsp90 binding domain (HS90BD). We aimed to study the role in NSP3 dimerization of a segment of the coiled-coil region adjoining the HS90BD. We used a vaccinia virus system to express NSP3 with point mutations in conserved amino acids in the coiled-coil region and determined the effects of these mutations on translation by metabolic labeling of proteins as well as on accumulation of stable NSP3 dimers by non-dissociating Western blot, a method that separates stable NSP3 dimers from the monomer/dimerization intermediate forms of the protein. Four of five mutations reduced the total yield of NSP3 and the formation of stable dimers (W170A, K171E, R173E and R187E:K191E), whereas one mutation had the opposite effects (Y192A). Treatment with the proteasome inhibitor MG132 revealed that stable NSP3 dimers and monomers/dimerization intermediates are susceptible to proteasome degradation. Surprisingly, mutants severely impaired in the formation of stable dimers were still able to inhibit host cell translation, suggesting that NSP3 dimerization intermediates are functional. Our results demonstrate that rotavirus NSP3 acquires its function prior to stable dimer formation and remain as a proteasome target throughout dimerization. PMID- 28738065 TI - Impact of controlled release urea on maize yield and nitrogen use efficiency under different water conditions. AB - Controlled release urea (CRU) has been widely adopted to increase nitrogen (N) use efficiency and maize production, but the impacts can range widely depending on water availability in the soil. In an experiment using Zhengdan 958 (a popular summer maize hybrid), three levels of water treatments (adequate water condition [W3], which maintained soil moisture at about 75% +/- 5% of the soil's field capacity; mild water stress [W2], which maintained moisture content at 55% +/- 5% of field capacity; and severe water stress [W1], which had a moisture content of 35% +/- 5% of field capacity) and four levels of controlled release urea fertilizer (N0, N1, N2 and N3 were 0, 105, 210 and 315 kg N ha-1, respectively) were compared in a rainout shelter system with soil. The results revealed that CRU had significant effects on maize yields and N use efficiencies under different water conditions. The mean yields increased with increasing water levels and showed significant differences. Under W1, the accumulation of dry matter and N were limited, and N internal efficiency (NIE) and the apparent recovery efficiency of applied N (REN) decreased with N increases; yields of N1, N2, and N3 were similar. Under W2, the dry matter and N accumulation, as well as the yield, showed an increasing trend with an increase in N application, and the NIE and REN of N3 showed no difference from N2. Under W3, yields of N2 and N3 were similar and they were significantly higher than that of N1, but the agronomic N use efficiency (ANUE), REN, and the physiological NUE (PNUE) of N2 were 54.2, 34.9, and 14.4% higher, respectively, than those of N3. N application beyond the optimal N rate did not consistently increase maize yield, and caused a decrease in N use efficiencies. Highest overall dry matter, N accumulation, and yields were observed with N3 under W2, and those showed no differences with N2 and N3 under W3. Under this experimental condition, the CRU of 210 kg ha-1 was optimized when soil moisture content was 75% +/- 5% of field capacity, but an N rate of 315 kg ha-1 was superior when soil moisture content during the entire growing season was maintained at 55% +/- 5% of field capacity. PMID- 28738066 TI - Expansion by whole genome duplication and evolution of the sox gene family in teleost fish. AB - It is now recognized that several rounds of whole genome duplication (WGD) have occurred during the evolution of vertebrates, but the link between WGDs and phenotypic diversification remains unsolved. We have investigated in this study the impact of the teleost-specific WGD on the evolution of the sox gene family in teleostean fishes. The sox gene family, which encodes for transcription factors, has essential role in morphology, physiology and behavior of vertebrates and teleosts, the current largest group of vertebrates. We have first redrawn the evolution of all sox genes identified in eleven teleost genomes using a comparative genomic approach including phylogenetic and synteny analyses. We noticed, compared to tetrapods, an important expansion of the sox family: 58% (11/19) of sox genes are duplicated in teleost genomes. Furthermore, all duplicated sox genes, except sox17 paralogs, are derived from the teleost specific WGD. Then, focusing on five sox genes, analyzing the evolution of coding and non-coding sequences, as well as the expression patterns in fish embryos and adult tissues, we demonstrated that these paralogs followed lineage-specific evolutionary trajectories in teleost genomes. This work, based on whole genome data from multiple teleostean species, supports the contribution of WGDs to the expansion of gene families, as well as to the emergence of genomic differences between lineages that might promote genetic and phenotypic diversity in teleosts. PMID- 28738068 TI - Age-dependent relationships between body mass index and mortality: Singapore longitudinal ageing study. AB - OBJECTIVES: The relationship between body mass index (BMI) with mortality risk, in particular the BMI category associated with the lowest all-cause and CVD-and stroke mortality and the BMI threshold for defining overweight or obesity in older persons is controversial. This study investigated the age-dependent associations of BMI categories with all-cause and cardiovascular disease (CVD) and stroke mortality. METHOD: Prospective cohort study (Singapore Longitudinal Ageing Studies) of older adults aged 55 and above, followed up from 2003 to 2011. Participants were 2605 Chinese with baseline BMI and other variables. Outcome Measurement: Mortality hazard ratios (HR) for all-cause and CVD and stroke mortality. RESULTS: Overall, BMI showed a U-shaped relationship with all-cause and CVD and stroke mortality, being lowest at Normal Weight-II category (BMI 23.0 24.9 kg/m2). Most evidently among the middle-aged (55-64 years), all-cause mortality risks relative to Normal Weight-II were elevated for underweight (30.0; HR = 4.05,p = 0.0423). Among the old (>=65 years), however, Overweight and Obese categories were not significantly associated with increased all-cause mortality (HR from 0.98 to 1.29), but Overweight-Obese was associated with increased CVD and stroke mortality (HR = 10.0, p = 0.0086). CONCLUSION: BMI showed a U-shaped relationship with mortality. Among older persons aged 65 and above, the overweight-or-obese category of BMI was not associated with excess all-cause mortality. PMID- 28738069 TI - Inoculation effects on root-colonizing arbuscular mycorrhizal fungal communities spread beyond directly inoculated plants. AB - Inoculation with arbuscular mycorrhizal fungi (AMF) may improve plant performance at disturbed sites, but inoculation may also suppress root colonization by native AMF and decrease the diversity of the root-colonizing AMF community. This has been shown for the roots of directly inoculated plants, but little is known about the stability of inoculation effects, and to which degree the inoculant and the inoculation-induced changes in AMF community composition spread into newly emerging seedlings that were not in direct contact with the introduced propagules. We addressed this topic in a greenhouse experiment based on the soil and native AMF community of a post-mining site. Plants were cultivated in compartmented pots with substrate containing the native AMF community, where AMF extraradical mycelium radiating from directly inoculated plants was allowed to inoculate neighboring plants. The abundances of the inoculated isolate and of native AMF taxa were monitored in the roots of the directly inoculated plants and the neighboring plants by quantitative real-time PCR. As expected, inoculation suppressed root colonization of the directly inoculated plants by other AMF taxa of the native AMF community and also by native genotypes of the same species as used for inoculation. In the neighboring plants, high abundance of the inoculant and the suppression of native AMF were maintained. Thus, we demonstrate that inoculation effects on native AMF propagate into plants that were not in direct contact with the introduced inoculum, and are therefore likely to persist at the site of inoculation. PMID- 28738067 TI - The prediction of late-onset preeclampsia: Results from a longitudinal proteomics study. AB - BACKGROUND: Late-onset preeclampsia is the most prevalent phenotype of this syndrome; nevertheless, only a few biomarkers for its early diagnosis have been reported. We sought to correct this deficiency using a high through-put proteomic platform. METHODS: A case-control longitudinal study was conducted, including 90 patients with normal pregnancies and 76 patients with late-onset preeclampsia (diagnosed at >=34 weeks of gestation). Maternal plasma samples were collected throughout gestation (normal pregnancy: 2-6 samples per patient, median of 2; late-onset preeclampsia: 2-6, median of 5). The abundance of 1,125 proteins was measured using an aptamers-based proteomics technique. Protein abundance in normal pregnancies was modeled using linear mixed-effects models to estimate mean abundance as a function of gestational age. Data was then expressed as multiples of-the-mean (MoM) values in normal pregnancies. Multi-marker prediction models were built using data from one of five gestational age intervals (8-16, 16.1-22, 22.1-28, 28.1-32, 32.1-36 weeks of gestation). The predictive performance of the best combination of proteins was compared to placental growth factor (PIGF) using bootstrap. RESULTS: 1) At 8-16 weeks of gestation, the best prediction model included only one protein, matrix metalloproteinase 7 (MMP-7), that had a sensitivity of 69% at a false positive rate (FPR) of 20% (AUC = 0.76); 2) at 16.1 22 weeks of gestation, MMP-7 was the single best predictor of late-onset preeclampsia with a sensitivity of 70% at a FPR of 20% (AUC = 0.82); 3) after 22 weeks of gestation, PlGF was the best predictor of late-onset preeclampsia, identifying 1/3 to 1/2 of the patients destined to develop this syndrome (FPR = 20%); 4) 36 proteins were associated with late-onset preeclampsia in at least one interval of gestation (after adjustment for covariates); 5) several biological processes, such as positive regulation of vascular endothelial growth factor receptor signaling pathway, were perturbed; and 6) from 22.1 weeks of gestation onward, the set of proteins most predictive of severe preeclampsia was different from the set most predictive of the mild form of this syndrome. CONCLUSIONS: Elevated MMP-7 early in gestation (8-22 weeks) and low PlGF later in gestation (after 22 weeks) are the strongest predictors for the subsequent development of late-onset preeclampsia, suggesting that the optimal identification of patients at risk may involve a two-step diagnostic process. PMID- 28738070 TI - Determinants associated with deprivation in multimorbid patients in primary care A cross-sectional study in Switzerland. AB - BACKGROUND: Deprivation usually encompasses material, social, and health components. It has been shown to be associated with greater risks of developing chronic health conditions and of worse outcome in multimorbidity. The DipCare questionnaire, an instrument developed and validated in Switzerland for use in primary care, identifies patients subject to potentially higher levels of deprivation. OBJECTIVES: To identifying determinants of the material, social, and health profiles associated with deprivation in a sample of multimorbid, primary care patients, and thus set priorities in screening for deprivation in this population. DESIGN: Secondary analysis from a nationwide cross-sectional study in Switzerland. PARTICIPANTS: A random sample of 886 adult patients suffering from at least three chronic health conditions. MAIN MEASURES: The outcomes of interest were the patients' levels of deprivation as measured using the DipCare questionnaire. Classification And Regression Tree analysis identified the independent variables that separated the examined population into groups with increasing deprivation scores. Finally, a sensitivity analysis (multivariate regression) confirmed the robustness of our results. KEY RESULTS: Being aged under 64 years old was associated with higher overall, material, and health deprivation; being aged over 77 years old was associated with higher social deprivation. Other variables associated with deprivation were the level of education, marital status, and the presence of depression or chronic pain. CONCLUSION: Specific profiles, such as being younger, were associated with higher levels of overall, material, and health deprivation in multimorbid patients. In contrast, patients over 77 years old reported higher levels of social deprivation. Furthermore, chronic pain and depression added to the score for health deprivation. It is important that GPs consider the possibility of deprivation in these multimorbid patients and are able to identify it, both in order to encourage treatment adherence and limit any forgoing of care for financial reasons. PMID- 28738071 TI - The PIT-trap-A "model-free" bootstrap procedure for inference about regression models with discrete, multivariate responses. AB - Bootstrap methods are widely used in statistics, and bootstrapping of residuals can be especially useful in the regression context. However, difficulties are encountered extending residual resampling to regression settings where residuals are not identically distributed (thus not amenable to bootstrapping)-common examples including logistic or Poisson regression and generalizations to handle clustered or multivariate data, such as generalised estimating equations. We propose a bootstrap method based on probability integral transform (PIT-) residuals, which we call the PIT-trap, which assumes data come from some marginal distribution F of known parametric form. This method can be understood as a type of "model-free bootstrap", adapted to the problem of discrete and highly multivariate data. PIT-residuals have the key property that they are (asymptotically) pivotal. The PIT-trap thus inherits the key property, not afforded by any other residual resampling approach, that the marginal distribution of data can be preserved under PIT-trapping. This in turn enables the derivation of some standard bootstrap properties, including second-order correctness of pivotal PIT-trap test statistics. In multivariate data, bootstrapping rows of PIT-residuals affords the property that it preserves correlation in data without the need for it to be modelled, a key point of difference as compared to a parametric bootstrap. The proposed method is illustrated on an example involving multivariate abundance data in ecology, and demonstrated via simulation to have improved properties as compared to competing resampling methods. PMID- 28738072 TI - Monitoring protected areas from space: A multi-temporal assessment using raptors as biodiversity surrogates. AB - Monitoring protected areas (PAs) is essential for systematic evaluation of their effectiveness in terms of habitat protection, preservation and representativeness. This study illustrates how the use of species distribution models that combine remote sensing data and information about biodiversity surrogates can contribute to develop a systematic protocol for monitoring PAs. In particular, we assessed the effectiveness of the Natura 2000 (N2000) network, for conserving and preserving the representativeness of seven raptor species in a highly-dynamic landscape in northwest Spain between 2001 and 2014. We also evaluated the cost-effectiveness of the N2000 network by using the total area under protection as a proxy for conservation costs. Overall, the N2000 network was found to poorly represent the habitats of the raptor species. Despite the low representativeness, this network showed a high degree of effectiveness due to increased overall habitat availability for generalist and forest specialist species between 2001 and 2014. Nevertheless, additional protected areas should be established in the near future to increase their representativeness, and thus ensure the protection of open-habitat specialist species and their priority habitats. In addition, proactive conservation measures in natural and semi natural ecosystems (in particular, montane heathlands) will be essential for long term protection of Montagu's harrier (species listed in the Annex I of the Bird Directive), and thus complying with the current European Environmental Legislation. This study sheds light on how the development and application of new protected area indices based on the combined use of freely-available satellite data and species distribution models may contribute substantially to the cost efficiency of the PA monitoring systems, and to the 'Fitness Check' process of EU Nature Directives. PMID- 28738073 TI - The N-terminal region of serum amyloid A3 protein activates NF-kappaB and up regulates MUC2 mucin mRNA expression in mouse colonic epithelial cells. AB - Serum amyloid A (SAA) is the major acute-phase protein and a precursor of amyloid A (AA) in AA amyloidosis in humans and animals. SAA isoforms have been identified in a wide variety of animals, such as SAA1, SAA2, SAA3, and SAA4 in mouse. Although the biological functions of SAA isoforms are not completely understood, recent studies have suggested that SAA3 plays a role in host defense. Expression of SAA3 is increased on the mouse colon surface in the presence of microbiota in vivo, and it increases mRNA expression of mucin 2 (MUC2) in murine colonic epithelial cells in vitro, which constitutes a protective mucus barrier in the intestinal tract. In this study, to identify responsible regions in SAA3 for MUC2 expression, recombinant murine SAA1 (rSAA1), rSAA3, and rSAA1/3, a chimera protein constructed with mature SAA1 (amino acids 1-36) and SAA3 (amino acids 37 103), and vice versa for rSAA3/1, were added to murine colonic epithelial CMT-93 cells, and the mRNA expressions of MUC2 and cytokines were measured. Inhibition assays with NF-kappaB inhibitor or TLR4/MD2 inhibitor were also performed. Up regulation of MUC2 mRNA expression was strongly stimulated by rSAA3 and rSAA3/1, but not by rSAA1 or rSAA1/3. Moreover, NF-kappaB and TLR4/MD2 inhibitors suppressed the increase of MUC2 mRNA expression. These results suggest that the major responsible region for MUC2 expression exists in amino acids 1-36 of SAA3, and that up-regulations of MUC2 expression by SAA3 and SAA3/1 are involved with activation of NF-kappaB via the TLR4/MD2 complex. PMID- 28738074 TI - Adversity, emotion recognition, and empathic concern in high-risk youth. AB - Little is known about how emotion recognition and empathy jointly operate in youth growing up in contexts defined by persistent adversity. We investigated whether adversity exposure in two groups of youth was associated with reduced empathy and whether deficits in emotion recognition mediated this association. Foster, rural poor, and comparison youth from Swaziland, Africa identified emotional expressions and rated their empathic concern for characters depicted in images showing positive, ambiguous, and negative scenes. Rural and foster youth perceived greater anger and happiness in the main characters in ambiguous and negative images than did comparison youth. Rural children also perceived less sadness. Youth's perceptions of sadness in the negative and ambiguous expressions mediated the relation between adversity and empathic concern, but only for the rural youth, who perceived less sadness, which then predicted less empathy. Findings provide new insight into processes that underlie empathic tendencies in adversity-exposed youth and highlight potential directions for interventions to increase empathy. PMID- 28738075 TI - Predicting preeclampsia from a history of preterm birth. AB - OBJECTIVE: To assess whether women with a history of preterm birth, independent on the presence of prelabour rupture of the membranes (PROM) and growth deviation of the newborn, are more likely to develop preeclampsia with preterm or preterm birth in a subsequent pregnancy. METHODS: We conducted a population-based cohort study, based on Medical Birth Registry of Norway between 1967 and 2012, including 742,980 women with singleton pregnancies who were followed up from their 1st to 2nd pregnancy. In the analyses we included 712,511 women after excluding 30,469 women with preeclampsia in the first pregnancy. RESULTS: After preterm birth without preeclampsia in the first pregnancy, the risk of preterm preeclampsia in the second pregnancy was 4-7 fold higher than after term birth (odds ratios 3.5; 95% confidence interval (CI) 3.0-4.0 to 6.5; 95% CI 5.1-8.2). The risk of term preeclampsia in the pregnancy following a preterm birth was 2-3 times higher than after term birth (odds ratios 1.6; 95% CI 1.5-1.8 to 2.6; 95% CI 2.0-3.4). After spontaneous non-PROM preterm birth and preterm PROM, the risk of preterm preeclampsia was 3.3-3.6 fold higher than after spontaneous term birth. Corresponding risks of term preeclampsia was 1.6-1.8 fold higher. No significant time trends were found in the effect of spontaneous preterm birth in the first pregnancy on preterm or term preeclampsia in the second pregnancy. CONCLUSIONS: The results suggest that preterm birth, regardless of the presence of PROM, and preeclampsia share pathophysiologic mechanisms. These mechanisms may cause preterm birth in one pregnancy and preeclampsia in a subsequent pregnancy in the same woman. The association was particularly evident with preterm preeclampsia. PMID- 28738076 TI - The comparison of CHCA solvent compositions for improving LC-MALDI performance and its application to study the impact of aflatoxin B1 on the liver proteome of diabetes mellitus type 1 mice. AB - In nanoflow liquid chromatography-matrix-assisted laser desorption/ionization tandem time-of-flight (nanoLC-MALDI-TOF/TOF) approaches, it is critical to directly apply small amounts of the sample elutes on the sample target using a nanoLC system due to its low flow rate of 200 ~ 300 nl/min. It is recommended to apply a sheath liquid containing a matrix with a several MUL/min flow rate at the end of the nanoLC column to ensure a larger co-eluted droplet for more reproducible sample spotting and avoid the laborious task of post-manual matrix spotting. In this study, to achieve a better nanoLC-MALDI performance on sample spotting, we first compared alpha-Cyano-4-hydroxycinnamic acid (CHCA) solvent composition for efficiently concentrating nanoLC elutes on an anchor chip. The solvent composition of isopropanol (IPA): acetonitrile (ACN):acetone:0.1% Trifluoroacetic acid (TFA) (2:7:7:2) provided strong and homogeneous signals with higher peptide ion yields than the other solvent compositions. Then, nanoLC-MALDI TOF/TOF was applied to study the impact of aflatoxin B1 on the liver proteome from diabetes mellitus type 1 mice. Aflatoxin B1 (AFB1), produced by Aspergillus flavus and Aspergillus parasiticus is a carcinogen and a known causative agent of liver cancer. To evaluate the effects of long-term exposure to AFB1 on type 1 diabetes mellitus (TIDM), the livers of T1DM control mice and mice treated with AFB1 were analyzed using isotope-coded protein labeling (ICPL)-based quantitative proteomics. Our results showed that gluconeogenesis, lipid, and oxidative phosphorylation mechanisms, normally elevated in T1DM, were disordered following AFB1 treatment. In addition, major urinary protein 1 (MUP1), an indicator of increased insulin sensitivity, was significantly decreased in the T1DM/AFB1 group and may have resulted in higher blood glucose levels compared to the T1DM group. These results indicate that T1DM patients should avoid the AFB1 intake, as they could lead to increased blood glucose levels and disorders of energy-producing mechanisms. PMID- 28738077 TI - Consequences of severe habitat fragmentation on density, genetics, and spatial capture-recapture analysis of a small bear population. AB - Loss and fragmentation of natural habitats caused by human land uses have subdivided several formerly contiguous large carnivore populations into multiple small and often isolated subpopulations, which can reduce genetic variation and lead to precipitous population declines. Substantial habitat loss and fragmentation from urban development and agriculture expansion relegated the Highlands-Glades subpopulation (HGS) of Florida, USA, black bears (Ursus americanus floridanus) to prolonged isolation; increasing human land development is projected to cause >= 50% loss of remaining natural habitats occupied by the HGS in coming decades. We conducted a noninvasive genetic spatial capture recapture study to quantitatively describe the degree of contemporary habitat fragmentation and investigate the consequences of habitat fragmentation on population density and genetics of the HGS. Remaining natural habitats sustaining the HGS were significantly more fragmented and patchier than those supporting Florida's largest black bear subpopulation. Genetic diversity was low (AR = 3.57; HE = 0.49) and effective population size was small (NE = 25 bears), both of which remained unchanged over a period spanning one bear generation despite evidence of some immigration. Subpopulation density (0.054 bear/km2) was among the lowest reported for black bears, was significantly female-biased, and corresponded to a subpopulation size of 98 bears in available habitat. Conserving remaining natural habitats in the area occupied by the small, genetically depauperate HGS, possibly through conservation easements and government land acquisition, is likely the most important immediate step to ensuring continued persistence of bears in this area. Our study also provides evidence that preferentially placing detectors (e.g., hair traps or cameras) primarily in quality habitat across fragmented landscapes poses a challenge to estimating density-habitat covariate relationships using spatial capture-recapture models. Because habitat fragmentation and loss are likely to increase in severity globally, further investigation of the influence of habitat fragmentation and detector placement on estimation of this relationship is warranted. PMID- 28738078 TI - Evaluation of MALDI-TOF mass spectrometry and MALDI BioTyper in comparison to 16S rDNA sequencing for the identification of bacteria isolated from Arctic sea water. AB - MALDI-TOF Mass Spectrometry in association with the MALDI BioTyper 3.1 software has been evaluated for the identification and classification of 45 Arctic bacteria isolated from Kandalaksha Bay (White Sea, Russia). The high reliability of this method has been already demonstrated, in clinical microbiology, by a number of studies showing high attribution concordance with other credited analyses. Recently, it has been employed also in other branches of microbiology with controversial performance. The phyloproteomic results reported in this study were validated with those obtained by the "gold standard" 16S rDNA analysis. Concordance between the two methods was 100% at the genus level, while at the species level it was 48%. These percentages appeared to be quite high compared with other studies regarding environmental bacteria. However, the performance of MALDI BioTyper changed in relation to the taxonomical group analyzed, reflecting known identification problems related to certain genera. In our case, attribution concordance for Pseudomonas species was rather low (29%), confirming the problematic taxonomy of this genus, whereas that of strains from other genera was quite high (> 60%). Among the isolates tested in this study, two strains (Exiguobacterium oxidotolerans and Pseudomonas costantinii) were misidentified by MALDI BioTyper due to absence of reference spectra in the database. Accordingly, missing spectra were acquired for the database implementation. PMID- 28738079 TI - Comparison between intra-articular ozone and placebo in the treatment of knee osteoarthritis: A randomized, double-blinded, placebo-controlled study. AB - OBJECTIVE: The aim of the trial was to determine the effectiveness of oxygen ozone injections on knee osteoarthritis concerning pain reduction, joint functional improvement, and quality of life. METHODS: In this randomized, double blinded, placebo controlled clinical trial, 98 patients with symptomatic knee osteoarthritis (OA) were randomized into two groups receiving intra-articular 20 MUg/ml of ozone (OZ) or placebo (PBO) for 8 weeks. The efficacy outcomes for knee OA were the Visual Analogue Scale (VAS), Lequesne Index, Timed Up and Go Test (TUG Test), SF-36, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and Geriatric Pain Measure (GPM). RESULTS: After 8 weeks of treatment, ozone was more effective than the placebo: VAS [mean difference (MD) = 2.16, p < 0.003 (CI 95% 0.42-3.89)], GPM [MD = 18.94, p < 0.004 (CI 95% 3.43-34.44)], LEQ [MD = 4.05, p < 0.001 (CI 95% 1.10-7.00)], WOMAC (P) [median of diff = 9.999, p = 0.019 (CI 95% 0.000-15.000)], WOMAC (JS) [median of diff = 12.499, p < 0.001 (CI 95% 0.000-12.500)], WOMAC (PF) = [median of diff = 11.760, p = 0.003 (CI 95% 4.409-19.119)], TUG (no statistical difference) and SF-36 (FC) [(MD = -25.82, p < 0.001 (CI 95% 33.65-17.99)], SF-36 (PH) [MD = -40.82, p < 0.001 (CI 95% -54.48 27.17)], SF-36 (GSH) [MD = -3.38, p < 0.001 (CI 95% -4.83-1.93)], SF-36 (SA) [MD = 2.17, p < 0.001 (CI 95% -19.67-8.24), SF-36 (EA) [MD = -35.37, p < 0.001 (CI 95% -48.86-21.89)]. Adverse events occurred in 3 patients (2 in the placebo group and 1 in the ozone group) and included only puncture accidents. CONCLUSIONS: The study confirms the efficacy of ozone concerning pain relief, functional improvement, and quality of life in patients with knee osteoarthritis. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number Register ISRCTNR55861167. PMID- 28738080 TI - Effects of exogenous glucagon-like peptide-2 and distal bowel resection on intestinal and systemic adaptive responses in rats. AB - OBJECTIVE: To determine the effects of exogenous glucagon-like peptide-2 (GLP-2), with or without massive distal bowel resection, on adaptation of jejunal mucosa, enteric neurons, gut hormones and tissue reserves in rats. BACKGROUND: GLP-2 is a gut hormone known to be trophic for small bowel mucosa, and to mimic intestinal adaptation in short bowel syndrome (SBS). However, the effects of exogenous GLP-2 and SBS on enteric neurons are unclear. METHODS: Sprague Dawley rats were randomized to four treatments: Transected Bowel (TB) (n = 8), TB + GLP-2 (2.5 nmol/kg/h, n = 8), SBS (n = 5), or SBS + GLP-2 (2.5 nmol/kg/h, n = 9). SBS groups underwent a 60% jejunoileal resection with cecectomy and jejunocolic anastomosis. All rats were maintained on parenteral nutrition for 7 d. Parameters measured included gut morphometry, qPCR for hexose transporter (SGLT-1, GLUT-2, GLUT-5) and GLP-2 receptor mRNA, whole mount immunohistochemistry for neurons (HuC/D, VIP, nNOS), plasma glucose, gut hormones, and body composition. RESULTS: Resection increased the proportion of nNOS immunopositive myenteric neurons, intestinal muscularis propria thickness and crypt cell proliferation, which were not recapitulated by GLP-2 therapy. Exogenous GLP-2 increased jejunal mucosal surface area without affecting enteric VIP or nNOS neuronal immunopositivity, attenuated resection-induced reductions in jejunal hexose transporter abundance (SGLT-1, GLUT-2), increased plasma amylin and decreased peptide YY concentrations. Exogenous GLP-2 attenuated resection-induced increases in blood glucose and body fat loss. CONCLUSIONS: Exogenous GLP-2 stimulates jejunal adaptation independent of enteric neuronal VIP or nNOS changes, and has divergent effects on plasma amylin and peptide YY concentrations. The novel ability of exogenous GLP-2 to modulate resection-induced changes in peripheral glucose and lipid reserves may be important in understanding the whole-body response following intestinal resection, and is worthy of further study. PMID- 28738081 TI - Comparative molecular analyses of invasive fall armyworm in Togo reveal strong similarities to populations from the eastern United States and the Greater Antilles. AB - The fall armyworm (Spodoptera frugiperda, J.E. Smith) is a noctuid moth that is a major and ubiquitous agricultural pest in the Western Hemisphere. Infestations have recently been identified in several locations in Africa, indicating its establishment in the Eastern Hemisphere where it poses an immediate and significant economic threat. Genetic methods were used to characterize noctuid specimens infesting multiple cornfields in the African nation of Togo that were tentatively identified as fall armyworm by morphological criteria. Species identification was confirmed by DNA barcoding and the specimens were found to be primarily of the subgroup that preferentially infests corn and sorghum in the Western Hemisphere. The mitochondrial haplotype configuration was most similar to that found in the Caribbean region and the eastern coast of the United States, identifying these populations as the likely originating source of the Togo infestations. A genetic marker linked with resistance to the Cry1Fa toxin from Bacillus thuringiensis (Bt) expressed in transgenic corn and common in Puerto Rico fall armyworm populations was not found in the Togo collections. These observations demonstrate the usefulness of genetic surveys to characterize fall armyworm populations from Africa. PMID- 28738082 TI - Short-term sleep deprivation leads to decreased systemic redox metabolites and altered epigenetic status. AB - Sleep is critical for repair as well as the rejuvenation processes in the body and many of these functions are regulated via underlying cellular metabolic homeostasis. Changes in sleep pattern are reported to alter such metabolic function resulting in altered disease susceptibility or behavior. Here, we measured the extent to which overnight total sleep deprivation (SD) in young adult humans can influence systemic (plasma-derived) redox-metabolism including the major antioxidant, glutathione as well as DNA methylation levels. Nineteen participants (n = 19, MU age = 21, SD = 3.09) underwent morning testing before and after overnight total SD. Biochemical measures before and after SD revealed that glutathione, ATP, cysteine, and homocysteine levels were significantly reduced following one night of sleep deprivation (all p's < 0.01). Parallel to the well-recognized fact that sleep deprivation (maintaining wakefulness) uses up metabolic reserves, we observed that morning cortisol levels were blunted after sleep deprivation. There were no significant correlations between self-reported or actigraphy-measured sleep and the biochemical measurements, strongly indicating that prior sleep behavior did not have any direct influence on the biochemical measures taken at baseline or after sleep deprivation. Results from the current investigation supports the previous literature implicating the induction of oxidative stress and ATP depletion with sleep deprivation. Furthermore, such altered antioxidant status can also induce downstream epigenetic changes. Although we did not measure the specific genes that were altered under the influence of such sleep deprivation, such epigenetic changes could potentially contribute towards disease predisposition. PMID- 28738083 TI - The influence of sex and trauma impact on the rupture site of the ulnar collateral ligament of the thumb. AB - PURPOSE AND HYPOTHESIS: Although sex- and gender-specific analyses have been gaining more attention during the last years they have rarely been performed in orthopaedic literature. The primary purpose of this study was to investigate whether for injuries of the UCL the specific location of the rupture is influenced by sex. A secondary study question addressed the sex-independent effect of trauma intensity on the rupture site of the UCL. METHODS: This study is a retrospective analysis of all patients with either a proximal or distal bony avulsion or with a mid-substance tear or ligament avulsion of the UCL treated surgically between 1992 and 2015 at two level-I trauma centres. Trauma mechanisms leading to the UCL injury were classified into the following categories: (1) blunt trauma (i.e., strains), (2) low-velocity injuries (e.g., fall from standing height, assaults), and (3) high-velocity injuries (e.g., sports injuries, motor vehicle accidents). After reviewing the surgical records, patients were divided into three groups, depending upon the ligament rupture site: (1) mid-substance tears, (2) proximal ligament or bony avulsions and (3) distal ligament or bony avulsions. Dependencies between the specific rupture site and the explanatory variables (sex, age, and trauma intensity) were evaluated using chi2 test and logistic regression analysis. RESULTS: In total, 1582 patients (1094 males, 488 females) met the inclusion criteria. Mean age was 41 years (range: 9-90 years). Taking into account the effects of sex on trauma intensity (p<0.001) and of trauma intensity on rupture site (p<0.001), mid-substance tears occurred more frequently in women, whereas men were more prone to distal ligament or bony avulsions (p<0.001). In other words, sex and rupture site correlated due to the effects of sex on trauma intensity and of trauma intensity on rupture site, but taking into account those effects there still was a significant effect of sex on rupture site. CONCLUSIONS: The results of this study demonstrate that with regression analysis both sex and trauma intensity allow to predict rupture site in UCL injuries. PMID- 28738084 TI - The Dkk3 gene encodes a vital intracellular regulator of cell proliferation. AB - Members of the Dickkopf (Dkk) family of Wnt antagonists interrupt Wnt-induced receptor assembly and participate in axial patterning and cell fate determination. One family member, DKK3, does not block Wnt receptor activation. Loss of Dkk3 expression in cancer is associated with hyperproliferation and dysregulated beta-catenin signaling, and ectopic expression of Dkk3 halts cancer growth. The molecular events mediating the DKK3-dependent arrest of beta-catenin driven cell proliferation in cancer cells are unknown. Here we report the identification of a new intracellular gene product originating from the Dkk3 locus. This Dkk3b transcript originates from a second transcriptional start site located in intron 2 of the Dkk3 gene. It is essential for early mouse development and is a newly recognized regulator of beta-catenin signaling and cell proliferation. Dkk3b interrupts nuclear translocation beta-catenin by capturing cytoplasmic, unphosphorylated beta-catenin in an extra-nuclear complex with beta TrCP. These data reveal a new regulator of one of the most studied signal transduction pathways in metazoans and provides a novel, completely untapped therapeutic target for silencing the aberrant beta-catenin signaling that drives hyperproliferation in many cancers. PMID- 28738085 TI - A Bayesian spatio-temporal model for forecasting Anaplasma species seroprevalence in domestic dogs within the contiguous United States. AB - This paper forecasts the 2016 canine Anaplasma spp. seroprevalence in the United States from eight climate, geographic and societal factors. The forecast's construction and an assessment of its performance are described. The forecast is based on a spatial-temporal conditional autoregressive model fitted to over 11 million Anaplasma spp. seroprevalence test results for dogs conducted in the 48 contiguous United States during 2011-2015. The forecast uses county-level data on eight predictive factors, including annual temperature, precipitation, relative humidity, county elevation, forestation coverage, surface water coverage, population density and median household income. Non-static factors are extrapolated into the forthcoming year with various statistical methods. The fitted model and factor extrapolations are used to estimate next year's regional prevalence. The correlation between the observed and model-estimated county-by county Anaplasma spp. seroprevalence for the five-year period 2011-2015 is 0.902, demonstrating reasonable model accuracy. The weighted correlation (accounting for different sample sizes) between 2015 observed and forecasted county-by-county Anaplasma spp. seroprevalence is 0.987, exhibiting that the proposed approach can be used to accurately forecast Anaplasma spp. seroprevalence. The forecast presented herein can a priori alert veterinarians to areas expected to see Anaplasma spp. seroprevalence beyond the accepted endemic range. The proposed methods may prove useful for forecasting other diseases. PMID- 28738087 TI - Exercise physiology with a left ventricular assist device: Analysis of heart-pump interaction with a computational simulator. AB - Patients with a Ventricular Assist Device (VAD) are hemodynamically stable but show an impaired exercise capacity. Aim of this work is to identify and to describe the limiting factors of exercise physiology with a VAD. We searched for data concerning exercise in heart failure condition and after VAD implantation from the literature. Data were analyzed by using a cardiorespiratory simulator that worked as a collector of inputs coming from different papers. As a preliminary step the simulator was used to reproduce the evolution of hemodynamics from rest to peak exercise (ergometer cycling) in heart failure condition. Results evidence an increase of cardiac output of +2.8 l/min and a heart rate increase to 67% of the expected value. Then, we simulated the effect of a continuous-flow VAD at both rest and exercise. Total cardiac output increases of +3.0 l/min (+0.9 l/min due to the VAD and +2.1 l/min to the native ventricle). Since the left ventricle works in a non-linear portion of the diastolic stiffness line, we observed a consistent increase of pulmonary capillary wedge pressure (from 14 to 20 mmHg) for a relatively small increase of end-diastolic volume (from 182 to 189 cm3). We finally increased VAD speed during exercise to the maximum possible value and we observed a reduction of wedge pressure (-4.5 mmHg), a slight improvement of cardiac output (8.0 l/min) and a complete unloading of the native ventricle. The VAD can assure a proper hemodynamics at rest, but provides an insufficient unloading of the left ventricle and does not prevent wedge pressure from rising during exercise. Neither the VAD provides major benefits during exercise in terms of total cardiac output, which increases to a similar extend to an unassisted heart failure condition. VAD speed modulation can contribute to better unload the ventricle but the maximal flow reachable with the current devices is below the cardiac output observed in a healthy heart. PMID- 28738086 TI - An essential EBV latent antigen 3C binds Bcl6 for targeted degradation and cell proliferation. AB - The latent EBV nuclear antigen 3C (EBNA3C) is required for transformation of primary human B lymphocytes. Most mature B-cell malignancies originate from malignant transformation of germinal center (GC) B-cells. The GC reaction appears to have a role in malignant transformation, in which a major player of the GC reaction is Bcl6, a key regulator of this process. We now demonstrate that EBNA3C contributes to B-cell transformation by targeted degradation of Bcl6. We show that EBNA3C can physically associate with Bcl6. Notably, EBNA3C expression leads to reduced Bcl6 protein levels in a ubiquitin-proteasome dependent manner. Further, EBNA3C inhibits the transcriptional activity of the Bcl6 promoter through interaction with the cellular protein IRF4. Bcl6 degradation induced by EBNA3C rescued the functions of the Bcl6-targeted downstream regulatory proteins Bcl2 and CCND1, which resulted in increased proliferation and G1-S transition. These data provide new insights into the function of EBNA3C in B-cell transformation during GC reaction, and raises the possibility of developing new targeted therapies against EBV-associated cancers. PMID- 28738088 TI - Virtual daily living test to screen for mild cognitive impairment using kinematic movement analysis. AB - Questionnaires or computer-based tests for assessing activities of daily living are well-known approaches to screen for mild cognitive impairment (MCI). However, questionnaires are subjective and computerized tests only collect simple performance data with conventional input devices such as a mouse and keyboard. This study explored the validity and discriminative power of a virtual daily living test as a new diagnostic approach to assess MCI. Twenty-two healthy controls and 20 patients with MCI were recruited. The virtual daily living test presents two complex daily living tasks in an immersive virtual reality environment. The tasks were conducted based on subject body movements and detailed behavioral data (i.e., kinematic measures) were collected. Performance in both the proposed virtual daily living test and conventional neuropsychological tests for patients with MCI was compared to healthy controls. Kinematic measures considered in this study, such as body movement trajectory, time to completion, and speed, classified patients with MCI from healthy controls, F(8, 33) = 5.648, p < 0.001, eta2 = 0.578. When both hand and head speed were employed in conjunction with the immediate free-recall test, a conventional neuropsychological test, the discrimination power for screening MCI was significantly improved to 90% sensitivity and 95.5% specificity (cf. the immediate free-recall test alone has 80% sensitivity and 77.3% specificity). Inclusion of the kinematic measures in screening for MCI significantly improved the classification of patients with MCI compared to the healthy control group, Wilks' Lambda = 0.451, p < 0.001. PMID- 28738089 TI - A Random Forest approach to predict the spatial distribution of sediment pollution in an estuarine system. AB - Modeling the magnitude and distribution of sediment-bound pollutants in estuaries is often limited by incomplete knowledge of the site and inadequate sample density. To address these modeling limitations, a decision-support tool framework was conceived that predicts sediment contamination from the sub-estuary to broader estuary extent. For this study, a Random Forest (RF) model was implemented to predict the distribution of a model contaminant, triclosan (5 chloro-2-(2,4-dichlorophenoxy)phenol) (TCS), in Narragansett Bay, Rhode Island, USA. TCS is an unregulated contaminant used in many personal care products. The RF explanatory variables were associated with TCS transport and fate (proxies) and direct and indirect environmental entry. The continuous RF TCS concentration predictions were discretized into three levels of contamination (low, medium, and high) for three different quantile thresholds. The RF model explained 63% of the variance with a minimum number of variables. Total organic carbon (TOC) (transport and fate proxy) was a strong predictor of TCS contamination causing a mean squared error increase of 59% when compared to permutations of randomized values of TOC. Additionally, combined sewer overflow discharge (environmental entry) and sand (transport and fate proxy) were strong predictors. The discretization models identified a TCS area of greatest concern in the northern reach of Narragansett Bay (Providence River sub-estuary), which was validated with independent test samples. This decision-support tool performed well at the sub-estuary extent and provided the means to identify areas of concern and prioritize bay-wide sampling. PMID- 28738090 TI - Maternal 25(OH)D concentrations >=40 ng/mL associated with 60% lower preterm birth risk among general obstetrical patients at an urban medical center. AB - BACKGROUND: Given the high rate of preterm birth (PTB) nationwide and data from RCTs demonstrating risk reduction with vitamin D supplementation, the Medical University of South Carolina (MUSC) implemented a new standard of care for pregnant women to receive vitamin D testing and supplementation. OBJECTIVES: To determine if the reported inverse relationship between maternal 25(OH)D and PTB risk could be replicated at MUSC, an urban medical center treating a large, diverse population. METHODS: Medical record data were obtained for pregnant patients aged 18-45 years between September 2015 and December 2016. During this time, a protocol that included 25(OH)D testing at first prenatal visit with recommended follow-up testing was initiated. Free vitamin D supplements were offered and the treatment goal was >=40 ng/mL. PTB rates (<37 weeks) were calculated, and logistic regression and locally weighted regression (LOESS) were used to explore the association between 25(OH)D and PTB. Subgroup analyses were also conducted. RESULTS: Among women with a live, singleton birth and at least one 25(OH)D test during pregnancy (N = 1,064), the overall PTB rate was 13%. The LOESS curve showed gestational age rising with increasing 25(OH)D. Women with 25(OH)D >=40 ng/mL had a 62% lower risk of PTB compared to those <20 ng/mL (p<0.0001). After adjusting for socioeconomic variables, this lower risk remained (OR = 0.41, p = 0.002). Similar decreases in PTB risk were observed for PTB subtypes (spontaneous: 58%, p = 0.02; indicated: 61%, p = 0.006), by race/ethnicity (white: 65%, p = 0.03; non-white: 68%, p = 0.008), and among women with a prior PTB (80%, p = 0.02). Among women with initial 25(OH)D <40 ng/mL, PTB rates were 60% lower for those with >=40 vs. <40 ng/mL on a follow-up test (p = 0.006); 38% for whites (p = 0.33) and 78% for non-whites (p = 0.01). CONCLUSIONS: Maternal 25(OH)D concentrations >=40 ng/mL were associated with substantial reduction in PTB risk in a large, diverse population of women. PMID- 28738091 TI - The second window ICG technique demonstrates a broad plateau period for near infrared fluorescence tumor contrast in glioblastoma. AB - INTRODUCTION: Fluorescence-guided surgery has emerged as a powerful tool to detect, localize and resect tumors in the operative setting. Our laboratory has pioneered a novel way to administer an FDA-approved near-infrared (NIR) contrast agent to help surgeons with this task. This technique, coined Second Window ICG, exploits the natural permeability of tumor vasculature and its poor clearance to deliver high doses of indocyanine green (ICG) to tumors. This technique differs substantially from established ICG video angiography techniques that visualize ICG within minutes of injection. We hypothesized that Second Window ICG can provide NIR optical contrast with good signal characteristics in intracranial brain tumors over a longer period of time than previously appreciated with ICG video angiography alone. We tested this hypothesis in an intracranial mouse glioblastoma model, and corroborated this in a human clinical trial. METHODS: Intracranial tumors were established in 20 mice using the U251-Luc-GFP cell line. Successful grafts were confirmed with bioluminescence. Intravenous tail vein injections of 5.0 mg/kg (high dose) or 2.5 mg/kg (low dose) ICG were performed. The Perkin Elmer IVIS Spectrum (closed field) was used to visualize NIR fluorescence signal at seven delayed time points following ICG injection. NIR signals were quantified using LivingImage software. Based on the success of our results, human subjects were recruited to a clinical trial and intravenously injected with high dose 5.0 mg/kg. Imaging was performed with the VisionSense Iridium (open field) during surgery one day after ICG injection. RESULTS: In the murine model, the NIR signal-to-background ratio (SBR) in gliomas peaks at one hour after infusion, then plateaus and remains strong and stable for at least 48 hours. Higher dose 5.0 mg/kg improves NIR signal as compared to lower dose at 2.5 mg/kg (SBR = 3.5 vs. 2.8; P = 0.0624). Although early (<= 6 hrs) visualization of the Second Window ICG accumulation in gliomas is stronger than late (>=24 hrs) visualization (SBR = 3.94 vs. 2.32; p<0.05) there appears to be a long plateau period of stable ICG NIR signal accumulation within tumors in the murine model. We call this long plateau period the "Second Window" of ICG. In glioblastoma patients, the delayed visualization of intratumoral NIR signal was strong (SBR 7.50 +/- 0.74), without any significant difference within the 19 to 30 hour visualization window (R2 = 0.019). CONCLUSION: The Second Window ICG technique allows neurosurgeons to deliver NIR optical contrast agent to human glioblastoma patients, thus providing real-time tumor identification in the operating room. This nonspecific tumor accumulation of ICG within the tumor provides strong signal to background contrast, and is not significantly time dependent between 6 hours to 48 hours, providing a broad plateau for stable visualization. This finding suggests that optimal imaging of the "Second Window of ICG" may be within this plateau period, thus providing signal uniformity across subjects. PMID- 28738092 TI - The efficacy of Jianpi Yiqi therapy for chronic atrophic gastritis: A systematic review and meta-analysis. AB - Jianpi Yiqi therapy (JYT) is a classical therapy in treating chronic atrophic gastritis (CAG), but the clinical effects of it are still contentious. The purpose of this article is to evaluate the efficacy and safety of JYT for CAG. Seven electronic databases including PubMed, Embase, Springer Link, CNKI (China National Knowledge Infrastructure), VIP (Chinese Scientific Journals Database), Wan-fang database, and CBM (Chinese Biomedicine Database) were searched from their inception to November 1, 2016. 13 randomized controlled trials (RCTs) with a total of 1119 participants were identified for analysis. Meta-analyses demonstrated that both JYT (RR 1.41; 95% CI 1.27, 1.57; P < 0.00001) and JYT + western medicine (RR 1.27; 95% CI 1.17, 1.38; P < 0.00001) were more efficacious than only western medicine. Furthermore, JYT had potential improvement on traditional Chinese medicine (TCM) symptoms scores such as stomachache, stomach distention, belching, fatigue, et al. In addition, no serious adverse events were reported in the selected trials. The Cochrane Collaboration's risk of bias tool was evaluated for the weaknesses of methodological quality, while the quality level of Grades of Recommendations Assessment Development and Evaluation (GRADE) evidence classification indicated "Very low". This meta-analysis indicates that JYT may have potential effects on the treatment of patients with CAG. However, due to limitations of methodological quality and small sample size of the included studies, further standardized research of rigorous design should be needed. PMID- 28738094 TI - Has psychopharmacology entered a blind alley? PMID- 28738093 TI - Experience with a second language affects the use of fundamental frequency in speech segmentation. AB - This study investigates whether listeners' experience with a second language learned later in life affects their use of fundamental frequency (F0) as a cue to word boundaries in the segmentation of an artificial language (AL), particularly when the cues to word boundaries conflict between the first language (L1) and second language (L2). F0 signals phrase-final (and thus word-final) boundaries in French but word-initial boundaries in English. Participants were functionally monolingual French listeners, functionally monolingual English listeners, bilingual L1-English L2-French listeners, and bilingual L1-French L2-English listeners. They completed the AL-segmentation task with F0 signaling word-final boundaries or without prosodic cues to word boundaries (monolingual groups only). After listening to the AL, participants completed a forced-choice word identification task in which the foils were either non-words or part-words. The results show that the monolingual French listeners, but not the monolingual English listeners, performed better in the presence of F0 cues than in the absence of such cues. Moreover, bilingual status modulated listeners' use of F0 cues to word-final boundaries, with bilingual French listeners performing less accurately than monolingual French listeners on both word types but with bilingual English listeners performing more accurately than monolingual English listeners on non-words. These findings not only confirm that speech segmentation is modulated by the L1, but also newly demonstrate that listeners' experience with the L2 (French or English) affects their use of F0 cues in speech segmentation. This suggests that listeners' use of prosodic cues to word boundaries is adaptive and non-selective, and can change as a function of language experience. PMID- 28738095 TI - A clinically useful screen for attention-deficit/hyperactivity disorder in adult psychiatric outpatients. AB - BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a serious illness that is frequently underdiagnosed in adults. The goal of this report from the Rhode Island Methods to Improve Diagnostic Assessment and Services project was to determine if it was possible to identify 1 or 2 ADHD criteria that could serve as "gate" criteria to screen for the disorder. METHODS: Psychiatric outpatients (N = 1,134) were evaluated using a semi-structured diagnostic interview for DSM-IV criteria of ADHD. We computed the sensitivity, specificity, and positive and negative predictive values of each of the 18 ADHD criteria to identify 1 or 2 criteria that could be used to screen for the disorder. We conducted a validation and cross-validation analysis by splitting the sample in half. RESULTS: In both the validation and cross-validation samples, a 2-item screen of difficulty sustaining attention and fidgetiness had a sensitivity of >90%. The negative predictive value of the 2-item screen was >95%. CONCLUSIONS: Clinicians can screen for ADHD in adults by inquiring about 2 features of the disorder (ie, difficulty sustaining attention and fidgetiness), the presence of which captures most patients with the disorder and the absence of which rules out the disorder. PMID- 28738096 TI - The placebo effect and its clinical associations in gambling disorder. AB - BACKGROUND: Although gambling disorder is prevalent and functionally impairing, no FDA-approved medications exist for its treatment. The ability of clinical trials to detect the benefits of active treatment has been hindered by an unusually high placebo response. Virtually nothing is known about baseline clinical characteristics that might predict placebo response in those with gambling disorder. METHODS: Participants (N = 152) assigned to placebo were pooled from multiple double-blind trials of gambling disorder. Participants were classified as placebo responders or non-responders based on a cut-off of 35% reduction in symptom severity on the Gambling Symptom Assessment Scale. Baseline group differences were characterized using t tests and equivalent non-parametric tests as appropriate. RESULTS: Fifty-one percent of individuals assigned to placebo showed a significant clinical response. Compared with non-responders, placebo responders remained in treatment for significantly longer, were more likely to report "enjoyment" as a trigger for gambling, and were less likely to state that "boredom" or "loneliness" triggered their gambling. Placebo responders and non-responders did not differ significantly in age, sex, age at symptom onset, baseline symptom severity, comorbidities, or likelihood of having received a previous treatment. CONCLUSIONS: Predictors of placebo response for gambling disorder appear markedly different from those reported for other mental illnesses. PMID- 28738098 TI - Somatization disorder and somatoform symptoms in systematically studied survivors of 10 disasters. AB - BACKGROUND: There is little agreement about the association of somatization with exposure to disaster trauma in the existing literature. METHODS: Pre-disaster and post-disaster psychiatric disorders, somatization disorder, and individual somatoform (medically unexplained) symptoms were assessed with structured diagnostic interviews in 811 directly exposed survivors of 10 disasters. RESULTS: Only 1 individual met criteria for post-disaster somatization disorder; there were no incident cases. Only 21% of all somatic symptoms reported were somatoform symptoms. Although 29% of the sample had >=1 post-disaster somatoform symptoms, only 13% of the sample had any incident somatoform symptoms, and only 1.5% of the sample had >1. CONCLUSIONS: Somatization disorder is not an observed outcome of disaster. Incidence of individual somatoform symptoms is relatively uncommon and represents a construct that is distinct from somatization disorder. Such symptoms appear to represent nonspecific distress or endemic symptoms in the population and are not necessarily causally related to the disaster. The only studies that have identified somatization symptoms in relation to disaster have used nondiagnostic symptom checklists. As illustrated by the findings from this study, nondiagnostic symptom checklists do not adequately substitute for structured diagnostic instruments in assessment of somatoform psychopathology. PMID- 28738099 TI - A case series on the effectiveness of lurasidone in patients with stuttering. AB - BACKGROUND: The prevalence of stuttering is approximately 1% of the population, affecting an estimated 3 million individuals in the United States. The dopamine hypothesis of stuttering explains that abnormally increased cerebral dopamine affects the balanced levels that maintain the basal ganglia circuits, which helps with timing cues in initiating speech. This is especially significant when considering treatment strategies. We report a reduction in stuttering with lurasidone, a potent D2 receptor antagonist with a relatively favorable adverse effects profile. METHODS: We conducted a non-randomized, open-label study of lurasidone in patients with stuttering (N = 7). Patients self-reported stuttering severity, locus of control, and avoidance using the Subjective Screening of Stuttering (SSS) scale and were assessed with the Clinical Global Impression (CGI) Scale. RESULTS: We observed a notable, statistically significant improvement in all areas of stuttering, as rated by the SSS scale. According to the CGI-Improvement Scale, 2 patients were scored as "very much improved" and 5 were scored as "much improved." CONCLUSIONS: This open-label study of lurasidone in patients with stuttering showed improvement in subjective symptoms, in CGI scores, and on the SSS scale. PMID- 28738097 TI - Impact of obsessive-compulsive personality disorder symptoms in Internet users. AB - BACKGROUND: Internet use is pervasive in many cultures. Little is known about the impact of obsessive-compulsive personality disorder (OCPD) symptoms on impulsive and compulsive psychopathologies in people who use the Internet. METHODS: Adult Internet users (N = 1,323) completed an online questionnaire quantifying OCPD symptoms, likely occurrence of select mental disorders (obsessive-compulsive disorder, attention-deficit/hyperactivity disorder [ADHD], problematic Internet use, generalized anxiety disorder), and personality questionnaires of impulsivity and compulsivity. Predictors of the presence of OCPD symptoms (endorsement of at least 4 of 8 DSM-5 criteria) were identified using binary logistic regression. RESULTS: In regression (P < .001, area under the curve, 0.77), OCPD symptoms were significantly associated with (in order of decreasing effect size) lower non planning impulsivity, higher ADHD symptoms, problematic Internet use, avoidant personality disorder, female sex, generalized anxiety disorder, and some types of compulsions (checking, dressing/washing). CONCLUSIONS: These data suggest that OCPD symptoms, defined in terms of at least 4 of 8 DSM criteria being met, are common in Internet users. OCPD symptoms were associated with considerably higher levels of psychopathology relating to both impulsive (ADHD) and compulsive (OCD related and problematic Internet use) disorders. These data merit replication and extension using standard in-person clinical assessments, because the current study relied on self-report over the Internet. PMID- 28738100 TI - Multiple neurotoxic effects of haloperidol resulting in neuronal death. AB - BACKGROUND: Several published studies have reported an association between antipsychotic medications, especially first-generation agents, and a decline in gray matter volume. This prompted us to review the possible neurotoxic mechanisms of first-generation antipsychotics (FGAs), especially haloperidol, which has been widely used over the past several decades. METHODS: A PubMed search was conducted using the keywords haloperidol, antipsychotic, neurotoxicity, apoptosis, oxidative stress, and neuroplasticity. No restrictions were placed on the date of the articles or language. Studies with a clearly described methodology were included. RESULTS: Animal, cell culture, and human tissue studies were identified. Thirty reports met the criteria for the search. All studies included haloperidol; a few also included other FGAs (fluphenazine and perphenazine) and/or second-generation agents (SGAs) (aripiprazole, paliperidone, and risperidone). A neurotoxic effect of haloperidol and other FGAs was a common theme across all studies. Minimal (mainly at high doses) or no neurotoxic effects were noted in SGAs. CONCLUSIONS: A review of the literature suggests that haloperidol exerts measurable neurotoxic effects at all doses via many molecular mechanisms that lead to neuronal death. A similar effect was observed in 2 other FGAs, but the effect in SGAs was much smaller and occurred mainly at high doses. A stronger binding to serotonin 5HT-2A receptors than to dopamine D2 receptors may have a neuroprotective effect among SGAs. Further studies are warranted to confirm these findings. PMID- 28738102 TI - Anti-NMDA receptor encephalitis presenting as a primary psychotic disorder. PMID- 28738101 TI - Psychiatric symptoms associated with porphyria: A case report and brief review. PMID- 28738103 TI - Phobia with hallucinations and PTSD: Can amygdala dysfunction be a common unified lesion in the RDoC sense? PMID- 28738104 TI - Psychosocial Profiles of Temporomandibular Disorder Pain Patients: Proposal of a New Approach to Present Complex Data. AB - AIMS: To propose a visual method to screen and assess psychosocial functioning in temporomandibular disorder (TMD) pain patients in comparison with age- and gender matched healthy controls by forming individual profiles and to evaluate the association between psychosocial profiles and quantitative sensory testing (QST) findings of TMD pain patients. METHODS: TMD patients (n = 58) and control participants (n = 41) completed a set of questionnaires profiling their psychosocial function, and QST was performed at the temporomandibular joint (TMJ) on both sides of the face in all participants. Psychosocial parameters from the Research Diagnostic Criteria for TMD (RDC/TMD), Oral Health Impact Profile (OHIP), and Pain Catastrophizing Scale (PCS) instruments were transformed into T scores, and QST parameters were transformed into z scores based on reference data. Group differences for psychosocial T scores were analyzed with t tests. T scores of psychosocial parameters and z scores of QST parameters were correlated using Spearman's correlation (rho). RESULTS: Most (96.6%) TMD pain patients exhibited one or more parameters indicative of psychosocial distress, with psychological disability scores being the scores most frequently encountered outside the reference 95% confidence intervals (CI). TMD patients were psychosocially more distressed with regard to all psychosocial parameters compared with controls (P < .009). After Bonferroni corrections, a significant correlation was detected between the sleep dysfunction parameter and mechanical detection threshold (MDT) in TMD pain patients (rho = 0.427, P < .001). CONCLUSION: T score psychosocial profiles created an easy overview of psychosocial function in TMD pain patients. Increased sensitivity to tactile stimuli was associated with higher sleep dysfunction T scores. PMID- 28738105 TI - Psychosocial and Behavioral Aspects of Pain and Perception of Oral Health. AB - AIMS: To evaluate the contribution of the psychosocial and behavioral aspects of pain to the perception of oral health in a sample of Brazilian dental patients. METHODS: This cross-sectional study involved 436 patients who sought dental care in the School of Dentistry of Sao Paulo State University and who reported some type of orofacial pain. The study group's mean age (+/- standard deviation [SD]) was 39.9 +/- 13.6 years, and the sample was 74.5% female. The Portuguese version of the Oral Health Impact Profile Short Form (OHIP-14) and the Multidimensional Pain Inventory (MPI) were used. The data were included in a structural equation model in which perception of oral health was considered the dependent variable. The evaluation of the contribution of psychosocial and behavioral aspects of pain to the perception of oral health was based on the statistical significance of causal paths (beta) evaluated by z tests (alpha = 5%). RESULTS: The fit of the models of OHIP-14 and MPI were adequate. Interference, self-control, negative mood, and punishing responses provided significant contributions to the perception of oral health. The structural model presented adequate fit to the data (explained variance = 28.0%). CONCLUSION: These findings provide evidence that psychosocial and behavioral aspects of pain such as interference of pain in activities, self-control, negative mood, and punishing responses contribute to the perception of oral health. PMID- 28738106 TI - Predictors of Clinically Significant Outcome for Adolescents with Temporomandibular Disorders. AB - AIMS: To evaluate and identify baseline characteristics of the adolescent patients included in two previous randomized controlled trials (RCTs) that may predict a clinically significant outcome after treatment of temporomandibular disorders (TMD) with an occlusal appliance (OA) or relaxation training (RT) in a clinical sample of adolescents. METHODS: This study combined two patient samples from the earlier RCTs for a total of 167 adolescents with frequent TMD pain (once a week or more often), diagnosed according to the Research Diagnostic Criteria for TMD. They were treated with OA, RT, or received information only (control). Outcome (response to treatment vs nonresponse) was assessed using four measures: the Patient Global Impression of Change (PGIC), pain intensity rated on a numeric rating scale (NRS), pain frequency levels, and pain severity levels prospectively recorded in a pain diary. Predictors of outcome were evaluated posttreatment for the whole sample and at 6 months follow-up for participants from the first trial. Associations and differences between groups obtained in the bivariate analyses were further examined in subsequent multivariate logistic regression analyses. RESULTS: At posttreatment, treatment condition (OA being more effective than RT/control), gender (boys being more responsive than girls), arthralgia (predicting lower response), lower levels of somatic complaints (predicting better response), and shorter TMD pain history (predicting better response) emerged as significant predictors of a clinical response. At 6-month follow-up, lower consumption of analgesics and shorter TMD pain history emerged as significant predictors of treatment outcome, while treatment condition approached significance after multivariate analysis. CONCLUSION: This study revealed that treatment condition and gender were the most consistent predictors of a clinically significant outcome across outcome measures in a clinical sample of adolescents with TMD. Treatment with OA reduced TMD pain in the adolescents. PMID- 28738107 TI - Acupuncture in Temporomandibular Disorder Myofascial Pain Treatment: A Systematic Review. AB - AIMS: To carry out a systematic review of clinical trials published up to 2015 to determine the effectiveness of acupuncture in treating myofascial pain in temporomandibular disorder (TMD) patients. METHODS: The databases used were the Cochrane Library, PubMed, Scopus, and Web of Science; the dates of the articles surveyed ranged from 1990 to May 2015. The inclusion criteria were: (1) publications in English, Portuguese, or Spanish; (2) controlled clinical trials; (3) patients with TMD of muscular origin; and (4) studies that used acupuncture or laser acupuncture only for treatment. Reference lists of the included articles were hand searched. RESULTS: A total of four randomized clinical trials using acupuncture (traditional, trigger point, and laser) for TMD treatment met the eligibility criteria and were included. Although the studies featured small sample sizes and short-term follow-up periods, acupuncture yielded results similar to those observed in groups treated with occlusal splints and were significantly superior than those obtained from placebo acupuncture-treated groups. CONCLUSION: Despite the weak scientific evidence supporting its efficacy, acupuncture treatment appears to relieve the signs and symptoms of pain in myofascial TMD. More controlled and randomized clinical trials with larger sample sizes are needed in this field of research to verify these initial findings. PMID- 28738108 TI - Prevalence, Course, and Associated Factors of Pain in the Temporomandibular Joint in Early Rheumatoid Arthritis: Results of a Longitudinal Cohort Study. AB - AIMS: To assess the prevalence, 3-year course, and associated factors of temporomandibular joint (TMJ) pain in patients with newly diagnosed rheumatoid arthritis (RA). METHODS: A total of 264 patients with newly diagnosed RA were included. Patients were assessed after 3 months, 6 months, 9 months, 1 year, 1.5 years, 2 years, and 3 years. TMJ pain was scored by manual palpation, and the prevalence of TMJ pain was calculated at baseline and at all seven follow-up intervals during 3 years. Factors assessed for a potential association with TMJ pain at baseline included: demographic factors (gender and age), disease-related factors (symptom duration, rheumatoid factor [RF], anti-cyclic citrullinated protein [anti-CCP], C-reactive protein [CRP], and Disease Activity Score 28 [DAS28]), and functional factors (Health Assessment Questionnaire [HAQ] and European Quality of Life 5 Dimensions Questionnaire [EQ5D]-anxiety/depression). A stepwise logistic regression model was used to determine factors associated with TMJ pain in patients with RA. RESULTS: The prevalence of TMJ pain in patients with RA was 10.6% at baseline, which decreased to 3.6% in the first year after inclusion and remained stable thereafter. Disease activity as determined by the DAS28 was significantly associated with TMJ pain (odds ratio [OR] = 1.51; 95% confidence interval [95% CI] = 1.12-2.05; P = .009) at baseline. A second logistic regression analysis was performed with the following variables of the DAS28: erythrocyte sedimentation rate (ESR), tender joint count, swollen joint count, and global health. Tender joint count (OR = 1.06; 95% CI = 1.01-1.12; P = .03) and global health (OR = 1.02; 95% CI = 1.00-1.03; P = .03) were significantly associated with TMJ pain at baseline. The remaining factors included in the analysis were not significantly associated with TMJ pain at baseline. CONCLUSION: The prevalence of TMJ pain in patients with newly diagnosed RA is approximately 10% and decreases during follow-up, especially in the first year. Disease activity is a risk factor for TMJ pain in patients with newly diagnosed RA. PMID- 28738109 TI - Are Glucose and Insulin Metabolism and Diabetes Associated with Migraine? A Community-Based, Case-Control Study. AB - AIMS: To investigate the association between glucose and insulin metabolism and migraine, as well as between diabetes mellitus (DM) and migraine, at a Chinese community level. METHODS: A community-based, case-control study was performed in Heihe City, China. A survey was conducted door to door by eight trained investigators. Migraine was diagnosed using the International Classification of Headache Disorders (ICHD-III) beta criteria. A total of 2,023 participants completed a questionnaire, underwent a physical examination, and donated fasting blood. After excluding 191 with reported DM, 1,832 participants were included in the study. Of these, 86 participants with migraine and 95 without migraine participated in a 75-g oral glucose tolerance test. Glycosylated hemoglobin (HbA1c) was assessed at 0 minutes and serum glucose and insulin levels were measured at 0, 30, 60, and 120 minutes after glucose loading. Data with skewed distributions were compared using rank sum test, and the associations between DM and migraine were analyzed with logistic regression. RESULTS: There were no significant differences in HbA1c, homeostatic model assessment-insulin resistance (HOMA-IR), beta-cell function index of HOMA, or quantitative insulin sensitivity check index (QUICKI) between the participants with migraine and without migraine. When participants without migraine were classified into DM, prediabetes, and normal glucose subgroups and compared with the corresponding migraine subgroups, participants in the migraine subgroup with prediabetes presented higher levels of fasting insulin and HOMA-IR and a lower QUICKI than the nonmigraine subgroup with prediabetes. Moreover, DM was negatively associated with migraine in the 181 subjects who participated in the OGTT; however, no association was found when all 1,832 participants were considered. CONCLUSION: Insulin resistance seems to exist in individuals with both migraine and prediabetes, and there is a possible negative association between DM and migraine. PMID- 28738110 TI - Validation of the Korean Migraine-Specific Quality of Life Questionnaire Version 2.1 in Episodic and Chronic Migraine. AB - AIMS: To evaluate the validity of the Korean Migraine-Specific Quality of Life Questionnaire version 2.1 (K-MSQ v 2.1) in patients with episodic migraine (EM) or chronic migraine (CM). METHODS: Subjects were recruited from a headache clinic and completed several self-report instruments, including the K-MSQ v 2.1, the Migraine Disability Assessment Scale (MIDAS), the Headache Impact Test-6 (HIT-6), the Migraine-Specific Quality of Life (MSQoL), the Patient Health Questionnaire-9 (PHQ-9), and the Generalized Anxiety Disorder-7 (GAD-7). Some of the subjects were assessed 4 weeks later and underwent the K-MSQ v 2.1 to examine test-retest reproducibility. Internal consistency and test-retest reproducibility were assessed to determine reliability. Construct validity was also assessed. Internal consistency (Cronbach's alpha) and test-retest reproducibility (intraclass correlation coefficients) were assessed to determine reliability. Pearson correlations were used to determine the validity. RESULTS: For the 180 eligible patients, the value of Cronbach's alpha for the three dimensions of the K-MSQ v. 2.1 (Role Function-Restrictive, Role Function-Preventive, and Emotional Function) were 0.954, 0.909, and 0.898, respectively, indicating excellent internal consistency. The intraclass correlation coefficients between baseline and the 4 week retest showed reliable reproducibility. The scores of the three dimensions for the K-MSQ v. 2.1 were well correlated with scores for the MIDAS, the HIT-6, the MSQoL, the PHQ-9, and the GAD-7. Internal consistency and construct validity showed similar tendencies in patients with EM and those with CM. CONCLUSION: The K-MSQ v 2.1 is a reliable and valid screening tool for evaluating QoL in patients with EM and CM. PMID- 28738111 TI - Topical Clonazepam Solution for the Management of Burning Mouth Syndrome: A Retrospective Study. AB - AIMS: To evaluate and compare the effectiveness of two concentrations of topical clonazepam solution in improving symptoms of burning mouth syndrome (BMS). METHODS: A retrospective chart review was conducted of patients diagnosed with BMS and managed with topical clonazepam solution between 2008 and 2015. A 0.5 mg/mL solution was prescribed until 2012, when this was changed to a 0.1 mg/mL solution. Patients were instructed to swish with 5 mL for 5 minutes and spit two to four times daily. The efficacies of the two concentrations were compared using patient-reported outcome measures at the first follow-up, including the reported percentage of improvement in burning symptoms and the change in burning severity from baseline ranked on an 11-point numeric rating scale (NRS). Response to treatment was compared between the two concentrations using Wilcoxon rank sum test. RESULTS: A total of 57 subjects were included, 32 in the 0.1-mg/mL cohort and 25 in the 0.5-mg/mL cohort, and evaluated at a median follow-up of 7 weeks. The median overall percentage improvement was 32.5% in the 0.1-mg/mL cohort and 75% in the 0.5-mg/mL cohort. The median reduction in NRS score was 0.5 points in the 0.1-mg/mL cohort and 6 points in the 0.5-mg/mL cohort. The use of either outcome measure revealed that the response to treatment with the 0.5-mg/mL solution was superior to that of the 0.1 mg/mL solution (P < .01). CONCLUSION: These findings suggest that a 0.5-mg/mL topical clonazepam solution is effective in the management of BMS. Future randomized clinical trials are warranted. PMID- 28738113 TI - Estrogen Status Gates Effects of Kappa-Opioid Receptor on Temporomandibular Joint Responsive Neurons at the Spinomedullary Junction in Female Rats. AB - AIMS: To determine whether estrogen status alters kappa-opioid inhibition of nociceptive processing by affecting temporomandibular joint (TMJ) input to neurons in the trigeminal subnucleus caudalis [Vc]/C1-2 region at the spinomedullary junction in female rats. METHODS: TMJ-responsive neurons were recorded in laminae I-II of the Vc/C1-2 region at the spinomedullary junction of ovariectomized female rats treated for 2 days with low-dose estradiol (LE group; 2 mg/day) or high-dose estradiol (HE group; 20 mg/day). Under isoflurane anesthesia, TMJ neurons were activated by adenosine triphosphate (ATP; 1 mM, 20 MUl), which was injected into the joint space before and after cumulative doses of a kappa-opioid receptor (KOR) agonist (U50488) given systemically (0.03, 0.3, and 3 mg/kg, intravenously) or by local application to the dorsal surface of the Vc/C1-2 region (1 and 10 nmol/30 MUl). Analysis of variance and Newman-Keuls test were performed to compare the data. RESULTS: Systemic U50488 caused a dose related inhibition of ATP-evoked neuronal activity in HE rats and reduced the size of the neuronal cutaneous receptive field (RF), while effects in LE rats were not significant. Systemic U50488 reduced the spontaneous activity of TMJ responsive neurons to similar levels in LE and HE groups. Locally applied U50488 inhibited ATP-evoked neuronal activity in HE rats, but not in LE rats. Systemic and local administration of the KOR antagonist nor-binaltorphinine (nor-BNI) partially reversed the decrease in Rmag induced by U50488, but had no effect on neurons from LE rats. CONCLUSION: These results indicate that KOR-dependent effects on TMJ-responsive neurons in the superficial laminae of the Vc/C1-2 region in female rats are differentially modified by high and low estrogen status. The site of action for estrogen-induced modulation of TMJ neuronal activity by KOR likely includes second-order neurons in the Vc/C1-2 region. PMID- 28738114 TI - I-SPY 2 Breast Cancer Trial as a Model for Innovation in Alzheimer Disease Therapies. PMID- 28738112 TI - Central Role of Protein Kinase A in Promoting Trigeminal Nociception in an In Vivo Model of Temporomandibular Disorders. AB - AIMS: To investigate cellular changes in the spinal trigeminal nucleus (STN) and trigeminal ganglion (TG) associated with trigeminal nociception mediated by inflammation in the temporomandibular joint (TMJ). METHODS: Male Sprague-Dawley rats (n = 86) were utilized to investigate cellular and behavioral responses to prolonged TMJ inflammation caused by bilateral injection of Complete Freund's Adjuvant (CFA) in the TMJ capsules. To investigate the cellular effects of protein kinase A (PKA) in the STN, rats were injected intrathecally with the selective PKA inhibitor KT5720 prior to injection of CFA into both TMJ capsules. Levels of calcitonin gene-related peptide (CGRP), active PKA, and ionized calcium binding adapter molecule 1 (Iba1) in the STN and expression of phosphorylated extracellular regulated kinases (p-ERK) in the TG were determined with immunohistochemistry (n >= 3 experiments per test condition). Nocifensive head withdrawal responses to mechanical stimulation of the cutaneous tissue over the TMJ were monitored following CFA injection in the absence or presence of KT5720 (n = 7). Statistical analysis was performed using parametric analysis of variance (ANOVA) tests. RESULTS: Intrathecal injection of KT5720 significantly inhibited the stimulatory effect of CFA on levels of CGRP, PKA, and Iba1 in the STN. In addition, administration of KT5720 decreased the average number of CFA-induced nocifensive withdrawal responses to mechanical stimulation and the CFA-mediated increase in p-ERK expression in the ganglion. CONCLUSION: These findings provide evidence that elevated PKA activity in the STN promotes cellular events temporally associated with trigeminal nociception caused by prolonged TMJ inflammation. PMID- 28738115 TI - Inconsistent Guideline Recommendations for Cardiovascular Prevention and the Debate About Zeroing in on and Zeroing LDL-C Levels With PCSK9 Inhibitors. PMID- 28738116 TI - Inclusion of Demographic-Specific Information in Studies Supporting US Food & Drug Administration Approval of High-Risk Medical Devices. PMID- 28738117 TI - Shining (Laser) Light on Traumatic Brain Injury Blood Biomarkers. PMID- 28738119 TI - Error in Figure Titles. PMID- 28738118 TI - Early Orthostatic Hypotension and Orthostatic Intolerance-More Than an Observation or Annoyance. PMID- 28738120 TI - Is Pediatric Long-term Care the Next Frontier in Infection Prevention and Control? PMID- 28738122 TI - A Survey of Unregulated Direct-to-Consumer Treatment Centers Providing Stem Cells for Patients With Heart Failure. PMID- 28738121 TI - Incidence, Risks, and Types of Infections in Pediatric Long-term Care Facilities. AB - Importance: The population of infants, children, and adolescents cared for at pediatric long-term care facilities is increasing in complexity and size and thus consumes substantial health care resources. Infections are a significant cause of morbidity and mortality in this population, but few recent data describe their incidence and effects. Objectives: To describe the types of infections diagnosed in residents of pediatric long-term care facilities, calculate infection rates, and identify risk factors for respiratory tract infections (RTIs). Design, Setting, and Participants: This prospective cohort study, which was part of a larger trial called Keep It Clean for Kids, was conducted from September 1, 2012, to December 31, 2015, at 3 pediatric long-term care facilities in New York. Residents of the facilities who were 21 years or younger and either residents or admitted during the study period (n = 717) were enrolled in the study. Medical records were reviewed to identify infections diagnosed by site clinicians. Main Outcomes and Measures: Incidence of infections, such as RTIs; skin and soft tissue infections; chronic comorbid conditions, including neurologic and respiratory disorders; and device use, including gastrostomy tubes and tracheostomies, was determined. Risk factors for RTIs were assessed by generalized linear mixed method regression modeling. Results: The 717 residents had a median (interquartile range) age at enrollment of 2.6 (0.4-9.1) years; 358 (49.9%) were male. Four hundred twenty-eight residents (59.7%) had feeding tubes and 215 (30.0%) had tracheostomies. Most chronic comorbid conditions were musculoskeletal or ambulation (532 residents [74.2%]), neurologic (505 [70.4%]), respiratory (361 [50.3%]), and gastrointestinal (230 [32.1%]) disorders, and 460 residents (64.2%) had 4 or more chronic comorbid conditions. Site clinicians diagnosed 2052 infections during the 3-year study period. Respiratory tract infections were most common and were diagnosed in 1291 residents (62.9%). The overall infection rate was 5.3 infections per 1000 resident-days, and RTI rates were 3.3 infections per 1000 resident-days. Overall infection rates and rates of RTI, skin and soft-tissue infection, urinary tract infection, and bloodstream infection varied among the 3 sites. In the multivariable model, younger age (incidence rate ratio [IRR], 1.05; 95% CI, 1.03-1.06), increased number of chronic comorbid conditions (IRR, 1.12; 95% CI, 1.06-1.19), and the use of feeding tubes (IRR, 1.34; 95% CI, 1.03-1.64) and tracheostomies (IRR, 1.40; 95% CI, 1.17-1.69) were associated with RTIs. Conclusions and Relevance: In this study, RTIs were the most common infections diagnosed, but modifiable risk factors for RTIs were not identified. Future work should focus on optimizing infection prevention and control strategies to reduce infections, particularly RTIs, in the pediatric long-term care population. PMID- 28738123 TI - Legalization of Same-Sex Marriage and Drop in Adolescent Suicide Rates: Association But Not Causation-Reply. PMID- 28738124 TI - Incorrect P Values in Results Section. PMID- 28738125 TI - Legalization of Same-Sex Marriage and Drop in Adolescent Suicide Rates: Association but Not Causation. PMID- 28738129 TI - Nontraditional Diagnoses in Minority Populations: White Disease, Brown Body. PMID- 28738128 TI - Possible Device Malfunction in a Dual-Chamber Pacemaker. PMID- 28738126 TI - Comparing Plasma Phospho Tau, Total Tau, and Phospho Tau-Total Tau Ratio as Acute and Chronic Traumatic Brain Injury Biomarkers. AB - Importance: Annually in the United States, at least 3.5 million people seek medical attention for traumatic brain injury (TBI). The development of therapies for TBI is limited by the absence of diagnostic and prognostic biomarkers. Microtubule-associated protein tau is an axonal phosphoprotein. To date, the presence of the hypophosphorylated tau protein (P-tau) in plasma from patients with acute TBI and chronic TBI has not been investigated. Objective: To examine the associations between plasma P-tau and total-tau (T-tau) levels and injury presence, severity, type of pathoanatomic lesion (neuroimaging), and patient outcomes in acute and chronic TBI. Design, Setting, and Participants: In the TRACK-TBI Pilot study, plasma was collected at a single time point from 196 patients with acute TBI admitted to 3 level I trauma centers (<24 hours after injury) and 21 patients with TBI admitted to inpatient rehabilitation units (mean [SD], 176.4 [44.5] days after injury). Control samples were purchased from a commercial vendor. The TRACK-TBI Pilot study was conducted from April 1, 2010, to June 30, 2012. Data analysis for the current investigation was performed from August 1, 2015, to March 13, 2017. Main Outcomes and Measures: Plasma samples were assayed for P-tau (using an antibody that specifically recognizes phosphothreonine-231) and T-tau using ultra-high sensitivity laser-based immunoassay multi-arrayed fiberoptics conjugated with rolling circle amplification. Results: In the 217 patients with TBI, 161 (74.2%) were men; mean (SD) age was 42.5 (18.1) years. The P-tau and T-tau levels and P-tau-T-tau ratio in patients with acute TBI were higher than those in healthy controls. Receiver operating characteristic analysis for the 3 tau indices demonstrated accuracy with area under the curve (AUC) of 1.000, 0.916, and 1.000, respectively, for discriminating mild TBI (Glasgow Coma Scale [GCS] score, 13-15, n = 162) from healthy controls. The P-tau level and P-tau-T-tau ratio were higher in individuals with more severe TBI (GCS, <=12 vs 13-15). The P-tau level and P-tau T-tau ratio outperformed the T-tau level in distinguishing cranial computed tomography-positive from -negative cases (AUC = 0.921, 0.923, and 0.646, respectively). Acute P-tau levels and P-tau-T-tau ratio weakly distinguished patients with TBI who had good outcomes (Glasgow Outcome Scale-Extended GOS-E, 7 8) (AUC = 0.663 and 0.658, respectively) and identified those with poor outcomes (GOS-E, <=4 vs >4) (AUC = 0.771 and 0.777, respectively). Plasma samples from patients with chronic TBI also showed elevated P-tau levels and a P-tau-T-tau ratio significantly higher than that of healthy controls, with both P-tau indices strongly discriminating patients with chronic TBI from healthy controls (AUC = 1.000 and 0.963, respectively). Conclusions and Relevance: Plasma P-tau levels and P-tau-T-tau ratio outperformed T-tau level as diagnostic and prognostic biomarkers for acute TBI. Compared with T-tau levels alone, P-tau levels and P tau-T-tau ratios show more robust and sustained elevations among patients with chronic TBI. PMID- 28738130 TI - Treatment of Cholesterol in 2017. PMID- 28738127 TI - Early-Onset Alzheimer Disease and Candidate Risk Genes Involved in Endolysosomal Transport. AB - Importance: Mutations in APP, PSEN1, and PSEN2 lead to early-onset Alzheimer disease (EOAD) but account for only approximately 11% of EOAD overall, leaving most of the genetic risk for the most severe form of Alzheimer disease unexplained. This extreme phenotype likely harbors highly penetrant risk variants, making it primed for discovery of novel risk genes and pathways for AD. Objective: To search for rare variants contributing to the risk for EOAD. Design, Setting, and Participants: In this case-control study, whole-exome sequencing (WES) was performed in 51 non-Hispanic white (NHW) patients with EOAD (age at onset <65 years) and 19 Caribbean Hispanic families previously screened as negative for established APP, PSEN1, and PSEN2 causal variants. Participants were recruited from John P. Hussman Institute for Human Genomics, Case Western Reserve University, and Columbia University. Rare, deleterious, nonsynonymous, or loss-of function variants were filtered to identify variants in known and suspected AD genes, variants in multiple unrelated NHW patients, variants present in 19 Hispanic EOAD WES families, and genes with variants in multiple unrelated NHW patients. These variants/genes were tested for association in an independent cohort of 1524 patients with EOAD, 7046 patients with late-onset AD (LOAD), and 7001 cognitively intact controls (age at examination, >65 years) from the Alzheimer's Disease Genetics Consortium. The study was conducted from January 21, 2013, to October 13, 2016. Main Outcomes and Measures: Alzheimer disease diagnosed according to standard National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer Disease and Related Disorders Association criteria. Association between Alzheimer disease and genetic variants and genes was measured using logistic regression and sequence kernel association test-optimal gene tests, respectively. Results: Of the 1524 NHW patients with EOAD, 765 (50.2%) were women and mean (SD) age was 60.0 (4.9) years; of the 7046 NHW patients with LOAD, 4171 (59.2%) were women and mean (SD) age was 77.4 (8.6) years; and of the 7001 NHW controls, 4215 (60.2%) were women and mean (SD) age was 77.4 (8.6) years. The gene PSD2, for which multiple unrelated NHW cases had rare missense variants, was significantly associated with EOAD (P = 2.05 * 10-6; Bonferroni-corrected P value [BP] = 1.3 * 10-3) and LOAD (P = 6.22 * 10-6; BP = 4.1 * 10-3). A missense variant in TCIRG1, present in a NHW patient and segregating in 3 cases of a Hispanic family, was more frequent in EOAD cases (odds ratio [OR], 2.13; 95% CI, 0.99-4.55; P = .06; BP = 0.413), and significantly associated with LOAD (OR, 2.23; 95% CI, 1.37-3.62; P = 7.2 * 10-4; BP = 5.0 * 10-3). A missense variant in the LOAD risk gene RIN3 showed suggestive evidence of association with EOAD after Bonferroni correction (OR, 4.56; 95% CI, 1.26-16.48; P = .02, BP = 0.091). In addition, a missense variant in RUFY1 identified in 2 NHW EOAD cases showed suggestive evidence of an association with EOAD as well (OR, 18.63; 95% CI, 1.62-213.45; P = .003; BP = 0.129). Conclusions and Relevance: The genes PSD2, TCIRG1, RIN3, and RUFY1 all may be involved in endolysosomal transport-a process known to be important to development of AD. Furthermore, this study identified shared risk genes between EOAD and LOAD similar to previously reported genes, such as SORL1, PSEN2, and TREM2. PMID- 28738131 TI - Wellness for Families of Children With Chronic Health Disorders. PMID- 28738132 TI - No Wonder No One Trusts Us. PMID- 28738133 TI - Sharing Knowledge for Health Care. PMID- 28738134 TI - Indocyanine Green Angiography and Optical Coherence Tomography Angiography of Choroidal Neovascularization in Age-Related Macular Degeneration. AB - Purpose: To compare the capability of indocyanine green angiography (ICGA) and optical coherence tomography angiography (OCTA) in detecting choroidal neovascularization (CNV). Methods: In this prospective study, patients with CNV detected with fluorescein angiography (FA) underwent ICGA and OCTA, spectral domain OCT (SD-OCT), and infrared or fundus color photographs. CNV lesions were outlined on ICGA and OCTA images, and the composition and size of the CNV was documented. Results: One hundred eighty-two eyes were included. With ICGA, well defined lesions were observed in 37.9%, partly defined in 44.5%, and undefined in 17% of eyes. On OCTA, well-defined, partly defined, and undefined vessels were observed in 53.8%, 27.5%, and 18.7% of eyes, respectively. There was a good correlation between CNV size measured with the two instruments (r = 0.84). However, OCTA underestimated CNV area by about 4.5% (slope coefficient with linear regression: 0.55, 95% confidence interval [CI]: 0.46 to 0.65; intercept: 0.27, 95% CI: -0.2 to 0.56). On ICGA, CNV composition was capillary in 28%, mature in 14.3%, and mixed (capillary and major neovascular complex) in 57.7% of eyes. Similarly, OCTA revealed capillary, mature, and mixed CNV in 28.9%, 15.9%, and 55.5% of eyes, respectively. Conclusions: OCTA provides the clinician the ability to perform precise structural and vascular assessment of CNV noninvasively. Our study is, to our knowledge, the largest OCTA analysis to date of CNV secondary to neovascular AMD analyzed simultaneously by ICGA and OCTA. PMID- 28738135 TI - Development of a Shortened Version of the Spatial Hearing Questionnaire (SHQ-S) for Screening Spatial-Hearing Ability. AB - Purpose: The Spatial Hearing Questionnaire (SHQ) was developed to address how to measure spatial-hearing ability in complex listening situations (Tyler, Perreau, & Ji, 2009). It has been translated and validated into various languages, including Chinese, Dutch, French, and Persian. Although the SHQ contains only 24 items, it could be time-consuming in a busy clinic to administer. The purposes of this study were to develop and validate a shortened version of the SHQ (SHQ-S) and to compare self-perceived spatial-hearing ability across adults with normal hearing (NH), hearing loss (HL), and cochlear implants (CIs). Method: This was a retrospective study. The full version of the SHQ was administered to measure self perceived spatial-hearing ability for 51 adults with NH at Augustana College, 47 adults with essentially mild to moderately severe sensorineural HL at Illinois State University, and 72 adult CI users at the University of Iowa. Exploratory factor analysis was performed for the full version for the data collected from adults with NH and HL. Appropriate items were chosen to develop the SHQ-S from the results of the exploratory factor analysis. Confirmatory factor analysis was then applied to test the factor structure of the SHQ-S for all participants. One way analysis of variance was used to compare the self-perceived spatial-hearing performance scores between the 3 groups. Results: The exploratory factor analysis revealed scores loaded on 2 factors. Six items from the full version were chosen accordingly. The results of the confirmatory factor analysis indicated that that a shortened version of 6 items is sufficient to measure spatial-hearing ability. The internal consistency reliability of the SHQ-S was high. The main effect of the one-way analysis of variance was significant for the groups, F(2, 167) = 36.0, p < .0001. The comparisons with the Tukey adjustment indicated that the NH group reported significantly better spatial-hearing ability than either the HL or the CI group (both adjusted p values < .05). There was no significant difference between the participants with HL and CI users. Conclusions: The psychometric characteristics of the 6-item SHQ-S were similar to those of the full version of the SHQ. We conclude that the SHQ-S is a reliable and valid tool for measuring spatial-hearing ability and screening for spatial-hearing difficulties. Participants with NH reported better spatial-hearing ability than those with HL or with CIs, whereas the CI users and participants with HL perceived similar spatial-hearing ability in the present study. PMID- 28738136 TI - Key Word Signing Usage of Adults With Intellectual Disabilities: Influence of Communication Partners' Sign Usage and Responsivity. AB - Purpose: In services for adults with intellectual disabilities, various staff members may have different key word signing (KWS) skills and conversational style. Little is known about how these clients use KWS with different staff members. Therefore, we observed staff-client conversations and examined how clients' KWS usage was shaped by staff members' KWS usage and conversational style. Method: Three 10-min dyadic conversations between an adult with moderate or severe intellectual disabilities (N = 15) and three familiar staff members were filmed and transcribed. The KWS usage and conversational responsivity in the transcriptions was analyzed at group (using generalized estimating equations), subgroup, and individual levels. Results: Clients appeared to produce significantly more KWS as partners imitated more signs and as partners were more responsive. There was a negative interaction between these two factors. Subgroup analyses showed that spontaneity of clients' KWS usage was a continuum. Conclusion: Findings suggest that staff can encourage clients' KWS usage by imitating manual signs but that clients' response efficiency should also be taken into account. PMID- 28738137 TI - Public Health and Economic Consequences of Vaccine Hesitancy for Measles in the United States. AB - Importance: Routine childhood vaccination is declining in some regions of the United States due to vaccine hesitancy, which risks the resurgence of many infectious diseases with public health and economic consequences. There are ongoing policy debates on the state and national level, including legislation around nonmedical (personal-belief) exemptions for childhood vaccination and possibly a special government commission on vaccine safety, which may affect vaccine coverage. Objective: To estimate the number of measles cases in US children and the associated economic costs under scenarios of different levels of vaccine hesitancy, using the case example of measles, mumps, and rubella (MMR) vaccination and measles. Design, Setting, and Participants: Publicly available data from the US Centers for Disease Control and Prevention were used to simulate county-level MMR vaccination coverage in children (age 2-11 years) in the United States. A stochastic mathematical model was adapted for infectious disease transmission that estimated a distribution for outbreak size as it relates to vaccine coverage. Economic costs per measles case were obtained from the literature. The predicted effects of increasing the prevalence of vaccine hesitancy as well as the removal of nonmedical exemptions were estimated. The model was calibrated to annual measles cases in US children over recent years, and the model prediction was validated using an independent data set from England and Wales. Main Outcomes and Measures: Annual measles cases in the United States and the associated public sector costs. Results: A 5% decline in MMR vaccine coverage in the United States would result in an estimated 3-fold increase in measles cases for children aged 2 to 11 years nationally every year, with an additional $2.1 million in public sector costs. The numbers would be substantially higher if unvaccinated infants, adolescents, and adult populations were also considered. There was variation around these estimates due to the stochastic elements of measles importation and sensitivity of some model inputs, although the trend was robust. Conclusions and Relevance: This analysis predicts that even minor reductions in childhood vaccination, driven by vaccine hesitancy (nonmedical and personal belief exemptions), will have substantial public health and economic consequences. The results support an urgent need to address vaccine hesitancy in policy dialogues at the state and national level, with consideration of removing personal belief exemptions of childhood vaccination. PMID- 28738138 TI - Vocabulary Facilitates Speech Perception in Children With Hearing Aids. AB - Purpose: We examined the effects of vocabulary, lexical characteristics (age of acquisition and phonotactic probability), and auditory access (aided audibility and daily hearing aid [HA] use) on speech perception skills in children with HAs. Method: Participants included 24 children with HAs and 25 children with normal hearing (NH), ages 5-12 years. Groups were matched on age, expressive and receptive vocabulary, articulation, and nonverbal working memory. Participants repeated monosyllabic words and nonwords in noise. Stimuli varied on age of acquisition, lexical frequency, and phonotactic probability. Performance in each condition was measured by the signal-to-noise ratio at which the child could accurately repeat 50% of the stimuli. Results: Children from both groups with larger vocabularies showed better performance than children with smaller vocabularies on nonwords and late-acquired words but not early-acquired words. Overall, children with HAs showed poorer performance than children with NH. Auditory access was not associated with speech perception for the children with HAs. Conclusions: Children with HAs show deficits in sensitivity to phonological structure but appear to take advantage of vocabulary skills to support speech perception in the same way as children with NH. Further investigation is needed to understand the causes of the gap that exists between the overall speech perception abilities of children with HAs and children with NH. PMID- 28738141 TI - Quantification of Chemical and Mechanical Effects on the Formation of the G Quadruplex and i-Motif in Duplex DNA. AB - The formation of biologically significant tetraplex DNA species, such as G quadruplexes and i-motifs, is affected by chemical (ions and pH) and mechanical [superhelicity (sigma) and molecular crowding] factors. Because of the extremely challenging experimental conditions, the relative importance of these factors on tetraplex folding is unknown. In this work, we quantitatively evaluated the chemical and mechanical effects on the population dynamics of DNA tetraplexes in the insulin-linked polymorphic region using magneto-optical tweezers. By mechanically unfolding individual tetraplexes, we found that ions and pH have the largest effects on the formation of the G-quadruplex and i-motif, respectively. Interestingly, superhelicity has the second largest effect followed by molecular crowding conditions. While chemical effects are specific to tetraplex species, mechanical factors have generic influences. The predominant effect of chemical factors can be attributed to the fact that they directly change the stability of a specific tetraplex, whereas the mechanical factors, superhelicity in particular, reduce the stability of the competing species by changing the kinetics of the melting and annealing of the duplex DNA template in a nonspecific manner. The substantial dependence of tetraplexes on superhelicity provides strong support that DNA tetraplexes can serve as topological sensors to modulate fundamental cellular processes such as transcription. PMID- 28738140 TI - High prevalence of subclinical cerebral infarction in patients with heart failure with preserved ejection fraction. AB - AIMS: Undetected atrial fibrillation (AF) may be common in the heart failure with preserved ejection fraction (HFpEF) population, and failure to detect this may lead to the missing of opportunities to prevent associated subclinical cerebral infarctions (SCIs) and cognitive decline. METHODS AND RESULTS: We studied 1527 participants in the Atherosclerosis Risk in Communities (ARIC) Study, who underwent echocardiography, brain magnetic resonance imaging (MRI) and detailed cognitive assessment during 2011-13. Prevalences of SCI as detected by brain MRI were compared among the following groups: participants with no HFpEF/no AF; those with no HFpEF/AF; those with HFpEF/no AF, and those with HFpEF/AF. Cognitive scores were also compared. Prevalences of HFpEF and AF in this sample were 13.2% and 5.7%, respectively. Participants with HFpEF but no prior diagnosis of AF had a high prevalence of SCI by brain MRI (29.3%), which was similar to those in the no HFpEF/AF (24.5%) and HFpEF/AF (23.5%) groups, but higher than that in the no HFpEF/no AF subjects (17.3%). The odds of having SCI were higher in participants with HFpEF/no AF than in the no HFpEF/no AF group even after adjustment for potential confounders (odds ratio 1.56, 95% confidence interval 1.06-2.30). Individuals with HFpEF and SCI had lower cognitive scores than the reference (no HFpEF/no SCI) and HFpEF/no SCI groups. CONCLUSIONS: Subclinical cerebral infarctions were prevalent in subjects in the ARIC cohort with HFpEF and no prior AF diagnosis and are associated with measurable cognitive deficits. Although other sources of emboli may be possible, these data suggest that paroxysmal AF may be underdiagnosed in this population. There may be a role for earlier anticoagulation in patients with HFpEF. PMID- 28738142 TI - Metabolomics Reveals Cu(OH)2 Nanopesticide-Activated Anti-oxidative Pathways and Decreased Beneficial Antioxidants in Spinach Leaves. AB - While the use of nanopesticides in modern agriculture continues to increase, their effects on crop plants are still poorly understood. Here, 4 week old spinach plants grown in an artificial medium were exposed via foliar spray to Cu(OH)2 nanopesticide (0.18 and 18 mg/plant) or Cu ions (0.15 and 15 mg/plant) for 7 days. A gas chromatography-time-of-flight-mass spectrometry metabolomics approach was applied to assess metabolic alterations induced by Cu(OH)2 nanopesticide in spinach leaves. Exposure to Cu(OH)2 nanopesticide and copper ions induced alterations in the metabolite profiles of spinach leaves. Compared to the control, exposure to 18 mg of Cu(OH)2 nanopesticide induced significant reduction (29-85%) in antioxidant or defense-associated metabolites including ascorbic acid, alpha-tocopherol, threonic acid, beta-sitosterol, 4-hydroxybutyric acid, ferulic acid, and total phenolics. The metabolic pathway for ascorbate and aldarate was disturbed in all exposed spinach plants (nanopesticide and Cu2+). Cu2+ is responsible for the reduction in antioxidants and perturbation of the ascorbate and aldarate metabolism. However, nitrogen metabolism perturbation was nanopesticide-specific. Spinach biomass and photosynthetic pigments were not altered, indicating that metabolomics can be a rapid and sensitive tool for the detection og earlier nanopesticide effects. Consumption of antioxidants during the antioxidant defense process resulted in reduction of the nutritional value of exposed spinach. PMID- 28738139 TI - Association of History of Dizziness and Long-term Adverse Outcomes With Early vs Later Orthostatic Hypotension Assessment Times in Middle-aged Adults. AB - Importance: Guidelines recommend assessing orthostatic hypotension (OH) 3 minutes after rising from supine to standing positions. It is not known whether measurements performed immediately after standing predict adverse events as strongly as measurements performed closer to 3 minutes. Objective: To compare early vs later OH measurements and their association with history of dizziness and longitudinal adverse outcomes. Design, Setting, and Participants: This was a prospective cohort study of middle-aged (range, 44-66 years) participants in the Atherosclerosis Risk in Communities Study (1987-1989). Exposures: Orthostatic hypotension, defined as a drop in blood pressure (BP) (systolic BP >=20 mm Hg or diastolic BP >=10 mm Hg) from the supine to standing position, was measured up to 5 times at 25-second intervals. Main Outcomes and Measures: We determined the association of each of the 5 OH measurements with history of dizziness on standing (logistic regression) and risk of fall, fracture, syncope, motor vehicle crashes, and all-cause mortality (Cox regression) over a median of 23 years of follow-up (through December 31, 2013). Results: In 11 429 participants (mean age, 54 years; 6220 [54%] were women; 2934 [26%] were black) with at least 4 OH measurements after standing, after adjustment OH assessed at measurement 1 (mean [SD], 28 [5.4] seconds; range, 21-62 seconds) was the only measurement associated with higher odds of dizziness (odds ratio [OR], 1.49; 95% CI, 1.18-1.89). Measurement 1 was associated with the highest rates of fracture, syncope, and death at 18.9, 17.0, and 31.4 per 1000 person-years. Measurement 2 was associated with the highest rate of falls and motor vehicle crashes at 13.2 and 2.5 per 1000 person-years. Furthermore, after adjustment measurement 1 was significantly associated with risk of fall (hazard ratio [HR], 1.22; 95% CI, 1.03-1.44), fracture (HR, 1.16; 95% CI, 1.01-1.34), syncope (HR, 1.40; 95% CI, 1.20-1.63), and mortality (HR, 1.36; 95% CI, 1.23-1.51). Measurement 2 (mean [SD], 53 [7.5] seconds; range, 43-83 seconds) was associated with all long-term outcomes, including motor vehicle crashes (HR, 1.43; 95% CI, 1.04-1.96). Measurements obtained after 1 minute were not associated with dizziness and were inconsistently associated with individual long-term outcomes. Conclusions and Relevance: In contrast with prevailing recommendations, OH measurements performed within 1 minute of standing were the most strongly related to dizziness and individual adverse outcomes, suggesting that OH be assessed within 1 minute of standing. PMID- 28738143 TI - Sustained High Nutrient Supply As an Allelopathic Trigger between Periphytic Biofilm and Microcystis aeruginosa. AB - Allelopathy among aquatic organisms, especially microorganisms, has received growing attention in recent years for its role in shaping interactions with bloom forming algae. Many studies have shown that allelopathy occurs and increases under nutrient limiting conditions. However, to date there is no reported direct evidence to indicate that allelopathy occurs under the condition of constant high nutrient supply. Here we report the allelopathic action of periphytic biofilm on bloom-forming cyanobacteria (Microcystis aeruginosa), which was triggered by the stress of high nutrient conditions, and continues while nutrients are maintained at high levels (trophic state index at 159 and 171). The experimental evidence indicates that the electron transport from photosystem II (PS II) to photosystem I (PS I) in M. aeruginosa is interrupted by the identified allelochemicals, (9Z) Octadec-9-enoic acid and (9Z)-Hexadec-9-enoic acid, leading to the failure of photosynthesis and the subsequent death of M. aeruginosa. Our findings indicate that the nutrient stress of constant high nutrient supply may be a newly recognized trigger causing allelopathy between microbial competitors, and therefore opening a new direction for the better management of ecological processes in cyanobacteria-dominated and hyper-eutrophic waters. PMID- 28738144 TI - Simulating Electron Dynamics in Polarizable Environments. AB - We propose a methodology for simulating attosecond electron dynamics in large molecular systems. Our approach is based on the combination of real time time dependent-density-functional theory (RT-TDDFT) and polarizable Molecular Mechanics (MMpol) with the point-charge-dipole model of electrostatic induction. We implemented this methodology in the software deMon2k that relies heavily on auxiliary fitted densities. In the context of RT-TDDFT/MMpol simulations, fitted densities allow the cost of the calculations to be reduced drastically on three fronts: (i) the Kohn-Sham potential, (ii) the electric field created by the (fluctuating) electron cloud which is needed in the QM/MM interaction, and (iii) the analysis of the fluctuating electron density on-the-fly. We determine conditions under which fitted densities can be used without jeopardizing the reliability of the simulations. Very encouraging results are found both for stationary and time-dependent calculations. We report absorption spectra of a dye molecule in the gas phase, in nonpolarizable water, and in polarizable water. Finally, we use the method to analyze the distance-dependent response of the environment of a peptide perturbed by an electric field. Different response mechanisms are identified. It is shown that the induction on MM sites allows excess energy to dissipate from the QM region to the environment. In this regard, the first hydration shell plays an essential role in absorbing energy. The methodology presented herein opens the possibility of simulating radiation induced electronic phenomena in complex and extended molecular systems. PMID- 28738145 TI - Giant Blistering of Nanometer-Thick Al2O3/ZnO Films Grown by Atomic Layer Deposition: Mechanism and Potential Applications. AB - Giant circular blisters of up to 300 MUm diameter and 10 MUm deflection have been produced on nanometer-thick Al2O3-on-ZnO stacks grown by atomic layer deposition at 150 degrees C followed by annealing at elevated temperatures. Their shape changes upon varied ambient pressures provide evidence that their formation is related to an anneal-induced outgassing combined with their impermeability. The former mainly occurs in the bottom ZnO layer that recrystallizes and releases residual hydroxide ions at elevated temperatures while the latter is dominantly contributed by the pinhole-free Al2O3 layer on top. Vibrations at a resonant frequency of ~740 kHz are mechanically actuated and optically probed from an individual blister. By modulating the thickness and stacking sequence of Al2O3 and ZnO, we further demonstrate a localized circular film swelling upon electron beam irradiation and its recovery after reducing the irradiation flux. The elastic blistering and the recoverable swelling of the nanometer-thick films represent a miniaturized event-driven mechanical system for potential functioning applications. PMID- 28738146 TI - High-Throughput Structural and Functional Characterization of the Thin Film Materials System Ni-Co-Al. AB - High-throughput methods were used to investigate a Ni-Co-Al thin film materials library, which is of interest for structural and functional applications (superalloys, shape memory alloys). X-ray diffraction (XRD) measurements were performed to identify the phase regions of the Ni-Co-Al system in its state after annealing at 600 degrees C. Optical, electrical, and magneto-optical measurements were performed to map functional properties and confirm XRD results. All results and literature data were used to propose a ternary thin film phase diagram of the Ni-Co-Al thin film system. PMID- 28738147 TI - Round Robin Study: Molecular Simulation of Thermodynamic Properties from Models with Internal Degrees of Freedom. AB - Thermodynamic properties are often modeled by classical force fields which describe the interactions on the atomistic scale. Molecular simulations are used for retrieving thermodynamic data from such models, and many simulation techniques and computer codes are available for that purpose. In the present round robin study, the following fundamental question is addressed: Will different user groups working with different simulation codes obtain coinciding results within the statistical uncertainty of their data? A set of 24 simple simulation tasks is defined and solved by five user groups working with eight molecular simulation codes: DL_POLY, GROMACS, IMC, LAMMPS, ms2, NAMD, Tinker, and TOWHEE. Each task consists of the definition of (1) a pure fluid that is described by a force field and (2) the conditions under which that property is to be determined. The fluids are four simple alkanes: ethane, propane, n-butane, and iso-butane. All force fields consider internal degrees of freedom: OPLS, TraPPE, and a modified OPLS version with bond stretching vibrations. Density and potential energy are determined as a function of temperature and pressure on a grid which is specified such that all states are liquid. The user groups worked independently and reported their results to a central instance. The full set of results was disclosed to all user groups only at the end of the study. During the study, the central instance gave only qualitative feedback. The results reveal the challenges of carrying out molecular simulations. Several iterations were needed to eliminate gross errors. For most simulation tasks, the remaining deviations between the results of the different groups are acceptable from a practical standpoint, but they are often outside of the statistical errors of the individual simulation data. However, there are also cases where the deviations are unacceptable. This study highlights similarities between computer experiments and laboratory experiments, which are both subject not only to statistical error but also to systematic error. PMID- 28738148 TI - Biofunctional Polymer-Lipid Hybrid High-Density Lipoprotein-Mimicking Nanoparticles Loading Anti-miR155 for Combined Antiatherogenic Effects on Macrophages. AB - A biofunctional polymer-lipid hybrid high-density lipoprotein-mimicking nanoparticle (HNP) loading anti-miR155 was constructed for combined antiatherogenic effects on macrophages. The HNP consisted of an anti-miR155 core condensed by acid-labile polyethylenimine (acid-labile PEI) polymers and a lipid bilayer coat that was decorated with apolipoprotein A-1, termed acid-labile PEI/HNP. The acid-labile PEI was synthesized with low-molecular-weight PEI and glutaraldehyde to reduce the cytotoxicity and facilitate nucleic acids escaping from acidic endolysosomes. The increased silencing efficiency of acid-labile PEI/HNP was ascribed to the clathrin-mediated endocytosis and successful endolysosomal escape. Decreased intracellular reactive oxygen species production and DiI-oxLDL uptake revealed the antioxidant activities of both anti-miR155 and HNP. Cholesterol efflux assay indicated the potential of HNP in reverse cholesterol transport. Collectively, the acid-labile PEI/HNP not only realized the efficacy of anti-miR155 in macrophages but also exerted the antiatherosclerotic biofunction of HNP. PMID- 28738149 TI - Supported and Unsupported Chiral Squaramides as Organocatalysts for Stereoselective Michael Additions: Synthesis of Enantiopure Chromenes and Spirochromanes. AB - Novel supported chiral bifunctional squaramides have been easily prepared starting from diamines derived from natural amino acids and commercially available aminoalkyl polystyrene resins. These squaramides behave as excellent stereoselective recoverable organocatalysts in different Michael additions, in neat conditions at room temperature. The reaction on 2-(2-nitrovinyl) phenol as electrophile lead, in excellent yields and enantioselectivities, to intermediates that can be easily transformed into 4H-chromenes, and spirochromanones. PMID- 28738150 TI - Nickel-Catalyzed beta,gamma-Dicarbofunctionalization of Alkenyl Carbonyl Compounds via Conjunctive Cross-Coupling. AB - A nickel-catalyzed conjunctive cross-coupling between non-conjugated alkenes, aryl iodides, and alkylzinc reagents is reported. Excellent regiocontrol is achieved utilizing an 8-aminoquinoline directing group that can be readily cleaved to unmask net beta,gamma-dicarbofunctionalized carboxylic acid products. Under optimized conditions, both terminal and internal alkene substrates provided the corresponding alkyl/aryl difunctionalized products in moderate to excellent yields. The methodology developed herein represents the first three-component 1,2 dicarbofunctionalization of non-conjugated alkenes involving a C(sp3)-C(sp3) reductive elimination step. PMID- 28738151 TI - Effect of Headgroup Variation on the Self-Assembly of Cationic Surfactants with Sulfonatocalix[6]arene. AB - The effect of headgroup variation on the association of supramolecular amphiphiles composed of 4-sulfonatocalix[6]arene (SCX6) and cationic surfactant possessing tetradecyl substituent was studied in aqueous solutions at pH 7. When the surfactant contained hydrophilic trimethylammonium, pyridinium, or 1 methylimidazolium headgroup, highly reversible temperature-responsive nanoparticle-supramolecular micelle transformation could be attained at appropriately chosen component mixing ratios and NaCl concentrations. In these cases, the substantial negative molar heat capacity change (DeltaCp) rendered nanoparticle formation strongly endothermic at low temperature, whereas the assembly to supramolecular micelle was always accompanied by enthalpy gain. The DeltaCp values became less negative when the charge density and the hydrophilic character of the surfactant headgroup diminished. The association of the more hydrophobic 6-methoxyquinolinium and quinolinium surfactants with SCX6 did not lead to supramolecular micelle formation because the self-assembly into nanoparticles was highly exothermic. PMID- 28738153 TI - Electronic Coupling for Donor-Bridge-Acceptor Systems with a Bridge-Overlap Approach. AB - Understanding the modulation of the electronic coupling in donor-acceptor systems connected through an aliphatic bridge is crucial from a fundamental point of view as well as for the development of organic electronics. In this work, we present a first-principles approach for the calculation of the electronic coupling (or transfer integrals) in such systems via a block-diagonalization of the Fock/Kohn Sham matrix of the supersystem, followed by a projection on the basis of the fragment orbitals of the donor and acceptor groups. The strength of the approach is that the bridge is shared by the donor and acceptor blocks in the diagonalization step, so that through-space and through-bond couplings are obtained simultaneously. The method is applied to two test sets: a series of fused-ring bridged systems and G(T)nG DNA oligomers. The results for the first set are compared to experiment and show an average error lower than 10%. For the DNA set, we show that the coupling may be significantly larger (and the decay with length slower) when the entire backbone is included. PMID- 28738154 TI - Modifying Surface Chemistry of Metal Oxides for Boosting Dissolution Kinetics in Water by Liquid Cell Electron Microscopy. AB - Dissolution of metal oxides is fundamentally important for understanding mineral evolution and micromachining oxide functional materials. In general, dissolution of metal oxides is a slow and inefficient chemical reaction. Here, by introducing oxygen deficiencies to modify the surface chemistry of oxides, we can boost the dissolution kinetics of metal oxides in water, as in situ demonstrated in a liquid environmental transmission electron microscope (LETEM). The dissolution rate constant significantly increases by 16-19 orders of magnitude, equivalent to a reduction of 0.97-1.11 eV in activation energy, as compared with the normal dissolution in acid. It is evidenced from the high-resolution TEM imaging, electron energy loss spectra, and first-principle calculations where the dissolution route of metal oxides is dynamically changed by local interoperability between altered water chemistry and surface oxygen deficiencies via electron radiolysis. This discovery inspires the development of a highly efficient electron lithography method for metal oxide films in ecofriendly water, which offers an advanced technique for nanodevice fabrication. PMID- 28738155 TI - Engineering Aromatic-Aromatic Interactions To Nucleate Folding in Intrinsically Disordered Regions of Proteins. AB - Aromatic interactions are an important force in protein folding as they combine the stability of a hydrophobic interaction with the selectivity of a hydrogen bond. Much of our understanding of aromatic interactions comes from "bioinformatics" based analyses of protein structures and from the contribution of these interactions to stabilizing secondary structure motifs in model peptides. In this study, the structural consequences of aromatic interactions on protein folding have been explored in engineered mutants of the molten globule protein apo-cytochrome b5. Structural changes from disorder to order due to aromatic interactions in two variants of the protein, viz., WF-cytb5 and FF cytb5, result in significant long-range secondary and tertiary structure. The results show that 54 and 52% of the residues in WF-cytb5 and FF-cytb5, respectively, occupy ordered regions versus 26% in apo-cytochrome b5. The interactions between the aromatic groups are offset-stacked and edge-to-face for the Trp-Phe and Phe-Phe mutants, respectively. Urea denaturation studies indicate that both mutants have a Cm higher than that of apo-cytochrome b5 and are more stable to chaotropic agents than apo-cytochrome b5. The introduction of these aromatic residues also results in "trimer" interactions with existing aromatic groups, reaffirming the selectivity of the aromatic interactions. These studies provide insights into the aromatic interactions that drive disorder-to-order transitions in intrinsically disordered regions of proteins and will aid in de novo protein design beyond small peptide scaffolds. PMID- 28738156 TI - Coherent Random Lasing from Dye Aggregates in Polydimethylsiloxane Thin Films. AB - The coherent random laser (CRL) from dye-doped polydimethylsiloxane (PDMS) has been investigated in both nanoparticle-doped (NP-doped) thin films and pure dye thin films. Compared with the literature, the pump threshold is only 1.5 mJ/cm2 in the pure dye thin film with a low dye concentration. The spontaneously formed micro-/nanocrystals of Pyrromethene 597 (PM597) dye support both gain and random feedback in the bulk of the PDMS during the sample preparation. When the SiO2 NPs were doped, the pump threshold was reduced to 0.75 mJ/cm2. The threshold increased after the film was peeled off from glass, which indicates that the photon localization effect of the leaky-waveguide structure plays an important role in the reduction of the CRL threshold. By a change in the pump stripe length or the thickness of the film, the peak wavelength red-shifts 6.7 or 5.93 nm, respectively. The PM597 dye molecule solubility changes, and they spontaneously aggregate in the process of toluene volatilization; the PDMS cures, which is the reason for the formation of PM597 micro-/nanocrystals. This thin film random laser with a low dye concentration can be used in integrated optoelectronics and display imaging. PMID- 28738157 TI - Calculations of n->pi* Transition Energies: Comparisons Between TD-DFT, ADC, CC, CASPT2, and BSE/GW Descriptions. AB - Using a large panel of theoretical approaches, namely, CC2, CCSD, CCSDR(3), CC3, ADC(2), ADC(3), CASPT2, time-dependent density functional theory (TD-DFT), and BSE/evGW, the two latter combined with different exchange-correlation functionals, we investigate the lowest singlet transition in 23 n->pi* compounds based on the nitroso, thiocarbonyl, carbonyl, and diazo chromophores. First, for 16 small derivatives we compare the transition energies provided by the different wave function approaches to define theoretical best estimates. For this set, it surprisingly turned out that ADC(2) offers a better match with CC3 than ADC(3). Next, we use 10 functionals belonging to the "LYP" and "M06" families and compare the TD-DFT and the BSE/evGW descriptions. The BSE/evGW results are less sensitive than their TD-DFT counterparts to the selected functional, especially in the M06 series. Nevertheless, BSE/evGW delivers larger errors than TD-CAM-B3LYP, which provides extremely accurate results in the present case, especially when the Tamm Dancoff approximation is applied. In addition, we show that, among the different starting points for BSE/evGW calculations, M06-2X eigenstates stand as the most appropriate. Finally, we confirm that the trends observed on the small compounds pertain in larger molecules. PMID- 28738152 TI - Natural Products and Their Mimics as Targets of Opportunity for Discovery. AB - Diverse structural types of natural products and their mimics have served as targets of opportunity in our laboratory to inspire the discovery and development of new methods and strategies to assemble polyfunctional and polycyclic molecular architectures. Furthermore, our efforts toward identifying novel compounds having useful biological properties led to the creation of new targets, many of which posed synthetic challenges that required the invention of new methodology. In this Perspective, selected examples of how we have exploited a diverse range of natural products and their mimics to create, explore, and solve a variety of problems in chemistry and biology will be discussed. The journey was not without its twists and turns, but the unexpected often led to new revelations and insights. Indeed, in our recent excursion into applications of synthetic organic chemistry to neuroscience, avoiding the more-traveled paths was richly rewarding. PMID- 28738158 TI - Efficient Interfacially Driven Vehiculization of Corticosteroids by Pulmonary Surfactant. AB - Pulmonary surfactant is a crucial system to stabilize the respiratory air-liquid interface. Furthermore, pulmonary surfactant has been proposed as an effective method for targeting drugs to the lungs. However, few studies have examined in detail the mechanisms of incorporation of drugs into surfactant, the impact of the presence of drugs on pulmonary surfactant performance at the interface under physiologically meaningful conditions, or the ability of pulmonary surfactant to use the air-liquid interface to vehiculise drugs to long distances. This study focuses on the ability of pulmonary surfactant to interfacially vehiculize corticosteroids such as beclomethasone dipropionate (BDP) or Budesonide (BUD) as model drugs. The main objectives have been to (a) characterize the incorporation of corticosteroids into natural and synthetic surfactants, (b) evaluate whether the presence of corticosteroids affects surfactant functionality, and (c) determine whether surfactant preparations enable the efficient spreading and distribution of BDP and BUD along the air-liquid interface. We have compared the performance of a purified surfactant from porcine lungs and two clinical surfactants: Poractant alfa, a natural surfactant of animal origin extensively used to treat premature babies, and CHF5633, a new synthetic surfactant preparation currently under clinical trials. Both, natural and clinical surfactants spontaneously incorporated corticosteroids up to at least 10% by mass with respect to phospholipid content. The presence of the drugs did not interfere with their ability to efficiently adsorb into air-liquid interfaces and form surface active films able to reach and sustain very low surface tensions (<2 mN/m) under compression-expansion cycling mimicking breathing dynamics. Furthermore, the combination of clinical surfactant with corticosteroids efficiently promoted the active diffusion of the drug to long distances along the air-liquid interface. This effect could not be mimicked by vehiculisation of corticosteroids in liposomes or in micellar emulsions similar to the formulations currently in use to deliver anti-inflammatory corticosteroids through inhalation. PMID- 28738159 TI - Light and Electrically Induced Phase Segregation and Its Impact on the Stability of Quadruple Cation High Bandgap Perovskite Solar Cells. AB - Perovskite material with a bandgap of 1.7-1.8 eV is highly desirable for the top cell in a tandem configuration with a lower bandgap bottom cell, such as a silicon cell. This can be achieved by alloying iodide and bromide anions, but light-induced phase-segregation phenomena are often observed in perovskite films of this kind, with implications for solar cell efficiency. Here, we investigate light-induced phase segregation inside quadruple-cation perovskite material in a complete cell structure and find that the magnitude of this phenomenon is dependent on the operating condition of the solar cell. Under short-circuit and even maximum power point conditions, phase segregation is found to be negligible compared to the magnitude of segregation under open-circuit conditions. In accordance with the finding, perovskite cells based on quadruple-cation perovskite with 1.73 eV bandgap retain 94% of the original efficiency after 12 h operation at the maximum power point, while the cell only retains 82% of the original efficiency after 12 h operation at the open-circuit condition. This result highlights the need to have standard methods including light/dark and bias condition for testing the stability of perovskite solar cells. Additionally, phase segregation is observed when the cell was forward biased at 1.2 V in the dark, which indicates that photoexcitation is not required to induce phase segregation. PMID- 28738160 TI - Atrial-selective K+ channel blockers: potential antiarrhythmic drugs in atrial fibrillation? AB - In the wake of demographic change in Western countries, atrial fibrillation has reached an epidemiological scale, yet current strategies for drug treatment of the arrhythmia lack sufficient efficacy and safety. In search of novel medications, atrial-selective drugs that specifically target atrial over other cardiac functions have been developed. Here, I will address drugs acting on potassium (K+) channels that are either predominantly expressed in atria or possess electrophysiological properties distinct in atria from ventricles. These channels include the ultra-rapidly activating, delayed outward-rectifying Kv1.5 channel conducting IKur, the acetylcholine-activated inward-rectifying Kir3.1/Kir3.4 channel conducting IK,ACh, the Ca2+-activated K+ channels of small conductance (SK) conducting ISK, and the two-pore domain K+ (K2P) channels (tandem of P domains, weak inward-rectifying K+ channels (TWIK-1), TWIK-related acid-sensitive K+ channels (TASK-1 and TASK-3)) that are responsible for voltage independent background currents ITWIK-1, ITASK-1, and ITASK-3. Direct drug effects on these channels are described and their putative value in treatment of atrial fibrillation is discussed. Although many potential drug targets have emerged in the process of unravelling details of the pathophysiological mechanisms responsible for atrial fibrillation, we do not know whether novel antiarrhythmic drugs will be more successful when modulating many targets or a single specific one. The answer to this riddle can only be solved in a clinical context. PMID- 28738161 TI - Belted driver fatalities: Time of death and risk by injury severity. AB - PURPOSE: This is a descriptive study of the fatality risk by injury severity and time of death for lap-shoulder-belted drivers without ejection in modern vehicles. It also determined the body region for severe injuries experienced by belted drivers using the most recent federal crash data. METHODS: 1997-2015 NASS CDS data were evaluated for fatally injured lap-shoulder-belted drivers without ejection in light vehicles of 1997+ model year (MY). The severity of injuries sustained by belted drivers was assessed by the Maximum Abbreviated Injury Scale (MAIS) and individual injuries by Abbreviated Injury Scale (AIS) and body region. The change in fatality risk with MAIS was fit with a Logist function. Time of death was determined using the variable DEATH, which is reported hourly in unequal intervals up to 24 h and then daily up to 30 days after the crash. The fraction (f) and cumulative fraction (F) of the deaths are reported for each time period up to 30 days. A power or logarithmic curve was fit to the data using the trendline functions in Excel. RESULTS: The NASS-CDS sample included 20,610,000 belted drivers with 37,974 fatalities from 1997 to 2015. The fraction of driver deaths increased with maximum injury severity (MAIS). For example, 17.4% of drivers died within 30 days with MAIS 4 injury. Virtually all drivers (99.7%) died with MAIS 6 injury. The change in fatality risk with injury severity was r = [1 + exp(10.159 - 2.088MAIS)]-1, R2 = 0.950. Overall, there were 19,772 driver deaths with MAIS 4-6 injury and 13,059 with MAIS 0-3 injury. In addition, 44.7% of driver deaths occurred within 1.5 h of the crash, 56.7% within 2.5 h, and 64.6% within 4.5 h after the crash. The cumulative fraction of the deaths (F) up to 30 days was fit with a logarithmic function. It was F = 0.0739ln(t) + 0.5302, R2 = 0.976, for deaths after 3.5 h. There were 19,772 driver deaths with 52,130 AIS 4+ injuries. On average, the driver experienced 2.64 AIS 4+ injuries most commonly to the head (44.5%) and thorax (38.1%). CONCLUSIONS: The risk for belted driver deaths exponentially increased with MAIS. A majority of deaths occurred within 2.5 h of the crash. On average, fatally injured drivers experienced 2.64 AIS 4+ injuries, primarily to the head and thorax. PMID- 28738162 TI - Neuropeptide Y and its receptors in ventricular endocardial endothelial cells. AB - Endocardial endothelial cells (EECs) constitute an important component of the heart. These cells form a monolayer that covers the cavities of the right (EECRs) and left (EECLs) ventricles. They play an important role in cardiac excitation contraction coupling via their secretion of cardioactive factors such as neuropeptide Y (NPY). They also contribute to cardiac pathology such as arrhythmia, hypertrophy, and heart failure. Differences between EECRs and EECLs contribute to tuning of circulating factors at the entry and exit of the ventricles. NPY, via activation of its receptors, modulates the excitation secretion coupling of EECs, thus, indirectly modulating cardiac function and remodeling. PMID- 28738163 TI - A local duplication of the Melanocortin receptor 1 locus in Astyanax. AB - In this study, we report evidence of a novel duplication of Melanocortin receptor 1 (Mc1r) in the cavefish genome. This locus was discovered following the observation of excessive allelic diversity in a ~820 bp fragment of Mc1r amplified via degenerate PCR from a natural population of Astyanax aeneus fish from Guerrero, Mexico. The cavefish genome reveals the presence of two closely related Mc1r open reading frames separated by a 1.46 kb intergenic region. One open reading frame corresponds to the previously reported Mc1r receptor, and the other open reading frame (duplicate copy) is 975 bp in length, encoding a receptor of 325 amino acids. Sequence similarity analyses position both copies in the syntenic region of the single Mc1r locus in 16 representative craniate genomes spanning bony fish (including Astyanax) to mammals, suggesting we discovered tandem duplicates of this important gene. The two Mc1r copies share ~89% sequence similarity and, within Astyanax, are more similar to one another compared to other melanocortin family members. Future studies will inform the precise functional significance of the duplicated Mc1r locus and if this novel copy number variant may have adaptive significance for the Astyanax lineage. PMID- 28738164 TI - Risk stratification in patients with heart failure: the value of considering both global longitudinal left ventricular strain and mechanical dispersion. AB - In previous studies, mechanical dispersion (MD) predicted ventricular arrhythmias independently of left ventricular ejection fraction (LVEF). Moreover, the combination of MD and global longitudinal strain (GLS) increased the prediction of arrhythmic events. We investigated the prognostic value of a new 2-dimensional strain index, GLS/MD, in patients with heart failure (HF). We analyzed 340 consecutive HF outpatients in sinus rhythm. Echocardiography was performed at 1.6 +/- 0.4 months after hospital discharge. The end point included sudden cardiac death, ventricular fibrillation, and sustained ventricular tachycardia (SCD/VA). During the follow-up period (36 +/- 9 months), SCD/VA occurred in 48 patients (14.1%). A multivariate Cox regression analysis, which included LVEF, early diastolic transmitral / mitral annular velocity ratio (E/E'), GLS, MD, and GLS/MD in the model, revealed that GLS/MD was the best independent predictor of SCD/VA (HR = 3.22, 95% confidence interval = 1.72-6.15, p = 0.03). Separate inclusion of LVEF, systolic mitral annular velocity, E/E', GLS, and MD together with GLS/MD showed that GLS/MD remained the best predictor of SCD/VA (each p < 0.05). The optimal GLS/MD cutoff value to predict SCA/VA was -0.20%/ms (80% sensitivity, 76% specificity). Irrespective of LVEF, free survival was significantly better in patients with GLS/MD <= -0.2%/ms (log-rank test, p < 0.001). In conclusion, GLS/MD may improve cardiovascular risk stratification in subjects with HF. PMID- 28738165 TI - Physical and Mechanical Therapies for Lower-Limb Problems in Juvenile Idiopathic ArthritisA Systematic Review with Meta-Analysis. AB - BACKGROUND: Juvenile idiopathic arthritis (JIA), a chronic, autoimmune, inflammatory joint disease, is the most common arthritis affecting children younger than 16 years. Children with JIA commonly experience lower-limb dysfunction and disability. We systematically reviewed the effectiveness of physical and mechanical therapies for lower-limb problems in JIA. METHODS: Randomized controlled trials of physical and mechanical interventions for lower limb problems in children with JIA were included. Primary outcome was pain. Secondary outcomes included disability, functional ability, and health-related quality of life. Several databases were searched for eligible studies. Authors of included studies and researchers in the field were contacted to identify additional studies. RESULTS: Two studies evaluating the effectiveness of customized/custom foot orthoses in treating foot and ankle pain in children with JIA (N = 100) were included. One study also evaluated simple cushioned inserts. Meta-analyses for comparisons between custom/customized foot orthoses and a control intervention after 3 months were not significant for the outcomes of pain (mean difference, -8.97; 95% confidence interval [CI], -18.01 to 0.07), child rated health-related quality of life (mean difference, 4.38; 95% CI, -3.68 to 12.44), and parent-rated health-related quality of life (mean difference, 1.77; 95% CI, -6.35 to 9.90). Meta-analyses were supported by sensitivity analyses. CONCLUSIONS: There is a paucity of research evaluating physical and mechanical therapies for lower-limb problems in JIA. No physical therapy has been evaluated in randomized controlled trials, and mechanical therapy evaluation is limited to foot orthoses and shoe inserts for foot and ankle pain. The existing research is hampered by small sample sizes. Until further research is conducted, the effectiveness of mechanical and physical therapies for lower-limb problems in JIA remains unclear. PMID- 28738166 TI - Ablation of toll-like receptor 4 mitigates cardiac mitochondrial dysfunction in hyperhomocysteinemia. AB - Hyperhomocysteinemia (HHcy) is a risk factor for adverse cardiovascular events; however, the mechanism for development of this disease is still unknown. Toll like receptor 4 (TRL4) is a molecule involved in the immune response pathway and is quickly becoming a receptor of interest in the field of hypertension. In this study, we hypothesized that ablation of TLR4 mitigates cardiac mitochondrial dysfunction in a model of HHcy. Five strains of mice (C57BL/6J, CBS+/-, C3H, CBS+/-/C3H, and C3H/HeOuJ) 10-12 weeks old were utilized. We found that HHcy causes heart hypertrophy and promotes oxidative stress while mice with HHcy and inactivated TLR4 showed significant improvement in examined parameters. A dominance of endothelial cell mitochondrial fission over mitochondrial fusion in HHcy and oxidative stress was observed, which may explain the endothelial cell loss and dysfunction that contributes to inward cardiac remodeling. PMID- 28738167 TI - Methylene blue improves mitochondrial respiration and decreases oxidative stress in a substrate-dependent manner in diabetic rat hearts. AB - Diabetic cardiomyopathy has been systematically associated with compromised mitochondrial energetics and increased generation of reactive oxygen species (ROS) that underlie its progression to heart failure. Methylene blue is a redox drug with reported protective effects mainly on brain mitochondria. The purpose of the present study was to characterize the effects of acute administration of methylene blue on mitochondrial respiration, H2O2 production, and calcium sensitivity in rat heart mitochondria isolated from healthy and 2 months (streptozotocin-induced) diabetic rats. Mitochondrial respiratory function was assessed by high-resolution respirometry. H2O2 production and calcium retention capacity were measured spectrofluorimetrically. The addition of methylene blue (0.1 MUmol.L-1) elicited an increase in oxygen consumption of mitochondria energized with complex I and II substrates in both normal and diseased mitochondria. Interestingly, methylene blue elicited a significant increase in H2O2 release in the presence of complex I substrates (glutamate and malate), but had an opposite effect in mitochondria energized with complex II substrate (succinate). No changes in the calcium retention capacity of healthy or diabetic mitochondria were found in the presence of methylene blue. In conclusion, in cardiac mitochondria isolated from diabetic and nondiabetic rat hearts, methylene blue improved respiratory function and elicited a dichotomic, substrate-dependent effect on ROS production. PMID- 28738168 TI - Role of age and injury mechanism on cervical spine injury tolerance from head contact loading. AB - OBJECTIVE: The objective of this study was to determine the influence of age and injury mechanism on cervical spine tolerance to injury from head contact loading using survival analysis. METHODS: This study analyzed data from previously conducted experiments using post mortem human subjects (PMHS). Group A tests used the upright intact head-cervical column experimental model. The inferior end of the specimen was fixed, the head was balanced by a mechanical system, and natural lordosis was removed. Specimens were placed on a testing device via a load cell. The piston applied loading at the vertex region. Spinal injuries were identified using medical images. Group B tests used the inverted head-cervical column experimental model. In one study, head-T1 specimens were fixed distally, and C7 T1 joints were oriented anteriorly, preserving lordosis. Torso mass of 16 kg was added to the specimen. In another inverted head-cervical column study, occiput-T2 columns were obtained, an artificial head was attached, T1-T2 was fixed, C4-C5 disc was maintained horizontal in the lordosis posture, and C7-T1 was unconstrained. The specimens were attached to the drop test carriage carrying a torso mass of 15 kg. A load cell at the inferior end measured neck loads in both studies. Axial neck force and age were used as the primary response variable and covariate to derive injury probability curves using survival analysis. RESULTS: Group A tests showed that age is a significant (P < .05) and negative covariate; that is, increasing age resulted in decreasing force for the same risk. Injuries were mainly vertebral body fractures and concentrated at one level, mid-to-lower cervical spine, and were attributed to compression-related mechanisms. However, age was not a significant covariate for the combined data from group B tests. Both group B tests produced many soft tissue injuries, at all levels, from C1 to T1. The injury mechanism was attributed to mainly extension. Multiple and noncontiguous injuries occurred. Injury probability curves, +/-95% confidence intervals, and normalized confidence interval sizes representing the quality of the mean curve are given for different data sets. CONCLUSIONS: For compression related injuries, specimen age should be used as a covariate or individual specimen data may be prescaled to derive risk curves. For distraction- or extension-related injuries, however, specimen age need not be used as a covariate in the statistical analysis. The findings from these tests and survival analysis indicate that the age factor modulates human cervical spine tolerance to impact injury. PMID- 28738169 TI - Behavior of sulfur mustard in sand, concrete, and asphalt matrices: Evaporation, degradation, and decontamination. AB - The evaporation, degradation, and decontamination of sulfur mustard on environmental matrices including sand, concrete, and asphalt are described. A specially designed wind tunnel and thermal desorber in combination with gas chromatograph (GC) produced profiles of vapor concentration obtained from samples of the chemical agent deposited as a drop on the surfaces of the matrices. The matrices were exposed to the chemical agent at room temperature, and the degradation reactions were monitored and characterized. A vapor emission test was also performed after a decontamination process. The results showed that on sand, the drop of agent spread laterally while evaporating. On concrete, the drop of the agent was absorbed immediately into the matrix while spreading and evaporating. However, the asphalt surface conserved the agent and slowly released parts of the agent over an extended period of time. The degradation reactions of the agent followed pseudo first order behavior on the matrices. Trace amounts of the residual agent present at the surface were also released as vapor after decontamination, posing a threat to the exposed individual and environment. PMID- 28738170 TI - Removal of PFOA in groundwater by Fe0 and MnO2 nanoparticles under visible light. AB - The main objective of this study was to find a cost-effective, efficient and environmentally-friendly solution to remove perfluorooctanic acid (PFOA) from groundwater by using Fe0 and MnO2 nanoparticles. The selected method was expected to be applicable to the remediation of PFOA-contaminated groundwater. Phytotoxicity of the nanoparticle treatment was studied to demonstrate the safe application of the nanomaterials. Zero-valent Fe (100 mg L-1) and MnO2 (100 mg L 1) nanoparticles, produced in our lab, were used to remove PFOA up to 10 mg L-1. The test was conducted under visible light with or without addition of 0.88 mol L 1 H2O2 in a pH range of 0.5-11.0 for a duration of 18 h. Using Fe nanoparticles, a higher percentage of PFOA was removed under extreme acidic environment of pH 0.5 than under the basic environment of pH 11.0, and a minimum removal rate was reached under the neutral environment. The Fe nanoparticles were more efficient than the MnO2 nanoparticles at pH 0.5 with a removal rate of 69.7% and 89.7% without and with H2O2 addition, respectively. Phytotoxicity study showed that the treatment by Fe nanoparticles under mild pH reduced the phytotoxicity of groundwater-associated PFOA to Arabidopsis thaliana. The Fe nanoparticles did not show negative effect to A. thaliana under the experimental conditions used in this study. PMID- 28738172 TI - Impact of polymeric membrane breakage on drinking water quality and an online detection method of the breakage. AB - Polymeric membrane has been widely used for the treatment of drinking water in China, and the total treating capacity has reached up to 3.8 million m3/d. However, the membrane breakage found in the membrane modules in many water treatment plants resulted in an increase in turbidity and bacterial amount in the membrane permeate. In this study, a membrane module running for 3 years in a full scale application was examined in terms of the breaking positions and the numbers of the broken fibers. It was found that most of the breaking positions were mainly on the outlet side of the module and that the distance from these points to the outlet was about 1/10-2/10 length of the membrane module. The lab-scale tests showed that the increase of the numbers of the breaking fibers in the membrane module (the breaking fibers were from 1 to 4 of 75 fibers) resulted in the increase in turbidity, particle count and the amount of total bacteria and coliform bacteria. Meanwhile, the water quality after the filtration with broken membrane fibers was similar to the quality of the raw water, which indicated that once the membrane fiber breakage occurred in the membrane module, the quality of drinking water after membrane filtration was significantly affected. Furthermore, the breaking position closer to the outlet side of the membrane module exposed much higher microbiological risk than those in the middle or near the bottom side. A pilot scale test was conducted by using a membrane module with 6600 fibers, and the effect of the membrane breakage (1-4 broken fibers) on water quality was also investigated. The results indicated that periodical backwashing caused drastic fluctuation of turbidity, particle count and the bacterial amount in the permeate water, which might be due to the washing force and self-blocking action inside the hollow fibers. Moreover, there is a good quantitative relationship (R2 = 0.945) between particle count and the bacterial amount, which indicated that an online detection of particle count can be used to evaluate the bacterial risk. It was also suggested that the online detection of particle count after backwashing within 100 s would be a quick and precise method to identify any fiber breakage in time. These results are very important for the safety issue in the application of polymeric membrane to water treatment plants. PMID- 28738171 TI - Emerging roles for TFEB in the immune response and inflammation. AB - Inflammation is a central feature of an effective immune response, which functions to eliminate pathogens and other foreign material, and promote recovery; however, dysregulation of the inflammatory response is associated with a wide variety of disease states. The autophagy-lysosome pathway is one of 2 major degradative pathways used by the cell and serves to eliminate long-lived and dysfunctional proteins and organelles to maintain homeostasis. Mounting evidence implicates the autophagy-lysosome pathway as a key player in regulating the inflammatory response; hence many inflammatory diseases may fundamentally be diseases of autophagy-lysosome pathway dysfunction. The recent identification of TFEB and TFE3 as master regulators of macroautophagy/autophagy and lysosome function raises the possibility that these transcription factors may be of central importance in linking autophagy and lysosome dysfunction with inflammatory disorders. Here, we review the current state of knowledge linking TFEB and TFE3 to the processes of autophagy and inflammation and highlight several conditions, which are linked by these factors. PMID- 28738173 TI - Simulating the meteorology and PM10 concentrations in Arizona dust storms using the Weather Research and Forecasting model with Chemistry (Wrf-Chem). AB - : Nine dust storms in south-central Arizona were simulated with the Weather Research and Forecasting with Chemistry model (WRF-Chem) at 2 km resolution. The windblown dust emission algorithm was the Air Force Weather Agency model. In comparison with ground-based PM10 observations, the model unevenly reproduces the dust-storm events. The model adequately estimates the location and timing of the events, but it is unable to precisely replicate the magnitude and timing of the elevated hourly concentrations of particles 10 um and smaller ([PM10]).Furthermore, the model underestimated [PM10] in highly agricultural Pinal County because it underestimated surface wind speeds and because the model's erodible fractions of the land surface data were too coarse to effectively resolve the active and abandoned agricultural lands. In contrast, the model overestimated [PM10] in western Arizona along the Colorado River because it generated daytime sea breezes (from the nearby Gulf of California) for which the surface-layer speeds were too strong. In Phoenix, AZ, the model's performance depended on the event, with both under- and overestimations partly due to incorrect representation of urban features. Sensitivity tests indicate that [PM10] highly relies on meteorological forcing. Increasing the fraction of erodible surfaces in the Pinal County agricultural areas improved the simulation of [PM10] in that region. Both 24-hr and 1-hr measured [PM10] were, for the most part, and especially in Pinal County, extremely elevated, with the former exceeding the health standard by as much as 10-fold and the latter exceeding health-based guidelines by as much as 70-fold. Monsoonal thunderstorms not only produce elevated [PM10], but also cause urban flash floods and disrupt water resource deliveries. Given the severity and frequency of these dust storms, and conceding that the modeling system applied in this work did not produce the desired agreement between simulations and observations, additional research in both the windblown dust emissions model and the weather research/physicochemical model is called for. IMPLICATIONS: While many dust storms can be considered to be natural, in semi-arid climates such storms often have an anthropogenic component in their sources of dust. Applying the natural, exceptional events policy to these storms with strong signatures of anthropogenic sources would appear not only to be misguided but also to stifle genuine regulatory efforts at remediation. Those dust storms that have resulted, in part, from passage over abandoned farm land should no longer be considered "natural"; policymakers and lawmakers need to compel the owners of such land to reduce its potential for windblown dust. PMID- 28738174 TI - Distribution of ion contents and microorganisms during the electro-bioremediation of petroleum-contaminated saline soil. AB - This study investigated the distribution of ion contents and microorganisms during the electro-bioremediation (EK-Bio) of petroleum-contaminated saline soil. The results showed that soil ions tend to accumulate around the electrodes, and the concentration was correlated with the distance from the electrodes. The average soil ion content was 7.92 g/kg around the electrodes (site A) and 0.55 g/kg at the furthest distance from the electrodes (site B) after 112 days of treatment, while the initial average content was 3.92 g/kg. Smooth linear (R2 = 0.98) loss of soil ions was observed at site C, which was closer to the electrodes than site B, and had a final average soil ion content of 1.96 g/kg. The dehydrogenase activity was much higher in EK-Bio test soil than in the Bio test soil after 28 days of treatment, and followed the order: site C > site B > site A. However, the soil dehydrogenase activity dropped continuously when the soil ion reached very high and low concentrations at sites A and B. The soil microbial community varied in sample sites that had different ion contents, and the soil microbial diversity followed the order: site C > site B > site A. The applied electric field clearly enhanced the biodegradation efficiency for soil petroleum contaminants. However, the biodegradation promotion effects were weakening in soils where the ion contents were extremely high and low (sites A and B). These results can provide useful information for EK-Bioremediation of organic-contaminated saline soil. PMID- 28738175 TI - Adenoid cystic carcinoma of the lacrimal gland in a 14-year-old male. AB - Adenoid cystic carcinoma (ACC) of the lacrimal gland is an aggressive, malignant epithelial neoplasm. This tumor is rarely seen in adults and even less commonly seen in children and adolescents; thus, there have been no large studies to date describing the optimal treatment of this malignancy in the pediatric population. Here, we report a case of lacrimal gland ACC in a 14-year-old male treated with neoadjuvant intra-arterial chemotherapy followed by globe-sparing tumor resection and chemoradiation. At 2-year follow-up, he remains disease free without evidence of tumor recurrence. PMID- 28738176 TI - Hope headquarters: recovery college. PMID- 28738177 TI - May 2017 (vol. 216, no. 5, page 522). PMID- 28738178 TI - Corrigendum to ''A glucose-targeted mixed micellar formulation outperforms Genexol in breast cancer cells'' [Euro. J. Pharmaceut. Biopharmaceut. 114 (2017) 305-316]. PMID- 28738180 TI - Editorial Comment. PMID- 28738179 TI - Erratum to "Establishing reference intervals for galectin-3 concentrations in serum requires careful consideration of its biological determinants" [Clin. Biochem. 50 (2017) 599-604]. PMID- 28738181 TI - Editorial Comment. PMID- 28738182 TI - Editorial Comment. PMID- 28738184 TI - Reply by Authors. PMID- 28738183 TI - Editorial Comment. PMID- 28738185 TI - Mother and child characteristics at birth and early age leukemia: a case-cohort population-based study. AB - OBJECTIVE: The population-based cancer registries (PBCR) and the Information System on Live Births in Brazil (Sistema de Informacoes sobre Nascidos Vivos [SINASC]) have information that enables the test for risk factors associated with leukemia at an early age. The aim of this study was to identify maternal and birth characteristics associated with early-age acute leukemia (EAL) in Brazil. METHODS: A case-cohort study was performed using secondary dataset information of PBCR and SINASC. The risk association variables were grouped into (i) characteristics of the child at birth and (ii) characteristics of maternal exposure during pregnancy. The case-control ratio was 1:4. Linkage was performed using R software; odds ratio (OR) and 95% confidence interval (CI) were calculated by logistic regression models. RESULTS: EAL was associated with maternal occupational exposure to chemicals (agricultural, chemical, and petrochemical industry; adjOR: 2.18, 95% CI: 1.16-4.10) and with birth defects (adjOR: 3.62, 95% CI: 1.19-11.00). CONCLUSIONS: The results of this study, with the identification of EAL risk factors in population-based case-cohort study, strengthen the knowledge and improve databases, contributing to investigations on risk factors associated with childhood leukemia worldwide. PMID- 28738186 TI - Neonatal screening: 9% of children with filter paper thyroid-stimulating hormone levels between 5 and 10MUIU/mL have congenital hypothyroidism. AB - OBJECTIVES: To determine the prevalence of congenital hypothyroidism in children with filter-paper blood-spot TSH (b-TSH) between 5 and 10MUIU/mL in the neonatal screening. METHODS: This was a retrospective study including children screened from 2003 to 2010, with b-TSH levels between 5 and 10MUIU/mL, who were followed up during the first two years of life when there was no serum TSH normalization. The diagnosis of congenital hypothyroidism was defined as serum TSH >=10MUIU/mL and start of levothyroxine treatment up to 2 years of age. RESULTS: Of the 380,741 live births, 3713 (1.04%) had filter paper TSH levels between 5 and 10MUIU/mL and, of these, 339 (9.13%) had congenital hypothyroidism. Of these, 76.11% of the cases were diagnosed in the first three months of life and 7.96% between 1 and 2 years of age. CONCLUSION: The study showed that 9.13% of the children with b-TSH levels between 5 and 10MUIU/mL developed hypothyroidism and that in approximately one-quarter of them, the diagnosis was confirmed only after the third month of life. Based on these findings, the authors suggest the use of a 5MUIU/mL cutoff for b-TSH levels and long-term follow-up of infants whose serum TSH has not normalized to rule out congenital hypothyroidism. PMID- 28738188 TI - Sleep characteristics and risk of dementia and Alzheimer's disease: The Atherosclerosis Risk in Communities Study. AB - INTRODUCTION: This study tested the hypotheses that late-midlife obstructive sleep apnea (OSA) and short and long sleep duration are associated with dementia over 15 years of follow-up. METHODS: A total of 1667 Atherosclerosis Risk in Communities Study participants underwent in-home polysomnography (1996-1998) and were followed for dementia. Dementia was defined by (1) hospitalization diagnosis codes (1996-2012) and (2) a comprehensive neurocognitive examination (2011-2013) with adjudication. RESULTS: OSA and sleep duration were not associated with risk of incident dementia. When using adjudicated outcomes, severe OSA (>=30 vs. <5 apnea-hypopnea events/hour) was associated with higher risk of all-cause dementia (risk ratio [95% confidence interval], 2.35 [1.06-5.18]) and Alzheimer's disease dementia (1.66 [1.03-2.68]); associations were attenuated with cardiovascular risk factor adjustment. Sleeping <7 versus 8 to <=9 hours was associated with higher risk of all-cause dementia (2.00 [1.03-3.86]). DISCUSSION: When adjudicated outcome definitions were used, late-midlife OSA and short sleep duration were associated with all-cause and Alzheimer's disease dementia in later life. PMID- 28738190 TI - In Reply. PMID- 28738189 TI - Surgical Landmarks to Locating the Main Trunk of the Facial Nerve in Parotid Surgery: A Systematic Review. AB - PURPOSE: The purpose of this study was to describe distances from commonly used anatomic landmarks to the main trunk of the facial nerve during parotid surgery. MATERIALS AND METHODS: A systematic search of the published literature was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. All studies from January 1, 1990 to January 1, 2017 that measured distances to the main trunk of the facial nerve from common anatomic landmarks were eligible. Inclusion criteria were English-language articles with distances measured from the main trunk of the facial nerve to anatomic landmarks. The primary outcome variable was the distance from the respective anatomic landmarks. Other variables included surgical approach, year, and existential status of subject (cadaveric or living). RESULTS: The search yielded 1,412 studies (1,397 by PubMed, 15 by reference searching), with 10 studies meeting the inclusion criteria. Within the 10 studies, there were 30 reported means and 375 dissected cadavers. The most common incision was the standard preauricular incision; the mean distances to the facial trunk from landmarks were 13.6 +/- 11.0 mm (n = 6 reported means) for the tragal pointer, 8.79 +/- 3.99 mm (n = 7 reported means) for the posterior belly of the digastric muscle, 10.5 +/- 1.4 mm (n = 4 reported means) for the tip of the mastoid process, 14.99 +/- 1.68 mm (n = 3 means) for the transverse process of C1, 3.79 +/- 2.92 mm (n = 6 means) for the tympanomastoid fissure, 9.80 +/- 0 mm (n = 1 mean) for the styloid process, and 11.77 +/- 1.42 mm (n = 3 means) for the external auditory meatus. Formal assessment of inter-study variability could not be assessed because of the small number of studies and measurements. CONCLUSION: There are substantial variations in measurements from anatomic landmarks to the main trunk of the facial nerve in the literature. Therefore, multiple landmarks can be used to identify the main trunk of the facial nerve during parotid surgery. The distances reported in this study can guide surgeons during parotid surgery to decrease the risk of facial nerve damage. PMID- 28738187 TI - Presymptomatic atrophy in autosomal dominant Alzheimer's disease: A serial magnetic resonance imaging study. AB - INTRODUCTION: Identifying at what point atrophy rates first change in Alzheimer's disease is important for informing design of presymptomatic trials. METHODS: Serial T1-weighted magnetic resonance imaging scans of 94 participants (28 noncarriers, 66 carriers) from the Dominantly Inherited Alzheimer Network were used to measure brain, ventricular, and hippocampal atrophy rates. For each structure, nonlinear mixed-effects models estimated the change-points when atrophy rates deviate from normal and the rates of change before and after this point. RESULTS: Atrophy increased after the change-point, which occurred 1-1.5 years (assuming a single step change in atrophy rate) or 3-8 years (assuming gradual acceleration of atrophy) before expected symptom onset. At expected symptom onset, estimated atrophy rates were at least 3.6 times than those before the change-point. DISCUSSION: Atrophy rates are pathologically increased up to seven years before "expected onset". During this period, atrophy rates may be useful for inclusion and tracking of disease progression. PMID- 28738191 TI - Comparison of Dental Implant Performance Following Vertical Alveolar Bone Augmentation With Alveolar Distraction Osteogenesis or Autogenous Onlay Bone Grafts: A Retrospective Cohort Study. AB - PURPOSE: The aim of this retrospective study was to compare the performance of implants placed after alveolar distraction osteogenesis (ADO) or autogenous onlay bone grafting (AOBG) based on implant survival, peri-implant bone resorption, and clinical parameters. MATERIALS AND METHODS: From February 2008 to July 2012, 17 patients (6 women and 11 men) with implant placement after ADO (group 1, n = 8) or AOBG (group 2, n = 9) were included in this retrospective study. In all, 37 implants were placed in group 1 and 22 implants were placed in group 2. Implant survival rate, peri-implant bone resorption, probe depth (PD), modified plaque index (mPI), and modified sulcus bleeding index (mSBI) were analyzed to evaluate implant prognosis. RESULTS: Successful reconstruction of vertical alveolar defects and uneventful implant placement were achieved in all patients in the 2 groups. After a mean follow-up of 47.9 +/- 13.3 months, implant survival was 97.3% (36 of 37) in group 1 and 95.5% (21 of 22) in group 2. No statistically relevant differences were observed. Peri-implant bone resorption was 1.29 +/- 0.59 mm in group 1, which was slightly higher than 1.24 +/- 0.87 mm in group 2 at last follow-up. The difference was not statistically relevant. Favorable peri implant conditions were indicated by PD, mPI, and mSBI in the 2 groups. CONCLUSIONS: ADO and AOBG can be used for correction of vertical alveolar defects with a reliable implant prognosis. Comparably high implant survival rates and favorable peri-implant conditions were attained. PMID- 28738192 TI - Maxillary Reconstruction Using Submental Artery Island Flap and Sagittal Mandibular Ramus/Coronoid Process Graft Pedicled With Temporalis Muscle. AB - PURPOSE: The purpose of this study is to describe maxillary reconstruction using the submental artery island flap and the sagittal mandibular ramus and coronoid process graft pedicled with the temporalis muscle through the modified lateral lip and submandibular approach. MATERIALS AND METHODS: From May 2013 to September 2016, 11 patients with maxillary defects secondary to maxillary cancer ablation who underwent maxillary reconstruction using a submental artery island flap and a sagittal mandibular ramus and coronoid process graft pedicled with the temporalis muscle through the modified lateral lip and submandibular approach were enrolled in this prospective study. RESULTS: All submental artery island flaps and sagittal mandibular ramus and coronoid process grafts were successful, with satisfactory functional and esthetic outcomes. No functional impairment at the donor site occurred in any case. CONCLUSION: The submental artery island flap combined with the sagittal mandibular ramus and coronoid process graft is a feasible and acceptable technique for maxillary reconstruction in older patients because it is safe, quick, and straightforward to harvest and it offers a very acceptable esthetic and satisfactory outcome, with the advantage of low morbidity of the donor site. When combined with the 3-dimensional virtual operative method, the technique can improve postoperative outcomes. PMID- 28738193 TI - Degree of Keratinization Is an Independent Prognostic Factor in Oral Squamous Cell Carcinoma. AB - PURPOSE: Keratinization is a routinely reported histologic feature in head and neck cancer. In contrast to numerous clinicopathologic parameters, the prognostic value of keratinization in oral squamous cell carcinoma (OSCC) is rarely reported in the literature. The purpose of this study was to review the outcome of patients with OSCC with a special focus on the degree of keratinization. PATIENTS AND METHODS: In this retrospective cohort study, we evaluated the medical records at the Department of Oral and Maxillofacial Surgery, Jena University Hospital, and investigated the outcome of patients with OSCC with disease-free survival and disease-specific survival according to the degree of keratinization. This research also analyzed common clinical and histologic parameters such as age, gender, tumor site, T category, N category, resection margin, lymphovascular invasion, and extracapsular spread. Descriptive statistics were performed, and survival was calculated by the Kaplan-Meier method. Prognostic factors were analyzed by multivariate Cox analysis. RESULTS: In the sample of 151 OSCC patients, with a median age of 57.5 years and a male-female ratio of 4.03:1, 119 had tumors with no or low keratinization (K0 to K2) and 32 had tumors with good or high keratinization (K3 or K4). More recurrences were seen in patients with OSCC with low keratinization (P = .0008). The 5-year disease-free survival rate was significantly decreased for OSCC with low keratinization (52.9%) compared with good or high keratinization (93.2%) (P = .0008). The 5-year disease-specific survival rate was reduced to 66.1% (P = .0136) for patients with OSCC with low keratinization. Multivariate analysis showed that extracapsular spread (P = .001) and keratinization (P = .002) are independent, significant prognostic factors for recurrence in OSCC. CONCLUSIONS: Besides extracapsular spread, the degree of keratinization seems to be an important prognostic factor for recurrence and survival in OSCC. Our results indicate that the degree of keratinization should be considered in decisions regarding treatment and prognosis for OSCC. PMID- 28738194 TI - Characterization and horizontal transfer of qacH-associated class 1 integrons in Escherichia coli isolated from retail meats. AB - The aim of this study was to examine the presence of genes responsible for resistance to quaternary ammonium compounds (QACs) and the association of qac genes with class 1 integrons in Escherichia coli isolated from retail meats. Among the 179 E. coli isolates tested, the minimum inhibitory concentrations (MICs) of benzalkonium chloride (BC) ranged from 4 to 64MUg/mL. PCR assays indicated that QAC-resistance genes sugE(c), ydgE/ydgF, mdfA, emrE and qacEDelta1 were commonly present (40.2%-88.3%) in these isolates, but qacE, qacF, qacH and sugE(p) were less prevalent (2.2%-28.5%). Seven different gene cassette arrangements were identified in 31 intI1-positive isolates. Three types of qacH sul3-associated non-classic integrons were observed in four isolates: dfrA12-orfF aadA2-cmlA1-aadA1-qacH-IS440-sul3, aadA2-cmlA1-aadA1-qacH-IS440-sul3 and dfrA1 aadA1-qacH-IS440-sul3. Non-classic class 1 integrons were located on plasmids of 100-150kb in these four isolates. Our results demonstrated that the qacH associated integrons located on 100 kb plasmids in two isolates could be transferred to an E. coli recipient, indicating the co-existence and co dissemination of disinfectant and antimicrobial resistance genes among bacterial species. PMID- 28738195 TI - Proteomic and genetics insights on the response of the bacteriocinogenic Lactobacillus sakei CRL1862 during biofilm formation on stainless steel surface at 10 degrees C. AB - Some lactic acid bacteria have the ability to form biofilms on food-industry surfaces and this property could be used to control food pathogens colonization. Lactobacillus sakei CR1862 was selected considering its bacteriocinogenic nature and ability to adhere to abiotic surfaces at low temperatures. In this study, the proteome of L. sakei CRL1862 grown either under biofilm on stainless steel surface and planktonic modes of growth at 10 degrees C, was investigated. Using two-dimensional gel electrophoresis, 29 out of 43 statistically significant spots were identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Ten proteins resulted up-regulated whereas 16 were down regulated during biofilm formation. Differentially expressed proteins were found to belong to carbohydrate, nucleotide, aminoacid and lipid metabolisms as well as translation, peptide hydrolysis, cell envelope/cell wall biosynthesis, adaption to atypical conditions and protein secretion. Some proteins related to carbohydrate and nucleotide metabolisms, translation and peptide degradation were overexpressed whereas those associated to stress conditions were synthesized in lower amounts. It seems that conditions for biofilm development would not imply a stressful environment for L. sakei CRL1862 cells, directing its growth strategy towards glycolytic flux regulation and reinforcing protein synthesis. In addition, L. sakei CRL1862 showed to harbor nine out of ten assayed genes involved in biofilm formation and protein anchoring. By applying qRT-PCR analysis, four of these genes showed to be up regulated, srtA2 being the most remarkable. The results of this study contribute to the knowledge of the physiology of L. sakei CRL1862 growing in biofilm on a characteristic food contact surface. The use of this strain as green biocide preventing L. monocytogenes post-processing contamination on industrial surfaces may be considered. PMID- 28738196 TI - Parental age and the risk of obsessive compulsive disorder and Tourette syndrome / chronic tic disorder in a nationwide population-based sample. AB - OBJECTIVES: Advancing paternal age has been associated with several neuropsychiatric disorders in children. However, there is limited understanding of this association with obsessive compulsive disorder (OCD) and Tourette syndrome/chronic tic disorder (TS/CT) with inconsistent findings. We examined the association between parental age and offspring OCD and TS/CT. METHODS: This nested case-control study used the Finnish Hospital Discharge Register (FHDR) to identify 1358 individuals with OCD and 1195 with TS/CT, born from 1991 to 2009 and diagnosed by 2010. Each case was matched with four controls from the Finnish Population Register (FPR), without diagnoses of OCD, TS/CT or severe or profound mental retardation. Conditional logistic regression was used to examine the association between parental age and OCD, TS/CT. RESULTS: A trend of increasing odds was seen with advancing maternal age. In the final model, offspring of mothers aged 35-39 years had a 1.3-fold increased odd (OR = 1,31, 95% confidence interval (95% CI:1.03-1.66)) of OCD compared with maternal aged 25-29 years. Offspring of fathers younger than 20 years had increased odds of TS/CT in the unadjusted analysis (OR = 2.43, 95% CI: 1.27-4.56). LIMITATIONS: The study limitations included using hospital diagnoses to identify cases, with limited diagnostic validity, and the possible over representation of moderate to severe cases. CONCLUSIONS: The lack of association between advancing paternal age and OCD is in contrast with schizophrenia, despite sharing demographic characteristics and possible shared neuropathology. Furthermore, these differences suggest different etiological pathways among TS/CT, autism spectrum disorder (ASD) and attention deficit/hyperactive disorder (ADHD), despite their frequently comorbid existence. PMID- 28738197 TI - Tracking changes in composition and amount of dissolved organic matter throughout drinking water treatment plants by comprehensive two-dimensional gas chromatography-quadrupole mass spectrometry. AB - Dissolved organic matter (DOM) can affect the performance of water treatment processes and produce undesirable disinfection by-products during disinfection. Several studies have been undertaken on the structural characterization of DOM, but its fate during drinking water treatment processes is still not fully understood. In this work, the nontargeted screening method of comprehensive two dimensional gas chromatography-quadrupole mass spectrometry (GC*GC-qMS) was used to reveal the detailed changes of different chemical classes of compounds in DOM during conventional and advanced drinking water treatment processes at three drinking water treatment plants in China. The results showed that when the dissolved organic carbon removal was low, shifts in the DOM composition could not be detected with the specific ultraviolet absorbance at 254nm, but the changes were clear in the three-dimensional fluorescence excitation-emission matrix or GC*GC-qMS analyses. Coagulation-sedimentation processes selectively removed 37 59% of the nitrogenous compounds, alcohols and aromatic hydrocarbons but increased the concentrations of halogen-containing compounds by 17-26% because of the contact time with chlorine in this step. Filtration was less efficient at removing DOM but preferentially removed 21-60% of the acids. However, other organic matter would be released from the filter (e.g., nitrogenous compounds, acids, and aromatic hydrocarbons). Biological activated carbon (BAC) treatment removed most of the compounds produced from ozonation, particularly ketones, alcohols, halogen-containing compounds and acids. However, it should be noted that certain highly polar or high molecular weight compounds not identified in this study might be released from the BAC bed. After the whole treatment processes, the concentrations of nitrogenous compounds, alcohols, alkenes, aromatic hydrocarbons and ketones were decreased more by the advanced treatment processes than by the conventional treatment processes. Alcohol and ketone removals were probably related to the reduction in protein-like materials. Alkane removal was probably related to the reduction in fulvic acid-like and humic acid like materials. PMID- 28738198 TI - Stability of cognitive development during the first five years of life in relation to heavy metal concentrations in umbilical cord blood: Mothers' and Children's Environmental Health (MOCEH) birth cohort study. AB - The objective of this study was to investigate stability of cognitive development during the first five years of life in relation to heavy metal concentrations in umbilical cord blood in Korean children. This research is part of the Mothers' and Children's Environmental Health (MOCEH) study, a multi-center prospective birth cohort study of pregnant women in Korea who were recruited from 2006 to 2010. We analyzed the complete follow-up data of children who were 5years-old in 2016. We measured lead, mercury, and cadmium levels in the umbilical cord blood of 251 children, and analyzed them, for whom neurodevelopmental data were available. We determined stability of cognitive development scores using three methods. First, we used partial correlation analyses to examine the stability of cognitive development at each measurement time. Second, we used Cramer's V to investigate the magnitude and direction of changes in cognitive development scores at each follow-up period among three groups (high, medium, and low scores). The results showed that cognitive development scores measured at the closest times had the strongest correlations, and the stability of cognitive development scores increased with age, from 6 to 60months. Groups at the extreme ends of cognitive development (high or low scores) had more stable scores, and this tendency was also stronger in infants >24months-old. The stability of cognitive development was unrelated to the umbilical cord level of heavy metals, based on analysis with Fisher's transformation. In conclusion, the present study showed that the cognitive development scores in a cohort of infants (6 to 60months-old) were stable. PMID- 28738199 TI - Acute ecotoxicity of coated colloidal goethite nanoparticles on Daphnia magna: Evaluating the influence of exposure approaches. AB - Synthesized iron oxide nanoparticles have been proposed as an alternative to non dispersed iron oxides for in situ environmental remediation. Their colloidal properties enable their injection into porous media, i.e. soils and aquifers, and offer a higher efficiency in removing contaminants. However, this dispersed state is also the cause of concerns over their environmental fate and toxicity, e.g., by increasing the exposure time to aquatic organisms in groundwater remediation activities. Therefore, the objective of in situ groundwater remediation is to establish local reactive barriers in the subsurface by injection by means of reactive colloids with a controllable mobility under in situ conditions and present as colloids as shortly as possible. In this work, we examined the toxicity of humic acid-coated colloidal goethite nanoparticles in Daphnia magna. The adaptation of the ecotoxicological standard tests for nanomaterials is intensely discussed to increase comparability and reliability of results. In the present study, the effect of different exposure conditions on goethite nanoparticles colloidal behaviour and acute Daphnia immobilization effects was investigated. For this purpose, iron concentration in the water column, aggregation state and acute effects were studied in: i) a standard test, ii) test design with exposure dispersions incubated for a week and iii) water accommodated fraction. Despite the different aggregation and settling of the particles found between the approaches tested, no differences in toxicity were observed. Coated nanoparticles were found clogging up the filtering apparatus, and/or adhered to the exoskeleton, hindering the swimming and molting, and causing the immobilization and death of the organisms at doses of >=943mg/L (EC50). The data suggests that the toxic potential of these nanoparticles is mainly related to the physical interaction with the daphnids. PMID- 28738200 TI - Global distribution of dissolved organic matter along the aquatic continuum: Across rivers, lakes and oceans. AB - Based on an extensive literature survey containing more than 12,000 paired measurements of dissolved organic carbon (DOC) concentrations and absorption of chromophoric dissolved organic matter (CDOM) distributed over four continents and seven oceans, we described the global distribution and transformation of dissolved organic matter (DOM) along the aquatic continuum across rivers and lakes to oceans. A strong log-linear relationship (R2=0.92) between DOC concentration and CDOM absorption at 350nm was observed at a global scale, but was found to be ecosystem-dependent at local and regional scales. Our results reveal that as DOM is transported towards the oceans, the robustness of the observed relation decreases rapidly (R2 from 0.94 to 0.44) indicating a gradual decoupling between DOC and CDOM. This likely reflects the decreased connectivity between the landscape and DOM along the aquatic continuum. To support this hypothesis, we used the DOC-specific UV absorbance (SUVA) to characterize the reactivity of the DOM pool which decreased from 4.9 to 1.7m2 * gC-1 along the aquatic continuum. Across the continuum, a piecewise linear regression showed that the observed decrease of SUVA occurred more rapidly in freshwater ecosystems compared to marine water ecosystems, suggesting that the different degradation processes act preferentially on CDOM rather than carbon content. The observed change in the DOM characteristics along the aquatic continuum also suggests that the terrestrial DOM pool is gradually becoming less reactive, which has profound consequences on cycling of organic carbon in aquatic ecosystems. PMID- 28738201 TI - Interbasin water transfer for the rehabilitation of a transboundary Mediterranean stream: An economic analysis. AB - Global demand for freshwater is increasing as human population grows, climate changes and water resources are being overexploited. Consequently, many freshwater ecosystems, particularly in water-stressed regions, are severely degraded. Here we present a unique case of an Interbasin Water Transfer (IWT) project aiming at ecosystem rehabilitation and recreation enhancement of an intermittent transboundary stream (Ayun, Israel). For the past century, water diversion at the Lebanese side had led to flow secession in the Israeli Ayun Nature Reserve during the dry season (May-November). To restore flow continuum, a sum of 0.5 million cubic meters of high quality freshwaters have been allocated annually during the dry months. The aim of this study is to evaluate the IWT project by: (1) examining the correlation between water flow in the Ayun and recreational visitation, and (2) performing a cost-benefit analysis of the IWT scheme, including non-market benefits. A time-series regression (Adj. R2 = 0.688, n = 125) shows that a 10% increase in water flow corresponds to a 2.1% increase in monthly visitors. An estimated 18.8% of the visitation rate between 2009 and 2015 can be attributed to the water reallocation project. Through a single-site travel cost model, we estimate the visitor's willingness to pay in US$ 37.8 per person per trip. When non-market benefits for recreation are included, the total benefits of the IWT project substantially exceed its costs. Our results suggest that IWT can be applied to restore water flow and enhance ecosystem services also in water-stressed regions. PMID- 28738202 TI - Predicting carbon benefits from climate-smart agriculture: High-resolution carbon mapping and uncertainty assessment in El Salvador. AB - Agroforestry management in smallholder agriculture can provide climate change mitigation and adaptation benefits and has been promoted as 'climate-smart agriculture' (CSA), yet has generally been left out of international and voluntary carbon (C) mitigation agreements. A key reason for this omission is the cost and uncertainty of monitoring C at the farm scale in heterogeneous smallholder landscapes. A largely overlooked alternative is to monitor C at more aggregated scales and develop C contracts with groups of land owners, community organizations or C aggregators working across entire landscapes (e.g., watersheds, communities, municipalities, etc.). In this study we use a 100-km2 agricultural area in El Salvador to demonstrate how high-spatial resolution optical satellite imagery can be used to map aboveground woody biomass (AGWB) C at the landscape scale with very low uncertainty (95% probability of a deviation of less than 1%). Uncertainty of AGWB-C estimates remained low (<5%) for areas as small as 250 ha, despite high uncertainties at the farm and plot scale (34-99%). We estimate that CSA adoption could more than double AGWB-C stocks on agricultural lands in the study area, and that utilizing AGWB-C maps to target denuded areas could increase C gains per unit area by 46%. The potential value of C credits under a plausible adoption scenario would range from $38,270 to $354,000 yr-1 for the study area, or about $13 to $124 ha-1 yr-1, depending on C prices. Considering farm sizes in smallholder landscapes rarely exceed 1-2 ha, relying solely on direct C payments to farmers may not lead to widespread CSA adoption, especially if farm-scale monitoring is required. Instead, landscape scale approaches to C contracting, supported by satellite-based monitoring methods such as ours, could be a key strategy to reduce costs and uncertainty of C monitoring in heterogeneous smallholder landscapes, thereby incentivizing more widespread CSA adoption. PMID- 28738204 TI - The fate of sotalol in aqueous chlorination: Kinetics, mechanisms and ecotoxicity assessment. AB - Unmetabolized pharmaceuticals often enter the water treatment plants and exposed to various treatment processes. Among these water treatment processes, disinfection is a process which involves the application of chemical oxidation to remove pathogen. Untreated pharmaceuticals from primary and secondary treatment have the potential to be exposed to the chemical oxidation process during disinfection. This study investigated the kinetics and mechanism of the degradation of sotalol during chlorination process. Chlorination with hypochlorous acid (HOCl) as main reactive oxidant has been known as one of the most commonly used disinfection methods. The second order rate constant for the reaction between sotalol and free available chlorine (FAC) was found to decrease from 60.1 to 39.1M-1min-1 when the pH was increased from 6 to 8. This result was mainly attributed by the decreased of HOCl concentration with increasing pH. In the real water samples, the presence of the higher amount of organic content was found to reduce the efficiency of chlorination in the removal of sotalol. This result showed that sotalol competes with natural organic matter to react with HOCl during chlorination. After 24h of FAC exposure, sotalol was found to produce three stable transformation by-products. These by-products are mainly chlorinated compounds. According to the acute and chronic toxicity calculated using ECOSAR computer program, the transformation by-products are more harmful than sotalol. PMID- 28738203 TI - Early detection monitoring for aquatic non-indigenous species: Optimizing surveillance, incorporating advanced technologies, and identifying research needs. AB - Following decades of ecologic and economic impacts from a growing list of nonindigenous and invasive species, government and management entities are committing to systematic early- detection monitoring (EDM). This has reinvigorated investment in the science underpinning such monitoring, as well as the need to convey that science in practical terms to those tasked with EDM implementation. Using the context of nonindigenous species in the North American Great Lakes, this article summarizes the current scientific tools and knowledge - including limitations, research needs, and likely future developments - relevant to various aspects of planning and conducting comprehensive EDM. We begin with the scope of the effort, contrasting target-species with broad-spectrum monitoring, reviewing information to support prioritization based on species and locations, and exploring the challenge of moving beyond individual surveys towards a coordinated monitoring network. Next, we discuss survey design, including effort to expend and its allocation over space and time. A section on sample collection and analysis overviews the merits of collecting actual organisms versus shed DNA, reviews the capabilities and limitations of identification by morphology, DNA target markers, or DNA barcoding, and examines best practices for sample handling and data verification. We end with a section addressing the analysis of monitoring data, including methods to evaluate survey performance and characterize and communicate uncertainty. Although the body of science supporting EDM implementation is already substantial, research and information needs (many already actively being addressed) include: better data to support risk assessments that guide choice of taxa and locations to monitor; improved understanding of spatiotemporal scales for sample collection; further development of DNA target markers, reference barcodes, genomic workflows, and synergies between DNA-based and morphology-based taxonomy; and tools and information management systems for better evaluating and communicating survey outcomes and uncertainty. PMID- 28738205 TI - Developing and applying a site-specific multimedia fate model to address ecological risk of oxytetracycline discharged with aquaculture effluent in coastal waters off Jangheung, Korea. AB - The overuse of oxytetracycline (OTC) in aquaculture has become a problem because of its chronic toxic effects on marine ecosystems. The present study assessed the ecological risk of OTC in the coastal waters near the Jangheung Flatfish Farm using a site-specific multimedia fate model to analyze exposure. Before the model was applied, its performance was validated by comparing it with field data. The coastal waters in the testbed were sampled and analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS) followed by solid-phase extraction (SPE). The concentrations of OTC measured varied from 7.05 to 95.39ng/L. The results of validating the models showed that the site-specific multimedia fate model performed better (root mean square error (RMSE): 24.217, index of agreement (IOA): 0.739) than conventional fugacity approaches. This result demonstrated the utility of this model in supporting effective future management of aquaculture effluent. The results of probabilistic risk assessment indicated that OTC from aquaculture effluent did not cause adverse effects, even in a maximum-use scenario. PMID- 28738206 TI - A preliminary study on the effects of lanthanum (III) on plant vitronectin-like protein and its toxicological basis. AB - Vitronectin-like protein (VN) is widely found outside plant plasma membranes. The VN molecular surface contains a large number of active groups that combine strongly with rare earth elements (REEs), which means that VN is a preferential binding target for REEs exhibiting their toxic effects, but the toxicological mechanism remains unknown. This study used transmission electron microscopy, circular dichroism, fluorescence spectrometry, ultraviolet-visible spectroscopy, X-ray photoelectron spectroscopy, and calculational chemistry (homology modeling, molecular dynamics simulation and quantum chemical calculation) to preliminarily investigate the effect of lanthanum [La(III)] as an REE, on the structure of VN and its toxicological mechanism. The results showed that low-concentration La(III) could cause micro-interference to the VN molecular structure through weak interactions, such as electrostatic attraction. High-concentration La(III) formed stable complexes with VN, which changed the average binding energy and electron cloud density of VN, loosened the molecular structure and increased the disorder of VN molecule. The results of building a 3D model of VN and simulating the interaction between La(III) and VN using calculational chemistry showed that La(H2O)73+ in solution could coordinately bind to the carboxyl-/carbonyl-O groups in the negatively charged areas on the VN molecular surface. Furthermore, one or more strong H-bonds were formed to enhance the stability of the La(H2O)73+-VN complexes. In summary, low La(III) concentrations could cause micro-interference to the VN molecular structure, whereas high La(III) concentrations could coordinately bind to VN to form stable La-VN complexes, which destroyed the molecular structure of VN; thus the toxicological basis by which La(III) exhibits its toxic effects is its binding to VN. PMID- 28738207 TI - Translocation of heavy metals from soils into floral organs and rewards of Cucurbita pepo: Implications for plant reproductive fitness. AB - Metals and metalloids in soil could be transferred into reproductive organs and floral rewards of hyperaccumulator plants and influence their reproductive success, yet little is known whether non-hyperaccumulator plants can translocate heavy metals from soil into their floral organs and rewards (i.e., nectar and pollen) and, if so, whether plant reproduction will be affected. In our studies, summer squash (Cucurbita pepo L. cv. Golden Apple) was exposed to heavy-metal treatments during bud stage to investigate the translocation of soil-supplemented zinc, copper, nickel and lead into its floral organs (pistil, anther and nectary) and rewards (nectar and pollen) as well as floral metal accumulation effects on its reproduction. The results showed that metals taken up by squash did translocate into its floral organs and rewards, although metal accumulation varied depending on different metal types and concentrations as well as floral organ/reward types. Mean foraging time of honey bees to each male and female flower of squash grown in metal-supplemented soils was shorter relative to that of plants grown in control soils, although the visitation rate of honeybees to both male and female flowers was not affected by metal treatments. Pollen viability, pollen removal and deposition as well as mean mass per seed produced by metal-treated squash that received pollen from plants grown in control soils decreased with elevated soil-supplemented metal concentrations. The fact that squash could translocate soil-supplemented heavy metals into floral organs and rewards indicated possible reproductive consequences caused either directly (i.e., decreasing pollen viability or seed mass) or indirectly (i.e., affecting pollinators' visitation behavior to flowers) to plant fitness. PMID- 28738208 TI - Plastid transformation and its application in metabolic engineering. AB - Metabolic pathway engineering by transgene expression from the plastid (chloroplast) genome offers significant attractions, including straightforward multigene engineering by pathway expression from operons, high transgene expression levels, and increased transgene containment due to maternal inheritance of plastids in most crops. In addition, it provides direct access to the large and diverse metabolite pools in chloroplasts and non-green plastid types. Here, we review recent progress with extending the toolbox for plastid engineering and highlight selected applications in the area of metabolic engineering, including the combined engineering of nuclear and plastid genomes for the production of artemisinic acid, the direct harness of chloroplast reducing power for the synthesis of dhurrin and the use of an edible host for the production of astaxanthin. PMID- 28738209 TI - Psoriasis: a mixed autoimmune and autoinflammatory disease. AB - In recent years marked progress has been made in our understanding of the critical biologic and immunologic pathways involved in psoriasis. Genetic studies have demonstrated that susceptibility to psoriasis involves components of both the adaptive and innate immune system and not surprisingly activation of both of these arms of the immune system is found in psoriatic skin. While adaptive immune responses predominate in chronic plaque psoriasis, innate and autoinflammatory responses dominate in pustular forms of psoriasis, with other clinical subtypes extending on a spectrum between plaque and pustular psoriasis. This makes psoriasis a unique disease where both autoimmune and autoinflammatory responses co-exist, with the balance between the two being critical in shaping its clinical presentation. PMID- 28738210 TI - Neural activity and emotional processing following military deployment: Effects of mild traumatic brain injury and posttraumatic stress disorder. AB - Posttraumatic Stress Disorder (PTSD) and mild traumatic brain injury (mTBI) are common comorbidities during military deployment that affect emotional brain processing, yet few studies have examined the independent effects of mTBI and PTSD. The purpose of this study was to examine distinct differences in neural responses to emotional faces in mTBI and PTSD. Twenty-one soldiers reporting high PTSD symptoms were compared to 21 soldiers with low symptoms, and 16 soldiers who reported mTBI-consistent injury and symptoms were compared with 16 soldiers who did not sustain an mTBI. Participants viewed emotional face expressions while their neural activity was recorded (via event-related potentials) prior to and following deployment. The high-PTSD group displayed increased P1 and P2 amplitudes to threatening faces at post-deployment compared to the low-PTSD group. In contrast, the mTBI group displayed reduced face-specific processing (N170 amplitude) to all facial expressions compared to the no-mTBI group. Here, we identified distinctive neural patterns of emotional face processing, with attentional biases towards threatening faces in PTSD, and reduced emotional face processing in mTBI. PMID- 28738212 TI - The pattern of self-harm in Fars Province in South Iran: A population-based study. AB - Non-suicidal self-harm includes cutting, scratching, burning and minor overdosing. There have been few studies that have examined the rate and pattern of self-harm among different individuals of the society. We performed a population-based study to determine different aspects of non-suicidal self-harm in cases referred to legal medicine organization of Fars Province and south Iran. In a population-based longitudinal survey, we applied data from cases referred to legal medicine organization of Fars province. The survey included questions about the history, method, frequency, age of onset and help-seeking for non-suicidal self-harm. The data about non-suicidal self-harm were collected since 2007 to 2011 and analyzed using students' T-test for continuous data and chi2 for binary or categorical data using SPSS ver. 21.0. Totally 2166 individuals were diagnosed who had ever harmed themselves. Self-injuries such as cutting, scratching and self-hitting were the most common forms of non-suicidal self-harm (83.2%). The mean age of onset was 25.7 +/- 2.6 years. Self-injury was more frequent in males and individuals with lower education levels mostly unemployed. The most frequent injury site was posterior side of the body for example shoulders (157; 9.8%) and the most type of the injury was bruise in 398(55.26%) cases. Hard objects (1197; 55.26%) were the most used devices for self-injury followed by cutting and sharp devices. Among those who reported non-suicidal self-harm, 56% had sought help while self-injury. We found a high prevalence of non-suicidal self-harm in different individuals of the society in Fars province since 2007 to 2011. Many mental-health symptoms as well as legal and financial gains should be evaluated for any association with this behavior. PMID- 28738211 TI - The immunopathology of dengue and Zika virus infections. AB - A large proportion of the world's population live in areas with dengue virus (DENV) transmission resulting in tens of millions of symptomatic dengue cases each year. Serious complications following DENV infection occur more frequently in those suffering from a second or subsequent infection implicating virus specific immunity as having a role in pathogenesis. In recent years outbreaks of the related Zika virus (ZIKV) have been associated with birth defects and neurological complications. As DENV and ZIKV share a viral vector sequential infections can occur. Given the sequence homology between the two viruses, the generation of cross-reactive immune responses is highly likely. This review examines the role immunopathogenesis plays during DENV infection as well as highlighting recent studies that demonstrate DENV immunity may have an effect on the outcome of ZIKV infection. PMID- 28738213 TI - Determinants of the magnitude of socioeconomic inequalities in mortality: A study of 17 European countries. AB - The magnitude of socioeconomic inequalities in mortality differs importantly between countries, but these variations have not been satisfactorily explained. We explored the role of behavioral and structural determinants of these variations, by using a dataset covering 17 European countries in the period 1970 2010, and by conducting multilevel multivariate regression analyses. Our results suggest that between-country variations in inequalities in current mortality can partly be understood from variations in inequalities in smoking, excessive alcohol consumption, and poverty. Also, countries with higher national income, higher quality of government, higher social transfers, higher health care expenditure and more self-expression values have smaller inequalities in mortality. Finally, trends in behavioral risk factors, particularly smoking and excessive alcohol consumption, appear to partly explain variations in inequalities in mortality trends. This study shows that analyses of variations in health inequalities between countries can help to identify entry-points for policy. PMID- 28738215 TI - Factors associated with appointment-keeping in an American University's dental clinic system: toward practice-based population health. PMID- 28738214 TI - Plasmodium falciparum in vitro continuous culture conditions: A comparison of parasite susceptibility and tolerance to anti-malarial drugs throughout the asexual intra-erythrocytic life cycle. AB - The continuous culture of Plasmodium falciparum is often seen as a means to an end, that end being to probe the biology of the parasite in question, and ultimately for many in the malaria drug discovery arena, to identify means of killing the parasite in order to treat malaria. In vitro continuous culture of Plasmodium falciparum is a fundamental requirement when undertaking malaria research where the primary objectives utilise viable parasites of a desired lifecycle stage. This investigation, and resulting data, compared the impact culturing Plasmodium falciparum long term (4 months) in different environmental conditions had on experimental outcomes and thus conclusions. The example presented here focused specifically on the effect culture conditions had on the in vitro tolerance of Plasmodium falciparum to standard anti-malarial drugs, including artemisinin and lumefantrine. Historical data from an independent experiment for 3D7-ALB (5% O2) was also compared with that obtained from this study. We concluded that parasites cultured for several months in media supplemented with a serum substitute such as Albumax II(r) or within hyperoxic conditions (21% O2), demonstrate highly variable responses to artemisinin and lumefantrine but not all anti-malarial drugs, when compared to those cultured in human serum in combination with Albumax II(r) under normoxic conditions (5% O2) for the parasite. PMID- 28738216 TI - Early time-related course of image findings in postmortem MRI: Typical findings and observer agreement in a porcine model. AB - PURPOSE: To assess early time-related image findings in postmortem magnetic resonance imaging (MRI) and to evaluate observer agreement in a porcine model. MATERIAL AND METHODS: Three pigs were examined by MRI at 15 different time points in the first 36h after death. Two observers independently recorded the postmortem interval (PMI) to the appearance of fluid collection (pleural space, interlobar and interlobular pulmonary fissures and hepatic interlobar fissures), gas accumulation (intrahepatic and intracardial) and blood clotting (aorta and intrahepatic venous vessels). Cohen's Kappa statistics and intraclass correlation coefficient (ICC) were used to evaluate intra- and interobserver agreement. RESULTS: Intrahepatic gas was evident after 12, 17 and 30h. Also, intracardiac gas was present in all animals. However, no chronological appearance has been observed. Blood clotting in the hepatic vein was observed within 3min, aortic clotting with a delay of 2-12h after death. Interlobular pulmonary fluid (median PMI: 2h, range 2-2h), pleural effusion (median PMI: 10.5h, range 9-12h) and hepatic interlobar fissure fluid (median PMI: 11.5h, range 11-12h) displayed a chronological appearance pattern. Qualitative and quantitative detection of most postmortem findings showed excellent intra- and interobserver agreement with Kappa values>0.8 or ICC>0.75. CONCLUSION: Pulmonary and hepatic fissural fluid collection as well as intravasal gas accumulation are early time-related image findings in postmortem MRI. The chronological appearance of these findings can be assessed with excellent observer agreement in a porcine model. PMID- 28738217 TI - Association between an indel polymorphism in the 3'UTR of COL1A2 and the risk of sudden cardiac death in Chinese populations. AB - Sudden cardiac death (SCD) describes the unexpected natural death from a cardiac cause within a short time period. Compelling evidence suggests the involvement of host genetic factors in SCD etiology. Identification of genetic variations predisposed to SCD enables genetic testing that may contribute to SCD diagnosis and risk stratification. Previous studies have suggested that dysregulation of pro-alpha2 chain of type I collagen, encoded by collagen type I alpha 2 chain (COL1A2) gene, was involved in cardiac disorders such as myocardial infarction, hypertrophic cardiomyopathy and atherosclerosis. By using a candidate-gene-based approach, we evaluated the association of a 7-base pair (7-bp) indel polymorphism (rs3917) in the 3'UTR of COL1A2 with the risk of SCD in a Chinese population (79SCD cases and 328 controls). Logistic regression analysis showed that the deletion allele of rs3917 significantly increased the risk of SCD [odds ratio (OR)=1.82; 95% confidence interval (CI)=1.08-3.06; P=0.0159]. Further genotype phenotype association analysis revealed that the deletion allele was markedly correlated with lower expression of COL1A2 in human myocardium tissues. The luciferase activity analysis in an in vitro reporter gene system suggested that rs3917 could regulate COL1A2 expression through interrupting the binding of miR 296-3p with COL1A2 in an allele-dependent manner, which in turn confer SCD risk. Our data provided initial evidence that rs3917 was highly relevant to SCD susceptibility, and this indel may become a potential marker for molecular diagnosis and genetic counseling of SCD. The replication of our studies and further functional studies are needed to validate our findings. PMID- 28738218 TI - Common variation in the autism risk gene CNTNAP2, brain structural connectivity and multisensory speech integration. AB - Three lines of evidence motivated this study. 1) CNTNAP2 variation is associated with autism risk and speech-language development. 2) CNTNAP2 variations are associated with differences in white matter (WM) tracts comprising the speech language circuitry. 3) Children with autism show impairment in multisensory speech perception. Here, we asked whether an autism risk-associated CNTNAP2 single nucleotide polymorphism in neurotypical adults was associated with multisensory speech perception performance, and whether such a genotype-phenotype association was mediated through white matter tract integrity in speech-language circuitry. Risk genotype at rs7794745 was associated with decreased benefit from visual speech and lower fractional anisotropy (FA) in several WM tracts (right precentral gyrus, left anterior corona radiata, right retrolenticular internal capsule). These structural connectivity differences were found to mediate the effect of genotype on audiovisual speech perception, shedding light on possible pathogenic pathways in autism and biological sources of inter-individual variation in audiovisual speech processing in neurotypicals. PMID- 28738219 TI - Finding features, figuratively. AB - Object concepts refer to unique clusters of properties that can be selectively activated or inhibited depending on what information is currently relevant. This conceptual "stretching" enables limitless new meanings to be generated, and figurative language provides a useful framework in which to study this conceptual flexibility. Here we probe the cognitive and neural mechanisms underlying the comprehension of novel metaphors as a means of understanding the conceptual flexibility inherent to language processing more generally. We show that novel metaphor comprehension involves the activation or inhibition of conceptual properties that are either relevant or irrelevant to the metaphor, and that left inferior frontal gyrus is recruited in this process, supporting a role for this region in the fine-tuning of conceptual meaning. Our results are consistent with a flexible, compositional account of conceptual structure in which semantic control mechanisms operate over conceptual properties during figurative language comprehension in order to create context-dependent meaning. PMID- 28738221 TI - Self-efficacy of physical education teachers in including students with cerebral palsy in their classes. AB - Children with cerebral palsy (CP) are often mainstreamed into the general education system, but are likely to be excluded from physical education (PE) classes. A questionnaire was constructed and utilized to measure PE teachers' self-efficacy (SE) toward inclusion of students with CP in each of three mobility categories (independent, using assistive devices, using wheelchair mobility) and the impact of experience and training on teachers' SE. Participants in the study were 121 PE teachers from different parts of Israel (mean age: 41.02+/-9.33 years; range: 25.00-59.00 years). Exploratory factor analysis was used to determine the structure of the sub-scales' factors' structure and Cronbach's Alpha reliability was satisfactory (range 0.872-0.941). Independent t-tests were calculated in order to compare the SE of teachers with and without adapted PE experience. Repeated Analysis of Variance was performed to measure within-group differences in SE. Results revealed that the PE teachers' SE in teaching students who use mobility assistive devices or wheelchairs was significantly lower compared to teaching those who walk and run unaided (F=19.11; p<0.001). The teachers' SE towards including CP children who independently ambulate was influenced (p<0.05; d=0.94) by the teacher's experience (elementary school practicum). SE in the mobility with assistive device group was also significantly influenced (p<0.05; d=0.1) by teaching experience (previous experience and having a specialization in adapted PE). Finally, SE when teaching the wheelchair mobility group was influenced by having an adapted PE specialization (p<0.05; d=0.82). Specialized training in this particular area should be enhanced to increase teachers' SE and enable greater participation of children with CP in general physical education classes. PMID- 28738220 TI - Adolescent peer networks and the moderating role of depressive symptoms on developmental trajectories of cannabis use. AB - This paper investigated how depressive symptoms moderate the role of peer cannabis use on developmental patterns of individual cannabis use from adolescence to young adulthood, controlling for a broad set of individual and family factors. Data from two sources were analyzed separately: two saturated schools in the National Longitudinal Study of Adolescent to Adult Health Waves I III (N=1550) covering 1994-2001; and three schools in the CARBIN study, covering 2012-2014. Discrete mixture models identified developmental trajectories of cannabis use in each data source, and logit models linked network and depressive symptom information to the trajectories. Five similar cannabis use trajectories were identified in both datasets: Nonuse, Low, Moderate, Increasing, and High. Peer cannabis use at baseline predicted higher individual cannabis use trajectories, controlling for a wide range of factors. However, the association between peer cannabis use and higher levels of use (Moderate and High) attenuated as the adolescent's level of depressive symptoms increased. Although these results may suggest that depression dampers adolescents' susceptibility to peer influence, these results are also consistent with the notion that depressed adolescents withdraw from their peer groups, distancing them from the initial source of peer influence over time. The resulting isolation may place adolescents at higher risk of adverse outcomes. PMID- 28738222 TI - Thinking inside the box: Spatial frames of reference for drawing in Williams syndrome and typical development. AB - BACKGROUND: Successfully completing a drawing relies on the ability to accurately impose and manipulate spatial frames of reference for the object that is being drawn and for the drawing space. Typically developing (TD) children use cues such as the page boundary as a frame of reference to guide the orientation of drawn lines. Individuals with Williams syndrome (WS) typically produce incohesive drawings; this is proposed to reflect a local processing bias. AIMS: Across two studies, we provide the first investigation of the effect of using a frame of reference when drawing simple lines and shapes in WS and TD groups (matched for non-verbal ability). METHODS AND PROCEDURES: Individuals with WS (N=17 Experiment 1; N=18 Experiment 2) and TD children matched by non-verbal ability drew single lines (Experiment One) and whole shapes (Experiment Two) within a neutral, incongruent or congruent frame. The angular deviation of the drawn line/shape, relative to the model line/shape, was measured. OUTCOMES AND RESULTS: Both groups were sensitive to spatial frames of reference when drawing single lines and whole shapes, imposed by a frame around the drawing space. CONCLUSIONS AND IMPLICATIONS: A local processing bias in WS cannot explain poor drawing performance in WS. PMID- 28738223 TI - Engineering resistance against viroids. AB - Viroids, the smallest infectious agents endowed with autonomous replication, are tiny single-stranded circular RNAs (~250 to 400nt) without protein-coding ability that, despite their simplicity, infect and often cause disease in herbaceous and woody plants of economic relevance. To mitigate the resulting losses, several strategies have been developed, the most effective of which include: firstly, search for naturally resistant cultivars and breeding for resistance, secondly, induced resistance by pre-infection with mild strains, thirdly, ribonucleases targeting double-stranded RNAs and catalytic antibodies endowed with intrinsic ribonuclease activity, fourthly, antisense, and sense, RNAs, fifthly, catalytic antisense RNAs derived from hammerhead ribozymes, and sixthly, hairpin RNAs and artificial small RNAs for RNA interference. The mechanisms underpinning these strategies, most of which have been implemented via genetic transformation, together with their present results and future potential, are the subject of this review. PMID- 28738224 TI - Meat from cattle slaughtered without stunning sold in the conventional market without appropriate labelling: A case study in Italy. AB - In the European Union, slaughter without stunning is allowed for religious slaughter to obtain halal and kosher meat. Especially in the case of Jewish slaughtering, cuts which are not deemed as kosher are sold to regular market without any specific labelling. This survey, conducted in Tuscany in 2016, aimed to quantify the carcasses rejected in relation to the type of religious slaughter. 656 bovines were slaughtered without stunning: 538 (82%) for halal and 118 (18%) for kosher. All carcasses slaughtered by the Islamic procedure (dhabiha) were considered halal, while 77.1% of carcasses slaughtered by the Jewish procedure (shechita) did not pass the approval. Carcasses were rejected after chest cavity inspection (50%) and after the lungs control (50%). This study provides an important insight in this field and postulates how to amalgamate the concepts of freedom of religion, as enshrined by the Charter of Fundamental Rights of the EU, with consumer rights and animal welfare. PMID- 28738225 TI - The effect of low-fat beef patties formulated with a low-energy fat analogue enriched in long-chain polyunsaturated fatty acids on lipid oxidation and sensory attributes. AB - A new low-energy gelled emulsion containing algae oil was developed as animal fat replacer. Its stability was evaluated under different storage conditions: 4V (4 degrees C/vacuum), 4NV (4 degrees C/no vacuum), 25V (25 degrees C/vacuum) and 25NV (25 degrees C/no vacuum). According to moisture, hardness, color and lipid oxidation data, 4 degrees C under vacuum (4V) was selected as the best condition. Once the gelled emulsion was characterized, its effectiveness as fat analogue was demonstrated in beef patties. Reformulated patties were produced with 100% of animal fat replacement and compared to conventional patties (9%fat). A 70%fat reduction was achieved in the new patties, mainly due to a reduction in the saturated fatty acids. Also, decreased n-6 (76%lower content) and increased eicosapentaenoic and docosahexaenoic acids (55%higher content) were noticed in the new formulation. The incorporation of the gelled emulsion containing reduced amount of n-6 fatty acids and increased amounts of long chain n-3 fatty acids (EPA+DHA) reduced the oxidation status of the patties and their sensory evaluation resulted in acceptable scores. PMID- 28738226 TI - Shock attenuation characteristics of three different military boots during gait. AB - Musculoskeletal injuries are related to the cushioning properties of boots in military populations. This study aimed to compare ground reaction force (GRF) and subjective perceived comfort from two different military boots supplied by the Brazilian Army with a commercial boot. Twenty army recruits volunteered for a GRF assessment during walking on a 10-m walkway and a perceived comfort test after 20min walking on a treadmill. Both experiments were conducted with three different military boots: CC10 (styrene-butadiene rubber - SBR - midsole 30mm thickness, 65 Shore A; 631.8g weight; supplied by the Brazilian Army); CC13 (SBR midsole 20.6mm thickness, 66 Shore A; 530.3g weight; supplied by the Brazilian Army) and CAT (polyurethane - PU - midsole 31.7mm thickness, 55 Shore A; 423g weight; commercially available). GRF was analyzed in the time (principal component analysis - PCA) and frequency (Blackman-Tukey) domains. No difference was found for the first and second peak forces or loading rate; however, significant influence from the military boots' design on GRF was found by PCA and frequency analysis. Loading factor presented higher values at early stance with lower force for CC10 compared to CC13 at these epochs. CC13 also presented higher power spectral density compared to CC10 at higher frequency bands. However, CAT was significantly more comfortable than CC10. These results suggest that the thicker SBR midsole boot was more effective in reducing impact, while the lightest boot with softer midsole hardness made with PU was the most comfortable. PMID- 28738227 TI - Rapid and reliable determination of p-nitroaniline in wastewater by molecularly imprinted fluorescent polymeric ionic liquid microspheres. AB - Rapid and efficient detecting trace amount of environmental p-nitroaniline (p-NA) is in urgent need for security concerns and pollution supervision. In this work we report the use of molecularly imprinted polymeric ionic liquid (MIPIL) microspheres to construct recognizable surfaces for detection of p-NA through fluorescence quenching. The p-NA imprinted microspheres are synthesized by precipitation polymerization upon co-polymerization of 3-(anthracen-9-ylmethyl)-1 vinyl-1H-imidazol-3-ium chloride (Fluorescent IL monomer) with ethyleneglycol dimethacrylate (EGDMA). The electron-rich group alkenyl imidazole in IL functional monomer can dramatically improve the emission of anthracene fluorophore and the pi-pi stacking, electronic, and hydrogen bond between p-NA and MIPIL can efficiently enhance the selective recognition force. The as synthesized MIPIL microspheres present spherical shape, high fluorescence emission intensity and specific recognition, which showed rapid detection rate (1min), stable reusable property (at least 4 time recycles), wonderful selectivity over several structural analogs, wide linear range (10nM to 10M) with a correlation coefficient of 0.992, and excellent sensitivity (LOD, 9nM). As synthesis and surface functionalization of MIPIL microspheres are well established, the methods reported in this work are facile, rapid and efficient for monitoring p-NA in environmental wastewater. PMID- 28738228 TI - Streptavidin-hydrogel prepared by sortase A-assisted click chemistry for enzyme immobilization on an electrode. AB - A tetrameric streptavidin (SA)-appended LPETG tag was site-specifically linked to azido-containing tri-glycine via sortase A catalysis and the resulting azido modified SA (SA-N3) was retained in the biotin-binding pocket. SA-N3 was polymerized with dibenzylcyclooctyne-modified branched poly(ethyleneglycol) (DBCO PEG) using azido-modified branched PEG (N3-PEG) as a spacer via copper-free click chemistry. The resulting SA-based hydrogel exhibited gel-like mechanical properties and could immobilize biotin-modified molecules through biotin-SA affinity. Glucose dehydrogenase (GDH) was immobilized in the SA-based hydrogel, and the hydrogel was then coated on a glassy carbon electrode (GCE) and used for the biocatalytic oxidation of glucose. The designed GCE exhibited better performance and stability compared with GDH chemically adsorbed onto a GCE. In addition, the designed GCE anode and a Pt-carbon cathode were assembled into a glucose/O2 fuel cell that provided a maximum power density and open circuit voltage of 11.8+/-0.56uWcm-2 and 0.17V, respectively. PMID- 28738229 TI - A facile one-step method for cell lysis and DNA extraction of waterborne pathogens using a microchip. AB - Globally, waterborne organisms are the primary causative agents for the transmission of various forms of diarrheal diseases. For accurate diagnosis, molecular tools have gained considerable attention in the recent past. Molecular tools require DNA as the starting material for diagnosis, and hence, a prerequisite is the quality and integrity of DNA. To obtain high quality DNA rapidly, we have fabricated a microchip in poly(dimethyl siloxane) (PDMS) by soft lithography process. The microchip facilitated in-flow coating of chitosan on the magnetic nanoparticles, which under external mechanical vibration caused cell lysis and released DNA in the supernatant. The released DNA was captured by the nanoparticles owing to its positive charge (chitosan coating). The magnetic nanoparticle-DNA complex was then isolated from the in-flow matrix using permanent magnet, Further, removal of the cell debris, proteins, and carbohydrates was done using wash buffer. DNA extracted using the microchip was pure with absorbance (260/280) ratio of 1.77+/-0.04, as compared to 1.79+/-0.03 obtained by TRIzol method. The complete isolation of the DNA using the microchip took ~ 15min as against>2h with a TRIzol method. Six gram-negative waterborne pathogens were used to demonstrate the efficacy of the microchip based DNA extraction process. The integrity of the isolated DNA was assessed by amplifying the 16S rRNA gene using Com1 and Com2 universal primers. The presence of a band at 407bp on gel electrophoresis confirmed the amplified product. Further, the gel image was used for quantification of the amplified product using ImageJ software. Higher regression values obtained using microchip confirmed better quality and integrity of the extracted DNA as opposed to the conventional method. The lower (<2%) relative standard deviation values obtained from the data suggested that the microchip process was reproducible. The quality and integrity of the obtained DNA proved the simplicity, rapidity, and sensitivity of the microchip-assisted DNA extraction process. PMID- 28738230 TI - Fluorinated tripodal receptors for potentiometric chloride detection in biological fluids. AB - Fluorinated tripodal compounds were recently reported to be efficient transmembrane transporters for a series of inorganic anions. In particular, this class of receptors has been shown to be suitable for the effective complexation of chloride, nitrate, bicarbonate and sulfate anions via hydrogen bonding. The potentiometric properties of urea and thiourea-based fluorinated tripodal receptors are explored here for the first time, in light of the need for reliable sensors for chloride monitoring in undiluted biological fluids. The ion selective electrode (ISE) membranes with tren-based tris-urea bis(CF3) tripodal compound (ionophore I) were found to exhibit the best selectivity for chloride over major lipophilic anions such as salicylate ( [Formula: see text] ) and thiocyanate ( [Formula: see text] ). Ionophore I-based ISEs were successfully applied for chloride determination in undiluted human serum as well as artificial serum sample, the slope of the linear calibration at the relevant background of interfering ions being close to Nernstian (49.8+/-1.7mV). The results of potentiometric measurements were confirmed by argentometric titration. Moreover, the ionophore I-based ISE membrane was shown to exhibit a very good long-term stability of potentiometric performance over the period of 10 weeks. Nuclear magnetic resonance (NMR) titrations, potentiometric sandwich membrane experiments and density functional theory (DFT) computational studies were performed to determine the binding constants and suggest 1:1 complexation stoichiometry for the ionophore I with chloride as well as salicylate. PMID- 28738232 TI - Molecular tools and emerging strategies for deep genetic/genomic refactoring of Pseudomonas. AB - The interest of the genus Pseudomonas largely relies on the virulence of some of its species for plants and animals (including humans). Yet, pathogenic features of some isolates coexist with others often present in environmental variants that promote plant growth and degrade chemical pollutants. Many of these traits can be traced to the intrinsic properties of the genomic chassis of this genus along with distinct genetic parts and devices. With the tools of Synthetic Biology these can be enhanced and/or repurposed for the sake of biological control, environmental remediation and whole-cell biocatalysis. In this article we take stock of both conceptual and technological developments that have allowed the virtual domestication of Pseudomonas (in particular P. putida) as a major biotechnological workhorse with a range of applications of industrial interest. Adoption of a suite of compositional and measurement standards is advocated for bringing Pseudomonas-based genetic engineering to a superior level of development. PMID- 28738233 TI - Association of the IL-15 and IL-15Ralpha genes with celiac disease. AB - Celiac disease is a chronic autoimmune condition triggered by dietary gluten in genetically predisposed individuals and the treatment is a strict gluten-free diet. The major predisposing genes are HLA-DQA1 and HLA-DQB1, but these are not sufficient for disease development. One of the candidate genes worth studying is interleukin (IL)-15 gene, together with its specific receptor, IL-15Ralpha, as they participate in promoting lymphocyte signaling and survival, and the establishment of appropriate conditions for villous atrophy, then acting as key players in the immunopathogenesis of CD. Here we analyze IL-15 and IL-15Ralpha genes in samples from the Spanish Consortium for Genetics of Celiac Disease (CEGEC) collection, identifying two regulatory single-nucleotide polymorphisms (SNP) that might be associated with celiac disease: rs4956400 (p-value 0.0112, OR 1.21, 95% CI 1.04-1.40) and rs11100722 (p-value 0.0087, OR 1.24, 95% CI 1.06 1.45), both located upstream the IL15 gene. When the expression of both genes was assessed, these two SNPs were found to be correlated with IL-15 higher protein expression. Besides, rs8177655 from IL15RA was also associated to mRNA IL-15 expression in CD patients. Finally, three SNPs from IL15RA intronic regions, rs2296141, rs3136614 and rs3181148, and another from its 3'UTR region, rs2229135, could be related to the age of diagnosis of celiac disease patients. PMID- 28738231 TI - Sliding-strip microfluidic device enables ELISA on paper. AB - This article describes a 3D microfluidic paper-based analytical device that can be used to conduct an enzyme-linked immunosorbent assay (ELISA). The device comprises two parts: a sliding strip (which contains the active sensing area) and a structure surrounding the sliding strip (which holds stored reagents-buffers, antibodies, and enzymatic substrate-and distributes fluid). Running an ELISA involves adding sample (e.g. blood) and water, moving the sliding strip at scheduled times, and analyzing the resulting color in the sensing area visually or using a flatbed scanner. We demonstrate that this device can be used to detect C-reactive protein (CRP)-a biomarker for neonatal sepsis, pelvic inflammatory disease, and inflammatory bowel diseases-at a concentration range of 1-100ng/mL in 1000-fold diluted blood (1-100ug/mL in undiluted blood). The accuracy of the device (as characterized by the area under the receiver operator characteristics curve) is 89% and 83% for cut-offs of 10ng/mL (for neonatal sepsis and pelvic inflammatory disease) and 30ng/mL (for inflammatory bowel diseases) CRP in 1000 fold diluted blood respectively. In resource-limited settings, the device can be used as a part of a kit (containing the device, a fixed-volume capillary, a pre filled tube, a syringe, and a dropper); this kit would cost ~ $0.50 when produced in large scale (>100,000 devices/week). This kit has the technical characteristics to be employed as a pre-screening tool, when combined with other data such as patient history and clinical signs. PMID- 28738234 TI - M1 homeopathic complex trigger effective responses against Leishmania (L) amazonensis in vivo and in vitro. AB - Leishmaniasis is a term referring to a range of clinical conditions caused by protozoan parasites of the genus Leishmania, Trypanosomatidae family, Kinetoplastida order that is transmitted by the bite of certain species of mosquitoes Phlebotominae subfamily. These parasites infect hosts wild and domestic mammals, considered as natural reservoirs and can also infect humans. Leishmania are obligate intramacrophage protozoa that have exclusively intracellular life style. This suggests that the amastigotes possess mechanisms to avoid killing by host cells. Cutaneous leishmaniasis, the most common form of the disease, causes ulcers on exposed parts of the body, leading to disfigurement, permanent scars, and stigma and in some cases disability. Many studies concluded that the cytokines profile and immune system of host have fundamental role in humans and animals natural self-healing. Conventional treatments are far from ideals and the search for new therapeutic alternatives is considered a strategic priority line of research by the World Health Organization. A promising approach in the field of basic research in homeopathy is the treatment of experimental infections with homeopathic drugs prepared from natural substances associations highly diluted, which comprise a combination of several different compounds considered as useful for a symptom or disease. Therefore, this study aimed to evaluate the effect of M1, a complex homeopathic product, in macrophage-Leishmania interaction in vitro and in vivo. It was used RAW cells lineage and BALB/c mice as a host for the promastigotes of L. amazonensis (WHOM/BR/75/Josefa). Several biochemical and morphological parameters were determined. Together, the harmonic results obtained in this study indicate that, in general, the highly diluted products trigger rapid and effective responses by living organisms, cells and mice, against Leishmania, by altering cytokines profile, by NO increasing (p<0.05), by decreasing parasitic load (p<0.001), and modifying classical maturation and biogenesis of parasitophorous vacuoles (p<0.001). M1 complex decreased endocytic index (p<0.001), and the % of infected macrophages (p<0.05), preventing the development of lesions (p<0.05) caused by L. amazonensis by increasing Th1 response (p<0.05). Therefore the M1complex can be a good candidate for a complementary therapy to conventional treatments, since all the parameters observed in vitro and in vivo improved. It could be an interesting clinical tool in association to a classical anti parasitic treatment, maybe resulting in better quality of life to the patients, with less toxicity. PMID- 28738235 TI - Treatment decisions in metastatic colorectal cancer - Beyond first and second line combination therapies. AB - Median overall survival (OS) of patients with metastatic colorectal cancer (mCRC) has reached up to 30months in recent clinical trials of first line therapies. Following disease progression after the standard in both, 1st and 2nd line, combination chemotherapy with monoclonal antibodies, many patients maintain a good performance status and a significant proportion is motivated to undergo further therapy. Choices of treatment beyond the second line setting for mCRC are therefore becoming increasingly important. New options have entered the therapeutic field recently: Regorafenib is a multikinase inhibitor approved for mCRC patients who have progressed on chemotherapy (including fluoropyrimidines, irinotecan, and oxaliplatin), plus VEGF inhibitor(s) and - if RAS wild-type - an anti-EGFR inhibitor. Regorafenib significantly improved OS, compared to placebo, in two phase III trials (CORRECT and CONCUR) in mCRC patients. Trifluridine/Tipiracil, an oral fluoropyrimidine, also resulted in significantly improved OS when compared to placebo in the phase III RECOURSE trial, which was conducted in a similar patient population to CORRECT. Reintroduction of previously administered therapy is another valid and commonly used approach, especially for those regimens which were discontinued before progression, e.g. if associated with cumulative toxicities, such as peripheral neuropathy or due to treatment breaks. Re-challenge of drugs to which patients developed resistance is also feasible although evidence for this strategy is limited. PMID- 28738236 TI - Early predictors of study success in a Dutch advanced nurse practitioner education program: A retrospective cohort study. AB - BACKGROUND: Study delay and attrition are major concerns in higher education. They cost time and effort, and threaten the availability of higher qualified professionals. Knowing early what factors contribute to delay and attrition may help prevent this. OBJECTIVE: The aim of this study was to examine whether student characteristics, including a literature study report grade as a proxy of cognitive abilities, predicted study success in a dual advanced nurse practitioner education program. METHODS: Retrospective cohort study, including all 214 students who between September 2009 and September 2015 started the two year program at the HAN University of Applied Sciences in Nijmegen, the Netherlands. Study success was defined as having completed the program within the envisaged period. Variables examined included: age, gender, previous education (bachelor's degree or in-service training in nursing), work setting (general health, mental health, public health, or nursing home care), and literature study report grade (from 1 to 10). A hierarchical logistic regression analysis was performed. RESULTS: Most students were female (80%), had a bachelor's degree in nursing (67%), and were employed in a general healthcare setting (58%). Mean age was 40.5years (SD 9.4). One hundred thirty-seven students (64%) had study success. Being employed in a general healthcare setting (p<=0.004) and a higher literature study report grade (p=0.001) were associated with a higher study success rate. CONCLUSION: In advanced nurse practitioner education, study success rate seems associated with the student's cognitive abilities and work field. It might be worthwhile to identify students 'at risk of failure' before the start of the program and offer them extra support. PMID- 28738237 TI - A case report of unexpected pathology within an incarcerated ventral hernia. AB - INTRODUCTION: Incidence of hernial appendicitis is 0.008%, most frequently within inguinal and femoral hernias. Up to 2.5% of appendectomy patients are found to have Crohn's disease. Elucidating the etiology of inflammation is essential for directing management. PRESENTATION OF CASE: A 51-year-old female with achondroplastic dwarfism, multiple cesarean sections, and subsequent massive incisional hernia, presented with ruptured appendicitis within her incarcerated hernia. She underwent diagnostic laparoscopy, appendectomy, intra-abdominal abscess drainage, and complete reduction of ventral hernia contents. She developed a nonhealing colocutaneous fistula, causing major disruptions to her daily life. She elected to undergo hernia repair with component separation for anticipated lack of domain secondary to her body habitus. Her operative course consisted of open abdominal exploration, adhesiolysis, colocutaneous fistula repair, ileocolic resection and anastomosis, and hernia repair with bioresorbable mesh. She tolerated the procedure well. Unexpectedly, ileocolic pathology demonstrated chronic active ileitis, diagnostic of Crohn's disease. DISCUSSION: Only two cases of hernial Crohn's appendicitis have been reported, both within Spigelian hernias. Appendiceal inflammation inside a hernia sac may be attributed to ischemia from extraluminal compression of the hernia neck. This case demonstrates a rare presentation of multiple concurrent surgical disease processes, each of which impact the patient's treatment plan. CONCLUSION: This is the first report of incisional hernia appendicitis with nonhealing colocutaneous fistulas secondary to Crohn's. It is a lesson in developing a differential diagnosis of an inflammatory process within an incarcerated hernia and management of the complications related to laparoscopic hernial appendectomy in a patient with undiagnosed Crohn's disease. PMID- 28738238 TI - Periprosthetic seroma with false-positive FDG PET-CT reactive nodes mistaken for metastases in a patient previously treated of metastasic melanoma. Potential source of diagnostic errors. AB - INTRODUCTION: FDG PET/CT is believed to be crucial in oncology, but its limited specificity represents a challenge. Prosthetic meshes used for repair abdominal defects may lead to false-positives FDG PET/CT uptake, over staging malignancies and inducing inappropriate treatments. A false-positive FDG PET/CT uptake mimicking metastatic disease during the follow-up of a previously treated metastatic melanoma patient is presented. PMID- 28738239 TI - Delayed graft duodenal perforation due to impacted food five years after simultaneous pancreas-kidney transplantation: A case report. AB - INTRODUCTION: Pancreas transplantation is the best treatment option in selected patients with type 1 diabetes mellitus. Here we report a patient with a nonmarginal duodenal perforation five years after a simultaneous pancreas-living donor kidney transplantation (SPLKT). PRESENTATION OF CASE: A 31-year old male who underwent SPLKT five years previously presented with severe abdominal pain. He had a marginal duodenal perforation four years later, treated by primary closure and drainage. Biopsy of the pancreas and duodenum graft at that time showed chronic rejection in the pancreas and acute inflammation with an ulcer in the duodenum. At presentation, computerized tomography scan showed mesenteric pneumatosis with enteric leak and ileal dilatation proximal to the anastomotic site. We performed emergent laparotomy and found a 1.0cm perforation at the nonmarginal, posterior wall of the duodenum. Undigested fiber-rich food was extracted from the site and an omental patch placed over the perforation. An ileostomy was created proximal to the omega loop for decompression and a drain placed nearby. The postoperative course was unremarkable. DISCUSSION: There are only eight previous cases of graft duodenal perforation in the literature. Fiber rich food residue passing through the anastomosis with impaction may have led to this perforation. CONCLUSION: When a patient is stable, even in the presence of delayed duodenal graft perforation, graft excision may not be necessary. Intraoperative exploration should include Doppler ultrasound examination of the vasculature to rule out thrombosis as a contributor to ischemia. Tissue biopsy should be performed to diagnose rejection. PMID- 28738240 TI - Computational training for the next generation of neuroscientists. AB - Neuroscience research has become increasingly reliant upon quantitative and computational data analysis and modeling techniques. However, the vast majority of neuroscientists are still trained within the traditional biology curriculum, in which computational and quantitative approaches beyond elementary statistics may be given little emphasis. Here we provide the results of an informal poll of computational and other neuroscientists that sought to identify critical needs, areas for improvement, and educational resources for computational neuroscience training. Motivated by this survey, we suggest steps to facilitate quantitative and computational training for future neuroscientists. PMID- 28738241 TI - Annotinolide F and lycoannotines A-I, further Lycopodium alkaloids from Lycopodium annotinum. AB - Seven lycopodine-type (annotinolide F and lycoannotines A-F), two lycodine-type (lycoannotines G and H), and one fawcettimine-type (lycoannotine I) previously undescribed naturally occurring Lycopodium alkaloids together with thirteen known ones were isolated from the whole plant of Lycopodium annotinum. Their structures and absolute configurations were determined by extensive spectroscopic methods, single-crystal X-ray diffraction, chemical transformation, and electronic circular dichroism (ECD) calculations. Among the isolates, annotinolide F, lycoannotines A and B are unusual 7,8-seco-lycopodane derivatives, and annotinolide F even further possesses a rare 8,5-lactone framework through a lactonization after the C-7/C-8 bond cleavage. Lycoannotine C is an uncommon 8,15 seco lycopodine-type alkaloid, whereas lycoannotine I represents the first example of a naturally occurring C-9/N bond cleavage product of fawcettimine-type alkaloid. Among them, only lycoannotine I was found to show considerable anti butyrylcholinesterase (anti-BuChE) activity. PMID- 28738242 TI - Specialized metabolites from the aerial parts of Centaurea polyclada DC. AB - The genus Centaurea L. (Asteraceae) is represented by 200 taxa in the flora of Turkey and several Centaurea species are used as herbal remedies against different conditions. Previous phytochemical investigations on this genus generally revealed the isolation of sesquiterpene lactones and flavonoid derivatives. In our continuous search on Centaurea genus, a phytochemical study was performed on Centaurea polyclada DC., an endemic of West Anatolia. Previously undescribed two sesquiterpene-amino acid conjugates, an elemane and an eudesmane derivative were isolated from the aerial parts of Centaurea polyclada, together with eight known compounds; two elemane derivatives, three flavonoids, a lignan, a phenolic glucoside and a phenylpropanoid glucoside. Structural elucidation of the compounds was based on spectroscopic evidence, including 1D and 2D NMR and high-resolution mass spectrometry, chemical degradation results and reference data comparison. Sesquiterpene-amino acid conjugates are representatives of an unusual group of sesquiterpenes, and elemane-amino acid conjugates are herein reported for the first time in nature. PMID- 28738243 TI - Both facilitatory and inhibitory impairments underlie age-related differences of proactive cognitive control across the adult lifespan. AB - We investigated two components of proactive cognitive control, response facilitation and response inhibition, in an adult lifespan sample (N=544, age range=18-91years) by administering two response-preparation tasks: a procue task, primarily involving facilitation, and an anticue task, involving both facilitation and inhibition. Cues in both tasks corresponded with the index and middle fingers of either the left or right hand. After a random preparation interval (PI) of 100-850ms following the onset of the cue signal, a single-target stimulus indicated the required response. Where procues were spatially aligned with the two fingers of the responding hand, anticues consistently indicated the two fingers of the opposite hand, requiring a remapping of cue location and response hand. This remapping requires inhibition to suppress the automatic activation of the ipsilateral responses. Previous research revealed typical reaction time (RT) profiles for procues and anticues as a function of PI. Whereas procues generate RT benefits (relative to a neutral-cue condition) already at short PIs, which increase with longer PIs, anticues generate RT costs at short PIs and RT benefits at longer PIs. Our results showed that, in the anticue task, older participants needed more preparation time to turn RT costs into RT benefits than younger participants, revealing an age-related deficit of response inhibition. Moreover, in both tasks, older participants were less able to increase RT benefits with longer PIs, revealing a deficit of response facilitation. We conclude that both facilitatory and inhibitory impairments contribute to age-related deficiencies in proactive cognitive control. PMID- 28738244 TI - DNA binding and unwinding by Hel308 helicase requires dual functions of a winged helix domain. AB - Hel308 helicases promote genome stability linked to DNA replication in archaea, and have homologues in metazoans. In the crystal structure of archaeal Hel308 bound to a tailed DNA duplex, core helicase domains encircle single-stranded DNA (ssDNA) in a "ratchet" for directional translocation. A winged helix domain (WHD) is also present, but its function is mysterious. We investigated the WHD in full length Hel308, identifying that mutations in a solvent exposed alpha-helix resulted in reduced DNA binding and unwinding activities. When isolated from the rest of Hel308, the WHD protein alone bound to duplex DNA but not ssDNA, and DNA binding by WHD protein was abolished by the same mutations as were analyzed in full-length Hel308. Isolated WHD from a human Hel308 homologue (HelQ) also bound to duplex DNA. By disrupting the interface between the Hel308 WHD and a RecA-like domain, a topology typical of Ski2 helicases, we show that this is crucial for ATPase and helicase activities. The data suggest a model in which the WHD promotes activity of Hel308 directly, through binding to duplex DNA that is distinct from ssDNA binding by core helicase, and indirectly through interaction with the RecA-like domain. We propose how the WHD may contribute to ssDNA translocation, resulting in DNA helicase activity or in removal of other DNA bound proteins by "reeling" ssDNA. PMID- 28738245 TI - Two-amino acids change in the nsp4 of SARS coronavirus abolishes viral replication. AB - Infection with coronavirus rearranges the host cell membrane to assemble a replication/transcription complex in which replication of the viral genome and transcription of viral mRNA occur. Although coexistence of nsp3 and nsp4 is known to cause membrane rearrangement, the mechanisms underlying the interaction of these two proteins remain unclear. We demonstrated that binding of nsp4 with nsp3 is essential for membrane rearrangement and identified amino acid residues in nsp4 responsible for the interaction with nsp3. In addition, we revealed that the nsp3-nsp4 interaction is not sufficient to induce membrane rearrangement, suggesting the participation of other factors such as host proteins. Finally, we showed that loss of the nsp3-nsp4 interaction eliminated viral replication by using an infectious cDNA clone and replicon system of SARS-CoV. These findings provide clues to the mechanism of the replication/transcription complex assembly of SARS-CoV and could reveal an antiviral target for the treatment of betacoronavirus infection. PMID- 28738246 TI - Crocin modulates IL-4/IL-13 signaling and ameliorates experimentally induced allergic airway asthma in a murine model. AB - Allergic asthma is a chronic respiratory disease with a prevalent T helper (Th2) mediated immune reaction. Crocin, the major bioactive constituent of saffron, has been reported in multiple studies to have numerous pharmacological activities, including prominent anti-oxidant activities. In the current study, the anti asthmatic potential of crocin was evaluated. Adult male Swiss Albino mice were administered 10mg of ovalbumin (OVA) mixed with 1mg of aluminum hydroxide intraperitoneally on days 0 and 7 and were administered crocin (25mg/kg) orally daily for 16days. Asthma progression was associated with significant increase in the lung/body weight index, inflammatory cell counts in bronchoalveolar lavage fluid (BALF), lung total protein content, and serious index of lung permeability, indicating pulmonary edema with accumulation of serous fluids within the lungs. Serum lactate dehydrogenase (LDH) activity and lung malondialdehyde (MDA) content were significantly increased, while lung superoxide dismutase (SOD) activity, reduced glutathione (GSH) levels, and serum and lung catalase activities were significantly decreased. These changes reflect significant pulmonary inflammation with concomitant disturbance of oxidant/antioxidant homeostasis. Moreover, tumor necrosis factor (TNF)-alpha, interleukin (IL)-4, and IL-13 contents in the lung were also significantly high after OVA sensitization. Crocin treatment significantly alleviated the OVA-induced allergic asthma-associated alterations in inflammatory and oxidative stress biomarkers. Crocin enhanced anti-oxidant defenses, reduced the incidence of oxidative stress, and restored pro inflammatory cytokines to normal levels. Histopathological analysis showed significant lung improvement in crocin-treated mice. In conclusion, crocin showed a significant protective effect against allergic asthma progression, which was associated with down-regulation of inflammatory cytokine expression and restoration of oxidant/antioxidant homeostasis. PMID- 28738247 TI - Asiatic acid inhibits LPS-induced inflammatory response in human gingival fibroblasts. AB - Asiatic acid, a triterpenoid component isolated from Centella asiatica (L.) Urban, possesses antioxidative and anti-inflammatory activities. In this study, we aimed to investigate the anti-inflammatory effects of asiatic acid both in vivo and in vitro. HGFs or RAW264.7 cells were treated with asiatic acid 1h before LPS treatment. Cell viability was measured by MTT assay. The levels of PGE2, NO, IL-6, and IL-8 were detected by ELISA. Protein expression levels were detected by western blot analysis. In vivo, asiatic acid significantly inhibited LPS-induced IL-6 and IL-8 expression levels in gingival tissues. In vitro, LPS induced PGE2, NO, IL-6, and IL-8 production was significantly attenuated by asiatic acid. Asiatic acid also inhibited p65 NF-kappaB phosphorylation induced by LPS in HGFs. The expression of PPAR-gamma was up-regulated by asiatic acid. Furthermore, GW9662, a PPAR-gamma inhibitor, attenuated the inhibitory effect of asiatic acid on PGE2, NO, IL-6, and IL-8 production. Our results suggest that asiatic acid activates PPAR-gamma, which subsequently inhibits LPS-induced NF kappaB activation and inflammatory mediators production. Asiatic acid may offer therapeutic potential for the treatment of periodontitis. PMID- 28738248 TI - The reliability and validity of measurements of human dental casts made by an intra-oral 3D scanner, with conventional hand-held digital callipers as the comparison measure. AB - AIM: Intra-oral 3D scanning of dentitions has the potential to provide a fast, accurate and non-invasive method of recording dental information. The aim of this study was to assess the reliability of measurements of human dental casts made using a portable intra-oral 3D scanner appropriate for field use. METHOD: Two examiners each measured 84 tooth and 26 arch features of 50 sets of upper and lower human dental casts using digital hand-held callipers, and secondly using the measuring tool provided with the Zfx IntraScan intraoral 3D scanner applied to the virtual dental casts. The measurements were repeated at least one week later. Reliability and validity were quantified concurrently by calculation of intra-class correlation coefficients (ICC) and standard errors of measurement (SEM). RESULTS: The measurements of the 110 landmark features of human dental casts made using the intra-oral 3D scanner were virtually indistinguishable from measurements of the same features made using conventional hand-held callipers. The difference of means as a percentage of the average of the measurements by each method ranged between 0.030% and 1.134%. The intermethod SEMs ranged between 0.037% and 0.535%, and the inter-method ICCs ranged between 0.904 and 0.999, for both the upper and the lower arches. The inter-rater SEMs were one-half and the intra-method/rater SEMs were one-third of the inter-method values. CONCLUSION: This study demonstrates that the Zfx IntraScan intra-oral 3D scanner with its virtual on-screen measuring tool is a reliable and valid method for measuring the key features of dental casts. PMID- 28738250 TI - Optimization of beam dump shielding for K-130 cyclotron at VECC. AB - A compact and efficient beam dump shield has been designed using Monte Carlo simulation code FLUKA to facilitate low background measurement of neutron and gamma rays using K130 cyclotron at Variable Energy Cyclotron Centre, Kolkata (VECC). Iron, lead and high density Polyethylene (HDPE) were considered in the design of the beam dump shield. Representative FLUKA simulation results have been validated using in-beam experiment performed on the same beam dump constituents. Experimental neutron and gamma-rays energy spectra have been found to be in fair agreement with the simulation results. Activation of various beam dump shield components were also carried out. PMID- 28738251 TI - Quantification of some elements of nuclear and industrial interest from zircon mineral using neutron activation analysis and passive gamma-ray spectroscopy. AB - A combined of various nuclear and analytical techniques were used for characterization of Egyptian zircon ore. Neutron activation analysis has been used for determination of the major, minor and trace elements from zircon ore. Non-destructive gamma-ray technique is also used for the radiometric analysis of zircon ore to quantify the natural radionuclides such as 238U, 235U, 232Th, 226Ra and 40K. Zircon ore has been characterized by different analytical tools such as Fourier transformer infrared (FTIR), X-ray fluorescence (XRF), powder X-ray diffraction (XRD), and scanning electron microscopy (SEM). In this study, a significant concentration of U, Th and rare earth elements (REEs) has been reported. The obtained results showed that the average activity concentration of 238U, 235U, 226Ra, 232Th and 40K are 4771+/-338, 230+/-17.1, 3588+/-125, 982+/ 47.7 and 217+/-48.5Bq/kg, respectively. The results indicated that 297, 318 and 838mg/Kg for U, Th, REEs, respectively, using NAA. These results are consistent with those obtained by gamma-ray spectroscopy and/or XRF. It can be concluded that zircon ore is a riche with a valuable nuclear materials such as U, Th, Zr, and Hf. It is also containing a REEs of economic and industrial interest. Also, the different radiation hazardous parameters were found much higher than the permissible values. PMID- 28738249 TI - New 1,3,4-oxadiazole/oxime hybrids: Design, synthesis, anti-inflammatory, COX inhibitory activities and ulcerogenic liability. AB - A series of new 1,3,4-oxadiazole/oxime hybrids were synthesized and designed as potent COX inhibitors. The prepared compounds were evaluated for their anti inflammatory, antioxidant and ulcerogenic activities. The results indicated that the prepared compounds exhibited remarkable anti-inflammatory activity with (69.60-109.60% of indomethacin activity) after 4h. In vitro COX inhibitory assay showed that compounds 6d and 7h are potent COX inhibitors with IC50 of (1.10 0.94) and (2.30-5.00) uM on both COX-1 and COX-2 respectively. Compound 7h was found to inhibit both COXs non-competitively with Ki values of 73uM and 89uM. Most of the tested compounds showed ulcer-free stomachs compared to indomethacin. PMID- 28738252 TI - Radioactivity analysis of soil samples taken from the western and northern shores of Lake Van, Turkey. AB - In this study, concentrations of the radioactive isotopes 226Ra, 232Th, 40K and 137Cs were measured in soil samples from the shores of Lake Van using a high purity germanium detector. Activity concentrations obtained for these nuclides were compared with world average values. The average 226Ra, 232Th and 40K activity concentrations calculated for the soil samples were higher than the world average values reported by UNSCEAR. The lowest 226Ra, 232Th and 40K activity concentrations were recorded in sample T-1 whereas the highest values were recorded in sample T-11. Concentrations of 137C in the samples ranged between 0.91 +/- 0.01 and 29.68 +/- 0.33Bqkg-1. In order to evaluate the radiological hazards resulting from natural radioactivity, radium equivalent activities, absorbed dose rates, and internal and external hazard indices were calculated and the results were compared with internationally recognized values. PMID- 28738253 TI - Size distribution and elastic properties of thermo-responsive polymer gel microparticles in suspension probed by ultrasonic spectroscopy. AB - The size distribution and the elasticity of thermo-responsive gel particles dispersed in water were examined in-situ by ultrasonic spectroscopy (US). Poly(N isopropylacrylamide) (PNIPAM) gel particles, undergoing volume phase transition at 34 degrees C were synthesized by redox polymerization in emulsion, and the temperature dependence of the acoustic properties was examined. The longitudinal velocity and the attenuation coefficient of particle exhibited a drastic change at the transition temperature, indicating the increase in the mechanical properties, such the longitudinal, bulk and shear moduli, due to the shrinkage of particles upon temperature stimulation. The shear modulus of monodisperse particles, and also the stiffness of the gel particles were evaluated. PMID- 28738254 TI - Stereoselective protein binding studies of 2-(2-hydroxypropanamido) benzoic acid enantiomers in rat, beagle dog and human plasma. AB - As the stereoselective plasma protein binding is an important factor for the differences in pharmacokinetic or pharmacodynamic properties of chiral drugs, we elucidated the binding of (R)-/(S)-HPABA to plasma protein. A UHPLC-MS/MS method was developed and validated to the quantitation and equilibrium dialysis method was applied to the separation of bound and unbound drugs. Protein binding reached equilibrium within 12h of incubation at 37 degrees C. Liquid-liquid extraction with ethyl acetate was used for sample preparation. The separation was achieved through a Thermo Syncronis C18 column (50mm*2.1mm, 1.7MUm; Thermo, USA) using gradient elution at a flow rate of 0.4ml/min. All of the recovery and matrix effect of the method met the requirements of analytical method validation. The plasma protein binding of (R)-/(S)-HPABA show significant species dependence in enantioselectivity. In addition, the results of molecular docking showed that the combining capacity of (R)-HPABA with HSA was higher than that of (S)-HPABA. PMID- 28738255 TI - Simultaneous identification and quantification of the common compounds of Viscum coloratum and its corresponding host plants by ultra-high performance liquid chromatography with quadrupole time-of-flight tandem mass spectrometry and triple quadrupole mass spectrometry. AB - Viscum coloratum is a perennial evergreen, semi-parasitic plant. It is generally used for treating cardiovascular diseases, cancer, hepatitis and hemorrhage. In this study, reliable methods were developed for the qualitative and quantitative analysis of the common constituents in Viscum coloratum and its corresponding host. In the rapid qualitative analysis, a method of ultra-high performance liquid chromatography and quadrupole time-of-flight tandem mass spectrometry was established for identification of the same compounds. Based on the retention times, accurate mass measurement and previous literatures, 23 components were clearly identified by comparison with reference substances. In the quantitative analysis, a method for Viscum coloratum and its corresponding host was developed by ultra-high performance liquid chromatography with triple quadrupole mass spectrometry. 13 common compounds of viscum coloratum and host plants from 19 batches were analyzed with a good linearity (r2>=0.9991), intra-day precision (RSD<=3.24%), inter-day precision (RSD<=3.31%), repeatability (RSD<=2.43%), stability (RSD<=2.63%), and recovery (98.2-102.4%). The overall limits of quantification were less than 5.0ng/mL. The results indicated that these effective and comprehensive methods can be applicable to simultaneous qualitative and quantitative analysis of these common compounds presented in Viscum coloratum and corresponding host plants. PMID- 28738256 TI - P53 and MITF/Bcl-2 identified as key pathways in the acquired resistance of NRAS mutant melanoma to MEK inhibition. AB - Activating mutations in Neuroblastoma RAS viral oncogene homolog (NRAS) are found in 15-30% of melanomas and are associated with a poor prognosis. Although MAP kinase kinase (MEK) inhibitors used as single agents showed a limited clinical benefit in patients with NRAS-mutant melanoma due to their rather cytostatic effect and high toxicity, their combination with other inhibitors of pathways known to cooperate with MEK inhibition may maximise their antitumour activity. Similarly, in a context where p53 is largely inactivated in melanoma, hyperexpression of Microphthalmia associated transcription factor (MITF) and its downstream anti-apoptotic targets may be the cause of the restraint cytotoxic effects of MEK inhibitors. Indeed, drug combinations targeting both mutant BRAF and MITF or one of its important targets Bcl-2 were effective in mutant BRAF melanoma but had no effect on acquired resistance. Therefore, we aimed to further investigate the downstream MITF targets that can explain this anti-apoptotic effect and to evaluate in parallel the effect of p53 reactivation on the promotion of apoptosis under MEK inhibition in a panel of Q61NRAS-mutant melanoma cells. First, we showed that MEK inhibition (pimasertib) led to a significant inhibition of cell proliferation but with a limited effect on apoptosis that could be explained by the systematic MITF upregulation. Mimicking the MITF effect via cyclic adenosine monophosphate activation conferred resistance to MEK inhibition and upregulated Bcl-2 expression. In addition, acquired resistance to MEK inhibition was associated with a strong activation of the anti-apoptotic signalling MITF/Bcl-2. More importantly, selective Bcl-2 inhibition by ABT-199 or Bcl-2 knockout using CRISPR/Cas9 system annihilated the acquired resistance and restored the sensitivity of NRAS-mutant melanoma cells to MEK inhibition. Strikingly and similarly, direct p53 reactivation (PRIMA-1Met, APR-246) also broke resistance and synergised with MEK inhibition to induce massive apoptosis in NRAS-mutant melanoma cells with wild-type or mutant p53. Hence, our data identify MITF/Bcl-2 as a key mechanism underlying resistance of NRAS-mutant melanoma cells to apoptosis by MEK inhibitors and paves the way for a promising drug combination that could prevent or reverse anti-MEK resistance in this group of patients. PMID- 28738257 TI - A systematic review of the quality of statistical methods employed for analysing quality of life data in cancer randomised controlled trials. AB - AIMS: Over the last decades, Health-related Quality of Life (HRQoL) end-points have become an important outcome of the randomised controlled trials (RCTs). HRQoL methodology in RCTs has improved following international consensus recommendations. However, no international recommendations exist concerning the statistical analysis of such data. The aim of our study was to identify and characterise the quality of the statistical methods commonly used for analysing HRQoL data in cancer RCTs. METHODS: Building on our recently published systematic review, we analysed a total of 33 published RCTs studying the HRQoL methods reported in RCTs since 1991. We focussed on the ability of the methods to deal with the three major problems commonly encountered when analysing HRQoL data: their multidimensional and longitudinal structure and the commonly high rate of missing data. RESULTS: All studies reported HRQoL being assessed repeatedly over time for a period ranging from 2 to 36 months. Missing data were common, with compliance rates ranging from 45% to 90%. From the 33 studies considered, 12 different statistical methods were identified. Twenty-nine studies analysed each of the questionnaire sub-dimensions without type I error adjustment. Thirteen studies repeated the HRQoL analysis at each assessment time again without type I error adjustment. Only 8 studies used methods suitable for repeated measurements. CONCLUSION: Our findings show a lack of consistency in statistical methods for analysing HRQoL data. Problems related to multiple comparisons were rarely considered leading to a high risk of false positive results. It is therefore critical that international recommendations for improving such statistical practices are developed. PMID- 28738258 TI - Open-label, multicentre, randomised, phase II study of the EpSSG and the ITCC evaluating the addition of bevacizumab to chemotherapy in childhood and adolescent patients with metastatic soft tissue sarcoma (the BERNIE study). AB - PURPOSE: We evaluated the role of bevacizumab as part of the multi-modality treatment of children and adolescents with metastatic rhabdomyosarcoma (RMS) or non-rhabdomyosarcoma soft tissue sarcoma (NRSTS). PATIENTS AND METHODS: Eligible patients aged >=6 months to <18 years were randomised to receive induction chemotherapy (four cycles of IVADo + five cycles of IVA, +/-bevacizumab), surgery and/or radiotherapy, followed by maintenance chemotherapy (12 cycles of low-dose cyclophosphamide + vinorelbine, +/-bevacizumab). The primary objective was event free survival (EFS) evaluated by an independent radiological review committee. RESULTS: One hundred and fifty-four patients were randomised to receive chemotherapy alone (n = 80) or with bevacizumab (n = 74). At the data cut-off for the primary efficacy analysis, median EFS was 14.9 months (95% confidence interval [CI]: 10.8-35.9) with chemotherapy and 20.6 months (95% CI: 15.2-24.9) with bevacizumab plus chemotherapy (stratified hazard ratio [HR] = 0.93; 95% CI: 0.61-1.41; P = 0.72). The HR for EFS in patients with RMS (n = 103) was 1.24 (95% CI: 0.73-2.09) versus 0.64 (95% CI: 0.32-1.26) for those with NRSTS (n = 49). Objective response rate was 36.0% (95% CI: 25.2-47.9) with chemotherapy and 54.0% (95% CI: 40.9-66.6) with bevacizumab plus chemotherapy (difference of 18.0%; 95% CI: 0.6-35.3). There were no treatment-related deaths and no increased incidence of grade 3/4 toxicities with bevacizumab. CONCLUSION: The addition of bevacizumab to chemotherapy appeared tolerable in children and adolescents with metastatic RMS/NRSTS, but the primary end-point of EFS did not show statistically significant improvement. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00643565. PMID- 28738260 TI - Attributions to new onset catatonic symptoms, late in the course of chronic schizophrenia. PMID- 28738259 TI - Reasons associated with treatment non-adherence in schizophrenia in a Pakistan cohort. AB - TREATMENT: non-adherence in patients with schizophrenia is the most common reason for a relapse of psychosis. In a cohort of participants in Pakistan who suffered a relapse of psychosis, we aimed to identify the principal factors associated with non-adherence, including any culture specific factors that might not be as significant in other jurisdictions. Semi-structured interviews were undertaken at four psychiatric hospitals in the Peshawar region in Pakistan with 55 participants (44 male and 11 female) diagnosed with schizophrenia, who had suffered a relapse of psychosis subsequent to treatment non-adherence. The five principal documented reasons for treatment non-adherence were: 1) alternative treatment pathway chosen with a traditional faith healers (n=53, 96.4%), 2) lack of insight (n=36, 65.5%), 3) poor economic status (n=33, 60.0%), 4) adverse effects of medications (n=33, 60.0%) and 5) utilising psycho-active substances as an alternative to psychotropic medications (n=27, 41.1%). A number of identified factors associated with a relapse of psychosis are potentially modifiable including the provision of a range of pharmacological options including second generation antipsychotic agents, long acting injectable antipsychotics and psycho therapeutic interventions including psycho-education. These interventions should prove cost effective and be associated with reduced relapse rates of psychosis. PMID- 28738261 TI - Neurosyphilis: An underdiagnosed entity. AB - Neurosyphilis has various clinical manifestations depending upon the stage of illness. However, it is not readily considered a differential diagnosis in early onset dementia and behavioral disturbances. This case report describes a patient presenting with disorganized behavior and later diagnosed with dementia in which neurosyphilis was found causative. This is followed by a pragmatic review of the diagnosis and treatment options for neurosyphilis. PMID- 28738262 TI - Systematic review of community health impacts of mountaintop removal mining. AB - BACKGROUND: The objective of this evaluation is to understand the human health impacts of mountaintop removal (MTR) mining, the major method of coal mining in and around Central Appalachia. MTR mining impacts the air, water, and soil and raises concerns about potential adverse health effects in neighboring communities; exposures associated with MTR mining include particulate matter (PM), polycyclic aromatic hydrocarbons (PAHs), metals, hydrogen sulfide, and other recognized harmful substances. METHODS: A systematic review was conducted of published studies of MTR mining and community health, occupational studies of MTR mining, and any available animal and in vitro experimental studies investigating the effects of exposures to MTR-mining-related chemical mixtures. Six databases (Embase, PsycINFO, PubMed, Scopus, Toxline, and Web of Science) were searched with customized terms, and no restrictions on publication year or language, through October 27, 2016. The eligibility criteria included all human population studies and animal models of human health, direct and indirect measures of MTR-mining exposure, any health-related effect or change in physiological response, and any study design type. Risk of bias was assessed for observational and experimental studies using an approach developed by the National Toxicology Program (NTP) Office of Health Assessment and Translation (OHAT). To provide context for these health effects, a summary of the exposure literature is included that focuses on describing findings for outdoor air, indoor air, and drinking water. RESULTS: From a literature search capturing 3088 studies, 33 human studies (29 community, four occupational), four experimental studies (two in rat, one in vitro and in mice, one in C. elegans), and 58 MTR mining exposure studies were identified. A number of health findings were reported in observational human studies, including cardiopulmonary effects, mortality, and birth defects. However, concerns for risk of bias were identified, especially with respect to exposure characterization, accounting for confounding variables (such as socioeconomic status), and methods used to assess health outcomes. Typically, exposure was assessed by proximity of residence or hospital to coal mining or production level at the county level. In addition, assessing the consistency of findings was challenging because separate publications likely included overlapping case and comparison groups. For example, 11 studies of mortality were conducted with most reporting higher rates associated with coal mining, but many of these relied on the same national datasets and were unable to consider individual-level contributors to mortality such as poor socioeconomic status or smoking. Two studies of adult rats reported impaired microvascular and cardiac mitochondrial function after intratracheal exposure to PM from MTR-mining sites. Exposures associated with MTR mining included reports of PM levels that sometimes exceeded Environmental Protection Agency (EPA) standards; higher levels of dust, trace metals, hydrogen sulfide gas; and a report of increased public drinking water violations. DISCUSSION: This systematic review could not reach conclusions on community health effects of MTR mining because of the strong potential for bias in the current body of human literature. Improved characterization of exposures by future community health studies and further study of the effects of MTR mining chemical mixtures in experimental models will be critical to determining health risks of MTR mining to communities. Without such work, uncertainty will remain regarding the impact of these practices on the health of the people who breathe the air and drink the water affected by MTR mining. PMID- 28738264 TI - Evidence of anomalous behavior of intermolecular interactions at low concentration of methanol in ethanol-methanol binary system. AB - At low concentrations of methanol in a binary system of ethanol and methanol, uniquely complex molecular interactions are reported here. Previous studies indicate that ethanol molecules form aggregates held together by hydrogen bonding (O-H-O) and also dispersive forces. Addition of small amount of methanol tends to break the hydrogen bond network of ethanol due to the larger polarity of methanol. This leads to the ethanol molecules becoming somewhat isolated from each other within a scaffolding network of methanol molecules, as seen from the present molecular dynamics simulations. This is an indication of a repulsive force that dominates among the two different alcohols. At higher molar concentration of methanol (Xm > 0.3817), the strength and extent (number) of formation of hydrogen bonds between ethanol and methanol increase. The geometry of molecular structure at high concentration favors the fitting of component molecules with each other. Intermolecular interactions in the ethanol-methanol binary system over the entire concentration range were investigated in detail using broadband dielectric spectroscopy, FTIR, surface tension and refractive index studies. Molecular dynamics simulations show that the hydrogen bond density is a direct function of the number of methanol molecules present, as the ethanol aggregates are not strictly hydrogen-bond constructed which is in agreement with the experimental results. PMID- 28738263 TI - Prenatal exposure to PM2.5 and birth weight: A pooled analysis from three North American longitudinal pregnancy cohort studies. AB - A common practice when analyzing multi-site epidemiological data is to include a term for 'site' to account for unmeasured effects at each location. This practice should be carefully considered when site can have complex relationships with important demographic and exposure variables. We leverage data from three longitudinal North American pregnancy cohorts to demonstrate a novel method to assess study heterogeneity and potential combinability of studies for pooled analyses in order to better understand how to consider site in analyses. Results from linear regression and fixed effects meta-regression models run both prior to and following the proposed combinability analyses were compared. In order to exemplify this approach, we examined associations between prenatal exposure to particulate matter and birth weight. Analyses included mother-child dyads (N=1966) from the Asthma Coalition on Community Environment and Social Stress (ACCESS) Project and the PRogramming of Intergenerational Stress Mechanisms (PRISM) study in the northeastern United States, and the Programming Research in Obesity, Growth, Environment and Social Stressors (PROGRESS) study in Mexico City. Mothers' daily third trimester exposure to particulate matter<=2.5MUm in diameter (PM2.5) was estimated using a validated satellite-based spatio temporally resolved model in all studies. Fenton birth weight for gestational age z-scores were calculated. Linear regression analyses within each cohort separately did not find significant associations between PM2.5 averaged over the third trimester and Fenton z-scores. The initial meta-regression model also did not find significant associations between prenatal PM2.5 and birthweight. Next, propensity scores and log linear models were used to assess higher order interactions and determine if sites were comparable with regard to sociodemographics and other covariates; these analyses demonstrated that PROGRESS and ACCESS were combinable. Adjusted linear regression models including a 2-level site variable according to the pooling indicated by the log linear models (ACCESS and PROGRESS as one level and PRISM as another) revealed that a 5MUg/m3 increase in PM2.5 was associated with a 0.075 decrease in Fenton z-score (p<0.0001); linear models including a 3-level site variable did not reveal significant associations. By assessing the combinability of heterogeneous populations prior to combining data using a method that more optimally accounts for underlying cohort differences, we were able to identify significant associations between prenatal PM2.5 exposure and birthweight that were not detected using standard methods. PMID- 28738265 TI - Ground state charge transfer complex formation of some metalloporphyrins with aromatic solvents: Further theoretical and experimental investigations. AB - In our earlier work (Chem. Phys. Letts. 592 (2014) 149-154), a new broad band was observed in the near infrared region (700-900nm) of the steady state absorption spectra of some metalloporphyrins (zinc tetraphenylporphyrin, zinc octaethylporphyrin and magnesium octaethylporphyrin) in aromatic solvents (chlorobenzene, 1,2-dichlorobenzene, benzonitrile, benzene and toluene) at high concentrations (~10-4molL-1). The band was ascribed to be due to ground state charge transfer complexation between solute and solvent molecules. In the present work, density functional theory calculations are carried out to study the possibility of such ground state charge transfer complex formation between zinc tetraphenylporphyrin and four aromatic solvents viz., benzene, toluene, chlorobenzene and benzonitrile with 1:1 and 2:1 solvent-solute stoichiometries. Also, we determined the association constants for the ground state charge transfer complex formation of zinc tetraphenylporphyrin and zinc octaethylporphyrin with two aromatic solvents (benzene and benzonitrile) by Benesi-Hildebrand method. PMID- 28738266 TI - ADHD symptoms impact smoking outcomes and withdrawal in response to Varenicline treatment for smoking cessation. AB - INTRODUCTION: Attention-Deficit/Hyperactivity Disorder (ADHD) is associated with nicotine dependence and difficulty quitting smoking. Few cessation trials specifically consider the impact of ADHD on treatment outcomes, including those testing established pharmacological therapies, such as varenicline. METHODS: The current study focused on the impact of pretreatment ADHD inattention (IN) and hyperactivity-impulsivity (HI) symptoms on treatment outcome in a randomized controlled trial of varenicline [N=205, average age=34.13(10.07), average baseline cigarettes per day=14.71(7.06)]. Given that varenicline's putative therapeutic mechanism is attenuation of withdrawal severity during abstinence, we also tested changes in withdrawal as a mediator of treatment effects in high and low ADHD groups. RESULTS: ADHD symptom severity in this sample was in the subclinical range. Cessation was associated with HI, but not IN, such that high HI individuals on varenicline reported the lowest smoking levels at the end of treatment across all groups (3.06cig/day for high HI vs 4.02cig/day for low HI). Individuals with high HI who received placebo had the highest smoking at the end of treatment (7.69cigs/day for high HI vs 5.56cig/day for low HI). Patterns continued at follow-up. Varenicline significantly reduced withdrawal for those with high HI, but not low HI. However, path models did not support an indirect effect of medication on reducing smoking via withdrawal in either group, suggesting that unmeasured variables are involved in varenicline's effect on reducing smoking. CONCLUSIONS: These data add to a gap in the smoking cessation literature regarding the impact of ADHD symptoms on the efficacy and mechanisms of frontline pharmacological treatments. PMID- 28738267 TI - Gram scale synthesis of A (type 2) and B (type 2) blood group tetrasaccharides through 1,6-anhydro-N-acetyl-beta-D-glucosamine. AB - Gram scale synthesis of A (type 2) and B (type 2) tetrasaccharides in the form of 3-aminopropyl glycosides is proposed starting from 3-O-benzoyl-1,6-anhydro-N acetylglucosamine. Its galactosylation followed by re-protection gave lactosamine derivative with single free 2'-OH group in total yield 75%. Standard fucosylation and next run of re-protection in total yield 88% gave a trisaccharide Fuc-Gal anhydroGlcNAc with single free 3'-OH group. Its standard alpha-galactosylation gave protected B (type 2) tetrasaccharide. For synthesis of correspondent A tetrasaccharide seven different 2-azido-2-deoxygalactosyl (GalN3) donors were tested: 6-O-acetyl-3,4-O-isopropylidene-GalN3 thioglycoside was shown to provide the best yield (89%) and stereoselectivity (alpha/beta = 24:1). Further 1,6 anhydro cycle opening, spacer-arming and complete deprotection resulted in the target 3-aminopropyl glycosides of A (type 2) and B (type 2) tetrasaccharides, yields 87 and 85% correspondingly. PMID- 28738268 TI - Descriptive epidemiology of primary malignant and non-malignant central nervous tumors in Spain: Results from the Girona Cancer Registry (1994-2013). AB - BACKGROUND: Systematic registration of non-malignant central nervous system (CNS) tumors is a rare practice among European cancer registries. Thus, the real burden of all CNS tumors across Europe is underestimated. The Girona Cancer Registry provides here the first data on CNS tumor incidence and survival trends in Spain for all histological types, including malignant and non-malignant tumors. METHODS: Data on all incident cases of primary CNS tumors notified to the Girona population-based cancer registry from 1994 to 2013 (n=2,131) were reviewed. Incidences rates (IRs) were standardized to the 2013 European population and annual percentage changes (EAPC) were estimated using a piecewise log linear model. 1- and 5-year observed (OS) and relative survival (RS) were also calculated. Results were expressed by sex, age-group, histological subtype and behavior. RESULTS: The overall IR was 16.85 and increased across the period of study (EAPC=+2.2%). The proportion and IRs of malignant (50.2%; IR=9.35) and non malignant cases (49.8%; IR=9.14) were similar; however, non-malignant tumors were more frequent in women (sex ratio=0.63). The most frequently reported histologies were meningioma (27.6%; IR=5.11) and glioblastoma (22.2%; IR=4.15), which also accounted for the highest and lowest 5-year RS (80.2%; 3.7%, respectively). Globally, 5-year RS was lower in men (42.6% vs. 58.3%, respectively) and in the elderly (64.9% for 0-14years vs. 23.0% for >74years). CONCLUSION: This study presents a comprehensive overview of the epidemiology of malignant and non malignant CNS primary tumors from the well-established region-wide Girona Cancer Registry (1994-2013). Incidence rates were recovered for all histologies. Survival is still dramatically associated to both age and histological subtype. PMID- 28738269 TI - An anti-inflammatory effect of red microalga polysaccharides in coronary artery endothelial cells. AB - BACKGROUND AND AIMS: Polysaccharides (PSs) produced by the red microalga Porphyridium sp. were reported to exhibit anti-inflammatory bioactivities in the human skin. The primary goal of the present research was to assess whether PSs attenuate inflammatory processes by interfering with tumour necrosis factor-alpha (TNF-alpha)-induced inflammation, in human coronary artery endothelial cells (HCAECs). METHODS: Functional and inflammatory markers were quantified in TNF alpha-stimulated HCAECs, with and without pre-treatment with PSs. The expression/activation of these markers was assessed by Western immunoblotting and a luciferase reporter assay. NO levels were measured using the Griess method and intracellular reactive oxygen stress (ROS) was determined with the fluorescent probe 2',7'-dichlorodihydro-fluorescein diacetate (H2DCFDA). RESULTS: The TNF alpha-induced up-regulation of inter-cellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1), nuclear factor kappa-light-chain enhancer of activated B cells (NF-kappaB) translocation, as well as IkappaB degradation were significantly attenuated in cells pre-treated with PSs. In addition, PSs were able to inhibit NF-kappaB activation as well as TNF-alpha induced oxidative stress in HCAECs. Endothelial function was also improved, as measured by increased nitric oxide (NO) formation and decreased endothelin (ET-1) protein expression. CONCLUSIONS: This is the first report that demonstrates the anti-inflammatory effect and vaso-relaxing property of red microalgae PSs in a HCAEC-TNF-alpha induced system. This study lays the foundation for basic research concerning the PS mode of action in biochemical processes involving endothelial dysfunction, and it also holds potential for applied research, possibly promoting the use of PSs as a therapeutic agent or food additive to improve vascular health. PMID- 28738270 TI - Chemical structure and correlation analysis of HIV-1 NNRT and NRT inhibitors and database-curated, published inhibition constants with chemical structure in diverse datasets. AB - Human immunodeficiency virus (HIV-1) reverse transcriptase is a major target for designing anti-HIV drugs. Developed inhibitors are divided into non-nucleoside analog reverse-transcriptase inhibitors (NNRTIs) and nucleoside analog reverse transcriptase inhibitors (NRTIs) depending on their mechanism. Given that many inhibitors have been studied and for many of them binding affinity constants have been calculated, it is beneficial to analyze the chemical landscape of these families of inhibitors and correlate these inhibition constants with molecular structure descriptors. For this, the HIV-1 RT data was retrieved from the ChEMBL database, carefully curated, and original literature verified, grouped into NRTIs and NNRTIs, analyzed using a hierarchical scaffold classification method and modelled with best multi-linear regression approach. Analysis of the HIV-1 NNRTIs subset results in ten different common structural parent types of oxazepanone, piperazinone, pyrazine, oxazinanone, diazinanone, pyridine, pyrrole, diazepanone, thiazole, and triazine. The same analysis for HIV-1 NRTIs groups structures into four different parent types of uracil, pyrimide, pyrimidione, and imidazole. Each scaffold tree corresponding to the parent types has been carefully analyzed and examined, and changes in chemical structure favorable to potency and stability are highlighted. For both subsets, descriptive and predictive QSAR models are derived, discussed and externally validated, revealing general trends in relationships between molecular structure and binding affinity constants in structurally diverse datasets. Data and QSAR models are available at the QsarDB repository (http://dx.doi.org/10.15152/QDB.202). PMID- 28738272 TI - Evolution of corresponding resistance genes in the water of fish tanks with multiple stresses of antibiotics and heavy metals. AB - Abuse of antibiotics and heavy metals in aquaculture has been widely concerned and might aggravate the spread of resistance genes in environment. To investigate the occurrence and proliferation of antibiotic resistance genes (ARGs) and heavy metal resistance genes (HMRGs), three commonly used antibiotics (tetracycline, sulfanilamide, cefotaxime) and two heavy metals (Zn and Cu) were designed to add individually or jointly in nine fish tanks including five individual exposure tanks of tetracycline (tet), sulfanilamide (sul), cefotaxime (cef), Cu, Zn and four combination exposure tanks of tetracycline + sulfanilamide (tet + sul), tetracycline + sulfanilamide + cefotaxime (tet + sul + cef), tetracycline + sulfanilamide + Cu (tet + sul + Cu), tetracycline + sulfanilamide + Zn (tet + sul + Zn) as well as the control during the experiment period of 180 days. Nineteen ARGs (tetA, tetB, tetC, tetD, tetE, tetG, tetM, tetO, tetQ, tetS, tetW, tetX, tetY, sul1, sul2, sul3, blaDHA, blaMOX, blaFOX), two HMRGs (copA, czcA) and the class 1 integron gene (intI 1) in fish tanks water were investigated. The results showed that the residual rate of antibiotics and heavy metals ranged from 0.03% to 2.46% and 9.25%-52.97%, respectively, positively related to their original concentration and types. Tetracycline resistance genes were more sensitive to antibiotics and easier to be induced and developed than sulfanilamide resistance genes and AmpC beta-lactamase resistance genes. The total relative abundances of ARGs in combined stresses exposure tanks (tet + sul, tet + sul + cef, tet + sul + Cu, tet + sul + Zn) were about 1.01-1.55 times more than the sum of their individual ones. The co-selective effects of cefotaxime on the abundance and diversity of tetracycline resistance genes were stronger than Zn and Cu. Besides, multivariate correlation analysis revealed that tetO, tetQ, tetW and sul3 were in significant correlation with the concentrations of Cu and Zn (r = 0.882-0.992, p < 0.05 or p < 0.01). The significant correlations between tetO and intI1 (p < 0.01), tetW and intI1 (p < 0.05), and sul3 and intI1 (p < 0.05) hinted a potentially serious and undesirable dissemination risk of ribosomal protection proteins gene of ARGs. PMID- 28738271 TI - Heterogeneous photocatalysis of tris(2-chloroethyl) phosphate by UV/TiO2: Degradation products and impacts on bacterial proteome. AB - The widespread, persistent and toxic organophosphorus esters (OPEs) have become one category of emerging environmental contaminants. Thus, it is in urgent need to develop a cost-effective and safe treatment technology for OPEs control. The current study is a comprehensive attempt to use UV/TiO2 heterogeneous photocatalysis for the degradation of a water dissolved OPEs, tris(2-chloroethyl) phosphate (TCEP). A pseudo-first order degradation reaction with a kobs of 0.3167 min-1 was observed, while hydroxyl radical may be the dominating reactive oxidative species. As the reaction proceeded, TCEP was transformed to a series of hydroxylated and dechlorinated products. The degradation efficiency was significantly affected by pH value, natural organic matters and anions, implying that the complete mineralization of TCEP would be difficult to achieve in actual water treatment process. Based on the proteomics analysis regarding the metabolism reactions, pathways and networks, the significant activation of transmembrane transport and energy generation in Escherichia coli exposed to preliminary degrading products suggested that they can be transported and utilized through cellular metabolism. Furthermore, the descending trend of stress resistance exhibited that the toxicity of products was obviously weakened as the treatment proceeded. In conclusion, hydroxylation and dechlorination of TCEP with incomplete mineralization were likewise effective for its detoxification, indicating that UV/TiO2 will be an alternative treatment method for OPEs control. PMID- 28738273 TI - Factors influencing warfarin control in Australia and Singapore. AB - INTRODUCTION: Warfarin is widely used for patients with non-valvular atrial fibrillation (NVAF). Variations in warfarin control, as measured by time in therapeutic range (TTR), have been reported across different regions and ethnicities, particularly between Western and Asian countries. However, there is limited data on comparative factors influencing warfarin control in Caucasian and Asian patients. Therefore, the aim of this study was to determine warfarin control and potential factors influencing this in patients with NVAF in Australia and Singapore. METHODS: Retrospective data was collected for patients receiving warfarin for January to June 2014 in Australia and Singapore. TTR was calculated for individuals with mean patient TTR used for analysis. Possible influential factors on TTR were analysed including age, gender, concurrent co-morbidities, and concurrent medication. RESULTS: The mean TTR was significantly higher in Australia (82%) than Singapore (58%). At both sites, chronic kidney disease significantly lowered this TTR. Further factors influencing control were anaemia and age<60years in Australia, and vascular disease, CHA2DS2-VASc score of 6, and concurrent platelet inhibitor therapy in Singapore. DISCUSSION: Warfarin control was significantly higher in Australia compared to Singapore, however chronic kidney disease reduced control at both sites. The different levels of control in these two countries, together with patient factors further reducing control may impact on anticoagulant choice in these countries with better outcomes from warfarin in Australia compared to Singapore. PMID- 28738274 TI - Discovery and assessment of water soluble coumarins as inhibitors of the coagulation contact pathway. AB - Over the last decade, the coagulation factor XIIa (FXIIa) has seen renewed interest as a therapeutic target. Indeed, its inhibition could offer a protection against thrombosis without increasing the risk of bleeding. Moreover, it could answer the need for a safe prevention of blood-contacting medical devices-related thrombosis. Among the FXII and FXIIa inhibitors already described in literature, organic small-molecular-weight inhibitors are rather left behind. In this study, we were focused on the discovery and assessment of water soluble small molecules. First, a search within our library of compounds flagged two promising hits. Indeed, enzymes and plasma assays suggested they have a greater activity on the contact factors (FXIa, plasma kallikrein and FXIIa) than on the TF pathway. Then, simple pharmacomodulations were undertaken with the aim to design more selective FXIIa inhibitors. This afforded compounds having different degrees of selectivity. All compounds were finally screened in whole blood using an 8 channel microfluidic model and thromboelastometry measurements. Interestingly, all molecules interfered with the thrombus formation and one of them could be considered as a small organic contact inhibitor. PMID- 28738275 TI - Early childhood myoclonic epilepsy: An independent genetic generalized epilepsy with myoclonic seizures as the main seizure type. AB - OBJECTIVE: To elucidate the characteristics of the myoclonic seizures alone, or predominant myoclonus combined with generalized tonic-clonic seizures (GTCS) and/or absences, in early childhood, and discuss its classification. METHODS: Forty-two children were retrospectively recruited between January 2006 and June 2015. RESULTS: The mean age of seizure onset was 40.5months. They were divided into 4 groups: myoclonic seizures alone; predominant myoclonus combined with GTCS; predominant myoclonus combined with absences; predominant myoclonus combined with both GTCS and absences. Interictal EEG showed generalized spike- or polyspike-wave discharges at 2-4Hz. Seizures were controlled in 22 patients at a mean age of 60.5months. The psychomotor development was normal (30/37) or mildly delayed (7/37). CONCLUSIONS: We reported a cohort of patients with early childhood myoclonic epilepsy (ECME), with the following characteristics: Seizures started below 5years old in otherwise normal children; Seizure types included myoclonic seizures alone or combined with GTCS and/or absences; Febrile or afebrile GTCS might appear firstly; Interictal EEG showed generalized spike- or polyspike-wave; Seizures usually were in remission before adolescence with normal development or mild cognitive or behavioral deficits in most. SIGNIFICANCE: ECME might be an independent epileptic syndrome not established by International League Against Epilepsy (ILAE) previously. PMID- 28738276 TI - The impact of accelerated high frequency rTMS on brain neurochemicals in treatment-resistant depression: Insights from 1H MR spectroscopy. AB - OBJECTIVE: Although accelerated repetitive transcranial magnetic stimulation (rTMS) designs seem to be able to alleviate mood over a relatively short period of time, no studies yet examined the cellular effects on neurochemicals with regard to working mechanisms, safety and neural integrity. METHODS: Eighteen right-handed antidepressant-free unipolar treatment resistant depressed (TRD) patients participated in this sham-controlled accelerated high frequency (aHF) rTMS 1H MR spectroscopy study applied to the left dorsolateral prefrontal cortex (DLPFC). Baseline measurements were compared to eighteen age- and gender-matched healthy controls. We explicitly focused on neurochemical concentrations in the bilateral DLPFC and rostral anterior cingulate cortex (rACC). RESULTS: Compared to healthy individuals, TRD patients displayed significantly lower baseline glutamatergic (sum absolute concentrations glutamate and glutamine) concentrations in the left DLPFC. aHF-rTMS does not significantly alter neurochemical concentrations in the three predefined brain regions. Clinical improvement was related to significant GABA concentration increases in the left DLPFC. CONCLUSIONS: Accelerated HF-rTMS treatment did not affect neural integrity in the examined regions. The observed GABA concentration increases suggest that the immediate therapeutic effects of aHF-rTMS could be mediated through a locally increased GABAergic inhibitory neurotransmission. SIGNIFICANCE: Although more statistical power is needed for reaching firm conclusions, aHF-rTMS does not appear to negatively influence neural integrity. PMID- 28738277 TI - New ruthenium compounds bearing semicarbazone 2-formylopyridine moiety: Playing with auxiliary ligands for tuning the mechanism of biological activity. AB - Two ruthenium(II) complexes Ru1 and Ru2 bearing as a one ligand 2,2'-bipyridine substituted by a semicarbazone 2-formylopyridine moiety (bpySC: 5-(4-{4'-methyl [2,2'-bipyridine]-4-yl}but-1-yn-1-yl)pyridine-2-carbaldehyde semicarbazone) and as the others 2,2'-bipyridine (bpy) and 4,7-diphenyl-1,10-phenanthroline (dip), respectively, as auxiliary ligands have been prepared. Their biological activity has been studied on murine colon carcinoma (CT26) and human lung adenocarcinoma (A549) cell lines. The anti-proliferative activity was dependent on the presence of bpy or dip in the complex, with one order of magnitude higher cytotoxicity for Ru2 (dip ligands). Ru1 (bpy ligands) exhibited a distinct increase in cytotoxicity going from 24 to 72h of incubation with cells as was not observed for Ru2. Even though both studied compounds were powerful apoptosis inducing agents, the mechanism of their action was entirely different. Ru1-incubated A549 cells showed a notable increase in cells number in the S-phase of the cell cycle, with concomitant decrease in the G2/M phase, while Ru2 promoted a cell accumulation in the G0/G1 phase. In contrast, Ru1 induced marginal oxidative stress in A549 cell lines even upon increasing the incubation time. Even though Ru1 preferably accumulated in lysosomes it triggered the apoptotic cellular death via an intrinsic mitochondrial pathway. Ru1-incubated A549 cells showed swelling and enlarging of the mitochondria. It was not observed in case of Ru2 for which mitochondria and endoplasmic reticulum were found as primarily localization site. Despite this the apoptosis induced by Ru2 was caspase-independent. All these findings point to a pronounced role of auxiliary ligands in tuning the mode of biological activity. PMID- 28738278 TI - Well-dispersed rhenium nanoparticles on three-dimensional carbon nanostructures: Efficient catalysts for the reduction of aromatic nitro compounds. AB - Rhenium nanoparticles (ReNPs) supported on ordered mesoporous carbon (OMC) as a catalyst (Re/OMC) through a solvent-evaporation induced self-assembly (ELSA) method were prepared. The synthesized heterogonous catalyst was fully characterized using X-ray diffraction, field emission transmission electron microscopy, N2 sorption, metal dispersion, thermogravimetric analysis, Raman, Fourier-transform infrared, and X-ray photon spectroscopies. In addition, the catalyst was applied to reduce the aromatic nitro compounds (ANCs) for the first time in aqueous media and the reactions were monitored by following the intensity changes in the UV-vis absorption spectra with respect to time. This method provides the advantages of obtaining a high rate constant (k), green reaction conditions, simple methodology, easy separation and easy workup procedures. Moreover, the catalyst can be easily recovered by centrifugation, recycled several times and reused without any loss of activity. The higher activity of this catalyst was attributed to higher dispersion and smaller particle size of ReNPs as observed from FE-TEM and XRD results. PMID- 28738279 TI - Development and modification of conventional Ouali model for tensile modulus of polymer/carbon nanotubes nanocomposites assuming the roles of dispersed and networked nanoparticles and surrounding interphases. AB - In this paper, conventional Ouali model for tensile modulus of composites is developed for polymer/carbon nanotubes (CNT) nanocomposites (PCNT) assuming the influences of filler network and dispersed nanoparticles above percolation threshold as well as the interphases between polymer host and nanoparticles which reinforce the nanocomposite and facilitate the networking. The developed model is simplified, because the characteristics of dispersed nanoparticles and surrounding interphase cannot significantly change the modulus of PCNT. The suggested model is compared to the experimentally measured modulus of some samples, which can calculate the percolation threshold of interphase regions and the possessions of interphase and filler network. The suggested model correctly predicts the influences of all parameters on the modulus. Thinner and longer CNT in addition to thicker interphase enhance the volume fraction of interphase which shifts the connectivity of interphase regions to smaller nanoparticle fraction and improves the modulus of PCNT. A very low level of percolation threshold significantly develops the modulus, but its high ranges have not any role. Among the studied parameters, the thickness and modulus of interphase between polymer host and networked nanoparticles play the most important roles in the modulus of PCNT. PMID- 28738280 TI - Cobalt fibers anchored with tin disulfide nanosheets as high-performance anode materials for lithium ion batteries. AB - Well-designed hierarchical nanostructured composites consisting of one dimensional cobalt fibers and thin tin disulfide nanosheets were successfully synthesized for the first time through a hydrothermal method. The SnS2 nanosheets were uniformly grown onto the Co fibers and were almost perpendicular to the Co fibers. The composites as one kind anode materials exhibited more remarkable lithium ion storage properties than SnS2 nanosheets. The composites exhibited a capacity of 500.5mAh/g after 100 cycles even at 1000mA/g. The improved electrochemical performance could be assigned to the Co fiber substrate support, which could provide short lithium ion and electron pathways, alleviate large volume expansion, contribute to the capacity, and offer mechanical stability for the anode electrode. This special designing perhaps could lay a foundation for the preparation of high performance lithium ion battery anode materials. PMID- 28738281 TI - EDTA functionalized Fe3O4/graphene oxide for efficient removal of U(VI) from aqueous solutions. AB - In this study, a regenerable magnetic ligand material (EDTA-mGO) was fabricated by binding chelating groups (EDTA) onto Fe3O4/graphene oxide and applied to remove U(VI) from aqueous solution. The sorption experiments were investigated under different experimental conditions, such as temperature, contact time and pH. EDTA-mGO showed fast removal capacity for U(VI) (<1.5h) with high sorption ability (277.43mg/g). The removal mechanisms mainly attributed to the metal binding organic ligand (EDTA) and the electrostatic attractions between U(VI) and oxygenic functional groups. In addition, the as-prepared EDTA-mGO dispersed in water could be easily collected after the sorption by the external magnetic field within 10s. The removal of U(VI) by EDTA-mGO followed the pseudo-second-order rate better than the pseudo-first-order. The thermodynamic data indicated the endothermic and the spontaneous nature of U(VI) sorption. Furthermore, the reproducibility studies suggested that EDTA-mGO has a good reusability and a high stability. PMID- 28738282 TI - Fouling behavior of silica nanoparticle-surfactant mixtures during constant flux dead-end ultrafiltration. AB - The increasing use of engineered nanoparticles in customer products results in their accumulation in water sources. In this experimental study, we investigated the role of surfactant type (cationic, anionic and non-ionic) and concentration on fouling development, nanoparticle rejection and fouling irreversibility during dead-end ultrafiltration of model silica nanoparticles. Our work demonstrates that the type of surfactant influences the nanoparticle stability, which in turn is responsible for differences in fouling behavior of the nanoparticles. Moreover, the surfactant itself interacts with the PES-PVP membrane and contributes to the fouling as well. We have shown that anionic SDS (sodium dodecylsulfate) does not interact extensively with the negatively charged silica nanoparticles and does not change significantly the surface charge and size of these nanoparticles. Adsorption of the cationic CTAB (cetyltrimethylammonium bromide) onto the silica nanoparticles causes charge transition and nanoparticle aggregation, whereas non-ionic TX-100 (Triton X-100) neutralizes the surface charge of the nanoparticles but does not change significantly the nanoparticle size. The most severe fouling development was observed for the silica nanoparticle - TX-100 system, where nanoparticles in the filtration cake formed exhibited the lowest repulsive interactions. Rejection of the nanoparticles was also highest for the mixture containing silica nanoparticles and TX-100. PMID- 28738283 TI - Visual and reversible carbon dioxide sensing enabled by doctor blade coated macroporous photonic crystals. AB - With significant impacts of carbon dioxide on global climate change, carbon dioxide sensing is of great importance. However, most of the existing sensing technologies are prone to interferences from carbon monoxide, or suffer from the use of sophisticated instruments. This research reports the development of reproducible carbon dioxide sensor using roll-to-roll compatible doctor blade coated three-dimensional macroporous photonic crystals. The pores are functionalized with amine groups to allow the reaction with carbon dioxide in the presence of humidity. The adsorption of carbon dioxide leads to red-shift and amplitude reduction of the optical stop bands, resulting in carbon dioxide detection with visible readout. The dependences of the diffraction wavelength on carbon dioxide partial pressure for various amine-functionalized photonic crystals and different humidities in the environment are systematically investigated. In addition, the reproducibility of carbon dioxide sensing has also been demonstrated in this research. PMID- 28738284 TI - Awareness, attitudes toward epilepsy, and first aid knowledge of seizures of hospital staff in Henan, China. AB - AIM: The aim of this study was to evaluate awareness of, attitudes toward, and first aid knowledge of seizures of hospital staff in Henan, China. METHOD: Two hundred nineteen hospital staff, including doctors, nurses, medical technicians, logisticians, and executives working at tertiary hospitals in Henan, China, completed the survey from March to September in 2016. The data comprised the demographic data section, awareness of epilepsy section, attitude toward epilepsy section, and first aid knowledge of seizure attack section. RESULTS: The participants obtained a mean score of 7.48+/-1.705 on the awareness of epilepsy section, and a mean score of 5.32+/-1.165 on the first aid knowledge of seizure attacks section. There were significant correlations between educational level (r=0.187, P=0.006), occupation (r=-0.244, P=0.000), and attitudes toward patients with epilepsy (r=0.351, P=0.000) with the awareness of epilepsy. There were significant correlations between age (r=0.170, P=0.014), educational status (r=0.139, P=0.040), and professional titles (r=0.197, P=0.004) with the first aid knowledge of seizures. CONCLUSION: The study showed that hospital staff had a moderate level of knowledge regarding epilepsy, and they generally displayed a positive attitude. It was also determined that as the awareness of epilepsy increased, they displayed more positive attitudes toward patients with epilepsy. The study also suggests that specialists working on epilepsy should provide more lectures and educational sessions to improve the knowledge of and attitude toward epilepsy and first aid knowledge of seizures among hospital staff. PMID- 28738285 TI - Molecular assessment, characterization, and differentiation of theca stem cells imply the presence of mesenchymal and pluripotent stem cells in sheep ovarian theca layer. AB - The ability of ovarian theca stem cells to differentiate into oocyte and theca cells may lead to a major advancement in reproductive biology and infertility treatments. However, there is little information about function, growth and differentiation potential of these immature cells. In this study adult sheep theca stem cells (TSCs) characteristics, and differentiation potential into osteocyte-like cells (OSLCs), adipocyte-like cells (ALCs), theca progenitor-like cells (TPCs), and oocyte-like cells (OLCs) were investigated. TSCs were isolated, cultured, and compared with mesenchymal stem cells (MSCs), fibroblast cells (FCs), and pluripotent embryonic ovarian cells (EO). Adherent TSCs were morphologically similar to FCs. Cell cycle analysis showed high proliferation capacity of TSCs. TSCs were positive for the mesenchymal cells surface markers, and also expressed POU5F1. Differentiation potential of TSCs into OSLCs and ALCs were confirmed by alizarin red and oil red staining respectively. OSTEOCALCIN and COL1 were expressed in OSLCs. ALCs were positive for PPARalpha and LPL. TPCs expressed theca specific genes (GLI2, GLI3, PTCH1, CYP17A1, 3beta-HSD and LHR) and secreted testosterone, dehydroepiandrostenedione (DHEA), androstenedione, progesterone and estradiol. Lipid droplets in these steroid cells were viewed by oil red staining. OLCs expressed oocyte-specific marker genes including, ZP3, ZP2, GDF9, SYCP3, PRDM1, STELLA, FRAGILIS, DAZL, as well as POU5F1, and showed separated sphere structure. Our results indicated that TSCs derived from ovarian follicles contain MSCs and pluripotent stem cells (PSCs) that can be differentiated into lineages of mesenchymal origin and are capable of differentiation into TPCs and OLCs under in vitro conditions. PMID- 28738286 TI - Emodin suppresses cadmium-induced osteoporosis by inhibiting osteoclast formation. AB - Environmental level of cadmium (Cd) exposure can induce bone loss. Emodin, a naturally compound found in Asian herbal medicines, could influence osteoblast/osteoclast differentiation. However, the effects of emodin on Cd induced bone damage are not clarified. The aim of this study was to investigate the role of emodin on Cd-induced osteoporosis. Sprague-Dawley male rats were divided into three groups which were given 0mg/L, 50mg Cd/L and 50mg Cd/L plus emodin (50mg/kg body weight). Bone histological investigation, microCT analysis, metabolic biomarker determination and immunohistochemical staining were performed at the 12th week. The bone mass and bone microstructure index of rats treated with Cd were obviously lower than in control. Cd markedly enhanced the osteoclast formation compared with control. Emodin significantly abolished the Cd-induced bone microstructure damage (p<0.05), osteoclast formation and increase of tartrate-resistant acid phosphatase 5b level (p<0.05). Our data further showed that emodin attenuated the Cd-induced inhibition of osteoprotegerin expression and stimulation of receptor activator for nuclear factor-kappa B ligand expression. Our data show that emodin suppresses the Cd-induced osteoporosis by inhibiting osteoclast formation. PMID- 28738287 TI - Perceived stress and poly-tobacco product use across adolescence: Patterns of association and gender differences. AB - Perceived stress-an endophenotype indicative of the tendency to appraise stress as frequent, unpredictable and unmanageable-is associated with adolescent cigarette smoking. It is unclear whether this association: (1) extends to alternative tobacco products, like electronic cigarettes and hookah (tobacco water pipe), which are increasingly popular among youth, and (2) differs by gender. In this report, data were drawn from a population-based longitudinal cohort of youth in Southern California. Perceived stress was assessed at baseline (7th or 8th grade; 2010). Electronic cigarette, hookah, combustible cigarette, and cigar use were assessed at a 4-year follow-up (11th or 12th grade; 2014). After adjusting for confounders, polytomous logistic regressions showed that a standardized baseline perceived stress score (M = 0, SD = 1) predicted electronic cigarette, hookah, combustible cigarette, and cigar use and a poly-tobacco use index at the 4-year follow-up in the overall sample. Interactions between perceived stress and gender were also observed (Interaction Ps < 0.05), which demonstrated that the association of perceived stress with tobacco product use and poly-use were stronger in females (ORs for current use range: 1.47 to 1.72) than males (ORs range: 0.93 to 1.31). Adjusting for baseline perceived stress, the change in perceived stress from baseline to follow-up was also positively associated with use and poly-use of most tobacco products in females and in males to some extent. In the current era in which teen use of alternative tobacco products is increasingly common, adolescent tobacco use and poly-use research and prevention strategies should address gender-specific origins of tobacco product use risk and consider perceived stress and other emotional endophenotypes in such risk pathways. PMID- 28738288 TI - It doesn't matter what you say: FMRI correlates of voice learning and recognition independent of speech content. AB - Listeners can recognize newly learned voices from previously unheard utterances, suggesting the acquisition of high-level speech-invariant voice representations during learning. Using functional magnetic resonance imaging (fMRI) we investigated the anatomical basis underlying the acquisition of voice representations for unfamiliar speakers independent of speech, and their subsequent recognition among novel voices. Specifically, listeners studied voices of unfamiliar speakers uttering short sentences and subsequently classified studied and novel voices as "old" or "new" in a recognition test. To investigate "pure" voice learning, i.e., independent of sentence meaning, we presented German sentence stimuli to non-German speaking listeners. To disentangle stimulus invariant and stimulus-dependent learning, during the test phase we contrasted a "same sentence" condition in which listeners heard speakers repeating the sentences from the preceding study phase, with a "different sentence" condition. Voice recognition performance was above chance in both conditions although, as expected, performance was higher for same than for different sentences. During study phases activity in the left inferior frontal gyrus (IFG) was related to subsequent voice recognition performance and same versus different sentence condition, suggesting an involvement of the left IFG in the interactive processing of speaker and speech information during learning. Importantly, at test reduced activation for voices correctly classified as "old" compared to "new" emerged in a network of brain areas including temporal voice areas (TVAs) of the right posterior superior temporal gyrus (pSTG), as well as the right inferior/middle frontal gyrus (IFG/MFG), the right medial frontal gyrus, and the left caudate. This effect of voice novelty did not interact with sentence condition, suggesting a role of temporal voice-selective areas and extra-temporal areas in the explicit recognition of learned voice identity, independent of speech content. PMID- 28738289 TI - Germinal center enhancement by extended antigen availability. AB - Vaccine elicitation of protective antibody responses has proved difficult for a number of important human pathogens, including HIV-1. The amount of somatic hypermutation associated with the development of broadly neutralizing antibodies against HIV has not been achieved using conventional immunization strategies. An underexplored aspect of vaccine design is modulation of antigen kinetics. Immunization strategies with extended antigen availability have recently been shown to enhance humoral responses. In this review, we explore the mechanisms through which sustained antigen availability can enhance germinal center responses and the potency of antibody responses. These potential mechanisms include shifting B cell recognition away from non-neutralizing immunodominant epitopes, altered kinetics of immune complex deposition, improved T follicular helper (Tfh) cell responses, enhanced affinity maturation, and enhanced development of B cell memory. Finally, we discuss immunization strategies that result in extended antigen availability. PMID- 28738290 TI - Cell targeting peptides as smart ligands for targeting of therapeutic or diagnostic agents: a systematic review. AB - Cell targeting peptides (CTP) are small peptides which have high affinity and specificity to a cell or tissue targets. They are typically identified by using phage display and chemical synthetic peptide library methods. CTPs have attracted considerable attention as a new class of ligands to delivery specifically therapeutic and diagnostic agents, because of the fact they have several advantages including easy synthesis, smaller physical sizes, lower immunogenicity and cytotoxicity and their simple and better conjugation to nano-carriers and therapeutic or diagnostic agents compared to conventional antibodies. In this systematic review, we will focus on the basic concepts concerning the use of cell targeting peptides (CTPs), following the approaches of selecting them from peptide libraries. We discuss several developed strategies for cell-specific delivery of different cargos by CTPs, which are designed for drug delivery and diagnostic applications. PMID- 28738291 TI - Inflammation-responsive self-regulated drug release from ultrathin hydrogel coating. AB - Heterotopic ossification(HO) is a potential severe complication after many biomaterial implanting surgeries, and the inflammation environment caused by the implanting-associated infections is considered as the main nosogenesis. Herein, an inflammation-responsive drug release system was designed by chemically conjugating indometacin (via ester group) onto hydrogel coating to realize local self-regulated drug release to prevent HO. In our strategy, poly(3 mercaptopropyl)trimethoxysilane-co-acrylic acrylate and polyvinyl alcohol (providing anchoring sites for drug molecules) were firstly synthesized and functionalized with ene-groups, then a hydrogel layer was formed and covalently attached onto thiol-modified substrate via thiol-ene click chemistry, followed by grafting indometacin. A porous structure of the attached hydrogel layer was observed by scanning electron microscopy, and the presence of drug molecules in the hydrogel layer was confirmed by X-ray photoelectron spectroscopy and UV-vis absorption spectra. The drug release could be triggered under the mimicking inflammation environment, and the release rate was responsive to the inflammation degree. In addition, after attaching the hydrogel coating, the substrate showed low cytotoxicity, and high promotion for cell adhesion and proliferation. The excellent hemocompatibility of the hydrogel coating was also demonstrated by prolonged clotting time and suppressed platelet adhesion. This work suggests that the inflammation-responsive indometacin conjugated hydrogel coating has great potential to be used for prophylaxis HO. PMID- 28738292 TI - U-shaped relationship between depression and body mass index in the Korean adults. AB - BACKGROUND: Although a number of studies have examined the relationship between depression and obesity, it is still insufficient to establish the specific pattern of relationship between depression and body mass index (BMI) categories. Thus, this study was aimed to investigate the relationship between depression and BMI categories. METHODS: A cross-sectional study was conducted for a cohort of 159,390 Korean based on Kangbuk Samsung Health Study (KSHS). Study participants were classified into 5 groups by Asian-specific cut-off of BMI (18.5, 23, 25 and 30kg/m2). The presence of depression was determined by Center for Epidemiologic Studies-Depression scales (CES-D)>=16 and>=25. The adjusted odd ratios (ORs) for depression were evaluated by multiple logistic regression analysis, in which independent variable was 5 categories of BMI and dependent variable was depression. Subgroup analysis was conducted by gender and age. RESULTS: When normal group was set as a reference, the adjusted ORs for depression formed U shaped pattern of relationship with BMI categories [underweight: 1.31 (1.14 1.50), overweight: 0.94 (0.85-1.04), obese group: 1.01 (0.91-1.12), severe obese group: 1.28 (1.05-1.54)]. This pattern of relationship was more prominent in female and young age group than male and elderly subgroup. BMI level with the lowest likelihood of depression was 18.5kg/m2 to 25kg/m2 in women and 23kg/m2 to 25kg/m2 in men. CONCLUSIONS: There was a U-shaped relationship between depression and BMI categories. This finding suggests that both underweight and severe obesity are associated with the increased risk for depression. PMID- 28738294 TI - Oral Mucosa Dose Parameters Predicting Grade >=3 Acute Toxicity in Locally Advanced Nasopharyngeal Carcinoma Patients Treated With Concurrent Intensity Modulated Radiation Therapy and Chemotherapy: An Independent Validation Study Comparing Oral Cavity versus Mucosal Surface Contouring Techniques. AB - PURPOSE: To determine whether volumes based on the contours of the mucosal surface instead of the oral cavity can be used to predict grade >=3 acute oral mucosa toxicity in patients with locally advanced nasopharyngeal carcinoma (LANPC) treated with concurrent intensity-modulated radiation therapy (IMRT) and chemotherapy. METHODS AND MATERIALS: A standardized method for the oral cavity (oral cavity contours, OCC) and a novel method for the mucosal surface (mucosal surface contours, MSC) were developed for the oral mucosa and prospectively applied to the radiation treatment plans of 92 patients treated with concurrent IMRT and chemotherapy for LANPC. Dose-volume histogram (DVH) data were extracted and then toxicity was analyzed. Receiver operating characteristic analysis and logistic regression were carried out for both contouring methods. RESULTS: Grade >=3 acute oral mucosa toxicity occurred to 20.7% (19/92) of patients in the study. A highly significant dose-volume relationship between oral mucosa irradiation and acute oral mucosa toxicity was supported by using both oral cavity and mucosal surface contouring techniques. In logistic regression, body weight loss was an independent factor related to grade >=3 acute toxicity for OCC and MSC (P=.017 and 0.005, respectively), and the independent factor of dosimetric parameters for OCC and MSC were V30Gy (P=.003) and V50Gy (P=.003) respectively. In the receiver operating characteristics curve, the areas under V30Gy of the OCC curves was 0.753 (P=.001), while the areas under V50Gy of MSC curves was 0.714 (P=.004); the cut-off value was 73.155% (sensitivity, 0.842; specificity, 0.671) and 14.32% (sensitivity, 0.842; specificity, 0.575), respectively. CONCLUSION: DVH analysis of mucosal surface volumes accurately predicts grade >=3 acute oral mucosa toxicity in patients with LANPC receiving concurrent IMRT and chemotherapy, but in clinical practice the MSC method appears no better than the OCC one. PMID- 28738293 TI - Oxytocin effects on emotional response to others' faces via serotonin system in autism: A pilot study. AB - The oxytocin (OT)-related serotonergic system is thought to play an important role in the etiology and social symptoms of autism spectrum disorder (ASD). However, no evidence exists for the relation between the prosocial effect of chronic OT administration and the brain serotonergic system. Ten male subjects with ASD were administered OT for 8-10 weeks in an open-label, single-arm, non randomized, uncontrolled manner. Before and during the OT treatment, positron emission tomography was used with the (11C)-3-amino-4-(2 [(demethylamino)methyl]phenylthio)benzonitrile(11C-DASB) radiotracer. Then binding of serotonin transporter (11C-DASB BPND) was estimated. The main outcome measures were changes in 11C-DASB BPND and changes in the emotional response to others' faces. No significant change was found in the emotional response to others' faces after the 8-10 week OT treatment. However, the increased serotonin transporter (SERT) level in the striatum after treatment was correlated significantly with increased negative emotional response to human faces. This study revealed a relation between changes in the serotonergic system and in prosociality after chronic OT administration. Additional studies must be conducted to verify the chronic OT effects on social behavior via the serotonergic system. PMID- 28738295 TI - Does the effect of one-day simulation team training in obstetric emergencies decline within one year? A post-hoc analysis of a multicentre cluster randomised controlled trial. AB - : Does the effect of one-day simulation team training in obstetric emergencies decline within one year? A post-hoc analysis of a multicentre cluster randomised controlled trial. J van de Ven, AF Fransen, E Schuit, PJ van Runnard Heimel, BW Mol, SG Oei OBJECTIVE: To investigate whether the effect of a one-day simulation based obstetric team training on patient outcome changes over time. STUDY DESIGN: Post-hoc analysis of a multicentre, open, randomised controlled trial that evaluated team training in obstetrics (TOSTI study).We studied women with a singleton pregnancy beyond 24 weeks of gestation in 24 obstetric units. Included obstetric units were randomised to either a one-day, multi-professional simulation-based team training focusing on crew resource management in a medical simulation centre (12 units) or to no team training (12 units). We assessed whether outcomes differed between both groups in each of the first four quarters following the team training and compared the effect of team training over quarters. Primary outcome was a composite outcome of low Apgar score, severe postpartum haemorrhage, trauma due to shoulder dystocia, eclampsia and hypoxic ischemic encephalopathy. RESULTS: During a one year period after the team training the rate of obstetric complications, both on the composite level and the individual component level, did not differ between any of the quarters. For trauma due to shoulder dystocia team training led to a significant decrease in the first quarter (0.06% versus 0.26%, OR 0.19, 95% CI 0.03 to 0.98) but in the subsequent quarters no significant reductions were observed. Similar results were found for invasive treatment for severe postpartum haemorrhage where a significant increase was only seen in the first quarter (0.4% versus 0.03%, OR 19, 95% CI 2.5-147), and not thereafter. CONCLUSION: The beneficial effect of a one-day, simulation-based, multiprofessional, obstetric team training seems to decline after three months. If team training is further evaluated or implemented, repetitive training sessions every three months seem therefore recommended. PMID- 28738296 TI - Mental distress, quality of life and social support in recurrent ovarian cancer patients during active chemotherapy. AB - BACKGROUND: Anxiety and depression are common sources of mental distress experienced by ovarian cancer patients. The purpose of this study was to identify changes in levels of mental distress during active chemotherapy, to characterize the impact of these changes on quality of life (QOL), and to study the potential buffering effect of social support in recurrent ovarian cancer patients. METHODS: Anxiety and depression were assessed at baseline and three months after initiation of active chemotherapy using hospital anxiety and depression scale (HADS). QOL was evaluated at the same time points using European Organization for Research and Treatment [EORCT] 30-item core quality of life questionnaire (QLQ C30) and QLQ-OV28. Social support was evaluated by perceived social support scale (PSSS) at baseline. RESULTS: Our results showed recurrent ovarian cancer patients had high rates of anxiety and depression. Levels of anxiety, but not depression, were significantly decreased following active chemotherapy. Notably, both anxiety and depression were significantly associated with poorer QOL on all functioning domains, global health and most symptom domains at both baseline and after chemotherapy. Social support was associated with improved mental state and several functioning and symptom domains of QOL. CONCLUSIONS: Our study reveals a high prevalence of mental distress and its profound detrimental impact on QOL in Chinese women with recurrent ovarian cancer. Social support is beneficial to alleviate mental distress and improve QOL. PMID- 28738297 TI - Endometrial stromal sarcoma-A retropsective analysis of factors affecting recurrence. AB - OBJECTIVE: To assess the factors associated with disease free survival and overall survival in endometrial stromal sarcoma (ESS). METHODS: This was a single institution retrospective analysis done at Amrita Institute of Medical Sciences. Records from January 2005 to October 2016 were analysed and 42 patients with ESS were identified. Clinicopathological, surgical management, adjuvant treatment and outcome data were collected. Disease free and overall survivals were analysed using Kaplan-Meier method and compared using log rank test. RESULTS: Out of 38 patients included in analysis 28 (73.7%) had low grade ESS (LGESS) and 10 (26.3%) had high grade ESS (HGESS). The median follow up period was 28 months (range 1 110 months). The 5year disease free survival (DFS) and overall survival (OS) for the entire cohort were 62.9 and 89.1% respectively. High grade ESS was significantly associated with recurrence on univariate analysis (p=0.045). Complete staging surgery in both HGESS and LGESS and adjuvant treatment in HGESS and advanced stage LGESS (cohort 1) were associated with improved 5-year DFS of 90.9% (p<0.001). Completion staging surgery in patients with initial incomplete surgery (cohort 3) was associated with improved 5-year DFS of 100% (p<0.001). Complete Staging surgery but no adjuvant treatment in HGESS and advanced stage LGESS (cohort 2) was associated with significantly poor 2-year DFS of 20% (5-year DFS rate 0%; as all patients recurred within 27 months) (P<0.001). Significantly reduced 5-year DFS rate of 25% (p<0.001) was also seen in cases where initial incomplete surgery was not followed by complete staging and adjuvant treatment (cohort 4). Adjuvant treatment in HGESS was associated with improved 5-year DFS of 66.7% (p=0.043). Resection of recurrent lesions were associated with improved mean survival of 41.2 months. CONCLUSION: Incomplete surgery and no adjuvant treatment in ESS are associated with poor DFS. Complete staging surgery is associated with improved DFS. Resection of recurrent disease is associated with survival advantage. PMID- 28738298 TI - Laparoscopic treatment of Dunbar syndrome: A case report. AB - BACKGROUND: Dunbar syndrome is a rare disorder due to external compression of the celiac trunk by the median arcuate ligament. The symptoms include abdominal pain, nausea and vomiting. Laparoscopic treatment was suggested as a safe procedure. The aim of this study is to present a case of Dunbar syndrome underwent laparoscopic treatment. CASEPRESENTATION: A 17-year-old female patient presented at emergency room with upper abdominal pain and dyspepsia, related to food intake. A selective arteriography of the celiac trunk revealed stenosis due to compression of the celiac artery. The decompression of the celiac trunk by the median arcuate ligament was performed. Postoperative course was uneventful and the patient was discharged on the 5th postoperative CONCLUSIONS: Laparoscopic division of the arcuate ligament in patients with Dunbar syndrome is feasible and safe. This procedure can be performed uneventful in order to restore quality of life of the patient. PMID- 28738301 TI - Effects of an in situ diesel oil spill on oxidative stress in the clam Anomalocardia flexuosa. AB - Intensive exploitation and transport of oil and derivatives are increasing the risk of coastal contamination by either dramatic disasters or diffuse sources. Tools for monitoring diffuse contamination, such as diesel oil that leaks from marine vessels are much needed. We experimentally tested the efficiency of antioxidant biomarkers as indicators of chronic exposure to diesel oil in a mudflat from the subtropical Bay of Paranagua, in southern Brazil. We examined the effects of three successive diesel oil spills, with two weeks of recovery time between exposures, on the edible clam Anomalocardia flexuosa. Previous studies have highlighted its potential as a bioindicator species for diesel oil contamination in subtropical and tropical ecosystems. Endpoints measured in gill and digestive gland homogenates included the activity of antioxidant enzymes SOD, GPx, GST and levels of lipid peroxides. PAHs concentration in sediments and soft tissue were also quantified. GST and SOD were the most responsive biomarkers to the exposure. There were significant but non-cumulative departures from control levels in organisms from treated samples, which were, in all cases, more common 48 h after each experimental spill. Biomarker responses were more evident in the digestive gland than in gills. This work validated the short-term responsiveness of biomarkers as measures of repeated pulsed in situ exposure to low concentrations of diesel oil. For their routine implementation into monitoring programs for tropical estuaries our general recommendations are 1) to include several reference sites, 2) to analyze biomarker data using a logarithmic-scale and 3) to interpret deviations from "normal" activity as multiplicative interval differences. PMID- 28738302 TI - Abnormal pinocytosis and valence-variable behaviors of cerium suggested a cellular mechanism for plant yield reduction induced by environmental cerium. AB - The environmental safety of cerium (Ce) applications in many fields has been debated for almost a century because the cellular effects of environmental Ce on living organisms remain largely unclear. Here, using new, interdisciplinary methods, we surprisingly found that after Ce(III) treatment, Ce(III) was first recognized and anchored on the plasma membrane in leaf cells. Moreover, some trivalent Ce(III) was oxidized to tetravalent Ce(IV) in this organelle, which activated pinocytosis. Subsequently, more anchoring sites and stronger valence variable behavior on the plasma membrane caused stronger pinocytosis to transport Ce(III and IV) into the leaf cells. Interestingly, a great deal of Ce was bound on the pinocytotic vesicle membrane; only a small amount of Ce was enclosed in the pinocytotic vesicles. Some pinocytic vesicles in the cytoplasm were deformed and broken. Upon breaking, pinocytic vesicles released Ce into the cytoplasm, and then these Ce particles self-assembled into nanospheres. The aforementioned special behaviors of Ce decreased the fluidity of the plasma membrane, inhibited the cellular growth of leaves, and finally, decreased plant yield. In summary, our findings directly show the special cellular behavior of Ce in plant cells, which may be the cellular basis of plant yield reduction induced by environmental Ce. PMID- 28738300 TI - Paternal and maternal preconception urinary phthalate metabolite concentrations and child behavior. AB - BACKGROUND: Prenatal phthalate exposure has been associated with behavioral problems and lower performance on measures of cognitive ability in children. However, the potential effect of phthalate exposure during the sensitive preconception period is unknown. OBJECTIVES: To estimate the association of maternal and paternal preconception urinary phthalate metabolite concentrations with child behavior and evaluate potential modification by child sex. METHODS: We used data from 166 children (111 singletons, 26 pairs of twins, and 1 set of triplets) born to 134 mothers and 100 fathers participating in a prospective preconception cohort study of subfertile couples from the Massachusetts General Hospital Fertility Center. We estimated mean maternal and paternal preconception exposures by averaging individual phthalate metabolite concentrations in multiple urine samples collected before pregnancy. We assessed children's behavior at 2-9 years of age by parent report using the Behavior Assessment System for Children-2 (BASC-2). We estimated the covariate-adjusted association between individual phthalate metabolite concentrations and the sum of di(2-ethylhexyl) phthalate metabolites (? DEHP) and behavior scores, and evaluated differences in associations by child sex using linear regression with Generalized Estimating Equations. Models were further adjusted for prenatal phthalate concentrations in sensitivity analyses. RESULTS: Each loge-unit increase in maternal and paternal preconception concentrations of ?DEHP was associated with a 2.0 (95% CI: - 3.2, - 0.7) and 1.8 (95% CI: - 3.1, - 0.4) point decrease in BASC-2 internalizing behavior scores among all children, respectively. We observed sex-specific associations for some phthalate biomarkers: among boys, maternal monoisobutyl phthalate (MiBP) was positively associated with externalizing behaviors, and paternal MiBP and mono-n-butyl phthalate were positively associated with internalizing behaviors. CONCLUSIONS: In this cohort, paternal and maternal preconception concentrations of some phthalate biomarkers were associated with specific aspects of child behavior, even after adjustment for prenatal concentrations. While additional research is warranted to confirm these results, our findings suggest that the preconception period of exposure may be a critical window for offspring neurodevelopment. PMID- 28738303 TI - Bio-accumulation of lanthanum from lanthanum modified bentonite treatments in lake restoration. AB - Lanthanum (La) modified bentonite (LMB) is one of the available mitigating agents used for the reduction of the phosphorus (P) recycling in eutrophic lakes. The potential toxicity of the La from LMB to aquatic organisms is a matter of concern. In this study the accumulation of La was investigated in the macrophyte Elodea nuttallii, in chironomid larvae and in several fish species during periods up to five years following in situ LMB applications. The application of LMB increased the La concentration of exposed plants and animals. During the first growing season following LMB applications, the La content of E. nuttallii increased 78 fold (3.98-310.68 MUg La g-1 DW) to 127 fold (2.46-311.44 MUg La g 1). During the second growing season following application, the La content decreased but was still raised compared to plants that had not been exposed. The La content of chironomids was doubled in the two years following LMB application, although the increase was not significant. Raised La concentrations in fish liver, bone, muscle and skin were observed two and five years following to LMB application. Liver tissues showed the highest La increase, ranging from 6 fold (0.046-0.285 MUg La g-1 DW) to ~20 fold (0.080-1.886 MUg La g-1, and 0.122-2.109 MUg La g-1) two years following application and from 6 fold (0.046-0.262 MUg La g 1) to 13 fold (0.013-0.167 MUg La g-1) after five years in pelagic and littoral fish. The La content of the liver from Anguilla anguilla (eel) had increased 94 fold (0.034-3.176 MUg La g-1) two years and 133 fold (0.034-4.538 MUg La g-1) five years following LMB application. No acute and chronic effects of La accumulation were observed and human health risks are considered negligible. We advocate the long-term study of effects of La accumulation following future LMB applications. PMID- 28738299 TI - The impact of BMI on non-malignant respiratory symptoms and lung function in arsenic exposed adults of Northern Chile. AB - BACKGROUND: Elevated body mass index (BMI) and arsenic are both associated with cancer and with non-malignant lung disease. Using a unique exposure situation in Northern Chile with data on lifetime arsenic exposure, we previously identified the first evidence of an interaction between arsenic and BMI for the development of lung cancer. OBJECTIVES: We examined whether there was an interaction between arsenic and BMI for the development of non-malignant lung disease. METHODS: Data on lifetime arsenic exposure, respiratory symptoms, spirometry, BMI, and smoking were collected from 751 participants from cities in Northern Chile with varying levels of arsenic water concentrations. Spirometry values and respiratory symptoms were compared across subjects in different categories of arsenic exposure and BMI. RESULTS: Adults with both a BMI above the 90th percentile (>33.9kg/m2) and arsenic water concentrations >=11ug/L exhibited high odds ratios (ORs) for cough (OR = 10.7, 95% confidence interval (CI): 3.03, 50.1), shortness of breath (OR = 14.2, 95% CI: 4.79, 52.4), wheeze (OR = 14.4, 95% CI: 4.80, 53.7), and the combined presence of any respiratory symptom (OR = 9.82, 95% CI: 4.22, 24.5). In subjects with lower BMIs, respiratory symptom ORs for arsenic water concentrations >=11ug/L were markedly lower. In never-smokers, reductions in forced vital capacity associated with arsenic increased as BMI increased. Analysis of the FEV1/FVC ratio in never-smokers significantly increased as BMI and arsenic concentrations increased. Similar trends were not observed for FEV1 alone or in ever-smokers. CONCLUSIONS: This study provides preliminary evidence that BMI may increase the risk for arsenic-related non-malignant respiratory disease. PMID- 28738304 TI - Bacteria contribute to pesticide degradation in cryoconite holes in an Alpine glacier. AB - Organic contaminants deposited on glacier snow and ice are subject to partitioning and degradation processes that determine their environmental fate and, consequently, their accumulation in ice bodies. Among these processes, organic compound degradation by supraglacial bacteria has been investigated to a lesser extent than photo- and chemical degradation. We investigated biodegradation of the organophosphorus insecticide chlorpyrifos (CPF), a xenobiotic tracer that accumulates on glaciers after atmospheric medium- and long range transport, by installing in situ microcosms on an Alpine glacier to simulate cryoconite hole systems. We found that biodegradation contributed to the removal of CPF from the glacier surface more than photo- and chemical degradation. The high concentration of CPF (2-3 MUg g-1 w.w.) detected in cryoconite holes and the estimated half-life of this compound (35-69 days in glacier environment) indicated that biodegradation can significantly reduce CPF concentrations on glaciers and its runoff to downstream ecosystems. The metabolic versatility of cryoconite bacteria suggests that these habitats might contribute to the degradation of a wide class of pollutants. We therefore propose that cryoconite acts as a "biofilter" by accumulating both pollutants and biodegradative microbial communities. The contribution of cryoconite to the removal of organic pollutants should be included in models predicting the environmental fate of these compounds in cold areas. PMID- 28738305 TI - Contamination characteristics and source apportionment of methylated PAHs in agricultural soils from Yangtze River Delta, China. AB - Alkylated PAHs (APAHs) have been shown to be more toxic and persistent than their non-alkylated parent compounds. However, little is known about the extent of soil contamination by these pollutants. To help understand agricultural soil pollution by these compounds at a regional scale, a total of 18 methylated PAHs (MPAHs, a major class of APAHs) in 243 soil samples were analyzed. These soil samples were collected from 11 sites in the Yangtze River Delta (YRD) region, a representative fast developing area in China. The total concentration of MPAHs (?18MPAHs) ranged from 5.5 to 696.2 ng/g dry soil, with methylnaphthalenes (M-NAPs) and methylphenanthrenes (M-PHEs) accounting for more than 70% of the compositional profile. Relatively high concentrations of ?18MPAHs were found in Jiaxing and Huzhou areas of Zhejiang province, as well as on the border between the cities of Wuxi and Suzhou. Different MPAH groups showed dissimilar spatial distribution patterns. The spatial distribution of lower molecular weight MPAHs was related to agricultural straw burning and emissions/depositions from industrial activities, whereas that of higher molecular weight MPAHs was much more a function of the total organic carbon (TOC) content of soil. Although coal, biomass (crop straw and wood), and petroleum combustion were identified to be the major emission sources for most of the sampling sites, the areas with relatively severe pollution with ?18MPAHs resulted from the localized hotspots of petroleum leakage. Isomeric MPAHs with methyl group substituted at 2- (beta) position exhibited significantly higher concentrations than those substituted at 1- (alpha) position. Results of this work help to understand soil pollution by MPAHs, and are useful for designing effective strategies for pollution control so as to ensure food safety in areas with fast economic growth. PMID- 28738306 TI - Adipocyte fatty acid binding protein 4 (FABP4) inhibitors. A comprehensive systematic review. AB - Small molecule inhibitors of adipocyte fatty acid binding protein 4 (FABP4) have attracted interest following the recent publications of beneficial pharmacological effects of these compounds. FABP4 is predominantly expressed in macrophages and adipose tissue where it regulates fatty acids (FAs) storage and lipolysis and is an important mediator of inflammation. In the past years, hundreds FABP4 inhibitors have been synthesized for effective atherosclerosis and diabetes treatments, including derivatives of niacin, quinoxaline, aryl quinoline, bicyclic pyridine, urea, aromatic compounds and other novel heterocyclic compounds. This review provides an overview of the synthesized and discovered molecules as adipocyte fatty acid binding protein 4 inhibitors (FABP4is) since the synthesis of the putative FABP4i, BMS309403, highlighting the interactions of the different classes of inhibitors with the targets. PMID- 28738307 TI - Pharmacological characterization and binding modes of novel racemic and optically active phenylalanine-based antagonists of AMPA receptors. AB - In order to map out molecular determinants for the competitive blockade of AMPA receptor subtypes, a series of racemic aryl-substituted phenylalanines was synthesized and pharmacologically characterized in vitro at native rat ionotropic glutamate receptors. Most of the compounds showed micromolar affinity and preference for AMPA receptors. Individual stereoisomers of selected compounds were further evaluated at recombinant homomeric rat GluA2 and GluA3 receptors. The most potent compound, (-)-2-amino-3-(6-chloro-2',5'-dihydroxy-5-nitro-[1,1' biphenyl]-3-yl)propanoic acid, the expected R-isomer showing Ki of 1.71 MUM at the GluA2 subtype, was found to competitively antagonize GluA2(Q)i receptors in TEVC electrophysiological experiments (Kb = 2.13 MUM). Molecular docking experiments allowed us to compare two alternative antagonist binding modes for the synthesized phenylalanines at the GluA2 binding core, showing the direction for further structural modifications. PMID- 28738308 TI - Antiproliferative and pro-apoptotic activities of 2'- and 4'-aminochalcones against tumor canine cells. AB - In the present study, a series of 2'- and 4'-aminochalcones were synthesized and their antiproliferative activity against a canine malignant histiocytic cell line (DH82) was evaluated. Particularly aminochalcones with a hydrophobic substituent on ring B proved to be potent antiproliferative agents. Among these compounds, aminochalcones 3, 4 and 11 inhibited the growth of DH82 cells, with IC50 values of 34.4, 31.4 and 38.2 MUM, respectively, and were three times more potent than etoposide (IC50 = 95.5 MUM). The selected chalcones induced death through apoptosis rather than necrosis in DH82 and non-tumorigenic Madin-Darby canine kidney cells (MDCK). Further experiments suggested that the aminochalcones interfere with the regulation of oncogenes/tumor suppressor genes. Aminochalcone 11 inhibited transcription of the TOPOIIalpha and TP53 genes and aminochalcone 4 down-regulated Sp1 protein expression in a concentration-dependent manner. PMID- 28738309 TI - Irradiation by blue light in the presence of a photoacid confers changes to colony morphology of the plant pathogen Colletotrichum gloeosporioides. AB - We used the photoacid 8-hydroxy-1,3,6-pyrenetrisulfonate (HPTS) that converts blue photons to acidic protons in water, with an efficiency of close to 100%, and determined that this treatment conferred changes to colony morphology of the plant pathogen Colletotrichum gloeosporioides. The time elapsed until hyphal collapse is noticed depends on both the laser intensity in mW/cm2, and the concentration of HPTS in the Agar hydrogel. The time elapsed until hyphal collapse is noticed varies by only +/-8% at HPTS concentrations of 500MUM and at lower concentrations of HPTS the variance increases as the inverse of the concentration. We found that the effect on C. gloeosporioides was photoacid concentration and irradiation dose dependent. In the presence of 500MUM of HPTS within the agar hydrogel-based medium, hyphae collapsed after 37+/-3.5min of irradiation at 405nm at an intensity of 25mW/cm2. We propose two mechanisms for such photo-alteration of C. gloeosporioides. One is based on the pH drop in the extracellular environment by the photo-protolytic process that the photoacid molecule undergoes. The second mechanism is based on an intracellular mechanism in which there is an uptake of HPTS into the interior of the fungus. We suggest that both mechanisms for photo-alteration which we found in this study may occur in plants during fungal infection. PMID- 28738310 TI - Postural response to predictable and nonpredictable visual flow in children and adults. AB - Children's (3-5years) and adults' postural reactions to different conditions of visual flow information varying in its frequency content was examined using a moving room apparatus. Both groups experienced four conditions of visual input: low-frequency (0.20Hz) visual oscillations, high-frequency (0.60Hz) oscillations, multifrequency nonpredictable visual input, and no imposed visual information. Analyses of the frequency content of anterior-posterior (AP) sway revealed that postural reactions to the single-frequency conditions replicated previous findings; children were responsive to low- and high-frequency oscillations, whereas adults were responsive to low-frequency information. Extending previous work, AP sway in response to the nonpredictable condition revealed that both groups were responsive to the different components contained in the multifrequency visual information, although adults retained their frequency selectivity to low-frequency versus high-frequency content. These findings are discussed in relation to work examining feedback versus feedforward control of posture, and the reweighting of sensory inputs for postural control, as a function of development and task context. PMID- 28738311 TI - Perception is key? Does perceptual sensitivity and parenting behavior predict children's reactivity to others' emotions? AB - When interacting with other people, both children's biological predispositions and past experiences play a role in how they will process and respond to social emotional cues. Children may partly differ in their reactions to such cues because they differ in the threshold for perceiving such cues in general. Theoretically, perceptual sensitivity (i.e., the amount of detection of slight, low-intensity stimuli from the external environment independent of visual and auditory ability) might, therefore, provide us with specific information on individual differences in susceptibility to the environment. However, the temperament trait of perceptual sensitivity is highly understudied. In an experiment, we tested whether school-aged children's (N=521, 52.5% boys, Mage=9.72years, SD=1.51) motor (facial electromyography) and affective (self report) reactivities to dynamic facial expressions and vocalizations is predicted by their (parent-reported) perceptual sensitivity. Our results indicate that children's perceptual sensitivity predicts their motor reactivity to both happy and angry expressions and vocalizations. In addition, perceptual sensitivity interacted with positive (but not negative) parenting behavior in predicting children's motor reactivity to these emotions. Our findings suggest that perceptual sensitivity might indeed provide us with information on individual differences in reactivity to social-emotional cues, both alone and in interaction with parenting behavior. Because perceptual sensitivity focuses specifically on whether children perceive cues from their environment, and not on whether these cues cause arousal and/or whether children are able to regulate this arousal, it should be considered that perceptual sensitivity lies at the root of such individual differences. PMID- 28738313 TI - High throughput phenotyping to accelerate crop breeding and monitoring of diseases in the field. AB - Effective implementation of technology that facilitates accurate and high throughput screening of thousands of field-grown lines is critical for accelerating crop improvement and breeding strategies for higher yield and disease tolerance. Progress in the development of field-based high throughput phenotyping methods has advanced considerably in the last 10 years through technological progress in sensor development and high-performance computing. Here, we review recent advances in high throughput field phenotyping technologies designed to inform the genetics of quantitative traits, including crop yield and disease tolerance. Successful application of phenotyping platforms to advance crop breeding and identify and monitor disease requires: (1) high resolution of imaging and environmental sensors; (2) quality data products that facilitate computer vision, machine learning and GIS; (3) capacity infrastructure for data management and analysis; and (4) automated environmental data collection. Accelerated breeding for agriculturally relevant crop traits is key to the development of improved varieties and is critically dependent on high-resolution, high-throughput field-scale phenotyping technologies that can efficiently discriminate better performing lines within a larger population and across multiple environments. PMID- 28738312 TI - Habitual sleep quality and diurnal rhythms of salivary cortisol and dehydroepiandrosterone in postmenopausal women. AB - Dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis has been suggested as a potential mechanism linking sleep and cardiometabolic disorders. However, the associations of two primary outputs of the HPA axis, cortisol and its antagonist dehydroepiandrosterone (DHEA), with sleep are less well studied. In the Nurses' Health Study II, 233 postmenopausal women provided five timed saliva samples over one day (immediately upon waking, 45min, 4h, and 10h after waking, and prior to going to sleep) to measure cortisol and DHEA. Of these, 209 completed assessment of their habitual sleep patterns using the Pittsburgh Sleep Quality Index (PSQI). We used piecewise linear mixed models to compare cross sectional associations of slopes reflecting diurnal cortisol and DHEA rhythms with overall sleep quality and with seven sub-components. Overall, we observed no differences in the diurnal patterns of cortisol or DHEA between good versus poor sleepers as assessed by the global PSQI score. However, longer sleep latency was associated with significantly reduced cortisol awakening rise (p=0.02). Poorer subjective sleep quality (p=0.02), shorter sleep duration (p=0.02), and lower sleep efficiency (p=0.03) were associated with slower rate of cortisol decline later in the day. Women reporting daytime dysfunction had a sharper cortisol decline early in the day (p=0.03) but a flattened decline later in the day (p=0.01). The differences in diurnal patterns of DHEA between good versus poor sleepers, though less pronounced, were similar in direction to those of cortisol. Self-reported sleep duration, efficiency, latency and daytime dysfunction were associated with altered diurnal rhythms of cortisol and, to a lesser extent, DHEA. These findings provide support for the interplay between sleep and the HPA axis that may contribute to cardiometabolic disease. PMID- 28738316 TI - "What kept me going": A qualitative study of avoidant responses to war-related adversity and perpetration of violence by former forcibly recruited children and youth in the Acholi region of northern Uganda. AB - This qualitative study investigates what, according to 36 former forcibly recruited women and men, enabled them to "keep on going" during and after their forced recruitment in the twenty-year-long civil war in northern Uganda. Furthermore, the study conveys the ways most of the former forcibly recruited kept on going and today cope with ongoing war-related adversity and difficult reintegration processes without relying on psycho-social intervention. Thirty five of the 36 women and men were forcibly recruited when they were children by the Lord's Resistance Army (LRA) from the Acholi region of northern Uganda. Over the course of five visits to the Acholi region from 2012 to 2016, 10 months of ethnographic fieldwork was carried out involving interviews and participant observation. The 36 Acholi women and men shared how they experienced and responded to suffering from brutal torture and being forced to perpetrate often lethal violence against fellow Acholi who had tried to escape the LRA. The article provides an overview of the responses to this war-related adversity and the results document how avoidant coping is the preferred and most common coping response among the 36 former forcibly recruited women and men in this study. We take an interdisciplinary approach to discussing how these avoidant coping responses resonate with psycho-traumatology research on responses to war-related trauma and with conceptualizations of resilience. We end with the argument that avoidant responses to war-related adversity, when faced in clinical and diagnostic settings, should not be understood exclusively from a biomedical perspective: Responses to war-related adversity must be carefully investigated in collaboration with the human beings who have experienced the war-related adversity and based on integrative and emic approaches that consider the locally situated notions of how to cope with adversity and "keep on going" in their own right. PMID- 28738315 TI - Dimensions of parenting among mothers and fathers in relation to social anxiety among female adolescents. AB - Social anxiety is the most common anxiety disorder among youth; theoretical and empirical work suggest specific parenting behaviors may be relevant. However, findings are inconsistent, particularly in terms of maternal as compared to paternal effects. In the current study, we evaluated the indirect effects of perceived psychological control on the relation between anxious rearing behaviors and child social anxiety among 112 community-recruited girls (ages 12-15 years). In addition to self-report, adolescent participants completed a laboratory-based social stress task. In line with hypotheses, results indicated indirect effects of psychological control on the relation between anxious rearing behaviors and child social anxiety in maternal but not paternal models. Findings are discussed in terms of their theoretical and empirical implications for clarifying the role of parental relations in adolescent social anxiety. PMID- 28738314 TI - Factors associated with cognitive impairment in a cohort of older homeless adults: Results from the HOPE HOME study. AB - BACKGROUND: We evaluated cognitive function and factors associated with cognitive impairment in a cohort of older homeless adults. We hypothesized that substance use and a history of traumatic brain injury would be associated with cognitive impairment. METHODS: We recruited 350 homeless individuals aged >=50 years using population-based sampling and conducted structured interviews and neuropsychological testing. We evaluated alcohol use with the Alcohol Use Disorder Identification Test, defining high-severity alcohol use as a total score >=16 or >=4 on the alcohol dependency sub-scale. We assessed global cognition with the Modified Mini-Mental State Test (3MS) and processing speed and executive function with the Trail Making Test (TMTB), defining impairment as performing 1.5 standard deviations below the standardized mean. We used multivariable logistic regression to examine the association between alcohol use and cognition. RESULTS: Participants had a median age of 58 years [IQR 54-61], 76.7% were men, and 79.9% were African American. A quarter (25.1%) of participants met criteria for impairment on the 3MS; 32.9% met criteria for impairment on TMTB. In models adjusted for sociodemographic variables and health conditions, high-severity alcohol use was associated with global cognitive impairment (AOR 2.39, CI 1.19 4.79) and executive dysfunction (AOR 3.09, CI 1.61-5.92). CONCLUSIONS: Older homeless adults displayed a prevalence of cognitive impairment 3-4 times higher than has been observed in general population adults aged 70 and older. Impaired cognition in older homeless adults could impact access to housing programs and the treatment of health conditions, including the treatment of alcohol use disorders. PMID- 28738317 TI - The application of Signalling Theory to health-related trust problems: The example of herbal clinics in Ghana and Tanzania. AB - In contexts where healthcare regulation is weak and levels of uncertainty high, how do patients decide whom and what to trust? In this paper, we explore the potential for using Signalling Theory (ST, a form of Behavioural Game Theory) to investigate health-related trust problems under conditions of uncertainty, using the empirical example of 'herbal clinics' in Ghana and Tanzania. Qualitative, ethnographic fieldwork was conducted over an eight-month period (2015-2016) in eight herbal clinics in Ghana and ten in Tanzania, including semi-structured interviews with herbalists (N = 18) and patients (N = 68), plus detailed ethnographic observations and twenty additional key informant interviews. The data were used to explore four ST-derived predictions, relating to herbalists' strategic communication ('signalling') of their trustworthiness to patients, and patients' interpretation of those signals. Signalling Theory is shown to provide a useful analytical framework, allowing us to go beyond the primary trust problem addressed by other researchers - cataloguing observable indicators of trustworthiness - and providing tools for tackling the trickier secondary trust problem, where the trustworthiness of those indicators must be ascertained. Signalling Theory also enables a basis for comparative work between different empirical contexts that share the underlying condition of uncertainty. PMID- 28738318 TI - Meeting report - New York Symposium on Quantitative Biology of the Cell. AB - In the city that never sleeps, great science never takes a break. On 15 January 2016, the 'New York Symposium on Quantitative Biology of the Cell', a one-day local meeting of the American Society for Cell Biology (ASCB), took place at Columbia University Medical Center in upper Manhattan. Focusing on the quantitative understanding of cellular and multicellular systems, this meeting created an otherwise rare opportunity for interaction among scientists at various career levels with differing but complementary backgrounds. Highlighting cutting edge experimental measurements and theoretical modeling, the symposium broke the barrier between disciplines and ignited a hopefully continuing regional dialogue on the emergent topic of quantitative biology of the cell. PMID- 28738319 TI - Meeting report - Intercellular interactions in context: towards a mechanistic understanding of cells in organs. AB - The Company of Biologists held the workshop 'Intercellular interactions in context: towards a mechanistic understanding of cells in organs' at historic Wiston House in West Sussex, UK, 5-8 February 2017. The meeting brought together around 30 scientists from disparate backgrounds - yet with a common interest of how tissue morphogenesis occurs and its dysregulation leads to pathologies - to intensively discuss their latest research, the current state of the field, as well as any challenges for the future. This report summarises the concepts and challenges that arose as key questions for the fields of cell, cancer and developmental biology. By design of the organizers - Andrew Ewald (John Hopkins University, MA), John Wallingford (University of Texas at Austin, TX) and Peter Friedl (Radboud University, Nijmegen, The Netherlands) - the attendee makeup was cross-sectional: both in terms of career stage and scientific background. This intermingling was mirrored in the workshop format; all participants - irrespective of career stage - were given equal speaking and question time, and all early-career researchers also chaired a session, which promoted an atmosphere for discussions that were open, egalitarian and supportive. This was particularly evident in the scheduled 'out-of-the-box' sessions, which provided an avenue for participants to raise ideas and concepts or to discuss specific problems they wanted feedback or clarification on. In the following, rather than act as court reporters and convey chronological accounting of presentations, we present the questions that arose from the workshop and should be posed to the field at large, by discussing the presentations as they relate to these concepts. PMID- 28738320 TI - Meeting report - Emerging Concepts in Cell Organization. AB - New concepts in cell organization emerged in a medieval castle during a snowy week in January 2017 in the middle of the Austrian Alps. The occasion was the 10th Annaberg EMBO workshop in Goldegg am See; organized by Gabriele Seethaler, Catherine Rabouille and Marino Zerial. There were 95 participants, including many who gave talks and presented posters, enjoying a familial and trusting atmosphere that stimulated lively exchange of (unpublished) results, new ideas and thoughts. PMID- 28738321 TI - Serum Phospholipid Fatty Acid Composition in Cystic Fibrosis Patients with and without Liver Cirrhosis. AB - BACKGROUND/AIMS: Cystic fibrosis (CF) liver disease is the third most frequent cause of death in CF patients. Although it alters fatty acid (FA) metabolism, data concerning the profile of FA in CF patients with liver cirrhosis is lacking. This study aimed to assess the FA composition of serum phospholipids in CF patients with and without liver cirrhosis. METHODS: The study comprised 25 CF patients with liver cirrhosis and 25 without it. We assessed Z-scores for body height and weight, lung function, exocrine pancreatic sufficiency and colonization with Pseudomonas aeruginosa. FAs' profile of serum glycerophospholipids was quantified by gas chromatography mass spectrometry. RESULTS: In CF patients with liver cirrhosis, the levels of C16:0 were higher and the amounts of C20:2n-6, C20:3n-6, C20:4n-6, and all the n-3 polyunsaturated FAs (PUFAs) (C18:3n-3, C20:5n-3, C22:5n-3, C22:6n-3) were lower than those in CF subjects without liver cirrhosis. The n-6/n-3, C20:4n-6/C18:2n-6, total n 6/C18:2n-6, C20:5n-3/C18:3n-3 and total n-3/C18:3n-3 ratios did not differ between the 2 groups. CONCLUSIONS: Liver cirrhosis may associate with profound abnormalities in the composition of serum glycerophospholipids FAs in CF patients. None of the analyzed clinical factors could explain the greater prevalence of low levels of PUFAs in this CF subgroup. PMID- 28738322 TI - Pediatric Obstructive Sleep Apnea: Where Do We Stand? AB - Pediatric obstructive sleep apnea (OSA) was initially described in 1976. In 1981, Dr. Guilleminault emphasized that pediatric OSA was different from the clinical presentation reported in adults. It was characterized by more disturbed nocturnal sleep than excessive daytime sleepiness, and presented more behavioral problems, particularly school problems, hyperactivity, nocturnal enuresis, sleep terrors, depression, insomnia, and psychiatric problems. The underlying causes of pediatric OSA are complex. Such factors as adenotonsillar hypertrophy, obesity, anatomical and neuromuscular factors, and hypotonic neuromuscular disease are also involved. Adenotonsillectomy (T&A) has been the recommended treatment for pediatric OSA, but in the recent past this practice has been placed very much in question. Therefore, we will discuss the mechanism of pediatric OSA and investigate obese and nonobese pediatric sleep-disordered breathing. Moreover, the important concept that dysfunction leads to the dysmorphism that impacts on the size of the upper airway has been advanced recently. Finally, the treatments of pediatric OSA, such as T&A, medication, the orthodontic approaches (rapid maxillary expansion, or mandibular advancement with functional appliances), positive airway pressure, and noninvasive treatment, such as myofunctional therapy (MFT), will be investigated. A "passive MFT" has been tried recently, but very few results exist. In conclusion, we have made progress in our understanding of pediatric OSA, and we can even recognize factors leading to its development or worsening. However, pediatricians and pediatric subspecialists are often unaware of the advances and the remedies available. PMID- 28738323 TI - The Role of Exogenous Hydrogen Sulfide in Free Fatty Acids Induced Inflammation in Macrophages. AB - BACKGROUND: This study aimed to investigate whether exogenous hydrogen sulfide (H2S) can protect the RAW264.7 macrophages against the inflammation induced by free fatty acids (FFA) by blunting NLRP3 inflammasome activation via a specific TLR4/NF-kappaB pathway. METHODS: RAW264.7 macrophages were exposed to increasing concentrations of FFA for up to 3 days to induce FFA-induced inflammation. The cells were pretreated with NaHS (a donor of H2S) before exposure to FFA. Cell viability, cell apoptosis, TLR4, NF-kappaB, NLRP3 inflammasome, IL-1beta, IL-18 and cleaved caspase-3 expression were measured by a combination of MTT assay, ELISA, and immunoblotting. RESULTS: H2S attenuated FFA-induced cell apoptosis, and reduced the expression of NLRP3, ASC, pro-caspase-1, caspase-1, IL- 1beta, IL 18 and caspase-3. In addition, H2S inhibited the FFA-induced activation of TLR4 and NF-kappaB. Furthermore, NLRP3 inflammasome activation was regulated by the TLR4 and NF-kappaB pathway. CONCLUSION: The present study demonstrated for the first time that H2S appears to suppress FFA-induced macrophage inflammation and apoptosis by inhibiting the TLR4/ NF-kappaB pathway and its downstream NLRP3 inflammasome activation. Thus H2S might possess potential in the treatment of diseases resulting from FFA overload like insulin resistance and type diabetes. PMID- 28738324 TI - The Link between Refractoriness and Neuroprogression in Treatment-Resistant Bipolar Disorder. AB - Treatment refractoriness remains one of the biggest challenges in the field of bipolar disorder (BD) as treatments are often suboptimal or unsatisfactory. Recent evidence points towards a potential link between the progressively evolving nature of BD, increased inflammation, and reduced treatment response. There are several medications and other somatic treatments available, but remission rates are low, and medication compliance is still problematic. Psychotherapeutic techniques appear to be promising in several disease states and in relapse prevention, but additional research is needed to determine who will benefit from what strategy the most. Current knowledge on the link between neuroprogression in BD and poor treatment response promotes the use of anti inflammatory and neuroprotective strategies in the early phases of BD. In the later stages of BD, mood stabilization and medication adherence would be essential in preventing additional brain changes and loss of cognitive reserve. Additional large-scale, longitudinal, and methodologically robust studies are urgently needed to develop effective therapeutic interventions for treatment resistant BD. PMID- 28738326 TI - Difficulty in the Cytodiagnosis of Mammary Analogue Secretory Carcinoma: Survey of 109 Cytologists with a Case Originating from a Minor Salivary Gland. AB - BACKGROUND: Mammary analogue secretory carcinoma (MASC) of the salivary gland shows morphologic similarities and shares an immunophenotype and characteristic ETV6-NTRK3 translocation with secretory carcinoma of the breast. We present a buccal case of MASC along with a survey-based debate about its cytologic diagnosis by fine-needle aspiration (FNA). CASE: FNA of the buccal nodule of a 58 year-old Japanese man was initially performed by 3 cytologists who gave different assessments of the Papanicolaou classification (i.e., class II, III, and V). To investigate the potential for discrepant diagnosis of MASC on a larger scale, we distributed a survey with questions about the cytological diagnosis of the present case to cytologists at other institutions. A total of 109 cytologists completed the survey, providing varying assessments of the Papanicolaou classification: class I/II (14%), class III (53%), and class IV/V (33%). Most of the respondents (72%) could not identify a particular tumor or disease. Even the respondents who identified a particular tumor suggested widely differing diagnoses, from a benign lesion to various malignant tumors. Only 2 respondents correctly identified MASC. CONCLUSION: Our experience and the results of the survey suggest difficulty in the cytodiagnosis of MASC. PMID- 28738325 TI - A Proposal of the European Association for the Study of Obesity to Improve the ICD-11 Diagnostic Criteria for Obesity Based on the Three Dimensions Etiology, Degree of Adiposity and Health Risk. AB - Diagnostic criteria for complex medical conditions caused by a multitude of both genetic and environmental factors should be descriptive and avoid any attribution of causality. Furthermore, the wording used to describe a disorder should be evidence-based and avoid stigmatization of the affected individuals. Both terminology and categorizations should be readily comprehensible for healthcare professionals and guide clinical decision making. Uncertainties with respect to diagnostic issues and their implications may be addressed to direct future clinical research. In this context, the European Association of the Study of Obesity (EASO) considers it an important endeavor to review the current ICD-11 Beta Draft for the definition of overweight and obesity and to propose a substantial revision. We aim to provide an overview of the key issues that we deem relevant for the discussion of the diagnostic criteria. We first discuss the current ICD-10 criteria and those proposed in the ICD 11 Beta Draft. We conclude with our own proposal for diagnostic criteria, which we believe will improve the assessment of patients with obesity in a clinically meaningful way. PMID- 28738327 TI - Updated Concepts on Treatment Outcomes for Obstructive Sleep Apnea. AB - Obstructive sleep apnea is a highly prevalent and poorly understood condition that not only leads to significant individual patient health damage, but carries a large societal cost secondary to excessive healthcare utilization, motor vehicle accidents, and work absenteeism. While a significant fund of knowledge about its damaging effects on the cardiovascular system and neural pathways has been gathered over the past few decades, the translation to direct patient care still presents numerous challenges. With the exception of clear issues such as socially unacceptable snoring and breathing irregularities, the exact cause and effect relationship between airway narrowing, hypoxemia, and sleep fragmentation with subjective sleep-related complaints and neurocognitive symptoms is less clear. Besides better-defined clinical diagnostic criteria, the need for clear serum, saliva, or urine biomarkers to assess the physiologic burden of disease remains a work in progress, as are well-defined long-term clinically relevant outcomes of interest. Here, readers will be guided to a critical evaluation on the current main metrics of sleep study, suggested steps on diagnostic and treatment goals, and introduced to the concept of a continuum of disease. PMID- 28738330 TI - The Brain-Gut Axis Contributes to Neuroprogression in Stress-Related Disorders. AB - There is a growing emphasis on the relationship between the complexity and diversity of the microorganisms that inhabit our gut (human gastrointestinal microbiota) and brain health. The microbiota-gut-brain axis is a dynamic matrix of tissues and organs including the brain, glands, gut, immune cells, and gastrointestinal microbiota that communicate in a complex multidirectional manner to maintain homeostasis. Changes in this environment may contribute to the neuroprogression of stress-related disorders by altering physiological processes including hypothalamic-pituitary-adrenal axis activation, neurotransmitter systems, immune function, and inflammatory responses. While appropriate, coordinated physiological responses, such as immune or stress responses, are necessary for survival, the contribution of repeated or chronic exposure to stress may predispose individuals to a more vulnerable state leaving them more susceptible to stress-related disorders. In this chapter, the involvement of the gastrointestinal microbiota in stress- and immune-mediated modulation of neuroendocrine, immune, and neurotransmitter systems and the consequential behavior is considered. We also focus on the mechanisms by which commensal gut microbiota can regulate neuroinflammation and further aim to exploit our understanding of their role in the effects of the microbiota-gut-brain axis on the neuroprogression of stress-related disorders as a consequence of neuroinflammatory processes. PMID- 28738328 TI - A Novel Role for MiR-520a-3p in Regulating EGFR Expression in Colorectal Cancer. AB - BACKGROUND/AIMS: MicroRNAs (miRNAs) have been consistently demonstrated to be involved in colorectal cancer as either tumour oncogenes or tumour suppressors. However, the detailed role of miR-520a-3p in colorectal cancer remains poorly understood. METHODS: Quantitative RT-PCR and western blotting assays were used to measure miR-520a-3p and EGFR expression levels in colorectal cancer tissues, respectively. Luciferase reporter assay was employed to validate the direct targeting of EGFR by miR-520a-3p. Cell migration, apoptosis and cell cycle assays were performed to analyse the biological functions of miR-520a-3p and EGFR in colorectal cancer cells. In vivo experiment was performed to analyse the effects of miR-520a-3p and EGFR on the growth of colorectal cancer xenografts in mice. RESULTS: In this study, we found that miR-520a-3p was most likely to target the EGFR 3'-UTR, which was experimentally validated. In addition, we investigated the biological effects of EGFR inhibition by miR-520a-3p both in vitro and In vivo and found that miR-520a-3p could suppress cell migration, promote apoptosis, lead to colorectal cancer cell cycle arrest at the G0/G1 phase, and decelerate tumour growth in xenograft mice, potentially by targeting EGFR. CONCLUSIONS: This study highlights a tumour suppressor role for miR-520a-3p in colorectal cancer via the regulation of EGFR expression. Thus, miR-520a-3p may be a novel molecular therapeutic target for colorectal cancer. PMID- 28738329 TI - Distinct Involvement of the Sonic Hedgehog Signaling Pathway in Gastric Adenocarcinoma of Fundic Gland Type and Conventional Gastric Adenocarcinoma. AB - BACKGROUND/AIMS: Gastric adenocarcinoma of fundic gland type (GAFG), which is a rare variant of gastric cancer, is reportedly associated with both Wnt/beta catenin signaling activation and guanine nucleotide binding protein, alpha stimulating complex (GNAS) mutations. This study aimed to elucidate potential roles of the Sonic hedgehog (Shh) signaling pathway in GAFG. METHODS: We performed immunostaining for beta-catenin and Shh signal-associated proteins, including Patched (Ptch), Smoothened (Smo), and Glioma-associated oncogene-1 (Gli1), and the direct sequencing of GNAS/BRAF/KRAS in 27 GAFGs, and compared them with 30 conventional gastric adenocarcinomas (CGAs). RESULTS: GAFGs exhibited significantly lower immunoreactivity scores for Ptch, Smo, and Gli1 than CGAs. Moreover, while the Ptch score was significantly lower in the GAFG tumor areas than in the non-neoplastic areas adjacent to GAFG, the score was significantly higher in the CGA tumor areas than in the non-neoplastic areas. Similar trends were observed in the scores for Smo and Gli1. beta-Catenin expression and GNAS mutations were found in 22 (81%) and 8 (30%) of the 27 GAFGs respectively. Gli1 expression was significantly associated with mutations in GNAS. CONCLUSION: GAFG and CGA exhibited distinct Ptch, Smo, and Gli1 expression patterns. Downregulation of the Shh signaling pathway, as well as activation of the Wnt/beta-catenin signaling pathway, may therefore be associated with tumorigenesis in GAFG. PMID- 28738332 TI - Neuroprogression and Immune Activation in Major Depressive Disorder. AB - Traditionally, the neurobiology of major depressive disorder (MDD) has been largely considered from the perspective of the state of major depressive episodes (MDE) versus being in remission, but the current accumulation of disease markers, largely acquired cross-sectionally, is strongly suggestive of neuroprogressive aspects of MDD. This chapter focuses on the changes in disease markers involved in the reorganization of the nervous system in MDD, including the translocator protein (TSPO; an index of microglial activation), glial fibrillary acidic protein (GFAP; an index of astroglial activation), [11C]harmine (a marker of monoamine oxidase A; MAO-A), and several other indices (metabotropic glutamate receptor 5 [mGluR5], excitatory amino acid transporters, and magnetic resonance imaging spectroscopy measurements) of glutamate dysregulation. These are markers of processes involved in immune activation, oxidative stress, and chronic glucocorticoid exposure. Positron emission tomography studies of the TSPO distribution volume, a marker of microglial activation, provide strong evidence for microglial activation throughout the gray matter of the brain during MDE of MDD. In postmortem studies, GFAP reductions in the orbitofrontal cortex, anterior cingulate cortex, and hippocampus indicate a deficit in reactive astroglia. Elevated MAO-A levels are present throughout the gray matter of the brain, including affect-modulating brain regions, starting in high-risk states for MDE such as the early postpartum period, perimenopause, heavy cigarette smoking, heavy alcohol intake, and prior to MDE recurrence. Evidence is accumulating for glutamate dysregulation, with some findings of reduced glutamate transporter density in the orbitofrontal cortex, and decreased mGluR5 density. Collectively, these changes suggest an imbalance in the immune system with increased microglial activation and decreased astroglial activation, continued elevations of the MAO-A level, and, likely, the development of extracellular glutamate dysregulation. Many of these imbalances involve processes implicated in increased oxidative stress, apoptosis, and neurodegeneration. Future studies are required to assess potential therapeutics targeting these processes to ameliorate progression of MDD. PMID- 28738331 TI - Future Perspectives in Sleep Medicine. AB - "Sleep Medicine" is now a specialty in its own right. Currently, there is increasing recognition of the very negative impact sleep disorders have on learning, education, safety, and quality of life. Technological advances will help us to break down diagnoses (e.g., narcolepsy has now been subdivided into types 1 and 2, depending upon the hypocretin levels in the spinal fluid) and to discover relationships to other bodily systems (e.g., type 1 narcolepsy potentially being an autoimmune disorder). The modern lifestyle of many, as characterized by a shortening of sleep periods, shift work, jet lag, and the need to be constantly available, means that advances in sleep medicine may result in a major understanding of more balanced "work-rest lifestyle" modifications. PMID- 28738333 TI - Updated Hypopharyngeal Surgery for Sleep Apnea. AB - The failure of traditional upper airway surgery such as uvulopalatopharyngoplasty has been attributed to lower airway obstruction related to base of tongue collapse. Multiple procedures, including glossectomy, tongue base radiofrequency, genioglossus advancement, and tongue suspension techniques, have been advocated to improve success rates. No consensus exists on which subsets of patients are best treated by individual approaches and direct comparative data are lacking. The selection of procedures must be based on individual patient needs and the relative potential benefits and risks. PMID- 28738334 TI - Time Course of Radiological Imaging and Variable Interindividual Symptoms in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Associated with p.Arg487His Mutation in the VCP Gene. AB - To our knowledge, this is the first study to report the time course of radiological imaging of 3 patients from 2 families with VCP-related amyotrophic lateral sclerosis (ALS) and dementia. Both families shared the same p.Arg487His mutation in the VCP gene encoding valosin-containing protein. The first patient started to have a typical form of ALS, followed by dementia 7 years later. The second patient, a brother of the first one, had frontotemporal dementia and parkinsonism. The third patient had simultaneous ALS and dementia. All patients seemed to have progressive brain atrophy as their clinical symptoms progressed. The common and characteristic finding was atrophy of the temporal lobes including the hippocampi. The relation between imaging findings and symptoms varied considerably among the 3 patients. PMID- 28738336 TI - Innate Immune Memory: Implications for Microglial Function and Neuroprogression. AB - Immunostimulatory insults such as stress and infection are risk factors for the development of several neuropsychiatric disorders characterized by neuroprogression. Inflammatory and neurotoxic molecules in the brain can cause disruptions in neurogenesis, neuronal excitability, synaptic transmission, synaptic plasticity, and neuronal survival - changes that characterize neuroprogression. We draw on recent findings in the immunology literature that peripheral innate immune cells are capable of retaining long-term memory of infectious insults and displaying long-lasting upregulated proinflammatory function in response to repeated infectious insults - a concept known as "innate immune memory." In turn, we hypothesize that microglia, the resident innate immune cells of the brain, are also capable of retaining long-term memory of infectious and noninfectious insults, including stress. Microglia are capable of producing a variety of proinflammatory neurotoxic cytokines and chemokines. Persistent upregulation of microglial proinflammatory function as a result of memory for immunostimulatory insults may therefore contribute to persistent and progressive inflammation in neuropsychiatric illnesses and be an important driver of neuroprogression. PMID- 28738335 TI - Miller-Dieker Syndrome due to a 5.5-Mb 17p Deletion in a 17;Y Pseudodicentric Chromosome. AB - Miller-Dieker syndrome (MDS) is a contiguous gene deletion syndrome in which almost all patients present de novo 17p13.3 deletions. We report on a male infant with MDS and an unusual unbalanced translocation involving chromosomes Y and 17 that resulted in a large 5.5-Mb 17pterp13.2 deletion and a karyotype with 45 chromosomes. Apart from the deletion of the MDS critical region, the deletion of additional distal genes seemed to have no major influence on the patient's phenotype, since he did not show any unusual clinical findings that are not commonly described in MDS patients. PMID- 28738337 TI - The History of Sleep Surgery. AB - Snoring and the subsequent diagnosis of obstructive sleep apnea (OSA) was a life threatening medical condition with no available treatment until the late 20th century. An early description of OSA was provided by Charles Dickens in his 1836 novel Pickwick Papers with the description of a "fat boy" who was thought to be lazy and always falling asleep but likely displayed hypersomnolence from OSA. It was not until 1976 that Ikematsu first described uvulopalatopharyngoplasty (UPPP) as an alternative surgical treatment of "snoring," with a reported cure rate of 81%. The only other surgical procedure for OSA was permanent tracheostomy, but patients suffered from social stigma from the visible stoma with skin flaps and complications such as tracheal granulomas and tracheitis. UPPP was introduced in the USA as an alternative to permanent tracheostomy by Fujita in 1981. Since then, multiple surgical approaches and combinations of approaches have surfaced, with variable success rates. PMID- 28738338 TI - Cognitive Impairment Is Reflected by an Increased Difference between Real and Imagined Timed Up and Go Test Performance. AB - BACKGROUND: Recent research suggests using an imaginary version of the Timed Up and Go test (TUG) for a first assessment of cognitive impairment. By using the time difference between a real (TUGr) and an imagined (TUGi) TUG task, the objective of this study was to examine the effect of cognitive impairment on motor imagery ability. METHODS: Fifty-two participants (mean age 69.3 +/- 4.0 years) with mild cognitive impairment or subjective cognitive impairment were included in this study. The time difference between the TUGr and the TUGi was used as the main outcome. The Trail Making Test part B (TMT B), the ratio between TMT A and TMT B, and the Montreal Cognitive Assessment (MoCA) battery were the main independent variables. RESULTS: The difference between TUGr and TUGi performance time and the TMT B performance time increased with decreasing cognitive function (p < 0.01). There was no relationship between TUGr and TUGi performance time and TMT B/A ratio. There were significant correlations between TUG time differences and the MoCA score (r = -0.489, p < 0.01), the TMT B (r = 0.364, p < 0.01), and the TMT B/A ratio (r = 0.377, p < 0.01). CONCLUSION: The combination of TUGr and TUGi may have added value in assessing cognitive impairment, which is a possible pre-stage of dementia. PMID- 28738339 TI - Lung Ultrasound B Lines: Etiologies and Evolution with Age. PMID- 28738340 TI - Novel Positional Devices for the Treatment of Positional Obstructive Sleep Apnea, and How This Relates to Sleep Surgery. AB - If untreated, obstructive sleep apnea (OSA) develops as a gradual progressive disease. In the early stage of the disease most patients with OSA are positional. The archetypical patient might progress from simple positional snoring via positional early-stage mild disease to less positional moderate and finally nonpositional severe OSA. At first, the apnea-hypopnea index (AHI) is high only in the supine position, and later is high in all sleeping positions. The phenomenon is reversible. After partial effective treatment, patients with severe OSA can reverse to less severe positional OSA or, in other words, the AHI drops more in the lateral position than in supine position. This has been shown for palatal surgery, multilevel surgery, bimaxillary osteotomies, and bariatric surgery. The absence or presence of positional dependency has a great influence on sleep surgery. First, the results of sleep surgery might be worse in positional patients. Second, the addition of positional therapy to sleep surgery might improve the overall outcome and, as such, enhance the indication of sleep surgery as an alternative to continuous positive airway pressure and mandibular advancement device treatment. PMID- 28738341 TI - Unmet Care Needs in the Oldest Old Primary Care Patients with Cognitive Disorders: Results of the AgeCoDe and AgeQualiDe Study. AB - BACKGROUND: In the future, an increase in health care needs in the elderly is expected. Reports on unmet care needs of the oldest old with cognitive disorders are pending. This study aims at exploring unmet needs in the oldest old primary care patients with mild cognitive impairment (MCI) and dementia. Furthermore, the association between sociodemographic and clinical factors and unmet needs ought to be analyzed. METHODS: Based on the study "Needs, Health Service Use, Costs and Health-Related Quality of Life in a Large Sample of Oldest-Old Primary Care Patients (85+)" (AgeQualiDe), 749 patients (unimpaired, MCI, and dementia) aged 85 years and older, their relatives (n = 421), and general practitioners (GPs) (n = 607) were assessed. Descriptive, inferential, and regression analyses were run. RESULTS: Most unmet needs were observed in dementia patients, although needs were less frequently rated as unmet by dementia patients themselves as compared to relatives and GPs. Unmet needs were associated with MCI and dementia; other risk factors were age, education, and marital status. CONCLUSION: This study provides first data on unmet needs according to different perceptions in the elderly with MCI and dementia in Germany. Need assessments should be part of medical examinations to ensure a high-quality health care in the elderly. PMID- 28738342 TI - A Succinct History of Sleep Medicine. AB - Although sleep and sleep disorders have been studied for centuries, it was the development of sophisticated tools to monitor eye movements, brain waves, and muscle tone in the mid-20th century that led to modern sleep research. These tools allowed neuroscientists to distinguish between different "states" or "phases" of sleep, and to relate these findings to sleep disorders. This review chronicles the groundbreaking work of the pioneers in this field, and the impact their findings have had on patients today. PMID- 28738343 TI - miR-26a/b Inhibit Tumor Growth and Angiogenesis by Targeting the HGF-VEGF Axis in Gastric Carcinoma. AB - BACKGROUND/AIMS: Abnormal expression of HGF is found in various cancers and correlates with tumor proliferation, metastasis and angiogenesis. However, the regulatory mechanism of the HGF-VEGF axis remains unclear. METHODS: The expression characteristic of HGF in human gastric cancer tissues was shown by an immunohistochemistry assay, and the expression levels of target protein were detected by Western blot. The relative levels of miR-26a/b and target mRNA were examined by qRT-PCR. We used bioinformatics tools to search for miRNAs that can potentially target HGF. A luciferase assay was used to confirm direct targeting. Furthermore, the functions of miR-26a/b and HGF were evaluated by cell proliferation and migration assays in vitro and by the mouse xenograft tumor model in vivo. RESULTS: We found that the HGF protein was clearly increased while miR-26a/b were dramatically down-regulated in gastric cancer. miR-26a/b directly bind to the 3'-UTR of HGF mRNA at specific targeting sites. We demonstrated that the repression of the HGF-VEGF pathway by miR-26a/b overexpression suppressed gastric cancer cell proliferation and migration. Furthermore, miR-26a/b also showed an anti-tumor effect in the xenograft mouse model by suppressing tumor growth and angiogenesis. CONCLUSIONS: miR-26a/b could suppress tumor tumorigenesis and angiogenesis by targeting the HGF-VEGF axis and could serve as a potential treatment modality for targeted therapy in the clinical treatment of gastric cancer. PMID- 28738344 TI - Quantitative Low-Dose Computed Tomography of the Lung Parenchyma and Airways for the Differentiation between Chronic Obstructive Pulmonary Disease and Asthma Patients. AB - BACKGROUND: It is difficult to differentiate between chronic obstructive pulmonary disease (COPD) and asthma in clinics; therefore, for diagnostic purposes, imaging-based measurements could be beneficial to differentiate between the two diseases. OBJECTIVES: We aim to analyze quantitative measurements of the lung and bronchial parameters that are provided by low-dose computed tomography (CT) to differentiate COPD and asthma from an imaging perspective. MATERIALS AND METHODS: 69 COPD patients, 52 asthma patients, and 20 healthy subjects were recruited to participate in CT imaging and pulmonary function tests (PFTs). Comparative analysis was performed to identify differences between COPD and asthma in CT measurements. PFT measurements enabled validation of the differentiation between COPD and asthma patients. RESULTS: There were significant differences among the COPD, asthma, and healthy control groups. The differences were more significant among the following: inspiratory emphysema index (EI)-950 (%), expiratory lung volume, expiratory mean lung density (MLD), and expiratory EI-950 (%) and EI-850 (%). The COPD group had a significantly higher EI-950 (%) than the asthma group (p = 0.008). There were significant differences among the three groups in lumen area (LA), wall area (WA), total area, and Pi10WA. The asthma group had significantly higher WA%/WV% than both the COPD (p = 0.002) and the control group (p = 0.012). There was high sensitivity in EI-950 (%), EI-850 (%) and expiratory MLD in the parenchyma and high sensitivity in LA and Pi10WA in small airways in the differential diagnosis of COPD and asthma. CONCLUSION: To aid the diagnosis, CT can provide quantitative measurements to differentiate between COPD and asthma patients. PMID- 28738345 TI - Water: The Case for a New Taxonomy. PMID- 28738346 TI - Synergistic Activity of Berberine with Azithromycin against Pseudomonas Aeruginosa Isolated from Patients with Cystic Fibrosis of Lung In Vitro and In Vivo. AB - BACKGROUND/AIMS: Pseudomonas aeruginosa (PA) is one of the major opportunistic pathogens which can cause chronic lung infection of cystic fibrosis (CF). The formation of PA biofilm promotes CF development and restricts the antimicrobial efficacies of current antibiotics. METHODS: The antimicrobial effects of azithromycin (AZM) and berberine (BER) alone and in combination were evaluated using microdilution method, checkerboard assay, time-kill test, qRT-PCR analysis and absorption method. The treatments of AZM and/or BER were further evaluated in an animal lung infection model via observing survival rate, bacterial burden and histopathology of lung, the levels of pro-/anti-inflammatory cytokines. RESULTS: AZM-BER were demonstrated to be synergistic against ten clinical PA isolates as well as the standard reference PA ATCC27853, in which PA03 was the most susceptible isolate to AZM-BER with FICI of 0.13 and chosen for subsequent experiments. The synergism of AZM-BER was further confirmed against PA03 in time kill test and scanning electron microscope (SEM) at their concentrations showing synergism. In PA03, we found that AZM-BER could significantly attenuate productions of a series of virulence factors including alginate, LasA protease, LasB protease, pyoverdin, pyocyanin, chitinase as well as extracellular DNA, and remarkably inhibit the levels of quorum sensing (QS) molecules and the expressions of lasI, lasR, rhlI, rhlR at 1/2*MIC, 1*MIC and 2*MIC. In the infection model, the mice survival were increased markedly, the inflammations of infected lungs were improved greatly along with reduced IL-6, IL-8 and ascended IL-10 at 0.8 mg/kg of AZM combined with 3.2 mg/kg of BER. CONCLUSION: BER might be a promising synergist to enhance the antimicrobial activity of AZM in vitro and in vivo. PMID- 28738347 TI - Negative Beliefs about Voices in Patients with Borderline Personality Disorder Are Associated with Distress: A Plea for Cognitive-Behavioural Therapy? AB - BACKGROUND: Auditory verbal hallucinations (AVH) are experienced by 21-54% of patients diagnosed with a borderline personality disorder (BPD), and ensuing distress is often high. Little is known about the beliefs these patients foster about their voices, and the influence thereof on distress and need for hospitalisation. METHODS: In a convenience sample of 38 BPD outpatients with AVH, data were collected with the aid of the Psychotic Symptom Rating Scales (PSYRATS), Beliefs about Voices Questionnaire (BAVQ), Social Comparison Rating Scale (SCRS), and Voice Power Differential Scale (VPDS). RESULTS: The majority of patients with BPD who experience AVH rate their voices as malevolent and omnipotent, and higher in social rank than themselves. Moreover, their resistance against them tends to be high. These parameters correlate positively and significantly with high levels of distress experienced in relation to these AVH. The need for hospitalisation, in turn, is associated with high scores for omnipotence of the voices and distress due to AVH. However, these findings could not be confirmed in regression analyses. CONCLUSIONS: As negative beliefs can be altered with cognitive-behavioural therapy (CBT), we expect CBT to be beneficial in the treatment of AVH in BPD patients, whether or not in combination with antipsychotic medication. PMID- 28738349 TI - Towards an Integrated View of Early Molecular Changes Underlying Vulnerability to Social Stress in Psychosis. AB - Psychotic disorders are heterogeneous and complex, involving many putative causal factors interacting along the course of disease development. Many of the factors implicated in the pathogenesis of psychosis also appear to be involved in disease onset and subsequent neuroprogression. Herein, we highlight the pertinent literature implicating inflammation and oxidative stress in the pathogenesis of psychosis, and the potential contribution of N-methyl-D-aspartate receptors (NMDARs). We also emphasize the role of peripubertal social stress in psychosis, and the ways in which hippocampal dysfunction can mediate dysregulation of the hypothalamic-pituitary-adrenal axis and cortisol release. Finally, we propose a model wherein inflammation and oxidative stress act as a first hit, producing altered parvalbumin interneuron development, NMDAR hypofunction, microglial priming, and sensitivity to a second hit of peripubertal social stress. With a greater understanding of how these factors interact, it may be possible to detect, prevent, and treat psychosis more effectively. PMID- 28738348 TI - Colistin Resistance in KPC-2- and SHV-5-Producing Klebsiella pneumoniae Clinical Isolates in Bulgaria. AB - BACKGROUND/AIMS: Colistin resistance is increasingly recognized among carbapenemase-producing Klebsiella pneumoniae isolates in several European regions. The current study documents the appearance of colistin resistance among KPC-2 and SHV-5-produning K. pneumoniae strains in Bulgaria. METHODS: Four colistin-resistant K. pneumoniae isolates were recovered from 2 patients hospitalized in the anesthesiology and resuscitation clinic of a tertiary care university hospital in Sofia, Bulgaria. Microbial identification and antimicrobial susceptibility testing was performed by Vitek 2 (Biomerieux, France). beta-Lactamase genes were amplified using a panel of primers for detection of all MBL-types, KPCs, plasmid-mediated AmpCs in single PCR reactions, OXA-type carbapenemases, extended-spectrum beta-lactamases (ESBLs) and TEM enzymes. The colistin-resistant mcr-1 gene was also investigated using previously described primers and conditions. Pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST) were used to investigate clonality. RESULTS: The 4 K. pneumoniae isolates exhibited colistin MICs >16 mg/L and showed multidrug-resistant phenotypes, remaining intermediately susceptible only to gentamicin. They were clustered into a single PFGE clonal type and MLST assigned them to sequence type 258. All isolates possessed KPC-2 carbapenemase and SHV-5 ESBL. They were negative for the plasmid-mediated colistin-resistant mcr-1 gene, possibly implying an intrinsic mechanism of resistance. CONCLUSIONS: Although colistin use in Bulgaria only started moderately during 2014, the findings of the current study notify the appearance of colistin resistance among carbapenemase producing Klebsiella species in another European region. PMID- 28738351 TI - Major Depression as a Neuroprogressive Prelude to Dementia: What Is the Evidence? AB - Epidemiological studies implicate chronic depression as a predisposing factor for dementia in later life. However, the link is incompletely understood and controversial. The aim of this review is to consider some of the biological factors that contribute to neuroprogressive brain dysfunction in late life as a consequence of prolonged, low-grade inflammation in the course of depressive episodes. As chronic inflammation is known to precipitate increased apoptosis of neurons and astrocytes, this could be a contributing factor to brain dysfunction. In addition, certain proinflammatory cytokines activate the neurotoxic derivatives of the tryptophan-kynurenine pathway. This results in the synthesis of the NMDA glutamate agonist, quinolinic acid, and kynurenine metabolites which initiate oxidative stress and insulin receptor resistance. As a consequence of these changes, combined with a structural and functional defect in brain mitochondria, glucose transport into the brain is affected. Due to the ensuing reduction in the metabolic energy needed to sustain brain function, brain cells die prematurely. These changes could provide a link between chronic inflammation and dementia, at least in some patients with recurrent and chronic depression. This outcome may be particularly true in poor responders and treatment-resistant depression. PMID- 28738350 TI - Unilateral Sensorineural Hearing Loss: Medical Context and Etiology. AB - OBJECTIVE: Unilateral sensorineural hearing loss (USNHL) is known to impact on school performance and social skills during childhood, but the etiologies remain unclear. The aim of this study was to assess various etiologies and to study the clinical contexts in this population. METHODS: The study is a retrospective review. Characteristics of hearing loss (HL), audiometric parameters, imaging, and genetic and medical contexts were analyzed. RESULTS: Eighty children were included. USNHL was profound in 68%, could be progressive in 19%, and become bilateral in 7.5% of cases. Inner ear malformations were identified in 41% of cases; cochlear nerve deficiency (CND) was frequent (33%). Cytomegalovirus (CMV) infection and genetic syndromes were confirmed in 10 and 6% of cases, respectively. CONCLUSION: Long-term hearing follow-up remains useful in USNHL as it can become bilateral. Looking to etiology, MRI should be the gold standard, as CND is frequently observed and screening for CMV infection should be systematic. Genetic etiologies appear to be different compared to bilateral HL. Further genetic research in this domain is needed. PMID- 28738352 TI - Future Perspectives in Sleep Surgery. AB - Over the past few decades there has been a significant increase in research focusing on the pathophysiology, diagnosis, and treatment of sleep apnea. However, there is still a long way to go in creating standard evidence-based medical practice for the diagnosis, evaluation, and treatment of sleep apnea patients. Current and future directions of sleep surgery and other treatments are discussed here. PMID- 28738353 TI - Inflammation Effects on Glutamate as a Pathway to Neuroprogression in Mood Disorders. AB - Neuroprogression is a term used to describe worsening psychopathology, poor treatment response, and declining cognitive and functional outcomes among patients with chronic mental disorders. Chronic inflammatory activation and glutamate-mediated excitotoxicity are two key etiological factors implicated in the development of neuroprogression. In this chapter, we hypothesize that the association between chronic inflammatory activation, neuroprogression, and glutamate dysregulation might be mediated by glial dysfunction. The role played by other mechanisms that increase glutamatergic activity, including oxidative stress and kynurenine pathway activation, will also be discussed, albeit briefly. We will conclude by providing a mechanistic model that draws upon our previous research, to link neuroimmune/neurotransmitter dysregulation to disrupted local neural activity and brain network connectivity eventually leading to a neuroprogressive course and associated clinical outcomes. PMID- 28738354 TI - Review of Extracorporeal Membrane Oxygenation and Dialysis-Based Liver Support Devices for the Use of Nephrologists. AB - Acute kidney injury in the intensive care unit (ICU) is a manifestation of an underlying severe illness that commonly involves other organ systems. Pulmonary, cardiac, and hepatic failures are the most prevalent. This article provides a simplified review of the technical aspects of extracorporeal cardiopulmonary and liver support devices used in the adult ICU patient, as well as a summary of the most relevant and up-to-date clinical evidence that supports their use. PMID- 28738355 TI - Impact of Renin-Angiotensin Aldosterone System Inhibition on Serum Potassium Levels among Peritoneal Dialysis Patients. AB - BACKGROUND: The chronic use of angiotensin-converting enzyme inhibitors or angiotensin II receptor blocker has been associated with hyperkalemia in patients with reduced renal function even after the initiation of hemodialysis. Whether such medications may cause a similar effect in peritoneal dialysis patients is not well established. So, the aim of our study was to analyze the impact of renin angiotensin-aldosterone inhibitors on the serum levels of potassium in a national cohort of peritoneal dialysis patients. METHOD: A prospective, observational, nationwide cohort study was conducted. We identified all incident patients on peritoneal dialysis that had angiotensin converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB) prescribed for at least 3 months and a similar period of time without these medications. Patients were divided into 4 groups: Groups I and III correspond to patients using, respectively, an ACEi or ARB and then got the drug suspended; Groups II and IV started peritoneal dialysis without the use of any renin-angiotensin aldosterone system inhibitor and then got, respectively, an ACEi or ARB introduced. Changes in potassium serum levels were compared using 2 statistical approaches: (1) the non-parametric Wilcoxon test for repeated measures and (2) a crossover analysis. RESULTS: Mean potassium serum levels at the first phase of the study for Groups I, II, III, and IV were, respectively, 4.46 +/- 0.79, 4.33 +/- 0.78, 4.41 +/- 0.63, and 4.44 +/- 0.56. Changes in mean potassium serum levels for Groups I, II, III, and IV were -0.10 +/- 0.60, 0.02 +/- 0.56, -0.06 +/- 0.46, and 0.03 +/- 0.50, respectively. CONCLUSION: The use of ACEi and ARB was not associated with a greater risk for hyperkalemia in stable peritoneal dialysis patients independently of residual renal function. PMID- 28738357 TI - Biphasically Modulating the Activity of Carboxypeptidase G2 with Ultrasound. AB - BACKGROUND/AIMS: Carboxypeptidase G2 (CPG2) has been used for cancer prodrug therapy to realize the targeted release of active drugs, but there yet lacks a means to modulate the CPG2 activity. Here ultrasound was used to modulate the CPG2 activity. METHODS: The activity of insonated CPG2 was determined, and then underlying biochemical (i.e., monomer, dimer and conformation) and ultrasonic (i.e., heat and cavitation) mechanisms were explored. RESULTS: Ultrasound (1.0 MHz) increased or decreased the enzymatic activity; the activity decreased as zero- or first-order kinetics, depending on the intensity. L1 (10 W/cm2 for 200 s) improved the activity via increasing the specific activity. L2 or L3 (20 W/cm2 for 1200 or 3000 s) decreased the activity via disassembling the dimer, degrading the monomer, inducing glycosylation, transforming conformation and decreasing the specific activity. An increase or a slight decrease of activity attributable to 10 W/cm2 was reversible, but the activity decrease due to 20 W/cm2 was irreversible. The enzymatic modulation was realized via cavitation. CONCLUSION: Ultrasound can biphasically modulate the CPG2 activity, and can be employed in the CPG2-prodrug therapy to adjust the release and moles of active drugs. PMID- 28738356 TI - Thermal Preconditioning May Prevent Tendon Adhesion by Up-Regulating HSP72 in Rats. AB - BACKGROUND/AIMS: The study aims to determine the effects of thermal preconditioning on tendon adhesion by regulating the expression of heat shock protein 72 (HSP72) in rat models. METHODS: Sixty male Wistar rats were collected and randomly assigned into the thermal preconditioning and control groups. During the 4th and 8th weeks following surgery, 15 rats were sacrificed in each period respectively, and their tendon adhesion was observed and evaluated. Biomechanical testing was performed to measure the tensile strength and gliding distance of tendons. Hematoxylin-eosin (HE) was used to observe the morphological structure of the tendons. Immunohistochemical staining, quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were used to detect the HSP72, fibroblast growth factor-2 (FGF-2), fibroblast growth factor receptor-1 (FGFR-1), beta-catenin, epithelial cell adhesion molecule (EPCAM), Tenomodulin and scleraxis protein expressions. Pearson correlation analysis was applied to analyze the correlation between HSP72 expression and tendon adhesion. RESULTS: At the 4th week after surgery, we found no differences in the tendon adhesion scores or mRNA and protein expressions of HSP72 between the thermal preconditioning and control groups. However, after the 8th week after surgery, the thermal preconditioning group had a lower tendon adhesion score and higher mRNA and protein expressions of HSP72 than the control group. During the same period, we found longer gliding distance and higher expression levels of FGF-2, FGFR-1, beta catenin, Tenomodulin and scleraxis, but lower EPCAM expression in the thermal preconditioning group. Pearson correlation analysis indicated that HSP72 mRNA and protein expression levels were negatively correlated with tendon adhesion. CONCLUSIONS: These findings provide evidence that thermal preconditioning may alleviate tendon adhesions via upregulation of HSP72 expression. PMID- 28738358 TI - Innovative Surgery for Obstructive Sleep Apnea: Nerve Stimulator. AB - Obstructive sleep apnea (OSA) as a multifactorial disease is treated with continuous positive airway pressure (CPAP) as the gold standard. Yet, if patients suffer from CPAP incompliance, traditional OSA surgery only targets morphological changes of the upper airway while neglecting functional issues. With the advent of upper airway stimulation, and in particular hypoglossal nerve stimulation as a treatment option, a highly effective, clinically proven and functional therapy with good evidence is available. This article gives a comprehensive overview of current and upcoming hypoglossal nerve stimulation systems (Inspire, ImThera, and Nyxoah), the specific advantages of this approach, the selection criteria and screening process, relevant clinical data, and a description of the different implantation procedures. Upper airway stimulation and hypoglossal nerve stimulation appears to be a long-term, low-morbidity treatment for moderate-to severe OSA patients suffering from CPAP incompliance. PMID- 28738359 TI - Predictors of Subclinical Inflammatory Obesity: Plasma Levels of Leptin, Very Low Density Lipoprotein Cholesterol and CD14 Expression of CD16+ Monocytes. AB - OBJECTIVE: Predictors of subclinical inflammatory obesity (SIO) can be important tools for early therapeutic interventions in obesity-related comorbidities. Waist circumference (WC) and BMI have different SIO sensitivity. We aimed to i) identify SIO predictors and ii) investigate whether CD16+ monocytes are associated with BMI- (generally) or WC-defined (centrally) obesity. METHODS: Anthropometric and metabolic/endocrine (namely catecholamines, adrenaline and noradrenaline) parameters were evaluated, and CD16+ monocytes were studied by flow cytometry in the peripheral blood from 63 blood donors, and compared and correlated to each other. Multiple linear regression analysis was performed to identify variables that best predict SIO. RESULTS: CD16+ monocyte counts were similar in BMI and WC groups. CD16+ monocytes from centrally obese (CO) showed a more inflammatory pattern, as compared to non-CO subjects. WC was sensitive to lipidemia and, in CO subjects, lipidemia was associated with a more inflammatory phenotype of CD16+ monocytes. These differences were not noticed between BMI groups. Adrenaline was correlated with CD16+ monocyte expansion with a lower inflammatory pattern. Leptin, very low-density lipoprotein cholesterol (VLDL-C), and CD14 expression of CD16+ monocytes were found to be CO predictors. CONCLUSIONS: WC-, but not BMI-defined obesity, was associated with a more inflammatory pattern of CD16+ monocytes, without monocyte expansion, suggesting that a monocyte maturation process rather than an independent arise of CD16+ monocytes occurs in CO. Thus, in a population with low cardiovascular risk, leptin, VLDL-C, and CD14 expression of CD16+ monocytes predict CO, constituting a putative tool for screening of SIO. PMID- 28738361 TI - Expression, Intracellular Localization, and Prognostic Value of Plasminogen Activator Inhibitor 1 and PAI-1 RNA-Binding Protein 1 in Primary and Recurrent Ovarian Cancer: A Study of the Tumor Bank Ovarian Cancer Network. AB - BACKGROUND: The plasminogen activator system plays a key role in ovarian cancer (OC) tumor progression. The plasminogen activator inhibitor type 1 (PAI-1) and the recently identified PAI-1 RNA binding protein 1 (PAI-RBP1) are primary regulators of plasminogen activation and thus are putative biomarkers for OC progression. METHODS: One hundred fifty six OC patients were analyzed to identify the presence of PAI-1 and PAI-RBP1 and subsequently correlated to clinicopathological parameters. Primary cells obtained from OC patient samples were applied in fluorescence microscopy analysis for examination of PAI-1 and PAI RBP1 distribution. RESULTS: PAI-1 and PAI-RBP1 have been found to be predictive markers for OC patients' outcome. PAI-1 levels significantly correlated with volume of ascites, FIGO staging, and lymph node status. PAI-RBP1 expression significantly correlated with age at first diagnosis, histological tumor type, presence of distant metastasis (pM), and recurrence. PAI-1 showed a trend toward association and PAI-RBP1 was significantly associated with progression-free survival. Notably, PAI-1 protein in recurrent OC tissues was exclusively localized in the nucleus. CONCLUSION: This study has shown that a combination of PAI-1 and PAI-RBP1 may represent novel prognostic factor for OC. Prospective trials are needed. PMID- 28738360 TI - Targeting Developmental Pathways: The Achilles Heel of Cancer? AB - Developmental pathways (e.g., Notch, Hippo, Hedgehog, Wnt, and TGF-beta/BMP/FGF) are networks of genes that act co-ordinately to establish the body plan, and disruptions of genes in one pathway can have effects in related pathways and may result in serious dysmorphogenesis or cancer. Interestingly, all developmental pathways are highly conserved cell signalling systems present in almost all multicellular organisms. In addition, they have a crucial role in cell proliferation, apoptosis, differentiation, and finally in organ development. Of note, almost all of these pathways promote oncogenesis through synergistic associations with the Hippo signalling pathway, and several lines of evidence have also indicated that these pathways (e.g., Wnt/beta-catenin) may be implicated in checkpoint inhibitor resistance (e.g., CTLA-4, PD-1, and PD-L1). Since Notch inhibition in vivo results in partial loss of its stemness features such as self-renewal, chemoresistance, invasive and migratory potential, and tumorigenesis, these highly conserved developmental pathways are regarded as being critical for regulation of self-renewal in both embryonic and adult stem cells and hence are likely to be implicated in the maintenance of cancer stem cells. Many small molecules are currently in preclinical and early clinical development, and only two compounds are approved for treatment of advanced or metastatic basal cell carcinoma (vismodegib and sonidegib). Furthermore, therapeutic targeting of cancer stem cells using drugs that disrupt activated developmental pathways may also represent an attractive strategy that is potentially relevant to many types of malignancy, notably blood cancers, where the evidence for leukaemia stem cells is well established. Future work will hopefully pave the way for the development of new strategies for targeting these pervasive oncogenic pathways. PMID- 28738362 TI - Advances in the Diagnosis of Obstructive Sleep Apnea: Drug-Induced Sleep Endoscopy. AB - Drug-induced sleep endoscopy was introduced in 1991 and has recently evolved into a pivotal instrument for patients in whom obstructive sleep apnea surgery is considered. Here, we discuss the indications, contraindications, technique, anesthesia, scoring systems, validity, and insights of the literature. PMID- 28738363 TI - Mild Cognitive Impairment and Driving Cessation: A 3-Year Longitudinal Study. AB - BACKGROUND/AIMS: Driving cessation is associated with significant morbidity in older people. People with mild cognitive impairment (MCI) may be at particular risk of this. Very little research has examined driving in this population. Given this, we sought to identify predictors of driving cessation in people with MCI. METHODS: One hundred and eighty-five people with MCI were recruited from 9 memory clinics around Australia. People with MCI and their carers reported their driving status and completed measures of cognition, function, neuropsychiatric symptoms, and medication use at regular intervals over a 3-year period. RESULTS: Of the 144 people still driving at baseline, 50 (27.0%) stopped driving during the study. Older age, greater cognitive and functional impairment, and greater decline in cognition and function at 6 months predicted subsequent driving cessation. Twenty nine of the 50 people (58%) who stopped driving were diagnosed with dementia during the study; all except one of whom ceased driving after their dementia diagnosis. CONCLUSION: A significant proportion of people diagnosed with MCI stop driving over the following 3 years. This cannot be entirely attributed to developing dementia. Easily assessable characteristics - such as age, cognition, and function - and changes in these measures over 6 months predict driving cessation. PMID- 28738364 TI - Risk Factors for Community-Acquired Pneumonia in Adults: A Systematic Review of Observational Studies. AB - We performed a systematic review of the literature to establish conclusive evidence of risk factors for community-acquired pneumonia (CAP). Observational studies (cross-sectional, case-control, and cohort studies) the primary outcome of which was to assess risk factors for CAP in both hospitalized and ambulatory adult patients with radiologically confirmed pneumonia were selected. The Newcastle-Ottawa Scale specific for cohort and case-control designs was used for quality assessment. Twenty-nine studies (20 case-control, 8 cohort, and 1 cross sectional) were selected, with 44.8% of them focused on elderly subjects >=65 years of age and 34.5% on mixed populations (participants' age >14 years). The median quality score was 7.44 (range 5-9). Age, smoking, environmental exposures, malnutrition, previous CAP, chronic bronchitis/chronic obstructive pulmonary disease, asthma, functional impairment, poor dental health, immunosuppressive therapy, oral steroids, and treatment with gastric acid-suppressive drugs were definitive risk factors for CAP. Some of these factors are modifiable. Regarding other factors (e.g., gender, overweight, alcohol use, recent respiratory tract infections, pneumococcal and influenza vaccination, inhalation therapy, swallowing disorders, renal and liver dysfunction, diabetes, and cancer) no definitive conclusion could be established. Prompt assessment and correction of modifiable risk factors could reduce morbidity and mortality among adult CAP patients, particularly among the elderly. PMID- 28738365 TI - Advances in Box Surgery for Obstructive Sleep Apnea: Genioglossus Advancement, Hyoid Suspension, and Maxillomandibular Advancement. AB - Box surgery for obstructive sleep apnea (OSA) patients consists of mandibular surgery, including genioglossus advancement, hyoid suspension, and maxillomandibular advancement, as an airway reconstruction. This surgery was developed in the early 1980s. Thereafter, techniques were modified in each surgery for the enhancement of outcome and prevention of complications. However, the indication for surgery remains poorly defined due to the dynamicity of the upper airway, variability of the phenotype in OSA patients, and absence of a representative method for the obstruction site in the upper airway. As a result, box surgery is performed restrictively. On the development of an evaluation method including radiologic and endoscopic examination during sleep, the indications and surgical outcomes of each box surgery should be standardized and reevaluated. In this review, the development and limitations of box surgery will be discussed for the positive future of this surgery. PMID- 28738366 TI - Neuroanatomical Correlates of Hypophonia in Subcortical Vascular Cognitive Impairment. AB - BACKGROUND/AIMS: Early detection and intervention may alter the disease course of subcortical vascular cognitive impairment (SVCI). Patients with SVCI have white matter ischemia that disrupts connections between the cortex and subcortical gray matter and therefore manifest various symptoms such as motor disturbances and behavioral/cognitive dysfunction. Reduced vocal loudness, or hypophonia, is one of the common motor symptoms of SVCI, but few studies have systematically investigated it in this patient population. The main purpose of this investigation was to identify neural pathways underlying hypophonia in patients with SVCI. METHODS: Eighty-eight patients with SVCI and 21 normal controls performed phonation tasks. Diffusion tensor imaging data from 73 patients were utilized to measure white matter changes associated with hypophonia. RESULTS: Correlational analyses between white matter fractional anisotropy values and the decibel level of the "sustained phonation" task identified the left midbrain cerebral peduncle (corticobulbar tract), external capsule, corona radiata/internal capsule, and bilateral frontal white matter as possible neural correlates for hypophonia. CONCLUSION: Our results support the notion that hypophonia in SVCI patients might be caused by the impairment of the pyramidal and extrapyramidal systems. This study provides a unique contribution towards understanding the neuropathology of hypophonic features in this population. PMID- 28738367 TI - Extensive Amplification of Telomeric Repeats in the Karyotypically Highly Diverse African Pygmy Mice. AB - Telomeres are ribonucleoprotein structures protecting the physical ends of eukaryotic chromosomes. However, telomeric sequences can also occur at non terminal regions of chromosomes, forming the so-called interstitial telomeric sequences (ITSs). Some ITSs are considered as relics of past chromosomal rearrangements and as such provide important insights into karyotype evolution. By FISH, we explored the distribution of telomeric motifs in the genome of a complex of mammalian species that has long been recognized for its extraordinary karyotypic diversity: the African pygmy mice. This survey involved 5 species, representing 10 highly diverse karyotypes with or without autosomal and sex autosome robertsonian (Rb) fusions. The study revealed that in species with an ancestral-like karyotype (i.e., no fusions; Mus mattheyi and M. indutus), only terminal telomeres were observed, whereas in species experiencing intense chromosomal evolution (e.g., M. minutoides, M. musculoides), a large amplification of telomeric repeats was also identified in the pericentromeric region of acrocentrics and most metacentrics. We concluded that (i) the mechanism of Rb fusion in the African pygmy mice is different than the one highlighted in the house mouse; (ii) the intensity of the ITS hybridization signal could be a signature of the age of formation of the Rb fusion; (iii) the large amplification of pericentromeric telomeric sequences in acrocentrics may mediate the formation of Rb fusions, and (iv) the ITSs on the sex-autosome fusion Rb(X.1) may participate to the insulation buffer between the sexual and autosomal arms to prevent X inactivation from spreading and silencing autosomal genes and allow the independent regulation of replication timing of both segments. PMID- 28738369 TI - Inflammatory and Innate Immune Markers of Neuroprogression in Depressed and Teenage Suicide Brain. AB - Several studies suggest that major depressive disorder (MDD) and bipolar disorder (BPD) are neuroprogressive illnesses. Besides clinical features, neurobiological mechanisms have been suggested to contribute to the neuroprogression of mood disorders. Biological factors that have been shown to contribute significantly toward the neuroprogressive course of these disorders are inflammatory markers, such as cytokines. Cytokines have been extensively investigated, primarily in the serum of MDD and BPD patients, and these studies show cytokine abnormalities in both adolescent and adult patients with mood disorders. However, cytokine abnormalities in the brain may also contribute toward neuroprogression, but brain cytokines have not been adequately investigated. To examine the role of cytokines in neuroprogression, we have studied the markers of adaptive and innate immunity in postmortem brain obtained from teenage and adult suicide victims and gene expression of cytokines and their membrane-bound receptors in lymphocytes of MDD and BPD patients. Cytokines and Toll-like receptors (TLRs) were studied in 24 teenage suicide victims and 24 normal control (NC) subjects, and also in 22 adult depressed suicide victims and 20 adult NC subjects. We found that the protein and mRNA expression of the proinflammatory cytokines tumor necrosis factor (TNF) alpha, interleukin (IL)-1beta, and IL-6 were significantly higher in the prefrontal cortex (PFC). We also found that the protein and mRNA expression of TLRs, which are major mediators of innate immunity, is increased in the PFC of adult depressed suicide victims and NC subjects. In patients, mRNA and protein expression of TNF-alpha, IL-1beta, and IL-6 was significantly increased in both MDD and BPD patients. Similarly, mRNA expression of some specific membrane-bound receptors, such as IL1R1, TNFR1, IL1RA, were significantly increased in lymphocytes of MDD and BPD patients. These studies indicate the existence of abnormal cytokines and TLRs in the brain of teenage and adult suicide victims. Future studies, including both teenage and adult postmortem samples, will be needed to further clarify the role of cytokines and TLRs in neuroprogression. PMID- 28738368 TI - Updated Minimally Invasive Surgery for Sleep-Related Breathing Disorders. AB - Sleep-related breathing disorders (SRBD) consist of a variety of clinical entities, ranging from primary snoring to severe obstructive sleep apnoea at the opposite extreme. Although it has no official definition, minimally invasive surgery infers surgery where the procedure is clinically less aggressive and may involve a much smaller incision or none at all. It also implies that such procedures may result in a quicker recovery and reduced morbidity, and that they are often conducted under local anaesthesia as day cases. Minimally invasive surgery in SRBD may be performed on its own or may be conducted in conjunction with other surgical procedures or in association with non-surgical treatment modalities such as oral appliances. Indeed, it may be considered in patients experiencing difficulty tolerating treatment with continuous positive airway pressure. This is with a view to improving the upper airway dimensions and thus reducing the pressure requirement with this type of treatment modality, hence improving its compliance and efficacy. Here we address the role of minimally invasive surgery in SRBD within various anatomical regions of the upper airway, namely the nose, soft palate, and the tongue. PMID- 28738371 TI - Robotic Obstructive Sleep Apnea Surgery. AB - Since the first report of the use of the da Vinci robotic system (Intuitive Surgical, Sunnyvale, CA, USA) in transoral robotic tongue base reduction for obstructive sleep apnea (OSA) was published in 2010, this surgical tool and technique has been used worldwide for the resection of tongue base tissue in the multilevel surgical treatment of OSA. The combined knowledge of the published literature on its use has enlightened sleep surgeons worldwide on this new yet evolving surgical tool. Here we will discuss the use of the da Vinci robotic system in the treatment of OSA, the pertinent surgical anatomy for a safe surgical procedure, the primary and secondary outcomes to expect in the multilevel and primary use of this technology in treating the tongue base, the predictors for success or failure, and the complications associated with this technique. We will also compare this technology with other existing techniques for treating OSA and look to the future for other similar technologies in this application. PMID- 28738370 TI - Drug-Level Monitoring on Admission for Presurgical Epilepsy Evaluation. AB - OBJECTIVE: Evaluation for surgical treatment is offered to patients who do not respond to antiepileptic drugs. Pseudo-pharmacoresistance (PPR) has been described in the context of impaired compliance, incorrect diagnosis of epilepsy or pharmacological interference resulting in too low blood levels. We were interested to determine the frequency and causes of PPR in patients admitted for presurgical evaluation. METHODS: We reviewed 553 drug levels in 199 patients and analyzed the relative frequency of drugs below reference range (10 and 20% below the range). RESULTS: Patients who had at least one serum level below the 10% cut off amounted to 33% and 9% of patients had at least one serum level below the 20% cut-off. Only in 2 patients (1%), this was due to poor compliance. Low levels were equally frequent in mono- or polytherapy. Drugs that were most frequently found out of range were phenytoin, valproate, and topiramate. In monotherapy, lamotrigine was often prescribed in too low dosages. CONCLUSION: Low drug levels are frequently observed in surgical candidates due to pharmacological interference or insufficient dosing. Poor compliance or incorrect diagnosis does not appear to be a significant concern in this patient group. Our data strengthen the need for regular drug monitoring even in advanced chronic epilepsy to avoid unnecessary health costs by too low and ineffective dosages. PMID- 28738372 TI - Advances in Oral Appliances for Obstructive Sleep Apnea. AB - Oral appliances that advance the mandible are widely used as alternatives to positive airway pressure (PAP) devices or as primary therapy for obstructive sleep apnea (OSA) in adults. Although PAP is more efficacious at lowering the polysomnographic indices of OSA, the clinical effectiveness of PAP and oral appliances is similar, and patients are more likely to adhere to oral appliance therapy than to PAP treatment. Clinical examination is used to determine the candidacy of oral appliances and to select a particular appliance for a given patient. Endoscopic examination of the pharynx may be used to help assess the potential for efficacy. Otherwise, if available, titration of mandibular protrusion during sleep may be performed prior to appliance production in order to assess efficacy. Once a patient is fitted with a titratable oral appliance, further advancement is usually performed at home to resolve the clinical symptoms and signs of OSA. Clinical follow-up is needed to assess the outcome, side effects, and adherence, as the long-term adherence rate is approximately 50%. Recent advances in oral appliance therapy include the development of embedded temperature sensors for adherence monitoring and the production of thinner, lighter appliances via 3D printing techniques. PMID- 28738373 TI - Neuroprogression in Schizophrenia and Psychotic Disorders: The Possible Role of Inflammation. AB - Schizophrenia is a disorder that shows a progressive course in 30-50% of the people concerned. The biology of chronification and progression is unclear. Genetic aspects may play a role, but details are unresolved. The fact that immune mediated and autoimmune disorders such as rheumatoid arthritis or multiple sclerosis have a very similar course as schizophrenia has focused the interest on the immunopathogenesis of schizophrenia. A clear immune marker for neuroprogression in schizophrenia or psychosis could not be identified up to now, but a proinflammatory immune state (increased markers of cellular immunity) is regularly found in schizophrenia, e.g., increased levels of cytokines such as interleukin-6 (IL-6). Moreover, the tryptophan/kynurenine metabolism is regulated via pro- and anti-inflammatory cytokines and is closely related to the glutamatergic neurotransmission. Certain molecules of this metabolism, such as quinolinic acid or 3OH-kynurenine, have neurotoxic effects and seem to play a role in chronification. Studies with immune/anti-inflammatory-based therapeutic approaches show that acuity or chronicity of the inflammation influence the outcome of therapeutic interventions. PMID- 28738374 TI - Multilevel Obstructive Sleep Apnea Surgery. AB - Continuous positive airway pressure (CPAP) is the primary treatment of obstructive sleep apnea/hypopnea syndrome (OSA). Most sleep physicians are in agreement that a certain number of OSA patients cannot or will not use CPAP. Although other conservative therapies, such as oral appliance, sleep hygiene, and sleep positioning, may help some of these patients, there are many who fail all conservative treatments. As sleep surgeons, we have the responsibility to screen patients for both symptoms and signs of OSA. As experts of upper airway diseases, we often view an airway clearly and help the patient understand the importance of assessment and treatment for OSA. Surgery for OSA is not a substitute for CPAP but is a salvage treatment for those who failed CPAP and other conservative therapies and therefore have no other options. Most early studies and reviews focused on the efficacy of uvulopalatopharyngoplasty, a single-level procedure for the treatment of OSA. Since OSA is usually caused by multilevel obstructions, the true focus on efficacy should be on multilevel surgical intervention. The purpose here is to provide an updated overview of multilevel surgery for OSA patients. PMID- 28738375 TI - Erratum. PMID- 28738376 TI - Evaluation of the Impact of Cognitive Training on Quality of Life in Patients with Multiple Sclerosis. AB - OBJECTIVE: The aim of this study was to evaluate the effectiveness of cognitive rehabilitation in a group of multiple sclerosis (MS) patients. METHODS: Thirty four patients were included in this study and randomly allocated either to treatment with multidisciplinary rehabilitation plus cognitive training or to treatment with multidisciplinary rehabilitation alone. RESULTS: After 3 months of cognitive treatment, the patients assigned to the rehabilitation plus cognitive training group displayed an improvement in the cognitive test of executive function and a marked improvement in quality of life (QoL). The patients treated with multidisciplinary rehabilitation without cognitive training improved in the physical composite score alone. Both groups of patients displayed an improvement in depression, though the improvement was confirmed at the 6-month follow-up examination (p = 0.036) only in patients treated with multidisciplinary rehabilitation plus cognitive training. CONCLUSIONS: Our results indicate that the multidisciplinary rehabilitation treatment is the best approach to treat MS. The specific effect of each treatment needs to be assessed to be able to determine its role within a multidisciplinary approach. Cognitive rehabilitation is an important aspect of this multidisciplinary approach insofar as it may improve the QoL of MS people. PMID- 28738377 TI - Updated Nasal Surgery for Obstructive Sleep Apnea. AB - Numerous studies report that difficulty breathing through the nose is associated with reduced sleep quality, increased daytime dysfunction, and increased risk of snoring and obstructive sleep apnea (OSA). Additionally, chronic nasal obstruction often complicates and limits successful medical device therapy for OSA, particularly with continuous positive airway pressure (CPAP). When medical evaluation and management of the nose is inadequate, surgical therapy to lower nasal resistance has been shown to substantially improve sleep and breathing outcome measures. Although nasal surgery in isolation does not have a consistent effect on the apnea-hypopnea index in OSA patients, it does have robust evidence on improving snoring, subjective sleep quality, daytime sleepiness, sleep-related quality of life measures, and other important OSA outcome measures. Furthermore, in OSA patients with sinonasal disease who are struggling with CPAP and other medical devices, sinonasal surgery also has the potential to lower pressure requirements and improve adherence rates. Nasal surgery plays a key adjunctive role in the management of an OSA patient population. PMID- 28738378 TI - Akt-mTOR Signaling Mediates Abnormalities in the Proliferation and Apoptosis of Ovarian Granulosa Cells in Patients with Polycystic Ovary Syndrome. AB - BACKGROUND/AIMS: Abnormal apoptosis of granulosa cells (GCs) is thought to involve in the pathogenesis of polycystic ovary syndrome (PCOS); however, the associated cellular and molecular mechanisms remain unclear. METHODS: Primary GCs were obtained from healthy women and women with PCOS. The cell proliferation and apoptosis were analyzed in insulin-stimulated and insulin receptor gene (INSR) siRNA-transfected GCs. The protein expression of Akt-mTOR-S6K1 signal molecules was measured by Western blot. RESULTS: This study showed that 1 nM of insulin significantly stimulated cell proliferation, induced cell apoptosis, and decreased the telomerase activity in GCs from both the healthy women and PCOS patients (p < 0.001), but silencing of INSR expression blocked the effects of insulin. Insulin induced significantly more apoptosis in GCs from PCOS patients than from healthy women (p < 0.01). Insulin significantly increased the ratio of p-Akt/Akt, the expression of mTOR protein, and the ratio of p-S6K1/S6K1 in GCs from normal control than in cells from PCOS patients (p < 0.001). CONCLUSION: Insulin-induced apoptosis of GCs, less activation of Akt-mTOR signaling, and reduction of telomerase activity may be associated with the pathogenesis of PCOS. PMID- 28738379 TI - Neurodegeneration, Neuroregeneration, and Neuroprotection in Psychiatric Disorders. AB - Prevention of deterioration of brain function over time is important in the long term management of chronic brain disorders such as dementia, schizophrenia, and mood disorders. Although the possibility of neurogenesis in the adult human brain is attractive, and there are psychiatric drugs proven to be effective inducers of neurogenesis in animals, we have yet to see their utility in clinical practice. The terms neurodegeneration and neuroregeneration are often used in a nonspecific manner. Neuroregeneration may mean neurogenesis, dendritogenesis, spinogenesis, or axonogenesis. The term "neuroprotection" is attractive clinically and may involve different mechanisms. Many causative and protective factors of neurodegeneration and neuroregeneration have been proposed. However, the specificity of these factors and agents and differential neuronal vulnerability factors have generally been ignored in past studies. It is also hard to separate disease-modifying from "neuroprotective" effects of a drug. The application of stringent long-term neuroanatomical, neurochemical, neurophysiological, and therapeutic efficacy criteria should improve future research in this important area. PMID- 28738380 TI - Scoring Neuropsychological Tests: What Corrections Need to be Considered? PMID- 28738381 TI - Cytological Criteria to Distinguish Phyllodes Tumour of the Breast from Fibroadenoma. AB - OBJECTIVE: To determine whether there are significant differences between fibroadenomas and phyllodes tumours with regard to selected cytomorphological features. STUDY DESIGN: A 10-year retrospective review was performed of patients who underwent excision of a fibroadenoma or phyllodes tumour and in whom a preoperative fine-needle aspiration was performed. The following cytological criteria were assessed: number of stromal and epithelial fragments, stromal-to epithelial ratio, stromal cellularity, stromal borders, stromal atypia, and proportion of background wavy spindled cells. Patient age, tumour laterality, and tumour size were recorded. RESULTS: Fifty fibroadenomas and 17 phyllodes tumours were included. Compared to phyllodes tumours, fibroadenomas had a larger number of epithelial fragments, a smaller number of stromal fragments, and a lower stromal-to-epithelial ratio. The stroma tended to be less cellular and less atypical compared to phyllodes tumours and the background cellular population contained fewer spindled cells. CONCLUSION: Fibroadenomas and phyllodes tumours differ with regard to various cytological features, aiding in their distinction on fine-needle aspiration biopsy. PMID- 28738382 TI - Advanced Concepts in the Pathophysiology of Obstructive Sleep Apnea. AB - The primary pathological event in the disorder obstructive sleep apnea (OSA) is the partial or complete closure of the pharyngeal airway during sleep in an individual with a widely patent airway during wakefulness. This yields an apnea or hypopnea with resulting hypoxia and hypercapnia, and most often requires an arousal to terminate the event. These events occur in a repetitive manner during sleep, yielding intermittent hypoxia and sleep fragmentation with their associated adverse effects on the health and quality of life of the afflicted individual. Here, we focus on the events leading up to these apneas and hypopneas, primarily addressing pharyngeal anatomy, upper airway muscle control, the respiratory arousal threshold, and ventilatory control instability in OSA pathophysiology. PMID- 28738384 TI - Sweet Taste Perception and Dental Caries in 13- to 15-Year-Olds: A Multicenter Cross-Sectional Study. AB - Dietary habits and, in particular, the intake frequency of sucrose are of major importance for the development of dental caries. The perception of sweet taste is believed to have an influence on sucrose intake and therefore affects the predisposition to dental caries. The aim was to study the caries experience and sweet taste perception and to further analyze the possible relationship between the 2 tested variables in 13- to 15-year-old children from 3 different geographical areas. A cross-sectional survey comprising 669 children (220 Italian, 224 Mexican, and 225 Saudi Arabian) was conducted. The children were examined in their school setting. A sweet taste perception level was determined by the sweet taste threshold (TT) and sweet taste preference (TP). The sweet test was performed with sucrose solutions varying in concentration from 1.63 to 821.52 g/L. The International Caries Detection and Assessment System (ICDAS) and DMFS indices were used to diagnose caries. The highest mean value for TT was found for Italian children followed by Saudi and Mexican. Saudi schoolchildren showed the highest mean values for TP and DMFS, followed by Italian and Mexican. A statistically significant difference for TP, TT, DMFS, and initial caries was found between the 3 countries. A weak yet positive correlation was found between taste perception (TT and TP) versus DMFS and manifest caries in all 3 countries (r = 0.137-0.313). The findings of the present study showed a variation in sweet taste perception between the 3 countries, which may influence the caries outcome of the children in the individual countries. PMID- 28738385 TI - Pharmacological and Nonpharmacological Interventions to Arrest Neuroprogression in Psychiatric Disorders. AB - The concept of neuroprogression describes the progressive course of the disorder and stresses the progressive, recurrent, and chronic course of the disease entity under consideration. It subsumes clinical manifestations of the disease process and may also entail morphological, biochemical, neurochemical, immunological, physiological, and genetic aspects that contribute to the progressive course of the disease in question. In an attempt to identify the appropriate agent or method that could arrest neuroprogression in psychiatric patients, we conducted an evaluation of the use of anti-inflammatory drugs under the perspective of current pharmacological and neurophysiological data. This evaluation included the use of nonsteroidal anti-inflammatory drugs (NSAIDs) as adjunctive treatment to conventional pharmacotherapy as well as the use of natural products exerting anti inflammatory properties (i.e., omega-3 fatty acids) given as adjunctive or monotherapeutic treatments in less severe cases. The therapeutic significance of nonpharmacological methods, such as psychotherapy, physical exercise, and body mind therapies, was also considered and will be discussed in this chapter. In conclusion, the role of psychotropic and select anti-inflammatory drugs in arresting neuroprogression is a very promising new frontier in psychiatric research and clinical practice. Modulators of a specific prostanoid synthase or receptor across the cyclooxygenase (COX)-2 downstream pathway along with new multitarget NSAIDs are expected to be tested by the pharmaceutical industry as potential agents to antagonize neuroprogression. Meanwhile, salicylates and selective COX-2 inhibitors could still be used in carefully selected subgroups of patients. Psychotherapy and nonpharmacological, stress-relieving methods should be considered as adjunctive tools to aid in arresting neuroprogression. PMID- 28738383 TI - Hydralazine is a Suitable Mimetic Agent of Hypoxia to Study the Impact of Hypoxic Stress on In Vitro Blood-Brain Barrier Model. AB - BACKGROUND/AIMS: Understanding cellular mechanisms induced by hypoxia is fundamental to reduce blood-brain barrier (BBB) disruption. Nevertheless, the investigation of hypoxia on cellular pathways is complex with true hypoxia because HIF-1alpha has a short lifetime and rapidly reverts back to a normoxic state. To overcome this difficulty, mimetic agents of the hypoxia pathway have been developed, including the gold standard CoCl2. In this study, we proposed to compare CoCl2 and hydralazine in order to determine a suitable mimetic agent of hypoxia for the study on the BBB. METHODS: We studied the cytotoxicity and the impact of these molecules on the integrity of an in vitro BBB model by comparing them to hypoxia controls. RESULTS: We showed that the impact of hypoxic stress in our in vitro BBB model is rather similar between hydralazine and CoCl2. Chemical hypoxic stress led to an increase of BBB permeability either with CoCl2 or hydralazine. Tight junction protein expressions showed that this chemical hypoxic stress decreased ZO-1 but not occluding expressions, and cells had set up a defence mechanism by increasing expression and activity of their efflux transporters. CONCLUSION: Our results demonstrated that hydralazine is a better mimetic agent and more suitable than CoCl2 because it had the same effect but without the cytotoxic effect on in vitro BBB cells. PMID- 28738386 TI - Exercise Capacity Impairment Can Predict Postoperative Pulmonary Complications after Liver Transplantation. AB - BACKGROUND: Postoperative respiratory complications (PRCs) are common after liver transplantation (LT) and contribute significantly to the related morbidity and mortality. OBJECTIVE: The aim of this paper was to determine the incidence of PRCs after LT and the value of simple exercise capacity measures as independent predictors of PRCs. METHODS: We conducted a prospective cohort study of consecutive adults submitted to LT at a University Hospital in Fortaleza Brazil from March 2013 to March 2015. At baseline, exercise capacity was assessed with the 6-minute walk test (6MWT) and the 6-minute step test (6MST), lung function was tested by spirometry, and respiratory muscle strength was measured by maximal respiratory pressure. Additional relevant pre- and intraoperative data were collected through interview and chart review, and their association with the incidence of PRCs was evaluated. RESULTS: The study included 100 subjects, 44% of whom presented at least 1 of the PRCs. In the univariate analysis, poor 6MST and 6MWT results and a longer preoperative cold ischemia time were associated with PRCs. The logistic regression analysis showed that PRCs were less likely to occur when preoperative walking distances were longer: the odds ratio (95% CI) was reduced to 0.589 (0.357-0.971) for each 50 m walked (p = 0.03). Likewise, PRCs were more likely to occur in patients with longer preoperative cold ischemia times: the odds ratio (95% CI) increased to 1.008 (1.002-1.015) for each minute (p = 0.01). CONCLUSION: The incidence of PRCs is high in LT patients. A prolonged cold ischemia time and preoperative 6MWT results were independent predictors of PRCs in this patient population. PMID- 28738388 TI - Updated Friedman Staging System for Obstructive Sleep Apnea. AB - In the practice of sleep medicine, the first step is identification of those patients at high risk for sleep apnea. Nearly every physician and every hospital has preferred methods of screening. Many patient questionnaires or surveys as well as some objective physical measurements have been suggested to predict the presence of sleep apnea. Screening is well established, and laboratory and home testing are widely available. An early assessment with a physical examination can help direct treatment planning. The Friedman tongue position, lingual tonsil hypertrophy grading, and the effects of oral positioning on the hypopharynx should be used in early assessment for treatment planning, and as screening tools to assess the sight of obstruction. Although these screening tools are not substitutes for drug-induced sleep endoscopy (DISE), they are crucial in early assessment as many patients do not require surgery or DISE early in the evaluation. PMID- 28738387 TI - False-Negative Rate of Papanicolaou Testing: A National Survey from the Thai Society of Cytology. AB - OBJECTIVE: To evaluate the performance of Papanicolaou smear screening in Thailand at the national level, and to propose recommendations for continuing quality control. STUDY DESIGN: This study was conducted by The Thai Society of Cytology and involved 124 laboratories in 76 provinces during 2010-2014. Random sampling suggested recalling of 10% of slides defined as negative at routine screenings (10% random rescreening [R10] model) directly from the reading unit. RESULTS: Out of 330,075 smears covered by the rescreening project throughout its 5-year duration, the rates of abnormal, unsatisfactory, and normal results were 0.63, 1.82, and 97.55%, respectively. Abnormal findings were largely represented by ASC-US (54%) and L-SIL (21%). The average false-negative rate (FNR) measured at the level of L-SIL and higher was 13.8%. CONCLUSION: The national project was developed to address the accuracy of cervical cancer screening and to promote internal quality assurance based on the R10, on-site surveys, and education. The major output parameters of this study (FNR and number and distribution of abnormal cases on rescreening) improved significantly in the main phase of the project (2012-2014), after revising substantial logistics issues encountered during the first 2 years of this study. This project provided objective measurable evidence related to the quality of cytology-based cervical cancer screening in Thailand. PMID- 28738390 TI - Erratum. PMID- 28738391 TI - Updated Palate Surgery for Obstructive Sleep Apnea. AB - Initially described in 1981, uvulopalatopharyngoplasty was the first surgical procedure specially designed at the palatal level for snoring and obstructive sleep apnea (OSA). To date, palatal surgery remains the most commonly used surgery for OSA. The advancement of this surgery over the past 30 years has been a process of evolution in concepts, examination, and technique to increase safety and effectiveness in the treatment of OSA. Concept changes have emerged in the disease etiology, purpose of surgery, treatment priorities, staging of operations, integration therapy, and surgical endpoints. Drug-induced sleep examination has become the mainstream for forming a surgical plan. The surgical technique has tended toward the functional expansion and stabilization of airway tissue instead of excision. Here, drug-induced sleep computed tomography is introduced. In addition, palatal surgery is further divided into palatoplasty and pharyngoplasty for individual clinical application. PMID- 28738389 TI - PDGF Promotes the Warburg Effect in Pulmonary Arterial Smooth Muscle Cells via Activation of the PI3K/AKT/mTOR/HIF-1alpha Signaling Pathway. AB - BACKGROUND/AIMS: The enhanced proliferation of pulmonary arterial smooth muscle cells (PASMCs) is a central pathological component in pulmonary arterial hypertension (PAH). Both the Warburg effect and platelet-derived growth factor (PDGF) are involved in the proliferation of PASMCs. However, the mechanism underlying the crosstalk between the Warburg effect and PDGF during PASMC proliferation is still unknown. We hypothesized that PDGF promotes the Warburg effect via activating the phosphatidylinositol 3-kinase (PI3K) signaling pathway and hypoxia-inducible factor 1-alpha (HIF-1alpha) in proliferative PASMCs. METHODS: PASMCs were derived from pulmonary arteries of SD rats; cell viability, the presence of metabolites, and metabolic enzyme activities assay were determined by MTT assays, kit assays and western blot analysis, respectively. RESULTS: PDGF promoted PASMC proliferation in a dose- and time-dependent manner, accompanied by an enhanced Warburg effect. Treatment with PDGFR antagonists, Warburg effect inhibitor and PDK1 inhibitor significantly inhibited PI3K signaling activation, HIF-1alpha expression and PASMC proliferation induced by PDGF, respectively. Furthermore, treatment with PI3K signaling pathway inhibitors remarkably suppressed PDGF-induced PASMC proliferation and the Warburg effect. CONCLUSION: microplate reader (Biotek, Winooski The Warburg effect plays a critical role in PDGF-induced PASMC proliferation and is mediated by activation of the PI3K signaling pathway and HIF-1alpha. PMID- 28738392 TI - Multiple Lymph Node Basin Drainage in Trunk Melanoma Is Not Associated with Survival of Sentinel Lymph Node-Positive Patients. AB - OBJECTIVES: This study was aimed at investigating the prognostic role of multiple lymph node basin drainage (MLBD) in patients with positive sentinel lymph node (SLN) biopsy. BACKGROUND: MLBD is frequently observed in patients with trunk melanoma undergoing SLN. The prognostic value of MLBD in SLN-positive patients is still debated. METHODS: Retrospective data from 312 trunk melanoma patients with positive SLN biopsy (1991-2012) at 6 Italian referral centres were gathered in a multicentre database. MLBD was defined at preoperative lymphoscintigraphy. Clinical and pathological data were analysed for their association with disease free interval (DFI) and disease-specific (DSS) survival. RESULTS: MLBD was identified in 34.6% of patients (108/312) and was significantly associated with >1 positive SLN (37 vs. 15.2%; p < 0.001) and with >1 positive lymph node (LN) after complete lymph node dissection (CLND) (50.9 vs. 34.8%; p = 0.033). No differences were observed according to drainage pattern in patients who had negative and positive non-SLN at CLND. MLBD was not associated with either DFI or DSS. Multivariate analyses showed that tumour thickness, ulceration, and number of metastatic LNs were associated with worse DFI and DSS, while regression confirmed its protective role in survival. CONCLUSION: In positive SLN patients, MLBD has no association with survival, which is mainly related to American Joint Committee on Cancer (AJCC) prognostic factors. Since the overall number of positive LNs drives the prognosis, the importance of a CLND in all the positive basins is confirmed. PMID- 28738394 TI - The Contribution of Adult Hippocampal Neurogenesis to the Progression of Psychiatric Disorders. AB - New neurons are continuously formed in the adult hippocampus of the human, nonhuman primate, and rodent throughout life though rates of neurogenesis precipitously decline with age to near zero levels at the end of the natural life span. Since its discovery in the 1960s, a large number of studies have documented numerous environmental and genetic factors which regulate adult neurogenesis. Chief among the positive regulators of neurogenesis are exercise and antidepressant drugs. Chief among the negative regulators of neurogenesis besides age are stress and inflammation. To the extent that many psychiatric disorders are comorbid with or causally related to stress and inflammation, decreased neurogenesis could be a partial contributor to the pathophysiology of the disorders. However, the functional significance of new neurons in behavior has yet to be established and is currently a hotly debated topic. Therefore, it is not clear whether changes in neurogenesis that occur alongside psychiatric illnesses are a cause or a consequence of the mediating factors such as stress, drug abuse, and inflammation, which are complexly involved in the disorders. It will be important moving forward to use modern technologies capable of instantaneously inactivating cohorts of new neurons to test their functional significance in behavior and the etiology of mental illnesses. PMID- 28738393 TI - Estrogen and Environmental Enrichment Differentially Affect Neurogenesis, Dendritic Spine Immunolabeling and Synaptogenesis in the Hippocampus of Young and Reproductively Senescent Female Rats. AB - BACKGROUND: Studies examining the ability of estrogen replacement therapy (ERT) to enhance memory in women, and in animal models, have not produced consistent results. However, studies examining the effects of activity and exposure to novel environments consistently find enhancement of memory. METHODS: An animal model of reproductive aging was used to determine if estradiol (E2) replacement, activity, and/or exposure to an enriched environment could act synergistically to improve memory, and neural correlates of memory. Young (3 months) and reproductively senescent (12 months) female rats were ovariectomized and received either vehicle or E2 treatment. Rats were assigned to 1 of 3 exposures; control: rats remained in their cage; maze control: rats were put into a pen where they could move and explore; enriched maze: rats were put into a pen with various items to climb on or investigate. The amount of time rats were active in each environment was measured. On the third day of exposure, one of the items in the enriched environment was exchanged, and the amount of time animals spent investigating the new item was used as a measure of memory. RESULTS: E2 increased activity, immunostaining for proliferating cell nuclear antigen, and synaptic markers, synaptophysin and spinophilin, in the hippocampus of all animals. However, E2- and activity-induced changes in these markers were more pronounced in young rats. Only young rats displayed improved recognition in response to E2. CONCLUSIONS: Older rats may need an extended period of ERT or increased activity before the benefits on memory become apparent. PMID- 28738395 TI - Outcomes of Preoperative and Postoperative Corticosteroid Therapies in Myasthenia Gravis. AB - AIMS: To compare the long-term outcomes of non-thymomatous myasthenia gravis (MG) patients receiving pre-thymectomy (Pre-CS) or post-thymectomy corticosteroid (Post-CS) therapy. METHODS: In a retrospective cohort study, 41 patients with MG were treated with Pre-CS therapy, and 110 were treated with Post-CS therapy. RESULTS: In the MG cohorts, 9 of 40 patients (22.5%) in the Pre-CS group vs. 28 of 105 patients (26.7%) in the Post-CS group achieved a complete remission (CR) at 1 year, 29.7% (11/37) vs. 38.6% (32/83) at 2 years and 36.4% (8/22) in the Pre CS group vs. 50.0% (28/56) in the Post-CS group achieved a CR at 5 years. For the entire population, Post-CS therapy (hazard rate [HR] 3.042, p = 0.020) was a positive predictor for remission, and a long preoperative interval (HR 0.936, p = 0.030) was a negative predictor. In 98 original ocular MG patients, Post-CS therapy (HR 2.663, p = 0.014) and an age at onset >=15 years (HR 4.865, p = 0.001) were positive predictors for remission. DISCUSSION: Post-CS therapy with a shorter preoperative interval increases the likelihood of CR in postpubertal and adult patients. PMID- 28738396 TI - Accepting Leadership Responsibility: Preparing Yourself to Lead Honestly, Humanely, and Effectively. AB - Many who enter management are ready and willing to accept the benefits of their positions, but not all are readily accepting the full responsibilities of leadership. All too frequently, modern leadership seems self-serving, with the needs and desires of the leaders taking precedence over the needs of the followers and even the needs of the clients or customers. True leadership, however, should primarily benefit the followers rather than the leader. Leaders lead and followers follow for essentially the same reason-fulfillment of needs-so leaders and followers are fundamentally little different from each other. Every manager at every level has organizational superiors, so every leader is a follower as well. A true leader among managers is one who subordinates personal needs to the organization's needs, places employees well above self in importance, models appropriate behavior for employees, and functions as a facilitator in the employees' continuing efforts to get the necessary work done efficiently and effectively. PMID- 28738397 TI - Effects of Self-management Education Through Telephone Follow-up in Diabetic Patients. AB - It is expected that the number of people living with diabetes rise especially in low- and middle-income countries. In Iran, more than four million adults have diabetes mellitus, and self-management education is essential for effective diabetes self-care. This study aimed to investigate the effect of self-management education with telephone follow-up in diabetic patients of rural areas of Fars province in Lamerd city, Iran. In this experimental study, 64 participants were randomly assigned to intervention and control groups (32 patients for each group). In the intervention group, the participants attended four educational sessions, each lasting 90 minutes. The control group received the usual care. Outcome measures were clinical variables and the patients' scores in Diabetes Self-Management Questionnaire (DSMQ) in the preintervention and postintervention phases. Effects of the intervention were analyzed using Mann-Whitney U test and analysis of covariance. Data of 60 patients (30 in each group) were analyzed. There were significant differences between the two groups in fasting blood sugar after 3 months of intervention. There was a significant difference between the intervention and control groups in DSMQ sum scale after adjusting for baseline value. In subscales of DSMQ, there were significant differences between the intervention and control groups in glucose management, dietary control, and physical activity, whereas no significant difference was found in health care use between the intervention and control groups. Self-management education with telephone follow-up in diabetic patients in rural areas is effective, especially in improving fasting blood sugar level and increasing scores of patients based on DSMQ. PMID- 28738398 TI - The Compatibility of Chlorhexidine and a Skin Care Product Line: A Real-World Analysis of Hospital-Acquired Infection Rates. AB - Chlorhexidine gluconate (CHG) use helps reduce hospital-acquired infections (HAIs). Chlorhexidine gluconate effectiveness can be reduced by use of skin care products. Although laboratory work can be performed to prove compatibility, such work has limitations. The purpose of this study was to compare HAI rates when CHG antiseptic wipes were used in conjunction with a silicone- and micronutrient based skin care product line (SMSP) and when CHG wipes were used without the SMSP. Using commercial distribution data, 17 hospitals that purchased both CHG wipes and SMSP were identified. Hospital-acquired infection rates from this group were compared with HAI rates from 18 hospitals that used CHG wipes, but not SMSP. Hospital-acquired infection information was obtained from the Leapfrog Group (www.hospitalsafetyscore.org/). Four infection rates were compared: (1) infection in the blood during an intensive care unit stay, (2) infection in the urinary tract during an intensive care unit stay, (3) surgical site infection after colon surgery, and (4) average infection rate from 1 to 3. There was no significant difference between the infection rates of the two groups (Ps ranged from .285 to .983). There was also no statistically significant association between hospital grade and product use (P = .194). When considering publicly available data on HAI, there was no measurable difference in HAI rates between facilities that use CHG wipes with or without an SMSP. The SMSP does not impact the efficacy of CHG wipes. PMID- 28738399 TI - Use of Smartphones for Clinical and Medical Education. AB - Smartphone use in clinical settings and in medical education has been on the rise, benefiting both health care and health care providers. Studies have shown, however, that some health care facilities and providers are reluctant to switch to smartphones due to the threat of mixing personal apps with clinical care applications and the possibility that distraction created by smartphone use could lead to medication errors and errors linked to procedures, treatments, or tests. The purpose of this research was to examine the effects of smartphones in a clinical setting and for medical education, to determine their overall impact. The methodology for this qualitative study was a literature review, conducted over five electronic databases. The search was limited to articles published in English, between 2010 and 2016. Forty-one sources that focused on the implementation of and the barriers to use of smartphones in clinical and medical education environments were referenced. These studies revealed that smartphones have more positive than negative effects on the ability to enhance patient care and medical education. Smartphone use is clearly an effective and efficient method of enhancing patient care and medical education in the health care industry. Access to health care as well is enhanced by the use of this tool. PMID- 28738400 TI - Noncultured Epidermal Cell Suspension, in Combination With Carbon Dioxide Laser, Improves Punch Grafting Complications. PMID- 28738401 TI - Serum Vitamins and Minerals at Diagnosis and Follow-up in Children With Celiac Disease. AB - OBJECTIVES: Children with celiac disease (CD) may experience deficiencies of several micronutrients. The objectives of the present study were to determine the prevalence of micronutrient deficiencies in children with CD at diagnosis, 6 months, and 18 months after the start of a gluten-free diet (GFD), and examine any correlation between micronutrient deficiencies, serum tissue transglutaminase (TtG) immunoglobulin A (IgA) antibody titers, and the degree of mucosal damage at diagnosis. METHODS: Children (<17 years) with CD had their serum vitamins, minerals, and anti-TtG IgA antibodies measured at diagnosis, 6 and 18 months after starting a GFD. Histopathological changes of duodenal biopsies at diagnosis were documented using modified MARSH classification. RESULTS: The medical records of 140 children (mean age at diagnosis 7.8 +/- 4.01 years, 87 girls [621%]) with CD were examined. At diagnosis, serum vitamin D was the most commonly deficient vitamin in 70% of children. Serum ferritin was subnormal in 34.5% with zinc in 18.6% children but only 12 (10.9%) children had iron deficiency anemia. There was no correlation between micronutrient deficiencies at diagnosis and serum TtG IgA antibody titers or the degree of villous atrophy. The majority of serum levels of measured micronutrients had normalized after 6 months of starting GFD except for vitamin D, which improved but remained subnormal. CONCLUSIONS: At diagnosis, most children with CD have vitamin D deficiency. The degree of micronutrient deficiencies does not correlate with the degree of villous atrophy or serum titers of anti-TtG IgA antibodies. PMID- 28738402 TI - Biodistribution of Liver-Derived Mesenchymal Stem Cells After Peripheral Injection in a Hemophilia A Patient. AB - BACKGROUND: With the exception of liver transplantation, there is no cure for hemophilia, which is currently managed by preemptive replacement therapy. Liver derived stem cells are in clinical development for inborn and acquired liver diseases and could represent a curative treatment for hemophilia A. The liver is a major factor VIII (FVIII) synthesis site, and mesenchymal stem cells have been shown to control joint bleeding in animal models of hemophilia. Adult-derived human liver stem cells (ADHLSCs) have mesenchymal characteristics and have been shown able to engraft in and repopulate both animal and human livers. Thus, the objectives were to evaluate the potency of ADHLSCs to control bleeding in a hemophilia A patient and assess the biodistribution of the cells after intravenous injection. METHODS: A patient suffering from hemophilia A was injected with repeated doses of ADHLSCs via a peripheral vein (35 million In oxine-labeled cells, followed by 125 million cells the next day, and 3 infusions of 250 million cells every 2 weeks thereafter; total infusion period, 50 days). RESULTS: After cell therapy, we found a temporary (15 weeks) decrease in the patient's FVIII requirements and severe bleeding complications, despite a lack of increase in circulating FVIII. The cells were safely administered to the patient via a peripheral vein. Biodistribution analysis revealed an initial temporary entrapment of the cells in the lungs, followed by homing to the liver and to a joint afflicted with hemarthrosis. CONCLUSION: These results suggest the potential use of ADHLSCs in the treatment of hemophilia A. PMID- 28738404 TI - Communication Skills to Increase Donor Consent Rate Based on the Concept of "Moral Imperative". PMID- 28738405 TI - Peripheral Vascular Disease and Death in Southern European Kidney Transplant Candidates: A Competing Risk Modeling Approach: Erratum. PMID- 28738403 TI - Developing Consensus-Based Priority Outcome Domains for Trials in Kidney Transplantation: A Multinational Delphi Survey With Patients, Caregivers, and Health Professionals. AB - BACKGROUND: Inconsistencies in outcome reporting and frequent omission of patient centered outcomes can diminish the value of trials in treatment decision making. We identified critically important outcome domains in kidney transplantation based on the shared priorities of patients/caregivers and health professionals. METHODS: In a 3-round Delphi survey, patients/caregivers and health professionals rated the importance of outcome domains for trials in kidney transplantation on a 9-point Likert scale and provided comments. During rounds 2 and 3, participants rerated the outcomes after reviewing their own score, the distribution of the respondents' scores, and comments. We calculated the median, mean, and proportion rating 7 to 9 (critically important), and analyzed comments thematically. RESULTS: One thousand eighteen participants (461 [45%] patients/caregivers and 557 [55%] health professionals) from 79 countries completed round 1, and 779 (77%) completed round 3. The top 8 outcomes that met the consensus criteria in round 3 (mean, >=7.5; median, >=8; proportion, >85%) in both groups were graft loss, graft function, chronic rejection, acute rejection, mortality, infection, cancer (excluding skin), and cardiovascular disease. Compared with health professionals, patients/caregivers gave higher priority to 6 outcomes (mean difference of 0.5 or more): skin cancer, surgical complications, cognition, blood pressure, depression, and ability to work. We identified 5 themes: capacity to control and inevitability, personal relevance, debilitating repercussions, gaining awareness of risks, and addressing knowledge gaps. CONCLUSIONS: Graft complications and severe comorbidities were critically important for both stakeholder groups. These stakeholder-prioritized outcomes will inform the core outcome set to improve the consistency and relevance of trials in kidney transplantation. PMID- 28738406 TI - Trophic Molecules Derived From Human Mesenchymal Stem Cells Enhance Survival, Function, and Angiogenesis of Isolated Islets After Transplantation: Erratum. PMID- 28738407 TI - Pain and learning in primary school: a population-based study. AB - Despite the frequency of pain among children, little is known about its effects on learning and school outcomes. The objective of this study was to quantify the association of pain and academic achievement while taking into account the presence of co-occurring emotional symptoms. A population-based stratified random sample of 1239 students aged 8 to 9 years from primary schools in Melbourne, Australia, was recruited for the Childhood to Adolescence Transition Study. Children indicated sites of pain that had lasted for a day or longer in the past month using a pain manikin. Depressive- and anxiety-related symptoms were assessed using child-reported items. National assessment results for reading and numeracy were used to measure academic achievement. Sixty-five percent of children reported pain in at least 1 body site and 16% reported chronic pain. Increasing number of pain sites was associated with poorer reading scores in a dose-response fashion (beta = -3.1; 95% confidence interval -4.9 to -1.3; P < 0.001). The association was only partly attenuated when adjusting for emotional symptoms (beta = -2.6; 95% confidence interval -4.5 to -0.8; P < 0.001) and was not moderated by emotional symptoms. Children with chronic pain were a year behind their peers in both reading and numeracy. Among primary school students, pain was associated with lower reading scores even after adjusting for the presence of emotional symptoms. Although population-based longitudinal studies will be required to ascertain consistency and possible causality, grounds exist for considering pain and emotional symptoms in the assessment of children with reading difficulties. PMID- 28738409 TI - Elements of Eoarchean life trapped in mineral inclusions. AB - Metasedimentary rocks from Isua, West Greenland (over 3,700 million years old) contain 13C-depleted carbonaceous compounds, with isotopic ratios that are compatible with a biogenic origin. Metamorphic garnet crystals in these rocks contain trails of carbonaceous inclusions that are contiguous with carbon-rich sedimentary beds in the host rock, where carbon is fully graphitized. Previous studies have not been able to document other elements of life (mainly hydrogen, oxygen, nitrogen and phosphorus) structurally bound to this carbonaceous material. Here we study carbonaceous inclusions armoured within garnet porphyroblasts, by in situ infrared absorption on approximately 10-21 m3 domains within these inclusions. We show that the absorption spectra are consistent with carbon bonded to nitrogen and oxygen, and probably also to phosphate. The levels of C-H or O-H bonds were found to be low. These results are consistent with biogenic organic material isolated for billions of years and thermally matured at temperatures of around 500 degrees C. They therefore provide spatial characterization for potentially the oldest biogenic carbon relics in Earth's geological record. The preservation of Eoarchean organic residues within sedimentary material corroborates earlier claims for the biogenic origins of carbon in Isua metasediments. PMID- 28738410 TI - No large population of unbound or wide-orbit Jupiter-mass planets. AB - Planet formation theories predict that some planets may be ejected from their parent systems as result of dynamical interactions and other processes. Unbound planets can also be formed through gravitational collapse, in a way similar to that in which stars form. A handful of free-floating planetary-mass objects have been discovered by infrared surveys of young stellar clusters and star-forming regions as well as wide-field surveys, but these studies are incomplete for objects below five Jupiter masses. Gravitational microlensing is the only method capable of exploring the entire population of free-floating planets down to Mars mass objects, because the microlensing signal does not depend on the brightness of the lensing object. A characteristic timescale of microlensing events depends on the mass of the lens: the less massive the lens, the shorter the microlensing event. A previous analysis of 474 microlensing events found an excess of ten very short events (1-2 days)-more than known stellar populations would suggest indicating the existence of a large population of unbound or wide-orbit Jupiter mass planets (reported to be almost twice as common as main-sequence stars). These results, however, do not match predictions of planet-formation theories and surveys of young clusters. Here we analyse a sample of microlensing events six times larger than that of ref. 11 discovered during the years 2010-15. Although our survey has very high sensitivity (detection efficiency) to short-timescale (1 2 days) microlensing events, we found no excess of events with timescales in this range, with a 95 per cent upper limit on the frequency of Jupiter-mass free floating or wide-orbit planets of 0.25 planets per main-sequence star. We detected a few possible ultrashort-timescale events (with timescales of less than half a day), which may indicate the existence of Earth-mass and super-Earth-mass free-floating planets, as predicted by planet-formation theories. PMID- 28738408 TI - cGAS surveillance of micronuclei links genome instability to innate immunity. AB - DNA is strictly compartmentalized within the nucleus to prevent autoimmunity; despite this, cyclic GMP-AMP synthase (cGAS), a cytosolic sensor of double stranded DNA, is activated in autoinflammatory disorders and by DNA damage. Precisely how cellular DNA gains access to the cytoplasm remains to be determined. Here, we report that cGAS localizes to micronuclei arising from genome instability in a mouse model of monogenic autoinflammation, after exogenous DNA damage and spontaneously in human cancer cells. Such micronuclei occur after mis-segregation of DNA during cell division and consist of chromatin surrounded by its own nuclear membrane. Breakdown of the micronuclear envelope, a process associated with chromothripsis, leads to rapid accumulation of cGAS, providing a mechanism by which self-DNA becomes exposed to the cytosol. cGAS is activated by chromatin, and consistent with a mitotic origin, micronuclei formation and the proinflammatory response following DNA damage are cell-cycle dependent. By combining live-cell laser microdissection with single cell transcriptomics, we establish that interferon-stimulated gene expression is induced in micronucleated cells. We therefore conclude that micronuclei represent an important source of immunostimulatory DNA. As micronuclei formed from lagging chromosomes also activate this pathway, recognition of micronuclei by cGAS may act as a cell-intrinsic immune surveillance mechanism that detects a range of neoplasia-inducing processes. PMID- 28738411 TI - Polygenic Risk for Hypertriglyceridemia Can Mimic a Major Monogenic Mutation. PMID- 28738412 TI - Sampling Utterances and Grammatical Analysis Revised (SUGAR): New Normative Values for Language Sample Analysis Measures. AB - Purpose: The purpose of this study was to document whether mean length of utterance (MLUS), total number of words (TNW), clauses per sentence (CPS), and/or words per sentence (WPS) demonstrated age-related changes in children with typical language and to document the average time to collect, transcribe, and analyze conversational language samples. Method: Participants were 385 typically developing children (ages 3;0-7;11 [years;months]), with a final sample size of 270 participants (133 males and 137 females). Fifty-utterance conversational language samples were collected using a language sampling protocol. Four language sample analysis (LSA) metrics (i.e., MLUS, TNW, CPS, WPS) were calculated from the samples. Results: Results indicated statistically significant age-related increases in the four metrics. The average time to collect, transcribe, and analyze each sample was 20.91 min (SD = 3.97; range = 10.55-33.37). Conclusion: MLUS, TNW, CPS, and WPS may be used with other assessment data to document age related changes in children's language. When used as part of an assessment, the results from all of the metrics should be considered. Considering results from only 1 individual metric is not encouraged. These results suggest LSA may be completed in approximately 20 min, which is less than the average time to administer a standardized, norm-referenced language assessment. PMID- 28738413 TI - Reliability and Repeatability of Cone Density Measurements in Patients With Stargardt Disease and RPGR-Associated Retinopathy. AB - Purpose: To assess reliability and repeatability of cone density measurements by using confocal and (nonconfocal) split-detector adaptive optics scanning light ophthalmoscopy (AOSLO) imaging. It will be determined whether cone density values are significantly different between modalities in Stargardt disease (STGD) and retinitis pigmentosa GTPase regulator (RPGR)-associated retinopathy. Methods: Twelve patients with STGD (aged 9-52 years) and eight with RPGR-associated retinopathy (aged 11-31 years) were imaged using both confocal and split-detector AOSLO simultaneously. Four graders manually identified cone locations in each image that were used to calculate local densities. Each imaging modality was evaluated independently. The data set consisted of 1584 assessments of 99 STGD images (each image in two modalities and four graders who graded each image twice) and 928 RPGR assessments of 58 images (each image in two modalities and four graders who graded each image twice). Results: For STGD assessments the reliability for confocal and split-detector AOSLO was 67.9% and 95.9%, respectively, and the repeatability was 71.2% and 97.3%, respectively. The differences in the measured cone density values between modalities were statistically significant for one grader. For RPGR assessments the reliability for confocal and split-detector AOSLO was 22.1% and 88.5%, respectively, and repeatability was 63.2% and 94.5%, respectively. The differences in cone density between modalities were statistically significant for all graders. Conclusions: Split-detector AOSLO greatly improved the reliability and repeatability of cone density measurements in both disorders and will be valuable for natural history studies and clinical trials using AOSLO. However, it appears that these indices may be disease dependent, implying the need for similar investigations in other conditions. PMID- 28738414 TI - Impact of Amyotrophic Lateral Sclerosis on Slow Tonic Myofiber Composition in Human Extraocular Muscles. AB - Purpose: To analyze the proportion and cross-sectional area of myofibers containing myosin heavy chain slow-twitch (MyHCI) and myosin heavy chain slow tonic (MyHCsto) in extraocular muscles of autopsied amyotrophic lateral sclerosis (ALS) patients with either spinal or bulbar site of disease onset. Methods: Whole muscle cross sections from the middle portion of the medial rectus were labeled with antibodies against MyHCI or MyHCsto and laminin. Myofibers labeled with the MyHC antibodies (MyHCI+sto) and the total number of myofibers were quantified in the orbital and global layer of 6 control individuals and 18 ALS patients. The cross-sectional area of myofibers labeled for either MyHC was quantified in 130 to 472 fibers/individual in the orbital and in 180 to 573 fibers/individual in the global layer of each specimen. Results: The proportion of MyHCI+sto myofibers was significantly smaller in the orbital and global layer of ALS compared to control individuals. MyHCI+sto myofibers were significantly smaller in the global layer than in the orbital layer of ALS, whereas they were of similar size in control subjects. The decreased proportion of MyHCI+sto fibers correlated significantly with the age of death, but not disease duration, in patients who had the bulbar-onset variant of ALS but not in patients with spinal variant. Conclusions: ALS, regardless of site of onset, involves a loss of myofibers containing MyHCI+sto. Only in bulbar-onset cases did aging seem to play a role in the pathophysiological processes underlying the loss of MyHCI+sto fibers. PMID- 28738415 TI - Monocarboxylate Transporters Mediate Fluorescein Uptake in Corneal Epithelial Cells. AB - Purpose: To determine the presence of monocarboxylate transporter (MCT) in human and rabbit corneal epithelium and its role in transcellular fluorescein transportation in the cornea. Methods: The presence of MCTs in human and rabbit corneal epithelium was determined by RT-PCR and immunohistochemistry. Intracellular fluorescein uptake experiment was performed using cultured human corneal epithelial cells (HCECs). The involvement of MCT in fluorescein uptake was determined by addition of MCT inhibitors to HCECs and acute dry eye model on New Zealand albino rabbits by spectrophotometry, corneal impression cytology, and external eye photographs. Results: MCT-1 and MCT-4 were identified in both human and rabbit corneal epithelia. A longer treatment period and a lower pH value in culture medium increased fluorescein uptake in HCECs. Fluorescein uptake in HCECs was decreased following addition of MCT inhibitors in a concentration-dependent manner. Impression cytology under fluorescent microscopy showed intracellular fluorescein staining in the rabbit cornea with acute dry eye treatment that was decreased following topical treatment of MCT inhibitors. Conclusions: Fluorescein ingress in corneal epithelial cells is mediated by the MCT family. Further study of MCT-mediated transport on HCECs may potentially benefit differential diagnosis and contribute better understandings of ocular surface disorders. PMID- 28738416 TI - Conditionally Immortal Slc4a11-/- Mouse Corneal Endothelial Cell Line Recapitulates Disrupted Glutaminolysis Seen in Slc4a11-/- Mouse Model. AB - Purpose: To establish conditionally immortal mouse corneal endothelial cell lines with genetically matched Slc4a11+/+ and Slc4a11-/- mice as a model for investigating pathology and therapies for SLC4A11 associated congenital hereditary endothelial dystrophy (CHED) and Fuchs' endothelial corneal dystrophy. Methods: We intercrossed H-2Kb-tsA58 mice (Immortomouse) expressing an IFN-gamma dependent and temperature-sensitive mutant of the SV40 large T antigen (tsTAg) with Slc4a11+/+ and Slc4a11-/- C57BL/6 mice. The growth characteristics of the cell lines was assessed by doubling time. Ion transport activities (Na+/H+ exchange, bicarbonate, lactate, and Slc4a11 ammonia transport) were analyzed by intracellular pH measurement. The metabolic status of the cell lines was assessed by analyzing TCA cycle intermediates via gas chromatography mass spectrometry (GC MS). Results: The immortalized Slc4a11+/+ and Slc4a11-/- mouse corneal endothelial cells (MCECs) remained proliferative through passage 49 and maintained similar active ion transport activity. As expected, proliferation was temperature sensitive and IFN-gamma dependent. Slc4a11-/- MCECs exhibited decreased proliferative capacity, reduced NH3:H+ transport, altered expression of glutaminolysis enzymes similar to the Slc4a11-/- mouse, and reduced proportion of TCA cycle intermediates derived from glutamine with compensatory increases in glucose flux compared with Slc4a11+/+ MCECs. Conclusions: This is the first report of the immortalization of MCECs. Ion transport of the immortalized endothelial cells remains active, except for NH3:H+ transporter activity in Slc4a11-/- MCECs. Furthermore, Slc4a11-/- MCECs recapitulate the glutaminolysis defects observed in Slc4a11-/- mouse corneal endothelium, providing an excellent tool to study the pathogenesis of SLC4A11 mutations associated with corneal endothelial dystrophies and to screen potential therapeutic agents. PMID- 28738417 TI - A Pharmacodynamic Analysis of Choroidal Neovascularization in a Porcine Model Using Three Targeted Drugs. AB - Purpose: To compare the efficacy of microneedle-delivered suprachoroidal (SC) pazopanib to intravitreal (Ivit) delivery of pazopanib, bevacizumab, or a fusion protein hI-con1 versus vehicle controls on choroidal neovascularization (CNV) growth in a pig model. Methods: Forty-one pigs were injected on the day of CNV induction (hI-con1 on postinduction day 14) with either 2.5 mg Ivit bevacizumab (n = 9), 1 mg Ivit pazopanib (n = 9), 300 Ivit MUg hI-con1 (n = 4), or 1 mg SC pazopanib (n = 9), vs. 10 vehicle controls (3 SC + 7 Ivit = 10). Pigs were euthanized at week 2 (11), 3 (8), 4 (11), and 8 (11), and eyes were fixed for histology. The size of the CNV was determined from histology, and CNV height was the primary outcome measure. Immunostaining for cytotoxic T-cells was performed in the hI-con1 study. Results: In 39 of 41 (95%) eyes, type 2 CNV lesions were identified. One CNV lesion was lost during dissection. One animal was euthanized due to surgical complications. For mean CNV size comparisons, Ivit pazopanib had smaller mean height measurements (90 +/- 20 MUm) versus controls (180 +/- 20 MUm; P = 0.009), and Ivit pazopanib had smaller maximum CNV height (173 +/- 43 MUm) compared to SC pazopanib (478 +/- 105 MUm; P = 0.018). The mean lesion size in hI con1-treated animals trended smaller than in controls (P = 0.11). Immunostaining did not detect cytotoxic T-cells. Conclusions: Intravitreal pazopanib and to a lesser extent hI-con1 reduced the size of CNV lesions. The pig model has nearly a 100% rate of type 2 CNV induction and is a reliable preclinical model with pharmacodynamics similar to humans. PMID- 28738419 TI - Posterior Staphylomas in Pathologic Myopia Imaged by Widefield Optical Coherence Tomography. AB - Purpose: To examine posterior staphylomas by widefield optical coherence tomography (WF-OCT) and three-dimensional magnetic resonance imaging (3D-MRI). Methods: Highly myopic patients (myopic refractive error >8.0 diopters or axial length >26.5 mm) who had previously undergone orbital 3D-MRI were examined by WF OCT. Results: The study included 100 eyes of 57 patients with a mean age of 67.9 +/- 10.7 years (range, 44-85 years) and mean axial length of 30.0 +/- 2.3 mm (range, 25.1-36.5 mm). All staphylomas detected on the 3D-MRI, except for two very large staphylomas, were visualized on the WF-OCT images. Morphologic hallmarks of the staphylomas were smoothly configured staphyloma border with a gradual thinning of the choroid and an inward protrusion of the sclera at the staphyloma edge. Comparing the detectability of the staphylomas on the WF-OCT images versus 3D-MRI revealed no significant difference between both techniques (P = 0.12; chi2 test). Comparing the staphyloma classification between both techniques showed a good concordance with a concordance index kappa of 0.61 (95% confidence interval: 0.50-0.72). A spatial relationship between the staphylomatous areas and the macula and optic nerve head was observed by WF-OCT. Conclusions: WF-OCT can provide tomographic images of posterior staphylomas in a resolution and size unachievable so far, and may replace 3D-MRI in assessing posterior staphylomas. Future studies using WF-OCT may explore the detailed morphologic characteristics of posterior staphylomas and give clues to the etiology of staphylomas. PMID- 28738418 TI - Molecular Pathway to Protection From Age-Dependent Photoreceptor Degeneration in Mef2 Deficiency. AB - Purpose: Photoreceptor degeneration in the retina is a major cause of blindness in humans. Elucidating mechanisms of degenerative and neuroprotective pathways in photoreceptors should afford identification and development of therapeutic strategies. Methods: We used mouse genetic models and improved methods for retinal explant cultures. Retinas were enucleated from Mef2d+/+ and Mef2d-/- mice, stained for MEF2 proteins and outer nuclear layer thickness, and assayed for apoptotic cells. Chromatin immunoprecipitation (ChIP) assays revealed MEF2 binding, and RT-qPCR showed levels of transcription factors. We used AAV2 and electroporation to express genes in retinal explants and electroretinograms to assess photoreceptor functionality. Results: We identify a prosurvival MEF2D PGC1alpha pathway that plays a neuroprotective role in photoreceptors. We demonstrate that Mef2d-/- mouse retinas manifest decreased expression of PGC1alpha and increased photoreceptor cell loss, resulting in the absence of light responses. Molecular repletion of PGC1alpha protects Mef2d-/- photoreceptors and preserves light responsivity. Conclusions: These results suggest that the MEF2-PGC1alpha cascade may represent a new therapeutic target for drugs designed to protect photoreceptors from developmental- and age dependent loss. PMID- 28738421 TI - Cardiovascular Disease Among Transgender Adults Receiving Hormone Therapy: A Narrative Review. AB - Recent reports estimate that 0.6% of adults in the United States, or approximately 1.4 million persons, identify as transgender. Despite gains in rights and media attention, the reality is that transgender persons experience health disparities, and a dearth of research and evidence-based guidelines remains regarding their specific health needs. The lack of research to characterize cardiovascular disease (CVD) and CVD risk factors in transgender populations receiving cross-sex hormone therapy (CSHT) limits appropriate primary and specialty care. As with hormone therapy in cisgender persons (that is, those whose sex assigned at birth aligns with their gender identity), existing research in transgender populations suggests that CVD risk factors are altered by CSHT. Currently, systemic hormone replacement for cisgender adults requires a nuanced discussion based on baseline risk factors and age of administration of exogenous hormones because of concern regarding an increased risk for myocardial infarction and stroke. For transgender adults, CSHT has been associated with the potential for worsening CVD risk factors (such as blood pressure elevation, insulin resistance, and lipid derangements), although these changes have not been associated with increases in morbidity or mortality in transgender men receiving CSHT. For transgender women, CSHT has known thromboembolic risk, and lower-dose transdermal estrogen formulations are preferred over high-dose oral formulations. In addition, many studies of transgender adults focus predominantly on younger persons, limiting the generalizability of CSHT in older transgender adults. The lack of randomized controlled trials comparing various routes and formulations of CSHT, as well as the paucity of prospective cohort studies, limits knowledge of any associations between CSHT and CVD. PMID- 28738420 TI - Variation in the Three-Dimensional Histomorphometry of the Normal Human Optic Nerve Head With Age and Race: Lamina Cribrosa and Peripapillary Scleral Thickness and Position. AB - Purpose: This study quantified the thickness and depth of the lamina cribrosa (LC) and peripapillary scleral thickness in high-resolution three-dimensional (3D) fluorescent reconstructions of the optic nerve head (ONH) in eyes from donors of African (AD) and European descent (ED). Methods: A total of 64 eyes (45 ED, 19 AD) from 51 normal donors were obtained within 6 hours of death and fixed at 10 mm Hg of pressure. The optic nerve head was trephined from the globe and digitally reconstructed at 1.5 * 1.5 * 1.5 MUm voxel resolution with an automated episcopic fluorescence technique. The load-bearing ONH connective tissue surfaces were manually delineated in 3D using custom software. Results: The lamina cribrosa and peripapillary sclera were significantly thinner in AD eyes adjusting for age and sex (LC was 24 +/- 11 MUm thinner; P = 0.0350; scleral was 56 +/- 22 MUm thinner; P = 0.0097). The lamina cribrosa was significantly thinner in females (23 +/- 11 MUm thinner; P = 0.0425). Age was not significantly associated with any morphologic parameter in the ED group. However, increasing age was associated with an increase in scleral thickness (1.3 MUm/year, P = 0.0499) and an increase in LC depth (2.3 MUm/year, P = 0.0035) in the AD group. The sclera was thickest in the superior and temporal regions while the LC was thinnest superiorly. Conclusions: Substantial sectorial and racial differences in LC and scleral morphology were observed, as well as increasing LC depth and scleral thickness with age in the AD group. Results suggest greater age-related remodeling of the load-bearing ONH connective tissues in eyes from AD individuals that could explain, in part, the greater predilection to glaucomatous injury seen in aged AD populations. PMID- 28738422 TI - Statin Denial: An Internet-Driven Cult With Deadly Consequences. PMID- 28738423 TI - Continued Statin Prescriptions After Adverse Reactions and Patient Outcomes: A Cohort Study. AB - Background: Many patients discontinue statin treatment, often after having a possible adverse reaction. The risks and benefits of continued statin therapy after an adverse reaction are not known. Objective: To examine the relationship between continuation of statin therapy (any prescription within 12 months after an adverse reaction) and clinical outcomes. Design: Retrospective cohort study. Setting: Primary care practices affiliated with 2 academic medical centers. Participants: Patients with a presumed adverse reaction to a statin between 2000 and 2011. Measurements: Information on adverse reactions to statins was obtained from structured electronic medical record data or natural-language processing of narrative provider notes. The primary composite outcome was time to a cardiovascular event (myocardial infarction or stroke) or death. Results: Most (81%) of the adverse reactions to statins were identified from the text of electronic provider notes. Among 28 266 study patients, 19 989 (70.7%) continued receiving statin prescriptions after the adverse reaction. Four years after the presumed adverse event, the cumulative incidence of the composite primary outcome was 12.2% for patients with continued statin prescriptions, compared with 13.9% for those without them (difference, 1.7% [95% CI, 0.8% to 2.7%]; P < 0.001). In a secondary analysis of 7604 patients for whom a different statin was prescribed after the adverse reaction, 2014 (26.5%) had a documented adverse reaction to the second statin, but 1696 (84.2%) of those patients continued receiving statin prescriptions. Limitations: The risk for recurrent adverse reactions to statins could not be established for the entire sample. It was also not possible to determine whether patients actually took the statins. Conclusion: Continued statin prescriptions after an adverse reaction were associated with a lower incidence of death and cardiovascular events. Primary Funding Source: Chinese National Key Program of Clinical Science, National Natural Science Foundation of China, and Young Scientific Research Fund of Peking Union Medical College Hospital. PMID- 28738424 TI - Use of high-throughput in vitro toxicity screening data in cancer hazard evaluations by IARC Monograph Working Groups. AB - Evidence regarding carcinogenic mechanisms serves a critical role in International Agency for Research on Cancer (IARC) Monograph evaluations. Three recent IARC Working Groups pioneered inclusion of the US Environmental Protection Agency (EPA) ToxCast program high-throughput screening (HTS) data to supplement other mechanistic evidence. In Monograph V110, HTS profiles were compared between perfluorooctanoic acid (PFOA) and prototypical activators across multiple nuclear receptors. For Monograph V112-113, HTS assays were mapped to 10 key characteristics of carcinogens identified by an IARC expert group, and systematically considered as an additional mechanistic data stream. Both individual assay results and ToxPi-based rankings informed mechanistic evaluations. Activation of multiple nuclear receptors in HTS assays showed that PFOA targets not only peroxisome proliferator activated receptors, but also other receptors. ToxCast assays substantially covered 5 of 10 key characteristics, corroborating literature evidence of "induces oxidative stress" and "alters cell proliferation, cell death or nutrient supply" and filling gaps for "modulates receptor-mediated effects." Thus, ToxCast HTS data were useful both in evaluating specific mechanistic hypotheses and in contributing to the overall evaluation of mechanistic evidence. However, additional HTS assays are needed to provide more comprehensive coverage of the 10 key characteristics of carcinogens that form the basis of current IARC mechanistic evaluations. PMID- 28738425 TI - Preparation and Characterization of PEGylated Iron Oxide-Gold Nanoparticles for Delivery of Sulforaphane and Curcumin. AB - Natural products have been used for the treatment of various diseases such as cancer. Curcumin (CUR) and sulforaphane (SF) have anti-cancer effects, but their application is restricted because of their low water solubility and poor oral bioavailability. To improve the bioavailability and solubility of SF and CUR, we performed an advanced delivery of SF and CUR with PEGylated gold coated Fe3O4 magnetic nanoparticles (PEGylated Fe3O4@Au NPs) to endorse SF and CUR maintenance as an effective and promising antitumor drugs. The structure of the synthesized nanocarrieris evaluated by, transmission electron microscopy (TEM) and Fourier transform infrared spectroscopy (FT-IR). The results revealed that the size of NPs was 20 nm. They were mono-dispersed in water, with high drug-loading capacity and stability. CUR and SF were encapsulated into NPs with loading capacity of 16.32+/-0.023% and 15.74+/-0.015% and entrapment efficiency of 74.57+/-0.14% and 72.20+/-0.18% respectively. The in-vitro study of SF and CUR loaded PEGylated Fe3O4@Au NPs on human breast adenocarcinoma cell line (SK-BR-3) confirmed that cytotoxicity of SF and CUR can enhance when they are loaded on PEGylated Fe3O4@Au NPs in comparison to Free SF and void CUR. The results of flow cytometry and real time PCR shown that nano-carriers can increase therapeutic effects of SF and CUR by apoptosis and necrosis induction as well as inhibiting of migration in SK-BR-3 cell line. PMID- 28738426 TI - Long Term Effects of Liraglutide in Japanese Patients with type 2 Diabetes Among the Subgroups with Different Renal Functions: Results of 2-Year Prospective Study. AB - Aims Very few studies have ever examined the effects of long-term (>1 year) administration of liraglutide in patients with type 2 diabetes mellitus (T2DM) and renal impairment. Therefore, we conducted a 2-year study to prospectively examine the effects of liraglutide in those patients. Methods A total of 148 patients with T2DM were enrolled and treated with liraglutide (0.6 or 0.9 mg/day). 97 patients completed the 2-year study without protocol deviations. These patients were divided into 3 groups according to the baseline estimated glomerular filtration ratio (eGFR) (in mL/min/1.73 m2): group A, >=60 (n=39); group B, >=30 to <60 (n=38); and group C, <30 (n=20). The changes in blood and urine variables, and echocardiographic left ventricular mass index (LVMI) from baseline to 2 years were analyzed in each group. Primary outcomes were changes of the renal parameters of eGFR and albuminuria after the treatment of liraglutide. Results Blood glucose and systolic blood pressure decreased significantly after 24 months of liraglutide treatment in all groups compared with baseline (p<0.05). The eGFR increased significantly in group B (p<0.05), and remained unchanged in groups A and C. Albuminuria and LVMI decreased significantly in all 3 groups compared with baseline (p<0.05). Conclusions These findings suggest that 2 years of liraglutide treatment in Japanese patients with T2DM and impaired renal function was effective in terms of suppressing the deterioration of renal function, and reducing albuminuria. Long-term liraglutide treatment also improved glycemic control and blood pressure, and reduced left ventricular hypertrophy in this study. PMID- 28738427 TI - Nanoemulsion: An Advanced Vehicle For Efficient Drug Delivery. AB - Advanced drug delivery system has now gained preference over the conventional drug delivery system. One such research is nanoemulsion which is famous among the researchers because of ease of formation, stability, clarity, increased absorption rate leading to increasing in bioavailability and potential to form a formulation with both lipophilic as well as the hydrophilic drug. Long lasting stability (up to years) and ability to encapsulate both lipophilic and hydrophilic drug has given this colloidal system a valuable position in drug delivery. This article contains information on components required for its fabrication, preparation methods and evaluation parameters along with its application in drug delivery and future aspects of this advanced drug delivery system. PMID- 28738429 TI - Erratum: Tibial Tubercle Osteotomy: Indication and Techniques. PMID- 28738428 TI - Association between Patient History and Physical Examination and Osteoarthritis after Ankle Sprain. AB - : Structural abnormalities on MRI are frequent after an ankle sprain. To determine the association between patient history, physical examination and early osteoarthritis (OA) in patients after a previous ankle sprain, 98 patients with persistent complaints were selected from a cross-sectional study. Patient history taking and physical examination were applied and MRI was taken. Univariate and multivariable analyses were used to test possible associations. Signs of OA (cartilage loss, osteophytes and bone marrow edema) were seen in the talocrural joint (TCJ) in 40% and the talonavicular joint (TNJ) in 49%. Multivariable analysis showed a significant positive association between swelling (OR 3.58, 95%CI 1.13;11.4), a difference in ROM of passive plantar flexion (OR 1.09, 95%CI 1.01;1.18) and bone edema in the TCJ. A difference in ROM of passive plantar flexion (OR 1.07, 95%CI 1.00;1.15) and pain at the end range of dorsiflexion/plantar flexion (OR 5.23, 95%CI 1.88;14.58) were associated with osteophytes in the TNJ. Pain at the end of dorsiflexion/plantar flexion, a difference in ROM of passive plantar flexion and swelling seem to be associated with features of OA (bone marrow edema, osteophytes) in the TCJ and TNJ. Our findings may guide physicians to predict structural joint abnormalities as signs of osteoarthritis. LEVEL OF EVIDENCE: 1b. PMID- 28738430 TI - Postoperative Stiffening after Bicruciate-Retaining Total Knee Arthroplasty. AB - Bicruciate-retaining (BCR) total knee arthroplasty (TKA) has recently experienced a resurgence of popularity. It may be a good option among a younger, more active population because it restores knee kinematics better than other prosthetic designs. Results obtained in the first 100 BCR TKAs implanted with a simplified gap-balancing technique are reported, with special attention paid to knee flexion, through comparison with a cohort of 100 posterior-stabilized (PS) TKAs. We conducted a retrospective comparative cohort study of 100 BCR TKAs (90 patients) and 100 PS TKAs (88 patients). Knees with a BCR TKA lost significantly more flexion PS TKA in the early postoperative period when their preoperative flexion was less than 130 degrees (loss of 40 degrees vs. loss of 24 degrees). Postoperative range of motion was similar between BCR TKA and PS TKA when preoperative knee flexion was 130 degrees or more, and when there was no preoperative flexion contracture. Postoperative stiffening seems to be more frequent and of greater magnitude after BCR TKA, compared with PS TKA, in patients suffering from preoperative flexion stiffness. Further investigation on the causes of this phenomenon is warranted. PMID- 28738431 TI - Results of Arthroscopic Synovectomy for Treatment of Synovial Lipomatosis (Lipoma Arborescens) of the Knee. AB - Synovial lipomatosis (SL; lipoma arborescens) is a tumor-like condition with villous proliferation of the synovium. The exact etiology of SL is still unknown. The knee is the most commonly involved part. The goal of this retrospective study was to report the results of arthroscopic synovectomy in patients with SL in their knee joints as well as to emphasize the importance of considering this pathology when treating patients with recurrent knee joint effusions. In total, 21 patients (8 females and 13 males) were evaluated retrospectively from May 2009 to July 2014. The mean follow-up period was 29.13 (range, 12-61) months. The mean duration of compliance was 22.76 (range, 7-61) months. All patients were evaluated by Knee Society score pre- and postoperatively. The mean preoperative and last follow-up Knee Society scores were 67.82 and 88.23 points, respectively. There was a significant difference between the preoperative and postoperative Knee Society scores (p = 0.0001). Histopathological examinations showed that the subsynovial layer exhibited diffuse replacement by mature fat cells that had formed villous projections. In addition, infiltration of mononuclear inflammatory cells was observed at different stages. SL is a nondestructive and benign tumor pathology of the knee joint without a clearly identified etiology. The main difficulty in diagnosis is lack of clinical practice. PMID- 28738432 TI - The Stem-Cell Market for the Treatment of Knee Osteoarthritis: A Patient Perspective. AB - The use of stem-cell therapies for the treatment of various musculoskeletal conditions, especially knee osteoarthritis (OA), is rapidly expanding, despite only low-level evidence to support its use. Centers offering these therapies are often marketing and charging patients out-of-pocket costs for such services. Therefore, the purpose of this study was to determine the current marketed: (1) prices and (2) clinical efficacy of stem-cell therapies for knee OA. This was a prospective cross-sectional study which queried 317 U.S. centers that offered direct-to-consumer stem-cell therapies for musculoskeletal conditions. A total of 273 of 317 centers were successfully contacted via phone or e-mail, using a simulated 57-year-old male patient with knee OA. Scripted questions were asked by the simulated patient to determine the marketed prices and clinical efficacy. Centers generally reported the proportion of patients who had "good results" or "symptomatic improvement." The mean price of a unilateral (same-day) stem-cell knee injection was $5,156 with a standard deviation of $2,446 (95% confidence interval [CI]: $4,550-5,762, n = 65). The mean proportion of claimed clinical efficacy was 82% with a standard deviation of 9.6% (95% CI: 79.0-85.5%, n = 36). Most American stem-cell centers offer therapies for knee OA. The cost of these therapies averages about $5,000 per injection, and centers claim that 80% of the patients had "good results" or "symptomatic improvement," denoting a gap between what is documented in the published literature and the marketing claims. These findings offer both patients and physicians insight into the current stem-cell market for knee OA. We hope that with this information, providers can more optimally make patients aware of discrepancies between what is being marketed versus the current evidence-based landscape of these therapies for knee OA. PMID- 28738434 TI - [Perception of the Liver Allocation System by Different Stakeholders]. AB - The German Transplant Law is the legal basis of the liver allocation system in Germany and is specified by the guidelines of the German Medical Association. These guidelines are based on current medical knowledge. The procedure of developing these guidelines was formalised and made transparent.This survey with 502 participants examines how four current aspects of the allocation system are perceived by different stakeholders (medical staff, patients on the liver transplant list or already transplanted, medical students and non-medical university personnel and students). A great majority of respondents considered the current organ allocation system to be fair. Physicians were given a great say on allocation rules. Most respondents assessed the chances of a patient on the transplant list to receive a donor organ over time as being worse than it really was. The respondents supported six month alcohol abstinence before patients with alcohol-related liver cirrhosis are listed for liver transplantation. The findings suggest that people trust that physicians develop fair allocation rules and appreciate the current liver allocation system. PMID- 28738435 TI - Abnormal Placental Cord Insertion and Adverse Pregnancy Outcomes: Results from a Prospective Cohort Study. PMID- 28738433 TI - Implantation of a Novel Cryopreserved Viable Osteochondral Allograft for Articular Cartilage Repair in the Knee. AB - Restoration and repair of articular cartilage injuries remain a challenge for orthopaedic surgeons. The standard first-line treatment of articular cartilage lesions is marrow stimulation; however, this procedure can often result in the generation of fibrous repair cartilage rather than the biomechanically superior hyaline cartilage. Marrow stimulation is also often limited to smaller lesions, less than 2 cm2. Larger lesions may require implantation of a fresh osteochondal allograft, though a short shelf life, size-matched donor requirements, potential challenges of bone healing, limited availability, and the relatively high price limit the wide use of this therapeutic approach. We present a straightforward, single-stage surgical technique of a novel reparative and restorative approach for articular cartilage repair with the implantation of a cryopreserved viable osteochondral allograft (CVOCA). The CVOCA contains full-thickness articular cartilage and a thin layer of subchondral bone, and maintains the intact native cartilage architecture with viable chondrocytes, growth factors, and extracellular matrix proteins to promote articular cartilage repair. We report the results of a retrospective case series of three patients who presented with articular cartilage lesions more than 2 cm2 and were treated with the CVOCA using the presented surgical technique. Patients were followed up to 2 years after implantation of the CVOCA and all three patients had satisfactory outcomes without adverse events. Controlled randomized studies are suggested for evaluation of CVOCA efficacy, safety, and long-term outcomes. PMID- 28738436 TI - Increased Neonatal Respiratory Morbidity Associated with Gestational and Pregestational Diabetes: A Retrospective Study. PMID- 28738437 TI - Long-Term Outcomes and Quality of Life in Patients after Soave Pull-Through Operation for Hirschsprung's Disease: An Observational Retrospective Study. AB - INTRODUCTION: Patients after pull-through operation for Hirschsprung's disease (HD) are at high risk of defecation disorders. This study aimed at investigating their long-term outcomes and quality of life (QoL) in comparison with controls. PATIENTS AND METHODS: Patients older than 5 years operated on for HD were interviewed to complete detailed questionnaires on bowel function. Patients without neurologic impairment were enrolled in a QoL survey to compare with controls matched for sex and age and selected randomly from the general population using sampling set in a ratio of four controls to one case of HD. RESULTS: In total, 53 operated patients were enrolled. Mean age of the patients was 16 +/- 8 years, with 68% boys. Rectosigmoid aganglionosis was the most seen form of HD in 38 (72%) cases. Open Soave was performed in 40 (75.5%) cases, and minimally invasive surgery Soave (MIS Soave) in 13 (24.5%) cases. At investigation, prevalence of fecal incontinence and constipation were 22.6 and 13.2%, respectively. Regarding QoL survey, 45 patients and 180 controls were enrolled, excluding 8 patients with neurologic impairment. Thirty-seven (82.2%) patients were classified as having a good QoL (score >= 9 points); whereas six had a fair QoL (5-8 points) and two had a poor QoL (< 5 points). QoL score in the cases and the controls were 10.2 +/- 2.5 and 11.9 +/- 0.4 points, respectively. Long aganglionosis form of HD was significantly associated with a low QoL (score < 8 points), adjusted odds ratio = 9, 95% confidence interval [1.3; 64.1] (p < 0.05). In subscales analyses, the prevalence of each dimension including fecal continence, school absenteeism, unhappiness or anxiety, food restriction, and peer rejection was significantly higher in operated patients than in controls (p <0.001). CONCLUSION: Although the QoL of patients operated on for HD in general was with good outcomes, fecal incontinence and constipation still are problematic issues and challenges in a high percentage of patients. Therefore, a long-term and multidisciplinary follow-up is essentially required for these patients. PMID- 28738438 TI - ? PMID- 28738439 TI - Terpenoids from the Oleo-Gum-Resin of Boswellia serrata and Their Antiplasmodial Effects In Vitro. AB - In the course of our ongoing search for new natural products as leads against protozoal diseases, the dichloromethane extract of Indian frankincense, the oleo gum-resin obtained from Boswellia serrata, showed in vitro activity against Plasmodium falciparum. Bioactivity-guided fractionation led to the isolation of eight diterpenes: (1S,3E,7E,11R)-verticilla-3,7,12(18)-triene (1), cembrene A (2), serratol (3), 1S,3E,7R,8R,11E-7,8-epoxy-cembra-3,11-dien-1-ol (4), incensole oxide (5), rel (1S,3R,7E,11S,12R)-1,12-epoxy-4-methylenecembr-7-ene-3, 11-diol (6), isoincensole oxide (7), and isodecaryiol (8). Furthermore, 10 triterpenes, namely, oleanolic acid (9), 11-keto-beta-boswellic acid (10), 3-epi-neoilexonol (11), uvaol (12), beta-boswellic aldehyde (13), 5alpha-tirucalla-8,24-dien-3alpha ol (14), isoflindissone lactone (15), isoflindissol lactone (16), rel (8R,9S,20R) tirucall-24-ene-3beta,20-diol (17), and rel (3alpha,8R, 9S,20R,24S)-20,24 epoxytirucalla-3,25-diol (18) as well as the sesquiterpene beta-bourbonene (19), the monoterpene carvacrol (20) and the phenyl propanoids methyleugenol (21), and p-methoxycinnamaldehyde (22) were isolated. All compounds were identified by mass spectrometry and nuclear magnetic resonance spectroscopic measurements. Compounds 6, 11, and 16-18 are described for the first time. Compounds 13 - 15 are isolated as natural products for the first time, compound 8 for the first time from a plant. Antiplasmodial IC50 values and cytotoxicity against L6 rat skeletal myoblasts were determined. Isoflindissone lactone (15) was the most active compound with an IC50 of 2.2 uM against P. falciparum and a selectivity index of 18. PMID- 28738440 TI - ISSR-Derived Species-Specific SCAR Marker for Rapid and Accurate Authentication of Ocimum tenuiflorum L. AB - Ocimum tenuiflorum has been widely used in traditional medicine and has high medicinal value. High volume trade of this potential medicinal plant species led to unscrupulous adulteration of both crude drugs as well as formulations. Morphology-based authentication is difficult in cases of incomplete or damaged samples and in dried herbal materials. In such cases, PCR-based molecular methods may aid in accurate identification. The present study aimed at developing species specific DNA marker(s) for the authentication of O. tenuiflorum. A species specific amplicon (279 bp) generated through an inter-simple sequence repeat marker (UBC 835) in all individuals of O. tenuiflorum was cloned, sequenced, and a primer pair was developed (designated as CIM-OT-835F/CIM-OT-835R). The newly developed sequence characterized amplified region marker was validated through PCR amplification in all available seven species of Ocimum, and its specificity for O. tenuiflorum was confirmed with the consistent generation of an amplicon of 177 bp. The developed marker can be used for accurate and rapid identification of the species for certification purposes and will be useful in quality control of medicinal preparations containing this important medicinal species. PMID- 28738441 TI - Neuromuscular Disorders in Children and Adolescents. PMID- 28738442 TI - Charting the future of cancer health disparities research: A position statement from the American Association for Cancer Research, the American Cancer Society, the American Society of Clinical Oncology, and the National Cancer Institute. PMID- 28738444 TI - Protein Coating of DNA Nanostructures for Enhanced Stability and Immunocompatibility. AB - Fully addressable DNA nanostructures, especially DNA origami, possess huge potential to serve as inherently biocompatible and versatile molecular platforms. However, their use as delivery vehicles in therapeutics is compromised by their low stability and poor transfection rates. This study shows that DNA origami can be coated by precisely defined one-to-one protein-dendron conjugates to tackle the aforementioned issues. The dendron part of the conjugate serves as a cationic binding domain that attaches to the negatively charged DNA origami surface via electrostatic interactions. The protein is attached to dendron through cysteine maleimide bond, making the modular approach highly versatile. This work demonstrates the coating using two different proteins: bovine serum albumin (BSA) and class II hydrophobin (HFBI). The results reveal that BSA-coating significantly improves the origami stability against endonucleases (DNase I) and enhances the transfection into human embryonic kidney (HEK293) cells. Importantly, it is observed that BSA-coating attenuates the activation of immune response in mouse primary splenocytes. Serum albumin is the most abundant protein in the blood with a long circulation half-life and has already found clinically approved applications in drug delivery. It is therefore envisioned that the proposed system can open up further opportunities to tune the properties of DNA nanostructures in biological environment, and enable their use in various delivery applications. PMID- 28738443 TI - Urethral injection therapy for urinary incontinence in women. AB - BACKGROUND: Urinary incontinence imposes a significant health and economic burden to society. Periurethral or transurethral injection of bulking agents is a minimally invasive surgical procedure used as one the surgical treatments of stress urinary incontinence (SUI) in adult women. OBJECTIVES: To assess the effects of periurethral or transurethral injection therapy on the cure or improvement of urinary incontinence in women. SEARCH METHODS: We searched the Cochrane Incontinence Group Specialised Trials Register (searched 8 November 2010) and the reference lists of relevant articles. SELECTION CRITERIA: All randomised or quasi-randomised controlled trials of treatment for urinary incontinence in which at least one management arm involved periurethral or transurethral injection therapy. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed methodological quality of each study using explicit criteria. Data extraction was undertaken independently and clarification concerning possible unreported data sought directly from the investigators. MAIN RESULTS: Excluding duplicate reports, we identified 14 trials (excluding one that was subsequently withdrawn from publication and not included in this analysis) including 2004 women that met the inclusion criteria. The limited data available were not suitable for meta-analysis because they all came from separate trials. Trials were small and generally of moderate quality.One trial of 45 women that compared injection therapy with conservative treatment showed early benefit for the injectable therapy with respect to continence grade (risk ratio (RR) 0.70, 95% confidence interval (CI) 0.52 to 0.94) and quality of life (mean difference (MD) 0.54, 95% CI 0.16 to 0.92). Another trial, comparing Injection of autologous fat with placebo, terminated early because of safety concerns. Two trials that compared injection with surgical management found significantly better objective cure in the surgical group (RR 4.77, 95% CI 1.96 to 11.64; and RR 1.69, 95% CI 1.02 to 2.79), although the latter trial data did not reach statistical significance if an intention-to-treat analysis was used.Eight trials compared different agents and all results had wide confidence intervals. Silicone particles, calcium hydroxylapatite, ethylene vinyl alcohol, carbon spheres and dextranomer hyaluronic acid combination gave improvements which were not shown to be more or less efficacious than collagen. Dextranomer hyaluronic acid compound treated patients appeared to have significantly higher rates of injection site complications (16% with the hyaluronic acid compound versus none with collagen; RR 37.78, 95% CI 2.34 to 610.12) and this product has now been withdrawn from the market.A comparison of periurethral and transurethral methods of injection found similar outcomes but a higher (though not statistically significant) rate of early complications in the periurethral group. One trial of 30 women showed a weak (but not clinically significant) advantage for patient satisfaction (data not suitable for analysis in RevMan) after mid-urethral injection in comparison to bladder neck injection but with no demonstrable difference in continence levels. AUTHORS' CONCLUSIONS: The available evidence base remains insufficient to guide practice. In addition, the finding that placebo saline injection was followed by a similar symptomatic improvement to bulking agent injection raises questions about the mechanism of any beneficial effects. One small trial comparing silicone particles with pelvic floor muscle training was suggestive of benefit at three months but it is not known if this was sustained, and the treatment was associated with high levels of postoperative retention and dysuria. Greater symptomatic improvement was observed with surgical treatments, though the advantages need to be set against likely higher risks. No clear-cut conclusions could be drawn from trials comparing alternative agents, although dextranomer hyaluronic acid was associated with more local side effects and is no longer commercially available for this indication. There is insufficient evidence to show superiority of mid-urethral or bladder neck injection. The single trial of autologous fat provides a reminder that periurethral injections can occasionally cause serious side effects. Also, a Brief Economic Commentary (BEC) identified three studies suggesting that urethral bulking agent might be more cost-effective compared with retropubic mid-urethral slings, transobturator or traditional sling procedure when used as an initial treatment in women without hypermobility or as a follow-up to surgery failure provided injection is kept minimal. However, urethral bulking agent might not be cost-effective when compared with traditional sling as an initial treatment of SUI when a patient is followed up for a longer period (15 months post-surgery). PMID- 28738445 TI - Population characteristics of Macrocheles glaber (Acari: Macrochelidae) and Stratiolaelaps scimitus (Acari: Laelapidae) reared on a mushroom fly Coboldia fuscipes (Diptera: Scatopsidae). AB - Subterranean predatory mites are important biological control agents of pests in soil. In order to understand the population characteristics of two predatory mites, Macrocheles glaber Muller and Stratiolaelaps scimitus Womersley, we studied their development, survival and fecundity data under laboratory conditions using Coboldia fuscipes Meigen as a food source and analyzed them with the age-stage, two-sex life table. Macrocheles glaber had a significantly shorter developmental time, oviposition period, longevity and lower fecundity than those of S. scimitus. The intrinsic rate of increase (r), finite rate of increase (lambda), net reproductive rate (R0 ), net predation rate (C0 ), and finite predation rate (omega) of M. glaber were significantly lower than those of S. scimitus. Both population parameters and computer simulation implied that S. scimitus is a potential powerful biocontrol agent compared to M. glaber. PMID- 28738446 TI - Single-stage versus two-stage arteriovenous loop microsurgical reconstruction: A meta-analysis of the literature. AB - BACKGROUND: Arteriovenous (AV) loops can be utilized in a single- or two-stage approach in free flap reconstruction when proper vessels are not available. However, there exists no consensus on which method leads to superior microsurgical and patient outcomes. The purpose of this article was to review single- versus two-stage AV loops utilized in free flap reconstruction with a focus on complications and overall outcomes. METHODS: A systematic review of AV loops for autologous free tissue transfer was conducted. Endpoints investigated included flap characteristics, timing to second stage, complications, and outcomes. A Student's t-test and forest plots were used for statistical analysis. RESULTS: Thirty-five unique papers discussed utilizing AV loops in a single- or two-stage approach, yielding 260 and 98 single- and two-stage AV loops, respectively. There was a statistically significant higher rate of major complications in two-stage as compared to single-stage AV loops. There was a non statistically significant difference in rate of minor complications in the single stage as compared to two-stage AV loops. Overall, there was a statistically significant higher success rate in the single-stage as compared to two-stage AV loops CONCLUSION: There was a statistically significant higher rate of major complications and failures in two-stage AV loops. As well-conducted randomized controlled studies are nearly impossible to perform in this population, the decision to pursue a single- versus two-stage reconstruction should ultimately be determined based on individual patient co-morbidities, the size and etiology of defect, and the type of free tissue transfer planned. PMID- 28738447 TI - Comparison of local versus general anesthesia in patients undergoing transcatheter aortic valve replacement: A meta-analysis. AB - BACKGROUND: Transcatheter aortic valve replacement (TAVR) is typically performed under general anesthesia (GA). However, there is increasing data supporting the safety of performing TAVR under local anesthesia/conscious sedation (LA). We performed a meta-analysis to gain better understanding of the safety and efficacy of LA versus GA in patients with severe aortic stenosis undergoing TAVR. METHODS AND RESULTS: We comprehensively searched EMBASE, PubMed, and Web of Science. Effect sizes were summarized using risk ratios (RRs) difference of the mean (DM), and 95% CIs (confidence intervals) for dichotomous and continuous variables respectively. Twenty-six studies and 10,572 patients were included in the meta analysis. The use of LA for TAVR was associated with lower overall 30-day mortality (RR, 0.73; 95% CI, 0.57-0.93; P = 0.01), use of inotropic/vasopressor drugs (RR, 0.45; 95% CI, 0.28-0.72; P < 0.001), hospital length of stay (LOS) (DM, -2.09; 95% CI, -3.02 to -1.16; P < 0.001), intensive care unit LOS (DM, 0.18; 95% CI, -0.31 to -0.04; P = 0.01), procedure time (DM, -25.02; 95% CI, 32.70 to -17.35; P < 0.001); and fluoroscopy time (DM, -1.63; 95% CI, -3.02 to 0.24; P = 0.02). No differences were observed between LA and GA for stroke, cardiovascular mortality, myocardial infarction, permanent pacemaker implantation, acute kidney injury, paravalvular leak, vascular complications, major bleeding, procedural success, conduction abnormalities, and annular rupture. CONCLUSION: Our meta-analysis suggests that use of LA for TAVR is associated with a lower 30-day mortality, shorter procedure time, fluoroscopy time, ICU LOS, hospital length of stay, and reduced need for inotropic support. PMID- 28738448 TI - Editorial: New 1.2 GHz NMR Spectrometers- New Horizons? AB - The latest ultrahigh-field NMR spectrometers are a huge technological challenge that require large financial investments. In his Guest Editorial, Harald Schwalbe justifies the need for spectrometers with higher magnetic field strengths. The important results from previous generations of high-field NMR spectrometers are discussed, and research areas are identified that will benefit from the latest spectrometers. PMID- 28738449 TI - PBPK Modeling of the Effect of Reduced Kidney Function on the Pharmacokinetics of Drugs Excreted Renally by Organic Anion Transporters. AB - Altered pharmacokinetics (PK) in subjects with chronic kidney disease (CKD) may lead to dosing adjustment of certain drugs in subjects with CKD. It can be valuable to quantitatively predict PK in CKD for the management of drug dosing in these subjects. We developed physiologically based pharmacokinetic (PBPK) models of seven renally eliminated drugs: adefovir, avibactam, entecavir, famotidine, ganciclovir, oseltamivir carboxylate, and sitagliptin. These drugs are all substrates of renal organic anion transporters (OATs). Drug models verified using PK data from healthy subjects (HS) were coupled with physiological models representing CKD that incorporated prior knowledge of effects of CKD on hepatic and renal elimination. The models reasonably described clinically observed PK changes in subjects with CKD (compared to subjects with normal renal function), with predicted AUC changes within 50% of the observed changes. PBPK models can be used to prospectively predict PK of renally eliminated OAT substrates in subjects with CKD. PMID- 28738450 TI - The Effect of Pressure on Organic Reactions in Fluids-a New Theoretical Perspective. AB - This Review brings a new perspective to the study of chemical reactions in compressed fluid media. We begin by reviewing the substantial insight gained from more than 50 years of experimental studies on organic reactions in solution under pressure. These led to a proper estimation of the critical roles of volume of activation (Delta? V) and reaction volume (DeltaV) in understanding pressure effect on rates and equilibria of organic reactions. A recently developed computational method, the XP-PCM (extreme pressure polarizable continuum model) method, capable of carrying out quantum mechanical calculations of reaction pathways of molecules under pressure, is introduced. A case study of the Diels Alder cycloaddition of cyclopentadiene with ethylene serves, in pedagogical detail, to describe the methodology. We then apply the XP-PCM method to a selection of other pericyclic reactions, including the parent Diels-Alder cycloaddition of butadiene with ethylene, electrocyclic ring-opening of cyclobutene, electrocyclic ring-closing of Z-hexatriene, the [1,5]-H shift in Z pentadiene, and the Cope rearrangement. These serve as examples of some of the most common combinations of Delta? V and DeltaV. Interesting phenomena such as a shift in a transition state along a reaction coordinate, a switch of rate determining step, and the possible turning of a transition state into a stable minimum are revealed by the calculations. A reaction volume profile, the change in the volume of the reacting molecules as the reaction proceeds, emerges as being useful. PMID- 28738451 TI - Psychiatric Co-morbidity in Patients With Irritable Bowel Syndrome at a Tertiary Care Center in Northern India. AB - Background/Aims: Irritable bowel syndrome (IBS) is a chronic psycho-physiological disorder. It is considered to be the most common functional gastrointestinal disorder, and about 50-90% of IBS patients have associated psychiatric co morbidity. We aimed to study psychiatric co-morbidities in patients with IBS visiting a tertiary care center. Methods: This was a cross-sectional case-control study conducted over a duration of one and a half years from January 2014 to July 2015. Patients were selected from the out-patient department of gastroenterology. About 160 patients with IBS who fulfilled the inclusion criteria and who gave written informed consent were selected as study cases. The healthy attendants of cases were selected as controls. A total of 200 controls were selected. Rome-III criteria were used to diagnose IBS. For diagnosing psychiatric disorders, we used the Mini International Neuropsychiatric Interview Schedule Plus. Results: Mean age of our cases and controls was 39.7 +/- 11.4 and 37.7 +/- 9.6 years, respectively. Females outnumbered males in our cases as well as their controls by a ratio of 2:1 approximately. Psychiatric disorders were seen in 84.4% of IBS patients as compared to 41.5% in controls. Major psychiatric disorders seen in our patients were generalized anxiety disorders (30.0%) and depression (28.0%). Conclusions: The majority of patients with IBS who present to a tertiary care center have co-morbid psychiatric disorders. We need to screen these patients for such co-morbidities and develop a holistic approach for better outcome in such cases. PMID- 28738453 TI - [Promoting hepatitis B elimination and laying emphasis on its economics evaluation]. AB - WHO has developed and issued global hepatitis B elimination program. Continuing hepatitis B immunization and conducting community based antiviral treatment for chronic hepatitis B are the most important strategies for hepatitis B elimination. According to the estimation of related cost by WHO, the cost of antiviral therapy would be very high. Great achievement has been made in hepatitis B immunization in China, but the prevalence of chronic hepatitis B is high. Elimination of hepatitis B needs a large amount of public resource, posing serious challenge to public health policy making. Economics research on hepatitis B prevention and treatment can provide evidence and technical support for hepatitis B elimination. In this column "Economic evaluations of hepatitis B" , the related articles in this issue summarize the progress in this research field, which is inspiring and encouraging. PMID- 28738452 TI - Prediction of Delayed Colonic Transit Using Bristol Stool Form and Stool Frequency in Eastern Constipated Patients: A Difference From the West. AB - Background/Aims: The correlation between the Bristol stool form scale (BSFS) and colonic transit time (CTT) has been reported in Western populations. Our study aims to study the relationship between BSFS, stool frequency, and CTT in Eastern patients with chronic constipation. Methods: A total of 144 chronic functional constipation patients underwent colonic transit study by using radio-opaque markers, anorectal manometry, and balloon expulsion test. Stool diary including stool forms and frequency was recorded. Delayed CTT was defined as the retention of more than 20.0% of radio-opaque markers in the colon on day 5. Results: Twenty five patients (17.4%) had delayed colonic transit. Mean 5-day BSFS (OR, 0.51; 95% CI, 0.34-0.79; P = 0.021) and stool frequency (OR, 0.60; 95% CI, 0.44-0.83; P = 0.002) were independently associated with delayed CTT by logistic regression analysis. Mean 5-day BSFS (area under the curve [AUC], 0.73; 95% CI, 0.62-0.84; P < 0.001) and stool frequency (AUC, 0.75; 95% CI, 0.63-0.87; P < 0.001) fairly predicted delayed CTT. The optimal mean 5-day BSFS of <= 3 provided 68.0% sensitivity, 69.7% specificity, and 69.4% accuracy, and the optimal stool frequency <= 2 bowel movements in 5 days provided 64.0% sensitivity, 83.1% specificity, and 84.0% accuracy for predicting delayed CTT. Conclusions: Both stool form and frequency were significantly associated with delayed CTT. Stool frequency <= 2 and BSFS 1-3 rather than BSFS 1-2 that was used in the Westerners could be used as surrogate for delayed CTT in Eastern patients with constipation. PMID- 28738454 TI - [Development of Markov models for economics evaluation of strategies on hepatitis B vaccination and population-based antiviral treatment in China]. AB - Objective: To construct the Markov models to reflect the reality of prevention and treatment interventions against hepatitis B virus (HBV) infection, simulate the natural history of HBV infection in different age groups and provide evidence for the economics evaluations of hepatitis B vaccination and population-based antiviral treatment in China. Methods: According to the theory and techniques of Markov chain, the Markov models of Chinese HBV epidemic were developed based on the national data and related literature both at home and abroad, including the settings of Markov model states, allowable transitions and initial and transition probabilities. The model construction, operation and verification were conducted by using software TreeAge Pro 2015. Results: Several types of Markov models were constructed to describe the disease progression of HBV infection in neonatal period, perinatal period or adulthood, the progression of chronic hepatitis B after antiviral therapy, hepatitis B prevention and control in adults, chronic hepatitis B antiviral treatment and the natural progression of chronic hepatitis B in general population. The model for the newborn was fundamental which included ten states, i.e. susceptiblity to HBV, HBsAg clearance, immune tolerance, immune clearance, low replication, HBeAg negative CHB, compensated cirrhosis, decompensated cirrhosis, hepatocellular carcinoma (HCC) and death. The susceptible state to HBV was excluded in the perinatal period model, and the immune tolerance state was excluded in the adulthood model. The model for general population only included two states, survive and death. Among the 5 types of models, there were 9 initial states assigned with initial probabilities, and 27 states for transition probabilities. The results of model verifications showed that the probability curves were basically consistent with the situation of HBV epidemic in China. Conclusion: The Markov models developed can be used in economics evaluation of hepatitis B vaccination and treatment for the elimination of HBV infection in China though the structures and parameters in the model have uncertainty with dynamic natures. PMID- 28738455 TI - [Cost-effectiveness and affordability of strategy for preventing mother-to-child transmission of hepatitis B in China]. AB - Objective: To evaluate the cost effectiveness of nationwide prevention of mother to child transmission (PMTCT) strategy for hepatitis B, and estimate the willing to pay and budget impacts on the PMTCT. Methods: The decision analytic Markov model for the PMTCT was constructed and a birth cohort of Chinese infants born in 2013 was used to calculate the cost-effectiveness of the PMTCT among them compared with those receiving no intervention. The parameters in the model were obtained from literatures of national surveys or Meta-analysis. The costs, cases of HBV-related diseases and quality-adjusted life-years (QALYs) were obtained from the societal and payer perspectives, respectively. The incremental cost effectiveness ratio (ICER) was used as measures of strategy optimization. One-way and probability sensitivity analysis were performed to explore the uncertainty of the primary results. In addition, cost-effectiveness acceptability curve and cost effectiveness affordability curves were drawn to illustrate the cost effectiveness threshold and financial budget of the PMTCT strategy. Results: The lifetime cost for PMTCT strategy was 4 063.5 yuan (RMB) per carrier, which was 37 829.7 yuan (RMB) lower compared with those receiving no intervention. Due to the strategy, a total of 24.516 1 QALYs per person would be gained, which was higher than that in those receiving no intervention. From societal perspective, the ICER was -59 136.6 yuan (RMB) per additional QALYs gained, indicating that the PMTCT is cost effective. The results were reliable indicated by one-way, multi-way and probability sensitivity analyses. By the CEAC, the willing to pay was much lower than the cost-effectiveness threshold. From the affordability curve of the PMTCT strategy, the annual budget ranged from 590.4 million yuan (RMB) to 688.8 million yuan (RMB), which was lower than the financial ability. Based on the results of cost-effectiveness affordability curves, the higher annual budget was determined, the higher probability of affordability for the PMTCT would be obtained under the same willing to pay state. Only when the annual budget reaches 688.8 million yuan (RMB), the goal of PMTCT would be fully realized. Conclusions: The PMTCT strategy in China was cost effective, and the cost is not beyond the financial budget needed and the willing to pay. The strategy, which is consistent with the global hepatitis B elimination efforts, should be conducted widely in China. PMID- 28738456 TI - [Cost-effectiveness of community-based treatment of chronic hepatitis B in China]. AB - Objective: Since eliminating hepatitis B in China would need considerable public health resources, the economics problem of the strategy of community-based antiviral treatment for chronic hepatitis B (CHB) has become an important issue. The cost-effectiveness and affordability of the strategy were evaluated in this study. Methods: According to the advocacy on eliminating hepatitis B by WHO and the comprehensive protocol of community based prevention of major infectious diseases and the guideline for CHB prevention and treatment in China, the decision analytic Markov model was constructed with the parameters from national surveys or Meta-analysis. A cohort population aged 20-59 years was used as study subjects. The strategy of CHB antiviral treatment was compared with the strategies of hepatitis B vaccination and non-intervention, respectively. The costs and disability-adjusted life years (QALYs) of the strategies were calculated from the societal and payer perspectives. The incremental cost effectiveness ratio (ICER) and the cost-effectiveness ratio (CER) were calculated for the comparison of the strategies. One-way and probability sensitivity analysis were performed for uncertainty of the results. And the cost effectiveness and affordability curves were introduced to estimate the budget impact on the strategies. Results: In the Chinese aged 20-59 years, the ICER of CHB antiviral treatment was 37 598.6 yuan (RMB) per QALYs and the ICERs were smaller in the low age groups, indicating that the antiviral treatment strategy is cost-effective and low age groups should be the priority population. The ICER of hepatitis B vaccination was -64 000.0 yuan (RMB) per QALYs, indicating that hepatitis B vaccination is cost saving. The CER of CHB antiviral treatment ranged from 731.8 to 1 813.3 yuan (RMB) per QALYs compared with hepatitis B vaccination, and the CER of CHB antiviral treatment was higher than that of hepatitis B vaccination in all age groups, indicating that hepatitis B vaccination would be more cost-effective than CHB antiviral treatment. The price of antiviral drug, entercavir, can influence the cost effectiveness of CHB antiviral treatment. If the price of entercavir declined half, CHB antiviral treatment would be cost saving. The probability sensitivity analysis showed that people's willing to pay for CHB antiviral treatment should not be ignored, although the results of economics evaluation of CHB antiviral treatment were reliable. The results of affordability analysis indicated that the antiviral treatment strategy could not be implemented with the budget lower than 30 million yuan (RMB), the probability of implementing the strategy was 42.6% if the budget reaches 127 million yuan (RMB), and only when the budget reaches 269 million yuan (RMB), the goal of CHB antiviral treatment strategy can be fully realized. Conclusions: Although the strategy of CHB antiviral treatment as prevention in Chinese aged 20-59 years is cost-effective, it is not an appropriate public health measure due to the high cost. The cost effectiveness would be higher by conducting hepatitis B vaccination and then antiviral treatment in susceptible population. PMID- 28738457 TI - [Survey of economic burden of hepatitis B-related diseases in 12 areas in China]. AB - Objective: Less surveys on the economic burden of hepatitis B (HB)-related diseases have been conducted in China, so the socioeconomic harm caused by the diseases is not clear and the key parameters for economic evaluation of hepatitis B prevention and treatment are lacking. This study aimed to analyze the direct, indirect and intangible expenditures of hospitalized patients with HB-related diseases during hospitalization and during a year in different areas of China. Methods: The hospitals for infectious diseases and the large general hospitals in 12 areas in China were selected in the study. All the inpatients with HB-related diseases were surveyed by cluster sampling of consecutive cases. The direct expenditure included direct medical cost and direct non-medical cost. The indirect expenditure, including work loss of patients and caregivers, were calculated by using human capital method for urban and rural populations in 12 areas. The intangible expenditure were reflected by willing to pay and stochastic tournament. The influencing factors of direct and indirect costs were identified by stepwise linear multi-variation regression analysis. Results: A total of 27 hospitals in 12 areas were included in the survey. A total of 4 718 cases were surveyed, the overall response rate was 77.7%. The average hospital stay was 29.2 days (27-34) and the hospitalization expenditure was averagely 16 832.80 yuan (RMB) per case, in which the highest proportion (61.2%) was medicine fees [10 365.10 yuan (RMB)]. The average direct expenditure and indirect expenditure were consistent with the severity of illness, which were 18 336.10 yuan (RMB) and 4 759.60 yuan (RMB) respectively, with the ratio of 3.85 ? 1. The direct medical expenditure [17 434.70 yuan (RMB)] were substantially higher than the direct non medical expenditure [901.40 yuan (RMB)]. It was found that the hospitalization expenses was highest in direct medical expenditure and the transportation expenses was highest in direct non-medical expenditures. Among the average indirect expenditure, the loss of income for the patients [3 832.50 yuan (RMB)] was higher than that for the caregivers [927.20 yuan (RMB)]. The total direct and indirect expenditure was highest for liver transplantation, followed by severe hepatitis, hepatocellular carcinoma and decompensated cirrhosis, acute hepatitis B, compensated cirrhosis and chronic hepatitis B. The influencing factors for both direct and indirect expenditure were high hospital level, severity of hepatitis B, living in urban area, antiviral therapy, long hospitalization and monthly income of family. For average 3.74 outpatient visits and 1.51 hospitalization, the average annual direct, indirect and intangible expenditure for HB-related diseases were 30 135.30, 6 253.80 and 44 729.90 yuan (RMB) [totally 81 119.00 yuan (RMB)], accounting for 37.3%, 7.7% and 55.0%, respectively. Of the annual direct medical expenditure [28 402.80 yuan (RMB)], which were much higher than non-medical expenditure [1 732.50 yuan (RMB)], hospitalization expenditure [26 074.20 yuan (RMB)] was higher than outpatient visit expenditure [4 061.10 yuan (RMB)]. The annual indirect expenditures for outpatient visit and hospitalization were 763.60 and 5 490.10 yuan (RMB), respectively. Of the annual intangible expenditure, the highest was that for primary hepatocellular carcinoma, followed by cirrhosis, chronic hepatitis B, severe hepatitis B, liver transplantation and acute hepatitis B. Conclusions: A heavy economic burden has been caused by HB-related diseases in China, and patients are more likely to rely on medical service rather than non-medical service. It is necessary to take effective treatment measures to prevent the adverse outcome of HB related diseases and achieve significant economic benefits. The influence of HB related diseases on mental health of the people can be reflected by an economics term, intangible expenditure. PMID- 28738458 TI - [Associations between season of birth and age both at menarche and at menopause]. AB - Objective: To examine the associations between season of birth and factors as age at menarche, age at menopause and reproductive span. Methods: A total of 285 186 female from the China Kadoorie Biobank, with complete data on critical variables and had menarche at 9-18 years old, were included. A total of 132 373 female with natural menopause were included for the analysis on age at menopause and reproductive span. Multiple linear regression models were used to assess the associations of birth season and the age at menarche, menopause, and reproductive span. Subgroup analyses were performed on birth cohorts and urban/rural residence. Results: Compared with the Spring-born (March, April, and May), participants who were born in Summer (June, July, and August), Autumn (September, October, and November), and Winter (December, January, and February) appeared late on both age at menarche and menopause. Multivariable-adjusted coefficients (95% CI) appeared as 0.14 (95% CI: 0.13-0.16), 0.26(95% CI: 0.24-0.27), 0.10 (95% CI: 0.08-0.12) for age at menarche respectively and 0.14 (95%CI: 0.08-0.20), 0.18 (95%CI: 0.12-0.24), 0.09 (95%CI: 0.03-0.16) for age at menopause respectively. No statistically significant association was found between the season of birth and reproductive span. The association was consistent between urban and rural residents and across the birth cohorts. Conclusions: female born in spring showed both earlier age on both menarche and menopause, compared to the ones born in other seasons. Our findings suggested that exposures in early life with some degree of seasonal variation might influence the development of female reproductive system. PMID- 28738459 TI - [Gene-gene interaction on central obesity in school-aged children in China]. AB - Objective: To investigate possible effect of 6 obesity-associated SNPs in contribution to central obesity and examine whether there is an interaction in the 6 SNPs in the cause of central obesity in school-aged children in China. Methods: A total of 3 502 school-aged children who were included in Beijing Child and Adolescent Metabolic Syndrome (BCAMS) Study were selected, and based on the age and sex specific waist circumference (WC) standards in the BCAMS study, 1 196 central obese cases and 2 306 controls were identified. Genomic DNA was extracted from peripheral blood white cells using the salt fractionation method. A total of 6 single nucleotide polymorphisms (FTO rs9939609, MC4R rs17782313, BDNF rs6265, PCSK1 rs6235, SH2B1 rs4788102, and CSK rs1378942) were genotyped by TaqMan allelic discrimination assays with the GeneAmp 7900 sequence detection system (Applied Biosystems, Foster City, CA, USA). Logistic regression model was used to investigate the association between 6 SNPs and central obesity. Gene-gene interactions among 6 polymorphic loci were analyzed by using the Generalized Multifactor Dimensionality Reduction (GMDR) method, and then logistic regression model was constructed to confirm the best combination of loci identified in the GMDR. Results: After adjusting gender, age, Tanner stage, physical activity and family history of obesity, the FTO rs9939609-A, MC4R rs17782313-C and BDNF rs6265 G alleles were associated with central obesity under additive genetic model (OR=1.24, 95%CI: 1.06-1.45, P=0.008; OR=1.26, 95%CI: 1.11-1.43, P=2.98*10(-4); OR=1.18, 95% CI: 1.06-1.32, P=0.003). GMDR analysis showed a significant gene gene interaction between MC4R rs17782313 and BDNF rs6265 (P=0.001). The best two locus combination showed the cross-validation consistency of 10/10 and testing accuracy of 0.539. This interaction showed the maximum consistency and minimum prediction error among all gene-gene interaction models evaluated. Moreover, the combination of MC4R rs17782313-C and BDNF rs6265-G was associated with an increased risk of central obesity after adjustment for gender, age, Tanner stage, physical activity and family history of obesity. Conclusions: Our study showed that FTO rs9939609-A, MC4R rs17782313-C and BDNF rs6265-G alleles were associated with central obesity, and statistical interaction between MC4R rs17782313-C and BDNF rs6265-G increased risk of central obesity in school-aged children in China. PMID- 28738460 TI - [Association between sleep and leukocyte telomere length in middle-aged and older adults]. AB - Objective: To understand the association between peripheral leukocytes telomere length (TL) and sleep in middle-aged and old adults. Methods: A total of 176 middle-aged and old adults were investigated by using the Pittsburgh Sleep Quality Index and questionnaire. TL was measured by fluorescence quantitative PCR. The correlation and regression analysis between sleep and telomere length was performed. Results: TL had a mean T/S ratio of 0.995+/-0.23. There was a negative correlation between TL and age (r=-0.241, P=0.003). With increasing age, sleep quality became worse (r=-0.230, P<0.01), the time to fall asleep became longer (r=0.227, P<0.01), sleep duration was shorter (r=-0.486, P<0.01), sleep efficiency became worse (r=-0.226, P<0.01). After controlling for the effects of gender, age, marital status, income level, residence, smoking, drinking, physical exercise and disease status, multiple linear regression analysis indicated that sleep quality (beta=0.057, P<0.01), time to fall asleep (beta=-0.046, P<0.01), sleep duration (beta=0.086, P<0.01) were independent influencing factors of telomere length, suggesting that the people who had better sleep quality, the shorter time to fall asleep, the longer sleep time would have longer telomere length. Conclusions: Sleep is a relevant factor affecting TL in middle-aged and elderly population. Good sleep may delay aging by slowing TL. We encourage to conduct health education about the importance of sleep quality in community. PMID- 28738461 TI - [Role of maternal drug use and environmental exposure during pregnancy and delivery pattern in allergic infants and toddlers]. AB - Objective: To understand correlation between maternal drug use and environmental exposure during pregnancy and delivery pattern and allergy in infants and toddlers, and provide theoretical bases for the early prevention and intervention of infantile allergies. Methods: Case control study based on cross-sectional investigation was conducted. Thirty-three cities were selected in China. Randomly cluster sampling method was used to select a community in each city as the study sample, the women with infants aged 0-24 months were interviewed in the form of face-to-face questionnaire survey. Infants and toddlers were divided into two groups: case group, including 2 113 children who had allergic symptoms and were diagnosed with allergic disease, and control group, including 6 303 children who never had symptoms of allergic disease. Results: Children whose parents had allergic disease histories were more likely to have allergic disease (OR=3.950) compared with the children whose mother or father had allergic disease histories (OR=2.277). Maternal use of antibiotics (OR=1.396), disinfector exposure (OR=1.386), smoking exposure (OR=1.301) during pregnancy and cesarean delivery (OR=1.255) were risk factors for allergic disease in infants and toddlers, the differences were significant (P<0.05). Conclusion: It is essential to conduct primary prevention of infant allergy during pregnancy, and it is necessary to avoid unnecessary cesarean delivery and irrational antibiotic use, disinfector and smoking exposures during pregnancy. PMID- 28738462 TI - [Risk factors of gout in Jinchang cohort: a Cox regression analysis]. AB - Objective: To explore the incidence and risk factors of gout in Jinchang cohort and provide scientific evidence for the prevention and control of gout. Methods: People without gout detected by baseline survey in Jinchang cohort were selected as study subjects. All the subjects were followed up through questionnaire interview, physical examination as well as laboratory test from January 24, 2013 to November 24, 2015. Cox regression model was used to analyze the risk factors for gout in Jinchang cohort. In addition, log-linear model was used to analyze the interaction between risk factors. Results: A total of 33 153 subjects were followed up, and there were 277 newly diagnosed gout cases in the cohort. The overall incidence of gout was 0.8%. The incidence of gout in males was higher than that in the females, but the incidence of gout in males and females was similar after the age of 60 years. Cox regression analysis showed that age >40 years (at age 40 to 59 years: HR=2.982, 95%CI: 1.503-5.981; at age 60 to 91 years: HR=2.588, 95%CI: 1.107-6.049), alcohol abuse (HR=2.234, 95% CI: 1.128 4.427), obesity (HR=2.204, 95% CI: 1.216-3.997), diabetes (HR=2.725, 95% CI: 1.500-4.950) and high uric acid (HR=5.963, 95%CI: 3.577-9.943) were risk factors for gout, while weekly beans intake >=0.25 kg (HR=0.528, 95%CI: 0.345-0.808) and regular physical exercise (HR=0.499, 95% CI: 0.286-0.869) were protective factors for gout. The analysis with log-linear model showed that there were two order effects between the risk factors. Conclusions: Age, beans intake, alcohol abuse, physical exercises, obesity, diabetes and high uric acid were important factors influencing the incidence of gout. It is important to have healthy lifestyle and dietary habits, receive regular health examination to prevent and control the incidence of gout in this cohort. PMID- 28738463 TI - [A cross-sectional study on dyslipidemia in migrants in Inner Mongolia Autonomous Region]. AB - Objective: To investigate the prevalence of dyslipidemia in migrants in Inner Mongolia Autonomous Region. Methods: A stratified multi-stage cluster equal size sampling was performed among the migrants aged >=18 years who were engaged in manufacturing, wholesale retail, accommodation and catering service, social service, construction and other and 1 501 migrants from five area in Inner Mongolia Autonomous Region was investigated by means of questionnaires survey, physical measurements and laboratory detection. Results: Complete data was obtained in 1 496 study subjects. The prevalence of dyslipidemia was 42.65% (638/1 496), the age-standardized prevalence was 42.05%; the prevalence of hypercholesterolemia, hypertriglyceridemia, combined hyperlipidemia and low high density lipoprotein hyperlipidemia were 4.90% (73/1 491), 14.76% (220/1 491), 4.83% (72/1 496), 25.27% (378/1 496), respectively. Dyslipidemia characterized by high triglyceride (HTG) and low high-density lipoprotein cholesterol (LHDL-C) accounted for 81.97% (523/638). The prevalence of dyslipidemia and HTG/LHDL-C dyslipidemia were similar, which increased significantly with age in both females and males, but was significantly higher in males. The prevalence among migrants with other occupations was highest. The prevalence of HTG/LHDL-C dyslipidemia didn't significantly increase with the duration of migration. However, the prevalence of high TG and dyslipidemia increased significantly with the duration of migration, the prevalence of high TG in age group <45 years showed the same characteristics. Conclusions: The prevalence of dyslipidemia in migrants in Inner Mongolia was high, and the main form was HTG/LHDL-C dyslipidemia. The prevalence in males, the middle aged and aged as well as those with other occupations were high. Migrants with longer duration of migration had higher prevalence of dyslipidemia. PMID- 28738464 TI - [Analysis on risk factors for norovirus outbreaks in Guangdong province, 2008 2015]. AB - Objective: To analyze transmission factors of norovirus outbreaks in Guangdong province during 2008-2015 and provide evidence for the prevention and control of norovirus infection. Methods: Epidemiological analysis was performed on the data of norovirus outbreaks reported in Guangdong from January 1, 2008 to December 31, 2015, which were obtained from the Public Health Emergency Management Information System of Guangdong province. The samples collected from the norovirus outbreaks were detected for norovirus by RT-PCR and the gene sequencing of the positive PCR products were performed. Results: A total of 96 norovirus outbreaks were reported in Guangdong during 2008-2015. Sixteen outbreaks were reported during 2008-2012 and 80 outbreaks were reported during 2013-2015 (83.3%). Eighty-two outbreaks (85.4%) occurred in schools. The infection routes included foodborne transmission in 39 outbreaks (40.6%), person to person transmission in 23 outbreaks (24.0%) and waterborne transmission in 8 outbreaks (7.3%). The gene sequencing results showed that variant GII.4/Sydney2012 was the predominant pathogen for 6 of the 20 outbreaks (30.0%) during 2012-2013. Variant GII.17 was the predominant pathogens for 33 of the 53 outbreaks (62.3%) during 2014-2015. Conclusion: The norovirus outbreaks in Guangdong during 2008-2015 were caused by foodborne and person to person transmissions of two emerging variant: GII.4/Sydney2012 and GII.17. PMID- 28738465 TI - [Influencing factors for non/low-response to hepatitis-B vaccine in infants of HBsAg positive mothers]. AB - Objective: To investigate the influencing factors for non/low-response to hepatitis B vaccine in infants of HBsAg-positive mothers. Methods: A total of 286 HBsAg-positive pregnant women and their infants were recruited from the Third People's Hospital of Taiyuan during July 2011 to January 2013. The infants were immunized with hepatitis B vaccine according to the 0-1-6 month vaccination schedule and followed up for 12 months. The serum HBV DNA level of mothers, neonates and infants were detected by electro chemilum inescence immunoassay kits and fluorescene quantiative polymerase chain rection. Results: Among 286 infants, the rate of non/low-response to hepatitis B vaccine was 18.53% (53/286). Non conditional logistic regression analysis indicated that the mother's HBV DNA level >=1*10(7) copies/ml (OR=2.592, 95%CI: 1.121-5.996) and natural birth (OR=1.932, 95%CI: 1.021-3.654) were the risk factors for non/low-response to hepatitis B vaccine, the risks were 2.592 times and 1.932 times higher compared with the infants whose mothers were HBV DNA negative and the infants whose mothers had cesarean delivery. There was no multiplicative or additive interaction between high HBV DNA load and natural birth (OR=1.055, 95%CI: 0.209 5.321), (RERI=1.617, 95%CI: -4.038-7.272; AP=0.364, 95%CI: -0.527-1.225; SI=1.195, 95%CI: 0.270-13.135). After stratified analysis of mother's HBV DNA level, delivery mode of mothers was not associated with non/low-response of their infants. Conclusion: The mother's load of HBV DNA>=1*10(7) copies/ml might be the factor for non/low-response to hepatitis B vaccine in infants of HBsAg positive mothers. PMID- 28738466 TI - [A large scale cohort study on AIDS in communities in Dali, Yunnan province, 2014 2015]. AB - Objective: To understand HIV incidence in community residents and epidemiological characteristics of newly detected HIV infection cases in Dali, Yunnan province. Methods: A cohort study was conducted among 146 720 community residents who were tested to be HIV negative during 2010-2011, they were followed-up from June 1, 2014 to May 31, 2015. Results: A total of 136 356 community residents received follow up (92.9%). The follow-up time was 0.23-5.40 years (medium: 3.43 years), cumulatively 459 675 person years, and 78 people were found to be HIV positive. The incidence rate of HIV infection was 0.170/1 000 person years. The incidence rate was 0.037/1 000 person years in age group 15-29 years, 0.288/1 000 person years in age group 30-44 years, 0.210/1 000 person years in age group 45-59 years, 0.204/1 000 person years in age >=60 years; 0.213/1 000 person years in males, 0.130/1 000 person years in females; 0.248/1 000 person years in Han ethnic group, 0.149/1 000 person years in Minorities; 0.194/1 000 in people with education level <= junior middle school, 0.046/1 000 person years in people with education level > junior middle school; 0.070/1 000 person years in the unmarried, 0.194/1 000 person years in the married and 0.425/1 000 person years in the divorced/widowed. Cox proportional hazards regression analysis showed that being male (HR=1.731), aged 30-44 years (HR=13.158), aged 45-59 years (HR=10.329), aged >=60 years (HR=8.291), unmarried (HR=3.162) and divorced/widowed (HR=2.689) were the risk factors for HIV infection, while the education level > junior middle school (HR=0.132) was the protective factor for HIV infection. Conclusions: By medium 3.43 years follow up, the cohort study showed that incidence rate HIV infection was 0.170/1 000 person years in the community residents in Dali. Male, middle aged and old people, people with low education level, the unmarried and the divorced/widowed had relatively higher risk to be infected with HIV, Close attention should be paid to the prevention and control of AIDS in these populations. PMID- 28738468 TI - [Analysis on spatial distribution of tuberculosis in China, 2012-2014]. AB - Objective: To analyze the spatial distribution of the incidence of tuberculosis (TB) in China from 2012 to 2014 and provide evidence for the prevention and control of TB. Methods: The database of TB in China from 2012 to 2014 was established by using geographical information system, the spatial distribution map was drawn, trend analysis and spatial autocorrelation analysis were conducted to explore the spatial distribution pattern of TB and identify hot areas. Results: The trend surface analysis showed that the incidence of TB decreased gradually from the west to the east in China, and the U type curve could reflect the TB distribution from the south to the north; Global spatial autocorrelation analysis showed the 2012-2014 global Moran's I were 0.366, 0.364 and 0.358 (P<0.01), suggesting that the incidence of TB had a spatial clustering in China; Local Getis-OrdG(i) spatial autocorrelation analysis by ArcGIS software showed that there was 11 cluster areas, 3 high incidence areas (Xinjiang, Tibet, Qinghai) and 8 low incidence areas (Beijing, Tianjin, Shanghai, Hebei, Inner Mongolia, Shanxi, Shandong, Jiangsu). Conclusion: The incidence of TB had obviously spatial clustering characteristic, the areas at high risk were mainly in the northwestern and plateau area in China. PMID- 28738467 TI - [Epidemiological survey of prevalence of HIV infection, syphilis and hepatitis C in female sex workers and other 6 risk populations in Tibet Autonomous Region]. AB - Objective: To understand the prevalence of HIV infection, syphilis and hepatitis C and related behavioral factors in female sex workers (FSWs) and other 6 risk populations in Tibet Autonomous Region. Methods: A cross-sectional survey was conducted among 2 000 FSWs, 200 men who have sex with men (MSM), 200 drug users, 1 200 male migrants, 5 600 young students, as well as hospital patients and pregnant women in Lhasa, Qamdo, Nyingchi, Xigaze Shannan, Ali and Nagqum from June to December 2015. Face to face interviews were conducted to collect their demographic and behavioral information, and blood samples were collected for the tests of HIV, syphilis and hepatitis C virus (HCV) antibodies. The enumeration data were described by using rate and constituent. Results: A total of 20 597 participants were involved in cross-sectional survey. The positive rates of HIV and syphilis antibodies were 5.81%(124/2 133) and 0.05% (1/2 133) respectively among FSWs. The positive rates of HIV and syphilis antibodies were the same (9.80%,10/102) among MSM. There were no HIV infection detected in among drug users, male migrants and young students, but the positive rates of syphilis antibody were 4.00%(4/100), 0.33%(4/1 297) and 0.08%(4/5 095) respectively. The positive rates of HIV and syphilis antibodies were 0.04%(2/5 565) and 1.64%(91/5 565) among hospital patients. The positive rates of HIV and syphilis antibodies were 0.11%(7/6 305) and 1.19%(75/6 305)among pregnant women. The positive rates of HCV antibody were 1.00% (1/100) among drug users and less than 0.50% in other risk populations. The overall consistent condom use rate was low. Conclusions: In Tibet, HIV infection mainly occurred in the MSM, syphilis mainly occurred in FSWs and MSM, HCV infection mainly occurred in drug users. The AIDS related knowledge awareness rate was low in these risk populations, and less of them received intervention service. PMID- 28738469 TI - [Analysis on geographic distribution of high blood pressure prevalence in children and adolescents aged 7-18 years in China, 2014]. AB - Objective: To understand and evaluate the characteristics of geographic distribution of high blood pressure prevalence in children and adolescents aged 7 18 years in China in 2014, and provide evidence for the prevention of hypertension in children and adolescents. Methods: The data of 2014 Chinese National Surveys on Students Constitution and Health conducting 31 provinces (except Hong Kong, Macao and Taiwan) were collected. A total of 216 299 children and adolescents who had complete blood pressure records were selected as study subjects. The low, middle and high prevalence areas were identified according to their high blood pressure detection rates in the children and adolescents,<4%, 4% 7% and >7%, to analyze the geographic distribution of high blood pressure prevalence in the children and adolescents. The environmental data in the capitals of 31 provinces in 2014 were collected to analyze the correlation between environmental factors and blood pressure Z score in the children and adolescents. Results: The average detection rates of high blood pressure was 6.4% in 31 provinces (1.5%-14.2%). The high prevalence areas were mainly distributed in the eastern China, especially the Circum-Bohai sea area, low prevalence areas were mainly distributed in the central and western areas of China and some provinces in the east. Correlation analysis results showed that the annual average temperature, annual average air humidity and local altitude were negatively correlated with blood pressure Z score, including diastolic and systolic blood pressure, in both boys and girls. The annual average sunshine time, PM(2.5) and PM(10) concentrations, content of SO(2) were positively correlated with blood pressure Z score in both boys and girls. Conclusions: There was a significant difference in high blood pressure of children and adolescents among 31 provinces. More attention should be paid to the children and adolescents living high prevalence area. And it is necessary to understand environmental factors which can affect the blood pressure of children and adolescents. PMID- 28738470 TI - [Prevalence of hypercholesterolemia and influence factors in residents aged 18-65 years in Beijing]. AB - Objective: To understand the prevalence of hypercholesterolemia and related risk factors in residents aged 18-65 years in Beijing and provide scientific evidence for the prevention and control of hypercholesterolemia. Methods: The data were collected from Beijing Non-communicable and Chronic Disease Survey and stratified cluster sampling method was used to select study subjects, and questionnaire investigation, physical measurement and laboratory examination were conducted to collect information. Results: The prevalence of hypercholesterolemia and borderline hypercholesterolemia was 6.26% and 21.34% respectively in 17 662 residents surveyed, the average total cholesterol level was (4.69+/-0.95) mmol/L. The prevalence of hypercholesterolemia was 6.33% in men and 6.20% in women, the difference was not significant (Z=1.64, P=0.10). The prevalence was higher inurban area than in suburb (6.73% vs. 5.59%; Z=-7.27, P<0.01). The prevalence of hypercholesterolemia increased with age (trend chi(2)=308.85, P<0.01). The trend was observed in men (trend chi(2)=81.65, P<0.01), in women (trend chi(2)=318.04, P<0.01), in urban area (trend chi(2)=201.77, P<0.01) and in suburb (trend chi(2)=114.65, P<0.01). Multiple logistic regression showed age, being female (OR=1.23, 95%CI: 1.04-1.45), overweight (OR=1.56, 95%CI: 1.34-1.81), obesity (OR=1.82, 95%CI: 1.54-2.16), smoking (OR=1.24, 95%CI: 1.03-1.50), alcohol use (OR=1.40, 95%CI: 1.12-1.75), beef and mutton intake >1 time per week (OR=1.19, 95%CI: 1.02-1.39) were risk factors. Conclusion: The prevalence of hypercholesterolemia in Beijing was lower than national level, and age, gender, location, BMI, smoking, alcohol use, beef and mutton intake were main influencing factors. PMID- 28738471 TI - [Association between phage-mediated shiga toxin and molecular distribution of CRISPR in Escherichia coli O26 ? H11 or NM]. AB - Objective: To investigate the association between phage-mediated shiga toxin and molecular distribution of CRISPR in Escherichia (E.) coli O26?H11 or NM. Methods: A total of 135 E. coli O26 ? H11 or NM strains were collected from NCBI database. Software CRT and CRISPR Finder were used to extract CRISPR and Excel was used to assign the spacer of unique number and type CRISPR. And the relationship between CRISPR and stx phage was analyzed. Results: All the 135 E. coli O26 ? H11 or NM strains had the CRISPR. For CRISPR1, CRISPR2.1, CRISPR2.2 and CRISPR3-4, 19, 22, 1 and 1 subtypes were found, respectively. According to the four CRISPR sites, the strains could be divided into 40 subtypes. Stx-phage was only observed in the group C of CRISPR. Compared with E. coli of stx-phage negative, E. coli with stx phage harbored more spacers. Conclusions: CRISPR loci was extensively existed in E. coli O26?H11 or NM, and many subtypes were found in these strains. The presence of stx-phage was related to the molecular distribution of CRISPR in E. coli O26?H11 or NM. CRISPR might be a valuable biomarker to identify strains with high virulent potential. PMID- 28738472 TI - [Effect of interleukin-6 and interleukin-12 on immune response to hepatitis B vaccination in infants of HBsAg-positive mothers]. AB - Objective: To explore the effect of interleukin-6 (IL-6) and Interleukin-12 (IL 12) on immune response to hepatitis B vaccination in infants of HBsAg-positive mothers. Methods: A total of 91 neonates whose mothers were HBsAg-positive were included and followed up for 12 months. HBV DNA and HBV serological markers in the peripheral blood of the neonates and infants were detected with fluorescence quantitative polymerase chain reaction (FQ-PCR) and chemiluminescence immunoassay (CLIA), and the levels of IL-6 and IL-12 in the peripheral blood of the neonates and infants were detected with enzyme-linked immunosorbent assay (ELISA). Results: The non-/hypo-response rate to hepatitis B vaccination was 35.16% (32/91) in the 91 infants. In the neonatal period and infantile period, the level of IL-6 in non-/hypo-response group was lower than that in high-response group, while the level of IL-12 was higher than that in high-response group, and there was significant difference (P<0.01). From the neonatal period to the infantile period, the level of IL-6 increased, while the level of IL-12 descended in both groups, and there was significant difference (P<0.01). Furthermore, the level of anti-HBs of infants was positively correlated with the level of IL-6 (r(s)=0.70, 0.79, P<0.01), and was negatively correlated with the level of IL-12 (r(s)=-0.71, -0.72, P<0.01) in the neonatal period and the infantile period. From the neonatal period to the infantile period, the increased level of IL-6 was positively associated with the level of anti-HBs (r(s)= -0.74, P<0.01), while the decreased level of IL-12 was negatively associated with the level of anti-HBs (r(s)=-0.42, P<0.01). The level of IL-6 was negatively correlated with the level of IL-12 in the neonatal period and the infantile period (r(s)=-0.68, -0.70, P<0.01). Conclusions: IL-6 might promote the immune response to hepatitis B vaccination in infants whose mothers were HBsAg-positive, while IL-12 might inhibit the immune response. IL-6 and IL-12 would affect the immune response to hepatitis B vaccination in infants of HBsAg-positive mothers at the same time. PMID- 28738473 TI - [HOOF genotyping characteristics of Brucella melitensis strains isolated in Ulanqab of Inner Mongolia Autonomous Region]. AB - Objective: To investigate the HOOF genotyping characteristics of 83 Brucella (B.) melitensis strains isolated in Ulanqab of Inner Mongolia Autonomous Region from 2012 to 2015. Methods: A total of 83 B. melitensis strains were detected by convention identification and AMOS-PCR, then HOOF protocol with eight VNTR locus were used for the genotyping of the strains, and the allelic diversity of each VNTR locus and the discriminatory power of VNTR typing of HOOF were assessed by Hunter-Gaston Discriminatory index. BioNumerics 5.0 was used for phylogenetic analysis and constructing dendrogram. Results: All of the isolates were identified as B. melitensis strains by two identification methods. The complete eight VNTR locus had higher polymophism and diversity index was 0.998; and diversity index of six locus (1, 2 and 4-7) were >=0.678, discriminatory power of HOOF was mainly from this six higher diversity index locus. The 83 B. melitensis strains were classified into eight clusters and 76 genotypes, 6 shared genotypes included 13 isolates, indicating that these brucellosis cases had epidemiological link, the other 70 strains had distinct genotypes, indicating that these cases had no epidemiological link. Conclusions: The epidemic of human brucellosis in Ulanqab was characterized by local and sporadic outbreaks. Cross infection was related with the transfer of the sources of infection. PMID- 28738474 TI - [HIV-1 drug resistance transmission threshold survey in Dehong prefecture of Yunnan province, 2015]. AB - Objective: To study the HIV-1 drug resistance transmission level in HIV infected persons receiving no antiviral therapy in Dehong prefecture of Yunnan province in 2015. Methods: A total of 72 plasma samples were collected from recently reported HIV-infected persons aged 16-25 years in Dehong from January to July 2015 for drug resistance gene detection. Results: Forty eight samples were successfully sequenced and analyzed. Among them, 31.2% (15/48) were from Chinese, and 68.8% (33/48) were from Burmese. Based on pol sequences, HIV genotypes included URF (52.08%, 25/48), CRF01_AE (16.67%, 8/48), RF07_BC (10.42%, 5/48), subtype B (6.25%, 3/48), subtype C (6.25%, 3/48), CRF57_BC (6.25%, 3/48) and CRF08_BC (2.08%, 1/48). One drug resistant mutation site to non-nucleoside analog reverse transcriptase inhibitor (NNRTI) and two drug resistant mutation site to nucleoside analog reverse transcriptase inhibitor (NRTI) were detected in four sequences. Based on the statistical method of HIV drug resistance threshold survey, the prevalence of HIV-1 drug resistant strain was 5%-15%. Conclusions: The proportion of Burmese among newly reported HIV-infected individuals aged 16 25 years in Dehong in 2015 was higher. HIV-1 genetic diversity was found in Dehong. The prevalence of HIV-1 drug resistant strain had reached a moderate level in Dehong. PMID- 28738475 TI - [Trend of caesarean section rate and puerpera characteristics: based on Robson classification]. AB - Objective: To analyze the trend in caesarean section rate and puerpera characteristics in hospital, and provide valuable information for maternal and child health policy making and clinical practice. Methods: A total of 12 041 women who delivered in the affiliated Chaohu Hospital of Anhui Medical University from October 1, 2010 to September 30, 2016 were selected. Based on Robson classification system, changes in the rate of caesarean delivery as well as its relationship with two-child policy and infant sex ratio were analyzed. Results: The overall caesarean section rate gradually decreased from 66.9% to 44.2% during the past six years. Respectively, the caesarean section rate in primiparae with singleton term babies decreased to 32.1% and the rate in multiparas without uterine scar decreased to 14.2%, and the rate in premature delivery decreased to 22.9%, the differences were significant (P<0.01). The proportion of vaginal delivery (R1, R3), multiparas with uterine scar (R5) and twins pregnancy (R8) increased. the differences were significant (P<0.01). The annual overall newly born sex ratio ranged from 110?100 to 128?100. In group R1, more babies were girls, the proportion was stable, more women with premature delivery and multiparas had boy babies, but the boy babies by multiparas without uterine scar obviously decreased in the last 2 years. Conclusions: Primiparae with singleton head birth, multipara without uterine scar and women with premature deliveries are the key population in the effort of reduction of caesarean section rate. The caesarean section rate and proportion were unstable in multiparas with uterine scar, breech deliveries and twin deliveries. The application of Robson classification system can improve the comparability of the surveillance data. PMID- 28738477 TI - [Meta-analysis on influence of psychological nursing on quality of life of AIDS patients]. AB - Objective: To evaluate the effect of psychological nursing intervention on the quality of life of AIDS patients. Methods: The experimental studies about the influence of psychological nursing intervention on the quality of life of AIDS patients were systematically retrieved in the following databases: PubMed, Web of Science, Cochrane Library, Chinese biomedical literature database (CBM), China journal full text database (CNKI), Wanfang database and VIP Chinese science and technology periodical database (VIP). The SF-36 scale scores in 8 dimensions were combined with Review Manager 5.3, the weighted mean difference and 95% CI of the value of the combined effects were calculated. Results: In addition to the dimension of physiological function, the differences in weighted mean of the remaining seven dimensions of SF-36 scales were significant, among which the average score of physiological function increased to 6.48, but the average score of emotional function increased up to 19.90. It can be considered that in addition to the dimension of physiological function, the score of the other dimensions were improved after the psychological nursing intervention. The results of sensitivity analysis showed that the differences in weighted means of the eight dimensions of SF-36 scale were significant, indicating that the quality of life of the observation group was higher than that of the control group. Conclusion: Psychological nursing intervention can improve the quality of life of AIDS patients, and it is suggested to use it in clinical practice. PMID- 28738476 TI - [Relationship between risk factors of liver cancer and onset age in Ningxia Hui Autonomous Region]. AB - Objective: To investigate the clinical data of patients with hepatocellular carcinoma in Ningxia Hui Autonomous Region through questionnaire survey, explore the association between the risk factors of liver cancer and the onset age of disease in this area and provide evidence for prevention and treatment of liver diseases. Methods: A retrospectively analysis was conducted in 250 patients with primary hepatocellular carcinoma by using their clinical data collected through questionnaire survey to understand the relationship between gender, smoking, alcohol use, hypertension, diabetes mellitus, hyperlipidemia, family history of liver cancer, liver cirrhosis, HBV infection, eating fish history and other factors and the incidence of hepatocellular carcinoma by univariate and logistic multivariate regression models. Results: Univariate regression analysis showed that hypertension, diabetes mellitus, hyperlipidemia and family history of liver cancer, HBV infection, cirrhosis, smoking, eating fish history were risk factors for the early onset of liver cancer, t=4.150, P<0.05; t=3.752, P<0.05; t=5.676, P<0.05; t=9.731, P<0.05; t=15.824, P<0.001; t=5.724, P<0.05; t=11.662, P<0.01; t=4.472, P<0.05, respectively, but logistic multivariate regression model analysis indicated that smoking, HBV infection were independent risk factors, OR=3.211(95%CI:1.134-4.642), OR=7.31(95%CI: 4.312-21.072). Conclusions: The risk factors affecting the age of liver cancer onset vary with area diet pattern alcohol use did not influenced the age of liver cancer onset, but smoking and HBV infection were the independent risk factors for early onset of liver cancer. It is necessary to strengthen the HBV infection prevention and control and advise people to quit smoking. PMID- 28738478 TI - [Less common variants association study and statistical analysis]. AB - In the past decade, based on the "common disease-common variant" hypothesis, genomewide association studies (GWAS) have been extensively used to dissect the genetic components of complex diseases and quantitative traits. However, the identified disease-associated common variants by GWASs can only explain small part of the corresponding disease heritability. "Common disease-rare variant" hypothesis has been proposed to explore the missed heritability. With the development of the next generation sequencing technology, various association studies of less common variants are ongoing. This paper provides an overview of the study designs and statistical tests of these variants. PMID- 28738479 TI - [Risk of bias assessment: (1) overview]. AB - This paper reviews the concept of risk of bias, followed by demonstrating why assessment of risk of bias in systematic reviews should be different from that of quality of evidence, methodological quality, reporting quality, precision, and external validity. We also discuss the recent development of tools for risk of bias assessment, the problems with the tools themselves, and the challenges in using these tools. This review may help systematic reviewers understand risk of bias assessment and the use of assessment tools. PMID- 28738480 TI - [Epidemiological study of sleep disorder in the elderly]. AB - As a common health problem in modern society, sleep disorder have a high incidence in the elderly population, which seriously affect the quality of life and physical and mental health of the elderly, and can even aggravate to cause diseases. This review summarizes main research findings in the field of sleep disorder during the past 20 years, describes the sleeping characteristics of elderly, the epidemiological distribution of sleep disorder and possible influencing factors, and finally suggests appropriate measures for the prevention of sleep disorder. PMID- 28738481 TI - [Progress in research of relationship between ambient air PM(2.5) and lung diseases]. AB - Fine Particulate Matter (PM(2.5)-particles with an aerodynamic diameter <=2.5 MUm) can penetrate deeply into the lung, deposit in the alveoli, and consequently impair lung function. Both short term and long term exposures to PM(2.5) are associated with the incidence of respiratory diseases (e.g. asthma, chronic obstructive pulmonary disease, lung cancer). This paper summarizes the effects of ambient air PM(2.5) exposure on human respiratory system revealed by epidemiological studies. PMID- 28738482 TI - [Viewpoint on treatment strategy choice for patientswith unprotected left main coronary artery lesion]. PMID- 28738483 TI - [Outcome analysis of patients undergoing percutaneous coronary intervention with or without prior coronary artery bypass grafting operation]. AB - Objective: To investigate the impact of previous coronary artery bypass grafting(CABG) on long-term outcomes in patients undergoing percutaneous coronary intervention(PCI). Methods: A total of 10 724 consecutive coronary heart disease patients undergoing PCI between January and December 2013 in Fuwai hospital were prospectively included in this research. According to CABG history, the patients were divided into CABG group(437 cases) and without CABG group(10 287 cases). The patients were followed up for 2 years. Major adverse cardiovascular and cerebrovascular events(MACCE) including death, myocardial infarction, revascularization and stroke, and in-stent thrombosis following PCI were compared between the 2 groups. Multivariate Cox regression analysis was used to identify independent risk factors of poor prognosis. Results: Compared with without CABG group, CABG group were older((61+/-10)years vs.(58+/-10)years, P<0.001), and more often had diabetes(35.7%(156/437) vs. 30.0%(3 082/10 287), P=0.012), hyperlipoidemia(73.9%(323/437) vs. 67.0%(6 888/10 287), P=0.003), previous myocardial infarction(31.1%(136/437) vs. 18.7%(1 925/10 287), P<0.001), PCI history(61.6%(269/437) vs. 23.0%(2 371/10 287), P<0.001), and cerebrovascular disease(7.1%(31/437) vs. 10.9%(1 119/10 287), P=0.013). After 2 years follow-up, rates of cardiac death(1.8%(8/437) vs. 0.6%(66/10 287), P=0.010), revascularization(11.2%(49/437) vs. 8.5%(877/10 287), P=0.049) and MACCE(15.1%(66/437) vs. 12.0%(1 231/10 287), P=0.049) were significantly higher in CABG patients than in without CABG group. There were no significant difference in all cause death(2.1%(9/437) vs. 1.2%(122/10 287), P=0.114), recurrence of myocardial infarction(2.3%(10/437) vs. 2.0%(204/10 287), P=0.600), stroke(1.1%(5/437) vs. 1.4%(140/10 287), P=0.701), and in-stent thrombosis(1.1%(5/437) vs. 0.6%(61/10 287), P=0.194). Multivariate Cox regression analysis showed that previous CABG was an independent risk factor of cardiac death(HR=2.13, 95%CI 1.02-4.46, P=0.045)and revascularization(HR=1.35, 95%CI 1.01 1.81, P=0.040). However, after propensity score matched analyses(429 pairs), previous CABG was no longer an independent risk factor of cardiac mortality (HR=0.97, 95% CI 0.37-2.54, P=0.954)and revascularization(HR=1.74, 95%CI 0.94 3.21, P=0.753). Conclusion: Previous CABG is not an independent risk factor of poor prognosis in coronary heart disease patients undergoing PCI. PMID- 28738484 TI - [Correlation between serum inflammatory cytokine levels and fibrous cap thickness of fibrofatty plaque in coronary culprit lesions]. AB - Objective: To identify the correlation between serum inflammatory cytokine levels including high sensitive C reactive protein (hs-CRP) and lipoprotein associated phospholipase (Lp-PLA2) and the fibrous cap thickness of fibrofatty plaque in coronary culprit lesions. Methods: Clinical data of 117 patients with selective coronary artery angiography diagnosed coronary artery disease admitted to our hospital from January 2015 to January 2016 were retrospective analyzed. According to type of coronary disease, patients were divided into 3 subgroups: SAP group (containing 47 stable angina patients), UAP group (containing 52 unstable angina patients), and NSTEMI group(containing 18 acute non ST segment elevation myocardial infarction patients). Serum hs-CRP and Lp-PLA2 levels were measured before subsequent procedures. The characteristics of the culprit lesions were detected by optical coherence tomogarpgy(OCT) before interventional treatment, and the correlation between hs-CRP and Lp-PLA2 and the fibrous cap thickness of fibrofatty plaque in coronary culprit lesions were analyzed. Results: (1) The serum levels of hs-CRP (2.13(1.04, 4.75)MUg/L vs. 1.02(0.60, 1.29)MUg/L and 1.30(1.03, 1.96)MUg/L, all P<0.05) and Lp-PLA2 ((394.8+/-61.4)mg/L vs. (140.1+/ 40.4)mg/L and (284.5+/-93.6)mg/L, all P<0.05) were significantly higher in NSTEMI group than in SAP group and UAP group, and serum levels of hs-CRP and Lp-PLA2 were significantly higher in UAP group than in SAP group (all P<0.05). (2)The fibrous cap thickness of fibrofatty plaque in coronary culprit lesions were smaller in NSTEMI group and UAP group than in SAP group(50(50, 60)MUm and 60(50, 90)MUm vs. 130(80, 190)MUm, all P<0.05), and there was no significantly difference between NSTEMI group and UAP group(P>0.05). Proportion of thin-cap fibroatheroma plaque(82.35%(14/18) vs. 19.15%(9/47) and 63.46%(33/52), all P<0.05), plaque rupture(55.56%(10/18)vs. 6.38%(3/47) and 28.85%(15/52), all P<0.05) and thrombosis(33.33%(6/18) vs. 4.26%(2/47) and 9.26%(5/52), all P<0.05) were significantly higher in NSTEMI group than in SAP group and UAP group. Proportion of calcifiacation in plaque was lower in NSTEMI group than in SAP group (11.11%(2/18)vs. 42.55%(20/47), P<0.05), and there was no significantly difference between NSTEMI group and UAP group(P>0.05). (3) Pearson correlation analysis showed that serum levels of hs-CRP(r=-0.233, P<0.05) and Lp-PLA2(r= 0.465, P<0.01)were negatively correlated with fibrous cap thickness of fibrofatty plaques. Spearman correlation analysis showed that serum levels of hs-CRP were positively correlated with plaque rupture(r=0.409, P<0.01) and thrombosis (r=0.227, P<0.05), and serum levels of Lp-PLA2 were also positively correlated with plaque rupture(r=0.499, P<0.01) and thrombosis(r=0.263, P<0.01). (4)Multiple logistic regression analysis showed that serum levels of Lp-PLA2 at baseline was independently related to thin-cap fibroatheroma plaque(OR=1.017, P<0.01). Conclusions: The serum levels of hs-CRP and Lp-PLA2 in NSTEMI patients are much higher than that in SAP and UAP patients, higher in UAP patients than in SAP patients. Prevalence of thin-cap fibroatheroma plaque, plaque rupture and thrombosis was significantly higher in the NSTEMI patients, while the prevalence of calcification in plaque is more often in SAP patients. Increased serum levels of Lp-PLA2 are independent risk factor of thin-cap fibroatheroma plaque formation. PMID- 28738486 TI - [Association between collateral circulation and myocardial viability evaluated by cardiac magnetic resonance imaging in patients with coronary artery chronic total occlusion]. AB - Objective: Late gadolinium enhancement(LGE) cardiac magnetic resonance imaging(CMR) was used to evaluate the myocardial viability of chronic total occlusion(CTO) in patients with coronary heart disease and to observe the relationship between collateral circulation and myocardium viability in these patients. Methods: This retrospective study included 40 patients with CTO diagnosed by invasive coronary angiography (CAG) from September 2015 to June 2016 in our department, all patients performed CMR examination within one week after CAG.The collateral circulation of CTO was graded with Rentrop classification as follows: poor or no collateral circulation group, moderate collateral circulation group and good collateral circulation group.According to CMR images, the delayed enhancement transmural extent of myocardial segments were scored, the ventricular wall motion of the myocardial segment were graded, and the wall motion score index (WMSI) was calculated.Spearman correlation analysis was used to analyze the relationship between the delayed enhancement transmural extent of myocardial segments and WMSI. Results: In the no or poor collateral group of 6 myocardial regions, 1 myocardial region had viable myocardium and 3 myocardial regions had no viable myocardium; in the moderate collateral group of 16 myocardial regions, 11 myocardial regions had viable myocardium and 5 myocardial regions had no viable myocardium; in the good collateral group of 24 myocardial regions, 21 myocardial regions had viable myocardium and 3 myocardial regions had no viable myocardium, there was significant difference between the groups (P=0.002). The WMSI of poor or no collateral circulation group, moderate collateral circulation group and good collateral circulation group were 1.54+/-0.50, 1.21+/-0.34 and 1.26+/-0.40, respectively, there was no significant difference between the groups (P=0.063). Spearman correlation analysis showed that the extent of delayed enhancement transmural extent of myocardial segment was significantly associated with WMSI (r=0.638, P<0.01). Conclusion: Collateral circulation in patients with chronic total occlusion can predict myocardial viability.Increase of Rentrop grade is linked with higher possibility of the presence of viable myocardium. PMID- 28738485 TI - [Impact and clinical outcome of intra-aortic balloon pump use during percutaneous coronary intervention]. AB - Objective: To observe the impact and clinical outcome of intra-aortic balloon pump(IABP) use in patients underwent percutaneous coronary intervention (PCI). Methods: From January 2013 to December 2013, 10 724 consecutive patients undergoing PCI were enrolled.After 2 years' follow-up, the incidence of major adverse cardiovascular and cerebrovascular events such as death, myocardial infarction, stent thrombosis, revascularization, recurrent stroke were recorded, propensity score was used to match baseline data, and the clinical outcomes in patients with IABP and non-IABP were compared. Results: The overall use of IABP was 1.3%(143/10 724), clinical and angiographic risks were significantly higher in IABP group than non-IABP group.The rate of cardiac shock was significantly higher (9.8%(14/143) vs. 0.2%(16/10 581), P<0.01) and left ventricular ejection fraction was significantly lower (54.3%+/-11.0% vs. 62.9%+/-7.2%, P<0.01) in the IABP group than in the non-IABP group.Patients in IABP group had a significantly higher rate of left main or triple-vessel disease (P<0.01), and their SYNTAX score, target lesion number, stent number were also significantly higher compared with non-IABP patients (all P<0.01). During the 2-year follow-up, all-cause mortality was significantly higher in IABP group than in non-IABP group (10.5%(15/142) vs. 1.1%(116/10 581), P<0.001). Multivariable analyses indicated that IABP was associated with increased mortality (HR=3.51, 95%CI 1.71-7.17, P=0.001). However, after propensity score matched analyses (137 pairs), IABP use was no longer an independent predictor of all-cause mortality (HR=2.09, 95%CI 0.72-6.13, P=0.177). Conclusions: In this single large center of coronary heart disease in China, the IABP usage was about 1.3%.Propensity score matched analyses showed that during the 2 years' follow-up, adverse effect including similar long term mortality is similar between PCI patients with or without IABP after adjusting for confounders. PMID- 28738487 TI - [Circadian blood pressure characteristics in hospitalized unstable angina pectoris patients with hypertension]. AB - Objective: To define the characteristic of circadian rhythm of blood pressure in unstable angina pectoris (UAP)patients with hypertension and its effects on the cardiovascular events. Methods: It was a prospective study.Based on coronary angiographic results, 742 consecutive hospitalized UAP patients with hypertension and 89 consecutive hospitalized hypertensive patients were recruited between September 2014 and December 2015 in this study. Clinical data and the results of 24-hour ambulatory blood pressure monitoring (ABPM) were analyzed. Results: The total prevalence of hypertension in UAP is about 77.1%(742/962) in our cohort. The decrease of night-time systolic and diastolic blood pressure in UAP patients complicated with hypertension was lower than that in hypertensive patients (P<0.05). The prevalence of dipper, non-dipper and reverse dipper pattern was 12.4%(92/742), 34.9%(259/742) and 52.7%(391/742) in UAP patients complicated with hypertension, 18.0%(16/89), 48.3%(43/89) and 33.7%(30/89) in hypertensive patients. Obviously, the abnormal circadian rhythm of blood pressure was more significant in UAP patients with hypertension than in hypertensive patients, characterized by higher reverse dipper pattern in UAP patients with hypertension compared to patients with hypertension(P=0.00), similar results were evidenced among the male and female patients and patients with various ages. Subgroup analysis showed that except similar results on the incidence of reverse dipper pattern in controlled blood pressure aged less than 45 years old, the incidence of reverse dipper pattern was all significantly higher in UAP patients complicating with hypertension than in hypertensive patients independent no matter blood pressure controlled or not (all P<0.05). After adjustment for sex, age, triglyceride, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and other risk factors, binary logistic regression analysis showed that reverse dipper pattern was independently associated with UAP(OR=1.53, 95%CI 1.12-2.61). Conclusions: This finding suggests that UAP patients with hypertension often have abnormal circadian rhythm, characterized by higher reverse dipper circadian pattern. Elevated nocturnal blood pressure is independently related to UAP. PMID- 28738488 TI - [Pathological features at autopsy in elderly patients with acute myocardial infarction]. AB - Objective: To analyze the cardiac pathological features of elderly coronary artery disease (CAD) patients (60 years and over) and evaluate the pathological features at autopsy and risk factors of patients with acute myocardial infarction (AMI). Methods: Data from 471 elderly patients (aged from 60 to 100 years old) with CAD confirmed by autopsy hospitalized in our hospital from April 1969 to October 2013 were retrospectively reviewed. Patients were divided into 2 groups: AMI group(n=128) with AMI as the primary cause of death and the rest served as control group(n=343). The pathological features of coronary lesion and related risk factors of AMI were analyzed. Results: In patients aged 60 and over with CAD, 48.8%(230/471) had severe coronary stenosis, 18.7%(88/471) had three-vessel disease, 71.8% cases (338/471) had left anterior descending artery(LAD)grade III and over stenosis, 29.9% (141/471) had LAD grade IV stenosis, 25.9%(122/471) had left main coronary artery(LM) grade III and over stenosis, 9.6%(45/471) had LM grade IV stenosis, 27.1%(128/471) had AMI. The first AMI accounts for 39.1%(50/128), and 60.9%(78/128) had both AMI and old MI. Compared with the control group, AMI group were younger ((77.1+/-11.6) years vs. (83.2+/-9.1) years, P<0.01), had more severe coronary artery stenosis lesion (77.3%(99/128) vs. 38.2%(131/343), P<0.01), higher coronary index which reflects the overall arteriosclerosis (9.9+/-2.8 vs. 8.0+/-2.5, P<0.01), more three-vessel disease (30.3%(43/128) vs. 13.7%(45/343), P<0.01), heavier heart weight ((447.8+/-90.6)g vs. (426.6+/-99.1)g, P<0.05), higher prevlence of pulmonary congestion or edema (57.8%(74/128) vs. 39.9%(137/343), P<0.01). Twenty-three cardiac ruptures (23/128, 18.0%) were observed in AMI group. Logistic regression analysis showed that grade IV LAD stenosis (OR=3.55, 95%CI 2.05-6.17, P<0.01), three-vessel disease(OR=2.47, 95%CI 1.30-4.67, P<0.01) were the independent risk factors of AMI in elderly patients with CAD. Conclusions: Severe coronary stenosis is common in CAD patients aged 60 and over. Patients aged 60 and over with AMI have more severe coronary artery stenosis lesion and heavier heart weight. Cardiac rupture is not uncommon in elderly patients with AMI. Severe LAD stenosis and three vessel disease are the independent risk factors of AMI in the elderly. PMID- 28738489 TI - [Trend analysis on the death rate of ischemic heart disease and cerebrovascular disease among Xuzhou residents from 2011 to 2015]. AB - Objective: To analyze the epidemiological characteristics and trend of ischemic heart disease and cerebrovascular disease mortality among Xuzhou residents from 2011 to 2015. Methods: The mortality data of the ischemic heart disease and cerebrovascular disease were obtained from the registration disease surveillance system covering the residents of the city from 2011 to 2015. Ischemic heart disease and cerebrovascular disease were identified according to the international classification of diseases (ICD-10), Ischemic heart diseases include I20 to I25 (angina pectoris, acute myocardial infarction, certain current complications following acute myocardial infarction, other acute ischemic heart diseases chronic ischemic heart disease); cerebrovascular diseases include I60 to I69 (subarachnoid hemorrhage, intracerebral hemorrhage, other non-traumatic hemorrhage, cerebral infarction, stroke not specified as hemorrhage or infarction, other cerebrovascular diseases, sequelae of cerebrovascular disease). Results: (1)From 2011 to 2015, the chronic ischemia Cardio-Cerebrovascular disease mortality of residents in Xuzhou was 261.2 per one hundred thousand (129 950/49 748 321), 269.9 per one hundred thousand(69 562/25 775 930)for male residents, 252.0 per one hundred thousand(60 388/23 972 391)for female residents, the mortality rate in men was significantly higher than that in women (P<0.05). The chronic ischemic Cardio-Cerebrovascular disease mortality rate of urban residents was 243.8 per one hundred thousand(17 049/6 993 787), which was lower than the rate of rural residents (264.0 per one hundred thousand(112 901/42 754 534), P<0.05). (2)From 2011 to 2015, the mortality rate of ischemic heart disease in Xuzhou city remained unchanged: 117.1 per one hundred thousand(11 416/9 747 768), 126.8 per one hundred thousand(12 177/9 600 745), 112.0 per one hundred thousand(11 184/9 986 877), 115.2 per one hundred thousand(11 697/10 151 842), 117.1 per one hundred thousand(12 019/10 261 089, P>0.05). The mortality rate of cerebrovascular disease were 154.0 per one hundred thousand(15 014/9 747 768), 155.9 per one hundred thousand(14 964/9 600 745), 143.5 per one hundred thousand(14 330/9 986 877), 135.5 per one hundred thousand(13 752/10 151 842), 130.6 per one hundred thousand(13 397/10 261 089)respectively, presented with a downward trend(P<0.05). The mortality rate of ischemic cerebrovascular disease were 62.7 per one hundred thousand(6 108/9 747 768), 74.7 per one hundred thousand(7 176/9 600 745), 72.3 per one hundred thousand(7 221/9 986 877), 70.9 per one hundred thousand(7 200/10 151 842)and 72.4 per one hundred thousand(7 431/10 261 089)respectively(P>0.05). The mortality rate of hemorrhagic cerebrovascular disease were 77.6 per one hundred thousand(7 562/9 747 768), 71.6 per one hundred thousand(6 873/9 600 745), 61.2 per one hundred thousand(6 115/9 986 877), 55.3 per one hundred thousand(5 613/10 151 842)and 46.4 per one hundred thousand(4 763/10 261 089)respectively, presented with a downward trend(P<0.05). (3)The average death age due to ischemic heart diseases of all residents was (77.0+/-13.1)years old, (76.4+/-13.2) years old among urban residents, (77.1+/ 7.1 )years old among rural residents, (74.3+/-13.5)years old for male residents, (80.0+/-12.0) years old for female residents. The average death age due to ischemic cerebrovascular diseases of all residents was (76.4+/-11.9)years old, (76.5+/-12.3) years old among urban residents, (76.4+/-11.9 )years old among rural residents, (74.3+/-12.2)years old among male residents, (79.0+/-11.1) years old among female residents. From 2011 to 2015, the death age due to ischemic heart diseases were (76.3+/-13.5), (77.2+/-13.0), (76.6+/-13.3), (77.1+/ 12.9)and(77.8+/-12.9)years old respectively; the death age due to cerebrovascular disease were (75.8+/-12.1), (76.3+/-11.8), (76.6+/-11.8), (76.6+/-12.0)and(77.1+/ 11.9)years old respectively. The Spearman rank correlation analysis showed that the death age due to ischemic heart disease and cerebrovascular disease increased year by year in the past 5 years. (r value was 0.033 and 0.038, respectively, all P<0.01). Conclusion: From 2011 to 2015, the mortality of hemorrhagic cerebrovascular disease decreased, while the mortality of ischemic cardiovascular and cerebrovascular diseases remained unchanged among Xuzhou residents. PMID- 28738490 TI - [The efficacy and safety of ultrafiltration for patients with heart failure: results from a single-center randomized controlled study]. AB - Objective: To evaluate the efficacy and safety of ultrafiltration in patients with heart failure. Methods: One hundred and thirty four cases of patients with heart failure, who hospitalized in our hospital from June 2010 to June 2016 were enrolled in this study. Random serial number was generated using SPSS 22.0 software, patients were then randomly divided into control group and ultrafiltration group with the proportion of 1?1 (67 cases in each group). Patients in the control group received standard therapy. Patients in the ultrafiltration group received ultrafiltration therapy for 8 hours. Curative effect was evaluated after 8 hours treatment in the control group and after 12 hours in the ultrafiltration group. Following parameters were compared between the two groups: body weight, dyspnea score and 6 minutes walking distance as well as blood pressure, heart rate, Na(+) , K(+) , Cl(-), pH, HCO(3)(-), Hb, PLT, Cr, BUN levels. Results: (1)Two patients died during run-in process and eventually 132 cases were chosen for final analysis (65 cases in control group and 67 cases in the ultrafiltration group). Gender, age, type of heart failure, dyspnea score, body weight at baseline were similar between the two groups. (2)Post therapy, patients' body weight decreased obviously, while dyspnea score and 6 minutes walking distance increased significantly in the ultrafiltration group compared to baseline(all P<0.05), and the improvement was significantly greater compared to control group(all P<0.05). (3)The safety index comparison of two groups: blood pressure, heart rate, Na(+) , K(+) , Cl(-), pH, HCO(3)(-), Hb, PLT, Cr, and BUN were similar between the two groups at baseline and post therapy. Conclusion: Ultrafiltration therapy is safe and effective to treat patients with heart failure. PMID- 28738491 TI - [Establishment of a model of hydrogen peroxide-induced injury in pulmonary artery endothelium cells and relevant mechanisms of oxidative stress]. AB - Objective: To establish a hydrogen peroxide (H(2)O(2)) induced injury model of pulmonary artery endothelial cells (PAECs) and explore the molecular mechanisms of oxidative stress on the structure and function of PAECs in this model. Methods: Human PAECs were treated with H(2)O(2) at different concentrations (25, 50, 100, 200, 400, 800, 1 600, 3 200, 6 400 MUmol/L) for 4 and 24 h, respectively. The PAECs survival curve was obtained according to the cell viability measured by CCK-8 assay. The cell apoptosis of PAECs was detected by flow cytometry. The reactive oxygen species (ROS) generation and mitochondrial activity were measured using small molecule fluorescent probes. Proteins were extracted and the phosphorylation levels of signal molecules in PAECs were detected by Western blot assays. Results: (1) The effect of H(2)O(2) at various concentrations on cell viability of PAECs: cell viability of PAECs decreased in proportion to increasing concentration of H(2)O(2) after incubation for 4 h. The half maximal inhibitory concentration (IC(50)) of PAECs exposed to H(2)O(2) for 4 and 24 h were 397.00 and 488.77 MUmol/L, respectively. (2) The effect of H(2)O(2) on cell apoptosis of PAECs: After H(2)O(2) incubation for 4 h, proportions of PAECs at late-apoptosis ((22.58+/-3.69) %) and necrotic stage( (11.86+/-4.27)%) were significantly higher than those of control PAECs at late-apoptosis stage( (3.41+/-1.44)%, P<0.01) and at necrotic stage ((1.94+/-1.15) % , P<0.05). The survival rate of PAECs post H(2)O(2) was dramatically lower than that of control PAECs ((7.98+/-3.21)% vs. (48.89+/-8.08)%, P<0.01). However, there is no statistical difference between both groups regarding to the early apoptosis. (3) The effect of H(2)O(2) on mitochondrial activity and ROS production of PAECs: the mitochondrial activity and ROS generation of PAECs treated by H(2)O(2) were significantly increased compared to those in control PAECs (P<0.01). (4) The effect of H(2)O(2) on signaling molecules in PAECs: there was a significant increase in phosphorylation level of Akt in PAECs incubated with H(2)O(2) for 30 minutes compared to that in control PAECs (P<0.01), while there was no significant difference in levels of Akt between H(2)O(2) treated PAECs and control PAECs. Phosphorylation level of JNK as well as p38 were also significantly upregulated in H(2)O(2) treated PAECs (P<0.01). Conclusion: H(2)O(2) at the concentration of 400 MUmol/L could induce human PAECs injuries via the regulation of Akt and MAPK signaling pathways. PMID- 28738492 TI - [Percutaneous transluminal septal myocardial ablation by microsphere embolisation for a patient with hypertrophic obstructive cardiomyophthy]. PMID- 28738493 TI - [A case of high impedance inducedby radiofrequency catheter ablation of accessory pathway]. PMID- 28738494 TI - [Congenital absence of left atrial appendage in a patient with paroxysmal ventricular tachycardia and atrial fibrillation]. PMID- 28738495 TI - [Value of hybrid intravascular imaging on the diagnosis and treatment of cardiovascular diseases]. PMID- 28738496 TI - [Progress in the relationship between von Willebrand factor and acute myocardial infarction]. PMID- 28738497 TI - Oeanolic acid protects against the hepatotoxicity of D-galactosame plus endotoxin in mice. AB - Oleanolic acid (OA) is a triterpenoid contained in many herbal medicines. The aim of this study was to investigate the protective effect of OA against D galactosame plus lipopolysaccharides (D-GalN/LPS)-induced acute liver injury and the underling mechanisms. Mice were randomly divided into normal control with vehicles only (corn oil), D-GalN/LPS only (700mg/10MUg/kg, ip), OA-po (200MUmol/kg in corn oil, po) plus D-GalN/LPS, and OA-sc (50MUmol/kg in 2% tween 80, sc) plus D-GalN/LPS groups. OA pretreatment was conducted twice daily for 4 consecutive days. Hepatotoxicity was evaluated by histopathology, serum enzyme activity, hepatic lipid peroxidation and GSH levels. To reveal the possible mechanisms of the protection, mRNA and protein expressions of toxicity-relevant genes and proteins were examined by real-time RT-PCR and western-blot analysis. Both OA-po and OA-sc at therapeutic doses successfully protected liver injury induced by D-GalN/LPS, as evidenced by reduced serum enzyme activities, prevented liver hemorrhage, massive necrosis, and reduced degenerative lesions. OA increased hepatic GSH contents and decreased lipid peroxidation (MDA) levels. Furthermore, OA significantly inhibited the mRNA expression of the tumor necrosis factor-alpha (TNF-alpha) and ER responsive gene Gadd45. D-GalN/LPS-induced activation of p-JNK and NF-kappaB p65, and protein overexpression of caspase-3, caspase-8, and COX2 were significantly suppressed by OA. These results clearly demonstrated OA-po is effective as OA-sc in protecting against D-GalN/LPS-induced liver injury, and the protection mechanisms are related to reduction of oxidative damage, suppression of TNFalpha-triggered signaling through the NF-kB and JNK pathways, thus reducing apoptosis and hepatocellular death. PMID- 28738498 TI - MicroRNA-299-3p suppresses proliferation and invasion by targeting VEGFA in human colon carcinoma. AB - Accumulating evidences have shown that microRNAs (miRNAs) are vital regulators and possess huge capabilities in post-transcriptional control. Although a large number of miRNAs have been identified to be dysregulated in human cancers especially in colon cancer, our understandings of the function of most miRNAs are still largely limited. In this study, we have demonstrated that miR-299-3p plays a critical role in suppressing colon carcinoma progression by targeting Vascular Endothelial Growth Factor A (VEGFA). We observed that miR-299-3p was down regulated in colon carcinoma tissues and colon cancer cell lines. The level of miR-299-3p was significantly negatively correlated with that of VEGFA mRNA level in colon carcinoma. More importantly, the low level of miR-299-3p predicted poor prognosis of colon cancer patients. Functionally, overexpression of miR-299-3p inhibited the proliferation and invasion of colon carcinoma cells and suppressed the growth of colon cancer xenografts in nude mice. Luciferase reporter assays showed that miR-299-3p could target VEGFA 3' UTR. In addition, up-regulation of miR-299-3p decreased VEGFA expression both in vitro and in vivo, showing that miR 299-3p plays a suppressive effect on VEGFA via post-transcriptional control. However, ectopical expression of VEGFA could abrogate this effect and also abolish miR-299-3p-induced inhibition of cell proliferation and invasion. Taken together, our study provides evidences showing that miR-299-3p functions as a suppressor in colon cancer by targeting VEGFA, suggesting that miR-299-3p might serve as a novel target for colon cancer therapy. PMID- 28738499 TI - Aqueous extract of Codium fragile suppressed inflammatory responses in lipopolysaccharide-stimulated RAW264.7 cells and carrageenan-induced rats. AB - Codium fragile (Suringar) Hariot has been used in Oriental medicine for the treatment of enterobiasis, dropsy, and dysuria and has been shown to have various biological effects. In this study, we evaluated the anti-inflammatory effects of aqueous extract of C. fragile (AECF) using in vitro and in vivo models. Nitric oxide (NO), prostaglandin E2 (PGE2), inflammatory-related mRNAs, and proteins were determined using the Griess assay, enzyme-linked immunosorbent assay (ELISA), reverse transcription-polymerase chain reaction (RT-PCR), and western blotting, respectively. Our results indicate that pretreatment of cells with AECF (50, 100 and 200MUg/mL) significantly inhibited LPS-induced secretion of NO and PGE2 in RAW264.7 cells without cytotoxicity. We also found that AECF (100 and 200MUg/mL) inhibited LPS-induced inducible NO synthase (iNOS) and cyclooxygenase (COX)-2 expression in a dose-dependent manner. Additionally, pretreatment of cells with AECF (100 and 200MUg/mL) inhibited LPS-induced production of inflammatory cytokines including tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-6. It also prevented the nuclear translocation of nuclear factor (NF)-kappaB by suppressing the phosphorylation and degradation of inhibitor of NF-kappaB (IkappaB)-alpha. Furthermore, AECF (100 and 200MUg/mL) inhibited the phosphorylation of the mitogen-activated protein kinases (MAPKs) extracellular signal-regulated kinase (ERK) 1/2, c-Jun N-terminal kinase (JNK), and p38. In addition, orally administered 50, 100, and 200mg/kg body weight of AECF dose-dependently suppressed carrageenan-induced rat paw edema thickness by 6%, 31%, and 50% respectively, after 4h. Furthermore, the anti-inflammatory effect was comparable to that observed in animals treated with the standard drug diclofenac sodium (56%) in vivo. Collectively, our results suggest that AECF exerts potential anti-inflammatory effects by suppressing NF-kappaB activation and MAPKs pathways in vitro, as well as inhibiting carrageenan-induced rat paw edema thickness in vivo. These findings indicate that AECF could be further developed as an anti-inflammatory drug. PMID- 28738501 TI - Inhibition of glycogen synthase kinase 3 increased subventricular zone stem cells proliferation. AB - The effects of Wnt signaling modifiers on cell proliferation, seem to be cell specific. Enhancing the proliferation of subventricular zone (SVZ) progenitors has been in the focus of research in recent years. Here we investigate the effect of CHIR99021, a Glycogen Synthase Kinase 3 (GSk-3) inhibitor, on SVZ progenitor's proliferation both in vivo and in vitro. Neural stem cells were extracted from the adult C57bl/6 by mincing and trypsin treatment followed by culturing in specific medium. Sphere cells formed within about 7-10days and were characterized by immunostaining. Number of spheres and their size was assessed following exposure to different concentration of CHIR99021 or vehicle. For in vivo studies, animals received intracerebroventricular (i.c.v.) injection of CHIR99021 or vehicle for four days. A subgroup of animals, after 4days treatment with CHIR99021 received intranasal kainic acid to induce local neurodegeneration in CA3 area of hippocampus. Inhibition of GSk-3 by CHIR99021 increased neural progenitor proliferation and the effect of CHIR99021 was long lasting so that the treated cells showed higher proliferation even after CHIR99021 removal. In vivo administration of CHIR99021 increased the number of neural progenitors at the rims of lateral ventricles especially when the treatment was followed by kainic acid administration which induces neural insult. Results showed that direct administration of CHIR99021 into the culture medium or animal brain increased the number of SVZ progenitors, especially when a neural insult was induced in the hippocampus. PMID- 28738500 TI - MiR-101-3p inhibits the growth and metastasis of non-small cell lung cancer through blocking PI3K/AKT signal pathway by targeting MALAT-1. AB - BACKGROUND: MiR-101-3p is an important tumor suppressor miRNA in many human cancers. This study was to investigate the role of miR-101-3p in the progression of non-small cell lung cancer (NSCLC) and its potential underlying mechanism. METHODS: In this study, the endogenous expression of miR-101-3p or MALAT-1 in cells was modulated by cell transfection assays. The regulatory interaction of miR-101-3p and MALAT-1 was examined by Luciferase reporter gene and RNA pull-down assays. The effect of miR-101-3p or MALAT-1 on NSCLC cells was evaluated by cell proliferation assays, wound-healing assays and transwell invasion assays. The mice tumor model was established to test the role of miR-101-3p and MALAT-1 in the growth and metastasis of NSCLC in vivo. RESULTS: The relative expression of miR-101-3p in NSCLC cells was significantly decreased; while MALAT-1 was significantly increased. Moreover, overexpression of miR-101-3p could significantly inhibit the proliferation, migration and invasion of NSCLC cells in vitro, as well as MALAT-1 expression. Further studies confirmed that miR-101-3p could specifically repress MALAT-1 expression through direct binding; MALAT-1 overexpression completely reversed the miR-101-3p-induced suppression on the viability, migration and invasion of NSCLC cells and MALAT-1 expression. Finally, we confirmed that miR-101-3p could block the MALAT-1-induced activation of PI3K/AKT signal pathway and resulted in the inhibition on the growth and metastasis of NSCLC cells in vivo. CONCLUSION: MiR-101-3p inhibited the growth and metastasis of NSCLC through blocking PI3K/AKT signal pathway by targeting MALAT-1. PMID- 28738502 TI - Formulation and optimization of lacidipine loaded niosomal gel for transdermal delivery: In-vitro characterization and in-vivo activity. AB - The aim of the present research work is to formulate lacidipine (LAC) loaded niosomes formulation for the management of hypertension by thin film hydration technique. The developed formulations were statistically optimized by four factors, three levels Box-Behnken design and were evaluated for vesicle size, entrapment efficiency, and flux. The optimized LAC niosomes was further evaluated for permeation depth by confocal laser scanning microscopy (CLSM) and converted to gel formulation. Further, the optimized LAC niosomes gel was evaluated for ex vivo permeation study, skin irritation study, stability study and pharmacodynamics study. The optimized LAC niosomes formulation showed vesicle size, entrapment efficiency and flux value of 676.98+/-10.92nm, 82.77+/-4.34% and 38.43+/-2.43MUg/cm2/h respectively, with spherical morphology. The comparative CLSM study showed that optimized LAC niosomes formulation has shown maximum permeation (70.75MUm) as compare to LAC liposomes formulation (58.26MUm). The optimized LAC niosomes gel showed skin permeation enhancement of 2.15 times as compare to control gel. Furthermore, in vivo antihypertensive activity showed significantly higher (p<0.001) reduction in blood pressure compared to oral suspension. Indeed, it was found that niosomal vesicles represented to be an efficient nano vesicular carrier for transdermal delivery of lacidipine. PMID- 28738503 TI - Integration of protein extraction with a stream of byproducts from marine macroalgae: A model forms the basis for marine bioeconomy. AB - The present study describes an advanced biorefinery model for marine macroalgae that assumes significant importance in the context of marine bio-economy. The method investigated in this study integrates the extraction of crude proteins with recovery of minerals rich sap, lipids, ulvan and cellulose from fresh biomass of Ulva lactuca. The protein content extracted was 11+/-2.12% on dry weight basis with recovery efficiency of 68.75+/-4.01%. The amino acid composition of crude protein fraction showed iso-leucine as the most abundant amino acid with 16.51+/-0.03% followed by histidine, arginine, tyrosine, serine, aspartic acid, threonine, phenyl alanine, leucine, alanine, lysine, glycine and glutamic acid (0.22+/-0.24%). The digestibility of protein was as high as 85.86+/ 5.92% indicating its suitability for use in food supplements. The protein production with co-recovery of other products would not only result in effective utilisation marine macroalgal resources but also forms the basis for marine bio economy. PMID- 28738504 TI - Prevention of melanin formation during aryl alcohol oxidase production under growth-limited conditions using an Aspergillus nidulans cell factory. AB - An Aspergillus nidulans cell factory was genetically engineered to produce an aryl alcohol oxidase (AAO). The cell factory initiated production of melanin when growth-limited conditions were established using stationary plates and shaken flasks. This phenomenon was more pronounced when the strain was cultured in a trickle bed reactor (TBR). This study investigated different approaches to reduce melanin formation in fungal mycelia and liquid medium in order to increase the enzyme production yield. Removal of copper from the medium recipe reduced melanin formation in agar cultures and increased enzyme activities by 48% in agitated liquid cultures. Copper has been reported as a key element for tyrosinase, an enzyme responsible for melanin production. Ascorbic acid (0.44g/L) stopped melanin accumulation, did not affect growth parameters and resulted in AAO activity that was more than two-fold greater than a control treatment with no ascorbic acid. PMID- 28738505 TI - Rethinking aqueous phase diffusion related isotope fractionation: Contrasting theoretical effects with observations at the field scale. AB - Aqueous phase diffusion-related isotope fractionation (DRIF) was investigated through modelling to determine under what subsurface conditions carbon isotope DRIF effects would be observable using typical sampling approaches. A dispersive enrichment factor was defined based on heavy and light isotopologue dispersion coefficients. For a given ratio of source concentration (C0) to method detection limit (MDL), the maximum DRIF in a system increased linearly with transverse dispersive enrichment factor. Using this linear relationship, the critical dispersion enrichment factor for which DRIF would not be observable was quantified. Dispersive enrichment factors for various contaminants (benzene, toluene, chlorinated compounds) were estimated using field scale transverse dispersion coefficients upscaled from compound specific or non-compound specific local scale dispersivity. All predicted dispersive enrichment factors with non compound specific dispersivity are smaller than critical values even for high C0/MDL ratios (e.g. 25,000), indicating DRIF would generally not be observable in systems where soil dispersivity is non-compound specific. To date, this finding has not been clearly articulated in the DRIF literature. While the calculated dispersive enrichment factors for some compounds with compound specific transverse dispersivity exceeded the critical values at which DRIF might become significant, the zones in which DRIF could potentially be observable were limited to bands below 0.5m wide on lateral plume edges. In aquifer-aquitard systems, DRIF was theoretically detectable only in thin aquifers (e.g. 0.5m) bounded by thick (e.g. meters) aquitards. DRIF due to back diffusion from aquitards would not be observable regardless of aquifer thickness. Simulations addressing the mixing effect in wells demonstrated that DRIF effects would be difficult to identify in the field without a sampling strategy (including smaller than industry norm well screen lengths, and fine sampling scales) expressly targeted towards that goal. The results of this study help identify what the required characteristics of such a field strategy might be. PMID- 28738506 TI - Taxonomy- or trait-based ecological assessment for tropical rivers? Case study on benthic diatoms in Mayotte island (France, Indian Ocean). AB - Diatom-based ecological quality assessment methods have been implemented and used regularly in the Water Framework Directive. These indices use the species' abundance profiles along a specific environmental gradient, which they aim to assess. However, this approach has several problematic issues including the unstable and fast-changing diatom taxonomy. The use of traits can be a solution if their responses to the environmental pressure are well-defined. Here, we developed taxonomy-based and trait-based diatom assemblage indices to assess the ecological status of riverine sites on a tropical island. The two indices are based on two sub-indices that measure the diatom assemblage response to a nutrient and organic matter/turbidity gradient. Both taxonomy- and trait-based indices correlated significantly with the selected environmental gradients of the test database, which was not used during index development. We showed that traits could be used for quality assessment of the Mayotte rivers and require much less effort than taxonomy-based indices. There were differences between the two types of indices, which are discussed in this paper. As a perspective for further studies, tests of trait-based indices among different eco-regions would be challenging. PMID- 28738507 TI - Gender-specific associations between serum isomers of perfluoroalkyl substances and blood pressure among Chinese: Isomers of C8 Health Project in China. AB - Previous studies have demonstrated associations of perfluoroalkyl substances (PFASs), a group of highly persistent chemicals ubiquitous in wildlife and humans, with hypertension, but the relationships are mixed. Furthermore, academic literature on the relationship between isomers of PFASs and blood pressure (BP) and hypertension in populations from a higher pollution area is scant. We studied 1612 Chinese adults, ages 22-96years old, from Shenyang, China, utilizing high performance liquid chromatography-mass spectrometry to analyze isomers of perfluorooctanesulfonate (PFOS), perfluorooctanoate (PFOA), and other PFASs in blood serum. We used a mercury sphygmomanometer to measure BP. Hypertension was defined as a mean systolic BP (SBP) of at least 140mmHg, and/or diastolic BP (DBP) of at least 90mmHg, and/or use of antihypertensive medications. The results showed that increased serum concentrations of all (both branched and linear) isomers of PFASs were associated with higher prevalence of hypertension. Adjusted odds ratios for hypertension per ln-unit (ng/mL) increase in PFASs ranged from 1.10 (95%CI: 1.04, 1.17) for perfluorobutanoic acid (PFBA) to 1.26 (95%CI: 1.12, 1.42) for 3+4+5m PFOS, and the estimated increases in mean SBP and DBP ranged from 0.80mmHg (95%CI: 0.25, 1.34) for PFBA to 4.51mmHg (95%CI: 3.52, 5.51) for 3+4+5m PFOS, and from 0.51mmHg (95%CI: 0.01, 1.01) for perfluorodecanesulfonate (PFDS) to 2.48 (1.80, 3.16) for perfluorononanoic acid (PFNA), respectively. Compared with linear PFASs isomers, we identified more and stronger associations among branched PFASs isomers and blood pressure. Furthermore, females exhibited consistently stronger effects than males. In conclusion, this study is the first of its kind to show that not only PFASs positively associated with elevated blood pressure, but also that branched PFAS isomers are more frequently associated with blood pressure than linear PFAS isomers. PMID- 28738508 TI - Modelling of airborne particulate matter concentration in underground stations using a two size-class conservation model. AB - This study presents an attempt of predictive modelling of airborne particulate matter in underground railway stations. The aerosol is represented by a set of simple, ordinary differential equations that describe apparent emission of two particles size-classes in relation with train traffic, ventilation and deposition. The parameters of the equations are identified numerically by a genetic algorithm and comply with their respective expected order of magnitude. A quantitative comparison of numerical results with experimental data from Paris underground station exhibits a good accordance. A qualitative comparison with results from the literature also supports the model. PMID- 28738510 TI - Degradation kinetics and mechanism of sulfadiazine and sulfamethoxazole in an agricultural soil system with manure application. AB - Recently, under the application of waste-water, manure and biosolids, antibiotics have been used massively in agriculture resulted in antibiotic resistance and potential environmental risks. In the present study, the removal of sulfadiazine (SDZ) and sulfamethoxazole (SMX) in an agricultural soil system was explored. All the experiments were conducted under different incubation conditions for 49days. The experimental results indicated that all the degradation processes could effectively follow a first-order kinetic model. Based on the analyses of these two antibiotics, SDZ had a higher reaction rate and a shorter DT50 value. Additionally, there were no marked differences in DT50 values at varying initial concentrations under the same conditions (p>0.05). Compared with the non-sterile soil, the degradation rates of SMX and SDZ were slower (<70%), and the associated DT50 values (>21days) were higher in the sterile soil. Because the biodegradation played a major role, it may be effective for the removal of these contaminants from the soils. The processes of SDZ and SMX degradations were slightly accelerated by applying manure (<20%). There were different accelerating effects on the removal of SDZ and SMX in soils by manure Single- and Repeated application, which may be related to the amount of manure during the degradation processes, and different methods of adding manure could only affect the degradation rate. The major intermediate products were derived from the hydroxylation, sulfonamide SN bond cleavage and aniline moiety oxidation. Therefore, the present study inferred that possible degradation pathways of SDZ and SMX were hydroxylation of the benzene ring, oxidation of the amine group at the benzene ring, ring open and SN bond cleavage. Results revealed that more attention should be paid to the transformation products because they could be more toxic than the parent compounds. PMID- 28738509 TI - Ambient sediment quality conditions in Minnesota lakes, USA: Effects of watershed parameters and aquatic health implications. AB - Surficial sediments were collected from 50 randomly selected Minnesota lakes, plus four a priori reference lakes, in 2007. The lakes encompassed broad geographic coverage of the state and included a variety of major land uses in the surrounding watersheds. Sediment samples were analyzed for a suite of metals, metalloids, persistent organic pollutants, total organic carbon, and particle size fractions. In addition, a small fish survey was conducted to assess PBDEs in both whole fish and fish tissues. Sediment quality in this set of lakes ranged from good (43%) to moderate (57%) based on an integrative measure of multiple contaminants. On an individual basis, some contaminants (e.g., arsenic, lead, DDD, and DDE) exceeded benchmark values in a small number of lakes that would be detrimental to benthic invertebrates. The sediments in two developed lakes tended to be more contaminated than sediments in lakes from other major watershed land uses. These differences were often statistically significant (p<0.05), particularly for lakes with developed versus cultivated land uses for arsenic, lead, zinc, and numerous PAH compounds. Multivariate statistical approaches were used on a subgroup of contaminants to show the two urban lakes, as well as a few northeastern Minnesota lakes, differed from the rest of the data set. Background threshold values were calculated for data with <80% nondetects. Source apportionment modeling of PAHs revealed that vehicle emissions and coal-related combustion were the most common sources. A general environmental forensic analysis of the PCDD/F data showed that ubiquitous combustion sources appeared to be important. BDE-209, a decaBDE, was detected in 84% of lake sediment samples, whereas fish at the top of the food chain (i.e., predator trophic group) had significantly higher (p<0.05) mean lipid-normalized concentrations of BDEs-47, 100, and 153 than lower trophic fish. These results will be used for future status and trends work. PMID- 28738511 TI - Litter thickness, but not root biomass, explains the average and spatial structure of soil hydraulic conductivity in secondary forests and coffee agroecosystems in Veracruz, Mexico. AB - Secondary forests and coffee agroecosystems are considered good alternatives for conservation of a high capacity for water filtration in the soil where tropical montane cloud forests (TMCF) once grew; however, it is not clear which characteristics of the vegetation modulate the field saturated hydraulic conductivity of the soil (Kfs) and whether these characteristics persist in such derived systems. Here, we explore how changes in vegetation between secondary forests and coffee agroecosystems have consequences for the average value and spatial variation of litter thickness and root biomass, and whether these differences can explain the Kfs and its spatial distribution. We found that the thickest litter, greatest total biomass and thickest roots are in the secondary forest of the north of the study area. The litter is spatially structured in patches of ca. 12m at plot scale in the secondary forest and coffee agroecosystem of the southern area. Like the Kfs, the thickness of the litter and biomass of the thick (>2mm), medium (1-2mm) and fine (<1mm) roots are spatially distributed on a north to south gradient at landscape scale. Our linear model indicates that geographic area (north or south), land use and litter thickness explain the Kfs and its spatial distribution along this gradient. Even on inclusion of the antecedent soil moisture and percentage of clays (found to explain Kfs in a previous study), it was not possible to eliminate from the model geographic area and land use, due to their high explanatory power. However, antecedent soil moisture became redundant on inclusion of the litter layer, which had a greater explanatory power. Our modeling suggests that undiscovered differences prevail between the geographic areas and secondary forest and coffee agroecosystems (possibly related to the edaphogenesis and management practices) that determine the Kfs. PMID- 28738512 TI - Effects of nitrogen deposition on soil microbial communities in temperate and subtropical forests in China. AB - Increasing nitrogen (N) deposition has aroused large concerns because of its potential negative effects on forest ecosystems. Although microorganisms play a vital role in ecosystem carbon (C) and nutrient cycling, the effect of N deposition on soil microbiota still remains unclear. In this study, we investigated the responses of microbial biomass C (MBC) and N (MBN) and microbial community composition to 4-5years of experimentally simulated N deposition in temperate needle-leaf forests and subtropical evergreen broadleaf forests in eastern China, using chloroform fumigation extraction and phospholipid fatty acid (PLFA) methods. We found idiosyncratic effects of N addition on microbial biomass in these two types of forest ecosystems. In the subtropical forests, N addition showed a significant negative effect on microbial biomass and community composition, while the effect of N addition was not significant in the temperate forests. The N addition decreased MBC, MBN, arbuscular mycorrhizal fungi, and the F/B ratio (ratio of fungi to bacteria biomass) in the subtropical forests, likely due to a decreased soil pH and changes in the plant community composition. These results showed that microbial biomass and community composition in subtropical forests, compared with the temperate forests, were sensitive to N deposition. Our findings suggest that N deposition may have negative influence on soil microorganisms and potentially alter carbon and nutrient cycling in subtropical forests, rather than in temperate forests. PMID- 28738513 TI - Mitigation of nonpoint source pollution in rural areas: From control to synergies of multi ecosystem services. AB - Nonpoint source (NPS) pollution produced by human activities in rural areas has induced excessive nutrient input into surface waters and the decline of water quality. The essence of NPS pollution is the transport of nutrients between soil and water. Traditional NPS pollution control strategies, however, are mainly based on the solid and liquid phases, with little focus on the bio-phase between water and soil. The pollutants produced from NPS can be regarded as a resource if recycled or reused in an appropriate way in the agricultural ecosystem. This mini review proposes novel strategies for NPS pollution control based on three phases (liquid, solid and bio-phase) and highlights the regulating services of an agricultural ecosystem by optimizing land use/cover types. PMID- 28738514 TI - Unraveling the impact of nanoscale zero-valent iron on the nitrogen removal performance and microbial community of anammox sludge. AB - Given the increasing use of nanoscale zero-valent iron (NZVI) particles for environmental remediation and wastewater treatment, their potential impact on anaerobic ammonium oxidation (anammox) bacteria was investigated in this study using anammox sludge. Batch assays showed that NZVI concentrations up to 200mgL-1 did not affect anammox activity, reactive oxygen species production, and cell membrane integrity. The nitrogen removal efficiency of the continuous-flow reactor fluctuated in the presence of 20 or 50mgL-1 NZVI, but it could return to normal over time, even at 200mgL-1 NZVI. 16S rDNA-based high-throughput sequencing indicated that although the presence of 10, 20, 50, and 200mgL-1 NZVI to some extent affected microbial composition, the anammox bacteria (Candidatus Kuenenia) never lost its dominance. The abundance of gene families that are related to the assimilation and utilization of iron was down-regulated in response to the stress of high-level NZVI. PMID- 28738515 TI - Characterization of carbon dioxide concentrating chemolithotrophic bacterium Serratia sp. ISTD04 for production of biodiesel. AB - Proteomics and metabolomics analysis has become a powerful tool for characterization of microbial ability for fixation of Carbon dioxide. Bacterial community of palaeoproterozoic metasediments was enriched in the shake flask culture in the presence of NaHCO3. One of the isolate showed resistance to NaHCO3 (100mM) and was identified as Serratia sp. ISTD04 by 16S rRNA sequence analysis. Carbon dioxide fixing ability of the bacterium was established by carbonic anhydrase enzyme assay along with proteomic analysis by LC-MS/MS. In proteomic analysis 96 proteins were identified out of these 6 protein involved in carbon dioxide fixation, 11 in fatty acid metabolism, indicating the carbon dioxide fixing potency of bacterium along with production of biofuel. GC-MS analysis revealed that hydrocarbons and FAMEs produced by bacteria within the range of C13 C24 and C11-C19 respectively. Presence of 59% saturated and 41% unsaturated organic compounds, make it a better fuel composition. PMID- 28738517 TI - Modelling long-term impacts of changes in climate, nitrogen deposition and ozone exposure on carbon sequestration of European forest ecosystems. AB - We modelled the effects of past and expected future changes in climate (temperature, precipitation), CO2 concentration, nitrogen deposition (N) and ozone (O3) exposure (phytotoxic ozone dose, POD) on carbon (C) sequestration by European forest ecosystems for the period 1900-2050. Tree C sequestration was assessed by using empirical response functions, while soil C sequestration was simulated with the process-based model VSD, combined with the RothC model. We evaluated two empirical growth responses to N deposition (linear and non-linear) and two O3 exposure relationships (linear function with total biomass or net annual increment). We further investigated an 'interactive model' with interactions between drivers and a 'multiplicative model', in which the combined effect is the product of individual drivers. A single deposition and climate scenario was used for the period 1900-2050. Contrary to expectations, growth observations at European level for the period 1950-2010 compared better with predictions by the multiplicative model than with the interactive model. This coincides with the fact that carbon responses in kgCha-1yr-1 per unit change in drivers, i.e. per degrees C, ppm CO2, kgNha-1yr-1 and mmolm-2yr-1 POD, are more in line with literature data when using the multiplicative model. Compared to 1900, the estimated European average total C sequestration in both forests and forest soils between 1950 and 2000 increased by 21% in the interactive model and by 41% in the multiplicative model, but observed changes were even higher. This growth increase is expected to decline between 2000 and 2050. The simulated changes between 1950 and 2000 were mainly due to the increase in both N deposition and CO2, while the predicted increases between 2000 and 2050 were mainly caused by the increase in CO2 and temperature, and to lesser extent a decrease in POD, counteracted by reduced N deposition. PMID- 28738516 TI - One-pot synthesis of three-dimensional Mn3O4 microcubes for high-level sensitive detection of head and neck cancer drug nimorazole. AB - We described a three-dimensional Mn3O4 microcubes (3D-Mn3O4MCs) synthesised via a facile hydrothermal route for the determination of nimorazole (NMZ), an important drug that used in the treatment of head and neck cancer. The 3D-Mn3O4 MCs possess large active area and high conductivity, and 3D-Mn3O4 MCs film modified screen printed carbon electrode (3D-Mn3O4MCs/SPCE) was fabricated which displayed excellent electrocatalytic ability towards NMZ. Under optimised working conditions, the modified electrode responded linearly to NMZ in the 0.025-8060uM concentration range and the detection limit was 6nM. A rapid, sensitive, selective, reproducible, and durable sensor was described. The practical feasibility of the sensor was demonstrated in human serum and NMZ tablet samples. The obtained results revealed the potential real-time applicability of the sensing device in biological analysis and pharmaceutical formulations. PMID- 28738519 TI - Magnetic iron oxide nanoparticles as novel and efficient tools for atherosclerosis diagnosis. AB - Cardiovascular complications derivate from atherosclerosis are the main cause of death in western world. An early detection of vulnerable atherosclerotic plaques is primordial for a better care of patients suffering the pathology. In this context nanotechnology has emerged as a promising tool to achieve this goal. Nanoparticles based on magnetic iron oxide (MNPs) have been extensively studied in cardiovascular diseases diagnosis, as well as in the treatment and diagnostic of other pathologies. The present review aims to describe and analyze the most current literature regarding to this topic, offering the level of detail required to reproduce the experimental tasks providing a critical input of the latest available reports. The current diagnostic features are presented and compared, highlighting their advantages and disadvantages. Information on novel technology intended to this purpose is also recompiled and in deep analyzed. Special emphasis is placed in magnetic nanotechnology, remarking the possibility to assess selective and multifunctional systems to the early detection of artherosclerotic pathologies. Finally, in view of the state of the art, the future perspectives about the trends on MNPs in artherosclerorsis diagnostic and treatment have also been addressed. PMID- 28738518 TI - Teucrium polium extract reverses symptoms of streptozotocin-induced diabetes in rats via rebalancing the Pdx1 and FoxO1 expressions. AB - BACKGROUND AND OBJECTIVE: Teucrium polium Lamiaceae. an antidiabetic traditional medicine was observed to stimulate insulin secretion and beta-cell mass restoration in pancreatic of diabetic rats. Bioactive compounds in T. polium such as terpenoids and flavonoids have a wide range of antioxidant properties. Given this background, our research was aimed at probing the effective molecular mechanism of T. polium which in turn protects the pancreatic beta-cells of diabetic rats through attenuation of streptozotocin-induced oxidative stress. MATERIALS AND METHODS: Induction of diabetes by streptozotocin (STZ) injection followed by treatment of the rats with T. polium extract (0.5g/kg) and glibenclamide as a standard drug (600MUg/kg) for six consecutive weeks. Besides, biochemical indexes including sera glucose and lipids were investigated once every two weeks. Moreover, oxidative stress markers were also measured in the sixth week of treatment to assess the antioxidant capacity of T. polium. Prior to sacrifice of rats, the oral glucose tolerance test was carried out and thereafter western blot analysis was performed on pancreatic tissues to detect the expression of JNK, FoxO1 and Pdx1 proteins in the experimental groups. RESULTS: Oral administration of T. polium extract not only disclosed the significant anti hyperglycemic potential of the plant, but also relieved dyslipidemia and oxidative stress related to diabetes. Furthermore, remarkable improvement of glucose tolerance was exhibited among the treated groups, confirming the presence of insulin in the blood. Subsequently, the effective molecular mechanism of T. polium was partially revealed by western blot analyses which detected considerable up-regulation of p-FoxO1 and Pdx1 proteins parallel to reduction of p-JNK expression among the treated diabetic rats. CONCLUSION: This study demonstrates that T. polium extract is able to restore the beta-cell mass and insulin secretion by regulation of pivotal transcription factor of the pancreatic beta-cells Pdx1 in JNK pathway. PMID- 28738520 TI - Dissolving microneedles for transdermal drug delivery: Advances and challenges. AB - Over the last number of years, a significant body of evidence has shown the benefit of using dissolving microneedles (DMNs) for transdermal drug delivery. These devices are prepared from a wide range of materials such as sugars and polymers. DMNs are mainly fabricated by micromolding, photopolymerization, drawing lithography and droplet-airborne blowing. In this review, we have focused on the advances made in the field in recent years using a representative set of studies. Although the list of studies is not exhaustive, they highlight the challenges encountered such as the need to increase mechanical strength as well as medication dose while ensuring fast release of the active ingredient. DMNs can be used to delivery low molecular drugs as well as peptides, proteins and other high molecular weight compounds. PMID- 28738521 TI - Ginkgo biloba exocarp extracts induces autophagy in Lewis lung cancer cells involving AMPK / mTOR / p70S6k signaling pathway. AB - OBJECTIVES: Ginkgo biloba L. is called a living fossil plant, and could be used for the treatment of cancer thousands of years ago in China. The extracts prepared from the Ginkgo biloba exocarp (Ginkgo biloba exocarp extracts, GBEE) has a significant anti-cancer effect. Autophagy plays an important role in the occurrence and development of cancer as programmed cell death (PCD) type II. Thus it would be interesting to study the effects and mechanisms of GBEE inducing autophagy in Lewis lung cancer (LLC) cells. METHODS: MTT method was used to detect the inhibitory effect of GBEE on LLC cells. Monodansylcadaverine (MDC) staining method was applied to observe the formation of acidic vacuoles in cells. The ultrastructure of LLC cells was observed using transmission electron microscope (TEM) to confirm the formation of autophagosomes. Quantify reverse transcription-polymerase chain reaction (qRT-PCR) was used to detect the mRNA levels of Beclin1 and Atg5. Western Blot was used to detect the protein levels of Beclin1, Atg5, LC3I/II, p-AMPK, AMPK, p-mTOR, mTOR, p-p70S6k and p70S6K in LLC cells. RESULTS: GBEE (5-160MUg/mL) inhibited the proliferation of LLC cells in vitro with the half maximal inhibitory concentration (IC50) value of 161.26MUg/mL. The formation and activation of acidic vacuoleswere increased by the action of GBEE (10, 20 and 40MUg/mL) on LLC cells. The autophagosomes were also increased. Meanwhile, it up-regulated both the mRNA and protein levels of Beclin1 and Atg5. The ratio of LC3-I/LC3-II protein was down-regulated. In addition, the protein level of p-AMPK was increased, and the p-mTOR and p-p70S6K was decreased. But the AMPK, mTOR and p70S6K proteins were not significantly changed. CONCLUSIONS: The inhibitory effect of GBEE on LLC is associate with inducing autophagy in LLC cells, which may be closely relevant to the regulation of AMPK/mTOR/p70S6k signaling pathways. PMID- 28738522 TI - Combination of NRP1-mediated iRGD with 5-fluorouracil suppresses proliferation, migration and invasion of gastric cancer cells. AB - Gastric cancer is one of the most of common cancers in the world. 5-Fluorouracil (5-FU) has been identified as one of the standard first-line chemotherapy drugs for locally advanced or metastatic gastric cancer. However, poor tumor penetration, bad selectivity and toxic side effects are the major limitations for the application of chemotherapy drugs in anticancer therapy. Recently, plenty of studies demonstrate that the novel tumor-homing peptide iRGD could promote the tumor-penetrating capability of chemotherapy drugs in multiple cancers, and neuropilin-1 (NRP1) protein is the critical mediator for iRGD. Here,we found that NRP1 protein expression was significantly up-regulated in gastric cancer tissues and cell lines by Immunohistochemistry and Western blot. And elevated NRP1 was notably associated with tumor differentiation (P=0.021), tumor size (P=0.004), tumor stage(P=0.028), lymph node metastasis(P=0.032), TNM tumor stage (P=0.006) and poorer prognosis. Functionally, the data of Methyl thiazolyl tetrazolium (MTT) assay, Colony formation assay and Transwell assay revealed that NRP1 could facilitate gastric cancer cells proliferation, migration and invasion. Furthermore, iRGD could strengthen the chemotherapy effect of 5-FU on gastric cancer cells through NRP1. Taken together, NPR1 might be a promising tumor target for gastric cancer, and combination of iRGD with 5-FU may be a novel and valuable approach to improving the prognosis of gastric cancer patients. PMID- 28738523 TI - A natriuretic peptides clearance receptor's agonist reduces pulmonary artery pressures and enhances cardiac performance in preclinical models: New hope for patients with pulmonary hypertension due to left ventricular heart failure. AB - BACKGROUND: In patients with left ventricular heart failure (HF), the development of pulmonary hypertension (PH) is common and represents a strong predictor of death. Despite recent advances in the pathophysiological understanding there is as yet no prospect of cure of this deadly clinical entity and the majority of patients continue to progress to right ventricular failure and die. Furthermore, there is no single medical treatment currently approved for PH related to HF. There is, therefore an urgent unmet need to identify novel pharmacological agents that will prevent the progressive increased or reverse the elevated pulmonary arterial pressures while enhancing cardiac performance in HF. METHOD AND RESULTS: We here reported, for the first time, using a pressure-loop (P-V) conductance catheter system, that a specific natriuretic peptides clearance receptors' agonist, the ring-deleted atrial natriuretic peptide analogue, cANF4-23 (cANF) reduces pulmonary artery pressures. Strikingly, the administration of the cANF in these mice decreased the RVSP by 50% (n=5, F 25.687, DF 14, p<0.001) and heart rate (HR) by 11% (n=5, F 25.69, DF 14, p<0.001) as well as enhancing cardiac performance including left ventricular contractility in mice. Most strikingly, mice lacking NPR-C were much more susceptible to develop HF, indicating that NPR C is a critical protective receptor in the heart. CONCLUSION: Natriuretic peptides clearance receptors' agonists may, therefore represent a novel and attractive therapeutic strategy for PH related to HF, and ultimately improves the life expectancy and quality for millions of people around the planet. PMID- 28738524 TI - Elevated microRNA-125b promotes inflammation in rheumatoid arthritis by activation of NF-kappaB pathway. AB - microRNA-125b (miR-125b) has been reported to be increased in rheumatoid arthritis (RA). However, the role of miR-125b in RA remains to be fully elucidated. We aimed to explore the functional role of miR-125b in RA, as well as the underlying mechanism. The expression of miR-125b in serum and synovial tissues of patients with RA and healthy controls was confirmed. In addition, the levels of miR-125b in lipopolysaccharide (LPS)-stimulated fibroblast-like synoviocytes (FLS) were also measured. FLS were transfected with miR-125b mimic, antisense oligonucleotides (ASO)-miR-125b, pcDNA-inhibitor of NF-kappaB (IkappaB) alpha or corresponding controls, and then stimulated with LPS or incubated with nuclear factor kappa B (NF-kappaB) inhibitors pyrrolidine dithiocarbamate (PDTC). The effects of miR-125b abnormal expression on pro-inflammatory cytokines including tumor necrosis factor (TNF)-alpha, interleukin (IL)-6 and IL-1beta and NF-kappaB pathway key factors phospho-p65 (p-p65) and IkappaB-alpha were assessed. Pearson correlation analysis was performed to assess the relationship between miR-125b expression and pro-inflammatory cytokines expression. Result showed that, the levels of miR-125b were significantly increased in RA serum and synovial tissues, as well as in LPS-stimulated FLS (P<0.01). miR-125b overexpression statistically increased the expression of TNF-alpha, IL-6, IL 1beta and p-p65 (P<0.05 or P<0.01), but markedly decreased IkappaB-alpha (P<0.05). Contrary results were obtained by miR-125b downregulation. Additionally, there were strong positive relationships between miR-125b and TNF alpha (R2=0.7569, P<0.000), IL-6 (R2=0.8479, P<0.000), and IL-1beta (R2=0.8037, P<0.000). Moreover, the upregulated levels of pro-inflammatory cytokines were markedly decreased by PDTC (P<0.01) and further downregulated by co-transfection with pcDNA-IkappaB-alpha (P<0.01). In conclusion, our results suggest that elevated miR-125b promotes inflammation in RA by activation of NF-kappaB pathway. PMID- 28738525 TI - Mesenchymal stem cells with IGF-1 and TGF- beta1 in laminin gel for osteochondral defects in rabbits. AB - OBJECTIVE: Healing of articular cartilage is still a challenge due to its limited potential to regenerate. In the present study, we evaluated allogenic bone marrow mesenchymal stem cells (BM-MSCs) alone or in combination with growth factors, insulin-like growth factor-1 (IGF-1) and transforming growth factor-beta1 (TGF beta1) in laminin scaffolds for healing of osteochondral defects. DESIGN: Osteochondral defects of 4mm (diameter) x 5mm (depth) were induced in the rabbit knee joints and treated with phosphate-buffered saline (PBS; control), BM-MSCs, BM-MSCs in laminin, BM-MSCs in laminin with IGF-1, or BM-MSCs in laminin with IGF 1 and TGF-beta1 in 10 animals each. Gross, radiographic, scanning electron microscopic (SEM) and histologic examinations besides chondrocyte-specific genes expression by quantitative real time qPCR were carried out at 8 and 12 weeks. RESULTS: Gross and SEM examination revealed superior morphology and surface architecture of the healing site in animals that received MSCs with IGF-1 or IGF 1 and TGF-beta1. The application of laminin composites containing MSCs with IGF-1 and TGF-beta1 significantly enhanced hyaline cartilage formation with improved cellular arrangement, proteoglycan deposition, clear tidemark zone and subchondral bone formation. However, regenerated tissue in defects that received only MSCs had poor tidemark zone and proteoglycans deposition Aggrecan and Coll2 expression was significantly higher in case of MSCs with growth factors. CONCLUSION: The treatment with BM-MSCs combined with IGF-1/TGF-beta1 into laminin gel scaffold might enhance the restoration of hyaline cartilage in osteochondral defect. PMID- 28738526 TI - The potential of chrysophanol in protecting against high fat-induced cardiac injury through Nrf2-regulated anti-inflammation, anti-oxidant and anti-fibrosis in Nrf2 knockout mice. AB - Cardiovascular complications induced by high fat are one of the most challenging health problems presently. Oxidative stress, inflammation and fibrosis are major components included in the pathology of diabetic cardiomyopathy. Nuclear factor erythroid 2-related factor 2 (Nrf2) has been reported as an essential therapeutic target in various diseases for its induction of anti-oxidant enzymes, and other protective enzymes. Additionally, a number of Nrf2 activators showed strong anti inflammatory properties. In the study, we calculated the Nrf2-dependent anti oxidant, anti-inflammatory and anti-fibrosis effects of chrysophanol in high fat diet-induced diabetic heart injury. The underlying mechanisms of chrysophanol were explored using H9C2 cells in vitro. For the in vivo experiment, cardiac injury was triggered in wild type (Nrf2+/+) and Nrf2-knockout (Nrf2-/-) mice by high fat diet, and chrysophanol was administered after high fat feeding for two weeks. In Nrf2+/+ mice, but not the Nrf2-/- animals, chrysophanol ameliorated metabolic disorders, improved cardiac function, reduced pathological changes, attenuated oxidative injury, down-regulated inflammatory response and fibrosis progression through regulating different signaling pathways. Our data indicated that the anti-oxidant, anti-inflammatory and anti-fibrosis effects of chrysophanol are regulated by Nrf2 expression. Thus, we supposed that chrysophanol could be used as a safe therapeutic strategy to ameliorate cardiac injury induced by high fat diet. PMID- 28738527 TI - Evaluation of heavy metal mobilization in creek sediment: Influence of RAC values and ambient environmental factors. AB - The risk assessment code (RAC) is a common method for assessing heavy metal (HM) mobility and their potential health risks, based on HM total concentration and chemical speciation. In this study, both the RAC and the influence of ambient environmental factors were investigated in a river sediment system. Sixty-eight sediment samples were collected from the main river system in Shanghai, China. The total concentration and chemical speciation of Cu, Zn, Ni, Pb, Cd, Cr, As, and Hg were determined in the samples. The influence of sediment environmental factors, such as acid-volatile sulfide (AVS), Fe & Mn, and total organic carbon (TOC), on total metal concentrations and speciation was also investigated. The relationship between the main environmental media and distribution of HMs was discussed using PCA and NMDS. The transfer-transformation behaviors of Pb, Ni, and Cr were mainly controlled by AVS and TOC while Zn, Cu, and Cd were influenced by Fe & Mn and TOC. The relationship between the RAC value of HM and environmental factors revealed that 7% of Cr, 23% of Ni, and 15% of Pb had a high risk of mobility at TOC values below 3.5% and sulfite contents below 10mmol/kg. In comparison, 29%, 10%, and 10% of Zn, Cu, and Cd, respectively, had a high risk of mobility at TOC<3.5% and Fe & Mn content >4*105mg/kg. Evidently, the chemical fractions of HM had a strong dependence on the S, Fe, Mn, and organic compounds in the sediment. This study provides a promising pathway for the rapid evaluation of potential risks from HMs in river sediments. PMID- 28738528 TI - Molecular basis for oxidative stress induced by simulated microgravity in nematode Caenorhabditis elegans. AB - Caenorhabditis elegans is an important in vivo assay system for toxicological studies. Herein, we investigated the role of oxidative stress and the underlying molecular mechanism for induced adverse effects of simulated microgravity. In nematodes, simulated microgravity treatment induced a significant induction of oxidative stress. Genes (mev-1, gas-1, and isp-1) encoding a molecular machinery for the control of oxidative stress were found to be dysregulated in simulated microgravity treated nematodes. Meanwhile, genes (sod-2, sod-3, sod-4, sod-5, aak 2, skn-1, and gst-4) encoding certain antioxidant defense systems were increased in simulated microgravity treated nematodes. Mutation of mev-1, gas-1, sod-2, sod 3, aak-2, skn-1, or gst-4 enhanced susceptibility to oxidative stress induced by simulated microgravity, whereas mutation of isp-1 induced a resistance to oxidative stress induced by simulated microgravity. Mutation of sod-2, sod-3, or aak-2 further suppressed the recovery effect of simulated microgravity toxicity in nematodes after simulated microgravity treatment for 1h. Moreover, administration of ascorbate could inhibit the adverse effects including the induction of oxidative stress in simulated microgravity treated nematodes. Mutation of any of the genes encoding metallothioneins or the genes of hsp-16.1, hsp-16.2 and hsp-16.48 encoding heat-shock proteins did not affect the induction of oxidative stress in simulated microgravity treated nematodes. Our results provide a molecular basis for the induction of oxidative stress in simulated microgravity treated organisms. PMID- 28738529 TI - Nitrogen-functionalization biochars derived from wheat straws via molten salt synthesis: An efficient adsorbent for atrazine removal. AB - N-doped porous carbon sheets (NPCS) resulted from wheat straws are fabricated through using molten salts via the carbonization-functionalization progress, which show unique hierarchical structure, large pore volume and high surface area with affluent micropores. Results indicate that there exist many hierarchical pores consisting of the single carbon sheet with ultrathin nature, owing to the template role of molten salt mixtures at high temperature. Such superior structure can bring about desired performance of adsorption capacity of 82.8mg/g and quick adsorption rate of 1.43L/(gh) with an initial concentration of 35mg/L at 25 degrees C. Langmuir and Freundlich models are adopted to interpret the adsorption behavior of atrazine and modified Freundlich and intraparticle diffusion (IPD) models are employed to characterize the dynamics of adsorption. Furthermore, nitrogen-functionalization biochars via molten salt synthesis should be further developed as a one-pot methodology to produce N-doped carbons, opening up a feasible approach for resource utilization of crop straws and other biomass wastes. PMID- 28738530 TI - Prenatal low-level phenol exposures and birth outcomes in China. AB - Phenolic compounds are among the endocrine disruptors which are widely used in daily life products. Studies in laboratory animals showed reproductive and developmental effects. In spite of widespread exposure to phenols, only few studies examined their effects on human development. This study was designed to investigate the relationship between antenatal phenol exposure and birth outcomes in a Chinese obstetric population. Four hundred ninety-six mother-infant pairs recruited from the Laizhou Wan prospective birth cohort in northern China between 2010 and 2013 were included in the study. We measured two phenol metabolites in maternal urine at delivery and examined their associations with birth outcomes including birth weight, crown-heel length, head circumference, gestational age, and ponderal index. Median levels of bisphenol A (BPA) and triclosan (TCS) in urine were 1.07 and 0.50MUg/g creatinine, respectively. After adjusting for confounders, a 10-fold increase in BPA levels was associated with a 0.63cm [95% confidence interval (CI): 0.25 to 1.01] increase in birth length among boys, but not among girls. No associations were found between TCS levels and any birth outcomes. The positive association of prenatal low-level BPA exposures with anthropometric measures observed among boys, suggests gender differences in the response to antenatal phenol exposure. Given the variability in urinary phenol levels reported during pregnancy, our findings based on levels of the target biomarkers in a single urine sample need to be confirmed in additional studies. PMID- 28738531 TI - Surface complexation modeling of Cu(II) sorption to montmorillonite-bacteria composites. AB - Surface complexation modeling, isothermal titration calorimetry, and batch adsorption were employed to characterize the adsorption of Cu onto montmorillonite, Pseudomonas putida X4, and their composites at mass ratios of 2:1, 6:1, and 12:1, respectively. Different enthalpy values were found for Cu adsorption to permanent (-6.43kJ/mol) and variable charge sites (8.51kJ/mol) on montmorillonite. The component additivity (CA) method was used to predict the adsorption of Cu on the composites by combining end member models for montmorillonite and P. putida. A reduced adsorption was observed at pH<5.5 due to physical blocking between montmorillonite and P. putida. By contrast, the enhanced binding at high pH levels was ascribed to the formation of bridging structures among the clay mineral-Cu-bacteria complexes. These deviations in the CA method were corrected by adding reactions of >RCOOH...XNa and >RCOOCuOHXNa. The increased adsorption of the composites confirmed the decrease of permanent negative charge sites and the formation of ternary complexes. The results help elucidate the effect of Cu adsorption onto clay minerals-bacteria composites. The newly developed "CA-site masking-bridging" model can be used to predict Cu speciation in systems in which the active interaction of bacteria and clay minerals occurs. PMID- 28738532 TI - Genipin attenuates cisplatin-induced nephrotoxicity by counteracting oxidative stress, inflammation, and apoptosis. AB - Cisplatin (CP) is a potent and widely used chemotherapeutic agent. However, the clinical benefits of CP are compromised because it elicits nephrotoxicity and ototoxicity. In this study, we investigated the nephroprotective effects of the phytochemical genipin (GP) isolated from the gardenia (Gardenia jasminoides) fruit, using a murine model of CP-induced nephropathy. GP pretreatment attenuated the CP-induced renal tissue injury by diminishing the serum blood urea nitrogen, creatinine, and cystatin C levels, as well as those of kidney injury molecule-1. In addition, GP attenuated the CP-induced oxidative/nitrative stress by suppressing the activation of NADPH oxidase, augmenting the endogenous antioxidant defense system, and diminishing the accumulation of 4-hydroxynonenal and 3-nitrotyrosine in renal tissues. Furthermore, reduced levels of proinflammatory cytokines such as tumor necrosis factor-alpha and interleukin-1 beta indicated that CP-induced renal inflammation was mitigated upon the treatment with GP. GP also attenuated the CP-induced activation of mitogen activated protein kinases, excessive activities of caspase-3/7 and poly(ADP ribose) polymerase, DNA fragmentation, and apoptosis. When administered 12h after the onset of kidney injury, GP showed a therapeutic effect by ameliorating CP induced nephrotoxicity. Moreover, GP synergistically enhanced the CP-induced cell death of T24 human bladder cancer cells. Collectively, our data indicate that GP attenuated the CP-induced renal tissue injury by abrogating oxidative/nitrative stress and inflammation and by blocking cell death pathways, thereby improving the renal function. Thus, our results suggest that the use of GP may be a promising new protective strategy against cisplatin-induced nephrotoxicity. PMID- 28738533 TI - MiR-200a expression in CD4+ T cells correlates with the expression of Th17/Treg cells and relevant cytokines in psoriasis vulgaris: A case control study. AB - The main aim of this study is to investigate the underlying relationship shared between microRNA-200a (miR-200a) and its link to concentrations of Th17 and Treg cells, mRNA expressions of their specific transcription factors retinoic acid related orphan receptor gammat (RORgammat) and head box protein 3 (FOXP3) and relevant cytokines in patients with psoriasis vulgaris (PV). A total of 189 patients previously diagnosed with PV were selected as the experimental group, whilst 109 healthy individuals as the control group. According to the psoriasis area and severity index (PASI), subjects in the experimental group were assigned into the severe group (95 cases) and the moderate group (94 cases). CD4+ T and Th17/Treg cells were extracted. MiR-200a expression and RORgammat and FoxP3 mRNA expressions were detected by qRT-PCR. Concentrations of Th17 and Treg cells were measured via flow cytometry. ELISA was conducted for serum IL-17, IL-23 and TGF beta levels. Correlation analysis was completed in accordance with the Pearson method. Compared with the moderate group, higher miR-200a expression, RORgammat mRNA expression, percentage of Th17, Th17/Treg ratio and levels of IL-17 and IL 23 exhibited in the severe group, whilst FoxP3 mRNA expression and, percentage of Treg as well as TGF-beta were lower. A same trend displayed when comparing the moderate group to the control group. We found that miR-200a expression, percentage of Th17, Th17/Treg ratio, IL-17 and IL-23 levels and RORgammat mRNA expression are positively correlated with PASI grade, while the percentage of Treg, TGF-beta level and FoxP3 mRNA expression are negatively correlated with PASI grade. The results also displayed that the percentage of Th17, Th17/Treg ratio, IL-17 and IL-23 levels and RORgammat mRNA expression are positively correlated with miR-200a expression, while the percentage seen in Treg and TGF betaand FoxP3 mRNA expression are negatively correlated with miR-200a expression. Our results provided a strong evidence that up-regulation of microRNA-200a in CD4+ T cells may induce immune dysfunction through Th17/Treg cells and relevant cytokines in PV patients. PMID- 28738534 TI - High expression of CD47 predicts adverse prognosis in Chinese patients and suppresses immune response in melanoma. AB - BACKGROUND: Cluster of differentiation 47 (CD47) negatively regulates macrophage phagocytosis and is correlated with adverse survival of multiple cancers. In melanoma patients, especially in Chinese melanoma patients, its prognostic value is unclear. In this study, we aim to study the prognostic value of CD47 in a Chinse melanoma patient cohort and its immunomodulation roles in mouse model. METHOD: 164 melanoma tissue specimens were collected. The expression of CD47 in these clinical samples was examined by immunohistochemistry staining (IHC). The correlation between CD47 expression and clinicopathological parameters was assessed by statistical analysis. Prognostic values CD47 expression were also investigated. In an animal model, effects of CD47 expression on immune infiltration were examined. RESULTS: CD47 expression was positively correlated with TNM stage, distant metastasis, and death of melanoma patients with the P value of 0.008, 0.018, and 0.032 respectively. High expression of CD47 was an independent prognostic marker of overall survival (HR=1.563, 95% CI: 1.069-2.285) and progression free survival (HR=1.542, 95% CI: 1.053-2.258) of Chinese melanoma patients. CONCLUSION: In conclusion, high expression of CD47 predicted poor survival in a Chinese melanoma patient cohort and impaired antitumor immune response in the animal model. Targeting CD47 might be a novel option for melanoma patients. PMID- 28738535 TI - Role of GAB1/PI3K/AKT signaling high glucose-induced cardiomyocyte apoptosis. AB - Gestational diabetes mellitus (GDM) is a risk factor for abnormal heart development. Previous work showed that a decrease of myocardial cells and an increase of apoptotic cells leading to heart defects under hyperglycemia, and many genes and protein have been found to play important roles in cardiomyocyte apoptosis. However, there are still many blind nodes in HG-induced cardiac apoptosis. Our study showed that down-regulation of GAB1 occurred concurrently with HG-induced cardiomyocytes apoptosis and in the heart tissues of offspring of diabetic rats in vitro and in vivo. MTT and apoptosis assay showed GAB1 played a key role in mediating HG-induced apoptosis of cardiomyocytes. Down-regulation of XIAP and increased activities of Caspase3/7 was associated with GAB1-mediated cardiomyocyte apoptosis in response to HG treatment. Further study showed that the phosphorylation levels of AKT (Ser473) decreased after HG treatment. Over expression of GAB1 resisted the reduction in AKT phosphorylation in response to HG. LY294002, which is an effective inhibitor of the PI3K/AKT signaling pathway, partly inhibited GAB1 to suppress apoptosis induced by HG in cardiomyocytes, and partly suppressed GAB1 to resist the decrease of XIAP in response to HG, indicating AKT signaling, XIAP, and Caspase3/7 participated in GAB1-mediated cardiomyocyte apoptosis in response to HG. Generally, we demonstrate a novel role of GAB1 and its down-stream signaling PI3K/AKT for modulating cardiomyocyte apoptosis in response to high glucose in vitro and vivo. PMID- 28738536 TI - Effect of apigenin, kaempferol and resveratrol on the gene expression and protein secretion of tumor necrosis factor alpha (TNF-alpha) and interleukin-10 (IL-10) in RAW-264.7 macrophages. AB - Polyphenols such as apigenin, kaempferol or resveratrol are typically found in plants, including fruits, vegetables, herbs and spices, which have a wide range of biological functions such as antioxidative, anti-inflammatory, vasodilative, anticoagulative and proapoptotic. Discovering such multifunctional compounds in widely consumed plant-based products - ones that both inhibit the release of TNF alpha from tissue macrophages and at the same time enhance the secretion of IL-10 - would be an important signpost in the quest for effective pharmacological treatment of numerous diseases that have an inflammatory etiology. The aim of the study is to investigate the impact of biologically active polyphenols such as apigenin, resveratrol and kaempferol on gene expression and protein secretion of IL-10 and TNF-alpha in line RAW-264.7. Cells were cultured under standard conditions. IL-10 and TNF-alpha genes expression were examined using QRT-PCR and to assess cytokines concentration ELISA have been used. Apigenin, kaempferol and resveratrol at a dose 30MUM significantly decrease the TNF-alpha expression and secretion. Apigenin decrease the IL-10 expression and secretion. Furthermore, increase in IL-10 secretion after administration of kaempferol and resveratrol were observed. In the process of administration of tested compounds before LPS, which activate macrophages, decrease of TNF-alpha secretion after apigenin and kaempferol and increase of IL-10 secretion after resveratrol were observed. The results of present work indicate that 1) apigenin, resveratrol and kaempferol may reduce the intensity of inflammatory processes by inhibiting the secretion of proinflammatory cytokine TNF-alpha, and resveratrol and kaempferol additionally by increasing the secretion of anti-inflammatory cytokine IL-10 2) the studies indicate the potentially beneficial - anti-inflammatory - impact of diet rich in products including apigenin, resveratrol and kaempferol. PMID- 28738537 TI - Phosphodiesterase inhibitor ameliorates neuronal injury in spinal cord ischemia/reperfusion injured rat model. AB - This study investigated the mechanisms responsible for the neuroprotective effect of sildenafil citrate (SFC) on ischemia-reperfusion spinal cord (SC) injuries. Balloon occlusion of the thoracic aorta was used to induce SC ischemia. The animals (n=30) were separated into three groups: sham, SC injury with saline, and SC injury with 5mg/kg i.p. SFC treatment (SFC). The Basso, Beattie, and Bresnahan (BBB) score was determined to assess neurological function at different time intervals after reperfusion. After 48h, histopathology of the SC was assessed by triphenyltetrazolium chloride (TTC) and Nissl staining. Myeloperoxidase (MPO) activity was estimated using an MPO assay kit. Western blot and ELISA assays were performed to estimate interleukin 1 & 10 (IL-1 & IL-10), tumour necrosis factor alpha (TNF-alpha), and nuclear factor (NF-kB) levels in SC tissue homogenates. The study results suggest that treatment with SFC significantly increased neurological function compared with the SC group. In addition, SFC treatment reduced MPO activity compared with the SC group, which subsequently inhibited the infiltration of neutrophils into the SC. There was a significant (p<0.01) decrease in the expression of IL-1 and TNF-alpha, and an increase in the expression of IL-10 in SFC tissue homogenates compared with SC tissues. Moreover, SFC treatment inhibited the activation of NF-kB in the SC after injury. This study shows that SFC exerts a neuroprotective effect on the SC after ischemia/reperfusion injury by attenuating inflammatory mediators. PMID- 28738538 TI - Diosmin improved cognitive deficit and amplified brain electrical activity in the rat model of traumatic brain injury. AB - OBJECTIVE: Traumatic brain injury (TBI) is one of the main causes of intellectual and cognitive disabilities in humans. Clinically, it is essential to limit the progress of cognitive impairment after TBI. It is reported that diosmin has a neuroprotective effect that can limit the progress of the impairment. The aim of this study was to evaluate the effects of diosmin on neurological score, memory, tumor necrosis factor-alpha (TNF-alpha) level and long-term potentiation in hippocampal dentate gyrus after the injury. METHODS: A total of ninety six adult male Wistar rats were used as test subjects in this study. The animals were randomly assigned into one of the following three groups (n=32/group): Sham, TBI and diosmin (100mg/kg, p.o for seven consecutive days before TBI induction). TBI was induced into the animals by Marmarou's method. Briefly, a 200g weight was dropped from a 1m height through a free-falling tube onto the head of the anesthetized rats. RESULTS: The veterinary coma scale scores, memory and long term potentiation in TBI group showed significant decrease at different times after the onset of TBI when compared with Sham (p<0.001). The TNF-alpha level in the hippocampus of the TBI group of animals was significantly higher than that found in the test subjects from the Sham group (p<0.001). The pre-treatment of the TBI group with diosmin significantly improved their neurological scores, memory and long-term potentiation (p<0.001) when compared with the TBI group. The TNF-alpha level in hippocampus of the diosmin group was significantly lower than the TBI group (p<0.001). CONCLUSION: Based on the results of the present study, pre-treatment with diosmin has protective effects against TBI-induced memory and long-term potentiation impairment. The effects of diosmin may be mediated through a decrement in the TNF-alpha concentration of hippocampus as a pro-inflammatory cytokine. PMID- 28738539 TI - LncRNA AB073614 regulates proliferation and metastasis of colorectal cancer cells via the PI3K/AKT signaling pathway. AB - The expression profiles of long noncoding RNAs (lncRNAs) in colorectal cancer (CRC) have remained unclear. LncRNA AB073614 is known to be upregulated in ovarian cancer and glioma tissues, and is associated with the occurrence and progression of those cancers. In the present study, we investigated the lncRNA AB073614 gene expression patterns in CRC cell lines and tissue samples from CRC patients, and then analyzed them for possible associations with various clinicopathological characteristics. Furthermore, the roles played by lncRNA AB073614 in CRC cell proliferation, apoptosis, cell cycle progression, migration, and invasion were examined in vitro by using gene knockdown and overexpression techniques. We detected the levels of lncRNA AB073614 in 28 paired CRC tissues and adjacent normal tissues by qRT-PCR, and our results revealed that AB073614 expression in 85.7% (24/28) of the CRC tissues was significantly higher than those in the paired normal tissues. Furthermore, the levels of AB073614 were closely related to tumor grade, size, cell differentiation status, and the presence of distant metastases. Knockdown of AB073614 expression significantly inhibited the proliferation, migration, and invasion of SW480 cells, and resulted in their increased rates of apoptosis and G1 phase cell cycle arrest, whereas overexpression of AB073614 produced the opposite effects. Finally, results of studies which used an agonist (740Y-P) and an inhibitor (LY294002) of the PI3K/AKT signaling pathway, as well as the results of western blot assays, indicated that lncRNA AB073614 exerts its effects by targeting the PI3K/AKT mediated signaling pathway. Taken together, our data indicate that lncRNA AB073614 acts to prevent CRC progression by affecting the PI3K/AKT signaling pathway, and may be useful as a novel prognostic or treatment agent for CRC. PMID- 28738540 TI - Regulatory players of DNA damage repair mechanisms: Role in Cancer Chemoresistance. AB - DNA damaging agents are most common in chemotherapeutic molecules that act against cancer. However, cancer cells possess inherent biological features to overcome DNA damages by activating various distinct repair mechanisms and pathways. Importantly, various oncogenes, cancer stem cells (CSCs), hypoxic environment, transcription factors and bystander signaling that are activated in the cancer cells influence DNA repair, thereby effectively repairing the DNA damage. Repaired cancer cells often become more resistance to further therapy and results in disease recurrence. In this review, we summarize how the various signaling pathways in cancer cells regulates DNA repair and induce chemoresistance. PMID- 28738541 TI - Research progress on osteoarthritis treatment mechanisms. AB - Osteoarthritis is a common disease and is frequently encountered in the older population; the incidence rises sharply with age. It is estimated that more than 360 million people suffer from OA. However, the pathogenesis of osteoarthritis remains unclear, and we cannot effectively prevent the progression of OA. The aim of this review was to explore the molecular markers and signaling pathways that induce chondrocyte apoptosis in OA. We searched, using the key words osteoarthritis, chondrocyte apoptosis, autophagy, endoplasmic reticulum stress, molecular targets, and biomarkers, in PubMed, Web of Science, and Google Scholar from 1994 to 2017. We also reviewed the signaling pathways and molecular markers associated with chondrocyte apoptosis and approaches aimed at inhibiting the apoptosis-inducing mechanism to at least delay the progression of cartilage degeneration in OA. This article provides an overview of targeted therapies and the related signaling pathways in OA. PMID- 28738543 TI - Phenolic compounds of Triplaris gardneriana can protect cells against oxidative stress and restore oxidative balance. AB - This work aimed to add value to an underexploited plant species from Brazil, Triplaris gardneriana. To that, the phenolic compounds profile of its seed ethanolic extract and fractions was examined by HPLC and the antioxidant capacity assessed using chemical assays as well as in vitro cell imaging. Twelve compounds were quantified and classified as either phenolic acids or flavonoids. The fractionation process did not generate fractions with different compositions except for chloroformic fraction, which showed only 6 out of 12 standard compounds used. DPPH assay revealed samples with a concentration-dependent radical scavenging activity, being methanolic fraction the one with the largest activity (SC50 11.45+/-0.02MUg/mL). Lipid peroxidation assessment, in the presence and absence of stress inducer, showed that particularly the ethanol extract (IC50 26.75+/-0.08MUg/mL) and the ethyl acetate fraction (IC50 6.14+/ 0.03MUg/mL) could inhibit lipid peroxidation. The ethyl acetate fraction performed best in chelating iron (48% complexation at 1000MUg/mL). Cell imaging experiments showed that the ethanolic extract could protect cells against oxidative stress as well as restore the oxidative balance upon stress induction. In conclusion, T. gardneriana seeds showed a promising phenolic compounds profile and antioxidant activity that may be further exploited. PMID- 28738542 TI - Protective effects of tannic acid on acute doxorubicin-induced cardiotoxicity: Involvement of suppression in oxidative stress, inflammation, and apoptosis. AB - Doxorubicin (DOX) is a highly effective drug, but its cardiotoxicity restricts its therapeutic index. Oxidative stress is the major etiopathological factor in DOX-induced cardiotoxicity. Tannic acid (TA) has various anti-cancer, antioxidant, and anti-inflammatory activities. The purpose of the study was to survey the possible effects of TA against acute DOX-induced cardiotoxicity. Male Sprague-Dawleyrats were randomly divided into five groups: control, DOX (10mg/kg) alone, DOX with TA (20 and 40mg/kg), or DOX withcaptopril (30mg/kg) treatments. TA or captopril was administered once daily for six days, and DOX was injected intraperitoneally on the fourth day. TA significantlyattenuated DOX myocardial effects. Pretreatment with TA caused a decrease in levels of the serum enzymes lactate dehydrogenase, creatine kinase, and creatine kinase isoenzyme-MB to normal values. As indicators of oxidative stress, the levels of glutathione peroxidasesuperoxide dismutase and catalasesignificantly increased while the levels of malondialdehyde decreased after TA treatment. Additionally, DOX provoked inflammatory responses by causing anincrease in levels of pro inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta), endothelin (ET)-1 levels, and nuclear factor kappa B (NF-kappaB) expression while TA pretreatment significantly inhibited TNF-alpha, IL-1beta, ET-1, and NF-kappaB. Furthermore, DOX induced apoptosis by increasing bcl-2like protein and caspase-3 activities and c-fos and c-jun levels while causing a decrease in B-cell lymphoma-2 levels. Overall, there was evidence that TA could inhibit DOX-induced cardiotoxicity by inhibiting oxidative stress, inflammation and apoptotic damage. PMID- 28738544 TI - A xylanase-aided enzymatic pretreatment facilitates cellulose nanofibrillation. AB - Although biological pretreatment of cellulosic fiber based on endoglucanases has shown some promise to facilitate cellulose nanofibrillation, its efficacy is still limited. In this study, a xylanase-aided endoglucanase pretreatment was assessed on the bleached hardwood and softwood Kraft pulps to facilitate the downstream cellulose nanofibrillation. Four commercial xylanase preparations were compared and the changes of major fiber physicochemical characteristics such as cellulose/hemicellulose content, gross fiber properties, fiber morphologies, cellulose accessibility/degree of polymerization (DP)/crystallinity were systematically evaluated before and after enzymatic pretreatment. It showed that the synergistic cooperation between endoglucanase and certain xylanase (Biobrite) could efficiently "open up" the hardwood Kraft pulp with limited carbohydrates degradation (<7%), which greatly facilitated the downstream cellulose nanofibrillation during mild sonication process (90Wh) with more uniform disintegrated nanofibril products (50-150nm, as assessed by scanning electron microscopy and UV-vis spectroscopy). PMID- 28738545 TI - Municipal wastewater treatment via co-immobilized microalgal-bacterial symbiosis: Microorganism growth and nutrients removal. AB - A symbiotic microalgal-bacterial system may be an optional technology for wastewater treatment. In this study, co-immobilized of a bacterium isolated from a municipal wastewater treatment plant (Pseudomonas putida) and a microalgae Chlorella vulgaris was used in the study of cell growth and nutrient removal during wastewater treatment under batch and continuous culture conditions. Under batch culture conditions, co-immobilization treatment significantly increased the cell density of C. vulgaris and P. putida compared with other treatments. The co immobilized treatment also showed higher removal of ammonium, phosphate and COD than any single treatment, indicating that the nutrient uptake capability of C. vulgaris and P. Putida was mutually enhanced mutually. When tested in continuous mode, the treatment with a hydraulic retention time of 24h at the organic load rate of 1159.2mgCODL-1d-1 was most appropriate for wastewater treatment. PMID- 28738546 TI - A new method for the simultaneous enhancement of methane yield and reduction of hydrogen sulfide production in the anaerobic digestion of waste activated sludge. AB - The biogas generated from anaerobic digestion (AD) also includes undesirable by product such as hydrogen sulfide (H2S), which must be removed before the biogas can be used as a clean energy source. Therefore, it is necessary to find an appropriate strategy to simultaneously enhance the methane yield and reduce H2S production. An efficient strategy-pretreating sludge at pH 10 for 8d and adjusting the system at neutral pH to produce methane for 20d-is reported for the synchronous enhancement of methane production and reduction of H2S production during AD. The experimental results showed that the cumulative methane yield was 861.2+/-6.1mL/g volatile solids (VS) of sludge pretreated at pH 10 in semi continuous stirred anaerobic reactors for 84d, an increase of 49.6% over the yield in the control. Meanwhile, the cumulative production of H2S was 144.1*10 4mL/g VS, 54.2% lower than that in the control. PMID- 28738547 TI - Effect of reflux ratio on nitrogen removal in a novel upflow microaerobic sludge reactor treating piggery wastewater with high ammonium and low COD/TN ratio: Efficiency and quantitative molecular mechanism. AB - A novel upflow microaerobic sludge reactor (UMSR) was constructed to treat manure free piggery wastewater with high NH4+-N and low COD/TN ratio. In the light of the potential effect of effluent reflux ratio (RR) on nitrogen removal, performance of the UMSR was evaluated at 35 degrees C and hydraulic retention time 8h with RR decreased from 45 to 25 by stages. A COD, NH4+-N and TN removal of above 77.1%, 80.0% and 86.6%, respectively, was kept with a RR over 35. To get an effluent of TN not more than 80mg/L with a TN load removal above 0.88kg/(m3.d), the RR should be at least 34. Real-time quantitative polymerase chain reaction of functional bacteria revealed that the RR of less than 34 stimulated ammonium oxidation but badly inhibited anammox, the dominant nitrogen removal pathway, resulting in the remarkable decrease of nitrogen removal in the reactor. PMID- 28738548 TI - Effect of thiosulfate on rapid start-up of sulfur-based reduction of high concentrated perchlorate: A study of kinetics, extracellular polymeric substances (EPS) and bacterial community structure. AB - Perchlorate (ClO4-) contamination is more and more concerned due to the hazards to humans. Based on the common primary bacterium (Helicobacteraceae) of both thiosulfate-acclimated sludge (T-Acc) and sulfur-acclimated sludge (S-Acc) for perchlorate reduction, the rapid start-up of sulfur-based perchlorate reduction reactor (SBPRR) was hypothesized by inoculating T-Acc. Furthermore, the performance of SBPRR, the SO42- yield, kinetics of ClO4- reduction and the extracellular polymeric substances (EPS) of biofilm confirmed the hypothesis. The start-up time of R3 (reactor inoculating T-Acc) was 0.18 and 0.21 times that of R1 (control) and R2 (reactor with the influent containing thiosulfate), respectively. The SO42- yield of R3 was lower than that of R2 and R1 with perchlorate removal rate 166.7mg/(Lh). The kinetic study and EPS demonstrated that inoculating T-Acc was beneficial for the development of biofilm. Consequently, the present study indicated that SBPRR can be rapidly and successfully started-up via inoculation of T-Acc. PMID- 28738549 TI - Chemical and structural characterization of char development during lignocellulosic biomass pyrolysis. AB - The chemical and structural changes of three lignocellulosic biomass samples during pyrolysis were investigated using both conventional and advanced characterization techniques. The use of ATR-FTIR as a characterization tool is extended by the proposal of a method to determine aromaticity, the calculation of both CH2/CH3 ratio and the degree of aromatic ring condensation ((R/C)u). With increasing temperature, the H/C and O/C ratios, XA and CH2/CH3 ratio decreased, while (R/C)u and aromaticity increased. The micropore network developed with increasing temperature, until the coalescence of pores at 1100 degrees C, which can be linked to increasing carbon densification, extent of aromatization and/or graphitization of the biomass chars. WAXRD-CFA measurements indicated the gradual formation of nearly parallel basic structural units with increasing carbonization temperature. The char development can be considered to occur in two steps: elimination of aliphatic compounds at low temperatures, and hydrogen abstraction and aromatic ring condensation at high temperatures. PMID- 28738550 TI - Employing Microbial Electrochemical Technology-driven electro-Fenton oxidation for the removal of recalcitrant organics from sanitary landfill leachate. AB - The feasibility of employing Microbial Electrochemical Technology (MET)-driven electro-Fenton oxidation was evaluated as a post-treatment of an anammox system treating sanitary landfill leachate. Two different MET configuration systems were operated using effluent from partial nitrification-anammox reactor treating mature leachate. In spite of the low organic matter biodegradability of the anammox's effluent (2401+/-562mgCODL-1; 237+/-57mgBOD5L-1), the technology was capable to reach COD removal rates of 1077-1244mgL-1d-1 with concomitant renewable electricity production (43.5+/-2.1Am-3NCC). The operation in continuous mode versus batch mode reinforced the removal capacity of the technology. The recirculation of acidic catholyte into anode chamber hindered the anodic efficiency due to pH stress on anodic electricigens. The obtained results demonstrated that the integrated system is a potentially applicable process to deal with bio-recalcitrant compounds present in mature landfill leachate. PMID- 28738552 TI - Nutrients removal and bacterial community structure for low C/N municipal wastewater using a modified anaerobic/anoxic/oxic (mA2/O) process in North China. AB - A modified anaerobic/anoxic/oxic (mA2/O) process based on utilizing the internal carbon source and adding polypropylene carriers was operated for 90d to investigate the nutrients removal performance and bacterial community. This system exhibited a stable and efficient performance, particularly, in removing the NH4+-N and total phosphorus. The results of high-throughput sequencing showed that the 13 dominant genera containing Pseudomonas, Comamonas, Arcobacter, Nitrobacteria, Nitrosospira, Nitrosomonas, Bacteroides, Flavobacterium, Rhizobium, Acinetobacter, Zoogloea, Rhodocyclus and Moraxella were shared by five zones, inferring that they were the essential players in treating low C/N (below 5.0) municipal wastewater around 10 degrees C. The average abundance of Nitrosospira (4.21%) was higher than that of Nitrosomonas (2.93%), suggested that Nitrosospira performed well under low temperature for nitrification. Additionally, both known Rhodocyclus-related PAOs and GAOs Competibacter were not detected possibly due to low temperature. Redundancy analysis (RDA) indicated that DO played more important roles in regulating bacterial community composition than HRT. PMID- 28738551 TI - Biomass saccharification is largely enhanced by altering wall polymer features and reducing silicon accumulation in rice cultivars harvested from nitrogen fertilizer supply. AB - In this study, two rice cultivars were collected from experimental fields with seven nitrogen fertilizer treatments. All biomass samples contained significantly increased cellulose contents and reduced silica levels, with variable amounts of hemicellulose and lignin from different nitrogen treatments. Under chemical (NaOH, CaO, H2SO4) and physical (hot water) pretreatments, biomass samples exhibited much enhanced hexoses yields from enzymatic hydrolysis, with high bioethanol production from yeast fermentation. Notably, both degree of polymerization (DP) of cellulose and xylose/arabinose (Xyl/Ara) ratio of hemicellulose were reduced in biomass residues, whereas other wall polymer features (cellulose crystallinity and monolignol proportion) were variable. Integrative analysis indicated that cellulose DP, hemicellulosic Xyl/Ara and silica are the major factors that significantly affect cellulose crystallinity and biomass saccharification. Hence, this study has demonstrated that nitrogen fertilizer supply could largely enhance biomass saccharification in rice cultivars, mainly by reducing cellulose DP, hemicellulosic Xyl/Ara and silica in cell walls. PMID- 28738553 TI - Response of soil physicochemical properties and enzyme activities to long-term reclamation of coastal saline soil, Eastern China. AB - Soil enzyme activity during different years of reclamation and land use patterns could indicate changes in soil quality. The objective of this research is to explore the dynamics of 5 soil enzyme activities (dehydrogenase, amylase, urease, acid phosphatase and alkaline phosphatase) involved in C, N, and P cycling and their responses to changes in soil physicochemical properties resulting from long term reclamation of coastal saline soil. Soil samples from a total of 55 sites were collected from a coastal reclamation area with different years of reclamation (0, 7, 32, 40, 63a) in this study. The results showed that both long term reclamation and land use patterns have significant effects on soil physicochemical properties and enzyme activities. Compared with the bare flat, soil water content, soil bulk density, pH and electrical conductivity showed a decreasing trend after reclamation, whereas soil organic carbon, total nitrogen and total phosphorus tended to increase. Dehydrogenase, amylase and acid phosphatase activities initially increased and then decreased with increasing years of reclamation, whereas urease and alkaline phosphatase activities were characterized by an increase-decrease-increase trend. Moreover, urease, acid phosphatase and alkaline phosphatase activities exhibited significant differences between coastal saline soil with 63years of reclamation and bare flat, whereas dehydrogenase and amylase activities remained unchanged. Aquaculture ponds showed higher soil water content, pH and EC but lower soil organic carbon, total nitrogen and total phosphorus than rapeseed, broad bean and wheat fields. Rapeseed, broad bean and wheat fields displayed higher urease and alkaline phosphatase activities and lower dehydrogenase, amylase and acid phosphatase activities compared with aquaculture ponds. Redundancy analysis revealed that the soil physicochemical properties explained 74.5% of the variation in soil enzyme activities and that an obvious relationship existed between soil nutrients and soil enzyme activities. These results will assist governmental evaluation of the quality of reclaimed coastal soil. PMID- 28738554 TI - Amperometric detector for gas chromatography based on a silica sol-gel solid electrolyte. AB - An electrochemical cell comprising a silica sol-gel solid electrolyte, a working electrode that protrudes into a gas phase, and reference and counter electrodes that contact the solid electrolyte comprises an amperometric detector for gas chromatography. Under potentiostatic conditions, a current related to the concentration of an analyte in the gas phase is produced by its oxidation at the three-phase boundary among the sol-gel, working electrode, and the gas phase. The sol-gel is processed to contain an electrolyte that also serves as a humidistat to maintain a constant water activity even in the presence the gas chromatographic mobile phase. Response was demonstrated toward a diverse set of analytes, namely hydrogen, 1,2-ethandithiol, phenol, p-cresol, and thioanisole. Using flow injection amperometry of hydrogen with He as the carrier gas, 90% of the steady-state current was achieved in < 1s at a flow rate of 20mLmin-1. A separation of 1,2-ethandithiol, phenol, p-cresol, and thioanisole at a 2.2mLmin-1 flow rate was achieved with respective detection limits (k = 3 criterion) of 4, 1, 3, and 70 ppmv when the working electrode potential was 800mV. PMID- 28738555 TI - Assessment of mercury speciation in feathers using species-specific isotope dilution analysis. AB - Seabirds are considered as effective sentinels of environmental marine contamination and their feathers are extensively used as non-lethal samples for contaminant biomonitoring. This tissue represents the main route for mercury (Hg) elimination in seabirds and contains predominantly methylmercury (MeHg). In this work, we developed a robust analytical technique for precise and accurate simultaneous quantification of MeHg, inorganic Hg (iHg) and consequently total Hg (THg), in feathers by gas-chromatography (GC)-ICPMS analyses using species specific isotope dilution technique. An optimisation of the extraction method was carried out by testing different extraction systems, reagents and spiking procedures using an internal reference feather sample. The procedure was validated for MeHg and THg concentrations with a human hair certified reference material. Microwave nitric acid extraction with spike addition before the extraction provided the best recovery and was chosen as the most appropriate species simultaneous extraction method (SSE). An additional assessment was performed by comparison of our developed extraction method and a MeHg specific extraction technique (MSE) classically used for Hg speciation studies on feathers. The developed method was applied to feather samples from a large number of seabirds from the Southern Ocean (penguins, albatrosses, petrels and skuas) to investigate the variability of Hg speciation across a large range of Hg exposure conditions and concentrations. In all cases, MeHg accounted for > 90% of THg, thus verifying the predominance of organic Hg over iHg in feathers. PMID- 28738556 TI - Development of a new sample preparation method based on liquid-liquid-liquid extraction combined with dispersive liquid-liquid microextraction and its application on unfiltered samples containing high content of solids. AB - A new sample preparation method based on liquid-liquid-liquid extraction combined with dispersive liquid-liquid microextraction followed by gas chromatography flame ionization detection has been reported for the extraction/preconcentration and determination of trace levels of twelve pesticide residues from different samples with high content of solids without filtration. This method consists of a three-phase system including an aqueous phase (sample solution), acetonitrile, and hexane. The extraction mechanism is based on different affinities of the substances from the sample matrices towards each of the involved phase, which provides a high selectivity to the process. In other words, interfering hydrophobic compounds are transferred into hexane and will not be present in the final extract. Furthermore, ionic and polar compounds are retained in the aqueous phase. Therefore, only semi-polar compounds such as the studied pesticides are extracted into acetonitrile. In this method, a homogeneous solution of the aqueous phase and acetonitrile (a water-soluble extraction solvent) forms two clearly separated phases in the presence of sodium sulfate (as a phase separation agent) and simultaneously the analytes are extracted into the fine droplets of the acetonitrile collected on the surface of the aqueous phase. To achieve high enrichment factors, the acetonitrile phase is mixed with 1,2-dibromoethane (as a preconcentration solvent) at uL-level to perform the following dispersive liquid liquid microextraction procedure. Several parameters that can affect extraction efficiency including kind and volume of extraction solvent, type and concentration of phase separation agent, hexane volume, kind of preconcentration solvent, and ionic strength were studied and optimized. Under the optimal conditions, extraction recoveries were obtained in the range of 53-93% and the calibration curves were linear in wide ranges with correlation coefficients >= 0.9983. Intra- (n = 6) and inter-day (n=5) precisions of the method were satisfactory with relative standard deviations less than or equal to 7% (at two concentrations of 10 and 50ugL-1 of each analyte). Moreover, the detection limits and enrichment factors of the target analytes were obtained in the ranges of 0.43 1.2ugL-1 and 264-464, respectively. Finally, the proposed method was applied on different fruit and vegetable samples and diazinon was determined in apple sample at a concentration of 0.030ugg-1. PMID- 28738557 TI - Multielemental analysis of 18 essential and toxic elements in amniotic fluid samples by ICP-MS: Full procedure validation and estimation of measurement uncertainty. AB - Amniotic fluid is the substantial factor in the development of an embryo and fetus due to the fact that water and solutes contained in it penetrate the fetal membranes in an hydrostatic and osmotic way as well as being swallowed by the fetus. Elemental composition of amniotic fluid influences the growth and health of the fetus, therefore, an analysis of amniotic fluid is important because the results would indicate abnormal levels of minerals or toxic elements. Inductively coupled plasma mass spectroscopy (ICP-MS) is often used for determination of trace and ultra-trace level elements in a wide range of matrices including biological samples because of its unique analytical capabilities. In the case of trace and ultra-trace level analysis detailed characteristics of analytical procedure as well as properties of the analytical result are particularly important. The purpose of this study was to develop a new analytical procedure for multielemental analysis of 18 elements (Al, As, Ba, Ca, Cd, Co, Cr, Cu, Mg, Mn, Ni, Pb, Sb, Se, Sr, U, V and Zn) in amniotic fluid samples using ICP-MS. Dynamic reaction cell (DRC) with two reaction gases, ammonia and oxygen, was involved in the experiment to eliminate spectral interferences. Detailed validation was conducted using 3 certified reference mterials (CRMs) and real amniotic fluid samples collected from patients. Repeatability for all analyzed analytes was found to range from 0.70% to 8.0% and for intermediate precision results varied from 1.3% to 15%. Trueness expressed as recovery ranged from 80% to 125%. Traceability was assured through the analyses of CRMs. Uncertainty of the results was also evaluated using single-laboratory validation approach. The obtained expanded uncertainty (U) results for CRMs, expressed as a percentage of the concentration of an analyte, were found to be between 8.3% for V and 45% for Cd. Standard uncertainty of the precision was found to have a greater influence on the combined standard uncertainty than on trueness factor. PMID- 28738558 TI - Elemental source attribution signatures for calcium ammonium nitrate (CAN) fertilizers used in homemade explosives. AB - Calcium ammonium nitrate (CAN) is a widely available fertilizer composed of ammonium nitrate (AN) mixed with some form of calcium carbonate such as limestone or dolomite. CAN is also frequently used to make homemade explosives. The potential of using elemental profiling and chemometrics to match both pristine and reprocessed CAN fertilizers to their factories of origin for use in future forensic investigations was examined. Inductively coupled plasma-mass spectrometry (ICP-MS) was used to determine the concentrations of 64 elements in 125 samples from 11 CAN stocks from 6 different CAN factories. Using Fisher ratio and degree-of-class-separation, the elements Na, V, Mn, Cu, Ga, Sr, Ba and U were selected for classification of the CAN samples into 5 factory groups; one group was two factories from the same fertilizer company. Partial least squares discriminant analysis (PLSDA) was used to develop a classification model which was tested on a separate set of samples. The test set included samples that were analyzed at a different time period and samples from factory stocks that were not part of the training set. For pristine CAN samples, i.e., unadulterated prills, 73% of the test samples were matched to their correct factory group with the remaining 27% undetermined using strict classification. The same PLSDA model was used to correctly match all CAN samples that were reprocessed by mixing with powdered sugar. For CAN samples that were reprocessed by mixing with aluminum or by extraction of AN with tap or bottled water, correct classification was observed for one factory group, but source matching was confounded with adulterant interference for two other factories. The elemental signatures of the water-insoluble (calcium carbonate) portions of CAN provided a greater degree of discrimination between factories than the water-soluble portions of CAN. In summary, this work illustrates the strong potential for matching unadulterated CAN fertilizer samples to their manufacturing facility using elemental profiling and chemometrics. The effectiveness of this method for source determination of reprocessed CAN is dependent on how much an adulterant alters the recovered elemental profile of CAN. PMID- 28738559 TI - A novel dianionic amino acid ionic liquid-coated PEG 4000 modified Fe3O4 nanocomposite for the magnetic solid-phase extraction of trypsin. AB - A novel magnetic extractant, PEG 4000 modified Fe3O4nanomaterial that coated with dianionic amino acid ionic liquid (Fe3O4@PEG@DAAAIL), was successfully synthesized and characterized. X-ray diffraction (XRD), transmission electron microscope (TEM), vibrating sample magnetometer (VSM), fourier transform infrared spectrometry (FT-IR), thermal gravimetric analysis (TGA) and zeta potentials were used to confirm that the novel nanocomposite was successfully synthesized. Subsequently, the prepared Fe3O4@PEG@DAAAIL nanocomposite was used as the extractant for trypsin coupled with magnetic solid-phase extraction (MSPE). The concentrations of trypsin in the supernatant were detected by UV-vis spectrophotometer at 278nm. The extraction ability turned out to be better than the other four kinds of extractants prepared in this work. Furthermore, the influence of a series of factors, such as extraction time and temperature, initial trypsin concentration, the value of pH and ionic strength, was systematically investigated. Under the optimal extraction condition, the extraction capacity for trypsin could reach up to 718.73mg/g, absolutely higher than that of other adsorbents reported. This satisfactory extraction capacity could be maintained unchangeable after at least eight days, and kept over 90% of initial extraction capacity after eight recycles. What's more, the activity of trypsin after extraction retained 92.29% of initial activity, verifying the biocompatibility of the prepared extractant. Finally, the developed Fe3O4@PEG@DAAAIL-MSPE method was successfully applied to the real sample analysis with satisfactory results. All of above proves the potential value of Fe3O4@PEG@DAAAIL-MSPE in the analysis of biomass. PMID- 28738560 TI - Novel metal nanoparticle-enhanced fluorescence for determination of trace amounts of fluoroquinolone in aqueous solutions. AB - Metal-enhanced fluorescence of fluoroquinolones (FQs) was first observed in aqueous solutions. In addition, a new type of silver nanoparticles (AgNP) was synthesized with simple and easy synthetic processes and environmentally friendly compounds. The effects of different concentrations of AgNPs on the fluorescence behaviours of ciprofloxacin (CIP), enrofloxacin (ENR) and lomefloxacin (LMF) in aqueous solutions were investigated, respectively. The experimental results demonstrated that the fluorescence peak shapes and the locations of the features in the excitation and emission spectra for each FQ that was mixed with AgNPs were almost the same as those of the standard FQs. An enhancement or quenching of the fluorescence can also be observed, depending on the exact conditions. Compared with the identical control samples that lack AgNPs, the fluorescence of each FQ in aqueous solutions was greatly enhanced by AgNPs with concentrations at a volume ratio of 5%. Moreover, at the optimum AgNP concentration, novel sensitive fluorometric methods for the separate determination of trace amounts of CIP, ENR and LMF in aqueous solutions were established. Under optimal experimental conditions, the linear dynamic ranges for the determination of CIP, ENR and LMF concentrations varied from 0.025 to 1.0mgL-1, 5.0 to 160ngL-1 and 0.01 to 0.8mgL 1, and the limits of detection were 90, 5 and 6ngL-1, respectively; the relative standard deviation was less than 1.2% (n = 9). The experimental recovery results for the determination of CIP, ENR and LMF in aqueous solutions ranged from 99% to 102%, 90% to 103% and 92% to 107%, respectively. Compared with the established method in which no AgNPs were added, the quantitation limits of the silver nanoparticle-enhanced fluorometric methods were approximately 2-fold lower for CIP, 2.6-fold lower for ENR and 4-fold lower for LMF. Significantly, the novel silver nanoparticle-enhanced fluorometric methods were successfully applied to directly determine CIP, ENR and LMF concentrations in pharmaceutical preparations, demonstrating the methods' advantages of simplicity, sensitivity and low cost. PMID- 28738561 TI - Silver triangular nanoplates as an high efficiently FRET donor-acceptor of upconversion nanoparticles for ultrasensitive "Turn on-off" protamine and trypsin sensor. AB - Silver triangular nanoplates (STNPs) as a high efficient fluorescence quenching reagent of upconversion nanoparticles (UCNPs) was used to constract a novel label free fluorescence nanosensor for ultrasensitive detection of protamine and trypsin based on fluorescence resonance energy transfer (FRET) between STNPs and UCNPs. In this assay, the negatively charged STNPs can bind with positively charged UCNPs through electrostatic interaction, and then quenched the fluorescence of UCNPs. When protamine was added to the mixture of UCNPs-STNPs, the STNPs interacted with protamine and then detached from the surface of UCNPs and aggregated, which result in the recovery of the fluorescence of UCNPs. Trypsin could catalyze the hydrolysis of protamine and effectively quench the fluorescence recovered by protamine. By measuring the changes of the fluorescence of UCNPs, the concentrations of protamine and trypsin were determined. Under the optimized conditions, the linear response range was obtained from 10 to 500ng/mL, 5-80ng/mL and with the low detection limit of 3.1ng/mL and 1.8ng/mL for protamine and trypsin, respectively. Meanwhile, the nanosensor shows good selectivity, sensitivity and can be successfully applied to detection of protamine and trypsin in serum samples. PMID- 28738562 TI - Comment on "Volatile methylsiloxanes in personal care products - Using QuEChERS as a "green" analytical approach" by Daniela Capela, Vera Homem, Arminda Alves, Lucia Santos. AB - In this recent paper, Capela et al. (2016) [1] describe an analytical method for determination of volatile methylsiloxanes (VMS) in a variety of personal care products (PCPs) using QuEChERS methodology (Lehotay et al., 2010) [2]. Subsequently, this method was then used by the authors to measure VMS levels in a cross-section of PCPs to estimate average daily dermal exposure, average daily inhalation exposure, and down the drain emissions of VMS components to the environment (Capela et al., 2016) [3]. The authors are commended for selecting a broad range of sample types for the investigation and for thoroughly describing the approaches used to validate the method. However, a careful analysis of the reported cyclic volatile methylsiloxane (cVMS) concentrations raises concerns that artifacts of cVMS analysis were not adequately controlled for in the method used to determine the cVMS concentrations in PCPs. The comments presented here apply beyond this particular article and serve as an opportunity to inform other researchers about the potential pitfalls and difficulties associated with cyclosiloxane analyses, even with what might appear to be a successfully validated method, while providing examples of the concerns and precautions that must be taken into consideration whenever analyzing for cVMS in complex matrices such as PCPs. PMID- 28738563 TI - Urinary volatile fingerprint based on mass spectrometry for the discrimination of patients with lung cancer and controls. AB - Profile signals of urine samples corresponding to patients with lung cancer and controls were obtained using a non-separative methodology. The method is based on the coupling of a headspace sampler, a programed temperature vaporizer and a mass spectrometer (HS-PTV-MS). With only a centrifugation step as prior sample treatment, the samples were subjected to the headspace generation process and the volatiles generated were introduced into the PTV where they were trapped in the Tenax(r) packed liner while the solvent was purged. Finally, the analytes were introduced directly, without separation, into the mass spectrometer which allows obtaining the fingerprint of the analyzed sample. The mass spectrum corresponding to the mass/charge ratios (m/z) ranging between 35 and 120amu (amu) contains the information related to the composition of the headspace and is used as the analytical signal for the characterization of the samples. Samples of 14 patients with some type of cancer and 24 healthy volunteers were analyzed and the profile signals were subjected to different chemometric techniques, including support vector machines (SVM), linear discriminant analysis (LDA) and partial least squares- discriminant analysis (PLS-DA), with the aim of differentiating the samples of patients with cancer from those of control. Values of 100% were obtained both in sensitivity and specificity in most cases. This methodology has been used previously, as described later, for the analysis of the fingerprint corresponding to saliva samples of patients and controls. However, up to date, the method has not been used in urine samples with the aim of fast discrimination between patients with cancer and controls. The advantages and disadvantages of using urine versus other types of matrices such as saliva are stated. In view of the results obtained in this work, the use of pattern recognition techniques with data corresponding to HS-PTV-MS profile signals is highly suitable as a first screening step to differentiate samples. In addition, it could be applied to a high number of samples in a relatively short period of time due to its high throughput. PMID- 28738564 TI - Determination of iodide and total iodine in estuarine waters by cathodic stripping voltammetry using a vibrating silver amalgam microwire electrode. AB - Iodide in natural waters is an important nutrient to aquatic organisms and its determination is of relevance to marine aquaculture. For this reason it is of interest to have a simple analytical method for determination of iodide in water samples. Iodide in seawater can be determined electrochemically by cathodic stripping voltammetry (CSV) with a mercury drop electrode which has environmental drawbacks. In an attempt to minimise the use of mercury in voltammetry, a vibrating silver amalgam microwire electrode is used here for the determination by CSV of iodide speciation in natural waters including seawater. Microwire electrodes were made from silver wires (diameter: 12.5um) and electrochemically coated with mercury. The electrode surface was stable for extended periods of analyses (at least one week) and was then replaced. The optimised conditions include a pH 8, a frequency of 500Hz and a deposition time of 60s, among others. The microwire was reactivated between scans using a conditioning potential at -3 V for 1s. The detection limit for iodide in seawater was found to be 0.7nM I- at a deposition time of 60s. The response increased linearly with the concentration of iodide in seawater up to 100nM I-. The method was successfully applied to various samples from the estuary of the river Mersey (Liverpool Bay). An existing procedure for iodine speciation was modified to enable determination of iodate and total iodine as well as iodide in estuarine waters. PMID- 28738565 TI - Zwitterionic hydrophilic interaction liquid chromatography-tandem mass spectrometry with HybridSPE-precipitation for the determination of intact cisplatin in human plasma. AB - Cisplatin is a first-line chemotherapeutic for the treatment of a wide variety of cancers since its discovery in the 1960s. Although various techniques have been reported for the measurement of total platinum in biological matrices, such as inductively coupled plasma-mass spectrometry and derivatization procedures, a specific, sensitive and robust assay for the quantification of intact cisplatin is still lacking. Therefore, we present a rapid, selective, sensitive, and reliable UHPLC-MS/MS based method for the determination of intact cisplatin in human plasma in support of a Phase II clinical trial. The optimal chromatographic behavior of cisplatin was achieved on a Syncronis HILIC column (50 * 2.1mm, 1.7um, zwitterionic stationary phase). The retention behavior of cisplatin on this zwitterion-based stationary phase was well described by an adsorptive interaction model. A simple sample preparation based on protein precipitation combined with the removal of phospholipids by HybridSPE-precipitation was developed. The method was proven to be free of a relative matrix effect. The assay was validated within a range of 20 - 10,000ng/mL using 100MUL of plasma sample. The intra and inter-day precisions were all less than 7.6%, and none of the bias was greater than 13.1%, thus corroborating that the developed method is precise and accurate. As a proof of concept, the assay has been successfully applied to plasma samples obtained from different patients who were enrolled in the Phase II trial and were treated with cisplatin. PMID- 28738566 TI - Preparation and evaluation of a novel N-benzyl-phenethylamino-beta-cyclodextrin bonded chiral stationary phase for HPLC. AB - A novel N-benzyl-phenethylamino-beta-cyclodextrin-bonded ordered mesoporous SBA 15 chiral stationary phase (BZCDP) for high-performance liquid chromatography (HPLC) was prepared. The structure and morphology of the ligand and the stationary phase were characterized by mass spectrometry, elemental analysis, infrared spectroscopy, scanning electron microscopy, transmission electron microscopy and thermogravimetric analysis. The enantiomers of chiral compounds including nine common beta-adrenergic blocker drugs (beta-blockers), eight dansyl amino acids (DNS-AA) and six flavanones were successfully separated by polar organic solvent and reversed-phase chromatography, respectively. The results showed that BZCDP was a kind of multimode chiral separation materials with an excellent chromatographic performance for the above compounds. In polar organic solvent mode, BZCDP can effectively separate beta-blockers, in which the enantioselectivity factors and resolutions of beta-blockers were up to 1.30 and 1.97 within 20min, respectively. Under the reversed-phase mode, BZCDP exhibited high enantioselectivities for DNS-AA, among them the resolution of dansyl tyrosine was 3.29 with 20min. BZCDP was also successfully used to separate the flavanone compounds with methanol or acetonitrile as mobile phase. The resolution of 4'-hydroxy flavanone enantiomers reached to 3.65 about 15min. Compared with the native beta-cyclodextrin and gamma-cyclodextrin-bonded stationary phases in the literature, the separation speed of BZCDP containing mono-N-benzyl phenethylamino-beta-cyclodextrin ligand was faster and the separation selectivity was better, which indicated that the N-benzyl-phenethylamino group could also take part in the chiral recognition. After further study, we found that in polar organic solvent mode, the inclusion and hydrogen bonding were the main forces of chiral separations, and in reversed-phase mode, the inclusion and hydrophobic interaction are the main driving forces for chiral separations. Besides excellent chromatographic performance, the home-made cyclodextrin column with mesoporous SBA-15 as the matrix was much cheaper than commercial columns, and good permeability, which can reduce the cost of test and provide fast separation. BZCDP has a good prospect in chiral drug analysis. PMID- 28738567 TI - Application of thermoresponsive hydrogel/gold nanorods composites in the detection of diquat. AB - Gallic acid (GA) was employed as a reducing agent for facile in situ preparation of gold nanorods (GNRs) in thermoresponsive P(NIPAM-NVP) hydrogel films. Based on the surface-enhanced Raman scattering (SERS) effect of GNRs and the enrichment effect of thermoresponsive hydrogel film on test molecules through a shrinkage process, the obtained P(NIPAM-NVP)/GNRs composites have been used as SERS substrate for the rapid detection of diquat. The influences of substrate pre treatment, laser wavelength, and sample treatment method on diquat determination have been investigated comprehensively. The results showed the composite material to be a good SERS substrate for highly sensitive detection and a promising preconcentration matrix of diquat. The limit of detection of the proposed protocol was estimated to be 2.7*10-13molL-1 for diquat. Notably, diquat could be concentrated with the enrichment factor of about 4 after three times swelling shrinking processes of the hydrogel film. PMID- 28738568 TI - Novel imidazole fluorescent poly(ionic liquid) nanoparticles for selective and sensitive determination of pyrogallol. AB - This paper reports novel imidazole fluorescent poly(ionic liquid) nanoparticles (FPILNs) of poly(1-[(4-methyphenyl)methyl]-3-vinyl-imidazolium bromide (poly([MVI]Br) for selective and sensitive determination of pyrogallol. An imidazole ionic liquid of 1-[(4-methyphenyl)methyl]-3-vinyl-imidazolium bromide ([MVI]Br) was synthesized and used as the only monomer to obtain poly([MVI]Br) possessing phenyl fluorophores using a radical polymerization technique. The obtained poly([MVI]Br) can form nanoparticles in water. Scanning electron microscopy and dynamic light scattering results revealed majority of poly([MVI]Br) FPILNs with diameters ranging from 40 to 400nm. Although [MVI]Br showed weak fluorescence intensity, poly([MVI]Br) FPILNs exhibited strong fluorescence intensity with a quantum yield of 0.192, which is attributed to the presence of significant number of phenyl fluorophores and rigid construction. The selective and sensitive determination of pyrogallol was achieved through fluorescence quenching of poly([MVI]Br) FPILNs, and the quenching was attributed to the oxidation of poly([MVI]Br) FPILNs by O2- produced by pyrogallol autoxidation. The poly([MVI]Br) FPILNs-based sensor demonstrated a good linear relationship between the extent of fluorescence quenching and the concentration of pyrogallol in a range of 0.05 - 10.0MUM, achieving a detection limit of 0.01MUM. Furthermore, the poly([MVI]Br) FPILNs-based assay detected pyrogallol in environmental water samples, suggesting its potential to be applied for practical purposes. PMID- 28738569 TI - Optoacoustic determination of analytical parameters and physicochemical constants in highly concentrated solutions of chromophores. AB - Determination of chromophores of various classes-rosaniline (fuchsine), cyanidin 3-O-glucoside, tris(1,10-phenanthroline) iron(II), and phenol red - in their concentrated solutions near their solubility limits is performed with the optoacoustic technique for optically dense solutions; light-absorption coefficients of samples range from 0.5 to 500cm-1. The assessment of these substances in organo-aqueous and organic solvents is possible up to ca. 0.1molL 1. Characteristic stability and rate constants of the chelation of iron(II) with 1,10-phenanthroline are determined. It was found that turbidities up to 200 FTU and dynamic viscosities up to 20mPas do not affect the determination. The determination of total anthocyanins (as cyanidin-3-O-glucoside) in bilberry and sweet-cherry juices agrees with the reference spectrophotometric method and demonstrates the possibilities of the optoacoustic technique for the analysis of real samples without dilution and with almost no sample preparation. PMID- 28738570 TI - Determination of selected bisphenols, parabens and estrogens in human plasma using LC-MS/MS. AB - In this study, a novel liquid chromatography - tandem mass spectrometry method for the simultaneous determination of bisphenols (BPA, BPS, BPF, BPAF), parabens (methyl-, ethyl-, propyl-, butyl-, benzyl-paraben) and estrogens (estrone, estradiol, estriol) in human plasma is presented. Since all analytes possess the phenolic group, dansyl chloride derivatization was applied in order to gain high sensitivity. The method was validated according to FDA guidelines, and all validation requirements were satisfactory. The lower limits of quantifications were 41.6, 54.9, 43.5 and 150.8pg/mL for BPA, BPS, BPF and BPAF; 172, 149, 171, 134 and 202pg/mL for methyl-, ethyl-, propyl-, butyl- and benzyl-paraben; 10.5, 6.7 and 9.4pg/mL for estrone, estradiol and estriol, respectively. This is the first method allowing the determination of plasma bisphenols, parabens and estrogens in one run, and also the first determination of BPF levels in human plasma. The method was used to examine the plasma levels of healthy normospermic men, where three times higher plasma levels of BPF than BPA were found. PMID- 28738571 TI - Determination of polycyclic aromatic hydrocarbons in infant formula using solid state urea clathrate formation with gas chromatography - tandem mass spectrometry. AB - An analytical method has been developed for the quantitative determination of the 16 EU priority polycyclic aromatic hydrocarbons (PAHs) in infant formula. Prior to analysis infant formula is subjected to sample preparation including the extraction of PAHs from the sample, transesterification of the triglyceride content of the extract to fatty acid methyl esters (FAMEs), and solid state urea clathrate formation to remove the FAMEs. Measurements were carried out with gas chromatography - tandem mass spectrometry. The developed method has been evaluated in terms of trueness, precision (repeatability), limit of detection (LOD), limit of quantification (LOQ), selectivity, sensitivity and linearity. Measurement range of 200-1500ngkg-1 was selected in accordance with the limit values set by the European Commission (835/2011/EC). LOD values were 75ngkg-1 for dibenzo(a,e)pyrene, dibenzo(a,i)pyrene and dibenzo(a,h)pyrene while 50ngkg-1 for the rest of the PAHs (benzo(c)fluorene, benzo(a)anthracene, cyclopenta(cd)pyrene, chrysene, 5-methylchrysene, benzo(b)fluoranthene, benzo(k)fluoranthene, benzo(j)fluoranthene, benzo(a)pyrene, indeno(1,2,3-cd)pyrene, dibenzo(a,h)anthracene, benzo(g,h,i)perylene, dibenzo(a,l)pyrene), LOQ was 200ngkg-1 for all 16 PAHs. Trueness ranged between -29.7 and 29.8% while precision values were between 0.5 and 24.7% (RSD, n=3). PMID- 28738572 TI - Sequential determination of nickel and cadmium in tobacco, molasses and refill solutions for e-cigarettes samples by molecular fluorescence. AB - In this work, a new procedure was developed for separation and preconcentration of nickel(II) and cadmium(II) in several and varied tobacco samples. Tobacco samples were selected considering the main products consumed by segments of the population, in particular the age (youth) and lifestyle of the consumer. To guarantee representative samples, a randomized strategy of sampling was used. In the first step, a chemofiltration on nylon membrane is carried out employing eosin (Eo) and carbon nanotubes dispersed in sodium dodecylsulfate (SDS) solution (phosphate buffer pH 7). In this condition, Ni(II) was selectively retained on the solid support. After that, the filtrate liquid with Cd(II) was re-conditioned with acetic acid /acetate buffer solution (pH 5) and followed by detection. A spectrofluorimetric determination of both metals was carried out, on the solid support and the filtered aqueous solution, for Ni(II) and Cd(II), respectively. The solid surface fluorescence (SSF) determination was performed at lambdaem = 545nm (lambdaex = 515nm) for Ni(II)-Eo complex and the fluorescence of Cd(II)-Eo was quantified in aqueous solution using lambdaem = 565nm (lambdaex = 540nm). The calibration graphs resulted linear in a range of 0.058-29.35MUgL-1 for Ni(II) and 0.124-56.20MUgL-1 for Cd(II), with detection limits of 0.019 and 0.041MUgL-1 (S/N = 3). The developed methodology shows good sensitivity and adequate selectivity, and it was successfully applied to the determination of trace amounts of nickel and cadmium present in tobacco samples (refill solutions for e-cigarettes, snuff used in narguille (molasses) and traditional tobacco) with satisfactory results. The new methodology was validated by ICP-MS with adequate agreement. The proposed methodology represents a novel fluorescence application to Ni(II) and Cd(II) quantification with sensitivity and accuracy similar to atomic spectroscopies, introducing for the first time the quenching effect on SSF. PMID- 28738573 TI - Stable isotope ratio analysis for authentication of red yeast rice. AB - Red yeast rice (RYR) is a dietary supplement obtained from rice fermented with the mould Monascus purpureus. It contains Monacolin K which is a hypocholesterolemic statin used to prevent cardiovascular diseases. The homologous prescription biosynthetic statin, lovastatin, is not chemically distinguishable from monacolin K. In this work we investigated whether delta13C and delta2H can distinguish monacolin K from lovastatin and can detect the presence of lovastatin in RYR. 18 samples of red yeast rice powder and 18 samples of lovastatin were collected. Monacolin K was isolated from RYR using preparative HPLC and together with lovastatin, was subjected to analysis of delta13C and delta2H using Isotope Ratio Mass Spectrometry. Thanks to the different photosynthetic cycles of the matrices used for their synthesis, monacolin K and lovastatin have different delta13C values (-29.60/00 +/- 0.6 and -16.70/00 +/- 2.6 respectively). delta2H is significantly (p < 0.001) lower in monacolin K but the ranges of values partially overlap with those of lovastatin. By defining a delta13C threshold value of -28.30/00 for monacolin K, addition of lovastatin from a minimum of 10% can be identified. delta13C analysis can be therefore proposed as a suitable tool for detecting the authenticity of RYR on the market. PMID- 28738574 TI - A highly selective and sensitive fluorescent probe for hypochlorous acid and its lysosome-targetable biological applications. AB - A novel lysosome-targetable fluorescence probe PT-1 based on a photoinduced electron transfer (PET) mechanism has been designed and synthesized. For comparison, the probe PT-2 without morpholine moiety as a lysosome-directing group was also synthesized and investigated. Probes PT-1 and PT-2 exhibited high selectivity, high sensitivity (with the detection limits down to the 10-10M range) and response in real time (within 10s) toward HOCl over other reactive oxygen species (ROS). Both PT-1 and PT-2 were cell permeable and enabled them to be used for monitoring of HOCl in living cells. Meanwhile, the probe PT-1 demonstrated an accurately lysosome-targeting ability, and was successfully applied to image of exogenous, endogenous produced HOCl in living cells. The success of subcellular imaging suggested that the probe PT-1 could be used in further applications for the investigation of biological functions and pathological roles of HOCl at organelle levels. PMID- 28738575 TI - Analytical methodology for the electro-catalytic determination of estradiol and progesterone based on graphene quantum dots and poly(sulfosalicylic acid) co modified electrode. AB - The goal of this study was to develop an electroanalytical method for the simultaneous determination of steroid hormones for the first time. The key factor in the electrochemical methods is the choice of suitable electrode materials. For this purpose, graphene quantum dots (GQDs) doped poly(sulfosalicylic acid) (PSSA) was immobilized on a glassy carbon electrode (GCE). Apart from exhibition strong and stable electrocatalytic response towards estradiol (E2) and progesterone (P4), the proposed sensor was able to distinguish two hormone's oxidation peaks clearly. Under the optimal conditions, for selective determination of E2, good linear relationships were obtained in the range of 0.001-6.0MUmolL-1, with detection limit of 0.23nmolL-1, and for P4 in the range of 0.001-6.0MUmolL-1, with the detection limit of 0.31nmolL-1. The prepared sensor possessed accurate and rapid response toward E2 and P4 with an improved stability, selectivity and repeatability. More importantly, the facile and environment-friendly electrochemical construction strategy provided here, may be open a cost-effective way for setting up nanocomposites or nanohybrid-based sensing platform, which extend the application of electrochemical sensor for the green, facile and sensitive analysis of electroactive compounds in biological systems and pharmaceutical formulations. PMID- 28738576 TI - Development of pH-responsive polymer and citrate aqueous two-phase system for extractive bioconversion of cefprozil. AB - A pH-responsive aqueous two-phase system (pH-ATPS) has been developed by sodium citrate and a recyclable pH-responsive polymer PADB6.8 that can response to the change of pH values. Phase separation mechanism is studied through Low field-NMR. All variables affecting the phase separation are evaluated. Phase characteristics (viscosity, density, interfacial tension) and phase separation kinetic are studied for understanding of separation process and operational parameters in applications. This pH-ATPS has the characters of low interfacial tension, high recovery leading efficient mass transfer and low cost. The proposed system can be used as a mild medium for extractive bioconversion with low cost. We applied this pH-ATPS in extractive bioconversion of cefprozil. Cefprozil is partitioned towards the polymer-rich phase while the substrates tended to be partitioned in the salt-rich phase. Extractive bioconversion of cefprozil in this pH-ATPS can improve yield of the enzymatic process and reduce the product hydrolysis in optimal conditions. The maximal conversion yield of cefprozil in the studied system is 91.0%. PMID- 28738578 TI - A simple method for the multi-elemental analysis of beer using total reflection X ray fluorescence. AB - A method of direct analysis for quantification of 15 inorganic elements (P, S, Cl, K, Ca, Mn, Fe, Ni, Cu, Zn, Br, As, Rb, Sr and Pb) in beers by Total Reflection X-Ray Fluorescence (TXRF) was developed. The experimental conditions were optimized. Direct analysis was compared with the acid digestion procedure to evaluate the effect matrix and the results were satisfactory. The evaluation of the accuracy and precision was realized by analysis of two certified reference materials of natural and waste water. For the majority of the elements, good agreement was achieved between the certified value and the value measured in the CRM's. Low detection limits were obtained and it was adequate to determine trace elements in beers and to quality control Pb and As, whose maximum limits are 200 and 100ugL-1, respectively. The relative standard deviation (RSD%) ranged from 2.4% to 10%. The method was applied to 30 beer samples collected in several regions of Brazil. The concentration ranges (mgL-1) for the studied analytes were: P: (37.40-140.85); S (10.32-50.73); Cl (82.74-281.7); K (183.8-418.5); Ca (9.82-96.0); Mn (0.06-1.42); Fe (0.07-1.57); Ni (< LLD-1.13); Cu (< LLD-0.32); Zn (0.02-1.98); As (< LLD-0.10); Br (0.01-2.04); Rb (< LLD-0.52); Sr (< LLD-0.41) and Pb (< LLD-0.18). Some beer samples showed As and Pb concentrations above the levels established by Brazilian legislation. The developed method is simple, fast, consumes low amounts of reagents and allows the determination of a large number of analytes simultaneously. TXRF proved to be attractive and useful for routine analysis. PMID- 28738577 TI - High-bright fluorescent carbon dot as versatile sensing platform. AB - The surface functionalization will introduce additional functional groups on carbon dots (CDs) surface and then enrich the properties of CDs. Here, we show the various surface functionalized CDs (-COOH, -OH, -SH, -NH2, etc, named as NS CDs) were synthesized with fascinating features, including high quantum efficiency (38.9%), long-term stability and good biocompatibility. Notably, it can serve as multifunction fluorescent probe in sensing system, including label free detections in hydrogen peroxide (H2O2) with a wide linear range (1.20 * 10-3 - 8.80 * 10-12M) and a low limit of detection (LOD, 1.00 * 10-12M); and glutathione, covering a concentration range of 2.00 * 10-3 - 1.00 * 10-7M and LOD of 1.00 * 10-7M. In addition, the NS-CDs as fluorescent probe could selectively detect metal ions (such as, Hg2+, 1.00 * 10-8 - 1.50 * 10-3M, 1.00 * 10-7M), antibiotics (tetracycline, 1.00 *10-10 - 2.50 * 10-5M, 1.00 *10-10M) and toxic pollutant (nitrobenzene, 5.00 * 10-7 to 1.00 * 10-3gL-1, 5.00 * 10-7gL-1) with wide linear range and satisfactory detection limits. PMID- 28738579 TI - Compositional engineering of VOPcPhO-TiO2 nano-composite to reduce the absolute threshold value of humidity sensors. AB - This research work demonstrates compositional engineering of an organic-inorganic hybrid nano-composites for modifying absolute threshold of humidity sensors. Vanadyl-2,9,16,23-tetraphenoxy-29H,31H-phthalocyanine (VOPcPhO), an organic semiconductor, doped with Titanium-dioxide nanoparticles (TiO2 NPs) has been employed to fabricate humidity sensors. The morphology of the VOPcPhO:TiO2 nano composite films has been analyzed by atomic force microscopy (AFM) and field emission scanning electron microscopy (FESEM). The sensors have been examined over a wide range of relative humidity i.e. 20-99% RH. The sensor with TiO2 (90nm) shows reduced sensitivity-threshold and improved linearity. The VOPcPhO:TiO2 (90nm) nano-composite film is comprised of uniformly distributed voids which makes the surface more favorable for adsorption of moisture content from environment. The VOPcPhO:TiO2 nano-composite based sensor demonstrates remarkable improvement in the sensing parameter when equated with VOPcPhO sensors. PMID- 28738580 TI - True lab-in-a-syringe technology for bioassays. AB - In our work, we introduced a novel concept of the lab-in-a-syringe tests. We solved the problem of detection in already published LIS tests by putting all the reaction and detection pads directly into the syringe barrel. We also used more layers to make the results visible for users. Two detection layouts: (i) with using rounded pads-based detection, and (ii) with using rectangular detection pads, were studied. As the proof of concept, we studied the determination of Ni(II) using dimethylglyoxime as the reagent and blocking of the interference of Fe(II). The calibrations for Ni(II) at the optimal conditions has excellent R2 of 0.998 with production costs of 0.2 USD per one test. PMID- 28738581 TI - The G-BHQ synergistic effect: Improved double quenching molecular beacons based on guanine and Black Hole Quencher for sensitive simultaneous detection of two DNAs. AB - We designed two double quenching molecular beacons (MBs) with simple structure based on guanine (G base) and Black Hole Quencher (BHQ), and developed a new analytical method for sensitive simultaneous detection of two DNAs by synchronous fluorescence analysis. In this analytical method, carboxyl fluorescein (FAM) and tetramethyl-6-carboxyrhodamine (TAMRA) were respectively selected as fluorophore of two MBs, Black Hole Quencher 1 (BHQ-1) and Black Hole Quencher 2 (BHQ-2) were respectively selected as organic quencher, and three continuous nucleotides with G base were connected to organic quencher (BHQ-1 and BHQ-2). In the presence of target DNAs, the two MBs hybridize with the corresponding target DNAs, the fluorophores are separated from organic quenchers and G bases, leading to recovery of fluorescence of FAM and TAMRA. Under a certain conditions, the fluorescence intensities of FAM and TAMRA all exhibited good linear dependence on their concentration of target DNAs (T1 and T2) in the range from 4 * 10-10 to 4 * 10-8molL-1 (M). The detection limit (3sigma, n = 13) of T1 was 3 * 10-10M and that of T2 was 2*10-10M, respectively. Compared with the existing analysis methods for multiplex DNA with MBs, this proposed method based on double quenching MBs is not only low fluorescence background, short analytical time and low detection cost, but also easy synthesis and good stability of MB probes. PMID- 28738582 TI - MetaboQC: A tool for correcting untargeted metabolomics data with mass spectrometry detection using quality controls. AB - Nowadays most metabolomic studies involve the analysis of large sets of samples to find a representative metabolite pattern associated to the factor under study. During a sequence of analyses the instrument signals can be subjected to the influence of experimental variability sources. Implementation of quality control (QC) samples to check the contribution of experimental variability is the most common approach in metabolomics. This practice is based on the filtration of molecular entities experiencing a variation coefficient higher than that measured in the QC data set. Although other robust correction algorithms have been proposed, none of them has provided an easy-to-use and easy-to-install tool capable of correcting experimental variability sources. In this research an R package -the MetaboQC- has been developed to correct intra-day and inter-days variability using QCs analyzed within a pre-set sequence of experiments. MetaboQC has been tested in two data sets to assess the correction effects by comparing the metabolites variability before and after application of the proposed tool. As a result, the number of entities in QCs significantly different between days was reduced from 86% to 19% in the negative ionization mode and from 100% to 13% in the positive ionization mode. Furthermore, principal component analysis allowed detecting the filtration of instrumental variability associated to the injection order. PMID- 28738583 TI - Application of headspace and direct immersion solid-phase microextraction in the analysis of organothiophosphates related to the Chemical Weapons Convention from water and complex matrices. AB - The successful application of headspace (HS) and direct immersion (DI) solid phase microextraction (SPME) for the unambiguous identification and characterization of a series of toxic thiophosphate esters, such as Amiton (I), from aqueous phases and complex matrices (e.g. grass and foliage) has been demonstrated. A Thermo Scientific gas chromatograph (GC) - tandem mass spectrometer (MS/MS) system with a TriPlus RSH(r) autosampler and a SPME tool was used to investigate the effect of different parameters that influence the extraction efficiency: e.g. pH of the sample matrix and extraction temperature. The developed methods were employed for the detection of several Amiton derivatives (Schedule II of the CWC) that are structurally closely related to each other; some of which are new and have not been reported in literature previously. In addition, a novel DI SPME method from complex matrices for the analysis of organophosphates related to the CWC was developed. The studies clearly show that DI SPME for complex matrices is superior to HS extraction and can potentially be applied to other related compounds controlled under the CWC. PMID- 28738584 TI - Production of stable and sensitive SERS substrate based on commercialized porous material of silanized support. AB - This paper reports accurate synthesis of a new type of surface-enhanced Raman spectroscopy (SERS) substrate based on gold nanoparticles decorated 201 red silanized diatomaceous supports. The developed SERS substrate is easy to fabricate, cost effective and offers sensitive rapid detection. The performance and stability of the SERS substrate was investigated and the results showed good SERS activity of substrate that can last for more than 6 months. Tiazophos and phosmet pesticides in aqueous solutions can be detected clearly at a low concentration of 0.01mg/L. The new substrate was applied to detect triazophos in apple pulp at 0.2mg/kg. The results indicate that this substrate have good potential in rapid monitoring of pesticide residues in fruits and could be suitable for field-based applications, and routine laboratory analysis of chemicals. PMID- 28738585 TI - Ordered mesoporous silica film as a novel fiber coating for solid-phase microextraction. AB - Ordered mesoporous silica (OMS) film supported on anodized titanium wire was fabricated as a new solid phase microextraction (SPME) fiber for the extraction of chlorophenols (CPs) from aqueous media followed by the determination with gas chromatography flame ionization detection (GC-FID). The supported OMS film was prepared via a solvent evaporation-induced self-assembly approach (EISA) combined with dip-coating technology. Commonly used fragile fused silica fiber was replaced by anodized titanium wire. The coating materials were characterized by N2 adsorption-desorption, Fourier transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM) and thermogravimetric (TG) analysis. The N2 adsorption-desorption results show the OMS material has well-ordered mesostructure with uniform pore diameter. The SEM images verify that the OMS film was successfully grafted onto the surface of anodized titanium wire. The resultant method based on the OMS fiber exhibited wide linear ranges (0.2-200MUgL 1), low detection limits (0.03-0.12MUgL-1) and good repeatabilities (6.2-9.8% for one fiber, 8.9-13.2% for fiber-to-fiber). No significant change was observed after being subjected into high temperature or immersed in organic solvents. The new fiber was successfully applied to the extraction and determination of three CPs compounds in the natural water samples. Thus, the OMS fiber is a promising alternative to the commercial fiber as it is easily and inexpensively prepared with high extraction capacity and good stability. PMID- 28738586 TI - Development of a solid-phase extraction method with simple MEKC-UV analysis for simultaneous detection of indole metabolites in human urine after administration of indole dietary supplement. AB - This work presents the development of a solid phase extraction method with simple MEKC-UV analysis for the simultaneous determination of indole-3-carbinol (I3C) and its metabolites (3, 3'-diindolylmethane (DIM), indole-3-carboxaldehyde (I3CAL), indole-3-acetonitrile (I3A)) in human urine after oral administration of an indole dietary supplement. Solid phase extraction (SPE) method was applied for the first time for simultaneous analysis of these indole metabolites. The MEKC separation method was developed in a previous work. Three commercial SPE cartridges, each with different sorbent materials, were investigated: Sep-Pak(r) C18, Oasis(r) HLB and Oasis(r) WCX. The Sep-Pak(r) C18 material provided the highest extraction recovery of 88-113% (n = 9), for the four target indole metabolites (I3C, DIM, I3CAL and I3A). The optimal washing and elution solutions were 40% methanol/water (v/v) and 100% methanol, respectively, and optimal elution volume was 2.0mL. The specificity of the proposed SPE method was evaluated with negative control urine samples (n = 10) from healthy volunteers who had not taken the dietary supplement or vegetables known to contain indole compounds. Linear calibration curves were in the range of 0.2-25MUgmL-1 (r2 > 0.998) using diphenylamine (DPA) as the internal standard. Intra-day and inter day precisions were 3.5-12.3%RSD and 2.7-14.1%RSD, respectively. Limits of detection and quantification were 0.05-0.10MUgmL-1 and 0.10-0.50MUgmL-1, respectively. The four target indole compounds were separated within only 5min by MEKC-UV analysis. Urine from 5 subjects who had taken a dietary supplement containing I3C and DIM were found to contain only the DIM metabolite at concentrations ranging from 0.10 to 0.35ugmL-1. Accuracy of the proposed method based on the percentage recovery of spiked urine samples were 70-108%, 82-116%, 82-132% and 80-100% for I3C, I3CAL, I3A and DIM, respectively. The Sep-Pak(r)C18 cartridge was highly effective in extraction and sample cleanup for the downstream simultaneous detection of urinary indole metabolites by MEKC-UV method. PMID- 28738587 TI - A novel calibration strategy based on background correction for quantitative circular dichroism spectroscopy. AB - When using circular dichroism (CD) spectroscopy for quantitative analysis, the samples to be analyzed must be free of light-absorbing interferences. However, in real-world samples, the presence of background absorbers is practically unavoidable. The difference in the matrices between the real-world samples to be analyzed and the standard samples (on which either univariate or multivariate calibration model was built) would result in systematic errors in the quantification results of CD spectroscopy. In this contribution, a novel calibration strategy for quantitative CD spectroscopic analysis was proposed. The main idea of the proposed calibration strategy is to project the CD spectra of both the standard samples and the real-world sample to be analyzed onto a projection space orthogonal to the space spanned by the background CD spectrum of the real-world sample and then build a multivariate calibration model on the transformed CD spectra of the standard samples. The performance of the proposed calibration strategy was tested and compared with conventional univariate and multivariate calibration methods in the quantification of Pb2+ in cosmetic samples using CD spectroscopy in combination with a G-quadruplex DNAzyme (e.g. PS2.M). Experiments results revealed that the proposed calibration strategy could mitigate the influence of the difference in the matrices between the standard samples and cosmetic samples and realized quantitative analysis of Pb2+ in cosmetic samples, with precision and accuracy comparable to atomic absorption spectroscopy. The proposed calibration strategy has the features of simplicity and effectiveness, its combination with CD spectroscopic probes can realize accurate and precise quantification of analytes in complex samples using CD spectroscopy. PMID- 28738588 TI - MALDI (matrix assisted laser desorption ionization) Imaging Mass Spectrometry (IMS) of skin: Aspects of sample preparation. AB - MALDI (matrix assisted laser desorption ionization) Imaging Mass Spectrometry (IMS) allows molecular analysis of biological materials making possible the identification and localization of molecules in tissues, and has been applied to address many questions on skin pathophysiology, as well as on studies about drug absorption and metabolism. Sample preparation for MALDI IMS is the most important part of the workflow, comprising specimen collection and preservation, tissue embedding, cryosectioning, washing, and matrix application. These steps must be carefully optimized for specific analytes of interest (lipids, proteins, drugs, etc.), representing a challenge for skin analysis. In this review, critical parameters for MALDI IMS sample preparation of skin samples will be described. In addition, specific applications of MALDI IMS of skin samples will be presented including wound healing, neoplasia, and infection. PMID- 28738589 TI - 2-aminopurine probe in combination with catalyzed hairpin assembly signal amplification for simple and sensitive detection of microRNA. AB - A quencher-free and enzyme-free fluorescent sensor was proposed to simply and sensitively detect miRNA via the target catalyzed hairpin assembly (CHA) signal amplification in combination with 2-aminopurine (2-AP) molecular beacon (MBs). This sensor contains two DNA hairpins termed as H1 and H2. H1 labeled by 2-AP needs no quenchers because 2-AP can be quenched through its stacking interaction with the adjacent bases. H2 is partially complementary to H1. In the presence of the target microRNA (miRNA), H1 is unfolded and produces the DNA/RNA complexes, enhancing the fluorescent signal. Then, the RNA of the DNA/RNA complexes can be displaced by H2 and the free miRNA can interact with another H1, resulting in the significant fluorescence enhancement of the system. This signal amplification process is enzyme-free, making the sensor more simple and cost effective. The detection limit of this sensor could be as low as 3.5pM. We further applied this assay to monitor the overexpressed miRNA-21 from human breast cancer cells to confirm its applicability. The proposed sensor could be used as a simple and sensitive platform for target miRNA detection, holding great potential for convenient monitoring of different miRNA biomarkers for early diagnosis of various cancers. PMID- 28738590 TI - Extracellular matrix characterization in plaques from carotid endarterectomy by a proteomics approach. AB - Extracellular matrix (ECM) is a fundamental component of multicellular organisms. Alteration of its structure and/or molecular composition are associated with several pathologies, among the others with atherosclerosis. To determine how the overall ECM architecture of a tissue as complex as the atheroma may change under varying pathological conditions constitutes a great technical challenge. This entails removing cell components and solubilisation of fibrillar proteins in order to allow enzymatic digestion and mass spectrometry analyses. This work aimed at testing and assessing an easy to use, standardized and reproducible proteomics protocol to map ECM proteins in carotid plaque specimens. To this end, plaques from endarterectomies were incubated in different buffers and the resulting solutions and tissue homogenates after incubation were processed for mass spectrometry. Comparison of the different workflows showed that 4M Guanidine treatment (following 0.5M NaCl and 0.08% SDS incubations) is the most promising in terms of ECM enrichment. The protocol can also be used to identify different and complementary classes of proteins both in plaque extracts and homogenates. PMID- 28738591 TI - Procedures for precise measurements of 135Cs/137Cs atom ratios in environmental samples at extreme dynamic ranges and ultra-trace levels by thermal ionization mass spectrometry. AB - Determination of 135Cs/137Cs atom ratios has the potential to be a powerful tool for nuclear forensics and monitoring environmental processes. We present optimized chemical separation techniques and thermal ionization mass spectrometry (TIMS) protocols to obtain precise 135Cs/137Cs atom ratios for a range of environmental sample types. We use a combination of double AMP-PAN separation and Sr-spec resin column purification to yield excellent separation from the alkali metals (Rb separation factor > 600), which normally suppress ionization of Cs. A range of emission activators for the ionization of Cs were evaluated and glucose solution yielded the optimal combination of a stable Cs+ beam, minimal low temperature polyatomic interferences and improved ionization efficiency. Mass spectrometric determination of low abundance 135Cs and 137Cs is compromised by the presence of a very large 133Cs+ beam, which may be scattered and cause significant spectral interferences. These are explored using multi-static Faraday cup - ion counter methods and a range of energy filter settings. The method is evaluated using environmental samples and standards from regions affected by fallout from Chernobyl (IAEA-330) and Fukushima nuclear disasters. Where the intensity of 133Cs+ is large relative to 135Cs+ and 137Cs+ (< 30cps), minor polyatomic interferences need to be considered. In the absence of a standard with 135, 137Cs/133Cs < 1 * 10-8, we explored the reproducibility of 135Cs/137Cs atom ratios at these high dynamic ranges and extremely low abundance (137Cs ~ 12 fg g 1) for sediments from an estuarine setting in SW England, UK. PMID- 28738592 TI - A unique red-emitting two-photon fluorescent probe with tumor-specificity for imaging in living cells and tissues. AB - Tumor-specific imaging can provide an attractive approach for the early detection and prognosis of cancer, as well as the precise image-guided tumor-removal surgery. Herein, we describe a unique red-emitting two-photon fluorescent probe (N-BN) for tumor-specific imaging. N-BN utilized Nile Red as the red-emitting two photon fluorophore and employed biotin as the tumor-specific ligand. In the presence of a variety of biomolecules or in different pH buffers, the fluorescence intensity of N-BN at 655nm showed no noticeable change. N-BN exhibited the remarkable two-photon absorption cross sections of 15.4g under excitation at 800nm. Under the guidance of biotin, N-BN can be applied for the imaging of biotin-receptor positive cancer cells over biotin-negative cells under red-emitting one- and two-photon manners. Assisted by high-definition three dimensional imaging, the living tumor tissues loaded with N-BN could display strong red two-photon fluorescence with a penetration depth of about 90um. Moreover, the in vivo and ex vivo imaging studies intuitively revealed that N-BN could track the tumor with highly tumor-specific property by a near-infrared manner. PMID- 28738593 TI - Boron nitride nanosheets as a platform for fluorescence sensing. AB - Hexagonal boron nitride nanosheets (BNNS), one kind of inorganic graphene analogue, exhibit high fluorescence quenching ability via the photo-induced electron transfer (PET) and different affinity toward single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA). As a proof of concept, the BNNS was first used as a sensing platform for the rapid detection of DNA and small molecules with high sensitivity and selectivity in this study. This strategy is versatile and quick fluorescence sensing of DNA and extensive DNA related analytes such as metal cations and small molecules. Moreover, this strategy might be available for the practical application in future. This work provides an avenue for understanding the interaction between two-dimensional nanomaterials and biomolecules and designing novel sensing strategies for extending the applications of nanomaterials in bioanalysis. PMID- 28738594 TI - Optical sensor for fluoride determination in tea sample based on evanescent-wave interaction and fiber-optic integration. AB - In this work, a miniaturized optical sensor was developed for fluoride determination in tea samples to evaluate their specific risks of fluorosis for public health based on evanescent-wave interaction. The sensor design was integrated on the optical fiber by utilizing the evanescent wave produced on the fiber surface to react with sensing reagents. According to the absorption change at 575nm, fluoride could be determined by colorimetric method and evaluated by Beer's law. With improved performances of small detection volume (1.2MUL), fast analysis (0.41min), wide linear range (0.01-1.4mgL-1), low detection limit (3.5MUgL-1, 3sigma) and excellent repeatability (2.34%), the sensor has been applied to fluoride determination in six different tea samples. Conventional spectrophotometry and ion chromatography were employed to validate the sensor's accuracy and potential application. Furthermore, this sensor fabrication provided a miniaturized colorimetric detection platform for other hazardous species monitoring based on evanescent wave interaction. PMID- 28738595 TI - Compound-specific delta13C and delta2H analysis of olive oil fatty acids. AB - Fatty acids are the most abundant biomolecules in olive oil. In this study, we describe the analytical method developed to measure the delta13C, and for the first time, the delta2H values of fatty acid methyl esters (FAMEs) extracted from olive oil triglycerides, after base-catalysed transesterification with methanol. The extracted FAMEs are analysed using Gas Chromatography Combustion/Pyrolysis Isotope Ratio Mass Spectrometry (GC-C/Py-IRMS). The method made it possible to obtain baseline separation between the peaks of the main FAMEs (C16, C18, C18:1, C18:2). The accuracy, precision and uncertainty of the whole method (from preparation to measurement) were determined. Furthermore, the impact of methylation on delta13C and delta2H values was investigated. The obtained performance of the method is satisfying and allow the determination of reliable data. As delta13C and delta2H determined in bulk olive oils already demonstrated to be able on a some extent in distinguishing products according to their geographical origins, what it is expected applying this new method, is the improvement of the capacity of provenance differentiation. PMID- 28738596 TI - Chromatographic separation of racemic praziquantel and its residual determination in perch by LC-MS/MS. AB - An enantioselective depletion study of praziquantel (PZQ) in perch muscle was done using a simple, sensitive and specific liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Two cyclic polypeptides and two cyclic saccharide chromatographic columns were evaluated. The new hydroxypropyl beta-cyclodextrin (HP-RSP) superficially porous particle (SPP) column produced the optimum separation and was selected for the study. Deuterium labeled PZQ-d11 was used as the internal standard. The method was linear over concentration ranges of 5.00 5.00*102MUgL-1 (r2>=0.99) for (-)-R-PZQ and (+)-S-PZQ. The average recoveries of R-PZQ and S-PZQ at three spiked levels of 5.00, 50.00 and 5.00*102MUgkg-1 ranged from 86.1% to 98.2%, and the intra-day and inter-day relative standard deviations were less than 5%. The decision limit (CCalpha) and detection capability (CCbeta) of R-PZQ and S-PZQ in perch muscle matrices were all 1.0MUgkg-1 and 5.0MUgkg-1, respectively. The method was successfully applied in monitoring the depletion of praziquantel enantiomers in perch muscle following oral administration. The elimination rate of R-PZQ and S-PZQ in perch muscle tissue is equivalent. PMID- 28738597 TI - Sensitive detection of sulfide based on the self-assembly of fluorescent silver nanoclusters on the surface of silica nanospheres. AB - Hydrogen sulfide is a toxic and flammable gaseous pollutant often emitted to air as a by-product of water supply, chemical, petroleum and coal industries. It can be transferred into sulfur dioxide in the air under some meteorologic conditions. Herein, we report a novel ratiometric fluorescence method for hydrogen sulfide based on silver nanoclusters and quantum dots. The silver nanoclusters have been self-assemblied onto the surface of silica spheres, which are embedded with red fluorescent quantum dots, to form a dual-emissive nanohybrid. Such dual-emissive nanohybrid has been applied for hydrogen sulfide detection on the basis of the interfacial interaction between silver nanoclusters and sulfide ions. The blue emission of Ag NCs is specifically prone to hydrogen sulfide due to surface binding and etching, but the red-emission of QDs within the silica nanospheres is inert against hydrogen sulfide. The different response of the two components to hydrogen sulfide results in fluorescence color variation from violet to red when the blue fluorescence is gradually quenched. This nanohybrid has been successfully demonstrated for the application in sensitive and selective detection of hydrogen sulfide in aqueous solution and gaseous state. PMID- 28738598 TI - Green and efficient sample preparation method for the determination of catalyst residues in margarine by ICP-MS. AB - Responding to the need for green and efficient methods to determine catalyst residues with suitable precision and accuracy in samples with high fat content, the present work evaluates a microwave-assisted ultraviolet digestion (MW-UV) system for margarines and subsequent determination of Ni, Pd and Pt using inductively coupled plasma mass spectrometry (ICP-MS). It was possible to digest up to 500mg of margarine using only 10mL of 4molL-1 HNO3 with a digestion efficiency higher than 98%. This allowed the determination of catalyst residues using the ICP-MS and free of interferences. For this purpose, the following experimental parameters were evaluated: concentration of digestion solution, sample mass and microwave irradiation program. The residual carbon content was used as a parameter to evaluate the efficiency of digestion and to select the most suitable experimental conditions. The accuracy evaluation was performed by recovery tests using a standard solution and certified reference material, and recoveries ranging from 94% to 99% were obtained for all analytes. The limits of detection for Ni, Pd and Pt using the proposed method were 35.6, 0.264 and 0.302ngg-1, respectively. When compared to microwave-assisted digestion (MW-AD) in closed vessels using concentrated HNO3 (used as a reference method for sample digestion), the proposed MW-UV could be considered an excellent alternative for the digestion of margarine, as this method requires only a diluted nitric acid solution for efficient digestion. In addition, MW-UV provides appropriate solutions for further ICP-MS determination with suitable precision (relative standard deviation < 7%) and accuracy for all evaluated analytes. The proposed method was applied to margarines from different brands produced in Brazil, and the concentration of catalyst residues was in agreement with the current legislation or recommendations. PMID- 28738599 TI - Development of a chemiluminescent DNA fibre optic genosensor to Hepatitis A Virus (HAV). AB - Hepatitis A virus (HAV) infection has caused substantial morbidity and economic losses to human society, presenting a major public health problem in many parts of the world. Despite the capability for low-concentration detection, current PCR based techniques are limited by the requirement of specialized lab equipment, trained personnel and a relatively large time-commitment. The need for a prompt in-field quantitative identification of HAV in real samples has led us to develop a chemiluminescent fibre optic genosensor system. In this study, a two-probe sandwich-type hybridization process was implemented on the tip of a fibre optic with an area of 0.12mm2. After optimization of the probes and the working conditions, we showed that the biosensor was able to work for both cDNA and RNA with a relatively large signal/noise ratio and a good sensitivity. An excellent specificity was also confirmed by screening with a broad range of other pathogen samples. The nucleic acid probes method was validated by optimized PCR and qPCR, and may thus be used when field testing would be required. PMID- 28738600 TI - Quantification of intercellular adhesion forces measured by fluid force microscopy. AB - The mechanics of cancer cell adhesion to its neighboring cells, homotypic or heterotypic, have significant impact on tumor progression and metastasis. Intercellular adhesion has been quantified previously using atomic force microscopy-based methods. Here we show the feasibility of the recently developed fluidic force microscopy (FluidFM) to measure adhesive forces exerted by breast cancer cells. Multiple cell pairs were assessed at precisely controlled, increasing contact durations by pressure-dependent immobilization of a cell at the probe tip. Eliminating chemical fixation of the cell at the tip ensured repeated use of the same probe and also minimized changes in cell physiology. Our data indicates distinct trends of adhesion forces between homotypic breast cancer cells compared to heterotypic adhesion between cancer-fibroblast and cancer epithelial cell pairs. Adhesion forces were similar for all three cell pairs at short contact duration (< 1min) but differed at longer contact period (30min). Our study suggests that FluidFM is a rapid efficient technique that could be used to assess heterogeneity in cellular adhesion at various stages of malignant transformation. PMID- 28738601 TI - Biosensor-assisted selection of optimal parameters for designing molecularly imprinted polymers selective to phosmet insecticide. AB - Molecularly imprinted polymers (MIPs) for phosmet insecticide were synthesized by batch polymerization. The affinity of functional monomers to phosmet was tested using an original method involving an electrochemical biosensor based on acetylcholinesterase inhibition. It was demonstrated that association of phosmet with appropriate functional monomers resulted in a decrease of enzyme inhibition. Using this method, it was shown that N,N-methylenebis(acrylamide) displayed the highest interactions with phosmet using DMSO as solvent. These results were in good accordance with those obtained by conventional computational modeling. Molecularly imprinted polymers (MIPs) and non-imprinted polymers (NIPs) were synthesized and adsorption isotherms were studied to describe their interaction with phosmet. Freundlich isotherm was able to fit phosmet adsorption on MIPs with good agreement (R2 = 0.9). The pre-exponential factor KF determined for MIPs was 1.439mg(1-N)g-1LN, more that 10 times higher than for NIPs (0.125mg(1-N)g-1. LN), indicating an increase of binding sites number and average affinity. PMID- 28738602 TI - Portable electrochemical system using screen-printed electrodes for monitoring corrosion inhibitors. AB - This work presents a portable electrochemical system for the continuous monitoring of corrosion inhibitors in a wide range of matrices including ethanol, seawater and mineral oil following simple dilution of the samples. Proof-of concept is demonstrated for the sensing of 2,5-dimercapto-1,3,5-thiadiazole (DMCT), an important corrosion inhibitor. Disposable screen-printed graphitic electrodes (SPGEs) associated with a portable batch-injection cell are proposed for the amperometric determination of DMCT following sample dilution with electrolyte (95% v/v ethanol + 5% v/v 0.1molL-1 H2SO4 solution). This electrolyte was compatible with all samples and the organic-resistant SPGE could be used continuously for more than 200 injections (100uL injected at 193uLs-1) free from effects of adsorption of DMCT, which have a great affinity for metallic surfaces, and dissolution of the other reported SPGE inks which has hampered prior research efforts. Fast (180h-1) and precise responses (RSD < 3% n = 10) with a detection limit of 0.3umolL-1 was obtained. The accuracy of the proposed method was attested through recovery tests (93-106%) and the reasonable agreement of results of DMCT concentrations in samples analyzed by both proposed and spectrophotometric (comparative) methods. PMID- 28738603 TI - Vortex-assisted liquid-liquid-liquid microextraction followed by high performance liquid chromatography for the simultaneous determination of fourteen phenolic acids in honey, iced tea and canned coffee drinks. AB - A vortex-assisted liquid-liquid-liquid microextraction method followed by high performance liquid chromatography-diode array detection for the determination of fourteen phenolic acids (cinnamic, m-coumaric, chlorogenic, syringic, ferulic, o coumaric, p-coumaric, vanillic, p-hydroxybenzoic, caffeic, 2, 4-dihydroxybenzoic, sinapic, gentisic and gallic acids) in honey, iced tea and canned coffee drink samples has been developed. The separation was achieved using a Poroshell 120-EC C18 column under a gradient elution at a flow rate of 0.6mLmin-1 and mobile phase composed of methanol and acetic acid (1%, v/v). Under the optimum chromatographic conditions, the fourteen phenolic acids were separated in less than 32min. The extraction was performed using a small volume (400uL) of ternary organic solvents (1-pentanol, propyl acetate and 1-hexanol) dispersed into the aqueous sample (10mL) and assisted by vortex agitation (2500rpm for 45s), the analytes were next back-extracted from the organic solvent using 0.02M KOH (40uL) with vortex speed and time of 2500rpm and 60s, respectively. Under these conditions, enrichment factors of 30-193-fold were achieved. The limits of detection (LODs) were 0.05 0.68ugL-1. Recoveries in honey, iced tea and canned coffee drinks were in the range 72.2-112%. The method was successfully applied for the determination of the phenolic acids in honey, iced tea and canned coffee drinks. PMID- 28738605 TI - Rapid one-pot synthesis of MMTA protected fluorescent gold nanoclusters for selective and sensitive detection of ferric ion. AB - Herein, we demonstrate a straightforward synthesis of fluorescent gold nanoclusters (AuNCs), employing 2-Mercapto-4-methyl-5-thiazoleacetic acid (MMTA) as a reducing and protecting agent by a rapid one-pot synthesis method with a short time of 20min. The as-synthesized MMTA-AuNCs exhibited bright blue emission with a strong peak centered at 430nm and the quantum yield (QY) was evaluated to be 4.0%. Based on the fluorescence quenching mechanism of a surface chelating reaction between MMTA and ferric ion (Fe3+), the MMTA-AuNCs were exploited as a fluorescence sensor for sensitive and selective detection of Fe3+. Two linear ranges of 9.9-3000.0nM and 3.0-1100MUM with a detection limit of 3.0nM were obtained. The detection limit was lower than the maximum level (0.3mgL-1, equivalent to 5.4MUM) of Fe3+ permitted in drinking water by the U.S. Environmental Protection Agency. Furthermore, the proposed fluorescent sensing system was successfully applied to the analysis of Fe3+ in real samples such as water and human serum samples with satisfactory recoveries. These results indicated that the as-prepared MMTA-AuNCs could pave an avenue for the development of sensing probes for detection of Fe3+ in environmental and biomedical applications. PMID- 28738606 TI - A label-free fluorometric assay for actin detection based on enzyme-responsive DNA-templated copper nanoparticles. AB - Herein, we develop a fluorescent strategy for label-free detection of actin by the in situ formation of double-stranded DNA (dsDNA) templated copper nanoparticles (CuNPs) and the digestion capability of deoxyribonuclease I (DNase I). In this design, the introduction of actin can effectively hinder the enzymic digestion owing to the exceptional target-mediated conformational structure between actin and DNase I. Consequently, the remaining adenine-thymine-rich dsDNA can act as an efficient template for fluorescent CuNPs (lambdaex = 340nm, lambdaem = 585nm) with a Mega-Stokes shifting (245nm). This novel fluorescent strategy exhibits several advantages such as low-cost and environmental-friendly, because it does not require the toxic organic dyes and laborious procedures. Under optimized experimental conditions, this method realizes a turn-on selective and sensitive response for actin with a detection limit of 0.12MUgmL-1 and a detection capability in complex biological media with satisfactory results. PMID- 28738604 TI - Electrochemical investigation and determination of procaterol hydrochloride on poly(glutamic acid)/carboxyl functionalized multiwalled carbon nanotubes/polyvinyl alcohol modified glassy carbon electrode. AB - Poly(glutamic acid) (P-GLU)/carboxyl functionalized multiwalled carbon nanotubes (MWCNTs-COOH)/polyvinyl alcohol (PVA) modified glassy carbon electrode (GCE) has been successfully prepared and the electrochemical behavior of procaterol hydrochloride (ProH) was studied. The results show that the as-prepared modified electrode exhibits a good electrocatalytic property towards the oxidation of ProH in 0.2M phosphate buffer solution (PBS) (pH 6.0) due to the enhanced oxidation peak current at ~+0.59V. Under optimal reaction conditions, the oxidation peak current of ProH is proportional to its concentration in the linear dynamic ranges of 0.060 - 8.0MUM (R = 0.9974), with a detection limit of 8.0 * 10-9M. Finally, this method was efficiently used for the determination of ProH in tablets and human urine with recoveries of 88.5~98.7% and 89.2 ~ 108.0%, respectively. PMID- 28738607 TI - Novel colorimetric assay for paraquat detection on-silica bead using negatively charged silver nanoparticles. AB - A simple, rapid, sensitive, and economical method based on colorimetry for the determination of paraquat, a widely used herbicide, was developed. Citrate-coated silver nanoparticles (AgNPs) were synthesized as the colorimetric probe. The mechanism of the assay is related to the aggregation of negatively charged AgNPs as induced by positively-charged paraquat resulting from coulombic attraction which causes the color to change from a deep greenish yellow to pale yellow in accordance with the concentrations of paraquat. Silica gel was exploited as the paraquat adsorbent for purification and pre-concentration prior to the direct determination with negatively charged AgNPs without the requirement of the elution step. The validity of the proposed approach was evaluated by spiking standard paraquat in water and plant samples. Recoveries of paraquat in water samples were 93.6% and 95.4% for groundwater and canal water, respectively, while those in plant samples were 89.5% and 86.6% for Chinese cabbage and green apple, respectively,after using the optimized extraction procedure. The absorbance of AgNPs at 400nm was linearly related to the concentration of paraquat over the range of 0.05-50mgL-1, with detection limits of 0.05mgL-1 for water samples, and 0.10mgL-1 for plant samples by naked eye determination. PMID- 28738608 TI - A fast bioanalytical method based on microextraction by packed sorbent and UPLC MS/MS for determining new psychoactive substances in oral fluid. AB - The emergence in recent years of potentially dangerous new psychoactive substances (NPS) that are not under international control has led to the development of multi-analyte procedures for their unequivocal quantification. A fast ultra-performance liquid chromatography-tandem mass spectrometry method (UPLC-MS/MS), in combination with a sample pretreatment based on microextraction by packed sorbent (MEPS), was for the first time used in this work for the simultaneous determination of NPS in oral fluid. This matrix is an effective alternative to typical biological samples for drug control in substitution therapy programs, and also for the prevention and reduction of traffic accidents. The proposed method allowed the separation and quantification of eleven synthetic cathinones, six opiates, scopolamine, cocaine and two metabolites in less than 3.0min by using appropriate isotope-labelled internal standards. The MEPS procedure, which is a miniaturized version of the SPE technique, is completed within 15min. The influence of variables such as the washing solution and eluent volumes, phase type, number of aspirate-dispense cycles and pH was investigated by using a 3441//16 asymmetric screening design and a response surface methodology based on a Doehlert design. The MEPS process performed optimally with a mixed-mode C8/SCX sorbent and a sample pH of 9. The proposed method was validated according to major guidelines and found to span the linear concentration range 0.5-500ngmL-1 (R2 >= 0.9903), and to be selective and precise (within- and between-day precision as %RSD were both lower than 13.7%). The accuracy, in terms of analyte extraction recovery, ranged from 75% to 125% for most of the analytes. The MEPS-UPLC-MS/MS method was successfully used to analyse twelve real samples from patients on a drug detoxification programme and proved an effective tool for drug monitoring. PMID- 28738609 TI - Pyridine-ring containing twisttetraazaacene: Synthesis, physical properties, crystal structure and picric acid sensing. AB - Novel pyridine-ring containing twisttetraazaacene 9,14-diphenylpyreno[4,5 g]isoquinoline (1) and its full-carbon derivative 9,14 diphenyldibenzo[de,qr]tetracene (2) have been synthesized and fully characterized. Studies showed that compound 1 could identify picric acid (PA) over other common nitro compounds with high selectivity and sensitivity. Upon the addition of PA, the emission peak of compound 1 in CH3CN was red shifted from 447 to 555nm with a fluorescence quenching efficiency as high as 95%, the detection limit was calculated to be 2.42MUM, while its full-carbon derivative (2) could not exhibit this kind of performance. The possible mechanism with the enhanced PA detection efficiency in pyridine-ring containing twisttetraazaacene (1) than its full-carbon derivative (2) was also investigated. PMID- 28738610 TI - A novel ''donor-pi-acceptor'' type fluorescence probe for sensing pH: mechanism and application in vivo. AB - A novel pH fluorescent probe 1-(pyren-1-yl)-3-(6-methoxypridin-3-yl)-acrylketone, (PMPA), which had a pyrene structure attached to methoxypyridine, was synthesized for monitoring extremely acidic and alkaline pH. The pH titrations indicated that PMPA displayed a remarkable emission enhancement with a pKa of 2.70 and responded linearly to minor pH fluctuations within the extremely acidic range of 1.26-3.97. Interestingly, PMPA also exhibited strong pH-dependent characteristics with pKa 9.32 and linear response to extreme-alkalinity range of 8.54-10.36. In addition, PMPA displayed a good selectivity, excellent photostability and large Stokes shift (167nm). Furthermore, the probe PMPA had excellent cell membrane permeability and was applied successfully to rapidly detect pH in living cells. pH value in these organs was closely related to many diseases, so these findings suggested that the probe had potential application in pH detecting for disease diagnosis. PMID- 28738611 TI - A novel electrochemical sensor based on WO3 nanorods-decorated poly(sodium 4 styrenesulfonate) functionalized graphene nanocomposite modified electrode for detecting of puerarin. AB - An electrochemical sensing platform was fabricated based on composition of poly(sodium 4-styrenesulfonate) (PSS), graphene (GN) and WO3 nanorods on glassy carbon electrode (GCE). The PSS-GN/WO3 nanocomposite significantly increased the oxidative activity of puerarin due to the individual merit and mutual effect of PSS-GN and WO3 nanorods which improved the performance of the electrochemical sensor with high sensitivity. Cyclic voltammetry (CV) and linear sweep voltammetry (LSV) measurements were used for the detection of puerarin. Under the optimal conditions, the oxidation peak currents of puerarin increased proportionally to the concentration within the range of 0.06-0.6MUmolL-1 and 0.6 6.0MUmolL-1, and the limit of detection was 0.04MUmolL-1. The proposed modified electrode was highly sensitive and was successfully applied to determine puerarin in the pharmaceutical sample and human plasma with satisfactory recoveries. The as-prepared PSS-GN/WO3/GCE electrochemical sensor offers a feasible way for designing simpler, low-cost, no toxic and environment-friendly sensors based on WO3 nanorods. PMID- 28738612 TI - Sorption-luminescence method for determination of terbium using Transcarpathian clinoptilolite. AB - Sorption-luminescent method for terbium determination based on natural Transcarpathian clinoptilolite without using of complex synthetic organic compounds and toxic solvents was proposed. Optimal luminophore preparation conditions are sorption of Tb(III) on zeolite in the borate buffer solution with pH 8.25 and further calcination of clinoptilolite-Tb(III) samples at 500 degrees C. For luminescence excitation the rays with wavelength of lambda = 220nm of were used. Luminescence intensity at lambda = 545nm was selected as analytical parameter for a quantitative terbium determination. Definable range of Tb(III) concentration with the detection limit of 1ngmL-1 is within of 3-1140ngmL-1. The proposed method can be used for the terbium determination in the presence of many rare earths. Sorption-luminescent method can be applied for determination of trace terbium ions in synthetic water solutions and in intermetallics. The proposed analytical method gave recoveries from 90% to 108% and R.S.D. from 0.78% to 6.2% determination of terbium. PMID- 28738613 TI - A selective distance-based paper analytical device for copper(II) determination using a porphyrin derivative. AB - Meso-tetrakis(1,2-dimethylpyrazolium-4-yl)porphyrin sulfonate (TDMPzP), a water soluble porphyrin derivative, was synthesized and used as a colorimetric reagent for Cu2+ detection on a microfluidic paper-based analytical device (uPAD) using distance-based quantification. TDMPzP showed a high selectivity for Cu2+ detection in aqueous solutions. When Cu2+ was added to the TDMPzP under acidic conditions, a color change from green to a pink was observed by the naked eye. Under optimized conditions, the application of this system to a distance-based MUPAD exhibited good analytical response. The presence of common metal ions (Al3+, Fe3+, Mg2+, Co2+, Mn2+, Zn2+, Pb2+, Cd2+, Sn2+, and Ni2+) did not interfere with Cu2+ detection within reasonable tolerance ratios. The lowest concentration of copper that could be measured was 1mgL-1 (1ppm) which meets the requirements for drinking water contamination regulations from the US Environmental Protection Agency (EPA) and World Health Organization (WHO) guidelines for drinking water. Real drinking water samples were analyzed to confirm the practical application of this system and the results showed good agreement with ICP-MS data. This distance-based uPAD based on TDMPzP for Cu2+ detection is convenient and effective for real-time drinking water analysis. PMID- 28738614 TI - In-situ synthesis of reduced graphene oxide/gold nanoparticles modified electrode for speciation analysis of copper in seawater. AB - In this paper, reduced graphene oxide/gold nanoparticle/Nafion (rGO/AuNP/Nafion) modified electrode was fabricated through in-situ synthesis and used for determination of copper ions in strong salt electrolyte (0.5M NaCl) by differential pulse anodic stripping voltammetry (DPASV). This in-situ synthesis procedure was based on the ion-exchange and electrochemical reduction. The use of rGO provided a larger electrode surface and the presence of more active sites, while electron transfer was accelerated by incorporating AuNPs. Nafion was utilized as a cation exchange polymer in which rGO and AuNPs could be tightly attached to the electrode surface. The physical and electrochemical characterizations of the as-prepared modified electrode were studied by transmission electron microscopy (TEM), scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDS) and cyclic voltammetry. AuNPs with diameter of 5-10nm on rGO decorated in the gold electrode surface were observed. Under the optimal conditions, the rGO/AuNP/Nafion electrode had a linear response to copper ions in the concentrations range from 20nM to 1MUM (R2 = 0.998), with the lowest detectable concentration of 8nM and the detection limit of 4nM (S/N = 3). Additionally, this electrode was successfully applied to the speciation analysis of copper (free, dissolved and total) in seawater. PMID- 28738615 TI - Electrochemical magneto immunosensor based on endogenous beta-galactosidase enzyme to determine enterotoxicogenic Escherichia coli F4 (K88) in swine feces using square wave voltammetry. AB - Diseases caused by enterotoxicogenic Escherichia coli F4 (K88) (ETEC F4) are a problem in swine production establishments. Due to the high rate of mortality and morbidity of E. coli infections, a rapid and accurate diagnosis is important in order to choose an appropriate treatment to reduce the economic impact. Therefore, an electrochemical magneto-immunosensor (EMI) was developed to detect and quantify ETEC F4 in swine feces samples through a direct non-competitive immunoassay. ETEC F4 was selectively captured by immunomagnetic separation. The detection principle was based on the activity of beta-galactosidase endogenous enzyme (beta-gal), which hydrolyses the p-aminophenyl-beta-D-galactopyranoside (p APG) producing p-aminophenol (p-AP), which was oxidized on a carbon screen printed electrode (CSPE) using square wave voltammetry (SWV). All parameters related to construction and electrochemical responses were optimized. The total analysis time to quantify ETEC F4 using the EMI was less than 2h and the limit of detection (LOD) was 33CFUmL-1. The perceptual relative error (%Er) was 20%. The magneto-immunosensor was validated versus conventional method of culture and plate count, obtaining a very good agreement. The EMI is simple, fast and economical to detect and quantify ETEC F4 in swine feces samples, being thus a valuable tool in swine production. PMID- 28738616 TI - 3D CuO nanosheet wrapped nanofilm grown on Cu foil for high-performance non enzymatic glucose biosensor electrode. AB - 3D binder-free CuO nanosheets wrapped nanofilms has been in situ synthesized on Cu substrate by a simple and facile procedure, with an aim of fabricating high performance glucose sensor. The complex morphology that the nanosheet grown on Cu subtract evolved into nanofilms and eventually converged to nanowires, is benefit for the mass transport and electro-catalysis. Compared the ECSA of the CuO modified electrode to that of the bare Cu electrode, the effective surface area during the electro-catalysis of the CuO/Cu electrode is much larger. The glucose sensor based on CuO products exhibited high sensitivity (4201MUAcm-2mM-1), low detection limit (0.5MUmol/L) and quick response time (0.7s). And the stability and selectivity is also fantastic. According to the serum sample analysis, it transpires that the CuO/Cu sensor displayed excellent recovery compared to the concentration values measured by medial method. So this material shows great potential applications in glucose sensors. PMID- 28738617 TI - Flexible immunosensor for the detection of salivary alpha-amylase in body fluids. AB - The development of a portable testing device for detecting Human Salivary alpha Amylase (HSA) is very timely since such an enzyme is a valuable biomarker for diagnosing many diseases and monitoring the human stress. We show that an easy-to use and robust device like the Quartz-Crystal Microbalance (QCM) can be a suitable platform for HSA sensing with a limit of detection of 1ug/mL (77 U/L). The functionalization of the gold surface is realized by the Photochemical Immobilization Technique (PIT), a powerful and simple method based on an appropriate UV-activation of antibodies. The resulting QCM-based immunosensor allows one to detect HSA in saliva by simple dilution and one-step protocol, whereas the measurement of HSA content in body fluids like urine and serum could be carried out by introducing an additional step consisting of analyte ballasting through the formation of sandwich complexes, which pushes the limit of detection to less than 10 U/L. The validation of the one-step protocol with a standard laboratory method like Phadebas test demonstrates the reliability of the proposed immunosensors, which can be applied to the amylase concentration in body fluids like blood serum and urine for which the physiological level is above 20 U/L. PMID- 28738618 TI - High sensitivity surface plasmon resonance biosensor for detection of microRNA and small molecule based on graphene oxide-gold nanoparticles composites. AB - A versatile and sensitive surface plasmon resonance (SPR) biosensor based on two layers of graphene oxide-gold nanoparticles (GO-AuNPs) composites was designed for the detection of microRNA (miRNA) and small molecule adenosine. The bottom layer, which acted as a functionalized substrate on the sensor chip, provided a high specific surface area convenient for the immobilization of capture DNA molecules. The upper layer served as a signal-amplification element. By employing these two layers of GO-AuNPs composites, the dual amplification strategy was achieved so that a measurement of miRNA-141 with a detection limit of 0.1fM was obtained. Moreover, the developed SPR biosensor showed decent selectivity toward miRNA-200 family members. Especially, the SPR biosensor demonstrated its applicability for the detection of miRNA-141 in cancer cell extractions, and the results obtained were consistent with those obtained by qRT-PCR. Interestingly, small molecule adenosine could also be detected using this SPR biosensor in combination with a split aptamer. Considering the superior sensitivity, selectivity and generality, this work promised much potential for the detection of various biomolecules. PMID- 28738619 TI - Simultaneous and sensitive electrochemical detection of dihydroxybenzene isomers with UiO-66 metal-organic framework/mesoporous carbon. AB - The zirconium-based MOF (UiO-66)/mesoporous carbon (MC) composite was synthesized using conventional hydrothermal method for the first time. The surface morphology and structure of UiO-66/MC composite were characterized by scanning electron microscopy (SEM), transmission electron microscope (TEM), Fourier transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD), and X-ray photoelectron spectroscopy (XPS). A novel electrochemical sensor based on UiO-66/MC was constructed for simultaneous and sensitive determination of dihydroxybenzene isomers (DBIs) of hydroquinone (HQ), catechol (CT) and resorcinol (RS). The proposed sensor displays excellent electrocatalytic activity toward the oxidation of HQ, CT and RS. The peak-to-peak potential separations between CT and HQ, and RS and CT are 0.130V and 0.345V, respectively. Under the optimized conditions, the electrochemical sensor shows a wide linear response in the concentration range of 0.5-100MUM, 0.4-100MUM and 30-400MUM with a detection limit of 0.056MUM, 0.072MUM and 3.51MUM (S/N = 3) for HQ, CT and RS, respectively. In addition, the sensor has superior sensitivity and electrochemical stability along with good reproducibility and anti-interference properties. The fabricated sensor was also applied for the determination of DBIs in the real water samples with satisfying results. PMID- 28738620 TI - Proteins in microbial synthesis of selenium nanoparticles. AB - Biogenic formation of nano-sized particles composed of various materials (in particular, selenium) by live microorganisms is widespread in nature. This phenomenon has been increasingly attracting the attention of researchers over the last decade not only owing to a range of diverse applications of such nanoparticles (NPs) in nanobiotechnology, but also because of the specificity of methodologies and mechanisms of NPs formation related to "green synthesis". In this mini-review, recent data are discussed on the multifaceted role of proteins in the processes of microbial reduction of selenium oxyanions and the formation of Se NPs. Besides the involvement of proteins in reducing selenites and selenates, their participation in the microbially driven growth and stabilisation of Se NPs is analysed, which results in the formation of unique nanostructured materials differing from those obtained chemically. This mini-review is thus focussed on proteins involved in microbial synthesis of Se NPs and on instrumental analysis of these processes and their products (biogenic nanostructured selenium particles functionalised by a surface-capping layer of various biomacromolecules). PMID- 28738621 TI - Determining heterocyclic aromatic amines in aqueous samples: A novel dispersive liquid-liquid micro-extraction method based on solidification of floating organic drop and ultrasound assisted back extraction followed by UPLC-MS/MS. AB - A novel dispersive liquid-liquid microextraction based on solidification of floating organic droplet combined with ultrasound assisted back extraction for the determination of four heterocyclic aromatic amines in natural water samples prior ultra high-performance liquid chromatography-tandem mass spectrometry was developed. The analytes were extracted from the water samples by a dispersive liquid-liquid microextraction procedure based on solidification of floating organic drop, which was performed by a mixture composed by a less dense than water extraction solvent, 1-undecanol, and a dispersive solvent, methanol. After that, a novel ultrasound assisted back extraction step was performed in order to make the clean-up/enrichment procedure compatible with the detection requirements. Under optimum conditions, linearity ranged from 2.2 to 50ngmL-1, with enrichment factors from 130 to 136-folds. Thus limits of detection between 0.7 and 2.9ngmL-1 were obtained. Precision of the method was evaluated in terms of repeatability, relative standard deviations varied from 4.3% to 6.7%. Relative recoveries ranged from 92% to 106% for all analytes. The satisfactory performance demonstrated that the proposed methodology has a strong potential for application in the multi-residue analysis of heterocyclic aromatic amines present in complex environmental matrices. PMID- 28738622 TI - A flow-based procedure exploiting the lab-in-syringe approach for the determination of ester content in biodiesel and diesel/biodiesel blends. AB - The ester content is an important parameter to be monitored in biodiesel for evaluation of the transesterification reaction yield and for assessing the purity of the final product. This is also a relevant quality parameter in diesel/biodiesel blends to avoid frauds, because legislation establishes a minimum amount of biodiesel to be added to diesel. The official method EN14103 requires the addition of an alternative internal standard (methyl nonadecanoate) for analysis of biodiesel from bovine tallow because the methyl heptadecanoate is found in high amounts in this product. In this work, it is proposed a fast, simple, practical, and environmental friendly flow-based spectrophotometric procedure, which exploits the formation of the violet complex between Fe(III) and the hydroxamate generated by the reactions of the alkyl esters with hydroxylamine. All involved steps are carried out inside the syringe pump of a sequential injection analyzer (lab-in-syringe approach). A single phase is attained by using ethanol as mediator solvent between the organic sample and aqueous soluble reagents. Linear responses for biodiesel samples and diesel/biodiesel blends were obtained from 4-99%(v/v) to 2.0-40%(v/v) methyl esters, described by the equations: A = 0.342 + 0.00305C (r = 0.997) and A = 0.174 + 0.00503C (r = 0.999), respectively. The analytical curve can be obtained by in-line dilution of a methyl linoleate stock solution. For biodiesel samples, the coefficient of variation (n = 10), limit of detection (99.7% confidence level), and sampling rate were estimated at 0.8%, 0.36%(v/v), and 15h-1, respectively, whereas the corresponding values for the blend samples were 0.20%, 0.03%(v/v), and 12h-1, respectively. The procedure consumes only 860MUg of hydroxylamine, 366MUg of Fe2(SO4)3.H2O, and 2.0mL ethanol and generates ca. 3.0mL of residue per determination. The results agreed with those obtained by official methods EN14103/2011 e EN14078, at the 95% confidence level. PMID- 28738623 TI - Analysis of illegal peptide drugs via HILIC-DAD-MS. AB - Biopharmaceuticals have established themselves as highly efficient medicines, and are still one of the fastest growing parts of the health-product industry. Unfortunately, the introduction of these promising new drugs went hand in hand with the creation of a black market for illegal and counterfeit biotechnology drugs. Particularly popular are the lyophilised peptides with a molecular weight of less than 5kDa. Most of them are meant for subcutaneous injection and are easily accessible via the internet. In recent years, different methods based on reversed phase liquid chromatography have been developed to detect and quantify these peptides. The emerging of more polar peptides however requires the introduction of other separation techniques. Therefore, we set out to develop and validate an analytical method based on hydrophilic interaction liquid chromatography (HILIC) to identify and quantify the most frequently encountered illegal peptides on the European market. For this objective, five different HILIC columns were selected and screened for their chromatographic performance. Among those columns, the ZIC HILIC column showed the best performance under the tested screening conditions in terms of resolution and symmetry factor for the targeted peptide set. Hence, the operational conditions were further optimised for the identification of illegal preparations via mass spectrometry (MS) and quantification via UV. Validation was performed via accuracy profiles based on the ISO 17025 guideline. The obtained validated HILIC-method allows for the detection and quantification of the most frequently encountered illegal peptides on the internet in a total run time of 35min including post gradient equilibration and online cleaning step. Combined with a previously developed RPLC method, the ZIC HILIC system allows for the detection and quantification of a wide spectrum of illicit peptide drugs available on the internet. Furthermore, the developed method could also be envisaged for the detection of new emerging polar peptide drugs. PMID- 28738624 TI - Multiplexed analysis combining distinctly-sized CdTe-MPA quantum dots and chemometrics for multiple mutually interfering analyte determination. AB - Semiconductor quantum dots (QDs) have demonstrated a great potential as fluorescent probes for heavy metals monitoring. However, their great reactivity, whose tunability could be difficult to attain, could impair selectivity yielding analytical results with poor accuracy. In this work, the combination in the same analysis of multiple QDs, each with a particular ability to interact with the analyte, assured a multi-point detection that was not only exploited for a more precise analyte discrimination but also for the simultaneous discrimination of multiple mutually interfering species, in the same sample. Three different MPA CdTe QDs (2.5, 3.0 and 3.8nm) with a good size distribution, confirmed by the FWHM values of 48.6, 55.4 and 80.8nm, respectively, were used. Principal component analysis (PCA) and partial least squares regression (PLS) were used for fluorescence data analysis. Mixtures of two MPA-CdTe QDs, emitting at different wavelength namely 549/566, 549/634 and 566/634nm were assayed. The 549/634nm emitting QDs mixture provided the best results for the discrimination of distinct ions on binary and ternary mixtures. The obtained RMSECV and R2CV values for the binary mixture were good, namely, from 0.01 to 0.08mgL-1 and from 0.74 to 0.89, respectively. Regarding the ternary mixture the RMSECV and R2CV values were good for Hg(II) (0.06 and 0.73mgL-1, respectively) and Pb(II) (0.08 and 0.87mg L-1, respectively) and acceptable for Cu(II) (0.02 and 0.51mgL-1, respectively). In conclusion, the obtained results showed that the developed approach is capable of resolve binary and ternary mixtures of Pb (II), Hg (II) and Cu (II), providing accurate information about lead (II) and mercury (II) concentration and signaling the occurrence of Cu (II). PMID- 28738625 TI - The screening of organic matter in mineral and tap water by UHPLC-HRMS. AB - It is highly desirable to screen for a large variety of organic compounds in water. Ultra-high performance liquid chromatography coupled to high-resolution mass spectrometry (UHPLC-HRMS) can analyse semi-polar to polar organic compounds in tap and mineral water. The use of UHPLC-HRMS is well consolidated for lipidomic, metabolomic and proteomic studies; based on the detection of a very large number of compounds of a variety of organic functions. Water analysis is usually performed by gas chromatography -mass spectrometry (GC-MS) techniques that are efficient for volatile organic compounds. Therefore the use of UHPLC HRMS as a screening method based on an untargeted omic approach for the analysis of organic compounds with polar functional groups is welcome. This UHPLC-HRMS method was developed and tested with tap water and mineral water. We analysed six different brands of mineral water from France, Spain, Norway and Brazil and tap water from Jandaia do Sul, PR, Brazil to test the approach and demonstrate how UHPLC-HRMS may be used as a screening method for water quality. Forty-seven different ions were observed in tap and mineral water and their intensities were submitted to principal component analysis (PCA) evaluation. Fifteen ions were identified comparing the mass spectrometric results to metabolomic and lipidomic libraries. PMID- 28738626 TI - Elimination of interference from water in KBr disk FT-IR spectra of solid biomaterials by chemometrics solved with kinetic modeling. AB - Infrared analysis of proteins and polysaccharides by the well known KBr disk technique is notoriously frustrated and defeated by absorbed water interference in the important amide and hydroxyl regions of spectra. This interference has too often been overlooked or ignored even when the resulting distortion is critical or even fatal, as in quantitative analyses of protein secondary structure, because the water has been impossible to measure or eliminate. Therefore, a new chemometric method was devised that corrects spectra of materials in KBr disks by mathematically eliminating the water interference. A new concept termed the Beer Lambert law absorbance ratio (R-matrix) model was augmented with water concentration ratios computed via an exponential decay kinetic model of the water absorption process in KBr, which rendered the otherwise indeterminate system of linear equations determinate and thus possible to solve in a formal analytic manner. Consequently, the heretofore baffling KBr water elimination problem is now solved once and for all. Using the new formal solution, efforts to eliminate water interference from KBr disks in research will be defeated no longer. Resulting spectra of protein were much more accurate than attenuated total reflection (ATR) spectra corrected using the well-accepted Advanced ATR Correction Algorithm. PMID- 28738627 TI - A novel pH probe based on ratiometric fluorescent properties of dicyanomethylene 4H-chromene platform. AB - We report here a ratiometric pH probe (Z)-2-(2-(2-(4-hydroxyphenyl)-2-(pyrrolidin 1-yl)vinyl) -4H-chromen-4-ylidene)-malononitrile over the pH range of 2.44-6.00. It was synthesized by Knoevenagel Reaction from dicyanomethylene-4H-chromene and pyrrolidine. This is the first example of pyrrolidine as a part of the product structure in Knoevenagel condensation. High selectivity and sensitivity for pH variation were observed with significant fluorescent ratiometric responses and a remarkable Stokes shift (about 138nm). The probe was stable in the studied solvent and no obvious fluorescence changes were detected in acidic media within one month at room temperature. PMID- 28738628 TI - MIP-MEPS based sensing strategy for the selective assay of dimethoate. Application to wheat flour samples. AB - The aim of this work was to demonstrate the potentialities of the use of a molecularly imprinted (MIP) sensor coupled to a microextraction by packed sorbent (MEPS) strategy for the selective and sensitive detection of dimethoate in real samples. A dimethoate-polypyrrole MIP film was realised by cyclic voltammetry (CV) on the surface of a glassy carbon electrode (GCE). Being dimethoate electro inactive, K3[Fe(CN)6] was used as probe for the indirect quantification of the analyte via the decrease of redox peaks observed upon binding of the target analyte. Detection of dimethoate at low nanomolar range was achieved with linearity in the 0.1-1nM range. Relative standard deviation calculated for different electrodes at 0.5nM of dimethoate was < 3% and selectivity was very satisfactory being the response for omethoate only 23% of dimethoate. A MEPS strategy for the extraction of dimethoate from a challenging matrix as wheat flour was then used in conjunction with the MIP electrochemical sensor. The procedure applied to flour samples spiked with dimethoate at 0.5 MRL, MRL, and 1.5 MRL gave very favourable comparison with a validated UHPLC-MS/MS method with deviations in the -21% /+17% range, demonstrating the feasibility of the approach as screening assay. This work clearly shows that the sequential use of a microextraction based procedure and electrochemical sensing system is low cost, easy to realise and use and can open new perspectives for the development of selective sensing system to be used in field or decentralised lab testing for the selective screening of target analytes. PMID- 28738629 TI - Innovative, simple and green ultrasound assisted-enzyme based hydrolytic microextraction method for manganese at trace levels in food samples. AB - We describe the usage of hydrolytic enzymes for the innovative, green and simple microextraction of manganese in food samples. The ultrasound assisted-enzyme based hydrolytic microextraction method (UA-EH-ME) was applied for the separation and determination of manganese in food samples prior to its micro-sampling flame atomic absorption spectrometric determination (MS-FAAS). Analytical parameters influenced on the enzyme based hydrolytic microextraction method such as pH, type of enzyme, amount of enzyme, temperature and time of ultrasonic waves were fully evaluated and optimized by using mg level of NCS ZC73033 scallion certified reference material. In the presented method, total manganese in 5.0mg of food samples was extracted to 800uL of aqueous phase at pH 1.0 by 0.75mg of pepsin as microextraction agent (hydrolytic enzyme). The procedure can be completed in 15min. These values are optimized conditions for the quantitative extraction of manganese from food samples. The most important advantage of the UA-EH-ME procedure is the using of mg level of pepsin for breaking down certain bonds of bio-molecules for extraction of manganese in very low levels of food samples. The limit of detection (LOD), the limit of quantification (LOQ), and relative standard deviation were found as 4.9mgkg-1, 16.3mgkg-1 and 4.8%, respectively. The manganese contents of the analysed food samples were in the range of 26 345mgkg-1. PMID- 28738630 TI - Simultaneous determination of paracetamol and ciprofloxacin in biological fluid samples using a glassy carbon electrode modified with graphene oxide and nickel oxide nanoparticles. AB - A simple and highly selective electrochemical method using a glassy carbon electrode (GCE) modified with graphene oxide (GO) and nickel oxide nanoparticles (NiONPs) was developed for the simultaneous determination of paracetamol (PAR) and ciprofloxacin (CIP). The electrochemical characterisation of the modified GCE was performed by cyclic voltammetry and electrochemical impedance spectroscopy. The morphological characterisation of the GO and NiONPs was performed by scanning electron microscopy and transmission electron microscopy. Under optimised conditions, using square wave voltammetry, the simultaneous determination of PAR and CIP using the NiONPs-GO-CTS: EPH/GCE sensor shows a linear concentration range from 0.10 to 2.9umolL-1 and 0.040-0.97umolL-1, with detection limits of 6.7 and 6.0 nmol L-1, respectively. The NiONPs-GO-CTS: EPH/GCE sensor showed good reproducibility, repeatability and stability. Furthermore, the proposed method was successfully applied for the simultaneous determination of PAR and CIP in synthetic biological fluid samples. PMID- 28738631 TI - A review: Aptamer-based analytical strategies using the nanomaterials for environmental and human monitoring of toxic heavy metals. AB - Recent developments in biotechnology offer the new methods for the sensitive detection of heavy metals based on the affinity and specificity of aptamers, as nucleic acid ligands selected from random sequence pools in vitro. Heavy metals have received considerable importance as the most toxic metallic pollutants which may cause serious environmental damages. They are classified as trace elements because of their presence in trace concentrations in various environmental matrices. Thus, the precise and sensitive methods to detect heavy metals are important to ensure human and environment safety. Aptamers as the biological probes, show high binding affinity which can often be directly translated into high detection sensitivity. On the other hand, high selectivity and stability make them possible to detect a wide range of targets, especially metallic ions. This review provides current progress of aptamers for environmental and biological monitoring of heavy metals using the nanomaterials mainly in two groups: (i) aptamer based biosensors (aptasensors) and (ii) aptamer based biosorbents (aptasorbents). The introduction of nanomaterials can efficiently increase the immobilization quantity of aptamers. Furthermore, they play an important role in the orientation and assembly density controlling of aptamers for the optimized recognition ability. PMID- 28738632 TI - Raman hyperspectral imaging in conjunction with independent component analysis as a forensic tool for explosive analysis: The case of an ATM explosion. AB - In this work, Raman hyperspectral imaging, in conjunction with independent component analysis, was employed as an analytical methodology to detect an ammonium nitrate fuel oil (ANFO) explosive in banknotes after an ATM explosion experiment. The proposed methodology allows for the identification of the ANFO explosive without sample preparation or destroying the sample, at quantities as small as 70MUgcm-2. The explosive was identified following ICA data decomposition by the characteristic nitrate band at 1044cm-1. The use of Raman hyperspectral imaging and independent component analysis shows great potential for identifying forensic samples by providing chemical and spatial information. PMID- 28738633 TI - Application of Raman spectroscopy for direct analysis of Carlina acanthifolia subsp. utzka root essential oil. AB - Carlina genus plants e.g. Carlina acanthifolia subsp. utzka have been still used in folk medicine of many European countries and its biological activity is mostly associated with root essential oils. In the present paper, Raman spectroscopy (RS) was applied for the first time for evaluation of essential oil distribution in root of C. acnthifolia subsp. utzka and identification of root structures containing the essential oil. Furthermore, RS technique was applied to assess chemical stability of oil during drying of plant material or distillation process. Gas chromatography-mass spectrometry was used for qualitative and quantitative analysis of the essential oil. The identity of compounds was confirmed using Raman, ATR-IR and NMR spectroscopy. Carlina oxide was found to be the main component of the oil (98.96% +/- 0.15). The spectroscopic study showed the high stability of essential oil and Raman distribution analysis indicated that the oil reservoirs were localized mostly in the structures of outer layer of the root while the inner part showed nearly no signal assigned to the oil. Raman spectroscopy technique enabled rapid, non-destructive direct analysis of plant material with minimal sample preparation and allowed straightforward, unambiguous identification of the essential oil in the sample. PMID- 28738634 TI - Determination of synthetic phosphodiesterase-5 inhibitors by LC-MS2 in waters and human urine submitted to dispersive liquid-liquid microextraction. AB - High-performance liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI-MS2) with a triple quadrupole is proposed for determining the synthetic phosphodiesterase-5 inhibitors, sildenafil, tadalafil and vardenafil, and the active metabolite N-desmethyl sildenafil. The method was successfully applied to the analysis of waters of different origins and human urine samples. Dispersive liquid-liquid microextraction (DLLME) was applied in the classical way for water analysis, whereas a previous extraction into an organic solvent was necessary for urine samples, the acetonitrile extract being used as dispersant solvent in the DLLME step. The analytes were determined by LC ESI-MS2 in the multiple reaction monitoring mode. Detection limits were in the 5 50 and 15-250ngL-1 ranges for water and urine samples, respectively. The repeatability was calculated using the relative standard deviation, obtaining values of between 3.6% and 10.1%. The enrichment factors were between 75 and 81. Accuracy of the procedure was calculated through recovery assays and average recoveries +/- SD (n = 48) of 93.6 +/- 3.5 and 91.1 +/- 3.5 were obtained for water and urine samples, respectively. None of the samples analyzed contained the target compounds, at least above the corresponding detection limits. PMID- 28738635 TI - Microwave-induced combustion: Thermal and morphological aspects for understanding the mechanism of ignition process for analytical applications. AB - In the present work, for the first time a systematic study was performed using an infrared camera and scanning electron microscopy (SEM) coupled to energy dispersive X-ray spectrometry (EDS) to evaluate the mechanisms involved in microwave-induced combustion method, which has been extensively used for sample preparation. Cellulose and glass fiber discs, wetted with the igniter solution (6molL-1 NH4NO3), were evaluated under microwave field in a monomode system. The temperature of the discs surface was recorded during microwave irradiation and the effect of NH4NO3 concentration and irradiation time on cellulose oxidation was evaluated. The morphology of the discs surface was characterized by SEM before and after irradiation in an inert atmosphere. According to the results, the surface temperature of the discs increased near to 100 degrees C and remained in this temperature for few seconds while water evaporate. After that, temperature increased over 200 degrees C due to the thermal decomposition of NH4NO3 salt, releasing a large amount of energy that accelerates cellulose oxidation. The higher the igniter concentration, the shorter was the microwave irradiation time for cellulose oxidation. The SEM images revealed that cellulose disc was more porous after microwave irradiation, enhancing oxygen diffusion within the paper and making easier its ignition. The EDS spectrum of cellulose and glass fiber discs showed that signal intensity for nitrogen decreased after microwave irradiation, showing that NH4NO3 was consumed during this process. Therefore, it was demonstrated that the ignition process is the result of synergic interaction of NH4NO3 thermal decomposition and organic matter oxidation (cellulose) releasing heat and feeding the chain reaction. PMID- 28738636 TI - One step hydrothermal synthesis and characterization of moss like MWCNT-Bi2S3 nanomaterial for solid phase extraction of copper. AB - The present work was designed with the aim to one step simple hydrothermal synthesis of moss like MWCNT-Bi2S3 nanomaterial as solid phase extraction sorbent for separation, preconcentration and determination of copper in tobacco and food samples. Cu(II) ions was strongly retained on the MWCNT-Bi2S3 nanomaterial at the pH 7.0 and was successfully desorbed by using 1.5mL of 4M HNO3. The copper concentration in eluent was determined by flame atomic absorption spectrometer. The certified reference material (NC SZC 73033 Scallion) was analyzed for the verification and accuracy of the proposed method. This work was interpreted statistically and found the analytical performance of the proposed method which consist of preconcentration factor (20), limit of quantification (13.1ugL-1) and relative standard deviation (2.2%), respectively. It was concluded that this method was applied for the detection of copper from different types of tobacco and food samples successfully. PMID- 28738637 TI - Sensitive detection of estriol hormone in creek water using a sensor platform based on carbon black and silver nanoparticles. AB - We report the electrochemical detection of estriol using carbon black nanoballs (CNB) decorated with silver nanoparticles (AgNP) as electrode material. Homogeneous, porous films on glassy carbon electrodes (GCE) were obtained, with diameters of 20 - 25nm for CNB and 5 - 6nm for AgNP. CNB/AgNP electrodes had increased conductivity and electroactive area in comparison with bare GCE and GCE/CNB, according to cyclic voltammetry and electrochemical impedance spectroscopy. The oxidation potential peak was also down shifted by 93mV, compared to the bare GC electrode. Differential pulse voltammetry data were obtained in 0.1molL-1 PBS (pH 7.0) to detect estriol without the purification step, in the linear range between 0.2 and 3.0umolL-1 with detection and quantification limits of 0.16 and 0.5umolL-1 (0.04 and 0.16mgL-1), respectively. The sensor was used to detect estriol in a creek water sample with the same performance as in the official methodology based on high performance liquid chromatography. PMID- 28738638 TI - Mixed matrix membranes incorporated with Ln-MOF for selective and sensitive detection of nitrofuran antibiotics based on inner filter effect. AB - The detection of antibiotics is critical and challenging due to the pervasive use of antibiotics had inevitably brought some negative impacts on ecosystem and human health. Herein, we reported an anti-interfere ability enhanced luminescent sensor of lanthanide metal-organic framework (Ln-MOF) filled mixed matrix membranes (MMMs), which combining the processibility of poly(methyl methacrylate) (PMMA) polymer with Ln-MOF of {[Tb2(AIP)2(H2O)10].(AIP).4H2O}n (Tb-AIP, where AIP is 5-aminoisophthalate) fillers. The as-fabricated Tb-AIP MMMs are stable in water with a wide pH range and exhibit characteristic blue emission of Tb3+. Significantly, the Tb-AIP MMMs show highly selective and sensitive to nitrofuran antibiotics (NFAs) via inner filter effect (IFE), and yet remain unaffected not only by other common antibiotics but also by other types of analytes (metal ions and anions) that may coexist. The limits of detection for nitrofurantoin (NFT) and nitrofurazone (NFZ) are 0.30 and 0.35MUM, respectively. As a proof of concept, the proposed MMMs sensor are demonstrated to be feasible for application in detecting NFAs in original water of Pearl River and bovine serum samples, the corresponding quenching constants and limits of detection are similar to their standard detections in an acceptable range. Furthermore, this MMMs sensor for NFAs detection was reversible after washing with deionized water. The luminescent Ln-MOF filled MMMs presented here provides a functional platform for simple yet useful in sensing of NFAs in environment and biology systems. PMID- 28738639 TI - A colorimetric indicator-displacement assay for cysteine sensing based on a molecule-exchange mechanism. AB - In this study, we developed an ingenious yet effective strategy for cysteine detection. The colorimetric cysteine assay is established through an indicator displacement process, where Cu2+ and pyrocatechol violet (PV) was employed as receptor and indicator, respectively. Proof-of-concept trials demonstrated that the stronger binding affinity of Cu2+ receptor toward cysteine than PV indicator endowed our colorimetric sensor with high selectivity and excellent sensitivity as well as with a lower detection limit (4.60MUM and 120uM, S/N =3) by UV-visible spectroscopy and the naked eye as the signal readout, respectively. More importantly, the proposed molecule-exchange process in the indicator displacement process could be successfully used to the fabrication of a colorimetric INHIBIT logic gate and even converted into a facile naked eye analysis through paper based analytical devices for conveniently and reliably detecting cysteine (CySH) in practical applications. PMID- 28738640 TI - New insights in forensic chemistry: NIR/Chemometrics analysis of toners for questioned documents examination. AB - Near-Infrared spectroscopy (NIRs) coupled to chemometrics was investigated for the first time as a new tool for the analysis of black toners to evaluate its application in forensic cases. Ten black toners from four manufacturers were included in this study and the acquired spectra were compared in order to differentiate toners. Multivariate statistical analysis based on Principal Component Analysis (PCA) was considered to develop a model of comparison of toners in questioned documents. Results demonstrated the capabilities of the approach NIR/Chemometrics to correctly identify toners when printed on different papers and to be not affected by the printing process. This study has shown that NIRs can be considered as a useful, fast, non-destructive tool providing the characterisation of toners in forensic caseworks. PMID- 28738641 TI - An interference-free and label-free sandwich-type magnetic silicon microsphere rGO-based probe for fluorescence detection of microRNA. AB - An interference-free and label-free sensing platform was developed for the highly sensitive detection of microRNA-21 (miRNA-21) in vitro by magnetic silicon microsphere (MNP)-reduced graphene oxide (rGO)-based sandwich probe. In this method, DNA capture probes (P1) were connected with MNPs at the 5' end and hybridized with completely complementary target miRNA. Subsequently, rGO was retained and induced the fluorescence quenching in the supernatant. Through the magnetic separation, the supernatant environment was simplified and the interference to analytical signal was eliminated. When DNA capture probe-modified magnetic silicon microspheres (MNP-P1) were adsorbed through rGO in the absence of a target and formed a sandwich structure, the formed nanostructure was easily removed from the solution by a magnetic field and the fluorescence intensity was maximally recovered. This proposed strategy, which both overcame the expensive and cumbersome fluorescent labeling, and eliminated interference to analytical signal for guaranteeing high signal-to-background ratio, exhibited high sensitivity with a detection limit as low as 0.098nM and special selectivity toward miRNA-21. The method was potentially applicable for not only detection of miRNA-21 but also various biomarker analyses just by changing capture probes. PMID- 28738642 TI - Terminal protection-mediated autocatalytic cascade amplification coupled with graphene oxide fluorescence switch for sensitive and rapid detection of folate receptor. AB - Folate receptor (FR) is over-expressed in most human tumors and has been regarded as biomarker and therapeutic target. Specific and sensitive detection of FR is essential for tumor treatment and drug development. Here, a specific, sensitive and rapid FR detection strategy was proposed based on terminal protection mediated autocatalytic cascade amplification coupled with graphene oxide fluorescence switch. Firstly, the specific binding of FR to the folate terminally labeled on a primary trigger DNA (PT-DNA) could protect the PT-DNA from exonuclease I degradation, converting FR detection to PT-DNA detection. Subsequently, the PT-DNA hybridized with the overhang of 3'-FAM labeled hairpin probe to initiate exonuclease III-assisted hydrolysis, accompanied with the PT DNA recycling and autonomous generation of secondary trigger DNA and fluorophore. The secondary trigger DNA could as a PT-DNA analogue for the successive hybridization and hydrolysis process, liberating numerous fluorophores within 40min. Finally, The fluorophores kept away from the surface of graphene oxide, achieving significantly amplified fluorescence signal. The specific interaction between FR and folate guaranteed the FR could be distinguished from other proteins with high selectivity. The high fluorescence quenching efficiency of graphene oxide guaranteed a low background. Due to the highly autocatalytic cascade amplification efficiency and low background, sensitive detection of FR had been achieved with the detection limit of 0.44pM. The recoveries from 92% to 107% were achieved by detecting FR in spiked human serum. These results indicate this strategy holds a great potential for reliable quantification of FR in clinical diagnosis and disease treatment. PMID- 28738643 TI - Facile preparation of 3-D floor-like ordered mesoporous carbon functionalized graphene composites and its application for selective enrichment of N-glycans from human serum. AB - Novel 3-D floor-like ordered mesoporous carbon functionalized graphene composites, FLOMC-GO, with high graphitized carbon contents were successfully synthesized using a soft template method. The one-pot sol-gel method was employed to prepare the silica soft template. Then, the sandwich-like composites were further combined together to form a 3-D structure through pre-carbonization and carbonization. During these procedures, the sulphonyl and sulfide bridges were formed by cross-linking processes to connect the phenyl rings. The prepared FLOMC GO was confirmed to have a large pore volume (1.03cm3g-1), high BET surface area (544.99m2g-1) and well-ordered mesoporous structure with a narrow pore-size concentrated at 3.74nm. The content of carbon reached 80% and was highly graphitized. By taking advantage of the interactions between carbon and glycans, FLOMC-GO was utilized to enrich N-linked glycans from OVA and human serum. As expected, excellent size-exclusion was found during the enrichment of N-glycans released from OVA, and 25 N-linked glycans were identified. The intensity of glycans enriched by FLOMC-GO was 7 times to the result of active carbon, while the ratio of OVA digestion to BSA interfering proteins increased to 1:50. Additionally, 31 N-linked glycans in total were enriched from human serum. The relatively easy synthesis as well as ability to enrich N-linked glycans with high selectivity and efficiency makes FLOMC-GO a promising adsorbent material for the discovery of human serum biomarkers for disease diagnosis. PMID- 28738644 TI - Biosensor for the characterisation of hMAO B inhibitors and the quantification of selegiline. AB - A novel human monoamine oxidase B (hMAO B) based biosensor for inhibitory measurements was developed. It allows both the characterisation of the type of enzyme inhibition and the sensitive and simple determination of inhibitors like selegiline hydrochloride. The sensor consists of a screen printed carbon working electrode modified with 20% manganese dioxide (MnO2) and the enzyme hMAO B, which was immobilised on the electrode via a dialysis membrane (regenerated cellulose, molecular weight cut-off 14000). Inhibition of hMAO B is evaluated by adding different concentrations of the inhibitor selegiline hydrochloride to the enzyme and applying a defined amount of the hMAO B substrate phenylethylamine (PEA). The enzymatically formed H2O2 is amperometrically detected at 0.4V vs. Ag/AgCl in a flow injection analysis (FIA) system. With 100uM PEA the sensor showed a linear correlation between peak height and inhibitor concentration in a range of 0.51 3.25ug/mL selegiline hydrochloride. LOD and LOQ were determined to be 0.15 and 0.51ug/mL, respectively. The sensor showed a repeatability of 3.7% and an intermediate precision of 8.1%. The inhibition-based biosensor was successfully employed to quantify selegiline hydrochloride in pharmaceutical samples. Kinetic studies via Lineweaver-Burk plot and enzyme quantity vs. current plot revealed that the inhibition is irreversible. PMID- 28738645 TI - Competitive fluorescence anisotropy/polarization assay for ATP using aptamer as affinity ligand and dye-labeled ATP as fluorescence tracer. AB - We developed an aptamer-based competitive fluorescence anisotropy (FA)/fluorescence polarization (FP) assay for adenosine triphosphate (ATP). Different from the traditional fluorescence polarization immunoassays for small molecules, here DNA aptamer against ATP was used as affinity ligand, and tetramethylrhodamine (TMR) labeled ATP served as fluorescent tracer. The binding between TMR-labeled ATP and aptamer gave large FA due to molecular volume increase and restricted rotation of the dye-labeled ATP. When ATP was added in solution, ATP competitively displaced the TMR-labeled ATP from aptamer affinity complex, causing decrease of FA of TMR-labeled ATP. The buffer containing MgCl2 and incubation at low temperature were preferred for large FA change in the FA assay. The FA change was further enhanced in this competitive FA assay by increasing the molecular weight of aptamer through extension of aptamer sequences or conjugating streptavidin protein on aptamer. This method allowed for the detection of ATP in the range from 0.5MUM to 1mM, generating the maximum FA change about 0.187 (corresponding maximum FP change about 0.242). The detection of ATP spiked in diluted urine or serum sample was achieved, showing capability for analysis in complex sample matrix. This assay also enabled the detection of the analogues of ATP, e.g. adenosine, adenosine monophosphate (AMP), and adenosine diphosphate (ADP) with similar sensitivity. This aptamer-based competitive FA assay takes advantages of aptamer in ease of synthesis, good thermal stability, and facile modulating the molecular mass of aptamer. PMID- 28738646 TI - Synthesis, characterization, and application of a novel multifunctional stationary phase for hydrophilic interaction/reversed phase mixed-mode chromatography. AB - A novel multifunctional stationary phase based on silica gel was synthesised starting from L- isoleucine and 4-phenylbutylamine and evaluated as a hydrophilic interaction/reversed-phase mixed-mode stationary phase for high-performance liquid chromatography (HPLC). The prepared stationary phase was characterized by elemental analysis, infrared spectroscopy (IR), scanning electron microscopy (SEM), Brunauer, Emmett and Teller (BET) and solid-state 13C nuclear magnetic resonance (NMR). The mechanisms involved in the chromatographic separation are multi-interaction, including hydrophobic, pi-pi, hydrogen-bonding, dipole-dipole and ion-dipole interactions. Based on these interactions, successful separation could be achieved among several aromatic compounds having different polarities under both hydrophilic interaction liquid chromatography (HILIC) and reversed phase (RP) condition. Nucleotides/nucleosides were separated in the HILIC mode. The effects of different separation conditions, such as pH value, mobile-phase content, column temperature, buffer concentration and flow rate, on the separation of nucleotides/nucleosides in HILIC mode were investigated. The seven nucleotides/nucleosides were separated within 22min, while six of them were separated within 10min by isocratic elution. To determine the influence of the new multifunctional stationary phase under the RP condition, a number of moderately and weakly polar and nonpolar compounds, such as 10 substituted anilines and eight substituted phenols were separated successfully under the RP condition within 14 and 15min, respectively. Additionally, nine mixtures of polar/nonpolar test compounds were simultaneously separated within 19min, while seven of them were separated within 12min, under HILIC/RP mixed-mode conditions. Chromatographic parameters, such as the retention factor and peak asymmetry factor, were calculated for all of the analytes, while the theoretical plate number was calculated for analytes separated by isocratic elution. Compared to traditional C18 and commercial HILIC columns, the new stationary phase exhibited both HILIC and RPLC performance, and the scope of analyte separation was thus enlarged. PMID- 28738647 TI - Development of an analytical methodology for obtaining quantitative mass concentrations from LAAP-ToF-MS measurements. AB - Laser ablation aerosol particle-time of flight mass spectrometer (LAAP-ToF-MS) measures the size number of particles, and chemical composition of individual particles in real-time. LAAP-ToF-MS measurements of chemical composition are difficult to quantify, mostly because the instrument sensitivities to various chemical species in the multicomponent atmospheric aerosol particles are unknown. In this study, we investigate a field-based approach for quantitative measurements of ammonium, nitrate, sulfate, OC, and EC, in size-segregated atmospheric aerosols, by LAAP-ToF-MS using concurrent measurements from high resolution time-of-flight aerosol mass spectrometer (HR-ToF-AMS), and multi-angle absorption photometer (MAAP). An optical particle counter (OPC) and a high resolution nanoparticle sizer (scanning mobility particle sizer, or SMPS), were used to measure the particle size distributions of the particles in order to correct the number concentrations. The intercomparison reveals that the degree of agreement of the mass concentrations of each compound measured with LAAP-ToF-MS and HR-ToF-AMS/MAAP increases in the following order NH4+ < SO42- < NO3- < EC < OC < Cl- with r2 values in the range of 0.4-0.95 and linear regression slopes ranging between 0.62 and 1.2. The factors that affect the mass concentrations measured by LAAP-ToF-MS are also discussed in details. Yet, the matrix effect remains one of the strongest limiting factor to achieve an absolute quantification of the aerosol chemical composition. In the future we suggest the development of a methodology based on the calculation of the response factors generated by different types of particles, which could possibly resolve certain difficulties associated with the matrix effect. PMID- 28738648 TI - Matrix interference evaluation employing GC and LC coupled to triple quadrupole tandem mass spectrometry. AB - Gas and liquid chromatography coupled to triple quadrupole tandem mass spectrometry are currently the most powerful tools employed for the routine analysis of pesticide residues in food control laboratories. However, whatever the multiresidue extraction method, there will be a residual matrix effect making it difficult to identify/quantify some specific compounds in certain cases. Two main effects stand out: (i) co-elution with isobaric matrix interferents, which can be a major drawback for unequivocal identification, and therefore false negative detections, and (ii) signal suppression/enhancement, commonly called the "matrix effect", which may cause serious problems including inaccurate quantitation, low analyte detectability and increased method uncertainty. The aim of this analytical study is to provide a framework for evaluating the maximum expected errors associated with the matrix effects. The worst-case study contrived to give an estimation of the extreme errors caused by matrix effects when extraction/determination protocols are applied in routine multiresidue analysis. Twenty-five different blank matrices extracted with the four most common extraction methods used in routine analysis (citrate QuEChERS with/without PSA clean-up, ethyl acetate and the Dutch mini-Luke "NL" methods) were evaluated by both GC-QqQ-MS/MS and LC-QqQ-MS/MS. The results showed that the presence of matrix compounds with isobaric transitions to target pesticides was higher in GC than under LC in the experimental conditions tested. In a second study, the number of "potential" false negatives was evaluated. For that, ten matrices with higher percentages of natural interfering components were checked. Additionally, the results showed that for more than 90% of the cases, pesticide quantification was not affected by matrix-matched standard calibration when an interferent was kept constant along the calibration curve. The error in quantification depended on the concentration level. In a third study, the "matrix effect" was evaluated for each commodity/extraction method. Results showed 44% of cases with suppression/enhancement for LC and 93% of cases with enhancement for GC.